PMID- 29258206 TI - The Dual Antioxidant/Prooxidant Effect of Eugenol and Its Action in Cancer Development and Treatment. AB - The formation of reactive oxygen species (ROS) during metabolism is a normal process usually compensated for by the antioxidant defense system of an organism. However, ROS can cause oxidative damage and have been proposed to be the main cause of age-related clinical complications and diseases such as cancer. In recent decades, the relationship between diet and cancer has been more studied, especially with foods containing antioxidant compounds. Eugenol is a natural compound widely found in many aromatic plant species, spices and foods and is used in cosmetics and pharmaceutical products. Eugenol has a dual effect on oxidative stress, which can action as an antioxidant or prooxidant agent. In addition, it has anti-carcinogenic, cytotoxic and antitumor properties. Considering the importance of eugenol in the area of food and human health, in this review, we discuss the role of eugenol on redox status and its potential use in the treatment and prevention of cancer. PMID- 29258208 TI - Scanning Electron Microscope (SEM) Evaluation of the Interface between a Nanostructured Calcium-Incorporated Dental Implant Surface and the Human Bone. AB - Purpose. The aim of this scanning electron microscope (SEM) study was to investigate the interface between the bone and a novel nanostructured calcium incorporated dental implant surface in humans. Methods. A dental implant (Anyridge(r), Megagen Implant Co., Gyeongbuk, South Korea) with a nanostructured calcium-incorporated surface (Xpeed(r), Megagen Implant Co., Gyeongbuk, South Korea), which had been placed a month earlier in a fully healed site of the posterior maxilla (#14) of a 48-year-old female patient, and which had been subjected to immediate functional loading, was removed after a traumatic injury. Despite the violent trauma that caused mobilization of the fixture, its surface appeared to be covered by a firmly attached, intact tissue; therefore, it was subjected to SEM examination. The implant surface of an unused nanostructured calcium-incorporated implant was also observed under SEM, as control. Results. The surface of the unused implant showed a highly-structured texture, carved by irregular, multi-scale hollows reminiscent of a fractal structure. It appeared perfectly clean and devoid of any contamination. The human specimen showed trabecular bone firmly anchored to the implant surface, bridging the screw threads and filling the spaces among them. Conclusions. Within the limits of this human histological report, the sample analyzed showed that the nanostructured calcium-incorporated surface was covered by new bone, one month after placement in the posterior maxilla, under an immediate functional loading protocol. PMID- 29258207 TI - Role of Galectins in Multiple Myeloma. AB - Galectins are a family of lectins that bind beta-galactose-containing glycoconjugates and are characterized by carbohydrate-recognition domains (CRDs). Galectins exploit several biological functions, including angiogenesis, regulation of immune cell activities and cell adhesion, in both physiological and pathological processes, as tumor progression. Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by the tight adhesion between tumoral PCs and bone marrow (BM) microenvironment, leading to the increase of PC survival and drug resistance, MM-induced neo-angiogenesis, immunosuppression and osteolytic bone lesions. In this review, we explore the expression profiles and the roles of galectin-1, galectin-3, galectin-8 and galectin-9 in the pathophysiology of MM. We focus on the role of these lectins in the interplay between MM and BM microenvironment cells showing their involvement in MM progression mainly through the regulation of PC survival and MM-induced angiogenesis and osteoclastogenesis. The translational impact of these pre-clinical pieces of evidence is supported by recent data that indicate galectins could be new attractive targets to block MM cell growth in vivo and by the evidence that the expression levels of LGALS1 and LGALS8, genes encoding for galectin-1 and galectin-8 respectively, correlate to MM patients' survival. PMID- 29258210 TI - Attitudinal, Behavioral, and Environmental Correlates of Child and Parent Self Efficacy in Walking to School. AB - As a critical social cognitive construct, self-efficacy plays a determinant role in children's walking to school (WTS). However, little is known about factors that are underlying children's and parents' self-efficacy in WTS. The purpose of this study is to examine behavioral, attitudinal, and environmental correlates of child self-efficacy and parent self-efficacy in WTS, and to assess differences in the correlates of child versus parent self-efficacy. Data were collected from students (N = 1224) and parents (N = 1205) from 81 elementary schools across Texas in 2009-2012. Binary logistic regressions were conducted to identify significant factors that are associated with children's self-efficacy and parents' self-efficacy. Results from this study showed that the parent self efficacy was more likely to be related to their own behaviors or attitudes, rather than the environmental factors or their child's input. The child self efficacy, however, was influenced not only by their own and parental behaviors or attitudes, but also by environmental factors. This study suggests that both parental and child self-efficacy are important factors to be considered when making decisions about school transportation. PMID- 29258211 TI - Vision-Based Target Finding and Inspection of a Ground Target Using a Multirotor UAV System. AB - In this paper, a system that uses an algorithm for target detection and navigation and a multirotor Unmanned Aerial Vehicle (UAV) for finding a ground target and inspecting it closely is presented. The system can also be used for accurate and safe delivery of payloads or spot spraying applications in site specific crop management. A downward-looking camera attached to a multirotor is used to find the target on the ground. The UAV descends to the target and hovers above the target for a few seconds to inspect the target. A high-level decision algorithm based on an OODA (observe, orient, decide, and act) loop was developed as a solution to address the problem. Navigation of the UAV was achieved by continuously sending local position messages to the autopilot via Mavros. The proposed system performed hovering above the target in three different stages: locate, descend, and hover. The system was tested in multiple trials, in simulations and outdoor tests, from heights of 10 m to 40 m. Results show that the system is highly reliable and robust to sensor errors, drift, and external disturbance. PMID- 29258209 TI - Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs). AB - The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality. PMID- 29258212 TI - Dietary Patterns in Relation to Metabolic Syndrome among Adults in Poland: A Cross-Sectional Study. AB - In several populations the associations between diet and the risk of metabolic syndrome have not been fully examined yet. The aim of the study is to identify the main dietary patterns among Polish adults and the evaluation of the relationships of these patterns with metabolic syndrome and its components. The study was conducted on a group of 7997 participants, aged between 37 and 66 years old. Dietary patterns were identified by factor analysis. Metabolic syndrome was defined according to the International Diabetes Federation. Three dietary patterns were identified and designated as: "Healthy", "Westernized" and "Traditional-carbohydrate". In the adjusted model, a higher score in the "Westernized" pattern aligns with a higher risk of abnormal glucose concentration (ptrend = 0.000), but with a lower risk of abnormal High-Density Lipoprotein Cholesterol HDL-cholesterol concentration (ptrend = 0.024). Higher scores in the "Traditional-carbohydrate" pattern were connected with the risk of abdominal obesity (ptrend = 0.001) and increased triglycerides concentration (ptrend = 0.050). Our results suggest that adherence to the "Traditional-carbohydrate" dietary pattern, characterized by higher intakes of refined grains, potatoes, sugar and sweets is associated with a higher risk of abdominal obesity and triglyceridemia. A "Westernized" dietary pattern on the other hand, is related to hyperglycemia. The study results can be used for community-based health promotion and intervention programs to prevent or better manage chronic diseases. PMID- 29258213 TI - Single Interdigital Transducer Approach for Gravimetrical SAW Sensor Applications in Liquid Environments. AB - Surface acoustic wave (SAW) devices are well known for mass-sensitive sensor applications. In biosensing applications, chemical and biochemically evoked binding processes on surfaces are detected in liquid environments using delay line or resonator sensor configurations, preferably in combination with the appropriate microfluidic devices. All configurations share the common feature of analyzing the transmission characteristic of the propagating SAW. In this paper, a novel SAW-based impedance sensor type is introduced which uses only one interdigital transducer (IDT), simultaneously as the SAW generator and the sensor element. Here, the input port reflection coefficient S11 is measured at the IDT instead of the commonly used S21 transmission forward gain parameter. Thus, a sharp and distinct peak of the S11 spectrum is obtained, enabling a comfortable direct readout of the sensor signal. Proof of the concept was gained by analyzing the specific binding of the 4-mercaptophenylacetic acid gold nanoparticles (MPA AuNP) directly to the IDT surface. The corresponding binding kinetic of the MPA AuNP on the functionalized gold surface has been analyzed and a sensitivity of 7.4 mOmega nM-1 has been determined. PMID- 29258214 TI - Extraction and Analysis of Respiratory Motion Using Wearable Inertial Sensor System during Trunk Motion. AB - Respiratory activity is an essential vital sign of life that can indicate changes in typical breathing patterns and irregular body functions such as asthma and panic attacks. Many times, there is a need to monitor breathing activity while performing day-to-day functions such as standing, bending, trunk stretching or during yoga exercises. A single IMU (inertial measurement unit) can be used in measuring respiratory motion; however, breathing motion data may be influenced by a body trunk movement that occurs while recording respiratory activity. This research employs a pair of wireless, wearable IMU sensors custom-made by the Department of Electrical Engineering at San Diego State University. After appropriate sensor placement for data collection, this research applies principles of robotics, using the Denavit-Hartenberg convention, to extract relative angular motion between the two sensors. One of the obtained relative joint angles in the "Sagittal" plane predominantly yields respiratory activity. An improvised version of the proposed method and wearable, wireless sensors can be suitable to extract respiratory information while performing sports or exercises, as they do not restrict body motion or the choice of location to gather data. PMID- 29258215 TI - Estimation of the Botanical Composition of Clover-Grass Leys from RGB Images Using Data Simulation and Fully Convolutional Neural Networks. AB - Optimal fertilization of clover-grass fields relies on knowledge of the clover and grass fractions. This study shows how knowledge can be obtained by analyzing images collected in fields automatically. A fully convolutional neural network was trained to create a pixel-wise classification of clover, grass, and weeds in red, green, and blue (RGB) images of clover-grass mixtures. The estimated clover fractions of the dry matter from the images were found to be highly correlated with the real clover fractions of the dry matter, making this a cheap and non destructive way of monitoring clover-grass fields. The network was trained solely on simulated top-down images of clover-grass fields. This enables the network to distinguish clover, grass, and weed pixels in real images. The use of simulated images for training reduces the manual labor to a few hours, as compared to more than 3000 h when all the real images are annotated for training. The network was tested on images with varied clover/grass ratios and achieved an overall pixel classification accuracy of 83.4%, while estimating the dry matter clover fraction with a standard deviation of 7.8%. PMID- 29258217 TI - Noisy Ocular Recognition Based on Three Convolutional Neural Networks. AB - In recent years, the iris recognition system has been gaining increasing acceptance for applications such as access control and smartphone security. When the images of the iris are obtained under unconstrained conditions, an issue of undermined quality is caused by optical and motion blur, off-angle view (the user's eyes looking somewhere else, not into the front of the camera), specular reflection (SR) and other factors. Such noisy iris images increase intra individual variations and, as a result, reduce the accuracy of iris recognition. A typical iris recognition system requires a near-infrared (NIR) illuminator along with an NIR camera, which are larger and more expensive than fingerprint recognition equipment. Hence, many studies have proposed methods of using iris images captured by a visible light camera without the need for an additional illuminator. In this research, we propose a new recognition method for noisy iris and ocular images by using one iris and two periocular regions, based on three convolutional neural networks (CNNs). Experiments were conducted by using the noisy iris challenge evaluation-part II (NICE.II) training dataset (selected from the university of Beira iris (UBIRIS).v2 database), mobile iris challenge evaluation (MICHE) database, and institute of automation of Chinese academy of sciences (CASIA)-Iris-Distance database. As a result, the method proposed by this study outperformed previous methods. PMID- 29258216 TI - Lab-on-a-Chip Platforms for Detection of Cardiovascular Disease and Cancer Biomarkers. AB - Cardiovascular disease (CVD) and cancer are two leading causes of death worldwide. CVD and cancer share risk factors such as obesity and diabetes mellitus and have common diagnostic biomarkers such as interleukin-6 and C reactive protein. Thus, timely and accurate diagnosis of these two correlated diseases is of high interest to both the research and healthcare communities. Most conventional methods for CVD and cancer biomarker detection such as microwell plate-based immunoassay and polymerase chain reaction often suffer from high costs, low test speeds, and complicated procedures. Recently, lab-on-a-chip (LoC)-based platforms have been increasingly developed for CVD and cancer biomarker sensing and analysis using various molecular and cell-based diagnostic biomarkers. These new platforms not only enable better sample preparation, chemical manipulation and reaction, high-throughput and portability, but also provide attractive features such as label-free detection and improved sensitivity due to the integration of various novel detection techniques. These features effectively improve the diagnostic test speed and simplify the detection procedure. In addition, microfluidic cell assays and organ-on-chip models offer new potential approaches for CVD and cancer diagnosis. Here we provide a mini review focusing on recent development of LoC-based methods for CVD and cancer diagnostic biomarker measurements, and our perspectives of the challenges, opportunities and future directions. PMID- 29258218 TI - In Vitro Investigation of the Interaction of Tolbutamide and Losartan with Human Serum Albumin in Hyperglycemia States. AB - Serum albumin is exposed to numerous structural modifications which affect its stability and activity. Glycation is one of the processes leading to the loss of the original properties of the albumin and physiological function disorder. In terms of long lasting states of the hyperglycemia, Advanced Glycation End products (AGEs) are formed. AGEs are responsible for cellular and tissue structure damage that cause the appearance of a number of health consequences and premature aging. The aim of the present study was to analyze the conformational changes of serum albumin by glycation-"fructation"-using multiple spectroscopic techniques, such as absorption (UV-Vis), fluorescence (SFM), circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy and evaluate of possible alteration of binding and competition between tolbutamide (TB, a first-generation sulfonylurea oral hypoglycemic drug) and losartan (LOS, an angiotensin II receptor (AT1) blocker used in hypertension (1st line with a coexisting diabetes)) in binding to non-glycated (HSA) and glycated (gHSAFRC) human serum albumin in high-affinity binding sites. The studies allowed us to indicate the structural alterations of human serum albumin as a result of fructose glycation. Changes in binding parameters, such as association ( K a ) or Stern-Volmer ( K S V ) constants suggest that glycation increases the affinity of TB and LOS towards albumin and affects interactions between them. The process of albumin glycation influences the pharmacokinetics of drugs, thus monitored pharmacotherapy is reasonable in the case of diabetes and hypertension polypharmacy. This information may lead to the development of more effective drug treatments based on personalized medicine for patients with diabetes. Our studies suggest the validity of monitored polypharmacy of diabetes and coexisting diseases. PMID- 29258219 TI - An Alternative Approach to Investigate Biofilm in Medical Devices: A Feasibility Study. AB - Biofilms are assemblages of bacterial cells irreversibly associated with a surface where moisture is present. In particular, they retain a relevant impact on public health since through biofilms bacteria are able to survive and populate biomedical devices causing severe nosocomial infections that are generally resistant to antimicrobial agents. Therefore, controlling biofilm formation is a mandatory feature during medical device manufacturing and during their use. In this study, combining a crystal violet staining together with advanced stereomicroscopy, we report an alternative rapid protocol for both qualitative and semi-quantitative biofilm determination having high specificity, high repeatability, and low variability. The suggested approach represents a reliable and versatile method to detect, monitor, and measure biofilm colonization by an easy, more affordable, and reproducible method. PMID- 29258220 TI - Advances in Spiropyrans/Spirooxazines and Applications Based on Fluorescence Resonance Energy Transfer (FRET) with Fluorescent Materials. AB - Studies on the following were reviewed: (1) the structure of spiropyrans and spirooxazines (two kinds of spiro compounds) under external stimuli and (2) the construction and applications of composite systems based on fluorescence resonance energy transfer (FRET) with fluorescent materials. When treated with different stimuli (light, acids and bases, solvents, metal ions, temperature, redox potential, and so on), spiropyrans/spirooxazines undergo transformations between the ring-closed form (SP), the ring-opened merocyanine (MC) form, and the protonated ring-opened form (MCH). This is due to the breakage of the spiro C-O bond and the protonation of MC, along with a color change. Various novel, multifunctional materials based on photochromic spiropyrans and spirooxazines have been successfully developed because of the vastly differently physiochemical properties posssed by the SP, MC and MCH forms. Among the three different structural forms, the MC form has been studied most extensively. The MC form not only gives complexes with various inorganic particles, biological molecules, and organic chemicals but also acts as the energy acceptor (of energy from fluorescent molecules) during energy transfer processes that take place under proper conditions. Furthermore, spiropyran and spirooxazine compounds exhibit reversible physicochemical property changes under proper stimuli; this provides more advantages compared with other photochromic compounds. Additionally, the molecular structures of spiropyrans and spirooxazines can be easily modified and extended, so better compounds can be obtained to expand the scope of already known applications. Described in detail are: (1) the structural properties of spiropyrans and spirooxazines and related photochromic mechanisms; (2) composite systems based on spiropyrans and spirooxazines, and (3) fluorescent materials which have potential applications in sensing, probing, and a variety of optical elements. PMID- 29258221 TI - Maternal Depressive Symptoms and Child Behavior among Mexican Women and Their Children. AB - Over 50% of mothers in rural Mexico have high depressive symptoms, and their children's health and development are likely to be negatively affected. A critical question is whether children vary in their vulnerability to the effects of high maternal depressive symptoms according to their indigenous ethnicity, maternal education, or household wealth. Our sample included 4442 mothers and 5503 children from an evaluation of Mexico's social welfare program. Maternal depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) Scale, and child behavior was measured using an adapted version of the Behavior Problems Index (BPI). Multiple linear regression models were used to explore the associations between maternal depressive symptoms and child behavior problems, and the heterogeneity of associations by indigenous ethnicity, maternal education, and household assets. We found that having greater maternal depressive symptoms was significantly associated with having a child with more behavior problems (beta = 0.114, p < 0.0001, [95% CI 0.101, 0.127]), in adjusted models. In tests of heterogeneity, the association between maternal depressive symptoms and child behavior problems was strongest in households with indigenous ethnicity, low maternal education, or in households with fewer assets. These results strengthen the case for effective mental health interventions in low- and middle-income countries, particularly among the most vulnerable families where mothers and children appear to be at the greatest risk. PMID- 29258222 TI - Combinative Scouring, Bleaching, and Cationization Pretreatment of Greige Knitted Cotton Fabrics for Facilely Achieving Salt-Free Reactive Dyeing. AB - In order to facilely achieve pretreatment and salt-free dyeing of greige knitted cotton fabrics, a combinative scouring, bleaching, and cationization pretreatment of the fabrics is designed in this study. The fabrics are first treated in a bath containing commercial scouring and bleaching agents, and then glycidyltrimethylammonium chloride (GTA) is directly added into the bath to achieve cationization of the fabrics. Utilization of the alkaline and high temperature conditions in scouring and bleaching process, cationization can facilely proceed in a short time. Optimal pretreatment conditions are as follows: greige knitted cotton fabrics are treated in a bath containing 4 g/L scouring agent and 6 g/L 30% hydrogen peroxide at 90 degrees C for 60 min, and then 30 g/L GTA and 3 g/L sodium hydroxide are added in the bath for another 15 min treatment. Fiber performances, including whiteness, water absorptivity, diffusion time, and capillary effect, are tested and evaluated. X-ray diffraction analysis, surface morphology, and thermal analysis of the pretreated cotton are also investigated and compared with that treated only with scouring and bleaching agents. Much higher dye fixation and color yield could be realized on the pretreated cotton in salt-free reactive dyeing. Colorimetric properties of the dyes are studied and good colorfastness of the dyes on the cationic fabrics are obtained. All of the above results show promising prospects of this combinative pretreatment in real application. PMID- 29258223 TI - Price and Availability of Sugar-Free, Sugar-Reduced and Low Glycemic Index Cereal Products in Northwestern Mexico. AB - Sugar-free (SF), sugar-reduced (SR), or low-glycemic-index (low GI) cereal products could be helpful for the dietary treatment of disorders related to glucose homeostasis. However, access and economic aspects are barriers that could hamper their consumption. Thus, the availability and price of such cereal products were evaluated in Northwestern Mexico. The products were categorized in 10 groups. The data were collected in five cities by store visitation (from November 2015 to April 2016). The availability in specialized stores and supermarkets was expressed as availability rates based on the total number of products. The price of the SF, SR, and low GI products were compared with their conventional counterparts. Availability rates were higher in supermarkets than in specialized stores by product numbers (14.29% versus 3.76%, respectively; p < 0.001) and by product categories (53.57% versus 26.92%, respectively; p < 0.001). Five categories of products labeled as SF, SR, and low GI (oats, cookies and crackers, flours, snacks, and tostadas/totopos) had higher prices than their conventional counterparts (p < 0.05). In conclusion, in Northwestern Mexico, the availability of SF, SR, and low GI cereal-based foods is relatively low, and these foods are more expensive than their conventional counterparts. PMID- 29258224 TI - The Benefits of the Citrus Flavonoid Diosmin on Human Retinal Pigment Epithelial Cells under High-Glucose Conditions. AB - We investigate diosmin for its effect on the ARPE-19 human retinal pigment epithelial cells exposed to high glucose, a model of diabetic retinopathy (DR). After incubation for 4 days with a normal (5 mmol/L) concentration of D-glucose, ARPE-19 cells were exposed separately to normal or high concentrations of D glucose (30 mmol/L) with or without diosmin at different concentrations (0.1, 1, 10 MUg/mL) for another 48 h. Next, we assessed cell viability, reactive oxygen species (ROS) generation and antioxidant enzyme activities. In order to examine the underlying molecular mechanisms, we meanwhile analyzed the expressions of Bax, Bcl-2, total and phosphorylated JNK and p38 mitogen-activated protein kinase (MAPK). Diosmin dose dependently enhanced cell viability following high glucose treatment in ARPE-19 cells. The activities of superoxide dismutase and glutathione peroxidase, as well as the levels of reduced glutathione were decreased, while it was observed that levels of ROS in high glucose cultured ARPE 19 cells increased. High glucose also disturbed Bax and Bcl-2 expression, interrupted Bcl-2/Bax balance, and triggered subsequent cytochrome c release into the cytosol and activation of caspase-3. These detrimental effects were ameliorated dose dependently by diosmin. Furthermore, diosmin could abrogate high glucose-induced apoptosis as well as JNK and P38 MAPK phosphorylation in ARPE-19 cells. Our results suggest that treatment ARPE-19 cells with diosmin halts hyperglycemia-mediated oxidative damage and thus this compound may be a candidate for preventing the visual impairment caused by DR. PMID- 29258225 TI - Stability of Signaling Pathways during Aging-A Boolean Network Approach. AB - Biological pathways are thought to be robust against a variety of internal and external perturbations. Fail-safe mechanisms allow for compensation of perturbations to maintain the characteristic function of a pathway. Pathways can undergo changes during aging, which may lead to changes in their stability. Less stable or less robust pathways may be consequential to or increase the susceptibility of the development of diseases. Among others, NF- kappa B signaling is a crucial pathway in the process of aging. The NF- kappa B system is involved in the immune response and dealing with various internal and external stresses. Boolean networks as models of biological pathways allow for simulation of signaling behavior. They can help to identify which proposed mechanisms are biologically representative and which ones function but do not mirror physical processes-for instance, changes of signaling pathways during the aging process. Boolean networks can be inferred from time-series of gene expression data. This allows us to get insights into the changes of behavior of pathways such as NF- kappa B signaling in aged organisms in comparison to young ones. PMID- 29258226 TI - Milk Technological Properties as Affected by Including Artichoke By-Products Silages in the Diet of Dairy Goats. AB - Traditional farming practices include the use of local agricultural by-products in the diet of ruminants. Artichoke harvesting and transformation yield high amounts of by-products that, if properly used, may reduce farming costs and the environmental impact of farming. The present study tests the inclusion of silages from artichoke by-products (plant and outer bracts) in the diet of dairy goats (0%, 12.5% and 25% inclusion) on the technological and sensory properties of milk during a five-month study. Milk composition, color, stability, coagulation and fermentation properties remained unaffected by diet changes. Panelists were not able to differentiate among yogurts obtained from those milks by discriminant triangular sensory tests. Silages of artichoke by-products can be included in isoproteic and isoenergetic diets for dairy goats, up to a 25% (feed dry matter), without negatively affecting milk technological and sensory properties whereas reducing feeding costs. PMID- 29258227 TI - Internal Nano Voids in Yttria-Stabilised Zirconia (YSZ) Powder. AB - Porous yttria-stabilised zirconia ceramics have been gaining popularity throughout the years in various fields, such as energy, environment, medicine, etc. Although yttria-stabilised zirconia is a well-studied material, voided yttria-stabilised zirconia powder particles have not been demonstrated yet, and might play an important role in future technology developments. A sol-gel synthesis accompanied by a freeze-drying process is currently being proposed as a method of obtaining sponge-like nano morphology of embedded faceted voids inside yttria-stabilised zirconia particles. The results rely on a freeze-drying stage as an effective and simple method for generating nano-voided yttria-stabilised zirconia particles without the use of template-assisted additives. PMID- 29258228 TI - Multi-Omic Biogeography of the Gastrointestinal Microbiota of a Pre-Weaned Lamb. AB - The digestive functions of the pre-weaned lamb gastrointestinal tracts (GITs) have been the subject of much research in recent years, but the microbial and host functions underlying these complex processes remain largely unknown. Here, we undertook a proof-of-principle metaproteogenomic investigation on luminal and mucosal samples collected from 10 GITs of a 30-day-old pre-weaned lamb. We demonstrate that the analysis of the diverse ecological niches along the GITs can reveal microbiota composition and metabolic functions, although low amounts of microbial proteins could be identified in the small intestinal and mucosal samples. Our data suggest that a 30-day lamb has already developed mature microbial functions in the forestomachs, while the effect of the milky diet appears to be more evident in the remaining GITs. We also report the distribution and the relative abundance of the host functions, active at the GIT level, with a special focus on those involved in digestive processes. In conclusion, this pilot study supports the suitability of a metaproteogenomic approach to the characterization of microbial and host functions of the lamb GITs, opening the way to further studies aimed at investigating the impact of early dietary interventions on the GIT microbiota of small ruminants. PMID- 29258229 TI - Metabolomics Strategy Using High Resolution Mass Spectrometry Reveals Novel Biomarkers and Pain-Relief Effect of Traditional Chinese Medicine Prescription Wu Zhu-Yu Decoction Acting on Headache Modelling Rats. AB - Headache is a common episodic or chronic neurologic disorder. Treatment options and diagnosis are restricted by an incomplete understanding of disease pathology and the lack of diagnostic markers. Wu-Zhu-Yu decoction (WZYD), a traditional Chinese medicine (TCM) formula containing four TCM herbs, is commonly used in the treatment of headache in China. To deeply understand more about headache and investigate the pain-relief mechanism of WZYD, a comprehensive metabolomics study combined with multivariate data processing strategy was carried out. An LC-high resolution mass spectrometry-based metabolomics approach was applied to characterize metabolic biomarker candidates. Multiple pattern recognition including principal component analysis-discriminant analysis, partial least squares-discriminant analysis and hierarchical cluster analysis were used to determine groups and confirm important variables. A total of 17 potential biomarkers were characterized and related metabolic pathways were identified. The study demonstrated that the established metabolomics strategy is a powerful approach for investigating the mechanism of headache attack and WZYD. In addition, the approach may highlight biomarkers and metabolic pathways and can capture subtle metabolite changes from headache, which may lead to an improved mechanism understanding of central nervous system diseases and TCM treatment. PMID- 29258231 TI - Hazardous Object Detection by Using Kinect Sensor in a Handle-Type Electric Wheelchair. AB - To ensure the safety of a handle-type electric wheelchair (hereinafter, electric wheelchair), this paper describes the applicability of using a Kinect sensor. Ensuring the mobility of elderly people is a particularly important issue to be resolved. An electric wheelchair is useful as a means of transportation for elderly people. Considering that the users of electric wheelchairs are elderly people, it is important to ensure the safety of electric wheelchairs at night. To ensure the safety of an electric wheelchair at night, we constructed a hazardous object detection system using commercially available and inexpensive Kinect sensors and examined the applicability of the system. We examined warning timing with consideration to the cognition, judgment, and operation time of elderly people. Based on this, a hazardous object detection area was determined. Furthermore, the detection of static and dynamic hazardous objects was carried out at night and the results showed that the system was able to detect with high accuracy. We also conducted experiments related to dynamic hazardous object detection during daytime. From the above, it showed that the system could be applicable to ensuring the safety of the handle-type electric wheelchair. PMID- 29258230 TI - Anti-Atherogenic Activity of Polyphenol-Rich Extract from Bee Pollen. AB - The aim of this study was to determine the effect of polyphenol-rich ethanol extract of bee pollen (EEP) on atherosclerosis induced by a high-fat diet in ApoE knockout mice. EEP was given with feed in two doses of 0.1 and 1 g/kg body mass (BM). The studies have been conducted in a period of 16 weeks. The following factors were estimated: total cholesterol (TC), oxidized low density lipoproteins (ox-LDL), asymmetric dimethylarginine (ADMA), angiotensin-converting enzyme (ACE) and angiotensin II (ANG II) in the 5th, 10th, 12th, 14th, and 16th week of the experiment. In the last, i.e., 16th week of the studies the development of coronary artery disease (CAD) was also estimated histopathologically. Supplementing diet with EEP resulted in decreasing TC level. EEP reduced oxidative stress by lowering the levels of ox-LDL, ADMA, ANG II and ACE. EEP protected coronary arteries by significantly limiting the development of atherosclerosis (the dose of 0.1 g/kg BM) or completely preventing its occurrence (the dose of 1 g/kg BM). The obtained results demonstrate that EEP may be useful as a potential anti-atherogenic agent. PMID- 29258232 TI - A Micro-Pressure Sensing Method Based on the Micropatterned Electrodes Filled with the Microspheres. AB - As the core component of the sense of touch, flexible pressure sensors are critical to synchronized interactions with the surrounding environment. Here, we introduce a new type of flexible capacitive pressure sensor based on a template of electrodes, with a one-dimensional pyramid micropatterned structure on a Polydimethylsiloxane (PDMS) substrate and a dielectric layer of polystyrene (PS) microspheres. The proposed sensor exhibits a stable and high sensing sensitivity of 0.741 kPa-1 to capacitance, good durability over 1000 cycles, and fast response time (<150 ms). Our flexible capacitive sensor responds not only to pressure but also to bending forces. Our device can be used to monitor the location and distribution of weight pressure. The proposed capacitive pressure sensor has itself been applied foreground in lots of aspects, such as electronic skins, wearable robotics, and biomedical devices. PMID- 29258233 TI - Acid-Induced Rearrangement of Epoxygermacranolides: Synthesis of Furanoheliangolides and Cadinanes from Nobilin. AB - The acid-induced rearrangement of three epoxyderivatives of nobilin 1, the most abundant sesquiterpene lactone in Anthemisnobilis flowers, was investigated. From the 1,10-epoxyderivative 2, furanoheliangolide 5 was obtained, while the 4,5 epoxy group of 3 did not react. Conversely, when the 3-hydroxy function of nobilin was acetylated (12), the 4,5-epoxy derivative did cyclize into cadinanes (15 and 16) under Lewis acid catalysis. The reactivity of the 4,5- and 1,10-epoxy derivatives of nobilin (2 and 3) was compared with that of parthenolide, and rationalized on the basis of quantum chemical calculations. All isolated reaction products were fully characterized by spectroscopic and computational methods, and their in vitro anti-protozoal activity was evaluated. The paper could provide new insights into the biosynthesis of this class of natural products. PMID- 29258234 TI - Time-Dependent Toxic and Genotoxic Effects of Zinc Oxide Nanoparticles after Long Term and Repetitive Exposure to Human Mesenchymal Stem Cells. AB - Zinc oxide nanoparticles (ZnO-NP) are widely spread in consumer products. Data about the toxicological characteristics of ZnO-NP is still under controversial discussion. The human skin is the most important organ concerning ZnO-NP exposure. Intact skin was demonstrated to be a sufficient barrier against NPs; however, defect skin may allow NP contact to proliferating cells. Within these cells, stem cells are the most important toxicological target for NPs. The aim of this study was to evaluate the genotoxic and cytotoxic effects of ZnO-NP at low dose concentrations after long-term and repetitive exposure to human mesenchymal stem cells (hMSC). Cytotoxic effects of ZnO-NP were measured by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Furthermore, genotoxicity was evaluated by the comet assay. For long-term observation over 6 weeks, transmission electron microscopy (TEM) was applied. The results of the study indicated cytotoxic effects of ZnO-NP beginning at high concentrations of 50 MUg/mL and genotoxic effects in hMSC exposed to 1 and 10 MUg/mL ZnO-NP. Repetitive exposure enhanced cyto- but not genotoxicity. Intracellular NP accumulation was observed up to 6 weeks. The results suggest cytotoxic and genotoxic potential of ZnO-NP. Even low doses of ZnO-NP may induce toxic effects as a result of repetitive exposure and long-term cellular accumulation. This data should be considered before using ZnO-NP on damaged skin. PMID- 29258235 TI - GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents. AB - A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-delta1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin. To investigate whether the thieno[2,3-b]pyridines modulate G protein-coupled receptors (GPCRs) other than A2A, a screen against 168 GPCRs was conducted. According to the results, ligand 1 modulates five receptors in the low uM region, four as an antagonist; CRL-RAMP3 (IC50-11.9 uM), NPSR1B (IC50-1.0 uM), PRLHR (IC50-9.3 uM), and CXCR4 (IC50-6.9 uM). Finally, one agonist, GPRR35, was found (EC50 of 7.5 uM). Molecular modelling showed good binding to all of the receptors investigated; however, none of these surpass the A2A receptor. Furthermore, the newly identified receptors are relatively modestly expressed in the cancer cell lines most affected by the thieno[2,3-b]pyridines, making them less likely to be the main targets of the mechanism of action for this compound class. Nevertheless, new modulators against GPCRs are of an interest as potential hits for further drug development. PMID- 29258236 TI - LC-MS/MS Detection of Karlotoxins Reveals New Variants in Strains of the Marine Dinoflagellate Karlodinium veneficum from the Ebro Delta (NW Mediterranean). AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the detection and quantitation of karlotoxins in the selected reaction monitoring (SRM) mode. This novel method was based upon the analysis of purified karlotoxins (KcTx-1, KmTx-2, 44-oxo-KmTx-2, KmTx-5), one amphidinol (AM-18), and unpurified extracts of bulk cultures of the marine dinoflagellate Karlodinium veneficum strain CCMP2936 from Delaware (Eastern USA), which produces KmTx-1 and KmTx-3. The limit of detection of the SRM method for KmTx-2 was determined as 2.5 ng on-column. Collision induced dissociation (CID) spectra of all putative karlotoxins were recorded to present fragmentation patterns of each compound for their unambiguous identification. Bulk cultures of K. veneficum strain K10 isolated from an embayment of the Ebro Delta, NW Mediterranean, yielded five previously unreported putative karlotoxins with molecular masses 1280, 1298, 1332, 1356, and 1400 Da, and similar fragments to KmTx-5. Analysis of several isolates of K. veneficum from the Ebro Delta revealed small-scale diversity in the karlotoxin spectrum in that one isolate from Fangar Bay produced KmTx-5, whereas the five putative novel karlotoxins were found among several isolates from nearby, but hydrographically distinct Alfacs Bay. Application of this LC MS/MS method represents an incremental advance in the determination of putative karlotoxins, particularly in the absence of a complete spectrum of purified analytical standards of known specific potency. PMID- 29258237 TI - Deciphering the Relationship between Obesity and Various Diseases from a Network Perspective. AB - The number of obesity cases is rapidly increasing in developed and developing countries, thereby causing significant health problems worldwide. The pathologic factors of obesity at the molecular level are not fully characterized, although the imbalance between energy intake and consumption is widely recognized as the main reason for fat accumulation. Previous studies reported that obesity can be caused by the dysfunction of genes associated with other diseases, such as myocardial infarction, hence providing new insights into dissecting the pathogenesis of obesity by investigating its associations with other diseases. In this study, we investigated the relationship between obesity and diseases from Online Mendelian Inheritance in Man (OMIM) databases on the protein-protein interaction (PPI) network. The obesity genes and genes of one OMIM disease were mapped onto the network, and the interaction scores between the two gene sets were investigated on the basis of the PPI of individual gene pairs, thereby inferring the relationship between obesity and this disease. Results suggested that diseases related to nutrition and endocrine are the top two diseases that are closely associated with obesity. This finding is consistent with our general knowledge and indicates the reliability of our obtained results. Moreover, we inferred that diseases related to psychiatric factors and bone may also be highly related to obesity because the two diseases followed the diseases related to nutrition and endocrine according to our results. Numerous obesity-disease associations were identified in the literature to confirm the relationships between obesity and the aforementioned four diseases. These new results may help understand the underlying molecular mechanisms of obesity-disease co-occurrence and provide useful insights for disease prevention and intervention. PMID- 29258238 TI - Stress Granule-Inducing Eukaryotic Translation Initiation Factor 4A Inhibitors Block Influenza A Virus Replication. AB - Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication. PMID- 29258240 TI - A Molecular Interpretation on the Different Penetration Enhancement Effect of Borneol and Menthol towards 5-Fluorouracil. AB - Borneol and menthol are terpenes that are widely used as penetration enhancers in transdermal drug delivery. To explore their penetration-enhancement effects on hydrophilic drugs, 5-fluorouracil (5-FU) was selected as a model drug. An approach that combined in vitro permeation studies and coarse-grained molecular dynamics was used to investigate their penetration-enhancement effect on 5-FU. The results showed that although both borneol and menthol imparted penetration enhancement effects on 5-FU, these differed in terms of their mechanism, which may account for the observed variations in penetration-enhancement effects. The main mechanism of action of menthol involves the disruption of the stratum corneum (SC) bilayer, whereas borneol involves multiple mechanisms, including the disruption of the SC bilayer, increasing the diffusion coefficient of 5-FU, and inducing the formation of transient pores. The findings of the present study improve our understanding of the molecular mechanism that is underlying 5-FU penetration-enhancement by borneol and menthol, which may be utilized in future investigations and applications. PMID- 29258239 TI - MicroRNA-132 Negatively Regulates Palmitate-Induced NLRP3 Inflammasome Activation through FOXO3 Down-Regulation in THP-1 Cells. AB - Saturated fatty acids were proposed to activate the NLRP3 inflammasome, a molecular platform that mediates the processing of interleukin (IL)-1beta and IL 18. However, the mechanisms underlying the miRNA-mediated regulation of palmitate (PA)-induced inflammasome activation are unclear. We examined the role of miR-132 in PA-induced NLRP3 inflammasome activation in THP-1 cells. To understand the regulatory role of miR-132 in inflammasome activation, we either overexpressed or suppressed miR-132 in THP-1 cells that expressed the NLRP3 inflammasome in response to stimulation by PA. We analyzed the mRNA and protein levels of NLRP3, caspase-1 p10, IL-18, and IL-1beta; caspase-1 activity; and IL-1beta secretion. The presence of PA activated the NLRP3 inflammasome and increased miR-132 expression. Overexpression of miR-132 reduced caspase-1 p10, IL-18, and IL-1beta, while the suppression of miR-132 enhanced inflammasome activation. In addition, miR-132 regulated the mRNA and protein expression of FOXO3, which is a potential target of miR-132 in these cells. FOXO3 suppression by small interfering RNA decreased NLRP3 inflammasome activity stimulated by PA. Knockdown of FOXO3 attenuated NLRP3 inflammasome activation by the miR-132 inhibitor. Based on these findings, we conclude that miR-132 negatively regulates PA-induced NLRP3 inflammasome activation through FOXO3 down-regulation in THP-1 cells. PMID- 29258241 TI - Associations of Older Taiwanese Adults' Personal Attributes and Perceptions of the Neighborhood Environment Concerning Walking for Recreation and Transportation. AB - This study examines the cross-sectional associations between personal and perceived neighborhood environment attributes regarding walking for recreation and transportation among older Taiwanese adults. Data related to personal factors, perceived environmental factors, and time spent engaging in transportation-related and recreational walking were obtained from 1032 older adults aged 65 years and above. The data were analyzed by carrying out an adjusted binary logistic regression. After adjusting for potential confounders, two commonly perceived environmental factors, the presence of sidewalks (PS) and the presence of a destination (PD), were positively associated with 150 min of walking for recreation. Different personal and perceived environmental factors were associated with walking for recreation and transportation. These findings suggest that policy-makers and physical activity intervention designers should develop both common and individual environmental strategies in order to improve and increase awareness of the neighborhood environment to promote recreational and transportation walking behaviors among older adults. PMID- 29258242 TI - Successful Treatment of Pulmonary and Cerebral Toxoplasmosis Associated with Pneumocystis Pneumonia in an HIV Patient. AB - In both the post and pre combination antiretroviral therapy (cART) era, Pneumocystis jirovecii and Toxoplasma gondii remain common opportunistic infectious agents. The common manifestations are pneumonia for P. jirovecii and brain abscess for T. gondii. Nevertheless, co-infection remains rare, and pulmonary toxoplasmosis is scarce, or may be underestimated because of its similarity with Pneumocystis jirovecii pneumonia. We reported an uncommon case of an AIDS patient (6 CD4 + T cells/mm3) with both pulmonary and cerebral toxoplasmosis associated with pneumocystis pneumonia. The patient presented with general weakness, fever and dyspnea. Pulmonary toxoplasmosis and pneumocystis were confirmed by microscopic examination and DNA detection in the bronchoalveolar lavage. Computed tomography imaging of the brain revealed a single characteristic cerebral toxoplasmosis lesion of the left capsular area. He was successful treated by trimethoprim/sulfamethoxaxole in conjunction with an early reintroduction of cART, and without IRIS development. During a 3-year follow-up, HIV viral load remained undetectable, and the patient did not relapse for toxoplasmosis or Pneumocystis pneumonia. PMID- 29258243 TI - Canadine from Corydalis turtschaninovii Stimulates Myoblast Differentiation and Protects against Myotube Atrophy. AB - Cachexia and sarcopenia are the main causes of muscle atrophy. These result in a reduction in the muscle fiber area, myo-protein content, and muscle strength, with various molecular modulators being involved. Although several reports have proposed potential therapeutic agents, no effective treatments have been found for muscle atrophy. We searched for myogenic modulators from medicinal plants to treat muscle diseases. We isolated six alkaloids from Corydalis turtschaninovii and evaluated their myogenic potential by using the MyoD reporter gene assay in C2C12 cells. Among the tested compounds, canadine showed the strongest transactivation of MyoD and increased MHC expression during myogenesis. The activation of p38 MAP kinase and Akt are major mechanisms that contribute to the myogenesis by canadine. Canadine increased the number of multinucleated and cylinder-shaped myotubes during myogenesis of C2C12 myoblasts. To determine the preventive effect of canadine in cancer-induced muscle wasting, differentiated C2C12 myotubes were treated with conditioned media from CT26 colon carcinoma culture (CT26 CM) in the presence of canadine. Canadine ameliorated the muscle protein degradation caused by CT26-CM by down-regulating the muscle specific-E3 ligases, MAFbx/atrogin-1 and MuRF1. In this study, we found that canadine from C. turtschaninovii stimulates myogenesis and also inhibits muscle protein degradation. Therefore, we suggest canadine as a protective agent against muscle atrophy. PMID- 29258244 TI - Molecular Pathogenesis of Radiation-Induced Cell Toxicity in Stem Cells. AB - Radiation therapy is an effective cancer therapy, but damage to normal tissues surrounding the tumor due to radiotherapy causes severe complications. The importance of the therapeutic area between tumor suppression and normal tissue injury has long been highlighted in radiation therapy. Recent advances in stem cell biology have shown that stem cell (SC) responses to genotoxic stresses of ionizing radiation can improve the therapeutic effect of radiation by repairing damaged cells. In contrast, cancer stem cells (CSCs), a small subpopulation of cells within tumors, are generally resistant to chemotherapy and radiotherapy and cause tumor recurrence. Although the underlying mechanisms are not clearly understood in detail, efforts are still underway to identify SC treatment or CSC resistant pathogenesis of DNA damage agents such as radiation therapy. In response to radiation, CSCs differ from normal SCs in their biological properties due to severe deregulation of the self-renewal ability in CSCs. Differences of cleavage mode, cell cycle characteristics, replication potential, and activation/inactivation of DNA damage treatment and cancer-specific molecular pathways between normal SCs and CSCs confer a malignant phenotype upon CSCs. However, further studies are needed to identify normal SC and CSC-specific targets. In this review, we summarize the current advances in research regarding how normal SCs and CSCs respond to ionizing radiation, with a special emphasis on cell toxicity, radiosensitivity, signaling networks, DNA damage response (DDR) and DNA repair. In addition, we discuss strategies to develop new diagnostic and therapeutic techniques for predicting responses to cancer treatment and overcoming radiation-related toxicity. PMID- 29258245 TI - Integrating Norm Activation Model and Theory of Planned Behavior to Understand Sustainable Transport Behavior: Evidence from China. AB - With increasing urbanization in China, many cities are facing serious environmental problems due to continuous and substantial increase in automobile transportation. It is becoming imperative to examine effective ways to reduce individual automobile use to facilitate sustainable transportation behavior. Empirical, theory-based research on sustainable transportation in China is limited. In this research, we propose an integrated model based on the norm activation model and the theory of planned behavior by combining normative and rational factors to predict individuals' intention to reduce car use. Data from a survey of 600 car drivers in China's three metropolitan areas was used to test the proposed model and hypotheses. Results showed that three variables, perceived norm of car-transport reduction, attitude towards reduction, and perceived behavior control over car-transport reduction, significantly affected the intention to reduce car-transport. Personal norms mediated the relationship between awareness of consequences of car-transport, ascription of responsibility of car-transport, perceived subjective norm for car-transport reduction, and intention to reduce car-transport. The results of this research not only contribute to theory development in the area of sustainable transportation behavior, but also provide a theoretical frame of reference for relevant policy makers in urban transport management. PMID- 29258246 TI - Microemulsion and Sol-Gel Synthesized ZrO2-MgO Catalysts for the Liquid-Phase Dehydration of Xylose to Furfural. AB - Two series of catalysts were prepared by sol-gel and microemulsion synthetic procedure (SG and ME, respectively). Each series includes both pure Mg and Zr solids as well as Mg-Zr mixed solids with 25%, 50% and 75% nominal Zr content. The whole set of catalysts was characterized from thermal, structural and surface chemical points of view and subsequently applied to the liquid-phase xylose dehydration to furfural. Reactions were carried out in either a high-pressure autoclave or in an atmospheric pressure multi-reactor under a biphasic (organic/water) reaction mixture. Butan-2-ol and toluene were essayed as organic solvents. Catalysts prepared by microemulsion retained part of the surfactant used in the synthetic procedure, mainly associated with the Zr part of the solid. The MgZr-SG solid presented the highest surface acidity while the Mg3Zr-SG one exhibited the highest surface basicity among mixed systems. Xylose dehydration in the high-pressure system and with toluene/water solvent mixture led to the highest furfural yield. Moreover, the yield of furfural increases with the Zr content of the catalyst. Therefore, the catalysts constituted of pure ZrO2 (especially Zr-SG) are the most suitable to carry out the process under study although MgZr mixed solids could be also suitable for overall processes with additional reaction steps. PMID- 29258249 TI - Strain Evolution in Cold-Warm Forged Steel Components Studied by Means of EBSD Technique. AB - Electron BackScatter Diffraction (EBSD) in conjunction with Field-Emission Environmental Scanning Electron Microscopy (FEG-ESEM) has been used to evaluate the microstructural and local plastic strain evolution in different alloys (AISI 1005, AISI 304L and Duplex 2205) deformed by a single-stage cold and warm forging process. The present work is aimed to describe the different behavior of the austenite and ferrite during plastic deformation as a function of different forging temperatures. Several topological EBSD maps have been measured on the deformed and undeformed states. Then, image quality factor, distributions of the grain size and misorientation have been analyzed in detail. In the austenitic stainless steel, the gamma-phase has been found to harden more easily, then alpha phase and gamma-phase in AISI 1005 and in duplex stainless steel, sequentially. Compared to the high fraction of continuous dynamic recrystallized austenitic zones observed in stainless steels samples forged at low temperatures, the austenitic microstructure of samples forged at higher temperatures, 600-700 degrees C, has been found to be mainly characterized by large and elongated grains with some colonies of fine nearly-equiaxed grains attributed to discontinuous dynamic recrystallization. PMID- 29258248 TI - Pomegranate (Punica granatum) Juice Shows Antioxidant Activity against Cutaneous Leishmaniasis-Induced Oxidative Stress in Female BALB/c Mice. AB - Leishmania species are parasites that multiply within phagocytes and cause several clinical diseases characterized by single or multiple ulcerations. One of the complications that can induce tissue damage and the resulting scars is caused by secondary bacterial infections. Studies to find new, effective, and safe oral drugs for treating leishmaniasis are being conducted since several decades, owing to the problems associated with the use of antimonials available. Previously, the antiparasitic and antioxidant properties of Punica granatum (pomegranate, P. granatum) have been reported. Therefore, in the present study, we aimed to investigate the antileishmanial activity of pomegranate aqueous juice in vitro and in female BALB/c mice. A 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in Leishmania major promastigotes and alterations in the antioxidant status, liver function, and skin histological changes in L. major infected mice orally treated with pomegranate juice alone and in combination with the antibiotic ciprofloxacin, were used to investigate the in vitro and in vivo antileishmanial activity of pomegranate juice, respectively. Oral P. granatum juice treatment significantly reduced the average size of cutaneous leishmaniasis lesions compared with that of the untreated mice. This antileishmanial activity of P. granatum was associated with enhanced antioxidant enzyme activities. Histopathological evaluation proved the antileishmanial activity of P. granatum, but did not reveal changes in the treated animals, compared to the positive control. In conclusion, P. granatum shows high and fast antileishmanial activity probably by boosting the endogenous antioxidant activity. PMID- 29258247 TI - Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin. AB - The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as 'annatto') originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2-/- SKH-1 mice confirming the NRF2-dependence of bixin-induced antioxidant and anti-inflammatory effects. In addition, bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) alpha/gamma agonist, and TLR (Toll-like receptor) 4/NFkappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination. PMID- 29258250 TI - Heavy Metal Pollution and Ecological Assessment around the Jinsha Coal-Fired Power Plant (China). AB - Heavy metal pollution is a serious problem worldwide. In this study, 41 soil samples and 32 cabbage samples were collected from the area surrounding the Jinsha coal-fired power plant (JCFP Plant) in Guizhou Province, southwest China. Pb, Cd, Hg, As, Cu and Cr concentrations in soil samples and cabbage samples were analysed to study the pollution sources and risks of heavy metals around the power plant. The results indicate that the JCFP Plant contributes to the Pb, Cd, As, Hg, Cu, and Cr pollution in nearby soils, particularly Hg pollution. Cu and Cr in soils from both croplands and forestlands in the study area derive mainly from crustal materials or natural processes. Pb, Cd and As in soils from croplands arise partly through anthropogenic activities, but these elements in soils from forestlands originate mainly from crustal materials or natural processes. Hg pollution in soils from both croplands and forestlands is caused mainly by fly ash from the JCFP Plant. The cabbages grown in the study area were severely contaminated with heavy metals, and more than 90% of the cabbages had Pb concentrations exceeding the permissible level established by the Ministry of Health and the Standardization Administration of the People's Republic of China. Additionally, 30% of the cabbages had As concentrations exceeding the permissible level. Because forests can protect soils from heavy metal pollution caused by atmospheric deposition, close attention should be given to the Hg pollution in soils and to the concentrations of Pb, As, Hg and Cr in vegetables from the study area. PMID- 29258251 TI - What Kills the Hindgut Flagellates of Lower Termites during the Host Molting Cycle? AB - Subsocial wood feeding cockroaches in the genus Cryptocercus, the sister group of termites, retain their symbiotic gut flagellates during the host molting cycle, but in lower termites, closely related flagellates die prior to host ecdysis. Although the prevalent view is that termite flagellates die because of conditions of starvation and desiccation in the gut during the host molting cycle, the work of L.R. Cleveland in the 1930s through the 1960s provides a strong alternate hypothesis: it was the changed hormonal environment associated with the origin of eusociality and its concomitant shift in termite developmental ontogeny that instigates the death of the flagellates in termites. Although the research on termite gut microbial communities has exploded since the advent of modern molecular techniques, the role of the host hormonal environment on the life cycle of its gut flagellates has been neglected. Here Cleveland's studies are revisited to provide a basis for re-examination of the problem, and the results framed in the context of two alternate hypotheses: the flagellate symbionts are victims of the change in host social status, or the flagellates have become incorporated into the life cycle of the eusocial termite colony. Recent work on parasitic protists suggests clear paths for exploring these hypotheses and for resolving long standing issues regarding sexual-encystment cycles in flagellates of the Cryptocercus-termite lineage using molecular methodologies, bringing the problem into the modern era. PMID- 29258252 TI - Pathogenic Acanthamoeba castellanii Secretes the Extracellular Aminopeptidase M20/M25/M40 Family Protein to Target Cells for Phagocytosis by Disruption. AB - Acanthamoeba is free-living protist pathogen capable of causing a blinding keratitis and granulomatous encephalitis. However, the mechanisms of Acanthamoeba pathogenesis are still not clear. Here, our results show that cells co-cultured with pathogenic Acanthamoeba would be spherical and floated, even without contacting the protists. Then, the Acanthamoeba protists would contact and engulf these cells. In order to clarify the contact-independent pathogenesis mechanism in Acanthamoeba, we collected the Acanthamoeba-secreted proteins (Asp) to incubate with cells for identifying the extracellular virulent factors and investigating the cytotoxicity process. The Asps of pathogenic Acanthamoeba express protease activity to reactive Leu amino acid in ECM and induce cell losing adhesion ability. The M20/M25/M40 superfamily aminopeptidase protein (ACA1_264610), an aminopeptidase be found in Asp, is upregulated after Acanthamoeba and C6 cell co-culturing for 6 h. Pre-treating the Asp with leucine aminopeptidase inhibitor and the specific antibodies of Acanthamoeba M20/M25/M40 superfamily aminopeptidase could reduce the cell damage during Asp and cell co incubation. These results suggest an important functional role of the Acanthamoeba secreted extracellular aminopeptidases in the Acanthamoeba pathogenesis process. This study provides information regarding clinically pathogenic isolates to target specific molecules and design combined drugs. PMID- 29258253 TI - Identification of the Sex-Biased Gene Expression and Putative Sex-Associated Genes in Eucommia ulmoides Oliver Using Comparative Transcriptome Analyses. AB - Eucommia ulmoides is a model representative of the dioecious plants with sex differentiation at initiation. Nevertheless, the genetic mechanisms of sexual dimorphism and sex determination in E. ulmoides remain poorly understood. In this study de novo transcriptome sequencing on Illumina platform generated >45 billion high-quality bases from fresh leaves of six male and female individuals of E. ulmoides. A total of 148,595 unigenes with an average length of 801 base-pairs (bp) were assembled. Through comparative transcriptome analyses, 116 differentially expressed genes (DEGs) between the males and the females were detected, including 73 male-biased genes and 43 female-biased genes. Of these DEGs, three female-biased genes were annotated to be related with the sexually dimorphic gutta content in E. ulmoides. One male-biased DEG was identified as putative MADS box gene APETALA3, a B class floral organ identity gene in the flowering plants. SNPs calling analyses further confirmed that the APETALA3-like gene was probably involved in the sex determination in E. ulmoides. Four other male-biased DEGs were potential sex-associated genes as well with segregated SNPs in accord with sex type. In addition, the SNPs density was 1.02 per kilobase (kb) in the expressed genes of E. ulmoides, implying a relatively high genetic diversity. PMID- 29258254 TI - Recognizing the SINEs of Infection: Regulation of Retrotransposon Expression and Modulation of Host Cell Processes. AB - Short interspersed elements (SINEs) are a family of retrotransposons evolutionarily derived from cellular RNA polymerase III transcripts. Over evolutionary time, SINEs have expanded throughout the human genome and today comprise ~11% of total chromosomal DNA. While generally transcriptionally silent in healthy somatic cells, SINE expression increases during a variety of types of stresses, including DNA virus infection. The relevance of SINE expression to viral infection was largely unexplored, however, recent years have seen great progress towards defining the impact of SINE expression on viral replication and host gene expression. Here we review the origin and diversity of SINE elements and their transcriptional control, with an emphasis on how their expression impacts host cell biology during viral infection. PMID- 29258255 TI - Structure Features and Anti-Gastric Ulcer Effects of Inulin-Type Fructan CP-A from the Roots of Codonopsis pilosula (Franch.) Nannf. AB - Radix Codonopsis has been used in traditional Chinese medicine for strengthening the immune system, improving poor gastrointestinal function, treating gastric ulcers and chronic gastritis and so on. In the present study, an inulin-type fructan CP-A was obtained from the roots of Codonopsis pilosula (Franch.) Nannf. and its structure was confirmed by MS and NMR as (2 -> 1) linked-beta-d fructofuranose. The protective effects of CP-A against ethanol-induced acute gastric ulcer in rats were intensively investigated. A Lacy assay demonstrated that CP-A-treated group (50 mg/kg) showed the gastric damage level 1, which was similar to the positive control group, while the model group exhibited the gastric damage level 3. The Guth assay demonstrated that the mucosa ulcer index for CP-A groups at the doses of 50 mg/kg and 25 mg/kg significantly decreased compared with that in the model group (p < 0.05). Meanwhile, CP-A significantly increased the activities of SOD and GSH-Px, and decreased the contents of MDA and NO, and the activity of MPO in gastric tissue in a dose-dependent manner (p < 0.05). The present research reported for the first time that inulin-type fructan CP-A were likely the potential component in Radix Codonopsis for treatment of acute gastric ulcers. PMID- 29258256 TI - Material State Awareness for Composites Part II: Precursor Damage Analysis and Quantification of Degraded Material Properties Using Quantitative Ultrasonic Image Correlation (QUIC). AB - Material state awareness of composites using conventional Nondestructive Evaluation (NDE) method is limited by finding the size and the locations of the cracks and the delamination in a composite structure. To aid the progressive failure models using the slow growth criteria, the awareness of the precursor damage state and quantification of the degraded material properties is necessary, which is challenging using the current NDE methods. To quantify the material state, a new offline NDE method is reported herein. The new method named Quantitative Ultrasonic Image Correlation (QUIC) is devised, where the concept of microcontinuum mechanics is hybrid with the experimentally measured Ultrasonic wave parameters. This unique combination resulted in a parameter called Nonlocal Damage Entropy for the precursor awareness. High frequency (more than 25 MHz) scanning acoustic microscopy is employed for the proposed QUIC. Eight woven carbon-fiber-reinforced-plastic composite specimens were tested under fatigue up to 70% of their remaining useful life. During the first 30% of the life, the proposed nonlocal damage entropy is plotted to demonstrate the degradation of the material properties via awareness of the precursor damage state. Visual proofs for the precursor damage states are provided with the digital images obtained from the micro-optical microscopy, the scanning acoustic microscopy and the scanning electron microscopy. PMID- 29258257 TI - AetMYC1, the Candidate Gene Controlling the Red Coleoptile Trait in Aegilops tauschii Coss. Accession As77. AB - The red coleoptile trait can help monocotyledonous plants withstand stresses, and key genes responsible for the trait have been isolated from Triticum aestivum, Triticum urartu, and Triticum monococcum, but no corresponding research has been reported for Aegilops tauschii. In this research, transcriptome analysis was performed to isolate the candidate gene controlling the white coleoptile trait in Ae. tauschii. There were 5348 upregulated, differentially-expressed genes (DEGs) and 4761 downregulated DEGs in red coleoptile vs. white coleoptile plants. Among these DEGs, 12 structural genes and two transcription factors involved in anthocyanin biosynthesis were identified. The majority of structural genes showed lower transcript abundance in the white coleoptile of accession 'As77' than in the red coleoptile of accession 'As60', which implied that transcription factors related to anthocyanin biosynthesis could be the candidate genes. The MYB and MYC transcription factors AetMYB7D and AetMYC1 were both isolated from Ae. tauschii accessions 'As60' and 'As77', and their transcript levels analyzed. The coding sequence and transcript level of AetMYB7D showed no difference between 'As60' and 'As77'. AetMYC1p encoded a 567-amino acid polypeptide in 'As60' containing the entire characteristic domains, bHLH-MYC_N, HLH, and ACT-like, belonging to the gene family involved in regulating anthocyanin biosynthesis. AetMYC1w encoded a 436-amino acid polypeptide in 'As77' without the ACT-like domain because a single nucleotide mutation at 1310 bp caused premature termination. Transient expression of AetMYC1p induced anthocyanin biosynthesis in 'As77' with the co-expression of AetMYB7D, while AetMYC1w could not cause induced anthocyanin biosynthesis under the same circumstances. Moreover, the transcript abundance of AetMYC1w was lower than that of AetMYC1p. AetMYC1 appears to be the candidate gene controlling the white coleoptile trait in Ae. tauschii, which can be used for potential biotech applications, such as producing new synthetic hexaploid wheat lines with different coleoptile colors. PMID- 29258258 TI - Galectins and Carcinogenesis: Their Role in Head and Neck Carcinomas and Thyroid Carcinomas. AB - Head and neck cancers are among the most frequently occurring cancers worldwide. Of the molecular drivers described for these tumors, galectins play an important role via their interaction with several intracellular pathways. In this review, we will detail and discuss this role with specific reference to galectins-1, -3, and -7 in angiogenesis, cell proliferation, and invasion as well as in cell transformation and cancer progression. Furthermore, we will evaluate the prognostic value of galectin expression in head and neck cancers including those with oral cavity, salivary gland, and nasopharyngeal pathologies. In addition, we will discuss the involvement of these galectins in thyroid cancers where their altered expression is proposed as a new diagnostic biomarker. PMID- 29258259 TI - Regulation of Polyamine Metabolism by Curcumin for Cancer Prevention and Therapy. AB - Curcumin (diferuloylmethane), the natural polyphenol responsible for the characteristic yellow pigment of the spice turmeric (Curcuma longa), is traditionally known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. In human cancer cell lines, curcumin has been shown to decrease ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine biosynthesis that is frequently upregulated in cancer and other rapidly proliferating tissues. Numerous studies have demonstrated that pretreatment with curcumin can abrogate carcinogen-induced ODC activity and tumor development in rodent tumorigenesis models targeting various organs. This review summarizes the results of curcumin exposure with regard to the modulation of polyamine metabolism and discusses the potential utility of this natural compound in conjunction with the exploitation of dysregulated polyamine metabolism in chemopreventive and chemotherapeutic settings. PMID- 29258260 TI - Strain Gauges Based on CVD Graphene Layers and Exfoliated Graphene Nanoplatelets with Enhanced Reproducibility and Scalability for Large Quantities. AB - The two-dimensional material graphene promises a broad variety of sensing activities. Based on its low weight and high versatility, the sensor density can significantly be increased on a structure, which can improve reliability and reduce fluctuation in damage detection strategies such as structural health monitoring (SHM). Moreover; it initializes the basis of structure-sensor fusion towards self-sensing structures. Strain gauges are extensively used sensors in scientific and industrial applications. In this work, sensing in small strain fields (from -0.1% up to 0.1%) with regard to structural dynamics of a mechanical structure is presented with sensitivities comparable to bulk materials by measuring the inherent piezoresistive effect of graphene grown by chemical vapor deposition (CVD) with a very high aspect ratio of approximately 4.86 * 108. It is demonstrated that the increasing number of graphene layers with CVD graphene plays a key role in reproducible strain gauge application since defects of individual layers may become less important in the current path. This may lead to a more stable response and, thus, resulting in a lower scattering.. Further results demonstrate the piezoresistive effect in a network consisting of liquid exfoliated graphene nanoplatelets (GNP), which result in even higher strain sensitivity and reproducibility. A model-assisted approach provides the main parameters to find an optimum of sensitivity and reproducibility of GNP films. The fabricated GNP strain gauges show a minimal deviation in PRE effect with a GF of approximately 5.6 and predict a linear electromechanical behaviour up to 1% strain. Spray deposition is used to develop a low-cost and scalable manufacturing process for GNP strain gauges. In this context, the challenge of reproducible and reliable manufacturing and operating must be overcome. The developed sensors exhibit strain gauges by considering the significant importance of reproducible sensor performances and open the path for graphene strain gauges for potential usages in science and industry. PMID- 29258262 TI - Microstructure, Pitting Corrosion Resistance and Impact Toughness of Duplex Stainless Steel Underwater Dry Hyperbaric Flux-Cored Arc Welds. AB - Duplex stainless steel multi-pass welds were made at 0.15 MPa, 0.45 MPa, and 0.75 MPa pressure, simulating underwater dry hyperbaric welding by the flux-cored arc welding (FCAW) method, with welds of normal pressure as a benchmark. The purpose of this work was to estimate the effect of ambient pressure on the microstructure, pitting corrosion resistance and impact toughness of the weld metal. The microstructure measurement revealed that the ferrite content in the weld metal made at 0.45 MPa is the lowest, followed by that of 0.75 MPa and 0.15 MPa. The analysis of potentiodynamic polarization tests at 30 degrees C and 50 degrees C demonstrated that the pitting corrosion resistance depends on the phases of the lower pitting resistance equivalent numbers (PREN), secondary austenite and ferrite. The weld metal made at 0.45 MPa had the best resistance to pitting corrosion at 30 degrees C and 50 degrees C with the highest PRENs of secondary austenite and ferrite. The weld metal made at 0.15 MPa displayed the lowest pitting corrosion resistance at 30 degrees C with the lowest PREN of secondary austenite, while the weld metal made at 0.75 MPa was the most seriously eroded after being tested at 50 degrees C for the lowest PREN of ferrite, with large cluster pits seen in ferrite at 50 degrees C. The impact tests displayed a typical ductile-brittle transition because of the body-centered cubic (BCC) structure of the ferrite when the test temperature was lowered. All the weld metals met the required value of 34 J at -40 degrees C according to the ASTM A923. The highest ferrite content corresponded to the worst impact toughness, but the highest toughness value did not correspond to the greatest austenite content. With the decreasing of the test temperature, the drop value of absorbed energy was correlated to the ferrite content. Additionally, in this work, the weld metal made at 0.45 MPa had the best combined properties of pitting resistance and impact toughness. PMID- 29258261 TI - Oligofructose Provides Laxation for Irregularity Associated with Low Fiber Intake. AB - Inadequate dietary fiber intake contributes to the prevalent irregularity and constipation in Western countries. Although eating adequate amounts of fibers from fiber-rich foods, foods with added fibers and dietary fiber supplements is considered the first option for improving laxation, the efficacy can vary among types of fibers. The present study is a randomized control trial that included healthy adult participants with <=3 bowel movements/week and a habitual low dietary fiber intake in a parallel design to evaluate the benefits for laxation by supplementing the daily diet with oligofructose (Orafti(r) P95; OF), a fermentable source of fiber and established prebiotic (n = 49); maltodextrin was the placebo (n = 48). After a run-in phase, OF was initially provided at 5 g/day, then increased to 10 and 15 g/day with four weeks for each phase. Stool frequency (bowel movements per week) for the OF and maltodextrin (MD) groups were initially similar (3.98 +/- 1.49 vs. 4.06 +/- 1.48), did not change for the placebo group, but increased for the OF group with the difference significant at 15 g/day (p = 0.023). Stool consistency was similar and remained unchanged at all doses for both groups. Gastrointestinal sensations were low for both groups. Laxation benefits were especially pronounced for participants with >13 g/day habitual dietary fiber intake, with significant laxation at 10 g and 15 g OF/day (p = 0.04 and p = 0.004, respectively) A daily supplement with a short-chain inulin-type fructan derived from chicory roots, i.e., oligofructose (Orafti(r) P95) provided a laxation effect without causing gastrointestinal (GI) distress for healthy participants with irregularity associated with low dietary fiber intake. PMID- 29258263 TI - Tussilagone Inhibits the Inflammatory Response and Improves Survival in CLP Induced Septic Mice. AB - Tussilagone, extracted from Tussilago farfara is an oriental medicine used for asthma and bronchitis. We investigated its mechanism of action, its inhibitory effects on lipopolysaccharide-induced inflammation in macrophages, and its impact on viability in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. Tussilagone suppressed the expression of the inflammatory mediators, nitric oxide and prostaglandin E2, and the inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and high-mobility group box 1 (HMGB1), in lipopolysaccharide-stimulated RAW 264.7 cells and peritoneal macrophages. Tussilagone also reduced the activation of the mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) involved in the activation of various inflammatory mediators in activated macrophages. Moreover, tussilagone administration (1 mg/kg and 10 mg/kg) produced decreased mortality and lung injury in CLP-activated septic mice. Augmented expression of cyclooxygenase (COX)-2 and TNF-alpha in pulmonary alveolar macrophages of septic mice were attenuated by tussilagone administration. Tussilagone also suppressed the induction of nitric oxide, prostaglandin E2, TNF alpha and HMGB1 in the serum of the septic mice. Overall, tussilagone exhibited protective effects against inflammation and polymicrobial sepsis by suppressing inflammatory mediators possibly via the inhibition of NF-kappaB activation and the MAP kinase pathway. These results suggest the possible use of tussilagone for developing novel therapeutic modalities for sepsis and other inflammatory diseases. PMID- 29258264 TI - Convenient Preparation of 18F-Labeled Peptide Probes for Potential Claudin-4 PET Imaging. AB - Since pancreatic cancer is often diagnosed in a late state of cancer development, diagnostic opportunities allowing early disease detection are highly sought after. As such, cancer expression of claudin proteins is markedly dysregulated, making it an attractive target for molecular imaging like positron emission tomography (PET). Claudins are a family of transmembrane proteins that have a pivotal role as members of the tight junctions. In particular, claudin-3 and claudin-4 are frequently overexpressed in pancreatic cancer. 18F-Labeled claudin selective peptides would provide access to a novel kind of imaging tools for pancreatic cancer. In this work we describe the synthesis of the first 18F labeled probes potentially suitable for PET imaging of claudin-4 expression. These probes were prepared using oxime ligation of 5-[18F]fluoro-5-deoxyribose (5 [18F]FDR) to claudin selective peptides. As a proof-of-principle, one of them, 5 [18F]FDR-Clone 27, was isolated in >98% radiochemical purity and in 15% radiochemical yield (EOB) within 98 min, and with a molar activity of 4.0 GBq/MUmol (for 30 MBq of tracer). Moreover, we present first biological data for the prepared 5-FDR-conjugates. These tracers could pave the way for an early diagnosis of pancreatic tumor, and thus improve the outcome of anticancer therapy. PMID- 29258266 TI - Open Knowledge about Slaughter on the Internet-A Case Study on Controversies. AB - Knowledge about slaughter of animals for human food is often perceived as controversial and therefore not made widely available. An open educational resource on the Internet about the slaughter of animals has created tension at launch but also resolved tension. Aiming to explore how this resource at the boundary between academia and society is perceived, a study was carried out with participants from slaughterhouses, universities, authorities and NGOs. Focus group sessions were video recorded and transcripts were coded using an interpretive thematic analysis. The results show that an open educational resource in addition to contributing to learning and awareness raising can also induce dialogue (and thus resolve tension) about animal welfare and contribute to animal welfare resilience. Our results also indicate that participants had diverse opinions about the influence of multimedia on attitudes towards animal slaughter. The use of additional instruments such as comment fields may lead to more knowledgeable citizens and socially robust knowledge, but has to be carefully weighed against the risk of false or fake data. PMID- 29258265 TI - Implication of Different HIV-1 Genes in the Modulation of Autophagy. AB - Autophagy is a complex cellular degradation pathway, which plays important roles in the regulation of several developmental processes, cellular stress responses, and immune responses induced by pathogens. A number of studies have previously demonstrated that HIV-1 was capable of altering the regulation of autophagy and that this biological process could be induced in uninfected and infected cells. Furthermore, previous reports have indicated that the involvement of HIV-1 in autophagy regulation is a complex phenomenon and that different viral proteins are contributing in its modulation upon viral infection. Herein, we review the recent literature over the complex crosstalk of the autophagy pathway and HIV-1, with a particular focus on HIV-1 viral proteins, which have been shown to modulate autophagy. PMID- 29258267 TI - cGAMP Promotes Germinal Center Formation and Production of IgA in Nasal Associated Lymphoid Tissue. AB - Induction of immunoglobulin (Ig) A in the mucosa of the upper respiratory tract and the nasal cavity protects against influenza virus infection. Cyclic dinucleotides (CDNs) are used as mucosal adjuvants to enhance the immunogenicity of intranasal influenza hemagglutinin (HA) vaccines. The adjuvant activity of 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) on Ig production was investigated in nasal-associated lymphoid tissue (NALT), serum of wild-type C57BL/6J, and stimulator of interferon genes (STING)-deficient mice, which do not recognize cGAMP. Mice were vaccinated intranasally with a HA vaccine with or without the cGAMP adjuvant. IgA and IgG production, T-cell responses, germinal center formation, and cytokine expression in NALT were assayed. cGAMP enhanced IgA and IgG production, and promoted T-cell responses. Intranasal administration of cGAMP activated both NALT and systemic immune cells, induced a favorable cytokine environment for IgA induction, and promoted germinal center formation. The cGAMP effect was STING-dependent. Taken together, cGAMP as an HA vaccine adjuvant promoted a STING-dependent NALT environment suitable for the enhancement of IgA production. PMID- 29258268 TI - Chemopreventive Potential of Raw and Roasted Pistachios Regarding Colon Carcinogenesis. AB - Pistachios are rich in health-promoting bioactive compounds such as B vitamins, gamma-tocopherol, polyphenols and dietary fiber, which could contribute to the reduction of colon cancer risk in terms of chemoprevention (Fischer, S.; Glei, M. Health-Potential of Nuts. Ernaehrungs Umsch. Int. 2013, 60, 206-215.). Since pistachios are often consumed roasted, the present study aims at investigating the influence of different roasting conditions (RC) on potential chemopreventive effects of pistachios in colon adenoma cells such as growth and apoptosis, genotoxic- and anti-genotoxic effects and modulation of gene expression of detoxifying enzymes (CAT, SOD2, GPx1, and GSTP1). Fermentation supernatants (FS) were obtained from raw and roasted (RC1 = 141 degrees C/25 min, RC2 = 160 degrees C/15 min and RC3 = 185 degrees C/21 min) pistachios after in vitro fermentation. FS of pistachios significantly reduced LT97 cell growth in a time- and dose-dependent manner. Compared to the blank control, pistachio FS (2.5%) led to a significant average reduction of H2O2-induced DNA damage (1.5-fold). Levels of CAT mRNA were significantly increased (1.3-fold, on average for 5% FS). Pistachio FS (5%) significantly increased the number of early apoptotic cells (up to 2.1-fold) and levels of caspase-3 activities (up to 6.9-fold). The present results confirm a chemopreventive potential of pistachios, which is mediated by growth inhibition, induction of apoptosis and anti-genotoxic effects, as well as induction of CAT. These effects remain mostly unaffected by roasting. PMID- 29258270 TI - Design and Performance Evaluation of an Electro-Hydraulic Camless Engine Valve Actuator for Future Vehicle Applications. AB - This paper details the new design and dynamic simulation of an electro-hydraulic camless engine valve actuator (EH-CEVA) and experimental verification with lift position sensors. In general, camless engine technologies have been known for improving fuel efficiency, enhancing power output, and reducing emissions of internal combustion engines. Electro-hydraulic valve actuators are used to eliminate the camshaft of an existing internal combustion engines and used to control the valve timing and valve duration independently. This paper presents novel electro-hydraulic actuator design, dynamic simulations, and analysis based on design specifications required to satisfy the operation performances. An EH CEVA has initially been designed and modeled by means of a powerful hydraulic simulation software, AMESim, which is useful for the dynamic simulations and analysis of hydraulic systems. Fundamental functions and performances of the EH CEVA have been validated through comparisons with experimental results obtained in a prototype test bench. PMID- 29258271 TI - Fabrication of GO/Cement Composites by Incorporation of Few-Layered GO Nanosheets and Characterization of Their Crystal/Chemical Structure and Properties. AB - Original graphene oxide (GO) nanosheets were prepared using the Hummers method and found to easily aggregate in aqueous and cement composites. Using carboxymethyl chitosan (CCS) as a dispersant, few-layered GO nanosheets (1-2 layers) were obtained by forming CCS/GO intercalation composites. The testing results indicated that the few-layered GO nanosheets could uniformly spread, both in aqueous and cement composites. The cement composites were prepared with GO dosages of 0.03%, 0.05% and 0.07% and we found that they had a compact microstructure in the whole volume. A special feature was determined, namely that the microstructures consisted of regular-shaped crystals created by self crosslinking. The X-ray diffraction (XRD) results indicated that there was a higher number of cement hydration crystals in GO/cement composites. Meanwhile, we also found that partially-amorphous Calcium-Silicate-Hydrate (C-S-H) gel turned into monoclinic crystals. At 28 days, the GO/cement composites reached the maximum compressive and flexural strengths at a 0.05% dosage. These strengths were 176.64 and 31.67 MPa and, compared with control samples, their increased ratios were 64.87% and 149.73%, respectively. Durability parameters, such as penetration, freeze-thaw, carbonation, drying-shrinkage value and pore structure, showed marked improvement. The results indicated that it is possible to obtain cement composites with a compact microstructure and with high performances by introducing CCS/GO intercalation composites. PMID- 29258269 TI - A Topology-Centric View on Mitotic Chromosome Architecture. AB - Mitotic chromosomes are long-known structures, but their internal organization and the exact process by which they are assembled are still a great mystery in biology. Topoisomerase II is crucial for various aspects of mitotic chromosome organization. The unique ability of this enzyme to untangle topologically intertwined DNA molecules (catenations) is of utmost importance for the resolution of sister chromatid intertwines. Although still controversial, topoisomerase II has also been proposed to directly contribute to chromosome compaction, possibly by promoting chromosome self-entanglements. These two functions raise a strong directionality issue towards topoisomerase II reactions that are able to disentangle sister DNA molecules (in trans) while compacting the same DNA molecule (in cis). Here, we review the current knowledge on topoisomerase II role specifically during mitosis, and the mechanisms that directly or indirectly regulate its activity to ensure faithful chromosome segregation. In particular, we discuss how the activity or directionality of this enzyme could be regulated by the SMC (structural maintenance of chromosomes) complexes, predominantly cohesin and condensin, throughout mitosis. PMID- 29258272 TI - Using the Kalman Algorithm to Correct Data Errors of a 24-Bit Visible Spectrometer. AB - To reduce cost, increase resolution, and reduce errors due to changing light intensity of the VIS SPEC, a new technique is proposed which applies the Kalman algorithm along with a simple hardware setup and implementation. In real time, the SPEC automatically corrects spectral data errors resulting from an unstable light source by adding a photodiode sensor to monitor the changes in light source intensity. The Kalman algorithm is applied on the data to correct the errors. The light intensity instability is one of the sources of error considered in this work. The change in light intensity is due to the remaining lifetime, working time and physical mechanism of the halogen lamp, and/or battery and regulator stability. Coefficients and parameters for the processing are determined from MATLAB simulations based on two real types of datasets, which are mono-changing and multi-changing datasets, collected from the prototype SPEC. From the saved datasets, and based on the Kalman algorithm and other computer algorithms such as divide-and-conquer algorithm and greedy technique, the simulation program implements the search for process noise covariance, the correction function and its correction coefficients. These components, which will be implemented in the processor of the SPEC, Kalman algorithm and the light-source-monitoring sensor are essential to build the Kalman corrector. Through experimental results, the corrector can reduce the total error in the spectra on the order of 10 times; for certain typical local spectral data, it can reduce the error by up to 60 times. The experimental results prove that accuracy of the SPEC increases considerably by using the proposed Kalman corrector in the case of changes in light source intensity. The proposed Kalman technique can be applied to other applications to correct the errors due to slow changes in certain system components. PMID- 29258273 TI - Microstrip Patch Sensor for Salinity Determination. AB - In this paper, a compact microstrip feed inset patch sensor is proposed for measuring the salinities in seawater. The working principle of the proposed sensor depends on the fact that different salinities in liquid have different relative permittivities and cause different resonance frequencies. The proposed sensor can obtain better sensitivity to salinity changes than common sensors using conductivity change, since the relative permittivity change to salinity is 2.5 times more sensitive than the conductivity change. The patch and ground plane of the proposed sensor are fabricated by conductive copper spray coating on the masks made by 3D printer. The fabricated patch and the ground plane are bonded to a commercial silicon substrate and then attached to 5 mm-high chamber made by 3D printer so that it contains only 1 mL seawater. For easy fabrication and testing, the maximum resonance frequency was selected under 3 GHz and to cover salinities in real seawater, it was assumed that the salinity changes from 20 to 35 ppt. The sensor was designed by the finite element method-based ANSYS high-frequency structure simulator (HFSS), and it can detect the salinity with 0.01 ppt resolution. The designed sensor has a resonance frequency separation of 37.9 kHz and reflection coefficients under -20 dB at the resonant frequencies. The fabricated sensor showed better performance with average frequency separation of 48 kHz and maximum reflection coefficient of -35 dB. By comparing with the existing sensors, the proposed compact and low-cost sensor showed a better detection capability. Therefore, the proposed patch sensor can be utilized in radio frequency (RF) tunable sensors for salinity determination. PMID- 29258274 TI - Condition Assessment of Foundation Piles and Utility Poles Based on Guided Wave Propagation Using a Network of Tactile Transducers and Support Vector Machines. AB - This paper presents a novel non-destructive testing and health monitoring system using a network of tactile transducers and accelerometers for the condition assessment and damage classification of foundation piles and utility poles. While in traditional pile integrity testing an impact hammer with broadband frequency excitation is typically used, the proposed testing system utilizes an innovative excitation system based on a network of tactile transducers to induce controlled narrow-band frequency stress waves. Thereby, the simultaneous excitation of multiple stress wave types and modes is avoided (or at least reduced), and targeted wave forms can be generated. The new testing system enables the testing and monitoring of foundation piles and utility poles where the top is inaccessible, making the new testing system suitable, for example, for the condition assessment of pile structures with obstructed heads and of poles with live wires. For system validation, the new system was experimentally tested on nine timber and concrete poles that were inflicted with several types of damage. The tactile transducers were excited with continuous sine wave signals of 1 kHz frequency. Support vector machines were employed together with advanced signal processing algorithms to distinguish recorded stress wave signals from pole structures with different types of damage. The results show that using fast Fourier transform signals, combined with principal component analysis as the input feature vector for support vector machine (SVM) classifiers with different kernel functions, can achieve damage classification with accuracies of 92.5% +/- 7.5%. PMID- 29258275 TI - Synthesis and Biocompatibility Studies of New Iminodiacetic Acid Derivatives. AB - BACKGROUND: Iminodiacetic acid (IDA) derivatives can be used as ligands to form complexes with technetium, with potential application as hepatobiliary diagnostic agents. The aim of this study was to synthesize five novel IDA derivatives and to compare their effects on plasma haemostasis with clinically approved ligands for technetium complexation. METHODS: The influence of synthesized IDA derivatives on plasma haemostasis was evaluated spectrophotometrically by clot formation and lysis test (CL-test), coagulation assay, Prothrombin Time and Activated Partial Tromboplastin Time. The effects of the tested compounds on erythrocytes were assessed using haemolysis assays, microscopy and flow cytometry studies. RESULTS: Despite their significant influence on the kinetic parameters of the process of clot formation and fibrinolysis, the tested ligands, at potential diagnostic concentrations, did not alter the overall potential of clot formation and lysis (CLAUC). At potential diagnostic concentrations (0.4 MUmol/mL) all the tested compounds showed no adverse effects on the membranes of RBCs (Red Blood Cells). CONCLUSION: IDA derivatives with methoxy substituents in aromatic ring, exert multidirectional effects on plasma haemostasis and should be considered safe as their significant impacts were mostly observed at 4 MUmol/mL, which is about 10 fold higher than the theoretical plasma concentrations of these compounds. PMID- 29258276 TI - Metabolomic Profiles of a Midge (Procladius villosimanus, Kieffer) Are Associated with Sediment Contamination in Urban Wetlands. AB - Metabolomic techniques are powerful tools for investigating organism-environment interactions. Metabolite profiles have the potential to identify exposure or toxicity before populations are disrupted and can provide useful information for environmental assessment. However, under complex environmental scenarios, metabolomic responses to exposure can be distorted by background and/or organismal variation. In the current study, we use LC-MS (liquid chromatography mass spectrometry) and GC-MS (gas chromatography-mass spectrometry) to measure metabolites of the midge Procladius villosimanus inhabiting 21 urban wetlands. These metabolites were tested against common sediment contaminants using random forest models and metabolite enrichment analysis. Sediment contaminant concentrations in the field correlated with several P. villosimanus metabolites despite natural environmental and organismal variation. Furthermore, enrichment analysis indicated that metabolite sets implicated in stress responses were enriched, pointing to specific cellular functions affected by exposure. Methionine metabolism, sugar metabolism and glycerolipid metabolism associated with total petroleum hydrocarbon and metal concentrations, while mitochondrial electron transport and urea cycle sets associated only with bifenthrin. These results demonstrate the potential for metabolomics approaches to provide useful information in field-based environmental assessments. PMID- 29258277 TI - Development of AlN/Epoxy Composites with Enhanced Thermal Conductivity. AB - AlN/epoxy composites with high thermal conductivity were successfully prepared by infiltrating epoxy into AlN porous ceramics which were fabricated by gelcasting of foaming method. The microstructure, mechanical, and thermal properties of the resulting composites were investigated. The compressive strengths of the AlN/epoxy composites were enhanced compared with the pure epoxy. The AlN/epoxy composites demonstrate much higher thermal conductivity, up to 19.0 W/(m.K), compared with those by the traditional particles filling method, because of continuous thermal channels formed by the walls and struts of AlN porous ceramics. This study demonstrates a potential route to manufacture epoxy-based composites with extremely high thermal conductivity. PMID- 29258279 TI - Preserving Traditional Botanical Knowledge: The Importance of Phytogeographic and Ethnobotanical Inventory of Peruvian Dye Plants. AB - Abstract: Peru is a megadiverse country with native species of all kinds, including dye plants, which have been used for hundreds of years by the local population. Despite the fact that many of these natural dyes are of a superior quality compared to synthetic ones and do not have the harmful effects that the latter may cause to human health, due to the lack of documentation and dissemination, ethnobotanical knowledge is unfortunately being lost with the passing of generations. In order to preserve and spread such valuable knowledge, this study conducted a comprehensive taxonomic, phytogeographic, and ethnobotanical inventory of dye plants based on periodical botanical explorations in selected locations of Northern Peru during the span of two decades. A critical review of the specialized bibliography was then carried out and the findings were verified with the personal knowledge and experience of both the researchers and the local and regional people. The results of the inventory record 32 species of dye plants from Northern Peru distributed in 22 families, of which the following stand out due to the number of species: Fabaceae (5), Anacardiaceae (2), Annonaceae (2), Asteraceae (2), Berberidaceae (2), Rosaceae (2), and Solanaceae (2). Of the 32 dye species identified, four are considered endemic from Peru: Berberisbuceronis J.F. Macbr., Caesalpiniapaipai Ruiz & Pav., Coreopsissenaria S.F. Blake & Sherf., and Lomatiahirsuta (Lam.) Diels. The study also found that species such as Bixaorellana L., Indigoferasuffruticosa Mill., Sambucusperuviana, and the lichen Usneabaileyi (Stirton) Zahlbr have not been commercially exploited in Peru despite the fact that they already constitute a great economic source for several countries. PMID- 29258280 TI - Four New Compounds Obtained from Cultured Cells of Artemisia annua. AB - Four new compounds obtained from cultured cells of Artemisia annua were reported. Products were detected by HPLC-ELSD/GC-MS and isolated by chromatographic methods. The structures of four new compounds, namely 6-hydroxy arteannuin I (1), 1-hydroxy arteannuin I (2), 2-hydroxy arteannuin J (3), and 14-hydroxy arteannuin J (4), were elucidated using their physico-chemical properties by NMR and MS data analyses. The results from the spontaneous oxidative experiment indicated that the biosynthesis of the new compounds was enzyme-catalyzed. Interestingly, the enzymes in the cultured cells of A. annua showed the abilities of substrate selective and region-selective hydroxylation of the sesquiterpene lactone. Furthermore, the artemisinin contents were increased by 50% and 80% compared to the control group after the addition of arteannuin I/J to the suspension-cultured cells of A. annua under light and dark culture conditions, respectively. PMID- 29258278 TI - Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies. AB - Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region (p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region (p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors. PMID- 29258281 TI - Low Levels of IgG Recognizing the alpha-1-Antitrypsin Peptide and Its Association with Taiwanese Women with Primary Sjogren's Syndrome. AB - The aim of this study was to examine oxidative stress and low level of alpha-1 antitrypsin (A1AT) in primary Sjogren's syndrome (pSS), and evaluate the associated autoreactivity against unmodified and their 4-hydroxy-2-nonenal (HNE) modified peptides with pSS. Two differentially expressed proteins, alpha-1-acid glycoprotein 1 (A1AG1) and A1AT, exhibited 2-fold differences, and their HNE modifications were identified by depleted-albumin and immunoglobulin G (IgG) serum protein, in-solution digestion, in-gel digestion, and nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) from pSS patients and age matched healthy controls (HCs). Furthermore, levels of proteins, confirmation of HNE modifications, HNE-protein adducts and autoreactivity against unmodified and their HNE-modified peptides were further validated. Levels of the HNE-protein adduct and A1AG1 were significantly higher in pSS patients than HCs, but levels of A1AT were significantly lower in pSS patients compared to HCs. Only the HNE modification of A1AT was confirmed. Our study suggests that elevated HNE-protein adduct, oxidative stress, level (odds ratio (OR) 4.877, p = 0.003), lowered A1AT level (OR 3.910, p = 0.010) and a decreased level of anti-A1AT50-63 IgG (OR 3.360, p = 0.010) showed an increased risk in pSS patients compared to HCs, respectively. PMID- 29258282 TI - Health Risk Assessment of Trace Metals in Various Environmental Media, Crops and Human Hair from a Mining Affected Area. AB - Long term exposure to trace metals in various media is of great concern for people living in known pollution sources, such as mining and industrial activities. Health risk assessment and human hair analysis can provide important information for local environmental management. Information on distribution characteristics of trace metals in soil, water, sediment, air, local crops, and human hair from a typical mining area in southern China was collected. Results show there exists severely trace metal contamination in soil, sediment, and air. Arsenic and Pb contents in the local children's hair are higher than the upper reference values, and the accumulation of residents' hair trace metals shows great correlation with the ingestion and inhalation pathways. Arsenic contributes 52.27% and 58.51% to the total non-cancer risk of adults and children, respectively. The cancer risk of Cd in adults and children are 4.66 and 3.22 times higher than the safe level, respectively. Ingestion exposure pathway of trace metals largely contributes to the total non-cancer and cancer effect. The metals As, Cd, and Pb are major risk sources and pollutants that should be given priority for management, and ingestion pathway exposure to trace metals through soil and crops should be controlled. PMID- 29258283 TI - Astragalus membranaceus-Polysaccharides Ameliorates Obesity, Hepatic Steatosis, Neuroinflammation and Cognition Impairment without Affecting Amyloid Deposition in Metabolically Stressed APPswe/PS1dE9 Mice. AB - Astragalus membranaceus is commonly used in traditional Chinese medicine for strengthening the host defense system. Astragalus membranaceus-polysaccharides is an effective component with various important bioactivities, such as immunomodulation, antioxidant, anti-diabetes, anti-inflammation and neuroprotection. In the present study, we determine the effects of Astragalus membranaceus-polysaccharides on metabolically stressed transgenic mice in order to develop this macromolecules for treatment of sporadic Alzheimer's disease, a neurodegenerative disease with metabolic risk factors. Transgenic mice, at 10 weeks old prior to the appearance of senile plaques, were treated in combination of administrating high-fat diet and injecting low-dose streptozotocin to create the metabolically stressed mice model. Astragalus membranaceus-polysaccharides was administrated starting at 14 weeks for 7 weeks. We found that Astragalus membranaceus-polysaccharides reduced metabolic stress-induced increase of body weight, insulin and insulin and leptin level, insulin resistance, and hepatic triglyceride. Astragalus membranaceus-polysaccharides also ameliorated metabolic stress-exacerbated oral glucose intolerance, although the fasting blood glucose was only temporally reduced. In brain, metabolic stress-elicited astrogliosis and microglia activation in the vicinity of plaques was also diminished by Astragalus membranaceus-polysaccharides administration. The plaque deposition, however, was not significantly affected by Astragalus membranaceus-polysaccharides administration. These findings suggest that Astragalus membranaceus polysaccharides may be used to ameliorate metabolic stress-induced diabesity and the subsequent neuroinflammation, which improved the behavior performance in metabolically stressed transgenic mice. PMID- 29258284 TI - Pure and Highly Nb-Doped Titanium Dioxide Nanotubular Arrays: Characterization of Local Surface Properties. AB - This paper presents the results of studies of the local surface properties of pure and highly Nb-doped (12 wt %) TiO2 nanotubes (TNT) using the X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) methods, respectively. XPS analysis showed that the pure TNT exhibit an evident over stoichiometry combined with high level of undesired C contaminations, which was confirmed by the relative concentration of specific elements O, Ti and C (with respect to all the surface atoms) equal to 0.46, 018 and 0.36, respectively. In turn, for the highly Nb-doped (12 wt %) TNT, a slightly different surface chemistry was observed because the relative concentration of specific elements O and Ti and, with respect to all the surface atoms, is slightly lower, that is, 0.42 and 0.12, respectively; this is directly related to the fact that Nb atoms appeared having the relative concentration at the level of 0.09, whereas the undesired C contaminations reached the same level (0.36), as is the case of pure TNT. In addition, SEM analysis confirms that there are evident free spaces between the specific slops containing several TNT, what was additionally confirmed by the contribution of specific surface bonding coming from the SiO2/Si substrate. The obtained information allowed us a new insight on the potential origin of aging effect at the surface of TNT in atmosphere being the undesired limitation for their potential application as the chemical resistive type sensors or in any other fields of their application related to their surface activity. PMID- 29258285 TI - Point-of-Care Diagnostics: Recent Advances and Trends. AB - Recent years have witnessed tremendous advances in point-of-care diagnostics (POCD), which are a result of continuous developments in biosensors, microfluidic, bioanalytical platforms, assay formats, lab-on-a-chip technologies, and complementary technologies. This special issue targets the critical advances in POCD and provides guided insights and directions for future research. PMID- 29258286 TI - Optimizing the Maximum Recovery of Dihydromyricetin from Chinese Vine Tea, Ampelopsis grossedentata, Using Response Surface Methodology. AB - This work provides an optimized extraction approach intended to maximize the recovery of dihydromyricetin (DHM) from Chinese vine tea (Ampelopsis grossedentata) leaves. The presented work adopts a Box-Behnken design as a response surface methodology to understand the role and influence of specific extraction parameters including: time, temperature, and solvent composition/ethanol (%) on DHM final yields. Initially, single factor experiments were used to delineate the role of above factors (temperature, time, and solvent composition) before proceeding with three factors-three levels Box-Behnken design with 17 separate runs to assess the effect of multifactorial treatments on DHM recovery rates. The collected data shows that independent variables (solvent composition, time, and temperature) can significantly affect DHM recovery rates with maximum yields resulting from a combined 60 degrees C, 60% aqueous ethanol, and 180 min treatment. From the empirical point of view, the above optimized extraction protocol can substantially enhance processing and profitability margins with a minimum need of interventions or associated costs. PMID- 29258287 TI - A DNA Barcode-Based RPA Assay (BAR-RPA) for Rapid Identification of the Dry Root of Ficus hirta (Wuzhimaotao). AB - Background: Wuzhimaotao (the dry root of Ficus hirta) is used as both medicine and food ingredient by the locals in areas around Nanling Mountains of China. Due to its very similar external morphologies with Duanchangcao (the root of Gelsemium elegans, which contains gelsemine that is extremely neurotoxic) and the associated growth of these two plants, incidents of food poisoning and even death frequently occur, resulting from the misuse of Duanchangcao as Wuzhimaotao. The aim of this study is to develop a fast, even, on-spot approach to identification of Wuzhimaotao. Methods: We used DNA barcode-based recombinase polymerase amplification (BAR-RPA) with species-specific primers targeting the internal transcribed spacer (ITS) region of the rDNA of F. hirta. BAR-RPA reaction time and temperature were optimized and the specificity and sensitivity of BAR-RPA species-specific primers were assessed. Results: This technique showed a high specificity and sensitivity to amplify the genomic DNA of F. hirta and allowed for rapid amplification (within 15 min) of the ITS region under a constant and mild temperature range of 37-42 degrees C without using thermocyclers. Conclusions: The BAR-RPA assay with a fast DNA extraction protocol provides a simple, energy-saving, and rapid method for identification of Wuzhimaotao in both laboratory and field settings. PMID- 29258288 TI - Unexpectedly large impact of forest management and grazing on global vegetation biomass. AB - Carbon stocks in vegetation have a key role in the climate system. However, the magnitude, patterns and uncertainties of carbon stocks and the effect of land use on the stocks remain poorly quantified. Here we show, using state-of-the-art datasets, that vegetation currently stores around 450 petagrams of carbon. In the hypothetical absence of land use, potential vegetation would store around 916 petagrams of carbon, under current climate conditions. This difference highlights the massive effect of land use on biomass stocks. Deforestation and other land cover changes are responsible for 53-58% of the difference between current and potential biomass stocks. Land management effects (the biomass stock changes induced by land use within the same land cover) contribute 42-47%, but have been underestimated in the literature. Therefore, avoiding deforestation is necessary but not sufficient for mitigation of climate change. Our results imply that trade offs exist between conserving carbon stocks on managed land and raising the contribution of biomass to raw material and energy supply for the mitigation of climate change. Efforts to raise biomass stocks are currently verifiable only in temperate forests, where their potential is limited. By contrast, large uncertainties hinder verification in the tropical forest, where the largest potential is located, pointing to challenges for the upcoming stocktaking exercises under the Paris agreement. PMID- 29258290 TI - Erratum: Genetic effects on gene expression across human tissues. AB - This corrects the article DOI: 10.1038/nature24277. PMID- 29258289 TI - Opening of the human epithelial calcium channel TRPV6. AB - Calcium-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues. Altered TRPV6 expression is associated with a variety of human diseases, including cancers. TRPV6 channels are constitutively active and their open probability depends on the lipidic composition of the membrane in which they reside; it increases substantially in the presence of phosphatidylinositol 4,5 bisphosphate. Crystal structures of detergent-solubilized rat TRPV6 in the closed state have previously been solved. Corroborating electrophysiological results, these structures demonstrated that the Ca2+ selectivity of TRPV6 arises from a ring of aspartate side chains in the selectivity filter that binds Ca2+ tightly. However, how TRPV6 channels open and close their pores for ion permeation has remained unclear. Here we present cryo-electron microscopy structures of human TRPV6 in the open and closed states. The channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an alpha-to-pi helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states. This gating mechanism, which defines the constitutive activity of TRPV6, is, to our knowledge, unique among tetrameric ion channels and provides structural insights for understanding their diverse roles in physiology and disease. PMID- 29258291 TI - Successful conservation of global waterbird populations depends on effective governance. AB - Understanding global patterns of biodiversity change is crucial for conservation research, policies and practices. However, for most ecosystems, the lack of systematically collected data at a global level limits our understanding of biodiversity changes and their local-scale drivers. Here we address this challenge by focusing on wetlands, which are among the most biodiverse and productive of any environments and which provide essential ecosystem services, but are also amongst the most seriously threatened ecosystems. Using birds as an indicator taxon of wetland biodiversity, we model time-series abundance data for 461 waterbird species at 25,769 survey sites across the globe. We show that the strongest predictor of changes in waterbird abundance, and of conservation efforts having beneficial effects, is the effective governance of a country. In areas in which governance is on average less effective, such as western and central Asia, sub-Saharan Africa and South America, waterbird declines are particularly pronounced; a higher protected area coverage of wetland environments facilitates waterbird increases, but only in countries with more effective governance. Our findings highlight that sociopolitical instability can lead to biodiversity loss and undermine the benefit of existing conservation efforts, such as the expansion of protected area coverage. Furthermore, data deficiencies in areas with less effective governance could lead to underestimations of the extent of the current biodiversity crisis. PMID- 29258292 TI - Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. AB - This corrects the article DOI: 10.1038/nature22364. PMID- 29258293 TI - Perovskite nickelates as electric-field sensors in salt water. AB - Designing materials to function in harsh environments, such as conductive aqueous media, is a problem of broad interest to a range of technologies, including energy, ocean monitoring and biological applications. The main challenge is to retain the stability and morphology of the material as it interacts dynamically with the surrounding environment. Materials that respond to mild stimuli through collective phase transitions and amplify signals could open up new avenues for sensing. Here we present the discovery of an electric-field-driven, water mediated reversible phase change in a perovskite-structured nickelate, SmNiO3. This prototypical strongly correlated quantum material is stable in salt water, does not corrode, and allows exchange of protons with the surrounding water at ambient temperature, with the concurrent modification in electrical resistance and optical properties being capable of multi-modal readout. Besides operating both as thermistors and pH sensors, devices made of this material can detect sub volt electric potentials in salt water. We postulate that such devices could be used in oceanic environments for monitoring electrical signals from various maritime vessels and sea creatures. PMID- 29258294 TI - Senescence-associated reprogramming promotes cancer stemness. AB - Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from EMU-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells. PMID- 29258296 TI - Erratum: Observation of the hyperfine spectrum of antihydrogen. AB - This corrects the article DOI: 10.1038/nature23446. PMID- 29258299 TI - Corrigendum: AMPA receptor-mediated regulation of a Gi-protein in cortical neurons. AB - This corrects the article DOI: 10.1038/39062. PMID- 29258298 TI - Large granulation cells on the surface of the giant star pi1 Gruis. AB - Convection plays a major part in many astrophysical processes, including energy transport, pulsation, dynamos and winds on evolved stars, in dust clouds and on brown dwarfs. Most of our knowledge about stellar convection has come from studying the Sun: about two million convective cells with typical sizes of around 2,000 kilometres across are present on the surface of the Sun-a phenomenon known as granulation. But on the surfaces of giant and supergiant stars there should be only a few large (several tens of thousands of times larger than those on the Sun) convective cells, owing to low surface gravity. Deriving the characteristic properties of convection (such as granule size and contrast) for the most evolved giant and supergiant stars is challenging because their photospheres are obscured by dust, which partially masks the convective patterns. These properties can be inferred from geometric model fitting, but this indirect method does not provide information about the physical origin of the convective cells. Here we report interferometric images of the surface of the evolved giant star pi1 Gruis, of spectral type S5,7. Our images show a nearly circular, dust-free atmosphere, which is very compact and only weakly affected by molecular opacity. We find that the stellar surface has a complex convective pattern with an average intensity contrast of 12 per cent, which increases towards shorter wavelengths. We derive a characteristic horizontal granule size of about 1.2 * 1011 metres, which corresponds to 27 per cent of the diameter of the star. Our measurements fall along the scaling relations between granule size, effective temperature and surface gravity that are predicted by simulations of stellar surface convection. PMID- 29258297 TI - Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. AB - Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss. PMID- 29258300 TI - Orbital misalignment of the Neptune-mass exoplanet GJ 436b with the spin of its cool star. AB - The angle between the spin of a star and the orbital planes of its planets traces the history of the planetary system. Exoplanets orbiting close to cool stars are expected to be on circular, aligned orbits because of strong tidal interactions with the stellar convective envelope. Spin-orbit alignment can be measured when the planet transits its star, but such ground-based spectroscopic measurements are challenging for cool, slowly rotating stars. Here we report the three dimensional characterization of the trajectory of an exoplanet around an M dwarf star, derived by mapping the spectrum of the stellar photosphere along the chord transited by the planet. We find that the eccentric orbit of the Neptune-mass exoplanet GJ 436b is nearly perpendicular to the stellar equator. Both eccentricity and misalignment, surprising around a cool star, can result from dynamical interactions (via Kozai migration) with a yet-undetected outer companion. This inward migration of GJ 436b could have triggered the atmospheric escape that now sustains its giant exosphere. PMID- 29258295 TI - Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. AB - Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-kappaB subunit gene RELA (ST EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat. PMID- 29258301 TI - Nature and Value of Freely Dissolved EPS Ecosystem Services: Insight into Molecular Coupling Mechanisms for Regulating Metal Toxicity. AB - Extracellular polymeric substances (EPSs) dispersed in natural waters play a significant role in relieving impacts to microbial survival associated with heavy metal release, yet little is known about the association of freely dissolved EPS ecosystem services with metal transformation in natural waters. Here, we demonstrate that dispersive EPSs mitigate the metal toxicity to microbial cells through an associative coordination reaction. Microtitrimetry coupled with fluorescence spectroscopy ascribes the combination of freely dissolved EPSs from Escherichia coli (E. coli) with Cu2+/Cd2+ to a coordination reaction associated with chemical static quenching. Fourier transform infrared spectroscopy (FTIR), X ray photoelectron spectroscopy (XPS), and computational chemistry confirm that carboxyl residues in protein-like substances of the EPSs are responsible for the coordination. Frontier molecular orbitals (MOs) of a deprotonated carboxyl integrate with the occupied d orbitals of Cu2+ and/or d, s orbitals of Cd2+ to form metal-EPS complexes. Microcosmic systems show that because the metal-EPS complexes decrease cellular absorbability of metals, E. coli survivals increase by 4.3 times for Cu2+ and 1.6 times for Cd2+, respectively. Based on bonding energies for six metals-EPS coordination, an associative toxic effect further confirms that increased bonding energies facilitate retardation of metals in the EPS matrix, protecting against E. coli apoptosis. PMID- 29258302 TI - Implications of Pony Lake Fulvic Acid for the Aggregation and Dissolution of Oppositely Charged Surface-Coated Silver Nanoparticles and Their Ecotoxicological Effects on Daphnia magna. AB - Citrate (Cit) and polyethylenimine (BPEI)-coated silver nanoparticles (AgNPs) were used to understand how the type of capping agents and surface charge affect their colloidal stability, dissolution, and ecotoxicity in the absence/presence of Pony Lake Fulvic Acid (PLFA). In the presence of PLFA, Cit-AgNPs were stabilized, while BPEI-AgNPs were aggregated. The aggregation of BPEI-AgNPs decreased with the time, and their stabilizing effect increased at high PLFA concentration. The dissolution also differed between both AgNPs and was influenced by the PLFA concentration. Generally, BPEI-AgNPs showed a lower amount of dissolved Ag than Cit-AgNPs. The dissolved Ag concentration decreased for both AgNPs at low PLFA concentration (5 mg/L). In contrast, the extent of nanoparticle dissolution increased at high PLFA concentration (30 mg/L) but only for BPEI AgNPs. In the absence of PLFA, the ecotoxicity of Cit-AgNPs to Daphnia magna was higher than that of BPEI-AgNPs. However, the ecotoxicity of AgNPs in the presence of PLFA was up to 70% lower than in their absence. We demonstrated that the differences in colloidal stability, dissolution, and ecotoxicity may be attributed to the different capping agents, surface charge, and concentration of natural organic matter (NOM) as well as to the formation of dissolved Ag complexes with NOM. PMID- 29258303 TI - Antibody-Based Fusion Proteins Allow Ca2+ Rewiring to Most Extracellular Ligands. AB - The Ca2+ signaling toolkit is the set of proteins used by living systems to generate and respond to Ca2+ signals. The selective expression of these proteins in particular tissues, cell types and subcellular locations allows the Ca2+ signal to regulate a diverse set of cellular processes. Through synthetic biology, the Ca2+ signaling toolkit can be expanded beyond the natural repertoire to potentially allow a non-natural ligand to control downstream cellular processes. To realize this potential, we exploited the ability of an antibody to bind its antigen exclusively in combination with the ability of the cytoplasmic domain of vascular endothelial growth factor receptor 2 (VEGFR2) to generate a Ca2+ signal upon oligomerization. Using protein fusions between antibody variants (i.e., nanobody, single-chain antibody and the monoclonal antibody) and the VEGFR2 cytoplasmic domain, Ca2+ signals were generated in response to extracellular stimulation with green fluorescent protein, mCherry, tumor necrosis factor alpha and soluble CD14. The Ca2+ signal generation by the stimulus did not require a stringent transition from monomer to oligomer state, but instead only required an increase in the oligomeric state. The Ca2+ signal generated by these classes of antibody-based fusion proteins can be rewired with a Ca2+ indicator or with an engineered Ca2+ activated RhoA to allow for antigen screening or migration to most extracellular ligands, respectively. PMID- 29258304 TI - Artificial Cell Fermentation as a Platform for Highly Efficient Cascade Conversion. AB - Because of its high specificity and stereoselectivity, cascade reactions using enzymes have been attracting attention as a platform for chemical synthesis. However, the sensitivity of enzymes outside their optimum conditions and their rapid decrease of activity upon dilution are drawbacks of the system. In this study, we developed a system for cascade enzymatic conversion in bacteria-shaped liposomes formed by hypertonic treatment, and demonstrated that the system can overcome the drawbacks of the enzymatic cascade reactions in bulk. This system produced final products at a level equivalent to the maximum concentration of the bulk system (0.10 M, e.g., 4.6 g/L), and worked even under conditions where enzymes normally lose their function. Under diluted conditions, the conversion rate of the artificial cell system was remarkably higher than that in the bulk system. Our results indicate that artificial cells can behave as a platform to perform fermentative production like microorganisms. PMID- 29258305 TI - Hierarchical Assembly of RNA Three-Dimensional Structures Based on Loop Templates. AB - The current RNA structure prediction methods cannot keep up the pace of the rapidly increasing number of sequences and the emerging new functions of RNAs. Template-based RNA three-dimensional structure prediction methods are restricted by the limited number of known RNA structures, and traditional motif-based search for the templates does not always lead to successful results. Here we report a new template search and assembly algorithm, the hierarchical loop template assembly method (VfoldLA). The method searches for templates for single strand loop/junctions instead of the whole motifs, which often renders no available templates, or short fragments (several nucleotides), which requires a long computational time to assemble and refine. The VfoldLA method has the advantage of accounting for local and nonlocal interloop interactions. Benchmark tests indicate that this new method can provide low-resolution predictions for RNA conformations at different levels of structural complexities. Furthermore, the VfoldLA-predicted conformations may also serve as reliable putative models for further structure prediction and refinements. VfoldLA is accessible at http://rna.physics.missouri.edu/vfoldLA . PMID- 29258306 TI - Electrochemical and Electrostatic Cleavage of Alkoxyamines. AB - Alkoxyamines are heat-labile molecules, widely used as an in situ source of nitroxides in polymer and materials sciences. Here we show that the one-electron oxidation of an alkoxyamine leads to a cation radical intermediate that even at room temperature rapidly fragments, releasing a nitroxide and carbocation. Digital simulations of experimental voltammetry and current-time transients suggest that the unimolecular decomposition which yields the "unmasked" nitroxide (TEMPO) is exceedingly rapid and irreversible. High-level quantum computations indicate that the collapse of the alkoxyamine cation radical is likely to yield a neutral nitroxide radical and a secondary phenylethyl cation. However, this fragmentation is predicted to be slow and energetically very unfavorable. To attain qualitative agreement between the experimental kinetics and computational modeling for this fragmentation step, the explicit electrostatic environment within the double layer must be accounted for. Single-molecule break-junction experiments in a scanning tunneling microscope using solvent of low dielectric (STM-BJ technique) corroborate the role played by electrostatic forces on the lysis of the alkoxyamine C-ON bond. This work highlights the electrostatic aspects played by charged species in a chemical step that follows an electrochemical reaction, defines the magnitude of this catalytic effect by looking at an independent electrical technique in non-electrolyte systems (STM BJ), and suggests a redox on/off switch to guide the cleavage of alkoxyamines at an electrified interface. PMID- 29258307 TI - Specificity versus Processivity in the Sequential Modification of DNA: A Study of DNA Adenine Methyltransferase. AB - A detailed analysis is carried out on both published experimental results and new experiments for the methylation kinetics of two-site DNA substrates (with site separations between 100 and 800 bp) catalyzed by bacterial DNA adenine methyltransferase (Dam). A previously reported rate enhancement for the second methylation event (relative to that of the first methylation) is shown to result from elevated substrate specificity for singly methylated DNA over that of unmethylated DNA and not processive turnover of both sites by the same copy of Dam. An elementary model is suggested that cleanly fits the experimental data over a broad range of intersite separations. The model hypothesizes a looping mediated interference between competing unmethylated Dam sites on the same DNA strand. PMID- 29258308 TI - Hydroxide Ligands Cooperate with Catalytic Centers in Metal-Organic Frameworks for Efficient Photocatalytic CO2 Reduction. AB - Converting CO2 into fuels via photochemical reactions relies on highly efficient and selective catalysts. We demonstrate that the catalytic active metal center can cooperate with neighboring hydroxide ligands to boost the photocatalytic CO2 reduction. Six cobalt-based metal-organic frameworks (MOFs) with different coordination environments are studied at the same reaction condition (photosensitizer, electron donor, water/organic mixed solvent, and visible light). In pure CO2 at 1.0 atm, the MOFs bearing MU-OH- ligands neighboring the open Co centers showed CO selectivities and turnover frequencies (TOFs) up to 98.2% and 0.059 s-1, respectively. More importantly, their TOFs reduced only ca. 20% when the CO2 partial pressure was reduced to 0.1 atm, while other MOFs reduced by at least 90%. Periodic density functional theory calculations and isotope tracing experiments showed that the MU-OH- ligands serve not only as strong hydrogen-bonding donors to stabilize the initial Co-CO2 adduct but also local proton sources to facilitate the C-O bond breaking. PMID- 29258309 TI - Surface Single-Atom Tailoring of a Gold Nanoparticle. AB - Surface single-atom tailoring of a gold nanoparticle, that is, adding, removing, or replacing one surface atom on a structure-resolved nanoparticle in a controlled manner, is very exciting yet challenging and has not been hitherto achieved. Herein we report the first realization of the introduction of a single sulfur atom onto the surface of the structure-unraveled Au60S6(SCH2Ph)36 nanoparticle. Single-crystal X-ray crystallography reveals that the as-obtained nanoparticle consists of one Au17 kernel protected by one Au20S3(SCH2Ph)18 and one unprecedented Au23S4(SCH2Ph)18 motif with the introduced sulfur atom included as a tetrahedral-coordinated MU4-S. The introduced sulfur leads to the changes of both internal structure and crystallographic arrangement. Unlike the case of 6HLH arrangement in Au60S6(SCH2Ph)36 crystals, the "ABAB" arrangement in Au60S7(SCH2Ph)36 crystals enhances the solid photoluminescence of amorphous Au60S7(SCH2Ph)36 and brings a slight redshift of the maximum emission. The extensive near-infrared emission provides Au60S7(SCH2Ph)36 potential applications in some fields such as anticounterfeiting, imaging, etc. PMID- 29258310 TI - Charge Order and Negative Thermal Expansion in V2OPO4. AB - The semivalent oxyphosphate V2OPO4 is found to have long-range V2+/V3+ charge ordering up to 605 K where a monoclinic to tetragonal structural transition and a switch from positive to negative thermal expansion are observed. V-V bonding within orbital polymer chains is proposed as the key factor in the novel switch of thermal expansion behavior, as loss of V-V bonding enables transverse oxygen motions to dominate the thermal expansion at high temperatures. Ferrimagnetic order of V2+ spin up and V3+ spin down states is observed below a magnetic ordering transition at 164 K, and susceptibility measurements evidence local spin pairing correlations to higher temperatures. PMID- 29258311 TI - Generation and Stability of the gem-Diol Forms in Imidazole Derivatives Containing Carbonyl Groups. Solid-State NMR and Single-Crystal X-ray Diffraction Studies. AB - The stability of gem-diol forms in imidazolecarboxaldehyde isomers was studied by solid-state nuclear magnetic resonance (ss-NMR) combined with single-crystal X ray diffraction studies. These methodologies also allowed determining the factors governing the occurrence of such rare functionalization in carbonyl moieties. Results indicated that the position of the carbonyl group is the main factor that governs the generation of geminal diols, having a clear and direct effect on hydration, since, under the same experimental conditions, only 36% of 5 imidazolecarboxaldehydes and 5% of 4-imidazolecarboxaldehydes were hydrated, as compared to 2-imidazolecarboxaldehydes, with which a 100% hydration was achieved. Not only did trifluoroacetic acid favor the addition of water to the carbonyl group but also it allowed obtaining single crystals. Single crystals of the gem diol and the hemiacetal forms 2-imidazolecarboxaldehyde and N-methyl-2 imidazolecarboxaldehyde, respectively, were isolated and studied through 1H ss NMR. Mass spectrometry and solution-state NMR experiments were also performed to study the hydration process. PMID- 29258312 TI - Genetic and Rare Disease of the CNS. Part I: Fatal Familial Insomnia (FFI). PMID- 29258314 TI - A Possible Repeal of the Orphan Drug Tax Credit? PMID- 29258315 TI - Influence of Structural Defects on Biomineralized ZnS Nanoparticle Dissolution: An in-Situ Electron Microscopy Study. AB - The dissolution of metal sulfides, such as ZnS, is an important biogeochemical process affecting fate and transport of trace metals in the environment. However, current studies of in situ dissolution of metal sulfides and the effects of structural defects on dissolution are lacking. Here we have examined the dissolution behavior of ZnS nanoparticles synthesized via several abiotic and biological pathways. Specifically, we have examined biogenic ZnS nanoparticles produced by an anaerobic, metal-reducing bacterium Thermoanaerobacter sp. X513 in a Zn-amended, thiosulfate-containing growth medium in the presence or absence of silver (Ag), and abiogenic ZnS nanoparticles were produced by mixing an aqueous Zn solution with either H2S-rich gas or Na2S solution. The size distribution, crystal structure, aggregation behavior, and internal defects of the synthesized ZnS nanoparticles were examined using high-resolution transmission electron microscopy (TEM) coupled with X-ray energy dispersive spectroscopy. The characterization results show that both the biogenic and abiogenic samples were dominantly composed of sphalerite. In the absence of Ag, the biogenic ZnS nanoparticles were significantly larger (i.e., ~10 nm) than the abiogenic ones (i.e., ~3-5 nm) and contained structural defects (e.g., twins and stacking faults). The presence of trace Ag showed a restraining effect on the particle size of the biogenic ZnS, resulting in quantum-dot-sized nanoparticles (i.e., ~3 nm). In situ dissolution experiments for the synthesized ZnS were conducted with a liquid-cell TEM (LCTEM), and the primary factors (i.e., the presence or absence structural defects) were evaluated for their effects on the dissolution behavior using the biogenic and abiogenic ZnS nanoparticle samples with the largest average particle size. Analysis of the dissolution results (i.e., change in particle radius with time) using the Kelvin equation shows that the defect bearing biogenic ZnS nanoparticles (gamma = 0.799 J/m2) have a significantly higher surface energy than the abiogenic ZnS nanoparticles (gamma = 0.277 J/m2). Larger defect-bearing biogenic ZnS nanoparticles were thus more reactive than the smaller quantum-dot-sized ZnS nanoparticles. These findings provide new insight into the factors that affect the dissolution of metal sulfide nanoparticles in relevant natural and engineered scenarios, and have important implications for tracking the fate and transport of sulfide nanoparticles and associated metal ions in the environment. Moreover, our study exemplified the use of an in situ method (i.e., LCTEM) to investigate nanoparticle behavior (e.g., dissolution) in aqueous solutions. PMID- 29258317 TI - Twenty-four-micrometer-pitch microelectrode array with 6912-channel readout at 12 kHz via highly scalable implementation for high-spatial-resolution mapping of action potentials. AB - A 24-MUm-pitch microelectrode array (MEA) with 6912 readout channels at 12 kHz and 23.2-MUVrms random noise is presented. The aim is to reduce noise in a "highly scalable" MEA with a complementary metal-oxide-semiconductor integration circuit (CMOS-MEA), in which a large number of readout channels and a high electrode density can be expected. Despite the small dimension and the simplicity of the in-pixel circuit for the high electrode-density and the relatively large number of readout channels of the prototype CMOS-MEA chip developed in this work, the noise within the chip is successfully reduced to less than half that reported in a previous work, for a device with similar in-pixel circuit simplicity and a large number of readout channels. Further, the action potential was clearly observed on cardiomyocytes using the CMOS-MEA. These results indicate the high scalability of the CMOS-MEA. The highly scalable CMOS-MEA provides high-spatial resolution mapping of cell action potentials, and the mapping can aid understanding of complex activities in cells, including neuron network activities. PMID- 29258318 TI - Crossed Czerny-Turner Spectrometer with Extended Spectrum Using Movable Planar Mirrors. AB - This study reports a crossed Czerny-Turner spectrometer with multiple mirrors to extend the inspected spectrum. A design example with two movable mirrors and a stationary planar mirror is experimentally demonstrated to offer two additional spectral bands, thereby leading to thrice the spectral range of the original Czerny-Turner spectrometer. The results indicate that the configurations to measure the three bands have almost identical parameters. The moving direction of the planar mirror and the plane of incidence are orthogonal; thus, the influence of mirror movement on the repeatability of the spectrum is minimized. In addition to the merits of cost-effectiveness and rapid inspection, the reported mechanism of mirror movement is applied to general spectrometers to extend the spectral coverage without sacrificing the resolution. PMID- 29258319 TI - Bridging the Cultural Divide Between Oncology and Palliative Care Subspecialties: Clinicians' Perceptions on Team Integration. AB - PURPOSE: Palliative care improves symptom burden, distress, patient and family satisfaction, and survival for patients with cancer. Oncology professional societies endorse the integration of palliative care into routine care for patients with advanced cancers. Despite this, cultural differences between medical subspecialties and the limited number of clinicians trained in palliative care lower the adoption of integrated care models. We assessed oncologists' and palliative care clinicians' perceptions about integrating oncology and palliative care using a nurse delivering palliative care to patients newly diagnosed with lung cancer. METHODS: We conducted semistructured telephone interviews with 7 oncology clinicians and 12 palliative care clinicians purposively sampled across 6 geographically diverse Department of Veterans Affairs medical centers (VAs). Oncologists were asked about their perspectives and experiences with consulting palliative care services. Palliative care clinicians were asked about their experiences with receiving consultations from subspecialties. Both were asked about utilizing a registered nurse to deliver telephone-based palliative care to patients newly diagnosed with lung cancer. Interviews were analyzed using traditional content analysis approaches. RESULTS: We identified 2 main themes: (1) tensions, differences, and mistrust between services occur in the least integrated teams and (2) open communication, sharing common goals, and promoting oncology "buy in" build trust and foster collaboration between teams. Clinicians described qualities important to possess to promote successful adoption of a nurse-led model of palliative care. CONCLUSIONS: Integration between oncology and palliative care among the 6 VA medical centers varies considerably. Nurses delivering palliative care embedded in oncology teams may facilitate the integration of these subspecialties. PMID- 29258320 TI - Characterization of a Novel HIV-1 Circulating Recombinant Form, CRF01_AE/B'/C (CRF96_cpx), in Yunnan, China. AB - Currently, complex HIV-1 recombinations among the B', C, and CRF01_AE genotypes have frequently arisen in Yunnan, China. A novel HIV-1 complex circulating recombinant form (CRF) consisting of B', C, and CRF01_AE (CRF96_cpx) was recently characterized from three epidemiologically unlinked individuals. Two strains of them were isolated from the injecting drug users in this study, the remaining one strain (JL. RL01) was obtained from a previous report in Jilin province. Phylogenetic analysis based on near full-length genome revealed that CRF96_cpx formed a distinct monophyletic cluster supported by a high bootstrap value of 100%, distantly related to all known HIV-1 subtypes/CRFs. CRF96_cpx had a CRF01_AE backbone with three subtype B' and C segments inserted, respectively, in the gag and pol region. Furthermore, subregion tree analysis showed that CRF01_AE backbone and subtype B segment inserted originated from a Thai-CRF01_AE lineage, whereas subtype C fragment inserted was from an India C lineage. They are different from previously documented CRF01_AE/B/C forms in its distinct backbone, inserted fragment size, and breakpoints. This highlighted the importance of continual monitoring of genetic diversity and complexity of HIV-1 strains in Yunnan, China. PMID- 29258321 TI - In Situ Raman Study of Liquid Water at High Pressure. AB - A pressure shift of Raman band of liquid water (H2O) may be an important tool for measuring residual pressures in mineral inclusions, in situ barometry in high pressure cells, and as an indicator of pressure-induced structural transitions in H2O. However, there was no consensus as to how the broad and asymmetric water Raman band should be quantitatively described, which has led to fundamental inconsistencies between reported data. In order to overcome this issue, we measured Raman spectra of H2O in situ up to 1.2 GPa using a diamond anvil cell, and use them to test different approaches proposed for the description of the water Raman band. We found that the most physically meaningful description of water Raman band is the decomposition into a linear background and three Gaussian components, associated with differently H-bonded H2O molecules. Two of these components demonstrate a pronounced anomaly in pressure shift near 0.4 GPa, supporting ideas of structural transition in H2O at this pressure. The most convenient approach for pressure calibration is the use of "a linear background + one Gaussian" decomposition (the pressure can be measured using the formula P (GPa) = -0.0317(3).DeltanuG (cm-1), where DeltanuG represents the difference between the position of water Raman band, fitted as a single Gaussian, in measured spectrum and spectrum at ambient pressure). PMID- 29258322 TI - Clinical and Sociocultural Factors Associated With Failure to Escalate Care of Deteriorating Patients. AB - In-hospital medical emergencies occur frequently. Understanding how clinicians respond to deteriorating patients outside the intensive care unit (ICU) could improve "rescue" interventions and rapid response programs. This was a qualitative study with interviews with 40 clinicians caring for patients who had a "Code Blue" activation or an unplanned ICU admission at teaching hospitals over 7 months. Four study physicians independently analyzed interview transcripts; refined themes were linked to the transcript using text analysis software. Nine themes were found to be associated with clinicians' management of deteriorating patients. Multiple human biases influence daily care for deteriorating hospitalized patients. A novel finding is that "moral distress" affects escalation behavior for patients with poor prognosis. Most themes indicate that ward culture influences clinicians to wait until the last minute to escalate care despite being worried about the patients' condition. PMID- 29258323 TI - Barriers and Benefits to the Use of Patient-Reported Outcome Measures in Routine Clinical Care: A Qualitative Study. AB - Patient-reported outcomes (PROs) provide information on how health care affects patient health and well-being and represent a patient-centered approach. Despite this potential, PROs are not widely used in clinical settings. Semi-structured focus groups were conducted with 3 stakeholder groups (patients, providers, and health care administrators) to determine the top 5 perceived barriers and benefits of PRO implementation. The Delphi technique was employed to obtain consensus and rank order responses. Patients perceived survey length to be important, whereas providers and administrators perceived time to collect data and patient health literacy, respectively, as the greatest barriers to PRO implementation. The greatest perceived benefits were the ability to track changes in clinical symptoms over time, improved quality of care, and better disease control among patients, providers, and administrators, respectively. These results may guide the development of novel frameworks for PRO implementation by addressing perceived barriers and building on the perceived benefits to encourage adoption of PROs. PMID- 29258324 TI - Evaluating the Utility of Facebook Reviews as a Hospital Quality Improvement Tool. PMID- 29258325 TI - Patient-Centered Morning Blood Collections. PMID- 29258326 TI - Origin and Spread of HIV-1 Subtype B Among Heterosexual Individuals in Bulgaria. AB - Human immunodeficiency virus (HIV) was originally introduced in Bulgaria through heterosexual transmission (HET) and later transferred to other vulnerable groups along with numerous more recent introductions from outside Bulgaria. To define the diversity, origins, and dynamics of the HIV-1 subtypes prevalent in HET population in Bulgaria, we applied phylogenetic and phylodynamic analyses using polymerase (pol) sequences from HET individuals to infer the spatiotemporal evolutionary history of the HIV-1 epidemic in this population in Bulgaria. High genetic diversity was found, including 13 different HIV-1 subtypes: 45.7% subtype B, 19.9% CRF01_AE, 7.5% CRF02_AG, 7.5% sub-subtypes A1 and A6, 7.1% subtype C, 5.3% subtype F1, 4.0% URFs, 1.2% CRF05_DF, 0.6% subtype G, 0.3% CRF04_cpx, 0.3% CRF29_BF, 0.3% CRF14_BG, and 0.3% subtype H. The estimated root of the subtype B in the phylogenetic tree dated back to the year 1980 largely due to multiple introductions of subtype B from outside the country. Several significant clades have been identified highlighting six different main epidemic entrances of subtype B dating from 1989 to 2007. The Bayesian skyline plot showed two different exponential growth periods starting in the 1980s to 1990 followed by a constant phase up to about 2008, with another exponential growth period from 2008 to the year 2012. The migration analysis identified dynamic pattern of gene flow and demonstrated that many HET probably acquired the infection abroad (14.6%), while only (6.6%) of non-HET were infected outside country. The phylogenetic analysis showed an intermixing between sequences from Bulgarians with sequences from other countries, suggesting different HIV introduction in this country followed by the internal spread through local transmission networks. PMID- 29258327 TI - Long-Acting Bronchodilator Use in the Management of Stable COPD. AB - OBJECTIVE: To review the management of chronic obstructive pulmonary disease (COPD), with a focus on updated information regarding the use of long-acting bronchodilators in the prevention of exacerbations and outcomes associated with this disease. DATA SOURCES: A literature search of the MEDLINE databases through November 2017 was conducted. All published articles regarding use of bronchodilator therapy in the management of COPD were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. STUDY SELECTION AND DATA EXTRACTION: Available English language data from reviews, abstracts, presentations, and clinical trials of the treatment of stable COPD with bronchodilator therapy in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: COPD is a prevalent medical condition worldwide that results in functional impairment, and worsened quality of life and overall health status. Numerous treatment options are available; the rationale for the optimal agents to utilize in a particular patient case is dependent on a multitude of patient-specific factors and severity of disease. In this review, a discussion of the role of long-acting bronchodilators, including long-acting beta agonists and long-acting muscarinic antagonists will be explored. Additionally, an update on the roles of novel delivery devices for delivering respiratory medications in this medical condition will be described. CONCLUSION: Although numerous treatment options are available, management of COPD remains a clinical challenge. Long-acting bronchodilators represent a significant class of medications that have the potential to reduce exacerbations and related hospitalizations and improve overall health outcomes. PMID- 29258328 TI - Skills to Enhance Positivity in Suicidal Adolescents: Results From an Open Development Trial. AB - "Skills to Enhance Positivity" (STEP) is a two-part positive affect program designed to decrease recurrent suicidal behavior in adolescents hospitalized due to suicide risk. Here, we describe the initial pilot phase in which the intervention was developed and modified based on a sample of 20 adolescent participants, aged 12 to 18 years old ( Mage = 15.9, SD = 1.5). STEP consisted of an in-person phase (four sessions) and a remote delivery phase (text messaging and phone calls). The inpatient sessions focused on psychoeducation of positive affect, mindfulness meditation, gratitude, and savoring. The remote delivery phase comprised of weekly phone calls and daily text messages to enhance mood monitoring and skills practice reminders. Average session attendance was 81%, and mean daily response rate to text messages was 73.6%, demonstrating high engagement. STEP was described as good or excellent by over 90% of parents and 100% of adolescents. Only one participant had a suicide attempt, and five were readmitted for suicidality in the following 6 months, fewer than comparable naturalistic studies. Although preliminary results are promising, larger randomized trials are needed to determine the efficacy of STEP in reducing suicidal behaviors. PMID- 29258329 TI - Using Mobile Technology to Reduce Engagement in Stereotypy: A Validation of Decision-Making Algorithms. AB - We developed an iOS app, the iSTIM, designed to support parents of children with autism spectrum disorders (ASD) in reducing common repetitive vocal and motor behavior (i.e., stereotypy). The purpose of our study was to preliminarily test the decision-making algorithms of the iSTIM using trained university students to implement the assessments and interventions. Specifically, we examined the effects of the iSTIM on stereotypy and functional engagement in 11 children with ASD within alternating treatment designs. Using the iSTIM reduced engagement in stereotypy for eight participants and increased functional engagement for four of those participants. Our results indicate that the iSTIM may decrease engagement in stereotypy but that some of the decision-making algorithms may benefit from modifications prior to testing with parents. PMID- 29258330 TI - Characterization of Envelope Surface Glycoprotein from HIV-2 Primary Isolates with Different Coreceptor Usage Profile. AB - The main goal of this work was to identify molecular signatures in envelope surface glycoprotein that may be correlated with coreceptor usage by different human immunodeficiency virus (HIV)-2 strains. From inspection of aligned HIV-2 sequences, we verified that V1/V2 region showed the highest degree of amino acid sequence heterogeneity, including polymorphisms in N-linked glycosylation sites, sequence, and length. Furthermore, we did not find any correlation between the net charge and specific amino acid positions in V3 region with any particular coreceptor usage pattern. In conclusion, we showed that for HIV-2, the genetic determinants for coreceptor usage are distinct from those of HIV-1. More specifically, we did not identify any molecular signature, based on discrete amino acid positions either in V1/V2 or in V3 regions, which could be assigned to the preferential usage of a specific coreceptor. PMID- 29258331 TI - Short Communication: Specimen Processing Impacts Tissue Tenofovir Pharmacokinetic Measurements. AB - Antiretroviral drug concentrations at sites of HIV exposure are important drivers that influence the development of HIV pre-exposure chemoprophylaxis strategies and regimens. We assessed the effect of collection method-in the presence or absence of tissue culture medium-on tenofovir (TFV) and tenofovir diphosphate (TFV-DP) concentrations in colonic biopsies. We find significant baseline interbiopsy variation in TFV (38% CV) and TFV-DP (33% CV) concentrations. Incubation in medium leads to a fluid absorption-driven twofold increase in tissue weight with a concomitant 75% decrease in weight-adjusted tissue TFV concentrations 120 min post-incubation. In contrast, adjusted TFV-DP concentrations decrease by only 25% during the same period, with this difference not achieving statistical significance. Although colonic biopsies should be collected in the absence of medium for accurate TFV concentrations, the presence of medium does not significantly impact TFV-DP-dependent pharmacokinetic or pharmacodynamic assays. Appropriate assessment of tissue drug concentrations should account for biopsy collection method and drug mechanism of action. PMID- 29258333 TI - Assessment of the acute toxicity of chlorpyrifos and cypermethrin to Heteropneustes fossilis and their impact on acetylcholinesterase activity. AB - In the present study, the acute toxicity of chlorpyrifos (an organophosphate, OP) and cypermethrin (a pyrethroid) pesticides was estimated for 96 h in Heteropneustes fossilis. The LC50 for chlorpyrifos (CPF) and cypermethrin was found to be 1.90 mg/L and 0.085 mg/L, respectively. The acetylcholinesterase (AChE, EC 3.1.1.7) activity in Heteropneustes fossilis exposed to both the insecticides was assayed in brain, muscle and gills. In general, tissue specific as well as dose-dependent decrease in the AChE activity was exhibited by both pesticides. In response to the increasing concentrations of chlorpyrifos and cypermethrin as well, a significant decrease in the activity of AChE was found in brain while muscle and gills exhibited lesser inhibition. Thus, the brain was the main target organ for both insecticides, followed by muscle and gills. Between the two pesticides chlorpyrifos acted as more potent AChE inhibitor than cypermethrin since more intense changes in behavioral pattern was observed with the chlorpyrifos. These changes indicate that the effects of these pesticides are at neural as well as neuromuscular level. PMID- 29258334 TI - A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014-2017) and perspectives. AB - Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of 'integrated pharmacokinetics of TCMs' from 2014 to 2017 and the part of 'reverse pharmacokinetics in drug discovery from natural medicines' in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb-drug interactions and herb-herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs. PMID- 29258335 TI - Targeting of microbubbles: contrast agents for ultrasound molecular imaging. AB - For contrast ultrasound imaging, the most efficient contrast agents comprise highly compressible gas-filled microbubbles. These micrometer-sized particles are typically filled with low-solubility perfluorocarbon gases, and coated with a thin shell, often a lipid monolayer. These particles circulate in the bloodstream for several minutes; they demonstrate good safety and are already in widespread clinical use as blood pool agents with very low dosage necessary (sub-mg per injection). As ultrasound is an ubiquitous medical imaging modality, with tens of millions of exams conducted annually, its use for molecular/targeted imaging of biomarkers of disease may enable wider implementation of personalised medicine applications, precision medicine, non-invasive quantification of biomarkers, targeted guidance of biopsy and therapy in real time. To achieve this capability, microbubbles are decorated with targeting ligands, possessing specific affinity towards vascular biomarkers of disease, such as tumour neovasculature or areas of inflammation, ischaemia-reperfusion injury or ischaemic memory. Once bound to the target, microbubbles can be selectively visualised to delineate disease location by ultrasound imaging. This review discusses the general design trends and approaches for such molecular ultrasound imaging agents, which are currently at the advanced stages of development, and are evolving towards widespread clinical trials. PMID- 29258336 TI - Ready-to-Use Therapeutic Food Made From Locally Available Food Ingredients Is Well Accepted by Children Having Severe Acute Malnutrition in Bangladesh. AB - BACKGROUND: With a prevalence of 3.1%, approximately, 450 000 children in Bangladesh are having severe acute malnutrition (SAM). There is currently no national community-based program run by government to take care of these children, one of the reasons being lack of access to ready-to-use therapeutic food (RUTF). OBJECTIVE: To develop RUTF using locally available food ingredients and test its acceptability. METHODS: A checklist was prepared for all food ingredients available and commonly consumed in Bangladesh that have the potential of being used for developing a RUTF. Linear programming was used to identify the combinations of nutrients that would result in an ideal RUTF. To test the acceptability of 2 local RUTFs compared to the prototype RUTF, Plumpy'Nut, a clinical trial with a crossover design was conducted among 30 children in the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh. The acceptability was determined by using the mean proportion of offered food consumed by the children themselves. RESULTS: Two RUTFs were developed, one based on chickpea and the other on rice-lentils. The total energy content of 100 g of chickpea and rice-lentil-based RUTF were 537.4 and 534.5 kcal, protein 12.9 and 13.5 g, and fat 31.8 and 31.1 g, respectively, without any significant difference among the group. On an average, 85.7% of the offered RUTF amount was consumed by the children in 3 different RUTF groups which implies that all types of RUTF were well accepted by the children. CONCLUSION: Ready-to-use therapeutic foods were developed using locally available food ingredients-rice, lentil, and chickpeas. Chickpea-based and rice-lentil-based RUTF were well accepted by children with SAM. PMID- 29258338 TI - Corrigendum. PMID- 29258337 TI - First Field Test of an Innovative, Wider Tape to Measure Mid-Upper Arm Circumference in Young Laotian Children. AB - BACKGROUND: Measurements of mid-upper arm circumference (MUAC) may result in measurement error due to incorrect placement along the arm or tight pulling of tape. To reduce the risk of these measurement errors, a new wider tape was developed. OBJECTIVE: To compare the measurement agreement and precision and the ease of use of the standard and wide MUAC tapes. METHODS: Mid-upper arm circumference was measured in 814 children aged 9 to 32 months with both tapes. The midpoint of the upper arm was measured with the standard tape and estimated with the wide tape. Standardization sessions were implemented to assess intra- and interobserver precision. RESULTS: Mid-upper arm circumference with the wide MUAC tape was significantly larger than the standard tape (mean [standard deviation]: 14.3 [1.0] cm vs 13.9 [1.0] cm; P < .001), resulting in a consistent bias of +0.41 cm. Forty-six (5.7%) children were identified with low MUAC <12.5 cm by standard tape compared with 10 (1.2%) by the wide tape ( P <.001). Because a new tape could be reproduced by correcting for this bias, we corrected measured results by subtracting 0.41 cm and mean MUAC by tape type was no longer significantly different. Intra- and interobserver technical error of measurement suggested a better precision with the wide MUAC tape. CONCLUSIONS: Despite simplifying the measurement by approximating the midpoint of the upper arm, the wide MUAC tape tended to have better precision than the standard MUAC tape. However, there was a consistent measurement bias of +0.41 cm in mean MUAC. This first field test yielded promising results and led to further product adjustments. PMID- 29258339 TI - Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides. AB - PURPOSE: To assess the effect of "N-Acetylation and C-Amidation" on the cellular uptake, cytotoxicity and performance of amphiphilic cell penetrating peptides (CPP) loaded with methotrexate (MTX). METHODS: Several CPPs were synthesized by solid phase peptide synthesis method. Some of these sequences were modified with pyroglutamic acid at N-terminus and benzylamine or memantine at C-terminus. The resultant nanomaterials were prepared due to the physical linkage between CPPs and MTX. The internalization and cytotoxicity of both CPP-MTX bioconjugates and unmodified CPPs against MCF-7 human breast adenocarcinoma cells was evaluated. RESULTS: N-l and C-terminal modification did not alter the toxicity of CPPs. Physical linkage of CPPs with MTX resulted in a lower drug loading efficiency in comparison with chemically conjugated CPP-MTX bio-conjugates. Both nano-complexes increase the toxic effect of MTX on MCF-7 cells. Furthermore, N- and C-terminal modification may cause a tangible reduction in cellular uptake of CPPs. CONCLUSION: In conclusion, it was shown that cytotoxicity of modified peptides which were physically linked with MTX, considerably higher than both physically loaded unmodified peptides and chemically conjugated peptides with MTX. Also, cell internalization was reduced after peptide end-protection. These findings confirmed the effectiveness of N- and C-terminal modifications on cell viability and CPPs internalization. PMID- 29258340 TI - NAT1 genotypic and phenotypic contribution to urinary bladder cancer risk: a systematic review and meta-analysis. AB - N-acetyltransferase 1 (NAT1), a polymorphic Phase II enzyme, plays an essential role in metabolizing heterocyclic and aromatic amines, which are implicated in urinary bladder cancer (BCa). This systematic review investigates a possible association between the different NAT1 genetic polymorphisms and BCa risk. Medline, PubMed, EMBASE, Scopus, Web of Science, OpenGrey, and BASE databases were searched to identify eligible studies. The random-effect model was used to calculate pooled effects estimates. Statistical heterogeneity was tested with Chi square and I2. Twenty case-control studies, including 5606 cases and 6620 controls, met the inclusion criteria. Pooled odds ratios (OR) analyses showed a statistically significant difference in NAT1*10 versus non-NAT1*10 acetylators in the total sample (OR: 0.87; 95% CI: 0.79-0.96) but was borderline among Caucasians (OR: 0.88 with 95% CI: 0.77-1.01). No statistically significant differences in BCa risk were found for: NAT1*10 versus NAT1*4 wild type (OR: 0.97; 95% CI: 0.78-1.19), NAT1 'Fast' versus 'Normal' acetylators (OR: 1.03; 95% CI: 0.84-1.27), and NAT1 'Slow' versus 'Fast' (OR: 2.32; 95% CI: 0.93-5.84) or 'Slow' versus 'Normal' acetylators (OR: 1.84; 95% CI: 0.92-3.68). When stratifying by smoking status, no statistically significant differences in BCa risk were found for NAT1*10 versus non-NAT1*10 acetylators among the different subgroups. Our study suggests a modest protective role for NAT1*10 and a possible risk contributory role for slow acetylation genotypes in BCa risk. Further research is recommended to confirm these associations. PMID- 29258341 TI - Sexual risk taking and the HIV care continuum in an online sample of men who have sex with men. AB - Antiretroviral Therapy (ART) suppresses HIV replication, reducing the risk of transmission. However, many people living with HIV in the US are not virally suppressed even after diagnosis and initiating ART, and may become disengaged from care at each stage of the HIV care continuum (HCC). In the current study we assessed the sexual risk behaviors of MSM by HCC stage. US MSM who completed an online survey (N = 12,995) in 2015 were categorized into 6 HCC groups. Mean age was 39.2 and a majority identified as White (49.6%). At every stage of the HCC, we found higher proportions of individuals engaged in care compared to CDC estimates. A majority of the sample was HIV-positive and engaged in care, with 67.2% of HIV-positive participants reporting viral suppression with ART. Across HCC groups, participants reported high rates of past 6-month condomless anal sex (CAS) (79.2%-84.8%) and CAS with serodiscordant or unknown status partners (38.0% 84.1%). Notably, MSM with unknown HIV serostatus reported the highest proportion of CAS and serodiscordant CAS. HIV-positive MSM not on ART were more likely to report an STI diagnosis (p < .002) compared to those unaware of their HIV status or HIV negative. Moreover, young Black MSM were less likely to be on ART (p < .002) or virally suppressed (p < .002) compared to older White MSM. Our findings highlight potentially problematic sexual risk behaviors among MSM by level of HCC engagement, which can impede the preventive impact of ART. Online platforms provide an avenue to assess the progress of MSM along the HCC, as well as other subpopulations in need of appropriate behavioral interventions to decrease HIV incidence. PMID- 29258342 TI - Gender differences in health-related quality of life at the time of a positive HIV test - a cross-sectional study in a resource-poor, high prevalence setting in Nairobi, Kenya. AB - Few studies have examined gender differences in sub-Saharan Africa, where HIV disproportionately affects women. Objectives of this cross-sectional study were to determine gender differences in HRQoL at the time of a positive HIV test, and whether factors associated with HRQoL differed between men and women. Adults testing HIV-positive were recruited from two clinics located in informal settlements. HRQoL was measured with the SF-12. Multiple linear regression was used to test whether there were gender differences in physical (PCS) and mental composite summary (MCS) scores. Separate models were built for men and women to examine factors associated with HRQoL. Between April 2013 and June 2015, 775 individuals from were recruited. The mean PCS score was higher in women (adjusted mean difference 2.49, 95% CI 0.54 to 4.44, p = 0.012). There was no significant gender difference in MCS scores. Similar factors were associated with better physical HRQoL in men and women: secondary education, younger age, higher CD4, and employment. Employment was the only factor associated with MCS in men, while less social support and low CD4 were associated with poorer MCS scores in women. Gender differences in factors related to HRQoL should be considered in broader policy and interventions to improve the HRQoL in those diagnosed with HIV. PMID- 29258343 TI - Lipid-coated calcium phosphate nanoparticle and beyond: a versatile platform for drug delivery. AB - In recent years, lipid-coated calcium-phosphate (LCP) nanoparticle has been developed as a versatile platform for delivery of various therapeutics including gene, protein/peptide, chemotherapeutics and theranostic agents. The high endosomal escape, coupled with the ability to efficiently encapsulate phosphorylated drugs or prodrugs, make LCP become attractive vehicle for drug delivery. Additionally, the principle behind LCP formulation has also allowed rational design of LCP-derived nanoparticles (NPs) with other solid core or lipid membrane to overcome the various drug delivery barriers. Here, we briefly review the history of the development of LCP NPs, highlight the optimisations and modulations in the development process, and summarise the major applications of LCP NPs and LCP-derived NPs in drug delivery. PMID- 29258344 TI - Mental Health Harm to Mothers When a Child Is Taken by Child Protective Services: Health Equity Considerations. PMID- 29258345 TI - Characterisation of an extract and fractions of Azadirachta indica flower on cholesterol lowering property and intestinal motility. AB - Azadirachta indica has long been used in traditional medicine. This study focused on isolation and characterisation of active ingredients in the extract, its fractions (NF-EA, NF-AQ, NF-G) and its effect on the cholesterol absorption activity. The NF-EA fraction was identified by marker compounds by LC-ESI QTOF/MS. Cholesterol absorption activity was performed by measuring the solubility and size of cholesterol micelles. The intestinal motility was also examined by isolated rat's ileum to test the contraction. The extract and its fractions consist of flavonoids and phenolic compounds, like quercetin, kaempferol and myricetin. We found that A. indica extract and NF-EA increase cholesterol micelles size, while the extract, NF-AQ, myricetin and quercetin, reduced the solubility of cholesterol in micelles. The extract and quercetin inhibited the contraction induced by KCl up to 29 and 18%, respectively, and also decreased CaCl2-induced contraction. This finding is in support to traditional uses of A. indica as cholesterol-lowering agents and regulator of gastrointestinal motility. PMID- 29258346 TI - The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous alpha-Lipoic Acid/Low Dose Naltrexone Protocol. AB - In this case report, we describe the treatment of a 64-year-old male patient diagnosed with metastatic renal cell carcinoma (RCC) in June of 2008. In spite of a left nephrectomy and the standard oncological protocols, the patient developed a solitary left lung metastasis that continued to grow. He was informed that given his diagnosis and poor response to conventional therapy, any further treatment would, at best, be palliative. The patient arrived at the Integrative Medical Center of New Mexico in August of 2010. He was in very poor health, weak, and cachectic. An integrative program-developed by one of the authors using intravenous (IV) alpha-lipoic acid, IV vitamin C, low-dose naltrexone, and hydroxycitrate, and a healthy life style program-was initiated. From August 2010 to August 2015, the patient's RCC with left lung metastasis was followed closely using computed tomography and positron emission tomography/computed tomography imaging. His most recent positron emission tomography scan demonstrated no residual increased glucose uptake in his left lung. After only a few treatments of IV alpha-lipoic acid and IV vitamin C, his symptoms began to improve, and the patient regained his baseline weight. His energy and outlook improved, and he returned to work. The patient had stable disease with disappearance of the signs and symptoms of stage IV RCC, a full 9 years following diagnosis, with a gentle integrative program, which is essentially free of side effects. As of November 2017 the patient feels well and is working at his full-time job. PMID- 29258347 TI - Interpersonal Communication in Response to an Intervention and Its Impact on Smoking Cessation Within a Low-Income Population. AB - BACKGROUND: It is a priority to develop population-based strategies for reducing barriers to smoking cessation among low-income populations. Harnessing secondary transmission such as interpersonal communication (IC) has helped to reduce tobacco use, but there is a dearth of quasi-experimental research that examines IC and the full spectrum of smoking cessation behaviors, particularly in the context of population-level programs. AIMS: Using quasi-experimental methods, we examined IC in response to a population-level intervention and its impact on the full spectrum of smoking cessation outcomes among low-income smokers. METHOD: We used propensity score matching; three different propensity score matching procedures were used to estimate and approximate experimental effects. We assessed four cessation outcomes: utilization of a free tobacco quitline (QL), making a quit attempt, and being smoke-free for 7 and 30 days at follow-up. We also examined predictors of IC. RESULTS: IC was significantly related to QL utilization (effect sizes ranging from 0.135 to 0.166), making a quit attempt (effect sizes ranging from 0.115 to 0.147), being smoke-free for 7 days (effect sizes ranging from 0.080 to 0.121), and being smoke-free for 30 days at follow-up (effect sizes ranging from 0.058 to 0.082). Program-related and participant characteristics predicted IC, such as receiving emotional direct mail materials and living with a fellow smoker. DISCUSSION: IC in response to a population-based program affected the cessation process, and IC had a marked impact on sustained cessation. CONCLUSION: Population-based programs should aim to harness psychosocial dynamics such as IC to promote sustained cessation among low-income populations. PMID- 29258348 TI - Advancing the Science of Behavioral Self-Management of Chronic Disease: The Arc of a Research Trajectory. AB - This article describes advances in the behavioral self-management of chronic disease from the perspective of a 25-year trajectory of National Institute of Health-funded research in arthritis and cardiopulmonary diseases that has sought to develop a transdisciplinary understanding of how applied behavioral science can be used to improve health behaviors, functional status, and health outcomes. The article traces the arc of a novel research program-conducted in collaboration with physician-scientists at Columbia, Weill Cornell Medical College, and New York University School of Medicine-that runs through social cognitive theory, behavioral economics, and the emerging science of positive psychology in an effort to develop promising new approaches to fostering the adoption and maintenance of health-related behavioral change. The article concludes with what has been learned and what the implications of the work are for advancing behavioral self-management and patient education to improve patient outcomes and achieve the compression of morbidity. PMID- 29258350 TI - Linkage to HIV care and its determinants in the late HAART era: a systematic review and meta-analysis. AB - Poor engagement into HIV care limits the effectiveness of highly active antiretroviral therapies (HAART) to improve survival and reduce transmission. The design of effective interventions to enhance linkage to care is dependent on evidence about rates of entry into HIV care. This is a systematic review and meta analysis on linkage measurement and its determinants in the late era of HAART (post-2003), in high-income countries. We searched the PubMed and Web of Science databases, restricting our sample to the late HAART era (post-2003) until February 2016, and to high-income countries. We retained only studies that produced quantified outcomes. We rejected the studies with a high risk of bias, and followed a standard meta-analytic approach. Because there was a high heterogeneity ( I 2 > 90%), the aggregated findings were based on a random effects model. A total of 43 studies were identified, all of them following a cohort of patients newly diagnosed until referred to specialized care. For a one month period, the meta-proportion was 71.1% (IC95%: 61.0%-81.2). For a three month duration, the meta-proportion of linkage to care was 77.0% (IC95%: 75.0% 79.0). For a one-year period, the meta-proportion was 76.3% (IC95%: 54.2%-98.4%). The proportions were lower when lab tests were used as referral indicator, with a pooled meta-proportion of 76.7% (IC95%: 73.0%-80.4), in comparison to a value of 80.8% (IC95%: 68.7%-92.9) for consultations. Being black or male were the most commonly observed determinants of delayed entry into care. Young people, injecting drug users, people with low socioeconomic status, or at a less advanced stage of disease also experienced lower proportions of timely linkage. Timely engagement into care is below 80% and specific sub-groups are particularly at risk of late entry. These findings confirm earlier evidence that linkage to care remains low, and that efforts should focus on vulnerable populations. PMID- 29258349 TI - Genomic identification of microbial species adhering to maxillofacial prostheses and susceptibility to different hygiene protocols. AB - This study investigated the microbial colonization of maxillofacial prostheses and support tissues using the Checkerboard DNA-DNA hybridization method, and the efficacy of 0.12% chlorhexidine gluconate, 10% Ricinus communis solutions, or brushing, on colony forming unit (CFU) reduction in monospecies biofilms (Candida glabrata, Staphylococcus aureus, Streptococcus mutans, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa) formed on two silicones (MDX 4 4210 and Bio-Skin). Biofilm was harvested from 43 maxillofacial prosthesis wearers for detection of 38 species of microorganisms. The CFU counts of the six above mentioned species were recorded after using the hygiene protocols. All 38 investigated species were identified in prostheses and tissues, with a higher prevalence in the prostheses. 0.12% chlorhexidine gluconate immersion showed the greatest antimicrobial effectiveness, followed by mechanical brushing protocols. MDX 4-4210 silicone produced lower CFU counts than Bio-Skin. PMID- 29258351 TI - Creatine kinase in relation to body fat in a Caucasian overweight and obese population. AB - We investigated the association between serum creatine kinase (CK) and body fat mass in an overweight and obese population. In this cross-sectional study, 454 Caucasian overweight and obese individuals recruited from a medical outpatient clinic and via newspaper advertising underwent dual-energy X-ray absorptiometry (DEXA). Serum CK was obtained along with supplementary blood samples. This report is based on a secondary analysis from a previous randomized controlled trial treating obesity with vitamin D3. Serum CK correlated negatively with body fat mass in men (r = -.18, p = .025) but not in women (r = -.11, p = .069). An insignificant negative trend for logCK across quartiles of fat mass in men was found (p = .098). CK did not associate significantly with lean mass, but lean mass correlated positively with fat mass in both groups (p < .0001). In a multivariate model, serum CK was inversely and independently related to fat mass in men. Fat mass decreased with 7.83 kg per unit logCK increase when adjusted for age and lean mass (95% CI -12.3 to -3.3, p = .001). These data support the view that circulating CK interacts with obesity in a favourable way independent of its muscular connection in men. CK was not associated with fat mass in women. PMID- 29258352 TI - Cultural adaptation and construct validation of the Arabic version of children's assessment of participation and enjoyment and preferences for activities of children measures. AB - PURPOSE: To establish the construct validity and internal consistency of the Arabic Children Assessment of Participation and Enjoyment (CAPE) and Preferences for Activities of Children (PAC) and to determine the effects of age, gender, and disability status on diversity and intensity of participation. METHODS: The World Health Organization guidelines for translation of measures were applied to translate the CAPE and PAC, 75 children with cerebral palsy (mean age = 10.7 +/- 2.9 years) and 75 children with typical development (mean age = 10.8 +/- 2.7 years) completed the translated measures. The construct validity of the translated measures was demonstrated by principle component analyses in addition to the known-groups method by examining the effects of age, gender, and presence of disability on diversity and intensity scores. The internal consistencies of the extracted components were examined by Cronbach's alpha. RESULTS: Four components emerged: (1) physical activities; (2) home-based activities; (3) self improvement activities; and (4) social activities. Cronbach's alpha varied from 0.61 (social activities) to 0.83 (physical activities). Age, gender, and disability were significant determinants of types of activities. CONCLUSIONS: The Arabic CAPE and PAC are culturally valid in measuring participation of children with or without disabilities in Jordan. The child's age, gender, and disability should be considered to provide participation-based plans of care that are considerate for children and their families. Implications for rehabilitation The Arabic CAPE and PAC are culturally valid measures for participation of children with or without disabilities in Jordan. The Arabic CAPE and PAC measures can guide participation-based plans of care that are meaningful and considerate for children and their families. Child age and gender should be considered to provide appropriate activities and to facilitate participation of children with and without disabilities. Families and service providers in Jordon are encouraged to provide children opportunities to participate in desired physical, self improvement, and social activities. PMID- 29258353 TI - A new abietane diterpenoid from the roots of Tripterygium regelii. AB - A new abietane diterpenoid, tripterregeline A (1), together with six known diterpenoids (2-7), were isolated from the roots of Tripterygium regelii. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparison with data reported in the literature. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1 7 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.58 to 21.06 MUM. PMID- 29258354 TI - Coping strategies and emotional well-being in children with disease-related pain. AB - Disease-related pain and the consequences of pain in children and families are important areas for further research inquiry. There are limited data on the relationship between children's emotional well-being, their experience of pain, and the strategies they employ to cope with pain within the context of serious medical illnesses. Understanding what strategies chronically ill children use to cope with pain and stress is essential for clinical intervention. This observational study examined the ways that children and adolescents with chronic diseases cope with pain and adapt to illness. The data were collected by self report measures and projective drawing techniques in a novel way to assess the emotional functioning in a mixed cohort of youth with disease-related pain (oncological, rheumatic, and cystic fibrosis). This protocol was administered to 47 children, aged 7-14, recruited from pediatric wards of hospitals of Trento and Rovereto (Italy). The results showed that coping strategies in youth with disease related pain differed across diagnoses and with self-representations (as part of the self-concept adaptive mode). We also provide evidence of the applicability of using projective drawing methods in assessing coping in youth with chronic illness and associated pain. PMID- 29258355 TI - Coping strategies of former prisoners of war mediate the intergenerational transmission of posttraumatic stress symptoms. AB - OBJECTIVES: Certain coping strategies, characterized by emotional coping or disengagement/ avoidance, have been linked to posttraumatic stress disorder (PTSD) and PTSD symptoms (PTSS). However, the role of primary trauma victims' coping strategies in the intergenerational transmission of PTSS is still lacking. This prospective study assessed the mediating role of former prisoners of war's (ex-POWs) coping strategies in the associations between ex-POWs' PTSS and their adult offspring's secondary PTSS in relation to their fathers' captivity and psychiatric symptomatology. DESIGN: A correlational, prospective study. METHOD: A sample from the 1973 Yom Kippur War composed of 79 Israeli ex-POW father offspring dyads completed self-report measures. Fathers were assessed in 2001 and 2008, and their adult offspring participated in 2014. RESULTS: ex-POWs' problem focused coping strategies of active coping and planning, as well as disengagement oriented coping strategies of alcohol and substance use and venting of emotions, were negatively associated with offspring's PTSS and psychiatric symptomatology. Importantly, ex-POWs' venting of emotions mediated the link between ex-POWs' PTSS and their offspring's secondary PTSS. CONCLUSIONS: Ex-POWs with PTSS might expose their offspring to dysregulated mood, behaviors, and cognitions. Special awareness should be given to the venting of emotions coping style as possible mechanism for the intergenerational transmission of captivity-related PTSS. PMID- 29258356 TI - Grave fraudulence in medical device research: a narrative review of the PIN seeding study for the Pinnacle hip system. AB - In 2001, DePuy, a wholly-owned subsidiary of Johnson & Johnson (J&J/DePuy), initiated a seeding study called the "Multi-center, Prospective, Clinical Evaluation of Pinnacle Acetabular Implants in Total Hip Arthroplasty" (PIN Study). J&J/DePuy designed this study to develop new business opportunities during the launch of their Pinnacle Hip System (PHS) and generate survivorship data for marketing. This article, the first review of a seeding trial for a medical device, examines internal company documents relating to the PIN Study; the analysis herein focuses on the integrity of J&J/DePuy's research practices in conception, implementation, and analysis. J&J/DePuy violated the study protocol and manipulated data; consented participants in violation of standards protecting human subjects; and did not secure Institutional Review Board approval for all study sites. J&J/DePuy used PIN Study results as the "fundamental selling point" for the PHS. Medical device seeding trials are distinct from previously documented pharmaceutical seeding trials because companies can profit directly from device sales and because these studies may be the first clinical evaluation of the device (as was the case for the PIN Study). Seeding trials are malleable marketing projects, not rigorous scientific studies. Regulatory bodies, physicians, and others should be vigilant for persuasive marketing accounts disguised as science. PMID- 29258357 TI - Penicillixanthone A, a marine-derived dual-coreceptor antagonist as anti-HIV-1 agent. AB - Marine micro-organisms have been proven to be excellent sources of bioactive compounds against HIV-1. Several natural products obtained from marine-derived Aspergillus fungi were screened for their activities to inhibit HIV-1 infection. Penicillixanthone A (PXA), a natural xanthone dimer from jellyfish-derived fungus Aspergillus fumigates, displayed potent anti-HIV-1 activity by inhibiting infection against CCR5-tropic HIV-1 SF162 and CXCR4-tropic HIV-1 NL4-3, with IC50 of 0.36 and 0.26 MUM, respectively. Molecular docking study was conducted to understand the possible binding mode of PXA with the CCR5/CXCR4. The results revealed that, the marine-derived PXA, as a CCR5/CXCR4 dual-coreceptor antagonist, presents a new type of potential lead product for the development of anti-HIV therapeutics. PMID- 29258358 TI - The long-term effects of endometrioma surgery on ovarian reserve: a prospective case-control study. AB - The objective of this study was to evaluate the long-term effects of endometrioma excision on ovarian reserve. This study evaluated the long-term effects of endometrioma excision on ovarian reserve. A total of 63 women were enrolled in this prospective case-control study; 21 women had histories of endometrioma surgery (study group), 21 women had diagnoses of endometrioma, and 21 healthy age matched women served as controls. Participants were recruited from the Department of Obstetrics and Gynecology, Inonu University Faculty of Medicine, between January 2007 and January 2016. The mean follow-up duration after endometrioma surgery was 30.4 +/- 18.0 months for the study group. The mean follicle stimulating hormone, luteinizing hormone and estradiol levels were similar among groups, but the anti-Mullerian hormone (AMH) level was significantly lower in the surgery group than in the control group (p < .001). The mean AMH level was 42% lower in the endometrioma surgery group than in the endometrioma group and 30% lower in the endometrioma group than in the control group (p = .080 and p = .160, respectively). Endometrioma has a detrimental effect on ovarian reserve, and decreased ovarian reserve compared with that in healthy fertile subjects without endometrioma is evident shortly after endometrioma excision. However, the endometrioma excision procedure does not significantly decrease the ovarian reserve in the long term. PMID- 29258359 TI - Discovery of antimicrobial compounds targeting bacterial type FAD synthetases. AB - The increase of bacterial strains resistant to most of the available antibiotics shows a need to explore novel antibacterial targets to discover antimicrobial drugs. Bifunctional bacterial FAD synthetases (FADSs) synthesise the flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These cofactors act in vital processes as part of flavoproteins, making FADS an essential enzyme. Bacterial FADSs are potential antibacterial targets because of differences to mammalian enzymes, particularly at the FAD producing site. We have optimised an activity-based high throughput screening assay targeting Corynebacterium ammoniagenes FADS (CaFADS) that identifies inhibitors of its different activities. We selected the three best high-performing inhibitors of the FMN:adenylyltransferase activity (FMNAT) and studied their inhibition mechanisms and binding properties. The specificity of the CaFADS hits was evaluated by studying also their effect on the Streptococcus pneumoniae FADS activities, envisaging differences that can be used to discover species-specific antibacterial drugs. The antimicrobial effect of these compounds was also evaluated on C. ammoniagenes, S. pneumoniae, and Mycobacterium tuberculosis cultures, finding hits with favourable antimicrobial properties. PMID- 29258360 TI - The role of beta-blockers in the management of chronic obstructive pulmonary disease. AB - INTRODUCTION: The use of beta-blockers in chronic obstructive pulmonary disease (COPD) is controversial, primarily due to concerns that they may worsen lung function and attenuate bronchodilator response. Areas covered: This review summarizes the reasons for and against the use of beta-blockers in COPD by evaluating the literature on the effects of these drugs on lung function, exacerbation rate, and mortality. The safety of beta-blockers in COPD patients with concomitant heart failure, an entity that is not always distinguishable from COPD exacerbations, is also explored. Expert commentary: The use of cardioselective beta-blockers appears safe in the management of cardiac comorbidities associated with COPD and may lower exacerbation and mortality risk. There is a growing body of evidence demonstrating the safety of beta-blockers in patients with acute heart failure, acute respiratory failure or sepsis, entities that could occur simultaneously with COPD exacerbations. However, randomized controlled trials are still lacking to confirm these results. PMID- 29258361 TI - Pharmacokinetic drug evaluation of dalbavancin for the treatment of skin infections. AB - INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSIs), defined as a bacterial infection of the skin with a lesion size area of at least 75 cm, are a leading cause of hospital admission and ambulatory care visits worldwide. Dalbavancin is a lipoglycopeptide antibiotic recently approved by the United States Food and Drug Administration (FDA) and by European Medicines Agency (EMA) for ABSSSIs. The authors review and provide updates of efficacy and safety by several studies on dalbavancin. Areas covered: A PubMed search was performed for relevant literature. We especially focused our attention on pharmacokinetics. Expert opinion: Dalbavancin provides an important new therapy for management of ABSSI, maintaining a spectrum of activity similar to vancomycin against gram positive organisms. Use of dalbavancin, with its 1-week-shot treatment, consist in a reduction of the length of hospital stay or in a reduction of hospital admissions, with important cost savings. PMID- 29258362 TI - Negative cognitive style and cortisol recovery accentuate the relationship between life stress and depressive symptoms. AB - When exposed to stressful life events, a significant number of adolescents will experience depressive symptoms. One model of depression suggests that individuals with a negative cognitive style are most vulnerable to depression following life stress. Alternatively, altered activation of the hypothalamic-pituitary-adrenal axis may explain vulnerability to depression following life stress. Each of these models plausibly explains the emergence of depressive symptoms during adolescence and have been investigated largely independently. The current study recruited a sample of urban adolescents (N = 179) to evaluate whether cortisol response to a laboratory stress induction and negative cognitive style are related and whether they independently interact with exposure to stressful life events to predict symptoms of depression. Negative cognitive style was not associated with cortisol response to the laboratory stressor. Rather, negative cognitive style and cortisol recovery independently interacted with stressful life events to predict current symptoms of depression. Results support a heterogeneous etiology of depression. PMID- 29258363 TI - 20-Year outcome of TFCC repairs. AB - The aims of this study were to investigate the functional result and rate of osteoarthritis 15-25 years after a TFCC-repair. Forty-seven patients completed the questionnaire Patient Rated Wrist Evaluation (PRWE), and 43 had new X-rays. Fifty-seven percent had a simultaneous arthroscopy. Sixteen patients had later additional surgery to the wrist, of these eight had a reoperation of the TFCC injury due to recurrent instability. Radiographs showed that 17.5% had developed radiocarpal osteoarthritis and 34% osteoarthritis in the distal radioulnar joint. The median PRWE result was 22.5. Patients with radiocarpal osteoarthritis and patients who had additional surgery had significantly worse scores. Patients who had undergone arthroscopy significantly less often had developed radiocarpal osteoarthritis. The result is acceptable but not impressive and efforts should be made to diagnose these injuries early and also diagnose associated injuries, advisably by arthroscopy. PMID- 29258364 TI - Comparative Study of NOTES Versus Endoscopic Ultrasound Gastrojejunostomy in Pigs: A Prospective Study. AB - BACKGROUND: Surgical gastrojejunal anastomosis (GJJ) is considered the standard palliative option for gastric outlet obstruction. The use of endoscopic GJJ has generated a lot of attention and has enlarged the horizon for patients with open surgery contraindications. Our study aimed to assess and compare 2 purely endoscopic GJJ approaches using a lumen-apposing hot tip double-flanged metal stent, with focus on technical and clinical success rates on experimental animals. METHODS: Two endoscopic GJJ techniques using a double-flanged self expandable metal stent were compared on 8 pigs. Natural orifice transluminal endoscopic surgery (NOTES) was used on 4 pigs, while the other group was subjected to an endoscopic ultrasound (EUS) balloon-guided approach. RESULTS: On a 21-day follow-up, both EUS and NOTES-GJJ were technically successful in all experimental animals, and necropsy confirmed full integrity of the anastomosis. Adhesions were confirmed only on 2 pigs after NOTES procedure. The mean time for GJJ-NOTES completion was 31.375 +/- 2.03, whereas EUS-GJJ was completed with a median time of 20.275 +/- 0.65. The stent distance from the stomach varied; in NOTES-GJJ it was 47.8 +/- 11.13 cm away from the pylorus, whereas in EUS-GJJ was at 37 +/- 1.85 cm. CONCLUSION: No major complications were encountered during both procedures. EUS-GJJ balloon-guided approach might be a more attractive technique by using sonographic guidance, because of less endoscopic instrument changing as well as in achieving the desired anastomotic distance. PMID- 29258365 TI - The effect of reactive oxygen species on cardiomyocyte differentiation of pluripotent stem cells. AB - The coordination of metabolic shift with genetic circuits is critical to cell specification, but the metabolic mechanisms that drive cardiac development are largely unknown. Reactive oxygen species (ROS) are not only the by-product of mitochondrial metabolism, but play a critical role in signalling cascade of cardiac development as a second messenger. Various levels of ROS appear differential and even oppose effect on selfrenewal and cardiac differentiation of pluripotent stem cells (PSCs) at each stage of differentiation. The intracellular ROS and redox balance are meticulous regulated by several systems of ROS generation and scavenging, among which mitochondria and the NADPH oxidase (NOX) are major sources of intracellular ROS involved in cardiomyocyte differentiation. Some critical signalling modulators are activated or inactivated by oxidation, suggesting ROS can be involved in regulation of cell fate through these downstream targets. In this review, the literatures about major sources of ROS, the effect of ROS level on cardiac differentiation of PSCs, as well as the underlying mechanism of ROS in the control of cardiac fate of PSC are summarised and discussed. PMID- 29258366 TI - Dynamic Characteristics of a New Three-Dimensional Linear Homeomorphic Saccade Model. AB - A linear homeomorphic eye movement model that produces 3D saccadic eye movements consistent with anatomical and physiological evidence is introduced in this second part of a two-paper sequence. Central to the model is the implementation of a time-optimal neural control strategy involving six linear muscle models that faithfully represent the dynamic characteristics of 3D saccades. The muscle is modeled as a parallel combination of viscosity [Formula: see text] and series elasticity [Formula: see text], connected to the parallel combination of active state tension generator [Formula: see text], viscosity element [Formula: see text], and length tension elastic element [Formula: see text]. The neural input for each muscle is separately maintained while the effective pulling direction is modulated by its respective pulley. The results demonstrate that a time-optimal, 2D commutative neural controller, together with the pulley system, actively functions to implement Listing's law during both static and dynamic simulations and provide an excellent match with the experimental data. The parameters and neural input to the muscles are estimated using a time domain system identification technique from saccade data, with an excellent match between the model estimates and the data. A total of 20 horizontal, 5 vertical and 62 oblique saccades are analyzed. PMID- 29258368 TI - Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder. AB - INTRODUCTION: The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED. Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of abuse needs to be assessed prior to prescribing. PMID- 29258367 TI - Evaluation of prolonged use of statins on the clinical and biochemical abnormalities and ovulation dysfunction in single young women with polycystic ovary syndrome. AB - OBJECTIVE: The aim of the current work was to investigate the effects of prolonged use of Statins on the clinical and biochemical abnormalities and ovulation dysfunction in young single women with polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: It was a randomized, double-blind, placebo controlled study. Where 200 single young women with PCOS were randomized into either 100 (n = 100) women using Simvastatin 20 mg daily considered as group A (study group), or 100 (n = 100) women using placebo and considered as group B (control group), for six months treatment period. The main outcome measures were the changes in serum androgen levels (testosterone, androstendione and dehydro epiandrostenion sulfate-DHEAS), LH, FSH, LH/FSH ratio and insulin resistance (IR), in addition to menstrual regularity, hirsutism, BMI and W/H ratio. Follow up of spontaneous ovulation, confirmed with both trans-abdominal sonography (TAS) and luteal serum progesterone had been performed as well. RESULT(S): After 6 months' treatment, in group A serum testosterone showed decreased level by 28%, with significant decrease of LH (40%) and a decline of the LH/FSH ratio (43%). There was also a clear decrease of total cholesterol (26%), low-density lipoprotein (LDL; 39%) and triglycerides (23%). IR did not show a significant difference in the two groups. High-density lipoprotein (HDL) increased by 17%. Improved menstrual regularity and decreased hirsutism, acne, ovarian volume, BMI had been clearly noticed in the study group. Spontaneous ovulation had been confirmed songoraphically (TAS), and biochemically (progesterone >10 ng) in 10 women (10%) in the study group compared to none in the control group. CONCLUSIONS: Long-term Statins' treatment was associated with clear improvement of all PCOS clinical and biochemical abnormalities, in addition to ovarian dysfunction as well. PMID- 29258369 TI - High treatment persistence rate and significant endoscopic healing among real life patients treated with vedolizumab - a Finnish Nationwide Inflammatory Bowel Disease Cohort Study (FINVEDO). AB - OBJECTIVES: The efficacy and tolerability of vedolizumab in the treatment of inflammatory bowel diseases (IBD) has been demonstrated in an extensive GEMINI clinical trial programme. Clinical trials represent highly selected patient populations and, therefore, it is important to demonstrate effectiveness in real life clinical practice. We set out to assess real-world treatment outcomes of vedolizumab in a nationwide cohort of treatment refractory Finnish Crohn's disease (CD) and ulcerative colitis (UC) patients. METHODS: This was a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centers with a diagnosis of UC or CD who had at least one vedolizumab infusion since the availability of the product in Finland, were included in the study. Data were collected retrospectively from medical charts at baseline, week 14, and month 6. The primary outcome measure was treatment persistence 24 weeks post-vedolizumab initiation. RESULTS: A total of 247 patients were included (108 CD, 139 UC). A total of 75.0% (n = 81) of all CD patients and 66.2% (n = 92) of all UC patients, were persistent on vedolizumab therapy for 6 months post treatment initiation. At month 6, 41.8% (28/67) of the treatment persistent CD patients and 73.3% (63/86) of the treatment persistent UC patients achieved clinical remission. Significant improvement in endoscopic scores were observed among treatment persistent patients (CD, n = 17, DeltaSES-CD=-5.5, p = .008; UC, n = 26, DeltaMayo endoscopic score =-0.5, p = .003) at month 6. CONCLUSIONS: Vedolizumab provides an effective and well-tolerated treatment option in real-world clinical practice even among treatment refractory IBD patients. PMID- 29258370 TI - The effect of thought importance on stress responses: a test of the metacognitive model. AB - Negative metacognitive beliefs are central determinants of distress in the metacognitive model of psychological vulnerability to stress. The current study tested this assertion in 75 undergraduate students assigned to either experimental (metacognitive belief manipulation) or control (no metacognitive belief manipulation) condition. All participants underwent a fake EEG, where they were told that the EEG would detect negative thoughts. The experimental subjects were informed that if they had a negative thought they may be exposed to a contingent burst of loud noise, while the control condition was told that they may be exposed to a burst of loud noise at random. Participants also underwent the Trier Social Stress Test. The results showed that on physiological measures (skin conductance level) there were no significant differences between groups. However, on self-report measures (positive and negative affect) participants in the experimental condition reported greater levels of negative affect and lower levels of positive affect in response to stress and maintained low positive affect at recovery. The results are consistent with the metacognitive model and suggest that metacognitive beliefs impact on positive and negative affect in reaction to and recovery from stress exposure. PMID- 29258371 TI - Attitudes of patients with psychiatric illness toward traditional healing. AB - BACKGROUND: The role of traditional healers in the community remains an issue of debate as they have a role in the community that could not be neglected. Traditional medicine can be a barrier for early intervention and treatment of psychiatric disorders. AIM: This study is a cross-sectional descriptive study that aims to evaluate the attitude of patients toward traditional healing in Khartoum teaching hospital in Sudan. METHOD: Patients who attended the outpatient clinic were asked about previous history of seeking treatment from traditional healers. A specific questionnaire was introduced to participants. Descriptive statistics was used to describe the data variables, and tabulated tables were used to calculate chi-square test for categorical data and the significance was set at p < .05. RESULTS: From a total of 131 subjects, there were 111 (84%) of patients who reported previous history of seeking traditional treatment for psychiatric illness. No significant difference was found between the two groups in terms of psychiatric diagnosis ( p = .559) or sociodemographic characteristics including age ( p = .740), gender ( p = .469) and educational level ( p = .226). The decision of seeking traditional treatment was mostly taken by families and the patients took the decision in only 27% of cases. The majority of participants (55.9%) believe that their psychiatric symptoms are due to evil eye, and 20.7% believe that the symptoms are due to magic. The type of traditional treatment was significantly related to gender ( p = .003) but not related to level of education ( p = .137). CONCLUSION: The vast majority of psychiatric patients have history of receiving traditional healing, and the decisions regarding treatment are taken by family in most of the cases. Further research is needed to evaluate future projects of providing psychoeducation to the community and to invite traditional healers to participate in channels of referral for cases that need early intervention with psychotropic medications. PMID- 29258372 TI - Stroke burden in Egypt: data from five epidemiological studies. AB - PURPOSE: Accurate data on the epidemiology of stroke in Egypt is scarce. The aim of this review is to address this issue based on available community-based studies and compare the resulting findings to those of other regional and international studies. METHOD: A systematic literature search was conducted to identify population-based epidemiological studies of stroke in Egyptians. Original articles published in English between 1990 and 2016 were included. Five studies from five different governorates in southern Egypt fulfilled the study criteria (Qena, Sohag, Assiut, New Valley and Red Sea). RESULTS: The mean and median crude prevalence rates (CPRs) across the five studies, which were conducted in southern Egypt were 721.6/100,000 and 655/100,000, respectively. The mean and median crude incidence rates (CIRs) were 187/100,000 and 180.5/100,000, respectively. The average CPR weighted by sample population size was 613/100,000 and the average CIR weighted by sample population size was 202/100,000. CONCLUSION: The incidence and prevalence of stroke in Egypt are high. More population-based studies are urgently needed in northern Egypt and in Cairo - the capital of Egypt. PMID- 29258373 TI - Kv1.3: a multifunctional channel with many pathological implications. PMID- 29258374 TI - Falls Prevention Process in Assisted Living Communities. AB - Falls are a significant issue for older adults, and many older adults who once received care in nursing homes now reside in assisted living communities (ALCs). ALC staff needs to address resident falls prevention; however, federal or state requirements or oversight are limited. This research explores falls prevention in Wisconsin ALCs in the context of the Kotter Change Model to identify strategies and inform efforts to establish a more consistent, proactive falls prevention process for ALCs. A mixed methods approach demonstrated inconsistency and variability in the use of falls risk assessments and prevention programs, which led to the development of standardized, proactive falls prevention process flowcharts. This process, as delineated, provides ALCs with an approach to organize a comprehensive falls reduction strategy. Findings highlight the importance of educating staff regarding assessments, resident motivation, falls prevention programs, and feedback, all key components of the falls prevention process. PMID- 29258375 TI - Motor asymmetry in goats during a stepping task. AB - Behavioural lateralization consists of perceptual and motor lateralization and provides adaptive advantages such as a general increase in brain efficiency. Motor laterality refers to the preferred use of either left or right limbs or organs to perform a specific task. We investigated motor laterality in goats (Capra hircus), using the First-stepping Task. During this task, the first foreleg used to step off a board after standing with both forelimbs was recorded. Subjects varied individually in their expression of motor lateralization with 36.6% of subjects showing individual-level asymmetries. However, goats as a group did not show a preference for a specific foreleg or lateralization in general. Our results support the hypothesis that the need to coordinate behaviour among conspecifics might be important for determining the presence of lateralization at the population level. We suggest that future research investigates how social complexity might affect population-level asymmetries, and whether stimuli with high emotional valence impact on lateralization presence and level (i.e., individual or population). PMID- 29258376 TI - The Consumption of Conventional and Nonconventional Medicines in an Italian Province: The Influence of Sociodemographic Factors and Health Beliefs. AB - Many studies have investigated the factors that influence the consumption of medicines. This article aims to compare how these factors affect both conventional medicines (prescription and over-the-counter (OTC) medicines) and nonconventional ones, also named as complementary and alternative medicines (CAM). A questionnaire was administered to a purposive sample of 4,074 inhabitants of the province of Mantua, Italy. Logical regressions were used to identify the variables influencing frequency of use. The consumption frequency of various types of medicines was associated not only with demographic aspects (such as gender, age, and education level) but also with everyday treatment strategies (such as self-medication habits and use of the Internet for medical aims) and health beliefs. From this last point of view, the use of conventional and nonconventional medicines is guided by 2 principal therapeutic attitudes, one aimed at removing all pathological aspects from everyday life and the other at contextualizing health problems within a broader philosophical search. PMID- 29258377 TI - Clinical Features of Kidney Transplant Recipients Admitted to the Intensive Care Unit. AB - INTRODUCTION: There is a paucity of data regarding the complications in kidney transplant patients who may require intensive care unit (ICU) management, despite being the most common solid organ transplant worldwide. OBJECTIVE: To identify the main reasons for ICU admission and to determine the factors associated with hospital mortality in kidney transplant recipients. DESIGN: This single-center retrospective cohort study was conducted between September 2013 and June 2014, including all consecutive kidney transplant patients requiring ICU admission. We collected data on patient demographics, transplant characteristics, clinical data, and prognostic scores. The independent determinants of hospital mortality were identified by multiple logistic regression analysis. We also assessed the performance of Simplified Acute Physiology Score 3 (SAPS 3) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. RESULTS: We analyzed data from 413 patients, the majority of whom were admitted late after renal transplantation (1169 days; 63-3003 days). The main reason for admission was sepsis (33.2%), followed by cardiovascular disease (16%). Age (odds ratio [OR] 1.05, confidence interval [CI], 1.01-1.09), SAPS 3 score (OR 1.04, CI, 1.01 1.08), the need for mechanical ventilation (OR 26.47, CI, 10.30-68.08), and vasopressor use (OR 3.34, CI, 1.37-8.13) were independently associated with hospital mortality. The performance of SAPS 3 and APACHE II scores was poor in this population and overestimated the mortality rates. CONCLUSION: Sepsis was the main reason for ICU admission in kidney transplant recipients, followed by cardiovascular disease. Age and disease severity were associated with hospital mortality. PMID- 29258378 TI - Hepatorenal syndrome: the clinical impact of vasoactive therapy. AB - INTRODUCTION: Hepatorenal syndrome (HRS) is a unique form of acute kidney injury seen in cirrhotic patients and associated with significant mortality and morbidity. Despite its impact, diagnosis and treatment of HRS remains challenging and this review aims to assess and compare the available vasoconstrictors used as first-line treatment for HRS. Areas covered: A literature review was undertaken on the use of vasoconstrictors in HRS, using PubMed/Medline database searches of: 'hepatorenal syndrome', 'HRS' and 'vasoconstrictor'. Expert commentary: Current diagnosis criteria are based on an exclusion-based approach using serum creatinine as a biomarker. However, this method relies on the measurement over a sustained period of time resulting in delayed treatment. Using urine biomarkers, the revised acute kidney injury guidelines and novel plasma expanders may improve diagnosis and the implementation of time-sensitive management of HRS. Vasoconstrictors are the first-line treatment for HRS, in which terlipressin is the vasoconstrictor of choice supported by current guidelines and a substantial clinical evidence base over other vasoconstrictors, such as noradrenaline or midodrine plus octreotide. Future developments in dosage and administrative techniques for terlipressin may have an important role to play in maintaining clinical efficacy whilst improving tolerability in the management of HRS. PMID- 29258379 TI - Auditory and visual naming tests for children. AB - Assessment of naming in children has been hampered by the use of tests that were developed, either to assess naming in adults or to assess related verbal functions in children. We developed comparable visual naming test (VNT) and auditory description naming (ANT) specifically for children. We collected normative data, not only for accuracy, typically the sole performance measure, but also for response time (RT) and reliance on phonemic cuing. The normative sample consisted of 200 typically developing children, ages 6-15, with 40 children per 2-year age group (6-7, 8-9, 10-11, 12-13, and 14-15). Children were tested individually by a trained examiner. Based on item analysis, naming tests were finalized at 36 items for ages 8-15 and 28 items for ages 6-7. Age stratified normative data are provided for accuracy, mean RT, tip-of-the-tongues (i.e., delayed but accurate responses plus items named following phonemic cueing), and a summary score, which incorporates all performance measures. Internal and test-retest reliability coefficients for both tests were reasonable. Accuracy scores were high across age groups, indicating that item names were within the mental lexicon of most typically developing children. By contrast, time and cue-based scores improved with age, reflecting greater efficiency in word retrieval with development. These complementary auditory naming and visual naming tests for children address a longstanding clinical need, improving upon the current standard with respect to the sensitivity of performance measures and the addition of an auditory verbal component to the assessment of naming in children. PMID- 29258380 TI - Multimycotoxin and fungal analysis of maize grains from south and southwestern Ethiopia. AB - The natural occurrence of fungi, mycotoxins and fungal metabolites was investigated in 100 samples of maize grains collected from south and southwestern Ethiopia in 2015. The maize samples were contaminated by Fusarium, Aspergillus and Penicillium species. Using liquid chromatography tandem mass spectrometry 127 secondary metabolites were analysed. Zearalenone was the most prevalent mycotoxin, occurring in about 96% of the samples. Zearalenone sulfate was the second most prevalent, present in 81% of the samples. Fumonisin B1 was detected in 70% of the samples with a mean level of 606 MUg kg-1 in positive samples, while FB2, FB3 and FB4 were detected in 62%, 51% and 60% of the maize samples with mean levels of 202, 136 and 85 MUg kg-1, respectively. Up to 8% of the samples were contaminated with aflatoxins, with a maximum level of aflatoxin B1 of 513 MUg kg-1. Results were higher than earlier reports for maize from Ethiopia. PMID- 29258381 TI - Diagnostic accuracy of the Montgomery-Asberg Depression Rating Scale parent report among adolescent psychiatric outpatients. AB - BACKGROUND: The diagnostic accuracy of the parent report of the Montgomery-Asberg Depression Rating Scale (MADRS-P) for the screening of major depressive disorder (MDD) in adolescents has not been evaluated. AIM: The aim was to explore the psychometric properties and diagnostic accuracy of the MADRS-P in general child and adolescent psychiatric outpatient services in Sweden. METHOD: The study was a validation and a diagnostic accuracy study. Consecutive adolescent psychiatric patients (n = 101, 45 males, mean age 15 years) were assessed with a diagnostic interview, the Kiddie Schedule of Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime version (K-SADS-PL), as a reference test. Thereafter, their parents reported on the MADRS-P. Both categorical MDD diagnoses and dimensional MDD symptom severity scores were obtained from the K SADS-PL. RESULTS: The internal consistency of the MADRS-P, measured with Cronbach's alpha, was 0.846. The concurrent validity, assessed by Spearman's rho as a correlation between the K-SADS MDD symptom severity score and the MADRS-P score, was 0.580. The area under the curve in a receiver operating characteristic analysis for all participants was 0.786 (95% confidence interval 0.694-0.877, p < .001). At a cut-off of 10, sensitivity was 0.86, specificity 0.54, positive predictive value 0.59 and negative predictive value 0.84. CONCLUSIONS: The parent rated MADRS-P showed similar psychometric properties as previously shown for the self-rated MADRS-S in adults. Although the MADRS-P has acceptable diagnostic accuracy for screening for MDD in adolescents in a general psychiatric setting, it cannot be used alone for diagnosing MDD. PMID- 29258382 TI - Efficacy of a Home-Based Exercise Program After Thyroidectomy for Thyroid Cancer Patients. AB - BACKGROUND: The objective of this study was to determine the effect of a home based exercise program on fatigue, anxiety, quality of life (QoL), and immune function of thyroid cancer patients taking thyroid hormone replacement after thyroidectomy. METHOD: This quasi-experimental study with a non-equivalent control group included 43 outpatients taking thyroid hormone replacement after thyroidectomy (22 in the experimental group and 21 in the control group). After education about the home-based exercise program, subjects in the experimental group underwent 12 weeks of aerobic, resistance, and flexibility exercise. A comparative analysis was conducted between the two groups. RESULTS: Patients in the experimental group were significantly less fatigued or anxious (p < 0.01). They reported significantly improved QoL (p < 0.05) compared to those in the control group. Natural killer cell activity was significantly higher in the exercise group compared to that in the control group (p < 0.05). CONCLUSION: A home-based exercise program is effective in reducing fatigue and anxiety, improving QoL, and increasing immune function in patients taking thyroid hormone replacement after thyroidectomy. Therefore, such a home-based exercise program can be used as an intervention for patients who are taking thyroid hormone replacement after thyroidectomy. PMID- 29258383 TI - The Use of a Shared Services Model for Mycobacteriology Testing: Lessons Learned. AB - OBJECTIVES: Public health laboratories (PHLs) provide essential services in the diagnosis and surveillance of diseases of public health concern, such as tuberculosis. Maintaining access to high-quality laboratory testing is critical to continued disease detection and decline of tuberculosis cases in the United States. We investigated the practical experience of sharing tuberculosis testing services between PHLs through the Shared Services Project. METHODS: The Shared Services Project was a 9-month-long project funded through the Association of Public Health Laboratories and the Centers for Disease Control and Prevention during 2012-2013 as a one-time funding opportunity to consortiums of PHLs that proposed collaborative approaches to sharing tuberculosis laboratory services. Submitting PHLs maintained testing while simultaneously sending specimens to reference laboratories to compare turnaround times. RESULTS: During the 9-month project period, 107 Mycobacterium tuberculosis complex submissions for growth based drug susceptibility testing and molecular detection of drug resistance testing occurred among the 3 consortiums. The median transit time for all submissions was 1.0 day. Overall, median drug susceptibility testing turnaround time (date of receipt in submitting laboratory to result) for parallel testing performed in house by submitting laboratories was 31.0 days; it was 43.0 days for reference laboratories. The median turnaround time for molecular detection of drug resistance results was 1.0 day (mean = 2.8; range, 0-14) from specimen receipt at the reference laboratories. CONCLUSIONS: The shared services model holds promise for specialized tuberculosis testing. Sharing of services requires a balance among quality, timeliness, efficiency, communication, and fiscal costs. PMID- 29258384 TI - Long-term survival after multimodality therapy including surgery for metastatic esophageal cancer. AB - BACKGROUND AND OBJECTIVES: Esophageal cancer (EC) remains an aggressive disease with a poor survival. Management of metastatic EC is limited to palliative chemotherapy (CT). Scientific contributions regarding the role of surgery are scarce and controversial. We analysed outcome of surgically treated metastatic EC patients. METHODS: We retrospectively identified surgically treated metastatic EC patients from our esophagectomy database. The aim of this study was to evaluate surgical complications, pathological response, oncological outcome and mean survival of these aggressively treated stage IV cancer patients. RESULTS: Twelve stage IV patients with disease presentation limited to outfield lymph node (LN) and/or liver metastasis were treated with an aggressive multimodality treatment including surgery. Mean age was 58 years (75% male, 75% Adenocarcinomas). Median postoperative hospital stay was 15 d. Radiological anastomotic leakage occurred in one patient. In hospital, mortality was nil. Complete resection was achieved in all but one. Metastatic recurrence occurred in 64% of R0 resected patients. At date of censoring, after a median follow-up of 22 months, 50% of the surgical resected patients are still alive and 33% are free of disease recurrence. Kaplan Meier curves show a possibility to long-term survival after aggressive multimodality therapy including surgery. CONCLUSIONS: In selected metastatic EC patients, multimodality treatment including surgery has an acceptable surgical outcome with a potentially long-term survival. PMID- 29258385 TI - A comparison of treatment results of the different treatment protocols in patients with poor ovarian response. AB - To compare the effect of the different protocols in patients receiving in vitro fertilization treatment due to poor ovarian response. Seventy-seven of the patients included in the study were treated with gonadotropin (450 IU) + GnRH antagonist (group 1), 84 of the patients were treated with gonadotropin (450 IU) + microdose GnRH analog (group 2), and 53 of the patients were treated with clomiphene citrate (100 mg/day) + gonadotropin (300 IU) + GnRH antagonist (Group 3). In assessing total gonadotropin dosage, patients in Group 3 detected significantly less gonadotropin as compared to the other two groups (p < .001). Group 1 were superior to the other two groups with respect to retrieved oocytes, meiosis II oocytes and number of embryos obtained at the end of the treatment. As for the evaluation of clinical pregnancy, although the highest pregnancy rate was in Group 3, this finding was not of statistical significance. Although increasing the dosage of gonadotropins for ovarian hyper stimulation treatment in patients with poor ovarian response is beneficial with respect to retrieved oocytes, meiosis II oocytes and number of embryos, the increased dosage does not provide a statistically significant increase in clinical pregnancy rates. PMID- 29258386 TI - Impact of Urgent Chemotherapy in Critically Ill Patients. AB - OBJECTIVE: Compare the mortality between critically ill patients who received urgent chemotherapy for a cancer-related life-threatening complication with matched patients (controls) who did not received it. DESIGN: Propensity score matched retrospective study. SETTING: Adult intensive care unit in an oncological hospital. PARTICIPANTS: All adults with solid tumor or hematological malignancies who received at least 1 day of urgent intravenous chemotherapy for a cancer related life-threatening complication. Using the propensity score method adjusted for 10 variables, patients who received urgent chemotherapy were matched to patients who did not. INTERVENTIONS: None. MAIN OUTCOMES MEASURES: Intensive care unit and hospital mortality. RESULTS: Forty-seven patients (57% with solid tumors and 43% with hematological malignancies) who received urgent chemotherapy were matched to 94 controls. At intensive care unit admission, patients were similar except that those who received urgent chemotherapy were less likely to have received chemotherapy previously (36% vs 85%; P < .01). The intensive care unit (48.9% vs 23.4%; P < .01) and hospital (76.6% vs 46.8%; P < .01) mortality of the patients who received urgent chemotherapy was higher than the controls. The subgroup analysis showed that the higher mortality was limited to patients with solid tumor. CONCLUSION: The use of urgent chemotherapy is associated with an increase in the intensive care unit and hospital mortality of unselected critically ill patients with solid tumors but not in patients with hematological malignancies. PMID- 29258387 TI - Microfluidic Encapsulation Supports Stem Cell Viability, Proliferation, and Neuronal Differentiation. AB - Stem cell encapsulation technology demonstrates much promise for the replacement of damaged tissue in several diseases, including spinal cord injury (SCI). The use of biocompatible microcapsules permits the control of stem cell fate in situ to facilitate the replacement of damaged/lost tissue. In this work, a novel customized microfluidic device was developed for the reproducible encapsulation of neural stem cells (NSCs) and dental pulp stem cells (DPSCs) within monodisperse, alginate-collagen microcapsules. Both cell types survived within the microcapsules for up to 21 days in culture. Stem cells demonstrated retention of their multipotency and neuronal differentiation properties upon selective release from the microcapsules, as demonstrated by high proliferation rates and the production of stem cell and neuronal lineage markers. When cell-laden microcapsules were transplanted into an organotypic SCI model, the microcapsules effectively retained the transplanted stem cells at the site of implantation. Implanted cells survived over a 10 day period in culture after transplantation and demonstrated commitment to a neural lineage. Our device provides a quick, effective, and aseptic method for the encapsulation of two different stem cell types (DPSCs and NSCs) within alginate-collagen microcapsules. Since stem cells were able to retain their viability and neural differentiation capacity within such microcapsules, this method provides a useful technique to study stem cell behavior within three-dimensional environments. PMID- 29258388 TI - Making a Case for Formal School-Based Oral Health Promotion: Oral Health Knowledge, Attitude and Practices of Pupils in Ibadan, Nigeria. AB - Background Providing evidence for institution of school-based oral health promotion programs is paramount in developing countries, due to increasing unmet dental needs impacting on quality of life of children. Aim To evaluate oral health knowledge, attitude and practices (KAP) of pupils in a country lacking formal school oral health promotion. Methods A cross-sectional study was conducted among 1,297 pupils in randomly selected primary schools in one city. Information on oral health KAP were obtained using interviewer-administered questionnaire. Responses to questions were graded, standardized, and data analyzed using SPSS. Results The mean age was 10.6 (+/-1.7) years. Mean KAP percentage scores were 18.1 (+/-5.0)%, 18.3 (+/-4.9)%, and 17.3 (+/-12.8)%, respectively. Older age, male gender, and previous dental consultations were significantly associated with higher KAP scores. Those who had been educated informally about oral health had higher mean KAP scores ( p = .013, p < .001, and p < .001, respectively). Previous oral health education and consultation with dentists were significant predictors of higher oral health practice scores. Conclusion Poor oral health KAP exists among the pupils. Those who had consulted the dentist or had oral health education had better KAP. These findings reinforce the need for formal school-based oral health promotion. PMID- 29258389 TI - Training Teachers to Teach Epidemiology in Middle and High Schools. AB - Objective The purpose of this study was to evaluate the outcomes of a workshop which was designed to prepare teachers to teach epidemiology to middle and high school students. Methods The workshop introduced the fundamental enduring understandings of epidemiology as well as a pedagogical framework for teaching it. Using an online questionnaire and telephone interviews, we assessed post workshop outcomes. Results The majority (80%) of workshop alumni had taught epidemiology with the most common approach (52%) being the inclusion of epidemiologic concepts into other courses. Teachers felt that learning epidemiology was a valuable experience for their students and reported that students found it engaging and relevant to their lives. Conclusions These preliminary findings suggest that there may be benefit to teaching epidemiology in middle and high schools. Further research should directly evaluate public health-related outcomes among students, such as improvements in health literacy and health behavior. PMID- 29258390 TI - Knowledge and Attitudes of Jordanian University Students Toward Epilepsy: A Cross Sectional Comparison Study. AB - People with epilepsy face stigma which arguably causes more suffering than the disease itself. The purpose of this study is to compare the knowledge and attitudes of nursing with nonnursing Jordanian university students toward epilepsy. A cross-sectional comparative, quantitative study was conducted. A newly structured questionnaire was developed to collect related data. The results revealed that there were 145(30.5%) nursing students and 331 (69.5%) nonnursing students with mean age of the participants was 22.9 years ( SD = 4.7) and 60% of them were men. Although the majority of the Jordanian university students were aware of epilepsy, their knowledge varied according to their major subject of study. Nursing students possessed a good knowledge of, and more positive attitudes toward, epilepsy compared with other nonnursing students. Therefore, universities are required to improve the knowledge of their students about epilepsy by integrating education about health and first aid course into their curriculum. PMID- 29258391 TI - Trends and Patterns of Corticosteroid Use During Coronary Artery Bypass Grafting Surgery in the United States. AB - BACKGROUND: Several clinical trials have documented clinical benefits associated with prophylactic corticosteroid administration at the time of coronary artery bypass graft (CABG) surgery, including a reduction in the risk of atrial fibrillation and hospital length of stay. Despite the published data, the extent to which providers have adopted the perioperative use of corticosteroids remains unknown. OBJECTIVES: To assess temporal trends, between-hospital variation, and determinants of perioperative intravenous corticosteroid use during CABG surgery. METHODS: We identified all patients admitted for CABG surgery in the Premier Healthcare Database (2003-2014), a large US-based inpatient database. We determined the proportion of patients administered prophylactic corticosteroids on the day of CABG surgery. Linear time-series models were used to estimate the rate and trend of corticosteroid use over time. Separate multivariable generalized estimating equation models were used to quantify the variation in and determinants of perioperative corticosteroid use. RESULTS: Of 401 788 eligible patients who underwent a CABG surgery between 2003 and 2014, 20% (n = 80 681) were administered intravenous prophylactic perioperative corticosteroids (methylprednisolone, dexamethasone, or hydrocortisone). Corticosteroid use increased from 17.5% in 2003 to 22.6% in 2014 (annual rate = 0.42%; P < .001). Individual hospitals accounted for >50% of variation in corticosteroid use. High between-hospital variation was also observed, and the probability of utilization was >=32.4% in the upper versus <=3.4% in the bottom quartiles of hospitals. CONCLUSION: Prophylactic corticosteroid administration during CABG has increased gradually since 2003. To further evaluate the risk-benefit trade-off associated with their use, we believe a large-scale outcomes study is warranted to assess this highly variable practice. PMID- 29258392 TI - Validation of a Patient-Completed Caprini Risk Assessment Tool for Spanish, Arabic, and Polish Speakers. AB - Targeted prophylaxis for venous thromboembolism (VTE) using the Caprini risk score (CRS) is effective reducing postoperative VTE. Despite its availability as preventive strategy, risk scoring remains underutilized. Critics to the CRS contend the time it takes to complete, and its limitation to English language. Aim is to create and validate patient-completed CRS tools for Spanish, Arabic, and Polish speakers. We translated the first patient-completed CRS to Spanish, Arabic, and Polish. We conducted a pilot study followed by the validation study. Using PASS version 11, we determined that a sample size of 37 achieved a power of 80%, to detect a difference of 0.1 between the null hypothesis correlation of 0.5 and the alternative hypothesis correlation of 0.7 using a 2-sided hypothesis test, significance level of .05. We tabulated and categorized scores using SPSS version 23 to estimate kappa, linear correlation, and Bland Altman test. kappa value >0.8 was defined as "almost perfect agreement." From 129 recruited patients, 50 (39%) spoke Spanish, 40 (31%) spoke Arabic, and 39 (30%) spoke Polish; average age 51 (16.69) years, 58 (45%) were men, with less than college education (67%). Mean (standard deviation) CRS was 5 (3.90), the majority (63%) above moderate VTE risk. We report excellent agreement comparing physician and patient results (kappa = 0.93) and high correlation 0.97 ( P < .01) for the overall score. Bland Altman did not show trend for extreme values. We created and validated the first Spanish, Arabic, and Polish versions of the patient-completed CRS, with excellent correlation and agreement when compared to CRS-trained physician-completed form. Based on these results, the physician needs to calculate the body mass index. Completing the form was not time-consuming. PMID- 29258393 TI - Postoperative Changes in the Systemic Inflammatory Milieu in Older Surgical Patients. AB - Dysregulated inflammation is a central component of wound healing following surgery. We prospectively enrolled older patients (n = 25, age 65 +/- 7 years) undergoing elective total knee arthroplasty or total hip arthroplasty secondary to advanced osteoarthritis (OA) and healthy controls (n = 48). Inflammatory, proangiogenic (vascular endothelial growth factor [VEGF], monocyte chemoattractant protein-1 [MCP-1], and interleukin-8 [IL-8]), and antiangiogenic (interferon gamma [IFN-gamma] and IL-4) factors were measured using a high sensitivity biochip. Patients with OA had significantly higher baseline VEGF (10.5 +/- 1.2 pg/mL vs 4.8 +/- 0.2 pg/mL, P < .001), MCP-1 (130.6 +/- 7.7 pg/mL vs 88.6 +/- 3.9 pg/mL, P < .0001), and IL-8 (4.0 +/- 0.5 pg/mL vs 2.6 +/- 0.1 pg/mL, P < .05). Postoperatively, the levels of VEGF (10.5 +/- 1.2 pg/mL vs 18.8 +/- 1.5 pg/mL, P < .001) and MCP-1 (130.6 +/- 7.7 pg/mL vs 153.1 +/- 11.5 pg/mL, P < .05) increased significantly. Baseline and postoperative MCP-1 levels correlated positively and significantly with age. The levels of IFN-gamma and IL 4 (which has anti-inflammatory properties) did not significantly differ at baseline in patients with OA compared to controls and did not significantly rise postoperatively. We conclude that systemic levels of pro-inflammatory and angiogenic proteins are increased in patients with OA and rise further postoperatively, while proteins that restrain inflammation and angiogenesis do not coordinately rise. These findings implicate imbalance in inflammatory pathways in OA that may contribute to its pathobiology. PMID- 29258394 TI - Quality of Anticoagulation With Warfarin at a Tertiary Hospital in Botswana. AB - Warfarin treatment requires regular and proper monitoring to avoid overanticoagulation and at the same time to prevent thromboembolic complications. This study assessed the quality of warfarin anticoagulation at Princess Marina Hospital in Botswana. This cross-sectional study consecutively enrolled patients who were on warfarin for at least 3 months in the outpatient medical clinic. The level of anticoagulation was determined by the time in therapeutic range (TTR) using the Rosendaal method that calculates the percentage of days when the international normalized ratio is in the therapeutic range (2.0-3.0). Poor anticoagulation control was defined as an estimated TTR <65%. We performed univariate and multivariate logistic regression to assess predictors of poor anticoagulation control. Of total, 410 (68.8% women) patients whose median age was 46 (interquartile range [IQR], 35-58) years were enrolled. Indications for warfarin included mechanical heart valves, 185 (45.1%); deep vein thrombosis, 114 (26.8%); and atrial fibrillation, 68 (17.8%). Of the 2004 tests (an average of 4.9 tests per patient) assessed, only 20% of the tests were within the therapeutic range. The median TTR was 30.8% (IQR, 15.2-52.7). Most (85.1%) patients had poor anticoagulation control. Cigarette smoking and pulmonary hypertension perfectly predicted poor anticoagulation. Hypertension was a predictor of poor anticoagulation control (adjusted odds ratio = 2.24; 95% confidence interval: 1.02-4.94). The quality of anticoagulant therapy with warfarin in Botswana patients is poor. The evidence calls for efforts to improve the level of anticoagulation control among patients on warfarin in Botswana. PMID- 29258395 TI - The third (III) road to cell transformation. PMID- 29258396 TI - The relationship of categorical and phonological verbal fluency to negative schizotypy and social functioning in a non-clinical sample. AB - INTRODUCTION: Research suggests that levels of schizotypy are related to cognitive and social functioning, with negative schizotypy being particularly related to deficits in verbal fluency (VF) and distinct social skills. Considering the possibility that different VF tasks may involve both shared and unique underlying processes, this study sought to examine the separate contributions of categorical and phonological forms of VF to social functioning in those with varying levels of negative schizotypy. METHODS: Face-to-face interviews were conducted in which 228 college students completed VF tasks, the SPQ-BR, and a social functioning questionnaire. RESULTS: Both phonological and categorical VF were inversely related to levels of negative schizotypy and inversely related to several social functioning domains. High and low levels of negative schizotypy groups were significantly different on elements of social engagement and interpersonal behaviour. In two instances, phonological VF appeared to moderate the relationships between negative schizotypy and specific elements of social functioning. CONCLUSIONS: These findings support a general link between verbal processing and social functioning among those with greater negative schizotypy. Possible avenues of future research are discussed. PMID- 29258398 TI - Pilot Study of Metabolomics and Psychoneurological Symptoms in Women With Early Stage Breast Cancer. AB - : Many women with breast cancer experience symptoms of pain, fatigue, and depression, collectively known as psychoneurologic (PN) symptoms, during and after chemotherapy treatment. Evidence that inflammatory dysfunction related to cancer and its treatments contributes to the development and persistence of PN symptoms through several interrelated pathways is accumulating. However, a major limiting factor in more precisely identifying the biological mechanisms underlying these symptoms is the lack of biological measures that represent a holistic spectrum of biological responses. Metabolomics allows for examination of multiple, co-occurring metabolic pathways and provides a systems-level perspective on biological mechanisms that may contribute to PN symptoms. METHODS: In this pilot study, we performed serum metabolome analysis using liquid chromatography high-resolution mass spectrometry of global and targeted metabolomics from the tryptophan pathway from archived samples from 19 women with early-stage breast cancer. We used paired t tests to compare metabolite concentrations and Pearson's correlation coefficients to examine concomitant changes in metabolite concentrations and PN symptoms before and after chemotherapy. RESULTS: Levels of pain, fatigue, and depression increased after chemotherapy. Compared with pre-chemotherapy, global metabolites post chemotherapy were characterized by higher concentrations of acetyl-l-alanine and indoxyl sulfate and lower levels of 5-oxo-l-proline. Targeted analysis indicated significantly higher kynurenine levels and kynurenine/tryptophan ratios post chemotherapy. Symptoms of pain and fatigue had strong associations with multiple global and several targeted metabolites. CONCLUSION: Results demonstrated that metabolomics may be useful for elucidating biological mechanisms associated with the development and severity of PN symptoms, specifically pain and fatigue, in women with early-stage breast cancer. PMID- 29258399 TI - Perceived Racial Discrimination and DNA Methylation Among African American Women in the InterGEN Study. AB - INTRODUCTION: Experiences of racial discrimination have been associated with poor health outcomes. Little is known, however, about how perceived racial discrimination influences DNA methylation (DNAm) among African Americans (AAs). We examined the association of experiences of discrimination with DNAm among AA women in the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) study. METHODS: The InterGEN study examines the effects of genetic and psychological factors on blood pressure among AA women and their children. Measures include the Major Life Discrimination (MLD) and the Race Related Events (RES) scales. In the present analysis, we examined discrimination and DNAm at baseline in the InterGEN study. The 850K EPIC Illumina BeadChip was used for evaluating DNAm in this epigenome-wide association study (EWAS). RESULTS: One hundred and fifty-two women contributed data for the RES-EWAS analysis and 147 for the MLD-EWAS analysis. Most were 30-39 years old, nonsmokers, had some college education, and had incomes =70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged >=70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010). PMID- 29258403 TI - A novel augmented venous-drainage model of cardiopulmonary bypass for deep hypothermic circulatory arrest without blood priming. AB - OBJECTIVE: Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are commonly used in cardiac surgery. However, the mortality and morbidity are still high in practice. Developing novel protective stategies and elucidating the underlying mechanisms for the pathophysiological consequences of DHCA have been hampered because of the absence of a satisfactory recovery animal model. The aim of this study was to establish a novel and safe DHCA model without blood priming in rats to study the pathophysiology of potential complications. METHODS: Ten adult male Sprague-Dawley rats (age, 14-16 weeks; weight, 200-300g) were used. The entire CPB circuit consisted of a modified reservoir, a custom-designed small-volume membrane oxygenator, a roller pump and a home-made heat exchanger, all of which were connected via silicon tubing. The volume of the priming solution was less than 10 ml. The right jugular vein, right carotid artery and left femoral artery were cannulated. The blood was drained from the right atrium through the right jugular vein and fed back to the rat via the left femoral artery. CPB was commenced at a full flow rate. The animals were cooled to a pericranial temperature of 18 degrees C and then subjected to 45 minutes of DHCA with global ischemia. Circulatory arrest was followed by rewarming and over 60 minutes of reperfusion. CPB was terminated carefully. Blood in the circuit was centrifuged and slowly transfused to achieve optimal hematocrit. Blood gas and hemodynamic parameters were recorded at each time point before CPB, during CPB and after CPB. RESULTS: All CPB and DHCA processes were achieved successfully. No rat died in our research. Blood gas analyses at different times were normal. Cardiac function and blood pressure were stable after the operation. The vital signs of all the rats were stable. CONCLUSION: The novel augmented venous drainage CPB and DHCA model in rats could be established successfully without blood priming. PMID- 29258404 TI - XEN Gel Implant: a new surgical approach in glaucoma. AB - INTRODUCTION: Glaucoma is a leading cause of blindness worldwide. Intraocular pressure (IOP) lowering is the only effective treatment strategy. Traditional glaucoma surgeries are generally considered to be unpredictable and associated with a high rate of complications. This has led to the development of a novel XEN Gel Implant, a type of minimally invasive glaucoma surgery (MIGS), lowering the IOP without extensive surgical dissection. Areas covered: A literature search was undertaken on PubMed using the terms XEN glaucoma, gelatin microstent, and MIGS. All the articles and case reports on XEN Gel Implant and selected articles on MIGS were studied and reviewed. We have discussed the results of most studies on XEN Gel Implant related to its efficacy, safety and success. Expert commentary: The XEN Gel Implant effectively lowers IOP and medication use, with a favorable safety profile. Long-term data on its success and cost-effectiveness are lacking. The studies have shown it to be without any serious adverse events and to have good safety profile encouraging future research on this novel implant. There is a need to correctly identify selection criteria for patients, who would benefit the most from the XEN Gel Implant. PMID- 29258405 TI - Evaluation of liver function by means of serum cytokeratin 18 and hepatocyte growth factor levels in patients with obstructive jaundice. AB - OBJECTIVE: To evaluate the serum levels of cytokeratin 18 (CK18) and hepatocyte growth factor (HGF) in obstructive jaundice patients before and after treatment and thereby to detect the possible role of CK18 and HGF in patients with obstructive jaundice. PATIENTS AND METHODS: Forty patients who had obstructive jaundice and 40 healthy control subjects were included in the study. Patients were treated using percutaneous, endoscopic or surgical approaches. Blood samples were obtained at the day before and 7 days after the intervention for obstructive jaundice. Serum HGF and CK18 concentrations were determined by ELISA method. RESULTS: There were statistically significant decreases in HGF, CK18, total bilirubin and direct bilirubin serum levels, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase activities and white blood cell count when compared with pre-treatment levels. CONCLUSION: Evaluating pre- and post-treatment serum HGF and CK18 levels suggested that there was an apoptosis in obstructive jaundice patients and this apoptosis decreased after the decompression of the biliary tract. We also demonstrated that HGF levels were altered at biliary obstruction compared to healthy controls and the levels of this biomarker also decreased after decompression of biliary obstruction. We concluded that these biomarkers can be used as predictors of liver injury in biliary obstruction. PMID- 29258406 TI - A contemporary look at FVIII inhibitor development: still a great influence on the evolution of hemophilia therapies. AB - INTRODUCTION: The development of inhibitors against factor VIII (FVIII) replacement therapy remains the most important challenge for clinicians in the treatment of hemophilia patients. This review focusses on risk factors and management of FVIII inhibitors, particularly in light of SIPPET study findings and subsequent analyses. Areas covered: A brief history and evolution of hemophilia therapies is provided, including an overview of conventional and new (including investigational) therapeutic approaches for the treatment of hemophilia. The SIPPET study, the first randomized clinical trial to demonstrate a lower incidence of inhibitors in previously untreated patients treated with plasma-derived FVIII products compared with recombinant FVIII products, has generated much debate. We review the SIPPET trial and reactions, in addition to preliminary observations from a single center's experience, the cost impact of inhibitors, recent findings from SIPPET subanalyses, and inhibitor development in previously-treated patients. Expert commentary: Despite recent advances in potential new treatment options for hemophilia, conventional factor replacement concentrates currently remain the cornerstone of treatment. It is paramount that clinicians familiarize themselves with the findings from the SIPPET trial and substudies, in order to better inform their patients and families on inhibitor risk factors and to aid the treatment decision-making process. PMID- 29258408 TI - Healthcare access for deaf patients - The legal and ethical perspectives. AB - Deaf patients are too often overlooked in our society despite requiring in-depth attention to their specific communication needs. If they are not able to communicate with healthcare professionals, they may be unable to access and receive appropriate care. Yet, medical providers who fail to address patients' linguistic difficulties breach their ethical and professional duties, and face potential malpractice lawsuits. This article aims to highlight the unequal access of medical care by deaf patients and the impact of language barriers. It also provides an overview of medical providers' ethical and legal duties to assist people with hearing disabilities and discusses the benefits of using professional interpreting services and offers recommendations to address the ethical and legal issues faced by medical professionals. PMID- 29258410 TI - Different cortical source activation patterns in children with attention deficit hyperactivity disorder during a time reproduction task. AB - Several neurocognitive studies have indicated that children with attention deficit/hyperactivity disorder (ADHD) exhibit cognitive deficits in perceptual timing functions; however, only a few electroencephalographic studies have investigated their time reproduction abilities. In the present research, 15 children with ADHD were studied along with 19 age-matched control subjects (aged 7-11 years) as they attempted to reproduce shorter (1000 ms) and longer (2200 ms) time intervals. Trial-mean event-related potential (ERP) and event-related spectral perturbation measures were used to compare the electroencephalography (EEG) source-level activity patterns of the ADHD and control subjects during the time-encoding and reproduction phases. For both short and long intervals, the performance of subjects with ADHD was significantly less accurate and more variable than that of the age-matched controls. During the encoding phase, the ADHD and control ERPs differed significantly for the midfrontal source cluster. The midfrontal P300 amplitude evoked by the onset of the encoding phase was significantly higher for the ADHD group. Similarly, the amplitude of contingent negative variation for the ADHD group was lower for the midfrontal independent component (IC) cluster during long-interval encoding. Theta event-related synchronization in the right occipital cluster also differed between groups during both the encoding and reproduction phases. Moreover, children with ADHD failed to show a frontal selection positivity component in the reproduction phase. Significant differences were found in the mean alpha power for the prefrontal source cluster during the time reproduction phase. These results suggest electrophysiological evidence for time perception deficiencies, selective visual processing disturbances, and working memory impairment in children with ADHD. PMID- 29258407 TI - Epidemiological patterns of mental disorders and stigma in a community household survey in urban slum and rural settings in Kenya. AB - PURPOSE: This study investigated the epidemiological patterns of mental illness and stigma in community households in Kenya using a cross-sectional community household survey among 846 participants. METHODS: A cross-sectional community household survey was conducted around urban slum (Kangemi) and rural (Kibwezi) selected health facilities in Kenya. All households within the two sites served by the selected health facilities were included in the study. To select the main respondent in the household, the oldest adult who could speak English, Kiswahili or both (the official languages in Kenya) was selected to participate in the interview. The Opinion about Mental Illness in Chinese Community (OMICC) questionnaire and the MINI-International Neuropsychiatric Interview-Plus Version 5 (MINI) tools were administered to the participants. Pearson's chi-square test was used to compare prevalence according to gender, while adjusted regression models examined the association between mental illness and views about mental illness, stratified by gender. RESULTS: The overall prevalence of mental illness was 45%, showing gender differences regarding common types of illness. The opinions about mental illness were similar for men and women, while rural respondents were more positively opinionated than urban participants. Overall, suffering from mental illness was associated with more positive opinions among women and more negative opinions among men. CONCLUSION: More research is needed into the factors explaining the observed differences in opinion about mental illness between the subgroups, and the impact of mental illness on stigma in Kenya in order to create an evidence-based approach against stigma. PMID- 29258409 TI - Effect of DJ-1 Downregulation on the Functions of the First Trimester Extravillous Trophoblasts. AB - DJ-1 ( PARK7) has been reported to be causative gene of Parkinson disease and also an oncogene. A loss in DJ-1 function can lead to cell death in neurodegenerative disease, or a gain of it can cause unregulated cell survival in cancer, respectively. DJ-1 protein is known to be expressed mainly in trophoblastic cells in the placenta with increased expression in the first trimester compared to later in term. However, its role in trophoblast regulation remains unknown. This study aimed to investigate the effect of DJ-1 regulation on a first trimester extravillous trophoblast cell line, HTR-8/SVneo. The effect of DJ-1 downregulation induced by small-interfering RNA on cell apoptosis, migration, and the pathway to regulate the cell function was assessed. Data of this study showed that DJ-1 downregulation increased apoptosis and reduced migration by regulating matrix metalloproteinase 2 and matrix metalloproteinase 9 in HTR-8/SVneo cells under both ambient and oxidative stress. Changes in cell function were demonstrated to be at least partly dependent on the AKT/S6 kinase beta-1 (S6K1) pathway. In summary, DJ-1 might play a protective role in maintaining trophoblastic cell functions through the AKT/S6K1-based pathway. PMID- 29258411 TI - Calreticulin affects hematopoietic stem/progenitor cell fate by impacting erythroid and megakaryocytic differentiation. AB - Calreticulin (CALR) is a chaperone protein that localizes primarily to the endoplasmic reticulum (ER) lumen where it is responsible for the control of proper folding of neo-synthesized glycoproteins and for the retention of calcium. Recently, mutations affecting exon 9 of the CALR gene have been described in approximately 40% of patients with myeloproliferative neoplasms (MPNs). Although the role of mutated CALR in the development of MPNs has begun to be clarified, there are still no data available on the function of wild-type (WT) CALR during physiological hematopoiesis. In order to shed light on the role of WT CALR during normal hematopoiesis, we performed gene silencing and overexpression experiments in Hematopoietic Stem Progenitor Cells (HSPCs). Our results showed that CALR overexpression is able to affect physiological hematopoiesis by enhancing both erythroid and megakaryocytic (MK) differentiation. In agreement with overexpression data, CALR silencing caused a significant decrease in both erythroid and MK differentiation of human HSPCs. Gene expression profiling (GEP) analysis showed that CALR is able to affect the expression of several genes involved in HSPCs differentiation towards both the erythroid and MK lineages. Moreover, GEP data also highlighted the modulation of several genes involved in ER stress response, unfolded protein response (UPR), DNA repair and of several genes already described to play a role in MPN development, such as pro inflammatory cytokines and hematological neoplasms-related markers. Altogether, our data unraveled a new and unexpected role for CALR in the regulation of normal hematopoietic differentiation. Moreover, by showing the impact of CALR on the expression of genes involved in several biological processes already described in cellular transformation, our data strongly suggest a more complex role for CALR in MPN development that goes beyond the activation of the THPO receptor and involves ER stress response, UPR and DNA repair. PMID- 29258412 TI - Association between TNF-a promoter -308G/A polymorphism and essential hypertension in the Asian population: A meta-analysis. AB - OBJECTIVE: The results of studies on the association between tumor necrosis factor-a -308G/A (TNF-a -308G/A) polymorphism, and susceptibility to essential hypertension are controversial. To derive a more precise estimation, we conducted a meta-analysis of all similar articles. METHODS: The summary effect odds ratios and 95% confidence intervals were obtained. Funnel plots and Egger's test were used to estimate publication bias, and heterogeneity was assessed by the chi square-based Q-test and I2 test. RESULTS: Nine studies (with 1437 cases and 1487 controls) were included. In the overall analysis, the combined results showed that there were significant differences in genotype distribution between essential hypertension cases and controls, AA+GA versus GG (OR = 1.53, 95% CI: 1.25-1.88, p < 0.00001). In the stratified analysis by country, we found that essential hypertension cases had a significantly higher frequency of AA+GA versus GG (OR = 1.47, 95% CI: 1.18-1.81, p = 0.0004) than control in the Asian population. CONCLUSIONS: This meta-analysis supports previous findings that TNF-a -308G/A polymorphism may increase the risk of essential hypertension, at least in the Asian population. PMID- 29258414 TI - Preface. PMID- 29258413 TI - From the Masters: What's past is prologue - building a future for vascular medicine. PMID- 29258415 TI - Editorial: Uncontrolled Hypertension and Related Comorbidities: A Clinician's Update. PMID- 29258416 TI - Preface. PMID- 29258417 TI - Editorial: Effects of Extra Virgin Olive Oil on the Immune-mediated Inflammatory Responses: Potential Clinical Applications. PMID- 29258419 TI - HISEA: HIerarchical SEed Aligner for PacBio data. AB - BACKGROUND: The next generation sequencing (NGS) techniques have been around for over a decade. Many of their fundamental applications rely on the ability to compute good genome assemblies. As the technology evolves, the assembly algorithms and tools have to continuously adjust and improve. The currently dominant technology of Illumina produces reads that are too short to bridge many repeats, setting limits on what can be successfully assembled. The emerging SMRT (Single Molecule, Real-Time) sequencing technique from Pacific Biosciences produces uniform coverage and long reads of length up to sixty thousand base pairs, enabling significantly better genome assemblies. However, SMRT reads are much more expensive and have a much higher error rate than Illumina's - around 10 15% - mostly due to indels. New algorithms are very much needed to take advantage of the long reads while mitigating the effect of high error rate and lowering the required coverage. METHODS: An essential step in assembling SMRT data is the detection of alignments, or overlaps, between reads. High error rate and very long reads make this a much more challenging problem than for Illumina data. We present a new pairwise read aligner, or overlapper, HISEA (Hierarchical SEed Aligner) for SMRT sequencing data. HISEA uses a novel two-step k-mer search, employing consistent clustering, k-mer filtering, and read alignment extension. RESULTS: We compare HISEA against several state-of-the-art programs - BLASR, DALIGNER, GraphMap, MHAP, and Minimap - on real datasets from five organisms. We compare their sensitivity, precision, specificity, F1-score, as well as time and memory usage. We also introduce a new, more precise, evaluation method. Finally, we compare the two leading programs, MHAP and HISEA, for their genome assembly performance in the Canu pipeline. DISCUSSION: Our algorithm has the best alignment detection sensitivity among all programs for SMRT data, significantly higher than the current best. The currently best assembler for SMRT data is the Canu program which uses the MHAP aligner in its pipeline. We have incorporated our new HISEA aligner in the Canu pipeline and benchmarked it against the best pipeline for multiple datasets at two relevant coverage levels: 30x and 50x. Our assemblies are better than those using MHAP for both coverage levels. Moreover, Canu+HISEA assemblies for 30x coverage are comparable with Canu+MHAP assemblies for 50x coverage, while being faster and cheaper. CONCLUSIONS: The HISEA algorithm produces alignments with highest sensitivity compared with the current state-of-the-art algorithms. Integrated in the Canu pipeline, currently the best for assembling PacBio data, it produces better assemblies than Canu+MHAP. PMID- 29258418 TI - Ectopically expressing MdPIP1;3, an aquaporin gene, increased fruit size and enhanced drought tolerance of transgenic tomatoes. AB - BACKGROUND: Water deficit severely reduces apple growth and production, is detrimental to fruit quality and size. This problem is exacerbated as global warming is implicated in producing more severe drought stress. Thus water efficiency has becomes the major target for apple breeding. A desired apple tree can absorb and transport water efficiently, which not only confers improved drought tolerance, but also guarantees fruit size for higher income returns. Aquaporins, as water channels, control water transportation across membranes and can regulate water flow by changing their amount and activity. The exploration of molecular mechanism of water efficiency and the gene wealth will pave a way for molecular breeding of drought tolerant apple tree. RESULTS: In the current study, we screened out a drought inducible aquaporin gene MdPIP1;3, which specifically enhanced its expression during fruit expansion in 'Fuji' apple (Malus domestica Borkh. cv. Red Fuji). It localized on plasma membranes and belonged to PIP1 subfamily. The tolerance to drought stress enhanced in transgenic tomato plants ectopically expressing MdPIP1;3, showing that the rate of losing water in isolated transgenic leaves was slower than wild type, and stomata of transgenic plants closed sensitively to respond to drought compared with wild type. Besides, length and diameter of transgenic tomato fruits increased faster than wild type, and in final, fruit sizes and fresh weights of transgenic tomatoes were bigger than wild type. Specially, in cell levels, fruit cell size from transgenic tomatoes was larger than wild type, showing that cell number per mm2 in transgenic fruits was less than wild type. CONCLUSIONS: Altogether, ectopically expressing MdPIP1;3 enhanced drought tolerance of transgenic tomatoes partially via reduced water loss controlled by stomata closure in leaves. In addition, the transgenic tomato fruits are larger and heavier with larger cells via more efficient water transportation across membranes. Our research will contribute to apple production, by engineering apples with big fruits via efficient water transportation when well watered and enhanced drought tolerance in transgenic apples under water deficit. PMID- 29258420 TI - Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy. AB - BACKGROUND: Non-adherence has been associated with reduced graft survival. The aim of this study was to investigate the immunological mechanisms underlying chronic renal allograft rejection using a model of non-adherence to immunosuppressive therapy. We used a MHC (major histocompatibility complex) mismatched rat model of renal transplantation (Brown Norway to Lewis), in which rats received daily oral cyclosporine A. In analogy to non-adherence to therapy, one group received cyclosporine A on alternating days only. Rejection was histologically graded according to the Banff classification. We quantified fibrosis by trichrome staining and intra-graft infiltration of T cells, B cells, and monocytes/macrophages by immunohistochemistry. The distribution of B lymphocytes was assessed using immunofluorescence microscopy. Intra-graft chemokine, chemokine receptor, BAFF (B cell activating factor belonging to the TNF family), and immunoglobulin G transcription levels were analysed by RT-PCR. Finally, we evaluated donor-specific antibodies (DSA) and complement-dependent cytotoxicity using flow cytometry. RESULTS: After 28 days, cellular rejection occurred during non-adherence in 5/6 animals, mixed with humoral rejection in 3/6 animals. After non-adherence, the number of T lymphocytes were elevated compared to daily immunosuppression. Monocyte numbers declined over time. Accordingly, lymphocyte chemokine transcription was significantly increased in the graft, as was the transcription of BAFF, BAFF receptor, and Immunoglobulin G. Donor specific antibodies were elevated in non-adherence, but did not induce complement dependent cytotoxicity. CONCLUSION: Cellular and humoral rejection, lymphocyte infiltration, and de novo DSA are induced in this model of non-adherence. PMID- 29258421 TI - In vivo imaging of epithelial wound healing in the cnidarian Clytia hemisphaerica demonstrates early evolution of purse string and cell crawling closure mechanisms. AB - BACKGROUND: All animals have mechanisms for healing damage to the epithelial sheets that cover the body and line internal cavities. Epithelial wounds heal either by cells crawling over the wound gap, by contraction of a super-cellular actin cable ("purse string") that surrounds the wound, or some combination of the two mechanisms. Both cell crawling and purse string closure of epithelial wounds are widely observed across vertebrates and invertebrates, suggesting early evolution of these mechanisms. Cnidarians evolved ~600 million years ago and are considered a sister group to the Bilateria. They have been much studied for their tremendous regenerative potential, but epithelial wound healing has not been characterized in detail. Conserved elements of wound healing in bilaterians and cnidarians would suggest an evolutionary origin in a common ancestor. Here we test this idea by characterizing epithelial wound healing in live medusae of Clytia hemisphaerica. RESULTS: We identified cell crawling and purse string mediated mechanisms of healing in Clytia epithelium that appear highly analogous of those seen in higher animals, suggesting that these mechanisms may have emerged in a common ancestor. Interestingly, we found that epithelial wound healing in Clytia is 75 to >600 times faster than in cultured cells or embryos of other animals previously studied, suggesting that Clytia may provide valuable clues about optimized healing efficiency. Finally, in Clytia, we show that damage to the basement membrane in a wound gap causes a rapid shift between the cell crawling and purse string mechanisms for wound closure. This is consistent with work in other systems showing that cells marginal to a wound choose between a super-cellular actin cable or lamellipodia formation to close wounds, and suggests a mechanism underlying this decision. CONCLUSIONS: 1. Cell crawling and purse string mechanisms of epithelial wound healing likely evolved before the divergence of Cnidaria from the bilaterian lineage ~ 600mya 2. In Clytia, the choice between cell crawling and purse string mechanisms of wound healing depends on interactions between the epithelial cells and the basement membrane. PMID- 29258422 TI - At the dawn of delegation? Experiences and attitudes of general practitioners in Germany - a questionnaire survey. AB - BACKGROUND: In the future, 'delegation' as task shifting from general practitioners (GPs) to non-physicians will be important in primary care. Therefore, the aim of this study was to evaluate the attitudes towards the concept of task shifting and to identify predictors of a positive attitude towards task shifting from the perspective of GPs. METHODS: This cross-sectional questionnaire study analysed attitudes towards the concept of task shifting and delegated tasks from the perspective of GPs who were recruited in the German federal state of Schleswig-Holstein. Descriptive statistics and binary regression analyses were computed to identify potential predictors of a positive attitude towards task shifting. RESULTS: Out of 1538 questionnaires distributed, 577 GP questionnaires were returned (response rate: 37.5%). A total of 53.2% of the respondents were male, and 37.3% were female. A positive attitude regarding task shifting was shown by 49% of the participating GPs. The highest level of agreement (95.2%) was found for time savings with task shifting, and a lower agreement (39%) was found regarding the lack of clarity concerning the responsibilities and legal aspects with regards to task shifting. The most frequently delegated tasks were recording electrocardiograms and measuring blood glucose levels. A positive attitude towards task shifting was positively associated with higher job satisfaction and a need for qualified staff. CONCLUSION: Our sample of GPs for this study was very open-minded towards the concept of task shifting. Germany is just beginning this delegation, but the implementation of task shifting depends on different aspects, such as legal requirements, adequate payment and qualified staff. Finally, there is a need for continuing professional development in primary care teams, especially for non clinical practice staff. PMID- 29258423 TI - The coding and noncoding transcriptome of Neurospora crassa. AB - BACKGROUND: Long non protein coding RNAs (lncRNAs) have been identified in many different organisms and cell types. Emerging examples emphasize the biological importance of these RNA species but their regulation and functions remain poorly understood. In the filamentous fungus Neurospora crassa, the annotation and characterization of lncRNAs is incomplete. RESULTS: We have performed a comprehensive transcriptome analysis of Neurospora crassa by using ChIP-seq, RNA seq and polysome fractionation datasets. We have annotated and characterized 1478 long intergenic noncoding RNAs (lincRNAs) and 1056 natural antisense transcripts, indicating that 20% of the RNA Polymerase II transcripts of Neurospora are not coding for protein. Both classes of lncRNAs accumulate at lower levels than protein-coding mRNAs and they are considerably shorter. Our analysis showed that the vast majority of lincRNAs and antisense transcripts do not contain introns and carry less H3K4me2 modifications than similarly expressed protein coding genes. In contrast, H3K27me3 modifications inversely correlate with transcription of protein coding and lincRNA genes. We show furthermore most lincRNA sequences evolve rapidly, even between phylogenetically close species. CONCLUSIONS: Our transcriptome analyses revealed distinct features of Neurospora lincRNAs and antisense transcripts in comparison to mRNAs and showed that the prevalence of noncoding transcripts in this organism is higher than previously anticipated. The study provides a broad repertoire and a resource for further studies of lncRNAs. PMID- 29258424 TI - Divergent regulation of Arabidopsis SAUR genes: a focus on the SAUR10-clade. AB - BACKGROUND: Small Auxin-Upregulated RNA (SAUR) genes encode growth regulators that induce cell elongation. Arabidopsis contains more than 70 SAUR genes, of which the growth-promoting function has been unveiled in seedlings, while their role in other tissues remained largely unknown. Here, we focus on the regulatory regions of Arabidopsis SAUR genes, to predict the processes in which they play a role, and understand the dynamics of plant growth. RESULTS: In this study, we characterized in detail the entire SAUR10-clade: SAUR8, SAUR9, SAUR10, SAUR12, SAUR16, SAUR50, SAUR51 and SAUR54. Overexpression analysis revealed that the different proteins fulfil similar functions, while the SAUR expression patterns were highly diverse, showing expression throughout plant development in a variety of tissues. In addition, the response to application of different hormones largely varied between the different genes. These tissue-specific and hormone specific responses could be linked to transcription factor binding sites using in silico analyses. These analyses also supported the existence of two groups of SAURs in Arabidopsis: Class I genes can be induced by combinatorial action of ARF BZR-PIF transcription factors, while Class II genes are not regulated by auxin. CONCLUSIONS: SAUR10-clade genes generally induce cell-elongation, but exhibit diverse expression patterns and responses to hormones. Our experimental and in silico analyses suggest that transcription factors involved in plant development determine the tissue specific expression of the different SAUR genes, whereas the amplitude of this expression can often be controlled by hormone response transcription factors. This allows the plant to fine tune growth in a variety of tissues in response to internal and external signals. PMID- 29258426 TI - Inferring defense-related gene families in Arabidopsis and wheat. AB - BACKGROUND: A large number of disease resistance genes or QTLs in crop plants are identified through conventional genetics and genomic tools, but their functional or molecular characterization remains costly, labor-intensive and inaccurate largely due to the lack of deep sequencing of large and complex genomes of many important crops such as allohexaploid wheat (Triticum aestivum L.). On the other hand, gene annotation and relevant genomic resources for disease resistance and other defense-related traits are more abundant in model plant Arabidopsis (Arabidopsis thaliana). The objectives of this study are (i) to infer homology of defense-related genes in Arabidopsis and wheat and (ii) to classify these homologous genes into different gene families. RESULTS: We employed three bioinformatics and genomics approaches to identifying candidate genes known to affect plant defense and to classifying these protein-coding genes into different gene families in Arabidopsis. These approaches predicted up to 1790 candidate genes in 11 gene families for Arabidopsis defense to biotic stresses. The 11 gene families included ABC, NLR and START, the three families that are already known to confer rust resistance in wheat, and eight new families. The distributions of predicted SNPs for individual rust resistance genes were highly skewed towards specific gene families, including eight one-to-one uniquely matched pairs: Lr21 NLR, Lr34-ABC, Lr37-START, Sr2-Cupin, Yr24-Transcription factor, Yr26 Transporter, Yr36-Kinase and Yr53-Kinase. Two of these pairs, Lr21-NLR and Lr34 ABC, are expected because Lr21 and Lr34 are well known to confer race-specific and race-nonspecific resistance to leaf rust (Puccinia triticina) and they encode NLR and ABC proteins. CONCLUSIONS: Our inference of 11 known and new gene families enhances current understanding of functional diversity with defense related genes in genomes of model plant Arabidopsis and cereal crop wheat. Our comparative genomic analysis of Arabidopsis and wheat genomes is complementary to the conventional map-based or marker-based approaches for identification of genes or QTLs for rust resistance genes in wheat and other cereals. Race-specific and race-nonspecific candidate genes predicted by our study may be further tested and combined in breeding for durable resistance to wheat rusts and other pathogens. PMID- 29258425 TI - From ground pools to treeholes: convergent evolution of habitat and phenotype in Aedes mosquitoes. AB - BACKGROUND: Invasive mosquito species are responsible for millions of vector borne disease cases annually. The global invasive success of Aedes mosquitoes such as Aedes aegypti and Aedes albopictus has relied on the human transport of immature stages in container habitats. However, despite the importance of these mosquitoes and this ecological specialization to their widespread dispersal, evolution of habitat specialization in this group has remained largely unstudied. We use comparative methods to evaluate the evolution of habitat specialization and its potential influence on larval morphology, and evaluate whether container dwelling and invasiveness are monophyletic in Aedes. RESULTS: We show that habitat specialization has evolved repeatedly from ancestral ground pool usage to specialization in container habitats. Furthermore, we find that larval morphological scores are significantly associated with larval habitat when accounting for evolutionary relationships. We find that Ornstein-Uhleinbeck models with unique optima for each larval habitat type are preferred over several other models based predominantly on neutral processes, and that OU models can reliably simulate real morphological data. CONCLUSIONS: Our results demonstrate that multiple lineages of Aedes have convergently evolved a key trait associated with invasive success: the use of container habitats for immature stages. Moreover, our results demonstrate convergence in morphological characteristics as well, and suggest a role of adaptation to habitat specialization in driving phenotypic diversity in this mosquito lineage. Finally, our results highlight that the genus Aedes is not monophyletic. PMID- 29258428 TI - Tweedie distributions for fitting semicontinuous health care utilization cost data. AB - BACKGROUND: The statistical analysis of health care cost data is often problematic because these data are usually non-negative, right-skewed and have excess zeros for non-users. This prevents the use of linear models based on the Gaussian or Gamma distribution. A common way to counter this is the use of Two part or Tobit models, which makes interpretation of the results more difficult. In this study, I explore a statistical distribution from the Tweedie family of distributions that can simultaneously model the probability of zero outcome, i.e. of being a non-user of health care utilization and continuous costs for users. METHODS: I assess the usefulness of the Tweedie model in a Monte Carlo simulation study that addresses two common situations of low and high correlation of the users and the non-users of health care utilization. Furthermore, I compare the Tweedie model with several other models using a real data set from the RAND health insurance experiment. RESULTS: I show that the Tweedie distribution fits cost data very well and provides better fit, especially when the number of non users is low and the correlation between users and non-users is high. CONCLUSION: The Tweedie distribution provides an interesting solution to many statistical problems in health economic analyses. PMID- 29258427 TI - Rooting phylogenetic trees under the coalescent model using site pattern probabilities. AB - BACKGROUND: Phylogenetic tree inference is a fundamental tool to estimate ancestor-descendant relationships among different species. In phylogenetic studies, identification of the root - the most recent common ancestor of all sampled organisms - is essential for complete understanding of the evolutionary relationships. Rooted trees benefit most downstream application of phylogenies such as species classification or study of adaptation. Often, trees can be rooted by using outgroups, which are species that are known to be more distantly related to the sampled organisms than any other species in the phylogeny. However, outgroups are not always available in evolutionary research. METHODS: In this study, we develop a new method for rooting species tree under the coalescent model, by developing a series of hypothesis tests for rooting quartet phylogenies using site pattern probabilities. The power of this method is examined by simulation studies and by application to an empirical North American rattlesnake data set. RESULTS: The method shows high accuracy across the simulation conditions considered, and performs well for the rattlesnake data. Thus, it provides a computationally efficient way to accurately root species-level phylogenies that incorporates the coalescent process. The method is robust to variation in substitution model, but is sensitive to the assumption of a molecular clock. CONCLUSIONS: Our study establishes a computationally practical method for rooting species trees that is more efficient than traditional methods. The method will benefit numerous evolutionary studies that require rooting a phylogenetic tree without having to specify outgroups. PMID- 29258430 TI - Long-duration general anesthesia influences the intelligence of school age children. AB - BACKGROUND: General anesthesia has been linked to impaired brain development in immature animals and young children. In this study the influence of orthopedic surgery under general anesthesia on the intelligence of school age children has been evaluated. METHODS: A total of 209 subjects aged 6-12 years were recruited and allocated into 4 groups according to the duration of general anesthesia, including a control group (n = 30), short (< 1 h, n = 49), moderate- (1-3 h, n = 51) and long-duration groups (> 3 h, n = 79), respectively. The intelligence quotient (IQ) of the subjects was measured by the Raven's Standard Progressive Matrices (RSPM) before and after orthopedic surgery under general anesthesia of various durations (vide supra). RESULTS: The IQ score decreased significantly in the long-duration group at 1 month post-operation compared with the pre-operation score (P < 0.001), and IQ did not recover completely at 3 months postoperatively (P < 0.05), but had recovered when measured at the 1-year follow-up. Moreover, this study showed that the development of children's intelligence was affected by the exposure time to anesthetics at a younger age (OR = 5.26, 95% CI:2.70-8.41, P < 0.001), having a mother with a low education level (OR = 2.71, 95% CI:1.24 6.14, P = 0.014) and premature birth (OR = 2.76, 95% CI:1.34-5.46, P = 0.005). CONCLUSIONS: More than 3 h general anesthesia influenced the IQ of school age children for up to 3 months after orthopedic surgery. Beside extended exposure time to anesthetics additional factors for post-operative IQ reduction were younger children age, mothers with low educational levels and premature birth. TRIAL REGISTRATION: Chinese Clinical Trial Registry with registration number ChiCTR-OOC-17013497 retrospectively registered on 11/23/2017. PMID- 29258429 TI - Mesenchymal stem cell conditioned medium alleviates oxidative stress injury induced by hydrogen peroxide via regulating miR143 and its target protein in hepatocytes. AB - BACKGROUND: To investigate the impact of miRNA (microRNA) on hepatic oxidative stress damage under the human mesenchymal stem cell conditioned medium (MSC-CM) and explore the roles of the beta-1 adrenergic receptor (ADRB1) and hexokinase 2 (HK2) in this process. METHODS: Hydrogen peroxide was used to induce oxidative stress injury in the human normal liver cell line L02. MSC-CM was separately prepared. After treatment with MSC-CM, the protective effects of MSC-CM on oxidative stress injury were assessed by changes in apoptosis, cell viability, cell cycle, and mitochondrial membrane potential. According to the microarray analysis, 19 disparately expressed miRNAs were selected for RT-PCR and miR143 identified as having significant differential expression in MSC-CM against oxidative stress injury. Subsequently, the predicted target proteins of miR143 were selected by bioinformatics software, and verified by western blot. In addition, down-regulation and up-regulation of miR143 expression and hydrogen peroxide induced hypoxia injury were carried out on L02 cells to study the role of miR143. RESULTS: MSC-CM significantly attenuated H2O2 induced oxidative stress injury. The expression of miR143 was increased following oxidative stress injury whereas it decreased after MSC-CM treatment. The expression levels of HK2 and ADRB1 regulated by miR143 and Bcl-2 decreased under H2O2 treatment but were restored following MSC-CM treatment. However the expression levels of Bax and BMF increased after H2O2 injury and decreased after MSC-CM treatment. Moreover over expression or down-regulation of miR143 aggravated or alleviated hepatocyte apoptosis respectively. CONCLUSIONS: MSC-CM may alleviate H2O2 induced oxidative stress injury by inhibiting apoptosis and adjusting miRNA expression. Moreover down-regulation of miR143 protects L02 cells from apoptosis and initiates an adaptive process by adjusting the expression of HK2 ADRB1 and apoptosis-related proteins. PMID- 29258431 TI - Fine regulation of ARF17 for anther development and pollen formation. AB - BACKGROUND: In Arabidopsis, the tapetum and microsporocytes are critical for pollen formation. Previous studies have shown that ARF17 is expressed in microsporocytes and tetrads and directly regulates tetrad wall synthesis for pollen formation. ARF17 is the direct target of miR160, and promoterARF17::5mARF17 (5mARF17/WT) transgenic plants, which have five silent mutations within the miR160-complementary domain, are sterile. RESULTS: Here, we found that ARF17 is also expressed in the tapetum, which was defective in arf17 mutants. Compared with arf17 mutants, 5mARF17/WT plants had abnormal tapetal cells and tetrads but were less vacuolated in the tapetum. Immunocytochemical assays showed that the ARF17 protein over-accumulated in tapetum, microsporocytes and tetrads of 5mARF17/WT plants at early anther stages, but its expression pattern was not affected during anther development. 5mARF17 driven by its native promoter did not rescue the arf17 male-sterile phenotype. The expression of 5mARF17 driven by the tapetum-specific promoter A9 led to a defective tapetum and male sterility in transgenic plants. These results suggest that the overexpression of ARF17 in the tapetum and microsporocytes of 5mARF17/WT plants leads to male sterility. Microarray data revealed that an abundance of genes involved in transcription and translation are ectopically expressed in 5mARF17/WT plants. CONCLUSIONS: Our work shows that ARF17 plays an essential role in anther development and pollen formation, and ARF17 expression under miR160 regulation is critical for its function during anther development. PMID- 29258432 TI - The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to Tapentadol in the treatment of low back pain: a pilot study comparing prospective and retrospective observational arms. AB - BACKGROUND: This pilot study was designed to compare the efficacy of ultramicronized palmitoylethanolamide (um-PEA) as add-on therapy to tapentadol (TP) with TP therapy only in patients suffering from chronic low back pain (LBP). METHODS: This pilot observational study consists in two arms: the prospective arm and the retrospective one. In the prospective arm patients consecutively selected received um-PEA as add-on therapy to TP for 6 months; in the retrospective arm patients were treated with TP only for 6 months. Pain intensity and neuropathic component were evaluated at baseline, during and after 6 months. The degree of disability and TP dosage assumption were evaluated at baseline and after 6 months. RESULTS: Statistical analysis performed with generalized linear mixed model on 55 patients (30 in the prospective group and 25 in the retrospective group) demonstrated that um-PEA as add-on treatment to TP in patients with chronic LBP, in comparison to TP alone, led to a significantly higher reduction in pain intensity, in the neuropathic component, the degree of disability and TP dosage assumption. No serious side effects were observed. CONCLUSION: Overall, the present findings suggest that um-PEA may be an innovative therapeutic intervention as add-on therapy to TP for the management of chronic LBP with a neuropathic component, as well as to improve patient quality of life. Additionally, this combination treatment allowed a reduction in TP dose over time and did not show any serious side effects. PMID- 29258433 TI - Similar genomic proportions of copy number variation within gray wolves and modern dog breeds inferred from whole genome sequencing. AB - BACKGROUND: Whole genome re-sequencing data from dogs and wolves are now commonly used to study how natural and artificial selection have shaped the patterns of genetic diversity. Single nucleotide polymorphisms, microsatellites and variants in mitochondrial DNA have been interrogated for links to specific phenotypes or signals of domestication. However, copy number variation (CNV), despite its increasingly recognized importance as a contributor to phenotypic diversity, has not been extensively explored in canids. RESULTS: Here, we develop a new accurate probabilistic framework to create fine-scale genomic maps of segmental duplications (SDs), compare patterns of CNV across groups and investigate their role in the evolution of the domestic dog by using information from 34 canine genomes. Our analyses show that duplicated regions are enriched in genes and hence likely possess functional importance. We identify 86 loci with large CNV differences between dogs and wolves, enriched in genes responsible for sensory perception, immune response, metabolic processes, etc. In striking contrast to the observed loss of nucleotide diversity in domestic dogs following the population bottlenecks that occurred during domestication and breed creation, we find a similar proportion of CNV loci in dogs and wolves, suggesting that other dynamics are acting to particularly select for CNVs with potentially functional impacts. CONCLUSIONS: This work is the first comparison of genome wide CNV patterns in domestic and wild canids using whole-genome sequencing data and our findings contribute to study the impact of novel kinds of genetic changes on the evolution of the domestic dog. PMID- 29258435 TI - Structural, expression and evolutionary analysis of the non-specific phospholipase C gene family in Gossypium hirsutum. AB - BACKGROUND: Nonspecific phospholipase C (NPC), which belongs to a phospholipase C subtype, is a class of phospholipases that hydrolyzes the primary membrane phospholipids, such as phosphatidylcholine, to yield sn-1, 2-diacylglycerol and a phosphorylated head-group. NPC plays multiple physiological roles in lipid metabolism and signaling in plants. To fully understand the putative roles of NPC genes in upland cotton, we cloned NPC genes from Gossypium hirsutum and carried out structural, expression and evolutionary analysis. RESULTS: Eleven NPC genes were cloned from G. hirsutum, which were found on chromosomes scaffold269.1, D03, A07, D07, A08, D11, and scaffold3511_A13. All GhNPCs had typical phosphoesterase domains and have hydrolase activity that acts on ester bonds. GhNPCs were annotated as phospholipase C, which was involved in glycerophospholipid metabolism, ether lipid metabolism, and biosynthesis of secondary metabolites. These GhNPCs showed differential expression patterns in distinct plant tissues and in response to various types of stress (low-phosphate, salt, drought, and abscisic acid). They also had different types and numbers of cis-element. GhNPCs could be classified into four subfamilies. Four pairs of GhNPCs were generated by whole-genome duplication and they underwent purifying selection. CONCLUSIONS: Our results suggested that GhNPCs are involved in regulating key abiotic stress responses and ABA signaling transduction, and they may have various functional roles for different members under complex abiotic stress conditions. Functional divergence may be the evolutionary driving force for the retention of four pairs of duplicate NPCs. Our analysis provides a solid foundation for the further functional characterization of the GhNPC gene family, and leads to potential applications in the genetic improvement of cotton cultivars. PMID- 29258436 TI - An optimized rapid bisulfite conversion method with high recovery of cell-free DNA. AB - BACKGROUND: Methylation analysis of cell-free DNA is a encouraging tool for tumor diagnosis, monitoring and prognosis. Sensitivity of methylation analysis is a very important matter due to the tiny amounts of cell-free DNA available in plasma. Most current methods of DNA methylation analysis are based on the difference of bisulfite-mediated deamination of cytosine between cytosine and 5 methylcytosine. However, the recovery of bisulfite-converted DNA based on current methods is very poor for the methylation analysis of cell-free DNA. RESULTS: We optimized a rapid method for the crucial steps of bisulfite conversion with high recovery of cell-free DNA. A rapid deamination step and alkaline desulfonation was combined with the purification of DNA on a silica column. The conversion efficiency and recovery of bisulfite-treated DNA was investigated by the droplet digital PCR. The optimization of the reaction results in complete cytosine conversion in 30 min at 70 degrees C and about 65% of recovery of bisulfite treated cell-free DNA, which is higher than current methods. CONCLUSIONS: The method allows high recovery from low levels of bisulfite-treated cell-free DNA, enhancing the analysis sensitivity of methylation detection from cell-free DNA. PMID- 29258434 TI - Genome-wide identification, characterization, and evolutionary analysis of flowering genes in radish (Raphanus sativus L.). AB - BACKGROUND: Radish (Raphanus sativus L.) belongs to the family Brassicaceae, and is an economically important root crop grown worldwide. Flowering is necessary for plant propagation, but it is also an important agronomic trait influencing R. sativus fleshy taproot yield and quality in the case of an imbalance between vegetative and reproductive growth. There is currently a lack of detailed information regarding the pathways regulating the flowering genes or their evolution in R. sativus. The release of the R. sativus genome sequence provides an opportunity to identify and characterize the flowering genes using a comparative genomics approach. RESULTS: We identified 254 R. sativus flowering genes based on sequence similarities and analyses of syntenic regions. The genes were unevenly distributed on the various chromosomes. Furthermore, we discovered the existence of R. sativus core function genes in the flowering regulatory network, which revealed that basic flowering pathways are relatively conserved between Arabidopsis thaliana and R. sativus. Additional comparisons with Brassica oleracea and Brassica rapa indicated that the retained flowering genes differed among species after genome triplication events. The R. sativus flowering genes were preferentially retained, especially those associated with gibberellin signaling and metabolism. Moreover, analyses of selection pressures suggested that the genes in vernalization and autonomous pathways were more variable than the genes in other R. sativus flowering pathways. CONCLUSIONS: Our results revealed that the core flowering genes are conserved between R. sativus and A. thaliana to a certain extent. Moreover, the copy number variation and functional differentiation of the homologous genes in R. sativus increased the complexity of the flowering regulatory networks after genome polyploidization. Our study provides an integrated framework for the R. sativus flowering pathways and insights into the evolutionary relationships between R. sativus flowering genes and the genes from A. thaliana and close relatives. PMID- 29258437 TI - Informal care relationships and residential aged care recommendations: evidence from administrative data. AB - BACKGROUND: The Australian government recognises the importance of informal care to enable ageing in place. Yet, few multivariable studies have examined aspects of informal care that alter the probability of entry to residential care in Australia. Existing Australian and international studies show differing effects of informal care on entry to residential care. METHODS: We utilise unique administrative data on aged care assessments collected from 2010 to 2013, consisting of 280,000 persons aged 65 and over. Logistic regression models were fitted to measure the propensity to be recommended care in a residential care setting, disaggregated by characteristics of informal care provision. RESULTS: Providing some explanation for the divergent findings in the literature, we show that close familial carer relationships (partner or child) and coresidence are associated with recommendations to live in the community. Weaker non coresidential friend or neighbour carer relationships are associated with recommendations to live in residential care for women, as are non-coresidential other relatives (not a child, partner or in-law) for both males and females. Non coresident carers who are in-laws (for females) or parents have no impact on assessor recommendations. Despite these significant differences, health conditions and assistance needs play a strong role in assessor recommendations about entry to residential care. CONCLUSION: Co-resident care clearly plays an important protective role in residential care admission. Government policy should consider the need for differential supports for co-resident carers as part of future aged care reform. PMID- 29258438 TI - SupremeTM laryngeal mask airway use in general Anesthesia for category 2 and 3 Cesarean delivery: a prospective cohort study. AB - BACKGROUND: The SupremeTM laryngeal mask airway (SLMA) is a single-use LMA with double lumen design that allows separation of the respiratory and the alimentary tract, hence potentially reducing the gastric volume and risk of aspiration. The purpose of this prospective cohort study is to evaluate the the role of the SLMA as an airway technique for women undergoing category 2 and 3 Cesarean delivery under general anesthesia. METHODS: We recruited 584 parturients who underwent category 2 or 3 Cesarean delivery under general anesthesia, in which 193 parturients underwent category 2 and 391 parturients underwent category 3 Cesarean delivery. The primary outcome was insertion success rate at 1st attempt in SLMA insertion. The secondary outcomes included anaesthetic, obstetric outcomes and maternal side effects associated with airway device. RESULTS: The 1st attempt insertion success rate was 98.3%, while the overall insertion success rate was 100%. The mean (Standard deviation) time to effective ventilation was 15.6 (4.4) seconds. Orogastric tube insertion was successful at the 1st attempt in all parturients. There was no clinical evidence of aspiration or regurgitation. No episodes of hypoxemia, laryngospasm or bronchospasm were observed intra-operatively. The incidence of complications was low and with good maternal satisfaction reported. CONCLUSIONS: The SLMA could be an alternative effective airway in category 2 and 3 parturients emergency Cesarean Delivery under general anesthesia in a carefully-selected obstetric population. TRIAL REGISTRATION: Clinical Trials Registration: Clinicaltrials.gov Registration NCT02026882 . Registered on December 31, 2013. PMID- 29258439 TI - Production and molecular characterization of bread wheat lines with reduced amount of alpha-type gliadins. AB - BACKGROUND: Among wheat gluten proteins, the alpha-type gliadins are the major responsible for celiac disease, an autoimmune disorder that affects about 1% of the world population. In fact, these proteins contain several toxic and immunogenic epitopes that trigger the onset of the disease. The alpha-type gliadins are a multigene family, encoded by genes located at the complex Gli-2 loci. RESULTS: Here, three bread wheat deletion lines (Gli-A2, Gli-D2 and Gli A2/Gli-D2) at the Gli-2 loci were generated by the introgression in the bread wheat cultivar Pegaso of natural mutations, detected in different bread wheat cultivars. The molecular characterization of these lines allowed the isolation of 49 unique expressed genes coding alpha-type gliadins, that were assigned to each of the three Gli-2 loci. The number and the amount of alpha-type gliadin transcripts were drastically reduced in the deletion lines. In particular, the line Gli-A2/Gli-D2 contained only 12 active alpha-type gliadin genes (-75.6% respect to the cv. Pegaso) and a minor level of transcripts (-80% compared to cv. Pegaso). Compensatory pleiotropic effects were observed in the two other classes of gliadins (omega- and gamma-gliadins) either at gene expression or protein levels. Although the comparative analysis of the deduced amino acid sequences highlighted the typical structural features of alpha-type gliadin proteins, substantial differences were displayed among the 49 proteins for the presence of toxic and immunogenic epitopes. CONCLUSION: The deletion line Gli-A2/Gli-D2 did not contain the 33-mer peptide, one of the major epitopes triggering the celiac disease, representing an interesting material to develop less "toxic" wheat varieties. PMID- 29258440 TI - De novo assembly and comparative analysis of the transcriptome of embryogenic callus formation in bread wheat (Triticum aestivum L.). AB - BACKGROUND: During asexual reproduction the embryogenic callus can differentiate into a new plantlet, offering great potential for fostering in vitro culture efficiency in plants. The immature embryos (IMEs) of wheat (Triticum aestivum L.) are more easily able to generate embryogenic callus than mature embryos (MEs). To understand the molecular process of embryogenic callus formation in wheat, de novo transcriptome sequencing was used to generate transcriptome sequences from calli derived from IMEs and MEs after 3d, 6d, or 15d of culture (DC). RESULTS: In total, 155 million high quality paired-end reads were obtained from the 6 cDNA libraries. Our de novo assembly generated 142,221 unigenes, of which 59,976 (42.17%) were annotated with a significant Blastx against nr, Pfam, Swissprot, KOG, KEGG, GO and COG/KOG databases. Comparative transcriptome analysis indicated that a total of 5194 differentially expressed genes (DEGs) were identified in the comparisons of IME vs. ME at the three stages, including 3181, 2085 and 1468 DEGs at 3, 6 and 15 DC, respectively. Of them, 283 overlapped in all the three comparisons. Furthermore, 4731 DEGs were identified in the comparisons between stages in IMEs and MEs. Functional analysis revealed that 271transcription factor (TF) genes (10 overlapped in all 3 comparisons of IME vs. ME) and 346 somatic embryogenesis related genes (SSEGs; 35 overlapped in all 3 comparisons of IME vs. ME) were differentially expressed in at least one comparison of IME vs. ME. In addition, of the 283 overlapped DEGs in the 3 comparisons of IME vs. ME, excluding the SSEGs and TFs, 39 possessed a higher rate of involvement in biological processes relating to response to stimuli, in multi-organism processes, reproductive processes and reproduction. Furthermore, 7 were simultaneously differentially expressed in the 2 comparisons between the stages in IMEs, but not MEs, suggesting that they may be related to embryogenic callus formation. The expression levels of genes, which were validated by qRT-PCR, showed a high correlation with the RNA-seq value. CONCLUSIONS: This study provides new insights into the role of the transcriptome in embryogenic callus formation in wheat, and will serve as a valuable resource for further studies addressing embryogenic callus formation in plants. PMID- 29258441 TI - Comparative transcriptome analysis of Glyphodes pyloalis Walker (Lepidoptera: Pyralidae) reveals novel insights into heat stress tolerance in insects. AB - BACKGROUND: Heat tolerance is a key parameter that affects insect distribution and abundance. Glyphodes pyloalis Walker (Lepidoptera: Pyralidae) is a devastating pest of mulberry in the main mulberry-growing regions and can cause tremendous losses to sericulture by directly feeding on mulberry leaves and transmitting viruses to Bombyx mori. Moreover, G. pyloalis shows a prominent capacity for adaptation to daily and seasonal temperature fluctuations and can survive several hours under high temperature. To date, the molecular mechanism underlying the outstanding adaptability of this pest to high temperature remains unclear. RESULTS: In this study, we performed comparative transcriptome analyses on G. pyloalis exposed to 25 and 40 degrees C for 4 h. We obtained 34,034 unigenes and identified 1275 and 1222 genes significantly upregulated or downregulated, respectively, by heat stress. Data from the transcriptome analyses indicated that some processes involved in heat tolerance are conserved, such as high expression of heat shock protein (HSP) genes and partial repression of metabolism progress. In addition, vitamin digestion and absorption pathways and detoxification pathways identified here provided new insights for the investigation of the molecular mechanisms of heat stress tolerance. Furthermore, transcriptome analysis indicated that immune and phosphatidylinositol signaling system have a close relationship with heat tolerance. In addition, the expression patterns of ten randomly selected genes, such as HSP and cytochrome P450, were consistent with the transcriptome results obtained through quantitative real-time PCR. CONCLUSIONS: Comparisons among transcriptome results revealed the upregulation of HSPs and genes involved in redox homeostasis, detoxication, and immune progress. However, many metabolism progresses, such as glycolysis/gluconeogenesis and fatty acid biosynthesis, were partially repressed. The results reflected that the heat tolerance of G. pyloalis is a fairly complicated process and related to a broad range of physiological regulations. Our study can improve understanding on the mechanisms of insect thermal tolerance. PMID- 29258442 TI - A tissue-based approach to selection of reference genes for quantitative real time PCR in a sheep osteoporosis model. AB - BACKGROUND: In order to better understand the multifactorial nature of osteoporosis, animal models are utilized and compared to healthy controls. Female sheep are well established as a model for osteoporosis induced by ovariectomy, calcium and vitamin D low diet, application of steroids, or a combination of these treatments. Transcriptional studies can be performed by applying quantitative real time PCR (RT-qPCR). RT-qPCR estimates mRNA-levels of target genes in relation to reference genes. A chosen set of reference genes should not show variation under experimental conditions. Currently, no standard reference genes are accepted for all tissue types and experimental conditions. Studies examining reference genes for sheep are rare and only one study described stable reference in mandibular bone. However, this type of bone differs from trabecular bone where most osteoporotic fractures occur. The present study aimed at identifying a set of reference genes for relative quantification of transcriptional activity of ovine spine bone and ovine in vitro differentiated mesenchymal stromal cells (MSC) for reliable comparability. METHODS: Twelve candidate reference genes belonging to different functional classes were selected and their expression was measured from cultured ovMSCs (n = 18) and ovine bone samples (n = 16), respectively. RefFinder was used to rank the candidate genes. RESULTS: We identified B2M, GAPDH, RPL19 and YWHAZ as the best combination of reference genes for normalization of RT-qPCR results for transcriptional analyses of these ovine samples. CONCLUSION: This study demonstrates the importance of applying a set of reference genes for RT-qPCR analysis in sheep. Based on our data we recommend using four identified reference genes for relative quantification of gene expression studies in ovine bone or for in vitro experiments with osteogenically differentiated ovine MSCs. PMID- 29258443 TI - Exogenous trehalose improves growth under limiting nitrogen through upregulation of nitrogen metabolism. AB - BACKGROUND: The trehalose (Tre) pathway has strong effects on growth and development in plants through regulation of carbon metabolism. Altering either Tre or trehalose 6-phosphate (T6P) can improve growth and productivity of plants as observed under different water availability. As yet, there are no reports of the effects of modification of Tre orT6P on plant performance under limiting nutrition. RESULTS: Here we report that nitrogen (N) metabolism is positively affected by exogenous application of Tre in nitrogen-deficient growing conditions. Spraying foliage of tobacco (Nicotiana tabacum) with trehalose partially alleviated symptoms of nitrogen deficiency through upregulation of nitrate and ammonia assimilation and increasing activities of nitrate reductase (NR), glycolate oxidase (GO), glutamine synthetase (GS) and glutamine oxoglutarate aminotransferase (GOGAT) with concomitant changes in ammonium (NH4+) and nitrate (NO3-) concentrations, glutamine and amino acids. Chlorophyll and total nitrogen content of leaves and rates of photosynthesis were increased compared to nitrogen-deficient plants without applied Tre. Total plant biomass accumulation was also higher in Tre -fed nitrogen-deficient plants, with a smaller proportion of dry weight partitioned to roots, compared to nitrogen deficient plants without applied Tre. Consistent with higher nitrogen assimilation and growth, Tre application reduced foliar starch. Minimal effects of Tre feeding were observed on nitrogen-sufficient plants. CONCLUSIONS: The data show, for the first time, significant stimulatory effects of exogenous Tre on nitrogen metabolism and growth in plants growing under deficient nitrogen. Under such adverse conditions metabolism is regulated for survival rather than productivity. Application of Tre can alter this regulation towards maintenance of productive functions under low nitrogen. This has implications for considering approaches to modifying the Tre pathway for to improve crop nitrogen-use efficiency and production. PMID- 29258445 TI - A biological network-based regularized artificial neural network model for robust phenotype prediction from gene expression data. AB - BACKGROUND: Stratification of patient subpopulations that respond favorably to treatment or experience and adverse reaction is an essential step toward development of new personalized therapies and diagnostics. It is currently feasible to generate omic-scale biological measurements for all patients in a study, providing an opportunity for machine learning models to identify molecular markers for disease diagnosis and progression. However, the high variability of genetic background in human populations hampers the reproducibility of omic-scale markers. In this paper, we develop a biological network-based regularized artificial neural network model for prediction of phenotype from transcriptomic measurements in clinical trials. To improve model sparsity and the overall reproducibility of the model, we incorporate regularization for simultaneous shrinkage of gene sets based on active upstream regulatory mechanisms into the model. RESULTS: We benchmark our method against various regression, support vector machines and artificial neural network models and demonstrate the ability of our method in predicting the clinical outcomes using clinical trial data on acute rejection in kidney transplantation and response to Infliximab in ulcerative colitis. We show that integration of prior biological knowledge into the classification as developed in this paper, significantly improves the robustness and generalizability of predictions to independent datasets. We provide a Java code of our algorithm along with a parsed version of the STRING DB database. CONCLUSION: In summary, we present a method for prediction of clinical phenotypes using baseline genome-wide expression data that makes use of prior biological knowledge on gene-regulatory interactions in order to increase robustness and reproducibility of omic-scale markers. The integrated group-wise regularization methods increases the interpretability of biological signatures and gives stable performance estimates across independent test sets. PMID- 29258444 TI - Evaluation of a field-deployable reverse transcription-insulated isothermal PCR for rapid and sensitive on-site detection of Zika virus. AB - BACKGROUND: The recent emergence of Zika virus (ZIKV) in Brazil and its precipitous expansion throughout the Americas has highlighted the urgent need for a rapid and reliable on-site diagnostic assay suitable for viral detection. Such point-of-need (PON), low-cost diagnostics are essential for ZIKV control in vulnerable areas with limited resources. METHODS: We developed and evaluated a ZIKV-specific field-deployable RT-iiPCR reagent set targeting the E gene for rapid detection of ZIKV in ZIKV-spiked human and mosquito specimens, and compared its performance to the Center for Disease Control and Prevention (CDC) and Pan American Health Organization (PAHO) RT-qPCR assays targeting the E and NS2B genes, respectively. RESULTS: These assays demonstrated exclusive specificity for ZIKV (African and Asian lineages), had limits of detection ranging from 10 to 100 in vitro transcribed RNA copies/MUl and detection endpoints at 10 plaque forming units/ml of infectious tissue culture fluid. Analysis of human whole blood, plasma, serum, semen, urine, and mosquito pool samples spiked with ZIKV showed an agreement of 90% (k = 0.80), 92% (k = 0.82), 95% (k = 0.86), 92% (k = 0.81), 90% (k = 0.79), and 100% (k = 1), respectively, between the RT-iiPCR assay and composite results from the reference RT-qPCR assays. Overall, the concurrence between the ZIKV RT-iiPCR and the reference RT-qPCR assays was 92% (k = 0.83). CONCLUSIONS: The ZIKV RT-iiPCR has a performance comparable to the reference CDC and PAHO RT-qPCR assays but provides much faster results (~1.5 h) with a field deployable system that can be utilized as a PON diagnostic with the potential to significantly improve the quality of the health care system in vulnerable areas. PMID- 29258446 TI - Transcriptome analysis of ruminal epithelia revealed potential regulatory mechanisms involved in host adaptation to gradual high fermentable dietary transition in beef cattle. AB - BACKGROUND: The transition from a high forage to a highly fermentable diet can induce digestive disorders in the rumen. To date, the host mechanisms that regulate the adaption to such dietary transition are largely unknown. To understand the molecular mechanisms involved in such phenomena, RNA-sequencing was performed to identify the changes in the transcriptome of ruminal epithelia during gradual transition from a diet containing 0% to 89% grain. RESULTS: In total, the expression of 11,044, 11,322 and 11,282 genes were detected in ruminal epithelia of beef heifers (n = 15) fed 0%, 72% and 89% barley grain diet, respectively. The transcriptome profiles of rumen epithelia differed between low grain diet (LGD) (0% grain) and high grain diet (HGD) (72% and 89%), and HGD tended to reduce the expression of genes involved in epithelial catalytic and binding activities. When diet was changed from 72% to 89% grain, the mean ruminal pH change was significantly different among individual heifers with five of them decreased (down group (DG); from 6.30+/-0.09 to 5.87+/-0.15, P < 0.01) and five of them increased (up group (UG); from 5.84+/-0.42 to 6.35+/-0.37, P < 0.05). The functional analysis of differentially expressed (DE) genes revealed inhibited "Immune response of leukocytes", "Attraction of phagocytes", and "Cell movement of leukocytes" (P < 0.05) functions (Z-score = -2.2, -2.2 and -2.0, respectively) in DG, and inhibited "Concentration of lipid" and "Proliferation of epithelial cells" functions in UG (Z-score = -2.0, and -1.8, respectively). In addition, the expression of genes involved in ketogenesis (HMGCL) and lipid synthesis (SREBF2, FABP4) was increased in DG, while the expression of ketogenesis (ACAT2, HMGCS) and cholesterol synthesis related genes (HMGC and FDPS) were deceased in UG. Furthermore, the upstream regulators were found to be involved in the regulation of immune response and cell cycle progress, and SNP (g.46834311A > G) in FABP4 was identified between two groups of animals (P < 0.1). CONCLUSION: The identified genes, upstream regulators, and SNP could be potential genetic markers that may account for the varied individual ruminal pH responses to the dietary transition stress. PMID- 29258447 TI - Delivery cost analysis of a reactive mass cholera vaccination campaign: a case study of ShancholTM vaccine use in Lake Chilwa, Malawi. AB - BACKGROUND: Cholera is a diarrheal disease that produces rapid dehydration. The infection is a significant cause of mortality and morbidity. Oral cholera vaccine (OCV) has been propagated for the prevention of cholera. Evidence on OCV delivery cost is insufficient in the African context. This study aims to analyze Shanchol vaccine delivery costs, focusing on the vaccination campaign in response of a cholera outbreak in Lake Chilwa, Malawi. METHODS: The vaccination campaign was implemented in two rounds in February and March 2016. Structured questionnaires were used to collect costs incurred for each vaccination related activity, including vaccine procurement and shipment, training, microplanning, sensitization, social mobilization and vaccination rounds. Costs collected, including financial and economic costs were analyzed using Choltool, a standardized cholera cost calculator. RESULTS: In total, 67,240 persons received two complete doses of the vaccine. Vaccine coverage was higher in the first round than in the second. The two-dose coverage measured with the immunization card was estimated at 58%. The total financial cost incurred in implementing the campaign was US$480275 while the economic cost was US$588637. The total financial and economic costs per fully vaccinated person were US$7.14 and US$8.75, respectively, with delivery costs amounting to US$1.94 and US$3.55, respectively. Vaccine procurement and shipment accounted respectively for 73% and 59% of total financial and economic costs of the total vaccination campaign costs while the incurred personnel cost accounted for 13% and 29% of total financial and economic costs. Cost for delivering a single dose of Shanchol was estimated at US$0.97. CONCLUSION: This study provides new evidence on economic and financial costs of a reactive campaign implemented by international partners in collaboration with MoH. It shows that involvement of international partners' personnel may represent a substantial share of campaign's costs, affecting unit and vaccine delivery costs. PMID- 29258448 TI - Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials. AB - BACKGROUND: Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. METHODS: Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28-42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28-42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. RESULTS: Pre treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia <=10,000 MUL-1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age <= 15 months, history of fever pre-treatment and enrolment haematocrit <=35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre treatment, enrolment parasitaemia <=50,000 MUL-1, parasitaemia one day post treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit >=37%, and parasitaemia >100,000 MUL-1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9-2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. CONCLUSION: After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ]. PMID- 29258449 TI - The rs738409 polymorphism of the PNPLA3 gene is associated with hepatic steatosis and fibrosis in Brazilian patients with chronic hepatitis C. AB - BACKGROUND: Prospective studies have shown that 80% of acute hepatitis C virus (HCV) cases progress to chronic infection; approximately 10-20% of patients with these conditions will develop liver cirrhosis within 2 to 3 decades, and 1-5% will develop liver cancer. Some studies have indicated that the rs738409 polymorphism of the PNPLA3 gene is associated with steatosis and the progression of advanced fibrosis. This study assessed the contribution of the PNPLA3 rs738409 polymorphism with regard to the steatosis and degree of liver fibrosis in Brazilian patients diagnosed with chronic hepatitis C. METHODS: A total of 290 patients were evaluated at the Clinics Hospital of the School of Medicine, University of Sao Paulo, between 2010 and 2015. The inclusion criteria were age >= 18 years and positive anti-HCV antibody and HCV RNA tests. The participants were evaluated based on medical consultation, blood tests, and liver biopsies conducted before specific antiviral therapies were applied. The associations between the rs738409 PNPLA3 gene polymorphism and steatosis and advanced fibrosis were tested under a recessive inheritance model using logistic regression analysis, including age, gender, BMI, ethnicity/color, HOMA-IR, alcohol intake, HCV genotype 3, and the rs58542926 TM6SF2 gene polymorphism as covariates. RESULTS: The mean age of the patients was 54.9 years old (range, 28 to 82 years), and 124 (42.8%) patients were male; 226 (77.9%) were white, 43 (14.8%) were pardo, and 21 (7.2%) were black Brazilians. Of the patients included in this study, 133 (45.9%) presented with the CC genotype, 63 (21.7%) with the CG genotype, and 94 (32.4%) with the GG genotype of the PNPLA3 gene I148M variant. We observed that the associations between PNPLA3 rs738409 GG genotype and steatosis was significant (OR: 2.16; 95% CI 1.26-3.72). The same genotype was associated to advanced fibrosis too (OR:2.64; 95% CI 1.26-5.53). CONCLUSIONS: Associations between the rs738409 polymorphism of the PNPLA3 gene genotype GG and hepatic steatosis and advanced fibrosis were observed. Studies are still needed to clarify the influence of these polymorphisms on hepatic steatosis and degree of fibrosis among individuals diagnosed with chronic hepatitis C. PMID- 29258450 TI - Serum cytokine profiles predict survival benefits in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective cohort study. AB - BACKGROUND: Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles. METHODS: Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-gamma, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-beta, TGF-alpha, TNF-alpha, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses. RESULTS: The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-alpha. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL 8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL 5, IL-8, TGF-alpha, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC. CONCLUSIONS: Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment. PMID- 29258451 TI - Population cigarette consumption in Great Britain: novel insights using retail sales data. AB - BACKGROUND: Accurate data to measure population cigarette consumption are vital for surveillance and for evaluating the impact of tobacco control policies. This study uses cigarette retail sales data to provide novel insights into trends and patterns in cigarette consumption in Great Britain. METHODS: Cigarette sales estimates derived from electronic sales from most large grocery stores and a weighted representative sample of smaller convenience stores were obtained from Nielsen. Data on the number of cigarette sticks sold per calendar month and per week were obtained for Scotland and England/Wales (combined) for the period January 2008 to December 2015. Cigarette consumption per adult smoker per month was calculated using survey-based smoking prevalence estimates and mid-year population estimates. RESULTS: Population cigarette consumption in Great Britain declined between 2008 and 2013. Cigarette sales have since stabilised at around 400 cigarettes per adult smoker per month. Cigarettes sold in 14- to 19-packs have substituted a sharp decline in 20-packs and now account for over half of all cigarettes sold in Great Britain. Cigarette consumption has been consistently higher in Scotland than England/Wales. This is due to higher sales of 20-packs in Scotland between 2008 and 2013, which has been substituted by higher sales of 14- to 19-packs in recent years. CONCLUSIONS: Cigarette retail sales data provide unique insights into levels and patterns of cigarette consumption and should be used for monitoring and evaluating tobacco control policy in Great Britain. PMID- 29258452 TI - How can we make international comparisons of infant mortality in high income countries based on aggregate data more relevant to policy? AB - BACKGROUND: Infant mortality rates are commonly used to compare the health of populations. Observed differences are often attributed to variation in child health care quality. However, any differences are at least partly explained by variation in the prevalence of risk factors at birth, such as low birth weight. This distinction is important for designing interventions to reduce infant mortality. We suggest a simple method for decomposing inter-country differences in crude infant mortality rates into two metrics representing risk factors operating before and after birth. METHODS: We used data from 7 European countries participating in the EURO-PERISTAT project in 2010. We calculated crude and birth weight-standardised stillbirth and infant mortality rates using Norway as the standard population. We decomposed between-country differences in crude stillbirth and infant mortality rates into the within-country difference in crude and birth weight-standardised stillbirth and infant mortality rates (metric 1), reflecting prenatal risk factors, and the between-country difference in birth weight-standardised stillbirth and infant mortality rates (metric 2), reflecting risk factors operating after birth. We also calculated birth weight-specific mortality. RESULTS: Using our metrics, we showed that for England, Wales and Scotland risk factors before and after birth contributed equally to the differences in crude stillbirth and infant mortality rates relative to Norway. In Austria, Czech Republic and Switzerland the differences were driven primarily by metric 1, reflecting high rate of low birth weight. The highest values of metric 2 observed in Poland partially reflected high rates of congenital anomalies. CONCLUSIONS: Our suggested metrics can be used to guide policy decisions on preventing infant deaths through reducing risk factors at birth or improving the care of babies after birth. Aggregate data tabulated by birth weight/gestational age should be routinely collected and published in high-income countries where birth weight is reported on birth certificates. PMID- 29258453 TI - Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study. AB - BACKGROUND: Preliminary evidence suggests that changes in plasma brain-derived neurotrophic factor (BDNF) levels may contribute to the occurrence of chemotherapy-associated cognitive impairment (CACI), and a previous study suggested that carriers of the BDNF Met homozygous genotype are protected from CACI. METHODS: This multicenter, prospective cohort study involved chemotherapy receiving early-stage breast cancer (ESBC) patients. Self-perceived cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) across three time points: Prior to chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). Plasma BDNF levels were quantified using enzyme linked immunosorbent assay. Genotyping was performed using Sanger Sequencing. RESULTS: A total of 51 chemotherapy-receiving ESBC patients (mean age: 52.6 +/- 9.5 years) were recruited, and 11 patients (21.6%) reported subjective cognitive impairment post-chemotherapy. Overall, there was a reduction in median plasma BDNF levels over time (T1: 5423.0 pg/ml; T2: 5313.6 pg/ml; T3: 4050.3 pg/ml; p < 0.01). After adjusting for confounding factors, longitudinal analysis revealed that BDNF levels were associated with self-reported concentration deficit (p = 0.032). Carriers of Val/Val (p = 0.011) and Val/Met (p = 0.003) BDNF genotypes demonstrated a significant reduction in plasma BDNF levels over time; however, plasma BDNF levels were similar across all time points among Met homozygous carriers (p = 0.107). CONCLUSION: There was a statistically significant change in BDNF levels post-chemotherapy in ESBC patients, and plasma BDNF levels were associated with self-perceived concentration deficit in patients receiving chemotherapy. PMID- 29258454 TI - Atypical acute retinal necrosis accompanied by Terson's syndrome: a case report. AB - BACKGROUND: Acute retinal necrosis (ARN) has characterized by panuveitis, vitritis, severe vaso-occlusive vasculitis, and diffuse necrotizing retinitis. There are no case reports on atypical ARN combined with Terson's syndrome. Herein, we report a case of ARN with atypical clinical features combined with Terson's syndrome that we successfully treated by intravitreal ganciclovir injection. CASE PRESENTATION: A 64-year-old man visited our eye clinic with a complaint of decreased visual acuity in his right eye. At the initial visit, his best corrected visual acuity was 20/125 in the right eye. Slit-lamp examination demonstrated mild hyperemia, keratic precipitates, and anterior chamber inflammatory reaction. Fundus examination revealed multiple diffuse white yellowish infiltrations in the peripheral retina combined with dot hemorrhages. Ultra-wide-field fluorescence angiography showed obstructive arteritis with peripheral non-perfusion and leakage from the retinal vessels. As a result of the PCR analysis, varicella zoster virus DNA was identified in the aqueous humor. Under the diagnosis with VZV-mediated ARN, we started with intravenous acyclovir and oral prednisolone. After 3 days of the above treatment, the anterior chamber inflammation and vitreous opacity were increased. On fundus examination, multiple whitish infiltrations were increased. In addition, newly developed vitreous and peripapillary hemorrhages were detected. On the T2 brain magnetic resonance imaging (MRI) demonstrated a sub-acute or old hemorrhagic infarction in the right occipital lobe, and contrast-enhancing lesions in the right basal ganglia. The spinal tapping was performed in the department of neurology in our hospital at the time when the patient complained of headache, and intracranial pressure was 31 mmHg. Under the diagnosis of ARN with Terson's syndrome, we started intravitreal ganciclovir (2 mg/0.5 ml) injections. After 5 intravitreal ganciclovir injections over a period of 8 months, the diffuse whitish infiltrating retinal lesions combined with dot hemorrhage were decreased. The vitreous and peripapillary hemorrhage was significantly reduced. There was no recurrence in the patient's right eye, in which his visual acuity had improved to 20/60. CONCLUSIONS: In the event of a poor response to traditional treatment such as intravenous acyclovir, intravitreal ganciclovir may have a role as an adjunctive therapy in patients of VZV associated ARN combined with Terson's syndrome. PMID- 29258455 TI - Motivations and barriers to uptake and use of female-initiated, biomedical HIV prevention products in sub-Saharan Africa: an adapted meta-ethnography. AB - BACKGROUND: Women bear a disproportionate burden of HIV throughout the world prompting extensive research into HIV prevention products for women which has met with varied success. With an aim of informing future policy and programming, this review examines the barriers and motivations to the uptake and use of female initiated products in sub-Saharan countries. METHODS: We conducted a systematic review as an adapted meta-ethnography of qualitative data focused on actual use of products. After deduplication, 10,581 and 3861 papers in the first and second round respectively were screened. Following the PRISMA guidance, 22 papers were selected and synthesized using Malpass's definitions of first, second, and third order constructs. First order constructs, consisting of participant data published in the selected papers, were extracted and categorised by second and third order constructs for analysis. A weight of evidence review was conducted to compare and assess quality across the papers. RESULTS: The 22 papers selected span 11 studies in 13 countries. We derived 23 s order constructs that were translated into seven overarching third order constructs: Sexual Satisfaction, Trust, Empowerment and Control, Personal Well-being, Product use in the social cultural environment, Practical Considerations, Risk Reduction, and Perceptions of Efficacy. Relationships and trust were seen to be as or more important for product use as efficacy. These constructs reveal an inherent inter-relationality where decision making around HIV prevention uptake and use cannot be binary or mono-faceted, but rather conducted on multiple levels. We developed a framework illustrating the central and proximal natures of constructs as they relate to the decision-making process surrounding the use of prevention products. CONCLUSIONS: Health systems, structural, and individual level HIV prevention interventions for women should adopt a holistic approach. Interventions should attend to the ways in which HIV prevention products can serve to reduce the likelihood of HIV transmission, as well as help to protect partnerships, enhance sexual pleasure, and take into account woman's roles in the social environment. Stigma, as well as sexuality, is likely to continue to influence product uptake and use and should be prominently taken into account in large-scale interventions. TRIAL REGISTRATION: Not applicable. PMID- 29258456 TI - Structural and functional network characteristics and facility delivery among women in rural Ghana. AB - BACKGROUND: Health facility births contribute to the prevention of maternal deaths. Although theoretical and empirical evidence suggest that social network characteristics influence facility delivery, examination of this relationship in sub-Saharan Africa is limited. We determined whether network structural and functional characteristics were associated with, or had an interactive effect on health facility delivery in rural Ghana. METHODS: Data on mothers (n = 783) aged 15-49 years came from a Maternal and Newborn Health Referral (MNHR) project in Ghana, and included egocentric network data on women's social network characteristics. Using multivariate logistic regression we examined the relationship between facility delivery and women's network structure and functions, as well as the interaction between network characteristics and facility delivery. RESULTS: Higher levels of instrumental support (e.g. help with daily chores or seeking health care [OR: 1.60, CI: 1.10-2.34]) and informational support (OR: 1.66, CI: 1.08-2.54) were significantly associated with higher odds of facility delivery. Social norms, such as knowing more women who had received pregnancy-related care in a facility, were significantly associated with higher odds of facility delivery (OR: 2.20, CI: 1.21-4.00). The number of network members that respondents lived nearby moderated the positive relationship between informational support and facility delivery. Additionally, informational support moderated the positive relationship between facility delivery and the number of women the respondents knew who had utilized a facility for pregnancy-related care. CONCLUSIONS: Social support from network members was critical to facilitating health facility delivery, and support was further enhanced by women's network structure and norms favoring facility delivery. Maternal health interventions to increase facility delivery uptake should target women's social networks. PMID- 29258457 TI - Photosensitive lichenoid skin reaction to capecitabine. AB - BACKGROUND: Capecitabine is an oral prodrug of fluorouracil, which is a common agent used in the management of many solid tumor malignancies. Dermatologic reaction is common with various chemotherapy agents but is not commonly reported in the use of capecitabine. When adverse reactions of rashes occur, the offending agent is typically removed. We report here an unusual case of photosensitive lichenoid rash due to capecitabine which is managed conservatively without major alteration in treatment. CASE PRESENTATION: Seventy-three year old female with a diagnosis of stage IV breast cancer undergoing management with capecitabine presents with a rash during the summer months that is biopsy proven to be lichenoid photosensitive rash with likely offending agent being capecitabine. Her treatment was initially held despite having response to treatment, started on topical steroids after evaluation by dermatology. Given her response to treatment, drug was resumed with instructions to use sun precaution, sunscreen, and to complete course of topical steroids until rash resolution. CONCLUSION: Drug-related rashes tend to lead to disruptions or alterations in treatments of malignancies, despite responses. Given the wide use of capecitabine in many different solid tumors, it is important to recognize this photosensitive related skin rash and to initiate appropriate precautions of sun safety and topical steroids to allow minimal disruptions in therapy and continue use of capecitabine. PMID- 29258458 TI - Improving the evaluation of cardiac function in rats at 7T with denoising filters: a comparison study. AB - BACKGROUND: We investigate the use of different denoising filters on low signal to-noise ratio cardiac images of the rat heart acquired with a birdcage volume coil at 7T. Accuracy and variability of cardiac function parameters were measured from manual segmentation of rat heart images with and without filtering. METHODS: Ten rats were studied using a 7T Varian system. End-diastolic and end-systolic volumes, ejection fraction and left ventricle mass (LVM) were calculated from manual segmentation by two experts on cine-FLASH short-axis slices covering the left ventricle. Series were denoised with an anisotropic diffusion filter, a whole variation regularization or an optimized Rician non-local means (ORNLM) filtering technique. The effect of the different filters was evaluated by the calculation of signal-to-noise (SNR) and contrast-to-noise (CNR) ratios, followed by a study of intra- and inter-expert variability of the measurement of physiological parameters. The calculated LVM was compared to the LVM obtained by weighing the heart ex vivo. RESULTS: The SNR and the CNR increased after application of the different filters. The performance of the ORNLM filter was superior for all the parameters of the cardiac function, as judged from the inter and intra-observer variabilities. Moreover, this filtering technique resulted in the lowest variability in the LVM evaluation. CONCLUSIONS: In cardiac MRI of rats, filtering is an interesting alternative that yields better contrast between myocardium and surrounding tissues and the ORNLM filter provided the largest improvements. PMID- 29258459 TI - "Once the delivery is done, they have finished": a qualitative study of perspectives on postnatal care referrals by traditional birth attendants in Ebonyi state, Nigeria. AB - BACKGROUND: While 79% of Nigerian mothers who deliver in facilities receive postnatal care within 48 h of delivery, this is only true for 16% of mothers who deliver outside facilities. Most maternal deaths can be prevented with access to timely and competent health care. Thus, the World Health Organization, International Confederation of Midwives, and International Federation of Gynecology and Obstetrics recommend that unskilled birth attendants be involved in advocacy for skilled care use among mothers. This study explores postnatal care referral behavior by TBAs in Nigeria, including the perceived factors that may deter or promote referrals to skilled health workers. METHODS: This study collected qualitative data using focus group discussions involving 28 female health workers, TBAs, and TBA delivery clients. The study conceptual framework drew on constructs in Fishbein and Ajzen's theory of reasoned action onto which we mapped hypothesized determinants of postnatal care referrals described in the empirical literature. We analyzed the transcribed data thematically, and linked themes to the study conceptual framework in the discussion to explain variation in TBA referral behavior across the maternal continuum, from the antenatal to postnatal period. RESULTS: Differences in TBA referral before, during, and after delivery appear to reflect the TBAs understanding of the added value of skilled care for the client and the TBA, as well as the TBA's perception of the implications of referral for her credibility as a maternal care provider among her clients. We also found that there are opportunities to engage TBAs in routine postnatal care referrals to facilities in Nigeria by using incentives and promoting a cordial relationship between TBAs and skilled health workers. CONCLUSIONS: Thus, despite the potential negative consequences TBAs may face with postnatal care referrals, there are opportunities to promote these referrals using incentives and promoting a cordial relationship between TBAs and skilled health workers. Further research is needed on the interactions between postnatal maternal complications, TBA referral behavior, and maternal perception of TBA competence. PMID- 29258460 TI - A case of proliferative diabetic retinopathy in which scintillating particles appeared in the intravitreal cavity after laser photocoagulation. AB - BACKGROUND: To report a case of proliferative diabetic retinopathy (PDR) exhibiting the appearance of scintillating particles presumed to be crystallin inside the intravitreal cavity after laser photocoagulation. CASE PRESENTATION: A 56-year-old male patient presented at our outpatient clinic after becoming aware of decreased vision in his right eye. Ocular examination performed at the patient's initial visit revealed a massive preretinal macular hemorrhage due to PDR in his right eye. Fundus fluorescein angiography revealed extensive retinal non-perfusion areas and neovascularization in both eyes. However, no opacity was observed in the intravitreal cavity of his left eye. Vitreous surgery was performed on the patient's right eye after ultrasonic phacoemulsification aspiration and intraocular lens implantation. Post surgery, the corrected VA in that eye improved from 0.1 to 1.0. In correlation with the treatment performed on the patient's right eye, we began panretinal photocoagulation on his left eye. Examination performed prior to the patient's third session of panretinal photocoagulation revealed a large number of scintillating particles in the posterior vitreous gel in front of the retina. Examination via slit-lamp microscopy revealed that the particles were of varied hues, and closely resembled a 'Christmas tree' cataract. No posterior vitreous detachment was observed, and since these particles were situated as if captured in the posterior vitreous gel, no eye-movement-associated mobility of the particles was observed. Since the cloudiness was not severe enough to interfere with photocoagulation, additional photocoagulation was performed, and the patient is currently under observation. Six months have now passed since the fourth photocoagulation procedure was performed, and there has been no change in the state of the particles. Optical coherence tomography imaging revealed no change before and after the panretinal photocoagulation. The corrected VA in his left eye has remained at 1.0 during the postoperative follow-up period. CONCLUSIONS: We speculate that the production of crystallin in the retina in this case was triggered by the photocoagulation procedure performed for diabetic retinopathy. PMID- 29258461 TI - Effects of interactions between common genetic variants and smoking on colorectal cancer. AB - BACKGROUND: Although genome-wide association studies (GWAS) have identified variants in approximately 40 susceptibility loci for colorectal cancer (CRC), there are few studies on the interactions between identified single-nucleotide polymorphisms (SNPs) and lifestyle risk factors. We evaluated whether smoking could modify associations between these genetic variants and CRC risk. METHODS: A total of 703 CRC patients and 1406 healthy controls were included in this case control study from the National Cancer Center in Korea. Thirty CRC susceptibility SNPs identified in previous GWAS were genotyped. A logistic regression model was used to examine associations between the SNPs and smoking behaviors by sex. The interaction was estimated by including an additional interaction term in the model. RESULTS: In men, an increased CRC risk was observed for longer durations (OR>28 vs. <=28years = 1.49 (95% CI = 1.11-1.98)), greater quantities (OR>=20 vs. <20cigarettes/day = 2.12 (1.61-2.79)), and longer pack-years of smoking (OR>=21 vs. <21pack-years = 1.78 (1.35-2.35)). In women, longer pack-years of smoking significantly increased CRC risk (OR>=5 vs. <5pack-years = 6.11 (1.10-34.00)). Moreover, there were significant interactions between smoking status and the polymorphisms rs1957636 at 14q22.3 (P interaction = 5.5 * 10-4) and rs4813802 at 20p12.3 (P interaction = 0.04) in men. Interactions between smoking status and the rs6687758 at 1q41 (P interaction = 0.03), duration and the rs174537 at 11q12.2 (P interaction = 0.05), and pack-years and the rs4813802 (P interaction = 0.04) were also found in women. CONCLUSIONS: Associations between susceptibility SNPs and CRC risk may be modified by smoking behaviors, supporting the existence of gene-smoking interactions. PMID- 29258462 TI - Determinants of unmet need for family planning in rural Burkina Faso: a multilevel logistic regression analysis. AB - BACKGROUND: Unmet need for family planning has implications for women and their families, such as unsafe abortion, physical abuse, and poor maternal health. Contraceptive knowledge has increased across low-income settings, yet unmet need remains high with little information on the factors explaining it. This study assessed factors associated with unmet need among pregnant women in rural Burkina Faso. METHOD: We collected data on pregnant women through a population-based survey conducted in 24 rural districts between October 2013 and March 2014. Multivariate multilevel logistic regression was used to assess the association between unmet need for family planning and a selection of relevant demand- and supply-side factors. RESULTS: Of the 1309 pregnant women covered in the survey, 239 (18.26%) reported experiencing unmet need for family planning. Pregnant women with more than three living children [OR = 1.80; 95% CI (1.11-2.91)], those with a child younger than 1 year [OR = 1.75; 95% CI (1.04-2.97)], pregnant women whose partners disapproves contraceptive use [OR = 1.51; 95% CI (1.03-2.21)] and women who desired fewer children compared to their partners preferred number of children [OR = 1.907; 95% CI (1.361-2.672)] were significantly more likely to experience unmet need for family planning, while health staff training in family planning logistics management (OR = 0.46; 95% CI (0.24-0.73)] was associated with a lower probability of experiencing unmet need for family planning. CONCLUSION: Findings suggest the need to strengthen family planning interventions in Burkina Faso to ensure greater uptake of contraceptive use and thus reduce unmet need for family planning. PMID- 29258463 TI - Vaccination of infants aged 0 to 11 months at the Yaounde Gynaeco-obstetric and pediatric hospital in Cameroon: how complete and how timely? AB - BACKGROUND: Vaccination is a major, but simple and cost effective public health intervention in the prevention of infectious diseases, especially in children. Nowadays, many children still miss scheduled vaccines in the Extended Program of Immunization (EPI) or are being vaccinated after the recommended ages.This study was aimed at assessing vaccination completeness and timeliness in children aged 0 to 11 months attending the vaccination clinic of the Yaounde Gynaeco-Obstetric and Pediatric Hospital. METHODS: This was an observational cross-sectional study over a period of 3 months (1st February to 30th April 2016). 400 mothers were interviewed and their children's vaccination booklets analyzed. Information on the children and the parents was collected using a pretested questionnaire. Data analysis was done using SPSS version 20 software. Bivariate and multivariate analysis with logistic regression was done to assess the determinants of completeness and timeliness. RESULTS: A total of 400 mother-infant pairs were sampled. The vaccination completeness rate was 96.3%. This rate varied between 99.50% for BCG and 94.36% for IPV. Most of the children were born at the Yaounde Gynaeco-Obstetric and Pediatric hospital where they were regularly receiving their vaccines. The proportion of correctly vaccinated infants was 73.3%. The most differed vaccines were BCG, PCV13 and IPV. Factors influencing immunization completeness were the father's profession and the mother's level of education. CONCLUSIONS: Despite the high immunization coverage, some children did not complete their EPI vaccines and many of them took at least one vaccine after the recommended age. PMID- 29258464 TI - Evaluation of unplanned dialysis as a predictor of mortality in elderly dialysis patients: a retrospective data analysis. AB - BACKGROUND: Increasing numbers of elderly patients are undergoing long-term dialysis. However, the role of dialysis in survival and quality of life is unclear, and poor outcomes may be associated with comorbidities rather than with age only. The initiation of unplanned dialysis in elderly patients with chronic kidney disease (CKD) has been reported to be associated with poor survival. We evaluated patient and practice factors associated with poor survival. METHODS: We performed a retrospective analysis of 90 consecutive elderly patients (>=75 years) with CKD initiated on long-term dialysis at our renal unit between October 2010 and February 2014. Six patients were excluded; data from 84 remaining patients (>=75 years) with end-stage renal disease undergoing planned or unplanned dialysis were analyzed. Patients were followed up until death or January 2015. Patient factors such as age at initiation of dialysis and comorbidities (i.e., diabetes mellitus, ischemic heart disease [IHD], peripheral vascular disease, cancer, chronic obstructive pulmonary disease, and cognitive dysfunction) were analyzed. Practice factors such as planned or unplanned initiation of dialysis were compared in relation to survival outcomes. "Unplanned dialysis" was defined as a patient with known CKD stage 4 or 5 who had not been evaluated by a nephrologist in the 3 months before dialysis initiation. RESULTS: The average age at dialysis initiation was 81.5 +/- 4.5 years), serum albumin level was 24.8 +/- 6 g/L, body mass index was 22.5 +/- 4.8 kg/m2, and glycated hemoglobin A1c level was 6.3 +/- 1.3. Overall, 51 (61%) and 33 (39%) patients underwent unplanned and planned dialysis, respectively. On univariate analysis, the presence of IHD, peripheral vascular disease, >=3 comorbidities, and unplanned initiation of dialysis were significantly related to death. On multivariate analysis, unplanned start of dialysis, ischemic heart diseases and peripheral vascular disease remained significant. Survival rates at 3 and 12 months were 38.6% vs. 90.9% and 14.4% vs. 73.6% for unplanned vs. planned dialysis, respectively (p < 0.001). Unplanned dialysis was significantly associated with greater mortality. CONCLUSIONS: In elderly dialysis patients, unplanned start of dialysis was associated with poor survival. Patient characteristics such as associated peripheral vascular disease and IHD were associated with poor survival. PMID- 29258465 TI - Market mechanisms for newborn health in Nepal. AB - BACKGROUND: In Nepal, hypothermia is a major risk factor for newborn survival, but the country's public health care sector has insufficient capacity to improve newborn survival given the burden imposed by distance to health facilities and cost. Low-cost technology to provide newborn thermal care in resource-limited environments exists, but lacks effective distribution channels. This study aims to develop a private sector distribution model for dedicated newborn thermal care technology to ensure equitable access to thermal protection and ultimately improve newborn health in Nepal. METHODS: We conducted a document analysis of newborn health policy in Nepal and a scoping literature review of approaches to newborn hypothermia in the region, followed by qualitative interviews with key stakeholders of newborn health in Nepal. RESULTS: Current solutions addressing newborn hypothermia range from high-technology, high-cost incubators to low-cost behavioral interventions such as skin-to-skin care. However, none of these interventions are currently implemented at scale. A distribution model that provides incentives for community health volunteers and existing public health services in Nepal can deliver existing low-cost infant warmers to disadvantaged mothers where and when needed. Newborn technology can serve as an adjunct to skin to-skin care and potentially create demand for newborn care practices. CONCLUSION: Harnessing market forces could promote public health by raising awareness of newborn challenges, such as newborn hypothermia, and triggering demand for appropriate health technology and related health promotion behaviors. Market approaches to promoting public health have been somewhat neglected, especially in economically disadvantaged and vulnerable populations, and deserve greater attention in Nepal and other settings with limited public health service delivery capacity. PMID- 29258466 TI - Cervical cytology and human papillomavirus among asymptomatic healthy volunteers in Vientiane, Lao PDR. AB - BACKGROUND: Cervical cancer is the most common cancer in women living in Vientiane, Lao People's Democratic Republic (PDR). This study examines cervical cytology using a liquid-based cytology (LBC) method and reports the presence of high-risk (HR) human papillomavirus (HPV). METHODS: We collected cervical samples from 1475 asymptomatic and healthy volunteers from six hospitals in Lao PDR. A total of 1422 volunteers (mean age 39.1 +/- 6.4 years, range 30-54 years) were included in the final analysis. We performed HPV typing using the polymerase chain reaction technique to detect HR-HPV samples with abnormal cytology. RESULTS: The overall rates of abnormal cytology and HR-HPV-positive in the samples were 9.3% (132/1422) and 47.7% (63/132), respectively. The samples with abnormal cytology included 13 high-grade squamous intraepithelial lesions and one squamous cell carcinoma case. The results showed that the most common type of HPV was HPV16 (20.5%) followed by HPV58 (9.1%). CONCLUSIONS: Healthy women in Vientiane, the capital of Lao PDR, have high rates of abnormal cervical cytology and are likely to be HR-HPV-positive. A system for detection and prevention of cervical cancer in these women should be developed in the near future. PMID- 29258467 TI - Risk of second primary cancers in cancer patients treated with cisplatin: a systematic review and meta-analysis of randomized studies. AB - BACKGROUND: Case reports, retrospective analyses, and observational studies have linked the use of cisplatin to increased risk of second cancers, especially life threatening secondary leukemia. We therefore performed a systematic review and meta-analysis to evaluate the risk of second cancers associated with receipt of cisplatin-based chemotherapy in randomized controlled trials (RCTs). METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant RCTs comparing cisplatin- versus non cisplatin-containing chemotherapy with data on second cancers. We extracted data about study characteristics and second cancers, especially leukemia/ myelodysplasia. The primary and secondary outcomes were the odds ratios (ORs) for all second cancers and for secondary leukemia/ myelodysplasia, respectively. RESULTS: We identified 28 eligible trials with 7403 patients. Second cancers were reported in 143 patients, including 75 patients in the cisplatin arm and 68 in the non-cisplatin arm (raw event rates of 1.91 and 1.96%, respectively). The pooled OR for risk of all second cancers associated with cisplatin-based chemotherapy was 0.95 (95% confidence interval (CI): 0.67-1.33, P = 0.76). Secondary leukemia/ myelodysplasia was reported in 14 patients on cisplatin arms and in 6 patients on non-cisplatin arms of 11 eligible RCTs with 2629 patients (raw event rates of 1.09 and 0.45%, respectively; pooled OR = 2.34, 95%CI 0.97 5.65, P = 0.06). CONCLUSION: Cisplatin was not associated with a significantly increased risk of second cancers compared with non-cisplatin-based chemotherapy. There is a non-significant trend to increased risk of leukemia/ myelodysplasia and the absolute risk was low. The concern about risk of second cancers should not influence decisions to use an efficacious regimen containing cisplatin. PMID- 29258469 TI - Blood pressure self-monitoring in pregnancy (BuMP) feasibility study; a qualitative analysis of women's experiences of self-monitoring. AB - BACKGROUND: Hypertensive disorders in pregnancy are a leading cause of maternal and fetal morbidity worldwide. Raised blood pressure (BP) affects 10% of pregnancies worldwide, of which almost half develop pre-eclampsia. The proportion of pregnant women who have risk factors for pre-eclampsia (such as pre-existing hypertension, obesity and advanced maternal age) is increasing. Pre-eclampsia can manifest itself before women experience symptoms and can develop between antenatal visits. Incentives to improve early detection of gestational hypertensive disorders are therefore strong and self-monitoring of blood pressure (SMBP) in pregnancy might be one means to achieve this, whilst improving women's involvement in antenatal care. The Blood Pressure Self-Monitoring in Pregnancy (BuMP) study aimed to evaluate the feasibility and acceptability of SMBP in pregnancy. METHODS: To understand women's experiences of SMBP during pregnancy, we undertook a qualitative study embedded within the BuMP observational feasibility study. Women who were at higher risk of developing hypertension and/or pre-eclampsia were invited to take part in a study using SMBP and also invited to take part in an interview. Semi-structured interviews were conducted at the women's homes in Oxfordshire and Birmingham with women who were self monitoring their BP as part of the BuMP feasibility study in 2014. Interviews were conducted by a qualitative researcher and transcribed verbatim. A framework approach was used for analysis. RESULTS: Fifteen women agreed to be interviewed. Respondents reported general willingness to engage with monitoring their own BP, feeling that it could reduce anxiety around their health during pregnancy, particularly if they had previous experience of raised BP or pre-eclampsia. They felt able to incorporate self-monitoring into their weekly routines, although this was harder post-partum. Self-monitoring of BP made them more aware of the risks of hypertension and pre-eclampsia in pregnancy. Feelings of reassurance and empowerment were commonly reported by the women in our sample. CONCLUSIONS: SMBP in pregnancy was both acceptable and feasible to women in this small pilot study. PMID- 29258468 TI - Variability of activity patterns across mood disorders and time of day. AB - BACKGROUND: Few actigraphy studies in mood disorders have simultaneously included unipolar (UP) and bipolar (BD) depression or BD mixed states as a separate subgroup from mania. This study compared objectively measured activity in UP, BD depression, mania and mixed states and examined if patterns differed according to time of day and/or diagnostic group. METHODS: Eighty -eight acutely admitted inpatients with mood disorders (52 UP; 18 mania; 12 BD depression; 6 mixed states) underwent 24 hours of actigraphy monitoring. Non-parametric analyses were used to compare median activity level over 24 h (counts per minute), two time series (64-min periods of continuous motor activity) in the morning and evening, and variability in activity across and within groups. RESULTS: There was no between-group difference in 24-h median level of activity, but significant differences emerged between BD depression compared to mania in the active morning period, and between UP and mania and mixed states in the active evening period. Within-group analyses revealed that UP cases showed several significant changes between morning and evening activity, with fewer changes in the BD groups. CONCLUSIONS: Mean activity over 24 hours has limited utility in differentiating UP and BD. In contrast, analysis of non-linear variability measures of activity at different times of day could help objectively distinguish between mood disorder subgroups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01415323 , first registration July 6, 2011. PMID- 29258470 TI - Health and healthcare disparities among U.S. women and men at the intersection of sexual orientation and race/ethnicity: a nationally representative cross sectional study. AB - BACKGROUND: Research has shown that sexual minorities (SMs) (e.g. lesbian, gay, and bisexual individuals), compared to their heterosexual counterparts, may engage in riskier health behaviors, are at higher risk of some adverse health outcomes, and are more likely to experience reduced health care access and utilization. However, few studies have examined how the interplay between race and sexual orientation impacts a range of health measures in a nationally representative sample of the U.S. POPULATION: METHODS: To address these gaps in the literature, we sought to investigate associations between sexual orientation identity and health/healthcare outcomes among U.S. women and men within and across racial/ethnic groups. Using 2013-2015 National Health Interview Survey data (N = 91,913) we employed Poisson regression with robust variance to directly estimate prevalence ratios (PR) comparing health and healthcare outcomes among SMs of color to heterosexuals of color and white heterosexuals, stratified by gender and adjusting for potential confounders. RESULTS: The sample consisted of 52% women, with approximately 2% of each sex identifying as SMs. Compared to their heterosexual counterparts, white (PR = 1.25 [95% confidence interval (CI): 1.08-1.45]) and black (1.54 [1.07, 2.20]) SM women were more likely to report heavy drinking. Hispanic/Latino SM women and men were more likely to experience short sleep duration compared to white heterosexual women (1.33 [1.06, 1.66]) and men (1.51 [1.21, 1.90). Black SM women had a much higher prevalence of stroke compared to black heterosexual women (3.25 [1.63, 6.49]) and white heterosexual women (4.51 [2.16, 9.39]). White SM women were more likely than white heterosexual women to be obese (1.31 [1.15, 1.48]), report cancer (1.40 [1.07, 1.82]) and report stroke (1.91 [1.16, 3.15]. White (2.41 [2.24, 2.59]), black (1.40[1.20, 1.63]), and Hispanic/Latino SM (2.17 [1.98, 2.37]) men were more likely to have been tested for HIV than their heterosexual counterparts. CONCLUSIONS: Sexual minorities had a higher prevalence of some poor health behaviors, health outcomes, and healthcare access issues, and these disparities differed across racial groups. Further research is needed to investigate potential pathways, such as discrimination, in the social environment that may help explain the relationship between sexual orientation and health. PMID- 29258472 TI - Pediatric non-diabetic ketoacidosis: a case-series report. AB - BACKGROUND: This study is to explore the clinical characteristics, laboratory diagnosis, and treatment outcomes in pediatric patients with non-diabetic ketoacidosis. METHODS: Retrospective patient chart review was performed between March 2009 to March 2015. Cases were included if they met the selection criteria for non-diabetic ketoacidosis, which were: 1) Age <= 18 years; 2) urine ketone positive ++ or >8.0 mmol/L; 3) blood ketone >3.1 mmol/L; 4) acidosis (pH < 7.3) and/or HCO3 < 15 mmol/L; 5) random blood glucose level < 11.1 mmol/L. Patients who met the criteria 1, 4, 5, plus either 2 or 3, were defined as non-diabetic ketoacidosis and were included in the report. RESULTS: Five patients with 7 episodes of non-diabetic ketoacidosis were identified. They all presented with dehydration, poor appetite, and Kussmaul breathing. Patients treated with insulin plus glucose supplementation had a quicker recovery from acidosis, in comparison to those treated with bicarbonate infusion and continuous renal replacement therapy. Two patients treated with bicarbonate infusion developed transient coma and seizures during the treatment. CONCLUSION: Despite normal or low blood glucose levels, patients with non-diabetic ketoacidosis should receive insulin administration with glucose supplementation to correct ketoacidosis. PMID- 29258471 TI - The influence of caregiver depression on adolescent mental health outcomes: findings from refugee settlements in Uganda. AB - BACKGROUND: Family-level predictors, including caregiver depression, are considered important influences on adolescent mental health. Adolescent depression and anxiety in refugee settings is known to be a significant public health concern, yet there is very limited literature from humanitarian settings focusing on the relationship between caregiver mental health and adolescent mental health. In the context of a larger study on child protection outcomes in refugee settings, researchers explored the relationship between caregiver depression and adolescent mental health in two refugee settlements, Kiryandongo and Adjumani, in Uganda. METHODS: Adolescents between 13 and 17 and their caregivers participated in a household survey, which included measures of adolescent anxiety and depression, and caregiver depression. Analysis was conducted using multiple logistic regression models, and results were reported for the full sample and for each site separately. RESULTS: In Kiryandongo, a one unit increase in a caregiver's depression score tripled the odds that the adolescent would have high levels of anxiety symptoms (AOR: 3.0, 95% CI: 1.4, 6.1), while in Adjumani, caregiver depression did not remain significant in the final model. Caregiver depression, gender and exposure to violence were all associated with higher symptoms of adolescent depression in both sites and the full sample, for example, a one unit increase in caregiver depression more than tripled the odds of higher levels of symptoms of adolescent depression (AOR: 3.6, 95% CI: 2.0, 6.2). Caregiver depression is a consistently significantly associated with adverse mental health outcomes for adolescents in this study. CONCLUSIONS: Adolescent well-being is significantly affected by caregiver mental health in this refugee context. Child protection interventions in humanitarian contexts do not adequately address the influence of caregivers' mental health, and there are opportunities to integrate child protection programming with prevention and treatment of caregivers' mental health symptoms. PMID- 29258473 TI - Proteomics analysis and proteogenomic characterization of different physiopathological human lenses. AB - BACKGROUND: The aim of the present study was to identify the proteomic differences among human lenses in different physiopathological states and to screen for susceptibility genes/proteins via proteogenomic characterization. METHODS: The total proteomes identified across the regenerative lens with secondary cataract (RLSC), congenital cataract (CC) and age-related cataract (ARC) groups were compared to those of normal lenses using isobaric tagging for relative and absolute protein quantification (iTRAQ). The up-regulated proteins between the groups were subjected to biological analysis. Whole exome sequencing (WES) was performed to detect genetic variations. RESULTS: The most complete human lens proteome to date, which consisted of 1251 proteins, including 55.2% previously unreported proteins, was identified across the experimental groups. Bioinformatics functional annotation revealed the common involvement of cellular metabolic processes, immune responses and protein folding disturbances among the groups. RLSC-over-expressed proteins were characteristically enriched in the intracellular immunological signal transduction pathways. The CC groups featured biological processes relating to gene expression and vascular endothelial growth factor (VEGF) signaling transduction, whereas the molecular functions corresponding to external stress were specific to the ARC groups. Combined with WES, the proteogenomic characterization narrowed the list to 16 candidate causal molecules. CONCLUSIONS: These findings revealed common final pathways with diverse upstream regulation of cataractogenesis in different physiopathological states. This proteogenomic characterization shows translational potential for detecting susceptibility genes/proteins in precision medicine. PMID- 29258474 TI - Full title: peripheral venous catheter complications in children: predisposing factors in a multicenter prospective cohort study. AB - BACKGROUND: Peripheral venous catheterization (PVC) is frequently used in children. This procedure is not free from potential complications. Our purpose was to identify the types and incidences of PVC complications in children and their predisposing factors in a developing country. METHODS: We conducted a prospective observational multicenter study in five pediatric and pediatric surgery departments over a period of 2 months. Two hundred fifteen PVC procedures were conducted in 98 children. The times of insertion and removal and the reasons for termination were noted, and the lifespan was calculated. Descriptive data were expressed as percentages, means, standard deviations, medians and interquartile ranges. The Chi2 test or the Fisher test, with hazard ratios and 95% confidence intervals (CI95%), as well as Student's t test or the Mann-Whitney U test were used to compare categorical and quantitative variables, respectively, in groups with and without complications. The Spearman test was used to determine correlations between the lifespan and the quantitative variables. The Kruskal Wallis test was used to test for differences in the median lifespan within 3 or more subgroups of a variable. Linear regression and logistic binary regression were used for multivariate analysis. A p-value <0.05 was considered significant. RESULTS: The mean lifespan was 68.82 +/- 35.71 h. A local complication occurred in 111 PIVC (51.9%) cases. The risk factors identified were a small catheter gauge (24-gauge) (p = 0.023), the use of a volume-controlled burette (p = 0.036), a longer duration of intravenous therapy (p < 0.001), a medical diagnosis of respiratory or infectious disease (p = 0.047), the use of antibiotics (p = 0.005), including cefotaxime (p = 0.024) and vancomycin (p = 0.031), and the use of proton pump inhibitors (p = 0.004).The lifespan of the catheters was reduced with the occurrence of a complication (p < 0.001), including the use of 24-gauge catheters (p = 0.001), the use of an electronic pump or syringe(p = 0.036) and a higher rank of the intravenous device in each patient (p = 0.010). CONCLUSIONS: PVC complications were frequent in our pediatric departments and are often associated with misuse of the device. These results could engender awareness among both doctors and nurses regarding the need for rationalization of the use of PVC and better adherence to the recommendations for the use of each drug and each administration method. PMID- 29258475 TI - Effects of demand-side incentives in improving the utilisation of delivery services in Oyam District in northern Uganda: a quasi-experimental study. AB - BACKGROUND: We evaluated the effects and financial costs of two interventions with respect to utilisation of institutional deliveries and other maternal health services in Oyam District in Uganda. METHODS: We conducted a quasi-experimental study involving intervention and comparable/control sub-counties in Oyam District for 12 months (January-December 2014). Participants were women receiving antenatal care, delivery and postnatal care services. We evaluated two interventions: the provision of (1) transport vouchers to women receiving antenatal care and delivering at two health centres (level II) in Acaba sub county, and (2) baby kits to women who delivered at Ngai Health Centre (level III) in Ngai sub-county. The study outcomes included service coverage of institutional deliveries, four antenatal care visits, postnatal care, and the percentage of women 'bypassing' maternal health services inside their resident sub-counties. We calculated the effect of each intervention on study outcomes using the difference in differences analysis. We calculated the cost per institutional delivery and the cost per unit increment in institutional deliveries for each intervention. RESULTS: Overall, transport vouchers had greater effects on all four outcomes, whereas baby kits mainly influenced institutional deliveries. The absolute increase in institutional deliveries attributable to vouchers was 42.9%; the equivalent for baby kits was 30.0%. Additionally, transport vouchers increased the coverage of four antenatal care visits and postnatal care service coverage by 60.0% and 49.2%, respectively. 'Bypassing' was mainly related to transport vouchers and ranged from 7.2% for postnatal care to 11.9% for deliveries. The financial cost of institutional delivery was US$9.4 per transport voucher provided, and US$10.5 per baby kit. The incremental cost per unit increment in institutional deliveries in the transport voucher system was US$15.9; the equivalent for the baby kit was US$30.6. CONCLUSION: The transport voucher scheme effectively increased utilisation of maternal health services whereas the baby-kit scheme was only effective in increasing institutional deliveries. The transport vouchers were less costly than the baby kits in the promotion of institutional deliveries. Such incentives can be sustainable if the Ministry of Health integrates them in the health system. PMID- 29258477 TI - Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability. AB - BACKGROUND: Massively parallel genetic sequencing allows rapid testing of known intellectual disability (ID) genes. However, the discovery of novel syndromic ID genes requires molecular confirmation in at least a second or a cluster of individuals with an overlapping phenotype or similar facial gestalt. Using computer face-matching technology we report an automated approach to matching the faces of non-identical individuals with the same genetic syndrome within a database of 3681 images [1600 images of one of 10 genetic syndrome subgroups together with 2081 control images]. Using the leave-one-out method, two research questions were specified: 1) Using two-dimensional (2D) photographs of individuals with one of 10 genetic syndromes within a database of images, did the technology correctly identify more than expected by chance: i) a top match? ii) at least one match within the top five matches? or iii) at least one in the top 10 with an individual from the same syndrome subgroup? 2) Was there concordance between correct technology-based matches and whether two out of three clinical geneticists would have considered the diagnosis based on the image alone? RESULTS: The computer face-matching technology correctly identifies a top match, at least one correct match in the top five and at least one in the top 10 more than expected by chance (P < 0.00001). There was low agreement between the technology and clinicians, with higher accuracy of the technology when results were discordant (P < 0.01) for all syndromes except Kabuki syndrome. CONCLUSIONS: Although the accuracy of the computer face-matching technology was tested on images of individuals with known syndromic forms of intellectual disability, the results of this pilot study illustrate the potential utility of face-matching technology within deep phenotyping platforms to facilitate the interpretation of DNA sequencing data for individuals who remain undiagnosed despite testing the known developmental disorder genes. PMID- 29258476 TI - Neighborhood walk score and selected Cardiometabolic factors in the French RECORD cohort study. AB - BACKGROUND: Walkable neighborhoods are purported to impact a range of cardiometabolic outcomes through increased walking, but there is limited research that examines multiple cardiometabolic outcomes. Additionally, few Walk Score (a novel measure of neighborhood walkability) studies have been conducted in a European context. We evaluated associations between neighborhood Walk Score and selected cardiometabolic outcomes, including obesity, hypertension and heart rate, among adults in the Paris metropolitan area. METHODS AND RESULTS: We used data from the second wave of the RECORD Study on 5993 participants recruited in 2011-2014, aged 34-84 years, and residing in Paris (France). To this existing dataset, we added Walk Score values for participants' residential address. We used multilevel linear models for the continuous outcomes and modified Poisson models were used for our categorical outcomes to estimate associations between the neighborhood Walk Score (both as a continuous and categorical variable) (0 100 score) and body mass index (BMI) (weight/height2 in kg/m2), obesity (kg/m2), waist circumference (cm), systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), hypertension (mmHg), resting heart rate (RHR) (beats per minute), and neighborhood recreational walking (minutes per week). Most participants lived in Walker's Paradise (48.3%). In multivariate models (adjusted for individual variables, neighborhood variables, and risk factors for cardiometabolic outcomes), we found that neighborhood Walk Score was associated with decreased BMI (beta: -0.010, 95% CI: -0.019 to -0.002 per unit increase), decreased waist circumference (beta: -0.031, 95% CI: -0.054 to -0.008), increased neighborhood recreational walking (beta: +0.73, 95% CI: +0.37 to +1.10), decreased SBP (beta: -0.030, 95% CI: -0.063 to -0.0004), decreased DBP (beta: 0.028, 95% CI: -0.047 to -0.008), and decreased resting heart rate (beta: -0.026 95% CI: -0.046 to -0.005). CONCLUSIONS: In this large population-based study, we found that, even in a European context, living in a highly walkable neighborhood was associated with improved cardiometabolic health. Designing walkable neighborhoods may be a viable strategy in reducing cardiovascular disease prevalence at the population level. PMID- 29258479 TI - Surgical treatment strategies for giant inguinoscrotal hernia - a case report with review of the literature. AB - BACKGROUND: An inguinoscrotal hernia is defined as "giant" if descending below the midpoint of the inner thigh of a patient in upright position. In developed countries this is a rare entity. In the literature different surgical techniques have been reported so far to achieve a successful treatment. CASE PRESENTATION: We present the case of a 63 year-old man suffering from a giant inguinoscrotal hernia, whom we treated using a combined open transabdominal and inguinal approach following an unsuccessful laparoscopic attempt. Meshes were placed in a premuscular position (Lichtenstein's procedure) and in a preperitoneal position. In addition, a reconstruction of the abdominal wall by modified components separation technique was performed. During the early postoperative period no complications were registered. Intensive care treatment was not necessary. The patient was discharged on postoperative day 8 in an excellent condition. Six months after surgery a scrotal hematocele was diagnosed and operatively removed. After a follow-up of 1.5 years neither hernia recurrence, nor chronic groin pain were recorded. The patient reported to be sexually active. His quality of life improved notably. Additionally, a Medline and PubMed database research was performed to create an overall picture of the existing surgical treatment strategies. Included were patients with diagnosis of primary giant inguinoscrotal hernia according to the given definition. Emergency interventions and cases without details of the surgical approach were excluded. CONCLUSIONS: Firstly, this report describes a novel, successful surgical treatment of a giant inguinoscrotal hernia without administering preoperative progressive pneumoperitoneum therapy or visceral resection. Secondly, we summarize cases previously reported as a practical guide for possible surgical therapy approaches. PMID- 29258478 TI - Pregnancy, prescription medicines and the potential risk of herb-drug interactions: a cross-sectional survey. AB - BACKGROUND: Pregnant women are routinely prescribed medicines while self medicating with herbal natural products to treat predominantly pregnancy related conditions. The aim of this study was to assess the potential for herb-drug interactions (HDIs) in pregnant women and to explore possible herb-drug interactions and their potential clinical significance. METHODS: A cross sectional survey of women during early pregnancy or immediately postpartum in North-East Scotland. Outcome measures included; Prescription medicines use excluding vitamins and potential HDIs assessed using Natural Medicines Comprehensive Database. RESULTS: The survey was completed by 889 respondents (73% response rate). 45.3% (403) reported the use of at least one prescription medicine, excluding vitamins. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1-12). A total of 91 different prescription medicines were reported by respondents using HNPs. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1-12). Thirty-four herb-drug interactions were identified in 23 (12.7%) women with the potential to increase the risk of postpartum haemorrhage, alter maternal haemodynamics, and enhance maternal/fetal CNS depression. Almost all were rated as moderate (93.9%), one as a potentially major (ginger and nifedipine) and only one minor (ondansetron and chamomile). CONCLUSION: Almost half of pregnant women in this study were prescribed medicines excluding vitamins and minerals and almost half of these used HNPs. Potential moderate to severe HDIs were identified in an eighth of the study cohort. Healthcare professionals should be aware that the concurrent use of HNPs and prescription medicines during pregnancy is common and carries potential risks. PMID- 29258480 TI - End of life care preferences among people of advanced age: LiLACS NZ. AB - BACKGROUND: Understanding end of life preferences amongst the oldest old is crucial to informing appropriate palliative and end of life care internationally. However, little has been reported in the academic literature about the end of life preferences of people in advanced age, particularly the preferences of indigenous older people, including New Zealand Maori. METHODS: Data on end of life preferences were gathered from 147 Maori (aged >80 years) and 291 non- Maori aged (>85 years), during three waves of Te Puawaitangi O Nga Tapuwae Kia Ora Tonu, Life and Living in Advanced Age (LiLACs NZ). An interviewer-led questionnaire using standardised tools and including Maori specific subsections was used. RESULTS: The top priority for both Maori and non-Maori participants at end of life was 'not being a burden to my family'. Interestingly, a home death was not a high priority for either group. End of life preferences differed by gender, however these differences were culturally contingent. More female Maori participants wanted spiritual practices at end of life than male Maori participants. More male non-Maori participants wanted to be resuscitated than female non- Maori participants. CONCLUSIONS: That a home death was not in the top three end of life priorities for our participants is not consistent with palliative care policy in most developed countries where place of death, and particularly home death, is a central concern. Conversely our participants' top concern - namely not being a burden - has received little research or policy attention. Our results also indicate a need to pay attention to diversity in end of life preferences amongst people of advanced age, as well as the socio-cultural context within which preferences are formulated. PMID- 29258481 TI - Cone-beam CT findings during prostate artery embolization for benign prostatic hyperplasia-induced lower urinary tract symptoms: a case report. PMID- 29258482 TI - Assessing the recovery from prerenal and renal acute kidney injury after treatment with single herbal medicine via activity of the biomarkers HMGB1, NGAL and KIM-1 in kidney proximal tubular cells treated by cisplatin with different doses and exposure times. AB - BACKGROUND: Acute kidney injury (AKI) is an initial factor in many kidney disorders. Pre- and intra-renal AKI biomarkers have recently been reported. Recovery from AKI by herbal medicine has rarely been reported. Thus, this study aimed to investigate the dose- and time-dependent effects of herbal medicines to protect against AKI in cisplatin-induced human kidney 2 (HK-2) cells by assessing the activities of high-mobility group box protein 1 (HMGB1), neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). METHODS: Proximal tubular HK-2 cell lines were treated with either 400 MUM of cisplatin for 6 h or 10 MUM of cisplatin for 24 h and then exposed to ten types of single herbal medicines, including Nelumbo nymphaea (NY) at a dose of 100 MUg/mL. The AKI biomarkers HMGB1, NGAL and KIM-1 were repeatedly measured by an ELISA assay at 2, 4, and 6 h in the group treated with 400 MUM of cisplatin to confirm necrotic cell death and at 6, 24, and 48 h in the group treated with 10 MUM of cisplatin to examine apoptotic cell death. Recovery confirm was conducted through in vivo study using ICR mice for 3 day NY or Paeonia suffruticosa intake. RESULTS: Cisplatin treatment at a concentration of 10 MUM decreased cell viability. Treatment with 400 MUM of cisplatin reduced HMBG1 activity and resulted in lactate dehydrogenase release. In longer exposure durations (up to 48 h), NGAL and KIM-1 exhibited activity from 24 h onward. Additionally, NY treatment resulted in an approximately 50% change in all three biomarkers. The time-dependent profiles of HMGB1, NGAL and KIM-1 activities up to 48 h were notably different; HMGB1 exhibited a 7-fold change at 6 h, and NGAL and KIM-1 exhibited 1.7-fold changes at 24 h, respectively. Consistently, serum and urine NGAL and KIM-1 activities were all reduced in ICR mice. CONCLUSIONS: Several single herbal medicines, including NY, have a potential as effectors of AKI due to their ability to inhibit the activation of HMGB1, NGAL and KIM-1 in an in vitro AKI-mimicked condition and simple in vivo confirm. Furthermore, an in vivo proof-of-concept study is needed. PMID- 29258483 TI - Developing a policy game intervention to enhance collaboration in public health policymaking in three European countries. AB - BACKGROUND: One of the key elements to enhance the uptake of evidence in public health policies is stimulating cross-sector collaboration. An intervention stimulating collaboration is a policy game. The aim of this study was to describe the design and methods of the development process of the policy game 'In2Action' within a real-life setting of public health policymaking networks in the Netherlands, Denmark and Romania. METHODS: The development of the policy game intervention consisted of three phases, pre intervention, designing the game intervention and tailoring the intervention. RESULTS: In2Action was developed as a role-play game of one day, with main focus to develop in collaboration a cross sector implementation plan based on the approved strategic local public health policy. CONCLUSIONS: This study introduced an innovative intervention for public health policymaking. It described the design and development of the generic frame of the In2Action game focusing on enhancing collaboration in local public health policymaking networks. By keeping the game generic, it became suitable for each of the three country cases with only minor changes. The generic frame of the game is expected to be generalizable for other European countries to stimulate interaction and collaboration in the policy process. PMID- 29258484 TI - Lung ultrasonography to diagnose community-acquired pneumonia in children. AB - BACKGROUND: Early diagnosis of community-acquired pneumonia (CAP) is essential to reduce the total burden of this disease. Traditionally, chest radiography (CR) is used to identify true CAP. However, CR is not a perfect diagnostic test for CAP. The use of lung ultrasonography (LUS) has been suggested as an alternative to overcome the problems associated with CR and increase the feasibility and accuracy of CAP diagnosis. LUS has largely been used for the diagnosis of several lung problems, including CAP, in adult patients with satisfactory results. Experience with LUS in children has grown over recent years. The main aim of this paper is to discuss the advantages and limits of LUS in the diagnosis of paediatric CAP. DISCUSSION: The presence of a consolidation pattern during LUS may represent pneumonia or atelectasis, although this conclusion is operator dependent. An overall agreement between LUS and CR was observed in most of the studies that were examined. In most reports where a disagreement between the two methods was found, CR was not able to identify the cases that were correctly diagnosed by LUS, particularly when CR was performed only with postero anterior/antero-posterior projection and consolidation was observed in lung areas that are poorly visualized by CR. However, the lack of standardized LUS methods is problematic. Finally, the real advantage of LUS for the diagnosis of CAP in children remains unclear. LUS is an interesting diagnostic modality that appears a useful first imaging test in children with suspected CAP. However, the methods used to perform LUS in children are not precisely standardized, and the diagnosis of interstitial CAP is inaccurate. Further studies are needed before LUS can be routinely used in everyday paediatric practice. PMID- 29258485 TI - Diversity of root-knot nematodes in Moroccan olive nurseries and orchards: does Meloidogyne javanica disperse according to invasion processes? AB - BACKGROUND: Root-knot nematodes (RKN) are major pest of olive tree (Olea europaea ssp. europaea), especially in nurseries and high-density orchards. Soil samples were collected from main olive growing areas of Morocco, to characterize Meloidogyne species and to discuss the contribution of biotic and abiotic factors in their spatial distribution. RESULTS: RKN were found in 159 soil samples out of 305 from nurseries (52.1% occurrence) and in 11 out of 49 soil samples from orchards (23.2% occurrence). Biochemical and molecular characterisation (PAGE esterase and SCAR) revealed the dominance of M. javanica both in nurseries and orchards with minor presence of M. incognita only in nurseries, and M. arenaria in only one nursery. RKN were distributed on aggregated basis. Frequent presence of M. javanica in orchards might have come from nurseries. In contrast, the detection of M. incognita in nurseries alone suggests that this species could not reproduce in orchards because of either the competition with other plant parasitic nematodes or unfit local habitats. The impact of environmental variables (climate, habitat origin and physicochemical characteristics of the substrates) on the distribution of Meloidogyne species is also discussed. CONCLUSION: Olive nurseries in Morocco are not able to guarantee the safety of rooted plants. As a result, olive production systems are exposed to strong RKN invasion risks. Consequently, the use of healthy substrates in nurseries may prevent plant-parasitic nematode induction in orchards. PMID- 29258486 TI - Laser-fabricated cell patterning stencil for single cell analysis. AB - Precise spatial positioning and isolation of mammalian cells is a critical component of many single cell experimental methods and biological engineering applications. Although a variety of cell patterning methods have been demonstrated, many of these methods subject cells to high stress environments, discriminate against certain phenotypes, or are a challenge to implement. Here, we demonstrate a rapid, simple, indiscriminate, and minimally perturbing cell patterning method using a laser fabricated polymer stencil. The stencil fabrication process requires no stencil-substrate alignment, and is readily adaptable to various substrate geometries and experiments. PMID- 29258487 TI - Ephemeral-habitat colonization and neotropical species richness of Caenorhabditis nematodes. AB - BACKGROUND: The drivers of species co-existence in local communities are especially enigmatic for assemblages of morphologically cryptic species. Here we characterize the colonization dynamics and abundance of nine species of Caenorhabditis nematodes in neotropical French Guiana, the most speciose known assemblage of this genus, with resource use overlap and notoriously similar external morphology despite deep genomic divergence. METHODS: To characterize the dynamics and specificity of colonization and exploitation of ephemeral resource patches, we conducted manipulative field experiments and the largest sampling effort to date for Caenorhabditis outside of Europe. This effort provides the first in-depth quantitative analysis of substrate specificity for Caenorhabditis in natural, unperturbed habitats. RESULTS: We amassed a total of 626 strain isolates from nine species of Caenorhabditis among 2865 substrate samples. With the two new species described here (C. astrocarya and C. dolens), we estimate that our sampling procedures will discover few additional species of these microbivorous animals in this tropical rainforest system. We demonstrate experimentally that the two most prevalent species (C. nouraguensis and C. tropicalis) rapidly colonize fresh resource patches, whereas at least one rarer species shows specialist micro-habitat fidelity. CONCLUSION: Despite the potential to colonize rapidly, these ephemeral patchy resources of rotting fruits and flowers are likely to often remain uncolonized by Caenorhabditis prior to their complete decay, implying dispersal-limited resource exploitation. We hypothesize that a combination of rapid colonization, high ephemerality of resource patches, and species heterogeneity in degree of specialization on micro habitats and life histories enables a dynamic co-existence of so many morphologically cryptic species of Caenorhabditis. PMID- 29258488 TI - Comparison of cortisol and inflammatory response between aged and middle-aged patients undergoing total hip arthroplasty: a prospective observational study. AB - BACKGROUND: To investigate the differences in the perioperative serum cortisol, C reactive protein (CRP) and interleukin-6 (IL-6) levels between aged and middle aged patients undergoing total hip arthroplasty (THA). METHODS: Sixty patients (30 aged and 30 middle-aged) undergoing THA for osteoarthritis between August 2016 and January 2017 participated in this study. Blood samples were collected preoperatively and at 6 hours, 24 hours and 3 days after surgery to measure the cortisol, CRP and IL-6 concentrations. The clinical outcomes were assessed using the visual analogue scale (VAS) pain score and Harris hip score (HHS). RESULTS: No significant differences were found between the two groups before the operation in the cortisol, IL-6 and CRP levels; the VAS score; or the HHS. Cortisol was significantly lower at 6 hours after surgery in the aged group than in the middle aged group (P < 0.05). IL-6 at 6 and 24 hours after surgery, CRP at 3 days after surgery and the VAS score at 6 and 24 hours after surgery in the aged group were significantly higher than those in the middle-aged group (P < 0.05). In the aged group, weak correlations were found between the cortisol concentration 6 hours after THA and the IL-6 level 24 hours after THA (r = -0.37, P = 0.04) and between the IL-6 level 6 hours after THA and the VAS score 24 hours after THA (r = 0.42, P = 0.02). CONCLUSION: Aged patients showed lower cortisol levels at 6 hours after surgery and higher IL-6 levels at 6 and 24 hours after surgery than middle aged patients undergoing THA. PMID- 29258489 TI - Self-rated health and perceived violence in the neighborhood is heterogeneous between young women and men. AB - BACKGROUND: Self-rated health (SRH) is the general perception of an individual's own health and a key indicator to measure health in population-based studies. Few studies have examined the association between perceived urban violence and SRH among young adults. There were an estimated 475,000 deaths in 2012 as a result of homicide on the world. Sixty percent of these deaths occurred among males aged 15 44 years, making homicide the third leading cause of death for this population group. This study aimed to determine and quantify the association between sex specific perception of violence in the neighborhood and SRH among young adults. METHODS: Participants included 955 young adults (18-29 years) residing in Belo Horizonte, Minas Gerais, Brazil between 2008 and 2009. Logistic regression analysis was used to estimate the strength of the associations. The perceived urban violence score was constructed from variables that assessed the respondents' insecurity and perception of fear and danger of suffering some form of violence in the neighborhood using exploratory factor analysis. RESULTS: 18,3% of respondents rated their health as fair/ poor/very poor. Among women, fair/ poor/very poor SRH was associated with age between 25 and 29 years, low socioeconomic status score, being dissatisfied with weight, not exercising regularly, not having a healthy diet, and having some chronic disease. Men who rated their health as fair/poor/very poor more frequently smoked, were dissatisfied with their weight, did not exercise regularly, consumed fewer fruits and vegetables, and had some chronic disease compared to men who rated their health as very good/good. In the final model, after adjusting for confounding variables, perceived violence in the neighborhood was associated with poor SRH in young women only (OR = 1.52; 95% CI: 1.04-2.21). CONCLUSION: The results indicate that public and health policies should implement interventions on the neighborhood physical and social environment to improve the perception of safety and have a positive impact on people's health, especially women. PMID- 29258490 TI - Cytotoxic, antioxidative, genotoxic and antigenotoxic effects of Horchata, beverage of South Ecuador. AB - BACKGROUND: "Horchata" is an herbal mixture infusion consumed in Southern Ecuador; 66% of its plants are anti-inflammatory medicinal plant, and 51% are analgesics. Anti-inflammatory substances can prevent carcinogenesis mediated by cytotoxic effects and can prevent DNA damage. The aim of this study was to evaluate the cytotoxicity and apoptotic/antigenotoxic effects of horchata as well as its mechanism. METHODS: Nine different varieties of horchata were prepared in the traditional way and then freeze-dried. Phytochemical screening tested for the presence of secondary metabolites using standard procedures and antioxidant activities. The cytotoxic activity was evaluated on cerebral astrocytoma (D-384), prostate cancer (PC-3), breast cancer (MCF-7), colon cancer (RKO), lung cancer (A 549), immortalized Chinese hamster ovary cells (CHO-K1), and human peripheral blood lymphocytes via a MTS assay. The pro-apoptotic effects were evaluated with Anexin V/Propidium Iodide and western blot of Bax, Bcl-2, TP53, and TP73. Induction and reduction of ROS were assessed by fluorimetry. Genotoxic and antigenotoxic effects were evaluated with a comet assay and micronuclei on binucleated cells. RESULTS: Five of nine horchatas had cytotoxic effects against D-384 while not affecting normal cells. These horchatas induce cell death by apoptosis modulated by p53/p73. In CHO-K1 cells, the horchatas decrease the damage induced by hydrogen peroxide and Mitomycin C measured in the comet and micronucleus assay respectively. CONCLUSIONS: The IC50 range of effective horchatas in D-384 was 41 to 122 MUg.mL-1. This effect may be related to its use in traditional medicine (brain tonic). On the other hand, immortalized Chinese hamster ovary cells (CHO-K1) and lymphocytes did not show a cytotoxic effect. The most potent horchata induced apoptosis via a p53/p73-mediated mechanism. The horchatas present antigenotoxic properties, which may be related to the antioxidant capacity. Future studies on horchata components are necessary to understand the interactions and beneficial properties. PMID- 29258491 TI - Dental and medical health status and oral health knowledge among visually impaired and sighted female schoolchildren in Riyadh: a comparative study. AB - BACKGROUND: The impact of visual impairment on oral health in the literature is inconclusive, and the available information on the medical and dental health status of visually impaired children is limited. The aim of this study was to evaluate the dental and medical health status, and to assess the oral health knowledge of visually impaired girls aged 6-12 years, and compare them to that of sighted children. METHODS: This analytical cross-sectional study was carried out on 79 visually impaired and 83 age-matched sighted female primary school children. The children's demographic data, medical history, and dental history were obtained through a validated questionnaire. The study population was examined to evaluate their dental caries status using the Decayed Missing Filled Teeth/Surface indices DMFT/DMFS/ and dmft/dmfs for permanent and primary teeth, respectively. Oral hygiene index (OHI), Plaque index (PI) and gingival index (GI) were obtained for periodontal evaluation. Pearson's Chi-square test and t-test were used for the statistical analyses. RESULTS: The general health for both groups was found to be good; however, 21.5% of the visually impaired children had systemic diseases compared with only 4.8% of the sighted children (P = 0.002). Statistically significant differences (P < 0.001) were found between the two groups with regards to OHI. Among the sighted children, 49.4% had good oral hygiene compared with only 22.8% of the visually impaired group. The plaque accumulation was found to be greater among the visually impaired group and gingivitis was also higher. The DMFS score was found to be higher (P = 0.03) among the visually impaired group. CONCLUSIONS: The visually impaired children had more medical conditions and poorer oral health status compared to their sighted peers. PMID- 29258492 TI - Oncology nurses' perceptions of obstacles and role at the end-of-life care: cross sectional survey. AB - BACKGROUND: Major obstacles exist in the care of patients at the end of life: lack of time, poor or inadequate communication, and lack of knowledge in providing care. Three possible nursing roles in care decision-making were investigated: Information Broker, Supporter, and Advocate. The purpose of this study was to examine obstacles faced by oncology nurses in providing end-of-life (EOL) care and to examine roles of nurses in providing care. METHODS: A descriptive, cross-sectional, correlational design was applied. The study was conducted at two major University Hospitals of Oncology in Lithuania that have a combined total of 2365 beds. The study sample consisted of 239 oncology registered nurses. Data collection tool included a questionnaire about assessment of obstacles and supportive behaviors, nursing roles, and socio-demographic characteristics. RESULTS: The two items perceived by respondents as the most intense obstacles to providing EOL care were The nurse's opinion on immediate patient care is not welcome, valued or discussed and. Family has no access to psychological help after being informed about the patient's diagnosis. The majority of respondents self-assigned the role of Supporter. CONCLUSIONS: Major obstacles in providing care included the nurse's opinion that immediate patient care was not valued, lack of nursing knowledge on how to treat the patient's grieving family, and physicians who avoided conversations with the patient and family members about diagnoses and prospects. In EOL care nurses most frequently acted as Supporters and less frequently as Advocates. PMID- 29258494 TI - A rare case of osteoblastoma combined with severe scoliosis deformity, coronal and sagittal imbalance. AB - BACKGROUND: Osteoblastoma is a rare and benign tumor which requires early diagnosis and surgical excision. Scoliosis is a common presentation following osteoblastoma. It is considered due to pain-provoked muscle spasm on the side of the lesion. Few researches about osteoblastoma combined with severe scoliosis have been reported. CASE PRESENTATION: A 14-year-old girl presents with progressive scoliosis deformity for 3 years, with gradually appeared low back pain and numbness of left leg. Radiographic results showed osteoblastic mass at the left side of L3-L4 with severe scoliosis deformity, pelvic obliquity and spinal imbalance. The patient underwent posterior tumor excision, spinal decompression, scoliosis correction, spinal fusion with auto-graft and instrumentation from T8-S1. The mass was found to be osteoblastoma. The patient had a full neurological recovery with no aggravate of scoliosis or spinal imbalance during the follow-up. CONCLUSIONS: This case emphasizes the importance of early diagnosis and surgical treatment of osteoblastoma. Early surgical excision will not only prevent neurological deficit but also the progression of scoliosis. Atypical scoliosis presence without pain requires carefully examination of whether a tumor exists. PMID- 29258493 TI - Antiplatelet mechanism of an herbal mixture prepared from the extracts of Phyllostachys pubescens leaves and Prunus mume fruits. AB - BACKGROUND: Bamboo (Phyllostachys pubescens) leaves and Japanese apricot (Mume fructus) fruit are traditionally recognized to be safe herbs broadly used for food and medicinal purposes in Southeast Asia. Our group previously explored their antiplatelet effects. This study was designed to confirm inhibition effects of PM21 (a 2:1 mixture of bamboo leaf extract and Japanese apricot fruit extract) on platelet aggregation and evaluate its potency to use as an herbal remedy to prevent and/or treat the diseases caused by platelet aggregation and thrombus formation. METHODS: Washed platelets were prepared and platelet aggregation was induced by adding 5 MUg/mL collagen. Anti-platelet effects of PM21 (75 mg/kg, 150 mg/kg, and 300 mg/kg for ex vivo and in vivo assays, and 50, 100, 200 MUg/mL for in vitro assays) were evaluated. In ex vivo assays, PM21 was orally administered to rats daily after overnight fasting for 3 days and blood was collected 1 h after the final treatment. In vivo antithrombotic effect of PM21 was observed from a carrageenan induced mouse tail thrombosis model. RESULTS: In ex vivo assay, PM21 inhibited platelet aggregation significantly. PM21 showed a strong antithrombotic effect by reducing significantly the length of mouse tail thrombus. PM21 increased intracellular cAMP level and reduced the release of ATP, TXA2, and serotonin. PM21 also reduced intracellular concentration of calcium ion, fibrinogen binding to integrin alphaIIbbeta3, and phosphorylation of ERK2, p38, PLCgamma2, and PI3 K. CONCLUSIONS: PM21 showed remarkable inhibitory effects on platelet aggregation and thrombus formation. Its inhibitory function seems to influence on GPVI binding to its ligand and subsequent initiation of a signaling cascade that involves activation of effector proteins and secretion of effector molecules, such as ATP, TXA2, serotonin, and Ca2+. PM21 also appears to exert its anti-platelet effect by deactivation of ERKs activation pathway as well as inhibition of fibrinogen binding to integrin alphaIIbbeta3. PMID- 29258495 TI - Observational study of patients in Spain with amyotrophic lateral sclerosis: correlations between clinical status, quality of life, and dignity. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that dramatically affects patients' quality of life (QoL) and dignity of life (DoL). We aimed to study the impact of ALS on QoL and DoL and how these evolve throughout the duration of the disease. METHODS: First, we performed an observational, descriptive study of 43 patients with ALS recruited from the ALS unit at our center and compared them with 20 healthy age- and sex-matched controls. Second, we performed a prospective cohort study, following up 23 patients with ALS over 3 months. All participants completed questionnaires about their functional status, QoL, and DoL. RESULTS: QoL and DoL were significantly worse in the ALS group than in controls (both p < 0.001). During the three-month follow-up in the ALS cohort, statistically significant declines were observed in clinical status and QoL. For clinical status, median scores on the ALS Functional Rating scale changed from 30.95 points at baseline to 27.24 points after 3 months (p = 0.0003). For QoL, median scores on the ALS Assessment Questionnaire changed from 124.19 points at baseline to 131.81 at 3 months (p = 0.0062). However, no significant differences were found between the DoL scores at baseline (48.14 points) and 3 months (45 points) (p-value = 0.12). CONCLUSIONS: ALS is a neurodegenerative disease that affects QoL and DoL alike. We found that clinical status and QoL both deteriorated in patients with ALS as the disease progressed, but that DoL was preserved. However, our findings are limited by small sample sizes. The preservation of DoL may be due to multiple factors, including the therapies provided by the ALS unit. These findings suggest that alongside QoL, DoL may be an important target in the management and care of ALS patients. PMID- 29258496 TI - Teaching young GPs to cope with psychosocial consultations without prescribing: a durable impact of an e-module on determinants of benzodiazepines prescribing. AB - BACKGROUND: Despite guidelines and campaigns to change prescribing behavior, General Practitioners (GPs) continue to overprescribe benzodiazepines (BZDs). New approaches to improve prescribing are needed. Using behavior change techniques and tailoring interventions to user characteristics are vital to promote behavior change. This study evaluated the impact of an e-module on factors known to determine BZD prescribing practice. METHODS: A tailored e-module that focuses on avoiding initial BZD prescriptions (and using psychological interventions as an alternative) was developed and offered to GPs in vocational training. Three self report assessments took place: at baseline, immediately after the module (short term) and at least six months after completion (long term). Assessed determinants include GPs' attitudes concerning treatment options, perceptions of the patient and self-efficacy beliefs. Readiness to adhere to prescribing guidelines was evaluated through assessing motivation, self-efficacy and implementability of non pharmacological interventions. Changes in determinants were analyzed using the Wilcoxon signed-rank test. Changes in readiness to adhere to guidelines was analyzed using the nonparametric McNemar Bowker test. RESULTS: A desirable, significant and durable impact on determinants of BZD prescribing was observed. GPs (n = 121) underwent desirable changes in their attitudes, perceptions and self-efficacy beliefs and these changes remained significant months after the intervention. Barriers to using a non-pharmacological approach often cited in literature remained absent and were not highlighted by the intervention. Furthermore a significant impact on GPs' readiness to adhere to guidelines was observed. Participants reported change in their ability to cope with psychosocial consultations and to have tried using non-pharmacological interventions. CONCLUSIONS: Tailoring an e-intervention to target group (GPs) characteristics appears to be successful in promoting behavioral change in GPs undertaking vocational training. Significant and lasting changes were observed in determinants of prescribing BZDs. The e-intervention resulted in a positive impact on participants' readiness to adhere to BZD prescribing guidance and their coping with psychosocial consultations. Investigating which mechanisms of change are responsible for the observed effectiveness could help to refine and improve future interventions. PMID- 29258497 TI - Non-invasive genetic monitoring involving citizen science enables reconstruction of current pack dynamics in a re-establishing wolf population. AB - BACKGROUND: Carnivores are re-establishing in many human-populated areas, where their presence is often contentious. Reaching consensus on management decisions is often hampered by a dispute over the size of the local carnivore population. Understanding the reproductive dynamics and individual movements of the carnivores can provide support for management decisions, but individual-level information can be difficult to obtain from elusive, wide-ranging species. Non invasive genetic sampling can yield such information, but makes subsequent reconstruction of population history challenging due to incomplete population coverage and error-prone data. Here, we combine a collaborative, volunteer-based sampling scheme with Bayesian pedigree reconstruction to describe the pack dynamics of an establishing grey wolf (Canis lupus) population in south-west Finland, where wolf breeding was recorded in 2006 for the first time in over a century. RESULTS: Using DNA extracted mainly from faeces collected since 2008, we identified 81 individual wolves and assigned credible full parentages to 70 of these and partial parentages to a further 9, revealing 7 breeding pairs. Individuals used a range of strategies to obtain breeding opportunities, including dispersal to established or new packs, long-distance migration and inheriting breeding roles. Gene flow occurred between all packs but inbreeding events were rare. CONCLUSIONS: These findings demonstrate that characterizing ongoing pack dynamics can provide detailed, locally-relevant insight into the ecology of contentious species such as the wolf. Involving various stakeholders in data collection makes these results more likely to be accepted as unbiased and hence reliable grounds for management decisions. PMID- 29258498 TI - Anatomical variations of the palmaris longus muscle including its relation to the median nerve - a proposal for a new classification. AB - BACKGROUND: The palmaris longus (PL) muscle is characterised by high morphological diversity, and its tendon crosses the median nerve (MN) at different levels. Due to the fact that the palmaris longus tendon is routinely harvested for reconstruction of other tendons, knowledge of its morphological variations is clinically important. Therefore, the purpose of the study was to suggest a new morphological classification of the PL muscle and characterise the relationship of its tendon to the median nerve. METHODS: Standard dissection was performed on 80 randomised and isolated upper limbs (40 left and 40 right) fixed in a 10% formalin solution. Measurements of muscle belly and tendon were obtained. The course and location of tendon insertion, as well as its relationship to the median nerve, were noted. RESULTS: The palmaris longus muscle was present in 92.5% of specimens. Three types of palmaris longus muscle were identified based on the morphology of its insertion (types I-III) and these were further subdivided into three subgroups (A-C) according to the ratio of the length of the muscle belly and its tendon. The most frequent was type I (78.8%), where the tendon attached to the palmar aponeurosis, and subtype B, where the tendon-to-belly ratio was 1-1.5 (41.1%). The mean distance from the interstyloid line to the crossing between the median nerve and the palmaris longus tendon was 31.6 mm. In addition, two types of palmaris longus were described. CONCLUSION: The presented classification of palmaris longus muscle types allows a better characterization of its diversity and may be useful in planning tendon grafting. PMID- 29258499 TI - SMS education for the promotion of diabetes self-management in low & middle income countries: a pilot randomized controlled trial in Egypt. AB - BACKGROUND: Due to the ubiquity of mobile phones in low and middle income countries, we aimed to examine the feasibility of SMS education among diabetic patients in Egypt, and assess the impact of educational text messages, compared to traditional paper-based methods, on glycemic control and self-management behaviors. METHODS: We conducted a 12-week randomized controlled trial at Misr University for Science & Technology hospital in Cairo-Egypt. Known as MUST diabetes awareness program, patients were included if they had diabetes, owned a mobile phone, and could read SMS messages or lived with someone that could read for them. Intervention patients received daily messages and weekly reminders addressing various diabetes care categories. We expected greater improvement in their glycemic control compared to controls who only received paper-based educational material. The primary outcome was the change in HbA1c, measured by the difference between endpoint and baseline values and by the number of patients who experienced at least 1% reduction from baseline to endpoint. Key secondary outcomes included blood glucose levels, body weight, treatment and medication adherence, self-efficacy, and diabetes knowledge. Data were analyzed using ANCOVA, chi-square, and t-tests. RESULTS: Thirty four intervention and 39 control patients completed the study. Over 12 weeks, 3880 messages were sent. Each intervention patient received 84 educational and 12 reminder messages plus one welcome message. Our primary outcome did not differ significantly (Delta 0.290; 95% CI -0.402 to 0.983; p = 0.406) between groups after 3 months, demonstrating a mean drop of -0.69% and -1.05% in the control and intervention group respectively. However, 16 intervention patients achieved the targeted 1% drop versus only 6 controls, suggesting clear association between study group and 1% HbA1c reductions (chi-square = 8.655; df = 1; p = 0.003). Secondary outcomes seemed in favor of intervention patients at endpoint, with considerable improvements in treatment and medication adherence, self-efficacy, and knowledge scores. Participants also indicated full satisfaction with the program. CONCLUSIONS: SMS education is a feasible and acceptable method for improving glycemic control and self-management behaviors among Egyptian diabetics. However, whether it is more effective than traditional paper-based methods needs further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02868320 . Registered 9 August 2016. Retrospectively registered. PMID- 29258500 TI - Anti-adipogenic effects of the traditional herbal formula Dohongsamul-tang in 3T3 L1 adipocytes. AB - BACKGROUND: Blood stasis syndrome (BSS) is a general pattern identification and refers to pathological stagnation of blood circulation, dysfunction of endothelial cells or metabolic disorder in traditional Korean medicine (TKM). Dohongsamul-Tang (DHSMT) is a well-known traditional herbal formula which used for treatment and prevention of BSS by promoting blood circulation in TKM. METHODS: Cytotoxicity of DHSMT was examined by cell counting kit-8 (CCK-8). We also investigated the anti-adipogenesis effect of DHSMT by using Oil Red O staining, intracellular triglyceride assay leptin ELISA and western blot analysis in 3T3-L1 adipocytes. In addition, the accumulation of adiponectin, resistin and plasminogen activator inhibitor-1 (PAI-1) were measured by magnetic bead panel kit. RESULTS: Oil Red O staining showed that DHSMT markedly reduced fat accumulation without affecting cell cytotoxicity. DHSMT also significantly decreased accumulation of triglyceride and adipokines such as leptin, adiponectin, resistin and PAI-1 compared with fully differentiated adipocytes. Furthermore, our results found that DHSMT significantly suppressed the adipocyte differentiation by downregulating adipogenic-specific transcriptional factors such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer binding proteins alpha (C/EBPalpha) and fatty acid binding protein 4 (FABP4) in adipocytes. CONCLUSIONS: Taken together, our findings provide that DHSMT has potential for treatment and prevention of obesity or MS related to BSS. PMID- 29258501 TI - Bone shortening of clavicular fractures: comparison of measurement methods. AB - BACKGROUND: The indication for operative treatment of clavicular fractures with bone shortening over 2 cm is much debated. Correct measurement of clavicular length is essential, and reliable measures of clavicular length are therefore highly requested by clinical decision-makers. The aim of this study was to investigate if three commonly scientifically used measurement methods were interchangeable to each other. METHODS: A retrospective study using radiographs collected as part of a previous study on clavicular fractures. Two independent raters measured clavicle shortening on 60 patients using conventional radiographs on two separate sessions. The two measurement methods described by Hill et al. and Silva et al. were used on unilateral pictures. Side difference measurements according to Lazarides et al. were made on panoramic radiographs. The measurements were analyzed using intraclass correlation, Weir's protocol for Standard error of measurement (SEM) and minimal detectable change (MDC), and Bland-Altman plots. RESULTS: None of the methods were directly interchangeable. The side difference method by Lazarides et al. was the most reliable of the three methods, but had a high proportion of post-fracture bone lengthening that indicated methodological problems. The Hill et al. and Silva et al. methods had high minimal detectable change, making their use unreliable. CONCLUSION: As all three measurement methods had either reliability or methodological issues, we found it likely that differences in measurement methods have caused the differences in clavicular length observed in scientific studies. PMID- 29258502 TI - Impaired ventricular filling limits cardiac reserve during submaximal exercise in people with type 2 diabetes. AB - BACKGROUND: Attenuated increases in ventricular stroke volume during exercise are common in type 2 diabetes and contribute to reduced aerobic capacity. The purpose of this study was to determine whether impaired ventricular filling or reduced systolic ejection were responsible for the attenuated stroke volume reserve in people with uncomplicated type 2 diabetes. METHODS: Peak aerobic capacity and total blood volume were measured in 17 people with diabetes and 16 non-diabetic controls with no evidence of cardiovascular disease. Left ventricular volumes and other systolic and diastolic functional parameters were measured with echocardiography at rest and during semi-recumbent cycle ergometry at 40 and 60% of maximal aerobic power and compared between groups. RESULTS: People with diabetes had reduced peak aerobic capacity and heart rate reserve, and worked at lower workloads than non-diabetic controls. Cardiac output, stroke volume and ejection fraction were not different at rest, but increased less in people with diabetes during exercise. Left ventricular end systolic volume was not different between groups in any condition but end diastolic volume, although not different at rest, was smaller in people with diabetes during exercise. Total blood volume was not different between the groups, and was only moderately associated with left ventricular volumes. CONCLUSIONS: People with type 2 diabetes exhibit an attenuated increase in stroke volume during exercise attributed to an inability to maintain/increase left ventricular filling volumes at higher heart rates. This study is the first to determine the role of filling in the blunted cardiac reserve in adults with type 2 diabetes. PMID- 29258503 TI - Development and validation of a new tool to measure the facilitators, barriers and preferences to exercise in people with osteoporosis. AB - BACKGROUND: Despite the widely known benefits of exercise and physical activity, adherence rates to these activities are poor. Understanding exercise facilitators, barriers, and preferences may provide an opportunity to personalize exercise prescription and improve adherence. The purpose of this study was to develop the Personalized Exercise Questionnaire (PEQ) to identify these facilitators, barriers, and preferences to exercise in people with osteoporosis. METHODS: This study comprises two phases, instrument design and judgmental evidence. A panel of 42 experts was used to validate the instrument through quantitative (content validity) and qualitative (cognitive interviewing) methods. Content Validity Index (CVI) is the most commonly used method to calculate content validity quantitatively. There are two kinds of CVI: Item-CVI (I-CVI) and Scale-level CVI (S-CVI). RESULTS: Preliminary versions of this tool showed high content validity of individual items (I-CVI range: 0.50 to 1.00) and moderate to high overall content validity of the PEQ (S-CVI/UA = 0.63; S-CVI/Ave = 0.91). Through qualitative methods, items were improved until saturation was achieved. The tool consists of 6 domains and 38 questions. The 6 domains are: 1) support network; 2) access; 3) goals; 4) preferences; 5) feedback and tracking; and 6) barriers. There are 35 categorical questions and 3 open-ended items. CONCLUSIONS: Using an iterative approach, the development and evaluation of the PEQ demonstrated high item-content validity for assessing the facilitators, barriers, and preferences to exercise in people with osteoporosis. Upon further validation it is expected that this measure might be used to develop more client-centered exercise programs, and potentially improve adherence. PMID- 29258504 TI - Dipeptidyl peptidase-4 inhibitor decreases the risk of atrial fibrillation in patients with type 2 diabetes: a nationwide cohort study in Taiwan. AB - BACKGROUND: Whether dipeptidyl peptidase-4 inhibitor (DPP4i) is associated with a lower risk of new-onset atrial fibrillation (AF) in patients with diabetes remains unclear. This study aimed to evaluate the risk of AF associated with use of DPP4i among a longitudinal cohort of patients with diabetes. METHODS: Over a 3 year period, 480,000 patients with diabetes were analyzed utilizing Taiwan's National Health Insurance Research Database and 90,880 patients taking metformin as first-line therapy were enrolled. Patients were further divided into two groups: (1) DPP4i users: those taking DPP4i and (2) non-DPP4i users: those prescribed other hypoglycemic agents (HAs) as second-line drug. Study end point was defined by diagnosis of AF, addition of any third-line HA, or the end of the study period (December 31, 2013), whichever came first. RESULTS: A total of 16,017 DPP4i users and 74,863 non-DPP4i users were eligible for the study. For the DPP4i group, most patients were prescribed sitagliptin (n = 12,180; 76%). Among the non-DPP4i group, most patients took sulfonylurea (n = 60,606; 81%) as their second-line medication. DPP4i users were associated with a lower risk of new-onset AF compared with non-DPP4i users after propensity-score weighting (hazard ratio 0.65; P < 0.0001). Subgroup analysis showed that DPP4i user were associated with a lower risk of new-onset AF compared with non-DPP4i users in most subgroups. Multivariate analysis indicated that use of DPP4i was associated with lower risk of new-onset AF and age > 65 years, presence of hypertension, and ischemic heart disease were independent risk factors for new-onset AF. CONCLUSIONS: Among patients with diabetes prescribed with metformin, the patients with DPP4i as second HA were associated with a lower risk of AF compared with the patients with other drugs as second HAs in real-world practice. PMID- 29258505 TI - Malaria prevalence in Mangaluru city area in the southwestern coastal region of India. AB - BACKGROUND: Malaria is highly prevalent in many parts of India and the Indian subcontinent. Mangaluru, a city in the southwest coastal region of Karnataka state in India, and surrounding areas are malaria endemic with 10-12 annual parasite index. Despite high endemicity, to-date, very little has been reported on the epidemiology and burden of malaria in this area. METHODS: A cross sectional surveillance of malaria cases was performed among 900 febrile symptomatic native people (long-time residents) and immigrant labourers (temporary residents) living in Mangaluru city area. During each of dry, rainy, and end of rainy season, blood samples from a group of 300 randomly selected symptomatic people were screened for malaria infection. Data on socio demographic, literacy, knowledge of malaria, and treatment-seeking behaviour were collected to understand the socio-demographic contributions to malaria menace in this region. RESULTS: Malaria is prevalent in Mangaluru region throughout the year and Plasmodium vivax is predominant species compared to Plasmodium falciparum. The infection frequency was found to be high during rainy season. Infections were markedly higher in males than females, and in adults aged 16-45 years than both younger and older age groups. Also, malaria incidence was high among immigrants compared to native population. In both groups, infection rate was directly correlated with their literacy level, knowledge on malaria, dwelling environment, and protective measures used. There was also a significant difference in treatment-seeking behaviour between these two groups. CONCLUSIONS: Malaria incidences in Mangaluru region are predominantly localized to certain hotspot areas within the city, where socioeconomically underprivileged and immigrant labourers are densely populated. These areas have inadequate sanitation and constant water stagnation, harbouring high vector density and contributing to high infection incidences. Additionally, people in these areas seldom practice preventive measures such as using bed nets. The high incidences of malaria in adults are due to minimal cloth wearing, and long working hours stretching to late evenings in places with high vector density. Instituting heightened preventive public measures by governments and creating awareness on using preventive protective and environmental hygienic measures through educational programmes may substantially reduce the risk of contracting infections in these areas and spreading to other areas. PMID- 29258506 TI - Predictive model identifies strategies to enhance TSP1-mediated apoptosis signaling. AB - BACKGROUND: Thrombospondin-1 (TSP1) is a matricellular protein that functions to inhibit angiogenesis. An important pathway that contributes to this inhibitory effect is triggered by TSP1 binding to the CD36 receptor, inducing endothelial cell apoptosis. However, therapies that mimic this function have not demonstrated clear clinical efficacy. This study explores strategies to enhance TSP1-induced apoptosis in endothelial cells. In particular, we focus on establishing a computational model to describe the signaling pathway, and using this model to investigate the effects of several approaches to perturb the TSP1-CD36 signaling network. METHODS: We constructed a molecularly-detailed mathematical model of TSP1-mediated intracellular signaling via the CD36 receptor based on literature evidence. We employed systems biology tools to train and validate the model and further expanded the model by accounting for the heterogeneity within the cell population. The initial concentrations of signaling species or kinetic rates were altered to simulate the effects of perturbations to the signaling network. RESULTS: Model simulations predict the population-based response to strategies to enhance TSP1-mediated apoptosis, such as downregulating the apoptosis inhibitor XIAP and inhibiting phosphatase activity. The model also postulates a new mechanism of low dosage doxorubicin treatment in combination with TSP1 stimulation. Using computational analysis, we predict which cells will undergo apoptosis, based on the initial intracellular concentrations of particular signaling species. CONCLUSIONS: This new mathematical model recapitulates the intracellular dynamics of the TSP1-induced apoptosis signaling pathway. Overall, the modeling framework predicts molecular strategies that increase TSP1-mediated apoptosis, which is useful in many disease settings. PMID- 29258507 TI - Prognostic significance of microvascular invasion in tumor stage for hepatocellular carcinoma. AB - BACKGROUND: The presence of microvascular invasion (McVI) in hepatocellular carcinoma (HCC) has been proposed as a cause of recurrence and poor survival, although this has not been officially emphasized in staging systems. Thus, we conducted a retrospective study to investigate the prognostic importance of McVI in tumor staging in patients with HCC who underwent hepatic resection. METHODS: A retrospective analysis was performed of patients who underwent hepatic resection for HCC at our center from 1994 to 2012. Patients with HCC were classified into four groups based on the presence of McVI and extent of gross vascular invasion (VI). RESULTS: The 5-year overall and recurrence-free survival rates of 676 patients were 63.3 and 42.6%, respectively. There was no difference in tumor recurrence or survival rate between patients with HCC and McVI without gross VI and those with gross VI confined to segmental/sectional branches. Multivariate analysis revealed that the extent of VI based on the presence of McVI and gross VI was independently associated with tumor recurrence and overall survival. CONCLUSIONS: McVI was revealed to be an important risk factor similar to gross VI confined to a segmental/sectional branch in patients with HCC who underwent hepatic resection. This finding should be considered when estimating the stage for prognosis. PMID- 29258508 TI - Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia. AB - BACKGROUND: Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008-2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs. RESULTS: Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population. CONCLUSIONS: Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations. PMID- 29258509 TI - Chemotherapy diminishes lipid storage capacity of adipose tissue in a preclinical model of colon cancer. AB - BACKGROUND: Accelerated loss of adipose tissue in cancer is associated with shorter survival, and reduced quality of life. Evidence is emerging suggesting tumour association with alterations in adipose tissue, but much less is known about drug-related mechanisms contributing to adipose atrophy. Identification of mechanisms by which tumour and cancer treatments, such as chemotherapy, affect adipose tissue are required to develop appropriate therapeutic interventions to prevent fat depletion in cancer. This pre-clinical study aimed to assess alterations in adipose tissue during the clinical course of cancer. METHODS: Fischer 344 rats bearing the Ward colorectal tumour were euthanized before chemotherapy, after 1- cycle, or 2-cycles of a combination chemotherapy consisting of Irinotecan (CPT-11) combined with 5-fluorouracil (5-FU), which recapitulates first line treatment for human colorectal cancer. Periuterine adipose tissue was isolated. Healthy rats served as a reference group. Histological analysis (hematoxylin and eosin), Real-time PCR (TaqMan) and proteomic analysis (LC-MS/MS) were performed. RESULTS: Larger adipocytes (3993.7 +/- 52.6 MUm2) in tumour-bearing animals compared to the reference group (3227.7 +/- 36.7 MUm2; p < 0.001) was associated with reduced expression of proteins involved in mitochondrial fatty acid oxidation. The presence of a tumour has a significant effect on phospholipid but not triglyceride fatty acid composition. There were greater proportions of saturated fatty acids concurrent with lower monounsaturated fatty acids within the PL fraction of adipocytes in tumour bearing animals. Chemotherapy treatment decreased the size of adipocytes (2243.9 +/- 30.4 MUm2; p < 0.001) and led to depletion of n-3 polyunsaturated fatty acids in adipose tissue triglyceride. Evaluation of the proteome profile revealed decreased expression of proteins involved in ATP generation, beta-oxidation, and lipogenesis. Overall, adipose tissue may not be able to efficiently oxidize fatty acids to provide energy to maintain energy demanding pathways like lipogenesis inside the tissue. CONCLUSIONS: In conclusion, metabolic adaptations to mitochondrial impairment may contribute to diminished lipid storage capacity of adipose tissue following chemotherapy delivery. PMID- 29258510 TI - Comparison of machine learning techniques to predict all-cause mortality using fitness data: the Henry ford exercIse testing (FIT) project. AB - BACKGROUND: Prior studies have demonstrated that cardiorespiratory fitness (CRF) is a strong marker of cardiovascular health. Machine learning (ML) can enhance the prediction of outcomes through classification techniques that classify the data into predetermined categories. The aim of this study is to present an evaluation and comparison of how machine learning techniques can be applied on medical records of cardiorespiratory fitness and how the various techniques differ in terms of capabilities of predicting medical outcomes (e.g. mortality). METHODS: We use data of 34,212 patients free of known coronary artery disease or heart failure who underwent clinician-referred exercise treadmill stress testing at Henry Ford Health Systems Between 1991 and 2009 and had a complete 10-year follow-up. Seven machine learning classification techniques were evaluated: Decision Tree (DT), Support Vector Machine (SVM), Artificial Neural Networks (ANN), Naive Bayesian Classifier (BC), Bayesian Network (BN), K-Nearest Neighbor (KNN) and Random Forest (RF). In order to handle the imbalanced dataset used, the Synthetic Minority Over-Sampling Technique (SMOTE) is used. RESULTS: Two set of experiments have been conducted with and without the SMOTE sampling technique. On average over different evaluation metrics, SVM Classifier has shown the lowest performance while other models like BN, BC and DT performed better. The RF classifier has shown the best performance (AUC = 0.97) among all models trained using the SMOTE sampling. CONCLUSIONS: The results show that various ML techniques can significantly vary in terms of its performance for the different evaluation metrics. It is also not necessarily that the more complex the ML model, the more prediction accuracy can be achieved. The prediction performance of all models trained with SMOTE is much better than the performance of models trained without SMOTE. The study shows the potential of machine learning methods for predicting all-cause mortality using cardiorespiratory fitness data. PMID- 29258511 TI - Association between increased visceral fat area and alterations in plasma fatty acid profile in overweight subjects: a cross-sectional study. AB - BACKGROUND: Visceral fat accumulation in overweight status has been resulted in changes of fatty acid profiles. The fatty acids profiles can be altered by fatty acid desaturase; the activity of which is highly associated with obesity and other metabolic diseases. We hypothesized that fatty acid composition, desaturase activity, and accumulation of visceral fat are interrelated. Thus, the aim of this study was to investigate the association between increased visceral fat area and alterations in plasma fatty acid profile in overweight subjects with different amounts of visceral fat. METHODS: Healthy overweight subjects (25.0 kg/m2 <= BMI < 30 kg/m2, n=232) were classified into lower (T1), middle (T2), and upper tertiles (T3) according to L4 visceral fat area (T1: <71.8 cm2, T2: 71.8 cm2-99.6 cm2, T3: >99.6 cm2). RESULTS: The T3 group showed higher amounts of cis 10-heptadecenoic acid and activity of C16 Delta9-desaturase and C18 Delta9 desaturase and lower activity of Delta5-desaturase than the T1 group. Additionally, the T3 group showed higher amounts of saturated fatty acids, myristic acid, palmitic acid, stearic acid, monounsaturated fatty acids, palmitoleic acid, oleic acid, n-6 polyunsaturated fatty acids, linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-3 PUFAs, and docosapentaenoic acid than the T1 and T2 groups. CONCLUSIONS: This study indicates that greater than a certain area (>99.6 cm2) of visceral fat is needed to observe altered levels of individual fatty acid species and desaturase activities. The results suggest that increased activity of C16 Delta9-desaturase and C18 Delta9 desaturase in parallel with decreased Delta5-desaturase activity may be a causative factor in disturbed fatty acid metabolism. PMID- 29258512 TI - Measurement of the translation and impact from a childhood obesity trial programme: rationale and protocol for a research impact assessment. AB - BACKGROUND: There is growing recognition amongst health and medical research funders and researchers that translation of research into policy and practice needs to increase and that more transparency is needed on how impacts are realised. Several approaches are advocated for achieving this, including co production of research or academic-practitioner research. The Population Health Unit (PHU) within the Hunter New England Local Health District in regional Australia, as an early adopter of this model, has been working to increase the likelihood that its research is translated into community health benefits. With the New South Wales Ministry of Health, the PHU responded to the burden of child overweight and obesity by combining service delivery with research expertise. The 'Good for Kids, Good for Life' (Good for Kids) dissemination trial was developed and implemented in seven community settings in the Hunter region of Australia between 2006 and 2010. This study aims to undertake a retrospective impact assessment to measure the research translation and impact of Good for Kids. METHODS: The method will be based upon the application of the Framework to Assess the Impact from Translational health research (FAIT), comprising three core elements, namely quantified metrics, economic assessment and a narrative of the process by which the research in question translates and generates impact. DISCUSSION: Increasingly, funders are interested both in the outcomes resulting from investments in health research and in the expected return on their investments. FAIT was developed specifically for this purpose and its use is anticipated to provide transparency to the pathway to translation and potentially drive increased investment in translational research programmes such as Good for Kids. PMID- 29258514 TI - The impact of a social prescribing service on patients in primary care: a mixed methods evaluation. AB - BACKGROUND: Social prescribing is targeted at isolated and lonely patients. Practitioners and patients jointly develop bespoke well-being plans to promote social integration and or social reactivation. Our aim was to investigate: whether a social prescribing service could be implemented in a general practice (GP) setting and to evaluate its effect on well-being and primary care resource use. METHODS: We used a mixed method evaluation approach using patient surveys with matched control groups and a qualitative interview study. The study was conducted in a mixed socio-economic, multi-ethnic, inner city London borough with socially isolated patients who frequently visited their GP. The intervention was implemented by 'social prescribing coordinators'. Outcomes of interest were psychological and social well-being and health care resource use. RESULTS: At 8 months follow-up there were no differences between patients referred to social prescribing and the controls for general health, depression, anxiety and 'positive and active engagement in life'. Social prescribing patients had high GP consultation rates, which fell in the year following referral. The qualitative study indicated that most patients had a positive experience with social prescribing but the service was not utilised to its full extent. CONCLUSION: Changes in general health and well-being following referral were very limited and comprehensive implementation was difficult to optimise. Although GP consultation rates fell, these may have reflected regression to the mean rather than changes related to the intervention. Whether social prescribing can contribute to the health of a nation for social and psychological wellbeing is still to be determined. PMID- 29258513 TI - Systems healthcare: a holistic paradigm for tomorrow. AB - Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness. Such influences may dysregulate networks and allow pathobiology to evolve, resulting in early clinical presentation that requires astute assessment and timely intervention for successful mitigation. Herein, we describe the components of relevant biological systems and the nature of progression from at-risk to manifest disease. We illustrate the systems approach by examining two relevant clinical examples: Alzheimer's and cardiovascular diseases. The implications of systems healthcare management are examined through the lens of economics, ethics, policy and the law. Finally, we propose the need to develop new educational paradigms to enhance the training of the health professional in an era of systems medicine. PMID- 29258515 TI - Production of fluorescent and cytotoxic K28 killer toxin variants through high cell density fermentation of recombinant Pichia pastoris. AB - BACKGROUND: Virus infected killer strains of the baker's yeast Saccharomyces cerevisiae secrete protein toxins such as K28, K1, K2 and Klus which are lethal to sensitive yeast strains of the same or related species. K28 is somewhat unique as it represents an alpha/beta heterodimeric protein of the A/B toxin family which, after having bound to the surface of sensitive target cells, is taken up by receptor-mediated endocytosis and transported through the secretory pathway in a retrograde manner. While the current knowledge on yeast killer toxins is largely based on genetic screens for yeast mutants with altered toxin sensitivity, in vivo imaging of cell surface binding and intracellular toxin transport is still largely hampered by a lack of fluorescently labelled and biologically active killer toxin variants. RESULTS: In this study, we succeeded for the first time in the heterologous K28 preprotoxin expression and production of fluorescent K28 variants in Pichia pastoris. Recombinant P. pastoris GS115 cells were shown to successfully process and secrete K28 variants fused to mCherry or mTFP by high cell density fermentation. The fluorescent K28 derivatives were obtained in high yield and possessed in vivo toxicity and specificity against sensitive yeast cells. In cell binding studies the resulting K28 variants caused strong fluorescence signals at the cell periphery due to toxin binding to primary K28 receptors within the yeast cell wall. Thereby, the beta-subunit of K28 was confirmed to be the sole component required and sufficient for K28 cell wall binding. CONCLUSION: Successful production of fluorescent killer toxin variants of S. cerevisiae by high cell density fermentation of recombinant, K28 expressing strains of P. pastoris now opens the possibility to study and monitor killer toxin cell surface binding, in particular in toxin resistant yeast mutants in which toxin resistance is caused by defects in toxin binding due to alterations in cell wall structure and composition. This novel approach might be easily transferable to other killer toxins from different yeast species and genera. Furthermore, the fluorescent toxin variants described here might likewise represent a powerful tool in future studies to visualize intracellular A/B toxin trafficking with the help of high resolution single molecule imaging techniques. PMID- 29258517 TI - R-wave synchronised atrial pacing in pediatric patients with postoperative junctional ectopic tachycardia: the atrioventricular interval investigated by computational analysis and clinical evaluation. AB - BACKGROUND: R-wave synchronised atrial pacing is an effective temporary pacing therapy in infants with postoperative junctional ectopic tachycardia. In the technique currently used, adverse short or long intervals between atrial pacing and ventricular sensing (AP-VS) may be observed during routine clinical practice. OBJECTIVES: The aim of the study was to analyse outcomes of R-wave synchronised atrial pacing and the relationship between maximum tracking rates and AP-VS intervals. METHODS: Calculated AP-VS intervals were compared with those predicted by experienced pediatric cardiologist. RESULTS: A maximum tracking rate (MTR) set 10 bpm higher than the heart rate (HR) may result in undesirable short AP-VS intervals (minimum 83 ms). A MTR set 20 bpm above the HR is the hemodynamically better choice (minimum 96 ms). Effects of either setting on the AP-VS interval could not be predicted by experienced observers. In our newly proposed technique the AP-VS interval approaches 95 ms for HR > 210 bpm and 130 ms for HR < 130 bpm. The progression is linear and decreases strictly (- 0.4 ms/bpm) between the two extreme levels. CONCLUSIONS: Adjusting the AP-VS interval in the currently used technique is complex and may imply unfavorable pacemaker settings. A new pacemaker design is advisable to allow direct control of the AP-VS interval. PMID- 29258516 TI - Neutrophil elastase in bronchiectasis. AB - The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF. In this context, NE seems to be a predictor of long-term clinical outcomes and a possible target of treatment. In order to better evaluate the role of NE in bronchiectasis, a systematic search of scientific evidence was performed.Two investigators independently performed the search on PubMed and included studies published up to May 15, 2017 according to predefined criteria. A final pool of 31 studies was included in the systematic review, with a total of 2679 patients. For each paper data of interest were extracted and reported in table.In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment. NE has also been associated with risk of exacerbation, time to next exacerbation and all cause mortality. This study reviews also the role of NE as a specific target of treatment in bronchiectasis. Inhibition of NE is at a very early stage and future interventional studies should evaluate safety and efficacy for new molecules and formulations. PMID- 29258518 TI - Associating liver partition and portal vein ligation for staged hepatectomy versus conventional two-stage hepatectomy: a systematic review and meta-analysis. AB - BACKGROUND: It is generally accepted that an insufficient future liver remnant is a major limitation of large-scale hepatectomy for patients with primary hepatocellular carcinoma. Conventional two-stage hepatectomy (TSH) is commonly considered to accelerate future liver regeneration despite its low regeneration rate. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which is characterized by a rapid regeneration, has brought new opportunities. METHODS: Relevant studies were identified by searching the selected databases up to September 2017. Then, a meta-analysis of regeneration efficiency, complication rate, R0 resection ratio, and short-term outcomes was performed. RESULTS: Ten studies, comprising 719 patients, were included. The overall analysis showed that ALPPS was associated with a larger hyperplastic volume and a shorter time interval (P < 0.00001) than TSH. ALPPS also exhibited a higher completion rate for second-stage operations (odds ratio, OR 9.50; P < 0.0001) and a slightly higher rate of R0 resection (OR 1.90; P = 0.11). Interestingly, there was no significant difference in 90-day mortality between the two treatments (OR 1.44; P = 0.35). CONCLUSIONS: These results indicate that compared with TSH, ALPPS possesses a stronger regenerative ability and better facilitates second-stage operations. However, the safety, patient outcomes, and patient selection for ALPPS require further study. PMID- 29258519 TI - Ethical challenges experienced by UK military medical personnel deployed to Sierra Leone (operation GRITROCK) during the 2014-2015 Ebola outbreak: a qualitative study. AB - BACKGROUND: As part of its response to the 2014 Ebola outbreak in west Africa, the United Kingdom (UK) government established an Ebola treatment unit in Sierra Leone, staffed by military personnel. Little is known about the ethical challenges experienced by military medical staff on humanitarian deployment. We designed a qualitative study to explore this further with those who worked in the treatment unit. METHOD: Semi-structured, face-to-face and telephone interviews were conducted with 20 UK military personnel deployed between October 2014 and April 2015 in one of three roles in the Ebola treatment unit: clinician; nursing and nursing assistant; and other medical support work, including infection control and laboratory and mortuary services. RESULTS: Many participants reported feeling ethically motivated to volunteer for deployment, but for some personal interests were also a consideration. A small minority had negative feelings towards the deployment, others felt that this deployment like any other was part of military service. Almost all had initial concerns about personal safety but were reassured by their pre-deployment 'drills and skills', and personal protective equipment. Risk perceptions were related to perceptions about military service. Efforts to minimise infection risk were perceived to have made good patient care more difficult. Significantly, some thought the humanitarian nature of the mission justified tolerating greater risks to staff. Trust in the military institution and colleagues was expressed; many participants referred to the ethical obligation within the chain of command to protect those under their command. Participants expected resources to be overwhelmed and 'empty beds' presented a significant and pervasive ethical challenge. Most thought more patients could and should have been treated. Points of reference for participants' ethical values were: previous deployment experience; previous UK/National Health Service experience; professional ethics; and, distinctly military values (that might not be shared with non-military workers). CONCLUSION: We report the first systematic exploration of the ethical challenges face by a Western medical military in the international response to the first major Ebola outbreak. We offer unique insights into the military healthcare workers' experiences of humanitarian deployment. Many participants expressed motivations that gave them common purpose with civilian volunteers. PMID- 29258520 TI - Metabolic Reponses to a physical exercise session in women with excess body mass: randomized clinical trial. AB - BACKGROUND: There are various factors that influence the effect of physical exercise on the lipid profile, among them the body mass index and calorie expenditure of the exercise are some of the main factors. To test the hypothesis that a physical exercise session based on caloric expenditure may acutely modify the glycemia and lipid values of women with excess body mass. METHODS: The study included 66 women, randomly divided into two groups, control and experimental, with BMI of 29 +/- 4.4 kg/m2 vs 29 +/- 4.3 kg/m2 (p = 0.45) sedentary and aged 23 +/- 3.8 vs 24 +/- 3.5 years, respectively (p = 0.25). After 12 h fasting, the volunteers underwent the first blood collection. The experimental group was submitted to a physical exercise session corresponding to energy expenditure of 250Kcal, of light intensity based the Borg Rating of Perceived Exertion (RPE), 12 h after the first blood collection. The control and experimental group volunteers underwent a second blood collection 24 h after the first. Glycemia, insulin status and lipid profile were measured and Homa IR and Homa-beta were calculated. The t-test for independent and dependent samples was used, and a level of significance of 5% was adopted. RESULTS: Physical exercise changed the glycemic response in both the intragroup analysis (before = 96 +/- 6.6 mg/dL vs after = 92 +/- 6.6 mg/dL), (p = 0.01), and in the intergroup analysis (control = Delta 0.9 +/- 6.1 vs experimental = Delta -4.1 +/- 6.3) (p = 0.02). No changes were shown for the Homa IR, Homa Beta and Insulin indexes. When the lipid profiles were evaluated, differences in HDL were shown in the intragroup analysis (before = 89 +/- 10.5 mg/dL vs. after = 91 +/- 10.3 mg/dL) (p = 0.04). For the other parameters (LDL, TG, Total Cholesterol, TG/HDL), no changes were shown. CONCLUSION: In women with excess body weight, a low intensity exercise session diminished the glycemia, but did not change the lipid response. TRIAL REGISTRATION: NCT03170973 . Retrospectively registered. PMID- 29258521 TI - Long-term trends in supply and sustainability of the health workforce in remote Aboriginal communities in the Northern Territory of Australia. AB - BACKGROUND: International evidence suggests that a key to improving health and attaining more equitable health outcomes for disadvantaged populations is a health system with a strong primary care sector. Longstanding problems with health workforce supply and turnover in remote Aboriginal communities in the Northern Territory (NT), Australia, jeopardise primary care delivery and the effort to overcome the substantial gaps in health outcomes for this population. This research describes temporal changes in workforce supply in government operated clinics in remote NT communities through a period in which there has been a substantial increase in health funding. METHODS: Descriptive and Markov switching dynamic regression analysis of NT Government Department of Health payroll and financial data for the resident health workforce in 54 remote clinics, 2004-2015. The workforce included registered Remote Area Nurses and Midwives (nurses), Aboriginal Health Practitioners (AHPs) and staff in administrative and logistic roles. MAIN OUTCOME MEASURES: total number of unique employees per year; average annual headcounts; average full-time equivalent (FTE) positions; agency employed nurse FTE estimates; high and low supply state estimates. RESULTS: Overall increases in workforce supply occurred between 2004 and 2015, especially for administrative and logistic positions. Supply of nurses and AHPs increased from an average 2.6 to 3.2 FTE per clinic, although supply of AHPs has declined since 2010. Each year almost twice as many individual NT government-employed nurses or AHPs are required for each FTE position. Following funding increases, some clinics doubled their nursing and AHP workforce and achieved relative stability in supply. However, most clinics increased staffing to a much smaller extent or not at all, typically experiencing a "fading" of supply following an initial increase associated with greater funding, and frequently cycling periods of higher and lower staffing levels. CONCLUSIONS: Overall increases in workforce supply in remote NT communities between 2004 and 2015 have been affected by continuing very high turnover of nurses and AHPs, and compounded by recent declines in AHP supply. Despite substantial increases in resourcing, an imperative remains to implement more robust health service models which better support the supply and retention of resident health staff. PMID- 29258522 TI - NFAT1-regulated IL6 signalling contributes to aggressive phenotypes of glioma. AB - BACKGROUND: We previously demonstrated that the local immune status correlated with the glioma prognosis. Interleukin-6 (IL6) was identified as an important local immune-related risk marker related to unfavourable prognosis. In this study, we further investigated the role and regulation of IL6 signalling in glioma. METHODS: The expression and prognostic value of IL6 and the IL6 receptor (IL6R) were explored in The Cancer Genome Atlas (TCGA) and REMBRANDT databases and clinical samples. Functional effects of genetic knockdown and overexpression of IL6R or IL6 stimulation were examined in vitro and in tumours in vivo. The effects of the nuclear factor of activated T cells-1 (NFAT1) on the promoter activities of IL6R and IL6 were also examined. RESULTS: High IL6- and IL6R expression were significantly associated with mesenchymal subtype and IDH wildtype gliomas, and were predictors of poor survival. Knockdown of IL6R decreased cell proliferation, invasion and neurosphere formation in vitro, and inhibited tumorigenesis in vivo. IL6R overexpression or IL6 stimulation enhanced the invasion and growth of glioma cells. TCGA database searching revealed that IL6- and IL6R-expression were correlated with that of NFAT1. In glioma cells, NFAT1 enhanced the promoter activities of IL6R and IL6, and upregulated the expression of both IL6R and IL6. CONCLUSION: NFAT1-regulated IL6 signalling contributes to aggressive phenotypes of gliomas, emphasizing the role of immunomodulatory factors in glioma malignant progression. PMID- 29258523 TI - Low-grade appendiceal mucinous neoplasm and endometriosis of the appendix. AB - BACKGROUND: A distended, mucous-filled appendix is known as an appendiceal mucocele. They are a rare form of an appendiceal mass and develop from both benign and malignant processes. Mucoceles can develop secondarily to an obstruction, such as from a fecalith, scarring or, rarely, endometriosis. Only 12 cases of non-neoplastic appendiceal mucoceles caused by endometriosis have been previously described. The association between neoplastic appendiceal mucoceles in the presence of endometriosis is described for the first time in this report. CASE PRESENTATION: A 57-year-old woman presented with a chief complaint of worsening abdominal pain over the past 3 months. Imaging studies revealed an appendiceal mass. Laparoscopic evaluation confirmed an appendiceal mucocele, and the patient underwent complete appendectomy. No evidence of mucinous or endometrial deposits were present within the abdominal cavity. Pathological diagnosis revealed low-grade appendiceal mucinous neoplasm (LAMN) with evidence of endometriosis within the muscularis propria of the appendix. The patient recovered without complications and her abdominal pain completely resolved. CONCLUSIONS: Endometriosis of the appendix is a rare manifestation and is most often identified as an incidental finding. Endometriosis leading to an obstructive mucocele of the appendix is an exceedingly rare finding, having only been described 12 times in the medical literature. LAMN in the presence of endometriosis of the appendix is described for the first time in this report. The association between appendiceal neoplasms in the presence of endometriosis requires further research in order to optimize operative treatment. PMID- 29258525 TI - Advancing perinatal patient safety through application of safety science principles using health IT. AB - BACKGROUND: The use of health information technology (IT) has been shown to promote patient safety in Labor and Delivery (L&D) units. The use of health IT to apply safety science principles (e.g., standardization) to L&D unit processes may further advance perinatal safety. METHODS: Semi-structured interviews were conducted with L&D units participating in the Agency for Healthcare Research and Quality's (AHRQ's) Safety Program for Perinatal Care (SPPC) to assess units' experience with program implementation. Analysis of interview transcripts was used to characterize the process and experience of using health IT for applying safety science principles to L&D unit processes. RESULTS: Forty-six L&D units from 10 states completed participation in SPPC program implementation; thirty-two (70%) reported the use of health IT as an enabling strategy for their local implementation. Health IT was used to improve standardization of processes, use of independent checks, and to facilitate learning from defects. L&D units standardized care processes through use of electronic health record (EHR)-based order sets and use of smart pumps and other technology to improve medication safety. Units also standardized EHR documentation, particularly related to electronic fetal monitoring (EFM) and shoulder dystocia. Cognitive aids and tools were integrated into EHR and care workflows to create independent checks such as checklists, risk assessments, and communication handoff tools. Units also used data from EHRs to monitor processes of care to learn from defects. Units experienced several challenges incorporating health IT, including obtaining organization approval, working with their busy IT departments, and retrieving standardized data from health IT systems. CONCLUSIONS: Use of health IT played an integral part in the planning and implementation of SPPC for participating L&D units. Use of health IT is an encouraging approach for incorporating safety science principles into care to improve perinatal safety and should be incorporated into materials to facilitate the implementation of perinatal safety initiatives. PMID- 29258524 TI - Using an intervention mapping approach to develop a discharge protocol for intensive care patients. AB - BACKGROUND: Admission into an intensive care unit (ICU) may result in long-term physical, cognitive, and emotional consequences for patients and their relatives. The care of the critically ill patient does not end upon ICU discharge; therefore, integrated and ongoing care during and after transition to the follow up ward is pivotal. This study described the development of an intervention that responds to this need. METHODS: Intervention Mapping (IM), a six-step theory- and evidence-based approach, was used to guide intervention development. The first step, a problem analysis, comprised a literature review, six semi-structured telephone interviews with former ICU-patients and their relatives, and seven qualitative roundtable meetings for all eligible nurses (i.e., 135 specialized and 105 general ward nurses). Performance and change objectives were formulated in step two. In step three, theory-based methods and practical applications were selected and directed at the desired behaviors and the identified barriers. Step four designed a revised discharge protocol taking into account existing interventions. Adoption, implementation and evaluation of the new discharge protocol (IM steps five and six) are in progress and were not included in this study. RESULTS: Four former ICU patients and two relatives underlined the importance of the need for effective discharge information and supportive written material. They also reported a lack of knowledge regarding the consequences of ICU admission. 42 ICU and 19 general ward nurses identified benefits and barriers regarding discharge procedures using three vignettes framed by literature. Some discrepancies were found. For example, ICU nurses were skeptical about the impact of writing a lay summary despite extensive evidence of the known benefits for the patients. ICU nurses anticipated having insufficient skills, not knowing the patient well enough, and fearing legal consequences of their writings. The intervention was designed to target the knowledge, attitudes, self-efficacy, and perceived social influence. Building upon IM steps one to three, a concept discharge protocol was developed that is relevant and feasible within current daily practice. CONCLUSION: Intervention mapping provided a comprehensive framework to improve ICU discharge by guiding the development process of a theory and empirically-based discharge protocol that is robust and useful in practice. PMID- 29258526 TI - Bringing patient-centered tuberculosis diagnosis into the light of day. AB - In 2015, the WHO End TB Strategy laid out ambitious goals to dramatically reduce tuberculosis (TB) deaths, incidence, and catastrophic costs through research, bold new strategies, and patient-centered care. In this commentary, recent evidence on sputum collection strategies for smear microscopy is reviewed, and the argument is made that redesigning smear microscopy as a patient-centered service offers the only realistic and widely available strategy to advance TB diagnostic care towards the initial End TB Strategy goals laid out for 2025. Finally, the successful adoption of same-day sputum smear microscopy as a model for patient-centered TB care is suggested to be synergistic with and to form part of the scale-up of new TB diagnostic tools.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0947-9. PMID- 29258527 TI - Case report: osteogenesis imperfecta, internal mammary artery graft & nitinol clips. AB - BACKGROUND: Osteogenesis imperfecta is a genetic disorder of connective tissue causing mostly left-sided heart valves and aortic root pathologies, but a coronary artery involvement reflecting an increased sensitivity to cardiovascular risk factors is also suspected in this patient population. CASE PRESENTATION: We report a 38-year-old patient with an osteogenesis imperfecta and a typical presentation of an acute myocardial infarction. The coronary angiogram showed a coronary 3-vessel disease. The patient underwent a bypass grafting surgery with the internal mammary artery. The sternum was closed using four nitinol clips and had totally stabilized at 4 months with excellent bone healing. CONCLUSIONS: With the successful clinical outcome in this patient severely affected by its osteogensis imperfecta, we underline the safe use of the LIMA, if precaution is taken towards the sternal bone, and its closure with nitinol clips. PMID- 29258529 TI - Postcardiotomy VA-ECMO for refractory cardiogenic shock. AB - Postcardiotomy cardiogenic shock (PCCS) is a rare but catastrophic syndrome that can occur following separation from cardiopulmonary bypass or at any time during the immediate postoperative course. The management of PCCS varies between clinicians, institutions and countries. The available evidence to guide this practice is limited. In their systematic review and meta-analysis, Khorsandi and colleagues report a synthesis of case-series pertinent to the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for PCCS. Whilst we acknowledge the potential survival benefit for carefully selected patients for what is ordinarily a condition with high mortality, we wish to comment on several aspects of the study in the context of its application to clinical practice. PMID- 29258528 TI - Social inequality, scientific inequality, and the future of mental illness. AB - BACKGROUND: Despite five decades of increasingly elegant studies aimed at advancing the pathophysiology and treatment of mental illness, the results have not met expectations. Diagnoses are still based on observation, the clinical history, and an outmoded diagnostic system that stresses the historic goal of disease specificity. Psychotropic drugs are still based on molecular targets developed decades ago, with no increase in efficacy. Numerous biomarkers have been proposed, but none have the requisite degree of sensitivity and specificity, and therefore have no usefulness in the clinic. The obvious lack of progress in psychiatry needs exploration. METHODS: The historical goals of psychiatry are reviewed, including parity with medicine, a focus on diagnostic reliability rather than validity, and an emphasis on reductionism at the expense of socioeconomic issues. Data are used from Thomas Picketty and others to argue that our failure to advance clinical care may rest in part on the rise in social and economic inequality that began in the 1970s, and in part on our inability to move beyond the medical model of specificity of disease and treatment. RESULTS: It is demonstrated herein that the historical goal of specificity of disease and treatment has not only impeded the advance of diagnosis and treatment of mental illness, but, in combination with a rapid increase in socioeconomic inequality, has led to poorer outcomes and rising mortality rates in a number of disorders, including schizophrenia, anxiety, and depression. CONCLUSIONS: It is proposed that Psychiatry should recognize the fact of socioeconomic inequality and its effects on mental disorders. The medical model, with its emphasis on diagnostic and treatment specificity, may not be appropriate for investigation of the brain, given its complexity. The rise of scientific inequality, with billions allocated to connectomics and genetics, may shift attention away from the need for improvements in clinical care. Unfortunately, the future prospects of those suffering from mental illness appear dim. PMID- 29258530 TI - Disruption of the c-Myc/miR-200b-3p/PRDX2 regulatory loop enhances tumor metastasis and chemotherapeutic resistance in colorectal cancer. AB - BACKGROUND: Metastasis is a major threat to colorectal cancer (CRC) patients. We have reported that peroxiredoxin-2 (PRDX2) is associated with CRC invasion and metastasis. However, the mechanisms regulating PRDX2 expression remain unclear. We investigate whether microRNAs (miRNAs) regulate PRDX2 expression in CRC progression. METHODS: Quantitative real-time polymerase chain reaction (qPCR) was used to measure microRNA-200b-3p (miR-200b-3p) expression. Immunohistochemistry (IHC) was performed to detect c-Myc and PRDX2 protein levels in CRC tissue samples (n = 97). Western blot was used to quantify PRDX2, c-Myc, AKT2/GSK3beta pathway-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins in CRC cells. Luciferase reporter assays were used to analyze the interaction between miR-200b-3p and 3'untranslated region (3'UTR) of PRDX2 mRNA and AKT2 mRNA as well as c-Myc and the miR-200b-3p promoter. Chromatin immunoprecipitation (ChIP) assay was used to evaluate binding of c-Myc to the miR 200b-3p promoter. Invasive assay and metastatic model were used to assess invasive and metastatic capacities of CRC cells in vitro and in vivo. Moreover, drug-induced apoptosis was measured by flow cytometry. RESULTS: We found that miR 200b-3p was significantly downregulated, whereas c-Myc and PRDX2 were upregulated in metastatic CRC cells and CRC tissues compared to their counterparts. An inverse correlation existed between c-Myc and miR-200b-3p, and between miR-200b 3p and PRDX2. We also found that PRDX2 was a target of miR-200b-3p. Importantly, overexpression of nontargetable PRDX2 eliminated the suppressive effects of miR 200b-3p on proliferation, invasion, EMT, chemotherapeutic resistance and metastasis of CRC cells. Moreover, c-Myc bound to the promoter of miR-200b-3p and repressed its transcription. In turn, miR-200b-3p disrupted the stability of c Myc protein by inducing c-Myc protein threonine 58 (T58) phosphorylation and serine 62 (S62) dephosphorylation via AKT2/GSK3beta pathway. CONCLUSIONS: Our findings reveal that the c-Myc/miR-200b/PRDX2 loop regulates CRC progression and its disruption enhances tumor metastasis and chemotherapeutic resistance in CRC. PMID- 29258531 TI - Malignant rhabdoid tumor in the renal allograft of an adult transplant recipient: a unique case of a rare tumor. AB - BACKGROUND: Renal transplant recipients have increased risk for developing malignant diseases because of immunosuppression or donor-to-recipient transmission. Malignant rhabdoid tumor (MRT) is a rare, highly aggressive and lethal tumor primarily affecting the kidney of infants and young children. MRT has not been reported in the renal allograft of an adult recipient after kidney transplantation. CASE PRESENTATION: In this report, a 47-year-old woman who received a kidney transplantation from an infant donor and developed a mass in the transplanted kidney is presented. Pathological examinations revealed a malignant tumor with rhabdoid cells morphologically and the loss of INI1 expression immunohistochemically. The diagnosis of malignant rhabdoid tumor in the transplanted kidney was made. We confirmed that donor-to-recipient malignancy transmission was the cause of MRT in the transplanted kidney by fluorescence in situ hybridization (FISH) and short tandem repeat (STR) analysis. CONCLUSION: To our knowledge, this is the first case of MRT in an adult renal allograft recipient. This report highlights the importance of the criteria for selection of donors to screen possible malignant tumors transmission. PMID- 29258532 TI - Canine angiostrongylosis in Sweden: a nationwide seroepidemiological survey by enzyme-linked immunosorbent assays and a summary of five-year diagnostic activity (2011-2015). AB - BACKGROUND: For the first time in Sweden, Angiostrongylus vasorum was detected on the island of Sydkoster in foxes and dogs in 2003. After sporadic detection of the parasite in foxes in southern Sweden, the first positive canine faecal sample on the mainland was found in 2011. Since then a total of 2882 faecal samples have been analysed with the Baermann test at the National Veterinary Institute (SVA) during the years 2011-2015; 20 of them being positive. Contemporaneously, of over 525 fox necropsies, only three were found to be infected. To gather a more accurate knowledge of A. vasorum occurrence in Sweden, a large scale seroepidemiological survey was performed and totally 3885 serum samples from dogs were tested for both the presence of circulating antigens and of specific antibodies to A. vasorum. RESULTS: In total, 0.10% (n = 4, 95% Confidence Intervals, CI 0.03-0.26%) of the dogs were positive for both antigen and antibodies, whereas 0.51% (n = 20, CI 0.31-0.79%) of the tested dogs were only antigen positive and 0.88% (n = 34, CI 0.61-1.22%) only positive for specific antibodies. Seropositive animals, as well as the majority of A. vasorum-positive faecal samples tested during the same period, were spread over central and southern Sweden. Annual prevalence of positive faecal dog samples and of necropsied A. vasorum positive foxes (coming from southern Sweden) varied from 0.3 to 0.9% (overall: 0.7%, CI 0.4-1.1%) and 0.0 to 1.4% (overall: 0.3%, CI 0.1 0.9%), respectively. CONCLUSIONS: The findings confirmed that A. vasorum has become established in various geographical areas of central and southern Sweden. Veterinarians and dog owners should be aware of the potential risks of infection in large areas of the country, since canine angiostrongylosis may be a fatal disease if left untreated. PMID- 29258533 TI - Incidental branch retinal artery occlusion on optical coherence tomography angiography presenting as segmental optic atrophy in a child: a case report. AB - BACKGROUND: Retinal artery occlusion is extremely rare in the pediatric population and most patients have risk factors. We report a case of a healthy child with segmental optic atrophy, complicated by incidental branch retinal artery occlusion (BRAO). CASE PRESENTATION: A 10-year-old boy who had a history of his mother's gestational diabetes presented with an inferonasal visual field defect in the left eye. His best-corrected visual acuities were 20/20 in both eyes (OU). Fundoscopic examination revealed segmental pallor of the left optic disc, thinning of the superotemporal rim, a relative superior entrance of the central retinal artery and superior peripapillary scleral halo. Fluorescein angiography showed patchy filling delays in the corresponding disc area without retinal vascular abnormalities. Spectral domain optical coherence tomography (SD OCT) via automated segmentation analysis demonstrated sectoral absence of the ganglion cell layer and retinal nerve fiber layer with thinning of the inner plexiform layer, inner nuclear layer and outer plexiform layer in the corresponding retina. OCT angiography (OCTA) showed focal attenuation of superficial and intermediate/deep capillary plexuses in the corresponding areas. Systemic evaluation was unremarkable. The patient was diagnosed with segmental optic atrophy caused by incidental BRAO. CONCLUSIONS: Retinal vascular occlusions are rare in childhood, and may present as segmental optic atrophy mimicking congenital anomalies. OCTA allows the detection of previous microvascular abnormalities in the chronic phase. To the best of our knowledge, this is the first report of a child with segmental optic atrophy presumably caused by BRAO, which was documented by SD OCT and OCTA in detail. PMID- 29258534 TI - A 3D subject-specific model of the spinal subarachnoid space with anatomically realistic ventral and dorsal spinal cord nerve rootlets. AB - BACKGROUND: The spinal subarachnoid space (SSS) has a complex 3D fluid-filled geometry with multiple levels of anatomic complexity, the most salient features being the spinal cord and dorsal and ventral nerve rootlets. An accurate anthropomorphic representation of these features is needed for development of in vitro and numerical models of cerebrospinal fluid (CSF) dynamics that can be used to inform and optimize CSF-based therapeutics. METHODS: A subject-specific 3D model of the SSS was constructed based on high-resolution anatomic MRI. An expert operator completed manual segmentation of the CSF space with detailed consideration of the anatomy. 31 pairs of semi-idealized dorsal and ventral nerve rootlets (NR) were added to the model based on anatomic reference to the magnetic resonance (MR) imaging and cadaveric measurements in the literature. Key design criteria for each NR pair included the radicular line, descending angle, number of NR, attachment location along the spinal cord and exit through the dura mater. Model simplification and smoothing was performed to produce a final model with minimum vertices while maintaining minimum error between the original segmentation and final design. Final model geometry and hydrodynamics were characterized in terms of axial distribution of Reynolds number, Womersley number, hydraulic diameter, cross-sectional area and perimeter. RESULTS: The final model had a total of 139,901 vertices with a total CSF volume within the SSS of 97.3 cm3. Volume of the dura mater, spinal cord and NR was 123.1, 19.9 and 5.8 cm3. Surface area of these features was 318.52, 112.2 and 232.1 cm2 respectively. Maximum Reynolds number was 174.9 and average Womersley number was 9.6, likely indicating presence of a laminar inertia-dominated oscillatory CSF flow field. CONCLUSIONS: This study details an anatomically realistic anthropomorphic 3D model of the SSS based on high-resolution MR imaging of a healthy human adult female. The model is provided for re-use under the Creative Commons Attribution-ShareAlike 4.0 International license (CC BY-SA 4.0) and can be used as a tool for development of in vitro and numerical models of CSF dynamics for design and optimization of intrathecal therapeutics. PMID- 29258535 TI - Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated. METHODS: We utilized a recently developed murine model of cytomegalovirus associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis. RESULTS: HLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a full-blown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host's immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone. CONCLUSION: Both virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model. PMID- 29258537 TI - Gender differences and typical nutrition concerns of the diets of preschool children - the results of the first stage of an intervention study. AB - BACKGROUND: Nutrition in children has an important influence on health both in childhood and adulthood. Actions aimed at improving children's nutrition are essential, not only to the children and their families, but also to the whole society. The aim of the study was to present the results of nutrient intake before starting a nutrition and physical activity intervention programme, to investigate gender differences in nutrient intake and to discuss whether the preschoolers' nutrient intake is similar to the intake of their peers from other countries. METHODS: Nutrient intake was estimated from seven-day weighed food records kept by parents and preschool staff individually for 122 4-6-year-old children who attended two preschools in Pila, north-western Poland. Nutrient intake was calculated using Dieta 4.0 computer programme including water intake and intake of nutrients from dietary supplements. Statistical analysis was performed using the IBM SPSS Statistics computer programme, version 21.0, according to gender. The study was approved by the Bioethics Committee of the Poznan University of Medical Sciences (reference number 886/08). RESULTS: Boys, in comparison to girls, were found to have statistically significantly higher intakes of total protein, total protein per kg of body weight, saturated fatty acids, total carbohydrates, available carbohydrates, lactose, sucrose, total water, vitamin A, beta-carotene, vitamin B2, vitamin B12, vitamin C, calcium, phosphorus, and magnesium. Statistically significantly higher percentage of girls than boys had intakes of vitamin E below AI. CONCLUSIONS: Gender was a significant factor of nutrient intake in the studied preschool children. The main nutritional concerns in the studied preschoolers' diets, irrespective of gender, are typical of the diets of preschool children from various parts of Europe and indicate the need to work out common nutritional strategies to improve preschoolers' nutrition across Europe to reduce future burden of diet-related diseases to the European societies. PMID- 29258536 TI - Down-regulation of miR-9* in the peripheral leukocytes of Huntington's disease patients. AB - BACKGROUND: Huntington's disease (HD), caused by expansion of a polyglutamine tract within HUNTINGTIN (HTT) protein, is an autosomal dominant neurodegenerative disease associated with a progressive neurodegeneration of striatum and cerebral cortex. Although a few studies have identified substantial microRNA (miRNA) alterations in central nervous tissues from HD patients, it will be more accessible to employ these molecular changes in peripheral tissues as biomarkers for HD. METHODS: We examined the expression levels of 13 miRNAs (miR-1, mirR-9, miR-9*, miR-10b, miR-29a, miR-29b, miR-124a, miR-132, miR-155, miR-196a, miR 196b, miR-330 and miR-615), 10 of which previously demonstrated alterations and 3 of which are potential regulators of differentially-expressed genes in brains of HD patients, in the peripheral leukocytes of 36 HD patients, 8 pre-symptomatic HD carriers and 28 healthy controls. RESULTS: We found expression levels of miR-9* was significantly lower in HD patients compared with those in healthy controls, while other miRNAs did not show significant difference between these two groups. However, there was no significant correlation between Unified Huntington's Disease Rating Scales (UHDRS) and levels of miR-9* in peripheral leukocytes of HD patients. CONCLUSION: Our findings indicate the potential of miR-9* in peripheral leukocyte as a signature of neurodegeneration in HD patients. PMID- 29258538 TI - Predominance of girls with cancer in families with multiple childhood cancer cases. AB - BACKGROUND: Recent studies indicate that one of four childhood cancers can be attributed to hereditary genetic abnormalities. METHODS: The Lund Childhood Cancer Genetic study includes newly diagnosed childhood cancer patients as well as childhood cancer survivors visiting the Department of Pediatrics or the Late Effect Clinic at Skane University Hospital, Lund, Sweden. Questionnaires regarding family history of cancer and blood samples were provided. Reported data were validated and extended by use of the Swedish Population- and Cancer Registries. Demographics in families with one case of childhood cancer (FAM1) were investigated and compared to families with multiple cases of childhood cancer (FAM > 1) as well as to childhood cancer in the general population. RESULTS: Forty-one out of 528 families (7.8%) had more than one case of childhood cancer. In 23 families the affected children were relatives up to a 3rd degree (4.4%). In FAM > 1, 69.2% of the children with leukemia and 60% of those with tumors in the central nervous system (CNS) had a childhood relative with matching diagnosis, both significantly higher than expected. Significantly more female than male patients were observed in FAM > 1 compared to FAM1. This female predominance was most striking in childhood leukemia (77% female) and also, yet to a lesser extent, in CNS tumors (68% female). CONCLUSIONS: We conclude that the high proportion of children with leukemia or CNS tumors in FAM > 1 having a childhood relative with the same diagnosis suggests a hereditary background. Moreover, we report a female predominance in childhood leukemia and childhood CNS tumors in FAM > 1, which may indicate a hereditary gender-specific risk factor in these families. PMID- 29258540 TI - Whole-exome sequencing identified a missense mutation in WFS1 causing low frequency hearing loss: a case report. AB - BACKGROUND: Low-frequency nonsyndromic hearing loss (LF-NSHL) is a rare, inherited disorder. Here, we report a family with LF-NSHL in whom a missense mutation was found in the Wolfram syndrome 1 (WFS1) gene. CASE PRESENTATION: Family members underwent audiological and imaging evaluations, including pure tone audiometry and temporal bone computed tomography. Blood samples were collected from two affected and two unaffected subjects. To determine the genetic background of hearing loss in this family, genetic analysis was performed using whole-exome sequencing. Among 553 missense variants, c.2419A -> C (p.Ser807Arg) in WFS1 remained after filtering and inspection of whole-exome sequencing data. This missense mutation segregated with affected status and demonstrated an alteration to an evolutionarily conserved amino acid residue. Audiological evaluation of the affected subjects revealed nonprogressive LF-NSHL, with early onset at 10 years of age, but not to a profound level. CONCLUSION: This is the second report to describe a pathological mutation in WFS1 among Korean patients and the second to describe the mutation in a different ethnic background. Given that the mutation was found in independent families, p.S807R possibly appears to be a "hot spot" in WFS1, which is associated with LF-NSHL. PMID- 29258539 TI - Critical appraisal of the role of volumetric modulated arc therapy in the radiation therapy management of breast cancer. AB - BACKGROUND: The aim of this review is the critical appraisal of the current use of volumetric modulated arc therapy for the radiation therapy management of breast cancer. Both clinical and treatment planning studies were investigated. MATERIAL AND METHODS: A Pubmed/MEDLINE search of the National Library of Medicine was performed to identify VMAT and breast related articles. After a first order rejection of the irrelevant findings, the remaining articles were grouped according to two main categories: clinical vs. planning studies and to some sub categories (pointing to significant technical features). Main areas of application, dosimetric and clinical findings as well as areas of innovations were defined. RESULTS: A total of 131 articles were identified and of these, 67 passed a first order selection. Six studies reported clinical results while 61 treatment dealed with treatment planning investigations. Among the innovation lines, the use of high intensity photon beams (flattening filter free), altered fractionation schemes (simultaneous integrated boost, accelerated partial breast irradiation, single fraction), prone positioning and modification of standard VMAT (use of dynamic trajectories or hybrid VMAT methods) resulted among the main relevant fields of interest. Approximately 10% of the publications reported upon respiratory gating in conjunction with VMAT. CONCLUSIONS: The role of VMAT in the radiation treatment of breast cancer seems to be consolidated in the in-silico arena while still limited evidence and only one phase II trial appeared in literature from the clinical viewpoint. More clinical reports are needed to fully proove the expected dosimetric benefits demonstrated in the planning investigations. PMID- 29258542 TI - Radiotherapy of MRI-detected involved internal mammary lymph nodes in breast cancer. AB - BACKGROUND: The internal mammary (IM) lymph node chain, along with the axillary nodal basin, is a first-echelon breast lymphatic draining site. A growing body of evidence supports irradiation of this region in node-positive breast cancer. This study evaluated the effectiveness of radiotherapy in treating magnetic resonance imaging (MRI)-detected abnormal IM lymph nodes in newly-diagnosed non-metastatic breast cancer. METHODS: A structured query was performed on an electronic institutional database to identify women with radiographic evidence of abnormal IM node(s) on breast MRI from 2005 to 2013. Manual review narrowed inclusion to patients with a primary diagnosis of non-metastatic breast cancer with abnormal IM node(s) based on pathologic size criteria and/or abnormal enhancement. RESULTS: Of the 7070 women who underwent pre-treatment MRI, 19 (0.3%) were identified on imaging to have a total of 25 abnormal pre-treatment IM lymph nodes, of which 96% were located in the first two intercostal spaces and 4% in the third space. A majority of the primary tumors were high-grade (94.7%) and hormone-receptor negative (73.7%), while 47.4% overexpressed HER-2/neu receptor. Axillary nodal disease was present in 89.5% of patients, while one patient had supraclavicular involvement. At a median follow-up of 38 months, 31.6% of patients had developed metastatic disease and 21.1% had died from their disease. Of the patients who received IM coverage, none had progressive disease within the IM lymph node chain. CONCLUSIONS: Radiologic evidence of pre-treatment abnormal IM chain lymph nodes was associated with advanced stage, high grade, and negative estrogen receptor status. The majority of positive lymph nodes were located within the first two intercostal spaces, while none were below the third. Radiation of the IM chain in combination with modern systemic therapy was effective in achieving locoregional control without surgical resection in this cohort of patients. PMID- 29258541 TI - Intravenous iron vs blood for acute post-partum anaemia (IIBAPPA): a prospective randomised trial. AB - BACKGROUND: Acute post-partum anaemia can be associated with significant morbidity including a predisposition for postnatal depression. Lack of clear practice guidelines means a number of women are treated with multiple blood transfusions. Intravenous iron has the potential to limit the need for multiple blood transfusions but its role in the post-partum setting is unclear. METHODS/DESIGN: IIBAPPA is a multi-centre randomised non-inferiority trial. Women with a primary post-partum haemorrhage (PPH) >1000 mL and resultant haemoglobin (Hb) 5.5-8.0 g/dL after resuscitation with ongoing symptomatic anaemia who are otherwise stable (no active bleeding) are eligible to participate. Patients with sepsis or conditions necessitating rapid Hb restoration are excluded. Eligible participants are randomised to receive a blood transfusion or a single dose of intravenous iron polymaltose calculated using the Ganzoni formula. Primary outcome measures include Hb, Ferritin and C-Reactive Protein levels on Day 7. Secondary outcomes evaluate (i) Hb, Ferritin and CRP levels on Day 14, 28, (ii) anaemia symptoms on Day 0, 7, 14 and 28 using structured health related quality of life questionnaires, (iii) treatment safety by assessing adverse reactions and infection endpoints and (iv) the quantitative impact of anaemia on breast feeding quality using a hospital designed questionnaire. DISCUSSION: If equivalence in Hb and ferritin levels, symptom scores and safety endpoints is demonstrated, intravenous iron may become the preferred treatment for women with acute post partum anaemia to minimise transfusion reactions and costs. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12615001370594 on 16th December, 2015 (prospective approval). PMID- 29258543 TI - The impact of interpretive and reductive front-of-pack labels on food choice and willingness to pay. AB - BACKGROUND: This study examined how front-of-pack labels and product healthfulness affect choice and willingness to pay across a range of foods. It was hypothesized that: (i) product choice and (ii) willingness to pay would be more aligned with product healthfulness when healthfulness was expressed through the Health Star Rating, followed by the Multiple Traffic Light, then the Daily Intake Guide, and (iii) the Nutrition Facts Panel would be viewed infrequently. METHODS: Adults and children aged 10+ years (n = 2069) completed an online discrete choice task involving mock food packages. A 4 food type (cookies, corn flakes, pizza, yoghurt) * 2 front-of-pack label presence (present, absent) * 3 front-of-pack label type (Daily Intake Guide, Multiple Traffic Light, Health Star Rating) * 3 price (cheap, moderate, expensive) * 3 healthfulness (less healthy, moderately healthy, healthier) design was used. A 30 s time limit was imposed for each choice. RESULTS: Of the three front-of-pack labels tested, the Health Star Rating produced the largest differences in choices, with 40% (95% CIs: 38%-42%) of respondents selecting the healthier variant, 33% selecting the moderately healthy variant (95% CIs: 31%-35%), and 23% (95% CIs: 21%-24%) selecting the less healthy variant of the four products included in the study. The Multiple Traffic Light led to significant differences in choices between healthier (35%, 95% CIs: 33%-37%) and less healthy products (29%, 95% CIs: 27%-31%), but not moderately healthy products (32%, 95% CIs: 30%-34%). No significant differences in choices were observed by product healthfulness when the Daily Intake Guide was present. Only the Health Star Rating resulted in a significantly greater willingness to pay for healthier versus less healthy products. The Nutrition Facts Panel was viewed for only 7% of all mock packages. CONCLUSIONS: Front-of-pack labels that are more interpretive, such as the Health Star Rating, can be more effective at directing consumers towards healthier choices than reductive front-of-pack labels such as the Daily Intake Guide. The study results provide policy makers with clear guidance on the types of front-of-pack labels that are most likely to achieve positive health outcomes at a population level. PMID- 29258544 TI - Correction to: Study protocol on establishment of sentinel sites network for contraceptive and abortion trends, needs and utilization of services in Zika virus affected countries. AB - CORRECTION: The original version of this article [1] unfortunately contained a mistake. All occurrences in the main text referring to the research carried out in the following countries: Brazil, Honduras and Columbia should instead be replaced with "Brazil, Honduras and Panama". The original version of this article has been updated to reflect this change. PMID- 29258545 TI - Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome. AB - BACKGROUND: Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome. METHODS: To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc-) is upregulated in Mecp2-null glia when compared to WT, the role of Xc- in the uptake of NAC and L-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan. RESULTS: We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc- was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc- for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival. CONCLUSIONS: These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT. PMID- 29258546 TI - Hippocampal calpain is required for the consolidation and reconsolidation but not extinction of contextual fear memory. AB - Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca2+ dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning. Moreover, recent studies have suggested distinct roles of calpain 1 and 2 in synaptic plasticity. However, the role of hippocampal calpain in memory processes, especially memory consolidation, reconsolidation, and extinction, is still unclear. In the current study, we demonstrated the critical roles of hippocampal calpain in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of calpain in the hippocampus on these memory processes, using the N-Acetyl-Leu-Leu-norleucinal (ALLN; calpain 1 and 2 inhibitor). Microinfusion of ALLN into the dorsal hippocampus impaired long-term memory (24 h memory) without affecting short-term memory (2 h memory). Similarly, this pharmacological blockade of calpain in the dorsal hippocampus also disrupted reactivated memory but did not affect memory extinction. Importantly, the systemic administration of ALLN inhibited the induction of c-fos in the hippocampus, which is observed when memory is consolidated. Our observations showed that hippocampal calpain is required for the consolidation and reconsolidation of contextual fear memory. Further, the results suggested that calpain contributes to the regulation of new gene expression that is necessary for these memory processes as a regulator of Ca2+ signal transduction pathway. PMID- 29258548 TI - Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome. AB - BACKGROUND: Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present two cases with novel mutations of AGRN of which we further investigated possible pathogenesis. RESULTS: Patient 1 had general limb weakness with fluctuation and deterioration in the afternoon and in hot weather. Patient 2 had early-onset weakness of lower extremities with suspected fluctuation in the early stages, which then progressed to the upper limbs. Both distal and proximal muscles were involved. Repetitive stimulation on EMG in both patients showed decrement in proximal and distal limbs. Patient 2 showed a marked response to salbutamol while Patient 1 did not. By targeted exome sequencing, two novel homozygous missense variants, p.L1176P and p.R1698C, in the SEA and LG2 domain of agrin were identified respectively. Further functional analysis revealed instability of the protein and impaired clustering of the acetylcholine receptor (AChR) by both mutations. CONCLUSIONS: The mutations identified in AGRN in our study may cause congenital myasthenic syndrome by damaging protein stability and interfering with AChR clustering. These results broaden the understandings on the phenotype, genotype and pathogenesis of this rare disorder. PMID- 29258547 TI - A preliminary analysis of hepatitis C virus in pancreatic islet cells. AB - BACKGROUND: An association between hepatitis C virus (HCV) and type 2 diabetes (T2D) is supported by numerous epidemiologic studies. We hypothesized that HCV could infect human pancreatic islet cells in vitro. METHODS: Measures of HCV RNA synthesis and protein production were used to evaluate HCV infection of pancreatic islets recovered from human donors. RESULTS: Significant co-staining of insulin and the HCV entry factor CD81 was observed in pancreatic islets. Positive- and negative-sense HCV RNA were detected in HCV-exposed islets at days 1, 3, 7, and 14 post-infection. The HCV core and NS3 proteins were expressed and increased with time providing further evidence of viral replication. Interferon and an HCV polymerase inhibitor reduced viral replication in islet cells. In HCV infected islets, TNFalpha levels were elevated at days 1, 3, and 7 post infection, while IL-6 levels were elevated at day 1 but not days 3 or 7. Overall, the expression of miR-122 was low in islets compared to the Huh7.5 hepatocyte derived cell line, although the relative expression of miR-122 increased in islet cells after viral infection (1, 6.63, and 5.83 at days 1, 3, and 7, respectively). CONCLUSIONS: In this pilot study, viral infection was demonstrated in pancreatic islet cells from multiple donors using complementary measures of viral replication, thus providing evidence of in vitro infection. Altered cytokine expression may contribute to the development of insulin deficiency, and understanding the etiology of diabetes in individuals with HCV infection may facilitate the development of novel treatment modalities and prevention strategies. This in vitro system provides an important model for mechanistic studies of HCV-pancreas interactions and facilitates future studies of the potential impact of viral infection on islet cell function. PMID- 29258549 TI - Effectiveness of home-based nutritional counselling and support on exclusive breastfeeding in urban poor settings in Nairobi: a cluster randomized controlled trial. AB - BACKGROUND: Exclusive breastfeeding (EBF) improves infant health and survival. We tested the effectiveness of a home-based intervention using Community Health Workers (CHWs) on EBF for six months in urban poor settings in Kenya. METHODS: We conducted a cluster-randomized controlled trial in Korogocho and Viwandani slums in Nairobi. We recruited pregnant women and followed them until the infant's first birthday. Fourteen community clusters were randomized to intervention or control arm. The intervention arm received home-based nutritional counselling during scheduled visits by CHWs trained to provide specific maternal infant and young child nutrition (MIYCN) messages and standard care. The control arm was visited by CHWs who were not trained in MIYCN and they provided standard care (which included aspects of ante-natal and post-natal care, family planning, water, sanitation and hygiene, delivery with skilled attendance, immunization and community nutrition). CHWs in both groups distributed similar information materials on MIYCN. Differences in EBF by intervention status were tested using chi square and logistic regression, employing intention-to-treat analysis. RESULTS: A total of 1110 mother-child pairs were involved, about half in each arm. At baseline, demographic and socioeconomic factors were similar between the two arms. The rates of EBF for 6 months increased from 2% pre-intervention to 55.2% (95% CI 50.4-59.9) in the intervention group and 54.6% (95% CI 50.0-59.1) in the control group. The adjusted odds of EBF (after adjusting for baseline characteristics) were slightly higher in the intervention arm compared to the control arm but not significantly different: for 0-2 months (OR 1.27, 95% CI 0.55 to 2.96; p = 0.550); 0-4 months (OR 1.15; 95% CI 0.54 to 2.42; p = 0.696), and 0 6 months (OR 1.11, 95% CI 0.61 to 2.02; p = 0.718). CONCLUSIONS: EBF for six months significantly increased in both arms indicating potential effectiveness of using CHWs to provide home-based counselling to mothers. The lack of any difference in EBF rates in the two groups suggests potential contamination of the control arm by information reserved for the intervention arm. Nevertheless, this study indicates a great potential for use of CHWs when they are incentivized and monitored as an effective model of promotion of EBF, particularly in urban poor settings. Given the equivalence of the results in both arms, the study suggests that the basic nutritional training given to CHWs in the basic primary health care training, and/or provision of information materials may be adequate in improving EBF rates in communities. However, further investigations on this may be needed. One contribution of these findings to implementation science is the difficulty in finding an appropriate counterfactual for community-based educational interventions. TRIAL REGISTRATION: ISRCTN ISRCTN83692672 . Registered 11 November 2012. Retrospectively registered. PMID- 29258551 TI - Community-based participatory research and integrated knowledge translation: advancing the co-creation of knowledge. AB - BACKGROUND: Better use of research evidence (one form of "knowledge") in health systems requires partnerships between researchers and those who contend with the real-world needs and constraints of health systems. Community-based participatory research (CBPR) and integrated knowledge translation (IKT) are research approaches that emphasize the importance of creating partnerships between researchers and the people for whom the research is ultimately meant to be of use ("knowledge users"). There exist poor understandings of the ways in which these approaches converge and diverge. Better understanding of the similarities and differences between CBPR and IKT will enable researchers to use these approaches appropriately and to leverage best practices and knowledge from each. The co creation of knowledge conveys promise of significant social impacts, and further understandings of how to engage and involve knowledge users in research are needed. MAIN TEXT: We examine the histories and traditions of CBPR and IKT, as well as their points of convergence and divergence. We critically evaluate the ways in which both have the potential to contribute to the development and integration of knowledge in health systems. As distinct research traditions, the underlying drivers and rationale for CBPR and IKT have similarities and differences across the areas of motivation, social location, and ethics; nevertheless, the practices of CBPR and IKT converge upon a common aim: the co creation of knowledge that is the result of knowledge user and researcher expertise. We argue that while CBPR and IKT both have the potential to contribute evidence to implementation science and practices for collaborative research, clarity for the purpose of the research-social change or application-is a critical feature in the selection of an appropriate collaborative approach to build knowledge. CONCLUSION: CBPR and IKT bring distinct strengths to a common aim: to foster democratic processes in the co-creation of knowledge. As research approaches, they create opportunities to challenge assumptions about for whom, how, and what is defined as knowledge, and to develop and integrate research findings into health systems. When used appropriately, CBPR and IKT both have the potential to contribute to and advance implementation science about the conduct of collaborative health systems research. PMID- 29258550 TI - The impact of antiretroviral therapy on iron homeostasis and inflammation markers in HIV-infected patients with mild anemia. AB - BACKGROUND: Anemia is frequent during HIV infection and is predictive of mortality. Although cART has demonstrated to reduce its prevalence, several patients still experience unresolved anemia. We aimed to characterize iron homeostasis and inflammation in HIV-infected individuals with mild anemia in relation to cART. METHODS: In this retrospective cohort study, HIV-infected patients with mild anemia, CD4+ cells > 200/mm3 at baseline, maintaining virological response for 12 months after cART starting were selected within the Standardized Management of Antiretroviral Therapy Cohort (MASTER) cohort. Several inflammation and immune activation markers and iron homeostasis indexes were measured in stored samples, obtained at cART initiation (T0) and 12 months later (T1). Patients were grouped on the basis of hemoglobin values at T1: group A (> 13 g/dl) and B (< 13 g/dl). Wilcoxon rank sum test was used to compare biomarker values. Pearson correlation coefficients were calculated for all variables. RESULTS: cART improved CD4+ and CD8+ cell counts and their ratio, but this effect was significant only in group A. Only these patients had mild iron deficiency at T0 and showed higher transferrin and lower percentage of transferrin saturation than patients of group B, but differences disappeared with cART. cART decreased inflammation in all patients, but group B had higher levels of all markers than group A, reaching statistical significance only for IL-8 values at T1 (16 vs 2.9 pg/ml; p = 0.017). Hepcidin and IL-6 levels did not show significant differences between groups. Hemoglobin levels both at T0 and T1 did not correlate with any marker. CONCLUSIONS: Baseline mild anemia in HIV-infected patients cannot always be resolved with durable efficient cART, possibly due to residual inflammation or immune activation rather than unbalanced iron homeostasis. Further research is needed on cytokine profiling to understand the mechanisms that induce anemia in HIV with suppressive cART. PMID- 29258552 TI - Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose. AB - BACKGROUND: Excess dietary fructose intake associated with metabolic syndrome and insulin resistance and increased risk of developing type 2 diabetes. Previous animal studies have reported that diabetic animals have significantly impaired behavioural and cognitive functions, pathological synaptic function and impaired expression of glutamate receptors. Correction of the antioxidant status of laboratory rodents largely prevents the development of fructose-induced plurimetabolic changes in the nervous system. We suggest a novel concept of efficiency of Stevia leaves for treatment of central diabetic neuropathy. METHODS: By in vivo extracellular studies induced spike activity of hippocampal neurons during high frequency stimulation of entorhinal cortex, as well as neurons of basolateral amygdala to high-frequency stimulation of the hippocampus effects of Stevia rebaudiana Bertoni plant evaluated in synaptic activity in the brain of fructose-enriched diet rats. In the conditions of metabolic disorders caused by fructose, antioxidant activity of Stevia rebaudiana was assessed by measuring the NOX activity of the hippocampus, amygdala and spinal cord. RESULTS: In this study, the characteristic features of the metabolic effects of dietary fructose on synaptic plasticity in hippocampal neurons and basolateral amygdala and the state of the NADPH oxidase (NOX) oxidative system of these brain formations are revealed, as well as the prospects for development of multitarget and polyfunctional phytopreparations (with adaptogenic, antioxidant, antidiabetic, nootropic activity) from native raw material of Stevia rebaudiana. Stevia modulates degree of expressiveness of potentiation/depression (approaches but fails to achieve the norm) by shifting the percentage balance in favor of depressor type of responses during high-frequency stimulation, indicating its adaptogenic role in plasticity of neural networks. Under the action of fructose an increase (3-5 times) in specific quantity of total fraction of NOX isoforms isolated from the central nervous system tissue (amygdala, hippocampus, spinal cord) was revealed. Stevia exhibits an antistress, membrane-stabilizing role reducing the level of total fractions of NOX isoforms from central nervous system tissues and regulates NADPH-dependent O2- -producing activity. CONCLUSION: Generally, in condition of metabolic disorders caused by intensive consumption of dietary fructose Stevia leaves contributes to the control of neuronal synaptic plasticity possibly influencing the conjugated NOX-specific targets. PMID- 29258554 TI - KBG syndrome. AB - CLINICAL DESCRIPTION: KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. The condition was named KBG syndrome after the initials of the last names of three original families reported in 1975. EPIDEMIOLOGY: The prevalence of KBG syndrome is not established. There are over 100 patients reported in the literature. It is likely that KBG syndrome is underreported due to incomplete recognition and very mild presentations of the disorder in some individuals. KBG syndrome is typically milder in females. ETIOLOGY: Causative variants in ANKRD11 have been identified in affected individuals. The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity. GENETIC COUNSELING: Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern. The syndrome displays inter- and intra-familial variability. PMID- 29258553 TI - Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function. AB - BACKGROUND: Clinical studies show that prenatal alcohol exposure (PAE) results in effects that persist into adulthood. Experimental animal models of moderate PAE demonstrate that young adults with PAE display potentiated sensitivity to light touch, clinically termed allodynia, following sciatic nerve chronic constriction injury (CCI) that coincides with heightened spinal glial, spinal macrophage, and peripheral immune responses. However, basal touch sensitivity and corresponding glial and leukocyte activation are unaltered. Therefore, the current study explored whether the enduring pathological consequences of moderate PAE on sensory processing are unmasked only following secondary neural insult. METHODS: In middle-aged (1 year) Long Evans rats that underwent either prenatal saccharin exposure (control) or moderate PAE, we modified the well-characterized model of sciatic neuropathy, CCI, to study the effects of PAE on neuro-immune responses in adult offspring. Standard CCI manipulation required 4 chromic gut sutures, while a mild version applied a single suture loosely ligated around one sciatic nerve. Spinal glial immunoreactivity was examined using immunohistochemistry. The characterization and functional responses of leukocyte populations were studied using flow cytometry and cell stimulation assays followed by quantification of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Data were statistically analyzed by ANOVA and unpaired t tests. RESULTS: The current report demonstrates that mild CCI generates robust allodynia only in PAE rats, while the pathological effects of PAE following the application of a standard CCI are revealed by enhanced allodynia and elevated spinal glial activation. Additionally, mild CCI increases spinal astrocyte activation but not microglia, suggesting astrocytes play a larger role in PAE induced susceptibility to aberrant sensory processing. Leukocyte populations from PAE are altered under basal conditions (i.e., prior to secondary insult), as the distribution of leukocyte populations in lymphoid organs and other regions are different from those of controls. Lastly, following in vitro leukocyte stimulation, only PAE augments the immune response to antigen stimulation as assessed by heightened production of TNF-alpha and IL-1beta. CONCLUSIONS: These studies demonstrate PAE may prime spinal astrocytes and peripheral leukocytes that contribute to enduring susceptibility to adult-onset neuropathic pain that is not apparent until a secondary insult later in life. PMID- 29258555 TI - Detection and full genome characterization of two beta CoV viruses related to Middle East respiratory syndrome from bats in Italy. AB - BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV), which belongs to beta group of coronavirus, can infect multiple host species and causes severe diseases in humans. Multiple surveillance and phylogenetic studies suggest a bat origin. In this study, we describe the detection and full genome characterization of two CoVs closely related to MERS-CoV from two Italian bats, Pipistrellus kuhlii and Hypsugo savii. METHODS: Pool of viscera were tested by a pan-coronavirus RT-PCR. Virus isolation was attempted by inoculation in different cell lines. Full genome sequencing was performed using the Ion Torrent platform and phylogenetic trees were performed using IQtree software. Similarity plots of CoV clade c genomes were generated by using SSE v1.2. The three dimensional macromolecular structure (3DMMS) of the receptor binding domain (RBD) in the S protein was predicted by sequence-homology method using the protein data bank (PDB). RESULTS: Both samples resulted positive to the pan-coronavirus RT-PCR (IT batCoVs) and their genome organization showed identical pattern of MERS CoV. Phylogenetic analysis showed a monophyletic group placed in the Beta2c clade formed by MERS-CoV sequences originating from humans and camels and bat-related sequences from Africa, Italy and China. The comparison of the secondary and 3DMMS of the RBD of IT-batCoVs with MERS, HKU4 and HKU5 bat sequences showed two aa deletions located in a region corresponding to the external subdomain of MERS-RBD in IT-batCoV and HKU5 RBDs. CONCLUSIONS: This study reported two beta CoVs closely related to MERS that were obtained from two bats belonging to two commonly recorded species in Italy (P. kuhlii and H. savii). The analysis of the RBD showed similar structure in IT-batCoVs and HKU5 respect to HKU4 sequences. Since the RBD domain of HKU4 but not HKU5 can bind to the human DPP4 receptor for MERS-CoV, it is possible to suggest also for IT-batCoVs the absence of DPP4 binding potential. More surveillance studies are needed to better investigate the potential intermediate hosts that may play a role in the interspecies transmission of known and currently unknown coronaviruses with particular attention to the S protein and the receptor specificity and binding affinity. PMID- 29258556 TI - Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype. AB - BACKGROUND: Extracellular lysophosphatidic acid (LPA) species transmit signals via six different G protein-coupled receptors (LPAR1-6) and are indispensible for brain development and function of the nervous system. However, under neuroinflammatory conditions or brain damage, LPA levels increase, thereby inducing signaling cascades that counteract brain function. We describe a critical role for 1-oleyl-2-hydroxy-sn-glycero-3-phosphate (termed "LPA" throughout our study) in mediating a motile and pro-inflammatory microglial phenotype via LPAR5 that couples to protein kinase D (PKD)-mediated pathways. METHODS: Using the xCELLigence system and time-lapse microscopy, we investigated the migrational response of microglial cells. Different M1 and M2 markers were analyzed by confocal microscopy, flow cytometry, and immunoblotting. Using qPCR and ELISA, we studied the expression of migratory genes and quantitated the secretion of pro-inflammatory cytokines and chemokines, respectively. Different transcription factors that promote the regulation of pro-inflammatory genes were analyzed by western blot. Reactive oxygen species (ROS) and nitric oxide (NO) production, phagocytosis, and microglial cytotoxicity were determined using commercially available assay kits. RESULTS: LPA induces MAPK family and AKT activation and pro-inflammatory transcription factors' phosphorylation (NF kappaB, c-Jun, STAT1, and STAT3) that were inhibited by both LPAR5 and PKD family antagonists. LPA increases migratory capacity, induces secretion of pro inflammatory cytokines and chemokines and expression of M1 markers, enhances production of ROS and NO by microglia, and augments cytotoxicity of microglial cell-conditioned medium towards neurons. The PKD family inhibitor blunted all of these effects. We propose that interference with this signaling axis could aid in the development of new therapeutic approaches to control neuroinflammation under conditions of overshooting LPA production. CONCLUSIONS: In the present study, we show that inflammatory LPA levels increased the migratory response of microglia and promoted a pro-inflammatory phenotype via the LPAR5/PKD axis. Interference with this signaling axis reduced microglial migration, blunted microglial cytotoxicity, and abrogated the expression and secretion of pro-inflammatory mediators. PMID- 29258558 TI - Hepatitis B virus x protein induces epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating long non-coding RNA. AB - BACKGROUND: It has been widely accepted that hepatitis B virus X protein (HBx) plays an important role in hepatocellular carcinoma (HCC). This study aimed to explore the function of long non-coding RNAs (lncRNAs) in the epithelial mesenchymal transition (EMT) induced by HBx. METHODS: The association between HBx and EMT markers was detected using immunohistochemistry in HCC tissues. The effect of HBx on HCC EMT was assessed through morphological analysis, transwell assay, metastatic in vivo study and detection of EMT markers. LncRNA microarray was used to screen the differently expressed lncRNAs. Small interfering RNA and Western blot were used to analyse the function and mechanism of the locked lncRNA. RESULTS: HBx was negatively correlated with the epithelial marker E cadherin but positively correlated with the mesenchymal marker vimentin in HCC tissues. HBx induced the mesenchymal phenotype and improved the metastatic ability of HCC cells. Meanwhile, HBx down-regulated E-cadherin, whereas it up regulated vimentin. In HCC cells, HBx altered the expression of 2002 lncRNAs by more than 2-fold. One of them was ZEB2-AS1. Inhibition of ZEB2-AS1 can compensate for the EMT phenotype and reverse the expression of EMT markers regulated by HBx. Additionally, HBx affected the Wnt signalling pathway. CONCLUSIONS: HBx promotes HCC cell metastasis by inducing EMT, which is at least partly mediated by lncRNAs. PMID- 29258557 TI - Moloney leukemia virus 10 (MOV10) inhibits the degradation of APOBEC3G through interference with the Vif-mediated ubiquitin-proteasome pathway. AB - BACKGROUND: MOV10 protein has ATP-dependent 5'-3' RNA helicase activity and belongs to the UPF1p superfamily. It can inhibit human immunodeficiency virus type 1 (HIV-1) replication at multiple stages and interact with apolipoprotein-B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G), a member of the cytidine deaminase family that exerts potent inhibitory effects against HIV-1 infection. However, HIV-1-encoded virion infectivity factor (Vif) protein specifically mediates the degradation of A3G via the ubiquitin-proteasome system (UPS). RESULTS: We demonstrate that MOV10 counteracts Vif-mediated degradation of A3G by inhibiting the assembly of the Vif-CBF-beta-Cullin 5-ElonginB-ElonginC complex. Through interference with UPS, MOV10 enhances the level of A3G in HIV-1 infected cells and virions, and synergistically inhibits the replication and infectivity of HIV-1. In addition, the DEAG-box of MOV10 is required for inhibition of Vif-mediated A3G degradation as the DEAG-box mutant significantly loses this ability. CONCLUSIONS: Our results demonstrate a novel mechanism involved in the anti-HIV-1 function of MOV10. Given that both MOV10 and A3G belong to the interferon antiviral system, their synergistic inhibition of HIV-1 suggests that these proteins may play complicated roles in antiviral functions. PMID- 29258559 TI - Immune-related redox metabolism of embryonic cells of the tick Rhipicephalus microplus (BME26) in response to infection with Anaplasma marginale. AB - BACKGROUND: It is well known that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in the control of pathogens and microbiota in insects. However, the knowledge of the role of ROS and RNS in tick-pathogen and tick-microbiota interactions is limited. Here, we evaluated the immune-related redox metabolism of the embryonic cell line BME26 from the cattle tick Rhipicephalus microplus in response to Anaplasma marginale infection. METHODS: A high-throughput qPCR approach was used to determine the expression profile of 16 genes encoding proteins involved in either production or detoxification of ROS and RNS in response to different microbial challenges. In addition, the effect of RNAi-mediated gene silencing of catalase, glutathione peroxidase, thioredoxin and protein oxidation resistance 1 in the control of infection with A. marginale was evaluated. RESULTS: Infection with A. marginale resulted in downregulation of the genes encoding ROS-generating enzymes dual oxidase and endoplasmic reticulum oxidase. In contrast, the genes encoding the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, thioredoxin, thioredoxin reductase and peroxiredoxin were upregulated. The gene expression pattern in response to infection with Rickettsia rickettsii and exposure to heat-killed microorganisms, Micrococcus luteus, Enterobacter cloacae or S. cerevisiae was the opposite of that triggered by A. marginale challenge. The simultaneous silencing of three genes, catalase, glutathione peroxidase, and thioredoxin as well as the oxidation resistance 1 gene by RNAi apparently favoured the colonization of BME26 cells by A. marginale, suggesting that the antioxidant response might play a role in the control of infection. CONCLUSIONS: Taken together, our results suggest that a general response of tick cells upon microbial stimuli is to increase ROS/RNS production. In contrast, A. marginale infection triggers an opposite profile, suggesting that this pathogen might manipulate the tick redox metabolism to evade the deleterious effect of the oxidant-based innate immune response. PMID- 29258560 TI - A clinical series using intensive neurorehabilitation to promote functional motor and cognitive skills in three girls with CASK mutation. AB - OBJECTIVES: Children with microcephaly face lifelong psychomotor, cognitive, and communications skills disabilities. Etiology of microcephaly is heterogeneous but presentation often includes seizures, hypotonia, ataxia, stereotypic movements, attention deficits, excitability, cognitive delays, and poor communication skills. Molecular diagnostics have outpaced available interventions and most children receive generic physical, speech, and occupational therapies with little attention to the efficacy of such treatments. Mutations in the X-linked intellectual disability gene (XLID) CASK is one etiology associated with microcephaly which produces mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH; OMIM# 300749). We pilot-tested an intensive therapy in three girls with heterozygous mutation in the gene CASK and MICPCH. Child A = 54 months; Child B = 89 months; and Child C = 24 months received a targeted treatment to improve gross/fine motor skills, visual-motor coordination, social interaction, and communication. Treatment was 4 h each weekday for 10 treatment days. Operant training promoted/refined goal-directed activities. The Peabody Developmental Motor Scales 2 was administered pre- and post-treatment. RESULTS: Child A gained 14 developmental months; Child B gained 20 developmental months; and Child C gained 39 developmental months. This case series suggests that children with MICPCH are responsive to intensive therapy aimed at increasing functional skills/independence. Trial Registration ClinicalTrials.gov Registration Number: NCT03325946; Release Date: October 30, 2017. PMID- 29258561 TI - A pilot investigation on DNA methylation modifications associated with complex posttraumatic symptoms in elderly traumatized in childhood. AB - OBJECTIVE: Complex posttraumatic stress disorder (CPTSD) is a newly proposed diagnosis in the International Classification of Diseases-version 11, which is currently intensively investigated. Childhood trauma is regarded as main source of CPTSD symptoms, even in later life. Induction of DNA methylation changes by childhood trauma may contribute to its long-lasting adverse health consequences. The current study analyzed the correlation of genome-wide DNA methylation profiles with complex posttraumatic sequelae in buccal epithelial cells from 31 elderly former indentured child laborers (Verdingkinder) using the Infinium Illumina 450k Human DNA methylation chip. RESULTS: DNA methylation modifications indicated experiment-wide significant associations with the following complex posttraumatic symptom domains: dissociation, tension reduction behavior and dysfunctional sexual behavior. Differentially methylated CpG sites were mapped to the genes huntington associated protein 1 (HAP1), RAN binding protein 2 (RANBP2) and proteasome subunit alpha 4 (PSMA4), respectively. In addition, the methylation of cg07225277 located in carnosine synthase 1 (CARNS1) correlated with trauma symptom complexity. Our pilot data suggest correlation of DNA methylation modifications with complex posttraumatic symptoms in elderly individuals subjected to prolonged and complex childhood trauma. More comprehensive and elaborated studies should be carried out to analyze epigenetic modifications associated with CPTSD. PMID- 29258563 TI - Complementing endozoochorous seed dispersal patterns by donkeys and goats in a semi-natural island ecosystem. AB - BACKGROUND: Endozoochory is, in grazing systems, a substantial vector for seed dispersal. It can play an important role in vegetation dynamics, especially in colonization processes through seed input on the vegetation and on the soil seed bank. We investigated the endozoochorous seed input of donkeys and goats on a semi-natural island ecosystem in the Mediterranean. Through germination experiments, we assessed the viable seed content of the dung of these grazing animals to estimate their suitability and efficiency for seed dispersal of the vegetation types of the island. RESULTS: We show different dispersal patterns of donkeys and goats. Goats disperse a high number of diaspores from shrubs while donkeys disperse more diaspores of grasses. In addition, goats disperse plants of greater growth height and donkeys plants of shorter height. These dispersal patterns are in accordance with the vegetation types of which donkeys and goats disperse indicator species. Both, donkeys and goats, feed on and disperse species of the vegetation types, open grassland and temporarily wet grassland. In addition, goats feed on and disperse diagnostic species of the semi-open maquis and preforest formations. CONCLUSIONS: Overall, our results show that donkeys and goats are complementing each other in their endozoochorous seed dispersal potential. This emphasizes the importance of both grazing animals for the vegetation dynamics of the semi-natural island ecosystem. Therefore, the adaption of the goat management to a traditional land management based on directed transhumance might maintain and enrich vegetation types. PMID- 29258562 TI - Leishmania infantum 5'-Methylthioadenosine Phosphorylase presents relevant structural divergence to constitute a potential drug target. AB - BACKGROUND: The 5'-methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and polyamine metabolism and in the methionine salvage pathway, is considered as a potential drug target against cancer and trypanosomiasis. In fact, Trypanosoma and Leishmania parasites lack de novo purine pathways and rely on purine salvage pathways to meet their requirements. Herein, we propose the first comprehensive bioinformatic and structural characterization of the putative Leishmania infantum MTAP (LiMTAP), using a comparative computational approach. RESULTS: Sequence analysis showed that LiMTAP shared higher identity rates with the Trypanosoma brucei (TbMTAP) and the human (huMTAP) homologs as compared to the human purine nucleoside phosphorylase (huPNP). Motifs search using MEME identified more common patterns and higher relatedness of the parasite proteins to the huMTAP than to the huPNP. The 3D structures of LiMTAP and TbMTAP were predicted by homology modeling and compared to the crystal structure of the huMTAP. These models presented conserved secondary structures compared to the huMTAP, with a similar topology corresponding to the Rossmann fold. This confirmed that both LiMTAP and TbMTAP are members of the NP-I family. In comparison to the huMTAP, the 3D model of LiMTAP showed an additional alpha helix, at the C terminal extremity. One peptide located in this specific region was used to generate a specific antibody to LiMTAP. In comparison with the active site (AS) of huMTAP, the parasite ASs presented significant differences in the shape and the electrostatic potentials (EPs). Molecular docking of 5' methylthioadenosine (MTA) and 5'-hydroxyethylthio-adenosine (HETA) on the ASs on the three proteins predicted differential binding modes and interactions when comparing the parasite proteins to the human orthologue. CONCLUSIONS: This study highlighted significant structural peculiarities, corresponding to functionally relevant sequence divergence in LiMTAP, making of it a potential drug target against Leishmania. PMID- 29258564 TI - Effectiveness of a campaign to implement chlorhexidine use for newborns in rural Haiti. AB - BACKGROUND: Chlorhexidine topical cord application is recommended to prevent umbilical cord infections in newborns delivered at home in low-resource settings. A community campaign introducing chlorhexidine for the first time in Haiti was developed. Traditional birth attendants (TBAs) were identified as implementers since they typically cut newborns' cords. TBAs were trained to apply chlorhexidine to the cord and demonstrate this procedure to the mother. Concurrently TBAs explained reasons for using chlorhexidine exclusively instead of traditional cord care practices. The campaign's effectiveness was evaluated 7 10 days post-delivery using a survey administered by community health workers (CHWs) to 198 mothers. RESULTS: Nearly all mothers heard about chlorhexidine use and applied it as instructed. Most mothers did not initially report using traditional cord care practices. With further probing, the majority reported covering the cord but few applied an unhygienic substance. No serious cord infections were reported. CONCLUSION: The campaign was highly successful in reaching mothers and achieving chlorhexidine use. In this study, the concomitant use of traditional cloth coverings or bindings of the cord did not appear harmful; however more research is needed in this area. This campaign provides a model for implementing chlorhexidine use, especially where trained TBAs and CHWs are present. PMID- 29258566 TI - 5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105 saporin. AB - BACKGROUND: Development of resistance to 5-fluorouracil (5-FU) is a major problem in treatment of various cancers including pancreatic cancer. In this study, we reveal important resistance mechanisms and photochemical strategies to overcome 5 FU resistance in pancreatic adenocarcinoma. METHODS: 5-FU resistant (5-FUR), epithelial-to-mesenchymal-like sub-clones of the wild type pancreatic cancer cell line Panc03.27 were previously generated in our lab. We investigated the cytotoxic effect of the endosomal/lysosomal-localizing photosensitizer TPCS2a (fimaporfin) combined with light (photochemical treatment, PCT) using MTS viability assay, and used fluorescence microscopy to show localization of TPCS2a and to investigate the effect of photodamage of lysosomes. Flow cytometric analysis was performed to investigate uptake of photosensitizer and to assess intracellular ROS levels. Expression and localization of LAMP1 was assessed using RT-qPCR, western blotting, and structured illumination microscopy. MTS viability assay was used to assess the effect of combinations of 5-FU, chloroquine (CQ), and photochemical treatment. Expression of CD105 was investigated using RT-qPCR, western blotting, flow cytometry, and fluorescence microscopy, and co localization of TPCS2a and anti-CD105-saporin was assessed using microscopy. Lastly, the MTS assay was used to investigate cytotoxic effects of photochemical internalization (PCI) of the anti-CD105-immunotoxin. RESULTS: The 5-FUR cell lines display hypersensitivity to PCT, which was linked to increased uptake of TPCS2a, altered lysosomal distribution, lysosomal photodamage and increased expression of the lysosomal marker LAMP-1 in the 5-FUR cells. We show that inhibition of autophagy induced by either chloroquine or lysosomal photodamage increases the sensitivity to 5-FU in the resistant cells. The three 5-FUR sub clones overexpress Endoglin (CD105). Treatment with the immunotoxin anti-CD105 saporin alone significantly reduced the viability of the CD105-expressing 5-FUR cells, whereas little effect was seen in the CD105-negative non-resistant parental cancer cell lines. Strikingly, using the intracellular drug delivery method photochemical internalization (PCI) by combining light-controlled activation of the TPCS2a with nanomolar levels of CD105-saporin resulted in strong cytotoxic effects in the 5-FUR cell population. CONCLUSION: Our findings suggested that autophagy is an important resistance mechanism against the chemotherapeutic drug 5-FU in pancreatic cancer cells, and that inhibition of the autophagy process, either by CQ or lysosomal photodamage, can contribute to increased sensitivity to 5-FU. For the first time, we demonstrate the promise of PCI-based targeting of CD105 in site-specific elimination of 5-FU resistant pancreatic cancer cells in vitro. In conclusion, PCI-based targeting of CD105 may represent a potent anticancer strategy and should be further evaluated in pre clinical models. PMID- 29258567 TI - Knowledge of bloodless medicine among nurses at the Medical/Surgical Directorate of Komfo Anokye Teaching Hospital, Ghana; a descriptive cross sectional study. AB - OBJECTIVE: This study assessed the knowledge of bloodless medicine (BM) among nurses at the medical and surgical directorate of Komfo Anokye Teaching Hospital. A paper questionnaire was administered to 322 nurses to obtain information on socio-demographic characteristics and knowledge of BM. RESULTS: More than half (52.1%) of the nurses were aware of BM. The major source of information on BM was from the internet. Out of the study population, 90.1% knew iron therapy as BM strategy. The largest proportions of the participants (51.2%) had witnessed BM treatment at the medical and surgical directorate with the Tot'hema (44.6%) being the major used drug. Flu-like symptoms (37.0%) and organ damage (50.0%) were the commonly known side effects of BM respectively. Most of the participants (97.5%) knew that doctors request for blood transfusion. The major known reason for demand of BM was religious beliefs (53.7%). Higher percentages (71.9%) of the participants were not aware of bloodless surgery although the few who were aware, had heard of this through an internet search. Participants were generally aware of BM but less knowledgeable of specific components of BM. There is the need for prompt hospital and public health education through workshops and in-service training. PMID- 29258565 TI - A core outcomes set for clinical trials of interventions for young adults with type 1 diabetes: an international, multi-perspective Delphi consensus study. AB - BACKGROUND: Achieving consensus from a range of relevant stakeholders about an agreed set of core outcomes to be measured and reported as a minimum in clinical trials has the potential to enhance evidence synthesis and make findings more relevant and applicable. Intervention research to improve outcomes for young adults with type 1 diabetes (T1DM) is hampered by inconsistent use of outcome measures. This population frequently struggles to manage their condition and reports suboptimal clinical outcomes. Our aim was to conduct an international, e Delphi consensus study to identify a core outcome set (COS) that key stakeholders (young adults with T1DM, diabetes health professionals, diabetes researchers and diabetes policy makers) consider as essential outcomes for future intervention research. METHODS: Using a list of 87 outcomes generated from a published systematic review, we administered two online surveys to a sample of international key stakeholders. Participants in the first survey (survey 1; n = 132) and the second survey (survey 2; n = 81) rated the importance of the outcomes. Survey 2 participants received information on total mean rating for each outcome and a reminder of their personal outcome ratings from Survey 1. Survey 2 results were discussed at a consensus meeting and participants (n = 12: three young adults with T1DM, four diabetes health professionals, four diabetes researchers and one diabetes policy maker) voted on outcomes. Final core outcomes were included provided that 70% of consensus group participants voted for their inclusion. RESULTS: Eight core outcomes were agreed for inclusion in the final COS: measures of diabetes-related stress; diabetes-related quality of life; number of severe hypoglycaemic events; self-management behaviour; number of instances of diabetic ketoacidosis (DKA); objectively measured glycated haemoglobin (HbA1C); level of clinic engagement; and perceived level of control over diabetes. CONCLUSIONS: This study is the first to identify a COS for inclusion in future intervention trials to improve outcomes for young adults with T1DM. Use of this COS will improve the quality of future research and increase opportunities for evidence synthesis. Future research is necessary to identify the most robust outcome measure instruments. PMID- 29258569 TI - Leishmania braziliensis SCD6 and RBP42 proteins, two factors with RNA binding capacity. AB - BACKGROUND: The study of RNA binding proteins (RBPs) is of great relevance for understanding processes like post-transcriptional control of gene expression. The post-transcriptional mechanisms are particularly important in Leishmania parasites and related trypanosomatids since transcriptional regulation is almost absent in them. Thus, RBPs should be essential during the development of these parasites and for survival strategies against the adverse conditions that they face during their life-cycle. This work was aimed to do a structural and biochemical characterization of two Leishmania braziliensis proteins, which were previously found in pull-down assays using an HSP70 RNA as bait. At that time, these proteins were annotated as hypothetical proteins (LbrM.25.2210 and LbrM.30.3080) in the GeneDB database. RESULTS: Structural analysis indicated that these two proteins belong to evolutionarily conserved families; thus, they have been renamed accordingly as LbSCD6 (LbrM.25.2210) and LbRBP42 (LbrM.30.3080). We have demonstrated experimentally that these proteins are RBPs, in agreement with their structural features. Both proteins were able to bind to the complete 3' UTR II region of HSP70-type II mRNA, and to an A + U rich element (ARE) present in that UTR. Cellular localization assays suggested that both proteins are mainly distributed in the cytoplasm of promastigotes growing at 26 degrees C, but they accumulate in foci around the nucleus when the parasites are under heat-shock conditions. Also, our study showed that steady-state levels of LbSCD6 and LbRBP42 transcripts decreased significantly during incubation of L. braziliensis promastigotes at heat-shock temperatures. However, in these conditions, the cellular content of both proteins remained unaltered. CONCLUSIONS: Our data suggest that LbSCD6 and LbRBP42, as occurs for their orthologues in other organisms, are involved in mRNA regulation, and probably they have a relevant role facing the stress conditions that L. braziliensis encounters during insect to-mammalian transmission. PMID- 29258568 TI - Establishing core outcome sets for phenylketonuria (PKU) and medium-chain Acyl CoA dehydrogenase (MCAD) deficiency in children: study protocol for systematic reviews and Delphi surveys. AB - BACKGROUND: Inherited metabolic diseases (IMD) are a large group of rare single gene disorders that are typically diagnosed early in life. There are important evidence gaps related to the comparative effectiveness of therapies for IMD, which are in part due to challenges in conducting randomized controlled trials (RCTs) for rare diseases. Registry-based RCTs present a unique opportunity to address these challenges provided the registries implement standardized collection of outcomes that are important to patients and their caregivers and to clinical providers and healthcare systems. Currently there is no core outcome set (COS) for studies evaluating interventions for paediatric IMD. This protocol outlines a study that will establish COS for each of two relatively common IMD in children, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. METHODS: This two-part study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Part 1 includes a rapid review and development of an evidence map to identify a comprehensive listing of outcomes reported in past studies of PKU and MCAD deficiency. The review follows established methods for knowledge synthesis, including a comprehensive search strategy, two stages of screening citations against inclusion/exclusion criteria by two reviewers working independently, and extraction of important data elements from eligible studies, including details of the outcomes collected and outcome measurement instruments. The review findings will inform part 2 of our study, a set of Delphi surveys to establish consensus on the highest priority outcomes for each condition. Healthcare providers, families of children with PKU or MCAD deficiency, and health system decision-makers will be invited to participate in two to three rounds of Delphi surveys. The design of the surveys will involve parents of children with IMD who are part of a family advisory forum. DISCUSSION: This protocol is a crucial step in developing the capacity to launch RCTs with meaningful outcomes that address comparative effectiveness questions in the field of paediatric IMD. Such trials will contribute high-quality evidence to inform decision-making by patients and their family members, clinicians, and policy makers. PMID- 29258570 TI - Impact of non-pyrethroid insecticide treated durable wall lining on age structure of malaria vectors in Muheza, Tanzania. AB - OBJECTIVE: Malaria vectors control interventions are designed to cause immediate killing or shorten mosquito lives, therefore does not allow enough time for the development of the parasites to infective stage. The wall lining is new malaria vectors control intervention in Tanzania where its impact on age structure is not well known. Therefore this study aimed at determining the impact of non pyrethroid durable wall lining on the age structure of malaria vectors. RESULTS: Higher proportions of An. gambiae sensu lato (57.1%, z = 2.66, P = 0.0077) and An. funestus (64.8%, z = 3.38, P = 0.001) were collected in the control clusters. Unexpectedly, significantly higher proportion of parous An. gambiae s. l. were collected in the intervention clusters (z = - 2.78, P = 0.0054). The wall lining intervention has demonstrated low impact on age structure of An. gambiae s. l., this call for further studies on the efficacy of the intervention. PMID- 29258571 TI - The forgotten value of the clinical examination to individualize and guide fluid resuscitation in patients with sepsis. PMID- 29258573 TI - Age-related differences in working hours among male and female GPs: an SMS-based time use study. AB - BACKGROUND: In several countries, the number of hours worked by general practitioners (GPs) has decreased, raising concern about current and impending workforce shortages. This shorter working week has been ascribed both to the feminisation of the workforce and to a younger generation of GPs who prefer more flexible working arrangements. There is, however, limited insight into how the impact of these determinants interact. We investigated the relative importance of differences in GPs' working hours in relation to gender, age, and employment position. METHODS: An analysis was performed on real-time monitoring data collected by sending SMS text messages to 1051 Dutch GPs, who participated during a 1-week time use study. We used descriptive statistics, independent sample t tests, and one-way ANOVA analysis to compare the working time of different GP groups. A path analysis was conducted to examine the difference in working time by gender, age, employment position, and their combinations. RESULTS: Female GPs worked significantly fewer hours than their male peers. GPs in their 50s worked the highest number of hours, followed by GPs age 60 and older. GPs younger than 40 worked the lowest number of hours. This relationship between working hours and age was not significantly different for women and men. As shown by path analysis, female GPs consistently worked fewer hours than their male counterparts, regardless of their age and employment position. The relationship between age and working hours was largely influenced by gender and employment position. CONCLUSIONS: The variation in working hours among GPs can be explained by the combination of gender, age, and employment position. Gender appears to be the most important predictor as the largest part of the variation in working hours is explained by a direct effect of this variable. It has previously been reported that the difference in working hours between male and female GPs had decreased over time. However, our findings suggest that gender remains a critical factor for variation in time use and for policy instruments such as health workforce planning. PMID- 29258572 TI - Effects of four antiplatelet/statin combined strategies on immune and inflammatory responses in patients with acute myocardial infarction undergoing pharmacoinvasive strategy: Design and rationale of the B and T Types of Lymphocytes Evaluation in Acute Myocardial Infarction (BATTLE-AMI) study: study protocol for a randomized controlled trial. AB - BACKGROUND: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. METHODS/DESIGN: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events. DISCUSSION: BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02428374 . Registered on 28 September 2014. PMID- 29258574 TI - MICRA: an automatic pipeline for fast characterization of microbial genomes from high-throughput sequencing data. AB - The increase in available sequence data has advanced the field of microbiology; however, making sense of these data without bioinformatics skills is still problematic. We describe MICRA, an automatic pipeline, available as a web interface, for microbial identification and characterization through reads analysis. MICRA uses iterative mapping against reference genomes to identify genes and variations. Additional modules allow prediction of antibiotic susceptibility and resistance and comparing the results of several samples. MICRA is fast, producing few false-positive annotations and variant calls compared to current methods, making it a tool of great interest for fully exploiting sequencing data. PMID- 29258575 TI - Association between ultrasound-detected synovitis and knee pain: a population based case-control study with both cross-sectional and follow-up data. AB - BACKGROUND: An important role for synovial pathology in the initiation and progression of knee osteoarthritis has been emphasised recently. This study aimed to examine whether ultrasonography-detected synovial changes associate with knee pain (KP) in a community population. METHODS: A case-control study was conducted to compare people with early KP (n = 298), established KP (n = 100) or no KP (n = 94) at baseline. Multinomial logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) between groups adjusted for radiographic osteoarthritis (ROA) severity and other confounding factors. After 1 year, 255 participants with early and established KP completed the follow-up questionnaire for changes in KP. Logistic regression with adjustment was used to determine predictors of KP worsening. RESULTS: At baseline, effusion was associated with early KP (OR 2.64, 95% CI 1.57-4.45) and established KP (OR 5.07, 95% CI 2.74-9.38). Synovial hypertrophy was also associated with early KP (OR 5.43, 95% CI 2.12-13.92) and established KP (OR 13.27, 95% CI 4.97-35.43). The association with effusion diminished when adjusted for ROA. Power Doppler signal was uncommon (early KP 3%, established KP 2%, controls 0%). Baseline effusion predicted worsening of KP at 1 year (OR 1.95, 95% CI 1.05-3.64). However, after adjusting for ROA, the prediction was insignificant (adjusted OR 0.95, 95% CI 0.44-2.02). CONCLUSIONS: Ultrasound effusion and synovial hypertrophy are associated with KP, but only effusion predicts KP worsening. However, the association/prediction is not independent from ROA. Power Doppler signal is uncommon in people with KP. Further study is needed to understand whether synovitis is directly involved in different types of KP. PMID- 29258576 TI - Tsetse fly (Glossina pallidipes) midgut responses to Trypanosoma brucei challenge. AB - BACKGROUND: Tsetse flies (Glossina spp.) are the prominent vector of African trypanosome parasites (Trypanosoma spp.) in sub-Saharan Africa, and Glossina pallidipes is the most widely distributed species in Kenya. This species displays strong resistance to infection by parasites, which are typically eliminated in the midgut shortly after acquisition from the mammalian host. Although extensive molecular information on immunity for the related species Glossina morsitans morsitans exists, similar information is scarce for G. pallidipes. METHODS: To determine temporal transcriptional responses of G. pallidipes to Trypanosoma brucei brucei challenge, we conducted Illumina based RNA-seq on midgut organ and carcass from teneral females G. pallidipes at 24 and 48 h post-challenge (hpc) with T. b. brucei relative to their respective controls that received normal blood meals (without the parasite). We used a suite of bioinformatics tools to determine differentially expressed and enriched transcripts between and among tissues, and to identify expanded transcripts in G. pallidipes relative to their orthologs G. m. morsitans. RESULTS: Midgut transcripts induced at 24 hpc encoded proteins were associated with lipid remodelling, proteolysis, collagen metabolism, apoptosis, and cell growth. Midgut transcripts induced at 48 hpc encoded proteins linked to embryonic growth and development, serine endopeptidases and proteosomal degradation of the target protein, mRNA translation and neuronal development. Temporal expression of immune responsive transcripts at 48 relative to 24 hpc was pronounced, indicative of a gradual induction of host immune responses the following challenge. We also searched for G. m. morsitans orthologous groups that may have experienced expansions in the G. pallidipes genome. We identified ten expanded groups in G. pallidipes with putative immunity-related functions, which may play a role in the higher refractoriness exhibited by this species. CONCLUSIONS: There appears to be a lack of strong immune responses elicited by gut epithelia of teneral adults. This in combination with a compromised peritrophic matrix at this stage during the initial phase of T. b. brucei challenge may facilitate the increased parasite infection establishment noted in teneral flies relative to older adults. Although teneral flies are more susceptible than older adults, the majority of tenerals are still able to eliminate parasite infections. Hence, robust responses elicited at a later time point, such as 72 hpc, may clear parasite infections from the majority of flies. The expanded G. m. morsitans orthologous groups in G. pallidipes may also be functionally associated with the enhanced refractoriness to trypanosome infections reported in G. pallidipes relative to G. m. morsitans. PMID- 29258577 TI - Biochemistry reference intervals for healthy elderly population in Asmara, Eritrea. AB - OBJECTIVE: There is a scarcity of reference interval studies on the elderly in Africa. This study establishes reference interval for the elderly for some commonly used biochemical parameters. In this study, 255 conveniently sampled, healthy elderly, participants meeting Clinical and Laboratory Standards Institute (CLSI C28-A3) guidelines were enrolled. The results obtained may have utility in clinical diagnosis, patient management and research. RESULTS: In general, the consensus reference interval established in this study tended to be higher than reference interval from Caucasian populations; but lower than those obtained from reference interval studies in several African countries. This pattern was observed in a number of analytes including Alanine aminotransferase; aspartate aminotransferase; alkaline phosphatase; sodium; potassium among others. Significant sex-related variations were also observed in total bilirubin; direct bilirubin; indirect bilirubin; albumin; sodium; chloride; plasma carbon dioxide, creatinine and anion gap. The results demonstrate that reference interval for Eritrean urban population differs from those derived from other African or North American populations. In this regard, the use of reference interval values obtained from Caucasian populations may result in misdiagnosis. PMID- 29258578 TI - Stunting and its determinant factors among children aged 6-59 months in Ethiopia. AB - BACKGROUND: Though Ethiopia has implemented different nutritional interventions, childhood stunting on which literature is limited continues as a severe public health problem. Thus, this study aimed to investigate stunting and its determinants among children aged 6-59 months in the predominantly rural northwest Ethiopia. METHODS: A community based cross-sectional study was conducted from May to June 2015 at Dabat Health and Demographic Surveillance System (HDSS) site. A total of 1295 mother-child pairs were included for analysis. An ordinal multivariable logistic regression analysis was carried out to identify the determinants of severe stunting. To show the strength of associations, both Crude Odds Ratio (COR) and Adjusted Odds Ratios (AOR) with a 95% Confidence Interval (CI) were estimated. Also, a P-value of <0.05 was used to declare statistical significance in the final model. RESULTS: The overall prevalence of stunting among children aged 6-59 months was 64.5%, of which about 37.7% and 26.8% were moderately and severely stunted, respectively. Farming occupation of mother [AOR = 1.45; 95% CI: 1.08, 1.93], lack of postnatal vitamin-A supplementation [AOR = 1.54; 95%: 1.19, 2.00], poorer household wealth status [AOR = 2.07; CI: 1.56, 2.75] and accessing family food from farms [AOR = 1.44; 95% CI: 1.09, 1.89] were identified as the key determinants of severe stunting. CONCLUSION: In the district, the magnitude of stunting was a critical public health concern. Therefore, emphasis should be given to improving mothers' postnatal vitamin A supplementation coverage and building knowledge about appropriate child feeding practices among farmer mothers and poorer households. PMID- 29258579 TI - Giant ovarian cyst masquerading as a massive ascites: a case report. AB - BACKGROUND: Giant ovarian cysts are tumours of the ovary presenting with diameters greater than 10 cm. Giant ovarian cysts have become rare in recent days as they are diagnosed and managed early due to the availability of good imaging modalities. The aim of this case report is to show how a huge cystic ovarian mass can mislead the diagnosis of ascites in a postmenopausal woman. Factors associated with late presentation of giant ovarian cysts in sub-Saharan Africa have also been discussed. CASE PRESENTATION: We present the case of a 65-year-old grand multiparous woman who was referred to our centre with a grossly distended abdomen misdiagnosed as a massive ascites. Abdominopelvic ultrasound scan revealed a right giant multiloculated ovarian cyst. She benefited from a cystectomy with an uneventful postoperative stay. Histopathology revealed mucinous cystadenoma. CONCLUSION: Large cystic ovarian tumours can present masquerading as massive ascites and misleading diagnosis as in this case report. We report this case to increase the suspicion index of a large ovarian cyst in all women presenting with massive ascites. PMID- 29258581 TI - Trend and outcome of notified children with tuberculosis during 2011-2015 in Kampala, Uganda. AB - BACKGROUND: The road map for childhood tuberculosis launched in 2013 provided strong renewed efforts focused towards zero deaths due to tuberculosis in children. From 2010, there were efforts to improve childhood tuberculosis diagnosis in Kampala and this study aimed to document the trend and outcome of tuberculosis in children over the period. METHODS: This was a retrospective study of tuberculosis data for Kampala city for the period 2011-2015. We extracted data from the unit TB registers in the 52 Diagnostic and treatment units (DTUs) in the Kampala. We report on data for children 0 to 14 years. RESULTS: We accessed 33,221 TB patient records of which 2333 (7.0% 95% CI 6.7 to 7.3) were children. The proportion of children with pulmonary TB was 80% (1870/2333) (95% CI 76.7 to 83.7 and extra-pulmonary TB accounted for 20% (463/2333) (CI 18.3 to 21.5). Among pulmonary TB cases, the clinically diagnosed were 82% (1530/1870) (95% CI 80.0 to 83.5) while the bacteriologically confirmed were 18% (340/1870) (95% CI 16.5 to 20.0). Among the bacteriologically confirmed, 45% (154/340) (95% CI 40.1 to 50.6) were smear positive. During the study period 2011 through 2015, the childhood TB notification rate declined as follows; 105, 76, 72, 88, and 74 per 100,000 respectively. The treatment success rate increased from 78% in 2011 to 83% in 2015. CONCLUSIONS: The TB notification rate among children in Kampala city showed a large decline during the period 2011 to 2015. There was a slight improvement in the treatment success rate among the children. PMID- 29258580 TI - Apoptosis and necroptosis of mouse hippocampal and parenchymal astrocytes, microglia and neurons caused by Angiostrongylus cantonensis infection. AB - BACKGROUND: Angiostrongylus cantonensis has been the only parasite among Angiostrongylidae to cause human central nervous system infection characterized by eosinophilic meningitis or meningoencephalitis. The mechanism of the extensive neurological impairments of hosts caused by A. cantonensis larvae remains unclear. The aim of the present study was to investigate apoptosis, necroptosis and autophagy in the brains of mice infected with A. cantonensis, which will be valuable for better understanding the pathogenesis of angiostrongyliasis cantonensis. METHODS: Functional and histological neurological impairments of brain tissues from mice infected with A. cantonensis were measured by the Morris water maze test and haematoxylin and eosin (H&E) staining, respectively. The transcriptional and translational levels of apoptosis-, necroptosis- and autophagy-related genes were quantified by quantitative real-time polymerase chain reaction (RT-PCR), and assessed by western blot and immunohistochemistry (IHC) analysis. Apoptotic and necroptotic cells and their distributions in infected brain tissues were analysed by flow cytometry and transmission electron microscopy (TEM). RESULTS: Inflammatory response in the central nervous system deteriorated as A. cantonensis infection evolved, as characterized by abundant inflammatory cell infiltration underneath the meninges, which peaked at 21 days post-infection (dpi). The learning and memory capacities of the mice were significantly decreased at 14 dpi, indicating prominent impairment of their cognitive functions. Compared with those of the control group, the mRNA levels of caspase-3, -4, -6, and RIP3 and the protein levels of caspase-4, cleaved caspase 3, cleaved caspase-6, RIP3, and pRIP3 were obviously elevated. However, no changes in the mRNA or protein levels of FADD, Beclin-1 or LC3B were evident, indicating that apoptosis and necroptosis, but not autophagy, occurred in the brain tissues of mice infected with A. cantonensis. The quantitative RT-PCR, western blot, IHC, flow cytometry and TEM results further revealed the apoptotic and necroptotic microglia, astrocytes and neurons in the parenchymal and hippocampal regions of infected mice. CONCLUSIONS: To our knowledge, we showed for the first time that A. cantonensis infection causes the apoptosis and necroptosis of microglia and astrocytes in the parenchymal and hippocampal regions of host brain tissues, further demonstrating the pathogenesis of A. cantonensis infection and providing potential therapeutic targets for the management of angiostrongyliasis. PMID- 29258582 TI - Gain +1 or Avoid -1: Validation of the German Regulatory Focus Questionnaire (RFQ). AB - BACKGROUND: The Regulatory Focus Questionnaire (RFQ) assesses regulatory promotion and prevention focus, which represent orientations towards gains or losses. The main objective of this study was to examine the psychometric properties of the newly translated German version. METHODS: A sample of 1024 participants answered the questionnaire and several related instruments. We used an online survey tool to collect this data. Data analysis was conducted using methods of exploratory and confirmatory factor analysis in SPSS and AMOS. RESULTS: The RFQ displayed acceptable reliability, while its correlations with other, related psychological constructs indicated good validity. Factor analysis showed good fit for a two-dimensional model. Tests of measurement invariance revealed clear evidence for metric invariance while scalar invariance remained uncertain. Differences in regulatory focus based on sociodemographic characteristics are reported and discussed. CONCLUSIONS: Overall, the RFQ can be recommended for application in fields dealing with motivation and goal attainment in a broad sense. PMID- 29258583 TI - Circulating cancer stem cell markers in breast carcinomas: a systematic review protocol. AB - BACKGROUND: Breast cancer is one of the most common types of cancer in women worldwide. Recent studies have provided strong support for the cancer stem cell (CSC) hypothesis, which suggests that many cancers, including breast cancer, are driven by a subpopulation of cells that display stem cell-like properties. The hypothesis that a subpopulation of circulating tumor cells (CTCs) possesses many CSC-like hallmarks is reinforced by the expression of related molecular markers between these two cell populations. The aim of this study is to systematically review primary studies and identify circulating CSC markers in breast cancer patients. METHODS AND DESIGN: Relevant observational studies evaluating the expression of circulating breast cancer stem cell markers through October 31, 2016, will be searched in PubMed, SCOPUS, Embase, ISI Web of Science, and Google Scholar with no restriction on language. Full copies of articles identified by the search and considered to meet the inclusion criteria will be obtained for data extraction and synthesis. Two quality assessment tools will be used for evaluating observational studies like case control, which are the Hoy et al. suggested tool and Newcastle-Ottawa Scale (NOS), respectively. Publication bias will be assessed by funnel plots or Egger's test (i.e., plots of study results against precision), and data synthesis will be performed using Stata software (Stata Corp V.12, TX, USA).This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). DISCUSSION: Detecting cancer stem cells in blood will help clinicians to monitor cancer patients by obtaining as many samples as needed with a non-invasive method and in any stages; it is not possible to repeat sampling on working on tissue samples. By identifying cancer stem cells early in blood, it will be possible to distinguish metastasis in early stages. SYSTEMATIC REVIEW REGISTRATION: CRD42016043810. PMID- 29258585 TI - Effects of endurance training on skeletal muscle mitochondrial function in Huntington disease patients. AB - BACKGROUND: Mitochondrial dysfunction may represent a pathogenic factor in Huntington disease (HD). Physical exercise leads to enhanced mitochondrial function in healthy participants. However, data on effects of physical exercise on HD skeletal muscle remains scarce. We aimed at investigating adaptations of the skeletal muscle mitochondria to endurance training in HD patients. METHODS: Thirteen HD patients and 11 healthy controls completed 26 weeks of endurance training. Before and after the training phase muscle biopsies were obtained from M. vastus lateralis. Mitochondrial respiratory chain complex activities, mitochondrial respiratory capacity, capillarization, and muscle fiber type distribution were determined from muscle samples. RESULTS: Citrate synthase activity increased during the training intervention in the whole cohort (P = 0.006). There was no group x time interaction for citrate synthase activity during the training intervention (P = 0.522). Complex III (P = 0.008), Complex V (P = 0.043), and succinate cytochrome c reductase (P = 0.008) activities increased in HD patients and controls by endurance training. An increase in mass specific mitochondrial respiratory capacity was present in HD patients during the endurance training intervention. Overall capillary-to-fiber ratio increased in HD patients by 8.4% and in healthy controls by 6.4% during the endurance training intervention. CONCLUSIONS: Skeletal muscle mitochondria of HD patients are equally responsive to an endurance-training stimulus as in healthy controls. Endurance training is a safe and feasible option to enhance indices of energy metabolism in skeletal muscle of HD patients and may represent a potential therapeutic approach to delay the onset and/or progression of muscular dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT01879267 . Registered May 24, 2012. PMID- 29258584 TI - Lymphocyte opioid receptors as innovative biomarkers of osteoarthritic pain, for the assessment and risk management of opioid tailored therapy, before hip surgery, to prevent chronic pain and opioid tolerance/addiction development: OpMarkArt (Opioids-Markers-Arthroprosthesis) study protocol for a randomized controlled trial. AB - BACKGROUND: The incidence of post-surgical chronic pain ranges between 20% and 40% in Europe. Osteoarthritis pain after prosthesis implantation is one of the most severe secondary syndromes, depending not only on surgery but also on organic changes before and after joints replacement. No data are available about risk factors. An excessive inflammatory response plays a central role but a best therapy is not defined yet. It is not clear whether opioid administration could influence post-surgical pain and lead to tolerance or addiction. Interestingly, the immune system, together with the nervous and peptidergic ones, is involved in hypersensibility. The connection across the three biological systems lies in the presence of opioid receptors on immune cells surface. Here, we show a method to analyze whether opioids could modulate lymphocytes, by proposing opioid receptors as biological markers to prevent chronic pain and opioid tolerance or addiction after hip surgery. METHODS/DESIGN: After institutional independent ethics committee approval, 60 patients, in pain and undergoing hip surgery, will be enrolled in a single-blind, randomized, phase IV, pilot study. Pain treatment will be selected inside a class of non-steroidal anti-inflammatory drugs (NAISDs) or paracetamol or a class of opioids, into three medication arms: 25 mg tapentadol twice daily; 75 mg tapentadol twice daily; NSAIDs or paracetamol in accordance with surgeon's custom. For each group, we will collect blood samples before, during and after surgery, to apply molecular analysis. We will perform lymphocyte opioid receptors genes and proteins expression and functional analysis. Data will be statistically analyzed. DISCUSSION: This project has the potential to obtain a personalized diagnostic kit, by considering lymphocyte opioid receptors as biological markers. Starting from a simple blood sample, it will be possible to decide the best therapy for a single patient. Using a noninvasive approach, we expect to fix a daily standard dose and timing, before and after surgery, to bypass hip chronic pain and the insurgence of tolerance or addiction. The analysis of opioid receptors sensitivity will help to identify the best drug administration in each specific case (tailored therapy). TRIAL REGISTRATION: ISRCTN, ISRCTN12559751 . Retrospectively registered on 23 May 2017. PMID- 29258586 TI - Identification of 24 new microsatellite loci in the sweat bee Lasioglossum malachurum (Hymenoptera: Halictidae). AB - OBJECTIVE: The objective here is to identify highly polymorphic microsatellite loci for the Palaearctic sweat bee Lasioglossum malachurum. Sweat bees (Hymenoptera: Halictidae) are widespread pollinators that exhibit an unusually large range of social behaviours from non-social, where each female nests alone, to eusocial, where a single queen reproduces while the other members of the colony help to rear her offspring. They thus represent excellent models for understanding social evolution. RESULTS: 24 new microsatellite loci were successfully optimized. When amplified across 23-40 unrelated females, the number of alleles per locus ranged from 3 to 17 and the observed heterozygosities 0.45 to 0.95. Only one locus showed evidence of significant deviation from Hardy Weinberg equilibrium. No evidence of linkage disequilibrium was found. These 24 loci will enable researchers to gain greater understanding of colony relationships within this species, an important model for the study of eusociality. Furthermore, 22 of the same loci were also successfully amplified in L. calceatum, suggesting that these loci may be useful for investigating the ecology and evolution of sweat bees in general. PMID- 29258587 TI - Association between mammographic breast density and histologic features of benign breast disease. AB - BACKGROUND: Over 40% of women undergoing breast screening have mammographically dense breasts. Elevated mammographic breast density (MBD) is an established breast cancer risk factor and is known to mask tumors within the dense tissue. However, the association of MBD with high risk benign breast disease (BBD) is unknown. METHOD: We analyzed data for 3400 women diagnosed with pathologically confirmed BBD in the Mayo Clinic BBD cohort from 1985-2001, with a clinical MBD measure (either parenchymal pattern (PP) or Breast Imaging Reporting and Data Systems (BI-RADS) density) and expert pathology review. Risk factor information was collected from medical records and questionnaires. MBD was dichotomized as dense (PP classification P2 or DY, or BI-RADS classification c or d) or non-dense (PP classification N1 or P1, or BI-RADS classification a or b). Associations of clinical and histologic characteristics with MBD were examined using logistic regression analysis to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Of 3400 women in the study, 2163 (64%) had dense breasts. Adjusting for age and body mass index (BMI), there were positive associations of dense breasts with use of hormone therapy (HT), lack of lobular involution, presence of atypical lobular hyperplasia (ALH), histologic fibrosis, columnar cell hyperplasia/flat epithelia atypia (CCH/FEA), sclerosing adenosis (SA), cyst, usual ductal hyperplasia, and calcifications. In fully adjusted multivariate models, HT (1.3, 95% CI 1.1-1.5), ALH (1.5, 95% CI 1.0-2.2), lack of lobular involution (OR 1.6, 95% CI 1.2-2.1, compared to complete involution), fibrosis (OR 2.2, 95% CI 1.9-2.6) and CCH/FEA (OR 1.3, 95% CI 1.0-1.6) remained significantly associated with high MBD. CONCLUSION: Our findings support an association between high risk BBD and high MBD, suggesting that risks associated with the latter may act early in breast carcinogenesis. PMID- 29258588 TI - Integrating phenotype ontologies with PhenomeNET. AB - BACKGROUND: Integration and analysis of phenotype data from humans and model organisms is a key challenge in building our understanding of normal biology and pathophysiology. However, the range of phenotypes and anatomical details being captured in clinical and model organism databases presents complex problems when attempting to match classes across species and across phenotypes as diverse as behaviour and neoplasia. We have previously developed PhenomeNET, a system for disease gene prioritization that includes as one of its components an ontology designed to integrate phenotype ontologies. While not applicable to matching arbitrary ontologies, PhenomeNET can be used to identify related phenotypes in different species, including human, mouse, zebrafish, nematode worm, fruit fly, and yeast. RESULTS: Here, we apply the PhenomeNET to identify related classes from two phenotype and two disease ontologies using automated reasoning. We demonstrate that we can identify a large number of mappings, some of which require automated reasoning and cannot easily be identified through lexical approaches alone. Combining automated reasoning with lexical matching further improves results in aligning ontologies. CONCLUSIONS: PhenomeNET can be used to align and integrate phenotype ontologies. The results can be utilized for biomedical analyses in which phenomena observed in model organisms are used to identify causative genes and mutations underlying human disease. PMID- 29258589 TI - A comparative study of chondroitin sulfate and heparan sulfate for directing three-dimensional chondrogenesis of mesenchymal stem cells. AB - BACKGROUND: Mesenchymal stem cells (MSCs) hold great promise for cartilage repair given their relative abundance, ease of isolation, and chondrogenic potential. To enhance MSC chondrogenesis, extracellular matrix components can be incorporated into three-dimensional (3D) scaffolds as an artificial cell niche. Chondroitin sulfate (CS)-containing hydrogels have been shown to support 3D chondrogenesis, but the effects of varying CS concentration and hydrogel stiffness on 3D MSC chondrogenesis remains elusive. Heparan sulfate (HS) is commonly used as a growth factor reservoir due to its ability to sequester growth factors; however, how it compares to CS in supporting 3D MSC chondrogenesis remains unknown. METHODS: We fabricated photocrosslinkable hydrogels containing physiologically relevant concentrations (0-10%) of CS or HS with two stiffnesses (~7.5 kPa and ~ 36 kPa) as a 3D niche for MSC chondrogenesis. RESULTS: CS is a more potent factor in enhancing MSC chondrogenesis, especially in soft hydrogels (~ 7.5 kPa). A moderate dosage of CS (5%) led to the highest amount of neocartilage deposition. Stiff hydrogels (~ 36 kPa) generally inhibited neocartilage formation regardless of the biochemical cues. CONCLUSIONS: Taken together, the results from this study demonstrated that CS-containing hydrogels at low mechanical stiffness can provide a promising scaffold for enhancing MSC-based cartilage tissue regeneration. PMID- 29258590 TI - Investigation of red blood cell mechanical properties using AFM indentation and coarse-grained particle method. AB - BACKGROUND: Red blood cells (RBCs) deform significantly and repeatedly when passing through narrow capillaries and delivering dioxygen throughout the body. Deformability of RBCs is a key characteristic, largely governed by the mechanical properties of the cell membrane. This study investigated RBC mechanical properties using atomic force microscopy (AFM) with the aim to develop a coarse grained particle method model to study for the first time RBC indentation in both 2D and 3D. This new model has the potential to be applied to further investigate the local deformability of RBCs, with accurate control over adhesion, probe geometry and position of applied force. RESULTS: The model considers the linear stretch capacity of the cytoskeleton, bending resistance and areal incompressibility of the bilayer, and volumetric incompressibility of the internal fluid. The model's performance was validated against force-deformation experiments performed on RBCs under spherical AFM indentation. The model was then used to investigate the mechanisms which absorbed energy through the indentation stroke, and the impact of varying stiffness coefficients on the measured deformability. This study found the membrane's bending stiffness was most influential in controlling RBC physical behaviour for indentations of up to 200 nm. CONCLUSIONS: As the bilayer provides bending resistance, this infers that structural changes within the bilayer are responsible for the deformability changes experienced by deteriorating RBCs. The numerical model presented here established a foundation for future investigations into changes within the membrane that cause differences in stiffness between healthy and deteriorating RBCs, which have already been measured experimentally with AFM. PMID- 29258591 TI - Cost-benefit and extended cost-effectiveness analysis of a comprehensive adolescent pregnancy prevention program in Zambia: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Early marriages, pregnancies and births are the major cause of school drop-out among adolescent girls in sub-Saharan Africa. Birth complications are also one of the leading causes of death among adolescent girls. This paper outlines a protocol for a cost-benefit analysis (CBA) and an extended cost effectiveness analysis (ECEA) of a comprehensive adolescent pregnancy prevention program in Zambia. It aims to estimate the expected costs, monetary and non monetary benefits associated with health-related and non-health outcomes, as well as their distribution across populations with different standards of living. METHODS: The study will be conducted alongside a cluster-randomized controlled trial, which is testing the hypothesis that economic support with or without community dialogue is an effective strategy for reducing adolescent childbearing rates. The CBA will estimate net benefits by comparing total costs with monetary benefits of health-related and non-health outcomes for each intervention package. The ECEA will estimate the costs of the intervention packages per unit health and non-health gain stratified by the standards of living. Cost data include program implementation costs, healthcare costs (i.e. costs associated with adolescent pregnancy and birth complications such as low birth weight, pre-term birth, eclampsia, medical abortion procedures and post-abortion complications) and costs of education and participation in community and youth club meetings. Monetary benefits are returns to education and averted healthcare costs. For the ECEA, health gains include reduced rate of adolescent childbirths and non-health gains include averted out-of-pocket expenditure and financial risk protection. The economic evaluations will be conducted from program and societal perspectives. DISCUSSION: While the planned intervention is both comprehensive and expensive, it has the potential to produce substantial short-term and long-term health and non-health benefits. These benefits should be considered seriously when evaluating whether such a program can justify the required investments in a setting with scarce resources. The economic evaluations outlined in this paper will generate valuable information that can be used to guide large-scale implementation of programs to address the problem of the high prevalence of adolescent childbirth and school drop-outs in similar settings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02709967. Registered on 2 March 2016. ISRCTN, ISRCTN12727868. Registered on 4 March 2016. PMID- 29258592 TI - Possible therapeutic effect of orally administered ribavirin for respiratory syncytial virus-induced acute respiratory distress syndrome in an immunocompetent patient: a case report. AB - BACKGROUND: Human respiratory syncytial virus usually causes self-limiting upper respiratory infection and occasionally causes pneumonia in immunocompromised hosts. Respiratory syncytial virus-induced severe pneumonia or acute respiratory distress syndrome in immunocompetent adults has been rarely described. Unfortunately, optimal treatment has not been established for this potentially fatal condition. We report a case of respiratory syncytial virus-induced acute respiratory distress syndrome occurring in a previously healthy man successfully treated with orally administered ribavirin. CASE PRESENTATION: An 81-year-old previously healthy Korean man presented with cough, dyspnea, and febrile sensation. He had hypoxemia with diffuse ground glass opacity evident on chest radiography, which progressed and required mechanical ventilation. All microbiological tests were negative except multiplex real-time reverse transcriptase polymerase chain reaction using respiratory specimen, which was positive for human adenovirus. Under the diagnosis of respiratory syncytial virus induced acute respiratory distress syndrome, orally administered ribavirin was administered and he recuperated completely without complications. CONCLUSION: This case demonstrates the potential usefulness of orally administered ribavirin as a therapeutic option for severe respiratory syncytial virus infection, at least in an immunocompetent host. PMID- 29258594 TI - Monitoring prescribing patterns using regression and electronic health records. AB - BACKGROUND: It is beneficial for health care institutions to monitor physician prescribing patterns to ensure that high-quality and cost-effective care is being provided to patients. However, detecting treatment patterns within an institution is challenging, given that medications and conditions are often not explicitly linked in the health record. Here we demonstrate the use of statistical methods together with data from the electronic health care record (EHR) to analyze prescribing patterns at an institution. METHODS: As a demonstration of our method, which is based on regression, we collect EHR data from outpatient notes and use a case/control study design to determine the medications that are associated with hypertension. We also use regression to determine which conditions are associated with a preferential use of one or more classes of hypertension agents. Finally, we compare our method to methods based on tabulation. RESULTS: Our results show that regression methods provide more reasonable and useful results than tabulation, and successfully distinguish between medications that treat hypertension and medications that do not. These methods also provide insight into in which circumstances certain drugs are preferred over others. CONCLUSIONS: Our method can be used by health care institutions to monitor physician prescribing patterns and ensure the appropriateness of treatment. PMID- 29258593 TI - Evaluations of the uptake and impact of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement and extensions: a scoping review. AB - BACKGROUND: The PRISMA Statement is a reporting guideline designed to improve transparency of systematic reviews (SRs) and meta-analyses. Seven extensions to the PRISMA Statement have been published to address the reporting of different types or aspects of SRs, and another eight are in development. We performed a scoping review to map the research that has been conducted to evaluate the uptake and impact of the PRISMA Statement and extensions. We also synthesised studies evaluating how well SRs published after the PRISMA Statement was disseminated adhere to its recommendations. METHODS: We searched for meta-research studies indexed in MEDLINE(r) from inception to 31 July 2017, which investigated some component of the PRISMA Statement or extensions (e.g. SR adherence to PRISMA, journal endorsement of PRISMA). One author screened all records and classified the types of evidence available in the studies. We pooled data on SR adherence to individual PRISMA items across all SRs in the included studies and across SRs published after 2009 (the year PRISMA was disseminated). RESULTS: We included 100 meta-research studies. The most common type of evidence available was data on SR adherence to the PRISMA Statement, which has been evaluated in 57 studies that have assessed 6487 SRs. The pooled results of these studies suggest that reporting of many items in the PRISMA Statement is suboptimal, even in the 2382 SRs published after 2009 (where nine items were adhered to by fewer than 67% of SRs). Few meta-research studies have evaluated the adherence of SRs to the PRISMA extensions or strategies to increase adherence to the PRISMA Statement and extensions. CONCLUSIONS: Many studies have evaluated how well SRs adhere to the PRISMA Statement, and the pooled result of these suggest that reporting of many items is suboptimal. An update of the PRISMA Statement, along with a toolkit of strategies to help journals endorse and implement the updated guideline, may improve the transparency of SRs. PMID- 29258595 TI - Improving phloroglucinol tolerance and production in Escherichia coli by GroESL overexpression. AB - BACKGROUND: Phloroglucinol is an important chemical which has been successfully produced by engineered Escherichia coli. However, the toxicity of phloroglucinol can enormously inhibit E. coli cell growth and viability, and the productivity is still too low and not economically feasible for industrial applications. Therefore, strain tolerance to toxic metabolites remains a key issue during the production of chemicals using biological processes. RESULTS: In the present work, we examined the impact of the native GroESL chaperone system with different overexpression levels on phloroglucinol tolerance and production in E. coli. The groESL gene was cloned into an expression vector, of which expression level was regulated by three different promoters (natural, tac and T7 promoter). Strain tolerance was evaluated employing viable cell counts and phloroglucinol production. In comparison with the control strain, all GroESL overexpressing strains showed good characteristics in cell viability and phloroglucinol synthesis. Strain which overexpressed GroESL under tac promoter was found to show the best tolerance in all of those tested, resulting in a 3.19-fold increase in viable cell numbers compared with control strain of agar-plate culture under the condition of 0.7 g/L phloroglucinol, and a 39.5% increase in phloroglucinol production under fed-batch fermentation. This engineered strain finally accumulated phloroglucinol up to 5.3 g/L in the fed-batch cultivation 10 h after induction, and the productivity was 0.53 g/L/h. To date, the highest phloroglucinol production was achieved in this work compared with the previous reports, which is promising to make the bioprocess feasible from the economical point. CONCLUSIONS: The data show that appropriate expression level of GroESL plays a critical role in improving phloroglucinol tolerance and production in E. coli, and maybe involve in controlling some aspects of the stress response system through upregulation of GroESL. GroESL overexpression is therefore a feasible and efficient approach for improvement of E. coli tolerance. PMID- 29258596 TI - The impact of social activities, social networks, social support and social relationships on the cognitive functioning of healthy older adults: a systematic review. AB - BACKGROUND: Social relationships, which are contingent on access to social networks, promote engagement in social activities and provide access to social support. These social factors have been shown to positively impact health outcomes. In the current systematic review, we offer a comprehensive overview of the impact of social activities, social networks and social support on the cognitive functioning of healthy older adults (50+) and examine the differential effects of aspects of social relationships on various cognitive domains. METHODS: We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analysis) guidelines, and collated data from randomised controlled trials (RCTs), genetic and observational studies. Independent variables of interest included subjective measures of social activities, social networks, and social support, and composite measures of social relationships (CMSR). The primary outcome of interest was cognitive function divided into domains of episodic memory, semantic memory, overall memory ability, working memory, verbal fluency, reasoning, attention, processing speed, visuospatial abilities, overall executive functioning and global cognition. RESULTS: Thirty-nine studies were included in the review; three RCTs, 34 observational studies, and two genetic studies. Evidence suggests a relationship between (1) social activity and global cognition and overall executive functioning, working memory, visuospatial abilities and processing speed but not episodic memory, verbal fluency, reasoning or attention; (2) social networks and global cognition but not episodic memory, attention or processing speed; (3) social support and global cognition and episodic memory but not attention or processing speed; and (4) CMSR and episodic memory and verbal fluency but not global cognition. CONCLUSIONS: The results support prior conclusions that there is an association between social relationships and cognitive function but the exact nature of this association remains unclear. Implications of the findings are discussed and suggestions for future research provided. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2012: CRD42012003248 . PMID- 29258598 TI - What methods do reviews of normative ethics literature use for search, selection, analysis, and synthesis? In-depth results from a systematic review of reviews. AB - BACKGROUND: (Semi-)systematic approaches to finding, analysing, and synthesising ethics literature on medical topics are still in their infancy. However, our recent systematic review showed that the rate of publication of such (semi )systematic reviews has increased in the last two decades. This is not only true for reviews of empirical ethics literature, but also for reviews of normative ethics literature. In the latter case, there is currently little in the way of standards and guidance available. Therefore, the methods and reporting strategies of such reviews vary greatly. The purpose of the follow-up study we present was to obtain deeper methodological insight into the ways reviews of normative literature are actually conducted and to analyse the methods used. METHOD: Our search in the PubMed, PhilPapers, and Google Scholar databases led to the identification of 183 reviews of ethics literature published between 1997 and 2015, of which 84 were identified as reviews of normative and mixed literature. Qualitative content analysis was used to extract and synthesise descriptions of search, selection, quality appraisal, analysis, and synthesis methods. We further assessed quantitatively how often certain methods (e.g. search strategies, data analysis procedures) were used by the reviews. RESULTS: The overall reporting quality varies among the analysed reviews and was generally poor even for major criteria regarding the search and selection of literature. For example, only 24 (29%) used a PRISMA flowchart. Also, only 55 (66%) reviews mentioned the information unit they sought to extract, and 12 (14%) stated an ethical approach as the theoretical basis for the analysis. Interpretable information on the synthesis method was given by 47 (60%); the most common methods applied were qualitative methods commonly used in social science research (83%). CONCLUSION: Reviews which fail to provide sufficient relevant information to readers have reduced methodological transparency regardless of actual methodological quality. In order to increase the internal validity (i.e. reproducibility) as well as the external validity (i.e. utility for the intended audience) of future reviews of normative literature, we suggest more accurate reporting regarding the goal of the review, the definition of the information unit, the ethical approach used, and technical aspects. PMID- 29258597 TI - Significant value of 18F-FDG-PET/CT in diagnosing small cervical lymph node metastases in patients with nasopharyngeal carcinoma treated with intensity modulated radiotherapy. AB - BACKGROUND: Little is known about the nature of metastasis to small cervical lymph nodes (SCLNs) in the patients with nasopharyngeal carcinoma (NPC) examined by using 18-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). The present study aimed to evaluate the diagnostic values of PET/CT in identifying metastasis in SCLNs in NPC patients. METHODS: Magnetic resonance images (MRI) and PET/CT scans for 470 patients with newly diagnosed, non-distant metastatic NPC were analyzed. Metastatic rates of SCLNs were defined by the positive number of SCLNs on PET/CT scans and total number of SCLNs on MRI scans. Receiver operating characteristic curve was applied to compare PET/CT-determined stage with MRI-determined stage. RESULTS: In total, 2082 SCLNs were identified, with 808 (38.8%) >= 5 and < 6 mm in diameter (group A), 526 (25.3%) >= 6 and < 7 mm in diameter (group B), 374 (18.0%) >= 7 and < 8 mm in diameter (group C), 237 (11.4%) >= 8 and < 9 mm in diameter (group D), and 137 (6.5%) >= 9 and < 10 mm in diameter (group E). The overall metastatic rates examined by using PET/CT for groups A, B, C, D, and E were 3.5%, 8.0%, 31.3%, 60.0%, and 83.9%, respectively (P < 0.001). In level IV/Vb, the metastatic rate for nodes >= 8 mm was 84.6%. PET/CT examination resulted in modification of N category and overall stage for 135 (28.7%) and 46 (9.8%) patients, respectively. The areas under curve of MRI-determined and PET/CT-determined overall stage were 0.659 and 0.704 for predicting overall survival, 0.661 and 0.711 for predicting distant metastasis-free survival, and 0.636 and 0.663 for predicting disease-free survival. CONCLUSIONS: PET/CT was more effective than MRI in identifying metastatic SCLNs, and the radiologic diagnostic criteria for metastatic lymph nodes in level IV/Vb should be re-defined. PMID- 29258599 TI - Transition in care from paramedics to emergency department nurses: a systematic review protocol. AB - BACKGROUND: Effective and efficient transitions in care between emergency medical services (EMS) practitioners and emergency department (ED) nurses is vital as poor clinical transitions in care may place patients at increased risk for adverse events such as delay in treatment for time sensitive conditions (e.g., myocardial infarction) or worsening of status (e.g., sepsis). Such transitions in care are complex and prone to communication errors primarily caused by misunderstanding related to divergent professional perspectives leading to misunderstandings that are further susceptible to contextual factors and divergent professional lenses. In this systematic review, we aim to examine (1) factors that mitigate or improve transitions in care specifically from EMS practitioners to ED nurses, and (2) effectiveness of interventional strategies that lead to improvements in communication and fewer adverse events. METHODS: We will search electronic databases (DARE, MEDLINE, EMBASE, Cochrane, CINAHL, Joanna Briggs Institute EBP; Communication Abstracts); gray literature (gray literature databases, organization websites, querying experts in emergency medicine); and reference lists and conduct forward citation searches of included studies. All English-language primary studies will be eligible for inclusion if the study includes (1) EMS practitioners or ED nurses involved in transitions for arriving EMS patients; and (2) an intervention to improve transitions in care or description of factors that influence transitions in care (barriers/facilitators, perceptions, experiences, quality of information exchange). Two reviewers will independently screen titles/abstracts and full texts for inclusion and methodological quality. We will use narrative and thematic synthesis to integrate and explore relationships within the data. Should the data permit, a meta analysis will be conducted. DISCUSSION: This systematic review will help identify factors that influence communication between EMS and ED nurses during transitions in care, and identify interventional strategies that lead to improved communication and decrease in adverse events. The findings can be used to develop an evidence-informed transitions in care tool that ensures efficient transfer of accurate patient information, continuity of care, enhances patient safety, and avoids duplication of services. This review will also identify gaps in the existing literature to inform future research efforts. TRIAL REGISTRATION: PROSPERO CRD42017068844. PMID- 29258600 TI - Towards a more effective and efficient governance and regulation of nanomaterials. AB - The uncertainty regarding the effects and risks of nanomaterials on human health and the environment, and how they should be tested and assessed in the context of current regulations, is clearly holding back the full exploitation of the innovative potential of nanomaterials. To reduce this uncertainty, the European Union funded NANoREG and ProSafe projects (jointly referred to as N1P) have made a critical evaluation of methods to test and assess these risks in the context of the current registration, evaluation, authorisation and restriction of chemicals (REACH) regulation. Where essential methods were lacking, new ones have been developed. For several existing methods, adjustments have been proposed. Possible improvements to the REACH regulation have also been identified in these projects. The results of N1P have been translated into recommendations for (European) policy makers and regulators. Part of them have a "no regret" character, meaning that the proposed actions can be considered as necessary, feasible, effective and cost efficient. The recommended measures proposed for data quality and data management will create a more solid information basis for risk assessment of nanomaterials. When implemented, the recommendations regarding REACH will improve the application of REACH in both a legal and scientific sense. In practical terms however, the application of REACH will remain complex, time-consuming and costly. Besides that, adapting and specifying the information requirements and test methods in REACH for nanomaterials that are now on the market, will not solve the regulatory hurdles for next generation (nano) materials. To better align the dynamic character of developing new materials and the static character of regulations, it is recommended to explore possibilities of a more future proof approach for securing the safety of new (nano) materials. PMID- 29258601 TI - Preliminary testing of the reliability and feasibility of SAGE: a system to measure and score engagement with and use of research in health policies and programs. AB - BACKGROUND: Few measures of research use in health policymaking are available, and the reliability of such measures has yet to be evaluated. A new measure called the Staff Assessment of Engagement with Evidence (SAGE) incorporates an interview that explores policymakers' research use within discrete policy documents and a scoring tool that quantifies the extent of policymakers' research use based on the interview transcript and analysis of the policy document itself. We aimed to conduct a preliminary investigation of the usability, sensitivity, and reliability of the scoring tool in measuring research use by policymakers. METHODS: Nine experts in health policy research and two independent coders were recruited. Each expert used the scoring tool to rate a random selection of 20 interview transcripts, and each independent coder rated 60 transcripts. The distribution of scores among experts was examined, and then, interrater reliability was tested within and between the experts and independent coders. Average- and single-measure reliability coefficients were computed for each SAGE subscales. RESULTS: Experts' scores ranged from the limited to extensive scoring bracket for all subscales. Experts as a group also exhibited at least a fair level of interrater agreement across all subscales. Single-measure reliability was at least fair except for three subscales: Relevance Appraisal, Conceptual Use, and Instrumental Use. Average- and single-measure reliability among independent coders was good to excellent for all subscales. Finally, reliability between experts and independent coders was fair to excellent for all subscales. CONCLUSIONS: Among experts, the scoring tool was comprehensible, usable, and sensitive to discriminate between documents with varying degrees of research use. Secondly, the scoring tool yielded scores with good reliability among the independent coders. There was greater variability among experts, although as a group, the tool was fairly reliable. The alignment between experts' and independent coders' ratings indicates that the independent coders were scoring in a manner comparable to health policy research experts. If the present findings are replicated in a larger sample, end users (e.g. policy agency staff) could potentially be trained to use SAGE to reliably score research use within their agencies, which would provide a cost-effective and time-efficient approach to utilising this measure in practice. PMID- 29258602 TI - Detection of PrPBSE and prion infectivity in the ileal Peyer's patch of young calves as early as 2 months after oral challenge with classical bovine spongiform encephalopathy. AB - In classical bovine spongiform encephalopathy (C-BSE), an orally acquired prion disease of cattle, the ileal Peyer's patch (IPP) represents the main entry port for the BSE agent. In earlier C-BSE pathogenesis studies, cattle at 4-6 months of age were orally challenged, while there are strong indications that the risk of infection is highest in young animals. In the present study, unweaned calves aged 4-6 weeks were orally challenged to determine the earliest time point at which newly formed PrPBSE and BSE infectivity are detectable in the IPP. For this purpose, calves were culled 1 week as well as 2, 4, 6 and 8 months post-infection (mpi) and IPPs were examined for BSE infectivity using a bovine PrP transgenic mouse bioassay, and for PrPBSE by immunohistochemistry (IHC) and protein misfolding cyclic amplification (PMCA) assays. For the first time, BSE prions were detected in the IPP as early as 2 mpi by transgenic mouse bioassay and PMCA and 4 mpi by IHC in the follicular dendritic cells (FDCs) of the IPP follicles. These data indicate that BSE prions propagate in the IPP of unweaned calves within 2 months of oral uptake of the agent. PMID- 29258603 TI - Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats. AB - BACKGROUND: Type 2 diabetes (T2D) is closely associated with liver fibrosis, but no effective treatments are currently available. This study was designed to investigate the therapeutic effects of ADSCs on insulin resistance, hyperglycemia, and liver fibrosis on T2D rats. METHODS: We first established a T2D rat model with liver fibrosis by using the combination of a high-fat diet (HFD), low-dose streptozotocin (STZ), and carbon tetrachloride (CCl4). Subsequently, the model rats were administrated by tail vein injection of PBS or ADSCs, respectively. Thereafter, insulin resistance and liver function were assessed by biochemical analysis, ELISA, histopathological examination, and q-PCR assay, respectively. Moreover, the molecular mechanisms of ADSCs on the effect of the TGF-beta1/SMAD3 signaling pathway were further analyzed. RESULTS: Our data showed that ADSC transplantation significantly alleviated insulin resistance and hyperglycemia in the liver-injured T2D rats. We also found that ADSC transplantation could attenuate liver injury by improving liver function and inhibiting pathological changes of liver fibrosis, as well as through downregulation of TGF-beta1 and phosphorylated SMAD3 both in vitro and in vivo. CONCLUSIONS: These findings suggested that ADSC transplantation can ameliorate insulin resistance, hyperglycemia, and liver fibrosis via suppressing TGF beta1/SMAD3 signaling, which may provide a potential treatment strategy for liver fibrosis of T2D. PMID- 29258604 TI - Water T2 as an early, global and practical biomarker for metabolic syndrome: an observational cross-sectional study. AB - BACKGROUND: Metabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic beta-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement. METHODS: Water T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression. RESULTS: Plasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma. CONCLUSIONS: Water T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual's metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis. PMID- 29258605 TI - miR-105/93-3p promotes chemoresistance and circulating miR-105/93-3p acts as a diagnostic biomarker for triple negative breast cancer. AB - BACKGROUND: Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20-30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. METHODS: The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student's t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93 3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. RESULTS: miR-105 and miR 93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/beta-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93 3p may serve as a powerful biomarker for TNBC, even in early-stage disease. CONCLUSIONS: miR-105/93-3p activates Wnt/beta-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC. PMID- 29258606 TI - Inflammation-associated microRNA changes in circulating exosomes of heart failure patients. AB - OBJECTIVE: MiR-486 and miR-146a are cardiomyocyte-enriched microRNAs that control cell survival and self-regulation of inflammation. These microRNAs are released into circulation and are detected in plasma or in circulating exosomes. Little is known whether heart failure affects their release into circulation, which this study investigated. RESULTS: Total and exosome-specific microRNAs in plasma of 40 heart failure patients and 20 controls were prepared using the miRVana Kit. We measured exosomal and total plasma microRNAs separately because exosomes serve as cargos that transfer biological materials and alter signaling in distant organs, whereas microRNAs in plasma indicate the level of tissue damage and are mostly derived from dead cells. qRT-PCR was used to quantify miR-486, miR-146a, and miR 16. Heart failure did not significantly affect plasma miR-486/miR-16 and miR 146a/miR-16 ratio, although miR-146a/miR-16 showed a trend of elevated expression (2.3 +/- 0.79, p = 0.27). By contrast, circulating exosomal miR-146a/miR-16 ratio was higher in heart failure patients (2.46 +/- 0.51, p = 0.05). miR-146a is induced in response to inflammation as a part of inflammation attenuation circuitry. Indeed, Tnfalpha and Gm-csf increased miR-146a but not miR-486 in the cardiomyocyte cell line H9C2. These results, if confirmed in a larger study, may help to develop circulating exosomal miR-146a as a biomarker of heart failure. PMID- 29258607 TI - Burden and correlates of mental health diagnoses among sex workers in an urban setting. AB - BACKGROUND: Women involved in both street-level and off-street sex work face disproportionate health and social inequities compared to the general population. While much research has focused on HIV and sexually transmitted infections (STIs) among sex workers, there remains a gap in evidence regarding the broader health issues faced by this population, including mental health. Given limited evidence describing the mental health of women in sex work, our objective was to evaluate the burden and correlates of mental health diagnoses among this population in Vancouver, Canada. METHODS: An Evaluation of Sex Workers Health Access (AESHA) is a prospective, community-based cohort of on- and off-street women in sex work in Vancouver, Canada. Participants complete interviewer-administered questionnaires semi-annually. We analyzed the lifetime burden and correlates of self-reported mental health diagnoses using bivariate and multivariable logistic regression. RESULTS: Among 692 sex workers enrolled between January 2010 and February 2013, 338 (48.8%) reported ever being diagnosed with a mental health issue, with the most common diagnoses being depression (35.1%) and anxiety (19.9%). In multivariable analysis, women with mental health diagnoses were more likely to identify as a sexual/gender minority (LGBTQ) [AOR=2.56, 95% CI: 1.72-3.81], to use non-injection drugs [AOR=1.85, 95% CI: 1.12-3.08], to have experienced childhood physical/sexual trauma [AOR=2.90, 95% CI: 1.89-4.45], and work in informal indoor [AOR=1.94, 95% CI: 1.12 - 3.40] or street/public spaces [AOR=1.76, 95% CI: 1.03-2.99]. CONCLUSIONS: This analysis highlights the disproportionate mental health burden experienced by women in sex work, particularly among those identifying as a sexual/gender minority, those who use drugs, and those who work in informal indoor venues and street/public spaces. Evidence-informed interventions tailored to sex workers that address intersections between trauma and mental health should be further explored, alongside policies to foster access to safer workspaces and health services. PMID- 29258608 TI - Education and exercise program improves osteoporosis knowledge and changes calcium and vitamin D dietary intake in community dwelling elderly. AB - BACKGROUND: Several educational intervention programs have been designed and developed to improve osteoporosis diagnosis and treatment. However, most of the prior studies focused on how educational intervention programs affected diagnosis and treatment of condition of osteoporosis. The purpose of this prospective and educational intervention study was to evaluate the changes in osteoporosis knowledge, osteoporosis self-efficacy, fall self-efficacy, physical exercise and changes in dietary pattern of calcium and vitamin D intake after osteoporosis education. METHODS: From November 1, 2015 to August 31, 2016, 271 eligible candidates (who were over 50 years old and from 23 different community centers) were recruited through an announcement made by the public office, by two health care providers. The intervention involved an individualized education program to allow for differences in antecedent educational levels regarding several aspects of osteoporosis, including osteoporosis knowledge, osteoporosis self-efficacy, awareness of self-efficacy risk factors relating to an accidental fall and nutritional education (including the importance of sufficient calcium and vitamin D intake). The researchers revisited the community centers three months after the initial visit. RESULTS: Of the 271 potential participants, 199 (73.4%; 43 men and 156 women) completed the education program and the second questionnaire. After education intervention, parameters including osteoporosis knowledge, osteoporosis self-efficacy and fall self-efficacy were improved (P < 0.0001). After education regarding percentage of calcium and vitamin D intake below recommended cut-offs, inadequate dietary calcium and vitamin D intake were decreased (P < 0.0001) from 89.4% (178/199) and 84.4% (168/199) to 79.9% (159/199) and 65.8% (131/199), respectively, at the three-month follow-up. (p = 0.038, p = 0.017). CONCLUSIONS: This prospective intervention study demonstrated that education on osteoporosis knowledge and regular exercise programs could improve osteoporosis self- efficacy, fall self-efficacy and increase dietary calcium and vitamin D intake. PMID- 29258609 TI - Complete remission of metastatic pheochromocytoma in 123I-metaiodobenzylguanidine scintigraphy after a single session of 131I-metaiodobenzylguanidine therapy: a case report. AB - BACKGROUND: Pheochromocytomas are rare neuroendocrine tumors, with a malignancy frequency of approximately 10%. The treatment of malignant pheochromocytoma is palliative, and the traditional management strategy has limited efficacy. Furthermore, no clear criteria exist for the treatment of metastatic pheochromocytoma, especially for unresectable lesions. We report a case of complete remission of metastatic pheochromocytoma in 123I-metaiodobenzylguanidine (MIBG) scintigraphy after a single session of 131I-MIBG therapy. CASE PRESENTATION: A 61-year-old woman had a right adrenal grand tumor and lymph node metastasis on the hilum of the right kidney, both of which incorporated MIBG. After surgery, immunostaining of a tumor specimen showed expression of the tumor makers chromogranin and synaptophysin. One year postoperatively, abdominal computed tomography revealed a local recurrence and retroperitoneal lymph node swelling. The local recurrence was positive for MIBG uptake, whereas the swollen retroperitoneal lymph nodes were negative. She underwent surgery again, but the local recurrence was unresectable because of rigid adhesion to the surrounding tissue. Immunostaining of an intraoperatively extracted swollen retroperitoneal lymph node showed expression of tumor markers. The patient then underwent a single session of 131I-MIBG therapy (7.4 GBq, 200 mCi), after which the residual lesions no longer incorporated MIBG, and a complete response in 123I- metaiodobenzylguanidine (MIBG) scintigraphy was achieved. The 131I-MIBG treatment was repeated 6 months later. None of the lesions were positive for MIBG uptake. CONCLUSIONS: 131I-MIBG therapy efficaciously treats unresectable lesions that are positive for MIBG uptake. PMID- 29258610 TI - Differentiation of nonhuman primate pluripotent stem cells into functional keratinocytes. AB - BACKGROUND: Epidermal grafting using cells derived from pluripotent stem cells will change the face of this side of regenerative cutaneous medicine. To date, the safety of the graft would be the major unmet deal in order to implement long term skin grafting. In this context, experiments on large animals appear unavoidable to assess this question and possible rejection. Cellular tools for large animal models should be constructed. METHODS: In this study, we generated monkey pluripotent stem cell-derived keratinocytes and evaluated their capacities to reconstruct an epidermis, in vitro as well as in vivo. RESULTS: Monkey pluripotent stem cells were differentiated efficiently into keratinocytes able to reconstruct fully epidermis presenting a low level of major histocompatibility complex class-I antigens, opening the way for autologous or allogeneic epidermal long-term grafting. CONCLUSIONS: Functional keratinocytes generated from nonhuman primate embryonic stem cells and induced pluripotent stem cells reproduce an in vitro and in-vivo stratified epidermis. These monkey skin grafts will be considered to model autologous or allogeneic epidermal grafting using either embryonic stem cells or induced pluripotent stem cells. This graft model will allow us to further investigate the safety, efficacy and immunogenicity of nonhuman primate PSC-derived epidermis in the perspective of human skin cell therapy. PMID- 29258611 TI - Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models. AB - BACKGROUND: Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra articular delivery of PGRN protects against osteoarthritis (OA) progression. The purpose of this study is to determine whether Atsttrin also has therapeutic effects in OA and the molecular mechanisms involved. METHODS: Surgically induced and noninvasive rupture OA models were established in mouse and rat, respectively. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry, and ELISA. Additionally, expressions of pain related markers, degenerative factors, and anabolic and catabolic markers known to be involved in OA were analyzed. Furthermore, the anabolic and anti-catabolic effects and underlying mechanisms of Atsttrin were determined using in-vitro assays with primary chondrocytes. RESULTS: Herein, we found Atsttrin effectively prevented the accelerated OA phenotype associated with PGRN deficiency. Additionally, Atsttrin exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erk1/2-dependent chondrocyte anabolism, while inhibiting TNFalpha/TNFR1-mediated inflammatory catabolism. CONCLUSIONS: These findings not only provide new insights into the role of PGRN and its derived engineered protein Atsttrin in cartilage homeostasis as well as OA in vivo, but may also lead to new therapeutic alternatives for OA as well as other relative degenerative joint diseases. PMID- 29258612 TI - Latent class models for Echinococcus multilocularis diagnosis in foxes in Switzerland in the absence of a gold standard. AB - BACKGROUND: In Europe the principal definitive host for Echinococcus multilocularis, causing alveolar echinococcosis in humans, is the red fox (Vulpes vulpes). Obtaining reliable estimates of the prevalence of E. multilocularis and relevant risk factors for infection in foxes can be difficult if diagnostic tests with unknown test accuracies are used. Latent-class analysis can be used to obtain estimates of diagnostic test sensitivities and specificities in the absence of a perfect gold standard. Samples from 300 foxes in Switzerland were assessed by four different diagnostic tests including necropsy followed by sedimentation and counting technique (SCT), an egg-PCR, a monoclonal and a polyclonal copro-antigen ELISA. Information on sex, age and presence of other cestode species was assessed as potential covariates in the Bayesian latent class models. Different Bayesian latent-class models were run, considering dichotomized test results and, additionally, continuous readings resulting in empirical ROC curves. RESULTS: The model without covariates estimated a true parasite prevalence of 59.5% (95% CI: 43.1-66.4%). SCT, assuming a specificity of 100%, performed best among the four tests with a sensitivity of 88.5% (95% CI: 82.7 93.4%). The egg-PCR showed a specificity of 93.4% (95% CI: 87.3-99.1%), although its sensitivity of 54.8% was found moderately low (95% CI: 48.5-61.0%). Relatively higher sensitivity (63.2%, 95% CI: 55.3-70.8%) and specificity (70.0%, 95% CI: 60.1-79.4%) were estimated for the monoclonal ELISA compared to the polyclonal ELISA with a sensitivity and specificity of 56.0% (95% CI: 48.0-63.9%) and 65.9% (95% CI: 55.8-75.6%), respectively. In the Bayesian models, adult foxes were found to be less likely infected than juveniles. Foxes with a concomitant cestode infection had double the odds of an E. multilocularis infection. ROC curves following a Bayesian approach enabled the empirical determination of the best cut-off point. While varying the cut-offs of both ELISAs, sensitivity and specificity of the egg-PCR and SCT remained constant in the Bayesian latent class models. CONCLUSIONS: Adoption of a Bayesian latent class approach helps to overcome the absence of a perfectly accurate diagnostic test and gives a more reliable indication of the test performance and the impact of covariates on the prevalence adjusted for diagnostic uncertainty. PMID- 29258613 TI - Dual-drug loaded nanoneedles with targeting property for efficient cancer therapy. AB - BACKGROUND: Since the anticancer drugs have diverse inhibited mechanisms to the cancer cells, the use of two or more kinds of anticancer agents may achieve excellent therapeutic effects, especially to the drug-resistant tumors. RESULTS: In this study, we developed a kind of dual drug [methotrexate (MTX) and 10 hydroxycamptothecine (HCPT)] loaded nanoneedles (DDNDs) with pronounced targeting property, high drug loading and prolonged drug release. The anti-solvent precipitation of the HCPT and MTX modified PEG-b-PLGA (PEG-b-PLGA-MTX, PPMTX) leads to nucleation of nanoneedles with nanocrystalline HCPT as the core wrapped with PPMTX as steric stabilizers. In vitro cell uptake studies showed that the DDNDs revealed an obviously targeting property and entered the HeLa cells easier than the nanoneedles without MTX modification. The cytotoxicity tests illustrated that the DDNDs possessed better killing ability to HeLa cells than the individual drugs or their mixture in the same dose, indicating its good synergistic effect and targeting property. The in vivo studies further confirmed these conclusions. CONCLUSIONS: This approach led to a promising sustained drug delivery system for cancer diagnosis and treatment. PMID- 29258614 TI - Necessary additional steps in ultrasound guided central venous catheter placement: getting to the heart of the matter. PMID- 29258616 TI - Exploring diet, exercise, chronic illnesses, occupational stressors and mental well-being of healthcare professionals in Punjab, Pakistan. AB - OBJECTIVE: This data set was compiled to assess mental well-being, dietary pattern and physical health parameters of health care professionals in Pakistan. DATA DESCRIPTION: The Warwick-Edinburgh mental well-being scale was first evaluated for the Pakistani population then used, along with other measures like body mass index, exercise and dietary habits to assess health and wellbeing of health care providers. The importance of the data lies in the fact that no previous records or data exists in our knowledge that used a subjective index to assess wellbeing in Pakistani population. Furthermore, this data may be used as part of a global analysis to find differences in well-being and health habits of health care providers in developing countries as opposed to developed countries. PMID- 29258617 TI - Erratum to: An information and communication technology-based centralized clinical trial to determine the efficacy and safety of insulin dose adjustment education based on a smartphone personal health record application: a randomized controlled trial. AB - After publication of the original article [1] it was noted that both the figures and captions and relating to Figs. 1 and 2 had been interchanged. PMID- 29258615 TI - What is the evidence that tau pathology spreads through prion-like propagation? AB - Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a "prion-like" mechanism involving transfer of abnormal tau seeds from a "donor cell" to a "recipient cell" and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a "prion-like" mechanism and proposes a number of recommendations for directing future research. Recommendations for definitions of frequently used terms in the tau field are presented in an attempt to clarify and standardize interpretation of research findings. Molecular and cellular factors affecting tau aggregation are briefly reviewed, as are potential contributions of physiological and pathological post-translational modifications of tau. Additionally, the experimental evidence for tau seeding and "prion-like" propagation of tau aggregation that has emerged from cellular assays and in vivo models is discussed. Propagation of tau pathology using "prion-like" mechanisms is expected to incorporate several steps including cellular uptake, templated seeding, secretion and intercellular transfer through synaptic and non-synaptic pathways. The experimental findings supporting each of these steps are reviewed. The clinical validity of these experimental findings is then debated by considering the supportive or contradictory findings from patient samples. Further, the role of physiological tau release in this scenario is examined because emerging data shows that tau is secreted but the physiological function (if any) of this secretion in the context of propagation of pathological tau seeds is unclear. Bona fide prions exhibit specific properties, including transmission from cell to cell, tissue to tissue and organism to organism. The propagation of tau pathology has so far not been shown to exhibit all of these steps and how this influences the debate of whether or not abnormal tau species can propagate in a "prion-like" manner is discussed. The exact nature of tau seeds responsible for propagation of tau pathology in human tauopathies remains controversial; it might be tightly linked to the existence of tau strains stably propagating peculiar patterns of neuropathological lesions, corresponding to the different patterns seen in human tauopathies. That this is a property shared by all seed-competent tau conformers is not yet firmly established. Further investigation is also required to clarify the relationship between propagation of tau aggregates and tau-induced toxicity. Genetic variants identified as risks factors for tauopathies might play a role in propagation of tau pathology, but many more studies are needed to document this. The contribution of selective vulnerability of neuronal populations, as an alternative to prion-like mechanisms to explain spreading of tau pathology needs to be clarified. Learning from the prion field will be helpful to enhance our understanding of propagation of tau pathology. Finally, development of better models is expected to answer some of these key questions and allow for the testing of propagation-centred therapies. PMID- 29258618 TI - A pilot study of an autologous tumor-derived autophagosome vaccine with docetaxel in patients with stage IV non-small cell lung cancer. AB - BACKGROUND: Tumor-derived autophagosome vaccines (DRibbles) have the potential to broaden immune response to poorly immunogenic tumors. METHODS: Autologous vaccine generated from tumor cells harvested from pleural effusions was administered to patients with advanced NSCLC with the objectives of assessing safety and immune response. Four patients were vaccinated and evaluable for immune response; each received two to four doses of vaccine. Study therapy included two cycles of docetaxel 75 mg/m2 on days 1 and 29 to treat the tumor, release hidden antigens and produce lymphopenia. DRibbles were to be administered intradermally on days 14, 43, 57, 71, and 85, together with GM-CSF (50 MUg/d x 6d, administered via SQ mini pump). Peripheral blood was tested for immune parameters at baseline and at each vaccination. RESULTS: Three of four patients had tumor cells available for testing. Autologous tumor-specific immune response was seen in two of the three, manifested by IL-5 (1 patient after 3 doses), and IFN-gamma, TNF-alpha, IL-5, IL 10 (after 4 doses in one patient). All 4 patients had evidence of specific antibody responses against potential tumor antigens. All patients came off study after 4 or fewer vaccine treatments due to progression of disease. No significant immune toxicities were seen during the course of the study. CONCLUSIONS: DRibble vaccine given with GM-CSF appeared safe and capable of inducing an immune response against tumor cells in this small, pilot study. There was no evidence of efficacy in this small poor-prognosis patient population, with treatment not feasible. Trial registration NCT00850785, initial registration date February 23, 2009. PMID- 29258619 TI - Effects of low-intensity pulsed ultrasound (LIPUS)-pretreated human amnion derived mesenchymal stem cell (hAD-MSC) transplantation on primary ovarian insufficiency in rats. AB - BACKGROUND: Human amnion-derived mesenchymal stem cells (hAD-MSCs) have the features of mesenchymal stem cells (MSCs). Low-intensity pulsed ultrasound (LIPUS) can promote the expression of various growth factors and anti inflammatory molecules that are necessary to keep the follicle growing and to reduce granulosa cell (GC) apoptosis in the ovary. This study aims to explore the effects of LIPUS-pretreated hAD-MSC transplantation on chemotherapy-induced primary ovarian insufficiency (POI) in rats. METHODS: The animals were divided into control, POI, hAD-MSC treatment, and LIPUS-pretreated hAD-MSC treatment groups. POI rat models were established by intraperitoneal injection of cyclophosphamide (CTX). The hAD-MSCs isolated from the amnion were exposed to LIPUS or sham irradiation for 5 consecutive days and injected into the tail vein of POI rats. Expression and secretion of growth factors promoted by LIPUS in hAD MSCs were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) in vitro. Estrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, GC apoptosis, Bcl2 and Bax expression, and pro-inflammatory cytokine levels in ovaries were examined. RESULTS: Primary hAD-MSCs were successfully isolated from the amnion. LIPUS promoted the expression and secretion of growth factors in hAD-MSCs in vitro. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation increased the body and reproductive organ weights, improved ovarian function, and reduced reproductive organ injuries in POI rats. Transplantation of hAD-MSCs increased the Bcl-2/Bax ratio and reduced GC apoptosis and ovarian inflammation induced by chemotherapy in ovaries. These effects could be improved by pretreatment with LIPUS on hAD-MSCs. CONCLUSION: Both hAD-MSC transplantation and LIPUS-pretreated hAD-MSC transplantation can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced POI. LIPUS-pretreated hAD-MSC transplantation is more advantageous for reducing inflammation, improving the local microenvironment, and inhibiting GC apoptosis induced by chemotherapy in ovarian tissue of POI rats. PMID- 29258620 TI - Refractory ventricular fibrillations after surgical repair of atrial septal defects in a patient with CACNA1C gene mutation - case report. AB - BACKGROUND: Congenital long QT syndrome (LQTS) can cause ventricular arrhythmic events with syncope and sudden death resulting from malignant torsades de pointes (TdP) followed by ventricular fibrillations (VFs). However, the syndrome is often overlooked prior to the development of arrhythmic events in patients with congenital heart diseases demonstrating right bundle branch block on electrocardiogram (ECG). We present a case of an adult patient with congenital heart disease who developed VFs postoperatively, potentially due to his mutation in a LQTS related gene, which was not identified on preoperative assessment due to incomplete evaluation of his family history. CASE PRESENTATION: A 64-year-old man was diagnosed as having multiple atrial septal defects. He presented with no symptoms of heart failure. His preoperative ECG showed complete right bundle branch block (CRBBB) with a corrected QT interval time of 478 ms. He underwent open-heart surgery to close the defects through median sternotomy access. Three hours after the operation, he developed multiple events of TdP and VFs in the intensive care unit. Cardiopulmonary resuscitation and multiple cardioversions were attempted for his repetitive TdP and VFs. He eventually reverted to sinus rhythm, and intravenous beta-blocker was administered to maintain the sinus rhythm. After this event, his family history was reviewed, and it was confirmed that his daughter and grandson had a medical history of arrhythmia. A genetic test confirmed that he had a missense mutation in CACNA1C, p.K1580 T, which is the cause for type 8. CONCLUSIONS: This case highlights the importance of paying attention to other ECG findings in patients with CRBBB, which can mask prolonged QT intervals. PMID- 29258621 TI - Maternal restrictive feeding and eating in the absence of hunger among toddlers: a cohort study. AB - BACKGROUND: Restrictive feeding by parents has been associated with greater eating in the absence of hunger (EAH) among children, a risk factor for obesity. However, few studies have examined the association between restrictive feeding and EAH longitudinally, raising questions regarding the direction of associations between restrictive feeding and child EAH. Our objective was to examine the bidirectional prospective associations between restrictive feeding and EAH among toddlers. METHODS: Low-income mother-child dyads (n = 229) participated when children were 21, 27, and 33 months old. Restriction with regard to food amount and food quality were measured with the Infant Feeding Styles Questionnaire. EAH was measured as kilocalories of food children consumed after a satiating meal. A cross-lagged analysis adjusting for child sex and weight-for-length z-score was used to simultaneously test cross-sectional and bidirectional prospective associations between each type of restriction and children's EAH. RESULTS: At 21 months, mothers of children with greater EAH reported higher restriction with regard to food amount (b = 0.17, p < .05). Restriction with regard to food amount at age 21 months was inversely associated with EAH at 27 months (b = -0.20, p < .05). Restriction with regard to food amount at 27 months was not associated with EAH at 33 months and restriction with regard to food quality was not associated with EAH. EAH did not prospectively predict maternal restriction. CONCLUSIONS: Neither restriction with regard to food amount nor food quality increased risk for EAH among toddlers. Current US clinical practice recommendations for parents to avoid restrictive feeding, and the potential utility of restrictive feeding with regard to food amount in early toddlerhood, deserve further consideration. PMID- 29258622 TI - Nasal colonization and antimicrobial susceptibility pattern of Staphylococcus aureus among pre-school children in Ethiopia. AB - BACKGROUND: Staphylococcus aureus is one of the bacterium that can asymptomatically colonize the human upper respiratory tract (i.e. nose and throat). Carriage of S. aureus, including methicillin resistant S. aureus, is common to children. The aim at this study was to determine the nasal colonization, associated factors and antimicrobial susceptibility patterns of S. aureus isolates among pre-school children in Debre Markos town. METHODS: Institutional-based cross sectional study was conducted. A total of 400 nasal swabs were collected from pre-school children from April to June, 2015 following standard microbiological methods. MRSA was detected using both Cefoxitin (30 MUg) and Oxacillin (6 MUg) (Oxoid Ltd. England) discs in combination and associated factors were assessed using self-administered pretested questionnaires, which were delivered to the children's parents/guardians. Statistical analysis of the data (logistic regression) was done using SPSS V-22. RESULTS: A total of 52 S. aureus isolate was recovered from 400 nasal swap samples. The prevalence of S. aureus among pre-School children was 13% (52/400). The susceptibility patterns of the isolates to commonly used antibiotics were: 84.62% to Chloramphenicol, 69.2% to Doxycycline and Tetracycline, 92.3% to Kanamycin, 7.7% to Ampicillin and Penicillin, 86.6% to Ceftriaxone, and 76.9% to Augmentin. All the isolates were sensitive to Oxacillin and Cefoxitin, mean there was no methicillin resistant S. aureus isolate, and also sensitive to Gentamycin, Erythromycin and Clindamycin. The main associated factors of nasal colonization of S. aureus in the study area was, having recurrent acute otitis media (AOM) [AOR = 2.37 (1.11, 5.06)], Children admission in hospital [AOR = 1.96 (1.03, 3.73)] and cough [AOR = 2.09 (1.08, 4.09)]. CONCLUSIONS: The prevalence of S. aureus nasal colonization among pre-school children was relatively low in absence of MRSA. Factors like; recurrent AOM, hospital admission and cough were significantly associated with S. aureus nasal colonization. Most of the isolates were resistant to beta-lactam drugs and sensitive to drugs like Gentamycin, Erythromycin, Clindamycin, Chloramphenicol, Doxycycline, Tetracycline, Kanamycin and Augmentin. PMID- 29258623 TI - Dynamic modeling of folliculogenesis signaling pathways in the presence of miRNAs expression. AB - BACKGROUND: TEK signaling plays a very important role in folliculogenesis. It activates Ras/ERK/MYC, PI3K/AKT/mTORC1 and ovarian steroidogenesis activation pathways. These are the main pathways for cell growth, differentiation, migration, adhesion, proliferation, survival and protein synthesis. RESULTS: TEK signaling on each of the two important pathways where levels of pERK, pMYC, pAkt, pMCL1 and pEIF4EBP1 are increased in dominant follicles and pMYC is decreased in dominant follicles. Over activation of ERK and MYC which are the main cell growth and proliferation and over activation of Akt, MCl1, mTORC1 and EIF4EBP1 which are the main cell survival and protein synthesis factors act as promoting factors for folliculogenesis. In case of over expression of hsa-miR-30d-3p and hsa-miR-451a, MYC activity level is considerably increased in subordinate follicles. Our simulation results show that in the presence of has-miR-548v and bta-miR-22-3p, downstream factors of pathways are inhibited. CONCLUSIONS: Our work offers insight into the design of natural biological procedures and makes predictions that can guide further experimental studies on folliculogenesis pathways. Moreover, it defines a simple signal processing unit that may be useful for engineering synthetic biology and genes circuits to carry out cell-based computation. PMID- 29258625 TI - Exposure to vitamin D from fortified margarine during fetal life and later risk of pre-eclampsia: the D-tect Study. AB - OBJECTIVE: To examine if fetal exposure to a small dosage of extra vitamin D from food fortification was associated with a decrease in the risk of pre-eclampsia later in life. DESIGN: Cancellation of the mandatory vitamin D fortification of margarine in 1985 created a societal experiment, with entire adjacent birth cohorts exposed or unexposed to extra vitamin D during fetal development. The Danish national medical health registries allowed the identification of pre eclampsia cases later in life among all exposed and unexposed female individuals. SETTING: Denmark. SUBJECTS: Women born between June 1983 and August 1988, who gave birth to their first child at age 14.5-27.5 years (n 32 621). RESULTS: OR (95 % CI) for pre-eclampsia among women exposed v. unexposed to extra vitamin D from fortification during fetal development was 0.86 (0.76, 0.97). Exposure to extra vitamin D was associated with further reduced odds of pre-eclampsia (0.49 (0.34, 0.72)) among current smokers, but not among former smokers and non smokers. CONCLUSIONS: Additional vitamin D in fetal life from food fortification seems to reduce the risk of pre-eclampsia later in life. The risk reduction may be particularly strong among women who smoke during pregnancy. PMID- 29258626 TI - The past as a work in progress. AB - Originating as a presidential address during the seventieth birthday celebrations of the British Society for the History of Science, this essay reiterates the society's long-standing commitment to academic autonomy and international cooperation. Drawing examples from my own research into female scientists and doctors during the First World War, I explore how narratives written by historians are related to their own lives, both past and present. In particular, I consider the influences on me of my childhood reading, my experiences as a physics graduate who deliberately left the world of science, and my involvement in programmes to improve the position of women in science. In my opinion, being a historian implies being socially engaged: the BSHS and its members have a responsibility towards the future as well as the past. Life can only be understood backwards; but it must be lived forwards. Soren Kierkegaard, Journals and Papers, 1843. PMID- 29258624 TI - A selenium species in cerebrospinal fluid predicts conversion to Alzheimer's dementia in persons with mild cognitive impairment. AB - BACKGROUND: Little is known about factors influencing progression from mild cognitive impairment to Alzheimer's dementia. A potential role of environmental chemicals and specifically of selenium, a trace element of nutritional and toxicological relevance, has been suggested. Epidemiologic studies of selenium are lacking, however, with the exception of a recent randomized trial based on an organic selenium form. METHODS: We determined concentrations of selenium species in cerebrospinal fluid sampled at diagnosis in 56 participants with mild cognitive impairment of nonvascular origin. We then investigated the relation of these concentrations to subsequent conversion from mild cognitive impairment to Alzheimer's dementia. RESULTS: Twenty-one out of the 56 subjects developed Alzheimer's dementia during a median follow-up of 42 months; four subjects developed frontotemporal dementia and two patients Lewy body dementia. In a Cox proportional hazards model adjusting for age, sex, duration of sample storage, and education, an inorganic selenium form, selenate, showed a strong association with Alzheimer's dementia risk, with an adjusted hazard ratio of 3.1 (95% confidence interval 1.0-9.5) in subjects having a cerebrospinal fluid content above the median level, compared with those with lower concentration. The hazard ratio of Alzheimer's dementia showed little departure from unity for all other inorganic and organic selenium species. These associations were similar in analyses that measured exposure on a continuous scale, and also after excluding individuals who converted to Alzheimer's dementia at the beginning of the follow up. CONCLUSIONS: These results indicate that higher amounts of a potentially toxic inorganic selenium form in cerebrospinal fluid may predict conversion from mild cognitive impairment to Alzheimer's dementia. PMID- 29258627 TI - Transcatheter therapy of anomalous systemic venous drainage. AB - Anomalous drainage of the right superior caval vein into the left atrium is a rare congenital anomaly that causes cyanosis and occult infection owing to right to-left shunting. Transcatheter management of this anomaly is unique and rarely reported. We report a 32-year-old man with a history of brain abscess, who was diagnosed with an anomalous right superior caval vein draining to the left atrium; right upper pulmonary vein and right middle pulmonary vein draining into the inferior portion of the right superior caval vein; and a left superior caval vein draining into the right atrium through the coronary sinus without a bridging vein. Pre-procedural planning was guided by three-dimensional printed model. The right superior caval vein was occluded with a 16-mm Amplatzer muscular Ventricular Septal Defect occluder inferior to the azygous vein, but superior to the entries of right upper and middle pulmonary veins. This diverted the right superior caval vein flow to the inferior caval vein system through the azygos vein in a retrograde manner and allowed the right upper pulmonary vein and right middle pulmonary vein flow to drain into the left atrium normally, achieving exclusion of right-to-left shunting and allowing normal drainage of pulmonary veins into the left atrium. At the 6-month follow-up, his saturation improved from 93 to 97% with no symptoms of superior caval vein syndrome. PMID- 29258628 TI - COST ANALYSIS OF PERIPHERALLY INSERTED CENTRAL CATHETER IN PEDIATRIC PATIENTS. AB - PURPOSE: A peripherally inserted central catheter (PICC) is a useful option in providing secure venous access, which enables patients to be discharged earlier with the provision of home care. The objective was to identify the costs associated with having a PICC from a societal perspective, and to identify factors that are associated with total PICC costs. METHODS: Data were obtained from a retrospective cohort of 469 hospitalized pediatric patients with PICCs inserted. Both direct and indirect costs were estimated from a societal perspective. Insertion costs, complication costs, nurse and physician assessment costs, inpatient ward costs, catheter removal costs, home care costs, travel costs, and the cost associated with productivity losses incurred by parents were included in this study. RESULTS: Based on catheter dwell time, the median total cost associated with a PICC per patient per day (including inpatient hospital costs) was $3,133.5 ($2,210.7-$9,627.0) in 2017 Canadian dollars ($1.00USD = $1.25CAD in 2017). The adjusted mean cost per patient per day was $2,648.2 ($2,402.4-$2,920.4). Excluding inpatient ward costs, the median total and adjusted costs per patient per day were $198.8 ($91.8-$2,475.8) and $362.7($341.0 $386.0), respectively. Younger age, occurrence of complications, more catheter dwell days, wards with more intensive care, and the absence of home care were significant factors associated with higher total PICC costs. CONCLUSIONS: This study has demonstrated the costs associated with PICCs. This information may be helpful for healthcare providers to understand PICC related cost in children and resource implications. PMID- 29258630 TI - ANALYSIS OF DUPLICATION AND TIMING OF HEALTH TECHNOLOGY ASSESSMENTS ON MEDICAL DEVICES IN EUROPE. AB - OBJECTIVES: Strengthening efforts toward better collaboration plays a pivotal role in the assessment of medical devices to reduce overlap and save resources. This study explored the level of duplication in health technology assessments (HTA) of medical devices in Europe and their respective timing in order to identify areas for better collaboration. METHODS: An analysis of European HTA reports of medical devices regarding overlaps in topics and timing in relation to market authorization was performed. We conducted a systematic search in the ADVANCE, Centre for Reviews and Dissemination, Syngerus, and POP databases, complemented by hand searching, to identify HTA reports published between 01/2003 and 07/2016 for a preselected cohort group of ten technologies. We analyzed the number of annual assessments per technology and evaluated activity patterns and timing in undertaking the HTA of the different institutes in Europe. RESULTS: The results revealed the amount of duplication in the European HTA production: the number of reports per technology ranged from minimum seven to maximum twenty-two over a time-span of 13.5 years. HTA institutes perform assessments at a similar time range within 5 to 10 years following market authorization. The timing of the initial assessment in relation to the granting of the CE-mark varies according to the particular technology. CONCLUSION: The findings suggest that efficient collaboration may help to save scarce resources and time of HTA institutes in Europe. Efficient collaboration as such needs to shift the focus beyond the time span of 1 year, and build on each's others work from previous assessments. PMID- 29258629 TI - Aspects of the History of Twin Research: Statistical Congresses in the 19th Century and Hellin's Law. AB - In the 19th century, a series of international statistical congresses began that were important for population studies, including twin research. The introduction of common rules for the national demographic registers enabled scientists to contribute to the genesis of statistical research. The congress in St. Petersburg in 1872, in particular, focused on the movements of the population, and how they should be registered. Among the facts to be recorded were in multiple births, the sex and number of children born alive or still-born, whether legitimate or illegitimate, and the age of the mother at the date of the births. During the history of twin research, Hellin's law has played a central role because it is an approximately correct association between the rates of multiple maternities. It has been mathematically proven that Hellin's law does not hold as a general rule. Analyses show divergences from the law that are difficult to explain and/or eliminate. Varying improvements of this law have been proposed. The majority of all studies of Hellin's law are based on empirical rates of multiple maternities, ignoring random errors. Such studies can never confirm the law, but only identify errors with respect to Hellin's law that are too large to be characterized as random. It is of particular interest to note and explain why the rates of higher multiple maternities are sometimes too high or too low when Hellin's law is used as a benchmark. Studies have shown that there were investigators before Hellin who have contributed substantially to Hellin's law. In this article, we re examine some old data sets and contributions in which Hellin's law has been evaluated and also analyze recent data. PMID- 29258633 TI - Dementia-Friendly Dentistry: Why Dementia Guidelines? AB - FGDP(UK) recently launched its dementia-friendly dentistry: good practice guidelines publication, which members will have received free-of-charge. Vice Dean and editor of the guidelines, Paul Batchelor, explains why the publication is necessary and why all practitioners should make the effort to incorporate these recommendations into their practice. PMID- 29258631 TI - Attention bias modification augments cognitive-behavioral group therapy for social anxiety disorder: a randomized controlled trial. AB - BACKGROUND: Cognitive-behavioral group therapy (CBGT) is a first-line treatment for social anxiety disorder (SAD). However, since many patients remain symptomatic post-treatment, there is a need for augmenting procedures. This randomized controlled trial (RCT) examined the potential augmentation effect of attention bias modification (ABM) for CBGT. METHODS: Fifty patients with SAD from three therapy groups were randomized to receive an 18-week standard CBGT with either ABM designed to shift attention away from threat (CBGT + ABM), or a placebo protocol not designed to modify threat-related attention (CBGT + placebo). Therapy groups took place in a large mental health center. Clinician and self-report measures of social anxiety and depression were acquired pre treatment, post-treatment, and at 3-month follow-up. Attention bias was assessed at pre- and post-treatment. RESULTS: Patients randomized to the CBGT + ABM group, relative to those randomized to the CBGT + placebo group, showed greater reductions in clinician-rated SAD symptoms post-treatment, with effects maintained at 3-month follow-up. Group differences were not evident for self report or attention-bias measures, with similar reductions in both groups. Finally, reduction in attention bias did not mediate the association between group and reduction in Liebowitz Social Anxiety Scale Structured Interview (LSAS) scores. CONCLUSIONS: This is the first RCT to examine the possible augmenting effect of ABM added to group-based cognitive-behavioral therapy for adult SAD. Training patients' attention away from threat might augment the treatment response to standard CBGT in SAD, a possibility that could be further evaluated in large-scale RCTs. PMID- 29258632 TI - Spirituality and religious coping are related to cancer-bereaved siblings' long term grief. AB - OBJECTIVE: Many bereaved siblings have still not come to terms with their grief many years after the loss, but few studies have focused on what can help. The aims of this study were to identify cancer-bereaved adolescents' and young adults' ways of coping with grief after loss of a sibling, and examine whether these ways of coping were related to their experience of having worked through their grief. METHOD: This nationwide survey of 174 cancer-bereaved siblings (73% participation rate) is based on one open-ended question about coping with grief ("What has helped you to cope with your grief after your sibling's death?") and one closed-ended question about siblings' long-term grief ("Do you think you have worked through your grief over your sibling's death?"). The open-ended question was analyzed with content analysis; descriptive statistics and Fisher's exact test were used to examine the relation between type of coping and siblings' long term grief. Result The siblings described four ways of coping: (1) thinking of their dead brother/sister and feeling and expressing their grief; (2) distracting or occupying themselves; (3) engaging in spiritual and religious beliefs/activities; and (4) waiting for time to pass. One of these categories of coping with grief, namely, engaging in spiritual and religious beliefs and activities, was associated with siblings' experience of having worked through their grief two to nine years after the loss (p = 0.016). Significance of results Those siblings who had used spirituality, religious beliefs, and activities to cope were more likely to have worked through their grief than those who had not. PMID- 29258634 TI - New Regulations on X-Ray Use: Likely Implications of IRR17 and IRMER18. AB - Professor Keith Horner, co-editor of FGDP(UK)'s selection criteria for dental radiography, analyses what the ionising radiation regulations 2017 and draft ionising radiation (medical exposure) regulations 2018 mean for dentists and dental practice teams. PMID- 29258635 TI - Research Abstracts Removable Prosthodontics. PMID- 29258636 TI - The Adventures of Dentures. PMID- 29258637 TI - Mandibular Implant Overdentures: Treatment and Medico-Legal Considerations. AB - The concept of a two-implant overdenture as the minimum standard of care or first choice treatment for the edentulous mandible was first proposed in 2002 and has since been backed by an overwhelming body of evidence supporting greater patient satisfaction and improved quality of life. This article examines the implant overdenture concept and its various options and discusses best practice from both the patient's and a medico-legal standpoint. PMID- 29258638 TI - Challenges in Treating the Class II Edentulous Patient. AB - With a significant portion of edentulous patients presenting with a skeletal Class II relationship, specific denture needs for this patient group need to be considered. This paper examines the factors that need to be taken into account to prevent common problems from occurring when providing full dentures for a Class II edentulous patient. PMID- 29258639 TI - Quality Assurance in Custom Dental Devices: A Technologist's Perspective. AB - Manufacturing of custom-made dental devices such as removable dentures, fixed prosthodontics and orthodontics are subject to the requirements of the Medical Devices Directive (MDD). Many dental laboratories often enhance these requirements by implementing quality assurance procedures that then provide enhanced consistency. this paper provides a dental technologist's view of some of the systems currently being used in dental laboratories to provide a quality assured product and associated issues. PMID- 29258640 TI - Do Differing Opinions on Prosthetic Procedures Make a Student's Life More Difficult? AB - Dental student Charlotte Gentry reflects on how the advice of experienced clinicians can cause confusion rather than clarity for fledgling dentists. PMID- 29258641 TI - Denture Stomatitis: Causes, Cures and Prevention. AB - Removable dentures are worn by 20% of the UK population and two thirds of these individuals have denture stomatitis. Poor oral hygiene is commonplace among this group, as is smoking and xerostomia, which also contribute to the development of denture stomatitis. A complex polymicrobial biofilm is able to proliferate on the surface of denture materials and matures to form visible denture plaque. This denture plaque biofilm stimulates a local inflammatory process that is detectable clinically as erythema, and hyperplasia. Systemically, denture plaque represents a potential risk factor for systemic disease, in particular aspiration pneumonia. Respiratory pathogens have been detected in the denture plaque and overnight denture wear has been linked to an increased risk of aspiration pneumonia. There is a general lack of evidence on the adequate management of denture stomatitis and we present a protocol for use in the primary care setting. PMID- 29258642 TI - Career Focus: Film Falsies. AB - Dental technician Gary Archer makes removable prosthodontic devices for hollywood movies. he shares some of the tricks of the trade with PDJ managing editor Amy Brewerton. PMID- 29258645 TI - In the national epidemiological bulletins - a selection from recent issues. PMID- 29258644 TI - A benefit-risk analysis of rotavirus vaccination, France, 2015. AB - IntroductionTwo vaccines available for protection against rotavirus gastroenteritis (RVGE), Rotarix and RotaTeq, have contributed to a large decrease in the incidence of paediatric diarrhoea in countries where they have been used. However, they have also led to a small increase in the risk of intussusception. Methods: We compare the number of prevented hospitalisations for RVGE to the number of vaccine-induced hospitalised intussusceptions in France. Results: With 9.5% coverage (French 2015 estimation), vaccination was estimated to prevent, annually, a median of 1,074 hospitalisations (2.5th and 97.5th percentiles (2.5th 97.5th): 810-1,378) and 1.4 deaths (2.5th-97.5th: 1.2-1.6) from RVGE. It was also estimated to cause, annually, 5.0 hospitalisations (2.5th-97.5th: 3.2-7.7) and 0.005 deaths (2.5th-97.5th: 0.001-0.015) from intussusception. The benefit-risk ratio is therefore 214 (2.5th-97.5th: 128-362) for hospitalisations and 273 (2.5th-97.5th: 89-1,228) for deaths. Under a hypothetical 92% coverage, rotavirus vaccination with Rotarix would avoid 10,459 (2.5th-97.5th: 7,702-13,498) hospitalisations for RVGE and induce 47.0 (2.5th-97.5th: 25.1-81.4) hospitalisations for intussusception annually, thereby preventing 13.7 (2.5th 97.5th: 11.1-15.2) deaths and inducing 0.05 (2.5th-97.5th: 0.01-0.15) deaths. Conclusion: The benefit-risk ratio in France is similar to that of other European countries. PMID- 29258646 TI - Epidemiology of hand, foot and mouth disease in China, 2008 to 2015 prior to the introduction of EV-A71 vaccine. AB - INTRODUCTION: Hand, foot and mouth disease (HFMD) is usually caused by several serotypes from human enterovirus A species, including enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16). Two inactivated monovalent EV-A71 vaccines have been recently licensed in China and monovalent CV-A16 vaccine and bivalent EV-A71 and CV-A16 vaccine are under development. METHODS: Using notifications from the national surveillance system, we describe the epidemiology and dynamics of HFMD in the country, before the introduction of EV-A71 vaccination, from 2008 through 2015. RESULTS: Laboratory-identified serotype categories, i.e. CV-A16, EV-A71 and other enteroviruses, circulated annually. EV-A71 remained the most virulent serotype and was the major serotype for fatal cases (range: 88.5-95.4%) and severe cases (range: 50.7-82.3%) across years. Except for 2013 and 2015, when other enteroviruses were more frequently found in mild HFMD (48.8% and 52.5%), EV A71 was more frequently detected from mild cases in the rest of the years covered by the study (range: 39.4-52.6%). The incidence rates and severity risks of HFMD associated with all serotype categories were the highest for children aged 1 year and younger, and decreased with increasing age. DISCUSSION/CONCLUSION: This study provides baseline epidemiology for evaluation of vaccine impact and potential serotype replacement. PMID- 29258647 TI - Cross-border outbreak of listeriosis caused by cold-smoked salmon, revealed by integrated surveillance and whole genome sequencing (WGS), Denmark and France, 2015 to 2017. AB - In August 2017, an outbreak of six listeriosis cases in Denmark was traced to cold-smoked salmon, using epidemiological investigations and whole-genome sequencing (WGS) analyses. Exchange of genome sequences allowed identification in France of a food isolate from a salmon-derived product and a human isolate from 2016 within the same cgMLST cluster as the Danish isolates (L2-SL8-ST8-CT771). The salmon product came from a third European Union country. WGS can rapidly link human cases and food isolates across Europe. PMID- 29258648 TI - Secular trends in incidence of acute gastroenteritis in general practice, France, 1991 to 2015. AB - We analysed 25 years of general practitioner (GP) visits for acute gastroenteritis (AG) surveillance in France, by the GP Sentinelles network. We searched for time trends of acute gastroenteritis incidence during winter periods. Data from emergency departments and drug reimbursement were additional data sources. A time-series analysis was performed using a generalised additive model for all data sources for the winter period. Virological data were incorporated and compared with the three data sources. The cumulative incidence of GP visits for winter AG exhibited an increasing trend from 1991 until 2008, when it reached 6,466 per 100,000 inhabitants. It decreased thereafter to 3,918 per 100,000 inhabitants in 2015. This decreasing trend was observed for all age groups and confirmed by the generalised additive model. For emergency department visits a decreasing trend was observed from 2004. Drug reimbursement data analyses demonstrated a decreasing trend from when data began in 2009. The incidence reported by GPs and emergency departments was lower following the emergence of norovirus GII.4 2012 (p < 0.0001). Winter AG incidences seem to follow long-term rising and decreasing trends that are important to monitor through continuous surveillance to evaluate the impact of prevention strategies, such as future immunisation against acute viral gastroenteritis. PMID- 29258649 TI - Influenza A(H3N2) virus variants and patient characteristics during a summer influenza epidemic in Taiwan, 2017. AB - We report a summer influenza epidemic caused by co-circulation of multiple influenza A(H3N2) variants in clade 3C.2a. Compared with other clades, a putative clade 3C.2a.3a was more commonly isolated from severely ill patients; 3C.2a.4 was more commonly isolated in outbreak cases. Time from vaccination to illness onset was significantly shorter in severely ill patients infected with clade 3C.2a.3; characteristics and outcomes of patients infected with different clades were similar. No resistance to antiviral medications was found. PMID- 29258650 TI - Re-evaluation of a 2014 multi-country European outbreak of Salmonella Enteritidis phage type 14b using recent epidemiological and molecular data. AB - A European multi-country outbreak of Salmonella Enteritidis phage type (PT) 14b occurred from March to November 2014 associated with the consumption of eggs. The outbreak involved more than 400 human cases from France, Luxembourg, Austria and the United Kingdom. In 2016-2017, it has been re-evaluated combining recent epidemiological results with latest molecular data. The outbreak was traced back to one large Bavarian egg producer with four distinct premises, three located in Bavaria, one in the Czech Republic. The outbreak isolates of S. Enteritidis PT 14b were grouped into three closely related clades by whole genome sequencing. Two of these clades could be referred to two Bavarian premises of the egg producer on the basis of epidemiological and molecular data, while epidemiological data presumably linked the third clade to another premises of the egg producer. Interestingly and in contrast to the situation in other European countries where several outbreaks were documented, all notified 91 laboratory confirmed cases of S. Enteritidis PT 14b from Bavaria were sporadic, singular cases not belonging to any epidemiological outbreaks. In conclusion, as demonstrated here, the resolution of food-related outbreaks with such a high discriminatory power is rare in outbreak investigation. PMID- 29258651 TI - Risk for malnutrition in patients prior to vascular surgery. AB - BACKGROUND: Malnutrition is an important risk factor for adverse post-operative outcomes. The prevalence of risk for malnutrition is unknown in patients prior to vascular surgery. We aimed to assess prevalence and associated factors of risk for malnutrition in this patient group. METHODS: Patients were assessed for risk for malnutrition by the Patient-Generated Subjective Global Assessment Short Form. Demographics and medical history were retrieved from the hospital registry. Uni- and multivariate analyses were performed to identify associated factors of risk for malnutrition. RESULTS: Of 236 patients, 57 (24%) were categorized as medium/high risk for malnutrition. In the multivariate analyses, current smoking (P = 0.032), female sex (P = 0.031), and being scheduled for amputation (P = 0.001) were significantly associated with medium/high risk for malnutrition. CONCLUSIONS: A substantial proportion (24%) of patients prior to vascular surgery is at risk for malnutrition, specifically smokers, females and patients awaiting amputation. Knowledge of these associated factors may help to appoint patients for screening. PMID- 29258652 TI - Phonemic feature involvement in lexical access in grades 3 and 5: Evidence from visual and auditory lexical decision tasks. AB - Numerous studies have evidenced the involvement of the phonological code during visual word recognition not only in skilled adult readers but also in child readers. Moreover, in skilled adult readers, visual word processing has been shown to be sensitive to phonetic details such as phonemic features (e.g., manner of articulation, place of articulation, voicing and nasality in French) which are typically involved in phonological lexicon access during speech processing. In contrast, it is not known whether and when visual word recognition is affected by phonemic features during learning to read. The present study investigates this issue in third and fifth graders. A lexical decision task was performed in visual and auditory modalities. Targets were French words (e.g., piano [piano]) and pseudowords created from target words. Mismatching was on the first phoneme. There were one-feature phoneme mismatch pseudowords (e.g., tiano) and multiple feature phoneme mismatch pseudowords (e.g., liano). The pseudowords were used as a marker of the sensitivity to phonemic features in phonological lexicon access. Phonemic feature effects were found in visual and auditory lexical decision tasks in both grades, indicating that phonological lexicon access involves phonemic features in print processing as in speech processing. In contrast, the absence of difference between both grades seems to indicate that this effect is independent of age or, more precisely, of phonological development and reading performance. PMID- 29258654 TI - Stent-Assisted Coil Embolization of 2 Complex Juxtarenal Penetrating Aortic Ulcers: An Unconventional Solution. PMID- 29258655 TI - Feasibility and Efficacy of Treating Cephalic Arch Stenosis with Viatorr Stents in Dialysis Patients. PMID- 29258656 TI - Renal Artery Embolization for the Treatment of Refractory Proteinuria in Three Pediatric Patients with Focal Segmental Glomerulosclerosis. PMID- 29258653 TI - Exploring the Role of Astroglial Glutamate Release and Association With Synapses in Neuronal Function and Behavior. AB - Astrocytes are stellate cells whose appearance can resemble a pointed star, especially when visualizing glial fibrillary acidic protein, a canonical marker for astrocytes. Accordingly, there is a commonly made connection between the points of light that shine in the night sky and the diffuse and abundant cells that buffer ions and provide support for neurons. An exceptional amount of function has been attributed to, negated for, and potentially reaffirmed for these cells, especially regarding their ability to release neuroactive molecules and influence synaptic plasticity. This makes the precise role of astrocytes in tuning neural communication seem difficult to grasp. However, data from animal models of addiction demonstrate that a variety of drug-induced molecular adaptations responsible for relapse vulnerability take place in astrocyte systems that regulate glutamate uptake and release. These findings highlight astrocytes as a critical component of the neural systems responsible for addiction, serving as a key component of the plasticity responsible for relapse and drug seeking. Here I assemble recent findings that utilize genetic tools to selectively manipulate or measure flux of internal calcium in astrocytes, focusing on G protein-coupled receptor-mediated mobilization of calcium and the induction of glutamate release. Further, I compile evidence regarding astrocyte glutamate release as well as astrocyte association with synapses with respect to the impact of these cellular phenomena in shaping synaptic transmission. I also place these findings in the context of the previous studies of Scofield et al., who explored the role of astrocytes in the nucleus accumbens in the neural mechanisms underlying cocaine seeking. PMID- 29258657 TI - Large-Volume Percutaneous Balloon Thromboembolectomy of the Lower-Limb Arteries. PMID- 29258659 TI - MR Imaging-Guided Free-Handed Core-Needle Biopsies in the Breast. PMID- 29258658 TI - Direct US-Guided Drainage Catheter Tract Puncture. PMID- 29258660 TI - Localized Hyperattenuations in the Intraluminal Thrombus May Predict Rupture of Abdominal Aortic Aneurysms. PMID- 29258661 TI - Erratum. PMID- 29258662 TI - "Snuffbox" Distal Radial Access. PMID- 29258663 TI - Ventricular False Aneurysm after Aortic Endograft. PMID- 29258664 TI - Fenestrated and Branched Endovascular Treatment of Recurrent Visceral Aortic Patch Aneurysm after Open Thoracoabdominal Repair. AB - The most common visceral revascularization technique during open repair of thoracoabdominal aortic aneurysms (TAAA) is the "inclusion technique," but its main long-term drawback is that the retained portion of the diseased aorta might be prone to further dilatation, thus giving rise to a recurrent visceral aortic patch aneurysm. This brief report presents 4 consecutive cases of visceral aortic patch aneurysms treated by means of fenestrated and branched endovascular approach with custom-made endografts. The procedures were technically successful in all 4 patients and no major complications were recorded at 11.9 months of follow-up. PMID- 29258665 TI - Initial Experience with Balloon-Occlusion Prostatic Artery Embolization. AB - Twelve patients underwent balloon-occlusion prostatic artery embolization (PAE) at a single center. Bilateral prostatic artery catheterization was achieved in all patients, but unilateral embolization was performed in 1 patient as a result of the presence of a prostatic arteriovenous fistula. Mean International Prostate Symptom Score and quality-of-life score decreased by 15 +/- 7 (P < .01) and 4 +/- 1 (P < .01) points, respectively, over a mean follow-up period of 22 weeks +/- 8. Only self-limiting minor complications were encountered. The initial experience with balloon-occlusion PAE suggests that it is technically feasible and can be performed safely. PMID- 29258666 TI - Transgluteal Prostatic Artery Embolization. PMID- 29258667 TI - Cell-free DNA Analysis in SCLC: Ready for Clinical Practice? PMID- 29258669 TI - Obesity Paradox in Lung Cancer Prognosis: Is MiR-26b the Achilles Heel? PMID- 29258668 TI - Evaluation of RET Gene Rearrangement by Fluorescence In Situ Hybridization in Malignant Mesothelioma. PMID- 29258670 TI - Reply to "Obesity Paradox in Lung Cancer Prognosis: Is MiR-26b the Achilles Heel?" PMID- 29258671 TI - Four-Year Complete Remission in a Patient with Metastatic Epidermal Growth Factor Receptor-Mutated Lung Cancer Treated with Two Cycles of Erlotinib. PMID- 29258672 TI - A Cascade of Pembrolizumab-Induced Autoimmune Toxicities with Mixed Responses to Corticosteroids. PMID- 29258673 TI - Acquired Resistance to Afatinib Due to T790M-Positive Squamous Progression in EGFR-Mutant Adenosquamous Lung Carcinoma. PMID- 29258674 TI - Surgical Outcomes After Neoadjuvant Chemotherapy and Ipilimumab for Non-Small Cell Lung Cancer. AB - BACKGROUND: The objective of this study was to evaluate the safety and feasibility of using neoadjuvant chemotherapy plus ipilimumab followed by surgery as a treatment strategy for stage II-IIIA non-small cell lung cancer. METHODS: From 2013 to 2017, postoperative data from patients who underwent surgery after neoadjuvant chemotherapy plus ipilimumab in the TOP1201 trial, an open label phase II trial (NCT01820754), were prospectively collected. The surgical outcomes from TOP1201 were compared with outcomes in a historical cohort of patients receiving standard preoperative chemotherapy followed by surgery identified from our institution's prospectively collected thoracic surgery database. RESULTS: In the TOP1201 trial, 13 patients were treated with preoperative chemotherapy and ipilimumab followed by surgery. In the historical cohort, 42 patients received preoperative chemotherapy by a platinum doublet regimen preoperative chemotherapy by a platinum doublet regimen without ipilimumab followed by lobectomy or pneumonectomy. The 30-day mortality in both groups was 0%. The most frequently occurring perioperative complications in the TOP1201 group were prolonged air leak (n = 2, 15%) and urinary tract infection (n = 2, 15%). The most common perioperative complication in the preoperative chemotherapy alone group was atrial fibrillation (n = 6, 14%). One patient (8%) had atrial fibrillation in the TOP1201 group. There was no apparent increased occurrence of adverse surgical outcomes for patients in the TOP1201 group compared with patients receiving standard of care neoadjuvant chemotherapy alone before surgery for stage II-IIIA non-small cell lung cancer. CONCLUSIONS: This report is the first to demonstrate the safety and feasibility of surgical resection after treatment with ipilimumab and chemotherapy in stage II-IIIA non-small-cell lung cancer. PMID- 29258675 TI - The Number of Refusals for Donor Organ Quality Does Not Impact Heart Transplant Outcomes in Children. AB - BACKGROUND: Waitlist mortality is more than 12% for pediatric heart transplantation, with strikingly high rates of organ refusal, many of which are due to donor quality. However, some centers use these organs despite refusals by other centers for donor quality. We hypothesize that the number of refusals for donor quality (RDQ) does not affect pediatric heart transplantation outcomes. METHODS: Pediatric heart transplants from 2000 to 2015 were identified using the United Network for Organ Sharing database and were matched against the potential transplant recipients dataset with donor refusal codes. Refusals for donor quality were counted for each organ. The population was divided into two groups: RDQ-low (0 to 3 RDQs, n = 3,404) and RDQ-high (>3 RDQs, n = 1,585). Posttransplant outcomes of both cohorts were analyzed. RESULTS: Of 4,989 pediatric heart transplants, 75% (n = 3,770) had 1 or more RDQ (median 3 RDQ; interquartile range, 1 to 7). The RDQ-lower group (0 to 3 RDQs) and the RDQ higher group (>3 RDQ) had similar posttransplant survival (p = 0.41) and freedom from retransplantation (p = 0.37). Both groups had similar posttransplant survival even for high-risk recipient cohorts: adolescents (p = 0.06), congenital heart disease (p = 0.87), retransplantation (p = 0.47), extracorporeal membrane oxygenation (p = 0.61), mechanical ventilation (p = 0.24), and poor renal function at transplant (p = 0.46). In addition, recipient subgroups who had donors with increasing number of RDQ (>6, >9, >12, and >15 RDQ) also had similar posttransplant survival compared with the RDQ-low group (p = 0.63, p = 0.62, p = 0.92, and p = 0.50, respectively). CONCLUSIONS: The outcome of pediatric heart transplantation is not affected by the number of RDQ, even for high-risk recipients. The use and interpretation of donor quality refusal code should be considered carefully while selecting or refusing donors in this era of supply and demand mismatch. PMID- 29258676 TI - A Tumor Necrosis Factor-alpha and Hypoxia-Induced Secretome Therapy for Myocardial Repair. AB - BACKGROUND: Poor viability and retention of transplanted bone marrow mesenchymal stem cells (BM-MSC) remains an obstacle in promoting healing after myocardial infarction (MI). This study aimed to understand the migratory, angiogenic, and cardioprotective effects induced by tumor necrosis factor (TNF)-alpha and hypoxia through rat BM-MSC (rBM-MSC) paracrine secretions, collectively referred to as secretome, after MI. METHODS: Secretome from rBM-MSC cultures treated with various combinations of H9c2 cardiomyoblast-conditioned medium, TNF-alpha, and hypoxia was initially collected. Immunocytochemistry, Western blot analyses, and transwell cell migration assays were conducted. In vivo, echocardiography was performed on rats with induced MI after their treatment with TNF-alpha and hypoxia-induced secretome. RESULTS: Immunocytochemistry confirmed the presence of TNF receptors 1 and 2 on rBM-MSCs. Western blot analyses of rBM-MSCs treated with TNF-alpha and hypoxia showed an overall increasing trend in the expression of antiinflammatory proteins and angiogenic and migratory cytokines (transforming growth factor-beta, fibroblast growth factor-2, angiopoietin-2, vascular endothelial growth factor-1). In addition, the TNF-alpha and hypoxia-induced secretome significantly increased the in vitro rBM-MSCs migration. In the rat MI model, the rats treated with the TNF-alpha and hypoxia-induced secretome had a significantly higher left ventricular fractional shortening than the control group. CONCLUSIONS: Our data suggest that after MI, rBM-MSCs secrete paracrine factors in response to TNF-alpha and hypoxia that work together to manipulate the microenvironment and decrease inflammation. In addition, these signaling factors trigger angiogenic and migratory effects at the site of the infarct to promote myocardial healing and improve the cardiac function. PMID- 29258677 TI - Sixteen-Year Experience of David and Bentall Procedures in Acute Type A Aortic Dissection. AB - BACKGROUND: To examine short-term and midterm outcomes after the David and Bentall procedures in patients with an acute type A aortic dissection. METHODS: Between 2001 and 2017, patients (n = 135) with acute type A aortic dissection underwent an aortic root replacement with either the David (n = 40) or Bentall (n = 95) procedure. Perioperative outcome, reoperation rate, aortic valve function, and long-term survival were evaluated. RESULTS: The median age of the entire cohort was 56 years. Rates of malperfusion (21%), shock (16%), history of renal failure (4%), and extent of surgery were similar between David and Bentall groups. However, the David group was significantly younger (45 versus 61 years) with less hypertension (45% versus 66%), coronary artery disease (0% versus 17%), valvulopathy (5% versus 19%), and prior cardiac surgery (5% versus 21%). Overall operative mortality was 9.6% (David 3% and Bentall 13%). Composite outcome comprising myocardial infarction, stroke, new-onset renal failure, and operative mortality was 18% in the entire cohort (David 5% and Bentall 23%). In the David group, the freedom of moderate aortic insufficiency was 95% at 10 years. The rate of reoperation for pathology of the proximal aorta or aortic valve was 0% and 2% for the David and Bentall groups, respectively. Ten-year Kaplan-Meier survival was 66% (95% confidence interval: 51% to 77%) for the entire cohort, with 98% (95% confidence interval: 84% to 99%) survival in the David group and 57% (95% confidence interval: 42% to 70%) survival in the Bentall group. CONCLUSIONS: Both the David and Bentall procedures are appropriate surgical approaches for aortic root replacement in select patients with an acute type A aortic dissection. PMID- 29258678 TI - Effects of alternate-day fasting or daily calorie restriction on body composition, fat distribution, and circulating adipokines: Secondary analysis of a randomized controlled trial. AB - BACKGROUND & AIMS: Indirect comparisons suggest that alternate-day fasting (ADF) may produce greater improvements in body composition, fat distribution, and/or the adipokine profile compared to daily calorie restriction (CR), but this has not been tested directly. In a pre-planned secondary analysis of a randomized controlled trial, we compared changes in the VAT:SAT ratio, FFM:total mass ratio, and the adipokine profile between ADF and CR. METHODS: Overweight and obese participants (n = 100) were randomized to 1) ADF (alternating every 24-h between consuming 25% or 125% of energy needs); 2) CR (consuming 75% of needs every day); or 3) control (consuming 100% of needs every day) for 24 wk. RESULTS: The VAT:SAT ratio did not change in any group. The FFM:total mass ratio increased in both ADF (0.03 +/- 0.00) and CR (0.03 +/- 0.01) compared to the control group (P < 0.01), with no differences between the intervention groups. Circulating leptin decreased in both the ADF group (-18 +/- 6%) and CR group (-31 +/- 10%) relative to the control group (P < 0.05), with no differences between the intervention groups. Circulating levels of adiponectin, resistin, IL-6, and TNF-alpha did not change in either intervention group relative to the control group. CONCLUSION: ADF and CR similarly improve the FFM:total mass ratio and reduce leptin after a 24-wk intervention. TRIAL REGISTRATION: Clinicaltrials.gov, number NCT00960505. PMID- 29258680 TI - Conditional Inference Tree for Multiple Gene-Environment Interactions on Myocardial Infarction. AB - BACKGROUND AND AIMS: Identifying gene-environment interaction in the context of multiple environmental factors has been a challenging task. We aimed to use conditional inference tree (CTREE) to strata myocardial infarction (MI) risk synthesizing information from both genetic and environmental factors. METHODS: We conducted a case-control study including 1440 Chinese men (730 MI patients and 710 controls). We first calculated a weighted genetic risk score (GRS) by combining 25 single nucleotide polymorphisms (SNPs) that had been identified to be associated with coronary artery diseases in previous genome wide association studies. We then developed a CTREE model to interpret the gene-environment interaction network in predicting MI. RESULTS: We detected high-order interactions between dyslipidemia, GRS, smoking status, age and diabetes. Of all the variables examined, high density lipoprotein cholesterol (HDL-C) of 1.25 mmlo/L was identified as the key discriminator. The subsequent splits of MI were low density lipoprotein cholesterol (LDL-C) of 4.01 mmol/L and GRS of 20.9. We found that individuals with HDL-C <=1.25 mmol/L, GRS >20.9 and lipoprotein (a) > 0.09 g/L had a higher risk of MI than those who at the lowest risk group (OR: 5.89, 95% CI: 3.99-8.69). This magnitude of MI risk was similar to the combination of HDL-C <=1.25 mmol/L, GRS <=20.9, smoking and lipoprotein (a) > 0.15 g/L (OR: 5.49, 95% CI: 3.51-8.58). CONCLUSIONS: The multiple interactions between genetic and environmental factors can be visually present via the CTREE approach. The tree diagram also simplifies the decision making procedure by answering a sequence of questions along the branches. PMID- 29258681 TI - 67-Year-Old Woman With an Adrenal Mass. PMID- 29258682 TI - 23-Year-Old Man With Jaundice and Elevated Liver Enzymes. PMID- 29258683 TI - 79-Year-Old Woman With Jaundice and Anemia. PMID- 29258679 TI - Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting. AB - CONTEXT: Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). OBJECTIVE: Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. EVIDENCE ACQUISITION: The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. EVIDENCE SYNTHESIS: The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. CONCLUSIONS: This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. PATIENT SUMMARY: Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR-targeting therapies, highlighting the need for novel therapeutic agents currently under development. PMID- 29258684 TI - 61-Year-Old Woman With Episodic Dysphagia and Chest Pain. PMID- 29258685 TI - Impact of microbial resistance on therapeutic decisions in sexually transmitted infections. PMID- 29258686 TI - Bioprofiling of Salvia miltiorrhiza via planar chromatography linked to (bio)assays, high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. AB - An affordable bioanalytical workflow supports the collection of data on active ingredients, required for the understanding of health-related food, superfood and traditional medicines. Targeted effect-directed responses of single compounds in a complex sample highlight this powerful bioanalytical hyphenation of planar chromatography with (bio)assays. Among many reports about biological properties of Salvia miltiorrhiza Bunge root (Danshen) and their analytical methods, the highly efficient direct bioautography (DB) workflow has not been considered so far. There was just one TLC-acetylcholinesterase (AChE) method with a poor zone resolution apart from our two HPTLC-DB studies, however, all methods were focused on the nonpolar extracts of Danshen (tanshinones) only. The current study on HPTLC-UV/Vis/FLD-(bio)assay-HRMS, followed by streamlined scale-up to preparative layer chromatography (PLC)-1H-NMR, aimed at an even more streamlined, yet comprehensive bioanalytical workflow. It comprised effect-directed screening of both, its polar (containing phenolics) and nonpolar extracts (containing tanshinones) on the same HPTLC plate, the biochemical and biological profiling with four different (bio)assays and elucidation of structures of known and unidentified active compounds. The five AChE inhibitors, salvianolic acid B (SAB), lithiospermic acid (LSA) and rosmarinic acid (RA) as well as cryptotanshinone (CT) and 15,16-dihydrotanshinone I (DHTI) were confirmed, but also unidentified inhibitors were observed. In the polar extracts, SAB, LSA and RA exhibited free radical scavenging properties in the 2,2-diphenyl-1 picrylhydrazyl assay. CT, DHTI and some unidentified nonpolar compounds were found active against Gram-positive Bacillus subtilis and Gram-negative Aliivibrio fischeri (LOD 12 ng/band for CT, and 5 ng/band for DHTI). For the first time, the most multipotent unidentified active compound zone in the B. subtilis, A. fischeri and AChE fingerprints of the nonpolar Danshen extract was identified as co-eluted band of 1,2-dihydrotanshinone and methylenetanshinquinone in the ratio of 2:1. PMID- 29258687 TI - Analysis of mortality and fixation failure in geriatric fractures using quantitative computed tomography. AB - OBJECTIVES: While osteoporosis has been shown to be a contributing factor in low energy fractures in the elderly, limited data exists regarding the correlation of bone mineral density (BMD) and T-Scores to mortality and failure of fracture fixation. This study seeks to determine the relationship between femoral neck BMD in elderly patients with typical geriatric fractures and mortality and fracture fixation failure using Quantitative Computed Tomography (QCT). MATERIALS AND METHODS: Patients over the age of 65 who sustained fractures of the proximal humerus, distal radius, pelvic ring, acetabulum, hip, proximal tibia, and ankle who also underwent a CT scan that included an uninjured femoral neck were retrospectively reviewed. QCT was used to assess bone mineral density and T scores. Mortality and fixation failure were recorded. Standard descriptive statistics, as well as logistic regression were used to correlate BMD and mortality, and BMD and fixation failure. RESULTS: Of the 173 patients initially screened, 150 met inclusion criteria. Patients who remained alive at the end of the study (LP) had significantly (P = .019) higher adjusted mean femoral neck BMD (0.502 g/cm2) than non-polytrauma patients who died (MNPT) (0.439 g/cm2) when controlling for age, time to mortality, follow up, CCI, and ASA. Patients who had fixation failure events (FE) had significantly (P = .002) lower adjusted mean femoral neck BMD (0.342 g/cm2) than patients without failure events (NE) (0.525 g/cm2) when controlling for age and time to radiographic follow-up. CONCLUSIONS: Our study illustrates that QCT is a reliable method for the determination of femoral neck BMD in elderly patients with geriatric fractures. Furthermore, lower BMD/T-Scores are associated with increased mortality and fixation failures in this patient population. PMID- 29258688 TI - [Web accessibility of Internet appointment scheduling in primary care]. AB - OBJECTIVE: To assess the accessibility level of Internet appointment scheduling in primary care and the fulfilment of the requirements of Spanish legislation. METHOD: Descriptive study of the accessibility of 18 web sites corresponding to the autonomic health services responsible for Internet appointment scheduling for primary health care services. The level of web accessibility was evaluated by means of five automated tools. RESULTS: Only six websites self-declared to be in compliance with level AA of WCAG 2.0. The level of web accessibility according to the legal requirements in Spain is low. The evaluation tools identified the main errors to be corrected. CONCLUSIONS: Most of the autonomic health services responsible for Internet appointment scheduling in primary care need to improve their level of web accessibility and ensure that it complies with Spanish legislation. PMID- 29258689 TI - Systematic review of guidelines in estimating social costs on drugs. AB - OBJECTIVE: To systematically review guidance documents for the estimation of the social cost of illegal drugs, and to define standards for this estimation. METHOD: A systematic literature search was conducted between April and May 2015 and updated in November 2015. Pubmed, Scopus, and Google Scholar were searched. Studies were included only if they provided indications of analytical methods for calculating the social cost of illegal drugs consumption. RESULTS: A total of 21 papers were selected for a final review. Four main areas of discussion were identified: a) alternative theories for the framework design; b) basic concepts definition; c) theoretical issues in the application of the framework and; d) definition of the cost matrix and its elements. The review exercise enabled the definition of two analytical approaches, which are proposed as references for estimation in the field. CONCLUSIONS: although social cost is a well-established method in the literature, there is a lack of agreement on the most appropriate approaches in the area of estimation of the social cost of illegal drugs consumption. Moreover, the two analytical approaches proposed are aimed at promoting more research focused at sophisticating the methodology in the field. PMID- 29258690 TI - Reliability of temporal bone high-resolution CT in patients with facial paralysis in temporal bone fracture. AB - OBJECTIVE: This study aimed to investigate the reliability of temporal bone high resolution CT (HRCT) in patients with traumatic facial paralysis. METHODS: HRCT with cross-sectional scanning and multi-planar reformation (MPR) was performed on 26 cases with traumatic facial paralysis, and the preoperative imaging manifestations were compared with surgical findings. RESULTS: Preoperative HRCT revealed fallopian canal damage at the posterior genu in 1 case, geniculate ganglion in 22 cases, labyrinthine segment in 4 cases, tympanic segment in 13 cases and mastoid segment in 0 case, while surgical findings confirmed fallopian canal damage at the posterior genu in 7 cases, geniculate ganglion in 23 cases, labyrinthine segment in 4 cases, tympanic segment in 17 cases and mastoid segment in 7 cases. The accuracy of temporal bone HRCT in revealing damage at those segments of fallopian canal was 14.3%, 95.7%, 100%, 76.5, and 0%, respectively. CONCLUSION: Temporal bone HRCT can generally estimate the extent of damage and provide important information for traumatic facial paralysis before surgery. However, it is unreliable in revealing the damage of fallopian canal at the posterior genu and mastoid segment. PMID- 29258691 TI - Flasking technique with alum crystals for fabricating definitive hollow bulb obturators. AB - Different techniques have been described for fabricating obturators for patients with maxillary defects. The hollow bulb obturator has emerged as the treatment of choice in most patients owing to its light weight, cleanliness, and ease of fabrication. This article presents a simplified flasking technique for fabricating a definitive, closed, hollow bulb obturator by using a potassium alum crystal. PMID- 29258692 TI - Fabrication of a nonmetal clasp denture supported by an intraoral scanner and CAD CAM. AB - This clinical report describes the management of a patient who had a metal allergy and had difficulty sitting in a dental chair for an extended period. The presented treatment used an intraoral scanner and computer-aided design and computer-aided manufacturing (CAD-CAM) to fabricate a nonmetal clasp denture. The described procedure may reduce patient discomfort and chair-time. PMID- 29258693 TI - Contemporary management and full mouth rehabilitation of a patient with Sjogren syndrome. AB - Sjogren syndrome is a chronic autoimmune disorder with xerostomia, increased tooth wear, high rates of caries, and repeated failure of dental restorations as the main oral symptoms. These render the prosthetic treatment challenging. This clinical report describes a contemporary approach to the treatment of a patient with Sjogren syndrome using translucent multilayered monolithic zirconia restorations and focuses on the treatment protocols before, during, and after the prosthetic treatment. PMID- 29258694 TI - Systematic intrafraction shifts of mediastinal lymph node targets between setup imaging and radiation treatment delivery in lung cancer patients. AB - BACKGROUND AND PURPOSE: Internal target motion results in geometrical uncertainties in lung cancer radiotherapy. In this study, we determined the intrafraction motion and baseline shifts of mediastinal lymph node (LN) targets between setup imaging and treatment delivery. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received intensity-modulated radiotherapy with a daily setup cone-beam CT (CBCT) scan used for online soft-tissue match on the primary tumor. At a total of 122 fractions, 5 Hz fluoroscopic kV images were acquired orthogonal to the MV treatment beam during treatment delivery. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections and in the intra-treatment kV images. Baseline shifts and changes in the respiratory motion amplitude between CBCT and treatment delivery were determined from the 3D trajectories. RESULTS: Systematic mean LN baseline shifts of 2.2 mm in the cranial direction (standard deviation (SD): 1.8 mm) and 1.0 mm in the posterior direction (SD: 1.2 mm) occurred between CBCT imaging and treatment delivery. The mean motion amplitudes during CBCT and treatment delivery agreed within 0.2 mm in all directions. CONCLUSIONS: Systematic cranial and posterior intrafraction baseline shifts between CBCT and treatment delivery were observed for mediastinal LN targets. Intrafraction motion amplitudes were stable. PMID- 29258695 TI - Nomogram to predict the benefit of additional induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Analysis of a multicenter, phase III randomized trial. AB - BACKGROUND AND PURPOSE: Recent clinical trials and network meta-analysis have suggested that the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) could improve survival in locoregionally advanced NPC (LANPC). We aimed to develop a nomogram to estimate the benefit of IC for individual patients based on the data from a multicenter, randomized, phase III trial (NCT01245959) comparing IC plus CCRT with CCRT alone. PARTICIPANTS AND METHODS: This study analyzed all 480 patients enrolled in the original trial. A nomogram was developed to predict 3-year failure-free survival (FFS) with or without IC. RESULTS: With a median follow-up of 45 months, the 3-year FFS rates were 80.3% and 72.4% in the IC plus CCRT group and CCRT group, respectively (P = 0.034). In multivariate analysis, T category, N category and treatment group were predictive of FFS and were incorporated into the nomogram. Gender was also included due to its clinical importance. This nomogram predicted that the magnitude of benefit from IC could vary significantly. CONCLUSION: We developed a convenient nomogram to estimate the benefit of IC for individual patients with LANPC. This tool can serve as a catalyst of individual treatment discussions and facilitator of informed decision-making. PMID- 29258696 TI - Residual stress of porcelain-fused to zirconia 3-unit fixed dental prostheses measured by nanoindentation. AB - OBJECTIVE: To evaluate the residual stress (nanoindentation based on hardness) of fatigued porcelain-fused to zirconia 3-unit fixed dental prostheses (FDP) with different framework designs. METHODS: Twenty maxillary 3-unit FDP replacing second-premolar (pontic) were fabricated with conventional framework-design (even thickness of 0.5mm and 9mm2 connector area) and modified framework-design (thickness of 0.5mm presenting lingual collar connected to proximal struts and 12mm2 connector area). Connector marginal ridges were loaded and the fractured and suspended FDPs were divided (n=3/each) into: (1) Fractured zirconia even thickness (ZrEvenF); (2) Suspended zirconia even-thickness (ZrEvenS); (3) Fractured zirconia with modified framework (ZrModF); (4) Suspended zirconia with modified framework (ZrModS); (5) Non-fatigued FDP with conventional framework design (Control). The FDPs were nanoindented at 0.03mm (Region of Interest (ROI) 1), 0.35mm (ROI 2) and 1.05mm (ROI 3) distances from porcelain veneer outer surface with peak load 4000MUN. The Linear Mixed Analysis of Variance (ANOVA) Model on ranks and Least Significant Difference Test on ranks (95%) were used. RESULTS: Highest rank hardness values were found for Control group and ZrModS, whereas the lowest values were found in ZrModF. Statistical differences (p=0.000) were found among all groups except for comparison between ZrModS and Control group (p=0.371). Hardness between ROIs were statistically significant different (p<0.001) where ROI 1 presented the lowest values. SIGNIFICANCE: Framework-design modification did not influence the residual stress of porcelain-fused to zirconia fatigued 3-unit FDP. Whereas fractured FDPs showed the highest residual stress compared to suspended and control FDPs. Residual stress increased as nanoindented away from framework. PMID- 29258697 TI - An Interview with Jennifer Dressman. PMID- 29258698 TI - Monitoring and controlling ovarian activity in wild felids. AB - In the past decade, studies on reproductive biology, endocrinology, and assisted reproductive technologies (ARTs) in the domestic cat have contributed to a lot of progress in conservation breeding of wild felids. However, the 36 species of the Felidae family have species- and individual-specific reproductive cycles and respond differently to exogenous hormones. Monitoring the ovarian cycle of wild felids can improve their natural breeding and maximize their reproductive success. Moreover, fundamental knowledge on the hormonal patterns of each feline species offers the opportunity to develop ARTs, particularly in threatened and endangered species. Currently, several ovarian activity control regimens have been established with higher precision for artificial insemination, oocyte aspiration and embryo transfer. In this review, we highlight the efforts made in ovarian control and its outcomes showing promising applications to enhance wild felid conservation. Currently, ovarian monitoring has been studied in two-thirds of the feline species with thorough reports on 16 species only. To increase the genetic diversity of shrinking populations of these wild felids there still is a critical need for better knowledge of feline reproductive biology. Sustained successes will be achieved by controlling several factors influencing pregnancy successes by natural and assisted breeding. PMID- 29258699 TI - Local control for vaginal botryoid rhabdomyosarcoma with pre-rectal transperineal surgical resection and autologous buccal graft vaginal replacement: A novel, minimally invasive, radiation-sparing approach. AB - PURPOSE: Localized vaginal rhabdomyosarcoma (RMS) is associated with a favorable prognosis, but strategies for local control remain controversial. The use of radiotherapy (RT) can have important long-term sequelae, while traditional resection involves major reconstructive surgery. We describe a new surgical approach employing a minimally-invasive resection and immediate reconstruction. MATERIALS AND METHODS: Records from 4 consecutive patients with localized vaginal RMS managed in 4 major pediatric referral centers were reviewed. All cases were performed with a standardized technique. RESULTS: Patients were diagnosed at a median age of 24months. Each underwent a total/subtotal vaginectomy with autologous buccal graft vaginal replacement. Final margins were focally positive in one patient and negative in three. None received radiotherapy. To date, all patients have patent buccal neovaginas, enjoy a favorable aesthetic result, and remain disease-free at a median follow-up of 35months. CONCLUSIONS: We report 4 cases of localized vaginal RMS successfully treated with a minimally invasive surgical approach. All patients have avoided radiation and remain disease-free. Our initial data suggest that surgical local control and immediate reconstruction are feasible and can spare these patients the long-term complications of RT. Longer follow-up is critical to ensure disease-free survival with a functional, successfully reconstructed neovagina. TYPE OF STUDY: Case series. LEVEL OF EVIDENCE: Level IV. PMID- 29258700 TI - Functional respiratory assessment before lung volume reduction in patients with emphysema. PMID- 29258701 TI - Response to Omalizumab in a Patient With Chronic Eosinophilic Pneumonia and Poor Response to Corticosteroids. PMID- 29258702 TI - Chlorine Inhalation Challenge in Humans: Development of a New Closed-Circuit Methodology. PMID- 29258703 TI - Gynaecological pathology: problematic areas, new concepts and emerging developments. PMID- 29258704 TI - Acute infection due to Mycobacterium marinum in a patient with ulcerative colitis and metabolic syndrome on infliximab therapy. PMID- 29258705 TI - Invasive pneumococcal disease in children under 16 years of age: Incomplete rebound in incidence after the maximum effect of PCV13 in 2012/13 in Germany. AB - OBJECTIVE: To identify a potential nadir of the impact of pneumococcal conjugate vaccination (PCV) in infancy on invasive pneumococcal diseases (IPD) in children under 16 in Germany. METHODS: Active surveillance on IPD based on two independent data sources with capture-recapture correction for underreporting. Annual incidence rates by age group, serotypes, site of infection, and relative incidence reduction compared to pre-vaccination period (1997-2001) at nadir and for the most recent season are reported. We calculated vaccine coverage at the age of 24 months using health insurance claims data. RESULTS: 96-97% of children had received at least two doses of PCV since 2009. The maximum impact on overall IPD incidence was achieved in 2012/13 (-48% [95% CI: -55%; -39%]) with a rebound to -26% [95% CI: -36%; -16%] in 2015/16. Non-PCV13 serotypes accounted for 84.1% of the IPD cases in 2015/16. The most frequent non-PCV serotypes in IPD in 2014/15 and 2015/16 were 10A, 24F, 15C, 12F, 38, 22F, 23B, and 15B. The impact at nadir was highest in children 0-1 years of age both in meningitis and non meningitis cases, whereas the impact for other age groups was higher for meningitis cases. The rebound mainly pertained to non-meningitis cases. CONCLUSION: The maximum impact of pneumococcal conjugate vaccination has been attained and signs of a rebound are apparent. Sustained surveillance for IPD in children is warranted to assess whether these trends will continue. There may be a need for vaccines using antigens common to all serotypes. PMID- 29258706 TI - Balloon Angioplasty Versus Stenting for the Treatment of Failing Arteriovenous Grafts: A Meta-Analysis. AB - PURPOSE: To assess the outcomes of plain balloon angioplasty versus stenting for the treatment of failed or malfunctioning chronic haemodialysis arteriovenous grafts (AVGs). METHODS: A systematic search of the literature was undertaken using the PUBMED, EMBASE, and Cochrane databases from January 2000 to September 2016 for articles comparing balloon angioplasty versus stenting in the management of failed or malfunctioning chronic haemodialysis AVGs. Results are reported as OR and 95% CI. RESULTS: The search identified eight studies (1051 patients). Balloon angioplasty alone was used in 521 patients (49.6%) and stenting in 530 patients (50.4%). At the time of the endovascular re-intervention, the mean life of AVGs was 807.7+/-115.4 days for the balloon angioplasty and 714.2+/-96.3 days for the stenting group (p=.92). All AVGs were located in the arm. Most procedures (98.1%) were performed across the venous anastomosis, while 88% of the patients in the stenting group received a stent graft. The technical success rate was significantly higher in the stenting group (OR 0.16, 95% CI 0.08-0.31, p<.001). At 12 months, loss of primary and secondary patency was significantly higher in patients undergoing plain balloon angioplasty compared with stenting (OR 3.54, 95% CI 2.18-5.74, p<.001, and OR 1.82, 95% 1.17-2.82, p=.008, respectively). CONCLUSION: Stenting is associated with better technical success and patency rates compared with plain angioplasty in treating failed or malfunctioning chronic haemodialysis AVGs, and thus it should be considered as the first line therapeutic option. PMID- 29258707 TI - Underdiagnosis of Chlamydia trachomatis and Chlamydia psittaci revealed by introduction of respiratory multiplex PCR assay with Chlamydiaceae family primers. AB - We describe unanticipated detection of respiratory infection with Chlamydia trachomatis and Chlamydia psittaci after introduction of respiratory multiplex polymerase chain reaction assay that includes Chlamydiaceae family primers. We detected cases of pediatric C. trachomatis and of adult C. psittaci infection in patients with previously unrecognized risk factors. Directed testing for C. trachomatis and C. psittaci based on clinical features and risk factors alone is likely to miss the majority of infected cases. PMID- 29258708 TI - A simple flow cytometry protocol to determine simultaneously live, dead and apoptotic stallion spermatozoa in fresh and frozen thawed samples. AB - Spermatozoa undergo apoptotic changes during the cryopreservation process. These changes, recently termed spermptosis, resemble the cryopreservation induced delayed onset of cell death observed after thawing of somatic cells. Due to its importance in cryobiology, methods to easily identify spermptotic cells are warranted. In this study, a well-validated method for identification of spermatozoa with caspase 3 activity was compared with use of the combination of Hoechst 33342 (H-42) and ethidium homodimer (Eth-1). Live, dead and apoptotic spermatozoa assessed with each method were compared using descriptive statistics and method agreement analysis. No differences were observed in the percentages of spermatozoa in each of the categories investigated with each method. Moreover the method agreement analysis indicated there were consistent findings using both methods The combination H-42/Eth-1 can be successfully used to determine apoptosis in addition to dead and live spermatozoa. Moreover the intensity of H 42 fluorescence (bright and dim populations) allows for distinguishing of live and dead sperm cells. PMID- 29258709 TI - Partial deoxygenation of extender improves sperm quality, reduces lipid peroxidation and reactive oxygen species during cryopreservation of buffalo (Bubalus bubalis) semen. AB - The present study was designed to investigate the effect of partial deoxygenation of extender on sperm quality, lipid peroxidation (LPO) and reactive oxygen species (ROS) in buffalo (Bubalus bubalis) during cryopreservation of semen. Semen extender was prepared freshly and split into three sub-extenders [Extender I: control (non-deoxygenated), Extender II (partially deoxygenated by using LN2 flushing) and Extender III (partially deoxygenated mechanically by vacuum pump)]. Amounts of dissolved oxygen (DO) were determined in all the three extenders and also in post-thaw semen. Ejaculates with mass motility of >=3+ and individual progressive motility of 70% or greater were collected from Murrah buffalo bulls and utilized in the study. Each semen sample was divided into Groups I (diluted with Extender I), II (diluted with Extender II) and III (diluted Extender III) with a maximum of 60 * 106 sperm/mL. French mini straws (0.25 mL) were filled with the extended semen samples, sealed with polyvinyl alcohol powder, kept for 3 h at 5 degrees C for equilibration and then stored in an automatic programmable freezer until the temperature of straws reached -145 degrees C followed by plunging the straws into liquid nitrogen (-196 degrees C). Semen samples were evaluated at pre-freeze and post-thaw stages for various variables [sperm motility, live sperm count, acrosomal integrity, hypo-osmotic swelling (HOS) response, LPO and ROS concentrations]. The mean DO was less (P < 0.05) in Extender II as compared to I and III. The DO was less (P < 0.05) in Group II (semen extended with Extender II) as compared with III (semen extended with Extender III) and I (semen extended with Extender I). The percentages for sperm motility, viability and intact acrosomes (PIA) were greater (P < 0.05) in Groups II and III as compared to the control group at the pre-freeze stage, while at the post-thaw stage, percentages of sperm motility, viability, PIA and HOS response were greater (P < 0.05) in Group II as compared with the control group and Group III. Pre-freeze HOS response (%) was greater (P < 0.05) in Group II as compared with the control and Group III. At the pre-freeze stage, sperm LPO and ROS were less (P < 0.05) in Groups II and III as compared with the control and at post thaw stage, spermatic LPO and ROS concentrations were less (P < 0.05) in Group II than in the control group and Group III. In conclusion, partial deoxygenation of extender improves sperm quality, reduces sperm LPO and ROS concentrations in buffalo during cryopreservation. Partial deoxygenation of the extender with LN2 flushing may be one of the ways for improving quality and fertility of frozen thawed buffalo sperm. PMID- 29258710 TI - Consolidated bioprocessing for sodium gluconate production from cellulose using Penicillium oxalicum. AB - The feasibility of consolidated bioprocessing for sodium gluconate production from cellulose was studied. A recombinant strain named z19 was constructed from Penicillium oxalicum wild-type strain 114-2 for simultaneous expression of glucose oxidase and catalase from Aspergillus niger. While keeping a cellulolytic ability similar with that of 114-2, z19 secreted certain amounts of glucose oxidase and catalase. Fed-batch and two-stage temperature control strategy (0-120 h, 30 degrees C; 120-192 h, 45 degrees C) was utilized for sodium gluconate production from cellulose (filter paper power), with 13.54 g/L of sodium gluconate obtained at the end of the fermentation. The results provide an alternative route for producing sodium gluconate from cellulose in a one-pot reaction. PMID- 29258711 TI - Mechanisms of aortic stenosis. AB - The pathobiology of degenerative aortic valve stenosis (AS) is complex and involves multiple features such as fibrosis, inflammation, oxidative stress, angiogenesis, hemorrhage, and osteogenic differentiation. We summarize the mechanism of valve calcification and angiogenesis which is necessary for calcifying processes. A promising therapeutic target is nuclear factor (NF) kappaB which activates bone morphogenetic protein (BMP)2 via interleukin-6. BMP2 activates Wnt signaling via msh homeobox 2 causing osteogenic differentiation. BMP2 also activates Runx2/Cbfa1 which is an osteoblast-specific transcription factor. Signals in the hypoxia-inducible factor-2 axis activated by the NF-kappaB signaling pathway also play important role in calcifying processes including angiogenesis. The reason why angiogenesis takes place in avascular valves is still unknown, but it is likely angiogenesis and angiogenesis-related hemorrhage play critical roles in the progression of AS. PMID- 29258712 TI - Discovery of orally efficacious RORgammat inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives. AB - A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor related orphan receptor-gamma t (RORgammat) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay. PMID- 29258713 TI - 1,5-Disubstituted 1,2,3-triazole linked disaccharides: Metal-free syntheses and screening of a new class of ribonuclease A inhibitors. AB - 1,5-Regioisomeric triazole linked disaccharides have been synthesized and screened for their inhibitory properties against ribonuclease A (RNase A). The angular constraint-driven 'crescent shaped' inhibitors accommodated themselves into the enzyme active site. An improved enzyme inhibition was observed with increased H-bonding ability of polar functional groups in the modified disaccharides. In this series, introduction of two carboxyl groups in the furanose rings elicited the best result with an inhibition constant of 50 +/- 3 uM. This is the first ever report on the use of disaccharides as RNase A inhibitors. PMID- 29258714 TI - Bacterial Flagellins: Does Size Matter? AB - The bacterial flagellum is the principal organelle of motility in bacteria. Here, we address the question of size when applied to the chief flagellar protein flagellin and the flagellar filament. Surprisingly, nature furnishes multiple examples of 'giant flagellins' greater than a thousand amino acids in length, with large surface-exposed hypervariable domains. We review the contexts in which these giant flagellins occur, speculate as to their functions, and highlight the potential for biotechnology to build on what nature provides. PMID- 29258715 TI - Neonatal Diabetes: Nurse Navigator Role. PMID- 29258716 TI - FreeStyle Libre and Dexcom G4 Platinum sensors: Accuracy comparisons during two weeks of home use and use during experimentally induced glucose excursions. AB - BACKGROUND AND AIMS: This study compared the accuracy of the FreeStyle Libre (Abbott, Alameda, CA) and Dexcom G4 Platinum (DG4P, Dexcom, San Diego, CA) CGM sensors. METHODS AND RESULTS: Twenty-two adults with type 1 diabetes wore the two sensors simultaneously for 2 weeks. Libre was used according to manufacturer specified lifetime (MSL); DG4P was used 7 days beyond MSL. At a clinical research center (CRC), subjects were randomized to receive the same breakfast with standard insulin bolus (standard) or a delayed and increased (delayed & increased) bolus to induce large glucose swings during weeks 1 and 2; venous glucose was checked every 5-15 min for 6 h. Subjects performed >=4 reference fingersticks/day at home. Accuracy was assessed by differences in mean absolute relative difference (%MARD) in glucose levels compared with fingerstick test (home use) and YSI reference (CRC). During home-stay the Libre MARD was 13.7 +/- 3.6% and the DG4P MARD 12.9 +/- 2.5% (difference not significant [NS]). With both systems MARD increased during hypoglycaemia and decreased during hyperglycaemia, without significant difference between sensors. In the euglycaemic range MARD was smaller with DG4P [12.0 +/- 2.4% vs 14.0 +/- 3.6%, p = 0.026]. MARD increased in both sensors following delayed & increased vs. standard bolus (Libre: 14.9 +/- 5.5% vs. 10.9 +/- 4.1%, p = 0.008; DG4P: 18.1 +/- 8.1% vs. 13.1 +/- 4.6%, p = 0.026); between-sensor differences were not significant (p = 0.062). Libre was more accurate during moderate and rapid glucose changes. CONCLUSIONS: DG4P and Libre performed similarly up to 7 days beyond DG4P MSL. Both sensors performed less well during hypoglycaemia but Libre was more accurate during glucose swings. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov (NCT02734745) April 12, 2016. PMID- 29258718 TI - Different MRI-defined tuber types in tuberous sclerosis complex: Quantitative evaluation and association with disease manifestations. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disorder with multisystem involvement. A magnetic-resonance (MRI) based classification of tubers into types A, B and C has been proposed. However, the relationship between different tuber types and their quantitative characteristics, also the non neurological manifestations of TSC remains unknown. AIMS: To quantitatively evaluate different MRI-defined tuber types and to explore their relationships with major disease manifestations in patients with tuberous sclerosis complex. METHODS: We performed quantitative manual assessment of tubers visible on T1W, T2W/FLAIR images and DW/ADC maps of 20 patients with TSC. Tubers were classified into types A, B and C based on their signal intensity on MRI. General clinical information and quantitative tuber characteristics were evaluated. Between-group comparisons were made using the nonparametric Mann-Whitney U test with Bonferroni correction. RESULTS: In total, 20 patients with 770 tubers were evaluated. Type A tubers were most numerous followed closely by Type B tubers, whereas Type C tubers were relatively rare. Tuber size was markedly different among the three tuber types: it increased from Type A to Type B to Type C. Infantile spasms, generalized-tonic clonic seizures, poor seizure control, cardiac rhabdomyomas, SEGA and developmental delay were not associated with quantitative tuber characteristics. Increased total Type B tuber load was associated with early onset epilepsy, while individually larger Type A and Type B tubers were associated with the presence angiomyolipoma (AML) and renal cysts. CONCLUSIONS: MRI-defined tuber types differ significantly in their size and number. Larger total Type B tuber load and larger individual Type A and Type B tubers were found to be most associated with early seizure onset and renal angiomyolipomas, respectively. One possible explanation for the observed differences in the clinical phenotype based on MRI-defined tuber types is not the intrinsic qualitative distinctions between different tuber types, but rather their individual size and total tuber load. PMID- 29258717 TI - Tolerogenic Ag-PLG nanoparticles induce tregs to suppress activated diabetogenic CD4 and CD8 T cells. AB - Type 1 diabetes (T1D) is mediated by destruction of pancreatic beta cells by autoantigen-specific CD4+ and CD8+ T cells, thus the ideal solution for T1D is the restoration of immune tolerance to beta cell antigens. We demonstrate the ability of carboxylated 500 nm biodegradable poly(lactide-co-glycolide) (PLG) nanoparticles PLG nanoparticles (either surface coupled with or encapsulating the cognate diabetogenic peptides) to rapidly and efficiently restore tolerance in NOD.SCID recipients of both activated diabetogenic CD4+ BDC2.5 chromagranin A specific and CD8+ NY8.3 islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP)-specific TCR transgenic T cells in an antigen-specific manner. Further, initiation and maintenance of Ag-PLG tolerance operates via several overlapping, but independent, pathways including regulation via negative co-stimulatory molecules (CTLA-4 and PD-1) and the systemic induction of peptide specific Tregs which were critical for long-term maintenance of tolerance by controlling both trafficking of effector T cells to, and their release of pro inflammatory cytokines within the pancreas, concomitant with selective retention of effector cells in the spleens of recipient mice. PMID- 29258719 TI - The role of liver resection in the management of intermediate and advanced stage hepatocellular carcinoma. A systematic review. AB - BACKGROUND: The ideal management for patients with intermediate and advanced stage hepatocellular carcinoma (HCC) is controversial. The main purpose of this systematic review is to examine the role of liver resection in patients with intermediate stage HCC (multinodular HCCs) and in advanced stage HCC [mainly patients with portal vein tumor thrombosis (PVTT)]. METHODS: A systematic search of the literature was performed in Pud Med and the Cochrane Library from 01.01.2000 to 30.06.2016. RESULTS: Twenty-three articles with 2412 patients with multinodular HCCs were selected. Also, 29 studies with 3659 patients with HCCs with macrovascular invasion were selected. In patients with multinodular HCCs the median post-operative morbidity was 25% and the 90-day mortality was 2.7%. The median survival was 37 months and the 5-year survival 35%. The 5-year survival was much better for patients with a number of HCCs <=3 vs. HCCs >3 (49% vs. 23%). In patients with macrovascular invasion, who underwent hepatic resection, the median post-operative morbidity was 33% and the in-hospital mortality 2.7%. The median survival was 15 months. The 3 and 5year survival was 33% and 20% respectively. Moreover a significant difference in survival was noted according to PVTT stage: 5- year survival for distal PVTT, PVTT of the main intrahepatic PV branch and PVTT extending to the main PV was 45%, 19% and 14.5% respectively. CONCLUSIONS: Liver resection in patients with multinodular HCCs and HCCs with PVTT offers satisfactory long-term survival and should be considered in selected patients. PMID- 29258720 TI - Safety of intraperitoneal Mitomycin C versus intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis of colorectal cancer undergoing cytoreductive surgery and HIPEC. AB - BACKGROUND: Colorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival. METHODS: In this retrospective cohort study patients with colorectal PC who underwent CRS-HIPEC between January 2010 and December 2016 were included. Until March 2014 patients had preferentially been treated with MMC and thereafter with oxaliplatin in an iso-osmotic glucose/electrolyte dialysis (Dianeal(r)) carrier solution. Main outcomes were postoperative complications, disease free survival (DFS) and overall survival (OS). Survival analyses and multivariable analyses were performed. RESULTS: One hundred four patients received MMC and 73 patients oxaliplatin. Postoperative complications did not differ between groups (44.2% (MMC) versus 43.8% (oxaliplatin); P = 0.958). Median DFS was 12.5 months (IQR 6.4-32.4) in the MMC group and 13.1 months (IQR 6.1-NA) in the oxaliplatin-group (P = 0.669). Median OS was 37.2 months (IQR 17.2-NA) in the MMC-group and 29.4 months (IQR 17.0-NA) in the oxaliplatin-group (P = 0.764). The type of chemotherapeutic agent did not influence OS in multivariable analysis (oxaliplatin versus MMC HR 1.09 (95%CI 0.58-2.06)). The HIPEC-phase was shorter for oxaliplatin (median 32 (IQR 31-34) versus 91 min (IQR 90-92) for MMC (P < 0.001)). CONCLUSION: Intraperitoneal oxaliplatin reduced the chemoperfusion time when compared to intraperitoneal MMC without adversely influencing complication rates or short-term survival. It may therefore be the preferential drug in CRS-HIPEC procedures for colorectal PC. PMID- 29258721 TI - Assessing the use of the anatomical method for the estimation of sub-adult stature in Black South Africans. AB - Stature estimation is rarely attempted in sub-adults due to the general lack of available standards as a result of the dearth of sufficiently large sub-adult skeletal collections with known demographic information. To overcome this problem sub-adult research mainly relies on modern imaging modalities. In the current study Magnetic Resonance Imaging (MRI) scans were used to assess the use of the anatomical method for stature estimation in sub-adults. A total of 53 Black South African sub-adult males (n=24) and females (n=29) aged between 10 and 17 years participated in the study by voluntarily completing a full-body MRI scan. A stadiometer was used to measure living stature prior to all MRI scans. Skeletal elements that contribute directly to stature were measured from the MRI scans using OsiriX and summed to compute the total skeletal height. Total skeletal height was calculated using the diaphyseal, maximum and physiological long bone lengths and correlated to living stature using Pearson's correlations. Subsequently least squares regression equations were generated for the estimation of sub-adult stature. Results indicated strong, statistically significant positive correlations between living stature and total skeletal heights in sub adult males, females and a combined sex sample. The regression equations were characterized by small standard error of estimates which are comparable to that reported for Black South African adults. Based on these results the anatomical method can be used to accurately describe living stature in Black South African sub-adults. This method is therefore encouraged as it will add valuable information when dealing with unknown sub-adult skeletal remains. PMID- 29258722 TI - Response. PMID- 29258723 TI - Response. PMID- 29258724 TI - Does oral radiocontrast affect image quality of abdominal sonography? AB - OBJECTIVE: Emergency Department patients with abdominal pain may require both an ultrasound (US) and computed tomography (CT) for an accurate diagnosis. Patients are often asked to drink oral radiocontrast while awaiting ultrasound, in order to better expedite a CT in the case of a non-diagnostic US. The impact of oral radiocontrast on US image quality has not been studied. We compared the quality of US images obtained before and after the ingestion of oral radiocontrast in healthy adult volunteers. METHODS: This was a prospective study in which adult volunteer subjects underwent sonographic studies of the aorta, the right upper quadrant, the right lower quadrant, and the Focused Assessment with Sonography in Trauma (FAST) examination. Initial studies were performed prior to ingestion of oral radiocontrast, with subsequent imaging occurring at 1 and 2hour post ingestion. All of the images from the sonographic exams were randomized and subsequently scored for quality by two emergency ultrasound fellowship trained emergency physicians with extensive experience in performing and interpreting US. RESULTS: 638 images from 240 exams were obtained from 20 subjects at three time points. Six exams were not scored due to inadequate images. There were no significant differences in image quality for any of the US exam types after the ingestion of oral radiocontrast at 1 and 2h. CONCLUSION: Ingestion of oral radiocontrast did not affect image quality of four common abdominal ultrasound examinations. PMID- 29258725 TI - Organization and Function of Non-dynamic Biomolecular Condensates. AB - Cells compartmentalize biochemical reactions using organelles. Organelles can be either membrane-bound compartments or supramolecular assemblies of protein and ribonucleic acid known as 'biomolecular condensates'. Biomolecular condensates, such as nucleoli and germ granules, have been described as liquid like, as they have the ability to fuse, flow, and undergo fission. Recent experiments have revealed that some liquid-like condensates can mature over time to form stable gels. In other cases, biomolecular condensates solidify into amyloid-like fibers. Here we discuss the assembly, organization, and physiological roles of these more stable condensates in cells, focusing on Balbiani bodies, centrosomes, nuclear pores, and amyloid bodies. We discuss how the material properties of these condensates can be explained by the principles of liquid-liquid phase separation and maturation. PMID- 29258726 TI - A systematic review of outcome measures utilised to assess self-management in clinical trials in patients with chronic pain. AB - OBJECTIVES: The aim of this review was to identify, appraise and synthesise the outcome measures used to assess self-management in patients with chronic pain. METHODS: Medline, Embase, CINAHL, PsycINFO, the Cochrane Library and Google Scholar were searched to identify quantitative measures used within randomised or non-randomised clinical trials to assess self-management in adults (>=18 years) with chronic pain. RESULTS: 25 RCTs published between 1998 and 2016 were included in this review. Studies included patients with chronic pain, hip/knee osteoarthritis, rheumatoid arthritis, chronic low back pain, fibromyalgia and chronic fatigue syndrome. Included studies utilised 14 different measures assessing a variety of constructs including self-efficacy (n = 19), coping (n = 4), empowerment (n = 2), pain attitude and management (n = 3), self-care (n = 1), role behaviour (n = 1) and multiple constructs of self-management (n = 1). The Chronic Pain Coping Inventory (CPCI) and Health Education Impact Questionnaire (heiQ) cover different self-management related constructs across the physical, mental and social health domains. CONCLUSION: The review identified 14 measures used as proxy measure to assess self-management in patients with chronic pain. These measures have good content and construct validity, and internal consistency. However additional research is required to develop their reliability, responsiveness and interpretability. PRACTICE IMPLICATIONS: Multi constructs measures (CPCI, heiQ) are suitable for assessing self-management. PMID- 29258727 TI - The role of preliminary hospitals in the management of a mass burn casualty disaster. AB - PURPOSE: The Formosa Fun Coast explosion is an internationally-known event that occurred in Taiwan on June 27th, 2015. The blast involved 495 casualties in total, with 253 patients receiving 2nd degree or deeper burns on greater than 40% of the total body surface area (TBSA). Questions were raised regarding whether these victims were sent to the appropriate hospitals or not. Therefore, we analyzed the effect of the initial admission destination in this study. MATERIAL AND METHODS: We retrospectively reviewed all of the victims from the explosion who were sent to the emergency department of Linkou and Keelung Chang Gung Memorial Hospitals. Patients were divided by direct admission and received via transfer. The basic demographics, the efficacy of the initial resuscitation and the clinical outcomes were analyzed. RESULTS: In total, forty-six patients were included. Thirty-five of them were primarily admitted, and eleven of them were received via transfer. Between the two groups, there was no significant difference in the resuscitation outcome. The ratio of delaying intubation was similar (14.3% vs 27.3%, p=0.322). The rate of delayed-detected ischemic events was significantly increased in the referral group (0% vs 27.3%, p=0.001). However, there was no amputation event in either group. No difference in mortality was observed between groups (5.7% vs 9.1%, p=0.692). CONCLUSION: Our preliminary findings suggest that local hospitals are capable of providing high quality acute care to mass casualty burn victims. Our results suggest that patients with suspected limb ischemia should be rapidly transferred to a regional burn center to ensure optimal care. Systemic pre-planning such as employing telemedicine and personnel collaboration, should be considered by the administration to maximize the function of preliminary hospitals in burn care. PMID- 29258728 TI - Presenting hypertension, burn injury, and mortality in combat casualties: Methodological issues. PMID- 29258729 TI - Adaptation of the Pittsburgh Sleep Quality Index in Chinese adults with type 2 diabetes. AB - BACKGROUND: Sleep disturbance is a major health issue in people with type 2 diabetes (T2DM). The Pittsburgh Sleep Quality Index (PSQI) has been the most widely used instrument to measure subjective sleep disturbance. Nevertheless, its factor structure in the context of T2DM has not been examined. The purpose of the study is to evaluate the factor structure of the PSQI in Chinese adults with T2DM and thereby to facilitate its use in clinical practice and research. METHODS: The PSQI (Chinese version) was administered to 240 patients with T2DM. Confirmatory factor analysis was conducted to examine the one-factor, adapted one-factor by removing the component "use of sleep medication", and the three-factor structure of the PSQI. Goodness-of-fit indices were used to evaluate the fit of the model. Construct validity of the resultant model was further examined using contrasted groups. Cronbach's alpha of the resultant model was obtained to evaluate its internal consistency. RESULTS: The three-factor model proposed by Cole et al. did not fit the sleep data. Confirmatory factor analysis supported the adapted one factor model with the PSQI global score as an indicator of overall sleep quality, and the goodness-of-fit indices for the adapted model were better compared to the original one-factor model. As expected, women, older adults, and patients with poor glycemic control had higher adapted PSQI global score (p < 0.01). Cronbach's alpha of the adapted PSQI was 0.78. CONCLUSION: The adapted PSQI was similar to the original PSQI in that only the component "use of sleep medication" was removed from the original scale and the one-factor scoring worked better. In contrast, the three-factor model has limited usefulness in this population. PMID- 29258730 TI - Differences in metabolite profiles caused by pre-analytical blood processing procedures. AB - Recently, the use of metabolomic analysis of human serum and plasma for biomarker discovery and disease diagnosis in clinical studies has been increasing. The feasibility of using a metabolite biomarker for disease diagnosis is strongly dependent on the metabolite's stability during pre-analytical blood processing procedures, such as serum or plasma sampling and sample storage prior to centrifugation. However, the influence of blood processing procedures on the stability of metabolites has not been fully characterized. In the present study, we compared the levels of metabolites in matched human serum and plasma samples using gas chromatography coupled with mass spectrometry and liquid chromatography coupled with mass spectrometry. In addition, we evaluated the changes in plasma metabolite levels induced by storage at room temperature or at a cold temperature prior to centrifugation. As a result, it was found that 76 metabolites exhibited significant differences between their serum and plasma levels. Furthermore, the pre-centrifugation storage conditions significantly affected the plasma levels of 45 metabolites. These results highlight the importance of blood processing procedures during metabolome analysis, which should be considered during biomarker discovery and the subsequent use of biomarkers for disease diagnosis. PMID- 29258731 TI - Characteristics and Visual Outcome of Refractory Retinal Vasculitis Associated With Antineutrophil Cytoplasm Antibody-Associated Vasculitides. AB - PURPOSE: To describe the clinical characteristics, therapies, visual outcomes, and prognoses of patients with retinal vasculitis associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). DESIGN: Retrospective case series. METHODS: Patients diagnosed with retinal vasculitis associated with AAV and at least 6 months of follow-up were included. Demographic data, systemic and ocular features, best-corrected visual acuity at the initial visit and latest visit, fluorescein angiography (FA) and indocyanine green angiography (ICGA) findings, therapy regimen, and outcome were collected from the Massachusetts Eye Research and Surgery Institution (MERSI) database from 2006 to 2017. RESULTS: Fourteen patients (22 eyes) were identified. Twelve had granulomatosis with polyangiitis (GPA) and 1 each had microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). FA showed that AAV affected small-to medium-size retinal vessels. Seven cases (50%) had both vein/venule and artery/arteriole involvement. Four cases co-presented with choroidal vasculitis. All of them failed various immunomodulatory therapies prior to referral to MERSI. Six patients received rituximab plus prednisone as their final therapy and 5 of them achieved remission. Four patients who failed cyclophosphamide previously were induced into remission by rituximab. Patients were followed for 33.4 +/- 25.5 (range 6-84) months. Nine of 14 patients (64.3%) achieved remission at their latest visit. Seventeen of 22 eyes (77.3%) met the criteria for a good (>=20/40) visual outcome. CONCLUSION: The majority of patients enjoyed a good visual outcome and achieved remission after aggressive treatment. Rituximab should be considered as an initial treatment for patients with refractory retinal vasculitis associated with AAV. PMID- 29258732 TI - Using a Regent Aortic Valve in a Small Annulus Mitral Position Is a Viable Option. AB - BACKGROUND: Outcome of mitral valve replacement in extreme scenarios of small mitral annulus with the use of the Regent mechanical aortic valve is not well documented. METHODS: Records were examined in 31 consecutive patients who underwent mitral valve replacement with the use of the aortic Regent valve because of a small mitral annulus. RESULTS: Mean age was 60 +/- 14 years. Mitral stenosis or mitral annulus calcification was present in 30 of 31 patients (97%). Concurrent procedures were performed in 17 of 31 patients (55%). Median valve size was 23 mm. Mean mitral gradient coming out of the operating room was 4.2 +/- 1.5 mm Hg and at follow-up echocardiogram performed at a median of 32 months after the procedure was 5.8 +/- 2.4 mm Hg. CONCLUSIONS: A Regent aortic mechanical valve can be a viable option with a larger orifice area than the regular mechanical mitral valve in a problematic situation of a small mitral valve annulus. Moreover, the pressure gradients over the valve are acceptable intraoperatively and over time. PMID- 29258733 TI - Percutaneous Radiofrequency Ablation of Obstructive Right Ventricular Giant Myxoma. AB - Surgical resection is the conventional therapeutic action for patients with an obstructive cardiac tumor. However, for patients in poor clinical condition, cardiac operation can be risky. We report on the successful percutaneous radiofrequency (RF) ablation treatment of a right ventricular giant myxoma in a 70-year-old woman with right ventricular outflow tract (RVOT) and pulmonary artery stenosis, who was unable to tolerate operation. The treatment was effective in relieving RVOT stenosis and improving symptoms. We believe the RF ablation may also be used as a supplementary technique for the treatment of obstructive cardiac tumors, when only partial resection is possible. PMID- 29258734 TI - Interventions to enhance effective communication during over-the-counter consultations in the community pharmacy setting: A systematic review. AB - BACKGROUND: Easy access to effective over-the-counter (OTC) treatments allows self-management of some conditions, however inappropriate or incorrect supply or use of OTC medicines can cause harm. Pharmacy personnel should support consumers in their health-seeking behaviour by utilising effective communication skills underpinned by clinical knowledge. OBJECTIVE: To identify interventions targeted towards improving communication between consumers and pharmacy personnel during OTC consultations in the community pharmacy setting. METHODS: Systematic review and narrative analysis. Databases searched were MEDLINE, EMBASE, Psycinfo, Cochrane Central Register and Cochrane Database of Systematic Reviews for literature published between 2000 and 30 October 2014, as well as reference lists of included articles. The search was re-run on 18 January 2016 and 25 September 2017 to maximise the currency. Two reviewers independently screened retrieved articles for inclusion, assessed study quality and extracted data. Full publications of intervention studies were included. Participants were community pharmacy personnel and/or consumers involved in OTC consultations. Interventions which aimed to improve communication during OTC consultations in the community pharmacy setting were included if they involved a direct measurable communication outcome. Studies reporting attitudes and measures not quantifiable were excluded. The protocol was published on Prospero Database of Systematic Reviews. RESULTS: Of 4978 records identified, 11 studies met inclusion criteria. Interventions evaluated were: face-to-face training sessions (n = 10); role-plays (n = 9); a software decision making program (n = 1); and simulated patient (SP) visits followed by immediate feedback (n = 1). Outcomes were measured using: SP methodology (n = 10) and a survey (n = 1), with most (n = 10) reporting a level of improvement in some communication behaviours. CONCLUSION: Empirical evaluation of interventions using active learning techniques such as face-to-face training with role-play can improve some communication skills. However interventions that are not fully described limit the ability for replication and/or generalisability. This review identified interventions targeting pharmacy personnel. Future interventions to improve communication should consider the consumer's role in OTC consultations. PMID- 29258735 TI - The effects of inspiratory muscle training based on the perceptions of patients with advanced lung disease: a qualitative study. AB - BACKGROUND: Advanced lung disease is a chronic non-neoplastic disease that compromises activities of daily living. Treatment includes pulmonary rehabilitation and inspiratory muscle training. Studies have shown the effectiveness of inspiratory muscle training in lung disease patients, but literature is scarce on the patients' perceptions about this topic. OBJECTIVE: To explore the perceptions of patients with advanced lung disease about inspiratory muscle training. METHODS: Qualitative study. Interviews were conducted using a semi-structured questionnaire regarding topics on the participation of patients in inspiratory muscle training and on daily activities performed before and after training. Interviews were transcribed and analyzed according to thematic content analysis. RESULTS: Ten patients (eight women and 2 men, ranging in age from 27 to 89 years) with inspiratory muscle weakness (maximal inspiratory pressure=44+/ 13.9cmH2O) were included. Five patients were diagnosed with Chronic Obstructive Pulmonary Disease, two with bronchiectasis and three with pulmonary fibrosis. All patients completed at least 80% of the total training sessions. The reports were grouped into four thematic categories: (1) impact of inspiratory muscle training on breathlessness (e.g., "I wasn't feeling as tired as I previously felt."); (2) change in daily activities (e.g., "I needed to go to the supermarket, I felt less tired doing it."); (3) improved mobility (e.g., "I could not stand for long periods [...] walking, for example [...] Now I stand more, I have more capability."); and (4) increased communication (e.g., "More power, right? Even in speaking [...] When I could, I felt my voice coming out better."). CONCLUSION: There were improvements in breathlessness, daily activities, mobility, and communication, which positively affected the psychological and social aspects of the patients. PMID- 29258736 TI - Trunk flexor and extensor muscle performance in chronic stroke patients: a case control study. AB - BACKGROUND: Although chronic stroke patients commonly show impairment of trunk muscle performance, this disability has only been analyzed in terms of peak torque. Therefore, other measures are needed for a more adequate description. OBJECTIVE: This study aimed to compare concentric muscle performance of trunk flexor/extensor muscles between chronic stroke patients and matched-healthy subjects. METHODS: 18 chronic stroke patients and 18 healthy subjects were matched according to their age, sex, body mass index and level of physical activity. After familiarization, trunk flexor/extensor concentric muscle strength was measured using an isokinetic dynamometer (Biodex Medical Systems Inc, Shirley, NY, USA) with 3 repetitions at a velocity of 60 degrees /s and 5 repetitions at a velocity of 120 degrees /s. Trunk muscular performance was characterized by peak torque, torque at 90 degrees , total work, and total work normalized by trunk mass. Student's t-test was used for independent samples (alpha=0.05) for group comparisons. RESULTS: All trunk muscle performance variables values investigated were significantly lower in chronic stroke patients when compared to matched-healthy subjects (p<=0.001). The obtained ratios of chronic stroke patients scores to that of the matched-healthy subjects at velocities of 60 degrees /s and 120 degrees /s were, respectively: flexor peak torque (60% & 53%)/extensor (54% & 53%); flexor torque at 90 degrees (56.20% & 36.58%)/extensor (57.92% & 30.65%); flexor total muscular work (51.27% & 38.03%)/extensor (47.97% & 39.52%); and flexor total muscular work normalized by trunk mass (55.57% & 40%)/extensor (51.40% & 42%). CONCLUSIONS: Chronic stroke patients showed decreased trunk muscle performance when compared to matched healthy subjects in all variables investigated. PMID- 29258737 TI - Diastolic Function Is Impaired in Patients With Prehypertension: Data From the EPIPorto Study. AB - INTRODUCTION AND OBJECTIVES: Hypertension causes subclinical changes in left ventricular structure and function, namely diastolic dysfunction. Diastolic dysfunction is a predictor of heart failure, being involved in the association between hypertension and heart failure with preserved ejection fraction. We aimed to determine whether patients with prehypertension have early changes in diastolic function in a large community-based cohort of asymptomatic adults. METHODS: A cross-sectional evaluation was performed of a community-based cohort consisting of 925 adults, aged 45 years or older, without known cardiovascular disease. All participants underwent detailed clinical and echocardiographic examination. The participants were categorized according to the European guidelines for the classification of office blood pressure (BP) levels as optimal, prehypertensive (normal and high-normal categories), and hypertensive. Diastolic function was evaluated by echocardiography using e' velocities and E/e' ratio. Diastolic dysfunction was defined using the 2016 ASE/EACVI Joint Recommendations and a 2017 clinically-oriented algorithm. RESULTS: In this cohort (61.5 +/- 10.5 years; 37% men), prehypertension was present in 30.4% and hypertension in 51.0%. Using optimal BP as the reference, there was a progressive decrease of e' velocity in prehypertensive and hypertensive individuals (12.2 +/- 3.5 vs 11.3 +/- 3.1 vs 9.6 +/- 2.9cm/s, respectively; P for trend < .001). After multivariable adjustment, both BP categories were independent predictors of a lower e' velocity (beta = -0.56, P = .035 for prehypertension and beta = -1.08, P < .001 for hypertension). CONCLUSIONS: In this large community-based cohort, adults with prehypertension already showed impaired cardiac relaxation before the onset of hypertension. PMID- 29258738 TI - Selection of the Best of the Year 2017 in Cardiovascular Imaging in Familial Cardiopathies. PMID- 29258740 TI - Performance evaluation of BD PhoenixTM, an automated microbiology system, for the screening of IMP-producing Enterobacteriaceae. AB - BD PhoenixTM is an automated bacterial identification and susceptibility testing system. Here, its performance in screening IMP-producing Enterobacteriaceae was evaluated. The system identified 97.8% of IMP producers as being nonsusceptible to imipenem or meropenem, which was higher than that identified by the broth microdilution method (91.3%, imipenem; 41.3%, meropenem). PMID- 29258739 TI - Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. AB - Triple negative breast cancer (TNBC), which constitutes 10%-20% of all breast cancers, is associated with aggressive progression, a high rate of metastasis, and poor prognosis. The treatment of patients with TNBC remains a great clinical challenge. Preclinical reports support the combination immunotherapy of cancer vaccines and immune checkpoint blockades in non-immunogenic tumors. In this study, we constructed nanoparticles (NPs) to deliver an mRNA vaccine encoding tumor antigen MUC1 to dendritic cells (DCs) in lymph nodes to activate and expand tumor-specific T cells. An anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) monoclonal antibody was combined with the mRNA vaccine to enhance the anti tumor benefits. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone. These data support both the NP as a carrier for delivery of mRNA vaccine and a potential combination immunotherapy of the NP based mRNA vaccine and the CTLA-4 inhibitor for TNBC. PMID- 29258741 TI - Chronic stress from adolescence to aging in the prefrontal cortex: A neuroimmune perspective. AB - The development of the organism is a critical variable which influences the magnitude, duration, and reversibility of the effects of chronic stress. Such factors are relevant to the prefrontal cortex (PFC), as this brain region is the last to mature, the first to decline, and is highly stress-sensitive. Therefore, this review will examine the intersection between the nervous system and immune system at glutamatergic synapses in the PFC across three developmental periods: adolescence, adulthood, and aging. Glutamatergic synapses are tightly juxtaposed with microglia and astrocytes, and each of these cell types exhibits their own developmental trajectory. Not only does chronic stress differentially impact each of these cell types across development, but chronic stress also alters intercellular communication within this quad-partite synapse. These observations suggest that developmental shifts in both neural and immune function across neurons, microglia, and astrocytes mediate shifting effects of chronic stress on glutamatergic transmission. PMID- 29258742 TI - Projections of health indicators for chronic disease under a semi-Markov assumption. AB - Chronic diseases are a growing public health problem due to the population aging. Their economic, social and demographic burden will worsen in years to come. Up to now, the method used to provide projections and assess the future disease burden makes a non-homogeneous Markov assumption in an illness-death model. Both age and calendar year have been taken into account in all parameter estimations, but the time spent with the disease was not considered. This work develops the method with a semi-Markov assumption to model mortality among the diseased and considering the time spent with the disease. The method is applied to estimate several health indicators for dementia in France in 2030. We find that mortality among the individuals with dementia depends on age, calendar year and disease duration, and it is greater for men than for women at all ages. The projections for 2030 suggest a 27% increase of the number of dementia cases. The model proposed in this work has flexible assumptions that make it adaptable to provide projections for various diseases. PMID- 29258743 TI - Association between metabolic syndrome and chronic kidney disease. PMID- 29258744 TI - Stabilizing specimens for routine ammonia testing in the clinical laboratory. AB - BACKGROUND: In vitro deamination generates ammonia in freshly collected blood specimens. To prevent this, samples for ammonia testing are usually collected on ice and run rapidly (e.g., within 1h). We developed a method to stabilize specimens for ammonia analysis. METHODS: Following plasma separation, 500MUmol/l cycloserine or a combination of 2mmol/l sodium borate with 5mmol/l l-serine were added to sample pools with normal or increased concentrations of ALT and/or GGT to inhibit deamination; and/or residual platelets were removed via centrifugation. Sample pools were then incubated at room temperature or 4 degrees C. Untreated sample pools were also incubated at -80 degrees C. Ammonia was measured at 0, 1, 2, 4, 8, 16, and 24h. RESULTS: When incubated at 4 degrees C without treatment, sample pools with enzymes within their reference limit had an increase of 0.5MUmol/l/h, whereas sample pools with ALT and/or GGT activity above their upper reference limit had an increase of 3.6MUmol/l/h (p<0.001). When sample pools were incubated at 4 degrees C with sodium borate/l-serine, the rate of ammonia increase was significantly reduced in samples with normal (0.3MUmol/l/h, p<0.001 vs. untreated controls) or high enzyme activity (0.1MUmol/l/h, p<0.001 vs. untreated controls). Independent of the ALT and/or GGT concentrations, storing the sample at -80 degrees C also preserved the specimens for ammonia analysis (0.2MUmol/l/h, p<0.001 vs. untreated controls). CONCLUSIONS: By combining sodium borate/l-serine with refrigeration, plasma ammonia specimens can be stabilized for >12h. PMID- 29258745 TI - Recovery from childhood community-acquired pneumonia in a developing country: Prognostic value of serum procalcitonin. AB - BACKGROUND: Childhood community-acquired pneumonia is a common and potentially life-threatening illness in developing countries. We assessed the prognostic value of serum procalcitonin level upon admission on clinical response to antibiotic treatment. METHODS: Out of 89 patients, the median (IQR) age was 19(12 29) months and 60% were boys. Viral (49.5%), typical bacterial (38%) and atypical bacterial (12.5%) infections as well as probable pneumococcal infections (26%) were diagnosed. RESULTS: Seventy-five (84%) children became afebrile <=48h after treatment. In 14 children who remained febrile after 48h of treatment, median[IQR] serum procalcitonin (ng/ml) level on admission was higher than in those with rapid recovery (2.1[0.8-3.7] vs 0.6[0.1-2.2]; P=0.025). In the slow responding children, pneumococcal infections were more common (71% vs 17%; P<0.001). Procalcitonin concentrations on admission were higher in children with pneumococcal pneumonia compared to children with non-pneumococcal pneumonia (2[0.7-4.2] vs 0.5[0.08-2.1]; P=0.002). The ROC curve found that <0.25ng/ml of serum procalcitonin had a high negative predictive value (93%[95%CI:80%-99%]) for pneumococcal infection. All children that remained febrile after 48h of treatment had procalcitonin >0.25ng/ml on admission. The majority of children with pneumonia in a developing country become afebrile within 48h after onset of antibiotic treatment. CONCLUSIONS: Serum procalcitonin <0.25ng/ml predicted rapid clinical response and non-pneumococcal etiology. PMID- 29258746 TI - NLRP3 inflammasome inhibition attenuates silica-induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells. AB - Silicosis is an incurable and progressive lung disease characterized by chronic inflammation and fibroblasts accumulation. Studies have indicated a vital role for epithelial-mesenchymal transition (EMT) in fibroblasts accumulation. NLRP3 inflammasome is a critical mediator of inflammation in response to a wide range of stimuli (including silica particles), and plays an important role in many respiratory diseases. However, whether NLRP3 inflammasome regulates silica induced EMT remains unknown. Our results showed that silica induced EMT in human bronchial epithelial cells (16HBE cells) in a dose- and time-dependent manner. Meanwhile, silica persistently activated NLRP3 inflammasome as indicated by continuously elevated extracellular levels of interleukin-1beta (IL-1beta) and IL 18. NLRP3 inflammasome inhibition by short hairpin RNA (shRNA)-mediated knockdown of NLRP3, selective inhibitor MCC950, and caspase-1 inhibitor Z-YVAD-FMK attenuated silica-induced EMT. Western blot analysis indicated that TAK1-MAPK Snail/NF-kappaB pathway involved NLRP3 inflammasome-mediated EMT. Moreover, pirfenidone, a commercially and clinically available drug approved for treating idiopathic pulmonary fibrosis (IPF), effectively suppressed silica-induced EMT of 16HBE cells in line with NLRP3 inflammasome inhibition. Collectively, our results indicate that NLRP3 inflammasome is a promising target for blocking or retarding EMT-mediated fibrosis in pulmonary silicosis. On basis of this mechanism, pirfenidone might be a potential drug for the treatment of silicosis. PMID- 29258747 TI - Direct sequencing of the white spot syndrome virus from Brazil: Genome assembly and new insights on phylogeny. AB - White spot syndrome virus (WSSV) has been the cause of great economic losses in world shrimp farming. In this work the genome of a Brazilian WSSV isolate was determined from direct sequencing of total DNA extracted from an infected whiteleg shrimp, and assembled based on a chimera template approach. Comparisons between WSSV-BR and other isolates revealed that the Brazilian virus has a relatively small genome, and is very similar to isolates from Thailand and Mexico. A phylogenetic relationship using different approaches has demonstrated that these isolates share a common evolutionary history. An analysis of conflicting phylogenetic signals also considering genomes of other isolates revealed that the evolutionary history of WSSV may be related to recombination events. We observed that these events can also be traced at some level by analyzing the homologous regions in the WSSV genome. The existence of recombination events introduces a new point of view that must be considered in the evolutionary history of WSSV. PMID- 29258748 TI - Omega-3 fatty acids protect retinal neurons in the DBA/2J hereditary glaucoma mouse model. AB - The purpose of this study was to evaluate the neuroprotective effects of omega-3 polyunsaturated fatty acid (omega3-PUFA) supplementation, alone or in combination with timolol eye drops, in a mouse model of hereditary glaucoma. DBA/2J mice (8.5 month-old) were assigned to an omega3-PUFAs + timolol, omega3-PUFAs only, timolol only, or an untreated group. Treated mice received a daily gavage administration of eicosapentaenoic acid (EPA) and docosahexaenoic acid and/or topical instillation of timolol (0.5%) once a day for 3 months. Blood was analysed regularly to determine omega3-PUFA levels and retinas were histologically analysed. Real-time PCR and Western blot were performed for retinal pro inflammatory cytokines and macrophages. Blood arachidonic acid/EPA ratio gradually decreased and reached the desired therapeutic range (1-1.5) after 4 weeks of daily gavage with omega3-PUFAs in the omega3-PUFAs + timolol and omega3 PUFAs only groups. Retinal ganglion cell densities were significantly higher in the omega3-PUFAs + timolol (1303.77 +/- 139.62/mm2), omega3-PUFAs only (768.40 +/ 52.44/mm2) and timolol only (910.57 +/- 57.28/mm2) groups than in the untreated group (323.39 +/- 95.18/mm2). omega3-PUFA supplementation alone or timolol alone, significantly increased protein expression levels of M1 macrophage-secreted inducible nitric oxide synthase and M2 macrophage-secreted arginase-1 in the retina, which led to significant decreases in the expression levels of tumour necrosis factor-alpha (TNF-alpha). omega3-PUFA supplementation alone also resulted in significantly reduced expression of interleukin-18 (IL-18). omega3 PUFA + timolol treatment had no effect on the expression level of any of the aforementioned mediators in the retina. Supplementation with omega3-PUFAs has neuroprotective effect in the retinas of DBA/2J mice that is enhanced when combined with timolol eye drops. The continued inflammation following omega3 PUFAs + timolol treatment suggests that downregulation of IL-18 and TNF-alpha may not be the only factors involved in omega3-PUFA-mediated neuroprotection in the retina. PMID- 29258749 TI - A simple method for measuring immune complex-mediated, Fc gamma receptor dependent antigen-specific activation of primary human T cells. AB - Immune complex (IC) deposition of IgG containing autologous antigens has been observed in autoimmunity. This can lead to IC-mediated antigen uptake and presentation by antigen presenting cells (APC) driving T cell dependent inflammation. IgG receptors (FcgammaRs) have been suggested to be involved in this process. Since ICs have been linked to autoimmune diseases, interfering with IC mediated effects on APCs and subsequent autoimmune T cell activation via FcgammaR blockade may be therapeutically beneficial. However, this is currently challenging due to a lack of translatable animal models and specific human in vitro assays to study IC-driven T cell responses. Here, we developed a simple cellular assay to study IC-mediated T cell activation in vitro using human peripheral blood mononuclear cells and tetanus toxoid as a model antigen. We observed that tetanus ICs led to a strong induction of T cell proliferation and release of pro-inflammatory cytokines, which are hallmarks of chronic inflammation. This process was exacerbated when compared to tetanus toxoid challenge alone. IC-mediated T cell effects were FcgammaR dependent and inhibited by high-dose intravenous IgG (IVIg), a drug often used for the clinical treatments of autoimmune diseases. Similar effects were also seen using a hepatitis antigen. Consequently, we propose our assay as a rapid yet robust alternative to more labour-intense and time-consuming protocols, for example involving separate maturation of dendritic cells followed by T cell co-culture to study antigen specific primary T cell activation. PMID- 29258750 TI - RNA-seq identifies integrin alpha of kuruma shrimp Marsupenaeus japonicus as a candidate molecular marker for phagocytic hemocytes. AB - Phagocytosis is main cellular immunity, however, it is still unknown or debated upon which types of hemocyte contributes phagocytosis in penaeid shrimps. The hemocyte characterization in kuruma shrimp have been mainly performed based on its morphology by microscopic observation. Therefore, establishment of molecular markers to distinguish phagocytic hemocytes is required. In this study, using magnetic fluorescent beads, we enriched phagocytic hemocytes and conducted RNA seq analysis between total and enriched phagocytic hemocytes. The data demonstrated functional difference between total and phagocytic hemocytes. In addition, a transcript homologous to integrin-alpha was highly expressed in phagocytic hemocytes, and named Mj-Intgalpha. Using anti-serum against Mj Intgalpha revealed that around 60% of total hemocytes and more than 90% of phagocytic hemocytes showed positive for Mj-Intgalpha. This study presents Mj Intgalpha as a candidate molecular marker for future functional characterization of hemocytes. PMID- 29258751 TI - Intraoperative and biomechanical studies of human vastus lateralis and vastus medialis sarcomere length operating range. AB - The vast majority of musculoskeletal models are not validated against primary experimental data. Conversely, most human experimental measurements are not explained theoretically using models to provide a mechanistic understanding of experimental results. Here we present a study with both primary human data and primary modeling data. Intraoperative sarcomere length was measured on the human vastus lateralis (VL) and vastus medialis (VM) muscles (n = 8) by laser diffraction. These data were compared to a biomechanical model based on muscle architecture and moment arms obtained independently from cadaveric specimens (n = 9). Measured VL sarcomere length ranged from about 3.2 um with the knee flexed to 45 degrees to 3.8 um with the knee flexed to 90 degrees . These values were remarkably close to theoretical predictions. Measured VM sarcomere length ranged from 3.6 um with the knee flexed to 45 degrees to 4.1 um with the knee flexed to 90 degrees . These values were dramatically longer than theoretical predictions. Our measured sarcomere length values suggest that human vasti may have differing functions with regard to knee extension and patellar stabilization. This report underscores the importance of validating experimental data to theoretical models and vice versa. PMID- 29258752 TI - Hydromethanolic extract of Rehum emodi exhibits significant antimicrobial activity against acute gastroenteriti bacterial strains. AB - Rehum emodi is an important medicinal herbal and has been reported to exhibit tremendous pharmacological potential. The present study was designed to evaluate the antibacterial activity of hydromethanolic extract of rhizome of Rehum emodi against the acute gastroenteriti bacterial strains. The antimicrobial activity was determined by micro-dilution method. Antioxidant activity was determined by DPPH assay and cytotoxicity by MTT assay. Phytochemical analysis was carried out by LC/MS analysis. The results of the present study showed that hydromethanolic extract of rhizome of Rehum emodi (REE) exhibited significant antimicrobial activity against the gastroenteriti bacterial strains. The MIC values ranged from 25 MUg/ml to 125 MUg/ml. Moreover, the cytotoxicity of the REE was evaluated against the human breast cell line FR-2 and it was observed that REE exerted minimal cytotoxic effects on these cells with an IC50 of 250 MUg/ml indicating that this extract is non-toxic to human cells. The phytochemical analysis revealed the presence of several secondery metabolites such as anthroquinones (anthrone, emodin, aloe emodin and rhein) flavonoids (quercetin, and naringenin) and phenolics (sinapinic acid and gallic acid) which could potentially be responsible for the activity of the extract. In conclusion REE could potentially prove to be useful in the treatment of acute gastroenteritis. PMID- 29258753 TI - Bovine intramammary infection associated immunogenic surface proteins of Streptococcus uberis. AB - In spite of the increasing prevalence of Streptococcus uberis mastitis, its pathogenesis and associated virulence factors are not clearly defined. The aim of this study was to identify virulence associated genes and their products that can be used to develop effective vaccine to control bovine S. uberis mastitis. S. uberis was co-cultured with primary bovine mammary epithelial cells (PBMEC) or infused into mammary gland of dairy cows. The messenger RNA (mRNA) from S. uberis associated with PBMEC after 2 h or 4 h of co-culture was purified and sequenced. Results showed that virulence-associated genes such as surface lipoprotein (slp), infection induced histidine kinase (iihK), infection induced response regulator (iirR) and extracellular sugar binding protein 1 and 2 (exsbP1 and exsbP2) were among the top-up-regulated genes. To verify this observation in vivo, quantitative real time PCR (qRT - PCR) was conducted on mRNA of S. uberis recovered from milk of infected mammary glands 24 h post infection. Results revealed that in vitro up-regulated virulence-associated genes were also significantly up regulated under in vivo conditions. The iihK and iirR are flanked by exsbP1 and exsbP2 genes and this entire operon seems to be involved in adaptation to glands micro-environment, survival and colonization of the bovine mammary glands. Based on immunogenic epitope prediction of proteins encoded by these up-regulated genes during early stages of host-bacterial interactions slp, exsbP1 and exsbP2 genes were selected, cloned and expressed in E. coli. The purified recombinant proteins (rSlP, rExsbP1 & rExsbP2) reacted strongly with convalescent serum from cows experimentally infected with S. uberis confirming that they are immunogenic. These proteins may serve as potential targets to develop an effective vaccine against S. uberis mastitis. PMID- 29258754 TI - The effects of dietary supplement of galactooligosaccharide on innate immunity, immune related genes expression and growth performance in zebrafish (Danio rerio). AB - The present study investigates the effect of different levels of galactooligosaccharide (GOS) on innate immune parameters, immune related genes expression as well as growth performance in zebrafish (Danio rerio). Four hundred and twenty fish (mean weight 45 +/- 0.1 mg) were supplied, randomly stocked in twelve aquaria assigned to four treatments. Zebrafish were fed with either control diet or control diet enriched with different levels (0.5, 1 and 2%) of GOS for eight weeks. At the end of feeding trial innate immune parameters (total immunoglobulin, total protein and alkaline phosphatase activity), immune related genes expression (interleukin 1 beta [il1b], Lysozyme [lyz], tumor necrosis factor alpha [tnf-alpha]) as well as growth performance were measured. Evaluation of immune parameters revealed significant (P < .05) increase of total protein and total Ig in zebrafish fed 1 or 2% GOS compared other treatments. However, in case of lysozyme activity no significant (P > .05) differences were noticed between GOS fed fish and control group. Also, in case of ALP activity, significant increase (P < .05) was observed in 2% GOS treatment. Gene expression studies revealed significant upregulation (P < .05) of tnf-alpha and lyz genes in GOS fed fish. While no significant (P > .05) difference was observed in case of il1b gene expression. Evaluation of growth performance at the end of feeding trial revealed no significant (P < .05) improvement in GOS fed groups. The present results revealed positive effects of GOS on innate immune parameters and related gene expression in zebrafish. PMID- 29258756 TI - Insulin antagonises pigment epithelium-derived factor (PEDF)-induced modulation of lineage commitment of myocytes and heterotrophic ossification. AB - Extensive bone defects arising as a result of trauma, infection and tumour resection and other bone pathologies necessitates the identification of effective strategies in the form of tissue engineering, gene therapy and osteoinductive agents to enhance the bone repair process. PEDF is a multifunctional glycoprotein which plays an important role in regulating osteoblastic differentiation and bone formation. PEDF treatment of mice and human skeletal myocytes at physiological concentration inhibited myogenic differentiation and activated Erk1/2 MAPK- dependent osteogenic transdifferentiation of myocytes. In mice, insulin, a promoter of bone regeneration, attenuated PEDF-induced expression of osteogenic markers such as osteocalcin, alkaline phosphatase and mineralisation for bone formation in the muscle and surrounding adipose tissue. These results provide new insights into the molecular aspects of the antagonising effect of insulin on PEDF dependent modulation of the differentiation commitment of musculoskeletal environment into osteogenesis, and suggest that PEDF may be developed as an effective clinical therapy for bone regeneration as its heterotopic ossification can be controlled via co-administration of insulin. PMID- 29258755 TI - Effects of dietary dandelion extract on intestinal morphology, antioxidant status, immune function and physical barrier function of juvenile golden pompano Trachinotus ovatus. AB - Intestinal morphology, antioxidant status, immune function and tight junction proteins mRNA expression were examined in golden pompano (Trachinotus ovatus) that fed respectively six diets containing dandelion extracts (DE) at 0, 0.5, 1, 2, 4 and 10 g kg-1 after 8 weeks feeding. The study indicated that dietary DE significantly improved intestinal antioxidant abilities by increasing SOD, CAT, T AOC activities and up-regulating intestinal cat, gpx mRNA levels, but by decreasing MDA content and down-regulating intestinal keap1 mRNA levels in golden pompano. Meanwhile, dietary DE improved intestinal morphology, suggesting that enhances intestinal digestion and absorption, by increasing muscle thickness, villus length, villus width and villus number in the foregut and hindgut; as well as villus number, villus width and muscle thickness in the midgut (P < .05). Dietary DE enhanced intestinal barrier function by increasing intestinal zo-1 and occludin mRNA levels, but by decreasing the mRNA levels of claudin-12 and claudin 15. Furthermore, dietary DE improved intestinal immunity via increasing goblet cells numbers and regulating expression of immune-related genes. In conclusion, dietary DE supplementation promoted intestine health by improving intestine morphology, immunity, antioxidant abilities and intestinal barrier in golden pompano. PMID- 29258757 TI - Involvement of brain-gut axis in treatment of cerebral infarction by beta-asaron and paeonol. AB - Cerebral infarction (CI) causes severe brain damage with high incidence. This study aimed to investigate the involvement of brain-gut axis in the treatment of CI by combined administration of beta-asaron and paeonol. Rat middle cerebral artery occlusion (MCAO) model was established, the interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in the rat peripheral blood were determined by ELISA assay, and brain tissue damage was evaluated by TUNNEL assay. The correlation of cholecystokinin (CCK) and nuclear factor-kappaB (NF-kappaB) signaling components between intestinal mucosa and prefrontal cortex of MCAO rats treated with beta-asaron and paeonol were analyzed by quantitative RT-PCR and western blotting. In vitro transwell co-culture was performed to confirm the correlated expression. The expression of CCK and NF-kappaB signaling components were closely correlated between the intestinal mucosa and prefrontal cortex of MCAO rats treated with beta-asaron and paeonol. The combined administration also regulates the IL-1beta and TNF-alpha in the MCAO rat peripheral blood and ameliorate the brain damage in MCAO rats. Elevated expression of related genes was observed in the cortical neurons co-cultured with intestinal mucosal epithelial cells treated by beta-asaron and paeonol. The brain-gut axis mediates the therapeutic effect of beta-asaron and paeonol for cerebral infarction through CCK and NF-kappaB signaling. PMID- 29258758 TI - Inhibition of thymidylate synthase affects neural tube development in mice. AB - Thymidylate synthase (TYMS) is a key enzyme in the de novo synthesis of 2' deoxythymidine-5'-monophosphate (dTMP) from 2'-deoxyuridine-5'-monophosphate (dUMP). Our aim was to investigate the role of dTMP dysmetabolism via inhibition of TYMS by an inhibitor, 5-fluorouracil (5-FU) in the occurrence of neural tube defects (NTDs). We found that a high incidence of NTDs occurred after treatment with 5-FU at 12.5 mg/kg body weight. TYMS activity was significantly inhibited with decreased dTMP and accumulation of dUMP after 5-FU injection. The proliferation of neuroepithelial cells were markedly inhibited in NTDs compared with control. Expressions of proliferating cell nuclear antigen and phosphohistone H3 were significantly decreased in NTDs, while phosphorylated replication protein A2, P53 and Caspase3 were significantly increased in NTDs compared with control. These results indicated that inhibition of TYMS affected the balance between proliferation and apoptosis in neuroepithelial cells, which might shed some lights on the mechanisms involved in NTDs. PMID- 29258759 TI - Expression profiles of cuticular protein genes in wing tissues during pupal to adult stages and the deduced adult cuticular structure of Bombyx mori. AB - We aimed to clarify the regulation of cuticular protein (CP) gene expression and the resulting insect cuticular layers by comparing the expression pattern of CP genes and related ecdysone-responsive transcription factor (ERTF) genes, the coding amino acid sequences of CP genes, and histological observation. The expression of CP and ERTF genes during pupal and adult stages was examined via qPCR. The number of CP genes expressed during pupal and adult stages decreased as compared to that during prepupal to pupation stages, particularly in CPRs. The peaks of transcripts were observed at P5, P6, P9, A0, and A1. The order of the ERTF and CP genes expression resembled that at prepupal and pupation stages, suggesting the relatedness of ERTFs with the same CP genes at both stages. Moreover, the order of expression of CP genes resembled that in prepupal to pupation stages, by which we presumed the spaces of CPs in the epicuticle, outer exocuticle, inner-exocuticle, endocuticle layer. PMID- 29258760 TI - Adult Reconstruction Studies Presented at AAOS and AAHKS 2011-2015 Annual Meetings. Is There a Difference in Future Publication? AB - BACKGROUND: The purpose of this study was to compare adult reconstruction abstracts presented at the American Academy of Orthopaedic Surgeons (AAOS) and the American Association of Hip and Knee Surgeons (AAHKS) annual meetings. METHODS: A total of 1355 podium and 1731 poster presentations from the adult reconstruction sections of the AAOS and AAHKS meetings from 2011 to 2015 were reviewed for publication in peer-reviewed literature. Authors who were added or removed from the original abstract and the final manuscript were recorded. The corresponding journals were assigned the most recent impact factor. The publication rates for each annual meeting, the mean changes in authorship and journal's impact factors were compared. RESULTS: There were 2129 abstracts presented at AAOS and 957 abstracts presented at AAHKS. The overall publication rate was different between AAOS and AAHKS (56% vs 60%, P = .030). Compared with AAOS, there were more AAHKS abstracts published in 2011 (57% vs 77%, P = .0008) and 2012 (57% vs 76%, P = .0001); however, there were no significant differences in 2013, 2014, or 2015. The mean overall change in authors was lower for AAOS compared with AAHKS abstracts (0.78 vs 1.06, P < .0001). The mean journal's impact factors for AAOS and AAHKS publications were also similar (2.86 vs 2.85, P = .874). CONCLUSION: AAOS and AAHKS abstracts presented in the adult reconstruction subspecialty had a similar overall rate of publication, change in authorship, and impact factor. It would be beneficial if further studies subdivided these into basic and clinical science and review articles. PMID- 29258761 TI - External Fixation vs Intramedullary Nailing for Knee Arthrodesis After Failed Infected Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The aim of this study is to compare intramedullary nailing with external fixation for knee arthrodesis after failed infected total knee arthroplasty (TKA). Primary outcome is radiographic union. Secondary outcomes include recurrent deep infection, revision arthrodesis, and amputation. METHODS: Systematic review and meta-analysis of studies comparing outcomes from intramedullary nailing and external fixation in patients with infected TKA undergoing arthrodesis procedures was performed. Randomized controlled trials and cohort studies were included. RESULTS: Intramedullary nailing achieves a significantly higher rate of radiographic union compared with external fixation (odds ratio [OR] 5.17, 95% confidence interval [CI] 2.74-9.75, P < .00001) at a mean follow-up of 44.22 months. There is no significant difference in the rate of recurrent deep infection (OR 0.91, 95% CI 0.38-2.15, P = .83) or amputation (OR 0.94, 95% CI 0.23-3.84, P = .93). The rate of revision arthrodesis procedures is significantly lower for intramedullary nailing compared with external fixation (OR 0.28, 95% CI 0.08-0.93, P = .04). CONCLUSION: Intramedullary nailing is more effective than external fixation with respect to several clinically important outcomes. Therefore, we recommend intramedullary nailing for achieving knee arthrodesis as a salvage procedure for infected TKA in the absence of specific indications for external fixation. PMID- 29258762 TI - The Joint Clinic: Managing Excess Demand for Hip and Knee Osteoarthritis Referrals Using a New Physiotherapy-Led Outpatient Service. AB - BACKGROUND: There are increasing problems with access to both outpatient assessment and joint replacement surgery for patients with hip or knee osteoarthritis. METHODS: Data were collected on all patients seen at the Joint Clinic over a 2-year period with minimum 12-month follow-up. Patients were assessed by a nurse and a physiotherapist, baseline scores and demographic details collected, and an individualized personal care plan developed. Patients could be referred for a first specialist assessment (FSA) if their severity justified surgical assessment. RESULTS: Three hundred fifty-eight patients were seen at Joint Clinic, of whom 150 (44%) had hip and 189 (56%) had knee OA. The mean age was 67.4 years and there were 152 men (45%) and 187 women (55%). The mean baseline Oxford score was 19.8 (standard deviation 8.2). Fifty-four patients were referred directly to FSA (mean Oxford score 13.0, standard deviation 6.7) and 89 after a subsequent review. The scores of patients referred for FSA were significantly worse than those managed in the Joint Clinic (P < .001). Of the 143 referred for FSA, 115 underwent or were awaiting surgery, 18 were recommended surgery but scored below prioritization threshold, and 10 were not recommended surgery. The Oxford scores of the 194 patients managed non-operatively improved from 22.0 to 25.0 (P = .0013). CONCLUSION: This study shows that the Joint Clinic was effective as a triage tool with 93% of those referred for FSA being recommended surgery. This has freed up surgeon time to see only those patients most in need of surgical assessment. PMID- 29258763 TI - Multiple Low-Dose Dexamethasone Further Improves Clinical Outcomes Following Total Hip Arthroplasty. AB - BACKGROUND: The recommended dose regimen of dexamethasone in total hip arthroplasty (THA) has not been determined. This study was performed to assess the effects of multiple low-dose dexamethasone on clinical outcomes after THA. METHODS: Two hundred ten patients undergoing THA received 3 doses of normal saline (Group A), 2 doses of intravenous dexamethasone and 1 dose of normal saline (Group B), or 3 doses of intravenous dexamethasone (Group C). The primary outcome was the visual analog scale (VAS) score for pain and nausea. The incidence of postoperative nausea and vomiting, use of analgesic and antiemetic rescue, C-reactive protein (CRP) level, range of motion, length of stay (LOS), and complications were also compared. RESULTS: The VAS score (dynamic pain and nausea) on postoperative day 1 was significantly lower in Groups C and B than Group A. On postoperative day 2, the VAS score (dynamic pain and nausea) was lower in Group C than Groups A and B. In Group C, patients had a lower incidence of postoperative nausea and vomiting and reduced use of analgesic and antiemetic rescue. The CRP level was lower in Group B than Group A. Group C had the lowest CRP level among all 3 groups. LOS was shorter in Group B than Group A, while Group C had an even shorter LOS than Group B. Range of motion was greater in Group C. No complications occurred in any group. CONCLUSION: The 3-dose dexamethasone regimen can further relieve postoperative pain, ameliorate postoperative nausea, provide additional inflammatory control, enhance mobility, and shorten LOS following THA. PMID- 29258765 TI - Clinicopathologic features of adult EBV-associated B-cell lymphoproliferative disease. AB - In the present study, 21 cases of adult/late-onset EBV-associated lymphoproliferative disease (AELPD) with an uncertain malignant potential were investigated with regard to their histomorphology, immunophenotype, clonal rearrangement of the heavy chain (IgH) and T-cell receptor (TCR) genes and clinical course. The cases were histomorphologically reevaluated and assigned to one of three morphological groups: mononucleosis-like, Hodgkin-like, or polymorphous. In addition, cases with or without detectable necrosis were investigated for differences in clinical outcome. Overall survival was highest in the group with Hodgkin-like morphology (4/4 patients), followed by patients with mononucleosis-like phenotype (4/5 patients surviving). Cases with polymorphous morphology showed the poorest survival rates with 7/12 patients dead of disease (58%). 4/6 patients with histologically detectable necrosis died (66%), but only 4/15 patients without necrosis (27%). 11/21 cases with AELPD showed clonal rearrangement for IgH (n = 4), TCR (n = 5) or IgH + TCR (n = 2). 5/11 patients with clonal rearrangement died (45%), and this percentage was similar in all of the three subgroups. In conclusion, the present study shows that polymorphous morphology and detection of necrosis in AELPD are frequently linked to a fatal clinical course, whereas Hodgkin-like morphology seems to be associated with a more favourable prognosis. Clonal rearrangement of IgH or TCR is frequent in AELPD, but prognosis is unpredictable from this feature. PMID- 29258764 TI - Aquaporin-1 and -5 are involved in the invasion and proliferation of soft tissue sarcomas. AB - BACKGROUND AND AIM: Recent studies of several carcinomas have reported that aquaporin possesses novel oncogenic properties. The aim of this study was to clarify the involvement of aquaporin-1 and -5 in the proliferation, invasion and metastasis of soft tissue sarcomas. MATERIALS AND METHODS: The expression of aquaporin-1 and -5 was immunohistochemically examined in 73 soft tissue sarcomas as well as in benign, locally aggressive soft tissue tumors, and in soft tissues of adult humans and human fetuses. The mRNA and protein expression of aquaporin-1 and -5 genes were quantified in 19 sarcoma tissues. RESULTS: Aquaporin-1 was expressed in the tumor cells of 37 (51%) and aquaporin-5 in 29 (40%) of 73 soft tissue sarcomas. Two expression patterns were identified: a differentiation dependent pattern, similar to their expression in adult human soft tissue and in benign soft tissue tumors, and an aggressiveness-related pattern, that is similar to their expression in the mesenchymal cells of the developing fetal limb. The latter expression pattern proved to be an independent prognostic factor for patients with soft tissue sarcoma, in which aquaporin-1 was related to the invasiveness, and aquaporin-5 to the proliferation of soft tissue sarcoma cells. CONCLUSION: These results indicate pivotal roles for aquaporin-1 and -5 in the aggressive growth and metastatic potential of soft tissue sarcomas, suggesting that they are promising targets for the treatment of patients with intractable soft tissue sarcoma. PMID- 29258766 TI - Rare frameshift mutations of putative tumor suppressor genes CSMD1 and SLX4 in colorectal cancers. PMID- 29258768 TI - Role of miR-1 expression in clear cell renal cell carcinoma (ccRCC): A bioinformatics study based on GEO, ArrayExpress microarrays and TCGA database. AB - PURPOSE: To investigate the clinical value and potential molecular mechanisms of miR-1 in clear cell renal cell carcinoma (ccRCC). METHODS: We searched the Gene Expression Omnibus (GEO), ArrayExpress, several online publication databases and the Cancer Genome Atlas (TCGA). Continuous variable meta-analysis and diagnostic meta-analysis were conducted, both in Stata 14, to show the expression of miR-1 in ccRCC. Furthermore, we acquired the potential targets of miR-1 from datasets that transfected miR-1 into ccRCC cells, online prediction databases, differentially expressed genes from TCGA and literature. Subsequently bioinformatics analysis based on aforementioned selected target genes was conducted. RESULTS: The combined effect was -0.92 with the 95% confidence interval (CI) of -1.08 to -0.77 based on fixed effect model (I2 = 81.3%, P < 0.001). No publication bias was found in our investigation. Sensitivity analysis showed that GSE47582 and 2 TCGA studies might cause heterogeneity. After eliminating them, the combined effect was -0.47 (95%CI: -0.78, -0.16) with I2 = 18.3%. As for the diagnostic meta-analysis, the combined sensitivity and specificity were 0.90 (95%CI: 0.61, 0.98) and 0.63 (95%CI: 0.39, 0.82). The area under the curve (AUC) in the summarized receiver operating characteristic (SROC) curve was 0.83 (95%CI: 0.80, 0.86). No publication bias was found (P = 0.15). We finally got 67 genes which were defined the promising target genes of miR-1 in ccRCC. The most three significant KEGG pathways based on the aforementioned genes were Complement and coagulation cascades, ECM-receptor interaction and Focal adhesion. CONCLUSION: The downregulation of miR-1 might play an important role in ccRCC by targeting its target genes. PMID- 29258767 TI - Immunohistochemical comparative analysis of GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 expression in WHO 2016 classified neuroepithelial tumours and their prognostic value. AB - Immunohistochemistry is routinely used in differential diagnosis of tumours of the central nervous system (CNS). The latest 2016 WHO 2016 revision now includes molecular data such as IDH mutation and 1p/19q codeletion thus restructuring glioma classification. Direct comparative information between commonly used immunohistochemical markers for glial tumours GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 concerning quality and quantity of expression and their relation to the new molecular markers are lacking. We therefore compared the immunohistochemical staining results of all five antibodies in 34 oligodendrogliomas, 106 ependymomas and 423 astrocytic tumours. GFAP expression was reduced in cases with higher WHO grade, oligodendroglial differentiation and in IDH wildtype diffuse astrocytomas. By contrast MAP - 2 expression was significantly increased in diffuse astrocytomas with IDH mutation, while NOGO - A expression was not associated with any molecular marker. WT - 1 expression was significantly decreased in tumours with IDH mutation and ATRX loss. OLIG - 2 was increased in IDH-mutant grade II astrocytomas and in cases with higher proliferation rate. In univariate survival analysis high WT - 1 expression was significantly associated with worse outcome in diffuse astrocytic tumours (log rank p < 0.0001; n = 211; median time: 280 days vs 562 days). None of the markers was prognostic in multivariate survival analysis. Among the evaluated markers MAP - 2, OLIG - 2 and WT - 1 showed the best potential to separate between glioma entities and can be recommended for a standardized immunohistochemical panel. PMID- 29258769 TI - Calcium and vitamin D in human health: Hype or real? AB - The incidence and prevalence of vitamin D deficiency are increasing worldwide. It is estimated that over 50% of the world's population have low vitamin D (i.e., hypovitaminosis D; serum levels below 30 ng/mL). In vitamin D inadequacy, human physiological systems work inefficiently. In humans, 80% of the vitamin D is synthesized in the presence of ultraviolet rays from sunlight; for the rest, we rely on diet and nowadays, supplements. The latter becomes important when one is exposed to less than optimal amounts of sunlight, inability to generate vitamin D in the skin efficiently, and/or having conditions that lead to decreased intestinal absorption or increased catabolism of vitamin D. The normal serum 25 hydroxyvitamin D [25(OH)D] level is around 30 ng/mL (75 nmol/L) and the optimal range is between 30 and 60 ng/mL (75-150 nmol/L). In 2011, the Institute of Medicine (IOM) suggested that 600IU of vitamin D is adequate for people below age 71 who are not exposed to sunshine. Although this might be relevant to the ambulatory healthy white Caucasians to achieve serum 25(OH)D level of 20 ng/mL, but it is insufficient for other ethnic groups. Moreover, the IOM recommendations are not suitable for those who live outside North America. Vitamin D requirements are higher during adolescence, pregnancy and lactation, and in many other disease conditions. Most clinicians consider 30 ng/mL as the minimum serum level of 25(OH)D necessary to maintain good health. In the absence of sunlight exposure and with daily oral intake of 600IU vitamin D, very few people would reach serum 25(OH)D level above 30 ng/mL. While an additional daily intake of 1000IU of vitamin D are required for people with lighter-skin color, those with darker complexion and the elderly, require a minimum of 2000IU/day to maintain serum 25(OH)D levels over 30 ng/mL; 5000 IU/day supplement is considered as the safe daily upper limit of supplementation. Vulnerable groups such as the disabled and/or house-bound, obese, with gastrointestinal abnormalities and/or malabsorption syndromes, institutionalized people (e.g., nursing homes, prisons, etc.), and pregnant and lactating women need approximately 4000IU per day for optimal physiological activity. Vitamin D is essential for gastrointestinal calcium absorption, mineralization of osteoid tissue and maintenance of serum ionized calcium level. It is also important for other physiological functions, such as muscle strength, neuromuscular coordination, hormone release, subduing autoimmunity, and curtailing the development of certain cancers. PMID- 29258770 TI - Microwave-assisted synthesis of novel 5-substituted benzylidene amino-2-butyl benzofuran-3-yl-4-methoxyphenyl methanones as antileishmanial and antioxidant agents. AB - A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC50 = 52.0 +/- 0.09 ug/ml), 4h (IC50 = 56.0 +/- 0.71 ug/ml) and 4l (IC50 = 59.3 +/- 0.55 ug/ml) were shown significant antileishmanial when compared with standard sodium stibogluconate (IC50 = 490.0 +/- 1.5 ug/ml). Antioxidant study revealed that compounds 4i (IC50 = 2.44 +/- 0.47 ug/ml) and 4l (IC50 = 3.69 +/- 0.44 ug/ml) have shown potent comparable activity when compared with standard ascorbic acid (IC50 = 3.31 +/- 0.34 ug/ml). Molecular docking study was carried out which replicating results of biological activity in case of initial hits 4f and 4h suggesting that these compounds have a potential to become lead molecules in drug discovery process. In silico ADME study was performed for predicting pharmacokinetic profile of the synthesised antileishmanial agents and expressed good oral drug like behaviour. PMID- 29258771 TI - Identification of novel small-molecule inhibitors of Zika virus infection. AB - The recent re-emergence of Zika virus (ZIKV), a member of the Flaviviridae family, has become a global emergency and a serious public health threat worldwide. ZIKV infection causes severe neuroimmunopathology and is particularly harmful to the developing fetuses of infected pregnant women causing various developmental abnormalities. Currently, there are no effective methods of preventing or treating ZIKV infection, and new treatment options are urgently needed. Therefore, we have used an in vitro plaque assay to screen a limited proprietary library of small organic compounds and identified highly bioactive leads, with the most active analogs showing activity in low picomolar range. Identified "hits" possess certain common structural features that can be used in the design of the next generation(s) of ZIKV inhibitors. Collectively, our findings suggest that identified compounds represent excellent template(s) for the development of inexpensive and orally available anti-Zika drugs. PMID- 29258772 TI - Discovery of novel benzo[b]thiophene tetrazoles as non-carboxylate GPR40 agonists. AB - GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model. PMID- 29258773 TI - Latch and trigger role for R445 in DAT transport explains molecular basis of DTDS. AB - A recent study reports on five different mutations as sources of dopamine transporter (DAT) deficiency syndrome (DTDS). One of these mutations, R445C, is believed to be located on the intracellular side of DAT distal to the primary (S1) or secondary (S2) sites to which substrate binding is understood to occur. Thus, the molecular mechanism by which the R445C mutation results in DAT transport deficiency has eluded explanation. However, the recently reported X-ray structures of the endogenous amine transporters for dDAT and hSERT revealed the presence of a putative salt bridge between R445 and E428 suggesting a possible mechanism. To evaluate whether the R445C effect is a result of a salt bridge interaction, the mutants R445E, E428R, and the double mutant E428R/R445E were generated. The single mutants R445E and E428R displayed loss of binding and transport properties of the substrate [3H]DA and inhibitor [3H]CFT at the cell surface while the double mutant E428R/R445E, although nonfunctional, restored [3H]DA and [3H]CFT binding affinity to that of WT. Structure based analyses of these results led to a model wherein R445 plays a dual role in normal DAT function. R445 acts as a component of a latch in its formation of a salt bridge with E428 which holds the primary substrate binding site (S1) in place and helps enforce the inward closed protein state. When this salt bridge is broken, R445 acts as a trigger which disrupts a local polar network and leads to the release of the N-terminus from its position inducing the inward closed state to one allowing the inward open state. In this manner, both the loss of binding and transport properties of the R445C variant are explained. PMID- 29258774 TI - Evaluating the emissions from the gasification processing of municipal solid waste followed by combustion. AB - In this study, we evaluated the emissions of pollutants generated from the combustion of syngas in the gasification of Municipal Solid Waste (MSW) in Brazil using a mobile grille gasifier fed with domestic waste without any previous separation or grinding. The basic syngas composition (H2, CH4 and CO) was analyzed by gas chromatography and the Lower Calorific Value was calculated, which ranged from 1.9 to 10.2 MJ/kg. In the monitoring of combustion gases (CO2, CO, NO, NO2, SO2 and Total Hydrocarbon Content), values were found for these pollutants that were lower than the values established by the Brazilian legislation, except for SO2. Regarding the determination of the emission of metals, values lower than those permissible in the legislation were found for the most toxic metals grouped as class I (Cd, Hg, Tl). Therefore, it was evident that gasification followed by the combustion of syngas from MSW without prior segregation at source has the advantages of having fewer process steps, allowing the low emission of pollutants into the environment and it avoids that the residues are deposited in landfills, which are generators of leachate and greenhouse gas (methane). PMID- 29258775 TI - Spatially distributed potential of landfill biogas production and electric power generation in Brazil. AB - Due to the relatively low investment, operation costs, and technical requirements, landfills are still the most widespread alternative for final disposal of municipal solid waste (MSW). The biogas produced in the landfill, a renewable energy source, may be an important alternative for electric power generation. Brazil has a significant number of operating landfills, which receive the most part of the collected MSW. However, the country has only 17 landfill biogas power plants (LBPPs), resulting in about 122 MW of capacity. The United Kingdom, for instance, which is about 3 times smaller than Brazil in population, has 442 LBPPs (corresponding to 1051 MW of capacity). This fact highlights a considerable unexplored potential of landfill biogas in Brazil. It is also important to estimate this potential throughout the country to provide information for the government, researchers and companies in decision making, planning and formulation of public policies regarding this use of landfill biogas. Therefore, this study aims at estimating the spatially distributed potential of landfill biogas production that can be used for electric power generation in Brazil from 2015 to 2045, considering two scenarios: (i) operating sanitary landfills and (ii) hypothetical scenario of Territorial Arrangements (TA) comprising every Brazilian city, considering one landfill per TA. The total installed capacity estimated in 2018 for scenario 1 is about 523 MW and 87% of this number are related to LBPPs bigger than 1 MW. In this same year, the total installed capacity estimated for scenario 2 is 768 MW and 95% of this number are related to LBPPs bigger than 1 MW. These results emphasize that Brazil has a considerable unexplored potential of landfill biogas and the importance of municipal consortiums for MSW management. PMID- 29258776 TI - Waste disposal and households' heterogeneity. Identifying factors shaping attitudes towards source-separated recycling in Bogota, Colombia. AB - Solid waste management in many cities of developing countries is not environmentally sustainable. People traditionally dispose of their solid waste in unsuitable urban areas like sidewalks and satellite dumpsites. This situation nowadays has become a serious public health problem in big Latin American conurbations. Among these densely-populated urban spaces, the Colombia's capital and main city stands out as a special case. In this study, we aim to identify the factors that shape the attitudes towards source-separated recycling among households in Bogota. Using data from the Colombian Department of Statistics and Bogota's multi-purpose survey, we estimated a multivariate Probit model. In general, our results show that the higher the household's socioeconomic class, the greater its effort for separating solid wastes. Likewise, our findings also allowed us to characterize household profiles regarding solid waste separation and considering each socioeconomic class. Among these profiles, we found that at lower socioeconomic classes, the attitudes towards solid waste separation are influenced by the use of Internet, the membership to an environmentalist organization, the level of education of the head of household and the homeownership. Hence, increasing the education levels within the poorest segment of the population, promoting affordable housing policies and facilitating Internet access for the vulnerable population could reinforce households' attitudes towards a greater source-separated recycling effort. PMID- 29258777 TI - Reply by Authors. PMID- 29258778 TI - Effects of deep sedation under mechanical ventilation on cognitive outcome in patients undergoing surgery for oral and maxillofacial cancer and microvascular reconstruction. AB - OBJECTIVE: Cognitive impairment after intensive care unit (ICU) admission is becoming increasingly recognized. High-dose deep sedation has been suggested to play an important role in the development of cognitive impairment. However, the impact of heavy sedation as a single cause in the development of cognitive impairment in ICU patients remains unclear. In this study we investigated whether a three-day deep sedation protocol could reduce cognitive function in mechanically ventilated non-critical patients. DESIGN: A prospective observational study was carried out. PATIENTS: A total of 17 surgical patients were studied. INTERVENTION: None. VARIABLES OF INTEREST: Cognitive function before and after ICU admission. RESULTS: Thirty-one patients requiring three days of sedation after microvascular reconstruction were initially enrolled in the study. Sedation in the ICU was maintained with propofol and dexmedetomidine combined with fentanyl. Cognitive function was assessed using a battery of 6 neuropsychological tests two days before surgery and three weeks after surgery. Finally, a total of 17 patients were included in the analysis. Cognitive impairment (defined as a decline of >20% from the pre-admission cognitive evaluation scores in at least two of 6 tests) was observed in 5 of the 17 patients (29%). However, there were no significant differences between the pre- and post-admission cognitive evaluations in 6 tests. CONCLUSIONS: Middle-term cognitive function can be impaired in some patients subjected to deep sedation during several days following maxillary-mandibular oral surgery with microvascular reconstruction. PMID- 29258779 TI - Ultrasound stroke volume variation induced by passive leg raising and fluid responsiveness: An observational cohort study. AB - OBJECTIVE: To assess the performance of the ultrasound measurement of stroke volume (SV) coupled to passive leg raising (PLR) in predicting fluid responsiveness (FR). DESIGN: A prospective cohort study was carried out in patients requiring volume expansion (VE). A transthoracic Doppler echocardiography (TTE) device was used for the measurement of SV. Four measurements were obtained: before and 90s after PLR, and before and after VE. The patients were subsequently classified according to their hemodynamic response to VE. Responders were defined by an increase in SV of at least 15% in response to VE. RESULTS: Thirty maneuvers were studied. An increase in SV>15% in response to PLR was recorded in 21 cases. Hemodynamic indices taken in the first stage showed significant differences in the distensibility index of the inferior vena cava (dIVC), in the velocity-time integral of aortic blood flow (VTIAo) and in SV, with respective p-values of 0.009, 0.012 and 0.025. The SV changes induced by VE were significantly correlated to the SV changes induced by PLR, with a Spearman coefficient of 0.77 and a linear equation y=0.82 x+1.68. Fluid responsiveness can be efficiently predicted by assessing the effects of PLR on SV monitored by Doppler TTE, with a sensitivity of 94.7% and a negative predictive value of 88%. CONCLUSION: Our data support the interest of Doppler TTE as an effective tool in predicting FR through the assessment of SV in response to PLR, in hemodynamically unstable patients. PMID- 29258780 TI - Microbiological contamination in high and low flow oxygen humidifiers: A systematic review. AB - AIM: To determine the risk of microbiological contamination with hospital use high- and low-flow bubbling humidifiers. METHODS: A systematic literature review was carried out in 6 databases. Observational or experimental studies published between 1990 and 2016 were selected, written in English or Spanish, and in which microbiological contamination with hospital use high- and low-flow bubbling humidifiers was investigated. RESULTS: A total of 12 articles were included: 4 analyzed the water from reusable humidifiers, 4 analyzed the water from prefilled system humidifiers, and the rest compared samples from both models. Microbial contamination was observed in all studies in which reusable humidifiers were evaluated, usually involving common bacteria from the skin flora, while potential pathogenic species were notified in 2 studies. No microbial contamination was isolated from reusable humidifiers, regardless of whether they had been consecutively used over time by a single patient or by several patients. CONCLUSION: On one hand, there seems to be a low risk of contamination during the first weeks of use of prefilled humidifiers, which allows multiple use in different patients, without a risk of cross-contamination. On the other hand, it should be underscored that handling reusable humidifiers without correct aseptic measures can increase the risk of contamination; replacing reusable humidifiers with prefilled models therefore could be the safest option. PMID- 29258781 TI - Complete rupture of the pancreas due to blunt abdominal trauma. PMID- 29258782 TI - Corticotherapy vs. Corticotherapy Plus Immunosuppressive Therapy in Acute Vogt Koyanagi-Harada Disease. AB - INTRODUCTION: Vogt-Koyanagi-Harada disease is a multisystem disorder characterized by a bilateral granulomatous panuveitis. Multiple therapeutic regimens have been used to control inflammation in acute uveitic stage to prevent irreversible visual loss. The purpose of this paper is to compare the effect, on functional and anatomic outcomes, of early treatment with standard corticotherapy vs. corticotherapy plus immunosuppressive (IMT) therapy in acute Vogt-Koyanagi Harada disease (Group A vs Group B). METHODS: A retrospective chart review of patients with Vogt-Koyanagi-Harada disease, with an evolution time of 2 weeks or less, who attended the Inflammatory Eye Disease Clinic, from 2001 to 2015. Data collected included demographic information, presenting features, treatment and improvement in visual acuity (VA). RESULTS: Sixteen charts were reviewed; 15 females (93.75%). Mean age: 30.81+/-10.53 years, follow-up time (months): 54.94+/ 43.43. Ten patients (66.6%) had IMT, azathioprine, methotrexate and cyclophosphamide. In group A, initial VA<20/200 in 66.7%; final VA was >=20/40 in 9 eyes (75%). In group B, initial VA<20/200 in 65%; final VA>=20/40 in 15 eyes (75%). In group A, VA improved faster at one and 3 months (ANOVA P<.057). Clinical characteristics in convalescent stage and complications were similar. Anterior chamber recurrences occurred in both groups and posterior pole recurrences were observed in group A. Time to first recurrence was similar (P<.279). Frequency of recurrence was 2.33+/-1.80 vs 1.5+/-0.79 (P<.01). At recurrence 15 patients were still having oral steroids, nine in group A, 6 in Group B. In group A, prednisone was given during more time: mean 15.17+/-12.08 months, and time to reach to 10mg dose was longer: 8.60+/-11.7 (P<.008 and P<.046). CONCLUSIONS: Adding IMT as first line therapy to corticosteroids, do not matter significantly in terms of final VA or development of visually significant complications. In the IMT plus corticosteroids group number of recurrences was significantly lower, and a steroid sparing effect was evident. PMID- 29258783 TI - Air Versus Ground Transportation in Isolated Severe Head Trauma: A National Trauma Data Bank Study. AB - BACKGROUND: The effect of prehospital helicopter emergency medical services (HEMS) on mortality has been analyzed previously in polytrauma patients with discordant results. OBJECTIVE: Our aim was to compare outcomes in patients with isolated severe blunt traumatic brain injuries (TBIs) transported by HEMS or ground emergency medical services (GEMS). METHODS: We conducted a National Trauma Data Bank study (2007-2014). All adult patients (>=16 years old) who sustained an isolated severe blunt TBI and were transported by HEMS or GEMS were included in the study. RESULTS: There were 145,559 patients who met the inclusion criteria. Overall, 116,391 (80%) patients were transported via GEMS and 29,168 (20%) via HEMS. Median transportation time was longer for HEMS patients (41 vs. 25 min; p < 0.001). HEMS patients were more likely to have hypotension (2.7% vs. 1.5%; p < 0.001), Glasgow Coma Scale (GCS) score < 9 (38.2% vs. 10.9%; p < 0.001), and head Abbreviation Injury Scale (AIS) score of 5 (20.1% vs. 9.7%; p < 0.001). Stepwise logistic regression analysis identified age >= 65 years old, male sex, hypotension, GCS score < 9, prehospital intubation, and head AIS scores 4 and 5 as independent predictors of mortality. Helicopter transportation was independently associated with improved survival (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.47-0.67; p < 0.001). Admission to a Level I trauma center was an independent predictor of survival (OR 0.64; 95% CI 0.53-0.82; p = 0.001). Regardless of head AIS, helicopter transport was an independent predictor of survival (AIS 3: OR 0.35; p < 0.001; AIS 4: OR 0.44; p < 0.001; AIS 5: OR 0.76; p < 0.001). A prolonged transport time was not an independent predictor of mortality. CONCLUSIONS: Helicopter transport, in adult patients with isolated severe TBI, is associated with improved survival. PMID- 29258784 TI - Methemoglobinemia in a Case of Paint Thinner Intoxication, Treated Successfully with Vitamin C. AB - BACKGROUND: Methemoglobin (MetHb) is an oxidized form of hemoglobin. It is a poor transporter of oxygen and is unable to deliver oxygen to the tissue. Globally, drug & toxin induced methemoglobinemia is more common as compared with the congenital form. Methemoglobinemia caused by paint thinner intoxication is rare. Methylene blue is well established as the first-line therapy for severe methemoglobinemia. CASE REPORT: A 25-year old man was brought to the Emergency Department after accidental consumption of paint thinner. On clinical examination, he had cyanosis and there were discrepancies in his pulse oximetry and arterial blood gas (ABG) analysis results. With this clue and supporting laboratory investigations, the diagnosis of toxin-induced methemoglobinemia was made. Due to the unavailability of methylene blue, alternative treatment with high-dose vitamin C was attempted, to which the patient responded. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The role of vitamin C in the treatment of methemoglobinemia has not been well established, with only a few published case reports. This patient had severe methemoglobinemia, with MetHb of 46.4%, which responded dramatically to vitamin C therapy, with no side effects. This case shows that high-dose vitamin C is safe and has the potential to be an effective alternative for the treatment of severe methemoglobinemia. In the presence of cyanosis, mismatch of pulse-oximetry and ABG-analysis are the key for the physician to suspect methemoglobinemia. PMID- 29258785 TI - Avian haemosporidians from rain forests in Madagascar: Molecular and morphological data of the genera Plasmodium, Haemoproteus and Leucocytozoon. AB - The diversity of the haemosporidian genera Plasmodium, Haemoproteus and Leucocytozoon in birds from rain forests in Madagascar is characterized combining techniques of PCR and microscopy and based on the examination of 72 host individuals of 23 species in 15 families. High total prevalence of haemosporidians (68%) is detected, with Leucocytozoon infections being predominant (59.7%) and lower comparable prevalence of Plasmodium (18.0%) and Haemoproteus (23.6%) infections. Using mitochondrial cytochrome b (cytb) marker, 23 genetically distinct lineages are identified: 9 of Plasmodium spp., 6 of Haemoproteus spp. and 8 of Leucocytozoon spp. Fifteen of all lineages have not been reported by previous studies. This study provides the first data on haemosporidian morphological and molecular diversity found in the endemic families Vangidae and Bernieriidae. Two haemoproteid species, Haemoproteus fuscae Mello and Fonseca, 1937 and H. killangoi Bennett and Peirce, 1981, are redescribed based on the present samples and linked to the cytb lineages hCELEC01 and hZOSMAD01, respectively. Phylogenetic analysis is performed to test the relationship of the discovered new lineages with parasites from closely related avian hosts suggesting that multiple colonisation of hosts by haemosporidian parasites has occurred on the island. PMID- 29258786 TI - Genetic and immune determinants of immune activation in HIV-exposed seronegative individuals and their role in protection against HIV infection. AB - Soon thereafter infection is established, hosts strive for an efficient eradication of microorganisms, with as limited tissue damage as possible, and durable immunological protection against re-infection. On the other hand, pathogens have developed countermeasures to escape host surveillance and to warrant diffusion to other hosts. In this molecular arms race the final results relies on multiple variables, including the genetic and immunologic e correlates of protection available for the host. In the field of HIV-infection, natural protection has been repeatedly associated to the presence of an immune activation state, at least in some cohorts of HESN (HIV-exposed seronegative). Indeed, these subjects, who naturally resist HIV-infection despite repeated exposure to the virus, are characterized by an increased expression of activation markers on circulating cells and greater production of immunological effector molecules both in basal condition and upon specific-stimulation. Although these results are not univocally shared, several publications emphasize the existence of a correlation between polymorphisms in genes associated with increased immune activation and the HESN phenotype. In this review, we will describe some of the genetic variants associated with protection against HIV infection. Understanding the basis of HIV resistance in HESN is mandatory to develop new preventative and therapeutic interventions. PMID- 29258787 TI - Involvement of mitochondrial haplogroups in myocardial infarction and stroke: A case-control study in Castile and Leon (Spain) population. AB - There are strong evidences that common mitochondrial DNA (mtDNA) haplogroups may influence the pathogenesis of cardiovascular diseases (CVDs). In this matched case-control study, we investigate the association between mtDNA haplogroups and two CVDs, myocardial infarction (MI) and stroke, and classical cardiovascular risk factors. Data obtained show that haplogroup H constitute a susceptibility risk factor for MI (p=0.001; OR=2.379, 95% CI [1.440-3.990]). Otherwise, our data also suggest a beneficial role of haplogroup J against hypertension (p=0.019; OR=0.348, 95% CI [0.144-0.840]). These results may provide some guidance for predicting the genetic risk of these diseases in different human populations through the differences in energy efficiency between haplogroups. PMID- 29258788 TI - Anaphylactic Reactions After Discontinuation of Hymenoptera Venom Immunotherapy: A Clonal Mast Cell Disorder Should Be Suspected. AB - BACKGROUND: Up to 75% of patients with severe anaphylactic reactions after Hymenoptera sting are at risk of further severe reactions if re-stung. Venom immunotherapy (VIT) is highly effective in protecting individuals with ascertained Hymenoptera venom allergy (HVA) and previous severe reactions. After a 3- to 5-year VIT course, most patients remain protected after VIT discontinuation. Otherwise, a lifelong treatment should be considered in high risk patients (eg, in mastocytosis). Several case reports evidenced that patients with mastocytosis and HVA, although protected during VIT, can re-experience severe and sometimes fatal reactions after VIT discontinuation. OBJECTIVE: To evaluate whether patients who lost protection after VIT discontinuation may suffer from clonal mast cell disorders. METHODS: The survey describes the characteristics of patients who received a full course of VIT for previous severe reactions and who experienced another severe reaction at re-sting after VIT discontinuation. Those with a Red Espanola de Mastocitosis score of 2 or more or a serum basal tryptase level of more than 25 ng/mL underwent a hematological workup (bone marrow biopsy, KIT mutation, expression of aberrant CD25) and/or skin biopsy. RESULTS: Nineteen patients (mean age, 56.3 years; 89.5% males) were evaluated. All of them had received at least 4 years of VIT and were protected. After VIT discontinuation they were re-stung and developed, in all but 1 case, severe anaphylactic reactions (12 with loss of consciousness, in the absence of urticaria/angioedema). Eighteen patients (94.7%) had a clonal mast cell disorder, 8 of them with normal tryptase. CONCLUSIONS: Looking at this selected population, we suggest that mastocytosis should be considered in patients developing severe reactions at re-sting after VIT discontinuation and, as a speculation, patients with mastocytosis and HVA should be VIT-treated lifelong. PMID- 29258789 TI - Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma. AB - BACKGROUND: Mepolizumab significantly reduces exacerbations in patients with severe eosinophilic asthma. The early identification of patients likely to receive long-term benefit from treatment could ensure effective resource allocation. OBJECTIVE: To assess potential continuation rules for mepolizumab in addition to initiation criteria defined as 2 or more exacerbations in the previous year and blood eosinophil counts of 150 cells/MUL or more at initiation or 300 cells/MUL or more in the previous year. METHODS: This post hoc analysis included data from 2 randomized, double-blind, placebo-controlled studies (NCT01000506 and NCT01691521) of mepolizumab in patients with severe eosinophilic asthma (N = 1,192). Rules based on blood eosinophils, physician-rated response to treatment, FEV1, Asthma Control Questionnaire (ACQ-5) score, and exacerbation reduction were assessed at week 16. To assess these rules, 2 key metrics accounting for the effects observed in the placebo arm were developed. RESULTS: Patients not meeting continuation rules based on physician-rated response, FEV1, and the ACQ-5 score still derived long-term benefit from mepolizumab. Nearly all patients failing to reduce blood eosinophils had counts of 150 cells/MUL or less at baseline. For exacerbations, assessment after 16 weeks was potentially premature for predicting future exacerbations. CONCLUSION: There was no evidence of a reliable physician-rated response, ACQ-5 score, or lung function-based continuation rule. The added value of changes in blood eosinophils at week 16 over baseline was marginal. Initiation criteria for mepolizumab treatment provide the best method for assessing patient benefit from mepolizumab treatment, and treatment continuation should be reviewed on the basis of a predefined reduction in long-term exacerbation frequency and/or oral corticosteroid dose. PMID- 29258790 TI - The Allergist's Role in Anaphylaxis and Food Allergy Management in the School and Childcare Setting. AB - Anaphylaxis and food allergy management in childcare facilities and schools are growing challenges. An increasing number of children experience severe allergic reactions on school grounds as evidenced by reports of epinephrine use. Data also suggest that the prevalence of food allergy may be increasing, with a large percentage of school-aged children at risk for anaphylaxis. Moreover, anaphylaxis may occur for the first time in a previously undiagnosed child at school or childcare setting, suggesting that general preparedness is essential. Management includes strategies for minimizing the risk of reactions and allergen exposures as well as readiness to recognize and treat allergic reactions of any severity. The primary objective of this report is to offer health care providers an overview of relevant evidence, resources, and expert opinion to assist with developing interprofessional collaborative counsel on school food allergy management and anaphylaxis preparedness with families, schools, and childcare settings. We present the current evidence base, suggest resources, and highlight areas of current controversy that warrant further study. PMID- 29258791 TI - Osteonecrosis of the Lunate Associated With Systemic Sclerosis: Report of 4 Cases. PMID- 29258792 TI - Neutrophilic Dermatosis of the Hands (Sweet Syndrome of the Hands) Associated With Rheumatoid Arthritis. PMID- 29258793 TI - Joint prosthesis infection by Streptococcus mutans. PMID- 29258794 TI - Cogan Syndrome and Spondyloarthritis: Case Report. PMID- 29258795 TI - Esophageal symptoms and their lack of association with high-resolution manometry in systemic sclerosis patients. AB - BACKGROUND: The esophageal involvement in systemic sclerosis (SSc) causes impact in the morbidity and mortality. High resolution manometry assesses esophageal involvement. Our aim was to categorize esophageal motor disorder in patients with SSc by HRM. METHODS: We carried out an observational, descriptive and cross sectional study. All patients underwent HRM as well as semi-structured interviews to assess frequency and severity of upper GI symptoms. Patients also completed the gastroesophageal reflux questionnaire (Carlsson-Dent). RESULTS: We included 19 patients with SSc, 1 with morphea, and 1 with scleroderma sine scleroderma. Dysphagia and heartburn were the most frequent symptoms (61% each). We found an abnormal HRM in 15 (71.4%) patients. We found no statistically significant association between clinical or demographic variables and an abnormal HRM, or between any upper GI symptom and HRM findings. CONCLUSION: We observed a high prevalence of esophageal symptoms and of HRM abnormalities. However, there was no clear association between symptomatology and HRM findings. HRM does not seem to accurately predict upper GI symptomatology. PMID- 29258796 TI - Direct cost of medical care in patients with gonarthrosis. AB - OBJECTIVE: To determine the cost of medical care in patients with gonarthrosis. MATERIAL AND METHODS: Cost study in patients over 40 years of age with gonarthrosis, diagnosed according to the radiological classification of Kellgren and Lawrence. The average annual cost (euros) was estimated taking the unit cost plus average use of services such as family medicine, imaging, laboratory, electrodiagnosis, orthopedics, hospitalization, physical therapy, surgery, nutrition, preoperative assessment and medication. Projections based on assumptions were made for three scenarios. RESULTS: Grade 2 gonarthrosis predominated at 39.7% (95% confidence interval, 33.8 - 45.6). The annual cost of care for a patient with gonarthrosis was ?108.87 in the intermediate scenario, ?86.73 in the lower cost scenario and ?132.60 in the higher cost scenario. For a population of 119,530,753 inhabitants, with 10,937,064 gonarthrosis patients, the annual cost in the intermediate scenario was ?1,190,685,273 and represented 4.48% of the health expenditure. CONCLUSION: The average annual cost of gonarthrosis is relatively low, but when related to prevalence and prevalence trends, it can become a serious problem for health services. PMID- 29258797 TI - Private Rheumatology in the Community of Madrid, Spain: Descriptive Study. AB - The status of private rheumatology is known, but there is no information on the kind of patients seen. This study describes the experience over a 3-year period in a private rheumatology practice in the Autonomous Community of Madrid. We collected demographic and descriptive data. Of 706 patients seen, almost half (46%) were there for their first visit, and 12% of patients who had asked for an appointment did not attend. The majority of patients were women (72.4%) with a median age of 44.3 years old (range 3-93). The most frequent diagnoses were osteoarthritis (20.9%), osteopenia/osteoporosis (16.8%), arthralgia (13.4%) and soft tissue disorder (9.6%). The majority of the patients had private insurance with Spanish companies, such as MAPFRE, Adeslas and Asisa. At least one quarter of ancillary tests ordered in the first visit were not revised on a second visit. PMID- 29258798 TI - Robustness in living organisms is homeostasis. AB - In order to survive and reproduce, living organisms must be robust, tolerate injuries and undergo repair. Robustness in living organisms compares to robustness in human inventions, such as buildings and machines, which have to withstand occasional damage to avoid critical dysfunctions. However, the nature of robustness is fundamentally different in biology and in engineering. In living organisms, robustness is provided by homeostatic mechanisms, whereas in buildings and machines, it is provided by the redundancy of key elements. In this short essay, I discuss the nature of robustness in living organisms, and argue that redundancy, while important in engineering, is rare in biology. PMID- 29258799 TI - Typical sensory organization test findings and clinical implication in acute vestibular neuritis. AB - OBJECTIVE: Sensory organization test (SOT) is used to evaluate postural instability. We wanted to characterize the SOT findings in patients with acute vestibular neuritis (VN). METHODS: Eighty-seven patients with VN were enrolled. The bithermal caloric and SOT were performed, and the results were compared with those from the dizziness handicap inventory (DHI). Abnormal SOT patterns were classified: severe, visual vestibular, vestibular, inconsistent, or normal patterns. The results were also analyzed by sensory analysis (somatosensory, visual, vestibular, and visual preference) and composite scores. RESULTS: Sixty one patients (70%) showed abnormal findings for conditions 5 and/or 6 (vestibular pattern), and half (30 of 61, 49%) of them showed additional abnormal results in more than conditions 5 and 6. In pattern analysis, the vestibular pattern (abnormal in conditions 5 and 6) was the most common pattern (36%), and the visual vestibular pattern (abnormal in conditions 4, 5, and 6) was the second most common (24%). In sensory analysis, vestibular dysfunction was observed in 59 patients (68%), visual dysfunction in 37 (43%), visual preference in 17 (20%), and somatosensory dysfunction in 5 (6%). Composite scores of SOT showed a significant correlation with the DHI scores, though no correlation was observed between DHI and caloric results (p<0.05). CONCLUSION: VN can adversely influence on postural instability, with more severe patterns as well as classical vestibular patterns, indicating that abnormal vestibular inputs can influence postural stability in all SOT conditions and subjective symptom in patients with acute VN is more closely associated with the postural instability rather than canal dysfunction. PMID- 29258800 TI - Why does the need for medication become a barrier to breastfeeding? A narrative review. AB - PROBLEM: The need for medication during lactation can contribute to the early cessation of breastfeeding. BACKGROUND: Breastfeeding women may require medication for acute or chronic health conditions. For some women this need for medication can become a barrier to breastfeeding; this is despite the fact that the majority of medications are considered to be compatible with lactation. AIM: This narrative review aims to investigate factors relating to medicines safety that could contribute to medication unnecessarily becoming a barrier to breastfeeding. METHODS: A selective literature search using PubMed, Scopus and Google Scholar was conducted over a 6-month period using the search terms "breastfeeding", "lactation", "medication" and "information". Articles were assessed to identify whether they addressed the impact of medication use on the decision to breastfeed. FINDINGS: Fifty six articles were identified as having appropriate discussion about decision making for the safe use of medication during lactation. Themes identified included variable and conflicting safety advice for medicines; difficulty interpreting risks associated with medicine use; societal pressures faced by the breastfeeding woman; and the varied knowledge and training of health professionals involved in the care of breastfeeding women. CONCLUSION: Poor quality of information about medicine safety during lactation can contribute to confusion in giving recommendations. This confusion can result in early cessation of breastfeeding or insufficient health care for the breastfeeding woman. PMID- 29258801 TI - Diversity of Borrelia spirochetes and other zoonotic agents in ticks from Kyiv, Ukraine. AB - Lyme borreliosis (LB) is caused by tick-borne spirochetes of the Borrelia burgdorferi sensu lato complex. LB is the most prevalent vector-borne illness in Ukraine, but current data on the prevalence of LB pathogens in their tick vector, Ixodes ricinus, are lacking. I. ricinus ticks may also carry Borrelia miyamotoi, an emerging relapsing fever group spirochete that has been implicated in human illness. Despite its zoonotic potential, the prevalence of B. miyamotoi in ticks has not been examined in Ukraine. Similarly, data on the prevalence of other important tick-borne pathogens, Anaplasma phagocytophilum, Babesia spp., Bartonella spp., Francisella tularensis, and Rickettsia spp., in ixodid ticks are scarce or even absent. Thus, the overall objective of this study was to investigate the prevalence of these tick-borne pathogens in questing I. ricinus and Dermacentor reticulatus ticks collected in recreational parks of Kyiv, the most densely populated city of Ukraine. A total of 182 adult I. ricinus, 98 nymphal I. ricinus, and 98 adult D. reticulatus ticks were molecularly analyzed for the presence of these pathogens. As a result, the study shows a greater diversity of Borrelia genospecies in questing I. ricinus ticks than previously reported. The most prevalent genospecies in adult I. ricinus ticks were B. afzelii (7.7%), followed by B. burgdorferi sensu stricto (s.s.) (2.2%) and B. garinii (0.5%). In contrast, B. burgdorferi s.s. was most dominant in unfed I. ricinus nymphs (67.3%). Moreover, B. afzelii was detected in 11.2% of nymphs, but only 1.0% of nymphal ticks were positive for B. garinii and B. valaisiana. Importantly, this study provides the first record of B. miyamotoi detected in I. ricinus ticks from Ukraine (1.1%). Furthermore, the report is also the first to document other vector-borne pathogens, Bartonella henselae, Rickettsia conorii, and Rickettsia mendelii, in ixodid ticks from Ukraine. In summary, this work offers the latest data on the diversity and prevalence of the important zoonotic tick-borne agents in questing ticks from Kyiv, Ukraine. The data will help to better gauge the risk associated with vector-borne infections to which residents and guests of Ukraine's capital may be exposed. PMID- 29258802 TI - A molecular algorithm to detect and differentiate human pathogens infecting Ixodes scapularis and Ixodes pacificus (Acari: Ixodidae). AB - The incidence and geographic range of tick-borne illness associated with Ixodes scapularis and Ixodes pacificus have dramatically increased in recent decades. Anaplasmosis, babesiosis, and Borrelia spirochete infections, including Lyme borreliosis, account for tens of thousands of reported cases of tick-borne disease every year. Assays that reliably detect pathogens in ticks allow investigators and public health agencies to estimate the geographic distribution of human pathogens, assess geographic variation in their prevalence, and evaluate the effectiveness of prevention strategies. As investigators continue to describe new species within the Borrelia burgdorferi sensu lato complex and to recognize some Ixodes-borne Borrelia species as human pathogens, assays are needed to detect and differentiate these species. Here we describe an algorithm to detect and differentiate pathogens in unfed I. scapularis and I. pacificus nymphs including Anaplasma phagocytophilum, Babesia microti, Borrelia burgdorferi sensu stricto, Borrelia mayonii, and Borrelia miyamotoi. The algorithm comprises 5 TaqMan real-time polymerase chain reaction assays and 3 sequencing protocols. It employs multiple targets for each pathogen to optimize specificity, a gene target for I. scapularis and I. pacificus to verify tick-derived DNA quality, and a pan Borrelia target to detect Borrelia species that may emerge as human disease agents in the future. We assess the algorithm's sensitivity, specificity, and performance on field-collected ticks. PMID- 29258803 TI - Antioxidant functionalized polymer capsules to prevent oxidative stress. AB - : Polymeric capsules exhibit significant potential for therapeutic applications as microreactors, where the bio-chemical reactions of interest are efficiently performed in a spatial and time defined manner due to the encapsulation of an active biomolecule (e.g., enzyme) and control over the transfer of reagents and products through the capsular membrane. In this work, catalase loaded polymer capsules functionalized with an external layer of tannic acid (TA) are fabricated via a layer-by-layer approach using calcium carbonate as a sacrificial template. The capsules functionalised with TA exhibit a higher scavenging capacity for hydrogen peroxide and hydroxyl radicals, suggesting that the external layer of TA shows intrinsic antioxidant properties, and represents a valid strategy to increase the overall antioxidant potential of the developed capsules. Additionally, the hydrogen peroxide scavenging capacity of the capsules is enhanced in the presence of the encapsulated catalase. The capsules prevent oxidative stress in an in vitro inflammation model of degenerative disc disease. Moreover, the expression of matrix metalloproteinase-3 (MMP-3), and disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5), which represents the major proteolytic enzymes in intervertebral disc, are attenuated in the presence of the polymer capsules. This platform technology exhibits potential to reduce oxidative stress, a key modulator in the pathology of a broad range of inflammatory diseases. STATEMENT OF SIGNIFICANCE: Oxidative stress damages important cell structures leading to cellular apoptosis and senescence, for numerous disease pathologies including cancer, neurodegeneration or osteoarthritis. Thus, the development of biomaterials-based systems to control oxidative stress has gained an increasing interest. Herein, polymer capsules loaded with catalase and functionalized with an external layer of tannic acid are fabricated, which can efficiently scavenge important reactive oxygen species (i.e., hydroxyl radicals and hydrogen peroxide) and modulate extracellular matrix activity in an in vitro inflammation model of nucleus pulposus. The present work represents accordingly, an important advance in the development and application of polymer capsules with antioxidant properties for the treatment of oxidative stress, which is applicable for multiple inflammatory disease targets. PMID- 29258804 TI - Prospective comparative study of characteristics associated with influenza A and B in adults. AB - OBJECTIVES: To describe and compare the epidemiological characteristics associated with influenza type A and B as well as the characteristics associated with influenza pneumonia. The secondary objective was to evaluate the performance of influenza rapid diagnostic tests (RDT) in the emergency department. PATIENTS AND METHODS: Prospective study, including 251 adult patients admitted to the emergency department during the 2013-2014 influenza outbreaks for flu-like illness confirmed by RT-PCR. RESULTS: A total of 106 patients were infected with influenza type B (42%) and 145 with influenza type A (58%). Mean age was 56 and the sex-ratio was 0.9. In a multivariate analysis, the only factor independently related with the type of influenza strain was the patient's age. Overall, 17% of influenza-infected patients were vaccinated and 38% presented with pneumonia, with no significant difference between strains. In a univariate analysis, the risk factors associated with the occurrence of pneumonia were age, vaccination, and chronic obstructive pulmonary disease. Only 22% of samples positive by RT-PCR for influenza B and 40% for influenza A were positive by RDT. CONCLUSION: Influenza type A and type B had similar clinical and biological signs, including severity. Influenza type B should not be neglected. Any emergency department may use the RDT for its ease-of-use and rapidity. However, its low sensitivity should be taken into consideration when interpreting results. PMID- 29258805 TI - American Society for Pain Management Nursing and Hospice and Palliative Nurses Association Position Statement: Pain Management at the End of Life. AB - Pain at the end of life continues to be of great concern as it may be unrecognized or untreated. Although nurses have an ethical obligation to reduce suffering, barriers remain regarding appropriate and adequate pain management at the end of life. This joint position statement from the American Society for Pain Management Nursing and Hospice and Palliative Nurses Association contains recommendations for nurses, prescribers, and institutions that would improve pain management for this vulnerable population. PMID- 29258806 TI - Renal function evaluation in liver cirrhosis: Preliminary report on the effect of the Royal Free Hospital Cirrhosis Glomerular Filtration Rate on the Model for End Stage Liver Disease (MELD). PMID- 29258807 TI - The intensity of continuous theta burst stimulation, but not the waveform used to elicit motor evoked potentials, influences its outcome in the human motor cortex. AB - BACKGROUND: Responses to continuous theta burst stimulation (cTBS) applied to the human primary motor cortex are highly variable between individuals. However, little is known about how to improve the after-effects of cTBS by adjusting the protocol characteristics. OBJECTIVE: We examined whether current directions adopted in the measurement of cortical motor excitability indexed as motor evoked potentials (MEPs) affect the responses to cTBS. We also tested whether the stimulus intensity of cTBS influences the after-effects. METHODS: Thirty-one healthy volunteers participated. The after-effects of cTBS with the conventional intensity of 80% of individual active motor threshold (AMT) (cTBS80%) were tested by measuring MEP amplitudes induced by not only posterior-anterior (PA) but also anterior-posterior (AP) and biphasic (PA-AP) currents. We also investigated cTBS with 65% AMT (cTBS65%) and 100% AMT (cTBS100%) in subjects who showed depression of MEP amplitudes after cTBS80%, as well as cTBS65% in subjects in whom facilitation of MEPs was induced by cTBS80%. RESULTS: Current directions in MEP measurement had no influence on the cTBS responses. In subjects whose MEPs were depressed by cTBS80%, cTBS100% partly induced MEP facilitation, while cTBS65% abolished the after-effects. In subjects who showed MEP facilitation by cTBS80%, cTBS65% partly induced MEP depression. CONCLUSIONS: Stimulus intensity of cTBS influenced the responses to cTBS, and lowering stimulus intensity induced the expected after-effects of cTBS in some subjects. PMID- 29258808 TI - Incomplete evidence that increasing current intensity of tDCS boosts outcomes. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is investigated to modulate neuronal function by applying a fixed low-intensity direct current to scalp. OBJECTIVES: We critically discuss evidence for a monotonic response in effect size with increasing current intensity, with a specific focus on a question if increasing applied current enhance the efficacy of tDCS. METHODS: We analyzed tDCS intensity does-response from different perspectives including biophysical modeling, animal modeling, human neurophysiology, neuroimaging and behavioral/clinical measures. Further, we discuss approaches to design dose response trials. RESULTS: Physical models predict electric field in the brain increases with applied tDCS intensity. Data from animal studies are lacking since a range of relevant low-intensities is rarely tested. Results from imaging studies are ambiguous while human neurophysiology, including using transcranial magnetic stimulation (TMS) as a probe, suggests a complex state-dependent non monotonic dose response. The diffusivity of brain current flow produced by conventional tDCS montages complicates this analysis, with relatively few studies on focal High Definition (HD)-tDCS. In behavioral and clinical trials, only a limited range of intensities (1-2 mA), and typically just one intensity, are conventionally tested; moreover, outcomes are subject brain-state dependent. Measurements and models of current flow show that for the same applied current, substantial differences in brain current occur across individuals. Trials are thus subject to inter-individual differences that complicate consideration of population-level dose response. CONCLUSION: The presence or absence of simple dose response does not impact how efficacious a given tDCS dose is for a given indication. Understanding dose-response in human applications of tDCS is needed for protocol optimization including individualized dose to reduce outcome variability, which requires intelligent design of dose-response studies. PMID- 29258809 TI - Could qSOFA and SOFA score be correctly estimating the severity of healthcare associated pneumonia? AB - The Japanese Respiratory Society newly updated the prognostic guidelines for pneumonia in 2017. Quick Sequential Organ Failure Assessment (qSOFA) and Sequential Organ Failure Assessment (SOFA) score are used to evaluate the severity of pneumonia and to select the therapy for pneumonia. This is a retrospective study at Aichi Medical University hospital from January to December of 2016 to investigate the accuracy and usefulness of qSOFA and SOFA score in evaluating the severity and prognosis of healthcare-associated pneumonia (HCAP). A total of 81 HCAP patients were enrolled in this study. Both the 30-day and in hospital mortality were 7.5% (6/81). qSOFA?2 was in 33/78 patients (42%) and <2 in 45/78 patients (58%), showing a 30-day mortality of 9.1% (3/33) and 6.7% (3/45) (p = 0.45), respectively. Comparing with qSOFA?2 and < 2 group, HCAP patients with qSOFA?2 had much higher A-DROP (31. v.s. 2.2, p < 0.001), CURB-65 (2.7 v.s. 1.9, p < 0.001), PSI (133 v.s. 114, p = 0.014), I-ROAD (2.7 v.s. 1.9, p < 0.001) and SOFA scores (3.8 v.s. 2.8, p < 0.001). With respect to the diagnostic value of predictive values for 30-day mortality among HCAP patients, the area under the receiver-operating characteristic curve for SOFA score was 0.930 with a statistical significance (p < 0.001). The SOFA score cutoff value was 4 and had a sensitivity of 20%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 68%. In conclusion, SOFA core could be one of the most useful tools in evaluating the severity of HCAP. PMID- 29258811 TI - Longer treatment with alternative non-drug reinforcement fails to reduce resurgence of cocaine or alcohol seeking in rats. AB - Provision of alternative non-drug reinforcement is among the most effective methods for treating substance use disorders. However, when alternative reinforcers become unavailable during treatment interruptions or upon cessation of treatment, relapse often occurs. Relapse following the loss of alternative reinforcement is known as resurgence. One factor that could reduce resurgence is longer duration of treatment with alternative reinforcement, but the available data are mixed. Further, the effects of length of treatment have previously only been examined with food seeking. The present experiments directly examined if duration of treatment impacted the magnitude of resurgence of cocaine or alcohol seeking in rats. First, rats were trained to self-administer cocaine (Experiment 1) or alcohol (Experiment 2) by performing a target behavior. Second, target behavior was extinguished and performing an alternative behavior produced an alternative non-drug (i.e., food) reinforcer. Finally, resurgence was assessed following removal of alternative reinforcement after either 5 or 20 sessions of treatment. Treatment duration did not differentially affect resurgence of cocaine seeking in Experiment 1 or Alcohol seeking in Experiment 2. These results suggest that extended treatment with alternative non-drug reinforcement may not decrease propensity to relapse. Further, these results may have implications for treatment of substance use disorders and for theories of resurgence. PMID- 29258813 TI - Novel ultrasound-based methods to assess liver disease: The game has just begun. AB - In the last 10 years the availability of ultrasound elastography allowed to diagnose and stage liver fibrosis in a non-invasive way and changed the clinical practice of hepatology. Newer ultrasound-based techniques to evaluate properties of the liver tissue other than fibrosis are emerging and will lead to a more complete characterization of the full spectrum of diffuse and focal liver disease. Since these methods are currently undergoing validation and go beyond elastography for liver tissue evaluation, they were not included in the recent guidelines regarding elastography issued by the European Federation of Societies in Ultrasound in Medicine and Biology. In this review paper, we outline the major advances in the field of ultrasound for liver applications, with special emphasis on techniques that could soon be part of the future armamentarium of ultrasound specialists devoted to the assessment of liver disease. Specifically, we discuss current and future ultrasound assessment of steatosis, spleen stiffness for portal hypertension, and elastography for the evaluation of focal liver lesions; we also provide a short glimpse into the next generation of ultrasound diagnostic methods. PMID- 29258810 TI - Sex differences in sleep apnea and comorbid neurodegenerative diseases. AB - Sleep apnea is a disorder, which increasingly affects people worldwide. Whether the associated hypoxic events during sleep are central or obstructive in origin, the end result is excessive daytime sleepiness and an increased risk for several comorbidities, such as cardiovascular and neurodegenerative disorders. Sleep apnea is diagnosed more frequently in men than women, suggesting a role of sex hormones in the pathology of the disease. Furthermore, there are sex differences in the development and progression of comorbid diseases associated with sleep apnea. Therefore, treatment of sleep apnea may be clinically relevant for prevention of subsequent sex-specific comorbid disorders. While the impact sleep apnea has on cardiovascular events has been the subject of many research studies, the role of sleep apnea in neurodegeneration is less established. Here we review known risk factors for sleep apnea and the implications of the observed sex differences in this disease. We also summarize the evidence and mechanisms for how sleep apnea may contribute to the onset of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. PMID- 29258814 TI - Cross-sectional evaluation of transmural healing in Crohn's disease: Mural and mesenteric parameters - Authors' reply. PMID- 29258812 TI - Evaluating bevacizumab in combination with FOLFIRI after the failure of platinum etoposide regimen in patients with advanced poorly differentiated neuroendocrine carcinoma: The PRODIGE 41-BEVANEC randomized phase II study. AB - INTRODUCTION: Patients with gastroenteropancreatic (GEP), metastatic or locally advanced, non-resectable, grade 3 poorly-differentiated neuroendocrine carcinoma (NEC) are treated with cisplatin (or carboplatin)-etoposide in first-line palliative chemotherapy (CT1). However, nearly all patients will develop resistance and there is no standard second-line treatment. AIM: PRODIGE 41 BEVANEC is an academic randomized, phase II study designed to evaluate the efficacy of bevacizumab in combination with FOLFIRI after failure of CT1 in unknown primary NEC and GEP-NEC. MATERIALS AND METHODS: The main eligibility criteria are age >=18 years, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy. RESULTS: A total of 124 patients will be randomly assigned (1:1) to receive either 5 mg/kg bevacizumab with FOLFIRI, or FOLFIRI alone, every 14 days until disease progression or unacceptable toxicity. The hypothesis is to demonstrate a 6-month overall survival for at least 50% of the patients in bevacizumab arm versus 35% in the control arm (FOLFIRI alone). Secondary endpoints are objective response, response duration, progression-free survival, toxicity, and biochemical response. CONCLUSION: The study is currently opened in France (NCT02820857). The first patient was randomized on September 6, 2017. PMID- 29258815 TI - Elevated serum antiphospholipid antibodies in adults with celiac disease. AB - BACKGROUND AND AIMS: An increased incidence of thrombosis is suggested in celiac disease. We explored serum levels of antiphospholipid antibodies in untreated and treated adult celiac disease patients. METHODS: A cohort of 179 biopsy-proven celiac disease patients (89 untreated, 90 on long-term gluten-free diet) and 91 non-celiac controls underwent clinical examination, assessment of celiac serology and enzyme immunoassay testing for anticardiolipin IgG and IgM, prothrombin IgG, and phosphatidylserine-prothrombin IgG and IgM. RESULTS: The level of antiphospholipid antibodies was higher in celiac disease patients compared with controls: anticardiolipin IgG 4.9 (0.7-33.8) vs 2.2 (0.4-9.6) U/ml, antiprothrombin IgG 2.9 (0.3-87.8) vs 2.1 (0.5-187.0) U/ml, antiphosphatidylserine-prothrombin IgG 6.9 (0.0-54.1) vs 2.3 (0.5-15.1) U/ml; p < 0.05 for all. Anticardiolipin IgG, antiprothrombin IgG and antiphosphatidylserine prothrombin IgG were higher in treated compared with untreated patients. The phenotype of celiac disease at presentation (gastrointestinal symptoms, malabsorption or anemia, and extraintestinal symptoms or screen-detected disease) had no effect on the level of serum antiphospholipid antibodies. CONCLUSION: The serum level of antiphospholipid antibodies is increased in adults with celiac disease. The higher level of antibodies in treated patients suggests that the increase is not gluten-dependent. The prothrombotic role of antiphospholipid antibodies in celiac disease warrants further studies. PMID- 29258816 TI - The Y. bercovieri Anbu crystal structure sheds light on the evolution of highly (pseudo)symmetric multimers. AB - Ancestral beta-subunit (Anbu) is homologous to HslV and 20S proteasomes. Based on its phylogenetic distribution and sequence clustering, Anbu has been proposed as the "ancestral" form of proteasomes. Here, we report biochemical data, small angle X-ray scattering results, negative-stain electron microscopy micrographs and a crystal structure of the Anbu particle from Yersinia bercovieri (YbAnbu). All data are consistent with YbAnbu forming defined 12-14 subunit multimers that differ in shape from both HslV and 20S proteasomes. The crystal structure reveals that YbAnbu subunits form tight dimers, held together in part by the Anbu specific C-terminal helices. These dimers ("protomers") further assemble into a low-rise left-handed staircase. The lock-washer shape of YbAnbu is consistent with the presence of defined multimers, X-ray diffraction data in solution and negative-stain electron microscopy images. The presented structure suggests a possible evolutionary pathway from helical filaments to highly symmetric or pseudosymmetric multimer structures. YbAnbu subunits have the Ntn-hydrolase fold, a putative S1 pocket and conserved candidate catalytic residues Thr1, Asp17 and Lys32(33). Nevertheless, we did not detect any YbAnbu peptidase or amidase activity. However, we could document orthophosphate production from ATP catalyzed by the ATP-grasp protein encoded in the Y. bercovieri Anbu operon. PMID- 29258817 TI - A Completely Reimplemented MPI Bioinformatics Toolkit with a New HHpred Server at its Core. AB - The MPI Bioinformatics Toolkit (https://toolkit.tuebingen.mpg.de) is a free, one stop web service for protein bioinformatic analysis. It currently offers 34 interconnected external and in-house tools, whose functionality covers sequence similarity searching, alignment construction, detection of sequence features, structure prediction, and sequence classification. This breadth has made the Toolkit an important resource for experimental biology and for teaching bioinformatic inquiry. Recently, we replaced the first version of the Toolkit, which was released in 2005 and had served around 2.5 million queries, with an entirely new version, focusing on improved features for the comprehensive analysis of proteins, as well as on promoting teaching. For instance, our popular remote homology detection server, HHpred, now allows pairwise comparison of two sequences or alignments and offers additional profile HMMs for several model organisms and domain databases. Here, we introduce the new version of our Toolkit and its application to the analysis of proteins. PMID- 29258819 TI - DichroCalc: Improvements in Computing Protein Circular Dichroism Spectroscopy in the Near-Ultraviolet. AB - A fully quantitative theory connecting protein conformation and optical spectroscopy would facilitate deeper insights into biophysical and simulation studies of protein dynamics and folding. The web server DichroCalc (http://comp.chem.nottingham.ac.uk/dichrocalc) allows one to compute from first principles the electronic circular dichroism spectrum of a (modeled or experimental) protein structure or ensemble of structures. The regular, repeating, chiral nature of secondary structure elements leads to intense bands in the far-ultraviolet (UV). The near-UV bands are much weaker and have been challenging to compute theoretically. We report some advances in the accuracy of calculations in the near-UV, realized through the consideration of the vibrational structure of the electronic transitions of aromatic side chains. The improvements have been assessed over a set of diverse proteins. We illustrate them using bovine pancreatic trypsin inhibitor and present a new, detailed analysis of the interactions which are most important in determining the near-UV circular dichroism spectrum. PMID- 29258818 TI - Remodeling of HIV-1 Nef Structure by Src-Family Kinase Binding. AB - The HIV-1 accessory protein Nef controls multiple aspects of the viral life cycle and host immune response, making it an attractive therapeutic target. Previous X ray crystal structures of Nef in complex with key host cell binding partners have shed light on protein-protein interactions critical to Nef function. Crystal structures of Nef in complex with either the SH3 or tandem SH3-SH2 domains of Src family kinases reveal distinct dimer conformations of Nef. However, the existence of these Nef dimer complexes in solution has not been established. Here we used hydrogen exchange mass spectrometry (HX MS) to compare the solution conformation of Nef alone and in complexes with the SH3 or the SH3-SH2 domains of the Src family kinase Hck. HX MS revealed that interaction with the Hck SH3 or tandem SH3 SH2 domains induces protection of the Nef alphaB-helix from deuterium uptake, consistent with a role for alphaB in dimer formation. HX MS analysis of a Nef mutant (position Asp123, a site buried in the Nef:SH3 dimer but surface exposed in the Nef:SH3-SH2 complex), showed a Hck-induced conformational change in Nef relative to wild-type Nef. These results support a model in which Src-family kinase binding induces conformational changes in Nef to expose residues critical for interaction with the MU1 subunit of adaptor protein 1 and the major histocompatibility complex-1 tail, and subsequent major histocompatibility complex-1 downregulation and immune escape of HIV-infected cells required for functional interactions with downstream binding partners. PMID- 29258820 TI - P53 modulates hepatic insulin sensitivity through NF-kappaB and p38/ERK MAPK pathways. AB - Besides its well-established oncosuppressor activity, the role of p53 in regulating metabolic pathways has been recently identified. Nevertheless, the function of p53 with respect to insulin resistance appears highly controversial. To address this issue, we investigated the expression of p53 in experimental model of insulin resistance. Then we used activator (nutlin-3alpha) and inhibitor (pifithrin-alpha, PFT-alpha) of p53 in HepG2 cell. Here we showed that p53 protein level was decreased in the hepatic tissue of high-fat diet-induced insulin resistance mice, genetically diabetic ob/ob mice and palmitate (PA) treated HepG2 cells. And high expression of phosphor-p38, ERK1/2 and nuclear factor kappa B (NF-kappaB) p65 accompanied with low expression of p53. But activation of p53 with nutlin-3alpha prevented PA-induced reduction of glucose consumption and suppression of insulin signaling pathways. At the same time, nutlin-3alpha downregulated the activation of NF-kappaB, p38 and ERK1/2 pathways upon stimulation with PA. In contrast, inhibition of p53 with PFT-alpha decreased glucose consumption and suppressed insulin signaling pathway. Furthermore, PFT alpha activated NF-kappaB, p38 and ERK1/2 pathways in HepG2 cells. Overall, these results suggest that p53 is involved in improving insulin sensitivity of hepatic cells via inhibition of mitogen-activated protein kinases (MAPKs) and NF-kappaB pathways. PMID- 29258821 TI - Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons. AB - To investigate the role of nitric oxide (NO)/reactive oxygen species (ROS) redox signaling in Parkinson's disease-like neurotoxicity, we used 1-methyl-4 phenylpyridinium (MPP+) treatment (a model of Parkinson's disease). We show that MPP+-induced neurotoxicity was dependent on ROS from neuronal NO synthase (nNOS) in nNOS-expressing PC12 cells (NPC12 cells) and rat cerebellar granule neurons (CGNs). Following MPP+ treatment, we found production of 8-nitroguanosine 3',5' cyclic monophosphate (8-nitro-cGMP), a second messenger in the NO/ROS redox signaling pathway, in NPC12 cells and rat CGNs, that subsequently induced S guanylation and activation of H-Ras. Additionally, following MPP+ treatment, extracellular signal-related kinase (ERK) phosphorylation was enhanced. Treatment with a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor attenuated MPP+-induced ERK phosphorylation and neurotoxicity. In conclusion, we demonstrate for the first time that NO/ROS redox signaling via 8-nitro-cGMP is involved in MPP+-induced neurotoxicity and that 8-nitro-cGMP activates H-Ras/ERK signaling. Our results indicate a novel mechanism underlying MPP+-induced neurotoxicity, and therefore contribute novel insights to the mechanisms underlying Parkinson's disease. PMID- 29258822 TI - LncRNA MALAT1 regulates oxLDL-induced CD36 expression via activating beta catenin. AB - The expression of scavenger receptors in macrophages regulating lipid uptake plays an important role in foam cell formation and the subsequent atherosclerotic plaque formation. Long non-coding RNA MALAT1 is abundantly expressed in THP-1 derived macrophages, and oxidized low-density lipoprotein promotes its transcription by qRT-PCR and RNA FISH detection. Through chemical inhibitor treatments and by performing a dual luciferase reporter analysis, we found that oxLDL induces MALAT1 transcription through the NF-kappaB pathway. The knockdown of MALAT1 using siRNA transfection affects lipid uptake in macrophages. To understand the details, we checked the scavenger receptors, which mainly control lipid uptake, and found that MALAT1 knockdown decreased CD36 expression. Additionally, we also incubated macrophages with actinomycin D, combined with a dual luciferase reporter analysis, and we found that MALAT1 influenced CD36 expression at the transcription level. We aim to investigate the detailed mechanism by which MALAT1 promotes CD36 transcription, and thus, we designed and synthesized biotin-TEG labeled oligonucleotides to precipitate the MALAT1 RNA-DNA protein complex in vivo. Combined with SDS-PAGE electrophoresis and a subsequent mass spectra analysis, beta-catenin, a transcription factor that promotes CD36 transcription, was found in the complex. By performing R-IPs, we validated that beta-catenin was bound to MALAT1 under the oxLDL treatment. In addition, using VAX939, a chemical inhibitor of beta-catenin, MALAT1 was demonstrated to promote CD36 transcription partly via beta-catenin. We also performed chips to detect whether MALAT1 affects beta-catenin accumulation in the binding sites of the CD36 promoter and found that MALAT1 knockdown decreases beta-catenin binding to the CD36 promoter and vice versa. In conclusion, oxLDL induced MALAT1 transcription and MALAT1 recruits beta-catenin to binding sites on the CD36 promoter to induce CD36 expression, which enhances lipid uptake in macrophages. PMID- 29258823 TI - Long non-coding RNA RMST silencing protects against middle cerebral artery occlusion (MCAO)-induced ischemic stroke. AB - Long non-coding RNAs (lncRNAs) have emerged as major regulators in neurological diseases, and clarifying their roles in cerebral ischemic injury may provide novel targets for treating ischemic stroke. In this study, we mainly studied the role of lncRNA-RMST in middle cerebral artery occlusion (MCAO)-induced mouse brain injury. We showed that RMST expression level was significantly up-regulated in oxygen-glucose deprivation (OGD)-treated primary hippocampal neuron, MCAO induced injured brain, and the plasma of patients with ischemic stroke. RMST silencing protected against MCAO-induced ischemic brain injury in vivo and OGD induced primary hippocampal neuron injury in vitro. Intracerebroventricular injection of RMST shRNA significantly decreased brain RMST expression, reduced brain infarct size, and improved neurological function. Collectively, this study provides evidence that lncRNA is involved in the pathogenesis of ischemic brain injury, and suggests a promising approach of RMST inhibition in treating ischemic stroke. PMID- 29258824 TI - Hypoxia-increased RAGE expression regulates chemotaxis and pro-inflammatory cytokines release through nuclear translocation of NF-kappa B and HIF1alpha in THP-1 cells. AB - The potential role of hypoxia in mediating the receptor for advanced glycation end products (RAGE) expression deserves to be confirmed. And the role of RAGE in hypoxia-induced chemotaxis and inflammation is still unclear. In present study, THP-1 cells were pretreated with siRNA to block HIF1alpha, NF-kappa B, or RAGE, followed by exposed to hypoxia (combined with H2O2 or SNP), and then RAGE expression, nuclear translocation of HIF1alpha and NF-kappa B, release of TNF alpha and IL-1beta, as well as expression of MCP-1 and CCR2 were measured. The results revealed that RAGE mRNA and protein in THP-1 cells were significantly increased after exposed into hypoxia atmosphere, especially into the solution containing SNP or H2O2. Moreover, SNP or H2O2 exposure could further amplify hypoxia-induced nuclear translocation of HIF-1alpha and NF-kappa B. Knockdown HIF 1alpha or NF-kappa B by siRNAs could reduce hypoxia- and oxidative stress-induced RAGE hyper-expression. And pretreatment THP-1 cells with RAGE siRNA or NF-kappa B siRNA could reduce hypoxia- and oxidative stress-induced expression of MCP-1 and CCR2, and release of TNF-alpha and IL-1beta. Thus, hypoxia not only increases RAGE expression in THP-1 cells by promoting nuclear translocation of NF-kappa B and HIF1alpha, but also regulates chemotaxis and pro-inflammatory cytokines release, which may be partially mediated through upregulation of RAGE expression. PMID- 29258825 TI - Role of diffusion-weighted MR imaging in predicting the grade of nonfunctional pancreatic neuroendocrine tumors. AB - PURPOSE: The purpose of this study was to describe the magnetic resonance imaging (MRI) findings including diffusion-weighted MRI of nonfunctional pancreatic neuroendocrine tumors (PanNETs) and their hepatic metastases, and investigate the relationships between MRI features and histopathological findings for each grade of PanNETs. MATERIALS AND METHODS: A total of 30 patients were included. There were 14 men and 16 women with a mean age of 61.60+/-11 (SD) years (range: 31 81years). PanNET lesions were analyzed qualitatively (signal intensities, contrast enhancement, lesion margins, presence of metastasis and characteristics of metastases) and quantitatively (signal intensity ratios, contrast enhancement indices and normalized apparent diffusion coefficient [ADC]). The relationships between MRI findings and histopathological findings were evaluated. RESULTS: Among 30 nonfunctional PanNETs, 11 were high-grade tumors, 10 were intermediate and 9 were low-grade tumors. All high grade PanNETs showed low to intermediate signal on T2-weighted images and ill-defined borders. All intermediate grade PanNETs had intermediate and 6 low grade PanNETs have high signal on T2-weighted images. Patients with hepatic metastases from high grade PanNETs had cystic component in 8/10 (80%) and wash-out in 7/10 (70%) whereas intermediate grade PanNETs had none (P<0.05). The normalized ADC values of high grade PanNETs was lower than those of intermediate and low grade PanNETs (P<0.05). CONCLUSION: The presence of cystic component or contrast wash-out in hepatic metastases correlates with high grade PanNETs. The pre-operative MRI combined with DWI has an important role in grading and surgical planning of PanNETs. PMID- 29258826 TI - A multi-substrate assay for finding physiologically effective inhibitors of myeloperoxidase. AB - Myeloperoxidase, an abundant neutrophil enzyme, promotes oxidative damage during inflammation by generating hypohalous acids and free radicals. Currently, there are no selective drugs to inhibit its adverse activity. This short-coming is partly due to the lack of screening assays that mimic the complex enzymatic activities of myeloperoxidase in vivo. We have developed an assay for myeloperoxidase activity that includes its major physiological substrates - chloride, thiocyanate, tyrosine, and urate. The multi-substrate assay monitors bleaching of 5-thio-2-nitrobenzoic acid and measures total oxidant production when hydrogen peroxide activates the enzyme. Known suicide inhibitors and tight binders tested positive in the assay, whereas compounds that merely convert myeloperoxidase to reducible enzyme intermediates were poor inhibitors. The new assay revealed that some aromatic compounds, including tryptamine, inhibit myeloperoxidase by binding reversibly to the enzyme. Our multi-substrate assay is selective for physiologically relevant inhibitors and has potential for identifying new classes of myeloperoxidase inhibitors. PMID- 29258827 TI - A carbon nanotube-enhanced real-time immuno-PCR for ultrasensitive detection of AHTN in water. AB - Polycyclic musks (PCMs) in the aquatic environment have become an emerging environmental issue because of their potential risk. The most commonly used method for analysis of PCMs is gas chromatography-mass spectrometer (GC-MS) with different sample extractions, which are somewhat expensive to operate, laborious and complex. In this paper, a carbon nanotube-enhanced real time immuno-PCR was developed for ultrasensitive detection of AHTN in water for the first time. The SWCNTs were used to immobilize numerous amino-DNA and polyclonal antibody to form polyclonal antibody-CNTs-DNA conjugates, which were used as a signal-amplifier in the proposed immunoassay system. This proposed carbon nanotube enhanced real time immuno-PCR assay was used to determine AHTN in water samples ranging from 5 pg/L 0.1 ng/L; using sample size as low as 10 MUL. This proposed carbon nanotube enhanced real time immuno-PCR is the most ultrasensitive one for determination of AHTN in water without pre-concentration or extractions; and it provide a potential way for ultra-trace AHTN detection in the aquatic environment. PMID- 29258828 TI - Glassy carbon electrode modified with carbon black for sensitive estradiol determination by means of voltammetry and flow injection analysis with amperometric detection. AB - A voltammetric method for fast and sensitive estradiol determination using carbon black modified glassy carbon electrode (CBGC) is proposed. The use of carbon black as a modifying layer led to obtain low detection limit (9.2.10-8 mol L-1 for a preconcentration time of 60 s) and stability of registered signals (measured as RSD is 1.3%, n = 7, estradiol concentration 0.5.10-6 mol L-1). Cyclic voltammetry study revealed that in phosphate media estradiol suffers irreversible one-proton and one-electron oxidation process. Under the optimum conditions, estradiol calibration curve was linear in the concentration range from 0.15.10-6 to 3.5.10-6 mol L-1. The proposed method enable to determine estradiol content in different pharmaceutical formulation with good recovery. Amperometric measurements of estradiol were performed as well to indicate the possibility of its fast and accurate determination under the flow conditions. PMID- 29258829 TI - Development of a pan-rickettsial molecular diagnostic test based on recombinase polymerase amplification assay. AB - Rickettsioses are zoonotic vector-transmitted bacterial infections leading to flu like symptoms and can progress to severe illness in humans. The gold standard for diagnosis of rickettsial infections is the indirect immunofluorescence assay, a serological method which is not suitable for pathogen identification during the acute phase of the disease. Therefore, several real-time PCR assays were developed. These assays are very sensitive, but require high-equipped laboratories and well-trained personnel. Hence, in this study, a rapid point-of need detection method was developed to detect all Rickettsia species. The 23S and 16S rRNA genes were targeted to develop a recombinase polymerase amplification (RPA) assay. Both 23S and 16S_RPA assays required between seven to ten minutes to amplify and detect one or ten DNA molecules/reaction, respectively. The 16S_RPA assay detected all tested species, whereas the 23S_RPA assay identified only species of the spotted fever and transitional rickettsial groups. All results were compared with real-time PCR assays directed against the same rickettsial genes. The RPA assays are easy to handle and produced quicker results in comparison to real-time PCRs. Both RPA assays were implemented in a mobile suitcase laboratory to ease the use in rural areas. This method can help to provide rapid management of rickettsial infections. PMID- 29258830 TI - Trichinella spiralis muscle larvae excretory-secretory products induce changes in cytoskeletal and myogenic transcription factors in primary myoblast cultures. AB - Trichinella spiralis infection in skeletal muscle culminates with nurse cell formation. The participation of excretory-secretory products of the muscle larvae has been implicated in this process through different studies performed in infected muscle and the muscle cell line C2C12. In this work, we developed primary myoblast cultures to analyse the changes induced by excretory-secretory products of the muscle larvae in muscle cells. Microarray analyses revealed expression changes in muscle cell differentiation, proliferation, cytoskeleton organisation, cell motion, transcription, cell cycle, apoptosis and signalling pathways such as MAPK, Jak-STAT, Wnt and PI3K-Akt. Some of these changes were further evaluated by other methodologies such as quantitative real-time PCR (qRT PCR) and western blot, confirming that excretory-secretory products of the muscle larvae treated primary mouse myoblasts undergo increased proliferation, decreased expression of MHC and up-regulation of alpha-actin. In addition, changes in relevant muscle transcription factors (Pax7, Myf5 and Mef2c) were observed. Taken together, these results provide new information about how T. spiralis could alter the normal process of skeletal muscle repair after ML invasion to accomplish nurse cell formation. PMID- 29258831 TI - Identification and characterization of proteins in the Amblyomma americanum tick cement cone. AB - The adaptation of hard ticks to feed for long periods is facilitated by the cement cone, which securely anchors the tick mouthparts onto host skin and protects the tick from being groomed off by the host. Thus, preventing tick cement deposition is an attractive target for the development of innovative tick control. We used LC-MS/MS sequencing to identify 160 Amblyomma americanum tick cement proteins that include glycine-rich proteins (GRP, 19%), protease inhibitors (12%), proteins of unknown function (11%), mucin (4%), detoxification, storage, and lipocalin at 1% each, and housekeeping proteins (50%). Spatiotemporal transcription analysis showing mRNA expression in multiple tick organs and transcript abundance increasing with feeding suggest that selected GRPs (n = 13) regulate multiple tick feeding functions, being classified as constitutively expressed (CE), feeding induced (FI), and up-regulated with feeding (UR). We show that transcription of CE GRPs is likely under the control of tick appetence associated factors in that mRNA abundance increased several thousand fold in 1 week old adult ticks, the time period that coincides with tick attainment of appetence. Given the high number of targets, we synthesized and injected unfed ticks with combinatorial (co) double stranded (ds)RNA and disrupted GRP mRNA in clusters according to similar transcription patterns: CE (n = 3), FI, (n = 4), and UR (n = 6) to streamline the work. Our data suggest that CE and FI GRPs are important for maintenance of the tick feeding site in that reddening and subsequent bleeding were observed around the mouthparts of CE and FI GRP co-dsRNA injected ticks during feeding. Furthermore, although not significantly different, indices for blood meal size and fecundity were apparently reduced in FI and UR ticks. We discuss our data with reference to A. americanum tick feeding physiology. PMID- 29258833 TI - A reference genome and methylome for the Plasmodium knowlesi A1-H.1 line. AB - Plasmodium knowlesi, a common parasite of macaques, is recognised as a significant cause of human malaria in Malaysia. The P. knowlesi A1H1 line has been adapted to continuous culture in human erythrocytes, successfully providing an in vitro model to study the parasite. We have assembled a reference genome for the PkA1-H.1 line using PacBio long read combined with Illumina short read sequence data. Compared with the H-strain reference, the new reference has improved genome coverage and a novel description of methylation sites. The PkA1 H.1 reference will enhance the capabilities of the in vitro model to improve the understanding of P. knowlesi infection in humans. PMID- 29258832 TI - Characterization of the Theileria parva sporozoite proteome. AB - East Coast fever is a lymphoproliferative disease caused by the tick-borne protozoan parasite Theileria parva. The sporozoite stage of this parasite, harboured and released from the salivary glands of the tick Rhipicephalus appendiculatus during feeding, invades and establishes infection in bovine lymphocytes. Blocking this initial stage of invasion presents a promising vaccine strategy for control of East Coast fever and can in part be achieved by targeting the major sporozoite surface protein p67. To support research on the biology of T. parva and the identification of additional candidate vaccine antigens, we report on the sporozoite proteome as defined by LC-MS/MS analysis. In total, 4780 proteins were identified in an enriched preparation of sporozoites. Of these, 2007 were identified as T. parva proteins, representing close to 50% of the total predicted parasite proteome. The remaining 2773 proteins were derived from the tick vector. The identified sporozoite proteins include a set of known T. parva antigens targeted by antibodies and cytotoxic T cells from cattle that are immune to East Coast fever. We also identified proteins predicted to be orthologs of Plasmodium falciparum sporozoite surface molecules and invasion organelle proteins, and proteins that may contribute to the phenomenon of bovine lymphocyte transformation. Overall, these data establish a protein expression profile of T. parva sporozoites as an important starting point for further study of a parasitic species which has considerable agricultural impact. PMID- 29258834 TI - Rapid and comprehensive discovery of unreported shellfish allergens using large scale transcriptomic and proteomic resources. PMID- 29258836 TI - Fitting success for three multifocal designs: Multicentre randomised trial. AB - PURPOSE: To determine if the discontinuation of commercially-available simultaneous vision Multifocal Soft Contact Lenses is independent from the multifocal design. To determine causes for discontinuation and psychosocial factors involved. METHODS: Multicentre single-blinded randomised controlled trial with external blinded evaluation for a three months follow-up period for three intervention groups. 150 single-vision soft wearers were randomly assigned a spherical near centred lens (S-CN), distance centred lens (CD) or aspherical near centred lens (A-CN). Cases of discontinuation, anxiety and quality of life were measured at one week and one month. RESULTS: 120 females and 30 males were included with an age range of 40-62 (48.79 +/- 5.23). At one month, the S-CN design had a statistically significant higher risk of discontinuation than the other two OR: 6.12 (95%CI 2.5-14.9). Twenty-eight subjects discontinued wearing S CN at first week (56%), while discontinuation of CD and A-CD were 15 (30%) and 11 (22%), with a statistically significant difference between S-CN design and the other two (p = 0.001). There were not statistically significant differences when direct comparison between discontinuation of CD and A-CN was made (p = 0.36). Thirty-two percent discontinued the use because of poor distance vision and 28% because of both poor distance and near vision. Psychosocial factors were not statistically significant. CONCLUSIONS: Discontinuation of Multifocal Soft Contact Lenses is dependent on the design. Most common cause for discontinuation is poor distance vision. Psychosocial factors do not impact on discontinuation rates. PMID- 29258835 TI - The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model. AB - Excessive glutamate in cerebrospinal fluid after subarachnoid hemorrhage (SAH) causes excitotoxic damage through calcium overloading and a subsequent apoptotic cascade. GluN1/GluN2B containing N-methyl-Daspartate (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) can play a leading role in glutamate mediated excitotoxicity. Here we report that Ifenprodil (100MUM), a negative allosteric modulator (NAM) of GluN1/GluN2B NMDA receptors, and JNJ16259685 (10MUM), a NAM of mGluR1, have an additive efficacy against glutamate (100MUM) induced Ca2+ release and cell apoptosis in primary cortical, hippocampal, and cerebellar granule neurons. Compared with intraperitoneal injection of Ifenprodil (10mg/kg) and JNJ16259685 (1mg/kg) separately, the combination therapy of Ifenprodil plus JNJ16259685 significantly improves the neurological deficit at 24h and 72h after experimental SAH. It reduces the number of TUNEL/DAPI-positive and activated caspase-3/NeuN-positive cells in cortical and hippocampal CA1 regions at 72h, decreases levels of glutamate in cerebrospinal fluid at 72h, and reduces the mitochondrial Ca2+ concentration. Meanwhile, the combination therapy attenuates apoptosis as shown by an increased Bcl-2 expression, decreased Bax expression and release of cytochrome c, and reduction of cleaved caspase-9 and caspase-3 at 24h after SAH. These findings indicate that targeting both the intracellular Ca2+ overloading and neuronal apoptosis using the Ifenprodil and JNJ16259685 is a promising new therapy for SAH. PMID- 29258837 TI - Reasons for Distress Among Burn Survivors at 6, 12, and 24 Months Postdischarge: A Burn Injury Model System Investigation. AB - OBJECTIVE: To identify important sources of distress among burn survivors at discharge and 6, 12, and 24 months postinjury, and to examine if the distress related to these sources changed over time. DESIGN: Exploratory. SETTING: Outpatient burn clinics in 4 sites across the country. PARTICIPANTS: Participants who met preestablished criteria for having a major burn injury (N=1009) were enrolled in this multisite study. INTERVENTIONS: Participants were given a previously developed list of 12 sources of distress among burn survivors and asked to rate on a 10-point Likert-type scale (0=no distress to 10=high distress) how much distress each of the 12 issues was causing them at the time of each follow-up. MAIN OUTCOMES MEASURES: The Medical Outcomes Study 12-Item Short-Form Health Survey was administered at each time point as a measure of health-related quality of life. The Satisfaction With Appearance Scale was used to understand the relation between sources of distress and body image. Finally, whether a person returned to work was used to determine the effect of sources of distress on returning to employment. RESULTS: It was encouraging that no symptoms were worsening at 2 years. However, financial concerns and long recovery time are 2 of the highest means at all time points. Pain and sleep disturbance had the biggest effect on ability to return to work. CONCLUSIONS: These findings can be used to inform burn-specific interventions and to give survivors an understanding of the temporal trajectory for various causes of distress. In particular, it appears that interventions targeted at sleep disturbance and high pain levels can potentially effect distress over financial concerns by allowing a person to return to work more quickly. PMID- 29258838 TI - Parental experiences after prenatal diagnosis of fetal abnormality. AB - For many pregnant women, prenatal testing is a routine component of contemporary pregnancy care. Receiving a prenatal diagnosis is frequently associated with intense feelings of shock and grief; the extent of which may be unrelated to the pregnancy gestation or the condition diagnosed. During this time of crisis, parents are often faced with important choices about their pregnancy. Levels of understanding and experiences of professional support throughout this time likely impact decisions that are made and how they are subsequently perceived. Despite considerable advances in prenatal testing technologies over the last 20 years there is a paucity of research examining parental experiences in-depth. Future advances such as prenatal exome sequencing will further increase the scope of prenatal testing and numbers of parents who receive a prenatal diagnosis. It is imperative that large-scale studies are performed to ensure that protocols are in place to adequately support couples at this time. PMID- 29258840 TI - Sleep-related hypermotor syndrome: an arousal parasomnia or nocturnal frontal lobe epilepsy? PMID- 29258839 TI - Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport. AB - Ion translocation across biological barriers is a fundamental requirement for life. In many cases, controlling this process-for example with neuroactive drugs demands an understanding of rapid and reversible structural changes in membrane embedded proteins, including ion channels and transporters. Classical approaches to electrophysiology and structural biology have provided valuable insights into several such proteins over macroscopic, often discontinuous scales of space and time. Integrating these observations into meaningful mechanistic models now relies increasingly on computational methods, particularly molecular dynamics simulations, while surfacing important challenges in data management and conceptual alignment. Here, we seek to provide contemporary context, concrete examples, and a look to the future for bridging disciplinary gaps in biological ion transport. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. PMID- 29258841 TI - A new microsporidium, Vairimorpha subcoccinellae n. sp. (Microsporidia: Burenellidae), isolated from Subcoccinella vigintiquatuorpunctata L. (Coleoptera: Coccinellidae). AB - A new microsporidium was isolated from Subcoccinella vigintiquatuorpunctata L. (Coleoptera: Coccinellidae), a pest of Galega officinalis L. in Turkey. Infection in larval and adult stages was systemic with mature spores produced in the midgut, gonads, Malpighian tubules and, most extensively, fat body tissues. The microsporidium was polymorphic with two sporulation sequences producing two types of spores, binucleate spores with 13-15 coils of the polar tube, and uninucleate spores with 7 coils of the polar tube that developed within a sporophorous vesicle (SPV) to form meiospores. The 16S small subunit rRNA (SSU rRNA) gene of the microsporidium was sequenced and compared with twenty-seven microsporidian sequences from GenBank. Based on the phylogenetic analysis of the SSU rRNA sequence, this microsporidium is unique within the Vairimorpha group. Morphological and genetic characters indicate that the described microsporidium is dissimilar to all known Vairimorpha species, and so is named here as Vairimorpha subcoccinellae n. sp. PMID- 29258842 TI - Pathological analysis of silkworm infected by two microsporidia Nosema bombycis CQ1 and Vairimorpha necatrix BM. AB - Microsporidia Nosema bombycis CQ1 can be vertically transmitted in silkworm Bombyx mori but Vairimorpha necatrix BM cannot. Therefore, the pathological differences in silkworm infected with these two microsporidia required clarification. Here, we compared the virulence of N. bombycis CQ1 and V. necatrix BM against silkworm. The pathological characteristics in intestine, testis and ovary were surveyed using paraffin sections, scanning electron microscopy and transmission electron microscopy. Our data firstly showed that the virulence of V. necatrix BM was weaker than that of N. bombycis CQ1. Secondly, the typical symptom of V. necatrix BM infection is making xenomas, which are full of pathogens in different stages, at the posterior of intestine. However, no xenomas were formed surrounding intestines infected with N. bombycis CQ1. Thirdly, N. bombycis CQ1 can cluster spores near the trachea while infecting ovaries. It is worth noting that N. bombycis CQ1 infected epithelial cells and connective tissues of ovaries, while V. necatrix BM did not. Although silkworm ovaries can not be infected by V. necatrix BM in vivo, it can infect embryonic and ovarian cell lines in vitro. This study is the first report about comparing infection features of N. bombycis CQ1 and V. necatrix BM in silkworm tissues and it provided elaborate and visual information of pathological characteristics which can help to explain the different transmission strategies of these two microsporidia. PMID- 29258843 TI - Comparative transcriptome and gene co-expression network analysis reveal genes and signaling pathways adaptively responsive to varied adverse stresses in the insect fungal pathogen, Beauveria bassiana. AB - Sensing, responding, and adapting to the surrounding environment are crucial for all living organisms to survive, proliferate, and differentiate in their biological niches. Beauveria bassiana is an economically important insect pathogenic fungus which is widely used as a biocontrol agent to control a variety of insect pests. The fungal pathogen unavoidably encounters a variety of adverse environmental stresses and defense response from the host insects during application of the fungal agents. However, few are known about the transcription response of the fungus to respond or adapt varied adverse stresses. Here, we comparatively analyzed the transcriptome of B. bassiana in globe genome under the varied stationary-phase stresses including osmotic agent (0.8 M NaCl), high temperature (32 degrees C), cell wall-perturbing agent (Congo red), and oxidative agents (H2O2 or menadione). Total of 12,412 reads were obtained, and mapped to the 6767 genes of the B. bassiana. All of these stresses caused transcription responses involved in basal metabolism, cell wall construction, stress response or cell rescue/detoxification, signaling transduction and gene transcription regulation, and likely other cellular processes. An array of genes displayed similar transcription patterns in response to at least two of the five stresses, suggesting a shared transcription response to varied adverse stresses. Gene co-expression network analysis revealed that mTOR signaling pathway, but not HOG1 MAP kinase pathway, played a central role in regulation the varied adverse stress responses, which was verified by RNAi-mediated knockdown of TOR1. Our findings provided an insight of transcription response and gene co-expression network of B. bassiana in adaptation to varied environments. PMID- 29258844 TI - The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value. AB - The aryl hydrocarbon receptor (AhR) is well-known for its major contributions to the cellular responses against environmental toxins and carcinogens. Notably, AhR has also emerged as a key transcription factor controlling many physiological processes including cell proliferation and apoptosis, differentiation, adhesion and migration, pluripotency and stemness. These novel functions have broadened our understanding of the signalling pathways and molecular intermediates interacting with AhR under both homeostatic and pathological conditions. Recent discoveries link AhR with the function of essential organs such as liver, skin and gonads, and with complex organismal structures including the immune and cardiovascular systems. The identification of potential endogenous ligands able to regulate AhR activity, opens the possibility of designing ad hoc molecules with pharmacological and/or therapeutic value to treat human diseases in which AhR may have a causal role. Integration of experimental data from in vitro and in vivo studies with "omic" analyses of human patients affected with cancer, immune diseases, inflammation or neurological disorders will likely contribute to validate the clinical relevance of AhR and the possible benefits of modulating its activity by pharmacologically-driven strategies. In this review, we will highlight signalling pathways involved in human diseases that could be targetable by AhR modulators and discuss the feasibility of using such molecules in therapy. The pros and cons of AhR-aimed approaches will be also mentioned. PMID- 29258845 TI - Polymer nanostructures for bioapplications induced by laser treatment. AB - Modification of polymer substrates can essentially change the properties of material and thereby it allows their usage in attractive fields of material research. Laser treatment can be successfully applied for change in physico chemical surface properties and/or for selective change of surface morphology with pattern construction. Three major applications of laser induced structures were described, cytocompatibility control, application as anti-bacterial substrate and plasmonic-based detection system. The construction of a second generation antibacterials using the synergic effect of either nanopatterning of polymers by application of a laser or noble metals deposition and consequent modification of nanostructures was presented. PMID- 29258846 TI - Bone marrow mesenchymal stromal cells alleviate brain white matter injury via the enhanced proliferation of oligodendrocyte progenitor cells in focal cerebral ischemic rats. AB - The effects of transplanting bone marrow mesenchymal stromal cells (BMSCs) for the treatment of white matter damage are not well understood, nor are the underlying mechanisms. Recent studies showed that endogenous oligodendrocyte progenitor cells (OPCs) can be stimulated to proliferate. Therefore, we explore the effects of BMSCs transplantation on white matter damage and the proliferation of OPCs in transient focal cerebral ischemic rats. BMSCs were transplanted into a group of rats that had undergone middle cerebral artery occlusion (MCAO) 24 h after reperfusion. The ratswere examined by MRI-T2 and DTI sequencesdynamically. The proliferating cells were labeled by 5-Bromo-2'-deoxyuridine (BrdU). The effects of BMSC transplantation on neurons, axons, myelination, and proliferating OPCs were examined by Nissl staining, MBP/NF-H and BrdU/NG2 immunofluorescence staining7 days after transplantation. More Nissl-stained neuronswere found and the FA value of MRI-DTI was significantly higher in the MCAO + BMSCs group than in the MCAOgroup (both P < .01). The fold change of MBP protein was significantly higher in the MCAO + BMSCs group than in the MCAO group (P < .01); the same was true of NF-H protein. Additionally, there were more BrdU+NG2+ cells in the SVZ areas of the MCAO + BMSCs group than in the MCAO group (P < .01). BMSCs thus were shown to alleviate neuronal/axonal injury and promote the proliferation of OPCs and formation of myelin sheath, significantly alleviating white matter damage in focal cerebral ischemic rats. PMID- 29258847 TI - Acute in vivo effect of valproic acid on the GABAergic system in rat brain: A [11C]Ro15-4513 microPET study. AB - gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system acting mainly through GABAA receptors. In the presence of high levels of GABA, an allosteric shift in the GABAA receptors can change the affinity of benzodiazepine (BZD) ligands. Valproic acid (VPA) is an anticonvulsant that enhances the level of endogenous GABA in the brain. The BZD ligand, Ro15-4513 has a high affinity for GABAA receptors containing the alpha5 subunit and can be used to investigate the GABA shift in the brains of living rats after VPA exposure. Seven Wistar rats were scanned using a Mediso NanoScan PET/MRI. A baseline 90-min dynamic [11C]Ro15-4513 PET scan was acquired prior to an intravenous injection of 50 mg/kg VPA, and was followed by a second [11C]Ro15 4513 PET scan. Standardized uptake values were obtained for regions of high GABA binding, including the hippocampus and amygdala, and low GABA binding such as the cerebellum. We showed a significant increase in [11C]Ro15-4513 uptake in hippocampus and amygdala, but no significant differences in cerebellar uptake, after acute VPA exposure. In contrast to several in vitro studies, we demonstrated a positive allosteric change in the GABAA receptors after pharmacologically enhanced GABA levels resulting in enhanced Ro15-4513 uptake. Knowledge of how subtypes of the GABAA receptors react will provide us with information useful to fine-tune pharmacological interventions and design receptor subtype specific drugs. PMID- 29258848 TI - ExoY, an actin-activated nucleotidyl cyclase toxin from P. aeruginosa: A minireview. AB - ExoY is one of four well-characterized Pseudomonas aeruginosa type 3 secretion system (T3SS) effectors. It is a nucleotidyl cyclase toxin that is inactive inside the bacteria, but becomes potently activated once it is delivered into the eukaryotic target cells. Recently, filamentous actin was identified as the eukaryotic cofactor that stimulates specifically ExoY enzymatic activity by several orders of magnitude. In this review, we discuss recent advances in understanding the biochemistry of nucleotidyl cyclase activity of ExoY and its regulation by interaction with filamentous actin. PMID- 29258849 TI - The good, the bad, and the suffering. Transient emotional episodes modulate the neural circuits of pain and empathy. AB - People's sensitivity to first-hand pain is affected by their ongoing emotions, with positive states (joy, amusement) exerting analgesic-like effects, and negative states (sadness, fear) often enhancing the subjective experience. It is however less clear how empathetic responses to others' pain are affected by one's own emotional state. Following embodied accounts that posit a shared representational code between self and others' states, it is plausible that pain empathy might be influenced by emotions in the same way as first-hand pain. Alternatively, other theories in psychology suggest that social resources (including empathetic reactions) might be enhanced by positive states, but inhibited by negative states, as only in the former case, one's mindset is sufficiently broad to take into consideration others' needs. To disambiguate between these opposing predictions, we conducted two experiments in which volunteers observed positive, neutral, or negative video clips, and subsequently either received painful thermal stimuli on their own body (first-hand pain), or observed images of wounded hands (others' pain). We measured subjective pain ratings as well as physiological responses and brain activity using fMRI. We found that, contrary to the case of first-hand pain, others' pain produced weaker galvanic responses and lower neural activity in anterior insula and middle cingulate cortex following negative (relative to neutral and positive) videos. Such inhibition was partially counteracted by personal empathy traits, as individuals with higher scores retained greater sensitivity to others' pain after negative emotion induction, in both behavioral and neural responses in medial prefrontal cortex. Furthermore, multivoxel pattern analysis confirmed similar neural representation for first-hand and others' pain in anterior insula, with representation similarity increasing the more the video preceding the observation of others' suffering was positive. These findings speak against the idea that emotion induction affects first-hand and others' pain in an isomorphic way, but rather supports the idea that contrary to negative emotions, positive emotions favors a broader access to social resources. PMID- 29258850 TI - Near infrared transillumination compared with radiography to detect and monitor proximal caries: A clinical retrospective study. AB - OBJECTIVE: To compare near infrared transillumination device, DIAGNOcam (DC) and bitewing radiography (BW) for the detection of proximal caries. MATERIALS AND METHODS: This retrospective analysis of DC and BW images of 18 students in dental medicine who had consented to the anonymous use of their dental record. The data included BW and DC images performed for a check-up in 2013, and corresponding follow-up images performed in 2015. Two observers rated 376 proximal surfaces on a 4-level dentin lesion scale and reached a unanimous rating for each surface. Calculated measures of agreement for each assessment method over time provided the reproducibility of the information obtained by each method. RESULTS: Agreement between 2013 and 2015 within each method was excellent (intraclass correlation coefficient, BW: 0.86, DC: 0.90). Agreement between DC and BW was similar for dentin lesion detection, but was low for enamel caries detection; DC detected more enamel caries than BW. Agreement between DC and BW was modest (0.33 in 2013 and 0.36 in 2015), chiefly because DC identified more enamel caries. CONCLUSION: This study shows that DC is as reliable as BW to detect proximal dentin lesions. DC detects proximal enamel lesions at an earlier stage than BW. DC enables clinicians to differentiate lesions limited to the enamel from lesions that have reached the enamel dentin junction. Regular monitoring with DC should help provide individualized preventive measures and early non-invasive caries management. CLINICAL SIGNIFICANCE: The early detection of enamel lesions with near infrared transillumination can help clinicians undertake early non invasive treatments to prevent or slow down the progression of initial proximal lesions. PMID- 29258851 TI - A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model. AB - OBJECTIVES: The aim of this study was to investigate if a synthetic granular calcium phosphate compound (CPC) and a composite bisphosphonate-linked hyaluronic acid-calcium phosphate hydrogel (HABP.CaP) induced similar or more amount of bone as bovine mineral in a modified sinus lift rabbit model. MATERIAL AND METHODS: Eighteen adult male New Zeeland White rabbits, received randomly one of the two test materials on a random side of the face, and bovine mineral as control on the contralateral side. In a sinus lift, the sinus mucosa was elevated and a titanium mini-implant was placed in the alveolar bone. Augmentation material (CPC, HABP.CaP or bovine bone) was applied in the space around the implant. The rabbits were euthanized three months after surgery and qualitative and histomorphometric evaluation were conducted. Histomorphometric evaluation included three different regions of interest (ROIs) and the bone to implant contact on each installed implant. RESULTS: Qualitative assessment (p = <.05), histomorphometric evaluations (p = < .01), and implant incorporation (p = <.05) showed that CPC and bovine mineral induced similar amount of bone and more than the HABP.CaP hydrogel. CONCLUSION: CPC induced similar amount of bone as bovine mineral and both materials induced more bone than HABP.CaP hydrogel. CLINICAL SIGNIFICANCE: The CPC is suggested as a synthetic alternative for augmentations in the maxillofacial area. PMID- 29258852 TI - Loss of inhibition in ipsilateral somatosensory areas following altered afferent nerve signaling from the hand. AB - Cutaneous stimulation of the hand results in increased neural activity in the contralateral primary somatosensory cortex (S1) in humans, whereas an inhibition of neurons is seen in the ipsilateral S1. The aim of this study was to assess changes in neural activity in the S1 bilaterally, with a focus on the ipsilateral hemisphere, following altered afferent nerve signaling from the hand. Three cohorts, all with altered afferent nerve signaling from the hand, participated in the study. There were: 18 patients with traumatic median nerve injury, 10 patients with vibration induced neuropathy and 11 healthy subjects who had their dominant hand and wrist immobilized for 72 h. In addition, 36 healthy subjects were included as controls. Each subject was examined using functional magnetic resonance imaging at 3 T. All three study cohorts showed enlarged activation in the contralateral S1 during tactile stimulation compared to healthy controls. Moreover, inhibition of the ipsilateral S1 was significantly decreased or completely lost. Thus, somatosensory areas of both hemispheres respond to changed afferent nerve signaling from the hand. The loss of inhibition of neurons in the ipsilateral S1 suggests an important role of the ipsilateral hemisphere in the cerebral adaptation following a change in afferent nerve signaling. PMID- 29258853 TI - Drosophila active zones: From molecules to behaviour. AB - In a constantly changing environment, neuronal circuits need to be updated and adjusted to elicit directed actions. Synaptic plasticity plays an important role in modulating such globally and locally acting networks. The active zone (AZ) is a protein-rich compartment of chemical synapses, where precisely orchestrated molecular interactions control synaptic vesicle (SV) fusion with the presynaptic membrane. The subsequent release of neurotransmitter substances onto postsynaptic receptor fields forms the basis of neuronal communication. Structural, functional and molecular features of AZs can differ significantly between systems, within one and the same neuron and at an individual site over time. Moreover, the properties of an AZ can be altered by changes in cellular activity. While it is recognized that such AZ plasticity modulates synaptic communication, our mechanistic understanding of its impact on neural network function and animal behaviour is far from complete. Research on Drosophila melanogaster has created an advantageous situation for investigating molecular mechanisms of AZ physiology in a behavioural context. The sophisticated genetic tools and excellent experimental accessibility of the fruit fly can now be combined with detailed anatomical information on the nervous system and quantifiable readouts of various behaviours at high resolution. Here, we review molecular studies of AZ structure and function at the neuromuscular junction (NMJ) and consider how mechanisms identified in the periphery may relate to the operation of central AZs. Our discussion emphasizes that the location of AZs in central networks defines sites of plasticity which shape animal behaviour. PMID- 29258854 TI - Ameliorative effects of Juniperus rigida fruit on oxazolone- and 2,4 dinitrochlorobenzene-induced atopic dermatitis in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruits of Juniperus rigida have been used in Korean traditional medicine for the treatment of inflammatory diseases in humans such as rheumatoid arthritis. AIM OF THE STUDY: This study aimed to investigate the anti-atopic properties of J. rigida fruit in in vivo murine atopic dermatitis (AD) models. METHODS AND RESULTS: BALB/c mouse ears ad SKH-1 hairless mice stimulated with oxazolone (4 weeks) and DNCB (3 weeks), respectively, were treated with the 1% Juniperus rigida fruit EtOH extract (JFE). The JFE improved AD symptoms in both oxazolone- and DNCB-induced AD mice by accelerating skin barrier recovery function and suppressing the overproduction of serum immunoglobulin E (IgE) and interleukin 4 (IL-4). The JFE was found to contain isoscutellarein-7-O-beta-xylopyranoside, cupressuflavone, podocarpusflavone A, and hinokiflavone as major components based on phytochemical analysis. Eight flavonoids were isolated from JFE, and of those, cupressuflavone and isoscutellarein-7-O-beta-xylopyranoside strongly down-regulated IL-4 expression and beta-hexosaminidase release in RBL-2H3 cells. CONCLUSION: Therapeutic attempts with J. rigida fruit and its active components might be useful in treating AD and related skin inflammatory diseases. PMID- 29258855 TI - Camptosorus sibiricus rupr aqueous extract prevents lung tumorigenesis via dual effects against ROS and DNA damage. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Camptosorus sibiricus Rupr (CSR) is a widely used herbal medicine with antivasculitis, antitrauma, and antitumor effects. However, the effect of CSR aqueous extract on B[a]P-initiated tumorigenesis and the underlying mechanism remain unclear. Moreover, the compounds in CSR aqueous extract need to be identified and structurally characterized. AIM OF THE STUDY: We aim to investigate the chemopreventive effect of CSR and the underlying molecular mechanism. MATERIALS AND METHODS: A B[a]P-stimulated normal cell model (BEAS.2B) and lung adenocarcinoma animal model were established on A/J mice. In B[a]P-treated BEAS.2B cells, the protective effects of CSR aqueous extract on B[a]P-induced DNA damage and ROS production were evaluated through flow cytometry, Western blot, real-time quantitative PCR, single-cell gel electrophoresis, and immunofluorescence. Moreover, a model of B[a]P-initiated lung adenocarcinoma was established on A/J mice to determine the chemopreventive effect of CSR in vivo. The underlying mechanism was analyzed via immunohistochemistry and microscopy. Furthermore, the new compounds in CSR aqueous extract were isolated and structurally characterized using IR, HR-ESI-MS, and 1D and 2D NMR spectroscopy. RESULTS: CSR effectively suppressed ROS production by re-activating Nrf2-mediated reductases HO-1 and NQO-1. Simultaneously, CSR attenuated the DNA damage of BEAS.2B cells in the presence of B[a]P. Moreover, CSR at 1.5 and 3 g/kg significantly suppressed tumorigenesis with tumor inhibition ratios of 36.65% and 65.80%, respectively. The tumor volume, tumor size, and multiplicity of B[a]P-induced lung adenocarcinoma were effectively decreased by CSR in vivo. After extracting and identifying the compounds in CSR aqueous extract, three new triterpene saponins were isolated and characterized structurally. CONCLUSIONS: CSR aqueous extract prevents lung tumorigenesis by exerting dual effects against ROS and DNA damage, suggesting that CSR is a novel and effective agent for B[a]P-induced carcinogenesis. Moreover, by isolating and structurally characterizing three new triterpene saponins, our study further standardized the quality of CSR aqueous extract, which could widen CSR clinical applications. PMID- 29258856 TI - Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers. AB - Over the past few years, multiple immune checkpoint blockers (ICBs) have achieved unprecedented clinical success and have been approved by regulatory agencies for the treatment of an increasing number of malignancies. However, only a limited fraction of patients responds to ICBs employed as a standalone intervention, calling for the development of combinatorial regimens. Radiation therapy (RT) stands out as a very promising candidate for this purpose. Indeed, RT mediates antineoplastic effects not only by cytotoxic and cytostatic mechanisms, but also by modulating immunological functions, both locally (within the irradiated field) and systemically. As combinatorial regimens involving RT and ICBs are being developed and clinically tested at an accelerating pace, it is paramount to identify biomarkers that reliably predict the likelihood of individual patients to respond. Here, we discuss emerging biomarkers that may potentially predict the response of cancer patients to RT plus ICBs. PMID- 29258858 TI - Emerging biomarkers for immunomodulatory cancer treatment of upper gastrointestinal, pancreatic and hepatic cancers. AB - Carcinomas of the oesophagus, stomach, pancreas and liver are common and account for a disproportionately high number of cancer deaths. There is a need for new treatment options for patients with advanced disease. Immunomodulatory treatments including immune checkpoint blockade offer a promising new approach, with efficacy shown in other solid tumour types. However, only a small proportion of patients with carcinomas of the oesophagus, stomach, pancreas and liver have responded to single agent checkpoint inhibitors, and there is a need for markers that are predictive of response to guide treatment of individual patients. Predictive markers may include epidemiological factors such as ethnicity, the genomic status of the tumour, circulating markers, expression of immune checkpoint molecules, and other features of the stromal/immune response at the site of the tumour. This review will focus on predictive biomarkers for immune checkpoint blockade in oesophageal, gastric, pancreatic and hepatocellular carcinomas, including the genomic context and immune landscape in which they occur. Pancreatic carcinomas are largely resistant to immune checkpoint inhibition in trials to date, therefore emerging immunomodulatory treatments in this tumour type are also reviewed. PMID- 29258859 TI - Risk perception of vervet monkeys Chlorocebus pygerythrus to humans in urban and rural environments. AB - Like other animals, primates respond to predation using behavioural adaptations. Hence, they should optimise their escape strategy under the risk of predation, and flee at a distance, referred to as flight initiation distance (FID), when the fitness-related benefits of staying are balanced against the costs of escape. However, there is an absence of FID studies in primates. In this study, we used vervet monkeys Chlorocebus pygerythrus, a medium-sized African cercopithecoid, as a model species to investigate the influence of environment type (urban and rural), group size (defined as the number of visible neighbours), sex and age on FID when approached by a human. We found significantly shorter FID among urban than rural monkeys; urban individuals delayed their escape compared to rural individuals. We found no relationship between FID and sex and age class, but FID was positively correlated with group size in both settings; urban monkeys live in smaller groups than monkeys in rural areas. As FID and group size are important predictors of predation risk perception in primates, results suggest that, despite probable effects of habituation, vervet monkeys in Uganda adjust their antipredator behaviour when coping with novel environments within human settlements. Our findings are consistent with some previous studies of risk perception in animals, and indicate that FID could be used as an alternative measure for predation risk in primates. PMID- 29258860 TI - Multiple trial inhibitory avoidance acquisition and retrieval are resistant to chronic stress. AB - Chronic mild stress (CMS) is a widely accepted animal model relevant to depression that among other consequences, is chiefly known to induce anhedonia, often assessed as decreased preference for sucrose solution. CMS is also known to affect cognition, particularly memory tasks. In this study we have employed the multiple-trial inhibitory avoidance memory task (MTIA) to assess CMS effects on memory acquisition and retrieval. MTIA consists of repeated exposures to the unconditioned stimulus until a learning criterion is reached. Wistar rats underwent CMS for 5 weeks, and sucrose consumption was assessed once a week. At the end of CMS, animals were evaluated in the MTIA task. Overall decreased sucrose solution preference was highly variable. Further analyses showed that a subset of animals expressed resilience while another subset was sensitive to stress. CMS did not affect the number of acquisition sessions before reaching criterion or retrieval latency of MTIA task in neither sensitive nor resilient groups. Although tasks that assess learning ability in animal models relevant to depression indicate cognitive deficits, the ability to learn the association between compartment crossing and the aversive electric foot shock, which is strongly dependent on emotional aspects, was intact. PMID- 29258857 TI - Understanding preanalytical variables and their effects on clinical biomarkers of oncology and immunotherapy. AB - Identifying a suitable course of immunotherapy treatment for a given patient as well as monitoring treatment response is heavily reliant on biomarkers detected and quantified in blood and tissue biospecimens. Suboptimal or variable biospecimen collection, processing, and storage practices have the potential to alter clinically relevant biomarkers, including those used in cancer immunotherapy. In the present review, we summarize effects reported for immunologically relevant biomarkers and highlight preanalytical factors associated with specific analytical platforms and assays used to predict and gauge immunotherapy response. Given that many of the effects introduced by preanalytical variability are gene-, transcript-, and protein-specific, biospecimen practices should be standardized and validated for each biomarker and assay to ensure accurate results and facilitate clinical implementation of newly identified immunotherapy approaches. PMID- 29258861 TI - Intraspecific variation of Centruroides sculpturatus scorpion venom from two regions of Arizona. AB - This study investigated geographic variability in the venom of Centruroides sculpturatus scorpions from different biotopes. Venom from scorpions collected from two different regions in Arizona; Santa Rita Foothills (SR) and Yarnell (Yar) were analyzed. We found differences between venoms, mainly in the two most abundant peptides; SR (CsEv2e and CsEv1f) and Yar (CsEv2 and CsEv1c) identified as natural variants of CsEv1 and CsEv2. Sequence analyses of these peptides revealed conservative amino acid changes between variants, which may underlie biological activity against arthropods. A third peptide (CsEv6) was highly abundant in the Yar venom compared to the SR venom. CsEv6 is a 67 amino acid peptide with 8 cysteines. CsEv6 did not exhibit toxicity to the three animal models tested. However, both venoms shared similarities in peptides that are predicted to deter predators. For example, both venoms expressed CsEI (lethal to chick) in similar abundance, while CsEd and CsEM1a (toxic to mammals) displayed only moderate variation in their abundance. Electrophysiological evaluation of CsEd and CsEM1a showed that both toxins act on the human sodium-channel subtype 1.6 (hNav 1.6). Complete sequencing revealed that both toxins are structurally similar to beta-toxins isolated from different Centruroides species that also target hNav 1.6. PMID- 29258862 TI - Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses. AB - Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5' cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay and virus-infected primary cells. Silvestrol was recently shown to have potent antiviral activity in Ebola virus infected human macrophages. We found that silvestrol is also a potent inhibitor of cap-dependent viral mRNA translation in CoV-infected human embryonic lung fibroblast (MRC-5) cells. EC50 values of 1.3 nM and 3 nM silvestrol were determined for MERS-CoV and HCoV-229E, respectively. For the highly pathogenic MERS-CoV, the potent antiviral activities of silvestrol were also confirmed using peripheral blood mononuclear cells (PBMCs) as a second type of human primary cells. Silvestrol strongly inhibits the expression of CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes. Furthermore, potential antiviral effects against human rhinovirus (HRV) A1 and poliovirus type 1 (PV), representing different species in the genus Enterovirus (family Picornaviridae), were investigated. The two viruses employ an internal ribosomal entry site (IRES) mediated translation initiation mechanism. For PV, which is known to require the activity of eIF4A, an EC50 value of 20 nM silvestrol was determined in MRC-5 cells. The higher EC50 value of 100 nM measured for HRV A1 indicates a less critical role of eIF4A activity in HRV A1 IRES-mediated translation initiation. Taken together, the data reveal a broad-spectrum antiviral activity of silvestrol in infected primary cells by inhibiting eIF4A-dependent viral mRNA translation. PMID- 29258863 TI - Fibrous cephalic plaques in tuberous sclerosis complex. AB - BACKGROUND: Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of patients with tuberous sclerosis complex (TSC). They constitute a major feature for TSC diagnosis and may present before other TSC-related cutaneous hamartomas. OBJECTIVE: To describe the clinical characteristics of FCPs in TSC. METHODS: A total of 113 patients with TSC were enrolled in an observational cohort study. Retrospective analysis of medical records and skin photography was performed. FCPs were categorized by anatomic location and size. RESULTS: FCPs were observed in 36% of patients (41 of 113). Of 62 total lesions, 58% were 1 to less than 5 cm, 13% were 5 cm or larger, and 29% were of unknown size mostly because of prior excision. The distribution of lesions was 39% on the forehead, 27% on the face (nonforehead), 3% on the neck, and 31% on the scalp. Fourteen patients had similar lesions less than 1 cm in diameter. Histopathologically, FCPs displayed dermal collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas. LIMITATIONS: Men were under-represented because the cohort was enriched for patients with TSC with lymphangioleiomyomatosis, which occurs in adult women. CONCLUSION: Two-fifths of FCPs presented on the forehead, with most of the remainder in other locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis of TSC. PMID- 29258864 TI - The burden of inbox-messaging systems and its effect on work-life balance in dermatology. PMID- 29258865 TI - Role of the orexin receptors within the nucleus accumbens in the drug priming induced reinstatement of morphine seeking in the food deprived rats. AB - Orexin plays a key role in mediating stress-induced drug relapse. However, the role of different types of orexinergic receptors that modulate stress-induced drug seeking remains unknown. The nucleus accumbens (NAc) has an important role in the reward system and receives orexinergic projections of the lateral hypothalamus. In addition, orexin interacts with other receptors that are involved in drug reinstatement. Therefore, in the present study, the role of orexin receptors in the NAc in morphine priming- induced reinstatement and the effect of food deprivation (FD) on drug reinstatement were examined. The extinguished morphine preference rats were tested for reinstatement following the 24-h FD condition after conditioning was induced. In the other groups, the animals were given intra-accumbal administration of SB334867 (01, 1 and 10 nM/0.5 MUl DMSO) as an orexin-1 receptor antagonist and TCSOX229 (1, 5 and 25 nM/0.5 MUl DMSO), as an orexin-2 receptor antagonist. The results showed that the blockade of two types of orexin receptors in the NAc remarkably attenuated the effect of FD on the drug reinstatement; however, they were more effective in FD condition. These findings indicate that the NAc is a brain area within which orexin has a fundamental role in the effect of stress on morphine-induced reinstatement and the effect of food deprivation- on the reinstatement of morphine. PMID- 29258866 TI - Suppression of NLRP3 attenuates hemorrhagic transformation after delayed rtPA treatment in thromboembolic stroke rats: Involvement of neutrophil recruitment. AB - BACKGROUND: Inflammation and neutrophils play pivotal roles in hemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rtPA) treatment in stroke; however, the contribution of Nod-like receptor protein 3 (NLRP3), a key component of the innate immune system, is not yet known. This study aimed to explore the role of NLRP3 in the delayed rtPA-induced HT and its association with the neutrophil recruitment. METHODS: Rats were subjected to thromboembolic focal cerebral ischemia and delayed rtPA treatment at 4 h after ischemia to mimic HT. NLRP3 short hairpin RNAs (shRNA) were administered 72 h before ischemia. Additionally, rabbit anti-rat neutrophil serum (inducing neutropenia) was administered before cerebral ischemia. The infarct volume, edema volume, neurological deficit, hemorrhages, blood-brain barrier (BBB) integrity and brain neutrophil recruitment were evaluated at 24 h after cerebral ischemia. RESULTS: Our results demonstrated that delayed rtPA treatment at 4 h after ischemia promoted the expression of NLRP3 in neurons, microglia and endothelial cells, degradation of BBB components, and HT. NLRP3 knockdown significantly attenuated NLRP3 expression, BBB disruption, and HT. It also improved neurological functions and reduced neutrophil recruitment. Rabbit anti-rat neutrophil serum, like NLRP3 shRNA, reduced hemorrhage score and hemorrhage volumes after rtPA treatment. Furthermore, the anti-rat neutrophil serum combined with NLRP3 shRNA didn't further increase the protective effect on HT compared to rabbit anti-rat neutrophil serum used alone. CONCLUSIONS: Together, our data suggest that NLRP3 inhibition can reduce neutrophil recruitment, which may contribute to the inhibitory effect on HT. PMID- 29258867 TI - Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. AB - There are numerous extra- and intra-cellular processes involved in the production of reactive oxygen species (ROS). Augmented ROS generation can cause the damage of biomolecules such as proteins, nucleic acid and lipids. ROS act as an intracellular signaling component and is associated with various inflammatory responses, chronic arthropathies, including rheumatoid arthritis (RA). It is well documented that ROS can activate different signaling pathways having a vital importance in the patho-physiology of RA. Hence, understanding of the molecular pathways and their interaction might be advantageous in the development of novel therapeutic approaches for RA. PMID- 29258868 TI - When exercise does not pay: Counterproductive effects of impending exercise on energy intake among restrained eaters. AB - Evidence suggests people may overestimate the effectiveness of future positive behaviour, leading to counterproductive behaviours in the present. Applied to weight-management, we hypothesize that inaccurate expectations about impending exercise may impede weight management by promoting overconsumption prior to exercise. This study aimed to determine how expectations about impending exercise and its potential ability to expend energy may influence i) energy intake before exercise and ii) overall energy balance (energy intake minus energy expended via exercise). Using a randomised, counterbalanced design, 21 inactive, overweight males, following a baseline session, completed two experimental trials: i) ad libitum snack meal (potato-crisps) followed by an exercise session (SE) and ii) ad-libitum snack meal only (SO). There was no main effect of condition (SE vs. SO) on ad-libitum snack intake (p = .917). However, after accounting for dietary restraint (covariate), a difference in snack intake between SE and SO was revealed (p = .050). Specifically, participants who scored higher in dietary restraint consumed more in the SE (vs. SO) session (162 +/- 359 kcal more) compared with participants who scored lower in dietary restraint (89 +/- 135 kcal less). Among restrained eaters, the relative (net) energy consumed after accounting for energy expended from exercise in SE was not different from the energy consumed in the SO condition, suggesting that energy expended via exercise in SE does not appear to negate extra energy consumed in this condition compared with SO. Of interest, desire to eat and prospective food consumption ratings at the start of the trial were greater (p <= .029) in SE compared with SO. Findings suggest that restrained-eaters are at risk of adopting compensatory eating behaviour that may impede negative energy balance typically resulting from exercise (i.e. expending insufficient energy to negate compensatory energy intake). PMID- 29258869 TI - Tactile recognition of visual stimuli: Specificity versus generalization of perceptual learning. AB - Sensory substitution devices aim at assisting a deficient sensory modality by means of another sensory modality. For instance, to perceive with visual-to tactile devices, users learn to recognize visual stimuli through their tactile conversion. A crucial characteristic of learning lies in the ability to generalize, that is, the ability to extend the acquired perceptual abilities to both new stimuli and new perceptual conditions. The study reported here investigated the perceptual learning of tactile alphanumerical stimuli. The learning protocol consisted in alternating a repeated list of symbols with lists of new symbols. A first experiment revealed that, when each list consisted of 4 stimuli, recognition performance improved over time only for the repeated list. This result suggests that learning a small set of stimuli involves stimulus specific learning strategies, preventing generalization. A second experiment revealed that increasing to six the set of learned stimuli results in higher generalization abilities. This result can be explained by greater difficulties in using stimulus-specific strategies in this case, thereby favouring the use of generalization strategies. Feature variability also appeared to be important to achieve generalization. Thus, as in visual perceptual learning, the involvement of stimulus-specific versus general strategies depends on task difficulty and feature variability. A third experiment highlighted that tactile perceptual learning generalizes to changes in orientation. These results are discussed in terms of brain plasticity as they influence the design of learning methods for using sensory substitution devices, with the aim to compensate visual impairments. PMID- 29258870 TI - Delayed neurochemical effects of prenatal exposure to MeHg in the cerebellum of developing rats. AB - Human fetuses and neonates are particularly vulnerable to methylmercury (MeHg) induced brain damage and are sensitive even to low exposure levels. Previous work of our group evidence that prenatal exposure to MeHg causes cognitive and behavioral alterations and disrupt hippocampus signaling. The current study aimed to investigate the effect of gestational exposure of rats to MeHg at low doses (1 or 2 mg/kg) on parameters of redox imbalance and key signaling pathways in the cerebellum of their offspring. Pregnant females received MeHg (treated group) or 0.9% saline water (control group) by gavage in alternated days from gestational day 5 (GD5) until parturition and analyzes were proceed in the cerebellum of 30 day-old pups. We found increased lipid peroxidation and protein carbonylation levels as well as decreased SH content in pups prenatally exposed to 2 mg/kg MeHg. In addition, misregulated SOD/catalase activities supported imbalanced redox equilibrium. We found decreased GSK3beta(Ser9) phosphorylation, suggesting activation of this enzyme and dephosphorylation/inhibition of ERK1/2 and JNK pathways. Increased PKAalpha catalytic subunit could be upstream of hyperphosphorylated c-Raf(Ser259) and downregulated MAPK pathway. In addition, we found raised levels of the Ca2+-dependent protein phosphatase 2 B (PP2B). We also found preserved immunohistochemical staining for both glial fibrillary acidic protein (GFAP) and NeuN in MeHg-exposed pups. Western blot analysis showed unaltered levels of BAX/BCL-XL, BAD/BCL-2 and active caspase 3. Together, these findings support absence of reactive astrocytes, neuronal damage and apoptotic cell death in the cerebellum of MeHg treated pups. The present study provides evidence that prenatal exposure to MeHg leads to later redox imbalance and disrupted signaling mechanisms in the cerebellum of 30-day-old pups potentially predisposing them to long-lasting neurological impairments in CNS. PMID- 29258871 TI - Phylogenetic and functional characterization of ten P450 genes from the CYP6AE subfamily of Helicoverpa armigera involved in xenobiotic metabolism. AB - The cotton bollworm, Helicoverpa armigera, is a generalist herbivore widely distributed over the world and is a major lepidopteran pest on cotton. Studies, especially from Asia, show that it relies on cytochrome P450 monooxygenases with broad substrate specificities to protect itself from pesticides. The number of P450s may have expanded in the processes of coping with the wide diversity of phytochemicals that the insect encounters among its numerous host plants. In order to examine the metabolic capabilities of these P450s, we focused here on all ten P450s of the Helicoverpa armigera CYP6AE subfamily, which can be easily induced by plant toxins and pyrethroids. These P450s, along with cytochrome P450 reductase, were heterologously expressed in insect cells and compared functionally. In vitro metabolism showed that all CYP6AE subfamily members can convert esfenvalerate to 4'-hydroxyesfenvalerate efficiently except CYP6AE20. In contrast, none of the recombinant CYP6AE enzymes could metabolise gossypol under our experimental conditions. Epoxidation capabilities were observed in the CYP6AE subfamily, aldrin can be converted to dieldrin at rates up to 0.45 +/- 0.04 pmol/min/pmol P450. Seven P450s in this subfamily can metabolise imidacloprid, but with lower efficiency than Bemisia tabaci CYP6CM1vQ. CYP6AE20 had virtually no metabolic competence to these four compounds but could metabolise several model fluorogenic substrates. These results showed the broad substrate spectrum of H. armigera CYP6AE P450s and suggest a limited role of gossypol upon the evolution of H. armigera CYP6AE genes. PMID- 29258873 TI - Perimenopausal bone histomorphometry before and after menopause. AB - Investigators and clinicians have had few normal bone histomorphometry data available to compare with those found in diseased patients, or in the results of treatments. The Goals and Objectives of this work are two-fold: 1. to present static and dynamic bone histomorphometry data from transilial bone biopsies performed on 76 healthy, premenopausal women. 2. To present paired static and dynamic bone histomorphometry data from bone biopsies on a subset (N=51 pairs) of these same healthy women whose biopsies were repeated 12months after their last menses. Statistical comparisons between the pre- and postmenopausal data are presented. These data will shrink this important gap, both for clinicians and investigators. We enrolled 76 healthy, premenopausal women over age 46, performed transilial bone biopsies after tetracycline labeling, and during a period of 9.5years, we re-biopsied 51 of them who passed through menopause and remained healthy the entire time. We also obtained serum biochemical measurements, and serial DXA exams during the period of observation. The dynamic bone histomorphometry demonstrated a doubling of bone remodeling, and increases in serum bone markers at the time of the second biopsy. Lumbar spine bone density also declined, and there were significant correlations between serum markers and histomorphometry variables. The data demonstrate that healthy menopause results in an important increase in bone remodeling, and a loss of bone density. We do not fully understand the mechanisms of these transmenopausal changes, but the data provide some clues that are helpful. PMID- 29258874 TI - Is fatty acid composition of human bone marrow significant to bone health? AB - The bone marrow adipose tissue (BMAT) is a conserved component of the marrow microenvironment, providing storage and release of energy and stabilizing the marrow extent. Also, it is recognized both the amount and quality of BMAT are relevant to preserve the functional relationships between BMAT, bone, and blood cell production. In this article we ponder the information supporting the tenet that the quality of BMAT is relevant to bone health. In the human adult the distribution of BMAT is heterogeneous over the entire skeleton, and both BMAT accumulation and bone loss come about with aging in healthy populations. But some pathological conditions which increase BMAT formation lead to bone impairment and fragility. Analysis in vivo of the relative content of saturated and unsaturated fatty acids (FA) in BMAT indicates site-related bone marrow fat composition and an association between increased unsaturation index (UI) and bone health. With aging some impairment ensues in the regulation of bone marrow cells and systemic signals leading to local chronic inflammation. Most of the bone loss diseases which evolve altered BMAT composition have as common factors aging and/or chronic inflammation. Both saturated and unsaturated FAs originate lipid species which are active mediators in the inflammation process. Increased free saturated FAs may lead to lipotoxicity of bone marrow cells. The pro-inflammatory, anti inflammatory or resolving actions of compounds derived from long chain poly unsaturated FAs (PUFA) on bone cells is varied, and depending on the metabolism of the parent n:3 or n:6 PUFAs series. Taking together the evidence substantiate that marrow adipocyte function is fundamental for an efficient link between systemic and marrow fatty acids to accomplish specific energy or regulatory needs of skeletal and marrow cells. Further, they reveal marrow requirements of PUFAs. PMID- 29258872 TI - Prdm13 is required for Ebf3+ amacrine cell formation in the retina. AB - Amacrine interneurons play a critical role in the processing of visual signals within the retina. They are highly diverse, representing 30 or more distinct subtypes. Little is known about how amacrine subtypes acquire their unique gene expression and morphological features. We characterized the gene expression pattern of the zinc-finger transcription factor Prdm13 in the mouse. Consistent with a developmental role, Prdm13 was expressed by Ptf1a+ amacrine and horizontal precursors. Over time, Prdm13 expression diverged from the transiently expressed Ptf1a and marked just a subset of amacrine cells in the adult retina. While heterogeneous, we show that most of these Prdm13+ amacrine cells express the transcription factor Ebf3 and the calcium binding protein calretinin. Loss of Prdm13 did not affect the number of amacrine cells formed during development. However, we observed a modest loss of amacrine cells and increased apoptosis that correlated with the onset timing of Ebf3 expression. Adult Prdm13 loss-of function mice had 25% fewer amacrine cells, altered calretinin expression, and a lack of Ebf3+ amacrines. Forcing Prdm13 expression in retinal progenitor cells did not significantly increase amacrine cell formation, Ebf3 or calretinin expression, and appeared detrimental to the survival of photoreceptors. Our data show that Prdm13 is not required for amacrine fate as a class, but is essential for the formation of Ebf3+ amacrine cell subtypes. Rather than driving subtype identity, Prdm13 may act by restricting competing fate programs to maintain identity and survival. PMID- 29258875 TI - Rebound vertebral fracture in the dental chair during a tooth extraction whilst on a treatment holiday from denosumab to avoid ONJ! PMID- 29258876 TI - The impact of ageing on male reproductive success in Drosophila melanogaster. AB - Male reproductive ageing has been mainly explained by a reduction in sperm quality with negative effects on offspring development and quality. In addition to sperm, males transfer seminal fluid proteins (Sfps) at mating; Sfps are important determinants of male reproductive success. Receipt of Sfps leads to female post-mating changes including physiological changes, and affects sperm competition dynamics. Using the fruit fly Drosophila melanogaster we studied ageing males' ability to induce female post-mating responses and determined the consequences of male ageing on their reproductive success. We aged males for up to 7weeks and assayed their ability to: i) gain a mating, ii) induce egg-laying and produce offspring, iii) prevent females from remating and iv) transfer sperm and elicit storage after a single mating. We found that with increasing age, males were less able to induce post-mating responses in their mates; moreover ageing had negative consequences for male success in competitive situations. Our findings indicate that with advancing age male flies transferred less effective ejaculates and that Sfp composition might change over a male's lifetime in quantity and/or quality, significantly affecting his reproductive success. PMID- 29258877 TI - Different response of acetylcholinesterases in salt- and detergent-soluble fractions of honeybee haemolymph, head and thorax after exposure to diazinon. AB - Organophosphate pesticide diazinon is a specific inhibitor of acetylcholinesterase (AChE), which is a common neurotoxicity biomarker in environmental studies. In honeybees, AChE exists in two forms having different physiological roles, one existing as a soluble form and the other as membrane bound. In most studies AChE activity has been analysed without paying considerable attention to different forms of AChE. In this study, we exposed honeybees Apis mellifera carnica for 10days to diazinon via oral exposure and analysed the total AChE activities in salt soluble (SS) and detergent soluble (DS) fractions. We assumed that SS fraction would preferentially contain the soluble AChE, but the DS fraction would contain only membrane AChE. On the contrary, our results showed that SS and DS fractions both contain soluble and membrane AChE and the latter has considerably higher activity. Despite this we obtained a differential response of AChE activity in SS and DS fractions when exposed to diazinon. The head/thorax AChE activity in DS fraction decreased, while the head/thorax AChE activity in SS fraction increased at sublethal concentrations. The AChE activity in honeybee hemolymph shown here for the first time is a salt soluble enzyme. Its activity remained unaltered after diazinon treatment. In conclusion, we provide evidence that varying results regarding AChE activity alterations upon stressor exposure are obtained when extracted through different procedures. In further environmental studies with honeybees this differential response of AChE activity should be given considerable attention because this affects the outcome of ecotoxicity study. PMID- 29258878 TI - Association of pre- and early post-transplant serum amino acids and metabolites of amino acids and liver transplant outcome. AB - The aim of the present study was to investigate association of serum amino (AA) acids and metabolites of AAs with post-transplant outcome in liver transplant recipients. Eighty-nine patients with end-stage liver diseases and available pre- and early post-transplant serum were characterised as patients with (GI) and without one-year mortality (GII) and patients with and without early graft dysfunction (EAD). A panel of pre- and early post-transplant serum levels of AAs and early and metabolites of tryptophan were measured using tandem mass spectrometry. Patient groups had significantly higher pre-transplant serum levels of phenylalanine, tryptophan, and tryptophan metabolites than healthy controls (for all p<0.001). Pre-transplant serum levels of all these parameters were significantly higher in GI than in GII (for all p<0.001). GI had a higher MELD score and re-transplantation number than GII (p<=0.005 for both investigations). Serum bilirubin on day 5 and serum phenylalanine on day 10 post-transplant were associated parameters of mortality, whereas day 1post-transplant phenylalanine and kynurenine and female gender were associated parameters of EAD. Our results indicate that pre- and early post-transplant levels of phenylalanine, tryptophan and metabolites of tryptophan are increased in patients and are associated with EAD and one-year mortality in liver transplant recipients. PMID- 29258879 TI - Mitochondrial gene order evolution in Mollusca: Inference of the ancestral state from the mtDNA of Chaetopleura apiculata (Polyplacophora, Chaetopleuridae). AB - The mitochondrial genome architecture of polyplacophorans has been usually regarded as being very ancient in comparison to all mollusks. However, even if some complete chiton mtDNAs have been recently sequenced, thorough studies of their evolution are lacking. To further expand the set of complete chiton mtDNAs and perform such analysis, we sequenced the mitochondrial genome of the Eastern beaded chiton Chaetopleura apiculata (Chaetopleuridae) using next-generation sequencing. With mitochondrial sequences from all available chiton mtDNAs, we also built a phylogeny on which we reconstructed the evolution of gene arrangement in this class. The arrangement of C. apiculata proved to be the most primitive known so far for polyplacophorans. Comparing this gene order to those of other molluscan classes, we found that it most probably is the original gene order of the last common ancestor to all extant Mollusca. The ancient mitochondrial genome organization of C. apiculata is an important information that may help reconstructing the phylogeny of Mollusca and their relationship with other lophotrochozoans. PMID- 29258880 TI - Aquatic long-distance dispersal and vicariance shape the evolution of an ostracod species complex (Crustacea) in four major Brazilian floodplains. AB - Cladogenesis is often driven by the interplay of dispersal and vicariance. The importance of long-distance dispersal in biogeography and speciation is increasingly recognised, but still ill-understood. Here, we study faunal interconnectivity between four large Brazilian floodplains, namely the Amazon, Araguaia, Pantanal (on Paraguay River) and Upper Parana River floodplains, investigating a species complex of the non-marine ostracod genus Strandesia. We use DNA sequence data from the mitochondrial COI and the nuclear Elongation Factor 1 alpha genes to construct molecular phylogenies and minimum spanning networks, to identify genetic species, analyse biogeographic histories and provide preliminary age estimates of this species complex. The Strandesia species complex includes five morphological and eleven genetic species, which doubles the known diversity in this lineage. The evolutionary history of this species complex appears to comprise sequences of dispersal and vicariance events. Faunal and genetic patterns of connectivity between floodplains in some genetic species are mirrored in modern hydrological connections. This could explain why we find evidence for (aquatic) long-distance dispersal between floodplains, thousands of kilometres apart. Our phylogenetic reconstructions seem to mostly indicate recent dispersal and vicariance events, but the evolution of the present Strandesia species complex could span up to 25 Myr, which by far exceeds the age of the floodplains and the rivers in their current forms. PMID- 29258881 TI - Prevalence and changes in analgesic medication utilisation 1 year prior to total joint replacement in an older cohort of patients. AB - OBJECTIVES: To evaluate the prevalence and change in analgesic medications use prior to joint replacement in older patients between 2001 and 2012. METHODS: A population based epidemiological study was conducted. Opioids, non-steroidal anti inflammatories (NSAIDs), paracetamol, corticosteroid injections, medications for neuropathic pain, hypnotics, and muscle relaxants supplied 1 year prior to total knee replacement (TKR, n = 15,517) and hip replacement (THR, n = 10,018) were assessed. Patient characteristics and surgical indication adjusted prevalence ratios (PRs) and 95% confidence intervals (CI) are provided. RESULTS: From 2001 to 2012, in the TKR cohort (median age 78.9) the prevalence of opioid use prior to surgery increased from 37% to 49% (PR = 1.01, 95% CI 1.00-1.01, P = 0.01), while in the THR cohort (median age 81.1) it increased from 44% to 54% (PR = 1.01, 95% CI 1.01-1.02, P < 0.001). Paracetamol use increased from 52% to 61% (PR = 1.0, 95% CI 1.0-1.0, P = 0.913) in the TKR cohort and from 55% to 67% (PR = 1.01, 95% CI 1.00-1.01, P = 0.005) in the THR cohort. Neuropathic pain medication use increased from 5% to 11% in the TKR cohort (PR = 1.04, 95% CI 1.02-1.06, P < 0.0001) and from 6% to 12% in the THR cohort (PR = 1.06, 95% CI 1.04-1.09, P < 0.0001). NSAID use decreased from 76% to 50% in the TKR cohort (PR = 0.96, 95% CI 0.95-0.96, P < 0.0001), and from 81% to 47% in THR cohort (PR = 0.95, 95% CI 0.94 0.95, P < 0.0001). Corticosteroid injections prevalence also decreased (TKR: 21 18%, PR = 0.97, 95% CI 0.96-0.97, P < 0.001, THR: 18-17%, PR = 0.97, 95% CI 0.96 0.98, P < 0.001). CONCLUSION: Pain medication utilization prior to joint replacement surgery changed significantly in this national older cohort of patients during the 2000s. PMID- 29258883 TI - Cartilage regeneration and ageing: Targeting cellular plasticity in osteoarthritis. AB - Ageing processes play a major contributing role for the development of Osteoarthritis (OA). This prototypic degenerative condition of ageing is the most common form of arthritis and is accompanied by a general decline, chronic pain and mobility deficits. The disease is primarily characterized by articular cartilage degradation, followed by subchondral bone thickening, osteophyte formation, synovial inflammation and joint degeneration. In the early stages, osteoarthritic chondrocytes undergo phenotypic changes that increase cell proliferation and cluster formation and enhance the production of matrix remodelling enzymes. In fact, chondrocytes exhibit differentiation plasticity and undergo phenotypic changes during the healing process. Current studies are focusing on unravelling whether OA is a consequence of an abnormal wound healing response. Recent investigations suggest that alterations in different proteins, such as TGF-beta/BMPs, NF-Kbeta, Wnt, and Cx43, or SASP factors involved in signalling pathways in wound healing response, could be directly implicated in the initiation of OA. Several findings suggest that osteoarthritic chondrocytes remain in an immature state expressing stemness-associated cell surface markers. In fact, the efficacy of new disease-modifying OA drugs that promote chondrogenic differentiation in animal models indicates that this may be a drug-sensible state. In this review, we highlight the current knowledge regarding cellular plasticity in chondrocytes and OA. A better comprehension of the mechanisms involved in these processes may enable us to understand the molecular pathways that promote abnormal repair and cartilage degradation in OA. This understanding would be advantageous in identifying novel targets and designing therapies to promote effective cartilage repair and successful joint ageing by preventing functional limitations and disability. PMID- 29258882 TI - Transcriptome comparison of meniscus from patients with and without osteoarthritis. AB - OBJECTIVE: To assess the impact of osteoarthritis (OA) on the meniscus by comparing transcripts and biological processes in the meniscus between patients with and without OA. DESIGN: RNA microarrays were used to identify transcripts differentially expressed (DE) in meniscus obtained from 12 OA and 12 non-OA patients. The non-OA specimens were obtained at the time of arthroscopic partial meniscectomy. Real-time PCR was performed on selected transcripts. Biological processes and gene-networking was examined computationally. Transcriptome signatures were mapped with 37 OA-related transcripts to evaluate how meniscus gene expression relates to that of OA cartilage. RESULTS: We identified 168 transcripts significantly DE between OA (75 elevated, 93 repressed) and non-OA samples (>=1.5-fold). Among these, CSN1S1, COL10A1, WIF1, and SPARCL1 were the most prominent transcripts elevated in OA meniscus, POSTN and VEGFA were most highly repressed in OA meniscus. Transcripts elevated in OA meniscus represented response to external stimuli, cell migration and cell localization while those repressed in OA meniscus represented histone deacetylase activity (related to epigenetics) and skeletal development. Numerous long non-coding RNAs (lncRNAs) were DE between the two groups. When segregated by OA-related transcripts, two distinct clustering patterns appeared: OA meniscus appeared to be more inflammatory while non-OA meniscus exhibited a "repair" phenotype. CONCLUSIONS: Numerous transcripts with potential relevance to the pathogenesis of OA are DE in OA and non-OA meniscus. These data suggest an involvement of epigenetically regulated histone deacetylation in meniscus tears as well as expression of lncRNAs. Patient clustering based on transcripts related to OA in articular cartilage confirmed distinct phenotypes between injured (non-OA) and OA meniscus. PMID- 29258885 TI - Identifying pathways affected by cancer mutations. AB - Mutations in 15 cancers, sourced from the COSMIC Whole Genomes database, and 297 human pathways, arranged into pathway groups based on the processes they orchestrate, and sourced from the KEGG pathway database, have together been used to identify pathways affected by cancer mutations. Genes studied in >=15, and mutated in >=10 samples of a cancer have been considered recurrently mutated, and pathways with recurrently mutated genes have been considered affected in the cancer. Novel doughnut plots have been presented which enable visualization of the extent to which pathways and genes, in each pathway group, are targeted, in each cancer. The 'organismal systems' pathway group (including organism-level pathways; e.g., nervous system) is the most targeted, more than even the well recognized signal transduction, cell-cycle and apoptosis, and DNA repair pathway groups. The important, yet poorly-recognized, role played by the group merits attention. Pathways affected in >=7 cancers yielded insights into processes affected. PMID- 29258884 TI - Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine. AB - Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action. PMID- 29258886 TI - The risk of fragility fractures in new users of dipeptidyl peptidase-4 inhibitors compared to sulfonylureas and other anti-diabetic drugs: A cohort study. AB - AIMS: Mixed evidence exists for the effect of incretin-based therapies on osteoporosis in type-2 diabetes. Therefore, we conducted a cohort study to determine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and common osteoporotic "fragility fractures" (upper extremity, hip, spine). METHODS: The UK-based Clinical Practice Research Datalink was used to identify adults without prior fractures receiving a new anti-diabetic drug or a new type-2 diabetes diagnosis between 2007 and 2016. The primary aim was to compare new users of DPP-4 inhibitors versus new-users of sulfonylureas (SU). The association between DPP-4 inhibitors and incident fractures was estimated using Cox proportional hazards models. Deciles of high-dimensional propensity scores and other anti-diabetic drugs were used as covariates. RESULTS: We identified 7993 and 26,636 new-users of DPP-4 inhibitors and SUs, respectively. At cohort entry, the mean age was 58.8, 40% were female, mean diabetes duration was 1.3 years, and 42% had A1c > 9%. Over 9 years (mean follow-up = 1.2 years), the incident rate of fragility fractures was lower among DPP-4 versus SU users (3.0/1000 vs. 5.2/1000 person-years; P-value = 0.007). After adjustment, there was no statistically significant difference in fracture risk (hazard ratio adjusted, aHR = 0.80, 95%CI 0.51-1.24; P-value = 0.3125). In a secondary analysis, DPP-4 inhibitors were not associated with a difference in fracture risk compared to insulin (aHR = 0.91, 95%CI 0.40-2.09); however were associated with a lower fracture risk versus thiazolidinediones (aHR = 0.47, 95%CI 0.26-0.83). Sensitivity analyses supported findings. CONCLUSIONS: DPP-4 inhibitors are not associated with an increased risk of fragility fractures compared with SUs or insulin; however, are associated with a lower risk versus thiazolidinediones. PMID- 29258888 TI - The first Special Issue on code biology - A bird's-eye view. PMID- 29258887 TI - Substantial atherosclerotic celiac axis stenosis is a new risk factor for biliary fistula after pancreaticoduodenectomy. AB - BACKGROUND: Biliary fistula (BF) is a major surgical complication that can develop after pancreaticoduodenectomy (PD) whose risk factors remain unclear. Substantial atherosclerotic celiac axis stenosis (SACAS) has not been reported to be one of them. METHODS: Data from 507 patients undergoing PD between Jan 1, 2013 and Dec 31, 2015 were retrospectively collected. Clinical data from patients with SACAS were studied, and the independent risk factors for BF underwent multivariate logistic regression analysis, including SACAS. RESULTS: BF occurred in 22 (4.3%) patients, and the incidence of BF was significantly higher in patients with SACAS than in those without it (27.0% vs 2.6%, P < .001). In the univariate analysis, BF was significantly related to SACAS, older age, a higher ASA score, history of coronary disease, greater blood loss and RBC transfusion during surgery, smaller CBD diameter and higher POD 1 BUN level. The multivariate analysis showed that only SACAS (OR 8.91, 95% CI 2.36-33.69, P = .001), older age (OR 1.08, 95% CI 1.01-1.15, P = .028) and smaller preoperative CBD (OR 0.79, 95% CI 0.69-0.92, P = .002) were independent risk factors for postoperative BF. CONCLUSION: Older age and a smaller preoperative CBD diameter are independent risk factors for BF after PD, which is consistent with the literature. In addition, SACAS is a new independent risk factor for BF. For patients with SACAS, postoperative drainage should be carefully managed to precisely observe the potential for BF. PMID- 29258889 TI - Association of Escherichia coli ST131 lineage with risk of urinary tract infection recurrence among young women. AB - OBJECTIVES: The aim of this study was to test the hypothesis that urinary tract infections (UTIs) caused by Escherichia coli of the sequence type 131 (ST131) lineage are more likely to recur than UTIs caused by other E. coli lineages. METHODS: Isolates from 221 young women with UTI caused by E. coli participating in a randomised controlled trial were used. Participants were followed for 6 months or until UTI recurrence. RESULTS: Sequence type was not associated with risk of recurrence. Isolates in the ST131 lineage were more resistant than other STs to quinolones (6.2% vs. 1.3%) but not trimethoprim/sulfamethoxazole (15.4% vs. 15.0%). CONCLUSIONS: These results do not support an increased risk of recurrent UTI among otherwise healthy women with UTI caused by E. coli ST131. PMID- 29258890 TI - Serotonergic and cholinergic modulation of functional brain connectivity: A comparison between young and older adults. AB - Aging is accompanied by changes in neurotransmission. To advance our understanding of how aging modifies specific neural circuitries, we examined serotonergic and cholinergic stimulation with resting state functional magnetic resonance imaging (RS-fMRI) in young and older adults. The instant response to the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was measured in 12 young and 17 older volunteers during a randomized, double blind, placebo-controlled, crossover study. A powerful dataset consisting of 522 RS-fMRI scans was obtained by acquiring multiple scans per subject before and after drug administration. Group * treatment interaction effects on voxelwise connectivity with ten functional networks were investigated (p < .05, FWE-corrected) using a non-parametric multivariate analysis technique with cerebrospinal fluid, white matter, heart rate and baseline measurements as covariates. Both groups showed a decrease in sensorimotor network connectivity after citalopram administration. The comparable findings after citalopram intake are possibly due to relatively similar serotonergic systems in the young and older subjects. Galantamine altered connectivity between the occipital visual network and regions that are implicated in learning and memory in the young subjects. The lack of a cholinergic response in the elderly might relate to the well-known association between cognitive and cholinergic deterioration at older age. PMID- 29258891 TI - Surface-enhanced tractography (SET). AB - In this work, we exploit the T1 weighted image in conjunction with cortical surface boundary to improve the precision of tractography under the cortex. We show that utilizing the cortical interface and a surface flow, to model the superficial white matter streamlines, enhance and improve tractography trajectory near the cortex. Our novel surface-enhanced tractography reduces the gyral bias, the length bias and the amount of false positive streamlines produced by tractography. This method improves the reproducibility and the cortical surface coverage of tractograms which are crucial for connectomics studies. The usage of cortical surfaces, extracted from the standardly acquired 1 mm isotropic T1, is a straightforward and effective way to improve existing tractography processing pipelines and structural connectivity studies. PMID- 29258892 TI - Enhanced Repair of UV-Induced DNA Damage by 1,25-Dihydroxyvitamin D3 in Skin Is Linked to Pathways that Control Cellular Energy. AB - Inadequately repaired post-UV DNA damage results in skin cancers. DNA repair requires energy but skin cells have limited capacity to produce energy after UV insult. We examined whether energy supply is important for DNA repair after UV exposure, in the presence of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), which reduces UV-induced DNA damage and photocarcinogenesis in a variety of models. After UV exposure of primary human keratinocytes, the addition of 1,25(OH)2D3 increased unscheduled DNA synthesis, a measure of DNA repair. Oxidative phosphorylation was depleted in UV-irradiated keratinocytes to undetectable levels within an hour of UV irradiation. Treatment with 1,25(OH)2D3 but not vehicle increased glycolysis after UV. 2-Deoxyglucose-dependent inhibition of glycolysis abolished the reduction in cyclobutane pyrimidine dimers by 1,25(OH)2D3, whereas inhibition of oxidative phosphorylation had no effect. 1,25(OH)2D3 increased autophagy and modulated PINK1/Parkin consistent with enhanced mitophagy. These data confirm that energy availability is limited in keratinocytes after exposure to UV. In the presence of 1,25(OH)2D3, glycolysis is enhanced along with energy-conserving processes such as autophagy and mitophagy, resulting in increased repair of cyclobutane pyrimidine dimers and decreased oxidative DNA damage. Increased energy availability in the presence of 1,25(OH)2D3 is an important contributor to DNA repair in skin after UV exposure. PMID- 29258893 TI - LMO4 Is a Disease-Provocative Transcription Coregulator Activated by IL-23 in Psoriatic Keratinocytes. AB - Psoriasis is an autoimmune disease characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes. LIM-domain only protein 4 (LMO4) is a transcription factor coregulator that promotes the assembly of multiprotein complexes to regulate mammary epithelium and keratinocyte differentiation and proliferation during embryogenesis. In this study, LMO4 has been found to be abundantly expressed in psoriatic epidermis. LMO4 expression is increased in human keratinocytes induced to differentiate by calcium ex vivo, and LMO4 overexpression induces spontaneous differentiation and growth acceleration of human keratinocytes in the absence of calcium. IL-23, a cytokine highly expressed in psoriatic skin lesions, induces differentiation and promotes proliferation of human keratinocytes. The IL-23-mediated effects are accompanied by an increase in LMO4 expression mediated by signal transducer and activator of transcription 3 through an IL-23/acutely transforming retrovirus AKT8 in rodent T-cell lymphoma/signal transducer and activator of transcription 3 pathway in keratinocytes. Knockdown of LMO4 effectively inhibits differentiation and growth of keratinocytes both ex vivo and in IL-23-injected ears of mice. LMO4 appears to mediate IL-23-related responses in psoriatic keratinocytes and is a potential therapeutic target in psoriasis. PMID- 29258894 TI - The Conundrum of Allogeneic Bone Marrow Transplantation for Epidermolysis Bullosa. AB - Epidermolysis bullosa is a heterogeneous group of heritable blistering disorders with considerable morbidity and mortality. Currently, there is no effective treatment or cure for epidermolysis bullosa, but bone marrow transplantation has been suggested to improve the clinical presentation and quality of life of some patients with the recessive dystrophic subtype of epidermolysis bullosa. In this issue, two studies (Hunefeld et al., and Egawa and Kabashima) address the issue whether bone marrow transplantation could be applied to patients with epidermolysis bullosa simplex with intraepidermal blistering. Utilizing a desmoglein-3 mouse model (Dsg3-/-) or keratin 5-specific reporter mice, the investigators show that transplanted bone marrow-derived cells migrate to the skin of bone marrow transplantation recipient mice, but these cells fail to transdifferentiate into epidermal keratinocytes, and there was no improvement in the clinical manifestations of the Dsg3-/- mice. Thus, further preclinical experimentation, possibly using mouse models that more faithfully recapitulate the epidermolysis bullosa simplex phenotype, is advisable before commencing clinical trials of bone marrow transplantation for epidermolysis bullosa simplex. PMID- 29258895 TI - Estimation of structure and stability of MurE ligase from Salmonella enterica serovar Typhi. AB - MurE ligase catalyzes the assembly of peptide moiety, an essential component of bacterial cell wall. We have explored the conformational stability and unfolding equilibrium behaviour of the protein MurE ligase by determining the conformational free energy, entropy and enthalpy parameters under stress conditions. MurE from Salmonella enterica Serovar Typhi was cloned, expressed and purified. Conformational changes associated with increasing concentration of GdmCl- and urea-induced denaturation of MurE were monitored using Circular Dichroism (CD) and fluorescence spectroscopies. The secondary structural content of protein estimated by CD experiment is in close agreement with the predicted MurE ligase structure by homology modeling. Denaturant-induced transition curve was analyzed for thermodynamic parameters. Average values for MurE ligase of DeltaGD0 = 3.13 kcal mol-1, m = 1.52 kcal mol-1 M-1 and Cm (=DeltaGD0/m) = 2.05 M were calculated in the presence of GdmCl whereas in the case of urea these were DeltaGD0 = 3.04 kcal mol-1, m = 1.20 kcal mol-1 M-1 and Cm (=DeltaGD0/m) = 2.53 M. The observed superposition of normalized transition curve of two independent optical properties suggested that GdmCl- and urea-induced denaturation follow a two-state process. PMID- 29258896 TI - Chelation by collagen in the immobilization of Aspergillus oryzae beta galactosidase: A potential biocatalyst to hydrolyze lactose by batch processes. AB - This work is the first study of the immobilization of Aspergillus oryzae beta galactosidase (Gal) on powdered collagen (Col) that had formed a chelate with aluminum (Col-Al-Gal). Other collagen treatments, including those with acetic acid, glutaraldehyde, and a combination of aluminum and glutaraldehyde (Col-Al Glu-Gal), were also tested. High-yield (superior to 80%) and high-efficiency (superior to 99%) immobilization was obtained for the derivatives Col-Al-Gal and Col-Al-Glu-Gal, even at high protein loads (500-1,000 mg g-1 of support). The storage stability of Gal immobilized on Col-Al and Col-Al-Glu resulted in Gal retaining approximately 60% of its initial activity after 90 days at 4 degrees C. The half-life values of derivatives Col-Al-Gal and Col-Al-Glu-Gal were higher than those of soluble enzyme at 65, 68, 70, and 73 degrees C. The derivatives Col-Al-Gal and Col-Al-Glu-Gal retained high enzyme activity in batch hydrolysis of lactose in permeate and lactose solutions for 50 and 60 cycles, respectively. Our results suggest that powdered collagen treated with aluminum, a low-cost support, is a promising support for the immobilization of beta-galactosidase. PMID- 29258897 TI - Reduction of enthalpy relaxation in gelatine films by addition of polyols. AB - The aim of this study was to evaluate the effect of plasticisers with different molecular weights (glycerol and sorbitol) on the structural relaxation kinetics of bovine gelatine films stored under the glass transition temperature (Tg). Plasticisers were tested at weight fractions of 0.0, 0.06 and 0.10. Films conditioned in environments under ~44% relative humidity gave moisture contents (w/w) in the range 0.14-0.18. The enthalpy relaxation (DeltaH) was determined using differential scanning calorimetry (DSC). Samples used had Tg values in the range 24-49 degrees C. After removing the thermal history (30 degrees C above Tg, 15 min), samples were isothermally stored at 10 degrees C below Tg for between 2 and 80 h. The addition of plasticisers induced a significant reduction in the rate of structural relaxation. The linearisation of DeltaH by plotting against the logarithm of ageing time showed a reduction in the slope of samples plasticised with both polyols. The reduction in relaxation kinetics may be related to the ability of polyols to act as enhancers of molecular packing, as recently reported using positron spectroscopy (PALS). However, a direct correlation between the relaxation kinetics and the plasticiser's molecular weight could not be established, suggesting that this phenomenon may be governed by complex molecular gelatin-plasticiser-water interactions. PMID- 29258898 TI - Biochemical characterization of a novel cold-active, halophilic and organic solvent-tolerant lipase from B. licheniformis KM12 with potential application for biodiesel production. AB - Nowadays, finding a talented lipase with high potency in biodiesel production has been attracted to researchers. In this study, an extracellular salt tolerant, cold-active and organic solvent-stable lipase producing bacterium was isolated from oil-contaminated environments located in Kerman province (Iran) and identified as Bacillus licheniformis KM12. Lipase was purified by 36.0% recovery and molecular weight was estimated about 33 kDa by SDS-PAGE. The optimal pH and temperature for lipase activity were found to be 8.0 and 35 degrees C, respectively. Lipase activity was remarkably increased about 37% after 20 min incubation at 20 degrees C. Km value of KM12 lipase was 0.53 mM for p nitrophenyl palmitate (p-NPP) and maximum activity was detected for pNP-decanoate and glyceryl-decanoate substrates. KM12 lipase displayed significant stability in different organic solvents after 7 and 21 days of incubation, especially in polar organic solvents. Biodiesel production with 78% yields was achieved with the one step addition of methanol at around 18 h by using Myrtus oil (as a non-edible oils feedstocks). These unique properties of KM12 lipase make it talented as a potential biocatalyst for biodiesel production. PMID- 29258899 TI - Preferential exclusion mechanism by carbohydrates on protein stabilization using thermodynamic evaluation. AB - Carbohydrates are widely used as additives for biopharmaceutical formulations, but the mechanisms by which they confer stability to and their applicability on protein stability remain undiscovered. Herein, we aimed to elucidate these mechanisms, by studying the thermodynamic changes using isothermal titration calorimetry and micro-differential scanning calorimetry. Furthermore, conventional biophysical analyses, namely circular dichroism, dynamic light scattering, and size-exclusion chromatography, were used to investigate the beneficial effects of carbohydrates on protein stability. Four representative carbohydrates (sucrose, fructose, mannitol, and trehalose) were evaluated at three different concentrations on etanercept, a fusion protein. Consequently, sucrose and trehalose increased the exothermic enthalpy while mixing together with protein along with different concentrations. The results were consistent with those of size-exclusion chromatography after accelerated storage. Nevertheless, non-covalent specific interactions between proteins and carbohydrates could not be detected. However, significant increases in exothermic enthalpy were observed due to the carbohydrates, indicating preferential exclusion of water molecules around etanercept moieties. This energy was maximal at the highest concentration of sucrose and trehalose (i.e., 250 mM). Thus, these carbohydrates consistently exhibited a beneficial effect on the aggregation and conformational stability of etanercept. Based on such findings, the stabilizing mechanism of carbohydrates is proposed herein. PMID- 29258900 TI - Cellular imaging and folate receptor targeting delivery of gum kondagogu capped gold nanoparticles in cancer cells. AB - In this study, the green synthesis of gum kondagogu capped gold nanoparticles (GK GNPs) was prepared using a naturally available polysaccharide. The anionic gum capped GK-GNPs enabled the successful coupling of folic acid (FA) and fluorescein isothiocyanate (FITC) to produce a fluorescently labelled GNP (F2-GNP). F2-GNPs were further characterized using different physicochemical methods Cellular viability, cellular imaging, and targeted delivery of F2-GNPs were further evaluated in both folate receptor positive (MCF-7) and folate receptor negative (A549) cancer cells. Physicochemical characterization revealed a nanoparticle with a small size (37 nm), smooth surface (surface charge of -23.7 mV), crystallinity of gold nanoparticles and existence of gum kondagogu in the F2 GNPs. Cellular uptake of F2-GNPs indicated a greater affinity towards folate receptor positive cells. This study shows that the F2-GNPs is as an effective nanocarrier for targeted drug delivery and cellular imaging via folate receptors. PMID- 29258901 TI - Association Between Low Plasma Level of Citrulline Before Allogeneic Hematopoietic Cell Transplantation and Severe Gastrointestinal Graft vs Host Disease. AB - BACKGROUND & AIMS: The gastrointestinal form of acute graft vs host disease increases morbidity and mortality following allogeneic hematopoietic cell transplantation. Plasma levels of citrulline, a non-proteinogenic amino acid, indicate functional enterocyte mass. We measured citrulline in patients before allogeneic hematopoietic cell transplantation and investigated its association with incidence and severity of gastrointestinal graft vs host disease. METHODS: We performed a retrospective study with 191 patients (69 women, 122 men; median age of 52 years) who underwent allogeneic hematopoietic cell transplantation for hematological malignancies at a tertiary center of France from January 2013 through April 2015. Levels of citrulline in plasma samples collected 30 days before graft infusion were measured by high performance liquid chromatography with tandem mass spectrometry. We assigned patients to groups with a high level of citrulline (>26 MUmol/L) or low level of citrulline (<=26 MUmol/L). The primary outcomes were difference between groups in incidence of stage 2-4 gastrointestinal graft vs host disease, death without hematological disease relapse (non-relapse mortality), relapse of the hematological disease, and overall survival through 2 years after transplantation. RESULTS: Ninety-six patients (50%) developed acute graft vs host disease and 37 (19%) developed a gastrointestinal form. Among patients with gastrointestinal involvement, 33 patients (89%) had stage 2-4 gastrointestinal graft vs host disease. In univariable analysis, low level of citrulline associated with higher cumulative incidence of stage 2-4 gastrointestinal graft vs host disease, non-relapse mortality, and shorter overall survival. In multivariable analysis, low level of citrulline was the only risk factor independently associated with stage 2-4 gastrointestinal graft vs host disease (hazard ratio, 3.06; 95% CI, 1.37-6.85; P = .007); it also associated with increased non-relapse mortality (hazard ratio, 2.29; 95% CI, 1.24-4.22; P = .008). CONCLUSIONS: In a retrospective study with 191 patients, we associated a low plasma level of citrulline before allogeneic hematopoietic cell transplantation with a higher risk for stage 2-4 gastrointestinal graft vs host disease and non-relapse mortality. This marker might be used to manage patients before allogeneic hematopoietic cell transplantation. PMID- 29258903 TI - Whole-exome sequencing demonstrates recurrent somatic copy number alterations and sporadic mutations in specialized stromal tumors of the prostate. AB - In a previous array comparative genomic hybridization study, we detected common deletions of chromosomes 13 and 14 in prostatic stromal sarcoma and stromal tumor of uncertain malignant potential (STUMP). In this study, we performed whole-exome sequencing (WES) and fluorescence in situ hybridization to explore somatic mutations in 1 low-grade stromal sarcoma, 1 high-grade stromal sarcoma, and 12 STUMPs including 5 cases of degenerative atypia type, 1 myxoid type, 1 phyllodes type, and 5 cases of recently described round cell type. WES was successful on 13 cases that revealed frequent somatic copy number alterations including losses of chromosomes 13 (11 cases), 14 (11 cases), and 1p (9 cases), and partial or complete loss of chromosome 10 (7 cases). Fluorescence in situ hybridization was done on 9 cases and showed compatible chromosome 13 copy numbers with the WES results. STUMPs and the low-grade stromal sarcoma carried moderate tumor mutation burdens that ranged from 1.23 to 7.24 mutations per megabase, while the high grade stromal sarcoma harbored a significantly higher mutation burden (11.55 mutations per megabase). Sporadic somatic mutations were observed, but no recurrent driver mutations could be discerned. In conjunction with prior array comparative genomic hybridization, we have demonstrated the consistent gene dosage profiles that support the clonal nature and the concept of specialized stromal tumors of the prostate as a distinctive tumor entity. PMID- 29258904 TI - Identification of T-cell receptor expression in EBV-positive neoplastic cells in extranodal NK/T-cell lymphoma, nasal-type, and comparison with T-cell receptor gene rearrangement by BIOMED-2 assay. AB - The cellular lineage of extranodal NK/T-cell lymphoma, nasal-type (ENKTL), is determined by expression of T-cell receptor (TR) or TR gene rearrangement. In ENKTL, from TR immunohistochemistry, it may often be difficult to decide whether TR-positive cells are tumor cells or not, especially when TR is expressed in a subset of tumor cells. To analyze TR expression pattern and TR rearrangement in T lineage ENKTL, we performed double immunofluorescence staining for Epstein-Barr virus-encoded small RNAs (EBER)/T-cell receptor (TCR) betaF1 and CD56/TCR betaF1 in 12 cases of ENKTL that showed TCR betaF1 expression in immunohistochemistry. TR gene rearrangement was analyzed using a commercial BIOMED-2 multiplex polymerase chain reaction system. Immunohistochemistry showed that all 12 cases expressed TCR betaF1 in a wide range of infiltrating cells from 100% to <1%. Two of them expressed both TCR betaF1 and TCR cgammaM1. EBER/TCR-betaF1-positivity was confirmed in 10 cases by double staining. One case failed to show EBER/TCR betaF1-positive cells but showed a CD56/TCR betaF1-positive result. Among 12 cases, 5 had poor-quality DNA, 3 of them showed no polymerase chain reaction product, and 2 cases showed nonspecific peak of low height. Five of 7 cases with good DNA quality demonstrated monoclonal TR gene rearrangement. Based on TR expression and TR gene rearrangement, 10 of 12 cases of ENKTL were decided as a T lineage tumor. In conclusion, because of common TR silence and poor DNA quality, consideration of both immunohistochemistry and TR gene rearrangement is necessary to determine the lineage of ENKTL. PMID- 29258902 TI - The selected biomarker analysis in 5 types of uterine smooth muscle tumors. AB - Uterine smooth muscle tumors (USMTs) consist of a group of histologically heterogeneous and clinically diverse diseases ranging from malignant leiomyosarcoma (LMS) to benign leiomyoma (ULM). The genetic alterations in LMS are complex, with some genetic alterations present in both LMS and other atypical histologic variants of USMT. In this study, we reviewed 119 USMTs with a diagnosis of LMS, smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, and cellular leiomyoma, as well as 46 ULMs and 60 myometrial controls. We selected 17 biomarkers highly relevant to LMS in 4 tumorigenic pathways including steroid hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]), cell cycle/tumor suppressor genes, AKT pathway markers, and associated oncogenes. ER and PR expression was significantly lower in LMS than smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, cellular leiomyoma, and ULM (P < .01). Sixty-five percent of LMSs showed complete loss of ER, and 75% of LMSs showed complete loss of PR. All cell cycle genes were differentially expressed in different types of tumor, but significant overlap was noted. More than 75% of LMSs had Ki-67 index greater than 33%, and only 5% in all other types of USMT. Expression of the selected oncogenes varied widely among different types of USMT. PR positivity and p53 had a borderline association with progression-free survival (P = .055 for PR and P = .0847 for p53). Furthermore, high PR expression was significantly associated with a longer overall survival (P = .0163, hazard ratio 0.198). Cell proliferative indices (Ki-67) and sex steroid hormone receptors were the most valuable markers in differentiating LMS from other USMT variants. PMID- 29258905 TI - Paip1 affects breast cancer cell growth and represents a novel prognostic biomarker. AB - Polyadenylate-binding protein-interacting protein 1 (Paip1) regulates translational initiation. Increasing evidence suggests that Paip1 plays important roles in cancer development and progression. This study explored the role of Paip1 in breast cancer progression and evaluated its prognostic value. The cellular location of Paip1 protein was determined using immunofluorescence. Then, Paip1 protein expression was evaluated by immunohistochemical staining in 119 breast cancers and 40 normal breast tissues. The correlation between Paip1 expression and the clinicopathologic features of breast cancer was evaluated using the chi2 test, and differences in survival curves were analyzed using log rank tests. The role of Paip1 in breast cancer proliferation and cell cycle progression was identified by siRNA transfection. Paip1 was expressed mainly in the cytoplasm of cancer cells and tissues. Expression was observed in 60.5% of the breast cancers (72/119), which was significantly higher than in normal breast tissues (17.5%; 7/40). High expression of Paip1 protein was associated with high histologic grade, late clinical stage, and a low survival rate. Multivariate analysis indicated that Paip1 was an independent prognostic factor. Additionally, Paip1 depletion by RNAi significantly decreased cell proliferation and induced cell cycle arrest. In conclusion, our study demonstrated that Paip1 promotes the growth of breast cancers and could be a prognostic biomarker and therapeutic target. PMID- 29258906 TI - A retrospective comparison of systematic reviews with same-topic rapid reviews. AB - OBJECTIVE: To compare rapid reviews (RRs) to same-topic systematic reviews (SRs) for methods, studies included, and conclusions. STUDY DESIGN AND SETTING: A retrospective comparison of studies comparing RRs and SRs by searching four scoping reviews published between 2007 and 2016. Reports were included if literature searches were conducted within 24 months of each other and had common research questions. Reviews were compared for duration, studies included, population, intervention, comparisons, outcomes, study designs, quality, methods, and conclusions. RESULTS: Six studies containing 16 review pairs were included, covering nine topics. Overall, RRs used abbreviated methods more often: no search of grey literature, employing one reviewer to screen studies, engaging fewer experts, including fewer studies, and providing shorter reports, with poorer reporting quality and faster completion. Reviews reported similar conclusions, with two exceptions: one SR did not include a key study; separately, two RRs failed to highlight an association with early mortality identified by the SR. RRs tended to provide less detail and fewer considerations. CONCLUSION: RRs used several methodological shortcuts compared with SRs on the same topic. It was challenging to discern methodological differences because of retrospective assessment and substantial nonreporting, particularly for RRs. PMID- 29258907 TI - Systematic reviews with published protocols compared to those without: more effort, older search. AB - OBJECTIVE: To explore trends in published protocols of systematic reviews (SRs) and to analyze how SRs with published protocols differ from those without. STUDY DESIGN AND SETTING: We searched PubMed up to December 31, 2016 to identify SR protocols. We also searched for the corresponding SR for each protocol published in 2012 and 2013 and matched this with an SR without published protocol by year and journal. RESULTS: The number of protocols published increased from 42 in 2012 to 404 in 2016; 125 were published in 2012 and 2013. One-third of SRs remained unpublished after 3-5 years. We included 80 SRs with protocols and 80 controls. SRs with protocols reported their methods more comprehensively than their controls, but their median time from search to submission was longer (325 vs. 122 days; P < 0.001). Almost two-thirds of the SRs with protocols and about 10% of the controls could be found in the International Prospective Register of Systematic Reviews (PROSPERO). CONCLUSION: Time from search to submission was longer for SRs with published protocols, while at the same time SRs with published protocols were better elaborated and reported. As quality, transparency, and currency are cornerstones of SRs, we suggest critically discussing the current practice of publishing SR protocols. PMID- 29258908 TI - Linear regression and the normality assumption. AB - OBJECTIVES: Researchers often perform arbitrary outcome transformations to fulfill the normality assumption of a linear regression model. This commentary explains and illustrates that in large data settings, such transformations are often unnecessary, and worse may bias model estimates. STUDY DESIGN AND SETTING: Linear regression assumptions are illustrated using simulated data and an empirical example on the relation between time since type 2 diabetes diagnosis and glycated hemoglobin levels. Simulation results were evaluated on coverage; i.e., the number of times the 95% confidence interval included the true slope coefficient. RESULTS: Although outcome transformations bias point estimates, violations of the normality assumption in linear regression analyses do not. The normality assumption is necessary to unbiasedly estimate standard errors, and hence confidence intervals and P-values. However, in large sample sizes (e.g., where the number of observations per variable is >10) violations of this normality assumption often do not noticeably impact results. Contrary to this, assumptions on, the parametric model, absence of extreme observations, homoscedasticity, and independency of the errors, remain influential even in large sample size settings. CONCLUSION: Given that modern healthcare research typically includes thousands of subjects focusing on the normality assumption is often unnecessary, does not guarantee valid results, and worse may bias estimates due to the practice of outcome transformations. PMID- 29258909 TI - Novel enzyme formulations for improved pharmacokinetic properties and anti inflammatory efficacies. AB - Anti-inflammatory enzymes promote the dissolution and excretion of sticky phlegm, clean the wound surface and accelerate drug diffusion to the lesion. They play important roles in treating different types of inflammation and pain. Currently, various formulations of anti-inflammatory enzymes are successfully prepared to improve the enzymatic characteristics, pharmacokinetic properties and anti inflammatory efficacies. The work was performed by systematically searching all available literature. An overall summary of current research about various anti inflammatory enzymes and their novel formulations is presented. The original and improved enzymatic characteristics, pharmacokinetic properties, action mechanisms, clinical information, storage and shelf life, treatment efficacies of anti-inflammatory enzymes and their different formulations are summarized. The influencing factors such as enzyme type, source, excipient, pharmaceutical technique, administration route and dosage are analyzed. The combined application of enzymes and other drugs are included in this paper. Anti-inflammatory enzymes were widely applied in treating different types of inflammation and diseases with accompanying edema. Their novel formulations increased enzymatic stabilities, improved pharmacokinetic properties, provided different administration routes, and enhanced anti-inflammatory efficacies of anti-inflammatory enzymes but decreased side effects and toxicity. Novel enzyme formulations improve and expand the usage of anti-inflammatory enzymes. PMID- 29258910 TI - Glucose-responsive insulin delivery for type 1 diabetes: The artificial pancreas story. AB - Insulin replacement therapy is integral to the management of type 1 diabetes, which is characterised by absolute insulin deficiency. Optimal glycaemic control, as assessed by glycated haemoglobin, and avoidance of hyper- and hypoglycaemic excursions have been shown to prevent diabetes-related complications. Insulin pump use has increased considerably over the past decade with beneficial effects on glycaemic control, quality of life and treatment satisfaction. The advent and progress of ambulatory glucose sensor technology has enabled continuous glucose monitoring based on real-time glucose levels to be integrated with insulin therapy. Low glucose and predictive low glucose suspend systems are currently used in clinical practice to mitigate against hypoglycaemia, and provide the first step towards feedback glucose control. The more advanced technology approach, an artificial pancreas or a closed-loop system, gradually increases and decreases insulin delivery in a glucose-responsive fashion to mitigate against hyper- and hypoglycaemia. Randomised outpatient clinical trials over the past 5 years have demonstrated the feasibility, safety and efficacy of the approach, and the recent FDA approval of the first single hormone closed-loop system establishes a new standard of care for people with type 1 diabetes. PMID- 29258911 TI - Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the primary drying step during freeze-drying. AB - Pharmaceutical batch freeze-drying is commonly used to improve the stability of biological therapeutics. The primary drying step is regulated by the dynamic settings of the adaptable process variables, shelf temperature Ts and chamber pressure Pc. Mechanistic modelling of the primary drying step leads to the optimal dynamic combination of these adaptable process variables in function of time. According to Good Modelling Practices, a Global Sensitivity Analysis (GSA) is essential for appropriate model building. In this study, both a regression based and variance-based GSA were conducted on a validated mechanistic primary drying model to estimate the impact of several model input parameters on two output variables, the product temperature at the sublimation front Ti and the sublimation rate msub. Ts was identified as most influential parameter on both Ti and msub, followed by Pc and the dried product mass transfer resistance alphaRp for Ti and msub, respectively. The GSA findings were experimentally validated for msub via a Design of Experiments (DoE) approach. The results indicated that GSA is a very useful tool for the evaluation of the impact of different process variables on the model outcome, leading to essential process knowledge, without the need for time-consuming experiments (e.g., DoE). PMID- 29258912 TI - Lactose oleate as new biocompatible surfactant for pharmaceutical applications. AB - Sugar fatty acid esters are an interesting class of non-ionic, biocompatible and biodegradable sugar-based surfactants, recently emerged as a valid alternative to the traditional commonly employed (e.g. polysorbates and polyethylene glycol derivatives). By varying the polar head (carbohydrate moiety) and the hydrophobic tail (fatty acid), surfactants with different physico-chemical characteristics can be easily prepared. While many research papers have focused on sucrose derivatives, relatively few studies have been carried out on lactose-based surfactants. In this work, we present the synthesis and the physico-chemical characterization of lactose oleate. The new derivative was obtained by enzymatic mono-esterification of lactose with oleic acid. Thermal, surface, and aggregation properties of the surfactant were studied in detail and the cytotoxicity profile was investigated by MTS and LDH assays on intestinal Caco-2 monolayers. Transepithelial electrical resistance (TEER) measurements on Caco-2 cells showed a transient and reversible effect on the tight junctions opening, which correlates with the increased permeability of 4 kDa fluorescein-labelled dextran (as model for macromolecular drugs) in a concentration dependent manner. Moreover, lactose oleate displayed a satisfactory antimicrobial activity over a range of Gram-positive and Gram-negative bacteria. Overall, the obtained results are promising for a further development of lactose oleate as an intestinal absorption enhancer and/or an alternative biodegradable preservative for pharmaceutical and food applications. PMID- 29258913 TI - Evaluation of dyslipidaemia and the impact of hypolipidemic therapy on prognosis in high and very high risk patients through the Hyperlipidaemia Therapy in tERtiary Cardiological cEnTer (TERCET) Registry. AB - The use of statins in the treatment of hyperlipidaemia leads to a significant decrease in cardiovascular (CV) endpoints, and therapy effects are proportional to the reduction of cholesterol levels. In Poland, information about the effects of statin therapy is scarcely available. The information gathered in the Hyperlipidaemia Therapy in the tERtiary Cardiological cEnTer (TERCET) Registry on high-risk and very high-risk patients might improve our knowledge on this issue and help to introduce suitable activities. The main aim of the TERCET Registry is to achieve the target value of low density lipoprotein cholesterol (LDL-C) during a 1-year follow-up: LDL-C <70 mg/dL in very high-risk patients and LDL-C <100 mg/dL in high-risk patients. All consecutive patients with either stable coronary artery disease (sCAD) or acute coronary syndrome (ACS) have been included in the Registry, and the information on all-cause mortality, nonfatal myocardial infarction (MI), and planned or ACS-caused revascularisation have been being gathered within 12-month follow-up. At the moment, the TERCET Registry includes 14,873 patients (66.8% male) at an average age of 64.8 +/- 10.2 with a significantly higher age of women (67.5 +/- 10.3 vs. 63.5 +/- 9.7; p < .001). The causes of hospitalisation were as the following: sCAD (n = 9375 patients, 63% of the investigated population), ST-elevated myocardial infarction (n = 2328 [15.6%]), non-ST-elevated myocardial infarction (n = 1700 [11.4%]), and unstable coronary artery disease (n = 1466 [10%]). 62,7% (n = 9144) of the patients were diagnosed with hyperlipidaemia before hospital admission, with no significant difference between male and female patients. The TERCET registry will allow unveiling real lipid profiles of the high- and very-high risk patients treated in the tertiary hospital. The results may play an essential role in establishing the patients' future clinical outcomes and help to assess if the lipid lowering therapy modifications changed the occurrence of CV endpoints. The registry data will summarize the number of patients unable to reach their LDL-C goals, and who in the future might become candidates suitable for new hypolipidemic therapies (ID: NCT03065543). PMID- 29258914 TI - Iron deficiency and iron deficiency anemia in children aged 6-36 months: Is there room for improvement of screening, prophylaxis and treatment? PMID- 29258915 TI - Cinnamon, a promising prospect towards Alzheimer's disease. AB - Over the last decades, an exponential increase of efforts concerning the treatment of Alzheimer's disease (AD) has been practiced. Phytochemicals preparations have a millenary background to combat various pathological conditions. Various cinnamon species and their biologically active ingredients have renewed the interest towards the treatment of patients with mild-to-moderate AD through the inhibition of tau protein aggregation and prevention of the formation and accumulation of amyloid-beta peptides into the neurotoxic oligomeric inclusions, both of which are considered to be the AD trademarks. In this review, we presented comprehensive data on the interactions of a number of cinnamon polyphenols (PPs) with oxidative stress and pro-inflammatory signaling pathways in the brain. In addition, we discussed the potential association between AD and diabetes mellitus (DM), vis-a-vis the effluence of cinnamon PPs. Further, an upcoming prospect of AD epigenetic pathophysiological conditions and cinnamon has been sighted. Data was retrieved from the scientific databases such as PubMed database of the National Library of Medicine, Scopus and Google Scholar without any time limitation. The extract of cinnamon efficiently inhibits tau accumulations, Abeta aggregation and toxicity in vivo and in vitro models. Indeed, cinnamon possesses neuroprotective effects interfering multiple oxidative stress and pro-inflammatory pathways. Besides, cinnamon modulates endothelial functions and attenuates the vascular cell adhesion molecules. Cinnamon PPs may induce AD epigenetic modifications. Cinnamon and in particular, cinnamaldehyde seem to be effective and safe approaches for treatment and prevention of AD onset and/or progression. However, further molecular and translational research studies as well as prolonged clinical trials are required to establish the therapeutic safety and efficacy in different cinnamon spp. PMID- 29258916 TI - Potential of selected Lamiaceae plants in anti(retro)viral therapy. AB - Constant search for new drugs with antiviral properties often extends to products of natural origin. Lamiaceae is one of the most important herbal families, well known for various biological and medicinal effects of a variety of aromatic spices, including thyme, mint, oregano, basil, sage, savory, rosemary, self-heal, hyssop, lemon balm and many others. The paper provides a review of antiviral potential of previously mentioned plants which has been demonstrated so far, with special emphasis on anti-HIV properties. Relevant articles were compiled by searching plant names combined with keywords describing antiviral activity. The antiviral effect is direct, with prominent activity against enveloped viral species. Initial stages of the viral life cycle are the most affected, as these plants appear to be targeting mainly viral structures responsible for attachment to target cells. In case of HIV, there is some activity against key enzymes in the viral life cycle. Even in the case of drug resistance, there is an equal susceptibility to applied herbal preparations. Some in vivo experiments suggest that use of Lamiaceae representatives could help in prevention and treatment of some viral diseases. A possible reduction of side effects of diseases and conventional drug therapy are also some aspects worth further investigations. PMID- 29258918 TI - Barriers to implementing the NICE guidelines for early-onset neonatal infection: cross-sectional survey of neonatal blood culture reporting by laboratories in the UK. AB - The National Institute for Health and Care Excellence published guidelines for managing early-onset neonatal infections in 2012. It recommended provision for reporting blood cultures (BCs) with growth detected or not detected at 36 h. To determine if this was followed, a telephone survey was conducted amongst lead biomedical scientists based at microbiology laboratories (N = 209) in the UK. Overall, 202/209 responded and 139/202 had on-site facilities for BCs. BC results with growth detected or not detected at 36 h were available out-of-hours in 36/139 (26.6%) and 66/139 (47.5%) neonatal units, respectively. Early discontinuation of antibiotics should lead to improved antibiotic stewardship. PMID- 29258917 TI - Clostridium difficile classification overestimates hospital-acquired infections. AB - BACKGROUND: Clostridium difficile infections occur frequently among hospitalized patients, with some infections acquired in hospital and others in the community. International guidelines classify cases as hospital-acquired if symptom onset occurs more than two days after admission. This classification informs surveillance and infection control, but has not been verified by empirical or modelling studies. AIM: To assess current classification of C. difficile acquisition using a simulation model as a reference standard. METHODS: C. difficile transmission was simulated in a range of hospital scenarios. The sensitivity, specificity and precision of classifications that use cut-offs ranging from 0.25 h to 40 days were calculated. The optimal cut-off that correctly estimated the proportion of cases that were hospital acquired and the balanced cut-off that had equal sensitivity and specificity were identified. FINDINGS: The recommended two-day cut-off overestimated the incidence of hospital acquired cases in all scenarios and by >100% in the base scenario. The two-day cut-off had good sensitivity (96%) but poor specificity (48%) and precision (52%) to identify cases acquired during the current hospitalization. A five-day cut-off was balanced, and a six-day cut-off was optimal in the base scenario. The optimal and balanced cut-offs were more than two days for nearly all scenarios considered (ranges: four to nine days and two to eight days, respectively). CONCLUSION: Current guidelines for classifying C. difficile infections overestimate the proportion of cases acquired in hospital in all model scenarios. To reduce misclassification bias, an infection should be classified as being acquired prior to admission if symptoms begin within five days of admission. PMID- 29258919 TI - Evaluation of economic burden of colonic surgical site infection at a Japanese hospital. AB - BACKGROUND: Several reports have been published regarding cost increases attributable to surgical site infections (SSIs) in Europe and the USA. However, such studies have been limited in Japan. AIM: To evaluate the economic burden of colorectal SSIs on hospitals in Japan. METHODS: This study was undertaken at a Japanese university hospital. Amongst 265 patients who had undergone colorectal surgery in the Department of Coloproctological Surgery between November 2014 and March 2016, 16 patients who developed SSIs and could be allocated a diagnosis procedure combination code were selected as SSI cases. Individual SSI cases were matched to non-SSI cases based on a combination of surgical category, age band, sex, wound class, presence of stoma and risk index. Median length of stay (LOS) and piecework reference cost were compared between SSI episodes and non-SSI episodes. FINDINGS: The median LOS for patients with SSI and without SSI was 25.5 [interquartile range (IQR) 21.5-39.3] and 16.5 (IQR 12.5-18.5) days, respectively (P<0.01). The median piecework reference cost for patients with SSI and without SSI was Y842,155 (IQR Y716,423-1,388,968) and Y575,795 (IQR Y529,638-680,105), respectively (P<0.01). CONCLUSION: SSIs led to a significant increase in LOS and economic burden. Although the SSI episodes appear to be more profitable than the non-SSI episodes, the economic profit for SSI episodes was less than that for non SSI episodes in the observation period, when opportunity costs were taken into account. PMID- 29258920 TI - Optimization of antimicrobial therapy in vancomycin-resistant enterococcal bacteraemia using a rapid detection Gram-positive blood culture assay. AB - Rapid molecular blood culture Gram-positive (BC-GP) assay can promptly identify vancomycin-resistant enterococcal (VRE) bloodstream infections (BSIs). We sought to evaluate patients with VRE BSI following the pre (N = 44) and post (N = 20) implementation of Verigene BC-GP assay. The average time to detection of VRE was 25.9 +/- 4.1h (95% confidence interval (CI): 17.6-34.1; P < 0.001) earlier with Verigene BC-GP assay. Compared to patients in the pre-Verigene BC-GP period, the mean adjusted difference in time to administration of anti-VRE therapy was 18.2 +/- 7.8h (95% CI: 2.5-33.8; P = 0.024) earlier among patients in the post Verigene BC-GP period. PMID- 29258921 TI - The choroid plexus epithelium as a novel player in the stomach-brain axis during Helicobacter infection. AB - Several studies suggest a link between shifts in gut microbiota and neurological disorders. Recently, we reported a high prevalence of Helicobacter suis (H. suis) in patients with Parkinson's disease. Here, we evaluated the effect of gastric H. suis infection on the brain in mice. One month of infection with H. suis resulted in increased brain inflammation, reflected in activation of microglia and cognitive decline. Additionally, we detected choroid plexus inflammation and disruption of the epithelial blood-cerebrospinal fluid (CSF) barrier upon H. suis infection, while the endothelial blood-brain barrier (BBB) remained functional. These changes were accompanied by leakage of the gastrointestinal barrier and low grade systemic inflammation, suggesting that H. suis-evoked gastrointestinal permeability and subsequent peripheral inflammation induces changes in brain homeostasis via changes in blood-CSF barrier integrity. In conclusion, this study shows for the first time that H. suis infection induces inflammation in the brain associated with cognitive decline and that the choroid plexus is a novel player in the stomach-brain axis. PMID- 29258922 TI - Flow virometry as a tool to study viruses. AB - In the last few decades, flow cytometry has redefined the field of biology, exponentially enhancing our understanding of cells, immunology, and microbiology. Flow cytometry recently gave birth to flow virometry, a new way to detect, analyze, and characterize single viral particles. Detection of viruses by flow cytometry is possible due to improvements in current flow cytometers, calibration, and tuning methods. We summarize the recent birth and novel uses of flow virometry and the progressive evolution of this tool to advance the field of virology. We also discuss the various flow virometry methods used to identify and analyze viruses. We briefly summarize other applications of flow virometry, including: virus detection, quantification, population discrimination, and viral particles' antigenic properties. Finally, we summarize how viral sorting will allow further progress of flow virometry to relate viral surface characteristics to infectivity properties. PMID- 29258923 TI - Circle scanning STED fluorescence correlation spectroscopy to quantify membrane dynamics and compartmentalization. AB - Quantifying molecular dynamics of cell membrane constituents is required to understand organization and function of biological membranes. Because of its complex structure unambiguous interpretation of molecular membrane dynamics requires high spatial and temporal resolution measurements. In this paper, we provide a comprehensive description of circle scanning fluorescence correlation spectroscopy and its combination with stimulated emission depletion microscopy (CS-STED-FCS). This method allows quantification of sub-diffusion processes and direct mapping of heterogeneities in membranes with high spatiotemporal resolution. We show how to use model membranes to calibrate and test the technique and how to apply it in the context of living cells to quantify membrane dynamics with high spatiotemporal resolution and good statistics. PMID- 29258924 TI - Assessing multiparametric drug response in tissue engineered tumor microenvironment models. AB - The tumor microenvironment is important in promoting treatment resistance of tumor cells via multiple mechanisms. However, studying this interaction often proves difficult. In vivo animal models are costly, time-consuming, and often fail to adequately predict human response to treatment. Conversely, testing drug response on human tumor cells in vitro in 2D cell culture excludes the important contribution of stromal cells and biophysical forces seen in the in vivo tumor microenvironment. Here, we present tissue-engineered models of both human brain and breast tumor microenvironments incorporating key stromal cell populations for assessing multiple mechanisms of therapeutic response using flow cytometry. We show our physiologically-relevant systems used to interrogate a variety of parameters associated with chemotherapeutic efficacy, including cell death, proliferation, drug uptake, and invasion of cancer and stromal cell populations. The use of flow cytometry allows for single cell, quantitative, and fast assessments of multiple outcomes affecting anti-tumor therapy failure. Our system can be modified to add and remove cellular components with ease, thereby enabling the study of individual cellular contributions in the tumor microenvironment. Together, our models and analysis methods illustrate the importance of developing fast, cost-effective, and reproducible methods to model complex human systems in a physiologically-relevant manner that may prove useful for drug screening efforts in the future. PMID- 29258925 TI - Non-clinical toxicity of beta-caryophyllene, a dietary cannabinoid: Absence of adverse effects in female Swiss mice. AB - beta-caryophyllene is a food additive that is found in food plants and has broad pharmacological potential. However, little toxicological information has been reported and its use is based on the fact that this bicyclic sesquiterpene is daily consumed as a plant food in much larger quantities than as a food additive. Thus, this study evaluated acute (14-day) and repeated-dose (28 days) oral beta caryophyllene toxicity in female Swiss mice analyzing changes in body weight, food intake, water intake, hematological and biochemical parameters, organ weight after necropsy, oxidative stress markers and histopathology of various tissues. Acute (300 and 2000 mg/kg) and repeated-dose (300 and 2000 mg/kg) toxicity studies were performed according to the Organization for Economic Cooperation and Development (OECD) guideline 423 and 407, respectively. There was absence of adverse clinical signs and mortality in any animal subjected to acute and repeated-dose toxicity study. In addition, no significant changes in body weight, food and water intake, oxidative stress biomarkers, hematological and biochemical parameters were observed when compared to control group from single-dose and repeated-dose toxicity study. Therefore, the results of this study provide an understanding of the toxicity profile of beta-caryophyllene which can be considered a compound with toxicity at doses higher than 2000 mg/kg body weight. PMID- 29258926 TI - No treatment-related effects with aryloxyalkanoate dioxygenase-12 in three 28-day mouse toxicity studies. AB - The aryloxyalkanoate dioxygenase-12 (AAD-12) protein is expressed in genetically modified soybean events DAS-68416-4 and DAS-444O6-6. Expression of the AAD-12 protein in soybeans confers tolerance to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) providing an additional herbicide choice to farmers. This enzyme acts by catalyzing the degradation of 2,4-D into herbicidally inactive metabolites. To meet evolving interpretation of regulations in the European Union, three separate 28-day repeat-dose oral mouse studies were conducted at increasing doses of up to 1100 mg AAD-12 protein/kg bw/day. No treatment-related effects were seen in any of these three studies. PMID- 29258927 TI - Quantifying the risk-reduction potential of new Modified Risk Tobacco Products. AB - Quantitative risk assessment of novel Modified Risk Tobacco Products (MRTP) must rest on indirect measurements that are indicative of disease development prior to epidemiological data becoming available. For this purpose, a Population Health Impact Model (PHIM) has been developed to estimate the reduction in the number of deaths from smoking-related diseases following the introduction of an MRTP. One key parameter of the model, the F-factor, describes the effective dose upon switching from cigarette smoking to using an MRTP. Biomarker data, collected in clinical studies, can be analyzed to estimate the effects of switching to an MRTP as compared to quitting smoking. Based on transparent assumptions, a link function is formulated that translates these effects into the F-factor. The concepts of 'lack of sufficiency' and 'necessity' are introduced, allowing for a parametrization of a family of link functions. These can be uniformly sampled, thus providing different 'scenarios' on how biomarker-based evidence can be translated into the F-factor to inform the PHIM. PMID- 29258928 TI - Predictive Value of Intraoperative Facial Motor Evoked Potentials in Vestibular Schwannoma Surgery Under 2 Anesthesia Protocols. AB - OBJECTIVE: We sought to validate the feasibility of facial motor evoked potential (FMEP) in facial nerve (FN) monitoring during vestibular schwannoma (VS) surgery under 2 anesthesia protocols and to examine its value for postoperative prognosis. METHODS: This prospective study included 106 patients with VS who underwent microsurgical excision between May 2014 and November 2016 at the Beijing Tiantan Hospital, Capital Medical University, China. All patients were investigated for FMEP elicited by transcranial electrical stimulation in the contralateral facial motor cortex. The patients randomly received total intravenous anesthesia or combined intravenous-inhalation anesthesia. Postoperative FN function was evaluated 7-10 days after surgery (short-term) and at the last follow-up (long-term) using the House-Brackmann (HB) grading system. HB grades 1 and 2 were deemed satisfactory, whereas HB grades 3-6 were deemed unsatisfactory. The value of the final-to-start FMEP ratio for predicting short term and long-term postoperative FN functions was examined. RESULTS: Valid FMEPs were obtained in 97 patients, which were recorded from the mentalis muscle. The FMEP amplitude ratio was significantly correlated with short-term and long-term postoperative FN functions. Receiver operating characteristic curve analysis showed that the FMEP ratio cut-off values of 77.4% (area under the curve = 0.797) and 56.9% (area under the curve = 0.900) predicted satisfactory FN function 7-10 days after surgery and at the last follow-up, respectively. No statistically significant difference was found in FMEP quantitative parameters between the 2 anesthesia protocols. CONCLUSION: The FMEP amplitude ratio is a valuable predictor for postoperative FN function. FMEP ratio >=57% is predictive of satisfactory long-term FN function. PMID- 29258930 TI - Utility of Intracranial Pressure Monitoring for Diagnosis of Idiopathic Intracranial Hypertension in the Absence of Papilledema. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is characterized by headaches, visual obscurations, and papilledema, and the diagnosis involves lumbar puncture (LP) with an elevated opening pressure (OP) >=20 cm H20. When papilledema is absent, the diagnosis becomes less clear. Some physicians have argued that the absence of papilledema rules out IIH, whereas others maintain that elevated OP is sufficient for diagnosis. METHODS: The authors performed a single-institution 4-year retrospective analysis of patients who underwent invasive intracranial pressure (ICP) monitoring for presumed IIH. RESULTS: A total of 22 patients were reviewed, and 13 had classic symptoms of IIH, documented elevated OP, and absence of papilledema; 5/13 (38%) patients had proven intracranial hypertension as shown by invasive ICP monitoring, whereas 8/13 (62%) had normal ICP. CONCLUSIONS: With the use of current diagnostic algorithms of clinical presentation and elevated OP, over half of patients without papilledema in our series would be falsely diagnosed with IIH, which could result in unnecessary medical and surgical intervention. Thus, elevated OP as determined by LP is insufficient to diagnose IIH. On the other hand, the absence of papilledema does not rule out intracranial hypertension. PMID- 29258929 TI - Survival of Ventricular and Periventricular High-Grade Gliomas: A Surveillance, Epidemiology, and End Results Program-Based Study. AB - BACKGROUND: Aggressiveness of surgical resection for periventricular/ventricular high-grade gliomas (HGGs) is determined by operative risks and assumed effectiveness of radiation therapy (RT) on residual tumor. We aimed to clarify the impact of surgery and postoperative RT on patient survival in a population based study. METHODS: This population-based study used the Surveillance, Epidemiology, and End Results (SEER) database. Patients with ventricular malignant tumors were screened for HGGs. In accordance with the World Health Organization (WHO) 2016 classification, we included cases with "diffuse astrocytic and oligodendroglial tumors," "other astrocytic tumors," "ependymal tumors," and "other gliomas". Tumor grading followed definitions established by the WHO with supplementation from SEER classifications. Only grades III and IV were included. Individual factors were assessed by hazard ratio (HR) from multivariable survival analysis using accelerated failure time (AFT) regression. RESULTS: We included 353 patients after application of inclusion and exclusion criteria. The mean patient age was 38.77 +/- 24.95 years, and the cohort was 61.5% male. Overall median survival was 12 months, with notable improvement over the last 3 decades. In a multivariate AFT model, older age (per 10-year increase, HR, 1.19; P < 0.001) was the sole nontreatment variable found to predict survival, whereas postoperative RT had a significant survival benefit (HR, 0.50; P < 0.001). No tumor characteristic (e.g., size, extent of invasion) predicted prognosis. Interestingly, neither partial resection nor TR/GTR was associated with improved outcome. CONCLUSIONS: The prognosis of ventricular HGGs is poor, with worse prognosis in older patients. We found no evidence to support aggressive surgical resection. Postoperative chemoradiation should be administered; however, the benefit of modification of the protocol for chemoradiation specifically for ventricular HGGs remains unknown and warrants further investigation. PMID- 29258931 TI - Transpedicular Excision of a Thoracic Intraspinal Osteochondroma in a Patient with Hereditary Multiple Exostoses and Brown-Sequard Syndrome. AB - BACKGROUND: Spinal osteochondroma is a rare but recognized cause of myelopathy. Brown-Sequard syndrome is a form of severe myelopathy characterized by a clinical picture of hemisection of the spinal cord. Brown-Sequard syndrome caused by osteochondroma is extremely rare, calling for individualized surgical procedures. CASE DESCRIPTION: We report a 16-year-old girl with hereditary multiple exostoses and a rare case of thoracic osteochondroma causing partial Brown-Sequard syndrome. Customized surgical procedures were designed to avoid iatrogenic spinal cord injury. The patient underwent neural decompression and tumor excision through a transpedicular approach. The surgical procedure consisted of 4 consecutive steps: 1) laminectomy, 2) costotransversectomy and pediculectomy, 3) extracavitary removal of the mass, and 4) pedicular fixation with fusion. Total resection of the tumor was achieved macroscopically without intraoperative spinal cord injury. The postoperative recovery was uneventful, and the patient returned to a normal life without evidence of recurrence at 24-month follow-up. CONCLUSIONS: For patients with hereditary multiple exostosis and new onset of neurologic symptoms, the possibility of a spinal osteochondroma should be considered. In the situation of an intraspinal exostosis protruding from the lateral side, customized surgical procedures with a transpedicular approach may be a valid way to minimize intraoperative neural injury and achieve a satisfactory outcome. PMID- 29258932 TI - Rupture Risk of Cerebral Arteriovenous Malformations During Pregnancy and Puerperium: A Single-Center Experience and Pooled Data Analysis. AB - OBJECTIVE: Whether rupture risk of cerebral arteriovenous malformation (AVM) is higher during pregnancy and puerperium remains controversial. This study aimed to compare risk of rupture in pregnant and nonpregnant female patients with AVM in a singer-center series and assess current evidence regarding rupture risk of AVM during pregnancy and puerperium by pooled data analysis. METHODS: We retrospectively reviewed female patients with AVM in our center from January 2006 to August 2017. Hemorrhage events and patient-years were calculated during exposure period and nonexposure period, which was defined as either the interval from birth until AVM obliteration or last follow-up after subtracting the exposure period. Poisson rate ratio analysis was used to compare hemorrhage rate between the 2 periods. Pooled data analysis was performed by up-to-date literature review via PubMed and EMBASE databases. RESULTS: In 264 female patients with AVM, overall annual hemorrhage rate for 222 total hemorrhages during an average of 7484 patient-years was 2.97%. Eight hemorrhages occurred in exposure periods, 214 hemorrhages occurred in nonexposure periods, and 155 hemorrhages occurred in nonexposure periods of reproductive-age patients, translating to annual hemorrhage rates of 5.40% in exposure periods, 2.92% in nonexposure periods, and 3.82% in nonexposure periods of reproductive-age patients. Pooled data analysis showed a higher annual hemorrhage rate in exposure periods than in nonexposure periods (5.59% vs. 2.52%; 95% confidence interval 1.52-6.70, P = 0.002). CONCLUSIONS: This study demonstrated an increase in annual rate of cerebral AVM hemorrhage during pregnancy and puerperium. Female reproductive-age patients with cerebral AVM may have higher risks of AVM rupture. Further evaluation by well-designed prospective or randomized cohort studies is needed. PMID- 29258933 TI - Comparison of Single-Level and Multilevel Decompressive Laminectomy for Multilevel Lumbar Spinal Stenosis. AB - OBJECTIVE: This study aimed to clarify whether multiple compressions of nerve roots resulted in poorer surgical outcome when patients were treated with single level decompressive laminectomy or multilevel decompressive laminectomy. To reach this we compared preoperative and postoperative Oswestry Disability Index (ODI) scores, Visual Analogue Scale (VAS) scores, and walking duration of multilevel lumbar spinal stenosis (LSS) patients treated with single-level and multilevel decompressive laminectomy. METHODS: This retrospective study included 112 consecutive patients undergoing lumbar decompressive surgery without arthrodesis for LSS between March 2010 and September 2013. Forty-eight patients were treated with single-level laminectomy and 64 patients were treated with multilevel laminectomy. ODI scores, VAS scores, and walking duration were measured for all patients preoperatively and 30 months after decompressive surgery. RESULTS: The mean age of the patients was 64.41 +/- 13.4 years. The ODI scores, VAS scores, and walking duration difference between patients treated with single-level laminectomy and multilevel laminectomy were statistically significant and higher for the first group (P < 0.05). There were more operative complications in patients treated with multilevel decompressive laminectomy; however, there was no statistically significant difference between single-level and multilevel decompressed patients regarding complications (P = 0.119). Four of the patients treated with multilevel decompressive laminectomy experienced postoperative spondylolisthesis needing posterior instrumented fusion. CONCLUSION: Recovery in terms of ODI scores, VAS scores, and walking duration was better in LSS patients undergoing single-level laminectomy than in those undergoing multilevel laminectomy. Also, the rates of operative complications and postoperative follow up spondylolisthesis were higher in patients treated with multilevel laminectomy. PMID- 29258934 TI - Lentivirus Is an Efficient and Stable Transduction Vector for Intervertebral Disc Cells. AB - OBJECTIVE: To evaluate transduction efficacy and sustainability of lentiviral vector for intervertebral disc cells both in vitro and in vivo. METHODS: Human nuclear pulposus and anulus fibrosus cells isolated from disc tissue of 28 patients during surgical disc procedures were cultured and subsequently transduced using recombinant lentivirus carrying a gene for enhanced green fluorescent protein at multiplicities of infection of 0, 15, 30, 60, 90, and 150. Cell viability was determined using the trypan blue exclusion test. Transduction efficiency was measured by fluorescence-activated cell sorting analysis. In vivo experiments were done by injecting lentivirus into rat intervertebral discs. Disc tissue was harvested 7, 14, 21, and 28 days after transduction, and enhanced green fluorescent protein expression was examined using an inverted fluorescent microscope. RESULTS: Intervertebral disc cells transduced with different doses of lentivirus showed equally good viabilities compared with cells in the control group, as determined by cell morphology and growth curves after transduction. The transduction ratio for disc cells after transduction reached its optimum of 97% at 60 multiplicities of infection, independent of patient age, sex, surgical procedure, diagnosis, disc level, or degeneration grade. In vivo frozen sections revealed that enhanced green fluorescent protein expression peaked on the 7th day and remained detectable the 28th day after transduction. No significant systemic symptoms were observed during the in vivo experiment. CONCLUSIONS: Lentivirus appears to be an efficient and stable transduction vector for intervertebral disc cells. It has potential as a gene therapy tool for treating human degenerative disc disease. PMID- 29258935 TI - Low Retrosigmoid Infratonsillar Approach to Lateral Medullary Lesions. AB - OBJECTIVE: In our study, we comprehensively detail the technique of the low retrosigmoid approach to the lateral medullary area, including the inferior cerebellar peduncle, postolivary sulcus, pontomedullary sulcus, and inferior olivary nucleus, as well as the lateral recess of the fourth ventricle. METHODS: Four formalin-fixed, silicone-injected, cadaveric human heads were examined under the operating microscope to demonstrate pertinent descriptive anatomy using the low retrosigmoid approach in a stepwise manner. Clinical parameters of a patient with a lateral medullary lesion were reviewed retrospectively to describe preoperative and postoperative examination and surgical details of the approach to the lateral medulla. RESULTS: The clinical case report describes a low retrosigmoid craniotomy performed to access the exiting points of cranial nerves IX (glossopharyngeal) and X (vagus), foramen of Luschka, inferior cerebellar peduncle (lateral medullary zone), postolivary sulcus, and olivary nucleus. The lesion was exposed using the inferior cerebellar peduncle and removed using standard microsurgical technique. CONCLUSIONS: The lower retrosigmoid infratonsillar approach provides excellent exposure to medullary safe entry zones, including the transolivary, postolivary sulcus, pontomedullary sulcus, and lateral medullary (inferior cerebellar peduncle) zones, for removal of lesions in this area. PMID- 29258936 TI - The Utility of Early Postoperative Head Computed Tomography in Brain Tumor Surgery: A Retrospective Analysis of 755 Cases. AB - OBJECTIVE: Scheduled early postoperative computed tomography (EPOCT) after craniotomy for brain tumor resection is standard at many institutions. We analyzed utility of preplanned EPOCT after elective craniotomy for brain tumor resection. METHODS: We retrospectively analyzed 755 brain tumor resections for which EPOCT was performed within 4 hours of surgery. Postoperative clinical neurologic examination results were classified into expected (baseline or predicted postoperative examination), changed (from baseline examination), and unreliable (sedated or baseline comatose patient). Scans were analyzed for unexpected and/or worrisome findings (e.g., hemorrhagic or ischemic stroke). In cases of unexpected findings, management changes were correlated to patient's neurologic examination. Demographic information, tumor histology, and tumor location were analyzed to determine risk factors for unexpected findings. RESULTS: Rate of unexpected EPOCT findings was 4.1%. Patients with expected postoperative examinations were at significantly lower risk of abnormal findings (odds ratio [OR] = 0.074, P < 0.001). Patients with intraventricular tumors (OR = 5.7, P = 0.001) were at higher risk compared with patients with metastatic tumors (OR = 0.24, P = 0.06). No unexpected EPOCT findings led to management changes in patients with expected postoperative neurologic examinations. All unexpected EPOCT findings in patients with changed postoperative neurologic examinations led to management changes. Patients with nonreliable neurologic examinations were at significantly higher risk for unexpected findings on EPOCT (OR = 6.33, P < 0.001) and subsequent management changes. CONCLUSIONS: Routine EPOCT is not indicated for patients undergoing brain tumor resection if postoperative neurologic examination is unchanged, as imaging is unlikely to result in management changes. EPOCT should be obtained in all patients with worrisome changes in examination or nonreliable examinations, as both groups have high rates of unexpected findings on imaging that lead to management changes. PMID- 29258937 TI - Iatrogenic Pseudoaneurysm of Superficial Temporal Artery After Surgery for Scaphocephaly: Case Report and Review of Literature. AB - BACKGROUND: Iatrogenic pseudoaneurysm of the superficial temporal artery after surgery for craniosynostosis is a complication that has never been described in the pertinent literature. Although reported for other types of surgeries, no case has been described in the pediatric population. CASE DESCRIPTION: We report on a case of pseudoaneurysm of the superficial temporal artery that occurred 9 days after corrective surgery for scaphocephaly. We also describe the management of this complication. CONCLUSION: Pseudoaneurysm is an exceptional complication in surgery for craniosynostosis, but it should be considered in case of swelling in the temporal region. PMID- 29258938 TI - Prospective Study of Neuroendoscopy versus Microscopy: 213 Cases of Microvascular Decompression for Trigeminal Neuralgia Performed by One Neurosurgeon. AB - OBJECTIVE: To compare the efficacy and complications of microvascular decompression (MVD) by complete neuroendoscopy versus microscopy for 213 cases of trigeminal neuralgia (TN). METHODS: Between January 2014 and January 2016, 213 patients with TN were randomly assigned to the neuroendoscopy (n = 105) or microscopy (n = 114) group for MVD via the suboccipital retrosigmoid approach. All procedures were performed by the same neurosurgeon. Follow-up was conducted by telephone interview. Statistical data were analyzed with the chi-square test, and a probability (P) value of <=0.05 was considered statistically significant. Chi-square test was conducted using SAS 9.4 software (SAS Institute, Cary, North Carolina, USA). RESULTS: There were no statistical differences between the 2 groups in pain-free condition immediately post procedure, pain-free condition 1 year post procedure, hearing loss, facial hypoesthesia, transient ataxia, aseptic meningitis, intracranial infections, and herpetic lesions of the lips. There were no instances of death, facial paralysis, cerebral hemorrhage, or cerebrospinal fluid leakage in either group. CONCLUSIONS: There were no significant differences in the cure rates or incidences of surgical complications between neuroendoscopic and microscopic MVD. PMID- 29258939 TI - Retrosigmoid Approach: Investigating the Role of a C-Shaped Skin Incision and Muscle Flaps in Improving Functional Outcome and Reducing Postoperative Pain. AB - OBJECTIVE: To investigate the impact on functional outcome and postoperative pain of a modified C-shaped skin incision and muscle flaps in patients undergoing mini craniotomy via a retrosigmoid approach (mCRSA). METHODS: Enrolled patients were studied prospectively and divided/assigned to group A, with a standard straight/lazy S-shaped incision, or to group B, with a modified C-shaped incision. The latter consisted of a 4-cm C-shaped skin incision with medial convexity (placed 8 cm lateral to the external occipital protuberance, with the lower edge terminating 1.5-2 cm above the mastoid tip), followed, after subperiosteal dissection, by superior and inferior reflection of the muscle flaps by stitches. RESULTS: Eighty patients, 40 in each group, were enrolled in the study. The overall complication rate was significantly lower (P < 0.0001) in group B. The incidence of cerebrospinal fluid (CSF) leak was 4% in group B versus 12% in group A; furthermore, no wound infection was recorded in group B, whereas 2 cases (4%) occurred in group A. Overall, group B patients had a higher satisfaction rate (P = 0.0002), and the prevalence of postoperative retroauricular pain/neck discomfort was significantly higher (P = 0.0002) in group A (30% vs. 0%). CONCLUSIONS: The modified C-shaped skin incision and muscle flaps technique provides superior surgical exposure with advantages over the standard straight/lazy S-shaped incision including no need for a self-retaining retractor and a shorter working distance. This study supports the research hypothesis that the landmarks-based design of the C-shaped incision may decrease the risk of occipital muscle/cutaneous nerve injuries and CSF leak, resulting in better functional outcomes. PMID- 29258940 TI - Predictors of Occurrence and Anatomic Distribution of Multiple Aneurysms in Patients with Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: The literature on multiple intracranial aneurysms (MIA) in patients with aneurysmal subarachnoid hemorrhage (aSAH) focuses largely on risk factor analysis and consists essentially of retrospective cohort studies of limited sample size, or studies in populations outside Europe and North America. The purpose of this cohort study was to identify predictors for aneurysm multiplicity and to investigate the anatomic distribution of MIA in a representative Western cohort of patients with aSAH. METHODS: The Swiss Study of Subarachnoid Hemorrhage (SOS) database includes anonymized data from all tertiary neurovascular facilities in Switzerland. The dataset for 2009-2014 was used to compare characteristics of patients with aSAH and MIA and those with a single intracranial aneurysm (SIA) by means of descriptive and multivariate regression analysis. RESULTS: Among 1689 unselected patients with aSAH, 467 had MIA (prevalence, 27.6%). The location of the ruptured index aneurysm was correlated with the probability of finding bystander aneurysms and predicted their likely anatomic distribution. Patients with a ruptured basilar artery aneurysm (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.30-3.44) or a ruptured middle cerebral artery aneurysm (OR, 1.86; 95% CI, 1.35-2.55) were at the greatest risk for having MIA. Larger size of the index aneurysm (OR per 1 mm, 1.03; 95% CI, 1.01-1.06) was also positively correlated with aneurysm multiplicity. Males were less likely than females to have MIA (OR, 0.79; 95% CI, 0.61-1.01). CONCLUSIONS: In patients with aSAH, the location of the ruptured index aneurysm is correlated with the probability of finding bystander aneurysms, and is predictive of the sites at which bystander aneurysms are most likely to be found. PMID- 29258941 TI - Technical Note: Preemptive Surgical Revision of Impending Deep Brain Stimulation Hardware Erosion. AB - BACKGROUND: While deep brain stimulation (DBS) is a relatively safe procedure, skin erosion is a commonly reported hardware complication that can threaten the DBS system. Patients with Parkinson disease are especially at risk for this complication due to their autonomic dysregulation and impaired nutrition. Early detection of impending skin erosion allows for intervention that may prevent hardware destruction. Here we report a novel technique to address this complication preemptively. We describe the use of an acellular dermal matrix to prevent skin erosion in 20 patients with Parkinson disease who were treated with DBS and showed signs of impending skin erosion. METHODS: Twenty patients with signs of impending hardware erosion were identified. An acellular dermal matrix was surgically placed under the at-risk skin overlying the DBS lead. RESULTS: None of the 20 patients treated with this technique went on to require further revision surgery or removal of hardware. CONCLUSIONS: Surgical placement of acellular dermal matrix in patients identified as having impending hardware erosions is a safe and cost-effective way to prevent hardware complications. PMID- 29258942 TI - Early Postoperative Magnetic Resonance Imaging Findings After Percutaneous Endoscopic Lumbar Discectomy and Their Correlations with Clinical Outcomes. AB - OBJECTIVE: To investigate the imaging features on early postoperative magnetic resonance imaging (MRI) after percutaneous endoscopic lumbar discectomy (PELD) and their correlations with surgical outcomes. METHODS: Forty-seven patients with lumbar disc herniation who underwent PELD were enrolled in this study. MRI scans were performed 1 week and 3 months after surgery. Imaging features on these MRI scans were evaluated. Clinical factors that might affect surgical outcomes were recorded. Multivariate logistic regression analysis was performed to assess all potential factors affecting short-term and midterm outcomes after PELD. RESULTS: On MRI scans 1 week postoperatively, a residual mass at the operated site was observed in 93.6% of cases. Of those, ipsilateral nerve root compression was observed in 70.2% of cases. These residual masses had intermediate signal intensity on Tl-weighted images but either hyperintensity (56.8%) or intermediate intensity (43.2%) on T2-weighted images. On MRI scans 3 months postoperatively, the residual masses had vanished in 82.8% of cases. Based on the results of logistic regression analysis, symptom duration <1 year (P = 0.033) and high T2 signal intensity of the residual mass (P = 0.004) correlated with better short term outcomes. However, no factor was correlated with midterm outcomes. CONCLUSIONS: A residual mass with ipsilateral nerve root compression on early postoperative MRI after PELD is common. Most of these residual masses will vanish within 3 months. "Nerve root compressed by a residual mass" on early postoperative MRI does not affect surgical outcomes. "High T2 signal intensity of the residual mass" is associated with better short-term outcomes after PELD but not midterm outcomes. PMID- 29258943 TI - Magnetic Resonance Angiographic Demonstration of Unusual Duplication of Left Vertebral Artery. AB - BACKGROUND: Vertebral artery origin and course anomalies have clinical importance in neck surgery and diagnostic angiography. CASE DESCRIPTION: A dual origin of the left vertebral artery from the aortic arch between the left common carotid and left subclavian arteries was incidentally detected by magnetic resonance angiography. CONCLUSION: Magnetic resonance angiography is an important imaging method to be preferred in evaluating vascular structures in the neck area. PMID- 29258944 TI - Management of Isolated Atlas Fractures: A Retrospective Study of 65 Patients. AB - BACKGROUND: Jefferson fractures, or burst fractures of the C1 vertebra, can be managed surgically or conservatively, depending on their stability. METHODS: We identified all patients who were treated for a C1 fracture at our institution between 1999 and 2016 for retrospective analysis. Patients with any other concurrent cervical fractures or nontraumatic etiology of fracture were excluded. Stability was defined as either lateral mass displacement >=7 mm on computed tomography or presence of transverse atlantal ligament disruption on magnetic resonance imaging. We collected data on patients' demographic, clinical, and radiographic presentation and identified variables independently associated with instability at presentation and failure to achieve fusion at follow-up. RESULTS: We identified 65 patients. On multivariable regression, instability at presentation was independently associated with atlantodens interval (odds ratio [OR] 2.357, 95% confidence interval [CI] [0.0629-1.271], P = 0.099) and type 3 fracture (OR 6.081, 95% CI [1.068-34.612], P = 0.042). Failure to achieve fusion was independently associated with age (OR 1.226, 95% CI [1.007-1.495], P = 0.043), motor vehicle collision as mechanism of injury (OR 22834.3, 95% CI [3.135 1.66e8], P = 0.027), and type 2 fracture (OR 168.537, 95% CI [1.743-16292.92], P = 0.028). Type 3 fracture was positively associated with halo vest for management (OR 17.171, 95% CI [2.882-102.289], P = 0.002) and negatively associated with a rigid cervical collar for management (OR 0.0616, 95% CI [0.0104-0.3653], P = 0.002). All 4 patients who underwent surgery presented with unstable fracture (P = 0.0187). CONCLUSIONS: Atlantodens interval, mechanism of injury, and fracture type affect Jefferson fracture management decisions and outcomes, including instability at presentation and fusion at follow-up. Most fractures were managed nonsurgically regardless of stability. PMID- 29258945 TI - Impacts of a Size Ratio on Outcome in Patients with Surgically Treated Unruptured Nondissecting Anterior Cerebral Artery Aneurysms. AB - BACKGROUND: Anterior cerebral artery aneurysms (ACAs) are characterized by higher rupture rate and small size at rupture. It was shown that the aneurysm/vessel size ratio, and not the absolute size, might predict the risk of rupture in small unruptured intracranial aneurysms. The present study aimed to investigate the relationship between a size ratio and outcome in patients with unruptured nondissecting ACA aneurysms (UNDAs). METHODS: A total of 187 consecutive patients with 12 A1 (6.2%), 149 anterior communicating artery (77%), and 33 distal ACA (17%) aneurysms were retrospectively evaluated. The size ratio was defined as (size of aneurysm)/(size of parent artery). Neurologic worsening (NW) was defined as an increase in score of 1 or more on the modified Rankin Scale (mRS). RESULTS: The mean age of the patient population was 63 +/- 11 years and 132 UNDAs (68%) were seen in women. Complete, partial neck clipping, and aneurysm trapping were archived in 188 (97%), 2 (1.0%), and 4 (2.1%) UNDAs, respectively. An excellent outcome (mRS score 0) at 12 months was archived in 177 (93%) UNDAs overall and 177 (95%) in UNDAs with preoperative mRS score of 0 (n = 186). Postoperative ischemic lesions (odds ratio, 193; 95% confidence interval, 17-2205; P < 0.0001) and the size ratio >3.0 (odds ratio, 11; 95% confidence interval, 1.2-105; P = 0.031) were related to 12-month NW on multivariate analysis. The aneurysm size was not related to 12-month NW. CONCLUSIONS: The present study showed that the size ratio, and not the absolute size, was related to 12-month NW in surgically treated UNDAs. PMID- 29258946 TI - Differential Tumor Progression Patterns in Skull Base Versus Non-Skull Base Meningiomas: A Critical Analysis from a Long-Term Follow-Up Study and Review of Literature. AB - BACKGROUND: To analyze the differences in tumor progression patterns and histopathologic characteristics between skull base meningiomas (SBMs) and non skull base meningiomas (NSBMs). METHODS: Retrospective data of 382 patients with SBMs and 200 patients with NSBMs who underwent primary microsurgical resection between January 1995 and December 2016 were analyzed. Data related to clinical history, neuroimaging, surgical technique, and follow-up were reviewed. A separate prospective cohort of 78 meningiomas operated on from June 2016 to July 2017 was analyzed (World Health Organization [WHO] grade and Ki-67 proliferation index) for biologic comparison. RESULTS: Skull base location, WHO grade II tumor, and subtotal resection were independent predictors of unfavorable outcome. The overall tumor progression rate in the SBM group (33%) was higher than in the NSBM group (19.7%) (P = 0.006) (mean follow-up period, 51 months). The 3-year, 5-year, and 10-year progression-free survival (PFS) was 78%, 60%, and 45% in the SBM group, whereas it was 90%, 80%, and 53% in the NSBM group, respectively. Interestingly, there was no difference in the median PFS after 10 years of follow up (SBMs 210 months vs. NSBM 212 months, P = 0.93). In the prospective cohort of 78 meningiomas, there was no statistically significant difference in the proportion of WHO grade I tumors and in the mean Ki-67 index of WHO grade I meningiomas between the 2 groups. CONCLUSION: There is a divergent tumor progression pattern for surgically treated SBMs vis-a-vis NSBMs. Differences in tumor biology and the proportion of Simpson grade I resections are likely attributable factors. PMID- 29258947 TI - A Novel Method to Measure the Tentorial Angle and the Implications on Surgeries of the Pineal Region. AB - OBJECTIVE: There is no standard way to define the angle of the tentorium. The current trend to use the Twining line to define this angle has significant pitfalls. The goal of the current study was to provide a new and accurate way to measure the tentorial angle and demonstrate its impact on surgeries of the pineal region. METHODS: A new technique (n-angle) to measure the tentorial angle was introduced using the floor of the fourth ventricle and the torcula. Comparisons with older techniques were made to illustrate reliability. Midline sagittal MR images were used to measure the tentorial angle in 240 individuals to obtain population-based data. A cohort of 8 patients who underwent either the infratentorial or the transtentorial approach to the pineal or upper vermian region were examined in search of correlations between tentorial angle and surgical approach. RESULTS: The data in this study showed that the Twining line technique understates the tentorial angle in people with low-lying torcula. The n angle is more reliable in reflecting the true steepness of the tentorium regardless of torcula position. On average, men have slightly steeper tentoriums. In the clinical cohort, all patients who underwent infratentorial surgery had tentorial angles <55 degrees , whereas the majority of patients who underwent transtentorial surgeries had angles >67 degrees . CONCLUSION: The n-angle provides a reliable and accurate way to describe the slope of the tentorium. The population-based average of 60 degrees may be a useful measurement to influence the choice of surgical approach, either under or through the tentorium, to the pineal region. PMID- 29258948 TI - Delayed Coil Migration After Treatment of Traumatic Pseudoaneurysm. AB - A teenager with epistaxis after head trauma was diagnosed with pseudoaneurysm of the internal carotid artery. Three years after the first aneurysm embolization, delayed coil migration was detected. Then the migrated coil was removed through nasal endoscopy. PMID- 29258949 TI - Outcome of Traumatic Brain Injury in the Elderly Population: A Tertiary Center Experience in a Developing Country. AB - BACKGROUND: The growing elderly population has contributed to an increasing incidence of traumatic brain injury (TBI) in this cohort worldwide. Here we describe our institutional experience in the management of TBI in elderly Indian patients. METHODS: This was a 3-year retrospective analysis of 73 consecutive patients age >=65 years admitted to our university hospital with TBI. Exclusion criteria included a history of concussion injury, chronic subdural hematoma (SDH), discharge against medical advice, and declared dead within 6 hours after arrival. Mode of injury, clinicoradiologic features, management, and outcomes were analyzed. The Glasgow Outcome Scale (GOS) was used to assess outcome. RESULTS: Our cohort was predominately male (82%). The mean patient age was 72.1 years (range, 65-97 years), and 20 were age >=75 years. Head injuries (HIs) were mild in 37 patients, moderate in 18, and severe in 18. The majority of injuries were contusions. Fifty-five patients (75%) were managed conservatively, and 18 (25%) underwent surgery. There were 7 deaths (9.5%). The rate of poor outcome was 26% overall, and 45% in patients age >=75 years. Poor outcome in severe HI was seen in 83% (15 of 18) of the entire cohort but in 100% (7 of 7) of the very elderly patients. On univariate analysis, age >=75 years, severe HI, acute SDH, and surgical management were significantly associated with poor outcome while acute SDH and surgical management were significant on multilogistic regression analysis. CONCLUSIONS: Age >=75 years, severe HI, and acute SDH are poor prognostic factors in patients with TBI. The benefit of surgery in these patients is unlikely, and surgery needs to weighed judiciously, keeping in mind the economics involved and the fate of caregivers, especially in developing countries. PMID- 29258951 TI - Use of photodynamic therapy in the treatment of bovine subclinical mastitis. AB - BACKGROUND: Bovine mastitis is a disease that causes a severe drawback in dairy production. Conventional treatments with antibiotic could leave antibiotic residues in the milk. The aim of this study was to evaluate the effect of photodynamic therapy in the treatment of bovine subclinical mastitis to develop an in vivo therapeutic protocol that could be used in routine farm practice, favoring the early return to production. METHODS: Forty cows with subclinical mastitis (n = 40) were divided into 4 groups (control, photodynamic therapy - PDT, light irradiation - LED, and photosensitizer - PS). Control group received no treatment, PDT group received application of 1.0 mL of 2.5% toluidine blue photosensitizer followed by LED irradiation at lambda = 635 nm, the LED group was treated with LED irradiation alone, and the PS group received only 2.5% toluidine blue dye. LED irradiation was applied to the mammary gland by means of an acrylic light guide coupled to the LED equipment. The PDT and LED groups were irradiated with 200 J/cm2 at three different positions inside the mammary gland. Milk samples were collected at 0 h, 12 h, 24 h after treatment for microbial identification and total bacterial count. RESULTS: The treatment of the PDT group showed significant difference p < 0.05, characterizing the efficiency of this technique with the reduction of the microorganisms Streptococcus dysgalactiae and coagulase-negative Staphylococcus. CONCLUSION: Photodynamic therapy was effective when applied in vivo for subclinical bovine mastitis. There was no need to separate the animal from production. PMID- 29258950 TI - MyD88 Mutation in Elderly Predicts Poor Prognosis in Primary Central Nervous System Lymphoma: Multi-Institutional Analysis. AB - BACKGROUND: Recent genetic analysis of primary central nervous system lymphoma (PCNSL) showed that the MyD88 L265P mutation, which is related to NF-kappaB signaling, was a genetic hallmark for PCNSL; thus it could serve as a genetic marker for diagnosis and a potential target for molecular therapy. However, the role of the MyD88 mutation in PCNSL has not been defined. In this study, we investigated the role of the MyD88 mutation and clinical features of PCNSL treated patients at several institutions to determine its significance as a prognostic factor. METHODS: Forty-one PCNSL (diffuse large B-cell type) patients from 8 institutions were included in this study. Their median age was 68 years; median follow-up was 26.7 months; median overall survival was 26.7 months; and their 1-year, 3-year, and 5-year survival rates were 75.6%, 58.5%, and 43.9%, respectively. Deoxyribonucleic acid was extracted from frozen tissue, and the MyD88 L265P mutation was evaluated by polymerase chain reaction and direct sequencing. RESULTS: The MyD88 L265P mutation was found in 61.0% (25/41) of cases. Kaplan-Meier analysis revealed that neither MyD88 L265P mutation nor age >65 years alone significantly predicted overall survival relative to MyD88 wild type and age <65. The MyD88 L265P mutation was predominantly present in patients aged >65 years. Among age >65 patients, the MyD88 L265P mutation portended a worse overall survival compared with the MyD88 wild type (11.5 vs. 56.2 months P < 0.04). CONCLUSION: The MyD88 L265P mutation predicted a poor prognosis in elderly PCNSL patients. A new tailor-made treatment strategy might be needed for these patients. PMID- 29258953 TI - Molecular chemotherapeutic potential of butein: A concise review. AB - Butein is a biologically active flavonoid isolated from the bark of Rhus verniciflua Stokes, which is known to have therapeutic potential against various cancers. Notably, butein inhibits cancer cell growth by inducing G2/M phase arrest and apoptosis. Butein-induced G2/M phase arrest is associated with increased phosphorylation of ataxia telangiectasia mutated (ATM) and Chk1/2, and consequently, with reduced cdc25C levels. In addition, butein-induced apoptosis is mediated through the activation of caspase-3, which is associated with changes in the expression of Bcl-2 and Bax proteins. Intriguingly, butein sensitizes cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via ERK-mediated Sp1 activation, which promotes the transcription of specific death receptor 5. Butein also inhibits the migration and invasion of human cancer cells by suppressing nuclear factor-kappaB- and extracellular signal regulated kinases 1/2-mediated expression of matrix metalloproteinase-9 and vascular endothelial growth factor. Additionally, butein downregulates the expression of human telomerase reverse transcriptase and causes a concomitant decrease in telomerase activity. These findings provide the basis for the pharmaceutical development of butein. The aim of this review is to provide an update on the mechanisms underlying the anticancer activity of butein, with a special focus on its effects on different cellular signaling cascades. PMID- 29258952 TI - 5-Aminolevulinic acid photodynamic therapy in refractory vulvar lichen sclerosus et atrophicus: Series of ten cases. AB - BACKGROUND: Vulvar lichen sclerosus et atrophicus (VLSA) is a chronic inflammatory skin disease of unknown etiology that mainly affects postmenopausal and perimenopausal women. The primary clinical symptoms of VLSA are itching, burning pain, and dyspareunia that can results in decreased quality of life. Existing therapies including topical corticosteroid ointment, topical calcineurin inhibitors, estrogens, are not very effective for treatment of VLSA. OBJECTIVE: To evaluate the effectiveness and safety of 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) in the treatment of VLSA. MATERIALS AND METHODS: Ten patients with VLSA who had failed conventional treatment received ALA-PDT. 10% 5-ALA in an oil-in-water emulsion was applied to the lesions and occluded with plastic film for 3 h, when the lesions were irradiated with 100 mW/cm2, 635 +/- 15 nm red light for 20 min. Treatments were repeated three times at 2-week intervals. Objective and subjective symptoms and signs of the vulvar lesions based on horizontal visual analogue scales were recorded at each treatment and 1, 3, and 6 months after the last session. The quality of life was assessed using dermatology life quality index (DLQI) questionnaire. RESULTS: All patients completed three ALA-PDT treatments and the follow-up visits. Clinical symptoms of itching disappeared completely in nine patients, one patient had itching decreased from severe to mild. All subjects showed objective improvement in lesions. The DLQI of all cases improved after treatment. The main side-effects of ALA-PDT were pain, erythema, and swelling. Side-effects were transient and tolerable. All patients reported being "satisfied" or "very satisfied" with their outcomes. CONCLUSIONS: ALA-PDT is an effective and safe approach for the treatment of VLSA. PMID- 29258954 TI - Supramolecular strategy for reducing the cardiotoxicity of bedaquiline without compromising its antimycobacterial efficacy. AB - Bedaquiline (BDQ) is a newly approved anti-tuberculosis drug in treating multidrug-resistant tuberculosis. However, it has very poor aqueous solubility and several case reports have proposed that BDQ has potential risk of cardiotoxicity to patients. In this present study, we have explored into employing host-guest interactions between a synthetic receptor, cucurbit[7]uril (CB[7]), and BDQ aiming to improve the solubility and reduce the inherent cardiotoxicity of BDQ. HPLC-UV test on the solubility of BDQ in the absence and in the presence of increasing concentrations of CB[7] suggested a host-dependent guest-solubility enhancements. Cardiovascular studies using an in vivo zebrafish model demonstrated that the cardiotoxicity of BDQ was indeed alleviated upon its complexations by the synthetic receptor. Furthermore, our in vitro antibacterial studies suggested that CB[7] formulated BDQ preserved its antimycobacterial efficacy against Mycobacterium smegmatis. Therefore, CB[7] may become a suitable pharmaceutical excipient in formulating BDQ for improving its physiochemical properties (such as solubility), and for alleviating its side effects (such as cardiotoxicity), while the antimycobacterial efficacy of BDQ may be well maintained. PMID- 29258955 TI - Evaluation of toxicological endpoints in female zebrafish after bisphenol A exposure. AB - Given the importance of bisphenol A (BPA) as a xenoestrogen and its potential effects on human and animal health, we evaluated BPA exposure's short-term effects on follicular development, yolk protein vitellogenin (VTG) production and aromatase expression in female zebrafish. Histological modifications were observed along with increased presence of atretic follicles. Whole-body VTG concentration increased with the dose of BPA exposure. In contrast, expression of Cyp19a mRNA in the ovaries of BPA-exposed fish exhibited an apparent non monotonic response curve, marked by downregulation at 1 MUg/L BPA, upregulation at 10 MUg/L BPA, and a return to downregulation at 100 MUg/L BPA and higher doses. Ovaries only exhibited significant increases in follicular atresia and VTG concentration after exposure to 100 MUg/L BPA and higher doses. Ovarian histopathology, aromatase Cyp19a transcript levels and whole-body VTG protein abundance may be good biomarkers for early detection of environmental BPA exposure. PMID- 29258956 TI - Approaches to assess IgE mediated allergy risks (sensitization and cross reactivity) from new or modified dietary proteins. AB - The development and introduction of new dietary protein sources has the potential to improve food supply sustainability. Understanding the potential allergenicity of these new or modified proteins is crucial to ensure protection of public health. Exposure to new proteins may result in de novo sensitization, with or without clinical allergy, or clinical reactions through cross-reactivity. In this paper we review the potential of current methodologies (in silico, in vitro degradation, in vitro IgE binding, animal models and clinical studies) to address these outcomes for risk assessment purposes for new proteins, and especially to identify and characterise the risk of sensitization for IgE mediated allergy from oral exposure. Existing tools and tests are capable of assessing potential crossreactivity. However, there are few possibilities to assess the hazard due to de novo sensitization. The only methods available are in vivo models, but many limitations exist to use them for assessing risk. We conclude that there is a need to understand which criteria adequately define allergenicity for risk assessment purposes, and from these criteria develop a more suitable battery of tests to distinguish between proteins of high and low allergenicity, which can then be applied to assess new proteins with unknown risks. PMID- 29258957 TI - Decreased macrophage phagocytic function due to xenobiotic exposures in vitro, difference in sensitivity between various macrophage models. AB - Both autoimmune disease prevalence and exposure to immunotoxic chemicals have increased the last decades. As a first screening of immunotoxic chemicals possibly affecting development of autoimmunity through attenuated macrophage function, we demonstrate a promising model measuring macrophage function in isolated peritoneal macrophages (PCM) from Wistar rats and C57Bl/6 mice. Immunotoxic effects of bisphenol A (BPA) and a selection of perfluoroalkyl acids (PFAAs) were analysed in vitro assessing phagocytic function of macrophages from different sources. Phagocytosis was reduced in PCM of C57Bl/6 mice and Wistar rats after BPA and perfluoroundecanoic acid (PFUnDA) exposure, but not in macrophages derived from human and rat monocyte derived macrophages (MDM). On the other hand, in vitro exposure to mixtures of persistent organic pollutants (POPs) showed similar reductions in rat PCM and rat and human MDM phagocytosis. Reduced phagocytosis was partly due to cytotoxicity. PCM isolated from non-obese diabetic (NOD) mice, interleukin 1alpha/beta knockout (IL-1KO) mice and new-born rats were less sensitive to the xenobiotics than PCM from adult wild type rodents. Finally, in vivo studies with NOD mice verified that POP exposure also decreased the number of pancreatic macrophages in pancreatic islets, reflecting early signs of autoimmunity development, similarly as previously described for BPA. PMID- 29258958 TI - Pubertal Progression in Female Adolescents with Progeria. AB - STUDY OBJECTIVE: This study identified the prevalence of menarche and coincident sexual characteristics in female adolescents with Hutchinson-Gilford Progeria Syndrome (HGPS). DESIGN: Data were examined to determine the prevalence of menarche in female adolescents older than 12 years; all were participants in clinical trials between 2007 and 2016. SETTING: Pediatric hospital in Boston, Massachusetts. PARTICIPANTS: Fifteen female adolescents, median age 15 (range, 12.0-20.3) years with a confirmed diagnosis of HGPS. INTERVENTIONS AND MAIN OUTCOME MEASURES: Report of menarche, anthropometric and serum hormonal measures, Tanner pubertal staging, and body composition using dual-energy x-ray absorptiometry. RESULTS: Nine of 15 (60%) participants reported spontaneous menarche at a median age of 14.4 years (range, 12.0-16.5 years). In those experiencing menarche vs not, median age was older (16.5 vs 13.6 years; P = .02), whereas body mass index did not differ (10.5 vs 10.4; P = .53) nor percentage body fat (19.4% vs. 19.3%; P = .98) or serum leptin levels (0.40 vs 0.40 ng/mL; P = .23). Among those who achieved menarche, 2 of 9 (22%) had Tanner II breast development and 2 of 9 (22%) exhibited Tanner II Pubic hair, all reflecting minimal pubertal development. Only early signs of puberty were similarly seen in the non-menstruating group, including 1 of 6 (17%) with Tanner II breasts and 2 of 6 (33%) with Tanner II pubic hair, and Tanner staging did not differ between those who reported menarche vs those who did not (each P = 1.0). None of the participants achieved Tanner IV or V thelarche over the course of the study. CONCLUSION: Menarche was achieved in more than half of adolescent girls with HGPS, in the setting of little to no physical signs of pubertal development and minimal body fat. PMID- 29258959 TI - Reply to the letter by D. Ollat and O. Barbier. PMID- 29258960 TI - Corticocancellous bone graft vs cancellous bone graft for the management of unstable scaphoid nonunion. AB - INTRODUCTION: This study was undertaken to determine whether corticocancellous bone grafting and cancellous bone grafting differ in terms of bone union rate, restoration of scaphoid anatomy, and wrist function when unstable scaphoid nonunions are concomitantly treated by screw fixation. MATERIALS AND METHODS: This is retrospective cohort study. In Group A (17 patients), unstable scaphoid nonunion was treated with corticocancellous graft harvested from the iliac crest and headless compression screw using volar approach. In Group B (18 patients), unstable scaphoid nonunion was treated with cancellous graft harvested from the distal radius or iliac crest and headless compression screw using volar approach Mean time to union was measured using CT image. Scaphoid deformity was also measured using lateral intrascaphoid angle and height to length ratio using CT images. Wrist functional status was assessed by measuring grip strength, wrist range of motion, and DASH score at 1 year postoperatively. RESULTS: Mean time to union was significantly greater in Group A (15 weeks vs. 11 weeks). No significant intergroup difference was observed for lateral intrascaphoid angle and height to length ratio after treatment of scaphoid nonunion. No significant intergroup difference was observed for grip strength, wrist range of motion, or DASH scores at 1 year postoperatively. CONCLUSIONS: Cancellous bone grafting was found to lead to earlier bone union than corticocancellous bone grafting and to similar restorations of scaphoid deformity and wrist function when scaphoid nonunion was treated by headless compression screw fixation and bone grafting. LEVEL OF EVIDENCE: Prognostic, III. PMID- 29258961 TI - Comments on: "Is amputation a viable treatment option in lower extremity trauma?" of M Barla, B Gavanier, M Mangin, J Parot, C Bauer, D Mainard published in Orthop Traumatol Surg Res 2017;103(6):971-975. PMID- 29258962 TI - Results of non-operative treatment of olecranon fracture in over 75-year-olds. AB - INTRODUCTION: Surgery is the gold-standard treatment of displaced olecranon fracture, but is associated with numerous complications, especially in the elderly. Functional results of non-operative treatment in this population have never been analyzed in a prospective study. STUDY HYPOTHESIS: Non-operative treatment of isolated olecranon fracture with stable elbow-joint in over 75-year olds gives functional results comparable to those of surgery as reported in the literature, with fewer complications. MATERIAL AND METHODS: A prospective study analyzed functional results of non-operative treatment of isolated closed Mayo I and II olecranon fracture with stable elbow, in patients aged >=75 years. The principal assessment criterion was functional recovery on the Mayo Elbow Performance Score (MEPS) and QuickDASH at 6 months. RESULTS: Twenty-two fractures in 21 patients were included. Mean MEPS was 95.26/100 (range, 85-100), and mean QuickDASH 4.3 (range, 0-29.55). Eighteen fractures showed osteoarthritis of the olecranon. There were no cases of elbow instability. There were no complications. DISCUSSION: Non-operative treatment of olecranon fracture in patients aged >=75 years provided excellent functional results at 6 months, without associated complications. TYPE OF STUDY: Single-center prospective observation cohort study. LEVEL OF EVIDENCE: 4. PMID- 29258963 TI - Secretory microRNAs as biomarkers of cancer. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression predominantly by inhibiting transcription and/or promoting degradation of target mRNAs also in addition to being involved in non-canonical mechanisms regulating transcription, translation and cell signaling processes. Extracellular secretory miRNAs, either in complex with specific proteins or encapsulated in microvesicles called exosomes, are transported between cells as means of intercellular communication. Secretory miRNAs in circulation remain functional after delivery to recipient cells, regulating target genes and their corresponding signaling pathways. Cancer cell secreted miRNA-mediated intercellular communication affects physiological processes associated with the disease, such as, angiogenesis, metabolic reprogramming, immune modulation, metastasis, and chemo-resistance. Given the stability of miRNAs in body fluids and their well-documented roles in deregulating cancer-relevant genetic pathways, there is considerable interest in developing secretory miRNAs as liquid biopsy biomarkers for detection, diagnosis and prognostication of cancer. In this review, we discuss salient features of miRNA biogenesis, secretion and function in cancer as well as the current state of secretory miRNA isolation and profiling methods. Furthermore, we discuss the challenges and opportunities of secretory miRNA biomarker assay development, which need to be addressed for clinical applications. PMID- 29258964 TI - Engineered monoculture and co-culture of methylotrophic yeast for de novo production of monacolin J and lovastatin from methanol. AB - As a promising one-carbon renewable substrate for industrial biotechnology, methanol has attracted much attention. However, engineering of microorganisms for industrial production of pharmaceuticals using a methanol substrate is still in infancy. In this study, the methylotrophic yeast Pichia pastoris was used to produce anti-hypercholesterolemia pharmaceuticals, lovastatin and its precursor monacolin J, from methanol. The biosynthetic pathways for monacolin J and lovastatin were first assembled and optimized in single strains using single copies of the relevant biosynthetic genes, and yields of 60.0mg/L monacolin J and 14.4mg/L lovastatin were obtained using methanol following pH controlled monoculture. To overcome limitations imposed by accumulation of intermediates and metabolic stress in monoculture, approaches using pathway splitting and co culture were developed. Two pathway splitting strategies for monacolin J, and four for lovastatin were tested at different metabolic nodes. Biosynthesis of monacolin J and lovastatin was improved by 55% and 71%, respectively, when the upstream and downstream modules were separately accommodated in two different fluorescent strains, split at the metabolic node of dihydromonacolin L. However, pathway distribution at monacolin J blocked lovastatin biosynthesis in all designs, mainly due to its limited ability of crossing cellular membranes. Bioreactor fermentations were tested for the optimal co-culture strategies, and yields of 593.9mg/L monacolin J and 250.8mg/L lovastatin were achieved. This study provides an alternative method for production of monacolin J and lovastatin and reveals the potential of a methylotrophic yeast to produce complicated pharmaceuticals from methanol. PMID- 29258965 TI - Tailored carbon partitioning for phototrophic production of (E)-alpha-bisabolene from the green microalga Chlamydomonas reinhardtii. AB - Photosynthetic microbial hosts such as cyanobacteria and eukaryotic microalgae have recently emerged as alternative engineering platforms for the sustainable light-driven bio-production of terpenoids. Many desirable compounds with numerous applications can be produced in microorganisms by heterologous expression of terpene synthases. However, success of green microbial systems has been hampered by issues such as insufficient enzyme expression titers and low flux to desired terpenoid products from carbon fixed during photosynthesis. This work demonstrates how the green microalga Chlamydomonas reinhardtii can be engineered to produce the sesquiterpene biodiesel precursor (E)-alpha-bisabolene. Through strategic genetic engineering, substantial enhancements of productivity were achieved by coordinated tuning of the isoprenoid metabolism, combining serial enzyme loading for terpene synthase overexpression and amiRNA-based repression of competing pathways. Up to 10.3 +/- 0.7mg bisabolene.g-1 cell dry weight could be produced in five days, which represents more than a 15-fold increase over single synthase expression strains. Investigation of strain performance in scale-up cultivations determined overall bisabolene productivity benefits from light:dark cycles. Mixotrophic cultivation can yield up to 11.0 +/- 0.5mg bisabolene per liter in seven days in these conditions, and phototrophic production of 3.9 +/- 0.2mg per liter was feasible. These achievements represent an important milestone in the engineering of C. reinhardtii towards the goal of designing sustainable, light-driven, green-cell algal bio-factories. PMID- 29258966 TI - Sensitive quantitative detection of somatic mosaic mutation in "double cortex" syndrome. AB - Somatic mutation of the lissencephaly-1 gene is a cause of subcortical band heterotopia ("double cortex"). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low-level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low-level mutation. Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation (LIS1 c.190A>T; p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. The high sensitivity of droplet digital PCR and the ability to target individual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA sample derived from formalin-fixed paraffin-embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted. PMID- 29258967 TI - Occipital ulegyria causing epilepsy and visual impairment: an easily overlooked epilepsy syndrome. AB - Ulegyria refers to scarring of the cerebral cortex usually arising from perinatal ischaemia. The scarring has a specific configuration in which small atrophic circumvolutions at the bottom of a sulcus underlie an intact spared gyral apex. This disconnection of overlying cortex may allow an "epileptogenic" island of cortex to generate seizures. Ulegyria is often associated with epilepsy and developmental delay, however, the syndromic association of visual impairment with epilepsy due to occipital ulegyria may not be recognised as a specific entity. Here, we report a series of five patients with occipital ulegyria who presented with widely variable seizure semiology and an array of visual deficits. In some patients, the link between the epilepsy and the visual impairment was not appreciated until they attended an epilepsy clinic. PMID- 29258968 TI - Refractory chronic epilepsy associated with neuronal auto-antibodies: could perisylvian semiology be a clue? AB - We report a case series of 10 patients with chronic medically refractory antibody positive autoimmune epilepsy and assess their common clinical features. Immune mediated seizures are most commonly reported in the context of encephalitis or encephalopathy, with few reports focusing on lone, chronic epilepsy in the outpatient setting. Our aim was to define the potential diagnostic clues that might be present in these cases, leading to consideration of an autoimmune cause of the epilepsy. We performed a retrospective review of all patients presenting to the outpatient department of our unit who underwent autoimmune screening. All patients with chronic epilepsy and a positive result for an antibody known to be associated with epilepsy were included. Sixty-three patients underwent testing. Thirteen returned a positive result, however, only 10 of these were patients which chronic epilepsy who did not present with an acute illness. Common features in these cases included: perisylvian semiology, EEG abnormalities in the mid temporal region, normal or non-specific MRI findings, depression, and head injury. In cases of medically refractory, lesion-negative epilepsy, with predominantly perisylvian semiology, clinicians should have a high level of suspicion for the diagnosis of autoimmune aetiologies and a low threshold to perform autoantibody screening. This is especially true if there are atypical electrographic findings, a previous history of head injury, or co-morbid depression. PMID- 29258969 TI - A case of anti-NMDA receptor encephalitis revealed by insular epilepsy. AB - Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system that typically manifests predominantly as a psychiatric disorder. However, other manifestations such as epileptic seizures, abnormal movements, and memory or language complications are not unusual. Here, we report the case of a young man who presented with a new-onset epilepsy, with ictal semiology suggestive of insular involvement; this hypothesis was supported by a PET-CT study. Anti-NMDAR antibodies were found in the CSF, confirming the diagnosis of anti-NMDAR encephalitis. A review of the literature reveals that epilepsy can be the first manifestation of NMDAR encephalitis, with a clear male predominance. Despite its rarity, neurologists should consider this diagnosis for any young patient developing a new-onset epilepsy with temporal or insular features, particularly if the patient is male. Other cognitive or behavioural signs, even very subtle, should also prompt diagnosis. PMID- 29258970 TI - Mowat-Wilson syndrome presenting with fever-associated seizures. AB - Mowat-Wilson syndrome (MWS) is a disorder caused by mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. Diagnosis of MWS can be challenging to neurologists, because its manifestations are diverse and the spectrum of genetic mutations are broad. Here, we describe two patients with MWS who initially showed atypical forms of fever-triggered seizures during childhood. Both had characteristic facial features, cognitive impairment, and genito-urinary anomalies consistent with MWS. By performing targeted next-generation sequencing (NGS) using a gene panel for epilepsy, we were able to identify a nonsense mutation (c.1965C>A) in the ZEB2 gene of one patient and a frameshift mutation (c.2348dupC) in the other patient. Fever-induced seizures can be presenting signs of MWS. MWS should be considered in the differential diagnosis of fever-induced seizures, especially when the patient has distinctive facial features and multiple anomalies, including cardiac, genito-urinary, and eye defects. PMID- 29258971 TI - Adult-onset Rasmussen encephalitis associated with focal cortical dysplasia. AB - Rasmussen encephalitis is a rare, devastating condition, typically presenting in childhood. Cases of adult-onset Rasmussen have also been described, but the clinical picture is less defined, rendering final diagnosis difficult. We present a case of adult-onset Rasmussen encephalitis with dual pathology, associated with focal cortical dysplasia and encephalitis. We interpreted the Rasmussen encephalitis to be caused by severe and continuous epileptic activity due to focal cortical dysplasia. The best therapeutic approach for such cases remains unclear. PMID- 29258972 TI - Characteristics of Articles About Human Papillomavirus Vaccination in Japanese Newspapers: Time-Series Analysis Study. AB - BACKGROUND: Media coverage and reports have a major influence on individual vaccination and other health-related activities. People use the media to seek information and knowledge on health-related behaviors. They obtain health-related information from media such as television and newspapers, and they trust such information. While several studies have examined the relation between media coverage and individual health, there is a lack of studies that have analyzed media reports of health information. In particular, we have found no analyses related to cervical cancer (human papillomavirus [HPV]) vaccine. OBJECTIVE: This study aimed to identify mentions of cervical cancer vaccine in Japan's printed news media and to determine their characteristics. METHODS: We used the archival databases of 2 Japanese newspapers, Yomiuri Shimbun (Yomidasu Rekishikan) and Asahi Shimbun (Kikuzo II Visual), for text mining. First, we created a database by extracting articles published between January 1, 2007, and December 31, 2014, that matched the terms "cervical cancer" AND "vaccination" in a keyword search. Then, we tallied the extracted articles based on the month of publication and number of characters in order to conduct a time-series analysis. RESULTS: We extracted a total of 219 articles. Of these, 154 (70.3%) were positive and 51 (23.3%) were negative toward HPV vaccination. Of the 51 negative articles, 4 (7.8%) were published before June 2013, when routine vaccination was temporarily discontinued due to concerns regarding side effects, and 47 (92.2%) were published since then. The negative reports commonly cited side effects, although prior to June 2013, these issues were hardly mentioned. Although foreign media reports mentioned side effects before routine vaccination was temporarily discontinued, fewer articles mentioned side effects than recommendations for vaccination. Furthermore, on June 13, 2013, the World Health Organization's advisory body Global Advisory Committee on Vaccine Safety issued a statement regarding the safety of HPV vaccines, but hardly any articles reported this statement. Rather, several articles were published about the side effects after June 2013. CONCLUSIONS: Since we consider media coverage to be a factor affecting human health behavior, the media should extensively report on the cost of not receiving cervical cancer vaccination, global trends concerning cervical cancer vaccination, and statements released by various agencies on the subject. PMID- 29258973 TI - Two-Way Social Media Messaging in Postoperative Cataract Surgical Patients: Prospective Interventional Study. AB - BACKGROUND: Social media offers a new way to provide education, reminders, and support for patients with a variety of health conditions. Most of these interventions use one-way, provider-patient communication. Incorporating social media tools to improve postoperative (postop) education and follow-up care has only been used in limited situations. OBJECTIVE: The aim of this study was to determine the feasibility and efficacy of two-way social media messaging to deliver reminders and educational information about postop care to cataract patients. METHODS: A total of 98 patients undergoing their first eye cataract surgery were divided into two groups: a no message group receiving usual pre- and postop care and a message group receiving usual care plus messages in a mobile social media format with standardized content and timing. Each patient in the message group received nine messages about hand and face hygiene, medication and postop visit adherence, and links to patient education videos about postop care. Patients could respond to messages as desired. Main outcome measures included medication adherence, postop visit adherence, clinical outcomes, and patients' subjective assessments of two-way messaging. The number, types, content, and timing of responses by patients to messages were recorded. RESULTS: Medication adherence was better in the message group at postop day 7, with high adherence in 47 patients (96%, 47/49) versus 36 patients (73%, 36/49) in the no message group (P=.004), but no statistically significant differences in medication adherence between the groups were noted at preop and postop day 30. Visit adherence was higher at postop day 30 in the message group (100%, 49/49) versus the no message group (88%, 43/49; P=.03) but was 100% (49/49) in both groups at postop day 1 and 7. Final visual outcomes were similar between groups. A total of 441 standardized messages were sent to the message group. Out of 270 responses generated, 188 (70%) were simple acknowledgments or "thank you," and 82 (30%) responses were questions that were divided into three general categories: administrative, postop care, and clinical issues. Out of the 82 question responses, 31 (11%) were about administrative issues, 28 (10%) about postop care, and 23 (9%) about clinical symptoms. All the messages about symptoms were triaged by nurses or ophthalmologists and only required reassurance or information. Patients expressed satisfaction with messaging. CONCLUSIONS: Two-way social media messaging to deliver postop information to cataract patients is feasible and improves early medication compliance. Further design improvements can streamline work flow to optimize efficiency and patient satisfaction. PMID- 29258974 TI - Partners in Parenting: A Multi-Level Web-Based Approach to Support Parents in Prevention and Early Intervention for Adolescent Depression and Anxiety. AB - Depression and anxiety disorders in young people are a global health concern. Various risk and protective factors for these disorders are potentially modifiable by parents, underscoring the important role parents play in reducing the risk and impact of these disorders in their adolescent children. However, cost-effective, evidence-based interventions for parents that can be widely disseminated are lacking. In this paper, we propose a multi-level public health approach involving a Web-based parenting intervention, Partners in Parenting (PIP). We describe the components of the Web-based intervention and how each component was developed. Development of the intervention was guided by principles of the persuasive systems design model to maximize parental engagement and adherence. A consumer-engagement approach was used, including consultation with parents and adolescents about the content and presentation of the intervention. The PIP intervention can be used at varying levels of intensity to tailor to the different needs of parents across the population. Challenges and opportunities for the use of the intervention are discussed. The PIP Web-based intervention was developed to address the dearth of evidence-based resources to support parents in their important role in their adolescents' mental health. The proposed public health approach utilizes this intervention at varying levels of intensity based on parents' needs. Evaluation of each separate level of the model is ongoing. Further evaluation of the whole approach is required to assess the utility of the intervention as a public health approach, as well as its broader effects on adolescent functioning and socioeconomic outcomes. PMID- 29258975 TI - Public Perceptions Regarding Use of Virtual Reality in Health Care: A Social Media Content Analysis Using Facebook. AB - BACKGROUND: Virtual reality (VR) technology provides an immersive environment that enables users to have modified experiences of reality. VR is increasingly used to manage patients with pain, disability, obesity, neurologic dysfunction, anxiety, and depression. However, public opinion regarding the use of VR in health care has not been explored. Understanding public opinion of VR is critical to ensuring effective implementation of this emerging technology. OBJECTIVE: This study aimed to examine public opinion about health care VR using social listening, a method that allows for the exploration of unfiltered views of topics discussed on social media and online forums. METHODS: In March 2016, NBC News produced a video depicting the use of VR for patient care. The video was repackaged by NowThis, a social media news website, and distributed on Facebook by Upworthy, a news aggregator, yielding 4.3 million views and 2401 comments. We used Microsoft Excel Power Query and ATLAS.ti software (version 7.5, Scientific Software Development) to analyze the comments using content analysis and categorized the comments around first-, second-, and third-order concepts. We determined self-identified gender from the user's Facebook page and performed sentiment analysis of the language to analyze whether the perception of VR differed by gender using a Pearson's chi-square test. RESULTS: Out of the 1614 analyzable comments, 1021 (63.26%) were attributed to female Facebook users, 572 (35.44%) to male users, and 21 (1.30%) to users of unknown gender. There were 1197 comments coded as expressing a positive perception about VR (74.16%), 251 coded as expressing a negative perception and/or concern (15.56%), and 560 coded as neutral (34.70%). Informants identified 20 use cases for VR in health care, including the use of VR for pain and stress reduction; bed-bound individuals; women during labor; and patients undergoing chemotherapy, dialysis, radiation, or imaging procedures. Negative comments expressed concerns about radiation, infection risk, motion sickness, and the ubiquity of and overall dependence on technology. There was a statistically significant association between the language valence of the Facebook post and the gender of the Facebook user; men were more likely to post negative perceptions about the use of VR for health care, whereas women were more likely to post positive perceptions (P<.001). CONCLUSIONS: Most informants expressed positive perceptions about the use of VR in a wide range of health care settings. However, many expressed concerns that should be acknowledged and addressed as health care VR continues to evolve. Our results provide guidance in determining where further research on the use of VR in patient care is needed, and offer a formal opportunity for public opinion to shape the VR research agenda. PMID- 29258977 TI - Estimation of Symptom Severity During Chemotherapy From Passively Sensed Data: Exploratory Study. AB - BACKGROUND: Physical and psychological symptoms are common during chemotherapy in cancer patients, and real-time monitoring of these symptoms can improve patient outcomes. Sensors embedded in mobile phones and wearable activity trackers could be potentially useful in monitoring symptoms passively, with minimal patient burden. OBJECTIVE: The aim of this study was to explore whether passively sensed mobile phone and Fitbit data could be used to estimate daily symptom burden during chemotherapy. METHODS: A total of 14 patients undergoing chemotherapy for gastrointestinal cancer participated in the 4-week study. Participants carried an Android phone and wore a Fitbit device for the duration of the study and also completed daily severity ratings of 12 common symptoms. Symptom severity ratings were summed to create a total symptom burden score for each day, and ratings were centered on individual patient means and categorized into low, average, and high symptom burden days. Day-level features were extracted from raw mobile phone sensor and Fitbit data and included features reflecting mobility and activity, sleep, phone usage (eg, duration of interaction with phone and apps), and communication (eg, number of incoming and outgoing calls and messages). We used a rotation random forests classifier with cross-validation and resampling with replacement to evaluate population and individual model performance and correlation-based feature subset selection to select nonredundant features with the best predictive ability. RESULTS: Across 295 days of data with both symptom and sensor data, a number of mobile phone and Fitbit features were correlated with patient-reported symptom burden scores. We achieved an accuracy of 88.1% for our population model. The subset of features with the best accuracy included sedentary behavior as the most frequent activity, fewer minutes in light physical activity, less variable and average acceleration of the phone, and longer screen on time and interactions with apps on the phone. Mobile phone features had better predictive ability than Fitbit features. Accuracy of individual models ranged from 78.1% to 100% (mean 88.4%), and subsets of relevant features varied across participants. CONCLUSIONS: Passive sensor data, including mobile phone accelerometer and usage and Fitbit-assessed activity and sleep, were related to daily symptom burden during chemotherapy. These findings highlight opportunities for long-term monitoring of cancer patients during chemotherapy with minimal patient burden as well as real-time adaptive interventions aimed at early management of worsening or severe symptoms. PMID- 29258978 TI - The Effectiveness of Text Messaging for Detection and Management of Hypertension in Indigenous People in Canada: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Hypertension, the leading cause of morbidity and mortality, affects more than 1 billion people and is responsible globally for 10 million deaths annually. Hypertension can be controlled on a national level; in Canada, for example, awareness, treatment, and control improved dramatically from only 16% in 1990 to 66% currently. The ongoing development, dissemination, and implementation of Hypertension Canada's clinical practice guidelines is considered to be responsible, in part, for achieving these high levels of control and the associated improvements in cardiovascular outcomes. A gap still exists between the evidence and the implementation of hypertension guidelines in Indigenous communities in Canada, as well as in low- and middle-income countries (LMICs). The rapid rise in the ownership and use of mobile phones globally and the potential for texting (short message service, SMS) to improve health literacy and to link the health team together with the patient served as a rationale for the Dream-Global study in both Canada and Tanzania. OBJECTIVE: The primary objective of the Dream-Global study is to assess the effect of innovative technologies and changes in health services delivery on blood pressure (BP) control of Indigenous people in Canada and rural Tanzanians with hypertension using SMS messages and community BP measurement through task shifting with transfer of the measures electronically to the patient and the health care team members. METHODS: This prospective, randomized blinded allocation study enrolls both adults with uncontrolled hypertension (medicated or unmedicated) and those without hypertension but at high risk of developing this condition who participate in a BP screening study. Participants will be followed for at least 12 months. RESULTS: The primary efficacy endpoint in this study will be assessed by analysis of variance. Descriptive data will be given with the mean and standard deviation for continuous data and proportions for ordinal data. Exploratory subgroup analyses will include analysis by community, sex, mobile phone ownership at baseline, and age. The knowledge gained from the text messages will be assessed using a questionnaire at study completion, and results will be compared between the groups. CONCLUSIONS: This study is expected to provide insights into the implementation of an innovative system of guidelines- and community-based treatment and follow-up for hypertension in Indigenous communities in Canada and in Tanzania, an example of an LMIC. These insights are expected to provide the information needed to plan scalable and sustainable interventions to control BP virtually anywhere in the world. TRIAL REGISTRATION: Clinicaltrials.gov NCT02111226; https://clinicaltrials.gov/ct2/show/NCT02111226 (Archived by WebCite at http://www.webcitation.org/6v7IdYzZh). PMID- 29258976 TI - Intervention to Match Young Black Men and Transwomen Who Have Sex With Men or Transwomen to HIV Testing Options (All About Me): Protocol for a Randomized Controlled Trial. AB - BACKGROUND: HIV testing is a critical component of HIV prevention and care. Interventions to increase HIV testing rates among young black men who have sex with men (MSM) and black transgender women (transwomen) are needed. Personalized recommendations for an individual's optimal HIV testing approach may increase testing. OBJECTIVE: This randomized trial tests the hypothesis that a personalized recommendation of an optimal HIV testing approach will increase HIV testing more than standard HIV testing information. METHODS: A randomized trial among 236 young black men and transwomen who have sex with men or transwomen is being conducted. Participants complete a computerized baseline assessment and are randomized to electronically receive a personalized HIV testing recommendation or standard HIV testing information. Follow-up surveys are conducted online at 3 and 6 months after baseline. RESULTS: The All About Me randomized trial was launched in June 2016. Enrollment is completed and 3-month retention is 92.4% (218/236) and has exceeded study target goals. CONCLUSIONS: The All About Me intervention is an innovative approach to increase HIV testing by providing a personalized recommendation of a person's optimal HIV testing approach. If successful, optimizing this intervention for mobile devices will widen access to large numbers of individuals. TRIAL REGISTRATION: ClinicalTrial.gov NCT02834572; https://clinicaltrials.gov/ct2/show/NCT02834572 (Archived by WebCite at http://www.webcitation.org/6vLJWOS1B). PMID- 29258979 TI - eHealth Literacy and Health Behaviors Affecting Modern College Students: A Pilot Study of Issues Identified by the American College Health Association. AB - BACKGROUND: The eHealth Literacy Scale (eHEALS) has been widely adopted by researchers to understand how eHealth literacy can be put into context. eHealth researchers need to know how to promote positive health behavior changes across college students, given the importance of the Internet to acquire and use health information. The American College Health Association identified a set of key health issues that affect college students today. By understanding how eHEALS might be related to college students' maintenance of their health and their use of online health resources, researchers will be provided with a better understanding of eHealth literacy and its pragmatic implications for health campaigns and future interventions. OBJECTIVE: The goal of the study was to examine what eHEALS reveals about college student health behaviors identified by the American College Health Association. To understand college student current health maintenance and their intentions to maintain their health and use online resources, the theory of planned behavior was used as the theoretical framework for the study. METHODS: Data were collected via a survey of 422 college students that included the eHEALS measure and questions about health issues based on the recommendations of the American College Health Association. These questions asked about college student current health, subsequent use of online health resources, and their intention to maintain their health and make use of such resources in the future. RESULTS: eHEALS was positively and significantly associated with all 8 areas of health issues identified by the American College Health Association for college student current maintenance of health and use of online health resources and for future intention of health maintenance and use of online resources. Key issues that emerged with eHealth literacy were maintaining safe sex practices and seeking out related information, seeking out information on an exercise regime, information on vaccinations, and maintaining a balanced diet. CONCLUSIONS: These results suggest several areas that may be targeted for future health campaigns toward college students. In addition, eHEALS was found to be a useful instrument for college students in the United States. Lastly, these results point to a need to deliver targeted information to college students, particularly since eHEALS captures literacy based on positively phrased items. PMID- 29258980 TI - Implementation of the Blended Care Self-Management Program for Caregivers of People With Early-Stage Dementia (Partner in Balance): Process Evaluation of a Randomized Controlled Trial. AB - BACKGROUND: Caring for a family member with dementia puts caregivers at risk of overburdening. Electronic health (eHealth) support for caregivers offers an opportunity for accessible tailored interventions. The blended care self management program "Partner in Balance" (PiB) for early-stage dementia caregivers was executed in Dutch dementia care organizations. The program combines face-to face coaching with tailored Web-based modules. Next to an evaluation of program effectiveness, an evaluation of sampling and intervention quality is essential for the generalizability and interpretation of results. OBJECTIVE: The aim of this study was to describe the process evaluation from the perspective of both family caregivers (participants) and professionals delivering the intervention (coaches) to determine internal and external validity before the effect analysis and aid future implementation. METHODS: Implementation, sampling, and intervention quality were evaluated with quantitative and qualitative data from logistical research data, coach questionnaires (n=13), and interviews with coaches (n=10) and participants (n=49). Goal attainment scaling was used to measure treatment-induced change. Analyses were performed with descriptive statistics and deductive content analysis. RESULTS: The participation rate of eligible caregivers was 51.9% (80/154). Recruitment barriers were lack of computer and lack of need for support. Young age and employment were considered recruitment facilitators. All coaches attended training and supervision in blended care self-management. Deviations from the structured protocol were reported on intervention time, structure, and feedback. Coaches described an intensified relationship with the caregiver post intervention. Caregivers appreciated the tailored content and positive feedback. The blended structure increased their openness. The discussion forum was appreciated less. Overall, personal goals were attained after the program (T>50). Implementation barriers included lack of financing, time, and deviating target population. CONCLUSIONS: Participants and coaches were satisfied with the intervention, but adapting the content to specific subgroups, for example, younger caregivers, was recommended. Implementation of the program requires more awareness of the benefits of blended care self-management programs and training in tailored self-management skills. TRIAL REGISTRATION: Dutch Trial Register (NTR): NTR4748; http://www.trialregister.nl (Archived by WebCite at http://www.webcitation.org/6vSb2t9Mg). PMID- 29258981 TI - Health App Use Among US Mobile Phone Users: Analysis of Trends by Chronic Disease Status. AB - BACKGROUND: Mobile apps hold promise for serving as a lifestyle intervention in public health to promote wellness and attenuate chronic conditions, yet little is known about how individuals with chronic illness use or perceive mobile apps. OBJECTIVE: The objective of this study was to explore behaviors and perceptions about mobile phone-based apps for health among individuals with chronic conditions. METHODS: Data were collected from a national cross-sectional survey of 1604 mobile phone users in the United States that assessed mHealth use, beliefs, and preferences. This study examined health app use, reason for download, and perceived efficacy by chronic condition. RESULTS: Among participants, having between 1 and 5 apps was reported by 38.9% (314/807) of respondents without a condition and by 6.6% (24/364) of respondents with hypertension. Use of health apps was reported 2 times or more per day by 21.3% (172/807) of respondents without a condition, 2.7% (10/364) with hypertension, 13.1% (26/198) with obesity, 12.3% (20/163) with diabetes, 12.0% (32/267) with depression, and 16.6% (53/319) with high cholesterol. Results of the logistic regression did not indicate a significant difference in health app download between individuals with and without chronic conditions (P>.05). Compared with individuals with poor health, health app download was more likely among those with self-reported very good health (odds ratio [OR] 3.80, 95% CI 2.38-6.09, P<.001) and excellent health (OR 4.77, 95% CI 2.70-8.42, P<.001). Similarly, compared with individuals who report never or rarely engaging in physical activity, health app download was more likely among those who report exercise 1 day per week (OR 2.47, 95% CI 1.6-3.83, P<.001), 2 days per week (OR 4.77, 95% CI 3.27-6.94, P<.001), 3 to 4 days per week (OR 5.00, 95% CI 3.52-7.10, P<.001), and 5 to 7 days per week (OR 4.64, 95% CI 3.11-6.92, P<.001). All logistic regression results controlled for age, sex, and race or ethnicity. CONCLUSIONS: Results from this study suggest that individuals with poor self-reported health and low rates of physical activity, arguably those who stand to benefit most from health apps, were least likely to report download and use these health tools. PMID- 29258982 TI - The "new favorite" of gene editing technology-single base editors. AB - Programmable nucleases are cutting edge genetic technology which edits targeted DNA sequences through generation of site-specific double-strand DNA breaks (DSBs). To improve the efficiency and precision of genetic modification, scientists have developed a single-base editing system (base editor) through combining of CRISPR/Cas9 system with cytosine deaminase. Compared with Cas9 system, this base editor can convert cytosine to thymine (C > T) at specific site more efficiently without inducing DSBs to avoid generation of indels. However, the base editor can only generate transition of pyrimidine but could not modify purines. Recently, Nature published a novel base editing system to convert adenine to guanine (ABEs, adenine base editors) through fusion of Cas9 nickase to a modified deaminase which is evolved through screening of random library based on tRNA adenine deaminase from E. coli. Here, we summarize the development of single-base editing tools and the latest research progress, especially the optimization process of ABEs, as well as the potential directions of the base editors. PMID- 29258983 TI - Genetic and epigeneticregulations of mammalian circadian rhythms. AB - The circadian clocks are vital to many organisms for their survival and adaption to the surrounding environment. More and more people are interested in the circadian clock and related researches. One of the key characteristics of this endogenous clock is its periodicity. Mechanisms underlying the mammalian circadian rhythms with ~24 h periodicity involve interlocked transcriptional and translational feedback loops. The circadian clock system in mammals consists of hierarchical structures, with the suprachiasmatic nucleus (SCN) as the central pacemaker and peripheral oscillators in other organs. In spite of the central and peripheral oscillators, the molecular mechanisms are the same within the SCN and peripheral organs. In the past decades, major achievements are accomplished by using forward and reverse genetics, as well as epigenetic approaches. In this review, we recapitulate the history of how clock-related genes were identified, and summarize the main achievements in genetics and epigenetics to understand the molecular underpinnings. We hope it can offer basic knowledge for further researches, a reference for experimental designs aiming to adjust organisms' homeostasis by modulating the clock, and provide a foundation to build interdisciplinary research networks. PMID- 29258984 TI - Research progress on 5hmC and TET dioxygenases in neurodevelopment and neurological diseases. AB - The development of the nervous system is coordinately regulated by multiple interacting factors. If a certain factor is altered or mutated, the coordinated developmental processes could be disrupted, resulting in neurological diseases. The 5-hydroxymethylcytosine (5hmC) is an intermediate product of the DNA demethylation processes. 5hmC and its metabolic enzymes, the ten-eleven translocation protein-TET family of dioxygenases, have recently been identified as new epigenetic players important in the regulation of the nervous system development, as well as in cognition, memory and other neurological functions. In various studies on neurodevelopment and neurodegeneration related diseases, the levels of 5hmC and TET proteins could be differentially regulated during development and/or disease pathogenesis, suggesting the potentially critical roles of 5hmC and TETs in these neural developmental and disease processes. In this review, we summarize the recent advances in research on 5hmC and TET dioxygenases in the regulation of neurodevelopment and neurological diseases, thereby providing significant insights on the involvements of 5hmC and TETs in neurodevelopment and on establishing new therapeutic strategies for human neurological diseases. PMID- 29258985 TI - Recent advances on the role of long non-coding RNA H19 in regulating mammalian muscle growth and development. AB - As one of the first identified long non-coding RNAs (lncRNAs), H19 plays a wide range of roles in vivo, including not only as a tumor suppressor and oncogene involved in disease process, but also as a regulator of growth and development of multiple tissues in mammalian embryos. The function of H19 in muscles (both skeletal and cardiac muscle) draws widespread attention due to the following two reasons. On one hand, H19 promotes myogenic differentiation and myogenesis of skeletal muscle satellite cells (SMSCs) via regulating Igf2 in cis. On the other hand, H19 also modulates the target genes in trans, including sponging let-7, miR 106 or miR-29 to mediate myocyte glucose uptake, cardiomyocyte proliferation and tendon repair, as well as promote embryonic development and muscle regeneration through binding to MBD1 as a chromatin modifier. In this review, we summarize the role of H19 in mammalian muscles, which will provide a reference for further research to unveil the molecular mechanism of muscle growth and development. PMID- 29258986 TI - The biological function of pigeon crop milk and the regulation of its production. AB - The pigeon (Columba livia) is one of the few birds capable of secreting nutrients to nourish squabs. During the incubation period, the crop of the parent pigeon will be thickened. When squabs are hatched, the crop milk will be secreted from the crop and fed to squabs. The nutritional benefits are similar between the pigeon crop milk and mammalian milk, and both of them are regulated by prolactin. Prolactin stimulates the proliferation of crop epithelial cells, which eventually slough to form the crop milk. Evidence suggests that the complex process may be associated with the transcription of the AnxIcp35 gene and the activation of JAK/STAT and Wnt signal pathways. In this review, we summarize the main components and the biological function of the crop milk, the histological changes of the crop and the regulatory mechanism of crop milk secretion. PMID- 29258987 TI - The application of MutMap in forward genetic studies based on whole-genome sequencing. AB - Classical forward genetic analysis relies on construction of complicated progeny populations and development of many molecular markers for linkage analysis in genetic mapping, which is both time- and cost-consuming. The recently developed MutMap is a new forward genetic approach based on high-throughput next-generation sequencing technologies. It is more efficient and affordable than traditional methods. Moreover, new extended methods based on MutMap have been developed: MutMap+, which is based on self-crossing; MutMap-Gap, which is used to recognize the causative variations occurring in genome gap regions; QTL-seq, a method similar to MutMap for mapping quantitative trait loci. These methods are free from constructing complicated mapping population, genetic hybridization and linkage information. They have greatly accelerated the identification of genetic elements associated with interested phenotypic variation. Here, we review the basic principles of MutMap, and discuss their future applications in next generation sequencing-based forward genetic mapping and crop improvement. PMID- 29258989 TI - Seven in 10 complaints reviewed under new GMC scheme are thrown out. PMID- 29258988 TI - The active component screening of Anoectochilus roxburghii and the functional study on inhibition of melanogenesis in zebrafish. AB - The aim of this study is to explore the active components of Anoectochilus roxburghii capable of inhibiting melanin formation using chemical separation and extraction and functional analysis. Anoectochilus roxburghii were extracted with alcohol and separated into three groups: the total extraction group, alcohol extracted group and alcohol precipitated group. Zebrafish embryos at 0.75 h post fertilization were exposed to various concentrations of the three groups of extracts, and analyzed at 72 h, using semi-quantitative RT-PCR and in situ hybridization. The results showed that the alcohol extracts inhibit melanogenesis most significantly in the zebrafish embryos. The mRNAs of melanin-related genes, such as silv, tyr, tyrp1a, were down-regulated by the alcohol extracts spatially and temporally. The alcohol extracts also inhibited the activity of tyrosinase, a key enzyme in melanogenesis, in a dosage dependent manner. In addition, the alcohol extracts also display a remarkable inhibitory effect on melanin synthesis through down-regulation of mRNAs of melanin-related genes and tyrosinase activity in zebrafish embryos, in which a large amount of melanin has already been synthesized. Such inhibitory effect could be reversed after the withdrawal of the alcohol extracts. Our results showed that the alcohol extracts of Anoectochilus roxburghii can significantly inhibit zebrafish melanogenesis, supporting the notion that Anoectochilus roxburghii could potentially be used in the development and production of natural whitening products. PMID- 29258990 TI - Police in Xinjiang province gather biometric data under guise of health programme. PMID- 29258991 TI - Genetic Architecture of the Cardiovascular Risk Proteome. AB - BACKGROUND: We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology. METHODS: We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmo Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels. RESULTS: We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants. CONCLUSIONS: We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research. PMID- 29258992 TI - Late diagnosis of a truncating WISP3 mutation entails a severe phenotype of progressive pseudorheumatoid dysplasia. AB - Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affected individuals may not receive optimal medical management. Here, we report a case of two siblings with a severe phenotype of progressive pseudorheumatoid dysplasia (PPD). Their onset of symptoms began at the age of 3 yr. Both were neglected in the past, and the patients presented with a very severe phenotype and unmitigated natural history. PPD is a rare autosomal recessive skeletal dysplasia characterized by progressive joint stiffness, swelling, and pain. Because of observed muscle wasting, weakness, and the lack of laboratory testing, the case had been initially misdiagnosed by the local physicians. We aimed to provide diagnostic support by a targeted next-generation sequencing gene panel (Illumina TruSight One) for Mendelian diseases (Mendeliome), and we identified a homozygous frameshift mutation in the gene WISP3 (c.868_869delAG, p.Ser290Leufs*12). Thus, early diagnosis and intervention may have decreased the severity and complication of the disease. PMID- 29258995 TI - Views on the Mental Health Act from the frontline. PMID- 29258993 TI - Circadian clocks: from stem cells to tissue homeostasis and regeneration. AB - The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep-to-wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock-controlled output genes, which results in tissue-specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging. PMID- 29258994 TI - Associations of Four Community Factors With Longitudinal Change in Hemoglobin A1c Levels in Patients With Type 2 Diabetes. AB - OBJECTIVE: To evaluate associations of community factors with glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS: We identified patients with type 2 diabetes who had an HbA1c >=7.5% (58 mmol/mol) and subsequent HbA1c testing within 90-270 days. We used mixed-effect models to assess whether treatment intensification (TI) and community domains (community socioeconomic deprivation [CSD], food availability, fitness assets, and utilitarian physical activity favorability [quartiled]) were associated with HbA1c change over 6 and 24 months, controlling for demographics, HbA1c, BMI, and time with evidence of type 2 diabetes. We evaluated whether community domains modified associations of TI with HbA1c change using cross product terms. RESULTS: There were 15,308 patients with 69,818 elevated HbA1c measures. The average reduction in HbA1c over 6 months was 0.07% less in townships with a high level of CSD (third quartile versus the first). Reductions were 0.10% greater for HbA1c in townships with the best food availability (versus worst). HbA1c reductions were 0.17-0.19% greater in census tracts in the second and third quartiles of utilitarian physical activity favorability versus the first. The association of TI with 6-month HbA1c change was weaker in townships and boroughs with the worst CSD (versus best) and in boroughs with the best fitness assets (versus worst). The association of TI with 24-month HbA1c change was weaker in census tracts with the worst CSD (versus third quartile) and strongest in census tracts most favorable for utilitarian physical activity (versus worst). CONCLUSIONS: Community domains were associated with HbA1c change and blunted TI effectiveness. PMID- 29258996 TI - In This Issue: December. PMID- 29258997 TI - Seven in 10 complaints reviewed under new GMC scheme are thrown out. PMID- 29258998 TI - Contractile reserve as a predictor of prognosis in patients with non-ischaemic systolic heart failure and dilated cardiomyopathy: a systematic review and meta analysis. AB - OBJECTIVE: Patients with non-ischaemic systolic heart failure (HF) and idiopathic dilated cardiomyopathy (DCM) are a heterogenous group with varied morbidity and mortality. Prognostication in this group is challenging. We performed a systematic review and meta-analysis to examine the significance of the presence of contractile reserve as assessed via stress imaging on mortality and hospitalisation. METHODS: A search for studies that non-invasively assessed contractile reserve in patients with DCM or non-ischaemic HF with reduced ejection fraction, stress imaging with follow-up data comparing outcomes. A range of imaging modalities and stressors were included. We examined primary endpoints of mortality and secondary endpoints of combined cardiovascular events including HF progression or hospitalisation. Our analysis compared endpoints in patients with contractile reserve and those without it. RESULTS: Nine prospective cohort studies were identified describing a total of 787 patients. These studies are methodologically but not statistically heterogenous (I2 = 31%). Using a random effect model, the presence of contractile reserve was associated with a significantly lower risk of mortality and cardiovascular events odds ratios of 0.20 (CI 0.11, 0.39) (P < 0.00001) and 0.13 (CI 0.04, 0.40) (P = 0.0004), respectively. CONCLUSION: Regardless of stressor and imaging modality and despite the significant methodological heterogeneity within the current data (imaging techniques and parameters), patients with non-ischaemic cardiomyopathy and reduced EF who demonstrate contractile reserve have a lower mortality, and lower events/hospitalisations. The presence of contractile reserve therefore offers a potential positive prognostic indicator when managing these patients. PMID- 29258999 TI - UK is a less attractive place to work, GMC warns, as reliance on overseas doctors increases. PMID- 29259001 TI - Apoptosis in megakaryocytes and platelets: the life and death of a lineage. AB - Despite their profoundly different cellular composition, size, and function, megakaryocytes and platelets both depend on restraint of the intrinsic (or "mitochondrial") apoptosis pathway by BCL-2 family prosurvival proteins for their development and viability. Activation of the pathway contributes to the clearance of megakaryocytes following platelet shedding and constrains platelet lifespan in the circulation. Important questions remain as to how apoptosis is initiated in these cells at steady state and in response to pathophysiological insults. PMID- 29259002 TI - Long-term survival of older patients with MDS treated with HMA therapy without subsequent stem cell transplantation. PMID- 29259003 TI - Normal plasma IgG inhibits HIT antibody-mediated platelet activation: implications for therapeutic plasma exchange. PMID- 29259000 TI - Genes Important for Schizosaccharomyces pombe Meiosis Identified Through a Functional Genomics Screen. AB - Meiosis is a specialized cell division that generates gametes, such as eggs and sperm. Errors in meiosis result in miscarriages and are the leading cause of birth defects; however, the molecular origins of these defects remain unknown. Studies in model organisms are beginning to identify the genes and pathways important for meiosis, but the parts list is still poorly defined. Here we present a comprehensive catalog of genes important for meiosis in the fission yeast, Schizosaccharomyces pombe Our genome-wide functional screen surveyed all nonessential genes for roles in chromosome segregation and spore formation. Novel genes important at distinct stages of the meiotic chromosome segregation and differentiation program were identified. Preliminary characterization implicated three of these genes in centrosome/spindle pole body, centromere, and cohesion function. Our findings represent a near-complete parts list of genes important for meiosis in fission yeast, providing a valuable resource to advance our molecular understanding of meiosis. PMID- 29259004 TI - A Transgenic Dual-Luciferase Reporter Mouse for Longitudinal and Functional Monitoring of T Cells In Vivo. AB - Adoptive T-cell therapy (ATT) efficacy is limited when targeting large solid tumors. The evaluation of ATT outcomes using accessory treatment would greatly benefit from an in vivo monitoring tool, allowing the detection of functional parameters of transferred T cells. Here, we generated transgenic bioluminescence imaging of T cells (BLITC) mice expressing an NFAT-dependent click-beetle luciferase and a constitutive Renilla luciferase, which supports concomitant in vivo analysis of migration and activation of T cells. Rapid transferability of our system to preestablished tumor models was demonstrated in the SV40-large T antigen model via both crossbreeding of BLITC mice into a T-cell receptor (TCR) transgenic background and TCR transduction of BLITC T cells. We observed rapid tumor infiltration of BLITC CD8+ T cells followed by a burst-like activation that mirrored rejection kinetics. Using the BLITC reporter in the clinically relevant H-Y model, we performed female to male transfers and detected H-Y-specific alloreactivity (graft-versus-host disease) in vivo In an H-Y solid tumor model, we found migration of adoptively transferred H-Y TCR-transgenic CD4+ T cells into the tumor, marked by transient activation. This suggests a rapid inactivation of infiltrating T cells by the tumor microenvironment, as confirmed by their expression of inhibitory receptors. In summary, the BLITC reporter system facilitates analysis of therapeutic parameters for ATT, is rapidly transferable to models of interest not restricted to tumor research, and is suitable for rapid screening of TCR clones for tumor rejection kinetics, as well as off-target effects. Cancer Immunol Res; 6(1); 110-20. (c)2018 AACR. PMID- 29259005 TI - Strengthening trauma care in China. PMID- 29259006 TI - ConsensusDriver Improves upon Individual Algorithms for Predicting Driver Alterations in Different Cancer Types and Individual Patients. AB - Existing cancer driver prediction methods are based on very different assumptions and each of them can detect only a particular subset of driver genes. Here we perform a comprehensive assessment of 18 driver prediction methods on more than 3,400 tumor samples from 15 cancer types, all to determine their suitability in guiding precision medicine efforts. We categorized these methods into five groups: functional impact on proteins in general (FI) or specific to cancer (FIC), cohort-based analysis for recurrent mutations (CBA), mutations with expression correlation (MEC), and methods that use gene interaction network-based analysis (INA). The performance of driver prediction methods varied considerably, with concordance with a gold standard varying from 9% to 68%. FI methods showed relatively poor performance (concordance <22%), while CBA methods provided conservative results but required large sample sizes for high sensitivity. INA methods, through the integration of genomic and transcriptomic data, and FIC methods, by training cancer-specific models, provided the best trade-off between sensitivity and specificity. As the methods were found to predict different subsets of driver genes, we propose a novel consensus-based approach, ConsensusDriver, which significantly improves the quality of predictions (20% increase in sensitivity) in patient subgroups or even individual patients. Consensus-based methods like ConsensusDriver promise to harness the strengths of different driver prediction paradigms.Significance: These findings assess state of-the-art cancer driver prediction methods and develop a new and improved consensus-based approach for use in precision oncology. Cancer Res; 78(1); 290 301. (c)2017 AACR. PMID- 29259007 TI - Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms. AB - Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib.Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. Cancer Res; 78(4); 922-37. (c)2017 AACR. PMID- 29259008 TI - CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16 1-Mediated ERK and BCL2/Cyclin D1 Pathways. AB - CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471 83. (c)2017 AACR. PMID- 29259009 TI - Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression. AB - RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155-68. (c)2017 AACR. PMID- 29259010 TI - LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self Renewal of Liver Cancer Stem-like Cells. AB - Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decreases during differentiation. LSD1 was responsible for maintaining CSC self renewal and tumorigenicity in HCC, and its overexpression was sufficient to drive self-renewal of non-CSC. Levels of acetylated LSD1 were low in CSC with high LSD1 activity, and these CSC were capable of self-renewal. Notch signaling activated LSD1 through induction of the sirtuin SIRT1, leading to deacetylation and activation of LSD1 and CSC self-renewal. Notably, we found that LSD1 expression was increased in cancer-associated fibroblasts (CAF) as an upstream driver of Notch3-mediated CSC self-renewal. In clinical specimens of HCC, the presence of CAF, LSD1, and Notch3 strongly associated with poor patient survival. Overall, our results reveal that CAF-induced expression of Notch3 is responsible for LSD1 activation in CSC, driving their self-renewal in HCC.Significance: These seminal findings illuminate a complex pathway in the tissue microenvironment of liver cancer, which is responsible for orchestrating the self-renewal of stem-like cancer cells, with potential implications to improve therapy and limit relapses. Cancer Res; 78(4); 938-49. (c)2017 AACR. PMID- 29259011 TI - Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer. AB - Temozolomide is a DNA-alkylating agent used to treat brain tumors, but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by coadministration of an artificial nucleoside (5-nitroindolyl-2'-deoxyriboside, 5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate, 5-nitroindolyl-2'-deoxyriboside triphosphate, in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth, its coadministration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5 NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacologic proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.Significance: Combinatorial treatment of glioblastoma with temozolomide and a novel artificial nucleoside that inhibits replication of damaged DNA can safely enhance therapeutic responses. Cancer Res; 78(4); 1083-96. (c)2017 AACR. PMID- 29259012 TI - FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes. AB - The prolyl hydroxylase domain-containing proteins (PHD1-3) and the asparaginyl hydroxlyase factor inhibiting HIF (FIH) are oxygen sensors for hypoxia-inducible factor-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here, we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis.Significance: These findings deepen understanding of oxygen-dependent gene regulation and cancer metastasis in response to hypoxia. Cancer Res; 78(5); 1184-99. (c)2017 AACR. PMID- 29259013 TI - The CARMA3-Bcl10-MALT1 Signalosome Drives NFkappaB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer. AB - The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1 responsive NFkappaB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFkappaB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFkappaB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFkappaB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NFkappaB signaling pathways to improve the treatment of this breast cancer subset.Significance: These findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers. Cancer Res; 78(5); 1225-40. (c)2017 AACR. PMID- 29259014 TI - ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors. AB - An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy, a combination previously shown to suppress drug-tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP, and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response associated with STING upregulation, promoting protumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.Significance: These findings reveal a novel function of the recently described ufmylation pathway, an ER stress survival signaling in drug-tolerant persister cells, which has important biological and therapeutic implications. Cancer Res; 78(4); 1044-57. (c)2017 AACR. PMID- 29259015 TI - Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression. AB - Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) that stimulate oncogenic signaling in TEC. In this study, we evaluated the cross-talk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mut p53 induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGFbeta signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state. TEC exposed to media conditioned by drug-treated CAFs exhibited a decrease in oncogenic signaling, as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGFbeta. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma cross-talk may offer a viable strategy to treat pancreatic cancer.Significance: In an established mouse model of pancreatic cancer, administration of the promising experimental drug Minnelide was found to actively deplete reactive stromal fibroblasts and to trigger tumor regression, with implications for stromal-based strategies to attack this disease. Cancer Res; 78(5); 1321-33. (c)2018 AACR. PMID- 29259016 TI - Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets. AB - The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here, we show that oncogenic RAS and BRAF induce perinuclear relocalization of several RAS pathway proteins, including the kinases CK2 and p ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2alpha colocalizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSC) are present in tumor cell lines, mouse lung tumors, and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GF) in nontransformed cells with delayed kinetics (4-6 hours), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the prosenescence transcription factor C/EBPbeta in primary MEFs undergoing senescence. Conversely, in tumor cells, C/EBPbeta activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBPbeta.Significance: In addressing the long-standing question of the difference between normal and oncogenic RAS pathway signaling, this study shows that oncogenic RAS specifically triggers constitutive endocytosis-dependent movement of effector kinases to a perinuclear region, thereby creating connections to unique downstream targets such as the core prosenescence and the inflammatory regulatory transcription factor C/EBPbeta. Cancer Res; 78(4); 891 908. (c)2017 AACR. PMID- 29259018 TI - Identification of physicians providing comprehensive primary care in Ontario: a retrospective analysis using linked administrative data. AB - BACKGROUND: Given the changing landscape of primary care, there may be fewer primary care physicians available to provide a broad range of services to patients of all age groups and health conditions. We sought to identify physicians with comprehensive primary care practices in Ontario using administrative data, investigating how many and what proportion of primary care physicians provided comprehensive primary care and how this changed over time. METHODS: We identified the pool of active primary care physicians in linked population-based databases for Ontario from 1992/93 to 2014/15. After excluding those who saw patients fewer than 44 days per year, we identified physicians as providing comprehensive care if more than half of their services were for core primary care and if these services fell into at least 7 of 22 activity areas. Physicians with 50% or less of their services for core primary care but with more than 50% in a single location or type of service were identified as being in focused practice. RESULTS: In 2014/15, there were 12 891 physicians in the primary care pool: 1254 (9.7%) worked fewer than 44 days per year, 1619 (12.6%) were in focused practice, and 1009 (7.8%) could not be classified. The proportion in comprehensive practice ranged from 67.5% to 74.9% between 1992/93 and 2014/15, with a peak in 2002/03 and relative stability from 2009/10 to 2014/15. Over this period, there was an increase of 8.8% in population per comprehensive primary care physician. INTERPRETATION: We found that just over two-thirds of primary care physicians provided comprehensive care in 2014/15, which indicates that traditional estimates of the primary care physician workforce may be too high. Although implementation will vary by setting and available data, this approach is likely applicable elsewhere. PMID- 29259017 TI - Tenascin-C Promotes Tumor Cell Migration and Metastasis through Integrin alpha9beta1-Mediated YAP Inhibition. AB - Tenascin-C is an extracellular matrix molecule that drives progression of many types of human cancer, but the basis for its actions remains obscure. In this study, we describe a cell-autonomous signaling mechanism explaining how tenascin C promotes cancer cell migration in the tumor microenvironment. In a murine xenograft model of advanced human osteosarcoma, tenascin-C and its receptor integrin alpha9beta1 were determined to be essential for lung metastasis of tumor cells. We determined that activation of this pathway also reduced tumor cell autonomous expression of target genes for the transcription factor YAP. In clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact. Taken together, our results illuminate how tumor cell deposition of tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression.Significance: These results illuminate how the extracellular matrix glycoprotein tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression by employing integrin alpha9beta1, abolishing actin stress fiber formation, inhibiting YAP and its target gene expression, with potential implications for cancer prognosis and therapy. Cancer Res; 78(4); 950-61. (c)2017 AACR. PMID- 29259019 TI - Optical coherence tomography angiography analysis of foveal microvascular changes and inner retinal layer thinning in patients with diabetes. AB - AIM: To evaluate the correlation between inner retinal layer thinning and the foveal microvasculature in type 2 diabetes using optical coherence tomography angiography (OCTA). METHODS: A cross-sectional study involved 155 diabetic eyes. All patients were divided into two groups based on diabetic retinopathy (DR) grade: no DR (NDR, n=80) and mild-to-moderate non-proliferative DR (NPDR, n=75). Foveal avascular zone (FAZ) area, FAZ circularity index, FAZ perimeter, vessel density and perfusion index of parafoveal and perifoveal area were calculated using OCTA. The thickness of the macular ganglion cell/inner plexiform layer (mGCIPL) was measured using OCT. RESULTS: In both superficial and deep retinal capillary layers (SRL and DRL), FAZ areas in the NDR (0.38 mm2 , 0.49 mm2) and NPDR (0.38 mm2, 0.48 mm2) were greater than those in the control (0.33 mm2, 0.43 mm2). The FAZ circularity index, vessel density and perfusion index in the NDR (0.63, 17.8/mm, 0.32) and NPDR (0.63, 17.5/mm, 0.32) were smaller than those in the control (0.69, 19.6/mm, 0.39). mGCIPL thickness was significantly correlated with FAZ area in the SRL and DRL, as well as with FAZ circularity index, vessel density and perfusion index in the NDR and NPDR. In multivariate regression analysis, the FAZ circularity index (OR=12.2) and vessel density of the parafovea (OR=1.95) were correlated with mGCIPL thinning. CONCLUSION: OCTA revealed that early foveal microcirculatory alterations in diabetic eyes were related to mGCIPL thickness, regardless of the presence of DR. The decrease in FAZ circularity and parafoveal vessel density were highly correlated with mGCIPL thinning. PMID- 29259020 TI - Genetic risk factors for late age-related macular degeneration in India. AB - BACKGROUND/AIMS: There are limited data from India on genetic variants influencing late age-related macular degeneration (AMD). We have previously reported associations from a population-based study in India (the India age related eye disease study (INDEYE)) of early AMD and single nucleotide polymorphisms (SNPs) in ARMS2/HTRA1 and no association with CFH, C2 or CFB. Late AMD cases were too few for meaningful analyses. We aimed to investigate SNPs for late AMD through case enrichment and extend the loci for early AMD. METHODS: Fundus images of late AMD hospital cases were independently graded by the modified Wisconsin AMD grading scheme. In total 510 cases with late AMD (14 geographic atrophy and 496 neovascular AMD (nvAMD)), 1876 with early AMD and 1176 with no signs of AMD underwent genotyping for selected SNPs. We investigated genotype and per-allele additive associations (OR and 95% CIs) with nvAMD or early AMD. Bonferroni adjusted P values are presented. RESULTS: We found associations with nvAMD for CFHY402H variant (rs1061170) (OR=1.99, 95% CI 1.67 to 2.37, P=10-6), ARMS2 (rs10490924) (OR=2.94, 95% CI 2.45 to 3.52, P=10-9), C2 (rs547154) (OR=0.67, 95% CI 0.53 to 0.85, P=0.01), ABCA1 (rs1883025) (OR=0.77, 95% CI 0.65 to 0.92, P=0.04) and an SNP near VEGFA (rs4711751) (OR=0.64, 95% CI 0.54 to 0.77, P=10-3). We found no associations of TLR3 (rs3775291), CFD (rs3826945), FRK (rs1999930) or LIPC (rs10468017) or APOE epsilon4 alleles with nvAMD or early AMD, nor between early AMD and rs1883025 or rs4711751. CONCLUSIONS: The major genetic determinants of nvAMD risk in India are similar to those in other ancestries, while findings for early AMD suggest potential differences in the pathophysiology of AMD development. PMID- 29259022 TI - Intersubject synchronisation analysis of brain activity associated with the instant effects of acupuncture: an fMRI study. AB - OBJECTIVE: To use a promising analytical method, namely intersubject synchronisation (ISS), to evaluate the brain activity associated with the instant effects of acupuncture and compare the findings with traditional general linear model (GLM) methods. METHODS: 30 healthy volunteers were recruited for this study. Block-designed manual acupuncture stimuli were delivered at SP6, and de qi sensations were measured after acupuncture stimulation. All subjects underwent functional MRI (fMRI) scanning during the acupuncture stimuli. The fMRI data were separately analysed by ISS and traditional GLM methods. RESULTS: All subjects experienced de qi sensations. ISS analysis showed that the regions activated during acupuncture stimulation at SP6 were mainly divided into five clusters based on the time courses. The time courses of clusters 1 and 2 were in line with the acupuncture stimulation pattern, and the active regions were mainly involved in the sensorimotor system and salience network. Clusters 3, 4 and 5 displayed an almost contrary time course relative to the stimulation pattern. The brain regions activated included the default mode network, descending pain modulation pathway and visual cortices. GLM analysis indicated that the brain responses associated with the instant effects of acupuncture were largely implicated in sensory and motor processing and sensory integration. CONCLUSION: The ISS analysis considered the sustained effect of acupuncture and uncovered additional information not shown by GLM analysis. We suggest that ISS may be a suitable approach to investigate the brain responses associated with the instant effects of acupuncture. PMID- 29259021 TI - Evolutionary expansion of DNA hypomethylation in the mammalian germline genome. AB - DNA methylation in the germline is among the most important factors influencing the evolution of mammalian genomes. Yet little is known about its evolutionary rate or the fraction of the methylome that has undergone change. We compared whole-genome, single-CpG DNA methylation profiles in sperm of seven species human, chimpanzee, gorilla, rhesus macaque, mouse, rat, and dog-to investigate epigenomic evolution. We developed a phylo-epigenetic model for DNA methylation that accommodates the correlation of states at neighboring sites and allows for inference of ancestral states. Applying this model to the sperm methylomes, we uncovered an overall evolutionary expansion of the hypomethylated fraction of the genome, driven both by the birth of new hypomethylated regions and by extensive widening of hypomethylated intervals in ancestral species. This expansion shows strong lineage-specific aspects, most notably that hypomethylated intervals around transcription start sites have evolved to be considerably wider in primates and dog than in rodents, whereas rodents show evidence of a greater trend toward birth of new hypomethylated regions. Lineage-specific hypomethylated regions are enriched near sets of genes with common developmental functions and significant overlap across lineages. Rodent-specific and primate-specific hypomethylated regions are enriched for binding sites of similar transcription factors, suggesting that the plasticity accommodated by certain regulatory factors is conserved, despite substantial change in the specific sites of regulation. Overall our results reveal substantial global epigenomic change in mammalian sperm methylomes and point to a divergence in trans-epigenetic mechanisms that govern the organization of epigenetic states at gene promoters. PMID- 29259024 TI - Inclusion criteria update for the rat intraluminal ischaemic model for preclinical studies. AB - Proper occlusion of the medial cerebral artery, as determined by laser Doppler monitoring, during cerebral ischaemia in rat models is an important inclusion criterion in experimental studies. However, successful occlusion of the artery does not always guarantee a reproducible infarct volume, which is crucial for validating the efficacy of new protective drugs. In a rat intraluminal ischaemic model, laser Doppler monitoring alone was compared with laser Doppler monitoring in combination with magnetic resonance angiography (MRA) and diffusion-weighted imaging (DWI). Twenty-eight animals showed successful occlusion and reperfusion determined with Doppler monitoring, with an infarct size at 24 h of 16.7+/-11.5% (determined as ischaemic damage with respect to the ipsilateral hemisphere volume). However, when arterial occlusion and infarct damage were analysed in these animals using MRA and DWI, respectively, 15 animals were excluded and only 13 animals were included, with an infarct size at 24 h of 21.6+/-6.1%, showing a variability in the infarct size significantly lower (P<0.05, F-test) than that obtained with Doppler monitoring alone. We also observed that blocking of the pterygopalatine artery (a maxillary artery that is usually occluded in the intraluminal ischaemic model) was not relevant for this model, at least in terms of infarct variability. These results show that laser Doppler monitoring is a necessary procedure, but not sufficient to guarantee a reproducible infarct volume, in a rat ischaemic model. Therefore, laser Doppler monitoring in combination with DWI and MRA represents a reliable inclusion protocol during ischaemic surgery for the analysis of new protective drugs. PMID- 29259023 TI - Sophisticated lessons from simple organisms: appreciating the value of curiosity driven research. AB - For hundreds of years, biologists have studied accessible organisms such as garden peas, sea urchins collected at low tide, newt eggs, and flies circling rotten fruit. These organisms help us to understand the world around us, attracting and inspiring each new generation of biologists with the promise of mystery and discovery. Time and time again, what we learn from such simple organisms has emphasized our common biological origins by proving to be applicable to more complex organisms, including humans. Yet, biologists are increasingly being tasked with developing applications from the known, rather than being allowed to follow a path to discovery of the as yet unknown. Here, we provide examples of important lessons learned from research using selected non vertebrate organisms. We argue that, for the purpose of understanding human disease, simple organisms cannot and should not be replaced solely by human cell based culture systems. Rather, these organisms serve as powerful discovery tools for new knowledge that could subsequently be tested for conservation in human cell-based culture systems. In this way, curiosity-driven biological research in simple organisms has and will continue to pay huge dividends in both the short and long run for improving the human condition. PMID- 29259025 TI - Noncanonical NF-kappaB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis. AB - Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens, resulting in chronic mucosal inflammation. Few spontaneous animal models of esophageal eosinophilia exist, with most studies relying on artificial sensitization procedures. NF kappaB-inducing kinase (NIK; MAP3K14) is a key signaling molecule of the noncanonical NF-kappaB (NFKB1) pathway, an alternative signaling cascade producing chemokines involved in lymphoid stroma development and leukocyte trafficking. Nik-/- mice have been shown to develop a hypereosinophilic syndrome in peripheral blood and major filtering organs; however, the gastrointestinal mucosa of these mice has not been well characterized. We show that Nik-/- mice develop significant, localized eosinophilic esophagitis that mimics human EoE, including features such as severe eosinophil accumulation, degranulation, mucosal thickening, fibrosis and basal cell hyperplasia. The remainder of the GI tract, including the caudal stomach, small intestine and colon, in mice with active EoE are unaffected, also similar to human patients. Gene expression patterns in esophageal tissue of Nik-/- mice mimics human EoE, with thymic stromal lymphopoetin (TSLP) in particular also elevated at the protein level. In gene expression data sets from human biopsy specimens, we further show that many genes associated with noncanonical NF-kappaB signaling are significantly dysregulated in EoE patients, most notably a paradoxical upregulation of NIK itself with concurrent upregulation of powerful protein-level destabilizers of NIK. These findings suggest that Nik-/- mice could be useful as a spontaneous model of specific features of EoE and highlight a novel role for noncanonical NF-kappaB signaling in human patients. PMID- 29259026 TI - Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia. AB - Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model. PMID- 29259027 TI - Helicobacter pylori infection of AZ-521 cells reveals a type IV secretion defect and VacA-independent CagA phosphorylation. PMID- 29259029 TI - Correction: Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis (doi: 10.1242/dmm.030114). PMID- 29259028 TI - Response to 'Helicobacter pylori infection of AZ-521 cells reveals a type IV secretion defect and VacA-independent CagA phosphorylation'. PMID- 29259030 TI - Optical Analysis of Glioma: Fourier-Transform Infrared Spectroscopy Reveals the IDH1 Mutation Status. AB - Purpose: Somatic mutations in the human cytosolic isocitrate dehydrogenase 1 (IDH1) gene cause profound changes in cell metabolism and are a common feature of gliomas with unprecedented predictive and prognostic impact. Fourier-transform infrared (FT-IR) spectroscopy addresses the molecular composition of cells and tissue and was investigated to deduct the IDH1 mutation status.Experimental Design: We tested the technique on human cell lines that were transduced with wild-type IDH1 or mutated IDH1 and on 34 human glioma samples. IR spectra were acquired at 256 positions from cell pellets or tissue cryosections. Moreover, IR spectra were obtained from fresh, unprocessed biopsies of 64 patients with glioma.Results:IDH1 mutation was linked to changes in spectral bands assigned to molecular groups of lipids and proteins in cell lines and human glioma. The spectra of cryosections of brain tumor samples showed high interpatient variability, for example, bands related to calcifications at 1113 cm-1 However, supervised classification recognized relevant spectral regions at 1103, 1362, 1441, 1485, and 1553 cm-1 and assigned 88% of the tumor samples to the correct group. Similar spectral positions allowed the classification of spectra of fresh biopsies with an accuracy of 86%.Conclusions: Here, we show that vibrational spectroscopy reveals the IDH1 genotype of glioma. Because it can provide information in seconds, an implementation into the intraoperative workflow might allow simple and rapid online diagnosis of the IDH1 genotype. The intraoperative confirmation of IDH1 mutation status might guide the decision to pursue definitive neurosurgical resection and guide future in situ therapies of infiltrative gliomas. Clin Cancer Res; 24(11); 2530-8. (c)2017 AACRSee related commentary by Hollon and Orringer, p. 2467. PMID- 29259031 TI - Fine particulate pollution and asthma exacerbations. AB - OBJECTIVE: As the results from epidemiological studies about the impact of outdoor air pollution on asthma in children are heterogeneous, our objective was to investigate the association between asthma exacerbation in children and exposure to air pollutants. METHODS: A database of 1 264 585 paediatric visits during the 2010-2015 period to the emergency rooms from 20 emergency departments (EDs) of 'Assistance Publique Hopitaux de Paris (APHP)', the largest hospital group in Europe, was used. A total of 47 107 visits were classified as asthma exacerbations. Concentration of air pollutants (nitrogen dioxide, ozone, fine particulate matter (PM) with an aerodynamic diameter smaller than 10 um (PM10) and 2.5 um (PM2.5)), as well as meteorological data, evolution of respiratory syncytial virus infection and pollen exposition, were collected on an hourly or daily basis for the same period using institutional databases. To assess the association between air pollution and asthma, mixed-effects quasi-Poisson regression modelling was performed. RESULTS: The only compound independently associated with ED visits for asthma was PM2.5 (P<10-4). The association between asthma exacerbation and PM2.5 was not linear, and a sigmoid function described the relationshipsatisfactorily. PM2.5 concentration, which gives half the maximum effect, was estimated at 13.5 ug/m3. CONCLUSIONS: We found an association between daily asthma exacerbation in paediatric visits to the ED and fine particulate air pollutants. PMID- 29259032 TI - Analysis of chromatin accessibility in decidualizing human endometrial stromal cells. AB - Spontaneous decidualization of the endometrium in response to progesterone signaling is confined to menstruating species, including humans and other higher primates. During this process, endometrial stromal cells (EnSCs) differentiate into specialized decidual cells that control embryo implantation. We subjected undifferentiated and decidualizing human EnSCs to an assay for transposase accessible chromatin with sequencing (ATAC-seq) to map the underlying chromatin changes. A total of 185,084 open DNA loci were mapped accurately in EnSCs. Altered chromatin accessibility upon decidualization was strongly associated with differential gene expression. Analysis of 1533 opening and closing chromatin regions revealed over-representation of DNA binding motifs for known decidual transcription factors (TFs) and identified putative new regulators. ATAC-seq footprint analysis provided evidence of TF binding at specific motifs. One of the largest footprints involved the most enriched motif-basic leucine zipper-as part of a triple motif that also comprised the estrogen receptor and Pax domain binding sites. Without exception, triple motifs were located within Alu elements, which suggests a role for this primate-specific transposable element (TE) in the evolution of decidual genes. Although other TEs were generally under-represented in open chromatin of undifferentiated EnSCs, several classes contributed to the regulatory DNA landscape that underpins decidual gene expression.-Vrljicak, P., Lucas, E. S., Lansdowne, L., Lucciola, R., Muter, J., Dyer, N. P., Brosens, J. J., Ott, S. Analysis of chromatin accessibility in decidualizing human endometrial stromal cells. PMID- 29259033 TI - Vasorin: a newly identified regulator of ovarian folliculogenesis. AB - Members of the TGF-beta superfamily take part in the control of folliculogenesis. Vasorin (Vasn) is a newly identified negative regulator of TGF-beta signaling whose possible involvement in ovarian physiology has never been studied. Here, we demonstrate that Vasn is expressed in the ovary by somatic cells of follicles, and that its expression is up-regulated by LH. We established a conditional knockout (cKO) mouse model in which Vasn is deleted specifically in granulosa cells of growing follicles from the secondary stage onwards. Using this model, we show that, upon hormonal stimulation, follicle ovulation size is almost 2-fold higher. This enhanced ovulatory response is associated with overactivation of the TGF-beta signaling pathway and a lower number of atretic antral follicles. Of importance, we demonstrate that the number of primordial follicles is reduced in prepubertal cKO mouse ovaries, which suggests that the production of VASN by growing follicles protects the ovarian reserve. Finally, analysis of systemic KO mice revealed that the ovarian reserve is almost 2.5-fold higher, which implies that Vasn may also play a role in primordial follicle formation. Overall, our findings reveal that Vasn is a new regulator that exerts an effect on several key ovarian functions, including folliculogenesis, maintenance of the ovarian reserve, and ovulation.-Rimon-Dahari, N., Heinemann-Yerushalmi, L., Hadas, R., Kalich-Philosoph, L., Ketter, D., Nevo, N., Galiani, D., Dekel, N. Vasorin: a newly identified regulator of ovarian folliculogenesis. PMID- 29259034 TI - Ablation of the mammalian lectin galectin-8 induces bone defects in mice. AB - Mice overexpressing galectin-8 [gal-8 transgenic (Tg)], a secreted mammalian lectin, exhibit enhanced bone turnover and reduced bone mass, similar to cases of postmenopausal osteoporosis. Here, we show that gal-8 knockout (KO) mice have increased bone mass accrual at a young age but exhibit accelerated bone loss during adulthood. These phenotypes can be attributed to a gal-8-mediated increase in receptor activator of NF-kappaB ligand (RANKL) expression that promotes osteoclastogenesis, combined with direct inhibition of osteoblast differentiation, evident by reduced bone morphogenetic protein (BMP) signaling, reduced phosphorylation of receptor regulated mothers against decapentaplegic homolog (R-SMAD) and reduced expression of osteoblast differentiation markers osterix, osteocalcin, runt-related transcription factor 2 (RUNX2), dentin matrix acidic phosphoprotein-1 (DMP1), and alkaline phosphatase. At the same time, gal-8 promotes expression of estrogen receptor alpha (ESR1). Accordingly, the rate of bone loss is accelerated in ovariectomized, estrogen-deficient gal-8 Tg mice, whereas gal-8 KO mice, having low levels of ESR1, are refractory to ovariectomy. Finally, gal-8 mRNA positively correlates with the mRNA levels of osteoclastogenic markers RANKL, tartrate-resistant acid phosphatase, and cathepsin K in human femurs. Collectively, these findings identify gal-8 as a new physiologic player in the regulation of bone mass.-Vinik, Y., Shatz-Azoulay, H., Hiram-Bab, S., Kandel, L., Gabet, Y., Rivkin, G., Zick, Y. Ablation of the mammalian lectin galectin-8 induces bone defects in mice. PMID- 29259035 TI - Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer. AB - Girdin is an actin-binding protein playing key roles in the development of various carcinomas. Although online tools have predicted nuclear localization of girdin with a high probability, convincing proof has rarely been provided until now. The purpose of this study was to discover girdin's precise subcellular distribution and the potential prognostic value corresponding to its localization. The subcellular distribution of girdin was detected in a human breast cancer cell line and in >800 samples of human breast tissue by clinical pathologic analysis. In this study, we discovered for the first time that girdin could attach to chromatin and interact with topoisomerase-IIalpha in nucleus. Cytoplasmic and nuclear girdin exhibited different roles in prognosis of breast cancer: cytoplasmic girdin expression was an independent prognostic factor for progression-free survival (PFS), whereas nuclear girdin expression was an independent prognostic factor for overall survival (OS). More important, combination cytoplasmic and nuclear girdin was an independent prognosis factor of both OS and PFS. In conclusion, our research results strongly recommend combination analysis of cytoplasmic and nuclear girdin for a precise prognostic prediction in breast cancer.-Zhang, H., Yu, F., Qin, F., Shao, Y., Chong, W., Guo, Z., Liu, X., Fu, L., Gu, F., Ma, Y. Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer. PMID- 29259036 TI - Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. AB - Bioactive sphingolipids are modulators of immune processes and their metabolism is often dysregulated in ulcerative colitis, a major category of inflammatory bowel disease (IBD). While multiple axes of sphingolipid metabolism have been investigated to delineate mechanisms regulating ulcerative colitis, the role of acid ceramidase (AC) in intestinal inflammation is yet to be characterized. Here we demonstrate that AC expression is elevated selectively in the inflammatory infiltrate in human and murine colitis. To probe for mechanistic insight into how AC up-regulation can impact intestinal inflammation, we investigated the selective loss of AC expression in the myeloid population. Using a model of intestinal epithelial injury, we demonstrate that myeloid AC conditional knockout mice exhibit impairment of neutrophil recruitment to the colon mucosa as a result of defective cytokine and chemokine production. Furthermore, the loss of myeloid AC protects from tumor incidence in colitis-associated cancer (CAC) and inhibits the expansion of neutrophils and granulocytic myeloid-derived suppressor cells in the tumor microenvironment. Collectively, our results demonstrate a tissue specific role for AC in regulating neutrophilic inflammation and cytokine production. We demonstrate novel mechanisms of how granulocytes are recruited to the colon that may have therapeutic potential in intestinal inflammation, IBD, and CAC.-Espaillat, M. P., Snider, A. J., Qiu, Z., Channer, B., Coant, N., Schuchman, E. H., Kew, R. R., Sheridan, B. S., Hannun, Y. A., Obeid, L. M. Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. PMID- 29259038 TI - One-hour glucose value as a long-term predictor of cardiovascular morbidity and mortality: the Malmo Preventive Project. AB - OBJECTIVE: To examine the predictive capability of a 1-h vs 2-h postload glucose value for cardiovascular morbidity and mortality. DESIGN: Prospective, population based cohort study (Malmo Preventive Project) with subject inclusion 1974-1992. METHODS: 4934 men without known diabetes and cardiovascular disease, who had blood glucose (BG) measured at 0, 20, 40, 60, 90 and 120 min during an OGTT (30 g glucose per m2 body surface area), were followed for 27 years. Data on cardiovascular events and death were obtained through national and local registries. Predictive capabilities of fasting BG (FBG) and glucose values obtained during OGTT alone and added to a clinical prediction model comprising traditional cardiovascular risk factors were assessed using Harrell's concordance index (C-index) and integrated discrimination improvement (IDI). RESULTS: Median age was 48 (25th-75th percentile: 48-49) years and mean FBG 4.6 +/- 0.6 mmol/L. FBG and 2-h postload BG did not independently predict cardiovascular events or death. Conversely, 1-h postload BG predicted cardiovascular morbidity and mortality and remained an independent predictor of cardiovascular death (HR: 1.09, 95% CI: 1.01-1.17, P = 0.02) and all-cause mortality (HR: 1.10, 95% CI: 1.05-1.16, P < 0.0001) after adjusting for various traditional risk factors. Clinical risk factors with added 1-h postload BG performed better than clinical risk factors alone, in predicting cardiovascular death (likelihood-ratio test, P = 0.02) and all-cause mortality (likelihood-ratio test, P = 0.0001; significant IDI, P = 0.0003). CONCLUSION: Among men without known diabetes, addition of 1-h BG, but not FBG or 2-h BG, to clinical risk factors provided incremental prognostic yield for prediction of cardiovascular death and all-cause mortality. PMID- 29259039 TI - Both invasiveness and proliferation criteria predict recurrence of non functioning pituitary macroadenomas after surgery: a retrospective analysis of a monocentric cohort of 120 patients. AB - INTRODUCTION: Additional robust criteria to predict early postoperative recurrence of non-functioning pituitary macroadenomas (NFMAs) are needed. Recently, a new classification of pituitary tumors has been proposed, which is based on both radiological and histological criteria and allows the grading into 5 groups of different potential aggressiveness. The aim of this study was to use this classification to further characterize predictive factors of recurrence in an independent series of NFMA. CASES AND METHODS: 120 patients operated for a NFMA were analyzed retrospectively. For each of them, the invasion of the cavernous and/or sphenoidal sinuses by the tumor was studied on the preoperative MRI and the proliferative character was based on precise histological and immunohistological examination. RESULTS: 26% (n = 31) of the adenomas were proliferative and 57% (n = 68) were invasive. The invasive lesions were larger (P < 0.001) and their removal was complete in only 82% of the cases. The distribution of NFMAs was as follows: 32% grade 1a, 11% (proliferative) grade 1b, 42% (invasive) grade 2a and 15% (proliferative and invasive) grade 2b. Their probability of recurrence at 5 years was 20, 39, 44 and 66%, respectively. A young age, the atypical character and the presence of postoperative residual tumor were all independent risk factors of recurrence (P < 0.025). DISCUSSION: The new clinicopathological classification proves to be very useful in predicting the risk of recurrence of non-functioning pituitary macroadenomas after a first surgery. In particular, grade 2b lesions showed an overall likelihood of recurrence that was 8.6 times greater than those of grade 1a. PMID- 29259037 TI - Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas. AB - OBJECTIVE: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). DESIGN AND METHODS: Eight GAs selected for RNA sequencing were equally divided into fast and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. RESULTS: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (-0.669 Asp substitutions retain activity. Surprisingly, oxidative maturation to form the prFMNiminium species is severely affected only for the R173A variant. In summary, the unusual irreversible isomerization of prFMN is light-dependent and probably proceeds via high-energy intermediates but is independent of the Glu-Arg-Glu network. Our results from mutagenesis, crystallographic, spectroscopic, and kinetic experiments indicate a clear role for the Glu-Arg-Glu network in both catalysis and oxidative maturation. PMID- 29259127 TI - Activated heterotrimeric G protein alphai subunits inhibit Rap-dependent cell adhesion and promote cell migration. AB - Our recent work uncovered novel roles for activated Galphai signaling in the regulation of neutrophil polarity and adhesion. GalphaiGTP-mediated enhancement of neutrophil polarization was dependent on inhibition of cAMP/PKA signaling, whereas reversal of Gbetagamma-stimulated adhesion was cAMP/PKA independent. To uncover the mechanism for Galphai regulation of adhesion, we analyzed the effects of constitutively active Galphai1(Q204L) expression on adhesion driven by constitutively active Rap1a(G12V) or its downstream effector Radil in neutrophil like HL-60 cells, or in HT-1080 fibrosarcoma cells. In HT-1080 cells, Rap1a(G12V) or Radil cause an increase in cell spreading and adhesion to fibronectin, which are both reversed by Galphai1(Q204L) but not WT Galphai1 In contrast, Galphai1(Q204L) did not reverse Rap1-GTP-interacting adaptor molecule (RIAM) dependent increases in cell adhesion. This indicates that adhesion regulation by Galphai-GTP occurs downstream of Rap1a and Radil, but is upstream of components such as integrins and talin that are regulated by both Radil and RIAM. HL-60 neutrophil-like cells expressing Rap1a(G12V) or Radil have an elongated phenotype because of enhanced uropod adhesion as they attempt to migrate on fibronectin. This elongated phenotype driven by Rap1a(G12V) or Radil is reversed by Galphai1(Q204L), but not by WT Galphai1 expression, suggesting that Galphai-GTP also regulates adhesion in immune cells at the level of, or downstream of, Radil. These data identify a novel role of Galphai-GTP in regulation of cell adhesion and migration. Cell migration involves cycles of adhesion and de-adhesion, and we propose that the dynamic spatiotemporal balance between Gbetagamma-promoted adhesion and Galphai-GTP reversal of adhesion is important for this process. PMID- 29259126 TI - Active-site copper reduction promotes substrate binding of fungal lytic polysaccharide monooxygenase and reduces stability. AB - Lytic polysaccharide monooxygenases (LPMOs) are a class of copper-containing enzymes that oxidatively degrade insoluble plant polysaccharides and soluble oligosaccharides. Upon reductive activation, they cleave the substrate and promote biomass degradation by hydrolytic enzymes. In this study, we employed LPMO9C from Neurospora crassa, which is active toward cellulose and soluble beta glucans, to study the enzyme-substrate interaction and thermal stability. Binding studies showed that the reduction of the mononuclear active-site copper by ascorbic acid increased the affinity and the maximum binding capacity of LPMO for cellulose. The reduced redox state of the active-site copper and not the subsequent formation of the activated oxygen species increased the affinity toward cellulose. The lower affinity of oxidized LPMO could support its desorption after catalysis and allow hydrolases to access the cleavage site. It also suggests that the copper reduction is not necessarily performed in the substrate-bound state of LPMO. Differential scanning fluorimetry showed a stabilizing effect of the substrates cellulose and xyloglucan on the apparent transition midpoint temperature of the reduced, catalytically active enzyme. Oxidative auto-inactivation and destabilization were observed in the absence of a suitable substrate. Our data reveal the determinants of LPMO stability under turnover and non-turnover conditions and indicate that the reduction of the active-site copper initiates substrate binding. PMID- 29259128 TI - Hepatitis B X-interacting protein promotes the formation of the insulin gene transcribing protein complex Pdx-1/Neurod1 in animal pancreatic beta-cells. AB - The activation of insulin gene transcription depends on multiple nuclear proteins, including the transcription factors PDX-1 and NEUROD1, which form a transcriptional complex. We recently reported that hepatitis B X-interacting protein (HBXIP, also termed LAMTOR5) can modulate glucose metabolism reprogramming in cancer cells. However, the physiological role of HBXIP in the modulation of glucose metabolism in normal tissues is poorly understood. Here, we report that Hbxip is an essential regulator of the effect of the Pdx-1/Neurod1 complex on insulin gene transcription in murine pancreatic beta-cells in vitro and in vivo We found that pancreatic beta-cell-specific Hbxip-knockout mice displayed higher fasting blood glucose levels and impaired glucose tolerance. Furthermore, Hbxip was involved in the regulation of insulin in the pancreas islets and increased insulin gene expression in rat pancreatic beta-cells. Mechanistically, Hbxip stimulated insulin enhancer activity by interacting with Pdx-1 and recruiting Neurod1 to Pdx-1. Functionally, we provide evidence that Hbxip is required for Pdx-1/Neurod1-mediated insulin expression in rat pancreatic beta-cells. Collectively, these results indicate that Hbxip is involved in the transcription of insulin by increasing the levels of the Pdx-1/Neurod1 complex in animal pancreatic beta-cells. Our finding provides the insight into the mechanism by which Hbxip stimulates the transcription of the insulin gene. PMID- 29259129 TI - Transmembrane region of bacterial chemoreceptor is capable of promoting protein clustering. AB - Many membrane proteins are known to form higher-order oligomers, but the degree to which membrane regions could facilitate protein complex assembly remains largely unclear. Clusters of chemotaxis receptors are among the most prominent structures in the bacterial cell membrane, and they play important functions in processing of chemotactic signals. Although much work has been done to elucidate mechanisms of cluster formation, it almost exclusively focused on cytoplasmic interactions among receptors and other chemotaxis proteins, whereas involvement of membrane-mediated interactions was only hypothesized. Here we used imaging of constructs composed of only a fluorescent protein and the TM helices of Tar to demonstrate that interactions between the lipid bilayer and transmembrane (TM) helices of Escherichia coli chemoreceptors alone are sufficient to mediate clustering. We found that the ability to cluster depends on the sequence or length of the TM helices, implying that certain conformations of these helices facilitate clustering, whereas others do not. Notably, observed sequence specificity was apparently consistent with differences in clustering between native E. coli receptors, with the TM sequence of better-clustering high abundance receptors being more efficient in promoting membrane-mediated complex formation. These results indicate that being more than just membrane anchors, TM helices could play an important role in the clustering and organization of membrane proteins in bacteria. PMID- 29259131 TI - Identification of essential amino acids for glucose transporter 5 (GLUT5) mediated fructose transport. AB - Intestinal fructose uptake is mainly mediated by glucose transporter 5 (GLUT5/SLC2A5). Its closest relative, GLUT7, is also expressed in the intestine but does not transport fructose. For rat Glut5, a change of glutamine to glutamic acid at codon 166 (p.Q166E) has been reported to alter the substrate-binding specificity by shifting Glut5-mediated transport from fructose to glucose. Using chimeric proteins of GLUT5 and GLUT7, here we identified amino acid residues of GLUT5 that define its substrate specificity. The proteins were expressed in NIH 3T3 fibroblasts, and their activities were determined by fructose radiotracer flux. We divided the human GLUT5 sequence into 26 fragments and then replaced each fragment with the corresponding region in GLUT7. All fragments that yielded reduced fructose uptake were analyzed further by assessing the role of individual amino acid residues. Various positions in the first extracellular loop, in the fifth, seventh, eighth, ninth, and tenth transmembrane domains (TMDs), and in the regions between the ninth and tenth TMDs and tenth and 11th TMDs were identified as being important for proper fructose uptake. Although the p.Q167E change did not render the human protein into a glucose transporter, molecular dynamics simulations revealed a drastic change in the dynamics and a movement of the intracellular loop connecting the sixth and seventh TMDs, which covers the exit of the ligand. Finally, we generated a GLUT7-GLUT5 chimera consisting of the N terminal part of GLUT7 and the C-terminal part of GLUT5. Although this chimera was inactive, we demonstrate fructose transport after introduction of four amino acids derived from GLUT5. PMID- 29259130 TI - Cathepsin B regulates hepatic lipid metabolism by cleaving liver fatty acid binding protein. AB - Synthesis and secretion of hepatic triglycerides (TAG) associated with very-low density lipoprotein (VLDL) play a major role in maintaining overall lipid homeostasis. This study aims to identify factors affecting synthesis and secretion of VLDL-TAG using the growth hormone-deficient Ames dwarf mouse model, which has reduced serum TAG. Proteomic analysis coupled with a bioinformatics driven approach revealed that these mice express greater amounts of hepatic cathepsin B and lower amounts of liver fatty acid-binding protein (LFABP) than their wildtype littermates. siRNA-mediated knockdown of cathepsin B in McA-RH7777 cells resulted in a 39% increase in [3H]TAG associated with VLDL secretion. Cathepsin B knockdown was accompanied by a 74% increase in cellular LFABP protein levels, but only when cells were exposed to 0.4 mm oleic acid (OA) complexed to BSA. The cathepsin B knockdown and 24-h treatment with OA resulted in increased CD36 expression alone and additively. Co-localization of LFABP and cathepsin B was observed in a distinct Golgi apparatus-like pattern, which required a 1-h OA treatment. Moreover, we observed co-localization of LFABP and apoB, independent of the OA treatment. Overexpression of cathepsin B resulted in decreased OA uptake and VLDL secretion. Co-expression of cathepsin B and cathepsin B-resistant mutant LFABP in McA-RH7777 cells resulted in an increased TAG secretion as compared with cells co-expressing cathepsin B and wildtype LFABP. Together, these data indicate that cathepsin B regulates VLDL secretion and free fatty acid uptake via cleavage of LFABP, which occurs in response to oleic acid exposure. PMID- 29259132 TI - Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity. AB - Histone deacetylase 6 (HDAC6), a class IIb HDAC, plays an important role in many biological and pathological processes. Previously, we found that ERK1, a downstream kinase in the mitogen-activated protein kinase signaling pathway, phosphorylates HDAC6, thereby increasing HDAC6-mediated deacetylation of alpha tubulin. However, whether HDAC6 reciprocally modulates ERK1 activity is unknown. Here, we report that both ERK1 and -2 are acetylated and that HDAC6 promotes ERK1 activity via deacetylation. Briefly, we found that both ERK1 and -2 physically interact with HDAC6. Endogenous ERK1/2 acetylation levels increased upon treatment with a pan-HDAC inhibitor, an HDAC6-specific inhibitor, or depletion of HDAC6, suggesting that HDAC6 deacetylates ERK1/2. We also noted that the acetyltransferases CREB-binding protein and p300 both can acetylate ERK1/2. Acetylated ERK1 exhibits reduced enzymatic activity toward the transcription factor ELK1, a well-known ERK1 substrate. Furthermore, mass spectrometry analysis indicated Lys-72 as an acetylation site in the ERK1 N terminus, adjacent to Lys 71, which binds to ATP, suggesting that acetylation status of Lys-72 may affect ERK1 ATP binding. Interestingly, an acetylation-mimicking ERK1 mutant (K72Q) exhibited less phosphorylation than the WT enzyme and a deacetylation-mimicking mutant (K72R). Of note, the K72Q mutant displayed decreased enzymatic activity in an in vitro kinase assay and in a cellular luciferase assay compared with the WT and K72R mutant. Taken together, our findings suggest that HDAC6 stimulates ERK1 activity. Along with our previous report that ERK1 promotes HDAC6 activity, we propose that HDAC6 and ERK1 may form a positive feed-forward loop, which might play a role in cancer. PMID- 29259133 TI - Differentiation-dependent antiviral capacities of amphibian (Xenopus laevis) macrophages. AB - Infections by ranaviruses such as Frog virus 3 (Fv3), are significantly contributing to worldwide amphibian population declines. Notably, amphibian macrophages (Mphis) are important to both the Fv3 infection strategies and the immune defense against this pathogen. However, the mechanisms underlying amphibian Mphi Fv3 susceptibility and resistance remain unknown. Mphi differentiation is mediated by signaling through the colony-stimulating factor-1 receptor (CSF-1R) which is now known to be bound not only by CSF-1, but also by the unrelated interleukin-34 (IL-34) cytokine. Pertinently, amphibian (Xenopus laevis) Mphis differentiated by CSF-1 and IL-34 are highly susceptible and resistant to Fv3, respectively. Accordingly, in the present work, we elucidate the facets of this Mphi Fv3 susceptibility and resistance. Because cellular resistance to viral replication is marked by expression of antiviral restriction factors, it was intuitive to find that IL-34-Mphis possess significantly greater mRNA levels of select restriction factor genes than CSF-1-Mphis. Xenopodinae amphibians have highly expanded repertoires of antiviral interferon (IFN) cytokine gene families, and our results indicated that in comparison with the X. laevis CSF-1-Mphis, the IL-34-Mphis express substantially greater transcripts of representative IFN genes, belonging to distinct gene family clades, as well as their cognate receptor genes. Finally, we demonstrate that IL-34-Mphi-conditioned supernatants confer IFN-mediated anti-Fv3 protection to the virally susceptible X. laevis kidney (A6) cell line. Together, this work underlines the differentiation pathways leading to Fv3-susceptible and -resistant amphibian Mphi populations and defines the molecular mechanisms responsible for these differences. PMID- 29259134 TI - Computational antimicrobial peptide design and evaluation against multidrug resistant clinical isolates of bacteria. AB - There is a pressing need for new therapeutics to combat multidrug- and carbapenem resistant bacterial pathogens. This challenge prompted us to use a long short term memory (LSTM) language model to understand the underlying grammar, i.e. the arrangement and frequencies of amino acid residues, in known antimicrobial peptide sequences. According to the output of our LSTM network, we synthesized 10 peptides and tested them against known bacterial pathogens. All of these peptides displayed broad-spectrum antimicrobial activity, validating our LSTM-based peptide design approach. Our two most effective antimicrobial peptides displayed activity against multidrug-resistant clinical isolates of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and coagulase-negative staphylococci strains. High activity against extended-spectrum beta-lactamase, methicillin-resistant S. aureus, and carbapenem-resistant strains was also observed. Our peptides selectively interacted with and disrupted bacterial cell membranes and caused secondary gene-regulatory effects. Initial structural characterization revealed that our most effective peptide appeared to be well folded. We conclude that our LSTM-based peptide design approach appears to have correctly deciphered the underlying grammar of antimicrobial peptide sequences, as demonstrated by the experimentally observed efficacy of our designed peptides. PMID- 29259136 TI - Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates the low density lipoprotein (LDL) receptor, elevating LDL cholesterol and accelerating atherosclerotic heart disease, making it a promising cardiovascular drug target. To achieve its maximal effect on the LDL receptor, PCSK9 requires autoproteolysis. After cleavage, PCSK9 retains its prodomain in the active site as a self-inhibitor. Unlike other proprotein convertases, however, this retention is permanent, inhibiting any further protease activity for the remainder of its life cycle. Such inhibition has proven a major challenge toward a complete biochemical characterization of PCSK9's proteolytic function, which could inform therapeutic approaches against its hypercholesterolemic effects. To address this challenge, we employed a cell-based, high-throughput method using a luciferase readout to evaluate the single-turnover PCSK9 proteolytic event. We combined this method with saturation mutagenesis libraries to interrogate the sequence specificities of PCSK9 cleavage and proteolysis-independent secretion. Our results highlight several key differences in sequence identity between these two steps, complement known structural data, and suggest that PCSK9 self-proteolysis is the rate-limiting step of secretion. Additionally, we found that for missense SNPs within PCSK9, alterations in both proteolysis and secretion are common. Last, we show that some SNPs allosterically modulate PCSK9's substrate sequence specificity. Our findings indicate that PCSK9 proteolysis acts as a commonly perturbed but critical switch in controlling lipid homeostasis and provide a new hope for the development of small-molecule PCSK9 inhibitors. PMID- 29259135 TI - Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains. AB - The copper-containing superoxide dismutases (SODs) represent a large family of enzymes that participate in the metabolism of reactive oxygen species by disproportionating superoxide anion radical to oxygen and hydrogen peroxide. Catalysis is driven by the redox-active copper ion, and in most cases, SODs also harbor a zinc at the active site that enhances copper catalysis and stabilizes the protein. Such bimetallic Cu,Zn-SODs are widespread, from the periplasm of bacteria to virtually every organelle in the human cell. However, a new class of copper-containing SODs has recently emerged that function without zinc. These copper-only enzymes serve as extracellular SODs in specific bacteria (i.e. Mycobacteria), throughout the fungal kingdom, and in the fungus-like oomycetes. The eukaryotic copper-only SODs are particularly unique in that they lack an electrostatic loop for substrate guidance and have an unusual open-access copper site, yet they can still react with superoxide at rates limited only by diffusion. Copper-only SOD sequences similar to those seen in fungi and oomycetes are also found in the animal kingdom, but rather than single-domain enzymes, they appear as tandem repeats in large polypeptides we refer to as CSRPs (copper-only SOD-repeat proteins). Here, we compare and contrast the Cu,Zn versus copper-only SODs and discuss the evolution of copper-only SOD protein domains in animals and fungi. PMID- 29259139 TI - Inner Workings: Companies seek food safety using a microbiome approach. PMID- 29259137 TI - Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. AB - The accumulation of aberrantly aggregated MAPT (microtubule-associated protein Tau) defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inclusions in the form of neurofibrillary tangles and Pick bodies and in some cases glial Tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 Tau variants for their ability to be seeded by exogenous Tau fibrils. Our findings revealed stark differences between FTDP-17 Tau variants in their ability to be seeded, with variants at Pro301 and Ser320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain Tau protein regions and unique residues, including the role of Pro301 in inhibiting Tau aggregation. We also revealed potential barriers in cross-seeding between three-repeat and four-repeat Tau isoforms. Overall, these differences alluded to potential mechanistic differences between wildtype and FTDP-17 Tau variants, as well as different Tau isoforms, in influencing Tau aggregation. Furthermore, by combining two FTDP-17 Tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that do not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate Tau aggregation without the need for exogenous Tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate Tau aggregation. PMID- 29259140 TI - Core Concept: Role player or cellular rubbish? Biologists debate the function of neutrophil extracellular traps. PMID- 29259138 TI - The outer-membrane protein TolC of Vibrio cholerae serves as a second cell surface receptor for the VP3 phage. AB - Receptor recognition is a key step in the initiation of phage infection. Previously, we found that VP3, the T7 family phage of the Vibrio cholerae serogroup O1 biotype El Tor, can adsorb the core oligosaccharide (OS) of lipopolysaccharides of V. cholerae However, some wildtype strains of V. cholerae possessing the intact OS gene cluster still have VP3 binding but are resistant to VP3 infection. Moreover, an OS gene-deletion mutant still exhibits weak VP3 binding, suggesting multiple factors are possibly involved in VP3 binding to V. cholerae Here, we report that the outer-membrane protein TolC of V. cholerae is involved in the host adsorption of VP3. We observed that TolC directly interacts with the VP3 tail fiber protein gp44 and its C-terminal domains, and we also found that three amino acid residues in the outside loops of TolC, at positions 78, 290, and 291, are critical for binding to gp44. Among the VP3-resistant wildtype V. cholerae strains, frequent amino acid residue mutations were observed in the loops around the sites 78, 290, and 291, which were predicted to be exposed to the cell surface. These findings reveal a co-receptor-binding mechanism for VP3 infection of V. cholerae and that both outer-membrane TolC and OS are necessary for successful VP3 infection of V. cholerae We conclude that mutations on the outside loops of the receptor may confer V. cholerae strains with VP3 phage resistance, enabling these strains to survive in environments containing VP3 or related phages. PMID- 29259142 TI - Correction for Jandhyala et al., "Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation". PMID- 29259143 TI - Positive Aspects of Caregiving and Its Correlates among Caregivers of Bipolar Affective Disorder. AB - OBJECTIVE: To evaluate the positive aspects of caregiving and its correlates (socio-demographic and clinical variables, caregiver burden, coping, quality of life, psychological morbidity) in the primary caregivers of patients with bipolar affective disorder (BPAD). METHODS: A total of 60 primary caregivers of patients with a diagnosis of BPAD were evaluated on the Scale for Positive Aspects of Caregiving Experience (SPACE) and the Hindi version of Involvement Evaluation Questionnaire, Family Burden Interview Schedule (FBIS), modified Hindi version of Coping Checklist, shorter Hindi version of the World Health Organization Quality of Life (WHOQOL-BREF), and Hindi translated version of 12-item General Health Questionnaire (GHQ-12). RESULTS: Caregivers of patients with BPAD had the highest mean score in the SPACE domain of Motivation for caregiving role (2.45), followed by Caregiver satisfaction (2.38) and Caregiving personal gains (2.20). The mean score was the lowest for the domain of Self-esteem and social aspect of caring (2.01). In terms of correlations, age of onset of BPAD had a negative correlation with various domains of SPACE. The mean number of total lifetime affective and depressive episodes correlated positively with Self-esteem and social aspect of caring. Caregiver satisfaction correlated negatively with FBIS domains of Disruption of routine family activities, Effect on mental health of others, and subjective burden. Coercion as a coping mechanism correlated positively with domains of Caregiving personal gains, Caregiver satisfaction, and the total score on SPACE. Three (Physical health, Psychological health, Environment) out of 5 domains of the WHOQOL-BREF correlated positively with the total SPACE score. No association was noted between GHQ-12 and SPACE scores. CONCLUSION: Positive caregiving experience in primary caregivers of patients with BPAD is associated with better quality of life of the caregivers. PMID- 29259144 TI - Antidepressants for Depression Associated with Traumatic Brain Injury: A Meta analytical Study of Randomised Controlled Trials. AB - INTRODUCTION: Depression following traumatic brain injury is experienced by 16% to 60% of affected patients. The present study aimed to update the best evidence based pharmacological treatments for tackling such chronic and debilitating disorders. METHODS: We systematically reviewed and meta-analysed randomised controlled trials published from 1990 until August 2017 that compared the efficacy of antidepressants with placebo in the treatment of post-traumatic brain injury depression. We searched MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials (CENTRAL). RESULTS: Four studies were eligible for the meta analysis. The antidepressants studied were the selective serotonin reuptake inhibitors sertraline and citalopram. The rate of non-responders at the end of the follow-up period was lower in the treatment groups compared with placebo (odds ratio = 0.42, 95% confidence interval: 0.15-1.17); this difference was not statistically significant (p = 0.10). In subgroup analysis of the studies that reported mean Hamilton Depression Rating Scale score differences between treatment and control groups in both baseline and endpoint evaluations, the pooled mean difference was reduced from 2.11 (95% confidence interval: -1.25 to 5.46) to -2.36 (95% confidence interval: -5.59 to 0.87), in favour of the treatment group, though not statistically significant (p = 0.06). No evidence of heterogeneity was detected. In the subgroup analysis according to the antidepressant used in the included studies, there was a trend towards statistical significance for sertraline only (odds ratio = 0.28, 95% confidence interval: 0.08-1.03; p = 0.05); this was not evident in the study that reported the use of citalopram (odds ratio = 0.83; 95% confidence interval: 0.15-4.64; p = 0.84). CONCLUSIONS: Sertraline might be effective, though not statistically significant, in treating patients with post-traumatic brain injury depression. Adequately powered randomised controlled trials - extended to the plethora of newer antidepressants aiming to prove their non-inferiority to the selective serotonin reuptake inhibitors studied - are needed to confirm our results. The dearth of quality studies of this devastating problem of public health is rather impressive. PMID- 29259145 TI - Fear of Fear and Broad Dimensions of Psychopathology over the Course of Cognitive Behavioural Therapy for Panic Disorder with Agoraphobia in Japan. AB - OBJECTIVE: To examine the relationship of fear of fear and broad dimensions of psychopathology in panic disorder with agoraphobia over the course of cognitive behavioural therapy in Japan. METHODS: A total of 177 Japanese patients with panic disorder with agoraphobia were treated with group cognitive behavioural therapy between 2001 and 2015. We examined associations between the change scores in Agoraphobic Cognitions Questionnaire or Body Sensations Questionnaire and the changes in subscales of Symptom Checklist-90 Revised during cognitive behavioural therapy controlling the change in panic disorder severity using multiple regression analysis. RESULTS: Reduction in Agoraphobic Cognitions Questionnaire score was related to a decrease in all Symptom Checklist-90 Revised (SCL-90-R) subscale scores. Reduction in Body Sensations Questionnaire score was associated with a decrease in anxiety. Reduction in Panic Disorder Severity Scale score was not related to any SCL-90-R subscale changes. CONCLUSIONS: Changes in fear of fear, especially maladaptive cognitions, may predict broad dimensions of psychopathology reductions in patients of panic disorder with agoraphobia over the course of cognitive behavioural therapy. For the sake of improving a broader range of psychiatric symptoms in patients of panic disorder with agoraphobia, more attention to maladaptive cognition changes during cognitive behavioural therapy is warranted. PMID- 29259146 TI - Increasing the Continuity of Care between Primary Care Provider and a Psychiatric Hospital in Singapore. AB - INTRODUCTION: People who have a mental illness and who are stable on their current treatment may be suitable for follow-up care with a community-based general practitioner. A general practitioner-partnership programme was designed in an institute in Singapore to facilitate the transition to community services. However, the rates of successful referrals were low. METHODS: Our study followed the format of a quality improvement project, and used administrative data from April 2014 to June 2016 to gauge the impact of the interventions chosen to improve uptake of referrals. Three potential areas of improvement were found based on interviews with 25 service users. RESULTS: During the 11 months of pre intervention period (April 2014 to February 2015), 64% of potentially suitable service users (152 of 238 referrals) transitioned to community services. Low transition was linked to 3 identified causes and consequently, case managers developed personalised financial counselling for service users, assisted in the application for financial supports, and dispelled misconceptions about service provider inability to treat mental illness. Over the 16 months of intervention period (March 2015 to June 2016), the follow-up rate for referrals rose to 92% (260 / 283 referrals). CONCLUSION: Given that financial support entitlements change, it is important for case managers to remain aware of changing policy. Misconceptions of service provider qualifications may have a great impact on service user's willingness to seek services from primary care providers. PMID- 29259147 TI - Feasibility and Clinical Utility of High-definition Transcranial Direct Current Stimulation in the Treatment of Persistent Hallucinations in Schizophrenia. AB - Persistent auditory verbal hallucination is a clinically significant problem in schizophrenia. Recent studies suggest a promising role for add-on transcranial direct current stimulation (tDCS) in treatment. An optimised version of tDCS, namely high-definition tDCS (HD-tDCS), uses smaller electrodes arranged in a 4x1 ring configuration and may offer more focal and predictable neuromodulation than conventional tDCS. This case report illustrates the feasibility and clinical utility of add-on HD-tDCS over the left temporoparietal junction in a 4x1 ring configuration to treat persistent auditory verbal hallucination in schizophrenia. PMID- 29259148 TI - Successful Recovery from Spontaneous Spinal Epidural Hematoma in a Patient Undergoing Hemodialysis. AB - BACKGROUND Spontaneous spinal epidural hematoma (SSEH) occurs in the spinal epidural space in the absence of traumatic or iatrogenic causes, and is considered to be a neurological emergency, as spinal cord compression may lead to neurological deficit. Prompt diagnosis of SSEH can be difficult due to the variety of presenting symptoms, which may resemble those of stroke. Patients who undergo hemodialysis (HD) are at risk of bleeding due to anticoagulation during dialysis and uremia. However, SSEH in HD patients undergoing HD has rarely been reported. CASE REPORT A 70-year-old Japanese man, who has been undergoing maintenance HD for the previous three years, was admitted to Kariya Toyota General Hospital, Aichi, Japan, with acute chest and abdominal pain, and with complete paraplegia. The patient denied any recent trauma or medical procedures. Magnetic resonance imaging showed an extensive hematoma in the thoracic and lumbar epidural space, extending from T8 to L5. The patient's symptoms improved within three hours following hospital admission, and after three days without HD treatment, the SSEH decreased in size, and the patient successfully recovered without residual neurological deficits and without requiring surgery. CONCLUSIONS The management of SSEH in patients undergoing HD can be difficult, due to anticoagulation during dialysis and uremia. Prompt diagnosis and close neurological monitoring are important for appropriate management. In patients whose symptoms improve within a short period, conservative management may be considered. PMID- 29259149 TI - Comparison of Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance (MR) Imaging to T1 Mapping in Characterization of Hepatic Alveolar Echinococcosis. AB - BACKGROUND The aim of this study was to compare intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM DW MRI) to T1 mapping for characterization of hepatic alveolar echinococcosis (HAE). MATERIAL AND METHODS Eighteen HAE patients confirmed by surgery were examined with conventional MRI, IVIM DWI MRI with 10 b values (range: 0-1,000 sec/mm2), and longitudinal relaxation time (T1) mapping. Diffusion coefficient (D), perfusion fraction (f), pseudo-diffusion coefficient (D*), and T1 relaxation time were calculated in solid components, perilesional components, and background liver parenchyma of HAE patients. The correlation between T1 relaxation time and IVIM-derived parameters was assessed by using the Pearson correlation test. RESULTS T1 relaxation times were significantly higher in solid components (820.58+/-331.24 ms) compared to background components (551.52+/-182.93 ms) of HAE patients (p<0.05). IVIM-derived D values were significantly higher in solid components (1.30+/-0.28*10^-3 mm2/sec) compared to perilesional components (0.88+/-0.28*10^-3 mm2/sec) and background liver parenchyma (0.97+/-0.27*10^-3 mm2/sec) of liver parenchyma. There were significant differences in f values between solid components (13.70+/ 7.66%), perilesional components (23.59+/-10.73%) and background liver parenchyma (30.78+/-10.18%). IVIM derived D* values were significantly lower in solid components (14.32+/-10.85*10^-3 mm2/sec) than in background liver parenchyma (30.06+/-15.68*10^-3 mm2/sec). Importantly, IVIM-derived f values were significantly correlated with T1 relaxation time: r=-0.337 (p<0.05). CONCLUSIONS Based on our image comparison, IVIM DWI MRI might be better than T1 mapping, and IVIM-derived f values might be a valuable index for characterization of HAE. PMID- 29259150 TI - Nanoscale geochemical and geomechanical characterization of organic matter in shale. AB - Solid organic matter (OM) plays an essential role in the generation, migration, storage, and production of hydrocarbons from economically important shale rock formations. Electron microscopy images have documented spatial heterogeneity in the porosity of OM at nanoscale, and bulk spectroscopy measurements have documented large variation in the chemical composition of OM during petroleum generation. However, information regarding the heterogeneity of OM chemical composition at the nanoscale has been lacking. Here we demonstrate the first application of atomic force microscopy-based infrared spectroscopy (AFM-IR) to measure the chemical and mechanical heterogeneity of OM in shale at the nanoscale, orders of magnitude finer than achievable by traditional chemical imaging tools such as infrared microscopy. We present a combination of optical microscopy and AFM-IR imaging to characterize OM heterogeneity in an artificially matured series of New Albany Shales. The results document the evolution of individual organic macerals with maturation, providing a microscopic picture of the heterogeneous process of petroleum generation. PMID- 29259151 TI - Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task. AB - Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty. PMID- 29259153 TI - Application of optimal band-limited control protocols to quantum noise sensing. AB - Essential to the functionality of qubit-based sensors are control protocols, which shape their response in frequency space. However, in common control routines out-of-band spectral leakage complicates interpretation of the sensor's signal. In this work, we leverage discrete prolate spheroidal sequences (a.k.a. Slepian sequences) to synthesize provably optimal narrowband controls ideally suited to spectral estimation of a qubit's noisy environment. Experiments with trapped ions demonstrate how spectral leakage may be reduced by orders of magnitude over conventional controls when a near resonant driving field is modulated by Slepians, and how the desired narrowband sensitivity may be tuned using concepts from RF engineering. We demonstrate that classical multitaper techniques for spectral analysis can be ported to the quantum domain and combined with Bayesian estimation tools to experimentally reconstruct complex noise spectra. We then deploy these techniques to identify previously immeasurable frequency-resolved amplitude noise in our qubit's microwave synthesis chain. PMID- 29259152 TI - Neural computations underpinning the strategic management of influence in advice giving. AB - Research on social influence has focused mainly on the target of influence (e.g., consumer and voter); thus, the cognitive and neurobiological underpinnings of the source of the influence (e.g., politicians and salesmen) remain unknown. Here, in a three-sided advice-giving game, two advisers competed to influence a client by modulating their own confidence in their advice about which lottery the client should choose. We report that advisers' strategy depends on their level of influence on the client and their merit relative to one another. Moreover, blood oxygenation-level-dependent (BOLD) signal in the temporo-parietal junction is modulated by adviser's current level of influence on the client, and relative merit prediction error affects activity in medial-prefrontal cortex. Both types of social information modulate ventral striatum response. By demonstrating what happens in our mind and brain when we try to influence others, these results begin to explain the biological mechanisms that shape inter-individual differences in social conduct. PMID- 29259154 TI - In situ inward epitaxial growth of bulk macroporous single crystals. AB - The functionalities of porous materials could be significantly enhanced if the materials themselves were in single-crystal form, which, owing to structural coherence, would reduce electronic and optical scattering effects. However, growing macroporous single crystals remains a fundamental challenge, let alone manufacturing crystals large enough to be of practical use. Here we demonstrate a straightforward, inexpensive, versatile method for creating macroporous gallium nitride single crystals on a centimetre scale. The synthetic strategy is built upon a disruptive crystal growth mechanism that utilises direct nitridation of a parent LiGaO2 single crystal rendering an inward epitaxial growth process. Strikingly, the resulting single crystals exhibit electron mobility comparable to that for bulk crystals grown by the conventional sodium flux method. This approach not only affords control of both crystal and pore size through synthetic modification, but proves generic, thus opening up the possibility of designing macroporous crystals in a wealth of other materials. PMID- 29259155 TI - Central IGF1 improves glucose tolerance and insulin sensitivity in mice. AB - Insulin-like growth factor 1 (IGF1) is a key factor for tissue growth and fuel metabolism. The potential function of central IGF1 remains unclear. We previously observed that IGF1 expression is increased in the hypothalamus of obese mice lacking STAT5 in the central nervous system (CNS). In this study, we explored the potential metabolic function of central IGF1 by intracerebroventricular (ICV) injection of IGF1, over-expression of central IGF1 by administering an adeno associated virus (AAV), and ICV injection of an anti-IGF1 antibody. Mice that over-expressed central IGF1 displayed increased appetite, improved glucose tolerance and insulin sensitivity, decreased Pomc levels in the hypothalamus, and increased UCP1 expression in brown fat tissue. This is the first study demonstrating that central IGF1 regulates several important metabolic functions. PMID- 29259157 TI - Ethnic differences in metabolite signatures and type 2 diabetes: a nested case control analysis among people of South Asian, African and European origin. AB - Accumulation of metabolites may mark or contribute to the development of type 2 diabetes mellitus (T2D), but there is a lack of data from ethnic groups at high risk. We examined sphingolipids, acylcarnitines and amino acids, and their association with T2D in a nested case-control study among 54 South Asian Surinamese, 54 African Surinamese and 44 Dutch in the Netherlands. Plasma metabolites were determined at baseline (2001-2003), and cumulative prevalence and incidence of T2D at follow-up (2011-2012). Weighted linear and logistic regression analyses were used to study associations. The mean level of most sphingolipids was lower, and amino-acid levels higher, in the Surinamese groups than among the Dutch. Surinamese individuals had higher mono- and polyunsaturated acylcarnitines and lower plasma levels of saturated acylcarnitine species than the Dutch. Several sphingolipids and amino acids were associated with T2D. Although only the shorter acylcarnitines seemed associated with prevalent T2D, we found an association of all acylcarnitines (except C0, C18 and C18:2) with incident T2D. Further analyses suggested a potentially different association of several metabolites across ethnic groups. Extension and confirmation of these findings may improve the understanding of ethnic differences and contribute to early detection of increased individual risk. PMID- 29259156 TI - Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer selective lethality. AB - Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131's ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras?PIK3IP1?PI3K signaling network. PMID- 29259159 TI - Experimental evidence supporting a global melt layer at the base of the Earth's upper mantle. AB - The low-velocity layer (LVL) atop the 410-km discontinuity has been widely attributed to dehydration melting. In this study, we experimentally reproduced the wadsleyite-to-olivine phase transformation in the upwelling mantle across the 410-km discontinuity and investigated in situ the sound wave velocity during partial melting of hydrous peridotite. Our seismic velocity model indicates that the globally observed negative Vs anomaly (-4%) can be explained by a 0.7% melt fraction in peridotite at the base of the upper mantle. The produced melt is richer in FeO (~33 wt.%) and H2O (~16.5 wt.%) and its density is determined to be 3.56-3.74 g cm-3. The water content of this gravitationally stable melt in the LVL corresponds to a total water content in the mantle transition zone of 0.22 +/ 0.02 wt.%. Such values agree with estimations based on magneto-telluric observations. PMID- 29259158 TI - Increased striatal activity in adolescence benefits learning. AB - Adolescence is associated with enhanced striatal activity in response to rewards. This has been linked to increased risk-taking behavior and negative health outcomes. However, striatal activity is also important for learning, yet it is unknown whether heightened striatal responses in adolescence also benefit cognitive learning performance. In this longitudinal fMRI study (736 scans spanning 5 years in participants ages 8-29), we investigate whether adolescents show enhanced striatal activity during feedback learning, and whether this enhanced activity is associated with better learning performance. Here we report that neural activity indicating sensitivity to informative value of feedback peaks in late adolescence and occurs in dorsal caudate, ventral caudate, and nucleus accumbens. Increased activity in dorsal and ventral caudate predicts better current and future learning performance. This suggests that enhanced striatal activity in adolescents is adaptive for learning and may point to adolescence as a unique life phase for increased feedback-learning performance. PMID- 29259160 TI - Dynamic patterns of information flow in complex networks. AB - Although networks are extensively used to visualize information flow in biological, social and technological systems, translating topology into dynamic flow continues to challenge us, as similar networks exhibit fundamentally different flow patterns, driven by different interaction mechanisms. To uncover a network's actual flow patterns, here we use a perturbative formalism, analytically tracking the contribution of all nodes/paths to the flow of information, exposing the rules that link structure and dynamic information flow for a broad range of nonlinear systems. We find that the diversity of flow patterns can be mapped into a single universal function, characterizing the interplay between the system's topology and its dynamics, ultimately allowing us to identify the network's main arteries of information flow. Counter-intuitively, our formalism predicts a family of frequently encountered dynamics where the flow of information avoids the hubs, favoring the network's peripheral pathways, a striking disparity between structure and dynamics. PMID- 29259161 TI - Revealing chiral cell motility by 3D Riesz transform-differential interference contrast microscopy and computational kinematic analysis. AB - Left-right asymmetry is a fundamental feature of body plans, but its formation mechanisms and roles in functional lateralization remain unclear. Accumulating evidence suggests that left-right asymmetry originates in the cellular chirality. However, cell chirality has not yet been quantitatively investigated, mainly due to the absence of appropriate methods. Here we combine 3D Riesz transform differential interference contrast (RT-DIC) microscopy and computational kinematic analysis to characterize chiral cellular morphology and motility. We reveal that filopodia of neuronal growth cones exhibit 3D left-helical motion with retraction and right-screw rotation. We next apply the methods to amoeba Dictyostelium discoideum and discover right-handed clockwise cell migration on a 2D substrate and right-screw rotation of subcellular protrusions along the radial axis in a 3D substrate. Thus, RT-DIC microscopy and the computational kinematic analysis are useful and versatile tools to reveal the mechanisms of left-right asymmetry formation and the emergence of lateralized functions. PMID- 29259163 TI - Increased ionization supports growth of aerosols into cloud condensation nuclei. AB - Ions produced by cosmic rays have been thought to influence aerosols and clouds. In this study, the effect of ionization on the growth of aerosols into cloud condensation nuclei is investigated theoretically and experimentally. We show that the mass-flux of small ions can constitute an important addition to the growth caused by condensation of neutral molecules. Under atmospheric conditions the growth from ions can constitute several percent of the neutral growth. We performed experimental studies which quantify the effect of ions on the growth of aerosols between nucleation and sizes >20 nm and find good agreement with theory. Ion-induced condensation should be of importance not just in Earth's present day atmosphere for the growth of aerosols into cloud condensation nuclei under pristine marine conditions, but also under elevated atmospheric ionization caused by increased supernova activity. PMID- 29259162 TI - Type I interferon-mediated autoinflammation due to DNase II deficiency. AB - Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans. PMID- 29259164 TI - Metas-Chip precisely identifies presence of micrometastasis in live biopsy samples by label free approach. AB - Detecting the micrometastasis is a major challenge in patients' survival. The small volume of the biopsied tissue results in limited number of histopathological samples and might reduce the rate of accurate diagnosis even by molecular technologies. We introduce a microelectronic biochip (named Metas-Chip) to detect the micrometastasis in unprocessed liquid or solid samples. It works based on the tendency of malignant cells to track single human umbilical vein endothelial cell (HUVEC)-sensing traps. Such cells detach themselves from the biopsied sample and invade the sensing traps by inducing membrane retraction and blebbing, which result in sharp changes in electrical response of the sensing elements. Metas-Chip identified the metastasis in more than 70 breast cancer patients, in less than 5 h. Moreover it detected the metastasis in lymph nodes of nine patients whom were missed by conventional pathological procedure. Multilevel IHC and real-time polymerase chain reaction (RT-PCR) tests confirmed the diagnosis. PMID- 29259166 TI - Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, due to homozygous mutations or deletions in the telomeric survival motoneuron gene 1 (SMN1). SMA is characterized by motor impairment, muscle atrophy, and premature death following motor neuron (MN) degeneration. Emerging evidence suggests that dysregulation of autophagy contributes to MN degeneration. We here investigated the role of autophagy in the SMNdelta7 mouse model of SMA II (intermediate form of the disease) which leads to motor impairment by postnatal day 5 (P5) and to death by P13. We first showed by immunoblots that Beclin 1 and LC3-II expression levels increased in the lumbar spinal cord of the SMA pups. Electron microscopy and immunofluorescence studies confirmed that autophagic markers were enhanced in the ventral horn of SMA pups. To clarify the role of autophagy, we administered intracerebroventricularly (at P3) either an autophagy inhibitor (3-methyladenine, 3-MA), or an autophagy inducer (rapamycin) in SMA pups. Motor behavior was assessed daily with different tests: tail suspension, righting reflex, and hindlimb suspension tests. 3-MA significantly improved motor performance, extended the lifespan, and delayed MN death in lumbar spinal cord (10372.36 +/- 2716 MNs) compared to control-group (5148.38 +/- 94 MNs). Inhibition of autophagy by 3-MA suppressed autophagosome formation, reduced the apoptotic activation (cleaved caspase-3 and Bcl2) and the appearance of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons, underlining that apoptosis and autophagy pathways are intricately intertwined. Therefore, autophagy is likely involved in MN death in SMA II, suggesting that it might represent a promising target for delaying the progression of SMA in humans as well. PMID- 29259167 TI - Model-free inference of direct network interactions from nonlinear collective dynamics. AB - The topology of interactions in network dynamical systems fundamentally underlies their function. Accelerating technological progress creates massively available data about collective nonlinear dynamics in physical, biological, and technological systems. Detecting direct interaction patterns from those dynamics still constitutes a major open problem. In particular, current nonlinear dynamics approaches mostly require to know a priori a model of the (often high dimensional) system dynamics. Here we develop a model-independent framework for inferring direct interactions solely from recording the nonlinear collective dynamics generated. Introducing an explicit dependency matrix in combination with a block-orthogonal regression algorithm, the approach works reliably across many dynamical regimes, including transient dynamics toward steady states, periodic and non-periodic dynamics, and chaos. Together with its capabilities to reveal network (two point) as well as hypernetwork (e.g., three point) interactions, this framework may thus open up nonlinear dynamics options of inferring direct interaction patterns across systems where no model is known. PMID- 29259165 TI - Unravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus. AB - Ruminococcus gnavus is a human gut symbiont wherein the ability to degrade mucins is mediated by an intramolecular trans-sialidase (RgNanH). RgNanH comprises a GH33 catalytic domain and a sialic acid-binding carbohydrate-binding module (CBM40). Here we used glycan arrays, STD NMR, X-ray crystallography, mutagenesis and binding assays to determine the structure and function of RgNanH_CBM40 (RgCBM40). RgCBM40 displays the canonical CBM40 beta-sandwich fold and broad specificity towards sialoglycans with millimolar binding affinity towards alpha2,3- or alpha2,6-sialyllactose. RgCBM40 binds to mucus produced by goblet cells and to purified mucins, providing direct evidence for a CBM40 as a novel bacterial mucus adhesin. Bioinformatics data show that RgCBM40 canonical type domains are widespread among Firmicutes. Furthermore, binding of R. gnavus ATCC 29149 to intestinal mucus is sialic acid mediated. Together, this study reveals novel features of CBMs which may contribute to the biogeography of symbiotic bacteria in the gut. PMID- 29259168 TI - Lower plate serpentinite diapirism in the Calabrian Arc subduction complex. AB - Mantle-derived serpentinites have been detected at magma-poor rifted margins and above subduction zones, where they are usually produced by fluids released from the slab to the mantle wedge. Here we show evidence of a new class of serpentinite diapirs within the external subduction system of the Calabrian Arc, derived directly from the lower plate. Mantle serpentinites rise through lithospheric faults caused by incipient rifting and the collapse of the accretionary wedge. Mantle-derived diapirism is not linked directly to subduction processes. The serpentinites, formed probably during Mesozoic Tethyan rifting, were carried below the subduction system by plate convergence; lithospheric faults driving margin segmentation act as windows through which inherited serpentinites rise to the sub-seafloor. The discovery of deep-seated seismogenic features coupled with inherited lower plate serpentinite diapirs, provides constraints on mechanisms exposing altered products of mantle peridotite at the seafloor long time after their formation. PMID- 29259170 TI - Genomic regression analysis of coordinated expression. AB - Co-expression analysis is widely used to predict gene function and to identify functionally related gene sets. However, co-expression analysis using human cancer transcriptomic data is confounded by somatic copy number alterations (SCNA), which produce co-expression signatures based on physical proximity rather than biological function. To better understand gene-gene co-expression based on biological regulation but not SCNA, we describe a method termed "Genomic Regression Analysis of Coordinated Expression" (GRACE) to adjust for the effect of SCNA in co-expression analysis. The results from analyses of TCGA, CCLE, and NCI60 data sets show that GRACE can improve our understanding of how a transcriptional network is re-wired in cancer. A user-friendly web database populated with data sets from The Cancer Genome Atlas (TCGA) is provided to allow customized query. PMID- 29259171 TI - Silica-grafted ionic liquids for revealing the respective charging behaviors of cations and anions in supercapacitors. AB - Supercapacitors based on activated carbon electrodes and ionic liquids as electrolytes are capable of storing charge through the electrosorption of ions on porous carbons and represent important energy storage devices with high power delivery/uptake. Various computational and instrumental methods have been developed to understand the ion storage behavior, however, techniques that can probe various cations and anions of ionic liquids separately remain lacking. Here, we report an approach to monitoring cations and anions independently by using silica nanoparticle-grafted ionic liquids, in which ions attaching to silica nanoparticle cannot access activated carbon pores upon charging, whereas free counter-ions can. Aided by this strategy, conventional electrochemical characterizations allow the direct measurement of the respective capacitance contributions and acting potential windows of different ions. Moreover, coupled with electrochemical quartz crystal microbalance, this method can provide unprecedented insight into the underlying electrochemistry. PMID- 29259169 TI - Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. AB - The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development. PMID- 29259172 TI - Extensive gene content variation in the Brachypodium distachyon pan-genome correlates with population structure. AB - While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely to be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution. PMID- 29259174 TI - A circular white-light flare with impulsive and gradual white-light kernels. AB - White-light flares are the flares with emissions visible in the optical continuum. They are thought to be rare and pose the most stringent requirements in energy transport and heating in the lower atmosphere. Here we present a nearly circular white-light flare on 10 March 2015 that was well observed by the Optical and Near-infrared Solar Eruption Tracer and Solar Dynamics Observatory. In this flare, there appear simultaneously both impulsive and gradual white-light kernels. The generally accepted thick-target model would be responsible for the impulsive kernels but not sufficient to interpret the gradual kernels. Some other mechanisms including soft X-ray backwarming or downward-propagating Alfven waves, acting jointly with electron beam bombardment, provide a possible interpretation. However, the origin of this kind of white-light kernel is still an open question that induces more observations and researches in the future to decipher it. PMID- 29259173 TI - CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. PMID- 29259175 TI - NLRP3 inflammasome is a key player in human vulvovaginal disease caused by Candida albicans. AB - The expression of host inflammatory and Candida albicans putative virulence factors was studied in women with vulvovaginal candidiasis (VVC; twenty) or colonized by the fungus but asymptomatic (carriers; fifteen) or non-colonized asymptomatic (ten subjects). Overexpression of genes encoding NLRP3 and caspase-1 inflammasome components sharply differentiated VVC patients from asymptomatic colonized or non-colonized women. Inflammasome expression was coupled with neutrophils recruitment in the vagina of VVC women and IL-1beta and IL-8 production. Both cytokines were present, though to a lower concentration, also in the vaginal fluid of colonized and non-colonized women. Secretory aspartyl proteinases (SAPs) and hyphae associated genes HWP1 and ECE1 were upregulated in VVC but with some differences among infected women. The most overexpressed SAP gene was SAP2, that correlated with neutrophils accumulation. Our data provide clinical evidence that the intracytoplasmic activation of NLRP3 inflammasome complex plays a critical, pathogenesis-relevant role in human VVC. PMID- 29259176 TI - Connecting Neuronal Cell Protective Pathways and Drug Combinations in a Huntington's Disease Model through the Application of Quantitative Systems Pharmacology. AB - Quantitative Systems Pharmacology (QSP) is a drug discovery approach that integrates computational and experimental methods in an iterative way to gain a comprehensive, unbiased understanding of disease processes to inform effective therapeutic strategies. We report the implementation of QSP to Huntington's Disease, with the application of a chemogenomics platform to identify strategies to protect neuronal cells from mutant huntingtin induced death. Using the STHdh Q111 cell model, we investigated the protective effects of small molecule probes having diverse canonical modes-of-action to infer pathways of neuronal cell protection connected to drug mechanism. Several mechanistically diverse protective probes were identified, most of which showed less than 50% efficacy. Specific combinations of these probes were synergistic in enhancing efficacy. Computational analysis of these probes revealed a convergence of pathways indicating activation of PKA. Analysis of phospho-PKA levels showed lower cytoplasmic levels in STHdh Q111 cells compared to wild type STHdh Q7 cells, and these levels were increased by several of the protective compounds. Pharmacological inhibition of PKA activity reduced protection supporting the hypothesis that protection may be working, in part, through activation of the PKA network. The systems-level studies described here can be broadly applied to any discovery strategy involving small molecule modulation of disease phenotype. PMID- 29259177 TI - Scale-invariant large nonlocality in polycrystalline graphene. AB - The observation of large nonlocal resistances near the Dirac point in graphene has been related to a variety of intrinsic Hall effects, where the spin or valley degrees of freedom are controlled by symmetry breaking mechanisms. Engineering strong spin or valley Hall signals on scalable graphene devices could stimulate further practical developments of spin- and valleytronics. Here we report on scale-invariant nonlocal transport in large-scale chemical vapor deposition graphene under an applied external magnetic field. Contrary to previously reported Zeeman spin Hall effect, our results are explained by field-induced spin filtered edge states whose sensitivity to grain boundaries manifests in the nonlocal resistance. This phenomenon, related to the emergence of the quantum Hall regime, persists up to the millimeter scale, showing that polycrystalline morphology can be imprinted in nonlocal transport. This suggests that topological Hall effects in large-scale graphene materials are highly sensitive to the underlying structural morphology, limiting practical realizations. PMID- 29259178 TI - Allosteric modulation of protein-protein interactions by individual lipid binding events. AB - The diverse lipid environment of the biological membrane can modulate the structure and function of membrane proteins. However, little is known about the role that lipids play in modulating protein-protein interactions. Here we employed native mass spectrometry (MS) to determine how individual lipid-binding events to the ammonia channel (AmtB) modulate its interaction with the regulatory protein, GlnK. The thermodynamic signature of AmtB-GlnK in the absence of lipids indicates conformational dynamics. A small number of lipids bound to AmtB is sufficient to modulate the interaction with GlnK, and lipids with different headgroups display a range of allosteric modulation. We also find that lipid chain length and stereochemistry can affect the degree of allosteric modulation, indicating an unforeseen selectivity of membrane proteins toward the chemistry of lipid tails. These results demonstrate that individual lipid-binding events can allosterically modulate the interactions of integral membrane and soluble proteins. PMID- 29259179 TI - Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. Here, we hypothesized that DNA methylation patterns would help predict disease outcome and therefore performed genome-wide DNA methylation profiling in a cohort of 39 patients. Unsupervised hierarchical clustering identifies three clusters of patients. Importantly, these clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Notably, all but one of 14 patients experiencing spontaneous resolution cluster together and closer to 22 healthy controls than to other JMML cases. Thus, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution. PMID- 29259180 TI - Beneficial mutation-selection dynamics in finite asexual populations: a free boundary approach. AB - Using a free boundary approach based on an analogy with ice melting models, we propose a deterministic PDE framework to describe the dynamics of fitness distributions in the presence of beneficial mutations with non-epistatic effects on fitness. Contrarily to most approaches based on deterministic models, our framework does not rely on an infinite population size assumption, and successfully captures the transient as well as the long time dynamics of fitness distributions. In particular, consistently with stochastic individual-based approaches or stochastic PDE approaches, it leads to a constant asymptotic rate of adaptation at large times, that most deterministic approaches failed to describe. We derive analytic formulas for the asymptotic rate of adaptation and the full asymptotic distribution of fitness. These formulas depend explicitly on the population size, and are shown to be accurate for a wide range of population sizes and mutation rates, compared to individual-based simulations. Although we were not able to derive an analytic description for the transient dynamics, numerical computations lead to accurate predictions and are computationally efficient compared to stochastic simulations. These computations show that the fitness distribution converges towards a travelling wave with constant speed, and whose profile can be computed analytically. PMID- 29259182 TI - Copper Nanowires through Oriented Mesoporous Silica: A Step towards Protected and Parallel Atomic Switches. AB - The formation of copper atomic contacts has been investigated. Copper nanowires were grown by electrochemical deposition, in the scanning electrochemical microscopy (SECM) configuration, from a platinum microelectrode to an indium tin oxide (ITO) substrate. Self-termination leaves copper filaments between the two electrodes with an atomic point contact at the ITO electrode. Histogram analysis shows that the conductance of this contact is close to, or less than, 1 G0. Atomic contacts were also fabricated on ITO electrodes covered with vertically aligned mesoporous silica films. Scanning Transmission Electron Microscopy images show that copper filaments occupy individual isolated nanopores. Contacts generated on bare ITO break down rapidly in sodium salicylate, whereas those generated in ITO/nanopores are unaffected; the nanopores protect the copper filaments. Finally, atomic switch behaviour was obtained using these ITO and ITO/nanopores electrodes. PMID- 29259181 TI - Comparison of the effect of omega-3 supplements and fresh fish on lipid profile: a randomized, open-labeled trial. AB - BACKGROUND: Dietary fish is a rich source of Omega-3 poly-unsaturated fatty acids (PUFAs). These compounds may have protective effect against cardiovascular events possibly by modifying lipid profiles. Consequently, fish oil supplements are produced commercially to complement low fish intake. It is not clear if both interventions have similar effects. The aim of this trial was to compare the anti hyperlipidemic effect of omega3 fatty acid supplements with fresh fish. METHOD: A total of 106 patients with hyperlipidemia were randomized. One group received 2 g/day of omega-3 capsules for a period of 8 weeks and the other group received a mean of 250 g trout fish twice weekly (for dinner and lunch) for the same time period. The effects of these diets on the lipid profile after the intervention were compared between the two groups. RESULTS: Data from 48 patients in fish oil group and 47 patients from fish group was used for final analysis. In both groups, total cholesterol, non-HDL cholesterol, triglyceride (TG) levels, and Castelli I index (total cholesterol/HDL ratio) were reduced significantly following the treatment; however, dietary-fish intake had a more pronounced effect (-85.08 +/- 74.82 vs. -30.75 +/- 89.00, P < 0.001; 75.06 +/- 35.43 vs. 16.93 +/- 40.21, P < 0.001; -66.55 +/- 30.79 vs. -12.7 +/- 35.48, P = 0.003; and 0.77 +/- 1.39 vs. -3.02 +/- 1.85, P < 0.001; respectively). HDL level was increased in both groups with a higher effect in dietary fish group (4.47 +/- 7.83 vs. 8.51 +/- 8.79, P = 0.022). Atherogenic (Log [TG/HDL ratio]) and Castelli II (LDL/HDL ratio) indices did not change in fish oil group while were reduced significantly by fresh fish consumption (-0.04 +/- 0.27 vs. -0.26 +/- 0.17, P < 0.001; and 0.15 +/- 0.7 vs. -1.32 +/- 1.15, P < 0.001, respectively). LDL level was increased in the supplementation group, while it was significantly reduced in the dietary-fish group (+18.7 +/- 24.97 vs. -22.75 +/- 27.28, P < 0.001). CONCLUSION: Consumption of fresh fish seems to be superior in positively modifying the lipid profiles which may have important translations in the occurrence of cardiovascular events. PMID- 29259183 TI - Nanoscale evolution of interface morphology during electrodeposition. AB - Control of interfacial morphology in electrochemical processes is essential for applications ranging from nanomanufacturing to batteries. Here, we quantify the evolution of an electrochemical growth front, using liquid cell electron microscopy to access unexplored length and time scales. During galvanostatic deposition of copper from an acidic electrolyte, we find that the growth front initially evolves consistent with kinetic roughening theory. Subsequently, it roughens more rapidly, consistent with diffusion-limited growth physics. However, the onset of roughening is strongly delayed compared to expectations, suggesting the importance of lateral diffusion of ions. Based on these growth regimes, we discuss morphological control and demonstrate the effects of two strategies, pulse plating and the use of electrolyte additives. PMID- 29259185 TI - A Micromagnetic Protocol for Qualitatively Predicting Stochastic Domain Wall Pinning. AB - Understanding dynamically-induced stochastic switching effects in soft ferromagnetic nanowires is a critical challenge for realising spintronic devices with deterministic switching behaviour. Here, we present a micromagnetic simulation protocol for qualitatively predicting dynamic stochastic domain wall (DW) pinning/depinning at artificial defect sites in Ni80Fe20 nanowires, and demonstrate its abilities by correlating its predictions with the results of focused magneto-optic Kerr effect measurements. We analyse DW pinning configurations in both thin nanowires (t = 10 nm) and thick nanowires (t = 40 nm) with both single (asymmetric) and double (symmetric) notches, showing how our approach provides understanding of the complex DW-defect interactions at the heart of stochastic pinning behaviours. Key results explained by our model include the total suppression of stochastic pinning at single notches in thick nanowires and the intrinsic stochasticity of pinning at double notches, despite their apparent insensitivity to DW chirality. PMID- 29259184 TI - Early Development of Network Oscillations in the Ferret Visual Cortex. AB - Although oscillations during development have been characterized in a wide range of neural systems, little is known about the interaction between these network oscillations and neuronal spiking, and the interactions among different oscillation frequencies. Here we recorded the spontaneous and visual-elicited local field potential (LFP) and multi-unit activity (MUA) in the visual cortex of freely-moving juvenile ferrets before and after eye-opening. We found that both the spontaneous and visually-elicited LFP power was increased after eye-opening, especially in higher frequency bands (>30 Hz). Spike LFP phase coupling was decreased for lower frequency bands (theta and alpha) but slightly increased for higher frequencies (high-gamma band). A similar shift towards faster frequencies also occurred for phase-amplitude coupling; with maturation, the coupling of the theta/alpha/beta band amplitude to the delta phase was decreased and the high gamma amplitude coupling to theta/alpha phase was increased. This shift towards higher frequencies was also reflected in the visual responses; the LFP oscillation became more entrained by visual stimulation with higher frequencies (>10 Hz). Taken together, these results suggest gamma oscillation as a signature of the maturation of cortical circuitry. PMID- 29259186 TI - Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. AB - Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies. PMID- 29259188 TI - Reservoir computing using dynamic memristors for temporal information processing. AB - Reservoir computing systems utilize dynamic reservoirs having short-term memory to project features from the temporal inputs into a high-dimensional feature space. A readout function layer can then effectively analyze the projected features for tasks, such as classification and time-series analysis. The system can efficiently compute complex and temporal data with low-training cost, since only the readout function needs to be trained. Here we experimentally implement a reservoir computing system using a dynamic memristor array. We show that the internal ionic dynamic processes of memristors allow the memristor-based reservoir to directly process information in the temporal domain, and demonstrate that even a small hardware system with only 88 memristors can already be used for tasks, such as handwritten digit recognition. The system is also used to experimentally solve a second-order nonlinear task, and can successfully predict the expected output without knowing the form of the original dynamic transfer function. PMID- 29259187 TI - The interhemispheric CA1 circuit governs rapid generalisation but not fear memory. AB - Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1-conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1-conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1-conCA1 circuit. PMID- 29259190 TI - Publisher Correction: Manipulation of Rat Movement via Nigrostriatal Stimulation Controlled by Human Visually Evoked Potentials. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29259189 TI - Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events. AB - Proteasome inhibitors, e.g. Bortezomib (BTZ) and Carfilzomib (CFZ), have demonstrated clinical efficacy against haematological cancers. Interestingly, several adverse effects are less common, compared to BTZ, in patients treated with CFZ. As the molecular details of these observations remain not well understood we assayed the pathophysiological effects of CFZ vs. BTZ in the Drosophila experimental model. Mass Spectrometry analyses showed that neither CFZ nor BTZ are hydrolysed in flies' tissues, while at doses inducing similar inhibition of the rate limiting for protein breakdown chymotrypsin-like (CT-L) proteasomal activity, CFZ treatment resulted in less intense increase of oxidative stress or activation of antioxidant and proteostatic modules. Also, despite comparable cardiotoxicity likely due to disrupted mitochondrial function, CFZ did not affect developmental processes, showed minimal neuromuscular defects and reduced to a lesser extent flies' healthspan. Studies in flies, human cancer cell lines and blood cells isolated from Multiple Myeloma patients treated with CFZ or BTZ revealed, that the increased BTZ toxicity likely relates to partial co inhibition of the caspase-like (C-L) proteasomal activity Supportively, co treating flies with CFZ and a C-L selective proteasome inhibitor exacerbated CFZ mediated toxicity. Our findings provide a reasonable explanation for the differential adverse effects of CFZ and BTZ in the clinic. PMID- 29259191 TI - Generalized laws of thermodynamics in the presence of correlations. AB - The laws of thermodynamics, despite their wide range of applicability, are known to break down when systems are correlated with their environments. Here we generalize thermodynamics to physical scenarios which allow presence of correlations, including those where strong correlations are present. We exploit the connection between information and physics, and introduce a consistent redefinition of heat dissipation by systematically accounting for the information flow from system to bath in terms of the conditional entropy. As a consequence, the formula for the Helmholtz free energy is accordingly modified. Such a remedy not only fixes the apparent violations of Landauer's erasure principle and the second law due to anomalous heat flows, but also leads to a generally valid reformulation of the laws of thermodynamics. In this information-theoretic approach, correlations between system and environment store work potential. Thus, in this view, the apparent anomalous heat flows are the refrigeration processes driven by such potentials. PMID- 29259192 TI - Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors. AB - Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores >=20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis. PMID- 29259193 TI - JAK/STAT and TGF-beta activation as potential adverse outcome pathway of TiO2NPs phototoxicity in Caenorhabditis elegans. AB - Titanium dioxide nanoparticles (TiO2NPs) are widely used nanoparticles, whose catalytic activity is mainly due to photoactivation. In this study, the toxicity of TiO2NPs was investigated on the nematode Caenorhabditis elegans, with and without UV activation. Comparative analyses across the four treatments revealed that UV-activated TiO2NPs led to significant reproductive toxicity through oxidative stress. To understand the underlying molecular mechanism, transcriptomics and metabolomics analyses were conducted, followed by whole genome network-based pathway analyses. Differential expression analysis from microarray data revealed only 4 DEGs by exposure to TiO2NPs alone, compared to 3,625 and 3,286 DEGs by UV alone and UV-activated TiO2NPs, respectively. Pathway analyses suggested the possible involvement of the JAK/STAT and TGF-beta pathways in the phototoxicity of TiO2NPs, which correlated with the observation of increased gene expression of those pathways. Comparative analysis of C. elegans response across UV activation and TiO2NPs exposure was performed using loss-of function mutants of genes in these pathways. Results indicated that the JAK/STAT pathway was specific to TiO2NPs, whereas the TGF-beta pathway was specific to UV. Interestingly, crosstalk between these pathways was confirmed by further mutant analysis. We consider that these findings will contribute to understand the molecular mechanisms of toxicity of TiO2NPs in the natural environment. PMID- 29259194 TI - Estimation of land-surface evaporation at four forest sites across Japan with the new nonlinear complementary method. AB - Evaporation from land surfaces is a critical component of the Earth water cycle and of water management strategies. The complementary method originally proposed by Bouchet, which describes a linear relation between actual evaporation (E), potential evaporation (Epo) and apparent potential evaporation (Epa) based on routinely measured weather data, is one of the various methods for evaporation calculation. This study evaluated the reformulated version of the original method, as proposed by Brutsaert, for forest land cover in Japan. The new complementary method is nonlinear and based on boundary conditions with strictly physical considerations. The only unknown parameter (alpha e) was for the first time determined for various forest covers located from north to south across Japan. The values of alpha e ranged from 0.94 to 1.10, with a mean value of 1.01. Furthermore, the calculated evaporation with the new method showed a good fit with the eddy-covariance measured values, with a determination coefficient of 0.78 and a mean bias of 4%. Evaluation results revealed that the new nonlinear complementary relation performs better than the original linear relation in describing the relationship between E/Epa and Epo/Epa, and also in depicting the asymmetry variation between Epa/Epo and E/Epo. PMID- 29259195 TI - Sixteen isostructural phosphonate metal-organic frameworks with controlled Lewis acidity and chemical stability for asymmetric catalysis. AB - Heterogeneous catalysts typically lack the specific steric control and rational electronic tuning required for precise asymmetric catalysis. Here we demonstrate that a phosphonate metal-organic framework (MOF) platform that is robust enough to accommodate up to 16 different metal clusters, allowing for systematic tuning of Lewis acidity, catalytic activity and enantioselectivity. A total of 16 chiral porous MOFs, with the framework formula [M3 L 2(solvent)2] that have the same channel structures but different surface-isolated Lewis acid metal sites, are prepared from a single phosphono-carboxylate ligand of 1,1'-biphenol and 16 different metal ions. The phosphonate MOFs possessing tert-butyl-coated channels exhibited high thermal stability and good tolerances to boiling water, weak acid and base. The MOFs provide a versatile family of heterogeneous catalysts for asymmetric allylboration, propargylation, Friedel-Crafts alkylation and sulfoxidation with good to high enantioselectivity. In contrast, the homogeneous catalyst systems cannot catalyze the test reactions enantioselectively. PMID- 29259196 TI - Inhaled nitrous oxide can reduce the pain perception in post Caldwell-Luc operation patients-a randomised trial. AB - To assess the efficiency of inhaled nitrous oxide (N2O) for the reduce the perception pain in extraction of iodoform gauze packing strips in post Caldwell Luc operation patients. This randomized single blind trial included a total of 47 patients, aged between 14-82 years, in which undergoing radical maxillary sinusotomy. Based on the randomization procedure, patients were treated with (experimental) or without (control) inhaled N2O. The visual analogue scale scores (VAS scores) of the pain perception and the headache duration time were comparatively studied. The average VAS score for pain perception was 3.92 in the N2O group and 7.87 in the control group. The average headache duration time was 0.12 hour in the N2O group and 13.09 hours in the control group. Both VAS scores for pain perception during the treatment and the average headache duration time were significantly reduced in the inhaled N2O group (P < 0.01). Reduced pain perception and headache duration time indicated that, the inhaled N2O method might be viable in extraction of iodoform gauze packing strips in post Caldwell Luc operation patients. PMID- 29259198 TI - Skyrmion electrical detection with the use of three-dimensional Topological Insulators/Ferromagnetic bilayers. AB - The effect of the magnetic skyrmion texture on the electronic transport properties of the TI surface state coupled to a thin-film FM is numerically investigated. It is shown that both Bloch (vortex) and Neel (hedgehog) skyrmion textures induce additional scattering on top of a homogeneous background FM texture which can modify the conductance of the system. The change in conductance depends on several factors including the skyrmion size, the dimensions of the FM and the exchange interaction strength. For the Neel skyrmion, the result of the interaction strongly depends on the skyrmion number N sk and the skyrmion helicity h. For both skyrmion types, significant change of the resistance can be achieved, which is in the order of kOmega. PMID- 29259197 TI - Catastrophic disassembly of actin filaments via Mical-mediated oxidation. AB - Actin filament assembly and disassembly are vital for cell functions. MICAL Redox enzymes are important post-translational effectors of actin that stereo specifically oxidize actin's M44 and M47 residues to induce cellular F-actin disassembly. Here we show that Mical-oxidized (Mox) actin can undergo extremely fast (84 subunits/s) disassembly, which depends on F-actin's nucleotide-bound state. Using near-atomic resolution cryoEM reconstruction and single filament TIRF microscopy we identify two dynamic and structural states of Mox-actin. Modeling actin's D-loop region based on our 3.9 A cryoEM reconstruction suggests that oxidation by Mical reorients the side chain of M44 and induces a new intermolecular interaction of actin residue M47 (M47-O-T351). Site-directed mutagenesis reveals that this interaction promotes Mox-actin instability. Moreover, we find that Mical oxidation of actin allows for cofilin-mediated severing even in the presence of inorganic phosphate. Thus, in conjunction with cofilin, Mical oxidation of actin promotes F-actin disassembly independent of the nucleotide-bound state. PMID- 29259200 TI - Earliest known lepisosteoid extends the range of anatomically modern gars to the Late Jurassic. AB - Lepisosteoids are known for their evolutionary conservatism, and their body plan can be traced at least as far back as the Early Cretaceous, by which point two families had diverged: Lepisosteidae, known since the Late Cretaceous and including all living species and various fossils from all continents, except Antarctica and Australia, and Obaichthyidae, restricted to the Cretaceous of northeastern Brazil and Morocco. Until now, the oldest known lepisosteoids were the obaichthyids, which show general neopterygian features lost or transformed in lepisosteids. Here we describe the earliest known lepisosteoid (Nhanulepisosteus mexicanus gen. and sp. nov.) from the Upper Jurassic (Kimmeridgian - about 157 Myr), of the Tlaxiaco Basin, Mexico. The new taxon is based on disarticulated cranial pieces, preserved three-dimensionally, as well as on scales. Nhanulepisosteus is recovered as the sister taxon of the rest of the Lepisosteidae. This extends the chronological range of lepisosteoids by about 46 Myr and of the lepisosteids by about 57 Myr, and fills a major morphological gap in current understanding the early diversification of this group. PMID- 29259199 TI - A hydrophobic anchor mechanism defines a deacetylase family that suppresses host response against YopJ effectors. AB - Several Pseudomonas and Xanthomonas species are plant pathogens that infect the model organism Arabidopsis thaliana and important crops such as Brassica. Resistant plants contain the infection by rapid cell death of the infected area through the hypersensitive response (HR). A family of highly related alpha/beta hydrolases is involved in diverse processes in all domains of life. Functional details of their catalytic machinery, however, remained unclear. We report the crystal structures of alpha/beta hydrolases representing two different clades of the family, including the protein SOBER1, which suppresses AvrBsT-incited HR in Arabidopsis. Our results reveal a unique hydrophobic anchor mechanism that defines a previously unknown family of protein deacetylases. Furthermore, this study identifies a lid-loop as general feature for substrate turnover in acyl protein thioesterases and the described family of deacetylases. Furthermore, we found that SOBER1's biological function is not restricted to Arabidopsis thaliana and not limited to suppress HR induced by AvrBsT. PMID- 29259201 TI - Magnolol inhibits venous remodeling in mice. AB - Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context - a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins. PMID- 29259202 TI - Identification of new genes associated to senescent and tumorigenic phenotypes in mesenchymal stem cells. AB - Although human mesenchymal stem cells (hMSCs) are a powerful tool for cell therapy, prolonged culture times result in replicative senescence or acquisition of tumorigenic features. To identify a molecular signature for senescence, we compared the transcriptome of senescent and young hMSCs with normal karyotype (hMSCs/n) and with a constitutional inversion of chromosome 3 (hMSC/inv). Senescent and young cells from both lineages showed differentially expressed genes (DEGs), with higher levels in senescent hMSCs/inv. Among the 30 DEGs in senescent hMSC/inv, 11 are new candidates for biomarkers of cellular senescence. The functional categories most represented in senescent hMSCs were related to cellular development, cell growth/proliferation, cell death, cell signaling/interaction, and cell movement. Mapping of DEGs onto biological networks revealed matrix metalloproteinase-1, thrombospondin 1, and epidermal growth factor acting as topological bottlenecks. In the comparison between senescent hMSCs/n and senescent hMSCs/inv, other functional annotations such as segregation of chromosomes, mitotic spindle formation, and mitosis and proliferation of tumor lines were most represented. We found that many genes categorized into functional annotations related to tumors in both comparisons, with relation to tumors being highest in senescent hMSCs/inv. The data presented here improves our understanding of the molecular mechanisms underlying the onset of cellular senescence as well as tumorigenesis. PMID- 29259204 TI - Ubiquitin Ligase Huwe1 Modulates Spermatogenesis by Regulating Spermatogonial Differentiation and Entry into Meiosis. AB - Spermatogenesis consists of a series of highly regulated processes that include mitotic proliferation, meiosis and cellular remodeling. Although alterations in gene expression are well known to modulate spermatogenesis, posttranscriptional mechanisms are less well defined. The ubiquitin proteasome system plays a significant role in protein turnover and may be involved in these posttranscriptional mechanisms. We previously identified ubiquitin ligase Huwe1 in the testis and showed that it can ubiquitinate histones. Since modulation of histones is important at many steps in spermatogenesis, we performed a complete characterization of the functions of Huwe1 in this process by examining the effects of its inactivation in the differentiating spermatogonia, spermatocytes and spermatids. Inactivation of Huwe1 in differentiating spermatogonia led to their depletion and formation of fewer pre-leptotene spermatocytes. The cell degeneration was associated with an accumulation of DNA damage response protein gammaH2AX, impaired downstream signalling and apoptosis. Inactivation of Huwe1 in spermatocytes indicated that Huwe1 is not essential for meiosis and spermiogenesis, but can result in accumulation of gammaH2AX. Collectively, these results provide a comprehensive survey of the functions of Huwe1 in spermatogenesis and reveal Huwe1's critical role as a modulator of the DNA damage response pathway in the earliest steps of spermatogonial differentiation. PMID- 29259205 TI - Action of lytic polysaccharide monooxygenase on plant tissue is governed by cellular type. AB - Lignocellulosic biomass bioconversion is hampered by the structural and chemical complexity of the network created by cellulose, hemicellulose and lignin. Biological conversion of lignocellulose involves synergistic action of a large array of enzymes including the recently discovered lytic polysaccharide monooxygenases (LPMOs) that perform oxidative cleavage of cellulose. Using in situ imaging by synchrotron UV fluorescence, we have shown that the addition of AA9 LPMO (from Podospora anserina) to cellulases cocktail improves the progression of enzymes in delignified Miscanthus x giganteus as observed at tissular levels. In situ chemical monitoring of cell wall modifications performed by synchrotron infrared spectroscopy during enzymatic hydrolysis demonstrated that the boosting effect of the AA9 LPMO was dependent on the cellular type indicating contrasted recalcitrance levels in plant tissues. Our study provides a useful strategy for investigating enzyme dynamics and activity in plant cell wall to improve enzymatic cocktails aimed at expanding lignocelluloses biorefinery. PMID- 29259206 TI - Films of Bacteria at Interfaces (FBI): Remodeling of Fluid Interfaces by Pseudomonas aeruginosa. AB - Bacteria at fluid interfaces endure physical and chemical stresses unique to these highly asymmetric environments. The responses of Pseudomonas aeruginosa PAO1 and PA14 to a hexadecane-water interface are compared. PAO1 cells form elastic films of bacteria, excreted polysaccharides and proteins, whereas PA14 cells move actively without forming an elastic film. Studies of PAO1 mutants show that, unlike solid-supported biofilms, elastic interfacial film formation occurs in the absence of flagella, pili, or certain polysaccharides. Highly induced genes identified in transcriptional profiling include those for putative enzymes and a carbohydrate metabolism enzyme, alkB2; this latter gene is not upregulated in PA14 cells. Notably, PAO1 mutants lacking the alkB2 gene fail to form an elastic layer. Rather, they form an active film like that formed by PA14. These findings demonstrate that genetic expression is altered by interfacial confinement, and suggest that the ability to metabolize alkanes may play a role in elastic film formation at oil-water interfaces. PMID- 29259207 TI - Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury. AB - Penile erection is a neurovascular event and neurologic or vascular disturbances are major causes of erectile dysfunction (ED). Radical prostatectomy for prostate cancer not only induces cavernous nerve injury (CNI) but also results in cavernous angiopathy, which is responsible for poor responsiveness to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2) is known as a Wnt signaling antagonist and is reported to promote mature and stable blood vessel formation. Here, we demonstrated in CNI mice that overexpression of DKK2 by administering DKK2 protein or by using DKK2-Tg mice successfully restored erectile function: this recovery was accompanied by enhanced neural regeneration through the secretion of neurotrophic factors, and restoration of cavernous endothelial cell and pericyte content. DKK2 protein also promoted neurite outgrowth in an ex vivo major pelvic ganglion culture experiment and enhanced tube formation in primary cultured mouse cavernous endothelial cells and pericytes co-culture system in vitro. In light of critical role of neuropathy and angiopathy in the pathogenesis of radical prostatectomy-induced ED, reprogramming of damaged erectile tissue toward neurovascular repair by use of a DKK2 therapeutic protein may represent viable treatment option for this condition. PMID- 29259203 TI - The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. AB - Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones. PMID- 29259208 TI - Interaction of local solidification and remelting during dendrite coarsening - modeling and comparison with experiments. AB - The microstructural evolution of dendrite coarsening during isothermal holding is simulated using a quantitative cellular automaton (CA) model involving the mechanisms of both solidification and melting. The present model encompasses the essential aspects of thermodynamics and kinetics, particularly the evolution/influence of composition, temperature, and curvature, leading to valid simulations of simultaneous solidification and melting. Model validation is performed through a comparison of the CA simulations with analytical predictions for a liquid pool migrating in the mushy zone of a SCN-0.3 wt.% ACE alloy due to temperature gradient zone melting. The model is applied to simulate the microstructural evolution of columnar dendrites of a SCN-2.0 wt.% ACE alloy during isothermal holding in a mushy zone. The simulation results are compared with those of a previous CA model that does not include the melting mechanism under otherwise identical conditions. The role of melting for dendrite coarsening is quantified, showing how the melting influences the coarsening process. The present model effectively reproduces the typical dendrite coarsening features as observed in experiments reported in the literature. The simulations reveal how local solidification and melting stimulate each other through the complicated interactions between phase transformation, interface shape variation, and solute diffusion. PMID- 29259209 TI - Hemographic indices are associated with mortality in acute heart failure. AB - Hemographic indices have been associated with clinical outcomes in patients with chronic heart failure. We therefore investigated the prognostic values of hemographic indices in patients hospitalized for acute heart failure (AHF). Patients hospitalized primarily for AHF were drawn from an intramural registry. Hemographic indices, including white blood cell counts, neutrophil counts, neutrophil-to-lymphocyte ratio, reciprocal of lymphocyte (RL) and platelet-to lymphocyte ratio were recorded. Among a total of 1923 participants (mean age 76 +/- 12 years, 68% men), 875 patients died during a mean follow-up of 28.6 +/- 20.7 months. Except for white blood cell counts, all the other hemographic indices were related to mortality, independently. In a forward stepwise Cox regression analysis among hemographic indices, RL was the strongest predictor (HR and 95% CI per-1SD:1.166,1.097-1.240) for mortality, after accounting for confounders. However, conditioned on the survivals, the hemographic indices were independently related to mortality within 3 years of follow-up, rather than beyond. Hemographic indices were independent risk factors of mortality in patients hospitalized for AHF, especially in patients with impaired left ventricular systolic function. As an acute presentation of inflammation, hemographic indices might be useful to identify subjects at risk of mortality soon after the index hospitalization. PMID- 29259210 TI - Efficient Direct Formic Acid Fuel Cells (DFAFCs) Anode Derived from Seafood waste: Migration Mechanism. AB - Commercial Pt/C anodes of direct formic acid fuel cells (DFAFCs) get rapidly poisoned by in-situ generated CO intermediates from formic acid non-faradaic dissociation. We succeeded in increasing the Pt nanoparticles (PtNPs) stability and activity for formic acid oxidation (DFAFCs anodic reaction) by embedding them inside a chitosan matrix obtained from seafood wastes. Atop the commercial Pt/C, formic acid (FA) is predominantly oxidized via the undesired poisoning dehydration pathway (14 times higher than the desired dehydrogenation route), wherein FA is non-faradaically dissociated to CO resulting in deactivation of the majority of the Pt active-surface sites. Surprisingly, PtNPs chemical insertion inside a chitosan matrix enhanced their efficiency for FA oxidation significantly, as demonstrated by their 27 times higher stability along with ~400 mV negative shift of the FA oxidation onset potential together with 270 times higher CO poisoning-tolerance compared to that of the commercial Pt/C. These substantial performance enhancements are believed to originate from the interaction of chitosan functionalities (e.g., NH2 and OH) with both PtNPs and FA molecules improving FA adsorption and preventing the PtNPs aggregation, besides providing the required oxygen helping with the oxidative removal of the adsorbed poisoning CO-like species at low potentials. Additionally, chitosan induced the retrieval of the Pt surface-active sites by capturing the in-situ formed poisoning CO intermediates via a so-called "migration mechanism". PMID- 29259212 TI - Three-Dimensional Bi-Continuous Nanoporous Gold/Nickel Foam Supported MnO2 for High Performance Supercapacitors. AB - A three-dimensional bi-continuous nanoporous gold (NPG)/nickel foam is developed though the electrodeposition of a gold-tin alloy on Ni foam and subsequent chemical dealloying of tin. The newly-designed 3D metal structure is used to anchor MnO2 nanosheets for high-performance supercapacitors. The formed ternary composite electrodes exhibit significantly-enhanced capacitance performance, rate capability, and excellent cycling stability. A specific capacitance of 442 Fg-1 is achieved at a scan rate of 5 mV s-1 and a relatively high mass loading of 865 MUg cm-2. After 2500 cycles, only a 1% decay is found at a scan rate of 50 mV s 1. A high power density of 3513 W kg-1 and an energy density of 25.73 Wh kg-1 are realized for potential energy storage devices. The results demonstrate that the NPG/nickel foam hybrid structure significantly improves the dispersibility of MnO2 and makes it promising for practical energy storage applications. PMID- 29259211 TI - GSTO1-1 plays a pro-inflammatory role in models of inflammation, colitis and obesity. AB - Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-inflammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct inflammatory disease models. GSTO1-1 deficiency ameliorates the inflammatory response stimulated by LPS and attenuates the inflammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 deficient mice show a more severe inflammatory response and increased escape of bacteria from the colon into the lymphatic system in a dextran sodium sulfate mediated model of inflammatory bowel disease. These responses are similar to those of TLR4 and MyD88 deficient mice in these models and confirm that GSTO1-1 is critical for a TLR4-like pro inflammatory response in vivo. In wild-type mice, we show that a small molecule inhibitor that covalently binds in the active site of GSTO1-1 can be used to ameliorate the inflammatory response to LPS. Our findings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of inflammation and suggest their possible application in the treatment of a range of inflammatory conditions. PMID- 29259213 TI - High Energy Density in Azobenzene-based Materials for Photo-Thermal Batteries via Controlled Polymer Architecture and Polymer-Solvent Interactions. AB - Energy densities of ~510 J/g (max: 698 J/g) have been achieved in azobenzene based syndiotactic-rich poly(methacrylate) polymers. The processing solvent and polymer-solvent interactions are important to achieve morphologically optimal structures for high-energy density materials. This work shows that morphological changes of solid-state syndiotactic polymers, driven by different solvent processings play an important role in controlling the activation energy of Z-E isomerization as well as the shape of the DSC exotherm. Thus, this study shows the crucial role of processing solvents and thin film structure in achieving higher energy densities. PMID- 29259214 TI - A Novel Design Approach for Self-Crack-Healing Structural Ceramics with 3D Networks of Healing Activator. AB - Self-crack-healing by oxidation of a pre-incorporated healing agent is an essential property of high-temperature structural ceramics for components with stringent safety requirements, such as turbine blades in aircraft engines. Here, we report a new approach for a self-healing design containing a 3D network of a healing activator, based on insight gained by clarifying the healing mechanism. We demonstrate that addition of a small amount of an activator, typically doped MnO localised on the fracture path, selected by appropriate thermodynamic calculation significantly accelerates healing by >6,000 times and significantly lowers the required reaction temperature. The activator on the fracture path exhibits rapid fracture-gap filling by generation of mobile supercooled melts, thus enabling efficient oxygen delivery to the healing agent. Furthermore, the activator promotes crystallisation of the melts and forms a mechanically strong healing oxide. We also clarified that the healing mechanism could be divided to the initial oxidation and additional two stages. Based on bone healing, we here named these stages as inflammation, repair, and remodelling stages, respectively. Our design strategy can be applied to develop new lightweight, self-healing ceramics suitable for use in high- or low-pressure turbine blades in aircraft engines. PMID- 29259215 TI - Site-specific chromosomal gene insertion: Flp recombinase versus Cas9 nuclease. AB - Site-specific recombination systems like those based on the Flp recombinase proved themselves as efficient tools for cell line engineering. The recent emergence of designer nucleases, especially RNA guided endonucleases like Cas9, has considerably broadened the available toolbox for applications like targeted transgene insertions. Here we established a recombinase-mediated cassette exchange (RMCE) protocol for the fast and effective, drug-free isolation of recombinant cells. Distinct fluorescent protein patterns identified the recombination status of individual cells. In derivatives of a CHO master cell line the expression of the introduced transgene of interest could be dramatically increased almost 20-fold by subsequent deletion of the fluorescent protein gene that provided the initial isolation principle. The same master cell line was employed in a comparative analysis using CRISPR/Cas9 for transgene integration in identical loci. Even though the overall targeting efficacy was comparable, multi loci targeting was considerably more effective for Cas9-mediated transgene insertion when compared to RMCE. While Cas9 is inherently more flexible, our results also alert to the risk of aberrant recombination events around the cut site. Together, this study points at the individual strengths in performance of both systems and provides guidance for their appropriate use. PMID- 29259216 TI - Cytokine profiling in healthy children shows association of age with cytokine concentrations. AB - Cytokine-based diagnostic assays are increasingly used in research and clinical practice. Assays developed for adults such as the interferon-gamma release assay for tuberculosis show inferior performance in children. Limited evidence suggests that release of cytokines is influenced by age but normal ranges of cytokines in children are lacking. Whole blood of healthy children (0-12 years) undergoing elective/diagnostic procedures was stimulated with SEB, PHA, Candida albicans for 24 hours or left unstimulated. Concentrations of eight cytokines were measured by multiplex bead-based immunoassays and associations with age and other factors quantified by regression analysis. 271 children (median age 5.2 years) were included. In unstimulated samples IL-1ra, IP-10 and TNF-alpha concentrations decreased by up to -60% with age. Following antigen stimulation, an age associated increase (ranging from +90% to +500%) was observed for all cytokines except IL-1ra (significant for IL-4, IFN-gamma and TNF-alpha). Inter-individual variability in cytokine concentrations was large with a coefficient of variation ranging from 42% to 1412%. Despite inter-individual variation age was identified as a strong influencing factor of cytokine concentrations. Age-specific normal values need to be considered for cytokine-based diagnostic purposes. These results are relevant for development of novel cytokine-based diagnostic assays and for optimal dosing of therapeutic agents targeting cytokines. PMID- 29259217 TI - Subthalamic nucleus detects unnatural android movement. AB - An android, i.e., a realistic humanoid robot with human-like capabilities, may induce an uncanny feeling in human observers. The uncanny feeling about an android has two main causes: its appearance and movement. The uncanny feeling about an android increases when its appearance is almost human-like but its movement is not fully natural or comparable to human movement. Even if an android has human-like flexible joints, its slightly jerky movements cause a human observer to detect subtle unnaturalness in them. However, the neural mechanism underlying the detection of unnatural movements remains unclear. We conducted an fMRI experiment to compare the observation of an android and the observation of a human on which the android is modelled, and we found differences in the activation pattern of the brain regions that are responsible for the production of smooth and natural movement. More specifically, we found that the visual observation of the android, compared with that of the human model, caused greater activation in the subthalamic nucleus (STN). When the android's slightly jerky movements are visually observed, the STN detects their subtle unnaturalness. This finding suggests that the detection of unnatural movements is attributed to an error signal resulting from a mismatch between a visual input and an internal model for smooth movement. PMID- 29259218 TI - No Evidence that Knops Blood Group Polymorphisms Affect Complement Receptor 1 Clustering on Erythrocytes. AB - Clustering of Complement Receptor 1 (CR1) in the erythrocyte membrane is important for immune-complex transfer and clearance. CR1 contains the Knops blood group antigens, including the antithetical pairs Swain-Langley 1 and 2 (Sl1 and Sl2) and McCoy a and b (McCa and McCb), whose functional effects are unknown. We tested the hypothesis that the Sl and McC polymorphisms might influence CR1 clustering on erythrocyte membranes. Blood samples from 125 healthy Kenyan children were analysed by immunofluorescence and confocal microscopy to determine CR1 cluster number and volume. In agreement with previous reports, CR1 cluster number and volume were positively associated with CR1 copy number (mean number of CR1 molecules per erythrocyte). Individuals with the McC b /McC b genotype had more clusters per cell than McC a /McC a individuals. However, this association was lost when the strong effect of CR1 copy number was included in the model. No association was observed between Sl genotype, sickle cell genotype, alpha+thalassaemia genotype, gender or age and CR1 cluster number or volume. Therefore, after correction for CR1 copy number, the Sl and McCoy polymorphisms did not influence erythrocyte CR1 clustering, and the effects of the Knops polymorphisms on CR1 function remains unknown. PMID- 29259219 TI - PiT2 regulates neuronal outgrowth through interaction with microtubule-associated protein 1B. AB - PiT2 is a member of the inorganic phosphate transporter family, and is extensively expressed in the nervous system. It was found that loop7 domain of PiT2 is not required for retroviral recognition and transport function. The exact functions of loop7 remain poorly understood. Here we show that loop7 of PiT2 is necessary for the transport of PiT2 protein to the cell surface. Further, loop7 is also related to the outgrowth of neurite in Neuro2A cells interacts with the light chain 1 of microtubule-associated protein 1B (MAP1B). PiT2 with mutated MAP1B binding sites affect neurite outgrowth whereas Pi transport function deficient mutants of PiT2 do not. We also show that Drosophila dPiT interacts with microtubule-associated protein Futsch, and dPiT is crucial for the normal development of neuromuscular junctions (NMJs). These results indicate that PiT2 might participate in the regulation of neuronal outgrowth by interacting with MAP1B and independently of its Pi transport function in the nervous system. PMID- 29259220 TI - Tailored plasmon-induced transparency in attenuated total reflection response in a metal-insulator-metal structure. AB - We demonstrated tailored plasmon-induced transparency (PIT) in a metal (Au) insulator (SiO2)-metal (Ag) (MIM) structure, where the Fano interference between the MIM waveguide mode and the surface plasmon polariton (SPP) resonance mode induced a transparency window in an otherwise opaque wavenumber (k) region. A series of structures with different thicknesses of the Ag layer were prepared and the attenuated total reflection (ATR) response was examined. The height and width of the transparency window, as well as the relevant k-domain dispersion, were controlled by adjusting the Ag layer thickness. To confirm the dependency of PIT on Ag layer thickness, we performed numerical calculations to determine the electric field amplitude inside the layers. The steep k-domain dispersion in the transparency window is capable of creating a lateral beam shift known as the Goos Hanchen shift, for optical device and sensor applications. We also discuss the Fano interference profiles in a omega - k two-dimensional domain on the basis of Akaike information criteria. PMID- 29259221 TI - Active, passive, and electronic cigarette smoking is associated with asthma in adolescents. AB - The present study investigated the associations of active, passive, and electronic cigarette (E-cigarette) smoking with asthma in Korean adolescents. We used the cross-sectional study of Korea Youth Risk Behavior Web-based Survey conducted in 2011, 2012 and 2013. Active smoking was classified into 4 groups (0 days, 1-5 days, 6-19 days, and >=20 days a month). Passive smoking was also categorized into 4 groups (0 days, 1-2 days, 3-4 days, and >=5 days a week). E cigarette was defined as yes or no in the last 30 days. Age, sex, obesity, region of residence, economic level, and parental educational level were adjusted for as confounders. Smoking variables were adjusted for one another. Adjusted odd ratios (AORs) and 95% confidence intervals (CIs) were calculated using multiple logistic regression analysis with complex sampling. In total, 2.3% (4,890/216,056) of participants reported asthma in the past 12 months. Active smoking was significantly associated with asthma (AOR [95% CI] of smoking >=20 days/month = 1.57 [1.38-1.77], P < 0.001). Passive smoking was also related with asthma (AOR [95% CI] of smoking >=5 days/week = 1.40 [1.28-1.53], P < 0.001). E-cigarette showed positive relation with asthma, although the effects of past smoking history could not be excluded (AOR [95% CI] = 1.12 [1.01-1.26], P = 0.027). PMID- 29259222 TI - Proposal for nanoscale cascaded plasmonic majority gates for non-Boolean computation. AB - Surface-plasmon-polariton waves propagating at the interface between a metal and a dielectric, hold the key to future high-bandwidth, dense on-chip integrated logic circuits overcoming the diffraction limitation of photonics. While recent advances in plasmonic logic have witnessed the demonstration of basic and universal logic gates, these CMOS oriented digital logic gates cannot fully utilize the expressive power of this novel technology. Here, we aim at unraveling the true potential of plasmonics by exploiting an enhanced native functionality - the majority voter. Contrary to the state-of-the-art plasmonic logic devices, we use the phase of the wave instead of the intensity as the state or computational variable. We propose and demonstrate, via numerical simulations, a comprehensive scheme for building a nanoscale cascadable plasmonic majority logic gate along with a novel referencing scheme that can directly translate the information encoded in the amplitude and phase of the wave into electric field intensity at the output. Our MIM-based 3-input majority gate displays a highly improved overall area of only 0.636 MUm2 for a single-stage compared with previous works on plasmonic logic. The proposed device demonstrates non-Boolean computational capability and can find direct utility in highly parallel real-time signal processing applications like pattern recognition. PMID- 29259223 TI - Plasmon-actuated nano-assembled microshells. AB - We present three-dimensional microshells formed by self-assembly of densely packed 5 nm gold nanoparticles (AuNPs). Surface functionalization of the AuNPs with custom-designed mesogenic molecules drives the formation of a stable and rigid shell wall, and these unique structures allow encapsulation of cargo that can be contained, virtually leakage-free, over several months. Further, by leveraging the plasmonic response of AuNPs, we can rupture the microshells using optical excitation with ultralow power (<2 mW), controllably and rapidly releasing the encapsulated contents in less than 5 s. The optimal AuNP packing in the wall, moderated by the custom ligands and verified using small angle x-ray spectroscopy, allows us to calculate the heat released in this process, and to simulate the temperature increase originating from the photothermal heating, with great accuracy. Atypically, we find the local heating does not cause a rise of more than 50 degrees C, which addresses a major shortcoming in plasmon actuated cargo delivery systems. This combination of spectral selectivity, low power requirements, low heat production, and fast release times, along with the versatility in terms of identity of the enclosed cargo, makes these hierarchical microshells suitable for wide-ranging applications, including biological ones. PMID- 29259225 TI - Peptide Sequencing Directly on Solid Surfaces Using MALDI Mass Spectrometry. AB - There are an increasing variety of applications in which peptides are both synthesized and used attached to solid surfaces. This has created a need for high throughput sequence analysis directly on surfaces. However, common sequencing approaches that can be adapted to surface bound peptides lack the throughput often needed in library-based applications. Here we describe a simple approach for sequence analysis directly on solid surfaces that is both high speed and high throughput, utilizing equipment available in most protein analysis facilities. In this approach, surface bound peptides, selectively labeled at their N-termini with a positive charge-bearing group, are subjected to controlled degradation in ammonia gas, resulting in a set of fragments differing by a single amino acid that remain spatially confined on the surface they were bound to. These fragments can then be analyzed by MALDI mass spectrometry, and the peptide sequences read directly from the resulting spectra. PMID- 29259224 TI - Leveraging uncertainty information from deep neural networks for disease detection. AB - Deep learning (DL) has revolutionized the field of computer vision and image processing. In medical imaging, algorithmic solutions based on DL have been shown to achieve high performance on tasks that previously required medical experts. However, DL-based solutions for disease detection have been proposed without methods to quantify and control their uncertainty in a decision. In contrast, a physician knows whether she is uncertain about a case and will consult more experienced colleagues if needed. Here we evaluate drop-out based Bayesian uncertainty measures for DL in diagnosing diabetic retinopathy (DR) from fundus images and show that it captures uncertainty better than straightforward alternatives. Furthermore, we show that uncertainty informed decision referral can improve diagnostic performance. Experiments across different networks, tasks and datasets show robust generalization. Depending on network capacity and task/dataset difficulty, we surpass 85% sensitivity and 80% specificity as recommended by the NHS when referring 0-20% of the most uncertain decisions for further inspection. We analyse causes of uncertainty by relating intuitions from 2D visualizations to the high-dimensional image space. While uncertainty is sensitive to clinically relevant cases, sensitivity to unfamiliar data samples is task dependent, but can be rendered more robust. PMID- 29259226 TI - Kv4.3 Modulates the Distribution of hERG. AB - This study examines the interaction between hERG and Kv4.3. The functional interaction between hERG and Kv4.3, expressed in a heterologous cell line, was studied using patch clamp techniques, western blot, immunofluorescence, and co immunoprecipitation. Co-expression of Kv4.3 with hERG increased hERG current density (tail current after a step to +10 mV: 26 +/- 3 versus 56 +/- 7 pA/pF, p < 0.01). Kv4.3 co-expression also increased the protein expression and promoted the membrane localization of hERG. Western blot showed Kv4.3 increased hERG expression by Hsp70. hERG and Kv4.3 co-localized and co-immunoprecipitated in cultured 293 T cells, indicating physical interactions between hERG and Kv4.3 proteins in vitro. In addition, Hsp70 interacted with hERG and Kv4.3 respectively, and formed complexes with hERG and Kv4.3. The alpha subunit of Ito Kv4.3 can interact with and modify the localization of the alpha subunit of IKr hERG, thus providing potentially novel insights into the molecular mechanism of the malignant ventricular arrhythmia in heart failure. PMID- 29259227 TI - Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways. AB - Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK. PMID- 29259228 TI - Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1 mutated phenotype of human breast cancer. AB - Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype. BRCA1 promoter hypermethylation and the BRCAness phenotype of BC cell lines were also studied. The purpose of this study was to determine the metabolic signature of HBOC syndrome and TNBC patients and to evaluate the potential contribution of the metabolites identified to the genetic diagnosis of breast cancer. The present results show the existence of a differential metabolic signature for BC cells based on the BRCA1 functionality. None of the studied BC cell lines presented hypermethylation of the BRCA1 promoter region. We provide evidence of the existence of free methylated nucleotides capable of distinguishing plasma samples from HBOC patients as BRCA1-mutated and BRCA1 non-mutated, suggesting that they might be considered as BRCA1-like biomarkers for TNBC and HBOC syndrome. PMID- 29259229 TI - The pesticide flupyradifurone impairs olfactory learning in Asian honey bees (Apis cerana) exposed as larvae or as adults. AB - Relatively little attention has focused on how pesticides may affect Asian honey bees, which provide vital crop pollination services and are key native pollinators. We therefore studied the effects of a relatively new pesticide, flupyradifurone (FLU), which has been developed, in part, because it appears safer for honey bees than neonicotinoids. We tested the effects of FLU on Apis cerana olfactory learning in larvae (lower dose of 0.033 ug/larvae/day over 6 days) and, in a separate experiment, adults (lower dose of 0.066 ug/adult bee/day) at sublethal, field-realistic doses given over 3 days. A worst-case field-realistic dose is 0.44 ug/bee/day. Learning was tested in adult bees. The lower larval dose did not increase mortality, but the lower adult dose resulted in 20% mortality. The lower FLU doses decreased average olfactory learning by 74% (larval treatment) and 48% (adult treatment) and reduced average memory by 48% (larval treatment) and 22% (adult treatment) as compared to controls. FLU at higher doses resulted in similar learning impairments. The effects of FLU, a pesticide that is reported to be safer than neonicotinoids for honey bees, thus deserve greater attention. PMID- 29259230 TI - Factors influencing neurocognitive function in patients with neuroepithelial tumors. AB - Though cognitive function is proven to be an independent predictor of survival in patients with intrinsic brain tumors, cognitive functions are still rarely considered. Aim of this study was to assess neurocognitive function and to identify risk factors for neurocognitive deficits. 103 patients with primary neuroepithelial tumors who received tumor resections or biopsies were included in this prospective study. The following data was acquired: mini-mental state examination, preoperative tumor volume, WHO grade, tumor entity and location, and the Karnofsky performance status scale. Furthermore, patients participated in extensive neuropsychological testing of attentional, memory and executive functions. General factors like age, clinical status, WHO grade, tumor volume and tumor location correlated with patients' neurocognitive functions. Affection of the parietal lobe resulted in significant impairment of attention and memory functions. Frontal lobe involvement significantly affected patients' abilities in planning complex actions and novel problem solving. Patients with temporal lesions were more likely to have impaired memory and executive functions. Comparing results among neuroepithelial tumor patients enables the identification of risk factors for cognitive impairment. General parameters such as age, KPS score, tumor size, and WHO grade are apart from the respective tumor location of high importance for neurocognitive function. PMID- 29259231 TI - A Novel Cell Line Based Orthotopic Xenograft Mouse Model That Recapitulates Human Hepatoblastoma. AB - Currently, preclinical testing of therapies for hepatoblastoma (HB) is limited to subcutaneous and intrasplenic xenograft models that do not recapitulate the hepatic tumors seen in patients. We hypothesized that injection of HB cell lines into the livers of mice would result in liver tumors that resemble their clinical counterparts. HepG2 and Huh-6 HB cell lines were injected, and tumor growth was monitored with bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). Levels of human alpha-fetoprotein (AFP) were monitored in the serum of animals. Immunohistochemical and gene expression analyses were also completed on xenograft tumor samples. BLI signal indicative of tumor growth was seen in 55% of HepG2- and Huh-6-injected animals after a period of four to seven weeks. Increased AFP levels correlated with tumor growth. MRI showed large intrahepatic tumors with active neovascularization. HepG2 and Huh-6 xenografts showed expression of beta-catenin, AFP, and Glypican-3 (GPC3). HepG2 samples displayed a consistent gene expression profile most similar to human HB tumors. Intrahepatic injection of HB cell lines leads to liver tumors in mice with growth patterns and biologic, histologic, and genetic features similar to human HB tumors. This orthotopic xenograft mouse model will enable clinically relevant testing of novel agents for HB. PMID- 29259232 TI - Cardiac Depression in Pigs after Multiple Trauma - Characterization of Posttraumatic Structural and Functional Alterations. AB - The purpose of this study was to define the relationship between cardiac depression and morphological and immunological alterations in cardiac tissue after multiple trauma. However, the mechanistic basis of depressed cardiac function after trauma is still elusive. In a porcine polytrauma model including blunt chest trauma, liver laceration, femur fracture and haemorrhage serial trans thoracic echocardiography was performed and correlated with cellular cardiac injury as well as with the occurrence of extracellular histones in serum. Postmortem analysis of heart tissue was performed 72 h after trauma. Ejection fraction and shortening fraction of the left ventricle were significantly impaired between 4 and 27 h after trauma. H-FABP, troponin I and extracellular histones were elevated early after trauma and returned to baseline after 24 and 48 h, respectively. Furthermore, increased nitrotyrosine and Il-1beta generation and apoptosis were identified in cardiac tissue after trauma. Main structural findings revealed alteration of connexin 43 (Cx43) and co-translocation of Cx43 and zonula occludens 1 to the cytosol, reduction of alpha-actinin and increase of desmin in cardiomyocytes after trauma. The cellular and subcellular events demonstrated in this report may for the first time explain molecular mechanisms associated with cardiac dysfunction after multiple trauma. PMID- 29259234 TI - Optical Bloch oscillation and Zener tunneling in the fractional Schrodinger equation. AB - We demonstrate optical Bloch oscillation (OBO) and optical Zener tunneling (OZT) in the fractional Schrodinger equation (FSE) with periodic and linear potentials, numerically and theoretically. We investigate in parallel the regular Schrodinger equation and the FSE, by adjusting the Levy index, and expound the differences between the two. We find that the spreading of the OBO decreases in the fractional case, due to the diminishing band width. Increasing the transverse force, due to the linear potential, leads to the appearance of OZT, but this process is suppressed in the FSE. Our results indicate that the adjustment of the Levy index can effectively control the emergence of OBO and OZT, which can inspire new ideas in the design of optical switches and interconnects. PMID- 29259233 TI - Cardiovascular disease progression in female Zucker Diabetic Fatty rats occurs via unique mechanisms compared to males. AB - Population studies have shown that compared to diabetic men, diabetic women are at a higher risk of cardiovascular disease. However, the mechanisms underlying this gender disparity are unclear. Our studies in young murine models of type 2 diabetes mellitus (T2DM) and cardiovascular disease show that diabetic male rats develop increased cardiac fibrosis and suppression of intracardiac anti-fibrotic cytokines, while premenopausal diabetic female rats do not. This protection from cardiac fibrosis in female rats can be an estrogen-related effect. However, diabetic female rats develop early subclinical myocardial deformation, cardiac hypertrophy via elevated expression of pro-hypertrophic miR-208a, myocardial damage, and suppression of cardio-reparative Angiotensin II receptor 2 (Agtr2). Diabetic rats of both sexes exhibit a reduction in cardiac capillary density. However, diabetic female rats have reduced expression of neuropilin 1 that attenuates cardiomyopathy compared to diabetic male rats. A combination of cardiac hypertrophy and reduced capillary density likely contributed to increased myocardial structural damage in diabetic female rats. We propose expansion of existing cardiac assessments in diabetic female patients to detect myocardial deformation, cardiac hypertrophy and capillary density via non-invasive imaging, as well as suggest miR-208a, AT2R and neuropilin 1 as potential therapeutic targets and mechanistic biomarkers for cardiac disease in females. PMID- 29259236 TI - Fabrication of highly conductive graphene/ITO transparent bi-film through CVD and organic additives-free sol-gel techniques. AB - Indium tin oxide (ITO) still remains as the main candidate for high-performance optoelectronic devices, but there is a vital requirement in the development of sol-gel based synthesizing techniques with regards to green environment and higher conductivity. Graphene/ITO transparent bi-film was synthesized by a two step process: 10 wt. % tin-doped ITO thin films were produced by an environmentally friendly aqueous sol-gel spin coating technique with economical salts of In(NO3)3.H2O and SnCl4, without using organic additives, on surface free energy enhanced (from 53.826 to 97.698 mJm-2) glass substrate by oxygen plasma treatment, which facilitated void-free continuous ITO film due to high surface wetting. The chemical vapor deposited monolayer graphene was transferred onto the synthesized ITO to enhance its electrical properties and it was capable of reducing sheet resistance over 12% while preserving the bi-film surface smoother. The ITO films contain the In2O3 phase only and exhibit the polycrystalline nature of cubic structure with 14.35 +/- 0.5 nm crystallite size. The graphene/ITO bi film exhibits reproducible optical transparency with 88.66% transmittance at 550 nm wavelength, and electrical conductivity with sheet resistance of 117 Omega/sq which is much lower than that of individual sol-gel derived ITO film. PMID- 29259235 TI - Transcriptomic analysis of mitochondrial TFAM depletion changing cell morphology and proliferation. AB - Human mitochondrial transcription factor A (TFAM) has been implicated in promoting tumor growth and invasion. TFAM activates mitochondrial DNA (mtDNA) transcription, and affects nuclear gene expression through mitochondrial retrograde signaling. In this study, we investigated the effects of TFAM depletion on the morphology and transcriptome of MKN45 gastric cancer cells. Morphology alteration became visible at 12 h after TFAM knockdown: the proportion of growth-arrested polygonal cells versus oval-shaped cells increased, reaching a half-maximum at 24 h and a near-maximum at 36 h. TFAM knockdown upregulated four genes and downregulated six genes by more than threefold at 24 h and similarly at 48 h. Among them, the knockdown of CFAP65 (cilia and flagella associated protein 65) or PCK1 (cytoplasmic phosphoenolpyruvate carboxykinase) rescued the effects of TFAM depletion on cell morphology and proliferation. PCK1 was found to act downstream of CFAP65 in calcium-mediated retrograde signaling. Furthermore, mtDNA depletion by 2',3'-dideoxycytidine was sufficient for induction of CFAP65 and PCK1 expression and inhibition of cell proliferation, but oxidative phosphorylation blockade or mitochondrial membrane potential depolarization was not. Thus, the TFAM-mtDNA-calcium-CFAP65-PCK1 axis participates in mitochondrial retrograde signaling, affecting tumor cell differentiation and proliferation. PMID- 29259237 TI - Adaptation of Stability during Perturbed Walking in Parkinson's Disease. AB - Gait and balance disorders are major problems that contribute to falls among subjects with Parkinson's disease (PD). Strengthening the compensatory responses through the use of balance perturbations may improve balance in PD. To date, it is unclear how PD affects the ability to react and adapt to perturbations delivered while walking. This study aims to investigate how PD affects the ability to walk, respond to balance perturbations, and produce acute short-term effects to improve compensatory reactions and gait stability. A cable-driven robot was used to train nine patients with PD and nine age-matched controls with multidirectional waist-pull perturbations while walking on a treadmill. Margin of stability and base of support were evaluated while walking without cables and reacting to the perturbations. PD was associated with a reduced stability in the forward direction and the inability to produce proactive anticipatory adjustments. Both groups were able to improve the response to the disturbances and produce short-term aftereffects of increased gait stability once the cables were removed. A single session of perturbation-based balance training produced acute effects that ameliorated gait instability in PD. This result is encouraging for designing new therapeutic interventions that remediate falls risk. PMID- 29259238 TI - Reduction in Step Height Variation and Correcting Contrast Inversion in Dynamic AFM of WS2 Monolayers. AB - A model has been developed to account for and prevent the anomalies encountered in topographic images of transition metal dichalcogenide monolayers using dynamic atomic force microscopy (dAFM). The height of WS2 monolayers measured using dAFM appeared to be increased or decreased, resulting from the interactions between the tip and the surface. The hydrophilic SiO2 substrate appeared higher than the weakly hydrophilic WS2 when the tip amplitude was low or at a high set point (high force). Large amplitudes and low set points corrected the step height inversion, but did not recover the true step height. Removing water from the sample resulted in an order of magnitude reduced variation in step height, but the WS2 appeared inverted except at low amplitudes and high set points. Our model explains the varying step heights in dAFM of TMDs as a result of varying tip sample interactions between the sample and substrate, in the presence or absence of capillaries. To eliminate contrast inversion, high amplitudes can be used to reduce the effect of capillary forces. However, when capillaries are not present, low amplitudes and high set points produce images with proper contrast due to tool operation in the repulsive regime on both materials. PMID- 29259239 TI - Change in Land Use and Evapotranspiration in the Manas River Basin, China with Long-term Water-saving Measures. AB - Widespread application of water-saving measures, especially advanced drip irrigation technologies, may significantly impact on the land use, and further potentially alter regional ecological environments in an arid area. In this study, the remote sensing and geographic information system technology were used to analyze the LANDSAT images (1976-2015) and the MOD16 evapotranspiration data (2000-2015) in the Manas River Basin (MRB), China where the water-saving technologies have experienced the past 40 years. Our results show that the area of the cultivated land was approximately doubled from 1976 to 2015 with a dynamic degree of cultivated land ranging from 1.7% to 4%. The reclamation rates were estimated at 9.5% in 1976 and 21.8% in 2015 and the comprehensive index of land use degree shows an increasing trend in the MRB. The evapotranspiration in the MRB suggests that the cultivated land is becoming more humid while the other regions are becoming more arid. Long-term change in the land use is mainly promoted due to the multiple years' efforts on development of the water-saving technologies. This study greatly improves our understanding of the interactions between change in ecological environments and human activities and may provide policy makers guidance of sustainable development at an arid area. PMID- 29259240 TI - Persistent social isolation reflects identity and social context but not maternal effects or early environment. AB - Individuals who are well integrated into society have greater access to resources and tend to live longer. Why some individuals are socially isolated and others are not is therefore puzzling from an evolutionary perspective. Answering this question requires establishing the mix of intrinsic and contextual factors that contribute to social isolation. Using social network data spanning up to half of the median adult lifespan in a gregarious primate, we found that some measures of social isolation were modestly repeatable within individuals, consistent with a trait. By contrast, social isolation was not explained by the identity of an animal's mother or the group into which it was born. Nevertheless, age, sex and social status each played a role, as did kin dynamics and familiarity. Females with fewer close relatives were more isolated, and the more time males spent in a new group the less isolated they became, independent of their social status. These results show that social isolation results from a combination of intrinsic and environmental factors. From an evolutionary perspective, these findings suggest that social isolation could be adaptive in some contexts and partly maintained by selection. PMID- 29259241 TI - Computational detection and quantification of human and mouse neutrophil extracellular traps in flow cytometry and confocal microscopy. AB - Neutrophil extracellular traps (NETs) are extracellular defense mechanisms used by neutrophils, where chromatin is expelled together with histones and granular/cytoplasmic proteins. They have become an immunology hotspot, implicated in infections, but also in a diverse array of diseases such as systemic lupus erythematosus, diabetes, and cancer. However, the precise assessment of in vivo relevance in different disease settings has been hampered by limited tools to quantify occurrence of extracellular traps in experimental models and human samples. To expedite progress towards improved quantitative tools, we have developed computational pipelines to identify extracellular traps from an in vitro human samples visualized using the ImageStream(r) platform (Millipore Sigma, Darmstadt, Germany), and confocal images of an in vivo mouse disease model of aspergillus fumigatus pneumonia. Our two in vitro methods, tested on n = 363/n =145 images respectively, achieved holdout sensitivity/specificity 0.98/0.93 and 1/0.92. Our unsupervised method for thin lung tissue sections in murine fungal pneumonia achieved sensitivity/specificity 0.99/0.98 in n = 14 images. Our supervised method for thin lung tissue classified NETs with sensitivity/specificity 0.86/0.90. We expect that our approach will be of value for researchers, and have application in infectious and inflammatory diseases. PMID- 29259242 TI - Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration. AB - Photoreceptor death is the root cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. The biosynthetic requirement of photoreceptors is among the highest in the body, and to meet this demand, photoreceptors maintain their ability to perform aerobic glycolysis. This highly regulated form of glycolysis allows cells to efficiently budget their metabolic needs and may be a critical link between photoreceptor function and survival. Pyruvate kinase muscle isozyme 2 (PKM2) is a key regulator of aerobic glycolysis. In the present study, we characterized the effect of PKM2 deletion on baseline functioning and survival of photoreceptors over time by utilizing a photoreceptor-specific, PKM2 knockout mouse model. We found that upon PKM2 deletion, PKM1 is upregulated in the outer retina and there is increased expression of genes involved in glucose metabolism, which led to chronic degenerative changes in the outer retina of these mice. We also discovered that this metabolic reprogramming provided a survival advantage to photoreceptors in an experimental model of retinal detachment. This study strongly supports the hypothesis that reprogramming metabolism may be a novel therapeutic strategy for photoreceptor neuroprotection during acute stress. PMID- 29259244 TI - Hydrogen and nitrogen codoping of anatase TiO2 for efficiency enhancement in organic solar cells. AB - TiO2 has high chemical stability, strong catalytic activity and is an electron transport material in organic solar cells. However, the presence of trap states near the band edges of TiO2 arising from defects at grain boundaries significantly affects the efficiency of organic solar cells. To become an efficient electron transport material for organic photovoltaics and related devices, such as perovskite solar cells and photocatalytic devices, it is important to tailor its band edges via doping. Nitrogen p-type doping has attracted considerable attention in enhancing the photocatalytic efficiency of TiO2 under visible light irradiation while hydrogen n-type doping increases its electron conductivity. DFT calculations in TiO2 provide evidence that nitrogen and hydrogen can be incorporated in interstitial sites and possibly form NiHi, NiHO and NTiHi defects. The experimental results indicate that NiHi defects are most likely formed and these defects do not introduce deep level states. Furthermore, we show that the efficiency of P3HT:IC60BA-based organic photovoltaic devices is enhanced when using hydrogen-doping and nitrogen/hydrogen codoping of TiO2, both boosting the material n-type conductivity, with maximum power conversion efficiency reaching values of 6.51% and 6.58%, respectively, which are much higher than those of the cells with the as-deposited (4.87%) and nitrogen-doped TiO2 (4.46%). PMID- 29259243 TI - A hippocampo-cerebellar centred network for the learning and execution of sequence-based navigation. AB - How do we translate self-motion into goal-directed actions? Here we investigate the cognitive architecture underlying self-motion processing during exploration and goal-directed behaviour. The task, performed in an environment with limited and ambiguous external landmarks, constrained mice to use self-motion based information for sequence-based navigation. The post-behavioural analysis combined brain network characterization based on c-Fos imaging and graph theory analysis as well as computational modelling of the learning process. The study revealed a widespread network centred around the cerebral cortex and basal ganglia during the exploration phase, while a network dominated by hippocampal and cerebellar activity appeared to sustain sequence-based navigation. The learning process could be modelled by an algorithm combining memory of past actions and model-free reinforcement learning, which parameters pointed toward a central role of hippocampal and cerebellar structures for learning to translate self-motion into a sequence of goal-directed actions. PMID- 29259246 TI - Structure and Interactions of A Host Defense Antimicrobial Peptide Thanatin in Lipopolysaccharide Micelles Reveal Mechanism of Bacterial Cell Agglutination. AB - Host defense cationic Antimicrobial Peptides (AMPs) can kill microorganisms including bacteria, viruses and fungi using various modes of action. The negatively charged bacterial membranes serve as a key target for many AMPs. Bacterial cell death by membrane permeabilization has been well perceived. A number of cationic AMPs kill bacteria by cell agglutination which is a distinctly different mode of action compared to membrane pore formation. However, mechanism of cell agglutinating AMPs is poorly understood. The outer membrane lipopolysaccharide (LPS) or the cell-wall peptidoglycans are targeted by AMPs as a key step in agglutination process. Here, we report the first atomic-resolution structure of thanatin, a cell agglutinating AMP, in complex with LPS micelle by solution NMR. The structure of thanatin in complex with LPS, revealed four stranded antiparallel beta-sheet in a 'head-tail' dimeric topology. By contrast, thanatin in free solution assumed an antiparallel beta-hairpin conformation. Dimeric structure of thanatin displayed higher hydrophobicity and cationicity with sites of LPS interactions. MD simulations and biophysical interactions analyses provided mode of LPS recognition and perturbation of LPS micelle structures. Mechanistic insights of bacterial cell agglutination obtained in this study can be utilized to develop antibiotics of alternative mode of action. PMID- 29259245 TI - ATP-degrading ENPP1 is required for survival (or persistence) of long-lived plasma cells. AB - Survival of antibody-secreting plasma cells (PCs) is vital for sustained antibody production. However, it remains poorly understood how long-lived PCs (LLPCs) are generated and maintained. Here we report that ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is preferentially upregulated in bone marrow LLPCs compared with their splenic short-lived counterparts (SLPCs). We studied ENPP1-deficient mice (Enpp1 -/- ) to determine how the enzyme affects PC biology. Although Enpp1 -/- mice generated normal levels of germinal center B cells and plasmablasts in periphery, they produced significantly reduced numbers of LLPCs following immunization with T-dependent antigens or infection with plasmodium C. chabaudi. Bone marrow chimeric mice showed B cell intrinsic effect of ENPP1 selectively on generation of bone marrow as well as splenic LLPCs. Moreover, Enpp1 -/- PCs took up less glucose and had lower levels of glycolysis than those of wild-type controls. Thus, ENPP1 deficiency confers an energetic disadvantage to PCs for long-term survival and antibody production. PMID- 29259248 TI - AAV vector-meditated expression of HLA-G reduces injury-induced corneal vascularization, immune cell infiltration, and fibrosis. AB - Over 1.5 million individuals suffer from cornea vascularization due to genetic and/or environmental factors, compromising visual acuity and often resulting in blindness. Current treatments of corneal vascularization are limited in efficacy and elicit undesirable effects including, ironically, vision loss. To develop a safe and effective therapy for corneal vascularization, adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by human leukocyte antigen G (HLA-G), was investigated. Self-complementary AAV cassettes containing codon optimized HLA-G1 (transmembrane) or HLA-G5 (soluble) isoforms were validated in vitro. Then, following a corneal intrastromal injection, AAV vector transduction kinetics, using a chimeric AAV capsid, were determined in rabbits. One week following corneal trauma, a single intrastromal injection of scAAV8G9-optHLA-G1 + G5 prevented corneal vascularization, inhibited trauma-induced T-lymphocyte infiltration (some of which were CD8+), and dramatically reduced myofibroblast formation compared to control treated eyes. Biodistribution analyses suggested AAV vectors persisted only in the trauma induced corneas; however, a neutralizing antibody response to the vector capsid was observed inconsistently. The collective data demonstrate the clinical potential of scAAV8G9-optHLA-G to safely and effectively treat corneal vascularization and inhibit fibrosis while alluding to broader roles in ocular surface immunity and allogenic organ transplantation. PMID- 29259249 TI - Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation. AB - Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid beta (Abeta) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Abeta pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App NL-G F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in App NL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App NL-G-F/NL-G F cortex as Abeta amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App NL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Abeta amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD. PMID- 29259250 TI - Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1. AB - The Snail transcription factor plays as a master regulator of epithelial mesenchymal transition (EMT), one of the steps of tumor metastasis. Snail enhances expressions of a lot of mesenchymal genes including the matrix degradation enzyme matrix metalloproteinases 9 (MMP9) and the EMT transcription factor zinc finger E-box binding homeobox 1 (ZEB1), however, the underlying mechanisms are not clarified. Herein, we investigated how Snail upregulated transcription of ZEB1 and MMP9 induced by the tumor promoter 12-O-tetradecanoyl phorbol 13-acetate (TPA) in hepatoma cell HepG2. According to deletion mapping and site directed mutagenesis analysis, the TPA-responsive elements on both MMP9 and ZEB1 promoters locate on a putative EGR1 and SP1 overlapping region coupled with an upstream proposed Snail binding motif TCACA. Consistently, chromatin immunoprecipitation (ChIP) assay showed TPA triggered binding of Snail, EGR1 and SP1 on MMP9 and ZEB1 promoters. Double ChIP further indicated TPA induced association of Snail with EGR1 and SP1 on both promoters. Also, electrophoresis mobility shift assay revealed TPA enhanced binding of Snail with a MMP9 promoter fragment. According to shRNA techniques, Snail was essential for gene expression of both ZEB1 and MMP9. In conclusion, Snail transactivates genes involved in tumor progression via direct binding to a specific promoter region. PMID- 29259251 TI - BKIP-1, an auxiliary subunit critical to SLO-1 function, inhibits SLO-2 potassium channel in vivo. AB - Auxiliary subunits are often needed to tailor K+ channel functional properties and expression levels. Many auxiliary subunits have been identified for mammalian Slo1, a high-conductance K+ channel gated by voltage and Ca2+. Experiments with heterologous expression systems show that some of the identified Slo1 auxiliary subunits can also regulate other Slo K+ channels. However, it is unclear whether a single auxiliary subunit may regulate more than one Slo channel in native tissues. BKIP-1, an auxiliary subunit of C. elegans SLO-1, facilitates SLO-1 membrane trafficking and regulates SLO-1 function in neurons and muscle cells. Here we show that BKIP-1 also serves as an auxiliary subunit of C. elegans SLO-2, a high-conductance K+ channel gated by membrane voltage and cytosolic Cl- and Ca2+. Comparisons of whole-cell and single-channel SLO-2 currents in native neurons and muscle cells between worm strains with and without BKIP-1 suggest that BKIP-1 reduces chloride sensitivity, activation rate, and single-channel open probability of SLO-2. Bimolecular fluorescence complementation assays indicate that BKIP-1 interacts with SLO-2 carboxyl terminal. Thus, BKIP-1 may serve as an auxiliary subunit of SLO-2. BKIP-1 appears to be the first example that a single auxiliary subunit exerts opposite effects on evolutionarily related channels in the same cells. PMID- 29259252 TI - Image-Guided Fluorescence Endomicroscopy: From Macro- to Micro-Imaging of Radiation-Induced Pulmonary Fibrosis. AB - Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect of radiation therapy (RT) of several cancers including lung and breast cancers. Current clinical methods to assess and monitor RIPF involve diagnostic computed tomography (CT) imaging, which is restricted to anatomical macroscopic changes. Confocal laser endomicroscopy (CLE) or fluorescence endomicroscopy (FE) in combination with a fibrosis-targeted fluorescent probe allows to visualize RIPF in real-time at the microscopic level. However, a major limitation of FE imaging is the lack of anatomical localization of the endomicroscope within the lung. In this work, we proposed and validated the use of x-ray fluoroscopy-guidance in a rat model of RIPF to pinpoint the location of the endomicroscope during FE imaging and map it back to its anatomical location in the corresponding CT image. For varying endomicroscope positions, we observed a positive correlation between CT and FE imaging as indicated by the significant association between increased lung density on CT and the presence of fluorescent fiber structures with FE in RT cases compared to Control. Combining multimodality imaging allows visualization and quantification of molecular processes at specific locations within the injured lung. The proposed image-guided FE method can be extended to other disease models and is amenable to clinical translation for assessing and monitoring fibrotic damage. PMID- 29259247 TI - RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML. PMID- 29259253 TI - Industrial-age doubling of snow accumulation in the Alaska Range linked to tropical ocean warming. AB - Future precipitation changes in a warming climate depend regionally upon the response of natural climate modes to anthropogenic forcing. North Pacific hydroclimate is dominated by the Aleutian Low, a semi-permanent wintertime feature characterized by frequent low-pressure conditions that is influenced by tropical Pacific Ocean temperatures through the Pacific-North American (PNA) teleconnection pattern. Instrumental records show a recent increase in coastal Alaskan precipitation and Aleutian Low intensification, but are of insufficient length to accurately assess low frequency trends and forcing mechanisms. Here we present a 1200-year seasonally- to annually-resolved ice core record of snow accumulation from Mt. Hunter in the Alaska Range developed using annual layer counting and four ice-flow thinning models. Under a wide range of glacier flow conditions and layer counting uncertainty, our record shows a doubling of precipitation since ~1840 CE, with recent values exceeding the variability observed over the past millennium. The precipitation increase is nearly synchronous with the warming of western tropical Pacific and Indian Ocean sea surface temperatures. While regional 20th Century warming may account for a portion of the observed precipitation increase on Mt. Hunter, the magnitude and seasonality of the precipitation change indicate a long-term strengthening of the Aleutian Low. PMID- 29259254 TI - Identification of long non-coding RNAs in the immature and mature rat anterior pituitary. AB - Many long non-coding RNAs (lncRNAs) have been identified in several types of human pituitary adenomas and normal anterior pituitary, some of which are involved in the pathogenesis of pituitary adenomas. However, a systematic analysis of lncRNAs expressed at different developmental stages of normal pituitary, particularly in rats, has not been performed. Therefore, we contrasted two cDNA libraries of immature (D15) and mature (D120) anterior pituitary in rat that were sequenced on an Illumina HiSeq Xten platform, and a total of 29,568,806,352 clean reads were identified. Notably, 7039 lncRNA transcripts corresponded to 4442 lncRNA genes, and 1181 lncRNA transcripts were significantly differentially expressed in D15 and D120. In addition, 6839 protein-coding genes (<100 kb upstream and downstream) were the nearest neighbors of 4074 lncRNA genes. An interaction network of lncRNAs and the follicle-stimulating hormone beta-subunit (FSHb) gene was constructed using the lncRNATargets platform, and three novel lncRNAs were obtained. Furthermore, we detected the expression of the novel lncRNAs and ten highly expressed lncRNAs that were randomly selected through quantitative PCR (qPCR). The rat anterior pituitary lncRNA content identified in this study provides a more in-depth understanding of the roles of these lncRNAs in hormone and reproduction development and regulation in mammals. PMID- 29259255 TI - Quantitative TEM imaging of the magnetostructural and phase transitions in FeRh thin film systems. AB - Equi-atomic FeRh is a very interesting material as it undergoes a magnetostructural transition from an antiferromagnetic (AF) to a ferromagnetic (FM) phase between 75-105 degrees C. Its ability to present phase co-existence separated by domain walls (DWs) above room temperature provides immense potential for exploitation of their DW motion in spintronic devices. To be able to effectively control the DWs associated with AF/FM coexistence in FeRh thin films we must fully understand the magnetostructural transition and thermomagnetic behaviour of DWs at a localised scale. Here we present a transmission electron microscopy investigation of the transition in planar FeRh thin-film samples by combining differential phase contrast (DPC) magnetic imaging with in situ heating. We perform quantitative measurements from individual DWs as a function of temperature, showing that FeRh on NiAl exhibits thermomagnetic behaviour consistent with the transition from AF to FM. DPC imaging of an FeRh sample with HF-etched substrate reveals a state of AF/FM co-existence and shows the transition from AF to FM regions proceeds via nucleation of small vortex structures, which then grow by combining with newly nucleated vortex states into larger complex magnetic domains, until it is in a fully-FM state. PMID- 29259256 TI - UV-B antagonises shade avoidance and increases levels of the flavonoid quercetin in coriander (Coriandrum sativum). AB - Despite controlling a diverse array of regulatory processes in plants, UV-B wavelengths (280-315 nm) are attenuated by common greenhouse materials such as glass and polycarbonate and are therefore depleted in many commercial growing environments. In this study, we analysed the architecture, pigment accumulation and antioxidant capacity of coriander (Coriandrum sativum, also known as cilantro) plants grown with and without supplementary UV-B (1.5 umol m-2 s-1). We demonstrate that UV-B limits stem elongation responses to neighbour proximity perception (shade avoidance), promoting a more compact plant architecture. In addition, UV-B increased leaf quercetin content and total antioxidant capacity. Arabidopsis thaliana mutants deficient in flavonoid biosynthesis were not impaired in shade avoidance inhibition, suggesting that UV-B-induced flavonoid synthesis is not a component of this response. Our results indicate that UV-B supplementation may provide a method to manipulate the architecture, flavour and nutritional content of potted herbs whilst reducing the deleterious impacts of dense planting on product quality. PMID- 29259257 TI - Coinfection takes its toll: Sea lice override the protective effects of vaccination against a bacterial pathogen in Atlantic salmon. AB - Vaccination is considered crucial for disease prevention and fish health in the global salmon farming industry. Nevertheless, some aspects, such as the efficacy of vaccines, can be largely circumvented during natural coinfections. Sea lice are ectoparasitic copepods that can occur with a high prevalence in the field, are frequently found in co-infection with other pathogens, and are highly detrimental to fish health. The aim of this case-control study was to evaluate the interaction between the detrimental effects of coinfection and the protective effects of vaccination in fish. We used the interaction between the sea louse Caligus rogercresseyi, the bacterial pathogen Piscirickettsia salmonis, and their host, the Atlantic salmon Salmo salar, as a study model. Our results showed that coinfection decreased the accumulated survival (AS) and specific growth rate (SGR) of vaccinated fish (AS = 5.2 +/- 0.6%; SGR = -0.05 +/- 0.39%) compared to a single infection of P. salmonis (AS = 42.7 +/- 1.3%; SGR = 0.21 +/- 0.22%). Concomitantly, the bacterial load and clinical signs of disease were significantly increased in coinfected fish. Coinfection may explain the reduced efficacy of vaccines in sea cages and highlights the need to test fish vaccines in more diverse conditions rather than with a single infection. PMID- 29259258 TI - A Prospective Investigation of Body Size, Body Fat Composition and Colorectal Cancer Risk in the UK Biobank. AB - Obesity has been consistently associated with a greater colorectal cancer risk, but this relationship is weaker among women. In the UK Biobank, we investigated the associations between body size (body mass index [BMI], height, waist circumference, and waist-to-hip ratio) and body fat composition (total body fat percentage and trunk fat percentage) measurements with colorectal cancer risk among 472,526 men and women followed for 5.6 years on average. Multivariable hazard ratios (HRs) and 95% confidence intervals (95%CI) for developing colorectal cancer (2,636 incident cases) were estimated using Cox proportional hazards models. Among men, when the highest and lowest fifths were compared, BMI (HR = 1.35, 95%CI: 1.13-1.61; Ptrend < 0.0001), waist circumference (HR = 1.66, 95%CI: 1.39-1.99; Ptrend < 0.0001), waist-to-hip ratio (HR = 1.58, 95%CI: 1.31 1.91; Ptrend < 0.0001), total body fat percentage (HR = 1.27, 95%CI: 1.06-1.53; Ptrend = 0.002), and trunk fat percentage (HR = 1.31, 95%CI: 1.09-1.58; Ptrend = 0.002) were associated with greater colorectal cancer risk. For women, only waist to-hip ratio (HR for highest versus lowest fifth = 1.33, 95%CI: 1.08-1.65; Ptrend = 0.005) was positively associated with colorectal cancer risk. Greater body size (overall and abdominal adiposity) was positively associated with colorectal cancer development in men. For women, abdominal adiposity, rather than overall body size, was associated with a greater colorectal cancer risk. PMID- 29259259 TI - Cell softening in malignant progression of human lung cancer cells by activation of receptor tyrosine kinase AXL. AB - To study the role of cell softening in malignant progression, Transwell assay and atomic force microscope were used to classify six human non-small cell lung cancer cell lines into two groups: a high motility-low stiffness (HMLS) group and a low motility-high stiffness (LMHS) group. We found a significant role of activity of the AXL receptor tyrosine kinase, which belongs to the TAM (Tyro3, AXL, Mer) family, in the stimulation of motility and cell softening. HMLS cells expressed higher AXL levels than LMHS cells and contained phosphorylated AXL. H1703 LMHS cells transfected with exogenous AXL exhibited increased motility and decreased stiffness, with low levels of actin stress fibre formation. Conversely, the AXL-specific inhibitor R428 and AXL-targeting siRNA reduced motility and increased stiffness in H1299 HMLS cells. Knockdown of AXL stimulated actin stress fibre formation, which inhibited tumour formation in a mouse xenograft model. The Ras/Rac inhibitor SCH 51344, which blocks disruption of actin stress fibres, exerted similar effects to AXL inactivation. We therefore propose that the Ras/Rac pathway operates downstream of AXL. Thus, AXL activation-induced cell softening promotes malignant progression in non-small cell lung cancer and represents a key biophysical property of cancer cells. PMID- 29259260 TI - Musical pitch classes have rainbow hues in pitch class-color synesthesia. AB - Synesthesia, an anomalous blending of senses in which stimulation of one sensory modality produces sensation in a different modality, provides a unique opportunity to study how multimodal information is represented in the human brain. We investigated how pitch classes (do, re, mi, etc.) are associated with the three dimensions of color (hue, saturation, and value/brightness) in 15 subjects who possessed "pitch class-color synesthesia". Across-subject averaging of reported colors revealed that pitch classes have rainbow hues, beginning with do-red, re-yellow, and so forth, ending with si-violet, accompanied by a decrease in saturation. Enharmonic pitch classes that referred to the same pitch class with a different name produced color sensations according to the name of the base pitch class, e.g., a reddish color for do-sharp and a yellowish color for re flat. Thus the main factor producing color sensations was the name, not the sound, of the note; behavioral experiments corroborated this interpretation. Pitch class-color synesthesia represents a newly described type of synesthesia that is distinct from the well-known crossmodal association between pitch height and value/brightness. Findings suggest that the two dimensions of musical pitch, pitch class and pitch height, are mapped to the hue-saturation plane and the value/brightness dimension of color, respectively. PMID- 29259261 TI - Quantum Correlations and Coherence of Polar Symmetric Top Molecules in Pendular States. AB - We consider two ultracold polar symmetric top molecules coupled by dipole-dipole interaction in an external electric field with appreciable intensity gradient, serving as the physical carrier of quantum information. Each molecule is induced to undergo pendular oscillations under the strong static electric field. Based on the pendular states of polar symmetric top molecules as candidate qubits, we investigate the bipartite quantum correlations of the two polar molecular system for the thermal equilibrium states, characterized by negativity and quantum discord, and then analyze the corresponding coherence, measured by relative entropy and l 1 norm. Furthermore, we also examine the dynamics of the entanglement and coherence of the system in the presence of intrinsic decoherence, and explore the relations of their temporal evolution with various physical system parameters for two different initial Bell states. It is found that quantum correlations and coherence of the two polar molecules in pendular states can be manipulated by adjusting appropriate reduced variables including external electric field, dipole-dipole interaction, ambient temperature and decoherence factor. Our findings could be used for molecular quantum computing based on rotational states. PMID- 29259262 TI - Coverage-dependent essential properties of halogenated graphene: A DFT study. AB - The significant halogenation effects on the essential properties of graphene are investigated by the first-principles method. The geometric structures, electronic properties, and magnetic configurations are greatly diversified under the various halogen adsorptions. Fluorination, with the strong multi-orbital chemical bondings, can create the buckled graphene structure, while the other halogenations do not change the planar s bonding in the presence of single orbital hybridization. Electronic structures consist of the carbon-, adatom- and (carbon, adatom)-dominated energy bands. All halogenated graphenes belong to holedoped metals except that fluorinated systems are middle-gap semiconductors at sufficiently high concentration. Moreover, the metallic ferromagnetism is revealed in certain adatom distributions. The unusual hybridization-induced features are clearly evidenced in many van Hove singularities of density of states. The structure- and adatom-enriched essential properties are compared with the measured results, and potential applications are also discussed. PMID- 29259263 TI - Clinical Implications of the Autophagy Core Gene Variations in Advanced Lung Adenocarcinoma Treated with Gefitinib. AB - EGFR-TKIs show dramatic treatment benefits for advanced lung adenocarcinoma patients with activating EGFR mutations. Considering the essential role of autophagy in EGFR-TKIs treatments, we hypothesized that genetic variants in autophagy core genes might contribute to outcomes of advanced lung adenocarcinoma treated with gefitinib. We systematically examined 27 potentially functional genetic polymorphisms in 11 autophagy core genes among 108 gefitinib-treated advanced lung adenocarcinoma patients. We found that ATG10 rs10036653, ATG12 rs26538, ATG16L1 rs2241880 and ATG16L2 rs11235604 were significantly associated with survival of lung adenocarcinoma patients (all P < 0.05). Among EGFR-mutant patients, ATG5 rs688810, ATG5 rs510432, ATG7 rs8154, ATG10 rs10036653, ATG12 rs26538, ATG16L1 rs2241880 and ATG16L2 rs11235604 significantly contributed to disease prognosis. We also found that ATG5 rs510432, ATG5 rs688810, ATG10 rs10036653 and ATG10 rs1864182 were associated with primary or acquired resistance to gefitinib. Functional analyses of ATG10 rs10036653 polymorphism suggested that ATG10 A allele might increase transcription factor OCT4 binding affinity compared to the T allele in lung cancer cells. Our results indicate that autophagy core genetic variants show potential clinical implications in gefitinib treatment, especially among advanced lung adenocarcinoma patients, highlighting the possibility of patient-tailored decisions during EGFR-TKIs based on both germline and somatic variation detection. PMID- 29259264 TI - Skin immunization by microneedle patch overcomes statin-induced suppression of immune responses to influenza vaccine. AB - Recent studies indicated that in elderly individuals, statin therapy is associated with a reduced response to influenza vaccination. The present study was designed to determine effects on the immune response to influenza vaccination induced by statin administration in a mouse model, and investigate potential approaches to improve the outcome of vaccination on the background of statin therapy. We fed middle aged BALB/c mice a high fat "western" diet (WD) alone or supplemented with atorvastatin (AT) for 14 weeks, and control mice were fed with the regular rodent diet. Mice were immunized with a single dose of subunit A/Brisbane/59/07 (H1N1) vaccine, either systemically or with dissolving microneedle patches (MNPs). We observed that a greater age-dependent decline in the hemagglutinin inhibition titers occurred in systemically-immunized mice than in MNP- immunized mice. AT dampened the antibody response in the animals vaccinated by either route of vaccine delivery. However, the MNP-vaccinated AT treated animals had ~20 times higher total antibody levels to the influenza vaccine than the systemically vaccinated group one month postvaccination. We propose that microneedle vaccination against influenza provides an approach to ameliorate the immunosuppressive effect of statin therapy observed with systemic immunization. PMID- 29259265 TI - Mast cells increase adult neural precursor proliferation and differentiation but this potential is not realized in vivo under physiological conditions. AB - There is growing evidence that both peripheral and resident immune cells play an important part in regulating adult neural stem cell proliferation and neurogenesis, although the contribution of the various immune cell types is still unclear. Mast cells, a population of immune cells known for their role in the allergic response, have been implicated in the regulation of adult hippocampal neurogenesis. Mast cell-deficient c-kitW-sh/W-sh mice have previously been shown to exhibit significantly decreased adult hippocampal neurogenesis and associated learning and memory deficits. However, given that numerous other cell types also express high levels of c-kit, the utility of these mice as a reliable model of mast cell-specific depletion is questionable. We show here, using a different model of mast cell deficiency (Mcpt5CreR26DTA/DTA), that precursor proliferation and adult neurogenesis are not influenced by mast cells in vivo. Interestingly, when applied at supraphysiological doses, mast cells can activate latent hippocampal precursor cells and increase subventricular zone precursor proliferation in vitro, an effect that can be blocked with specific histamine receptor antagonists. Thus, we conclude that while both mast cells and their major chemical mediator histamine have the potential to affect neural precursor proliferation and neurogenesis, this is unlikely to occur under physiological conditions. PMID- 29259266 TI - Associations of genetic polymorphisms in pTEN/AKT/mTOR signaling pathway genes with cancer risk: A meta-analysis in Asian population. AB - : The pTEN/AKT/mTOR signaling pathways play a critical role in balancing cell proliferation, differentiation, and survival. Recent studies researched the associations of core genes in the pTEN/AKT/mTOR pathway polymorphisms with the cancer susceptibility; however, the results are inconclusive. Therefore, a systematically meta-analysis was performed to evaluate the association between the five SNPs (mTOR rs2295080 and rs2536, AKT1 rs2494750 and rs2494752, pTEN rs701848) and cancer risk by systematic review of the literature in 31 eligible studies. The results showed a significant decreased risk between rs2295080 TG, GG genotype, and GG/TG genotypes and overall cancer [TG vs.TT: OR(95% CI) = 0.82(0.76, 0.89), GG/TG vs. TT: OR(95% CI) = 0.82(0.76, 0.88), and GG vs. TG/TT: OR(95% CI) = 0.67(0.51, 0.88)] and the subgroup of urinary system cancer and digestive system cancer. Moreover, the SNP rs701848 CC, TC genotype showed significantly increased the overall cancer risk both in dominant model [CC/TC vs. TT: OR(95% CI) = 1.25(1.15, 1.36)] and recessive model [CC vs. TC/TT: OR(95% CI) = 1.20(1.09, 1.32)], and digestive system cancer and urinary system cancer. In addition, AG genotype and GG/AG genotype of rs2494752 was associated with increased risk of cancer. Therefore, this meta-analysis provided genetic risk factors for carcinogenesis and the most valid cancer prevalence estimate for Asian population. PMID- 29259268 TI - Publisher Correction: Enhanced unbiased sampling of protein dynamics using evolutionary coupling information. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29259267 TI - Dysregulation of Mir-196b in Head and Neck Cancers Leads to Pleiotropic Effects in the Tumor Cells and Surrounding Stromal Fibroblasts. AB - The miR-196 family members have been found dysregulated in different cancers. Therefore, they have been proposed as promising biomarkers and therapeutic targets. This study is the first to investigate the role of miR-196b in the development and progression of head and neck squamous cell carcinomas (HNSCC), and also the impact on the surrounding tumor microenvironment. Increased miR-196b levels were detected in 95% of primary tumors and precancerous lesions, although no significant differences were observed between non-progressing versus progressing dysplasias. Furthermore, increased levels of both miR-196a and miR 196b were successfully detected in saliva samples from HNSCC patients. The functional consequences of altered miR-196 expression were investigated in both HNSCC cell lines and cancer-associated fibroblasts (CAFs) by transfection with specific pre-miR precursors. Results showed that both miR-196a and miR-196b elicit cell-specific responses in target genes and downstream regulatory pathways, and have a distinctive impact on cell proliferation, migration and invasion. These data reveal the early occurrence and prevalence of miR-196b dysregulation in HNSCC tumorigenesis, suggesting its utility for early diagnosis and/or disease surveillance and also as a non-invasive biomarker in saliva. The pleiotropic effects of miR-196a/b in HNSCC cell subpopulations and surrounding CAFs may complicate a possible therapeutic application. PMID- 29259269 TI - Deep-learning-based ghost imaging. AB - In this manuscript, we propose a novel framework of computational ghost imaging, i.e., ghost imaging using deep learning (GIDL). With a set of images reconstructed using traditional GI and the corresponding ground-truth counterparts, a deep neural network was trained so that it can learn the sensing model and increase the quality image reconstruction. Moreover, detailed comparisons between the image reconstructed using deep learning and compressive sensing shows that the proposed GIDL has a much better performance in extremely low sampling rate. Numerical simulations and optical experiments were carried out for the demonstration of the proposed GIDL. PMID- 29259270 TI - IFNgamma induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV positive gastric carcinoma. AB - Programmed death-ligand 1 (PD-L1) acts as an immune checkpoint inhibitor in various cancers. PD-L1 is known to be more frequently expressed in EBV (+) gastric cancer (GC). However, the mechanisms underlying the regulation of PD-L1 expression in EBV (+) GC remain unclear. We investigated the basal and inducible PD-L1 expressions in GC cells. PD-L1 expression was upregulated upon treatment with IFNgamma in both EBV (-) and EBV (+) GC cells. Upon stimulation with the same concentration of IFNgamma for 24 h, EBV (+) SNU-719 cells showed dramatically higher PD-L1 expression levels by activating JAK2/STAT1/IRF-1 signaling than those of EBV (-) AGS cells. PD-L1 promoter assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that IFNgamma-inducible PD-L1 overexpression is primarily mediated by the putative IRF 1alpha site of the PD-L1 promoter in EBV (+) SNU-719 cells. Moreover, EBNA1 knockdown reduced both constitutive and IFNgamma-inducible PD-L1 promoter activity by decreasing the transcript and protein levels of JAK2 and subsequently STAT1/IRF-1/PD-L1 signaling. EBNA1 is suggested to be moderately enhance both constitutive and IFNgamma-inducible PD-L1 expression in EBV (+) GC cells. Thus, the signaling proteins and EBNA1 that regulate PD-L1 expression are potential therapeutic targets in EBV (+) GC. PMID- 29259271 TI - Clearance of a persistent picornavirus infection is associated with enhanced pro apoptotic and cellular immune responses. AB - Long-term persistent viral infections cause substantial morbidity and associated economic losses in human and veterinary contexts. Yet, the mechanisms associated with establishment of persistent infections are poorly elucidated. We investigated immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in micro-dissected compartments of the bovine nasopharynx by microarray. The use of laser-capture microdissection allowed elucidation of differential gene regulation within distinct anatomic compartments critical to FMDV infection. Analysis of samples from transitional and persistent phases of infection demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. Specifically, it was demonstrated that clearance of FMDV from the nasopharyngeal mucosa was associated with upregulation of targets associated with activation of T cell-mediated immunity. Contrastingly, gene regulation in FMDV carriers suggested inhibition of T cell activation and promotion of Th2 polarization. These findings were corroborated by immunofluorescence microscopy which demonstrated relative abundance of CD8+ T cells in the nasopharyngeal mucosa in association with clearance of FMDV. The findings presented herein emphasize that a critical balance between Th1 and Th2 -mediated immunity is essential for successful clearance of FMDV infection and should be considered for development of next generation vaccines and antiviral products. PMID- 29259272 TI - Shear-Assisted Production of Few-Layer Boron Nitride Nanosheets by Supercritical CO2 Exfoliation and Its Use for Thermally Conductive Epoxy Composites. AB - Boron nitride nanosheets (BNNS) hold the similar two-dimensional structure as graphene and unique properties complementary to graphene, which makes it attractive in application ranging from electronics to energy storage. The exfoliation of boron nitride (BN) still remains challenge and hinders the applications of BNNS. In this work, the preparation of BNNS has been realized by a shear-assisted supercritical CO2 exfoliation process, during which supercritical CO2 intercalates and diffuses between boron nitride layers, and then the exfoliation of BN layers is obtained in the rapid depressurization process by overcoming the van der Waals forces. Our results indicate that the bulk boron nitride has been successfully exfoliated into thin nanosheets with an average 6 layers. It is found that the produced BNNS is well-dispersed in isopropyl alcohol (IPA) with a higher extinction coefficient compared with the bulk BN. Moreover, the BNNS/epoxy composite used as thermal interface materials has been prepared. The introduction of BNNS results in a 313% enhancement in thermal conductivity. Our results demonstrate that BNNS produced by supercritical CO2 exfoliation show great potential applications for heat dissipation of high efficiency electronics. PMID- 29259274 TI - Gastrectomy compared to oesophagectomy for Siewert II and III gastro-oesophageal junctional cancer in relation to resection margins, lymphadenectomy and survival. AB - It is unclear whether gastrectomy or oesophagectomy offer better outcomes for gastro-oesophageal junction (GOJ) cancer. A total of 240 patients undergoing total gastrectomy (n = 85) or oesophagectomy (n = 155) for Siewert II-III GOJ adenocarcinoma were identified from a Swedish prospective population-based nationwide cohort. The surgical approaches were compared in relation to non radical resection margins (main outcome) using multivariable logistic regression, providing odds ratios (ORs) and 95% confidence intervals (CIs), mean number of removed lymph nodes with standard deviation (SD) using ANCOVA, assessing mean differences and 95% CIs, and 5-year mortality using Cox regression estimating hazard ratios (HRs) and 95% CIs. The models were adjusted for age, sex, comorbidity, tumour stage, and surgeon volume. The non-radical resection rate was 15% for gastrectomy and 14% for oesophagectomy, and the adjusted OR was 1.61 (95% CI 0.68-3.83). The mean number of lymph nodes removed was 14.2 (SD +/- 9.6) for gastrectomy and 14.2 (SD +/- 10.4) for oesophagectomy, with adjusted mean difference of 2.4 (95% CI-0.2-5.0). The 5-year mortality was 76% following gastrectomy and 75% following oesophagectomy, with adjusted HR = 1.07 (95% CI 0.78-1.47). Gastrectomy and oesophagectomy for Siewert II or III GOJ cancer seem comparable regarding tumour-free resection margins, lymph nodes removal, and 5 year survival. PMID- 29259273 TI - Increased plasma IL-17, IL-31, and IL-33 levels in chronic spontaneous urticaria. AB - Chronic spontaneous urticaria (CSU) is considered in a subset of patients to be an autoimmune disorder. Interleukin(IL)-17, IL-31, and IL-33 are involved in some immune response. The aim of this study was to quantify plasma IL-17, IL-31, and IL-33 levels in CSU patients and to examine their relationships with disease severity. Plasma IL-17, IL-31, and IL-33 concentration were measured in 51 CSU patients and 20 healthy subjects (HCs). Plasma IL-17 (P < 0.001), IL-31 (P < 0.001), and IL-33 (P < 0.001) concentrations were significantly higher in CSU patients when compared with those of HCs. Concerning UAS7, severe group of CSU patients had significantly higher IL-17 levels than the moderate and mild groups (P = 0.028 and 0.007, respectively), and significantly higher IL-33 concentrations than the mild group (P = 0.026). Regarding only pruritus, severe group of patients had significantly higher IL-31 levels than the mild group (P = 0.003). The IL-33 levels in the total IgE positive group were significantly higher than that of negative group (P = 0.010). Our results showed higher plasma levels of IL-17, IL-31, and IL-33 among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of CSU. PMID- 29259275 TI - Comparing Stroop-like and Simon Effects on Perceptual Features. AB - Stroop-like and Simon tasks produce two sources of interference in human information processing. Despite being logically similar, it is still debated whether the conflicts ensuing from the two tasks are resolved by the same or different mechanisms. In the present study, we compare two accounts of the Stroop like effect. According to the Perceptual Account, the Stroop-like effect is due to Stimulus-Stimulus congruence. According to the Decisional Account, the Stroop like effect results from the same mechanisms that produce the Simon effect, that is, Stimulus-Response compatibility. In two experiments we produced Stroop-like and Simon effects by presenting left/right-located stimuli consisting of a colored square surrounded by a frame of the same color as the square or of a different color. Results showed that discriminating either the color of the square (Experiment 1) or that of the frame (Experiment 2) yielded additive Stroop like and Simon effects. In addition, the patterns of temporal distributions of the two effects were different. These results support the Perceptual Account of the Stroop-like effect and the notion that the Stroop-like effect and the Simon effect occur at different processing stages and are attributable to different mechanisms. PMID- 29259277 TI - Dental caries in the fossil record: a window to the evolution of dietary plasticity in an extinct bear. AB - During the late Pleistocene of North America (~36,000 to 10,000 years ago), saber toothed cats, American lions, dire wolves, and coyotes competed for prey resources at Rancho La Brea (RLB). Despite the fact that the giant short-faced bear (Arctodus simus) was the largest land carnivoran present in the fauna, there is no evidence that it competed with these other carnivores for prey at the site. Here, for the first time, we report carious lesions preserved in specimens of A. simus, recovered from RLB. Our results suggest that the population of A. simus from RLB was more omnivorous than the highly carnivorous populations from the Northwest. This dietary variation may be a consequence of different competitive pressures. PMID- 29259276 TI - Long-term carbon sink in Borneo's forests halted by drought and vulnerable to edge effects. AB - Less than half of anthropogenic carbon dioxide emissions remain in the atmosphere. While carbon balance models imply large carbon uptake in tropical forests, direct on-the-ground observations are still lacking in Southeast Asia. Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha-1 per year (95% CI 0.14-0.72, mean period 1988-2010) above-ground live biomass. These results closely match those from African and Amazonian plot networks, suggesting that the world's remaining intact tropical forests are now en masse out-of-equilibrium. Although both pan-tropical and long-term, the sink in remaining intact forests appears vulnerable to climate and land use changes. Across Borneo the 1997-1998 El Nino drought temporarily halted the carbon sink by increasing tree mortality, while fragmentation persistently offset the sink and turned many edge-affected forests into a carbon source to the atmosphere. PMID- 29259279 TI - Measurement of Nanowire Optical Modes Using Cross-Polarization Microscopy. AB - A method to detect optical modes from vertical InGaAs nanowires (NWs) using cross polarization microscopy is presented. Light scattered from the optical modes in the NWs is detected by filtering out the polarized direct reflection with a crossed polarizer. A spectral peak and a valley were seen to red-shift with increasing NW diameter in the measured spectra. The peak was assigned to scattering from the TE01 optical mode and the valley was an indication of the HE11 mode, based on finite-element and scattering matrix method simulations. The cross-polarization method can be used to experimentally determine the spectral positions of the TE01 and HE11 optical modes. The modes are significantly more visible in comparison to conventional reflectance measurements. The method can be beneficial in the characterization of NW solar cells, light-emitting diodes and lasers where precise mode control is required. PMID- 29259278 TI - The Perception of Operational Sex Ratios by Voice. AB - Adult sex ratios in a local environment are linked to a wide variety of reproductive behaviors in humans and other animals. When sex ratios are biased, the more numerous sex faces increased competition for mates and is more likely to yield to the sociosexual preferences of the less numerous sex. Despite widespread evidence of the relationship between sex ratios and behavior, we know little about whether or how sex ratios are encoded and perceived. In two experiments men and women showed perceived sex ratios that correlated with actual sex ratios after 1500 ms exposures to groups of simultaneous voices. However, men perceived more female voices than women did, and women perceived more male voices than men did. Women showed better accuracy than men, but only when sex ratios departed markedly from 50%. Increasing the number of simultaneous voices reduced accuracy, but only at extreme sex ratios. Talker age also significantly affected perceived sex ratios, suggesting that perceived operational sex ratios are adaptively linked to the reproductive viability of the local population. The results suggest that listeners automatically encode vocal sex ratio information and that perceived sex ratios are influenced by characteristics of the local population and characteristics of the listener. PMID- 29259280 TI - Electrophysiology of the rhythmic defecation program in nematode Heterorhabditis megidis. AB - The nervous system controls most rhythmic behaviors, with a remarkable exception. In Caenorhabditis elegans periodic defecation rhythm does not appear to involve the nervous system. Such oscillations are studied in detail with genetic and molecular biology tools. The small size of C. elegans cells impairs the use of standard electrophysiological methods. We studied a similar rhythmic pacemaker in the noticeably larger gut cells of Heterorhabditis megidis nematode. H. megidis defecation cycle is driven by a central pattern generator (CPG) associated with unusual all-or-none hyper-polarization "action potential". The CPG cycle period depends on the membrane potential and CPG cycling also persisted in experiments where the membrane potential of gut cells was continuously clamped at steady voltage levels. The usual excitable tissue description does not include the endoderm or imply the generation of hyper-polarization spikes. The nematode gut cells activity calls for a reevaluation of the excitable cells definition. PMID- 29259281 TI - Effects of resistance exercise on endothelial progenitor cell mobilization in women. AB - This study aimed to determine the effect of a single bout of resistance exercise at different intensities on the mobilization of circulating EPCs over 24 hours in women. In addition, the angiogenic factors stromal cell-derived factor 1 (SDF 1alpha), vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1 alpha (HIF-1alpha) and erythropoietin (EPO) were measured as potential mechanisms for exercise-induced EPCs mobilization. Thirty-eight women performed a resistance exercise session at an intensity of 60% (n = 13), 70% (n = 12) or 80% (n = 13) of one repetition maximum. Each session was comprised of three sets of 12 repetitions of four exercises: bench press, dumbbell curl, dumbbell squat, and standing dumbbell upright row. Blood was sampled at baseline and immediately, 6 hours, and 24 hours post-exercise. Circulating EPC and levels of VEGF, HIF-1alpha and EPO were significantly higher after exercise (P < 0.05). The change in EPCs from baseline was greatest in the 80% group (P < 0.05), reaching the highest at 6 hours post-exercise. The change in EPCs from baseline to 6 hours post-exercise was correlated with the change in VEGF (r = 0.492, P = 0.002) and HIF-1alpha (r = 0.388, P = 0.016). In general, a dose-response relationship was observed, with the highest exercise intensities promoting the highest increases in EPCs and angiogenic factors. PMID- 29259283 TI - A 100,000 Scale Factor Radar Range. AB - The radar cross section of an object is an important electromagnetic property that is often measured in anechoic chambers. However, for very large and complex structures such as ships or sea and land clutters, this common approach is not practical. The use of computer simulations is also not viable since it would take many years of computational time to model and predict the radar characteristics of such large objects. We have now devised a new scaling technique to overcome these difficulties, and make accurate measurements of the radar cross section of large items. In this article we demonstrate that by reducing the scale of the model by a factor 100,000, and using near infrared wavelength, the radar cross section can be determined in a tabletop setup. The accuracy of the method is compared to simulations, and an example of measurement is provided on a 1 mm highly detailed model of a ship. The advantages of this scaling approach is its versatility, and the possibility to perform fast, convenient, and inexpensive measurements. PMID- 29259282 TI - Analysis of killing of growing cells and dormant and germinated spores of Bacillus species by black silicon nanopillars. AB - Black silicon (bSi) wafers with a high density of high-aspect ratio nanopillars have recently been suggested to have mechanical bactericidal activity. However, it remains unclear whether bSi with the nanopillars can kill only growing bacterial cells or also dormant spores that are harder to kill. We have reexamined the cidal activity of bSi on growing cells, dormant and germinated spores of B. subtilis, and dormant spores of several other Bacillus species by incubation on bSi wafers with and without nanopillars. We found that the bSi wafers with nanopillars were indeed very effective in rupturing and killing the growing bacterial cells, while wafers without nanopillars had no bactericidal effect. However, bSi wafers with or without nanopillars gave no killing or rupture of dormant spores of B. subtilis, Bacillus cereus or Bacillus megaterium, although germinated B. subtilis spores were rapidly killed. This work lays a foundation for novel bactericidal applications of bSi by elucidating the limits of mechanical bactericidal approaches. PMID- 29259284 TI - Measuring Temperature Induced Phase Change Kinetics in Subcutaneous Adipose Tissues Using Near Infrared Spectroscopy, MR Imaging and Spectroscopy and OCT. AB - Monitoring phase transition in adipose tissue and formation of lipid crystals is important in Cryo-procedures such as Selective Cryolipolysis (SC). We exploited a Near-Infrared Spectroscopy (NIRS) method to monitor the onset of fat phase transition (freezing/melting) in human abdominal adipose tissue. The changes in optical scattering were compared to Differential Scanning Calorimetry (DSC) measurements as the gold standard method for measuring phase transition. For some samples, concurrent in vitro measurements of optical scattering using NIRS and the MR signal parameters (T2*) as well as spectral parameters using MR Spectroscopy were performed in a 3 T MR scanner during a cooling/heating cycle. To further investigate phase-transition in adipose tissue in microscopic level, an identical cooling/heating procedure was replicated on a small piece of fat harvested from the same tissue while being imaged under Optical Coherence Tomography (OCT). For all methods, their relationship with temperature shows inflexions in a narrow range, characteristic of lipid phase transition. In particular, the good agreement between DSC and Optical measurements suggests that such NIRS methods can be used to improve dosimetry and to minimize variations of clinical outcome for cryo-procedures. PMID- 29259285 TI - Peroxisome proliferator-activated receptor alpha agonist suppresses neovascularization by reducing both vascular endothelial growth factor and angiopoietin-2 in corneal alkali burn. AB - We investigated the effect of a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist ophthalmic solution in wound healing using a rat corneal alkali burn model. After instillation of a selective agonist of PPARalpha, fenofibrate, onto the burned cornea, PPARalpha-positive cells were observed in vascular endothelial cells, and there was upregulation of mRNA of PPARalpha in corneal stroma. Fenofibrate suppressed expression of neutrophils and macrophages during the early phase, and development of neovascularization and myofibroblast generation during the late phase. Fenofibrate reduced not only mRNA expression of vascular endothelial growth factor-A but also angiopoietin-1 and angiopoietin-2. Furthermore, fenofibrate suppressed scar formation by reducing type III collagen expression. These data suggest that a PPARalpha agonist ophthalmic solution might be a new strategy for treating corneal wounds through not only anti-inflammatory effects but also by preventing neovascularization. PMID- 29259286 TI - Extracting random numbers from quantum tunnelling through a single diode. AB - Random number generation is crucial in many aspects of everyday life, as online security and privacy depend ultimately on the quality of random numbers. Many current implementations are based on pseudo-random number generators, but information security requires true random numbers for sensitive applications like key generation in banking, defence or even social media. True random number generators are systems whose outputs cannot be determined, even if their internal structure and response history are known. Sources of quantum noise are thus ideal for this application due to their intrinsic uncertainty. In this work, we propose using resonant tunnelling diodes as practical true random number generators based on a quantum mechanical effect. The output of the proposed devices can be directly used as a random stream of bits or can be further distilled using randomness extraction algorithms, depending on the application. PMID- 29259287 TI - Synergistic enhancing effect for mechanical and electrical properties of tungsten copper composites using spark plasma infiltrating sintering of copper-coated graphene. AB - Successful applications of WCu alloys in high voltage electrical switches require their high strength and excellent conductivity. Unfortunately, the strategies for increasing their strength such as doping with fine particles and alloying often significantly decrease their conductivity. In this paper, we developed a new pathway for fabricating WCu alloys using spark plasma infiltrating sintering of copper-coated graphene (Cu@Gr) composite powders. Cu@Gr was found to partially prevent the formation of WC after sintering, and graphene was uniformly distributed on the surfaces of network Cu phases. Electrical conductivity of 38.512 M.S/m, thermal conductivity of 264 W.m-1.K-1 and microhardness of 278 HV were achieved for the sintered WCu composites doped with only 0.8 wt.% Cu@Gr powders, which showed 95.3%, 24.3%, 28% enhancement compared with those from the conventional sintering using the undoped WCu powders. PMID- 29259288 TI - The role of the strain induced population imbalance in Valley polarization of graphene: Berry curvature perspective. AB - Real magnetic and lattice deformation gauge fields have been investigated in honeycomb lattice of graphene. The coexistence of these two gauges will induce a gap difference between two valley points (K and K') of system. This gap difference allows us to study the possible topological valley Hall current and valley polarization in the graphene sheet. In the absence of magnetic field, the strain alone could not generate a valley polarization when the Fermi energy coincides exactly with the Dirac points. Since in this case there is not any imbalance between the population of the valley points. In other words each of these gauges alone could not induce any topological valley-polarized current in the system at zero Fermi energy. Meanwhile at non-zero Fermi energies population imbalance can be generated as a result of the external strain even at zero magnetic field. In the context of Berry curvature within the linear response regime the valley polarization (both magnetic free polarization, Pi0, and field dependent response function, chi alpha ) in different values of gauge fields of lattice deformation has been obtained. PMID- 29259289 TI - Resolution of habitat-associated ecogenomic signatures in bacteriophage genomes and application to microbial source tracking. AB - Just as the expansion in genome sequencing has revealed and permitted the exploitation of phylogenetic signals embedded in bacterial genomes, the application of metagenomics has begun to provide similar insights at the ecosystem level for microbial communities. However, little is known regarding this aspect of bacteriophage associated with microbial ecosystems, and if phage encode discernible habitat-associated signals diagnostic of underlying microbiomes. Here we demonstrate that individual phage can encode clear habitat related 'ecogenomic signatures', based on relative representation of phage encoded gene homologues in metagenomic data sets. Furthermore, we show the ecogenomic signature encoded by the gut-associated phiB124-14 can be used to segregate metagenomes according to environmental origin, and distinguish 'contaminated' environmental metagenomes (subject to simulated in silico human faecal pollution) from uncontaminated data sets. This indicates phage-encoded ecological signals likely possess sufficient discriminatory power for use in biotechnological applications, such as development of microbial source tracking tools for monitoring water quality. PMID- 29259290 TI - The complex resistomes of Paenibacillaceae reflect diverse antibiotic chemical ecologies. AB - The ecology of antibiotic resistance involves the interplay of a long natural history of antibiotic production in the environment, and the modern selection of resistance in pathogens through human use of these drugs. Important components of the resistome are intrinsic resistance genes of environmental bacteria, evolved and acquired over millennia, and their mobilization, which drives dissemination in pathogens. Understanding the dynamics and evolution of resistance across bacterial taxa is essential to address the current crisis in drug-resistant infections. Here we report the exploration of antibiotic resistance in the Paenibacillaceae prompted by our discovery of an ancient intrinsic resistome in Paenibacillus sp. LC231, recovered from the isolated Lechuguilla cave environment. Using biochemical and gene expression analysis, we have mined the resistome of the second member of the Paenibacillaceae family, Brevibacillus brevis VM4, which produces several antimicrobial secondary metabolites. Using phylogenomics, we show that Paenibacillaceae resistomes are in flux, evolve mostly independent of secondary metabolite biosynthetic diversity, and are characterized by cryptic, redundant, pseudoparalogous, and orthologous genes. We find that in contrast to pathogens, mobile genetic elements are not significantly responsible for resistome remodeling. This offers divergent modes of resistome development in pathogens and environmental bacteria. PMID- 29259291 TI - Whole transcriptome profiling reveals major cell types in the cellular immune response against acute and chronic active Epstein-Barr virus infection. AB - Epstein-Barr virus (EBV) is a common human pathogen that infects over 95% of the population worldwide. In the present study, the whole transcriptome microarray data were generated from peripheral blood mononuclear cells from Chinese children with acute infectious mononucleosis (AIM) and chronic active EBV infection (CAEBV) that were also compared with a publicly available microarray dataset from a study of American college students with AIM. Our study characterized for the first time a broad spectrum of molecular signatures in AIM and CAEBV. The key findings from the transcriptome profiling were validated with qPCR and flow cytometry assays. The most important finding in our study is the discovery of predominant gammadelta TCR expression and gammadelta T cell expansion in AIM. This finding, in combination with the striking up-regulation of CD3, CD8 and CD94, suggests that CD8+ T cells and CD94+ NK cells may play a major role in AIM. Moreover, the unique up-regulation of CD64A/B and its significant correlation with the monocyte marker CD14 was observed in CAEBV and that implies an important role of monocytes in CAEBV. In conclusion, our study reveals major cell types (particularly gammadelta T cells) in the host cellular immune response against AIM and CAEBV. PMID- 29259292 TI - Maintenance use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk. AB - BACKGROUND: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may have a preventive effect against prostate cancer. However, evidence is limited and still controversial, especially considering non-aspirin non-steroidal anti inflammatory drugs (NSAIDs). METHODS: Swedish nationwide population-based cohort study including all long-term (>=180 days) adult male users of aspirin (n = 419,931) or NSAIDs (n = 223,437) followed from the first dispense date until the first cancer diagnosis, death or 31 December 2012, whichever occurred first. The risk of prostate cancer was measured as standardized incidence ratios (SIR) and 95% confidence intervals (CI), assessing duration of use, age and concomitant statins intake, comparing to the general male background population of the same age in Sweden. RESULTS: The overall SIR suggests that maintenance use of aspirin decreases the risk of prostate cancer (SIR = 0.87, 95% CI 0.85-0.88), in particular if used >=5 years (SIR = 0.31, 95% CI 0.30-0.32). The overall risk was decreased (SIR = 0.87, 95% CI 0.85-0.90) among other NSAIDs users, and again in particular among longer-term users (>=3 years) with SIR = 0.58 (95% CI 0.53 0.63). When statins users were excluded from all aspirin users, there was no remaining association with prostate cancer (SIR = 0.99, 95% CI 0.96-1.02), only if taken >=5 years (SIR = 0.31, 95% CI 0.29-0.34). For non-aspirin NSAIDs users, the protective effect remained after exclusion of statins users (SIR = 0.92, 95% CI 0.88-0.95). CONCLUSIONS: This population-based cohort study provides evidence for a protective effect of aspirin and other NSAIDs against prostate cancer, in particular for longer durations of use, yet concomitant use of statins strongly influences the risk among aspirin users. PMID- 29259293 TI - Prostate-specific antigen (PSA) density in the diagnostic algorithm of prostate cancer. AB - BACKGROUND: Screening for prostate cancer using prostate-specific antigen (PSA) alone leads to un-necessary biopsying and overdiagnosis. PSA density is easily accessible, but early evidence on its use for biopsy decisions was conflicting and use of PSA density is not commonly recommended in guidelines. METHODS: We analyzed biopsy outcomes in 5291 men in the population-based STHLM3 study with PSA >= 3 ng/ml and ultrasound-guided prostate volume measurements by using percentages and regression models. PSA density was calculated as total PSA (ng/ml) divided by prostate volume (ml). Main endpoint was clinically significant cancer (csPCa) defined as Gleason Score >= 7. RESULTS: The median PSA-density was 0.10 ng/ml2 (IQR 0.075-0.14). PSA-density was associated with the risk of finding csPCa both with and without adjusting for the additional clinical information age, family history, previous biopsies, total PSA and free/total PSA (OR 1.06; 95% CI:1.05-1.07 and OR 1.07, 95% CI 1.06-1.08). Discrimination for csPCa was better when PSA density was added to a model with additional clinical information (AUC 0.75 vs. 0.73, P < 0.05). The proportion of men with Gleason Score 6 (ISUP 1) was similar across stratas of PSA-density. Omitting prostate biopsy for men with PSA-density <=0.07 ng/ml2 would save 19.7% of biopsy procedures, while missing 6.9% of csPCa. PSA-density cutoffs of 0.10 ng/ml2 and 0.15 ng/ml2 resulted in detection of 77% (729/947) and 49% (461/947) of Gleason Score >=7 tumors. CONCLUSIONS: PSA-density might inform biopsy decisions, and spare some men from the morbidity associated with a prostate biopsy and diagnosis of low grade prostate cancer. PMID- 29259294 TI - 20 years-A retrospective of prostate cancer and prostatic diseases. PMID- 29259295 TI - CRISPR/Cas9-based knockouts reveal that CpRLP1 is a negative regulator of the sex pheromone PR-IP in the Closterium peracerosum-strigosum-littorale complex. AB - Heterothallic strains of the Closterium peracerosum-strigosum-littorale (C. psl.) complex have two sexes, mating-type plus (mt+) and mating-type minus (mt-). Conjugation between these two sexes is regulated by two sex pheromones, protoplast-release-inducing protein (PR-IP) and PR-IP Inducer, which are produced by mt+ and mt- cells, respectively. PR-IP mediates the release of protoplasts from mt- cells during mating. In this study, we examined the mechanism of action of CpRLP1 (receptor-like protein 1), which was previously identified in a cDNA microarray analysis as one of the PR-IP-inducible genes. Using CRISPR/Cas9 technology, we generated CpRLP1 knockout mutants in mt- cells of the C. psl. complex. When the knockout mt- cells were mixed with wild-type mt+ cells, conjugation was severely reduced. Many cells released protoplasts without pairing, suggesting a loss of synchronization between the two mating partners. Furthermore, the knockout mutants were hypersensitive to PR-IP. We conclude that CpRLP1 is a negative regulator of PR-IP that regulates the timing of protoplast release in conjugating C. psl. cells. As the first report of successful gene knockout in the class Charophyceae, this study provides a basis for research aimed at understanding the ancestral roles of genes that are indispensable for the development of land plants. PMID- 29259296 TI - Surface molecular structure defects and laser-induced damage threshold of fused silica during a manufacturing process. AB - Laser induced damage of fused silica is a serious problem for high power laser systems, and damage precursors are mainly induced by manufacturing processes. In this work, fused silica samples were prepared from a manufacturing process including grinding, polishing and etching procedures. The chemical disorder of the prepared samples was inspected by using fluorescence microscopy and ultra violet fluorescence spectrometer. The physical disorder was characterized by using Infrared and Raman spectrometer. Laser induced damage thresholds (LIDTs) were measured in R-on-1 mode by 355 nm 6.4 ns laser pulse. Results showed that with the manufacturing processes transforming from grinding to etching, the magnitude of fluorescence point defects reduced while their types did not change, the Si-O-Si bonds of prepared samples were strained and the strained bonds were mitigated. The LIDTs increased with the reducing of fluorescence defects and strained Si-O-Si bonds. However, these structural defects can not be eliminated by the current manufacturing process. Improvements may be needed to eliminate the structural defects for a higher LIDT of fused silica. PMID- 29259297 TI - Hyperstretching DNA. AB - The three-dimensional structure of DNA is highly susceptible to changes by mechanical and biochemical cues in vivo and in vitro. In particular, large increases in base pair spacing compared to regular B-DNA are effected by mechanical (over)stretching and by intercalation of compounds that are widely used in biophysical/chemical assays and drug treatments. We present single molecule experiments and a three-state statistical mechanical model that provide a quantitative understanding of the interplay between B-DNA, overstretched DNA and intercalated DNA. The predictions of this model include a hitherto unconfirmed hyperstretched state, twice the length of B-DNA. Our force fluorescence experiments confirm this hyperstretched state and reveal its sequence dependence. These results pin down the physical principles that govern DNA mechanics under the influence of tension and biochemical reactions. A predictive understanding of the possibilities and limitations of DNA extension can guide refined exploitation of DNA in, e.g., programmable soft materials and DNA origami applications. PMID- 29259298 TI - The after-hours circadian mutant has reduced phenotypic plasticity in behaviors at multiple timescales and in sleep homeostasis. AB - Circadian clock is known to adapt to environmental changes and can significantly influence cognitive and physiological functions. In this work, we report specific behavioral, cognitive, and sleep homeostatic defects in the after hours (Afh) circadian mouse mutant, which is characterized by lengthened circadian period. We found that the circadian timing irregularities in Afh mice resulted in higher interval timing uncertainty and suboptimal decisions due to incapability of processing probabilities. Our phenotypic observations further suggested that Afh mutants failed to exhibit the necessary phenotypic plasticity for adapting to temporal changes at multiple time scales (seconds-to-minutes to circadian). These behavioral effects of Afh mutation were complemented by the specific disruption of the Per/Cry circadian regulatory complex in brain regions that govern food anticipatory behaviors, sleep, and timing. We derive statistical predictions, which indicate that circadian clock and sleep are complementary processes in controlling behavioral/cognitive performance during 24 hrs. The results of this study have pivotal implications for understanding how the circadian clock modulates sleep and behavior. PMID- 29259299 TI - Two novel mutations identified in ADCC families impair crystallin protein distribution and induce apoptosis in human lens epithelial cells. AB - Congenital cataract (CC) is a clinical and genetically heterogeneous eye disease that primarily causes lens disorder and even amblyopic blindness in children. As the mechanism underlying CC is genetically inherited, identification of CC associated gene mutations and their role in protein distribution are topics of both pharmacological and biological research. Through physical and ophthalmic examinations, two Chinese pedigrees with autosomal dominant congenital cataract (ADCC) were recruited for this study. Mutation analyses of CC candidate genes by next-generation sequencing (NGS) and Sanger sequencing revealed a novel missense mutation in CRYBB2 (p.V146L) and a deletion mutation in CRYAA (p.116_118del). Both mutations fully co-segregated were not observed in unaffected family members or in 100 unrelated healthy controls. The CRYBB2 missense mutation disrupts the distribution of CRYBB2 in human lens epithelial cells (HLEpiCs), and the CRYAA deletion mutation causes hyperdispersion of CRYAA. Furthermore, these two crystallin mutations result in aberrant expression of unfolded protein response (UPR) marker genes as well as apoptosis in HLEpiCs. Collectively, these findings broaden the genetic spectrum of ADCC. PMID- 29259301 TI - Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr -/- mice. AB - Atherosclerotic cardiovascular disease is a leading cause of death in the western world. Increased plasma triglyceride and cholesterol levels are major risk factors for this disease. Carboxylesterase 1 (Ces1/Ces1g) has been shown to play a role in metabolic control. So far, the role of mouse Ces1/Ces1g deficiency in atherosclerosis is not elucidated. We generated Ces1/Ces1g -/- mice. Compared to wild-type mice, Ces1/Ces1g -/- mice had reduced plasma cholesterol levels. We then generated Ces1g -/- Ldlr -/- double knockout (DKO) mice, which were fed a Western diet for 16 weeks. Compared to Ldlr -/- mice, DKO mice displayed decreased plasma cholesterol and TG levels and reduced atherosclerotic lesions. Interestingly, knockdown of hepatic Ces1/Ces1g in Apoe -/- mice resulted in hyperlipidemia and exacerbated Western diet-induced atherogenesis. Mechanistically, global inactivation of Ces1/Ces1g inhibited intestinal cholesterol and fat absorption and Niemann-Pick C1 like 1 expression, and increased macrophage cholesterol efflux by inducing ATP-binding cassette subfamily A member 1 (ABCA1) and ABCG1. Ces1/Ces1g ablation also promoted M2 macrophage polarization and induced hepatic cholesterol 7alpha-hydroxylase and sterol 12alpha-hydroxylase expression. In conclusion, global loss of Ces1/Ces1g protects against the development of atherosclerosis by inhibiting intestinal cholesterol and triglyceride absorption and promoting macrophage cholesterol efflux. PMID- 29259300 TI - Protein kinase D2: a versatile player in cancer biology. AB - Protein kinase D2 (PKD2) is a serine/threonine kinase that belongs to the PKD family of calcium-calmodulin kinases, which comprises three isoforms: PKD1, PKD2, and PKD3. PKD2 is activated by many stimuli including growth factors, phorbol esters, and G-protein-coupled receptor agonists. PKD2 participation to uncontrolled growth, survival, neovascularization, metastasis, and invasion has been documented in various tumor types including pancreatic, colorectal, gastric, hepatic, lung, prostate, and breast cancer, as well as glioma multiforme and leukemia. This review discusses the versatile functions of PKD2 from the perspective of cancer hallmarks as described by Hanahan and Weinberg. The PKD2 status, signaling pathways affected in different tumor types and the molecular mechanisms that lead to tumorigenesis and tumor progression are presented. The latest developments of small-molecule inhibitors selective for PKD/PKD2, as well as the need for further chemotherapies that prevent, slow down, or eliminate tumors are also discussed in this review. PMID- 29259303 TI - Broadband absorption and enhanced photothermal conversion property of octopod like Ag@Ag2S core@shell structures with gradually varying shell thickness. AB - Photothermal conversion materials have promising applications in many fields and therefore they have attracted tremendous attention. However, the multi functionalization of a single nanostructure to meet the requirements of multiple photothermal applications is still a challenge. The difficulty is that most nanostructures have specific absoprtion band and are not flexible to different demands. In the current work, we reported the synthesis and multi-band photothermal conversion of Ag@Ag2S core@shell structures with gradually varying shell thickness. We synthesized the core@shell structures through the sulfidation of Ag nanocubes by taking the advantage of their spatially different reactivity. The resulting core@shell structures show an octopod-like mopgorlogy with a Ag2S bulge sitting at each corner of the Ag nanocubes. The thickness of the Ag2S shell gradually increases from the central surface towards the corners of the structure. The synthesized core@shell structures show a broad band absorption spectrum from 300 to 1100 nm. Enhanced photothermal conversion effect is observed under the illuminations of 635, 808, and 1064 nm lasers. The results indicate that the octopod-like Ag@Ag2S core@shell structures have characteristics of multi band photothermal conversion. The current work might provide a guidance for the design and synthesis of multifunctional photothermal conversion materials. PMID- 29259304 TI - Mosquitoes in urban green spaces: using an island biogeographic approach to identify drivers of species richness and composition. AB - Mosquitoes are well known for their epidemiological importance as vectors of a wide range of human pathogens. Despite the many studies on medically important species, little is known about the diversity patterns of these insects in urban green spaces, which serve as shelter and refuge for many native and invasive species. Here, we investigate drivers of mosquito richness and composition in nine urban parks in the city of Sao Paulo, Brazil. Using the equilibrium theory of island biogeography, we tested predictive models for species richness and composition and performed nestedness analysis. We also investigated whether species loss tends to benefit vector mosquitoes. In the period 2011 to 2013, a total of 37,972 mosquitoes belonging to 73 species and 14 genera were collected. Our results suggest there is a species-area relationship, an increase in species similarity as richness is lost and a nested species composition pattern. Seven of the eight most commonly found species are considered vectors of human pathogens, suggesting a possible link between species loss and increased risk of pathogen transmission. Our data highlight the need for studies that seek to understand how species loss may affect the risk of infectious diseases in urban areas. PMID- 29259302 TI - Modelling neuroanatomical variation during childhood and adolescence with neighbourhood-preserving embedding. AB - Brain development is a dynamic process with tissue-specific alterations that reflect complex and ongoing biological processes taking place during childhood and adolescence. Accurate identification and modelling of these anatomical processes in vivo with MRI may provide clinically useful imaging markers of individual variability in development. In this study, we use manifold learning to build a model of age- and sex-related anatomical variation using multiple magnetic resonance imaging metrics. Using publicly available data from a large paediatric cohort (n = 768), we apply a multi-metric machine learning approach combining measures of tissue volume, cortical area and cortical thickness into a low-dimensional data representation. We find that neuroanatomical variation due to age and sex can be captured by two orthogonal patterns of brain development and we use this model to simultaneously predict age with a mean error of 1.5-1.6 years and sex with an accuracy of 81%. We validate this model in an independent developmental cohort. We present a framework for modelling anatomical development during childhood using manifold embedding. This model accurately predicts age and sex based on image-derived markers of cerebral morphology and generalises well to independent populations. PMID- 29259306 TI - Quantum-mechanical analysis of effect of alloying elements on epsilon-martensite start temperature of steels. AB - With regard to the transformation mechanism of austenitic high manganese steel, the prediction of the epsilon-martensite start temperature is a critical consideration in alloy design. Evaluation of the epsilon-martensite start temperature makes it possible to predict the microstructure and to understand the phase transformation occurring during deformation. Here we use the quantum mechanical calculation of random alloys to understand the physics for epsilon martensitic transformation in steels. We could find the linear relationship between the measured epsilon-martensite start temperatures and the crystal structure stability for various compositions. We also could estimate the effect of several alloying elements. It is expected that the effect of decreasing the temperatures for the same amount of alloying elements addition will be larger moving farther from Group VIII. By creating a free-energy model that reflects the temperature effect, we were able to calculate the average driving force required for the epsilon-martensitic transformations. PMID- 29259305 TI - Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis. AB - Genome-wide association studies (GWASs) have identified a number of loci for psoriasis but largely ignored non-additive effects. We report a genotypic variability-based GWAS (vGWAS) that can prioritize non-additive loci without requiring prior knowledge of interaction types or interacting factors in two steps, using a mixed model to partition dichotomous phenotypes into an additive component and non-additive environmental residuals on the liability scale and then the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups genome widely. The vGWAS identified two genome wide significant (P < 5.0e-08) non-additive loci HLA-C and IL12B that were also genome-wide significant in an accompanying GWAS in the discovery cohort. Both loci were statistically replicated in vGWAS of an independent cohort with a small sample size. HLA-C and IL12B were reported in moderate gene-gene and/or gene environment interactions in several occasions. We found a moderate interaction with age-of-onset of psoriasis, which was replicated indirectly. The vGWAS also revealed five suggestive loci (P < 6.76e-05) including FUT2 that was associated with psoriasis with environmental aspects triggered by virus infection and/or metabolic factors. Replication and functional investigation are needed to validate the suggestive vGWAS loci. PMID- 29259307 TI - Higher plasticity in feeding preference of a generalist than a specialist: experiments with two closely related Helicoverpa species. AB - Herbivorous insects have been categorized as generalists or specialists depending on the taxonomic relatedness of the plants they use as food or oviposition substrates. The plasticity in host plant selection behavior of species belonging to the two categories received little attention. In the present work, fifth instar caterpillars of the generalist herbivore Helicoverpa armigera and its closely related species, the specialist Helicoverpa assulta, were fed on common host plants or artificial diet, after which their feeding preference was assessed individually by using dual - and triple- plant choice assays. Results show both the two Helicoverpa species have a preference hierarchy for host plants. Compared to the fixed preference hierarchy of the specialist H. assulta, the generalist H. armigera exhibited extensive plasticity in feeding preference depending on the host plant experienced during larval development. Whereas the specialist H. assulta exhibited a rigid preference in both dual and triple-plant choice assays, our findings demonstrate that the generalist H. armigera expressed stronger preferences in the dual-plant choice assay than in the triple-plant choice assay. Our results provide additional evidence supporting the neural constraints hypothesis which predicts that generalist herbivores make less accurate decisions than specialists when selecting plants. PMID- 29259309 TI - Nanoconfined water can orient and cause long-range dipolar interactions with biomolecules. AB - Surface properties are generally determined by the top most surface layer also defining how molecules adsorb onto it. By exploring effects due to interactions with deeper subsurface layers, however, long-range interaction forces were found to also significantly contribute to molecular adsorption, in which hydration of the subsurface region is the key factor. Water molecules confined to a subsurface amphiphilic gradient are confirmed to cause these long-range dipolar interactions by preferential orientation, thus significantly changing the way how a protein interacts with the surface. These findings imply future exploitation of an additional factor to modulate adsorption processes. PMID- 29259308 TI - Comparison between Listeria sensu stricto and Listeria sensu lato strains identifies novel determinants involved in infection. AB - The human pathogen L. monocytogenes and the animal pathogen L. ivanovii, together with four other species isolated from symptom-free animals, form the "Listeria sensu stricto" clade. The members of the second clade, "Listeria sensu lato", are believed to be solely environmental bacteria without the ability to colonize mammalian hosts. To identify novel determinants that contribute to infection by L. monocytogenes, the causative agent of the foodborne disease listeriosis, we performed a genome comparison of the two clades and found 151 candidate genes that are conserved in the Listeria sensu stricto species. Two factors were investigated further in vitro and in vivo. A mutant lacking an ATP-binding cassette transporter exhibited defective adhesion and invasion of human Caco-2 cells. Using a mouse model of foodborne L. monocytogenes infection, a reduced number of the mutant strain compared to the parental strain was observed in the small intestine and the liver. Another mutant with a defective 1,2-propanediol degradation pathway showed reduced persistence in the stool of infected mice, suggesting a role of 1,2-propanediol as a carbon and energy source of listeriae during infection. These findings reveal the relevance of novel factors for the colonization process of L. monocytogenes. PMID- 29259311 TI - The impact of elevated C-reactive protein level on the prognosis for oro hypopharynx cancer patients treated with radiotherapy. AB - The purpose of this study was to investigate an association between the prognosis for oro-hypopharynx squamous cell carcinoma treated with radiation therapy and the pre-therapeutic level of C-reactive protein (CRP). Patient with oro hypopharyngeal squamous cell carcinoma who underwent definitive radiotherapy in our institution from January 2002 to August 2016 were enrolled. The patient were divided into elevated CRP (over 0.3 mg/dl) group and normal CRP groups, according to pre-treatment serum levels. There were 276 evaluable patients, and the median follow up was 41 months, ranging from 2 to 171 months. The 3-year OS and CSS for all enrolled patients were 67.0% and 72.8%, respectively. The OS and CSS rates were significantly worse in the elevated CRP group than in the normal CRP group, according to Kaplan-Meier survival curves analysed by a Log-rank test (p = 0.005 and p < 0.001, respectively). Multivariate analyses indicated that serum CRP levels remained independent predictors for both OS (HR: 1.588, p = 0.022) and CSS (HR: 1.989, p = 0.005). The pre-treatment CRP level is an independent predictor of treatment prognosis in patients with oro-hypopharyngeal cancer who underwent definitive radiotherapy. Especially, it is curious that an elevated CRP serum level is a significant predictor of loco-regional recurrence. PMID- 29259310 TI - Clinical and Immunological Effects of rhIL-2 Therapy in Eastern Chinese Patients with Multidrug-resistant Tuberculosis. AB - It is urgent to find an optimised therapy regimen for the control of MDR-TB globally. This study aimed to evaluate the efficiacy and safety of a combined regimen of rhIL-2 injection and standard chemotherapy within 18-month duration in a randomized controlled trial conducted in 14 centres in eastern China. From Jan. 2009 to July. 2016, 271 MDR-TB cases were enrolled and followed up in two groups, 142 cases in study group while 129 cases in control group. Clinical efficacy, safety and immune activity (Th1, Th17, Treg, IFN-gamma, IL-17) among the two groups were evaluated and compared. After 24-month following up, cure rate in IL 2 group show higher than that in control group (56% VS 36%, P < 0.01). Rate of mycobacterium clearance (sputum negative) within 3 months was significantly higher in IL-2 group (74% VS 59%, P < 0.05) with no adverse events raised. Patients after rhIL-2 treatment showed increasing of Th1 populations and decreasing of Th17 and Regulatory T cells (Treg) populations, while levels of IL 17A, ROR-gammat, and Foxp3 mRNA decreased and level of IFN-gamma mRNA increased in PBMCs. Thus, rhIL-2 combined regimen within shorter duration achieved high conversion and success rates and improved Th1/Th17 immune responses, with no safety concerns emerging in MDR-TB patients. PMID- 29259312 TI - Conditions and Regulation of Mixed Culture to Promote Shiraia bambusicola and Phoma sp. BZJ6 for Laccase Production. AB - Mixing cultures induces the biosynthesis of laccase in mixed cells, produces signal molecules, and regulates the production of mixed-cell metabolites. The fungal strain, which promotes laccase production, has been isolated and screened from the host bamboos of endophytic fungi and identified as Phoma sp. BZJ6. When the culture medium is mainly composed of soluble starch, yeast extract, and Phoma sp., the laccase output can reach 4,680 U/L. Nitric oxide (NO) and reactive oxygen species (ROS) were found to promote the regulation of laccase synthesis. Plasma membrane NAD(P)H oxidase inhibitors and NO-specific quenchers can inhibit not only the accumulation of ROS induced and NO synthesis but also the biosynthesis of laccase. The results indicate that the accumulation of superoxide anion radical (O2-) and hydrogen peroxide (H2O2) induced by the mixed culture was partially dependent on NO. The mixed culture can also reduce the biomass, increase the synthesis of total phenolics and flavonoids, and enhance the activity of phenylalanine ammonia-lyase and chalcone isomerase. This phenomenon is probably the result of the activated phenylpropanoids-flavonoid pathway. Results confirmed that the mixture culture is advantageous for laccase production and revealed that NO, O2-, and H2O2 are necessary signal molecules to induce laccase synthesis. PMID- 29259313 TI - Tuck-in Lamellar keratoplasty with an lenticule obtained by small incision lenticule extraction for treatment of Post- LASIK Ectasia. AB - Corneal ectasia is a rare but serious post-operative complication of LASIK. Our main aim was to describe and evaluate the efficacy and safety of tuck-in lamellar keratoplasty with an lenticule obtained by SMILE for treatment of Post LASIK Ectasia. Tuck-in lamellar keratoplasty was performed on three post-LASIK cornea ectasia patients (three eyes) with central corneal thickness less than 400 um. Each patient was monitored for at least 12 months. Our primary outcomes measured pre and post-operatively included: Anterior segment optical coherence tomography(AS-OCT), corneal topography and monitored by slit-lamp microscopy. The mean total corneal thickness preoperatively and 1 day, 1 month, 3 months and 12 months post-op were 360.00 +/- 32.07 um, 590.00 +/- 10.00 um, 536.67 +/- 11.54 um, 523.33 +/- 37.85 um, 466.67 +/- 41.63 um. The mean lenticule implanted 1 day, 1 month, 3 months and 12 months post-op were 173.33 +/- 41.63 um,136.67 +/- 25.16 um, 133.33 +/- 40.41 um, 130.00 +/- 17.32 um. There was no evidence of immune rejection or other complications. Tuck-in lamellar keratoplasty with an lenticule obtained by SMILE seems to be a safe and alternative surgical approach in the treatment of post - LASIK cornea ectasia, especially for severe cases with cornea thickness less than 400 MUm. PMID- 29259314 TI - Lectin activity of the pneumococcal pilin proteins. AB - Streptococcus pneumoniae is a leading cause of morbidity and mortality globally. The Pilus-1 proteins, RrgA, RrgB and RrgC of S. pneumoniae have been previously assessed for their role in infection, invasive disease and as possible vaccine candidates. In this study we have investigated the glycan binding repertoire of all three Pilus-1 proteins, identifying that the tip adhesin RrgA has the broadest glycan recognition of the three proteins, binding to maltose/cellobiose, alpha/beta linked galactose and blood group A and H antigens. RrgB only bound mannose, while RrgC bound a subset of glycans also recognized by RrgA. Adherence of S. pneumoniae TIGR4 to epithelial cells was tested using four of the oligosaccharides identified through the glycan array analysis as competitive inhibitors. The blood group H trisaccharide provided the best blocking of S. pneumoniae TIGR4 adherence. Adherence is the first step in disease, and host glycoconjugates are a common target for many adhesins. This study has identified Pilus-1 proteins as new lectins involved in the targeting of host glycosylation by S. pneumoniae. PMID- 29259316 TI - Correction of a Disease Mutation using CRISPR/Cas9-assisted Genome Editing in Japanese Black Cattle. AB - Isoleucyl-tRNA synthetase (IARS) syndrome is a recessive disease of Japanese Black cattle caused by a single nucleotide substitution. To repair the mutated IARS gene, we designed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) to create a double-strand break near the mutation site. CRISPR/Cas9 and donor DNA that contained a synonymous codon for the correct amino acid and an Aequorea coerulescens Green Fluorescent Protein (AcGFP) cassette with a piggyBac transposase recognition site at both ends were introduced into bovine fetal fibroblast (BFF) cells isolated from a homozygous mutant calf. Recombinant cells were enriched on the basis of expression of AcGFP, and two cell lines that contained the repaired allele were subcloned. We generated somatic cell nuclear transfer (SCNT) embryos from the repaired cells and transferred 22 blastocysts to recipient cows. In total, five viable fetuses were retrieved at Days 34 and 36. PiggyBac transposase mRNA was introduced into BFF cells isolated from cloned foetuses and AcGFP-negative cells were used for second round of cloning. We transferred nine SCNT embryos to recipient cows and retrieved two fetuses at Day 34. Fetal genomic DNA analysis showed correct repair of the IARS mutation without any additional DNA footprint. PMID- 29259315 TI - Single-Particle Discrimination of Retroviruses from Extracellular Vesicles by Nanoscale Flow Cytometry. AB - Retroviruses and small EVs overlap in size, buoyant densities, refractive indices and share many cell-derived surface markers making them virtually indistinguishable by standard biochemical methods. This poses a significant challenge when purifying retroviruses for downstream analyses or for phenotypic characterization studies of markers on individual virions given that EVs are a major contaminant of retroviral preparations. Nanoscale flow cytometry (NFC), also called flow virometry, is an adaptation of flow cytometry technology for the analysis of individual nanoparticles such as extracellular vesicles (EVs) and retroviruses. In this study we systematically optimized NFC parameters for the detection of retroviral particles in the range of 115-130 nm, including viral production, sample labeling, laser power and voltage settings. By using the retroviral envelope glycoprotein as a selection marker, and evaluating a number of fluorescent dyes and labeling methods, we demonstrate that it is possible to confidently distinguish retroviruses from small EVs by NFC. Our findings make it now possible to individually phenotype genetically modified retroviral particles that express a fluorescent envelope glycoprotein without removing EV contaminants from the sample. PMID- 29259317 TI - Integrated transcriptomic analysis of Trichosporon Asahii uncovers the core genes and pathways of fluconazole resistance. AB - Trichosporon asahii (T. asahii) has emerged as a dangerous pathogen that causes rare but life-threatening infections. Its resistance to certain antifungal agents makes it difficult to treat, especially for patients undergoing long-term antibiotic therapy. In this study, we performed a series of fluconazole (FLC) perturbation experiments for two T. asahii strains, a clinical isolate stain CBS 2479 (T2) and an environmental isolate strain CBS 8904 (T8), to uncover potential genes and pathways involved in FLC resistance. We achieved 10 transcriptomes of T2 and T8 that were based on dose and time series of FLC perturbations. Systematic comparisons of the transcriptomes revealed 32 T2 genes and 25 T8 genes that are highly sensitive to different FLC perturbations. In both T2 and T8 strains with the phenotype of FLC resistance, the processes of oxidation reduction and transmembrane transport were detected to be significantly changed. The antifungal susceptibility testing of FLC and penicillin revealed their resistance pathways are merged. Accumulated mutations were found in 564 T2 and 225 T8 genes, including four highly mutated genes that are functionally related to the target of rapamycin complex (TOR). Our study provides abundant data towards genome-wide understanding of the molecular basis of FLC resistance in T. asahii. PMID- 29259318 TI - Molecular cloning and functional characterisation of an H+-pyrophosphatase from Iris lactea. AB - Tonoplast H+-pyrophosphatases (VPs) mediate vacuolar Na+ sequestration, a process important for salt tolerance of plants. The function of VP in the highly drought- and salt-tolerant perennial Iris lactea under salt stress is unclear. Here, we isolated IlVP from I. lactea and investigated its function in transgenic tobacco. IlVP was found to comprise 771 amino acid residues and showed 88% similarity with Arabidopsis AtVP1. IlVP was mainly expressed in shoots and was up-regulated by salt stress. Overexpression of IlVP enhanced growth of transgenic tobacco plants compared with wild-type (WT) plants exposed to salt stress. Transgenic plants accumulated higher quantities of Na+ and K+ in leaves, stems, and roots under salt stress, which caused higher leaf relative water content and decreased cell membrane damage compared with WT plants. Overall, IlVP encoding a tonoplast H+ pyrophosphatase can reduce Na+ toxicity in plant cells through increased sequestration of ions into vacuoles by enhanced H+-pyrophosphatase activity. PMID- 29259319 TI - Plant-plant competition outcomes are modulated by plant effects on the soil bacterial community. AB - Competition is a key process that determines plant community structure and dynamics, often mediated by nutrients and water availability. However, the role of soil microorganisms on plant competition, and the links between above- and belowground processes, are not well understood. Here we show that the effects of interspecific plant competition on plant performance are mediated by feedbacks between plants and soil bacterial communities. Each plant species selects a singular community of soil microorganisms in its rhizosphere with a specific species composition, abundance and activity. When two plant species interact, the resulting soil bacterial community matches that of the most competitive plant species, suggesting strong competitive interactions between soil bacterial communities as well. We propose a novel mechanism by which changes in belowground bacterial communities promoted by the most competitive plant species influence plant performance and competition outcome. These findings emphasise the strong links between plant and soil communities, paving the way to a better understanding of plant community dynamics and the effects of soil bacterial communities on ecosystem functioning and services. PMID- 29259321 TI - Tracing halogen and B cycling in subduction zones based on obducted, subducted and forearc serpentinites of the Dominican Republic. AB - Serpentinites are important reservoirs of fluid-mobile elements in subduction zones, contributing to volatiles in arc magmas and their transport into the Earth's mantle. This paper reports halogen (F, Cl, Br, I) and B abundances of serpentinites from the Dominican Republic, including obducted and subducted abyssal serpentinites and forearc mantle serpentinites. Abyssal serpentinite compositions indicate the incorporation of these elements from seawater and sediments during serpentinization on the seafloor and at slab bending. During their subduction and subsequent lizardite-antigorite transition, F and B are retained in serpentinites, whilst Cl, Br and I are expelled. Forearc mantle serpentinite compositions suggest their hydration by fluids released from subducting altered oceanic crust and abyssal serpentinites, with only minor sediment contribution. This finding is consistent with the minimal subduction of sediments in the Dominican Republic. Forearc mantle serpentinites have F/Cl and B/Cl ratios similar to arc magmas, suggesting the importance of serpentinite dehydration in the generation of arc magmatism in the mantle wedge. PMID- 29259320 TI - Phototaxis as a Collective Phenomenon in Cyanobacterial Colonies. AB - Cyanobacteria are a diverse group of photosynthetic bacteria that exhibit phototaxis, or motion in response to light. Cyanobacteria such as Synechocystis sp. secrete a mixture of complex polysaccharides that facilitate cell motion, while their type 4 pili allow them to physically attach to each other. Even though cells can respond individually to light, colonies are observed to move collectively towards the light source in dense finger-like projections. We present an agent-based model for cyanobacterial phototaxis that accounts for slime deposition as well as for direct physical links between bacteria, mediated through their type 4 pili. We reproduce the experimentally observed aggregation of cells at the colony boundary as a precursor to finger formation. Our model also describes the changes in colony morphology that occur when the location of the light source is abruptly changed. We find that the overall motion of cells toward light remains relatively unimpaired even if a fraction of them do not sense light, allowing heterogeneous populations to continue to mount a robust collective response to stimuli. Our work suggests that in addition to bio chemical signalling via diffusible molecules in the context of bacterial quorum sensing, short-ranged physical interactions may also contribute to collective effects in bacterial motility. PMID- 29259322 TI - Hubness of strategic planning and sociality influences depressive mood and anxiety in College Population. AB - Depressive mood and anxiety can reduce cognitive performance. Conversely, the presence of a biased cognitive tendency may serve as a trigger for depressive mood-anxiety. Previous studies have largely focused on group-wise correlations between clinical-neurocognitive variables. Using network analyses for intra individual covariance, we sought to decipher the most influential clinical neurocognitive hub in the differential severity of depressive-anxiety symptoms in a college population. Ninety college students were evaluated for depressive anxiety symptoms, Minnesota multiphasic personality inventory-2(MMPI-2), and neuro-cognition. Weighted and undirected version of the intra-individual covariance networks, comprised of 18 clinical-neurocognitive variables satisfied small-worldness and modular organization in the sparsity range of K = 0.20-0.21. Furthermore, betweenness centrality of perseverative error for the Wisconsin card sorting test was reduced in more depressive individuals; higher anxiety was related to the increased betweenness centrality of MMPI-2 clinical scale 0(Si). Elevated edge-betweenness centrality of covariance between the MMPI-2 clinical scale 7(Pt) versus commission error of the continuous performance test predicted more anxiety higher than depressive mood. With intra-individual covariance network of clinical-neurocognitive variables, this study demonstrated critical drivers of depressive mood[attenuated influence of strategic planning] or anxiety[domination of social introversion/extroversion, in addition to the influence of compulsivity-impulsivity covariance as a shortcut component among various clinical-neurocognitive features]. PMID- 29259323 TI - INTEGRATE-Vis: a tool for comprehensive gene fusion visualization. AB - Despite the increasing quantity of tools for accurately predicting gene fusion candidates from sequencing data, we are still faced with the critical challenge of visualizing the corresponding gene fusion products to infer their biological consequence (i.e. novel protein and increased gene expression). This is currently accomplished by manually inspecting and inferring the biological consequence of top scoring gene fusion candidates. This labor-intensive process could be made easier by automating the annotation of gene fusion products and generating easily interpretable visualizations. We developed a gene fusion visualization tool, called INTEGRATE-Vis, that generates comprehensive, highly customizable, publication-quality graphics focused on annotating each gene fusion at the transcript- and protein-level and assessing expression within an individual sample or across a patient cohort. INTEGRATE-Vis is the first comprehensive gene fusion visualization tool to help a user infer the potential consequence of a gene fusion event. It has potential utility in both research and clinical settings. INTEGRATE-Vis is available at https://github.com/ChrisMaherLab/INTEGRATE-Vis . PMID- 29259324 TI - Revisiting medial preoptic area plasticity induced in male mice by sexual experience. AB - Sexual experience in male rodents, induced by a first exposure to a receptive female, improves efficiency of following copulations. In mice, the mechanisms supporting this improvement are poorly understood. We characterized molecular modifications of the mouse hypothalamic medial preoptic area (mPOA), the main integrative structure for male sexual behaviour, after a single mating event. This paradigm induced long-lasting behavioural improvements and mPOA morphological changes, evidenced by dendritic spine maturation and an increase in the acetylated and tri-methylated forms of histone H3. Ejaculation affected testosterone, progesterone and corticosterone levels in both naive and experienced mice, but sexual experience did not modify basal plasma or hypothalamic levels of steroids. In contrast to studies carried out in rats, no changes were observed, either in the nitrergic system, or in sex steroid receptor levels. However, levels of glutamate- and calcium-associated proteins, including PSD-95, calbindin and the GluN1 subunit of the NMDA receptor, were increased in sexually experienced male mice. The Iba-1 microglial marker was up-regulated in these animals suggesting multicellular interactions induced within the mPOA by sexual experience. In conclusion, plasticity mechanisms induced by sexual experience differ between rat and mouse, even if in both cases they converge to potentiation of the mPOA network. PMID- 29259325 TI - Clinical characteristics and molecular epidemiology of hepatitis E in Shenzhen, China: a shift toward foodborne transmission of hepatitis E virus infection. AB - Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in China. Recently, a shift in molecular epidemiology from hepatitis E genotype 1 (HEV-1) to hepatitis E genotype 4 (HEV-4) has been observed in Northern China, marking a switch from human-to-human transmission to zoonosis. However, similar data from cities in Southern China are lacking. This observational study of human hepatitis E cases in Shenzhen, a metropolitan city in the Pearl River Delta region, aimed to describe the clinical features and molecular epidemiology of hepatitis E in Southern China. Over a 55-month period, we identified 20 patients with acute hepatitis E. Most were middle-aged men, and 50% of patients had concomitant liver disease, of whom 70% were identified to have non-alcoholic fatty liver disease; such patients had a trend toward higher liver enzymes. Quantitative real-time RT-PCR using archived serum samples showed that 12 patients had hepatitis E viremia at presentation. Sequencing of the RNA-dependent RNA polymerase gene was performed for five of these patients, and phylogenetic analysis revealed that these five HEV isolates belonged to subgenotype 4b and were clustered with swine HEV isolates from Southern China. Combined with other studies showing similar findings, this suggests that the molecular epidemiology of hepatitis E in China is evolving toward low-level endemicity driven by foodborne transmission from seafood or pork products. The importance of concomitant liver disease, in particular non-alcoholic fatty liver disease, as a risk factor for severe hepatitis E requires further study. PMID- 29259326 TI - Incidence of anogenital warts in Liuzhou, south China: a comparison of data from a prospective study and from the national surveillance system. AB - To determine the incidence of anogenital warts (AGWs) in the Chinese general population, we compared the data from a prospective study and from the National Notifiable Disease Report System (NNDRS). A cohort study including 2378 women and 2309 men aged 18-55 years old enrolled from Liuzhou, China, was conducted with three scheduled visits at 6-month intervals from May 2014 to March 2016. And, a questionnaire survey was performed to collect the diagnosis history of AGWs at the enrollment visit. The data on reported AGW cases of Liuzhou in the NNDRS from 2006 to 2015 were also analyzed. Overall, the incidence rates of AGWs in the prospective study, in the self-reported diagnosis during past 12 months and in the NNDRS were 1.26 per 1000 person-years (95% confidence interval (CI): 0.16 2.37), 2.35 (95% CI: 1.17-4.20) and 0.183 (95% CI: 0.178-0.187), respectively. Human papillomavirus 6 or 11 were found in all the AGW biopsy samples (10/10). The onset time of AGWs in women was earlier, and the cumulative risk increased more quickly at a young age along with each subsequent younger birth cohort (P<0.0001), whereas slight differences were observed in the different male birth cohorts (P=0.0785). The sexual behavior of individuals and their sexual partners had a strong relationship with self-reported AGWs. Our study indicates that the incidence of AGWs in China is as high as that in developed countries, and the data based on the national surveillance system seriously underestimate the real disease burden of AGWs. PMID- 29259327 TI - Longevity of antibody and T-cell responses against outer membrane antigens of Orientia tsutsugamushi in scrub typhus patients. AB - Scrub typhus, caused by Orientia tsutsugamushi infection, has been a serious public health issue in the Asia-Pacific region, with rising incidence and sporadic outbreaks. However, human protective immunity against specific antigens has been poorly characterized for this bacterium. In addition, immunity produced in early vaccine trials or even after natural infections, did not last long and had poor cross-reactivity among various genotypes. Here, we systematically investigated the kinetics and magnitude of specific adaptive immunity against two membrane antigens, 56 kDa type-specific antigen (TSA56) and surface cell antigen A (ScaA), that are involved in bacterial adhesion and invasion of the host in 64 recovered scrub typhus patients. Antibody responses to the bacterial antigens in patients were generally short-lived and waned to baseline levels 2 years after recovery. The anti-TSA56 IgG responses were predominantly composed of the IgG1 and IgG3 subclasses and persisted for up to 1 year after recovery, whereas IgG specific to ScaA primarily consisted of more transient IgG1, with limited responses by other subclasses. Cellular immunity, including CD4 and CD8 T-cells specific to membrane antigens, also rapidly declined from 1 year after infection, as measured by enzyme-linked immunospot (ELISPOT) assays and flow cytometry. The short longevity of antigen-specific adaptive immunity might be attributable to limited memory responses, as observed in earlier vaccine studies using whole bacterial antigens. Finally, we identified HLA-A*0201-restricted and highly conserved CD8 T-cell epitopes in the TSA56 antigen, which may be valuable tools for assessing cellular immunity against O. tsutsugamushi and developing an effective scrub typhus vaccine. PMID- 29259330 TI - Gut microbiota in 2017: Contribution of gut microbiota-host cooperation to drug efficacy. PMID- 29259328 TI - Disordered oropharyngeal microbial communities in H7N9 patients with or without secondary bacterial lung infection. AB - Secondary bacterial lung infection (SBLI) is a serious complication in patients with H7N9 virus infection, and increases disease severity. The oropharyngeal (OP) microbiome helps prevent colonisation of respiratory pathogens. We aimed to investigate the OP microbiome of H7N9 patients with/without secondary bacterial pneumonia using 16S rRNA gene sequencing. OP swab samples were collected from 51 H7N9 patients (21 with SBLI and 30 without) and 30 matched healthy controls (HCs) and used for comparative composition, diversity and richness analyses of microbial communities. Principal coordinates analysis successfully distinguished between the OP microbiomes of H7N9 patients and healthy subjects, and the OP microbiome diversity of patients with SBLI was significantly increased. There was significant dysbiosis of the OP microbiome in H7N9 patients, with an abundance of Leptotrichia, Oribacterium, Streptococcus, Atopobium, Eubacterium, Solobacterium and Rothia species in patients with SBLI, and Filifactor, Megasphaera and Leptotrichia species in patients without SBLI, when compared with HCs. Importantly, Haemophilus and Bacteroides species were enriched in HCs. These findings revealed dysbiosis of the OP microbiota in H7N9 patients, and identified OP microbial risk indicators of SBLI, suggesting that the OP microbiome could provide novel and non-invasive diagnostic biomarkers for early microbiota targeted prophylactic therapies for SBLI prevention. PMID- 29259329 TI - Dengue viruses in Papua New Guinea: evidence of endemicity and phylogenetic variation, including the evolution of new genetic lineages. AB - Dengue is the most common cause of mosquito-borne viral disease in humans, and is endemic in more than 100 tropical and subtropical countries. Periodic outbreaks of dengue have been reported in Papua New Guinea (PNG), but there is only limited knowledge of its endemicity and disease burden. To help elucidate the status of the dengue viruses (DENVs) in PNG, we performed envelope (E) gene sequencing of DENV serotypes 1-4 (DENV 1-4) obtained from infected patients who traveled to Australia or from patients diagnosed during local DENV transmission events between 2001 and 2016. Phylogenetic analysis and comparison with globally available DENV sequences revealed new endemic PNG lineages for DENV 1-3 which have emerged within the last decade. We also identified another possible PNG lineage for DENV-4 from 2016. The DENV-1 and 3 PNG lineages were most closely related to recent lineages circulating on Pacific island nations while the DENV-2 lineage and putative DENV-4 PNG lineage were most similar to Indonesian sequences. This study has demonstrated for the first time the co-circulation of DENV 1-4 strains in PNG and provided molecular evidence of endemic DENV transmission. Our results provide an important platform for improved surveillance and monitoring of DENVs in PNG and broaden the global understanding of DENV genetic diversity. PMID- 29259333 TI - Unfolded protein response: Pro-survival clock sUPRession. PMID- 29259331 TI - Characterization of Soybean WRKY Gene Family and Identification of Soybean WRKY Genes that Promote Resistance to Soybean Cyst Nematode. AB - WRKY proteins are a superfamily of plant transcription factors with important roles in plants. WRKY proteins have been extensively analyzed in plant species including Arabidopsis and rice. Here we report characterization of soybean WRKY gene family and their functional analysis in resistance to soybean cyst nematode (SCN), the most important soybean pathogen. Through search of the soybean genome, we identified 174 genes encoding WRKY proteins that can be classified into seven groups as established in other plants. WRKY variants including a WRKY-related protein unique to legumes have also been identified. Expression analysis reveals both diverse expression patterns in different soybean tissues and preferential expression of specific WRKY groups in certain tissues. Furthermore, a large number of soybean WRKY genes were responsive to salicylic acid. To identify soybean WRKY genes that promote soybean resistance to SCN, we first screened soybean WRKY genes for enhancing SCN resistance when over-expressed in transgenic soybean hairy roots. To confirm the results, we transformed five WRKY genes into a SCN-susceptible soybean cultivar and generated transgenic soybean lines. Transgenic soybean lines overexpressing three WRKY transgenes displayed increased resistance to SCN. Thus, WRKY genes could be explored to develop new soybean cultivars with enhanced resistance to SCN. PMID- 29259334 TI - The comeback of hand drawing in modern life sciences. AB - Scientific manuscripts are full of images. Since the birth of the life sciences, these images were in a form of hand drawings, with great examples from da Vinci, Hooke, van Leeuwenhoek, Remak, Buffon, Bovery, Darwin, Huxley, Haeckel and Gray's Anatomy to name a few. However, in the course of the past century, photographs and simplified schematics have gradually taken over as a way of illustrating scientific data and concepts, assuming that these are 'accurate' representations of the truth. Here, we argue for the importance of reviving the art of scientific drawings as a way of effectively communicating complex scientific ideas to both specialists and the general public. PMID- 29259332 TI - Plasma sample based analysis of gastric cancer progression using targeted metabolomics. AB - Gastric carcinogenesis is a multifactorial process described as a stepwise progression from non-active gastritis (NAG), chronic active gastritis (CAG), precursor lesions of gastric cancer (PLGC) and gastric adenocarcinoma. Gastric cancer (GC) 5-year survival rate is highly dependent upon stage of disease at diagnosis, which is based on endoscopy, biopsy and pathological examinations. Non invasive GC biomarkers would facilitate its diagnosis at early stages leading to improved GC prognosis. We analyzed plasma samples collected from 80 patients diagnosed with NAG without H. pylori infection (NAG-), CAG with H. pylori infection (CAG+), PLGC and GC. A panel of 208 metabolites including acylcarnitines, amino acids and biogenic amines, sphingolipids, glycerophospholipids, hexoses, and tryptophan and phenylalanine metabolites were quantified using two complementary quantitative approaches: Biocrates AbsoluteIDQ(r)p180 kit and a LC-MS method designed for the analysis of 29 tryptophan pathway and phenylalanine metabolites. Significantly altered metabolic profiles were found in GC patients that allowing discrimination from NAG-, CAG+ and PLGC patients. Pathway analysis showed significantly altered tryptophan and nitrogen metabolic pathways (FDR P < 0.01). Three metabolites (histidine, tryprophan and phenylacetylglutamine) discriminated between non-GC and GC groups. These metabolic signatures open new possibilities to improve surveillance of PLGC patients using a minimally invasive blood analysis. PMID- 29259335 TI - Mitochondria: back to the future. PMID- 29259336 TI - Gene expression: The yin and yang of enhancer-promoter interactions. PMID- 29259337 TI - Patients' and professionals' preferences in terms of the attributes of home enteral nutrition products in Spain. A discrete choice experiment. AB - BACKGROUND/OBJECTIVES: To elicit and compare preferences in terms of the attributes of home enteral nutrition (HEN) among patients and physicians, using a discrete choice experiment (DCE). SUBJECTS/METHODS: A DCE comprising eight choice scenarios, with six HEN attributes (tolerability, adaptation to comorbidities, nutrition and calories, handling, connections and information; two levels each) was designed. The Relative Importance (RI) for patients and physicians of each attribute was estimated. Sociodemographic and clinical variables, as well as additional questions (n = 8) were compiled to analyze possible explanatory variables and other preferences. RESULTS: A total of 148 HEN patients (71 needing caregivers to answer on their behalf) and 114 physicians completed the DCE. The most important attributes for patients were adaptation to comorbidities (33% RI), tolerability (33% RI), and nutrition and calories (26% RI). Significantly, younger patients had stronger preferences for tolerability whereas elderly ones (>=75 years) were more concerned about handling. In comparison, physicians gave a higher RI to tolerability, and nutrition and calories compared to patients (p = 0.002). Overall, a higher percentage of physicians answered that HEN characteristics such as easy-handling bags (85.1 vs. 64.9%; p = 0.001), container material (69.3 vs. 57.1%; p = 0.003) or reusable containers (79.8 vs. 70.3%; p = 0.01) were "important" or "very important" compared to patients. CONCLUSIONS: Our findings showed that although patients and physicians have a similar perception about the relevance of different HEN attributes, the relative weight given to each one varies between them. Therefore, both points of view should be considered when choosing a HEN product in order to improve patients' satisfaction and clinical outcomes. PMID- 29259338 TI - The validity of dietary assessment methods to accurately measure energy intake in children and adolescents who are overweight or obese: a systematic review. AB - The accurate assessment of energy intake in children and adolescents is an important outcome measure for clinical and population-based research. This systematic review aimed to determine the validity of dietary assessment methods to measure energy intake in children and adolescents who are classified as overweight or obese by comparison with doubly labelled water. Five electronic databases were searched using keywords. Of the 5263 papers identified, seven papers describing six studies met the inclusion criteria. Studies were included in the review if participants were classified as overweight or obese, aged 0-18 years old, if they estimated energy intake via a dietary assessment method and if they compared this to total energy expenditure measured via the doubly labelled water method. All studies were cross-sectional in nature, and each used one dietary assessment method, including 14-day-food record (FR; n = 1), 24 h dietary recall (n = 1), 8-day FR (n = 1), 9-day FR (n = 1), 3-day FR (n = 1) and diet history interview (n = 1). Sample sizes ranged from 9 to 59 participants, with the majority of studies including less than 30 participants (n = 4). Mis reporting was evident in all of the studies, with under-reporting (n = 5) more frequent than over-reporting (n = 1). Findings from this review suggest that a 24 h dietary recall and diet history interview were the most accurate methods at the group level for children aged 4-14 years, where the parent or combined child and parent were the reporters. PMID- 29259339 TI - The SENS algorithm-a new nutrient profiling system for food labelling in Europe. AB - BACKGROUND/OBJECTIVES: In response to the European regulation on nutrition and health claims, France proposed in 2008 the SAIN,LIM profiling system that classifies foods into four classes based on a nutrient density score called 'SAIN', a score of nutrients to limit called 'LIM', and one primary threshold on each score. We present here the SENS algorithm, a new nutrient profiling system adapted from the SAIN,LIM to be operational for simplified nutrition labelling in line with the European regulation on food information to consumers. SUBJECTS/METHODS: The main changes made to SAIN,LIM to get SENS were to introduce food categories and sub-categories ('Beverages', 'Added Fats' and 'Other Solid Foods' sub-categorised into 'cereals', 'cheese', 'other dairy products', 'eggs', 'fish' and 'others'), reduce the number of nutrients, introduce category-specific nutrients and category-specific weighting for some nutrients, replace French recommendations with European reference intakes, and add secondary thresholds. Each food and non-alcoholic beverage from the 2013-CIQUAL French composition database (n = 1065) was assigned one SENS class. Distribution of foods according to the four SENS classes was described by food groups (n = 26). RESULTS: The SENS classification was consistent with the recommendations to consume large amounts of whole grains, vegetables and fruits, and moderate intake of fats, sugars, meats, caloric beverages and salt. For most groups (19/26), foods were distributed across at least three SENS classes. CONCLUSIONS: The SENS is a nutrition-sensitive system that discriminates foods between and within food categories. It preserves the strengths of the initial SAIN,LIM while making it operational for simplified nutrition labelling in Europe. PMID- 29259340 TI - Restricted access or access all areas? a new cadherin-like protein upregulated in the inflamed esophagus. PMID- 29259342 TI - Non-structural protein 1 of H3N2 influenza A virus induces nucleolar stress via interaction with nucleolin. AB - The nucleolus is a stress sensor associated with cell cycle progression and a central hub for the replication of pathogenic RNA viruses. However, the role of nucleolus in influenza A virus infection has not been well studied. Here we show that the interaction between NS1 protein of influenza A/Shantou/602/06 (H3N2) and nucleolin, a ubiquitous protein of nucleolus repressed RNA Pol I-dependent transcription via establishing hyper-methylation in the UCE of rRNA gene promoter. NS1 expressed cells showed significant association of ribosomal proteins with MDM2, and p53 accumulation, suggesting induced nucleolar stress. Disruption of the interaction of NS1 with nucleolin or overexpression of nucleolin in NS1 expressed cells revived RNA Pol I-dependent transcription, indicating nucleolin could be one target for NS1 to repress rRNA synthesis of host cells. Our present study suggests that NS1 protein of H3N2 could induce nucleolar stress based on epigenetic alteration of rRNA gene promoter via interaction with nucleolin. PMID- 29259341 TI - Impact of the G84E variant on HOXB13 gene and protein expression in formalin fixed, paraffin-embedded prostate tumours. AB - The HOXB13 G84E variant is associated with risk of prostate cancer (PCa), however the role this variant plays in PCa development is unknown. This study examined 751 cases, 450 relatives and 355 controls to determine the contribution of this variant to PCa risk in Tasmania and investigated HOXB13 gene and protein expression in tumours from nine G84E heterozygote variant and 13 wild-type carriers. Quantitative PCR and immunohistochemistry showed that HOXB13 gene and protein expression did not differ between tumour samples from variant and wild type carriers. Allele-specific transcription revealed that two of seven G84E carriers transcribed both the variant and wild-type allele, while five carriers transcribed the wild-type allele. Methylation of surrounding CpG sites was lower in the variant compared to the wild-type allele, however overall methylation across the region was very low. Notably, tumour characteristics were less aggressive in the two variant carriers that transcribed the variant allele compared to the five that did not. This study has shown that HOXB13 expression does not differ between tumour tissue of G84E variant carriers and non-carriers. Intriguingly, the G84E variant allele was rarely transcribed in carriers, suggesting that HOXB13 expression may be driven by the wild-type allele in the majority of carriers. PMID- 29259344 TI - Targeted therapies: Strategies for mature T cell cancers. PMID- 29259345 TI - Metabolism: Adapting to the environment. PMID- 29259343 TI - Simple 3,4-Dihydroxy-L-Phenylalanine Surface Modification Enhances Titanium Implant Osseointegration in Ovariectomized Rats. AB - Osteoporosis presents a challenge to the long-term success of osseointegration of endosseous implants. The bio-inspired 3,4-dihydroxy-L-phenylalanine (Dopa) coating is widely used as a basic layer to bind osteogenetic molecules that may improve osseointegration. To date, little attention has focused on application of Dopa alone or binding inhibitors of bone resorption in osteoporosis. Local use of a bisphosphonate such as zoledronic acid (ZA), an inhibitor of osteoclast mediated bone resorption, has been proven to improve implant osseointegration. In this study, ovariectomized rats were divided into four groups and implanted with implants with different surface modifications: sandblasted and acid-etched (SLA), SLA modified with Dopa (SLA-Dopa), SLA modified with ZA (SLA-ZA), and SLA modified with Dopa and ZA (SLA-Dopa + ZA). Measurement of removal torque, micro computed tomography and histology revealed a greater extent of bone formation around the three surface-modified implants than SLA-controls. No synergistic effect was observed for combined Dopa + ZA coating. Microarray analysis showed the Dopa coating inhibited expression of genes associated with osteoclast differentiation, similarly to the mechanism of action of ZA. Simple Dopa modification resulted in a similar improvement in osseointegration compared to ZA. Thus, our data suggest simple Dopa coating is promising strategy to promote osseointegration of implants in patients with osteoporosis. PMID- 29259346 TI - Orgasm and SCI: what do we know? AB - STUDY DESIGN: narrative review OBJECTIVES: To determine the percentage of persons with SCI able to achieve orgasm and ejaculation, the associations between ejaculation and orgasm and the subjective and autonomic findings during these events, and the potential benefits with regards to spasticity. SETTING: Two American medical centers METHODS: Data bases were searched for the terms orgasm and SCI and ejaculation and SCI. Search criteria were human studies published in English from 1990 to 12/2/2016. RESULTS: Approximately 50% of sexually active men and women report orgasmic ability after SCI. There is a relative inability of persons with complete lower motor neuron injuries affecting the sacral segments to achieve orgasm. Time to orgasm is longer in persons with SCIs than able-bodied (AB) persons. With orgasm, elevated blood pressure (BP) occurs after SCI in a similar fashion to AB persons. With penile vibratory stimulation and electroejaculation, BP elevation is common and prophylaxis is recommended in persons with injuries at T6 and above. Dry orgasm occurs approximately 13% of times in males. Midodrine, vibratory stimulation, clitoral vacuum suction, and 4 aminopyridine may improve orgasmic potential. CONCLUSIONS: Depending on level and severity of injury, persons with SCIs can achieve orgasm. Sympathetically mediated changes occur during sexual response with culmination at orgasm. Future research should address benefits of orgasm. Additionally, inherent biases associated with studying orgasm must be considered. PMID- 29259347 TI - Administration of assessment instruments during the first rehabilitation of patients with spinal cord injury: a retrospective chart analysis. AB - STUDY DESIGN: Retrospective chart analysis. OBJECTIVES: To examine which professionals administered which assessment instruments in which patient in clinical practice during first rehabilitation after newly acquired spinal cord injury (SCI) and the differences in the frequencies of different assessments between patient groups. SETTING: Specialized SCI acute care and rehabilitation clinic. METHODS: Patients after SCI, aged 18 years and above, admitted for first rehabilitation between December 2014 and December 2015 were analyzed. Descriptive statistics of 54 selected assessments. p values based on the chi 2 test were calculated for assessments used in both paraplegic and tetraplegic patients. RESULTS: One hundred and nineteen patients were screened. Forty-one assessments were administered, of which 10 on average more than once per patient. The most frequently used assessments were Spinal Cord Independence Measure III (7.7 times per patient), Skin Assessment (3.6 times), and Manual Muscle Test (3.2 times for Lower Extremities; 2.5 times for Upper Extremities). The American Spinal Injury Association Impairment Scale was administered on average 1.9 times per patient. More variation in the number of assessments per patient was observed in patients with complete and incomplete lesions compared to patients with paraplegia and tetraplegia. CONCLUSION: Assessments covering neurological functioning, mobility, and self-care are used in clinical practice during first rehabilitation of patients with SCI, while others covering autonomic functioning, pain, participation, or quality of life are still missing. Based on these observations and national and international requirements, a meaningful standard for an assessment toolkit, applicable in general and in specific subgroups, needs to be defined and implemented. PMID- 29259348 TI - Cold pressor test in spinal cord injury-revisited. AB - STUDY DESIGN: Systematic review. OBJECTIVES: A spinal cord injury (SCI) commonly results in alterations of cardiovascular physiology. In order to investigate such alterations, the cold pressor test (CPT) has been used as an established challenge test. This review summarizes the basic physiology underlying a CPT, discusses potential mechanisms responsible for abnormal pressor responses following SCI, and highlights the utility of CPT in the SCI population. SETTING: Canada and Switzerland. METHODS: We have completed a comprehensive review of studies that have investigated the effect of foot or hand CPT on hemodynamic indices in individuals with SCI. RESULTS: Depending on the level of spinal cord lesion and the location of cold application, i.e., above or below the lesion, mean arterial pressure typically increases (ranging between 4 and 23 mmHg), while heart rate responses demonstrated either a decrease or an increase (ranging between -4 and 24 bpm) during CPT. The increase in blood pressure during foot CPT in high-level lesions might not necessarily be attributed to a physiological CPT response as seen in able-bodied individuals, but rather due to a reflexic sympathetic discharge below the level of lesion, known as autonomic dysreflexia. CONCLUSIONS: Further investigations in a wider range of individuals with SCI including incomplete injuries might be helpful to examine the ability of CPT assessing the integrity of the autonomic nervous system following SCI. Furthermore, additional autonomic tests are needed to emphasize the integrity of autonomic pathways and to account for the complexity of the autonomic nervous system. PMID- 29259349 TI - Are Fusion Transcripts in Relapsed/Metastatic Head and Neck Cancer Patients Predictive of Response to Anti-EGFR Therapies? AB - Prediction of benefit from combined chemotherapy and the antiepidermal growth factor receptor cetuximab is a not yet solved question in head and neck squamous cell carcinoma (HNSCC). In a selected series of 14 long progression-free survival (PFS) and 26 short PFS patients by whole gene and microRNA expression analysis, we developed a model potentially predictive of cetuximab sensitivity. To better decipher the "omics" profile of our patients, we detected transcript fusions by RNA-seq through a Pan-Cancer panel targeting 1385 cancer genes. Twenty-seven different fusion transcripts, involving mRNA and long noncoding RNA (lncRNA), were identified. The majority of fusions (81%) were intrachromosomal, and 24 patients (60%) harbor at least one of them. The presence/absence of fusions and the presence of more than one fusion were not related to outcome, while the lncRNA-containing fusions resulted enriched in long PFS patients (P = 0.0027). The CD274-PDCD1LG2 fusion was present in 7/14 short PFS patients harboring fusions and was absent in long PFS patients (P = 0.0188). Among the short PFS patients, those harboring this fusion had the worst outcome (P = 0.0172) and increased K-RAS activation (P = 0.00147). The associations between HNSCC patient's outcome following cetuximab treatment and lncRNA-containing fusions or the CD274-PDCD1LG2 fusion deserve validation in prospective clinical trials. PMID- 29259351 TI - Pregnancy with concomitant pancreatic cancer. AB - We report a rare case of pregnancy with concomitant pancreatic cancer. At 28 weeks' gestation, the patient was diagnosed with a large tumoral mass in the head of the pancreas. She had a cesarean section at 32 weeks' gestation due to premature labor and underwent surgery for pancreatic cancer in her third month postpartum. PMID- 29259350 TI - Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome. AB - Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS. PMID- 29259352 TI - Mechanism of Restoration of Forelimb Motor Function after Cervical Spinal Cord Hemisection in Rats: Electrophysiological Verification. AB - The objective of this study was to electrophysiologically assess the corticospinal tracts of adult rats and the recovery of motor function of their forelimbs after cervical cord hemisection. Of 39 adult rats used, compound muscle action potentials (CMAPs) of the forelimbs of 15 rats were evaluated, before they received left C5 segmental hemisection of the spinal cord, by stimulating the pyramid of the medulla oblongata on one side using an exciting microelectrode. All 15 rats exhibited contralateral electrical activity, but their CMAPs disappeared after hemisection. The remaining 24 rats received hemisection first, and CMAPs of 12 rats were assessed over time to study their recovery time. All of them exhibited electrical activity of the forelimbs in 4 weeks after surgery. The remaining 12 rats received additional right C2 segmental hemisection, and variation of CMAPs between before and after surgery was examined. The right side of the 12 rats that received the additional hemisection exhibited no electrical activity in response to the stimulation of the pyramids on both sides. These results suggest that changes in path between the resected and healthy sides, activation of the ventral corticospinal tracts, and propriospinal neurons were involved in the recovery of motor function after cervical cord injury. PMID- 29259354 TI - Greetings from the editorial committee. PMID- 29259353 TI - Effects of Extremely Low-Frequency Electromagnetic Fields on Neurogenesis and Cognitive Behavior in an Experimental Model of Hippocampal Injury. AB - Exposure to extremely low-frequency electromagnetic fields may induce constant modulation in neuronal plasticity. In recent years, tremendous efforts have been made to design a suitable strategy for enhancing adult neurogenesis, which seems to be deterred due to brain senescence and several neurodegenerative diseases. In this study, we evaluated the effects of ELF-EMF on neurogenesis and memory, following treatment with trimethyltin chloride (TMT) as a neurotoxicant. The mice in all groups (n = 56) were injected with BrdU during the experiment for seven consecutive days to label newborn cells. Spatial memory was assessed by the Morris water maze (MWM) test. By the end of the experiment, neurogenesis and neuronal differentiation were assessed in the hippocampus, using immunohistochemistry and Western blot analysis. Based on the findings, exposure to ELF-EMF enhanced spatial learning and memory in the MWM test. ELF-EMF exposure significantly enhanced the number of BrdU+ and NeuN+ cells in the dentate gyrus of adult mice (P < 0.001 and P < 0.05, resp.). Western blot analysis revealed significant upregulation of NeuroD2 in ELF-EMF-exposed mice compared to the TMT treated group (P < 0.05). These findings suggest that ELF-EMF might have clinical implications for the improvement of neurodegenerative processes and could help develop a novel therapeutic approach in regenerative medicine. PMID- 29259355 TI - Comparative study of ProTaper gold, reciproc, and ProTaper universal for root canal preparation in severely curved root canals. AB - Aim: The aim of this study is to evaluate the root canal transportation, centering ability, and instrumentation times with the ProTaper Gold (Dentsply Tulsa Dental, Tulsa, OK, USA), Reciproc (VDW, Munich, Germany), and ProTaper Universal (Dentsply Maillefer, Ballaigues, Switzerland) using cone-beam computed tomography (CBCT). Materials and Methods: Thirty mesial root canals of mandibular first molars with curvature angles of 35 degrees -70 degrees and radii of 2-6 mm were included in the study. Root canal instrumentation was performed up to F2 or R25. The instrumentation times were recorded. CBCT scanning was performed both pre- and post-instrumentation. Root canal transportation and the centering ratio were calculated for groups, and the data were analyzed using a one-way ANOVA and least significant difference post hoc tests for the instrumentation time, root canal transportation, and centering ratio at the 95% confidence level (P = 0.05). Results: At 3, 5, and 7 mm levels, there was no significant difference in the root canal transportation and centering ratio among the groups (P > 0.05). There were significant differences between the Reciproc and ProTaper Universal groups in the instrumentation times (P < 0.05). Conclusion: Root canal transportation and the centering ratio with the ProTaper Gold were similar to those obtained with the ProTaper Universal and Reciproc. PMID- 29259356 TI - In vitro fracture resistance of composite-resin-veneered zirconia crowns. AB - Aims: The aim of this study is to investigate the fracture load to failure and damage mode of the composite resin-veneered zirconia crowns preparing with two different zirconia surface treatments compared conventional porcelain-veneered zirconia crowns. Materials and Methods: Metallic molar-shape dies prepared with 10 degrees convergence angle a 1.5 mm deep chamfer finish line were used. Two groups of composite-resin-veneered zirconia crowns were prepared using different surface treatment (Group A - sandblasting and Group B - glaze-on technique). Group C (conventional porcelain-veneered zirconia crowns) was served as control. Load to failure test was performed to evaluate the fracture resistance of the crowns using a universal testing machine. One-way ANOVA was used to evaluate the differences of mean values (P < 0.05) followed by Tukey's honest significance test multiple comparisons. Results: The mean fracture load to failure of Group A was 1078.45 +/- 72.3, Group B was 1215.68 +/- 100.76, and Group C (control) was 1203.67 +/- 88.05. Modes of failure are 100% bulk fracture of the core through the veneering materials for Group B and C. However, Group A showed 40% delamination of composite veneering leaving zirconia coping exposed. Conclusions: Group B and C showed significant higher load to failure than Group A. Four specimens of Group A revealed the delamination of composite resin veneering. PMID- 29259357 TI - Evaluation of canal transportation after preparation with Reciproc single-file systems with or without glide path files. AB - Background: Canal transportation is a common sequel caused by rotary instruments. Aims: The purpose of the present study is to evaluate the degree of transportation after the use of Reciproc single-file instruments with or without glide path files. Methods: Thirty resin blocks with L-shaped canals were divided into three groups (n = 10). Group 1 - canals were prepared with Reciproc-25 file. Group 2 - glide path file-G1 was used before Reciproc. Group 3 - glide path files G1 and G2 were used before Reciproc. Pre- and post-instrumentation images were superimposed under microscope, and resin removed from the inner and outer surfaces of the root canal was calculated throughout 10 points. Results: Statistical analysis was performed with Kruskal-Wallis test and post hoc Dunn test. For coronal and middle one-thirds, there was no significant difference among groups (P > 0.05). For apical section, transportation of Group 1 was significantly higher than other groups (P < 0.05). Conclusion: Using glide path files before Reciproc single-file system reduced the degree of apical canal transportation. PMID- 29259358 TI - Effect of instrument speed when used in reciprocating motion on root canal transportation and centering ability. AB - Aim: This study aims to evaluate the root canal transportation, centering ability, and instrumentation times after root canal preparation using reciprocating motion at 300 rotations per minute (rpm) and 600 rpm. Materials and Methods: Twenty mesial root canals of mandibular first molars with curvature angles of 35 degrees -70 degrees and radii of 2-6 mm were included in the study. Root canal instrumentation was performed using R25 according to the manufacturer's instructions at 300 rpm or 600 rpm (n = 10). Cone-beam computed tomography scanning was performed both pre- and post-instrumentation. Root canal transportation and the centering ratio were calculated for both the groups, and the data were analyzed using independent sample t-test for the instrumentation time, root canal transportation, and centering ratio at the 95% confidence level (P = 0.05). Results: At the three levels (3 mm, 5 mm, and 7 mm), there were no significant differences in centering ratio between the groups (P > 0.05). At 3 mm, 600 rpm resulted in more transportation than 300 rpm. However, there were no significant differences in the root canal transportation between the groups at 5 mm and 7 mm levels (P > 0.05). Conclusion: At the 3 mm level, 600 rpm resulted in more transportation than 300 rpm. However, centering ratio was similar at both 600 rpm and 300 rpm. PMID- 29259359 TI - Spectrophotometric analysis of coronal discoloration induced by white mineral trioxide aggregate and Biodentine: An in vitro study. AB - Aims: The aim of this study was to evaluate the specific chromatic alterations in tooth crowns induced by two different endodontic restorative materials. Settings and Design: This in vitro study was conducted at the Department of Conservative Dentistry, KMCT Dental College, Kozhikode, Kerala. Subjects and Methods: Forty five freshly extracted, fully developed, single-rooted teeth were prepared and randomly assigned to two experimental groups (n = 15 each) and one negative control group (n = 15). Group 1 consists of white mineral trioxide aggregate (WMTA), Biodentine formed Group 2, and controls formed Group 3. Double-beam ultraviolet spectrophotometer equipment was used to assess the coronal discoloration as determined by CIE L*, a*, and b* and their corresponding total values. Results: At baseline, no significant difference was detected for CIE values between the groups. Group 1 showed a significant decrease in L*, a*, and b* values over time. The color change with WMTA led to clinically perceptible crown discoloration after 6 weeks which exceeded the perceptible threshold for the human eye, i.e., DeltaE > 3.3. No changes were observed with Biodentine. Conclusions: Materials used in endodontics may stain teeth. WMTA induced clinically perceptible crown discoloration, whereas Biodentine demonstrated color stability. PMID- 29259360 TI - Influence of root canal obturation using gutta-percha with three different sealers on root reinforcement of endodontically treated teeth. An in vitro comparative study of mandibular incisors. AB - Aim: The purpose of this in vitro study was to evaluate the vertical force required to fracture mandibular incisor teeth, obturated using gutta-percha with three different sealers. Materials and Methods: Seventy-five extracted mandibular incisors with intact and fully formed apices, exhibiting single root and canal were acquired. The teeth were decoronated obtaining a root segments of 15 mm and were divided into five groups (n = 15). Group 1: left uninstrumented and unfilled (negative control). For groups 2-5, samples were instrumented using Protaper NEXT (X1 and X2). Group 2: left unobturated (positive control). Groups 3-5 were obturated using lateral compaction by gutta-percha and three sealers (AH Plus(r), Apexit(r), and EndoSequence(r) BioCeramicTM). All the samples were prepared for fracture testing and vertical load was applied till fracture. Statistical analysis was performed using ANOVA and Tukey's post hoc test, for the data recorded of the force required in Newton (N). Results: The load required to fracture exhibited a significant difference. The intergroup analysis revealed, samples obturated using bioceramic sealer exhibited higher fracture resistance (P < 0.01). Conclusion: The use of gutta-percha and a root canal sealer reinforces the root dentin, leading to increased fracture resistance against vertical forces. Bioceramic sealer group in them exhibited better results. PMID- 29259361 TI - Comparative evaluation of smear layer removal by chitosan and ethylenediaminetetraacetic acid when used as irrigant and its effect on root dentine: An in vitro atomic force microscopic and energy-dispersive X-ray analysis. AB - Aim: This study was undertaken to evaluate the efficacy of smear layer removal and nanostructural and chemical changes caused by chitosan and ethylenediaminetetraacetic acid (EDTA) on tooth surface using atomic force microscopic analysis and energy-dispersive X-ray (EDX) analysis. Methodology: Forty single-rooted premolars were decoronated to a standard length of 15 mm and enlarged to Protaper F3 with irrigation of 1 mL 1% NaOCl and deionized water. Specimens were then divided into 4 groups with 10 samples each and subjected to final rinse with 17% EDTA solution, 0.2% and 0.5% chitosan solution for 1 min. Samples were sectioned into 2 halves. One half of sample from each group were subjected to EDX analysis to check the calcium/phosphate (Ca/P) ratio. The second half of sample from each group subjected to atomic force microscopy (AFM) analysis to study the smear layer removal and nanostructural changes. Statistical analysis was done using ANOVA and Chi-square test. Results: The AFM images showed no difference in the elimination of smear layer. The quantitative analysis using AFM showed EDTA group had significantly higher surface alteration than chitosan. EDX analysis showed that the Ca/P ratio of root dentine in EDTA group is significantly lower than chitosan group. Conclusion: Chitosan is an effective chelating agent with less alteration in radicular dentine. PMID- 29259362 TI - A comparative evaluation of accuracy of three electronic apex locators using histological section as gold standard: An ex vivo study. AB - Introduction: The aim of the present study was to comparatively evaluate the accuracy of iRoot, iPex II, and Propex pixi apex locator using histological sections as the gold standard. Materials and Methods: Thirty patients indicated for extraction of single-rooted permanent teeth with single canal system were selected. Working lengths (WLs) of teeth were determined using iRoot, iPex II, and Propex pixi. Teeth were then extracted, and the files were reintroduced to the anatomic apex to measure anatomic canal length (ACL) and fixed at the ACL using flowable composite. The apical 4 mm of the roots were longitudinally shaved away to visualize the canal under a stereomicroscope at *24 magnification. Digital photographs were evaluated to measure the distance between the major diameter and minor diameter. Thus, the WL, that is, the minor diameter length (MDL) was ascertained. Results: Measurements of mean WLs within +/-0.5 mm of minor diameter were 90% acceptable for iRoot, 86.66% for iPex II, and 80% for Propex pixi when compared with mean MDL as obtained from the histological sections. Conclusions: All apex locators have been shown to produce acceptable level of accuracy which clearly indicates their reliability in determining the WL. PMID- 29259363 TI - Alternating versus continuous rotation: Root canal transportation and centering ratio with the ProTaper Next. AB - Background: The technique of alternating rotation has been used with NiTi rotary instruments to increase the resistance to fracture compared with conventional continuous rotation. However, it is still not clear what type of instrumentation could provide better results in the preservation of the original canal anatomy. Aim: The aim of this study is to determine the influence of the type of rotation on canal transportation and centering ability using cone-beam computed tomography (CBCT) imaging. Materials and Methods: In total, 50 mesial canals of mandibular molars with curvatures between 30 degrees and 60 degrees were divided into two experimental groups (n = 25 each) according to the type of movement employed with the ProTaper Next (PTN) instruments: Group A (alternating rotation) and Group B (continuous rotation). Canals were scanned before and after instrumentation using a CBCT scanner to evaluate root canal transportation and the centering ratio at 3, 5, and 7 mm from the apex. Data were analyzed statistically using Student's t test; the significance level was set at P < 0.05. Results: There was no significant difference between the groups in canal transportation or the centering ratio at any of the three studied cross sections (3, 5, and 7 mm). Conclusions: PTN instruments promoted minimal apical transportation and remained relatively centered within the root canal, with no significant difference between alternating and continuous rotation. PMID- 29259364 TI - Effect of protective coating on microhardness of a new glass ionomer cement: Nanofilled coating versus unfilled resin. AB - Background and Objectives: EQUIATM is a new gastrointestinal (GI) system with high compressive strength, surface microhardness (MH), and fluoride release potential. This in vitro study aimed to assess the effect of aging and type of protective coating on the MH of EQUIATM GI cement. Materials and Methods: A total of 30 disc-shaped specimens measuring 9 mm in diameter and 2 mm in thickness were fabricated of EQUIATM GI and divided into three groups of G-Coat nanofilled coating (a), no coating (b) and margin bond (c). The Vickers MH value of specimens was measured before (baseline) and at 3 and 6 months after water storage. Data were analyzed using repeated measures ANOVA. Results: Group B had significantly higher MH than the other two groups at baseline. Both G-Coat and margin bond increased the surface MH of GI at 3 and 6 months. The MH values of G Coat and margin bond groups did not significantly increase or decrease between 3 and 6 months. Conclusion: The increase in MH was greater in the G-Coat compared to the margin bond group in the long-term. Clinically, margin bond may be a suitable alternative when G-Coat is not available. PMID- 29259365 TI - A comparative clinical evaluation of accuracy of six apex locators with intraoral periapical radiograph in multirooted teeth: An in vivo study. AB - Aim: The purpose of this clinical study was to compare and clinically, to evaluate the accuracy of six apex locators with intra oral periapical (IOPA) radiograph in multirooted teeth. Materials and Methods: A total of 90 multirooted teeth (maxillary and mandibular molars) with irreversible, infected or necrotic pulp tissue and completely formed roots were included in this study and were divided randomly into six groups (Root ZX II, Raypex 6, I-Root, Romiapex A-15, Sybron Endo Mini and Root ZX mini). The working length was determined using six different apex locators, and the accuracy of the apex locators was compared with IOPA radiographs, to be categorized as accurate, short, and long or beyond. Results: A total of 270 canals were evaluated, of which 233 (86.3%) canals exhibited acceptable working length, 28 (10.4%) canals exhibited short working length, and only 9 (3.3%) canals exhibited working length beyond the apex. There were a statistically significant results in all the groups (P < 0.05) and the comparison between the groups was statistically insignificant. Conclusion: The repeatability with that of apex locators is of great advantage, but the information gained from the radiographs cannot be obtained by any other means. Therefore, it is recommended that radiograph and apex locators are the best combinations in accurately determining the working length and the successful endodontics. PMID- 29259366 TI - Comparing the effectiveness of four desensitizing toothpastes on dentinal tubule occlusion: A scanning electron microscope analysis. AB - Introduction: Dentin hypersensitivity (DH) is a sudden short sharp pain best explained by hydrodynamic theory. Several agents are available throughout the market that can treat DH either by blocking the nerves that helps in conducting pain or by blocking the open dentinal tubules. The aim of the present study was to compare the tubule occluding efficacy of four different desensitizing dentifrices under scanning electron microscope (SEM). Materials and Methods: Sixty-two dentin blocks measuring 5 mm * 5 mm * 3 mm were obtained from extracted human molar teeth and were randomly divided into five groups: Group 1 - no treatment (control, n = 2); Group 2 - Pepsodent Pro-sensitive relief and repair (n = 15); Group 3 - Sensodyne repair and protect (n = 15); Group 4 - Remin Pro (n = 15); Group 5 - Test toothpaste containing 15% nano-hydroxyapatite (n-HA) crystals (n = 15). The specimens were brushed for 2 min/day for 14 days and stored in artificial saliva. After final brushing, specimens were gold sputtered and viewed under SEM at *2000 magnification. Results obtained were statistically analyzed using nonparametric Kruskal-Wallis test and least significant difference post hoc test. Results: All test groups showed significant increase in dentin tubule occlusion as compared to control group. The highest percentage of tubules occluded was shown by Group 4 and Group 5 which was significantly different from other groups (P <= 0.05), and there was no significant difference in tubule occlusion among them. Conclusion: Newer desensitizing dentifrices containing 15% n-HA and Remin Pro can provide effective tubule occlusion and thereby reduce the pain and discomfort caused by DH. PMID- 29259367 TI - Cone-beam computed tomography as advanced diagnostic aid in endodontic treatment of molars with multiple canals: Two case reports. AB - The purpose of these case reports is to emphasize the importance of knowledge regarding the root canal morphology and current diagnostic aids one should have as both of these important factors going to affect the prognosis of the endodontic treatment. These two case reports describe the maxillary and mandibular first molars with multiple canals. After clinical and radiographic diagnosis, additional help of cone-beam computed tomography (CBCT) of mandibular molar has been taken to evaluate the morphology and canal pattern; while maxillary molar was evaluated using CBCT scan to evaluate the canal configuration and obturation. In CBCT evaluation, the mandibular molar was diagnosed with six separated canals with three mesial and three distal canals and with radix paramolaris and radix entomolaris. The maxillary molar had five canals with three mesiobuccal (MB) canals. Both molars were instrumented with conventional hand and rotary file systems and obturated by conventional lateral compaction method. The axial images from CBCT show Vertucci Type VIII canal pattern in both roots of first mandibular molars and in MB root of maxillary first molar Sert and Bayirli Type XVIII canal configuration and no accessory canal in distobuccal and palatal root. With the recent innovations in diagnostic and operating aids, we can come across many variations in the root canal morphology of both mandibular and maxillary teeth, especially multi-rooted one (i.e., molars), and the knowledge of which leads to successful endodontic treatment with an excellent prognosis. PMID- 29259368 TI - Clinical applications of ferric sulfate in dentistry: A narrative review. AB - Ferric sulfate (FS) has been commonly used as a local hemostatic agent for more than three decades in dentistry. Even though the hemostatic mechanism of FS is questioned, it seems that agglutination of blood proteins occurs due to the reaction of blood with ferric and sulfate ions in acidic pH. FS has gained widespread importance as a pulpotomy medicament in contemporary dentistry; nevertheless, it has several applications in different fields of dentistry which was paid little attention. Hence, the purpose of this paper is to review the various applications of FS in dentistry, along with restorative dentistry and endodontics. PMID- 29259369 TI - Endodontic management of contralateral mandibular first molars with six root canals. AB - The knowledge of variations in root canal morphology is essential for a successful endodontic outcome. Contralateral mandibular molar with six root canals is a rare entity. Root canal treatment of mandibular molars with aberrant canal configuration can be diagnostically and technically challenging. While dealing with variant mandibular molars, mishaps may happen. This case report describes variations in contralateral mandibular molars and also an endodontic mishap while managing them. PMID- 29259370 TI - Pancreatic acinar cell carcinoma: A review on molecular profiling of patient tumors. AB - Pancreatic carcinomas with acinar differentiation are rare, accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma (PACC), pancreatoblastoma, and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4, BRAF, BRCA2, TP53, RB1, MEN1, JAK-1, BRCA-1, BRCA-2, and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore, molecular profiling of PACC should be an option for patients with refractory PACC. PMID- 29259371 TI - Probiotics for gastrointestinal disorders: Proposed recommendations for children of the Asia-Pacific region. AB - Recommendations for probiotics are available in several regions. This paper proposes recommendations for probiotics in pediatric gastrointestinal diseases in the Asia-Pacific region. Epidemiology and clinical patterns of intestinal diseases in Asia-Pacific countries were discussed. Evidence-based recommendations and randomized controlled trials in the region were revised. Cultural aspects, health management issues and economic factors were also considered. Final recommendations were approved by applying the Likert scale and rated using the GRADE system. Saccharomyces boulardii CNCM I-745 (Sb) and Lactobacillus rhamnosus GG (LGG) were strongly recommended as adjunct treatment to oral rehydration therapy for gastroenteritis. Lactobacillus reuteri could also be considered. Probiotics may be considered for prevention of (with the indicated strains): antibiotic-associated diarrhea (LGG or Sb); Clostridium difficile-induced diarrhea (Sb); nosocomial diarrhea (LGG); infantile colic (L reuteri) and as adjunct treatment of Helicobacter pylori (Sb and others). Specific probiotics with a history of safe use in preterm and term infants may be considered in infants for prevention of necrotizing enterocolitis. There is insufficient evidence for recommendations in other conditions. Despite a diversity of epidemiological, socioeconomical and health system conditions, similar recommendations apply well to Asia pacific countries. These need to be validated with local randomized-controlled trials. PMID- 29259372 TI - Down-regulation of miR-30a-3p/5p promotes esophageal squamous cell carcinoma cell proliferation by activating the Wnt signaling pathway. AB - AIM: To investigate the potential role of microRNA-30a (miR-30a) in esophageal squamous cell carcinoma (ESCC). METHODS: Expression of miR-30a-3p/5p was analyzed using microarray data and fresh ESCC tissue samples. Both in vitro and in vivo assays were used to investigate the effects of miR-30a-3p/5p on ESCC cell proliferation. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis was performed to explore underlying mechanisms involved in ESCC, and then, assays were carried out to verify the potential molecular mechanism of miR-30a in ESCC. RESULTS: Low expression of miR-30a-3p/5p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC. Knock-down of miR-30a 3p/5p promoted ESCC cell proliferation. Increased miR-30a-3p/5p expression inhibited the Wnt signaling pathway by targeting Wnt2 and Fzd2. CONCLUSION: Down regulation of miR-30a-3p/5p promotes ESCC cell proliferation by activating the Wnt signaling pathway through inhibition of Wnt2 and Fzd2. PMID- 29259373 TI - Mesenchymal stem cells rescue acute hepatic failure by polarizing M2 macrophages. AB - AIM: To investigate whether M1 or M2 polarization contributes to the therapeutic effects of mesenchymal stem cells (MSCs) in acute hepatic failure (AHF). METHODS: MSCs were transfused into rats with AHF induced by D-galactosamine (DGalN). The therapeutic effects of MSCs were evaluated based on survival rate and hepatocyte proliferation and apoptosis. Hepatocyte regeneration capacity was evaluated by the expression of the hepatic progenitor surface marker epithelial cell adhesion molecule (EpCAM). Macrophage polarization was analyzed by M1 markers [CD68, tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), inducible nitric oxide synthase (INOS)] and M2 markers [CD163, interleukin (IL)-4, IL-10, arginase 1 (Arg-1)] in the survival and death groups after MSC transplantation. RESULTS: The survival rate in the MSC-treated group was increased compared with the DPBS treated control group (37.5% vs 10%). MSC treatment protected rats with AHF by reducing apoptotic hepatocytes and promoting hepatocyte regeneration. Immunohistochemical analysis showed that MSC treatment significantly increased the expression of EpCAM compared with the control groups (P < 0.001). Expression of EpCAM in the survival group was significantly up-regulated compared with the death group after MSC transplantation (P = 0.003). Transplantation of MSCs significantly improved the expression of CD163 and increased the gene expression of IL-10 and Arg-1 in the survival group. IL-4 concentrations were significantly increased compared to the death group after MSC transplantation (88.51 +/- 24.51 pg/mL vs 34.61 +/- 6.6 pg/mL, P < 0.001). In contrast, macrophages showed strong expression of CD68, TNF-alpha, and INOS in the death group. The concentration of IFN-gamma was significantly increased compared to the survival group after MSC transplantation (542.11 +/- 51.59 pg/mL vs 104.07 +/- 42.80 pg/mL, P < 0.001). CONCLUSION: M2 polarization contributes to the therapeutic effects of MSCs in AHF by altering levels of anti-inflammatory and pro-inflammatory factors. PMID- 29259374 TI - Improved experimental model of hepatic cystic hydatid disease resembling natural infection route with stable growing dynamics and immune reaction. AB - AIM: To investigate a safer way to set up the disease model of cystic echinococcosis without contamination risk and develop a novel experimental murine model of hepatic cystic echinococcosis. METHODS: C57B/6 mice were injected with human protoscolices of three different concentrations via the portal vein. The mice were followed for 10 mo by ultrasound, gross anatomy, and pathological and immunological examinations. The protoscolex migration in the portal vein, hydatid cyst growth, host immune reaction, and hepatic histopathology were examined periodically. RESULTS: The infection rates in the mice in the high, medium, and low concentration groups were 90%, 100%, and 63.6%, respectively. The protoscolices migrated in the portal vein with blood flow, settled in the liver, and developed into orthotopic hepatic hydatid cysts, resembling the natural infection route and course. CONCLUSION: We have established an improved experimental model of hepatic cystic echinococcosis with low biohazard risk but stable growing dynamics and immune reaction. It is especially useful for new anti parasite medication trials against hydatid disease. PMID- 29259375 TI - Recurrence in node-negative advanced gastric cancer: Novel findings from an in depth pathological analysis of prognostic factors from a multicentric series. AB - AIM: To analyze the clinicopathological characteristics of patients with both node-negative gastric carcinoma and diagnosis of recurrence during follow-up. METHODS: We enrolled 41 patients treated with curative gastrectomy for pT2-4aN0 gastric carcinoma between 1992 and 2010, who developed recurrence (Group 1). We retrospectively selected this group from the prospectively collected database of 4 centers belonging to the Italian Research Group for Gastric Cancer, and compared them with 437 pT2-4aN0 patients without recurrence (Group 2). We analyzed lymphatic embolization, microvascular infiltration, perineural infiltration, and immunohistochemical determination of p53, Ki67, and HER2 in Group 1 and in a subgroup of Group 2 (Group 2bis) of 41 cases matched with Group 1 according to demographic and pathological characteristics. RESULTS: T4a stage and diffuse histotype were associated with recurrence in the group of pN0 patients. In-depth pathological analysis of two homogenous groups of pN0 patients, with and without recurrence during long-term follow-up (groups 1 and 2bis), revealed two striking patterns: lymphatic embolization and perineural infiltration (two parameters that pathologists can easily report), and p53 and Ki67, represent significant factors for recurrence. CONCLUSION: The reported pathological features should be considered predictive factors for recurrence and could be useful to stratify node-negative gastric cancer patients for adjuvant treatment and tailored follow-up. PMID- 29259376 TI - Albumin as a prognostic marker for ulcerative colitis. AB - AIM: To evaluate the role of albumin at the time of ulcerative colitis (UC) diagnosis in predicting the clinical course of disease. METHODS: Nationwide cohort of patients with newly diagnosed UC in the Veterans Affairs health care system was identified and divided into two categories: hypoalbuminemia (i.e., <= 3.5 gm/dL) or normal albumin levels (i.e., > 3.5 gm/dL) at the time of UC diagnosis. The exposure of interest was presence of hypoalbuminemia defined as albumin level <= 3.5 g/dL at the time of UC diagnosis. Patients were then followed over time to identify the use of >= 2 courses of corticosteroids (CS), thiopurines, anti-TNF medications and requirement of colectomy for UC management. RESULTS: The eligible study cohort included 802 patients, but 92 (11.4%) patients did not have their albumin levels checked at the time of UC diagnosis, and they were excluded. A total of 710 patients, who had albumin levels checked at time of UC diagnosis, were included in our study. Amongst them, 536 patients had a normal albumin level and 174 patients had hypoalbuminemia. Patients with hypoalbuminemia at diagnosis had a higher likelihood of >= 2 courses of CS use (adjusted HR = 1.7, 95%CI: 1.3-2.3), higher likelihood of thiopurine or anti- TNF use (adjusted HR = 1.72, 95%CI: 1.23-2.40) than patients with normal albumin level at diagnosis. There was a trend of higher likelihood of colectomy in hypoalbuminemic patients, but it was not statistically significant (Adjusted HR = 1.7, 95%CI: 0.90-3.25). CONCLUSION: Hypoalbuminemia at disease diagnosis can serve as a prognostic marker to predict the clinical course of UC at the time of diagnosis. PMID- 29259378 TI - Impact of homogeneous pathologic response to preoperative chemotherapy in patients with multiple colorectal liver metastases. AB - AIM: To analyze the homogeneity of pathologic response to preoperative chemotherapy (PRPC) after chemotherapy in patients with multiple liver metastases (LM). METHODS: From September 2011 to August 2014, patients with at least two LM undergoing preoperative chemotherapy prior to resection were included in this retrospective, single-center study. The endpoints were PRPC homogeneity (according to both the Rubbia-Brandt and MD Anderson classifications), the impact of PRPC on the MDT decision, factors associated with homogeneous PRPC and overall survival of patients with vs. without homogeneous PRPC. RESULTS: seventy-three patients with a total of 88 liver resections (including 15 two-stage procedures) were included in the study. The homogeneous PRPC rate was 55% according to the Rubbia-Brandt classification and 53% according to the MD Anderson classification. The MDT decision was modified by the PRPC in only 2.7% of patients (n = 2). CONCLUSION: The PRPC was homogeneous in only one half of patients and had very little influence on the MDT decision. PMID- 29259377 TI - Pretransplantation fetal-maternal microchimerism in pediatric liver transplantation from mother. AB - AIM: To investigate the rates of pretransplantation fetal-maternal microchimerism (MC) and its effect on rejection in children receiving maternal liver grafts. METHODS: DNA or blood samples before liver transplantation (LT) were available in 45 pediatric patients and their mothers. The presence of pretransplantation MC to non-inherited maternal antigens (NIMAs) (NIMA-MC) in the peripheral blood was tested using nested PCR-single-strand conformation polymorphism analysis for the human leukocyte antigen (HLA)-DRB1 alleles. NIMA-MC was successfully evaluated in 26 of the 45 children. Among these 45 pediatric LT recipients, 23 children (51.1%) received transplants from maternal donors and the other 22 from non maternal donors. RESULTS: Among these 26 children, pretransplantation NIMA-MC was detected in 23.1% (n = 6), 6.1 (range, 0.8-14) years after birth. Among the children with a maternal donor, the rate of biopsy-proven cellular rejection (BPCR) was 0% in patients with NIMA-MC positivity (0/3) and those with HLA-DR identity with the mother (0/4), but it was 50% in those with NIMA-MC negativity (5/10). Patients with NIMA-MC positivity or HLA-DR identity with the mother showed significantly lower BPCR rate compared with NIMA-MC-negative patients (0% vs 50%, P = 0.04). NIMA-MC-positive patients tended to show lower BPCR rate compared with NIMA-MC-negative patients (P = 0.23). CONCLUSION: The presence of pretransplantation NIMA-MC or HLA-DR identity with the mother could be associated with BPCR-free survival in pediatric recipients of LT from maternal donors. PMID- 29259379 TI - Two-step method for creating a gastric tube during laparoscopic-thoracoscopic Ivor-Lewis esophagectomy. AB - AIM: To introduce a two-step method for creating a gastric tube during laparoscopic-thoracoscopic Ivor-Lewis esophagectomy and assess its clinical application. METHODS: One hundred and twenty-two patients with middle or lower esophageal cancer who underwent laparoscopic-thoracoscopic Ivor-Lewis esophagectomy at Liaoning Cancer Hospital and Institute from March 2014 to March 2016 were included in this study, and divided into two groups based on the procedure used for creating a gastric tube. One group used a two-step method for creating a gastric tube, and the other group used the conventional method. The two groups were compared regarding the operating time, surgical complications, and number of stapler cartridges used. RESULTS: The mean operating time was significantly shorter in the two-step method group than in the conventional method group [238 (179-293) min vs 272 (189-347) min, P < 0.01]. No postoperative death occurred in either group. There was no significant difference in the rate of complications [14 (21.9%) vs 13 (22.4%), P = 0.55] or mean number of stapler cartridges used [5 (4-6) vs 5.2 (5-6), P = 0.007] between the two groups. CONCLUSION: The two-step method for creating a gastric tube during laparoscopic thoracoscopic Ivor-Lewis esophagectomy has the advantages of simple operation, minimal damage to the tubular stomach, and reduced use of stapler cartridges. PMID- 29259381 TI - Gender differences in ghrelin, nociception genes, psychological factors and quality of life in functional dyspepsia. AB - AIM: to evaluate gender differences in the aspect of ghrelin, nociception-related genes and psychological aspects and the quality of life (QoL) in Korean functional dyspepsia (FD) patients. METHODS: Total of 191 persons were prospectively enrolled between March 2013 and May 2016 in Seoul National Bundang Hospital, and classified into control and FD group based on ROME III criteria. Questionnaire included assessment for dyspepsia symptoms, QoL and anxiety or depression. Preproghrelin and nociception genes in the gastric mucosa and plasma acyl/des-acyl ghrelin were measured. RESULTS: Lower level of plasma acyl ghrelin in FD patients compared to control was significant only in male (15.9 fmol/mL vs 10.4 fmol/mL, P = 0.017). Significantly higher mRNA expressions of nerve growth factor and transient receptor potential vanilloid receptor 1 were observed in male (P = 0.002 and P = 0.014, respectively) than in female. In contrast, female FD patients had a higher anxiety and depression score than male FD (P = 0.029), and anxiety score was correlated with epigastric pain only in female FD patients (female: Spearman rho = 0.420, P = 0.037). The impairment of overall QoL was more prominent in female FD patients than male patients (5.4 +/- 0.3 vs 6.5 +/- 0.3, P = 0.020). CONCLUSION: Gender differences of ghrelin and nociception-related genes in male and psychological factors in female underlie FD symptoms. More careful assessment of psychological or emotional status is required particularly for the female FD patients. PMID- 29259380 TI - Clinical value of liver and spleen shear wave velocity in predicting the prognosis of patients with portal hypertension. AB - AIM: To explore the relationship of liver and spleen shear wave velocity in patients with liver cirrhosis combined with portal hypertension, and assess the value of liver and spleen shear wave velocity in predicting the prognosis of patients with portal hypertension. METHODS: All 67 patients with liver cirrhosis diagnosed as portal hypertension by hepatic venous pressure gradient in our hospital from June 2014 to December 2014 were enrolled into this study. The baseline information of these patients was recorded. Furthermore, 67 patients were followed-up at 20 mo after treatment, and liver and spleen shear wave velocity were measured by acoustic radiation force impulse at the 1st week, 3rd month and 9th month after treatment. Patients with favorable prognosis were assigned into the favorable prognosis group, while patients with unfavorable prognosis were assigned into the unfavorable prognosis group. The variation and difference in liver and spleen shear wave velocity in these two groups were analyzed by repeated measurement analysis of variance. Meanwhile, in order to evaluate the effect of liver and spleen shear wave velocity on the prognosis of patients with portal hypertension, Cox's proportional hazard regression model analysis was applied. The ability of those factors in predicting the prognosis of patients with portal hypertension was calculated through receiver operating characteristic (ROC) curves. RESULTS: The liver and spleen shear wave velocity in the favorable prognosis group revealed a clear decline, while those in the unfavorable prognosis group revealed an increasing tendency at different time points. Furthermore, liver and spleen shear wave velocity was higher in the unfavorable prognosis group, compared with the favorable prognosis group; the differences were statistically significant (P < 0.05). The prognosis of patients with portal hypertension was significantly affected by spleen hardness at the 3rd month after treatment [relative risk (RR) = 3.481]. At the 9th month after treatment, the prognosis was affected by liver hardness (RR = 5.241) and spleen hardness (RR = 7.829). The differences between these two groups were statistically significant (P < 0.05). The ROC analysis revealed that the area under the curve (AUC) of spleen hardness at the 3rd month after treatment was 0.644, while the AUCs of liver and spleen hardness at the 9th month were 0.579 and 0.776, respectively. These might predict the prognosis of patients with portal hypertension. CONCLUSION: Spleen hardness at the 3rd month and liver and spleen shear wave velocity at the 9th month may be used to assess the prognosis of patients with portal hypertension. This is hoped to be used as an indicator of predicting the prognosis of patients with portal hypertension. PMID- 29259382 TI - Efficacy of combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients: A randomized study. AB - AIM: To assess the effects of a combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients. METHODS: A two-center, randomized, open-label, prospective study was conducted. Japanese patients who met the criteria were randomized to trial group and the combination diuretic group (received 7.5 mg of tolvaptan) or the conventional diuretic group (received 40 mg of furosemide) for 7 d in addition to the natriuretic drug which was used prior to enrolment in this study. The primary endpoint was the change in body weight from the baseline. Vital signs, fluid intake, and laboratory and urinary data were assessed to determine the pharmacological effects after administration of aquaretic and natriuretic drugs. RESULTS: A total of 56 patients were randomized to receive either tolvaptan (n = 28) or furosemide (n = 28). In the combination and conventional diuretic groups, the average decrease in body weight from the baseline was 3.21 +/- 3.17 kg (P < 0.0001) and 1.75 +/- 2.36 kg (P = 0.0006), respectively, when measured on the final dosing day. Following 1 wk of treatment, a significantly greater reduction in body weight was observed in the combination diuretic group compared to that in the conventional diuretic group (P = 0.0412). CONCLUSION: Compared to a conventional diuretic therapy with only a natriuretic drug, a combination diuretic therapy with natriuretic and aquaretic drugs is more effective for patients with cirrhotic ascites. PMID- 29259383 TI - Double-balloon enteroscopy-assisted dilatation avoids surgery for small bowel strictures: A systematic review. AB - AIM: To evaluate the therapeutic role of double-balloon enteroscopy (DBE) in small bowel strictures and to propose a standard approach to small bowel strictures. METHODS: Systematic review of studies involving DBE in patients with small bowel strictures. Only studies limited to small bowel strictures were included and those with ileo-colonic strictures were excluded. RESULTS: In total 13 studies were included, in which 310 patients were dilated. The average follow up time was 31.8 mo per patient. The complication rate was 4.8% per patient and 2.6% per dilatation. Surgery was avoided in 80% of patients. After the first dilatation, 46% were treated with re-dilatation and only 17% required surgery. CONCLUSION: DBE-assisted dilatation avoids surgery in 80% of patients with small bowel strictures and is safe and effective. We propose a standardized approach to small bowel strictures. PMID- 29259384 TI - Impact of inflammatory bowel disease activity and thiopurine therapy on birth weight: A meta-analysis. AB - AIM: To investigate the effect of disease activity or thiopurine use on low birth weight and small for gestational age in women with inflammatory bowel disease (IBD). METHODS: Selection criteria included all relevant articles on the effect of disease activity or thiopurine use on the risk of low birth weight (LBW) or small for gestational age (SGA) among pregnant women with IBD. Sixty-nine abstracts were identified, 35 papers were full text reviewed and, only 14 of them met inclusion criteria. Raw data were extracted to generate the relative risk of LBW or SGA. Quality was assessed using the Newcastle Ottawa Scale. RESULTS: This meta-analysis is reported according to PRISMA guidelines. Fourteen studies met inclusion criteria, and nine reported raw data suitable for meta-analysis. We found an increased risk ratio of both SGA and LBW in women with active IBD, when compared with women in remission: 1.3 for SGA (4 studies, 95%CI: 1.0-1.6, P = 0.04) and 2.0 for LBW (4 studies, 95%CI: 1.5-2.7, P < 0.0001). Women on thiopurines during pregnancy had a higher risk of LBW (RR 1.4, 95%CI: 1.1-1.9, P = 0.007) compared with non-treated women, but when adjusted for disease activity there was no significant effect on LBW (RR 1.2, 95%CI: 0.6-2.2, P = 0.6). No differences were observed regarding SGA (2 studies; RR 0.9, 95%CI: 0.7-1.2, P = 0.5). CONCLUSION: Women with active IBD during pregnancy have a higher risk of LBW and SGA in their neonates. This should be considered in treatment decisions during pregnancy. PMID- 29259385 TI - Midgut neuroendocrine tumor presenting with acute intestinal ischemia. AB - Neuroendocrine tumors represent a heterogeneous group of neoplasms that arise from neuroendocrine cells and secrete various peptides and bioamines. While gastrointestinal neuroendocrine tumors, commonly called carcinoids, account for about 2/3 of all neuroendocrine tumors, they are relatively rare. Small intestine neuroendocrine tumors originate from intestinal enterochromaffin cells and represent about 1/4 of small intestine neoplasms. They can be asymptomatic or cause nonspecific symptoms, which usually leads to a delayed diagnosis. Imaging modalities can aid diagnosis and surgery remains the mainstay of treatment. We present a case of a jejunal neuroendocrine tumor that caused nonspecific symptoms for about 1 year before manifesting with acute mesenteric ischemia. Abdominal X rays revealed pneumatosis intestinalis and an abdominal ultrasound and computed tomography confirmed the diagnosis. The patient was submitted to segmental enterectomy. Histopathological study demonstrated a neuroendocrine tumor with perineural and arterial infiltration and lymph node metastasis. The postoperative course was uneventful and the patient denied any adjuvant treatment. PMID- 29259386 TI - Endoscopic submucosal dissection in a patient with esophageal adenoid cystic carcinoma. AB - We report the first use of endoscopic submucosal dissection (ESD) for the treatment of a patient with adenoid cystic carcinoma of the esophagus (EACC). An 82-year-old woman visited our hospital for evaluation of an esophageal submucosal tumor. Endoscopic examination showed a submucosal tumor in the middle third of the esophagus. The lesion partially stained with Lugol's solution, and narrow band imaging with magnification showed intrapapillary capillary loops with mild dilatation and a divergence of caliber in the center of the lesion. Endoscopic ultrasound imaging revealed a solid 8 mm * 4.2 mm tumor, primarily involving the second and third layers of the esophagus. A preoperative biopsy was non diagnostic. ESD was performed to resect the lesion, an 8 mm submucosal tumor. Immunohistologically, tumor cells differentiating into ductal epithelium and myoepithelium were observed, and the tissue type was adenoid cystic carcinoma. There was no evidence of esophageal wall, vertical stump or horizontal margin invasion with pT1b-SM2 staining (1800 MUm from the muscularis mucosa). Further studies are needed to assess the use of ESD for the treatment of patients with EACC. PMID- 29259387 TI - Simultaneous liver, pancreas-duodenum and kidney transplantation in a patient with hepatitis B cirrhosis, uremia and insulin dependent diabetes mellitus. AB - Simultaneous liver, pancreas-duodenum, and kidney transplantation has been rarely reported in the literature. Here we present a new and more efficient en bloc technique that combines classic orthotopic liver and pancreas-duodenum transplantation and heterotopic kidney transplantation for a male patient aged 44 years who had hepatitis B related cirrhosis, renal failure, and insulin dependent diabetes mellitus (IDDM). A quadruple immunosuppressive regimen including induction with basiliximab and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids was used in the early stage post-transplant. Postoperative recovery was uneventful and the patient was discharged on the 15th postoperative day with normal liver and kidney function. The insulin treatment was completely withdrawn 3 wk after operation, and the blood glucose level remained normal. The case findings support that abdominal organ cluster and kidney transplantation is an effective method for the treatment of end-stage liver disease combined with uremia and IDDM. PMID- 29259389 TI - Retracted: Induction of Heat Shock Protein Expression in Cervical Epithelial Cells by Human Semen. AB - [This retracts the article DOI: 10.1155/S1064744999000046.]. PMID- 29259388 TI - Genital Tract Infections in an Isolated Community: 100 Women of the Principe Island. AB - Objective: To characterize the vaginal microbiome and the rate of sexually transmitted infections (STIs) in the women of Principe (Sao Tome and Principe). Methods: Cross-sectional study of 100 consecutive women, invited for a free appointment and cervical cancer screening. A vaginal slide (wet mount microscopy) and a cervical sample (ThinPrep(r)) (Pap test, high risk human papillomavirus [HR HPV], N. gonorrhea [NG], T. vaginalis [TV], and C. trachomatis [CT]) were obtained. Results: TV, NG, CT, and HIV were found in 8.0%, 2.0%, 3.0%, and 2.0%, respectively, and were more prevalent in younger women. HR-HPV was positive in 36.7%; 2 were positive for HPV18, but none for HPV16. Coinfection of HPV with other STIs was 8.3%. Prevalence of abnormal vaginal flora (AVF) was 82.5%, mostly bacterial vaginosis (BV) 54.6%, and moderate/severe aerobic vaginitis (msAV) 25.8%. HR-HPV was not related to BV (p = 0.67). The association of abnormal Pap test with msAV was not significant (p = 0.08). Conclusion: The prevalence of NG, CT, TV, and HR-HPV was according to expected, while that of HR-AVF was higher. The surprisingly low prevalence of HPV16 and HPV18 must be considered in the design of programs for prevention and vaccination; this setting can be useful as a model for postvaccination scenarios. PMID- 29259390 TI - Effect of subretinal injection on retinal structure and function in a rat oxygen induced retinopathy model. AB - Purpose: Subretinal injections are used to deliver agents in experimental studies of retinal diseases, often through viral vectors. However, few studies have investigated the effects of subretinal injections alone on the structure and function of the healthy or diseased retina, particularly in models of oxygen induced retinopathy (OIR). We report on the effects of subretinal injections in a rat OIR model, which is used to study mechanisms of retinopathy of prematurity. Methods: Within 6 h of birth, neonatal rat pups were exposed to repeated cycles of oxygen between 50% and 10% O2 every 24 h for 14 days and subsequently moved to room air. On postnatal day 8 (P8), animals were treated in both eyes with advancement of the injection needle into the vitreous (pilot-treated) or with a subretinal PBS injection (sPBS-treated) or were left untreated (untreated). Additional control animals were exposed to microscope light after eyelid opening only (light-treated). Retinal fundus images were recorded on P26. Areas of the avascular retina and intravitreal neovascularization were determined in flat mounted retinas stained with isolectin B4 on P32. Retinal function of the respective eyes was assessed with the Ganzfeld electroretinogram (ERG) on P31 or P32 and with focal ERG in the central retina on P28 or P29. The thickness of the retinal layers was measured with spectral domain optical coherence tomography (OCT) on P30 and in opsin- and TO-PRO 3-stained retinal cryosections from pups euthanized on P32. Two sections were analyzed in each pup. For each section, three images of three different locations were analyzed accounting for 18 thickness measurements per pup. Results: Compared to untreated animals, the avascular area of the retina was greater in the pilot-treated (p<0.05) and sPBS treated eyes (p<0.01), and the sPBS-treated eyes had a greater avascular retinal area compared to the pilot-treated eyes (p<0.01). The intravitreal neovascular area was larger in the sPBS-treated eyes compared to the untreated eyes (p<0.01). The outer nuclear and outer segment layers were thinner in the pilot- (p<0.01) and sPBS-treated eyes (p<0.05) compared to the untreated eyes as measured with OCT and immunohistochemical staining of the retinal cryosections. Compared to the untreated eyes, the amplitudes of the scotopic a- and b-waves in the Ganzfeld ERG were reduced in the pilot-treated eyes (p<0.001 and p<0.01, respectively), but only the a-wave was reduced in the sPBS-treated eyes (p<0.001). The a-wave amplitude in the focal ERG was reduced in the pilot- and sPBS-treated eyes, and no difference was seen in the b-wave amplitude between any of the groups. There was no difference between the light-treated and untreated eyes in the areas of the avascular retina or intravitreal neovascularization or Ganzfeld or focal ERG. Conclusions: Pilot injections alone without injection into the subretinal space resulted in an increased avascular retinal area, reduced thickness of the photoreceptors, and reduced ERG function compared to the untreated animals. Although subretinal PBS injections further increased the areas of avascular retina and intravitreal neovascularization and resulted in similar retinal thinning compared to the pilot treatment, inner retinal function was improved, as evidenced by higher Ganzfeld b-wave amplitudes. Differences in the Ganzfeld and focal ERGs may indicate that the peripheral retina is more susceptible to remote beneficial effects from potential protective mechanisms induced by subretinal injection. This study stresses the importance of appropriate controls in experiments with subretinal delivery of agents. PMID- 29259391 TI - Melatonin partially protects 661W cells from H2O2-induced death by inhibiting Fas/FasL-caspase-3. AB - Purpose: Previous studies have shown that melatonin (MEL) signaling is involved in the modulation of photoreceptor viability during aging. Recent work by our laboratory suggested that MEL may protect cones by modulating the Fas/FasL caspase-3 pathway. In this study, we first investigated the presence of MEL receptors (MT1 and MT2) in 661W cells, then whether MEL can prevent H2O2-induced cell death, and last, through which pathway MEL confers protection. Methods: The mRNA and proteins of the MEL receptors were detected with quantitative PCR (q PCR) and immunocytochemistry, respectively. To test the protective effect of MEL, 661W cells were treated with H2O2 for 2 h in the presence or absence of MEL, a MEL agonist, and an antagonist. To study the pathways involved in H2O2-mediated cell death, a Fas/FasL antagonist was used before the exposure to H2O2. Finally, Fas/FasL and caspase-3 mRNA was analyzed with q-PCR and immunocytochemistry in cells treated with H2O2 and/or MEL. Cell viability was analyzed by using Trypan Blue. Results: Both MEL receptors (MT1 and MT2) were detected at the mRNA and protein levels in 661W cells. MEL partially prevented H2O2-mediated cell death (20-25%). This effect was replicated with IIK7 (a melatonin receptor agonist) when used at a concentration of 1 uM. Preincubation with luzindole (a melatonin receptor antagonist) blocked MEL protection. Kp7-6, an antagonist of Fas/FasL, blocked cell death caused by H2O2 similarly to what was observed for MEL. Fas, FasL, and caspase-3 expression was increased in cells treated with H2O2, and this effect was prevented by MEL. Finally, MEL treatment partially prevented the activation of caspase-3 caused by H2O2. Conclusions: The results demonstrate that MEL receptors are present and functional in 661W cells. MEL can prevent photoreceptor cell death induced by H2O2 via the inhibition of the proapoptotic pathway Fas/FasL-caspase-3. PMID- 29259392 TI - Association of HMGB1 with oxidative stress markers and regulators in PDR. AB - Purpose: We investigated the link among the proinflammatory cytokine high mobility group box 1 (HMGB1) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of oxidative DNA damage, the endothelial adhesion molecule and oxidase enzyme vascular adhesion protein-1 (VAP-1), and the inducible cytoprotective molecule heme oxygenase-1 (HO-1) in proliferative diabetic retinopathy (PDR). We correlated the levels of these molecules with clinical disease activity and studied the proinflammatory activities of HMGB1 on rat retinas and human retinal microvascular endothelial cells (HRMECs). Methods: Vitreous samples from 47 PDR and 19 non-diabetic patients, epiretinal membranes from 11 patients with PDR, human retinas (16 from diabetic patients and 16 from non-diabetic subjects), rat retinas, and HRMECs were studied by enzyme-linked immunosorbent assay, immunohistochemistry, western blot immunofluorescence, and RT-PCR analyses. In addition, we assessed the adherence of leukocytes to HMGB1-stimulated HRMECs. Results: HMGB1, 8-OHdG, and soluble VAP-1 (sVAP-1) levels were significantly higher in vitreous samples from PDR patients than in those from non-diabetics (p = 0.001, <0.0001, <0.0001, respectively). The HMGB1, 8-OHdG, sVAP-1, and HO-1 levels in PDR with active neovascularization were significantly higher than those in inactive PDR (p = 0.025, <0.0001, <0.0001, 0.012, respectively). Significant positive correlations were observed between the levels of HMGB1 and the levels of 8-OHdG (r = 0.422; p = 0.001) and sVAP-1 (r = 0.354; p = 0.004) and between the levels of 8-OHdG and the levels of sVAP-1 (r = 0.598; p<0.0001). In epiretinal membranes, VAP-1 and 8-OHdG were expressed in vascular endothelial cells and stromal cells. Significant increases in the VAP-1 mRNA and protein levels were detected in the RPE, but not in the neuroretina of diabetic patients. Treatment of HRMEC with HMGB1, diabetes induction, and an intravitreal injection of HMGB1 in normal rats induced a significant upregulation of the adhesion molecule intercellular adhesion molecule-1 (ICAM-1) in HRMECs and retinas. On the other hand, the expressions of vascular cell adhesion molecule-1 and VAP-1 were not affected. Oral administration of the HMGB1 inhibitor glycyrrhizin in rats attenuated the diabetes-induced upregulation of the retinal ICAM-1 expression. Treatment of HRMECs with HMGB1 increased leukocyte adhesion and induced the upregulation of 8-OHdG and HO-1 and the membranous translocation of VAP-1. Conclusions: Our results suggest a potential link among the proinflammatory cytokine HMGB1, VAP-1, oxidative stress, and HO-1 in the pathogenesis of PDR. PMID- 29259393 TI - The retina/RPE proteome in chick myopia and hyperopia models: Commonalities with inherited and age-related ocular pathologies. AB - Purpose: Microarray and RNA sequencing studies in the chick model of early optically induced refractive error have implicated thousands of genes, many of which have also been linked to ocular pathologies in humans, including age related macular degeneration (AMD), choroidal neovascularization, glaucoma, and cataract. These findings highlight the potential relevance of the chick model to understanding both refractive error development and the progression to secondary pathological complications. The present study aimed to determine whether proteomic responses to early optical defocus in the chick share similarities with these transcriptome-level changes, particularly in terms of dysregulation of pathology-related molecular processes. Methods: Chicks were assigned to a lens condition (monocular +10 D [diopters] to induce hyperopia, -10 D to induce myopia, or no lens) on post-hatch day 5. Biometric measures were collected following a further 6 h and 48 h of rearing. The retina/RPE was then removed and prepared for liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) on an LTQ-Orbitrap Elite. Raw data were processed using MaxQuant, and differentially abundant proteins were identified using moderated t tests (fold change >=1.5, Benjamini-Hochberg adjusted p<0.05). These differentially abundant proteins were compared with the genes and proteins implicated in previous exploratory transcriptome and proteomic studies of refractive error, as well as the genes and proteins linked to the ocular pathologies listed above for which myopia or hyperopia are risk factors. Finally, gene set enrichment analysis (GSEA) was used to assess whether gene sets from the Human Phenotype Ontology database were enriched in the lens groups relative to the no lens groups, and at the top or bottom of the protein data ranked by Spearman's correlation with refraction at 6 and 48 h. Results: Refractive errors of -2.63 D +/- 0.31 D (mean +/- standard error, SE) and 3.90 D +/- 0.37 D were evident in the negative and positive lens groups, respectively, at 6 h. By 48 h, refractive compensation to both lens types was almost complete (negative lens 9.70 D +/- 0.41 D, positive lens 7.70 D +/- 0.44 D). More than 140 differentially abundant proteins were identified in each lens group relative to the no lens controls at both time points. No proteins were differentially abundant between the negative and positive lens groups at 6 h, and 13 were differentially abundant at 48 h. As there was substantial overlap in the proteins implicated across the six comparisons, a total of 390 differentially abundant proteins were identified. Sixty-five of these 390 proteins had previously been implicated in transcriptome studies of refractive error animal models, and 42 had previously been associated with AMD, choroidal neovascularization, glaucoma, and/or cataract in humans. The overlap of differentially abundant proteins with AMD-associated genes and proteins was statistically significant for all conditions (Benjamini-Hochberg adjusted p<0.05), with over-representation analysis implicating ontologies related to oxidative stress, cholesterol homeostasis, and melanin biosynthesis. GSEA identified significant enrichment of genes associated with abnormal electroretinogram, photophobia, and nyctalopia phenotypes in the proteins negatively correlated with ocular refraction across the lens groups at 6 h. The implicated proteins were primarily linked to photoreceptor dystrophies and mitochondrial disorders in humans. Conclusions: Optical defocus in the chicks induces rapid changes in the abundance of many proteins in the retina/RPE that have previously been linked to inherited and age-related ocular pathologies in humans. Similar changes have been identified in a meta-analysis of chick refractive error transcriptome studies, highlighting the chick as a model for the study of optically induced stress with possible relevance to understanding the development of a range of pathological states in humans. PMID- 29259395 TI - Cervical Spine Mechanism for Reproduction of the Biomechanical Behaviours of the Human Neck during Rotation-Traction Manipulation. AB - Rotation-traction (RT) manipulation is a commonly used physical therapy procedure in TCM (traditional Chinese medicine) for cervical spondylosis. This procedure temporarily separates the C3 and C4 cervical vertebrae from each other when a physician applies a jerky action while the neck is voluntarily turned by the patient to a specific position as instructed by the physician, where the cervical vertebrae are twisted and locked. However, a high rate of cervical injury occurs due to inexperienced physician interns who lack sufficient training. Therefore, we developed a cervical spine mechanism that imitates the dynamic behaviours of the human neck during RT manipulation. First, in vivo and in vitro experiments were performed to acquire the biomechanical feature curves of the human neck during RT manipulation. Second, a mass-spring-damper system with an electromagnetic clutch was designed to emulate the entire dynamic response of the human neck. In this system, a spring is designed as rectilinear and nonlinear to capture the viscoelasticity of soft tissues, and an electromagnetic clutch is used to simulate the sudden disengagement of the cervical vertebrae. Test results show that the mechanism can exhibit the desired behaviour when RT manipulation is applied in the same manner as on humans. PMID- 29259394 TI - Characterizing the effect of supplements on the phenotype of cultured macrophages from patients with age-related macular degeneration. AB - Purpose: Oral vitamin and mineral supplements reduce the risk of visual loss in age-related macular degeneration (AMD). However, the pathways that mediate this beneficial effect are poorly understood. Macrophages may exert oxidative, inflammatory, and angiogenic effects in the context of AMD. We aim to assess if oral supplements can modulate the macrophage phenotype in this disease. Methods: Monocytes were isolated from patients with neovascular AMD (nvAMD), cultured, matured to macrophages, and polarized to classical [M1 (stimulated by IFNgamma and lipopolysaccharide (LPS))] and alternative [M2 (stimulated with IL-4 and IL 13)] phenotypes. Combinations of antioxidants including lutein+zeaxanthin (1 MUM; 0.2 MUM), zinc (10 uM), carnosic acid (2 uM), beta-carotene (2 uM), and standardized tomato extract containing lycopene and other tomato phytonutrients were added to the culture media. Levels of anti-inflammatory, antioxidant, and pro-angiogenic gene and protein expression were then evaluated. Results: Combinations of lutein and carnosic acid with zinc and standardized tomato extract or with beta-carotene yielded an antioxidative, anti-inflammatory, and antiangiogenic effect in M1 and M2 macrophages. These effects manifested in the upregulation of antioxidative genes (HMOX1, SOD1) and the downregulation of pro angiogenic genes and pro-inflammatory genes (SDF-1, TNF-alpha, IL-6, MCP-1). Lutein monotherapy or a combination of lutein and zinc had less effect on the expression of these genes. Conclusions: Combinations of supplements can modify the expression of genes and proteins that may be relevant for the involvement of macrophages in the pathogenesis of AMD. Further studies are required to evaluate if the modulation of the macrophage phenotype partially accounts for the beneficial effect of oral supplements in AMD and if modification of the AREDS formula can improve its effect on macrophages. PMID- 29259397 TI - Ovarian tissue cryopreservation in young cancer patients for fertility preservation. AB - Several options are currently available to preserve fertility and give female cancer survivors a chance to have children at a later date, including the cryopreservation of embryos, oocytes, and ovarian tissue. Selection of the most suitable strategy to preserve fertility depends on the type and timing of anticancer therapy, the cancer, the patient's age, and the presence of the patient's partner. Several studies have shown that the ovarian tissue can be successfully frozen and later grafted in the human womb. To date, approximately 30 live births have been achieved after the transplantation of frozen-thawed ovarian tissue. At present, the standard procedure for cryopreservation of ovarian tissue is the slow-cooling method. The slow-cooling method uses an optimal cooling rate for the target cells, and relies on extracellular ice crystals to gradually dehydrate and equilibrate the tissue. Several groups reported that slow cooling is more efficient than vitrification for the cryopreservation of human ovarian tissue. However, vitrification can be performed under a variety of conditions, and therefore, the choice of methods is important. In addition, vitrification traps aqueous solutions in an amorphous, "vitreous" solid phase that prevents ice crystal formation in tissues. Vitrification methods that were developed using mice and monkey have recently been shown to improve the viability of vitrified ovarian tissues. In this review article, recent topics of ovarian tissue cryopreservation are described. PMID- 29259396 TI - Galactomannan in Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Pulmonary Aspergillosis with Nonneutropenic Patients. AB - Background: We evaluated the utility of galactomannan (GM) in bronchoalveolar lavage fluid (BALF) for the diagnosis of invasive pulmonary aspergillosis (IPA) in nonneutropenic patients. Methods: A total of 183 patients were included in the final analysis. Bronchoscopies and the detection of GM in BALF were all performed on them. Results: Ten cases of IPA were diagnosed. ROC data demonstrated that, for diagnosing IPA, an optimal cutoff value for GM in BALF of 0.76 yielded a sensitivity of 100.0% and a specificity of 76.2%. Symptoms and radiological findings had no significant difference between proven or probable IPA group and non-IPA group. In our case-control analysis, although nine patients with false positive results received treatment with Piperacillin/tazobactam, there was no significant difference between case and control group. Conclusions: BALF GM detection is a valuable adjunctive diagnostic tool. Our retrospective study suggests that the optimal value of GM detection in BALF is 0.76 in nonneutropenic patients. PMID- 29259398 TI - The relationship between p53 codon 72 genetic polymorphism and sperm parameters. A study of men with varicocele. AB - Purpose: Regulation of the apoptotic process has an important role in spermatogenesis. p53 has a prominent function in apoptosis and recent data suggest a relationship between varicocele and p53 codon 72 polymorphism and male infertility. This prompted us to study the relationship between this polymorphism and spermatic parameters. Methods: We studied 134 subjects with varicocele admitted consecutively to the outpatients Department of Infertility at the University of Rome La Sapienza. We investigated in these subjects the effect of a strong apoptosis inducer, the p53 codon 72 *Arg/*Arg genotype, on spermatic parameters.The p53 codon 72 genotype was determined by DNA analysis. Results: The proportion of spermatozoa with abnormal (curvilinear) motility is higher in men with the *Arg/*Arg genotype than in men carrying the *Pro allele (p = 0.003). No statistical significant relationship has been observed with spermatozoa concentration and atypical spermatozoa. Conclusions: We conclude: the p53 codon 72*Arg/*Arg genotype, with its strong apoptotic effects, negatively influences spermatozoa motility and male fertility. PMID- 29259399 TI - The role of signaling pathways on proliferation and self-renewal of cultured bovine primitive germ cells. AB - Purpose: Gonocytes are primitive male germ cells residing in the neonatal testes and are unipotent in nature, but also have pluripotent stem cell ability in mice under appropriate culture conditions. This study was performed to elucidate the molecular mechanisms of self-renewal and survival of cultured bovine gonocytes. Methods: Gonocytes were isolated from neonatal bull calves and were cultured in DMEM/F12 supplemented with 15 % knock-out serum replacement (KSR) and glial cell derived neurotrophic factor (GDNF). Cells were analyzed six days after culturing for cell-signaling molecular markers. Results: Colony formation was observed 3-4 days after being cultured. Addition of GDNF enhanced mitogen-activated protein kinase 1/2 (MAPK1/2) phosphorylation and activated the MAPK signaling pathway. Inhibition of MAPK signaling reduced cell proliferation and abolished colony formation. However, inhibition of phosphoinositide 3-kinase-AKT (PI3K-AKT) signaling, a dominant pathway for self-renewal of mouse germ cells, did not show any effects on cultured bovine gonocytes. Expression of cell cycle-related regulators cyclin D2 and cyclin-dependent kinase 2 (CDK2) was downregulated with inhibition of MAPK signaling. Conclusions: These results indicate activation of MAPK plays a critical role in self-renewal and survival of bovine gonocytes via cyclin D1 and CDK2. PMID- 29259400 TI - Effects of Hachimijiogan, a Kampo powder, on epididymidis sperm characteristics in healthy male rats. AB - Purpose: Hachimijiogan (HJG, Rehmannia Eight Formula), a kidney-replenishing Kampo formula, is clinically known to be effective in the treatment of male infertility with oligozoospermia. The purpose of this study was to evaluate the effect of HJG on the epididymal sperm characteristics and related serum hormone changes in rats in an attempt to determine its mechanism. Methods: Male Wistar Imamichi rats (233.4 +/- 5.2 g, nine weeks old) were assigned randomly to four groups (n = 6 for each group). Apart from one control group treated with distilled water, the other groups were administered HJG consecutively for 9-11 days with doses of 250, 500 and 1,000 mg/kg. After the last administration the caude epididymides were quickly removed under anesthesia for assessing sperm characteristics. Additionally, the testes, seminal vesicles, prostate and adrenal glands were removed surgically and their wet weights measured. Results: Results showed that HJG increased sperm numbers and motility as well as the weights of seminal vesicles and adrenal glands at lower doses. Moreover, HJG decreased serum levels of testosterone and luteinizing hormone while increasing follicle stimulating hormone levels. Conclusions: Our findings may support the conclusion that a lower dosage of HJG has an effect on improving local spermatogenous environments by activating adrenal functions and/or promoting local androgen activity. PMID- 29259401 TI - Regulation of gonadotropin secretion by monitoring energy availability. AB - Nutrition is a principal environmental factor influencing fertility in animals. Energy deficit causes amenorrhea, delayed puberty, and suppression of copulatory behaviors by inhibiting gonadal activity. When gonadal activity is impaired by malnutrition, the signals originating from an undernourished state are ultimately conveyed to the gonadotropin-releasing hormone (GnRH) pulse generator, leading to suppressed secretion of GnRH and luteinizing hormone (LH). The mechanism responsible for energetic control of gonadotropin release is believed to involve metabolic signals, sensing mechanisms, and neuroendocrine pathways. The availabilities of blood-borne energy substrates such as glucose, fatty acids, and ketone bodies, which fluctuate in parallel with changes in nutritional status, act as metabolic signals that regulate the GnRH pulse generator activity and GnRH/LH release. As components of the specific sensing system, the ependymocytes lining the cerebroventricular wall in the lower brainstem integrate the information derived from metabolic signals to control gonadotropin release. One of the pathways responsible for the energetic control of gonadal activity consists of noradrenergic neurons from the solitary tract nucleus in the lower brainstem, projecting to the paraventricular nucleus of the hypothalamus. Further studies are needed to elucidate the mechanisms underlying energetic control of reproductive function. PMID- 29259402 TI - The role of antiphospholipid antibodies (aPls) in infertile women: the long lasting experience. AB - Antiphospholipid antibodies (aPls) are generally characterized as heterogeneous and non-specific autoantibodies directed against various phospholipids such as cardiolipin, ph-serine, ph-inositol, ph-acid, ph-glycerol, ph-sphyngomyelin, ph choline, annexins, and co-factor beta2-glycoprotein I. aPls occur not only during autoimmune diseases but also during infectious diseases, essential hypertension, neurological complication, metabolic diseases, some drug abuse, and transplant loss. aPls are very often found in connection with reproductive failure such as repeated pregnancy loss and/or missed abortion, intrauterine fetal death, in preeclampsia, and repeated delivery of hypothrophic fetus. The presence of aPls, thrombosis, and fertility failure create primary or secondary antiphospholipid syndrome. This article explains some aspects and clinical and laboratory significance of the aPls in female infertility. PMID- 29259403 TI - Autophagic activity as an indicator for selecting good quality embryos. AB - Is it possible to predict the quality of embryos that appear to be morphologically identical when viewed under a microscope? Thirty-five years have passed since the world's first human birth from in vitro fertilization. While the dissemination of assisted reproduction technologies during this time has been remarkable, the evaluation of embryo quality in both humans and mice currently relies entirely on morphological observation. More efficient infertility treatments will likely be possible if high-quality embryos can be selected by screening. To develop a novel quality evaluation method that does not rely on morphology, we focused on autophagy, one of the molecular mechanisms essential for the early embryonic development. Autophagy is a massive cytoplasmic degradation pathway mediated by the lysosome. Our previous studies have demonstrated that fertilization-induced autophagy is essential for preimplantation embryonic development. This autophagy is thought to supply the nutrients and amino acids necessary for maintaining subsequent embryo development, through the bulk degradation of maternal cytoplasmic factors that are accumulated during oogenesis. Here, we briefly summarize autophagy and its physiological function, and describe a recently developed method for using autophagic activity as an indicator to predict embryo quality. PMID- 29259404 TI - Hormonal therapy for non-obstructive azoospermia: basic and clinical perspectives. AB - Microdissection testicular sperm extraction (micro-TESE) combined with intracytoplasmic sperm injection is a standard therapeutic option for patients with non-obstructive azoospermia (NOA). Hormonal treatment has been believed to be ineffective for NOA because of high gonadotropin levels; however, several studies have stimulated spermatogenesis before or after micro-TESE by using anti estrogens, aromatase inhibitors, and gonadotropins. These results remain controversial; however, it is obvious that some of the patients showed a distinct improvement in sperm retrieval by micro-TESE, and sperm was observed in the ejaculates of a small number of NOA patients. One potential way to improve spermatogenesis is by optimizing the intratesticular testosterone (ITT) levels. ITT has been shown to be increased after hCG-based hormonal therapy. The androgen receptor that is located on Sertoli cells plays a major role in spermatogenesis, and other hormonal and non-hormonal factors may also be involved. Before establishing a new hormonal treatment protocol to stimulate spermatogenesis in NOA patients, further basic investigations regarding the pathophysiology of spermatogenic impairment are needed. Gaining a better understanding of this issue will allow us to tailor a specific treatment for each patient. PMID- 29259405 TI - Clomiphene citrate affects the receptivity of the uterine endometrium. AB - Purpose: To investigate whether clomiphene citrate (CC) affects uterine receptivity or not, we evaluated pregnancy rates (PR) during the hormone replacement cycle (HRC) according to the period between the last day of CC administration and the day of embryo transfer (ET). Methods: From March 2008 through March 2010, a total of 378 treatment cycles among 378 patients who received CC and had to avoid fresh ET due to a thin uterine endometrium were recruited. All patients underwent thawed ET using HRC. PRs were evaluated according to the period between the last CC treatment and the day of ET. Results: PR for the groups in which the period between the last CC treatment and the day of ET increased to more than 91 days were significantly higher than that for group in which the period was less than 90 days (p < 0.05). Conclusions: A lower PR was shown by the patients who underwent thawed ET in the HRC within 90 days after their last CC treatment, which shows that CC affects the receptivity of the uterine endometrium. PMID- 29259406 TI - Cabergoline administration prevents development of moderate to severe ovarian hyperstimulation syndrome and it contributes to reduction in ovarian volume. AB - Purpose: The aim of this study was to determine the prophylactic effects of cabergoline on ovarian hyperstimulation syndrome (OHSS) after oocyte retrieval. Methods: A total of 187 women underwent controlled ovarian stimulation using gonadotropin releasing hormone (GnRH) agonist long protocol or flexible GnRH antagonist protocol for in vitro fertilization. They responded excessively to ovulation induction, and fresh embryo transfers were canceled. Sixty-one patients in the intervention group were administered oral cabergoline (0.5 mg) three times after oocyte retrieval (day 0, 2, and 4 following the oocyte retrieval). Ultrasonography and blood examination were performed on the seventh day following oocyte retrieval. The main outcomes measured were the incidence of OHSS, estimated ovarian volumes, ascites, hematocrits, and white blood cell counts. Results: The incidence of moderate to severe OHSS was lower after cabergoline administration (9.8 vs. 23.0 %, p = 0.03). The ovarian volumes reduced after intervention (96.2 vs. 145.5 cm3, p = 0.008). The reduction was evident in the patients with agonist long protocol (92.1 vs. 167.5 cm3, p = 0.0005). No significant differences were observed for other factors. Conclusions: Cabergoline has a favorable effect on the prevention of moderate to severe OHSS affiliated with ovarian volume reduction. PMID- 29259408 TI - In vitro fertilization embryo development from caffeine-treated murine sperm. AB - Purpose: To evaluate the effect of long-term caffeine administration on murine sperm and subsequent in vitro fertilization (IVF). Methods: Male mice were injected with various doses (0, 0.2 and 1.0 mg/mouse/day) of caffeine for 1 month. After sperm collection, the IVF rate and embryo development to the blastocyst stage were evaluated. Results: The mean body weight significantly decreased in the 1.0 mg/day treatment group compared to the control group (P < 0.01). Testicular weight and histological features did not differ, and total blood testosterone was no different in spite of the difference between 0.2 and 1.0 mg/day of caffeine. The IVF rate differed significantly between the control group [100/105 (95.2 %)] and 0.2 mg/day group [106/121 (87.6 %)] (P < 0.05). Furthermore, blastocyst formation was significantly and dose-dependently lower with higher caffeine levels: control group: 85/100 (85.0 %); 0.2 mg/day group: 84/106 (79.2 %) (P < 0.05); 1.0 mg/day group: 64/102 (62.7 %) (P < 0.001). Conclusions: Caffeine treatment affected body weight of male mice. However, testicular weight, histological features and total blood testosterone concentration were not statistically different. In addition, following IVF using sperm from these mice, blastocyst formation decreased in a dose-dependent manner. These findings suggest that embryo development from oocytes fertilized with sperm from caffeine-administered male mice is negatively affected. PMID- 29259407 TI - Simple gamete preservation and artificial reproduction of mammals using micro insemination techniques. AB - Assisted reproductive technology (ART) has been applied in various procedures as an effective breeding method in experimental, domestic, and wild animals, and for the treatment of human infertility. Micro-insemination techniques such as intracytoplasmic injection of spermatozoa and spermatids are now routinely used ART tools. With these techniques, even immotile and immature sperm cells can be employed as donors for producing the next generation. Gamete preservation, another ART tool, has contributed to reproductive regulation, worldwide transportation, and disease protection of animal strains, and the preserved gametes have been effectively used for the production of offspring. ART is now an indispensable tool in mammalian reproduction. This review covers the latest ART tools, with a particular emphasis on micro-insemination and gamete preservation, and discusses the future direction of mammalian artificial reproductive technology. PMID- 29259409 TI - Insulin resistance in nonobese Japanese women with polycystic ovary syndrome is associated with poorer glucose tolerance, delayed insulin secretion, and enhanced insulin response. AB - Purpose: To determine the prevalence of insulin resistance (IR) and impaired glucose tolerance (IGT) in PCOS patients, the optimal screening method, and to compare our findings between nonobese and obese Japanese women with PCOS. Methods: Ninety-eight PCOS patients were included in this research from 2006 to 2013. Glucose tolerance test (OGTT) was performed. Serum glucose and insulin concentration were assayed before and 30, 60, and 120 min after taking 75 g of glucose. Results: All examined metabolic parameters were significantly favorable in the nonobese subjects, below 25 kg/m2. HOMA-IR, fasting insulin, glucose120, and insulin120 showed strong correlations with BMI. A total of 1.4 % of nonobese women had IR based on fasting insulin or HOMA-IR. However, 15.5 % (11/71) of nonobese women had IR as determined by a continuous increase of serum insulin level in OGTT. In comparison, the prevalence of IR among the obese women ranged from 41 to 59 %. AUCglucose, glucose60, glucose120, and insulin120 in nonobese women with a continuous insulin increase were higher than those without such a continuous increase. Conclusions: All examined metabolic parameters were significantly correlated with BMI. As the presence of a continuous increase of insulin level reflects to some degree poorer glucose tolerance, delayed insulin secretion, and enhanced insulin response compared with non-continuous insulin increase, OGTT might not been excluded to determine IR and IGT for nonobese women with PCOS. PMID- 29259410 TI - Menstrual restoration in severe panhypopituitarism many years after cranial irradiation for suprasellar germinoma. AB - Purpose: We report a very rare case showing menstrual restoration in severe pan hypopituitarism many years after cranial irradiation for suprasellar germinoma. Case: A 30-year-old, almost primarily amenorrheic woman with severe panhypopituitarism presented with cyclic genital bleeding for the previous five months. She had menstruated once, when she was 13 years old. When she was 14 years old, she was diagnosed with a suprasellar germinoma measuring 10 mm in diameter, which led to diabetes insipidus. Cranial irradiation with a total dose of 24 Gy and chemotherapy resulted in complete tumor remission. She developed severe hypopituitarism [luteinizing hormone (LH) = 0.4 mIU/mL, follicle stimulating hormone (FSH) = 1.7 mIU/mL, and serum estradiol (E2) level < 10 pg/mL]. She had received multiple hormone replacement therapies for many years. When she was 29 years old, she expressed a desire to become pregnant. Serum gonadotropin and E2 levels increased (LH = 5.8 mIU/mL, FSH = 5.9 mIU/mL, and E2 = 58 pg/mL). She conceived with clomiphene therapy, and then delivered a healthy baby. Eight months after parturition, her basal body temperature and serum progesterone levels indicated recovery of ovulatory cycles. Ten months after parturition, she also spontaneously conceived. Conclusion: Menstrual restoration is very rare in severe panhypopituitarism after cranial irradiation. A relatively low dose of irradiation and small tumor size may have contributed to the recovery of menstruation in our patient. PMID- 29259412 TI - NK cell abnormality and its treatment in women with reproductive failures such as recurrent pregnancy loss, implantation failures, preeclampsia, and pelvic endometriosis. AB - The regulation of uterine and peripheral blood natural killer (NK) cells has been associated with problems related to reproductive immunology such as recurrent pregnancy loss (RPL), implantation failure or preeclampsia. NKp46, one of the natural cytotoxicity receptors (NCRs), is a unique marker that functions in NK cell cytotoxicity and cytokine production. Expression of NKp46 on NK cells is lower in women with recurrent pregnancy loss and pregnancy-induced hypertension. Moreover, expression of NKp46 on peritoneal fluid NK cells is lower in women with pelvic endometriosis. Therefore, evaluation of NKp46 on peripheral blood NK cells may provide a means of screening for reproductive abnormalities. Recently, a new type of NK cell, the NK22 cell, has been reported. This cell may be a regulator not only of the mucosal barrier but also of reproduction. For women with RPL showing abnormal uterine and/or peripheral blood NK cells, both intravenous immunoglobulin treatment and intralipid treatment have been reported. The effects of these treatments are still controversial, and further studies are needed in order to clarify their true impact. The present review examines variations in the expression of NCRs on NK cells, the participation of NK22 cells in reproduction, and the possible use of intravenous immunoglobulin or intralipid treatment for women with recurrent pregnancy loss and NK cell abnormality. PMID- 29259411 TI - Making the first decision: lessons from the mouse. AB - Pre-implantation development encompasses a period of 3-4 days over which the mammalian embryo has to make its first decision: to separate the pluripotent inner cell mass (ICM) from the extra-embryonic epithelial tissue, the trophectoderm (TE). The ICM gives rise to tissues mainly building the body of the future organism, while the TE contributes to the extra-embryonic tissues that support embryo development after implantation. This review provides an overview of the cellular and molecular mechanisms that control the critical aspects of this first decision, and highlights the role of critical events, namely zytotic genome activation, compaction, polarization, asymmetric cell divisions, formation of the blastocyst cavity and expression of key transcription factors. PMID- 29259414 TI - Declining semen quality and steadying seminal plasma ions in heat-stressed boar model. AB - Purpose: There are increasing concerns about infertility of male exposure to high environmental temperatures. Nevertheless, the relationship between heat and accessory sex gland secretion underlying the high ambient temperature-induced poor semen quality has not yet been addressed. Methods: In the present study, five boars were used as an animal model to evaluate semen quality and the secretory function of accessory sex glands. After the boars received 3 days of heat exposure, semen collection was standardized to 18 continual times with a 3 day interval to determine the semen variables of semen volume, semen concentration, abnormal spermatozoa, seminal plasma composition, and testosterone level in the seminal plasma and serum. Results: The total sperm count was lowest by the end of week 2. The higher abnormal spermatozoa percentage were observed by the end of week 2 and persisted until week 6 after heat exposure. Additionally, there was no significant change in semen volume, testosterone level, and concentrations of ions and total protein in the seminal plasma before and after heat exposure. Conclusions: A single 3-day heat exposure caused poor semen quality, but did not disturb accessory sex gland secretion in boars. Declining semen quality might be mainly due to the damaged germ cells, which were sensitive to elevated temperature in hot summer months. PMID- 29259413 TI - Oocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies. AB - In recent years, postponement of marriage and childbearing in women of reproductive age has led to an increase in the incidence of age-related infertility. The reproductive aging process in women is assumed to occur due to a decrease in both the quantity and quality of the oocytes, with the ultimate result being a decline in fecundity. This age-related decline in fecundity is strongly dependent on oocyte quality, which is critical for fertilization and subsequent embryo development. Aged oocytes display increased chromosomal abnormality and dysfunction of cellular organelles, both of which factor into oocyte quality. In particular, mitochondrial dysfunction has been suggested as a major contributor to the reduction in oocyte quality as well as to chromosomal abnormalities in aged oocytes and embryos. Participation of oxidative stress in the oocyte aging process has been proposed because oxidative stress has the capacity to induce mitochondrial dysfunction and directly damage many intracellular components of the oocytes such as lipids, protein, and DNA. In an attempt to improve mitochondrial function in aged oocytes, several therapeutic strategies have been investigated using both animal models and assisted reproductive technology. Here, we review the biological mechanisms and present status of therapeutic strategies in the female reproductive aging field and indicate possible future therapeutic strategies. PMID- 29259415 TI - The effect of moderate to severe endometriosis on expression of growth differentiation factor-9 mRNA in human granulosa cells under controlled ovarian hyperstimulation. AB - Purpose: To investigate the effect of moderate to severe endometriosis on mRNA expression of growth differentiation factor-9 (GDF-9) in the granulosa cells of mature follicles. Methods: Follicular fluid (FF) was obtained from 13 patients with moderate to severe endometriosis and 11 without endometriosis, as a control group, and GDF-9 protein levels in both were assayed by western blotting. mRNA expression by GDF-9 and LH receptor (LHR) in granulosa cells obtained from all patients in the study were investigated by StepOne Real-Time PCR. Results: Although GDF-9 in FF from patients with endometriosis was no different from that of controls, GDF-9 mRNA expression in granulosa cells of patients with endometriosis was statistically significantly lower than for the control group. The number of oocytes and high-quality embryos was positively correlated with GDF 9 mRNA expression in controls but not in patients with endometriosis Moreover, a negative correlation was identified between GDF-9 mRNA expression and serum estrogen and progesterone levels in the control group, whereas no correlation was observed for the endometriosis group. Conclusions: Moderate to severe endometriosis can significantly reduce GDF-9 mRNA expression in the granulosa cells of patients with the disease compared with those without, thus causing poor oocyte maturation and lower embryo quality. PMID- 29259416 TI - A case of primary ciliary dyskinesia treated with ICSI using testicular spermatozoa: case report and a review of the literature. AB - Purpose: To investigate whether or not intracytoplasmic sperm injection (ICSI) using spermatozoa extracted from testis (TESE-ICSI) is a more effective treatment than ICSI with ejaculated spermatozoa (EJ-ICSI) for primary ciliary dyskinesia (PCD). Methods: We reported a case of PCD in which we performed TESE-ICSI after repeated failure of EJ-ICSI. Together with data from previous case reports, we compared the fertilization rate and pregnancy outcome of TESE-ICSI and EJ-ICSI. Results: In our case, TESE-ICSI improved the morphology of spermatozoa and fertilization rate. However, the outcome was only a biochemical pregnancy. According to the analysis combined with previous reports, there was no difference in the fertilization rate and pregnancy outcome parameters between TESE-ICSI and EJ-ICSI. Conclusions: TESE-ICSI for PCD may improve the fertilization rate compared to EJ-ICSI. However, it does not necessarily improve the pregnancy outcome for a patient with primary ciliary dyskinesia. PMID- 29259417 TI - Conceptus implantation and placentation: molecules related to epithelial mesenchymal transition, lymphocyte homing, endogenous retroviruses, and exosomes. AB - Processes of conceptus implantation and placentation, unique to mammalian reproduction, have been extensively studied. It was once thought that processes of these events varied greatly, notably between invasive and noninvasive modes of implantation and/or placentation. Regardless of the mode of implantation, however, physiological and biochemical processes in conceptus implantation to the maternal endometrium including the kinds of gene expression and their products are now considered not to differ so much. Recent progress has identified that in addition to the hormones, cytokines, proteases and cell adhesion molecules classically characterized, epithelial-mesenchymal transition, molecules related to lymphocyte homing, the expression of endogenous retroviruses and possibly exosomes are all required for the progression of conceptus implantation to placentation. In this review, therefore, new findings related to these events are integrated into the context of conceptus implantation to the maternal endometrium. PMID- 29259419 TI - Predictive factors of successful sperm retrieval on microdissection testicular sperm extraction in Japanese men. AB - Purpose: To evaluate retrospectively the outcomes of microdissection testicular sperm extraction (micro-TESE) in men with nonobstructive azoospermia (NOA) and to identify the parameters predicting successful sperm retrieval in this cohort of patients. Methods: After excluding patients with normal testicular volume and serum follicle-stimulating hormone (FSH) level who received conventional TESE, this study included 329 consecutive NOA patients undergoing micro-TESE at our institution. The significance of several factors, including age, testicular volume, etiology and serum levels of FSH, luteinizing hormone (LH) and serum testosterone (T), as predictors of successful sperm retrieval, was evaluated. Results: Of the 329 men included in this series, 246 (74.8 %), 40 (12.2 %), and 43 (13.1 %) were pathologically diagnosed with Sertoli cell only, maturation arrest, and hypospermatogenesis, respectively. Spermatozoa were retrieved in 97 (29.5 %) of these 329 men by micro-TESE. Older age and non-idiopathic etiology were significantly associated with the probability of successful sperm retrieval; however, there were no significant effects of testicular volume as well as serum levels of FSH, LH, and T on sperm retrieval outcome. Furthermore, Johnsen score of the micro-TESE specimen showed a significant association with whether spermatozoa were successfully retrieved. Univariate analysis of preoperative parameters identified older age and non-idiopathic etiology as significant predictors of successful sperm retrieval, of which only etiology appeared to be independently related to successful sperm retrieval on multivariate analysis. Conclusions: Spermatozoa are significantly less likely to be successfully retrieved by micro-TESE in men with idiopathic azoospermia. PMID- 29259418 TI - Preimplantation genetic diagnosis/screening by comprehensive molecular testing. AB - Although embryo screening by preimplantation genetic diagnosis (PGD) has become the standard technique for the treatment of recurrent pregnancy loss in couples with a balanced gross chromosomal rearrangement, the implantation and pregnancy rates of PGD using conventional fluorescence in situ hybridization (FISH) remain suboptimal. Comprehensive molecular testing, such as array comparative genomic hybridization and next-generation sequencing, can improve these rates, but amplification bias in the whole genome amplification method remains an obstacle to accurate diagnosis. Recent advances in amplification procedures combined with improvements in the microarray platform and analytical method have overcome the amplification bias, and the data accuracy of the comprehensive PGD method has reached the level of clinical laboratory testing. Currently, comprehensive PGD is also applied to recurrent pregnancy loss due to recurrent fetal aneuploidy or infertility with recurrent implantation failure, known as preimplantation genetic screening. However, there are still numerous problems to be solved, including misdiagnosis due to somatic mosaicism, cell cycle-related background noise, and difficulty in diagnosis of polyploidy. The technology for comprehensive PGD also requires further improvement. PMID- 29259420 TI - Successful pregnancy by vitrified-warmed embryo transfer for a woman with Kallmann syndrome. AB - Purpose: Kallmann syndrome is a genetic disorder characterized by hypogonadotropic hypogonadism and anosmia. We report the case of a 31-year-old woman with Kallmann syndrome who successfully gave birth after intracytoplasmic sperm injection (ICSI) and vitrified-warmed embryo transfer, despite relatively ineffective ovarian stimulation. Method: A 30 year-old woman with primary amenorrhea wished to achieve pregnancy. Diagnostic testing results were consistent with Kallmann syndrome. Follicular stimulation was started with human menopausal gonadotropin (hMG; 150 IU/day). After 28 days of treatment, 4 follicles were observed (total hMG; 4200 IU), with a dominant follicle diameter of 23 mm. Ovum pick-up was performed and 2 oocytes, one at metaphase II (MII) and one at the germinal vesicle stage, were obtained. Piezo-ICSI was performed on the MII oocyte and an 8-cell stage embryo was cryopreserved on day 3. Subsequently, embryo transfer was performed after endometrial preparation. Result: A gestational sac and embryo heart activity were confirmed by ultrasonographic monitoring, and a healthy male infant weighing 3246 g was delivered by Caesarean section after 41 weeks 3 days of gestation. Conclusion: This is the first report of a healthy delivery after vitrified-warmed embryo transfer for a woman with Kallmann syndrome. Our experience suggests that ICSI and vitrified-warmed embryo transfer are effective for women with Kallmann syndrome. PMID- 29259421 TI - Molecular and cellular events involved in the completion of blastocyst implantation. AB - Blastocyst implantation is an interactive process between the embryo and the uterus. The synchronization of embryonic development with uterine differentiation to a receptive state is essential for a successful pregnancy. The period of uterine receptivity for implantation is limited. Although implantation involves the interaction of numerous signaling molecules, our understanding of the hierarchical mechanisms that coordinate with the embryo-uterine dialogue is not yet sufficient to prevent infertility caused by implantation failure. This review highlights our knowledge on uterine receptivity and hormonal regulation of blastocyst implantation in mice. We also discuss the adhesion molecules, cross linker proteins, extracellular proteins, and matricellular proteins involved in blastocyst implantation. Furthermore, our recent study reveals that selective proteolysis in an activated blastocyst is associated with the completion of blastocyst implantation after embryo transfer. A better understanding of uterine and blastocyst biology during the peri-implantation period would facilitate further development of reproductive technology. PMID- 29259422 TI - Epigenetics of sex determination in mammals. AB - Epigenetics is the study of changes in gene function that cannot be explained by changes in DNA sequence. A mammalian body contains more than two hundred types of cells. Since all of them are derived from a single fertilized egg, their genotypes are identical. However, the gene expression patterns are different between the cell types, indicating that each cell type has unique own "epigenotype". Epigenetic gene regulation mechanisms essentially contribute to various processes of mammalian development. The essence of epigenetic regulation is the structural change of chromatin to modulate gene activity in a spatiotemporal manner. DNA methylation and histone modifications are the major epigenetic mechanisms. Sex determination is the process for gender establishment. There are two types of sex-determining mechanisms in animals, environmental sex determination (ESD) and genotypic sex determination (GSD). Recent studies have provided some evidence that epigenetic mechanisms play indispensable roles in ESD and GSD. Some fishes undergo ESD, in which DNA methylation is essentially involved. GSD is employed in therian mammals, where Sry (sex-determining region on the Y chromosome) triggers testis differentiation from undifferentiated gonads. Sry expression is tightly regulated in a spatiotemporal manner. A recent study demonstrated that histone modification is involved in Sry regulation. In this review, we discuss the role of epigenetic mechanisms for sex determination in mammals and other vertebrates. PMID- 29259423 TI - Preimplantation genetic diagnosis: an update on current technologies and ethical considerations. AB - The aim of reproductive medicine is to support the birth of healthy children. Advances in assisted reproductive technologies and genetic analysis have led to the introduction of preimplantation genetic diagnosis (PGD) for embryos. Indications for PGD have been a major topic in the fields of ethics and law. Concerns vary by nation, religion, population, and segment, and the continued rapid development of new technologies. In contrast to the ethical augment, technology has been developing at an excessively rapid speed. The most significant recent technological development provides the ability to perform whole genome amplification and sequencing of single embryonic cells by microarray or next-generation sequencing methods. As new affordable technologies are introduced, patients are presented with a growing variety of PGD options. Simultaneously, the ethical guidelines for the indications for testing and handling of genetic information must also rapidly correspond to the changes. PMID- 29259426 TI - An evaluation of the Gifu Model in a trial for a new regional oncofertility network in Japan, focusing on its necessity and effects. AB - Purpose: We evaluated our 2-year experience of the regional oncofertility network in Gifu Prefecture (GPOFS) in order to establish a more sophisticated regional oncofertility networking model in Japan. Methods: Questionnaires were distributed twice in January 2013 to 57 departments in 35 hospitals that provide cancer treatment in Gifu Prefecture, before the establishment of the regional oncofertility network. The number and type of disease of the referred adolescent and young adult (AYA) cancer patients who visited the oncofertility clinic in Gifu University Hospital via the GPOFS were analyzed. Results: The majority of regional oncologists are aware of the need to provide information about oncofertility to their patients, but they cannot provide sufficient information due to their lack of knowledge about reproductive medicine. Eighty-one AYA patients were referred to our clinic for oncofertility counseling in the first 2 years after the establishment of the GPOFS. Conclusions: The GPOFS as the first regional oncofertility network in Japan has just started and may be working to help both AYA cancer patients and their oncologists. The nationwide establishment of the regional oncofertility network model could help both AYA cancer patients and oncologists. PMID- 29259425 TI - Update of Wnt signaling in implantation and decidualization. AB - Embryonic development into an implantation-competent blastocyst, synchronized uterine transformation into a receptive stage, and an intimate cross-talk between the activated blastocyst and the receptive uterus are essential for successful implantation, and therefore for subsequent pregnancy outcome. Evidence accumulating during recent years has underlined the importance of the Wnt signaling pathway in mammalian implantation and decidualization. Herein, this review focuses on the current state of knowledge regarding Wnt signaling in multiple implantation and decidualization events: pre-implantation embryo development, blastocyst activation for implantation, uterine development, and decidualization. PMID- 29259427 TI - The effects of platelet lysate on maturation, fertilization and embryo development of NMRI mouse oocytes at germinal vesicle stage. AB - Purpose: Improving in vitro maturation could increase the rate of pregnancy from oocytes matured in vitro. Consequently, patients will be prevented from using gonadotropin with its related side effects. In this study, the maturation medium was enriched by platelet lysate (PL), then maturation and subsequent developments were monitored. Methods: Oocytes at germinal vesicle stage with cumulus cells (cumulus-oocyte complex) and without cumulus cells (denuded oocytes) were obtained from mature female mice. The maturation medium was enriched by 5 and 10 % PL and 5 % PL + 5 % fetal bovine serum (FBS) as experimental groups; the control groups' media consisted of 5 and 10 % FBS. After 18 h, the matured oocytes were collected and, after fertilization, subsequent development was monitored. Results: The rates of maturation, fertilization and 2-cell embryo development for the denuded oocyte groups in experimental media 5 % PL and 5 % PL + 5 % FBS were significantly higher than those of the control groups (P < 0.05), while the results for the cumulus-oocyte complex groups were similar between the experimental groups and control groups. Conclusions: The results of this study indicated that platelet lysate could improve the maturation rate in the absence of granulosa cells compared to media with FBS. This extract also had positive effects on fertilization and embryo development. PMID- 29259424 TI - Sperm dysfunction and ciliopathy. AB - Sperm motility is driven by motile cytoskeletal elements in the tail, called axonemes. The structure of axonemes consists of 9 + 2 microtubules, molecular motors (dyneins), and their regulatory structures. Axonemes are well conserved in motile cilia and flagella through eukaryotic evolution. Deficiency in the axonemal structure causes defects in sperm motility, and often leads to male infertility. It has been known since the 1970s that, in some cases, male infertility is linked with other symptoms or diseases such as Kartagener syndrome. Given that these links are mostly caused by deficiencies in the common components of cilia and flagella, they are called "immotile cilia syndrome" or "primary ciliary dyskinesia," or more recently, "ciliopathy," which includes deficiencies in primary and sensory cilia. Here, we review the structure of the sperm flagellum and epithelial cilia in the human body, and discuss how male fertility is linked to ciliopathy. PMID- 29259428 TI - The impact of elevated thyroid stimulating hormone on female subfertility. AB - Purpose: Hypothyroidism is known to have a negative impact on female reproduction even in subclinical form, subclinical hypothyroidism (SH). This study aimed to investigate the association between elevated TSH level and reproductive outcome. Methods: We retrospectively evaluated a total of 203 infertile women who first visited our infertility treatment division from January 1, 2009 to August 31, 2012, including 13 patients with TSH above 4.5 mIU/l (elevated-TSH patients), 11 of whom were diagnosed as SH, and 190 patients with normal TSH (normo-TSH patients). We evaluated them according to reproductive outcome, including clinical pregnancy, miscarriage, and live birth until April 31, 2014. We also aimed to redefine the upper limit of normal serum TSH level. Results: Multivariate analysis showed significant influence of elevated TSH on clinical pregnancy, although miscarriage and live birth were not affected. In addition, we revealed that the rate of decreased ovarian reserve and unexplained infertility was increased in patients with elevated TSH levels. Conclusions: We found an association between elevated TSH and the decreased rate of clinical pregnancy. This might be related to an ovulatory disorder and pathophysiology of unexplained infertility. These results may reinforce the usefulness of TSH screening in infertility population. PMID- 29259429 TI - Anti-Mullerian hormone as a marker of ovarian reserve: What have we learned, and what should we know? AB - Ovarian reserve reflects the quality and quantity of available oocytes. This reserve has become indispensable for the better understanding of reproductive potential. Measurement of the serum anti-Mullerian hormone (AMH) level allows quantitative evaluation of ovarian reserve. It has been applied to a wide range of clinical conditions, and it is well established that the measurement of serum AMH levels is more useful than qualitative evaluation based on the menstrual cycle. AMH levels are monitored during infertility treatments; in patients undergoing medically assisted reproductive technology; and in the diagnosis of ovarian failure, polycystic ovarian syndrome, and granulosa cell tumor. It is also useful in the evaluation of iatrogenic ovarian damage. Population-based studies have indicated a potential role for serum AMH in the planning of reproductive health management. While AMH is currently the best measure of ovarian reserve, its predictive value for future live births remains controversial. Furthermore, there is a serious practical issue in the interpretation of test results, as currently available assay kits use different assay ranges and coefficients of variation due to the absence of an international reference standard. The pros and cons of the serum AMH level as a definitive measure of ovarian reserve merits further review in order to guide future research. PMID- 29259430 TI - The development of surgical sperm extraction and new challenges to improve the outcome. AB - Surgical sperm extraction with intracytoplasmic sperm injection has become widespread worldwide and is regarded as the sole option for patients with azoospermia. However, the sperm retrieval rate remains unsatisfactorily low, particularly for men with non-obstructive azoospermia (NOA). Therefore, the technical challenges associated with improving the sperm retrieval rate for men with NOA are being addressed. The most successful method developed to date is microdissection testicular sperm extraction (micro-TESE), which is rapidly becoming recognized as a useful technique due to its relatively high sperm retrieval rate and low complication rate. However, even with micro-TESE, the sperm retrieval rate for men with NOA remains at 30-60 %, with an even lower birth rate. The technical challenges associated with improving the outcomes of surgical sperm extraction are being approached through the use of ultrasound and optimal surgical devices such as narrow band imaging, multiphoton microscopy, and optical coherent tomography. In addition to the difficulties related to searching for sperm, medical treatments that induce spermatogenesis remain controversial. For example, varicocele repair prior to surgical sperm extraction and hormonal therapy before and after TESE have been extensively examined. We herein briefly summarized the development process in surgical sperm extraction up to the present and technical challenges to improve the outcomes of surgical sperm extraction. PMID- 29259431 TI - Observation of human embryonic behavior in vitro by high-resolution time-lapse cinematography. AB - Assisted reproductive technology (ART) has yielded vast amounts of information and knowledge on human embryonic development in vitro; however, still images provide limited data on dynamic changes in the developing embryos. Using our high resolution time-lapse cinematography (hR-TLC) system, we were able to describe normal human embryonic development continuously from the fertilization process to the hatched blastocyst stage in detail. Our hR-TLC observation also showed the embryonic abnormality of a third polar body (PB)-like substance likely containing a small pronucleus being extruded and resulting in single-pronucleus (1PN) formation, while our molecular biological investigations suggested the possibility that some 1PN embryos could be diploid, carrying both maternal and paternal genomes. Furthermore, in some embryos the extruded third PB-like substance was eventually re-absorbed into the ooplasm resulting in the formation of an uneven-sized, two-PN zygote. In addition, other hR-TLC observations showed that cytokinetic failure was correlated with equal-sized, multi-nucleated blastomeres that were also observed in the embryo showing early initiation of compaction. Assessment combining our hR-TLC with molecular biological techniques enables a better understanding of embryonic development and potential improvements in ART outcomes. PMID- 29259432 TI - Age-associated events in bovine oocytes and possible countermeasures. AB - Maternal aging profoundly affects oocyte quality. This has become common knowledge in industrialized countries and extensive studies addressing the causes and possible countermeasures against age-associated deterioration of oocytes suggest that mitochondrial dysfunction is a causal factor in infertility. However, almost all studies addressing age-associated events in oocytes have used mice as an animal model, and the reproductive life of mice is very short, making it difficult to study the gradual decline in fertility observed in humans. In the present review, age-associated changes in the quality and quantity of bovine oocytes and possible countermeasures related to mitochondrial quality control are introduced. PMID- 29259435 TI - Intracytoplasmic sperm injection into oocytes matured in vitro and early embryonic development in the owl monkey (Aotus lemurinus). AB - Purpose: We explored the possibility of employing intracytoplasmic sperm injection (ICSI), involving oocytes and sperm of owl monkeys, to increase the availability of this species for investigations relating to malaria, etc., by increasing the number of animals in our laboratory. Methods: Two owl monkeys (a female and a male), raised at the Amami Laboratory of the University of Tokyo, were used. Follicular oocytes surrounded with cumulus cells were cultured in vitro for approximately 25 h and cumulus cells were removed with 0.1 % hyaluronidase. Because of the poor motility of caudal epididymal sperm, sperm were injected without adding polyvinylpyrrolidone to immobilize them. The ICSI procedure was performed by an individual with considerable experience of human ICSI. Results: We were able to produce two owl monkey embryos using ICSI of oocytes that matured to MII stage. Both embryos reached the 10-cell stage at 98 h after ICSI and showed signs of compaction, but failed to cleave further. Conclusions: Although we successfully produced owl monkey embryos after ICSI, the embryos did not develop to the blastocyst stage. Many parameters need to be studied further, including superovulation, selection of culture media, and selection of good quality sperm in order to achieve successful ICSI in the owl monkey. PMID- 29259434 TI - Testicular function among testicular cancer survivors treated with cisplatin based chemotherapy. AB - Purpose: The aim of our study was to identify the clinical predictors of spermatogenesis recovery in testicular cancer (TC) patients after chemotherapy and to determine the recuperation period for spermatogenesis. Methods: Patients treated for TC from January 1982 to November 2001 at Chiba University Hospital were retrospectively assessed. Thirty-five patients who met the following criteria were examined-(i) underwent both high orchiectomy and cisplatin-based chemotherapy; (ii) had semen analyses and hormonal measurements; and (iii) were alive with no evidence of disease. Clinical variables associated with normalization of spermatogenesis after chemotherapy were examined. Time to recover normospermia was also evaluated using Kaplan-Meier analysis. Results: The observation period was 13.3 +/- 5.6 years. Reappearance of sperm was confirmed in 85.7 % of patients, and 54.3 % of patients recovered normospermia. Age at diagnosis <25 years (p = 0.0057), number of chemotherapy cycles <4 cycles (p = 0.0042), and follicle-stimulating hormone at the end of chemotherapy <18 mIU/ml (p = 0.0220) were independent factors related to post-chemotherapy normalization of semen findings. The median (95 % CI) time to recover normospermia was 40 (range 22-96) months. Conclusions: These findings help to predict whether spermatogenesis will recover and its timing. They may also help clinicians identify and manage TC patients at a higher risk of prolonged azoospermia after chemotherapy. PMID- 29259436 TI - Twin pregnancy in a 51-year-old woman who underwent autologous cryopreservation at the age of 36 years: case report. AB - Climacteric women are able to become pregnant using oocytes donated earlier in life. However, adverse effects on such donated oocytes have been identified. We report a case of a successful dichorionic diamniotic twin pregnancy achieved using autologous fertilized cryopreserved oocytes in a climacteric woman. A 51 year-old woman became pregnant using autologous fertilized oocytes that had been frozen for 15 years. On her first visit, multiple leiomyoma of the uterus and gestational diabetes mellitus were diagnosed, and proteinuria began to appear at 30 weeks. In spite of our concerns these complications did not exacerbate and the clinical course for both mother and neonates was favorable. This is the first report of a live twin birth achieved using autologous cryopreserved oocytes in a climacteric woman. This case report may be of value to women who desire postponement of their infertility treatment and the professional assisted reproduction community. PMID- 29259433 TI - Management of non-obstructive azoospermia. AB - Non-obstructive azoospermia (NOA) is defined as no sperm in the ejaculate due to failure of spermatogenesis and is the most severe form of male infertility. The etiology of NOA is either intrinsic testicular impairment or inadequate gonadotropin production. Chromosomal or genetic abnormalities should be evaluated because there is a relatively high incidence compared with the normal population. Although rare, NOA due to inadequate gonadotropin production is a condition in which fertility can be improved by medical treatment. In contrast, there is no treatment that can restore spermatogenesis in the majority of NOA patients. Consequently, testicular extraction of sperm under an operating microscope (micro TESE) has been the first-line treatment for these patients. Other treatment options include varicocelectomy for NOA patients with a palpable varicocele and orchidopexy if undescended testes are diagnosed after adulthood, although management of these patients remains controversial. Advances in retrieving spermatozoa more efficiently by micro-TESE have been made during the past decade. In addition, recent advances in biotechnology have raised the possibility of using germ cells produced from stem cells in the future. This review presents current knowledge about the etiology, diagnosis, and treatment of NOA. PMID- 29259437 TI - Uterine anatomy and function on cine magnetic resonance imaging. AB - The female reproductive organ undergoes dynamic morphological changes under the influence of hormonal stimuli, and particularly those mediated by estrogen and progesterone. The uterus changes both its morphological appearance and its functional movements in function of these influences. Functionally, the uterus is known to exert two kinds of inherent contractility: sustained uterine contractions and uterine peristalsis. The former is focal and consists of the sporadic bulging of the myometrium, while the latter is rhythmic and manifests itself as the subtle stripping movement in the subendometrial myometrium. The mechanisms underlying these uterine movements, their relationship and their correlation to age, pharmaceutical administration, and a variety of gynecologic and obstetrical problems remain under discussion. Cine MR imaging may offer the potential to directly observe the changes undergone by the uterus in relation to important functions such as fertility and menstrual problems. PMID- 29259439 TI - Clinical management of endometriosis-associated infertility. AB - Endometriosis is a common chronic benign disease that affects reproductive age women and causes chronic pelvic pain and infertility. Despite its prevalence, the exact mechanisms of the pathogenesis of endometriosis-associated infertility are unknown, and precise standards of management have not yet been established. Medical and surgical treatments for endometriosis have different effects on the chance of conception, either spontaneously or via assisted reproductive technologies (ART). In this manuscript, we review the literature from years 1979 to 2015 to report on the proposed mechanism of endometriosis-associated infertility, the staging system of endometriosis for pregnancy outcomes and the current management of patients with endometriosis-associated infertility. PMID- 29259438 TI - Roles of epidermal growth factor (EGF)-like factor in the ovulation process. AB - Luteinizing hormone (LH) surge stimulates preovulatory follicles to induce the ovulation process, including oocyte maturation, cumulus expansion, and granulosa cell luteinization. The matured oocytes surrounded by an expanded cumulus cell layer are released from follicles to the oviduct. However, LH receptors are dominantly expressed in granulosa cells, but less in cumulus cells and are not expressed in oocytes, indicating that the secondary factors expressed and secreted from LH-stimulated granulosa cells are required for the induction of the ovulation process. Prostaglandin and progesterone are well-known factors that are produced in granulosa cells and then stimulate in both granulosa and cumulus cells. The mutant mice of prostaglandin synthase (Ptgs2KO mice) or progesterone receptor (PRKO mice) revealed that the functions were essential to accomplish the ovulation process, but not to induce the ovulation process. To identify the factors initiating the transfer of the stimuli of LH surge from granulosa cells to cumulus cells, M. Conti's lab and our group performed microarray analysis of granulosa cells and identified the epidermal growth factor (EGF)-like factor, amphiregulin (AREG), epiregulin (EREG), and beta-cellulin (BTC) that act on EGF receptor (EGFR) and then induce the ERK1/2 and Ca2+-PLC pathways in cumulus cells. When each of the pathways was down-regulated using a pharmacological approach or gene targeting study, the induction of cumulus expansion and oocyte maturation were dramatically suppressed, indicating that both pathways are inducers of the ovulation process. However, an in vitro culture study also revealed that the EGFR-induced unphysiological activation of PKC in cumulus cells accelerated oocyte maturation with low cytostatic activity. Thus, the matured oocytes are not arrested at the metaphase II (MII) stage and then spontaneously form pronuclei. The expression of another type of EGF-like factor, neuregulin 1 (NRG1), that does not act on EGFR, but selectively binds to ErbB3 is observed in granulosa cells after the LH surge. NRG1 supports EGFR-induced ERK1/2 phosphorylation, but reduces PKC activity to physiological level in the cumulus cells, which delays the timing of meiotic maturation of oocytes to adjust the timing of ovulation. Thus, both types of EGF-like factor are rapidly induced by LH surge and then stimulate cumulus cells to control ERK1/2 and PKC pathways, which results in the release of matured oocytes with a fertilization competence. PMID- 29259440 TI - Vitrification of embryos and oocytes for fertility preservation in cancer patients. AB - As survival rates and the life expectancy of those with malignancy have increased, more women in their reproductive years are referred for fertility preservation. Chemotherapy and radiotherapy can severely affect ovarian function, and the effect is irreversible. Therefore, it is optimal to attempt fertility preservation before chemotherapy and radiotherapy are initiated. Oocyte and embryo cryopreservation is the most common option for fertility preservation in women. Several reports have proven that embryo and oocyte cryopreservation can achieve a successful pregnancy. This review discusses the impact of chemotherapy and radiotherapy on ovarian function, and the importance of oocyte and embryo cryopreservation for fertility preservation. In addition, the current status of pregnancy outcomes and potential for cryopreserved oocytes to result in live births in cancer patients was reviewed. This may provide useful information for decision-making in cancer patients regarding oocyte and embryo cryopreservation and fertility preservation. PMID- 29259442 TI - Predicting suitable timing for artificial reproductive technology treatment in aged infertile women. AB - It has been widely accepted that the age of women plays a fundamental role in fecundity, and age-related fertility decline has one of the most significant and detrimental effects on the success rate of infertility treatment. Therefore, treatment cycles of non-in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment for infertile women of advanced aged have been limited due to their lack of efficacy, and they are often optimized, compared to IVF/ICSI treatment. Recent trends in infertility treatment apparently indicate that IVF/ICSI treatment, including egg donation, is frequently offered to aged women for first-line management, despite its heavy burden, but hasty IVF/ICSI treatment should be avoided, considering its socioeconomic problems. It is important to distinguish women who could conceive by non-IVF/ICSI treatment, although the optimization of non-IVF/ICSI treatment protocols remains poorly understood. This review focuses on extracting aged patients who have higher chance of conceiving with non-IVF/ICSI treatment and providing necessary and sufficient infertility treatment. After initial evaluation for fertility, including tubal factor, male factor, the presence of endometriosis and/or adenomyosis, and ovarian reserve, the outcomes of fertility treatment can be predicted to some extent in aged infertile women. PMID- 29259443 TI - A case of gradually manifesting McCune-Albright syndrome with a 10-year follow up. AB - McCune-Albright syndrome (MAS) is characterized by fibrous dysplasia (FD) of bone, cafe-au-lait skin pigmentation, and precocious puberty. Here we report a case of a 12-year-old girl with MAS presenting sexual precocity as initial signs, followed by FD of bone with her growth. She was referred to our hospital because of breast budding and abnormal genital bleeding at the age of 2.8 years. On physical examination, her height and weight were greater than two standard deviations of the mean ranges. Hormonal analysis revealed an elevated serum estradiol and suppressed luteinizing hormone and follicle-stimulating hormone production. Her bone age had advanced, and a 16-mm monocystic lesion was observed on her right ovary by pelvic ultrasonography. Considering the clinical and paraclinical findings, precocious pseudopuberty was suspected and periodic observations were started. Her estrogen "flare up" was transient and she had repeated similar episodes three times in the following 7 years. She complained of pain in her right hip at the age of 9.6 years, which was diagnosed as FD of bone by fluorodeoxyglucose-positron emission tomography. Although no cafe-au-lait skin pigmentation was observed, we made a preliminary diagnosis of MAS. Because clinical evidence for MAS can appear later in the course of recurrent autonomous cysts, careful observation and periodical assessments of patients with suspected MAS is necessary. PMID- 29259444 TI - Introducing Reproductive Medicine and Biology as a completely Open Access Publication. PMID- 29259441 TI - Fertility preservation through gonadal cryopreservation. AB - Fertility preservation is an area of immense interest in today's society. The most effective and established means of fertility preservation is cryopreservation of gametes (sperm and oocytes) and embryos. Gonadal cryopreservation is yet another means for fertility preservation, especially if the gonadal function is threatened by premature menopause, gonadotoxic cancer treatment, surgical castration, or diseases. It can also aid in the preservation of germplasm of animals that die before attaining sexual maturity. This is especially of significance for valuable, rare, and endangered animals whose population is affected by high neonatal/juvenile mortality because of diseases, poor management practices, or inbreeding depression. Establishing genome resource banks to conserve the genetic status of wild animals will provide a critical interface between ex-situ and in-situ conservation strategies. Cryopreservation of gonads effectively lengthens the genetic lifespan of individuals in a breeding program even after their death and contributes towards germplasm conservation of prized animals. Although the studies on domestic animals are quite promising, there are limitations for developing cryopreservation strategies in wild animals. In this review, we discuss different options for gonadal tissue cryopreservation with respect to humans and to laboratory, domestic, and wild animals. This review also covers recent developments in gonadal tissue cryopreservation and transplantation, providing a systematic view and the advances in the field with the possibility for its application in fertility preservation and for the conservation of germplasm in domestic and wild species. PMID- 29259446 TI - Observation of the dynamics of follicular development in the ovary. AB - The number of ovulated oocytes is different among mammals but does not vary much within the same species. In order to sustain periodic ovulation, follicular development must be coordinated at the tissue level. Elucidating the regulatory mechanisms of follicular development is difficult because the ovary has a complicated structure and it takes a long time for primordial follicles to develop into Graafian follicles. Therefore, it is not possible to observe follicular development by conventional experiments. The authors previously developed a new ovarian tissue culture method that enabled the observation of follicular development from the early follicle stage. These findings indicated that follicular interactions are important in regulating follicular development and ovulation. This review describes the current methods of observing follicular development in the ovary and the regulatory mechanisms of follicular development. PMID- 29259447 TI - Equilibrium between anti-oxidants and reactive oxygen species: a requisite for oocyte development and maturation. AB - Reactive oxygen species (ROS) are required for cellular functioning and are controlled by anti-oxidants. The ROS influence the follicles, oocytes, endometrium, and their environment. The luteinizing hormone surge initiates a massive recruitment of ROS that modulates major reproductive functions namely, oocyte maturation, ovarian steroidogenesis, corpus luteal function, and luteolysis. The anti-oxidant system balances ROS generation and maintains the cellular functions. Both enzymatic and non-enzymatic anti-oxidants namely, vitamins and minerals are present in the follicles and protect the oocytes from the damaging effects of ROS. The overproduction of ROS leads to oxidative stress that affects the quality of oocytes and subsequent anovulation. Although researchers have tried to establish the role of ROS and anti-oxidants in oocyte development, still this aspect needs to be revisited. This review discusses the importance of the ROS and anti-oxidant balance that is required for the development and maturation of oocytes. There are increasing data on the activity of ROS and anti-oxidants in supporting oocyte development and maturation. However, extensive research is required to identify the safe physiological concentration and duration of both the ROS and anti-oxidants that are required to facilitate oocyte development and maturation during in vitro and in vivo conditions. PMID- 29259448 TI - Permeability of the plasma membrane to water and cryoprotectants in mammalian oocytes and embryos: Its relevance to vitrification. AB - The permeability of the plasma membrane to water and cryoprotectants is one of the important factors for determining the suitable condition for the vitrification of mammalian oocytes and embryos. Water and cryoprotectants move slowly through oocytes and early embryos, principally by simple diffusion, in the mouse, bovine, pig, and human. In contrast, water, glycerol, and ethylene glycerol move rapidly through morulae and blastocysts, principally by facilitated diffusion via aquaporin 3, in the mouse and bovine; whereas, in the pig, the permeability to water and these cryoprotectants increases not at the morula stage but at the blastocyst stage and further increases at the expanded blastocyst stage. Dimethyl sulfoxide also moves rapidly via channels other than aquaporin 3 in the mouse. In contrast, propylene glycol moves through morulae and blastocysts principally by simple diffusion in the mouse, bovine, and pig, as through oocytes. Therefore, the permeability of mammalian oocytes and embryos at early stages to water and cryoprotectants is low, but that of embryos at later stages to water and some cryoprotectants is markedly high by channel processes, although species specificity exists in some cases. PMID- 29259449 TI - Analyzing the risk factors for a diminished oocyte retrieval rate under controlled ovarian stimulation. AB - Aim: To investigate which risk factors contribute to a lower oocyte retrieval ratio in women who are receiving controlled ovarian hyperstimulation. Methods: The authors retrospectively analyzed 329 in vitro fertilization (IVF) cycles under controlled ovarian hyperstimulation by using a gonadotropin-releasing hormone antagonist or agonist at Osaka Medical College, Japan. The patients were classified into five groups: advanced age, male infertility, severe endometriosis, tubal infertility, and unexplained infertility. The primary outcomes were the patients' age, oocyte retrieval ratio, serum basal follicle stimulating hormone, total dose of gonadotropin, and the clinical outcome. A secondary outcome was the stepwise multivariate logistic regression analysis to assess the factors associated with the failure of oocyte retrieval. Results: The oocyte retrieval ratio declined significantly with the patient's age. The ratio of endometriosis in unsuccessful cases was significantly higher than that in successful cycles. Advanced age and endometriosis were the factors that were significantly associated with a lowered oocyte retrieval rate. Conclusion: Advanced age and endometriosis are high-risk factors that contribute to oocyte retrieval failure in infertile patients who are receiving IVF treatment. PMID- 29259445 TI - Molecular mechanism of estrogen-estrogen receptor signaling. AB - 17beta-Estradiol (E2), as the main circulating estrogen hormone, regulates many tissue and organ functions in physiology. The effects of E2 on cells are mediated by the transcription factors and estrogen receptor (ER)alpha and ERbeta that are encoded by distinct genes. Localized at the peri-membrane, mitochondria, and the nucleus of cells that are dependent on estrogen target tissues, the ERs share similar, as well as distinct, regulatory potentials. Different intracellular localizations of the ERs result in dynamically integrated and finely tuned E2 signaling cascades that orchestrate cellular growth, differentiation, and death. The deregulation of E2-ER signaling plays a critical role in the initiation and progression of target tissue malignancies. A better understanding of the complex regulatory mechanisms that underlie ER actions in response to E2 therefore holds a critical trajectory for the development of novel prognostic and therapeutic approaches with substantial impacts on the systemic management of target tissue diseases. PMID- 29259450 TI - Phase III trial comparing the efficacy and safety of recombinant- or urine derived human chorionic gonadotropin for ovulation triggering in Japanese women diagnosed with anovulation or oligo-ovulation and undergoing ovulation induction with follitropin-alfa. AB - Aim: Outside of Japan, recombinant-human chorionic gonadotropin (r-hCG) is widely used for the induction of final follicular maturation and early luteinization in women undergoing ovulation induction; whereas in Japan, urine-derived hCG (u-hCG) is predominantly used. The primary objective of this study was to demonstrate the non-inferiority of r-hCG to u-hCG for ovulation induction, as assessed by the ovulation rate. Methods: This was an open-label, parallel-group, randomized, multicenter, phase III trial in Japanese women with anovulation or oligo ovulation secondary to hypothalamic-pituitary dysfunction or polycystic ovary syndrome, undergoing ovulation induction with recombinant-human follicle stimulating hormone. The women were randomized (2:1) to receive either a single 250 MUg s.c. dose of r-hCG or a single 5000 IU i.m. dose of u-hCG for ovulation triggering. Results: Eighty-one women were randomized to either r-hCG (n=54) or u hCG (n=27). Ovulation occurred in 100% of the participants and treatment with r hCG was observed to be non-inferior to u-hCG for ovulation induction. Overall, the type and severity of adverse events were as expected for women receiving fertility treatment. Conclusion: This study demonstrated that r-hCG was non inferior to u-hCG for inducing ovulation. Furthermore, r-hCG demonstrated an expected safety profile, with no new safety concerns identified. PMID- 29259451 TI - Phase III trial of 8% vaginal progesterone gel for luteal phase support in Japanese women undergoing in vitro fertilization and fresh embryo transfer cycles. AB - Aim: This study evaluated the efficacy and safety of vaginal progesterone gel that was administered daily for luteal phase support as part of in vitro fertilization/embryo transfer (IVF/ET) cycles in Japanese women. Methods: This was a phase III, multicenter, open-label, single-arm trial in Japanese women undergoing IVF/ET, using the Japanese Society of Obstetrics and Gynecology 2009 registry as a historical control. The primary objective was to demonstrate the non-inferiority, with regard to the clinical pregnancy rate per ET, of vaginal progesterone gel that was administered once daily, compared with the historical standard value in IVF/ET cycles in Japan. The biochemical pregnancy (positive serum beta-hCG pregnancy test but no clinical pregnancy) rate per ET also was investigated, as were the safety and tolerability of the vaginal progesterone gel. Results: Of the 178 women who were enrolled, 123 underwent IVF/ET. The clinical pregnancy rate per ET was non-inferior in the prospective arm, compared with the historical population. The biochemical pregnancy rate per ET was 7.3%. The safety profile of the vaginal progesterone gel was as expected, with no new safety issue identified. Conclusion: The vaginal progesterone gel was efficacious, with a safety profile as expected, in this study in Japanese women undergoing IVF/ET cycles. PMID- 29259452 TI - Immobilized pH in culture reveals an optimal condition for somatic cell reprogramming and differentiation of pluripotent stem cells. AB - Aim: One of the parameters that greatly affects homeostasis in the body is the pH. Regarding reproductive biology, germ cells, such as oocytes or sperm, are exposed to severe changes in pH, resulting in dramatic changes in their characteristics. To date, the effect of the pH has not been investigated regarding the reprogramming of somatic cells and the maintenance and differentiation of pluripotent stem cells. Methods: In order to investigate the effects of the pH on cell culture, the methods to produce induced pluripotent stem cells (iPSCs) and to differentiate embryonic stem cells (ESCs) into mesendoderm and neuroectoderm were performed at each medium pH from 6.6 to 7.8. Using the cells of the Oct4-GFP (green fluorescent protein) carrying mouse, the effects of pH changes were examined on the timing and colony formation at cell reprogramming and on the cell morphology and direction of the differentiation of the ESCs. Results: The colony formation rate and timing of the reprogramming of the somatic cells varied depending on the pH of the culture medium. In addition, mesendodermal differentiation of the mouse ESCs was enhanced at the high pH level of 7.8. Conclusion: These results suggest that the pH in the culture medium is one of the key factors in the induction of the reprogramming of somatic cells and in the differentiation of pluripotent stem cells. PMID- 29259453 TI - Polycystic ovary syndrome: early diagnosis and intervention are necessary for fertility preservation in young women with endometrial cancer under 35 years of age. AB - Aim: Polycystic ovary syndrome (PCOS) is a significant risk factor for premenopausal endometrial cancer (EC) and/or atypical endometrial hyperplasia (AEH). The aim was to elucidate the clinical background and detailed menstrual history of EC and/or AEH in young women with PCOS. Methods: From January 2001 to December 2013, women under 35 years of age who had been diagnosed with EC and/or AEH and who had been treated at Kumamoto University Hospital, Japan, were recruited. The patients' clinical characteristics, clinical stages of EC and/or AEH, medication and operation methods, endocrine profiles, and menstrual history were assessed retrospectively. Results: Of all the cases of EC and/or AEH, 25 (4.6%) were under 35 years of age. The mean age was 29.0 years and all the patients were nulligravida. The clinical stages of EC and/or AEH that were identified included: AEH (five cases), stage IA (18 cases), IB (one case), and IIIA (one case). Fourteen (56%) cases met the criteria for PCOS. Both the Body Mass Index and Homeostatic Model Assessment-insulin resistance were significantly higher in the patients with PCOS than in the patients without PCOS. Medroxyprogesterone acetate therapy was not effective for the patients with PCOS and they underwent a hysterectomy more often than the patients without PCOS. All the patients with PCOS exhibited irregular menstruation or amenorrhea, the mean duration of which was 13.1 years before PCOS and EC and/or AEH were diagnosed. Conclusion: Although both the patients with and without PCOS had irregular menstruation, the patients with PCOS were less likely to have fertility-sparing surgery than the patients without PCOS because they had more advanced disease or failed to respond to medroxyprogesterone acetate therapy. PMID- 29259454 TI - Management of ovarian hyperstimulation syndrome with abdominal compartment syndrome, based on intravesical pressure measurement. AB - There are few reports on abdominal compartment syndrome that are caused by ovarian hyperstimulation syndrome (OHSS). Here, a case of a 29 year old woman is reported in which intravesical pressure measurement was useful in the management of severe OHSS that had been complicated by abdominal compartment syndrome. The patient's urinary output and general condition did not improve after the initial treatment. The woman's intra-abdominal pressure was evaluated indirectly, based on her intravesical pressure, and was found to be significantly elevated. The patient's urinary volume increased after a 14 mm Hg decrease in the intravesical pressure was achieved by the drainage of ascitic fluid. Intravesical pressure measurement was useful in the management of the general condition of this patient with OHSS. PMID- 29259455 TI - Human male infertility and its genetic causes. AB - Background: Infertility affects about 15% of couples who wish to have children and half of these cases are associated with male factors. Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations/deletions of several Y chromosome genes. Many researchers have analyzed genes in the AZF region on the Y chromosome; however, in 2003 the SYCP3 gene on chromosome 12 (12q23) was identified as causing azoospermia by meiotic arrest through a point mutation. Methods: We mainly describe the SYCP3 and PLK4 genes that we have studied in our laboratory, and add comments on other genes associated with human male infertility. Results: Up to now, The 17 genes causing male infertility by their mutation have been reported in human. Conclusions: Infertility caused by nonobstructive azoospermia (NOA) is very important in the field of assisted reproductive technology. Even with the aid of chromosomal analysis, ultrasonography of the testis, and detailed endocrinology, only MD-TESE can confirm the presence of immature spermatozoa in the testes. We strongly hope that these studies help clinics avoid ineffective MD-TESE procedures. PMID- 29259456 TI - Protein biomarkers for male artificial insemination subfertility in bovine spermatozoa. AB - Background: Although artificial insemination (AI) technique is an established biotechnology for bovine reproduction, the results of AI (conception rates) have a tendency to decline gradually. To our annoyance, moreover, AI-subfertile bulls have been occasionally found in the AI centers. To resolve these serious problems, it is necessary to control the sperm quality more strictly by the examinations of sperm molecules. Methods: We reviewed a number of recent articles regarding potentials of bovine sperm proteins as the biomarkers for bull AI subfertility and also showed our unpublished supplemental data on the bull AI subfertility associated proteins. Main findings: Bull AI-subfertility is caused by the deficiency or dysfunctions of various molecules including regulatory proteins of ATP synthesis, acrosomal proteins, nuclear proteins, capacitation related proteins and seminal plasma proteins. Conclusion: In order to control the bovine sperm quality more strictly by the molecular examinations, it is necessary to select suitable sperm protein biomarkers for the male reproductive problems which happen in the AI centers. PMID- 29259458 TI - Theory about the Embryo Cryo-Treatment. AB - Background: To create hypothesis, which can give a logical explanation related to the benefits of freezing/thawing embryos. Cryopreservation is not only a technology used for storing embryos, but also a method of embryo treatment that can potentially improve the success rate in infertile couples. Methods: From the analysis of multiple results in assisted reproductive technology, which have no satisfactory explanation to date, we found evidence to support a 'therapeutic' effect of the freezing/thawing of embryos on the process of recovery of the embryo and its subsequent implantation. Results: Freezing/thawing is a way to activate the endogenous survival and repair responses in preimplantation embryos. Several molecular mechanisms can explain the higher success rate of ET using thawed embryos compared to fresh ET in women of advanced reproductive age, the higher miscarriage rate in cases of thawed blastocyst ET compared to thawed ET at early cleavage embryo, and the higher perinatal parameters of born children after thawed ET. Embryo thawing induces a stress. Controlled stress is not necessarily detrimental, because it generates a phenomenon that is counteracted by several known biological responses aimed to repair mitochondrial damage of membrane and protein misfolding. The term for favorable biological responses to low exposures to stress is called hormesis. Conclusions: This thesis will summarize the role of cryopreservation in the activation of a hormetic response, preserving the mitochondrial function, improving survival, and having an impact on the process of implantation, miscarriage, and the development of pregnancy. PMID- 29259459 TI - Assisted reproductive technology in Japan: a summary report of 1992-2014 by the Ethics Committee, Japan Society of Obstetrics and Gynecology. AB - Aim: The Japan Society of Obstetrics and Gynecology implemented a registry report system for the clinical practice of assisted reproductive technology in 1986. The aggregated results from 1992 to 2014 are reported herein. Methods and Results: The total number of registered treatments was 393 745 cycles, of which 66 550 were pregnancy cycles and 46 008 were cycles with a live birth. Compared to the number of registered treatments in 2008, when the cycle-based registry was newly introduced, there was a 2.07-fold increase in the total number of treatments and a 2.25-fold increase in the number of cycles with a live birth. As the average age of patients who receive assisted reproductive technology has become markedly higher year by year, the most common age of those patients who received assisted reproductive technology in 2014 was 40 years. Conclusion: The total numbers of both assisted reproductive technology treatments and assisted reproductive technology live births are likely to be higher in the future. In addition, the trend toward aging patients seems to be continuing into the future. PMID- 29259457 TI - Animal-cell culture media: History, characteristics, and current issues. AB - Background: Cell culture technology has spread prolifically within a century, a variety of culture media has been designed. This review goes through the history, characteristics and current issues of animal-cell culture media. Methods: A literature search was performed on PubMed and Google Scholar between 1880 and May 2016 using appropriate keywords. Results: At the dawn of cell culture technology, the major components of media were naturally derived products such as serum. The field then gradually shifted to the use of chemical-based synthetic media because naturally derived ingredients have their disadvantages such as large batch-to batch variation. Today, industrially important cells can be cultured in synthetic media. Nevertheless, the combinations and concentrations of the components in these media remain to be optimized. In addition, serum-containing media are still in general use in the field of basic research. In the fields of assisted reproductive technologies and regenerative medicine, some of the medium components are naturally derived in nearly all instances. Conclusions: Further improvements of culture media are desirable, which will certainly contribute to a reduction in the experimental variation, enhance productivity among biopharmaceuticals, improve treatment outcomes of assisted reproductive technologies, and facilitate implementation and popularization of regenerative medicine. PMID- 29259460 TI - Possible ability of bovine follicular fluid to attract migrating bull spermatozoa. AB - Aim: To examine the potential of bovine follicular fluid (BFF) to attract bull spermatozoa. Methods: The ability of the BFF to attract bull sperm was evaluated by observing changes in sperm migration after being placed in a cross-column chamber. The movement parameters of the heads and flagella of the sperm that were attracted to the BFF were analyzed by using the Computer Assisted Sperm Analysis system. Results: It was observed that 61.6% of the bull sperm migrated toward the BFF when the BFF was used at a concentration of 0.1%, but 67.2% of the sperm did not migrate toward the BFF at a concentration of 10%. Relatively larger numbers of both precapacitated and postcapacitated bull sperm migrated toward the BFF (0.1%). The ability of the 0.1% BFF to attract sperm probably affected both the normal artificial insemination (AI) fertility sperm and the poor AI fertility spermatozoa. The flagellar curvilinear ratio of the sperm winding to the 0.1% BFF was significantly higher than that of the prewinding sperm. Conclusion: These results could suggest that BFF potentially attracts bull sperm at a certain concentration, irrespective of the capacitation status of the sperm. Although the mechanism by which this attraction occurs remains unclear, these data imply that it could be related to BFF-dependent changes in the sperm flagellar curvilinear ratio. PMID- 29259461 TI - Treatment period and medical care costs to achieve the first live birth by assisted reproductive technology are lower in the single embryo transfer period than in the double embryo transfer period: a retrospective analysis of women younger than 40 years of age. AB - Aim: It was examined whether the single embryo transfer policy makes the treatment period longer for couples to achieve their first live birth by assisted reproductive technology. Methods: This study retrospectively analyzed women who started assisted reproductive technology at younger than 40 years of age in the authors' organization. The treatment periods for couples to achieve the first live birth by assisted reproductive technology, between the women who started assisted reproductive technology from 2004 to 2009 (the double embryo transfer period group, n=250), in which the double embryo transfer was predominant, and the women who started assisted reproductive technology from 2010 to 2015 (the single embryo transfer period group, n=298), in which the single embryo transfer was predominant, were compared. Results: The age at the start of assisted reproductive technology, pregnancy rate per embryo transfer, and rate of women who achieved a live birth by assisted reproductive technology per number of women who tried assisted reproductive technology were all significantly higher in the single embryo transfer period group. Among the women who achieved a live birth by assisted reproductive technology, the incidence of multiple births and severe ovarian hyperstimulation syndrome, the treatment period, and medical care costs needed to achieve the first live birth were all significantly lower in the single embryo transfer period group. Conclusion: In the single embryo transfer period group, those women who were younger than 40 years of age achieved their first live birth by assisted reproductive technology more safely, quickly, and reasonably. PMID- 29259462 TI - Functional role of the Tau protein in epithelial ovarian cancer cells. AB - Aim: The microtubule-associated Tau protein is a marker of paclitaxel sensitivity in ovarian cancer. The aim of the present study was to elucidate the function of the Tau protein in epithelial ovarian cancer. Methods: The correlation between Tau protein expression and the response to paclitaxel by using several ovarian cancer cell lines was investigated. Results: A Western blot showed that the expression level of the Tau protein was the highest in the TOV112D cells. A cell counting kit showed that the proliferation rates were more inhibited in the cells with down-regulated Tau protein than in the control cells, both with and without paclitaxel treatment. The proliferation rates of the control cells and the TOV112D cells also were compared with Tau protein overexpression. The level of cell proliferation was more inhibited in the cells that overexpressed the Tau protein, compared to the control cells, both with and without paclitaxel treatment. It was shown that both the down-regulation and the overexpression of the Tau protein were related to the inhibition of TOV112D cell proliferation. Early and late apoptosis of the TOV112D cells that were transfected with Tau cDNA plasmid construct or Tau small interfering RNA significantly increased. Conclusion: These findings suggest that the molecular targeting of the Tau protein could be a potential treatment for ovarian cancer. PMID- 29259463 TI - Pregnancy outcomes after assisted reproductive procedures with embryos that had been derived from affected and unaffected ovaries among women with small unilateral endometriomas. AB - Aim: To clarify the effects of small endometriomas on in vitro fertilization (IVF) outcomes. In the present study, the potential impact of small ovarian endometriomas on the quantitative and qualitative outcomes of IVF was evaluated in the same individual. Methods: A retrospective analysis was performed, in which 118 infertile women with unilateral endometriomas that were <40 mm in size and who underwent IVF or intracytoplasmic sperm injection were evaluated. Single frozen embryo transfer cycles were performed, with separate data collections for both the affected and the unaffected ovaries, which allowed for an evaluation of the implantation rate. Results: The mean antral follicular count and the number of follicular flushings, retrieved oocytes, and obtained embryos were significantly lower for the endometrioma-containing ovary than for the contralateral, intact ovary. No significant difference was observed regarding the blastocyst retrieval and good-quality blastocyst retrieval rates, pregnancy rate, and clinical pregnancy or live birth rate. Conclusion: Although the patients with a small endometrioma had a decreased ovarian reserve, they had lower pregnancy rates. The decision to transfer an embryo from an endometrioma-containing ovary or from a contralateral, intact ovary also might not influence the pregnancy rate. PMID- 29259464 TI - Expression of cytokine-induced neutrophil chemoattractant suppresses tumor necrosis factor alpha expression and thereby prevents the follicles from undergoing atresia and apoptosis. AB - Aim: Cytokine-induced neutrophil chemoattractant (CINC/gro) is a CXC family chemokine, similar to interleukin-8 in rats, and is one of the factors that regulates ovulation. However, the mechanism that regulates atresia of the ovaries postovulation is not clearly defined. Methods: Whether antibody-blocking of CINC/gro can alter the number of ovulated oocytes and modulate neutrophil infiltration was investigated. The effect of the antibody on the level of inflammatory cytokine production and follicular atresia was examined. Apoptosis was measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and via analysis of the messenger RNA expression of Bcl-2 and Bcl2-associated X (Bax). Results: The anti-CINC/gro antibody treatment decreased the number of ovulated oocytes. The messenger RNA levels of cyclooxygenase-2 and interleukin-1 beta were decreased by the antibody treatment, whereas that of tumor necrosis factor (TNF) alpha was increased. The TUNEL analysis revealed a larger number of apoptotic cells in the antibody group, compared with those in the control group, as well as a significant increase in the Bax/Bcl-2 ratio 24 hours after human chorionic gonadotropin administration. Conclusion: These findings suggest that ovulation is accelerated by neutrophil infiltration into the theca layer. The CINC/gro appears to synergize with interleukin-1 beta for ovulation. By contrast, the data suggest that CINC/gro expression suppresses TNF alpha expression and that CINC/gro expression therefore prevents the follicles from undergoing atresia and apoptosis. PMID- 29259465 TI - Is human chorionic gonadotropin supplementation beneficial for frozen and thawed embryo transfer in estrogen/progesterone replacement cycles?: A randomized clinical trial. AB - Aim: Human chorionic gonadotropin (hCG) is used frequently for luteal support in fresh in vitro fertilization cycles as it induces progesterone secretion from the ovaries after oocyte retrieval and modulates the endometrium for implantation in fresh cycles. In contrast, hCG is not usually used for the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement cycles because ovulation is suppressed. However, several studies have shown that luteinizing hormone and hCG receptors are present in the human endometrium and that hCG can directly induce the decidualization of endometrial stromal cells in vitro. Thus, this study evaluated whether hCG supplementation can be beneficial for cryopreserved-thawed embryo transfer in estrogen/progesterone replacement cycles. Methods: One-hundred-and seventy-three cryopreserved-thawed embryo transfer cycles with estrogen/progesterone replacement were divided randomly into two groups. Transdermal oestradiol was used in combination with vaginal progesterone suppositories for HR. The embryo transfer was performed on day 17 and/or day 20 of the HR therapy cycle in both groups. In Group A, 3000 IU of hCG was administered on days 17, 20, and 23. In Group B, hCG was not used. Results: There was no significant difference in the average age of the patients, the average number of previous assisted reproductive technology cycles, or the average number of embryo transfers between the two groups. The rates of pregnancy and implantation per embryo were 37.2% and 25.3%, respectively, in Group A and 35.6% and 21.7%, respectively, in Group B. The pregnancy and implantation rates were similar in both groups. Conclusion: Supplementation with hCG is not beneficial for cryopreserved-thawed embryo transfer in estrogen/progesterone replacement cycles. PMID- 29259466 TI - Overexpression of microRNA-542-3p attenuates the differentiating capacity of endometriotic stromal cells. AB - Aim: Endometriosis is defined as the presence of endometrial glandular and stromal cells outside of the uterine cavity. A previous study reported that microRNA (miR)-542-3p plays a critical role in eutopic endometrial decidualization. This study aims to clarify the potential role of miR-542-3p and the target gene, IGFBP-1 (insulin-like growth factor-binding protein 1), in the impairment of the decidualizing capacity of human ectopic endometrial stromal cells (HEcESCs). Methods: In vitro analysis of primary undifferentiated and decidualizing human eutopic endometrial stromal cells (HEuESCs) and HEcESCs was conducted. The primary HEuESCs or HEcESCs were expanded in culture and decidualized with 8-bromo-cyclic adenosine monophosphate (8-bromo-cAMP) and medroxyprogesterone acetate (MPA). Results: The morphological and biological differentiating capacities of the HEcESCs were markedly impaired. In contrast to the HEuESCs, the HEcESCs that were treated with the decidual stimulus retained the mesenchymal phenotype and capacity for migration. The down-regulation of miR 542-3p in the HEcESCs treatment with 8-bromo-cAMP and MPA was much weaker than that of the HEuESCs. High expression of miR-542-3p led to a significant decrease in the expression of IGFBP1 in the HEcESCs. Conclusion: Impairment of the differentiating capacity by the overexpression of miR-542-3p could influence the capacity for migration and invasion of endometriotic cells in an ectopic environment. PMID- 29259467 TI - Clinical outcome of various metformin treatments for women with polycystic ovary syndrome. AB - Aim: Polycystic ovary syndrome (PCOS) is an ovulatory disorder and insulin resistance and diabetes are involved in its pathophysiology. Metformin, an anti diabetic agent, has been reported to be useful to induce ovulation. Methods: Metformin treatment was classified into four types: (1) clomiphene-metformin combination treatment for clomiphene-resistant patients; (2) clomiphene-metformin combination for clomiphene-sensitive patients; (3) clomiphene-metformin combination for naive patients; and (4) metformin monotherapy. The patients underwent physical, endocrinological, and clinical examinations for their ovulation rates, pregnancy rates, and follicular development. Results: The ovulation rates, pregnancy rates, and single follicular development were not significantly different among the clomiphene-metformin combination treatment groups. In the Body Mass Index (BMI) subanalysis, the pregnancy rate was higher in the BMI>=30 kg/m2 group than in the other three groups with a BMI of <=30 kg/m2 in both cycles and cases. The ovulation rates and pregnancy rates were significantly higher in the group with a fasting insulin of >=15 MUU/mL than in the groups with a fasting insulin of <15 MUU/mL in both cycles and cases. Conclusion: Clomiphene-metformin combination treatment appears to be useful, at least for clomiphene-resistant patients, and a BMI of >30 kg/m2 and a fasting insulin of >=15 MUU/mL appear to be predictors of a good result with this treatment. PMID- 29259468 TI - Genetic risk of Klinefelter's syndrome in assisted reproductive technology. AB - Aim: The main cause of Klinefelter's syndrome (KS) has been believed to be XY sperm. Accordingly, in the intracytoplasmic sperm injection treatment of patients with KS, hereditary KS has been a concern. Therefore, this study attempted to estimate the risk before and after the assisted reproductive technology. Methods: First, in order to validate the safety of the gametes of the patients with KS, a fluorescent in situ hybridization (FISH) analysis, following an original cell identification method using 1052 testicular gametes of 30 patients, was conducted. Second, in the resultant 45 babies, cytogenetic and physical-cognitive screening data were analyzed. In addition, a first attempt was conducted to investigate the origin of the extra X chromosome in 11 patients with KS by using 12 X-chromosome short tandem repeat (STR) analysis in order to estimate the paternal contribution to KS. Results: No sex chromosomally abnormal gamete was found in the FISH analysis and the babies were normal genetically, physically, and cognitively. In the STR, it was confirmed that most (7/11) of the patients with KS resulted from the fertilization of the XX oocytes, suggesting that a baby with KS that had been reported previously might not have resulted from XY sperm. Conclusion: These results indicate that the risk of assisted reproductive technology for patients with KS is not as high as previously expected. PMID- 29259469 TI - Effects of endometrial injury on frozen-thawed blastocyst transfer in hormone replacement cycles. AB - Aim: To evaluate whether local endometrial injury would improve the pregnancy rates after frozen-thawed blastocyst transfer in cycles with hormone replacement. Methods: Seventy-seven patients who were aged <40 years with a history of at least three unsuccessful embryo transfers and who underwent frozen-thawed blastocyst transfer during hormone replacement cycles between February and June, 2013 were studied. They were allocated into two groups based on the last digit of their clinical record number: an experimental group (n=22), excluding patients who withheld consent or who were unable to undergo treatment, and a control group (n=55). In the experimental group, the endometrium was scratched once with an endometrial sampler during the luteal phase of the cycle preceding the embryo transfer. Results: There was no significant difference in the baseline characteristics between the groups. The clinical pregnancy rate was 6% in the experimental group and 22% in the control group. Among these, the ongoing pregnancy rate was 100% in the experimental group and 50% in the control group. Conclusion: Endometrial injury might increase the pregnancy rates after frozen thawed blastocyst transfer and decrease the risk of miscarriage in patients with a history of unsuccessful embryo transfers. PMID- 29259470 TI - Potential of zygotes to produce live births can be identified by the size of the male and female pronuclei just before their membranes break down. AB - Aim: To determine whether there are differences in size between the male and female pronuclei immediately before the pronuclear membrane breakdown (PNMBD) and to evaluate whether pronuclear size differences influence normal birth rates. Methods: Time-lapse photography was used to measure the size of each pronucleus, while the outcome of 71 frozen-thawed single blastocyst transfers in patients receiving hormone therapy was analyzed retrospectively. The pronuclear measurements were made 4 hours before the PNMBD, corresponding to 16-20 hours after insemination or intracytoplasmic sperm injection, and immediately before the PNMBD. The differences in the areas between the pronuclei in the zygotes that were associated with the live births were compared with those that were associated with the failed pregnancies. Results: The average difference in the area between the pronuclei 4 hours before and immediately before the PNMBD in the patients with a live birth was significantly smaller than in the patients with a failed birth. In addition, the average area difference in the patients with a successful birth was significantly smaller when the measurements were made immediately before the PNMBD, compared with the measurements 4 hours before the PNMBD. Such differences were not detected among the patients who did not achieve a birth. Conclusion: The birth of healthy babies resulted from zygotes that contained pronuclei of similar size when the measurements were made immediately before the PNMBD. Evaluating the size of each pronucleus immediately before the PNMBD provides an effective indicator of the embryo's potential at an early stage of development. PMID- 29259471 TI - Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure. AB - Aim: Although a thin endometrium has been well recognized as a critical factor in implantation failure, little information is available regarding the molecular mechanisms. The present study investigated these mechanisms by using genome-wide mRNA expression analysis. Methods: Thin and normal endometrial tissue was obtained from a total of six women during the mid-luteal phase of the menstrual cycle. The transcriptomes were analyzed with a microarray. Differentially expressed genes were classified according to Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The study identified 318 up-regulated genes and 322 down-regulated genes in the thin endometrium, compared to the control endometrium. The GO and KEGG pathway analyses indicated that the thin endometrium possessed aberrantly activated immunity and natural killer cell cytotoxicity that was accompanied by an increased number of inflammatory cytokines, such as IFN-gamma. Various genes that were related to metabolism and anti-oxidative stress were down-regulated in the thin endometrium. Conclusion: Implantation failure in the thin endometrium appears to be associated with an aberrantly activated inflammatory environment and aberrantly decreased response to oxidative stress. PMID- 29259472 TI - Birthweights and Down syndrome in neonates that were delivered after frozen thawed embryo transfer: The 2007-2012 Japan Society of Obstetrics and Gynecology National Registry data in Japan. AB - Aim: To evaluate the use of frozen embryos on the outcome of assisted reproductive technology (ART), a retrospective study of the Japanese Assisted Reproductive Technology Registry data during the years 2007-2012 was conducted. Methods: A total of 124 946 singleton neonates who reached term gestation following ART from 2007-2012, with 80 660 achieved through frozen-thawed embryo transfer (ET) and 44 286 being achieved through fresh ET, were analyzed for their birthweights and chromosomal abnormalities. Results: The birthweight of the neonates from the frozen-thawed ETs was significantly higher than that of those from the fresh ETs throughout all the study years. The frequency of Down syndrome was 0.17% for the fresh ETs and 0.13% for the frozen-thawed ETs in the period 2007-2012. This study showed that frozen-thawed ETs result in a constant increase of the average birthweight between 37 and 41 weeks gestational age and lower frequencies of Down syndrome. Conclusion: Frozen-thawed ETs were comparable to the fresh ET method, with the exceptions of higher birthweights and a lower frequency of Down syndrome in the neonates that were born from frozen-thawed ET. The increase in birthweights was not proportional to the gestational ages. This cannot be explained with any well-known mechanism. The frequency of chromosomal abnormalities needs detailed data for analysis. PMID- 29259473 TI - Japan Society for Reproductive Medicine RMB Best Paper Award. PMID- 29259474 TI - Fertility preservation of patients with testicular cancer. AB - Background: Testicular cancer (TC) is one of the most common malignancies in young men of reproductive age. Although TC is a curable malignancy with a high survival rate, its treatment requires various cytotoxic modalities and negatively impacts spermatogenesis; therefore, the fertility preservation of patients with TC has been studied. Methods: In order to give an overview of fertility preservation in patients with TC, the literature was reviewed. Original and review articles were identified and examined on the basis of PubMed database searches. Results: Chemotherapy and radiotherapy damage spermatogenesis and retroperitoneal lymph node dissection negatively impacts ejaculatory function. Testicular sperm extraction facilitates successful sperm retrieval in patients with TC with postchemotherapy azoospermia. Although preserved sperm is used with a very low frequency (8%), the conception rates in those who have used sperm are not inferior. Conclusion: The number of studies is limited, and because numerous treatment factors affect fertility, outstanding questions remain about preserving the fertility of patients with TC. Further studies are necessary in order to determine the best means of preventing and treating infertility in patients with TC. PMID- 29259475 TI - Impact of metabolic disorders on prostate cancer growth: Androgen and insulin resistance perspectives. AB - Background: A high prevalence of cancers in metabolic disorders, like metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM), recently has been noted, including prostate cancer (PC), which is androgen-sensitive. However, the pathological relationship among testosterone and insulin and insulin-like growth factor (IGF)-1 signaling in relation to MetS and T2DM with PC remains unclear. Methods: Papers were reviewed, including those by the authors. Results: In MetS or the initial stage of T2DM accompanying insulin resistance, insulin and IGF-1 signaling could be essential for PC growth. In the advanced stage of T2DM, the decrease in insulin secretion might work against PC growth. A decrease in testosterone concentration with T2DM also might suppress PC proliferation. Androgen deprivation therapy in patients with PC might increase the risk of MetS and/or T2DM and consequently cardiovascular events. Certain drugs for T2DM treatment, such as metformin and glucagon-like peptide-1 analog, potentially might be useful for the treatment of PC. Conclusion: The improvement of insulin resistance appears to be essential for the prevention of PC growth. Further studies are needed to clarify the complicated pathophysiology of metabolic disorders in PC growth. PMID- 29259477 TI - Weight reduction using a formula diet recovers menstruation in obese patients with an ovulatory disorder. AB - Aim: To determine the effectiveness of a formula diet in weight reduction and the recovery of menstruation in obese patients with ovulatory disorders. Methods: After the enrollment of 39 obese women with ovulatory disorders, they replaced one or two of their three normal meals with a microdiet (MD) (240 kcal/meal) for 24 weeks. Physical, endocrinological, and biochemical tests were conducted before and at 12 and 24 weeks of the study. Of the 39 women enrolled, 26 were not taking clomiphene. They were divided into three groups according to their body weight outcomes and then analyzed for menstruation recovery. Results: A weight reduction of >=5% was observed in 31 (81.5%) of the 39 women. There were significant decreases in the body weight and Body Mass Index during the study. Menstruation returned in 18 (69%) of the 26 patients without clomiphene treatment, with the recovery being significantly more prevalent in the groups (totally 81.0%) that exhibited a 5%-10% weight reduction and >=10% weight reduction, compared to the group with a <5% weight reduction. Conclusion: The use of a formula diet effectively reduced the patients' body weight and led to the recovery of menstruation in these obese patients with ovulatory disorders. PMID- 29259478 TI - Clinical outcomes of infertility treatment for women with adenomyosis in Japan. AB - Aim: A multicenter, retrospective survey was conducted in order to investigate the current clinical status of adenomyosis in Japan. Methods: The questionnaires covered the management of infertile women with adenomyosis and the outcomes of infertility treatment in women with adenomyosis. The questionnaires were sent to 1149 facilities in Japan. Results: The data were obtained on 535 infertile women with adenomyosis from 190 facilities. Regarding management, infertility treatment was performed without pretreatment for adenomyosis in 37 facilities, after medication in eight facilities, and after an operation in four facilities. Management policies were not established in 106 facilities. Regarding outcomes, the pregnancy rate was 41.7% and the abortion rate was 29.8%. Eighty-five patients received medication and 89 patients underwent surgery as a pretreatment before infertility treatment, while 361 patients had no pretreatment. In relation to the type of adenomyosis, 162 patients had the focal type and 336 patients had the diffuse type. The pregnancy rate and abortion rate were not affected by pretreatment or the type of adenomyosis. Conclusion: The management policy for infertile women with adenomyosis has not been established. The pregnancy rate of infertility treatment is about 40%. There were no data to suggest that medication or surgery as a pretreatment for adenomyosis increased the pregnancy rate in infertile women. PMID- 29259476 TI - In vitro maturation of human immature oocytes for fertility preservation and research material. AB - Aim: In recent years, the importance of fertility preservation (FP) has increased. In vitro maturation (IVM), an important technique in FP, has started to be used in the clinic, but controversies persist regarding this technique. Here, a survey of IVM for FP is provided. Methods: Based on a literature review, the applications of FP, methods of FP, IVM of oocytes that had been collected in vivo and ex vivo, maturation of oocytes after IVM for FP, cryopreservation of oocytes for FP, explanation of the procedures to patients, and recent research on FP using IVM were investigated. Results: Although IVM for FP remains controversial, the application of FP is expected to expand. Depending on the age and disease status of the patient, various methods of oocyte collection and ovarian stimulation, as well as various needle types and aspiration pressures, have been reported. The maturation rate of IVM in FP ranges widely and requires optimization in the future. In regard to cryopreservation for matured oocytes, the vitrification method is currently recommended. Conclusion: Regarding FP for patients with cancer, the treatment of cancer is prioritized; thus, the time and use of medicines are often constrained. As several key points regarding IVM remain unclear, well-designed and specific counseling for patients is necessary. PMID- 29259479 TI - Retrospective comparative study of the factors affecting birthweights in frozen thawed embryo transfer, compared to fresh embryo transfer. AB - Aim: Several studies have indicated that the cause of the increased birthweight of frozen-thawed embryos was associated with assisted reproductive technology (ART) procedures, such as cryopreservation. In the present study, the mean birthweight of singletons was compared between the ovulatory and hormone replacement therapy (HRT) cycles in order to investigate the primary factor that leads to higher birthweights from frozen-thawed embryo transfer (FET). Methods: This retrospective study was carried out from January 2011 to December 2014 on 2738 singletons who were born at 37-41 weeks' gestation, following ART in a single facility. The mean birthweight of the singletons who were born after a fresh embryo transfer (ET) was compared to the mean birthweight of the singletons who were born after a FET. In the FET cycles, the mean birthweight of the singletons was compared between the ovulatory and HRT cycles. Results: The mean birthweight of the singletons who were born after a FET was significantly higher than that of the singletons who were born after a fresh ET. In the FET cycles, the birthweight from the HRT cycles was significantly higher than that from the ovulatory cycles. Among the HRT cycles, there was no difference between the birthweight of the singleton who were born from a blastocyst transfer and those who were born from a cleavage-stage ET. Conclusion: The primary factor to affect the birthweight of singletons might be the pre/postET hormonal environment of the endometrium and not the stage of the transferred embryo nor the frozen-thawed procedure itself. PMID- 29259480 TI - Efficacy of the endometrial receptivity array for repeated implantation failure in Japan: A retrospective, two-centers study. AB - Aim: This study aimed to assess the efficacy of the endometrial receptivity array (ERA) as a diagnostic tool and the impact of personalized embryo transfer (pET) for the treatment of patients with recurrent implantation failure (RIF) in Japan. Methods: Fifty patients with a history of RIF with frozen-thawed blastocyst transfers were recruited from July, 2015 to April, 2016. Endometrial sampling for the ERA and histological dating and a pET according to the ERA were performed. The receptive (R) or non-receptive (NR) status of the endometrium as a result of the first ERA, endometrial dating, and pregnancy rates after the pET were analyzed. Results: Of the patients with RIF, 12 (24%) were NR. Among them, eight (66.7%) were prereceptive. A clinical follow-up was possible in 44 patients who underwent the pET. The pregnancy rates were 58.8% per patient and 35.3% per first pET in the R patients and 50.0% per patient and 50.0% per first pET in the NR patients. Discrepancies between the ERA results and histological dating were seen more in the NR patients than in the R patients. Conclusions: For patients with unexplained RIF, there is a significance in searching for their personal window of implantation (WOI) using the ERA, considering the percentage of those who were NR and the pregnancy rates that resulted from the pET. By transferring euploid embryos in a personal WOI, much better pregnancy rates are expected. PMID- 29259481 TI - After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby. AB - Aim: An immune etiology for idiopathic recurrent miscarriage is an important issue because a fetus is allogenetically different from the mother. Type 1 T helper (Th1) and Type 2 (Th2) cells have important functions in immune responses and there is a general agreement that pregnancy is associated with Th2 cell dominance. The purpose of this case report is to establish the effectiveness of an immunosuppressive treatment for a patient who had 11 consecutive miscarriages despite several treatments, such as anticoagulation, that showed elevated Th1/Th2 cell ratios. Methods: This patient visited our clinic following 11 consecutive miscarriages between 2009 and 2014 that occurred between 5 and 8 weeks' gestation. The Th1/Th2 cell ratio was evaluated after the 12th conception and she received an immunosuppressive treatment (tacrolimus; 1 mg/d). Results: The Th1/Th2 cell ratio was elevated after the 12th conception, but the patient miscarried, with a normal karyotype of chorionic villi despite the immunosuppressive treatment. After the 13th conception, she began receiving treatment with 2 mg/d of tacrolimus at 4 weeks' gestation, which was continued until delivery. Conclusion: For recurrent miscarriage cases that show an elevated Th1/Th2 cell ratio after achieving pregnancy, immunosuppressive treatment with tacrolimus could be effective. PMID- 29259483 TI - Epigenetic regulation of the pathological process in endometriosis. AB - Background: Endometriosis is one of the most common gynecological diseases that greatly compromises the quality of life in affected individuals. A growing body of evidence shows that the remodeling of retrograde endometrial tissues to the ectopic endometriotic lesions involves multiple epigenetic alterations, such as DNA methylation, histone modification, and microRNA expression. Methods: This article retrospectively reviewed the studies that were related to the epigenetic regulatory factors that contribute to the development and maintenance of endometriosis. A literature search was performed in order to collect scientific articles that were written in English by using the key words of "endometriosis," "epigenetics," "DNA methylation," "histone modification," and "microRNA." Results: Epigenetic modifications, including DNA methylation, histone modification, and microRNA expression, are involved in the pathogenesis of endometriosis. These epigenetic players are regulated or tuned by microenvironmental cues, such as locally produced estradiol, proinflammatory cytokines, and hypoxic stress, and reciprocally regulate the process or response to those stimuli. Conclusion: Understanding the molecular mechanisms that underlie these epigenetic regulatory processes would shed light on the etiology and/or progression of endometriosis and facilitate the development of novel therapeutic strategies. PMID- 29259484 TI - Semen cryopreservation as an oncofertility treatment in 122 Japanese men with cancer: A decade-long study. AB - Purpose: Oncofertility is a subspecialty that is concerned with helping patients with cancer preserve their ability to have children in the future. For men, sperm banking is an established way to preserve fertility. The aim was to determine the prefreeze semen characteristics and reproductive outcomes according to cancer type for men who chose semen cryopreservation. Methods: The records of 122 men with cancer who requested semen cryopreservation at the authors' hospital from 2006 to 2015 were reviewed. The mean patient age when the semen was cryopreserved was 33.6 years. Results: The 122 men who banked sperm during the study period had the following types of cancer: testicular (44.3%), hematological (31.1%), digestive (8.2%), and other types (16.4%). The mean sperm concentration by cancer type was 30.5 * 106/mL for testicular, 45.0 * 106/mL for hematological, 40.5 * 106/mL for digestive, and 68.4 * 106/mL for the other types. The mean sperm motility by cancer type was 59.6% for testicular, 50.1% for hematological, 43.0% for digestive, and 44.8% for the other types. For 12 (9.8%) men who used the banked semen, there were five (41.7%) clinical pregnancies. Conclusion: Semen cryopreservation is a simple procedure that can be accomplished quickly and can preserve fertility. PMID- 29259482 TI - Uterus transplantation: Toward clinical application in Japan. AB - Background: In recent years, uterus transplantation (UTx) has been applied as the treatment for patients with uterine factor infertility worldwide. Thus, the clinical application of UTx in Japan should be considered through both the history of UTx technology development in the world and future prospects. Methods: Recent information on UTx was collected via a literature survey and the Internet. Results: Basic research using various animals has been done mainly since 2000. In 2014, the world's first UTx baby was born in Sweden. In total, 24 UTx procedures have been performed at 10 institutes in nine countries and five births were obtained (as of May, 2017). In Japan, the "Project Team for Uterus Transplantation" initiated UTx experiments in 2008 and the "Japan Society for Uterus Transplantation" was organized in March, 2014. In the rest of the world, the "International Society for Uterus Transplantation" was established in January, 2016. Conclusion: Uterus transplantation is still under development as a reproductive medicine tool and organ transplant procedure. A collaborative system that is not limited by facilities and specialties should strive to build an "all Japan" team. PMID- 29259485 TI - Prenatal undernutrition disrupted the sexual maturation, but not the sexual behavior, in male rats. AB - Purpose: Exposure to various stressors, including psychological, metabolic, and immune, in the perinatal period induces long-lasting effects in physiological function and increase the risk of metabolic disorders in later life. In the present study, sexual maturation and sexual behavior were assessed in prenatally undernourished mature male rats. Methods: All the pregnant rats were divided into the maternal normal nutrition (mNN) group and the maternal undernutrition (mUN) group. The mUN mothers received 50% of the amount of the daily food intake of the mNN mothers. Preputial separation and sexual behavior were observed in randomly selected pups of the mNN and mUN groups. Results: The body weight of the mothers was significantly lighter in the mUN group than in the mNN group. Similarly, the pups in the mUN group showed a significantly lower body weight than those in the mNN group from postnatal day (PND) 1 to PND 15. The preputial separation day was significantly delayed in the mUN group, compared to the mNN group. Sexual behavior did not show any significant difference between the two groups. Conclusion: These findings indicated that prenatal undernutrition delayed sexual maturation, but did not suppress sexual behavior, in mature male rats. PMID- 29259486 TI - Complications and outcomes of pregnant women with adenomyosis in Japan. AB - Purpose: To investigate the impact of adenomyosis on the complications and outcomes of pregnancy in Japan. Methods: We carried out a multicenter retrospective questionnaire survey. A questionnaire regarding pregnancy complications and the outcomes of pregnancy was sent to 725 facilities. Results: Data were obtained on the cases of 272 pregnant women with adenomyosis from 65 facilities. The complications of pregnancy included miscarriage before 12 weeks of pregnancy (14.8%), miscarriage after 12 weeks of pregnancy (9.9%), preterm delivery (24.4%), fetal growth restriction (11.8%), pregnancy-induced hypertension (9.9%), intrauterine infection (7.3%), and cervical incompetency (5.3%). The rates of pregnancy complications in the three groups classified according to pretreatment for adenomyosis (no pretreatment, medication, surgery) did not differ to a statistically significant extent. The rates of miscarriage (>12 weeks) and cervical incompetency increased according to the size of the adenomyosis. The rates of pregnancy-induced hypertension and uterine infection in patients with diffuse-type adenomyosis were higher than that in patients with focal-type adenomyosis. Conclusions: Our results show that the increased size and diffuse type of adenomyosis are associated with adverse pregnancy outcome. We should be aware of the higher incidence of pregnancy-induced hypertension and uterine infection in patients with diffuse-type adenomyosis. PMID- 29259487 TI - Evidence of exposure to chemicals and heavy metals during pregnancy in Japanese women. AB - Purpose: Prenatal exposure to environmental chemicals is a growing concern, because such exposures have been shown to be associated with various diseases. The levels of chemicals and heavy metals in maternal blood, cord blood, maternal urine and amniotic fluid in Japanese pregnant women were investigated. Methods: A total of 145 women, including 14 fetal growth restriction cases, were included in the present study. The levels of phthalates (di[2-ethylhexyl]phthalate and mono[2 ethylhexyl]phthalate), perfluorinated compounds (perfluorooctane sulfonate, perfluorohexanoic acid, perfluorooctanoic acid, and perfluorononanoic acid), pesticides (dimethylphosphate, dimethylthiophosphate, diethylphosphate, diethylthiophosphate, 3-phenoxybenzoic acid, and octachlorodipropyl ether), bisphenol A, nicotine (nicotine, nornicotine, cotinine, norcotinine, and trans-3' hydroxycotinine), polybrominated diphenyl ethers, and heavy metals were measured. The relationship between fetal growth and the levels of chemicals and heavy metals were investigated. Results: Phthalates, perfluorinated compounds, pesticides, polybrominated diphenyl ethers, and heavy metals were detected in high frequency, whereas nicotine and bisphenol A were almost negative. Phthalates, perfluorinated compounds, and several heavy metals were transferred to the fetus. High perfluorononanoic acid levels in the maternal blood and cord blood, and low perfluorooctanoic acid level in the cord blood were significantly and negatively associated with fetal growth. Conclusions: The present study showed that pregnant women in Japan and their fetuses are exposed to a variety of chemicals and heavy metals. PMID- 29259488 TI - Evaluation of transfer media containing different concentrations of hyaluronan for human in vitro fertilization. AB - Purpose: The aim of the present prospective study was to investigate the efficacy of hyaluronan (HA) using two different concentrations as embryo transfer media for in vitro fertilization embryo transfer cycles. Methods: A total of 169 cycles undergoing fresh embryo transfer on day 2 or 3, 561 cycles undergoing frozen thawed embryo transfer on day 2 or 3, and 484 cycles of frozen-thawed blastocyst transfer were included in this study. Patients were randomly divided into two groups: transferred with low (l-HA) or high (h-HA) concentrations of HA in transfer media. Results: In the case of fresh embryo transfer cycles, no significant differences were observed in the pregnancy (l-HA 27.2%, h-HA 31.2%), implantation (l-HA 22.1%, h-HA 24.2%), or abortion (l-HA 24.0%, h-HA 20.8%) rates between the two groups. In the case of frozen-thawed embryo transfer cycles, no significant differences were noted in the pregnancy (l-HA 20.9%, h-HA 22.9%), implantation (l-HA 13.4%, h-HA 15.8%), or abortion (l-HA 17.2%, h-HA 21.5%) rates. In the case of frozen-thawed blastocyst transfer cycles, no significant differences were observed in the pregnancy (l-HA 46.0%, h-HA 41.8%), implantation (l-HA 45.8%, h-HA 41.3%), or abortion (l-HA 17.6%, h-HA 26.9%) rates. Conclusion: The present results showed that pregnancy, implantation, and abortion rates with transfer media containing different HA concentrations were similar. PMID- 29259489 TI - Reactive oxygen species measured in the unprocessed semen samples of 715 infertile patients. AB - Purpose: To determine whether reactive oxygen species (ROS) in semen samples could be measured with the MonolightTM 3010 Luminometer. Methods: Using the MonolightTM 3010 Luminometer, the ROS was measured in the unprocessed semen samples of infertile male patients, as well as the luminescence of 190 semen samples. The samples were classified as "luminescence-detectable" (n = 89) and "luminescence-undetectable" (n = 101). Thereafter, the luminescence of the semen samples that had been obtained from the 715 infertile patients was measured and compared by using Sperm Motility Analyzing System measurements. Moreover, in order to investigate the ROS measurement consistency, the chemiluminescence values of 84 samples were measured concurrently by using the MonolightTM 3010 Luminometer and the 1251 LuminometerTM. Results: The semen volume, sperm motility, and progressive motility of the samples were significantly higher in the luminescence-undetectable samples. The sperm motility, straight-line velocity, curvilinear velocity, mean amplitude head displacement, beat cross frequency, and progressive motility showed an inverse correlation with the logarithmic-transformed luminescence level in the luminescence-detected samples. The integrated chemiluminescence levels in the 84 samples were correlated. Conclusion: The substance that was measured in the unprocessed semen with the MonolightTM 3010 Luminometer and stimulated chemiluminescence is ROS. PMID- 29259490 TI - Age-specific serum anti-Mullerian hormone concentration in Japanese women and its usefulness as a predictor of the ovarian response. AB - Purpose: To compare the ovarian response predictive ability of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2) and to determine the age-specific distribution of serum AMH concentrations of Japanese women. Methods: This was a multicenter (four-site), observational, analytic, cross-sectional Japanese study consisting of two parts: Study 1 (the prediction of the ovarian response of 236 participants who were undergoing controlled ovarian stimulation [COS]) and Study 2 (the distribution of the AMH concentration with an assay of 417 healthy women who were aged 20-49 years and who had normal menstrual cycles). Results: The AMH had a significantly higher predictive value for the normal and high responders than FSH and E2 as a stronger correlation between the ovarian response and AMH was observed than for FSH and E2. The serum AMH concentration decreased proportionally with age. Conclusion: The AMH concentration correlated well with the oocyte count in the patients who were undergoing COS for in vitro fertilization and was shown to predict the risk of ovarian hyperstimulation syndrome among these patients. PMID- 29259491 TI - Effects of fertility preservation in patients with breast cancer: A retrospective two-centers study. AB - Purpose: To assess the efficacy of fertility preservation (FP) and the impact of chemotherapy on the reproductive potential of Japanese patients with breast cancer. Methods: Sixty-two patients with breast cancer visited the authors' centers from October, 2003 to June, 2015. They were divided into two groups according to the treatment: oocyte or embryo vitrification for FP before cancer treatment (group A) or infertility treatment after cancer treatment (group B). Group B was divided into two subgroups, B1 (no chemotherapy) and B2 (postchemotherapy), in order to analyze the effect of anticancer drugs on ovarian reserves and assisted reproductive technology outcomes. The number of retrieved oocytes, vitrified oocytes or embryos, and pregnancy rates were analyzed and compared: group A compared to group B1 compared to group B2. Results: The patients in groups A and B1 underwent egg collection without any chemotherapy. The numbers of collected oocytes and vitrified embryos were significantly higher in groups A and B1 than in group B2. Nearly 50% of the in vitro fertilization patients who underwent an embryo transfer (ET) became pregnant, including two patients in group A who underwent a vitrified-warmed ET. Among the pregnant women, 70% did not have chemotherapy. Conclusion: For patients with breast cancer, FP with unfertilized oocytes or embryos before chemotherapy seems to be promising for achieving higher pregnancy rates, with no risk of minimal residual disease. PMID- 29259492 TI - Intra-follicular kisspeptin levels are related to oocyte maturation and gonadal hormones in patients who are undergoing assisted reproductive technology. AB - Purpose: To assess the kisspeptin concentrations in follicular fluid and their relationship with clinical outcomes during assisted reproductive technology. Methods: Thirty-nine patients who were aged 24-40 years and underwent oocyte retrieval for in vitro fertilization/intracytoplasmic sperm injection participated in this study. In 65 follicular fluid samples that had been obtained from 30 patients and their blood samples, the kisspeptin levels were measured in order to investigate the correlations with their gonadal hormone levels. Venous blood samples were collected from 14 patients to investigate their plasma kisspeptin levels across different phases of assisted reproductive technology. Results: The follicular fluid kisspeptin level was significantly higher than that of the plasma level and was positively associated with the follicular fluid estradiol concentration and with the serum estradiol and number of mature oocytes. In the plasma, the maximum concentration of kisspeptin was observed on the day of ovum pick-up and on the day of embryo transfer during ovarian stimulation for assisted reproductive technology. Conclusion: Kisspeptin was present in the follicular fluid and the plasma kisspeptin concentration was affected by ovarian stimulation. Kisspeptin appears to affect oocyte maturation and ovulation. PMID- 29259493 TI - Gamma-aminobutyric acidA receptor agonist, muscimol, increases KiSS-1 gene expression in hypothalamic cell models. AB - Purpose: Accumulating evidence indicates that hypothalamic kisspeptin plays a pivotal role in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. In this study, the direct action of the gamma-aminobutyric acid (GABA)A receptor agonist on kisspeptin-expressing neuronal cells was examined. Methods: A hypothalamic cell model of rat hypothalamic cell line R8 (rHypoE8) cells and primary cultures of neuronal cells from fetal rat brains were stimulated with a potent and selective GABAA receptor agonist, muscimol, to determine the expression of the KiSS-1 gene. Results: Stimulation of the rHypoE8 cells with muscimol significantly increased the level of KiSS-1 messenger (m)RNA expression. The ability of muscimol to increase the level of KiSS-1 mRNA also was observed in the primary cultures of the neuronal cells from the fetal rat brains. The muscimol-induced increase in KiSS-1 mRNA expression was completely inhibited in the presence of the GABAA receptor antagonist. Although muscimol increased the expression of KiSS-1, the natural compound, GABA, failed to induce the expression of KiSS-1 in the rHypoE8 cells. Muscimol did not modulate gonadotropin-releasing hormone expression in either the rHypoE8 cells or the primary cultures of the fetal rat brains. Conclusions: This study's observations suggest that the activation of the GABAA receptor modulates the HPG axis by increasing kisspeptin expression in the hypothalamic neurons. PMID- 29259494 TI - Leydig cell tumor of the testis, presenting with azoospermia. AB - Case: A case of Leydig cell tumor, associated with azoospermia, is presented. Outcome: The levels of sex hormones obviously were decreased, including luteinizing hormone (LH) and follicle-stimulating hormone (FSH), with elevated testosterone. Computed tomography revealed no adrenal gland tumor, but a significant calcification in the right scrotal content was observed. He received a right radical orchiectomy and then he was unable to ejaculate. An endocrine panel revealed significantly decreased levels of testosterone and the low LH level had remained. Hormone replacement therapy with combined LH and FSH successfully recovered and preserved spermatogenesis. Conclusions: Although the patient's sexual function deteriorated after surgery, hormone replacement therapy was successful in establishing spermatogenesis. PMID- 29259495 TI - Bilateral tubal pregnancies after a single-embryo transfer. AB - Case: To present an extremely rare case of bilateral tubal pregnancies following a single-embryo transfer in a woman with a 4 year history of infertility prior to seeking assisted reproductive technology. Outcome: A pregnancy resulted from the transfer of an embryo that had been thawed from a frozen blastocyst during a hormone replacement cycle. An ultrasound that was performed at 5 weeks and 5 days of gestation revealed a gestational sac, embryo, and heartbeat in the right fallopian tube and similar signs of a gestational sac in the left fallopian tube. A laparoscopy revealed clear signs of an ectopic pregnancy in the ampulla of the right fallopian tube. Signs of swelling also were seen in the ampulla of the left fallopian tube. As the possibility of bilateral tubal pregnancies could not be ruled out, both fallopian tubes were removed. Pathological tests revealed chorionic villi and trophoblasts in both the left and right fallopian tubes. Conclusion: All previously reported cases of bilateral tubal pregnancies have been a result of multiple ovulations or multiple-embryo transfer and no case of bilateral tubal pregnancies after a single-embryo transfer has ever been reported. No genetic testing was performed; thus, it cannot be definitively stated that the divided chorionic villi and trophoblasts came from only one embryo. PMID- 29259497 TI - A Blessing. PMID- 29259496 TI - Immunosenescence in aging: between immune cells depletion and cytokines up regulation. AB - Background: The immunosenescence is a relatively recent chapter, correlated with the linear extension of the average life began in the nineteenth century and still in progress. The most important feature of immunosenescence is the accumulation in the "immunological space" of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens (inhalant allergens, food, etc.). This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by poor contact with viral infections and parasitic diseases. Furthermore the immunosenescence is characterized by a particular "remodelling" of the immune system, induced by oxidative stress. Apoptosis plays a central role in old age, a period in which the ability of apoptosis can change. The remodelling of apoptosis, together with the Inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in the innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells and dendritic cells, acting up to the establishment of a adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes. The markers of "Inflammaging" in adaptive immunity in centenarians are characterized by a decrease in T cells "naive." The reduction of CD8 virgins may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of T cell virgin (CD95-), which are replaced with the clonal expansion of CD28-T cells. Conclusions: The increase of pro-inflammatory cytokines is associated with dementia, Parkinson's disease, atherosclerosis, diabetes type 2, sarcopenia and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases. PMID- 29259498 TI - The Tricuspid Insufficiency-Pulsating Varicocele Connection: A Syndrome and Its History. PMID- 29259499 TI - Predictors of High-Sensitivity Cardiac Troponin T Elevation in Patients with Acute Paroxysmal Supraventricular Tachycardia and Ischemic Heart Disease. AB - We studied the predictors and patterns of high-sensitivity cardiac troponin T (hs cTnT) elevation in patients with paroxysmal supraventricular tachycardia (PSVT) in the presence and absence of ischemic heart disease. During calendar year 2013, we enrolled 70 of 72 consecutive adult patients with PSVT who presented at our center within 4 hours after the onset of tachycardia. On the basis of increased hs-cTnT at either of 2 initial measurements, we divided patients into groups (hs cTnT-positive and hs-cTnT-negative), to study the predictors of enzyme elevation. We then divided the hs-cTnT-positive patients into 2 groups-those with and those without ischemic heart disease-and compared hs-cTnT changes. We observed hs-cTnT elevation in 52 of the 70 patients (74.3%). The hs-cTnT-positive patients were significantly older (P=0.008) and had a significantly higher duration of tachycardia (P=0.01). Older age, the presence of chest pain, lower diastolic blood pressure, and longer duration of tachycardia increased the odds of enzyme elevation. Among patients with elevated hs-cTnT levels, the baseline and maximal hs-cTnT levels were significantly higher in ischemic patients (P=0.01 and P=0.003, respectively). The increase in hs-cTnT seemed to be higher and longer in ischemic patients, although this was not statistically significant (P=0.908). Finally, hs-cTnT did not decrease to baseline levels within 48 hours in either group. We found that hs-cTnT levels increased in all our patients with PSVT, more so in those with ischemic heart disease. PMID- 29259500 TI - Quantitative Evaluation of Coronary Plaque Progression by Computed Tomographic Angiography. AB - Understanding plaque formation in patients at risk for coronary artery disease the leading cause of morbidity and death in the world-enables physicians to better determine whether and how to treat these individuals. We used computed tomographic angiography to quantitatively evaluate the progression of nonculprit coronary plaques along the full length of the right coronary artery in 21 patients with acute coronary syndrome. Each right coronary artery was analyzed in sequential, 3-mm-long segments, and the minimum luminal area, plaque burden, and plaque volume within each segment were evaluated at baseline and at 12-month follow-up. Serial remodeling of the right coronary artery was also evaluated. In total, 625 arterial segments were analyzed. At 12-month follow-up, the plaque burden had increased slightly by 0.34% (interquartile range [IQR], -4.32% to 6.35%; P=0.02), and the plaque volume was not significantly changed (0.33 mm3; IQR, -3.05 to 3.54; P=0.213). The minimum luminal area decreased 0.05 mm2 (IQR, 1.33 to 0.87 mm2; P=0.012), and this was accompanied by vessel reduction, as evidenced by negative remodeling in 43% of the 625 segments. We conclude that serial computed tomographic angiography can be used to quantitatively evaluate the morphologic progression of coronary plaques. PMID- 29259501 TI - Left Circumflex Coronary Artery as the Culprit Vessel in ST-Segment-Elevation Myocardial Infarction. AB - The prevalence of the left circumflex coronary artery (LCx) as the culprit vessel in ST-segment-elevation myocardial infarction (STEMI) is reportedly lowest among that of the 3 main epicardial arteries, and has not been described for non-STEMI (NSTEMI) and stable angina pectoris. We sought to define the distribution of culprit arteries in these clinical presentations and suggest mechanisms for the differences. We reviewed 189 coronary angiograms of patients with STEMI, 203 with NSTEMI, and 548 with stable angina (n=940), and compared distributions of stenotic and culprit coronary arteries (lesions prompting intervention). Obstructive coronary lesions (>=50% narrowing) were more prevalent in the left anterior descending coronary artery (LAD) (36%-38%) and similar in the LCx and right coronary artery (RCA) (27%-29%), regardless of clinical presentation (P <0.01). In NSTEMI and stable angina, culprit vessels and total obstructive disease had the same distribution. In STEMI, however, a culprit LCx was significantly less prevalent (17%) than was total obstructive disease (27%; P <0.01), or a culprit LAD (47%) or RCA (34%) (both P <0.001). In our computed tomographic angiographic model of coronary longitudinal strain (percentage of shortening), LCx strain was only 1.5% +/- 2.4%, versus 9.5% +/- 2.9% for LAD strain and 10.1% +/- 3.9% for RCA strain. In STEMI, LCx plaques seem less prone to rupturing. Culprit and total disease distributions are similar in NSTEMI and angina, suggesting a different ischemic pathophysiology in these presentations. Lower LCx longitudinal strain might contribute to reduced plaque rupture in STEMI. PMID- 29259504 TI - The Rise and Fall of Estrogen Therapy: Is Testosterone for "Manopause" Next? PMID- 29259502 TI - Left Ventricular Reconstruction for Postinfarction Left Ventricular Aneurysm: Review of Surgical Techniques. AB - Different surgical techniques, each with its own advantages and disadvantages, have been used to reverse adverse left ventricular remodeling due to postinfarction left ventricular aneurysm. The most appropriate surgical technique depends on the location and size of the aneurysm and the scarred tissue, the patient's preoperative characteristics, and surgeon preference. This review covers the reconstructive surgical techniques for postinfarction left ventricular aneurysm. PMID- 29259505 TI - Transcatheter Aortic Valve Replacement in Women. PMID- 29259506 TI - Progress in Endovascular Aortic Repair for Women. PMID- 29259507 TI - Management of Chronic Venous Disease. PMID- 29259508 TI - Hypertension and Pregnancy. PMID- 29259510 TI - Stent Choice in Very Large Left Main Lesions in 3 Patients. AB - Interventionalists encounter widely different coronary anatomies during left main coronary artery stenting. Optimal percutaneous coronary intervention in left main disease necessitates stents that achieve adequate apposition and adapt to frequently disparate diameters in the same lesion, without the need for overexpansion. Until recently, stent designs have hampered the treatment of very large lesions in left main arteries. Postdilation of the stents beyond their recommended diameters can cause restenosis, thrombosis, or arterial dissection. We report successful angiographic outcomes after our deployment of different stents in 3 patients, present our rationale for choosing each stent, and discuss considerations that influence the percutaneous treatment of severe left main disease. PMID- 29259511 TI - Tolerance of Sustained Ventricular Fibrillation During Continuous-Flow Left Ventricular Assist Device Support. AB - The widespread use of continuous-flow left ventricular assist devices for mechanical circulatory support has shown that long-term hemodynamic support is possible, even when a clinical "pulse" cannot be detected. We present the incidental discovery of ventricular fibrillation in 6 alert, hemodynamically stable patients supported only by a continuous-flow device (HeartMate II, n=5; Jarvik 2000, n=1). Ventricular fibrillation was found in 3 patients during routine outpatient follow-up visits and in 3 awaiting discharge from the hospital after device placement. Diagnosis was confirmed by electrocardiographic and echocardiographic studies. The average duration of mechanical circulatory support before ventricular fibrillation occurred was 221 +/- 362 days (range, 5-864 d). All patients were conscious and ambulatory at the time of the arrhythmia. Three patients reported symptoms-primarily fatigue, nausea, and exertional dyspnea-that prompted evaluation. Serum chemistry analysis of blood drawn immediately after diagnosis showed no changes that suggested end-organ dysfunction. Three patients died of unrelated complications an average of 3.9 yr (range, 360-2,270 d) after the event. Two of the remaining 3 patients eventually underwent successful pump explantation, and one is on ongoing support. Our experience shows that it is possible for patients with continuous-flow left ventricular assist devices to remain hemodynamically stable while in ventricular fibrillation. Additional investigation is needed to determine whether defibrillator settings for these patients should be adjusted to limit delivery of shock therapy. PMID- 29259513 TI - Torsades de Pointes after Ondansetron Infusion in 2 Patients. AB - Drugs that prolong the electrocardiographic QT interval increase the risk of ventricular arrhythmias, particularly torsades de pointes. Ondansetron, a 5 hydroxytryptamine type 3 receptor antagonist antiemetic, is one such drug. We present the cases of 2 patients who were given intravenous ondansetron and subsequently developed torsades de pointes. Both had normal QT intervals at baseline but were discovered to have risk factors that predisposed them to drug induced QT prolongation and ventricular arrhythmias. We briefly review the mechanisms for torsades de pointes caused by QT-prolonging medications, describe characteristics that increase patients' susceptibility to drug-induced QT prolongation, and call attention to the risk of ventricular arrhythmias in patients who are given ondansetron. PMID- 29259512 TI - Managing Stenotic Septal Perforator Branches. AB - Coronary artery disease of the septal perforator branches can lead to clinical ischemia and conduction abnormalities. Performing interventional procedures in these vessels is frequently impossible because they are small, which makes it difficult to approach them and to select appropriate equipment. Larger septal perforator branches have been treated percutaneously in a few patients; however, the clinical effectiveness and long-term outcomes are not known. We present our experience in managing obstructive septal perforator branch stenosis in 4 patients. PMID- 29259514 TI - Dabigatran-Induced Spontaneous Hemopericardium and Cardiac Tamponade. AB - Four novel oral anticoagulant agents are currently available for the prevention and treatment of thromboembolic events in patients with nonvalvular atrial fibrillation. We present an unusual case of spontaneous hemopericardium and tamponade in an 87-year-old man with atrial fibrillation who was taking one such agent, dabigatran, as thromboprophylaxis. Our case highlights both a rare bleeding complication of dabigatran use and the effectiveness of idarucizumab, its newly approved reversal agent. Especially in elderly patients, we recommend that clinicians evaluate risk factors, closely monitor patient status, and consider alternatives to the newer anticoagulants when the risk of bleeding is high. PMID- 29259515 TI - Intravascular Ultrasound-Guided Cardiac Intervention in a Fontan Patient with Allergy to Contrast Media. AB - Allergy to contrast media is hazardous in patients who need multiple cardiac catheterizations. We describe the case of a 16-year-old boy who presented with fatigue and cyanosis. He had undergone a Fontan operation 14 years previously, after which he developed an allergy to iodinated contrast media. Contrast echocardiograms by manual injection of microbubbles suggested the presence of a venovenous collateral vessel from the brachiocephalic vein draining into the pulmonary vein. We used intravascular ultrasound as the sole imaging method to identify the target vessel and to guide deployment of an Amplatzer Vascular Plug II. The patient experienced immediate improvement in his systemic saturation. Our experience shows that intravascular ultrasound may be a feasible alternative to standard imaging methods in patients with congenital heart disease who need cardiac interventional procedures and are allergic to contrast media. PMID- 29259516 TI - Is the Pacemaker Functioning Properly? PMID- 29259517 TI - Intracranial and Bilateral Subclavian Arterial Aneurysms Associated with True Aortic Coarctation. PMID- 29259518 TI - Genome Surgery and Gene Therapy in Retinal Disorders. AB - The emergence of genome surgery techniques like the clustered regularly interspaced short palindromic repeats (CRISPR) editing technology has given researchers a powerful tool for precisely introducing targeted changes within the genome. New modifications to the CRISPR-Cas system have been made since its recent discovery, such as high-fidelity Cas9 variants to reduce off-target effects and transcriptional activation/silencing with CRISPRa/CRISPRi. The applications of CRISPR-Cas and gene therapy in ophthalmic diseases have been necessary and fruitful, especially given the impact of blinding diseases on society and the large number of monogenic disorders of the eye. This review discusses the impact that CRISPR-Cas has had on furthering our understanding of disease mechanisms and potential therapies for inherited eye diseases. Furthermore, we explore a brief overview of recent and ongoing gene therapy clinical trials in retinal diseases, and conclude with the implications of genome surgery on the outlook of future therapeutic interventions. PMID- 29259519 TI - The Application of CRISPR/Cas9 for the Treatment of Retinal Diseases. AB - The CRISPR/Cas9 system of genome editing has revolutionized molecular biology, offering a simple, and relatively inexpensive method of creating precise DNA edits. It has potential application in gene therapy treatment of retinal diseases providing targeted disruption, alteration, or transcriptional regulation of pathogenic genes. In vivo studies have demonstrated therapeutic benefit for a variety of diseases. Despite this, there are many challenges to clinical use of CRISPR/Cas9, including editing efficiency, off-target effects, and disease heterogeneity. This review details the mechanisms of the CRISPR/Cas9 system and the treatment strategies that can be applied to retinal diseases. It gives an overview of in vivo studies published to date and discusses the challenges and potential solutions to the wide-scale clinical use of CRISPR/Cas9 as a therapeutic intervention. PMID- 29259520 TI - Gene Therapy for Color Blindness. AB - Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in CNGA3, CNGB3, GNAT2, PDE6H, PDE6C, or ATF6. Animal models of Cnga3, Cngb3, and Gnat2 have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a Cnga3-/- mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective. PMID- 29259521 TI - Nuclease-Mediated Gene Therapies for Inherited Metabolic Diseases of the Liver. AB - Inherited metabolic diseases (IMDs) of the liver represent a vast and diverse group of rare genetic diseases characterized by the loss or dysfunction of enzymes or proteins essential for metabolic pathways in the liver. Conventional gene therapy involving adeno-associated virus (AAV) serotype 8 vectors provide therapeutically high levels of hepatic transgene expression facilitating the correction of the disease phenotype in pre-clinical studies and are currently being evaluated in clinical trials for multiple IMDs. However, insertional mutagenesis and immunogenicity risks as well as efficacy limitations represent major drawbacks for the AAV system. Genome editing tools, particularly the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated protein 9 (Cas9) system, offer multiple advantages over conventional gene transfer and have the potential to further advance the promises of gene therapy. Here, we provide a critical assessment of conventional gene therapy and genome editing approaches for therapeutic correction of the most investigated metabolic liver disorders, namely familial hypercholesterolemia, hemophilia, ornithine transcarbamylase deficiency, hereditary tyrosinemia type 1, and alpha-1 antitrypsin deficiency. In addition, we elaborate on the barriers and future directions for advancing novel nuclease mediated gene therapies for IMDs. PMID- 29259522 TI - Applications of CRISPR/Cas9 in the Mammalian Central Nervous System. AB - Within the central nervous system, gene regulatory mechanisms are crucial regulators of cellular development and function, and dysregulation of these systems is commonly observed in major neuropsychiatric and neurological disorders. However, due to a lack of tools to specifically modulate the genome and epigenome in the central nervous system, many molecular and genetic mechanisms underlying cognitive function and behavior are still unknown. Although genome editing tools have been around for decades, the recent emergence of inexpensive, straightforward, and widely accessible CRISPR/Cas9 systems has led to a revolution in gene editing. The development of the catalytically dead Cas9 (dCas9) expanded this flexibility even further by acting as an anchoring system for fused effector proteins, structural scaffolds, and RNAs. Together, these advances have enabled robust, modular approaches for specific targeting and modification of the local chromatin environment at a single gene. This review highlights these advancements and how the combination of powerful modulatory tools paired with the versatility of CRISPR-Cas9-based systems offer great potential for understanding the underlying genetic and epigenetic contributions of neuronal function, behavior, and neurobiological diseases. PMID- 29259523 TI - Therapeutic Peptide Nucleic Acids: Principles, Limitations, and Opportunities. AB - Since their invention in 1991, peptide nucleic acids (PNAs) have been used in a myriad of chemical and biological assays. More recently, peptide nucleic acids have also been demonstrated to hold great potential as therapeutic agents because of their physiological stability, affinity for target nucleic acids, and versatility. While recent modifications in their design have further improved their potency, their preclinical development has reached new heights due to their combination with recent advancements in drug delivery. This review focuses on recent advances in PNA therapeutic applications, in which chemical modifications are made to improve PNA function and nanoparticles are used to enhance PNA delivery. PMID- 29259524 TI - Genetic Code Expansion and Optoproteomics. AB - Nature has invented photoreceptor proteins that are involved in sensing and response to light in living organisms. Genetic code expansion (GCE) technology has provided new tools to transform light insensitive proteins into novel photoreceptor proteins. It is achieved by the site-specific incorporation of unnatural amino acids (Uaas) that carry light sensitive moieties serving as "pigments" that react to light via photo-decaging, cross-linking, or isomerization. Over the last two decades, various proteins including ion channels, GPCRs, transporters, and kinases have been successfully rendered light responsive owing to the functionalities of Uaas. Very recently, Cas9 protein has been engineered to enable light activation of genomic editing by CRISPR. Those novel proteins have not only led to discoveries of dynamic protein conformational changes with implications in diseases, but also facilitated the screening of ligand-protein and protein-protein interactions of pharmacological significance. This review covers the genetic editing principles for genetic code expansion and design concepts that guide the engineering of light-sensitive proteins. The applications have brought up a new concept of "optoproteomics" that, in contrast to "optogenetics," aims to combine optical methods and site-specific proteomics for investigating and intervening in biological functions. PMID- 29259525 TI - Adeno-associated Virus (AAV) Dual Vector Strategies for Gene Therapy Encoding Large Transgenes. AB - The use of adeno-associated viral (AAV) vectors for gene therapy treatments of inherited disorders has accelerated over the past decade with multiple clinical trials ongoing in varying tissue types and new ones initiating every year. These vectors are exhibiting low-immunogenicity across the clinical trials in addition to showing evidence of efficacy, making it clear they are the current standard vector for any potential gene therapy treatment. However, AAV vectors do have a limitation in their packaging capacity, being capable of holding no more than ~5kb of DNA and in a therapeutic transgene scenario, this length of DNA would need to include genetic control elements in addition to the gene coding sequence (CDS) of interest. Given that numerous diseases are caused by mutations in genes with a CDS exceeding 3.5kb, this makes packaging into a single AAV capsid not possible for larger genes. Due to this problem, yet with the desire to use AAV vectors, research groups have adapted the standard AAV gene therapy approach to enable delivery of such large genes to target cells using dual AAV vector systems. Here we review the AAV dual vector strategies currently employed and highlight the virtues and drawbacks of each method plus the likelihood of success with such approaches. PMID- 29259526 TI - Science and Bioethics of CRISPR-Cas9 Gene Editing: An Analysis Towards Separating Facts and Fiction. AB - Since its emergence in 2012, the genome editing technique known as CRISPR-Cas9 and its scientific use have rapidly expanded globally within a very short period of time. The technique consists of using an RNA guide molecule to bind to complementary DNA sequences, which simultaneously recruits the endonuclease Cas9 to introduce double-stranded breaks in the target DNA. The resulting double stranded break is then repaired, allowing modification or removal of specific DNA bases. The technique has gained momentum in the laboratory because it is cheap, quick, and easy to use. Moreover, it is also being applied in vivo to generate more complex animal model systems. Such use of genome editing has proven to be highly effective and warrants a potential therapy for both genetic and non genetic diseases. Although genome editing has the potential to be a transformative therapy for patients it is still in its infancy. Consequently, the legal and ethical frameworks are yet to be fully discussed and will be an increasingly important topic as the technology moves towards more contentious issues such as modification of the germline. Here, we review a number of scientific and ethical issues which may potentially influence the development of both the technology and its use in the clinical setting. PMID- 29259527 TI - Potential of Gene Editing and Induced Pluripotent Stem Cells (iPSCs) in Treatment of Retinal Diseases. AB - The advent of gene editing has introduced the ability to make changes to the genome of cells, thus allowing for correction of genetic mutations in patients with monogenic diseases. Retinal diseases are particularly suitable for the application of this new technology because many retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA), are monogenic. Moreover, gene delivery techniques such as the use of adeno associated virus (AAV) vectors have been optimized for intraocular use, and phase III trials are well underway to treat LCA, a severe form of inherited retinal degeneration, with gene therapy. This review focuses on the use of gene editing techniques and another relatively recent advent, induced pluripotent stem cells (iPSCs), and their potential for the study and treatment of retinal disease. Investment in these technologies, including overcoming challenges such as off target mutations and low transplanted cell integration, may allow for future treatment of many debilitating inherited retinal diseases. PMID- 29259530 TI - An Appreciation of The Gene: An Intimate History by Siddhartha Mukherjee and a Call for Expanded Training in the Responsible Conduct of Research. AB - The Gene: An Intimate History by Siddhartha Mukherjee, first published in 2016, is a comprehensive and fascinating recounting of the discovery of the gene and genetics research from wrinkled peas to CRISPR/Cas9 and all the details in between. In Mukherjee's sweeping history, the science is clearly depicted but also tightly integrated into the political movements and world events that it spawned, both hopeful and detestable. Two stories from The Gene are the central focuses of this article. One story is driven by the desire of Eugenicists in early 20th century America to rid the population of defective traits. The second is driven by the late 20th century promise of gene therapy to rid individuals of fatal inherited diseases. Both stories are tragic and serve as cautionary tales. These and other "case studies" in the role of science in society moved this reader to ask: what level of ethical and professional training is appropriate for today's emerging scientists? In this article, the intent and the limitations of mandated Responsible Conduct of Research (RCR) training for science and engineering graduate students are reviewed and explicated, and the obligations of scientists to themselves and others are discussed. Extrapolating from the stories in the book to the types of events and conflicts that may arise to challenge practicing scientists, a few constructive recommendations are offered for an expansion of the traditional RCR syllabus. PMID- 29259529 TI - Genome Editing: Past, Present, and Future. AB - The CRISPR-Cas genome editing tools have been adopted rapidly in the research community, and they are quickly finding applications in the commercial sector as well. Lest we lose track of the broader context, this Perspective presents a brief review of the history of the genome editing platforms and considers a few current technological issues. It then takes a very limited view into the future of this technology and highlights some of the societal issues that require examination and discussion. PMID- 29259528 TI - Yeast Still a Beast: Diverse Applications of CRISPR/Cas Editing Technology in S. cerevisiae. AB - The recent discovery and use of CRISPR/Cas9 gene editing technology has provided new opportunities for scientific research in many fields of study including agriculture, genetic disorders, human disease, biotechnology, and basic biological research. The ability to precisely target DNA sequences and either remove, modify, or replace genetic sequences provides a new level of control in nearly all eukaryotic organisms, including budding yeast. Given the many discoveries made in Saccharomyces cerevisiae over the past decades spanning genetics, cell biology, and biochemistry, as well as the development of new technologies that have allowed high throughput screening, robotic automation, and a platform for synthetic genome engineering, the yeast community has also started to recognize the utility and complementary nature of CRISPR-based methodologies. Here we present and review a variety of recent uses of Cas9 in budding yeast-both nuclease dependent and independent applications spanning traditional gene editing and replacement, to transcriptional modulation, to novel uses including the development of living circuitry or robotic platforms for synthetic genome construction. Yeast continues to serve as a powerful model system, yet it can still benefit from use of CRISPR for basic research, industrial application, and innovation of new Cas9-based applications. PMID- 29259531 TI - CRISPR, Patents, and the Public Health. AB - Patent issues surrounding CRISPR, the revolutionary genetic editing technology, may have important implications for the public health. Patents maintain high prices for novel therapies, limiting patient access. Relatedly, insurance coverage for expensive therapies is waning. Patents also misallocate research and development resources to profitable disease indications rather than those that necessarily impinge on the public health. And it is unclear how CRISPR therapies will figure into the current regulatory framework for biosimilars. Policy makers and physicians should consider these issues now, before CRISPR therapies become widely adopted-and entrenched-in the marketplace. PMID- 29259532 TI - Gene Editing in Humans: Towards a Global and Inclusive Debate for Responsible Research. AB - In December 2016, the Opinion Group of the Bioethics and Law Observatory (OBD) of the University of Barcelona launched a Declaration on Bioethics and Gene Editing in Humans analyzing the use of genome editing techniques and their social, ethical, and legal implications through a multidisciplinary approach. It focuses on CRISPR/Cas9, a genome modification technique that enables researchers to edit specific sections of the DNA sequence of humans and other living beings. This technique has generated expectations and worries that deserve an interdisciplinary analysis and an informed social debate. The research work developed by the OBD presents a set of recommendations addressed to different stakeholders and aims at being a tool to learn more about CRISPR/Cas9 while finding an appropriate ethical and legal framework for this new technology. This article gathers and compares reports that have been published in Europe and the USA since the OBD Declaration. It aims at being a tool to foster a global and interdisciplinary discussion of this new genome editing technology. PMID- 29259533 TI - Regulatory Considerations for Gene Therapy Products in the US, EU, and Japan. AB - Developers of gene therapy products (GTPs) must adhere to additional regulation beyond that of traditional small-molecule therapeutics, due to the unique mechanism-of-action of GTPs and the subsequent novel risks arisen. We have provided herein a summary of the regulatory structure under which GTPs fall in the United States, the European Union, and Japan, and a comprehensive overview of the regulatory guidance applicable to the developer of GTP. Understanding the regulatory requirements for seeking GTP market approval in these major jurisdictions is crucial for an effective and expedient path to market. The novel challenges facing GTP developers is highlighted by a case study of alipogene tiparvovec (Glybera). PMID- 29259534 TI - Application of Image Processing Techniques in Molecular Imaging of Cancer. PMID- 29259536 TI - Chemical constituents and anti-inflammatory activity of leaf essential oil of Nigerian grown Chenopodium album L. AB - Hydrodistilled leaves of Chenopodiumalbum yielded 0.64 % v/w of essential oil. GC and GC/MS analyses of the oil revealed that the bulk of the oil was constituted by aromatic compounds (60.1 %). The abundant constituents of the oil were: p- cymene (40.9 %), ascaridole (15.5 %), pinane-2-ol (9.9 %), alpha-pinene (7.0 %), beta-pinene (6.2 %) and alpha-terpineol (6.2 %). The oil displayed strong anti inflammatory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA) - induced ear edema in mice. PMID- 29259535 TI - One-Pot Aqueous Synthesis of Fluorescent Ag-In-Zn-S Quantum Dot/Polymer Bioconjugates for Multiplex Optical Bioimaging of Glioblastoma Cells. AB - Cancer research has experienced astonishing advances recently, but cancer remains a major threat because it is one of the leading causes of death worldwide. Glioblastoma (GBM) is the most malignant brain tumor, where the early diagnosis is vital for longer survival. Thus, this study reports the synthesis of novel water-dispersible ternary AgInS2 (AIS) and quaternary AgInS2-ZnS (ZAIS) fluorescent quantum dots using carboxymethylcellulose (CMC) as ligand for multiplexed bioimaging of malignant glioma cells (U-87 MG). Firstly, AgInS2 core was prepared using a one-pot aqueous synthesis stabilized by CMC at room temperature and physiological pH. Then, an outer layer of ZnS was grown and thermally annealed to improve their optical properties and split the emission range, leading to core-shell alloyed nanostructures. Their physicochemical and optical properties were characterized, demonstrating that luminescent monodispersed AIS and ZAIS QDs were produced with average sizes of 2.2 nm and 4.3 nm, respectively. Moreover, the results evidenced that they were cytocompatible using in vitro cell viability assays towards human embryonic kidney cell line (HEK 293T) and U-87 MG cells. These AIS and ZAIS successfully behaved as fluorescent nanoprobes (red and green, resp.) allowing multiplexed bioimaging and biolabeling of costained glioma cells using confocal microscopy. PMID- 29259537 TI - A Hierarchical Bayesian Model for the Identification of PET Markers Associated to the Prediction of Surgical Outcome after Anterior Temporal Lobe Resection. AB - We develop an integrative Bayesian predictive modeling framework that identifies individual pathological brain states based on the selection of fluoro deoxyglucose positron emission tomography (PET) imaging biomarkers and evaluates the association of those states with a clinical outcome. We consider data from a study on temporal lobe epilepsy (TLE) patients who subsequently underwent anterior temporal lobe resection. Our modeling framework looks at the observed profiles of regional glucose metabolism in PET as the phenotypic manifestation of a latent individual pathologic state, which is assumed to vary across the population. The modeling strategy we adopt allows the identification of patient subgroups characterized by latent pathologies differentially associated to the clinical outcome of interest. It also identifies imaging biomarkers characterizing the pathological states of the subjects. In the data application, we identify a subgroup of TLE patients at high risk for post-surgical seizure recurrence after anterior temporal lobe resection, together with a set of discriminatory brain regions that can be used to distinguish the latent subgroups. We show that the proposed method achieves high cross-validated accuracy in predicting post-surgical seizure recurrence. PMID- 29259538 TI - Reliability of Glutamate Quantification in Human Nucleus Accumbens Using Proton Magnetic Resonance Spectroscopy at a 70-cm Wide-Bore Clinical 3T MRI System. AB - The human nucleus accumbens is a challenging region to study using proton magnetic resonance spectroscopy (1H-MRS) on a 70-cm wide-bore clinical 3T MRI system. The aim of this study was to investigate the reliability for quantitative measurement of glutamate concentration in the nucleus accumbens using a 70-cm wide-bore clinical 3T MRI. 1H-MRS of the nucleus accumbens was acquired using the Point-Resolved Spectroscopic Sequence (PRESS) with echo time of 40 ms from 10 healthy volunteers (5 female; age range: 18-30 years) on two separate visits (a baseline, and 1-month time point). The Java-based Magnetic Resonance User Interface (jMRUI) software package was used to quantitatively measure the absolute metabolite concentrations. The test-retest reliability and reproducibility were assessed using intraclass correlations coefficients (ICC), and coefficients of variation (CV). Glutamate concentrations were similar across visits (P = 0.832). Reproducibility measures for all metabolites were good with CV ranging from 7.8 to 14.0%. The ICC values of all metabolites for the intra class measures were excellent (ICC > 0.8), except that the reliability for Glx (glutamate + glutamine) was good (ICC = 0.768). Pearson correlations for all metabolites were all highly significant (r = 0.636-0.788, P < 0.05). In conclusion, the short-echo-time PRESS can reliably obtain high quality glutamate spectrum from a ~3.4 cm3 voxel of the nucleus accumbens using a 70-cm wide-bore clinical 3T MRI. PMID- 29259539 TI - The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses. AB - L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4) expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Muller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3-/-) mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3-/- mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3-/- mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported. PMID- 29259541 TI - Connexin43 Containing Gap Junction Channels Facilitate HIV Bystander Toxicity: Implications in NeuroHIV. AB - Human immunodeficiency virus-1 (HIV-1) infection compromises the central nervous system (CNS) in a significant number of infected individuals, resulting in neurological dysfunction that ranges from minor cognitive deficits to frank dementia. While macrophages/microglia are the predominant CNS cells infected by HIV, our laboratory and others have shown that HIV-infected astrocytes, although present in relatively low numbers with minimal to undetectable viral replication, play key role in NeuroAIDS pathogenesis. Our laboratory has identified that HIV "hijacks" connexin (Cx) containing channels, such as gap junctions (GJs) and hemichannels (HCs), to spread toxicity and apoptosis to uninfected cells even in the absence of active viral replication. In this study, using a murine model with an astrocyte-directed deletion of Cx43 gene (hGFAP-cre Cx43fl/fl) and control Cx43fl/fl mice, we examined whether few HIV-infected human astrocytoma cells (U87 CD4-CCR5), microinjected into the mouse cortex, can spread toxicity and apoptosis through GJ-mediated mechanisms, into the mouse cells, which are resistant to HIV infection. In the control Cx43fl/fl mice, microinjection of HIV-infected U87-CD4 CCR5 cells led to apoptosis in 84.28 +/- 6.38% of mouse brain cells around the site of microinjection, whereas hGFAP-cre Cx43fl/fl mice exhibited minimal apoptosis (2.78 +/- 1.55%). However, simultaneous injection of GJ blocker, 18alpha-glycyrrhetinic acid, and Cx43 blocking peptide along with microinjection of HIV-infected cells prevented apoptosis in Cx43fl/fl mice, demonstrating the Cx43 is essential for HIV-induced bystander toxicity. In conclusion, our findings demonstrate that Cx43 expression, and formation of GJs is essential for bystander apoptosis during HIV infection. These findings reveal novel potential therapeutic targets to reduce astrocyte-mediated bystander toxicity in HIV-infected individuals because despite low to undetectable viral replication in the CNS, Cx channels hijacked by HIV amplify viral neuropathogenesis. PMID- 29259540 TI - Homeostasis of the Intraparenchymal-Blood Glutamate Concentration Gradient: Maintenance, Imbalance, and Regulation. AB - It is widely accepted that glutamate is the most important excitatory neurotransmitter in the central nervous system (CNS). However, there is also a large amount of glutamate in the blood. Generally, the concentration gradient of glutamate between intraparenchymal and blood environments is stable. However, this gradient is dramatically disrupted under a variety of pathological conditions, resulting in an amplifying cascade that causes a series of pathological reactions in the CNS and peripheral organs. This eventually seriously worsens a patient's prognosis. These two "isolated" systems are rarely considered as a whole even though they mutually influence each other. In this review, we summarize what is currently known regarding the maintenance, imbalance and regulatory mechanisms that control the intraparenchymal-blood glutamate concentration gradient, discuss the interrelationships between these systems and further explore their significance in clinical practice. PMID- 29259542 TI - Capsaicin Enhances Glutamatergic Synaptic Transmission to Neonatal Rat Hypoglossal Motor Neurons via a TRPV1-Independent Mechanism. AB - We investigated whether capsaicin modulated synaptic transmission to hypoglossal motor neurons (HMNs) by acting on transient receptor potential vanilloid type 1 (TRPV1) receptors. Using whole-cell patch clamp recording from neonatal rat HMNs, we found that capsaicin increased spontaneous excitatory post-synaptic current (sEPSC) frequency and amplitude. Interestingly, the only effect of capsaicin on spontaneous inhibitory post-synaptic currents (sIPSCs) was a significant decrease in sIPSC amplitude without altering frequency, indicating a post-synaptic mechanism of action. The frequency of miniature excitatory post-synaptic currents (mEPSCs), recorded in the presence of tetrodotoxin (TTX), was also increased by capsaicin, but capsaicin did not alter mEPSC amplitude, consistent with a pre synaptic mechanism of action. A negative shift in membrane current (Iholding) was elicited by capsaicin under both recording conditions. The effect of capsaicin on excitatory synaptic transmission remained unchanged in the presence of the TRPV1 antagonists, capsazepine or SB366791, suggesting that capsaicin acts to modulate EPSCs via a mechanism which does not require TRPV1 activation. Capsaicin, however, did not alter evoked excitatory post-synaptic currents (eEPSCs) or the paired-pulse ratio (PPR) of eEPSCs. Repetitive action potential (AP) firing in HMNs was also unaltered by capsaicin, indicating that capsaicin does not change HMN intrinsic excitability. We have demonstrated that capsaicin modulates glutamatergic excitatory, as well as glycinergic inhibitory, synaptic transmission in HMNs by differing pre- and post-synaptic mechanisms. These results expand our understanding regarding the extent to which capsaicin can modulate synaptic transmission to central neurons. PMID- 29259543 TI - Neural Progenitor Cell Polarity and Cortical Development. AB - Neurons populating the cerebral cortex are generated during embryonic development from neural stem and progenitor cells in a process called neurogenesis. Neural stem and progenitor cells are classified into several classes based on the different location of mitosis (apical or basal) and polarity features (bipolar, monopolar and non-polar). The polarized architecture of stem cells is linked to the asymmetric localization of proteins, mRNAs and organelles, such as the centrosome and the Golgi apparatus (GA). Polarity affects stem cell function and allows stem cells to integrate environmental cues from distinct niches in the developing cerebral cortex. The crucial role of polarity in neural stem and progenitor cells is highlighted by the fact that impairment of cell polarity is linked to neurodevelopmental disorders such as Down syndrome, Fragile X syndrome, autism spectrum disorders (ASD) and schizophrenia. PMID- 29259544 TI - Dichotomous Effects of Mu Opioid Receptor Activation on Striatal Low-Threshold Spike Interneurons. AB - Striatal low-threshold spike interneurons (LTSIs) are tonically active neurons that express GABA and nitric oxide synthase and are involved in information processing as well as neurovascular coupling. While mu opioid receptors (MORs) and their ligand encephalin are prominent in the striatum, their action on LTSIs has not been investigated. We addressed this issue carrying out whole-cell recordings in transgenic mice in which the NPY-expressing neurons are marked with green fluorescent protein (GFP). The MOR agonist (D-Ala(2), N-MePhe(4), Gly-ol) enkephalin (DAMGO) produced dual effects on subpopulations of LTSIs. DAMGO caused inhibitory effects, accompanied by decreases of spontaneous firing, in 62% of LTSIs, while depolarizing effects (accompanied by an increase in spontaneous firing) were observed in 23% of LTSIs tested. The dual effects of DAMGO persisted in the presence of tetrodotoxin (TTX), a sodium channel blocker or in the presence of the nicotinic acetylcholine receptor antagonist mecamylamine. However, in the presence of either the GABAA receptor antagonist picrotoxin or the muscarinic cholinergic receptor antagonist atropine, DAMGO only elicited inhibitory effects on LTSIs. Furthermore, we found that DAMGO decreased the amplitude and frequency of spontaneous GABAergic events. Unexpectedly, these effects of DAMGO on spontaneous GABAergic events disappeared after blocking of the muscarinic and nicotinic cholinergic blockers, showing that GABA inputs to LTSIs are not directly modulated by presynaptic MORs. These finding suggest that activation of MORs affect LTSIs both directly and indirectly, through modulation of GABAergic and cholinergic tones. The complex balance between direct and indirect effects determines the net effect of DAMGO on LTSIs. PMID- 29259546 TI - Neither Cholinergic Nor Dopaminergic Enhancement Improve Spatial Working Memory Precision in Humans. AB - Acetylcholine and dopamine are neurotransmitters that play multiple important roles in perception and cognition. Pharmacological cholinergic enhancement reduces excitatory receptive field size of neurons in marmoset primary visual cortex and sharpens the spatial tuning of visual perception and visual cortical fMRI responses in humans. Moreover, previous studies show that manipulation of cholinergic or dopaminergic signaling alters the spatial tuning of macaque prefrontal cortical neurons during the delay period of a spatial working memory (SWM) task and can improve SWM performance in macaque monkeys and human subjects. Here, we investigated the effects of systemic cholinergic and dopaminergic enhancement on the precision of SWM, as measured behaviorally in human subjects. Cholinergic transmission was increased by oral administration of 5 mg of the cholinesterase inhibitor donepezil, and dopaminergic signaling was enhanced with 100 mg levodopa/10 mg carbidopa. Each neurotransmitter system was separately investigated in double-blind placebo-controlled studies. On each trial of the SWM task, a square was presented for 150 ms at a random location along an invisible circle with a radius of 12 degrees of visual angle, followed by a 900 ms delay period with no stimulus shown on the screen. Then, the square was presented at new location, displaced in either a clockwise (CW) or counterclockwise (CCW) direction along the circle. Subjects used their memory of the location of the original square to report the direction of displacement. SWM precision was defined as the amount of displacement corresponding to 75% correct performance. We observed no significant effect on SWM precision for either donepezil or levodopa/carbidopa. There was also no significant effect on performance on the SWM task (percent correct across all trials) for either donepezil or levodopa/carbidopa. Thus, despite evidence that acetylcholine and dopamine regulate spatial tuning of individual neurons and can improve performance of SWM tasks, pharmacological enhancement of signaling of these neurotransmitters does not substantially affect a behavioral measure of the precision of SWM in humans. PMID- 29259547 TI - A Radial Glia Fascicle Leads Principal Neurons from the Pallial-Subpallial Boundary into the Developing Human Insula. AB - The human insular lobe, in the depth of the Sylvian fissure, displays three main cytoarchitectonic divisions defined by the differentiation of granular layers II and IV. These comprise a rostro-ventral agranular area, an intermediate dysgranular area, and a dorso-caudal granular area. Immunohistochemistry in human embryos and fetuses using antibodies against PCNA, Vimentin, Nestin, Tbr1, and Tb2 reveals that the insular cortex is unique in that it develops far away from the ventricular zone (VZ), with most of its principal neurons deriving from the subventricular zone (SVZ) of the pallial-subpallial boundary (PSB). In human embryos (Carnegie stage 16/17), the rostro-ventral insula is the first cortical region to develop; its Tbr1+ neurons migrate from the PSB along the lateral cortical stream. From 10 gestational weeks (GW) onward, lateral ventricle, ganglionic eminences, and PSB grow forming a C-shaped curvature. The SVZ of the PSB gives rise to a distinct radial glia fiber fascicle (RGF), which courses lateral to the putamen in the external capsule. In the RGF, four components can be established: PF, descending from the prefrontal PSB to the anterior insula; FP, descending from the fronto-parietal PSB toward the intermediate insula; PT, coursing from the PSB near the parieto-temporal junction to the posterior insula, and T, ascending from the temporal PSB and merging with components FP and PT. The RGF fans out at different dorso-ventral and rostro-caudal levels of the insula, with descending fibers predominating over ascending ones. The RGF guides migrating principal neurons toward the future agranular, dysgranular, and granular insular areas, which show an adult-like definition at 32 GW. Despite the narrow subplate, and the absence of an intermediate zone except in the caudal insula, most insular subdivisions develop into a 6-layered isocortex, possibly due to the well developed outer SVZ at the PSB, which is particularly prominent at the level of the dorso-caudal insula. The small size of the initial PSB sector may, however, determine the limited surface expansion of the insula, which is in contrast to the exuberant growth of the opercula deriving from the adjacent frontal-parietal and temporal VZ/SVZ. PMID- 29259548 TI - Differential Effects of Parkinson's Disease on Interneuron Subtypes within the Human Anterior Olfactory Nucleus. AB - Synucleinopathies (including alpha-synucleinopathies), which include Parkinson's disease (PD), manifest themsevles early on (stage 1) in the olfactory system; preferentially in the anterior olfactory nucleus (AON). In particular, the non motor, early manifestations of PD include hyposmia, which is the partial loss of the sense of smell. The neural basis of hyposmia in PD, however, is poorly understood; but the AON appears to be a key structure in the disease's progression. We analyzed whether alpha-synuclein was involved in the differential interneuron vulnerability associated with PD in the retrobulbar, cortical anterior and cortical posterior divisions of the AON. First, we determined the expression of the calcium binding interneuron markers, calretinin, calbindin and parvalbumin, as well as non-calcium binding interneuron marker, somatostatin, in neuronal cell bodies alone (cells/mm2) and in neuronal cell bodies and neurites (% of area fraction) of post-mortem tissue from PD cases and age-matched controls (n = 4 for each) by immunofluorescent confocal microscopy. Results indicated that parvalbumin expression was upregulated in neuronal cell bodies throughout the anterior olfactory nucleus of PD cases compared with controls. Furthermore, there was increased calbindin, calretinin and parvalbumin expression in the cell bodies and neurites of neurons in the retrobulbar division and also increased parvalbumin expression in the neurites of neurons in the cortical division; calretinin expression was also increased in neuronal cell bodies and neurites in the cortical posterior division. Second, we analyzed the co-localization of the above markers with alpha-synuclein, with results indicating that alpha-synuclein co-localized with the calcium-binding proteins, but only partially with somatostatin. Taken together, these results indicate differential expression levels among different neural markers in the divisions of the AON in PD cases and point to several possibilities, among them: possible neuroprotective mechanisms of calcium-binding proteins against alpha-synuclein; and the differential involvement of somatostatin in alpha-synuclein-positive cell bodies and neurites. PMID- 29259545 TI - Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control. AB - The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease. PMID- 29259549 TI - Frequency-Specific Functional Connectivity Density as an Effective Biomarker for Adolescent Generalized Anxiety Disorder. AB - Several neuropsychiatric diseases have been found to influence the frequency specific spontaneous functional brain organization (SFBO) in resting state, demonstrating that the abnormal brain activities of different frequency bands are associated with various physiological and psychological dysfunctions. However, little is known about the frequency specificities of SFBO in adolescent generalized anxiety disorder (GAD). Here, a novel complete ensemble empirical mode decomposition with adaptive noise method was applied to decompose the time series of each voxel across all participants (31 adolescent patients with GAD and 28 matched healthy controls; HCs) into four frequency-specific bands with distinct intrinsic oscillation. The functional connectivity density (FCD) of different scales (short-range and long-range) was calculated to quantify the SFBO changes related to GAD within each above frequency-specific band and the conventional frequency band (0.01-0.08 Hz). Support vector machine classifier was further used to examine the discriminative ability of the frequency-specific FCD values. The results showed that adolescent GAD patients exhibited abnormal alterations of both short-range and long-range FCD (S-FCD and L-FCD) in widespread brain regions across three frequency-specific bands. Positive correlation between the State Anxiety Inventory (SAI) score and increased L-FCD in the fusiform gyrus in the conventional frequency band was found in adolescents with GAD. Both S-FCD and L-FCD in the insula in the lower frequency band (0.02 0.036 Hz) had the highest classification performance compared to all other brain regions with inter-group difference. Furthermore, a satisfactory classification performance was achieved by combining the discrepant S-FCD and L-FCD values in all frequency bands, with the area under the curve (AUC) value of 0.9414 and the corresponding sensitivity, specificity, and accuracy of 87.15, 92.92, and 89.83%, respectively. This study indicates that the alterations of SFBO in adolescent GAD are frequency dependence and the frequency-specific FCD can potentially serve as a valuable biomarker in discriminating GAD patients from HCs. These findings may provide new insights into the pathophysiological mechanisms of adolescent GAD. PMID- 29259551 TI - Investigating the Functional Utility of the Left Parietal ERP Old/New Effect: Brain Activity Predicts within But Not between Participant Variance in Episodic Recollection. AB - A success story within neuroimaging has been the discovery of distinct neural correlates of episodic retrieval, providing insight into the processes that support memory for past life events. Here we focus on one commonly reported neural correlate, the left parietal old/new effect, a positive going modulation seen in event-related potential (ERP) data that is widely considered to index episodic recollection. Substantial evidence links changes in the size of the left parietal effect to changes in remembering, but the precise functional utility of the effect remains unclear. Here, using forced choice recognition of verbal stimuli, we present a novel population level test of the hypothesis that the magnitude of the left parietal effect correlates with memory performance. We recorded ERPs during old/new recognition, source accuracy and Remember/Know/Guess tasks in two large samples of healthy young adults, and successfully replicated existing within participant modulations of the magnitude of the left parietal effect with recollection. Critically, however, both datasets also show that across participants the magnitude of the left parietal effect does not correlate with behavioral measures of memory - including both subjective and objective estimates of recollection. We conclude that in these tasks, and across this healthy young adult population, the generators of the left parietal ERP effect do not index performance as expected. Taken together, these novel findings provide important constraints on the functional interpretation of the left parietal effect, suggesting that between group differences in the magnitude of old/new effects cannot always safely be used to infer differences in recollection. PMID- 29259550 TI - Longitudinal Diffusion Tensor Imaging-Based Assessment of Tract Alterations: An Application to Amyotrophic Lateral Sclerosis. AB - Objective: The potential of magnetic resonance imaging (MRI) as a technical biomarker for cerebral microstructural alterations in neurodegenerative diseases is under investigation. In this study, a framework for the longitudinal analysis of diffusion tensor imaging (DTI)-based mapping was applied to the assessment of predefined white matter tracts in amyotrophic lateral sclerosis (ALS), as an example for a rapid progressive neurodegenerative disease. Methods: DTI was performed every 3 months in six patients with ALS (mean (M) = 7.7; range 3 to 15 scans) and in six controls (M = 3; range 2-5 scans) with the identical scanning protocol, resulting in a total of 65 longitudinal DTI datasets. Fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), radial diffusivity (RD), and the ratio AD/RD were studied to analyze alterations within the corticospinal tract (CST) which is a prominently affected tract structure in ALS and the tract correlating with Braak's neuropathological stage 1. A correlation analysis was performed between progression rates based on DTI metrics and the revised ALS functional rating scale (ALS-FRS-R). Results: Patients with ALS showed an FA and AD/RD decline along the CST, while DTI metrics of controls did not change in longitudinal DTI scans. The FA and AD/RD decrease progression correlated significantly with ALS-FRS-R decrease progression. Conclusion: On the basis of the longitudinal assessment, DTI-based metrics can be considered as a possible noninvasive follow-up marker for disease progression in neurodegeneration. This finding was demonstrated here for ALS as a fast progressing neurodegenerative disease. PMID- 29259552 TI - Commentary: Neural substrates of embodied natural beauty and social endowed beauty: An fMRI study. PMID- 29259553 TI - Indication of Cognitive Change and Associated Risk Factor after Thoracic Surgery in the Elderly: A Pilot Study. AB - Background: This pilot study investigated the effects of partial pulmonary lobectomy lung surgery on cognitive functions of elderly Japanese patients. It is recognized that elderly patients undergoing surgery have increased risk of Postoperative Cognitive Decline (POCD), a condition in which learning, memory, and processing speed is greatly reduced after surgery. Since elderly patients are more likely to exhibit symptoms of POCD, the incidence is increasing as the population receiving surgery is aging. Methods: Cognitive function was measured for all subjects (n = 12) before and after surgery using three different cognitive tests: Mini-Mental Status Exam-Japanese (MMSE-J), Frontal Assessment Battery (FAB), and a computerized Cogstate Brief Battery (CBB). Changes in these measures indicate changes in cognitive function. In addition, the 12-item General Health Questionnaire (GHQ-12), the Geriatric Depression Scale (GDS), and the 5 item Quality of Life questionnaire (QOL-5) were administered at each time point to measure mental and emotional state. Changes in outcome measures were analyzed via Wilcoxon signed-rank test. Exploratory correlation analysis was conducted using Spearman's rho. Results: Data show a decline in detection (DET; p = 0.045) and identification (IDN; p = 0.038). Spearman's correlation coefficient show a significant correlation between postoperative DET scores and postoperative IDN scores (rho = 0.78, p = 0.005), a significant correlation between change in IDN and baseline GHQ-12 scores (rho = -0.595, p = 0.027), and a significant correlation between change in one-back (OBK) scores and duration of anesthesia (rho = -0.72, p = 0.012). Discussion: This was the first report to examine cognitive decline after major thoracic surgery in Japanese patients. Previous studies have evidenced that POCD is a common phenomenon after surgery, and that age is a major risk factor. The CCB measured significant change in two cognitive domains: attention and psycomotor function. This study clarified that decline in cognition is detectable in certain measures after thoracic surgery in the elderly Japanese patient population. Additionally, longer anesthetic exposure may negatively impact attention and working memory, and preoperative mental wellbeing is a possible predictor of POCD. These preliminary results have important implications and support the need for future studies. PMID- 29259554 TI - Strengthening of Existing Episodic Memories Through Non-invasive Stimulation of Prefrontal Cortex in Older Adults with Subjective Memory Complaints. AB - Episodic memory is critical to daily life functioning. This type of declarative memory declines with age and is the earliest cognitive function to be compromised in Alzheimer's disease (AD). Subjective memory complaints are commonly reported by older adults and have been considered a risk factor for developing AD. The possibilities for prevention of memory disorders in older adults have increased substantially in recent years. Previous studies have shown that anodal transcranial Direct Current Stimulation (tDCS) applied over the left lateral prefrontal cortex (PFC) after a contextual reminder strengthened existing verbal episodic memories, conceivably through reconsolidation, in elderly people. In this study, we hypothesized that anodal tDCS applied over the left lateral PFC after a contextual reminder would improve delayed memory retrieval relative to placebo (sham) stimulation in elderly individuals with SMC. Twenty-two subjects learned a list of words. Twenty-four hour later, tDCS (anodal or placebo) was applied over the left lateral PFC after a contextual reminder. Memory retrieval was tested 48h and 30 days later. These findings showed that anodal tDCS over the left lateral PFC strengthened existing episodic memories, a behavioral effect documented by improved recognition up to 30 days, relative to placebo stimulation. This study suggests that tDCS after a contextual reminder can induce long-lasting beneficial effects by facilitating the consolidation processes and opens up the possibility to design specific non-invasive interventions aimed at preventing memory decline in this at-risk population. PMID- 29259555 TI - Membrane Transporters for Bilirubin and Its Conjugates: A Systematic Review. AB - Background: Bilirubin is a highly-hydrophobic tetrapyrrole which binds to plasma albumin. It is conjugated in the liver to glucuronic acid, and the water-soluble glucuronides are excreted in urine and bile. The membrane transporters of bilirubin diglucuronide are well-known. Still undefined are however the transporters performing the uptake of bilirubin from the blood into the liver, a process known to be fast and not rate-limited. The biological importance of this process may be appraised by considering that in normal adults 200-300 mg of bilirubin are produced daily, as a result of the physiologic turnover of hemoglobin and cellular cytochromes. Nevertheless, research in this field has yielded controversial and contradicting results. We have undertaken a systematic review of the literature, believing in its utility to improve the existing knowledge and promote further advancements. Methods: We have sourced the PubMed database until 30 June 2017 by applying 5 sequential searches. Screening and eligibility criteria were applied to retain research articles reporting results obtained by using bilirubin molecules in membrane transport assays in vitro or by assessing serum bilirubin levels in in vivo experiments. Results: We have identified 311 articles, retaining 44, reporting data on experimental models having 6 incremental increases of complexity (isolated proteins, membrane vesicles, cells, organ fragments, in vivo rodents, and human studies), demonstrating the function of 19 membrane transporters, encoded by either SLCO or ABC genes. Three other bilirubin transporters have no gene, though one, i.e., bilitranslocase, is annotated in the Transporter Classification Database. Conclusions: This is the first review that has systematically examined the membrane transporters for bilirubin and its conjugates. Paradoxically, the remarkable advancements in the field of membrane transport of bilirubin have pointed to the elusive mechanism(s) enabling bilirubin to diffuse into the liver as if no cellular boundary existed. PMID- 29259556 TI - The Oncopig Cancer Model as a Complementary Tool for Phenotypic Drug Discovery. AB - The screening of potential therapeutic compounds using phenotypic drug discovery (PDD) is being embraced once again by researchers and pharmaceutical companies as an approach to enhance the development of new effective therapeutics. Before the genomics and molecular biology era and the consecutive emergence of targeted-drug discovery approaches, PDD was the most common platform used for drug discovery. PDD, also known as phenotypic screening, consists of screening potential compounds in either in vitro cellular or in vivo animal models to identify compounds resulting in a desirable phenotypic change. Using this approach, the biological targets of the compounds are not taken into consideration. Suitable animal models are crucial for the continued validation and discovery of new drugs, as compounds displaying promising results in phenotypic in vitro cell based and in vivo small animal model screenings often fail in clinical trials. Indeed, this is mainly a result of differential anatomy, physiology, metabolism, immunology, and genetics between humans and currently used pre-clinical small animal models. In contrast, pigs are more predictive of therapeutic treatment outcomes in humans than rodents. In addition, pigs provide an ideal platform to study cancer due to their similarities with humans at the anatomical, physiological, metabolic, and genetic levels. Here we provide a mini-review on the reemergence of PDD in drug development, highlighting the potential of porcine cancer models for improving pre-clinical drug discovery and testing. We also present precision medicine based genetically defined swine cancer models developed to date and their potential as biomedical models. PMID- 29259557 TI - Red Blood Cell Passage of Small Capillaries Is Associated with Transient Ca2+ mediated Adaptations. AB - When red blood cells (RBCs) pass constrictions or small capillaries they need to pass apertures falling well below their own cross section size. We used different means of mechanical stimulations (hypoosmotic swelling, local mechanical stimulation, passing through microfluidic constrictions) to observe cellular responses of human RBCs in terms of intracellular Ca2+-signaling by confocal microscopy of Fluo-4 loaded RBCs. We were able to confirm our in vitro results in a mouse dorsal skinfold chamber model showing a transiently increased intracellular Ca2+ when RBCs were passing through small capillaries in vivo. Furthermore, we performed the above-mentioned in vitro experiments as well as measurements of RBCs filterability under various pharmacological manipulations (GsMTx-4, TRAM-34) to explore the molecular mechanism of the Ca2+-signaling. Based on these experiments we conclude that mechanical stimulation of RBCs activates mechano-sensitive channels most likely Piezo1. This channel activity allows Ca2+ to enter the cell, leading to a transient activation of the Gardos channel associated with K+, Cl-, and water loss, i.e., with a transient volume adaptation facilitating the passage of the RBCs through the constriction. PMID- 29259558 TI - Modest Static Pressure Suppresses Columnar Epithelial Cell Growth in Association with Cell Shape and Cytoskeletal Modifications. AB - Intraluminal pressure elevation can cause degenerative disorders, such as ileus and hydronephrosis, and the threshold is fairly low and constant, 20-30 cm H2O. We previously devised a novel two-chamber culture system subjecting cells cultured on a semipermeable membrane to increased culture medium height (water pressure up to 60 cm H2O). Here, we sought to determine how a continuous pressure load of ~30 cm H2O affects proliferating epithelial cells with special interest in the link with cell morphology. We cultured several different cell lines using the low static pressure-loadable two-chamber system, and examined cell growth, cell cycle, and cell morphology. Madin-Darby canine kidney (MDCK) columnar epithelial cells were growth-suppressed in a manner dependent on static water pressure ranging from 2 to 50 cm H2O, without cell cycle arrest at any specific phase. Two other types of columnar epithelial cells exhibited similar phenotypes. By contrast, spherical epithelial and mesenchymal cells were not growth suppressed, even at 50 cm H2O. Phalloidin staining revealed that 50 cm H2O pressure load vertically flattened and laterally widened columnar epithelial cells and made actin fiber distribution sparse, without affecting total phalloidin intensity per cell. When the mucosal protectant irsogladine maleate (100 nM) was added to 50-cm-high culture medium, MDCK cells were reduced in volume and their doubling time shortened. Cell proliferation and morphology are known to be regulated by the Hippo signaling pathway. A pressure load of 50 cm H2O enhanced serine-127 phosphorylation and cytoplasmic retention of YAP, the major constituent of this pathway, suggesting that Hippo pathway was involved in the pressure-induced cell growth suppression. RNA sequencing of MDCK cells showed that a 50 cm H2O pressure load upregulated keratin 14, an intermediate filament, 12-fold. This upregulation was confirmed at the protein level by immunofluorescence, suggesting a role in cytoskeletal reinforcement. These results provide evidence that cell morphology and the cytoskeleton are closely linked to cell growth. Pathological intraluminal pressure elevation may cause mucosal degeneration by acting directly on this linkage and the Hippo pathway. PMID- 29259559 TI - Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells. AB - Intraluminal contents and their movement along the gastrointestinal tract create shear stress and mechanical stretch on the gut wall. While the shear stress is important in the initiation of immediate physiological responses, the circumferential mechanical stretch, such as that in obstructive bowel disorders, exerts long-lasting impacts on bowel functions by mainly affecting the deeper muscularis externae. Recent studies demonstrate that mechanical stretch alters gene transcription in gut smooth muscle cells (SMC), and the stretch-altered gene expression (mechano-transcription) may play a critical role in pathogenesis of motility dysfunction and abdominal pain in obstruction. Specifically, stretch induced cyclo-oxygenase-2 and other pro-inflammatory mediators in gut SMC account for impairments of muscle contractility. Mechano-transcription of pain mediators such as nerve growth factor may contribute to visceral hypersensitivity, by sensitizing primary sensory neurons. This review aims to highlight the novel findings of mechano-transcription in the gut, and to discuss the signaling mechanisms and pathophysiological significance of mechano-transcription. PMID- 29259560 TI - The Energetics during the World's Most Challenging Mountain Ultra-Marathon-A Case Study at the Tor des Geants(r). AB - Purpose: To provide insights into the energy requirements as well as the physiological adaptations of an experienced 50-year-old ultra-marathon male athlete during the world's most challenging mountain ultra-marathon (MUM). Methods: The international race supporting the study was the Tor des Geants(r), characterized by 330 km with +24,000 m D+ to be covered within 150 h. Before the MUM, we assessed the peak oxygen uptake ([Formula: see text]) by means of an incremental graded running test. During the MUM we monitored six ascents (once per race day) with a portable gas analyzer, a GPS and a finger pulse oximeter. We then calculated the net metabolic cost per unit of distance (C), the vertical metabolic cost (Cvert) and the mechanical efficiency of locomotion (Effmech) throughout the six uphills monitored. We further monitored the distance covered, speed, altimetry and D+ from the GPS data as well as the pulse oxygen saturation with the finger pulse oximeter. Results: Subject's [Formula: see text] was 48.1 mL.kg-1.min-1. Throughout the six uphills investigated the mean exercise intensity was 57.3 +/- 6.0% [Formula: see text] and 68.0 +/- 8.7% HRpeak. C, Cvert and Effmech were 11.4 +/- 1.9 J.kg-1.m-1, 57.9 +/- 15.2 J.kg-1.[Formula: see text], and 17.7 +/- 4.8%, respectively. The exercise intensity, as well as C, Cvert, and Effmech did not consistently increase during the MUM. Conclusions: For the first time, we described the feasibility of assessing the energy requirements as well as the physiological adaptations of a MUM in ecologically valid environment settings. The present case study shows that, despite the distance performed during the MUM, our participant did not experience a metabolic fatigue state. This is likely due to improvements in locomotor efficiency as the race progressed. PMID- 29259561 TI - Aberrant Spatial and Temporal Prefrontal Activation Patterns in Medication-Naive Adults with ADHD. AB - Previous near-infrared spectroscopy (NIRS) studies using a verbal fluency task (VFT) have consistently reported that adults with attention-deficit hyperactivity disorder (ADHD) showed significantly smaller oxygenated-hemoglobin [oxy-Hb] activations in the prefrontal cortex (PFC) compared to those in healthy controls (HC). Despite this consistent evidence of brain dysfunction in ADHD, ADHD is currently diagnosed based only on subjective clinical and scoring measures, which are often unreliable. Hence, it is necessary to establish objective neuroimaging biomarkers for ADHD. While most NIRS studies have utilized averaged [oxy-Hb] values during the whole task period for group comparisons, we used a cluster based non-parametric randomization test to compare the [oxy-Hb] time-course changes with a 0.1-s time resolution between drug-naive adults with ADHD and HC, which may provide us with more details regarding abnormal prefrontal activation patterns in ADHD. A total of 101 participants, consisting of 63 drug-naive adult individuals with ADHD and 38 HC, were included in this study. We identified that adults with ADHD showed significantly smaller [oxy-Hb] activations than those in HC at spatially and temporally connected clusters located in the bilateral PFC (more prominent on the left) and temporal brain region (more prominent on the left). We further found that aberrant [oxy-Hb] activation differs according to the time period during the task or according to brain location. Our findings indicate more detailed aberrant prefrontal and temporal activation patterns of ADHD compared with those in previous studies, possibly representing a biological marker for ADHD. PMID- 29259562 TI - Early Adverse Caregiving Experiences and Preschoolers' Current Attachment Affect Brain Responses during Facial Familiarity Processing: An ERP Study. AB - When being placed into more benign environments like foster care, children from adverse rearing backgrounds are capable of forming attachment relationships to new caregivers within the first year of placement, while certain problematic social behaviors appear to be more persistent. Assuming that early averse experiences shape neural circuits underlying social behavior, neurophysiological studies on individual differences in early social-information processing have great informative value. More precisely, ERP studies have repeatedly shown face processing to be sensitive to experience especially regarding the caregiving background. However, studies on effects of early adverse caregiving experiences are restricted to children with a history of institutionalization. Also, no study has investigated effects of attachment security as a marker of the quality of the caregiver-child relationship. Thus, the current study asks how adverse caregiving experiences and attachment security to (new) caregivers affect early- and mid latency ERPs sensitive to facial familiarity processing. Therefore, pre-school aged foster children during their second year within the foster home were compared to an age matched control group. Attachment was assessed using the AQS and neurophysiological data was collected during a passive viewing task presenting (foster) mother and stranger faces. Foster children were comparable to the control group with regard to attachment security. On a neurophysiological level, however, the foster group showed dampened N170 amplitudes for both face types. In both foster and control children, dampened N170 amplitudes were also found for stranger as compared to (foster) mother faces, and, for insecurely attached children as compared to securely attached children. This neural pattern may be viewed as a result of poorer social interactions earlier in life. Still, there was no effect on P1 amplitudes. Indicating heightened attentional processing, Nc amplitude responses to stranger faces were found to be enhanced in foster as compared to control children. Also, insecurely attached children allocated more attentional resources for the neural processing of mother faces. The study further confirms that early brain development is highly sensitive to the quality of caregiving. The findings are also relevant from a developmental perspective as miswiring of neural circuits may possibly play a critical role in children's psycho-social adjustment. PMID- 29259563 TI - Psychosocial Interventions and Wellbeing in Individuals with Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - Purpose: A number of studies, including systematic reviews, show beneficial effects of psychosocial interventions for people with diabetes mellitus; however, they have not been assessed using meta-analysis. The purpose of this meta analysis of randomized controlled trials is to investigate the effects of psychosocial interventions on depressive and anxiety symptoms, quality of life and self-efficacy in individuals with diabetes mellitus. Methods: The databases Pubmed, MEDLINE, CINAHL, PsycINFO, Scopus, Web of Science and SocINDEX were searched with no year restriction. Eligible studies were randomized controlled trials published in English that included individuals diagnosed with diabetes mellitus, aged 18 years or above, who engaged in a psychosocial intervention, with outcome measures addressing depressive or anxiety symptomology, quality of life or self-efficacy. Eligible studies needed to compare the intervention to usual care. Study selection was completed using Covidence and meta-analysis was undertaken using Comprehensive Meta-Analysis software. Results: Seven studies were included in the meta-analysis. Five studies investigated the effects of psychosocial interventions and showed a medium to large benefit for depressive symptoms (SMD: -0.70; CI: -1.27, -0.13) which persisted at follow up (SMD: -1.54, CI: -2.97, -0.12). Similar results were not seen immediately post-intervention in the three studies that assessed anxiety symptoms (SMD: -0.30; CI: -0.69, 0.10); however, a medium beneficial effect was seen at follow up (SMD = -0.61, CI = 0.92 to -0.31). Small benefits were seen in the three studies assessing quality of life outcomes (SMD: 0.30, CI: 0.06, 0.55). No benefit was seen in the two studies assessing self-efficacy (SMD: 0.23, CI: -0.11, 0.57). Conclusions: The results of the current study provide preliminary evidence that psychosocial interventions, compared to usual care, reduce depressive symptoms, and may improve quality of life in individuals with diabetes. However, only a few studies were included and the clinical significance of these findings is unknown. PMID- 29259564 TI - The Impact of School Climate and School Identification on Academic Achievement: Multilevel Modeling with Student and Teacher Data. AB - School climate is a leading factor in explaining student learning and achievement. Less work has explored the impact of both staff and student perceptions of school climate raising interesting questions about whether staff school climate experiences can add "value" to students' achievement. In the current research, multiple sources were integrated into a multilevel model, including staff self-reports, student self-reports, objective school records of academic achievement, and socio-economic demographics. Achievement was assessed using a national literacy and numeracy tests (N = 760 staff and 2,257 students from 17 secondary schools). In addition, guided by the "social identity approach," school identification is investigated as a possible psychological mechanism to explain the relationship between school climate and achievement. In line with predictions, results show that students' perceptions of school climate significantly explain writing and numeracy achievement and this effect is mediated by students' psychological identification with the school. Furthermore, staff perceptions of school climate explain students' achievement on numeracy, writing and reading tests (while accounting for students' responses). However, staff's school identification did not play a significant role. Implications of these findings for organizational, social, and educational research are discussed. PMID- 29259565 TI - The Effect of Forced Language Switching during Divergent Thinking: A Study on Bilinguals' Originality of Ideas. AB - In the present study we experimentally manipulated language switching among bilinguals who indicated to be more or less habitual language switchers in daily life. Our aim was to investigate the impact of forced language switching on originality of produced ideas during divergent thinking, conditional on the level of habitual language switching. A sample of bilinguals was randomly assigned to perform alternate uses tasks (AUT's), which explicitly required them to either switch languages, or to use only one language while performing the tasks. We found that those who were instructed to switch languages during the AUT's were able to generate ideas that were on average more original, than those who were instructed to use only one language during the AUT's, but only at higher levels of habitual language switching. At low levels of habitual language switching, the effect reversed, and participants who were instructed to use only one language found ideas that were on average more original, than participants who were required to switch languages during the AUT's. Implications and limitations are discussed. PMID- 29259566 TI - Intrinsic Altruism or Social Motivation-What Does Pupil Dilation Tell Us about Children's Helping Behavior? PMID- 29259568 TI - Directionality in Aesthetic Judgments and Performance Evaluation: Sport Judges and Laypeople Compared. AB - Left-to-right readers are assumed to demonstrate a left-to-right bias in aesthetic preferences and performance evaluation. Here we tested the hypothesis that such bias occurs in left-to-right reading laypeople and gymnastic judges (n = 48 each) when asked to select the more beautiful image from a picture pair showing gymnastic or non-gymnastic actions (Experiment 1) and to evaluate videos of gymnasts' balance beam performances (Experiment 2). Overall, laypeople demonstrated a stronger left-to-right bias than judges. Unlike judges, laypeople rated images with left-to-right trajectory as more beautiful than content-wise identical images with right-to-left trajectory (Experiment 1). Also, laypeople tended to award slightly more points to videos showing left-to-right as opposed to right-to-left oriented actions (Experiment 2); however, in contrast to initial predictions the effect was weak and statistically unreliable. Collectively, judges, when considered as a group, seem less prone to directional bias than laypeople, thus tentatively suggesting that directionality may be an issue for unskilled but not for skilled judging. Possible mechanisms underlying the skill effect in Experiment 1 and the absence of clear bias in Experiment 2 are discussed alongside propositions for a broadening of perspectives in future research. PMID- 29259569 TI - Proposal for a Five-Step Method to Elicit Expert Judgment. AB - Elicitation is a commonly used tool to extract viable information from experts. The information that is held by the expert is extracted and a probabilistic representation of this knowledge is constructed. A promising avenue in psychological research is to incorporated experts' prior knowledge in the statistical analysis. Systematic reviews on elicitation literature however suggest that it might be inappropriate to directly obtain distributional representations from experts. The literature qualifies experts' performance on estimating elements of a distribution as unsatisfactory, thus reliably specifying the essential elements of the parameters of interest in one elicitation step seems implausible. Providing feedback within the elicitation process can enhance the quality of the elicitation and interactive software can be used to facilitate the feedback. Therefore, we propose to decompose the elicitation procedure into smaller steps with adjustable outcomes. We represent the tacit knowledge of experts as a location parameter and their uncertainty concerning this knowledge by a scale and shape parameter. Using a feedback procedure, experts can accept the representation of their beliefs or adjust their input. We propose a Five-Step Method which consists of (1) Eliciting the location parameter using the trial roulette method. (2) Provide feedback on the location parameter and ask for confirmation or adjustment. (3) Elicit the scale and shape parameter. (4) Provide feedback on the scale and shape parameter and ask for confirmation or adjustment. (5) Use the elicited and calibrated probability distribution in a statistical analysis and update it with data or to compute a prior-data conflict within a Bayesian framework. User feasibility and internal validity for the Five-Step Method are investigated using three elicitation studies. PMID- 29259567 TI - Using Functional Analysis as a Framework to Guide Individualized Treatment for Negative Symptoms. AB - Although numerous interventions are available for negative symptoms, outcomes have been unsatisfactory with pharmacological and psychological interventions producing changes of only limited clinical significance. Here, we argue that because negative symptoms occur as a complex syndrome caused and maintained by numerous factors that vary between individuals they are unlikely to be treated effectively by the present "one size fits all" approaches. Instead, a well founded selection of those interventions relevant to each individual is needed to optimize both the efficiency and the efficacy of existing approaches. The concept of functional analysis (FA) can be used to structure existing knowledge so that it can guide individualized treatment planning. FA is based on stimulus-response learning mechanisms taking into account the characteristics of the organism that contribute to the responses, their consequences and the contingency with which consequences are tied to the response. FA can thus be flexibly applied to the level of individual patients to understand the factors causing and maintaining negative symptoms and derive suitable interventions. In this article we will briefly introduce the concept of FA and demonstrate-exemplarily-how known psychological and biological correlates of negative symptoms can be incorporated into its framework. We then outline the framework's implications for individual assessment and treatment. Following the logic of FA, we argue that a detailed assessment is needed to identify the key factors causing or maintaining negative symptoms for each individual patient. Interventions can then be selected according to their likelihood of changing these key factors and need to take interactions between different factors into account. Supplementary case vignettes exemplify the usefulness of functional analysis for individual treatment planning. Finally, we discuss and point to avenues for future research guided by this model. PMID- 29259570 TI - Galvanic Tongue Stimulation Inhibits Five Basic Tastes Induced by Aqueous Electrolyte Solutions. AB - Galvanic tongue stimulation (GTS) modulates taste sensation. However, the effect of GTS is contingent on the electrode polarity in the proximity of the tongue. If an anodal electrode is attached in the proximity of the tongue, an electrical or metallic taste is elicited. On the other hand, if only cathodal electrode is attached in the proximity of the tongue, the salty taste, which is induced by electrolyte materials, is inhibited. The mechanism of this taste inhibition is not adequately understood. In this study, we aim to demonstrate that the inhibition is cause by ions, which elicit taste and which migrate from the taste sensors on the tongue by GTS. We verified the inhibitory effect of GTS on all five basic tastes induced by electrolyte materials. This technology is effective for virtual reality systems and interfaces to support dietary restrictions. Our findings demonstrate that cathodal-GTS inhibits all the five basic tastes. The results also support our hypothesis that the effects of cathodal-GTS are caused by migrating tasting ions in the mouth. PMID- 29259571 TI - A Public Database of Immersive VR Videos with Corresponding Ratings of Arousal, Valence, and Correlations between Head Movements and Self Report Measures. AB - Virtual reality (VR) has been proposed as a methodological tool to study the basic science of psychology and other fields. One key advantage of VR is that sharing of virtual content can lead to more robust replication and representative sampling. A database of standardized content will help fulfill this vision. There are two objectives to this study. First, we seek to establish and allow public access to a database of immersive VR video clips that can act as a potential resource for studies on emotion induction using virtual reality. Second, given the large sample size of participants needed to get reliable valence and arousal ratings for our video, we were able to explore the possible links between the head movements of the observer and the emotions he or she feels while viewing immersive VR. To accomplish our goals, we sourced for and tested 73 immersive VR clips which participants rated on valence and arousal dimensions using self assessment manikins. We also tracked participants' rotational head movements as they watched the clips, allowing us to correlate head movements and affect. Based on past research, we predicted relationships between the standard deviation of head yaw and valence and arousal ratings. Results showed that the stimuli varied reasonably well along the dimensions of valence and arousal, with a slight underrepresentation of clips that are of negative valence and highly arousing. The standard deviation of yaw positively correlated with valence, while a significant positive relationship was found between head pitch and arousal. The immersive VR clips tested are available online as supplemental material. PMID- 29259572 TI - Genetic and Environmental Influences on Gambling: A Meta-Analysis of Twin Studies. AB - Disentangling the genetic and environmental influences of gambling is important for explaining the roots of individual differences in gambling behavior and providing guidance for precaution and intervention, but we are unaware of any comprehensive and systematic quantitative meta-analysis. We systematically identified 18 twin studies on gambling in the meta-analysis. The correlation coefficients within monozygotic (MZ) and dizygotic (DZ) twins, along with the corresponding sample size, were used to calculate the proportion of the total variance accounted for by additive genes (A), dominant genes (D), the shared environment (C), and the non-shared environment plus measurement error (E). We further assessed the moderating effects of gambling assessment (symptom oriented assessment vs. behavior oriented assessment), age, and sex. The whole sample analyses showed moderate additive genetic (a2 = 0.50) and non-shared environmental influences (e2 = 0.50) on gambling. The magnitude of the genetic influence (a2) was higher for disordered gambling assessed with symptom oriented assessment (53%) than for general gambling assessed with behavior oriented assessment (41%). Additionally, the magnitude of the genetic influence (a2) was higher for adults (53%) than adolescents (42%). Genetic influence (a2) was greater for male (47%) gambling than female (28%) gambling. Shared environment had noticeable effects on female gambling (c2 = 14%) but zero effect on male gambling. In conclusion, gambling behavior was moderately heritable and moderately influenced by non-shared environmental factors. Gambling assessment, age, and sex significantly moderated the magnitude of genetic and environmental influences on gambling. Note that the number of studies might serve as a limitation. PMID- 29259573 TI - A Developmental Approach to Machine Learning? AB - Visual learning depends on both the algorithms and the training material. This essay considers the natural statistics of infant- and toddler-egocentric vision. These natural training sets for human visual object recognition are very different from the training data fed into machine vision systems. Rather than equal experiences with all kinds of things, toddlers experience extremely skewed distributions with many repeated occurrences of a very few things. And though highly variable when considered as a whole, individual views of things are experienced in a specific order - with slow, smooth visual changes moment-to moment, and developmentally ordered transitions in scene content. We propose that the skewed, ordered, biased visual experiences of infants and toddlers are the training data that allow human learners to develop a way to recognize everything, both the pervasively present entities and the rarely encountered ones. The joint consideration of real-world statistics for learning by researchers of human and machine learning seems likely to bring advances in both disciplines. PMID- 29259574 TI - The Relationship between Binge Eating Disorder and Suicidality: A Systematic Review. AB - Background: We carried out a systematic review analyzing the relation between binge eating disorder (BED), a recent addition to the eating disorders in DSM-5, and suicidality (i.e., suicidal ideation or attempted and/or committed suicide) by synthesizing the relevant studies' qualitative data. Methods: We conducted, according to PRISMA guidelines, a systematic search of the literature on PubMed, Scopus, ISI Web of Science, PsycINFO, Google Scholar, and ScienceDirect. Search terms were "binge eating disorder" combined with the "AND" Boolean operator and "suicid*." Results: The initial search identified 4,014 records, of which 17 research reports met the predefined inclusion criteria and were analyzed. BED was found to be significantly associated with a marked increase in suicidal behaviors and suicidal ideation (SI). The presence and severity of BED were found to be relevant predictive factors for suicidality, notably in association with mood disorders and specific psychological features, while a high body mass index (BMI) did not always affect suicidality. BED has usually been associated with suicide risk, particularly when occurring with another psychiatric disorder and/or in an adolescent population. Conclusion: Pursuant to these findings, it is necessary to consider both dysfunctional eating behavior and related psychopathological factors that may induce SI and suicidal behavior in BED, aiming to identify patients and subgroups of patients needing greater clinical psychological attention to most effectively prevent and treat suicidality. PMID- 29259575 TI - Visually Induced Dizziness in Children and Validation of the Pediatric Visually Induced Dizziness Questionnaire. AB - Aims: To develop and validate the Pediatric Visually Induced Dizziness Questionnaire (PVID) and quantify the presence and severity of visually induced dizziness (ViD), i.e., symptoms induced by visual motion stimuli including crowds and scrolling computer screens in children. Methods: 169 healthy (female n = 89; recruited from mainstream schools, London, UK) and 114 children with a primary migraine, concussion, or vestibular disorder diagnosis (female n = 62), aged 6-17 years, were included. Children with primary migraine were recruited from mainstream schools while children with concussion or vestibular disorder were recruited from tertiary balance centers in London, UK, and Pittsburgh, PA, USA. Children completed the PVID, which assesses the frequency of dizziness and unsteadiness experienced in specific environmental situations, and Strength and Difficulties Questionnaire (SDQ), a brief behavioral screening instrument. Results: The PVID showed high internal consistency (11 items; alpha = 0.90). A significant between-group difference was noted with higher (i.e., worse) PVID scores for patients vs. healthy participants (U = 2,436.5, z = -10.719, p < 0.001); a significant difference was noted between individual patient groups [chi2(2) = 11.014, p = 0.004] but post hoc analysis showed no significant pairwise comparisons. The optimal cut-off score for discriminating between individuals with and without abnormal ViD levels was 0.45 out of 3 (sensitivity 83%, specificity 75%). Self-rated emotional (U = 2,730.0, z = -6.169) and hyperactivity (U = 3,445.0, z = -4.506) SDQ subscale as well as informant (U = 188.5, z = -3.916) and self-rated (U = 3,178.5, z = -5.083) total scores were significantly worse for patients compared to healthy participants (p < 0.001). Conclusion: ViD is common in children with a primary concussion, migraine, or vestibular diagnosis. The PVID is a valid measure for identifying the presence of ViD in children and should be used to identify and quantify these symptoms, which require specific management incorporating exposure to optokinetic stimuli. PMID- 29259576 TI - Obstructive Sleep Apnea Phenotypes and Markers of Vascular Disease: A Review. AB - Obstructive sleep apnea (OSA) is a chronic and heterogeneous disorder that leads to early mortality, stroke, and cardiovascular disease (CVD). OSA is defined by the apnea-hypopnea index, which is an index of OSA severity that combines apneas (pauses in breathing) and hypopneas (partial obstructions in breathing) associated with hypoxemia. Yet, other sleep metrics (i.e., oxygen nadir, arousal frequency), along with clinical symptoms and molecular markers could be better predictors of stroke and CVD outcomes in OSA. The recent focus on personalized medical care introduces the possibility of a unique approach to the treatment of OSA based on its phenotypes, defined by pathophysiological mechanisms and/or clinical presentation. We summarized what is known about OSA and its phenotypes, and review the literature on factors or intermediate markers that could increase stroke risk and CVD in patients with OSA. The OSA phenotypes where divided across three different domains (1) clinical symptoms (i.e., daytime sleepiness), (2) genetic/molecular markers, and (3) experimental data-driven approach (e.g., cluster analysis). Finally, we further highlight gaps in the literature framing a research agenda. PMID- 29259577 TI - Corrigendum: Dedifferentiation Does Not Account for Hyperconnectivity after Traumatic Brain Injury. AB - [This corrects the article on p. 297 in vol. 8, PMID: 28769858.]. PMID- 29259579 TI - Daptomycin Resistance in Clinical MRSA Strains Is Associated with a High Biological Fitness Cost. AB - Daptomycin remains as one of the main treatment options for Methicillin-Resistant Staphylococcus aureus (MRSA). Sporadic resistance cases reported in patients treated with either daptomycin or glycopeptides are a growing concern. In a previous study, we described a clinical case of a patient with a community acquired MRSA infection resistant to daptomycin and with intermediate resistance to vancomycin who developed a recurrent infection with a susceptible isogenic strain. In the present work, we further investigated the sequential events to determine whether the switch from a daptomycin resistance to a susceptible phenotype was due to a phenomenon of resistance reversion or recurrent infection with a susceptible strain. Pairwise competition experiments showed that the susceptible clinical recurrent SA6850 strain had increased fitness when compared to the resistant counterpart SA6820 strain. In fact, although we have demonstrated that reversion of daptomycin resistance to daptomycin susceptible can occur in vitro after serial passages in drug-free media, phylogenetic analysis suggested that the in vivo process was the result of a recurrent infection with a previous susceptible isolate carried by the patient rather than a resistance reversion of the strain. Whole genome sequence of evolved strains showed that daptomycin resistance in MRSA is associated with a high fitness cost mediated by mutations in mprF gene, revealed as a key element of the biological cost. Moreover, we determined that daptomycin resistance-associated fitness cost was independent of vancomycin intermediate resistance phenotype, as demonstrated in additional clinical MRSA vancomycin susceptible strains. This study highlights important observations as, despite daptomycin offers a useful treatment option for the patients with persistent infections, it has to be carefully monitored. The high fitness cost associated to daptomycin resistance may explain the reduced dissemination of daptomycin resistance and the absence of daptomycin reported outbreaks. PMID- 29259580 TI - Rapid in Vitro Quantification of S. aureus Biofilms on Vascular Graft Surfaces. AB - Objectives: Increasing resistance of microorganisms and particularly tolerance of bacterial biofilms against antibiotics require the need for alternative antimicrobial substances. S. aureus is the most frequent pathogen causing vascular graft infections. In order to evaluate the antimicrobial efficacy, quantification of the bacterial biofilms is necessary. Aim of the present study was the validation of an in vitro model for quantification of bacterial biofilm on vascular graft surfaces using three different assays. Methods: Standardized discs of vascular graft material (Dacron or PTFE) or polystyrene (PS) as control surface with 0.25 cm2 surface area were inoculated with 10-3 diluted overnight culture of three biofilm-producing S. aureus isolates (BEB-029, BEB-295, SH1000) in 96-well PS culture plates. After incubation for 4 and 18 h, the biofilm was determined by three different methods: (a) mitochondrial ATP concentration as measure of bacterial viability (ATP), (b) crystal violet staining (Cry), and (c) vital cell count by calculation of colony-forming units (CFU). The experiments were performed three times. Quadruplicates were used for each isolate, time point, and method. In parallel, bacterial biofilms were documented via scanning electron microscopy. Results: All three methods could quantify biofilms on the PS control. Time needed was 0:40, 13:10, and 14:30 h for ATP, Cry, and CFU, respectively. The Cry assay could not be used for vascular graft surfaces due to high unspecific background staining. However, ATP assay and CFU count showed comparable results on vascular graft material and control. The correlations between ATP and CFU assay differed according to the surface and incubation time and were significant only after 4 h on Dacron (BEB-029, p = 0.013) and on PS (BEB 029, p < 0.001). Between ATP and Cry assay on PS, a significant correlation could be detected after 4 h (BEB-295, p = 0.027) and after 18 h (all three strains, p < 0.026). The reproducibility of the ATP-assay presented as inter-assay-variance of 2.1 and as intra-assay variance of 8.1 on polystyrene. Conclusion: The in-vitro model reproducibly quantifies biofilm on standardized vascular graft surfaces with ATP assay as detection system. The ATP assay allows accelerated microbial quantification, however the correlation with the CFU assay may be strain- and surface-dependent. PMID- 29259578 TI - T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. AB - Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for T1D, and some individuals develop life-threatening complications. Pancreas and islet transplantation have been attractive therapeutic approaches; however, transplants containing insulin-producing cells are vulnerable to both recurrent autoimmunity and conventional allograft rejection. Current immune suppression treatments subdue the immune system, but not without complications. Ideally a successful approach would target only the destructive immune cells and leave the remaining immune system intact to fight foreign pathogens. This review discusses the autoimmune diabetes disease process, diabetic complications that warrant a transplant, and alloimmunity. First, we describe the current understanding of autoimmune destruction of beta cells including the roles of CD4 and CD8 T cells and several possibilities for antigen-specific tolerance induction. Second, we outline diabetic complications necessitating beta cell replacement. Third, we discuss transplant recognition, potential sources for beta cell replacement, and tolerance-promoting therapies under development. We hypothesize that a better understanding of autoreactive T cell targets during disease pathogenesis and alloimmunity following transplant destruction could enhance attempts to re establish tolerance to beta cells. PMID- 29259581 TI - Toward Understanding Phage:Host Interactions in the Rumen; Complete Genome Sequences of Lytic Phages Infecting Rumen Bacteria. AB - The rumen is known to harbor dense populations of bacteriophages (phages) predicted to be capable of infecting a diverse range of rumen bacteria. While bacterial genome sequencing projects are revealing the presence of phages which can integrate their DNA into the genome of their host to form stable, lysogenic associations, little is known of the genetics of phages which utilize lytic replication. These phages infect and replicate within the host, culminating in host lysis, and the release of progeny phage particles. While lytic phages for rumen bacteria have been previously isolated, their genomes have remained largely uncharacterized. Here we report the first complete genome sequences of lytic phage isolates specifically infecting three genera of rumen bacteria: Bacteroides, Ruminococcus, and Streptococcus. All phages were classified within the viral order Caudovirales and include two phage morphotypes, representative of the Siphoviridae and Podoviridae families. The phage genomes displayed modular organization and conserved viral genes were identified which enabled further classification and determination of closest phage relatives. Co-examination of bacterial host genomes led to the identification of several genes responsible for modulating phage:host interactions, including CRISPR/Cas elements and restriction modification phage defense systems. These findings provide new genetic information and insights into how lytic phages may interact with bacteria of the rumen microbiome. PMID- 29259582 TI - Experimental Oral Herpes Simplex Virus-1 (HSV-1) Co-infection in Simian Immunodeficiency Virus (SIV)-Infected Rhesus Macaques. AB - Herpes simplex virus 1 and 2 (HSV-1/2) similarly initiate infection in mucosal epithelia and establish lifelong neuronal latency. Anogenital HSV-2 infection augments the risk for sexual human immunodeficiency virus (HIV) transmission and is associated with higher HIV viral loads. However, whether oral HSV-1 infection contributes to oral HIV susceptibility, viremia, or oral complications of HIV infection is unknown. Appropriate non-human primate (NHP) models would facilitate this investigation, yet there are no published studies of HSV-1/SIV co-infection in NHPs. Thus, we performed a pilot study for an oral HSV-1 infection model in SIV-infected rhesus macaques to describe the feasibility of the modeling and resultant immunological changes. Three SIV-infected, clinically healthy macaques became HSV-1-infected by inoculation with 4 * 108 pfu HSV-1 McKrae on buccal, tongue, gingiva, and tonsils after gentle abrasion. HSV-1 DNA was shed in oral swabs for up to 21 days, and shedding recurred in association with intra-oral lesions after periods of no shedding during 56 days of follow up. HSV-1 DNA was detected in explant cultures of trigeminal ganglia collected at euthanasia on day 56. In the macaque with lowest baseline SIV viremia, SIV plasma RNA increased following HSV-1 infection. One macaque exhibited an acute pro-inflammatory response, and all three animals experienced T cell activation and mobilization in blood. However, T cell and antibody responses to HSV-1 were low and atypical. Through rigorous assessesments, this study finds that the virulent HSV-1 strain McKrae resulted in a low level HSV-1 infection that elicited modest immune responses and transiently modulated SIV infection. PMID- 29259583 TI - Inhibition of Tissue Matrix Metalloproteinases Interferes with Mycobacterium tuberculosis-Induced Granuloma Formation and Reduces Bacterial Load in a Human Lung Tissue Model. AB - Granulomas are hallmarks of pulmonary tuberculosis (TB) and traditionally viewed as host-protective structures. However, recent evidence suggest that Mycobacterium tuberculosis (Mtb) uses its virulence factors to stimulate the formation of granuloma. In the present study, we investigated the contribution of matrix metalloproteinases (MMPs), host enzymes that cause degradation of the extracellular matrix, to granuloma formation and bacterial load in Mtb-infected tissue. To this end, we used our lung tissue model for TB, which is based on human lung-derived cells and primary human monocyte-derived macrophages. Global inhibition of MMPs in the Mtb-infected tissue model reduced both granuloma formation and bacterial load. The infection caused upregulation of a set of MMPs (MMP1, 3, 9, and 12), and this finding could be validated in lung biopsies from patients with non-cavitary TB. Data from this study indicate that MMP activation contributes to early TB granuloma formation, suggesting that host-directed, MMP targeted intervention could be considered as adjunct therapy to TB treatment. PMID- 29259584 TI - Causes and Consequences of Flavivirus RNA Methylation. AB - Mosquito-borne flaviviruses are important human pathogens that represent global threats to human health. The genomes of these positive-strand RNA viruses have been shown to be substrates of both viral and cellular methyltransferases. N7 methylation of the 5' cap structure is essential for infection whereas 2'-O methylation of the penultimate nucleotide is required for evasion of host innate immunity. N6-methylation of internal adenosine nucleotides has also been shown to impact flavivirus infection. Here, I summarize recent progress made in understanding roles for methylation in the flavivirus life-cycle and discuss relevant emerging hypotheses. PMID- 29259585 TI - Thermal-Stability and Reconstitution Ability of Listeria Phages P100 and A511. AB - The study evaluated the thermal-stability of Listeria phages P100 and A511 at temperatures simulating the preparation of ready-to-eat meats. The phage infectivity after heating to 71 degrees C and holding for a minimum of 30 s, before eventually cooling to 4 degrees C were examined. Higher temperatures of 75, 80, and 85 degrees C were also tested to evaluate their effect on phages thermal-stability. This study found that despite minor differences in the amino acid sequences of their structural proteins, the two phages responded differently to high temperatures. P100 activity declined at least 10 log (PFU mL-1) with exposure to 71 degrees C (30 s) and falling below the limit of detection (1 log PFU mL-1) while, A511 dropped from 108 to 105 PFU mL-1. Cooling resulted in partial reconstitution of P100 phage particles to 103 PFU mL-1. Exposure to 75 degrees C (30 s) abolished A511 activity (8 log PFU mL-1) and both phages showed reconstitution during cooling phase after exposure to 75 degrees C. P100 exhibited reconstitution after treatment at 80 degrees C (30 s), conversely A511 showed no reconstitution activity. Heating P100 to 85 degrees C abolished the reconstitution potential. Substantial differences were found in thermal-stability and reconstitution of the examined phages showing A511 to be more thermo-stable than P100, while P100 exhibited reconstitution during cooling after treatment at 80 degrees C which was absent in A511. The differences in predicted melting temperatures of structural proteins of P100 and A511 were consistent with the observed differences in thermal stability and morphological changes observed with transmission electron microscopy. PMID- 29259586 TI - Responses of Microbial Community Composition to Temperature Gradient and Carbon Steel Corrosion in Production Water of Petroleum Reservoir. AB - Oil reservoir production systems are usually associated with a temperature gradient and oil production facilities frequently suffer from pipeline corrosion failures. Both bacteria and archaea potentially contribute to biocorrosion of the oil production equipment. Here the response of microbial populations from the petroleum reservoir to temperature gradient and corrosion of carbon steel coupons were investigated under laboratory condition. Carbon steel coupons were exposed to production water from a depth of 1809 m of Jiangsu petroleum reservoir (China) and incubated for periods of 160 and 300 days. The incubation temperatures were set at 37, 55, and 65 degrees C to monitoring mesophilic, thermophilic and hyperthermophilic microorganisms associated with anaerobic carbon steel corrosion. The results showed that corrosion rate at 55 degrees C (0.162 +/- 0.013 mm year-1) and 37 degrees C (0.138 +/- 0.008 mm year-1) were higher than that at 65 degrees C (0.105 +/- 0.007 mm year-1), and a dense biofilm was observed on the surface of coupons under all biotic incubations. The microbial community analysis suggests a high frequency of bacterial taxa associated with families Porphyromonadaceae, Enterobacteriaceae, and Spirochaetaceae at all three temperatures. While the majority of known sulfate-reducing bacteria, in particular Desulfotignum, Desulfobulbus and Desulfovibrio spp., were predominantly observed at 37 degrees C; Desulfotomaculum spp., Thermotoga spp. and Thermanaeromonas spp. as well as archaeal members closely related to Thermococcus and Archaeoglobus spp. were substantially enriched at 65 degrees C. Hydrogenotrophic methanogens of the family Methanobacteriaceae were dominant at both 37 and 55 degrees C; acetoclastic Methanosaeta spp. and methyltrophic Methanolobus spp. were enriched at 37 degrees C. These observations show that temperature changes significantly alter the microbial community structure in production fluids and also affected the biocorrosion of carbon steel under anaerobic conditions. PMID- 29259587 TI - Niche Partitioning of the N Cycling Microbial Community of an Offshore Oxygen Deficient Zone. AB - Microbial communities in marine oxygen deficient zones (ODZs) are responsible for up to half of marine N loss through conversion of nutrients to N2O and N2. This N loss is accomplished by a consortium of diverse microbes, many of which remain uncultured. Here, we characterize genes for all steps in the anoxic N cycle in metagenomes from the water column and >30 MUm particles from the Eastern Tropical North Pacific (ETNP) ODZ. We use an approach that allows for both phylogenetic identification and semi-quantitative assessment of gene abundances from individual organisms, and place these results in context of chemical measurements and rate data from the same location. Denitrification genes were enriched in >30 MUm particles, even in the oxycline, while anammox bacteria were not abundant on particles. Many steps in denitrification were encoded by multiple phylotypes with different distributions. Notably three N2O reductases (nosZ), each with no cultured relative, inhabited distinct niches; one was free-living, one dominant on particles and one had a C terminal extension found in autotrophic S-oxidizing bacteria. At some depths >30% of the community possessed nitrite reductase nirK. A nirK OTU linked to SAR11 explained much of this abundance. The only bacterial gene found for NO reduction to N2O in the ODZ was a form of qnorB related to the previously postulated "nitric oxide dismutase," hypothesized to produce N2 directly while oxidizing methane. However, similar qnorB-like genes are also found in the published genomes of many bacteria that do not oxidize methane, and here the qnorB-like genes did not correlate with the presence of methane oxidation genes. Correlations with N2O concentrations indicate that these qnorB like genes likely facilitate NO reduction to N2O in the ODZ. In the oxycline, qnorB-like genes were not detected in the water column, and estimated N2O production rates from ammonia oxidation were insufficient to support the observed oxycline N2O maximum. However, both qnorB-like and nosZ genes were present within particles in the oxycline, suggesting a particulate source of N2O and N2. Together, our analyses provide a holistic view of the diverse players in the low oxygen nitrogen cycle. PMID- 29259588 TI - Structure-Function Relationship of Aminopeptidase P from Pseudomonas aeruginosa. AB - PepP is a virulence-associated gene in Pseudomonas aeruginosa, making it an attractive target for anti-P. aeruginosa drug development. The encoded protein, aminopeptidases P (Pa-PepP), is a type of X-prolyl peptidase that possesses diverse biological functions. The crystal structure verified its canonical pita bread fold and functional tetrameric assembly, and the functional studies measured the influences of different metal ions on the activity. A trimetal manganese cluster was observed at the active site, elucidating the mechanism of inhibition by metal ions. Additionally, a loop extending from the active site appeared to be important for specific large-substrate binding. Based on the structural comparison and bacterial invasion assays, we showed that this non conserved surface loop was critical for P. aeruginosa virulence. Taken together, these findings can extend our understanding of the catalytic mechanism and virulence-related functions of Pa-PepP and provide a solid foundation for the design of specific inhibitors against pathogenic-bacterial infections. PMID- 29259589 TI - Complete Genome Sequencing of Mycobacterium bovis SP38 and Comparative Genomics of Mycobacterium bovis and M. tuberculosis Strains. AB - Mycobacterium bovis causes bovine tuberculosis and is the main organism responsible for zoonotic tuberculosis in humans. We performed the sequencing, assembly and annotation of a Brazilian strain of M. bovis named SP38, and performed comparative genomics of M. bovis genomes deposited in GenBank. M. bovis SP38 has a traditional tuberculous mycobacterium genome of 4,347,648 bp, with 65.5% GC, and 4,216 genes. The majority of CDSs (2,805, 69.3%) have predictive function, while 1,206 (30.07%) are hypothetical. For comparative analysis, 31 M. bovis, 32 M. bovis BCG, and 23 Mycobacterium tuberculosis genomes available in GenBank were selected. M. bovis RDs (regions of difference) and Clonal Complexes (CC) were identified in silico. Genome dynamics of bacterial groups were analyzed by gene orthology and polymorphic sites identification. M. bovis polymorphic sites were used to construct a phylogenetic tree. Our RD analyses resulted in the exclusion of three genomes, mistakenly annotated as virulent M. bovis. M. bovis SP38 along with strain 35 represent the first report of CC European 2 in Brazil, whereas two other M. bovis strains failed to be classified within current CC. Results of M. bovis orthologous genes analysis suggest a process of genome remodeling through genomic decay and gene duplication. Quantification, pairwise comparisons and distribution analyses of polymorphic sites demonstrate greater genetic variability of M. tuberculosis when compared to M. bovis and M. bovis BCG (p <= 0.05), indicating that currently defined M. tuberculosis lineages are more genetically diverse than M. bovis CC and animal-adapted MTC (M. tuberculosis Complex) species. As expected, polymorphic sites annotation shows that M. bovis BCG are subjected to different evolutionary pressures when compared to virulent mycobacteria. Lastly, M. bovis phylogeny indicates that polymorphic sites may be used as markers of M. bovis lineages in association with CC. Our findings highlight the need to better understand host-pathogen co-evolution in genetically homogeneous and/or diverse host populations, considering the fact that M. bovis has a broader host range when compared to M. tuberculosis. Also, the identification of M. bovis genomes not classified within CC indicates that the diversity of M. bovis lineages may be larger than previously thought or that current classification should be reviewed. PMID- 29259590 TI - The Intriguing Evolutionary Journey of Enteroinvasive E. coli (EIEC) toward Pathogenicity. AB - Among the intestinal pathogenic Escherichia coli, enteroinvasive E. coli (EIEC) are a group of intracellular pathogens able to enter epithelial cells of colon, multiplicate within them, and move between adjacent cells with a mechanism similar to Shigella, the ethiological agent of bacillary dysentery. Despite EIEC belong to the same pathotype of Shigella, they neither have the full set of traits that define Shigella nor have undergone the extensive gene decay observed in Shigella. Molecular analysis confirms that EIEC are widely distributed among E. coli phylogenetic groups and correspond to bioserotypes found in many E. coli serogroups. Like Shigella, also in EIEC the critical event toward a pathogenic life-style consisted in the acquisition by horizontal gene transfer of a large F type plasmid (pINV) containing the genes required for invasion, intracellular survival, and spreading through the intestinal mucosa. In Shigella, the ample gain in virulence determinants has been counteracted by a substantial loss of functions that, although important for the survival in the environment, are redundant or deleterious for the life inside the host. The pathoadaptation process that has led Shigella to modify its metabolic profile and increase its pathogenic potential is still in infancy in EIEC, although maintenance of some features typical of E. coli might favor their emerging relevance as intestinal pathogens worldwide, as documented by recent outbreaks in industrialized countries. In this review, we will discuss the evolution of EIEC toward Shigella like invasive forms going through the epidemiology, including the emergence of new virulent strains, their genome organization, and the complex interactions they establish with the host. PMID- 29259591 TI - Natural Selection in Synthetic Communities Highlights the Roles of Methylococcaceae and Methylophilaceae and Suggests Differential Roles for Alternative Methanol Dehydrogenases in Methane Consumption. AB - We describe experiments that follow species dynamics and gene expression patterns in synthetic bacterial communities including species that compete for the single carbon substrate supplied, methane, and species unable to consume methane, which could only succeed through cooperative interactions. We demonstrate that these communities mostly select for two functional guilds, methanotrophs of the family Methylococcaceae and non-methanotrophic methylotrophs of the family Methylophilaceae, these taxonomic guilds outcompeting all other species included in the synthetic mix. The metatranscriptomics analysis uncovered that in both Methylococcaceae and Methylophilaceae, some of the most highly transcribed genes were the ones encoding methanol dehydrogenases (MDH). Remarkably, expression of alternative MDH genes (mxaFI versus xoxF), previously shown to be subjects to the rare Earth element switch, was found to depend on environmental conditions such as nitrogen source and methane and O2 partial pressures, and also to be species specific. Along with the xoxF genes, genes encoding divergent cytochromes were highly expressed in both Methylophilaceae and Methylococcaceae, suggesting their function in methanol metabolism, likely encoding proteins serving as electron acceptors from XoxF enzymes. The research presented tested a synthetic community model that is much simplified compared to natural communities consuming methane, but more complex than the previously utilized two-species model. The performance of this model identifies prominent species for future synthetic ecology experiments and highlights both advantages of this approach and the challenges that it presents. PMID- 29259592 TI - Characterization of the Sorbitol Utilization Cluster of the Probiotic Pediococcus parvulus 2.6: Genetic, Functional and Complementation Studies in Heterologous Hosts. AB - Pediococcus parvulus 2.6 secretes a 2-substituted (1,3)-beta-D-glucan with prebiotic and immunomodulatory properties. It is synthesized by the GTF glycosyltransferase using UDP-glucose as substrate. Analysis of the P. parvulus 2.6 draft genome revealed the existence of a sorbitol utilization cluster of six genes (gutFRMCBA), whose products should be involved in sorbitol utilization and could generate substrates for UDP-glucose synthesis. Southern blot hybridization analysis showed that the cluster is located in a plasmid. Analysis of metabolic fluxes and production of the exopolysaccharide revealed that: (i) P. parvulus 2.6 is able to metabolize sorbitol, (ii) sorbitol utilization is repressed in the presence of glucose and (iii) sorbitol supports the synthesis of 2-substituted (1,3)-beta-D-glucan. The sorbitol cluster encodes two putative regulators, GutR and GutM, in addition to a phosphoenolpyruvate-dependent phosphotransferase transport system and sorbitol-6-phosphate dehydrogenase. Therefore, we investigated the involvement of GutR and GutM in the expression of gutFRMCBA. The promoter-probe vector pRCR based on the mrfp gene, which encodes the fluorescence protein mCherry, was used to test the potential promoter of the cluster (P gut ) and the genes encoding the regulators. This was performed by transferring by electrotransformation the recombinant plasmids into two hosts, which metabolize sorbitol: Lactobacillus plantarum and Lactobacillus casei. Upon growth in the presence of sorbitol, but not of glucose, only the presence of P gut was required to support expression of mrfp in L. plantarum. In L. casei the presence of sorbitol in the growth medium and the pediococcal gutR or gutR plus gutM in the genome was required for P gut functionality. This demonstrates that: (i) P gut is required for expression of the gut cluster, (ii) P gut is subjected to catabolic repression in lactobacilli, (iii) GutR is an activator, and (iv) in the presence of sorbitol, trans-complementation for activation of P gut exists in L. plantarum but not in L. casei. PMID- 29259594 TI - Evaluation of Sanitizing Methods for Reducing Microbial Contamination on Fresh Strawberry, Cherry Tomato, and Red Bayberry. AB - Strawberries, cherry tomatoes, and red bayberries, which are the most popular types of fresh produce in China, are vulnerable to microbial contamination. In this study, different sanitizing methods [treatment with 2% organic acids, 0.02% sodium hypochlorite (SH), 0.1% sodium chlorite (SC), and 0.1% acidified sodium chlorite (ASC)] were applied to fresh strawberry, cherry tomato, and red bayberry, and their abilities to reduce aerobic bacteria, Escherichia coli O157:H7, mold, yeast, and Salmonella Typhimurium were evaluated. The commercially used SH method reduced the background microbiota on strawberry, cherry tomato, and red bayberry by 0.20-2.07 log cfu/g. The ASC method reduced background microbiota (except for mold) on strawberry and cherry tomato by more than 3.0 log cfu/g. ASC was the only sanitizer that significantly reduced mold on red bayberry, and lactic acid was the only organic acid sanitizer that effectively reduced yeast on red bayberry. The ASC method had the best sterilizing effect on the three fresh fruits and also required the shortest sanitizing time and low chlorite content. The application of ASC method significantly reduced the microbiota on retail grocery samples, and the effect was similar to that achieved by sanitizing methods comparison. PMID- 29259593 TI - Viral tRNA Mimicry from a Biocommunicative Perspective. AB - RNA viruses have very small genomes which limits the functions they can encode. One of the strategies employed by these viruses is to mimic key factors of the host cell so they can take advantage of the interactions and activities these factors typically participate in. The viral RNA genome itself was first observed to mimic cellular tRNA over 40 years ago. Since then researchers have confirmed that distinct families of RNA viruses are accessible to a battery of cellular factors involved in tRNA-related activities. Recently, potential tRNA-like structures have been detected within the sequences of a 100 mRNAs taken from human cells, one of these being the host defense interferon-alpha mRNA; these are then additional to the examples found in bacterial and yeast mRNAs. The mimetic relationship between tRNA, cellular mRNA, and viral RNA is the central focus of two considerations described below. These are subsequently used as a preface for a final hypothesis drawing on concepts relating to mimicry from the social sciences and humanities, such as power relations and creativity. Firstly, the presence of tRNA-like structures in mRNAs indicates that the viral tRNA-like signal could be mimicking tRNA-like elements that are contextualized by the specific carrier mRNAs, rather than, or in addition to, the tRNA itself, which would significantly increase the number of potential semiotic relations mediated by the viral signals. Secondly, and in particular, mimicking a host defense mRNA could be considered a potential new viral strategy for survival. Finally, we propose that mRNA's mimicry of tRNA could be indicative of an ancestral intracellular conflict in which species of mRNAs invaded the cell, but from within. As the meaning of the mimetic signal depends on the context, in this case, the conflict that arises when the viral signal enters the cell can change the meaning of the mRNAs' internal tRNA-like signals, from their current significance to that they had in the distant past. PMID- 29259595 TI - Current Demands for Food-Approved Liposome Nanoparticles in Food and Safety Sector. AB - Safety of food is a noteworthy issue for consumers and the food industry. A number of complex challenges associated with food engineering and food industries, including quality food production and safety of the food through effective and feasible means can be explained by nanotechnology. However, nanoparticles have unique physicochemical properties compared to normal macroparticles of the same composition and thus could interact with living system in surprising ways to induce toxicity. Further, few toxicological/safety assessments have been performed on nanoparticles, thereby necessitating further research on oral exposure risk prior to their application to food. Liposome nanoparticles are viewed as attractive novel materials by the food and medical industries. For example, nanoencapsulation of bioactive food compounds is an emerging application of nanotechnology. In several food industrial practices, liposome nanoparticles have been utilized to improve flavoring and nutritional properties of food, and they have been examined for their capacity to encapsulate natural metabolites that may help to protect the food from spoilage and degradation. This review focuses on ongoing advancements in the application of liposomes for food and pharma sector. PMID- 29259597 TI - Humans in a Dish: The Potential of Organoids in Modeling Immunity and Infectious Diseases. AB - For many decades, human infectious diseases have been studied in immortalized cell lines, isolated primary cells from blood and a range of animal hosts. This research has been of fundamental importance in advancing our understanding of host and pathogen responses but remains limited by the absence of multicellular context and inherent differences in animal immune systems that result in altered immune responses. Recent developments in stem cell biology have led to the in vitro growth of organoids that faithfully recapitulate a variety of human tissues including lung, intestine and brain amongst many others. Organoids are derived from human stem cells and retain the genomic background, cellular organization and functionality of their tissue of origin. Thus they have been widely used to characterize stem cell development, numerous cancers and genetic diseases. We believe organoid technology can be harnessed to study host-pathogen interactions resulting in a more physiologically relevant model that yields more predictive data of human infectious diseases than current systems. Here, we highlight recent work and discuss the potential of human stem cell-derived organoids in studying infectious diseases and immunity. PMID- 29259596 TI - Molecular Evolution of the VP1 Gene in Human Norovirus GII.4 Variants in 1974 2015. AB - Human norovirus (HuNoV) is a leading cause of viral gastroenteritis worldwide, of which GII.4 is the most predominant genotype. Unlike other genotypes, GII.4 has created various variants that escaped from previously acquired immunity of the host and caused repeated epidemics. However, the molecular evolutionary differences among all GII.4 variants, including recently discovered strains, have not been elucidated. Thus, we conducted a series of bioinformatic analyses using numerous, globally collected, full-length GII.4 major capsid (VP1) gene sequences (466 strains) to compare the evolutionary patterns among GII.4 variants. The time scaled phylogenetic tree constructed using the Bayesian Markov chain Monte Carlo (MCMC) method showed that the common ancestor of the GII.4 VP1 gene diverged from GII.20 in 1840. The GII.4 genotype emerged in 1932, and then formed seven clusters including 14 known variants after 1980. The evolutionary rate of GII.4 strains was estimated to be 7.68 * 10-3 substitutions/site/year. The evolutionary rates probably differed among variants as well as domains [protruding 1 (P1), shell, and P2 domains]. The Osaka 2007 variant strains probably contained more nucleotide substitutions than any other variant. Few conformational epitopes were located in the shell and P1 domains, although most were contained in the P2 domain, which, as previously established, is associated with attachment to host factors and antigenicity. We found that positive selection sites for the whole GII.4 genotype existed in the shell and P1 domains, while Den Haag 2006b, New Orleans 2009, and Sydney 2012 variants were under positive selection in the P2 domain. Amino acid substitutions overlapped with putative epitopes or were located around the epitopes in the P2 domain. The effective population sizes of the present strains increased stepwise for Den Haag 2006b, New Orleans 2009, and Sydney 2012 variants. These results suggest that HuNoV GII.4 rapidly evolved in a few decades, created various variants, and altered its evolutionary rate and antigenicity. PMID- 29259598 TI - The Essential UPP Phosphatase Pair BcrC and UppP Connects Cell Wall Homeostasis during Growth and Sporulation with Cell Envelope Stress Response in Bacillus subtilis. AB - The bacterial cell wall separates the cell from its surrounding and protects it from environmental stressors. Its integrity is maintained by a highly regulated process of cell wall biosynthesis. The membrane-located lipid II cycle provides cell wall building blocks that are assembled inside the cytoplasm to the outside for incorporation. Its carrier molecule, undecaprenyl phosphate (UP), is then recycled by dephosphorylation from undecaprenyl pyrophosphate (UPP). In Bacillus subtilis, this indispensable reaction is catalyzed by the UPP phosphatases BcrC and UppP. Here, we study the physiological function of both phosphatases with respect to morphology, cell wall homeostasis and the resulting cell envelope stress response (CESR). We demonstrate that uppP and bcrC represent a synthetic lethal gene pair, which encodes an essential physiological function. Accordingly, cell growth and morphology were severely impaired during exponential growth if the overall UPP phosphatase level was limiting. UppP, but not BcrC, was crucial for normal sporulation. Expression of bcrC, but not uppP, was upregulated in the presence of cell envelope stress conditions caused by bacitracin if UPP phosphatase levels were limited. This homeostatic feedback renders BcrC more important during growth than UppP, particularly in defense against cell envelope stress. PMID- 29259599 TI - Epidemiology of Danish Aeromonas salmonicida subsp. salmonicida in Fish Farms Using Whole Genome Sequencing. AB - Furunculosis, a serious infection caused by the bacterium Aeromonas salmonicida subsp. salmonicida is common in sea-reared rainbow trout production in Denmark. Developing an effective control strategy requires knowledge of the epidemiology, as well as the genomic and virulent variability of the Danish A. salmonicida subsp. salmonicida isolates. To obtain this, the genomes of 101 A. salmonicida subsp. salmonicida, including 99 Danish isolates, one Scottish strain and the type strain NCIMB 1102, were sequenced using the Illumina HiSeq platform. Isolates were de novo assembled, examined for presence of plasmids, virulence and iron acquisition proteins, genomic islands, and antibiotic resistance genes. Single Nucleotide Polymorphisms were aligned and subjected to Bayesian temporal phylogenetic and maximum likelihood tree reconstruction using the published genome of A. salmonicida subsp. salmonicida A449 as reference. Bayesian temporal phylogenetic reconstruction suggests that four major introductions of A. salmonicida subsp. salmonicida into Denmark have occurred. The introductions correlate with the freshwater and subsequent seawater expansion of rainbow trout production. Initial transmission of the bacterium could have been from seawater to freshwater or vice versa, and most minor clades include a mixture of strains from different fresh- and seawater farms. Genomic variation of A. salmonicida subsp. salmonicida mostly appeared to be associated with their plasmids and plasmid encoded virulence factors. Nine A. salmonicida subsp. salmonicida isolates harbored worldwide known antibiotic resistance genes against several antibiotics and there is an indication that 33% of the isolates contained the genomic island AsaGEI1b. These findings not only support the usefulness of whole genome sequencing for genetic studies of homogeneous bacteria in general, but provide novel information about the Danish A. salmonicida subsp. salmonicida population, with implications for vaccine development in efforts to better protect Danish rainbow trout in the future. PMID- 29259600 TI - Rhinovirus Biology, Antigenic Diversity, and Advancements in the Design of a Human Rhinovirus Vaccine. AB - Human rhinovirus (HRV) remains a leading cause of several human diseases including the common cold. Despite considerable research over the last 60 years, development of an effective vaccine to HRV has been viewed by many as unfeasible due, in part, to the antigenic diversity of circulating HRVs in nature. Over 150 antigenically distinct types of HRV are currently known which span three species: HRV A, HRV B, and HRV C. Early attempts to develop a rhinovirus vaccine have shown that inactivated HRV is capable of serving as a strong immunogen and inducing neutralizing antibodies. Yet, limitations to virus preparation and recovery, continued identification of antigenic variants of HRV, and logistical challenges pertaining to preparing a polyvalent preparation of the magnitude required for true efficacy against circulating rhinoviruses continue to prove a daunting challenge. In this review, we describe HRV biology, antigenic diversity, and past and present advances in HRV vaccine design. PMID- 29259602 TI - Editorial: Genetics of Acquired Antimicrobial Resistance in Animal and Zoonotic Pathogens. PMID- 29259601 TI - Preclinical Development and Production of Virus-Like Particles As Vaccine Candidates for Hepatitis C. AB - Hepatitis C Virus (HCV) infects 2% of the world's population and is the leading cause of liver disease and liver transplantation. It poses a serious and growing worldwide public health problem that will only be partially addressed with the introduction of new antiviral therapies. However, these treatments will not prevent re-infection particularly in high risk populations. The introduction of a HCV vaccine has been predicted, using simulation models in a high risk population, to have a significant effect on reducing the incidence of HCV. A vaccine with 50 to 80% efficacy targeted to high-risk intravenous drug users could dramatically reduce HCV incidence in this population. Virus like particles (VLPs) are composed of viral structural proteins which self-assemble into non infectious particles that lack genetic material and resemble native viruses. Thus, VLPs represent a safe and highly immunogenic vaccine delivery platform able to induce potent adaptive immune responses. Currently, many VLP-based vaccines have entered clinical trials, while licensed VLP vaccines for hepatitis B virus (HBV) and human papilloma virus (HPV) have been in use for many years. The HCV core, E1 and E2 proteins can self-assemble into immunogenic VLPs while inclusion of HCV antigens into heterogenous (chimeric) VLPs is also a promising approach. These VLPs are produced using different expression systems such as bacterial, yeast, mammalian, plant, or insect cells. Here, this paper will review HCV VLP based vaccines and their immunogenicity in animal models as well as the different expression systems used in their production. PMID- 29259603 TI - Staphylococcal Adhesion and Host Cell Invasion: Fibronectin-Binding and Other Mechanisms. AB - Opportunistic bacteria from the genus Staphylococcus can cause life-threatening infections such as pneumonia, endocarditis, bone and joint infections, and sepsis. This pathogenicity is closely related to their capacity to bind directly to the extracellular matrix or to host cells. Adhesion is indeed the first step in the formation of biofilm or the invasion of host cells, which protect the bacteria from the host immune system and facilitate chronic infection. Adhesion relies on the expression of a repertoire of surface proteins called adhesins, notably microbial surface components recognizing adhesive matrix molecules. In this short review, we discuss the main pathway (FnBP-Fn-alpha5beta1 integrin), as well as alternatives, through which Staphylococcus aureus adheres to and then invades non-professional phagocytic cells. We then examine the corresponding mechanisms for coagulase negative staphylococci. There is currently a little understanding of the molecular mechanisms that lead to internalization. Filling this gap in the literature would therefore be an important step toward limiting the duration of staphylococci infections in clinical practice. PMID- 29259604 TI - Novel Non-Histocompatibility Antigen Mismatched Variants Improve the Ability to Predict Antibody-Mediated Rejection Risk in Kidney Transplant. AB - Transplant rejection is the critical clinical end-point limiting indefinite survival after histocompatibility antigen (HLA) mismatched organ transplantation. The predominant cause of late graft loss is antibody-mediated rejection (AMR), a process whereby injury to the organ is caused by donor-specific antibodies, which bind to HLA and non-HLA (nHLA) antigens. AMR is incompletely diagnosed as donor/recipient (D/R) matching is only limited to the HLA locus and critical nHLA immunogenic antigens remain to be identified. We have developed an integrative computational approach leveraging D/R exome sequencing and gene expression to predict clinical post-transplant outcome. We performed a rigorous statistical analysis of 28 highly annotated D/R kidney transplant pairs with biopsy-confirmed clinical outcomes of rejection [either AMR or T-cell-mediated rejection (CMR)] and no-rejection (NoRej), identifying a significantly higher number of mismatched nHLA variants in AMR (ANOVA-p-value = 0.02). Using Fisher's exact test, we identified 123 variants associated mainly with risk of AMR (p-value < 0.001). In addition, we applied a machine-learning technique to circumvent the issue of statistical power and we found a subset of 65 variants using random forest, that are predictive of post-tx AMR showing a very low error rate. These variants are functionally relevant to the rejection process in the kidney and AMR as they relate to genes and/or expression quantitative trait loci (eQTLs) that are enriched in genes expressed in kidney and vascular endothelium and underlie the immunobiology of graft rejection. In addition to current D/R HLA mismatch evaluation, additional mismatch nHLA D/R variants will enhance the stratification of post-tx AMR risk even before engraftment of the organ. This innovative study design is applicable in all solid organ transplants, where the impact of mitigating AMR on graft survival may be greater, with considerable benefits on improving human morbidity and mortality and opens the door to precision immunosuppression and extended tx survival. PMID- 29259607 TI - Associations between Viral Infection History Symptoms, Granulocyte Reactive Oxygen Species Activity, and Active Rheumatoid Arthritis Disease in Untreated Women at Onset: Results from a Longitudinal Cohort Study of Tatarstan Women. AB - To evaluate the effects of infectious episodes at early stages of rheumatoid arthritis (eRA) development, 59 untreated eRA patients, 77 first-degree relatives, from a longitudinal Tatarstan women cohort, were included, and compared to 67 healthy women without rheumatoid arthritis (RA) in their family history. At inclusion, informations were collected regarding both the type and incidence of infectious symptom episodes in the preceding year, and granulocyte reactive oxygen species (ROS) were studied at the basal level and after stimulation with serum-treated zymosan (STZ). In the eRA group, clinical [disease activity score (DAS28), health assessment questionnaire] and biological parameters associated with inflammation (erythrocyte sedimentation rate, C reactive protein) or with RA [rheumatoid factor, anticyclic citrullinated peptide (anti-CCP2) antibodies] were evaluated. An elevated incidence of infection events in the previous year characterized the eRA and relative groups. In addition, a history of herpes simplex virus (HSV) episodes was associated with disease activity, while an elevated incidence of anti-CCP2 autoantibody characterized eRA patients with a history of viral upper respiratory tract infection symptoms (V URI). Granulocyte ROS activity in eRA patients was quantitatively [STZ peak and its area under the curve (AUC)] and qualitatively (STZ time of peak) altered, positively correlated with disease activity, and parameters were associated with viral symptoms including HSV exacerbation/recurrence, and V-URI. In conclusion, our study provides arguments to consider a history of increased viral infection symptoms in RA at the early stage and such involvement needs to be studied further. PMID- 29259606 TI - Detection of Quiescent Radioresistant Epithelial Progenitors in the Adult Thymus. AB - Thymic aging precedes that of other organs and is initiated by the gradual loss of thymic epithelial cells (TECs). Based on in vitro culture and transplantation assays, recent studies have reported on the presence of thymic epithelial progenitor cells (TEPCs) in young adult mice. However, the physiological role and properties of TEPC populations reported to date remain unclear. Using an in vivo label-retention assay, we previously identified a population of quiescent but non senescent TECs. The goals of this study were therefore (i) to evaluate the contribution of these quiescent TECs to thymic regeneration following irradiation induced acute thymic injury and (ii) to characterize their phenotypic and molecular profiles using flow cytometry, immunohistology, and transcriptome sequencing. We report that while UEA1+ cells cycle the most in steady state, they are greatly affected by irradiation, leading to cell loss and proliferative arrest following acute thymic involution. On the opposite, the UEA1- subset of quiescent TECs is radioresistant and proliferate in situ following acute thymic involution, thereby contributing to thymic regeneration in 28- to 30-week-old mice. UEA1- quiescent TECs display an undifferentiated phenotype (co-expression of K8 and K5 cytokeratins) and express high levels of genes that regulate stem cell activity in different tissues (e.g., Podxl and Ptprz1). In addition, two features suggest that UEA1- quiescent TECs occupy discrete stromal niches: (i) their preferential location in clusters adjacent to the cortico-medullary junction and (ii) their high expression of genes involved in cross talk with mesenchymal cells. The ability of UEA1- quiescent TECs to participate to TEC regeneration qualifies them as in vivo progenitor cells particularly relevant in the context of regeneration following acute thymic injury. PMID- 29259605 TI - Role of Monocyte/Macrophages during HIV/SIV Infection in Adult and Pediatric Acquired Immune Deficiency Syndrome. AB - Monocytes/macrophages are a diverse group of cells that act as first responders in innate immunity and then as mediators for adaptive immunity to help clear infections. In performing these functions, however, the macrophage inflammatory responses can also contribute to pathogenesis. Various monocyte and tissue macrophage subsets have been associated with inflammatory disorders and tissue pathogeneses such as occur during HIV infection. Non-human primate research of simian immunodeficiency virus (SIV) has been invaluable in better understanding the pathogenesis of HIV infection. The question of HIV/SIV-infected macrophages serving as a viral reservoir has become significant for achieving a cure. In the rhesus macaque model, SIV-infected macrophages have been shown to promote pathogenesis in several tissues resulting in cardiovascular, metabolic, and neurological diseases. Results from human studies illustrated that alveolar macrophages could be an important HIV reservoir and humanized myeloid-only mice supported productive HIV infection and viral persistence in macrophages during ART treatment. Depletion of CD4+ T cells is considered the primary cause for terminal progression, but it was reported that increasing monocyte turnover was a significantly better predictor in SIV-infected adult macaques. Notably, pediatric cases of HIV/SIV exhibit faster and more severe disease progression than adults, yet neonates have fewer target T cells and generally lack the hallmark CD4+ T cell depletion typical of adult infections. Current data show that the baseline blood monocyte turnover rate was significantly higher in neonatal macaques compared to adults and this remained high with disease progression. In this review, we discuss recent data exploring the contribution of monocytes and macrophages to HIV/SIV infection and progression. Furthermore, we highlight the need to further investigate their role in pediatric cases of infection. PMID- 29259608 TI - A Larger Chocolate Chip-Development of a 15K Theobroma cacao L. SNP Array to Create High-Density Linkage Maps. AB - Cacao (Theobroma cacao L.) is an important cash crop in tropical regions around the world and has a rich agronomic history in South America. As a key component in the cosmetic and confectionary industries, millions of people worldwide use products made from cacao, ranging from shampoo to chocolate. An Illumina Infinity II array was created using 13,530 SNPs identified within a small diversity panel of cacao. Of these SNPs, 12,643 derive from variation within annotated cacao genes. The genotypes of 3,072 trees were obtained, including two mapping populations from Ecuador. High-density linkage maps for these two populations were generated and compared to the cacao genome assembly. Phenotypic data from these populations were combined with the linkage maps to identify the QTLs for yield and disease resistance. PMID- 29259609 TI - Disturbance Is an Important Driver of Clonal Richness in Tropical Seagrasses. AB - Clonality is common in many aquatic plant species, including seagrasses, where populations are maintained through a combination of asexual and sexual reproduction. One common measure used to describe the clonal structure of populations is clonal richness. Clonal richness is strongly dependent on the biological characteristics of the species, and how these interact with the environment but can also reflect evolutionary scale processes especially at the edge of species ranges. However, little is known about the spatial patterns and drivers of clonal richness in tropical seagrasses. This study assessed the spatial patterns of clonal richness in meadows of three tropical seagrass species, Thalassia hemprichii, Halodule uninervis, and Halophila ovalis, spanning a range of life-history strategies and spatial scales (2.5-4,711 km) in Indonesia and NW Australia. We further investigated the drivers of clonal richness using general additive mixed models for two of the species, H. uninervis and H. ovalis, over 8 degrees latitude. No significant patterns were observed in clonal richness with latitude, yet disturbance combined with sea surface temperature strongly predicted spatial patterns of clonal richness. Sites with a high probability of cyclone disturbance had low clonal richness, whereas an intermediate probability of cyclone disturbance and the presence of dugong grazing combined with higher sea surface temperatures resulted in higher levels of clonal richness. We propose potential mechanisms for these patterns related to the recruitment and mortality rates of individuals as well as reproductive effort. Under a changing climate, increased severity of tropical cyclones and the decline in populations of mega-grazers have the potential to reduce clonal richness leading to less genetically diverse populations. PMID- 29259611 TI - A Structurally Specialized Uniform Wall Layer is Essential for Constructing Wall Ingrowth Papillae in Transfer Cells. AB - Transfer cells are characterized by wall labyrinths with either a flange or reticulate architecture. A literature survey established that reticulate wall ingrowth papillae ubiquitously arise from a modified component of their wall labyrinth, termed the uniform wall layer; a structure absent from flange transfer cells. This finding sparked an investigation of the deposition characteristics and role of the uniform wall layer using a Vicia faba cotyledon culture system. On transfer of cotyledons to culture, their adaxial epidermal cells spontaneously trans-differentiate to a reticulate architecture comparable to their abaxial epidermal transfer cell counterparts formed in planta. Uniform wall layer construction commenced once adaxial epidermal cell expansion had ceased to overlay the original outer periclinal wall on its inner surface. In contrast to the dense ring-like lattice of cellulose microfibrils in the original primary wall, the uniform wall layer was characterized by a sparsely dispersed array of linear cellulose microfibrils. A re-modeled cortical microtubule array exerted no influence on uniform wall layer formation or on its cellulose microfibril organization. Surprisingly, formation of the uniform wall layer was not dependent upon depositing a cellulose scaffold. In contrast, uniform wall cellulose microfibrils were essential precursors for constructing wall ingrowth papillae. On converging to form wall ingrowth papillae, the cellulose microfibril diameters increased 3-fold. This event correlated with up-regulated differential, and transfer-cell specific, expression of VfCesA3B while transcript levels of other cellulose biosynthetic-related genes linked with primary wall construction were substantially down-regulated. PMID- 29259610 TI - Domesticated, Genetically Engineered, and Wild Plant Relatives Exhibit Unintended Phenotypic Differences: A Comparative Meta-Analysis Profiling Rice, Canola, Maize, Sunflower, and Pumpkin. AB - Agronomic management of plants is a powerful evolutionary force acting on their populations. The management of cultivated plants is carried out by the traditional process of human selection or plant breeding and, more recently, by the technologies used in genetic engineering (GE). Even though crop modification through GE is aimed at specific traits, it is possible that other non-target traits can be affected by genetic modification due to the complex regulatory processes of plant metabolism and development. In this study, we conducted a meta analysis profiling the phenotypic consequences of plant breeding and GE, and compared modified cultivars with wild relatives in five crops of global economic and cultural importance: rice, maize, canola, sunflower, and pumpkin. For these five species, we analyzed the literature with documentation of phenotypic traits that are potentially related to fitness for the same species in comparable conditions. The information was analyzed to evaluate whether the different processes of modification had influenced the phenotype in such a way as to cause statistical differences in the state of specific phenotypic traits or grouping of the organisms depending on their genetic origin [wild, domesticated with genetic engineering (domGE), and domesticated without genetic engineering (domNGE)]. In addition, we tested the hypothesis that, given that transgenic plants are a construct designed to impact, in many cases, a single trait of the plant (e.g., lepidopteran resistance), the phenotypic differences between domGE and domNGE would be either less (or inexistent) than between the wild and domesticated relatives (either domGE or domNGE). We conclude that (1) genetic modification (either by selective breeding or GE) can be traced phenotypically when comparing wild relatives with their domesticated relatives (domGE and domNGE) and (2) the existence and the magnitude of the phenotypic differences between domGE and domNGE of the same crop suggest consequences of genetic modification beyond the target trait(s). PMID- 29259612 TI - Desiccation Treatment and Endogenous IAA Levels Are Key Factors Influencing High Frequency Somatic Embryogenesis in Cunninghamia lanceolata (Lamb.) Hook. AB - Cunninghamia lanceolata (Lamb.) Hook (Chinese fir) is an important tree, commercially and ecologically, in southern China. The traditional regenerating methods are based on organogenesis and cutting propagation. Here, we report the development of a high-frequency somatic embryogenesis (SE) regeneration system synchronized via a liquid culture from immature zygotic embryos. Following synchronization, PEM II cell aggregates were developmentally equivalent in appearance to cleaved zygotic embryos. Embryo and suspensor growth and subsequent occurrence of the apical and then the cotyledonary meristems were similar for zygotic and SE embryo development. However, SE proembryos exhibited a more reddish coloration than zygotic proembryos, and SE embryos were smaller than zygotic embryos. Mature somatic embryos gave rise to plantlets on hormone-free medium. For juvenile explants, low concentrations of endogenous indole-3-acetic acid in initial explants correlated with improved proembryogenic mass formation, and high SE competency. Analysis of karyotypes and microsatellites detected no major genetic variation in the plants regenerated via SE, and suggest a potential in the further development of this system as a reliable methodology for true-to type seedling production. Treatment with polyethylene glycol (PEG) and abscisic acid (ABA) were of great importance to proembryo formation and complemented each other. ABA assisted the growth of embryonal masses, whereas PEG facilitated the organization of the proembryo-like structures. SOMATIC EMBRYOGENESIS RECEPTOR KINASE SERK) and the WUSCHEL homeobox (WOX) transcription factor served as molecular markers during early embryogenesis. Our results show that ClSERKs are conserved and redundantly expressed during SE. SERK and WOX transcript levels were highest during development of the proembryos and lowest in developed embryos. ClWOX13 expression correlates with the critical transition from proembryogenic masses to proembryos. Both SERK and WOX expression reveal their applicability in Chinese fir as markers of early embryogenesis. Overall, the findings provided evidence for the potential of this system in high fidelity Chinese fir seedlings production. Also, SE modification strategies were demonstrated and could be applied in other conifer species on the basis of our hormonal, morphological and molecular analyses. PMID- 29259613 TI - To Produce or to Survive: How Plastic Is Your Crop Stress Physiology? AB - Abiotic stress causes major crop losses and is considered a greater challenge than biotic stress. Comparisons of the number of published articles and patents regarding these different types of stresses, and the number of commercially released crops designed to tolerate different types of stresses, revealed a huge gap in the bench-to-field transfer rate of abiotic stress-tolerant crops, as compared to crops designed to tolerate biotic stress. These differences underscore the complexity of abiotic stress-response mechanisms. Here, we suggest that breeding programs favoring yield-related quantitative physiological traits (QPTs; e.g., photosynthesis rate or stomatal conductance) have canalized those QPTs at their highest levels. This has affected the sensitivity of those QPTs to changing environmental conditions and those traits have become less plastic. We also suggest that breeding pressure has had an asymmetric impact on different QPTs, depending on their sensitivity to environmental conditions and their interactions with other QPTs. We demonstrate this asymmetric impact on the regulation of whole-plant water balance, showing how plastic membrane water content, stomatal conductance and leaf hydraulic conductance interact to canalize whole-organ water content. We suggest that a QPT's plasticity is itself an important trait and that understanding this plasticity may help us to develop yield-optimized crops. PMID- 29259614 TI - The Value of Native Plants and Local Production in an Era of Global Agriculture. AB - For addressing potential food shortages, a fundamental tradeoff exists between investing more resources to increasing productivity of existing crops, as opposed to increasing crop diversity by incorporating more species. We explore ways to use local plants as food resources and the potential to promote food diversity and agricultural resilience. We discuss how use of local plants and the practice of local agriculture can contribute to ongoing adaptability in times of global change. Most food crops are now produced, transported, and consumed long distances from their homelands of origin. At the same time, research and practices are directed primarily at improving the productivity of a small number of existing crops that form the cornerstone of a global food economy, rather than to increasing crop diversity. The result is a loss of agro-biodiversity, leading to a food industry that is more susceptible to abiotic and biotic stressors, and more at risk of catastrophic losses. Humans cultivate only about 150 of an estimated 30,000 edible plant species worldwide, with only 30 plant species comprising the vast majority of our diets. To some extent, these practices explain the food disparity among human populations, where nearly 1 billion people suffer insufficient nutrition and 2 billion people are obese or overweight. Commercial uses of new crops and wild plants of local origin have the potential to diversify global food production and better enable local adaptation to the diverse environments humans inhabit. We discuss the advantages, obstacles, and risks of using local plants. We also describe a case study-the missed opportunity to produce pine nuts commercially in the Western United States. We discuss the potential consequences of using local pine nuts rather than importing them overseas. Finally, we provide a list of edible native plants, and synthesize the state of research concerning the potential and challenges in using them for food production. The goal of our synthesis is to support more local food production using native plants in an ecologically sustainable manner. PMID- 29259615 TI - Silencing of D-Lactate Dehydrogenase Impedes Glyoxalase System and Leads to Methylglyoxal Accumulation and Growth Inhibition in Rice. AB - D-Lactate is oxidized by two classes of D-lactate dehydrogenase (D-LDH), namely, NAD-dependent and NAD-independent D-LDHs. Little is known about the characteristics and biological functions of D-LDHs in rice. In this study, a functional NAD-independent D-LDH (LOC_Os07g06890) was identified in rice, as a result of alternative splicing events. Characterization of the expression profile, subcellular localization, and enzymatic properties of the functional OsD LDH revealed that it is a mitochondrial cytochrome-c-dependent D-LDH with high affinity and catalytic efficiency. Functional analysis of OsD-LDH RNAi transgenic rice demonstrated that OsD-LDH participates in methylglyoxal metabolism by affecting the activity of the glyoxalase system and aldo-keto reductases. Under methylglyoxal treatment, silencing of OsD-LDH in rice resulted in the accumulation of methylglyoxal and D-lactate, the decrease of reduced glutathione in leaves, and ultimately severe growth inhibition. Moreover, the detached leaves of OsD-LDH RNAi plants were more sensitive to salt stress. However, the silencing of OsD-LDH did not affect the growth under photorespiration conditions. Our results provide new insights into the role of NAD-independent D-LDHs in rice. PMID- 29259616 TI - PaCYP78A9, a Cytochrome P450, Regulates Fruit Size in Sweet Cherry (Prunus avium L.). AB - Sweet cherry (Prunus avium L.) is an important fruit crop in which fruit size is strongly associated with commercial value; few genes associated with fruit size have, however, been identified in sweet cherry. Members of the CYP78A subfamily, a group of important cytochrome P450s, have been found to be involved in controlling seed size and development in Arabidopsis thaliana, rice, soybean, and tomato. However, the influence of CYP78A members in controlling organ size and the underlying molecular mechanisms in sweet cherry and other fruit trees remains unclear. Here, we characterized a P. avium CYP78A gene PaCYP78A9 that is thought to be involved in the regulation of fruit size and organ development using overexpression and silencing approaches. PaCYP78A9 was significantly expressed in the flowers and fruit of sweet cherry. RNAi silencing of PaCYP78A9 produced small cherry fruits and PaCYP78A9 was found to affect fruit size by mediating mesocarp cell proliferation and expansion during fruit growth and development. Overexpression of PaCYP78A9 in Arabidopsis resulted in increased silique and seed size and PaCYP78A9 was found to be highly expressed in the inflorescences and siliques of transgenic plants. Genes related to cell cycling and proliferation were downregulated in fruit from sweet cherry TRV::PaCYP78A9-silencing lines, suggesting that PaCYP78A9 is likely to be an important upstream regulator of cell cycle processes. Together, our findings indicate that PaCYP78A9 plays an essential role in the regulation of cherry fruit size and provide insights into the molecular basis of the mechanisms regulating traits such as fruit size in P. avium. PMID- 29259618 TI - A Reliable and Non-destructive Method for Monitoring the Stromal pH in Isolated Chloroplasts Using a Fluorescent pH Probe. AB - The proton gradient established by the pH difference across a biological membrane is essential for many physiological processes, including ATP synthesis and ion and metabolite transport. Currently, ionophores are used to study proton gradients, and determine their importance to biological functions of interest. Because of the lack of an easy method for monitoring the proton gradient across the inner envelope membrane of chloroplasts (DeltapHenv), whether the concentration of ionophores used can effectively abolish the DeltapHenv is not proven for most experiments. To overcome this hindrance, we tried to setup an easy method for real-time monitoring of the stromal pH in buffered, isolated chloroplasts by using fluorescent pH probes; using this method the DeltapHenv can be calculated by subtracting the buffer pH from the measured stromal pH. When three fluorescent dyes, BCECF-AM [2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein acetoxymethyl ester], CFDA-SE [5(6)-Carboxyfluorescein diacetate succinimidyl ester] and SNARF-1 carboxylic acid acetate succinimidyl ester were incubated with isolated chloroplasts, BCECF-AM and CFDA-SE, but not the ester-formed SNARF-1 were taken up by chloroplasts and digested with esterase to release high levels of fluorescence. According to its relatively higher pKa value (6.98, near the physiological pH of the stroma), BCECF was chosen for further development. Due to shielding of the excitation and emission lights by chloroplast pigments, the ratiometric fluorescence of BCECF was highly dependent on the concentration of chloroplasts. By using a fixed concentration of chloroplasts, a highly correlated standard curve of pH to the BCECF ratiometric fluorescence with an r-square value of 0.98 was obtained, indicating the reliability of this method. Consistent with previous reports, the light-dependent formation of DeltapHenv can be detected ranging from 0.15 to 0.33 pH units upon illumination. The concentration of the ionophore nigericin required to collapse the DeltapHenv was then studied. The establishment of a non-destructive method of monitoring the stromal pH will be valuable for studying the roles of the DeltapHenv in chloroplast physiology. PMID- 29259617 TI - Differentially Expressed microRNAs and Target Genes Associated with Plastic Internode Elongation in Alternanthera philoxeroides in Contrasting Hydrological Habitats. AB - Phenotypic plasticity is crucial for plants to survive in changing environments. Discovering microRNAs, identifying their targets and further inferring microRNA functions in mediating plastic developmental responses to environmental changes have been a critical strategy for understanding the underlying molecular mechanisms of phenotypic plasticity. In this study, the dynamic expression patterns of microRNAs under contrasting hydrological habitats in the amphibious species Alternanthera philoxeroides were identified by time course expression profiling using high-throughput sequencing technology. A total of 128 known and 18 novel microRNAs were found to be differentially expressed under contrasting hydrological habitats. The microRNA:mRNA pairs potentially associated with plastic internode elongation were identified by integrative analysis of microRNA and mRNA expression profiles, and were validated by qRT-PCR and 5' RLM-RACE. The results showed that both the universal microRNAs conserved across different plants and the unique microRNAs novelly identified in A. philoxeroides were involved in the responses to varied water regimes. The results also showed that most of the differentially expressed microRNAs were transiently up-/down regulated at certain time points during the treatments. The fine-scale temporal changes in microRNA expression highlighted the importance of time-series sampling in identifying stress-responsive microRNAs and analyzing their role in stress response/tolerance. PMID- 29259620 TI - HLA-DR Genotyping and Mitochondrial DNA Analysis Reveal the Presence of Family Burials in a Fourth Century Romano-British Christian Cemetery. AB - In Colchester, Britain's oldest recorded town, during the Roman period there were areas which were clearly used solely as cemeteries. One of the most significant is at Butt Road, which includes a late Roman probable Christian cemetery with an associated building, apparently a church, that overlies and developed from a pagan inhumation cemetery. DNA was extracted from the long bones (femurs) of 29 individuals, mostly from a large complex of burials centered on two timber vaults. These were thought to comprise a number of family groupings, deduced from osteological analysis, stratigraphical and other considerations. The use of a modified version of the silica-based purification method recovered nanogram quantities of DNA/gram of bone. Two-stage amplification, incorporating primer extension preamplification-polymerase chain reaction, permitted simultaneous amplification of both mitochondrial and nuclear DNA. Sequence-specific oligonucleotide probes yielded human leukocyte antigen (HLA)-DR typing of seven samples, with four revealing the infrequent HLA-DR10 genotype. Examination of the control region of mitochondrial DNA (mtDNA) by direct sequencing revealed polymorphisms yet to be reported in the modern population. HLA-DRB typing and mtDNA analysis affirmatively supported kinship among some, if not all, individuals in the "vault complex" and demonstrate a continental European origin of the individuals investigated. PMID- 29259619 TI - Draft Sequencing of the Heterozygous Diploid Genome of Satsuma (Citrus unshiu Marc.) Using a Hybrid Assembly Approach. AB - Satsuma (Citrus unshiu Marc.) is one of the most abundantly produced mandarin varieties of citrus, known for its seedless fruit production and as a breeding parent of citrus. De novo assembly of the heterozygous diploid genome of Satsuma ("Miyagawa Wase") was conducted by a hybrid assembly approach using short-read sequences, three mate-pair libraries, and a long-read sequence of PacBio by the PLATANUS assembler. The assembled sequence, with a total size of 359.7 Mb at the N50 length of 386,404 bp, consisted of 20,876 scaffolds. Pseudomolecules of Satsuma constructed by aligning the scaffolds to three genetic maps showed genome wide synteny to the genomes of Clementine, pummelo, and sweet orange. Gene prediction by modeling with MAKER-P proposed 29,024 genes and 37,970 mRNA; additionally, gene prediction analysis found candidates for novel genes in several biosynthesis pathways for gibberellin and violaxanthin catabolism. BUSCO scores for the assembled scaffold and predicted transcripts, and another analysis by BAC end sequence mapping indicated the assembled genome consistency was close to those of the haploid Clementine, pummel, and sweet orange genomes. The number of repeat elements and long terminal repeat retrotransposon were comparable to those of the seven citrus genomes; this suggested no significant failure in the assembly at the repeat region. A resequencing application using the assembled sequence confirmed that both kunenbo-A and Satsuma are offsprings of Kishu, and Satsuma is a back-crossed offspring of Kishu. These results illustrated the performance of the hybrid assembly approach and its ability to construct an accurate heterozygous diploid genome. PMID- 29259621 TI - The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases. AB - The process of advanced glycation leads to the generation and accumulation of an heterogeneous class of molecules called advanced glycation endproducts, or AGEs. AGEs are produced to accelerated degrees in disorders such as diabetes, renal failure, inflammation, neurodegeneration, and in aging. Further, AGEs are present in foods and in tobacco products. Hence, through both endogenous production and exogenous consumption, AGEs perturb vascular homeostasis by a number of means; in the first case, AGEs can cause cross-linking of long-lived molecules in the basement membranes such as collagens, thereby leading to "vascular stiffening" and processes that lead to hyperpermeability and loss of structural integrity. Second, AGEs interaction with their major cell surface signal transduction receptor for AGE or RAGE sets off a cascade of events leading to modulation of gene expression and loss of vascular and tissue homeostasis, processes that contribute to cardiovascular disease. In addition, it has been shown that an enzyme, which plays key roles in the detoxification of pre-AGE species, glyoxalase 1 (GLO1), is reduced in aged and diabetic tissues. In the diabetic kidney devoid of Ager (gene encoding RAGE), higher levels of Glo1 mRNA and GLO1 protein and activity were observed, suggesting that in conditions of high AGE accumulation, natural defenses may be mitigated, at least in part through RAGE. AGEs are a marker of arterial aging and may be detected by both biochemical means, as well as measurement of "skin autofluorescence." In this review, we will detail the pathobiology of the AGE-RAGE axis and the consequences of its activation in the vasculature and conclude with potential avenues for therapeutic interruption of the AGE-RAGE ligand-RAGE pathways as means to forestall the deleterious consequences of AGE accumulation and signaling via RAGE. PMID- 29259622 TI - Noni (Morinda citrifolia) Modulates the Hypothalamic Expression of Stress- and Metabolic-Related Genes in Broilers Exposed to Acute Heat Stress. AB - Heat stress (HS) adversely affects growth performance and inflicts heavy economic losses to the poultry industry. There is, therefore, a critical need to identify new alternative strategies to alleviate the negative effects induced by HS. The tropic medicinal plant, Morinda citrifolia (Noni), is being used in livestock nutrition, however the literature is limited and conflicting for its impact on growth performance. The present study aimed to determine the effect of Noni on feeding and drinking behavior as well as on the hypothalamic expression of stress and metabolic-related genes in broiler chickens exposed to acute HS. A total of 480 1 day-old male broiler chicks were randomly assigned to 12 controlled environmental chambers. Birds were subjected to two environmental conditions (TN, 25 degrees C vs. HS, 35 degrees C for 2 h) and fed two diets (control vs. 0.2% Noni) in a 2 * 2 factorial design. Feed intake and core body temperature (BT) were recorded during HS period. Blood was collected and hypothalamic tissues were harvested for target gene and protein analyses. Acute HS-broilers exhibited higher BT (~1 degrees C), spent less time eating with a significant decrease in feed intake, and spent more time drinking along with higher drinking frequency compared to those maintained under TN conditions. Although Noni supplementation did not improve feed intake, it significantly delayed (~30 min) and reduced the BT-induced by HS. At molecular levels and under HS conditions, Noni supplementation down regulated the hypothalamic expression of HSP90 and its related transcription factors HSF1, 2, and 4, increased orexin mRNA levels, and decreased the phosphorylation levels of AMPKalpha1/2Thr172 and mTORSer2481. Together, these data indicated that Noni supplementation might modulate HS response in broilers through central orexin-AMPK-mTOR pathways. PMID- 29259623 TI - Headwater Capture Evidenced by Paleo-Rivers Reconstruction and Population Genetic Structure of the Armored Catfish (Pareiorhaphis garbei) in the Serra do Mar Mountains of Southeastern Brazil. AB - Paleo-drainage connections and headwater stream-captures are two main historical processes shaping the distribution of strictly freshwater fishes. Recently, bathymetric-based methods of paleo-drainage reconstruction have opened new possibilities to investigate how these processes have shaped the genetic structure of freshwater organisms. In this context, the present study used paleo drainage reconstructions and single-locus cluster delimitation analyses to examine genetic structure on the whole distribution of Pareiorhaphis garbei, a 'near threatened' armored catfish from the Fluminense freshwater ecoregion in Southeastern Brazil. Sequences of two mitochondrial genes (cytochrome b and cytochrome c oxidase subunit 1) were obtained from five sampling sites in four coastal drainages: Macae (KAE), Sao Joao (SJO), Guapi-Macacu [sub-basins Guapiacu (GAC) and Guapimirim (GMI)], and Santo Aleixo (SAL). Pronounced genetic structure was found, involving 10 haplotypes for cytB and 6 for coi, with no haplotypes shared between localities. Coalescent-based delineation methods as well as distance-based methods revealed genetic clusters corresponding to each sample site. Paleo-drainage reconstructions showed two putative paleo-rivers: an eastern one connecting KAE and SJO; and a western one merging in the Guanabara Bay (GAC, GMI, and SAL). A disagreement was uncovered between the inferred past riverine connections and current population genetic structure. Although KAE and SJO belong to the same paleo-river, the latter is more closely related to specimens from the Guanabara paleo-river. This discordance between paleo-drainage connections and phylogenetic structure may indicate an ancient stream-capture event in headwaters of this region. Furthermore, all analyses showed high divergence between KAE and the other lineages, suggesting at least one cryptic species in the latter, and that the nominal species should be restricted to the Macae river basin, its type locality. In this drainage, impacts such as the invasive species and habitat loss can be especially threatening for such species with a narrow range. Our results also suggest that freshwater fishes from headwaters in the Serra do Mar mountains might have different biogeographical patterns than those from the lowlands, indicating a complex and dynamic climatic and geomorphological history. PMID- 29259624 TI - Construction of a High-Density Genetic Map from RNA-Seq Data for an Arabidopsis Bay-0 * Shahdara RIL Population. AB - High-density genetic maps are essential for high resolution mapping of quantitative traits. Here, we present a new genetic map for an Arabidopsis Bayreuth * Shahdara recombinant inbred line (RIL) population, built on RNA-seq data. RNA-seq analysis on 160 RILs of this population identified 30,049 single nucleotide polymorphisms (SNPs) covering the whole genome. Based on a 100-kbp window SNP binning method, 1059 bin-markers were identified, physically anchored on the genome. The total length of the RNA-seq genetic map spans 471.70 centimorgans (cM) with an average marker distance of 0.45 cM and a maximum marker distance of 4.81 cM. This high resolution genotyping revealed new recombination breakpoints in the population. To highlight the advantages of such high-density map, we compared it to two publicly available genetic maps for the same population, comprising 69 PCR-based markers and 497 gene expression markers derived from microarray data, respectively. In this study, we show that SNP markers can effectively be derived from RNA-seq data. The new RNA-seq map closes many existing gaps in marker coverage, saturating the previously available genetic maps. Quantitative trait locus (QTL) analysis for published phenotypes using the available genetic maps showed increased QTL mapping resolution and reduced QTL confidence interval using the RNA-seq map. The new high-density map is a valuable resource that facilitates the identification of candidate genes and map-based cloning approaches. PMID- 29259625 TI - Prevalence and Factors Associated with Self-Medication in Dermatology in Togo. AB - Objective: This study aimed to determine the prevalence of and factors associated with self-medication in dermatology in Lome, Togo. Methods: We conducted an analytical cross-sectional study from February to April 2016 in 2 dermatology departments in Lome. Univariate and multivariate logistic regression models were carried out to identify possible factors associated with self-medication. Results: A total of 711 patients were included in the study. The mean age (+/-SD) of the patients was 26.6 +/- 6.9 years and the sex ratio (male/female) was 0.6. The main dermatologic diseases recorded were immunoallergic dermatoses (39.7%) and infectious skin diseases (22.6%). Two-thirds (481/711; 66.7%) of the patients had practiced self-medication before consultation in dermatology units. In multivariate analysis, factors associated with self-medication were female sex (aOR = 1.44; 95% CI = [1.01, 2.05]), duration of dermatologic disease more than one year (aOR = 1.79; IC = [1.19, 2.68]), adnexal dermatoses (aOR = 2.31; 95% IC = [1.03-5.21]), keratinization disorders (aOR = 4.23; 95% CI = [1.36-13.13]), and fungal skin infections (aOR = 5.43; 95% CI = [2.20, 13.38]). Conclusion: Our study confirms that self-medication practice is very common among patients with dermatologic diseases in Lome and has identified associated factors. PMID- 29259626 TI - Hiatoplasty with Crura Buttressing versus Hiatoplasty Alone during Laparoscopic Sleeve Gastrectomy. AB - Introduction: In obese patients with hiatal hernia (HH), laparoscopic sleeve gastrectomy (LSG) with cruroplasty is an option but use of prosthetic mesh crura reinforcement is debated. The aim was to compare the results of hiatal closure with or without mesh buttressing during LSG. Methods: Gastroesophageal reflux disease (GERD) was assessed by the Health-Related Quality of Life (GERD-HRQL) questionnaire before and after surgery in two consecutive series of patients with esophageal hiatus <= 4 cm2. After LSG, patients in group A (12) underwent simple cruroplasty, whereas in group B patients (17), absorbable mesh crura buttressing was added. Results: At mean follow-up of 33.2 and 18.1 months for groups A and B, respectively (p = 0.006), the mean preoperative GERD-HRQL scores of 16.5 and 17.7 (p = 0.837) postoperatively became 9.5 and 2.4 (p = 0.071). In group A, there was no difference between pre- and postoperative scores (p = 0.279), whereas in group B, a highly significant difference was observed (p = 0.002). The difference (Delta) comparing pre- and postoperative mean scores between the two groups was significantly in favor of mesh placement (p = 0.0058). Conclusions: In obese patients with HH and mild-moderate GERD, reflux symptoms are significantly improved at medium term follow-up after cruroplasty with versus without crura buttressing during LSG. PMID- 29259627 TI - Mediastinal Lymph Node Metastases in Thyroid Cancer: Characteristics, Predictive Factors, and Prognosis. AB - Background: Mediastinal lymph node metastases (MLNM) have not been extensively studied. The aim of this study is to investigate the characteristics, predictive factors, and prognosis of MLNM in thyroid cancer. Methods: This is a retrospective study based on the thyroid cancer patients with MLNM at our institution from 2008 to 2015. Results: In total, 73 thyroid cancer patients with positive MLNM were included in this study. It contained sixty patients (82.2%) with papillary thyroid carcinoma (PTC), twelve (16.4%) with medullary thyroid carcinoma, and one (1.4%) with anaplastic thyroid carcinoma. Forty-eight patients had the surgery as initial treatment. Fifty-three (72.6%) patients remained disease-free, and fifteen (20.5%) developed a regional recurrence. Distant metastases occurred in four (5.5%) patients and five (6.8%) patients died. Five year overall survival rate and disease-free survival (DFS) rate of the PTC patients for initial treatment are 95.4% and 77.2%, respectively. Extrathyroidal extension and multiple lymph nodes involved were associated with DFS in PTC patients. Conclusions: Initial therapeutic control is very important for the thyroid cancer patients. Extrathyroidal extension and multiple mediastinal lymph nodes involved were the influence factors of prognosis in the thyroid cancer patients with MLNM. PMID- 29259628 TI - Relative Efficacy of Quercetin Compared with Benzydamine Hydrochloride in Minor Aphthae: A Prospective, Parallel, Double Blind, Active Control, Preliminary Study. AB - Background and Objectives: Recurrent aphthous stomatitis is an inflammatory condition present since ancient era wherein numerous treatment modalities have been tried. But complete eradication of the disease has not been possible and hence newer agents are being introduced. One such agent is a flavonoid named quercetin with proven antioxidant, anti-inflammatory, and ulcer healing properties. Methods: 40 patients with minor aphthous ulcers were divided equally into two groups: A and B. Group A patients were advised to apply quercetin gel and Group B patients were advised to take benzydamine hydrochloride mouth wash. Clinical evaluation including assessment of ulcer size and pain score and questionnaire about the acceptability of both the drugs in terms of taste and ease of application was carried out. Each criterion was compared and statistically analyzed. Results: There was statistically significant reduction in the mean score of pain sensation and ulcer area in both the groups. Quercetin showed statistically highly significant ulcer size reduction as compared to benzydamine hydrochloride. Conclusion: From the present study, it is evident that quercetin is safe, well tolerated, and effective therapy which promotes complete ulcer healing in a short duration of time. PMID- 29259629 TI - Qualitative Analysis of Microbial Dynamics during Anaerobic Digestion of Microalgal Biomass in a UASB Reactor. AB - Anaerobic digestion (AD) is a microbiologically coordinated process with dynamic relationships between bacterial players. Current understanding of dynamic changes in the bacterial composition during the AD process is incomplete. The objective of this research was to assess changes in bacterial community composition that coordinates with anaerobic codigestion of microalgal biomass cultivated on municipal wastewater. An upflow anaerobic sludge blanket reactor was used to achieve high rates of microalgae decomposition and biogas production. Samples of the sludge were collected throughout AD and extracted DNA was subjected to next generation sequencing using methanogen mcrA gene specific and universal bacterial primers. Analysis of the data revealed that samples taken at different stages of AD had varying bacterial composition. A group consisting of Bacteroidales, Pseudomonadales, and Enterobacteriales was identified to be putatively responsible for the hydrolysis of microalgal biomass. The methanogenesis phase was dominated by Methanosarcina mazei. Results of observed changes in the composition of microbial communities during AD can be used as a road map to stimulate key bacterial species identified at each phase of AD to increase yield of biogas and rate of substrate decomposition. This research demonstrates a successful exploitation of methane production from microalgae without any biomass pretreatment. PMID- 29259630 TI - Abdominopelvic Tuberculosis Secondary to a Nontuberculous Mycobacterium in an Immunocompetent Patient. AB - Tuberculosis (TB) remained as one of the top 10 causes of death worldwide despite an overall decline in its incidence rate globally. Extrapulmonary TB is uncommon and only accounts for 10-20% of overall TB disease burden. Abdominopelvic TB is the sixth most common location of extrapulmonary TB. The symptoms and signs are often insidious and nonspecific. Diagnosing abdominopelvic TB can be very challenging at times and poses great difficulties to the clinician. Infection with nontuberculous Mycobacterium (NTM) is even rarer especially in an immunocompetent patient. We report a case of NTM in abdominopelvic TB. A 37-year old foreign worker, para 3, presented with a one-week history of suprapubic pain associated with fever. An assessment showed presence of a right adnexal mass. She was treated as tuboovarian abscess with intravenous antibiotics. Unfortunately, she did not respond. She underwent exploratory laparotomy. Intraoperatively, features of the mass were suggestive of a right mature cystic teratoma with presence of slough and cheesy materials all over the abdominal cavity as well as presence of ascites. Diagnosis of NTM was confirmed with PCR testing using the peritoneal fluid. This case was a diagnostic dilemma due to the nonspecific clinical presentation. Management of such rare infection was revisited. PMID- 29259631 TI - Evaluating the efficacy of mixture of Boswellia carterii, Zingiber officinale, and Achillea millefolium on severity of symptoms, anxiety, and depression in irritable bowel syndrome patients. AB - Background: Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal disorders (FGIDs) that affects in different aspects of life and patients experienced depression and anxiety more than others. There are several herbal medicines with positive effects in these patients. The aim of this study is to evaluate the effects of mixture of Boswellia carterii, Zingiber officinale, and Achillea Millefolium on severity of symptoms, anxiety, and depression in IBS patients. Materials and Methods: This clinical trial study was done in sixty IBS patients (with mild-to-moderate symptoms) divided into two case and control groups. Patients were assessed at the beginning, 1 month, and 3 months after by IBS-severity scoring system (IBS-SSS) and Hospital Anxiety and Depression Scale. IBS-SSS is used for quality of life evaluation too. Results: Sixty IBS patients (with mild to moderate symptoms) with a mean age of 38.75 +/- 11.74 participated that 55.4% of cases and 72.8% of controls were men. The most prevalent type of IBS was the mixed type of IBS. The mean score of abdominal pain severity and frequency, bloating score, and depression and anxiety score were decreased in patients administered herbal medication, but changes in these variables in controls were not statistically significant. The changes in quality of life score between cases and controls were significant in men (P = 0.01) although it was not significant in women. Conclusion: A mixture of B. Carterii, Z. officinale, and A. millefolium is effective in eliminating IBS symptoms and its related depression and anxiety and using herbal medicine in IBS treatment is suggested. PMID- 29259632 TI - Epidemiology of Q fever in Iran: A systematic review and meta-analysis for estimating serological and molecular prevalence. AB - Background: Q fever is endemic in Iran, thus, we conducted a systematic review and meta-analysis on epidemiology of Coxiella burnetii among humans and animals in Iran. Materials and Methods: A systematic search was performed to identify all articles reporting C. burnetii prevalence in Iranian humans or animals, published from January 2000 to January 2015. Data from articles were extracted, and a pooled estimate of prevalence with corresponding 95% confidence interval (CI) was calculated using random effect method. Results: In this review, 27 papers were identified. The pooled seroprevalence of Q fever in animals was 27% (CI 95%: 23% 32%). The prevalence was 33% (CI 95%: 22%-45%) in goats, 27% (CI 95%: 21%-32%) in sheep, and 17% (CI 95%: 5%-28%) in cattle. The bacterial DNA was detected in 5% (95% CI: 3%-9%) of milk samples, and it was higher in cattle (10%; 95% CI: 6% 16%) than sheep (2%; 95% CI: 0-7%) and goats (4%; 95% CI: 0-12%). Conclusion: C. burnetii DNA or its antibody has been frequently detected among ruminants. Since these animals can transmit the infection to humans, Q fever could be a potential health problem in Iran. PMID- 29259633 TI - Association between unfavorable lipid profile and glycemic control in patients with type 2 diabetes mellitus. AB - Background: Recent studies hypothesize that dyslipidemia can predict glycated hemoglobin (HbA1c) and could be important contributing factor to the pathogenesis of type 2 diabetes mellitus (DM2). Therefore, we aimed to evaluate the influence of lipid parameters on long-term glycemic control in DM2. Materials and Methods: A total of 275 sedentary DM2 (mean [+/-standard deviation] age 60.6 [+/-10.0] years) who volunteered to participate in this cross-sectional study were enrolled. Anthropometric (body weight, body hight, and waist circumference), biochemical parameters (fasting glucose, HbA1c, lipid parameters, creatinine), as well as blood pressure were obtained. Results: Total cholesterol (odds ratio [OR] =1.30, 95% confidence interval [CI] [1.02-1.66], P = 0.032), triglycerides (OR = 1.34, 95% CI (1.07-1.67), P = 0.010), and low density lipoprotein cholesterol (OR = 1.42, 95% CI [1.10-1.83], P = 0.006) were the independent predictors of higher HBA1c, and as they increased by 1 mmol/L each, probabilities of higher HBA1c increased by 30%, 34%, and 42%, respectively. Low level of high-density lipoprotein cholesterol (HDL-c) was found to be the independent predictor of higher HBA1c (OR = 0.44, 95% CI [0.20-0.67], P = 0.039), and increase in HDL-c by 1 mmol/L, reduced the probability of higher HBA1c by 56%. Conclusion: Unfavorable lipid profile can predict HbA1c level in DM2 patients. Early diagnosis of dyslipidemia, as well as its monitoring and maintaining good lipids control can be used as a preventive measure for optimal long-term glycemic control. PMID- 29259635 TI - Can cool dialysate alleviate restless leg syndrome in hemodialysis patients? PMID- 29259634 TI - Prevalence of hepatitis C infection in Iranian hemodialysis patients: An updated systematic review and meta-analysis. AB - Background: Hepatitis C virus (HCV) is a major cause of liver disease and a potential cause of substantial morbidity and mortality. This study aims to provide a comprehensive evidence on HCV Infection in Iranian hemodialysis (HD) patients we conducted a systematic review. Materials and Methods: In this systematic review and meta-analysis, through a comprehensive search of literature until January of 2016, we estimated the pooled prevalence of hepatitis C infection in Iranian HD patients. Using Medical Subject Headings terms, Emtree, and related equal Persian key words for Iranian databases and also international databases of PubMed and NLM Gateway (for MEDLINE), and SCOPUS. Interest outcome of HCV infection prevalence was confirmed based on positive hepatitis B surface antigen of blood samples. Random effect meta-analysis was used to estimate pooled prevalence of HCV infection in Iranian HD patients, date and language, HD patients, in adult HD patients, Institute of Scientific Information, Iran-doc, irrespective of age, living in Iran. Searches run through main domestic databanks of Iran-Medex, renal transplantation, Scientific Information Database, the relevant literature-searched concentrating on HCV infection. Results: Through searching steps, 305 publications were found from them following the excluding duplicates and overlapping studies 54 studies relevant to HCV prevalence in Iranian HD zcxw patients, with number of 23921 participants, remained in our analyses. The overall results of test of heterogeneity demonstrate sever heterogeneity between reported prevalence (I2 = 96.62%, Chi-square = 1566, P < 0.001). Due to sever heterogeneity results of random effect meta-analysis showed that the estimated pooled prevalence was 11% (95% confidence interval [CI] =10% 13%). The pooled prevalence base on polymerase-chain reaction, recombinant immunoblot assay, and enzyme-Linked Immunosorbant Antibody method were 11% (95% CI = 6%-15%), 9% (95% CI = 5-13) and 12% (95% CI = 10-14), respectively. In line with previous studies, the present finding shows the significant variation in the rate of HCV in dialysis units among the regions in Iran. Conclusion: Present paper is the comprehensive updated systematic review on HCV prevalence in the Iranian HD patients. Our findings provide the reliable evidence for promotion of policies and interventional programs. PMID- 29259637 TI - Accelerated rigor mortis: A case letter. PMID- 29259636 TI - The relationship between fruit and vegetable intake with gastroesophageal reflux disease in Iranian adults. AB - Background: Findings from studies that investigated the relationship between fruit and vegetable intake with gastroesophageal reflux disease (GERD) were inconsistent. We aimed to assess the relationship between fruit and vegetable consumption and GERD among a large group of Iranian adults. Materials and Methods: In this cross-sectional study on 3979 adults, a validated food frequency questionnaire was used to assess usual dietary intakes including fruits and vegetables. The presence of heartburn sometimes or more during the past 3 months were considered as having GERD. Results: The prevalence of GERD among study population was 23.9%. After adjustment for potential confounding factors, those with the highest consumption of fruits had 25% lower risk for GERD, in comparison to those with the lowest intake (odds ratio [OR] = 0.75, 95% confidence interval [CI]: 0.59-0.97). Vegetable intake was not significantly related to the risk of GERD in crude or multivariable-adjusted models. However, participants with the highest intake of fruits and vegetables had 33% lower risk of GERD (OR = 0.67, 95% CI: 0.51-0.88), after adjustment for confounders. Women with the highest fruit and vegetable intake had 36% lower risk for GERD (OR = 0.64, 95% CI: 0.45 0.91). Overweight/obese participants in the last tertile of fruit consumption had 42% lower risk for GERD, in comparison to the first category (OR = 0.58, 95% CI: 0.42-0.83). Furthermore, participants with body mass index higher than 25 kg/m2 and higher intake of fruits and vegetables had 53% lower risk for GERD (OR = 0.47, 95% CI: 0.32-0.69). Conclusion: We found inverse associations between fruit intake as well as fruit and vegetable intake and risk of GERD among Iranian adults. PMID- 29259638 TI - An atypical presentation of pulmonary sequestration. AB - Pulmonary sequestration (PS) is a rare congenital malformation of the lower respiratory tract and is commonly complicated by recurrent infections and presents with respiratory failure. We report an atypical clinical presentation of postprandial abdominal pain and cramps in a patient with intralobar PS. PMID- 29259639 TI - Effect of Nepeta bracteata Benth. on allergic rhinitis symptoms: A randomized double-blind clinical trial. AB - Background: Allergic rhinitis (AR) is one of the health problems in the world. It is necessary to develop new treatment procedure for control of this disease. The aim of this study was to assess the effect of Zofa (Nepeta bracteata Benth) on AR patients. Materials and Methods: In this double-blind randomized clinical trial study, 71 patients (37 patients in treatment and 34 in placebo group) participated. In treatment group, N. bracteata syrup (NBS) was used for 4 weeks as three times a day. The efficacy of the drug regarding AR symptoms (rhinorrhea, sneezing, nasal obstruction, itchy nose, and ocular symptoms) were evaluated through a visual analog scale (VAS) by 0-10 before administration and at the end of the whole treatment period. The collected information was entered in the SPSS software (version 18) and was analyzed using the Fisher's exact test, Chi-square test, independent sample t-test, and paired sample test. Results: The improvement of AR symptoms in the group receiving NBS was significantly higher compared to control group (4.73 +/- 1.84 vs. 0.38 +/- 2.06; P < 0.0001). Furthermore, the mean of total VAS before and after the treatment (in case group) was 7.10 +/- 1.92 and 2.37 +/- 1.76, respectively (P < 0.001). Conclusion: The results of this study indicate that N. bracteata has significant effects on improving the symptoms of AR. Hence, it can be a good alternative to AR symptoms relief. PMID- 29259640 TI - Effectiveness and Safety of the Combination of the Traditional Chinese Medicine Prescription Jade Screen and Desloratadine in the Treatment of Chronic Urticaria: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Objective: The aim of this study is to systematically evaluate the clinical efficacy and safety of the traditional Chinese medicine prescription Jade Screen combined with desloratadine in the treatment of chronic urticaria. Methods: Two researchers independently conducted literature searches. The extracted data were analyzed using Rev Man 5.2.3 software. The established retrieval time range of the various databases was up to 15 March, 2017. Results: Sixteen randomized controlled trials were included in this study. The results of the meta-analysis showed that the total effective rate of using Jade Screen and desloratadine in combination to treat chronic urticaria was higher than that with desloratadine alone (P < 0.00001), while its recurrence rate (P < 0.00001) and symptom score (P = 0.006) were both significantly lower than the latter. The rate of adverse reaction in the combination group was lower than that when orally taking desloratadine alone (P = 0.74), and the serum level of total IgE in the combination group was lower than that when orally taking desloratadine alone (P = 0.82); however, the results of the rate of adverse reaction and the serum level of total IgE were insignificant. Conclusion: Using Jade Screen and desloratadine together to treat chronic urticaria gains a better clinical effect than using desloratadine alone. PMID- 29259641 TI - Icariin Prevents IL-1beta-Induced Apoptosis in Human Nucleus Pulposus via the PI3K/AKT Pathway. AB - Purpose: To explore the effect and possible mechanism of icariin, a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum that was applied to IL-1beta pretreated human nucleus pulposus (NP) cells. Methods: Human NP cells were isolated from intervertebral discs of patients with scoliosis and lumbar spondylolisthesis. The cells were divided into five groups: A (blank control); B (20 ng/ml IL-1beta); C (20 ng/ml IL-1beta + 20 MUM icariin); D (20 MUM icariin + 20 ng/ml IL-1beta + 25 MUM LY294002); E (20 ng/ml IL-1beta + 25 MUM LY294002). For each of the five groups, the CCK8, apoptosis rates, ROS rates, and JC-1 rates were determined and an electron micrograph was performed. Different expression levels of apoptosis proteins and proteins in the PI3K/AKT pathway were detected via western blot. Results: We found that the damage effects on human nucleus pulposus cells from 20 ng/ml of IL-1beta exposure were attenuated by icariin. When the PI3K/AKT pathway was blocked by LY294002, a specific inhibitor of this pathway, the protective effect of icariin was impaired. In summary, icariin might be a protective traditional Chinese medicine, which prevents inflammation-induced degeneration of intervertebral discs partly through the PI3K/AKT pathway. PMID- 29259642 TI - Ethnopharmacological Evaluation of Breu Essential Oils from Protium Species Administered by Inhalation. AB - Background: Breu is an aromatic oleoresin which has been used by Amazonian traditional communities as a remedy for headaches and migraines by burning and inhaling the smoke produced during its combustion. This study evaluated the antinociceptive and sedative activities of formulations containing breu essential oils administered by inhalation. Methods: Five different formulations (A-E) containing breu essential oils were evaluated for their sedative and antinociceptive activities in mice. They were delivered for 20 minutes using an inhalation chamber coupled with a nebulizer and the air inside was collected by static headspace and analyzed by GC-FID. Results: All nebulized formulations had similar chemical compositions and major compounds as the original essential oils. None of them resulted in significant increase in response time during the hot plate test. In the formalin test, Formulation E showed a significant inhibition of licking responses in the early (46.8%) and late (60.2%) phases. Formulation B was effective (36.9%) in the first phase and Formulation D (37.9%) in the second. None of the formulations presented sedative effects. Conclusion: Breu essential oils, when inhaled, may present antinociceptive and anti-inflammatory properties without sedation. Additionally, nebulization proved to be an efficient method for administration of formulations containing these essential oils. PMID- 29259643 TI - Dahuang Zexie Decoction Protects against High-Fat Diet-Induced NAFLD by Modulating Gut Microbiota-Mediated Toll-Like Receptor 4 Signaling Activation and Loss of Intestinal Barrier. AB - Increasing evidence suggests that intestinal dysbiosis, intestinal barrier dysfunction, and activated Toll-like receptor 4 (TLR4) signaling play key roles in the pathogenesis of NAFLD. Dahuang Zexie Decoction (DZD) has been verified to be effective for treating NAFLD, but the mechanisms remain unclear. In this study, we investigated the effects of DZD on NAFLD rats and determined whether such effects were associated with change of the gut microbiota, downregulated activity of the TLR4 signaling pathway, and increased expressions of tight junction (TJ) proteins in the gut. Male Sprague Dawley rats were fed high-fat diet (HFD) for 16 weeks to induce NAFLD and then given DZD intervention for 4 weeks. We found that DZD reduced body and liver weights of NAFLD rats, improved serum lipid levels and liver function parameters, and relieved NAFLD. We further found that DZD changed intestinal bacterial communities, inhibited the intestinal TLR4 signaling pathway, and restored the expressions of TJ proteins in the gut. Meanwhile ten potential components of DZD had been identified. These findings suggest that DZD may protects against NAFLD by modulating gut microbiota-mediated TLR4 signaling activation and loss of intestinal barrier. However, further studies are needed to clarify the mechanism by which DZD treats NAFLD. PMID- 29259644 TI - Therapeutic Effect and Mechanism of Oxytropis falcata Gel on Deep Second-Degree Burn in Rats. AB - Oxytropis falcata has long been used to treat inflammation, sores, and bleeding in Tibet. However, the burn remedy and underlying molecular mechanisms are not well understood. This study is aimed at assessing the effect of Oxytropis falcate gel (OFG) on deep second-degree burn rats and exploring its mechanism. Wistar rats with second-degree burn were treated with OFG and silver sulfadiazine. Immunohistochemical detections for EGF and VEGF were performed, and ELISA detections for EGF, VEGF, p38, and IL-1beta in serum were determined. Rats treated with OFG (25, 50 g/kg) consisted of the major rhamnocitrin-3-O-beta neohesperidoside significantly accelerated incrustation (P < 0.001) and decrustation (P < 0.001). According to HE staining, edema and infiltration of inflammatory cells decrease apparently with good hyperplasia and incrustation in administration groups (7 d). The expressions of EGF and CD34 in OFG (25, 50 g/kg) treatment increased obviously from immunohistochemical assessment (7 d). Serum EGF expression reached 321.27 +/- 7.20 ng/mL by OFG treatment, while p38 (P < 0.05) and IL-1beta (P < 0.05) levels were significantly lower than the model and vehicle groups from day 1 to day 7. OFG possesses potential wound healing activities. The mechanism may be related to the increasing of biosynthesis and the releasing of EGF and CD34 and the decreasing p38 and IL-1beta levels. PMID- 29259645 TI - In Vivo Evaluation of Galla chinensis Solution in the Topical Treatment of Dermatophytosis. AB - Aim: Dermatophytosis is one of the main fungal diseases in humans and animals all over the world. Galla chinensis, a traditional medicine, has various pharmacological effects. The goal of this study was to evaluate the treatment effect of Galla chinensis solution (GCS) on dermatophytosis-infected dogs (Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, resp.). Methods: The treatment effects of GCS were evaluated by mycological cure rates and clinical score comprised of three indices, including inflammation, hair loss, and lesion scale. Results: The results showed that, in the three models of dermatophytosis, GCS significantly (P < 0.05) improved skin lesions and fungal eradication. GCS (10% and 5%) had higher efficacy compared to the positive control (Tujingpi Tincture). The fungal eradication efficacy exceeds 85% after treatment with GCS (10%, 5%, and 2.5%) on day 14. Conclusion: The GCS has antidermatophytosis effect in dogs, which may be a candidate drug for the treatment of dermatophytosis. PMID- 29259646 TI - Antioxidant, Antiglycation, and Hypoglycaemic Effect of Seriphium plumosum Crude Plant Extracts. AB - Diabetes is a severely debilitating metabolic disorder characterised by chronic hyperglycaemia. Traditional medicinal plants provide an important avenue for the development of novel antidiabetic agents. The antidiabetic potential of the methanol, acetone, and hexane extracts of S. plumosum was assessed using different parameters. These included secondary metabolite quantification, hypoglycaemic, cytotoxic effects, and GLUT4 translocation augmentation on C2C12 cells. The methanol extract contained the highest amount of total phenolic and flavonoid compounds and showed enhanced antioxidant activity. The methanol extracts had the best DPPH scavenging (EC50 = 0.72 mg/ml) and ferric reducing powers (EC50 = 2.31 mg/ml). The hexane extract resulted in the highest glucose uptake activity of 35, 77% with respect to all other treatments after a 6-hour exposure period. Immunocytochemistry technique further revealed that the increased glucose utilisation may be due to increased membrane fused GLUT4 molecules in C2C12 cells. The hexane extract was also shown to upregulate the phosphorylation of p70 S6 kinase and Akt1/2. The study highlights a probable insulin-mimetic activity of the hexane extract via the augmentation of Akt1/2 phosphorylation which is involved in the GLUT4 translocation pathway. Furthermore, the study represents the first report on the cytotoxic effect, GLUT4 translocation, and glucose uptake potential of S. plumosum. PMID- 29259648 TI - The Effects of Natural Chinese Medicine Aconite Root, Dried Ginger Rhizome, and Coptis on Rectal and Skin Temperatures at Acupuncture Points. AB - The 4 properties of Chinese materia medica refer to cold, hot, warm, and cool. In the present study, the effects of the Coptis, the prepared aconite root, and dried ginger rhizome were compared with regard to the rectal and skin temperature changes of the related body surface acupuncture points (Dazhui, Zhiyang, Mingmen, Zhongwan, and Shenque). The investigation aimed to explore the thermal sensitive points, which can reflect the cold and hot properties of the Chinese herbs. This study showed that the prepared aconite root and dried ginger rhizome exhibited a warming effect on the body temperature, whereas the warming sensitive points were Zhongwan, Shenque, Dazhui, and Zhiyang. Coptis exhibited both a warming and a cooling effect on the body temperature, and the cooling sensitive point was Dazhui. The concomitant effect of these three Chinese herbs on the regulation of the body temperature was reflected by Dazhui. However, there are still some limitations and one-sidedness. For instance, the cold and hot property of some herbs cannot be fully reflected through relevant acupoints on the conception and governor vessels. More detecting sites such as ears and internal organs will be selected for further exploration of Chinese herbs' cold and hot property. PMID- 29259647 TI - Efficacy and Safety of Compound Kushen Injection on Patients with Advanced Colon Cancer: A Meta-Analysis of Randomized Controlled Trials. AB - Objective: The efficacy and safety of Compound Kushen Injection (CKI) on advanced colon cancer remain controversial. We undertook a systematic meta-analysis of randomized controlled clinical studies on this issue. Methods: A comprehensive literature search was conducted by searching the following electronic databases: PubMed, Cochrane, Chinese Biological Medical disc, Chinese National Knowledge Infrastructure, and Wan-Fang Database in China by the end of January 31, 2017, without language restriction. Meta-analysis was performed by using the random effects model to estimate the summary odd ratio (OR) with 95% confidence interval (CI) according to the study design. Stata 12.0 software was used for data analysis. The heterogeneity, sensitivity, and publication bias were assessed, respectively. Results: A total of 14 trials met the inclusion criteria in present meta-analysis. The results suggested that CKI combined with chemotherapeutic drugs was favorable for the treatment of advanced colon cancer and could improve the patients' life quality. Funnel plot analysis and Egger's test suggested that there was not significant publication bias, and the sensitivity analysis indicated stable results. Conclusion: The current evidence suggested that CKI is favorable to improve the efficacy of chemotherapeutic drugs in patients with advanced colon cancer. PMID- 29259649 TI - Chloroform Extract of Artemisia annua L. Relaxes Mouse Airway Smooth Muscle. AB - Artemisia annua L. belongs to the Asteraceae family, which is indigenous to China. It has valuable pharmacological properties, such as antimalarial, anti inflammatory, and anticancer properties. However, whether it possesses antiasthma properties is unknown. In the current study, chloroform extract of Artemisia annua L. (CEAA) was prepared, and we found that CEAA completely eliminated acetylcholine (ACh) or high K+-elicited (80 mM) contractions of mouse tracheal rings (TRs). Patch-clamp technique and ion channel blockers were employed to explore the underlying mechanisms of the relaxant effect of CEAA. In whole-cell current recording, CEAA almost fully abolished voltage-dependent Ca2+ channel (VDCC) currents and markedly enhanced large conductance Ca2+-activated K+ (BK) channel currents on airway smooth muscle cells (ASMCs). In single channel current recording, CEAA increased the opening probability but had no effect on the single channel conductance of BK channels. However, under paxilline-preincubated (a selective BK channel blocker) conditions, CEAA only slightly increased BK channel currents. These results indicate that CEAA may contain active components with potent antiasthma activity. The abolished VDCCs by CEAA may mainly contribute to the underlying mechanism through which it acts as an effective antiasthmatic compound, but the enhanced BK currents might play a less important role in the antiasthmatic effects. PMID- 29259650 TI - Cytologic features of primary monophasic synovial sarcoma of the thyroid gland. AB - Synovial sarcoma (SS) is a rare soft tissue tumor, commonly arising in para articular areas of extremities, but can also present in the head and neck area. However, primary SS of the thyroid gland is an extremely rare tumor which has been reported only five times in previous English literatures. This report presents fine needle aspiration (FNA) cytology of primary monophasic SS of the thyroid gland. A 47-year- old woman incidentally detected thyroid nodule in the isthmus of right thyroid gland on an ultrasonography by regular health check-up. Because the possibility of malignancy could not be ruled out, FNA and surgical resection were performed. The cytological, histopathological, immunohistochemical, and molecular genetic study of SYT-SSX transcript were discussed. For the past 3 years of follow-up after surgery, no recurrence or metastasis has been identified. PMID- 29259651 TI - A case of painful ankle swelling: Cytomorphological clues and pitfalls. PMID- 29259652 TI - Cytomorphological spectrum of epididymal nodules: An institution's experience. AB - Background: Epididymal lesions are uncommon in clinical practice. Few case series has been described in the literature documenting the role of cytology in the evaluation of epididymal nodules. This study was undertaken to analyze the cytomorphology of epididymal nodules and to evaluate role of fine-needle aspiration biopsy (FNAB) in early definitive diagnosis of epididymal nodules. Materials and Methods: A total of seventy cases of epididymal nodules were aspirated over a period of 6 years in the Department of Pathology. These cases were taken from the cytology record as a part of this study. The aspiration was performed using 22/23-gauge needle. Smears were stained with May-Grunwald-Giemsa and Papanicolaou stains. Special stains and immunocytochemistry were performed, wherever required. Results: The cytological features were adequate to establish the diagnosis in sixty cases. The lesions diagnosed were tuberculosis 16 (22.85%), spermatoceles 12 (17.14%), benign cystic lesion 8 (11.42%), encysted hydrocele 8 (11.42%), acute suppurative lesion 6 (8.57%), filariasis 4 (5.71%), chronic epididymitis 3 (4.28%), nodular fasciitis 1 (1.42%), epidermal inclusion cyst 1 (1.42%), and cystic adenomatoid tumor 1 (1.42%). Ten cases were inadequate to establish the diagnosis. FNAB was useful in diagnosis of 86% of cases. Infectious lesions of the epididymis were more common than neoplastic lesions. Patients with infection responded well to medical treatment. Conclusions: FNAB is an easily available technique for palpable lesions of epididymis, and it helps in making an early, near definitive diagnosis of epididymal lesions. It also helps to avoid unnecessary surgical interventions and helps in timely management. PMID- 29259653 TI - Cytokeratin 20/p53 dual immunocytochemistry for improving the diagnostic accuracy of urine liquid-based cytology in the detection of urothelial neoplasm: A retrospective study. AB - Backgrounds: Dual immunocytochemistry (DIC) with cytokeratin (CK) 20 and p53 in liquid-based cytology is a tool for improving the accuracy of urine cytology (UC). This study was conducted to compare the diagnostic accuracy of UC alone with that of UC combined with CK20/p53 DIC. Methods: We retrieved urine samples collected between January 2015 and March 2016 stored in PreservCyt(r)solution that were from cases categorized as malignant, highly suspicious, suspicious, and atypical and that were matched with a subsequent biopsy. We re-prepared 63 samples of 28 patients for DIC and blindly evaluated 63 pairs of original Papanicolaou smears and DIC. Results: Of the 63 samples, 11 could not be analyzed because of the low number of atypical urothelial cells, and the results of the remaining 52 samples were as follows: 34 positive and 18 negative. The positive predictive value of DIC was 100%, and the negative predictive value was 78%. Fifteen DIC-positive cases, histologically proven as malignant were originally diagnosed as highly suspicious (4), suspicious (8), and atypical (3), which were strongly suggestive of "urothelial carcinoma". Four negative cases, histologically confirmed as non-neoplastic cases, were filtered from false positivity. Conclusions: Despite the small sample size, this study demonstrated the diagnostic utility, high sensitivity, and positive predictive value of CK20/p53 DIC, especially in cases with a small number of single malignant cells or cellular clusters of reactive atypical urothelial cells. Thus, CK20/p53 DIC can be used for improving diagnostic accuracy of UC, either as an ancillary method to cytology or as a part of a potential future diagnostic panel to improve patient diagnosis and management. PMID- 29259654 TI - A case of large cell neuroendocrine carcinoma of the uterine cervix misdiagnosed as adenocarcinoma in Thinprep cytology test. AB - Large cell neuroendocrine carcinoma (LCNEC) of uterine cervix is a rare malignancy with aggressive behavior and poor clinical outcome even in its early stage. Few cytopathologic features of cervical LCNEC have been reported previously. A 57-year-old postmenopausal African American female, presented to the local health department with a chief complaint of heavy vaginal bleeding. A 45-year-old female presented with 20 months of vaginal pruritus and foul odor. Cervical malignancy was suspected by pelvis magnetic resonance imaging. Thinprep cytology test demonstrated ball-like tumor cell clusters in a necrotic background. Cytologic diagnosis of adenocarcinoma was rendered. However, the histologic and immunohistochemical examination of cervical biopsy revealed the LCNEC of the uterine cervix. Due to its rarity, LCNEC may pose a diagnostic challenge in cervical cytology. Cytopathologists should pay attention to the cytological features of cervical LCNEC, such as rosettoid pattern, nuclear molding, and thin nuclear membrane for differentiation from other mimics. PMID- 29259655 TI - Continuation with clozapine after eosinophilia: a case report. AB - Background: Clozapine-induced eosinophilia had been reported in several studies about blood dyscrasias in clozapine-treated patient. The largest study with 2404 patients in Italy found the incidence of 2.2% by criteria of more than 0.4 * 109/l. Associated cases of pancreatitis, hepatitis, colitis, nephritis, and myocarditis were reported. Interestingly, incidence of myocarditis is high in Australia, but low in the rest of the world. In the following, we will present a case of clozapine-induced eosinophilia which spontaneous resolution was noted under continuation of clozapine. Case presentation: "Mr. L" was a 54-year-old single, jobless man. He had treatment-resistant chronic schizophrenia with onset at age 28. He had received electroconvulsive therapy twice prior to this admission. After admission, a trial of clozapine was started with an initial dose of 100 mg/day, and gradually titrated to 200 mg/day. He experienced notable improvement after 2 weeks with decreased auditory hallucinations and no more self harm behaviors, but he also developed eosinophilia. A medical workup was performed and showed no signs of end-organ inflammation. We continued clozapine use and closely monitored complete blood count with a differential test to track his eosinophil count by the recommendation of the hematology service. His eosinophil count decreased then and remained within normal limits 3 weeks later. The dosage of clozapine was gradually raised as high as 400 mg/day. His psychotic symptoms got partial remission and continued to show no signs of end-organ inflammation at the time of discharge. Conclusions: The pathophysiology of clozapine-induced eosinophilia is still unknown, but resolution of eosinophilia despite ongoing clozapine treatment suggests the possibility of an acute allergic reaction. Signs or symptoms of organ inflammation are important for management of eosinophilia. In this case report, we demonstrated that if eosinophilia occurred without signs or symptoms of organ inflammation, it may be justified to continue clozapine use under careful monitoring. PMID- 29259656 TI - Psycho-oncology in Australia: a descriptive review. AB - Australia has a thriving Psycho-Oncology research and clinical community. In this article, the Australian health system in which Psycho-Oncology is embedded is described. Clinical Psycho-Oncology services are outlined, in terms of their composition, processes and reach. The development of the internationally ground breaking Australian Psychosocial guidelines for the care of adults with cancer is described. Two large Psycho-Oncology organisations which are strongly linked to mainstream Oncology organisations are discussed: the Australian Psycho-Oncology Society (OzPos, a primarily clinician-led and focused organisation) and the Psycho-Oncology Co-operative Research Group (PoCoG, a national cancer clinical trial group). OzPos is a special interest group within the Clinical Oncology Society of Australia, while PoCoG is one of 14 cancer clinical trial groups funded by the national government. It is these strong connections with major multidisciplinary cancer organisations, and a culture of collaboration and co operation, that have made Psycho-Oncology grow and thrive in Australia. Examples of large collaborative programs of Psycho-Oncology research are provided, as well as the mechanisms used to achieve these outcomes. PMID- 29259657 TI - The 10th anniversary of patient safety in surgery. PMID- 29259658 TI - Type 1 diabetes does not impair the physical capacity of non-sedentary adolescents. AB - Background: Type 1 diabetes patients have a higher risk of developing hypoglycemia or hyperglycemia during physical activity, which may compromise their safety during exercise but results regarding the exercise capacity of patients with type 1 DM when compared to control subjects have been contradictory. Aim: To evaluate if type 1 diabetes affects the capacity of adolescents to exercise. Methods: The study enrolled 37 adolescents in stage 2-4 of the Tanner scale, aged from 10 to 14 years, 21 with type 1 diabetes and 16 without any chronic diseases. All subjects performed an incremental submaximal exercise test in a cycle ergometer. At the end of every test stage, glycemia and blood lactate levels were measured. During the test, heart rate was monitored and the Borg rating of perceived exertion (RPE) was used to assess fatigue. Results: The two groups displayed no significant differences in anthropometric variables. The response to exercise, as evaluated by Borg RPE (p = 0.829), maximum oxygen uptake (VO2max) (p = 0.977), heart rate (p = 0.998), maximum load (p = 0.977), absolute load at lactate threshold (p = 0.377) and relative load at lactate threshold (p = 0.282), was also similar between the control and the type 1 diabetes group. Finally, there were no significant correlations between HbA1c levels, VO2max, duration of disease and pre-test glycemia levels. Conclusions: We detected no significant differences in lactate threshold, VO2max and heart rate during exercise between healthy adolescents and non-sedentary adolescents with type I diabetes, indicating that both groups had similar physical fitness and, therefore, that type 1 diabetes is not an obstacle for physical activity. This study was approved by the ethical committee of the Hospital Israelita Albert Einstein (Ethical Committee Number: 53638416.9.0000.0071) and free and informed consent was obtained from all participants and their legal representatives. PMID- 29259660 TI - Postoperative narrow complex tachycardia presenting with low cardiac output. PMID- 29259659 TI - Pregnancy-related conditions and premature coronary heart disease in adult offspring. AB - Objective: To investigate the association between complications during pregnancy and premature coronary heart disease in adult offspring. Methods: We conducted a population-based case-control study of 153 Indonesian patients with a first acute coronary syndrome (ACS) (age <=55 years) and 153 age-matched and sex-matched controls. Data on complications during pregnancy (high blood pressure, preterm delivery) and maternal infections in pregnancy were obtained, together with sociodemographic data, clinical profiles, laboratory measurements and adulthood cardiovascular disease (CVD) risk factors at hospital admission or enrolment. Conditional logistic regression was performed to assess the association between overall pregnancy complications, and specific groupings of complications and premature ACS. Results: Pregnancy-related hypertension and infection were more common in mothers of cases than controls. Pregnancy complications were associated with premature offspring ACS (OR 2.9, 95% CI 1.4 to 6.0, p=0.004), and the association persisted in fully adjusted analyses (ORadjusted 4.5, 1.1 to 18.1, p=0.036). In subgroup analyses, pregnancy-related high blood pressure (ORadjusted 5.0, 1.0 to 24.7, p=0.050) and maternal infections (ORadjusted 5.2, 1.1 to 24.2, p=0.035) were associated with offspring ACS. Conclusions: Offspring of mothers with complications during pregnancy have an increased risk for premature ACS in adulthood, which may be of particular relevance in populations in transition, where the incidence of both pregnancy-related morbidity and CVD are high. PMID- 29259661 TI - Synthesis and supramolecular properties of regioisomers of mononaphthylallyl derivatives of gamma-cyclodextrin. AB - Monosubstituted derivatives of gamma-cyclodextrin (gamma-CD) are suitable building blocks for supramolecular polymers, and can also serve as precursors for the synthesis of other regioselectively monosubstituted gamma-CD derivatives. We prepared a set of monosubstituted 2I-O-, 3I-O-, and 6I-O-(3-(naphthalen-2-yl)prop 2-en-1-yl) derivatives of gamma-CD using two different methods. A key step of the first synthetic procedure is a cross-metathesis between previously described regioisomers of mono-O-allyl derivatives of gamma-CD and 2-vinylnaphthalene which gives yields of about 16-25% (2-5% starting from gamma-CD). To increase the overall yields, we have developed another method, based on a direct alkylation of gamma-CD with 3-(naphthalen-2-yl)allyl chloride as the alkylating reagent. Highly regioselective reaction conditions, which differ for each regioisomer in a used base, gave the monosubstituted isomers in yields between 12-19%. Supramolecular properties of these derivatives were studied by DLS, ITC, NMR, and Cryo-TEM. PMID- 29259662 TI - Pyrene-nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies. AB - Fluorescent pyrene-linker-nucleobase (nucleobase = thymine, adenine) conjugates with carbonyl and hydroxy functionalities in the linker were synthesized and characterized. X-ray single-crystal structure analysis performed for the pyrene C(O)CH2CH2-thymine (2) conjugate reveals dimers of molecules 2 stabilized by hydrogen bonds between the thymine moieties. The photochemical characterization showed structure-dependent fluorescence properties of the investigated compounds. The conjugates bearing a carbonyl function represent weak emitters as compared to compounds with a hydroxy function in the linker. The self-assembly properties of pyrene nucleobases were investigated in respect to their binding to single and double strand oligonucleotides in water and in buffer solution. In respect to the complementary oligothymidine T10 template in water, compounds 3 and 5 both show a self-assembling behavior according to canonical base-base pairing. However, in buffer solution, derivative 5 was much more effective than 3 in binding to the T10 template. Furthermore the adenine derivative 5 binds to the double-stranded (dA)10-T10 template with a self-assembly ratio of 112%. Such a high value of a self-assembly ratio can be rationalized by a triple-helix-like binding, intercalation, or a mixture of both. Remarkably, compound 5 also shows dual staining pattern in living HeLa cells. Confocal microscopy confirmed that 5 predominantly stains mitochondria but it also accumulates in the nucleoli of the cells. PMID- 29259663 TI - 15N-Labelling and structure determination of adamantylated azolo-azines in solution. AB - Determining the accurate chemical structures of synthesized compounds is essential for biomedical studies and computer-assisted drug design. The unequivocal determination of N-adamantylation or N-arylation site(s) in nitrogen rich heterocycles, characterized by a low density of hydrogen atoms, using NMR methods at natural isotopic abundance is difficult. In these compounds, the heterocyclic moiety is covalently attached to the carbon atom of the substituent group that has no bound hydrogen atoms, and the connection between the two moieties of the compound cannot always be established via conventional 1H-1H and 1H-13C NMR correlation experiments (COSY and HMBC, respectively) or nuclear Overhauser effect spectroscopy (NOESY or ROESY). The selective incorporation of 15N-labelled atoms in different positions of the heterocyclic core allowed for the use of 1H-15N (JHN) and 13C-15N (JCN) coupling constants for the structure determinations of N-alkylated nitrogen-containing heterocycles in solution. This method was tested on the N-adamantylated products in a series of azolo-1,2,4 triazines and 1,2,4-triazolo[1,5-a]pyrimidine. The syntheses of adamantylated azolo-azines were based on the interactions of azolo-azines and 1-adamatanol in TFA solution. For azolo-1,2,4-triazinones, the formation of mixtures of N adamantyl derivatives was observed. The JHN and JCN values were measured using amplitude-modulated 1D 1H spin-echo experiments with the selective inversion of the 15N nuclei and line-shape analysis in the 1D 13S spectra acquired with selective 15N decoupling, respectively. Additional spin-spin interactions were detected in the 15N-HMBC spectra. NMR data and DFT (density functional theory) calculations permitted to suggest a possible mechanism of isomerization for the adamantylated products of the azolo-1,2,4-triazines. The combined analysis of the JHN and JCN couplings in 15N-labelled compounds provides an efficient method for the structure determination of N-alkylated azolo-azines even in the case of isomer formation. The isomerization of adamantylated tetrazolo[1,5 b][1,2,4]triazin-7-ones in acidic conditions occurs through the formation of the adamantyl cation. PMID- 29259664 TI - A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic. AB - An assembled suite of flow-based transformations have been used to rapidly scale up the production of a novel auxin mimic-based herbicide which was required for preliminary field trials. The overall synthetic approach and optimisation studies are described along with a full description of the final reactor configurations employed for the synthesis as well as the downstream processing of the reaction streams. PMID- 29259665 TI - A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC-HRMS monitoring of the reaction pathway. AB - The novel cascade two-stage reaction between itaconimides and 1,2-diamino-4 phenylimidazole proceeds regio- and chemoselectively to form tetrahydroimidazo[1,5-b]pyridazines and includes nucleophilic C-addition by the activated C=C double bond and subsequent intramolecular recyclization of the intermediate with the amino group involved. PMID- 29259666 TI - Rh(II)-mediated domino [4 + 1]-annulation of alpha-cyanothioacetamides using diazoesters: A new entry for the synthesis of multisubstituted thiophenes. AB - A new approach towards the synthesis of multisubstituted thiophenes is elaborated based on Rh(II)-catalyzed domino reactions of acyclic diazoesters with alpha cyanothioacetamides. It provides a way for the preparation of 5-amino-3 (alkoxycarbonylamino)thiophene-2-carboxylates, 2-(5-amino-2 methoxycarbonylthiophene-3-yl)aminomalonates and (2-cyano-5-aminothiophene-3 yl)carbamates with the preparative yields of up to 67%. It was also shown that alpha-cyanothioacetamides easily interact with dirhodium carboxylates to give rather stable 2:1 complexes, resulting in an evident decrease in the efficiency of the catalytic process at moderate temperatures (20-30 degrees C). PMID- 29259667 TI - Synthesis of 1,3-cis-disubstituted sterically encumbered imidazolidinone organocatalysts. AB - A variety of novel imidazolidinone-based organocatalysts with bulky substituents were synthesized under mild reaction conditions starting from easily accessible substrates. Different natural and unnatural amino acid methyl amides were cyclized with aromatic carbaldehydes to yield two diastereomeric MacMillan-type catalysts. Special emphasis was put on bulky residues such as mesityl and pyrene moieties. PMID- 29259669 TI - Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles. AB - Isocyanide-based multicomponent reactions (IMCRs) allow the construction of relatively complex molecules through a one-pot synthesis. The combination of IMCRs in a consecutive or sequential fashion further extends the complexity of the molecules obtained. Herein, we report the efficient application of this approach to the synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles. Our strategy was accomplished in only three steps: first, a one-pot hydrazino-Ugi azide four-component reaction; second a hydrazinolysis and finally an additional hydrazino-Ugi-azide reaction. This sequence provides the title compounds in moderate to excellent yields. The products synthesized herein contain functional groups within their structures that can be easily modified to obtain new acylhydrazino 1,5-disubstituted tetrazoles. PMID- 29259668 TI - What contributes to an effective mannose recognition domain? AB - In general, carbohydrate-lectin interactions are characterized by high specificity but also low affinity. The main reason for the low affinities are desolvation costs, due to the numerous hydroxy groups present on the ligand, together with the typically polar surface of the binding sites. Nonetheless, nature has evolved strategies to overcome this hurdle, most prominently in relation to carbohydrate-lectin interactions of the innate immune system but also in bacterial adhesion, a process key for the bacterium's survival. In an effort to better understand the particular characteristics, which contribute to a successful carbohydrate recognition domain, the mannose-binding sites of six C type lectins and of three bacterial adhesins were analyzed. One important finding is that the high enthalpic penalties caused by desolvation can only be compensated for by the number and quality of hydrogen bonds formed by each of the polar hydroxy groups engaged in the binding process. In addition, since mammalian mannose-binding sites are in general flat and solvent exposed, the half-lives of carbohydrate-lectin complexes are rather short since water molecules can easily access and displace the ligand from the binding site. In contrast, the bacterial lectin FimH benefits from a deep mannose-binding site, leading to a substantial improvement in the off-rate. Together with both a catch-bond mechanism (i.e., improvement of affinity under shear stress) and multivalency, two methods commonly utilized by pathogens, the affinity of the carbohydrate-FimH interaction can be further improved. Including those just described, the various approaches explored by nature to optimize selectivity and affinity of carbohydrate-lectin interactions offer interesting therapeutic perspectives for the development of carbohydrate-based drugs. PMID- 29259670 TI - A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone. AB - Spinetoram, a mixture of 3'-O-ethyl-5,6-dihydrospinosyn J (XDE-175-J, major component) and 3'-O-ethylspinosyn L (XDE-175-L, minor component), is a novel kind of green and efficient insecticide with a broad range of action against various insects. Nowadays, spinetoram is widely used in agriculture and food storage. This work reports a 7-step semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J from spinosyn A aglycone. The C9-OH and C17-OH of the aglycone are successively connected to 3-O-ethyl-2,4-di-O-methylrhamnose and D-forosamine after selective protection and deprotection steps. Then, with 10% Pd/C as catalyst, the 5,6 double bond of the macrolide was selectively reduced to afford 3'-O-ethyl-5,6 dihydrospinosyn J. In addition, the 3-O-ethyl-2,4-di-O-methylrhamnose is synthesized from rhamnose which is available commercially, while the D-forosamine and aglycone are obtained via the hydrolysis of spinosyn A. High yields were obtained in each step, and all intermediates in the synthesis were characterized by 1H NMR, 13C NMR and MS techniques. This study can be helpful for developing an efficient chemical synthesis of spinetoram, and it also offers opportunities to synthesize spinosyn analogues and rhamnose derivatives. PMID- 29259671 TI - Palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides. AB - An efficient palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides has been developed. The reaction proceeds under mild reaction conditions with high efficiency and excellent functional group tolerance, even towards formyl and hydroxy groups. Preliminary mechanistic studies reveal that a secondary trifluoromethylated alkyl radical is involved in the reaction. PMID- 29259672 TI - Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones. AB - Background: Due to the high reactivity towards various C-nucleophiles, trifluoromethylketimines are known to be useful reagents for the synthesis of alpha-trifluoromethylated amine derivatives. However, decarboxylative reactions with malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to beta-trifluoromethyl-beta amino acid derivatives and to their partially saturated heterocyclic analogues. Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones, unique heterocyclic ketimines, react with malonic acid under organic base catalysis to regioselectively provide either Michael- or Mannich-type decarboxylative addition products depending on solvent polarity. Malonic mono(thio)esters give exclusively Michael-type products. The two regioisomeric products can be converted into saturated (2-oxohexahydropyrimidin-4-yl)acetic acid derivatives by mild hydrogenation of the endocyclic C=C double bond in the presence of Pd/C as catalyst. The cis-stereoisomers selectively formed upon reduction of the Michael type products were structurally determined by X-ray diffraction. As a result of this study, a number of novel acetic acid derivatives containing trifluoromethylated, partially or fully saturated 2-oxopyrimidine cores were prepared and characterized as promising building blocks. Conclusions: Regio- and stereoselective protocols have been developed for the synthesis of novel isomeric 4(6)-trifluoromethylated 1,2,3,4-tetrahydro- and perhydro-(2-oxopyrimidin-4 yl)acetic acid derivatives. PMID- 29259673 TI - Electrophilic trifluoromethylselenolation of terminal alkynes with Se (trifluoromethyl) 4-methylbenzenesulfonoselenoate. AB - Herein the nucleophilic addition of Se-(trifluoromethyl) 4 methylbenzenesulfonoselenoate, a stable and easy-to-handle reagent, to alkynes is described. This reaction provides trifluoromethylselenylated vinyl sulfones with good results and the method was extended also to higher fluorinated homologs. The obtained compounds are valuable building blocks for further syntheses of fluoroalkylselenolated molecules. PMID- 29259675 TI - Retinal regeneration by transplantation of retinal tissue derived from human embryonic or induced pluripotent stem cells. AB - Rodent studies have recently demonstrated substantial integration of transplanted photoreceptors, with potential synaptic connection and functional restoration. Consequently, photoreceptor transplantation therapy for retinitis pigmentosa is attracting a growing interest in the field of translational research. Differentiation strategies for the formation of three-dimensional (3D) retinal tissue that are suitable for graft preparation have also been introduced via the use of human embryonic stem cells (hESCs) and human induced pluripotent stem cells. We have recently shown that hESC-derived retinal tissue (hESC-retina) can survive, mature, and potentially integrate with host secondary neurons following transplantation into two established primate models of retinal degeneration. Our data demonstrated the feasibility of deploying hESC-retina transplantation as a new remedy with which to restore the vision of patients with end-stage retinal degenerative diseases. In the present mini-review, we provide a short introduction of photoreceptor transplantation research. PMID- 29259674 TI - Roles of hepatic stellate cells in liver inflammation: a new perspective. AB - Connected with the intestinal tract through the portal circulation, liver sinusoids function as the first line of defense against extrahepatic stimuli such as bacterial products and other toxic substances. Hepatic stellate cells (HSCs) are pericytes residing in the perisinusoidal space, between sinusoidal endothelial cells and hepatocytes, store vitamin A, and regulate sinusoidal circulation. Following chronic hepatitis, HSCs actively produce extracellular matrices and cause liver fibrosis. In spite of their close position to the liver sinusoids, however, whether HSCs contribute to liver inflammation has remained elusive. Evidence now accumulates to suggest that HSCs actively take part in the regulation of various forms of liver inflammation. Upon inflammatory stimuli from the sinusoids, HSCs produce various inflammatory molecules and interact with other liver cells, thereby recruiting and then activating infiltrating leukocytes and ultimately causing hepatocyte death. On the other hand, HSCs also exert hepatoprotective effects through inhibition of cytokine and chemokine production or induction of immunosuppressive cell population. HSCs therefore integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma, either amplifying liver inflammation or suppressing parenchymal damage through immunoregulatory signaling depending on the context. PMID- 29259676 TI - A new era for Inflammation and Regeneration. PMID- 29259677 TI - Joint-preserving regenerative therapy for patients with early-stage osteonecrosis of the femoral head. AB - Osteonecrosis of the femoral head is an intractable disease often occurring in patients aged 30-40 years that can cause femoral head collapse, pain, and gait disturbance. Background factors, including corticosteroid use, alcohol intake, and idiopathic causes, have been indicated. It is estimated that 70-80 % of osteonecrosis patients experience femoral head collapse, for which total hip arthroplasty is considered the most effective treatment, even in young patients. Thus, there is a crucial need for developing a minimally invasive regenerative therapy as a preventive surgery for femoral head collapse: this has been an important area of research in the past decades. Core decompression, the most popular minimally invasive surgery for osteonecrosis of the femoral head, has been used for a long time; however, it has been insufficient to prevent femoral head collapse. For further improvement in therapeutic efficacy, cell transplantation and the use of artificial bone and growth factors have been proposed in addition to core decompression. Since 2000, newer therapies such as autologous bone marrow cell transplantation and the embedding of metal implant rods have been developed in Europe and the USA; however, these approaches have yet to become a global standard. This practical review summarizes applied state of-the-art regenerative therapy-based core decompression. We introduce the clinical application of recombinant human fibroblast growth factor (rhFGF)-2 impregnated gelatin hydrogel for patients with precollapse osteonecrosis of the femoral head. Radiography and computed tomography have confirmed bone regeneration inside the femoral heads around the region of rhFGF-2 gelatin hydrogel administration. With further development, the minimally invasive method, which can be expected to promote bone regeneration in necrotic areas, could become a useful early-stage treatment for osteonecrosis of the femoral head. Patients can resume their daily routine soon after surgery, and the procedure is inexpensive. As such, it is a promising regenerative therapy that can be actively employed in osteonecrosis of the femoral head before femoral head collapse. PMID- 29259678 TI - Usefulness of nailfold videocapillaroscopy for systemic sclerosis. AB - Systemic sclerosis is a complex disease that involves "autoimmunity," "inflammation," "fibrosis," and "vasculopathy." Microvascular damage and dysfunction particularly represent the earliest morphological and functional markers of systemic sclerosis. These morphological changes and progressions can be detected by nailfold videocapillaroscopy (NVC). In 2013, the American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) proposed a new set of criteria for systemic sclerosis for the first time in 30 years. Items are given a weighted score, and a score more than 9 indicates systemic sclerosis. These classification criteria encompass a broader spectrum of systemic sclerosis patients including those with early stage and with excellent sensitivity and specificity. Notably, nailfold capillary abnormalities were one of the new items in the criteria. Moreover, these abnormalities are also markers of systemic sclerosis severity and progression, as reduced capillary density has been associated with a high risk of developing digital skin ulcers and pulmonary arterial hypertension. Since microvascular damage and dysfunction represent early markers of systemic sclerosis, qualitative and semi-quantitative assessment of videocapillaroscopy images is expected in clinical application and treatment outcome assessment. Despite the potential for targeted therapies in systemic sclerosis, there is no established therapy as yet. This may be due to several reasons. First, no fully validated outcome measures exist. Second, diagnosis of systemic sclerosis is often delayed and early intervention is difficult. Moreover, systemic sclerosis has clinical heterogeneity. Appropriate use of NVC helps to overcome these issues. Moreover, NVC may be useful in evaluating the pathogenesis of systemic sclerosis. PMID- 29259679 TI - BAFF- and APRIL-targeted therapy in systemic autoimmune diseases. AB - B cells play a pivotal role in autoimmunity not only by producing pathogenic autoantibodies but also by modulating immune responses via the production of cytokines and chemokines. The B cell-activating factor/a proliferation-inducing ligand (BAFF/APRIL) system promotes B cell survival and differentiation and thus plays a prominent role in the pathogenesis of autoimmune diseases. Currently, BAFF and APRIL inhibitors are in clinical trials for systemic lupus erythematosus with significant efficacy. However, several studies have demonstrated the efficacy of the BAFF/APRIL blockade which showed considerable variability in the response to B cell-targeted therapy. This may indicate substantial heterogeneity in the pathogenesis of autoimmune diseases. Therefore, objective markers that can predict the effect of BAFF/APRIL-blocking agents could be valuable to the precision medicine linked clinically and to cost-effective therapy. PMID- 29259682 TI - Therapeutic intervention of inflammatory/immune diseases by inhibition of the fractalkine (CX3CL1)-CX3CR1 pathway. AB - Inflammatory and immune responses are generated locally by the selective invasion and accumulation of the immune cells into the lesion site. The infiltration process of the immune cells into the tissue from the blood through the vascular endothelial cells is closely regulated by a number of chemotactic factors and cell adhesion molecules. Fractalkine (FKN)/CX3CL1 is a membrane-bound chemokine possessing a chemokine/mucin hybrid structure and a transmembrane domain and has a dual function as an adhesion molecule and a chemoattractant. FKN is mainly expressed on activated endothelial cells, activated fibroblasts, and osteoblasts. Its receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, monocytes/macrophages, and osteoclasts. To date, a lot of key functional aspects of the FKN-CX3CR1 axis has been identified: (1) the rapid capture and firm adhesion of immune cells to vascular endothelial cells, (2) chemotaxis, (3) the enhancement of the transmigration to other chemokines, (4) the crawling behavior of the monocytes that patrol on vascular endothelial cells, (5) the retention of monocytes as the accessory cells of the inflamed endothelium to recruit inflammatory cells, and (6) the survival of the macrophage. In this review, we will focus on the pathological role of FKN in rheumatoid arthritis (RA) and the physiological role of FKN on osteoclast differentiation. Furthermore, we will discuss the therapeutic potential of anti-FKN mAb for RA patients and its distinct mode of action from other cytokine inhibitors. PMID- 29259680 TI - Metabolic regulation by secreted phospholipase A2. AB - Within the phospholipase A2 (PLA2) superfamily that hydrolyzes phospholipids to yield fatty acids and lysophospholipids, the secreted PLA2 (sPLA2) enzymes comprise the largest family that contains 11 isoforms in mammals. Individual sPLA2s exhibit unique distributions and specific enzymatic properties, suggesting their distinct biological roles. While sPLA2s have long been implicated in inflammation and atherosclerosis, it has become evident that they are involved in diverse biological events through lipid mediator-dependent or mediator independent processes in a given microenvironment. In recent years, new biological aspects of sPLA2s have been revealed using their transgenic and knockout mouse models in combination with mass spectrometric lipidomics to unveil their target substrates and products in vivo. In this review, we summarize our current knowledge of the roles of sPLA2s in metabolic disorders including obesity, hepatic steatosis, diabetes, insulin resistance, and adipose tissue inflammation. PMID- 29259681 TI - GM-CSF as a therapeutic target in autoimmune diseases. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been known as a hematopoietic growth factor and immune modulator. Recent studies revealed that GM CSF also had pro-inflammatory functions and contributed to the pathogenicity of Th17 cells in the development of Th17-mediated autoimmune diseases. GM-CSF inhibition in some animal models of autoimmune diseases showed significant beneficial effects. Therefore, several agents targeting GM-CSF are being developed and are expected to be a useful strategy for the treatment of autoimmune diseases. Particularly, in clinical trials for rheumatoid arthritis (RA) patients, GM-CSF inhibition showed rapid and significant efficacy with no serious side effects. This article summarizes recent findings of GM-CSF and information of clinical trials targeting GM-CSF in autoimmune diseases. PMID- 29259683 TI - RANKL system in vascular and valve calcification with aging. AB - Vascular and cardiac valve calcification is associated with cardiovascular mortality in the general population. Increasing clinical and experimental evidence suggests that inflammation accelerates the progression of calcification, which has molecules in common with bone metabolism. For example, osteopontin (OPN), osteoprotegerin (OPG), receptor activator of the nuclear factor kappaB ligand (RANKL), and alkaline phosphatase (ALP) are proposed to play central roles in the calcification or demineralization of atherosclerotic lesions and the calcification of cardiac valves. Abnormalities in the balance of these proteins may lead to perturbations in vascular/valve calcification. "How to prevent calcification" is a common task based on conventional data; however, several pathological findings indicate that heavily calcified plaques are stable, which may not lead to coronary events. Vulnerable plaques tend to be either noncalcified or only mildly or moderately calcified. "How to treat calcification," which depends on the details of the specific patient, thus remains a difficult challenge. In addition to the detection of calcification, characterization as well as quantification of it is necessary for optimal treatment of this pathology in the future. PMID- 29259684 TI - Complement-targeted therapy: development of C5- and C5a-targeted inhibition. AB - The complement system is a major effector of humoral immunity and natural immunity. The complement system has three independent pathways of complement activation: a classical pathway, an alternative pathway, and a lectin pathway. These pathways converge to a common pathway that activates C3. This pathway also leads to the formation of various bioactive molecules such as C5a and the formation of membrane attack complex on the surface of target cells. In the past, the only preparations with anti-complementary action were C1 inhibitors (C1-INH), but an anti-C5 monoclonal antibody (eculizumab) appeared a few years ago, and this antibody has yielded encouraging results. In addition, a C5a receptor (C5aR) antagonist is in the clinical trial phase, and this antagonist should also prove efficacious. Anti-complement agents have garnered attention as a new treatment strategy for refractory inflammatory diseases. PMID- 29259685 TI - Roles of renin-angiotensin system and Wnt pathway in aging-related phenotypes. AB - The renin-angiotensin system (RAS) regulates diverse cellular responses and is crucial for normal organ development and function. On the other hand, RAS exerts deleterious effects promoting cardiovascular and multiple organ damage and contributes to promoting various aging-related diseases and aging-related decline in multiple organ functions. RAS blockade has been shown to prevent the progression of aging-related phenotypes and promote longevity. Wnt signaling pathway also plays a major role in the regulation of mammalian pathophysiology and is essential for organismal survival, and furthermore, it is substantially involved in the promotion of aging process. In this way, both RAS signaling and Wnt signaling have the functions of antagonistic pleiotropy during the process of growth and aging. Our recent study has demonstrated that an anti-aging effect of RAS blockade is associated with down-regulation of canonical Wnt signaling pathway, providing evidence for the hierarchical relationship between RAS signaling and Wnt signaling in promoting aging-related phenotypes. Here, we review how RAS signaling and Wnt signaling regulate the aging process and promote aging-related diseases. PMID- 29259686 TI - Dysfunctional immunoproteasomes in autoinflammatory diseases. AB - Recent progress in DNA sequencing technology has made it possible to identify specific genetic mutations in familial disorders. For example, autoinflammatory syndromes are caused by mutations in gene coding for immunoproteasomes. These diseases include Japanese autoinflammatory syndrome with lipodystrophy, Nakajo Nishimura syndrome, joint contractures, muscular atrophy, microcytic anemia, panniculitis-associated lipodystrophy syndrome, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. Causal mutations of these syndromes are present in gene coding for subunits of the immunoproteasome. Importantly, a genetically modified mouse that lacks the catalytic subunit of immunoproteasomes does not always develop an autoinflammatory syndrome. Analysis of causal gene mutations, assessment of patients' phenotypic changes, and appropriate animal models will be indispensable for clarifying the underlying mechanisms responsible for the development of autoinflammatory syndromes and establishing curative approaches. PMID- 29259687 TI - Inflammatory predisposition predicts disease phenotypes in muscular dystrophy. AB - Duchenne muscular dystrophy is an incurable genetic disease that presents with skeletal muscle weakness and chronic inflammation and is associated with early mortality. Indeed, immune cell infiltration into the skeletal muscle is a notable feature of the disease pathophysiology and is strongly associated with disease severity. Interleukin (IL)-10 regulates inflammatory immune responses by reducing both M1 macrophage activation and the production of pro-inflammatory cytokines, thereby promoting the activation of the M2 macrophage phenotype. We previously reported that genetic ablation of IL-10 in dystrophic mice resulted in more severe phenotypes, in regard to heart and respiratory function, as evidenced by increased macrophage infiltration, high levels of inflammatory factors in the muscle, and progressive cardiorespiratory dysfunction. These data therefore indicate that IL-10 comprises an essential immune-modulator within dystrophic muscles. In this review, we highlight the pivotal role of the immune system in the pathogenesis of muscular dystrophy and discuss how an increased understanding of the pathogenesis of this disease may lead to novel therapeutic strategies. PMID- 29259688 TI - Inflammatory responses in the initiation of lung repair and regeneration: their role in stimulating lung resident stem cells. AB - The lungs are the primary organs for respiration, the process by which carbon dioxide and oxygen are exchanged. The alveolus, which is the site of gas exchange in the lungs, consists of multiple cell types including alveolar epithelial cells, lung capillary endothelial cells and fibroblasts. Because of their complexity, lung parenchymal cells including epithelial lineage have been thought to have a lower rate of cellular turnover in adult lung. However, accumulating observations suggest that the turnover of parenchymal cells in adult lungs is essential for maintaining homeostasis during the steady state as well as for the repair and regeneration after lung injury. After lung injury by harmful pathogens, inflammation occurs to protect the host. Although excessive inflammation damages lung tissue, inflammatory cells are essential for regeneration because they remove harmful pathogens as well as debris derived from apoptotic and necrotic cells. In addition, subsets of inflammatory cells, especially phagocytic monocytes, produce cytokines and growth factors to resolve inflammation and promote tissue regeneration by stimulating tissue-resident stem cells. Recent advances in the biology of lung-resident stem cells, especially those addressing epithelial lineage, have revealed that there are several cellular populations capable of self-renewal that can differentiate into airway and/or alveolar epithelial cells. A part of these populations does not exist in the steady state but emerges after lung injury, suggesting that signals induced by inflammation may play an important role in initiating the proliferation and differentiation of lung stem or progenitor cells. Understanding the interaction between inflammatory responses and tissue-resident stem cells would help elucidate the pathogenesis of inflammatory lung diseases and promote the discovery of new therapeutic targets. PMID- 29259689 TI - The pathological role of vascular aging in cardio-metabolic disorder. AB - Chronological aging is linked to cellular senescence, and there is accumulating evidence for a pathological role of cellular senescence in age-related disorders such as obesity, diabetes, and heart failure. The protein p53 has a central role in cellular senescence, and p53 expression in cardiomyocytes, vascular endothelial cells, adipocytes, and immune cells leads to the development of heart failure and diabetes. It is widely accepted that formation of capillary networks is critical for morphogenesis of organs and maintenance of homeostasis. Capillary rarefaction and hypoxia promote pathological changes in the myocardium of the failing heart, causing systolic dysfunction. Capillary rarefaction and hypoxia also cause dysfunction of brown adipose tissue (BAT), leading to systemic metabolic disorders with promotion of diabetes. Vascular endothelial cell senescence develops in heart failure and diabetes and is responsible for progression of these age-related disorders. In a murine model of left ventricular pressure overload, increased expression of p53 in vascular endothelial cells and bone marrow cells promotes inflammatory cell infiltration into the heart, contributing to cardiac remodeling and systolic dysfunction. Metabolic stress up regulates p53 expression in endothelial cells, while reducing the phosphorylation of endothelial nitric oxide synthase (eNOS) and glucose transporter (GLUT)1 expression in these cells. These changes lead to suppression of mitochondrial biogenesis and glucose uptake in the skeletal muscle and promote the development of systemic metabolic dysfunction. Suppression of vascular aging and vascular dysfunction is critically important for maintenance of organ homeostasis and is essential for prevention or treatment of heart failure, obesity, and diabetes. PMID- 29259691 TI - Inflammation and regeneration in cross-organs. PMID- 29259690 TI - Age-related sarcopenia and its pathophysiological bases. AB - Age-related loss of the skeletal muscle and its function is known as sarcopenia. Definition and diagnostic criteria for sarcopenia have been outlined as consensus statements from several study groups, including usual gait speed, grip strength, and skeletal muscle mass. Whereas underlying mechanisms and pathophysiology of sarcopenia remains to be clarified, recent studies have suggested that chronic inflammatory status as well as lifestyle-related factors in older individuals might contribute to the process and progress of sarcopenia. PMID- 29259692 TI - Liver regeneration and fibrosis after inflammation. AB - The liver is a unique organ with an extraordinary capacity to regenerate upon various injuries. In acute and transient liver injury by insults such as chemical hepatotoxins, the liver in rodents returns to the original architecture by proliferation and remodeling of the remaining cells within a week. In contrast, chronic liver inflammation due to various etiologies, e.g., virus infection and metabolic and immune disorders, results in liver fibrosis, often leading to cirrhosis and carcinogenesis. In both acute and chronic inflammation, a variety of immune and non-immune cells in the liver is involved in the processes resulting in either regeneration or fibrosis. In addition, chronic hepatitis often accompanies proliferation of atypical biliary cells, also known as liver progenitor cells or oval cells. Although the origin of liver progenitor cells and its contribution to hepatic repair is still under intense debate, recent studies have revealed a regulatory role for immune cells in progenitor proliferation and differentiation. In this review, we summarize recent studies on liver regeneration and fibrosis in the viewpoint of inflammation. PMID- 29259693 TI - The pathophysiological role of acute inflammation after spinal cord injury. AB - Traumatic spinal cord injury (SCI) causes irreparable severe motor and sensory dysfunction. Mechanical trauma rapidly leads to blood-spinal cord barrier disruption, neural cell death, axonal damage, and demyelination, followed by a cascade of secondary injury that expands the additional inflammatory reaction at the lesion site. Although the role of inflammation in this phase is complex, a number of studies have suggested that inflammatory responses spread the damage to the surrounding tissue, induce apoptotic cell death, and impair spontaneous regeneration and functional recovery. However, recent advances in experimental technology, such as the depletion antibodies for a specific fraction of inflammatory cells and the genetically engineered mice deficient only in specific cells, suggest the beneficial aspects of inflammatory cells, such as a neuroprotective effect, the removal of cellular debris, and the attenuation of the inflammatory reaction in general. In this review, I summarize our recent findings about the biological role of inflammatory cells, especially infiltrating neutrophils and activated microglia after SCI. A better understanding of the pathophysiological role of inflammation in the acute phase of SCI will aid in the development of therapeutic strategy to enhance the functional recovery after SCI. PMID- 29259694 TI - Mycobacterium avium infection induces the resistance of the interferon-gamma response in mouse spleen cells at late stages of infection. AB - Background: Bacterial infections cause an increase in the population of hematopoietic stem cells (HSCs). To investigate the downstream factors associated with hematopoietic stem cells, mice are infected with Mycobacterium avium (M. avium). Results: Mycobacterium avium (M. avium) infection induces the enlargement of the spleen and changes in histopathology, including changes to the lineage populations. A dramatic expansion of Lin-c-kit+Sca-1+ (KSL) cells in mouse bone marrow cells and spleen cells was detected 4 weeks after infection with M. avium; however, there was no difference in the engraft activity between infected and un infected mouse bone marrow cells. We tested the cytokine and cytokine-related gene expression after M. avium infection and found that IFN-gamma expression increased and peaked at 4 weeks in both bone marrow and spleen cells. The expression of Sca-1 gene peaked at 4 weeks in the bone marrow but peaked at 2 weeks in spleen cells, although the Sca-1 surface marker peaked at 4 weeks after infection in both bone marrow and spleen cells. Interferon regulatory factor-2 (IRF-2) expression did not change in the bone marrow cells, whereas it decreased in spleen cells at 4 weeks and IRF-1 expression was up-regulated in both bone marrow and spleen cells after infection. However, the up-regulation of IRF-1 was not correlated with IFN-gamma expression in the M. avium-infected mouse spleen cells. Conclusions: This finding suggests that the IFN-gamma production mediated by M. avium infection alters the population of KSL cells during host defense, and the down-regulation of the IFN-gamma response in spleen cells occurs at the late stage after M. avium infection. PMID- 29259695 TI - Receptor-associated prorenin system contributes to development of inflammation and angiogenesis in proliferative diabetic retinopathy. AB - The renin-angiotensin system (RAS) plays a potential role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor of several diseases including diabetes. So far, using animal disease models, we have shown molecular mechanisms, in which tissue RAS stimulates retinal angiogenesis, and the critical roles of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction, referred to as the receptor-associated prorenin system (RAPS). Moreover, we recently reported that the protein levels of prorenin and soluble (P)RR increased in the vitreous fluids obtained from patients with proliferative diabetic retinopathy (PDR), suggesting the association of (P)RR with vascular endothelial growth factor (VEGF)-driven angiogenic activity in human PDR, and also showed a close relationship between the vitreous renin activity and VEGF-induced pathogenesis of diabetic retinopathy. Our data using animal disease models and human clinical samples suggest that both vitreous RAS and retinal RAPS play critical roles in the molecular pathogenesis of diabetic retinopathy. PMID- 29259696 TI - Heart regeneration for clinical application update 2016: from induced pluripotent stem cells to direct cardiac reprogramming. AB - Cardiovascular disease remains a major cause of death for which current therapeutic regimens are limited. Following myocardial injury, endogenous cardiac fibroblasts, which account for more than half of the cells in the heart, proliferate and synthesize extracellular matrix, leading to fibrosis and heart failure. As terminally differentiated cardiomyocytes have little regenerative capacity following injury, the development of cardiac regenerative therapy is highly desired. Embryonic stem and induced pluripotent stem (iPS) cells are promising tools for regenerative medicine. However, these stem cells demonstrate variable cardiac differentiation efficiency and tumorigenicity, which must be resolved prior to clinical regenerative applications. Until the last decade, an established theory was that cardiomyocytes could only be produced from fibroblasts through iPS cell generation. In 2010, we first reported cardiac differentiation from fibroblasts by direct reprogramming, and we demonstrated that various cardiac reprogramming pathways exist. This review summarizes the latest trends in stem cell and regenerative research regarding iPS cells, a partial reprogramming strategy, and direct cardiac reprogramming. We also examine the many recent advances in direct cardiac reprogramming and explore the suitable utilization of these methods for regenerative medicine in the cardiovascular field. PMID- 29259697 TI - Organ dysfunction as a new standard for defining sepsis. AB - Despite advances in intensive care and the widespread use of standardized care included in the Surviving Sepsis Campaign Guidelines, sepsis remains a leading cause of death, and the prevalence of sepsis increases concurrent with the aging process. The diagnosis of sepsis was originally based on the evidence of persistent bacteremia (septicemia) but was modified in 1992 to incorporate systemic inflammatory response syndrome (SIRS). Since then, SIRS has become the gold standard for the diagnosis of sepsis. In 2016, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine published a new clinical definition of sepsis that is called Sepsis-3. In contrast to previous definitions, Sepsis-3 is based on organ dysfunctions and uses a sequential organ failure (SOFA) score as an index. Thus, patients diagnosed with respect to Sepsis 3 will inevitably represent a different population than those previously diagnosed. We assume that this drastic change in clinical definition will affect not only clinical practice but also the viewpoint and focus of basic research. This review intends to summarize the pathophysiology of sepsis and organ dysfunction and discusses potential directions for future research. PMID- 29259699 TI - Immunosuppressive effect of mesenchymal stem cell-derived exosomes on a concanavalin A-induced liver injury model. AB - Background: This study aimed to evaluate the effect of mesenchymal stem cell (MSC)-derived exosomes on an immune-induced liver injury model. MSCs show a unique function to modulate immune reaction although the molecular mechanisms are still under investigation. Exosomes are a nanoparticle containing microRNA and many ligands and are recognized as important factors secreted from MSC to express their function. This research is undertaken to evaluate the effect of MSC-derived exosome on concanavalin-A (con-A)-induced liver injury. Methods: Exosomes were collected from the supernatant of MSC from the bone marrow of C57B6 mice with ultracentrifugation. The collected exosomes or MSCs were injected intravenously into liver injury mice that had been prepared by the intravenous con-A injection. Liver and serum samples were collected 24 h later to evaluate the macro- and microscopic images, the alanine aminotransferase (ALT), and cytokine messenger RNA (mRNA) expression levels. Phenotypical change of non-parenchymal liver cells was also evaluated by flow cytometry. Liver localization of PKH26 after the injection of PKH26-labeled exosomes or MSCs was observed by microscope. Each result was statistically analyzed with Student's t test. Results: PKH was observed in the liver after PKH-labeled exosomes were injected into mouse, whereas it was only observed in the lung in a mouse group receiving PKH-leveled MSC. There were decreases in ALT, liver necrotic areas, and the extent of apoptosis indicated by the single-stranded DNA index of groups that received multiple injections of MSC-derived exosomes, but an increase in the Ki-67 index. The mRNA expression of anti-inflammatory cytokines was enhanced. The number of Treg was increased among NPCs in a group receiving exosomes multiple times. Conclusions: Suppression of con-A-induced liver injury by injection of exosomes was observed as same extent as MSC. Considering the advantage of exosomes as its non-living nature and dosing adjustability over MSC, exosome will be one alternative of MSC transplantation. PMID- 29259700 TI - Neuroprotective effects of human umbilical cord-derived mesenchymal stem cells on periventricular leukomalacia-like brain injury in neonatal rats. AB - Background: Periventricular leukomalacia (PVL) is a type of multifactorial brain injury that causes cerebral palsy in premature infants. To date, effective therapies for PVL have not been available. In this study, we examined whether mesenchymal stem cells (MSCs) possess neuroprotective property in a lipopolysaccharide (LPS)-induced neonatal rat PVL-like brain injury. Methods: Human umbilical cord-derived MSCs (UCMSCs) were used in this study. Four-day-old rats were intraperitoneally injected with LPS (15 mg/kg) to cause the PVL-like brain injury and were treated immediately after the LPS-injection with UCMSCs, conditioned medium prepared from MSCs (UCMSC-CM) or interferon-gamma (IFN-gamma) pretreated MSC (IFN-gamma-UCMSC-CM). To assess systemic reaction to LPS-infusion, IFN-gamma in sera was measured by ELISA. The brain injury was evaluated by immunostaining of myelin basic protein (MBP) and caspase-3. RT-PCR was used to quantitate pro-inflammatory cytokine levels in the brain injury, and the expression of tumor necrosis factor-stimulated gene-6 (TSG-6) or indoleamine 2,3 dioxygenase (IDO) to evaluate anti-inflammatory or immunomodulatory molecules in UCMSCs, respectively. A cytokine and growth factor array was employed to investigate the cytokine secretion profiles of UCMSCs. Results: Elevated serum IFN-gamma was observed in LPS-infused rats. The expression of IL-6, tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and monocyte chemoattractant protein 1 (MCP-1) were increased in the brain by LPS-infusion in comparison to saline infused control. LPS-infusion increased caspase-3-positive cells and decreased MBP-positive area in neonatal rat brains. A cytokine and growth factor array demonstrated that UCMSCs secreted various cytokines and growth factors. UCMSCs significantly suppressed IL-1beta expression in the brains and reversed LPS caused decrease in MBP-positive area. UCMSC-CM did not reverse MBP-positive area in the injured brain, while IFN-gamma-UCMSC-CM significantly increased MBP positive area compared to control (no treatment). IFN-gamma-pretreatment increased TSG-6 and IDO expression in UCMSCs. Conclusion: We demonstrated that bolus intraperitoneal infusion of LPS caused PVL-like brain injury in neonatal rats and UCMSCs infusion ameliorated dysmyelination in LPS-induced neonatal rat brain injury. Conditioned medium prepared from IFN-gamma-pretreated UCMSCs significantly reversed the brain damage in comparison with UCMSC-CM, suggesting that the preconditioning of UCMSCs would improve their neuroprotective effects. The mechanisms underline the therapeutic effects of MSCs on PVL need continued investigation to develop a more effective treatment. PMID- 29259698 TI - Dissecting cellular senescence and SASP in Drosophila. AB - Cellular senescence can act as both tumor suppressor and tumor promoter depending on the cellular contexts. On one hand, premature senescence has been considered as an innate host defense mechanism against carcinogenesis in mammals. In response to various stresses including oxidative stress, DNA damage, and oncogenic stress, suffered cells undergo irreversible cell cycle arrest, leading to tumor suppression. On the other hand, recent studies in mammalian systems have revealed that senescent cells can drive oncogenesis by secreting diverse proteins such as inflammatory cytokines, matrix remodeling factors, and growth factors, the phenomenon called senescence-associated secretory phenotype (SASP). However, the mechanisms by which these contradictory effects regulate tumor growth and metastasis in vivo have been elusive. Here, we review the recent discovery of cellular senescence in Drosophila and the mechanisms underlying senescence mediated tumor regulation dissected by Drosophila genetics. PMID- 29259701 TI - Quantitative assessment of angiogenesis and pericyte coverage in human cell derived vascular sprouts. AB - Background: Pericytes, surrounding the endothelium, fulfill diverse functions that are crucial for vascular homeostasis. The loss of pericytes is associated with pathologies, such as diabetic retinopathy and Alzheimer's disease. Thus, there exists a need for an experimental system that combines pharmacologic manipulation and quantification of pericyte coverage during sprouting angiogenesis. Here, we describe an in vitro angiogenesis assay that develops lumenized vascular sprouts composed of endothelial cells enveloped by pericytes, with the additional ability to comparatively screen the effect of multiple small molecules simultaneously. For automated analysis, we also present an ImageJ plugin tool we developed to quantify sprout morphology and pericyte coverage. Methods: Human umbilical vein endothelial cells and human brain vascular pericytes were coated on microcarrier beads and embedded in fibrin gels in a 96 well plate to form lumenized vascular sprouts. After treatment with pharmacologic compounds, sprouts were fixed, stained, and imaged via optical z-sections over the area of each well. The maximum intensity projections of these images were stitched together to form montages of the wells, and those montages were processed and analyzed. Results: Vascular sprouts formed within 4-12 days and contained a patent lumen surrounded by a layer of human endothelial cells and pericytes. Using our workflow and image analysis, pericyte coverage after treatment with various compounds was successfully quantified. Conclusions: Here we present a robust in vitro assay using primary human vascular cells that allows researchers to analyze the effects of multiple compounds on sprouting angiogenesis and pericyte coverage. Our ImageJ plugin offers automated evaluation across multiple different vascular parameters, such as sprout length, cell density, branch points, and pericyte coverage. PMID- 29259702 TI - Epithelial stem cell culture: modeling human disease and applications for regenerative medicine. AB - The inability to maintain the immaturity of stem cell populations in vitro restricts the long-term expansion of various types of human epithelial stem cells. However, recent technical advances in epithelial stem cell culture have led to the development of novel in vitro strategies for regenerating epithelial tissues and for closely mimicking human diseases such as cancer and inflammation. Specifically, improvements in culture conditions provided by small molecules in combination with three-dimensional (3D) culture approaches have facilitated the establishment of in vitro systems that recapitulate biological properties in epithelial organs, and these systems may be used to model disease. In this review article, we describe the biological significance of technical improvements in the development of these methods, focusing on human epithelial cells, including stratified and columnar epithelial cells. We also discuss the potential and future perspectives of this technology, which is only beginning to be explored. PMID- 29259703 TI - Prostaglandin E2-EP2 signaling as a node of chronic inflammation in the colon tumor microenvironment. AB - Background: Colorectal cancer is the third most common cancer. Involvement of prostaglandin (PG) system in the pathogenesis of colorectal cancer has been suggested from clinical studies demonstrating therapeutic effect of NSAIDs including aspirin or selective COX-2 inhibitors. However, mechanisms on how PG regulates inflammatory responses leading to colorectal cancer development remain obscure. Further, careful attention is needed to use these drugs for a long time because of adverse effects due to non-specific inhibition of physiological PG production in addition to pathological one, making the development of alternatives to aspirin important. Recent studies using mouse model of colitis associated colon cancer, azoxymethane (AOM)-dextran sodium sulfate (DSS) model, have revealed some of the mechanisms on how PG regulates inflammation in lesions and proposed PG receptor as a therapeutic target. Main body of abstract: Among each PG receptor subtype examined, prostaglandin E receptor 2 (EP2) signaling specifically contributes to colorectal cancer formation and inflammation in lesions of AOM-DSS model. EP2 is expressed in neutrophils, infiltrated major inflammatory cells, and tumor-associated fibroblasts (TAFs) in the tumor stroma of this mouse model and also in clinical specimen from ulcerative colitis associated colorectal cancer. Bone marrow transfer experiments between wild-type and EP2-deficient mice have confirmed the involvement of EP2 signaling in these two types of cells in the pathogenesis of the disease. EP2 signaling in both types of cells regulates the transition to and maintenance of inflammation in multiple steps to shape the tumor microenvironment which contributes to trigger and promote colorectal cancer. In this process, PGE2-EP2 signaling synergizes with TNF-alpha to amplify TNF-alpha-induced inflammatory responses, forms a positive feedback loop involving COX-2-PGE2-EP2 signaling to exacerbate PG mediated inflammation once triggered, and alternates active cell populations participating in inflammation through forming self-amplification loop among neutrophils. Thus, EP2 signaling functions as a node of inflammatory responses in the tumor microenvironment. Based on such a notion, EP2 can become a strong candidate for therapeutic target of colorectal cancer treatment. Indeed, in AOM DSS model, a selective EP2 antagonist, PF-04418948, potently suppresses colorectal tumor formation. Short conclusion: PGE2-EP2 signaling functions as a node of chronic inflammation which shapes the tumor microenvironment and thus is a strong candidate of target for the chemoprevention of colorectal cancer. PMID- 29259704 TI - Effect of human umbilical cord blood stem cell transplantation on oval cell response in 2-AAF/CCL4 liver injury model: experimental immunohistochemical study. AB - Background: Oval cells, specific liver progenitors, are activated in response to injury. The human umbilical cord blood (hUCB) is a possible source of transplantable hepatic progenitors and can be used in cases of severe liver injury. We detected the effect of hUCB stem cell transplantation on natural response of oval cells to injury. Methods: Twenty-four female albino rats were randomly divided into three groups: (A) control, (B) liver injury with hepatocyte block, and (C) hUCB transplanted group. Hepatocyte block was performed by administration of 2-acetylaminofluorene (2-AAF) for 12 days. CCL4 was administrated at day 5 from experiment start. Animals were sacrificed at 9 days post CCL4 administration, and samples were collected for biochemical and histopathological analysis. Oval cell response to injury was evaluated by the percentage of oval cells in the liver tissue and frequency of cells incorporated into new ducts. Results: Immunohistochemical analysis of oval cell response to injury was performed. There was significant deviation in the hUCB-transplanted (4.9 +/- 1.4) and liver injury groups (2.4 +/- 0.9) as compared to control (0.89 +/- 0.4) 9 days post injury. Detection of oval cell response was dependant on OV 6 immunoreactivity. For mere localization of cells with human origin, CD34 antihuman immunoreactivity was performed. There was no significant difference in endogenous OV-6 immunoreactivity following stem cell transplantation as compared to the liver injury group. Conclusions: In vivo transplantation of cord blood stem cells (hUCB) does not interfere with natural oval cell response to liver injury. PMID- 29259705 TI - The roles of RGMa-neogenin signaling in inflammation and angiogenesis. AB - Repulsive guidance molecule (RGM) is a glycosylphosphatidylinositol (GPI) anchored glycoprotein that has diverse functions in the developing and pathological central nervous system (CNS). The binding of RGM to its receptor neogenin regulates axon guidance, neuronal differentiation, and survival during the development of the CNS. In the pathological state, RGM expression is induced after spinal cord injury, and the inhibition of RGM promotes axon growth and functional recovery. Furthermore, RGM expression is also observed in immune cells, and RGM regulates inflammation and neurodegeneration in autoimmune encephalomyelitis. RGMa induces T cell activation in experimental autoimmune encephalomyelitis (EAE), which is the animal model of multiple sclerosis (MS). RGM is expressed in pathogenic Th17 cells and induces neurodegeneration by binding to neogenin. Angiogenesis is an additional key factor involved in the pathophysiology of EAE. Via neogenin, treatment with RGMa can suppress endothelial tube formation; this finding indicates that RGMa inhibits neovascularization. These observations suggest the feasibility of utilizing the RGMa-neogenin signaling pathway as a therapeutic target to overcome inflammation and neurodegeneration. This review focuses on the molecular mechanisms of inflammation and angiogenesis via RGM-neogenin signaling. PMID- 29259706 TI - Pharmacological targeting of bone marrow mesenchymal stromal/stem cells for the treatment of hematological disorders. AB - The therapeutic effects of mesenchymal stromal/stem cells (MSCs) are mainly based on three characteristics: immunomodulation, tissue regeneration, and hematopoietic support. Cell therapy using culture-expanded MSCs is effective in some intractable bone and hemato-immune disorders; however, its efficacy is limited. In this article, we review the previous efforts to improve the clinical outcomes of cell therapy using MSCs for such disorders. We describe pharmacological targeting of endogenous bone marrow-derived MSCs as a crucial quality-based intervention to establish more effective MSC-based therapies. PMID- 29259707 TI - Isolation of dental pulp stem cells with high osteogenic potential. AB - Dental pulp stem cells/progenitor cells (DPSCs) can be easily obtained and can have excellent proliferative and mineralization potentials. Therefore, many studies have investigated the isolation and bone formation of DPSCs. In most previous reports, human DPSCs were traditionally isolated by exploiting their ability to adhere to plastic tissue culture dishes. DPSCs isolated by plastic adherence are frequently contaminated by other cells, which limits the ability to investigate their basic biology and regenerative properties. Additionally, the proliferative and osteogenic potentials vary depending on the isolated cells. It is very difficult to obtain cells of a sufficient quality to elicit the required effect upon transplantation. Considering clinical applications, stem cells used for regenerative medicine need to be purified in order to increase the efficiency of bone regeneration, and a stable supply of these cells must be generated. Here, we review the purification of DPSCs and studies of cranio-maxillofacial bone regeneration using these cells. Additionally, we introduce the prospective isolation of DPSCs using specific cell surface markers: low-affinity nerve growth factor and thymocyte antigen 1. PMID- 29259708 TI - Applications of reconstituted inflammasomes in a cell-free system to drug discovery and elucidation of the pathogenesis of autoinflammatory diseases. AB - The inflammasome, typically consisting of a Nod-like receptor, apoptosis associated speck-like protein, and pro-caspase-1, has recently been identified as a huge intracellular complex, which plays a crucial role in interleukin-1 maturation or specific physiological functions. Two Nod-like receptors, such as nucleotide-binding oligomerization domains-containing protein (Nod)1 and Nod2, interact with the receptor-interacting protein serine-threonine kinase (RIPK)2 accompanied by Ikappa-B kinase (IKK) complexes to construct the nodosome, leading to nuclear factor (NF)-kappaB activation. The aberrant activation of inflammasomes or nodosomes causes autoinflammatory diseases. Therefore, inflammasomes may be attractive targets to treat autoinflammatory diseases. Our aim is to develop reconstituted inflammasomes in a cell-free system to discover specific molecular-target drugs and elucidate the molecular pathogenesis of autoinflammatory diseases. In this review, we describe reconstituted inflammasomes in a cell-free system. PMID- 29259709 TI - Role of fibroblast growth factors in bone regeneration. AB - Bone is a metabolically active organ that undergoes continuous remodeling throughout life. However, many complex skeletal defects such as large traumatic bone defects or extensive bone loss after tumor resection may cause failure of bone healing. Effective therapies for these conditions typically employ combinations of cells, scaffolds, and bioactive factors. In this review, we pay attention to one of the three factors required for regeneration of bone, bioactive factors, especially the fibroblast growth factor (FGF) family. This family is composed of 22 members and associated with various biological functions including skeletal formation. Based on the phenotypes of genetically modified mice and spatio-temporal expression levels during bone fracture healing, FGF2, FGF9, and FGF18 are regarded as possible candidates useful for bone regeneration. The role of these candidate FGFs in bone regeneration is also discussed in this review. PMID- 29259710 TI - Regulation of blood vascular permeability in the skin. AB - Regulation of blood vessel permeability is essential for the homeostasis of peripheral tissues. This regulation controls the trafficking of plasma contents, including water, vitamins, ions, hormones, cytokines, amyloids, lipoproteins, carrier proteins, and immunoglobulins. The properties of blood vessels vary among tissues based on their structural differences: continuous, fenestrated, or sinusoidal. These three types of blood vessels have different charge and size barrier properties. The anionic luminal glycocalyx layer on endothelial cells establishes the "charge barrier" that repels the attachment of negatively charged blood cells and plasma molecules. In contrast, the "size barrier" of blood vessels largely relies on the interendothelial junctions (IEJs) between endothelial cells, which define the paracellular permeability. As in most peripheral tissues, blood capillaries in the skin are composed of continuous and/or fenestrated blood vessels that have relatively tighter IEJs compared to those in the internal organs. Small vesicles in the capillary endothelium were discovered in the 1950s, and studies have since confirmed that blood endothelial cells transport the plasma contents by endocytosis and subsequent transcytosis and exocytosis-this process is called transcellular permeability. The permeability of blood vessels is highly variable as a result of intrinsic and extrinsic factors. It is significantly elevated upon tissue inflammations as a result of disabled IEJs and increased paracellular permeability due to inflammatory mediators. An increase in transcellular permeability during inflammation has also been postulated. Here, we provide an overview of the general properties of vascular permeability based on our recent observations of murine skin inflammation models, and we discuss its physiological significance in peripheral homeostasis. PMID- 29259711 TI - Recent advances in the treatment of skin involvement in systemic sclerosis. AB - Skin fibrosis is a devastating clinical condition commonly seen in skin restricted and systemic disorders. The goal of skin fibrosis treatment is the restoration of abnormally activated dermal fibroblasts producing the excessive amount of extracellular matrix, which is generally a final consequence of the complex disease process including the activation of vascular and immune systems. Among various skin fibrotic conditions, the molecular mechanisms underlying dermal fibroblast activation have been mostly well studied in systemic sclerosis (SSc). SSc is a multisystem autoimmune and vascular disease resulting in extensive fibrosis of the skin and various internal organs. Since SSc pathogenesis is believed to include all the critical components regulating tissue fibrosis, the studies on anti-fibrotic drugs against SSc provide us much useful information regarding the strategy for the treatment of various skin fibrotic conditions. In the recent decade, as is the case with other autoimmune and inflammatory diseases, the molecular targeting therapy with monoclonal antibody has been clinically well examined in SSc. Promising clinical outcomes are so far reported in tocilizumab (an anti-IL-6 receptor antibody), rituximab (an anti-CD20 antibody), and fresolimumab (an anti-TGF-beta antibody). The analysis of gene expression profiles in skin lesions of SSc patients treated with tocilizumab or fresolimumab revealed a critical role of monocyte-macrophage lineage cells in the development of skin fibrosis and the involvement of IL-6 and TGF-beta in the activation of those cells. Considering that B cells modulate the differentiation and activation of macrophages, favorable clinical outcomes of rituximab treatment imply the central role of B cell/monocyte-macrophage lineage cell axis in the pathogenesis of SSc. This scenario may be applicable at least partly to other skin fibrotic conditions. In this review article, the currently available data on these drugs are summarized and the future directions are discussed. PMID- 29259712 TI - Pathophysiology and therapeutic potential of cardiac fibrosis. AB - Inflammatory and fibrotic responses to myocardial damage are essential for cardiac repair; however, these responses often result in extensive fibrotic remodeling with impaired systolic function. Recent reports have suggested that such acute phase responses provide a favorable environment for endogenous cardiac regeneration, which is mainly driven by the division of pre-existing cardiomyocytes (CMs). Existing CMs in mammals can re-acquire proliferative activity after substantial cardiac damage, and elements other than CMs in the physiological and/or pathological environment, such as hypoxia, angiogenesis, and the polarity of infiltrating macrophages, have been reported to regulate replication. Cardiac fibroblasts comprise the largest cell population in terms of cell number in the myocardium, and they play crucial roles in the proliferation and protection of CMs. The in vivo direct reprogramming of functional CMs has been investigated in cardiac regeneration. Currently, growth factors, transcription factors, microRNAs, and small molecules promoting the regeneration and protection of these CMs have also been actively researched. Here, we summarize and discuss current studies on the relationship between cardiac inflammation and fibrosis, and cardiac regeneration and protection, which would be useful for the development of therapeutic strategies to treat and prevent advanced heart failure. PMID- 29259714 TI - Cancer cell reprogramming to identify the genes competent for generating liver cancer stem cells. AB - The cancer stem cell (CSC) hypothesis postulates that cancer originates from the malignant transformation of stem/progenitor cells and is considered to apply to many cancers, including liver cancer. Identification that CSCs are responsible for drug resistance, metastasis, and secondary tumor appearance suggests that these populations are novel obligatory targets for the treatment of cancer. Here, we describe our new method for identifying potential CSC candidates. The reprogramming of cancer cells via induced pluripotent stem cell (iPSC) technology is a novel therapy for the treatment and for the study of CSC-related genes. This technology has advantages for studying the interactions between CSC-related genes and the cancer niche microenvironment. This technology may also provide a useful platform for studying the genes involved in the generation of CSCs before and after reprogramming, and for elucidating the mechanisms underlying cancer initiation and progression. The present review summarizes the current understanding of transcription factors involved in the generation of liver CSCs from liver cancer cell-derived iPSCs and how these contribute to oncogenesis, and discusses the modeling of liver cancer development. PMID- 29259715 TI - Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases. AB - Mesenchymal stem cell (MSC) therapies have been used in clinical trials in various fields. These cells are easily expanded, show low immunogenicity, can be acquired from medical waste, and have multiple functions, suggesting their potential applications in a variety of diseases, including liver disease and inflammatory bowel disease. MSCs help prepare the microenvironment, in response to inflammatory cytokines, by producing immunoregulatory factors that modulate the progression of inflammation by affecting dendritic cells, B cells, T cells, and macrophages. MSCs also produce a large amount of cytokines, chemokines, and growth factors, including exosomes that stimulate angiogenesis, prevent apoptosis, block oxidation reactions, promote remodeling of the extracellular matrix, and induce differentiation of tissue stem cells. According to ClinicalTrials.gov, more than 680 clinical trials using MSCs are registered for cell therapy of many fields including liver diseases (more than 40 trials) and inflammatory bowel diseases (more than 20 trials). In this report, we introduce background and clinical studies of MSCs in liver disease and inflammatory bowel diseases. PMID- 29259716 TI - Resident fibroblasts in the kidney: a major driver of fibrosis and inflammation. AB - Background: Chronic kidney disease (CKD) is a leading cause of end stage renal disease (ESRD) and cardiovascular morbidity and mortality worldwide, resulting in a growing social and economic burden. The prevalence and burden of CKD is anticipated to further increase over the next decades as a result of aging. Main body of abstract: In the pathogenesis of CKD, irrespective of the etiology, resident fibroblasts are key players and have been demonstrated to play crucial roles for disease initiation and progression. In response to injury, resident fibroblasts transdifferentiate into myofibroblasts that express alpha smooth muscle actin (alphaSMA) and have an increased capacity to produce large amounts of extracellular matrix (ECM) proteins, leading to renal fibrosis. In addition to this fundamental role of fibroblasts as drivers for renal fibrosis, growing amounts of evidence have shown that resident fibroblasts are also actively involved in initiating and promoting inflammation during kidney injury. During the myofibroblastic transition described above, resident fibroblasts activate NF kappaB signaling and produce pro-inflammatory cytokines and chemokines, promoting inflammation. Furthermore, under aging milieu, resident fibroblasts transdifferentiate into several distinct phenotypic fibroblasts, including CXCL13/CCL19-producing fibroblasts, retinoic acid-producing fibroblasts, and follicular dendritic cells, in response to injury and orchestrate tertiary lymphoid tissue (TLT) formation, which results in uncontrolled aberrant inflammation and retards tissue repair. Anti-inflammatory agents can improve myofibroblastic transdifferentiation and abolish TLT formation, suggesting that targeting these inflammatory fibroblasts can potentially ameliorate kidney disease. Short conclusion: Beyond its conventional role as an executor of fibrosis, resident fibroblasts display more pro-inflammatory phenotypes and contribute actively to driving inflammation during kidney injury. PMID- 29259717 TI - The crystal-induced activation of NLRP3 inflammasomes in atherosclerosis. AB - Atherosclerosis is an inflammatory disease, which is accompanied by the deposition of cholesterol-rich lipids and the infiltration of macrophages. Other well-known features of atherosclerotic lesions include the deposition of cholesterol crystals and calcium phosphate crystals; however, their pathophysiological role remains unclear. Recent studies suggest that cholesterol crystals play a pivotal role in activation of NLRP3 inflammasomes, which regulate caspase-1 activation and the subsequent processing of IL-1beta, in atherosclerotic lesions. NLRP3 inflammasomes are essential for the initiation of vascular inflammation during the progression of atherosclerosis. Therefore, the regulatory mechanisms of NLRP3 inflammasomes are regarded as potential targets for atherosclerosis treatment. Here, we review the current knowledge regarding the role of NLRP3 inflammasomes in the progression of atherosclerosis and the prospects for therapeutic approaches targeting NLRP3 inflammasomes. PMID- 29259718 TI - Effects of acute exposure to low-dose radiation on the characteristics of human bone marrow mesenchymal stromal/stem cells. AB - Background: In recent years, increasing attention has been paid to the effects of low-dose irradiation on human health. We examined whether low-dose irradiation affected the functions of mesenchymal stromal/stem cells (MSCs), which are tissue/organ-supportive stem cells, derived from bone marrow (BM). Methods: Normal human BM-MSCs from five healthy individuals were used in this study. Culture-expanded BM-MSCs were exposed to 0.1 gray (Gy) of gamma-radiation (Cesium 137) at a rate of 0.8 Gy/min (Ir-MSCs), and their expansion, multi differentiation, and hematopoiesis-supportive capabilities were investigated. Results: The expansion of BM-MSCs was transiently delayed after low-dose gamma irradiation compared with that of non-irradiated BM-MSCs (non-Ir-MSCs) in two out of five lots. Adipogenic and osteogenic differentiation capabilities were not significantly affected by low-dose irradiation, although one lot of BM-MSCs tended to have transiently reduced differentiation. When human BM hematopoietic stem/progenitor cells (HPCs) were co-cultured with Ir-MSCs, the generation of CD34+CD38+ cells from HPCs was enhanced compared with that in co-cultures with non-Ir-MSCs in two out of five lots. The mRNA expression level of interleukin (IL)-6 was increased and those of stem cell factor (SCF) and fms-related tyrosine kinase 3 ligand (Flt3L) were decreased in the affected lots of Ir-MSCs. In the other three lots of BM-MSCs, a cell growth delay, enhanced generation of CD34+CD38+ cells from HPCs in co-culture, and a combination of increased expression of IL-6 and decreased expression of SCF and Flt3L were not observed. Of note, the characteristics of these affected Ir-MSCs recovered to a similar level as those of non-Ir-MSCs following culture for 3 weeks. Conclusions: Our results suggest that acute exposure to low-dose (0.1 Gy) radiation can transiently affect the functional characteristics of human BM-MSCs. PMID- 29259713 TI - The etiopathogenesis of atopic dermatitis: barrier disruption, immunological derangement, and pruritus. AB - Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future. PMID- 29259719 TI - Roles of nitric oxide and ethyl pyruvate after peripheral nerve injury. AB - Short-lived reactive nitrogen species and reactive oxygen species have acquired significant attention in the field of biomedical science. Nitric oxide (NO), which was thought to be an unstable gas and pollutant, is now regarded as a gas transmitter like H2S and CO. NO is synthesized inside the mammalian body by l arginine via three different isoforms of NO synthase whereas pyruvate is a glycolysis product and substrate for TCA cycle. Due to poor solubility and stability, therapeutic potential of pyruvate is limited. Ethyl pyruvate (EP) is now considered as a suitable replacement of pyruvate. In this paper, we will try to focus the effect of NO and EP in Schwann cell dedifferentiation, proliferation, nerve degeneration, and regeneration during Wallerian degeneration (WD) of peripheral nerve injury along with their neuroprotective effects, cardiovascular functioning, support in hepatic complication, etc. PMID- 29259720 TI - Cell transfer technology for tissue engineering. AB - We recently developed novel cell transplantation method "cell transfer technology" utilizing photolithography. Using this method, we can transfer ex vivo expanded cells onto scaffold material in desired patterns, like printing of pictures and letters on a paper. We have investigated the possibility of this novel method for cell-based therapy using several disease models. We first transferred endothelial cells in capillary-like patterns on amnion. The transplantation of the endothelial cell-transferred amnion enhanced the reperfusion in mouse ischemic limb model. The fusion of transplanted capillary with host vessel networks was also observed. The osteoblast- and periodontal ligament stem cell-transferred amnion were next transplanted in bone and periodontal defects models. After healing period, both transplantations improved the regeneration of bone and periodontal tissues, respectively. This method was further applicable to transfer of multiple cell types and the transplantation of osteoblasts and periodontal ligament stem cell-transferred amnion resulted in the improved bone regeneration compared with single cell type transplantation. These data suggested the therapeutic potential of the technology in cell-based therapies for reperfusion of ischemic limb and regeneration of bone and periodontal tissues. Cell transfer technology is applicable to wide range of regenerative medicine in the future. PMID- 29259722 TI - Human LYPD8 protein inhibits motility of flagellated bacteria. AB - Background: We previously reported that the mouse Ly6/Plaur domain containing 8 (mLypd8), a GPI-anchored protein highly and selectively expressed on colonic epithelia, contributes to segregation of intestinal microbiota and intestinal epithelia and is critical for prevention of intestinal inflammation. In addition, it was found that human LYPD8 (hLYPD8) is expressed in the colonic epithelia and expression of hLYPD8 is reduced in some ulcerative colitis patients. However, the molecular characteristics and functions of hLYPD8 remain unclear. In this study, we generated the hLYPD8 protein and characterized its functions. Methods: To analyze the characteristics and functions of the hLYPD8 protein, recombinant FLAG tagged hLYPD8 protein was generated by two kinds of protein expression systems: a mammalian cell expression system and a Pichia pastoris expression system. Recombinant hLYPD8 protein was analyzed by western blot analysis or deglycosylation assay. The effect of the protein on flagellated bacteria was examined by ELISA assay and motility assay using semi-agar plates. Results: hLYPD8 was a highly N-glycosylated GPI-anchored protein, like mLypd8. Moreover, recombinant hLYPD8 protein generated by the Pichia pastoris expression system using the SuperMan5 strain, which enabled production of a large number of proteins with human-like glycosylation, presented the high binding affinity and the motility inhibitory function to flagellated bacteria, such as Proteus mirabilis. Conclusions: These results demonstrated that hLYPD8 inhibits the motile activity of flagellated bacteria, many of which are involved in intestinal inflammation. The supplementation of recombinant hLYPD8 protein might be a novel therapeutic approach for intestinal inflammation of inflammatory bowel diseases. PMID- 29259721 TI - Characterization of polydactyly-derived chondrocyte sheets versus adult chondrocyte sheets for articular cartilage repair. AB - Background: We previously conducted a first-in-human clinical study of articular cartilage repair using autologous chondrocyte sheets and confirmed the regeneration of hyaline-like cartilage in all eight patients. However, regenerative medicine with autologous chondrocyte sheets requires the harvesting of tissue from healthy regions, and the quality of this tissue varies between individuals. To overcome such limitations, allogeneic transplantation is a promising treatment method, particularly for articular cartilage repair. In this study, we investigated the characteristics of polydactyly-derived chondrocyte sheets fabricated from the chondrocytes of young polydactyly donors. Methods: Polydactyly-derived chondrocyte (PD) sheets were fabricated from the tissue obtained from eight polydactyly donors (average age = 13.4 months). To create these PD sheets, chondrocytes at passage 2 or 3 were seeded on temperature responsive culture inserts and cultured for 2 weeks. For comparison, adult chondrocyte sheets were fabricated from tissue obtained from 11 patients who underwent total knee arthroplasty (TKA; average age = 74 years). To create these TKA sheets, chondrocytes and synovial cells were cocultured, and the chondrocyte sheets were triple-layered according to the protocol from our previous clinical study. Cell count, cell viability, cell surface markers, cell histology, and humoral factors secreted by the sheets were characterized and compared between the PD sheets and TKA sheets. Results: Polydactyly-derived chondrocytes proliferated rapidly to establish a layered structure with sufficient extracellular matrix and formed sheets that could be easily manipulated without tearing. Similar to TKA sheets, PD sheets expressed aggrecan and fibronectin at the protein level and the surface markers CD44, CD81, and CD90, which are characteristic of mesenchymal cells. PD sheets also produced significantly higher levels of transforming growth factor beta-1 and lower levels of matrix metalloproteinase-3 than those produced by TKA sheets, suggesting that young polydactyly-derived chondrocytes have advantages as a potential cell source. Conclusions: PD sheets exhibited characteristics thought to be important to chondrocyte sheets as well as proliferative capacity that may facilitate provision of a stable supply in the future. PMID- 29259723 TI - Effects of CTLA4-Ig on human monocytes. AB - Background: Abatacept, a CTLA4-Ig fusion protein attenuates T cell activation by inhibiting the CD80/86-CD28 costimulatory pathway that is required for the proper T cell activation and thus displays beneficial effects in the treatment of rheumatoid arthritis (RA). Although some studies have disclosed the in vitro effects of this biological agent on the immune-competent cells, the precise mechanisms of action in RA still remain unclear. The current studies were therefore undertaken to explore the effects of abatacept on monocytes in detail. Methods: Monocytes from healthy donors were cultured in the presence of staphylococcal enterotoxin B (SEB) with pharmacologically attainable concentrations of abatacept or control IgG-Fc. The expression of CD80 and CD86 and the induction of apoptosis of monocytes were measured by flow cytometry. The expression of CD80 and CD86 messenger RNA (mRNA) was determined by quantitative RT-PCR. Results: Abatacept promoted apoptosis of SEB-stimulated monocytes. The induction of apoptosis of monocytes by these biological agents was reversed by the addition of IgG, but not IgG-F(ab')2 fragments. Furthermore, abatacept significantly suppressed the expression of CD80, but not that of CD86 at protein levels. Finally, abatacept significantly suppressed the expression of mRNA for CD80 of monocytes stimulated with SEB, but not that of CD86. Conclusions: These results demonstrate that one of the mechanisms of action of abatacept involves the induction of apoptosis of monocytes, which involves interaction with Fc receptor on monocytes. Moreover, the data also demonstrate that abatacept selectively suppresses the expression of CD80 at mRNA levels. PMID- 29259725 TI - Imaging of inflammation and regeneration: a novel trend dissecting dynamic features of biological phenomena in vivo. PMID- 29259724 TI - Introduction of vasculature in engineered three-dimensional tissue. AB - Background: With recent developments in tissue engineering technology, various three-dimensional tissues can be generated now. However, as the tissue thickness increases due to three-dimensionalization, it is difficult to increase the tissue scale without introduction of blood vessels. Main text: Many methods for vasculature induction have been reported recently. In this review, we introduced several methods which are adjustable vascularization in three-dimensional tissues according to three steps. First, "selection" provides potents for engineered tissues with vascularization ability. Second, "assembly technology" is used to fabricate tissues as three-dimensional structures and simultaneously inner neo vasculature. Third, a "perfusion" technique is used for maturation of blood vessels in three-dimensional tissues. In "selection", selection of cells and materials gives the ability to promote angiogenesis in three-dimensional tissues. During the cell assembly step, cell sheet engineering, nanofilm coating technology, and three-dimensional printing technology could be used to produce vascularized three-dimensional tissues. Perfusion techniques to perfuse blood or cell culture medium throughout three-dimensional tissues with a unified inlet and outlet could induce functional blood vessels within retransplantable three dimensional tissues. Combination of each step technology allows simulation of perivascular microenvironments in target tissues and drive vascularization in three-dimensional tissues. Conclusion: The biomimetic microenvironment of target tissues will induce adequate cell-cell interaction, distance, cell morphology, and function within tissues. It could be accelerated for vascularization within three-dimensional tissues and give us the functional tissues. Since vascularized three-dimensional tissues are highly functional, they are expected to contribute to the development of regenerative medicine and drug safety tests for drug discovery in the future. PMID- 29259727 TI - Inhibition of lysosomal Ca2+ signalling disrupts dendritic spine structure and impairs wound healing in neurons. AB - A growing body of evidence suggests that lysosomes, which have traditionally been regarded as degradative organelles, can function as Ca2+ stores, regulated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). We previously demonstrated that in hippocampal pyramidal neurons, activity-dependent Ca2+ release from these stores triggers fusion of the lysosome with the plasma membrane. We found that the physiological role of this Ca2+-dependent fusion was to maintain the long-term structural enlargement of dendritic spines induced by synaptic activity. Here, we examined the pathophysiological consequences of lysosomal dysfunction in hippocampal pyramidal neurons by chronically inhibiting lysosomal Ca2+ signalling using the NAADP antagonist, NED-19. We found that within just 20 hours, inhibition of lysosomal function led to a profound intracellular accumulation of lysosomal membrane. This was accompanied by a significant change in dendritic spine structure, which included a lengthening of dendritic spines, an increase in the number of filipodia, and an overall decrease in spine number. Inhibition of lysosomal function also inhibited wound healing in neurons by preventing lysosomal fusion with the plasma membrane. Neurons were therefore more susceptible to injury. Our findings suggest that dysfunction in lysosomal Ca2+ signalling and lysosomal fusion with the plasma membrane may contribute to the loss of dendritic spines and neurons seen in neurological disorders, such as Niemann-Pick disease type C1, in which lysosomal function is impaired. PMID- 29259726 TI - Does Toxoplasma infection increase sexual masochism and submissiveness? Yes and no. AB - The parasite Toxoplasma needs to get from its intermediate hosts, e.g. rodents, to its definitive hosts, cats, by predation. To increase the probability of this occurrence, Toxoplasma manipulates the behavior of its hosts, for example, by the demethylation of promoters of certain genes in the host's amygdala. After this modification, the stimuli that normally activate fear-related circuits, e.g., the smell of a cat in mice, or smell of leopards in chimpanzees, start to additionally co-activate sexual arousal-related circuits in the infected animals. In humans, the increased attraction to masochistic sexual practices was recently observed in a study performed on 36,564 subjects. Here I show that lower rather than higher attraction to sexual masochism and submissiveness among infected subjects is detected if simple univariate tests instead of multivariate tests are applied to the same data. I show and discuss that when analyzing multiple effects of complex stimuli on complex biological systems we need to use multivariate techniques and very large data sets. We must also accept the fact that any single factor usually explains only a small fraction of variability in the focal variable. PMID- 29259728 TI - Control of cytoskeletal dynamics during cellular responses to pore forming toxins. AB - Following damage by pore forming toxins (PFTs) host cells engage repair processes and display profound cytoskeletal remodeling and concomitant plasma membrane (PM) blebbing. We have recently demonstrated that host cells utilize similar mechanisms to control cytoskeletal dynamics in response to PFTs and during cell migration. This involves assembly of cortical actomyosin bundles, reorganisation of the endoplasmic reticulum (ER) network, and the interaction between the ER chaperone Gp96 and the molecular motor Non-muscle Myosin Heavy Chain IIA (NMHCIIA). Consequently, Gp96 regulates actomyosin activity, PM blebbing and cell migration, and protects PM integrity against PFTs. In addition, we observed that PFTs increase association of Gp96 and ER vacuoles with the cell surface or within PM blebs loosely attached to the cell body. Similarly, gut epithelial cells damaged by PFTs in vivo were shown to release microvilli structures or directly purge cytoplasmic content. Cytoplasmic purging involves profound cytoskeletal remodeling and ER vacuolation, suggesting that our observations recapitulate recovery processes in vivo. Here, we discuss our findings in light of the current understanding of PM repair mechanisms and in vivo recovery responses to PFTs. PMID- 29259729 TI - Cell cycle-dependent regulation of plant infection by the rice blast fungus Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae forms a specialized infection structure called appressorium which uses a turgor-driven mechanical process to breach the leaf cuticle and gain entry into plant tissue. Appressorium development and plant infection are regulated by cell cycle progression and critically depend upon two, temporally separated S-phase checkpoints. Following conidial germination on the rice leaf surface, an S-phase checkpoint is essential for appressorium differentiation and operates through the DNA damage response pathway. By contrast, appressorium maturation and penetration peg development require S progression that depends on turgor control. In this mini-review, we describe cellular mechanisms associated with cell cycle-dependent regulation of appressorium development and the potential operation of morphogenetic checkpoint control of plant infection. PMID- 29259730 TI - Assessment of bacterial communities of black soybean grown in fields. AB - Since the domestication of soybean (Glycine max) about 4,500 years ago, thousands of local cultivars have been developed around the world. In Japan, black soybeans grown in the mountainous region of central Kyoto and Hyogo prefectures, called the Tamba region, are well known for large seeds and palatability. The yields of black soybean in the Tamba region of Kyoto have decreased during the past few decades, and the involvement of rhizosphere microbes in the yield decline has been suggested. We analyzed bacterial communities of the soybean rhizosphere on 7 farms managed under different strategies. Non-metric multidimensional scaling showed shifts of bacterial communities from bulk to rhizosphere soil and the difference among the farms. The relative abundance of the Proteobacteria and Firmicutes was higher in rhizosphere soil than in bulk soil, whereas that of the Acidobacteria was higher in bulk soil. To clarify the possible relationship between bacterial communities and soybean growth, we used ConfeitoGUIplus software (version 1.2.0), based on the Confeito algorithm, which is designed to detect highly interconnected modules in a correlation network by using a unique inter-modular index with network density. One module was extracted from the rhizosphere soil community and two from bulk soil communities, suggesting the involvement of these bacteria in soybean growth. PMID- 29259731 TI - ER-driven membrane contact sites: Evolutionary conserved machineries for stress response and autophagy regulation? AB - Endoplasmic Reticulum (ER), spreading in the whole cell cytoplasm, is a central player in eukaryotic cell homeostasis, from plants to mammals. Beside crucial functions, such as membrane lipids and proteins synthesis and outward transport, the ER is able to connect to virtually every endomembrane compartment by specific tethering molecular machineries, which enables the establishment of membrane membrane contact sites. ER-mitochondria contact sites have been shown to be involved in autophagosome biogenesis, the main organelle of the autophagy degradation pathway. More recently we demonstrated that also ER-plasma membrane contact sites are sites for autophagosomes assembly, suggesting that more generally ER-organelles contacts are involved in autophagy and organelle biogenesis. Here we aim to discuss the functioning of ER-driven contact sites in mammals and plants and more in particular emphasize on their recently highlighted function in autophagy to finally conclude on some key questions that may be useful for further research in the field. PMID- 29259733 TI - Editorial for Cancer Virtual Issue. PMID- 29259734 TI - Chemical Compounds as Inhibitors of Kinase Activity for the Treatment of Cancer and COPD. PMID- 29259732 TI - Edaravone, a Synthetic Free Radical Scavenger, Enhances Alteplase-Mediated Thrombolysis. AB - The combination of alteplase, a recombinant tissue plasminogen activator, and edaravone, an antioxidant, reportedly enhances recanalization after acute ischemic stroke. We examined the influence of edaravone on the thrombolytic efficacy of alteplase by measuring thrombolysis using a newly developed microchip based flow-chamber assay. Rat models of embolic cerebral ischemia were treated with either alteplase or alteplase-edaravone combination therapy. The combination therapy significantly reduced the infarct volume and improved neurological deficits. Human blood samples from healthy volunteers were exposed to edaravone, alteplase, or a combination of alteplase and edaravone or hydrogen peroxide. Whole blood was perfused over a collagen- and thromboplastin-coated microchip; capillary occlusion was monitored with a video microscope and flow-pressure sensor. The area under the curve (extent of thrombogenesis or thrombolysis) at 30 minutes was 69.9% lower in the edaravone-alteplase- than alteplase-treated group. The thrombolytic effect of alteplase was significantly attenuated in the presence of hydrogen peroxide, suggesting that oxidative stress might hinder thrombolysis. D-dimers were measured to evaluate these effects in human platelet-poor plasma samples. Although hydrogen peroxide significantly decreased the elevation of D dimers by alteplase, edaravone significantly inhibited the decrease. Edaravone enhances alteplase-mediated thrombolysis, likely by preventing oxidative stress, which inhibits fibrinolysis by alteplase in thrombi. PMID- 29259735 TI - Ubiquitin-Specific Inhibitors for the Treatment of Cancers, Autoimmune, and Infectious Diseases. PMID- 29259736 TI - Synthesis of Novel Selenides Bearing Benzenesulfonamide Moieties as Carbonic Anhydrase I, II, IV, VII, and IX Inhibitors. AB - A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for the inhibition of five human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, VII, and IX. These enzymes are involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors. The investigated compounds showed potent inhibitory action against hCA II, VII, and IX, in the low nanomolar range, thus making them of interest for the development of isoform-selective inhibitors and as candidates for biomedical applications. PMID- 29259737 TI - Novel Polyamine-Naphthalene Diimide Conjugates Targeting Histone Deacetylases and DNA for Cancer Phenotype Reprogramming. AB - A series of hybrid compounds was designed to target histone deacetylases and ds /G-quadruplex DNAs by merging structural features deriving from Scriptaid and compound 1. Compound 6 binds different DNA arrangements, inhibits HDACs both in vitro and in cells, and is able to induce a reduction of cell proliferation. Moreover, compound 6 displays cell phenotype-reprogramming properties since it prevents the epithelial to mesenchymal transition in cancer cells, inducing a less aggressive and migratory phenotype, which is one of the goals of present innovative strategies in cancer therapies. PMID- 29259738 TI - Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions. AB - Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki ~ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 MUM (1-2 MUg/mL) against the H37Ra isolate of M. tuberculosis. PMID- 29259739 TI - EGFR-Targeted Magnetic Nanovectors Recognize, in Vivo, Head and Neck Squamous Cells Carcinoma-Derived Tumors. AB - Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors with high morbidity and mortality that have remained mostly unchanged over the past decades. The epidermal growth factor receptor (EGFR) is often overexpressed and activated in these tumors and strongly contributes to their pathogenesis. Still, EGFR-targeted therapies such as monoclonal antibodies and kinase inhibitors have demonstrated only limited improvements in the clinical outcome of this disease. Here, we take advantage of the extraordinary affinity of EGF for its cognate receptor to specifically target magnetite-containing nanoparticles to HNSCC cells and mediate, in vitro, their cellular upload. On the basis of this, we show efficient accumulation, in vivo, of such nanoparticles in subcutaneous xenograft tumor tissues in sufficient amounts to be able to mediate visualization by magnetic resonance imaging. Overall, our EGF-coated nanosystem may warrant, in the near future, novel and very efficient theranostic approaches to HNSCC. PMID- 29259740 TI - Radiochemical Synthesis and Evaluation of 13N-Labeled 5-Aminolevulinic Acid for PET Imaging of Gliomas. AB - The endogenous amino acid, 5-aminolevulinic acid (5-ALA), has received significant attention as an imaging agent, including ongoing clinical trials for image-guided tumor resection due to its selective uptake and subsequent accumulation of the fluorescent protoporphyrin IX in tumor cells. Based on the widely reported selectivity of 5-ALA, a new positron emission tomography imaging probe was developed by reacting methyl 5-bromolevulinate with [13N] ammonia. The radiotracer, [13N] 5-ALA, was produced in high radiochemical yield (65%) in 10 min and could be purified using only solid phase cartridges. In vivo testing in rats bearing intracranial 9L glioblastoma showed peak tumor uptake occurred within 10 min of radiotracer administration. Immunohistochemical staining and fluorescent imaging was used to confirm the tumor location and accumulation of the tracer seen from the PET images. The quick synthesis and rapid tumor specific uptake of [13N] 5-ALA makes it a potential novel clinical applicable radiotracer for detecting and monitoring tumors noninvasively. PMID- 29259741 TI - 2-Arylidene Hydrazinecarbodithioates as Potent, Selective Inhibitors of Cystathionine gamma-Lyase (CSE). AB - Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role. We describe the discovery and development of a novel series of potent CSE inhibitors that show increased activity over the benchmark inhibitor and, importantly, display high selectivity for CSE versus CBS. PMID- 29259742 TI - Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH. AB - Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD + CCl4 model. PMID- 29259743 TI - Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo. AB - In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI 2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies. PMID- 29259744 TI - In Silico HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors. AB - We present the outcome of an in silico high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, SR 17398, with an indazole core. Docking studies guided design efforts that led to inhibitors with increased activity vs ULK1 (IC50 < 50 nM). The most advanced molecules in this inhibitor series (3a and 3g) hold promise for further development into selective ULK1 molecular probes to interrogate the biology of ULK1 and to assess whether selectively targeting autophagy is an effective anticancer strategy. PMID- 29259745 TI - Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design. AB - Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo-based program, to identify an indazole based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives. Biological evaluation revealed that these indazole-containing fragments inhibited FGFR1-3 in the range of 0.8-90 MUM with excellent ligand efficiencies of 0.30 0.48. Some compounds exhibited moderate selectivity toward individual FGFRs, indicating that further optimization using SBDD may lead to potent and selective inhibitors of the FGFR family. PMID- 29259746 TI - Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells. AB - Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2 NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate cancer cell lines, respectively, under hypoxic conditions. Radiolabeling of 2-NIPAM with 125I was accomplished through a Cu(I)-mediated azide-alkyne cycloaddition reaction. The 125I-conjugate demonstrated 13.6 and 17.8% lower efflux rates for DU145 and PC-3 cells, correspondingly, under hypoxic conditions, suggesting that the increased retention is likely due to the known intracellular trapping mechanism. In conclusion, these studies demonstrate the potential of 2-NIPAM in serving as a trapping agent for radiopharmaceutical development. PMID- 29259747 TI - Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. AB - A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, 8, displayed interesting potencies, including against nitroreductase mutant Mycobacterium tuberculosis. However, recent nuclear magnetic resonance analyses of two trace byproducts, isolated from early process optimization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for 8, stimulating further investigation. Following our discovery that the reported compound was a 6 nitroimidazooxazole derivative, we developed a de novo synthesis of authentic 8 via nitration of the chiral des-nitro imidazooxazine alcohol 26 in trifluoroacetic or acetic anhydride, and verified its identity through an X-ray crystal structure. Unfortunately, 8 displayed no antitubercular activity (MICs > 128 MUM), whereas the second byproduct (3'-methyl pretomanid) was eight-fold more potent than pretomanid in the aerobic assay. These findings further clarify target specificities for bicyclic nitroimidazoles, which may become important in the event of any future clinical resistance. PMID- 29259748 TI - Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia. AB - Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19. PMID- 29259749 TI - Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor. AB - Coordination of the ammonium group of Lys32 in the active site of human macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one instead of a quinoline is investigated. Both gas- and aqueous-phase DFT calculations for model systems indicate potential benefits for the added hydrogen bond with the lactam carbonyl group, while FEP results are neutral. Three crystal structures are reported for complexes of MIF with 3a, 4a, and 4b, which show that the desired hydrogen bond is formed with O-N distances of 2.8-3.0 A. Compound 4b is the most potent new MIF inhibitor with Ki and Kd values of 90 and 94 nM; it also has excellent aqueous solubility, 288 MUg/mL. Consistent with the FEP results, the naphthyridinones are found to have similar potency as related quinolines in spite of the additional protein-ligand hydrogen bond. PMID- 29259750 TI - Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV 1 Protease Inhibitors. AB - Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718. PMID- 29259751 TI - Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors. AB - A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3 triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors. PMID- 29259752 TI - Long-Lasting and Fast-Acting in Vivo Efficacious Antiplasmodial Azepanylcarbazole Amino Alcohol. AB - With ~429,000 deaths in 2016, malaria remains a major infectious disease where the need to treat the fever symptoms, but also to provide relevant post-treatment prophylaxis, is of major importance. An azepanylcarbazole amino alcohol is disclosed with a long- and fast-acting in vivo antiplasmodial efficacy and meets numerous attributes of a desired post-treatment chemoprophylactic antimalarial agent. The synthesis, the parasitological characterization, and the animal pharmacokinetics and pharmacodynamics of this compound are presented along with a proposed target. PMID- 29259753 TI - Discovery of APD371: Identification of a Highly Potent and Selective CB2 Agonist for the Treatment of Chronic Pain. AB - The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain. PMID- 29259755 TI - Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia. AB - Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable pi-pi stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate. PMID- 29259754 TI - Discovery of New Sulfonamide Carbonic Anhydrase IX Inhibitors Incorporating Nitrogenous Bases. AB - Incorporation of the purine/pyrimidine moieties as tails to classical benzenesulfonamide scaffolds afforded two series of human (h) carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The compounds were designed according to the molecular hybridization approach, in order to modulate the interaction with different CA isozymes and exploit the antitumor effect of uracil and adenine derivatives in parallel and synergic mode to the inhibition of the tumor associated hCA IX. The sulfonamides were investigated as inhibitors of four isoforms, cytosolic hCA I/II and transmembrane hCA IV/IX. The inhibitory profiles were dependent on the length and positioning of the spacer connecting the two pharmacophores. X-ray crystallography demonstrated the binding mode of an inhibitor to hCA II and hCA IX-mimic. Compounds endowed with the best hCA IX inhibitory efficacy were evaluated for antiproliferative activity against HT-29 colon cancer cell lines. The in vitro results suggest multiple mechanisms of action are responsible for the compounds' cytotoxic efficacy. PMID- 29259756 TI - VU6010608, a Novel mGlu7 NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5 (trifluoromethoxy)phenyl)benzamides. AB - Herein, we report the structure-activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5 (trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (Kp 1.9 5.8 and Kp,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies. PMID- 29259757 TI - Novel Naphthalimide Aminothiazoles as Potential Multitargeting Antimicrobial Agents. AB - A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the piperazine derivative 4d displayed superior antibacterial activity against MRSA and Escherichia coli with MIC values of 4 and 8 MUg/mL, respectively, to reference drugs. The most active compound 4d showed low toxicity against mammalian cells with no obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy and efficient membrane permeability. Preliminarily investigations revealed that compound 4d could not only bind with gyrase-DNA complex through hydrogen bonds but could effectively intercalate into MRSA DNA to form 4d-DNA supramolecular complex, which might be responsible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule 4d could be effectively stored and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding process. PMID- 29259758 TI - SAR Studies of Indole-5-propanoic Acid Derivatives To Develop Novel GPR40 Agonists. AB - G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, 8h (EC50 = 58.6 nM), 8i (EC50 = 37.8 nM), and 8o (EC50 = 9.4 nM), were identified as potent GPR40 agonists with good GSIS effects. PMID- 29259759 TI - Correction to "Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure". AB - [This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.]. PMID- 29259760 TI - Lung function in severe pediatric asthma: a longitudinal study in children and adolescents in Brazil. AB - Background: In severe asthma, high doses of inhaled corticosteroids (ICS) are used in order to achieve clinical and functional control. This study aimed to evaluate lung function in outpatients (children and adolescents) with severe asthma in Brazil, all of whom were treated with high doses of ICS. We evaluated all spirometry tests together and by ICS dose: 800 and > 800 ug/day. Methods: This was a 3-year longitudinal study in which we analyzed 384 spirometry tests in 65 severe asthma patients (6-18 years of age), divided into two groups by the dose of ICS (budesonide or equivalent): 800 and > 800 ug/day. Results: At baseline, the forced expiratory volume in one second (FEV1) and the FEV1/forced vital capacity (FVC) ratio were both < 80% of the predicted values in 50.8% of the patients. The median age of the patients was 10.4 years (interquartile range 7.8-13.6 years). In the sample as a whole, there were significant increases in FEV1% and in the FEV1/FVC% ratio (p = 0.01 and p < 0.001, respectively) over the course of the study. In the > 800 ug/day group, there were no statistical increases or decreases in FEV1, the FEV1/FVC ratio, or forced expiratory flow between 25 and 75% of the FVC (FEF25-75%), when calculated as percentages of the predicted values. However, the z-score for FEF25-75% showed a statistically significant reduction, in the sample as a whole and in the > 800 ug/day group. Also in the > 800 ug/day group, there was a significant reduction in the post bronchodilator FEV1% (p = 0.004). Conclusions: The fact that the spirometric parameters (as percentages of the predicted values) remained constant in the > 800 ug/day group, whereas there was a gain in lung function in the sample as a whole, suggests an early plateau phase in the > 800 ug/day group. However, there was some loss of lung function in the > 800 ug/day group, as evidenced by a decrease in the z-score for FEF25-75%, suggesting irreversible small airway impairment, and by a reduction in the post-bronchodilator FEV1%, suggesting reduced reversibility of airway obstruction. Among children and adolescents with severe asthma, the use of ICS doses higher than those recommended for age does not appear to improve lung function. PMID- 29259761 TI - Towards understanding the molecular mechanism of cardiolipin transport in Salmonella typhimurium: interactions between an essential inner membrane protein YejM and its newly found ligand, YejL. AB - Salmonella typhimurium is responsible for over 35% of all foodborne illness related hospitalizations in the United States. This Gram-negative bacterium possesses an inner and an outer membrane (OM), the latter allowing its survival and replication within host tissues. During infection, OM is remodeled by transport of glycerophospholipids across the periplasm and into the OM. Increased levels of cardiolipin in the OM were observed upon PhoPQ activation and led to the discovery of YejM; an inner membrane protein essential for cell growth involved in cardiolipin binding and transport to the OM. Another protein that might be playing a role in cardiolipin transport is YejL, as its gene is localized upstream of yejm on the same operon. Here we report how YejM was engineered to facilitate crystal growth and X-ray diffraction analysis. Furthermore, we present for the first time that YejL is a ligand for YejM. Successful structure determination of YejM and YejL will help us understand how they interact and how YejM facilitates cardiolipin transport to the OM. Ultimately, yejm, being an essential gene, may lead to new drug targets inhibiting the pathogenic properties of S. typhimurium. PMID- 29259762 TI - A bibliometric analysis of the global research on sofosbuvir. AB - In this article, we examine the research on sofosbuvir with a bibliometric analysis of global research production. The study of sofosbuvir has been a field of intense research in the past few years, with Latin American contributions playing a modest role. With continued drug development and approval of hepatitis C antivirals, research is expected to increase. Our findings will assist scholars and policy makers in their efforts to improve scientific research policies, with the goal of maximizing the access to treatments, especially in low and middle income countries. PMID- 29259764 TI - Utility of massive open online courses (MOOCs) concerning outbreaks of emerging and reemerging diseases. AB - The emergence and re-emergence of infectious diseases such as Ebola, chikungunya, and Zika increase the necessity of knowledgeable and skilled health professionals. Massive open online courses (MOOCs) arise as opportunities that allow people around the world to participate in higher education courses. A search was conducted on specialized MOOC platforms to find courses related to outbreaks, using terms included in the list of the WHO disease outbreaks from January 1st to December 31 st, 2016. We found seven courses about Ebola, two about Zika, three about the dynamics of epidemics and pandemics, and only one course about dengue, chikungunya, and malaria. Most of the courses were conducted in English. The courses on Ebola, Zika and chikungunya were released after their last outbreak. MOOCs could be used to learn about health issues of global relevance, and with the necessity of fast divulgation of knowledge and skills. Translating the courses into more languages could give these courses more traction, and allow participation of professionals in regions affected by these outbreaks. PMID- 29259763 TI - Blinding in trials of interventional procedures is possible and worthwhile. AB - In this paper, we have used evidence from our earlier review of surgical randomised controlled trials with a placebo arm to show that blinding in trials of interventional procedures is feasible, and that many creative methods can be used to make the active and the placebo procedure as similar as possible. We give examples of ingenious strategies used to simulate the active procedure and make the placebo control indistinguishable from the active treatment. We discuss why it is important to blind of patients, assessors, and caregivers and the types of bias that may occur in interventional trials. Finally, we describe the benefits of blinding, from the obvious ones such as avoiding bias, as well as less evident benefits such as avoiding patient drop out in the control arm. PMID- 29259765 TI - Case Report: Managing a giant, high-grade carotid body tumor in a resource limited setting. AB - Herein we report the management of a giant, high-grade and vascular carotid body tumor in a young woman. She presented with slowly progressive neck swelling. Vascular imaging revealed a left-sided, high-grade giant carotid body tumor (> 8cm). The tumor was completely excised by caudocranial subadventitial dissection. Histology of the tumor revealed a characteristic Zellballen pattern of the lesion, suggestive of a paraganglioma. The patient made an uneventful recovery. We also discuss newer insights regarding the management of such highly vascular lesions. PMID- 29259766 TI - A short review on the potential of coffee husk gasification for sustainable energy in Uganda. AB - Agricultural biomass is widely recognized as a clean and renewable energy source, with increasing potential to replace conventional fossil fuels in the energy market. Uganda, like other developing countries, has a high dependency (91%) on wood fuel, leading to environmental degradation. With a coffee production of 233 Metric Tonnes per annum, relating to 46.6 Mega Tonnes of coffee husks from processing, transforming these husks into syngas through gasification can contribute to resolving the existing energy challenges. The objective of this article is to briefly review the energy potential of coffee husks through gasification, and how the gasification process could increase energy recoveries for coffee farmers. Previous findings indicate that the 46.6 Mega Tonnes per year of coffee husks generated in Uganda, with a heating value of 18.34 MJ/kg, is capable of generating 24 GWh of energy. This will address a 0.7% portion of the energy situation in Uganda, while protecting the environment. PMID- 29259768 TI - Continuous outcome logistic regression for analyzing body mass index distributions. AB - Body mass indices (BMIs) are applied to monitor weight status and associated health risks in populations. Binary or multinomial logistic regression models are commonly applied in this context, but are only applicable to BMI values categorized within a small set of defined ad hoc BMI categories. This approach precludes comparisons with studies and models based on different categories. In addition, ad hoc categorization of BMI values prevents the estimation and analysis of the underlying continuous BMI distribution and leads to information loss. As an alternative to multinomial regression following ad hoc categorization, we propose a continuous outcome logistic regression model for the estimation of a continuous BMI distribution. Parameters of interest, such as odds ratios for specific categories, can be extracted from this model post hoc in a general way. A continuous BMI logistic regression that describes BMI distributions avoids the necessity of ad hoc and post hoc category choice and simplifies between-study comparisons and pooling of studies for joint analyses. The method was evaluated empirically using data from the Swiss Health Survey. PMID- 29259769 TI - Detection of illicit online sales of fentanyls via Twitter. AB - A counterfeit fentanyl crisis is currently underway in the United States. Counterfeit versions of commonly abused prescription drugs laced with fentanyl are being manufactured, distributed, and sold globally, leading to an increase in overdose and death in countries like the United States and Canada. Despite concerns from the U.S. Drug Enforcement Agency regarding covert and overt sale of fentanyls online, no study has examined the role of the Internet and social media on fentanyl illegal marketing and direct-to-consumer access. In response, this study collected and analyzed five months of Twitter data (from June-November 2015) filtered for the keyword "fentanyl" using Amazon Web Services. We then analyzed 28,711 fentanyl-related tweets using text filtering and a machine learning approach called a Biterm Topic Model (BTM) to detect underlying latent patterns or "topics" present in the corpus of tweets. Using this approach we detected a subset of 771 tweets marketing the sale of fentanyls online and then filtered this down to nine unique tweets containing hyperlinks to external websites. Six hyperlinks were associated with online fentanyl classified ads, 2 with illicit online pharmacies, and 1 could not be classified due to traffic redirection. Importantly, the one illicit online pharmacy detected was still accessible and offered the sale of fentanyls and other controlled substances direct-to-consumers with no prescription required at the time of publication of this study. Overall, we detected a relatively small sample of Tweets promoting illegal online sale of fentanyls. However, the detection of even a few online sellers represents a public health danger and a direct violation of law that demands further study. PMID- 29259770 TI - Case Report: A rare cause of oral bullae: Angina bullosa hemorrhagica. AB - Angina bullosa hemorrhagica (ABH) is a benign disorder of the oral cavity. Clinically, oral, blood-filled blisters are seen. To give a proper diagnosis, one should rule out any other cause. We aim to present this case in order to emphasize this rare cause of oral bullae which is necessary to be differentiated from many serious dermatological and hematological disorders. PMID- 29259767 TI - The protective effectiveness of control interventions for malaria prevention: a systematic review of the literature. AB - Background: Thanks to a considerable increase in funding, malaria control interventions (MCI) whose efficacy had been demonstrated by controlled trials have been largely scaled up during the last decade. Nevertheless, it was not systematically investigated whether this efficacy had been preserved once deployed on the field. Therefore, we sought the literature to assess the disparities between efficacy and effectiveness and the effort to measure the protective effectiveness (PE) of MCI. Methods: The PubMed database was searched for references with keywords related to malaria, to control interventions for prevention and to study designs that allow for the measure of the PE against parasitemia or against clinical outcomes. Results: Our search retrieved 1423 references, and 162 articles were included in the review. Publications were scarce before the year 2000 but dramatically increased afterwards. Bed nets was the MCI most studied (82.1%). The study design most used was a cross-sectional study (65.4%). Two thirds (67.3%) were conducted at the district level or below, and the majority (56.8%) included only children even if the MCI didn't target only children. Not all studies demonstrated a significant PE from exposure to MCI: 60.6% of studies evaluating bed nets, 50.0% of those evaluating indoor residual spraying, and 4/8 showed an added PE of using both interventions as compared with one only; this proportion was 62.5% for intermittent preventive treatment of pregnant women, and 20.0% for domestic use of insecticides. Conclusions: This review identified numerous local findings of low, non significant PE -or even the absence of a protective effect provided by these MCIs. The identification of such failures in the effectiveness of MCIs advocates for the investigation of the causes of the problem found. Ideal evaluations of the PE of MCIs should incorporate both a large representativeness and an evaluation of the PE stratified by subpopulations. PMID- 29259771 TI - Phenotype and genotype of lactic acid bacteria (LAB) isolated from the tiger grouper Epinephelus fuscoguttatus alimentary tract. AB - Lactic acid bacteria (LAB) have been isolated successfully from the tiger grouper Epinephelusfuscoguttatus intestine. However, their genus or species have not been identified. Therefore, the objective of the present study was to characterize the three isolated LAB (KSBU-12C, KSBU-5Da, and KSBU-9) based on their phenotype and genotype. The LAB phenotype was examined by observing morphological features including cell morphology, spore production and motility. The physiological tests were performed in 6.5% NaCl at the temperatures of 10 oC and 45 oC, and the biochemical tests were evaluated based on the production of enzymes catalase, oxidase and arginine dehydrolase, following the Standard Analytical Profile Index, API 50 CH kit. The genotype was examined based on 16S rDNA gene sequence analysis , and the products were analyzed using the BLAST (Basic Local Alignment Search Tool) NCBI database. The three isolates (KSBU-5Da, KSBU-12C, and KSBU-9) were categorized into the genus Enterococcus. 16S rDNA sequence analysis indicated that the isolates had 99% similarity to E. hirae ATCC 9790, registered in GenBank with accession number NR_075022.1. It was concluded that the three LAB isolates taken from the tiger grouper Epinephelus fuscoguttatus are E. hirae. PMID- 29259772 TI - Genetics in the 21st Century: Implications for patients, consumers and citizens. AB - The first human genome project, completed in 2003, uncovered the genetic building blocks of humankind. Painstakingly cataloguing the basic constituents of our DNA ('genome sequencing') took ten years, over three billion dollars and was a multinational collaboration. Since then, our ability to sequence genomes has been finessed so much that by 2017 it is possible to explore the 20,000 or so human genes for under L1000, in a matter of days. Such testing offers clues to our past, present and future health, as well as information about how we respond to medications so that truly 'personalised medicine' is now a reality. The impact of such a 'genomic era' is likely to have some level of impact on all of us, even if we are not directly using healthcare services ourselves. We explore how advancements in genetics are likely to be experienced by people, as patients, consumers and citizens; and urge policy makers to take stock of the pervasive nature of the technology as well as the human response to it. PMID- 29259773 TI - Identification of organic pigments in tattoo inks and permanent make-ups using MALDI-TOF mass spectrometry. AB - Nowadays, about 12% of the European and 20% of the US population are tattooed. Rising concerns regarding consumer safety, led to legal restrictions on tattoo inks and permanent make-up (PMU) inks. Restrictions also include bans on certain hazardous colourants. Both ink types use organic pigments for colour-giving, plus inorganic pigments for white and black and colour tones. Pigments are only sparingly soluble in common solvents and occur as suspended particles in the ink matrix. Their detection and identification therefore pose a major challenge for laboratories involved in monitoring the legal compliance of tattoo inks and PMUs. We overcame this challenge by developing a matrix-assisted laser desorption ionisation time-of-flight mass spectrometry method, which included an easy sample clean up. The method proved to be capable of detecting and identifying organic pigments in almost all of the tested ink samples. Method validation and routine deployment during market surveys showed the method to be fit for purpose. Pigment screening of 396 tattoo inks and 55 PMUs taken from the Swiss market between 2009 and 2017 lead to the following conclusions: Pigment variety is much greater in tattoo inks (18) than in PMUs (10); four prohibited pigments (Pigment Green 7, Pigment Red 122, Pigment Violet 19 and 23) were found in both ink types; for PMUs, these four pigments made up 12% of the pigment findings, compared to 32% for tattoo inks. Therefore, legal compliance of PMUs was at a higher level. A comparison of pigments found with those declared on tattoo ink labels clearly showed that banned pigments are rarely declared, but rather masked by listing not present legal pigments and label forging; therefore, highlighting the urgency of widespread market controls. PMID- 29259774 TI - Advancing psychosocial care in cancer patients. AB - Cancer is a devastating disease causing significant psychological problems among patients and their families. In the past few decades, there have been growing implementation and dissemination of screening methods for the psychological consequences of cancer, including distress, depression, anxiety, post-traumatic stress, and demoralisation. Also, guidelines for the management of psychological distress have been developed and endorsed by a number of scientific cancer associations. This review examines some of the most significant related issues, also focusing on recent advances in psychosocial and psychopharmacological interventions as a part of a mandatory, integrated, and comprehensive approach to cancer care. PMID- 29259775 TI - Premature ejaculation: challenging new and the old concepts. AB - Premature ejaculation remains a difficult condition to manage for patients, their partners, and the clinician. Whilst prevalence rates are estimated to be 20-40%, determining a diagnosis of premature ejaculation is difficult, as the definition remains both subjective and ill-defined in the clinical context. As our understanding of the ejaculatory pathway has improved, new opportunities to treat the condition have evolved with mixed results. In this review, we explore some of these controversies surrounding the aetiology, diagnosis, and treatment of this condition and discuss potential novel therapeutic options. PMID- 29259776 TI - Emerging concepts and recent advances in basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common malignancy worldwide, arising from non-keratinizing cells within the basal layer of the epidermis. The incidence of BCC continues to rise annually, increasing the burden of management of these carcinomas and the morbidity associated with their treatment. While surgical interventions such as Mohs micrographic surgery and surgical excision are the standard of care and yield the highest cure rates, the number of non-surgical interventions approved for the treatment of BCC continues to expand. We review various surgical and non-surgical approaches to the treatment of BCC, focusing on targeted molecular therapies that are approved for locally advanced or recurrent disease. PMID- 29259777 TI - An update on phloem transport: a simple bulk flow under complex regulation. AB - The phloem plays a central role in transporting resources and signalling molecules from fully expanded leaves to provide precursors for, and to direct development of, heterotrophic organs located throughout the plant body. We review recent advances in understanding mechanisms regulating loading and unloading of resources into, and from, the phloem network; highlight unresolved questions regarding the physiological significance of the vast array of proteins and RNAs found in phloem saps; and evaluate proposed structure/function relationships considered to account for bulk flow of sap, sustained at high rates and over long distances, through the transport phloem. PMID- 29259778 TI - The emerging landscape of in vitro and in vivo epigenetic allelic effects. AB - Epigenetic mechanisms that cause maternally and paternally inherited alleles to be expressed differently in offspring have the potential to radically change our understanding of the mechanisms that shape disease susceptibility, phenotypic variation, cell fate, and gene expression. However, the nature and prevalence of these effects in vivo have been unclear and are debated. Here, I consider major new studies of epigenetic allelic effects in cell lines and primary cells and in vivo. The emerging picture is that these effects take on diverse forms, and this review attempts to clarify the nature of the different forms that have been uncovered for genomic imprinting and random monoallelic expression (RME). I also discuss apparent discrepancies between in vitro and in vivo studies. Importantly, multiple studies suggest that allelic effects are prevalent and can be developmental stage- and cell type-specific. I propose some possible functions and consider roles for allelic effects within the broader context of gene regulatory networks, cellular diversity, and plasticity. Overall, the field is ripe for discovery and is in need of mechanistic and functional studies. PMID- 29259779 TI - Uterine fibroids - what's new? AB - Uterine fibroids are the commonest benign tumours of women and affect all races with a cumulative lifetime risk of around 70%. Despite their high prevalence and the heavy economic burden of treatment, fibroids have received remarkably little attention compared to common female malignant tumours. This article reviews recent progress in understanding the biological nature of fibroids, their life cycle and their molecular genetic origins. Recent progress in surgical and interventional management is briefly reviewed, and medical management options, including treatment with selective progesterone receptor modulators, are also discussed. PMID- 29259780 TI - Recent advances in the management of non-small cell lung cancer. AB - Lung cancer is the number one cause of cancer-related death in both men and women. However, over the last few years, we have witnessed improved outcomes that are largely attributable to early detection, increased efforts in tobacco control, improved surgical approaches, and the development of novel targeted therapies. Currently, there are several novel therapies in clinical practice, including those targeting actionable mutations and more recently immunotherapeutic agents. Immunotherapy represents the most significant step forward in eradicating this deadly disease. Given the ever-changing landscape of lung cancer management, here we present an overview of the most recent advances in the management of non-small cell lung cancer. PMID- 29259781 TI - Fragile X syndrome and fragile X-associated disorders. AB - Fragile X syndrome (FXS) is caused by a full mutation on the FMR1 gene and a subsequent lack of FMRP, the protein product of FMR1. FMRP plays a key role in regulating the translation of many proteins involved in maintaining neuronal synaptic connections; its deficiency may result in a range of intellectual disabilities, social deficits, psychiatric problems, and dysmorphic physical features. A range of clinical involvement is also associated with the FMR1 premutation, including fragile X-associated tremor ataxia syndrome, fragile X associated primary ovarian insufficiency, psychiatric problems, hypertension, migraines, and autoimmune problems. Over the past few years, there have been a number of advances in our knowledge of FXS and fragile X-associated disorders, and each of these advances offers significant clinical implications. Among these developments are a better understanding of the clinical impact of the phenomenon known as mosaicism, the revelation that various types of mutations can cause FXS, and improvements in treatment for FXS. PMID- 29259782 TI - Chikungunya: vaccines and therapeutics. AB - Chikungunya virus (CHIKV) has come to prominence as a global, re-emerging pathogen over the last two decades, progressing from sporadic, remote outbreaks to worldwide explosive epidemics. From contained, though considerable, outbreaks in the southern Indian Ocean, parts of South America and the Caribbean, CHIKV continues to be a significant pathogen in Southeast Asia and India. CHIKV circulates during epidemics through an urban mosquito-to-human transmission cycle, and with no available treatments or licensed vaccines to specifically target CHIKV disease, limiting transmission relies on vector control, which poses significant challenges, especially in developing countries. This review summarizes the current findings and progress in the development of safe, effective and affordable therapeutics and vaccines for CHIKV disease. PMID- 29259783 TI - Recent advances in understanding and managing T-cell lymphoma. AB - Owing to the rarity of peripheral T-cell lymphoma (PTCL) and the heterogeneity of subtypes, there are no compelling data to guide the therapeutic approaches for such patients. Over the years, there have been remarkable advances in molecular subtyping and treatment of PTCL, although there are still many areas to be explored. In this review, we summarize recent updates on the evolution of understanding and treatment for PTCL. PMID- 29259785 TI - Student experiences and perceptions of compulsory research projects: a veterinary perspective. AB - Background: Although research underpins clinical work, many students training to be clinicians are not inherently interested in developing research skills. Aim: To characterise and understand veterinary student experiences and perceptions of compulsory research projects. Methods: This was an explanatory sequential mixed methods study, with a questionnaire survey of an entire cohort informing purposive selection for focus group discussions. Student views were triangulated with staff questionnaire data. Results: About a third of the cohort felt that the project had not been worthwhile or had not fostered useful skills. Focus group data analysis identified fragility of motivation and lack of clear schemata for the research process as key themes. Students were easily demotivated by typical research challenges and lack of schemata contributed to a poor understanding of the rationale for the project, encouraging highly extrinsic forms of motivation. Triangulation with staff questionnaire data indicated that staff understood students' challenges, but were more likely than students to consider it to be a valuable learning experience. Conclusions: Findings support ongoing curriculum development and emphasise that, to optimise motivation, engagement and learning, students training to be clinicians need a clear rationale for research, based on development of critical inquiry skills as a core clinical competency. PMID- 29259784 TI - Prospective cohort study to assess rates of contagious disease in pre-weaned UK dairy heifers: management practices, passive transfer of immunity and associated calf health. AB - Dairy calves are vulnerable to infectious diseases, particularly diarrhoea and bovine respiratory disease (BRD), causing mortality and reducing welfare and growth. A prospective cohort study was performed on 11 UK dairy farms to determine the underlying causes for calf disease. This first paper describes the incidence, timing and duration of infectious disease, mortality rates, passive transfer of immunity and key management practices that may contribute to disease incidence. Heifer calves were recruited in the first week of life (n=492) and a blood sample taken to measure IgG and total protein (TP). Each animal was examined weekly for nine weeks using a standardised health scoring system. Recruitment of calves occurred between August and February. Four farms provided supplementary colostrum to more than 75 per cent of calves born, whereas on the remainder only 0 to 19 per cent were supplemented. Mean serum IgG and TP were 19.0+/-10 and 56.7+/-10.3 mg/ml respectively, with 20.7 per cent (95CI: 17.2 to 24.7 per cent) of all calves classified as having failure of passive transfer (IgG <10 mg/ml). The overall preweaning mortality rate was 4.5 per cent. (95 per cent CI: 2.9 to 6.8 per cent). During this period,48.2 per cent of all calves (range 24.1 to 74.4 per cent between farms) were diagnosed with diarrhoea and 45.9 per cent (range 20.4 to 77.8 per cent) with BRD. The incidence rates were 7.8 cases of diarrhoea and 10.1 cases of BRD per 100 calf weeks at risk, respectively. Rates of infectious disease were therefore high despite relatively good passive transfer. PMID- 29259786 TI - Necessity to evaluate PI3K/Akt signalling pathway in proarrhythmia. AB - The incidence of QT prolongation and torsades de pointes is on the rise due to the use of cardiovascular and non-cardiovascular drugs. Robust efforts have been made and are still ongoing to understand the underlying mechanisms that can enhance or prevent the development of drug-induced proarrhythmia. A caveat in the use of antiarrhythmic drugs is the ability to obtain safe action potential prolongation therapeutic effects, through IKr blockade. This remains as yet completely unachievable, as blockers of the potassium channel have not provided complete safe measures. Because of this, efforts at understanding the mechanisms of proarrhythmia have continued. PI3K/Akt signalling pathway appears to possess some potential advantage in this regard because cardiomyocytes intracellular dialysis with phosphatidylinositol (3,4,5)-trisphosphate (PIP3) normalises ion channel alterations and eliminates proarrhythmic features. However, there is a conundrum. Increased activities of PIP3 signalling can enhance cell proliferation and survival, and reduced activities of PIP3 signalling can lead to proarrhythmia. PI3K inhibitors used in cancer treatment have been found to cause proarrhythmia, and represent a potential avenue for the research and evaluation of potential effectiveness of a battery of antiarrhythmic and cancer drugs that are either currently in use or in development. Despite this knowledge, limited information is available on PI3K/Akt signalling and arrhythmogenesis. This highlights the need to search for new ways to improve testing of antiarrhythmic drugs and increase our understanding in PI3K/Akt signalling and arrhythmogenesis. PMID- 29259787 TI - Renin-angiotensin system inhibitors in patients with or without ischaemic mitral regurgitation after acute myocardial infarction. AB - Objective: Little is known about the long-term effects of renin-angiotensin system inhibitors (RASI) on cardiovascular events in patients after acute myocardial infarction (AMI) with ischaemic mitral regurgitation (IMR). The purpose of this study was to investigate the association of RASI with the incidence of adverse cardiac events in patients with or without IMR after AMI. Methods: We reviewed charts of 1208 consecutive patients admitted with AMI who underwent emergency coronary angiography between 2000 and 2012. After excluding patients who died within 30 days, 551 patients were diagnosed to have mild or greater MR by transthoracic echocardiography (patients with IMR); the remaining 505 patients had no or trivial MR (non-IMR patients). Results: Of the study patients, 395 (72%) patients with IMR and 403 (80%) non-IMR patients received RASI. Survival analysis showed that freedom from cardiac death and the composite of cardiac death and heart failure (HF) was significantly higher in patients with IMR receiving RASI than in those not receiving RASI (P<0.001 and P<0.001, respectively). Moreover, adjusted survival analysis using the inverse probability treatment weighting method showed a significant association of RASI therapy with reduced cardiac death (P=0.010) and the composite of cardiac death and HF (P=0.044) in patients with IMR. However, in non-IMR patients, there were no significant associations between RASI therapy and the outcome measures. Conclusions: RASI therapy was associated with a lower incidence of adverse cardiac events in patients with IMR after AMI, but not in patients without IMR. PMID- 29259788 TI - All-cause mortality and major cardiovascular outcomes comparing percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: a meta-analysis of short-term and long-term randomised trials. AB - Objective: We compared percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) for the treatment of left main coronary artery (LMCA) disease by conducting a systematic review and meta-analysis of randomised controlled trials (RCTs). Methods: RCTs of PCI versus CABG in patients with LMCA stenosis were identified from MEDLINE, the Cochrane Library and search of bibliographies to November 2016. Study-specific HRs with 95% CIs were aggregated for all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE), and other cardiovascular events at time points of 30 days, 1 year and 3 years and beyond. Results: Six RCTs comprising 4700 patients were included. There were no significant differences in risk of all-cause mortality in pooled analysis of relevant trials at 30 days (0.61, 95% CI 0.27 to 1.36), 1 year (0.66, 95% CI 0.42 to 1.04), and 3 years and beyond (1.04, 95% CI 0.81 to 1.33), comparing PCI with CABG. There was no significant difference in the risk of MACCE at 30 days (0.72, 95% CI 0.51 to 1.03) and 1 year (1.16, 95% CI 0.94 to 1.44); however, PCI was associated with a higher risk of MACCE compared with CABG during longer-term follow-up (1.27, 95% CI 1.12 to 1.44). Composite outcome of death, stroke or myocardial infarction was lower with PCI at 30 days (0.67, 95% CI 0.49 to 0.92). Repeat revascularisation was increased at 1 year and at 3 years and beyond for PCI. Conclusions: All-cause mortality rates are not significantly different between PCI and CABG at short-term and long-term follow-up. However, PCI is associated with a reduction in the risk of major cardiovascular outcomes at short term follow-up in patients with LMCA stenosis; but at long term, MACCE rate is increased for PCI. PMID- 29259789 TI - Markedly increased intake of refined carbohydrates and sugar is associated with the rise of coronary heart disease and diabetes among the Alaskan Inuit. PMID- 29259790 TI - Complement levels and risk of organ involvement in patients with systemic lupus erythematosus. AB - Objective: Complement plays a major role in SLE. Complement participation has been linked to disease activity and damage. Our objective was to estimate the association of complement behaviour with clinical manifestations, visceral injury and mortality in patients with SLE. Methods: Complement determinations (C3 and C4 levels) were analysed in patients with SLE (fulfilling American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC)criteria) seen at a university hospital between 2000 and 2013. Patients were grouped in those with permanent C3 and/or C4 low values (low complement group), those with C3 and C4 constant normal values (normal complement group) and those with fluctuant values (periods of normal and periods of low values: fluctuant group). Clinical characteristics and mortality were analysed and compared between groups. Results: 270 patients with SLE were included (242 females, 89.6%), mean age at diagnosis was 34.2 years (SD 15.8). 75 patients had fluctuant levels of complement, 79 patients had persistent low complement levels and 116 had normal complement levels. Lupus glomerulonephritis was more frequent in patients with fluctuant levels (75%, 56% and 49%, respectively, p=0002). The normal complement group had less frequency of haematological involvement and anti double stranded DNA (dsDNA) antibodies. At the end of the follow-up, 53% of the patients had damage (SLICC/ACR >=1). In a Cox proportional hazard model age at diagnosis, neurological impairment, thrombocytopaenia and corticosteroids were associated with more damage, while hydroxychloroquine was a protective factor. There were no differences between complements groups on accumulated damage. Ten year survival rate was 93%, 93.5% and 92% for the normal complement group, the persistently low group and the fluctuant group, respectively. Conclusions: Patients with constant normal complement had lower prevalence of haematological involvement and anti-dsDNA, while patients with fluctuant complement had higher renal impairment. Neither the persistent low complement nor the fluctuant complement groups had increased mortality and/or visceral damage. PMID- 29259791 TI - Diagnostic accuracy of high-resolution MRI as a method to predict potentially safe endoscopic and surgical planes in patients with early rectal cancer. AB - Introduction: Early rectal cancer (ERC) assessment should include prediction of the potential excision plane to safely remove lesions with clear deep margins and feasibility of organ preservation. Method: MRI accuracy for differentiating <=T1sm2 (partially preserved submucosa) or <=T2 (partially preserved muscularis) versus >T2 tumours was compared with the gold standard of pT stage T1sm1/2 versus <=pT2 versus >pT2. N stage was also compared. The MRI protocol employed a standard surface phased array coil with a high resolution (0.6*0.6*3 mm resolution). The staging data were analysed from a prospectively recorded database of all ERC (<=mrT3b) treated by primary surgery. Results: Of 65 0.7 suggesting good agreement. 44 out of 65 patients underwent radical surgery and 22 out of 44 were <=mrT2. MRI accuracy to predict lymph node status was 84% (95% CI 70% to 92%), PPV 71% and NPV 90%. Among the 21 out of 65 (32%) patients undergoing local excision or TEM, 20 out of 21 were staged as MR<=T2 and confirmed as such by pathology. On follow-up, none had relapse. If the decision had been made to offer local excision on MRI TN staging rather than clinical assessment, a significant increase in organ preservation surgery from 32% to 60% would have been observed (difference 23%, 95% CI 9% to 35%). Conclusions: MRI is a useful tool for multidisciplinary teams (MDTs) wishing to optimise treatment options for ERC; these study findings will be validated in a prospective multicentre trial. PMID- 29259792 TI - PCR detection of segmented filamentous bacteria in the terminal ileum of patients with ulcerative colitis. AB - Objectives: Segmented filamentous bacteria (SFB) have been detected in a wide range of different animal. Recently, the presence of SFB-like bacteria was shown in biopsies of the terminal ileum and ileocecal valve of both patients with ulcerative colitis and control subjects. The aim of this study was to verify whether PCR methods could be used for the detection of SFB in biopsy of patients with ulcerative colitis and its relationships with the disease stage. Methods: PCR methods were used to identify SFB in biopsies from the terminal ileum of patients with ulcerative colitis, showing that this approach represents a useful tool for the detection of SFB presence and analysis of the bacterial load. Results: Our analysis detected SFB in all faecal samples of children at the time of weaning, and also show that putative SFB sequences are present in both patients with ulcerative colitis and control subjects. Results obtained using real-time quantitative PCR analysis confirm the presence of putative SFB sequences in samples from the terminal ileum of patients with ulcerative colitis and in control subjects. Conclusions: The presence of putative SFB sequence in both patients with ulcerative colitis and control subject suggests that SFB cannot be considered as being uniquely associated with the disease. The second conclusion is that among the patients with ulcerative colitis, a tendency does exist for active disease samples to show higher SFB load, opening new perspectives about possible identification and pharmacological manipulation of SFB-mediated processes for new therapeutic strategy. PMID- 29259795 TI - Coping with weight stigma: development and validation of a Brief Coping Responses Inventory. AB - People who are overweight or obese are frequently stigmatized because of their weight, but there has been limited exploration of how people cope with these experiences. The Coping Responses Inventory (CRI) assesses a wide range of coping strategies in response to weight stigma; however, its length (99 items) may have prevented it from being widely used. The aim of the current research (four studies; total N = 1,391) was to develop and validate a Brief CRI. This 10-item measure consists of two subscales that assess core coping responses to weight stigma: reappraisal and disengagement coping. Reappraisal coping is an adaptive form of coping that is associated with greater well-being, whereas disengagement coping reflects a maladaptive form of coping that is associated with poorer well being. The Brief CRI provides a quick and effective way to assess coping with weight stigma, and its use has the potential to advance an understanding of the consequences of weight stigma. PMID- 29259793 TI - Effect of physical exercise on sarcopaenia in patients with overt hepatic encephalopathy: a study protocol for a randomised controlled trial. AB - Introduction: Limited data are currently available for patients with overt hepatic encephalopathy (OHE)) receiving physical exercise (PE). The aim of the current study is to prospectively examine the effect of PE on sarcopaenia in patients with OHE. Methods and analysis: At the time of patient recruitment, a precise assessment for nutritional status and daily physical activities will be performed in each subject. Study participants will be randomly assigned into two groups: (1) the PE group and (2) the control group. In the PE group, we will conduct guidance to study participants once a month at the outpatient nutrition guidance room. We will also instruct them to do exercise with >3 metabolic equivalents (mets; energy consumption in physical activities/resting metabolic rate) for 60 min per day and to do exercise >23 mets per week. Improvement of sarcopaenia as defined by muscle mass and muscle strength at 3 months after the randomisation will be the primary endpoint. Sarcopaenia will be defined based on the current Japanese guidelines. We prospectively compared the improvement of sarcopaenia in the two groups. Ethics and dissemination: This study has received approval from the Institutional Review Board at Hyogo college of medicine (approval no. 2768). Final data will be publicly disseminated irrespective of the study results. A report releasing study results will be submitted for publication in an appropriate journal after completion of data collection. Trial registration number: UMIN000029248; Pre-results. No patient is registered at the submission of our manuscript. PMID- 29259794 TI - Weight loss and frequency of body-weight self-monitoring in an online commercial weight management program with and without a cellular-connected 'smart' scale: a randomized pilot study. AB - Objective: Evaluate the effects of an online commercial weight management program, with and without provision of a 'smart' scale with instructions to weigh daily and weekly tailored feedback, on weight loss and the frequency of body weight self-monitoring. Methods: Participants (N = 92; body mass index 27-40 kg/m2) were randomized to 6 months of no-cost access to the Weight Watchers Online (WWO) platform alone, or enhanced with a cellular-connected 'smart' scale, instructions to weigh daily and weekly pre-scripted email feedback (Weight Watchers Online Enhanced [WWO-E]). The number of days that weight was self monitored (via 'smart' scale in WWO-E and manually in WWO) was recorded automatically across the 6-month trial. Objective weight was measured at baseline, 3 and 6 months. Results: While both groups achieved statistically significant weight loss, mean +/- standard error weight loss did not differ between WWO-E and WWO at 3 months (5.1 +/- 0.6 kg vs. 4.0 +/- 0.7 kg, respectively; p = 0.257) or 6 months (5.3 +/- 0.6 kg vs. 3.9 +/- 0.7 kg, respectively; p = 0.116). However, a greater proportion of WWO-E lost >=5% of initial body weight at 3 months (52.2% vs. 28.3%; p = 0.033), but not 6 months (43.5% vs. 30.4%; p = 0.280), compared with WWO. Mean +/- standard deviation days with self-monitored weight was higher in WWO-E (80.5 +/- 5.6; 44.7% of days) than WWO (12.0 +/- 1.0; 6.7% of days; p < 0.001) across the 6-month study period. Conclusions: This is the first study to show that provision of a 'smart' scale with weekly tailored feedback substantially increased the frequency of self weighing and the proportion of participants achieving an initial clinically significant >=5% weight loss (52% vs. 28%) in an online commercial weight management program. Both WWO and WWO-E produced significant weight loss over 6 months. While mean weight losses were slightly greater in the enhanced group, the difference was not statistically significant in this small sample. This study provides support for the clinical utility of online commercial weight management programs and the potential for supporting technology such as 'smart' scales to improve adherence to body-weight self-monitoring and clinical outcomes. PMID- 29259796 TI - Health Professionals' perceptions of insurance coverage for weight loss services. AB - Objective: To examine health professionals' (HPs) perceptions of top challenges and solutions in obesity care, and whether these perceptions differ by patient panel income level. Methods: A 2014 national cross-sectional survey of HPs in nutrition, nursing, behavioural or mental health, exercise and pharmacy was analysed. The dependent variables were identification of insurance coverage for their services as a top (1) challenge or (2) solution for obesity care. The independent variable was self-reported income distribution of HPs' patient panels, which was dichotomized as 'lower-income' if 'mostly low income' or 'higher-income' if 'mostly not low income/evenly split between low-income and not low-income'. Multivariate logistic regression with survey weights was used. Results: Among 450 HPs, mean age was 44.9 years; 86% were women; 44% had lower income panels. Overall, 25% of HPs endorsed insurance coverage as a current challenge, and 58% viewed improved coverage as a solution. HPs with lower and higher-income patient panels were similarly likely to identify coverage as a challenge (28% vs. 20%, p = 0.33) and benefits expansion as a solution (47% vs. 64%, p = 0.08). Conclusions: Most HPs perceive insurance coverage for their services to benefit patient weight loss. While the Affordable Care Act expands obesity counselling coverage to many lower-income patients, legislation increasing access to benefits for all patients regardless of insurance type may be beneficial. PMID- 29259797 TI - Underweight vs. overweight/obese: which weight category do we prefer? Dissociation of weight-related preferences at the explicit and implicit level. AB - Objective: Although stigma towards obesity and anorexia is a well-recognized problem, no research has investigated and compared the explicit (i.e. conscious) and implicit (i.e. unconscious) preferences between these two conditions. The present study conducted this investigation in a sample of 4,806 volunteers recruited at the Project Implicit website (https://implicit.harvard.edu). Methods: Explicit and implicit preferences were assessed among different weight categories (i.e. underweight, normal weight and overweight/obese) by means of self-reported items and the Multi-category Implicit Association Test, respectively. Results: Preferences for the normal weight category were found both at the explicit and implicit levels when this category was compared with overweight/obese and underweight categories. On the contrary, when the underweight category was contrasted with the obese/overweight category, results differed at the explicit and implicit levels: pro-underweight preferences were observed at the explicit level, while pro-overweight/obese preferences were found at the implicit level. Conclusions: These results indicate that preferences between overweight/obese and underweight categories differ at the explicit and implicit levels. This dissociation may have important implications on behaviour and decision-making. PMID- 29259798 TI - The relationship between health eating and overweight/obesity in Canada: cross sectional study using the CCHS. AB - Objective: The relationship between Canada's Food Guide (CFG) adherence and overweight/obesity at the population level is unknown. Our objective was to explore the association between overweight/obesity and CFG adherence in Canada. Methods: Using 24-h dietary recall data from the Canadian Community Health Survey (CCHS), we conducted a cross-sectional analysis of Canadians' consumption of four predefined food types from CFG (grain products, vegetables and fruit, milk and alternatives, meat and alternatives). Respondents aged 18 to 65 years with measured BMI were included. The total number of servings in each food group was compared with the number of recommended servings in CFG to determine adherence. Linear regression was used to explore the association between overweight/obesity and CFG adherence. Results: Participants who met the minimum servings in vegetables and fruit had a lower measured BMI. Also, participants who met the minimum servings in meat and alternatives had a higher measured BMI. These associations were observed for the sample as a whole and for those with overweight/obesity, and, for meat and alternatives, among women. Conclusion: There is evidence that following the CFG recommendation is associated with measured BMI, for some food groups. This relationship needs to be validated using longitudinal data. PMID- 29259799 TI - Effects of monthly feedback of VFA measured by dual BIA method in Japanese patients with obesity: a randomized controlled study. AB - Objective: To investigate the effects of monthly feedback of changes in visceral fat area (VFA) as measured by dual bioelectrical impedance analysis method and the importance of VFA in individuals with obesity. Methods: Thirty-eight Japanese patients with obesity underwent VFA measurements. The feedback group was given feedback on VFA measurements each month for 4 months. The control group underwent VFA measurements at the beginning and end of the study but was not informed of the results. All the study participants completed eating behaviour and weight efficacy lifestyle questionnaires. Results: Mean age was 53.9 (14.3) years; mean body mass index was 30.6 (4.3) kg m-2. At the 4-month follow-up, there was no significant difference in VFA reduction between the control and feedback groups ( 4.4% vs. -3.0%; 95% CI, -3.8 to 5.5). In post-hoc analysis using the overall group irrespective of allocation, changes of eating style were significantly associated with a reduction in VFA at 4 months (p = 0.034). Conclusions: Monthly feedback on changes in VFA does not reduce VFA. More frequent feedback may be required. In post-hoc analysis, changes of eating style were associated with a reduction in VFA. PMID- 29259800 TI - Accuracy of self-reported height, weight and waist circumference in a Japanese sample. AB - Objective: Inconsistent results have been found in prior studies investigating the accuracy of self-reported waist circumference, and no study has investigated the validity of self-reported waist circumference among Japanese individuals. This study used the diagnostic standard of metabolic syndrome to assess the accuracy of individual's self-reported height, weight and waist circumference in a Japanese sample. Methods: Study participants included 7,443 Japanese men and women aged 35-79 years. They participated in a cohort study's baseline survey between 2007 and 2011. Participants' height, weight and waist circumference were measured, and their body mass index was calculated. Self-reported values were collected through a questionnaire before the examination. Results: Strong correlations between measured and self-reported values for height, weight and body mass index were detected. The correlation was lowest for waist circumference (men, 0.87; women, 0.73). Men significantly overestimated their waist circumference (mean difference, 0.8 cm), whereas women significantly underestimated theirs (mean difference, 5.1 cm). The sensitivity of self-reported waist circumference using the cut-off value of metabolic syndrome was 0.83 for men and 0.57 for women. Conclusions: Due to systematic and random errors, the accuracy of self-reported waist circumference was low. Therefore, waist circumference should be measured without relying on self-reported values, particularly in the case of women. PMID- 29259801 TI - Treatment with liraglutide may improve markers of CVD reflected by reduced levels of apoB. AB - Background: Dislipidaemia and increased levels of apolipoprotein B (apoB) in individuals with obesity are risk factors for development of cardiovascular disease (CVD). The aim of this study was to investigate the effect of weight loss and weight maintenance with and without liraglutide treatment on plasma lipid profiles and apoB. Methods: Fifty-eight individuals with obesity (body mass index 34.5 +/- 3.0 kg/m2 [mean +/- SD]) were included in this study. After 8 weeks on a very low-calorie diet (800 kcal/day), participants were randomized to weight maintenance with meal replacements with or without liraglutide (1.2 mg daily) for 1 year. Plasma samples from before and after weight loss and after 1 year of weight maintenance were subjected to nuclear magnetic resonance-based lipidomics analysis. Results: After an 8-week low-calorie diet, study participants lost 12.0 +/- 2.9 kg (mean +/- SD) of their body weight, which was reflected in their lipid profiles (80 out of 124 lipids changed significantly), including reduced levels of apoB, total cholesterol, free cholesterol, remnant cholesterol, triglycerides, low-density lipoprotein and very low-density lipoprotein subclasses. After 1 year of maintained weight loss, the majority of the lipids had returned to pre-weight loss levels even though weight loss was successfully maintained in both groups. Interestingly, apoB levels remained low in the liraglutide treated group (apoB change: 0.03 +/- 0.02 mmol/L, p = 0.4) in contrast to an increase in the control group (apoB change: 0.06 +/- 0.07 mmol/L, p = 0.02). Conclusion: An 8-week low calorie diet, in individuals with obesity, reduced plasma levels of lipids and the atherogenic marker apoB. After 1 year of weight maintenance, only study participants treated with liraglutide maintained reduced levels of apoB, despite similar body weight maintenance. Treatment with liraglutide may therefore reduce apoB levels and thus reflect lower CVD risk. Including apoB measurements in clinical practice when monitoring patients with dislipidemia or CVD might prove to be useful. PMID- 29259802 TI - The effect of the GLP-1 analogue Exenatide on functional connectivity within an NTS-based network in women with and without obesity. AB - Objective: The differential effect of GLP-1 agonist Exenatide on functional connectivity of the nucleus tractus solitaries (NTS), a key region associated with homeostasis, and on appetite-related behaviours was investigated in women with normal weight compared with women with obesity. Methods: Following an 8-h fast, 19 female subjects (11 lean, 8 obese) participated in a 2-d double blind crossover study. Subjects underwent functional magnetic resonance imaging at fast and 30-min post subcutaneous injection of 5 MUg of Exenatide or placebo. Functional connectivity was examined with the NTS. Drug-induced functional connectivity changes within and between groups and correlations with appetite measures were examined in a region of interest approach focusing on the thalamus and hypothalamus. Results: Women with obesity reported less hunger after drug injection. Exenatide administration increased functional connectivity of the left NTS with the left thalamus and hypothalamus in the obese group only and increased the correlation between NTS functional connectivity and hunger scores in all subjects, but more so in the obese. Conclusions: Obesity can impact the effects of Exenatide on brain connectivity, specifically in the NTS and is linked to changes in appetite control. This has implications for the use of GLP-1 analogues in therapeutic interventions. PMID- 29259803 TI - Preliminary evidence supports circulating microRNAs as prognostic biomarkers for type 2 diabetes. AB - Background: Circulating microRNAs are emerging as potential prognostic biomarkers for the development of type 2 diabetes. However, microRNAs are also associated with complications from impaired glucose metabolism (e.g. endothelial cell function). Prior studies have not evaluated for associations between trajectories of circulating microRNAs with trajectories of fasting blood glucose over time and the responses to behavioral interventions to reduce risk. This study performed longitudinal assessment of microRNAs and fasting blood glucose and identified relationships between microRNAs and behavioral risk reduction interventions. Methods: MicroRNAs (n = 353) were measured in subsets (n = 10, n = 8) of participants from previously completed clinical trials that studied behavioral risk reduction interventions. Fasting blood glucose trajectories were associated with changes in 45 microRNAs over 12 months. Results: Following a 3-month physical activity and dietary intervention compared with baseline, 13 microRNAs were differentially expressed. Seven microRNAs (i.e. miR-106b, miR-20b, miR-363, miR-486, miR-532, miR-92a and miR-93) were commonly identified between the two analyses. Conclusions: Further studies are needed to determine which microRNAs are prognostic biomarkers of risk for type 2 diabetes versus consequences of impaired glucose metabolism. Additional future directions of this research are to differentiate whether microRNAs are prognostic and/or diagnostic biomarkers for risk for type 2 diabetes and predictive biomarkers of responses to risk reduction interventions. PMID- 29259805 TI - Video analysis of high-magnitude head impacts in men's collegiate lacrosse. AB - Background/aim: Lacrosse is one of the fastest growing sports in the USA. Efforts to minimise head injuries focus on promoting safe play through player and coach education, rules enforcement and use of effective protective equipment. The study aims to determine event characteristics of high-magnitude head impacts in men's collegiate lacrosse competitions through video analysis. Methods: Seventeen Division I men's collegiate lacrosse players wore instrumented helmets that collected biomechanical measures of head impacts. During 15 competitions, the magnitude of linear acceleration, rotational velocity and helmet impact location were recorded. Impacts with linear accelerations above a 70 g threshold were correlated with video to confirm impact location and to determine event characteristics-source of impact and player activity at the time of impact. Results: A total of 122 high-magnitude impacts were reviewed on video. Player-to player contact (n=94, 77.0%) was the most common impact mechanism, followed by stick-to-player contact (n=11, 9.0%). Impacts occurred most often when the athlete was delivering a body check (n=39, 32.0%), fighting for loose ball possession (n=35, 28.7%) or attacking the goal (n=35, 28.7%). The most frequent impact locations were the front of the helmet (n=46, 37.8%) and the left side of the helmet (n=26, 21.3%). Conclusions: In men's collegiate lacrosse games, the majority of high-magnitude head impacts resulted from player-to-player contact when the sensored athlete did not have possession of the ball. Video analysis provides the game context for head impact mechanisms, which is critical to developing sport-specific injury prevention strategies. PMID- 29259804 TI - Acute kidney injury associated with endurance events-is it a cause for concern? A systematic review. AB - Introduction: A growing body of evidence suggests even small rises in serum creatinine (SCr) are of considerable clinical relevance. Given that participants in endurance events are exposed to potential (repeated) renal insults, a systematic review was undertaken to collate current evidence for acute kidney injury (AKI), complicating such events. Methods: A systematic review of studies and case reports meeting inclusion criteria on Medline and EMBASE (inception to October 2015). Included: studies with markers of renal function before and after endurance or ultraendurance events; case reports of severe AKI. Two reviewers assessed risk of bias using the Newcastle-Ottawa scale. Results: Eleven case report publications (n=27 individuals) of severe AKI, were retrieved, with risk factors including systemic illness or nephrotoxic medications usually identified. From 30 studies of endurance and ultraendurance events, mean rise in SCr was 29 (+/-12.3) umol/L after marathon or ultramarathon (17 studies, n=568 participants) events. Where follow-up tests were conducted, SCr returned to baseline within 48 hours. Rises in biomarkers suggest potential parenchymal insult, rather than simply muscle breakdown. However, evidence of long-term deleterious effects is lacking. Conclusions: Raised levels of SCr are reported immediately after endurance events. It is not clear whether this is either clinically significant, or if repeated participation predisposes to long-term sequelae. The aetiology of severe exercise-associated AKI is usually multifactorial, with risk factors generally identified in the rare cases reported. On-site biochemistry, urine analysis and biomarkers of AKI may help identify collapsed runners who are at significant short-term risk and allow suitable follow-up. PMID- 29259806 TI - Concussion knowledge and experience among Welsh amateur rugby union coaches and referees. AB - Background: Rugby union is a collision sport where participants are at high risk of sustaining a concussion. In settings where there is little qualified medical supervision, certain stakeholders (eg, coaches and officials) should possess sufficient knowledge in regard to the recognition and management of concussion. Aim: The aim of this study was to assess the knowledge and experience of various aspects of concussion among coaches and referees involved in Welsh amateur rugby union. Methods: A questionnaire was distributed to 1843 coaches and 420 referees. Results: A total of 333 coaches and 283 referees completed the questionnaire (18% and 68% response rates, respectively). Participants exhibited greater knowledge of concussion symptom recognition relative to knowledge of both the consequences of concussion and associated return-to-play protocols, both of which could be considered poor. There were no differences in knowledge levels between coaches and referees or between participants with or without a history of concussion. Two thirds of participants incorrectly believed that headgear could prevent concussion, and nearly 30% of coaches reported having witnessed other coaches allowing a potentially concussed player to continue playing. Conclusions: Identification of several misconceptions indicates that concussion management within Welsh amateur rugby union needs to be improved, warranting a multi-faceted educational intervention. PMID- 29259807 TI - Weaker lower extremity muscle strength predicts traumatic knee injury in youth female but not male athletes. AB - Background: The role of lower extremity (LE) muscle strength for predicting traumatic knee injury in youth athletes is largely unknown. Aims: The aim was to investigate the influence of LE muscle strength on traumatic knee injury in youth female and male athletes. Methods: 225 athletes (40% females) from sport senior high schools in Sweden were included in this case-control study. The athletes recorded any traumatic knee injury that had occurred during their high-school period in a web-based injury form. A one repetition maximum (1RM) barbell squat test was used to measure LE muscle strength. The 1RM was dichotomised to analyse 'weak' versus 'strong' athletes according to the median (weakmedian vs strongmedian). Results: 63 traumatic knee injuries, including 18 ACL injuries, were registered. The majority of injured female athletes were in the weak group compared with the strong group (p=0.0001). The odds of sustaining a traumatic knee injury and an ACL injury was 9.5 times higher and 7 times higher, respectively, in the weakmedian group compared with the strongmedian group in females (p <=0.011). A relative 1RM squat <=1.05 kg (105% of bodyweight) was established as the best cut-off value to distinguish high versus low risk of injury in female athletes. No strength-injury relationships were observed for the male athletes (p >=0.348). Conclusions: Weaker LE muscle strength predicted traumatic knee injury in youth female athletes, but not in males. This suggests that LE muscle strength should be included in injury screening in youth female athletes. PMID- 29259808 TI - How is rating of perceived capacity related to VO2max and what is VO2max at onset of training? AB - Objective: To evaluate how rating of perceived capacity (RPC) is related to maximal oxygen uptake (VO2max) and examine VO2max at onset of training in healthy adults. Methods: In total, 125 newly registered fitness centre members, equally men and women, answered the RPC scale and performed a treadmill test for measurement of VO2max. Eligible criteria were <4 weeks of fitness centre membership, physically inactive, >=18 years and not pregnant. The RPC is a one page scale (1-20) based on metabolic equivalent tasks, where the individual chooses the most strenuous activity that can be sustained for at least 30 min. Results: The Bland-Altman plot demonstrated a tendency of overestimation, meaning that the participants ranked their own aerobic capacity 17.5% higher than objectively measured values of VO2max. The mean difference between the two methods were +4.92+/-1.96 and +6.35+/-1.96 mL/min/kg VO2 in men and women, respectively. The Pearson correlation coefficient was moderate, with r=0.426 (p<0.01). A linear regression analysis showed that both age and VO2max were significant predictors of RPC (p<0.01). Measured VO2max at onset of fitness centre membership was in men aged 38.7+/-11.7 and women aged 34.7+/-9.9, 40.5+/ 7.2 and 35.0+/-6.0 mL/min/kg, respectively. Estimated VO2max from the RPC scale was 45.7+/-9.8 and 41.4+/-10.1 mL/min/kg in men and women, respectively. Conclusions: The RPC seems less accurate at the individual level and may overestimate VO2max. Still, it may be considered useful in large-scale studies. PMID- 29259810 TI - Capturing effort and recovery: reactive and recuperative cortisol responses to competition in well-trained rowers. AB - Background/aim: It is well known that physical strain is associated with increased cortisol production. And although mental stress elevates cortisol concentrations as well, little is known of the independent and/or combined effects of both on the secretion of cortisol. Aim of the study was to investigate the day-to-day cortisol dynamics associated with training, performance and recuperation and the immediate responses to mental stress and physical endurance under competitive conditions. Methods: Sixteen freshmen competitive male rowers were prospectively followed from Thursday to Tuesday with an intermediate competition on Saturday and Sunday. On all days, three saliva samples were collected within 30 min after awakening to assess the cortisol awakening rise (CAR). Additionally, five saliva samples were collected previously to and immediately after all races during the regatta weekend. Results: CAR values peaked during competition days and recovered during the 2 days after. Cortisol concentrations significantly increased during and after all races. Furthermore, although response patterns did not differ, the morning races showed significantly higher cortisol levels compared with the levels measured during the afternoon races. This likely reflects the normal diurnal rhythm of corticosteroids. Conclusions: These results indicate that cortisol levels of athletes might be sensitive for both immediate responses to competition and, in case of CAR, (midterm) recovery phasing. Consequently, monitoring cortisol responses during training and competition may provide valuable information regarding how athletes cope with competition-induced stress and their recovery status during the days following. This insight might help to plan future training loads and recovery. PMID- 29259809 TI - The addition of a tension night splint to a structured home rehabilitation programme in patients with chronic plantar fasciitis does not lead to significant additional benefits in either pain, function or flexibility: a single-blinded randomised controlled trial. AB - Objective: To identify any improvements in pain or function in patients with chronic plantar fasciitis following the use of a tension night splint (TNS). Methods: Single-blinded randomised controlled trial, with participants split evenly between intervention group (TNS + home exercise programme/HEP) and control group (HEP only). Follow-up at 3 months, with interim data at 6 weeks. Results: 40 patients recruited. Mean age 52.1 years, 33% male, mean body mass index 30.8 kg/m2, mean duration of symptoms of 25 months. Improvement in self-reported 'average pain' in the intervention group from 6.8/10 at baseline to 5.6/10 at 6 weeks, and 5.3/10 at 3 months (both clinically and statistically significant at both time points), compared with control group of 7.1/10 at baseline to 6.2/10 at 6 weeks and 5.6/10 at 3 months (significant only at 3 months). Improvements in self-reported 'worst pain', 'pain walking' and 'pain first thing in the morning' in both groups at all time periods. Improvements were seen in revised Foot Function Index at all time points in both groups, but limited changes seen in flexibility and no significant changes in anxiety or depression Hospital Anxiety and Depression Scale domains or sleep quality in either group. However, no differences were seen between the outcomes seen in the two groups for the majority of the measures studied. Conclusions: Improvements in pain and some functional measures seen in both groups, with few, if any, differences seen in outcomes between the intervention group compared with the control group. However, ongoing pain symptoms were reported in both groups, suggesting that 'help' rather than 'cure' was obtained for the majority. There is a possibility of earlier benefit seen in the intervention group compared with the control group, but data are unclear and further work may be needed. Trial registration number: ClinicalTrials.gov: NCT02546115; results. PMID- 29259811 TI - Perceptions of group exercise courses and instructors among Quebec adults. AB - Background: Group exercise courses are popular among adults, but dropout rates are high. Studies of relationships between participants' perceptions and their participation might highlight factors to target to improve adherence and re enrolment. Methods: We used a mixed-methods approach to analyse perceptions of group exercise courses and instructors among 463 adults. Participants completed the Exercise Barriers and Benefits Scale, questionnaires on perceptions of the instructor and course, and non-participation. We assessed participation from weeks 2-4 and 5-10, and re-enrolment. We analysed relationships between perceptions and re-enrolment using linear regression and mediation analyses. We conducted group interviews with 11 participants. Results: Predictors of re enrolment included early participation (beta=0.11, P=0.029) and perceptions of the group social climate (P=0.027). Perceptions of the group mediated the relationship between early participation and re-enrolment (95% CI 0.0036 to 0.0471): early participation predicted more positive perceptions (beta=2.11, P=0.003), which predicted re-enrolment (beta=0.01, P=0.006). Qualitative analyses highlighted instructors' roles in promoting social exchange and integrating participants into the group. Conclusions: The social climate of group exercise courses is a key factor predicting re-enrolment. Early participation predicts re enrolment on its own, and also promotes positive perceptions of the group. Instructors can target these factors by sensitising participants to the importance of early participation, and promoting social exchange. PMID- 29259812 TI - Psychometric evaluation of commonly used game-specific skills tests in rugby: A systematic review. AB - Objectives: To (1) give an overview of commonly used game-specific skills tests in rugby and (2) evaluate available psychometric information of these tests. Methods: The databases PubMed, MEDLINE CINAHL and Africa Wide information were systematically searched for articles published between January 1995 and March 2017. First, commonly used game-specific skills tests were identified. Second, the available psychometrics of these tests were evaluated and the methodological quality of the studies assessed using the Consensus-based Standards for the selection of health Measurement Instruments checklist. Studies included in the first step had to report detailed information on the construct and testing procedure of at least one game-specific skill, and studies included in the second step had additionally to report at least one psychometric property evaluating reliability, validity or responsiveness. Results: 287 articles were identified in the first step, of which 30 articles met the inclusion criteria and 64 articles were identified in the second step of which 10 articles were included. Reactive agility, tackling and simulated rugby games were the most commonly used tests. All 10 studies reporting psychometrics reported reliability outcomes, revealing mainly strong evidence. However, all studies scored poor or fair on methodological quality. Four studies reported validity outcomes in which mainly moderate evidence was indicated, but all articles had fair methodological quality. Conclusion: Game-specific skills tests indicated mainly high reliability and validity evidence, but the studies lacked methodological quality. Reactive agility seems to be a promising domain, but the specific tests need further development. Future high methodological quality studies are required in order to develop valid and reliable test batteries for rugby talent identification. Trial registration number: PROSPERO CRD42015029747. PMID- 29259813 TI - Sport and exercise medicine research activity in the Arab world: a 15-year bibliometric analysis. AB - Background: The role of sports in decreasing the prevalence of many diseases has led to a growing interest in the field of sport and exercise medicine. But sport and exercise medicine still remains new to the Arab world, waiting to be explored. The aim of this study is to describe and characterise sport and exercise medicine research activity in the Arab world between 2002 and 2016. Methods: The PubMed database was used to search for publications related to sport and exercise medicine. Publications were classified according to the country of origin and filtered to include publications between 2002 and 2016. Research output was analysed with respect to gross domestic product (GDP) and population of each country. Results: A total of 1148 papers related to sport and exercise medicine were found to be published in the Arab countries between 2002 and 2016. Sport-and-exercise-medicine-related publications constituted 0.86% of the total biomedical research papers published in the Arab world and 0.49% of the world's sport and exercise medicine literature. The number of sport-and-exercise-medicine related publications per country ranged from zero to 352, with Qatar occupying the top spot. Tunisia ranked first with respect to publications per average GDP, while Qatar ranked first with respect to publications per average population. Comoros, Mauritania, Somalia, Sudan and Yemen were found to have no publications related to sport and exercise medicine. Conclusion: Sport and exercise medicine is a novel field in the Arab world. Recognising the barriers facing sport and exercise medicine research and exploring them meticulously remains an essential part of the plan to improve the Arab world's output and contribution in this field. PMID- 29259814 TI - Diagnosis of psychosocial risk factors in prevention of low back pain in athletes (MiSpEx). AB - Background: Low back pain (LBP) is a common pain syndrome in athletes, responsible for 28% of missed training days/year. Psychosocial factors contribute to chronic pain development. This study aims to investigate the transferability of psychosocial screening tools developed in the general population to athletes and to define athlete-specific thresholds. Methods: Data from a prospective multicentre study on LBP were collected at baseline and 1-year follow-up (n=52 athletes, n=289 recreational athletes and n=246 non-athletes). Pain was assessed using the Chronic Pain Grade questionnaire. The psychosocial Risk Stratification Index (RSI) was used to obtain prognostic information regarding the risk of chronic LBP (CLBP). Individual psychosocial risk profile was gained with the Risk Prevention Index - Social (RPI-S). Differences between groups were calculated using general linear models and planned contrasts. Discrimination thresholds for athletes were defined with receiver operating characteristics (ROC) curves. Results: Athletes and recreational athletes showed significantly lower psychosocial risk profiles and prognostic risk for CLBP than non-athletes. ROC curves suggested discrimination thresholds for athletes were different compared with non-athletes. Both screenings demonstrated very good sensitivity (RSI=100%; RPI-S: 75%-100%) and specificity (RSI: 76%-93%; RPI-S: 71%-93%). RSI revealed two risk classes for pain intensity (area under the curve (AUC) 0.92(95% CI 0.85 to 1.0)) and pain disability (AUC 0.88(95% CI 0.71 to 1.0)). Conclusions: Both screening tools can be used for athletes. Athlete-specific thresholds will improve physicians' decision making and allow stratified treatment and prevention. PMID- 29259815 TI - Fall-related accidents among hikers in the Austrian Alps: a 9-year retrospective study. AB - Objective: To analyse the circumstances of fatal and non-fatal mountain hiking accidents caused by falls. Methods: The study was designed as a retrospective analysis. Mountain hiking accidents caused by falls were documented during a 9 year period (2006-2014). After screening of all data for potential exclusion criteria the final sample size of 5368 accidents and 5665 victims was included into the analyses. Main outcome measures were details about accidents, victims, type of trail and surface. Results: The annual number of accidents showed a continuous increase from 467 in 2006 to 700 in 2014. In total, 5.8% of all victims died during the 9-year period. 75.3% of the hikers fell during descent and 80.9% of the victims had their accident on a marked hiking trail or small path. The sex ratio for non-fatal accidents was 55% female and 45% male; for fatal accidents the female-to-male ratio was 28%:72%. Mean age of all victims was 52.5+/-17.5 years and victims of fatalities were about 5 years older compared with victims of non-fatal accidents (57.5+/-16.5 vs 52.2+/-17.5 years, P<0.01). Conclusion: Descent is the most risky part for accidents caused by falls during mountain hiking. Male hikers are at greater risk for fatalities independent of age and this is associated with accidents occurring in pathless terrain. The death rate from falls was 6%. We recommend a critical self-assessment of the individual capabilities and mountain hiking skills and adequate planning of the hiking tours for mountain hikers. PMID- 29259816 TI - Exercise genetics: seeking clarity from noise. PMID- 29259817 TI - Biosimilars as a strategy to improve sustainability. PMID- 29259818 TI - Admission of critically ill patients with cancer to the ICU: many uncertainties remain. PMID- 29259819 TI - Effects of physical activity on depressive symptoms during breast cancer survivorship: a meta-analysis of randomised control trials. AB - BackgroundBreast cancer is one of the most common cancers affecting women worldwide, and depressive symptoms are disturbing side effects of cancer diagnosis and treatment. Physical activity and exercise have emerged as an alternative treatment in handling psychological distress throughout breast cancer survivorship. AimThe aim of this review was to present the results of (1) physical activity and (2) exercise interventions in terms of type and duration regarding depressive symptoms among breast cancer survivors during and after treatment. The hypothesis was that cancer survivors who are engaged with physical activity will demonstrate statistically significant lower levels of depressive symptoms when compared with non-exercising control groups. MethodsWe searched PubMed, Elsevier and Google Scholar for recent articles published between January 2011 and November 2016. Fourteen randomised control trials with 1701 patients in total were assessed. ResultsSignificant differences in levels were found between exercise intervention groups and control groups, while moderate aerobic exercise interventions with an optimal duration of >=135 min for up to 12 weeks are significantly more beneficial in depressive symptoms when it comes to patients under treatment than resistance, aerobicandresistance training and yoga interventions. ConclusionsIt is concluded that when progressive exercise programmes are prescribed according to the individual needs, capabilities and preferences of breast cancer survivors, they offer a valid alternative to depression mood management throughout the course of survivorship. PMID- 29259820 TI - National survey of Ebola-related knowledge, attitudes and practices before the outbreak peak in Sierra Leone: August 2014. AB - Background: The 2014-2015 Ebola epidemic in West Africa was the largest ever to occur. In the early phases, little was known about public knowledge, attitudes and practices (KAP) relating to Ebola virus disease (Ebola). Data were needed to develop evidence-driven strategies to address gaps in knowledge and practice. Methods: In August 2014, we conducted interviews with 1413 randomly selected respondents from 9 out of 14 districts in Sierra Leone using multistage cluster sampling. Where suitable, Ebola-related KAP questions were adapted from other internationally validated questionnaires related to infectious diseases. Results: All respondents were aware of Ebola. When asked unprompted, 60% of respondents could correctly cite fever, diarrhoea and vomiting as signs/symptoms of Ebola. A majority of respondents knew that avoiding infected blood and bodily fluids (87%) and contact with an infected corpse (85%) could prevent Ebola. However, there were also widespread misconceptions such as the belief that Ebola can be prevented by washing with salt and hot water (41%). Almost everyone interviewed (95%) expressed at least one discriminatory attitude towards Ebola survivors. Unprompted, self-reported actions taken to avoid Ebola infection included handwashing with soap (66%) and avoiding physical contact with patients with suspected Ebola (40%). Conclusion: Three months into the 2014 Ebola outbreak in Sierra Leone, our findings suggest there was high awareness of the disease but misconceptions and discriminatory attitudes toward survivors remained common. These findings directly informed the development of a national social mobilisation strategy and demonstrated the importance of KAP assessment early in an epidemic. PMID- 29259821 TI - What we have learnt (so far) about deliberative dialogue for evidence-based policymaking in West Africa. AB - Policy decisions do not always take into account research results, and there is still little research being conducted on interventions that promote their use, particularly in Africa. To promote the use of research evidence in Africa, deliberative dialogue workshops are increasingly recommended as a means to establish evidence-informed dialogue among multiple stakeholders engaged in policy decision-making. In this paper, we reflect on our experiences of conducting national workshops in six African countries, and we propose operational recommendations for those wishing to organise deliberative dialogue. Our reflective and cross-sectional analysis of six national deliberative dialogue workshops in which we participated shows there are many specific challenges that should be taken into account when organising such encounters. In conclusion, we offer operational recommendations, drawn from our experience, to guide the preparation and conduct of deliberative workshops. PMID- 29259822 TI - Efficacy of a bovine colostrum and egg-based intervention in acute childhood diarrhoea in Guatemala: a randomised, double-blind, placebo-controlled trial. AB - Background: Treatments for paediatric diarrhoeal disease are limited. We assessed the impact of a bovine colostrum and egg-based treatment designed to reduce diarrhoea duration through non-specific and pathogen-directed mechanisms in children. Methods: Randomised, double-blind, placebo-controlled trial of PTM202, derived from bovine colostrum and hyperimmune hen's egg on the duration of acute diarrhoeal disease in Guatemalan children. PTM202 contains specific immunoglobulins that target rotavirus, enterotoxigenic Escherichia coli, Shiga toxin-producing E. coli and Salmonella. Children aged 6-35 months presenting to three sites (one rural and two urban) with acute non-bloody diarrhoea were computer randomised to receive three daily doses of PTM202 or placebo. The primary outcome was the post-treatment duration of diarrhoea assessed in the per protocol population. Diarrhoeal pathogens were identified in stool by multiplex PCR (FilmArray Gastrointestinal-Panel, BioFire, Salt Lake City, Utah, USA). Key secondary outcomes included postdiarrhoeal weight gain and impact on diarrhoeal duration stratified by study site and presence of PTM202-targeted organisms in stool at enrolment. Safety was assessed in all participants. Results: From 9 March 2015 to 25 January 2016, 325 children were enrolled, and 301 (154 intervention and 147 placebo) were analysed for the primary outcome. No difference in diarrhoea duration was observed between intervention and placebo in the total population, but a significant reduction was observed in the treatment group among children with at least one targeted pathogen in stool (HR=1.46, P=0.02), an effect most pronounced in urban subjects (HR 2.20, P=0.007) who had fewer stool pathogens and better nutritional status. No impact on 2-week or 4 week weight gain was noted. No adverse events attributed to PTM202 occurred. Conclusion: Results demonstrate the potential to target specific pathogens occurring in children with acute non-bloody diarrhoea and shorten illness duration using a novel, safe, nutrition-based intervention. PTM202 may represent a new tool to ameliorate the effects of acute diarrhoeal disease in low/middle income populations. Trial registration number: NCT02385773; Results. PMID- 29259823 TI - 'We lost because of his drunkenness': the social processes linking alcohol use to self-harm in the context of daily life stress in marriages and intimate relationships in rural Sri Lanka. AB - Introduction: Harmful alcohol use has been found to cause detriment to the consumers and those around them. Research carried out in Sri Lanka has described the socioeconomic consequences to families owing to alcohol consumption. However, the social processes around alcohol use and how it could result in behaviour such as self-harm was unclear. With an outset in daily life stressors in marriages and intimate relationships we explored alcohol use in families with a recent case of self-harm. Methods: Qualitative data were collected for 11 months in 2014 and 2015 in the North Central and North Western provinces of Sri Lanka. Narrative life story interviews with 19 individuals who had self-harmed where alcohol was involved and 25 of their relatives were conducted. Ten focus group discussions were carried out in gender and age segregated groups. An inductive content analysis was carried out. Results: Participants experienced two types of daily life stressors: non-alcohol-related stressors, such as violence and financial difficulties, and alcohol-related stressors. The alcohol-related stressors aggravated the non-alcohol-related daily life stressors within marriages and intimate relationships, which resulted in conflict between partners and subsequent self-harm. Women were disproportionately influenced by daily life stressors and were challenged in their ability to live up to gendered norms of marriage. Further, women were left responsible for their own and their husband's inappropriate behaviour. Self-harm appeared to be a possible avenue of expressing distress. Gendered alcohol and marriage norms provided men with acceptable excuses for their behaviour, whether it was alcohol consumption, conflicts or self-harm. Conclusions: This study found that participants experienced both alcohol-related and non-alcohol-related daily life stressors. These two categories of daily life stressors, gender inequalities and alcohol norms should be considered when planning alcohol and self-harm prevention in this setting. Life situations also reflected larger community and structural issues. PMID- 29259824 TI - Health system effects of implementing integrated community case management (iCCM) intervention in private retail drug shops in South Western Uganda: a qualitative study. AB - Background: Intervening in private drug shops to improve quality of care and enhance regulatory oversight may have health system effects that need to be understood before scaling up any such interventions. We examine the processes through which a drug shop intervention culminated in positive unintended effects and other dynamic interactions within the underlying health system. Methods: A multifaceted intervention consisting of drug seller training, supply of diagnostics and subsidised medicines, use of treatment algorithms, monthly supervision and community sensitisation was implemented in drug shops in South Western Uganda, to improve paediatric fever management. Focus group discussions and in-depth interviews were conducted with stakeholders (drug sellers, government officials and community health workers) at baseline, midpoint and end line between September 2013 and September 2015. Using a health market and systems lens, transcripts from the interviews were analysed to identify health system effects associated with the apparent success of the intervention. Findings: Stakeholders initially expressed caution and fears about the intervention's implications for quality, equity and interface with the regulatory framework. Over time, these stakeholders embraced the intervention. Most respondents noted that the intervention had improved drug shop standards, enabled drug shops to embrace patient record keeping, parasite-based treatment of malaria and appropriate medicine use. There was also improved supportive supervision, and better compliance to licensing and other regulatory requirements. Drug seller legitimacy was enhanced from the community and client perspective, leading to improved trust in drug shops. Conclusion: The study showed how effectively using health technologies and the perceived efficacy of medicines contributed to improved legitimacy and trust in drug shops among stakeholders. The study also demonstrated that using a combination of appropriate incentives and consumer empowerment strategies can help harmonise common practices with medicine regulations and safeguard public health, especially in mixed health market contexts. PMID- 29259825 TI - Corrigendum to "Relationship between the Direction of Ophthalmic Artery Blood Flow and Ocular Microcirculation before and after Carotid Artery Stenting". AB - [This corrects the article DOI: 10.1155/2016/2530914.]. PMID- 29259826 TI - Dietary Fiber Intake among Normal-Weight and Overweight Female Health Care Workers: An Exploratory Nested Case-Control Study within FINALE-Health. AB - Socioeconomic factors affect choice of diet, that is, dietary fiber intake. Underreporting of food consumption in diet surveys has been reported higher in low-income, low-education groups compared to high-income, high-education groups. This paper examines in a socioeconomic homogenous low-income low-education group of females the relation between dietary fiber intake and overweight and scrutinizes if the level of underreporting is equally large in normal-weight and overweight groups. Thirty-four female health care workers classified as either normal-weight (N = 18) or obese (N = 16) based on BMI, fat percentage, and waist circumference participated. A detailed food-diary was used to record their dietary intake in 9 days. Average dietary fiber intake in the normal-weight group was 2.73 +/- 0.65 g/MJ, while it was 2.15 +/- 0.64 g/MJ for the women in the obese group. In both groups, the overall food intake was underreported. In spite of a significantly lower dietary fiber intake in the obese group, the present population of women working within health care all showed an overall low dietary fiber intake and a general underreporting of food intake. These results indicate a clear need for dietary advice especially on fiber intake to increase general health and decrease weight. PMID- 29259827 TI - Risk Factors of Underweight in Children Aged 6-59 Months in Ethiopia. AB - Background: Undernutrition in early childhood has irreversible and long-lasting implications. Hence, this study was aimed at assessing risk factors of child undernutrition. Methods: A community-based cross-sectional study was conducted on 642 households with mothers to children pairs aged 6-59 months selected by a multistage systematic random sampling method. Child anthropometric measurements on weight were recorded using standardized and calibrated weighing scales. Weight for-age was compared to the 2007 WHO growth reference by WHO Anthro software. Data were entered using Epi-Info and analyzed using SPSS. Bivariate and multivariate logistic regression analyses were used to evaluate the association between underweight children and their predictors; both crude and adjusted odds ratios with 95% confidence interval were reported. Results: One-fourth (25%) of the children were underweight. Child age (AOR: 2.36), gender (AOR: 1.82), illness (AOR: 0.09), maternal decision making power (AOR: 0.07), maternal education (AOR: 0.19), employment/occupation (AOR: 5.29), and household income (AOR: 4.16) were found to be independent and significant predictors of underweight children. Conclusion: Significant proportion of the children were underweight. Maternal decision-making power persists as a strong predictor of children's weight. Therefore, intervention programs focusing on improving mothers' decision-making power on child nutrition would contribute to the efforts towards alleviating the problem. PMID- 29259828 TI - Formulation, Characterization, and In Vitro Evaluation of Transdermal Patches for Inhibiting Crystallization of Mefenamic Acid. AB - The crystallization of mefenamic acid in transdermal patch is a major problem that makes the patch unstable and decreases the drug release. The additive was used to inhibit crystallization of a mefenamic acid. Among the different types of additives, polyvinylpyrrolidone (PVP) K30 and PVP K90 were studied and found to be highly effective in inhibiting the crystallization of the drug. The PVP presented as a solubilizer agent for mefenamic acid in matrix patches at the different ratio between drug : PVP, 1 : 2 and 1 : 2.5 for using PVP K30 and 1 : 1.5 and 1 : 2 for using PVP K90. The characterizations showed the homogeneous patches without the crystal form of the mefenamic acid in matrix patches. The release profiles of the mefenamic acid from the patches were investigated by Franz diffusion cells. Over the first 1 h, the release behavior of mefenamic acid from the patches obviously increased when PVP was used as a crystallization inhibitor. However, the ratio between drug : PVP K90 at 1 : 2 was found to be the most effective in increasing the drug release from patch. Thus, the PVP could be used as a crystallization inhibitor for mefenamic acid in matrix patches which will increase the drug release. PMID- 29259829 TI - Antibacterial Activity of Free Fatty Acids from Hydrolyzed Virgin Coconut Oil Using Lipase from Candida rugosa. AB - Free fatty acids (FFAs) were obtained from hydrolyzed virgin coconut oil (VCO) by Candida rugosa lipase (CRL). Four factors' influence on hydrolysis degree (HD) was examined. The best hydrolysis conditions in order to get the highest HD value were determined at VCO to buffer ratio 1 : 5 (w/w), CRL concentration 1.5% (w/w oil), pH 7, and temperature 40 degrees C. After 16 hours' reaction, the HD value achieved 79.64%. FFAs and residual hydrolyzed virgin coconut oil (HVCO) were isolated from the hydrolysis products. They were tested for their antibacterial activity against Gram-negative and Gram-positive bacteria, which can be found in contaminated food and cause food poisoning. FFAs showed their inhibition against Bacillus subtilis (ATCC 11774), Escherichia coli (ATCC 25922), Salmonella enteritidis (ATCC 13076), and Staphylococcus aureus (ATCC 25923) at minimum inhibitory concentration (MIC) of 50%, 60%, 20%, and 40%, respectively. However, VCO and HVCO did not show their antibacterial activity against these tested bacteria. PMID- 29259830 TI - Iatrogenic Cushing's Syndrome with Subsequent Adrenal Insufficiency in a Patient with Psoriasis Vulgaris Using Topical Steroids. AB - Iatrogenic Cushing's syndrome (ICS) is usually related to prolonged and/or high dose oral or parenteral steroid use. Psoriasis vulgaris (PV) is chronic inflammatory disease and characterized by periods of attack and remission. Topical steroid (TS) is the first choice of treatment for localized and mild PV. The development of systemic side effects of the steroids is usually not observed after TS application. But the risk of developing ICS still exists. In the literature, there are a few adult cases who developed ICS and subsequent adrenal insufficiency associated with TS. In this article, a male patient with PV developing ICS and secondary adrenal insufficiency after treatment of TS for 12 years is presented. PMID- 29259831 TI - Sport-Related Portal Vein Thrombosis: An Unusual Complication. AB - Portal vein thrombosis (PVT) is an uncommon condition usually associated with hypercoagulable states or liver cirrhosis. PVT due to sports-related injuries is rarely reported and, to the best of our knowledge, only two cases have been reported thus far. Brazilian jiu-jitsu (BJJ) is a form of martial arts and is considered very safe with minimal risk for injury. It has growing popularity worldwide. Here, we report the first case of PVT secondary to abdominal trauma related to the practice of (BJJ) in an otherwise healthy 32-year-old man with no other traditional risk factors for PVT. PMID- 29259833 TI - Small Split Doses of CD34+ Peripheral Blood Stem Cells to Support Repeated Cycles of Nonmyeloablative Chemotherapy. AB - Cumulative myelosuppression is the main limiting factor for administration of repeated cycles of chemotherapy. We present a case series of five pediatric patients with high-risk solid malignancies who received small split peripheral blood stem cells (PBSC) doses of less than 1 * 106/kg CD34+ cells obtained after a single leukapheresis procedure and given after repeated cycles of ICE (ifosfamide, carboplatin, and etoposide) chemotherapy. Mean duration to absolute neutrophil count (ANC) recovery to >1000/mm3 and platelet recovery to >50 * 103/mm3 was 17.1 and 24.3 days. Using split doses of PBSC prevented prolonged neutropenia after repeated cycles of submyeloablative chemotherapy. PMID- 29259832 TI - Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies. AB - Chronic Mucocutaneous Candidiasis (CMC) is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF) (c.1154 C>T, p.Thr385Met) in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT) was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported. PMID- 29259834 TI - A Patient with Non-Hodgkin Lymphoma and Nonspecific Interstitial Pneumonia during Ibrutinib Therapy. AB - We present a 74-year-old male with nonspecific interstitial pneumonia (NSIP) during treatment with ibrutinib for mantle cell lymphoma. Previously, the patient had received six cycles of bendamustine and rituximab and six cycles of R-CHOP, followed by rituximab maintenance therapy. Respiratory tract complications of ibrutinib other than infectious pneumonia have not been mentioned in larger trials, but individual case reports hinted to a possible association with the development of pneumonitis. In our patient, the onset of alveolitis that progressed towards NSIP together with the onset of ibrutinib treatment suggests causality. One week after ibrutinib was discontinued, nasal symptoms resolved first. A follow-up CT showed a reduction in the reticular hyperdensities and ground-glass opacities, suggestive of restitution of the lung disease. To our knowledge, this is the first case showing a strong link between ibrutinib and interstitial lung disease, strengthening a previous report on subacute pneumonitis. Our findings have clinical implications because pulmonary side effects were reversible at this early stage. We, therefore, suggest close monitoring for respiratory side effects in patients receiving ibrutinib. PMID- 29259836 TI - Squamous Cell Carcinoma of Suprapubic Cystostomy Site in a Patient with Long-Term Suprapubic Urinary Catheter. AB - Patients with long-term suprapubic cystostomy can rarely develop squamous cell carcinoma (SCC) of the suprapubic cystostomy tract. In addition to the few reported cases in the literature, this paper reports a case of suprapubic cystostomy SCC in an 88-year-old man without bladder involvement. Vigilance about any abnormal lesion at the site of suprapubic cystostomy is important among health providers and patients for early detection of SCC. PMID- 29259835 TI - Efficacy of Rituximab in a Systemic Lupus Erythematosus Patient Presenting with Diffuse Alveolar Hemorrhage. AB - Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE). Although infrequent, its mortality is very high. While there are no established therapeutic guidelines, DAH has been traditionally managed with high-dose intravenous (IV) corticosteroids, cyclophosphamide, and plasma exchange. The efficacy of alternative therapies such as rituximab has been described only in a few cases. Herein, we report a 25-year-old Hispanic man who presented with acute-onset SLE manifested by polyarthralgia, nephritis, seizures, pancytopenia, severe hypocomplementemia, and elevated anti-dsDNA antibodies. His disease course was complicated by DAH. His condition was refractory to high-dose intravenous (IV) methylprednisolone pulses, IV cyclophosphamide, and plasmapheresis. Given the lack of clinical response, he was started on IV rituximab 375 mg/m2 weekly for a total of four courses. He rapidly improved after the first two doses. Over the next seven months, he did not present recurrent pulmonary symptoms. Follow-up chest computed tomography did not show residual abnormalities. This case, together with other reports, suggests that rituximab is an effective therapeutic option for DAH in SLE. PMID- 29259837 TI - Chemical Characterization and Biological Activities of Essential Oil Obtained from Mint Timija Cultivated under Mineral and Biological Fertilizers. AB - Cultivation of mint timija (Mentha suaveolens subsp. timija (Briq.) Harley) constitutes a promising solution to the conservation and sustainable utilization of this Moroccan endemic and threatened species. Optimized agronomic practices require mineral and/or biological fertilizer applications. The aim of this study was to determine the effects of application of a complete (N, P, and K) mineral fertilizer and vesicular arbuscular mycorrhizae (VAM) inoculation on the composition, antioxidant, and insecticidal properties of mint timija essential oils (EOs). The GC-MS analyses identified 27 components representing more than 99.9% of the total oils. Menthone (40.7-49.3%), pulegone (31.3-36.5%), and isomenthone (2.5-4.4%) were found to be the main constituents. Cultivation of mint timija with mineral fertilizer and VAM inoculation induced an increase in menthone content and a parallel decrease of pulegone. Both treatments enhanced the antioxidant activity of the investigated EOs in all assays (IC50 ranged from 2.34 +/- 0.03 mg/mL to 6.82 +/- 0.25 mg/mL), while no significant difference in the toxicities of these oils against Tribolium confusum du Val. has been observed. Overall, we conclude that cultivation using complete mineral fertilizer and VAM inoculation could be useful in modulating the chemical composition and enhancing the antioxidant activity of the EO of this endemic Moroccan species. PMID- 29259838 TI - Erratum: A case of astroblastoma: Radiological and histopathological characteristics and a review of current treatment options. AB - [This corrects the article on p. S1008 in vol. 7, PMID: 28144474.]. PMID- 29259839 TI - Passive protection against anthrax in mice with plasma derived from horses hyper immunized against Bacillus anthracis Sterne strain. AB - In this study, equine source polyclonal anti-Bacillus anthracis immunoglobulins were generated and utilized to demonstrate passive protection of mice in a lethal challenge assay. Four horses were hyper-immunized with B. anthracis Sterne strain for approximately one year. The geometric mean anti-PA titer in the horses at maximal response following immunization was 1:77,936 (Log2 mean titer 16.25, SEM +/- 0.25 95% CI [15.5 -17.0]). The geometric mean neutralizing titer at maximal response was 1:128 (Log2 mean titer 7, SEM +/- 0.0, 95% CI 7). Treatment with hyper-immune plasma or purified immunoglobulins was successful in passively protecting A/J mice from a lethal B. anthracis Sterne strain challenge. The treatment of mice with hyper-immune plasma at time 0 h and 24 h post-infection had no effect on survival, but did significantly increase mean time to death (p < 0.0001). Mice treated with purified immunoglobulins at time 0 h and 24 h post infection in showed significant increase in survival rate (p < 0.001). Bacterial loads in lung, liver and spleen tissue were also assessed and were not significantly different in mice treated with hyper-immune plasma from placebo treated control mice. Mice treated with purified antibodies demonstrated mean colony forming units/gram tissue fourfold less than mice receiving placebo treatment (p < 0.0001). Immunotherapeutics harvested from horses immunized against B. anthracis Sterne strain represent a rapidly induced, inexpensive and effective expansion to the arsenal of treatments against anthrax. PMID- 29259840 TI - How many species of mammals are there in Brazil? New records of rare rodents (Rodentia: Cricetidae: Sigmodontinae) from Amazonia raise the current known diversity. AB - Background: Since 1996, when Vivo questioned how many species of mammals occur in Brazil, there has been a huge effort to assess this biodiversity. In this contribution, we present new records for rare species of the sigmodontine rodent genera Rhagomys and Neusticomys previously unknown to Brazilian Amazon. We provided detailed information on the morphologic variation to allow the proper identification of these species. We also furnished updated information on their collection, aiming to establish hypothesis of their geographic distribution, based on SDM's, aiming to hypothesize potential occurrence areas for these species. Methods: Rodent specimens were sampled in separate inventories in two sites of Rondonia State (Hydroelectric Dam Jirau and Parque Nacional de Pacaas Novos) and one site in Para State (Pacaja), Brazil, and were compared to specimens from museum collections to apply appropriate names. The SDM were conducted using two algorithms for rare species, MaxEnt and randomForest (RF), and were based on seven localities for Rhagomys, and 10 for Neusticomys. Results: All specimens were collected with pitfall traps. One specimen of genus Rhagomys was trapped in the Hydroelectric Dam Jirau. We identified this specimen as R. longilingua, and the SDM species indicates suitable areas for its occurrence at high elevations near on the Andes and lowlands of Amazon Basin to the South of the Rio Amazonas. Two specimens of Neusticomys were recorded, and we identified the specimen from Pacaas Novos as N. peruviensis, with SDM suggesting main areas of occurrence on Western Amazon. We applied the name N. ferreirai to the specimen from Pacaja, with SDM recovering suitable areas in Eastern Amazon. Discussion: We reinforced the importance of pitfall traps on the study of Neotropical rodents. We described morphologic variation within and among all species that do not invalidate their specific status, but in the near future a re-evaluation will be mandatory. The new records extended the species distribution considerably. SDM was successful to predict their distributions, as the two algorithms presented important differences in range size recovered by the models that can be explained by differences in the thresholds used for the construction of the models. Most suitable areas coincide with the areas facing most of the deforestation in Amazon. We added two rare species of sigmodontine rodents to the list of Brazilian Mammals, which now comprises 722 species (or 775 valid nominal taxa). Although more information is available than in 1996, it is essential that mammal experts maintain inventory and revisionary programs to update and revise this information. This is even more important, as changes in Brazilian environmental legislation are being discussed, suggesting reduced need for environmental impact reports prior to beginning commercial enterprises, resulting in the loss of information about native biodiversity in the affected areas. PMID- 29259841 TI - Unraveling the structure and composition of Varadero Reef, an improbable and imperiled coral reef in the Colombian Caribbean. AB - Coral reefs are commonly associated with oligotrophic, well-illuminated waters. In 2013, a healthy coral reef was discovered in one of the least expected places within the Colombian Caribbean: at the entrance of Cartagena Bay, a highly polluted system that receives industrial and sewage waste, as well as high sediment and freshwater loads from an outlet of the Magdalena River (the longest and most populated river basin in Colombia). Here we provide the first characterization of Varadero Reef's geomorphology and biological diversity. We also compare these characteristics with those of a nearby reference reef, Baru Reef, located in an area much less influenced by the described polluted system. Below the murky waters, we found high coral cover of 45.1% (+/-3.9; up to 80% in some sectors), high species diversity, including 42 species of scleractinian coral, 38 of sponge, three of lobster, and eight of sea urchin; a fish community composed of 61 species belonging to 24 families, and the typical zonation of a Caribbean fringing reef. All attributes found correspond to a reef that, according to current standards should be considered in "good condition". Current plans to dredge part of Varadero threaten the survival of this reef. There is, therefore, an urgent need to describe the location and characteristics of Varadero as a first step towards gaining acknowledgement of its existence and garnering inherent legal and environmental protections. PMID- 29259843 TI - Tris(1,3-dichloro-2-propyl) phosphate disrupts dorsoventral patterning in zebrafish embryos. AB - Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a high-production volume organophosphate flame retardant widely used within the United States. Within zebrafish, initiation of TDCIPP exposure at 0.75 h post-fertilization (hpf) results in genome-wide alterations in methylation during cleavage (2 hpf) as well as epiboly delay or arrest (at higher concentrations) during late-blastula and early-gastrula (4-6 hpf). To determine whether these TDCIPP-induced effects were associated with impacts on the transcriptome, embryos were exposed to vehicle (0.1% DMSO) or 2 uM TDCIPP from 0.75 hpf to 6 hpf, and total RNA was extracted from triplicate embryo pools per treatment and hybridized onto duplicate Affymetrix Zebrafish Gene 1.0 ST Arrays per RNA sample. Based on transcriptome wide profiling, TDCIPP resulted in a significant impact on biological processes involved in dorsoventral patterning and bone morphogenetic protein (BMP) signaling. Consistent with these responses, TDCIPP exposure also resulted in strongly dorsalized embryos by 24 hpf-a phenotype that mimicked the effects of dorsomorphin, a potent and selective BMP inhibitor. Moreover, the majority of dorsalized embryos were preceded by epiboly arrest at 6 hpf. Our microarray data also revealed that the expression of sizzled (szl)-a gene encoding a secreted Frizzled-related protein that limits BMP signaling-was significantly decreased by nearly 4-fold at 6 hpf. Therefore, we used a splice-blocking morpholino to test the hypothesis that knockdown of szl phenocopies TDCIPP-induced delays in epiboly progression. Interestingly, contrary to our hypothesis, injection of szl MOs did not affect epiboly progression but, similar to chordin (chd) morphants, resulted in mildly ventralized embryos by 24 hpf. Overall, our findings suggest that TDCIPP-induced epiboly delay may not be driven by decreased szl expression, and that TDCIPP-induced dorsalization may-similar to dorsomorphin-be due to interference with BMP signaling during early zebrafish development. PMID- 29259842 TI - Multi-scale and multi-site resampling of a study area in spatial genetics: implications for flying insect species. AB - The use of multiple sampling areas in landscape genetic analysis has been recognized as a useful way of generalizing the patterns of environmental effects on organism gene flow. It reduces the variability in inference which can be substantially affected by the scale of the study area and its geographic location. However, empirical landscape genetic studies rarely consider multiple sampling areas due to the sampling effort required. In this study, we explored the effects of environmental features on the gene flow of a flying long-horned beetle (Monochamus galloprovincialis) using a landscape genetics approach. To account for the unknown scale of gene flow and the multiple local confounding effects of evolutionary history and landscape changes on inference, we developed a way of resampling study areas on multiple scales and in multiple locations (sliding windows) in a single large-scale sampling design. Landscape analyses were conducted in 3*104 study areas ranging in scale from 220 to 1,000 km and spread over 132 locations on the Iberian Peninsula. The resampling approach made it possible to identify the features affecting the gene flow of this species but also showed high variability in inference among the scales and the locations tested, independent of the variation in environmental features. This method provides an opportunity to explore the effects of environmental features on organism gene flow on the whole and reach conclusions about general landscape effects on their dispersal, while limiting the sampling effort to a reasonable level. PMID- 29259844 TI - Ankle sprain as a work-related accident: status of proprioception after 2 weeks. AB - Purpose: This study aims at verifying whether proprioception is abnormal or not, two weeks after a grade 1 and 2 ankle sprain in the scope of work-related accident. Methods: A descriptive, observation and transversal study was designed to compare speed, movement and oscilation of centre of pressure in employees of companies signed up to a mutual company. Participants' healthy feet comprised the control group, and feet that had undergone an ankle sprain due to a work-related accident comprised the cases group. The following stability tests were undertaken to both the healthy and injuried feet using a force plate: Monopodal Romberg test with eyes open, Monopodal Romberg test with eyes open on a 30 mm thick foam rubber, Monopodal Romberg test with eyes closed, and Romberg test as monopodal support with eyes closed on a 30 mm thick foam rubber. A multiple logistic regression analysis was performed. From the results of this regression model the COR curve test was performed. Results: 71.7% accuracy in the predictions was attained. The equation was as follows: Condition (injured or healthy) = 0.052?% RGC AP Movement - 0.81?MREO AP Movement. The variable MREO antero-posterior movement was used in the COR curve methodology. The area under the curve was greater than 0.65 and at a 95% confidence interval the 0.75 value was included, which in our case was the injured subject condition. Values for sensitivity, specificity, positive predictive value and negative predictive value were 0.667, 0.633, 64.5%, and 65.5%, respectively. Conclusion: The participants in this study showed a diminished capacity for postural control in an ankle two weeks after an ankle sprain. PMID- 29259845 TI - Information from dynamic length changes improves reliability of static ultrasound fascicle length measurements. AB - Purpose: Various strategies for improving reliability of fascicle identification on ultrasound images are used in practice, yet these strategies are untested for effectiveness. Studies suggest that the largest part of differences between fascicle lengths on one image are attributed to the error on the initial image. In this study, we compared reliability results between different strategies. Methods: Static single-image recordings and image sequence recordings during passive ankle rotations of the medial gastrocnemius were collected. Images were tracked by three different raters. We compared results from uninformed fascicle identification (UFI) and results with information from dynamic length changes, or data-informed tracking (DIT). A second test compared tracking of image sequences of either fascicle shortening (initial-long condition) or fascicle lengthening (initial-short condition). Results: Intra-class correlations (ICC) were higher for the DIT compared to the UFI, yet yielded similar standard error of measurement (SEM) values. Between the initial-long and initial-short conditions, similar ICC values, coefficients of multiple determination, mean squared errors, offset-corrected mean squared errors and fascicle length change values were found for the DIT, yet with higher SEM values and greater absolute fascicle length differences between raters on the first image in the initial-long condition and on the final image in the initial-short condition. Conclusions: DIT improves reliability of fascicle length measurements, without lower SEM values. Fascicle length on the initial image has no effect on subsequent tracking results. Fascicles on ultrasound images should be identified by a single rater and care should be taken when comparing absolute fascicle lengths between studies. PMID- 29259846 TI - CD4 count and tuberculosis risk in HIV-positive adults not on ART: a systematic review and meta-analysis. AB - Background: CD4 cell count in adults with human immunodeficiency virus (HIV) infection (PLHIV) not receiving antiretroviral therapy (ART) influences tuberculosis (TB) risk. Despite widespread use in models informing resource allocation, this relationship has not been systematically reviewed. Methods: We systematically searched MEDLINE, Aidsinfo, Cochrane review database and Google Scholar for reports in English describing TB incidence stratified by updated CD4 cell count in cohorts of HIV-positive adults (age >=15 years) not on ART (PROSPERO protocol no: CRD42016048888). Among inclusion criteria were: reporting precision for TB incidence, repeated CD4 measurements, and TB incidence reported for those not on ART or monotherapy. Study quality was assessed via the Newcastle Ottawa tool for cohort studies. A Bayesian hierarchical model was fitted to estimate the pooled factor increase in TB incidence with respect to CD4 cell count decrement. Results: A total of 1,555 distinct records were identified from which 164 full text articles were obtained. Common reasons for exclusion of full texts were: no valid TB incidence, no repeat CD4 measurements, and not reporting TB incidence by ART status. The seven studies included reported on 1,206 TB cases among 41,271 individuals, with a typical median follow-up of four years. Studies were generally rated as moderate or high quality. Our meta-analysis estimated a 1.43 (95% credible interval: 1.16-1.88)-fold increase in TB incidence per 100 cells per mm3 decrease in CD4 cell count. Discussion: Our analysis confirms previous estimates of exponential increase in TB incidence with declining CD4 cell count in adults, emphasizing the importance of early ART initiation to reduce TB risk in PLHIV. PMID- 29259847 TI - Regulating the UAS/GAL4 system in adult Drosophila with Tet-off GAL80 transgenes. AB - The UAS/GAL4 system is the most used method in Drosophila melanogaster for directing the expression of a gene of interest to a specific tissue. However, the ability to control the temporal activity of GAL4 with this system is very limited. This study constructed and characterized Tet-off GAL80 transgenes designed to allow temporal control of GAL4 activity in aging adult muscles. By placing GAL80 under the control of a Tet-off promoter, GAL4 activity is regulated by the presence or absence of tetracycline in the diet. Almost complete inhibition of the expression of UAS transgenes during the pre-adult stages of the life cycle is obtained by using four copies and two types of Tet-off GAL80 transgenes. Upon treatment of newly emerged adults with tetracycline, induction of GAL4 activity is observed but the level of induction is influenced by the concentration of the inducer, the age, the sex and the anatomical location of the expression. The inhibition of GAL4 activity and the maintenance of induced expression are altered in old animals. This study reveals that the repressive ability of GAL80 is affected by the age and sex of the animal which is a major limitation to regulate gene expression with GAL80 in aged Drosophila. PMID- 29259848 TI - The shell morphology of the latest Cretaceous (Maastrichtian) trionychid turtle Helopanoplia distincta. AB - Background: Helopanoplia distincta is an extinct soft-shelled turtle (Pan Trionychidae) for which the type specimen is a fragmentary costal and the inguinal notch portion of the left hypoplastron from the Late Cretaceous (Maastrichtian) Lance Formation of Wyoming, USA that bear a distinct surface sculpture pattern consisting of raised tubercles. Over the course of the past few decades, a number of additional, fragmentary specimens from the Late Cretaceous (Maastrichtian) Hell Creek Formation of Montana and North Dakota have been referred to this taxon based on the presence of these tubercles, but a more complete understanding of the anatomy and phylogenetic relationships of this distinctive soft-shelled turtle is still outstanding. Methods: We here figure and describe shell remains of eight fossils referable to Helopanoplia distincta from the Hell Creek Formation of Montana and North Dakota that, in combination, document nearly all aspects of the shell morphology of this taxon. We furthermore explore the relationships of this fossil turtle by inserting it into a modified phylogenetic analysis of pan-trionychid relationships. Results: The new fossil material thoroughly supports the validity of Helopanoplia distincta. In addition to its unique surface sculpture pattern, this turtle can be diagnosed relative to all other named pan-trionychids by the presence of a distinct corner along the margin of costals II, the complete covering of costal ribs I-VI by metaplastic bone, midline contact of the main plastral elements, hyoplastral shoulder, presence of a lateral, upturned margin on the hyo/hypoplastron that is covered dorsally and laterally by sculptured metaplastic bone, a single, lateral hyoplastral process, and the apomorphic presence of fine scallops along the margin of costals VIII, formation of a laterally embraced, rounded nuchal, anteriorly rounded costals I, distally expanded costals II, and narrow costals VII. A phylogenetic analysis places Helopanoplia distincta as sister to the clade formed by Plastomenus thomasii and Hutchemys spp., thereby confirming its identity as a plastomenid. The vast majority of Helopanoplia distincta material has been recovered from fine-grained overbank deposits, thereby supporting the hypothesis that this turtle favored ponded waters. PMID- 29259849 TI - Genome-wide characterization and expression profiling of NAC transcription factor genes under abiotic stresses in radish (Raphanus sativus L.). AB - NAC (NAM, no apical meristem; ATAF, Arabidopsis transcription activation factor and CUC, cup-shaped cotyledon) proteins are among the largest transcription factor (TF) families playing fundamental biological processes, including cell expansion and differentiation, and hormone signaling in response to biotic and abiotic stresses. In this study, 172 RsNACs comprising 17 membrane-bound members were identified from the whole radish genome. In total, 98 RsNAC genes were non uniformly distributed across the nine radish chromosomes. In silico analysis revealed that expression patterns of several NAC genes were tissue-specific such as a preferential expression in roots and leaves. In addition, 21 representative NAC genes were selected to investigate their responses to heavy metals (HMs), salt, heat, drought and abscisic acid (ABA) stresses using real-time polymerase chain reaction (RT-qPCR). As a result, differential expressions among these genes were identified where RsNAC023 and RsNAC080 genes responded positively to all stresses except ABA, while RsNAC145 responded more actively to salt, heat and drought stresses compared with other genes. The results provides more valuable information and robust candidate genes for future functional analysis for improving abiotic stress tolerances in radish. PMID- 29259850 TI - The paradoxical role of tumor-infiltrating immune cells in lung cancer. AB - Lung cancer remains one of the leading causes of death worldwide, and lung cancers have often already metastasized when diagnosed. Numerous studies have noted the infiltration of immune cells in the lung cancer microenvironment, but these cells play a dualistic role, i.e. they suppress and/or promote tumor development and growth based on tumor progression and different cytokines in the microenvironment. These tumor-infiltrating immune cells create different microenvironments depending on their type and interaction. Chemokines act as a bridge in this process by recruiting immune cells to the tumor site and they regulate the phenotypes and functions of those cells. The current review summarizes current knowledge about the tumor-infiltrating immune cells in lung cancer as well as the mechanisms involved in suppression and promotion of tumor development and growth. PMID- 29259851 TI - Fibrodysplasia ossificans progressiva: Basic understanding and experimental models. AB - Fibrodysplasia ossificans progressive (FOP) is an extremely rare autosomal dominant disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification that can induce a disabling second skeleton. Spontaneously occurring flare-ups can cause inflammatory soft tissue to swell, followed by progressive and disabling heterotopic endochondral ossification. FOP is very rare, with an estimated incidence of one case per two million individuals. There is no definitive treatment for FOP, but the longevity of patients with FOP can be extended by early diagnosis and appropriate prevention of flares-up. Some promising treatment strategies and targets have recently been reported. The current review describes the classical phenotype and genotype of FOP, useful methods of diagnosing the condition, therapeutic approaches and commonly used drugs, and experimental models used to study this disease. PMID- 29259852 TI - Epidemiology, diagnosis, and treatment of Wilson's disease. AB - Wilson's disease (WD) is an autosomal recessive disease caused by a mutation of the ATP7B gene, resulting in abnormal copper metabolism. The major clinical features of WD include liver disease, neurological disorders, K-F rings, and osteoporosis. The prevalence of WD in China is higher than that in Western countries. Early diagnosis and lifelong treatment will lead to better outcomes. Drugs such as sodium dimercaptosuccinate (Na-DMPS), Zn, and Gandou Decoction can be used to treat WD. Some studies have shown that the combination of traditional Chinese medicine and Western medicine is the best approach to treating WD. In order to identify better treatments, this article describes the specific clinical symptoms of Wilson's disease, its diagnosis, and treatment options. PMID- 29259854 TI - Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease. AB - Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia. A rare variant of the TREM2 gene encoding p.Arg47His causes a 3 fold increase in the risk for late-onset Alzheimer's disease (LOAD). A recent study demonstrated that a rare coding variant p.Ser209Phe in the ABI family member 3 (ABI3) gene, a regulator of actin cytoskeleton organization, confers risk of developing of LOAD, although the pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized. We investigated the cell type-specific expression of ABI3 in the brains derived from four non-neurological controls (NC), ten AD and five NHD cases by immunohistochemistry. We identified an intense ABI3 immunoreactivity chiefly on a subset of microglia with ramified or amoeboid morphology located in the grey matter and the white matter of the frontal cortex and the hippocampus of NC, AD, and NHD cases. The immunolabeled area of ABI3-positive microglia was not significantly different among NC, AD, and NHD cases due to great variability from case to case. The clusters of ABI3-immunoreactive microglia were found exclusively in AD brains and they were associated with amyloid plaques. Although these observations do not actively support the view that ABI3-immunoreactive microglia play a central role in the development of leukoencephalopathy in NHD brains and the neurodegeneration in AD brains, the intense expression of ABI3 on microglia might regulate their migration under conditions of health and disease in the central nervous system (CNS). PMID- 29259853 TI - Infection after total knee arthroplasty and its gold standard surgical treatment: Spacers used in two-stage revision arthroplasty. AB - Periprosthetic joint infection (PJI) is one of the most devastating postoperative complications of total knee arthroplasty (TKA). Treatment varies depending on the type of infection, but two-stage revision arthroplasty using an antibiotic spacer is considered to be the gold standard of treatment. Several types of spacers are available at the moment, each with different benefits and indications, and these spacers may be improved in the future. The primary goals of selecting a given spacer are to locally deliver antibiotics and to preserve soft tissue. Use of an appropriate spacer subsequently decreases the difficulty of the second revision, the operating time, and ultimately the risk of postoperative complications. PMID- 29259855 TI - Estradiol and proinflammatory cytokines stimulate ISG20 expression in synovial fibroblasts of patients with osteoarthritis. AB - Interferon stimulated gene 20-kDa (ISG20) has been implicated in the pathology of osteoarthritis (OA) and it has been separately found to be responsive to estrogen stimulation. OA disproportionately affects women, and especially older women, suggesting some role of reproductive hormones in its pathology. The current study characterized the expression of ISG20 following stimulation with estradiol (E2) and proinflammatory cytokines in OA synovial fibroblasts (OASFs). E2 and the proinflammatory cytokines interleukin-6 (IL-6), lipopolysaccharide (LPS), and tumor necrosis factor alpha (TNF-alpha) were used to stimulate OASFs in vitro. The expression of ISG20 before and after stimulation was detected using quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting. E2 and proinflammatory cytokine (IL-6, LPS and TNF-alpha) stimulation significantly induced the expression of ISG20 both at the messenger RNA (mRNA) and protein level. Moreover, the induction was time- and dose-dependent. Small interfering RNA (siRNA) was transfected into OASFs, and expression of the inflammatory factors interleukin-1alpha (IL-1alpha), IL-6, and interleukin-10 (IL 10) was detected using RT-qPCR. Silencing ISG20 with siRNA inhibited the expression of IL-1alpha, IL-6, and IL-10. Thus, expression of ISG20 was regulated by estradiol and proinflammatory factors, while ISG20 in turn regulated the expression of other inflammatory factors. These data support the contention that ISG20 plays a role in the inflammatory process of OA. PMID- 29259856 TI - The expression profile of IFITM family gene in rats. AB - The interferon-inducible transmembrane proteins (IFITMs) are a family of small transmembrane proteins belonging to the interferon (IFN)-stimulated gene (ISG) superfamily and strongly induced by IFNs. In this paper, we studied the expression profile of IFITMs in 32 organ tissues. The IFITM mRNA expression profile showed that IFITM1, IFITM2 and IFITM3 were expressed in each tissue, especially, in spermatophore, spermaduct, testicle and epididymis. The expression of IFITM1, IFITM2 and IFITM3 showed a trend from high to low. Except for IFITM3 and IFITM6, the others IFITMs were highly expressed in the bone marrow, and the expression level of them was higher in the tibia than that in other parts of the long bones. In liver, the relative expression of IFITM1 and IFITM3 was higher than that of other members. The expression level of IFITM5 was the highest in bone marrow, successively in pancreas, and it was low in skin, smooth muscle and fat. Interestingly, the expression profile of IFITM2 and IFITM7 in tissues was similar to IFITM5. The expression of IFITM2, IFITM5 and IFITM10 were higher in smooth muscle than that in skeletal muscle. IFITM2, IFITM5, IFITM7 and IFITM10 were both highly expressed in esophagus and trachea. In addition, the expression of IFITM6 in eyes was high, and also in pancreas, gallbladder and bone. In the present study, we systematically analyzed the mRNA expression profile of IFITMs in 32 organ tissues, providing the foundation for the study of the function of the IFITMs. PMID- 29259857 TI - Differences of basic and induced autophagic activity between K562 and K562/ADM cells. AB - Patients with acute myeloid leukemia (AML) often have a poor prognosis due to drug resistance, which is regarded as a tough problem during the period of clinical therapeutics. It has been reported that autophagy, an important event in various cellular processes, plays a crucial role in mediating drug-resistance to cancer cells. Our study attempts to comparatively investigate the differences of basic and induced autophagic activity between drug-sensitive and multidrug resistant AML cells. The level of basic autophagy in K562/ADM cells was higher than that in K562 cells, which could be characterized by more cytosolic contents packaged autophagic vacuoles in K562/ADM cells when compared to that in K562 cells. The observation of MDC staining showed that the fluorescent intensity of autophagosomes in K562/ADM cells was stronger than that in K562 cells. The expression of Beclin1 and the ratio of LC3-II to LC3-I were distinctly higher in K562/ADM cells, however, P62 protein was relatively lower in K562/ADM cells. Furthermore, we found that nutrient depletion could induce autophagic activity of both cell lines. However, autophagic activity of K562/ADM cells was always maintained at a higher level in contrast with K562 cells. ADM (Adriamycin) was also capable of inducing autophagic activity of K562 and K562/ADM cells, but the autophagic alteration in K562 cells appeared earlier. Taken together, our findings suggest that autophagy exerts an important effect on formation and maintenance of drug-resistance in AML cells. PMID- 29259858 TI - In vivo quantification of amyloid burden in TTR-related cardiac amyloidosis. AB - Cardiac transthyretin-related (ATTR) amyloidosis is a severe cardiomyopathy for which therapeutic approaches are currently under development. Because non invasive imaging techniques such as cardiac magnetic resonance imaging and echocardiography are non-specific, the diagnosis of ATTR amyloidosis is still based on myocardial biopsy. Thus, diagnosis of ATTR amyloidosis is difficult in patients refusing myocardial biopsy. Furthermore, myocardial biopsy does not allow 3D-mapping and quantification of myocardial ATTR amyloid. In this report we describe a 99mTc-DPD-based molecular imaging technique for non-invasive single step diagnosis, three-dimensional mapping and semiquantification of cardiac ATTR amyloidosis in a patient with suspected amyloid heart disease who initially rejected myocardial biopsy. This report underlines the clinical value of SPECT based nuclear medicine imaging to enable non-invasive diagnosis of cardiac ATTR amyloidosis, particularly in patients rejecting biopsy. PMID- 29259859 TI - MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome. AB - Altered global methylation levels revealed LINE-1 methylation in young mothers of Down syndrome (DS) compared to controls suggesting the possibility of impaired DNA methylation causing abnormal segregation of chromosome 21. Methylene Tetrahydrofolate Reductase (MTHFR) is one of the major enzymes of the folate metabolism pathway. MTHFR gene polymorphism has been associated with maternal risk for DS. Studies have revealed that increased MTHFR promoter methylation results in the reduction of MTHFR protein activity further leading to increased risk of various diseases. The aim of this study is to compare the levels of MTHFR promoter methylation in all three study groups. A total of 120 subjects were recruited for the study and was divided into the following three groups: Group I (mothers of DS without Congenital Heart Defects (CHD), n = 40); Group II (mothers of DS with CHD, n = 40); and Group III (age matched control mothers, n = 40). Genomic DNA was isolated from 2 ml peripheral blood and bisulfite treatment was done to convert all unmethylated cytosines into uracil followed by PCR amplification for MTHFR promoter region and Sanger's sequencing. Results showed that there was a two fold increase in methylated promoter region of MTHFR gene in group II compared to other groups. None of the methylation pattern was observed in the control group. MTHFR promoter methylation affects folate metabolism which is known to play a role in chromosomal breakage, abnormal chromosomal segregation and genomic instability and therefore a developmental defect in the form of congenital cardiac anomaly. PMID- 29259860 TI - Steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at NPHS1 and ADCK4 genes in two Chinese siblings. AB - Hereditary nephrotic syndrome often presents with steroid-resistance and onset within the first year of life. Mutations in genes highly expressed in podocytes have been found in two thirds of these patients, especially NPHS1 and NPHS2 among at least 29 genetic causes that have been discovered. We reported two siblings with steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at NPHS1 (c.1339G>A, p.E447K) and ACDK4 (c.748G>C, p.D250H) genes. The siblings presented with steroid-resistant nephrotic syndrome and pathological lesions of focal segmental glomerulosclerosis (FSGS), while the elder sister also developed hypertension, renal failure and cardiac dysfunction. PMID- 29259862 TI - Disseminated mucormycosis: A sinister cause of neutropenic fever syndrome. AB - A 15 year old girl presented with complaints of prolonged fever and recurrent episodes of hemoptysis. Initial investigation showed pancytopenia and radiological imaging was suggestive of necrotizing pneumonia. Subsequently, mucor was isolated from bronchoalveolar lavage fluid, but even on appropriate medications her condition kept deteriorating. She had multiple bouts of hemoptysis and a repeat imaging of chest showed dissemination of mucormycosis to pulmonary vein and heart. Bone marrow biopsy identified acute lymphoblastic leukemia (ALL) as the cause of pancytopenia. She was planned for bronchial artery embolization and chemotherapy for ALL, but consent was not given and she left our institute against medical advice. Our case highlights the importance of keeping a high index of suspicion for disseminated mucormycosis in neutropenic patients, as any delay in diagnosis and treatment could have grave consequences. PMID- 29259861 TI - Inflammatory fibroid polyp of the gastric antrum presenting as hypovolemic shock: Case report and literature review. AB - Inflammatory fibroid polyps (IFP) are an extremely rare entity that arise within the submucosa of the gastrointestinal tract, and represent less than 0.1% of all gastric polyps. They are most commonly localized to the gastric antrum, small intestines and recto-sigmoid colon. IFPs are most commonly found incidentally upon endoscopic evaluation in the absence of symptoms. Presenting symptoms depend on the location of the tumor, although polyps located in the stomach most commonly present with epigastric pain and early satiety. Classic histologic features include perivascular onion skinning of spindle cells with an abundance of eosinophilic infiltration. The prompt diagnosis and management of IFP is essential due to its underlying risk for intussusception, outlet obstruction and acute hemorrhage. In addition, recent evidence has shown that IFP is driven by an activating mutation in the platelet derived growth factor receptor alpha (PDGFRA) gene, suggesting a neoplastic etiology. Herein, we discuss a case of a 65-year old woman with an inflammatory fibroid polyp of the gastric antrum who initially presented with early hypovolemic shock and melena. Diagnosis was made by endoscopic visualization, biopsy and immunohistochemical analysis. PMID- 29259863 TI - Expanded dengue syndrome in secondary dengue infection: A case of biopsy proven rhabdomyolysis induced acute kidney injury with intracranial and intraorbital bleeds. AB - Dengue fever is endemic in the Indian subcontinent and can have myriad presentations. The term expanded dengue syndrome (EDS) is used for atypical manifestations in dengue fever. We present a rare case of EDS in a patient with secondary dengue infection who developed rhabdomyolysis induced acute kidney injury (RAKI) along with intracranial and intraorbital bleeds. Patient was successfully managed in our institute and was discharged in stable condition. To the best of our knowledge, this is the only reported case of simultaneous occurrence of these complications in a dengue patient. This case is being presented to make clinicians aware of the spectrum of dengue infection. PMID- 29259864 TI - An up-date on epigenetic and molecular markers in testicular germ cell tumors. AB - Testicular germ cell tumor (TGCT) is the most common solid malignancy occurring in young men between 20 and 34 years of age, and its incidence has increased significantly over the last decades. Clinically several types of immunohistochemical markers are useful and sensitive. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency related cells but not in normal adult germ cells and they include OCT3/4, HMGA1 and 2, NANOG, SOX2, and LIN28. Gene expression in TGCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TGCT subtypes that reflect the normal developmental switch in primordial germ cells from an under to normally methylated genome. PMID- 29259865 TI - Interface conditions of roughness-induced superoleophilic and superoleophobic surfaces immersed in hexadecane and ethylene glycol. AB - Interface conditions are an important property that can affect the drag of fluid flow. For surfaces with different oleophobicity, the boundary slip at the solid oil interface is mostly larger than that at the solid-water interface. Roughness is a key factor for the wettability of superoleophilic/superoleophobic surfaces, and it has been found to affect the effective value of slip length in measurements. Moreover, there are no studies on the effect of roughness on slip at interfaces between oil and superoleophilic/superoleophobic surfaces. A theoretical description of the real surface roughness is yet to be found. Results show that the effective slip length is negative and decreases with an increasing root mean squared (RMS) roughness of surfaces, as the increasing roughness enhances the area with discontinuous slip at the solid-liquid interface. The underlying mechanisms are analyzed. The amplitude parameters of surface roughness could significantly inhibit the degree of boundary slip on both superoleophilic surfaces in Wenzel state and superoleophobic surfaces in Cassie state immersed in oil. The oleic systems were likely to enhance boundary slip and resulted in a corresponding reduction in drag with decreasing roughness on the solid-oil interfaces. PMID- 29259866 TI - Alternating current magnetic susceptibility of a ferronematic. AB - We report on experimental studies focusing on the dynamic ac magnetic susceptibility of a ferronematic. It has been shown recently, that in the isotropic phase of a ferronematic, a weak dc bias magnetic field of a few oersteds increases the ac magnetic susceptibility. This increment vanishes irreversibly if the substance is cooled down to the nematic phase, but can be reinduced by applying the dc bias field again in the isotropic phase [Tomasovicova, N. et al. Soft Matter2016, 12, 5780-5786]. The effect has no analogue in the neat host liquid crystal. Here, we demonstrate that by doubling the concentration of the magnetic nanoparticles, the range of the dc bias magnetic field to which the ferronematic is sensitive without saturation can be increased by about two orders of magnitude. This finding paves a way to application possibilities, such as low magnetic field sensors, or basic logical elements for information storage. PMID- 29259867 TI - PTFE-based microreactor system for the continuous synthesis of full-visible spectrum emitting cesium lead halide perovskite nanocrystals. AB - Colloidal perovskite nanocrystals comprised of all inorganic cesium lead halide (CsPbX3, X = Cl, Br, I or a mixture thereof) have potential as optical gain materials due to their high luminescence efficiency. In this work, cesium lead halide nanocrystals are continuously synthesized via a microreactor system consisting of poly(tetrafluoroethylene) (PTFE) capillaries. The synthesized nanocrystals possess excellent optical properties, including a full width at half maximum of 19-35 nm, high fluorescence quantum yield of 47.8-90.55%, and photoluminescence emission in the range of 450-700 nm. For the same precursor concentrations, the photoluminescence emission peak generally increases with increasing reaction temperature, revealing a controllable temperature effect on the photoluminescence characteristics of the synthesized nanocrystals. For quantum dots synthesized with a Br/I ratio of 1:3, a slight blue shift was observed for reaction temperatures greater than 100 degrees C. This PTFE-based microreactor system provides the unique capability of continuously synthesizing high-quality perovskite nanocrystals that emit over the full visible spectrum with applications ranging from displays and optoelectronic devices. PMID- 29259868 TI - Direct writing of gold nanostructures with an electron beam: On the way to pure nanostructures by combining optimized deposition with oxygen-plasma treatment. AB - This work presents a highly effective approach for the chemical purification of directly written 2D and 3D gold nanostructures suitable for plasmonics, biomolecule immobilisation, and nanoelectronics. Gold nano- and microstructures can be fabricated by one-step direct-write lithography process using focused electron beam induced deposition (FEBID). Typically, as-deposited gold nanostructures suffer from a low Au content and unacceptably high carbon contamination. We show that the undesirable carbon contamination can be diminished using a two-step process - a combination of optimized deposition followed by appropriate postdeposition cleaning. Starting from the common metal organic precursor Me2-Au-tfac, it is demonstrated that the Au content in pristine FEBID nanostructures can be increased from 30 atom % to as much as 72 atom %, depending on the sustained electron beam dose. As a second step, oxygen-plasma treatment is established to further enhance the Au content in the structures, while preserving their morphology to a high degree. This two-step process represents a simple, feasible and high-throughput method for direct writing of purer gold nanostructures that can enable their future use for demanding applications. PMID- 29259869 TI - Nanoprofilometry study of focal conic domain structures in a liquid crystalline free surface. AB - This work presents the first high-resolution nanoprofilometry study consisting of nanoscale resolution surface profile measurements and high-quality visualization of a the free surface of a liquid crystal-air boundary. The capabilities of this new experimental method, as applied for liquid crystal free boundaries, are discussed. The formation of focal conic domain structures at the smectic-A-air free boundary was detected and studied. PMID- 29259870 TI - Ferrocholesteric-ferronematic transitions induced by shear flow and magnetic field. AB - We study the unwinding of the ferrocholesteric helical structure induced by a combined action of a magnetic field and a shear flow. Both influences are able to induce the ferrocholesteric-ferronematic transition independently; however, the differences between the magnetic field orientation and the flow alignment direction lead to a competition between magnetic and hydrodynamic mechanisms of influence on the ferrocholesteric structure. We analyze various orientations of a magnetic field relative to the direction of a shear flow. The pitch of the ferrocholesteric helix is obtained as function of the strength and the orientation angle of the magnetic field, the shear velocity gradient and a reactive parameter. Phase diagrams of ferrocholesteric-ferronematic transition and the pitch of the ferrocholesteric helix as functions of the material and the governing parameters are calculated. We find out that imposing a shear flow leads to a shift of the magnetic field threshold. The value of the critical magnetic field depends on the magnetic field orientation, the velocity gradient, and the viscous coefficients. We show that the interplay of a magnetic field and a shear flow can induce reentrant orientational transitions that are ferrocholesteric ferronematic-ferrocholesteric. PMID- 29259871 TI - Amplified cross-linking efficiency of self-assembled monolayers through targeted dissociative electron attachment for the production of carbon nanomembranes. AB - The determination of the negative ion yield of 2'-chloro-1,1'-biphenyl (2-Cl-BP), 2'-bromo-1,1'-biphenyl (2-Br-BP) and 2'-iodo-1,1'-biphenyl (2-I-BP) upon dissociative electron attachment (DEA) at an electron energy of 0 eV revealed cross section values that were more than ten times higher for iodide loss from 2 I-BP than for the other halogenides from the respective biphenyls (BPs). Comparison with dissociative ionization mass spectra shows that the ratio of the efficiency of electron impact ionization induced fragmentation of 2-I-BP, 2-Br BP, and 2-Cl-BP amounts to approximately 1:0.7:0.6. Inspired by these results, self-assembled monolayers (SAMs) of the respective biphenyl-4-thiols, 2-Cl-BPT, 2 Br-BPT, 2-I-BPT as well as BPT, were grown on a Au(111) substrate and exposed to 50 eV electrons. The effect of electron irradiation was investigated by X-ray photoelectron spectroscopy (XPS), to determine whether the high relative DEA cross section for iodide loss from 2-I-BPT as compared to 2-Br-BP and 2-Cl-BP is reflected in the cross-linking efficiency of SAMs made from these materials. Such sensitization could reduce the electron dose needed for the cross-linking process and may thus lead to a significantly faster conversion of the respective SAMs into carbon nanomembranes (CNMs) without the need for an increased current density. XPS data support the notation that DEA sensitization may be used to achieve more efficient electron-induced cross-linking of SAMs, revealing more than ten times faster cross-linking of 2-I-BPT SAMs compared to those made from the other halogenated biphenyls or from native BPT at the same current density. Furthermore, the transfer of a freestanding membrane onto a TEM grid and the subsequent investigation by helium ion microscopy (HIM) verified the existence of a mechanically stable CNM created from 2-I-BPT after exposure to an electron dose as low as 1.8 mC/cm2. In contrast, SAMs made from BPT, 2-Cl-BPT and 2-Br-BPT did not form stable CNMs after a significantly higher electron dose of 9 mC/cm2. PMID- 29259872 TI - Robust nanobubble and nanodroplet segmentation in atomic force microscope images using the spherical Hough transform. AB - Interfacial nanobubbles (NBs) and nanodroplets (NDs) have been attracting increasing attention due to their potential for numerous applications. As a result, the automated segmentation and morphological characterization of NBs and NDs in atomic force microscope (AFM) images is highly awaited. The current segmentation methods suffer from the uneven background in AFM images due to thermal drift and hysteresis of AFM scanners. In this study, a two-step approach was proposed to segment NBs and NDs in AFM images in an automated manner. The spherical Hough transform (SHT) and a boundary optimization operation were combined to achieve robust segmentation. The SHT was first used to preliminarily detect NBs and NDs. After that, the so-called contour expansion operation was applied to achieve optimized boundaries. The principle and the detailed procedure of the proposed method were presented, followed by the demonstration of the automated segmentation and morphological characterization. The result shows that the proposed method gives an improved segmentation result compared with the thresholding and circle Hough transform method. Moreover, the proposed method shows strong robustness of segmentation in AFM images with an uneven background. PMID- 29259873 TI - Interactions of low-energy electrons with the FEBID precursor chromium hexacarbonyl (Cr(CO)6). AB - Interactions of low-energy electrons with the FEBID precursor Cr(CO)6 have been investigated in a crossed electron-molecular beam setup coupled with a double focusing mass spectrometer with reverse geometry. Dissociative electron attachment leads to the formation of a series of anions by the loss of CO ligand units. The bare chromium anion is formed by electron capture at an electron energy of about 9 eV. Metastable decays of Cr(CO)5- into Cr(CO)4-, Cr(CO)4- into Cr(CO)3- and Cr(CO)3- into Cr(CO)2- are discussed. Electron-induced dissociation at 70 eV impact energy was found to be in agreement with previous studies. A series of Cr(CO) n C+ (0 <= n <= 3) cations formed by C-O cleavage is described for the first time. The metastable decay of Cr(CO)6+ into Cr(CO)5+ and collision induced dissociation leading to bare Cr+, are discussed. In addition, doubly charged cations were identified and the ration between doubly and singly charged fragments was determined and compared with previous studies, showing considerable differences. PMID- 29259874 TI - Localized growth of carbon nanotubes via lithographic fabrication of metallic deposits. AB - We report on the fabrication of carbon nanotubes (CNTs) at predefined positions and controlled morphology, for example, as individual nanotubes or as CNT forests. Electron beam induced deposition (EBID) with subsequent autocatalytic growth (AG) was applied to lithographically produce catalytically active seeds for the localized growth of CNTs via chemical vapor deposition (CVD). With the precursor Fe(CO)5 we were able to fabricate clean iron deposits via EBID and AG. After the proof-of-principle that these Fe deposits indeed act as seeds for the growth of CNTs, the influence of significant EBID/AG parameters on the deposit shape and finally the yield and morphology of the grown CNTs was investigated in detail. Based on these results, the parameters could be optimized such that EBID point matrixes (6 * 6) were fabricated on a silica surface whereby at each predefined site only one CNT was produced. Furthermore, the localized fabrication of CNT forests was targeted and successfully achieved on an Al2O3 layer on a silicon sample. A peculiar lift-up of the Fe seed structures as "flakes" was observed and the mechanism was discussed. Finally, a proof-of-principle was presented showing that EBID deposits from the precursor Co(CO)3NO are also very effective catalysts for the CNT growth. Even though the metal content (Co) of the latter is reduced in comparison to the Fe deposits, effective CNT growth was observed for the Co-containing deposits at lower CVD temperatures than for the corresponding Fe deposits. PMID- 29259875 TI - Inelastic electron tunneling spectroscopy of difurylethene-based photochromic single-molecule junctions. AB - Diarylethene-derived molecules alter their electronic structure upon transformation between the open and closed forms of the diarylethene core, when exposed to ultraviolet (UV) or visible light. This transformation results in a significant variation of electrical conductance and vibrational properties of corresponding molecular junctions. We report here a combined experimental and theoretical analysis of charge transport through diarylethene-derived single molecule devices, which are created using the mechanically controlled break junction technique. Inelastic electron tunneling (IET) spectroscopy measurements performed at 4.2 K are compared with first-principles calculations in the two distinct forms of diarylethenes connected to gold electrodes. The combined approach clearly demonstrates that the IET spectra of single-molecule junctions show specific vibrational features that can be used to identify different isomeric molecular states by transport experiments. PMID- 29259876 TI - Synthesis of [{AgO2CCH2OMe(PPh3)} n ] and theoretical study of its use in focused electron beam induced deposition. AB - The synthesis, chemical and physical properties of [{AgO2CCH2OMe} n ] (1) and [{AgO2CCH2OMe(PPh3)} n ] (2) are reported. Consecutive reaction of AgNO3 with HO2CCH2OMe gave 1, which upon treatment with PPh3 produced 2. Coordination compound 2 forms a 1D coordination polymer in the solid state as evidenced by single crystal X-ray structure analysis. The coordination geometry at Ag+ is of the [3 + 1] type, whereby the carboxylate anions act as bridging ligands. The formation of PPh3-Ag(I) coordinative bonds results in distorted T-shaped AgPO2 units, which are stabilized further by an additional O-Ag dative bond. TG and TG MS measurements show that 1 and 2 decompose at 190-250 degrees C (1) and 260-300 degrees C (2) via decarboxylation, involving Ag-P (2), C-C and C-O bond cleavages to give elemental silver as confirmed by PXRD studies. In order to verify if polymeric 2 is suitable as a FEBID precursor for silver deposition, its vapor pressure was determined (p170 degrees C = 5.318 mbar, ?Hvap = 126.1 kJ mol 1), evincing little volatility. Also EI and ESI mass spectrometric studies were carried out. The dissociation of the silver(I) compound 2 under typical electron driven FEBID conditions was studied by DFT (B3LYP) calculations on monomeric [AgO2CCH2OMe(PPh3)]. At an energy of the secondary electrons up to 0.8 eV elimination of PPh3 occurs, giving Ag+ and O2CCH2OMe-. Likewise, by release of PPh3 from [AgO2CCH2OMe(PPh3)] the fragment [AgO2CCH2OMe]- is formed from which Ag+ and O2CCH2OMe- is generated, further following the first fragmentation route. However, at 1.3 eV the initial step is decarboxylation giving [AgCH2OMe(PPh3)], followed by Ag-P and Ag-C bond cleavages. PMID- 29259878 TI - Enhanced photoelectrochemical water splitting performance using morphology controlled BiVO4 with W doping. AB - Nanostructures exhibit numerous merits to improve the efficiency in solar-to energy conversion. These include shortened carrier collection pathways, an increased volume ratio between depletion layer and bulk, enhanced light capture due to multiple light scattering in nanostructures, and a high surface area for photochemical conversion reactions. In this study, we describe the synthesis of morphology-controlled W-doped BiVO4 by simply tuning the solvent ratio in precursor solutions. Planar and porous W-doped BiVO4 thin films were prepared and compared. The porous film, which exhibits increased surface area and enhanced light absorption, has displayed enhanced charge separation and interfacial charge injection. Our quantitative analysis showed an enhancement of about 50% of the photoelectrochemical performance for the porous structure compared to the planar structure. This enhancement is attributed to improved light absorption (13% increase), charge separation (14% increase), and interfacial charge injection (20% increase). PMID- 29259877 TI - The role of ligands in coinage-metal nanoparticles for electronics. AB - Coinage-metal nanoparticles are key components of many printable electronic inks. They can be combined with polymers to form conductive composites and have been used as the basis of molecular electronic devices. This review summarizes the multidimensional role of surface ligands that cover their metal cores. Ligands not only passivate crystal facets and determine growth rates and shapes; they also affect size and colloidal stability. Particle shapes can be tuned via the ligand choice while ligand length, size, omega-functionalities, and chemical nature influence shelf-life and stability of nanoparticles in dispersions. When particles are deposited, ligands affect the electrical properties of the resulting film, the morphology of particle films, and the nature of the interfaces. The effects of the ligands on sintering, cross-linking, and self assembly of particles in electronic materials are discussed. PMID- 29259879 TI - Patterning of supported gold monolayers via chemical lift-off lithography. AB - The supported monolayer of Au that accompanies alkanethiolate molecules removed by polymer stamps during chemical lift-off lithography is a scarcely studied hybrid material. We show that these Au-alkanethiolate layers on poly(dimethylsiloxane) (PDMS) are transparent, functional, hybrid interfaces that can be patterned over nanometer, micrometer, and millimeter length scales. Unlike other ultrathin Au films and nanoparticles, lifted-off Au-alkanethiolate thin films lack a measurable optical signature. We therefore devised fabrication, characterization, and simulation strategies by which to interrogate the nanoscale structure, chemical functionality, stoichiometry, and spectral signature of the supported Au-thiolate layers. The patterning of these layers laterally encodes their functionality, as demonstrated by a fluorescence-based approach that relies on dye-labeled complementary DNA hybridization. Supported thin Au films can be patterned via features on PDMS stamps (controlled contact), using patterned Au substrates prior to lift-off (e.g., selective wet etching), or by patterning alkanethiols on Au substrates to be reactive in selected regions but not others (controlled reactivity). In all cases, the regions containing Au-alkanethiolate layers have a sub-nanometer apparent height, which was found to be consistent with molecular dynamics simulations that predicted the removal of no more than 1.5 Au atoms per thiol, thus presenting a monolayer-like structure. PMID- 29259880 TI - Gene expression of an arabinogalactan lysine-rich protein CaAGP18 during vegetative and reproductive development of bell pepper (Capsicum annuum L.). AB - Lysine-rich (Lys-rich) proteins encoded by AGP17, AGP18, and AGP19 genes are cell wall-associated glycopeptides related to sexual reproduction in flowering plants. This subclass belongs to classical arabinogalactan proteins (AGPs) widely studied in model plants like Arabidopsis. In this study, we identified the CaAGP18 cDNA from bell pepper (Capsicum annuum L.), as well as its expression pattern during vegetative and reproductive development. The deduced amino acid sequence revealed a Lys-rich AGP18 protein of 238 amino acids residues in length with an estimated molecular mass of 22.85 kDa and an isoelectric point of 9.7. The protein is predicted as canonical AGP due to the presence of a small Lys-rich region and a C terminal sequence essential for posttranslational modification with a glycosylphosphatidylinositol (GPI). Phylogenetic analysis showed that CaAGP18 is clustered together with NtAGP18, SpAGP18, StAGP18 and NaAGP18 from Solanaceae species. CaAGP18 expression through plant phenological stages had the highest transcription level in leaves at the seedling stage, whereas in reproductive organs there was a significant up-regulation in pistils during anthesis, also in petals 2 days post-anthesis (DPA), and in fruit at the expansion stage. Our results open future research for possible roles of CaAGP18 in cell expansion as a wall-associated plasticizer and reproductive processes like pistil interactions and petal cell death. PMID- 29259881 TI - Culture of Spirogyra sp. in a flat-panel airlift photobioreactor. AB - Spirogyra is a green filamentous freshwater algae on which recent studies reveal several promising properties and potential application possibilities in biotechnology. However, little is known about cultivation of Spirogyra and even less about large-scale cultivations in closed growth systems. Therefore, the aim of the present study was to elaborate the growth kinetics of Spirogyra sp. in a commercially available and scalable photobioreactor. For this purpose, Spirogyra sp. was grown indoors in distinct flat-panel airlift photobioreactors equipped with culture-flow directing installations. Hereby, special attention was laid on light administration and specific light availability and it was found that Spirogyra sp., in combination with the photobioreactor in question, required high photon-flux densities (100 umol m-2 s-1 gDW-1) for maximum proliferation which is in accordance with its abundance in epipelagial waters in nature. Applying photon flux densities of up to 1400 umol m-2 s-1, a maximum volumetric productivity and final biomass concentration of 1.15 gDW L-1 day-1 and 14.28 gDW L-1 were achieved, respectively, the highest to be reported for the alga. To the knowledge of the authors, this is the first report on the growth of Spirogyra in a flat panel photobioreactor. PMID- 29259882 TI - Production and biochemical characterization of alpha-glucosidase from Aspergillus niger ITV-01 isolated from sugar cane bagasse. AB - Aspergillus niger ITV-01 presents amylolytic activity, identified as alpha glucosidase, an enzyme that only produces alpha-d-glucose from soluble starch and that presents transglucosylase activity on alpha-d-glucopyranosyl-(1-4)-alpha-d glucopyranose (maltose) (200 gL-1). Biochemical characterization was performed on A. niger ITV-01 alpha-glucosidase; its optimum parameters were pH 4.3, temperature 80 degrees C but stable at 40 degrees C, with an energy of activation (Ea) 176.25 kJ mol-1. Using soluble starch as the substrate, Km and Vmax were 5 mg mL-1 and 1000 U mg-1, respectively. As alpha-glucosidase is not a metalloenzyme, calcium and EDTA did not have any effect on its activity. The molecular weight was estimated by SDS-PAGE to be about 75 kDa. It was also active in methanol and ethanol. When ammonium sulfate (AS) and yeast extract (YE) nitrogen sources and calcium effect were evaluated, the greatest activity occurred using YE and calcium, as opposed to AS media where no activity was detected. The results obtained showed that this enzyme has industrial application potential in the processes to produce either ethanol or malto-oligosaccharides from alpha-d-glucopyranosyl-(1-4)-alpha-d-glucopyranose (maltose). PMID- 29259883 TI - Optimization of decolorization process in agar production from Gracilaria lemaneiformis and evaluation of antioxidant activities of the extract rich in natural pigments. AB - Gracilaria lemaneiformis is mainly used as a raw material source for agar industry, and its extract is rich in natural pigments with antioxidant activities. In this study, a solvent reflux extraction method for decolorization of G. lemaneiformis has been developed in agar production. The extraction conditions were optimized as follows: solvent-to-material ratio, 50:1; ethanol concentration, 70%; number of extractions, 3; extraction time, 0.5 h, under which the total antioxidant yield of the extract reached 2.89 +/- 0.88 mg/g dried seaweeds. Their IC50 values of DPPH radical scavenging activity, hydroxyl radical scavenging activity and superoxide anion scavenging activity were 21.91 +/- 1.8 mg/L, 40.59 +/- 1.5 mg/L and 160.87 +/- 2.8 mg/L, respectively. Further isolation and spectroscopic analysis of natural pigments suggested the strong antioxidant capacities were attributed to chlorophyll derivatives. The results indicate that the decolorization process was able to improve the agar quality, and the extract containing lots of natural pigments had antioxidant activities which may be used in functional food and cosmetics. PMID- 29259884 TI - Assessment of genetic diversity in lettuce (Lactuca sativa L.) germplasm using RAPD markers. AB - The importance of germplasm characterization is an important link between the conservation and utilization of plant genetic resources in various breeding programmes. In the present study, genetic variability and relationships among 25 Lactuca sativa L. genotypes were tested using random amplified polymorphic DNA (RAPD) molecular markers. A total of 45 random decamer oligonucleotide primers were examined to generate RAPD profiles, out of these reproducible patterns were obtained with 22 primers. A total of 87 amplicon were obtained, out of which all were polymorphic and 7 were unique bands. The level of polymorphism across genotypes was 100% as revealed by RAPD. Genetic similarity matrix, based on Jaccard's coefficients ranged from 13.7 to 84.10% indicating a wide genetic base. Dendrogram was constructed by unweighted pair group method with arithmetic averages method. RAPD technology could be useful for identification of different accessions as well as assessing the genetic similarity among different genotypes of lettuce. The study reveals the limited genetic base and the needs to diversify using new sources from the germplasm. PMID- 29259885 TI - Isolation and characterization of systemic acquired resistance marker gene PR1 and its promoter from Brassica juncea. AB - Systemic acquired resistance (SAR) is an inducible defense response in plants that provides enhanced resistance against a variety of pathogens. In this regard, SAR marker gene PR1 (pathogenesis-related gene 1) was isolated from Brassica juncea and was named as BjPR1. The amino acid sequence of BjPR1 protein showed 99, 92, and 78% similarity with known PR1 proteins of Brassica rapa, Brassica napus, and Arabidopsis thaliana, respectively. Quantitative real-time PCR (qRT PCR) analysis showed increased expression of BjPR1 gene both in local (infected) and distal (non-infected) leaves of B. juncea after Alternaria brassicae infection, whereas mechanical wounding showed expression only in local (wounded) leaves but not in distal (unwounded) leaves. Moreover, BjPR1 gene was strongly induced by salicylic acid (SA), whereas no such induction was observed following jasmonic acid (JA) or abscisic acid (ABA) treatments. To further elucidate gene regulation pattern of BjPR1, 2 kb promoter region of BjPR1 was isolated and subjected to in silico analysis which identified many potential cis-regulatory elements associated with plant defense as well as signaling pathways. The transient GUS expression analysis showed strong expression of GUS gene driven by BjPR1 promoter after SA treatment, while as ABA and JA downregulates GUS gene expression compared to control. In addition, BjPR1 promoter was significantly induced by wounding at local tissues. Hence, these results highlight the multiple role of BjPR1 gene in response to biotic and abiotic stresses. In addition, the present study also reported BjPR1 promoter as stress-specific inducible promoter that can be ideal candidate for controlling the expression of biotic stress response genes in transgenic plants. PMID- 29259886 TI - Batch growth kinetic studies of locally isolated cyanide-degrading Serratia marcescens strain AQ07. AB - The evaluation of degradation and growth kinetics of Serratia marcescens strain AQ07 was carried out using three half-order models at all the initial concentrations of cyanide with the values of regression exceeding 0.97. The presence of varying cyanide concentrations reveals that the growth and degradation of bacteria were affected by the increase in cyanide concentration with a total halt at 700 ppm KCN after 72 h incubation. In this study, specific growth and degradation rates were found to trail the substrate inhibition kinetics. These two rates fitted well to the kinetic models of Teissier, Luong, Aiba and Heldane, while the performance of Monod model was found to be unsatisfactory. These models were used to clarify the substrate inhibition on the bacteria growth. The analyses of these models have shown that Luong model has fitted the experimental data with the highest coefficient of determination (R2) value of 0.9794 and 0.9582 with the lowest root mean square error (RMSE) value of 0.000204 and 0.001, respectively, for the specific rate of degradation and growth. It is the only model that illustrates the maximum substrate concentration (Sm) of 713.4 and empirical constant (n) of 1.516. Tessier and Aiba fitted the experimental data with a R2 value of 0.8002 and 0.7661 with low RMSE of 0.0006, respectively, for specific biodegradation rate, while having a R2 value of 0.9 and RMSE of 0.001, respectively, for specific growth rate. Haldane has the lowest R2 value of 0.67 and 0.78 for specific biodegradation and growth rate with RMSE of 0.0006 and 0.002, respectively. This indicates the level of the bacteria stability in varying concentrations of cyanide and the maximum cyanide concentration it can tolerate within a specific time period. The biokinetic constant predicted from this model demonstrates a good ability of the locally isolated bacteria in cyanide remediation in industrial effluents. PMID- 29259887 TI - Combining sestc engineered A. niger with sestc engineered S. cerevisiae to produce rice straw ethanol via step-by-step and in situ saccharification and fermentation. AB - The development of agricultural residue ethanol has a profound effect on the environment protection and energy supply. To increase the production efficiency of straw ethanol and reduce operation progress, the single-enzyme-system-three cellulase gene (sestc) engineered Aspergillus niger and sestc engineered Saccharomyces cerevisiae were combined to produce ethanol using the pretreated rice straw as the substrate. The present results showed that both the step-by step and in situ saccharification and fermentation can effectively produce ethanol using rice straw as the carbon substrate. The conversion rates of ethanol were 12.76 and 14.56 g per 1 kg of treated rice straw, respectively, via step-by step and in situ processes. In situ process has higher ethanol conversion efficiency of rice straw and fewer operation processes as compared with step-by step process. Therefore, in situ saccharification and fermentation is a more economical and effective pathway to convert rice straw into ethanol. This study provides a reference to the conversion of lignocellulosic residues into ethanol with a combination of two kinds of sestc engineered strains. PMID- 29259888 TI - Larvicidal activity and in vitro regulation of rotenoids from Cassia tora L. AB - The search for new insecticidal natural products is very important viewing the global incidence of malaria. In the present study, rotenoids viz., sumatrol, rotenone, tephrosin, rotenol, deguelin, and elliptone were identified from the plant parts and callus culture of Cassia tora L. Maximum content of rotenoids was observed in roots (1.96% +/- 0.03) and minimum in the stem (0.52% +/- 0.02). Rotenoid showed larvicidal activity against Anopheles stephensi larvae (LC50 120.61 ppm; P < 0.05). To enhance the production of rotenoids in vitro, the callus culture of C. tora was supplemented with different concentrations of precursors (phenylalanine and methionine). More than onefold increase in the rotenoid content was observed as compared to the control. The present study highlights the insecticidal potential of rotenoids from C. tora. Moreover, the enhanced production of rotenoids using precursors can be exploited commercially. PMID- 29259889 TI - A low degenerate primer pool improved the efficiency of high-efficiency thermal asymmetric interlaced PCR to amplify T-DNA flanking sequences in Arabidopsis thaliana. AB - We employed hi-TAIL-PCR to identify T-DNA loci in our Arabidopsis activation tagging library and only a total of 28 (39%) insertion sites from 72 samples were characterized when the recommended primer pools, C1 and C2 were used. By comparison, we found C1 harboring relatively low degeneracy was more efficient to amplify the flanking sequences of T-DNA insertion than C2. We replaced the degenerate sequences in long arbitrary degenerate (LAD) primers with a piece of 16-bp degenerate sequence originally used in TAIL-PCR, which had the relatively low degeneracy. Our results showed that the new LAD primer pool N increased the valid amplifications and a total of 37 (51%) T-DNA loci were identified, indicating a more effective amplification of T-DNA flanking sequences in A. thaliana. PMID- 29259890 TI - Bioethanol production from rice husk using different pretreatments and fermentation conditions. AB - Bioethanol is an environmentally friendly alternative to petroleum energy sources. This study evaluated the effects of H2O, HCl, NaOH and FeCl3 pretreated rice husk feedstocks on the production of bioethanol. The pretreatments were carried out using water, 0.1 M HCl, NaOH and FeCl3 at 121 degrees C for 15 min, followed by simultaneous saccharification and fermentation (SSF) as well as separate hydrolysis and fermentation (SHF). The raw and pretreated lignocellulosic feedstocks were analyzed using Fourier transform infrared spectroscopy. Saccharification and fermentation were accomplished using Trichoderma reesei cellulase and Saccharomyces cerevisiae, respectively. The products obtained after saccharification and fermentation were collected and analyzed for reducing sugars and ethanol contents using 3,5-dinitrosalicylic acid and high-performance liquid chromatography, respectively. Enzyme hydrolysis of the FeCl3 and HCl treated samples resulted in hydrolysates containing 3.845 and 3.402 mg/ml glucose equivalent, respectively. In all pretreatments, SSF for each pretreatment produced more ethanol than the SHF method; the FeCl3 pretreatment gave the highest ethanol yield of 3.011 +/- 0.034 and 3.802 +/- 0.041% in the SHF and SSF methods, respectively. Utilization of FeCl3 pretreatment of rice husk is a potential option for bioethanol production in the future. PMID- 29259891 TI - Molecular identification and genetic analysis of cherry cultivars using capillary electrophoresis with fluorescence-labeled SSR markers. AB - Molecular identification and genetic analysis of cherry are necessary for solving the problem of synonyms and homonyms that occur in cherry production. In this study, capillary electrophoresis with fluorescent-labeled simple sequence repeat (SSR) primers was used to identify 63 cherry cultivars (varieties and rootstocks) planted in Shaanxi province, China. A total of 146 alleles were amplified by 10 SSR primer pairs, ranging from 10 to 20 per locus (mean: 14); among the SSR primer pairs, genotype number ranged from 12 to 26 (mean: 18). The mean values of gene diversity, heterozygosity, and polymorphism information content were 0.7549 (range 0.4011-0.8782), 0.5952 (range 0.3810-0.9683), and 0.7355 (range 0.3937 0.8697), respectively. An unweighted pair-group method with arithmetic average cluster analysis was used to separate the cherry cultivars. A model-based structure analysis separated the cultivars into three populations, which was consistent with the results of a phylogenic and principal component analysis. Based on Bayes' rule, the cultivars were further subdivided into seven populations. Some of the 63 cherry cultivars that are often confused in production were distinguished, and DNA fingerprinting of cherry cultivars was established. This research will significantly assist in the identification of cherry cultivars at the molecular level. PMID- 29259892 TI - Transition from early intervention program to primary school in children with autism spectrum disorder. AB - AIM: To evaluate the characteristics that are associated with successful transition to school outcomes in preschool aged children with autism. METHODS: Twenty-one participants transitioning from an early intervention program were assessed at two time points; at the end of their preschool placement and approximately 5 mo later following their transition to school. Child characteristics were assessed using the Mullen Scales of Early Learning, Vineland Adaptive Behaviour Scales, Social Communication Questionnaire and the Repetitive Behaviour Scale. Transition outcomes were assessed using Teacher Rating Scale of School Adjustment and the Social Skills Improvement System Rating Scales to provide an understanding of each child's school adjustment. The relationship between child characteristics and school outcomes was evaluated. RESULTS: Cognitive ability and adaptive behaviour were shown to be associated with successful transition to school outcomes including participation in the classroom and being comfortable with the classroom teacher. These factors were also associated with social skills in the classroom including assertiveness and engagement. CONCLUSION: Supporting children on the spectrum in the domains of adaptive behaviour and cognitive ability, including language skills, is important for a successful transition to school. Providing the appropriate support within structured transition programs will assist children on the spectrum with this important transition, allowing them to maximise their learning and behavioural potential. PMID- 29259893 TI - Neonatal pyknocytosis in a preterm dizygotic twin. AB - Infantile pyknocytosis (IP) is a rare, self-limited neonatal haemolytic anaemia that may require multiple blood transfusions. Only a little more than 50 cases have been reported in the medical literature, and the great majority of them concerns term infants. The etiology of IP is not well understood; most likely it results from a transient extra-corpuscular factor, whose nature is unknown, transmitted from mother to child or, alternatively, from a deficiency of an anti oxidative agent. We report the case of two preterm twins, one of which suffered from IP and developed severe anaemia at age 2 wk, while the other was unaffected. Although no specific agent was identified as the cause of anaemia and IP, we speculate that the transmission of an agent from mother to child was unlikely, as only twin one suffered from IP. Smelly greenish diarrhoea occurred just before the presentation of IP, suggesting that the same agent led to both the diarrhoea and the oxidative injury. Because IP may remain underdiagnosed, it should be considered in cases of early unexplained severe hemolytic anemia. PMID- 29259894 TI - Suppression of corneal neovascularization by curcumin via inhibition of Wnt/beta catenin pathway activation. AB - AIM: To investigate whether curcumin suppressed corneal neovascularization (CNV) formation via inhibiting activation of Wnt/beta-catenin pathway. METHODS: Suture induced CNV was established on Sprague-Dawley (SD) rats. Curcumin were daily administrated by subconjunctival injection. Phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6) and nuclear accumulation of beta catenin, two indicators of activated Wnt/beta-catenin pathway, were determined by Western-blot analysis in subconfluent/proliferating human microvascular endothelial cells (HMEC) and neovascularized corneas. Wnt3a conditioned medium (WCM) were harvested from Wnt3a expressing cells. WCM-induced cell proliferation and endothelial tubular formation capacity was measured by MTT assay and Matrigel assay, respectively. RESULTS: Phosphorylation of LRP6 and nuclear accumulation of beta-catenin was significantly increased in subconfluent/proliferating endothelial cells. Activation of Wnt/beta-catenin pathway by WCM markedly promotes HMEC proliferation and tubular formation. Curcumin inhibited LRP6 phosphorylation and nuclear accumulation of beta-catenin. In addition, curcumin attenuated WCM-induced HMEC proliferation and disrupted tubular structure of endothelial cells on Matrigel. Meanwhile curcumin suppressed suture-induced CNV and inhibited LRP6 phosphorylation as well as beta-catenin accumulation in SD rats. CONCLUSION: Taken together, activation of Wnt/beta-catenin pathway could be involved in endothelial proliferation during suture-induced CNV formation and curcumin attenuated CNV formation via inhibition of Wnt/beta-catenin pathway activation. PMID- 29259895 TI - Age-related changes of corneal endothelial cell in healthy Chinese tree shrew measured by non-contact specular microscope. AB - AIM: To determine the impact of age on the morphology of endothelial cells and central corneal thickness (CCT) in Chinese tree shrew. METHODS: One-hundred and twenty eyes of 60 healthy Chinese tree shrews were studied. Based on age, the tree shrews were divided into four groups. After general anesthesia, the images of endothelium were acquired using non-contact specular microscope Topcon 3000P. Eight parameters of corneal endothelial cells were measured by built-in software, including CCT, endothelial cell density (ECD), percent hexagonality (HG%), coefficient of variability (CV), size of minimal cell (Smin), size of maximal cell (Smax), average cells size (Savg) and size standard deviation (Ssd). Data were analyzed using STATA software. The differences of eight parameters among groups and correlations with age were analyzed. RESULTS: In all studied animals, the average CCT was 249.6+/-20.29 um (202-301 um), ECD was 3080.72+/- 460.76 cells/mm2 (1239.6-4047.6 cells/mm2) and CV was 29.10+/-7.60 (13.6-54.6). CV was significantly different among different groups (P<0.001). Strong correlation with age was found in ECD, Smax, Savg, Ssd and CV. CONCLUSION: Cornea of Chinese tree shrews had half CCT of human cornea and similar ECD, CV and size of corneal endothelial cells. Young adult tree shrews had higher ECD, HG% and low CV. ECD, Smax, Savg, Ssd and CV correlated with age significantly. PMID- 29259896 TI - Involvement of Rho-associated coiled-coil kinase signaling inhibition in TGF beta1/Smad2, 3 signal transduction in vitro. AB - AIM: To research the effect of Y-27632, a selective Rho-associated coiled-coil kinase (ROCK) inhibitor, on TGF-beta1/Smad2, 3 signal transduction in ocular Tenon's capsule fibroblasts (OTFs). METHODS: Primary ocular Tenon's capsule fibroblasts had been cultured in vitro. The effect of Y27632 on proliferation of OTF stimulated by lysophosphatidic acid (LPA) was evaluated by MTT colorimetric assay so as to sift out the proper concentrations range of Y-27632 for the next experiment. Real time-polymerase chain reactor (RT-PCR) was to analyze the changes of Smad2 and Smad3 genes of cells affected by Y-27632, though unaffected by transforming growth factor-beta1 (TGF-beta1). Proteins of Smad2, Smad3, phosphorylated Smad2 (Ser245/250/255), and phosphorylated Smad3 (Ser423/425/203) were respectively quantified by Western blot after OTFs were successively incubated by TGF-beta1 and Y-27632. Meanwhile, alpha-smooth muscular actin (alpha SMA) protein was also quantified after the small intervening gene fragments of human Smad2 and Smad3 were designed, synthesized, and then transfected to OTFs. RESULTS: Y-27632 significantly inhibited OTFs proliferation stimulated by LPA. Also Y-27632 significantly suppressed the expressions of Smad2 mRNA, Smad2, 3 proteins expressions, Smad3 phosphorylation at the carboxylic terminals of Ser423/425/203 which had been radically promoted by TGF-beta1. SiRNA-Smad2, 3 suppressed alpha-SMA expressions, but less effectively than Y-27632. CONCLUSION: The inhibition of ROCK signaling may be a potential therapeutic candidate for the treatment of the filtration channel fibrosis. PMID- 29259897 TI - Pioglitazone ameliorates retinal ischemia/reperfusion injury via suppressing NLRP3 inflammasome activities. AB - AIM: To explore the role of Pioglitazone (Pio) on a mouse model of retinal ischemia/reperfusion (I/R) injury and to elucidate the potential mechanism. METHODS: Retinal ischemia was induced in mice by increasing the intraocular pressure, and Pio was administered 4h though periocular injection before I/R. The number of cells in the ganglion cell layer (GCL) was counted 7d after retinal I/R injury. Glial fibrillary acidic protein (GFAP), nuclear factor-kappa B (NF kappaB), p38, phosphorylated-p38, PPAR-gamma, interleukin-1beta (IL-1beta), Toll like receptor 4 (TLR4), NLRP3, cleaved caspase-1, caspase-1 were determined by real-time polymerase chain reaction and Western blotting. RESULTS: Pio promoted the survival of retinal cells in GCL following retinal I/R injury (P<0.05). Besides, retinal I/R injury stimulated the expression of GFAP and TLR4, which were partially reversed by Pio treatment (P<0.05). Retinal I/R injury-upregulated expression of NLRP3, cleaved caspase-1, IL-1beta was attenuated after Pio treatment (P<0.05). Moreover, I/R injury induced activation of NF-kappaB and p38 were inhibited by Pio treatment (P<0.05). CONCLUSION: Pio promotes retinal ganglion cells survival by suppressing I/R-induced activation of TLR4/NLRP3 inflammasomes via inhibiting NF-kappaB and p38 phosphorylation. PMID- 29259898 TI - Clinical and experimental study on angiopoietin-like protein 8 associated with proliferative diabetic retinopathy. AB - AIM: To confirm the role of angiopoietin-like protein 8 (Angptl 8) in proliferative diabetic retinopathy (PDR). METHODS: The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy (NDR) patients (idiopathic macular hole patients) were collected and the expression of Angptl 8 was detected by enzyme linked immune-sorbent assay (ELISA). Experimental diabetes mice model was induced with streptozotocin. The expression of glycosylated hemoglobin and Angptl 8 in sera was detected. Recombinant Angptl 8 was re-infused into wild type (WT) diabetic mice and spatial frequency threshold and contrast sensitivity were measured. In vitro retinal pigment epithelium (RPE) were stimulated by recombinant Angptl 8 for 24h. MMT assay were used to detect cell proliferation. At the same time, qRT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells. RESULTS: The expression of Angptl 8 was markedly increased in the sera and aqueous humor of PDR patients (F=99.02, P<0.0001 in sera; t=10.42, P<0.0001 in aqueous). After successfully establishing the diabetic mice model, we found that glycosylated hemoglobin and Angptl 8 expression levels were increased. Re-infusion of recombinant Angptl 8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity (P<0.01). In vitro, RPE cells stimulated by recombinant Angptl 8 could increase the relative absorbance of MMT assay (1.486+/-0.042 vs 1.000+/ 0.104, P<0.05) and proliferating cell nuclear antigen (PCNA) expression (0.55+/ 0.01 vs 0.29+/-0.03, P<0.05). The proliferative effect of Angptl 8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A1 (4.973+/-0.205 vs 2.720+/-0.197, P<0.05), cyclin F (5.690+/-0.219 vs 4.297+/ 0.292, P<0.05) and E2F2 (2.297+/-0.102 vs 1.750+/-0.146, P<0.05), and reducing the expression of proliferation-inhibiting factors cdkn1 (2.370+/-0.074 vs 3.317+/-0.135, P<0.05) and cdkn2 (4.793+/-0.065 vs 5.387+/-0.149, P<0.05). CONCLUSION: The expression of Angptl 8 is increased in PDR, and the increased Angptl 8 can promote proliferation and increase proliferation-related factors. PMID- 29259899 TI - Infliximab relieves blood retinal barrier breakdown through the p38 MAPK pathway in a diabetic rat model. AB - AIM: To clarify the mechanism of infliximab treatment in diabetic macular edema (DME) and to provide a new alternative therapy for DME. METHODS: Rats were randomly divided into the control group, the model group and the infliximab treatment group. A diabetic rat model was created. The concentration of TNF-alpha in the vitreous body was detected by ELISA. The expressions of B-Raf, p38, claudin-1 and occludin in the retina were detected by Western blot. The integrity of the blood retinal barrier (BRB) was measured using Evan's blue as a tracer. RESULTS: After three months and six months of the diabetes model, the vitreous TNF-alpha level in the model group was higher than that of the control group. It was also higher in treated group than that of the control group but was lower than that of the model group. The differences among the three groups were statistically significant (at 3mo, F=857.098, P<0.001; 6mo, F=1261.897, P<0.001). The retina B-Raf and p38 levels in the model group were higher than that of the control group. They were also higher in treated group than that of the control group but were lower than that of the model group. The differences among the three groups were statistically significant (B-Raf at 3mo, F=106.596, P<0.001 and at 6mo, F=200.681, P<0.001; p38 at 3mo, F=41.662, P<0.001 and at 6mo, F=67.979, P<0.001). The retina claudin-1 and occludin levels in the model group were lower than that of the control group. They were also lower in treated group than that of the control group but were higher than that of the model group. The differences among three groups were statistically significant (claudin-1 at 3mo, F=139.088, P<0.001 and at 6mo, F=128.415, P<0.001; occludin at 3mo, F=92.733, P<0.001 and at 6mo, F=104.478, P<0.001). The retinal Evans blue leakage in the model group was higher than that of the control group. It was also higher in treated group than that of the control group but was lower than that of the model group. The differences among the three groups were statistically significant (at 3mo, F=447.946, P<0.001; at 6mo, F=1610.732, P<0.001). CONCLUSION: In a diabetic rat model, infliximab may relieve TNF-alpha induced BRB breakdown via the B-Raf and p38 signaling pathway. PMID- 29259900 TI - Anterior lamellar recession for management of upper eyelid cicatricial entropion and associated eyelid abnormalities. AB - AIM: To evaluate the functional and aesthetic outcomes of upper eyelid cicatricial entropion (UCE) correction using anterior lamellar recession (ALR) with addressing the associated conditions including dermatochalasis, brow ptosis, blepharoptosis, and lid retraction. METHODS: Chart review of patients with upper lid cicatricial entropion who had undergone ALR from 2013 to 2016 was reviewed. Success was defined as the lack of any lash in contact with the globe, no need for a second procedure, and acceptable cosmesis at the final follow up. RESULTS: Sixty eight patients (97 eyelids) were operated by ALR with simultaneous correction of associated lid problems in each case when necessary. The mean follow-up time was 17.8mo (range, 6.0-24.0mo). Concomitantly, levator tucking was performed in 19 eyelids (19.6%), upper lid retractor recession in 18 eyelids (18.6%), and internal browpexy in 31 eyelids (32.0%). In 95.8% of patients (95%CI: 0.85-0.96), satisfactory functional and cosmetic outcome was achieved with a single surgical procedure. CONCLUSION: Based on the principles of lamellar recession and concurrently addressing the associated lid problems, this approach is an effective and safe treatment of UCE. PMID- 29259901 TI - Timing and approaches in congenital cataract surgery: a four-year, two-layer randomized controlled trial. AB - AIM: To compare visual prognoses and postoperative adverse events of congenital cataract surgery performed at different times and using different surgical approaches. METHODS: In this prospective, randomized controlled trial, we recruited congenital cataract patients aged 3mo or younger before cataract surgery. Sixty-one eligible patients were randomly assigned to two groups according to surgical timing: a 3-month-old group and a 6-month-old group. Each eye underwent one of three randomly assigned surgical procedures, as follows: surgery A, lens aspiration (I/A); surgery B, lens aspiration with posterior continuous curvilinear capsulorhexis (I/A+PCCC); and surgery C, lens aspiration with posterior continuous curvilinear capsulorhexis and anterior vitrectomy (I/A+PCCC+A-Vit). The long-term best-corrected visual acuity (BCVA) and the incidence of complications in the different groups were compared and analyzed. RESULTS: A total of 57 participants (114 eyes) with a mean follow-up period of 48.7mo were included in the final analysis. The overall logMAR BCVA in the 6 month-old group was better than that in the 3-month-old group (0.81+/-0.28 vs 0.96+/-0.30; P=0.02). The overall logMAR BCVA scores in the surgery B group were lower than the scores in the A and C groups (A: 0.80+/-0.29, B: 1.02+/-0.28, and C: 0.84+/-0.28; P=0.007). A multivariate linear regression revealed no significant relationships between the incidence of complications and long-term BCVA. CONCLUSION: It might be safer and more beneficial for bilateral total congenital cataract patients to undergo surgery at 6mo of age than 3mo. Moreover, with rigorous follow-up and timely intervention, the postoperative complications in these patients are treatable and do not compromise visual outcomes. PMID- 29259902 TI - Clinical outcomes of a new diffractive multifocal intraocular lens. AB - AIM: To evaluate clinical outcomes after implantation of a new diffractive aspheric multifocal intraocular lens (IOL) with +3.00 addition power. METHODS: This is a retrospective, consecutive case series of cataract patients who underwent bilateral implantation of the Optiflex MO/HF D012 (Moss Vision Inc. Ltd, London, UK) multifocal IOL. Patients followed for 6mo were included in the study. Data on distance, intermediate and near visual acuity, refractive error [manifest spherical equivalent (MSE)], contrast sensitivity, adverse events, subjective symptoms, spectacle independence and patient satisfaction [visual function questionnaire (VFQ)-25 questionnaire] were retrieved from electronic medical records and analyzed. RESULTS: Forty eyes of 20 patients with a mean age of 66.7+/-8.5y (range: 53-82) were included in the study. Mean uncorrected distance, near and intermediate visual acuity remained stable through postoperative visits and was 0.19+/-0.19 logMAR, Jaeger 4 and Jaeger 3 respectively at the 6mo visit. At the end of postoperative 6mo, MSE was -0.14+/ 0.42 diopters (D) and 98% of the eyes were within 1.00 D of target refraction. Postoperative low contrast (10%) visual acuity remained stable (P=0.54) through follow up visits with a mean of 0.35+/-0.17 logMAR at the 6mo visit. There were no reported adverse events. None of the patients reported subjective symptoms of halo or glare. Spectacle independence rate was 90%. Mean VFQ-25 questionnaire score was 93.5+/-6.12. CONCLUSION: The Optiflex MO/HF-DO12 IOL was safely implanted and successfully restored distance, intermediate and near visual acuity without impairing contrast sensitivity. High levels of spectacle independence were achieved at all distances including intermediate distance. PMID- 29259903 TI - Outcomes of small gauge pars plicata vitrectomy for patients with persistent fetal vasculature: a report of 105 cases. AB - AIM: To evaluate the surgical outcomes in eyes with persistent fetal vasculatures (PFV) managed by small gauge pars plicata vitrectomy. METHODS: Consecutive patients with PFV treated by small gauge pars plicata vitrectomy at Beijing Tongren Eye Center between January 2010 and January 2013 were retrospectively reviewed. RESULTS: A total of 118 eyes of 105 patients with PFV were included and undergone small gauge pars plicata vitrectomy, of which 84 (71.2%) eyes had lensectomy and 16 (13.6%) eyes had lens aspiration and immediate intraocular lens implantation. The percentage of sutured scleral incision of 23 gauge vitrectomy (71.7%, 33/46) was higher than that of the 25 gauge vitrectomy (18.1%, 13/72). At last follow-up, visual acuity remained stable in 34 eyes (28.8%) and improved in 84 eyes (71.2%). Age at surgery (less than 2y), anterior type of PFV, and immediate IOL implantation were associated with postoperative improved visual acuity. Sixty five (55.1%) eyes had retinal detachment preoperatively, among which 33 (50.8%, 33/65) eyes had retinal reattachment or partial retinal reattachment. CONCLUSION: The results suggest that cases with PFV have a potential for developing good visual acuity after small gauge pars plicata vitrectomy with favorable anatomic outcomes and acceptable rate of serious surgical complications. PMID- 29259904 TI - A new strategy to interpret OCT posterior pole asymmetry analysis for glaucoma diagnosis. AB - AIM: To detect early glaucoma by optical coherence tomography (OCT) posterior pole asymmetry analysis. METHODS: Totally 39 eyes from 39 healthy subjects, 40 eyes from 40 mild glaucoma patients, 33 eyes from 33 moderate glaucoma patients and 41 eyes from severe glaucoma patients were included in this study. All subjects underwent posterior pole asymmetry analysis (PPAA) of OCT and the posterior pole area was divided into three zones. Means, standard deviations and 95% confidence intervals of each zone asymmetry in control group were assessed. Retina thickness asymmetry (RTA) of different stage of glaucoma were compared for each zone, and receiver operating characteristic (ROC) curves were made to test the efficacy of strategies using different zones to discriminate glaucomatous eyes from the healthy ones. RESULTS: In a healthy population, RTA of the centre zone showed the minimal mean value (3.085 um), standard deviation (1.756), and the narrowest 95% confidence interval (from 2.360 to 3.810 um). It was only in the center zone that RTA exhibited significant difference between control and moderate glaucoma group (P<0.01), as well as control and severe glaucoma group (P<0.00001). The strategy utilized in the center zone had the strongest diagnostic capability (zone 3 AUROC=0.816, P=0.0016) in comparison to that of the periphery area (zone 1 AUROC=0.675, P=0.0016; zone 2 AUROC=0.623, P=0.0197), the whole posterior pole involved interpreting strategy showed inferior diagnostic power than the centre zone dependent strategy (z=2.851, P=0.0044). CONCLUSION: Utilizing the posterior pole centre zone to interpret OCT PPAA results are more effective than making use of the whole posterior pole map. PMID- 29259905 TI - Negative effects of transthyretin in high myopic vitreous on diabetic retinopathy. AB - AIM: To analyze the relationship between vitreous transthyretin (TTR) levels, high myopia and diabetic retinopathy (DR). METHODS: We selected 6722 individuals from the southern Jiangsu Province for diabetes and ophthalmic examinations. The TTR concentration in the vitreous of 50 patients with high myopia and diabetes, 50 patients with only DR, and 20 healthy controls were determined by ELISA. Key factors in Tie2 pathway in DR development including vascular endothecial growth factor (VEGF), Tie2, Angpt1, Angpt2, vascular endothelial growth factor receptor (VEGFR) 1 and VEGFR2 were also detected by ELISA. RESULTS: The prevalence of DR in patients with diabetes and myopia [<6.00 diopter (D)], diabetes and high myopia (>6.00 D), and diabetes without myopia were 11.1%, 2.5%, and 60.0%, respectively. The vitreous TTR concentration of patients with diabetes and high myopia was approximately 6.5- and 4.2-times higher than those of patients with DR and healthy controls, respectively (P<0.05). Following the vitreous TTR concentration, the levels of VEGF, Tie2, Angpt1, Angpt2, VEGFR1 and VEGFR2 in vitreous of diabetes and high myopia patients, DR patients and healthy controls were detected as dramatically fluctuated. CONCLUSION: The results suggest that TTR can affect the vitreous contents of key factors in Tie2 pathway for neovascularization, and there should be a protective association between abundant TTR levels in the vitreous of highly myopic patients and a decreased risk of DR. PMID- 29259906 TI - Subfoveal choroidal thickness and volume in severe internal carotid artery stenosis patients. AB - AIM: To demonstrate the differences of retinal and choroidal structure changes in internal carotid artery (ICA) patients of China by enhanced-depth imaging optical coherence tomography (EDI-OCT). METHODS: A retrospective review was conducted of 46 patients with a diagnosis of ICA stenosis greater than 65% on only one side (the opposite ICA Stenosis had less than 40% stenosis) from June 2015 through June 2016. All of the patients were combined with amaurosis fugax, but without any abnormality with other ocular examination. Thickness and volume of choroid and retina were manually measured by EDI-OCT. Differences were compared between ICA stenosis eyes and fellow eyes. RESULTS: There were no significant differences in the retinal thickness, macular retinal nerve fiber layer (mRNFL) thickness, inner thickness, or outer retinal thickness between the ICA Stenosis group and the control group (P=0.834, 0.187, 0.552, and 0.903, respectively). The mean central choroidal thickness of the ICA Stenosis group was significantly lower than that of the control group (239.70+/-23.76 um vs 257.46+/-22.13 um, P<0.001). The percentage of ICA stenosis was significantly associated with the central choroidal thickness, central retinal thickness, foveal center choroidal volume, and foveal center retinal volume (r=0.854, 0.678, 0.729, and 0.785, respectively; P<0.001). There were no significant differences in the retinal and choroidal volume values in the 4 inner and 4 outer sectors between the two groups. CONCLUSION: The choroidal thickness in severe ICA stenosis eyes is lower than in fellow eyes. The choroidal thinning may occur before the retinal changes in patients with ocular ischemic syndrome. Evaluations of choroidal thickness may be useful to choose the optimal therapeutic schedule for ICA patients. PMID- 29259907 TI - The impact of macular surgery in different grades of epiretinal membrane. AB - AIM: To assess the impact of macular surgery on the functional and anatomic outcomes of the patients in different grades of epiretinal membrane (ERM). METHODS: Seventy-one eyes of 71 patients who underwent 23-gauge transconjunctival sutureless pars plana vitrectomy for primary isolated ERM were evaluated in this study. RESULTS: There were 38 females (53.5%) and 33 males (46.5%). The average age of the patients was 68.1y (range 42-89y). Mean follow up period was 14mo (range 6-26mo). The cases were divided into two subgroups of cellophane maculopathy (CM) and macular pucker (MP). An improvement was observed in the postoperative best-corrected visual acuity (BCVA), as well as a decrement in central foveal thickness (CFT) in both groups (both of these being statistically significant; P=0.001). In comparison between two groups, it was found that there was a significant improvement on BCVA and CFT in CM group than MP group (P=0.01). Furthermore, the postoperative fundus findings regarding RPE alterations and macular edema were significantly higher in MP group when compared to the CM group (P=0.01). CONCLUSION: ERM and internal limiting membrane peeling surgery can lead to a significant reduction of CFT and visual improvements in idiopathic ERM. A long-term ERM persistence will cause unrecoverable retinal damage and visual loss. PMID- 29259908 TI - Optic nerve compression: the role of the lamina cribrosa and translaminar pressure. AB - AIM: To describe the morphological changes of the lamina cribrosa (LC) in patients with optic nerve compression. METHODS: Cross-sectional study. Twenty eyes with optic nerve compression, affected by Graves' ophthalmopathy (GO) were compared with 18 refractive error-matched healthy eyes. The following examinations were performed: best-corrected visual acuity (BCVA), intraocular pressure, optic nerve echography, visual field, SD-OCT including the retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and LC thickness and extent. RESULTS: A-scan revealed significant differences in the subarachnoid space (SAS) between the affected and control groups. LC thickness and LC area were 233 um (SD 23) and 0.41 mm2 (SD 0.19), respectively. Average GCC thickness (P=0.0005), LC thickness (P=0.001), MD (P=0.001) and PSD (P=0.001) differed significantly between the two groups; whereas LC area (P=0.2) and average RFNL (P=0.1) did not. CONCLUSION: Optic nerve compression reduces the SAS thereby altering the morphology of LC thickness and causing GCC damage. PMID- 29259909 TI - Prevalence and treatment patterns of ranibizumab and photodynamic therapy in a tertiary care setting in Malaysia. AB - AIM: To describe the prevalence and changes in treatment patterns of ranibizumab and photodynamic therapy (PDT) among retinal disease patients who attended the Ophthalmology Clinic in the tertiary care Hospital Selayang from 2010 to 2014. METHODS: Study subjects were recruited retrospectively using the Electronic Medical Record (EMR) database software in Hospital Selayang. Demographic data, medical history, diagnostic procedure, treatments and diagnosis of patients were recorded. RESULTS: The five-year analysis included 821 patients with a mean age of 65.9+/-11.73y. Overall, there were a higher number of males (63.1%) and a higher number of Chinese (47.4%) patients. Among the 821 patients, 62.9% received ranibizumab injection followed by 19.2% PDT therapy and 17.9% had ranibizumab combined with PDT therapy. Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) were the most common retinal eye diseases reported, recording prevalence of 25.0% and 45.6%, respectively. The trend in ranibizumab treatment was reported to increase while PDT showed a decrease in trend from year 2010 to 2014. In terms of treatment, following multiple logistic regression, AMD was associated with the subjects being more likely to have received ranibizumab monotherapy (P<0.001) while PCV was associated with more likely to have received PDT (P<0.001) and PDT combined with ranibizumab therapy (P<0.001). CONCLUSION: The tertiary care setting in Malaysia is consistent with management of patients from other countries whereby ranibizumab is the most common treatment given to patients with AMD, while PCV patients most commonly receive PDT and ranibizumab combined with PDT therapy. PMID- 29259910 TI - Scientometric analysis of published papers in global ophthalmology in the past ten years. AB - AIM: To investigate the published papers of ophthalmology in past ten years and explore the development of ophthalmology. METHORDS: The data of this study retrieved from Science Citation Index Expanded and downloaded online in November 2017, including all the papers with publication year from 2007-2016 were analyzed. The papers were based on the Web of Science category and the journals were based on the Journal Citation Report category. RESULTS: The number of ophthalmology papers increased from 7450 to 9089 during 2007 to 2017. The average rate increased 2.2% annually. USA accounts for one thirds of the total and two thirds of the highly cited papers. In Asia, China, Japan and South Korea were in Top 10 by the number of ophthalmology papers. UK, Germany, Japan and Australia also had great impact in global ophthalmology. The hot spots included endothelial growth factor, optical coherence tomography and open-angle glaucoma. CONCLUSION: USA is in the leading position in global ophthalmology. Part of Asian countries play an important role in the development of ophthalmology, but the impact needs to be improved. PMID- 29259911 TI - Diverse roles of macrophages in intraocular neovascular diseases: a review. AB - Macrophages are involved in angiogenesis, and might also contribute to the pathogenesis of intraocular neovascular diseases. Recent studies indicated that macrophages exert different functions in the process of intraocular neovascularization, and the polarization of M1 and M2 phenotypes plays extremely essential roles in the diverse functions of macrophages. Moreover, a large number of cytokines released by macrophages not only participate in macrophage polarization, but also associate with retinal and choroidal neovascular diseases. Therefore, macrophage might be considered as a novel therapeutic target to the treatment of pathological neovascularization in the eye. This review mainly summarizes diverse roles of macrophages and discusses the possible mechanisms in retinal and choroidal neovascularization. PMID- 29259913 TI - Trans-epithelial accelerated corneal cross-linking for keratoconus in children. AB - The aim of the study is to evaluate the safety and efficacy of trans-epithelial accelerated corneal cross-linking (TE-ACXL) in children with progressive keratoconus. Retrospective, case-series of 23 eyes of 14 children who underwent TE-ACXL. Evaluations were performed at baseline and 1, 3, 6, 12 and 18mo postoperatively. Mean follow-up time of 23.82+/-3.15mo and mean age was 13.7+/ 1.4y (range 11 to 16y). Mean preoperative uncorrected distance visual acuity changed from 0.92+/-0.45 logMAR (20/160) to 0.71+/-0.40 logMAR (20/100) (P=0.001). Mean keratometry (Km) changed from 53.87+/- 6.03 to 53.00+/-5.81 (P=0.001). Pachymetry did not have significant changes at last follow-up (P=0.30). The mean preoperative sphere was -5.58+/-2.48 and -4.89+/-4.66 D (P=0.11) at last follow-up; refractive cylinder from -5.58+/-2.48 to -5.02+/-2.23 (P=0.046). In conclusion, tomographic and refractive stability are shown in over 91% of eyes with pediatric progressive keratoconus who underwent TE-ACXL. PMID- 29259912 TI - Smartphones, tele-ophthalmology, and VISION 2020. AB - Telemedicine is an emerging field in recent medical achievements with rapid development. The "smartphone" availability has increased in both developed and developing countries even among people in rural and remotes areas. Tele-based services can be used for screening ophthalmic diseases and also monitoring patients with known diseases. Electronic ophthalmologic records of the patients including captured images by smartphones from anterior and posterior segments of the eye will be evaluated by ophthalmologists, and if patients require further evaluations, they will be referred to experts in the relevant field. Eye diseases such as cataract, glaucoma, age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity are the most common causes of blindness in many countries and beneficial use of teleophthalmology with smartphones will be a good way to achieve the aim of VISION 2020 all over the world. Numerous studies have shown that teleophthalmology is similar to the conventional eye care system in clinical outcomes and even provides more patient satisfaction as it saves time and cost. This review explains how teleophthalmology helps to improve patient outcomes through smartphones. PMID- 29259914 TI - Ultrasound reliability in detection of retinal tear in acute symptomatic posterior vitreous detachment with vitreous hemorrhage. AB - Cross-sectional study of 75 consecutive patients presenting with acute symptomatic posterior vitreous detachment (ASPVD) and vitreous hemorrhage was conducted at University Eye Clinic, University Hospital "Sveti Duh", Zagreb, Croatia. To check ultrasound reliability in detecting retinal tears in patients with ASPVD, transpalpebral ultrasound of the eye and the orbit was performed followed by fundus examination initially and in 6wk period. In 13 (17%) patients membranous lesion with ultrasound characteristics of retinal tear was detected. Ophthalmoscopy confirmed the diagnosis in 8/13 patients. In 62/75 patients neither ultrasound nor clinical examination revealed retinal tear. Sensitivity of ultrasound examination was 100%, specificity 92%, positive predictive value 62% and negative predictive value 100%. Ultrasound proved to be a reliable and accurate method for detection of retinal tears in ASPVD. Given the high sensitivity and negative predictive value, negative result on B-scan ultrasound excludes the probability of the retinal tear with a high degree of certainty. PMID- 29259915 TI - Paracentesis following intravitreal drug injections in maintaining physiologic ocular perfusion pressure. AB - A retrospective analysis was performed of patients who received a paracentesis immediately following an intravitreal injection of bevacizumab or triamcinolone acetonide. These patients were previously diagnosed as having glaucoma, ocular hypertension, or had responded previously with sustained elevated intraocular pressure. Of 1661 procedures were performed. Totally 219 (13%) of the injections were on phakic patients. A median (SD) of 210 uL (40 uL) of aqueous was removed during each paracentesis. There were no reported incidences of any complications. We propose performing a paracentesis immediately following intravitreal injections for patients at risk for ocular hypertension, glaucoma, and retinal vein or artery occlusion. PMID- 29259916 TI - Comparison of surgical outcome of trabeculectomy and phacotrabeculectomy in Chinese glaucoma patients. AB - Our study retrospectively reviewed the surgical outcomes up to 3mo of 38 consecutive Chinese glaucoma patients who underwent trabeculectomy (n=18) or phacotrabeculectomy (n=20). Baseline age, visual acuity, and intraocular pressure were comparable. Intraocular pressure from post-operative 1d to 3mo were similar between 2 groups. Complete success was achieved in 65% of phacotrabeculectomy, and 66.7% of trabeculectomy cases; while failure occurred in 16.7% of phacotrabeculectomy, and 10% of trabeculectomy cases at 3mo. Phacotrabeculectomy group consistently showed better improvement in visual acuity. Diffuse blebs occurred in 65% of phacotrabeculectomy and 83% of trabeculectomy eyes; and flat blebs in 35% of phacotrabeculectomy, but none after trabeculectomy. There was more hypotony (5% vs 0) after phacotrabeculectomy. To conclude, phacotrabeculectomy and trabeculectomy demonstrated comparable intraocular pressure control up to 3mo post-operatively. However, phacotrabeculectomy patients had better visual acuity improvement. Nonetheless, more diffuse bleb and less hypotony were present following trabeculectomy. PMID- 29259917 TI - A novel suturing technique for filtering glaucoma surgery: the accordion suture. AB - AIM: To present a novel scleral flap suturing technique for filtering glaucoma surgery in order to control high postoperative intraocular pressure (IOP). METHODS: Description of 'the accordion suture' technique for mitomycin C augmented trabeculectomy. In cases of postoperative high IOP, pulling the loop of the suture helps to lift up the scleral flap by an even pressure on both edges. By means of this technique, the scleral flap opens up in an "accordion" manner, thus preventing flap obstruction and providing adequate aqueous flow. RESULTS: Our study group consisted of 8 eyes of 8 patients with neovascular glaucoma. Mean age of the subjects was 67.42+/-8.21y and female/male ratio was 4/4. Mean preoperative IOP was 37+/-7.48 mm Hg. Mitomycin C augmented trabeculectomy was carried out on the subjects without any complications. The scleral flap closure is performed with three separate sutures; initially, our accordion suture through the center of the flap, and two releasable sutures on both corners. All the patients received removal of two side releasable sutures concomitant with pulling the accordion suture, without any complications. The average traction time was 3.5+/-0wk postoperatively. The mean postoperative IOP was 11.37+/-2.72 mm Hg. No suture related complications were observed. CONCLUSION: This technique can be the suture of choice for filtering glaucoma surgery in experienced hands by its easy learning curve for precisely indicated patients. PMID- 29259918 TI - Corneal matrix repair therapy with the regenerating agent in neurotrophic persistent epithelial defects. PMID- 29259919 TI - Lyme Borrelia as the etiological factor in three cases of primary inflammatory choriocapillaropathies. PMID- 29259920 TI - Optical coherence tomography angiography in retinal cavernous hemangioma. PMID- 29259921 TI - Regarding successful use of 23G cutter for anterior vitrectomy and scleral fixated intraocular lens implantation. PMID- 29259922 TI - Exploring Virulence Determinants of Filamentous Fungal Pathogens through Interactions with Soil Amoebae. AB - Infections with filamentous fungi are common to all animals, but attention is rising especially due to the increasing incidence and high mortality rates observed in immunocompromised human individuals. Here, Aspergillus fumigatus and other members of its genus are the leading causative agents. Attributes like their saprophytic life-style in various ecological niches coupled with nutritional flexibility and a broad host range have fostered the hypothesis that environmental predators could have been the actual target for some of their virulence determinants. In this mini review, we have merged the recent findings focused on the potential dual-use of fungal defense strategies against innate immune cells and soil amoebae as natural phagocytes. Well-established virulence attributes like the melanized surface of fungal conidia or their capacity to produce toxic secondary metabolites have also been found to be protective against the model amoeba Dictyostelium discoideum. Some of the recent advances during interaction studies with human cells have further promoted the adaptation of other amoeba infection models, including the wide-spread generalist Acanthamoeba castellanii, or less prominent representatives like Vermamoeba vermiformis. We further highlight prospects and limits of these natural phagocyte models with regard to the infection biology of filamentous fungi and in comparison to the phagocytes of the innate immune system. PMID- 29259925 TI - Declining rate of autopsies: implications for anatomic pathology residents. PMID- 29259923 TI - Exploring the Anti-quorum Sensing and Antibiofilm Efficacy of Phytol against Serratia marcescens Associated Acute Pyelonephritis Infection in Wistar Rats. AB - Quorum Sensing (QS) mechanism, a bacterial density-dependent gene expression system, governs the Serratia marcescens pathogenesis through the production of virulence factors and biofilm formation. The present study demonstrates the anti quorum sensing (anti-QS), antibiofilm potential and in vivo protective effect of phytol, a diterpene alcohol broadly utilized as food additive and in therapeutics fields. In vitro treatment of phytol (5 and 10 MUg/ml) showed decreasing level of biofilm formation, lipase and hemolysin production in S. marcescens compared to their respective controls. More, microscopic analyses confirmed the antibiofilm potential of phytol. The biofilm related phenomenons such as swarming motility and exopolysccharide productions were also inhibited by phytol. Furthermore, the real-time analysis elucidated the molecular mechanism of phytol which showed downregulation of fimA, fimC, flhC, flhD, bsmB, pigP, and shlA gene expressions. On the other hand, the in vivo rescue effect of phytol was assessed against S. marcescens associated acute pyelonephritis in Wistar rat. Compared to the infected and vehicle controls, the phytol treated groups (100 and 200 mg/kg) showed decreased level of bacterial counts in kidney, bladder tissues and urine samples on the 5th post infection day. As well, the phytol treatment showed reduced level of virulence enzymes such as lipase and protease productions compared to the infected and vehicle controls. Further, the infected and vehicle controls showed increasing level of inflammatory markers such as malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) productions. In contrast, the phytol treatment showed decreasing level of inflammatory markers. In histopathology, the uninfected animal showed normal kidney and bladder structure, wherein, the infected animals showed extensive infiltration of neutrophils in kidney and bladder tissues. In contrast, the phytol treatment showed normal kidney and bladder tissues. Additionally, the toxic effect of phytol (200 mg/kg) was assessed by single dose toxicity analysis. No changes were observed in hematological, biochemical profiles and histopathological analysis of vital organs in phytol treated animals compared to the untreated controls. Hence, this study suggested the potential use of phytol for its anti-QS, antibiofilm and anti inflammatory properties against S. marcescens infections and their associated inflammation reactions. PMID- 29259924 TI - Growth of Chlamydia pneumoniae Is Enhanced in Cells with Impaired Mitochondrial Function. AB - Effective growth and replication of obligate intracellular pathogens depend on host cell metabolism. How this is connected to host cell mitochondrial function has not been studied so far. Recent studies suggest that growth of intracellular bacteria such as Chlamydia pneumoniae is enhanced in a low oxygen environment, arguing for a particular mechanistic role of the mitochondrial respiration in controlling intracellular progeny. Metabolic changes in C. pneumoniae infected epithelial cells were analyzed under normoxic (O2 ~ 20%) and hypoxic conditions (O2 < 3%). We observed that infection of epithelial cells with C. pneumoniae under normoxia impaired mitochondrial function characterized by an enhanced mitochondrial membrane potential and ROS generation. Knockdown and mutation of the host cell ATP synthase resulted in an increased chlamydial replication already under normoxic conditions. As expected, mitochondrial hyperpolarization was observed in non-infected control cells cultured under hypoxic conditions, which was beneficial for C. pneumoniae growth. Taken together, functional and genetically encoded mitochondrial dysfunction strongly promotes intracellular growth of C. pneumoniae. PMID- 29259926 TI - Machine learning enhanced virtual autopsy. PMID- 29259928 TI - Pseudoxanthoma elasticum. PMID- 29259929 TI - Holoprosencephaly. PMID- 29259927 TI - Gelatinous transformation of bone marrow: rare or underdiagnosed? AB - Gelatinous transformation of the bone marrow (GTBM) is a rare hematologic entity, which was first described by Paul Michael in 1930. GTBM is mostly associated with caloric intake/anorexia nervosa, although it also has been described accompanying other pathologic conditions, such as malignancy, systemic lupus erythematosus, HIV infections. Even though the diagnostic features of the hematopoietic tissue, such as hypoplasia, adipose cell atrophy, and deposition of a gelatinous substance in the bone marrow (which stains with Alcian blue at pH 2.5) are quite specific, the underlying pathogenic mechanisms remain poorly understood. Considering the evidence of reversibility-notably in cases of malnutrition and anorexia-this entity should be kept high on cards as a possible differential diagnosis of patients presenting with cytopenias and associated weight loss or starvation, especially in developing countries with nutritionally deprived populations. On an extensive review of the literature aimed at comprehensively addressing the evolution of the GTBM from the past century until now, we conclude that the lack of clinical suspicion and awareness regarding this pathologic entity has led to misdiagnosis and delayed diagnosis. PMID- 29259930 TI - Intravascular large B-cell lymphoma with multi-organ failure presenting as a pancreatic mass: a case with atypical presentation and definite diagnosis postmortem. AB - Intravascular large B-cell lymphoma (IVLBCL) is a very rare extra nodal lymphoma that tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules while sparing the organ parenchyma. The cause of its affinity for the vascular bed remains unknown. Because of its rarity and unremarkable clinical presentation, a timely diagnosis of IVLBCL is very challenging. Here, we describe a case of IVLBCL presenting as pancreatic mass that was ultimately diagnosed at autopsy. A 71-year-old Caucasian female presented with a 3-month history of fatigue, abdominal pain, and weight loss. She was referred to the emergency room with a new diagnosis of portal vein thrombosis and lactic acidosis. During her hospital course she was found to have a 1.9 * 1.8 cm lesion in the pancreatic tail on imaging; The cytologic specimen on the mass showed a high-grade lymphoma. A bone marrow biopsy showed no involvement. The patient's condition rapidly deteriorated and she, later, died due to multi-organ failure. An autopsy revealed diffuse intravascular invasion in multiple organs by the lymphoma cells. Based on our literature review-and to the best of our knowledge-there are virtually no reports describing the presentation of this lymphoma with a discernible tissue mass and associated multi-organ failure. The immunophenotypic studies performed revealed de novo CD5+ intravascular large B cell lymphoma, which is known to be aggressive with very poor prognosis. Although it is a very rare lymphoma, it should be considered as a potential cause of multi organ failure when no other cause has been identified. A prompt tissue diagnosis, appropriate high-dose chemotherapy and stem cell transplantation remain the only viable alternative to achieve some kind of remission. PMID- 29259932 TI - Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review. AB - Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UC OGC) is a rare and poorly described pancreatic malignancy. It is comprised of mononuclear, pleomorphic, and undifferentiated cells as well as osteoclast-like giant cells (OGC's). It constitutes less than 1% of pancreatic non-endocrine neoplasia and is twice as likely to occur in females as in males. Its histopathologic properties remain poorly understood. It is suspected that UC-OGC is of epithelial origin that can then transition to mesenchymal elements. As part of this study, we describe a case of a malignant pancreatic neoplasm that was discovered in a 69-year old patient as an incidental finding. We also provide an overview of previously published data to highlight UC-OGC's clinical and pathologic features. PMID- 29259931 TI - Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease. AB - Sickle cell disease encompasses a wide range of genotypic presentation with particular clinical features. The entity affects millions of people, particularly those whose ancestors came from sub-Saharan Africa and other countries in the Western Hemisphere, Saudi Arabia, and India. Currently, the high frequency of S and C genes reflects natural selection through the protection of heterozygotes against severe malaria, the high frequency of consanguineous marriages, improvement of some public health policies and the nutritional standards in the poorer countries where newborns are now living long enough to present for diagnosis and management. Although there is a high burden of the disease, in many countries, the new-born sickle cell screening test is being performed and is rendering an early diagnosis; however, it is still difficult for sickle cell patients to find proper treatment and adequate follow-up. Moreover, in many countries, patients are neither aware of their diagnosis nor the care they should receive to prevent complications; also, they do not receive adequate genetic counseling. Hemoglobin SC (HbSC) disease is the most frequent double sickle cell heterozygosis found in Brazil. The clinical course tends to be more benign with fewer hospitalizations compared with double homozygotic SS patients. However, HbSC patients may present severe complications with a fatal outcome. We report the case of a 36-year-old man who presented to the emergency care facility with symptoms consistent with the diagnosis of sickling crisis. The outcome was unfavorable and death occurred just hours after admission. The autopsy revealed a generalized vaso-occlusive crisis by sickled red cells, bone marrow necrosis, and fat embolism syndrome. PMID- 29259933 TI - Nominata of the Reviewers of the volume 7, 2017. PMID- 29259934 TI - The Prevalence of Malnutrition in Iranian Elderly: A Review Article. AB - Background: The elderly population following the improvement in health status and life expectancy in developing countries is increasing. Malnutrition causes decreased quality of life and increased mortality in elderly. This study aimed to review systematically and meta-analysis of studies assessing the prevalence of malnutrition among Iranian elderly people over 60 yr of age using Mini Nutritional Assessment (MNA). Methods: This systematic review and meta-analysis was conducted in 2016 to estimate the overall malnutrition prevalence. Data were collected using the following keywords: prevalence, elderly, aging, malnutrition, nutrition, nutritional assessment, nutritional status, health status, mini nutritional assessment, MNA and Iran in PubMed, Scopus, Google Scholar, Iranmedex, Magiran, and SID. Computer software CMA: Two were applied to estimate the overall prevalence of malnutrition. Results: Seventeen of 811 articles were included in our analyses. The overall estimated prevalence of malnutrition among elderly based on the random effect model was 12.2% (95% CI 8-18.5). In subgroups, the prevalence of malnutrition among elderly living in home based on the fixed effect model was 9.2% (95% CI 7.1-11.9) and prevalence of malnutrition among elderly residents of nursing homes based on the random effect model was 21.6% (95% CI 12-38.6). Conclusion: Given the increase in the elderly population in future and the prevalence rate of malnutrition among them as well as the higher prevalence of malnutrition in elderly care centers, more attention to this population group is a matter of necessity. PMID- 29259935 TI - Dexmedetomidine Based Sedation for Post-surgery Critically Ill Adults: A Meta analysis of Randomized Controlled Trials. AB - Background: Using dexmedetomidine (Dex) as a sedative agent may benefit the clinical outcomes of post-surgery patients. We reviewed randomized controlled trials (RCTs) to assess whether use of a Dex could improve the outcomes in post surgery critically ill adults. Methods: We searched Medline, Embase, PubMed, and the Cochrane databases for RCTs comparing Dex with propofol or a placebo in post operative patients, all included RCTs should be published in English before Jul 2016. Citations meeting inclusion criteria were full screened, and trial available data were abstracted independently and the Cochrane risk of bias tool was used for quality assessment. Results: Sixteen RCTs involving 2568 patients were subject to this meta-analysis. The use of a Dex sedative regimen was associated with a reduce delirium prevalence [odd ratio (OR):0.33, 95% confidence intervals (CI): 0.24-0.45, I2= 5%, P<0.001], a shorter the length of ICU stay [mean difference (MD): -0.60, 95%CI: -0.69 to -0.50, I2=40%, P<0.001] and the length of hospital stay [MD: -0.68, 95%CI: -1.21 to -0.16, I2=0%, P=0.01]. However, using of Dex could not shorter the duration of mechanical ventilation [MD: -10.18. 95%CI: -31.08-10.72, I2=99%, P=0.34], but could shorter the time to extubation in post-surgery patients [MD: -47.46, 95%CI: -84.63-10.67, I2=98%, P=0.01]. Conclusion: The use of a Dex sedative regimen was associated with a reduce delirium prevalence, a shorter the length of ICU and hospital stay, and a shorter time to extubation in post-surgery critical ill patients. PMID- 29259936 TI - Human Cystic Echinococcosis in Different Geographical Zones of Iran: An Observational Study during 1995-2014. AB - Background: Cystic Echinococcosis (CE) is a serious zoonotic parasitic disease in Iran. This study aimed to show the trend of the confirmed disease from 1995 to 2014 and to describe some of epidemiological aspects of the disease in Iran. Methods: This retrospective study has been designed based on data collected from 8518 cases of CE among various geographical locations of Iran. Results: The average annual number of human cases of CE was 274.8. Among 31 provinces of Iran, Razavi Khorasan from northeast part of Iran was the highest human CE infected province with the 1801 cases and Hormozgan Province in south part of the country showed the lowest the disease with the only one case of CE in 2009. Liver and lungs with the infection rate of 61% and 20%, respectively are the most infected organs, 53% of patients had one cyst in the bodies and the number of cysts in 8% of cases was more than 3 cysts. Altogether, 41% of CE cases were treated by surgery, 11% with chemotherapy and 48 % with mixed surgery and chemotherapy. Conclusion: Human CE is a major health problem in Iran and it is necessary to establish basic control programs. It is crucial to setting up standard diagnostic methods for early diagnosis, effective treatment, plan educational schedule for different social levels and control the disease in both definitive and intermediate hosts. PMID- 29259937 TI - Effects of Immunocytokine Combined with Cattle Encephalon Glycoside and Ignotin on CTGF, HO-1 and NT-3 in Patients with Type 2 Diabetic Peripheral Neuropathy. AB - Background: This study was designed to explore the correlation of connective tissue growth factor (CTGF), heme oxygenase (HO-1), neurotrophic factors (NT-3) with type 2 diabetic peripheral neuropathy, as well as the changes after immune cytokine alone and combined with cattleencephalon glycoside and ignotin treatment. Methods: Seventy-six patients with type 2 diabetes and peripheral neuropathy charged into People's Hospital of Rizhaolanshan, China from 2014-2016 were selected. The severity of neuropathy was evaluated by TCSS. Pearson analysis was used to analyze the correlation between the degree of neuropathy and CTGF, HO 1 and NT-3. The patients were randomly divided into control group and observation group, n=38. The control group accepted TGF-beta1 treatment on the basis of controlling diet and blood sugar, while the observation group was treated with cattle encephalon glycoside and ignotin injection on the basis of control group. CTGF, HO-1, NT-3 concentration in the blood and nerve conductive velocity (NCV) were detected and analyzed before and after treatment. Results: CTGF(r=-0.865), HO-1(r=-0.706), NT-3(r=-0.587) was negatively correlated with TCSS scores. After treatment, the concentrations of CTGF, HO-1and NT-3 in the observation group were higher than the control group (P<0.05). In moderate and severe lesions, the concentrations of CTGF, HO-1and NT-3 in the observation group were higher than the control group (P<0.05). The conduction velocity of nerve increased with the increase of CTGF, HO-1 and NT-3 concentrations. The obvious effective rate and total effective rate of observation group were both higher than the control group. Conclusion: Immune cytokine TGF-beta1 combined with cattle encephalon glycoside and ignotin injection could improve the contents of CTGF, HO-1 and NT 3, and be better to treat the peripheral neuropathy of type 2 diabetes. PMID- 29259938 TI - Knowledge Management Orientation: An Innovative Perspective to Hospital Management. AB - Background: By considering innovation as a new project in hospitals, all the project management's standard steps should be followed in execution. This study investigated the validation of a new set of measures in terms of providing a procedure for knowledge management-oriented innovation that enriches the hospital management system. Methods: The relation between innovation and all the knowledge management areas, as the main constructs of project management, was illustrated by referring to project management standard steps and previous studies. Through consultations and meetings with a committee of professional project managers, a questionnaire was developed to measure ten knowledge management areas in hospital's innovation process. Additionally, a group of experts from hospital managers were invited to comment on the applicability of the questionnaires by considering if the items are measurable in hospitals practically. Results: A close-ended, Likert-type scale items, consisted of ten sections, were developed based on project management body of knowledge thorough Delphi technique. It enables the managers to evaluate hospitals' situation to be aware whether the organization follows the knowledge management standards in innovation process or not. By pilot study, confirmatory factor analysis and exploratory factor analysis were conducted to ensure the validity and reliability of the measurement items. Conclusion: The developed items seem to have a potential to help hospital managers and subsequently delivering new products/services successfully based on the standard procedures in their organization. In all innovation processes, the knowledge management areas and their standard steps help hospital managers by a new tool as questionnaire format. PMID- 29259940 TI - Assessment of Orthographic Similarity of Drugs Names between Iran and Overseas Using the Solar Model. AB - Background: The recognition of patient safety is now occupying a prominent place on the health policy agenda since medical errors can result in adverse events. The existence of confusing drug names is one of the most common causes of medication errors. In Iran, the General Office of Trademarks Registry (GOTR), for four years (2010-2014) was responsible for approving drug proprietary names. This study aimed to investigate the performance of the GOTR in terms of drug names orthographic similarity using the SOLAR model. Methods: First, 100 names were randomly selected from the GOTR's database. Then, each name was searched through pharmaceutical websites including Martindale (the Complete Drug Reference published by Pharmaceutical Press), Drugs.com and Medicines Complete. Pair of drugs whose names look orthographically similar with different indications were identified. Then, the SOLAR model was utilized to determine orthographic similarity between all pair of drug names. Results: The mean of match values of these 100 pairs of drug was 77% indicating the high risk of similarity. The match value for most of the reviewed pairs (92%) was high (>=66%). This value was medium (>= 33% and <66%) just for 8% of the pairs of drug. These results indicate high risk of confusion due to similarity of drug names. Conclusion: The stewardship of the GOTR in patient safety considerations is fundamentally problematic. Thus, as a best practice, we recommend that proprietary names of drugs be evaluated by an entity within the health system. While an entity within the health system should address patient safety considerations, the GOTR is responsible for intellectual property rights. PMID- 29259939 TI - Effect of High-quality Nursing on Improvement of Anxiety and Depression of Patients with Acute Stroke in MRI Examination. AB - Background: We aimed to evaluate the effect of high-quality nursing on improvement of anxiety and depression of patients with acute stroke in magnetic resonance imaging (MRI) examination. Methods: A total of 120 patients diagnosed as acute stroke for the first time were enrolled in Liaocheng People's Hospital from 2016-2017 and randomly divided into control group (n=60) and observation group (n=60). All patients received cerebral MRI examination at 6h and 24h after admission and before discharge. The control group was treated with routine nursing, while the observation group was treated with high-quality nursing, and the specific nursing measures included the establishment of high-quality nursing group, full evaluation of the severity of disease, timely solving of difficulties in MRI examination, understanding of the patient's anxiety and depression, establishment of personal information files before discharge, etc. The completion rate and average duration of examination, the improvement of anxiety and depression and the nursing satisfaction were compared between the two groups. Results: In observation group, the completion rate of MRI examination was significantly increased (P=0.035), the average duration was shortened (P=0.011), the anxiety and depression scores (self-rating anxiety scale (SAS) and self rating depression scale (SDS)) were improved obviously (P=0.006 and 0.009), and the nursing satisfaction score and rate was increased (P=0.000 and 0.027); the differences were statistically significant (P<0.05). Conclusion: High-quality nursing can significantly improve the anxiety and depression of patients with acute stroke in MRI examination, which has a better application value in increasing the completion rate of examination, shortening the duration of examination and improving the nursing satisfaction. PMID- 29259941 TI - Social Anxiety and Internet Addiction among Rural Left-behind Children: The Mediating Effect of Loneliness. AB - Background: At present, the mental health of rural left-behind children is a major social problem in China. Internet addiction, social anxiety, and loneliness are common psychological and behavioral problems among rural left-behind children, but the relationships among these issues have not been clearly identified. Methods: A total of 432 junior year 1 to senior year 3 students were randomly selected from 2 rural middle schools in Hunan Province of China as the research subjects. The Internet Addiction Disorder Diagnostic Scale, Social Anxiety Subscale of the Self-Consciousness Scale (SASS-CS), and University of California Los Angeles Loneliness Scale were employed to measure the degree of Internet addiction, feelings of social fear, social avoidance behavior, and the level of loneliness among the research subjects. Results: The rate of Internet addiction among rural left-behind middle school students was 18.27%, and was correlated with the length of time their parents spent at home as well as whether one or both parents migrated for work. Positive correlations were found among Internet addiction, social anxiety, and loneliness. Loneliness was found to play a mediating role in the relationship between social anxiety and Internet addiction among rural left-behind middle school students. Conclusion: Social anxiety and loneliness both increase the likelihood of Internet addiction in rural left-behind middle school students and social anxiety can affect Internet addiction through loneliness, implying an urgent need to strengthen care for rural left-behind children, reduce their loneliness, and thereby effectively alleviate the problem of Internet addiction among rural left-behind middle school students. PMID- 29259942 TI - Prevalence of Health-risk Behaviors among Government Schools' Students in Jordan. AB - Background: Adolescence is a developmental stage associated with many behavioural fluctuations and health risks behaviours. In this study, various health risk behaviours among Government school students in Jordan were assessed. Methods: This cross-sectional descriptive study recruited 1256 students from 20 secondary schools all over the country. Students completed the Global School-based Student Health Survey (GSHS, 2009-2012). The study was conducted in the period between Feb 2016 and Aug 2016. Chi-square (x2) was used to examine differences among the demographic variables. Results: Students scored low in eating breakfast, eating fruit, vegetables, and milk products. However, students scored moderately in hand and mouth hygiene. Students showed minimal incidences of physical attack and physical fight. Although suicidal attempts were not significantly reported, complaining from worries, feeling of sadness and hopelessness were moderately scored. The majority of physical activities were reported from walking or riding bicycles. However, three hours per day was the average of time spent on sitting activities. Students scored lowest in school absenteeism and the majority described their classmates as kind and helpful. Parental control on students' home activities was regarded. Conclusion: In comparison with 2004 and 2007 statistics, students revealed improvements in physical activity, and reduced physical attacks and injuries. Future researchers are encouraged to discover factors associated with these changes. PMID- 29259943 TI - A Robust and Accurate Non-rigid Medical Image Registration Algorithm Based on Multi-level Deformable Model. AB - Background: Compared to the rigid image registration task, the non-rigid image registration task faces much more challenges due to its high degree of freedom and inherent requirement of smoothness in the deformation field. The purpose was to propose an efficient coarse-to-fine non-rigid medical image registration algorithm based on a multilevel deformable model. Methods: In this paper, a robust and efficient coarse-to-fine non-rigid medical image registration algorithm is proposed. It contains three level deformation models, i.e., the global homography model, the local mesh-level homography model, and the local B spline FFD (Free-Form Deformation) model. The coarse registration is achieved by the first two level models. In the global homography model, a robust algorithm for simultaneous outliers (error matched feature points) removal and model estimation is applied. In the local mesh-level homography model, a new similarity measure is proposed to improve the robustness and accuracy of local mesh based registration. In the fine registration, a local B-spline FFD model with normalized mutual information gradient is employed. Results: We verified the effectiveness of each stage of the proposed registration algorithm with many non rigid transformation image pairs, and quantitatively compared our proposed registration algorithm with the HBFFD method which is based on the control points of multi-resolution. The experimental results show that our algorithm is more accurate than the hierarchical local B-spline FFD method. Conclusion: Our algorithm can achieve high precision registration by coarse-to-fine process based on multi-level deformable model, which ourperforms the state-of-the-art methods. PMID- 29259944 TI - The Comparison of Sensitivity and Specificity of ELISA-based Microneutralization Test with Hemagglutination Inhibition Test to Evaluate Neutralizing Antibody against Influenza Virus (H1N1). AB - Background: The most common serological assay to measure anti-influenza antibodies is hemagglutination inhibition (HI) assay. Recently, neutralizing antibodies against influenza virus infection or vaccination can also be detected using microneutralization assays and occasionally, have greater sensitivity than the standard HI assays. The study aimed to compare the sensitivity and specificity of ELISA-based microneutralization (microNT-ELISA) and conventional HI assays in order to detect influenza H1N1 virus antibodies. Methods: MicroNT ELISA was set up according to the WHO Manual on Influenza Diagnosis and Surveillance in Virology Department of Tehran University of Medical Sciences for the detection of neutralizing antibodies against H1N1 influenza virus in 2013. Fifty serum samples were analyzed with both HI and microNT-ELISA assays. Correlation between methods was calculated by linear regression analysis. Results: The linear correlation coefficient squares, R2, of microNT-ELISA and HI test was 0.61 (P<0.0001) and we observed a high index of coincidence between the two tests. According to McNemar's test, there was no statistically significant difference between these two assays (P>0.05). Conclusion: The sensitivity and specificity of microNT-ELISA assay were high (87% and 73%, respectively) and closely related to gold standard test results. Therefore, microNT-ELISA is recommended as an alternative or complementary test to conventional HI assay for serological and epidemiological purposes. PMID- 29259945 TI - Emerging Intestinal Microsporidia Infection in General Population in Jiroft District, Southeastern Iran: A Cross-sectional Study in 2013-2014. AB - Background: Microsporidia have been reported as the cause of opportunistic infections in immunocompromised patients in Iran and other countries. There is no data on prevalence of intestinal microsporidia in healthy population of Iran. This study aimed to provide preliminary data on the present status of microsporidia infection in the local healthy population in Jiroft, Kerman Province from southeastern Iran in 2013-2014. Methods: Fresh stool samples were randomly collected from 418 residents in rural 209 (50%) and urban 209 (50%) areas of Jiroft. All of the collected samples were concentrated with conventional formalin-ether, stained with Ryan blue. Microscopic examination was performed with high magnification on each sample separately for the demonstration of microsporidia spores. Results: Microsporidial spores were identified in 41 out of 418 (9.8%) samples including 16.41(39%) from rural areas and 25.41(61%) from urban areas. In general, there was no significant difference between sex, age, job, education, and contact with soil and livestock, water supply, gastrointestinal disorders and microsporidia infection among general population in Jiroft. Conclusion: Intestinal microsporidia infection without clinical manifestations is prevalent in general population resident in southeastern Iran. Appropriate molecular methods are needed for microsporidia species identification. PMID- 29259948 TI - Investigating the Appropriateness of Admission and Hospitalization at a Teaching Hospital: A Case of a Developing Country. AB - Background: Reduction of inappropriate use of health services can decrease health care costs without harming the quality of services. This study aimed to investigate inappropriate admission and hospitalization at Afzalipour Hospital of Kerman, Iran. Methods: Inappropriate admission and hospitalization were assessed via a cross-sectional study on 400 patients in Kerman Afzalipour Hospital, Kerman, Iran in 2015. The Iranian version of the Appropriateness Assessment Protocol was used for data collection. Chi-square tests and logistic regression were used to analyze the data. Results: The rate of inappropriate admissions and hospitalization were 7.6% and 9% respectively. There was no significant relationship between inappropriate admissions and any of the studied variables; however, there was a significant relationship between inappropriate hospitalization and age, length of stay and hospital departments. Conclusion: If standard measures of admission and hospitalization execute correctly, unnecessary hospitalization rate can be reduced, so more patients can be treated and cost and workload of hospital personnel can be moderated. PMID- 29259946 TI - Genetic Analysis of Mu and Kappa Opioid Receptor and COMT Enzyme in Cancer Pain Tunisian Patients Under Opioid Treatment. AB - Background: Pain and its opioid treatments are complex measurable traits. Responses to morphine in terms of pain control is likely to be determined by many factors, including the underlying pain sensitivity of the patient, along with nature and extent of the painful process, concomitant medications, genetic and other clinical and environmental factors. This study investigated genetic polymorphisms implicated in the inter-individual pain response variability to opioid treatment in the Tunisian population. Methods: This prospective association study investigated seven variations in the OPRM1, OPRK1 and COMT gene, which encode Mu and KAPPA opioid receptors, and Catechol-O methyltransferase enzyme respectively, in a cohort of 129 Tunisian cancer pain patients under oral morphine treatment. Genotyping was performed by simple probe probes on Light Cyler for rs17174629, rs1799972, rs1799971, rs1051659, rs1051660 and rs4680 and by PCR assay for the indel in the promoter region of OPRK1 (rs35566036). A statistical associations study between dose (continuous), dose escalation (yes/no) and SNP or haplotypes were investigated using linear multiple regressions and logistic regressions respectively adjusted on metastases and pain covariates in the R software. Results: We detected significant association of the rs1051660 adjusted on metastasis and pain (P=0.02), no other association has been detected between the 7 polymorphisms screened and the dose of morphine needed for pain relief. Conclusion: This can be explained by the strong genetic heterogeneity in the cosmopolitan areas where our patients were recruited for this study, compared to more homegenous population recruited in other studies. PMID- 29259947 TI - Prevalence of Trichinella spp. Infections in Hunted Wild Boars in Northern Iran. AB - Background: Trichinellosis is an important and neglected foodborne zoonotic infectious disease in worldwide. The most human outbreaks in recent years have been related to consumption of wild boar meat. This cross-sectional study determined the prevalence of Trichinella spp. infections in hunted wild boars in northern Iran. Methods: Thirty-five hunted wild boars were subjected in this study in 2015. All samples were examined by conventional artificial digestion method to detect of muscle larvae. Genomic DNA was extracted by phenol-chloroform method from isolated larvae. To identify the Trichinella species, a PCR-based method was applied using the internal transcribed spacer 2 (ITS2) and mitochondrial small-subunit ribosomal RNA (rRNA) gene sequences. Results: The overall prevalence of Trichinella spp. infection was 5.7% (2/35, 95%CI= 0-13.4). The mean larval burdens in two positive samples were 0.05 and 6 larvae per gr tissue muscle, respectively. The PCR reaction, using specific primers, yielded two 367 bp and 195 bp bands on agarose gel for ITS 2 and rrnS, respectively. Conclusion: There is a hidden burden of Trichinella spp. infection in wild boar population in Iran. Moreover, T. britovi is the prevalent species circulating in wild boars of Iran. Therefore, education of the hunters and other consumers should be performed about the risk of consumption of raw or undercooked meat and meat products from wild boars. PMID- 29259949 TI - The Evaluation of Urban Community Health Centers in Relation to Family Physician and Primary Health Care in Southern Iran. AB - Background: Shiraz University of Medical Sciences, Iran has developed a new version of health urban posts called Urban Community Health Center (UCHC) with primary aim of improving primary health care (PHC) in urban areas. The aim of present study was to evaluate this newly developed model of UCHC in Ghaleno, a suburban region of Shiraz, Iran in 2014. Methods: Besides descriptive analysis of foregoing model and considering its goal, plan, and dimensions, a qualitative study was carried out using in-depth interview with four managers of this model in Ghaleo region as well as the family physicians (FPs) of the model. Data were analyzed using conventional content analysis. Results: Evaluation of this model in 7-month period after implementation, showed that population coverage was raised from 23% to 84%, a remarkable and increasing achievement of 61%. The universal package is a protocol for providing healthcare services based on PHC.The descriptive study of the model based on physicians view, explored real FP, population's satisfaction, importance of physician's assistant, and payment system reform in the model. Conclusion: Ghaleno model has unique objectives in providing healthcare services in urban areas. The findings of this study call for further evaluation, specifically in quality care services. The success and continuation of this model demand the support of policy makers. PMID- 29259950 TI - The Impact of a Preventive Dentistry Programme on Oral Health: A Pilot Study. PMID- 29259951 TI - Life Skills Education for Malaysian Institutionalised Adolescents: Knowledge, Needs and Priorities: A Qualitative Pilot Study. PMID- 29259952 TI - Evaluation of Thermal Imaging System of the Scrotum in Patients with Varicocele. PMID- 29259953 TI - Association between Body Mass Index and Self Body Image Perception. PMID- 29259954 TI - A Case Study of the Relationship between Basic Psychological Needs and General Health among Old People. PMID- 29259955 TI - An Unlikely Aid: Fighting HIV through TV. PMID- 29259956 TI - The Future Prospects of Testis Cancer in the World. PMID- 29259957 TI - Province Disparity on Female Breast Cancer in Iran. PMID- 29259958 TI - Bone Density Status in Bleeding Disorders: Where Are We and What Needs to Be Done? AB - Bleeding disorders, including hemophilia, can be seen in every ethnic population in the world. Among various bleeding disorders, reduced bone density has been addressed in hemophilia A. In recent years, there has been an increasing interest in addressing osteopenia and osteoporosis in hemophilia A. There is little or no study about the possible susceptibility of other individuals with bleeding disorders to reduced bone density. Questions have been raised about the role of blood coagulation factors in bone mineralization. This review provides new insight and ideas for further survey in the field of bleeding disorders and reduced bone density. PMID- 29259959 TI - Fexaramine Inhibits Receptor Activator of Nuclear Factor-kappaB Ligand-induced Osteoclast Formation via Nuclear Factor of Activated T Cells Signaling Pathways. AB - Background: Osteoclasts are bone resorbing cells and are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Fexaramine has been developed as an agonist for the farnesoid X receptor (FXR). This study investigated the effects of fexaramine on receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-induced osteoclast formation and signaling pathways. Methods: Osteoclasts were formed by culturing mouse bone marrow-derived macrophages (BMMs) with macrophage colony-stimulating factor (M-CSF) and RANKL. Bone resorption assays were performed using dentine slices. The mRNA expression level was analyzed by real-time polymerase chain reaction. Western blotting assays were conducted to detect the expression or activation level of proteins. Lipopolysaccharide-induced osteoclast formation was performed using a mouse calvarial model. Results: Fexaramine inhibited RANKL induced osteoclast formation, without cytotoxicity. Furthermore, fexaramine diminished the RANKL-stimulated bone resorption. Mechanistically, fexaramine blocked the RANKL-triggered p38, extracellular signal-regulated kinase, and glycogen synthase kinase 3beta phosphorylation, resulting in suppressed expression of c-Fos and NF of activated T cells (NFATc1). Consistent with the in vitro anti-osteoclastogenic effect, fexaramine suppressed lipopolysaccharide induced osteoclast formation in the calvarial model. Conclusions: The present data suggest that fexaramine has an inhibitory effect on osteoclast differentiation and function, via downregulation of NFATc1 signaling pathways. Thus, fexaramine could be useful for the treatment of bone diseases associated with excessive bone resorption. PMID- 29259960 TI - Factors Affecting Bone Mineral Density Measurement after Fracture in South Korea. AB - Background: Prior osteoporotic fractures are strongly associated with the subsequent fractures. To prevent this, the diagnosis of osteoporosis following an osteoporotic fracture is important. The measurement of bone mineral density (BMD) is the first step for the diagnosis and management of osteoporosis. Therefore, the purposes of this study are 1) to evaluate the rate of BMD measurement after osteoporotic fracture in Korean population; and 2) determine the associated factors with BMD measurement after fractures among Korean patients. Methods: From database of Health Insurance Review & Assessment Service, we identified patients with osteoporotic fractures happened in 2010. The BMD examinations were evaluated by using procedure codes. We evaluated the rate of BMD measurement within 6 months after fracture according to gender, age group (10-year incremental), type of insurance, residency area (rural vs. urban), type of medical institute, department, history of depression, rheumatoid arthritis, medical history suggestive of secondary osteoporosis, osteoporosis-induced drug, and number of family members. Results: During study period, about a half (53.9%) of patients with osteoporotic fractures had BMD measurement. Men, younger age, urban residency, and depression history were associated with low rate of BMD measurement. However, increasing age, use of glucocorticoid use, osteoporosis inducing comorbid disease including rheumatologic disease, and osteoporosis induced drug user were associated with higher likelihood of BMD measurement. Conclusions: Our results showed that about a half of patients with osteoporotic fractures had BMD measurement in South Korea, and provided the basic information to encourage management after fracture by educating not only patient but also physician about post-fracture management. PMID- 29259962 TI - Serum Vitamin D Level Related to Coffee Consumption in Korean Young Adults Using the 5th Korea National Health and Nutrition Examination Survey. AB - Background: Even young adults are highly interested in their osteological health, yet their calcium intake does not match the level of such interest. Increase in bone loss is known to be associated with higher intake of caffeine and coffee consumption among the young Korean is rising steadily. This study was conducted to reveal the relationship between coffee consumption and serum vitamin D level in Korean young adults. Methods: This study analyzed potential difference in lifestyle and concentration of vitamin D in blood in relation to coffee intake frequency of 2,523 subjects on the basis of data from the 5th Korea National Health and Nutrition Examination Survey. Results: According to the analysis, groups of males, with high income, frequent social activity followed by alcohol consumption and smoking, and high rate of dining out showed a high frequency of coffee consumption. Vitamin D concentration among the groups was 16.2+/-5.3 mL and 80.3% of them were considered to be vitamin D-deficient. All the groups appeared to have deficiencies compared to males who did not consume caffeine at all. Conclusions: The practice of having an adequate amount of coffee is needed, and more efforts should be done to improve vitamin D intake among young adults. PMID- 29259961 TI - Relationship between Serum 25-hydroxy-vitamin D Concentration and Risk of Metabolic Syndrome in Patients with Fatty Liver. AB - Background: The vitamin D deficiency rate in Koreans is still high and dietary intake is insufficient. The purpose of this study was to provide basic data for the management of metabolic syndrome (MetS) by analyzing the effect of vitamin D levels on the MetS in patients with fatty liver. Methods: We analyzed the MetS ratio and serum 25-hydroxy-vitamin D (25[OH]D) concentration in 151 adults diagnosed with fatty liver by using obesity index and blood profiles. We collected data on demographic factors, nutrient intake, and lifestyle habits. Results: The mean 25(OH)D concentration of all subjects was 14 ng/mL and the insufficiency and deficiency rates were 40.4% and 29.8%. The proportion of MetS was 38.4% and the mean 25(OH)D level of MetS group was 12.1 ng/mL. Low-density lipoprotein cholesterol, triglyceride, and blood glucose were higher in the MetS group than in the normal group, and the waist circumference of the male was significantly higher than that of the normal group. The results showed that the lower the vitamin D concentration, the higher the risk of MetS (odds ratio, 1.47, 95% confidence interval, 0.98-2.81; P=0.043). Conclusions: These results suggest that serum 25(OH)D levels may be a risk factor for MetS in patients with fatty liver. PMID- 29259963 TI - Comparison of Bone Mineral Density and Appendicular Lean Body Mass between Osteoporotic Distal Radius Fracture and Degenerative Rotator Cuff Tear in Women Patients. AB - Background: Authors assessed lean body mass (fat free tissue), upper and lower, and bone mineral density (BMD) in patients of osteoporotic bone distal radius fracture (DRF) and degenerative rotator cuff tear (RCT) patients of shoulder. We predict inferior muscle mass and osteoporosis are more frequent in DRF group than RCT group. Methods: Between January 2016 and June 2017, overall 38 of DRF and 30 of RCT were eligible for this retrospective comparison study after excluding of patients with compounding factors. BMD and other body composition, fat and lean body mass, were assessed with a single dual energy X-ray absorptiometry in one hospital. Results: T-score of spine were -2.2 and -1.6 in DRF and RCT patients with significant difference (P=0.040). Final BMD score, lower score of patient between spine and femoral score, of both group also presented difference with significance, -2.4 of DRF and -1.9 of RCT patients (P=0.047). Diagnosis of osteoporosis was confirmed in 19 patients (50%) from DRF compared with 9 patients (30%) from RCT. The mean lean soft tissue mass of the arm was 3.7 kg and 3.8 kg in the DRF and RCT, respectively, without significant difference (P=0.882). The mean lean body mass of the leg was 11.0 kg and 10.5 kg in the DRF and RCT, respectively, without significant difference (P=0.189). The relative overall appendicular lean mass was not significantly different between groups. Conclusions: Even though BMD difference, we did not find muscle mass difference between DRF and RCT patients. PMID- 29259964 TI - Prevalence of Osteoporosis in Korean Patients with Chronic Obstructive Pulmonary Disease and Their Health-related Quality of Life According to the Korea National Health and Nutrition Examination Survey 2008-2011. AB - Background: In this study, we evaluated the prevalence of osteoporosis, risk factors associated with osteoporosis, and health-related quality of life (HRQOL) in clinically stable chronic obstructive pulmonary disease (COPD) patients. Methods: A total of 1,081 COPD patients were recruited from the Korea National Health and Nutrition Examination Survey (KNHANES) from July 2008 to May 2011. Bone mineral densities at the lumbar spine, femoral neck, and total proximal femur were measured using dual energy X-ray absorptiometry. HRQOL was assessed using the EuroQOL-5 dimensions (EQ-5D) questionnaire. To identify factors associated with osteoporosis and HRQOL in patients with COPD, multivariate regression analyses was performed. Results: Of the 1,081 COPD patients, 191 (17.7%) were diagnosed with osteoporosis. There were significant differences in age, sex, smoking status, education level, house income, and body mass index (BMI) between the osteoporotic and non-osteoporotic groups. COPD patients with osteoporosis had significantly lower EQ-5D scores than the controls. In multivariate analyses, older age (odds ratio [OR]=1.10, P<0.001) was risk factor for osteoporosis. And patients of male sex (OR=0.06, P<0.001), high house income (OR=0.75, P=0.045), and high BMI (OR=0.74, P<0.001) were less likely to have osteoporosis. In addition, osteoporosis was associated with poor HRQOL (beta= 0.21, P=0.023). Conclusions: The prevalence of osteoporosis in COPD patients based on the 2008 to 2011 KNHANES data were relatively lower than that in physician-diagnosed COPD patients. In these COPD patients, older age, female sex, low household income, and low BMI increased the risk for osteoporosis. PMID- 29259965 TI - Clinical Characteristics, Causes and Survival in 115 Cancer Patients with Parathyroid Hormone Related Protein-mediated Hypercalcemia. AB - Background: The aim of this study is to determine the proportion of cancers presenting with parathyroid hormone (PTH) related protein (PTHrP)-mediated hypercalcemia, examine the clinical and biochemical characteristics, identify predictive factors for survival. And we also compared those characteristics between solid organ and hematologic malignancy groups. Methods: Cancer patients with PTHrP-mediated hypercalcemia who were treated at Chonnam National University Hospital in Korea from January 2005 to January 2015 were retrospectively reviewed. Results: Of all 115 patients, solid organ malignancies were the most common etiology (98 cases, 85.2%), with squamous cell carcinoma (50 cases, 43.4%), adenocarcinoma (27 cases, 23.4%). Interestingly, hepatocellular carcinoma (HCC; 18 cases, 15.7%) and cholangiocarcinoma (11 cases, 9.6%) were much more common causes than other previous reports. Hematologic malignancy was less common (17 cases, 14.8%), with multiple myeloma (9 cases, 7.8%) and non-Hodgkin's lymphoma (5 cases, 4.3%). Overall median survival was only 37 days. There was significant difference in median survival between two groups (35 days for solid organ malignancy and 72 days for hematologic malignancy; P=0.015). Cox regression analysis identified age, the type of malignancy and the time interval of developing hypercalcemia after cancer diagnosis as independent predictive factors for survival time. Conclusions: PTHrP-mediated hypercalcemia was most frequently caused by solid organ malignancy. However, HCC and cholangiocarcinoma were important causes of PTHrP-mediated hypercalcemia may be due to geographic differences in cancer incidence in Korean population. Age, the type of malignancy and the time interval of developing hypercalcemia after cancer diagnosis were independent poor predictive factors for survival time. PMID- 29259966 TI - X-linked Hypophosphatemic Rickets, del(2)(q37.1;q37.3) Deletion Syndrome and Mosaic Turner Syndrome, mos 45,X/46,X, del(2)(q37.1;q37.3) in a 3-year-old Female. AB - There are currently no published cases that report concomitant Turner syndrome (TS), 2q37 deletion syndrome and X-linked hypophosphatemic rickets (XLH). Interestingly, since the clinical phenotypes of TS and 2q37 deletion syndrome overlap, the correct diagnosis may be missed without a standardized approach to genetic testing consisting of both karyotype and microarray. Both chromosome anomalies have been associated with short stature and a variety of skeletal abnormalities however to date no reports have associated these syndromes in association with a phosphate regulating endopeptidase homolog, X-linked (PHEX) gene deletion resulting in XLH. We report a 3-year-old female with 3 concurrent genetic disorders including a 9.98 Mb terminal deletion of chromosome 2: del(2)(q37.1;q37.3), XLH secondary to a small microdeletion of part of the PHEX gene, and mosaic TS (mos 45,X[32]/46,X[18]). This is the first case report of a patient with 2q37 deletion syndrome and mosaic TS (mos 45,X[32]/46,X[18]) found to have XLH secondary to an interstitial constitutional PHEX gene deletion. Her severe phenotype and multiple genotypic findings reinforce the importance of thorough genetic testing in the setting of complicated phenotypic presentations. PMID- 29259967 TI - Prognostic Impact of Cirrhosis in Patients with Intrahepatic Cholangiocarcinoma following Hepatic Resection. AB - Background: Prognostic impact of cirrhosis in patients with intrahepatic cholangiocarcinoma (ICC) upon hepatic resection remains unclear due to lack of studies in the literature. Methods: A total of 106 resected patients with ICC were reviewed, including 25 patients (23.6%) with cirrhosis and 81 noncirrhotic patients (76.4%). Subgroups of cirrhotic patients with and without hepatitis B virus (HBV) infection were studied. Results: The impact of cirrhosis on the overall survival (OS) (hazard ratio [HR], 0.901; 95% confidence interval [CI], 0.510 to 1.592; P = 0.720) and the relapse-free survival (RFS) (HR, 0.889; 95% CI, 0.509 to 1.552; P = 0.678) revealed no statistical significance. Furthermore, HBV-associated cirrhotic patients and the other cirrhotic patients demonstrated no statistical difference on survival outcomes (1 yr OS, 60.0% versus 70.0%; 5 yr OS, 10.0% versus 0%; P = 0.744; 1 yr RFS, 53.3% versus 30.0%; 5 yr RFS, 10.0% versus 0%; P = 0.279). In patients with cirrhosis, tumor size larger than 5 cm was found to be the foremost factor that was independently associated with poor prognosis. Conclusion: The presence of liver cirrhosis did not significantly affect prognosis of patients with ICC after resection. Downstaging modality may be in need for patients with ICC underlying cirrhosis, which remains to be validated in future studies. PMID- 29259969 TI - In Search of the Reason for the Breathing Effect of MIL53 Metal-Organic Framework: An ab Initio Multiconfigurational Study. AB - Multiconfigurational methods are applied to study electronic properties and structural changes in the highly flexible metal-organic framework MIL53(Cr). Via calculated bending potentials of angles, that change the most during phase transition, it is verified that the high flexibility of this material is not a question about special electronic properties in the coordination chemistry, but about overall linking of the framework. The complex posseses a demanding electronic structure with delocalized spin density, antifferomagnetic coupling and high multi-state character requiring multiconfigurational methods. Calculated properties are in good agreement with known experimental values confirming our chosen methods. PMID- 29259968 TI - Drought Response in Wheat: Key Genes and Regulatory Mechanisms Controlling Root System Architecture and Transpiration Efficiency. AB - Abiotic stresses such as, drought, heat, salinity, and flooding threaten global food security. Crop genetic improvement with increased resilience to abiotic stresses is a critical component of crop breeding strategies. Wheat is an important cereal crop and a staple food source globally. Enhanced drought tolerance in wheat is critical for sustainable food production and global food security. Recent advances in drought tolerance research have uncovered many key genes and transcription regulators governing morpho-physiological traits. Genes controlling root architecture and stomatal development play an important role in soil moisture extraction and its retention, and therefore have been targets of molecular breeding strategies for improving drought tolerance. In this systematic review, we have summarized evidence of beneficial contributions of root and stomatal traits to plant adaptation to drought stress. Specifically, we discuss a few key genes such as, DRO1 in rice and ERECTA in Arabidopsis and rice that were identified to be the enhancers of drought tolerance via regulation of root traits and transpiration efficiency. Additionally, we highlight several transcription factor families, such as, ERF (ethylene response factors), DREB (dehydration responsive element binding), ZFP (zinc finger proteins), WRKY, and MYB that were identified to be both positive and negative regulators of drought responses in wheat, rice, maize, and/or Arabidopsis. The overall aim of this review is to provide an overview of candidate genes that have been identified as regulators of drought response in plants. The lack of a reference genome sequence for wheat and non-transgenic approaches for manipulation of gene functions in wheat in the past had impeded high-resolution interrogation of functional elements, including genes and QTLs, and their application in cultivar improvement. The recent developments in wheat genomics and reverse genetics, including the availability of a gold standard reference genome sequence and advent of genome editing technologies, are expected to aid in deciphering of the functional roles of genes and regulatory networks underlying adaptive phenological traits, and utilizing the outcomes of such studies in developing drought tolerant cultivars. PMID- 29259970 TI - Potential Use of Human Periapical Cyst-Mesenchymal Stem Cells (hPCy-MSCs) as a Novel Stem Cell Source for Regenerative Medicine Applications. AB - Mesenchymal stem cells (MSCs) are attracting growing interest by the scientific community due to their huge regenerative potential. Thus, the plasticity of MSCs strongly suggests the utilization of these cells for regenerative medicine applications. The main issue about the clinical use of MSCs is related to the complex way to obtain them from healthy tissues; this topic has encouraged scientists to search for novel and more advantageous sources of these cells in easily accessible tissues. The oral cavity hosts several cell populations expressing mesenchymal stem cell like-features, furthermore, the access to oral and dental tissues is simple and isolation of cells is very efficient. Thus, oral derived stem cells are highly attractive for clinical purposes. In this context, human periapical cyst mesenchymal stem cells (hPCy-MSCs) exhibit characteristics similar to other dental-derived MSCs, including their extensive proliferative potential, cell surface marker profile and the ability to differentiate into various cell types such as osteoblasts, adipocytes and neurons. Importantly, hPCy MSCs are easily collected from the surgically removed periapical cysts; this reusing of biological waste guarantees a smart source of stem cells without any impact on the surrounding healthy tissues. In this review, we report the most interesting research topics related to hPCy-MSCs with a newsworthy discussion about the future insights. This newly discovered cell population exhibits interesting and valuable potentialities that could be of high impact in the future regenerative medicine applications. PMID- 29259971 TI - ALK1Fc Suppresses the Human Prostate Cancer Growth in in Vitro and in Vivo Preclinical Models. AB - Prostate cancer is the second most common cancer in men and lethality is normally associated with the consequences of metastasis rather than the primary tumor. Therefore, targeting the molecular pathways that underlie dissemination of primary tumor cells and the formation of metastases has a great clinical value. Bone morphogenetic proteins (BMPs) play a critical role in tumor progression and this study focuses on the role of BMP9- Activin receptor-Like Kinase 1 and 2 (ALK1 and ALK2) axis in prostate cancer. In order to study the effect of BMP9 in vitro and in vivo on cancer cells and tumor growth, we used a soluble chimeric protein consisting of the ALK1 extracellular domain (ECD) fused to human Fc (ALK1Fc) that prevents binding of BMP9 to its cell surface receptors and thereby blocks its ability to activate downstream signaling. ALK1Fc sequesters BMP9 and the closely related BMP10 while preserving the activation of ALK1 and ALK2 through other ligands. We show that ALK1Fc acts in vitro to decrease BMP9 mediated signaling and proliferation of prostate cancer cells with tumor initiating and metastatic potential. In line with these observations, we demonstrate that ALK1Fc also reduces tumor cell proliferation and tumor growth in vivo in an orthotopic transplantation model, as well as in the human patient derived xenograft BM18. Furthermore, we also provide evidence for crosstalk between BMP9 and NOTCH and find that ALK1Fc inhibits NOTCH signaling in human prostate cancer cells and blocks the induction of the NOTCH target Aldehyde dehydrogenase member ALDH1A1, which is a clinically relevant marker associated with poor survival and advanced-stage prostate cancer. Our study provides the first demonstration that ALK1Fc inhibits prostate cancer progression, identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. Altogether, these findings support the validity of ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity. PMID- 29259972 TI - (A Critical Appraisal of) Classification of Hypereosinophilic Disorders. AB - Hypereosinophilia (HE) is a heterogeneous condition that can be reported in various (namely inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. In 1975, Chusid et al. published the first diagnostic criteria of hypereosinophilic syndromes (HES). Over the years, as both basic and clinical knowledge improved, several updates have been suggested, with a focus on better distinguishing isolated or asymptomatic eosinophilia from diseases with specific eosinophil-related organ damage. Moreover, underlying molecular and cellular mechanisms of eosinophilia gradually became the cornerstone of successive attempts to classify HE-related diseases. In 2011, the International Cooperative Working Group on Eosinophil Disorders criteria emerged from a multidisciplinary Working Conference on Eosinophil Disorders and Syndromes, and provided substantial contribution to the clarification of general concepts and definitions in the field of HE. Yet, owing to the low prevalence of HE/HES, to the numerous diseases encompassed in the spectrum of HE-related disorders (with sometimes overlapping phenotypes), many questions are left unanswered (e.g., the need to better standardize the use of modern molecular tools, or the clinical relevance of distinguishing different subtypes of idiopathic HES). Here, we review the current state of knowledge in the fields of classification and diagnosis criteria of HE-related diseases, with emphasis on the analysis of both strengths and weaknesses of present concepts and their usefulness in daily practice. PMID- 29259975 TI - Relationship between Smoking and Acute Mountain Sickness: A Meta-Analysis of Observational Studies. AB - Aims: Previous epidemiological investigations of the relationship between smoking and acute mountain sickness (AMS) risk yielded inconsistent findings. Therefore, a meta-analysis of observational studies was performed to determine whether smoking is related to the development of AMS. Methods: Searches were performed on PubMed, Scopus, Embase, and Web of Science for relevant studies that were published before November 2016 reporting smoking prevalence and AMS. Two evaluators independently selected studies, extracted data, and assessed study quality. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were obtained using random-effects models. Subgroup analyses were performed according to the type of participant, altitude, and study design. Results: A total of 11 observational studies involving 7,106 participants, 2,408 of which had AMS, were eligible for inclusion in this meta-analysis. The summary RR for AMS comparing smokers to nonsmokers was 1.02 (95% CI: 0.83 to 1.26). Specific analyses for altitude, type of participant, and study design yielded similar results. There was significant heterogeneity for all studies (Q = 37.43; P < 0.001; I2 = 73%, 95% CI: 51% to 85%). No publication bias was observed (Egger's test: P = 0.548, Begg's test: P = 0.418). Conclusions: The meta-analysis indicates that no difference was found in AMS risk with regard to smoking status. PMID- 29259974 TI - The Kv7 Channel and Cardiovascular Risk Factors. AB - Potassium channels play a pivotal role in the regulation of excitability in cells such as neurons, cardiac myocytes, and vascular smooth muscle cells. The KCNQ (Kv7) family of voltage-activated K+ channels hyperpolarizes the cell and stabilizes the membrane potential. Here, we outline how Kv7 channel activity may contribute to the development of the cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions and hypotheses regarding previous and future research have been raised. Alterations in the Kv7 channel may contribute to the development of cardiovascular disease (CVD). Pharmacological modification of Kv7 channels may represent a possible treatment for CVD in the future. PMID- 29259973 TI - Mediterranean Diet: Prevention of Colorectal Cancer. AB - Colorectal cancer (CRC) is the third most common cancer diagnosis and the second and third leading cause of cancer mortality in men and women, respectively. However, the majority of CRC cases are the result of sporadic tumorigenesis via the adenoma-carcinoma sequence. This process can take up to 20 years, suggesting an important window of opportunity exists for prevention such as switching toward healthier dietary patterns. The Mediterranean diet (MD) is a dietary pattern associated with various health benefits including protection against cardiovascular disease, diabetes, obesity, and various cancers. In this article, we review publications available in the PubMed database within the last 10 years that report on the impact of a MD eating pattern on prevention of CRC. To assist the reader with interpretation of the results and discussion, we first introduce indexes and scoring systems commonly used to experimentally determine adherence to a MD, followed by a brief introduction of the influence of the MD pattern on inflammatory bowel disease, which predisposes to CRC. Finally, we discuss key biological mechanisms through which specific bioactive food components commonly present in the MD are proposed to prevent or delay the development of CRC. We close with a discussion of future research frontiers in CRC prevention with particular reference to the role of epigenetic mechanisms and microbiome related to the MD eating pattern. PMID- 29259976 TI - Phylogenetic Diversity in Core Region of Hepatitis C Virus Genotype 1a as a Factor Associated with Fibrosis Severity in HIV-1-Coinfected Patients. AB - High hepatitis C virus (HCV) genetic diversity impacts infectivity/pathogenicity, influencing chronic liver disease progression associated with fibrosis degrees and hepatocellular carcinoma. HCV core protein is crucial in cell-growth regulation and host-gene expression. Liver fibrosis is accelerated by unknown mechanisms in human immunodeficiency virus-1- (HIV-1-) coinfected individuals. We aimed to study whether well-defined HCV-1a core polymorphisms and genetic heterogeneity are related to fibrosis in a highly homogeneous group of interferon treated HIV-HCV-coinfected patients. Genetic heterogeneity was weighed by Faith's phylogenetic diversity (PD), which has been little studied in HCV. Eighteen HCV/HIV-coinfected patients presenting different liver fibrosis stages before anti-HCV treatment-initiation were recruited. Sampling at baseline and during and after treatment was performed up to 72 weeks. At inter/intrahost level, HCV-1a populations were studied using molecular cloning and Sanger sequencing. Over 400 complete HCV-1a core sequences encompassing 573 positions of C were obtained. Amino acid substitutions found previously at positions 70 and 91 of HCV-1b core region were not observed. However, HCV genetic heterogeneity was higher in mild than in severe fibrosis cases. These results suggest a potential utility of PD as a virus-related factor associated with chronic hepatitis C progression. These observations should be reassessed in larger cohorts to corroborate our findings and assess other potential covariates. PMID- 29259977 TI - Potential Role of MicroRNA-375 as Biomarker in Human Cancers Detection: A Meta Analysis. AB - The association between circulating microRNA-375 (miR-375) expression and cancers has been studied; however, the results are inconsistent. We searched PubMed, Embase, and Web of Science for studies concerning the diagnostic value of miR-375 for cancer. The bivariate meta-analysis model was employed to summarize sensitivity, specificity, and diagnostic odds ratio (DOR) for miR-375 in the diagnosis of cancer. Summary receiver operating characteristic (SROC) curve analysis and the area under the curve (AUC) were also used to check the overall test performance. A total of 645 cancer patients and 421 cancer-free individuals from 12 studies were contained in this meta-analysis. The summary estimates revealed that the pooled sensitivity was 78% (95% confidence interval (CI): 64% 87%), the specificity was 74% (95% CI: 62%-84%), the DOR was 10.04 (95% CI: 6.01 16.77), and the AUC was 0.82 (95% CI: 0.79-0.85). In addition, we found that the diagnostic effect of miR-375 varies according to the race and cancer type. Our data suggest that miR-375 profiling has a potential to be used as a screening test for cancers but the specific race and cancer should be considered. More studies on the diagnostic value of miR-375 for cancer are needed in the future. PMID- 29259978 TI - Protective Effects of Genistein against Mono-(2-ethylhexyl) Phthalate-Induced Oxidative Damage in Prepubertal Sertoli Cells. AB - Mono-(2-ethylhexyl) phthalate (MEHP) and genistein are two of the most prevalent endocrine-disrupting chemicals (EDCs) that present in the environment and food. However, how these two EDCs would affect prepubertal Sertoli cells development was rarely studied. In this study, primary prepubertal Sertoli cells were isolated from 22-day-old Sprague Dawley rats and exposed to MEHP at 1 MUmol/L, 10 MUmol/L, and 100 MUmol/L (M1, M10, and M100), genistein at 10 MUmol/L (G), and their combination (G + M1, G + M10, and G + M100). Cell proliferation inhibition rate, apoptosis and necrosis rate, and cellular redox state were evaluated. Our results revealed that MEHP could significantly increase cell proliferation inhibition rate, apoptosis rate, necrosis rate, and intracellular reactive oxidative species level. However, coadministration of genistein could partially alleviate MEHP-induced prepubertal Sertoli cells oxidative injuries via enhancement of testicular antioxidative enzymes activities and upregulation of Nrf2 and HO-1, indicating that genistein could partially attenuate MEHP-induced prepubertal Sertoli cells damage through antioxidative action and may have promising future on its curative role for attenuating other EDCs-induced reproductive disorders. PMID- 29259979 TI - Effects of Target Temperature Management on the Outcome of Septic Patients with Fever. AB - Objectives: To investigate the effects of target temperature management on hemodynamic changes, inflammatory and immune factors, and clinical outcomes of sepsis patients with fever. Methods: Patients diagnosed with sepsis with a core temperature of >=39 degrees C were randomly divided into two groups: a low temperature group (LT group: 36.5 degrees C-38 degrees C) and a high-temperature group (HT group: 38.5 degrees C-39.5 degrees C). A target core temperature was achieved within 6 hrs posttreatment and maintained for 24 hrs. Then, the hemodynamic changes, inflammatory and immune factors, and clinical outcomes were evaluated. Results: Compared with the HT group, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) showed a significant decrease in the LT group (P < 0.05). In contrast, IL 4 and IL-10 were higher in the LT group than in the HT group (P < 0.05). The CD4 T lymphocyte (CD4+), CD8-T lymphocyte (CD8+), and monocytic human leukocyte antigen-DR (mHLA-DR) in the LT group were higher than in the HT group (P < 0.05). The ICU stay and the anti-infection treatment costs were higher in the LT group (P < 0.05). Conclusion: Low-temperature management of patients resulted in a low level of proinflammatory cytokines. Excessive temperature control in sepsis patients with fever may be harmful. PMID- 29259981 TI - Association between Single Nucleotide Polymorphisms in Vitamin D Receptor Gene Polymorphisms and Permanent Tooth Caries Susceptibility to Permanent Tooth Caries in Chinese Adolescent. AB - Purpose: Dental caries is a multifactorial infectious disease. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene were associated with susceptibility to permanent tooth caries in Chinese adolescents. Method: A total of 200 dental caries patients and 200 healthy controls aged 12 years were genotyped for VDR gene polymorphisms using the PCR-restriction fragment length polymorphism (PCR-RFLP) assay. All of them were examined for their oral and dental status with the WHO criteria, and clinical information such as the Decayed Missing Filled Teeth Index (DMFT) was evaluated. Genomic DNA was extracted from the buccal epithelial cells. The four polymorphic SNPs (Bsm I, Taq I, Apa I, and Fok I) in VDR were assessed for both genotypic and phenotypic susceptibilities. Results: Among the four examined VDR gene polymorphisms, the increased frequency of the CT and CC genotype of the Fok I VDR gene polymorphism was associated with dental caries in 12-year-old adolescent, compared with the controls (X2 = 17.813, p <= 0.001). Moreover, Fok I polymorphic allele C frequency was significantly increased in the dental caries cases, compared to the controls (X2 = 14.144, p <= 0.001, OR = 1.730, 95% CI = 1.299-2.303). However, the other three VDR gene polymorphisms (Bsm I, Taq I, and Apa I) showed no statistically significant differences in the caries groups compared with the controls. Conclusion: VDR-Fok I gene polymorphisms may be associated with susceptibility to permanent tooth caries in Chinese adolescent. PMID- 29259980 TI - CYLD Deubiquitinase Negatively Regulates High Glucose-Induced NF-kappaB Inflammatory Signaling in Mesangial Cells. AB - Nuclear factor-kappa B (NF-kappaB) is the key part of multiple signal transduction of inflammation in the pathogenesis of diabetic nephropathy (DN). The ubiquitin-proteasome system is extensively involved in the regulation of the NF-kappaB pathway. Cylindromatosis (CYLD) has deubiquitinase activity and acts as a negative regulator of the NF-kappaB signaling pathway. However, the association between CYLD and NF-kappaB inflammatory signaling in DN is unclear. In the present study, mouse glomerular mesangial cells (GMCs) and rat GMCs were stimulated by elevated concentrations of glucose (10, 20, and 30 mmol/L high glucose) or mannitol as the osmotic pressure control. CYLD was overexpressed or suppressed by transfection with a CYLD expressing vector or CYLD-specific siRNA, respectively. Our data showed that high glucose significantly inhibited the protein and mRNA expression of CYLD in a dose- and time-dependent manner (both p < 0.05). siRNA-mediated knockdown CYLD facilitated the high glucose-induced activation of NF-kappaB signaling and triggered the release of MCP-1, IL-6, and IL-8 (all p < 0.05). However, these high glucose-mediated effects were blunted by overexpression of CYLD (p < 0.05). The present results support the involvement of CYLD in the regulation of NF-kappaB inflammatory signaling induced by elevated glucose, implicating CYLD as a potential therapeutic target of DN. PMID- 29259982 TI - Pharmacokinetics, Tissue Distribution, and Metabolism Study of Icariin in Rat. AB - Icariin is one of the predominant flavonoids contained in Herba Epimedii (Yin yang-huo in Chinese), a well-known Chinese medicine for the treatment of cancers and immune system diseases. Although Herba Epimedii has been widely used in China and there are so many and various research reports on the herbal drug and its main flavones, very limited data is available on the tissue distribution and biotransformation of icariin. In the present study, a liquid chromatographic method combined with electrospray ionization tandem mass spectrometry was developed to quantify the concentration of icariin in rat plasma and various tissues collected at different time points after oral administration of the total flavonoid extract of Herba Epimedii at a dose of 0.69 g/kg (corresponding to 42 mg/g icariin). Biological samples were processed by simple protein precipitation. Genistein was chosen as internal standard. The method was successfully applied to plasma pharmacokinetic and tissue distribution studies of icariin in rat. As a result, it was worth noting that the tissue distribution characteristics of icariin exhibited a significant gender difference. Moreover, in vivo metabolism of icariin was also investigated. A total of 11 potential metabolites were found in rat feces collected in different time periods after oral and intramuscular administration of icariin. In vivo metabolic pathways were involved in hydrolysis, demethylation, oxidation, and conjugation. The preclinical data would be useful for fully understanding in vivo disposition of this compound and interpreting the mechanism of its biological response. PMID- 29259983 TI - First Characterization of the Neospora caninum Dense Granule Protein GRA9. AB - The obligate intracellular apicomplexan parasite Neospora caninum (N. caninum) is closely related to Toxoplasma gondii (T. gondii). The dense granules, which are present in all apicomplexan parasites, are important secretory organelles. Dense granule (GRA) proteins are released into the parasitophorous vacuole (PV) following host cell invasion and are known to play important roles in the maintenance of the host-parasite relationship and in the acquisition of nutrients. Here, we provide a detailed characterization of the N. caninum dense granule protein NcGRA9. The in silico genomic organization and key protein characteristics are described. Immunofluorescence-based localization studies revealed that NcGRA9 is located in the dense granules and is released into the interior of the PV following host cell invasion. Immunogold-electron microscopy confirmed the dense granule localization and showed that NcGRA9 is associated with the intravacuolar network. In addition, NcGRA9 is found in the "excreted secreted antigen" (ESA) fraction of N. caninum. Furthermore, by analysing the distribution of truncated versions of NcGRA9, we provide evidence that the C terminal region of this protein is essential for the targeting of NcGRA9 into the dense granules of N. caninum, and the truncated proteins show reduced secretion. PMID- 29259985 TI - Effects of Electrostatic Field on Osteoblast Cells for Bone Regeneration Applications. AB - Many external stimulations have been shown to promote bone regeneration. The effects of an alternating current (AC) electrostatic field, one of external stimulations, generated from a device with high voltage and low current output on human osteoblastic cell line have been investigated in this study. We investigated how human osteoblasts responded to an AC electrostatic field, and the output parameters were set as 1 kV and 160 MUA. Our results showed that, under such condition, the AC electrostatic field had a downregulation effect on the production ability of alkaline phosphatase and type 1 collagen expression. However, the expression of osteocalcin gene was elevated on the end of EFID treatment suggesting that AC electrostatic field might be a potential stimulation for accelerating the differentiation of osteoblastic cells. PMID- 29259987 TI - Reversible Data Hiding in FTIR Microspectroscopy Images with Tamper Indication and Payload Error Correction. AB - Fourier transform infrared (FTIR) microspectroscopy images contain information from the whole infrared spectrum used for microspectroscopic analyses. In combination with the FTIR image, visible light images are used to depict the area from which the FTIR spectral image was sampled. These two images are traditionally acquired as separate files. This paper proposes a histogram shifting-based data hiding technique to embed visible light images in FTIR spectral images producing single entities. The primary objective is to improve data management efficiency. Secondary objectives are confidentiality, availability, and reliability. Since the integrity of biomedical data is vital, the proposed method applies reversible data hiding. After extraction of the embedded data, the FTIR image is reversed to its original state. Furthermore, the proposed method applies authentication tags generated with keyed Hash-Based Message Authentication Codes (HMAC) to detect tampered or corrupted areas of FTIR images. The experimental results show that the FTIR spectral images carrying the payload maintain good perceptual fidelity and the payload can be reliably recovered even after bit flipping or cropping attacks. It has been also shown that extraction successfully removes all modifications caused by the payload. Finally, authentication tags successfully indicated tampered FTIR image areas. PMID- 29259984 TI - mTOR-Dependent Cell Proliferation in the Brain. AB - The mammalian Target of Rapamycin (mTOR) is a molecular complex equipped with kinase activity which controls cell viability being key in the PI3K/PTEN/Akt pathway. mTOR acts by integrating a number of environmental stimuli to regulate cell growth, proliferation, autophagy, and protein synthesis. These effects are based on the modulation of different metabolic pathways. Upregulation of mTOR associates with various pathological conditions, such as obesity, neurodegeneration, and brain tumors. This is the case of high-grade gliomas with a high propensity to proliferation and tissue invasion. Glioblastoma Multiforme (GBM) is a WHO grade IV malignant, aggressive, and lethal glioma. To date, a few treatments are available although the outcome of GBM patients remains poor. Experimental and pathological findings suggest that mTOR upregulation plays a major role in determining an aggressive phenotype, thus determining relapse and chemoresistance. Among several activities, mTOR-induced autophagy suppression is key in GBM malignancy. In this article, we discuss recent evidence about mTOR signaling and its role in normal brain development and pathological conditions, with a special emphasis on its role in GBM. PMID- 29259986 TI - Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications. AB - Glioblastoma multiforme (GBM) is the most hostile type of brain cancer. Its aggressiveness is due to increased invasion, migration, proliferation, angiogenesis, and a decreased apoptosis. In this review, we discuss the role of key regulators of apoptosis in GBM and glioblastoma stem cells. Given their importance in the etiology and pathogenesis of GBM, these signaling molecules may represent potential therapeutic targets. PMID- 29259988 TI - Increased Circulating Th17 but Decreased CD4+Foxp3+ Treg and CD19+CD1dhiCD5+ Breg Subsets in New-Onset Graves' Disease. AB - Th17 and regulatory lymphocyte subsets such as Tregs and Bregs have been reported to play important roles in autoimmune diseases. The aim of this work was to perform quantitative studies of circulating Th17, Tregs, and Bregs in patients with new-onset Graves' disease (GD). Twenty GD patients and 20 healthy controls were involved in this study. Blood samples were taken for flow cytometry detection of CD4+IL-17+ Th17, CD4+Foxp3+ Tregs, and CD19+CD1dhiCD5+ Bregs and meanwhile, for real-time PCR measurement of gene expressions of RORgammat, IL-17 and IL-10. The proportions of Tregs and Bregs as well as the Foxp3 gene expression but not IL-10 were significantly decreased in GD group compared with the healthy controls. The frequency of Th17 together with the gene expressions of RORgammat and IL-17 were significantly increased in the GD group. Furthermore, the Th17/Treg ratio was also significantly higher in GD group. A significant positive correlation between Th17 and TSAb (r = 0.656, p < 0.001) but significant negative correlations between Treg/Breg and TSAb (r = -0.339, p = 0.032; r = 0.759, p < 0.001) were identified among the participants. This study indicated that increased Th17 and impaired Treg responses, along with a decreased number of CD19+CD1dhiCD5+ Breg cells, were involved in GD pathogenesis. PMID- 29259989 TI - Functional Recovery of Cranial Nerves in Patients with Traumatic Orbital Apex Syndrome. AB - Objective: Traumatic orbital apex syndrome (TOAS) is a rare disease characterized by the damage of cranial nerves (CNs) II, III, IV, and VI. The aim of our study was to analyze the functional recovery of CNs in TOAS and discuss the management of these patients. Methods: We retrospectively reviewed 28 patients with TOAS treated in the Department of Neurosurgery, Shanghai Changzheng Hospital from February 2006 to February 2016. Functional recovery of CNs was evaluated based on extraocular muscle movement and visual perception. Follow-up duration was at least 6 months. Results: There were 26 males and 2 females with a mean age of 35.3 years. The most common cause of TOAS was traffic accident. CN IV suffered the lightest injury among CNs III, IV, and VI. CN II achieved obvious improvement at 3-month follow-up, while other CNs enjoyed evident improvement at 6-month follow-up. There was no significant difference between conservative treatment and surgical decompression. Conclusion: CNs passing through orbital apex region might recover to different degrees several months after proper management. Clinical decision should be individualized and surgical decompression could be considered with evidence of fracture, hematoma, or deformation. PMID- 29259990 TI - Arthroscopic Management for the Unstable Inferior Leaf of the Lateral Meniscus Anterior Horn and Associated Cysts through a Direct Inframeniscal Portal: A Retrospective Study. AB - Introduction: To investigate the clinical results of arthroscopic management for the unstable inferior leaf of the lateral meniscus anterior horn and associated cysts through an inframeniscal portal. Methods: From March 2005 to October 2014, 64 patients with an unstable inferior leaf of the lateral meniscus anterior horn and associated cysts underwent arthroscopic management with an inframeniscal portal. The mean age of the patients was 36.9 years (range, 18 to 49 years). The mean follow-up period was 28 months (range, 24 to 44 months). Clinical results were assessed using physical examination, the Lysholm knee score, and postoperative magnetic resonance scanning. Results: The median Lysholm score improved significantly at 1 year after surgery and at final follow-up. Magnetic resonance scanning at least one year after the operation revealed no recurrent meniscal tears or cysts. No reoperations were required after an average follow-up of 28 months. All patients reported significant symptomatic relief after the operation. They had full range of motion at three months and returned to normal activities and sports one year after surgery. Conclusion: The direct inframeniscal portal can provide an effective approach to manage lesions in the anterior horn of the lateral meniscus with predictable clinical outcomes. PMID- 29259992 TI - Corrigendum to "Functional Virtual Flow Cytometry: A Visual Analytic Approach for Characterizing Single-Cell Gene Expression Patterns". AB - [This corrects the article DOI: 10.1155/2017/3035481.]. PMID- 29259991 TI - Enhancement of Angiogenesis by Ultrasound-Targeted Microbubble Destruction Combined with Nuclear Localization Signaling Peptides in Canine Myocardial Infarction. AB - Objective: This study aimed to develop a gene delivery system using ultrasound targeted microbubbles destruction (UTMD) combined with nuclear localization signal (NLS) and investigate its efficacy and safety for therapeutic angiogenesis in canine myocardial infarction (MI) model. Methods: Fifty MI dogs were randomly divided into 5 groups and transfected with Ang-1 gene plasmid: (i) group A: only injection of microbubbles and Ang-1 plasmid; (ii) group B: only UTMD mediated gene transfection; (iii) group C: UTMD combined with classical NLS mediated gene transfection; (iv) group D: UTMD combined with mutational NLS mediated transfection; and (v) group E: UTMD combined with classical NLS in the presence of a nucleus transport blocker. The mRNA and protein expression of Ang-1 gene, microvessel density (MVD) cardiac troponin I (cTnI), and cardiac function were determined after transfection. Results: The expression of mRNA and protein of Ang 1 gene in group C was significantly higher than that of the other groups (all P < 0.01). The MVD of group C was 10.2-fold of group A and 8.1-fold of group E (P < 0.01). The cardiac function in group C was significant improvement without cTnI rising. Conclusions: The gene delivery system composed of UTMD and NLS is efficient and safe. PMID- 29259993 TI - A Study on Cytotoxic and Apoptotic Potential of a Triterpenoid Saponin (3-O-alpha L-Arabinosyl Oleanolic Acid) Isolated from Schumacheria castaneifolia Vahl in Human Non-Small-Cell Lung Cancer (NCI-H292) Cells. AB - Lung cancer is the major cause of cancer death among men. A number of natural compounds have proven to be useful in the treatmet of lung cancer. This study was aimed to determine cytotoxic and apoptotoic effects of a natural compound 3-O alpha-L-arabinosyl oleanolic acid (3-O-L-AO) isolated from Schumacheria castaneifolia in non-small-cell lung cancer (NCI-H292) cells. Cytotoxic effects of 3-O-L-AO were determined by Sulforhodamine B (SRB) assay and apoptotic effects were tested by evaluating (a) apoptotsis related morphological changes, (b) caspase 3/7 activity, and (c) expression of Bax, p53, and survivin genes. Oxidative stress markers (reactive oxygen species (ROS), glutathione-S transferase (GST), and glutathione (GSH)) were also analysed in 3-O-L-AO treated NCI-H292 cells. 3-O-L-AO exerted potent cytotoxic effects in NCI-H292 cells while being less cytotoxic to normal lung (MRC-5) cells. Exposure to 3-O-L-AO caused upregulation of Bax and p53 and downregulation of survivin in NCI-H292 cells. Activation of caspase 3/7 and morphological features related to apoptosis further confirmed 3-O-L-AO induced apoptosis. Furthermore, elevated ROS and GST levels and decreased GSH levels suggested 3-O-L-AO can induce apoptosis, possibly causing oxidative stress in NCI-H292 cells. Overall results suggest that 3-O-L-AO can be considered as an effective anticancer agent for the treatment of lung cancer. PMID- 29259995 TI - Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies. AB - Objective: To evaluate whether the anti-LINGO-1 antibody has immunomodulatory effects. Methods: Human peripheral blood mononuclear cells (hPBMCs), rat splenocytes, and rat CD4+ T cells were assessed to determine whether LINGO-1 was expressed and was inducible. Anti-LINGO-1 Li81 (0.1-30 MUg/mL) effect on proliferation/cytokine production was assessed in purified rat CD4+ T cells and hPBMCs stimulated with antibodies to CD3 +/- CD28. In humans, the effect of 2 opicinumab (anti-LINGO-1/BIIB033; 30, 60, and 100 mg/kg) or placebo IV administrations was evaluated in RNA from blood and CSF samples taken before and after administration in phase 1 clinical trials; paired samples were assessed for differentially expressed genes by microarray. RNA from human CSF cell pellets was analyzed by quantitative real-time PCR for changes in transcripts representative of cell types, activation markers, and soluble proteins of the adaptive/innate immune systems. ELISA quantitated the levels of CXCL13 protein in human CSF supernatants. Results: LINGO-1 is not expressed in hPBMCs, rat splenocytes, or rat CD4+ T cells; LINGO-1 blockade with Li81 did not affect T-cell proliferation or cytokine production from purified rat CD4+ T cells or hPBMCs. LINGO-1 blockade with opicinumab resulted in neither significant changes in immune system gene expression in blood and CSF, nor changes in CXCL13 CSF protein levels (clinical studies). Conclusions: These data support the hypothesis that LINGO-1 blockade does not affect immune function. Classification of evidence: This study provides Class II evidence that in patients with MS, opicinumab does not have immunomodulatory effects detected by changes in immune gene transcript expression. PMID- 29259994 TI - Perceptions of Dietary Habits and Risk for Type 2 Diabetes among Congolese Immigrants. AB - Objective: To explore the perceptions of dietary habits and type 2 diabetes risk among Congolese immigrants living in the US. Methods: Data were collected from 20 in-depth interviews and photo-elicitation techniques conducted with Congolese immigrants. The PEN-3 cultural model was used as a guide to analyze the data collected. Results: Participants identified positive, existential, and negative perceptions, enablers, and nurturers associated with dietary habits and type 2 diabetes risk. Participants also acknowledged intrinsic cultural ways of understanding and interpreting the interaction between dietary habits and type 2 diabetes risk among the Congolese people which may influence their health-seeking practices. Conclusions: The findings underscore the importance of culture and how sociocultural factors may play a role with designing culturally appropriate interventions aimed at addressing the risk for type 2 diabetes among Congolese immigrants in the US. PMID- 29259996 TI - Phenotypic and functional complexity of brain-infiltrating T cells in Rasmussen encephalitis. AB - Objective: To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile. Methods: The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-cell receptor (TCR) deep sequencing. Identification of clonally expanded T-cell clones (TCCs) was achieved by combining flow cytometry sorting of CD4+ and CD8+ T cells and high-throughput TCR Vbeta-chain sequencing. The most abundant brain-infiltrating TCCs were isolated and functionally characterized. Results: We found that CD4+, CD8+, and also gammadelta T cells infiltrate the brain tissue in RE. Further analysis surprisingly revealed that not only brain-infiltrating CD8+ but also CD4+ T cells are clonally expanded in RE. All 3 subsets exhibited a Tc1/Th1 phenotype characterized by the production of interferon (IFN)-gamma and TNF. Broad cytokine profiling at the clonal level showed strong production of IFN-gamma and TNF and also secretion of interleukin (IL)-5, IL-13, and granzyme B, both in CD4+ and CD8+ T cells. Conclusions: CD8+ T cells were until now considered the central players in the immunopathogenesis of RE. Our study adds to previous findings and highlights that CD4+ TCCs and gammadelta T cells that secrete IFN-gamma and TNF are also involved. These findings underline the complexity of T-cell immunity in RE and suggest a specific role for CD4+ T cells in orchestrating the CD8+ T-cell effector immune response. PMID- 29259997 TI - Evidence of B-cell dysregulation in severe CNS inflammation after alemtuzumab therapy. PMID- 29259998 TI - Safety and preliminary efficacy of deep transcranial magnetic stimulation in MS related fatigue. AB - Objective: To conduct a randomized, sham-controlled phase I/IIa study to evaluate the safety and preliminary efficacy of deep brain H-coil repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex (PFC) and the primary motor cortex (MC) in patients with MS with fatigue or depression (NCT01106365). Methods: Thirty-three patients with MS were recruited to undergo 18 consecutive rTMS sessions over 6 weeks, followed by follow-up (FU) assessments over 6 weeks. Patients were randomized to receive high-frequency stimulation of the left PFC, MC, or sham stimulation. Primary end point was the safety of stimulation. Preliminary efficacy was assessed based on changes in Fatigue Severity Scale (FSS) and Beck Depression Inventory scores. Randomization allowed only analysis of preliminary efficacy for fatigue. Results: No serious adverse events were observed. Five patients terminated participation during treatment due to mild side effects. Treatment resulted in a significant median FSS decrease of 1.0 point (95%CI [0.45,1.65]), which was sustained during FU. Conclusions: H-coil rTMS is safe and well tolerated in patients with MS. The observed sustained reduction in fatigue after subthreshold MC stimulation warrants further investigation. ClinicalTrialsgov identifier: NCT01106365. Classification of evidence: This study provides Class III evidence that rTMS of the prefrontal or primary MC is not associated with serious adverse effects, although this study is underpowered to state this with any precision. PMID- 29259999 TI - Progressive inner nuclear layer dysfunction in non-optic neuritis eyes in MS. AB - Objective: To investigate primary retinal functional changes in non-optic neuritis (ON) eyes of patients with MS by full-field electroretinography (ERG). Methods: Seventy-seven patients with relapsing-remitting MS with no history of clinical ON in at least 1 eye and 30 healthy controls were recruited in the cohort study. Full-field ERGs were recorded, and retinal optical coherence tomography scans were performed to assess the thicknesses of peripapillary retinal nerve fiber layer (RNFL) and retinal ganglion cell layer-inner plexiform layer (GCL-IPL). Annual MRI scans were also carried out to evaluate the disease activity in the brain. Patients were followed up for 3 years. Results: At baseline, a delayed b-wave peak time was observed in the cone response (p < 0.001), which was associated with the thicknesses of RNFL and GCL-IPL. The peak time of the delayed b-wave also correlated with the Expanded Disability Status Scale, T2 lesion volume, and disease duration. During the 3-year follow-up, progressive ERG amplitude reduction was observed (both a- and b-waves, p < 0.05). There was a correlation between the b-wave amplitude reduction and longitudinal RNFL loss (p = 0.001). However, no correlation was found between longitudinal ERG changes and disease activity in the brain. Conclusions: This study demonstrated progressive inner nuclear layer dysfunction in MS. The borderline a-wave changes suggested some outer retinal dysfunction as well. The correlation between full field ERG changes and retinal ganglion cell loss suggested that there might be subclinical retinal pathology in MS affecting both outer and inner retinal layers. PMID- 29260000 TI - Chemical potential-electric double layer coupling in conjugated polymer polyelectrolyte blends. AB - Conjugated polymer-polyelectrolyte blends combine and couple electronic semiconductor functionality with selective ionic transport, making them attractive as the active material in organic biosensors and bioelectronics, electrochromic displays, neuromorphic computing, and energy conversion and storage. Although extensively studied and explored, fundamental knowledge and accurate quantitative models of the coupled ion-electron functionality and transport are still lacking to predict the characteristics of electrodes and devices based on these blends. We report on a two-phase model, which couples the chemical potential of the holes, in the conjugated polymer, with the electric double layer residing at the conjugated polymer-polyelectrolyte interface. The model reproduces a wide range of experimental charging and transport data and provides a coherent theoretical framework for the system as well as local electrostatic potentials, energy levels, and charge carrier concentrations. This knowledge is crucial for future developments and optimizations of bioelectronic and energy devices based on the electronic-ionic interaction within these materials. PMID- 29260001 TI - Normalizing serum hepcidin but not alpha-1-antitrypsin level during effective treatment of chronic hepatitis C. AB - Aim of the study: We investigated the impact of pegylated interferon alpha-2 in combination with ribavirin (PEG-IFNalpha/RBV) treatment on hepcidin and alpha-1 antitrypsin concentrations in the serum of patients with chronic hepatitis C. Material and methods: We measured serum concentrations of hepcidin, prohepcidin and alpha-1-antitrypsin by enzyme-linked immunosorbent assays in patients with chronic hepatitis C before and during antiviral therapy. Results: Hepcidin concentrations were increased in both genotype 1b and 3a hepatitis C virus (HCV) infected patients as compared with the control group. During treatment of patients infected with genotype 1b HCV hepcidin levels gradually declined, reaching significantly lower values at the treatment termination than before therapy. Treatment responders showed an increased concentration of hepcidin at week 4 of therapy and a subsequent decrease to values significantly lower than observed among non-responders at week 48 of treatment. alpha-1-antitrypsin concentration was not affected by the treatment efficacy. Conclusions: Successful therapy of patients persistently infected with HCV was associated with restoration of serum hepcidin concentration to values similar to the control group. Differential dynamics of hepcidin during PEG-IFNalpha/RBV therapy in responders and non-responders might indicate the direct influence of viral eradication on iron homeostasis. PMID- 29260002 TI - Profile of extrahepatic portal venous obstruction among children in Central India. AB - Introduction: There is a paucity of data regarding the clinical profile of children with extrahepatic portal venous obstruction (EHPVO) from Central India. Material and methods: Retrospective analysis of 30 children with EHPVO treated between 2002 and 2012. Results: The median age of presentation was 12.5 years (range 5-14 years) and median duration of symptoms was 3.2 years (range 0.3-10 years). Home delivery was noted in 30 cases (100%), umbilical sepsis in 8 (27%) and history of cow dung application over the umbilical cord in 2 cases (6.7%). Twenty-two cases (73.4%) presented with upper gastrointestinal (GI) bleeding while 18 (60%) were referred for pancytopenia and/or hypersplenism. The patients underwent a median of 3.2 sessions of endoscopic therapy for varices. Most patients (19/30, 63.4%) dropped out of serial endotherapy due to the paucity of funds. Shunt surgery was performed in 7 patients. Conclusions: Home delivery and umbilical sepsis are significant risk factors for EHPVO. Most patients present with GI bleeding and do well on endoscopic treatment/shunt surgery. PMID- 29260003 TI - Why sensitive bacteria are resistant to hospital infection control. AB - BACKGROUND: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. METHODS: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio (IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. RESULTS: For the resistant strain, there were large reductions in hospital acquired infections (0.1 <= IRR <= 0.6) and smaller reductions in community acquired infections (0.2 <= IRR <= 0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 <= IRR <= 0.9), while community acquisitions could increase or decrease (0.9 <= IRR <= 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. CONCLUSIONS: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally. This follows from differences in their adaptation to hospital- and community-based transmission. Observed lack of effectiveness of control measures for sensitive strains does not provide evidence that infection control interventions have been ineffective in reducing resistant strains. PMID- 29260004 TI - Comparative genomics identifies male accessory gland proteins in five Glossina species. AB - Accessory gland proteins (ACPs) are important reproductive proteins produced by the male accessory glands (MAGs) of most insect species. These proteins are essential for male insect fertility, and are transferred alongside semen to females during copulation. ACPs are poorly characterized in Glossina species (tsetse fly), the principal vector of the parasite that causes life-threatening Human African Trypanosomiasis and Animal trypanosomiasis in endemic regions in Africa. The tsetse fly has a peculiar reproductive cycle because of the absence of oviposition. Females mate once and store sperm in a spermathecal, and produce a single fully developed larva at a time that pupates within minutes of exiting their uterus. This slow reproductive cycle, compared to other insects, significantly restricts reproduction to only 3 to 6 larvae per female lifespan. This unique reproductive cycle is an attractive vector control strategy entry point. We exploit comparative genomics approaches to explore the diversity of ACPs in the recently available whole genome sequence data from five tsetse fly species ( Glossina morsitans, G. austeni, G. brevipalpis, G. pallidipes and G. fuscipes). We used previously described ACPs in Drosophila melanogaster and Anopheles gambiae as reference sequences. We identified 36, 27, 31, 29 and 33 diverse ACP orthologous genes in G. austeni, G. brevipalpis, G. fuscipes, G. pallidipes and G. morsitans genomes respectively, which we classified into 21 functional classes. Our findings provide genetic evidence of MAG proteins in five recently sequenced Glossina genomes. It provides new avenues for molecular studies that evaluate potential field control strategies of these important vectors of human and animal disease. PMID- 29260005 TI - Prosopometamorphopsia and alexia following left splenial corpus callosum infarction: Case report and literature review. AB - Background: Lesions to the posterior section of the corpus callosum, called the splenium, and the immediate area have been separately associated with perceived visual distortions of the face (prosopometamorphopsia) or difficulty reading (alexia). Case report: This case report describes a right-handed patient who complained of prosopometamorphopsia associated with the lower part of the face and alexia following infarction of the left splenium in the corpus callosum. Conclusions: The splenium and adjacent retrosplenial cortex facilitate the transfer of visual information and memory function between the two hemispheres of the brain and along the Papez circuit, respectively. We believe that damage to this singular area of the brain could bring about several concurrent yet disparate symptoms, such as the reported prosopometamorphopsia and alexia with this patient. PMID- 29260006 TI - High PR3-ANCA positivity in a patient with chronic inflammatory demyelinating polyneuropathy. AB - Proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) is reported to be highly specific to vasculitis compared to myeloperoxidase (MPO)-ANCA. We report a case of a 19-year-old woman with chronic inflammatory demyelinating polyneuropathy (CIDP) with high PR3-ANCA positivity. The patient responded well to intravenous immunoglobulin plus oral steroid, and showed no signs of systemic vasculitis during the subsequent 10 months of follow-up. Our present case suggests that CIDP may accompany high PR3-ANCA levels, which should be differentiated from axonal neuropathy due to vasculitis. PMID- 29260007 TI - Sleep Apnea in Multiple System Atrophy of Cerebellar Type: A 3.0 T MRS/Volumetry Pilot Study. PMID- 29260008 TI - Functional validation and expression analysis of myotubes converted from skin fibroblasts using a simple direct reprogramming strategy. AB - Previously, we reported that MyoD, a master gene for myogenic cells, could efficiently convert primary skin fibroblasts into myoblasts and myotubes, thereby effecting direct reprogramming. In this study, we further demonstrated that MyoD expressing primary fibroblasts displayed rapid movement in culture, with a movement velocity that was significantly faster, almost four times, than mouse primary myoblasts. MyoD-transduced cells obtained the characteristics of Ca2 + release and electrically-stimulated contraction, which was comparable to C2C12 myotubes, suggesting that the essential features of muscle were observed in the transduced cells. Furthermore, the ability to fuse to the host myoblasts means that gene transfer from MyoD-transduced cells to host muscle cells could be obtained by cell fusion. In comparison with the iPS method (indirect reprogramming), our transduction method has a low risk for tumorigenesis and carcinogenesis because the starting cells are fibroblasts and the transduced cells are myoblasts, both normal and mortal cells. Accordingly, MyoD transduction of human skin fibroblasts using the adenoviral vector is a simple, inexpensive and promising candidate as a new cell transplantation therapy for patients with muscular disorders. PMID- 29260009 TI - Adult-onset of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) syndrome with hypothyroidism and psychiatric disorders. AB - Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a clinical syndrome associated with mitochondrial disorders (MIDs). This report illustrates a case of MELAS syndrome with hypothyroidism and psychiatric disorders, which is different from the common clinical manifestations of MELAS syndrome, such as exercise intolerance, migraine-like headaches, hearing loss and seizures etc. There are considerable interests in the possibility that mitochondrial dysfunction may play a role in the pathogenesis of endocrine dysfunctions and psychiatric disorders in MELAS syndrome. PMID- 29260010 TI - Musical, visual and cognitive deficits after middle cerebral artery infarction. AB - The perception of music can be impaired after a stroke. This dysfunction is called amusia and amusia patients often also show deficits in visual abilities, language, memory, learning, and attention. The current study investigated whether deficits in music perception are selective for musical input or generalize to other perceptual abilities. Additionally, we tested the hypothesis that deficits in working memory or attention account for impairments in music perception. Twenty stroke patients with small infarctions in the supply area of the middle cerebral artery were investigated with tests for music and visual perception, categorization, neglect, working memory and attention. Two amusia patients with selective deficits in music perception and pronounced lesions were identified. Working memory and attention deficits were highly correlated across the patient group but no correlation with musical abilities was obtained. Lesion analysis revealed that lesions in small areas of the putamen and globus pallidus were connected to a rhythm perception deficit. We conclude that neither a general perceptual deficit nor a minor domain general deficit can account for impairments in the music perception task. But we find support for the modular organization of the music perception network with brain areas specialized for musical functions as musical deficits were not correlated to any other impairment. PMID- 29260011 TI - Isolated pons involvement in Posterior Reversible Encephalopathy Syndrome: Case report and review of the literature. AB - Background: Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical radiological syndrome, usually reversible and with a favorable prognosis, which recognizes a variety of etiologies and clinical patterns and is likely due to an impairment in cerebral blood flow autoregulation. It is typically characterized by subcortical, predominantly parieto-occipital, vasogenic brain oedema in patients with acute-subacute neurological symptoms. Infratentorial oedema on neuroimaging has been mostly described in association with the typical supratentorial pattern and seldom as isolated. Case report: We report a case of PRES with isolated pons involvement on MRI. A woman affected by Turner syndrome, epilepsy, slight mental deficiency, obesity and hypothyroidism, experienced a progressive gait and standing impairment, worsening in the last 2 weeks. At admission blood pressure was 220/110 mmHg. Brain MRI showed a wide FLAIR signal hyperintensity on T2-weighted sequences affecting the entire pons, without contrast enhancement. Clonidine, doxazosine, furosemide and telmisartan were effective in restoring normal blood pressure. Pons hyperintensity completely resolved on MRI 3 weeks later, together with return to normal neurological examination. Conclusions: Though isolated infratentorial involvement in PRES recognizes several causes, hypertension, which is a common feature in Turner syndrome, would have played a key role in our case with solely pons MRI T2 hyperintensity. PMID- 29260012 TI - Time-courses of plasma IL-6 and HMGB-1 reflect initial severity of clinical presentation but do not predict poor neurologic outcome following subarachnoid hemorrhage. AB - Objective: Patients with aneurysmal subarachnoid hemorrhage (aSAH) experience high mortality and morbidity. Neuroinflammation causes brain damage expansion after aSAH. Due to the complexity of the inflammatory response multiple biomarkers are needed to evaluate its' progression. We studied inflammatory process after aSAH by measuring two inflammatory biomarkers, interleukin-6 (IL-6) and high-mobility group box 1 (HMGB1) at simultaneous time-points after aSAH. Methods: In this prospective population-based study, IL-6 and HMGB1 were measured in aSAH patients (n = 47) for up to five days. Plasma concentrations of IL-6 and HMGB1 were measured at 0, 12 and 24 h after hospital admission, and thereafter daily for up to five days or until the patient was transferred from the intensive care unit (ICU). The patients' neurological outcomes were evaluated with the modified Rankin Scale at six months after aSAH. Results: A high IL-6 level during the first day after aSAH was associated with a severe initial clinical presentation (p = 0.002) and infection during follow-up (p = 0.031). The HMGB1 level did not associate with these parameters. There was no correlation between IL-6 and HMGB1 levels at any time point during the follow-up. The concentrations of IL-6 and HMGB1 were not associated with neurological outcome. Conclusions: High initial IL-6 values seem to reflect the intensity of the inflammatory response but not the brain damage per se. An early inflammatory response might even be beneficial since although elevated IL-6 levels were observed in patients with a more severe initial clinical presentation, they were not associated with neurological outcome. The lack of correlation between IL-6 and HMGB1 questions the role of macrophages in the process of the secretion of these inflammatory markers after aSAH, instead pointing to the activation of alternative pro inflammatory pathways. PMID- 29260013 TI - Popular stroke knowledge in Brazil: A multicenter survey during "World Stroke Day". AB - Context and objective: Cerebrovascular disease is one of the most important causes of death and disability worldwide. The patient's inability to identify the warning signs of stroke substantially delays the search for emergency services, which is related directly to a worse outcome. Thus, during the 2011 Stroke Campaign in Brazil, a survey was conducted to identify the lay population's knowledge with regard to the recognition, treatment, and prevention of stroke. Design and setting: This retrospective, cross-sectional, multicenter study was held in cities throughout southeastern Brazil. Methods: The campaign was conducted by students of several medical schools under the guidance of neurologists (assistants and professors). The students traveled to various public areas in Sao Paulo, Campinas, Sorocaba, Taubate, and Pouso Alegre, where information about stroke was distributed and a specific questionnaire was administered. Results: A total of 1304 people answered the questionnaire: 43.9% claimed to know what a stroke was, 65% knew someone who has had the disease, 35% knew > 3 risk factors for stroke, and 28.8% knew a preventive measure. Further, 17.9% was able to list at least 3 signs or symptoms of a stroke, 33.6% was aware that they should activate the emergency service, and 3.1% would have checked the time at which the signs and symptoms had developed. Conclusion: Despite the severity of stroke, the population that we analyzed has a low level of knowledge. Campaigns should increase the lay population's understanding of this disease, thus improving its prevention and treatment and contributing to public health politics. PMID- 29260015 TI - Evolution into moyamoya disease in an infant with internal carotid artery aneurysms. AB - Introduction: Moyamoya disease (MMD) is characterized by progressive stenosis and occlusion in the terminal portion of both internal carotid arteries (ICAs) and the formation of an abnormal vascular network. Because of the fragile structure of the collateral vessels, MMD is frequently accompanied by intracranial aneurysms that are mainly located within the abnormal basal network or the circle of Willis. However, the association between MMD and aneurysms of the ICAs has never been reported previously. Case report: A 1-month-old infant presented with a decreased level of consciousness and arterial infarction in the right frontal and temporal lobes. Brain computed tomography angiography results showed aneurysms in both ICAs and occlusions of the distal part of the aneurysms without moyamoya collateral vessels. Aspirin therapy was initiated, and his clinical status stabilized. At 12 months of age, collateral networks of small vessels were found in the distal part of both ICAs, and MMD had evolved. At 24 months of age, he remains on aspirin therapy, and no further ischemic events have occurred. Conclusions: This is the first report of MMD in which ICA aneurysms and occlusions developed bilaterally in early infancy without moyamoya collateral vessels. Our case indicates that angiogenesis at the base of the brain may occur following extracellular matrix remodeling at the terminal portion of the ICAs. PMID- 29260014 TI - Regional glucose hypometabolic spread within the primary motor cortex is associated with amyotrophic lateral sclerosis disease progression: A fluoro deoxyglucose positron emission tomography study. AB - Objective: Here we investigate the process of neurodegeneration in amyotrophic lateral sclerosis (ALS). The relationship between the cortical field spreading of glucose metabolic decreases in the primary motor cortex (PMC) and the progression of corresponding extremity dysfunction was evaluated using [18F] fluoro deoxyglucose (FDG)-positron emission tomography (PET). Methods: Patients with ALS underwent [18F] FDG-PET and the resulting datasets were individually contrasted against healthy controls using the NEUROSTAT software. The extent ratio was defined as the proportion of pixels with a significant Z-score decrease within regions of the primary motor cortex (precentral gyrus or paracentral lobule) opposite to the impaired upper extremities (UEs) or lower extremities (LEs), respectively. Clinical symptoms in all extremities were assessed using an upper motor neuron (UMN) score and the MRC (Medical Research Council) sum score upon physical examination. Cross-sectional correlations were analysed between clinical symptoms, the duration of these symptoms, and the extent ratio. Results: Nineteen regions of the primary motor cortex corresponding to symptomatic limb in 10 participants were evaluated. In the corresponding region of the primary motor cortex, the extent ratio increased (same meaning as hypometabolic area spread) in association with symptom duration (rs = 0.5, p = 0.03). Neither UMN nor lower motor neuron (LMN) scores were correlated with symptom duration. Three out of 19 impaired regions did not show upper motor neuron (UMN) signs upon physical examination. The extent ratio and UMN score-controlled symptom duration were partially correlated (rs = 0.5, p = 0.05). Conclusions: In patients with ALS, glucose metabolism decreased in the impaired side of the primary motor cortex depending on the clinical symptom progression in the corresponding extremities, regardless of the presence of clinical UMN signs. A decrement in glucose metabolism on FDG-PET corresponding to symptoms in the primary motor cortex might be an indicator of the time-dependent course of ALS neurodegeneration. PMID- 29260016 TI - Association between exercise habits and subcortical gray matter volumes in healthy elderly people: A population-based study in Japan. AB - Background and aims: The relationship between exercise and subcortical gray matter volume is not well understood in the elderly population, although reports indicate that exercise may prevent cortical gray matter atrophy. To elucidate this association in the elderly, we measured subcortical gray matter volume and correlated this with volumes to exercise habits in a community-based cohort study in Japan. Methods: Subjects without mild cognitive impairment or dementia (n = 280, 35% male, mean age 73.1 +/- 5.9 years) were evaluated using the Mini-Mental State Examination (MMSE), an exercise habit questionnaire, and brain magnetic resonance imaging. Subcortical gray matter volume was compared between groups based on the presence/absence of exercise habits. The MMSE was re-administered 3 years after the baseline examination. Results: Ninety-one subjects (32.5%) reported exercise habits (exercise group), and 189 subjects (67.5%) reported no exercise habits (non-exercise group). Volumetric analysis revealed that the volumes in the exercise group were greater in the left hippocampus (p = 0.042) and bilateral nucleus accumbens (left, p = 0.047; right, p = 0.007) compared to those of the non-exercise group. Among the 195 subjects who received a follow-up MMSE examination, the normalized intra-cranial volumes of the left nucleus accumbens (p = 0.004) and right amygdala (p = 0.014)showed significant association with a decline in the follow-up MMSE score. Conclusion: Subjects with exercise habits show larger subcortical gray matter volumes than subjects without exercise habits in community-dwelling elderly subjects in Japan. Specifically, the volume of the nucleus accumbens correlates with both exercise habits and cognitive preservation. PMID- 29260017 TI - Convergence spasm due to aquaporin-positive neuromyelitis optica spectrum disorder. AB - A female 27 presented with nausea and diplopia for 1 week. On examination she had normal vertical gaze but would develop convergence with miosis whenever she made horizontal saccades. Pupils were 6 mm and unreactive to light. MRI showed extensive hyperintensity in the dorsal midbrain and thalamus. Spinal MRI and CSF were both normal. Serum aquaporin-4-antibody was positive. She was treated with steroids and plasmapheresis and after 3 months convergence spasm resolved but pupils remained unreactive. Neuromyelitis optica often presents with brainstem signs, rarely a dorsal midbrain syndrome. Convergence spasm is occasionally of organic neurologic origin. PMID- 29260018 TI - Reliability, factor analysis and internal consistency calculation of the Insomnia Severity Index (ISI) in French and in English among Lebanese adolescents. AB - Objectives: Our goal is to validate and to verify the reliability of the French and English versions of the Insomnia Severity Index (ISI) in Lebanese adolescents. Study design: A cross-sectional study was implemented. Methods: 104 Lebanese students aged between 14 and 19 years participated in the study. The English version of the questionnaire was distributed to English-speaking students and the French version was administered to French-speaking students. A scale (1 to 7 with 1 = very well understood and 7 = not at all) was used to identify the level of the students' understanding of each instruction, question and answer of the ISI. The scale's structural validity was assessed. The factor structure of ISI was evaluated by principal component analysis. The internal consistency of this scale was evaluated by Cronbach's alpha. To assess test-retest reliability the intraclass correlation coefficient (ICC) was used. Results: The principal component analysis confirmed the presence of a two-component factor structure in the English version and a three-component factor structure in the French version with eigenvalues > 1. The English version of the ISI had an excellent internal consistency (alpha = 0.90), while the French version had a good internal consistency (alpha = 0.70). The ICC presented an excellent agreement in the French version (ICC = 0.914, CI = 0.856-0.949) and a good agreement in the English one (ICC = 0.762, CI = 0.481-890). The Bland-Altman plots of the two versions of the ISI showed that the responses over two weeks' were comparable and very few outliers were detected. Conclusion: The results of our analyses reveal that both English and French versions of the ISI scale have good internal consistency and are reproducible and reliable. Therefore, it can be used to assess the prevalence of insomnia in Lebanese adolescents. PMID- 29260019 TI - Influenza A (H3N2)-induced rhabdomyolysis complicating anterior compartment syndrome: Serial changes in muscle MRI T2 fat suppression imaging. AB - Background: Rhabdomyolysis with influenza infection is rarely reported in adults. We report here influenza A induced rhabdomyolysis and anterior compartment syndrome (ACS). Case report: This case report describes a 43-year-old woman exhibiting influenza A induced rhabdomyolysis. High levels of creatine kinase (97,000 IU/L) and high titer of anti-influenza A virus antibody (H3N2) (320 *) with negative anti-influenza B virus antibody were observed. T2 fat suppression muscle MRI imaging showed high-intensity signals in rectus femoris, vastus lateralis, adductor magnus, and semimembranosus (SM) muscles. The existence of ACS was suspected out. Muscle biopsy showed that fiber size variations exist without infiltration of inflammatory cells. The symptoms and muscle MRI findings of T2 fat suppression imaging was markedly improved. Conclusions: Muscle MRI T2 fat suppression imaging is a useful method to monitor influenza A induced rhabdomyolysis. We should keep in mind the possibilities of rhabdomyolysis and ACS in patients with influenza A infection presenting serious muscle pain. PMID- 29260021 TI - Isolated body lateropulsion caused by lower lateral medullary infarction. PMID- 29260020 TI - Time dependent transition of the levels of protein-conjugated acrolein (PC-Acro), IL-6 and CRP in plasma during stroke. AB - Objective: Measurement of plasma levels of protein-conjugated acrolein (PC-Acro) together with IL-6 and CRP can be used to identify silent brain infarction (SBI) with high sensitivity and specificity. The aim of this study was to determine how these biomarkers vary during stroke. Methods: Levels of PC-Acro, IL-6 and CRP in plasma were measured on day 0, 2, 7 and 14 after the onset of ischemic or hemorrhagic stroke. Results: After the onset of stroke, the level of PC-Acro in plasma was elevated corresponding to the size of stroke. It returned to near control levels by day 2, and remained similar through day 14. The degree of the decrease in PC-Acro on day 2 was greater when the size of brain infarction or hemorrhage was larger. An increase in IL-6 and CRP occurred after the increase in PC-Acro, and it was well correlated with the size of the injury following infarction or hemorrhage. The results suggest that acrolein becomes a trigger for the production of IL-6 and CRP, as previously observed in a mouse model of stroke and in cell culture systems. The increase in IL-6 and CRP was also correlated with poor outcome judging from mRS. Conclusion: The results indicate that the degree of the decrease in PC-Acro and the increase in IL-6 and CRP from day 0 to day 2 was correlated with the size of brain infarction, and the increase in IL-6 and CRP with poor outcome at discharge. PMID- 29260022 TI - Epidemiology of migraine among students in Mali. AB - Migraine is a debilitating but benign disease that can affect the quality of life of patients, disrupt the emotional relationships and impact on educational and vocational activities. The aim of our work was to study the epidemiology and impact of migraine in schools in the urban district of GAO in Mali. This is a cross-sectional study among students in the city of Gao. The survey was conducted in 11 schools, each of which represented a cluster. The study involved 733 students and diagnosis of migraine was made according to the 2004 IHS criteria except the criterion for the number of crises. The overall prevalence of migraine in school was 17.3% (95% CI [14.6% to 20%]). The headache prevalence among students was 20% (95% CI [16.91% to 23.09]), it was significantly higher 23.0% in girls than in boys 14.8% (p < 0.01). About its impact on school life, 63.8% of students had experienced absenteeism due to migraine from 1 to 14 days in the last quarter preceding the survey with a limiting concentration in 19.2% of students with migraine. In conclusion, migraine is common among students of Gao, it is more important in female. It has a negative impact on academic performance. It is therefore necessary to control its management to reduce the extent of the disease in this environment. PMID- 29260024 TI - Unihemispheric central nervous system vasculitis. AB - Patients with primary central nervous system vasculitis (PCNSV) usually manifest with multiple enhancing bilateral hemispheric lesions. We presented an extremely rare clinical course and follow-up of a patient with PCNSV affecting only a single (right) hemisphere. A 33-year-old previously healthy man presented with a left hand clonic seizure followed by a secondary generalized tonic-clonic seizure and dysarthria. MRI brain revealed multiple hyperintense lesions confined to only the right hemisphere with contrast enhancement, involving both white and grey matters. He was treated with a methylprednisolone for 5 days followed by prednisone for suspected acute disseminated encephalomyelitis without improvements. He was presented again with left-sided weakness, transient dysarthria and black objects in left visual field. MRI brain was unchanged. MR angiogram and conventional cerebral angiogram were normal. Autoimmune work-ups were all negative. A brain biopsy showed evidence of PCNSV. He was then successfully treated with intravenous cyclophosphamide followed by oral azathioprine. On a follow-up 3 years later, he remains asymptomatic on azathioprine and a repeat MRI showed all areas of enhancement were gone. PMID- 29260023 TI - Definition, prevalence and predictive factors of benign multiple sclerosis. AB - Background: Multiple sclerosis (MS) is characterized by a great inter-individual variability in disease course and severity. Some patients experience a rather mild course, controversially called 'benign MS' (BMS). The usefulness of this entity in clinical practice remains unclear. Methods: We performed a literature search in PubMed, Web of Science and Cochrane Library databases from November 1980 to December 2015, using the following key words: benign multiple sclerosis, diagnosis, imaging, prognosis, predictive, natural history and predefined inclusion criteria. Results: Our search yielded 26 publications. Most definitions were based on the Expanded Disease Status Scale (EDSS), which is heavily weighted towards physical disability. Between 30 and 80% of relapsing-remitting MS patients have EDSS < 3 or 4 at 10 years after onset. Having only one relapse in the first 5 years and EDSS <= 2 at 5 years or EDSS <= 3 at 10 years appears to be predictive for a prolonged benign disease course, without protecting against disease progression at a later stage. Evidence on the predictive value of MRI parameters remains limited. Conclusions: Current BMS definitions have some predictive value for future physical disability, but do not take into account the age at EDSS and the potentially disrupting effects of non-EDSS symptoms and cognitive impairment. It appears to correspond to mild RRMS in the first decades and its prevalence varies. Since early and accurate prediction of BMS is not yet possible, the clinical relevance is limited. Research approaches are suggested. PMID- 29260025 TI - Anterior clinoid mucocele causing optic neuropathy: A case report and review of literature. AB - A 66 year old Indian gentleman presented with a 3 days history of headache and gradual progressive loss of vision in his eft eye, ophthalmological assessment showed no light perception in his left eye with papilledema and afferent papillary defect. Computed tomography (CT) and Magnetic Resonance Imaging (MRI) were done and showed an expanding lesion in the left anterior clinoid process encroaching upon the left orbital apex and optic nerve with features suggestive of a mucocele. Patient was started on dexamethasone, and urgent craniotomy was undertaken, where marsupialization and resection of left anterior clinoid mucocele was done, and histopathologic examination of the operative specimen was consistent with a mucocele. Post-operatively, patient was kept on dexamethasone for few days, with uneventful outcome, and his follow up at 6 months showed complete recovery of his vision from no light perception to 6/12 in the affected eye. PMID- 29260026 TI - Brain biopsy to aid diagnosis of neuro-Behcet's disease: Case report and literature review. AB - Central nervous system involvement in Behcet's disease (Neuro-Behcet's disease: NBD) has been reported to present diverse clinical and pathological manifestations. A few cases presenting with neurological symptoms preceding other systemic features are difficult to be diagnosed. Here we suggest the clinical benefit of brain biopsy with a case of NBD initially presenting neurological symptoms. PMID- 29260028 TI - Cerebrospinal fluid analysis in individuals with diabetes-related dementia. AB - *CSF P-tau and Abeta42 show normal levels in diabetes-related dementia.*Diabetes related dementia may have a different underlying pathology from AD.*CSF analysis is useful for the differentiation of diabetes-related dementia from AD. PMID- 29260027 TI - Does cerebral large-artery disease contribute to cognitive impairment? AB - Purpose: Although many patients with cerebral large-artery disease (CLAD) show impaired cognitive performance, the risk factors remain unclear in this population. The objective of this study was to evaluate cognitive impairment and its risk factors in patients with CLAD. Methods: We recruited non-demented patients with CLAD from our hospital. CLAD was defined as occlusion or stenosis of over 50% in the carotid artery or middle cerebral artery. We collected patients' biographical data and vascular lesion and imaging data, including periventricular hyperintensity (PVH) and cerebral perfusion. The patients were divided into two groups: cognitive impairment-plus (CoI +) and normal (CoI -) groups, according to their Montreal Cognitive Assessment (MoCA) scores, with a cut-off value of 26. The factors associated with cognitive impairment were examined. Result: Of the 176 patients with CLAD (mean age 70.2 +/- 8.3, 40 female), 136 (77.2%) were classified as cognitively impaired. Multivariate analysis indicated that the CoI + group was associated with older age (odds ratio (OR): 1.09, P = 0.011), drinking habit (OR: 7.15, P = 0.003), increased PVH (OR: 3.46, P = 0.003), and decreased cerebral perfusion (OR: 0.897, P = 0.007). Analyses of the MoCA subscores indicated that attention, memory, and orientation were impaired in the CoI + group. Conclusion: Impaired cognition was observed in some of the non-demented patients with CLAD. Older age, drinking habit, severe PVH and decreased cerebral perfusion contributed to their poor cognitive performance. Strict treatment of atherosclerosis and intervention for CLAD might be necessary to prevent cognitive decline in these patients. PMID- 29260029 TI - A structural MRI study of cholinergic pathways and cognition in multiple sclerosis. AB - Background: White matter hyperintensities (WMH) in the cholinergic pathways are associated with cognitive performance in Alzheimer's disease. This study aimed to evaluate the relationship between the volume reduction of cholinergic pathways and cognitive function in patients with multiple sclerosis (MS). Methods: Thirty two MS patients underwent a brain MRI and cognitive measurements including the Mini-Mental State Examination (MMSE) and the Japanese version of the Montreal Cognitive Assessment (MoCA-J). The extent of WMH within the cholinergic pathways was assessed using the Cholinergic Pathways Hyperintensities Scale (CHIPS). Computerized WMH volumes were also obtained. FreeSurfer was used to measure regional volumes including the cortical and subcortical volumes. The correlations among the CHIPS, the WMH volume, and the clinical data were assessed, in addition to the correlations between the cognitive scores and regional volumes measured by FreeSurfer. Results: The CHIPS score and the WMH volume were strongly positively correlated with each other (r = 0.87, P < 0.001). The CHIPS score had significantly negative correlations with the MMSE (r = - 0.49, P = 0.003) and the MoCA-J (r = - 0.47, P = 0.005) results. The WMH volume had significantly negative correlations with the MMSE (r = - 0.54, P = 0.001) and the MoCA-J (r = - 0.57, P < 0.001) results. In the analysis by FreeSurfer, both the MMSE and MoCA-J scores had significant positive correlations only with the volume of the corpus callosum. Conclusions: The CHIPS score tended to be less sensitive to the WMH volume in cognitive function evaluation, although the difference did not reach the level of statistical significance. Thus the CHIPS method may not be as effective in MS patients. PMID- 29260030 TI - Pre-stroke glycemic control is associated with early neurologic deterioration in acute atrial fibrillation-related ischemic stroke. AB - Background: It has been suggested that AF-related ischemic stroke (IS) that is accompanied by atherosclerotic burden have poorer outcomes. The aim of this study was to investigate the importance of pre-stroke glycemic control (PSGC) on the early neurologic deterioration (END) of patients with acute AF-related IS. Methods: We retrospectively recruited 121 patients with AF-related IS who also had Diabetes mellitus (DM). The HbA1C level was measured in all subjects. END was defined as an increase in the National Institute of Health Stroke Scale (NIHSS) score of 4 NIHSS points within 7 days of symptom onset compared to the initial NIHSS score. Results: In this study, 20.7% (25 patients) were classified as having a poor PSGC status with a HbA1C level above 8.0%. In the univariate analysis, a poor PSGC status (p < 0.01), smoking (p = 0.01), severe neurologic deficits at admission (p = 0.01), and a larger size of ischemic lesions on DWI (p < 0.01) were associated with the occurrence of END. In the multivariate model, a poor PSGC status (p = 0.02) and larger size of ischemic lesions on MRI (p < 0.01) were independent predictors of END in acute AF-related IS. Conclusion: The HbA1c level upon admission was independently associated with significant prediction of END in acute AF-related IS. PMID- 29260031 TI - Effect of blood pressure variability on early neurological deterioration in single small subcortical infarction with parental arterial disease. AB - Background and purpose: Early neurological deterioration (END) is not uncommon in acute single small subcortical infarct (SSSI), especially in those with parental arterial disease (PAD). The purpose of this study was to elucidate the effect of BP variability on the development of END as well as functional outcome at 90 days in SSSI and to determine whether the effect is linked to the status of parent artery. Methods: Consecutive patients with acute SSSI were prospectively recruited from the First People's Hospital of Yangzhou between Aug 2013 and Jul 2016. END was defined as an NIHSS score increased >= 2 during the first 72 h compared with the initial NIHSS score. Functional outcome at 90 days after onset was assessed using the modified Rankin Score (mRS) and dichotomized as good (0-2) and poor (>= 3). During this period, the parameters of BP variability such as BPmax-min, BPSD, and BPCV (equal to [SD * 100] / mean) were calculated. Results: A total of 296 patients were included in the analysis. Of these, 30 (38.5%) SSSI associated with PAD and 53 (24.3%) without developed END respectively. Logistic regression analysis demonstrated that SBPmax (OR 1.036, 95% CI 1.005-1.069), SBPSD (OR 1.177, 95% CI 1.021-1.356), SBPcv (OR 1.306, 95% CI 1.049-1.626), DBPmax (OR 1.141, 95% CI 1.042-1.250), DBPmax-min (OR 1.085, 95% CI 1.015-1.160), DBPSD (OR 1.369, 95% CI 1.032-1.816), and DBPCV (OR 1.281, 95% CI 1.028-1.597) were all the independent predictors of END after acute SSSI associated with PAD. However, for those without PAD, none of the BP parameters was found significantly associated with END. Also, BP parameters were not related to the poor outcome at 90 days after onset. Conclusions: Our study demonstrated that the acute in hospital BP variability was associated with the development of END in patients with acute SSSI. However, its impact varies depending on the status of parent artery. PMID- 29260032 TI - Longitudinal clinical and neuro-radiological findings in a patient with leukoencephalopathy with brain calcifications and cysts (Labrune syndrome). AB - Since she was 4 years old, the patient had exhibited frequent convulsive seizures, and she experienced severe headaches and depression in adulthood. At the age of 37 years, cerebral calcifications were detected, but she exhibited no cognitive or motor problems. She suffered a cerebral haemorrhage at 49 years old and experienced cognitive dysfunction, dysarthria, dysphagia, and left hemiparesis as sequelae. After undergoing gastrostomy, she exhibited very slow cognitive deterioration associated with speech disturbance over more than 10 years. She also gradually developed limb spasticity with Babinski signs. Repeated computerised tomography scans revealed unexpected changes including 2 cysts that appeared separately after small haemorrhages, an intracerebral haemorrhage, and intra-cyst bleeding. These longitudinal scans also showed progressive ventricular dilatation and expansion of the leukoencephalopathy, but there were no apparent changes in the intracranial calcifications. Magnetic resonance imaging revealed numerous microbleeds, and magnetic resonance angiography revealed irregularity of the cerebral artery walls with stoppage. Her SNORD118 gene exhibited compound heteromutation of c.38C > G and c.116G > C on different alleles. She was finally diagnosed with leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) at the age of 61 years. Past reports have suggested that diffuse cerebral microangiopathy underlies Labrune syndrome's pathogenesis, but we speculate that cerebral macroangiopathy may also underlie it. PMID- 29260033 TI - Inhibition of the primary motor cortex and the upgoing thumb sign. AB - Background: The upgoing thumb sign has been frequently observed in patients with minor strokes and transient ischemic attacks as an indicator of brain involvement. We assessed the effect of primary motor cortex (M1) inhibition in the development of the upgoing thumb sign. Methods: Used repetitive Transcranial Magnetic Stimulation (rTMS, 1 Hz frequency for 15 min, 1s ISI, 900 pulses) at 60% of resting motor threshold to inhibit the right or left primary motor cortex of 10 healthy individuals. Participants were examined before and after rTMS by a neurologist who was blind to the site of motor cortex inhibition. Results: 10 neurological intact participants (5 women/5 men) were recruited for this study. 2 cases were excluded due to pre-existing possible thumb signs. After the inhibition of the primary motor cortex, in 6 subjects out of 8, we observed a thumb sign contralateral to the site of primary motor cortex inhibition. In one subject an ipsilateral thumbs sign was noted. In another case, we did not find an upgoing thumb sign. Conclusion: The upgoing thumb sign is a subtle neurological finding that may be related to the primary motor cortex or corticospinal pathways involvements. PMID- 29260034 TI - The utility of ultrasound in showing a unique cause of posterior interosseous nerve syndrome. PMID- 29260035 TI - Successful systemic thrombolysis with rtPA in a patient with history of a life threatening rtPA-associated orolingual angioedema. PMID- 29260036 TI - Utility of nerve conduction studies for diagnosis of injury to the medial branch of the superficial radial nerve. AB - Introduction: The clinical utility of nerve conduction study (NCS) for the distal medial branch of the superficial radial nerve (SRN) has not yet been clarified. Therefore, we investigated the clinical utility of NCS in patients with suspected SRN injury and compared the results with those in healthy control subjects. Methods: Bilateral NCS of the medial branch of the SRN was performed in two patients with suspected injury of the medial branch of the SRN, and in 20 healthy control subjects. A surface recording electrode was placed at the medial side of the metacarpophalangeal joint of the thumb. The SRN was then stimulated at a location 12 cm proximal from the recording electrode. Results: The mean sensory nerve action potential in the two patients was significantly lower than that of the controls (6.75 +/- 0.92 vs. 23.8 +/- 8.2 MUV, P < 0.05). The side-to-side differences in sensory nerve action potential in the two patients were significantly higher than in the controls (55 +/- 7.1 vs. 11 +/- 7.8%, P < 0.05). Conclusions: NCS may be useful for diagnosing injury of the medial branch of the SRN. PMID- 29260037 TI - Cefepime induced neurotoxicity: A case series and review of the literature. AB - Cefepime is a fourth generation cephalosporin which is bactericidal for broad spectrum of organisms. This is a case-series of three patients who presented to our hospital with confusion secondary to cefepime use to treat urinary tract infection (UTI) and health care associated pneumonia (HCAP), after excluding other common etiologies of altered mental status (AMS). Of these three patients, one had progressive expressive aphasia and the other two demonstrated asynchronous myoclonic activity of the limbs. The symptoms were seen within four to five days of initiating the treatment and resolved within three days of discontinuation of cefepime. Acute structural abnormalities were excluded by computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. Electroencephalogram (EEG) showed diffuse slowing activity with triphasic waves consistent with encephalopathy. In one patient, renal function was within normal limits, whereas it was abnormal in two patients. To our knowledge, this is the first report of cefepime induced asynchronous myoclonus and expressive aphasia in a patient with normal kidney function. PMID- 29260039 TI - Intracerebral hemorrhage after IV tPA for stroke as early symptom of ANCA associated vasculitis. AB - Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare diseases characterized by a necrotizing small-vessel vasculitis and circulating ANCA that comprise granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (EGPA). Acute ischemic stroke (AIS) can be a manifestation of central nervous system (CNS) involvement in these diseases. Furthermore, intracerebral hemorrhage (ICH) is a potential complication of these necrotizing vasculitides. We describe a case of AAV who presented with acute ischemic stroke and developed multiple ICHs after administration of IV tPA. We propose that patients with AAV are more prone to develop hemorrhage in the presence of IV tPA and discuss the possible underlying pathogenesis. We suggest that AAV should be considered a contraindication for administration of IV tPA. PMID- 29260040 TI - Cognitive impairment in neuromyelitis optica spectrum disorders: A comparison of the Wechsler Adult Intelligence Scale-III and the Wechsler Memory Scale Revised with the Rao Brief Repeatable Neuropsychological Battery. AB - Background: Approximately 55% of patients with neuromyelitis optica spectrum disorder (NMOSD) show cognitive impairment as evaluated using the Rao Brief Repeatable Neuropsychological Battery (BRBN), but this frequency appears to be higher than the frequency of specific brain lesions in NMOSD. Objective: We studied whether cognitive impairment could be observed in NMOSD patients with no or minor non-specific brain lesions. Methods: We evaluated cognitive function in 12 NMOSD and 14 MS patients using the Wechsler Adult Intelligence Scale-III (WAIS III), the Wechsler Memory Scale-Revised (WMS-R), and the BRBN. We judged as cognitively impaired patients whose scores were below the average by 2 standard deviations or greater in 2 or more cognitive domains. Results: Cognitive impairment was observed in 5 MS patients (35.7%) and in the only NMOSD patient (8.3%) with symptomatic brain lesions, but not in the other NMOSD patients who had no or minor non-specific brain lesions. Meanwhile, 5 NMOSD (41.7%) and 4 MS (28.6%) patients who had normal cognition according to the WAIS-III and WMS-R were assessed as cognitively impaired by the BRBN (which is not standardized for age). Conclusions: Cognitive function in NMOSD patients with no or mild non specific brain lesions was preserved according to the WAIS-III and WMS-R. PMID- 29260038 TI - Can suitable candidates for levodopa/carbidopa intestinal gel therapy be identified using current evidence? AB - Advanced Parkinson's disease (APD) is characterized by increased functional disability, caused by motor complications, the presence of axial symptoms, and emergent disease- and drug-related non-motor symptoms. One of the advanced therapies available is intrajejunal infusion of levodopa/carbidopa intestinal gel (LCIG); however, patient selection for this treatment is sometimes difficult, particularly because of overlapping indications with other alternatives. In recent years, strong evidence has supported the use of LCIG in treating motor fluctuations associated with APD, and several clinical studies provide emerging evidence for additional benefits of LCIG treatment in certain patients. This article provides an overview of the published literature on the benefits, limitations, and drawbacks of LCIG in relation to PD symptoms, the psychosocial impact of the disease, and the quality of life of patients, with the aim of determining candidates for whom treatment with LCIG would be beneficial. According to current evidence, patients with APD (defined as inability to achieve optimal control of the disease with conventional oral treatment), a relatively well-preserved cognitive-behavioral status, and good family/caregiver would count as suitable candidates for LCIG treatment. Contraindications in the opinion of the authors are severe dementia and active psychosis. PMID- 29260041 TI - Cognitive functions in newly diagnosed patients with HIV infection in a tertiary health facility: Assessment using community screening interview for dementia. AB - Introduction: Neurocognitive dysfunction is a detrimental complication of HIV infection. In this study we attempt to characterize the pattern of cognitive dysfunction in a sample of Nigerian patients with newly diagnosed HIV infection. Methods: We conducted a prospective study in which 50 patients with newly diagnosed HIV infection were studied along with 50 normal control subjects. The participants were evaluated with the medical history, general, physical and neurological examination. Laboratory evaluation and chest X-Ray were done for all patients. The Community Screening Interview for Dementia (CSID) questionnaire was administered to all the study participants. Results: About 70% of the patients were in advanced disease stage. The mean age (SD) of the patients and controls in years were 36.44 +/- 8.22 and 35.40 +/- 11.53 respectively. More than half (56%) of the patients had secondary level of education (12 years of education). About 20% of the patients had severe neurocognitive impairment while 48% had minor neurocognitive disorder. The patients with HIV infection performed poorly in the domains of language, memory, orientation, attention/calculation and praxis relative to controls (p < 0.05).There were no significant effect of gender, age, sex and level of education on cognitive functions in the patients (p > 0.05) but the presence of opportunistic infections had negative impact on the performances on orientation and total CSID scores in the patients with HIV infection (p < 0.05). Conclusion: Patients with newly diagnosed HIV infection have poor cognitive functions when compared to normal controls and some presence of opportunistic infections in the patient is a significant risk factor for cognitive impairment. PMID- 29260042 TI - Conjunctival squamous papilloma refractory to interferon alpha-2b in a patient on systemic immunosuppression (tacrolimus). AB - Purpose: To describe a case of diffuse conjunctival papilloma in an immunocompromised individual on tacrolimus that was refractory to treatment with interferon alpha-2b, but responded to topical mitomycin-c. Observations: A 79 year-old Caucasian female with a history of a liver transplant twenty years ago, who was immunosuppressed with tacrolimus (2 mg daily) presented with a diffuse conjunctival and corneal squamous papilloma. Following treatment with four weekly subconjunctival interferon-alpha2b injections (3 million units/0.5 mL) and 3 months of topical interferon-alpha2b therapy (1 million units/mL), four times daily, slow progression was documented. The patient was switched to topical mitomycin-c drops (0.04%) administered four times daily (one week on and one week off) with dramatic regression of the tumor. Conclusions and importance: In cases of conjunctival squamous papilloma that do not respond readily to topical interferon, topical mitomycin-c is an alternate therapeutic option. We hypothesize that use of tacrolimus may have contributed to the lack of response to topical interferon-alpha2b. PMID- 29260043 TI - Oculocardiac reflex elicited by orbital floor fracture and inferior globe displacement. AB - Purpose: To review the physiology, presentation and management of the oculocardiac reflex (OCR) by describing a case of the OCR associated with an orbital foreign body and complete ocular prolapse through a large orbital floor fracture in a 40-year-old male following a motor vehicle accident. Observations: The patient demonstrated marked bradycardia and hypotension necessitating intubation and medical therapy for autonomic shock. A computed tomography (CT) showed a total blow out floor fracture and complete dislocation of a radiographically intact globe with uninterrupted rectus muscle attachments into the left maxillary sinus. He was taken to the operating room for urgent repair resulting in subsequent termination of severe OCR. Conclusions and importance: The oculocardiac reflex can precipitate marked bradycardia and hypotension in the setting of trauma with significant orbital and maxillofacial injury. Prompt identification and management with vagolytic agents or definitive surgical intervention may prevent morbidity or mortality. PMID- 29260044 TI - Isolated presumed optic nerve gumma, a rare presentation of neurosyphilis. AB - Purpose: The incidence of syphilitic infections continues to rise and represents a major public health concern, particularly in patients co-infected with human immunodeficiency virus (HIV). The infection has a multitude of clinical presentations and is often referred to as the 'great imitator.' We present a rare case of an isolated presumed syphilitic optic nerve gumma and characterize it using newer imaging modalities. Observations: A 36-year-old HIV-positive man, compliant with treatment, presented with a five day history of decreased vision in the left eye. On examination his visual acuity was 20/30 with mild dyschromatopsia and an inferior altitudinal field defect in the left eye. Funduscopy demonstrated small cup to disc ratios bilaterally and a swollen and hyperemic left optic disc. Following five months of stable vision, the patient's vision in the left eye declined to 20/60, associated with diffuse visual field loss and continued swelling of the left optic disc. Subsequent magnetic resonance imaging with contrast demonstrated enhancement of the left optic nerve, and his serologies were positive for syphilis. Fluorescein angiography and optical coherence tomography were used to better characterize the lesion being most consistent with a syphilitic optic nerve gumma. Conclusions and importance: Gummas of the central nervous system are a rare presentation of neurosyphilis and the last reported gumma of the optic nerve was in 1990. Such lesions have not been characterized using newer imaging modalities including optical coherence tomography and fluorescein angiography, both of which may assist in the diagnosis of this rare entity. With the increased prevalence of syphilis and remarkable response to therapy, syphilitic gummas should be considered in at-risk patients presenting with an optic neuropathy. PMID- 29260045 TI - A case of ophthalmomyiasis interna in the Pacific Northwest. AB - Purpose: We report a case of ophthalmomyiasis interna successfully removed in toto with pars plana vitrectomy. Observations: An 84-year-old woman with recent close contact with lambs presented with a new floater. Examination revealed subretinal tracks pathognomonic for ophthalmomyiasis and a larva suspended in the vitreous. The larva was successfully removed in toto with pars plana vitrectomy by aspiration through the vitreous cutter. Conclusions and importance: Aspiration with pars plana vitrectomy can be considered a primary therapeutic modality for botfly larvae suspended in the vitreous. In our case, in toto removal of the larvae reduced the risk of inflammatory reaction. PMID- 29260046 TI - Outcomes in bullous retinal detachment. AB - Purpose: To report two patients with giant retinal tear (GRT) associated retinal detachment in the setting of baseball trauma. Observations: Two patients presented with retinal detachment associated with GRT following blunt trauma with a baseball. The first was a superotemporal GRT detachment treated with scleral buckling, pars plana vitrectomy, endolaser, and silicone oil injection. He subsequently underwent cataract surgery with silicone oil removal and at two year follow up the retina with attached with best-corrected visual acuity of 20/20. The second case was an inferotemporal GRT detachment treated initially with laser demarcation, however the tear progressed to a retinal detachment that was then treated with pars plana vitrectomy and lensectomy, endolaser, perfluoro-octane (PFO), and silicone oil injection. At the one year follow up, the retina was attached and the best-corrected visual acuity was 20/30. Conclusions and importance: GRTs are an uncommon cause of retinal detachment. While pars plana vitrectomy with tamponade is standard in GRT management, there is variability in the use of scleral buckling and PFO in these cases. This is in contrast to retinal dialysis where scleral buckle alone can yield favorable results. Though a baseball ocular trauma is common, retinal involvement is rare compared to other sports injuries such as those occurring with tennis, soccer and golf. Sports trauma remains an important cause of retinal injury and patients should be counseled on the need for eye protection. PMID- 29260047 TI - Bilateral acute simultaneous onset anterior uveitis presumed secondary to erlotinib: A report of two cases. AB - Purpose: To report two new cases of presumed erlotinib-associated bilateral acute simultaneous-onset anterior uveitis effectively treated with topical steroids. Observations: Two patients were referred to the uveitis clinic with bilateral acute simultaneous onset, anterior uveitis six weeks after starting the chemotherapeutic agent erlotinib. Frequent topical steroid were started and the inflammation responded swiftly and completely. Conclusions and importance: Bilateral acute simultaneous onset anterior uveitis is a potential side effect associated with erlotinib use that has not been well described. Physicians should be aware of this potential association in patients with recent treatment with erlotinib who complain of blurred vision, photophobia, or redness of the eyes. In some cases, the inflammation responds well to topical therapy and medication can be continued. PMID- 29260048 TI - Optical coherence tomography angiography of iris microhemangiomatosis. AB - Purpose: To report optical coherence tomography angiography (OCTA) of iris microhemangiomatosis. Observations: A 75-year-old asymptomatic Caucasian man was found to have bilateral pupillary vascular lesions during cataract evaluation. Visual acuity was counting fingers in the right eye (OD) and 20/40 in the left eye (OS) with normal intraocular pressures in both eyes (OU). In each eye there were multifocal, round, dark red, pinpoint vascular tufts at the pupillary margin, randomly distributed and numbering 1 in OD and 7 in OS, each measuring 0.2-0.3 mm in diameter and without active bleeding or hyphema. Fundus examination OU was normal. By fluorescein angiography, the multifocal pupillary vascular tufts demonstrated mild staining without leakage. By OCTA, the tufts were clearly delineated and were fed by normal appearing radial iris vessels. OCT b-scan documented the optically dense vascular tufts at 0.1 mm in thickness and angio overlay confirmed blood flow emanating from the deep iris stroma. Observation was recommended with the option of cataract surgery to improve vision. Conclusions and importance: Non-invasive imaging of iris microhemangiomatosis with OCTA delineates the vascular lesion with flow arising from the posterior iris stroma. PMID- 29260049 TI - Incontinentia pigmenti with secondary Raynaud's phenomenon: A case report and review of the literature. AB - Purpose: To describe a patient with incontinentia pigmenti (IP) and Raynaud's phenomenon (RP). Observations: A 5 year-old girl with history of IP was noted to have RP. Visual acuity was unaffected in both eyes, and fundus examination demonstrated regressed peripheral neovascularization. Photos of the patient's hands demonstrated pale discoloration associated with exposure to cold. Conclusions and importance: IP, known to affect small cerebral and retinal blood vessels, can also affect the small blood vessels in the extremities, resulting in secondary RP. PMID- 29260050 TI - Severe corneal ulcer with progression to endophthalmitis and high-grade bacteremia. AB - Purpose: Bacterial sepsis is a common consequence of many infectious processes. Here, we describe a case of a woman with a corneal ulcer who went on to develop group B streptococcal (GBS) endophthalmitis, bacteremia, and eventual loss of the eye. Observations: A previously healthy, immunocompetent, middle aged, contact lens wearing female who, after freshwater boating in her contact lenses, developed a red, painful eye. She was initially prescribed an hourly topical steroid by an outside optometrist but worsening of her condition prompted her to present to our Emergency Department. Despite aggressive initial management, the patient went on to develop GBS endophthalmitis, sepsis with high-grade bacteremia, and eventual loss of the eye. Conclusions and importance: Eye care providers should exercise caution when prescribing frequent, potent corticosteroids when an infectious etiology is in the differential diagnosis. PMID- 29260051 TI - A case of complex macula-off retinal detachment following traumatic globe rupture. PMID- 29260052 TI - Spasm of the near reflex: A case report. AB - Purpose: Spasm of the near reflex (SNR) is a triad of miosis, excess accommodation and excess convergence. Primary SNR is most often functional in origin We aim to highlight the clinical features which distinguish primary convergence from other conditions with a similar presentation but more sinister underlying aetiology, for example bilateral abducens nerve palsy. Observations: There is a paucity of published data on SNR, in particular diagnostic criteria and treatment. We report a case of SNR of functional origin in an otherwise healthy young female and discuss the clinical features that differentiate this condition from similar conditions with underlying neurological origin. Conclusions and importance: SNR is predominantly a clinical diagnosis, and often leads to patients undergoing unnecessary investigations and sometimes treatment. Recognising the salient features that differentiate it could potentially avoid this. PMID- 29260053 TI - Identifying rhegmatogenous detachments in bullous retinoschisis with optical coherence tomography studies. AB - Purpose: To demonstrate a novel technique for capturing optical coherence tomography images of peripheral retina and its application in identifying rhegmatogenous retinal detachments within bullous retinoschisis. Observations: We report two patients presenting with bullous retinoschisis noted on clinical examination. After performing optical coherence tomography studies utilizing our image acquisition technique these lesions were found to be associated with rhegmatogenous retinal detachments. Both patients were subsequently treated without further complications. Conclusions and importance: The image acquisition technique described herein allows visualization of peripheral retina utilizing optical coherence tomography studies to identify areas of rhegmatogenous retinal detachment within bullous retinoschisis that are otherwise difficult to discern. PMID- 29260054 TI - The superficial and deep retinal capillary plexus in cases of fovea plana imaged by spectral-domain optical coherence tomography angiography. AB - Purpose: To describe the appearance of the superficial and deep retinal capillary plexi in three patients with fovea plana of differing severity using spectral domain optical coherence tomography angiography (OCTA). Observations: In the first case of grade 1 fovea plana (a patient with 20/25 vision), OCTA showed an orderly branching pattern of vessels from the superficial and deep retinal plexi extending to the center of the fovea. The second case of grade 3 fovea plana (20/30 vision) showed some disruption of the orderly vascular pattern with small caliber vessels from both superficial and deep layers densely covering the fovea center. Case 3 represented a patient with grade 4 fovea plana associated with PAX6 mutation and poor visual acuity. OCTA revealed a disorganized pattern of large and small caliber vessels from the superficial capillary network extending into the center of the fovea. Conclusions and importance: Previously available imaging modalities were unable to specifically target different layers of the retinal vasculature. Using OCTA we have been able to show progressive changes in the vascular pattern in the deep and superficial retinal layers of patients with different grades of fovea plana. This novel imaging technique may play a role in the classification and assessment of patients with fovea plana. PMID- 29260055 TI - Isolated endogenous Fusarium endophthalmitis in an immunocompetent adult after a thorn prick to the hand. AB - Purpose: To report the case of an immunocompetent adult presenting with endogenous Fusarium endophthalmitis. Observations: A woman in her thirties presented with symptoms and signs of a unilateral anterior uveitis. After initial improvement with topical corticosteroids, she continued to develop a panuveitis with an associated drop in vision to counting fingers. A vitreous biopsy confirmed Fusarium solani by 18S rRNA fungal gene detection and PCR sequencing. Despite treatment with pars plana vitrectomy, intravitreal amphotericin B and systemic voriconazole her visual outcome was poor. Detailed review of her antecedent history revealed the route of acquisition to be a thorn prick to the hand two weeks prior to presentation. Conclusions and importance: This patient's endophthalmitis most likely resulted from cutaneous inoculation of Fusarium solani with subsequent hematogenous spread. Endogenous Fusarium endophthalmitis is well recognized in the immunocompromised but is very rarely seen in the immunocompetent. This case highlights the importance of thorough history-taking and consideration of fungal endophthalmitis in the differential diagnosis of a treatment-refractory uveitis. PMID- 29260056 TI - Corneal edema and keratitis following selective laser trabeculoplasty. AB - Purpose: To describe three cases of keratitis following Selective Laser Trabeculoplasty (SLT). Observations: Three females with a history of glaucoma presented with corneal edema, keratitis (endothelial, epithelial) and decreased visual acuity shortly after SLT. There was variable resolution of symptoms after starting treatment with oral antiherpetics and topical steroids. Conclusions and importance: With the increase in usage of SLT as a treatment for glaucoma and subsequent reports of keratitis, it is imperative for ophthalmic surgeons to be aware of herpes simplex as a possible risk factor. Prompt treatment with antivirals and steroids can potentially prevent scarring and permanent damage to the cornea. PMID- 29260057 TI - Case report of the family transmission of Streptococcus pyogenes orbital cellulitis. AB - Purpose: This is a case report of an unusual case of the family transmission of Streptococcus pyogenes infection in three siblings. One brother contracted the infection which resulted in orbital cellulitis of two of his siblings, in the absence of anatomical or immunological predisposing factors. Observations: A young boy contracted an uncomplicated S pyogenes upper respiratory tract infection. The twin brother closely followed by the older sister both developed a S pyogenes orbital cellulitis a couple of days later. Conclusions and importance: To our knowledge, this is the first case ever reported of family transmission of orbital cellulitis. This highlights the importance of early diagnosis and treatment of S pyogenes, and the role of throat cultures as means of diagnosis even in the absence of symptoms or signs of pharyngitis. PMID- 29260058 TI - A case of non-arteritic anterior ischemic optic neuropathy after completion of Harvoni therapy. AB - Purpose: To report the first reported case of non-arteritic anterior ischemic optic neuropathy (NAION) associated with the use of Harvoni (Gilead Sciences, Foster City, CA, USA), a newly approved treatment for Hepatitis C. Observations: We report a case of NAION in a hepatitis C patient who completed Harvoni therapy just prior to presentation. Harvoni was suspected to be the causative agent given a lack of NAION risk factors in an otherwise healthy young patient. Conclusions and importance: NAION is an acute, painless vision loss that typically affects adults over 50. The mechanism of NAION remains uncertain although numerous associations have been identified including certain medications. Harvoni, a combination drug of ledipasvir/sofosbuvir, is a recently FDA-approved treatment for Hepatitis C. To date, however, no ophthalmological side effects have been reported with its use. Continued surveillance of patients treated with Harvoni will be needed to determine if additional events are observed in the future. PMID- 29260059 TI - Hypertensive crisis with massive retinal and choroidal infarction. PMID- 29260060 TI - Ciliary body metastasis from renal cell carcinoma successfully treated with intravitreal bevacizumab. AB - Purpose: To report an innovative new treatment option for ciliary body tumor metastasis from renal cell carcinoma treated with intravitreal bevacizumab. Observations: A 70-year-old Caucasian man presented with a ciliary body tumor as a result from metastasis from renal cell carcinoma. It was preferable to treat the ciliary body tumor in the least invasive manner possible based on the patient's health, systemic metastasis, and the invasiveness of local resection. The tumor was treated with intravitreal bevacizumab for attempted tumor regression. Complete tumor resolution occurred following three injections. Conclusions and importance: There is no consensus on treatment for ciliary body metastases from renal cell carcinoma. Based on the successful result of our patient, intravitreal bevacizumab could be an acceptable treatment option for this type of intraocular tumor. It affords a relatively non-invasive method of tumor regression without undergoing major intraocular surgery. PMID- 29260061 TI - Femtosecond laser-assisted cataract surgery in anterior lenticonus due to Alport syndrome. AB - Purpose: We describe a case of bilateral anterior lenticonus in a patient with Alport syndrome treated with femtosecond laser-assisted cataract surgery (FLACS). Observations: FLACS was performed without complication, and a desirable postoperative visual acuity was achieved. Conclusions and importance: Femtosecond laser-assisted cataract surgery is an effective approach for managing patients with anterior lenticonus secondary to Alport syndrome. PMID- 29260062 TI - Cavernous sinus syndrome associated with metastatic colorectal cancer and perineural spread along the trigeminal nerve. AB - Purpose: We report the case of a patient with cavernous sinus syndrome associated with biopsy-confirmed metastasis from colorectal cancer. Observations: A patient known for laryngeal carcinoma and metastatic colorectal carcinoma presented with symptoms of left trigeminal neuralgia and progressive, near-complete ophthalmoplegia. Magnetic resonance imaging (MRI) revealed a mass in the left cavernous sinus, extending into Meckel's cave with perineural spread along the mandibular branch of the left trigeminal nerve. A transsphenoidal biopsy was performed and demonstrated metastatic colon adenocarcinoma. We review the existing literature on colorectal cancer associated cavernous sinus syndrome. Conclusions and importance: Cavernous sinus metastasis from colorectal cancer is exceedingly rare. We report the second case of this entity with histopathologic confirmation, and the first case with concurrent perineural spread involving the trigeminal nerve. Cavernous sinus metastasis may represent a poor prognostic factor in colorectal cancer. PMID- 29260063 TI - Results with the Boston Type I keratoprosthesis after Acanthamoeba keratitis. AB - Purpose: To report the outcomes of implantation of the Boston Type I keratoprosthesis in three patients with Acanthamoeba keratitis (AK), a severe infection that can lead to significant visual loss. Observations: Case series reporting three patients with difficult cases of AK that needed multiple corneal transplantations and glaucoma surgeries. All patients were implanted with the Boston Type I keratoprosthesis device. The main outcomes measure were the visual function and anatomical retention after implantation of the Boston Type I keratoprosthesis. All patients retained the device over the long-term and had good visual function. In one patient a retroprosthetic membrane developed and in another patient an epithelial lip developed over the anterior surface of the keratoprosthesis. The visual acuities range from 20/25 to 20/80 in the implanted eyes. Conclusions and importance: The Boston Type I keratoprosthesis resulted in good anatomic and functional results after multiple graft failures after AK. PMID- 29260064 TI - Bilateral uveitis following intravenous immunoglobulin administration. AB - Purpose: To report a case of bilateral acute anterior uveitis in an adult female occurring following the administration of intravenous immunoglobulin (IVIG). Observations: A 44-year-old female patient was commenced on IVIG following presentation to hospital with upper limb neuropathic pain. Within two days, she developed bilateral red, painful photophobic eyes. Examination revealed bilateral acute anterior uveitis and IVIG was ceased. Investigations for autoimmune or infective causes for the uveitis were unremarkable. Complete resolution of the uveitis was achieved with topical corticosteroids and cessation of IVIG. Conclusions and importance: Clinicians should be aware of the possibility of uveitis as an adverse effect of IVIG. Early identification of the offending medication and its cessation in this case were associated with a good visual prognosis. PMID- 29260065 TI - Purtscher's retinopathy as the presenting manifestation of immune thrombocytopenic purpura. AB - Purpose: To report the case of a 52-year-old man with Purtscher's retinopathy as the presenting manifestation of immune thrombocytopenic purpura (ITP). Observations: Treatment with corticosteroids led to the resolution of hematologic findings within 1 week, and normal visual acuity was achieved after 2 months with no additional treatment. Conclusions and importance: This is the first reported association between Purtscher's retinopathy and ITP. Complement activation has been implicated in the pathogenesis of both ITP and Purtscher's retinopathy, and we suggest that the patient's systemic process accounted for the retinal findings. PMID- 29260066 TI - Acute up-beating nystagmus in a pregnant woman with hyperemesis gravidarum. AB - Purpose: To describe a case of sudden onset of nystagmus in a pregnant patient with hyperemesis gravidarum. Observations: Sixteen days after onset of persistent nausea and uncontrollable vomiting, a 12 week pregnant woman presented up-beating nystagmus, mild memory impairment and reduced sensitivity in the lower limbs. Laboratory tests presented thiamine deficiency and magnetic resonance imaging showed bilateral medial thalami and midbrain lesions. Because of suspected Wernicke's encephalopathy, the patient was treated with thiamine replacement and significant improvement of symptoms took place. Conclusions and importance: Uncontrollable vomiting can lead to malabsorption of vitamin B1 causing acute onset of nystagmus. PMID- 29260067 TI - Severe bilateral optic nerve and retinal hypoperfusion in a patient with acute respiratory distress syndrome and septic shock. AB - Purpose: To report a case of bilateral central retinal artery occlusion with both anterior and posterior ischemic optic neuropathy. Observations: A 65-year-old Caucasian woman presented with acute respiratory distress syndrome and septic shock. After treatment with vasopressors and prolonged prone positioning, she was noted to be bilaterally completely blind on hospitalization day 12. Evaluation revealed evidence of bilateral central retinal artery occlusion and bilateral ischemic optic neuropathy. Magnetic resonance imaging of the orbits demonstrated severe restricted diffusion of both optic nerves consistent with ischemia. Both central retinal artery occlusion and ischemic optic neuropathy have been reported in cases of severe hypotension, blood loss, and prone positioning, most often postoperatively after spinal surgery. Conclusions and importance: To our knowledge, this is the first reported case of bilateral central retinal artery occlusion with both anterior and posterior ischemic optic neuropathy, presumed due to the combination of severe systemic hypotension, hypoxemia due to the respiratory distress syndrome, and prolonged prone positioning. PMID- 29260068 TI - Tuberculous uveitis presenting as pigmented hypopyon - A case report. AB - Purpose: Hypopyon in the eye is an alarming sign. A case of tuberculous uveitis which presented with pigmented hypopyon has been described. The aim of this paper is to report pigmented hypopyon, a rare presentation of tuberculous uveitis in a diabetic patient. Observations: A 42-year-old patient with diabetes with a known history of miliary tuberculosis, on anti-tubercular therapy since two months presented with complaints of pain and redness followed by diminution of vision in the right eye since one month. Visual acuity was counting fingers close to face in right eye. Anterior chamber (AC) showed grade 4 cells and flare with a pigmented hypopyon measuring two mm. Fundus details were not made out. B scan revealed increased choroidal thickness with moderate vitritis. Routine blood counts revealed leucopenia and anemia suggestive of an immunosuppressed state. AC tap analysis was not helpful in diagnosis initially. Patient was lost to follow up and presented one month later with three - fourth of AC having hypopyon. AC wash was done and the AC sample evaluation revealed acid fast bacilli. Polymerase chain reaction results confirmed it to be Mycobacterium tuberculosis. Conclusions and importance: Tuberculous anterior uveitis thus presenting as pigmented hypopyon is very rare and can cause diagnostic difficulties. High index of suspicion in tuberculosis endemic areas is a must for a prompt diagnosis. A possible association between immunosuppression and pigmented hypopyon may exist and needs to be studied further. PMID- 29260069 TI - Atypical intravitreal growth of retinoblastoma with a multi-branching configuration. AB - Purpose: To report the clinical and histopathological findings of atypical intravitreal growth of a retinoblastoma with a multi-branching configuration. Observations: A 7-month-old boy was referred to our hospital due to leukocoria in the right eye. Ophthalmic examinations identified multi-branching vessels surrounded by diaphanous tissue behind the lens in the right eye. Imaging modalities showed microphthalmos, band-shaped calcification, and cystic lesions in that eye. Because it was difficult to rule out congenital anomalies such as persistent fetal vasculature due to the atypical clinical features of retinoblastoma, we performed a biopsy using a limbal approach. An intraoperative rapid pathological examination led to the definitive diagnosis of retinoblastoma. The right eye was enucleated and postoperative adjuvant chemotherapy was administered. Immunohistochemical staining of the enucleated eyeball showed that the tumoral cells and diaphanous tumoral tissue around the vessels were positive for neuron-specific enolase and Ki-67 and partially positive for glial fibrillary acidic protein (GFAP). The vessels of the diaphanous tissues near the tumoral mass were stained by GFAP and those behind the lens were stained faintly. Conclusions and importance: We described an atypical retinoblastoma of pseudo persistent fetal vasculature with a multi-branching configuration, which expanded the clinical spectrum of retinoblastoma. Such a specific growth pattern of the embryonic tumor might occur with a combination of retinal development, retinal vasculature, and hyaloid vascular system. PMID- 29260070 TI - Ocular dirofilariasis: Ophthalmic implication of climate change on vector-borne parasites. AB - Purpose: To describe a geographically rare case of ophthalmic dirofilariasis. Observations: An 81-year-old male of good socioeconomic status living in the state of Michigan in the United States, presented to the eye clinic with a painful red left eye. He had not traveled outside of the state of Michigan in over three years. He was found to have a 7 cm long subconjunctival roundworm, which was ultimately extracted. Conclusions and importance: With increasing global temperatures, ocular dirofilariasis is being introduced in more northern climates and should be included in the differential diagnosis in areas previously isolated from these vector-borne parasites. PMID- 29260071 TI - Transient anisocoria in a patient treated with nebulized ipratropium bromide. AB - Purpose: We present a case report of a 44-year old female patient with complicated pneumonia who developed anisocoria after treatment with inhaled ipratropium bromide. Discontinuation of ipratropium bromide treatment led to complete resolution of anisocoria. Observation: A 44-year old female patient was admitted to the Department of Pulmonology due to high body temperature (40.0 degrees C), coughing and general weakness. After a general examination and tests the patient was diagnosed with right-sided pneumonia. Since spirometry test showed signs of bronchial obstruction, pulmonologist indicated inhalation therapy with ipratropium bromide. Soon after ipratropium bromide therapy was initiated, the patient noticed enlarged left pupil and stated that some aerosol reached her left eye during the inhalation therapy. After consulting neurology and monitoring neurological signs, ipratropium bromide treatment was discontinued. Twenty-four hours after discontinuing the ipratropium bromide treatment anisocoria was completely resolved. Conclusions and importance: Presence of anisocoria may be a concerning neurological sign. If there are no other neurological or ophthalmological signs and symptoms and a recent ipratropium bromide inhalation treatment exists in the patient's history, we should consider iatrogenic side effect of drugs as a possible reason of anisocoria and possibly spare the patient extensive and invasive diagnostic procedures that can also raise costs of treatment significantly. Observing neurological status and testing with 1% pilocarpine solution may be necessary to determine the etiology of this condition. PMID- 29260072 TI - Orbital 'pseudo-abscess' in a patient with spontaneous subluxation of globe: A case report. AB - Purpose: We describe this case and review the literature, to allow this to be a cautionary tale in the interpretation of fluid collections in the setting of spontaneous globe subluxations (GS). Observations: A 58 year old female, with a past medical history of globe subluxation, was diagnosed radiographically with an orbital abscess, and managed with an orbitotomy. However, no abscess was identified operatively and subsequent imaging showed only extravasation of serous fluid. Conclusions and importance: We postulate that in the case here, the fluid collection posterior to the globe was in fact due to increase venous congestion and decrease venous return posteriorly from the globe to the cone, leading to an efflux of clear serous fluid. We postulate that in the case of GS without other clinical indications suggesting orbital abscess one can consider a posterior globe collection of fluid to be an extravasation of serous fluid, secondary to increased venous congestion. PMID- 29260073 TI - Endothelial keratoplasty for posterior polymorphous corneal dystrophy in a 4 month-old infant. AB - Purpose: To report a case of endothelial keratoplasties (EKs) performed in a 4 month old with a posterior polymorphous corneal dystrophy. Observations: A 4 month old infant underwent Descemet membrane endothelial keratoplasty (DMEK) for posterior polymorphous corneal dystrophy. The graft was found to be dislocated on day 5 post-operatively and an attempt to unfold the DMEK scroll and re-bubble was not successful. The patient was then treated successfully with bilateral Descemet stripping automated endothelial keratoplasty (DSAEK). At 3 years of follow-up, her visual acuity was 20/70 in the right and 20/60 in the left eye with good endothelial cell counts. Conclusions and importance: and Importance: This study reports the youngest case of EKs performed at the age of 4 months in an infant. This is also the first reported case of attempted DMEK highlighting its challenges in infants. DSAEK remains a good treatment option for endothelial dysfunction secondary to posterior polymorphous corneal dystrophy in infants even after failed DMEK. PMID- 29260074 TI - Bilateral orbital marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue in a patient with hepatitis B virus infection. AB - Purpose: To report a case of marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the bilateral orbit with chronic hepatitis B virus (HBV) infection. Observations: A 72-year-old man with chronic HBV infection presented with a bilateral proptosis with slight restriction of ocular motility for 9 months. Computed tomographic images showed well-defined, isodense masses in the bilateral superolateral orbit. Magnetic resonance images showed isointense on T1-and hyperintense on T2-weighted images, with bilateral involvements of the lateral rectus muscles reaching the superior orbital fissures. These masses molded along the globe contour. Incisional biopsies via upper eyelid crease were performed on both lesions. The immunohistopathological diagnosis was MALT lymphoma. Conclusions and importance: This case showed a possible association between orbital MALT lymphoma and HBV. PMID- 29260075 TI - Topiramate-induced macular neurosensory retinal detachment. AB - Purpose: To present a previously unreported retinal side-effect from topiramate use in two cases. Observations: Macular neurosensory retinal detachments were seen in two patients shortly after beginning oral topiramate. The macular detachments resolved shortly after discontinuing this medication. Conclusions and importance: As these two cases represent the first reports of topiramate-induced macular neurosensory retinal detachment, clinicians should be aware of this potential ocular side effect when administering this medication. PMID- 29260076 TI - Melanosis oculi. PMID- 29260077 TI - Femtosecond laser-assisted cataract surgery and implantable miniature telescope. AB - Purpose: This paper is a case report of the use of femtosecond laser for cataract surgery to implant an implantable miniature telescope for a patient with large central areas of geographic atrophy. Observations: On postoperative day 1 the patient's uncorrected visual acuity at near was 20/50. The cornea was clear and the patient reported no problem with navigation without occupational therapy training. Conclusions and importance: To our knowledge and confirmed by the manufacturer of the implantable miniature telescope this is the first case ever reported of a patient who has undergone femtosecond laser cataract surgery with corneal astigmatism correction and implantation of the implantable miniature telescope. This is also the first case report of the preoperative use of microperimetry and visual electrophysiology to evaluate a patient's postoperative potential visual acuity. The success of the procedure illustrated the importance of meticulous preoperative planning, the combined use of state-of-the-art technologies and the seamless teamwork in order to achieve the best clinical outcome for patients who undergo implantation of the implantable miniature telescope. PMID- 29260078 TI - Reversal of carotid dissection-induced ocular and cerebral ischemia by stenting. AB - Purpose: To present an example of how close clinical monitoring of a patient with acute Horner syndrome from carotid artery dissection may be critical in reversing neurologic dysfunction. Observations: A patient whose initial neuro-ophthalmic manifestation was Horner syndrome, but who evolved over 14 days to display transient monocular vision loss, ipsilateral ocular ischemic syndrome, and episodic contralateral hemiparesis. Digital subtraction angiography demonstrated progressive ipsilateral carotid occlusion with lack of collateral flow. The patient underwent stenting with rapid reversal of transient monocular visual loss and hemiparesis. Follow-up examination several months later confirmed complete resolution of all clinical abnormalities. Conclusions and importance: This case displayed protracted evolution of ischemic manifestations following carotid artery dissection and their prompt reversal with stenting. This case emphasizes the value of close clinical attention to a patient with acute Horner syndrome because manifestations may appear more than 10 days after event onset that impel intervention for the dissection. PMID- 29260079 TI - A stepping stone in treating dendritic keratitis. AB - Purpose: To report the outcome of self-retained amniotic membrane after debridement in recurrent dendritic keratitis. Observations: A 70-year-old female with a recurrent dendritic corneal ulcer received debridement followed by placement of self-retained amniotic membrane. Five days after treatment, the patient experienced a complete resolution of symptoms, marked reduction of inflammation, complete re-epithelialization of the cornea and improvement of visual acuity. The corneal surface remained stable for 18 months despite noncompliance in using antiviral therapy. Conclusions and importance: Self retained amniotic membrane after debridement appears effective in treating dendritic keratitis. While early debridement is crucial to remove the infected corneal epithelium, amniotic membrane was shown to enhance the healing without scarring or recurrence. Besides the known anti-inflammatory and anti-scarring effects of the amniotic membrane, it may have a potential topical antiviral effect that warrants further investigation. PMID- 29260080 TI - Moraxella atlantae keratitis presenting with an infectious ring ulcer. AB - Purpose: Moraxella atlantae is a rare pathogen. Keratitis from this organism has never been specifically reported or described. In this report we provide the first clinical description and photograph of Moraxella atlantae infectious keratitis. Observations: A 41 year-old man presented with a three day history of left eye pain. He was found to have a corneal ring ulcer and infiltrate from which Moraxella atlantae was cultured. The patient was successfully treated with intensive topical gatifloxacin (0.5%) and fortified tobramycin (1.5%); oral doxycycline was added to reduce corneal thinning. The patient's infection resolved with a residual scar and final best corrected visual acuity of 20/200 OS. Conclusions and importance: Moraxella atlantae can present as a ring-shaped infectious corneal infiltrate and ulcer. Ring infiltrates have been observed with other microorganisms, including several other gram negative bacteria and classically, acanthamoeba. Frequently presumed to be purely immunologic, corneal ring infiltrates can have a number of other etiologies, including infectious and toxic. There are different types of immunologic rings as well, making differentiation of corneal rings sometimes difficult for the ophthalmologic generalist and subspecialist alike. In this paper we discuss characteristics of various corneal ring infiltrates, along with their immune pathophysiology. Infectious rings are distinguished from immunologic Wessely rings. PMID- 29260081 TI - Bilateral cataract formation via acute spontaneous fracture of the lens following treatment of hyperglycemic hyperosmolar syndrome. AB - Purpose: Acute development of cataracts that may be transient is known to occur during correction of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Nettleship in 1885 was the first to describe the presence of a transient cataract in three diabetic patients that grew worse and eventually cleared with treatment.1 We present a case of irreversible cataracts formed by nuclear fracture of the crystalline lens after hyperglycemia correction, an entity that has not yet been described. Observations: A 67 year-old Caucasian man presented with sudden bilateral vision loss one week after a week-long hospitalization in the intensive care unit for correction of hyperglycemia in the setting of hyperglycemic hyperosmolar syndrome requiring an insulin drip. This was caused by spontaneous fractures of the lens nuclei causing bilateral irreversible cataracts. The patient underwent uncomplicated bilateral cataract extraction resulting in restoration of normal vision. Conclusions and importance: Acute transient cataracts that develop during correction of hyperglycemic hyperosmolar syndrome are thought to result from osmotic lens swelling. In this case report, internal fracture of the lens was produced by mechanical forces generated in the process of lens swelling occurring as a consequence of initial hyperglycemia and its subsequent correction. This case represents a rare ocular complication of hyperglycemia correction, and provides new evidence that mechanical forces can be part of diabetic cataractogenesis. PMID- 29260082 TI - Resection and anterior transposition of the inferior oblique muscle for treatment of inferior rectus muscle hypoplasia with esotropia. AB - Purpose: To report a case of inferior rectus muscle hypoplasia with esotropia, which was treated successfully by resection and anterior transposition of the inferior oblique muscle. Observations: A 1-year-old boy presented with esotropia. He had esotropia of 15-30 degrees and intermittent left hypertropia. At the age of 3 years, the alternate prism cover test showed esotropia of 35Delta and left hypertropia of 25Delta. Magnetic resonance imaging of the orbit revealed left inferior rectus muscle dysgenesis. Strabismus surgery was performed and a hypoplastic left inferior rectus muscle was identified. We performed bilateral medial rectus muscle recession, and resection and anterior transposition of the left inferior oblique muscle. Nine months after the surgery, the patient had esotropia of 8Delta and left hypertropia of 6Delta. Conclusions and importance: Resection and anterior transposition of the inferior oblique muscle is useful for hypoplasia of the inferior rectus muscle accompanied by horizontal strabismus. PMID- 29260083 TI - Lithium-induced downbeat nystagmus. AB - We report the case of a 76-year old lady under lithium carbonate for a bipolar disorder who presented with a suspected optic neuritis. A typical lithium-induced downbeat nystagmus was observed. Discontinuation of lithium therapy resulted in frank improvement in visual acuity and disappearance of the nystagmus. PMID- 29260084 TI - Metallic intraocular foreign body as detected by magnetic resonance imaging without complications- A case report. AB - Purpose: To describe a case and present unique images of a metallic intraocular foreign body that was identified in a 12-year-old male patient who underwent routine magnetic resonance imaging (MRI) to assess neurodevelopmental delay. Observations: We present MRI and diagnostic imaging of a metallic intraocular foreign body in a young patient with no known history of trauma or reason for the existence of metal in the eye area. Computed tomography scan was performed to confirm the presence of the intraocular foreign body, followed by optical coherence tomography and electroretinogram to assess visual status. It was determined that no surgical intervention was currently required as no visual impairment or ocular toxicity was identified. The patient continues to be monitored. Conclusions and importance: This case presentation highlights the novel imaging features of a metallic intraocular foreign body, unexpectedly detected with MRI. PMID- 29260085 TI - Migration of segmental arteriolar fluorescein staining peripherally in eye with idiopathic recurrent branch retinal arterial occlusion. AB - Purpose: To report a novel finding in a case of idiopathic recurrent branch retinal arterial occlusions. Observations: We report our findings in a 31-year old woman with an idiopathic recurrent branch retinal arterial occlusions (BRAOs) who was followed in our clinic for 16 years. Repeated fluorescein angiographies were performed to evaluate the idiopathic recurrent BRAOs. The findings showed multiple segmental arteriolar staining in the fundus. These staining were found at locations with and without branch retinal arterial occlusions. Repeated fluorescein angiography showed that these staining migrated toward the periphery. The speed of the migration of the staining was about 0.64 +/- 0.22 mm/day with a range of 0.43-0.85 mm/day in the posterior pole of the eye. In each of the BRAO, the staining did not cause branch retinal arterial occlusions in the peripheral retina again. Conclusions and importance: Segmental arteriolar staining that migrates towards the periphery may be a clue to the etiology of this disease process. PMID- 29260087 TI - Optical coherence tomography angiography of diffuse unilateral subacute neuroretinitis. AB - Purpose: Diffuse unilateral subacute neuroretinitis (DUSN) is often a challenging diagnosis to make. We present a DUSN case with its multimodal imaging to aid in the diagnosis, emphasizing the observations on optical coherence tomography angiography (OCTA). Observations: The evolution of a DUSN case is presented. Fundus photography and OCTA aided in the identification of the nematode. Conclusions and importance: DUSN is a difficult diagnosis to establish. We report the first case to our knowledge in which OCTA aided in the diagnosis of DUSN. PMID- 29260086 TI - Retinal findings in membranoproliferative glomerulonephritis. AB - Purpose: To assess the evolution of retinal findings in patients with membranoproliferative glomerulonephritis (MPGN) by funduscopy, intravenous fluorescein angiography and optical coherence tomography. Observations: Three women and one man were followed for a period of 1.5-37 years. Four patients (8 eyes) had drusen detected at first fundus exam at age 24, 29, 50 and 55. Three patients (6 eyes) had diffuse thickening of Bruch's membrane, and two patients (3 eyes) had detachment of the retinal pigment epithelium with serous retinal detachment. Drusen tended to widen over a period of 10-year follow-up in one case. Conclusions and importance: Drusen remain the ocular stigmata for MPGN occuring at an early age. The retinal disease is progressive with gradual thickening of Bruch's membrane and occurrence of retinal pigment epithelium detachment. PMID- 29260088 TI - Acute hypotony maculopathy following the initiation of a topical aqueous suppressant in a patient with a history of panuveitis without prior filtering surgery. AB - Purpose: To report a case of profound hypotony maculopathy as a complication of single-agent glaucoma therapy in a patient with a history of panuveitis without previous filtering surgery. Observations: A 70-year old Hispanic male with a history of resolved bilateral panuveitis, chronic angle closure glaucoma, and pars plana vitrectomy was started on topical timolol 0.5% daily in the left eye for mildly elevated intraocular pressure (15 mmHg). The patient returned 1.5 weeks later with new onset hypotony (1 mmHg), chorioretinal folds, and cystoid macular edema in the same eye without associated signs of inflammation. The drop was discontinued. The patient returned 1 month later with normalized eye pressure and improved vision with near-resolution of chorioretinal changes on optical coherence tomography (OCT). Conclusions and importance: Hypotony maculopathy is most commonly seen following glaucoma filtering surgery and ocular trauma. The development of hypotony maculopathy following the administration of topical glaucoma medication alone is rare. Our case is the first to our knowledge to describe the rapid onset of visually significant hypotony maculopathy characterized by profound OCT changes upon the administration of a single topical glaucoma agent in a patient without prior filtering surgery. Treatment with glaucoma medications in patients with complex ocular histories including uveitis and vitreoretinal surgery requires caution and close follow-up. PMID- 29260089 TI - Neovascularization of the iris in retinoschisis. AB - Purpose: To report the association of rubeosis iridis with chronic bullous degenerative peripheral retinoschisis. Observations: A 63-year-old female presented with acute hyphema and neovascularization of the iris in association with elevated intraocular pressure. Posterior segment examination including imaging revealed no vascular occlusion as a potential cause. However, large, peripheral bullous retinoschisis was noted in the right eye. No nonperfusion aside from that seen within the schism detachment, or neovascularization of the retina on wide-field fundus photography or fluorescein angiography was noted. Bullous retinoschisis was also found in the left eye. The patient was treated conservatively with prednisolone acetate and timolol eye drops. Conclusions and importance: Chronic bullous retinoschisis can be associated with anterior segment neovascularization such as rubeosis iridis, presumably due to non-perfusion within the retinoschisis cavity. PMID- 29260090 TI - A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 (GDF3) in a female with unilateral anophthalmia and skeletal anomalies. AB - Purpose: The genetic causes of anophthalmia, microphthalmia and coloboma remain poorly understood. Missense mutations in Growth/Differentiation Factor 3 (GDF3) gene have previously been reported in patients with microphthalmia, iridial and retinal colobomas, Klippel-Feil anomaly with vertebral fusion, scoliosis, rudimentary 12th ribs and an anomalous right temporal bone. We used whole exome sequencing with a trio approach to study a female with unilateral anophthalmia, kyphoscoliosis and additional skeletal anomalies. Observations: Exome sequencing revealed that the proposita was heterozygous for c.796C > T, predicting p.Arg266Cys, in GDF3. Sanger sequencing confirmed the mutation and showed that the unaffected mother was heterozygous for the same missense substitution. Conclusions and importance: Although transfection studies with the p.Arg266Cys mutation have shown that this amino acid substitution is likely to impair function, non-penetrance for the ocular defects was apparent in this family and has been observed in other families with sequence variants in GDF3. We conclude p.Arg266Cys and other GDF3 mutations can be non-penetrant, making pathogenicity more difficult to establish when sequence variants in this gene are present in patients with structural eye defects. PMID- 29260091 TI - Poor prognosis of elderly individuals >80 years of age with acute retinal necrosis. AB - Purpose: To report the clinical features and prognosis of acute retinal necrosis (ARN) in elderly (>80 years of age) individuals. Methods: Six consecutive patients with unilateral ARN who attended the Department of Ophthalmology at Yamaguchi University Hospital between 2014 and 2015 were retrospectively reviewed. Clinical characteristics, causative virus, time from symptom onset to physician visit, visual acuity at presentation and final visit, and treatment were evaluated and compared between the three elderly and three middle-aged (<80 years) patients. Results: Varicella zoster virus (VZV) DNA was detected in aqueous humor by the polymerase chain reaction in all six cases. The mean +/- SD time between symptom onset and medical attention was 18.0 +/- 8.7 and 8.3 +/- 1.5 days in the elderly and middle-aged groups, respectively. All patients were treated with intravenous aciclovir, oral prednisolone, and a nonsteroidal anti inflammatory drug, and five of the six patients also received oral valaciclovir and underwent vitrectomy. The final best corrected visual acuity of the affected eye was worse for the elderly patients (20/400, hand motion, and light perception negative) than for the middle-aged patients (20/15, 20/50, and 20/25). Conclusions and importance: ARN in the elderly individuals of the present study was caused by VZV infection and associated with a poorer visual prognosis compared with that of middle-aged patients. A delay in the onset of antiviral treatment might contribute to the poor prognosis of elderly patients with ARN. PMID- 29260092 TI - Bilateral cavernous sinus thrombosis with septic lung lesions resulting from a nasal abscess. PMID- 29260093 TI - Cardinal features of superior oblique myokymia: An infrared oculography study. AB - Purpose: Superior oblique myokymia (SOM) is a rare eye movement disorder characterized by unilateral oscillopsia and binocular diplopia. Our study aimed to better understand SOM using infrared oculography. Methods: We examined and recorded five patients with SOM. Results: Binocular infrared oculography showed that in primary gaze, all patients exhibited torsional oscillations, which worsened in infraduction and abduction and improved in supraduction and adduction. Saccades showed increased downward saccade amplitudes but normal peak velocities. During fixation in primary gaze, removal of target led to extorsion and supraduction, unmasking underlying superior oblique weakness. Conclusions and importance: Our data suggest both weakness and activity-dependent hyperactivity of the trochlear motor unit, supporting a model of injury followed by aberrant regeneration. PMID- 29260094 TI - Cicatricial ectropion in a patient treated with dupilumab. AB - Purpose: To describe a case of bilateral conjunctivitis and cicatricial ectropion associated with dupilumab therapy for atopic dermatitis. Observations: Severe hyperemia of the conjunctiva and eyelid margins, as well as cicatricial ectropion, began two months after starting weekly dupilumab injections for atopic dermatitis. The findings worsened over the next several months and improved after discontinuing dupilumab. Conclusions and importance: Dupilumab is a promising intervention in the management of atopic dermatitis and asthma, however, little is known about its potential ocular adverse effects. We report the first case of dupilumab-associated ocular inflammation leading to cicatricial ectropion. PMID- 29260095 TI - Hypertensive retinopathy as the initial presentation of neuroblastoma. AB - Purpose: To describe a case of a patient who presented with hypertensive retinopathy and was found to have neuroblastoma. Observations: Neuroblastoma has three main ocular presentations. As a primary disease, it can present with a paraneoplastic syndrome in the form of opsoclonus, or it can present as a Horner's syndrome from its effect on the cervical sympathetic ganglia. Metastatic disease can present as a triad of periorbital edema, ecchymosis and proptosis from orbital bone involvement. Hypertension is a rare systemic presentation of neuroblastoma. We report the case of a two-year-old girl whose initial presentation of neuroblastoma was hypertensive retinopathy. Conclusions and importance: To our knowledge, this is the first reported case of neuroblastoma presenting as hypertensive retinopathy. Our case highlights the importance of a multidisciplinary approach and thorough systemic work up of ocular findings in order to arrive at an appropriate diagnosis. PMID- 29260096 TI - An unusual case of acute angle-closure glaucoma following deep anterior lamellar keratoplasty using the "big bubble" technique. AB - Purpose: To report the first case of acute angle closure due to a high-pressure Descemet membrane detachment following deep anterior lamellar keratoplasty (DALK) using the "big bubble" technique. Observations: A 25-year-old man underwent DALK surgery for keratoconus using the "big bubble" technique in which an air bubble is injected in deep stroma to promote dissection of underlying Descemet membrane from stroma. Surgery was uneventful and the patient was discharged home in good conditions. On post-operative day 1, the patient came back with severe periocular pain. Intra-ocular pressure was found to be 38 mmHg. Anterior-segment OCT revealed a "double anterior chamber" created by a high-pressure Descemet detachment that was occluding the pupil and causing secondary acute angle closure glaucoma. The patient was brought back promptly to the operating room where the high-pressure chamber was properly evacuated, allowing Descemet membrane to properly reattach to stroma. Conclusions and importance: Inability to recognize stroma from Descemet membrane during the dissection of the "big bubble technique" can result in failure to evacuate the high-pressure Descemet membrane detachment, putting the patient at risk for acute angle closure glaucoma from occlusion of the pupil. Proper dissection of stroma from underlying DM is a challenging and crucial step in the "big bubble" technique. Several methods, such as the injection of small bubbles in the anterior chamber or the use of intra-operative anterior segment OCT could be employed to prevent such a complication. PMID- 29260097 TI - CDH3 gene related hypotrichosis and juvenile macular dystrophy - A case with a novel mutation. AB - Purpose: CDH3-related hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal-recessive entity characterized by congenital sparse scalp hair and macular dystrophy, leading to severe central visual loss. We report a family with HJMD caused by a novel CDH3 gene mutation and review the mutation spectrum in HJMD. A detailed phenotypic assessment for patients whose molecular results were reported previously is also summarized. Observations: We present a 13-year-old Turkish girl who experienced gradual bilateral visual deterioration with marked hair loss. Hair-pull test results and scalp skin texture were normal. The eyebrows and eyelashes were normal, and no abnormality in the teeth, nails, or limbs was detected. Fundus examination revealed bilateral ring-shaped atrophy of the retinal pigment epithelium with patchy intraretinal pigment clumping at the posterior pole. DNA sequencing analysis detected a novel homozygous deletion (c.447_467del (p.149_156del)) in exon 5 of the CDH3 gene of the patient. Both healthy parents and an older brother were heterozygous for the mutation. Conclusions and importance: This case of HJMD was related to a novel homozygous mutation, termed c.447_467del (p.149_156del). These findings have significance for the future mutational analysis and genetic counseling of families with HJMD, particularly in our region. The presence of sparse hair in childhood, with or without limb anomalies, should alert clinicians to request an eye consultation. Pediatricians, dermatologists, and ophthalmologists should be aware of the rarely seen entity of juvenile macular dystrophy with hypotrichosis. PMID- 29260098 TI - Management of incision failure during small incision lenticule extraction because of conjunctivochalasis. AB - Purpose: We report a case of incision failure during small incision lenticule extraction (SMILE) and its management. Observations: The incision could not be made using the femtosecond laser because of a redundant conjunctiva, so it was instead done manually using a diamond knife. The lenticule was successfully separated and extracted. Three months after the procedure, the uncorrected distance visual acuity was 20/20 and no complication was observed. Conclusions and importance: This case demonstrates that the conjunctiva should be carefully examined before SMILE. If a complication occurs because of conjunctivochalasis, it can be resolved with proper management without compromising the patient's visual acuity. PMID- 29260099 TI - Reversal of cilioretinal artery occlusion with intra-arterial tissue plasminogen activator. AB - Purpose: To present the reversal of a cilioretinal artery occlusion with the use of intra-arterial tissue plasminogen activator. Observations: A monocular 74 year old male presented with a cilioretinal artery occlusion. Treatment with intra arterial tissue plasminogen activator 7 hours after the onset of symptoms led to a complete restoration of vision. Conclusions and importance: Early intervention with tissue plasminogen activator reversed acute onset loss of vision from cilioretinal artery occlusion. PMID- 29260100 TI - A unique case of valsalva retinopathy in a conch blower. AB - Purpose: Valsalva hemorrhagic retinopathy is a form of preretinal hemorrhage that develops after a valsalva maneuver, leading to rupture of the superficial retinal capillaries. Here, we report a case of valsalva retinopathy secondary to blowing a conch, the first case report of its kind. The patient blew conch, which was part of his daily ritual to pray to God as he was a Hindu priest. Observations: A 58-year-man developed an acute decrease in vision to 5/60 in his right eye after blowing the conch while performing "Puja," which is the act of praying to God in Hindu culture. Ophthalmoscopy showed a fresh preretinal hemorrhage over the macula in his right eye. YAG laser membranotomy was performed, and his vision returned to 6/6. Conclusions and importance: Conch "Shankha" is a religious instrument used routinely in Hindu culture. Its mechanism is very much similar to that of a wind instrument. This is the first case report of valsalva retinopathy caused by conch blowing. PMID- 29260101 TI - Antiphosphospholipid syndrome presenting with amaurosis fugax and cotton wool spots. AB - Purpose: To describe the importance of considering vaso-occlusive disease on the differential diagnosis of a patient presenting with amaurosis fugax (AF) and unilateral cotton wool spots (CWS). Observations: A 69-year-old female with history of obesity, hyperlipidemia and recent orthopedic surgery, presented with 3 days of worsening monocular AF and CWS in the right eye. She was diagnosed with antiphosphospholipid syndrome based on positive serologic testing for antiphosphatidylserine IgM, anticardiolipin IgM. The patient was treated with lipid lowering medication, long-term aspirin, and has followed a weightloss and physical therapy program under medical supervision. The CWS resolved and AF symptoms have not recurred. Conclusions and importance: Antiphospholipid syndrome can be considered in the differential diagnosis of patients presenting with AF, assymetric CWS, and/or rapid progression of symptoms. PMID- 29260102 TI - Tocilizumab as a steroid sparing agent for the treatment of Graves' orbitopathy. AB - Purpose: To describe the effect of tocilizumab in two patients with thyroid associated orbitopathy (TAO). Observations: We present two patients with TAO who could not tolerate corticosteroids and had a reduction in clinical and laboratory markers of inflammatory activity with subsequent tocilizumab therapy. Conclusions and importance: The IL-6 receptor antibody tocilizumab is a promising candidate for the treatment of TAO because it selectively targets a key inflammatory mediator and has a favorable side effect profile. Our report demonstrates that tocilizumab can achieve further reduction in inflammatory activity after treatment with corticosteroids. Importantly, we and others have observed a decrease in the level of thyroid stimulating immunoglobulin (TSI) with tocilizumab treatment. This suggests an upstream effect in the inflammatory cascade. Although the impact of tocilizumab on long-term outcome is unknown at this time, we believe that early disruption of the inflammatory process may prevent late complications and decrease the need for rehabilitative surgery. PMID- 29260103 TI - Crystalline lens dislocation secondary to bacterial endogenous endophthalmitis. AB - Purpose: To present an unusual case of endogenous endophthalmitis secondary to Group A streptococcus (GAS) that resulted in dislocation of the crystalline lens. Observations: An immunocompetent 51-year-old man presented to the emergency room (ER) with upper respiratory infection (URI) symptoms and painful right eye. He was diagnosed with URI and viral conjunctivitis and discharged on oral azithromycin and polytrim eyedrops. He returned to the ER 30 h later with sepsis and findings consistent with endophthalmitis, including light perception only vision. Ophthalmology was consulted at this time and an emergent vitreous tap and injection was performed. Both blood and vitreous cultures grew an atypical non hemolytic variant of GAS (Streptococcus pyogenes). The primary source of infection was presumed to be secondary to pharyngitis or cutaneous dissemination. Final vision in the affected eye was no light perception, likely from a combination of anterior segment scarring, posterior segment damage, and hypotony. Interestingly, head computed tomography (CT) at the initial ER presentation showed normal lens position, but repeat CT at re-presentation revealed posterior dislocation of the lens. Conclusions and importance: Endophthalmitis secondary to GAS has been sparsely reported in the literature, and this case highlights a unique clinical presentation. We suspect that this atypical non-hemolytic strain may have evaded detection on initial pharyngeal cultures. Additionally, we hypothesize that GAS-mediated protease release resulted in breakdown of the zonular fibers and subsequent lens dislocation. Ophthalmologists should be aware of GAS and its devastating intraocular manifestations. PMID- 29260104 TI - Treatment of cystic cavities in X-linked juvenile retinoschisis: The first sequential cross-over treatment regimen with dorzolamide. AB - Purpose: To report the first sequential cross-over treatment with the longest ophthalmic follow-up in a case of X-linked juvenile retinoschisis (XLRS) successfully treated with topical dorzolamide. Observations: A healthy 34 year old man presented with one month history of decreased visual acuity in his left eye. Funduscopy was significant for a blunted and cystoid-like foveal reflex in both eyes. The macular OCT showed cystic foveal changes OU. The patient was diagnosed with XLRS and was observed. On two subsequent follow-ups, a significant decrease in the patient's visual acuity warranted the use of topical dorzolamide for treating the cystic foveal changes, which completely resolved two months post treatment initiation. Conclusion and importance: Previous reports showed the benefit of dorzolamide in treating foveal cystic cavities in XLRS. To our knowledge, this is the first case of XLRS demonstrating the benefits of topical dorzolamide based on a sequential cross-over treatment regimen. It may also represent a case with the longest ophthalmic follow-up providing, in consequence, long-term understanding of the natural history and complications of this rare disease After ruling out major causes of cystoid macular edema, XLRS patients presenting with worsening of their visual acuities due to larger cystic macular changes may benefit from an alternating ON/OFF regimen of topical dorzolamide, which offers a significant treatment advantage outweighing its well-known side effects. Our study consolidates the importance of "medication vacation" by showing its efficacy in providing anatomical and visual functional improvements in patients with chronic cystic macular changes. PMID- 29260105 TI - Invasive Streptococcus viridans sphenoethmoiditis leading to an orbital apex syndrome. AB - Purpose: Orbital apex syndrome due to spread of infectious sinusitis is a serious disease, often with an insidious presentation with few ophthalmic signs and symptoms. Failure to recognize and treat infectious orbital apex syndrome early portends a grave prognosis, including profound, permanent visual loss and potentially death. Herein we describe a representative case and discuss the relevant aspects of prompt diagnosis and treatment. Observations: An unusual case of infectious orbital apex syndrome due to contiguous spread of Streptococcus viridans sphenoethmoiditis in a hospitalized, immunosuppressed patient with acute myelogenous leukemia is presented. Given the few clinic signs and subtle imaging findings, a delay in diagnosis occurred resulting in vision loss to light perception and internal carotid artery occlusion within the cavernous sinus. A brief literature review of orbital apex syndromes is presented. Conclusion and importance: A high clinical suspicion for orbital apex syndrome must be maintained in the appropriate circumstance given the subtle clinical signs and imaging, as well as the potential devastating morbidity of the disease process. Prompt diagnosis and treatment is crucial to patient survival and preservation of vision. PMID- 29260106 TI - Acute bacterial endophthalmitis after scleral buckling surgery with chandelier endoillumination. AB - Purpose: The non-contact wide-angle viewing system (WAVS) with chandelier endoillumination is being used more commonly during scleral buckling surgery for rhegmatogenous retinal detachments although its safety has not been established. We report our findings in a case of bacterial endophthalmitis that developed after scleral buckling surgery with WAVS and chandelier endoillumination. Observations: A 42-year-old man underwent scleral buckling surgery for a rhegmatogenous retinal detachment in his right eye using a WAVS with chandelier endoillumination. Three days after the surgery, the patient noticed a marked decrease in his vision with ocular pain. Slit-lamp examination showed dense infiltration in the anterior chamber and vitreous body. Pars plana vitrectomy with antibiotic irrigation was done immediately, and Staphylococcus epidermidis was detected in the vitreous fluid. After vancomycin 6/day for 4 weeks, the inflammation gradually subsided, and the visual acuity recovered to 20/20 in 3 months. Conclusions and importance: Acute bacterial endophthalmitis can develop after scleral buckling surgery performed with WAVS and chandelier endoillumination. PMID- 29260107 TI - Recovery of outer retinal laminations on optical coherence tomography after treatment of cancer associated retinopathy. AB - Purpose: To report novel optical coherence tomography findings in a case of anti alpha-enolase cancer associated retinopathy. Observations: An elderly female presented with bilateral decreased vision and a recent diagnosis of ovarian carcinoma. Optical coherence tomography demonstrated bilateral loss of outer retinal structures and macular edema. Serum testing found antibodies against alpha-enolase and 82-84 kDa proteins. Outer retinal structures showed recovery, macular edema resolved and repeat anti-retinal antibody testing became negative following cancer therapy and topical difluprednate treatment. Conclusions and importance: Cancer associated retinopathy is a paraneoplastic disease that results in damage to retinal structures through an autoimmune response. The damage is generally considered to be irreversible; however, in rare cases, such as observed here, retinal structures may demonstrate recovery after treatment. PMID- 29260108 TI - Unilateral pigmented paravenous retinochoroidal atrophy with retinitis pigmentosa in the contralateral eye: A case report. AB - Purpose: We describe a sporadic case of unilateral pigmented paravenous retinochoroidal atrophy (PPRCA) with retinitis pigmentosa (RP) in the contralateral eye. Observations: a 24-year-old female aware of the narrowing of visual field was examined at our hospital. Funduscopic examination revealed left eye showing retinochroidal atrophy along the retinal veins with pigment accumulation while right eye showing peripheral diffuse retinal pigmented epithelium atrophy with bone spicule pigmentation. Fundus autofluorescence, electroretinogram, visual field test and optic coherent tomography were also performed and obtained results were compatible with funduscopic observation. Conclusions and importance: Simultaneous manifestation of PPRCA and RP observed in this case is rare and supports a shared genetic basis between the two diseases. Further genetic investigations are needed to elucidate the etiology and to properly manage PPRCA. PMID- 29260109 TI - A case of congenital retinal macrovessel in an otherwise normal eye. AB - Purpose: To present the case of a 37-year-old female with a foveal macrovessel. Observations: The patient had an incidental finding of congenital retinal macrovessel (CRM) in the left eye on optical coherence tomography (OCT). Visual acuity was normal, and slit lamp and dilated fundus examinations were otherwise unremarkable. OCT angiography (OCTA) imaging allowed for visualization of the depth profile of the vessel as well as the foveal avascular zone (FAZ). The FAZ and foveal pit were both smaller in the affected eye compared to the fellow eye. Conclusions and importance: We describe findings of OCTA imaging in a patient with CRM. Previous reports have relied on examination using fluorescein angiography, which does not provide sufficient axial resolution to discern the different vascular plexuses. This report further characterizes how this rare condition can affect foveal morphology and retinal vasculature. PMID- 29260110 TI - Surgical treatment outcome of medically refractory huge giant papillary conjunctivitis. AB - Purpose: To compare the surgical outcome of excision of giant papillae with and without amniotic membrane in a patient with bilateral medically refractory giant papillary conjunctivitis (GPC). Observations: 27-year-old Chinese lady presented with bilateral itchy eyes, discomfort and fullness of upper lids for past two years. She was a long-term contact lens user but stopped completely 2 years ago. Not a known atopic, she had unusually large giant papillae involving both upper tarsal conjunctiva. She had used topical olopatadine(0.1%), intermittent dexamethasone(0.1%) and also underwent intralesional injection of Triamcinolone (40mg/ml) twice on each side without any improvement in past two years. We decided to excise the papillae with amniotic membrane transplantation (AMT) in left eye and only excision in the right eye. The results were compared after 2 years. Giant papillae were excised in both eyes under regional anesthesia on separate occasions. The left eye received AMT in addition to excision. A symblepharon ring was applied and left in place for two weeks in both eyes. She was treated with topical Prednisolone acetate (1%) and Levofloxacin 4 times a day for a month. Postoperative period was unremarkable and she recovered well. In 2 years follow-up, the upper tarsal conjunctiva was smooth in both eyes and there was no evidence of any recurrences. Conclusion and Importance: Excision of giant papillae is a treatment option for cases with refractory GPC. Additional AMT after excision may not be necessary as there was no difference in surgical outcome. PMID- 29260112 TI - Persistent pseudomyopia following a whiplash injury in a previously emmetropic woman. AB - Purpose: Accommodative spasm, which manifests as ciliary muscle spasm, convergent strabismus or miosis, is a recognised consequence of head trauma. In whiplash cases, cervical spine hyperextension poses a risk of contra-coup injury and brainstem trauma, and is known to affect the visual system. However, to date, no cases of accommodative spasm due to whiplash injury have been reported. Observations: We present the case of a 34-year-old female who developed sudden onset blurred distance vision after a rear impact car crash, having previously been emmetropic. Her unaided distance visual acuity was 20/70 in the right eye and 20/20 in the left. Best-corrected visual acuity in the right eye was 20/20 with a correction that progressed from -1.75 to -3.50 DS over the 12 months following the accident.This patient's sudden unilateral myopia, with unilaterally increased amplitude of accommodation suggests pseudomyopia due to accommodative spasm. Magnetic resonance imaging showed no evidence of injury to her brain stem, frontal lobes or oculomotor nerve. The patient is now well adjusted with a 3.50DS corrective lens for the right eye. Conclusions and importance: The accommodation reflex is susceptible to injury at the occipital lobe, frontal eye fields, Edinger-Westphal nuclei and oculomotor nerves. As such it should be examined in patients who present with visual disturbances following whiplash injury.It is important that such cases are identified at presentation, as early intervention can improve outcomes in accommodative spasm and reduce the long term psychological effects often associated with whiplash injuries. PMID- 29260111 TI - Corneal graft failure due to migration of OzurdexTM implant into the anterior chamber. AB - Purpose: We report a case of corneal endothelial graft failure secondary to dexamethasone intravitreal implant (OzurdexTM) migration into the anterior chamber (AC). Observations: A 53-year-old man with a history of bilateral idiopathic chronic uveitis, had a right anterior vitrectomy and AC intraocular lens (ACIOL) with a peripheral iridotomy. He received an intravitreal OzurdexTM implant for right cystoid macular oedema (CMO). Three months later he developed pseudophakic bullous keratopathy and underwent a Descemet stripping automated endothelial keratoplasty (DSAEK), combined with IOL exchange (ACIOL explantation followed by scleral fixated posterior chamber IOL). He developed recurrent CMO post-operatively, for which he had a second OzurdexTM implant. Six weeks following the implant he presented with reduced vision and corneal graft failure with migration of the OzurdexTM implant into the AC. Despite prompt surgical removal of the implant, the graft did not recover and he underwent a repeat DSAEK. Conclusions and importance: Ophthalmologists should be aware of this adverse event and the importance of early implant removal to reduce the risk of permanent corneal oedema. PMID- 29260113 TI - Successful long-term treatment of paraneoplastic optic neuropathy with mycophenolate mofetil, prednisone, and plasmapheresis. AB - Purpose: To report long-term follow-up of a case of paraneoplastic optic neuropathy (PON) successfully treated with combination therapy. Observations: We present a confirmed case of PON from cutaneous melanoma with nearly six years of meticulous follow-up in which vision was preserved and disease remission was successfully induced with combination mycophenolate mofetil, prednisone, and plasmapheresis therapy. Conclusions and importance: Treatment of PON and long term follow-up are not well described in the literature. In our case of PON, vision was preserved and disease remission was achieved with mycophenolate mofetil, prednisone, and plasmapheresis. Such information may be useful for future cases of PON. PMID- 29260115 TI - Changes in choroidal blood flow and choroidal thickness after treatment in two cases of pediatric anisohypermetropic amblyopia. AB - Purpose: We aimed to examine the changes in choroidal blood flow (CBF) and central choroidal thickness (CCT) in children with anisohypermetropic amblyopia using laser speckle flowgraphy (LSFG) and enhanced depth imaging optical coherence tomography (EDI-OCT). Observations: The patients were both 6-year-old Japanese male children with complaints of worsening right visual acuity and were diagnosed with anisohypermetropic amblyopia. The decimal best-corrected visual acuities (BCVAs) in cases 1 and 2 were both 0.5. In both cases, LSFG results demonstrated CBF impairment in amblyopic eyes compared with fellow eyes. EDI-OCT results also showed that the CCTs of amblyopic eyes were greater than those of fellow eyes at the initial visit. Several months after the first visit, the decimal BCVAs in both cases had improved to 1.0 because of treatment. Further, the CBF gradually increased along with a decrease in the CCT of the amblyopic eye. The axial lengths and spherical powers of the amblyopic eyes in the two cases were not different during follow-up. Conclusions and importance: We have determined the changes in CBF and CCT in two children with anisohypermetropic amblyopia for the first time. CBF impairments may be involved in the pathogenesis of anisohypermetropic amblyopia, and LSFG may be useful in examining CBF in pediatric anisohypermetropic amblyopia. PMID- 29260114 TI - Ocular sporotrichosis: A frequently misdiagnosed cause of granulomatous conjunctivitis in epidemic areas. AB - Purpose: Sporotrichosis is a subcutaneous mycosis caused by Sporothrix sp., a dimorphic fungus. Although the cutaneous form is the most frequent form, the ocular presentation has been increasingly diagnosed in epidemic areas. We describe three cases of ocular sporotrichosis with the involvement of the ocular adnexa due to autoinoculation without trauma with successful antifungal treatment. Observations: Patient 1: A 68-year-old woman presented with granulomatous conjunctivitis of the right eye with an ulcerated nodule on the right temporal region for 5 months. Patient 2: A 46-year-old woman with conjunctival hyperemia of the left eye with associated periorbital edema and erythema for the past 4 months was referred to the Dermatology Department due to an ulcerated nodule on the left malar region. Patient 3: A 14-year-old boy presented to the emergency department with inferior palpebral edema with a 5-day evolution. Specimens were obtained from the lesions of the three patients, and the cultures were positive for Sporothrix sp. The three cases were diagnosed as ocular sporotrichosis and were successfully treated with itraconazole (200-400 mg/d). Two of the three patients developed sequelae such as conjunctival fibrosis and symblepharon. Conclusions and importance: We emphasize the importance of the ophthalmologist being familiar with the diagnosis and management of this rare and frequently misdiagnosed form of sporotrichosis. PMID- 29260116 TI - Swept-source optical coherence tomographic findings in eyes with metastatic choroidal tumor. AB - Purpose: To report the swept-source optical coherence tomographic (OCT) findings in two eyes with choroidal metastases. Observations: Two patients with choroidal metastasis were studied. The metastasis was from a breast cancer in Case 1 and from a lung cancer in Case 2. In Case 1, swept-source OCT showed a highly reflective solid tumor with low optical reflective tissues that had replaced the choroidal tissue. Swept-source OCT was able to image the choroidal mass where other fundus imaging methods such as fluorescein angiography did not show the mass. Ophthalmoscopy of Case 2 showed hemorrhages in the inner retina, on the tumor, and in the vitreous. Swept-source OCT showed a subretinal mass with a steeple-crowned cap and a ruptured Bruch's membrane on the tumor. Conclusion and importance: Swept-source OCT imaging can detect the inner structure of a choroidal mass and retina around it in good detail. PMID- 29260117 TI - Parallel ocular and serologic course in a patient with early Sjogren's syndrome markers. AB - Purpose: To report on a case of a young female with progressing dry eye symptoms and evolving autoimmune markers consistent with a presentation of early Sjogren's syndrome (SS). Observations: A 32 year-old female presented with chronic dry eye symptoms refractory to artificial tears. Slit lamp examination revealed punctate epithelial erosions, decreased tear break-up time, and decreased tear lake bilaterally. Initial tests for ocular surface inflammation (InflammaDry, Quidel, San Diego) and systemic autoantibodies (antinuclear antibodies, anti-SSA/Ro and anti-SSB/La) were negative. After 4 months of persistent ocular symptoms and signs, ocular surface inflammation was detected via InflammaDry and blood results included a positive antinuclear antibody (1:160), rheumatoid factor (IgG 25.3 EU/ml), and carbonic anhydrase 6 (IgM 20.2 EU/ml), but persistently negative anti SSA/Ro and anti-SSB/La antibodies. Conclusions and importance: Taken together, these findings were suggestive of early Sjogren's syndrome with simultaneous appearance of both ocular and serum biomarkers. Novel autoantibodies testing in suspected patients can guide early intervention and potentially improve both the glandular and extra-glandular function in patients. PMID- 29260118 TI - Projection-resolved optical coherence tomography angiography exhibiting early flow prior to clinically observed retinal angiomatous proliferation. AB - Purpose: The purpose of this study is to analyze early retinal angiomatous proliferation (RAP) utilizing a novel imaging modality, Projection-Resolved Optical Coherence Tomography Angiography (PR-OCTA). Observations: Five months prior to the diagnosis of a RAP lesion, cross-sectional PR-OCTA demonstrated flow in the outer retina contiguous with the deep retinal capillary plexus (DCP) and adjacent to a small pigment epithelial detachment. After development of a clinically visible RAP lesion, cross-sectional PR-OCTA demonstrated the RAP lesion connecting DCP and sub-retinal pigment epithelial neovascularization. Conclusions & importance: This is the first report of PR-OCTA demonstrating abnormal flow in the outer retina prior to the development of a clinically detectable RAP lesion. PR-OCTA may be useful for surveillance and to help further characterize and stage RAP lesions. PMID- 29260119 TI - One-year outcomes of ziv-aflibercept for macular edema in central retinal vein occlusion. AB - Purpose: To report the 12-month efficacy and safety outcomes of intravitreal ziv aflibercept in macular edema secondary to central retinal vein occlusion (CRVO). Methods: Interventional case series documenting 12-month outcomes of intravitreal ziv-aflibercept (1.25 mg in 0.05 mL) in 6 patients with treatment-naive macular edema secondary to CRVO. All patients had comprehensive ophthalmic examination, spectral domain optical coherence tomography at baseline and all follow-up visits, and fluorescein. Retreatment decisions were based on recurrence or persistence of intraretinal or subretinal fluid, deterioration in visual acuity (VA), increase in central subfield thickness (CST) by >= 50 MUm from the previous visit, or lowest recorded CST. Results: Participants had (2 males, 4 females) an average age of 53.5 years. From baseline to 12 months, the mean logMAR VA improved from 0.86 (Snellen ~ 20/145) to 0.33 (Snellen ~ 20/40), central macular thickness decreased from 519 MUm to 255 MUm, and total macular volume decreased from 14.7 mm3 to 7.1 mm3. No eyes had uveitis, cataract progression, intraocular pressure (IOP) elevations, or systemic adverse events. Conclusions and importance: Ziv-aflibercept achieves favorable intermediate-term functional and structural outcomes in macular edema secondary to CRVO. No safety concerns were raised. Low-cost ziv-aflibercept may thus be useful for CRVO in resource-poor countries. Further prospective studies in larger cohorts are needed further establish the efficacy and safety of this agent. PMID- 29260120 TI - Purtscher-like retinopathy associated with cerebro- or cardiovascular surgery. AB - Purpose: To report the findings in five patients of Purtscher-like retinopathy that developed after cerebro- or cardiovascular surgeries. Observations: Three women and two men with a mean age of 56.6 years were studied. They had had cerebro- or cardiovascular disease that was treated by major vascular surgery. Postoperatively, all of the patients developed multiple patches of retinal whitening in the area corresponding to the radial peripapillary capillaries in the posterior pole of the eye uni- or bilaterally. In two patients, the optic nerve head was involved which affected their vision severely. Hematological examinations showed hypercoagulable state after the surgeries. The retinal pathologies abated with time. Conclusions and importance: These results indicate that major cardio- or cerebrovascular surgeries can cause Purtscher-like retinopathy. The hypercoagulable state and specific structures of the radial peripapillary capillaries may play a role in pathogenesis of this disease. PMID- 29260121 TI - Late extrusion of intrastromal corneal ring segments: A report of two cases. AB - Purpose: To report two cases of patients with late extrusion following uneventful implantation of intrastromal corneal ring segments (ICRS) for myopia. Observations: Two patients with previously implanted ICRS for low myopia presented with spontaneous onset of extrusion of their ICRS, one at 7 years post operatively and the other at 17 and 20 years. Both cases underwent explantation and maintained excellent best-corrected visual acuity. These cases represent the longest reported intervals between implantation of the ICRS and subsequent extrusion. Conclusions and importance: Late extrusion can occur many years following implantation of ICRS, even in eyes without pre-existing thinning or ectasia. The technique for explantation described herein can result in favorable clinical outcomes in such cases. These cases demonstrate the importance of long term follow up of eyes that have undergone ICRS implantation. PMID- 29260122 TI - Unusual Straatsma Syndrome - How dogmatic is a bad prognosis? AB - Purpose: To show that Straatsma Syndrome can have a good outcome and to highlight an unusual presentation of this disease. Observations: A four-year-old boy presents with severe right eye amblyopia in association with high myopia, esotropia, heterochromia iridum and extensive myelinated retinal fibers involving both temporal arcades and the optic nerve head. Right eye initial visual acuity was less than 20/400 for distance and less than R6W10 for near. Left eye examination was unremarkable. Despite the indicators for bad prognosis, intensive occlusion therapy was prescribed. Parents were strongly involved in the treatment regimen. After four months, the patient presented an unexpected good visual recovery both for distance and near, that has persisted until present. Right eye visual acuity is 20/30 with -9.00 dioptres contact lens for distance and R2W1 for near. Esotropia also improved to 12 prism dioptres. Fundoscopic alterations and heterochromia iridum have remained stable. Spectral-domain optical coherence tomography images of the right eye showed thinner superior outer ring measurements. Conclusions and importance: Straatsma Syndrome can present with heterochromia iridum. When strabismus is present, early surgery should be withheld. Intensive treatment of Straatsma Syndrome can yield an unexpected good result, despite initial high degree anisometropia and low vision acuity. PMID- 29260123 TI - Photoreceptor disruption and vision loss associated with central serous retinopathy. AB - Purpose: To present ophthalmic imaging findings in the case of a 40-year-old male with sustained visual loss after a single episode of acute central serous retinopathy (CSR). Observations: A male subject presented with visual acuity decline to 20/50 OS and was diagnosed with acute CSR. The initial pigment epithelial detachment and subretinal fluid resolved within 6 weeks, but visual acuity remained impaired. Using directional optical coherence tomography (D-OCT) and confocal and split-detector adaptive optics scanning light ophthalmoscopy (AOSLO), we imaged pathologic alterations in the photoreceptor mosaic of the affected eye. A foveal region of intermittent missing cones, a temporal parafoveal region of confluent missing cones, and a nasal parafoveal region of misdirected cones were observed. Conclusions and Importance: Pathologic alterations in photoreceptor microanatomy underlie residual visual acuity deficits in this case of acute CSR. Observations of missing cones correlated well across all imaging modalities in the fovea and the temporal parafoveal region of missing cones. However, in the nasal parafovea where cones were present but misdirected, D-OCT and AOSLO may be able to identify and image photoreceptors with greater fidelity as compared to non-directional SDOCT (spectral domain OCT). D-OCT may thus have a clinical role in rapidly assessing photoreceptor mosaic integrity in pathology. PMID- 29260125 TI - Comparison of the reliability and efficacy of LigaSure hemorrhoidectomy and a conventional Milligan-Morgan hemorrhoidectomy in the surgical treatment of grade 3 and 4 hemorrhoids. AB - Objective: The aim of this study was to compare the clinical results of LigaSure assisted hemorrhoidectomy and Milligan-Morgan hemorrhoidectomy as a conventional method in our clinic. Materials and Methods: Patients who underwent LigaSure assisted hemorrhoidectomy or conventional hemorrhoidectomy for grade 3 and 4 hemorrhoids in our clinic between 2009 and 2014 were included in this study. The patient data were reviewed by screening records. Gender, age, preoperative hemoglobin and hematocrit levels, operation time, presence of thrombosis, number of packages, hospitalization time, early and late postoperative complications, prolonged pain presence, and follow-up period were recorded. Results: In this period, surgical interventions were performed on 365 patients diagnosed with hemorrhoids. Among these, 159 underwent LigaSure-assisted operations, while 206 were operated on by conventional methods. One hundred forty-four (39.5%) cases were female, while 221 (60.5%) cases were male. The median age of the patients was 40 (19-82) years in the LigaSure group and 41 (16-78) years in the conventional method group. The operation time was 15 (4-60) min in the LigaSure group and 20 (6-40) min in the conventional method group. Postoperative analgesics were given to the 182 (88.3%) cases in the conventional group and 107 (67.3%) cases in the LigaSure group. The time required for returning to normal daily activity was 6 (1-15) days in the LigaSure group and 7 (1-30) days in the conventional method group. Conclusion: In this study, LigaSure was determined to be superior to a conventional method in terms of operation time, hospitalization period, postoperative analgesic requirements, time required for returning to normal daily activity, and postoperative bleeding. PMID- 29260124 TI - Utility of optical coherence tomography angiography in detecting glaucomatous damage in a uveitic patient with disc congestion: A case report. AB - Purpose: To report a case of uveitic glaucoma with a congested optic disc where optical coherence tomography angiography (OCT-A) provided diagnostic utility in assessing glaucomatous damage but optical coherence tomography (OCT) alone had limited utility. Observations: We report a case of a 33-year-old Caucasian female referred to the USC Roski Eye Institute for uncontrolled intraocular pressure (IOP) in the left eye. She was managed by an outside provider for 6 months, where her IOP ranged from 28 to 42 mm Hg in the left eye on maximally tolerated medical therapy. Her clinical exam was consistent with Herpes family trabeculitis, optic nerve congestion, and possible glaucomatous damage. Initial evaluation of the optic nerve by standard modalities (fundus exam and OCT) was limited by optic nerve congestion; however, OCT-A showed peripapillary hypoperfusion, as commonly observed in glaucomatous eyes. She underwent aqueous shunt implantation for elevated IOPs poorly controlled by medications. Conclusions and importance: OCT-A can be a useful tool in the evaluation of glaucoma in instances where disc congestion masks both nerve excavation and retinal nerve fiber thinning normally seen on exam and on standard OCT of the optic nerve. PMID- 29260126 TI - Contribution of an educational video to surgical education in laparoscopic appendectomy. AB - Objective: With recent widespread advances in laparoscopy, providing education on this subject has become a significant challenge. The aim of this study was to determine the degree of contribution made by surgeons to laparoscopic education through an educational video. Material and Methods: A total of 40 volunteer general surgery residents and specialists participated in our study. Before watching the approximately six-minute educational video prepared for laparoscopic appendectomy, the participants were asked to fill out participant information forms and information measurement questionnaire forms. After the video, the participants were asked to fill out the information measurement questionnaire forms a second time; additionally, attitude evaluation forms and education evaluation questionnaire forms were presented to the participants for completion, and statistical analysis was performed. Furthermore, the total watching duration and the number of times the video was paused were recorded. Results: A total of 40 surgeons participated in the study (75% residents and 25% specialists). When the results of the information determination questionnaire forms filled out by the resident and specialist groups before and after the video were compared, it was observed that the scores of both groups significantly increased after watching the video (p=0.001). A statistical significance was identified between the length of time the video was watched and the education evaluation form scores of the participants (p<0.01). It was observed that the longer the video was watched, the greater the increase in the education evaluation scores. The results of the attitude evaluation forms implied that the video could be produced more professionally. Conclusion: Although education is an inevitable requirement of laparoscopic surgery, many teaching methods are available. Awareness-enhancing videos prepared on this topic can be efficient in providing laparoscopic education. PMID- 29260127 TI - An unusual cause of hypercalcemic crisis: Water-clear cell double parathyroid adenoma. AB - Objective: To evaluate the clinical characteristics of a patient operated for water-clear cell adenoma and to discuss these in the light of relevant literature. Material and Methods: PubMed and Google Scholar were searched to identify articles related to water-clear cell adenoma using the following keywords: parathyroid tissue, parathyroid gland, parathyroid cells, parathyroid adenoma, parathyroid hyperplasia, water-clear-cell, and water clear cell. The search included case reports, review articles, and original articles that had been published between January 1990 and November 2014 without any restrictions on language. All articles that contained information on the study population and treatment related data were identified and retrieved. In addition, an evaluation was of a case of a 47-year-old male patient with PHC who was treated at our clinic was conducted. Results: A total of 19 patients, including our new case, (age range: 18 to 81 years, mean+/-SD: 57.47+/-16.31 years) were included in the analysis. Eleven patients were female. Information about adenoma location was available from studies involving 17 patients and they indicated the following distribution of locations: left inferior (n=10), right superior (n=4). When preoperative imaging methods were examined, a false negative result was given by ultrasonography in 28.5% of patients and only 57.1% were positive on scintigraphy. Concomitant thyroid papillary carcinoma was determined in 1 patient. The mean tissue dimensions were 3.47+/-1.73 cm (range, 0.8-6.8 cm). Conclusion: Water-clear cell adenoma, which shows similar clinical characteristics to other parathyroid adenomas, is an uncommon cause of hyperparathyroidism. PMID- 29260128 TI - Emergency cases following elective colonoscopy: Iatrogenic colonic perforation. AB - Objective: Our aim in this study was to present the cases of our patients who contracted colonic perforation during elective colonoscopy and became emergency cases; we also discuss treatment modalities along with literature reports on the subject. Material and Methods: Cases of patients who contracted iatrogenic colonic perforation following endoscopy of the colorectal system between January 2009 and December 2015 at Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital's Endoscopy Unit were reviewed retrospectively. Results: Within the duration of the study, 5.586 patients underwent colonoscopies at our hospital; 7 (0.12%) of these patients contracted iatrogenic colonic perforation. Three (42.8%) of these patients were male, four (57.2%) were female, and their mean age was 69 years (46 to 84). Six (85.7%) patients were diagnosed intraoperationally, while one (14.3%) patient was diagnosed 12 hours after the procedure. The perforation area was the sigmoid colon in six patients and the ascending colon in one patient; all patients underwent surgery. Four patients were discharged with no complications. One of the remaining three patients had enterocutaneous fistula, one had acute renal failure, and one died of sepsis. Conclusion: The progress of perforation due to colonoscopy varies according to the underlying diseases, the mechanism of perforation formation, the treatment modality used, and the experience of the physicians treating the patient. Special attention should be paid to senior and comorbid patients receiving therapeutic procedures during colonoscopy. PMID- 29260129 TI - Evaluation of perioperative nutritional status with subjective global assessment method in patients undergoing gastrointestinal cancer surgery. AB - Objective: This study was designed to evaluate the perioperative nutritional status of patients undergoing surgery for gastrointestinal cancer using Subjective Global Assessment and surgeon behavior on nutritional support. Material and Methods: We recruited 100 patients undergoing surgery for gastrointestinal cancer in one university and two state teaching hospitals. Subjective Global Assessment was administered to evaluate preoperative and postoperative nutritional status. Fifty-two patients in the state hospitals (Group 1) and 48 in the university hospital were assessed. Anthropometric and biochemical measurements were performed. Changes in preoperative Subjective Global Assessment scores and scores at the time of discharge and types of nutritional support were compared. Subjective Global Assessment-B was regarded as moderate and Subjective Global Assessment-C as heavy malnutrition. Results: Ten patients had Subjective Global Assessment-B and 29 had Subjective Global Assessment-C malnutrition in Group 1 and nine had Subjective Global Assessment-B and 31 had Subjective Global Assessment-C malnutrition in Group 2 during preoperative assessment. Respective numbers in postoperative assessment were 12 for Subjective Global Assessment-B and 30 for Subjective Global Assessment-C in Group 1 and 14 for Subjective Global Assessment-B and 26 for Subjective Global Assessment-C in Group 2. There was no difference between two groups. Nutritional methods according to Subjective Global Assessment evaluation in pre- and postoperative periods were not different between the groups. Conclusion: This study demonstrated that the malnutrition rate is high among patients scheduled for gastrointestinal cancer surgery and the number of surgeons were inadequate to provide perioperative nutritional support. Both university and state hospitals had similar shortcomings. Subjective Global Assessment is an easy and reliable test and if utilized will be helpful to detect patients requiring nutritional support. PMID- 29260130 TI - Comparison of open appendectomy and laparoscopic appendectomy with laparoscopic intracorporeal knotting and glove endobag techniques: A prospective observational study. AB - Objective: Despite the recent increase in the use of laparoscopic appendectomy procedures to treat acute appendicitis, laparoscopic appendectomy is not necessarily the best treatment modality. The aim of this study is to examine the value of laparoscopic intracorporeal knotting and glove endobag in terms of various parameters and in terms of reducing the costs related to laparoscopic appendectomy procedures. Material and Methods: Seventy-two acute appendicitis patients who underwent laparoscopic appendectomy and open appendectomy surgery were enrolled in the study and were evaluated prospectively. The patients were divided into two groups: group 1 was treated with laparoscopic appendectomy using laparoscopic intracorpreal knotting and glove endobag (n=36) and group 2 was treated with open appendectomy (n=36). The two groups were statistically compared in terms of preoperative symptoms and signs, laboratory and imaging findings, operation time and technique, pain score, gas and stool outputs, duration of hospital stay, return to normal activity, and complications. Results: No statistically significant differences were found between the groups in relation to gender, age, body mass index, or pre-operation findings, which included loss of appetite, vomiting, time when pain started, displacement of pain, defense, rebound, imaging methods, and laboratory and pathology examinations (p>0.05). Moreover, there were no differences between the groups with respect to drain usage, hospital stay time, or complications (p>0.05). In contrast, a statistically significant difference was found between the groups in terms of operation time, pain scores, gas-stool outputs, and return to normal activity in the laparoscopic appendectomy group (p=0.001). Conclusion: Laparoscopic appendectomy can be performed in a facile, safe, and cost-effective manner with laparoscopic intracorporeal knotting and glove endobag. By using these techniques, the use of expensive instruments can be avoided when performing laparoscopic appendectomy. PMID- 29260131 TI - Is it possible to reduce the surgical mortality and morbidity of peptic ulcer perforations? AB - Objective: Peptic ulcer perforation is a life-threatening situation requiring urgent surgical treatment. A novel vision in peptic ulcer perforation is necessary to fill the gaps created by antiulcer medication, aging of the patients, and presentation of resistant cases in our era. In this study, we aimed to share our findings regarding the effects of various risk factors and operative techniques on the mortality and morbidity of patients with peptic ulcer perforation. Material and Methods: Data from 112 patients presenting at our Training and Research Hospital Emergency Surgery Department between January 2010 and December 2015 who were diagnosed with PUP through physical examination and laboratory and radiological tests and operated at the hospital have been retrospectively analyzed. Patients were divided into three groups based on morbidity (Group 1), mortality (Group 2), and no complication (Group 3). Results: Of the 112 patients included in the study, morbidity was observed in 21 (18.8%), mortality in 11 (9.8%), and no complication was observed in 80 (71.4%), who were discharged with cure. The differences between group for the average values of the perforation diameter and American Society of Anesthesiologists, Acute Physiology and Chronic Health Evaluation II, and Mannheim Peritonitis Index scores were statistically significant (p<0.001 for each). The average values for the group with mortality were significantly higher than those of the other groups. Conclusion: In this study where we investigated risk factors for increased morbidity and mortality in PUPs, there was statistically significant difference between the average values for age, body mass index, perforation diameter, and Acute Physiology and Chronic Health Evaluation II and Mannheim Peritonitis Index scores among the three groups, whereas the amount of subdiaphragmatic free air did not differ. PMID- 29260132 TI - Clinicopathological analysis of appendiceal mucinous tumors: A single-center experience. AB - Objective: Appendiceal mucinous tumors can be encountered in four different types. The clinical approach varies according to these types and the severity of the present disease. We aimed to share clinical, radiological, and pathological features and surgical options of the patients diagnosed with mucinous tumors at our center. Material and Methods: Between August 2009 and March 2016, 757 patients underwent appendectomy for presumed diagnosis of acute appendicitis at the Department of Surgery, Kahramanmaras Sutcu Imam University School of Medicine, Kahramanmaras, Turkey. Among them, demographic, clinical, and histopathological characteristics of patients who diagnosed with appendiceal mucinous tumors were retrospectively analyzed. This study was approved by our faculty's human ethics committee. Results: Incidence of mucinous tumor was 1.71%. Mean age of a total of 13 cases including 6 women and 7 men was 52.4+/-21.6 years (Range: 25-83 years). On preoperative diagnosis, acute appendicitis was detected in 8 patients, perforated appendicitis and periappendiceal abscess in two patients, and suspicious cecal mass in two patients. One patient had an operation for uterine leiomyoma. On histopathological examination, four patients were diagnosed with simple mucinous cyst, four with mucinous cystadenoma, three with mucosal hyperplasia, and two with mucinous cystadenocarcinoma. Mean duration of hospital stay was 5.1+/-4.7 days. One patient died from septic shock on first day, one from respiratory failure on 14th day, and one from cardiac arrest on 20th day. The average follow-up duration for the other 10 patients was 44 months (ranging from 1 to 78 months). No recurrence or death occurred in these patients over the course of follow-up. Conclusion: Intraoperative clinical diagnosis of appendiceal mucinous tumors is rarely seen. Close histopathological and cytological examination of the specimen is required to separate malignant tumors from benign ones. The treatment varies depending on different types and the severity of the disease. PMID- 29260133 TI - Clinicopathological features of gastroenteropancreatic neuroendocrine tumors: A retrospective evaluation of 42 cases. AB - Objective: Neuroendocrine tumors arise from neuroendocrine cells in any part of the body; approximately two thirds of these tumors are located in the gastrointestinal tract and pancreas. Although gastroenteropancreatic neuroendocrine tumors are known as rare neoplasms, their prevalence has recently increased due to advanced diagnostic methods and increased awareness of the disorder. In the present study, we aimed to review patients who were treated and followed up for gastroenteropancreatic neuroendocrine tumors at our clinic in terms of clinical picture, pathological findings, and prognosis. Material and Methods: Data from 42 patients diagnosed with gastroenteropancreatic neuroendocrine tumors who were treated and followed up at our Training and Research Hospital from August 2011 to December 2015 were retrospectively evaluated. Results: A total of 42 patients aged 17-81 years (mean age 46.9 years) were enrolled in the study. The most common symptom was abdominal pain, which was seen in 31 (73.8%) patients. gastroenteropancreatic neuroendocrine tumors were detected in the stomach (n=5, 35.7%), appendix (n=11, 26.2%), rectum (n=6, 14.3%), pancreas (n=4, 9.5%), ileum and colon (n=2, 4.8%), and duodenum and jejunum (n=1, 2.4%). Local excision was performed in seven (16.7%) patients. Nine (21.4%) patients underwent gastric wedge resections, either by a laparoscopic procedure (n=3) or by open surgery (n=6). Total gastrectomy and laparoscopic subtotal gastrectomy were performed on three (7.1%) patients and two patients (4.8%), respectively. After the surgical procedures, the patients were followed up for a mean period of 36 months (15-57 months); the one-year and three-year survival rates were determined to be 100% and 97.6%, respectively. Conclusion: Management of gastroenteropancreatic neuroendocrine tumors requires accumulation of knowledge and experience to establish a standardized approach. Therefore, we believe that collecting regular national data from these cases in every country will contribute to understanding the details of this entity worldwide. PMID- 29260134 TI - The effects of sleeve gastrectomy on shoe size one year after surgery. AB - Objective: The aim of this study is to evaluate the effects of sleeve gastrectomy on shoe size one year after the procedure. To our knowledge, no study has yet been conducted addressing this issue. Material and Methods: Patients who were prepared for sleeve gastrectomy were eligible for the study, and all data and preoperative shoe sizes were recorded in our prospective database. At the 12th month of follow-up, each patient's excess weight loss % was calculated, and their shoe sizes were recorded by verbal report. Arbitrary or half-size changes were not taken into consideration. The probability of a change in shoe size and the effects of age, sex, preoperative body mass index, and 12th month excess weight loss % on this change were investigated. p<0.05 was regarded as statistically significant. Results: The subjects of the study were 212 patients who completed their 12-month follow-ups after sleeve gastrectomy between January 2012 and February 2016. The mean shoe size was 41.5; this decreased to 40.5 one year after sleeve gastrectomy (p<0.001). In patients with body mass index (BMI)>50, both the mean decrease (p=0.008) and the percentage of at least two size decreases (p=0.009) were significantly higher than those in patients with BMI<40. Age, sex, and excess weight loss % did not have any significant effects on shoe size. Conclusion: Sleeve gastrectomy was clearly associated with decrease in shoe size after 12 months. Only preoperative body mass index was found to be directly associated with this decrease. PMID- 29260135 TI - Laparoscopic surgery in distal pancreatic tumors. AB - Objective: Laparoscopic distal pancreatectomy is increasingly being used in the surgical treatment of corpus and distal pancreatic tumors. In this study, patients who underwent laparoscopic or open distal pancreatectomy for benign or malignant causes were evaluated in terms of tumor characteristics and perioperative outcomes. Material and Methods: We retrospectively reviewed data from a total of 27 distal pancreatectomy cases performed for benign or malignant causes in the General Surgery Department between January 2013 and December 2015. Groups were compared according to the demographic characteristics of patients, operation type (laparoscopic or open, with splenectomy or spleen preservation), operation time, surgical site infection (superficial, deep wound infection, or intra-abdominal abscess), pancreatic fistula development, and histopathological examination results. Results: Both groups were similar in terms of age, sex, and body mass index (p=0.42). Tumor diameter was similar (p=0.18). The total number of resected lymph nodes was similar in both groups (p=0.6). Pancreatic fistula developed in one patient in each group. Mean hospital stay duration and the amount of intraoperative bleeding were similar in both groups. The laparoscopy group had a markedly lower overall morbidity rate (p=0.08). There was no mortality observed in the study subjects. Conclusion: Laparoscopic distal pancreatectomy can be safely performed as a minimally invasive procedure in experienced centers and in selected cases without increasing perioperative complication rates, particularly in benign cases. Although oncological outcomes are acceptable for malignant cases, future prospective controlled studies are necessary for more reliable evaluation. PMID- 29260136 TI - Central hepatectomy: A valuable option to avoid posthepatectomy liver insufficiency in patients requiring extensive liver resection. PMID- 29260137 TI - Splenic hamartoma is a rare cause of abdominal pain: Case report and literature review. AB - Hamartoma is a rare benign tumor of the spleen. It is often asymptomatic and diagnosed incidentally. In this study, we report the case of a 51-year-old female patient who was admitted to our department for intermittent epigastric pain since the last 6 months and left upper quadrant fullness. She was diagnosed with splenic hamartoma histopathologically after splenectomy. Although splenic hamartoma is very rare, it must be included in the differential diagnosis of splenic mass-forming lesions. PMID- 29260138 TI - Giant multicystic malignant pheochromocytoma. AB - Pheochromocytoma is a rare tumor originating from the embryonic neural crest and secreting high levels of catecholamines. The average tumor size is approximately 7 cm, and the average weight is approximately 200 g in the previous publications. Sometimes these tumors may be bigger. In this report, a case of multicystic malignant pheochromocytoma with a huge size is presented, which is seldom reported in the past. A 37-year-old male patient was referred to our hospital for etiological investigation of his recently diagnosed hypertension. Contrast enhanced computed tomography (CT) examination was performed for further evaluation of the lesion and surrounding tissues. The lesion was 18*8*13 cm in size. It had lobulated margins, large cystic components, and peripheral and septal contrast enhancement. The levels of metanephrine, normetanephrine, adrenaline, noradrenaline, vanilmandelic acid, and dopamine were significantly elevated. The patient was prepared for surgery. In the pathological evaluation, the mass weighed 1018 g and was 18*8*13 cm in size. He was diagnosed with malignant pheochromocytoma. After eight months, a CT examination showed a recurrent mass, liver metastasis, and distant metastasis. The patient received chemotherapy and radiotherapy. Multicystic malignant pheochromocytoma may reach huge sizes without causing any symptoms. PMID- 29260139 TI - A rare soft tissue tumor located in the trunk: Ossifying fibromyxoid tumor. AB - Ossifying fibromyxoid tumor (OFMT), a rare soft tissue tumor, is generally located in the extremities with a distinct morphology characterized by bland, small cells lying in a fibromyxoid stroma and a peripheral rim of the lamellar bone. These tumors mostly express Leu-7, neuron specific enolase in addition to S 100 and vimentin. Some tumors may have malignant cytological features with aggressive behavior but even in classical morphology, recurrence or metastasis can be detected. Thus, the outcome of the tumor remains a mystery and depends on the different results detected during the follow up. Herein, we report a case of OFMT regarding this entity in the differential diagnosis of subcutaneous masses. PMID- 29260140 TI - Invasive papillary breast carcinoma, solid variant with neuroendocrine differentiation. AB - Invasive papillary carcinoma, solid variant is a rarely observed breast tumor. It is encountered in patients of advanced ages and has a good prognosis. After the physical examination, mammography, and ultrasonography examinations, modified radical mastectomy were applied to the 72-year-old patient, who came to our hospital complaining of a mass in the left breast. During the macroscopic analysis, a well-limited, necrotic, and bleeding tumor with a diameter of 7 cm was found in the left breast, covering almost the whole area. The case was diagnosed as invasive papillary carcinoma, solid variant with neuroendocrine differentiation, which has been reported in the literature as a result of the histopathological and immunohistochemical analysis. PMID- 29260141 TI - A rare case of non-surgical vocal cord paralysis: Vocal cord hematoma. AB - Although vocal cord paralysis (VCP) following thyroidectomy is primarily associated with surgical trauma, it is not the sole etiology. Vocal cord paralysis following thyroidectomy can be caused by a vocal cord hematoma with an incidence of 1.4% due to direct injury during orotracheal intubation. In this article, we present a case of VCP caused by vocal cord hematoma. A 32-year-old male patient who has been receiving propylthiouracil treatment for toxic multinodular goiter since 10 years was admitted to our hospital to be operated because of persisting complaints. The patient was hospitalized for sutureless thyroidectomy after he became euthyroid. Preoperative fiberoptic laryngoscopy performed by the ear, nose, and throat department revealed bilaterally motile vocal folds and a completely open airway. Patient underwent sutureless total thyroidectomy with a vessel sealing device (LigasureTM LF1212, Covidien, CO), and a minivac drainage system was placed in the thyroid lodge. On the morning of the first postoperative day, 50 mL of serosanguinous fluid was drained. The patient's voice was normal, and there was no ecchymosis. Postoperative fiberoptic laryngoscopy revealed a hematoma near the right vocal fold and paralysis of the right vocal fold; however, the airway was open. It should be kept in mind that VCP is not solely due to surgery but can also result from intubation, as observed in this case. PMID- 29260142 TI - Myxoglobulosis in the appendix. AB - Myxoglobulosis is a specific type of mucocele consisting of mucoid material. It is characterized by opaque, transparent globules that resemble "fish eggs" or "frogspawns". It is generally diagnosed incidentally during an appendectomy or an autopsy. In this paper, we aim to present the case of a 58-year-old male patient who was referred to our hospital because of abdominal pain and loss of appetite. The patient underwent an appendectomy. Opaque intraluminal globules were found in the appendectomy material. The globules resembled pearls and they were 2-3 mm in diameter. After histopathological examinations, the patient was diagnosed with myxoglobulosis accompanied with acute appendicitis. According to our research, this is the first case of myxoglobulosis in our country. PMID- 29260143 TI - Single-incision laparoscopic adrenalectomy in a patient with acute hypokalemic paralysis due to primary hyperaldosteronism. AB - Acute hypokalemic paralysis is a relatively rare cause of acute weakness. It may resolve spontaneously; however, it may be a potential life-threatening condition. Hypertension may be considered the most important finding in combination with hypokalemic paralysis for raising the suspicion of primary hyperaldosteronism (PHA). A 55-year-old hypertensive Mexican woman was admitted to the Emergency Unit with a sudden onset of generalized paralysis. An endocrinological workup and an abdominal magnetic resonance imaging revealed PHA with a 1.5 cm left adrenal tumor. After preoperative medication, left adrenalectomy was performed with single-incision laparoscopic surgery (SILS). The duration of the surgery was 45 min, and no postoperative complication was encountered. The patient was discharged after 24 h. Hypokalemic paralysis may be due to different conditions, but it may raise the suspicion of PHA in combination with a history of generally mild hypertension. Laparoscopic adrenalectomy is the preferred operation for unilateral adrenal adenomas that cause PHA. Single-incision laparoscopic surgery is a step-forward technique that improves the cosmesis, decreases access-related morbidity, and increases the postoperative recovery. We report a case with acute hypokalemic paralysis due to PHA and treated with SILS. PMID- 29260144 TI - Pneumatosis cystoides intestinalis: A rare cause of intraabdominal free air. AB - Pneumatosis cystoides intestinalis is a rarely seen disease characterized by cysts filled with multiple gases in the wall of the small or large intestine. Many factors have been suggested in the etiology and pathogenesis, including peptic ulcer, pyloric stenosis, and endoscopic trauma. Because various clinical characteristics and symptoms are observed together, diagnosis is generally difficult. It may be a cause of free air observed on direct radiographs. Treatment is directed at the cause and although there is generally a good course, it can sometimes lead to severe complications. In this paper, we present the case of a 33-year old male being prepared for surgery for pyloric stenosis due to a peptic ulcer. In the preoperative tests, because acid was determined within the abdomen and free air below the diaphragm, pneumatosis cystoides intestinalis was considered in the differential diagnosis. Definitive diagnosis was made during the operation and surgical treatment was applied. PMID- 29260145 TI - Editorial comment on: 'Colonoscopic perforations: Single center experience and review of the literature'. PMID- 29260146 TI - Authors' reply. PMID- 29260148 TI - Authors' reply. PMID- 29260147 TI - Editorial comment on: 'Evaluation of the Alvarado scoring system in the management of acute appendicitis'. PMID- 29260149 TI - Self-assembly of heteroleptic dinuclear silver(i) complexes bridged by bis(diphenylphosphino)ethyne. AB - We present a study of the self-assembling behaviour in solution of Ag[PF6] with one equivalent of an N^N ligand (N^N = 6,6'-dimethyl-2,2'-bipyridine (6,6' Me2bpy) or 2,2':6',2''-terpyridine (tpy)), together with either 0.5 or one equivalent of the bridging ligand bis(diphenylphosphino)ethyne (dppa). Each product contains a dinuclear cation, with one or two dppa ligands bridging the two Ag+ centres; 6,6'-Me2bpy and tpy, respectively, act as chelating ligands. The compounds have been analysed in solution using NMR spectroscopic methods (1H, 1H{31P}, COSY, NOESY, 13C, HMQC and HMBC), including room and low temperature measurements. 31P{1H} NMR spectra recorded at different temperatures allow a deeper insight into the dynamic equilibrium processes. In addition, solution 31P 109Ag HSQC spectroscopic measurements were performed and show, inter alia, the ratio of the splitting in the F1 dimension and the 1J31P-109Ag coupling constant in the fully coupled HSQC. Single crystal X-ray diffraction yielded two pseudo polymorphic structures for the doubly-bridged [Ag2(dppa)2(tpy)2][PF6]2 and one for the singly-bridged [Ag2(dppa)(6,6'-Me2bpy)2][PF6]2. PMID- 29260151 TI - Chem/bio sensing with non-classical light and integrated photonics. AB - Modern quantum technology currently experiences extensive advances in applicability in communications, cryptography, computing, metrology and lithography. Harnessing this technology platform for chem/bio sensing scenarios is an appealing opportunity enabling ultra-sensitive detection schemes. This is further facilliated by the progress in fabrication, miniaturization and integration of visible and infrared quantum photonics. Especially, the combination of efficient single-photon sources together with waveguiding/sensing structures, serving as active optical transducer, as well as advanced detector materials is promising integrated quantum photonic chem/bio sensors. Besides the intrinsic molecular selectivity and non-destructive character of visible and infrared light based sensing schemes, chem/bio sensors taking advantage of non classical light sources promise sensitivities beyond the standard quantum limit. In the present review, recent achievements towards on-chip chem/bio quantum photonic sensing platforms based on N00N states are discussed along with appropriate recognition chemistries, facilitating the detection of relevant (bio)analytes at ultra-trace concentration levels. After evaluating recent developments in this field, a perspective for a potentially promising sensor testbed is discussed for reaching integrated quantum sensing with two fiber coupled GaAs chips together with semiconductor quantum dots serving as single photon sources. PMID- 29260150 TI - A square planar gold(iii) bis-(1,1'-dimethyl-3,3'-methylene-diimidazol-2,2' diylidene) trication as an efficient and selective receptor towards halogen anions: the cooperative effect of AuX and XHC interactions. AB - Treatment of the tricationic gold(iii) [Au(MeImCH2ImMe)2](PF6)3 complex 1-3PF6 (Im = imidazol-2-ylidene) with excess halides affords complexes 1-3X (X = Cl, Br, and I), resulting from counter anion PF6-/X- exchange. The 1H chemical shift of the CH3 groups and particularly that of the CH2 linker in DMSO-d6 are different in the three complexes, thus suggesting selective XHC interactions. Complex 13+ can therefore be used as a halide sensor in DMSO and water. The host-guest interaction between the tricationic gold(iii) complex and the halides Cl-, Br- and I- in solution and in the solid state has been investigated by means of NMR titration experiments, DFT calculations and X-ray structure analysis. The electrostatic interaction between the halides and the triple formal positive charge on the metal centre, together with the CHX hydrogen bonding between the NHC ligand and halides, contributes to the formation of stable supramolecular aggregates in solution and in the solid state. The complexing properties of 13+ are strongly influenced by the nature of the solvent. Formation of the 1 : 1 and 1 : 2 species (1X2+ and 1X2+) is observed in DMSO-d6, while that of only the 1 : 1 aggregates (1X2+) is observed in D2O (X = Cl, Br, and I). Moreover, the selectivity towards the various halides is reversed in the two solvents, being in the order Cl- > Br- > I- in DMSO-d6 and I- > Br- > Cl- in D2O. The formation constants of the species 1X2+ and 1X2+ in DMSO and 1X2+ in water have been determined by fitting the NMR titration curves. PMID- 29260152 TI - Unravelling the nature of glyphosate binding to goethite surfaces by ab initio molecular dynamics simulations. AB - Investigation of the interaction between glyphosate (GLP) and soil minerals is essential for understanding GLP's fate in the environment. Whereas GLP-goethite binding has been discussed extensively, the impact of water as well as of different goethite surface planes has not been studied yet. In this contribution, periodic density functional theory-based molecular dynamics simulations are applied to explore possible binding mechanisms for GLP with three goethite surface planes (010, 001, and 100) in the presence of water. The investigation included several binding motifs of monodentate (M) and bidentate (B) type. It was found that the binding stability increases in the order M@001 < M@010 < (2O + 2Fe) B@100 < M@100 < (1O + 2Fe) B@001 < (2O + 1Fe) B@010. This behavior has been traced to the presence of intramolecular H-bonds (HBs) in GLP as well as intermolecular HBs between GLP and water, GLP and goethite, and water and goethite. These interactions are accompanied by proton transfer from GLP to water and to goethite, and from water to goethite as well as water dissociation at the goethite surface. Further, it was observed that the OH- species can replace the adsorbed GLP at the goethite surface, which could explain the well-known drastic drop in GLP adsorption at high pH. The present results highlight the role of water in the GLP-goethite interaction and provide a molecular level perspective on available experimental data. PMID- 29260153 TI - Spin-selectable, region-tunable negative differential resistance in graphene double ferromagnetic barriers. AB - We propose a graphene device that can generate spin-dependent negative differential resistance (NDR). The device is composed of a sufficiently wide and short graphene sheet and two gated EuO strips deposited on top of it. This scheme avoids the graphene edge tailoring required by previous proposals. More importantly, we find a clear indication of a spin selectivity and a region tunability in the spin-dependent NDR: by changing the top gates of the device, NDR for spin up only, spin down only, or both spins (occurring sequentially) can be respectively realized; meanwhile, the central position of the NDR region in each case can be monotonously tuned over a wide range of bias voltage. These remarkable features are attributed to a gate controllability of the spin dependent resonance levels in the device hence their deviations from the Fermi energy and the Dirac point in the source electrode respectively. They add a spin and a bias degree of freedom to the conventional NDR, which paves the way for designing a whole new class of NDR circuits. PMID- 29260154 TI - Ionic liquids with trichloride anions for oxidative dissolution of metals and alloys. AB - Ionic liquids (ILs) with trichloride anions ([Cl3]-) combined with different cations were synthesised by bringing chlorine gas into contact with the corresponding chloride (Cl-) ILs at room temperature. These trichloride ILs safely store chlorine and are useful as oxidising agents for dissolution of various metals and alloys under mild conditions. PMID- 29260155 TI - Electrochemical microdevices for rapid and on-site determination of the minimum inhibitory concentration of antibiotics. AB - A tool for rapid selection of appropriate antibiotics may be useful to maximize the benefits of their effectiveness against severe infectious diseases. In this study, we propose a microdevice that works with surface tension-driven sample introduction and impedance measurements for on-site, rapid estimation of suitable antibiotics. PMID- 29260156 TI - Enhancing the magnetic anisotropy energy by tuning the contact areas of Ag and Ni at the Ag/Ni interface. AB - Modifying the interfacial conditions of magnetic layers by capping with overlayers can efficiently enhance the magnetic functionality of a material. However, the mechanisms responsible for this are closely related to the crystalline structure, compositional combinations, and interfacial quality, and are generally complex. In this contribution, we explored the use of Ag ultrathin overlayers on annealed . A method for preparing magnetic layers with different levels of enhanced magnetic anisotropy energy was developed. The method essentially involves simply modifying the contact area of the metallic/magnetic interface. A rougher interface results in a larger contact area between the Ag and Ni layers, resulting in an increase in magnetic anisotropy energy. Moreover, post-annealing treatments led to the segregation of Ni atoms, thus making the enhancement in the coercive force even more efficient. A model permits an understanding of the contact area and a strategy for enhancing the magnetic anisotropy energy and the coercive force was developed. Our approaches and the developed model promise to be helpful in terms of developing potential applications of ultrathin magnetic layers in the area of spintronics. PMID- 29260157 TI - Lattice mismatch as the descriptor of segregation, stability and reactivity of supported thin catalyst films. AB - The increasing demand and high prices of advanced catalysts motivate a constant search for novel active materials with reduced contents of noble metals. The development of thin films and core-shell catalysts seems to be a promising strategy along this path. Using density functional theory we have analyzed a number of surface properties of supported bimetallic thin films with the composition A3B (where A = Pt and Pd, and B = Cu, Ag and Au). We focus on the surface segregation, dissolution stability and surface electronic structure. We also address the chemisorption properties of Pd3Au thin films supported by different substrates, by probing the surface reactivity with CO. We find a strong influence of the support in the case of mono- and bilayers, while the surface strain seems to be the predominant factor in determining the surface properties of supported trilayers and thicker films. In particular, we show that the studied properties of the supported trilayers can be predicted from the lattice mismatch between the overlayer and the support. Namely, if the strain dependence of the corresponding quantities for pure strained surfaces is known, the properties of strained supported trilayers can be reliably estimated. The obtained results can be used in the design of novel catalysts and predictions of the surface properties of supported ultrathin catalyst layers. PMID- 29260158 TI - Chemical strategies to unravel bacterial-eukaryotic signaling. AB - The common language of bacteria and higher life forms is a lexicon of small molecules that the research community is only beginning to decipher. While many new signaling molecules have been discovered in recent years, the identification of their targets is mostly lagging. This review will focus on the latest chemical probe based research aimed at understanding how bacteria interact chemically with mammals and plants. In general, chemical biology strategies remain under-utilized in this complex field of research, with a few key exceptions, and we hope that this review encourages others to implement these techniques in their research. Specifically, we highlight the chemical biology techniques used in recent studies, especially activity-based protein profiling, that have been applied to unravel the chemical mechanisms of interkingdom interactions. PMID- 29260159 TI - Pronounced exciton and coherent phonon dynamics in BiI3. AB - Trivalent bismuth compounds featuring octahedral halide coordination, such as BiI3, double-perovskite structures and vacancy-ordered perovskite derivatives, have recently attracted considerable attention as potential environmentally benign thin film materials for solar light-harvesting and optoelectronic applications aiming to replace toxic lead-based perovskites. Yet, their photovoltaic performance still lags considerably behind their lead-counterparts. Improving their performance requires a detailed knowledge of the photoinduced carrier dynamics and kinetics in these systems. In the current study, we present a detailed investigation of layered BiI3. The compound exhibits pronounced exciton dynamics which is associated with a characteristic second-derivative type feature in the transient absorption spectra. Accurate time constants are assigned to carrier cooling and recombination processes. Pronounced coherent oscillations are observed in the kinetic traces indicating strong electron-phonon coupling. Analysis of the coherences recovers the steady-state Raman spectrum of BiI3 with a dominant mode of Ag symmetry at 114 cm-1, associated with the zone center C(Gamma) phonon. The line position is well reproduced by DFT calculations. In terms of the carrier lifetime, high absorption coefficient and band-gap position, BiI3 is a promising candidate as a photovoltaic material but challenges posed are the difficulty to split the strongly bound excitons which are confined in the 2D layers and the efficient extraction of electrons and holes at n- and p-selective contacts, beside well-known issues regarding high resistivity and the intrinsic softness of this material. PMID- 29260160 TI - Validating an optimized GAFF force field for liquid crystals: TNI predictions for bent-core mesogens and the first atomistic predictions of a dark conglomerate phase. AB - The GAFF-LCFF force field [N. J. Boyd et al., Phys. Chem. Chem. Phys., 2015, 17, 24851] is tested and further improved for use in the simulation of bent-core liquid crystal mesogens. Atomistic simulations are carried out on four systems of bent-core nematogens based on a central bis-(phenyl)oxadiazole (ODBP) motif, providing excellent agreement with experimental, TNI, transition temperatures. Simulations of one bent-core system (C5-Ph-ODBP-Ph-OC12) indicate the presence of a dark conglomerate (DC) phase, with the prediction of a highly unusual nematic to DC phase transition. PMID- 29260161 TI - Ca-Al double-substituted strontium hexaferrites with giant coercivity. AB - We demonstrate that the simultaneous substitution of calcium and aluminum for strontium and iron in strontium hexaferrite results in a significant increase of coercivity up to a record high of 21.3 kOe. We propose that the effect is originated from a crystal structure distortion causing an increase of the magnetocrystalline anisotropy. PMID- 29260162 TI - A comprehensive study of catalytic, morphological and electronic properties of ligand-protected gold nanoclusters using XPS, STM, XAFS, and TPD techniques. AB - Ultra-small gold nanoclusters were synthesized via a ligand exchange method and deposited onto different TiO2 supports to study their properties. STM imaging revealed that the as-synthesized gold nanoclusters had 2-D morphology consisting of monolayers of gold atoms. Subsequent XPS, XAFS, and CO oxidation TPD results indicated that heat treatments of gold clusters at different temperatures significantly altered their electronic and catalytic properties due to ligand deprotection and cluster agglomeration. PMID- 29260163 TI - A reversible fluorescent probe based on C[double bond, length as m-dash]N isomerization for the selective detection of formaldehyde in living cells and in vivo. AB - Formaldehyde (FA) is an endogenously produced reactive carbonyl species (RCS) through biological metabolic processes whose concentration is closely related to human health and disease. Noninvasive and real-time detection of FA concentration in organisms is very important for revealing the physiological and pathological functions of FA. Herein, we design and synthesize a reversible fluorescent probe BOD-NH2 for the detection of FA in living cells and in vivo. The probe is composed of two moieties: the BODIPY fluorophore and the primary amino group response unit. The probe undergoes an intracellular aldimine condensation reaction with FA and forms imine (C[double bond, length as m-dash]N) which will result in C[double bond, length as m-dash]N isomerization and rotation to turn off the fluorescence of the probe. It is important that the probe can show a reversible response to FA. The probe BOD-NH2 has been successfully applied for detecting and imaging FA in the cytoplasm of living cells. BOD-NH2 is capable of detecting fluctuations in the levels of endogenous and exogenous FA in different types of living cells. The probe can be used to visualize the FA concentration in fresh hippocampus and the probe can further qualitatively evaluate the FA concentrations in ex vivo-dissected organs. Moreover, BOD-NH2 can also be used for imaging in mice. The above applications make our new probe a potential chemical tool for the study of physiological and pathological functions of FA in cells and in vivo. PMID- 29260164 TI - Angstrom-scale probing of paramagnetic centers location in nanodiamonds by 3He NMR at low temperatures. AB - In this article a method to assess the location of paramagnetic centers in nanodiamonds was proposed. The nuclear magnetic relaxation of adsorbed 3He used as a probe in this method was studied at temperatures of 1.5-4.2 K and magnetic fields of 100-600 mT. A strong influence of the paramagnetic centers of the sample on the 3He nuclear spin relaxation time T1 was found. Preplating the nanodiamond surface with adsorbed nitrogen layers allowed us to vary the distance from 3He nuclei to paramagnetic centers in a controlled way and to determine their location using a simple model. The observed T1 minima in temperature dependences are well described within the frame of the suggested model and consistent with the concentration of paramagnetic centers determined by electron paramagnetic resonance. The average distance found from the paramagnetic centers to the nanodiamond surface (0.5 +/- 0.1 nm) confirms the well-known statement that paramagnetic centers in this type of nanodiamond are located in the carbon shell. The proposed method can be applied to detailed studies of nano-materials at low temperatures. PMID- 29260165 TI - Structure analysis of collagen fibril at atomic-level resolution and its implications for intra-fibrillar transport in bone biomineralization. AB - Bone is a hierarchical biocomposite material in which a collagen fibril matrix self-assembled in a three-dimensional (3-D) pseudohexagonal array controls many important processes in mineralization such as providing the pathways by which calcium and phosphate species are delivered and a template for the earliest nucleation sites, determining the spatial distribution of the mineral and the topology for binding of associated non-collagenous proteins. However, the structural characteristics of collagen molecules in the fibril remain unclear at the atomic level. Here we performed the first large-scale molecular dynamics simulations to provide a comprehensive all-atom structural analysis of the entire fibril of Type I collagen including intra-fibrillar water distribution. We found that the ideal fibril structure is preserved in specific sites where the earliest nucleation occurs, but is severely distorted in areas that mineralize later. In detail, the ideal pseudohexagonal structure is well-preserved in the overlap zone (c1, c2 and b bands), in the a bands of the hole zone but is severely distorted at the hole/overlap transition (d and c3 bands). As a result, the expected uniform "channel," formed by connecting holes in adjacent unit cells along the b axis, and having dimensions of 1.5 nm height along the a-axis and width of 40 nm along the c-axis is not formed. The expected uniform channel of 1.5 nm height is preserved only in the a bands in a narrow sub-channel region only 5.8 nm wide. At the hole/overlap transition, an irregular, tortuous sub-channel of widely varying dimensions (~1.8-4.0 nm height * ~3.0 nm width) is formed. The well-defined sub channel in the a bands along with their preferred orientation of charged amino acid residues could facilitate faster molecular diffusion than the tortuous sub channels and ionic interactions, thus providing the first nucleation sites. Intra fibrillar water occupies nano-spaces and shows low density (~0.7 g cm-3), which should promote dehydration of ion species. These results provide the first atomic level understanding of the structure of the collagen fibril and the properties of the aqueous compartments within the fibril, which offer a physical, chemical and steric explanation for calcium phosphate infiltration paths and for the initiation of mineralization at the a band collagen fibril. The mechanism revealed here for the observed specificity of collagen biomineralization in bone formation ultimately contributes to the biochemical and biomechanical functions of the skeleton. PMID- 29260166 TI - Bacteria assisted protein imprinting in sol-gel derived films. AB - A hierarchical imprinting strategy was used to create protein imprints in a silicate film with a high binding capacity as well as selectivity toward the imprint protein and little specificity towards other proteins. In the first part of this work, rod-shaped bacteria were used as templates to create imprints in silica films of various thicknesses to open up the silica framework and increase the surface area exposed to solution. In the second part, the protein (e.g., cytochrome c (CYC) or green fluorescent protein (GFP)) was covalently attached to the surface of Bacillus subtilis and this protein-bacteria complex served as the imprint moiety. Atomic force microscopy and scanning electron microscopy were used to image the micron-size rod-shaped bacteria imprints formed on the silica surface. Fluorescence microscopy, which was used to follow the fabrication process with GFP as the representative protein, clearly demonstrated protein imprinting, protein removal and protein rebinding as well as protein specificity. Visible absorption spectroscopy using CYC as the imprint protein demonstrated relatively fast uptake kinetics and also good specificity against other proteins including bovine serum albumin (BSA), horseradish peroxidase (HRP), glucose oxidase (GOD), and lysozyme (LYZ). Collectively this work demonstrates a new surface bio-imprinting approach that generates recognition sites for proteins and provides a viable means to increase the binding capacity of such imprinted thin films. PMID- 29260167 TI - Hierarchical TiO2-x imbedded with graphene quantum dots for high-performance lithium storage. AB - Hierarchical TiO2-x imbedded with graphene quantum dots was synthesized through a facile synthetic route and investigated as an anode material for lithium-ion batteries. It delivers a high specific capacity and excellent rate capability (160.1 mA h g-1 at 10 C after 500 cycles). PMID- 29260168 TI - Intrinsic sources of high thermal conductivity of CdSiP2 determined by first principle anharmonic calculations. AB - CdSiP2 is an outstanding mid-infrared nonlinear optical crystal material with high thermal conductivity. However, the microscopic physics behind its thermal transport behavior is still unclear. In this study, we have investigated the source of the thermal conductivity of CdSiP2 based on anharmonicity lattice dynamics (ALD) and the first-principle calculation. The results are well accordance with the experimental measurement in a wide temperature range. Based on our results, the acoustic phonon lifetime of CdSiP2 is higher than that of the thermoelectric and semiconducting materials reported in previous studies, which is induced by the low lattice anharmonicity demonstrated by CdSiP2. The mode dependent thermal conductivity is obtained with the contribution of optical phonons being significant (27%) above 300 K; this is mainly due to the high phonon group velocity and relatively long phonon lifetime of low-energy optical phonons (80-200 cm-1). A high lifetime of acoustic phonons and remarkable contribution of low-energy optical phonons can be responsible for the high thermal conductivity of CdSiP2. PMID- 29260169 TI - Open and closed forms of the interpenetrated [Cu2(Tae)(Bpa)2](NO3)2.nH2O: magnetic properties and high pressure CO2/CH4 gas sorption. AB - Two closed and one open structural forms of the interpenetrated [Cu2(Tae)(Bpa)2](NO3)2.nH2O (H2Tae = 1,1,2,2-tetraacetylethane, Bpa = 1,2-bis(4 pyridyl)ethane) cationic coordination polymer have been synthesized. Three crystallographically related interpenetrated "ths" cationic nets encapsulate water molecules and nitrate anions giving rise to the closed structural forms of [Cu2(Tae)(Bpa)2](NO3)2.nH2O. Depending on the location of water molecules and nitrate groups, two different closed forms with 5.5 and 3.6 crystallization water molecules have been obtained. The thermal activation of the closed structures gives rise to a 29% expansion of the unit cell. This closed to open transformation is reversible, and is triggered by the loss or uptake of solvent. The high pressure gas adsorption experiments show similar selectivity values towards CO2 for CO2/CH4 mixtures to that showed by some metal organic frameworks without unsaturated metal sites, and isosteric heats for CO2 adsorption similar to that for the HKUST-1 compound. PMID- 29260170 TI - Analyses of trajectory on-the-fly based on the global reaction route map. AB - A methodology to analyze a trajectory on-the-fly (TOF) based on a global reaction route map consisting of intrinsic reaction coordinate (IRC) pathways is proposed. By using the distance functions in the configurational space, the location of each point on the trajectories is detected, providing a dynamical picture that the molecular system goes over several minima and transition states in the reaction path network. In its application to structural transformations of an Au5 cluster, a variety of reaction routes are obtained, and the hopping from one IRC to another IRC (IRC-jump) is analyzed. The branching of trajectories over many minima on the potential energy surface via valley-ridge transition points is also discussed. PMID- 29260171 TI - Bioconcentration, bioaccumulation, biomagnification and trophic magnification: a modelling perspective. AB - We present a modelling perspective on quantifying metrics of bio-uptake of organic chemicals in fish. The models can be in concentration, partition ratio, rate constant (CKk) format or fugacity, Z and D value (fZD) format that are shown to be exactly equivalent, each having it merits. For most purposes a simple, parameter-parsimonious one compartment steady-state model containing some 13 parameters is adequate for obtaining an appreciation of the uptake equilibria and kinetics for scientific and regulatory purposes. Such a model is first applied to the bioaccumulation of a series of hypothetical, non-biotransforming chemicals with log KOW (octanol-water partition ratio) values of 4 to 8 in 10 g fish ranging in lipid contents to deduce wet-weight and lipid normalized concentrations, bioaccumulation and biomagnification factors. The sensitivity of biomagnification factors to relative lipid contents is discussed. Second, a hypothetical 5 species linear food chain is simulated to evaluate trophic magnification factors (TMFs) showing the critical roles of KOW and biotransformation rate. It is shown that lipid normalization of concentrations is most insightful for less hydrophobic chemicals (log KOW < 5) when bio-uptake is largely controlled by respiratory intake and equilibrium (equi-fugacity) is approached. For more hydrophobic chemicals when dietary uptake kinetics dominate, wet weight concentrations and BMFs are more insightful. Finally, a preferred strategy is proposed to advance the science of bioaccumulation using a combination of well-designed ecosystem monitoring, laboratory determinations and modelling to confirm that the perceived state of the science contained in the models is consistent with observations. PMID- 29260172 TI - Controllable dissociation of H2O on a CeO2(111) surface. AB - Splitting water on metal oxide surfaces plays a key role in surface catalytic reactions. Continuously tuning the molecular/dissociative states of H2O can be expected to achieve controllable catalysis. In this work, we propose a promising method to split water on a CeO2(111) surface and uncover the dissociation mechanism. According to first-principles calculations, we demonstrate that tensile strain facilitates water dissociation on the CeO2(111) surface due to the enhancement of hybridization between the 4f states of surface Ce and the 2p states of the dissociated H2O. More importantly, strain-induced water dissociation could also apply to other metal oxide surfaces, such as PaO2(111), ThO2(111), and CaO(100). It is proposed that different behaviors of the oxygen 2p band center shift for molecular and dissociative H2O are responsible for tensile strain-induced water dissociation on metal oxide surfaces. The results indicate that Ag(111) or Au(111) can serve as substrates to realize water dissociation on ultra-thin CeO2(111) films. Our studies provide an effective approach for tuning the surface reactions of metal oxide surfaces by modulating lattice parameters. PMID- 29260173 TI - Fucoidan inhibits amyloid-beta-induced toxicity in transgenic Caenorhabditis elegans by reducing the accumulation of amyloid-beta and decreasing the production of reactive oxygen species. AB - Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. As the aging population is increasing, AD is becoming one of the leading causes of disability and death among the elderly. However, currently there is no cure for this disease. Fucoidan is a complex sulfated polysaccharide mainly found in brown seaweed. Recent studies have shown that fucoidan is neuroprotective and may have potential to be used for treating and/or preventing neurodegenerative diseases such as AD. In this study, we investigated the effects and possible mechanisms of fucoidan on Abeta induced toxicity in a transgenic Caenorhabditis elegans (C. elegans) AD model. The results showed that the supplementation of fucoidan alleviated the paralyzed phenotype induced by Abeta. The number of Abeta deposits in the AD animals was reduced by fucoidan treatment. Further analysis of the levels of Abeta showed that fucoidan significantly decreased the accumulation of Abeta in transgenic AD C. elegans. It was found that fucoidan treatment elevated the activity of proteosomes; therefore, fucoidan might decrease Abeta accumulation by promoting proteolysis. In addition, fucoidan treatment reduced the production of reactive oxygen species (ROS) stimulated by Abeta induction. These results suggested that fucoidan might exert its protective effects against Abeta-induced toxicity in transgenic AD C. elegans by reducing the accumulation of toxic Abeta and decreasing Abeta-induced production of ROS, thus ameliorating the progression of the AD phenotype. PMID- 29260174 TI - Isostructural lanthanide-based metal-organic frameworks: structure, photoluminescence and magnetic properties. AB - A series of the anhydrous lanthanide-based metal-organic frameworks (Ln-MOFs) were successfully synthesized under hydrothermal conditions of Ln(iii) ions with 3,4'-oxybis(benzoate) (3,4'-oba), oxalate (ox) and 1,10-phenanthroline (phen). Structural analyses revealed that they are isostructural 3D open-frameworks with the formula of [Ln(3,4'-oba) (phen)(ox)0.5]n (Ln = Sm for 1, Eu for 2, Gd for 3, Tb for 4, and Dy for 5) and the topology of {33.43.58.6}. Within the 3D structure, the [LnO6N2] units are bridged by ox to form [Ln2ox] dimers and then are further connected by 3,4'-oba ligands. These complexes feature high chemical stabilities in common solvents, boiling water, and acidic (pH = 3) and alkaline (pH = 13) solutions and high thermal stability even up to 400 degrees C. The photoluminescence and magnetic properties were studied. Especially, 2 shows bright red emission with a high luminescence efficiency of 40.51%. We mainly discuss the luminescence properties of 2 in common solvents and inorganic ions. It shows luminescence stability in common solvents and the ability to detect ammonia and Fe3+ ions under a long excitation wavelength (350 nm). Significantly, magnetic studies reveal that the Dy-MOF, 5, shows a typical single-molecule magnetic behavior. Under zero dc field, compound 5 shows temperature and frequency dependent out-of-phase (chi''M) signals, indicating the existence of slow magnetic relaxation. PMID- 29260175 TI - Neutral two-dimensional organometallic-organic hybrid polymers based on pentaphosphaferrocene, bipyridyl linkers and CuCl. AB - The reaction of the Pn ligand complex [Cp*Fe(eta5-P5)] (1: Cp* = eta5-C5Me5) with CuCl in the presence of 4,4'-bipyridine or 1,2-di(4-pyridyl)ethylene leads to the formation of three unprecedented neutral 2D organometallic-organic hybrid networks, the constitutional isomers [Cu2Cl2{Cp*Fe(MU3,eta5:1:1-P5)}(MU,eta1:1 C10H8N2)]n (2 and 3) and the coordination polymer [(CuCl)2{Cp*Fe(MU3,eta5:1:1 P5)}(MU,eta1:1-C12H10N2)]n (4) with isomeric square (2 and 3) and honeycomb (4) layer topologies. PMID- 29260176 TI - On the study of the C6+ ion beam and gamma-ray induced effect on structural and luminescence properties of Eu doped LiNaSO4: explanation of TSL mechanism using PL, TL and EPR study. AB - The present paper reports on the gamma-ray and C6+ ion beam induced effect on the structural and luminescence properties of Eu doped LiNaSO4 phosphors synthesized via wet the chemical method. The material was irradiated by 60Co and 137Cs gamma rays and 75 MeV C6+ ions in a fluence range varying from 2 * 1010 to 1 * 1012 ion per cm2. The ion induced modified properties were investigated using X-ray diffraction (XRD), micro-Raman spectroscopy, photoluminescence (PL), thermoluminescence (TL) and electron paramagnetic resonance (EPR) studies. The XRD and micro-Raman results confirm the loss of crystallinity and elongation of the lattice parameters after ion beam irradiation. The presence of both divalent as well as trivalent states of Eu ions at multiple sites of LiNaSO4 is observed by PL study. Irradiation of the LiNaSO4:Eu phosphor with a C6+ ion beam modifies the population of the valence state of the doped rare earth Eu ion and enhances the TL sensitivity of this phosphor. The nature of the prominent TL glow curve is identical for both gamma-ray and C6+ ion beam irradiated materials while additional deep trap levels appear in the latter due to the formation of several types of cation and anion vacancy. The electron paramagnetic resonance (EPR) technique also supports the presence of the Eu ion at multiple sites and provides information regarding several types of radical produced after gamma-ray and C6+ ion irradiation. Finally, a mechanism is presented for the thermally stimulated luminescence phenomenon on the basis of our observed results from the PL, TL and EPR studies. The reason behind ion beam irradiation induced modification of the TL properties and enhancement of luminescence intensity is also explained in this report. PMID- 29260177 TI - Preparation and reactivity of a square-planar PNP cobalt(ii)-hydrido complex: isolation of the first {Co-NO}8-hydride. AB - The synthesis of a square-planar cobalt(ii) hydrido complex supported by a pyrrole-based PNP ligand has been reinvestigated and its reactivity with various small molecules examined. Preparation of the complex was accomplished by treatment of the corresponding chloride complex, [CoCl(tBuPNP)] (tBuPNP = anion of 2,5-bis((di-tert-butylphosphino)methyl)pyrrole), with di-iso-butylaluminum hydride (DIBAL). Reaction of [CoCl(tBuPNP)] with other hydride sources such as NaEt3BH and LiAlH4 resulted in mixtures of the desired Co(ii) hydride along with the reduced Co(i) species, [Co(N2)(tBuPNP)], as the primary product. The hydride complex exhibits facile migratory insertion chemistry with CO2 producing the corresponding Co(ii) formate complex. When the Co-H complex is reacted with nitric oxide, the first example of a cobalt nitrosyl hydride complex is produced. PMID- 29260178 TI - Highly-luminescent Eu,Sm,Mn-doped CaS up/down conversion nano-particles: application to ultra-sensitive latent fingerprint detection and in vivo bioimaging. AB - Due to their unique properties, rare-earth doped upconversion luminescence (UCL) nanomaterials are of considerable scientific interest. Meanwhile, alkaline-earth sulfide materials based on a completely different electron trapping (ET) mechanism demonstrate extremely high UCL efficiencies, which are several dozens of times more than those of conventional fluoride UCL nanomaterials. However, the large particle size, easy hydrolysis, and difficulty in achieving uniform dispersion have precluded bioassay applications. Herein, we have synthesized super-bright Eu,Sm,Mn-doped CaS nanoparticles of ~30 nm average particle size using a reverse microemulsion technique. The UCL quantum yield was up to nearly 60%. Modification of the nanoparticles with an organic layer allows their stable dispersion throughout aqueous solutions without significant loss of the fluorescence intensity. We demonstrate the application of the novel UCL materials to latent fingerprint detection, deep tissue imaging, and in vivo bioimaging. PMID- 29260179 TI - Prospects for efficient solar energy upconversion using metalloporphyrins as dual absorber-upconverters. AB - The novel potential use of selected metalloporphyrins as dual absorber upconverters in solar photovoltaics is discussed. Additional efficiencies are available if use can be made of the porphyrin's short-lived S2 state, which is formed directly by excitation in the strong Soret transition in the blue-violet and also by absorption in the Q bands followed by rapid intersystem crossing and upconversion by triplet-triplet annihilation. The main challenge in realizing a working photovoltaic based on such a protocol is that energy must be extracted from the S2 state of the porphyrin within its picosecond lifetime. The structure property relationships that may be used to select metalloporphyrins with the longest possible intrinsic lifetimes are outlined. The prospects for energy extraction from S2via ultrafast electron transfer or ultrafast resonant electronic energy transfer within a solid structure designed to maximize efficiency are discussed. Both MOF and pendant porphyrin polymer structures offer reasonable possibilities. PMID- 29260180 TI - Fe(ii) and Co(ii) N-methylated CYCLEN complexes as paraSHIFT agents with large temperature dependent shifts. AB - Several complexes of Co(ii) or Fe(ii) with 1,4,7,10-tetraazacyclododecane (CYCLEN) appended with 1,7-(6-methyl)2-picolyl groups are studied as 1H NMR paraSHIFT agents (paramagnetic shift agents) for the registration of temperature. Two of the complexes, [Co(BMPC)]2+ and [Fe(BMPC)]2+, contain methyl groups only on the methyl picolyl pendents. Two other complexes, [Co(2MPC)]2+ and [Fe(2MPC)]2+, contain picolyl groups and also methyl groups on the macrocyclic amines. All macrocyclic complexes are in high spin form as shown by solution magnetic moments in the range of 5.0-5.9MUBM and 5.3-5.8MUBM for Co(ii) and Fe(ii) complexes, respectively. The 1H NMR spectra of both of the Fe(ii) complexes and one of the Co(ii) complexes are consistent with a predominant diastereomeric form in deuterium oxide solutions. The highly shifted methyl proton resonances for [Co(2MPC)]2+ appear at 164 and -113 ppm for macrocycle and pendent picolyl methyls and show temperature coefficients of -0.58 ppm degrees C 1 and 0.49 ppm degrees C-1, respectively. Fe(ii) complexes have less shifted methyl proton resonances and smaller temperature coefficients. The 1H resonances of [Fe(2MPC)]2+ appear at 105 ppm and -46 ppm with corresponding temperature coefficients (CT) of -0.29 ppm degrees C-1 and 0.22 ppm degrees C-1, respectively. The relatively narrow linewidths of [Fe(2MPC)]2+, however, produce superior CT/FWHM values of 0.44 and 0.31 degrees C-1 for the N-methyl and picolyl proton resonances where FWHM is the full width at half maximum of the 1H resonance. The crystal structure of [Co(BMPC)]Cl2 shows a six-coordinate Co(ii) bound to the macrocyclic amines and two pendent picolyl groups. The distorted trigonal prismatic geometry of the complex resembles that of an analogous complex containing four 6-methyl-2-picolyl groups, in which only two picolyl pendents are coordinated. PMID- 29260181 TI - Reshaped fecal gut microbiota composition by the intake of high molecular weight persimmon tannin in normal and high-cholesterol diet-fed rats. AB - It has been proposed that the gut microbiome may be related to obesity, and diet induced obesity may induce changes in the gut microbiota composition. Our previous studies suggested that persimmon tannin (PT), which is highly polymerized and non-absorbable in the intestine, showed anti-hyperlipidemic and cholesterol-lowering effects in animal models. Considering that the possible composition modification effects of PT on intestinal bacteria might contribute to its anti-hyperlipidemic and cholesterol-lowering effects in vivo, in this study, we determined whether the PT administration could modify the gut microbiota in both normal diet-fed and high-cholesterol (HC) diet-fed rats, and how PT altered the bacterial composition in both normal and HC fed rats. Sprague-Dawley rats were randomly divided into eight groups, and fed with either a normal or an HC diet supplemented with or without a low/medium/high dose of PT (50 (LPT), 100 (MPT), 200 (HPT) mg per kg body weight (BW) per day, respectively) for 4 weeks. On days 0, 7, 14, 21 and 28, feces were collected and prepared for the microbiota and physicochemical analysis. The results showed that LPT and MPT supplementation significantly altered the gut microbiota composition by increasing the Bacteroidetes/Proteobacteria ratio in both normal diet-fed and HC diet-fed rats. LPT also decreased the Firmicutes/Bacteroidetes ratio in normal diet-fed rats and MPT decreased the Firmicutes/Bacteroidetes ratio in HC diet-fed rats. Both LPT and MPT supplementation induced a significant alteration in specific bacterial species after 14 days of treatment. The relative abundance of Bifidobacterium sp. and Lactobacillus sp. was increased by both LPT and MPT treatment, and that of Escherichia coli and Enterococcus was reduced. Our data also indicate that there is a correlation between the changes in bacterial composition and the changes in short-chain fatty acid (SCFA) metabolism. However, HPT supplementation altered the gut microbiota at the phylum and species levels in an adverse way. PMID- 29260182 TI - Auto-generated iron chalcogenide microcapsules ensure high-rate and high-capacity sodium-ion storage. AB - Sodium-ion batteries (SIBs) are regarded as promising alternative energy-storage devices to lithium-ion batteries (LIBs). However, the trade-off of between energy density and power density under high mass-loading conditions restricts the application of SIBs. Herein, we synthesized an FeSe@FeS material via a facile solid-state reaction. A microcapsule architecture was spontaneously achieved in this process, which facilitated electron transport and provided stable diffusion paths for Na ions. The FeSe@FeS material exhibits a high capacity retention (485 mA h g-1 at 3 A g-1 after 1400 cycles) and superior rate capability (230 mA h g-1 at 10 A g-1 after 1600 cycles) in the half-cell test. Furthermore, superior cycling stability is achieved in the full-cell test. The high mass-loaded FeSe@FeS electrodes (8 mg cm-2) realize a high areal capacity retention of 2.8 mA h cm-2 and high thermal stability. PMID- 29260183 TI - Mobilization of iron from ferritin: new steps and details. AB - Much evidence indicates that iron stored in ferritin is mobilized through protein degradation in lysosomes, but concerns about this process have lingered, and the mechanistic details of its aspects are lacking. In the studies presented here, 59Fe-labeled ferritin was induced by preloading hepatic (HepG2) cells with radiolabeled Fe. Placing these cells in a medium containing desferrioxamine resulted in the loss of ferritin-59Fe, but adding high concentrations of reducing agents or modulating the internal GSH concentration failed to alter the rates of ferritin-59Fe release. Confocal microscopy showed that Fe deprivation increased the movement of ferritin into lysosomes and hyperaccumulation was observed when lysosomal proteolysis was inhibited. It also resulted in the rapid movement of DMT1 to lysosomes, which was inhibited by bafilomycin. Ferrihydrite crystals isolated from purified rat liver/spleen ferritin were solubilized at pH 5 and 7 by GSH, ascorbate, citrate and lysosomal fluids obtained from livers and J774a.1 macrophages. The inhibition of DMT1/Nramp2 and siRNA knockdown of Nramp1 each reduced the transfer of 59Fe from lysosomes to the cytosol; and hepatocyte specific knockout of DMT1 in mice prevented the release of Fe from the liver responding to EPO treatment, but did not inhibit lysosomal ferritin degradation. We conclude that ferritin-Fe mobilization does not occur through changes in cellular concentrations of reducing/chelating agents but by the coordinated movement of ferritin and DMT1 to lysosomes, where the ferrihydrite crystals exposed by ferritin degradation dissolve in the lysosomal fluid, and the reduced iron is transported back to the cytosol via DMT1 in hepatocytes, and by both DMT1 and Nramp1 in macrophages, prior to release into the blood or storage in ferritin. PMID- 29260184 TI - Amaranth addition to enzymatically modified wheat flour improves dough functionality, bread immunoreactivity and quality. AB - Consumers with gluten-related disorders require gluten-free (GF) foods to avoid an immune response. Alternative to the use of non-gluten containing grains to prepare GF bread, the gluten reactivity has been greatly reduced using a proline specific cleavage enzyme, however, the gluten functionality was lost. The aim of this study was to evaluate the effect of adding an amaranth flour blend (AFB) to enzymatically modified wheat-flour proteins on dough functionality and to evaluate the immunoreactivity and acceptability of the prepared bread. First, wheat flour (20% w/v, substrate) was hydrolyzed using 8.4 U mg-1 protein Aspergillus niger prolyl-endopeptidase (AnPEP) for 8 h at 40 degrees C under constant agitation. Four types of breads were prepared with the same formulation except for the type of flour (14% w.b.): wheat flour (WF), WF-AFB unmodified not incubated, WF-AFB unmodified incubated and WF-AFB modified. The protein composition and free thiols were analyzed before and after amaranth addition, and the flour and bread proteins were run using SDS-PAGE and immune-detected in blots with IgA from celiac disease patients. The immunoreactive gluten content, specific volume and bread acceptability were evaluated. The polymeric proteins and free thiol groups of WF decreased after AnPEP treatment. The electrophoretic patterns of the modified flour and bread proteins were different and the IgA immunodetection in blots was highly reduced, particularly for the higher molecular weight subunits. The addition of AFB to the modified wheat flour prepared using AnPEP improved the dough functionality by increasing the thiol groups and allowed the preparation of a sensorially acceptable bread with only 60 mg kg-1 immunoreactive gluten. PMID- 29260185 TI - Electrochemical biosensor for cancer cell detection based on a surface 3D micro array. AB - The detection of rare circulating tumour cells (CTCs) in patients' blood is crucial for the early diagnosis of cancer, highly precise cancer therapy and monitoring therapeutic outcomes in real time. In this study we have developed an efficient strategy to capture and detect CTCs from the blood of cancer patients using a benzoboric acid modified gold-plated polymeric substrate with a regular 3D surface array. Compared with the smooth substrate, the substrate with the surface 3D microarrays exhibited a higher capture efficiency, i.e. 3.8 times that afforded by the smooth substrate. Additionally, due to the reversible reaction between the benzoboric acid on the 3D microarray and the sialic acid on CTCs, our strategy allowed for easy detachment of the captured CTCs from the substrate without causing critical damage to the cells. This will be of benefit for gaining further access to these rare cells for downstream characterization. The proposed strategy provides several advantages, including enhanced capture efficiency, high sensitivity, low cost and recovery of isolated CTCs, and could become a promising platform for early stage diagnosis of cancer. PMID- 29260186 TI - A hydrazone based probe for selective sensing of Al(iii) and Al(iii)-probe complex mediated secondary sensing of PPi: framing of molecular logic circuit and memory device and computational studies. AB - A hydrazone-based conjugate Nap-hyz-pyz (H3L3) with potential N2O2 donor atoms was found to act as a dual channel (colori- and fluori-metric) sensor towards Al3+ and PPi in H2O-MeOH (6 : 4, v/v) at pH 7.2 (40 mM HEPES buffer) at 25 degrees C. The formation constants, Kf = (3.49 +/- 1.77) * 104 and (3.78 +/- 0.1) * 104 M-1, of the sensor towards Al3+ were determined by absorption and fluorescence titrations, respectively. The 1 : 1 stoichiometry of the reaction was determined by Job's method and confirmed by ESI-MS+ (m/z) studies. The LOD for Al3+, as determined by the 3sigma method, was found to be 114.54 nM. Most strikingly, the addition of ~115 MUM PPi to the Nap-hyz-pyz-Al3+ ensemble (20 MUM ligand and 74 MUM Al3+) leads to complete quenching of fluorescence. The fluorescence response of Nap-hyz-pyz towards Al3+ was not perturbed by the presence of 5 equivalents or more of other ions and inorganic anions. The structure of the [Al(L3)(H2O)] complex was delineated by DFT calculations. TD-DFT studies were performed to investigate various spectral transitions. Based on changes in the fluorescence intensities of Nap-hyz-pyz in the presence of Al3+ and PPi at 487 nm, INHIBIT and molecular logic gates were constructed and interpreted. The probe was found to be bio-compatible and cell permeable with no or negligible cytotoxicity; thus, it provides a good opportunity for in vitro cell imaging studies of these ions. The presence of ATP or Pi did not interfere with the fluorescent detection of PPi. Thus, these evident and excellent sensing capabilities of Nap-hyz-pyz towards Al3+ and PPi were further scrutinized in HepG2 cell lines. PMID- 29260187 TI - Coupling effects in 3D plasmonic structures templated by Morpho butterfly wings. AB - This paper presents the study of the coupling effects of three dimensional (3D) plasmonic nanostructures templated by Morpho butterfly wings. Different from the random deposition of metallic nanoparticles (NPs) or conformal coating of metallic layers on butterfly wings reported previously, the 3D plasmonic nanostructures studied in this work consist of gold (Au) nanostrips quasi periodically arranged in 3D, which allows us to investigate the plasmonic coupling effects. Through refractive index (RI) matching, the plasmonic coupling can be differentiated from the optical contribution of butterfly wings. By tuning the deposition thickness of Au from 30 to 90 nm, the plasmonic coupling effects between the 3D Au nanostrips are gradually enhanced. In particular, the near field coupling results in two resonant modes and enhances the surface-enhanced Raman scattering (SERS) signals. PMID- 29260188 TI - A Short History of Bioengineering Research in Ireland. AB - In July 2018, Ireland will host the World Congress of Biomechanics in Dublin. This Congress is held once every 4 yr and is the premier meeting worldwide in its field, with over 3000 people expected to visit Dublin in July. The awarding of the 2018 Congress to Ireland is a reflection of the strength of biomechanics and bioengineering research in this country. To mark this event, herein we describe the development of biomechanics and bioengineering research in Ireland over the past 40 yr, which has grown in parallel with the medical device industry as well as the expansion of Government investment in science, innovation, and a knowledge based economy. The growth of this activity has resulted in Ireland becoming established as a global hub in the field. PMID- 29260189 TI - Chicago. PMID- 29260190 TI - Novel Mutations in PRPF31 Causing Retinitis Pigmentosa Identified Using Whole Exome Sequencing. AB - Purpose: The purpose of this study was to investigate the disease-causing mutations for retinitis pigmentosa (RP) patients and function of mutations. Methods: We recruited RP families and sporadic RP patients, and performed whole exome sequencing (WES) to screen for sequence variations. Subsequently, we investigated the expression of green fluorescent protein (GFP) merged expression vectors containing PRPF31 wild type (WT) and its variants. We determined protein stability by cycloheximide (CHX) treatment. Results: Two frameshift variants, c.547delG (p.E183fs) and c.804delG (p.L268fs), and one stopgain variant, c.1060C>T (p.R354X), in the pre-mRNA processing factor 31 gene (PRPF31) were identified in three RP families. In comparison with WT, the expressions of GFP fused PRPF31 (GFP-PRPF31) protein with the mutation c.547delG or c.804delG in HEK293 cells were significantly reduced. However, the expression of GFP-PRPF31 containing the stopgain mutation (GFP-PRPF31sg) was increased. CHX treatment of HEK293 showed the GFP-PRPF31sg protein was more stable than GFP-PRPF31 WT. The WT protein expression was localized in the nuclei, and the mutants in both nuclei and cytoplasm. We screened for PRPF31 mutations in 131 sporadic RP patients by WES and successfully identified three novel mutations: c.G781C (p.G261R), c.A1373T (p.Q458L), and c.C1222T (p.R408W). Conclusions: Our study revealed novel mutations of PRPF31 in RP. Our results also showed that the two mutations (c.547delG or c.804delG) affect gene expression and GFP-PRPF31sg has increased protein stability. PMID- 29260191 TI - Effect of Age-Related Human Lens Sutures Growth on Its Fluid Dynamics. AB - Purpose: Age-related nuclear cataract is the opacification of the clear ocular lens due to oxidative damage as we age, and is the leading cause of blindness in the world. A lack of antioxidant supply to the core of ever-growing ocular lens could contribute to the cause of this condition. In this project, a computational model was developed to study the sutural fluid inflow of the aging human lens. Methods: Three different SOLIDWORKS computational fluid dynamics models of the human lens (7 years old; 28 years old; 46 years old) were created, based on available literature data. The fluid dynamics of the lens sutures were modelled using the Stokes flow equations, combined with realistic physiological boundary conditions and embedded in COMSOL Multiphysics. Results: The flow rate, volume, and flow rate per volume of fluid entering the aging lens were examined, and all increased over the 40 years modelled. However, while the volume of the lens grew by ~300% and the flow rate increased by ~400%, the flow rate per volume increased only by very moderate ~38%. Conclusions: Here, sutural information from humans of 7 to 46 years of age was obtained. In this modelled age range, an increase of flow rate per volume was observed, albeit at very slow rate. We hypothesize that with even further increasing age (60+ years old), the lens volume growth would outpace its flow rate increases, which would eventually lead to malnutrition of the lens nucleus and onset of cataracts. PMID- 29260192 TI - Patchy Chorioretinal Atrophy Changes at the Posterior Pole After Ranibizumab for Myopic Choroidal Neovascularization. AB - Purpose: To investigate the potential role of ranibizumab treatment on the development or enlargement of chorioretinal atrophy (CRA) at the posterior pole in eyes with myopic choroidal neovascularization (mCNV). Methods: This observational case series included patients having high myopia spherical equivalent refractive error >= -6.00 diopters, axial length (AxL) >= 26.0 mm in both eyes, and mCNV treated with ranibizumab 0.5 mg in one eye, who were retrospectively enrolled. Areas of CRA in treated and fellow eyes were measured on fundus autofluorescence images at baseline, 12, and 24 months. The CRA hypoautofluorescent lesions were divided in two groups: perilesional atrophy, corresponding to area around the mCNV, and patchy extralesional atrophy, corresponding to CRA between the temporal vascular arcades. Results: Thirty-six eyes of 18 patients were included. The mean perilesional CRA size significantly increased from baseline to 12 months (3.5 +/- 10.6 mm2, P = 0.02) and 24 months (4.4 +/- 11.7 mm2, P = 0.038) in the treated eye. In treated and not treated eyes, patchy extralesional CRA at the posterior pole increased significantly from baseline to 12 and 24 months follow-up. None of the fellow eyes developed mCNV. No significant relationship was found between the number of injections, AxL, age, and perilesional and patchy extralesional CRA in the treated and not treated eyes (P > 0.05). Conclusions: In eyes with pathologic myopia and mCNV, intravitreal injections of ranibizumab should not be considered as a contributing risk factor worsening the natural course of CRA, even though the risk of the perilesional CRA enlargement should be taken into account. PMID- 29260193 TI - Corneal and Retinal Neuronal Degeneration in Early Stages of Diabetic Retinopathy. AB - Purpose: To examine the neuronal structural integrity of cornea and retina as markers for neuronal degeneration in nonproliferative diabetic retinopathy (NPDR). Methods: Participants were recruited from the broader Brisbane community, Queensland, Australia. Two hundred forty-one participants (187 with diabetes and 54 nondiabetic controls) were examined. Diabetic retinopathy (DR) was graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), corneal nerve fiber tortuosity (CNFT), full retinal thickness, retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), focal (FLV) and global loss volumes (GLV), hemoglobin A1c (HbA1c), nephropathy, neuropathy, and cardiovascular measures were examined. Results: The central zone (P = 0.174), parafoveal thickness (P = 0.090), perifovea (P = 0.592), RNFL (P = 0.866), GCC (P = 0.798), and GCC GLV (P = 0.338) did not differ significantly between the groups. In comparison to the control group, those with very mild NPDR and those with mild NPDR had significantly higher focal loss in GCC volume (P = 0.036). CNFL was significantly lower in those with mild NPDR (P = 0.004) in comparison to the control group and those with no DR. The CNBD (P = 0.094) and CNFT (P = 0.458) did not differ between the groups. Conclusions: Both corneal and retinal neuronal degeneration may occur in early stages of diabetic retinopathy. Further studies are required to examine these potential markers for neuronal degeneration in the absence of clinical signs of DR. PMID- 29260194 TI - Corneal Aberrations in Former Preterm Infants: Results From The Wiesbaden Prematurity Study. AB - Purpose: To compare corneal aberrations in former preterm infants to that of full term infants. Methods: A prospective cross-sectional study was carried out measuring the corneal shape with Scheimpflug imaging in former preterm infants of gestational age (GA) <=32 weeks and full-term infants with GA >=37 weeks now being aged between 4 to 10 years. The main outcome measures were corneal aberrations including astigmatism (Zernike: Z2-2; Z22), coma (Z3-1; Z31), trefoil (Z3-3; Z33), spherical aberration (Z40) and root-mean square of higher-order aberrations (RMS HOA). Multivariable analysis was performed to assess independent associations of gestational age groups and of retinopathy of prematurity (ROP) occurrence with corneal aberrations adjusting for sex and age at examination. Results: A total of 259 former full-term and 226 preterm infants with a mean age of 7.2 +/- 2.0 years were included in this study. Statistical analysis revealed an association of extreme prematurity (GA <=28 weeks) with higher-order and lower order aberrations of the total cornea. Vertical coma was higher in extreme prematurity (P < 0.001), due to the shape of the anterior corneal surface, while there was no association with trefoil and spherical aberration. ROP was not associated with higher-order aberrations when adjusted for gestational age group. Conclusions: This study demonstrated that specific corneal aberrations were associated with extreme prematurity rather than with ROP occurrence. PMID- 29260195 TI - Diabetic Retinopathy and Macular Edema Quality-of-Life Item Banks: Development and Initial Evaluation Using Computerized Adaptive Testing. AB - Purpose: The purpose of this study was to assess the psychometric properties of diabetic retinopathy (DR) and diabetic macular edema (DME) quality-of-life (QoL) item banks and determine the utility of the final calibrated item banks by simulating a computerized adaptive testing (CAT) application. Methods: In this clinical, cross-sectional study, 514 participants with DR/DME (mean age +/- SD, 60.4 +/- 12.6 years; 64% male) answered 314 items grouped under nine QoL item pools: Visual Symptoms (SY); Ocular Comfort Symptoms (OS); Activity Limitation (AL); Mobility (MB); Emotional (EM); Health Concerns (HC); Social (SC); Convenience (CV); and Economic (EC). The psychometric properties of the item pools were assessed using Rasch analysis, and CAT simulations determined the average number of items administered at high and moderate precision levels. Results: The SY, MB, EM, and HC item pools required minor amendments, mainly involving removal of six poorly worded, highly misfitting items. AL and CV required substantial modification to resolve multidimensionality, which resulted in two new item banks: Driving (DV) and Lighting (LT). Due to unresolvable psychometric issues, the OS, SC, and EC item pools were not pursued further. This iterative process resulted in eight operational item banks that underwent CAT simulations. Correlations between CAT and the full item banks were high (range, 0.88-0.99). On average, only 3.6 and 7.2 items were required to gain measurement at moderate and high precision, respectively. Conclusions: Our eight psychometrically robust and efficient DR/DME item banks will enable researchers and clinicians to accurately assess the impact and effectiveness of treatment therapies for DR/DME in all areas of QoL. PMID- 29260196 TI - Development and Validation of a Risk Score for Age-Related Macular Degeneration: The STARS Questionnaire. AB - Purpose: To develop and validate a risk score for AMD based on a simple self administered questionnaire. Methods: Risk factors having shown the most consistent associations with AMD were included in the STARS (Simplified Thea AMD Risk-Assessment Scale) questionnaire. Two studies were conducted, one in Italy (127 participating ophthalmologists) and one in France (80 participating ophthalmologists). During 1 week, participating ophthalmologists invited all their patients aged 55 years or older to fill in the STARS questionnaire. Based on fundus examination, early AMD was defined by the presence of soft drusen and/or pigmentary abnormalities and late AMD by the presence of geographic atrophy and/or neovascular AMD. Results: The Italian and French samples consisted of 12,639 and 6897 patients, respectively. All 13 risk factors included in the STARS questionnaire showed significant associations with AMD in the Italian sample. The area under the receiving operating characteristic curve for the STARS risk score, derived from the multivariate logistic regression in the Italian sample, was 0.78 in the Italian sample and 0.72 in the French sample. In both samples, less than 10% of patients without AMD were classified at high risk, and less than 13% of late AMD cases were classified as low risk, with a more intermediate situation in early AMD cases. Conclusions: STARS is a new, simple self-assessed questionnaire showing good discrimination of risk for AMD in two large European samples. It might be used by ophthalmologists in routine clinical practice or as a self-assessment for risk of AMD in the general population. PMID- 29260197 TI - The Intraocular Lens as a Drug Delivery Device: In Vitro Screening of Pharmacologic Substances for the Prophylaxis of Posterior Capsule Opacification. AB - Purpose: Numerous pharmacologic substances have been proposed for preventing posterior capsule opacification (PCO). The following trial was to compare those drugs to find more suitable options. IOL should then be modified by the pharmaceuticals as a drug-delivery device. Methods: A systematic literature search was performed to identify published substances. FHL-124 was used to determine cell proliferation and toxicity using a dye reduction test (XTT). Prescreened substances showing a reduction on cell growth without being toxic were soaked into an IOL. Those IOL were tested for their effect on PCO in an anterior-segment model and the human ex vivo capsular bag model. Toxicity on a corneal endothelial cell line (CEC-SV40) was determined. Release kinetics of methotrexate from the IOL was measured. Toxicity testing in both cell lines was done in serum-free conditions. All growth assays were exposed to 10% fetal calf serum (FCS)-supplemented medium. Results: The substances inhibited cell growth at the following EC50: caffeic acid phenethyl ester 1.6 +/- 0.9 nM, disulfiram 359 +/- 33 nM, methotrexate 98.0 +/- 29.7 nM, rapamycin 70.2 +/- 14.0 pM, and retinoic acid 1.1 +/- 0.12 nM. All but disulfiram showed an effect in the anterior segment model when soaked into an IOL. Long-term inhibitory effects in the human capsular bag model were observed for caffeic acid phenethyl ester and methotrexate IOLs. Only methotrexate and disulfiram did not show any toxicity on endothelial cells. Methotrexate was released constantly from the hydrophilic IOL for 2 weeks. Conclusions: We could identify caffeic acid phenethyl ester and methotrexate in vitro as potential candidates for IOL modification for PCO prophylaxis. PMID- 29260198 TI - Micro- and Nanoscale Topographies on Silk Regulate Gene Expression of Human Corneal Epithelial Cells. AB - Purpose: Corneal basement membrane has topographical features that provide biophysical cues to direct cell adherence, migration, and proliferation. In this study, we hypothesize that varying topographic pitch created on silk films can alter epithelial cell morphology, adhesion, and the genetic expression involved in cytoskeletal dynamics-related pathways. Methods: Silicon wafers with parallel ridge widths of 2000, 1000, and 800 nm were produced and used to pattern silk films via soft lithography. Human corneal epithelial cells were cultured onto silk. After 72 hours of incubation, images were taken to study cell morphology and alignment. Cytoskeletal structures were studied by immunofluorescent staining. RNA was collected from cultured cells to perform RNA-Seq transcriptome analysis using the Illumina Hiseq 2500 sequencing system. Differentially expressed genes were identified using DNAstar Qseq then verified using quantitative real-time PCR. These genes were used to perform pathway analyses using Ingenuity Pathways Analysis. Results: Primary human corneal epithelial cell alignment to the surface pattern was the greatest on 1000-nm features. Fluorescent microscopy of f-actin staining showed cell cytoskeleton alignment either in parallel (2000 nm) or perpendicular (1000 and 800 nm) to the long feature axis. Z-stack projection of vinculin staining indicated increased focal adhesion formation localized on the cellular basal surface. RNA-seq analysis revealed differentially expressed genes involved in actin organization, integrin signaling, and focal adhesion kinase signaling (-log (P)>5). Conclusions: Patterned silk film substrates may serve as a scaffold and provide biophysical cues to corneal epithelial cells that change their gene expression, alter cellular adherence, morphology, and may offer a promising customizable material for use in ocular surface repair. PMID- 29260201 TI - Graphic Medicine: The Best of 2017. PMID- 29260199 TI - Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation. AB - Purpose: To assess the association between systemic levels of inflammation associated proteins and severe retinopathy of prematurity (ROP) in extremely preterm infants. Methods: We collected whole blood on filter paper on postnatal days 1, 7, 14, 21, and 28 from 1205 infants born before the 28th week of gestation, and measured the concentrations of 27 inflammation-associated, angiogenic, and neurotrophic proteins. We calculated odds ratios with 95% confidence intervals for the association between top quartile concentrations of each protein and prethreshold ROP. Results: During the first three weeks after birth, high concentrations of VEGF-R1, myeloperoxidase (MPO), IL-8, intercellular adhesion molecule (ICAM)-1, matrix metalloproteinase 9, erythropoietin, TNF alpha, and basic fibroblast growth factor were associated with an increased risk for prethreshold ROP. On day 28, high levels of serum amyloid A, MPO, IL-6, TNF alpha, TNF-R1/-R2, IL-8, and ICAM-1 were associated with an increased risk. Top quartile concentrations of the proinflammatory cytokines TNF-alpha and IL-6 were associated with increased risks of ROP when levels of neuroprotective proteins and growth factors, including BDNF, insulin-like growth factor 1, IGFBP-1, VEGFR 1 and -2, ANG-1 and PlGF, were not in the top quartile. In contrast, high concentrations of NT-4 and BDNF appeared protective only in infants without elevated inflammatory mediators. Conclusions: Systemic inflammation during the first postnatal month was associated with an increased risk of prethreshold ROP. Elevated concentrations of growth factors, angiogenic proteins, and neurotrophins appeared to modulate this risk, and were capable of reducing the risk even in the absence of systemic inflammation. PMID- 29260200 TI - Improvement of Photoreceptor Targeting via Intravitreal Delivery in Mouse and Human Retina Using Combinatory rAAV2 Capsid Mutant Vectors. AB - Purpose: Effective intravitreal gene delivery to cells of the central retina (i.e., photoreceptors) would be of substantial benefit for treating patients with retinal diseases, such as achromatopsia, where retinal detachment from a subretinal may be harmful. Previous studies demonstrated that mutation of the recombinant adeno-associated virus (rAAV) capsid through introduction of peptide insertions or amino acid substitutions dramatically alters vector tropism. Herein, we evaluate the photoreceptor transduction efficiency of three rAAV2/2 based capsid mutant vectors: rAAV2/2[7m8], rAAV2/2[QuadYF+TV], and a chimeric vector incorporating both mutations (termed rAAV2/2[MAX]) following intravitreal delivery in mice. Furthermore, we evaluate the transduction efficiency of rAAV2/2[MAX] using explanted human central retinal samples to address clinical translatability. Methods: Vectors containing a GFP or mCherry reporter gene were intravitreally injected into C57BL/6J or Nrl-EGFP mice, respectively. Transduction was assessed in vivo utilizing a custom multiline confocal scanning laser ophthalmoscope. Injected Nrl-EGFP mouse retinas were used to quantify transduced photoreceptors using flow cytometry. Postmortem human retinal tissue was cultured following administration of rAAV2/2[MAX]. C57BL/6J retinas and human explants were cryosectioned to determine vector tropism. Results: The chimeric vector rAAV2/2[MAX] transduced significantly higher proportions of the retina than did either single mutant serotypes following intravitreal delivery in murine retina, including inner retinal cells and photoreceptors. Vector rAAV2[MAX] demonstrated transduction of human photoreceptors and ganglion cells. Conclusions: Transduction observed via rAAV2/2[MAX] indicates that combining mutations with complementary mechanisms of action in a single vector results in enhanced transduction. rAAV2/2[MAX] also presented the ability to transduce human photoreceptors and ganglion cells, indicating potential for efficient intravitreal vector delivery. PMID- 29260202 TI - Medical Schools in the United States, 2016-2017. PMID- 29260203 TI - Graduate Medical Education, 2016-2017. PMID- 29260204 TI - Is Medical Education a Public or a Private Good?: Insights From the Numbers. PMID- 29260205 TI - Guidelines for Statistical Analysis Plans. PMID- 29260206 TI - Cervical Pessary to Prevent Preterm Birth. PMID- 29260207 TI - Blood Test Results-Pronto. PMID- 29260208 TI - First Treatment Approved for Rare Blood Cancer. PMID- 29260209 TI - FDA Pursues Unproven Cancer Claims. PMID- 29260210 TI - Diagnosis and First-Line Treatment of Chronic Sinusitis. PMID- 29260211 TI - Colonoscopy Surveillance After Colorectal Cancer Resection. PMID- 29260213 TI - The War Surgeon. PMID- 29260214 TI - Suicide Risk Behaviors Among Sexual Minority Adolescents in the United States, 2015. PMID- 29260215 TI - Benefits and Risks of Machine Learning Decision Support Systems. PMID- 29260216 TI - Benefits and Risks of Machine Learning Decision Support Systems. PMID- 29260217 TI - Benefits and Risks of Machine Learning Decision Support Systems. PMID- 29260218 TI - Benefits and Risks of Machine Learning Decision Support Systems. PMID- 29260219 TI - Benefits and Risks of Machine Learning Decision Support Systems. PMID- 29260220 TI - Chronic Traumatic Encephalopathy in Football Players. PMID- 29260221 TI - Chronic Traumatic Encephalopathy in Football Players. PMID- 29260222 TI - Benefits and Risks of Machine Learning Decision Support Systems-Reply. PMID- 29260223 TI - Chronic Traumatic Encephalopathy in Football Players-Reply. PMID- 29260224 TI - Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections. AB - Importance: Acute respiratory tract infections account for the majority of antibiotic exposure in children, and broad-spectrum antibiotic prescribing for acute respiratory tract infections is increasing. It is not clear whether broad spectrum treatment is associated with improved outcomes compared with narrow spectrum treatment. Objective: To compare the effectiveness of broad-spectrum and narrow-spectrum antibiotic treatment for acute respiratory tract infections in children. Design, Setting, and Participants: A retrospective cohort study assessing clinical outcomes and a prospective cohort study assessing patient centered outcomes of children between the ages of 6 months and 12 years diagnosed with an acute respiratory tract infection and prescribed an oral antibiotic between January 2015 and April 2016 in a network of 31 pediatric primary care practices in Pennsylvania and New Jersey. Stratified and propensity score-matched analyses to account for confounding by clinician and by patient-level characteristics, respectively, were implemented for both cohorts. Exposures: Broad-spectrum antibiotics vs narrow-spectrum antibiotics. Main Outcomes and Measures: In the retrospective cohort, the primary outcomes were treatment failure and adverse events 14 days after diagnosis. In the prospective cohort, the primary outcomes were quality of life, other patient-centered outcomes, and patient-reported adverse events. Results: Of 30 159 children in the retrospective cohort (19 179 with acute otitis media; 6746, group A streptococcal pharyngitis; and 4234, acute sinusitis), 4307 (14%) were prescribed broad-spectrum antibiotics including amoxicillin-clavulanate, cephalosporins, and macrolides. Broad-spectrum treatment was not associated with a lower rate of treatment failure (3.4% for broad-spectrum antibiotics vs 3.1% for narrow-spectrum antibiotics; risk difference for full matched analysis, 0.3% [95% CI, -0.4% to 0.9%]). Of 2472 children enrolled in the prospective cohort (1100 with acute otitis media; 705, group A streptococcal pharyngitis; and 667, acute sinusitis), 868 (35%) were prescribed broad-spectrum antibiotics. Broad-spectrum antibiotics were associated with a slightly worse child quality of life (score of 90.2 for broad-spectrum antibiotics vs 91.5 for narrow-spectrum antibiotics; score difference for full matched analysis, -1.4% [95% CI, -2.4% to -0.4%]) but not with other patient centered outcomes. Broad-spectrum treatment was associated with a higher risk of adverse events documented by the clinician (3.7% for broad-spectrum antibiotics vs 2.7% for narrow-spectrum antibiotics; risk difference for full matched analysis, 1.1% [95% CI, 0.4% to 1.8%]) and reported by the patient (35.6% for broad-spectrum antibiotics vs 25.1% for narrow-spectrum antibiotics; risk difference for full matched analysis, 12.2% [95% CI, 7.3% to 17.2%]). Conclusions and Relevance: Among children with acute respiratory tract infections, broad spectrum antibiotics were not associated with better clinical or patient-centered outcomes compared with narrow-spectrum antibiotics, and were associated with higher rates of adverse events. These data support the use of narrow-spectrum antibiotics for most children with acute respiratory tract infections. PMID- 29260226 TI - Effect of Cervical Pessary on Spontaneous Preterm Birth in Women With Singleton Pregnancies and Short Cervical Length: A Randomized Clinical Trial. AB - Importance: Spontaneous preterm birth is a major cause of perinatal morbidity and mortality. It is unclear if a cervical pessary can reduce the risk of spontaneous preterm delivery. Objective: To test whether in asymptomatic women with singleton pregnancies and no prior spontaneous preterm birth but with short cervical length on transvaginal ultrasound, use of a cervical pessary would reduce the rate of spontaneous preterm birth at less than 34 weeks of gestation. Design, Setting, and Participants: Parallel-group, nonblinded, randomized clinical trial conducted from March 1, 2016, to May 25, 2017, at a single center in Italy. Asymptomatic women with singleton gestations, no previous spontaneous preterm births, and cervical lengths of 25 mm or less at 18 weeks 0 days to 23 weeks 6 days of gestation were eligible. Interventions: Patients were randomized 1:1 to receive either cervical pessary (n = 150) or no pessary (n = 150). The pessary was removed between 37 weeks 0 days and 37 weeks 6 days of gestation or earlier if clinically indicated. The control group received standard care. For cervical length of 20 mm or shorter, women in both groups were prescribed vaginal progesterone, 200 mg/d, until 36 weeks 6 days of gestation. No bed rest or activity restriction was recommended. Main Outcomes and Measures: The primary end point was spontaneous preterm birth at less than 34 weeks of gestation. Secondary outcomes were adverse events. Results: Among 300 women who were randomized (mean age, 29 [SD, 6.3] years; mean gestational age, 22 [SD, 1.3] weeks), 100% completed the trial. The primary end point occurred in 11 women (7.3%) in the pessary group and 23 women (15.3%) in the control group (between-group difference, -8.0% [95% CI, -15.7% to -0.4]; relative risk, 0.48 [95% CI, 0.24 0.95]). During follow-up, the pessary group had a higher rate of increased or new vaginal discharge (86.7% vs 46.0%; between-group difference, +40.7% [95% CI, +30.1%-+50.3%]; relative risk, 1.88 [95% CI, 1.57-2.27]). Conclusions and Relevance: Among women without prior spontaneous preterm birth who had asymptomatic singleton pregnancies and short transvaginal cervical length, use of a cervical pessary, compared with no pessary use, resulted in a lower rate of spontaneous preterm birth at less than 34 weeks of gestation. The results of this single-center, nonblinded study among selected pregnant women require confirmation in multicenter clinical trials. Trial Registration: clinicaltrials.gov Identifier: NCT02716909. PMID- 29260228 TI - Walking the Shoreline: Erosion, Regrowth, and Professional Formation. PMID- 29260225 TI - Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. AB - Importance: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (>= 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures: Progression-free survival (tested at alpha = .046). The secondary end point was overall survival (tested hierarchically at alpha = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration: clinicaltrials.gov Identifier: NCT00916409. PMID- 29260231 TI - Tuberculosis Update 2017. PMID- 29260229 TI - Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. AB - Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility. Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders. Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration-registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials. Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items. Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials. PMID- 29260232 TI - Latest Report on Health Effects of Climate Change. PMID- 29260233 TI - Preexisting Antibody Titer Associated With Severe Dengue. PMID- 29260234 TI - Evaluation of a multidisciplinary rehabilitation programme for elderly patients with hip fracture: A prospective cohort study. AB - OBJECTIVE: To investigate the effectiveness and cost of an 18-month multi disciplinary Comprehensive Fragility Fracture Management Program (CFFMP) for fragility hip fracture patients. DESIGN: Prospective cohort study. PATIENTS: Elderly patients with hip fracture were recruited at their first postoperative follow-up in 2 district hospitals. The intervention group comprised patients from the hospital undergoing CFFMP, and the control group comprised patients from another hospital undergoing conventional care. CFFMP provided geri-orthopaedic co management, physician consultations, group-exercise and vibration-therapy. Timed up-and-go test (TUG), Elderly Mobility Scale (EMS), Berg Balance Scale (BBS) and fall risk screening (FS) were used to assess functional performance. Incidences of falls and secondary fractures, the cost of the programme and related healthcare resources were recorded. RESULTS: A total of 76 patients were included in the intervention group (mean age 77.9 years ((standard deviation; SD) 6.1) ) and 77 in the control group (79.9 (SD 7.2)), respectively. The re-fracture rate in the control group (10.39%) was significantly higher than in the intervention group (1.32%) (p = 0.034). The intervention group improved significantly in TUG, EMS and FS after a 1-year programme. The overall healthcare costs per patient in the intervention and control groups were US$22,450 and US$25,313, respectively. CONCLUSION: Multi-disciplinary CFFMP is effective, with reduced overall cost, reduced length of hospital stay and reduced secondary fracture rate. The rehabilitation community service favours rehabilitation and improved quality of life of hip fracture patients. PMID- 29260235 TI - External validation of approaches to prediction of falls during hospital rehabilitation stays and development of a new simpler tool. AB - OBJECTIVES: To test the external validity of 4 approaches to fall prediction in a rehabilitation setting (Predict_FIRST, Ontario Modified STRATIFY (OMS), physiotherapists' judgement of fall risk (PT_Risk), and falls in the past year (Past_Falls)), and to develop and test the validity of a simpler tool for fall prediction in rehabilitation (Predict_CM2). PARTICIPANTS: A total of 300 consecutively-admitted rehabilitation inpatients. METHODS: Prospective inception cohort study. Falls during the rehabilitation stay were monitored. Potential predictors were extracted from medical records. RESULTS: Forty-one patients (14%) fell during their rehabilitation stay. The external validity, area under the receiver operating characteristic curve (AUC), for predicting future fallers was: 0.71 (95% confidence interval (95% CI): 0.61-0.81) for OMS (Total_Score); 0.66 (95% CI: 0.57-0.74) for Predict_FIRST; 0.65 (95% CI 0.57-0.73) for PT_Risk; and 0.52 for Past_Falls (95% CI: 0.46-0.60). A simple 3-item tool (Predict_CM2) was developed from the most predictive individual items (impaired mobility/transfer ability, impaired cognition, and male sex). The accuracy of Predict_CM2 was 0.73 (95% CI: 0.66-0.81), comparable to OMS (Total_Score) (p = 0.52), significantly better than Predict_FIRST (p = 0.04), and Past_Falls (p < 0.001), and approaching significantly better than PT_Risk (p = 0.09). CONCLUSION: Predict_CM2 is a simpler screening tool with similar accuracy for predicting fallers in rehabilitation to OMS (Total_Score) and better accuracy than Predict_FIRST or Past_Falls. External validation of Predict_CM2 is required. PMID- 29260236 TI - Precision medicine for cardiovascular disease : Learning lessons from cardiomyopathies. AB - Evidence-based medicine has considerably advanced the treatment of highly prevalent cardiovascular diseases. Its implementation was driven by multicenter interventional trials in treatment and placebo cohorts, propelling numerous biomedical innovations toward standard of care. While a uniform treatment can be effective in such disease cohorts ("one size fits all"), it neglects the genetic and phenotypic individuality of a single patient and his or her disease. Accordingly, a recent observation was made that several newer "mega" trials, demanding considerable resources for their execution, showed statistically significant differences in outcome, however, with small overall efficacies that render implementation in the clinics unlikely. To overcome this concerning development, new methods for individualized treatment of cardiovascular disease are required. Rarer conditions, such as distinct cardiomyopathies, may deliver the blueprint for a paradigm shift: deep and precise phenotyping of individual patients by a multimodal approach and development of targeted treatments for smaller groups ("one treatment for many") or even for single patients ("one treatment of some"). PMID- 29260237 TI - [Anticoagulation in geriatric patients with atrial fibrillation : With what and for whom no more?] AB - Based on established risk scores, such as the CHA2DS2-VASc score, the indications for oral anticoagulation are given for patients over 65 years old with atrial fibrillation and even more so for patients over 75 years old. Before beginning anticoagulation a geriatric assessment for evaluation of the cognitive ability, the activities of daily living and the risk of falling should be made because of the known complications of anticoagulation. Geriatric patients with non-valvular atrial fibrillation (AF) are increasingly being treated with non-vitamin K antagonist oral anticoagulants (NOAC) to prevent ischemic stroke. The European Society for Cardiology (ESC) guidelines for the management of AF recommended NOACs as the preferred treatment and vitamin K antagonists (VKA) only as an alternative option. Meanwhile, apixaban, rivaroxaban, and edoxaban as factor Xa inhibitors and dabigatran as a thrombin inhibitor, are more commonly used in clinical practice in patients with AF. Although, these drugs have pharmacodynamics and pharmacokinetic similarities and are often grouped together, it is important to recognize that the pharmacology and dose regimens differ between compounds. Especially in elderly patients the new drugs have interesting advantages compared to VKA, i. e., less drug-drug interactions with concomitant medication and a more favorable risk-benefit ratio mostly driven by the reduction of bleeding. Treatment of anticoagulation in elderly patients requires weighing the serious risk of stroke with an equally high risk of major bleeding and pharmacoeconomic considerations. The easier practicality of NOACs in routine practice must be emphasized as no international normalized ratio (INR) monitoring is necessary and the interruption of treatment for planned interventions is uncomplicated. A regular monitoring of the indications for NOACs is indispensable (as for all other medications). Especially elderly patients have the greatest benefit from NOAC along with a low renal elimination rate and they should certainly not be withheld from elderly patients who have a clear need for oral anticoagulation. PMID- 29260239 TI - [Cardiac Arrest Center-of course always with intensive care medicine]. PMID- 29260241 TI - Impact of overbite and overjet on oral health-related quality of life of children and adolescents. AB - BACKGROUND: Usually, morphological parameters of the teeth are recorded to help assess the indication for orthodontic treatment. It is assumed that significant deviations from average values compromise the quality of life. The aim of this study is to analyse the impact of overbite and overjet on oral health-related quality of life (OHRQoL) of children and adolescents. PATIENTS AND METHODS: A total of 748 subjects, aged 9.5-15.5 years, participated in the LIFE child project of the University of Leipzig, where they underwent a general medical and dental examination. Overbite and overjet were measured, and aberrations of the OHRQoL were recorded by the probands themselves, who completed the German version of the Child Perceptions Questionnaire (CPQ-G11-14). The OHRQoL is divided into four domains ("oral symptoms", "functional limitations", "emotional well-being" and "social well-being") and is analysed by means of a CPQ score depending on age, gender, socioeconomic status and orthodontic treatment. RESULTS: On average, the participants listed 10.5 (+/-13.1) problem issues on a CPQ scale ranging from 0 to 140. Subjects with current orthodontic treatment had a CPQ score about 2.5 (+/-2.4) higher than those without treatment. The aberrations were mainly observed in the domains "oral symptoms" and "functional limitations". Multiple linear regression showed that deviations of the overbite had only little influence on the OHRQoL, but deviations of an overjet-especially of >6 mm increased the CPQ summary score about 6 points. CONCLUSION: Children and adolescents with overjet deviations of >6 mm in comparison to the norm are associated with significant limitations of the OHRQoL. However, overbite deviations have only little influence. PMID- 29260242 TI - [Update on gunshot wounds to extremities]. AB - Due to recent rampage and terror attacks in Europe, gunshot wounds have become a focus of attention even though they are still rare in Europe. Approximately 50% of gunshot wounds affect the extremities and to understand the sequelae, a basic knowledge of wound ballistics is indispensable. The energy transmitted from the bullet to the tissue is responsible for the severity of the injury and is dependent on the type of weapon and ammunition. A differentiation is made between low-energy injuries caused, e.g. by pistols and high-energy injuries mostly caused by rifles. The higher energy transfer to the tissue in high-energy injuries, results in a temporary wound cavity in addition to the permanent wound channel with extensive soft tissue damage. High-energy gunshot fractures are also more extensive compared to those of low energy injuries. Debridement seems to be necessary for almost all gunshot wounds. Fractures should be temporarily stabilized with an external fixator due to contamination. PMID- 29260240 TI - A cyclic pathway of P2 * 7, bradykinin, and dopamine receptor activation induces a sustained articular hyperalgesia in the knee joint of rats. AB - OBJECTIVE: We investigated whether: (1) P2 * 7 receptor activation by its agonist (BzATP) induces articular hyperalgesia in the rat's knee joint via inflammatory mechanisms and (2) activation of P2 * 7 receptors by endogenous ATP contributes to the articular hyperalgesia induced by bradykinin, TNF-alpha, IL-1beta, CINC-1, PGE2, and dopamine. METHODS: The articular hyperalgesia was quantified using the rat knee joint incapacitation test. The knee joint inflammation, characterized by the concentration of pro-inflammatory cytokines and by neutrophil migration, was quantified in the synovial lavage fluid by ELISA and myeloperoxidase enzyme activity assay, respectively. RESULTS: BzATP induced a dose-dependent articular hyperalgesia in the rat's knee joint that was significantly reduced by the selective antagonists for P2 * 7, bradykinin B1 or B2 receptors, beta1 or beta2 adrenoceptors, and by pre-treatment with Indomethacin. BzATP induced a local increase of TNF-alpha, IL-1beta, IL-6, and CINC-1 concentration and neutrophil migration into the knee joint. The co-administration of the selective P2 * 7 receptor antagonist A-740003 significantly reduced the articular hyperalgesia induced by bradykinin and dopamine, but not by TNF-alpha, IL-1beta, CINC-1, and PGE2. CONCLUSIONS: P2 * 7 receptor activation induces articular hyperalgesia mediated by the previous inflammatory mediator release. P2 * 7 receptor-induced articular hyperalgesia is sustained by the involvement of this purinergic receptor in bradykinin and dopamine-induced hyperalgesia in the knee joint. PMID- 29260243 TI - [Perioperative handling of antidiabetic drugs]. AB - Diabetes mellitus is the most frequent metabolic disorder in the western world with a prevalence of 3% in adults under 65 years of age and 14.3% in adults over 65 years of age. Due to the increasing age of our population, the number of patients taking oral antidiabetic drugs has increased. Thus, operating physicians must make a risk-adapted decision whether the medication can be continued perioperatively or if certain drugs must be paused, and if so, with what risks. Operative interventions can lead to a number of metabolic shifts, which change the normal glucose metabolism. Hyperglycemia in the perioperative period is a risk factor for postoperative sepsis, dysfunction of the endothelium, cerebral ischemia and poor wound healing. Due to perioperative fasting oral antidiabetic medication can lead to severe hypoglycemia if taken during this period. This leads to an increased morbidity and mortality in the perioperative period and extends the duration of stay in the intensive care unit (ICU) as well as the overall hospital stay. Oral antidiabetic medication should be paused on the day of the operation and restarted in line with the gradual postoperative return to solid food. Especially metformin, the most commonly used medication in the treatment of type 2 diabetes, should be paused perioperatively due to the severe side effect of lactate acidosis. PMID- 29260244 TI - [The use of tumor therapeutics in the perioperative period]. AB - In 2010 Germany had 447,300 new cases of cancer. From 2000 to 2010 the incidence of cancer increased by 21% in men and by 14% in women. The change in the age structure with an aging population is the crucial influencing factor. Various cancer types can now be treated by oral antitumor agents used as a chronic medication. Physicians must decide whether the oral antitumor agents can be continued perioperatively or if certain drugs must be paused and if so, with what risks. Oral antitumor agents are a very heterogeneous group of medication. The use of oral antitumor agents during the perioperative period has not been thoroughly examined, but most often a perioperative interruption is recommended. In general, poor wound healing is a frequent complication of this group of medication. The handling of oral antitumor agents in the perioperative period should be based on an individual decision with consideration of the desired therapy goal as well as the individual prognosis. In general, all oral antitumor agents are chronic medication and are continued until a loss of efficacy or intolerable side effects occur. A potentially curative therapy should be paused for the shortest possible time in order not to jeopardize the remission already achieved. Furthermore, generally accepted recommendations concerning the interval between chemotherapy and a planned operation have not yet been established. A rough rule of thumb could be to plan the operation after the regeneration of the blood count or at the same point in time of the next planned chemotherapy. PMID- 29260245 TI - [Cerebral amyloid angiopathy associated with inflammation]. AB - Cerebral amyloid angiopathy (CAA) associated with inflammation is a rare form of a potentially reversible encephalopathy in a subgroup of patients with CAA. The cerebral amyloid deposition can in isolated cases induce an inflammation predominantly of the cerebral blood vessels and a multifocal edema of the cerebral white matter. The courses can occur as monophasic, relapsing remitting and primarily progressive forms. We present seven cases with different courses of the disease and give an overview of the pathophysiology, clinical aspects and treatment of the disease with reference to the current literature. The cases presented show a very different and often difficult differential diagnostic clinical picture and all showed a significant improvement under steroid medication without signs of recurrence of the disease during the course. The recognition and early consistent treatment of inflammatory forms of CAA with and without direct inflammatory involvement of vessels can be decisive for successful treatment. PMID- 29260247 TI - [Allergen nomenclature]. PMID- 29260246 TI - [Allogeneic bone transplantation in hip revision surgery : Indications and potential for reconstruction]. AB - The increasing number of people having joint replacements will lead to increasing numbers of revision operations. The transplantation of allogeneic bones might reconstruct bone defects and improve long-term anchorage of the implant. A sufficient primary stability of the implanted construct is necessary to achieve osseous incorporation as well as tight contact between the implanted allogeneic and host bones. Transplantation of bone can contribute to downgrading acetabular defects and so avoid bigger reinforcement implants. An improvement of bone stock due to reconstruction of femoral bony defects might also reduce the size of the stem necessary since the indication might be limited in case of extensive bone defects. According to good longterm results of modular revision stems the Impaction-Bone-Grafting has not yet generally been established. PMID- 29260248 TI - [Chronic, refractory ulcer on the ring finger : Manifestation of distal epithelioid sarcoma]. AB - The epithelioid sarcoma classic, "distal" type was first published in 1970. It is a very rare, malignant, aggressive subcutaneous soft tissue sarcoma that shows characteristic positivity for both epithelial and mesenchymal immunohistochemical markers. It grows very slowly and mostly presents in young men. Clinically the tumor is characterized as a coarse cutaneous or subcutaneous nodular induration that often ulcerates in the course of the disease. An association with trauma is often described and can lengthen time to diagnosis. Most frequently it is found on the flexural side of fingers, the back of the hands, soles of the feet, and extensor sides of arms and legs. Specific for this type of sarcoma is the progression along nerves, tendons, and fasciae. Treatment of choice should be wide excision of the tumor, sentinel node biopsy, and possibly even localized postoperative radiation therapy. Unfortunately the epithelioid sarcoma is very likely to recur and is then associated with metastases in the lung and lymph nodes. PMID- 29260249 TI - [If zinc oxide is a problem : Combinations with glucocorticoids]. PMID- 29260250 TI - ["Moving on to pastures new" : Festschrift for Alexander Berghaus]. PMID- 29260251 TI - [Functional testing in internal medicine]. PMID- 29260252 TI - [Functional diagnostics in endocrinology]. AB - When investigating many endocrinological diseases, basal laboratory parameters are not sufficient to distinguish between physiological and pathological hormone secretion. Functional diagnostics plays a decisive role in this context. Stimulation and suppression tests are used depending on whether under- or over function needs to be diagnosed. This review article discusses selected functional tests, each of which plays an important role in current guidelines. Indications and test principles, including their performance, reliability, and limitations, are discussed. Topics covered include the ACTH stimulation test for the diagnosis of adrenal cortex insufficiency and the dexamethasone inhibition test for suspected Cushing's syndrome, as well as functional tests for the diagnosis of primary hyperaldosteronism, pheochromocytoma, acromegaly, growth hormone deficiency, thyroid nodules and suspicion of medullary thyroid carcinoma, insulinoma, and Zollinger-Ellison syndrome. Functional tests that are explicitly not recommended are also addressed. PMID- 29260253 TI - Rates of glycaemic deterioration in a real-world population with type 2 diabetes. AB - AIMS/HYPOTHESIS: There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on 'time to failure' methods, yet determining a 'coefficient of failure' has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration. METHODS: An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual's observed HbA1c measures from the first eligible HbA1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA1c measure was time dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution. RESULTS: The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA1c per year. CONCLUSIONS/INTERPRETATION: We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management. PMID- 29260254 TI - From Molecules to Life: Quantifying the Complexity of Chemical and Biological Systems in the Universe. AB - Life is a complex phenomenon and much research has been devoted to both understanding its origins from prebiotic chemistry and discovering life beyond Earth. Yet, it has remained elusive how to quantify this complexity and how to compare chemical and biological units on one common scale. Here, a mathematical description of molecular complexity was applied allowing to quantitatively assess complexity of chemical structures. This in combination with the orthogonal measure of information complexity resulted in a two-dimensional complexity space ranging over the entire spectrum from molecules to organisms. Entities with a certain level of information complexity directly require a functionally complex mechanism for their production or replication and are hence indicative for life like systems. In order to describe entities combining molecular and information complexity, the term biogenic unit was introduced. Exemplified biogenic unit complexities were calculated for ribozymes, protein enzymes, multimeric protein complexes, and even an entire virus particle. Complexities of prokaryotic and eukaryotic cells, as well as multicellular organisms, were estimated. Thereby distinct evolutionary stages in complexity space were identified. The here developed approach to compare the complexity of biogenic units allows for the first time to address the gradual characteristics of prebiotic and life-like systems without the need for a definition of life. This operational concept may guide our search for life in the Universe, and it may direct the investigations of prebiotic trajectories that lead towards the evolution of complexity at the origins of life. PMID- 29260255 TI - Percutaneous Treatment of Scalp Arteriovenous Fistulas by Direct Puncture and Polydocanol Sclerotherapy : Report of 2 Cases with Long-term Follow-up. PMID- 29260256 TI - Mechanical Thrombectomy in Basilar Artery Occlusion : Presence of Bilateral Posterior Communicating Arteries is a Predictor of Favorable Clinical Outcome. AB - BACKGROUND: Mechanical thrombectomy (MT) of basilar artery occlusions (BAO) is a subject of debate. We investigated the clinical outcome of MT in BAO and predictors of a favorable outcome. MATERIAL AND METHODS: A total of 104 MTs of BAO (carried out between 2010 and 2016) were analyzed. Favorable outcome as a modified Rankin scale (mRS) <= 2 at 90 days was the primary endpoint. The influence of the following variables on outcome was investigated: number of detectable posterior communicating arteries (PcoAs), patency of basilar tip, completeness of BAO and posterior circulation Alberta Stroke Program early computed tomography score (PC-ASPECTS). Secondary endpoints were technical periprocedural parameters including symptomatic intracranial hemorrhage (sICH). RESULTS: The favorable clinical outcome at 90 days was 25% and mortality was 43%. The rate of successful reperfusion, i.e. modified thrombolysis in cerebral infarction (mTICI) >= 2b was 82%. Presence of bilateral PcoAs (area under the curve, AUC: 0.81, odds ratio, OR: 4.2, 2.2-8.2; p < 0.0001), lower National Institute of Health Stroke Scale (NIHSS) on admission (AUC: 0.74, OR: 2.6, 1.3 5.2; p < 0.01), PC-ASPECTS >= 9 (AUC: 0.72, OR: 4.2, 1.5-11.9; p < 0.01), incomplete BAO (AUC: 0.66, OR: 2.6, 1.4-4.8; p < 0.001), and basilar tip patency (AUC: 0.66, OR: 2.5, 1.3-4.8; p < 0.01) were associated with a favorable outcome. Stepwise logistic regression analysis revealed that the strongest predictors of favorable outcome at 90 days were bilateral PcoAs, low NIHSS on admission, and incomplete BAO (AUC: 0.923, OR: 7.2, 3-17.3; p < 0.0001). CONCLUSION: The use of MT for BAO is safe with high rates of successful reperfusion. Aside from baseline NIHSS and incomplete vessel occlusion, both known predictors of favorable outcome in anterior circulation events, we found that collateral flow based on the presence or absence of PcoAs had a decisive prognostic impact. PMID- 29260258 TI - Reproducibility of shear wave elastography measuresof the Achilles tendon. AB - OBJECTIVE: To assess the reproducibility of shear wave elastography (SWE) measures in the Achilles tendon (AT) in vivo. MATERIALS AND METHODS: Shear wave velocity (SWV) of 14 healthy volunteers [7 males, 7 females; mean age 26.5 +/- 3.8 years, mean height 171.6 +/- 10.9 cm, mean Victorian Institute of Sports Assessment Achilles questionnaire (VISA-A) score 99.4 +/- 1.2] was measured with the foot relaxed and fixed at 90 degrees . Data were collected over five consecutive measures and 5 consecutive days. RESULTS: Mean SWV values ranged from 7.91 m/s-9.56 m/s +/- 0.27-0.50 m/s. Coefficient of variation (CV), correlations and intra-class correlation coefficient (ICC) scores ranged from 2.9%-6.3%, 0.4 0.7 and 0.54-0.85 respectively. No significant differences were noted for longitudinal or transverse data with respect to protocol or time and no significant differences were noted for foot position in transverse data. Significant differences in SWV values were noted between foot positions for longitudinal scanning (p = <0.05), with a relaxed foot position providing SWV values on average 0.47 m/s faster than a fixed position. Increased reproducibility was obtained with the foot relaxed. ICC between operators was 0.70 for transverse and 0.80 for longitudinal scanning. CONCLUSIONS: Reproducible SWE measures were obtained over a 1-h period as well as a period of 5 consecutive days with more reliable measures obtained from a longitudinal plane using a relaxed foot position. SWE also has a high level of agreement between operators making SWE a reproducible technique for quantitatively assessing the mechanical properties of the human AT in vivo. PMID- 29260259 TI - Academic musculoskeletal radiology: influences for gender disparity. AB - INTRODUCTION: Research productivity is one of the few quintessential gauges that North American academic radiology departments implement to determine career progression. The rationale of this study is to quantify the relationship of gender, research productivity, and academic advancements in the musculoskeletal (MSK) radiology to account for emerging trends in workforce diversity. METHODS: Radiology residency programs enlisted in the Fellowship and Residency Electronic Interactive Database (FREIDA), Canadian Resident Matching Service (CaRMS) and International Skeletal Society (ISS) were searched for academic faculty to generate the database for gender and academic profiles of MSK radiologists. Bibliometric data was collected using Elsevier's SCOPUS archives, and analyzed using Stata version 14.2. RESULTS: Among 274 MSK radiologists in North America, 190 (69.34%) were men and 84 (30.66%) were women, indicating a statistically significant difference (chi2 = 6.34; p value = 0.042). The available number of female assistant professors (n = 50) was more than half of the male assistant professors (n = 88), this ratio however, plummeted at higher academic ranks, with only one-fourth of women (n = 11) professors compared to men (n = 45). The male MSK radiologist had 1.31 times the odds of having a higher h-index, keeping all other variables constant. CONCLUSIONS: The trend of gender disparity exists in MSK radiology with significant underrepresentation of women in top tiers of academic hierarchy. Even with comparable h-indices, at the lower academic ranks, a lesser number of women are promoted relative to their male colleagues. Further studies are needed to investigate the degree of influence research productivity has, in determining academic advancement of MSK radiologists. PMID- 29260261 TI - Microalgae-bacteria biofilms: a sustainable synergistic approach in remediation of acid mine drainage. AB - Microalgae and bacteria offer a huge potential in delving interest to study and explore various mechanisms under extreme environments. Acid mine drainage (AMD) is one such environment which is extremely acidic containing copious amounts of heavy metals and poses a major threat to the ecosystem. Despite its extreme conditions, AMD is the habitat for several microbes and their activities. The use of various chemicals in prevention of AMD formation and conventional treatment in a larger scale is not feasible under different geological conditions. It implies that microbe-mediated approach is a viable and sustainable alternative technology for AMD remediation. Microalgae in biofilms play a pivotal role in such bioremediation as they maintain mutualism with heterotrophic bacteria. Synergistic approach of using microalgae-bacteria biofilms provides supportive metabolites from algal biomass for growth of bacteria and mediates remediation of AMD. However, by virtue of their physiology and capabilities of metal removal, non-acidophilic microalgae can be acclimated for use in AMD remediation. A combination of selective acidophilic and non-acidophilic microalgae together with bacteria, all in the form of biofilms, may be very effective for bioremediation of metal-contaminated waters. The present review critically examines the nature of mutualistic interactions established between microalgae and bacteria in biofilms and their role in removal of metals from AMDs, and consequent biomass production for the yield of biofuel. Integration of microalgal-bacterial consortia in fuel cells would be an attractive emerging approach of microbial biotechnology for AMD remediation. PMID- 29260262 TI - [Use of cannabinoids for chemotherapy-induced nausea and vomiting]. PMID- 29260260 TI - On being the right size: antibody repertoire formation in the mouse and human. AB - The immune systems of all mammals include populations of B cells producing antibodies with incredibly diverse specificities. Repertoire diversity has been described as the "miracle of immunology," and it was long thought to be the result of essentially stochastic processes. Recently, however, analysis of high throughput gene sequencing data has shown that hard-wired biases in these processes result in antibody repertoires that are broadly predictable. The repertoires of mice and humans are both predictable, but they are strikingly different. In this review, features of the naive antibody repertoires of the two species are contrasted. We show that the mouse repertoire includes a conspicuous population of public clonotypes that are shared by different individuals of an inbred strain. These clonotypes are the result of gene rearrangements that involve little gene processing. By skewing repertoire formation toward such sequences, which probably target commonly encountered pathogens, it may be that the relatively small mouse repertoire is appropriate and effective despite its size. Species like the mouse face challenges that are a direct consequence of their small body sizes and the limitations this places on the antibody arsenal particularly early in ontogeny. We propose that it is the differences in the naive repertoires of mice and humans, and the differences in the ways these repertoires are used, which ensure that the very different biological needs of the two species are met. The processes that contribute to repertoire formation may appear to be stochastic, but in both species, evolution has left little to chance. PMID- 29260263 TI - Systematic Literature Review on the Incidence and Prevalence of Heart Failure in Children and Adolescents. AB - While the epidemiology of adult heart failure has been extensively researched, this systematic review addresses the less well characterized incidence and prevalence of pediatric HF. The search strategy used Cochrane methodology and identified 83 unique studies for inclusion. Studies were categorized according to whether the HF diagnosis was reported as primary (n = 10); associated with other cardiovascular diseases (CVDs) (n = 49); or associated with non-CVDs (n = 24). A narrative synthesis of the evidence is presented. For primary HF, the incidence ranged from 0.87/100,000 (UK and Ireland) to 7.4/100,000 (Taiwan). A prevalence of 83.3/100,000 was reported in one large population-based study from Spain. HF etiology varied across regions with lower respiratory tract infections and severe anemia predominating in lower income countries, and cardiomyopathies and congenital heart disease major causes in higher income countries. Key findings for the other categories included a prevalence of HF associated with cardiomyopathies ranging from 36.1% (Japan) to 79% (US); associated with congenital heart disease from 8% (Norway) to 82.2% (Nigeria); associated with rheumatic heart diseases from 1.5% (Turkey) to 74% (Zimbabwe); associated with renal disorders from 3.8% (India) to 24.1% (Nigeria); and associated with HIV from 1% (US) to 29.3% (Brazil). To our knowledge, this is the first systematic review of the topic and strengthens current knowledge of pediatric HF epidemiology. Although a large body of research was identified, heterogeneity in study design and diagnostic criteria limited the ability to compare regional data. Standardized definitions of pediatric HF are required to facilitate cross regional comparisons of epidemiological data. PMID- 29260267 TI - [Responsibilities and concepts for undergraduate and postgraduate medical education in Germany : A plea for a reorientation]. AB - BACKGROUND: Undergraduate medical education in Germany takes place in the medical faculties of universities, whereas postgraduate medical education takes place in nearly all hospitals under the aegis of medical associations. Both phases of the medical qualification process live on their own; the communication between the two responsible bodies is negligible. Previous reforms have always tackled undergraduate education only, whereas postgraduate education takes place without public attention. OBJECTIVE: This position paper discusses the origins and consequences of the complete separation between undergraduate and postgraduate medical education in Germany with regard to responsible bodies, learning objectives, and didactical concepts. On the basis of this critical analysis, proposals are presented to narrow the gap between the two phases. MATERIALS AND METHODS: This paper is based on several sources: data from historical documents, information retrieved from the internet on educational concepts in other OECD countries as well as intensive discussions among the authors. RESULTS AND DISCUSSION: The dissociation between under- and postgraduate education has historical reasons. Over a longer period of time the German Federal States reduced their responsibility for postgraduate education in favor of medical associations. The authors propose steps towards a better integration of both sequences, towards seeing the educational process as a continuum. In such a concept, medical associations would have a greater influence on undergraduate education and - vice versa - medical faculties on the postgraduate phase. PMID- 29260264 TI - A new piperazine derivative: 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1 yl)-2-methoxyethan-1-one with antioxidant and central activity. AB - In the scope of a research program aimed at developing new drugs for the treatment of central nervous system diseases, we describe herein the synthesis and pharmacological evaluation of 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one (LQFM180). This compound showed antioxidant activity in two models, electroanalytical assays, and DPPH activity. Moreover, in behavioral tests as the open field test LQFM180 (9.4, 18.8, and 37.6 mg/kg, per oral (p.o.)), we detected anxiolytic-like activity. In the sodium pentobarbital induced sleep test, LQFM180, in all doses, decreased the latency to sleep and increased sleep duration, indicating central depressant activity; moreover, in the chimney test, LQFM180 did not alter motor activity. LQFM180 (18.8 mg/kg, p.o.) increased the time and number of entries on open arms in the elevated plus maze test, suggesting anxiolytic-like activity, which was reversed by NAN-190 and p-chlorophenylalanine, indicating a role of the serotonergic pathway on this effect. In the forced swimming test, LFQM180 (18.8 mg/kg, p.o.) decreased immobility time, suggesting antidepressant-like activity, which was reversed by monoaminergic antagonists, indicating a role for the serotonergic, noradrenergic, and dopaminergic pathways. Competition binding assays showed that LQFM180 was able to bind to the alpha1B, 5-HT1A, and D2 receptors, however, within the low micromolar range. We conclude that LQFM180 should be considered as a scaffold for drug candidate development. PMID- 29260265 TI - Schisandrin C enhances mitochondrial biogenesis and autophagy in C2C12 skeletal muscle cells: potential involvement of anti-oxidative mechanisms. AB - The molecular study of muscles is needed to overcome chronic inflammation and maintenance of muscles in the human body. Schisandrin C is a pharmacological compound derived from the fruit of Schisandra chinensis and has many characteristics including anti-inflammation, anti-tumor, and anti-oxidation. However, the cellular and molecular mechanisms of Schisandrin C are still not well understood especially in skeletal muscle. Therefore, the present study was evaluated whether the properties of Schisandrin C in C2C12 skeletal muscle cells involved maintenance of cellular homeostasis and protection against oxidative damage. Differentiated C2C12 cells were exposed to H2O2 to induce oxidative stress. The characteristics of anti-oxidants, anti-inflammation, autophagy, and mitochondrial biogenesis were tested by Western blotting. Confocal microscopy was also used to observe mitochondrial activity. Schisandrin C inhibited inflammatory molecules with enhancing anti-oxidant activity and reducing reactive oxygen species (ROS) even in the presence of H2O2. The dual anti-inflammation and anti oxidant roles of Schisandrin C regulated the translocation of nuclear factor kappa B (NF-kappaB) and nuclear factor erythroid 2-related factor-2 (Nrf-2) to nucleus followed by inhibition of the mitogen-activated protein kinase (MAPK) pathway. Schisandrin C promoted the expression of autophagy and mitochondrial biogenesis molecules. Furthermore, the effect of Schisandrin C increased the mitochondrial activity against oxidative stress. Consequently, the action of Schisandrin C enhanced the regulation of autophagy and mitochondrial biogenesis with potential involvement of anti-oxidative mechanisms including the MAPKs/Nrf 2/heme oxygenase-1 signaling pathway in C2C12 skeletal muscle cells exposed to oxidative stress. Therefore, Schisandrin C may be considered as a beneficial compound for several muscle inflammations. PMID- 29260268 TI - Computation of the inverse additive relationship matrix for autopolyploid and multiple-ploidy populations. AB - KEY MESSAGE: Rules to generate the inverse additive relationship matrix (A -1 ) are defined to enable the adoption restricted maximum likelihood (REML) and best linear unbiased prediction (BLUP) in autopolyploid populations with multiple ploidy levels. Many important agronomic, horticultural, ornamental, forestry, and aquaculture species are autopolyploids. However, the adoption of restricted maximum likelihood (REML), for estimating co/variance components, and best linear unbiased prediction (BLUP), for predicting breeding values, has been hampered in autopolyploid breeding by the absence of an appropriate means of generating the inverse additive relationship matrix (A -1 ). This paper defines rules to generate the A -1 of autopolyploid populations comprised of individuals of the same or different ploidy-levels, including populations exhibiting (1) odd numbered ploidy levels (e.g. triploids), (2) sex-based differences in the probability that gametic genes are identical by descent and (3) somatic chromosome doubling. Inbreeding, due to double reduction, in autopolyploid founders in the absence of mating among relatives is also accounted for. A previously defined approach is modified, whereby rules are initially defined to build an inverse matrix of kinship coefficients (K -1 ), which is then used to generate A -1 . An R package (polyAinv; https://github.com/mghamilton/polyAinv ) to implement these rules has been developed and examples of analyses provided. The adoption of REML and BLUP methods made possible by these new rules has the potential to provide further insights into the quantitative genetic architecture of autopolyploid and multiple-ploidy populations, improve estimates of breeding values, and increase genetic gains made through recurrent selection. PMID- 29260270 TI - Vascular Complications After Chin Augmentation Using Hyaluronic Acid. AB - Vascular complications after hyaluronic acid (HA) filling of the chin have rarely been reported. In this report, two cases of vascular occlusion after HA augmentation of the mentum are presented. The first case involved local skin necrosis that resulted from a massive microcirculatory embolism and/or external compression of the chin skin microvasculature. The second case involved vascular compromise in the tongue that resulted from HA injection in the chin. The diagnosis was established on the basis of interventional angiography findings. Concerning the pathogenesis, we hypothesized that the filler embolus flowed into the branches of the deep lingual artery through the rich vascular anastomoses among the submental, sublingual, and deep lingual arteries, after being accidentally injected into the submental artery (or its branches). Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29260269 TI - Fluorescence-based monitoring of electronic state and ion exchange kinetics with FCS and related techniques: from T-jump measurements to fluorescence fluctuations. AB - In this review, we give a historical view of how our research in the development and use of fluorescence correlation spectroscopy (FCS) and related techniques has its roots and how it originally evolved from the pioneering work of Manfred Eigen, his colleagues, and coworkers. Work on temperature-jump (T-jump) experiments, conducted almost 50 years ago, led on to the development of the FCS technique. The pioneering work in the 1970s, introducing and demonstrating the concept for FCS, in turn formed the basis for the breakthrough use of FCS more than 15 years later. FCS can be used for monitoring reaction kinetics, based on fluctuations at thermodynamic equilibrium, rather than on relaxation measurements following perturbations. In this review, we more specifically discuss FCS measurements on photodynamic, electronic state transitions in fluorophore molecules, and on proton exchange dynamics in solution and on biomembranes. In the latter case, FCS measurements have proven capable of casting new light on the mechanisms of proton exchange at biological membranes, of central importance to bioenergetics and signal transduction. Finally, we describe the transient-state (TRAST) spectroscopy/imaging technique, sharing features with both relaxation (T jump) and equilibrium fluctuation (FCS) techniques. TRAST is broadly applicable for cellular and molecular studies, and we briefly outline how TRAST can provide unique information from fluorophore blinking kinetics, reflecting e.g., cellular metabolism, rare molecular encounters, and molecular stoichiometries. PMID- 29260271 TI - Reconstruction of Mandibular Contour Using Individualized High-Density Porous Polyethylene (Medpor(r)) Implants Under the Guidance of Virtual Surgical Planning and 3D-Printed Surgical Templates. AB - BACKGROUND: The mandibular contour plays a significant role in the beautiful and youthful look but the reconstruction remains a challenging problem. The objective of this study was to evaluate the use of individualized high-density porous polyethylene (Medpor(r)) implants for comprehensive reconstruction of mandibular contour with the aid of computer-aided design/computer-aided manufacturing (CAD/CAM). METHODS: From 2010 to 2014, 12 patients with mandibular contour deformities were enrolled in our retrospective study. Mandible models and individualized surgical templates were fabricated by three-dimensional (3D) printing and Medpor(r) implants were made according to the surgical templates. The Medpor(r) implants were used for both unilateral and bilateral mandibular contour deformities. In four cases, simultaneous mandibular orthognathic surgery was performed with unilateral mandibular contour reconstruction. RESULTS: Eleven patients had a reposeful postoperative recovery with no complication. Delayed infection was shown in one patient and the Medpor(r) implant was removed. All the 11 patients had the mandibular contour reconstructed satisfactorily. CONCLUSION: The technique and cases presented demonstrate the utility of Medpor(r) implants with CAD/CAM in comprehensive mandibular contour reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29260273 TI - Fatal meningococcemia mimicking intra-abdominal emergency. PMID- 29260272 TI - Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. AB - PURPOSE: Guidelines for shock recommend mean arterial pressure (MAP) targets for vasopressor therapy of at least 65 mmHg and, until recently, suggested that patients with underlying chronic hypertension and atherosclerosis may benefit from higher targets. We conducted an individual patient-data meta-analysis of recent trials to determine if patient variables modify the effect of different MAP targets. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized controlled trials of higher versus lower blood pressure targets for vasopressor therapy in adult patients in shock (until November 2017). After obtaining individual patient data from both eligible trials, we used a modified version of the Cochrane Collaboration's instrument to assess the risk of bias of included trials. The primary outcome was 28-day mortality. RESULTS: Included trials enrolled 894 patients. Controlling for trial and site, the OR for 28-day mortality for the higher versus lower MAP targets was 1.15 (95% CI 0.87-1.52). Treatment effect varied by duration of vasopressors before randomization (interaction p = 0.017), but not by chronic hypertension, congestive heart failure or age. Risk of death increased in higher MAP groups among patients on vasopressors > 6 h before randomization (OR 3.00, 95% CI 1.33 6.74). CONCLUSIONS: Targeting higher blood pressure targets may increase mortality in patients who have been treated with vasopressors for more than 6 h. Lower blood pressure targets were not associated with patient-important adverse events in any subgroup, including chronically hypertensive patients. PMID- 29260274 TI - Spontaneous regression of an idiopathic arteriovenous fistula of the right vertebral artery. AB - A previously healthy 53-year-old male presented with a 2-month history of pulsatile tinnitus, worsening headaches, and neck pain. Given the clinical symptoms, a workup was initiated to assess for a vascular etiology such as a dural arteriovenous fistula. PMID- 29260275 TI - Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel. AB - PURPOSE: Bleeding is one of the possible adverse events during clopidogrel therapy. The CYP2C19 gene is the most significant genetic factor which influences response to clopidogrel treatment. We aimed to examine the contribution of the CYP2C19 gene to bleeding occurrence during clopidogrel therapy in Serbian patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: This case-control study included 53 patients who experienced bleeding and 55 patients without bleeding. Bleeding events were defined and classified using the Bleeding Academic Research Consortium (BARC) criteria. All patients were prescribed daily doses of clopidogrel during the 1-year follow-up after PCI. The CYP2C19*17 (c.-806C>T, rs12248560), rs11568732 (c.-889T>G, CYP2C19*20), CYP2C19*2 (c.681G>A; rs4244285) and CYP2C19*3 (c.636G>A; rs4986893) variants were analysed in all 108 patients. Additionally, sequencing of all nine exons, 5'UTR and 3'UTR in the rs11568732 carriers was performed. RESULTS: Association between bleeding (BARC type >= 2) and the CYP2C19*17 variant was not observed [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.2-1.1; p = 0.107). The rs11568732 variant showed significant association with bleeding (OR, 3.7; 95% CI, 1.12-12.44; p = 0.025). Also, we found that the rs11568732 variant appears independently of haplotype CYP2C19*3B, which is contrary to the previous findings. CONCLUSIONS: Our results indicate the absence of CYP2C19*17 influence and turn the attention to the potential significance of the rs11568732 variant in terms of adverse effects of clopidogrel. However, it is necessary to conduct an independent conformation study in order to verify this finding. Also, an analysis of the functional implication of the rs11568732 variant is necessary in order to confirm the significance of this variant, both in relation to its influence on gene expression and in relation to its medical significance. PMID- 29260276 TI - Prevalence of pain and pharmacological pain treatment among old people in nursing homes in 2007 and 2013. AB - PURPOSE: Many elderly people living in nursing homes experience pain and take analgesic medication. The aim of this study was to analyze the prevalence of pain and pharmacological pain treatment among people living in nursing homes in Sweden, in two large, comparable, samples from 2007 to 2013. METHODS: Cross sectional surveys were performed in 2007 and 2013, including all residents in nursing homes in the county of Vasterbotten, Sweden. A total of 4933 residents (2814 and 2119 respectively) with a mean age of 84.6 and 85.0 years participated. Of these, 71.1 and 72.4% respectively were cognitively impaired. The survey was completed by the staff members who knew the residents best. RESULTS: The prescription of opioids became significantly more common while the use of tramadol decreased significantly. The staff reported that 63.4% in 2007 and 62.3% in 2013 had experienced pain. Of those in pain, 20.2% in 2007 and 16.8% in 2013 received no treatment and 73.4 and 75.0% respectively of those with pain, but no pharmacological treatment, were incorrectly described by the staff as being treated for pain. CONCLUSIONS: There has been a change in the pharmacological analgesic treatment between 2007 and 2013 with less prescribing of tramadol and a greater proportion taking opioids. Nevertheless, undertreatment of pain still occurs and in many cases, staff members believed that the residents were prescribed analgesic treatment when this was not the case. PMID- 29260277 TI - "Lacher de ballons" or "release of balloons" sign. PMID- 29260278 TI - Role of contrast-enhanced ultrasound in evaluation of the bowel. AB - Contrast-enhanced ultrasound (CEUS) of the gastrointestinal tract provides vascular information helpful for characterizing masses and other pathologies in and around the bowel, similar to contrast applications in other solid organs. However, the use of microbubble contrast agents for the bowel provides additional unique contributions as it gives both subjective and objective information about mural and mesenteric blood flow, invaluable for the determination of disease activity in those many patients affected by inflammatory bowel disease (IBD). IBD is a lifelong chronic disease and has its peak age of onset in adolescence or young adult life. Today, we have moved away from treating patient's symptoms and strive instead to alter the course of disease by obtaining mucosal healing. Expensive and aggressive biologic therapies and lack of agreement of patient's symptoms with their disease activity and complications necessitate frequent imaging surveillance, which must be safe, readily available, inexpensive, and effective. Ultrasound with the benefit of contrast enhancement meets these requirements and is shown in meta-analysis to be equivalent to CT and MRI scans for these indications. PMID- 29260279 TI - The "leather bottle" stomach. PMID- 29260280 TI - Peri-tumoral hyperintensity on hepatobiliary phase of gadoxetic acid-enhanced MRI in hepatocellular carcinomas: correlation with peri-tumoral hyperplasia and its pathological features. AB - PURPOSE: Peri-tumoral hyperintensity (P-hyperintensity) is occasionally seen in hepatocellular carcinoma (HCC) on the hepatobiliary (HB) phase of gadoxetic acid enhanced MRI (EOB-MRI). A recent study reported peri-tumoral hyperplasia (P hyperplasia) associated with over-expression of glutamine synthetase (GS) in HCC or metastatic carcinoma. The aim of this study was to analyze the correlation between P-hyperintensity on the HB phase and GS expression indicating P hyperplasia and reveal its pathological features. METHODS: Seventy-seven surgically resected HCCs from 68 patients were analyzed. The grade of P hyperintensity on HB phase was divided according to the degree of the peri tumoral hyperintense signal: grade 0 (no P-hyperintensity), grade 1 (less than 50% of the tumor border), grade 2 (50%-80%), grade 3 (80%-100%). Immunohistochemical staining for GS and organic anion transporter polypeptides (OATP)1B3 was performed. The relationships among P-hyperplasia (peri-tumoral GS expression) and OATP1B3 expression, P-hyperintensity, and pathological features of the tumor were analyzed. RESULTS: Thirty-four HCCs were classified as P hyperintensity grade 0, 29 HCCs as grade 1,10 nodules as grade 2, and 4 HCCs as grade 3. P-hyperplasia was observed in 3/34 (8.8%) P-hyperintensity grade 0, 16/29 (55.2%) grade 1, 9/10 (90%) grade 2, and 4/4 (100%) grade 3. The incidence of P-hyperplasia was significantly increased in P-hyperintensity grades 1-3 compared with grade 0 (p < 0.0001). Hepatocytes in all P-hyperplasia sites demonstrated definite OATP1B3 expression. Microscopic hepatic venous invasion was significantly increased in P-hyperintensity-positive HCCs compared with negative HCCs (p = 0.0017). CONCLUSIONS: P-hyperintensity on HB phase in HCC may indicate p-hyperplasia with GS and OATP1B3 expression and a higher incidence of microscopic hepatic venous invasion. PMID- 29260281 TI - Uncommon evolutions and complications of common benign liver lesions. AB - Frequently encountered on abdominal imaging studies, the majority of common benign liver lesions are asymptomatic, confidently diagnosed by imaging, and do not require further workup, follow-up, or treatment. The increasing use of multimodality liver imaging, has allowed the recognition of uncommon evolutions of common benign liver lesions such as size changes, fibrotic regression, and content and vascularization changes, and their complications such as rupture, hemorrhage, thrombosis, extrinsic compression, and malignancy. The purpose of this pictorial review is to describe and illustrate the incidence and diagnostic features of these uncommon evolutions and complications on cross-sectional imaging, mainly on computed tomography and magnetic resonance imaging, with emphasis on those imaging clues which are helpful in the differential diagnosis or indicate the need for treatment. PMID- 29260283 TI - Enhancing bioactive peptide release and identification using targeted enzymatic hydrolysis of milk proteins. AB - Milk proteins have been extensively studied for their ability to yield a range of bioactive peptides following enzymatic hydrolysis/digestion. However, many hurdles still exist regarding the widespread utilization of milk protein-derived bioactive peptides as health enhancing agents for humans. These mostly arise from the fact that most milk protein-derived bioactive peptides are not highly potent. In addition, they may be degraded during gastrointestinal digestion and/or have a low intestinal permeability. The targeted release of bioactive peptides during the enzymatic hydrolysis of milk proteins may allow the generation of particularly potent bioactive hydrolysates and peptides. Therefore, the development of milk protein hydrolysates capable of improving human health requires, in the first instance, optimized targeted release of specific bioactive peptides. The targeted hydrolysis of milk proteins has been aided by a range of in silico tools. These include peptide cutters and predictive modeling linking bioactivity to peptide structure [i.e., molecular docking, quantitative structure activity relationship (QSAR)], or hydrolysis parameters [design of experiments (DOE)]. Different targeted enzymatic release strategies employed during the generation of milk protein hydrolysates are reviewed herein and their limitations are outlined. In addition, specific examples are provided to demonstrate how in silico tools may help in the identification and discovery of potent milk protein derived peptides. It is anticipated that the development of novel strategies employing a range of in silico tools may help in the generation of milk protein hydrolysates containing potent and bioavailable peptides, which in turn may be used to validate their health promoting effects in humans. Graphical abstract The targeted enzymatic hydrolysis of milk proteins may allow the generation of highly potent and bioavailable bioactive peptides. PMID- 29260282 TI - Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases. AB - Proteases, sharp yet unforgivable tools of every cell, require tight regulation to ensure specific non-aberrant cleavages. The relatively recent discovered class of intramembrane proteases has gained increasing interest due to their involvement in important signaling pathways linking them to diseases including Alzheimer's disease and cancer. Despite tremendous efforts, their regulatory mechanisms have only started to unravel. There is evidence that the membrane composition itself can regulate intramembrane protease activity and specificity. In this review, we highlight the work on gamma-secretase and rhomboid proteases and summarize several studies as to how different lipids impact on enzymatic activity. PMID- 29260284 TI - Improvement of imprinting effect of ionic liquid molecularly imprinted polymers by use of a molecular crowding agent. AB - We aimed to improve the imprinting effect of ionic liquid molecularly imprinted polymers (MIPs) by use of a molecular crowding agent. The ionic liquid 1-vinyl-3 ethylimidazolium tetrafluoroborate ([VEIm][BF4]) was used as the functional monomer and aesculetin was used as the template molecule in a crowding environment, which was made up of a tetrahydrofuran solution of polystyrene. The ionic liquid MIPs that were prepared in the crowding environment displayed an enhanced imprinting effect. NMR peak shifts of active hydrogen of aesculetin suggested that interaction between the functional monomer and the template could be increased by the use of a crowding agent in the self-assembly process. The retention and selectivity of aesculetin were affected greatly by high molecular crowding, the amount of high molecular weight crowding agent, and the ratio of [VEIm][BF4] to aesculetin. The optimal MIPs were used as solid-phase extraction sorbents to extract aesculetin from Cichorium glandulosum. A calibration curve was obtained with aesculetin concentrations from 0.0005 to 0.05 mg mL-1 (correlation coefficient R 2 of 0.9999, y = 1519x + 0.0923). The limit of quantification was 0.12 MUg mL-1, and the limit of detection was 0.05 MUg mL-1. The absolute recovery of aesculetin was (80 +/- 2)% (n = 3), and the purity of aesculetin was (92 +/- 0.5)% (n = 5). As a conclusion, molecular crowding is an effective approach to obtain ionic liquid MIPs with high selectivity even in a polar solvent environment. PMID- 29260286 TI - Bowel ultrasound for predicting surgical management of necrotizing enterocolitis: a systematic review and meta-analysis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating inflammatory disease of the intestinal tract that represents a significant source of morbidity and mortality in preterm infants. Imaging of the abdomen is valuable for timely diagnosis and close monitoring of disease progression in NEC. Bowel ultrasound (US) is increasingly being recognized as an important imaging tool for evaluating NEC that provides additional detail than plain abdominal radiographs. OBJECTIVE: To identify bowel US findings associated with surgical management or death in infants with NEC. MATERIALS AND METHODS: We searched Embase, PubMed, and the Cumulative Index to Nursing and Allied Health Literature for studies investigating the association between bowel US findings and surgical management or death in NEC. Selected articles were evaluated for quality of study methodology using the Newcastle-Ottawa Scale, and aggregate statistics for odds ratio (OR) and 95% confidence interval were calculated. RESULTS: Of 521 articles reviewed, 11 articles comprising 748 infants were evaluated for quality. Nine of the studies were retrospective and from single-center experiences. Pooled analysis showed that focal fluid collections (OR 17.9, 3.1-103.3), complex ascites (OR 11.3, 4.2-30.0), absent peristalsis (OR 10.7, 1.7-69.0), pneumoperitoneum (OR 9.6, 1.7-56.3), bowel wall echogenicity (OR 8.6, 3.4-21.5), bowel wall thinning (OR 7.11.6-32.3), absent perfusion (OR 7.0, 2.1-23.8), bowel wall thickening (OR 3.9, 2.4-6.1) and dilated bowel (OR 3.5, 1.8-6.8) were associated with surgery or death in NEC. In contrast, portal venous gas (OR 3.0, 0.8-10.6), pneumatosis intestinalis (OR 2.1, 0.9-5.1), increased bowel perfusion (OR 2.6, 0.6-11.1) and simple ascites (OR 0.54, 0.1-2.5) were not associated with surgery or death. CONCLUSION: This meta-analysis identified several bowel US findings that are associated and not associated with surgery or death in NEC. Bowel US may be useful for early identification of high-risk infants with NEC who may benefit from more aggressive treatment, including surgery. Future studies are needed to determine whether the addition of bowel US in NEC evaluation would improve outcomes. PMID- 29260287 TI - Change in liver, spleen and bone marrow magnetic resonance imaging signal intensity over time in children with solid abdominal tumors. AB - BACKGROUND: Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with solid abdominal tumors. OBJECTIVE: To assess changes in liver, spleen and bone marrow T2-weighted MRI signal intensity over time and their relationship to blood transfusion history in children with solid abdominal tumors. MATERIALS AND METHODS: In this retrospective study we measured liver, spleen and bone marrow signal intensity on axial T2-weighted MR images obtained December 2009 through February 2016 in children with hepatoblastoma, neuroblastoma, ganglioneuroblastoma and Wilms tumor. All signal intensity measurements were normalized to paraspinal muscle signal intensity. We used linear mixed models (including a day*day quadratic term) to determine whether organ signal intensity changed over time and whether change was associated with blood transfusion volume or tumor type. RESULTS: We included 133 children (mean age at diagnosis =2.9 years); 56 had neuroblastoma, 42 hepatoblastoma, 28 Wilms tumor and 7 ganglioneuroblastoma. Seventy-nine (59.4%) children received transfusions (median: 8 transfusions, range: 1-30; mean volume: 1,148.5 mL). Hepatic, splenic and bone marrow signal intensity ratios changed quadratically over time for the study population, initially decreasing and then increasing (P<0.0001). Children receiving less than the mean blood transfusion volume showed no significant change in tissue signal intensity, while those receiving more than the mean volume showed significant changes in signal intensity over time (P<0.0001). Compared to children with Wilms tumor, those with neuroblastoma exhibited significantly lower hepatic (P=0.03) signal intensity ratios. CONCLUSION: Liver, spleen and bone marrow T2-weighted MRI signal intensity ratios change over time in some pediatric patients with solid abdominal tumors, likely from tissue iron deposition related to blood transfusions and perhaps because of tumor type. PMID- 29260288 TI - Remarkable improvement in serum 25-hydroxyvitamin levels among hip fracture patients over a 12-year period: a prospective study in South-eastern Finland. AB - : Hypovitaminosis D is a problem among hip fracture patients. In a 1-year cohort study comprising 245 hip fracture patients (mean age of females 81 years and males 78 years) from south-eastern Finland, the mean 25-hydroxyvitamin D [S 25(OH)D] concentration was 73(SD 31) nmol/L. Vitamin D supplementation has been integrated into our current practice. INTRODUCTION: The objectives of this study are to verify vitamin D levels among hip fracture patients and to compare the results with a similar study conducted in the same two hospitals covering the same geographic area 12 years ago. METHODS: A prospective cohort comprising 245 Caucasian hip fracture patients was enrolled in the study in two acute hospitals in south-eastern Finland (61 degrees N) over a 12-month period in 2015-2016. The S-25(OH)D was measured using 25-hydroxyvitamin D electrochemiluminescence binding assay. The S-25(OH)D concentrations were compared with the corresponding concentrations of a similar cohort analyzed in the same two hospitals 12 years ago. RESULTS: Of the 245 patients, 70% were women with a mean age of 81 (SD 10) years, while the men had a mean age of 78 (SD 12) years (p < 0.01). The total mean S-25(OH)D concentration was 73 (SD 31.3) nmol/L. Regional differences were found: 15% in hospital A and 36% in hospital B had a S-25(OH(D level < 50 nmol/L, and the mean S-25(OH)D level was 79.2 (SD 31.7) nmol/L in hospital A and 62.4 (SD 27.5) nmol/L in hospital B (p < 0.001). No differences were found in S-25(OH)D concentrations by either the place of residence or the time of year. Overall, the percentage of patients with a sufficient vitamin D level (> 50 nmol/L) was remarkably higher in 2015-2016 (77%) than in 2003-2004 (22%). CONCLUSION: Our results indicate that vitamin D supplementation has been widely integrated into our current practice. However, regional differences were found in the S-25(OH)D concentrations for which the reasons are unknown. PMID- 29260289 TI - Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption. AB - : Abaloparatide, a novel PTH1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. Abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality. INTRODUCTION: Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos). METHODS: Sixty-five 9-18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n = 17) or abaloparatide (0.2, 1, or 5 MUg/kg/day; n = 16/dose level), while Sham controls received s.c. vehicle (n = 15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed. RESULTS: At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams. CONCLUSIONS: Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters. PMID- 29260290 TI - Appropriateness criteria for treatment of osteoporotic vertebral compression fractures. AB - The purpose of this study was to review and summarise the literature on appropriateness criteria for treatment of osteoporotic vertebral compression fractures (OVCF), with appropriateness defined as a treatment where the expected benefits outweigh the expected harms, confirmed by available evidence and expert opinion. A comprehensive search of peer-reviewed publications (PubMed, EMBASE) and grey literature was performed. To be included for analysis, documents had to be a review article (e.g. clinical guideline or meta-analysis), focus on OVCF and make a statement on treatment appropriateness. Eleven publications fulfilled the eligibility criteria. Among the five publications that made recommendations about non-surgical management (NSM), there is agreement that conservative methods are appropriate in OVCF patients who have low level of pain, and that the majority of patients should be treated with conservative methods before other treatments are initiated. All publications made recommendations about vertebral augmentation procedures (VAP), i.e. vertebroplasty (VP) and/or balloon kyphoplasty (BKP). VAP are mostly considered appropriate in patients with high level of pain who do not respond to NSM. However, results cannot be generalised due to heterogeneity of treatment recommendations and patient selection. Although there is a consensus that NSM should be considered as the first-line treatment, there is more heterogeneity in treatment recommendations for VAP. This could most likely be explained by an insufficient clinical evidence base for VAP and heterogeneity of OVCF patients, leading to greater reliance on expert opinion affecting the quality of evidence in the primary sources. PMID- 29260291 TI - A dedicated Fracture Liaison Service telephone program and use of bone turnover markers for evaluating 1-year persistence with oral bisphosphonates. AB - : Telephone call intervention did not improve alendronate persistence in Fracture Liaison Service (FLS) patients in this study. A bone turnover marker cut-off point for alendronate persistence is proposed for individual FLS patients. INTRODUCTION: FLS aims to prevent subsequent fractures, which should include improving patients' persistence with prescribed oral bisphosphonates. We studied the influence of telephone calls and the predictive value of changes in bone turnover markers (BTMs) for evaluating persistence with alendronate. METHODS: Postmenopausal women with a recent fracture and osteoporosis who started alendronate were randomized to receive three phone calls (PC) (after 1, 4, and 12 months) or no phone calls (no PC). s-CTX and P1NP were measured at baseline and after 3, 6, 9, and 12 months. As a reference group, 30 postmenopausal osteopenic patients with a recent fracture were analyzed as well. Persistence was assessed using the Dutch National Switch Point Pharmacies-GPs database and cross referenced with PC, no PC, and BTM changes. Cut-off values of BTMs were calculated based on least significant change (LSC) and also on underrunning median values of the untreated osteopenic postmenopausal reference group with a recent fracture. RESULTS: Out of 119 patients, 93 (78%) completed 12 months follow-up (45 PC and 48 no PC). Mean age was 69 years. Persistence was similar in PC and no PC participants. The cut-off value > 29% (< 415 ng/L) as LSC of s-CTX and > 36% (< 53.1 MUg/L) as LSC of P1NP was determined optimally showing alendronate persistence after 1 year (being 93 and 88%, respectively). CONCLUSIONS: In this context, telephone calls did not improve persistence. In around 90% of patients, 1-year alendronate persistence was confirmed by achieving LSC of s-CTX and of P1NP at 12 months. PMID- 29260293 TI - In memory of Professor Satoshi Matsumoto. PMID- 29260292 TI - Vitamin D supplementation and bone turnover in advanced heart failure: the EVITA trial. AB - : Low vitamin D status is common in patients with heart failure and may influence bone health. A daily vitamin D dose of 4000 IU (moderately high dose) for 3 years had however no effect on parameters of bone metabolism, even in patients with very low vitamin D status. INTRODUCTION: Low vitamin D status is common in patients with heart failure (HF) and has been related to disturbed bone turnover. The present study investigated the effect of a daily vitamin D3 dose of 4000 IU on bone turnover markers (BTMs) in patients with advanced HF and 25 hydroxyvitamin D (25OHD) concentrations < 75 nmol/L. METHODS: In this pre specified secondary analysis of a randomized controlled trial, we assessed in 158 male HF patients (vitamin D group: n = 80; placebo group: n = 78) between-group differences in calciotropic hormones (25OHD, 1,25-dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone [iPTH]), and BTMs (cross-linked C telopeptide of type I collagen, bone-specific alkaline phosphatase, undercarboxylated osteocalcin). Comparisons were performed at the end of a 3-year vitamin D supplementation period with adjustments for baseline values. RESULTS: Compared with placebo, vitamin D increased 25OHD on average by 54.3 nmol/L. At study termination, 25OHD and 1,25(OH)2D were significantly higher (P < 0.001 and P = 0.007, respectively), whereas iPTH tended to be lower in the vitamin D group than in the placebo group (P = 0.083). BTMs were initially within their reference ranges and did not differ significantly between groups at study termination, neither in the entire study cohort nor when data analysis was restricted to the subgroup of patients with initial 25OHD concentrations < 30 nmol/L (n = 54) or to patients with initial hyperparathyroidism (n = 65) (all P values > 0.05). CONCLUSIONS: A daily vitamin D3 dose of 4000 IU did not influence BTMs. Data indicate that vitamin D supplementation will not lower bone turnover in male patients with heart failure. PMID- 29260294 TI - Fatty filum terminale (FFT) as a secondary tethering element in children with closed spinal dysraphism. AB - PURPOSE: The purpose of this study was to assess the prevalence of FFT as an additional tethering element in children operated for closed spinal dysraphism, where FFT was not the primary tethering pathology. METHODS: This is a retrospective study of 195 children (< 18 years of age) who underwent surgery for closed spinal dysraphism and did not have FFT as the primary diagnosis. All patients were operated during the period 2005-2017 by a single surgeon. The commonest diagnosis was a lipomyelomeningocele (LMMC, n = 81, 41.5%), followed by split cord malformations (SCM, types I and II, n = 61, 31.3%), dermal sinus (n = 28, 14.4%), and dermoid cyst (n = 10, 5.1%). Factors such as age and sex, presenting symptoms, intraoperative findings, and radiological presence of a FFT on a magnetic resonance imaging (MRI) were documented, and the relationship between the primary diagnoses and presence of FFT was analyzed. RESULTS: FFT as a secondary finding was seen in 63 patients (32.3%). The mean age of the cohort was 54 months (4.5 years) and the sex distribution was relatively even (51.8% girls). The commonest symptom at presentation was a swelling in the back, followed by lower limb weakness. The mean duration of symptoms was nearly 30 months. FFT was seen on the MRI and confirmed intraoperatively in 55 patients (28.2%). There were 8 patients (4.1%) where a FFT was seen intraoperatively, but was not diagnosed on the preoperative MRI. In 16 patients, FFT was seen > 2 segments away from the primary tethering pathology, 8 of which mandated a second skin incision for sectioning of the FFT. Secondary FFT was most commonly associated with a SCM (types I and II combined) and was seen in 42.6% of those patients. It was least commonly associated with intradural dermoid cysts. CONCLUSION: The presence of a secondary FFT should be considered and actively sought on preoperative thin-slice T1W axial MR images in the sacral region in all patients with spinal dysraphism. Even if a FFT is not seen on preoperative MR images, the filum should be explored and sectioned if it is in the vicinity of the primary surgical field, especially in patients with SCM. PMID- 29260295 TI - Expansion of gene clusters, circular orders, and the shortest Hamiltonian path problem. AB - Clusters of paralogous genes such as the famous HOX cluster of developmental transcription factors tend to evolve by stepwise duplication of its members, often involving unequal crossing over. Gene conversion and possibly other mechanisms of concerted evolution further obfuscate the phylogenetic relationships. As a consequence, it is very difficult or even impossible to disentangle the detailed history of gene duplications in gene clusters. In this contribution we show that the expansion of gene clusters by unequal crossing over as proposed by Walter Gehring leads to distinctive patterns of genetic distances, namely a subclass of circular split systems. Furthermore, when the gene cluster was left undisturbed by genome rearrangements, the shortest Hamiltonian paths with respect to genetic distances coincide with the genomic order. This observation can be used to detect ancient genomic rearrangements of gene clusters and to distinguish gene clusters whose evolution was dominated by unequal crossing over within genes from those that expanded through other mechanisms. PMID- 29260296 TI - Lithium-Associated Hypercalcemia: Pathophysiology, Prevalence, Management. AB - BACKGROUND: Lithium-associated hypercalcemia (LAH) is an ill-defined endocrinopathy. The aim of the present study was to determine the prevalence of hypercalcemia in a cohort of bipolar patients (BP) with and without concomitant lithium treatment and to study surgical outcomes for lithium-associated hyperparathyroidism. METHODS: Retrospective data, including laboratory results, surgical outcomes and medications, were collected from 313 BP treated with lithium from two psychiatric outpatient units in central Sweden. In addition, data were collected from 148 BP without lithium and a randomly selected control population of 102 individuals. Logistic regression was used to compare odds of hypercalcemia in these respective populations. RESULTS: The prevalence of lithium associated hypercalcemia was 26%. Mild hypercalcemia was detected in 87 out of 563 study participants. The odds of hypercalcemia were significantly higher in BP with lithium treatment compared with BP unexposed to lithium (adjusted OR 13.45; 95% CI 3.09, 58.55; p = 0.001). No significant difference was detected between BP without lithium and control population (adjusted OR 2.40; 95% CI 0.38, 15.41; p = 0.355). Seven BP with lithium underwent surgery where an average of two parathyroid glands was removed. Parathyroid hyperplasia was present in four patients (57%) at the initial operation. One patient had persistent disease after the initial operation, and six patients had recurrent disease at follow-up time which was on average 10 years. CONCLUSION: The high prevalence of LAH justifies the regular monitoring of calcium homeostasis, particularly in high-risk groups. If surgery is necessary, bilateral neck exploration should be considered in patients on chronic lithium treatment. Prospective studies are needed. PMID- 29260297 TI - Highly sensitive and specific detection of Giardia duodenalis, Entamoeba histolytica, and Cryptosporidium spp. in human stool samples by the BD MAXTM Enteric Parasite Panel. AB - Detection of intestinal protozoan parasites by light microscopy is cumbersome, needs experienced personnel, and may lack sensitivity and/or specificity as compared with molecular-based stool assays. Here, we evaluated the BD MAXTM Enteric Parasite Panel, i.e., a multiplex real-time PCR assay for simultaneous detection of Giardia duodenalis, Entamoeba histolytica, and cryptosporidia (Cryptosporidium parvum and C. hominis), by examining 200 positive human stool samples (138 * G. duodenalis, 27 * E. histolytica, 35 * Cryptosporidium spp.) and 119 controls including 18 samples with E. dispar. The majority of the samples, i.e., 153/200 (76.5%) positive samples and 66/119 (55.5%) controls, were confirmed by multiplex in-house PCR detecting the same parasites as the BD MAXTM Enteric Parasite Panel. The BD MAXTM assay did not yield false-positive results. Sensitivity and specificity were 97.8% (95% CI, 93.3-99.4%) and 100% (95% CI, 97.4-100%) for G. duodenalis, 100% (95% CI, 84.5-100%) and 100% (95% CI, 98.4 100%) for E. histolytica, and 100% (95% CI, 87.7-100%) and 100% (95% CI, 98.3 100%) for cryptosporidia, and similar data were obtained when only the 219 PCR confirmed samples were analyzed. Thus, the BD MAXTM Enteric Parasite Panel provides a highly sensitive and specific tool for the laboratory diagnosis of three predominant protozoan parasites causing enteritis. PMID- 29260298 TI - Screening of chemical compound libraries identified new anti-Toxoplasma gondii agents. AB - Toxoplasma gondii is the etiological agent of toxoplasmosis, a common parasitic disease that affects nearly one-third of the human population. The primary infection can be asymptomatic in healthy individuals but may prove fatal in immunocompromised individuals. Available treatment options for toxoplasmosis patients are limited, underscoring the urgent need to identify and develop new therapies. Non-biased screening of libraries of chemical compounds including the repurposing of well-characterized compounds is emerging as viable approach to achieving this goal. In the present investigation, we screened libraries of natural product and FDA-approved compounds to identify those that inhibited T. gondii growth. We identified 32 new compounds that potently inhibit T. gondii growth. Our findings are new and promising, and further strengthen the prospects of drug repurposing as well as the screening of a wide range of chemical compounds as a viable source of alternative anti-parasitic therapeutic agents. PMID- 29260299 TI - [Updates to the WHO classification of bone tumours]. AB - The fourth edition of the WHO Classification of Soft Tissue and Bone Tumours, published in 2013, extends the approach to describe genetics and pathology of these tumours in the context of epidemiological, clinical and imaging data, which was adopted in the third edition. Added are a few new entities, reclassifications and renamings. The most important point, also of clinical relevance and with consequences for treatment, is the introduction of a stratification of bone tumours based on their biological behaviour into three groups (benign, intermediate, malignant) in analogy to soft tissue tumours. PMID- 29260300 TI - The recovery of the PT-INR to less than 1.3 predicts survival in patients with severe acute liver injury. AB - BACKGROUND: Acute liver failure is a potentially fatal disease of various etiologies for which liver transplantation is the only known curative treatment. Although the decision-making on transplantation is largely dependent on the severity of liver injury (based on predicting a fatal outcome), a statistical analysis to predict "survival" has not been extensively conducted. In this study, we investigate the medical history of patients in two distinct areas of Japan with the aim of identifying the predictors of survival in patients with acute liver injury (ALI). METHODS: Datasets of 301 patients with ALI in two distinct areas (93 in southern Kyushu and 208 in northern Tohoku) of Japan, who were treated from 2004 to 2014, were included in the analysis. RESULTS: Among the enrolled 301 cases, 263 patients survived without transplantation. A PT-INR of >= 1.3 during the clinical course was found to be adequate for predicting a poor prognosis, because all of the fatal cases emerged from this population (hazard ratios: southern Kyushu, 0.2827; northern Tohoku, 0.1862). All surviving patients showed a reduction in their PT-INR during treatment, whereas the PT-INR did not decrease in the patients with a poor prognosis. A PT-INR of < 1.3 on days 7 and 8 efficiently predicted transplant-free survival (log-rank test: southern Kyushu, P = 0.0030; northern Tohoku, P = 0.0022). CONCLUSIONS: A PT-INR of >= 1.3 during the clinical course might identify cases with a poor prognosis, while the recovery of the PT-INR to < 1.3 predicts transplant-free survival. PMID- 29260301 TI - Regional Hounsfield unit measurement of screw trajectory for predicting pedicle screw fixation using cortical bone trajectory: a retrospective cohort study. AB - BACKGROUND: The sufficiency of screw anchoring is a critical factor for achieving successful spinal fusion; however, no reliable method for predicting pedicle screw fixation has been established. Recently, Hounsfield units (HU) obtained from computed tomography (CT) was developed as a new reliable tool to determine the bone quality. The purpose of the present study was to demonstrate the utility of regional HU measurement of the screw trajectory to predict the primary and long-term fixation strength of pedicle screws. METHOD: The insertional torque of pedicle screws using the cortical bone trajectory technique was measured intraoperatively in 92 consecutive patients who underwent single-level posterior lumbar interbody fusion. The cylindrical area of each screw was plotted on the preoperative CT image by precisely confirming the screw position, and the screw trajectory was measured in HU. First, three parameters: the bone mineral density (BMD) of the femoral neck and lumbar vertebrae, and regional HU values of the screw trajectory, were correlated with the insertional torque and compared among three groups. Next, pedicle screw loosening was evaluated by postoperative CT obtained 12 months after surgery, and clinical and imaging data were analyzed to assess whether regional HU values could be used as a predictor of screw loosening. RESULTS: Regional HU values of the screw trajectory (r = 0.75, p < 0.001) had stronger correlation with the insertional torque than the femoral BMD (r = 0.59, p < 0.001) and lumbar BMD (r = 0.55, p < 0.001). The incidence of screw loosening was 4.6% (16/351). Multivariate logistic regression analysis revealed that regional HU value (odds ratio = 0.70; 95% confidence interval = 0.56-0.84; p = 0.018) was an independent risk factor significantly affected screw loosening. CONCLUSIONS: Regional HU values of the screw trajectory could be a strong predictor of both primary and long-term screw fixation in vivo. PMID- 29260302 TI - Prevalence of Monovalent Copper Over Divalent in Killing Escherichia coli and Staphylococcus aureus. AB - This study opens the investigation series focused on antimicrobial effects of copper (Cu) compared to silver (Ag), which is currently used to treat wound infection in burn victims as well as in chronic wounds. Noticeably, in its ionized state, Cu is more commonly present as Cu2+ rather than as Cu+, while electronic configuration similarity of Cu+ and Ag+ indicates that actually it may be the active state. To test this hypothesis, effect of Cu+ and Cu2+, using Ag+ ions and metallic copper as controls on Escherichia coli and Staphylococcus aureus bacteria, was examined under anaerobic conditions. Cu+ was produced by two different methods, and its effect on microorganism growth was tested using a syringe and Petri dish methods. It was found that the presence of Cu+ causes a dramatic depletion in the viability of both microorganisms. Metallic copper did not have any effect on the viability, whereas Cu2+ and Ag+ ions had much lower activity than Cu+ ions. Minimal inhibitory concentration of Cu+ for E. coli was twice lower than that of Cu2+. The obtained results show that Cu+ proves to be a potent antimicrobial agent. PMID- 29260304 TI - Denali, Tulip, and Option Inferior Vena Cava Filter Retrieval: A Single Center Experience. AB - PURPOSE: To compare the technical success of filter retrieval in Denali, Tulip, and Option inferior vena cava filters. MATERIALS AND METHODS: A retrospective analysis of Denali, Gunther Tulip, and Option IVC filters was conducted. Retrieval failure rates, fluoroscopy time, sedation time, use of advanced retrieval techniques, and filter-related complications that led to retrieval failure were recorded. RESULTS: There were 107 Denali, 43 Option, and 39 Tulip filters deployed and removed with average dwell times of 93.5, 86.0, and 131 days, respectively. Retrieval failure rates were 0.9% for Denali, 11.6% for Option, and 5.1% for Tulip filters (Denali vs. Option p = 0.018; Denali vs. Tulip p = 0.159; Tulip vs. Option p = 0.045). Median fluoroscopy time for filter retrieval was 3.2 min for the Denali filter, 6.75 min for the Option filter, and 4.95 min for the Tulip filter (Denali vs. Option p < 0.01; Denali vs. Tulip p < 0.01; Tulip vs. Option p = 0.67). Advanced retrieval techniques were used in 0.9% of Denali filters, 21.1% in Option filters, and 10.8% in Tulip filters (Denali vs. Option p < 0.01; Denali vs. Tulip p < 0.01; Tulip vs. Option p < 0.01). DISCUSSION: Filter retrieval failure rates were significantly higher for the Option filter when compared to both the Denali and Tulip filters. Retrieval of the Denali filter required significantly less amount of fluoroscopy time and use of advanced retrieval techniques when compared to both the Option and Tulip filters. The findings of this study indicate easier retrieval of the Denali and Tulip IVC filters when compared to the Option filter. PMID- 29260303 TI - BAH1 an E3 Ligase from Arabidopsis thaliana Stabilizes Heat Shock Factor sigma32 of Escherichia coli by Interacting with DnaK/DnaJ Chaperone Team. AB - In Escherichia coli, the DnaK/DnaJ chaperone can control the stability and activity of sigma32, which is the key factor in heat shock response. Heterologous expression of eukaryotic molecular chaperones protects E. coli from heat stress. Here, we show that BAH1, an E3 ligase from plant that has a similar zinc finger domain to DnaJ, can perform block the effect of DnaK on sigma32 in Escherichia coli. By constructing a chimeric DnaJ protein, with the J-domain of DnaJ fused to BAH1, we found BAH1 could partially compensate for the DnaJ' zinc finger domain in vivo, and that it was dependent on the zinc finger domain of BAH1. Furthermore, BAH1 could interact with both sigma32 and DnaK to increase the level of HSPs, such as GroEL, DnaK, and sigma32. These results suggested that the zinc finger domain was conserved during evolution. PMID- 29260305 TI - Are We Overtreating Renal Angiomyolipoma: A Review of the Literature and Assessment of Contemporary Management and Follow-Up Strategies. AB - Renal angiomyolipoma (AML) are benign tumours composed of fat, muscle, and disorganised blood vessels. Historic treatment algorithms for sporadic AML based on size fail to consider additional risk factors such as tumour vascularity and pseudoaneurysm formation. As AML is now predominantly incidental, rupture is rare and its mortality low. The recent publication of the largest longitudinal series to date also suggest that growth is uncommon, challenging existing surveillance paradigms. The evidence assessing treatment strategies in AML are reviewed, with particular emphasis on incidental sporadic AML. The relative merits of various AML treatments are discussed, and areas of clinical uncertainty highlighted. PMID- 29260306 TI - Spontaneous Regression of an Intracranial Aneurysm Following Remote Aneurysm Clipping: Evaluation with High-Resolution Vessel Wall MRI. AB - Spontaneous regression of an unruptured aneurysm is very rare. We present a case of a 64-year-old woman with an unruptured cerebral aneurysm in which spontaneous regression occurred after contralateral clipping. High-resolution magnetic resonance imaging showed that the aneurysm had decreased in size and there was no evidence of thrombus. Level of Evidence Case, Level IV. PMID- 29260308 TI - A technical case report on use of tubular retractors for anterior cervical spine surgery. AB - PURPOSE: The authors put-forth this technical report to establish the feasibility of performing an anterior cervical corpectomy and fusion (ACCF) and a two-level anterior cervical discectomy and fusion (ACDF) using a minimally invasive approach with tubular retractors. METHODS: First case: cervical spondylotic myelopathy secondary to a large postero-inferiorly migrated disc treated with corpectomy and reconstruction with a mesh cage and locking plate. Second case: cervical disc herniation with radiculopathy treated with a two-level ACDF. Both cases were operated with minimally invasive approach with tubular retractor using a single incision. Technical aspects and clinical outcomes have been reported. RESULTS: No intra or post-operative complications were encountered. Intra operative blood loss was negligible. The patients had a cosmetic scar on healing. Standard procedure of placement of tubular retractors is sufficient for adequate surgical exposure with minimal invasiveness. CONCLUSION: Minimally invasive approach to anterior cervical spine with tubular retractors is feasible. This is the first report on use of minimally invasive approach for ACCF and two-level ACDF. PMID- 29260307 TI - Emerging roles for sphingolipids in cellular aging. AB - Aging is a gradual loss of physiological functions as organisms' progress in age. Although aging in multicellular organisms is complex, some fundamental mechanisms and pathways may be shared from the single cellular yeast to human. Budding yeast Saccharomyces cerevisiae has been established model system for aging studies. A yeast cell divides asymmetrically to produce two cells that differ in size and age. The one that is smaller coming from bud is a newborn cell that with a full replicative potential head irrespective of the replicative age of its mother-the larger cell from which the bud grows out before division. The age asymmetry between daughter and mother is thought to be dependent on asymmetric segregation of certain factors such as protein aggregates, extrachromosomal DNA (ERCs) and dysfunctional organelles during successive cell divisions of the yeast replicative lifespan (RLS). It is also thought that certain plasma membrane proteins, in particular multidrug-resistant (MDR) proteins, asymmetrically partition between the mother and the bud based on the age of the polypeptides. Functional decline associated with the molecular aging of those proteins contributes to the fitness decline at advance age. In our recent study, we showed that sphingolipids facilitate the age-dependent segregation of MDRs between daughter and mother cell. In this review, we highlight and discuss the potential mechanisms by which sphingolipids regulate the aging process in yeast and cells of vertebrate animals including human. PMID- 29260310 TI - Reply to letter to the editor about radiotherapy in the management of heel spur pain. PMID- 29260309 TI - HIV Infection, Pulmonary Tuberculosis, and COPD in Rural Uganda: A Cross Sectional Study. AB - PURPOSE: HIV is associated with chronic obstructive pulmonary disease (COPD) in high resource settings. Similar relationships are less understood in low resource settings. We aimed to estimate the association between HIV infection, tuberculosis, and COPD in rural Uganda. METHODS: The Uganda Non-communicable Diseases and Aging Cohort study observes people 40 years and older living with HIV (PLWH) on antiretroviral therapy, and population-based HIV-uninfected controls in rural Uganda. Participants completed respiratory questionnaires and post-bronchodilator spirometry. RESULTS: Among 269 participants with spirometry, median age was 52 (IQR 48-55), 48% (n = 130) were ever-smokers, and few (3%, n = 9) reported a history of COPD or asthma. All participants with prior tuberculosis (7%, n = 18) were PLWH. Among 143 (53%) PLWH, median CD4 count was 477 cells/mm3 and 131 (92%) were virologically suppressed. FEV1 was lower among older individuals (- 0.5%pred/year, 95% CI 0.2-0.8, p < 0.01) and those with a history of tuberculosis (- 14.4%pred, 95% CI - 23.5 to - 5.3, p < 0.01). COPD was diagnosed in 9 (4%) participants, eight of whom (89%) were PLWH, six of whom (67%) had a history of tuberculosis, and all of whom (100%) were men. Among 287 participants with complete symptom questionnaires, respiratory symptoms were more likely among women (AOR 3.9, 95% CI 2.0-7.7, p < 0.001) and those in homes cooking with charcoal (AOR 3.2, 95% CI 1.4-7.4, p = 0.008). CONCLUSION: In rural Uganda, COPD may be more prevalent among PLWH, men, and those with prior tuberculosis. Future research is needed to confirm these findings and evaluate their broader impacts on health. PMID- 29260311 TI - Body mass index, hip function and surgeon volume are independent predictors of dislocation: an analysis of 4334 total hip replacements. AB - The aim of this study was to identify pre-operative and intra-operative factors that are predictive of dislocation following primary total hip replacement (THR). Data were prospectively collected for a consecutive series of 4334 THRs undertaken over a 14-year period. Ninety-eight (2.3%) of the 4334 patients had one or more dislocation post-operatively. A body mass index (BMI) of >= 35 (p < 0.001), a Harris Hip Score (HHS) of <= 41 (p < 0.001) and a low-volume surgeon (p < 0.001), which was defined as performing fewer than 43 THRs per annum, were identified as independent predictors of dislocation using logistic regression analysis. Using these three variables in differing combinations the risk of dislocation varied from 0.5 to 10.4%. Patients at high risk of dislocation, with a BMI of >= 35 and a pre-operative HHS of <= 41, undergoing surgery by a low volume surgeon had a dislocation rate of 10.5%, but this decreased to 2.3% when operated on by a high-volume surgeon. These risk factors could be used to identify patients at high risk of dislocation, and modification of these factors, such as weight loss to achieve a BMI of <= 35 or referral to a high-volume surgeon, may decrease the risk of dislocation and the resulting secondary morbidity. PMID- 29260312 TI - [Dwarf with gigantic future potential]. PMID- 29260313 TI - Post-operative cognitive decline (POCD) after gynaecologic surgery: current opinions and future applications. AB - OBJECTIVE: Postoperative cognitive decline (POCD) is known to occur quite frequently after a cardiac surgery, especially in older population. Few studies specifically focused on its incidence and characteristics in gynecological setting. METHODS: Current opinions and future applications of POCD studies in gynecological setting have been discussed. RESULT: There are still many questions and issues about POCD in gynecological setting that remain unanswered as well as numerous research fields that have not been still explored. In particular, from this article emerges the need of further studies in gynecological setting focusing on: (a) the evaluation of long-term effect of POCD (e.g. over 3 months after surgery); (b) elderly population; (c) a wide range of cognitive functions (memory, attention, concentration, orientation, etc.); (d) the evaluation of risk and protective factors for subsequent POCD development; (e) the relationships between POCD and previous psychological or neuroendocrine factors; (f) the difference on POCD outcomes between different anaesthesia and disorders. CONCLUSION: Promoting studies on this topic is significant for the reduction of sociosanitary costs, mortality rates, social dependences and the likelihood of comorbidity. PMID- 29260314 TI - Coordinated radiation protection research in Europe: is it the beginning of a new era? PMID- 29260315 TI - Is working memory training in older adults sensitive to music? AB - Evidence in the literature suggests that listening to music can improve cognitive performance. The aim of the present study was to examine whether the short- and long-term gains of a working memory (WM) training in older adults could be enhanced by music listening-the Mozart's Sonata K448 and the Albinoni's Adagio in G minor-which differ in tempo and mode. Seventy-two healthy older adults (age range: 65-75 years) participated in the study. They were divided into four groups. At each training session, before starting the WM training activities, one group listened to Mozart (Mozart group, N = 19), one to Albinoni (Albinoni group, N = 19), one to white noise (White noise group, N = 16), while one served as an active control group involved in other activities and was not exposed to any music (active control group, N = 18). Specific training gains on a task like the one used in the training, and transfer effects on visuo-spatial abilities, executive function and reasoning measures were assessed. Irrespective of listening condition (Mozart, Albinoni, White noise), trained groups generally outperformed the control group. The White noise group never differed from the two music groups. However, the Albinoni group showed larger specific training gains in the criterion task at short-term and transfer effects in the reasoning task at both short-and long term compared to the Mozart group. Overall the present findings suggest caution when interpreting the effects of music before a WM training, and are discussed according to aging and music effect literature. PMID- 29260317 TI - Effects of long-term cysteamine treatment in patients with cystinosis. AB - Cystinosis is a rare autosomal-recessive lysosomal storage disease with high morbidity and mortality. It is caused by mutations in the CTNS gene that encodes the cystine transporter, cystinosin, which leads to lysosomal cystine accumulation. Patients with infantile nephropathic cystinosis, the most common and most severe clinical form of cystinosis, commonly present with renal Fanconi syndrome by 6-12 months of age, and without specific treatment, almost all will develop end-stage renal disease (ESRD) by 10-12 years of age. Early corneal cystine crystal deposition is a hallmark of the disease. Cystinosis also presents with gastrointestinal symptoms (e.g., vomiting, decreased appetite, and feeding difficulties) and severe growth retardation and may affect several other organs over time, including the eye, thyroid gland, gonads, pancreas, muscles, bone marrow, liver, nervous system, lungs, and bones. Cystine-depleting therapy with cysteamine orally is the only specific targeted therapy available for managing cystinosis and needs to be combined with cysteamine eye drops for corneal disease involvement. In patients with early treatment initiation and good compliance to therapy, long-term cysteamine treatment delays progression to ESRD, significantly improves growth, decreases the frequency and severity of extrarenal complications, and is associated with extended life expectancy. Therefore, early diagnosis of cystinosis and adequate life-long treatment with cysteamine are essential for preventing end-organ damage and improving the overall prognosis in these patients. PMID- 29260316 TI - Game-based training of flexibility and attention improves task-switch performance: near and far transfer of cognitive training in an EEG study. AB - There is a demand for ways to enhance cognitive flexibility, as it can be a limiting factor for performance in daily life. Video game training has been linked to advantages in cognitive functioning, raising the question if training with video games can promote cognitive flexibility. In the current study, we investigated if game-based computerized cognitive training (GCCT) could enhance cognitive flexibility in a healthy young adult sample (N = 72), as measured by task-switch performance. Three GCCT schedules were contrasted, which targeted: (1) cognitive flexibility and task switching, (2) attention and working memory, or (3) an active control involving basic math games, in twenty 45-min sessions across 4-6 weeks. Performance on an alternating-runs task-switch paradigm during pretest and posttest sessions indicated greater overall reaction time improvements after both flexibility and attention training as compared to control, although not related to local switch cost. Flexibility training enhanced performance in the presence of distractor-related interference. In contrast, attention training was beneficial when low task difficulty undermined sustained selective attention. Furthermore, flexibility training improved response selection as indicated by a larger N2 amplitude after training as compared to control, and more efficient conflict monitoring as indicated by reduced Nc/CRN and larger Pe amplitude after training. These results provide tentative support for the efficacy of GCCT and suggest that an ideal training might include both task switching and attention components, with maximal task diversity both within and between training games. PMID- 29260319 TI - Effects of light-emitting diode (LED) with a mixture of wavelengths on the growth and lipid content of microalgae. AB - Integrations of two-phase culture for cell growth and lipid accumulation using mixed LED and green LED wavelengths were evaluated with the microalgae, Phaeodactylum tricornutum, Isochrysis galbana, Nannochloropsis salina, and Nannochloropsis oceanica. Among the single and mixed LED wavelengths, mixed LED produced higher biomass of the four microalgae, reaching 1.03 g DCW/L I. galbana, followed by 0.95 g DCW/L P. tricornutum, 0.85 g DCW/L N. salina, and 0.62 g DCW/L N. oceanica than single LED or fluorescent lights at day 10. Binary combination of blue and red LEDs could produce the high biomass and photosynthetic pigments in the four microalgae. The highest lipid accumulation during second phase with the exposure to green LED wavelengths was 56.0% for P. tricornutum, 55.2% for I. galbana, 53.0% for N. salina, and 51.0% for N. oceanica. The major fatty acid in the four microalgae was palmitic acid (C16:0) accounting for 38.3-47.3% (w/w) of the total fatty acid content. PMID- 29260318 TI - The utility of surveillance biopsies in pediatric kidney transplantation. AB - BACKGROUND: Surveillance biopsies (SBs) are performed in some pediatric kidney transplant programs, based on data obtained in earlier immunosuppressive eras that the treatment of subclinical acute rejection results in better graft survival. The benefit of SBs for patients on modern immunosuppression regimens is unclear. We have therefore evaluated the clinical utility of SBs in a population of children receiving a kidney transplant. METHODS: We have performed SBs at 3, 6 and 12 months post-transplantation as standard of care at our institution since 2013 in patients on a regimen of rabbit anti-thymocyte globulin, tacrolimus, mycophenolate and rapid steroid taper (RST; steroids maintained in some exceptions). We reviewed pathology reports of 82 SBs from 34 transplants in 34 children for all abnormal findings and adequacy of specimens. Clinical records were reviewed for changes in management resulting from SB findings and for significant procedure complications. RESULTS: Of the 82 biopsies, 41 (50%) had abnormal findings separate from fibrosis, including five Banff Grade I rejections, ten borderline rejections, six calcineurin-inhibitor nephrotoxicity, four BK-virus nephropathy, five recurrent disease and three acute pyelonephritis. Moderate or more fibrosis was present in nine of the 82 (11%) biopsies. Management changes due to SB findings occurred in nine cases (11.0%). The proportion of abnormal findings or management changes did not differ between the RST or steroid-based groups. Patients performing clean intermittent catheterization showed inflammatory changes often read as rejection, but were managed differently. Three biopsies were deemed inadequate. No significant complications occurred. CONCLUSIONS: A high percentage of the SBs performed under modern immunosuppression showed abnormal findings even when fibrosis was excluded. However, management changes due to the SB findings were less frequent, although they occurred in a clinically meaningful percentage of cases. Complications or inadequate specimens were rare. PMID- 29260320 TI - Quantitative analysis of hydrogen peroxide with special emphasis on biosensors. AB - Determination of hydrogen peroxide (H2O2) has become essential in pharmaceutical, biological, clinical and environmental studies. The conventional detection methods of H2O2 such as colourimetry, titration, chromatography, spectrophotometry, fluorimetry, chemiluminescence have limited success, due to their poor selectivity and sensitivity, long analysis time and lack of long-term reliability and reproducibility. The biosensors overcome these limitations because of their simplicity, rapidity, selectivity and high sensitivity. This review describes the principle, analytic parameters, merits and demerits of various methods of H2O2 determination with special emphasis on biosensors. The classification of biosensors based on various materials/nanomaterials and electrodes have been described in detail. The recent advances in vivo sensing and bio-sensing of H2O2 by hemoglobin nanoparticles are also presented. The significant challenges and future perspective for highly selective H2O2 detection are discussed. PMID- 29260322 TI - Assessing N w-hydroxy-L-arginine applicability as a novel ethnic specific estrogen-negative breast cancer marker. AB - In our prior study we identified N w-hydroxy-L-arginine (NOHA) as a simple, yet sensitive indicator for estrogen negative (ER-) breast cancer early-prognosis, but not estrogen positive (ER+), and to offer ethnic selectivity for ER- detection. However, the ability of NOHA to assess ER- breast tumor based on disease progression, and tumor severity needs further delineation. Also, the overall NOHA storage stability needs to be validated. To assess the NOHA predictive capability based on disease progression, ER-/ER+ 3D-spheroids (from breast tumor cell lines of human origin) were cultured for 10 weeks. We found only ER- 3D-spheroid cultured for 10 weeks to show a gradual reduction in NOHA (both in culture medium and 3D-spheroid lysates) that correlated with a progressive increase in cellular NOS2 expression and NOS2 activity (measured as total nitrites). We additionally identified the NOHA-NOS2 correlation to be ethnically selective between ER- African American versus ER- Caucasian groups. Interestingly, such NOHA reduction was observed earlier in ER- culture medium (viz., after week 1) than from ER- 3D-spheroids lysates (viz., at the end of 3 weeks). When categorized based on 3D-spheroid grade, we found a >= 68% NOHA reduction in ER- spheroids that were <= 3 weeks old, that was categorized as "low grade" (based on tumor size <= 250 um, and with cellular characteristics identical to healthy cells). A substantial reduction in NOHA of >= 87% occurred with ER- 3D-spheroids grown for 6 weeks, which were categorized as "intermediate grade" (with tumor size of >= 400 um, and with less characteristic similarity to control spheroids). These in vitro findings thus suggest a distinct correlation between NOHA reduction and ER- tumor grade. Such distinctive correlation between NOHA and ER- tumor grade was additionally observed in de-identified clinical samples where a onefold higher reduction in NOHA occurred in grade-2 than with grade-1 de-identified patient plasma (when compared with control), and such correlation offered ethnic selectivity between ER- African American and ER- Caucasian groups. Of additional interest, when NOHA overall storage stability was assessed by incubating patient plasma and culture medium spiked with 75 pg/ml NOHA at multiple incubation temperatures and time-points, we found NOHA to maintain its stability for up to 6 weeks in culture medium and for 7 days in plasma at 4 degrees C and below. These results thus provide the first evidence of NOHA as a stable indicator to monitor ER- disease progression and tumor severity in ethnically distinctive populations. PMID- 29260321 TI - Efficacy of an Internet-based depression intervention to improve rates of treatment in adolescent mothers. AB - Approximately 400,000 adolescents give birth in the USA annually. Although one half experience depressive symptoms, less than 25% comply with referrals for depression evaluation and treatment. The current study tested the effectiveness of an Internet-based depression intervention on seeking depression treatment. Based upon the theory of planned behavior (TPB), the intervention included vignettes, questions and answers, and resources. Before the intervention, immediately after the intervention, and 2 weeks later the adolescent mothers (n = 151) answered questions related to TPB variables and depression treatment. Data were compared to adolescent mothers (n = 138) in the control group. Data were collected in community organizations or home visits for the control group. Adolescent mothers in the intervention group answered questions and completed the intervention from a computer of their choice. The adolescents were primarily African American (89.2%), less than high school educated (51.7%), had given birth in last year (97.1%), with a mean age 18.2 years. The intervention led to significant changes in attitude, perceived control, intention to seek mental health treatment, and actually seeking depression treatment. Untreated postpartum depression dramatically impacts a mother's relationship with her child, her functioning at work and school, health care-seeking behaviors, mothering skills, and her development as well as the development of her child. An Internet-based depression intervention is an inexpensive method to increase rates of depression treatment. PMID- 29260324 TI - Toshiharu (Toshi) Nagatsu: an appreciation. PMID- 29260323 TI - Occurrences and changes of disinfection by-products in small water supply systems. AB - The small water supply systems (WSSs) often report high concentrations of disinfection by-products (DBPs) in drinking water. In this study, occurrences of trihalomethanes (THMs) and haloacetic acids (HAAs) in Newfoundland and Labrador (NL), Canada, were investigated from 441 WSSs for a period of 18 years (1999 2016). The WSSs were divided into groundwater (GWP) and surface water (SWP) systems, which were further classified into eight sub-groups (P1-P8) based on the population served (<= 100; 101-250; 251-500; 501-1000; 1001-3000; 3001-5000; 5001 10,000; and 10,000+, respectively). The DBPs with probable and possible carcinogenic forms were estimated. Overall, 31.1% of WSSs were GWP, in which averages of THMs and HAAs were 32.2 and 27.7 MUg/L, respectively, while the SWP had averages of THMs and HAAs of 97.6 and 129.2 MUg/L, respectively. The very small WSSs (P1-P3) of GWP had averages of THMs and HAAs in the ranges of 29.1 43.5 and 15.8-64.3 MUg/L, respectively. The P1-P3 of SWP had averages of THMs and HAAs in the ranges of 92.6-112.8 and 108.0-154.0 MUg/L, respectively, which often exceeded the Canadian guideline limits. If the samples represented the populations homogenously, the total populations exposed to THMs or HAA5 above the guideline values would be in the range of 132.08-181.38 in thousands (30.3-41.6% of total populations). The probable and possible carcinogenic forms of THMs in GWP and SWP were in the ranges of 4.8-48.8 and 4.4-7.0% of THMs, respectively. In HAAs, carcinogenic forms were in the ranges of 82.6-98.4 and 97.6-98.7%, respectively. The findings indicated that the SWP might need further attention to better protect human health. PMID- 29260325 TI - Environmental evaluation of the life cycle of elephant grass fertilization Cenchrus purpureus (Schumach.) Morrone-using chemical fertilization and biosolids. AB - Law 12305/10, National Solid Waste Policy of Brazil, banned the disposal in landfills of any solid waste that could be converted to another use. Sludge produced at Industrial Wastewater Treatment Plants, which contains components characteristic of fertilizers, falls into this category. This type of sludge, also known as a biosolid, has great potential to replace commercial chemical fertilization. The use of biosolids in agriculture allows for compliance with new legislation, reducing the burden on landfills and reusing a waste product. The present paper utilizes the life cycle assessment methodology to compare the carbon footprint associated with the use of different quantities of biosolid and selected chemical fertilizers in the production of elephant grass. The IPCC 2013 GWP 100a method, which is based on data published by the Intergovernmental Panel on Climate Change, was selected as the environmental assessment method. The method expresses the emissions of greenhouse gases generated, in kilograms of CO2 equivalent, over a time horizon of 100 years. The biosolid quantities used were based on the Brazilian Environment Council Resolution 375. The chemical fertilizer used contained urea, simple superphosphate, and potassium chloride. The use of biosolids in the amounts calculated according to Brazilian standards resulted in a carbon footprint approximately 17.7% lower than the use of the chemical fertilization mix, with similar productivity in both cases. The transportation of biosolids to the experimental area was responsible for the majority of emissions associated with the use of biosolids. Urea synthesis was the largest contributor to emissions resulting from the use of commercial chemical fertilizer, accounting for 73.6% of total emissions. PMID- 29260326 TI - Porous zirconia ceramic as an alternative to dentin for in vitro dentin barriers cytotoxicity test. AB - OBJECTIVES: This study assessed the potential of porous zirconia ceramic as an alternative to dentin via an in vitro dentin barrier cytotoxicity test. METHODS: The permeability of dentin and porous zirconia ceramic was measured using a hydraulic-conductance system, and their permeability was divided into two groups: high and low. Using an in vitro dentin barrier test, the cytotoxicity of dental materials by dentin and porous zirconia ceramic was compared within the same permeability group. The L-929 cell viability was assessed by MTT assay. RESULTS: The mean (SD) permeability of the high and low group for dentin was 0.334 (0.0873) and 0.147 (0.0377) MUl min-1 cm-2 cm H2O-1 and for zirconia porous ceramic was 0.336 (0.0609) and 0.146 (0.0340) MUl min-1 cm-2 cm H2O-1. The cell viability of experimental groups which are the low permeability group was higher than that of the high permeability group for both dentin and porous zirconia ceramic as a barrier except for Maxcem EliteTM by porous zirconia ceramic. There was no significant difference between dentin and porous zirconia ceramic in cell viability, within either the high or low permeability group for all materials. The SD for cell viability of the porous zirconia ceramic was less than that of the dentin, across all materials within each permeability group, except for Maxcem EliteTM in the high permeability group. CONCLUSIONS: Porous zirconia ceramic, having similar permeability to dentin at the same thickness, can be used as an alternative to dentin for in vitro dentin barrier cytotoxicity tests. CLINICAL RELEVANCE: In vitro dentin barrier cytotoxicity tests when a standardized porous zirconia ceramic was used as a barrier could be useful for assessing the potential toxicity of new dental materials applied to dentin before applying in clinical and may resolve the issue of procuring human teeth when testing proceeds. PMID- 29260327 TI - Cytotoxicity in vitro, cellular uptake, localization and apoptotic mechanism studies induced by ruthenium(II) complex. AB - Ruthenium-based complexes have been regarded as one of the most potential metal based candidates for anticancer therapy. Herein, two ruthenium (II) methylimidazole complexes [Ru(MeIm)4(4npip)]2+ (complex 1) and [Ru(MeIm)4(4mopip)]2+ (complex 2) were synthesized and evaluated for their in vitro anticancer activities. The results showed that these ruthenium (II) methylimidazole complexes exhibited moderate antitumor activity comparable with cisplatin against A549, NCI-H460, MCF-7 and HepG2 human cancer cells, but with less toxicity to a human normal cell line HBE. Intracellular distribution studies suggested that complex 2 selectively localized in the mitochondria. Mechanism studies indicated that complex 2 caused cell cycle arrest at G0/G1 phase by regulating cell cycle relative proteins and induced apoptosis through intrinsic pathway, which involved mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage. Further, studies by western blotting suggested that MAPK and AKT signaling pathways were involved in complex 2-induced apoptosis, and they were regulated by the level of ROS. Overall, these findings suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent in the treatment of cancers. PMID- 29260328 TI - Vivo-morpholino oligomers strongly inhibit dengue virus replication and production. AB - Dengue virus (DENV) infection is a worldwide public health problem, which can cause severe dengue hemorrhagic fever (DHF) and life-threatening dengue shock syndrome (DSS). There are currently no anti-DENV drugs available, and there has been an intensive search for effective anti-DENV agents that can inhibit all four DENV serotypes. In this study, we tested whether vivo-morpholino oligomers (vivo MOs), whose effect on DENV infection has not previously been studied, can inhibit DENV infection. Vivo-MOs were designed to target the top of 3' stem-loop (3' SL) in the 3' UTR of the DENV genome and tested for inhibition of DENV infection in monkey kidney epithelial (Vero) cells and human lung epithelial carcinoma (A549) cells. The results showed that vivo-MOs could bind to a DENV RNA sequence and markedly reduce DENV-RNA, protein, and virus production in infected Vero and A549 cells. Vivo-MOs at a concentration of 4 uM could inhibit DENV production by more than 104-fold when compared to that of an untreated control. In addition, vivo MOs also inhibited DENV production in U937 cells and primary human monocytes. Therefore, vivo-MOs targeting to the 3' SL in the 3' UTR of DENV genomes are effective and have the potential to be developed as anti-DENV agents. PMID- 29260329 TI - Recognition of six additional cystoviruses: Pseudomonas virus phi6 is no longer the sole species of the family Cystoviridae. AB - Cystoviridae is a family of bacterial viruses (bacteriophages) with a tri segmented dsRNA genome. It includes a single genus Cystovirus, which has presently only one recognised virus species, Pseudomonas virus phi6. However, a large number of additional dsRNA phages have been isolated from various environmental samples, indicating that such viruses are more widespread and abundant than previously recognised. Six of the additional dsRNA phage isolates (Pseudomonas phages phi8, phi12, phi13, phi2954, phiNN and phiYY) have been fully sequenced. They all infect Pseudomonas species, primarily plant pathogenic Pseudomonas syringae strains. Due to the notable genetic and structural similarities with Pseudomonas phage phi6, we propose that these viruses should be included into the Cystovirus genus (and consequently into the Cystoviridae family). Here, we present an updated taxonomy of the family Cystoviridae and give a short overview of the properties of the type member phi6 as well as the putative new members of the family. PMID- 29260330 TI - Anesthetic activity and the electrostatic potential (revisited). AB - A survey of the fascinating history of anesthetics and the many critical findings that have improved our understanding of anesthetic activity is followed by an expanded analysis of the electrostatic potentials of 27 molecules and two noble gases with anesthetic activities ranging from high to totally inactive. We again find that an intermediate value for the internal charge separation (polarity) Pi appears to be an important factor in anesthetic activity. Other electrostatic potential features that favor high anesthetic activity include the presence of at least one strongly positive site on the molecule and regions of weakly to moderately negative electrostatic potential. For 14 molecules with consistent anesthetic activity data, we find a reasonable multivariable correlation that reflects the above features and also includes a measure of molecular size, reflecting the polarizability. The commonalities found in the electrostatic potential data for the active anesthetics suggest that anesthetics interact via their positive and/or negative sites in noncovalent reversible interactions with target sites, perhaps in brain proteins. PMID- 29260331 TI - Climatic influences on the breeding biology of the agile frog (Rana dalmatina). AB - Severe population declines of amphibians have been shown to be attributed to climate change. Nevertheless, the various mechanisms through which climate can influence population dynamics of amphibians remain to be assessed, notably to disentangle the relative synergetic or antagonistic influences of temperature and precipitations on specific life history stages. We investigated the impact of rainfall and temperature on the egg-clutch abundance in a population of agile frog (Rana dalmatina) during 29 years (1987-2016) on 14 breeding sites located in Brenne Natural Park, France. Specifically, we examined the influence of environmental conditions occurring during five temporal windows of the year cycle corresponding to specific life history stages. Overall, our results suggest that the year-to-year fluctuations of egg-clutch abundances in Brenne Natural Park were partly dependent on local climatic conditions (rainfall and temperature). Climate seemed to influence breeding frogs during the autumn-winter period preceding reproduction. Spring and summer conditions did not influence reproduction. Additionally, we failed to detect effects of climatic conditions on newly metamorphosed individuals. Other factors such as density dependence and inter-specific interactions with introduced predators are likely to play a significant role in reproduction dynamics of the studied frog populations. PMID- 29260332 TI - Comparative efficacy of locally isolated fungal strains for Pb(II) removal and recovery from water. AB - The present investigation aimed to study and compare the efficiency of non-viable fungal isolates to remove divalent lead (Pb(II)) from aqueous streams. The selected fungal isolates showed identity with Aspergillus caespitosus, Aureobasidium sp. RBSS-303 and Aspergillus flavus HF5 as confirmed using gene sequencing of ITS regions of the ribosomal DNA (rDNA). The obtained equilibrium data for Pb(II) biosorption of A. caespitosus fitted better to Langmuir isotherm with maximum sorption capacity of 351.0 mg/g and A. sp. RBSS-303 and A. flavus HF5 showed good fit to Freundlich isotherm with maximum sorption capacity of 271.5 and 346.3 mg/g respectively. The values of thermodynamic factors ascertained the nature of adsorption process is endothermic with A. caespitosus and A. flavus HF5 but exothermic with A. sp. RBSS-303. The experimental data for Pb(II) biosorption fits very well to pseudo second order kinetic model. With HCl the maximum 85.5, 75.3, 73.7% recovery of Pb(II) was obtained from A. caespitosus, A. sp. RBSS-303 and A. flavus HF5, respectively. The observed percentage loss in sorption capacity of Pb(II) was 3.9% by A. flavus HF5, 12.2% by A. caespitosus and 26.6% by A. sp. RBSS-303 after five cyclic studies of sorption and desorption. Results from the study confirmed the efficiency order of A. caespitosus > A. flavus HF5 > A. sp. RBSS-303 to remove and recover Pb(II) from aqueous solution. Finally, the fungal biosorbents can be used as soil conditioning agent after compositing into valuables fungal protein. PMID- 29260333 TI - Improved visualization of breast tissue on a dedicated breast PET system through ergonomic redesign of the imaging table. AB - BACKGROUND: Breast lesions closer than 2 cm to the chest wall are difficult to position in the field of view of dedicated breast PET (db-PET) systems. This inability to detect such lesions is a significant limitation of these systems. The primary objective of this study was to determine if modifications to the design of the imaging table and detector used for a db-PET system would enable improved visualization of breast tissue close to the chest wall. All studies were performed on a commercially available db-PET system (Mammi-PET). A central square section of the imaging table, containing the standard 180-mm circular aperture, was modified such that it could be removed and replaced by thinner sections with a larger aperture. Additional changes were made to the cover plate of the detector array and the patient mattress. A total of 60 patients were studied. After administration of F-18 FDG, 30 patients were imaged with a 220-mm-diameter aperture and the standard aperture, and 30 patients with a 200-mm aperture and the standard aperture. On all scans, the length of breast tissue in the field of view was measured as the greatest extent of tissue from the nipple back to the posterior edge of the breast. Image quality and patient comfort were recorded. RESULTS: Averaged over both breasts, relative to the standard aperture, the increase in breast length was 12.5 + 7.7 mm with the 220-mm aperture, and 12.3 + 6.5 mm with the 200-mm aperture (p < 0.05 for both apertures). In ~ 5% of cases, the larger apertures resulted in some degradation in image quality due to closer proximity to cardiac/hepatic activity. In 10-20% of cases, movement of the breast tissue was observed as the detector ring was moved to scan the anterior region of the breast. The patient survey indicated no significant difference in the comfort level between the standard aperture and either of the prototype apertures. CONCLUSIONS: Modifications to the image table and system resulted in a significant gain in the volume of breast tissue that could be imaged on the db PET system and should allow better visualization of lesions close to the chest wall. PMID- 29260334 TI - From Editor-in-Chief. PMID- 29260335 TI - Controlled Synthesis of BaYF5:Er3+, Yb3+ with Different Morphology for the Enhancement of Upconversion Luminescence. AB - In this work, Er3+/Yb3+-codoped BaYF5 with different sizes and shapes have been synthesized by a simple solvothermal method. By changing the fluoride source, pH value, solvent, surfactants, Yb3+ concentration, temperature, and reaction time, the optimum synthetic conditions of BaYF5:Er3+, Yb3+ were found to improve the upconversion luminescent properties. It is found that the emission intensity of green and red light is enhanced for several times by the way of using NaBF4 as a fluoride source with the comparison of NH4F and NaF. Moreover, the effects of different surfactants are not the same. Adding 5% polyetherimide (PEI) as surfactant can also improve the upconversion emission. On the contrary, when sodium citrate (CIT) as another surfactant was used to add, the sizes of the nanocrystals were gradually increased and the luminous properties also declined. PMID- 29260336 TI - Development of a HEC-HMS-based watershed modeling system for identification, allocation, and optimization of reservoirs in a river basin. AB - One of the primary objectives of river basin planning and management is to assess the behavior of the river towards man-made and natural changes. In recent times, the self-purifying capacity of the river is found to be substantially affected because of extensive use of water for agricultural and industrial purposes. Any variation in the flow regime of a river poses a severe impact on the aquatic ecosystem, which affects its self-purifying capacity. Diverting river water for industrial and agricultural uses through dams and barrages reduces the natural flow rate of the river. The present study develops a novel approach by coupling Watershed Modeling System (WMS ver. 10.1) with linear optimization to provide an alternate means of water supply for such users. To explain the effectiveness of the model, a case study on the Ganges river basin of India has been considered. The ecosystem of the Ganges provides such a magnificent biological fabric, that its self-purifying capacity exceeds that of any other river water across the globe. However, the industries found in the river's most polluted stretch consume around 1200 million liters of water every day. In addition, 80% of the river water diverts at Narora barrage for agricultural purposes. As a result, the flow of the river in dry seasons is as less as 300 m3/s. The study suggests the need to develop economically feasible and efficient storage reservoirs to store the rainwater, which can be used to supply industrial and agricultural needs. The WMS software is used to acquire the watershed basin, outlet location, simulated runoff volume, proposed reservoir site, and the hydrograph using the monitored rainfall data of 5 years (2010-2014). The simulated runoff volume is then used to develop an optimization model to determine the required capacity of each reservoir using LINGO software (ver. 16.0). Four different storage reservoirs are proposed in the selected industrial sites of Unnao district, Uttar Pradesh, India. These reservoirs can supply the needs of industries, and thus reducing their dependency on the river Ganges. The model developed herein acts as an effective tool for giving a possible solution to large-scale water supply problems in the river basins, and also guides the decision makers towards restoring the stream flow. PMID- 29260337 TI - The contribution of 7q33 copy number variations for intellectual disability. AB - Copy number variations (CNVs) at the 7q33 cytoband are very rarely described in the literature, and almost all of the cases comprise large deletions affecting more than just the q33 segment. We report seven patients (two families with two siblings and their affected mother and one unrelated patient) with neurodevelopmental delay associated with CNVs in 7q33 alone. All the patients presented mild to moderate intellectual disability (ID), dysmorphic features, and a behavioral phenotype characterized by aggressiveness and disinhibition. One family presents a small duplication in cis affecting CALD1 and AGBL3 genes, while the other four patients carry two larger deletions encompassing EXOC4, CALD1, AGBL3, and CNOT4. This work helps to refine the phenotype and narrow the minimal critical region involved in 7q33 CNVs. Comparison with similar cases and functional studies should help us clarify the relevance of the deleted genes for ID and behavioral alterations. PMID- 29260338 TI - A case of ramucirumab-related gastrointestinal perforation in gastric cancer with small bowel metastasis. AB - BACKGROUND: Ramucirumab is a monoclonal antibody targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Ramucirumab either alone or in combination with paclitaxel (PTX) has been found to be safe and effective for patients with previously treated advanced gastric cancer. One of the serious adverse events associated with ramucirumab is gastrointestinal (GI) perforation. CASE PRESENTATION: We report the case of a 67-year-old man who developed a ramucirumab related GI perforation while undergoing treatment for gastric cancer with small bowel metastasis. He underwent laparoscopic total gastrectomy following neoadjuvant chemotherapy in January 2015 and was diagnosed with hepatic and bone recurrence in October 2015. Ramucirumab in combination with PTX was administered for one and half months after first-line chemotherapy failure. He presented with abdominal pain 7 days after the last ramucirumab dose, and emergency exploratory surgery revealed a small intestinal perforation. Pathological findings indicated that it occurred in a zone containing a small intestinal tumor, which was found to be metastasis of the gastric cancer. He had no postoperative complications, but chemotherapy was not reintroduced and he died 3 months later. CONCLUSION: We present a recent case of ramucirumab-related gastrointestinal perforation in gastric cancer with small bowel metastasis. This case is rare, but important to consider. PMID- 29260339 TI - Molecular characterisation of two novel starch granule proteins 1 in wild and cultivated diploid A genome wheat species. AB - Starch synthase IIa, also known as starch granule protein 1 (SGP-1), plays a key role in amylopectin biosynthesis. The absence of SGP-1 in cereal grains is correlated to dramatic changes in the grains' starch content, structure, and composition. An extensive investigation of starch granule proteins in this study revealed a polymorphism in the electrophoretic mobility of SGP-1 between two species of wheat, Triticum urartu and T. monococcum; this protein was, however, conserved among all other Triticum species that share the A genome inherited from their progenitor T. urartu. Two different electrophoretic profiles were identified: SGP-A1 proteins of T. urartu accessions had a SDS-PAGE mobility similar to those of tetraploid and hexaploid wheat species; conversely, SGP-A1 proteins of T. monococcum ssp. monococcum and ssp. boeoticum accessions showed a different electrophoretic mobility. The entire coding region of the two genes was isolated and sequenced in an attempt to explain the polymorphism identified. Several single nucleotide polymorphisms (SNPs) responsible for amino acid changes were identified, but no indel polymorphism was observed to explain the difference in electrophoretic mobility. Amylose content did not differ significantly among T. urartu, T. monococcum ssp. boeoticum and T. monococcum ssp. monococcum, except in one accession of the ssp. boeoticum. Conversely, several interspecific differences were observed in viscosity properties (investigated as viscosity profiles using a rapid visco analyzer-RVA profiles) of these cereal grains. T. monococcum ssp. boeoticum accessions had the lowest RVA profiles, T. urartu accessions had an intermediate RVA profile, whereas T. monococcum ssp. monococcum showed the highest RVA profile. These differences could be associated with the numerous amino acid and structural changes evident among the SGP-1 proteins. PMID- 29260340 TI - Molecular structures enumeration and virtual screening in the chemical space with RetroPath2.0. AB - BACKGROUND: Network generation tools coupled with chemical reaction rules have been mainly developed for synthesis planning and more recently for metabolic engineering. Using the same core algorithm, these tools apply a set of rules to a source set of compounds, stopping when a sink set of compounds has been produced. When using the appropriate sink, source and rules, this core algorithm can be used for a variety of applications beyond those it has been developed for. RESULTS: Here, we showcase the use of the open source workflow RetroPath2.0. First, we mathematically prove that we can generate all structural isomers of a molecule using a reduced set of reaction rules. We then use this enumeration strategy to screen the chemical space around a set of monomers and predict their glass transition temperatures, as well as around aminoglycosides to search structures maximizing antibacterial activity. We also perform a screening around aminoglycosides with enzymatic reaction rules to ensure biosynthetic accessibility. We finally use our workflow on an E. coli model to complete E. coli metabolome, with novel molecules generated using promiscuous enzymatic reaction rules. These novel molecules are searched on the MS spectra of an E. coli cell lysate interfacing our workflow with OpenMS through the KNIME Analytics Platform. CONCLUSION: We provide an easy to use and modify, modular, and open source workflow. We demonstrate its versatility through a variety of use cases including molecular structure enumeration, virtual screening in the chemical space, and metabolome completion. Because it is open source and freely available on MyExperiment.org, workflow community contributions should likely expand further the features of the tool, even beyond the use cases presented in the paper. PMID- 29260341 TI - Consensus-based cross-European recommendations for the identification, measurement and valuation of costs in health economic evaluations: a European Delphi study. AB - OBJECTIVES: Differences between country-specific guidelines for economic evaluations complicate the execution of international economic evaluations. The aim of this study was to develop cross-European recommendations for the identification, measurement and valuation of resource use and lost productivity in economic evaluations using a Delphi procedure. METHODS: A comprehensive literature search was conducted to identify European guidelines on the execution of economic evaluations or costing studies as part of economic evaluations. Guideline recommendations were extracted by two independent reviewers and formed the basis for the first round of the Delphi study, which was conducted among European health economic experts. During three written rounds, consensus (agreement of 67% or higher) was sought on items concerning the identification, measurement and valuation of costs. RESULTS: Recommendations from 18 guidelines were extracted. Consensus among 26 panellists from 17 European countries was reached on 61 of 68 items. The recommendations from the Delphi study are to adopt a societal perspective, to use patient report for measuring resource use and lost productivity, to value both constructs with use of country-specific standardized/unit costs and to use country-specific discounting rates. CONCLUSION: This study provides consensus-based cross-European recommendations on how to measure and value resource use and lost productivity in economic evaluations. These recommendations are expected to support researchers, healthcare professionals, and policymakers in executing and appraising economic evaluations performed in international contexts. PMID- 29260342 TI - Predictors for a further local in-brain progression after re-craniotomy of locally recurrent cerebral metastases. AB - Treatment of recurrent cerebral metastases is an emerging challenge due to the high local failure rate after surgery or radiosurgery and the improved prognosis of patients with malignancies. A total of 36 patients with 37 metastases who underwent surgery for a local in-brain progression of a cerebral metastasis after previous metastasectomy were retrospectively analyzed. Degree of surgical resection on an early postoperative MRI within 72 h after surgery was correlated with the local in-brain progression rate and overall survival. Complete surgical resection of locally recurrent cerebral metastases as confirmed by early postoperative MRI could only be achieved in 37.8%. Detection of residual tumor tissue on an early MRI following recurrent metastasis surgery correlated with further local in-brain progression when defining a significance level of p = 0.05 but not after Sidak or Bonferroni significance level correction for multiple testing: However, definite local tumor control could finally be achieved in 91.9% after adjuvant therapy. Overall survival after recurrent metastasectomy was significantly higher as predicted by diagnosis-specific graded prognostic assessment (12.9 +/- 2.3 vs. 8.4 +/- 0.7 months; p < 0.0001). However, our series involved a limited number of heterogeneous patients. A larger, prospective, and controlled study is required. Considering the adequate local tumor control achieved in the vast majority of patients, surgery of recurrent metastases may represent one option in a multi-modal treatment approach of patients suffering from locally recurrent cerebral metastases. PMID- 29260343 TI - Graphene/Polyaniline Aerogel with Superelasticity and High Capacitance as Highly Compression-Tolerant Supercapacitor Electrode. AB - Superelastic graphene aerogel with ultra-high compressibility shows promising potential for compression-tolerant supercapacitor electrode. However, its specific capacitance is too low to meet the practical application. Herein, we deposited polyaniline (PANI) into the superelastic graphene aerogel to improve the capacitance while maintaining the superelasticity. Graphene/PANI aerogel with optimized PANI mass content of 63 wt% shows the improved specific capacitance of 713 F g-1 in the three-electrode system. And the graphene/PANI aerogel presents a high recoverable compressive strain of 90% due to the strong interaction between PANI and graphene. The all-solid-state supercapacitors were assembled to demonstrate the compression-tolerant ability of graphene/PANI electrodes. The gravimetric capacitance of graphene/PANI electrodes reaches 424 F g-1 and retains 96% even at 90% compressive strain. And a volumetric capacitance of 65.5 F cm-3 is achieved, which is much higher than that of other compressible composite electrodes. Furthermore, several compressible supercapacitors can be integrated and connected in series to enhance the overall output voltage, suggesting the potential to meet the practical application. PMID- 29260344 TI - Integrative network-based approach identifies central genetic and transcriptomic elements in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) has gained considerable attention as it oversteps about 15% of the deaths caused by breast cancer in women and is well known for its aggressive impact, high proliferation rate, intensity of tumor, and metastasis. In this study, we have given a new insight into TNBC, by introducing an integrative network methodology to understand the complexity of the candidate genes in TNBC. In the course of this analysis, the central network was constructed by refining the candidate genes present in the various databases. Eventually, the hub genes SRC, EGFR, JUN, CTNNB1, and MYC were derived using distinct topological parameters such as degree, betweenness centrality, closeness centrality, and clustering coefficient, which implicated a central role in TNBC. Furthermore, the identified hub genes were validated by utilizing molecular complex detection cluster analysis. A regulatory network was constructed to locate the transcriptional factors regulating these hub genes via MatInspector. Interestingly, we characterized that ZF02, MZF1, and PLAG are the common transcription factors which activate the hub genes. Moreover, a functional enrichment pathway was obtained from ClueGo, which depicted that all the hub genes have a significant role in toxicity-associated pathways as well as physiochemical featured pathways. In a nutshell, these prioritized genes could be the way out to uncover the molecular and therapeutic targets, leading to the development of personalized medicine for TNBC. PMID- 29260345 TI - Palivizumab in the prevention of severe respiratory syncytial virus infection in children with congenital heart disease; a novel cost-utility modeling study reflecting evidence-based clinical pathways in Spain. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection remains one of the major reasons of re-hospitalization among children with congenital heart disease (CHD). This study estimated the cost-effectiveness of palivizumab prophylaxis versus placebo, in Spain, from the societal perspective, using a novel cost effectiveness model reflecting evidence-based clinical pathways. METHODS: A decision-analytic model, combining a decision tree structure in the first year and a Markov structure in later years, was constructed to evaluate the benefits and costs associated with palivizumab versus no prophylaxis among children with CHD. In the first year of the model, children were at risk of mild (i.e. medically attended, MA-RSV) and severe (hospitalized, RSV-H) RSV infection. The impact of delayed corrective CHD surgery due to RSV infection and the consequence of performed surgery despite severe infection were considered. In later years, patients were at risk of developing asthma and allergic sensitization as sequelae of RSV infection. Input data for the model were derived from the pivotal clinical trial and systematic literature reviews. Indirect costs included parental absence from work and nosocomial infections. In agreement with Spanish guidelines, costs and effects were discounted at 3%. RESULTS: Over a lifetime horizon, palivizumab prophylaxis yielded 0.11 and 0.07 additional quality-adjusted life years (QALYs) and life years (LYs), respectively, at additional costs of ? 1,693, resulting in an ICER of ? 15,748 per QALY gained and ? 24,936 per LY gained. Probabilistic sensitivity analyses demonstrated that the probability of palivizumab prophylaxis being cost-effective at a ? 30,000 per QALY threshold was 92.7%. The ICER remained below this threshold for most extreme scenario analyses. CONCLUSIONS: The model demonstrated that palivizumab prophylaxis results in more QALYs than no prophylaxis in children with CHD. Palivizumab prophylaxis was shown to be a cost effective health care intervention according to the commonly accepted standards of cost-effectiveness in Spain (ICER below the threshold of ? 30,000 per QALY). PMID- 29260346 TI - Assessment of mitral regurgitation by 3-dimensional proximal flow convergence using magnetic resonance imaging: comparison with echo-Doppler. AB - To test the feasibility of assessing mitral regurgitation (MR) severity using cardiac magnetic resonance (CMR) 4D velocity vectors to quantify regurgitant volume (RVol) by analysis of the proximal flow convergence, compared to Doppler based proximal isovelocity surface area (PISA) and CMR volume-based methods. In a prospectively designed study, 27 patients with various grades of MR underwent CMR and echo-Doppler on the same day. By CMR, multiple slices were obtained parallel to the mitral valve by phase-contrast imaging, using 3D velocity vectors, as well as short-axis cine images for left and right ventricular volume measurements. Using dedicated software developed in our laboratory, the perimeter of the proximal flow convergence region was semi-automatically measured for each temporal phase, and for each short-axis slice. The CMR-PISA RVol was calculated as the sum of PISA perimeters throughout systole, multiplied by slice width. For comparison, CMR-volumetric RVol was calculated by 2 methods: Volumetric (difference between left and right ventricular stroke volumes) and Flow-based (stroke volume -aortic flow). Echo-PISA RVol was calculated by echo-Doppler based PISA method. RVol by CMR-PISA correlated highly with echo-PISA (r = 0.87) and with CMR-volumetric (r = 0.86) and CMR-flow (r = 0.72). For comparison Doppler RVol and CMR-volume-based RVol had r = 0.83. On average CMR-PISA was 16 +/- 25 ml less than echo-PISA, but 12 +/- 22 ml larger than CMR-volumetric RVol. The observed 3D shape of the PISA envelope by 4D-CMR resembled a hemiellipsoid rather than a hemisphere. This feasibility study suggests that CMR-based 4D-PISA may be able to assess MR severity quantitatively without any geometric assumptions. PMID- 29260348 TI - Medical Image Retrieval with Compact Binary Codes Generated in Frequency Domain Using Highly Reactive Convolutional Features. AB - Efficient retrieval of relevant medical cases using semantically similar medical images from large scale repositories can assist medical experts in timely decision making and diagnosis. However, the ever-increasing volume of images hinder performance of image retrieval systems. Recently, features from deep convolutional neural networks (CNN) have yielded state-of-the-art performance in image retrieval. Further, locality sensitive hashing based approaches have become popular for their ability to allow efficient retrieval in large scale datasets. In this paper, we present a highly efficient method to compress selective convolutional features into sequence of bits using Fast Fourier Transform (FFT). Firstly, highly reactive convolutional feature maps from a pre-trained CNN are identified for medical images based on their neuronal responses using optimal subset selection algorithm. Then, layer-wise global mean activations of the selected feature maps are transformed into compact binary codes using binarization of its Fourier spectrum. The acquired hash codes are highly discriminative and can be obtained efficiently from the original feature vectors without any training. The proposed framework has been evaluated on two large datasets of radiology and endoscopy images. Experimental evaluations reveal that the proposed method significantly outperforms other features extraction and hashing schemes in both effectiveness and efficiency. PMID- 29260347 TI - Apolipoprotein M Protects Against Lipopolysaccharide-Induced Acute Lung Injury via Sphingosine-1-Phosphate Signaling. AB - It had been demonstrated that apolipoprotein M (apoM) is an important carrier of sphingosine-1-phosphate (S1P) in blood, and the S1P has critical roles in the pathogenesis of sepsis-induced acute lung injury (ALI). In the present study, we investigated whether apoM has beneficial effects in a mouse model after lipopolysaccharide (LPS)-induced ALI. Forty-eight mice were divided into two groups: male C57BL/6 wild-type (apoM+/+) group (n = 24) and apoM gene-deficient (apoM-/-) group (n = 24) and then randomly subdivided into four subgroups (n = 6 each) according to different intraperitoneal (i.p.) injection: control group, W146 group, LPS group, and LPS + W146 group. Serum levels of interleukin-1 beta (IL-1beta) and mRNA levels of IL-1beta, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), lung histology, wet/dry weight ratio, and immunohistochemistry were measured at 3 h after the baseline and compared in each group. Our results clearly demonstrated that IL-1beta mRNA levels and other inflammatory biomarkers were significantly increased in the lungs of LPS-induced ALI apoM-/- mice compared to those of the apoM+/+ mice. Moreover, when apoM+/+ mice were treated with W146, a S1P receptor (S1PR1) antagonist, these inflammatory biomarkers could be significantly upregulated by LPS-induced ALI. Therefore, it suggests that apoM-S1P-S1PR1 signaling might underlie the pathogenesis of ALI and apoM could have physiological benefits to alleviate LPS induced ALI. PMID- 29260349 TI - Neural Mechanisms of Attentional Switching Between Pain and a Visual Illusion Task: A Laser Evoked Potential Study. AB - Previous studies demonstrated that pain induced by a noxious stimulus during a distraction task is affected by both stimulus-driven and goal-directed processes which interact and change over time. The purpose of this exploratory study was to analyse associations of aspects of subjective pain experience and engagement with the distracting task with attention-sensitive components of noxious laser-evoked potentials (LEPs) on a single-trial basis. A laser heat stimulus was applied to the dorsum of the left hand while subjects either viewed the Rubin vase-face illusion (RVI), or focused on their pain and associated somatosensory sensations occurring on their stimulated hand. Pain-related sensations occurring with every laser stimulus were evaluated using a set of visual analogue scales. Factor analysis was used to identify the principal dimensions of pain experience. LEPs were correlated with subjective aspects of pain experience on a single-trial basis using a multiple linear regression model. A positive LEP component at the vertex electrodes in the interval 294-351 ms (P2) was smaller during focusing on RVI than during focusing on the stimulated hand. Single-trial amplitude variations of the P2 component correlated with changes in Factor 1, representing essential aspects of pain, and inversely with both Factor 2, accounting for anticipated pain, and the number of RVI figure reversals. A source dipole located in the posterior region of the cingulate cortex was the strongest contributor to the attention-related single-trial variations of the P2 component. Instantaneous amplitude variations of the P2 LEP component during switching attention towards pain in the presence of a distracting task are related to the strength of pain experience, engagement with the task, and the level of anticipated pain. Results provide neurophysiological underpinning for the use of distraction analgesia acute pain relief. PMID- 29260350 TI - Atomistic computer simulations on multi-loaded PAMAM dendrimers: a comparison of amine- and hydroxyl-terminated dendrimers. AB - Poly(amidoamine) (PAMAM) dendrimers have been extensively studied as delivery vectors in biomedical applications. A limited number of molecular dynamics (MD) simulation studies have investigated the effect of surface chemistry on therapeutic molecules loading, with the aim of providing insights for biocompatibility improvement and increase in drug loading capacity of PAMAM dendrimers. In this work, fully atomistic MD simulations were employed to study the association of 5-Fluorouracil (5-FU) with amine (NH2)- and hydroxyl (OH) terminated PAMAM dendrimers of generations 3 and 4 (G3 and G4). MD results show a 1:12, 1:1, 1:27, and 1:4 stoichiometry, respectively, for G3NH2-FU, G3OH-FU, G4NH2-FU, and G4OH-FU complexes, which is in good agreement with the isothermal titration calorimetry results. The results obtained showed that NH2-terminated dendrimers assume segmented open structures with large cavities and more drug molecules can encapsulate inside the dendritic cavities of amine terminated dendrimers. However, OH-terminated have a densely packed structure and therefore, 5-FU drug molecules are more stable to locate close to the surface of the dendrimers. Intermolecular hydrogen bonding analysis showed that 5-FU drug molecules have more tendency to form hydrogen bonds with terminal monomers of OH terminated dendrimers, while in NH2-terminated these occur both in the inner region and the surface. Furthermore, MM-PBSA analysis revealed that van der Waals and electrostatic energies are both important to stabilize the complexes. We found that drug molecules are distributed uniformly inside the amine and hydroxyl terminated dendrimers and therefore, both dendrimers are promising candidates as drug delivery systems for 5-FU drug molecules. PMID- 29260351 TI - Correction to: Cancer driver G-protein coupled receptor (GPCR) induced beta catenin nuclear localization: the transcriptional junction. AB - The original version of this article unfortunately contained a mistake. The family name of Beatrice Uziely was mistakenly spelled as Uzieky. The correct name is now presented above. PMID- 29260352 TI - Concise Commentary: Is Nrf2 a Master Regulator of Intestinal Fibrosis? PMID- 29260353 TI - Speckle-Type POZ Protein Down-Regulates Matrix Metalloproteinase 2 Expression via Sp1/PI3K/Akt Signaling Pathway in Colorectal Cancer. AB - BACKGROUND: Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM: In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS: The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS: SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS: SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments. PMID- 29260354 TI - Understanding the Targeting and Uptake of HIV Testing Among Gay and Bisexual Men Attending Sexual Health Clinics. AB - We assessed trends in HIV testing outcomes during a period of clinic-based initiatives introduced to increase HIV testing among gay and bisexual men (GBM) attending sexual health clinics (SHCs) in New South Wales (NSW). A cohort of 25,487 HIV-negative GBM attending 32 SHCs in NSW (2009-2015) was classified into six sub-groups each year based on client-type (new/existing), risk-status (low/high-risk), and any recent HIV testing. Poisson regression methods were used to assess HIV testing outcomes in sub-groups of GBM. HIV testing outcomes and the sub-groups with greatest statistically significant annual increases were: individuals attending (26% in high-risk existing clients with recent testing); testing uptake (4% in low-risk existing clients with no recent testing); testing frequency (6% in low-risk existing clients with no recent testing and 5% in high risk existing clients with recent testing); and total tests (31% in high-risk existing clients with recent testing). High-risk existing clients with recent testing had a 13% annual increase in the proportional contribution to total tests. Our findings show improved targeting of testing to high-risk GBM at NSW SHCs. The clinic-based initiatives should be considered for translation to other similar settings. PMID- 29260355 TI - Vestibular impairment in chronic inflammatory demyelinating polyneuropathy. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a common, treatable, autoimmune peripheral neuropathy considered to produce imbalance by weakness and proprioceptive impairment rather than vestibular impairment. We measured semicircular canal vestibular function in 21 CIDP patients (15M/6F) by the video head impulse test and postural stability with a battery comprising the modified Clinical Test of Sensory Integration and Balance, the Berg Balance Scale, the Dynamic Gait Index, the Fall Efficiency Scale, and the International Cooperative Ataxia Rating Scale. Of the 21 patients, 16 had vestibular impairment, ranging from mild-affecting just a single semicircular canal, to severe-affecting all 6 canals. Although the severity of the vestibular impairment did not correlate either with the severity of the postural imbalance or of the peripheral neuropathy, our data show that vestibular impairment is an additional challenge to balance that some CIDP patients will face. PMID- 29260356 TI - Brain diffusion tensor imaging changes in cerebrotendinous xanthomatosis reversed with treatment. AB - Cerebrotendinous xanthomatosis (CTX, MIM 213700) is a rare autosomal recessive lipid storage disorder caused by CYP27A1 mutations. Treatment with chenodeoxycholic acid (CDCA) may slow the progression of the disease and reverse some symptoms in a proportion of patients. In a non-consanguineous Caucasian family, two siblings with CTX were evaluated before treatment and prospectively followed-up every 6 months after starting CDCA therapy, using systematic clinical examination, neuropsychological tests, laboratory tests, electroencephalography (EEG) and brain MRI, diffusion tensor imaging (DTI) and tractography. A 30-year old patient and her 27-year-old brother were referred for progressive spastic paraparesis. Both had epilepsy, learning difficulties, chronic diarrhoea and juvenile-onset cataracts. CTX was diagnosed by increased cholestanol levels and compound heterozygosity for CYP27A1 mutations. Therapy with CDCA led to resolution of chronic diarrhoea, normalisation of serum cholestanol and EEG, and a progressive improvement in gait, cognition and seizure control. Before treatment, conventional brain MRI showed no CTX-related abnormalities for the proband and no cerebellar abnormalities for the brother, while DTI showed reduced fractional anisotropy (FA) and tract-density in the cerebellum and widespread cerebral reductions of FA in both patients, compared to a group of 35 healthy controls. Repeated DTI after starting therapy showed progressive increases of cerebellar tract density and of cerebral FA. In patients with CTX, therapy with CDCA may lead to significant clinical improvement, with normalisation of biochemical and electrophysiological biomarkers. DTI and tractography may detect changes when the conventional MRI is unremarkable and may provide potential neuroimaging biomarkers for monitoring treatment response in CTX, while the conventional MRI remains unchanged. PMID- 29260357 TI - Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction: expanding the genotype-phenotype spectrum. AB - A subset of patients with polyglucosan body myopathy was found to have underlying mutations in the RBCK1 gene. Affected patients may display diverse symptoms ranging from skeletal muscular weakness, cardiomyopathy to chronic autoinflammation and immunodeficiency. It was suggested that the exact localization of the mutation within the gene might be responsible for the specific phenotype, with N-terminal mutations causing severe immunological dysfunction and mutations in the middle or C-terminal part leading to a myopathy phenotype. We report the clinical, immunological and genetic findings of two unrelated individuals suffering from a childhood-onset RBCK1-asscociated disease caused by the same homozygous truncating mutation (NM_031229.2:c.896_899del, p.Glu299Valfs*46) in the middle part of the RBCK1 gene. Our patients suffered from a myopathy with cardiac involvement, but in contrast to previous reports on mutations in this part of the gene, also displayed signs of autoinflammation and immunodeficiency. Our report suggests that RBCK1 mutations at locations that were previously thought to lack immunological features may also present with immunological dysfunction later in the disease course. This notably broadens the genotype-phenotype correlation of RBCK1-related polyglucosan body myopathy. PMID- 29260358 TI - Abnormal human chorionic gonadotropin (hCG) trends after transfer of multiple embryos resulting in viable singleton pregnancies. AB - PURPOSE: The purpose of this study is to investigate whether abnormal hCG trends occur at a higher incidence among women conceiving singleton pregnancies following transfer of multiple (two or more) embryos (MET), as compared to those having a single embryo transfer (SET). METHODS: Retrospective cohort study was performed of women who conceived singleton pregnancies following fresh or frozen autologous IVF/ICSI cycles with day 3 or day 5 embryo transfers between 2007 and 2014 at a single academic medical center. Cycles resulting in one gestational sac on ultrasound followed by singleton live birth beyond 24 weeks of gestation were included. Logistic regression models adjusted a priori for patient age at oocyte retrieval and day of embryo transfer were used to estimate the Odds Ratio of having an abnormal hCG rise (defined as a rise or < 66% in 2 days) following SET as compared to MET. RESULTS: Among patients receiving two or more embryos, 6.1% (n = 84) had abnormal hCG rises between the first and second measurements, compared to 2.7% (n = 17) of patients undergoing SET (OR 2.16, 95% CI 1.26-3.71). Among patients with initially abnormal hCG rises who had a third level checked (89%), three-quarters had normal hCG rises between the second and third measurements. CONCLUSIONS: Patients who deliver singletons following MET were more likely to have suboptimal initial hCG rises, potentially due to transient implantation of other non-viable embryo(s). While useful for counseling, these findings should not change standard management of abnormal hCG rises following IVF. The third hCG measurements may clarify pregnancy prognosis. PMID- 29260359 TI - An effort toward molecular neuroeconomics of food deprivation induced food hoarding in mice: focus on xanthine oxidoreductase gene expression and xanthine oxidase activity. AB - The crucial role of xanthine oxidoreductase (XOR) gene and its active isoform, xanthine oxidase (XO), in purine metabolism and cellular oxidative status led us to investigative their fluctuations in food deprivation induced food hoarding in mice. After, 10 h food deprivation, mice that hoarded lesser than 5 g were considered as 'low-hoarders' while mice that hoarded higher than 20 g were considered as 'high-hoarders'. Mice who hoarded between 5 to 20 g of food were excluded from study. An increase (1.133-fold) in encephalic XOR expression has been found in high-hoarders compared with low-hoarders without sex consideration. An increase (~ 50-fold) in encephalic XOR in female high-hoarders vs. female low hoarders while a decrease (0.026-fold) in encephalic XOR in male high-hoarders vs. male low-hoarders demonstrated that food deprivation is associated with sex dependent alteration in XOR expression. The encephalic and hepatic XO activities were not different in male high-hoarders vs. male low-hoarders while encephalic XO activity has been also increased significantly in female high-hoarders (~ 4 times) compared to female low-hoarders. The plasma and hepatic XO activities tended to be increased in female high-hoarders as compared to female low hoarders, however the uric acid levels in plasma, liver and brain tissues were not altered in female high-hoarders as compared to female low-hoarders. In sum, this study generally proposed that different gene expression space is behind of hoarding behavior in a food-deprived mouse model. Specifically, this is the first study that examined the levels of encephalic XO activity and XOR expression in hoarding behavior, although additional studies are requested. PMID- 29260360 TI - Neonatal hyperglycemia induces cell death in the rat brain. AB - Several studies have examined neonatal diabetes, a rare disease characterized by hyperglycemia and low insulin levels that is usually diagnosed in the first 6 month of life. Recently, the effects of diabetes on the brain have received considerable attention. In addition, hyperglycemia may perturb brain function and might be associated with neuronal death in adult rats. However, few studies have investigated the damaging effects of neonatal hyperglycemia on the rat brain during central nervous system (CNS) development, particularly the mechanisms involved in the disease. Thus, in the present work, we investigated whether neonatal hyperglycemia induced by streptozotocin (STZ) promoted cell death and altered the levels of proteins involved in survival/death pathways in the rat brain. Cell death was assessed using FluoroJade C (FJC) staining and the expression of the p38 mitogen-activated protein kinase (p38), phosphorylated-c Jun amino-terminal kinase (p-JNK), c-Jun amino-terminal kinase (JNK), protein kinase B (Akt), phosphorylated-protein kinase B (p-Akt), glycogen synthase kinase 3beta (Gsk3beta), B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) protein were measured by Western blotting. The main results of this study showed that the metabolic alterations observed in diabetic rats (hyperglycemia and hypoinsulinemia) increased p38 expression and decreased p-Akt expression, suggesting that cell survival was altered and cell death was induced, which was confirmed by FJC staining. Therefore, the metabolic conditions observed during neonatal hyperglycemia may contribute to the harmful effect of diabetes on the CNS in a crucial phase of postnatal neuronal development. PMID- 29260361 TI - Sex-dependent association of preoperative hematologic markers with glioma grade and progression. AB - Neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte ratio, the systemic immune-inflammation index (SII), and red blood cell distribution width (RDW), have been recognized as promising predictors for histological grade and prognosis in multiple cancer types. However, few investigations illustrated the impacts of sex on the clinical utility of hematologic markers. Patients with primary gliomas were retrospectively reviewed. The association between grade and inflammatory markers by sex were investigated by univariate and multivariate analysis. The discrimination ability of logistic regression model was evaluated by the area under the receiver-operating characteristic curve (AUC) for high-grade glioma (HGG). Kaplan-Meier progressionfree survival (PFS) curves were plotted to assess the prognostic value of RDW. In subgroup analysis, distinctively elevated NLR and SII levels were exclusively present in male HGGs group (p = 0.001); whereas RDW notably increased in female HGGs group (p = 0.001). On multivariate analysis, increased odds ratio of HGGs was exclusively observed for female patients with elevated RDW (odds ratio = 1.589). Moreover, regression model developed by RDW exhibited an excellent discriminative ability for the prediction of HGGs in female patients (AUC = 0.817). Median progression time with RDW < 13.2 versus RDW >= 13.2 was 62.5 versus 33.0 months (log rank p = 0.017). Older females (>= 45 years) with increased RDW levels portended worse survival (HR 3.693, 95% CI 1.747 8.325, p = 0.001). Meanwhile, the significant association of RDW levels with PFS in male subgroup was not observed (p > 0.05). In conclusion, superior to NLR and SII, RDW would be sex-specific predictor for tumor grade and progression for HGG female patients. PMID- 29260362 TI - Discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis. AB - When distant metastases are discovered, it is important to determine receptor profiles of these lesions through histologic examination. However, brain metastasis sites are difficult to reach to be routinely biopsied. The purpose of this study was to determine expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer brain metastasis (BCBM) and the existence of discordance between primary breast cancer and brain metastasis. A total of 37 patients who underwent craniotomies for metastatic brain tumors arising from breast cancer at National Cancer Center (NCC) of Korea between 2002 and 2014 were retrospectively reviewed. Clinicopathologic data were collected from electronic medical records. Receptor profiles of primary breast cancer and brain metastasis in each patient were identified. Data of ER, PR, and HER2 expression in brain metastasis were available in electronic medical records for 21 (56.8%) of 37 cases. Results of ER, PR, and HER2 expression were positive in 47.6, 42.9, and 38.1% of patients with brain metastasis, respectively. Receptor conversion occurred in 11 (52.4%) of 21 patients (for ER, 9.5%; for PR, 38.1%; for HER2, 23.8%). Overall survival was longer in patients with concordant receptor expression patterns between primary breast cancer and brain lesion compared to that in patients with discordant patterns. However, such difference was not statistically significant (discordant vs. concordant median survival: 19.2 versus 31.1 months, p = 0.181). Receptor conversion in BCBMs was observed in over 50% of Korean patients used in this study. HER2 conversion was observed in 23.8% of patients in this study. Therefore, if resistance to anti-HER2 treatment is suspected in patients with BCBM, biopsy is needed to determine receptor profiles of brain lesion. PMID- 29260363 TI - Correction to: Whole chromosome painting reveals independent origin of sex chromosomes in closely related forms of a fish species. AB - ere, we report that a paragraph from the "Discussion" section of Cioffi et al. (2011; p. 1070, 4th paragraph of column 1) was transcribed (with only minor edits) from an introductory paragraph previously published in Chromosome Research by O'Meally et al. PMID- 29260364 TI - Evaluation of vertebral body fractures using susceptibility-weighted magnetic resonance imaging. AB - PURPOSE: To test the diagnostic performance of susceptibility-weighted MRI (sMRI) for the evaluation of vertebral body fractures versus standard MRI-sequences, using CT as reference standard. METHODS: In this prospective study 88 vertebral fractures (45 healed, 43 non-healed) were detected in 39 patients who underwent T1/T2/TIRM MRI-sequences and sMRI. All fractures were evaluated with CT as reference standard. In all modalities/sequences, displacement and height of the posterior vertebral body cortex and visibility of fracture lines and cortical breaks were assessed. Sensitivity, specificity and inter-reader agreement between MRI and CT were calculated. RESULTS: sMRI demonstrated highest diagnostic accuracy for detection of posterior vertebral body cortex involvement (sensitivity: 98 %/specificity: 100 %), fracture lines (86 %/99 %) and cortical breaks (93 %/100 %) versus T1/T2/TIRM sequences. Regarding evaluation of posterior vertebral body cortex displacement and height, sMRI demonstrated the closest intermodality agreement (R2=0.96; 95 % CI -0.92-0.89/R2=0.97; 95 % CI 1.67-1.23) with CT and the closest interobserver agreement (R2=0.97; 95 % CI 0.71-1.01). CONCLUSION: sMRI allows reliable evaluation of vertebral body fractures with regard to posterior vertebral body cortex displacement and height, cortical breaks and fracture lines with higher accuracy versus standard MRI, especially in patients with non-healed vertebral body fractures. KEY POINTS: * sMRI allows a reliable evaluation of vertebral body fractures. * sMRI has higher accuracy than standard-MRI for evaluation of vertebral body fractures. * sMRI is especially useful in patients with non-healed vertebral body fractures. PMID- 29260365 TI - Prognostic importance of peritoneal lesion-to-primary tumour standardized uptake value ratio in advanced serous epithelial ovarian cancer. AB - OBJECTIVES: Using preoperative PET/CT, we evaluated the prognostic value of preoperative [18F]FDG uptake ratio between various metastatic lesions and primary tumour in patients with advanced serous epithelial ovarian cancer (EOC). METHODS: We retrospectively reviewed patients with International Federation of Gynecology and Obstetrics (FIGO) stage III, IV serous EOC who underwent preoperative [18F]FDG PET/CT scans. Clinico-pathological variables and PET/CT parameters such as maximum standardized uptake value of the ovarian cancer (SUVovary), pelvic or para-aortic LN (SUVLN), peritoneal (SUVperit) and distant extra-peritoneal (SUVdist) metastatic lesions, and the metastatic lesion-to-ovarian cancer standardized uptake value ratio were assessed. RESULTS: Clinico-pathological data were retrospectively reviewed for 97 eligible patients. The median progression free survival (PFS) was 18 months (range, 6-90 months) and 59 (60.8 %) patients experienced recurrence. In multivariate regression analysis, older age (p = 0.035, hazard ratio (HR) 1.032, 95 % CI 1.002-1.062), and high SUVperit/SUVovary (p = 0.046, HR 1.755, 95 % CI 1.011-3.047) were independent risk factors of recurrence. Patient group categorized by SUVperit/SUVovary showed significant difference in PFS (Log-Rank test, p = 0.001). CONCLUSIONS: In patients with advanced serous EOC, preoperative SUVperit/SUVovary measured by [18F]FDG PET/CT provides significant incremental performance for prediction of recurrence. KEY POINTS: * PET/CT data from advanced serous epithelial ovarian cancer patients were analysed. * Prognostic value of SUV ratio between metastatic and primary tumour was investigated. * SUV perit /SUV ovary provides incremental performance for prediction of recurrence. PMID- 29260366 TI - Feasibility of free-breathing dynamic contrast-enhanced MRI of gastric cancer using a golden-angle radial stack-of-stars VIBE sequence: comparison with the conventional contrast-enhanced breath-hold 3D VIBE sequence. AB - OBJECTIVES: To investigate the feasibility and diagnostic value of free breathing, radial, stack-of-stars three-dimensional (3D) gradient echo (GRE) sequence ("golden angle") on dynamic contrast-enhanced (DCE) MRI of gastric cancer. METHODS: Forty-three gastric cancer patients were divided into cooperative and uncooperative groups. Respiratory fluctuation was observed using an abdominal respiratory gating sensor. Those who breath-held for more than 15 s were placed in the cooperative group and the remainder in the uncooperative group. The 3-T MRI scanning protocol included 3D GRE and conventional breath-hold VIBE (volume-interpolated breath-hold examination) sequences, comparing images quantitatively and qualitatively. DCE-MRI parameters from VIBE images of normal gastric wall and malignant lesions were compared. RESULTS: For uncooperative patients, 3D GRE scored higher qualitatively, and had higher SNRs (signal-to noise ratios) and CNRs (contrast-to-noise ratios) than conventional VIBE quantitatively. Though 3D GRE images scored lower in qualitative parameters compared with conventional VIBE for cooperative patients, it provided images with fewer artefacts. DCE parameters differed significantly between normal gastric wall and lesions, with higher Ve (extracellular volume) and lower Kep (reflux constant) in gastric cancer. CONCLUSIONS: The free-breathing, golden-angle, radial stack-of-stars 3D GRE technique is feasible for DCE-MRI of gastric cancer. Dynamic enhanced images can be used for quantitative analysis of this malignancy. KEY POINTS: * Golden-angle radial stack-of-stars VIBE aids gastric cancer MRI diagnosis. * The 3D GRE technique is suitable for patients unable to suspend respiration. * Method scored higher in the qualitative evaluation for uncooperative patients. * The technique produced images with fewer artefacts than conventional VIBE sequence. * Dynamic enhanced images can be used for quantitative analysis of gastric cancer. PMID- 29260368 TI - Development of 13 microsatellite markers for Castanopsis tribuloides (Fagaceae) using next-generation sequencing. AB - Catanopsis tribuloides is a climax tree species commonly distributed in evergreen forests and has been used to restore degraded areas in northern Thailand. To aid in study of genetic diversity of the species, microsatellite markers, which are specific to C. tribuloides, were developed using whole genome sequencing by next generation sequencing technology. The primers for microsatellite were developed and screened for optimal annealing temperature by PCR assay. The loci primers specific with C. tribuloides, 13 polymorphic microsatellite primers were successfully developed. The results from genetic information analyzing showed the number of alleles presented were between 2 and 24. Accordingly, the expected and observed heterozygosity obtained were between 0.298 and 0.920 and 0.364 to 1.000, respectively. Null allele frequency was presented 0.000-0.199. Genetic information was generated 10 loci primers significantly deviated from Hardy Weinberg Equilibrium. All 13 primer pairs of loci were not significant with linkage disequilibrium. A set of microsatellite markers in this study could be applied to gene flow, genetic structure and population genetic studies in the future. PMID- 29260367 TI - Larger volume and different functional connectivity of the amygdala in women with premenstrual syndrome. AB - OBJECTIVES: To assess structural and functional changes of the amygdala due to premenstrual syndrome (PMS) using magnetic resonance imaging (MRI). METHODS: Twenty PMS patients and 21 healthy control (HC) subjects underwent a 6-min resting-state fMRI scan during the luteal phase as well as scanning high resolution T1-weighted images. Subcortical amygdala-related volume and functional connectivity (FC) were estimated between the two groups. Each subject completed a daily record of severity of problems (DRSP) to measure the severity of clinical symptoms. RESULTS: Greater bilateral amygdalae volumes were found in PMS patients compared with HC subjects, and PMS patients had increased FC between the amygdala and certain regions of the frontal cortex (e.g. medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), right precentral gyrus), the right temporal pole and the insula, as well as decreased FC between the bilateral amygdalae and the right orbitofrontal cortex and right hippocampus. The strength of FC between the right amygdala and right precentral gyrus, left ACC and left mPFC were significantly and positively correlated with DRSP scores in PMS patients. CONCLUSIONS: Our findings may improve our understanding of the neural mechanisms involved in PMS. KEY POINTS: * Functional and structural MRI used to explore amygdala in PMS patients. * Aberrant amygdala structural and functional connectivity were found in PMS patients. * Amygdala strength FC was positively correlated with individual clinical symptom scores. PMID- 29260369 TI - Predictors of right ventricular pacing and pacemaker dependence in transcatheter aortic valve replacement patients. AB - PURPOSE: Transcatheter aortic valve replacement (TAVR) is an increasingly prevalent therapy in patients with severe symptomatic aortic stenosis. Conduction disturbances requiring permanent pacemaker (PPM) implantation are a known complication of TAVR. This study investigated the progression of cardiac conduction disease in the post-TAVR pacemaker population and identified predictors of post-TAVR right ventricular (RV) pacing dependence. METHODS: Prospectively collected echocardiographic, ECG, and PPM interrogation data of 262 consecutive patients who underwent TAVR with placement of a balloon-expandable valve at one institution from March 2012 to October 2016 were analyzed. RESULTS: A total of 25 patients (11.1%) required post-TAVR PPM implantation. Seventeen patients who received PPMs did not require RV pacing at 30 days. Nine of these 17 patients had no RV pacing requirement within 10 days. Pre-existing right bundle branch block (RBBB) (OR 105.4, 4.52-2458.5, p = 0.0002), bifascicular block (OR 12.50, 1.60-97.65, p = 0.02), intra-procedural complete heart block (OR 12.83, 1.26-130.52, p = 0.03), and QRS duration > 120 ms (OR 70.43, 3.23-1535.22, p = 0.0002) on pre-TAVR ECG were associated with RV pacing dependence at 30 days. CONCLUSIONS: Sixty-eight percent of patients meeting post-procedural guideline indications for PPM did not require RV pacing at 30 days. Fifty-two percent of these patients demonstrated recovery of sinus node function or AV conduction within 10 days post-implant. RBBB, intra-procedural complete heart block, bifascicular block, and QRS duration > 120 ms were associated with RV pacing dependence at 30 days. These findings suggest that post-TAVR conduction disturbances may be acutely reversible in a significant proportion of patients receiving PPM within 10-30 days of implant. PMID- 29260370 TI - Sensory properties of the caudal aspect of the macaque's superior parietal lobule. AB - In the superior parietal lobule (SPL), the anterior part (area PE) is known to process somatosensory information, while the caudalmost part (areas V6Av and V6) processes visual information. Here we studied the visual and somatosensory properties of the areas PEc and V6Ad located in between the somatosensory and visual domains of SPL. About 1500 neurons were extracellularly recorded in 19 hemispheres of 12 monkeys (Macaca fascicularis). Visual and somatosensory properties of single neurons were generally studied separately, while in a subpopulation of neurons, both the sensory properties were tested. Visual neurons were more represented in V6Ad and somatosensory neurons in PEc. The visual neurons of these two areas showed similar properties and represented a large part of the contralateral visual field, mostly the lower part. In contrast, somatosensory neurons showed remarkable differences. The arms were overrepresented in both the areas, but V6Ad represented only the upper limbs, whereas PEc both the upper and lower limbs. Interestingly, we found that in both the areas, bimodal visual-somatosensory cells represented the proximal part of the arms. We suggest that PEc is involved in locomotion and in the control of hand/foot interaction with the objects of the environment, while V6Ad is in the control of the object prehension specifically performed with the upper limbs. Neuroimaging and lesion studies from literature support a strict homology with humans. PMID- 29260371 TI - Analysis of the vasculature by immunohistochemistry in paraffin-embedded brains. AB - The brain vasculature can be investigated in different ways ranging from in vivo to biochemical analysis. Immunohistochemistry is a simple and powerful technique that can also be applied to archival tissues. However, staining of brain vessels on paraffin sections has been challenging. In this study, we developed an optimized method that can be used in paraffin-embedded mouse and human brain tissues derived from healthy controls and neurological disorders such as Alzheimer's disease. We subsequently showed that this method is fully compatible with the detection of glial cells and key markers of Alzheimer's disease including amyloid beta and phosphorylated Tau protein. Furthermore, we observed that the length of microvasculature in hippocampus of TgCRND8 Alzheimer's disease mouse model is reduced, which is correlated with the decreased blood flow in hippocampus as determined by arterial spin labeling perfusion magnetic resonance imaging. Finally, we determined that the microvasculature length in two other Alzheimer's disease mouse models, APP and PS1 double-transgenic mice and P301S Tau-transgenic mice, is also shortened in the dentate gyrus. Thus, we have established a new, simple and robust method to characterize the brain vasculature in the mouse and human brain. PMID- 29260372 TI - Changes in neocortical and hippocampal microglial cells during hibernation. AB - Mammalian hibernation proceeds alongside a wide range of complex brain adaptive changes that appear to protect the brain from extreme hypoxia and hypothermia. Using immunofluorescence, confocal microscopy, quantitative analysis methods and intracellular injections, we have characterized microglia morphological changes that occur in the neocortex and hippocampus of the Syrian hamster during hibernation. In euthermic hamsters, microglial cells showed the typical ramified/resting morphology with multiple long, thin and highly-branched processes homogeneously immunostained for Iba-1. However, during torpor, microglial cell process numbers increase significantly accompanied by a shortening of the Iba-1 immunoreactive processes, which show a fragmented appearance. Adaptative changes of microglial cells during torpor coursed with no expression of microglial cell activation markers. We discuss the possibility that these morphological changes may contribute to neuronal damage prevention during hibernation. PMID- 29260373 TI - Minority Veterans Are More Willing to Participate in Complex Studies Compared to Non-minorities. AB - BACKGROUND: Minorities are an underrepresented population in clinical trials. A potential explanation for this underrepresentation could be lack of willingness to participate. The aim of our study was to evaluate willingness to participate in different hypothetical clinical research scenarios and to evaluate the role that predictors (e.g. health literacy) could have on the willingness of minorities to participate in clinical research studies. METHODS: We conducted a mixed-methods study at the Miami VA Healthcare system and included primary care patients with hypertension. We measured willingness to participate as a survey of four clinical research scenarios that evaluated common study designs encountered in clinical research and that differed in degree of complexity. Our qualitative portion included comments about the scenarios. RESULTS: We included 123 patients with hypertension in our study. Of the entire sample, ninety-three patients were minorities. Seventy per cent of the minorities were willing to participate, compared to 60 per cent of the non-minorities. The odds ratio (OR) of willingness to participate in simple studies was 0.58; 95 per cent CI 0.18-1.88 p=0.37 and the OR of willingness to participate in complex studies was 5.8; 95 per cent CI 1.10-1.31 p=0.03. In complex studies, minorities with low health literacy cited obtaining benefits (47 per cent) as the most common reason to be willing to participate. Minorities who were not willing to participate, cited fear of unintended outcomes as the main reason. CONCLUSIONS: Minorities were more likely to be willing to participate in complex studies compared to non-minorities. Low health literacy and therapeutic misconception are important mediators when considering willingness to participate in clinical research. PMID- 29260374 TI - Post-Herpetic Autoimmune Encephalitis. PMID- 29260375 TI - Changing characteristics of hospital admissions but not the children admitted-a whole population study between 2000 and 2013. AB - : There are increasing numbers of emergency medical paediatric admissions. Our hypothesis was that characteristics of children and details of their emergency admissions are also changing over time. Details of emergency admissions in Scotland 2000-2013 were analysed. There were 574,403 emergency admissions, median age 2.3 years. The age distribution, proportion of boys and socioeconomic status of children admitted were essentially unchanged. Emergency admissions rose by 49% from 36/1000 children per annum to 54/1000 between 2000 and 2013. Emergency admissions that were discharged on the same day rose by 186% from 8.6/1000 to 24.6/1000. The mean duration of emergency admission fell from 1.7 to 1.0 days. The odds for an emergency admission with upper respiratory infection, "viral infection", tonsillitis, bronchiolitis and lower respiratory tract infection all rose. In contrast the odds for an emergency admission with asthma and gastroenteritis fell. CONCLUSIONS: The demographics of children with emergency admissions have not changed substantially but characteristics of admissions have changed considerably, in particular admissions which are short stay and due to respiratory infection are much more common. The fall in the absolute number of children with some acute medical diagnoses suggests that the rise in admissions is not necessarily inexorable. What is Known: * Emergency admission prevalence is rising in many countries across Europe. What is New: * Our paper is the first to comprehensively analyse emergency medical paediatric admissions by exploring how characteristics of admissions and the children admitted have changed over time for a whole population. * The "take home message" is that whilst characteristics of emergency admissions have changed (e.g. number, duration of stay, readmissions, diagnoses), the characteristics of the children have not changed. PMID- 29260376 TI - Desmopressin use in pediatric nocturnal enuresis patients: is there a sex difference in prescription patterns? AB - : Desmopressin is a long-established treatment for nocturnal enuresis with clear guidelines regarding its usage. A sex difference in renal sensitivity has recently been reported in adults. The objective of this study was to investigate real-life desmopressin prescription in the Danish pediatric population, and prescription patterns which may reflect a sex difference in pediatric usage. Formulation, dose, treatment duration, and safety (hyponatremia) were investigated. 40,596 children received 214,220 desmopressin prescriptions between 2004 and 2011 in the Danish National Prescription Registry. Data were linked to hyponatremia diagnoses from the National Patient Registry. Although the lowest recommended dose of desmopressin oral lyophilisate is 120 MUg, around a fifth of children were prescribed 60 MUg for long-term use. A greater proportion of girls (22.6%) than boys (19.8%) received this low dose. Treatment duration was longer for boys than girls on oral lyophilisate (mean 489-524 vs. 414-462 days) and tablet (0.1 mg: 204 vs. 161 days). Prescribed daily dose was consistent with time between prescriptions, indicating no significant drug holidays. There were no admissions for hyponatremia during the observation period. CONCLUSION: Danish national prescription data on pediatric desmopressin dosage are consistent with a greater sensitivity to desmopressin in girls than boys. Further studies are required. What is Known: * Desmopressin has been used for pediatric nocturnal enuresis for decades * Recent evidence suggests a sex difference in desmopressin sensitivity in adults What is New: * For the first time, desmopressin prescription practices in nocturnal enuresis are documented for an entire country * A higher proportion of girls than boys received a low dose of desmopressin, consistent with the sex difference in sensitivity reported in adults. PMID- 29260377 TI - Characterization of Gladiolus Germplasm Using Morphological, Physiological, and Molecular Markers. AB - Estimation of variability and genetic relationships among breeding materials is one of the important strategies in crop improvement programs. Morphological (plant height, spike length, a number of florets/spike), physiological (chlorophyll content, chlorophyll fluorescence, and rapid light curve parameters) and Directed amplification of minisatellite DNA (DAMD) markers were used to investigate the relationships among 50 Gladiolus cultivars. Cluster analysis based on morphological data, physiological characteristics, molecular markers, and cumulative data discriminated all cultivars into seven, five, seven, and six clusters in the unweighted pair-group method using arithmetic mean (UPGMA) dendrogram, respectively. The results of the principal coordinate analysis (PCoA) also supported UPGMA clustering. Variations among the Gladiolus cultivars at phenotypic level could be due to the changes in physiology, environmental conditions, and genetic variability. DAMD analysis using 10 primers produced 120 polymorphic bands with 80% polymorphism showing polymorphic information content (PIC = 0.28), Marker index (MI = 3.37), Nei's gene diversity (h = 0.267), and Shannon's information index (I = 0.407). Plant height showed a positive significant correlation with Spike length and Number of florets/spike (r = 0.729, p < 0.001 and r = 0.448, p = 0.001 respectively). Whereas, Spike length showed positive significant correlation with Number of florets/spike (r = 0.688, p < 0.001) and Chlorophyll content showed positive significant correlation with Electron transport rate (r = 0.863, p < 0.001). Based on significant morphological variations, high physiological performance, high genetic variability, and genetic distances between cultivars, we have been able to identify diverse cultivars of Gladiolus that could be the potential source as breeding material for further genetic improvement in this ornamental crop. PMID- 29260379 TI - Perspectives on Monitoring Youth with Ongoing Mental Health Problems in Primary Health Care: Family Physicians Are "Out of the Loop". AB - Children's mental health (CMH) problems often recur. Following specialized mental health treatment, youth may require monitoring and follow-up. For these youth, primary health care is highly relevant, as family physicians (FPs) are the only professionals who follow patients across the lifespan. The current study gained multiple perspectives about (1) the role of FPs in caring for youth with ongoing/recurring CMH problems and (2) incorporating routine mental health monitoring into primary health care. A total of 33 interviews were conducted, including 10 youth (aged 12-15) receiving CMH care, 10 parents, 10 CMH providers, and 3 FPs. Using grounded theory methodology, a theme of FPs being "out of the loop" or not involved in their patient's CMH care emerged. Families perceived a focus on the medical model by their FPs and believed FPs lacked mental health expertise. Findings indicate a need for improved collaboration between CMH providers and FPs in caring for youth with ongoing CMH problems. PMID- 29260378 TI - omega-3 Fatty Acid Synergized Novel Nanoemulsifying System for Rosuvastatin Delivery: In Vitro and In Vivo Evaluation. AB - The present study was undertaken to improve rosuvastatin (RSV) bioavailability and pharmacological response through formation of SNES using Perilla frutescens oil as lipid carrier. The composition of oil was estimated by fatty acid methyl ester (FAME) analysis using gas chromatography. Solubility of RSV in Perilla frutescens oil and Cremophor EL was 25.0 +/- 3.0 and 60.0 +/- 5.0 mg/mL, respectively. Later, nanophasic maps and a central composite design were employed to determine the maximum nanoemulsion region and further optimize SNES in this study. Finally, the optimized formulation was evaluated in vitro and in vivo. FAME analysis revealed that PUFA content was 70.3% of total fatty acid. Optimized SNES formulation demonstrated particle size of 17.90 nm, dissolution 98.80%, cloud point 45 degrees C, emulsification time 2 min, and viscosity 241.41 +/- 5.52 cP. The hypolipidemic property of SNES was further explored using Triton X 100-induced hyperlipidemic rat model, and there were reductions of serum cholesterol, triglyceride, and LDL and VLDL levels in the SNES-treated group as compared to the toxic control. Pharmacokinetic study of SNES revealed significantly higher C max (60.13 +/- 25.43 ng/mL) and AUC0-infinity (6195 +/- 42.38 ng h/mL) vis-a-vis marketed tablet (284.80 +/- 13.44 ng/mL, 3131.72 +/- 51.93 ng h/mL, respectively). RSV was successfully incorporated into omega-3 fatty acid-based SNES with improved pharmacokinetic parameters (~ 2-fold improved bioavailability) and better hypolipidemic properties, owing to the synergistic effects of hepatic lipid regulation itself. The results clearly explicated that omega-3 fatty acid-based SNES effectively enhanced bioavailability and pharmacological responses of RSV, suggesting that these formulations may be useful as alternative for hyperlipidemia treatment in future drug design perspective. PMID- 29260380 TI - Atypical PT anatomy in children with autism spectrum disorder with expressive language deficits. AB - Deficits in communication are a core feature of autism spectrum disorder (ASD), however, structural language abilities are highly variable, ranging from minimally verbal to superior linguistic skills. Differences in the anatomy of cortical language regions, including anterior and posterior areas, have been found in ASD. It remains unclear, however, if anatomical differences distinguish individuals with impaired expressive language from those without such deficits. In addition, anatomical differences have not been explored in children with extremely low expressive language. This study included 34 boys with ASD, 7-11 years old, including an expressive language impaired group (n = 17) and an average-high language group (n = 17). The language impaired group was subdivided into a low (n = 9) and extremely low (n = 8) language subgroup for exploratory analyses to determine whether children with ASD with extremely low expressive language abilities exhibit distinct anatomy. Gray matter volume of the pars triangularis, pars opercularis, and planum temporale (PT) were measured on MRIs. PT volume was smaller in the ASD group with expressive language impairment relative to those without language deficits. The right PT volume was also positively correlated with language scores. The exploratory analyses revealed differences in the left PT, with smaller volume in the extremely low language subgroup, relative to the average and moderately low language groups. Results suggest that smaller PT volumes in both hemispheres are associated with severe language impairments in ASD. The PT may therefore, be a biomarker of language outcome in young children with ASD, with more studies of PT anatomy necessary. PMID- 29260381 TI - The neural basis of kinesthetic and visual imagery in sports: an ALE meta - analysis. AB - Imagery is a widely spread technique in the sport sciences that entails the mental rehearsal of a given situation to improve an athlete's learning, performance and motivation. Two modalities of imagery are reported to tap into distinct brain structures, but sharing common components: kinesthetic and visual imagery. This study aimed to investigate the neural basis of those types of imagery with Activation Likelihood Estimation algorithm to perform a meta - analysis. A systematic search was used to retrieve only experimental studies with athletes or sportspersons. Altogether, nine studies were selected and an ALE meta - analysis was performed. Results indicated significant activation of the premotor, somatosensory cortex, supplementary motor areas, inferior and superior parietal lobule, caudate, cingulate and cerebellum in both imagery tasks. It was concluded that visual and kinesthetic imagery share similar neural networks which suggests that combined interventions are beneficial to athletes whereas separate use of those two modalities of imagery may seem less efficient from a neuropsychological approach. PMID- 29260383 TI - Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome. AB - The increased levels of intracellular reactive oxygen species (ROS) in granulosa cells (GCs) may affect the pregnancy results in women with polycystic ovary syndrome (PCOS). In this study, we compared the in vitro fertilization and embryo transfer (IVF-ET) results of 22 patients with PCOS and 25 patients with tubal factor infertility and detected the ROS levels in the GCs of these two groups. Results showed that the PCOS group had significantly larger follicles on the administration day for human chorionic gonadotropin than the tubal factor group (P < 0.05); however, the number of retrieved oocytes was not significantly different between the two groups (P > 0.05). PCOS group had slightly lower fertilization, cleavage, grade I/II embryo, clinical pregnancy, and implantation rates and higher miscarriage rate than the tubal factor group (P > 0.05). We further found a significantly higher ROS level of GCs in the PCOS group than in the tubal factor group (P < 0.05). The increased ROS levels in GCs caused GC apoptosis, whereas NADPH oxidase 2 (NOX2) specific inhibitors (diphenyleneiodonium and apocynin) significantly reduced the ROS production in the PCOS group. In conclusion, the increased ROS expression levels in PCOS GCs greatly induced cell apoptosis, which further affected the oocyte quality and reduced the positive IVF-ET pregnancy results of women with PCOS. NADPH oxidase pathway may be involved in the mechanism of ROS production in GCs of women with PCOS. PMID- 29260382 TI - The Interplay Between Epithelial-Mesenchymal Transition (EMT) and the Thyroid Hormones-alphavbeta3 Axis in Ovarian Cancer. AB - Ovarian cancer is a highly metastatic disease. The metastatic potential is enhanced by epithelial to mesenchymal transition (EMT) in which alphavbeta3 integrin plays a role. Thyroid hormones (L-thyroxine, T4, and 3,5,3'-triiodo-L thyronine, T3) bind this integrin, and we hypothesized that the thyroid hormone alphavbeta3 axis may be involved in EMT activity in ovarian cancer. The transcription (mRNA), protein abundance (westerns), and protein localization (fluorescence microscopy) of several EMT markers were studied in ovarian cancer cells (OVCAR-3, A2780, and SKOV-3) treated with 1 nM T3 or 100 nM T4 for 1-24 h. The protein levels of beta-catenin, and its downstream targets, zeb-1, slug, and vimentin, were significantly induced by both hormones, while the effect on transcription was limited. The pre-incubation of the cells overnight with two integrin inhibitors, RGD (0.1-10 MUM) or alphavbeta3 blocking antibody (1-100 ng/mL), prevented the induction of beta-catenin by T3 and zeb-1 by T4, indicating direct integrin involvement. The transcription of the mesenchymal markers, beta catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, was inhibited. Our results suggest a novel role for the thyroid hormone-alphavbeta3 axis in EMT, with possible implications for ovarian cancer metastasis. PMID- 29260384 TI - Predictive factors for metal ion levels in metal-on-metal total hip arthroplasty. AB - INTRODUCTION: Although metal-on-metal (MoM) total hip arthroplasty (THA) and hip resurfacings (HR) have similar bearing surfaces and comparable wear rates, metal ion levels and risk of failure are higher for MoM-THA. The mechanism behind the increased metal ion levels in large head MoM-THA is not completely understood. The current study aims to identify predictive factors for increased metal ion levels in unilateral and bilateral large head MoM-THA. MATERIALS AND METHODS: 99 Birmingham modular MoM-THA in 87 patients with metal ion levels at least 36 months after index procedure were analyzed. Mean follow-up time was 61.3 months (range 37-108) and the relationship of the following variables (gender, age, BMI, follow-up time, UCLA Activity Score, cup inclination, femoral head size, bilateral surgery) on metal ion levels were analyzed with multivariate regression models. RESULTS: Multivariate regression analysis revealed that bilateral MoM-THA surgery (p < 0.001) had a positive predictive effect on cobalt serum levels, while BMI had a negative (p = 0.018). Female gender (p = 0.012), activity (p = 0.001) and bilateral MoM-THA (p = 0.004) were positively correlated with chromium levels. Positive independent predictors for the cobalt-chromium ratio in the multivariate analysis were overall follow-up time (p = 0.004), bilateral MoM-THA (p < 0.001) and femoral head size (p = 0.007). CONCLUSIONS: The data of the current study suggest that bilateral MoM-THA, increased patient activity levels and female gender are associated with increased chromium levels. Patients with larger component size, longer follow-up time and bilateral MoM-THAs have an increased cobalt-chromium ratio. These patients might be at increased risk for adverse local soft tissue reactions secondary to corrosion. Continuous close monitoring is recommended and bearing-surface change should be discussed if local tissue reactions occur. PMID- 29260385 TI - Characterization of N2O emissions and associated microbial communities from the ant mounds in soils of a humid tropical rainforest. AB - Tropical rainforest soils harbor a considerable diversity of soil fauna that contributes to emissions of N2O. Despite their ecological dominance, there is limited information available about the contribution of epigeal ant mounds to N2O emissions in these tropical soils. This study aimed to determine whether ant mounds contribute to local soil N emissions in the tropical humid rainforest. N2O emission was determined in vitro from individual live ants, ant-processed mound soils, and surrounding reference soils for two trophically distinct and abundant ant species: the leaf-cutting Atta mexicana and omnivorous Solenopsis geminata. The abundance of total bacteria, nitrifiers (AOA and AOB), and denitrifiers (nirK, nirS, and nosZ) was estimated in these soils using quantitative PCR, and their respective mineral N contents determined. There was negligible N2O emission detected from live ant individuals. However, the mound soils of both species emitted significantly greater (3-fold) amount of N2O than their respective surrounding reference soils. This emission increased significantly up to 6-fold in the presence of acetylene, indicating that, in addition to N2O, dinitrogen (N2) is also produced from these mound soils at an equivalent rate (N2O/N2 = 0.57). Functional gene abundance (nitrifiers and denitrifiers) and mineral N pools (ammonium and nitrate) were significantly greater in mound soils than in their respective reference soils. Furthermore, in the light of the measured parameters and their correlation trends, nitrification and denitrification appeared to represent the major N2O-producing microbial processes in ant mound soils. The ant mounds were estimated to contribute from 0.1 to 3.7% of the total N2O emissions of tropical rainforest soils. PMID- 29260387 TI - Optimization of the production of an extracellular and thermostable amylolytic enzyme by Thermus thermophilus HB8 and basic characterization. AB - The objective of this study was to determine the potential of Thermus thermophilus HB8 for accumulating a high level of extracellular, thermostable amylolytic enzyme. Initial production tests indicated clearly that only very low levels of amylolytic activity could be detected, solely from cells after extraction using the mild, non-ionic detergent Triton X-100. A sequential optimization strategy, based on statistical designs, was used to enhance greatly the production of extracellular amylolytic activity to achieve industrially attractive enzyme titers. Focus was placed on the optimal level of initial biomass concentration, culture medium composition and temperature for maximizing extracellular amylolytic enzyme accumulation. Empirical models were then developed describing the effects of the experimental parameters and their interactions on extracellular amylolytic enzyme production. Following such efforts, extracellular amylolytic enzyme accumulation was increased more than 70 fold, with enzyme titers in the 76 U/mL range. The crude extracellular enzyme was thereafter partially characterized. The optimal temperature and pH values were found to be 80 degrees C and 9.0, respectively. 100% of the initial enzyme activity could be recovered after incubation for 24 h at 80 degrees C, therefore, proving the very high thermostability of the enzyme preparation. PMID- 29260386 TI - Changes in bacterial and archaeal communities during the concentration of brine at the graduation towers in Ciechocinek spa (Poland). AB - This study evaluates the changes in bacterial and archaeal community structure during the gradual evaporation of water from the brine (extracted from subsurface Jurassic deposits) in the system of graduation towers located in Ciechocinek spa, Poland. The communities were assessed with 16S rRNA gene sequencing (MiSeq, Illumina) and microscopic methods. The microbial cell density determined by direct cell count was at the order of magnitude of 107 cells/mL. It was found that increasing salt concentration was positively correlated with both the cell counts, and species-level diversity of bacterial and archaeal communities. The archaeal community was mostly constituted by members of the phylum Euryarchaeota, class Halobacteria and was dominated by Halorubrum-related sequences. The bacterial community was more diverse, with representatives of the phyla Proteobacteria and Bacteroidetes as the most abundant. The proportion of Proteobacteria decreased with increasing salt concentration, while the proportion of Bacteroidetes increased significantly in the more concentrated samples. Representatives of the genera Idiomarina, Psychroflexus, Roseovarius, and Marinobacter appeared to be tolerant to changes of salinity. During the brine concentration, the relative abundances of Sphingobium and Sphingomonas were significantly decreased and the raised contributions of genera Fabibacter and Fodinibius were observed. The high proportion of novel (not identified at 97% similarity level) bacterial reads (up to 42%) in the 16S rRNA gene sequences indicated that potentially new bacterial taxa inhabit this unique environment. PMID- 29260388 TI - Vitamin "G"arden: a qualitative study exploring perception/s of horticultural therapy on a palliative care ward. AB - PURPOSE: In a palliative care setting, the preservation of quality of life is of particular importance. Horticultural therapy (HT) is reported as an excellent way to improve physical as well as psychological well-being, reduce levels of anxiety and depression, and promote social interaction. The use of horticultural interventions in palliative care has not yet been explored. The aim of this study was to explore the effects of HT in patients and team members on a palliative care ward. METHODS: This study was based on a qualitative methodology, comprising 20 semistructured interviews with 15 advanced cancer patients participating in HT and with 5 members of the palliative care team. Interviews were analyzed using NVivo 10 software based on thematic analysis. RESULTS: The results revealed the following themes: (1) well-being, (2) variation of clinical routine, (3) creation, and (4) building relationships. Patients experienced positive stimulation through HT, were distracted from daily clinical routines, enjoyed creative work, and were able to build relationships with other patients. HT was also welcomed by the members of the palliative care team. Thirty-six percent of the patients did not meet the inclusion criteria, and 45% could not participate in the second or third HT session. CONCLUSIONS: Our study showed that the availability of HT was highly appreciated by the patients as well as by the palliative care team. Nevertheless, the dropout rate was high, and therefore, it might be more feasible to integrate green spaces into palliative care wards. PMID- 29260389 TI - Potential curability and perception of received information in esophageal cancer patients. AB - PURPOSE: This study aimed to evaluate patients' perceived receipt of information according to the possibility of cure in esophageal cancer. METHODS: One hundred and twelve consecutive patients presenting at the multidisciplinary visit at the Veneto Institute of Oncology for esophageal cancer between 2014 and 2016 were included in the study. The Italian version of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires C30 (core questionnaire), OG25 (esophago-gastric cancer module), and INFO25 (information module) were used. RESULTS: Candidates for palliative treatment were less informed about the disease (adjusted mean difference - 11.5, 95% CI - 23.0 to - 0.02) and less satisfied with information provided (adjusted mean difference - 18.3, 95% CI - 31.9 to - 4.7) than candidates for curative treatment. In addition, candidates for palliative treatment wanted to receive more information than candidates for curative treatment (adjusted mean difference 26.1, 95% CI 0.5 to 51.6). Better quality of life was associated with satisfaction of received information (beta = 0.77, p < 0.0001) and of receiving information about things that the patient can do to help himself (beta = 0.26, p = 0.04). More anxiety was associated to receiving more information about disease (beta = 0.46, p = 0.02) but less information about things that the patient can do to help himself (beta = - 0.38, p = 0.02). CONCLUSIONS: Candidates for palliative treatment were less satisfied with information about the disease and wanted to receive more information. Additionally, some aspects of quality of life were found to be associated with perceived receipt of information. Appropriate training in communication of prognostic information may improve clinical management of incurable cancer patients. PMID- 29260390 TI - Parent perspectives and preferences for strategies regarding nonsedated MRI scans in a pediatric oncology population. AB - PURPOSE: Children with cancer frequently require MRI scans for clinical purposes. Sedation with general anesthesia (GA) is often used to promote compliance, reduce motion, and alleviate anxiety. The use of GA for MRI scans is costly in terms of time, personnel, and medications. In addition, prominent risks are associated with anesthesia exposure in patients with complex medical conditions. Successful behavioral interventions have been implemented in clinical research settings to promote scan success and compliance. To our knowledge, parent/caregiver acceptability of behavioral interventions to promote nonsedated MRI has not been systematically investigated in a medically complex population. As a first step toward developing a protocol-based intervention to promote nonsedated scanning, we conducted a survey to explore parental perspectives regarding acceptability of nonsedated scanning and to gain information regarding preference for specific behavioral interventions to facilitate nonsedated MRI exams. METHODS: Parents or guardians of 101 patients diagnosed with childhood cancer participated in a semi structured survey via telephone. The sample was stratified by age group (8-12 years; 13-18 years), gender, and diagnosis (solid tumor (ST), brain tumor (BT), and acute lymphoblastic leukemia (ALL)). RESULTS: The majority of parents indicated that nonsedated MRI scans would be acceptable. Reduced anesthesia exposure was the most frequently identified benefit, followed by decreased irritability post-MRI scan, and shorter appointment time. Challenges included fear of movement and noise during scans and change in routine, with parents of younger children and those with a history of sedated exams identifying more challenges. Behavioral intervention preference differed by patient age and gender; however, education was ranked as most preferred overall. CONCLUSION: Parents of children treated for cancer consider behavior interventions to promote nonsedated scanning as acceptable. Patient characteristics should be considered when tailoring behavioral interventions. Results can inform future studies of behavioral interventions to promote nonsedated MRI scans. Future research should also investigate the risks associated with failed exams, both in terms of patient medical care and cost effectiveness. PMID- 29260391 TI - Applying pre-participation exercise screening to breast cancer survivors: a cross sectional study. AB - PURPOSE: Clinical guidelines recommend that breast cancer (BrCa) survivors be prescribed exercise. However, clinicians often do not prescribe exercise citing the presence of multiple health issues found among cancer survivors. No study has examined the proportion of BrCa survivors that can be prescribed a community/home based unsupervised exercise program safely and independently, without further medical investigations or supervision. METHODS: Participants included BrCa survivors who received treatment at a university healthcare system between 2009 and 2014. We applied previously identified published guidelines for health conditions that may impede BrCa survivors from completing a community/home-based exercise program. Logistic regression models were used to quantify the magnitude of the association between demographic and clinical characteristics and the ability to perform community/home-based exercise. RESULTS: Among 667 BrCa survivors, 65 to 75% was classified as able to complete community/home-based exercise as recommended by the clinical guidelines. Older age, black race, treatment with chemotherapy, and treatment with radiation were associated with the potential need for further medical evaluation prior to starting exercise. CONCLUSIONS: A large proportion of BrCa survivors can be prescribed community/home-based exercise program safely and independently, without further medical investigations or supervision. Future research will be needed to determine how to identify the subset of BrCa survivors that may benefit from medical evaluation prior to starting exercise in a manner that does not interrupt clinical oncology workflow. Approximately 35% of BrCa survivors may benefit from medical evaluation prior to starting community/home-based exercise. PMID- 29260392 TI - Nose profile morphology and accuracy study of nose profile estimation method in Scottish subadult and Indonesian adult populations. AB - This study investigated nose profile morphology and its relationship to the skull in Scottish subadult and Indonesian adult populations, with the aim of improving the accuracy of forensic craniofacial reconstruction. Samples of 86 lateral head cephalograms from Dundee Dental School (mean age, 11.8 years) and 335 lateral head cephalograms from the Universitas Padjadjaran Dental Hospital, Bandung, Indonesia (mean age 24.2 years), were measured. The method of nose profile estimation based on skull morphology previously proposed by Rynn and colleagues in 2010 (FSMP 6:20-34) was tested in this study. Following this method, three nasal aperture-related craniometrics and six nose profile dimensions were measured from the cephalograms. To assess the accuracy of the method, six nose profile dimensions were estimated from the three craniometric parameters using the published method and then compared to the actual nose profile dimensions.In the Scottish subadult population, no sexual dimorphism was evident in the measured dimensions. In contrast, sexual dimorphism of the Indonesian adult population was evident in all craniometric and nose profile dimensions; notably, males exhibited statistically significant larger values than females. The published method by Rynn and colleagues (FSMP 6:20-34, 2010) performed better in the Scottish subadult population (mean difference of maximum, 2.35 mm) compared to the Indonesian adult population (mean difference of maximum, 5.42 mm in males and 4.89 mm in females).In addition, regression formulae were derived to estimate nose profile dimensions based on the craniometric measurements for the Indonesian adult population. The published method is not sufficiently accurate for use on the Indonesian population, so the derived method should be used. The accuracy of the published method by Rynn and colleagues (FSMP 6:20-34, 2010) was sufficiently reliable to be applied in Scottish subadult population. PMID- 29260393 TI - The application of the Kvaal method to estimate the age of live Korean subjects using digital panoramic radiographs. AB - Dental age estimation of the living is limited because observing the histological structure of teeth is difficult. Therefore, several methods have been proposed to estimate age by observing changes on dental radiographs of pulpal size caused by secondary dentin deposition. This study aims to evaluate the validity of the Kvaal method to estimate the ages of Korean subjects using digital panoramic radiographs and formulate regression equations for use in Korean subjects. We included 266 Korean subjects (age 21-69 years) visiting Chosun University Dental Hospital (Gwangju, South Korea). The pulpal size and width of six tooth types (maxillary central incisor, lateral incisor, second premolar, mandibular lateral incisor, canine, and first premolar) were measured on digital panoramic radiographs according to the Kvaal method. Statistical interobserver/intraobserver reliabilities were calculated to evaluate the reproducibility of the measured values, and correlations between actual ages and measured values were identified. The differences between the predicted ages and the actual age were analyzed. Paewinsky method was also applied and its validity was evaluated. In addition, a series of new regression equations for the age estimation of Korean subjects was produced. When both methods were applied directly to the teeth of the subjects, significant differences were observed between the estimated and chronological ages. The length-related parameters of the teeth of subjects calculated by the original Kvaal method showed no significant correlation. A regression equation derived from the width parameters without the length ratios is proposed for use in Korean subjects. PMID- 29260394 TI - Validation and evaluation of measuring methods for the 3D documentation of external injuries in the field of forensic medicine. AB - Three-dimensional (3D) measurement techniques are gaining importance in many areas. The latest developments brought more cost-effective, user-friendly, and faster technologies onto the market. Which 3D techniques are suitable in the field of forensic medicine and what are their advantages and disadvantages? This wide-ranging study evaluated and validated various 3D measurement techniques for the forensic requirements. High-tech methods as well as low-budget systems have been tested and compared in terms of accuracy, ease of use, expenditure of time, mobility, cost, necessary knowhow, and their limitations. Within this study, various commercial measuring systems of the different techniques were tested. Based on the first results, one measuring system was selected for each technique, which appeared to be the most suitable for the forensic application or is already established in forensic medicine. A body of a deceased, a face and an injury of a living person, and a shoe sole were recorded by 11 people with different professions and previous knowledge using the selected systems. The results were assessed and the personal experiences were evaluated using a questionnaire. In addition, precision investigations were carried out using test objects. The study shows that the hand-held scanner and photogrammetry are very suitable for the 3D documentation of forensic medical findings. Their moderate acquisition costs and easy operation could lead to more frequent application in forensic medicine in the future. For special applications, the stripe-light scanner still has its justification due to its high precision, the flexible application area, and the high reliability. The results show that, thanks to the technological advances, the 3D measurement technology will have more and more impact on the routine of the forensic medical examination. PMID- 29260395 TI - Detection of autophagy processes during the development of nonarticulated laticifers in Euphorbia kansui Liou. AB - MAIN CONCLUSION: Autophagy is involved in cytoplasmic degradation through directly engulfing cytosol and organelles by autophagosomes and then fusing with lysosome-like vesicles during the development of nonarticulated laticifers in Euphorbia kansui Liou. Autophagy has been reported to play an important role in a wide range of eukaryotic organisms during responses to various abiotic and biotic stresses. However, until recently, the functions of autophagy in normal plant differentiation and development were still in their infancy. Nonarticulated laticifers, a type of secretory tissue in plants, undergo the degradation of cytosol and organelles during their development. However, little evidence of autophagy in laticifer differentiation has been provided. In the present study, using anti-ATG8 antibody-Alexa Fluor 488, Lyso-Tracker Red (LTR) and monodansylcadaverine (MDC) as markers for detecting autophagosomes, as well as autophagy-related structures, we observed that the green fluorescence of ATG8a largely colocalized with the red fluorescence of LTR and purple fluorescence of MDC and the quantity of autophagosomes experienced a trend from less to more to less during laticifer development. Additionally, we described the autophagy process during the development of nonarticulated laticifers in Euphorbia kansui Liou at the ultrastructural level in detail. In addition, further immunogold TEM studies also verified the presence of autophagosomes, autolysosomes and lysosome like structures in laticifers. Taken together, these results suggest that autophagy contributes to the development of the nonarticulated laticifers in E. kansui Liou and that autophagosomes fuse with lysosome-like structures for degradation. These results will lay an important foundation for further studies on laticifer regulation. PMID- 29260396 TI - Fungal and herbivore elicitation of the novel maize sesquiterpenoid, zealexin A4, is attenuated by elevated CO2. AB - MAIN CONCLUSION: Chemical isolation and NMR-based structure elucidation revealed a novel keto-acidic sesquiterpenoid, termed zealexin A4 (ZA4). ZA4 is elicited by pathogens and herbivory, but attenuated by heightened levels of CO 2 . The identification of the labdane-related diterpenoids, termed kauralexins and acidic sesquiterpenoids, termed zealexins, demonstrated the existence of at least ten novel stress-inducible maize metabolites with diverse antimicrobial activity. Despite these advances, the identity of co-occurring and predictably related analytes remains largely unexplored. In the current effort, we identify and characterize the first sesquiterpene keto acid derivative of beta-macrocarpene, named zealexin A4 (ZA4). Evaluation of diverse maize inbreds revealed that ZA4 is commonly produced in maize scutella during the first 14 days of seedling development; however, ZA4 production in the scutella was markedly reduced in seedlings grown in sterile soil. Elevated ZA4 production was observed in response to inoculation with adventitious fungal pathogens, such as Aspergillus flavus and Rhizopus microsporus, and a positive relationship between ZA4 production and expression of the predicted zealexin biosynthetic genes, terpene synthases 6 and 11 (Tps6 and Tps11), was observed. ZA4 exhibited significant antimicrobial activity against the mycotoxigenic pathogen A. flavus; however, ZA4 activity against R. microsporus was minimal, suggesting the potential of some fungi to detoxify ZA4. Significant induction of ZA4 production was also observed in response to infestation with the stem tunneling herbivore Ostrinia nubilalis. Examination of the interactive effects of elevated CO2 (E-CO2) on both fungal and herbivore-elicited ZA4 production revealed significantly reduced levels of inducible ZA4 accumulation, consistent with a negative role for E-CO2 on ZA4 production. Collectively, these results describe a novel beta-macrocarpene derived antifungal defense in maize and expand the established diversity of zealexins that are differentially regulated in response to biotic/abiotic stress. PMID- 29260397 TI - The microtubule-associated RING finger protein 1 (OsMAR1) acts as a negative regulator for salt-stress response through the regulation of OCPI2 (O. sativa chymotrypsin protease inhibitor 2). AB - MAIN CONCLUSION: Our results suggest that a rice E3 ligase, OsMAR1, physically interacts with a cytosolic protein OCPI2 and may play an important role under salinity stress. Salt is an important abiotic stressor that negatively affects plant growth phases and alters development. Herein, we found that a rice gene, OsMAR1 (Oryza sativa microtubule-associated RING finger protein 1), encoding the RING E3 ligase was highly expressed in response to high salinity, water deficit, and ABA treatment. Fluorescence signals of its recombinant proteins were clearly associated with the microtubules in rice protoplasts. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) showed that OsMAR1 interacted with a cytosolic protein OCPI2 (O. sativa chymotrypsin protease inhibitor 2) and led to its degradation via the 26S proteasome. Heterogeneous overexpression of OsMAR1 in Arabidopsis showed retarded root growth compared with that of control plants, and then led to hypersensitivity phenotypes under high salinity stress. Taken together, OsMAR1 negatively regulates the salt-stress response via the regulation of the OCPI2 protein in rice. PMID- 29260398 TI - Integrated Bioinformatics Analysis of Potential Biomarkers for Prostate Cancer. AB - The aim was to expound the pathogenesis of prostate cancer and to identify the potentially biomarkers for prostate cancer (PC). DNA methylation microarray data GSE38240 containing 8 prostate cancer metastases and 4 normal prostate samples as well as gene expression profile data GSE26910 containing 6 prostate primary tumors and 6 normal samples were used. Differentially expressed genes (DEGs) and differently methylated sites of PC were screened and the regulatory network was constructed with DEGs-related transcription factors (TFs). The obtained hub genes were subjected to protein-protein interaction network analysis. Enrichment analysis of down-regulated DEGs were performed. Total 351 DEGs including 190 down regulated and 161 up-regulated genes and 3234 differently methylated sites were identified. In total 69 DEGs-related TFs were found. Regulatory network contained 1301 nodes and 2527 connection pairs and that FOXA1 (forkhead box A1), BZRAP1-AS1 (benzodiazapine receptor associated protein 1 antisense RNA 1) and KRT8 (keratin 8) were the top three nodes of it. The enriched GO terms were mainly biological activity of the blood and cells-related. Total 29 DEGs (such as AGTR1, angiotensin II receptor, type 1) and 57 none-DEGs involved in the PPI network. Biological functions in blood circulation and the involved AGTR1 may play important roles in PC by gene-methylation. Besides, BZRAP1-AS1 may be novel biomarker related with PC. PMID- 29260399 TI - Stigma Perceived and Experienced by Adults with Type 1 Diabetes: Linguistic Adaptation and Psychometric Validation of the Danish Version of the Type 1 Diabetes Stigma Assessment Scale (DSAS-1 DK). AB - OBJECTIVES: We aimed to (a) culturally and linguistically adapt the Type 1 Diabetes Stigma Assessment Scale (DSAS-1) from English (for Australia) into Danish and (b) examine psychometric properties of the measure among Danish adults with type 1 diabetes. METHODS: We performed a forward-backward translation, face validity interviews with experts and cognitive debriefing of the Danish version (DSAS-1 DK) with ten adults from the target group. The DSAS-1 DK was then completed by 1594 adults with type 1 diabetes. Electronic clinical records provided age, diabetes duration, diabetes-related complications, and glycemic control [glycated hemoglobin (HbA1c)]. We examined internal consistency, construct validity and structural validity of the DSAS-1 DK using exploratory and confirmatory factor analysis in a cross-validation design. RESULTS: The translated measure was found acceptable by the experts and target group, with only minor adaptations required for the Danish context. The DSAS-1 DK structure was best represented by a three-factor model representing the subscales 'Treated Differently,' 'Blame and Judgement,' and 'Identity Concern' (alpha = 0.88-0.89). The results also provided some support for calculation of a total score (19-item scale; alpha = 0.75). The subscales and total scale demonstrated satisfactory convergent and discriminant validity. Good structural validity was demonstrated for the three-factor model for four out of five indices [normed chi 2 = 4.257, goodness-of-fit index (GFI) = 0.923, root mean square error of approximation (RMSEA) = 0.065, standardized root mean square residual (SRMSR) = 0.0567, comparative fit index (CFI) = 0.93]. CONCLUSION: The DSAS-1 DK has a confirmed three-factor structure, consistent with the original Australian English version. The measure is now validated and available to advance research into the stigma perceived and experienced by adults with type 1 diabetes in a Danish context. PMID- 29260400 TI - No modifying effect of nutritional status on statins therapy in relation to all cause death in older patients with coronary artery disease. AB - BACKGROUND: Statins therapy in the secondary prevention of coronary artery disease (CAD) is associated with a lower risk of adverse cardiovascular events. However, little is known regarding the association of elderly patients with nutritional risk on statin therapy. AIMS: To investigate whether older patients with CAD who were at nutritional risk gain similar survival benefit from statins therapy as their counterparts without nutritional risk. METHODS: We conducted a retrospective hospital-based cohort study among 1705 patients with CAD who were older than 65 years of age, using coronary heart disease database from 2008 to 2012. Nutritional status of included patients was gauged using the geriatric nutritional risk index. After stratification by nutritional status, the hazard of all-cause death was compared between those with or without statins therapy. RESULTS: Of the 1705 patients included in the study (mean age 72 years; 73% male), all-cause death occurred in 146 (9.2%) patients with statins use and in 33 (26.2%) patients without statins use. The rate of all-cause death was higher in patients not receiving statins irrespective of nutritional status. After adjustments for potential confounders, the HR with statins use was 0.33 (95% CI 0.20-0.55) in patients without nutritional risk and 0.47 (95% CI 0.22-1.00) in patients with nutritional risk. No interaction effect was detected between nutritional status and statins use in relation to all-cause death (P value for interaction effect 0.516). CONCLUSION: Despite of the patient's nutritional status, statins therapy as a secondary prevention in elderly CAD patients was associated with decreased risk of all-cause death. PMID- 29260401 TI - The impact of post-resistance exercise protein consumption on subsequent appetite and daily energy intake of sarcopenic older men: a pilot study. AB - BACKGROUND: Because of its satiating effect, it has been widely purported that a high-protein beverage may reduce subsequent appetite and food intake in healthy aged individuals, therefore annihilating any supplemental effect. AIMS: The goal of the study was to examine the impact of a post-exercise protein supplement from dairy products in the hours following resistance exercise on subsequent energy intake, sensation of hunger, appetite and satiety in sarcopenic older men. METHODS: A randomized double-blind crossover study with three experimental conditions was performed. Nine sarcopenic older (64 +/- 3 years) men participated in three experimental conditions: post-exercise protein supplementation made from (1) cow's milk (13 g of proteins); (2) rice milk (isocaloric protein-free beverage) and (3) water (control). Subsequent energy intake was measured with a test buffet and a food record over the rest of the day. Assessment of appetite, satiety and hunger were obtained by visual analogue scales at various times before and after the buffet. RESULTS: Appetite, feeling of hunger and satiety and subsequent energy intake were not significantly different between the three experimental conditions. However, when participants were supplemented with cow's milk, total fat intake during the day of the intervention was significantly lower than with other supplements (p <= 0.05). CONCLUSION: Post-exercise consumption of protein supplements made from dairy products appear not to compromise daily nutritional behavior and does not confer the anticipated negative impact on nutritional intake in sarcopenic older men. PMID- 29260402 TI - Writing an effective literature review : Part I: Mapping the gap. PMID- 29260403 TI - Bilateral deficit of spring-like behaviour during hopping in sprinters. AB - PURPOSE: Unilateral leg stiffness is a key contributor to sprint running speed, thereby great bilateral deficit (BLD) of leg stiffness would be expected to be observed in sprinters. However, it remains clear only BLD of leg stiffness at the preferred hopping frequency in non-sprinters. The purpose of this study was to clarify the BLD of spring-like behaviour in hopping at various frequencies and the effect of chronic adaptation via sprint running experience on BLD during the hopping. METHODS: Fifteen male experienced sprinters and 12 male novices participated in this study. They were instructed to hop in place at three frequencies (2.0, 2.5, and 3.0 Hz), and to perform hopping with maximal effort. Ground reaction forces (GRF) of both legs during the hopping were recorded using two force plates. RESULTS: At higher hopping frequencies during the unilateral and bilateral hopping, smaller peak value of vertical GRF (F max) and greater leg stiffness (K leg) were significantly observed. The BLD index of F max and the BLD index of K leg were significantly smaller at higher hopping frequencies. No significant differences of BLD index of F max and BLD index of K leg were observed between sprinters and novices. CONCLUSION: Our results demonstrate that neuromuscular inhibition in the contralateral leg changes during the hopping based on hopping frequency. This suggests that plyometric training in the beginning of rehabilitation should involve bilateral jumping at a high frequency. In experienced sprinters, detailed mechanics of chronic neuromuscular adaptation via unilateral facilitation of spring-like behaviour should be assessed by measuring electromyographic activity. PMID- 29260404 TI - New treatment options for lipid-lowering therapy in subjects with type 2 diabetes. AB - Dyslipidemias represent a variety of quantitative and/or qualitative lipoprotein abnormalities. According to etiology, we distinguish primary dyslipidemias with strictly genetic background and secondary ones with their origin in other disease or pathological states. Diabetic dyslipidemia is a type of secondary dyslipidemia and plays an important role in determining the cardiovascular risk of subjects with type 2 diabetes. In these patients, insulin resistance is responsible for overproduction and secretion of atherogenic very low density lipoprotein. In addition, insulin resistance promotes the production of small dense low-density lipoprotein (LDL) and reduces high-density lipoprotein (HDL) production. Cardiovascular disease remains a leading cause of morbidity and mortality in diabetic patients. Previous results support the role for small, dense LDL particles in the etiology of atherosclerosis and their association with coronary artery disease. Moreover, lowering LDL cholesterol reduces the risk of cardiovascular death. Therefore, the European guidelines for the management of dyslipidemias recommend an LDL cholesterol goal < 100 mg/dL in diabetic subjects without cardiovascular events. Moreover, if triglycerides (TG) are elevated (> 400 mg/dL), they recommend a non-HDL cholesterol goal < 130 mg/dL in diabetic individuals without cardiovascular events. Statins are the first line of LDL lowering therapy in diabetic patients and combined therapy with ezetimibe and statins could be useful in very high cardiovascular risk diabetic subjects. Furthermore, the effect of a fibrate as an add-on treatment to a statin could improve the lipid profile in diabetic individuals with high TG and low HDL cholesterol. Regarding new therapies, recent data from phase III trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably decrease LDL cholesterol. Thus, they may be useful in diabetic patients with concomitant diseases such as familial dyslipidemia, recurrent cardiovascular events, and elevated LDL cholesterol after second drug administration in addition to maximal statin dose or statin intolerance. PMID- 29260405 TI - A principal component analysis based data fusion method for ECG-derived respiration from single-lead ECG. AB - An ECG-derived respiration (EDR) algorithm based on principal component analysis (PCA) is presented and applied to derive the respiratory signals from single-lead ECG. The respiratory-induced variabilities of ECG features, P-peak amplitude, Q peak amplitude, R-peak amplitude, S-peak amplitude, T-peak amplitude and RR interval, are fused by PCA to yield a better surrogate respiratory signal than other methods. The method is evaluated on data from the MIT-BIH polysomnographic database and validated against a "gold standard" respiratory obtained from simultaneously recorded respiration data. The performance of fusion algorithm is assessed by comparing the EDR signals to a reference respiratory signal, using the quantitative evaluation indexes that include true positive (TP), false positive (FP), false negative (FN), sensitivity (SE) and positive predictivity (PP). The statistically difference is significant among the PCA data fusion method and the EDR methods based on the RR intervals and the RS amplitudes, showing that PCA data fusion algorithm outperforms the others in the extraction of respiratory signals from single-lead ECGs. PMID- 29260406 TI - Feasibility study for production and quality control of Yb-175 as a byproduct of no carrier added Lu-177 preparation for radiolabeling of DOTMP. AB - Skeletal uptake of beta- emitters of DOTMP complexes is used for the bone pain palliation. In this study, two moderate energy beta- emitters, 177Lu (T1/2 = 6.7 days, Ebetamax = 497 keV) and 175Yb (T1/2 = 4.2 days, Ebetamax = 480 keV), are considered as potential agents for the development of the bone-seeking radiopharmaceuticals. Since the specific activity of the radiolabelled carrier molecules should be high, the non-carrier-added (NCA) radionuclides have an effective role in nuclear medicine. Many researchers have presented the synthesis of NCA 177Lu. Among these separation techniques, extraction chromatography has been considered more capable than other methods. In this study, a new approach, in addition to production of NCA 177Lu by EXC procedure is using pure 175Yb that was usually considered as a waste material in this method but because of high radionuclidic purity of 175Yb produced by this method we used it for radiolabeling as well as NCA 177Lu. To obtain optimum conditions, some effective factors on separation of Lu/Yb by EXC were investigated. The NCA 177Lu and pure 175Yb were produced with radionuclidic purity of 99.99 and 99.97% respectively by irradiation of enriched 176Yb target in thermal neutron flux of 5 * 1013 n/cm2 s for 14 days. 177Lu-DOTMP and 175Yb-DOTMP were obtained with high radiochemical purities (> 95%) under optimized reaction conditions. Two radiolabeled complexes exhibited excellent stability at room temperature. Biodistribution studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation of activity in other non-target organs for two radiolabelled complexes. PMID- 29260407 TI - Does thiol-disulphide balance show oxidative stress in different MEFV mutations? AB - Many studies have shown that oxidative stress levels increase in patients with Familial Mediterranean Fever (FMF). Thiols are a class of compounds that include a sulfhydryl group (-SH) and can react with free oxygen radicals to protect tissues. We aimed to investigate thiol-disulphide homeostatic status in FMF patients and examined the effect of different mutations in the MEFV gene on the thiol-disulphide balance. We investigated thiol-disulphide parameters in patients with FMF and healthy controls. To determine the differential effect of MEFV gene mutations on thiol-disulphide balance, subjects were divided into five groups based on homozygous or compound heterozygous exon 10 and nonexon 10 mutations. Tests of thiol-disulphide homeostasis were conducted using the automated spectrophotometric method. Patients with FMF had significantly lower native thiol [433.8 umol/l (243.3-536.4) vs. 484.1 umol/L (340.2-612.3), p < 0.001], total thiol levels [459.7 umol/L (281.3-575.4) vs. 529.9 umol/L (363-669.5), p < 0.001], and disulphide levels [14.0 umol/l (2.7-33.3) vs. 24.4 umol/l (7.2-36.6), p < 0.001] compared to the control group. Moreover, disulphide/native thiol (3.4 +/- 1.7 vs. 4.7 +/- 1.3, p < 0.001) and disulphide/total thiol (3.1 +/- 1.4 vs. 4.3 +/- 1.0 p < 0.001) were also detected lower in the FMF group compared to the control group. But the native thiol/total thiol ratios (93.6 +/- 2.9 vs. 91.3 +/- 2.1, p < 0.001) were higher in the FMF group. There was no significant difference between the native thiol, total thiol, and disulphide levels of individuals with nonexon 10 homozygous or compound heterozygous (Group 1), nonexon 10-exon 10 compound heterozygous (Group 2), exon 10 homozygous or compound heterozygous (Group 3), and heterozygous (Group 4) mutations. However, these parameters significantly differed from those of the healthy control group. Since no differences were found in our study between thiol and disulfide levels of Groups 1, 2 and 3, we believe that this rate cannot be shown as an indicator of oxidative damage in different mutations of FMFs. To the best of our knowledge, this study is the first study that demonstrates the effect of different FMF mutations on the thiol-disulphide balance. PMID- 29260408 TI - Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives. AB - This article describes the practical considerations in the clinical medical treatment in dementia with Lewy body (DLB) patients. It is illustrated with the voice of a DLB sufferer and his wife. According to our experience, emanating from a 15 year collaboration between a doctor and a nurse at a memory clinic, there are several possible therapeutical entrances. However, the order in which the medication is introduced is of great importance to avoid aggravation of other DLB symptoms. We start the treatment with cholinesterase inhibitor and memantine, and; thereafter, we treat the most disturbing symptom. Thereafter, we consider if orthostatic hypotension is present and treat it. In the treatment of depression and anxiety it is beneficial to use agents affecting both noradrenalin and serotonin. Dysphagia may be lethal but can be improved with carbohydrate drinks. These and other aspects are commented upon from our experience and are also reflected in relation to studies evaluating the existing level of evidence. PMID- 29260409 TI - Application of updated guidelines on diastolic dysfunction in patients with severe sepsis and septic shock. AB - BACKGROUND: Left ventricular diastolic dysfunction is suggested to be associated with higher mortality in severe sepsis and septic shock, yet the methods of diagnosis described in the literature are often inconsistent. The recently published 2016 American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) guidelines offer the opportunity to apply a simple pragmatic diagnostic algorithm for the detection of diastolic dysfunction; however, it has not been tested in this cohort. AIMS: We sought to assess the applicability in septic patients of recently published 2016 ASE/EACVI guidelines on diastolic dysfunction compared with the 2009 ASE guidelines. Our hypothesis was that there would be poor agreement in classifying patients. METHODS: Prospective observational study includes patients identified as having severe sepsis and septic shock. Patients underwent transthoracic echocardiography on day 1 and day 3 of their ICU admission. Patients with normal and abnormal (ejection fraction < 52%) systolic function had their diastolic function stratified according to both the 2009 ASE and 2016 ASE/EACVI guidelines. RESULTS: On day 1 echocardiography, of the 62 patients analysed, 37 (60%) had diastolic dysfunction according to the 2016 ASE/EACVI guideline with a further 23% having indeterminate diastolic function, compared to the 2009 ASE guidelines where only 13 (21%) had confirmed diastolic dysfunction with 46 (74%) having indeterminate diastolic dysfunction. On day 3, of the 55 patients studied, 22 patients (40%) were defined as having diastolic dysfunction, with 6 (11%) having indeterminate diastolic dysfunction according to the 2016 ASE/EACVI guidelines, compared to the 2009 guidelines where 11 (20%) were confirmed to have diastolic dysfunction and 41 (75%) had indeterminate diastolic function. Systolic dysfunction was identified in 18 of 62 patients (29%) on day 1 and 18 of 55 (33%) on day 3. These patients were classified as having abnormal diastolic function in 94 and 89% with the 2016 guidelines on day 1 and day 3, respectively, compared with 50 and 28% using the 2009 guidelines. The 2016 guidelines had less patients with indeterminate diastolic function on days 1 and 3 (11 and 6%) compared to the 2009 guidelines (50 and 72%). Normal systolic function was identified in 44 patients on day 1 and 37 on day 3. In this group, abnormal diastolic function was present in 45 and 54% on days 1 and 3 according to the 2016 ASE/EACVI guidelines, compared with 9 and 16% using the 2009 guidelines, respectively. In those with normal systolic function, the 2016 guidelines had less indeterminate patients with 30 and 16% on days 1 and 3, respectively, compared to 84 and 76% in the 2009 guidelines. CONCLUSION: The 2016 ASE/EACVI diastolic function guidelines identify a significantly higher incidence of dysfunction in patients with severe sepsis and septic shock compared to the previous 2009 guidelines. Although the new guidelines seem to be an improvement, issues remain with the application of guidelines using traditional measures of diastolic dysfunction in this cohort. PMID- 29260410 TI - Suprachoroidal drainage with collagen sheet implant- a novel technique for non penetrating glaucoma surgery. AB - PURPOSE: Our purpose was both to introduce the new technique of suprachoroidal drainage with collagen sheet implantation as a novel technique of non-penetrating glaucoma surgery and to present first results of a prospective pilot study. METHODS: A superficial rectangular sclera flap of half-scleral thickness sized 4 * 4.5 mm is dissected anteriorly until clear cornea. Then, a second scleral flap is created underneath the first one sized 3.5x4mm and is cut down full-thickness to the choroid exposing the suprachoroidal space. The flap is then bluntly prepared until the scleral spur is reached. Sharp dissection above the sclera spur exposes Schlemm's canal, which is located directly anteriorly. Schlemm's canal is unroofed, juxtacanalicular meshwork is peeled and the deep flap is cut off at its base. An absorbable collagen sheet (Ologen(r), Dahlhausen, Cologne, Germany) is placed into the suprachoroidal space at the level of the ciliary body, and the superficial sclera flap is sutured tightly to prevent leakage. RESULTS: We prospectively analyzed 65 eyes that underwent suprachoroidal drainage with collagen sheet implantation. Mean reduction of intraocular pressure after 3 months was 35.1% (from 21.0 +/- 4.3 mmHg to 13.5 +/- 3.4 mmHg)(p < 0.01) and after 12 months 35.6% (from 21.0 +/- 4.3 mmHg to 13.5 +/- 3.0 mmHg)(p < 0.01). The number of topical IOP-reducing medication decreased significantly from 3.5 +/ 0.7 to 0.6 +/- 0.9 and to 0.9 +/- 1.1 after 3 and 12 months, respectively (p < 0.01). No serious complications occurred. CONCLUSION: Suprachoroidal drainage with collagen sheet implantation seems to be a safe and effective surgical technique for non-penetrating glaucoma surgery that yields the opportunity of a sufficient IOP reduction for eyes unsuitable for canaloplasty. PMID- 29260412 TI - Inner morphological and chemical differentiation of Boehmeria species. AB - The present study was designed to establish quality control parameters for pharmacognostic evaluation and differentiation of eight locally derived Boehmeria species, B. gracilis, B. nivea, B. pannosa, B. platanifolia, B. quelpaertensis, B. spicata, B. splitgerbera, B. tricuspis, and two varieties named B. japonica var. longispica, B. nivea var. concolor, which have been utilized as the folk medicine, 'Mo-Si-Pool' in Korea. Although the outer morphological study of these species had been reported, there is no pharmacognostical description yet. Therefore, inner morphological evaluation on leaf midrib, petiole and stem of eight Boehmeria species and two varieties was accomplished along with preliminary phytochemical analysis by HPLC-DAD profiling. The microscopic data showed discriminative inner morphological characteristics such as collenchyma cell layer, thickness of cortex and xylem, frequency of druse and hairs, and number of vascular bundles. The HPLC profiles exhibited more than four characteristic peaks. The molecular ions of the four peaks (1-4) were tentatively identified by ESI-MS, and their structures were identified by NMR spectroscopy to be the flavonoids, rutin (1), isoquercetin (2) and kaempferol-3-O-rutinoside (3), and a phenanthroquinolizidine alkaloid, (-)-cryptopleurine (4). While compounds 1 and 2 were detected in all samples, compound 4 was determined only in B. japonica var. longispica, B. pannosa and B. quelpaertensis and B. splitgerbera. These findings provide the initial scientific criteria for proper identification and establishment of standards for use of Boehmeria species in traditional medicine. PMID- 29260411 TI - Malignancy Risk and Recurrence with Psoriasis and its Treatments: A Concise Update. AB - Psoriasis is a common inflammatory cutaneous disease that affects approximately 120 million people worldwide. Systemic treatments have significantly improved disease burden, but concerns persist regarding their association with increased risk of malignancy. Patients with psoriasis have a slightly elevated baseline risk of lymphoproliferative diseases. Studies on methotrexate and cyclosporine, as well as older biological agents such as tumor necrosis factor inhibitors, have found no increased risk of non-cutaneous solid tumors; however, positive associations between cutaneous squamous cell carcinomas and certain therapies have been found. There is conflicting evidence regarding the risk of lymphoma and melanoma. Further studies are needed to determine the long-term safety of newer psoriasis treatments (interleukin [IL]-12/23, IL-17, Janus kinase 1/3, and phosphodiesterase-4 inhibitors), specifically their safety in patients with a history of cancer. This review summarizes the most recent studies on malignancy risk from psoriasis, and its treatments in patients and cancer survivors, with the highest available level of evidence. PMID- 29260413 TI - Berberine protects HK-2 cells from hypoxia/reoxygenation induced apoptosis via inhibiting SPHK1 expression. AB - Renal ischemia reperfusion injury (RIRI) refers to the irreversible damage for renal function when blood perfusion is recovered after ischemia for an extended period, which is common in clinical surgeries and has been regarded as a major risk for acute renal failures (ARF) that is accompanied with unimaginably high morbidity and mortality. Hypoxia during ischemia followed by reoxygenation via reperfusion serves as a major event contributing to cell apoptosis, which has been widely accepted as the vital pathogenesis in RIRI. Preventing apoptosis in renal tubular epithelial cell has been considered as effective method for blocking RIRI. In this paper, we established a hypoxia/reoxygenation (H/R) injury model in human proximal tubular epithelial HK-2 cells. Here, we found increased SPHK1 levels in H/R injured HK-2 cells, which could be significantly down regulated after berberine treatment. Berberine has been reported to exert a protective effect on H/R-induced apoptosis of HK-2 cells. So, in our present study, we planned to investigate whether SPHK1 participated in the anti-apoptosis process of berberine in H/R injured HK-2 cells. Our study confirmed the protective effect of berberine against H/R-induced apoptosis in HK-2 cells through promoting cells viability, inhibiting cells apoptosis, and down regulating p-P38, caspase-3, caspase-9 as well as SPHK1, while up regulating the ratio of Bcl-2/Bax. However, SPHK1 overexpression in HK-2 cells induced severe apoptosis, which can be significantly ameliorated with additional berberine treatment. We concluded that berberine could remarkably prevent H/R-induced apoptosis in HK-2 cells through down-regulating SPHK1 expression levels, and the mechanisms included the suppression of p38 MAPK activation and mitochondrial stress pathways. PMID- 29260415 TI - Critical Appraisal of Multivariable Prognostic Scores in Heart Failure: Development, Validation and Clinical Utility. AB - Optimal management of heart failure requires accurate risk assessment. Many prognostic risk models have been proposed for patient with chronic and acute heart failure. Methodological critical issues are the data source, the outcome of interest, the choice of variables entering the model, the validation of the model in external population. Up to now, the proposed risk models can be a useful tool to help physician in the clinical decision-making. The availability of big data and of new methods of analysis may lead to developing new models in the future. PMID- 29260414 TI - Orthorexic eating behaviors related to exercise addiction and internal motivations in a sample of university students. AB - PURPOSE: This research explored the exercise tendencies and motivations of individuals varying in orthorexia symptomatology. METHOD: Participants were 411 university students, who completed the Eating Habits Questionnaire alongside measures of exercise activity and addiction in Study 1 (a modified version of the Leisure-Time Exercise Questionnaire, the Exercise Addiction Inventory, and the Compulsive Exercise Test) and various exercise motivations in Study 2 (the Behavioural Regulations in Exercise Questionnaire and the Exercise Motivations Inventory-2). RESULTS: Orthorexia symptomatology was positively correlated with aerobic and strength-training exercise levels; all measures of exercise addiction; all measures of internal exercise motivation; and nearly all measures of exercise motivation for the purposes of psychological, social, health, and body improvement. Symptomatology was not significantly related to either measure that specifically assessed external motivation to exercise. CONCLUSION: Individuals high in orthorexia symptomatology are internally driven to exercise for the purposes of improving their physical and mental health, but these strong motivations also lead to exercise addiction characterized by a compulsive need to follow a rigid schedule of intensive exercise even in the face of injury, illness, or other problems. LEVEL OF EVIDENCE: Level V, descriptive cross sectional study. PMID- 29260416 TI - A Resumable Fluorescent Probe BHN-Fe3O4@SiO2 Hybrid Nanostructure for Fe3+ and its Application in Bioimaging. AB - A multifunctional fluorescent probe BHN-Fe3O4@SiO2 nanostructure for Fe3+ was designed and developed. It has a good selective response to Fe3+ with fluorescence quenching and can be recycled using an external magnetic field. With adding EDTA (2.5 * 10-5 M) to the consequent product Fe3+-BHN-Fe3O4@SiO2, Fe3+ can be removed from the complex, and its fluorescence probing ability recovers, which means that this constituted on-off type fluorescence probe could be reversed and reused. At the same time, the probe has been successfully applied for quantitatively detecting Fe3+ in a linear mode with a low limit of detection 1.25 * 10-8 M. Furthermore, the BHN-Fe3O4@SiO2 nanostructure probe is successfully used to detect Fe3+ in living HeLa cells, which shows its great potential in bioimaging detection. PMID- 29260417 TI - The Comprehensive Complication Index: a New Measure of the Burden of Complications After Hyperthermic Intraperitoneal Chemotherapy. AB - BACKGROUND: Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) are complex surgeries with multiple comorbidities. The Clavien-Dindo classification (CDC) is the most commonly used method to report surgical morbidity, but limits it to the highest-grade complication. The Comprehensive Complication Index (CCI) is a score ranging from 0 to 100, calculated using all 30-day complications and their treatment after abdominal surgery. The aim of this study is to assess the CCI's validity in the HIPEC patient population. METHODS: A review of our institutional cytoreduction database from 2009 to 2015 was undertaken. Patient demographics, pathology, Peritoneal Carcinomatosis Index (PCI), complications and their treatments, and length of stay (LOS) were reviewed. The CCI was calculated for each patient. Linear regression was used to assess whether the CCI and CDC were predictors of LOS. RESULTS: Of 157 patients reviewed, 110 (70.1%) underwent HIPEC. The majority were female (77, 66.9%), and the mean age was 53.7 years. Mean PCI was 13.2 [interquartile range (IQR) 7-18]. Median CDC was grade 2 (IQR 0-2), and only 9.8% had CDC of grade 4 or higher. Mean CCI was 21.4, while the median was 20.9 (IQR 0-30.8). Mean LOS was 16.2 days, while the median was 11 days (IQR 8-15 days). The CCI strongly correlated with LOS with coefficient of 0.46 [95% confidence interval (CI) 0.38-0.54, p = 0.000]. CONCLUSIONS: The CCI is an adequate tool to capture all complications and their overall burden in patients having undergone HIPEC. This study shows that the CCI can predict LOS and could be used to quantify and compare the burden of multiple complications. PMID- 29260418 TI - Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant. METHODS: A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease. RESULTS: Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant. CONCLUSIONS: Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved. PMID- 29260419 TI - Comparative Effectiveness of Preoperative Paravertebral Block for Post-Mastectomy Reconstruction: A Systematic Review of the Literature. AB - INTRODUCTION: Paravertebral block (PVB) has emerged as a viable strategy for improving postoperative outcomes in breast surgery; however, it is unclear whether these benefits extend to recipients of post-mastectomy reconstruction (PMR). METHODS: A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Library electronic databases was conducted for all studies matching the a priori inclusion criteria (inception to 1 March 2017). Independent assessment by two reviewers, in stages, of the title/abstract and full text was performed. Data relating to study design, patient characteristics, PVB medications and technique, and outcomes, including pain, opioid consumption, length of stay (LOS), postoperative nausea and vomiting (PONV), and PVB-related complications was abstracted. RESULTS: Of the 1243 identified articles, nine met the inclusion criteria, accounting for 936 patients (PVB, n = 518; non-PVB, n = 418) in two randomized controlled trials (RCT) and seven retrospective cohort studies. Of these studies, six described PVB for prosthetic PMR, and three described PVB for autologous PMR. Overall, there is a subtle trend towards improved pain control, less opioid requirement and shorter LOS, while PONV was largely unchanged in patients receiving PVB for PMR. In two studies, technical failure was reported at 7.4 and 10%, although no study reported a PVB-related complication. Study quality varied, and risk of bias in the included studies was high. Heterogeneity precluded a meta-analysis. CONCLUSIONS: Although recent reports and RCTs advocate for PVB use in PMR, our review highlights significant heterogeneity and knowledge gaps that must be addressed in order for PVB to become part of the optimal anesthetic protocol in PMR. PMID- 29260420 TI - Physical characteristics of players within the Australian Football League participation pathways: a systematic review. AB - BACKGROUND: Australian football (AF) players require endurance, strength, speed, and agility to be successful. Tests assessing physical characteristics are commonly used for talent identification; however, their ability to differentiate between players across the Australian Football League's (AFL) participation pathway remains unclear. The objective of this review was to quantify the physical characteristics of male AF players across the AFL participation pathway. METHODS: A search of databases was undertaken. Studies examining tests of physical performance were included, with 27 meeting the inclusion/exclusion criteria. Study appraisal was conducted using a checklist of selection criteria. RESULTS: The 20-m sprint time was the most reported test, followed by vertical jump (VJ), AFL planned agility, and 20-m multi-stage fitness test (MSFT). The fastest times for 20-m sprint were for Elite AFL players (range 2.94-3.13 s), with local-level players the slowest (3.22-4.06 s). State Junior Under (U) 18s (58-66 cm) had higher jumps than senior players, with the lowest jumps reported for Local U10s (mean 31 cm). No elite-level data were reported for the AFL planned agility or 20-m MSFT. AFL planned agility times were only reported for talent pathway levels, with large performance variability evident across all levels (8.17-9.12 s). Only mean 20-m MSFT scores were reported from Local U10s to National Draft Camp (6.10-13.50 shuttles). CONCLUSIONS: Talent pathway players exhibit similar mean test scores irrespective of the physical test, with the exception of 20-m sprint and VJ. Physical tests can discriminate between local participation level players but are less useful within the AFL talent pathway. PMID- 29260421 TI - Index-based assessment of suitability of water quality for irrigation purpose under Indian conditions. AB - Agriculture is a major sector in India which contributes around 14% of country's gross domestic product (GDP). Being an agriculture-based country, good quality of water for irrigation has been a prime requisite. Highly growing population and accelerated industrial development are causing anthropogenic pollution to both surface and groundwater on one side and geogenic contamination like arsenic, fluoride, high dissolved solids, sodicity, and iron in groundwater on other side. As a result, ensuring safe water quality for the irrigation has become a major challenge to both the central and state governments. The present irrigation water quality standards being followed in India have been set by the Central Pollution Control Board (CPCB) and Central Ground Water Board (CGWB) in the year 2000. These standards are solely based on four parameters, namely electrical conductivity, sodium percentage, sodium absorption ratio, and residual sodium carbonate, which are quite subjective and many times are not capable to exactly decide the quality of irrigation water particularly when there are large variations in the source water quality. Therefore, in the present paper, an indices-based approach is presented for categorization of irrigation water quality. These indices are mathematical equations that transform water quality data into a numeric value, which describes the quality of irrigation water. The proposed irrigation water quality index (IWQI), which is based on 12 parameters, classifies the water into five categories, viz. excellent, good, medium, bad, and very bad in the same manner as given by the CPCB and CGWB. In order to give proper rating to various parameters of the index, weights are computed using Saaty's analytic hierarchy process (AHP)-based multiple criteria decision analysis (MCDA) approach. This approach minimizes the subjectivity in assessment of weights and improves understanding of water quality issues by generating an overall index to describe the status of water quality. The proposed index will be beneficial for the water management authorities in ensuring safe water to the stakeholders. PMID- 29260422 TI - Teaching Recovery Techniques: evaluation of a group intervention for unaccompanied refugee minors with symptoms of PTSD in Sweden. AB - In 2015, a total of 35,369 unaccompanied refugee minors (URMs) sought asylum in Sweden. In a previous study of 208 URMs, we found that 76% screened positive for PTSD. This study aimed to (1) evaluate the indicated prevention program Teaching Recovery Techniques (TRT) in a community setting and describe the program's effects on symptoms of PTSD and depression in URMs; and (2) examine participants' experiences of the program. The study included 10 groups. Methods for evaluation included the Children's Revised Impact of Event Scale (CRIES-8) and the Montgomery-Asberg Depression Rating Scale Self-report (MADRS-S) at baseline and at post-intervention. Qualitative interviews were conducted with 22 participating URMs to elicit their experiences. Pre- and post-measures were available for 46 participants. At baseline, 83% of the participants reported moderate or severe depression and 48% suicidal ideation or plans. Although more than half (62%) of the participants reported negative life events during the study period, both PTSD (CRIES-8) and depression (MADRS-S) symptoms decreased significantly after the intervention (p = 0.017, 95% CI - 5.55; - 0.58; and p < 0.001, 95% CI - 8.94; - 2.88, respectively). The qualitative content analysis resulted in six overall categories: social support, normalisation, valuable tools, comprehensibility, manageability, and meaningfulness when the youth described their experiences of the program, well reflecting TRT's program theory. Overall, results indicate that TRT, delivered in a community setting, is a promising indicated preventive intervention for URMs with PTSD symptoms. This successful evaluation should be followed up with a controlled study. PMID- 29260423 TI - Maghemite Nanoparticles Acts as Nanozymes, Improving Growth and Abiotic Stress Tolerance in Brassica napus. AB - Yttrium doping-stabilized gamma-Fe2O3 nanoparticles were studied for its potential to serve as a plant fertilizer and, through enzymatic activity, support drought stress management. Levels of both hydrogen peroxide and lipid peroxidation, after drought, were reduced when gamma-Fe2O3 nanoparticles were delivered by irrigation in a nutrient solution to Brassica napus plants grown in soil. Hydrogen peroxide was reduced from 151 to 83 MUM g-1 compared to control, and the malondialdehyde formation was reduced from 36 to 26 mM g-1. Growth rate of leaves was enhanced from 33 to 50% growth compared to fully fertilized plants and SPAD-measurements of chlorophyll increased from 47 to 52 suggesting improved agronomic properties by use of gamma-Fe2O3 nanoparticles as fertilizer as compared to chelated iron. PMID- 29260424 TI - Subareolar breast abscess in male patients: a report of two patients with a literature review. AB - BACKGROUND: Subareolar breast abscess (SBA) is a rare infectious disease of the breast in male patients. CASE PRESENTATION: Herein, we report two male patients with SBA. Patient 1 was initially diagnosed with a malignant tumor based on imaging findings; ultrasonography revealed a hypoechoic mass with blood flow. Patient 2 was diagnosed with inflammatory changes to his nipple; ultrasonography findings supported the diagnosis with an irregular hypoechoic mass with blood flow. Both patients received a cytological or histological biopsy preoperatively, which showed an abscess without malignant cells. CONCLUSION: These cases serve as an important reminder to consider complete resection of the tumor including the responsible mammary duct (tumor and duct resection (TDR)) for curative therapy of SBA. PMID- 29260425 TI - Study of the properties of doxorubicin-resistant cells affected by acute leucosis. AB - The stiffness of cell membrane was found to be one of the factors determining resistance of a cell in vitro to antibiotic doxorubicin action. Membranes of surviving cells are negatively charged (-35 - -30 mV) and have high values of stiffness (2.2-5.1 MURa) at the doxorubicin concentrations in the medium of 1-500 MUg/ml. If the drug concentration and exposure time are being increased, only cells with 'soft' membrane (0.25-1 MURa) and positive surface potential (15-29 mV) survive. The data obtained have important prognostic value in studying drug resistance of tumour blood cells and can be used as objective markers of efficiency of the antitumor therapy. PMID- 29260426 TI - The use of prophylactic anticoagulation during induction and consolidation chemotherapy in adults with acute lymphoblastic leukemia. AB - Treatment for acute lymphoblastic leukemia (ALL) in adults confers a high risk of venous thromboembolic (VTE) complications. We describe the implementation and results of prophylactic anticoagulation guidelines in adults (18-50 years) treated on a Dana-Farber Cancer Institute ALL pediatric inspired consortium protocol from 2007 to 2013. A high rate of asparaginase related toxicity events, including thrombosis, resulted in a protocol amendment adding guidelines for prophylactic anticoagulation and a modified asparaginase dose and schedule. After excluding patients with Philadelphia positive ALL, a cohort of 36 patients were treated after the protocol amendment with prophylactic anticoagulation and compared to 49 patients who received no prophylactic anticoagulation. Bleeding complications were not significantly different in those treated with prophylactic anticoagulation compared with those enrolled prior to the amendment (p = 0.26). No patients on prophylactic anticoagulation had grade >= 3 bleeding. Prior to the amendment, the 2 year cumulative incidence of VTE post-induction was 41% compared to 28% while on prophylactic anticoagulation (p = 0.32). The 2 year cumulative incidence pulmonary embolus pre-amendment was 16% compared with 8% post-amendment (p = 0.34). Prophylactic anticoagulation can be safely administered to adults with ALL without increasing the number or severity of bleeding events and, in addition to modifications in the asparaginase regimen, resulted in a reduction in the cumulative incidence of VTE. PMID- 29260427 TI - Efficacy and safety of dabigatran in patients with atrial fibrillation scheduled for transoesophageal echocardiogram-guided direct electrical current cardioversion: a prospective propensity score-matched cohort study. AB - Patients with atrial fibrillation (AF) are predisposed to a hypercoagulable state and are at an increased risk for thromboembolic events when undergoing procedures. This study investigated the long-term efficacy and safety of newly initiated anticoagulation with dabigatran versus uninterrupted vitamin K antagonist (VKA) therapy in patients with AF scheduled for transesophageal echocardiogram (TEE)-guided direct electrical current cardioversion (DCC). Consecutive adult patients with persistent AF scheduled to undergo DCC were included in the study. Patients received dabigatran 110 mg or 150 mg twice daily (bid) or VKA at therapeutic doses for at least 3 weeks before and 4 weeks after DCC. All patients underwent anamnestic, clinical, electrocardiographic and echocardiographic evaluation at each follow-up visit, and were followed up for a total period of 2 years. The primary efficacy outcome was the composite of stroke/transient ischaemic attack and systemic embolism. The primary safety outcome was major bleeding. 176 patients receiving dabigatran (77% dabigatran 150 mg bid) were propensity score-matched to 176 patients on VKA therapy. A low incidence of atrial thrombus (0.6%) at TEE was found in both groups (0.6%). The acute cardioversion success rate was 85.1% in the dabigatran group (149/175) and 83.4% in the VKA group (146/175). During the follow-up period, a similar low incidence of thromboembolic events (0.6%) was reported in both groups; the bleeding safety profile tended to favour dabigatran over VKA (1.1% vs 1.7%; P = 0.3). Newly initiated anticoagulation with dabigatran in patients with nonvalvular AF scheduled for TEE-guided DCC seems to be as effective and safe as uninterrupted VKA therapy, during long-term follow up. PMID- 29260428 TI - Parrot Beak Nails Revisited: Case Series and Comprehensive Review. AB - The term "parrot beak nail" describes a morphologic change of the nail plate characterized by excessive forward curvature. It may be associated with systemic disease or, most commonly, occurs as an idiopathic finding complicated by delayed nail plate trimming. The characteristics of parrot beak nails in ten men are described, and the features of this acquired nail deformity are reviewed. Of the ten patients, six presented with concurrent neuropathies that resulted in frequent foot injuries or falls. While the true incidence of parrot beak nails is unknown, this nail deformity occurred in 2.1 % of patients seen by a single physician during a 3-month period. In conclusion, parrot beak nails secondary to poor nail care may lead to functional impairment, tissue injury, and subsequent infections. Therefore, it is important for clinicians to look for these nail lesions on cutaneous examination and recommend frequent nail trimmings to individuals with parrot beak nails. PMID- 29260429 TI - Intraarticular arthrofibrosis of the knee alters patellofemoral contact biomechanics. AB - BACKGROUND: Arthrofibrosis in the suprapatellar pouch and anterior interval can develop after knee injury or surgery, resulting in anterior knee pain. These adhesions have not been biomechanically characterized. METHODS: The biomechanical effects of adhesions in the suprapatellar pouch and anterior interval during simulated quadriceps muscle contraction from 0 to 90 degrees of knee flexion were assessed. Adhesions of the suprapatellar pouch and anterior interval were hypothesized to alter the patellofemoral contact biomechanics and increase the patellofemoral contact force compared to no adhesions. RESULTS: Across all flexion angles, suprapatellar adhesions increased the patellofemoral contact force compared to no adhesions by a mean of 80 N. Similarly, anterior interval adhesions increased the contact force by a mean of 36 N. Combined suprapatellar and anterior interval adhesions increased the mean patellofemoral contact force by 120 N. Suprapatellar adhesions resulted in a proximally translated patella from 0 to 60 degrees , and anterior interval adhesions resulted in a distally translated patella at all flexion angles other than 15 degrees (p < 0.05). CONCLUSIONS: The most important finding in this study was that patellofemoral contact forces were significantly increased by simulated adhesions in the suprapatellar pouch and anterior interval. Anterior knee pain and osteoarthritis may result from an increase in patellofemoral contact force due to patellar and quadriceps tendon adhesions. For these patients, arthroscopic lysis of adhesions may be beneficial. PMID- 29260430 TI - Effect of postoperative radiotherapy on survival in duodenal adenocarcinoma: a propensity score-adjusted analysis of Surveillance, Epidemiology, and End Results database. AB - PURPOSE: The use of adjuvant treatment has not been sufficiently investigated in duodenal adenocarcinoma. This study evaluated the effect of postoperative radiotherapy (PORT) on survival outcomes in this rare malignancy. METHODS: We identified patients who were diagnosed between 2004 and 2013 in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and disease specific survival (DSS) were analyzed before and after propensity score matching. RESULTS: Among the 701 eligible patients, 116 (17%) underwent PORT. There were no significant differences in OS and DSS according to receipt of PORT in the unmatched population (P = 0.982 and 0.496, respectively), whereas the propensity matched analysis showed improved OS and DSS with PORT (P = 0.053 and 0.019, respectively). No receipt of PORT was an independent poor prognostic factor in multivariate analysis of both OS (P = 0.022) and DSS (P = 0.005). The potential survival benefits of PORT were observed in subgroups of T4 stage, larger tumor size, higher lymph node ratio, and total/radical resection. CONCLUSIONS: We provide useful insights into the therapeutic role of PORT in adenocarcinoma of the duodenum. Adjuvant strategy with PORT needs to be considered in locally advanced tumors. PMID- 29260431 TI - E-cigarette and waterpipe use in two adolescent cohorts: cross-sectional and longitudinal associations with conventional cigarette smoking. AB - Alternative tobacco products are increasing in popularity. An important question is whether their use is associated with or even leads to conventional smoking, but large-scale (European) studies are scarce. In two cohorts of Dutch adolescents (Cohort I n = 6819, mean age = 13.8 SD = 1.1, 48.2% female; Cohort II n = 2758, mean age = 17.3 SD = 1.8, 61.3% female), we investigated use of electronic (e)-cigarettes with nicotine, e-cigarettes without nicotine and waterpipe. Generalized estimating equation modelling was conducted with ever conventional smoking as the dependent variable (0 = no, 1 = yes) and ever alternative tobacco use as the independent variable, correcting for clustering within schools, age, sex and education in both cohorts. In a subsample (n = 2100), the association between alternative tobacco use at baseline and conventional smoking 6 months later was tested, taking into account smoking propensity (based on personality, susceptibility to peer pressure and smoking intentions). Ever use prevalence was 13.7% for e-cigarettes with nicotine, 29.4% for e-cigarettes without nicotine and 22.1% for waterpipe in Cohort I and 12.3, 27.6 and 45.3% respectively in Cohort II. Ever smokers had tried alternative tobacco products more often than never smokers. Among never-smoking adolescents at baseline, alternative tobacco use predicted ever smoking 6 months later (e cigarettes with nicotine OR 11.90 95% CI 3.36-42.11; e-cigarettes without nicotine OR 5.36 95% CI 2.73-10.52; waterpipe OR 5.36 95% CI 2.78-10.31). This association was strongest for adolescents with a low baseline risk of smoking. Experimenting with alternative tobacco products is common among Dutch youth. Alternative tobacco use predicts (future) smoking, especially among adolescents with a low smoking propensity. PMID- 29260432 TI - Extracellular expression of a novel beta-agarase from Microbulbifer sp. Q7, isolated from the gut of sea cucumber. AB - A novel endo-type beta-agarase was cloned from an agar-degrading bacterium, Microbulbifer sp. Q7 (CGMCC No. 14061), that was isolated from sea cucumber gut. The agarase-encoding gene, ID2563, consisted of 1800 bp that encoded a 599 residue protein with a signal peptide of 19 amino acids. Sequence analysis suggested that the agarase belongs to the GH16 family. The agarase was expressed in Escherichia coli with a total activity of 4.99 U/mL in fermentation medium. The extracellular enzyme activity accounted for 65.73% of the total activity, which indicated that the agarase can be extracellularly secreted using the wild type signal peptide from Microbulbifer sp. Q7. The agarase exhibited maximal activity at approximately 40 degrees C and pH 6.0. It was stable between pH 6.0 and pH 9.0, which was a much wider range than most of the reported agarases. The agarase was sensitive to some metal ions (Cu2+, Zn2+ and Fe3+), but was resistant to urea and SDS. The agarase hydrolyzed beta-1,4-glycosidic linkages of agarose, primarily yielding neoagarotetraose and neoagarohexaose as the final products. These indicate that this recombinant agarase can be an effective tool for the preparing functional neoagaro-oligosaccharides. PMID- 29260433 TI - Coordinated targeting of MMP-2/MMP-9 by miR-296-3p/FOXCUT exerts tumor suppressing effects in choroidal malignant melanoma. AB - Choroidal melanoma is the most common intraocular tumor in adults, and overexpression of matrix metalloproteinase-2 or matrix metalloproteinase-9 (MMP 2/MMP-9) is associated with angiogenesis and tumor metastasis of the choroidal malignant melanoma (CMM). This study aims to investigate the functions and mechanisms of microRNA or long non-coding RNA-targeted MMP-2/MMP-9 in CMM. We demonstrated that expressions of MMP-2/MMP-9 were increased in CMM tissues and C918 cells in comparison with normal choroidal melanocytes. Bio-informatics prediction and our experiments validated that MMP-2 and MMP-9 were simultaneously targeted by miR-296-3p and FOXC1 promoter upstream transcript (FOXCUT); the latter two exerted tumor-suppressing effects on CMM cells by inhibiting cell proliferation, cell cycle progression, migration, invasion, and induction of cell apoptosis. Furthermore, significant downregulations of miR-296-3p and FOXCUT were found in C918 cells compared with choroidal melanocytes from the unaffected eyes, and a positive correlation was observed between their levels in three cases of eye malignant melanomas. Our data indicated that MMP-2/MMP-9 was coordinately targeted by two non-coding RNAs, miR-296-3p and FOXCUT, which were decreased, and tumor-suppressing factors in CMM. Further study will show the possibility of developing them as therapeutic candidates for CMM. PMID- 29260434 TI - Study of binding interaction of rivaroxaban with bovine serum albumin using multi spectroscopic and molecular docking approach. AB - BACKGROUND: Rivaroxaban is a direct inhibitor of coagulation factor Xa and is used for venous thromboembolic disorders. The rivaroxaban interaction with BSA was studied to understand its PK and PD (pharmacokinetics and pharmacokinetics) properties. Multi-spectroscopic studies were used to study the interaction which included UV spectrophotometric, spectrofluorometric and three dimensional spectrofluorometric studies. Further elucidation of data was done by molecular simulation studies to evaluate the interaction behavior between BSA and rivaroxaban. RESULTS: Rivaroxaban quenched the basic fluorescence of BSA molecule by the process of static quenching since rivaroxaban and BSA form a complex that results in shift of the absorption spectra of BSA molecule. A decline in the values of binding constants was detected with the increase of temperatures (298 308 K) and the binding constants were in range from 1.32 * 105 to 4.3 * 103 L mol 1 indicating the instability of the BSA and rivaroxaban complex at higher temperatures. The data of number of binding sites showed uniformity. The site marker experiments indicated site I (sub-domain IIA) as the principal site for rivaroxaban binding. The thermodynamic study experiments were carried at the temperatures of 298/303/308 K. The ?G0, ?H0 and ?S0 at these temperatures ranged between - 24.67 and - 21.27 kJ mol-1 and the values for ?H0 and ?S0 were found to be - 126 kJ mol-1 and ?S - 340 J mol-1 K-1 The negative value of ?G0 indicating spontaneous binding between the two molecules. The negative values in ?H0 and ?S0 indicated van der Waals interaction and hydrogen bonding were involved during the interaction between rivaroxaban and BSA. CONCLUSIONS: The results of molecular docking were consistent with the results obtained from spectroscopic studies in establishing the principal binding site and type of bonds between rivaroxaban and BSA. PMID- 29260435 TI - Role of serotonin in the intestinal mucosal epithelium barrier in weaning mice undergoing stress-induced diarrhea. AB - Stress-induced diarrhea is a frequent and challenging threat to humans and domestic animals. Serotonin (5-HT) has been shown to be involved in the pathological process of stress-induced diarrhea. However, the role of 5-HT in stress-induced diarrhea remains unclear. A stress-induced diarrhea model was established in 21-day-old ICR weaning mice through an intragastric administration of 0.25 mL of 0.4 g/mL folium sennae and restraint of the hind legs with adhesive tape for 4 h to determine whether 5-HT regulates the mucosal barrier to cause diarrhea. Mice with decreased levels of 5-HT were pretreated with an intraperitoneal injection of 300 mg/kg p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor. After 5 days of treatment, the stress level, body weight and intestinal mucosal morphology indexes were measured. Compared to the controls, the mice with stress-induced diarrhea displayed a stress reaction, with increased corticosterone levels, as well as increased 5-HT-positive cells. However, the mice with stress-induced diarrhea exhibited decreased body weights, villus height to crypt depth ratios (V/C), and Occludin and Claudin1 expression. The PCPA injection reversed these effects in mice with different degrees of stress-induced diarrhea. Based on these findings, inhibition of 5-HT synthesis relieved the stress response and improved the health of the intestinal tract, including both the intestinal absorption capacity, as determined by the villus height and crypt depth, and the mucosal barrier function, as determined by the tight junction proteins of epithelial cell. PMID- 29260436 TI - Perovskite Solar Cells Fabricated by Using an Environmental Friendly Aprotic Polar Additive of 1,3-Dimethyl-2-imidazolidinone. AB - Perovskite solar cells (PSCs) have great potentials in photovoltaics due to their high power conversion efficiency and low processing cost. PSCs are usually fabricated from PbI2/dimethylformamide solution with some toxic additives, such as N-methyl pyrrolidone and hexamethylphosphoramide. Here, we use an environmental friendly aprotic polar solvent, 1,3-dimethyl-2-imidazolidinone (DMI), to fabricate perovskite films. By adding 10 vol% DMI in the precursor solution, high-quality perovskite films with smooth surface are obtained. By increasing annealing temperature from 100 to 130 degrees C, the average grain size of the perovskite increases from ~ 216 to 375 nm. As a result, the efficiency of the PSCs increases from 10.72 to 14.54%. PMID- 29260437 TI - Time perception is not for the faint-hearted? Physiological arousal does not influence duration categorisation. AB - Distortions of duration perception provoked by emotion-induced arousal changes are explained by modifications of an internal clock pace. Yet, uncertainty still abounds regarding whether changes of arousal induced by physical exercise yield such temporal distortions. Here, we report two experiments aiming to test separately the impact of, on the one hand, a physical induction of arousal and, on the other hand, a task delay on duration categorisation. In Experiment 1, participants performed a duration categorisation task before and after heart-rate manipulation (increase, decrease, or no change). Duration overestimation was observed after HR manipulation, irrespective of the condition, implying that changes of physiological arousal alone cannot explain the temporal bias observed. In Experiment 2, participants performed the duration task twice without delay or arousal manipulation, and no overestimation was observed. Together, these results suggest that the overestimation observed in the context of a delayed duration categorisation task is related to a distortion of memorised standard durations caused by time lag rather than by a physiological arousal effect. PMID- 29260438 TI - Novel flat and wide meniscal repair material improves the ultimate load of knot breakage in a porcine trans-capsular meniscal repair model. AB - BACKGROUND: In the meniscal repair procedures, a high ultimate load capacity and low cyclic creep at the repair site are favorable and lead to good biological incorporation of the tear site after surgery. Previous biomechanical tensile tests of the meniscal sutures have identified the suture knot as the weakest point. We hypothesized that the strength of a suture knot depends on the suture shape, and therefore, we compared three differently shaped suture materials composed of the same material and quantity per length. The purpose of this study was to determine whether a novel flat and wide repair material (FWRM), which consists of braided multi-threads that are cross-sectionally flat and wide, improves the ultimate load of knot breakage in a biomechanical experiment using a porcine trans-capsular meniscal repair model. METHODS: Eighteen fresh-frozen porcine knees (n = 6 in each group) were used. A longitudinal tear in the middle segment of the medial meniscus was created and repaired with a trans-capsular inside-out method using the following suture materials: No. 2-0 braided polyester conventional suture, hollow suture, and FWRM. After the separation of the inner segment of the meniscus with leaving, the suture stability of the repaired menisci was biomechanically analyzed with a video camera system for widening after a cyclic load between 5 and 20 N was applied 300 times. Ultimate failure load and stiffness at 5 mm/ min were also analyzed. RESULTS: We found no significant difference in suture widening after cyclic load tests [conventional suture, mean 0.51 mm (S.D. 0.39 mm); hollow suture, mean 0.23 mm (S.D. 0.11 mm); and FWRM, mean 0.54 mm (S.D. 0.08 mm)]. The failure mode in all specimens was knot breakage. Compared with those of the other groups, the ultimate failure load of FWRM was statistically significantly higher in the load-to-failure tests (conventional suture, mean 58.8 N [S.D. 8.25 N]; hollow suture, mean 79.4 N [S.D. 10.2 N]; and FWRM, mean 97.4 N [S.D. 3.65 N]; p < 0.05). CONCLUSION: FWRM improves the ultimate load of knot breakage without altering stability. This material may contribute to safe and stable meniscus repair. PMID- 29260439 TI - Eye Movement Research in the Twenty-First Century-a Window to the Brain, Mind, and More. AB - The study of eye movements not only addresses debilitating neuro-ophthalmological problems but has become an essential tool of basic neuroscience research. Eye movements are a classic way to evaluate brain function-traditionally in disorders affecting the brainstem and cerebellum. Abnormalities of eye movements have localizing value and help narrow the differential diagnosis of complex neurological problems. More recently, using sophisticated behavioral paradigms, measurement of eye movements has also been applied to disorders of the thalamus, basal ganglia, and cerebral cortex. Moreover, in contemporary neuroscience, eye movements play a key role in understanding cognition, behavior, and disorders of the mind. Examples include applications to higher-level decision-making processes as in neuroeconomics and psychiatric and cognitive disorders such as schizophrenia and autism. Eye movements have become valued as objective biomarkers to monitor the natural progression of disease and the effects of therapies. As specific genetic defects are identified for many neurological disorders, ocular motor function often becomes the cornerstone of phenotypic classification and differential diagnosis. Here, we introduce other important applications of eye movement research, including understanding movement disorders affecting the head and limbs. We also emphasize the need to develop standardized test batteries for eye movements of all types including the vestibulo-ocular responses. The evaluation and treatment of patients with cerebellar ataxia are particularly amenable to such an approach. PMID- 29260440 TI - Frequency and prognostic impact of basic critical care echocardiography abnormalities in patients with acute respiratory distress syndrome. AB - BACKGROUND: Among intensive care unit (ICU) patients with acute respiratory distress syndrome (ARDS), apart from acute cor pulmonale (ACP), the frequency and prognostic impact of basic critical care echocardiography (BCCE) abnormalities are not well defined. METHODS: Observational study of patients with ARDS, admitted from September 2012 to May 2014, who underwent BCCE within 48 h of admission to a 20-bed medical ICU. We examined the association of two major BCCE detected abnormalities (left ventricular ejection fraction < 40% and severe ACP) with ICU/hospital mortality and ICU/hospital length of stay. Multivariable models adjusted for age and illness severity. RESULTS: Of 234 patients with ARDS (age 62.3 +/- 14.3 years; 88/37.6% female; APACHE II 26.8 +/- 8.3; 26.5% ICU mortality; 32.1% hospital mortality), 94 (40.2%) had at least one major BCCE detected abnormality. The more common major BCCE abnormality found was severe ACP (28.2%), followed by left ventricular ejection fraction < 40% (16.2%). On multivariate analysis, only severe ACP remained significantly associated with ICU/hospital mortality. Hospital mortality for mild, moderate and severe ARDS was 17.0, 27.9 and 50.0%, respectively (without severe ACP), and was 29.2, 48.3 and 53.8%, respectively (with severe ACP). CONCLUSIONS: BCCE abnormalities were common, but only severe ACP had prognostic significance in ARDS, identifying patients who are at increased risk of ICU and hospital mortality. The presence of severe ACP appears to upstage ARDS severity by one level. PMID- 29260441 TI - Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats. AB - Binge drinking affects the onset and progression of human immunodeficiency virus (HIV)-associated neurological disorders. The HIV-1 transgenic (HIV-1Tg) rat was created with a gag- and pol-deleted HIV-1 viral genome to mimic HIV-infected patients receiving combination anti-retroviral therapy (cART). Docosahexaenoic acid (DHA) is a marine compound that modulates inflammatory responses. Using HIV 1Tg rats subjected to binge exposure to ethanol (EtOH), this study examined whether DHA could reduce the detrimental neurological effects of EtOH and HIV proteins. Young adult male HIV-1Tg and F344 control rats received 4 mL/kg/day saline as a control (Saline group), 20 mg/kg/day DHA (DHA group), 4.8 g/kg/day 52% w/v EtOH (EtOH group), or 4.8 g/kg/day 52% w/v EtOH and 20 mg/kg/d DHA (DHA + EtOH group) by gavage for 5 weeks (n = 6 per group). EtOH was administrated on days 5, 6, and 7 of each week. Locomotor activity (LMA) was assessed using open field tests before and 45, 90, 135, and 180 min after each treatment. Repeated binge EtOH exposure gradually decreased LMA measured before daily treatments in HIV-1Tg and F344 rats, an effect that was reversed by DHA only in the HIV-1Tg rats. Decreased LMA of rats after treatment and under the influence of EtOH was less pronounced, and the reversal effect of DHA did not reach statistical significance. The plasma endotoxin level was significantly higher in HIV-1Tg rats than in F344 rats. IL-6 and IL-18 expression in the striatum was significantly higher in the HIV-1Tg EtOH group than in the F344 EtOH group. DHA significantly decreased the high levels of IL-6, IL-18, and NF-kappaB expression observed in the HIV-1Tg EtOH group. DHA appears to ameliorate inflammation and consequently lessen the reductions in LMA produced by the combination of EtOH and HIV-1 viral proteins. PMID- 29260443 TI - Medulla Oblongata Hemorrhage and Reverse Takotsubo Cardiomyopathy. AB - BACKGROUND: Acute brain injury with strong surges of adrenergic outflow has resulted in takotsubo cardiomyopathy, but there are surprisingly few reports of takotsubo cardiomyopathy after intracranial hemorrhage, and none have been described from hemorrhage within the brainstem. RESULTS: We describe a patient with reverse and reversible cardiomyopathy following a hemorrhage in the lateral medulla oblongata. While it is limited in size, the location of the hemorrhage caused acute systolic failure with left ventricular ejection fraction of 27% and vasopressor requirement for cardiogenic shock and pulmonary edema. There was full recovery after 7 days. METHODS: Detailed case report. CONCLUSION: Hemorrhage into medulla oblongata pressor centers may result in acute, reversible, stress-induced cardiomyopathy, affirming the adrenergic origin of this condition. PMID- 29260442 TI - Cellular senescence in the aging and diseased kidney. AB - The program of cellular senescence is involved in both the G1 and G2 phase of the cell cycle, limiting G1/S and G2/M progression respectively, and resulting in prolonged cell cycle arrest. Cellular senescence is involved in normal wound healing. However, multiple organs display increased senescent cell numbers both during natural aging and after injury, suggesting that senescent cells can have beneficial as well as detrimental effects in organismal aging and disease. Also in the kidney, senescent cells accumulate in various compartments with advancing age and renal disease. In experimental studies, forced apoptosis induction through the clearance of senescent cells leads to better preservation of kidney function during aging. Recent groundbreaking studies demonstrate that senescent cell depletion through INK-ATTAC transgene-mediated or cell-penetrating FOXO4-DRI peptide induced forced apoptosis, reduced age-associated damage and dysfunction in multiple organs, in particular the kidney, and increased performance and lifespan. Senescence is also involved in oncology and therapeutic depletion of senescent cells by senolytic drugs has been studied in experimental and human cancers. Although studies with senolytic drugs in models of kidney injury are lacking, their dose limiting side effects on other organs suggest that targeted delivery might be needed for successful application of senolytic drugs for treatment of kidney disease. In this review, we discuss (i) current understanding of the mechanisms and associated pathways of senescence, (ii) evidence of senescence occurrence and causality with organ injury, and (iii) therapeutic strategies for senescence depletion (senotherapy) including targeting, all in the context of renal aging and disease. PMID- 29260444 TI - Utility of a patient-reported outcome in measuring functional impairment during autologous stem cell transplant in patients with multiple myeloma. AB - BACKGROUND: We aimed to determine the utility of a patient-reported outcome (PRO) as it relates to patient performed testing (PPT) for measuring functional status in multiple myeloma patients after autologous hematopoietic stem cell transplantation (auto-HCT). METHODS: Symptom interference on walking (a PRO) was measured by the MD Anderson Symptom Inventory (MDASI). PPT was assessed via 6-min walk test (6MWT). Mixed effects modeling was used to examine (1) the longitudinal relationship between the MDASI score and 6MWT distance and (2) the MDASI scores between patients who did or did not complete the 6WMT. Receiver operating characteristic (ROC) curve analysis was performed to quantify the construct validity of the PRO by differentiating performance status. RESULTS: Seventy-nine patients were included. Mean 6MWT distance significantly correlated with MDASI walking interference score (PRO) over the first month of auto-HCT (est = 6.09, p = 0.006). There was a significantly higher completion rate for MDASI versus 6MWT at each time point (p < 0.01). Patients who completed the 6MWT reported less interference on walking during the study period (est = 1.61, p < 0.0001). Finally, the PRO demonstrated significant construct validity for measuring functioning status with MDASI-walking against ECOG-PS as the anchor (AUC = 0.77, 95% CI 0.60-0.94, p = 0.003). CONCLUSION: The PRO of MDASI-walking interference is a valid physical functioning measure, correlating with an objective functional measure (6MWT) in MM patients undergoing auto-HCT. As patients with poorer functional status during therapy are less likely to complete PPT, this PRO may offer a more practical quantitative measure of functioning in patients. PMID- 29260445 TI - COSMIN Risk of Bias checklist for systematic reviews of Patient-Reported Outcome Measures. AB - PURPOSE: The original COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was developed to assess the methodological quality of single studies on measurement properties of Patient Reported Outcome Measures (PROMs). Now it is our aim to adapt the COSMIN checklist and its four-point rating system into a version exclusively for use in systematic reviews of PROMs, aiming to assess risk of bias of studies on measurement properties. METHODS: For each standard (i.e., a design requirement or preferred statistical method), it was discussed within the COSMIN steering committee if and how it should be adapted. The adapted checklist was pilot-tested to strengthen content validity in a systematic review on the quality of PROMs for patients with hand osteoarthritis. RESULTS: Most important changes were the reordering of the measurement properties to be assessed in a systematic review of PROMs; the deletion of standards that concerned reporting issues and standards that not necessarily lead to biased results; the integration of standards on general requirements for studies on item response theory with standards for specific measurement properties; the recommendation to the review team to specify hypotheses for construct validity and responsiveness in advance, and subsequently the removal of the standards about formulating hypotheses; and the change in the labels of the four-point rating system. CONCLUSIONS: The COSMIN Risk of Bias checklist was developed exclusively for use in systematic reviews of PROMs to distinguish this application from other purposes of assessing the methodological quality of studies on measurement properties, such as guidance for designing or reporting a study on the measurement properties. PMID- 29260446 TI - Comorbidity amplifies the effects of post-9/11 posttraumatic stress disorder trajectories on health-related quality of life. AB - PURPOSE: The present study aims to examine the impact of physical and mental health comorbidities on the association between post-9/11 posttraumatic stress disorder (PTSD) trajectories over 10 years and health-related quality of life (HRQOL) among 9/11-exposed persons. METHODS: 30,002 responding adult World Trade Center Health Registry enrollees reporting no pre-9/11 PTSD were studied. PTSD trajectories (chronic, delayed, remitted, no PTSD) were defined based on a 17 item PTSD Checklist-Specific to 9/11 across three waves of survey data. Three indicators of poor HRQOL were defined based on CDC HRQOL-4 measures. We computed age-adjusted prevalence of physical and mental health comorbidity (depression/anxiety) by PTSD trajectory and used modified Poisson regression to assess the effect of PTSD trajectory on poor HRQOL prevalence, accounting for comorbidity. RESULTS: Age-adjusted prevalence of overall comorbid conditions was 95.8 and 61.4% among the chronic and no-PTSD groups, respectively. Associations between 9/11-related PTSD trajectories and poor HRQOL were significant and became greater when comorbidity was included. Adjusted prevalence ratios were elevated for fair/poor health status (APR 7.3, 95% CI 6.5, 8.2), >= 14 unhealthy days (4.7; 95% CI 4.4, 5.1), and >= 14 activity limitation days during the last 30 days (9.6; 95% CI 8.1, 11.4) in the chronic PTSD group with physical and mental health comorbidity compared to those without PTSD and comorbidity; similar associations were observed for delayed PTSD. CONCLUSIONS: Ten years post-9/11 physical and mental health comorbidities have a substantial impact on the PTSD trajectories and HRQOL association. The need for early identification and treatment of PTSD and comorbidity should be emphasized to potentially improve HRQOL. PMID- 29260448 TI - Dancing Intercorporeality: A Health Humanities Perspective on Dance as a Healing Art. AB - As a contribution to the burgeoning field of health humanities, this paper seeks to explore the power of dance to mitigate human suffering and reacquaint us with what it means to be human through bringing the embodied practice of dance into dialogue with the work of the French philosopher Maurice Merleau-Ponty. Merleau Ponty's conceptualisation of subjectivity as embodied and of intersubjectivity as intercorporeality frees us from many of the constraints of Cartesian thinking and opens up a new way of thinking about how dance functions as a healing art through its ability to ground and reconnect us with self, world, and others--with our humanity. It is argued that through a Merleau-Pontian framework, we can come to appreciate the true potential of dance as a positive and deeply humanising experience, demonstrating how expressive arts practice understood through the lens of philosophical theory can open up new dimensions of understanding and experience in relation to well-being and self- (and other-) care. PMID- 29260449 TI - Low minute ventilation episodes during anesthesia recovery following intraperitoneal surgery as detected by a non-invasive respiratory volume monitor. AB - An electrical impedance-based noninvasive respiratory volume monitor (RVM) accurately reports minute volume, tidal volume and respiratory rate. Here we used the RVM to quantify the occurrence of and evaluate the ability of clinical factors to predict respiratory depression in the post-anesthesia care unit (PACU). RVM generated respiratory data were collected from spontaneously breathing patients following intraperitoneal surgeries under general anesthesia admitted to the PACU. Respiratory depression was defined as low minute ventilation episode (LMVe, < 40% predicted minute ventilation for at least 2 min). We evaluated for associations between clinical variables including minute ventilation prior to opioid administration and LMVe following the first PACU administration of opioid. Also assessed was a low respiratory rate (< 8 breaths per minute) as a proxy for LMVe. Of 107 patients, 38 (36%) had LMVe. Affected patients had greater intraoperative opioid dose, P = 0.05. PACU opioids were administered to 45 (42.1%) subjects, of which 27 (25.2%) had LMVe (P = 0.42) within 30 min following opioid. Pre-opioid minute ventilation < 70% of predicted normal value was associated with LMVe, P < 0.01, (sensitivity = 100%, specificity = 81%).Low respiratory rate was a poor predictor of LMVe (sensitivity = 11.8%). Other clinical variables (e.g., obstructive sleep apnea) were not found to be predictors of LMVe. Using RVM we identified that mild, clinically nondetectable, respiratory depression prior to opioid administration in the PACU was associated with the development of substantial subsequent respiratory depression during the PACU stay. PMID- 29260447 TI - A review of global outlook on fluoride contamination in groundwater with prominence on the Pakistan current situation. AB - Several million people are exposed to fluoride (F-) via drinking water in the world. Current review emphasized the elevated level of fluoride concentrations in the groundwater and associated potential health risk globally with a special focus on Pakistan. Millions of people are deeply dependent on groundwater from different countries of the world encompassing with an elevated level of fluoride. The latest estimates suggest that around 200 million people, from among 25 nations the world over, are under the dreadful fate of fluorosis. India and China, the two most populous countries of the world, are the worst affected. In Pakistan, fluoride data of 29 major cities are reviewed and 34% of the cities show fluoride levels with a mean value greater than 1.5 mg/L where Lahore, Quetta and Tehsil Mailsi are having the maximum values of 23.60, 24.48, > 5.5 mg/L, respectively. In recent years, however, other countries have minimized, even eliminated its use due to health issues. High concentration of fluoride for extended time period causes adverse effects of health such as skin lesions, discoloration, cardiovascular disorders, dental fluorosis and crippling skeletal fluorosis. This review deliberates comprehensive strategy of drinking water quality in the global scenario of fluoride contamination, especially in Pakistan with prominence on major pollutants, mitigation technologies, sources of pollution and ensuing health problems. Considering these verities, health authorities urgently need to establish alternative means of water decontamination in order to prevent associated health problems. PMID- 29260450 TI - The pressure exerted on the tongue during intubation with simultaneous cervical spine immobilisation: a comparison between four videolaryngoscopes and the Macintosh laryngoscope-a manikin study. AB - Excessive pressures exerted on the tongue during intubation may be associated with serious complications and may make intubation more difficult. The aim of this study was to evaluate five different intubating devices in the hands of experienced anaesthetists during simulated conditions of reduced cervical spine mobility. Forty senior anaesthetists participated in the study (female = 18, male = 22). The mean pressure exerted on the tongue during intubation was recorded with a standard manometer. The overall intubation success rate as well as the difference in exerted pressures between female and male anaesthetists were also assessed. The five studied devices were used by each participant and they were randomly chosen. Each anaesthetists participating in the study had over 15 years of clinical anaesthetic practice. The mean pressure exerted on the tongue during intubation was significantly lower when the videolaryngoscopes (VLs) were used (p < 0.0001 for each of the studied VL). There were failed intubation attempts with all of the studied devices, the highest failure rate was in the Airtraq(r) group, 10 in 40 (25%). Female anaesthetists exerted lower pressures during intubation with all studied devices (except the Airtraq(r)). However, the difference was only significant for the Macintosh laryngoscope (p = 0.0083). The blades of VLs exerted lower pressures on the tongue during intubation than the Macintosh laryngoscope blade. Their use may be associated with less complications. Furthermore, male anaesthetists exerted higher pressures on the soft tissues although this was neither statistically nor clinically significant. There was higher failed intubation rate in the male anaesthetist group. PMID- 29260451 TI - Amyloid beta-Derived Diffusible Ligands (ADDLs) Induce Abnormal Autophagy Associated with Abeta Aggregation Degree. AB - Autophagy is disturbed in Alzheimer's disease (AD) and maintaining normal autophagy homeostasis is a new therapeutic strategy for AD treatment. Amyloid beta-derived diffusible ligands (ADDLs), the most toxic species of which are oligomeric forms of amyloid beta peptide (Abeta) that originate from amyloid beta precursor protein (APP) via autophagy; however, whether ADDLs are involved in autophagy-related AD pathogenesis remains unclear. In this study, we primarily defined the specific subsets of ADDLs, A-0, A-12, A-24, and A-48, which were generated from ADDL aggregation mixtures at different time courses of assembly. The secondary structures of ADDL subsets were detected by circular dichroism (CD). Neuronal or non-neuronal cells were exposed to the subsets of ADDLs in vitro, and then, autophagic markers were detected. Our results first showed that exogenous or endogenous LC3 puncta (autophagosomes) were induced in the cytoplasm of cells exposed to ADDLs and that the LC3 puncta were the strongest with A-24 exposure. Then, the CD spectroscopy data also indicated that the proportion of alpha-helices decreased, whereas the proportion of beta-strands and beta-turns increased during ADDL assembly from 0 to 24 h. In addition, the quantitative Western blot data demonstrated that the ratio of LC3B-II/I was significantly increased, and SQSTM1/p62 decreased over time. Finally, our results indicated that the level of phosphorylated p70 S6 kinase (p-p70 S6 kinase), which is a substrate protein in the MTOR pathway, and the ratio of p-p70 S6 kinase/p70 S6 kinase significantly decreased following A-24 exposure. Taken together, our data suggest that ADDL-induced abnormal autophagy is correlated with Abeta aggregation degree and the MTOR pathway, which might contribute to ADDL-induced AD pathogenesis. PMID- 29260452 TI - Emerging Roles of Sirtuin 6 in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease that is imposing an increasing burden on society. Currently, AD is the leading cause of senile dementia worldwide. Despite the long existence of AD, there is lack of therapies for AD, suggesting that new and effective treatment strategy must be explored. At present, sirtuin pathway has attracted attention from the researchers due to its promising results in laboratory models of aging. In addition, our understanding in the roles of sirtuin 6 in AD has expanded. It has been identified to be involved in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation, which ultimately regulate life span. Recent findings also demonstrate that sirtuin 6 is lacking in AD patients, proposing that it can be a new potential therapeutic target in AD. Therefore, exploring on how sirtuin 6 is related in AD manifestation may accelerate the research of AD further and benefits future AD patients. Keeping that in mind, this review aims to highlight the possible roles of sirtuin 6 in AD manifestation. PMID- 29260453 TI - Hot Genes in Schizophrenia: How Clinical Datasets Could Help to Refine their Role. AB - We investigated the effect of a set of SNPs within 5 genes identified by GWASs as possible risk genes for schizophrenia (SCZ) in two independent samples, comprising 176 SCZ patients and 326 controls of Korean origin and 83 SCZ patients and 194 controls of Italian origin. The PANSS was used to assess psychopathology severity and antipsychotic response (AR). Several clinical features were assessed at recruitment. In the Korean sample, the SP4 gene haplotype rs2282888-rs2237304 rs10272006-rs12673091 (p = 0.02) was associated with SCZ. In the Italian sample, PPP3CC rs11780915 (genotypic: p = 0.006; allelic: p = 0.001) and rs2249098 (genotypic: p = 0.0004; allelic: p = 0.00006) were associated with SCZ, as well as the PPP3CC rs11780915-rs10108011-rs2249098 and the ZNF804A rs7603001-rs1344706 haplotypes (p = 0.03 and p = 0.02). Several RORA variants were associated with AR in both the samples, although only the haplotype rs1020729-rs1871858 in the Korean sample survived to the statistical correction (p = 0.01). Exploratory analyses suggested that: (1) PPP3CC, ST8SIA2, and SP4 genes may modulate psychotic symptoms, and (2) RORA and ZNF804A genes may influence AR. Our results partially support a role for these genes in SCZ and AR. Analyses in well phenotyped samples may help to refine the role of the genes identified by GWASs. PMID- 29260454 TI - Neuroprotective effect of treadmill exercise possibly via regulation of lysosomal degradation molecules in mice with pharmacologically induced Parkinson's disease. AB - Dysfunction of mitophagy, which is a selective degradation of defective mitochondria for quality control, is known to be implicated in the pathogenesis of Parkinson's disease (PD). However, how treadmill exercise (TE) regulates mitophagy-related molecules in PD remains to be elucidated. Therefore, we aimed to investigate how TE regulates alpha-synuclein (alpha-syn)-induced neurotoxicity and mitophagy-related molecules in the nigro-striatal region of 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-mice. Our data showed that TE exhibited a significant restoration of tyrosine hydroxylase and motor coordination with suppression of alpha-syn expression, hallmarks of PD, possibly via up-regulation of lysosomal degradation molecules, LAMP-2 and cathepsin L, with down-regulation of p62, LC3-II/LC3-I ratio, PINK1 and parkin in the substantia nigra of MPTP mice. Therefore, these results suggest that treadmill exercise can be used as a non-invasive intervention to improve the pathological features and maintain a healthier mitochondrial network through appropriate elimination of defective mitochondria in PD. PMID- 29260455 TI - Iodine-Containing Mass-Defect-Tuned Dendrimers for Use as Internal Mass Spectrometry Calibrants. AB - Calibrants based on synthetic dendrimers have been recently proposed as a versatile alternative to peptides and proteins for both MALDI and ESI mass spectrometry calibration. Because of their modular synthetic platform, dendrimer calibrants are particularly amenable to tailoring for specific applications. Utilizing this versatility, a set of dendrimers has been designed as an internal calibrant with a tailored mass defect to differentiate them from the majority of natural peptide analytes. This was achieved by incorporating a tris-iodinated aromatic core as an initiator for the dendrimer synthesis, thereby affording multiple calibration points (m/z range 600-2300) with an optimized mass-defect offset relative to all peptides composed of the 20 most common proteinogenic amino acids. Graphical abstract ?. PMID- 29260457 TI - Correction to: Tocilizumab: A Review in Rheumatoid Arthritis. AB - The article Tocilizumab: A Review in Rheumatoid Arthritis, written by Lesley J. Scott, was originally published Online First without open access. After publication in volume 77, issue 17, pages 1865-1879 F. Hoffmann-La Roche Ltd requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by F. Hoffmann-La Roche Ltd. Further details may be found at http://www.medengine.com/Redeem/68FBF06068F81EA7 . The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. PMID- 29260456 TI - Degradation of the Neonicotinoid Pesticides in the Atmospheric Pressure Ionization Source. AB - During the analysis of neonicotinoid pesticide standards (thiamethoxam, clothianidin, imidacloprid, acetamiprid, and thiacloprid) by mass spectrometry, the degradation of these pesticides (M-C=N-R is degraded into M-C=O, M is the skeleton moiety, and R is NO2 or CN) was observed in the atmospheric pressure ionization interfaces (ESI and APCI). In APCI, the degradation of all the five neonicotinoid pesticides studied took place, and the primary mechanism was in source ion/molecule reaction, in which a molecule of water (confirmed by use of H218O) attacked the carbon of the imine group accompanying with loss of NH2R (R=NO2, CN). For the nitroguanidine neonicotinoid pesticides (R=NO2, including thiamethoxam, clothianidin, and imidacloprid), higher auxiliary gas heater temperature also contributed to their degradation in APCI due to in-source pyrolysis. The degradation of the five neonicotinoid pesticides studied in ESI was not significant. In ESI, only the nitroguanidine neonicotinoid pesticides could generate the degradation products through in-source fragmentation mechanism. The degradation of cyanoamidine neonicotinoid pesticides (R=CN, including acetamiprid and thiacloprid) in ESI was not observed. The degradation of neonicotinoid pesticides in the ion source of mass spectrometer renders some adverse consequences, such as difficulty interpreting the full-scan mass spectrum, reducing the sensitivity and accuracy of quantitative analysis, and misleading whether these pesticides have degraded in the real samples. Therefore, a clear understanding of these unusual degradation reactions should facilitate the analysis of neonicotinoid pesticides by atmospheric pressure ionization mass spectrometry. Graphical Abstract. PMID- 29260458 TI - The Risk of Thrombocytopenia During Valproic Acid Therapy: A Critical Summary of Available Clinical Data. AB - Valproate is an effective anti-epileptic and mood stabilizer drug, but its prescription may be complicated by the development of thrombocytopenia. The purpose of the present manuscript is to provide a critical overview about the risk of thrombocytopenia during treatment with valproate. A search of the main database sources has been conducted to identify relevant papers about the topic. In the studies with a larger sample size (> 150 subjects), thrombocytopenia occurred in 12-18% of subjects receiving treatment with valproate. Advanced age, female gender, and high doses were found to be risk factors for the development of thrombocytopenia during treatment with valproate. Future research is needed to clarify the clinical impact of the occurrence of thrombocytopenia during valproate treatment (e.g., the risk of life-threatening events such as stroke or the development of thrombocytopenia during short- versus long-term administration, or oral versus intravenous formulations). PMID- 29260459 TI - Hospital Admissions due to Dysglycaemia and Prescriptions of Antidiabetic Medications in England and Wales: An Ecological Study. AB - INTRODUCTION: Hypoglycaemia and hyperglycaemia are common adverse events associated with antidiabetic medications. They are also a common cause of hospital admissions for people with diabetes. The objective of the study was to explore the trends in hospital admissions due to hypoglycaemia and hyperglycaemia and in the prescriptions of antidiabetic medications in England and Wales. METHODS: We conducted an observational study during the period 1999-2016. Hospital admission data for patients from all age groups were extracted from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Data on prescriptions of antidiabetic medications were extracted from the Prescription Cost Analysis database from 2004 to 2016. RESULTS: Between 1999 and 2016, the hospital admission rate increased by 173.0% [from 17.2 (95% CI 16.9 17.6) to 47.1 (95% CI 46.5-47.6) per 100,000 persons] for hypoglycaemia and by 147.0% [from 22.8 (95% CI 22.4-23.2) to 56.3 (95% CI 55.7-56.9) per 100,000 persons] for hyperglycaemia. The prescription rate for all antidiabetic medications increased between 2004 and 2016 by 116.0% [from 373.0 (95% CI 373.0 373.0) to 806.0 (95% CI 806.0-806.0) prescriptions per 1000 persons]. There was a parallel increase in the rate of antidiabetic medication prescriptions during the same study period, with correlation coefficients of 0.94 for hypoglycaemia and 0.98 for hyperglycaemia, respectively. CONCLUSIONS: There have been parallel increases in the rate of admissions due to dysglycaemia and the rate of antidiabetic prescriptions in England and Wales. Further analytical studies are required to investigate whether increased admission for dysglycaemia is associated with increased use of antidiabetic medications. PMID- 29260460 TI - Rationale and Design for the J-DISCOVER Study: DISCOVERing the Treatment Reality of Type 2 Diabetes in a Real-World Setting in Japan-A Protocol. AB - INTRODUCTION: It is estimated that 642 million adults worldwide will have diabetes by 2040, with 80-90% of these having type 2 diabetes mellitus (T2DM). While many new antidiabetic agents have been introduced in recent years, approximately 40% of T2DM patients still fail to achieve the recommended target HbA1c of < 7.0%. Furthermore, many patients with T2DM in Japan are treated by practitioners other than diabetes specialists; therefore, the exact treatment patterns of T2DM in Japan are difficult to quantify. AIMS: J-DISCOVER aims to address the lack of data on the management of T2DM by providing real-world data on disease management patterns and associated outcomes in a large number of Japanese T2DM patients who are initiating second-line therapy. DESIGN AND SETTING: Part of the global DISCOVER study program, J-DISCOVER will follow 2000 T2DM patients recruited from 141 sites across Japan who are aged >= 20 years. Recruitment began in September 2014 and follow-up will end in December 2018. The primary objective is to describe the long-term disease management patterns and clinical evolution of patients with T2DM inadequately controlled with a first line antidiabetic therapy who initiate a second-line antidiabetic treatment. We will assess the associations between treatment patterns, including the line of antidiabetic medication used, as well as clinical and patient-reported outcomes. The primary endpoint is the mean change in HbA1c between baseline and at 6, 12, 24, and 36 months in the overall population and for patients receiving each class of second-line antidiabetic treatment. PLANNED OUTPUTS: A peer-reviewed publication reporting real-world results and implications for clinical practice. CONCLUSION: By enrolling and following a large number of patients with T2DM across Japan, J-DISCOVER is expected to provide important real-world clinical data for the development of future T2DM treatment guidelines. FUNDING: AstraZeneca K.K. and Ono Pharmaceutical Co., Ltd., Osaka Japan. CLINICAL TRIAL REGISTRATION: NCT02226822. PMID- 29260461 TI - A role of heme side-chains of human hemoglobin in its function revealed by circular dichroism and resonance Raman spectroscopy. AB - Structural changes of heme side-chains of human adult hemoglobin (Hb A) upon ligand (O2 or CO) dissociation have been studied by circular dichroism (CD) and resonance Raman (RR) spectroscopies. We point out the occurrence of appreciable deformation of heme side-chains like vinyl and propionate groups prior to the out of-plane displacement of heme iron. Referring to the recent fine resolved crystal structure of Hb A, the deformations of heme side-chains take place only in the beta subunits. However, these changes are not observed in the isolated beta chain (beta4 homotetramer) and, therefore, are associated with the alpha-beta inter subunit interactions. For the communications between alpha and beta subunits in Hb A regarding signals of ligand dissociation, possible routes are proposed on the basis of the time-resolved absorption, CD, MCD (magnetic CD), and RR spectroscopies. Our finding of the movements of heme side-chains would serve as one of the clues to solve the cooperative O2 binding mechanism of Hb A. PMID- 29260462 TI - Agglomerated novel spray-dried lactose-leucine tailored as a carrier to enhance the aerosolization performance of salbutamol sulfate from DPI formulations. AB - Spray-drying allows to modify the physicochemical/mechanical properties of particles along with their morphology. In the present study, L-leucine with varying concentrations (0.1, 0.5, 1, 5, and 10% w/v) were incorporated into lactose monohydrate solution for spray-drying to enhance the aerosolization performance of dry powder inhalers containing spray-dried lactose-leucine and salbutamol sulfate. The prepared spray-dried lactose-leucine carriers were analyzed using laser diffraction (particle size), differential scanning calorimetry (thermal behavior), scanning electron microscopy (morphology), powder X-ray diffraction (crystallinity), Fourier transform infrared spectroscopy (interaction at molecular level), and in vitro aerosolization performance (deposition). The results showed that the efficacy of salbutamol sulfate's aerosolization performance was, in part, due to the introduction of L-leucine in the carrier, prior to being spray-dried, accounting for an increase in the fine particle fraction (FPF) of salbutamol sulfate from spray-dried lactose-leucine (0.5% leucine) in comparison to all other carriers. It was shown that all of the spray-dried carriers were spherical in their morphology with some agglomerates and contained a mixture of amorphous, alpha-lactose, and beta-lactose. It was also interesting to note that spray-dried lactose-leucine particles were agglomerated during the spray-drying process to make coarse particles (volume mean diameter of 79 to 87 MUm) suitable as a carrier in DPI formulations. PMID- 29260463 TI - Driving restrictions for Dutch patients with an implantable cardioverter defibrillator : Compliance and associated factors. AB - BACKGROUND: Dutch patients with an implantable cardioverter defibrillator (ICD) are restricted from driving for two months after implantation or shocks. This requires significant lifestyle adjustments and is one of the primary concerns of ICD patients. Previous studies indicated that compliance with the driving restrictions is poor, but insight in socio-demographic, clinical and psychological factors associated with compliance is limited. Hence, this study aimed to explore compliance with the driving restrictions and associated factors in a large sample of Dutch ICD patients. METHOD: Dutch ICD patients (N = 313) completed an elaborative set of questionnaires at time of implantation and at four months after implantation, assessing socio-demographic, psychological and driving-related characteristics. Clinical data were collected from the patients' medical records. RESULTS: A substantial subgroup (28%) of the patient sample (median age 64 (interquartile range = 55-71), 81% male) reported to have been noncompliant with the driving restrictions. Univariate analysis indicated that noncompliant patients more often considered refusing the ICD due to the restrictions, compared to compliant patients (19% versus 10%, p = 0.02). Multivariate analysis showed that the feeling of understanding the reason behind the driving restrictions was associated with better compliance (odds ratio = 2.16, 95% confidence interval 1.02-4.56, p = 0.04). No other socio-demographic, clinical, psychological or driving-related factors were associated with compliance. CONCLUSION: A large number of ICD patients does not comply with the driving restrictions after implantation. This study emphasised the importance of the patient's feeling of understanding the reason behind the restrictions. PMID- 29260464 TI - Veno-arterial extracorporeal membrane oxygenation in addition to primary PCI in patients presenting with ST-elevation myocardial infarction. AB - INTRODUCTION: Primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI) can cause great haemodynamic instability. Veno arterial extracorporeal membrane oxygenation (VA-ECMO) can provide haemodynamic support in patients with STEMI but data on outcome and complications are scarce. METHODS: An in-hospital registry was conducted enrolling all patients receiving VA-ECMO. Patients were analysed for medical history, mortality, neurological outcome, complications and coronary artery disease. RESULTS: Between 2011 and 2016, 12 patients underwent pPCI for STEMI and received VA-ECMO for haemodynamic support. The majority of the patients were male (10/12) with a median age of 63 (47-75) years and 4 of the 12 patients had a history of coronary artery disease. A cardiac arrest was witnessed in 11 patients. The left coronary artery was compromised in 8 patients and 4 had right coronary artery disease. All patients were in Killip class IV. Survival to discharge was 67% (8/12), 1-year survival was 42% (5/12), 2 patients have not yet reached the 1-year survival point but are still alive and 1 patient died within a year after discharge. All-cause mortality was 42% (5/12) of which mortality on ECMO was 33% (4/12). Patient-related complications occurred in 6 of the 12 patients: 1 patient suffered major neurological impairment, 2 patients suffered haemorrhage at the cannula site, 2 patients had limb ischaemia and 1 patient had a haemorrhage elsewhere. There were no VA-ECMO hardware malfunctions. CONCLUSION: VA-ECMO in pPCI for STEMI has a high survival rate and neurological outcome is good, even when the patient is admitted with a cardiac arrest. PMID- 29260465 TI - Don't judge the myocardium by its cover : The incremental value of cardiac magnetic resonance imaging in left ventricular hypertrophy. PMID- 29260467 TI - Morphological, biochemical, and histopathological postmortem ocular indices following subchronic exposure to cadmium and/or lead in a rabbit model. AB - Cadmium (Cd) and lead (Pb) are ubiquitous environmental pollutants. There is a dearth of information on the mutual interaction between the antemortem metal intoxication and the postmortem changes of the eye. Thus, this study aimed to follow the morphological, biochemical, histopathological ocular perturbations and the retinal DNA damage up to 8 h postmortem (PM) in Cd and/or Pb intoxicated rabbits. The animals orally received 5 mg Cd Cl2/kg bw and/or 12.5 mg lead acetate/kg bw for 30 consecutive days. At time of death, eye pupil of different groups had a normal diameter except Pb-intoxicated group had marked myosis. After 8 h of death, different rabbit's eye corneas appeared wrinkled and covered with thin white cloud while the pupils were in the mydriatic stage. Up to 8 h PM, the individual exposure to Cd or Pb resulted in a significant elevation in GGT, urea, K, DNA damage and obvious retinal lesions. However, their co-exposure evoked an antagonistic outcome. The eye of Cd and/or Pb intoxicated rabbit showed mildly degenerated tissue of cornea and sclera and the presence of irregular eosinophilic droplets of variably size in the lens with a gradual degeneration and vacuolization in the different cell layers of retina especially ganglion up to 8 h PM. Also, by increasing post mortem interval (PMI), retinal DNA damage in Cd and/or Pb intoxicated group significantly decreased. It is concluded that Cd and/or Pb intoxication induced ocular alterations which retain the same trend in correlation with PMI as natural deaths except for the retinal DNA damage. Also, the simultaneous exposure to Cd and Pb evoked an antagonistic outcome in the eye. The findings of the current study should be taken into consideration when estimating PMI in areas with high Cd and/or Pb contamination. PMID- 29260469 TI - On possibilities of using global monitoring in effective prevention of tailings storage facilities failures. AB - Protection of common natural goods is one of the greatest challenges man faces every day. Extracting and processing natural resources such as mineral deposits contributes to the transformation of the natural environment. The number of activities designed to keep balance are undertaken in accordance with the concept of integrated order. One of them is the use of comprehensive systems of tailings storage facility monitoring. Despite the monitoring, system failures still occur. The quantitative aspect of the failures illustrates both the scale of the problem and the quantitative aspect of the consequences of tailings storage facility failures. The paper presents vast possibilities provided by the global monitoring in the effective prevention of these failures. Particular attention is drawn to the potential of using multidirectional monitoring, including technical and environmental monitoring by the example of one of the world's biggest hydrotechnical constructions-Zelazny Most Tailings Storage Facility (TSF), Poland. Analysis of monitoring data allows to take preventive action against construction failures of facility dams, which can have devastating effects on human life and the natural environment. PMID- 29260468 TI - What do we know about exposure of Iranians to cadmium? Findings from a systematic review. AB - Cadmium is an important environmental contaminant. High consumption of chemical fertilizers and industrial activities in recent decades has caused people to be worried about exposure to cadmium. There is no policy for environmental and biological monitoring of exposure to cadmium in the general population in Iran. This study was aimed to review cadmium content in consuming foods and biological samples in Iran, systematically. We developed a comprehensive search strategy and used it to search on Web of Science, Scopus, Science Direct, and Scientific Information Database until 28 December 2016. The totals of 285 articles were identified and finally 31 original papers were selected. Cadmium contamination was found in Iranian food groups such as rice, cereal and legumes, canned tuna fish, vegetables, fruit juice, and egg. This study showed that cadmium amount in 75% of the consumed rice samples (domestic and imported) was higher than the maximum limits approved by institute of standards and industrial research of Iran. Lettuce samples in Yazd were recorded the highest concentration of cadmium compared to other studies. In addition, high amount of cadmium was observed in the blood of the general population. Regarding the cadmium contamination in food and blood samples in Iran, policies must be adopted to reduce exposure to cadmium through different matrices as much as possible. PMID- 29260470 TI - Multi-phase transformation model of water quality in the sluice-controlled river reaches of Shayinghe River in China. AB - To better understand the complex transformation mechanisms of pollutants in different phases in sluice-controlled river reaches (SCRRs), a multi-phase transformation model of water quality is proposed. This model mainly describes the interactions of the water body, suspended matter, deposited sediments, and organisms. Mathematical expressions were first derived to describe the mass transportation processes in different phases of the river system. The multi-phase transformation model in SCRRs was then established with defined physical mechanisms. Monitored data from the operation of Huaidian sluice were used to identify and validate the parameters of the transformation model and to simulate the spatial and temporal changes of pollutants in different phases. Four findings were made from the results. Firstly, the concentration values of pollutants in each phase in the upper and lower river reaches of the sluice are affected by flow, mode of sluice operation, and algal growth and enrichment. Secondly, the reaction processes in the upper and lower river reaches of the sluice indicate different dominant mechanisms according to the change in sluice operation. Thirdly, sluice operation leads to stronger exchanges between the water body and external materials because of the increased water disturbance. Fourthly, in the early period of the experiment, changes in the alga concentrations were mainly affected by water movement. In the later period, changes in the alga concentrations were mainly affected by the obstruction of the sluice in the upstream section, while these were affected by flow velocity, flow volume, and changes in nutrient concentration in the downstream section. PMID- 29260471 TI - Effectiveness of a theory-based mobile phone text message intervention for improving protective behaviors of pregnant women against air pollution: a randomized controlled trial. AB - : Health impact of exposure to air pollution is a public health concern. The aim of this study was to investigate an extended parallel process model (EPPM)-based mobile phone text message intervention for improving protective behaviors against air pollution among pregnant women. In this randomized controlled trial (IRCT2016102810804N8), 130 pregnant women were randomly assigned into either experimental or control groups. A valid and reliable questionnaire was used to collect data. Experimental group received mobile phone intervention on a daily basis for 2 months. Control group received usual care, only. Data were analyzed using SPSS 15 applying t test, chi-square, and Wilcoxon and Mann-Whitney U test. Although before intervention, there were no significant differences between different structures of EPPM (P > 0.05), after intervention, there were statistically significant differences between perceived severity, response efficacy, self-efficacy, and protective behaviors between two groups (P < 0.05). Implementing EPPM based-mobile phone intervention could promote protective behaviors against air pollution among pregnant women. The present study might be used as a framework for evidence-based health promotion regarding air pollution risk communication and self-care behaviors. TRIAL REGISTRATION: IRCT2016102810804N8. PMID- 29260472 TI - Environmental and biological monitoring of exposures to VOCs in a petrochemical complex in Iran. AB - Exposure to volatile organic compounds (VOCs) can cause cancers in human. This study aimed to measure the concentration of four VOCs including benzene, styrene, ethylbenzene, and phenol in ambient air of a petrochemical complex in Iran. Also, their urinary metabolites including phenol, mandelic acid (MA), and phenylglyoxylic acid (PGA) in the workers were monitored. Urine samples were collected before and after the 8-h workshift according to the NIOSH methods. They were analyzed by a gas chromatograph coupled with a flame ionization detector (GC FID). High levels of the ambient VOCs were detected in the units of recovery and olefin. The levels of ethylbenzene and phenol were less than the guidelines suggested by NIOSH and ACGIH. However, in some cases, the amounts of benzene and styrene were higher than the guidelines. Excellent positive correlations were observed between VOCs exposure and their urinary metabolites (r 2 > 0.90), except for benzene (r 2 = 0.26). Our finding verified that urinary biomarkers can be applied as bioindicators for ambient exposure to VOCs. There is a risk of exposure to high levels of the pollutants in some of the sites, and it is necessary to adopt some preventive measures to reduce health risk. PMID- 29260473 TI - Safety assessment of gasification biochars using Folsomia candida (Collembola) ecotoxicological bioassays. AB - Biochar is a product of the thermal decomposition of biomass under a limited supply of oxygen and can be deriving from pyrolysis or gasification. As the product is rich in highly recalcitrant carbon, it has been proposed as a soil amendment to improve soil fertility and to stock carbon in soils. However, the contaminant compounds present in biochar could represent potential environmental threats. The gasification biochar is a promising by-product, but its effects on soil microarthropods are still nearly unknown. The aim of this study was to assess, using a prognosis approach, any ecotoxicological consequences of four biochars (conifer, poplar, grape marc, and wheat straw) on the springtail Folsomia candida. This was assessed through a series of tests: an avoidance behavior test, a survival and reproduction test, and a test based on the hatching of eggs. Biochars were tested at different concentrations (pulverized and diluted w/w with an artificial standard soil). The results showed that the springtails did not tend to avoid the biochars' substrates up to the rate of 2-5%, but any higher levels of concentration caused the animals to keep away from it. While mortality was negatively affected only in the grape marc biochar, reproduction was significantly reduced in all biochars considered. The hatching of the eggs was anticipated at even the lowest concentrations of herbaceous biochars, while a severe delay was observed in both concentrations tested of the conifer biochar. The endpoints considered were negatively affected by pH, polycyclic aromatic hydrocarbons, and heavy metals (in order of importance). The findings confirmed the potential adverse effects that gasification biochars could have on soil microarthropods and demonstrated the necessity of introducing these tests into biochar characterization protocols. PMID- 29260474 TI - Arsenic exposure to breast-fed infants: contaminated breastfeeding in the first month of birth. AB - Humans are exposed to heavy metals through ingestion, inhalation, and dermal absorption. Exposure to these chemicals may be possible during lactation. Although breastfeeding has import benefits of physical growth and development of breastfed infants, it may be a source of exposure to toxicants. The present study was conducted to determine infant exposure to the arsenic via breastfeeding. The milk samples were collected from the 150 volunteering mothers three times during the first month of lactation after delivery. The average arsenic concentration in breast milk samples was measured by atomic absorption spectrometer (AAS). The demographic parameters of lactating mothers were collected by a questionnaire and were analyzed using SPSS 18 software. Arsenic was not detectable in 71 of 150 samples (47.3%). The highest arsenic concentration was 3.73 MUg/L, and overall mean of arsenic concentration was 0.87 +/- 0.66 MUg/L. The daily infant intake of arsenic ranged in the 0.01-0.17 MUg/kg of body weight, which is below the limit of daily permissible intake for adults. Our results showed the need to strengthen national food safety programs and to further promote avoidance of unhealthy foods consuming during pregnancy. Most of the study samples had detectable levels of arsenic indicate that there was maternal exposure prior to pregnancy, nevertheless, it is recommended that the toxic metal levels should be regularly monitored in biological environments. PMID- 29260475 TI - Entities contribution to total employment in China after 1978 reforms: urban and rural perspective. AB - The paper specifically looks at the rural-urban interaction and contribution of various entities or agents to the total employment in China, rural China, and urban China. The study concentrated on the total employment after 1978 reforms. The paper looked at the 1978-2004 reform and after 2004 reform. It was revealed that 1978-2004 reform hindered the flow of labor from rural to urban but after 2004 reform promoted the flow of labor force from rural to urban China the development, which resulted in a drastic reduction in the rural labor force. Before the reforms, state- and collective-owned units were the only entities that were employing people in China. Even though private enterprises were allowed after the reforms, the leading role of the state- and collective-owned units persist. State-owned units contribute immensely to the total employment in China and urban employment, but its contribution to employment in rural China is negative. Collective-owned and cooperative units show a positive contribution to employment in rural areas but its contribution to the total employment in China is negative. Units with funds from Hong Kong, Macao, and Taiwan and rural private enterprises also contribute positively to total employment in China. Cooperative units, joint holding corporations Ltd., foreign-funded units, and rural self employed individuals contribute negatively to the total employment in China. Collective-owned and cooperative units contribute negatively to employment in the urban areas. Urban and rural private enterprises and rural self-employed individuals contribute positively to urban employment. PMID- 29260476 TI - The characteristic and influence factors of extinction depth of shallow groundwater on the high-latitude region: a case study on the Sanjiang Plain, northeast China. AB - Accurate estimation of extinction depth of shallow groundwater (EDSG) and identification of its influence factors are important for sustainable management of groundwater resources, ecological protection, and human health in intensively irrigated region. In this study, the ratio of actual groundwater depth and EDSG (RAE) method was used to understand the spatial variability of EDSG in the Sanjiang Plain, one of China's largest grain production bases and China's largest inland freshwater wetland region. The study showed a large spatial variation of EDSG in the region. Spatially, the sites, which were in the northeast and center had the deepest and the shallowest EDSG, whereby, indicate that it has higher and lower pumping potential capacity. Many factors including climate, soil parameters, vegetation and topography affected the EDSG. We also identified an area of 3.86 * 1010 m2, which accounting for 35.3% of the entire Sanjiang Plain, has exceeded the ESGD by over exploited for years. Knowledge of the variation and influence factors of EDSG for a certain plant system and the current shallow groundwater condition in the higher latitude region can be a key to the development of preventive actions for large quantity pumping groundwater and protection regional and sustainable development of irrigated agriculture. PMID- 29260466 TI - Targeting Neuroinflammation to Treat Alzheimer's Disease. AB - Over the past few decades, research on Alzheimer's disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that upon engagement of pattern recognition receptors-induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets. PMID- 29260477 TI - Comprehensive evaluation on low-carbon development of coal enterprise groups. AB - Scientifically evaluating the level of low-carbon development in terms of theoretical and practical significance is extremely important to coal enterprise groups for implementing national energy-related systems. This assessment can assist in building institutional mechanisms that are conducive for the economic development of coal business cycle and energy conservation as well as promoting the healthy development of coal enterprises to realize coal scientific development and resource utilization. First, by adopting systematic analysis method, this study builds low-carbon development evaluation index system for coal enterprise groups. Second, to determine the weight serving as guideline and criteria of the index, analytic hierarchy process (AHP) is applied using integrated linear weighted sum method to evaluate the level of low-carbon development of coal enterprise groups. Evaluation is also performed by coal enterprise groups, and the process comprises field analysis and evaluation. Finally, industrial policies are proposed regarding the development of low-carbon coal conglomerate strategies and measures. This study aims mainly to guide the low-carbon development of coal enterprise groups, solve the problem of coal mining and the destruction of ecological environment, support the conservation of raw materials and various resources, and achieve the sustainable development of the coal industry. PMID- 29260478 TI - Interaction of pesticides with natural and synthetic solids. Evaluation in dynamic and equilibrium conditions. AB - Interactions between pesticides (paraquat, glyphosate, 2,4-D, atrazine, and metsulfuron methyl) and soil organic and inorganic components have been studied in batch experiments by performing adsorption, dissolution, and chemical and photochemical degradation under different conditions. The obtained results confirm that the affinity of a pesticide to the solid surface depends on the nature of both and shows that each reactant strongly affects the mobility of the other one, e.g., anionic pesticides promote the dissolution of the solid humic acid but if this last is retained into the inorganic matrix enhances the adsorption of a cationic pesticide. Adsorption also seems to protect the bonded specie to be chemical degraded, such as shown in two pesticide/clay systems at constant pH. The use of mesoporous silicas could result in a good alternative for pesticide remediation. In fact, the solid shows high adsorption capacity towards paraquat and its modification with TiO2 nanoparticles increases not only the pesticide adsorption but also seems to catalyze its degradation under UV light to less-toxic metabolites. UV-VIS spectroscopy was relevant and novel in such sense. Electrostatic interactions, hydrogen and coordinative bonds formations, surface complexations and hydrophobic associations play a key role in the fate of mentioned pesticides on soil and ground/surface water environments. PMID- 29260479 TI - The hydrogen and oxygen isotopic compositions of precipitation in a forested watershed of the South Qinling Mts., China. AB - The stable isotopic compositions (deltaD and delta18O) of precipitation were firstly investigated from May 2012 to November 2013 in the Jinshui River basin of the South Qinling Mts., China. The local meteoric water lines (LMWLs) based on all daily and monthly precipitation-weighted data were defined as deltaD = 8.32 delta18O + 12.57 (r 2 = 0.957, n = 47, p < 0.001) and deltaD = 8.11 delta18O + 11.59 (r 2 = 0.946, n = 15, p < 0.001), respectively. The fluctuations of daily deuterium excess (d-excess) values indicated the mixing moisture sources from the monsoon circulation during the rainy season and the local moisture recycling during the dry season in the river basin. The monthly precipitation-weighted values of d-excess confirmed the moisture sources and determined the temporal variations in moisture supply for the river basin. The precipitation amount and temperature effects were found to be significant, with amount gradient of - 0.060/00/mm for daily delta18O variability and temperature gradients of - 1.51 and - 0.440/00/ degrees C for daily deltaD and d-excess variability, respectively. However, the isotopes of local precipitation during precipitation events were almost unaffected by relative humidity due to overwhelming recycled moisture at relative humidity > 85%. The results of this research provide an effective method for tracing the local water hydrologic cycle in the South Qinling Mts., China. PMID- 29260480 TI - Natural vs anthropogenic components in sediments from the Po River delta coastal lagoons (NE Italy). AB - The Sacca di Goro and Sacca di Scardovari are two coastal lagoons of the Po River delta facing the northern Adriatic Sea. They are sensitive ecosystems both from the naturalistic and socio-economic point of view, since they are included in a natural park and are high productivity shellfish sites. Bottom sediments from the two lagoons have been analysed for their textural and geochemical (major and trace elements by XRF) composition in order to identify natural backgrounds and anthropogenic inputs. OC, N and delta13COC data have been also carried out by EA IRMS to highlight the association of heavy metals with inorganic or organic sedimentary components. Results show that abundances of siderophile (Cr, Ni, Co) heavy metals in samples from the two lagoons are generally in the range of those recorded in alluvial sediments from the neighbours and are associated with the finest (clayey) fraction. Among chalcophile heavy metals, Pb and Zn display significant enrichments relative to the local geochemical backgrounds suggesting anthropogenic sources. They appear to be preferentially associated with the sedimentary organic matter that, according to the isotopic composition, is mainly formed by the incorporation of different proportions of macroalgae and macrophytes that have a significant bioaccumulation capacity. Taking into consideration that the extent of the algal biomass is sensitive to anthropogenic pressure and climatic changes, the trace element budget of sediments from these lagoons has to be monitored in the future, also to assess the impact of heavy metals on shellfish production. PMID- 29260481 TI - Effect of environmental factors on enhanced adsorption and photocatalytic regeneration of molecular imprinted TiO2 polymers for fluoroquinolones. AB - The molecular imprinting technique combined with photocatalysis was used in the removal of fluoroquinolones. In this study, we prepared molecular imprinted polymers (MIPs) and investigated the adsorption and photocatalytic regeneration performance, followed by the effect of different environmental factors and photoproduct identification. Compared with non-imprinted polymers (NIPs) and P25, MIPs had a better adsorption performance towards norfloxacin with the removal efficiency of 77.1% in 1 h. pH, humic acid, and high valence ions had significant effects on the adsorption performance. Under neutral condition, the adsorption effect of MIPs was better than that of acidic and alkaline condition. The removal efficiency declined to 25.9% when pH reached 11. The removal efficiency gradually improved with the concentration of humic acid increasing. The adsorption efficiency of MIPs in surface water was only 12.6% lower than that of ultrapure water, which indicated that molecular imprinting process improved the anti interference property. The photodegradation rate was 0.114 min-1 when the concentration of norfloxacin was 1 mg L-1. Norfloxacin was oxidized with aldehyde group or hydroxyl. The adsorption removal efficiency of MIPs did not decline apparently after 11 adsorption-photocatalytic regeneration cycles, which suggested that the in-situ regeneration and sustainable use of MIPs were achievable in organic pollutant control. PMID- 29260483 TI - Prophylactic Potential of Synbiotic (Lactobacillus casei and Inulin) in Malnourished Murine Giardiasis: an Immunological and Ultrastructural Study. AB - Giardiasis is a re-emerging infectious disease with outbreaks reported globally specially in children and malnourished individuals leading to malabsorption, growth retardation, and severe diarrhea. Thus, in the present study, prophylactic administration of synbiotic as the functional food was used to assess its antigiardial potential in malnourished murine giardiasis. Interestingly, prior administration of synbiotic (Lactobacillus casei + inulin) even to malnourished Giardia-infected mice led to increased body mass, small intestine mass, lactobacilli counts, and reduced severity of giardiasis as evident by decreased cyst and trophozoite counts. Synbiotic therapy further boosted the innate and acquired immune response resulting into increase in nitric oxide, antigiardial secretory IgA and IgG antibody levels along with IL-6 and IL-10 cytokines, and decreased levels of inflammatory TNF-alpha cytokine in both serum and intestinal fluid in malnourished-synbiotic-Giardia-infected mice compared with malnourished Giardia-infected mice. More specifically, histopathological and scanning electron microscopy analysis of the small intestine also confirmed the modulatory potentials of synbiotic in malnourished-synbiotic-Giardia mice which had less cellular and mucosal damage compared with severely damaged, mummified, and blunted villi in malnourished-Giardia-infected mice. Taken together, this is the first experimental study to report that prior supplementation of synbiotic restored the gut morphology and improved the immune status of the malnourished Giardia-infected mice, and could be considered as the prophylactic adjunct therapy for malnourished individuals. PMID- 29260482 TI - Toxicity of nanotitanium dioxide (TiO2-NP) on human monocytes and their mitochondria. AB - The effect of nanotitanium dioxide (TiO2-NP) in human monocytes is still unknown. Therefore, an understanding of probable cytotoxicity of TiO2-NP on human monocytes and underlining the mechanisms involved is of significant interest. The aim of this study was to assess the cytotoxicity of TiO2-NP on human monocytes. Using biochemical and flow cytometry assessments, we demonstrated that addition of TiO2-NP at 10 MUg/ml concentration to monocytes induced cytotoxicity following 12 h. The TiO2-NP-induced cytotoxicity on monocytes was associated with intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation, and depletion of glutathione. According to our results, TiO2-NP triggers oxidative stress and organelles damages in monocytes which are important cells in defense against foreign agents. Finally, our findings suggest that use of antioxidants and mitochondrial/lysosomal protective agents could be of benefit for the people in the exposure with TiO2-NP. PMID- 29260485 TI - Managing Variant Interpretation Discrepancies in Hereditary Cancer: Clinical Practice, Concerns, and Desired Resources. AB - Variant interpretation is a complex process, and classification may vary between sources. This study aimed to determine the practice of cancer genetic counselors regarding discrepancies in variant interpretation and to identify concerns when counseling these discrepancies. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. The vast majority of counselors (93%) had seen a variant interpretation discrepancy in practice. A large majority (96%) of respondents indicated that they conducted their own research on reported variants. Most respondents cited variant databases as the most common resource utilized in researching variants. Approximately 33% of counselors spent 45 min or more of extra time researching a discrepancy compared to researching a variant with a single classification. When asked how they approached counseling sessions involving variant interpretation discrepancies, the free responses emphasized that counselors considered family history, clinical information, and psychosocial concerns, showing that genetic counselors tailored the session to each individual. Discrepancies in variant interpretation are an ongoing concern for clinical cancer genetic counselors, as demonstrated by the fact that counselors desired further resources to aid in addressing these discrepancies, including a centralized database (89%), guidelines from a major organization (88%), continuing education about the issue (74%), and functional studies (58%). Additionally, most respondents reported that the ideal database would be owned by a non-profit organization (59%) and obtain information directly from laboratories (91%). This investigation was the first to address these discrepancies from a clinical point of view. The study demonstrates that discrepancies in variant interpretation are a concern for clinical cancer genetic counselors and outlines the need for additional support. PMID- 29260484 TI - Breast Cancer Genetics Knowledge and Testing Intentions among Nigerian Professional Women. AB - Genetic testing services for breast cancer are well established in developed countries compared to African populations that bear a disproportionate burden of breast cancer (BC). The objective of this study is to examine the knowledge of professional Nigerian women about BC genetics and their intentions to utilize genetic testing services when it is made available in Nigeria. In this study, 165 lecturers and 189 bankers were recruited and studied using a validated self administered questionnaire. The respondents' mean age was 34.9 years (SD = 10.9), 6.5% had family history of BC, and 84.7% had limited knowledge of breast cancer genetics. The proportion of women with genetic testing intentions for breast cancer was 87.3%. Health care access (OR = 2.35, 95% CI, 1.07-5.13), religion (OR = 3.51, 95% CI, 1.03-11.92), and perceived personal risk if a close relative had breast cancer (OR = 2.31, 95% CI, 1.05-5.08) independently predicted testing intentions. The genetic testing intentions for BC were high despite limited knowledge about breast cancer genetics. Promotion of BC genetics education as well as efforts to make BC genetic testing services available in Nigeria at reduced cost remains essential. PMID- 29260486 TI - An Evidence-Based, Community-Engaged Approach to Develop an Interactive Deliberation Tool for Pediatric Neuromuscular Trials. AB - Duchenne/Becker muscular dystrophy (DBMD) and spinal muscular atrophy (SMA) are rare neuromuscular disorders that present challenges to therapeutic and clinical trial decision making. We developed an interactive, evidence-based online tool designed to encourage thoughtful deliberation of the pros and cons of trial participation and to inform meaningful discussions with healthcare providers. Prior research demonstrates the importance of tool availability at the time each family is considering trial participation, which may be prior to the informed consent process. The tool is intended to be easily modified to other pediatric disease communities. Tool development was informed by prior qualitative research, literature reviews, and stakeholder input. Specific items were derived based on an online exploratory questionnaire of parents whose children participated in a trial for DBMD or SMA to understand motivations for participation. Parent participants in the exploratory survey reported strong impact of altruistic and individual benefit motivations and placed much greater emphasis on anticipated trial benefits than on harms when making participation decisions. We used this data to develop the evidence-based deliberation tool using a community-engaged approach. We initially targeted the tool for DBMD while using SMA survey data to evaluate ease of transition to that population. We conducted two iterative sets of activities to inform development and refinement of the tool: (1) community engagement of key stakeholders and (2) user experience testing. These activities suggest that the tool may increase deliberation and the weighing of benefits and harms. Ongoing evaluation will determine the acceptability and efficacy of this online intervention. PMID- 29260487 TI - Bilingual Cancer Genetic Education Modules for the Deaf Community: Development and Evaluation of the Online Video Material. AB - Health information about inherited forms of cancer and the role of family history in cancer risk for the American Sign Language (ASL) Deaf community, a linguistic and cultural community, needs improvement. Cancer genetic education materials available in English print format are not accessible for many sign language users because English is not their native or primary language. Per Center for Disease Control and Prevention recommendations, the level of literacy for printed health education materials should not be higher than 6th grade level (~ 11 to 12 years old), and even with this recommendation, printed materials are still not accessible to sign language users or other nonnative English speakers. Genetic counseling is becoming an integral part of healthcare, but often ASL users are not considered when health education materials are developed. As a result, there are few genetic counseling materials available in ASL. Online tools such as video and closed captioning offer opportunities for educators and genetic counselors to provide digital access to genetic information in ASL to the Deaf community. The Deaf Genetics Project team used a bilingual approach to develop a 37-min interactive Cancer Genetics Education Module (CGEM) video in ASL with closed captions and quizzes, and demonstrated that this approach resulted in greater cancer genetic knowledge and increased intentions to obtain counseling or testing, compared to standard English text information (Palmer et al., Disability and Health Journal, 10(1):23-32, 2017). Though visually enhanced educational materials have been developed for sign language users with multimodal/lingual approach, little is known about design features that can accommodate a diverse audience of sign language users so the material is engaging to a wide audience. The main objectives of this paper are to describe the development of the CGEM and to determine if viewer demographic characteristics are associated with two measurable aspects of CGEM viewing behavior: (1) length of time spent viewing and (2) number of pause, play, and seek events. These objectives are important to address, especially for Deaf individuals because the amount of simultaneous content (video, print) requires cross-modal cognitive processing of visual and textual materials. The use of technology and presentational strategies is needed that enhance and not interfere with health learning in this population. PMID- 29260488 TI - Feeding behavior of feedlot lambs fed diets containing levels of cassava wastewater. AB - In this study, we evaluated the effects of including cassava wastewater in the diet on the feeding behavior of feedlot lambs in 35 male uncastrated Santa Ines * Dorper crossbred lambs at an approximate age of 3 months, with an average live weight of 20.0 +/- 3.4 kg. Diets were formulated with hay of cassava shoots (roughage) and a concentrate based on corn and soybean, with a roughage:concentrate ratio of 50:50, plus inclusion of cassava wastewater at the levels of 0, 12, 24, 36, or 48 g/kg of the total diet. Feeding behavior was evaluated between the 46th and 52nd days of the experiment. Increasing cassava wastewater levels in the diet reduced (P < 0.05) the intakes (kg/day) of dry matter and neutral detergent fiber as well as the efficiency of rumination (g/cud and g/h) of dry matter and neutral detergent fiber. The other behavioral parameters were not affected by wastewater inclusion in the diet. Therefore, the inclusion of up to 48 g/kg of cassava wastewater on fresh matter of diets is not recommended for feedlot lambs. PMID- 29260489 TI - Virus neutralization technique as a tool to evaluate the virological profile for bovine viral diarrhea virus infection in dairy water buffalo (Bubalus bubalis) herds. AB - Serological evidence shows that the bovine viral diarrhea virus (BVDV) infections are present in Brazilian dairy and beef water buffalo herds. As few reports describe the BVDV infection profile the aim of this study was to evaluate the dynamics of BVDV circulation in Brazilian dairy water buffalo herds through analysis of the seropositivity rate and the titer range of anti-BVDV neutralizing antibodies in a group of animals that are considered sentinels. Blood samples (n = 305) were obtained from unvaccinated, asymptomatic young water buffalos from four dairy herds randomly identified as A (n = 106), B (n = 62), C (n = 119), and D (n = 18). The detection and titration of anti-BVDV neutralizing antibodies were evaluated by the virus neutralization test according to the World Organization for Animal Health. Analysis of the results revealed two distinct epidemiological conditions. The first is represented by herds A and C where high rates of seropositive animals (A = 39.6%; C = 51.3%) and high and very variable antibodies titers suggested active BVDV infection. The other condition is represented by herds B and D with low rates of seropositive animals (B = 8.1%; D = 11.1%) and low and little variable antibodies titers suggesting an epidemiological condition of infection stability. Some variables were observed in herds with a distinct BVDV infection profile. Herds with active infection were big, open herds, and had more management practices. In contrast, the herds with infection stability were small, closed herds with few management practices. These results highlight the importance of evaluation, monitoring, and control of BVDV infection also in dairy water buffalo herds. PMID- 29260490 TI - Growth traits of crossbreds of Ankole with Brown Swiss, Holstein Friesian, Jersey, and Sahiwal cattle in Rwanda. AB - The objective of the study was to compare body weights and growth from birth to 18 months of age of various groups of crossbred cattle born from 1999 to 2007, being crossbreds of Ankole (A) with Brown Swiss (B), Holstein Friesian (F), Jersey (J), and Sahiwal (S). Average weights were 26.5 kg at birth, 161 kg at weaning, and 226 kg at 18 months. Both season and sex significantly affected birth weight (BW), weight at 8 and 18 months (W8 and W18), and average daily gain from weaning to 18 months (ADG18) and, unlike season, sex significantly affected average daily gain to 8 months and weaning age. The general trend was that average daily gain attained a maximum before weaning and thereafter decreased until 18 months. Least square means for AB and AF calves were comparable and significantly differed only for W18 and ADG18. AJ had the lowest BW but was comparable with AS, AJxS, and ASxJ for W8, age-adjusted weaning weight, and W18. Generally, AF was heavier than other breed groups, but the difference was smaller than expected probably because environmental conditions did not allow full expression of genetic potential for growth. PMID- 29260491 TI - Molecular detection of Chlamydophila abortus, Coxiella burnetii, and Mycoplasma agalactiae in small ruminants' aborted fetuses in southern Iran. AB - Abortion in sheep and goats has become increasingly important worldwide because of the significant economic losses and potential zoonotic implication of commonly involved pathogens. Therefore, this cross-sectional study was conducted in southern Iran to detect the Chlamydophila abortus and Coxiella burnetii, as zoonotic pathogens, and Mycoplasma agalactiae, as a neglected abortifacient agent in small ruminants' aborted fetuses, by using polymerase chain reaction (PCR). From a total of 300 aborted fetuses (183 sheep and 117 goats), 46 samples (15.5%) were positive by PCR, 11% for C. abortus, 2% for C. burnetii, and 3% for M. agalactiae. Also, the association of suggested risk factors with abortion due to these bacterial agents was investigated using univariable and multivariable logistic regression. Results of the statistical analysis showed significant association of C. abortus with flock size (OR = 2.82, P = 0.014), season (P < 0.05), and the number of pregnancy in the aborted dam (OR = 2.5, P = 0.05). Our results indicated that C. abortus has a relatively substantial role in small ruminant abortions, and C. burnetii and M. agalactiae are likely important abortifacient agents in our region, too. Regarding veterinary and/or public health importance of these bacterial agents, more attention from veterinary and/or human health services and, maybe, a surveillance system for control and prevention of them are recommended. PMID- 29260492 TI - Excessive Activation of NMDA Receptors Induced Neurodevelopmental Brain Damage and Cognitive Deficits in Rats Exposed to Intrauterine Hypoxia. AB - Intrauterine hypoxia is one of the most common stressors in fetuses, which can lead to abnormal brain development and permanent neurological deficits in adulthood. Neurological disorder excitotoxicity induced by hypoxia or ischemia may involve N-methyl-D-aspartate receptors (NMDARs), which are known to participate in the maturation and plasticity of developmental neurons. Inhibition of NMDARs has been reported to improve neurological outcomes in traumatic brain injuries and Alzheimer's disease. Here, we investigated if antenatal blockade of NMDARs induced by memantine could alleviate neurodevelopmental brain damage and long-term cognitive deficits in intrauterine hypoxia rats. Pregnant rats were assigned to four groups: air control, air + memantine, hypoxia, and hypoxia + memantine. The rats were exposed to hypoxic conditions (FiO2 = 0.095-0.115) for 8 h/day (hypoxia group) or given a daily memantine injection (5 mg/kg, i.p.) before hypoxia exposure from pregnant day 19 (G19) to G20 (hypoxia + memantine group).The influence of NMDARs antenatal blockade by memantine on intrauterine hypoxia-induced brain developmental damage and cognitive function was then studied. Intrauterine hypoxia resulted in decreased fetal body weight, brain weight, cognitive function, hippocampal neuron numbers, and Ki-67 proliferation index in the hippocampus. Memantine preventive treatment in pregnant rats before hypoxia exposure alleviated the aforementioned damage in vivo. Excessive activation of NMDARs contributes to fetal brain developmental damage and cognitive ability impairment induced by intrauterine hypoxia, which could be alleviated by antenatal memantine preventative treatment. PMID- 29260493 TI - Effects of Scopolamine and Melatonin Cotreatment on Cognition, Neuronal Damage, and Neurogenesis in the Mouse Dentate Gyrus. AB - It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment. PMID- 29260494 TI - Developmental Exposure to Low Levels of Ethinylestradiol Affects Play Behavior in Juvenile Female Rats. AB - Juvenile social play contributes to the development of adult social and emotional skills in humans and non-human animals, and is therefore a useful endpoint to study the effects of endocrine disrupters on behavior in animal models. Ethinylestradiol (EE2) is a widely produced, powerful synthetic estrogen that is widespread in the environment mainly because is a component of the contraceptive pill. In addition, fetuses may be exposed to EE2 when pregnancy is undetected during contraceptive treatment. To understand whether exposure to EE2 during gestation or lactation affects social play, we exposed 72 female Sprague-Dawley rats to EE2 or vehicle either during gestation (gestation day (GD) 5 through GD 20) or during lactation (from postnatal day (PND) 1 through PND 21). Two doses of EE2 were used to treat the dams: a lower dose in the range of possible environmental exposure (4 ng/kg/day) and a higher dose equivalent to that received during contraceptive treatment (400 ng/kg/day). Behavioral testing was carried out between PND 40 and 45. A principal component analysis of frequencies of behavioral items observed during play sessions identified three main components: defensive-like play, aggressive-like play, and exploration. Aggressive-like play was significantly increased by both doses of EE2, and the gestational administration was in general more effective than the lactational one. Defensive-like play and exploration were not significantly affected by treatment. This research showed that low and very low doses of EE2 that mimic clinical or environmental exposure during development can affect important aspects of social behavior even during restricted time windows. PMID- 29260495 TI - Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells from Cisplatin-Induced Neurotoxicity by Activating the NGF-Signaling Pathway. AB - Cisplatin is a highly effective chemotherapeutic drug that is toxic to the peripheral nervous system. Findings suggest that axons are early targets of the neurotoxicity of cisplatin. Although many compounds have been reported as neuroprotective, there is no effective treatment against the neurotoxicity of cisplatin. Caffeic acid phenethyl ester (CAPE) is a propolis component with neuroprotective potential mainly attributed to antioxidant and anti-inflammatory mechanisms. We have recently demonstrated the neurotrophic potential of CAPE in a cellular model of neurotoxicity related to Parkinson's disease. Now, we have assessed the neurotrophic and neuroprotective effects of CAPE against cisplatin induced neurotoxicity in PC12 cells. CAPE (10 MUM) attenuated the inhibition of neuritogenesis and the downregulation of markers of neuroplasticity (GAP-43, synapsin I, synaptophysin, and 200-kD neurofilament) induced by cisplatin (5 MUM). This concentration of cisplatin does not affect cell viability, and it was used in order to assess the early neurotoxic events triggered by cisplatin. When a lethal dose of cisplatin was used (IC50 = 32 MUM), CAPE (10 MUM) increased cell viability. The neurotrophic effect of CAPE is not dependent on NGF nor is it additive to the effect of NGF, but it might involve the activation of the NGF high-affinity receptors (trkA). The involvement of other neurotrophin receptors such as trkB and trkC is unlikely. This is the first study to demonstrate the protective potential of CAPE against the neurotoxicity of cisplatin and to suggest the involvement of trkA receptors in the neuroprotective mechanism of CAPE. Based on these findings, the beneficial effect of CAPE on cisplatin-induced peripheral neuropathy should be further investigated. PMID- 29260496 TI - Evaluation of CNTNAP2 gene rs2107856 polymorphism in Turkish population with pseudoexfoliation syndrome. AB - PURPOSE: To investigate rs2107856 single-nucleotide polymorphism (SNP) of CNTNAP2 gene in Turkish population with pseudoexfoliation and to correlate clinical characteristics with the genotypic profile. MATERIALS AND METHODS: Forty-three patients with pseudoexfoliation syndrome (PXS), 46 patients with pseudoexfoliation glaucoma (PXG) and 99 healthy controls were enrolled. Comprehensive ophthalmological examination, central corneal thickness measurement and retinal nerve fiber layer thickness analysis of the peripapillary area were performed. Blood samples of 2 mL with EDTA were obtained and sent for genetic analysis. The role of the detected polymorphism on disease tendency along with the genotype and allele frequencies in each group was evaluated. RESULTS: The mean age of the groups was 70.0 +/- 8.0 (range 51-86) in PXS, 71.2 +/- 8.8 (range 51-93) in PXG and 64.6 +/- 8.3 (range 51-91) in controls. The percentages of homozygote individuals were 11.6, 10.9, 21.2%, and heterozygote individuals were 41.9, 45.7, 42.4% in patients with PXS, PXG and controls, respectively. There was no statistically significant difference between groups in terms of both genotype and allele frequencies of rs2107856 (p = 0.429 and p = 0.178, respectively). Retinal nerve fiber layer thickness did not differ between SNP-positive and SNP negative individuals in PXG, and there was no significant difference between genotype and age, sex, best corrected visual acuity, intraocular pressure, central corneal thickness, cup/disk ratio and retinal nerve fiber layer thickness in any of the groups (p > 0.05). CONCLUSION: rs2107856 SNP of CNTNAP2 gene has no association with PXS and PXG in the evaluated Turkish population. PMID- 29260497 TI - Equine pericardium for tectonic globe repair. AB - PURPOSE: To describe the use of equine pericardium as an off-label temporary emergency treatment of scleral and corneal perforations. METHODS: Three eyes of two male patients aged 34 and 38 years were included, i.e. a case with a history of severe bilateral thermal burn undergoing phacoemulsification complicated by tearing of the main port causing iris exposure and a patient with bilateral corneal perforation secondary to non-infectious corneal melt due to presumed ocular non-steroid anti-inflammatory drug abuse. The equine pericardium patch was soaked in balanced salt solution, trimmed and sutured over the perforated area with interrupted nylon 10-0 sutures. Slit-lamp photographs were taken before and immediately after surgery as well as at 2 and 5 months postoperatively. RESULTS: A watertight closure of the perforation was achieved in both cases. No evidence of infection, severe inflammation, leakage or hypotony was detected throughout the observation period. The first patient developed a pseudopterygium over the pericardium patch 5 months after surgery. The second patient showed at 2 months a bilateral melt of the pericardium and loosening of the sutures. After removal of the latter, a tectonically stable scar was evident in both eyes. CONCLUSION: Equine pericardium offered an effective primary treatment in cases of non infectious globe perforation and may be considered when other materials, e.g. amniotic membrane, corneal or scleral allografts, are not readily available. Further studies may further elucidate the safety and efficacy profile of this biomaterial in ophthalmic surgery. PMID- 29260498 TI - Ocular biometric changes with different accommodative stimuli using swept-source optical coherence tomography. AB - PURPOSE: To evaluate ocular biometric changes with different accommodative stimuli using a new swept-source optical biometer. METHODS: Only the right eye was analyzed. Each subject was measured six times with the IOLMaster 700 swept source optical biometer (Carl Zeiss Meditec, Jena, Germany) with the subject looking at the stimulus shown by the instrument and with the subject looking at a target placed outside the instrument at 0D of vergence. Axial length (AL), anterior chamber depth (ACD), central corneal thickness (CCT), lens thickness (LT), white-to-white (WTW), and keratometry readings (K1 and K2) were evaluated in both cases. To assess if the changes found may affect the intraocular (IOL) power calculation for surgical applications, we have applied some formulae, using the software provided by the optical biometer manufacturer, to the ocular parameters found in both situations for three different types of IOLs. RESULTS: No statistically significant differences were found for AL, CCT, WTW, K1 and K2 between the subject looking at the stimulus of the biometer and looking at the outside target at 0D of vergence (p > 0.05). However, the measurement of ACD revealed a statistically significant reduction of 20 microns (p = 0.03) and, on the contrary, LT increased significantly 30 microns (p = 0.02). ACD and LT changes were highly correlated (R 2 = 0.91). As for the IOL power calculation, in all cases, the mean change was lower than 0.25 D both for IOL power selection and residual refraction. CONCLUSIONS: Although ACD and LT change significantly with different accommodative stimuli measured by swept-source optical biometry, these changes are not clinically relevant. PMID- 29260499 TI - Choroidal osteoma and pattern dystrophy of retinal pigment epithelium. AB - PURPOSE: To describe co-occurrence of choroidal osteoma in a patient with pattern dystrophy of retinal pigment epithelium. METHODS: Clinical case report RESULTS: A young female presented with decreased vision in the right eye due to decalcification of choroidal osteoma. Multimodal imaging including fundus autofluorescence, fluorescein angiography and optical coherence tomography showed features of pattern dystrophy of retinal pigment epithelium that simulates the Stargardt disease. CONCLUSIONS: This co-occurrence of choroidal osteoma and pattern dystrophy is likely to be incidental. Multimodal imaging may help in differentiating pattern dystrophy of retinal pigment epithelium that simulates Stargardt disease from Stargardt disease. PMID- 29260500 TI - Baseline demographics, clinical features, and treatment protocols of 240 patients with optic neuropathy: experiences from a neuro-ophthalmological clinic in the Aegean region of Turkey. AB - PURPOSE: To analyze the demographic patterns, clinical characteristics, and treatment protocols of optic neuropathies. MATERIALS AND METHODS: The hospital data of patients with optic neuropathy admitted to the Department of Neuro ophthalmology in a tertiary referral center in Turkey between January 2010 to January 2017 were retrospectively analyzed. Demographic patterns, clinical features, treatment protocols, and the natural disease courses were assessed. RESULTS: The total number of patients with optic neuropathy seen over this period was 240, which consist of 43 with idiopathic optic neuritis (17.9%), 40 with multiple sclerosis-related optic neuritis (16.7%), 12 with chronic relapsing inflammatory optic neuritis (5.0%), 12 with atypical optic neuritis (5.0%), 11 with neuromyelitis optica spectrum disorders-related optic neuritis (4.6%), 90 with non-arteritic ischemic optic neuropathy (37.5%), 4 with arteritic ischemic optic neuropathy (1.7%), 10 with traumatic optic neuropathy (4.1%), 6 with compressive optic neuropathy (2.5%), and 12 with mitochondrial optic neuropathy [9 with toxic optic neuropathy (3.7%) and 3 with Leber's hereditary optic neuropathy (1.2%)]. There were 101 males (42%) and 139 females (58%). The mean age was 43.34 +/- 15.86 years. CONCLUSION: This study reported the demographics, clinical characteristics, and treatment protocols of optic neuropathies in a neuro-ophthalmology specialty clinic at a tertiary referral center in Turkey during the past decade. The data may be useful in assessing the global status of optic neuropathies. PMID- 29260501 TI - Central corneal thickness and corneal volume changes in eyes with and without pseudoexfoliation after uneventful phacoemulsification. AB - AIM: To investigate the effects of uneventful phacoemulsification on central corneal thickness (CCT) and corneal volume (CV) in pseudoexfoliative eyes during a 3 months postoperative period and compare these changes to eyes without pseudoexfoliation (PEX) syndrome. Another purpose of this study was to compare the CCT measurements done by ultrasound pachymetry (UP) with those done by the Oculus Pentacam. MATERIAL AND METHOD: A total of 42 eyes of 42 consecutive patients with cataracts and PEX syndrome that underwent uneventful phacoemulsification were enrolled in this prospective study. A control group of 42 eyes of 42 patients with cataracts/without PEX was employed for comparison. CV and CCT measurements were obtained preoperatively and at 1 and 3 months postoperatively with the Pentacam. CCT values were also measured with UP. T test and Wilcoxon sign test were used to compare the variables. RESULTS: The mean age of the patients was 72.1 +/- 8.3 and 66.6 +/- 9.6 years in PEX and non-PEX group, respectively. In both groups, there were no significant differences between preoperative and postoperative CV (Fig. 1), CCT by the Pentacam (Fig. 2) and CCT by UP (Fig. 3) values (p > 0.05). CCT measurements obtained by two devices were also similar, and there were no statistically significant differences (p > 0.05). Changes in CV and CCT remained stabile at 3 months postoperatively. CONCLUSION: Eyes with and without PEX syndrome exhibit similar corneal features before and after phacoemulsification. A surgery in early stages of cataracts in PEX syndrome, not only provides a non-complicated surgery, but also leads to a less damaged cornea similar to eyes without PEX. PMID- 29260502 TI - Posttraumatic acute choroidopathy. AB - PURPOSE: To report a case of acute choroidopathy following a blunt ocular trauma. METHODS: Ocular examination included dilated fundus examination and optical coherence tomography enhanced depth imaging (OCT-EDI). PATIENTS: Single-patient case report. CASE REPORT: A 10-year-old boy was referred following a blunt trauma to the right eye. The visual acuity diminished to 20/200 and mild hemorrhage was found in the anterior chamber. The fundoscopy was unremarkable. An OCT-EDI revealed a choroidal thickening and detachment at the macula. Six month later, the choroidal morphology resolved and the visual acuity improved. CONCLUSIONS: This study reported a case of acute choroidopathy associated with temporary thickening of the choroid and separation of the Haller's layer from the sclera. OCT-EDI helped to detect and monitor the morphological changes in the apparently normal-looking macular choroid after ocular trauma. Further case reports with long term follow-up are needed to clarify the clinical impact of posttraumatic acute choroidopathy. PMID- 29260503 TI - Symmetry and its role in the crossmodal correspondence between shape and taste. AB - Despite the rapid growth of research on the crossmodal correspondence between visually presented shapes and basic tastes (e.g., sweet, sour, bitter, and salty), most studies that have been published to date have focused on shape contour (roundness/angularity). Meanwhile, other important features, such as symmetry, as well as the underlying mechanisms of the shape-taste correspondence, have rarely been studied. Over two experiments, we systematically manipulated the symmetry and contours of shapes and measured the influences of these variables on shape-taste correspondences. Furthermore, we investigated a potential underlying mechanism, based on the common affective appraisal of stimuli in different sensory modalities. We replicated the results of previous studies showing that round shapes are associated with sweet taste, whereas angular shapes are associated with sour and bitter tastes. In addition, we demonstrated a novel effect that the symmetry group of a shape influences how it is associated with taste. A significant relationship was observed between the taste and appraisal scores of the shapes, suggesting that the affective factors of pleasantness and threat underlie the shape-taste correspondence. These results were consistent across cultures, when we compared participants from Taiwanese and Western (UK, US, Canada) cultures. Our findings highlight that perceived pleasantness and threat are culturally common factors involved in at least some crossmodal correspondences. PMID- 29260504 TI - Modeling and Control of a Delayed Hepatitis B Virus Model with Incubation Period and Combination Treatment. AB - In this paper, a hepatitis B virus (HBV) model with an incubation period and delayed state and control variables is firstly proposed. Furthermore, the combination treatment is adopted to have a longer-lasting effect than mono therapy. The equilibrium points and basic reproduction number are calculated, and then the local stability is analyzed on this model. We then present optimal control strategies based on the Pontryagin's minimum principle with an objective function not only to reduce the levels of exposed cells, infected cells and free viruses nearly to zero at the end of therapy, but also to minimize the drug side effect and the cost of treatment. What's more, we develop a numerical simulation algorithm for solving our HBV model based on the combination of forward and backward difference approximations. The state dynamics of uninfected cells, exposed cells, infected cells, free viruses, CTL and ALT are simulated with or without optimal control, which show that HBV is reduced nearly to zero based on the time-varying optimal control strategies whereas the disease would break out without control. At last, by the simulations, we prove that strategy A is the best among the three kinds of strategies we adopt and further comparisons have been done between model (1) and model (2). PMID- 29260505 TI - Vancomycin Dosing and Monitoring: Critical Evaluation of the Current Practice. AB - After more than six decades of its use as the mainstay antibiotic for the treatment of multidrug-resistant Gram-positive bacterial infections, dosing and monitoring of vancomycin therapy have not been optimized. The current vancomycin therapeutic guidelines recommend empiric doses of 15-20 mg/kg administered by intermittent infusion every 8-12 h in patients with normal kidney function. Additionally, the guidelines recommend trough concentration of 15-20 mg/L as a therapeutic goal for adult patients with severe infections. This review critically discusses the current guidelines considering the basic pharmacokinetics and pharmacodynamics of vancomycin and the recent published reports from clinical studies. More in-depth discussion will be focused on (1) providing evidence of advantages of administering vancomycin by continuous infusion compared to intermittent infusion; (2) revising the current practice of trough-only monitoring versus the area under concentration-time curve (AUC); and (3) assessing the current practice of weight-based dosing versus AUC-based dosing. Using the gathered information presented in this paper, two user-friendly and scientifically based dosing strategies are proposed to improve the efficiency of vancomycin dosing while avoiding the risk of nephrotoxicity and minimizing the cost of therapeutic drug monitoring. PMID- 29260506 TI - New immunotherapy-based approach in allogeneic hematopoietic stem cell transplantation. PMID- 29260507 TI - Safety and efficacy of daratumumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma. AB - : Daratumumab in combination with bortezomib and dexamethasone (DVd) has demonstrated longer progression-free survival than combination of bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM). In this multicenter, open-label, phase-1 study, the safety, efficacy, and pharmacokinetics (PK) of DVd were evaluated in Japanese patients with RRMM. Eight patients with RRMM aged between 54 and 82 years were enrolled and treated with DVd regimen. Primary endpoints were tolerability and safety. Secondary endpoints were overall response rate (ORR), very good partial response (VGPR) or better, complete response (CR) or better, time to response (TTR), PK, and immunogenicity. All patients (n = 8) experienced Grade >= 3 treatment-emergent adverse events (TEAE), with thrombocytopenia (n = 6, 75%) being the most frequent. Mild Grade <= 2 infusion-related reactions were reported in five patients. Serious TEAEs were herpes zoster, nasopharyngitis, and prostate cancer (n = 1 each). Three dose limiting toxicities were observed in two patients. No death or disease progression was reported as of the study cut-off date. ORR was 100% (2 CRs or better, 2 VGPRs, 4 PRs). The median TTR was 0.9 months. PK profiles were comparable to previous studies. The DVd regimen showed acceptable safety with favorable efficacy in Japanese patients with RRMM. CLINICAL TRIAL REGISTRATION NUMBER: NCT02497378. PMID- 29260508 TI - A Systematic Review of the Cost-Effectiveness of Biologics for Ulcerative Colitis. AB - BACKGROUND: Ulcerative colitis (UC) is a chronic autoimmune inflammation of the colon. The condition significantly decreases quality of life and generates a substantial economic burden for healthcare payers, patients and the society in which they live. Some patients require chronic pharmacotherapy, and access to novel biologic drugs might be crucial for long-term remission. The analyses of cost-effectiveness for biologic drugs are necessary to assess their efficiency and provide the best available drugs to patients. OBJECTIVE: Our aim was to collect and assess the quality of economic analyses carried out for biologic agents used in the treatment of UC, as well as to summarize evidence on the drivers of cost-effectiveness and evaluate the transferability and generalizability of conclusions. METHODS: A systematic database review was conducted using MEDLINE (via PubMed), EMBASE, Cost-Effectiveness Analysis Registry and CRD0. Both authors independently reviewed the identified articles to determine their eligibility for final review. Hand searching of references in collected papers was also performed to find any relevant articles. The reporting quality of economic analyses included was evaluated by two reviewers using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement checklist. We reviewed the sensitivity analyses in cost-effectiveness analyses to identify the variables that may have changed the conclusions of the study. Key drivers of cost-effectiveness were selected by identifying uncertain parameters that caused the highest change of the results of the analyses compared with base case results. RESULTS: Of the 576 identified records, 87 were excluded as duplicates and 16 studies were included in the final review; evaluations for Canada, the UK and Poland were mostly performed. The majority of the evaluations revealed were performed for infliximab (approximately 75% of total volume); however, some assessments were also performed for adalimumab (50%) and golimumab (31%). Only three analyses were conducted for vedolizumab, whereas no relevant studies were found for etrolizumab and tofacitinib. The reporting quality of the included economic analyses was assessed as high, with an average score of 21 points per 24 maximum possible (range 14-23 points according to the ISPOR CHEERS statement checklist). In the case of most analyses, quality-adjusted life-years were used as a clinical outcome, and endpoints such as remission, response and mucosal healing were less common. The higher clinical effectiveness (based on response rates) of biological treatment over non-biological treatments was presented in revealed analyses. The incremental cost-utility ratios for biologics, compared with standard care, varied significantly between the studies and ranged from US$36,309 to US$456,979. The lowest value was obtained for infliximab and the highest for the treatment scheme including infliximab 5 mg/kg and infliximab 10 mg/kg + adalimumab. The change of utility weights and clinical parameters had the most significant influence on the results of the analysis; the variable related to surgery was the least sensitive. CONCLUSIONS: Limited data on the cost-effectiveness of UC therapy were identified. In the majority of studies, the lack of cost-effectiveness was revealed for biologics, which was associated with their high costs. Clinical outcomes are transferable to other countries and could be generalized; however, cost inputs are country-specific and therefore limit the transferability and generalizability of conclusions. The key drivers and variables that showed the greatest effect on the analysis results were utility weights and clinical parameters. PMID- 29260509 TI - Synergistic anticancer effect of panobinostat and topoisomerase inhibitors through ROS generation and intrinsic apoptotic pathway induction in cervical cancer cells. AB - PURPOSE: Various combinations of drugs may be effective in the treatment of different types of cancer. Previously, we have shown that combinations of the histone deacetylase inhibitor panobinostat and the topoisomerase inhibitors topotecan or etoposide act synergistically, but the underlying mode of action has remained unknown. Here, we aimed at uncovering the mechanisms underlying this synergism. METHODS: The effects of (combinations of) panobinostat and topotecan or etoposide on cervical cancer-derived HeLa and SiHa cells were assessed using morphological evaluations, scratch wound healing assays, cell cycle analyses, AO/EB staining assays, Annexin V/PI staining assays, reactive oxygen species (ROS) and mitochondrial membrane potential measurements and Western blotting. RESULTS: We found that combinations of panobinostat and the topoisomerase inhibitors topotecan or etoposide synergistically enhanced the induction of apoptosis in both HeLa and SiHa cells. This enhanced apoptosis induction was found to be mediated through increased ROS production and induction of the mitochondrial apoptotic pathway. We also found that the combination treatment resulted in inhibition of the PI3K/AKT and NF-kappaB pro-survival pathways and in activation of the ERK pathway, which is associated with intrinsic apoptosis. CONCLUSIONS: From our data we conclude that combinations of panobinostat and the topoisomerase inhibitors topotecan or etoposide provoke strong cell death responses in cervical cancer-derived cells via induction of the intrinsic apoptotic pathway. Since this drug combination may potentially be effective in the treatment of cervical cancer, further preclinical investigations are warranted. PMID- 29260510 TI - Interventions for managing taste disturbances. AB - BACKGROUND: The sense of taste is very much essential to the overall health of an individual. It is a necessary component to enjoy one's food, which in turn provides nutrition to an individual. Any disturbance in taste perception can hamper quality of life in such patients by influencing their appetite, body weight and psychological well-being. Taste disorders have been treated using different modalities of treatment and there is no consensus for the best intervention. Hence this Cochrane Review was undertaken. This is an update of the Cochrane Review first published in November 2014. OBJECTIVES: To assess the effects of interventions for the management of patients with taste disturbances. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 4 July 2017); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017 Issue 6) in the Cochrane Library (searched 4 July 2017); MEDLINE Ovid (1946 to 4 July 2017); Embase Ovid (1980 to 4 July 2017); CINAHL EBSCO (1937 to 4 July 2017); and AMED Ovid (1985 to 4 July 2017). The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for trials. Abstracts from scientific meetings and conferences were searched on 25 September 2017. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing any pharmacological agent with a control intervention or any non-pharmacological agent with a control intervention. We also included cross-over trials in the review. DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently, and in duplicate, assessed the quality of trials and extracted data. Wherever possible, we contacted trial authors for additional information. We collected adverse events information from the trials. MAIN RESULTS: We included 10 trials (581 participants), nine of which we were able to include in the quantitative analyses (566 participants). We assessed three trials (30%) as having a low risk of bias, four trials (40%) at high risk of bias and three trials (30%) as having an unclear risk of bias. We only included studies on taste disorders in this review that were either idiopathic, or resulting from zinc deficiency or chronic renal failure.Of these, nine trials with 544 people compared zinc supplements to placebo for patients with taste disorders. The participants in two trials were children and adolescents with respective mean ages of 10 and 11.2 years and the other seven trials had adult participants. Out of these nine, two trials assessed the patient-reported outcome for improvement in taste acuity using zinc supplements (risk ratio (RR) 1.40, 95% confidence interval (CI) 0.94 to 2.09; 119 participants, very low-quality evidence). We meta-analysed for taste acuity improvement using objective outcome (continuous data) in idiopathic and zinc deficient taste disorder patients (standardised mean difference (SMD) 0.44, 95% CI 0.23 to 0.65; 366 participants, three trials, very low-quality evidence). We also analysed one cross-over trial separately using the first half of the results for taste detection (mean difference (MD) 2.50, 95% CI 0.93 to 4.07; 14 participants, very low-quality evidence), and taste recognition (MD 3.00, 95% CI 0.66 to 5.34; 14 participants, very low-quality evidence). We meta-analysed taste acuity improvement using objective outcome (dichotomous data) in idiopathic and zinc-deficient taste disorder patients (RR 1.42, 95% 1.09 to 1.84; 292 participants, two trials, very low-quality evidence). Out of the nine trials using zinc supplementation, four reported adverse events like eczema, nausea, abdominal pain, diarrhoea, constipation, decrease in blood iron, increase in blood alkaline phosphatase, and minor increase in blood triglycerides.One trial tested taste discrimination using acupuncture (MD 2.80, 95% CI -1.18 to 6.78; 37 participants, very low-quality evidence). No adverse events were reported in the acupuncture trial.None of the included trials could be included in the meta analysis for health-related quality of life in taste disorder patients. AUTHORS' CONCLUSIONS: We found very low-quality evidence that was insufficient to conclude on the role of zinc supplements to improve taste acuity reported by patients and very low-quality evidence that zinc supplements improve taste acuity in patients with zinc deficiency/idiopathic taste disorders. We did not find any evidence to conclude the role of zinc supplements for improving taste discrimination, or any evidence addressing health-related quality of life due to taste disorders.We found very low-quality evidence that is not sufficient to conclude on the role of acupuncture for improving taste discrimination in cases of idiopathic dysgeusia (distortion of taste) and hypogeusia (reduced ability to taste). We were unable to draw any conclusions regarding the superiority of zinc supplements or acupuncture as none of the trials compared these interventions. PMID- 29260511 TI - [Construction and Fluorescence Analysis of the Recombinant Listeria ivanovii Strain Expressing Green Fluorescent Protein]. AB - OBJECTIVE: Constructing the recombinant Listeria ivanovii strain expressing green fluorescent protein to provide an important tool for study of Listeria ivanovii. METHODS: The promoter of Listeria monocytogenes Listeriolysin O (phly) and the green fluorescent protein (GFP) gene were fused by SOEing PCR,and then ligated the fusion gene into plasmid pCW to result in recombinant plasmid pCW-phly-GFP. Recombinant plasmid was electroporated into Listeria ivanovii,and fluorescence microscope was used to analyze the expression of GFP. To observe the stability of recombinant plasmid and the stable expression of GFP in Listeria ivanovii,bacteria were cultured in the BHI broth with or without erythromycin for several generations. The stability of recombinant plasmid pCW-phly-GFP and fluorescent protein in each generation of bacteriawas studied by extracting plasmids and observing fluorescence. RESULTS: The exactness of recombinant plasmid pCW-phly-GFP was confirmed with restrictive endonuclease assay and sequence analysis. Under the fluorescence microscope,the green fluorescence was obvious in Listeria ivanovii carried with pCW-phly-GFP. The recombinant plasmid pCW-phly-GFP was stable in Listeria ivanovii and the GFP kept expressing in a high level under the pressure of erythromycin. CONCLUSION: The prokaryotic expression plasmid pCW-phly-GFP containing GFP gene was successfully constructed. Listeria ivanovii carried with the plasmid efficiently expressed GFP. This research provides an important tool for further study of Listeria ivanovii as a vaccine carrier. PMID- 29260512 TI - [Construction and Evaluation of a Novel TB Vaccine Candidate Based on inlB1 Gene Attenuated Listeria ivanovii]. AB - OBJECTIVE: To construct a novel tuberculosis vaccine candidate LIDeltainlB1-Ag85C by knocking out the inlB1 gene of Listeria ivanovii (LI) recombinant strain LI Ag85C,and study the biological characteristics of the attenuated strain in vitro and in vivo. METHODS: Targeting plasmid carrying inlB1 upstream and downstream sequences was constructed and electroporated into LI-Ag85C competent cells. Afterward inlB1 gene was knocked out by homologous recombination. Recombinant attenuated strain LIDeltainlB1-Ag85C and parental strain LI-Ag85C were tested in growth characteristics,hemolyticability,the adhesion and invasion tendency to HepG2 in vitro and the median lethal dose (LD50) for C57BL/6 mice in vivo. RESULTS: Genome sequence of the attenuated tuberculosis vaccine candidate LIDeltainlB1-Ag85C was as expected. The attenuated strain and the parental strain showed the similar growth curve in vitro. The adhesion rates of the two strains were 6.66% and 7.46%,respectively,and the invasion rate of them were 0.031% and 0.042% respectively. LIDeltainlB1-Ag85C seemed having a lower adhesion and invasion rates to HepG2 cells,however the difference had no significance. The hemolytic ability of recombinant strain was the same as to the parental strain. The LD50 of LIDeltainlB1-Ag85C and LI-Ag85C for C57BL/6 mice were 3.2*108 CFU/per mouse and 6.7*107 CFU/per mouse,respectively. LIDeltainlB1-Ag85C showed a significantly decrease in animal virulence. CONCLUSION: A novel tuberculosis vaccine candidate LIDeltainlB1-Ag85C based on attenuated Listeria ivanovii was successfully constructed with a significant decrease in toxicity. PMID- 29260513 TI - [The Study of Methylated Regulation MicroRNA in Pancreatic Carcinoma Cell and Its Effect on Cell Proliferation,Migration and Invasion]. AB - OBJECTIVE: To study the epigenetic regulation of pancreatic carcinoma related microRNA (miR34a,miR34b,miR148a and miR203a) expression by gene promoter methylation,and its effect on the proliferation,migration and invasion of pancreatic carcinoma cells. METHODS: The pancreatic carcinoma cells were divided into two groups:control group and treatment group.Control group was treated with 0 MUmol/L DNA methyltransferase inhibitor 5-Aza-CdR and treatment group was treated with 60 MUmol/L 5-Aza-CdR. The methylation status of microRNA gene promoter regions was detected by MSP (methylation-specific PCR). The microRNAs' expression levels were evaluated by real-time PCR. The CCK-8 assay,wound healing assay and Transwell assay were employed to study the proliferation,migration and invasion of pancreatic carcinoma cells,respectively. RESULTS: The results of MSP showed that the methylated band of the treated group was weaker than that of the untreated group and the unmethylated band of the treated group was stronger than that of the untreated group. Real-time PCR results showed that the relative expression levels of microRNAs in the treatment group were higher than those in the control group ( P<0.05). The CCK-8 assay showed that inhibition rate of the treatment group showed dose-dependent effect with the increase of drug concentration. Wound healing assay showed that the wound healing rate of Treatment group was lower than that of untreated group ( P<0.01). The results of transwell assay showed that the number of migrated cells in the treated group was less than that in the untreated group ( P<0.01). CONCLUSION: Decreased methylation levels in microRNA promoter region caused by 5-Aza-CdR treatment increased the expression of miR34a,miR34b ,miR148a and miR203a,leading to inhibition of the proliferation,migration and invasion of pancreatic carcinoma cells. PMID- 29260514 TI - [Construction of Vectors Expressing Inhibiting Peptides for Nuclear Import and Its Effect on Growth and Migration of HeLa Cell]. AB - OBJECTIVE: To construct the expression vectors for red fluorescent protein fused with inhibiting peptides for nuclear import (Bimax),and explore the location of Bimax and its potential effects on cell proliferation and migration in HeLa cells. METHODS: Two kinds of polynucleotide encoding inhibiting peptides for nuclear import were synthesis respectively and subsequently annealed for inserting into vector pDs-Red-C1. The recombinant plasmids were transfected into competent bacterial DH-5alpha. After transfection,the positive bacteria were picked up for DNA sequencing. The recombinant plasmids pDs-Red-Bimax2,pDs-Red Bimax1 and negative plasmid pDs-Red-C1 were transfected into HeLa cells respectively according to Lipofectamine2000 protocol. After transfection,the expression and location of red fluorescent protein were observed with fluorescence microscope. Furthermore,MTT assay and cell-migration assay were used to detect the proliferation and migration of Bimax transducted cells. RESULTS: DNA sequencing showed that the polynucleotides encoding Bimax1 or Bimax2 were inserted into pDs-Red-C1 vector successfully. After transfected into HeLa cells,the inhibiting peptide induced red fluorescent protein locating in nuclear. Furthermore,either the fusion protein RFP-Bimax1 or RFP-Bimax2 can suppress the proliferation and migration of HeLa cells. CONCLUSION: The expression vectors for red fluorescent protein fused with inhibiting peptides for nuclear import were successfully constructed. In addition,the fusion proteins were expressed and located in nuclear and suppressed the proliferation and migration of tumor cells. PMID- 29260515 TI - [miR-155/BACH1 Signaling Pathway in Human Lung Adenocarcinoma Cell Death Induced by Arsenic Trioxide]. AB - OBJECTIVE: To explore the changes of micro RNA 155 (miR-155),BTB and CNC homologous protein 1 (BACH1),quinone oxidoreductase 1 (NQO1) and heme-oxygenase-1 (HO-1) in the process of arsenic trioxide-induced cell death,and to clarify the relationship between miR-155 and BACH1,providing experimental basis for the sensitivity of arsenic trioxide (ATO) treatment. METHODS: Human lung adenocarcinoma cell line A549 cells were treated with different concentrations of ATO. MTT assay and total antioxidant capacity detection kit were used to determine cell viability and total antioxidant capacity,respectively. BACH1,NQO1 and HO-1 protein expression were probed by Western blot and real-time fluorescence quantitative (qRT-PCR) was utilized to test the miR-155 level. A549 cells were transfected with miR-155 mimic and its negative control,then the expression level of miR-155 was detected by qRT-PCR,and these cells were treated with 20 MUmol/L for 24 h followed by MTT and Western blot detection. RESULTS: 10 MUmol/L ATO significantly reduced the cell viability in A549 cells. 10 MUmol/L and 20 MUmol/L ATO treatment activated BACH1 expression and inhibited miR 155,NQO1 and HO-1 expression,leading to decreased total antioxidant capacity. Importantly,the cell death induced by 20 MUmol/L ATO was significantly decreased in miR-155 mimic transfection cells in comparison with non-transfected cells and miR-155 mimic negative control transfected cells. Moreover,high expression of miR 155 reduced BACH1 activation and increased NQO1 and HO-1 expression in cells treated with 20 MUmol/L ATO ( P<0.05). CONCLUSION: Restraining total antioxidant capacity contributes to ATO induced cell death,the underlying mechanisms may be that ATO can activate BACH1 expression through inhibition of the miR-155 level,leading to subsequent inhibition of NQO1 and HO-1 expression. Taken together,these data suggest that miR-155 and BACH1 could be used as sensitivity targets for ATO treatment in lung cancer. PMID- 29260516 TI - [Effect of Recombinant Antigen Ferritin on DC Induce Immune Response]. AB - OBJECTIVE: To explore the immunoreaction against protoscolex infection by the recombinant ferritin of echinococcus granulosus (rEg.ferritin) immunized mice. METHODS: Bone marrow deriedstem cells (BMDCs) were collected and exposed in different antigens by cell culture and included 6 groups,there were hydatid fluid (HF) group (HF 30 MUg/mL),rEg.ferritin group (rEg.ferritin 1 MUg/mL), rEg.ferritin+LPS group (rEg.ferritin 1 MUg/mL and LPS 100 ng/mL),HF+LPS group (HF 30 MUg/mL and LPS 100 ng/mL),LPS group (LPS 100 ng/mL) and control (not add antigen). Morphology of BMDCs in different groups were detected by scan electron microscope (SEM). Phagocytic-ability,T cell multiplication capability and surface marker expression of BMDCs in different groups were detected by flow cytometry.Cytokines of Th1 [interleukin (IL)-12p70,tumor necrosis factor-alpha (TNF-alpha)] and Th2 (IL-6 and IL-10) in surpernatant of BMDCs in different groups were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: rEg.ferritin or rEg.ferritin+LPS stimulated BMDCs maturation, which the dendrites number of BMDCs in these 2 groups were more and longer than control ,HF and HF+LPS groups ( P<0.05), and induced higher levels of surface molecules major histocompatibility complexII (MHCII),CD80,CD86 and CD40,also had strong ability to induce T cell multiplication than control,HF,HF+LPS groups ( P<0.05),but had weak phagocytosis than HF group,and secreted higher levels of IL-6,IL-12p70,TNF alpha and IL-10 than control group. CONCLUSION: BMDCs are stimulated with rEg.ferritin and became maturation. By activating T cell and releasing more cytokines of Th1 and Th2,rEg.ferrtin can induce BMDCs to produce Th1 and Th2 immunoreaction. PMID- 29260517 TI - [Radix Angelicae Sinensis and Radix Hedysari Enhance Radiosensitivity of Human Liver Cancer Cells to 12C6+Radiation]. AB - OBJECTIVE: To determine the effect of Radix Angelicae Sinensis and Radix Hedysari (RAS-RH) on radiosensitivity of human liver cancer H22 cells to heavy ion 12C6+and its possible mechanism. METHODS: The experiment involved a comparison of proliferation of H22 cells (detected by CCK-8 assay) between four groups: control,drug (RAS-RH),radiation,and combination (RAS-RH+radiation). H22 cells were treated with different doses of radiation alone or radiation followed by RAS RH. The radiation enhancement effect of RAS-RH on H22 was detected by Colony forming assay. The effect of RAS-RH on the apoptosis of H22 cells was detected by flow cytometry. The influence of RAS-RH on the expression levels of related protein Survivin and Caspase-9 was investigated by Western blot. RESULTS: RAS-RH inhibited the proliferation of H22 cells,with a time and dose dependency [inhibitory concentration 20% (IC20)=(117.60+/-2.15) mg/L]. The survival rate of H22 cells decreased significantly with the increase of heavy ion 12C6+. The two survival curves produced by the Graph Pad Prism 5.0 software were clearly separated. The combination group demonstrated smaller shoulder area at low dosage and lower survival rate of cells compared with radiation group,with a sensitization enhancement ratio (SER) of 1.39+/-0.07. The combination group (100 mg/L RAS-RH+2 Gy) had higher apoptosis rate and Caspase-9 protein expression level,and lower Survivin protein expression level,compared with other 3 groups ( P<0.01). CONCLUSION: RAS-RH has radiation sensitization effect on human hepatocellular carcinoma H22 cells. The mechanism may be related to down regulation of Survivin protein expression and up regulation of Caspase-9 protein expression. PMID- 29260518 TI - [Effects of LncRNA H19 on Proliferation of Human Colorectal Cancer SW620 Cells]. AB - OBJECTIVE: To determine the expression level of long non-coding RNA (lncRNA) imprinted maternallyexpressed transcript (H19) in colorectal cancer tissues and its effect on proliferation of colorectal cancer SW620 cells. METHODS: Real-time quantitative PCR (qRT-PCR) was applied to detect the expression of H19 in 20 paired tumor tissues and adjacent normal tissues,and in normal NCM460 cells and colorectal cancer SW480,HCT116 and SW620 cells. The specific small interfering RNA for H19 (si-H19 group) or negative control sequence (si-NC group) were transfected into SW620 cells. Proliferation of the transfected cells was detected using flow cytometry,CCK8 assay and clone formation experiment. The expressions of CyclinD1 and cyclin dependent kinase 4 (CDK4) were detected by qRT-PCR and Western blot. RESULTS: The expression levels of H19 in colorectal cancer tissues and cells were higher compared with those in adjacent normal tissues and normal NCM460 cells. Lower H19 level,cell activities and cell clone numbers were found in si-H19 transfected cells compared with those in si-NC transfected cells ( P<0.05). si-H19transfected cells had decreased expression of CyclinD1 and CDK4 ( P<0.05). CONCLUSION: H19expression in colorectal cancer is high. Knock-down H19 expression can inhibit proliferation of colorectal cancer cells,which provides a potential strategy for targeted therapy of colorectal cancer. PMID- 29260519 TI - [Expression of CLDN1 and Its Nuclear Distribution in Esophageal Squamous Carcinoma]. AB - OBJECTIVE: To determine the expression of tight junction protein CLDN1 in esophageal squamous carcinoma (ESCC) and to explore the effect of CLDN1 on the biological function of ESCC TE-11 cells. METHODS: This study collected 30 ESCC tissues,30 adjacent normal tissues and 30 distal esophageal tissues to detected the expression of CLDN1 in tissue microaary by immunohistochemistry method. Western blot was employed to determine the expression of CLDN1 in 15 ESCC tissues and cell lines,and then the distribution of CLDN1 in tumor cells and normal esophageal epithelial cells was analyzed. Lentivirus containing the sequence of CLDN1 shRNA was constructed and transfected into TE-11 cells,the transfection efficiency and intracellular distribution was determined by Western blot and flow cytometry. Cell proliferation was detected by CCK-8,the invasion and migration ability of cells was determined with Transwell. Cytoskeleton changes was observed by laser scanning confocal microscope. RESULTS: Immunohistochemical results showed no significant difference between the cancer tissues and adjacent tissues in term of the positive rate of CLDN1 ( P>0.05). CLDN1 was highly expressed in highly and moderately differentiated ESCC tissues,but its expression was significantly decreased in poorly differentiated cancer tissues. Western blot revealed that CLDN1 was mainly distributed in the nucleus of TE-11 cells. The proliferation of TE-11 cells,as well as invasion and migration ability,were declined obviously when the expression of CLDN1 being down-regulated,while the cytoskeleton protein fluorescence intensity deceased. CONCLUSION: The expression of CLDN1 in ESCC tissue is associated with its differentiation and may promote carcinogenesis in TE-11 cells. PMID- 29260520 TI - [Effect of Aspirin on Brain Metastasis of Lung Cancer and Its Possible Mechanism]. AB - OBJECTIVE: To determine the effect of prostaglandin E2 (PGE2) on brain metastasis of lung cancer,and to explore the possible mechanism of aspirin (PGE2 inhibitor) reducing brain metastasis of lung cancer. METHODS: Radioimmunoassay was performed to measure the expression level of PGE2 in cell supernatant collected from cells treated with or without aspirin (8 mmol/L) at different time points. After establishing in vitro blood-brain barrier (BBB) model using Transwell, lung cancer cells was added to upper chamber of transwell and was then treated with aspirin (8 mmol/L). Western blot was used to examine the expression of occludin protein in brain microvascular endothelial cells. The permeability changes of BBB model in vitro were determined using horseradish peroxides. The number of lung cancer cells passing through BBB model in vitro was counted with Hemocytometer. Effect of aspirin on brain metastasis of lung cancer was observed in nude mice in the animal level. RESULTS: PGE2 level decreased and reached minimum level 120 min after aspirin treatment in lung cancer cells culture fluid. Occludin expression increased and reached maximum level 120 min after aspirin treatment in brain microvascular endothelial cells. At the same time,permeability of BBB and number of lung cancer cells passing through BBB also reached the lowest value 120 min after aspirin treatment. Aspirin significantly reduced the incidence of brain metastasis of lung cancer in animal model. CONCLUSION: Aspirin reduced occurrences of the brain metastasis of lung cancer in animal model,which may be caused by inhibition of PGE2 released by lung cancer cells and upregulation of occludin expression therefore leading to decrease in BBB permeability. PMID- 29260521 TI - [Research on Relationship of HIF-1 Signaling Pathway and Postmenstrual Osteoporosis]. AB - OBJECTIVE: Exploring the role of hypoxia-induceibal factor-1 (HIF-1) signaling pathway in postmenstrual osteoporosis (PMOP) and how to play a role in PMOP. METHODS: Sixty C57BL/6J female mouse were randomly divided into 4 groups: sham operation group (A group),ovariectomized PMOP group (B group),HIF-1 alpha inhibitor 2-methoxy estradiol (2ME2) treatment group(D group) and solvent control group(C group),15 mice in each group. There months after modeling,the metabolism product of mouse bone tissue including serum propeptide of typeI procollagen (PINP),C-terminal telopeptide-I (CTX-1) and serum estrogen were quantified by enzyme-linked immunosorbent assay (ELISA). Changes of bone structure were observed on HE stained tissue sections. Regulation products of HIF-1 signaling pathway including HIF-1alpha,HIF-1beta,specific prolyl hydroxylases (PHD),Hipple Lindau tumor suppressor protein (VHL),and factor inhibiting HIF (FIH) were measured by immuno-histochenmistry staining. Osteoclasts derived from OVX-mice were treated with inhibitors of extracellular regulated protein kinases (ERK),protein kinase B (Akt) and nuclear factor kappa B (NF-kappaB) signaling pathways. HIF-1alpha expression were detected by Western blot to obtain a rudimentary knowledge of possible mechanism of up-regulation of HIF-1alpha in osteoclasts of postmenospausal osteoporosis. RESULTS: Metabolism product of mouse bone tissue of B group were higher than A group ( P<0.001). The positive expression of HIF-1-alpha protein was found in osteoclasts,and the expression of HIF-1-alpha protein in bone marrow region was higher than that in A group ( P<0.001), while the change od HIF-1beta,PHD,VHL,and FIH were not obviously. After the HIF-1alpha inhibitor treatment,markers of bone resorption of bone metabolism in ovariectomized mice reduced and the osteoporosis get greatly relieved ( P<0.001). HIF-1alpha expression was down-regulated in osteoclasts of OVX-mice after treated with inhibitors of ERK,Akt and NF-kappaB signaling pathways ( P<0.05). CONCLUSION: HIF-1 signaling pathway get involved in the pathological evolution of osteoporosis after menopause,and inhibition of HIF-1 can significantly improve the severity of osteoporosis after menopause. ERK,Akt and NF-kappaB signaling pathways may involve in the up-regulation of HIF-1 signaling pathway in osteoclasts of PMOP. PMID- 29260522 TI - [Protective Effect and Its Possible Mechanism of Ulinastatin on Lung Injury Induced by Hip Fracture]. AB - OBJECTIVE: To investigate the protective effect and its possible mechanism of ulinastatin on lung injury caused by hip fracture. METHODS: Total 24 SD rats were randomly divided into control,hip fracture and hip fracture+ulinastatin groups (n=8). The rats of hip fracture and hip fracture+ulinastatin groups made the left hip fracture. The tail vein of rats of hip fracture+ulinastatin group were injected with 50 000 U/kg ustodin before made fracture model. Killed rats 24 h after mold building. Serum mtDNA,tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in bronchoalveolar lavage fluid,Toll like receptor-9 (TLR9) and nuclear factor (NF)-kappaB protein expression in lung tissue,wet/dry ratio and pathological scores of lung were detected in all three groups. RESULTS: Serum mtDNA,TNF-alpha and IL-6 in bronchoalveolar lavage fluid,TLR9 and NF-kappaB protein expressions in lung tissue,wet/dry ratio and pathological scores of lung in hip fracture group were significantly higher than those in control group ( P<0.05). Ulinastatin significantly reduced the levels of serum mtDNA,TNF-alpha and IL-6 in bronchoalveolar lavage fluid,TLR9 and NF-kappaB protein expressions in lung tissue,as well as wet/dry ratio and pathological scores of lung ( P<0.05). CONCLUSION: Ulinastatin might could provide protection on lung injury in hip fracture,and mtDNA-TLR9-NF-kappaB pathway may play the role of reducing inflammatory level in the process. PMID- 29260523 TI - [The Role of Long Chain Non-coding RNA-Paupar in the Process of Bupivacaine Induced Neurotoxicity]. AB - OBJECTIVE: To observe the expression mode and modulation effects of lncRNA-Paupar in the process of bupivacaine induced neurotoxicity. METHODS: Dorsal root ganglion (DRG) neurons were cultured and neurotoxicity model was produced on it. And the expression of lncRNA-Paupar was evaluated by qRT-PCR. Lnc-Paupar specific siRNA-P and random control group siRNA-C were constructed,200 nmol/L siRNA P,siRNA-C were transfected into ganglion cells and the apoptosis rate of transfected cells were observed by TUNEL method. The JNK and phosphorylated JNK (p-JNK) protein expression were observed with Western blot,respectively. RESULTS: LncRNA-Paupar was significantly up-regulated during the process of bupivacaine induced neurotoxicity and siRNA mediated lncRNA-Paupar down-regulation protected DRG neurons cells from apoptosis. Both JNK and p-JNK protein were reduced in siRNA transfected cells exemplified by Western blot. CONCLUSION: LncRNA-Paupar could induced neurotoxicity through JNK pathway. PMID- 29260524 TI - [Expression and Significance of PI-PLCepsilon1 in Colon Cancer]. AB - OBJECTIVE: To study the expression and clinical significance of phosphoinositide specific phospholipase Cepsilon1 (PI-PLCepsilon1) in the pathogenesis of colon cancer. METHODS: qRT-PCR and immunohistochemistry were used to detect the expression of PI-PLCepsilon1in the 42 cases of colon cancer tissues and their corresponding adjacent tissues. And the effects of tumor differentiation and tumor site on the expression PI-PLCepsilon1 of colon cancer tissues were compared. RESULTS: The results of qRT-PCR showed that the expression of PI PLCepsilon1in colon cancer tissue significantly lower than that in the adjacent tissue ( P<0.05). The expression of PI-PLCepsilon1gene of colon cancer tissue was not effected by tumor differentiation and tumor site ( P>0.05). The results of immuno-histochemistry showed that the positive expression rate of PI-PLCepsilon1 protein in colon cancer tissue was significantly lower than that in the adjacent tissue ( P<0.05). The positive expression rate of PI-PLCepsilon1 protein was not effected by tumor differentiation ( P>0.05),but the expression was different in tumor site ( P<0.05). CONCLUSION: Expression of PI-PLCepsilon1 was reduced in colon tissue and barely to tumor differentiation. PMID- 29260525 TI - [The Association Between the Polymorphisms of miRNA Biogenesis Related Genes(DICER,DROSHA and RAN)and Unexplained Recurrent Spontaneous Abortion in Chinese Women]. AB - OBJECTIVE: To explore the association between polymorphisms of miRNA biogenesis related gene DICER,DROSHA,RAN and unexplained recurrent spontaneous abortion (URSA) in Chinese women. METHODS: We recruited 217 patients with URSA (URSA group) and 390 healthy controls who were fertile women with history of more than one successful pregnancy outcome (control group) from June 2013 to December 2015 in the West China Second University Hospital of Sichuan University. The control group was recruited from regular physical examination and prepregnancy check for women of childbearing age during the same period. A case-control study was performed to analyze polymorphism of miRNA machinery genes,including DICER rs3742330,DROSHA rs10719, RAN rs14035,by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: The frequencies of genotypes and alleles of DICER rs3742330,DROSHA rs10719,and RAN rs14035 showed no difference between URSA patients and control group (all P>0.05). DICER rs3742330/DROSHA rs10719 GG/TC+TT combinations were synergistically associated with increased URSA risk [odds ratio (OR)=1.657,95% confidence interval (CI)=1.006-2.731, P=0.047]. Although DICER rs3742330/RAN rs14035 GG / TT+TC combinations was significantly higher in the URSA group than in the control group,there was no statistical significance (OR=1.977,95%CI=0.956-4.087, P=0.066). However,DROSHA10719/RAN14035 TT+TC/TT+TC had no significant correlation with URSA (OR=0.958,95%CI=0.679-1.353, P=0.808). CONCLUSION: Our study demonstrated the relationship between URSA development and combined genotype of DICER rs3742330/DROSHA rs10719 GG/TC+TT. PMID- 29260526 TI - [Intake of Pickled Vegetables and Colorectal Cancer]. AB - OBJECTIVE: To explore the association between intake of pickled vegetables and colorectal cancer (CRC),including the interactions between pickled vegetables and other dietary habits. METHODS: A 1:1 matched case-control study was undertaken,involving 400 patients with newly histopathologically diagnosed CRC and 400 healthy residents matched by age and gender. The participants were asked to complete a questionnaire. Conditional logistic regression models were established to identify risk factors of CRC and interactions between these factors. Additive interactions were analyzed using relative excess risk of interaction (RERI),attributable proportion of interaction (AP),and synergy index (S). RESULTS: Excessive intake of pickled vegetables (more than 3 times per week) increased the risk of CRC [odds ratio (OR)=2.703,95% confidence interval (CI): 1.866-3.916]. There was no multiplicative interaction between pickled vegetables and other dietary habits. Additive interactions were detected between pickled vegetables and cured meat,tea and bean products: with a RERI of 3.172 (95%CI: 0.834-5.518),2.131 (95%CI: 0.115-4.417) and 2.503 (95%CI: 0.760 4.246),respectively; an AP of 0.472 (95%CI: 0.245-0.699),0.386 (95%CI: 0.122 0.650) and 0.493 (95%CI: 0.253-0.732),respectively; and a S of 2.244 (95%CI: 1.266-3.978),1.893 (95%CI: 1.050-3.416) and 2.586 (95%CI:1.168-5.723) ,respectively. CONCLUSION: Excessive intake of pickled vegetables may be a risk factor of CRC. Cured meats and pickled vegetables might have a synergistic effect on CRC. However,tea and bean products might be antagonistic to the risk imposed by pickled vegetables on CRC. PMID- 29260527 TI - [Detection and Analysis of Human Parainfluenza Virus Infection in Hospitalized Adults with Acute Respiratory Tract Infections]. AB - OBJECTIVE: To investigate the prevalence and gene characteristics of different groups of human parainfluenza virus (HPIV) infection in hospitalized adults with acute respiratory tract infections (ARI). METHODS: RT-PCR was used to detect HPIV hemagglutinin (HA) DNA,which was extracted from sputum samples of 1 039 adult patients with ARI from March,2014 to June,2016. The HA gene amplified from randomly selected positive samples were sequenced to analyze the homology and variation. RESULTS: 10.6% (110/1 039) of these samples were positive for HPIV,including 8 cases of HPIV-1,22 cases of HPIV-2,46 cases of HPIV-3 and 34 cases of HPIV-4. Detectable rate varied among different groups of HPIV according to seasons of the year and ages of patients. No significant differences were found between the positive samples and the reference sequences. Compared with different reference strains of different regions,the genetic distance of nucleotide is the smallest between the strains tested in this study and the reference strains of other provinces and cities in China. CONCLUSION: In Chengdu region,HPIV virus is highly detected in ARI,all subtypes were detected with HPIV 3 being the main subtype. PMID- 29260528 TI - [Role of HPA and HPT Axis in Anxiety Disorder Complicated with Diabetes Mellitus]. AB - OBJECTIVE: To determine the mediating role of hypothalamic-pituitary-adrenal axis (HPA) and hypothalamic-pituitary-thyroid axis (HPT) axis in anxiety disorder in patients with diabetes mellitus. METHODS: A total of 562 hospitalized patients with anxiety disorder participate in the study. Serum thyroid-stimulating hormone (TSH),total triiodothyronine (TT3),free triiodothyronine (FT3),total tetraiodothyronine (TT4),free tetraiodothyronine (FT4) ,adrenocorticotropic hormone (ACTH) and cortisol (PTC) were measured. Glucose tolerance test (OGTT) was performed,estimating insulin resistance index (HOMA IR) and insulin sensitivity index (WBISI). RESULTS: Of the participants,83 (14.8%) had diabetes. In those who were younger than 40 yr.,the diabetic patients were more likely to have abnormal FT4 and HPT ( P<0.05). The patients with diabetes were more likely to be older (OR=1.067, 95%CI:1.041-1.094, P=0.000) and have higher FT4 (OR=1.104, 95%CI:1.022-1.193, P=0.012) and PTC (OR=1.001, 95%CI:1.000-1.003, P=0.025) . Insulin resistance index increased while insulin sensitivity index decreased ( P<0.05) with abnormal PTC and HPA axis. Insulin sensitivity index decreased ( P<0.05) when ACTH,HPT axis,FT4 and TT3 were abnormal. CONCLUSION: Abnormal HPA or HPT axis mediates diabetic complications in patients with anxiety disorder. Early interventions on neuroendocrine hormone abnormality may help prevent diabetes in patients with anxiety disorder. PMID- 29260529 TI - [Anxiety and Depression in Patients with Neuromyelitis Optica]. AB - OBJECTIVE: To assess anxiety and depression in patients with neuromyelitis optica (NMO). METHODS: Eligible patients with NMO were assessed with Hamilton anxiety rating scale-14 (HARS-14),Hamilton depression rating scale-21 (HDRS-21) and expanded disability status scale (EDSS). RESULTS: A total of 65 NMO patients [(39.85+/-10.36) yr., male/female: 5/60) participated in this study. They had a median EDSS score of 2.5 and a mean score of (37.37+/-20.44) for bodily pain. About 76.9% of patients were NMO-IgG seropositive. The participants had (11.03+/ 6.95) HARS-14 scores and (11.74+/-7.78) HDRS-21 scores,with 27.69% (18/65) being diagnosed with anxiety and 24.62% (16/65) being depressed. The EDSS scores were correlated with HARS-14 scores (r=0.285, P=0.004) and HDRS-21 scores (r=0.328, P=0.008). Bodily pain was negatively correlated with HARS-14 scores (r=-0.561, P<0.001) and HDRS-21 scores (r=-0.496, P<0.001). Relapse was correlated with anxiety (r=0.285, P=0.022). Age,sex,duration of disease,and serum NMO-IgG were not correlated with HARS-14 scores and HDRS-21 scores. The logistic regression model identified bodily pain as a predictor of anxiety and depression in NMO patients (OR=1.052,1.046,respectively P<0.05). CONCLUSION: Disability and bodily pain are associated with anxiety and depression in NMO patients,while relapse is associated with anxiety only. Bodily pain is a predictor of anxiety and depression in NMO patients. PMID- 29260530 TI - [Establishment of Reference Value of Hs-cTnT in Sichuan Region and Its Diagnostic Value in Patients with Chest Pain]. AB - OBJECTIVE: To establish the reference value of high sensitive cardiac troponin T (hs-cTnT) and the efficiency of reference value in the diagnosis of chest pain. METHODS: Volunteers from eight independent communities in Chengdu,Sichuan were selected with detailed records of physical examination,electrocardiogram,ultrasound examination. The level of hs-cTnT for healthy volunteers was tested to determine ninety-ninth percentile references according to sex and ages. 2 249 patients with chest pain in the emergency department of Western China Hospital from July 2009 to July 2014 were enrolled to measure the efficiency of reference value for diagnosing acute myocardial infarction (AMI). RESULTS: There were 1 305 volunteers included finally. Among them,the mean hs-cTnT level of male was 4.3 (3.2-5.9) ng/L,which was significantly higher than that of female 3.0 (3.0-3.1) ng/L ( P<0.01) . The correlation coefficient between age and hs-cTnT level was 0.43 (male) and 0.29 (female),and the P-value was less than 0.01. The 99th percentile values of male were 10.8 ng/L,15.4 ng/L and 19.7 ng/L for <45 yr.,45-<60 yr. and >=60 yr.,respectively. Those values of female were 4.6 ng/L,8.9 ng/L,18.8 ng/L,respectively. There was no difference in sensitivity and specificity between the value we figured out and manufactures provided (14.0 ng/L) for those<60 yr.. For the patients >=60 yr.,the sensitivity and negative predictive value did not show diversity ( P>0.05) but the specificity and positive predictive value showed significant difference (male: 0.67 vs. 0.56 and 0.83 vs. 0.79, P<0.05;female:0.75 vs. 0.68 and 0.74 vs. 0.69, P<0.05). CONCLUSION: We recommends that the ninety ninth percentile reference value of patients<60 yr. should be 14.0 ng/L,while 20.0 ng/L for those patients>=60 yr. PMID- 29260531 TI - [Assessment of Left Atrial Appendage Size and Morphology by Enhanced Cardiac Computed Tomography in Patients with Non-valvular Atrial Fibrillation]. AB - OBJECTIVE: This study was designed to investigate left atrial appendage (LAA) size and morphology characteristics in patients with non-valvular atrial fibrillation (NVAF) by enhanced cardiac computed tomography (CT) scanning,and to evaluate the predictive value of these parameters for thromboembolic risk. METHODS: A total of 189 NVAF patients were prospectively enrolled during December 2012 to January 2014 in West China Hospital of Sichuan University. Fifty-two atrial tachycardia patients without organ dysfunction were also recruited as controls. All subjects were scheduled for radiofrequency ablation and underwent enhanced cardiac CT scan. The clinical characteristics,comorbid diseases,anticoagulant therapy,and AF chronicity were collected and CHA2DS2-VASc score was calculated for the assessment of thromboembolic risk. The NVAF cohort was also divided further into LAA thrombus present (n=13) and absent (n=176) subgroup according to LAA with thrombus or not. Differencesin size and morphology characteristics of the LAA were compared among controls and different CHA2DS2 VASc thromboembolic risk subgroups,and between LAA thrombus and non-thrombus group. In addition,logistic regression analysis was used to identify whether these parameters predict thrombus formation independent of the CHA2DS2-VASc score in NVAF patients. RESULTS: Compared with controls,NVAF patients had significantly bigger orifice size. Windsock and cactus-type LAA were main morphology in controls,while the distribution of the four kinds of LAA types were similar in NVAF patients. The orifice and volume of the LAA were increased with increasing CHA2DS2-VASc riskscore,and chicken wing-type LAA was the predominant prevalence in low-intermediate thromboembolic risk subgroup while cauliflower in high thromboembolic risk subgroup. Compared with non-thrombus patients,LAA thrombussubgroup exhibited a significantly increased orifice and volume,and higher prevalenceof the cauliflower shaped LAA. Logistic regression showed that the LAA orifice and cauliflower shape were independent predictors for thrombus formation in patients with NVAF following adjustment for the CHA2DS2-VASc score. CONCLUSION: Cardiac images obtained with CTis feasible for the analysis of LAA size and morphology,and these parameters provide incremental value in assessing the LAA thrombus risk in patients with NVAF. PMID- 29260532 TI - [Effects of Group Cognitive Behavioral Therapy on Social Anxiety Disorders]. AB - OBJECTIVE: To evaluate the effect of group cognitive behavioral therapy (GCBT) on social anxiety disorders (SAD). METHODS: A total of 50 patients with SAD were recruited in this study. A survey containing the Liebowitz social anxiety scale (LSAS),the automatic thoughts questionnaire (ATQ),the fear of negative evaluation questionnaire (FNE),the social support rating scale (SSRS),the tridimensional personality questionnaire (TPQ),and the egna minnen barndoms uppfostran (EMBU) was administered before and (one week) after the GCBT,including in the 50 healthy controls. About 21 patients completed the eight-week GCBT (once a week,2 h a session). Follow-up surveys were conducted on 40 patients (22 patients treated with GCBT and 18 untreated) over a 1-5 year period. RESULTS: Significant differences were found between the SAD patients and healthy controls in thinking mode,personality characteristics,social support,parental rearing styles,and social anxiety symptoms. Significant decrease in social anxiety symptom ( t=4.06, P=0.000) , negative automatic thoughts ( t=4.58, P=0.000) and fear for rejection ( t=3.85, P=0.000) were observed after the GCBT therapy. Such improvement was positively correlated with subjective social support (r=0.361, P=0.022) ,and negatively correlated with rejection of father (r=-0.431, P=0.005) . There was also statistical difference between the patients with and without the GCBT therapy ( P=0.033) . CONCLUSION: GCBT treatment can relieve SAD symptoms by changing the negative cognitive of SAD patients. Social support and rejection of father affects the prognosis of SAD. PMID- 29260533 TI - [Effect of Proton Pump Inhibitors on Severe Acute Pancreatitis--a Prospective Randomized Trial]. AB - OBJECTIVE: To evaluate the effect of proton pump inhibitors (PPIs) therapy on severe acute pancreatitis (SAP) patients. METHODS: Forty five patients with SAP recruited in our center from October 2015 to October 2016,were randomly assigned into two groups: convention group (C group,n=21) and convention+esomeprazole group (C+E group,n=24). C+E group received esomeprazole 40 mg/d intravenously for 1 week,whereas C group only received baseline treatment. Serum C-reactive protein (CRP),interleukin-6 (IL-6) and interleukin-8 (IL-8),tumor necrosis factor-alpha (TNF-alpha) and procalcitonin (PCT) were detected by ELISA on the first day (baseline) and the seventh day. Acute physiology and chronic health evaluation II scores (APACHE II),systemic inflammatory response syndrome scores (SIRS) and modified Marshall scoring system (Marshall) were obtained at 1 d (baseline),3 d and 7 d. Upper gastrointestinal manifestation (peptic ulcer) and gastric pH were detected by endoscopic examination at 7 d. Fecal occult blood test was performed at 7 d. RESULTS: No significant difference was found in CRP,IL-6,IL-8,TNF-alpha and PCT between the two groups ( P>0.05),also no difference in APACHE II,SIRS and Marshall scores ( P>0.05). The gastric pH was remarkably higher in C+E group when compared to C group (5.02+/-1.61 vs.2.83+/-1.08, P<0.001). There was no significant difference in the incidence of peptic ulcer and the rate of positive fecal occult blood between the two groups. CONCLUSION: PPIs therapy did not show benefit on alleviating systemic inflammatory response and clinical scores in SAP patients,and didn't improve the prevention of peptic ulcer and gastrointestinal hemorrhage. PMID- 29260534 TI - [Risk Factors for Blood Transfusion in Women with Postpartum Hemorrhage: a Case control Study]. AB - OBJECTIVE: To investigate the risk factors for increased red blood cells (RBCs) transfusion ratio in the women with postpartum hemorrhage (PPH). METHODS: This case-control study obtained the inpatient medical records of 112 441 pregnant women from 37 hospitals in 2011. There were 4 131 women diagnosed with PPH,record data of those patients were analyzed,including basic characteristics of patients,the level of hospital,pregnancy related complications,prenatal hemoglobin (Hb),mode of delivery,details of postpartum blood loss and blood transfusion,and maternal and neonatal outcomes. Multiple logistic regression analysis was used to identify risk factors for increased RBCs transfusion ratio. RESULTS: There were 61 339 (54.6%) out of 112 441 women received with Cesarean section and 637 (15.4%) out of 4 131 women with PPH had blood transfusion,one to four units of RBCs were sufficient for a majority of those patients. It demonstrated that level of hospital,multiple,placenta preiva,abruptio placenta,pre-eclampsia or eclampsia,pre-delivery hemoglobin,gestational age and labor method were independent risk factors for RBCs transfusion. CONCLUSION: Cesarean section and pregnant complications are important risk factors for blood transfusion in women with PPH . PMID- 29260535 TI - [Application of Echocardiography to Support Transapical Transcatheter Aortic Valve Implantation in Patients with Aortic Regurgitation]. AB - OBJECTIVE: To explore the role of echocardiography in pre-procedural,peri procedural and post-procedural stages of transapical transcatheter aortic valve implantation (TAVI) in patients with aortic regurgitation (AR). METHODS: 31 patients with pure/dominant AR at a high risk on surgery were enrolled in this study. The degree of their aortic regurgitation was evaluated before TAVI,as well as the related diameters of aortic root and the left ventricular systolic function measured by transthoracic echocardiography (TTE). TEE was used to reevaluate the valve pathology after general anesthesia. TEE in combination with fluoroscopy provided accurate position of the prosthetic valve for implantation. TEE was also used to monitor complications and to evaluate immediate post procedure paravalvular regurgitation. The post TAVI follow-up included valve heamodynamic status,complications,left ventricular systolic function and left ventricular mass index (LVMI) measured by TEE. RESULTS: Transapical TAVI was successful in 29 of the 31 patients: 23 experienced no or little paravalvular regurgitation; 6 had mild paravalvular regurgitation. The left ventricular end diastolic diameter (LVDd) and left ventricular mass index (LVMI) of the patients decreased significantly one week after TAVI,which progressed until one month later ( P<0.05) . The left ventricular ejection (EF) of the patients also decreased one week after TAVI ( P<0.05) ,but it resumed to the pre-procedural level one month later. CONCLUSION: Transapical TAVI is a potentially safe and effective therapy for patients with pure/dominant AR at a high risk on open-heart surgery. Echocardiography plays an important role in pre-procedural evaluation,peri-procedural monitoring and post-procedural follow-up in TAVI. PMID- 29260536 TI - [Prevalence of Overweight and Obesity in Adult Populations in Mianyang,Sichuan Province]. AB - OBJECTIVE: To determine the prevalence of overweight and obesity in adult populations in Mianyang,Sichuan province. METHODS: A questionnaire survey involving physical examinations were conducted in 262 434 adults (>=18 yr.) selected through multi-stage random sampling from November 2014 to September 2015 in Mianyang city. RESULTS: Among the people surveyed,79 981 (30.48%) were overweight,and 23 010 (8.77%) had obesity. The male participants had a higher percentage (32.28%) of overweight than females (29.10%, P<0.01),but lower obesity rate (8.53%) than females (8.95%, P<0.01). Those aged 50-59 yr. had the highest prevalence of overweight (39.26%) and obesity (12.07%). The participants with up to junior middle school education were most likely to be overweight (35.02%) and obese (10.57%). Overweight and obesity were most prevalent in the unemployed: 36.87% and 12.65%,respectively. Fucheng had higher prevalence of overweight (30.01%) and obesity (10.14%) than Jiangyou (29.97% and 7.46% respectively,all P<0.01). The prevalence of overweight and obesity was higher in the smokers (32.88% and 9.46%) than in the non-smokers (30.02% and 8.64%,all P<0.01). Those who drank alcohols had higher prevalence of overweight and obesity (33.43% and 9.72%) than those who did not drink alcohols (29.78% and 8.54% respectively,all P<0.01). CONCLUSION: High prevalence of overweight and obesity in adult populations in Mianyang is evident,especially in those who are 50-59 years old,unemployed,drinking alcohols,smoking,and have low educational level. PMID- 29260537 TI - Diffuse optical tomography using semiautomated coregistered ultrasound measurements. AB - Diffuse optical tomography (DOT) has demonstrated huge potential in breast cancer diagnosis and treatment monitoring. DOT image reconstruction guided by ultrasound (US) improves the diffused light localization and lesion reconstruction accuracy. However, DOT reconstruction depends on tumor geometry provided by coregistered US. Experienced operators can manually measure these lesion parameters; however, training and measurement time are needed. The wide clinical use of this technique depends on its robustness and faster imaging reconstruction capability. This article introduces a semiautomated procedure that automatically extracts lesion information from US images and incorporates it into the optical reconstruction. An adaptive threshold-based image segmentation is used to obtain tumor boundaries. For some US images, posterior shadow can extend to the chest wall and make the detection of deeper lesion boundary difficult. This problem can be solved using a Hough transform. The proposed procedure was validated from data of 20 patients. Optical reconstruction results using the proposed procedure were compared with those reconstructed using extracted tumor information from an experienced user. Mean optical absorption obtained from manual measurement was 0.21+/-0.06 cm-1 for malignant and 0.12+/-0.06 cm-1 for benign cases, whereas for the proposed method it was 0.24+/-0.08 cm-1 and 0.12+/-0.05 cm-1, respectively. PMID- 29260538 TI - Optical coherence tomography in gastroenterology: a review and future outlook. AB - Optical coherence tomography (OCT) is an imaging technique optically analogous to ultrasound that can generate depth-resolved images with micrometer-scale resolution. Advances in fiber optics and miniaturized actuation technologies allow OCT imaging of the human body and further expand OCT utilization in applications including but not limited to cardiology and gastroenterology. This review article provides an overview of current OCT development and its clinical utility in the gastrointestinal tract, including disease detection/differentiation and endoscopic therapy guidance, as well as a discussion of its future applications. PMID- 29260540 TI - Conservative management of adult neurogenic lower urinary tract dysfunction. AB - Neurogenic lower urinary tract dysfunction (NLTUD) is commonly encountered in neuro-rehabilitation settings and is caused by a variety of pathologies. The management of spinal cord injury (SCI) has been the model of reference for the approach to NLTUD due to many other diseases of the central and peripheral nervous system. The decline in renal-related mortality in SCI patients after the introduction of clean intermittent catheterization in association with pharmacological treatment (antimuscarinics in particular), and the algorithms proposed since 1998 by the International Consultations on Incontinence underline the need of early assessment and treatment of urinary incontinence and/or urinary retention in neuropathic patients. The aim of this brief review was to provide useful guidelines for physiatrists and neurologists in order to early and correctly manage all types of NLUTDS, well knowing that a correct management is useful not only for avoiding renal failure, but also for improving urinary continence, voiding dysfunction, and the quality of life of patients. The rehabilitation treatment consists of conservative, noninvasive or minimally invasive techniques, in the context of which intermittent catheterization and pharmacotherapy represent the more important modalities. After a brief description of specific interventions, the management of NLTUD in stroke, Parkinson's disease, multiple sclerosis and SCI patients is underlined, emphasizing the importance of a dedicated team in rehabilitation units. PMID- 29260541 TI - Simple Ciprofloxacin Resistance Test and Determination of Minimal Inhibitory Concentration within 2 h Using Raman Spectroscopy. AB - Resistant bacteria are spreading worldwide, which makes fast antibiotic susceptibility testing and determination of the minimal inhibitory concentration (MIC) urgently necessary to select appropriate antibiotic therapy in time and, by this, improve patient's outcome and, at the same time, avoid inappropriate treatment as well as the unnecessary use of broad spectrum antibiotics that would foster further spread of resistant bacteria. Here, a simple and fast Raman spectroscopy-based procedure is introduced to identify antimicrobial susceptibilities and determine the MIC within only 2 h total analysis, marking a huge time savings compared to established phenotypic methods nowadays used in diagnostics. Sample preparation is fast and easy as well as comparable to currently established tests. The use of a dielectrophoresis chip allows automated collection of the bacteria in a micron-sized region for high-quality Raman measurement directly from bacterial suspensions. The new Raman spectroscopic MIC test was validated with 13 clinical E. coli isolates that show a broad range of ciprofloxacin resistance levels and were collected from patients with blood stream infection. Micro-Raman spectroscopy was able to detect ciprofloxacin induced changes in E. coli after only 90 min interaction time. Principal component analysis as well as a simple computed ratio of the Raman marker bands at 1458 and 1485 cm-1 show a clear concentration-dependent effect. The MIC values determined with the new Raman method are in good agreement with MICs obtained by reference methods (broth microdilution, Vitek-2, E-test) and can be used to provide a classification as sensitive, intermediate, or resistant using the clinical breakpoints provided by EUCAST. PMID- 29260542 TI - Nanoscale PtO2 Catalysts-Loaded SnO2 Multichannel Nanofibers toward Highly Sensitive Acetone Sensor. AB - PtO2 nanocatalysts-loaded SnO2 multichannel nanofibers (PtO2-SnO2 MCNFs) were synthesized by single-spinneret electrospinning combined with apoferritin and two immiscible polymers, i.e., poly(vinylpyrrolidone) and polyacrylonitrile. The apoferritin, which can encapsulate nanoparticles within a small inner cavity (8 nm), was used as a catalyst loading template for an effective functionalization of the PtO2 catalysts. Taking advantage of the multichannel structure with a high porosity, effective activation of catalysts on both interior and exterior site of MCNFs was realized. As a result, under high humidity condition (95% RH), PtO2 SnO2 MCNFs exhibited a remarkably high acetone response (Rair/Rgas = 194.15) toward 5 ppm acetone gases, superior selectivity to acetone molecules among various interfering gas species, and excellent stability during 30 cycles of response and recovery toward 1 ppm acetone gases. In this work, we first demonstrate the high suitability of multichannel semiconducting metal oxides structure functionalized by apoferritin-encapsulated catalytic nanoparticles as highly sensitive and selective gas-sensing layer. PMID- 29260543 TI - Three-Dimensional Microstructured Azobenzene-Containing Gelatin as a Photoactuable Cell Confining System. AB - In materials science, there is a considerable interest in the fabrication of highly engineered biomaterials that can interact with cells and control their shape. In particular, from the literature, the role played by physical cell confinement in cellular structural organization and thus in the regulation of its functions has been well-established. In this context, the addition of a dynamic feature to physically confining platforms aiming at reproducing in vitro the well known dynamic interaction between the cells and their microenvironment would be highly desirable. To this aim, we have developed an advanced gelatin-based hydrogel that can be finely micropatterned by two-photon polymerization and stimulated in a controlled way by light irradiation thanks to the presence of an azobenzene cross-linker. Light-triggered expansion of gelatin microstructures induced an in-plane nuclear deformation of physically confined NIH-3T3 cells. The microfabricated photoactuable gelatin shown in this work paves the way to new "dynamic" caging culture systems that can find applications, for example, as "engineered stem cell niches". PMID- 29260539 TI - Clinical translation of handheld optical coherence tomography: practical considerations and recent advancements. AB - Since the inception of optical coherence tomography (OCT), advancements in imaging system design and handheld probes have allowed for numerous advancements in disease diagnostics and characterization of the structural and optical properties of tissue. OCT system developers continue to reduce form factor and cost, while improving imaging performance (speed, resolution, etc.) and flexibility for applicability in a broad range of fields, and nearly every clinical specialty. An extensive array of components to construct customized systems has also become available, with a range of commercial entities that produce high-quality products, from single components to full systems, for clinical and research use. Many advancements in the development of these miniaturized and portable systems can be linked back to a specific challenge in academic research, or a clinical need in medicine or surgery. Handheld OCT systems are discussed and explored for various applications. Handheld systems are discussed in terms of their relative level of portability and form factor, with mention of the supporting technologies and surrounding ecosystem that bolstered their development. Additional insight from our efforts to implement systems in several clinical environments is provided. The trend toward well-designed, efficient, and compact handheld systems paves the way for more widespread adoption of OCT into point-of-care or point-of-procedure applications in both clinical and commercial settings. PMID- 29260544 TI - Natural Organochlorines as Precursors of 3-Monochloropropanediol Esters in Vegetable Oils. AB - During high-temperature refining of vegetable oils, 3-monochloropropanediol (3 MCPD) esters, possible carcinogens, are formed from acylglycerol in the presence of a chlorine source. To investigate organochlorine compounds in vegetable oils as possible precursors for 3-MCPD esters, we tested crude palm, soybean, rapeseed, sunflower, corn, coconut, and olive oils for the presence of organochlorine compounds. Having found them in all vegetable oils tested, we focused subsequent study on oil palm products. Analysis of the chlorine isotope mass pattern exhibited in high-resolution mass spectrometry enabled organochlorine compound identification in crude palm oils as constituents of wax esters, fatty acid, diacylglycerols, and sphingolipids, which are produced endogenously in oil palm mesocarp throughout ripening. Analysis of thermal decomposition and changes during refining suggested that these naturally present organochlorine compounds in palm oils and perhaps in other vegetable oils are precursors of 3-MCPD esters. Enrichment and dose-response showed a linear relationship to 3-MCPD ester formation and indicated that the sphingolipid-based organochlorine compounds are the most active precursors of 3-MCPD esters. PMID- 29260545 TI - C8-Linked Pyrrolobenzodiazepine Monomers with Inverted Building Blocks Show Selective Activity against Multidrug Resistant Gram-Positive Bacteria. AB - Antimicrobial resistance has become a major global concern. Development of novel antimicrobial agents for the treatment of infections caused by multidrug resistant (MDR) pathogens is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents initially discovered and isolated from natural sources. Recently, C8-linked PBD biaryl conjugates have been shown to be active against some MDR Gram-positive strains. To explore the role of building block orientations on antibacterial activity and obtain structure activity relationship (SAR) information, four novel structures were synthesized in which the building blocks of previously reported compounds were inverted, and their antibacterial activity was studied. The compounds showed minimum inhibitory concentrations (MICs) in the range of 0.125-32 MUg/mL against MDR Gram-positive strains with a bactericidal mode of action. The results showed that a single inversion of amide bonds reduces the activity while the double inversion restores the activity against MDR pathogens. All inverted compounds did not stabilize DNA and lacked eukaryotic toxicity. The compounds inhibit DNA gyrase in vitro, and the most potent compound was equally active against both wild-type and mutant DNA gyrase in a biochemical assay. The observed activity of the compounds against methicillin resistant S. aureus (MRSA) strains with equivalent gyrase mutations is consistent with gyrase inhibition being the mechanism of action in vivo, although this has not been definitively confirmed in whole cells. This conclusion is supported by a molecular modeling study showing interaction of the compounds with wild-type and mutant gyrases. This study provides important SAR information about this new class of antibacterial agents. PMID- 29260546 TI - Polydopamine-Coated Magnetic Molecularly Imprinted Polymers with Fragment Template for Identification of Pulsatilla Saponin Metabolites in Rat Feces with UPLC-Q-TOF-MS. AB - In this work, a modified pretreatment method using magnetic molecularly imprinted polymers (MMIPs) was successfully applied to study the metabolites of an important botanical with ultraperformance liquid chromatography/quadrupole time of-flight mass spectrometry (UPLC-Q-TOF-MS). The MMIPs for glucoside-specific adsorption was used to identify metabolites of Pulsatilla chinensis in rat feces. Polymers were prepared by using Fe3O4 nanoparticles as the supporting matrix, d glucose as fragment template, and dopamine as the functional monomer and cross linker. Results showed that MMIPs exhibited excellent extraction performance, large adsorption capacity (5.65 mg/g), fast kinetics (60 min), and magnetic separation. Furthermore, the MMIPs coupled with UPLC-Q-TOF-MS were successfully utilized for the identification of 17 compounds including 15 metabolites from the Pulsatilla saponin metabolic pool. This study provides a reliable protocol for the separation and identification of saponin metabolites in a complex biological sample, including those from herbal medicines. PMID- 29260547 TI - Cognitive Improving Effects by Highbush Blueberry (Vaccinium crymbosum L.) Vinegar on Scopolamine-Induced Amnesia Mice Model. AB - The present study aimed to evaluate the preventive effects of highbush blueberry (Vaccinium corymbosum L.) vinegar (BV) on cognitive functions in a scopolamine (Sco)-induced amnesia model in mice. In this study, Sco (1 mg/kg, intraperitoneal injection) was used to induce amnesia. ICR mice were orally administered donepezil (5 mg/kg), blueberry extract (120 mg/kg), and BV (120 mg/kg) for 7 days. After inducing cognitive impairment by Sco, a behavioral assessment using behavior tests (i.e., Y-maze and passive avoidance tests) was performed. The BV group showed significantly restored cognitive function in the behavioral tests. BV facilitated cholinergic activity by inhibiting acetylcholinesterase activity, and enhanced antioxidant enzyme activity. Furthermore, BV was found to be rehabilitated in the cornu ammonis 1 neurons of hippocampus. In our study, we demonstrated that the memory protection conferred by BV was linked to activation of brain-derived neurotrophic factor (BDNF)/cAMP response element binding protein (CREB)/serine-threonine kinase (AKT) signaling. PMID- 29260548 TI - Characterization of the Potent Odorants Contributing to the Characteristic Aroma of Beijing Douzhi by Gas Chromatography-Olfactometry, Quantitative Analysis, and Odor Activity Value. AB - Beijing douzhi (BD) is a traditional snack in Beijing, China, and it has been listed as a part of Beijing's intangible cultural heritage. The potent odorants that contribute to the characteristic aroma of BD were investigated by analyzing the isolates from solvent-assisted flavor evaporation (SAFE) and simultaneous distillation-extraction. Using aroma extract dilution analysis based on gas chromatography-mass spectrometry and gas chromatography-olfactometry, 31 aroma active compounds with flavor dilution (FD) factors ranging from 1 to 2187 were identified by comparison of their odor characteristics, MS data, and retention indices with those of reference compounds. To further determine their contribution to the aroma of BD, the odorants isolated using SAFE with FD factors >=9 were quantified, and their odor activity values (OAVs; ratio of concentration to the respective odor threshold in water) were calculated. Eleven compounds were found to have OAVs >= 1, which indicated they were the potent odorants that contributed substantially to the characteristic aroma of BD. Among the 11 odorants, (E,Z)-2,6-nonadienal, eugenol, methional, p-cresol, 1-octen-3-one, and 3-methylbutanoic acid were not previously identified in BD. PMID- 29260549 TI - Regiodivergent Stereoselective Access to Fused Alkylideneazetidines. AB - Following recent advances in the generalization and simplification of 2H-azetine synthesis, a regiodivergent approach to fused 2- and 3-alkylideneazetines was designed via the intermediate formation of unprecedented vinylazetine structures. Concise sequences to the latter are described from which an expected unsaturated fused ring system was isolated with very high yields and regio- and stereoselectivities by [4 + 2] cycloadditions. PMID- 29260550 TI - Study of the Construction of the Tiacumicin B Aglycone. AB - Our study of the synthesis of the aglycone of tiacumicin B is discussed here. We imagined two possible strategies featuring a main retrosynthetic disconnection between C13 and C14. The first strategy was based on Suzuki-Miyaura cross coupling of 1,1-dichloro-1-alkenes, but the failure of this pathway led us to use a Pd/Cu-dual-catalyzed cross-coupling of alkynes with allenes that had never been implemented before in a total synthesis context. We used density functional theory calculations to guide our strategic choices concerning a [2.3]-Wittig rearrangement step and the final ring-size selective Yamaguchi macrolactonization. This led to two syntheses of the aglycone of tiacumicin B, with one of last generation delivering ultimately an adequately protected and glycosylation-ready aglycone. PMID- 29260551 TI - Identification and Characterization of Diacylglycerol Acyltransferase from Oleaginous Fungus Mucor circinelloides. AB - Acyl-CoA:diacylglycerol acyltransferase (DGAT) is a pivotal regulator of triacylglycerol (TAG) synthesis. The oleaginous fungus Mucor circinelloides has four putative DGATs: McDGAT1A, McDGAT1B, McDGAT2A, and McDGAT2B, classified into the DGAT1 and DGAT2 subfamilies, respectively. To identify and characterize DGATs in M. circinelloides, these four genes were expressed in Saccharomyces cerevisiae H1246 (TAG-deficient quadruple mutant), individually. TAG biosynthesis was restored only by the expression of McDGAT2B, and TAG content was significantly higher in the mutants with McDGAT2B expression than in a S. cerevisiae mutant with endogenous DGA1 expression. McDGAT2B prefers saturated fatty acids to monounsaturated fatty acids and has an obvious preference for C18:3 (omega-6) according to the results of substrate preference experiments. Furthermore, only the mRNA expression pattern of McDGAT2B correlated with TAG biosynthesis during a fermentation process. Our experiments strongly indicate that McDGAT2B is crucial for TAG accumulation, suggesting that it may be an essential target for metabolic engineering aimed at increasing lipid content of M. circinelloides. PMID- 29260552 TI - Alkaline Phosphatase-Catalyzed Amplification of a Fluorescence Signal for Flow Cytometry. AB - Despite the expanding use of flow cytometry, its detection limit is not satisfactory for many antigen proteins with low copy numbers. Herein, we describe an alkaline phosphatase (AP)-based technique to amplify the fluorescence signal for cell staining applications. We designed a fluorescent substrate that acquires membrane permeability upon dephosphorylation by AP. By using the substrate, the fluorescence signal of cells in flow cytometry could be successfully amplified to give a much stronger signal than the cells labeled using a conventional fluorophore-modified antibody. PMID- 29260553 TI - Ordered Mesoporous Tin Oxide Semiconductors with Large Pores and Crystallized Walls for High-Performance Gas Sensing. AB - Owing to their distinct chemical and physical properties, mesoporous metal oxide semiconductors have shown great application potential in catalysis, electrochemistry, energy conversion, and energy storage. In this study, mesoporous crystalline SnO2 materials have been synthesized through an evaporation-induced co-assembly (EICA) method using poly(ethylene oxide)-b polystyrene diblock copolymers as the template, tin chlorides as the tin sources, and tetrahydrofuran as the solvent. By controlling conditions of the co-assembly process and employing a carbon-supported thermal treatment strategy, highly ordered mesoporous SnO2 materials with a hexagonal mesostructure (space group P63/mmc) and crystalline pore walls can be obtained. The mesoporous SnO2 is employed for fabricating gas sensor nanodevices which exhibit an excellent sensing performance toward H2S with high sensitivity (170, 50 ppm) and superior stability, owing to its high surface area (98 m2/g), well-connected mesopores of ca. 18.0 nm, and high density of active sites in the crystalline pore walls. The chemical mechanism study reveals that both SO2 and SnS2 are generated during the gas sensing process on the SnO2-based sensors. PMID- 29260554 TI - Theoretical Treatment of Ion Transfers in Two Polarizable Interface Systems When the Analyte Has Access to Both Interfaces. AB - A new theory is presented to tackle the study of transfer processes of hydrophilic ions in two polarizable interface systems when the analyte is initially present in both aqueous phases. The treatment is applied to macrointerfaces (linear diffusion) and microholes (highly convergent diffusion), obtaining analytical equations for the current response in any voltammetric technique. The novel equations predict two signals in the current-potential curves that are symmetric when the compositions of the aqueous phases are identical while asymmetries appear otherwise. The theoretical results show good agreement with the experimental behavior of the "double transfer voltammograms" reported by Dryfe et al. in cyclic voltammetry (CV) ( Anal. Chem. 2014 , 86 , 435 - 442 ) as well as with cyclic square wave voltammetry (cSWV) experiments performed in the current work. The theoretical treatment is also extended to the situation where the target ion is lipophilic and initially present in the organic phase. The theory predicts an opposite effect of the lipophilicity of the ion on the shape of the voltammograms, which is validated experimentally via both CV and cSWV. For the above two cases, simple and manageable expressions and diagnosis criteria are derived for the qualitative and quantitative study of ion lipophilicity. The ion-transfer potentials can be easily quantified from the separation between the two signals making use of explicit analytical equations. PMID- 29260555 TI - Investigation of Silver Nanoparticle Induced Lipids Changes on a Single Cell Surface by Time-of-Flight Secondary Ion Mass Spectrometry. AB - Lipids are the main component of the cell membrane. They not only provide structural support of cells but also directly participate in complex cellular metabolic processes. Lipid signaling is an important part of cell signaling. Evidence showed that abnormal cellular metabolism may induce lipids changes. Besides, owing to single cell heterogeneity, it is necessary to distinguish different behaviors of individual cells. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a sensitive surface analysis technique with high spatial resolution, which is useful in single cell surface analysis. Herein, we used ToF-SIMS to investigate silver nanoparticle induced lipids changes on the surface of single macrophage cells. Delayed extraction mode of ToF-SIMS was used to simultaneously obtain high mass resolution of mass spectra and high spatial resolution of single cell chemical imaging. Principle component analysis (PCA) results showed good agreement with the cytotoxicity assay results. Clear distinctions were observed between the cell groups treated with high or low dose of silver nanoparticles. The loadings plots revealed that the separation was mainly due to changes of cholesterol and diacylglycerol (DAG) as well as monoacylglycerol (MAG). Meanwhile, the chemical mapping of single cell components showed that cholesterol and DAG tend to migrate to the surrounding of the cells after high dose silver nanoparticles (Ag NPs) treatment. Our results demonstrated the feasibility of ToF-SIMS for characterizing the changes of the lipids on a single cell surface, providing a better understanding of the mechanism of cell nanoparticle interactions at the molecular level. PMID- 29260556 TI - Digital Single Virus Electrochemical Enzyme-Linked Immunoassay for Ultrasensitive H7N9 Avian Influenza Virus Counting. AB - Electrochemistry has been widely used to explore fundamental properties of single molecules due to its fast response and high specificity. However, the lack of efficient signal amplification strategies and quantitative method limit its clinical application. Here, we proposed a digital single virus electrochemical enzyme-linked immunoassay (digital ELISA) for H7N9 avian influenza virus (H7N9 AIV) counting by integration of digital analysis, bifunctional fluorescence magnetic nanospheres (bi-FMNs) with monolayer gold nanoparticles (Au NPs) modified microelectrode array (MA). Bi-FMNs are fabricated by coimmobilizing polyclonal antibody (pAb) and alkaline phosphatase (ALP). At most, one target will be captured per bi-FMNs by controlling the proportion of bi-FMNs to target concentrations (>=5:1). The introduction of digital analysis can solve signal fluctuation and the reliability of single virus detection, enabling the digital ELISA to be sensitively and accurately applied for H7N9 AIV detection with a low detection limit of 7.8 fg/mL, which is greatly promising in single biomolecular detection, early diagnosis of disease, and practical application. PMID- 29260557 TI - Keikipukalides, Furanocembrane Diterpenes from the Antarctic Deep Sea Octocoral Plumarella delicatissima. AB - During a 2013 cruise in the Southern Ocean we collected specimens of the octocoral Plumarella delicatissima between 800 and 950 m depth. Five new furanocembranoid diterpenes, keikipukalides A-E (1-5), the known diterpene pukalide aldehyde (6), and the known norditerpenoid ineleganolide (7) were isolated from the coral. These Plumarella terpenes lack mammalian cytotoxicity, while 2-7 display activity against Leishmania donovani between 1.9 and 12 MUM. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy and mass spectrometry, and keikipukalides A and E were confirmed by X-ray crystallography. PMID- 29260558 TI - Static and Dynamic Measurement of Dopamine Adsorption in Carbon Fiber Microelectrodes Using Electrochemical Impedance Spectroscopy. AB - In this study, electrochemical impedance spectroscopy was used for the first time to study the adsorption of dopamine in carbon fiber microelectrodes. In order to show a proof-of-concept, static and dynamic measurements were taken at potentials ranging from -0.4 to 0.8 V versus Ag|AgCl to demonstrate the versatility of this technique to study dopamine without the need of its oxidation. We used electrochemical impedance spectroscopy and single frequency electrochemical impedance to measure different concentrations of dopamine as low as 1 nM. Moreover, the capacitance of the microelectrodes surface was found to decrease due to dopamine adsorption, which is dependent on its concentration. The effect of dissolved oxygen and electrochemical oxidation of the surface in the detection of dopamine was also studied. Nonoxidized and oxidized carbon fiber microelectrodes were prepared and characterized by optical microscopy, scanning electron microscopy, cyclic voltammetry, and electrochemical impedance spectroscopy. Optimum working parameters of the electrodes, such as frequency and voltage, were obtained for better measurement. Electrochemical impedance of dopamine was determined at different concentration, voltages, and frequencies. Finally, dynamic experiments were conducted using a flow cell and single frequency impedance in order to study continuous and real-time measurements of dopamine. PMID- 29260559 TI - Cationic Palladium(II)-Catalyzed Reductive Cyclization of Alkynyl Cyclohexadienones. AB - A cationic palladium(II)-catalyzed reductive cyclization of cyclohexadienone containing 1,6-enynes by using ethanol as a hydrogen donor and solvent was successfully developed. This procedure offers convenient access to cyclohexenone annulated heterocycles under mild reaction conditions. The reaction was initiated by hydropalladation of the alkyne and was quenched by addition of the intramolecular conjugate alkene. This possible mechanism was preliminarily demonstrated by deuterium-labeling experiments. PMID- 29260560 TI - Fe(II)/Fe(III)-Catalyzed Intramolecular Didehydro-Diels-Alder Reaction of Styrene ynes. AB - The intramolecular didehydro-Diels-Alder reaction of styrene-ynes was catalyzed by Fe(II) and Fe(III) to produce various naphthalene derivatives under microwave heating conditions. Mechanistic calculations found that the Fe(II) catalyst activates the styrenyl diene in an inverse-electron-demand Diels-Alder reaction, and the consecutive dehydrogenation reaction can be promoted by either Fe(II) catalyzed direct dehydrogenation or an Fe(III)-catalyzed rearomatization/dehydrogenation pathway. PMID- 29260561 TI - Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Triggered Isothermal Amplification for Site-Specific Nucleic Acid Detection. AB - A novel CRISPR/Cas9 triggered isothermal exponential amplification reaction (CAS EXPAR) strategy based on CRISPR/Cas9 cleavage and nicking endonuclease (NEase) mediated nucleic acids amplification was developed for rapid and site-specific nucleic acid detection. CAS-EXPAR was primed by the target DNA fragment produced by cleavage of CRISPR/Cas9, and the amplification reaction performed cyclically to generate a large number of DNA replicates which were detected using a real time fluorescence monitoring method. This strategy that combines the advantages of CRISPR/Cas9 and exponential amplification showed high specificity as well as rapid amplification kinetics. Unlike conventional nucleic acids amplification reactions, CAS-EXPAR does not require exogenous primers, which often cause target independent amplification. Instead, primers are first generated by Cas9/sgRNA directed site-specific cleavage of target and accumulated during the reaction. It was demonstrated this strategy gave a detection limit of 0.82 amol and showed excellent specificity in discriminating single-base mismatch. Moreover, the applicability of this method to detect DNA methylation and L. monocytogenes total RNA was also verified. Therefore, CAS-EXPAR may provide a new paradigm for efficient nucleic acid amplification and hold the potential for molecular diagnostic applications. PMID- 29260562 TI - Three Sequential C-N Bond Formations: tert-Butyl Nitrite as a N1 Synthon in a Three Component Reaction Leading to Imidazo[1,2-a]quinolines and Imidazo[2,1 a]isoquinolines. AB - tert-Butyl nitrite serves the dual role of an oxidant as well as a N1 synthon in a multicomponent reaction involving quinolines, isoquinolines, and styrenes. Herein, two sp2 C-H functionalizations of styrenes and one sp2 C-H functionalization of quinolines and isoquinolines lead to the formation of fused quinolines and isoquinolines via three sequential C-N bond formations. PMID- 29260563 TI - Smart Nanoparticles Undergo Phase Transition for Enhanced Cellular Uptake and Subsequent Intracellular Drug Release in a Tumor Microenvironment. AB - Inefficient cellular uptake and intracellular drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. To overcome both problems, we designed a smart nanoparticle that undergoes phase transition in a tumor microenvironment (TME). The smart nanoparticle is generated using a lipid-polypetide hybrid nanoparticle, which comprises a PEGylated lipid monolayer shell and a pH-sensitive hydrophobic poly-l histidine core and is loaded with the antitumor drug doxorubicin (DOX). The smart nanoparticle undergoes a two-step phase transition at two different pH values in the TME: (i) At the TME (pHe: 7.0-6.5), the smart nanoparticle swells, and its surface potential turns from negative to neutral, facilitating the cellular uptake; (ii) After internalization, at the acid endolysosome (pHendo: 6.5-4.5), the smart nanoparticle dissociates and induces endolysosome escape to release DOX into the cytoplasm. In addition, a tumor-penetrating peptide iNRG was modified on the surface of the smart nanoparticle as a tumor target moiety. The in vitro studies demonstrated that the iNGR-modified smart nanoparticles promoted cellular uptake in the acidic environment (pH 6.8). The in vivo studies showed that the iNGR-modified smart nanoparticles exerted more potent antitumor efficacy against late-stage aggressive breast carcinoma than free DOX. These data suggest that the smart nanoparticles may serve as a promising delivery system for sequential uptake and intracellular drug release of antitumor agents. The easy preparation of these smart nanoparticles may also have advantages in the future manufacture for clinical trials and clinical use. PMID- 29260565 TI - Driving Structural Transitions in Molecular Simulations Using the Nonequilibrium Candidate Monte Carlo. AB - Hybrid simulation procedures which combine molecular dynamics with Monte Carlo are attracting increasing attention as tools for improving the sampling efficiency in molecular simulations. In particular, encouraging results have been reported for nonequilibrium candidate protocols, in which a Monte Carlo move is applied gradually, and interleaved with a process that equilibrates the remaining degrees of freedom. Although initial studies have uncovered a substantial potential of the method, its practical applicability for sampling structural transitions in macromolecules remains incompletely understood. Here, we address this issue by systematically investigating the efficiency of the nonequilibrium candidate Monte Carlo on the sampling of rotameric distributions of two peptide systems at atomistic resolution both in vacuum and explicit solvent. The studied systems allow us to directly probe the efficiency with which a single or a few slow degrees of freedom can be driven between well-separated free-energy minima and to explore the sensitivity of the method toward the involved free parameters. In line with results on other systems, our study suggests that order-of-magnitude gains can be obtained in certain scenarios but also identifies challenges that arise when applying the procedure in explicit solvent. PMID- 29260564 TI - Modular Three-Component Synthesis of 4-Aminoquinolines via an Imidoylative Sonogashira/Cyclization Cascade. AB - We developed a one-pot, two-stage synthetic route to substituted 4 aminoquinolines involving an imidoylative Sonogashira coupling followed by acid mediated cyclization. This three-component reaction affords pharmaceutically valuable 4-aminoquinolines in a one-pot procedure from readily available starting materials. The reaction tolerates various substituents on the arene as well as the use of secondary and even primary isocyanides. Additionally, the wide tolerance for functionalized isocyanides allows for the one-pot synthesis of various substituted chloroquine analogues as well as other medicinally relevant products. PMID- 29260566 TI - Computational Study of Uracil Tautomeric Forms in the Ribosome: The Case of Uracil and 5-Oxyacetic Acid Uracil in the First Anticodon Position of tRNA. AB - Tautomerism is important in many biomolecular interactions, not least in RNA biology. Crystallographic studies show the possible presence of minor tautomer forms of transfer-RNA (tRNA) anticodon bases in the ribosome. The hydrogen positions are not resolved in the X-ray studies, and we have used ab initio calculations and molecular dynamics simulations to understand if and how the minor enol form of uracil (U), or the modified uracil 5-oxyacetic acid (cmo5U), can be accommodated in the tRNA-messenger-RNA interactions in the ribosome decoding center. Ab initio calculations on isolated bases show that the modification affects the keto-enol equilibrium of the uracil base only slightly; the keto form is dominant (>99.99%) in both U and cmo5U. Other factors such as interactions with the surrounding nucleotides or ions would be required to shift the equilibrium toward the enol tautomer. Classical molecular simulations show a better agreement with the X-ray structures for the enol form, but free energy calculations indicate that the most stable form is the keto. In the ribosome, the enol tautomers of U and cmo5U pair with a guanine forming two hydrogen bonds, which do not involve the enol group. The oxyacetic acid modification has a minor effect on the keto-enol equilibrium. PMID- 29260568 TI - Molecular Dynamics Simulations of Strain-Induced Phase Transition of Poly(ethylene oxide) in Water. AB - We study the dilute aqueous solutions of poly(ethylene oxide) (PEO) oligomers that are subject to an elongating force dipole acting on both chain ends using atomistic molecular dynamics. By increasing the force, liquid-liquid demixing can be observed at room temperature far below the lower critical solution temperature. For forces above 35 pN, fibrillar nanostructures are spontaneously formed related to a decrease in hydrogen bonding between PEO and water. Most notable is a rapid decrease in the bifurcated hydrogen bonds during stretching, which can also be observed for isolated single chains. The phase-segregated structures display signs of chain ordering, but a clear signature of the crystalline order is not obtained during the simulation time, indicating a liquid liquid phase transition induced by chain stretching. Our results indicate that the solvent quality of the aqueous solution of PEO depends on the conformational state of the chains, which is most likely related to the specific hydrogen-bond induced solvation of PEO in water. The strain-induced demixing of PEO opens the possibility to obtain polymer fibers with low energy costs because crystallization starts via the strain-induced demixing in the extended state only. PMID- 29260567 TI - Stoichiometry, Absolute Abundance, and Localization of Proteins in the Bacillus cereus Spore Coat Insoluble Fraction Determined Using a QconCAT Approach. AB - Spores of Bacillus cereus pose a threat to food safety due to their high resistance to the heat or acid treatments commonly used to make food microbiologically safe. Spores may survive these treatments and later resume growth either on foodstuffs or, after ingestion, upon entering the gut they are capable of producing toxins, which cause either vomiting or diarrhea. The outer layers of the spore, the spore coat and exosporium, consist primarily of proteins that may serve as potential biomarkers for detection. The major morphogenetic protein CotE is important for correct assembly and attachment of the outermost layer, the exosporium, and by extension retention of many proteins. However, characterization of the proteins affected by deletion of CotE has been limited to electrophoretic patterns. Here we report the effect of CotE deletion on the insoluble fraction of the spore proteome through liquid chromatography-Fourier transform tandem mass spectrometry (LC-FTMS/MS) analysis. A total of 560 proteins have been identified in both mutant and wild-type spore coat isolates. A further 163 proteins were identified exclusively in wild-type spore isolates indicating that they are dependent on CotE for their association with the spore. Several of these are newly confirmed as associated with the exosporium, namely BC_2569 (BclF), BC_3345, BC_2427, BC_2878, BC_0666, BC_2984, BC_3481, and BC_2570. A total of 153 proteins were only identified in DeltaCotE spore isolates. This was observed for proteins that are known or likely to be interacting with or are encased by CotE. Crucial spore proteins were quantified using a QconCAT reference standard, the first time this was used in a biochemically heterogeneous system. This allowed us to determine the absolute abundance of 21 proteins, which spanned across three orders of magnitude and together covered 5.66% +/- 0.51 of the total spore weight. Applying the QconCAT methodology to the DeltaCotE mutant allowed us to quantify 4.13% +/- 0.14 of the spore total weight and revealed a reduction in abundance for most known exosporium associated proteins upon CotE deletion. In contrast, several proteins, either known or likely to be interacting with or encased by CotE (i.e., GerQ), were more abundant. The results obtained provide deeper insight into the layered spore structure such as which proteins are exposed on the outside of the spore. This information is important for developing detection methods for targeting spores in a food safety setting. Furthermore, protein stoichiometry and determination of the abundance of germination mediating enzymes provides useful information for germination and outgrowth model development. PMID- 29260569 TI - Photocurrent Spectroscopy of Perovskite Solar Cells Over a Wide Temperature Range from 15 to 350 K. AB - Solar cells based on metal halide perovskite thin films show great promise for energy generation in a range of environments from terrestrial installations to space applications. Here we assess the device characteristics of the prototypical perovskite solar cells based on methylammonium lead triiodide (CH3NH3PbI3) over a broad temperature range from 15 to 350 K (-258 to 77 degrees C). For these devices, we observe a peak in the short-circuit current density and open-circuit voltage at 200 K (-73 degrees C) with decent operation maintained up to 350 K. We identify the clear signature of crystalline PbI2 contributing directly to the low-temperature photocurrent spectra, showing that PbI2 plays an active role (beyond passivation) in CH3NH3PbI3 solar cells. Finally we observe a blue-shift in the photocurrent spectrum with respect to the absorption spectrum at low temperature (15 K), allowing us to extract a lower limit on the exciton binding energy of 9.1 meV for CH3NH3PbI3. PMID- 29260570 TI - Topological Origins of Bound States in the Continuum for Systems with Conical Intersections. AB - Bound states in the continuum (BSCs) were reported in a linear vibronic coupling model with a conical intersection (CI) [Cederbaum et al. Phys. Rev. Lett. 2003, 90, 013001]. It was also found that these states are destroyed within the Born Oppenheimer approximation (BOA). We investigate whether a nontrivial topological or geometric phase (GP) associated with the CI is responsible for BSCs. To address this question we explore modifications of the original 2D two-state linear vibronic coupling model supporting BSCs. These modifications either add GP effects after the BOA or remove the GP within a two-state problem. Using the stabilization graph technique we have shown that the GP is crucial for emergence of BSCs. PMID- 29260571 TI - Mechanism of Urea Crystal Dissolution in Water from Molecular Dynamics Simulation. AB - Molecular dynamics simulations are used to determine the mechanism of urea crystal dissolution in water under sink conditions. Crystals of cubic and tablet shapes are considered, and results are reported for four commonly used water models. The dissolution rates for different water models can differ considerably, but the overall dissolution mechanism remains the same. Urea dissolution occurs in three stages: a relatively fast initial stage, a slower intermediate stage, and a final stage. We show that the long intermediate stage is well described by classical rate laws, which assume that the dissolution rate is proportional to the active surface area. By carrying out simulations at different temperatures, we show that urea dissolution is an activated process, with an activation energy of ~32 kJ mol-1. Our simulations give no indication of a significant diffusion layer, and we conclude that the detachment of molecules from the crystal is the rate-determining step for dissolution. The results we report for urea are consistent with earlier observations for the dissolution of NaCl crystals. This suggests that the three-stage mechanism and classical rate laws might apply to the dissolution of other ionic and molecular crystals. PMID- 29260572 TI - Hypoxia as an independent predictor of adverse outcomes in pulmonary embolism. AB - Background The purpose of this study was to investigate the correlation between the computed tomography pulmonary artery obstruction index and parameters of functional lung impairment in acute pulmonary embolism, and establish the value of these parameters in prognosticating right ventricular dysfunction and 30-day mortality. Methods This study included 322 consecutive patients (mean age 45.6 +/ 13.2 years, 46.9% male) with acute pulmonary embolism, free of other cardiopulmonary disease, who underwent computed tomography pulmonary angiography. Correlations of arterial CO2, O2, and alveolar-arterial oxygen gradient with the computed tomography pulmonary artery obstruction index, measured using the Qanadli score, were analyzed. Logistic regression was used to identify independent predictors of right ventricular dysfunction and 30-day mortality. Results Of the 322 patients, 196 (60.9%) had right ventricular dysfunction, and 58 (18.0%) died within 30 days. The pulmonary artery obstruction index had a significant correlation with partial pressures of arterial O2 ( r = -0.887, p < 0.001) and CO2 ( r = -0.618, p = 0.019) and alveolar-arterial oxygen gradient ( r = +0.874, p < 0.001). Arterial O2 pressure had a good predictive accuracy and discriminative power for both right ventricular dysfunction (sensitivity 80.6%, specificity 85.1%, area under the curve 0.91) and 30-day mortality (sensitivity 77.8%, specificity 82.0%, area under the curve 0.89). Conclusions In patients with acute pulmonary embolism, free of other cardiopulmonary disease, parameters of functional impairment have a strong correlation with computed tomography pulmonary artery obstruction index. Hypoxia is an independent predictor of both right ventricular dysfunction and 30-day mortality in these patients. PMID- 29260573 TI - Innovation in nuclear medicine instrumentation: looking back and moving forward. PMID- 29260574 TI - Ghosts, tigers and landmines in the nursery: Attachment narratives of loss in Tamil refugee children with dead or missing fathers. AB - OBJECTIVE: To build an account of how bereaved Tamil refugee and asylum seeker children, resettled in Australia, had processed the loss of their dead or missing fathers. METHOD: Phenomenological and discourse analysis was applied to attachment narratives of nine children (aged 11-17 years) and their surviving mothers in families that lost fathers in war-related circumstances. The narratives were analysed through the lens of Crittenden's Dynamic-Maturational Model of Attachment and Adaptation (DMM) and Klass' cross-cultural model of grief. RESULTS: Two divergent pathways - 'burying the past' and 'reifying the past' - emerged, encompassing the children's contrasting patterns of information processing regarding loss and trauma (dismissing or preoccupying) and representation of the past (distant-buried or rich-reconstructed). Each pathway reflected a strategic compromise between the constraints and resources presented to the child by the circumstances of the loss (ambiguous or confirmed), the response of their surviving parent (stricken or stoic) and the collective narrative surrounding the loss (silenced or valorised). CONCLUSION: The DMM's conceptualisation of attachment as self-protective strategies for navigating danger was helpful in explaining the contrasting adaptations of refugee children to loss and trauma. However, to understand the multivalent meanings of these adaptations, there was a need to situate child-parent attachment relationships within the wider sociocultural reconfigurations arising from contexts of political violence. PMID- 29260575 TI - Increased diffusion and decreased perfusion in epiphyses of femoral heads detected via intravoxel incoherent motion after closed reduction in children with developmental dysplasia of the hip. AB - Background Patients with developmental dysplasia of the hip (DDH) may have decreased blood supply to the femoral heads. Finding a non-invasive method to evaluate whether the femoral heads in patients with DDH are ischemic is paramount for orthopedic surgeons. Purpose To identify whether parameters reflecting perfusion and diffusion in intravoxel incoherent motion (IVIM) sequences can be used to assess ischemia in femoral heads in patients with DDH after closed reduction. Material and Methods Twenty-eight patients with DDH who had undergone closed reduction were enrolled. IVIM data were acquired using a 3-T magnetic resonance scanner, regions of interest were placed on the epiphyses; ADCslow, ADCfast, f, and ADCfast*f were measured. A Mann-Whitney U test was performed to compare ADCslow, ADCfast, f, and ADCfast*f between the lesion and control sides. Receiver operating characteristic curves were generated with respective cut-off values. The lesion sides were classified based on the International Hip Dysplasia Institute (IHDI) classification. ADCslow, ADCfast, f, and ADCfast*f were compared among the groups. Results ADCslow was higher and ADCfast, f, and ADCfast*f were lower on the lesion sides ( P = 0.000-0.002). The optimal cut-off value for ADCfast*f, ADCfast, ADCslow, and f were 0.030, 0.626, 0.000251, and 0.636, respectively. Higher IHDI classification scores on the lesion side were associated with lower ADCfast, f, and ADCfast*f, and higher ADCslow values. Conclusion IVIM is a promising method to investigate the perfusion and diffusion of epiphyses of femoral heads. PMID- 29260576 TI - Quantification of pancreatic fat with dual-echo imaging at 3.0-T MR in clinical application: how do the corrections for T1 and T2* relaxation effect work and simplified correction strategy. AB - Background Dual-echo imaging is a routine clinical magnetic resonance (MR) sequence affected by T1 and T2* relaxation effect in fat quantification. The separate impacts of T1 and T2* relaxation effect in pancreatic fat quantification using dual-echo imaging at 3.0-T MR have not been reported in detail. Purpose To demonstrate the separate T1 and T2* relaxation effect on pancreatic fat quantification by dual-echo imaging at 3.0-T MR and the simplified correction strategy is discussed for convenient clinical application. Material and Methods Twenty-one non-alcoholic fatty liver disease (NAFLD) participants with high risk of pancreatic steatosis were included. Pancreatic fat fractions (FF) by dual-echo imaging with different corrections were compared to that of proton magnetic resonance spectroscopy (1H-MRS). Correlation analysis and Bland-Altman analysis were applied. Results The FF by 1H-MRS was 5.9 +/- 1.7%. Significant positive correlation (all P < 0.01) was found between FF by 1H-MRS and each dual-echo imaging, in which T1 and T2* correction showed the best correlation (r = 0.95, FF = 6.2 +/- 1.7%) and no correction showed the worst correlation (r = 0.86, FF = 5.2 +/- 2.0%), and the simplified T1 and T2* correction manifested as r = 0.93 and FF = 6.3 +/- 1.8%. FF by T1 and T2* correction showed the best agreement, while T1 correction showed the worst agreement as compared to that of 1H-MRS. Conclusion T1 and T2* correction shows the best performance while no correction dual-echo imaging remains clinical available which may benefit from prior OP echo. Simplified correction using single T2* (32.6 ms) of water and fat is recommended for convenient clinical application in absence of obvious pancreatic iron overload. PMID- 29260577 TI - Coronary computed tomography in heart transplant patients: detection of significant stenosis and cardiac allograft vasculopathy, image quality, and radiation dose. AB - Background Cardiac allograft vasculopathy (CAV) is an accelerated form of atherosclerosis unique to heart transplant (HTX) patients. Purpose To investigate the detection of significant coronary artery stenosis and CAV, determinants of image quality, and the radiation dose in coronary computed tomography angiography (CCTA) of HTX patients with 64-slice multidetector CT (64-MDCT). Material and Methods Fifty-two HTX recipients scheduled for invasive coronary angiography (ICA) were prospectively enrolled and underwent CCTA before ICA with intravascular ultrasound (IVUS). Results Interpretable CCTA images were acquired in 570 (95%) coronary artery segments >=2 mm in diameter. Sensitivity, specificity, and positive and negative predictive values of CCTA for the detection of segments with significant stenosis (lumen reduction >=50%) on ICA were 100%, 98%, 7.7%, and 100%, respectively. Twelve significant stenoses were located in segments with uninterpretable image quality or vessel diameter <2 mm; only one was eligible for intervention. IVUS detected CAV (maximal intimal thickness >=0.5 mm) in 33/41 (81%) patients; CCTA and ICA identified CAV (any wall or luminal irregularity) in 18 (44%) and 14 (34%) of these 33 patients, respectively. The mean estimated radiation dose was 19.0 +/- 3.4 mSv for CCTA and 5.7 +/- 3.3 mSv for ICA ( P < 0.001). Conclusion CCTA with interpretable image quality had a high negative predictive value for ruling out significant stenoses suitable for intervention. The modest detection of CAV by CCTA implied a limited value in identifying subtle CAV. The high estimated radiation dose for 64-MDCT is of concern considering the need for repetitive examinations in the HTX population. PMID- 29260578 TI - The Primary Care Obesity Network: Translating Expert Committee Guidelines on Childhood Obesity Into Practice. AB - Childhood obesity remains a serious public health threat. There is an urgent need for innovative, effective, and sustainable interventions for childhood obesity that are multisector, integrated, and pragmatic. Using the 2007 Expert Committee on the Assessment, Prevention, and Treatment of Child and Adolescent Overweight and Obesity as a guide, a tertiary care obesity program at a children's hospital established the Primary Care Obesity Network (PCON). This article describes the structure, implementation, resources, and outcome measures of the PCON, a network of primary care practices and a tertiary care obesity center established to prevent and treat childhood obesity in Central Ohio. This program offers an opportunity to assess how and whether the expert committee guidelines can be translated into practice. As Accountable Care Organizations strive to provide services through the lens of improving population health, the PCON can serve as an example for addressing childhood obesity. PMID- 29260579 TI - Profiling long noncoding RNA of multi-tissue transcriptome enhances porcine noncoding genome annotation. AB - AIM: To construct a comprehensive pig noncoding transcriptome and further enhance porcine noncoding genome annotation. MATERIALS & METHODS: We performed a tissue based long noncoding RNA (lncRNA) profiling via exploiting 32,212 nonredundant lncRNA isoforms corresponding to 18,676 lncRNA loci across 34 normal pig tissues using high-throughput sequencing. Furthermore, the potential relationship between our identified lncRNAs and known protein-coding genes were globally assessed via a comprehensive computation-based strategy, developing a genome-wide lncRNA targeted genome draft for further functional studies on noncoding genes. RESULTS & CONCLUSION: Among these lncRNAs, ubiquitously expressed lncRNA appeared at a higher level compared with tissue-specific one. Findings herein provide insight into comprehensive knowledge of porcine noncoding RNAs and further enhance pig noncoding annotation. For ease of accessing the information of the identified lncRNAs, we deposited those with high confidence in the publicly available NONCODE database, providing a valuable resource for facilitating pig noncoding genomic studies. PMID- 29260580 TI - The dominance of bacterial genotypes leads to susceptibility variations under sublethal antibiotic pressure. AB - AIM: To investigate the collective resistance of the bacteria population with resistant horizontal gene transfer under sublethal bactericide pressure. MATERIALS & METHODS: By employing qualitative analysis of ordinary differential equations, particularly bifurcation theory and several numerical simulations, a modified 4D ordinary differential equation model describing antibiotic susceptibility variations induced by sublethal antibiotic pressure is analyzed in detail. RESULTS: The long-term behaviors and collective resistance of different bacterial genotype populations in different sublethal bactericide concentration subintervals exhibit high levels of heterogeneity and are determined by the protection provided by resistant genes on chromosome or plasmid, their fitness costs, plasmid segregation rate and sublethal bactericide pressure. CONCLUSION: First, the possible mechanism of antibiotic susceptibility variations is the dominance of different bacterial genotypes under sublethal bactericide pressure, rather than persistence, tolerance or resistance. Additionally, the combination of vertical genetic transfer, horizontal genetic transfer and plasmid segregation can lead to unique switch between two states of different bacterial genotypes. PMID- 29260581 TI - Dietary phenolic acids reverse insulin resistance, hyperglycaemia, dyslipidaemia, inflammation and oxidative stress in high-fructose diet-induced metabolic syndrome rats. AB - This study investigated the influence of caffeic, ferulic, gallic and protocatechuic acids on high-fructose diet-induced metabolic syndrome in rats. Oral administration of the phenolic acids significantly reversed high-fructose diet-mediated increase in body mass index and blood glucose. Furthermore, phenolic acids restored high-fructose diet-mediated alterations in metabolic hormones (insulin, leptin and adiponectin). Similarly, elevated tumour necrosis factor-alpha, interleukin-6 and -8 were significantly lowered. Administration of phenolic acids restored High-fructose diet-mediated increase in the levels of lipid parameters and indices of atherosclerosis, cardiac and cardiovascular diseases. High-fructose diet-mediated decrease in activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase) and increase in oxidative stress biomarkers (reduced glutathione, lipid peroxidation products, protein oxidation and fragmented DNA) were significantly restored by the phenolic acids. The result of this study shows protective influence of caffeic acid, ferulic acid, gallic acid and protocatechuic acid in high-fructose diet-induced metabolic syndrome. PMID- 29260583 TI - The ability of clinical balance measures to identify falls risk in multiple sclerosis: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the ability of clinical measures of balance to distinguish fallers from non-fallers and to determine their predictive validity in identifying those at risk of falls. DATA SOURCES: AMED, CINAHL, Medline, Scopus, PubMed Central and Google Scholar. First search: July 2015. Final search: October 2017. REVIEW METHODS: Inclusion criteria were studies of adults with a definite multiple sclerosis diagnosis, a clinical balance assessment and method of falls recording. Data were extracted independently by two reviewers. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 scale and the modified Newcastle-Ottawa Quality Assessment Scale. Statistical analysis was conducted for the cross-sectional studies using Review Manager 5. The mean difference with 95% confidence interval in balance outcomes between fallers and non-fallers was used as the mode of analysis. RESULTS: We included 33 studies (19 cross-sectional, 5 randomised controlled trials, 9 prospective) with a total of 3901 participants, of which 1917 (49%) were classified as fallers. The balance measures most commonly reported were the Berg Balance Scale, Timed Up and Go and Falls Efficacy Scale International. Meta-analysis demonstrated fallers perform significantly worse than non-fallers on all measures analysed except the Timed Up and Go Cognitive ( p < 0.05), but discriminative ability of the measures is commonly not reported. Of those reported, the Activities-specific Balance Confidence Scale had the highest area under the receiver operating characteristic curve value (0.92), but without reporting corresponding measures of clinical utility. CONCLUSION: Clinical measures of balance differ significantly between fallers and non-fallers but have poor predictive ability for falls risk in people with multiple sclerosis. PMID- 29260582 TI - Sipuleucel-T for the treatment of prostate cancer: novel insights and future directions. AB - Sipuleucel-T, an autologous cellular immunotherapy manufactured from antigen presenting cells primed to recognize prostatic acid phosphatase, was the first immunotherapy product approved by the US FDA. It was approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer after it was shown to provide a survival advantage. Additional studies have examined its use in other clinical settings and in combination with other approved and investigational immunotherapy agents. This review will discuss the pivotal trials leading to approval, will outline some of the biomarkers associated with its efficacy and will review some of the ongoing combination strategies. Maximizing the efficacy of sipuleucel-T through better patient selection or through combination approaches remains the challenge of the future. PMID- 29260584 TI - Longitudinal modeling to predict vital capacity in amyotrophic lateral sclerosis. AB - OBJECTIVES: Death in amyotrophic lateral sclerosis (ALS) patients is related to respiratory failure, which is assessed in clinical settings by measuring vital capacity. We developed ALS-VC, a modeling tool for longitudinal prediction of vital capacity in ALS patients. METHODS: A gradient boosting machine (GBM) model was trained using the PRO-ACT (Pooled Resource Open-access ALS Clinical Trials) database of over 10,000 ALS patient records. We hypothesized that a reliable vital capacity predictive model could be developed using PRO-ACT. RESULTS: The model was used to compare FVC predictions with a 30-day run-in period to predictions made from just baseline. The internal root mean square deviations (RMSD) of the run-in and baseline models were 0.534 and 0.539, respectively, across the 7L FVC range captured in PRO-ACT. The RMSDs of the run-in and baseline models using an unrelated, contemporary external validation dataset (0.553 and 0.538, respectively) were comparable to the internal validation. The model was shown to have similar accuracy for predicting SVC (RMSD = 0.562). The most important features for both run-in and baseline models were "Baseline forced vital capacity" and "Days since baseline." CONCLUSIONS: We developed ALS-VC, a GBM model trained with the PRO-ACT ALS dataset that provides vital capacity predictions generalizable to external datasets. The ALS-VC model could be helpful in advising and counseling patients, and, in clinical trials, it could be used to generate virtual control arms against which observed outcomes could be compared, or used to stratify patients into slowly, average, and rapidly progressing subgroups. PMID- 29260585 TI - Intraoperative visualisation of functional structures facilitates safe frameless stereotactic biopsy in the motor eloquent regions of the brain. AB - BACKGROUND: For stereotactic brain biopsy involving motor eloquent regions, the surgical objective is to enhance diagnostic yield and preserve neurological function. To achieve this aim, we implemented functional neuro-navigation and intraoperative magnetic resonance imaging (iMRI) into the biopsy procedure. The impact of this integrated technique on the surgical outcome and postoperative neurological function was investigated and evaluated. METHOD: Thirty nine patients with lesions involving motor eloquent structures underwent frameless stereotactic biopsy assisted by functional neuro-navigation and iMRI. Intraoperative visualisation was realised by integrating anatomical and functional information into a navigation framework to improve biopsy trajectories and preserve eloquent structures. iMRI was conducted to guarantee the biopsy accuracy and detect intraoperative complications. The perioperative change of motor function and biopsy error before and after iMRI were recorded, and the role of functional information in trajectory selection and the relationship between the distance from sampling site to nearby eloquent structures and the neurological deterioration were further analyzed. RESULTS: Functional neuro navigation helped modify the original trajectories and sampling sites in 35.90% (16/39) of cases to avoid the damage of eloquent structures. Even though all the lesions were high-risk of causing neurological deficits, no significant difference was found between preoperative and postoperative muscle strength. After data analysis, 3mm was supposed to be the safe distance for avoiding transient neurological deterioration. During surgery, the use of iMRI significantly reduced the biopsy errors (p = 0.042) and potentially increased the diagnostic yield from 84.62% (33/39) to 94.87% (37/39). Moreover, iMRI detected intraoperative haemorrhage in 5.13% (2/39) of patients, all of them benefited from the intraoperative strategies based on iMRI findings. CONCLUSIONS: Intraoperative visualisation of functional structures could be a feasible, safe and effective technique. Combined with intraoperative high-field MRI, it contributed to enhance the biopsy accuracy and lower neurological complications in stereotactic brain biopsy involving motor eloquent areas. PMID- 29260586 TI - Factors That Influence Campus Dwelling University Students' Facility to Practice Healthy Living Guidelines. AB - Background Young adult university students living on campus are at an increased risk of developing lifestyle habits that encourage unintentional weight gain. Purpose The purpose of this study was to identify the individual and contextual factors that influence campus dwelling university students' facility to practice healthy living guidelines that reduce their risk of unintentional weight gain. Lifestyle practices included nutrition, physical activity, and sleep. Methods For seven days, 48 campus dwelling students recorded their activities and reflected on how closely they were able to follow recommended healthy living guidelines. Recorded data were supplemented by follow-up focus groups. All data were analyzed using thematic analysis. Results Students described multiple factors and conditions that influenced their facility to practice healthy living guidelines for nutrition, activity, and sleep. Many students' lifestyle practices put them at an increased risk of unintentional weight gain. Conclusions The campus environment challenges student's facility to practice healthy living guidelines. Nurses can intervene to build individual student capacity and to advocate for environmental polices that increase students' facility to choose lifestyle practices that promote health, lessen their risk of unintentional weight gain, and reduce their risk of developing chronic illness. PMID- 29260587 TI - Right ventricular longitudinal strain: a tool for diagnosis and prognosis in light-chain amyloidosis. AB - OBJECTIVES: Light-chain (AL) amyloidosis can lead to an infiltrative cardiomyopathy with increased wall thickness (IWT) of very poor prognosis. Our primary aim was to analyse the right ventricle (RV) in patients with IWT to discriminate AL amyloidosis from IWT due to hypertrophic cardiomyopathy (HCM) or to arterial hypertension (HTN). Our secondary aim was to assess if RV dysfunction predicts overall mortality in cardiac AL amyloidosis. METHODS: We retrospectively and consecutively compared clinical, biological and echocardiographic data of 315 patients with IWT: 105 biopsy-proven AL amyloidosis patients, 105 patients with HCM and 105 patients with HTN. The prognostic value of these parameters was analysed in the AL amyloidosis group. RESULTS: Free-wall right ventricular longitudinal strain (FWRVLS) worse than -21.2% discriminates AL amyloidosis [area under the curve (AUC) = 0.744)] from patients with IWT due to other aetiologies. In AL amyloidosis, FWRVLS is the strongest echocardiographic prognostic marker with AUC =0.722 and -16.5% as the optimal cut-off value, beyond which overall mortality increases significantly. It is also the only independent echocardiographic predictor of overall mortality (HR =1.113; 95%CI 1.029-1.204; p = .007), even when adjusted to the Mayo stage and global left ventricular longitudinal strain. CONCLUSIONS: FWRVLS should be considered in the diagnostic and prognostic workup in light-chain amyloidosis. PMID- 29260588 TI - Upfront treatment of elderly myeloma patients: an overview and update. AB - INTRODUCTION: Multiple myeloma is primarily a disease of older age, with a median age of 70 years at diagnosis. Management of the disease in this diverse population is challenging, in the face of comorbidities and frailties. Areas covered: This review discusses the management challenges of elderly myeloma patients in view of the current evidence and propose for performing a formal objective assessment of the functional status to guide choice of treatment. Expert commentary: The approval of many antimyeloma medications with various mechanisms of action in the past two decades had sparked the debate about choosing the best combination, duration of therapy, role of transplant and the possibility to cure myeloma after being changed to a chronic disease. Indeed, among these debates are the choice of treatment for the elderly population and approaches that might help in clinical decision making particularly with the encouraging response and survival results of newer therapies. In this population, a balance between efficacy and toxicity is required to achieve prolongation of survival while maintaining the quality of life. Objective assessment of functional status might help in this task. Prospective randomized trials specifically addressing the needs for this population is certainly required to allow for more informed treatment decisions. PMID- 29260589 TI - Ultrasound-guided intrauterine device insertion: a step closer to painless insertion: a randomised control trial. PMID- 29260590 TI - Ovulatory status and menstrual cycle duration assessed by self-collection of urine on pH strips in a population-based sample of French women not using hormonal contraception. AB - BACKGROUND: Assessing menstrual cycle function in the general population using a non-invasive method is challenging, both in non-industrialized and industrialized countries. SUBJECTS AND METHODS: The Observatory of Fecundity in France (Obseff) recruited on a nationwide basis a random sample of 943 women aged 18-44 years with unprotected intercourse. A sub-study was set up to assess the characteristics of a menstrual cycle by using a non-invasive method adapted to the general population. Voluntary women were sent a collection kit by the post and requested to collect urine samples on pH strips, together with daily recording of reproductive-related information during a full menstrual cycle. A total of 48 women collected urine every day, whereas 160 women collected urine every other day. Immunoassays were used to measure pregnanediol-3-alpha glucuronide, estrone-3-glucuronide and creatinine. Ovulation occurrence and follicular phase duration were estimated using ovulation detection algorithms, compared to a gold standard consisting of three external experts in reproductive medicine. RESULTS: Every other day urine collection gave consistent results in terms of ovulation detection with every day collection (intraclass coefficient of correlation, 0.84, 95% confidence interval, 0.76-0.98). The proportion of anovulatory menstrual cycles was 8%. The characteristics of the ovulatory cycles were length 28 (26-34), follicular phase 16 (12-23), luteal phase 13 (10-16) days median (10th-90th percentiles). DISCUSSION-CONCLUSION: Assessing menstrual cycle characteristics based on urine sample spot only collected every other day in population-based studies through a non-invasive, well accepted and cost-limited procedure not requiring any direct contact with the survey team appears feasible and accurate. PMID- 29260591 TI - Subacute Encephalopathy With Seizures in Alcoholics (SESA) Presenting as Focal Nonconvulsive Status Epilepticus. AB - PURPOSE: To acquaint readers with the underrecognized subacute encephalopathy with seizures in chronic alcoholics (SESA) that has more recently been associated with different types of status epilepticus. METHODS: Case reports and review of the literature on SESA and nonconvulsive status epilepticus (NCSE). RESULTS: Two cases: one with alternating bifrontoparietal NCSE, and one with focal, confusional NCSE, with imaging and EEG correlates. CONCLUSION: Underrecognized SESA may present as NCSE with focal clinical, EEG and reversible diffusion weighted MRI abnormalities, warranting expedited diagnosis and antiseizure treatment to minimize morbidity. PMID- 29260593 TI - Determinants of glucose metabolism and the role of NPY in the progression of insulin resistance in chronic migraine. AB - Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic beta-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, beta-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and beta-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or beta-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal beta-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system. PMID- 29260592 TI - How do aggregated patient-reported outcome measures data stimulate health care improvement? A realist synthesis. AB - Objectives Internationally, there has been considerable debate about the role of data in supporting quality improvement in health care. Our objective was to understand how, why and in what circumstances the feedback of aggregated patient reported outcome measures data improved patient care. Methods We conducted a realist synthesis. We identified three main programme theories underlying the use of patient-reported outcome measures as a quality improvement strategy and expressed them as nine 'if then' propositions. We identified international evidence to test these propositions through searches of electronic databases and citation tracking, and supplemented our synthesis with evidence from similar forms of performance data. We synthesized this evidence through comparing the mechanisms and impact of patient-reported outcome measures and other performance data on quality improvement in different contexts. Results Three programme theories were identified: supporting patient choice, improving accountability and enabling providers to compare their performance with others. Relevant contextual factors were extent of public disclosure, use of financial incentives, perceived credibility of the data and the practicality of the results. Available evidence suggests that patients or their agents rarely use any published performance data when selecting a provider. The perceived motivation behind public reporting is an important determinant of how providers respond. When clinicians perceived that performance indicators were not credible but were incentivized to collect them, gaming or manipulation of data occurred. Outcome data do not provide information on the cause of poor care: providers needed to integrate and interpret patient reported outcome measures and other outcome data in the context of other data. Lack of timeliness of performance data constrains their impact. Conclusions Although there is only limited research evidence to support some widely held theories of how aggregated patient-reported outcome measures data stimulate quality improvement, several lessons emerge from interventions sharing the same programme theories to help guide the increasing use of these measures. PMID- 29260594 TI - Contraceptive sales after the Zika epidemic. PMID- 29260595 TI - The Affect Regulation in Cancer framework: Understanding affective responding across the cancer trajectory. AB - Affective dimensions of cancer have long been a central concern in the field of psycho-oncology. Recent developments in the field of affective science suggest the value of incorporating insights from the burgeoning literature on affect regulation. Accordingly, the objective of this article is to build on prior work in this area by applying a process-oriented affect regulation framework to the various phases of the cancer trajectory. The Affect Regulation in Cancer framework is adapted from Gross' process model of emotion regulation, and its aim is to integrate recent advances in affective science with work in the field of psycho-oncology. The basic elements of the affect generative and affect regulatory processes are outlined across the various phases of the cancer trajectory. Our proposed model provides a useful heuristic framework in advancing research on the ways people manage their affective responses throughout the cancer trajectory. PMID- 29260596 TI - Transverse myelitis following methotrexate treatment of ectopic pregnancy: a case report. AB - OBJECTIVE: Ectopic pregnancy is a common condition in the field of gynaecology, often treated with methotrexate. Adverse effects are common and usually mild. Severe adverse events are rare amongst patients treated with MTX for this condition. CASE: A 26-year-old healthy woman was admitted and treated medically with MTX for an ectopic pregnancy. The patient was treated in the standard drug labelled protocol with an intramuscular injection of 78 mg of MTX according to body surface area. Soon after, the patient presented to the emergency department with symptoms of bilateral paresthesia of the lower limbs which ascended to the pelvis. After a thorough work up and imaging via MRI a diagnosis of transverse myelitis was made. Treatment was successful with corticosteroids and symptoms subsided. CONCLUSIONS: We propose that MTX should be used with caution and severe toxicity should be kept in mind with high index of awareness for any symptom development following treatment, especially neurological one. PMID- 29260597 TI - A review of adolescent autobiographical memory and the implications for assessment of unaccompanied minors' refugee determinations. AB - The number of unaccompanied asylum-seeking children (UASC) is increasing, and unlike those who arrive with their parents, UASC are subject to interview to determine refugee status. The limited amount of objective evidence available in most asylum claims means that the UASC's account of their experiences often becomes key in deciding whether or not the young person is granted protection. Research indicates that assumptions about human memory influence decision-makers' views on asylum seekers' accounts; however, these do not necessarily appear to fit with the published research on autobiographical memory and may lead to an unfair decision. Therefore, understanding the nature and limitations of autobiographical memory is key to a fair refugee determination process. A literature review of published research on autobiographical memory among adolescents was undertaken across four databases. In total, 45 papers were identified which were thematically organised into three areas: development of autobiographical memory, contextual influences and impact of psychopathology. From this review, conclusions are drawn about what can be reasonably expected of an adolescent's autobiographical memory generally and more specifically when the unique characteristics of UASC are taken into account. We also discusss how commonly used credibility indicators in refugee status determinations for minors are problematic in light of this research. It is important that the psychological evidence on the nature of autobiographical memory in adolescents is considered in asylum processing of UASC. PMID- 29260598 TI - Blueberry by-product used as an ingredient in the development of functional cookies. AB - A by-product of blueberry juice industries was used as an ingredient to develop fiber-enriched cookies. The blueberry pomace, once ground and dried, was used as an ingredient in cookie formulation. A control cookie was elaborated as reference. Cookies were analyzed for composition and functional properties. The fiber content obtained in the fiber-enriched cookie allows it to be labeled as "high fiber" in the European Union and as a "source of fiber" in MERCOSUR. The fiber-enriched cookie presented highly increased values on the antioxidant capacity and the polyphenol content when compared against the control cookie. Sensory evaluation was performed. Acceptability of the fiber-enriched cookie reached a value of 5.3 in a nine-point hedonic scale. Further strategies should be necessary in order to achieve an acceptable product. Cookies were subjected to an in vitro digestive process. Results show that the cookies' phytochemicals are bioaccessible and potentially bioavailable. Therefore, eating this type of food would represent an increase in the amount of antioxidants ingested and redound to a health benefit. In addition to improving both nutritional and functional properties of cookies, the present development represents an innovative strategy for a more sustainable growth of fruit juice industries. PMID- 29260599 TI - Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors. AB - INTRODUCTION: Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib. Promising results are notable in patients with peripheral T cell lymphoma in particular, forming the basis for the first phase 3 randomized trial of alisertib. Although it did show encouraging response rates, it failed to demonstrate superiority over the comparator arm at an interim analysis, halting further enrollment. Expert opinion: Despite disappointing early results, alisertib remains under investigation in a number of cancer types both as monotherapy and in combination with traditional cytotoxic chemotherapy, with encouraging results. Most common toxicities in early trials include myelosuppression alopecia, mucositis and fatigue. The relatively manageable toxicity profile of alisertib along with ease of dosing may allow it to be combined with other oral agents or traditional chemotherapy across a wide variety of malignancy types. PMID- 29260600 TI - Recent insights into human bronchial proteomics - how are we progressing and what is next? AB - INTRODUCTION: The human respiratory system is highly prone to diseases and complications. Many lung diseases, including lung cancer (LC), tuberculosis (TB), and chronic obstructive pulmonary disease (COPD) have been among the most common causes of death worldwide. Cystic fibrosis (CF), the most common genetic disease in Caucasians, has adverse impacts on the lungs. Bronchial proteomics plays a significant role in understanding the underlying mechanisms and pathogenicity of lung diseases and provides insights for biomarker and therapeutic target discoveries. Areas covered: We overview the recent achievements and discoveries in human bronchial proteomics by outlining how some of the different proteomic techniques/strategies are developed and applied in LC, TB, COPD, and CF. Also, the future roles of bronchial proteomics in predictive proteomics and precision medicine are discussed. Expert commentary: Much progress has been made in bronchial proteomics. Owing to the advances in proteomics, we now have better ability to isolate proteins from desired cellular compartments, greater protein separation methods, more powerful protein detection technologies, and more sophisticated bioinformatic techniques. These all contributed to our further understanding of lung diseases and for biomarker and therapeutic target discoveries. PMID- 29260601 TI - An association study between SCFD1 rs10139154 variant and amyotrophic lateral sclerosis in a Chinese cohort. AB - BACKGROUND: A recent genome-wide association study (GWAS) demonstrated that the Sec1 family domain containing 1 (SCFD1) gene is associated with amyotrophic lateral sclerosis (ALS). The objective of our study was to investigate the association between the single nucleotide polymorphism (SNP) rs10139154 in the SCFD1 gene and ALS in a Chinese cohort. METHODS: A cohort of 1074 sporadic ALS (SALS) patients from the Department of Neurology at the West China Hospital of Sichuan University were genotyped for rs10139154 using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. In addition, 927 unrelated healthy controls (HCs) from the same region were included. RESULTS: After adjusting for age and sex, no significant differences in the genotype distributions and allele frequencies in the allelic, additive, dominant or recessive genetic models were found between SALS and HCs and between patients with spinal onset and bulbar onset. Remarkably, rs10139154 was shown to be associated with the age at onset (AAO) of ALS patients. Consistently, ALS patients with the "CC" genotype have an earlier mean AAO than that of patients with a "CG" and "CG + GG" genotype (p = 0.002 and 0.001, respectively). CONCLUSION: Our results suggest that there is a lack of association of SCFD1 rs10139154 with the risk for ALS in a large Chinese population, but this variant may modulate the age of onset of ALS. These findings add further evidence to the suspected implication of the SCFD1 gene in the pathogenesis of disease in our ALS population. PMID- 29260602 TI - An evaluation of two novel capillaroscopy techniques in suspected scleroderma spectrum disorders: A single-centre cross-sectional study. AB - OBJECTIVES: The primary aim was to evaluate the diagnostic performance of digital photographs taken with a smartphone camera using both a lens attachment and, separately, a dermatoscope. The secondary aims were to assess the influence of prior capillaroscopy experience and familiarity with the novel techniques on diagnostic accuracy. METHODS: All patients referred for capillaroscopy between May 2016 and January 2017 were eligible for inclusion. Nailfolds were classified by widefield microscopy before proceeding double-blinded to nailfold photography using both novel techniques. Randomised photographs were assessed by three independent investigators and results were compared to widefield microscopy. Sensitivity, specificity, inter- and intra-observer variability were calculated. RESULTS: Sixty-five participants contributed over 1000 digital photographs for assessment. The 'smartphone-lens' technique performed with moderate sensitivity (65%; 58-72) and high specificity (90%; 84-96). The 'smartphone-dermatoscope' technique performed with higher sensitivity (74%; 66-82) and excellent specificity (95%; 88-100) and was used more accurately by a novice. Prior assessor experience with nailfold capillaroscopy in general and prior experience with the novel techniques positively modulated the diagnostic accuracy. CONCLUSION: New technologies, in this case utilising a smartphone camera, could help to improve accessibility to nailfold capillaroscopy, an important diagnostic tool and putative biomarker in scleroderma-spectrum disorders, whilst retaining accurate results. PMID- 29260603 TI - Efficacy of the cognitive orientation to daily occupational performance with Brazilian children with developmental coordination disorder. AB - BACKGROUND: Children with Developmental Coordination Disorder (DCD) have difficulties performing daily activities which reflects negatively on participation, impacting their lives. OBJECTIVES: To examine the effects of the cognitive orientation to daily occupational performance Approach (CO-OP Approach) protocol on occupational performance and satisfaction of Brazilian children who have DCD; to examine whether children could transfer strategies and skills learned during CO-OP to untrained goals. METHODS: A pre-post group comparison design with eight boys aged 6-10 years old. Children participated in 12 CO-OP sessions with their parents twice a week, with an extra session added to the protocol for parents' orientation. The Canadian Occupational Performance Measure and the Performance Quality Rating Scale were used as outcome measures. The study was registered by the United States Institutes of Health at ClinicalTrials.gov (NCT03112746). RESULTS: Intervention resulted in higher, clinically and statistically significant, occupational performance measures according to parents, children's, and external evaluators' perspectives. All children improved occupational performance on their selected goals and five children could transfer the ability to use cognitive strategies to tasks not addressed in therapy. CONCLUSIONS: This study provides initial directions for future research to investigate the applicability and to implement CO-OP approach on pediatric settings in Brazil. PMID- 29260604 TI - The role of mental health and addiction among high-cost patients: a population based study. AB - AIMS: Previous work found that, among high-cost patients, those with a majority of mental health and addiction (MHA)-related costs (>50%) incur over 30% more costs than other high-cost patients. However, this work did not examine other high-cost patients in depth or whether they had any MHA-related costs. The objective of this analysis was to examine the role of MHA-related care among other high-cost patients. METHODS: Using administrative healthcare data from Ontario, Canada, this study selected all patients in the 90th percentile of the cost distribution in 2012. It focused primarily on two groups based on the percentage of MHA-related costs relative to total costs: (1) high-cost patients with some MHA-related costs (0% > and <50%) and (2) high-cost patients with no MHA-related costs (0%). We examined socio-demographic and clinical characteristics, utilization and costs for both groups, and modeled patient-level costs using appropriate regression techniques. We also compared these groups with high-cost patients with a majority of MHA-related costs (>50%). RESULTS: High cost patients with some MHA-related costs incurred over 40% more costs than those without ($27,883 vs $19,702). Patients with some MHA-related costs were older, lived in poorer neighborhoods, and had higher levels of comorbidity compared to those without. After controlling for relevant variables, having any type of MHA related utilization increased costs by $2,698. Having a diagnosis of psychosis had a large impact on costs. LIMITATIONS: This study did not examine children and adolescents. We were only able to account for 91% of all costs incurred by the public third-party payer; addiction-related costs from community-based agencies were not available. CONCLUSIONS: High-cost patients with MHA incur higher costs compared to those without. When considering interventions aimed at high-cost patients, policy-makers should consider their complex nature, specifically both their physical and MHA-related comorbidities. PMID- 29260605 TI - Impact on affected families and society of severe rotavirus infections in Swedish children assessed in a prospective cohort study. AB - BACKGROUND: Few prospective cohort studies have estimated the overall impact of severe rotavirus gastroenteritis (RVGE) leading to hospitalization on families and society. We assessed human and economic resources needed to care for an affected average child aged <5 years in Sweden. METHODS: The study was conducted in Astrid Lindgren Children's Hospital which serves approximately 14% of all Swedish children <5 years of age. All children admitted with acute gastroenteritis in the study period were tested for rotavirus. Health care consumption was collected prospectively and publically available unit costs used to calculate direct costs. Non-medical and indirect costs were collected in interviews with families using a standardized questionnaire during the hospital stay and approximately 14 days post-discharge. RESULTS: 144/206 children (70%) with laboratory-confirmed RVGE were included. The median age was 14 months. The average total cost per hospitalized child was ?3894, of which ?2169 (56%) was due to direct healthcare-related costs (including Emergency Department visits and in patient care), ?104 (2%) to non-medical direct costs and ?1621 (42%) to indirect costs due to productivity loss. Carers of children with severe RVGE were absent from work on average five days per study child: four days during hospitalization of affected child and one day due to gastroenteritis in the carer. CONCLUSIONS: Costs for RVGE are dominated by direct costs which are similar to some other countries in Europe, but indirect costs due to productivity loss are also important, and should be considered in decisions to introduce rotavirus vaccines into national vaccination programmes. PMID- 29260606 TI - Diffusion-weighted imaging of normal appearing corticospinal tracts in patients with multiple sclerosis. AB - Aim To determine if there are differences in ADC values between normal appearing corticospinal tracks in patients with MS compared to ADC values in controls. Material and methods The study population comprised 62 consecutive MS patients (36 women and 26 men; mean age 36.45+/-8.63 years). 50 control subjects with no neurological disabilities or intracranial were included the study (32 women and 18 men; mean age 40.18+/-12.25 years). All ADC maps were independently evaluated by two experienced radiologists. ROI of approximately 15-18 mm2 in capsula interna and 10-12 mm2 in mesencephalon were placed bilaterally for measurement of ADC values. Three circular ROIs were placed-one each side for internal capsule and 6 total ROIs from right and left internal capsule were averaged for each patient. Mesencephelon ADC measurements were performed similarly. Result The mean ADC values of the left internal capsule in MS patients were significiantly lower than the control group (p:0.002). No statistically significant difference was found between the MS patients and control group mean ADC values of the right internal capsule (p>0.05). The mean ADC values of the right and left mesencephalon in MS patients were significiantly lower than the control group (respectively; p:0.031, p<0.001). The mean ADC values of the left internal capsule were significiantly lower than the right internal capsule in MS patients (p<0.001). The mean ADC values of the left mesencephalon were significiantly lower than the right mesencephalon in MS patients (p<0.001). Conclusion The mean ADC values of the normal-appearing corticospinal tract in MS patients were significantly lower than the control group except for the right internal capsule. PMID- 29260607 TI - Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis. PMID- 29260608 TI - Tonic regulation of middle meningeal artery diameter by ATP-sensitive potassium channels. AB - Activation of ATP-sensitive potassium (KATP) channels in arterial smooth muscle (ASM) contributes to vasodilation evoked by a variety of endogenous and exogenous compounds. Although controversial, activation of KATP channels by neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating peptide (PACAP) in the trigeminovascular system, including the middle meningeal artery (MMA), has been linked to migraine headache. The objective of the current study was to determine if ongoing KATP channel activity also influences MMA diameter. In the absence of other exogenous compounds, the KATP channel inhibitors glibenclamide and PNU37883A induced constriction of isolated and pressurized MMAs. In contrast, KATP channel inhibition did not alter cerebral artery diameter. Consistent with tonic KATP activity in MMA, glibenclamide also induced ASM membrane potential depolarization and increased cytosolic Ca2+. Inhibitors of cAMP-dependent protein kinase (PKA) abolished basal KATP activation in MMA and caused a marked decrease in sensitivity to the synthetic KATP channel opener, cromakalim. In vivo MMA constriction in response to gibenclamide was observed using two-photon imaging of arterial diameter. Together these results indicate that PKA-mediated tonic KATP channel activity contributes to the regulation of MMA diameter. PMID- 29260609 TI - Test-retest agreement and reliability of the Six Spot Step Test in persons with multiple sclerosis. AB - BACKGROUND: The Six Spot Step Test (SSST) extends traditional walking outcomes in persons with multiple sclerosis (PwMS) by further challenging components of coordination and balance. Nonetheless, the test-retest agreement of the SSST has not been investigated. OBJECTIVE: To determine the within-day, day-to-day, and inter-rater agreement and reliability of the SSST in PwMS. A secondary aim was to investigate the validity of handheld timing. METHODS: A total of 38 PwMS with an Expanded Disability Status Scale (EDSS) <6.5 completed two SSSTs with a 5-minute break in-between. After 2 days, this procedure was repeated. Bland-Altman analysis was performed to determine the 95% Limits of Agreement (LOA) and Intraclass Correlation Coefficient (ICC) was calculated. In a subgroup of 18 PwMS, the SSSTs were video-recorded and timed by a second investigator. RESULTS: The relative LOA within and between days were +/-15% and +/-19%, while ICC were 0.987 and 0.983, respectively. A minor learning effect was found over four tests. The handheld timing error was +/-0.5 seconds when compared to video-based timing. CONCLUSION: The SSST has an acceptable within- and between-day agreement and reliability. For interventional purposes, a change of >19% can be regarded as a real change. Valid timing can be performed by a handheld stopwatch. PMID- 29260610 TI - Corrigendum. PMID- 29260611 TI - A two-stage approach for estimating the parameters of an age-group epidemic model from incidence data. AB - Age-dependent dynamics is an important characteristic of many infectious diseases. Age-group epidemic models describe the infection dynamics in different age-groups by allowing to set distinct parameter values for each. However, such models are highly nonlinear and may have a large number of unknown parameters. Thus, parameter estimation of age-group models, while becoming a fundamental issue for both the scientific study and policy making in infectious diseases, is not a trivial task in practice. In this paper, we examine the estimation of the so-called next-generation matrix using incidence data of a single entire outbreak, and extend the approach to deal with recurring outbreaks. Unlike previous studies, we do not assume any constraints regarding the structure of the matrix. A novel two-stage approach is developed, which allows for efficient parameter estimation from both statistical and computational perspectives. Simulation studies corroborate the ability to estimate accurately the parameters of the model for several realistic scenarios. The model and estimation method are applied to real data of influenza-like-illness in Israel. The parameter estimates of the key relevant epidemiological parameters and the recovered structure of the estimated next-generation matrix are in line with results obtained in previous studies. PMID- 29260612 TI - Using the "Surprise Question" in Nursing Homes: A Prospective Mixed-Methods Study. AB - BACKGROUND: The "Surprise Question" (SQ) is often used to identify patients who may benefit from a palliative care approach. The time frame of the typical question (a 12-month prognosis) may be unsuitable for identifying residents in nursing homes since it may not be able to differentiate between those who have a more imminent risk of death within a cohort of patients with high care needs. OBJECTIVE: To examine the accuracy and acceptability of 3 versions of the SQ with shortened prognostication time frames (3 months, 6 months, and "the next season") in the nursing home setting. DESIGN: A prospective mixed-methods study. SETTING/PARTICIPANTS: Forty-seven health-care professionals completed the SQ for 313 residents from a nursing home in Ontario, Canada. A chart audit was performed to evaluate the accuracy of their responses. Focus groups and interviews were conducted to examine the participants' perspectives on the utility of the SQ. RESULTS: Of the 301 residents who were included in the analysis, 74 (24.6%) deaths were observed during our follow-up period. The probability of making an accurate prediction was highest when the seasonal SQ was used (66.7%), followed by the 6-month (58.9%) and 3-month (57.1%) versions. Despite its high accuracy, qualitative results suggest the staff felt the seasonal SQ was ambiguous and expressed discomfort with its use. CONCLUSION: The SQ with shortened prognostication periods may be useful in nursing homes and provides a mechanism to facilitate discussions on palliative care. However, a better understanding of palliative care and increasing staff's comfort with prognostication is essential to a palliative care approach. PMID- 29260613 TI - Documentation of Crucial Information Relating to Critically Ill Patients. AB - BACKGROUND: Medical decision-making has evolved to the modern model of shared decision-making among patients, surrogate decision-makers, and medical providers. As such, informed consent discussions with critically ill patients often should include larger discussions relating to values and goals of care. Documentation of care options and prognosis serves as an important component of electronic communication relating to patient preferences among care providers. OBJECTIVE: This retrospective chart review study sought to evaluate the prevalence of documentation of critical data, care options, prognosis, and medical plan, within primary team and palliative care consult team documentation. RESULTS: Three hundred two electronic medical records were reviewed. There was a significant difference in documentation between palliative care and primary teams for prognosis (83% vs 32%, P < .001), care options (82% vs 50%, P < .001), and care plan (82% vs 46%, P < .001). CONCLUSIONS: Our retrospective chart review study demonstrated a significant difference in documentation between primary and palliative care teams. We acknowledge that review of documentation cannot be extrapolated to the presence or absence of conversations between providers and patients and/or surrogates. Additional studies to evaluate this connection would be advantageous. PMID- 29260614 TI - Neuroimaging findings in Pallister-Killian syndrome. AB - Pallister-Killian syndrome (PKS) is a rare chromosomal duplication disorder caused by additional copies of the short arm of chromosome 12 (12p). Clinically PKS is characterized by craniofacial dysmorphism with neonatal frontotemporal alopecia, hypertelorism, and low-set ears as well as kyphoscoliosis, severe intellectual disability, epilepsy, and abnormal muscle tone. Comprehensive high resolution brain MR findings of PKS in childhood have not been previously illustrated in the medical literature. We present detailed neuroimaging findings from a child with PKS and thoroughly review previously reported structural brain abnormalities in this patient population. MRI abnormalities common to PKS include cerebral volume loss, malformations of cortical development, corpus callosum dysgenesis, white matter disease, and craniofacial malformations. In our patient, new findings of perisylvian with occipital polymicrogyria, vermian dysplasia, brachium pontis signal abnormality, dural anomalies, and unilateral atlas assimilation were noted. Micrencephaly and cortical dysplasia provide a likely explanation for severe intellectual disability and epilepsy in this patient population. PMID- 29260616 TI - Corrigendum. PMID- 29260615 TI - Preliminary evidence for cerebral capillary shunting in adults with sickle cell anemia. AB - Elevated flow velocities in adults with sickle cell anemia (SCA) may cause rapid erythrocyte transit through capillaries. This phenomenon could present as dural venous sinus hyperintensity on arterial spin labeling (ASL)-MRI and could be indicative of capillary shunting. Here, the prevalence of ASL venous hyperintensities and association with relevant physiology in adults with SCA was investigated. SCA ( n = 46) and age-matched control ( n = 16) volunteers were recruited for 3.0 T MRI. Pseudo-continuous ASL-MRI was acquired for cerebral blood flow (CBF) calculation and venous hyperintensity determination; venous signal intensity and a categorical venous score (three raters; 0 = no hyperintensity, 1 = focal hyperintensity, and 2 = diffuse hyperintensity) were recorded. Flow velocity in cervical internal carotid artery segments was determined from phase contrast data (venc = 40 cm/s) and whole-brain oxygen extraction fraction (OEF) was determined from T2-relaxation-under-spin-tagging MRI. Cerebral metabolic rate of oxygen was calculated as the product of OEF, CBF, and blood oxygen content. ASL venous hyperintensities were significantly ( p < 0.001) more prevalent in SCA (65%) relative to control (6%) participants and were associated with elevated flow velocities ( p = 0.03). CBF ( p < 0.001), but not OEF, increased with increasing hyperintensity score. Prospective trials that evaluate this construct as a possible marker of impaired oxygen delivery and stroke risk may be warranted. PMID- 29260617 TI - Organized Social Activity, Physical Exercise, and the Risk of Insomnia Symptoms Among Community-Dwelling Older Adults. AB - OBJECTIVES: To compare the risk of insomnia symptoms among community-dwelling older adults who participated and did not participate in organized social activity and physical exercise. DESIGN: Secondary data analysis of a prospective cohort study. MATERIAL AND METHODS: Community-dwelling older adults >=65 years of age with no insomnia symptoms at baseline were included in the study. Participants were followed up yearly for 3 years. Insomnia symptoms, social activity, and physical exercise status of study participants were assessed at baseline and during follow-up. RESULTS: Study participants who reported engaging in organized social activity and low-intensity physical exercise and organized social activity and high-intensity physical exercise were less likely to report insomnia symptoms during follow-up compared with those who did not engage in any activity. CONCLUSION: These results suggest beneficial effect of organized social activity and physical exercise in maintaining sleep quality in old age. PMID- 29260618 TI - Progesterone for preventing pregnancy termination after initiation of medical abortion with mifepristone. AB - INTRODUCTION: Abortion is often a difficult and traumatic decision for a woman to make. Perhaps greater distress occurs when a woman commences a medical abortion but then changes her mind and wishes to keep the now-threatened pregnancy. One published case series detailed a potential method to counter/reverse the abortifacient effect of mifepristone by administering parenteral progesterone in such situations. OBJECTIVES: The present report details cases of women in similar circumstances who have been treated with progesterone. The aims were to document occurrences of where women have changed their mind after commencing medical abortion, as well as to explore some of the controversies and clinical issues surrounding their circumstances. METHODS: Women who had commenced medical abortion by ingesting mifepristone but who had not taken misoprostol independently contacted a national pregnancy support service the same day. Those meeting criteria for treatment received progesterone pessaries per vaginum for two weeks. RESULTS: Cases: 28-year-old woman, 6 weeks plus 1 day gestation; 35 year-old woman, 8 weeks plus 5 days gestation; and 27-year-old woman, 7 weeks plus 3 days gestation. Outcomes respectively were: healthy male baby delivered at 39 weeks gestation; healthy male baby delivered at term; and completed medical abortion. CONCLUSIONS: Women have changed their mind after commencing medical abortion. Progesterone use in early pregnancy is low risk and its application to counter the effects of mifepristone in such circumstances may be clinically beneficial in preserving her threatened pregnancy. Further research is required, however, to provide definitive evidence. PMID- 29260619 TI - Mental fatigue alters the speed and the accuracy of the ball in table tennis. AB - This study aimed at evaluating the effects of mental and muscle fatigue on table tennis performance. Mental fatigue (MF) was induced by completion of 90 minutes of the AX-CPT; muscle fatigue was induced by completion of an eccentric exercise performed with the elbow flexors (biceps fatigue, BF) or the knee extensors (quadriceps fatigue, QF). The control condition consisted of watching a movie. Stroke parameters (speed and accuracy of the ball), as well as feelings of fatigue and force production capacity of the elbow flexors (BF, MF and control conditions) and knee extensors (QF condition), were assessed pre and post fatigue protocols. Feelings of fatigue increased post fatigue protocols. Force production capacity decreased only in the BF and QF conditions. BF and MF induced a decrease in accuracy. This decrease in accuracy was associated with an increased ball speed in the BF condition, and a decreased ball speed in the MF condition. QF had a negligible effect on stroke performance. Our results suggest that both mental fatigue, and muscle fatigue, significantly impair table tennis performance and therefore coaches should take into account both the physical and mental state of table tennis players to optimize performance. PMID- 29260620 TI - The safety profile of Polyoxidonium in daily practice: results from postauthorization safety study in Slovakia. AB - AIM: This study assessed the safety of Polyoxidonium(r) 6 mg lyophilisate for solution for injection in routine practice with a special focus on signs or symptoms of potential adverse renal effects. MATERIALS & METHODS: A local, multicenter, prospective, open-label, noninterventional, uncontrolled postauthorization safety study was conducted in 15 healthcare centers in Slovakia. Adult patients who received commercially available Polyoxidonium 6 mg lyophilisate for solution for injection as a part of their routine care were observed for one cycle of treatment, consisting of five or ten injections. For safety assessment, adverse events were monitored with a special focus on signs or symptoms of potential adverse renal effects. At the end of the study, investigators and subjects rated the overall tolerance of Polyoxidonium treatment as well as improvement. Data collection was based on the review of medical records and routine examination of subjects. RESULTS: In total, 502 subjects were enrolled and 498 (99.2%) subjects completed the study. 19 (3.8%) subjects experienced a total of 34 adverse events. Only one (0.1%) subject experienced eight adverse drug reactions (ADRs): restlessness, fatigue, feeling hot (n = 2), pyrexia (n = 3) and asthenia. There were no renal ADRs or serious ADRs. At the end of the study, both investigators and subjects very positively rated global tolerability and global improvement. CONCLUSION: Polyoxidonium was well tolerated in the heterogenous population of patients, mostly with chronic recurrent bacterial or viral infections. No renal ADRs were reported in this postauthorization safety study, which was designed with a special focus on identifying potential adverse renal effects. PMID- 29260621 TI - Immunologic treatment of Parkinson's disease. PMID- 29260622 TI - Surrogate end points for overall survival in trials of PD-(L)1 inhibitors for urinary cancers: a systematic review. AB - AIM: Numerous trials for PD-(L)1 inhibitors in the management of advanced urinary cancers (urothelial carcinoma and renal cell carcinoma) were published recently. It is not known exactly what should be the optimal surrogate end point for overall survival (OS) in this context. MATERIALS & METHODS: PubMed database and ASCO meeting library were searched till August 2017. Eligible studies included prospective clinical studies evaluating PD-(L)1 inhibitors for the management of advanced urothelial carcinoma or renal cell carcinoma. The review author extracted relevant data on the characteristics of participants and the outcomes of the different studies. In order to conduct a proper correlation analysis, normality testing using Shapiro-Wilk test was first used. Based on the result of the normality testing, either Pearson's product-moment correlation or Spearman's rank correlation was used. RESULTS: Thirteen trials (nine urothelial carcinoma and four renal cell carcinoma trials) with 2792 participants were included. The correlation of overall response rate with median OS was very weak to weak (for urothelial carcinoma: r = -0.120, n = 9, p = 0.758; for renal cell carcinoma: r = -0.397, n = 6, p = 0.436). Likewise, the correlation of progression-free survival with median OS was very weak to weak (for urothelial carcinoma: r = -0.024, n = 8, p = 0.955; for renal cell carcinoma: r = 0.394, n = 6, p = 0.440). On the other hand, 1-year survival rate may be a better surrogate end point for median OS (for urothelial carcinoma: r = 0.806, n = 8, p = 0.016; for renal cell carcinoma: r = 0.941, n = 6, p = 0.005). CONCLUSION: RECIST-defined overall response rate and progression-free survival are not reliable surrogate end points for median OS in trials of PD-(L)1 inhibitor therapy for urinary cancers. The use of other surrogate end points (e.g., 1-year survival) in early phase studies may be considered. PMID- 29260623 TI - PD-1/PD-L1 in disease. AB - AIM: Expression of PD-1 on T/B cells regulates peripheral tolerance and autoimmunity. Binding of PD-1 to its ligand, PD-L1, leads to protection against self-reactivity. In contrary, tumor cells have evolved immune escape mechanisms whereby overexpression of PD-L1 induces anergy and/or apoptosis of PD-1 positive T cells by interfering with T cell receptor signal transduction. PD-L1 and PD-1 blockade using antibodies are in human clinical trials as an alternative cancer treatment modality. Areas covered: We describe the role of PD-1/PD-L1 in disease in the context of autoimmunity, neurological disorders, stroke and cancer. CONCLUSION: For immunotherapy/vaccines to be successful, the expression of PD L1/PD-1 on immune cells should be considered, and the combination of checkpoint inhibitors and vaccines may pave the way for successful outcomes to disease. PMID- 29260624 TI - Immunotherapy in relapsed mesothelioma. PMID- 29260625 TI - Immune-mediated thrombocytopenia and hypothyroidism in a lung cancer patient treated with nivolumab. AB - Patients treated with immune checkpoint inhibitors can develop various immunological complications; however, few cases of immune thrombocytopenia occurring in association with the administration of these agents have so far been reported. We herein report the case of a 62-year-old Japanese man with non-small cell lung cancer who developed immune thrombocytopenia and hypothyroidism during nivolumab therapy. After the second administration of the drug, his peripheral blood platelet count rapidly decreased to 1.6 * 104/MUl with a petechial rash and symptoms associated with a low thyroid function. Nivolumab-induced immune thrombocytopenia and hypothyroidism were suspected based on the presence of platelet-associated IgG, an increased level of autoantibodies to thyroglobulin and thyroid peroxidase and an enlarged thyroid gland. The patient eventually made a full recovery after treatment with oral prednisolone and levothyroxine. Further investigations and the accumulation of data are necessary to elucidate the precise mechanisms underlying the autoimmune responses that occur in patients treated with immune checkpoint inhibitors. PMID- 29260626 TI - Investigation of antitumor effects of Lactobacillus crispatus in experimental model of breast cancer in BALB/c mice. AB - AIM: To evaluate the effect of intraperitoneal injections of heat-killed Lactobacillus crispatus on breast tumor size and overall survival of Balb/c mouse received 4T1 mammary carcinoma. Materials and methods: Different doses of L. crispatus have been injected intraperitoneally in BALB/c mice. RESULTS: Tumor size was decreased in the experiment group treated with 1 * 108 bacteria/200 MUl. Treatment with 1 * 108 bacteria/200 MUl resulted in survival improvement. The myeloid-derived suppressor cells and reactive oxygen species production have been increased in all groups. Cox2 expression decreased in tumor tissues of the mice treated with 108 bacteria/200 MUl. The expressions of Arginase and iNos increased in the spleen and tumor tissues of those treated with 5 * 108 bacteria/200 MUl. CONCLUSION: We have shown the protective effect of L. crispatus on survival of tumor-bearing mice. PMID- 29260627 TI - Induction of the cell survival kinase Sgk1: A possible novel mechanism for alpha phenyl-N-tert-butyl nitrone in experimental stroke. AB - Nitrones (e.g. alpha-phenyl-N-tert-butyl nitrone; PBN) are cerebroprotective in experimental stroke. Free radical trapping is their proposed mechanism. As PBN has low radical trapping potency, we tested Sgk1 induction as another possible mechanism. PBN was injected (100 mg/kg, i.p.) into adult male rats and mice. Sgk1 was quantified in cerebral tissue by microarray, quantitative RT-PCR and western analyses. Sgk1+/+ and Sgk1-/- mice were randomized to receive PBN or saline immediately following transient (60 min) occlusion of the middle cerebral artery. Neurological deficit was measured at 24 h and 48 h and infarct volume at 48 h post-occlusion. Following systemic PBN administration, rapid induction of Sgk1 was detected by microarray (at 4 h) and confirmed by RT-PCR and phosphorylation of the Sgk1-specific substrate NDRG1 (at 6 h). PBN-treated Sgk1+/+ mice had lower neurological deficit ( p < 0.01) and infarct volume ( p < 0.01) than saline treated Sgk1+/+ mice. PBN-treated Sgk1-/- mice did not differ from saline-treated Sgk1-/- mice. Saline-treated Sgk1-/- and Sgk1+/+ mice did not differ. Brain Sgk3:Sgk1 mRNA ratio was 1.0:10.6 in Sgk1+/+ mice. Sgk3 was not augmented in Sgk1 /- mice. We conclude that acute systemic treatment with PBN induces Sgk1 in brain tissue. Sgk1 may play a part in PBN-dependent actions in acute brain ischemia. PMID- 29260628 TI - Editorial: Management of Elevated Heart Rate in Essential Hypertension: Pathophysiological Insights and Therapeutic Approach. PMID- 29260629 TI - New Urologic Oncology Drugs and The New Toxicities. PMID- 29260630 TI - Legends in Urology. PMID- 29260632 TI - Biologic and epidemiologic evidence assessing if statins prevent prostate cancer. AB - INTRODUCTION: During their lives, 1 in 8 men will be diagnosed with prostate cancer. Several drugs have been shown to decrease prostate cancer risk, but have not been widely used in prostate cancer prevention because of concerns about side effects and cost-effectiveness. Statins are indicated for prevention of cardiovascular disease, have an excellent benefit to risk profile, and some studies suggest that statins may reduce the risk of prostate cancer. MATERIALS AND METHODS: We performed a systematic search of Medline (Ovid), EMBASE (Ovid), and PubMed. This search informed a narrative review of the biological rationale for why statins may reduce prostate cancer risk and an evaluation of the existing epidemiological evidence to determine whether further studies are needed to assess the true impact of statins on prostate cancer risk. RESULTS: Statins may help prevent the development of prostate cancer through inhibition of sustained proliferative signals (androgen and Ras/Rho), sensitizing potentially malignant cells to programmed cell death, minimizing inflammation, reducing angiogenesis, and impeding invasiveness by blocking adhesion molecules. The epidemiologic literature examining the effect of statin use on overall prostate cancer diagnosis is highly heterogeneous, with relative risks of 0.26 to 2.94. Out of 33 published studies, 5 show an increased risk of prostate cancer with statin use, 10 demonstrate a decreased risk, and 18 suggest no effect. CONCLUSION: There is a compelling pre-clinical rationale for statins as potential chemopreventive agents. However, large, population-based studies with long pre-diagnosis drug exposure data are needed to investigate the impact of statin exposure on prostate cancer incidence. PMID- 29260633 TI - Two-stage classifiers that minimize PCA3 and the PSA proteolytic activity testing in the prediction of prostate cancer recurrence after radical prostatectomy. AB - INTRODUCTION: Early biochemical recurrence after prostate cancer surgery is associated with higher risk of aggressive disease and cancer specific death. Many new tests are being developed that will predict the presence of indicators of aggressive disease like early biochemical recurrence. Since recurrence occurs in less than 10% of patients treated for prostate cancer, validation of such tests will require expensive testing on large patient groups. Moreover, clinical application of the validated test requires that each new patient be tested. In this report we introduce a two-stage classifier system that minimizes the number of patients that must be tested in both the validation and clinical application of any new test for recurrence. MATERIALS AND METHODS: Expressed prostatic secretion specimens were prospectively collected from 450 patients prior to robot assisted radical prostatectomy for prostate cancer. Patients were followed for 2.5 years for evidence of biochemical recurrence. Standard clinical parameters, the levels proteolytic activity of prostate specific antigen (PSA) and the levels of PCA3 RNA, PSA RNA and TMPRSS2:ERG fusion RNA were determined in each prospective patient specimen for subsequent correlation with biochemical recurrence. RESULTS: While levels of PCA3 and PSA proteolytic activity (PPA) in prostatic secretions provided an effective pre-surgical predictor of early biochemical recurrence in prostate cancer, application of the two-stage classifier shows that only 60% of the patients need these tests. CONCLUSION: Two stage classifiers can provide a parsimonious approach to both the validation and clinical application of biomarker-based tests. Adoption of the two-stage neutral zone classifier can reduce unnecessary testing in prostate cancer treatment. PMID- 29260634 TI - Laparoendoscopic single-site surgery for treatment of urachal remnants. AB - INTRODUCTION: To evaluate safety and excellent cosmetic outcome with laparoendoscopic single-site surgery (LESS). In this study, we compared the usefulness and efficacy of LESS versus conventional laparoscopic surgery for the treatment of urachal remnants. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 20 consecutive patients who underwent either conventional laparoscopic surgery or LESS from January 2007 to February 2015 at Kansai Medical University Hospital. Ten patients underwent surgery using the standard laparoscopic 3-port technique, and 10 patients underwent LESS. The patients included 12 males and 8 females (mean age, 24.5 years; range, 10-68 years). The patients' characteristics, surgical data, and postoperative pain assessment results were retrospectively collected and analyzed. RESULTS: The median operative time, pneumoperitoneal surgery time, and estimated blood loss did not differ between the LESS and conventional laparoscopic groups. However, the total incision length was longer in the conventional laparoscopic group than in the LESS group. The degree of pain at 2 to 5 days postoperatively according to the Wong-Baker FACES Pain Rating Scale was lower in the LESS group than in the conventional laparoscopic group (p < 0.05). CONCLUSIONS: Less is a possible option in the surgical treatment for urachal remnants. In this very small cohort, there is no conversion to traditional laparoscopic surgery or open surgery. This technique is possibly feasible and may achieve less pain. Accumulation of surgical outcomes especially in safety and cosmesis is required to be an established method. PMID- 29260635 TI - Comparison of two indices to annotate complications after radical nephroureterectomy. AB - INTRODUCTION: The Clavien-Dindo (CD) and Comprehensive Complication Index (CCI) are two grading systems that annotate adverse events following surgical procedures. We compare these two classification systems in a cohort of patients undergoing radical nephroureterectomy (RNU). MATERIALS AND METHODS: The charts of 110 consecutive RNU patients were reviewed for complications occurring within 30 days of surgery. Grading by the CD classification system and values for CCI were calculated. Bivariate and multivariate analysis identified associations between perioperative variables and complications, as well as relationship to hospital length of stay. RESULTS: Sixty-seven men and 43 women with a median age of 71, body mass index of 29, estimated glomerular filtration rate (eGFR) of 64 mL/min/1.73 m2, and Charlson score of 4 were included. Seventy-five percent underwent a minimally invasive RNU, 47% had a lymph node dissection, and 7% received neoadjuvant chemotherapy. Median hospital length of stay was 4 days (range, 2-22). Overall, 39 patients (35%) experienced a total of 56 complications including 12 major (>= Clavien III) and 44 minor. Median CCI patients with complications cohort was 20.9 (range, 8.7-100). The upper quartile of CCI (> 75th %) was associated with higher Charlson score (p = 0.03), lower baseline eGFR (p = 0.005), intraoperative transfusion (p = 0.004), and absence of symptoms at presentation (p = 0.015). Major CD complications were associated with these same variables. On multivariate analysis, only the upper quartile of CCI was associated with length of stay (8.25 versus 5.61 days, p < 0.0001) whilst major CD complications were not (7.98 versus 6.32, p = 0.211). CONCLUSIONS: The CCI and CD classification schemes are both associated with similar baseline and perioperative characteristics for RNU patients. However, the cumulative nature of CCI appears to permit more accurate prediction of length of stay following surgery compared to the CD system. PMID- 29260636 TI - Effective treatment of neurogenic detrusor overactivity in multiple sclerosis patients using desmopressin and mirabegron. AB - INTRODUCTION: Multiple sclerosis (MS) is the commonest progressive neurological disease affecting young people. With advancing disease, management of neurogenic detrusor overactivity (NDO) based on antimuscarinics may prove inadequate and if based on botulinum toxin, may necessitate clean intermittent self catheterization. The aim of the study was to evaluate the effectiveness of combined mirabegron and desmopressin administration in the treatment of NDO in patients with MS. MATERIALS AND METHODS: Sixty patients diagnosed with MS and NDO were evaluated. All had received treatment with solifenacin 10 mg/daily for 3 months and were displeased with the results. Patients were divided in four groups. In Group A (n = 15) patients continued receiving solifenacin 10 mg/daily; in Group B (n = 15) patients received mirabegron 50 mg/daily; in Group C (n = 15) patients received desmopressin 120 mcg/daily and in Group D (n = 15) patients received mirabegron 50 mg/daily and desmopressin 120 mcg/daily. All patients were assessed with a 3 day bladder diary at the beginning and at the end of the treatment. RESULTS: All patients in Groups A, B and C did not demonstrate statistically significant changes at the end of the treatment period in their 3 day bladder diary and in the presence of urinary infections. In Group D, a statistically significant improvement was noted in the mean change from baseline to end of treatment in micturition episodes (3.5 +/- 0.4 micturition/24h), in urgency episodes (2.3 +/- 0.2) and mean number of urinary incontinence (1.0 +/- 0.2 episodes/24h). CONCLUSIONS: Treatment with mirabegron and desmopressin revealed both effectiveness and safety in patients with NDO and MS. PMID- 29260637 TI - Assessment of bilateral supine and prone tubeless percutaneous nephrolithotomy. AB - INTRODUCTION: To assess the outcome of same-session bilateral tubeless percutaneous nephrolithotomy (BPCNL) in supine and prone positions and to compare them to unilateral tubeless PCNL (UPCNL). MATERIALS AND METHODS: Consecutive PCNL patients treated at two institutions between 2006-2016 were analyzed. Tubeless BPCNL was performed when indicated. RESULTS: Fifty-eight patients underwent BPCNLs [30 supine (SBPCNL) and 28 prone (PBPCNL)], while 1395 patients underwent UPCNLs. Demographics and baseline data were similar for all groups (p > 0.05). SBPCNL had a longer operating time (124 +/- 38 minutes versus 105 +/- 36 minutes; p = 0.49) and a significantly longer hospital stay (3.6 +/- 1.9 versus 2.4 +/- 1.3 days, respectively; p = 0.019) in comparison to PBPCNL. Seven planned BPCNLs were converted to UPCNL, resulting in a BPCNL success rate of 58/65 (89%). When compared to UPCNL, BPCNL patients had a significantly increased postoperative creatinine level (0.74 +/- 0.3 versus -0.04 +/- 0.8 g/dL; p = 0.07E-7), a decreased postoperative hemoglobin level (2 +/- 1.1 versus 1.4 +/- 1.7 mg/dL; p = 0.026), a higher blood transfusion rate (9% versus 2%; p = 0.023), and a longer hospital stay (3 +/- 1.7 versus 1.6 +/- 1.7 days; p = 0.001E-4). Stone-free and overall complication rates were similar for both groups. CONCLUSION: BPCNL can be routinely offered to patients with a bilateral indication. BPCNL is associated with higher blood transfusion rates and longer hospital stays, but it may spare patients from repeat anesthesia and hospitalization. SBPCNL takes longer to perform than PBCNL, but without clinical ramifications. PMID- 29260638 TI - AdVance sling use decreasing relative to artificial urinary sphincters. AB - INTRODUCTION: To evaluate the percent of AdVance male sling usage relative to artificial urinary sphincters (AUS) over a 9 year period since its introduction in order to assess trends across the United States. MATERIALS AND METHODS: As a surrogate for procedures performed, we reviewed device utilization trends of the AdVance sling and AUS broken down by American Urological Association (AUA) section. ANOVA testing between years was used to determine purchasing trends with p values of < 0.05 considered statistically significant. RESULTS: Relative to AUS, AdVance sling percentage significantly increased from 36% in 2007 to 48% in 2008 (p = 0.032). Sling percentage then remained stable over the next 3 years from 2008-2011 with no significant percent change between years (p = NS). Compared with 2008-2011, AdVance usage decreased in 2012 to 29% (p = 0.002) and remained stable at this decreased relative level through 2015 (p = NS, difference between years 2012-2015). Comparing incontinence procedures across AUA sections, the Southeast section performed the highest percentage of male stress urinary incontinence procedures, including 27% of all AdVance slings and 25% of all artificial sphincters. CONCLUSION: Proportion of AdVance sling usage relative to AUS increased after its introduction through 2008. Usage remained stable at an increased level for the next3 years. More recent years have found decreased AdVance usage and a resurgence of the artificial urinary sphincter. Reasons for these trends remain speculative. PMID- 29260639 TI - Importance of counseling and patient selection in treatment of male stress incontinence. PMID- 29260640 TI - Ultrasound self-referral does not increase utilization in pediatric urology. AB - INTRODUCTION: Costs of radiologic imaging are rising. The goal of this study is to examine the utilization practices of pediatric urologists who have access to in-office ultrasound imaging when managing children with primary hydronephrosis. MATERIALS AND METHODS: A retrospective cross sectional study was performed of children <= 5 years old with an isolated diagnosis of hydronephrosis. Ultrasound utilization was evaluated by tallying the number of ultrasounds obtained during the time each child was followed. Imaging frequency was determined from orders given by each overseeing physician. Ultrasounds were performed at either the practitioner's clinic or at outside radiology facilities based on insurance regulations. Analysis compared ordering frequency between imaging completed at the clinic versus outside radiology facilities. RESULTS: Of 1,816 ultrasounds ordered, 1,102 were performed at the practitioner's clinic and 714 at outside radiology centers. Overall, the number of ultrasounds obtained in the practitioner's clinic was 0.33 ultrasound studies per patient per month, in contrast to 0.38 obtained in outside radiology settings. Ultrasound utilization for low, intermediate and high grades of hydronephrosis in practitioner's clinic versus outside was 0.39 versus 0.31, 0.31 versus 0.31, and 0.37 versus 0.39 respectively. There were no significant differences in ultrasound ordering frequency for all groups compared. CONCLUSIONS: There is no increase in ultrasound utilization for managing primary hydronephrosis in children, regardless of whether the study was self or outside referral. Honest and ethical utilization of self-owned radiologic equipment is possible and allows for timing monitoring, physician and patient convenience, and potential cost savings. PMID- 29260641 TI - Benign fibrous pseudotumor resulting in orchiectomy despite intraoperative frozen section. AB - Fibrous pseudotumors are rare benign lesions that originate within the paratesticular tissues. Local excision is the preferred method of treatment of these tumors over radical orchiectomy, however a definitive diagnosis must be made beforehand given the similarity of these tumors to malignant entities. We present a case of fibrous pseudotumor of the tunica vaginalis and cauda epididymis. A diagnosis of fibrous pseudotumor could not be established despite the use of intraoperative frozen section, therefore necessitating radical orchiectomy. PMID- 29260642 TI - Subcutaneous emphysema following cystoscopic clot evacuation. AB - Gross hematuria is a common urologic problem which often requires surgical intervention. While generally a safe procedure, clot evacuation can have serious complications. Here we describe the case of an 85-year-old male who developed extensive subcutaneous emphysema following a small extraperitoneal bladder perforation during a clot evacuation. While our patient did well with expectant management, subcutaneous emphysema can lead to serious complications and any endourologic procedure should be stopped once crepitus is noted. PMID- 29260643 TI - Blueprint unknown: a case for multidisciplinary management of advanced penile mycosis fungoides. AB - A 64-year-old man presented with a 2 week history of progressive phimosis and painful ulcer on his penile meatus. He underwent penile preserving excision, and subsequent pathological examination confirmed T-cell non-Hodgkin lymphoma with immunohistochemical features of large cell transformation of mycosis fungoides. The penis was further treated with local external beam radiotherapy consisting of 27 Gy in 15 fractions and systemic mini-CHOP chemotherapy. An organ-preserving tissue response has since been achieved. This case is the first of its kind in the literature and firmly highlights the role of multidisciplinary management for this rare malignancy. PMID- 29260644 TI - Recurrent renal cell carcinoma presenting as a solitary left ventricular mass. AB - A 73-year-old male with a remote history of renal cell carcinoma presented with an asymptomatic left ventricular mass. Biopsy of the mass revealed a late recurrence of his renal cell carcinoma. Given the size and location of the mass, resection was not possible. Treatment with pazopanib was initiated with good clinical response. PMID- 29260645 TI - Clock Gene Period in the Chagas Disease Vector Triatoma infestans (Hemiptera: Reduviidae). AB - To contribute to a better understanding of the molecular bases of the circadian biological rhythms in Chagas disease vectors, in this work we identified functional domains in the sequences of the clock protein PERIOD (PER) in Rhodnius prolixus and Triatoma infestans and analyzed the expression of the PER gene at mRNA level in T. infestans. The PER protein sequences comparison among these species and those from other insects revealed that the most similar regions are the PAS domains and the most variable is the COOH-terminal. On the other hand, the per gene expression in nervous tissue of adult T. infestans varies with a daily canonical rhythm in groups of individuals maintained under photoperiod (light/dark, LD) and constant dark (DD), showing a significant peak of expression at sunset. The pattern of expression detected in LD persists under the DD condition. As expected, in the group maintained in constant light (LL), no daily increase was detected in per transcript level. Besides, the presence of per transcript in different tissues of adult individuals and in nervous tissue of nymphs evidenced activity of peripheral clocks in adults and activity of the central clock in nymphs of T. infestans. PMID- 29260646 TI - Epidemiology of Campylobacter Infections among Children in Egypt. AB - Campylobacter is a frequently isolated bacterial pathogen among children with diarrhea. Data are lacking on the distribution and spectrum of disease associated with Campylobacter species and Campylobacter jejuni capsular polysaccharide (CPS) types. This information is essential because current vaccine research seeks to target specific CPS types. An effective CPS-conjugate vaccine will need to cover CPS types that are both common and associated with severe disease. The US Naval Medical Research Unit-3 conducted several prospective cohort studies researching diarrheal disease in Egypt from 1995 to 2003. In total, 1,057 children were enrolled and followed to a maximum age of 36 months. We analyzed Campylobacter positive stool samples that were collected while subjects were symptomatic, along with corresponding clinical data. Of 441 Campylobacter isolates, 322 represented primary infections (189 C. jejuni, 127 Campylobacter coli, six unspeciated). There were 19 C. jejuni CPS types identified; eight accounted for 63.5% of primary C. jejuni infections. We also screened for the presence of the type-6 secretion system (T6SS), a putative virulence determinant. The T6SS was found in 18.0% of C. coli isolates and 57.6% of C. jejuni isolates (P < 0.001), and was not uniformly distributed among CPS types (P < 0.001). Strains with the T6SS were not associated with more severe disease. Clinical presentations across species and CPS types appeared similar. This study adds to the growing epidemiological data and also provides some analysis of the clinical spectrum associated with infection by specific Campylobacter species, C. jejuni capsule types, and possible virulence determinants. PMID- 29260647 TI - Schistosoma haematobium Egg Excretion does not Increase after Exercise: Implications for Diagnostic Testing. AB - Children are frequently invited to exercise before micturition, as it is believed that this activity will result in higher Schistosoma haematobium egg excretion, and hence, increases sensitivity of microscopic diagnoses. However, the evidence of this recommendation is scant. In the study presented here, 257 children, aged 2-15 years from south Cote d'Ivoire, provided urine samples for microscopy on consecutive days; one sample without prior exercise and one sample after exercise. Comparing the same individuals without and with prior exercise, sample positivity for S. haematobium (25.7% versus 23.0%, P = 0.31) and mean egg counts (10.2 eggs/10 mL versus 8.5 eggs/10 mL, P = 0.45) did not differ. Exercise before urine collection does not appear to increase S. haematobium egg excretion. PMID- 29260648 TI - Enteroparasites in Preschool Children on the Pacific Region of Nicaragua. AB - The aim of this study was to determine for the first time the prevalence of enteroparasites in preschool children originating from the seven departments of the Pacific region in Nicaragua. One stool sample of each of 1,217 children, from 6 months to 5 years of age, was collected and personal data were recorded on delivery of the container. Samples fixed in 10% formalin were processed by a formol-acetate concentration and a modified Ziehl-Neelsen technique. The overall prevalence of enteroparasite infections was 68.2% with a total of at least 20 species. Blastocystis hominis (45.5%), Giardia intestinalis (31.7%), Trichuris trichiura (8.2%), and Ascaris lumbricoides (5.2%) were the most prevalent protozoa and helminth species in the total study as well as in all departments. Protozoan prevalence presented a statistically significant difference by gender (male: 69.6%; female: 46.7%; P < 0.001), and males presented a higher T. trichiura infection rate than females (male: 9.9%; female 6.4%; P < 0.035). Protozoan prevalence increased with age with a statistically significant difference (P < 0.001). Helminths were always more prevalent in urban areas (P < 0.0002). Protozoan infections result statistically higher than helminth infections so that water-based transmission could be suspected. Based on the differences with respect to species and parasite prevalence between the seven departments in the Pacific region of Nicaragua, the exploration of local factors associated with the transmission of enteroparasites should also be considered to reduce infection. PMID- 29260649 TI - Are Infants Less than 6 Months of Age a Neglected Group for Anemia Prevention in Low-Income Countries? AB - Anemia is a major public health problem that affects mainly children, predominantly in low-income countries and most often due to iron deficiency (ID). Administration of iron supplements to prevent and treat ID anemia in malaria endemic areas has been controversial for decades; however, recent World Health Organization guidelines recommend universal iron supplementation for children in highly prevalent anemia settings, including those where malaria is endemic. However, infants younger than 6 months of age have been exempted from this recommendation because ID is not considered prevalent at this age and because of assumptions-without evidence-that they are protected from ID through breast milk. To achieve full impact of anemia prevention targeting infants less than 6 months of age who are at highest risk of ID, operational studies that conclusively demonstrate the effectiveness and safety of delivering iron supplements to young infants in settings with a high burden of infectious diseases, including malaria, are needed. PMID- 29260650 TI - Impact of Sickle Cell Trait and Naturally Acquired Immunity on Uncomplicated Malaria after Controlled Human Malaria Infection in Adults in Gabon. AB - Controlled human malaria infection (CHMI) by direct venous inoculation (DVI) with 3,200 cryopreserved Plasmodium falciparum sporozoites (PfSPZ) consistently leads to parasitemia and malaria symptoms in malaria-naive adults. We used CHMI by DVI to investigate infection rates, parasite kinetics, and malaria symptoms in lifelong malaria-exposed (semi-immune) Gabonese adults with and without sickle cell trait. Eleven semi-immune Gabonese with normal hemoglobin (IA), nine with sickle cell trait (IS), and five nonimmune European controls with normal hemoglobin (NI) received 3,200 PfSPZ by DVI and were followed 28 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction (qPCR) and for malaria symptoms. End points were time to parasitemia and parasitemia plus symptoms. PfSPZ Challenge was well tolerated and safe. Five of the five (100%) NI, 7/11 (64%) IA, and 5/9 (56%) IS volunteers developed parasitemia by TBS, and 5/5 (100%) NI, 9/11 (82%) IA, and 7/9 (78%) IS by qPCR, respectively. The time to parasitemia by TBS was longer in IA (geometric mean 16.9 days) and IS (19.1 days) than in NA (12.6 days) volunteers (P = 0.016, 0.021, respectively). Five of the five, 6/9, and 1/7 volunteers with parasitemia developed symptoms (P = 0.003, NI versus IS). Naturally adaptive immunity (NAI) to malaria significantly prolonged the time to parasitemia. Sickle cell trait seemed to prolong it further. NAI plus sickle cell trait, but not NAI alone, significantly reduced symptom rate. Twenty percent (4/20) semi-immunes demonstrated sterile protective immunity. Standardized CHMI with PfSPZ Challenge is a powerful tool for dissecting the impact of innate and naturally acquired adaptive immunity on malaria. PMID- 29260651 TI - The Epidemiology of Imported Acute Infectious Diseases in Zhejiang Province, China, 2011-2016: Analysis of Surveillance Data. AB - To explore epidemiological characteristics of imported acute infectious diseases between 2011 and 2016 in Zhejiang province, China. Data of imported infectious diseases from 2011 to 2016 was collected from the China Information System for Disease Control and Prevention in Zhejiang province, and subsequently analyzed for epidemiological characteristics. A survey was conducted to investigate clinicians' abilities to diagnose these diseases in Zhejiang province. From 2011 to 2016, 1,241 cases of imported acute infectious disease were reported in Zhejiang province, including 1,078 malaria cases, 156 dengue cases, three chikungunya fever cases and four Zika cases. Between 2011 and 2016, incidences of these diseases increased (P < 0.001). For malaria, male adults for labor export were the most affected group. Seasonal fluctuation was not obvious. Plasmodium falciparum was the main malaria type (822 cases) and most cases were acquired from African Region (791/822, 96.1%). Plasmodium vivax cases (194 cases) were mainly from African Region (78/194, 40.2%) and South-East Asia Region (51/194, 26.3%). Meanwhile, for dengue, adults and tourists were the most affected groups. The incidence of dengue was particularly high in August and October. The percent of correct clinician responses in the survey of diagnosis knowledge was 54.6% (standard deviation = 21.0%); this percentage was particularly low in general practitioners and clinicians from township hospitals. The capabilities of clinicians to diagnose these diseases were low and should be improved. Efforts should be made in improving and disseminating proper preventive measures of high risk populations, surveillance of imported cases, and prevention and control of local epidemics. PMID- 29260652 TI - Case Report: Reversible Cerebral Vasoconstriction Syndrome in Cerebral Malaria. AB - Cerebral malaria is a severe complication of falciparum malaria that occurs infrequently in adults. Here, we describe the case of a 21-year-old man who presented with fever and headache 13 days after returning from a 12-day trip to Kenya and was subsequently diagnosed with falciparum malaria. Complications of cerebral malaria developed within 1 day after the initiation of therapy with intravenous quinine, and the patient entered a deep coma. Magnetic resonance angiography (MRA) revealed multiple vasoconstrictions in his brain. The resulting neurocognitive disorders that persisted after parasite clearance improved gradually, as confirmed by MRA, enabling the patient to perform activities of daily living upon discharge. In this case of cerebral malaria, the MRA findings indicated the involvement of reversible cerebral vasoconstriction syndrome. PMID- 29260653 TI - Hybrid Collapse Confirms the Specific Status of Triatoma bahiensis Sherlock and Serafim, 1967 (Hemiptera, Triatominae), an Endemic Species in Brazil. AB - Six to seven million people worldwide are estimated to be infected with Trypanosoma cruzi, the etiologic agent of Chagas disease transmitted mainly by triatomines. Triatoma bahiensis was recently collected in the Brazilian state of Bahia and revalidated using different approaches. The main criterion used to define a "good" biological species is reproductive isolation, so we evaluated the cytogenetics of first-generation (F1) hybrids resulting from the experimental cross between T. bahiensis females and Triatoma lenti males to possibly characterize the postzygotic isolation associated with the hybrid breakdown. All cells analyzed presented a karyotype of 2n = 22 and a pair of univalent autosomes. This chromosome behavior represents hybrid collapse and underscores the specific status of T. bahiensis. Thus, we have characterized the presence of the hybrid collapse phenomenon in an experimental cross, and we confirm the specific status of T. bahiensis, thus contributing to the Triatominae taxonomy. PMID- 29260654 TI - Impact Evaluation of Seasonal Malaria Chemoprevention under Routine Program Implementation: A Quasi-Experimental Study in Burkina Faso. AB - Seasonal malaria chemoprevention (SMC) for children < 5 is a strategy that is gaining popularity in West African countries. Although its efficacy to reduce malaria incidence has been demonstrated in trials, the effects of SMC implemented in routine program conditions, outside of experimental contexts, are unknown. In 2014 and 2015, a survey was conducted in 1,311 households located in Kaya District (Burkina Faso) where SMC had been recently introduced. All children < 72 months were tested for malaria and anemia. A pre-post study with control group was designed to measure SMC impact during high transmission season. A difference in-differences approach was coupled in the analysis with propensity score weighting to control for observable and time-invariant nonobservable confounding factors. SMC reduced the parasitemia point and period prevalence by 3.3 and 24% points, respectively; this translated into protective effects of 51% and 62%. SMC also reduced the likelihood of having moderate to severe anemia by 32%, and history of recent fever by 46%. Self-reported coverage for children at the first cycle was 83%. The SMC program was successfully added to a package of interventions already in place. To our knowledge, with prevalence < 10% during the peak of the transmission season, this is the first time that malaria can be reported as hypo-endemic in a sub-Sahelian setting in Burkina Faso. SMC has great potential, and along with other interventions, it could contribute to approaching the threshold where elimination strategies will be envisioned in Burkina Faso. PMID- 29260655 TI - Spontaneously Arrested Transmission of Cysticercosis in a Highly Endemic Village with a Very Low Migration Rate. AB - Taenia solium cysticercosis is difficult to eliminate without interventions or societal development. Atahualpa is a rural Ecuadorian village with documented low migration rate, where domestic pig raising is common and human cysticercosis is endemic. To assess neurocysticercosis (NCC) prevalence, 1,273 villagers aged >= 20 years underwent neuroimaging studies, which showed calcified lesions in 121 (9.5%) individuals, but no active disease. Likewise, positive reactions, apparently nonspecific, were found in only 3/200 subjects by the use of a monoclonal antibody-based enzyme-linked immunosorbent assay to detect T. solium antigens in urine. Only 2/418 pigs reacted to three antibody bands on serum western blot and none to more than three bands. This is the first time that spontaneously arrested T. solium transmission is documented in a known endemic village. Understanding why active transmission stopped could provide insights on potential targets for control interventions. Atahualpa could provide an optimal scenario for longitudinal studies on the consequences of calcified NCC. PMID- 29260656 TI - Recombinase Polymerase Amplification Combined with a Lateral Flow Strip for the Detection of Plasmodium knowlesi. AB - The aim of this study was to develop a recombinase polymerase amplification (RPA) combined with a lateral flow (LF) strip method for specific diagnosis of Plasmodium knowlesi. With incubation at 37 degrees C, the 18S rRNA gene of P. knowlesi was successfully amplified within 12 minutes. By adding a specifically designed probe to the reaction solution, the amplified RPA product can be visualized on a LF strip. The RPA assay exhibited high sensitivity with limits of detection down to 10 parasites/MUL of P. knowlesi. Nonetheless, it was demonstrated that all P. knowlesi (N = 41) and other Plasmodium sp. (N = 25) were positive while negative samples (N = 8) were negative. Therefore, a combination of RPA and LF strip detection is a highly promising approach with the potential to be suitable for use in resource-limited settings. PMID- 29260657 TI - Impact of Enhanced Health Interventions for United States-Bound Refugees: Evaluating Best Practices in Migration Health. AB - With an unprecedented number of displaced persons worldwide, strategies for improving the health of migrating populations are critical. United States-bound refugees undergo a required overseas medical examination to identify inadmissible conditions (e.g., tuberculosis) 2-6 months before resettlement, but it is limited in scope and may miss important, preventable infectious, chronic, or nutritional causes of morbidity. We sought to evaluate the feasibility and health impact of diagnosis and management of such conditions before travel. We offered voluntary testing for intestinal parasites, anemia, and hepatitis B virus infection, to U.S.-bound refugees from three Thailand-Burma border camps. Treatment and preventive measures (e.g., anemia and parasite treatment, vaccination) were initiated before resettlement. United States refugee health partners received overseas results and provided post-arrival medical examination findings. During July 9, 2012 to November 29, 2013, 2,004 refugees aged 0.5-89 years enrolled. Among 463 participants screened for seven intestinal parasites overseas and after arrival, helminthic infections decreased from 67% to 12%. Among 118 with positive Strongyloides-specific antibody responses, the median fluorescent intensity decreased by an average of 81% after treatment. The prevalence of moderate-to severe anemia (hemoglobin < 10 g/dL) was halved from 14% at baseline to 7% at departure (McNemar P = 0.001). All 191 (10%) hepatitis B-infected participants received counseling and evaluation; uninfected participants were offered vaccination. This evaluation demonstrates that targeted screening, treatment, and prevention services can be conducted during the migration process to improve the health of refugees before resettlement. With more than 250 million migrants globally, this model may offer insights into healthier migration strategies. PMID- 29260658 TI - Origin of a High-Latitude Population of Aedes aegypti in Washington, DC. AB - An overwintering population of Aedes aegypti has been documented in the Capitol Hill neighborhood of Washington, DC, since 2011. Mitochondrial cytochrome oxidase I (mtCOI) sequence data presented in a previous study traced the origin to the New World. Here, we use microsatellite and 14,071 single nucleotide polymorphisms along with mitochondrial DNA (mtDNA) sequences on Washington Ae. aegypti samples and samples from potential sources to further narrow the origin of this population. Genetically, Washington Ae. aegypti are closest to populations in Florida, meaning this is the most likely source. Florida experienced the first mosquito-borne transmission of dengue in the United States after decades of absence of this disease, as well as local transmission of chikungunya and Zika in recent years. This suggests that the Capitol Hill, Washington, DC population of Ae. aegypti is capable of transmitting viruses such as dengue, chikungunya, and Zika in modern US city environments. PMID- 29260659 TI - Comparison of Mass Azithromycin Coverage Targets of Children in Niger: A Cluster Randomized Trachoma Trial. AB - Repeated oral azithromycin distribution targeted only to children has proven effective in reducing the ocular Chlamydia that causes trachoma. Here, we assess whether an enhanced coverage target of at least 90% of children is superior to the World Health Organization recommendation of at least 80%. Twenty-four trachoma-endemic communities in Matameye, Niger, were randomized to a single day of azithromycin distribution aiming for at least 80% coverage or up to 4 days of treatment and > 90% coverage of children under age 12. All distributions were biannual. Children < 5 years of age and adults > 15 years were monitored for ocular Chlamydia infection by polymerase chain reaction every 6 months for 36 months in children and at baseline and 36 months in adults. Ocular Chlamydia prevalence in children decreased from 24.9% (95% confidence interval [CI] 15.9 33.8%) to 4.4% (95% CI 0.6-8.2%, P < 0.001) at 36 months in the standard coverage arm and from 15.6% (95% CI 10.0-21.2%) to 3.3% (95% CI 1.0-5.5%; P < 0.001) in the enhanced coverage arm. Enhanced coverage reduced ocular Chlamydia prevalence in children more quickly over time compared with standard (P = 0.04). There was no difference between arms at 36 months in children (2.4% lower with enhanced coverage, 95% CI 7.7-12.5%; P = 0.60). No infection was detected in adults at 36 months. Increasing antibiotic coverage among children from 80% to 90% may yield only short term improvements for trachoma control programs. Targeting treatment to children alone may be sufficient for trachoma control in this setting. PMID- 29260660 TI - Toxoplasma gondii Infection in the United States, 2011-2014. AB - Toxoplasma gondii can cause severe neurologic and ocular disease when transmitted congenitally and in immunosuppressed persons. Sera collected in the National Health and Nutrition Examination Survey 2011 through 2014 in 13,507 persons >= 6 years old were tested for T. gondii immunoglobulin (Ig) G and IgM antibodies, and in those both IgG and IgM antibody positive, for IgG avidity. Overall, 11.14% (95% confidence limits [CL] 9.88%, 12.51%) were seropositive for T. gondii IgG antibody (age-adjusted seroprevalence 10.42% [95% CL 9.19%, 11.76%]); in women aged 15-44 years, the age-adjusted T. gondii IgG seroprevalence was 7.50% (95% CL 6.00%, 9.25%). In multivariable analysis, risk for IgG seropositivity increased with age and was higher in males; persons living below the poverty level; persons with <= a high school education compared with those with > a high school education; and non-Hispanic black, Mexican American, and foreign born non Hispanic white persons compared with U.S.-born non-Hispanic white persons. Overall, 1.16% (95% CL 0.94%, 1.42%) were T. gondii IgM antibody positive and 0.71%, (95% CL 0.54%, 0.92%) were both IgM and IgG antibody positive. In multivariable analysis, the significant risk factors for being both IgM and IgG positive were older age, crowding, and non-U.S. birth origin compared with U.S. born persons. Among those positive for both IgM and IgG antibody, almost all had high avidity (all women aged 15-44 years had high avidity). Toxoplasma gondii antibody prevalence remains relatively low in the United States, although it is higher in non-U.S.-born persons, males, and some minority and socioeconomically disadvantaged groups. PMID- 29260661 TI - Visceral Leishmaniasis in Traveler to Guyana Caused by Leishmania siamensis, London, UK. AB - The parasite Leishmania siamensis is a zoonotic agent of leishmaniasis; infection in animals has been documented in Europe and the United States. Reported authochthonous human infections have been limited to Thailand. We report a case of human visceral Leishmania siamensis infection acquired in Guyana, suggesting colonization in South America. PMID- 29260662 TI - Costs of Conjunctivitis Outbreak, Reunion Island, France. AB - During January-April 2015, a major outbreak of conjunctivitis on Reunion Island caused a large public health impact. On the basis of general practitioner consultations, emergency department visits, and eye medication sales during the 13-week epidemic, we estimated a total healthcare cost of ?3,341,191 from the outbreak. PMID- 29260663 TI - Nipah Virus Contamination of Hospital Surfaces during Outbreaks, Bangladesh, 2013 2014. AB - Nipah virus (NiV) has been transmitted from patient to caregivers in Bangladesh presumably through oral secretions. We aimed to detect whether NiV-infected patients contaminate hospital surfaces with the virus. During December 2013-April 2014, we collected 1 swab sample from 5 surfaces near NiV-infected patients and tested surface and oral swab samples by real-time reverse transcription PCR for NiV RNA. We identified 16 Nipah patients; 12 cases were laboratory-confirmed and 4 probable. Of the 12 laboratory-confirmed cases, 10 showed NiV RNA in oral swab specimens. We obtained surface swab samples for 6 Nipah patients; 5 had evidence of NiV RNA on >1 surface: 4 patients contaminated towels, 3 bed sheets, and 1 the bed rail. Patients with NiV RNA in oral swab samples were significantly more likely than other Nipah patients to die. To reduce the risk for fomite transmission of NiV, infection control should target hospital surfaces. PMID- 29260664 TI - Inonotosis in Patient with Hematologic Malignancy. AB - We report a lung-invasive fungal disease with possible cutaneous needle tract seeding in a patient with a febrile neutropenia caused by the Basidiomycetes mold Inonotus spp. Although rare, Inonotus spp. should be added to the list of microorganisms causing invasive fungal disease in neutropenic patients with hematologic malignancies. PMID- 29260665 TI - Rodent Abundance and Hantavirus Infection in Protected Area, East-Central Argentina. AB - We captured 3 hantavirus rodent hosts in Otamendi Natural Reserve, Argentina, during 2007-2012. Hantavirus antibodies were found only in Akodon azarae grass mice, mainly in males and old animals. Higher abundance of this species was associated with warm and rainy weather and high water levels, which peaked after a strong El Nino event. PMID- 29260666 TI - Leprosy in Nonimmigrant Canadian Man without Travel outside North America, 2014. AB - In Canada, Hansen disease (leprosy) is rare and not considered in diagnoses for nonimmigrant patients. We report Mycobacterium leprae infection in a Canadian man whose sole travel was to Florida, USA. The M. leprae isolate was identified as armadillo-associated genotype 3I-2-v1. Travelers to the southern United States should avoid contact with armadillos. PMID- 29260667 TI - High Seroprevalence of Jamestown Canyon Virus among Deer and Humans, Nova Scotia, Canada. AB - Using residual serum samples from Nova Scotia, Canada, we found that 87.8% of tested deer and an estimated 20.6% of the human population were infected with Jamestown Canyon virus. Human seropositivity reached 48.2% in 1 region. This virus may be an underrecognized cause of disease in Nova Scotia. PMID- 29260668 TI - Investigation of Canine-Mediated Human Rabies Death, Haiti, 2015. AB - In Haiti, an investigation occurred after the death of a 4-year-old girl with suspected rabies. With tips provided by community members, the investigation led to the identification of 2 probable rabies-related deaths and 16 persons bitten by rabid dogs, 75% of which chose postexposure prophylaxis. Community engagement can bolster rabies control. PMID- 29260669 TI - Emmonsia helica Infection in HIV-Infected Man, California, USA. AB - Emmonsia-like fungi have rarely been reported from North America. We report a fatal case of E. helica infection in a man with advanced HIV infection from California, USA, who had progressive respiratory failure and a brain abscess. PMID- 29260670 TI - Investigation of Pneumonic Plague, Madagascar. PMID- 29260671 TI - Zika Virus Testing and Outcomes during Pregnancy, Florida, USA, 2016. AB - Zika virus infection during pregnancy can lead to congenital Zika syndrome. Implementation of screening programs and interpretation of test results can be particularly challenging during ongoing local mosquitoborne transmission. We conducted a retrospective chart review of 2,327 pregnant women screened for Zika virus in Miami-Dade County, Florida, USA, during 2016. Of these, 86 had laboratory evidence of Zika virus infection; we describe 2 infants with probable congenital Zika syndrome. Delays in receipt of laboratory test results (median 42 days) occurred during the first month of local transmission. Odds of screening positive for Zika virus were higher for women without health insurance or who did not speak English. Our findings indicate the increase in screening for Zika virus can overwhelm hospital and public health systems, resulting in delayed receipt of results of screening and confirmatory tests and the potential to miss cases or delay diagnoses. PMID- 29260672 TI - Mammalian Pathogenesis and Transmission of Avian Influenza A(H7N9) Viruses, Tennessee, USA, 2017. AB - Infections with low pathogenicity and highly pathogenic avian influenza A(H7N9) viruses affected poultry in 4 states in the southeastern United States in 2017. We evaluated pathogenicity and transmission of representative viruses in mouse and ferret models and examined replication kinetics in human respiratory tract cells. These viruses can cause respiratory infections in mammalian models. PMID- 29260673 TI - Ocular Vaccinia Infection in Dairy Worker, Brazil. AB - We studied a clinical case of vaccinia virus that caused an ocular manifestation in a dairy worker in Brazil. Biologic and molecular analyses identified a co infection with 2 isolates from different Brazilian vaccinia virus phylogenetic groups. PMID- 29260674 TI - Epidemiology of Cutaneous Leishmaniasis Outbreak, Waziristan, Pakistan. AB - During 2013-2015, prevalence of cutaneous leishmaniasis in war-affected Waziristan areas was 3.61% by PCR. Youths (1-15 years of age) were more susceptible. Internal transcribed spacer 1 PCR followed by restriction fragment length polymorphism analysis identified Leishmania tropica in 215 samples and Leishmania major in 6 samples. PMID- 29260675 TI - Phylogeny and Immunoreactivity of Norovirus GII.P16-GII.2, Japan, Winter 2016-17. AB - During the 2016-17 winter season in Japan, human norovirus GII.P16-GII.2 strains (2016 strains) caused large outbreaks of acute gastroenteritis. Phylogenetic analyses suggested that the 2016 strains derived from the GII.2 strains detected during 2010-12. Immunochromatography between 2016 strains and the pre-2016 GII.2 strains showed similar reactivity. PMID- 29260676 TI - Estimation of Undiagnosed Naegleria fowleri Primary Amebic Meningoencephalitis, United States1. AB - Primary amebic meningoencephalitis is an acute, rare, typically fatal disease. We used epidemiologic risk factors and multiple cause-of-death mortality data to estimate the number of deaths that fit the typical pattern for primary amebic meningoencephalitis; we estimated an annual average of 16 deaths (8 male, 8 female) in the United States. PMID- 29260677 TI - Detection and Circulation of a Novel Rabbit Hemorrhagic Disease Virus in Australia. AB - The highly virulent rabbit hemorrhagic disease virus (RHDV) has been widely used in Australia and New Zealand since the mid-1990s to control wild rabbits, an invasive vertebrate pest in these countries. In January 2014, an exotic RHDV was detected in Australia, and 8 additional outbreaks were reported in both domestic and wild rabbits in the 15 months following its detection. Full-length genomic analysis revealed that this virus is a recombinant containing an RHDVa capsid gene and nonstructural genes most closely related to nonpathogenic rabbit caliciviruses. Nationwide monitoring efforts need to be expanded to assess if the increasing number of different RHDV variants circulating in the Australian environment will affect biological control of rabbits. At the same time, updated vaccines and vaccination protocols are urgently needed to protect pet and farmed rabbits from these novel rabbit caliciviruses. PMID- 29260678 TI - Serologic Evidence of Fruit Bat Exposure to Filoviruses, Singapore, 2011-2016. AB - To determine whether fruit bats in Singapore have been exposed to filoviruses, we screened 409 serum samples from bats of 3 species by using a multiplex assay that detects antibodies against filoviruses. Positive samples reacted with glycoproteins from Bundibugyo, Ebola, and Sudan viruses, indicating filovirus circulation among bats in Southeast Asia. PMID- 29260679 TI - Melioidosis, Singapore, 2003-2014. AB - In contrast with northern Australia and Thailand, in Singapore the incidence of melioidosis and co-incidence of melioidosis and pneumonia have declined. Burkholderia pseudomallei deep abscesses increased 20.4% during 2003-2014. These trends could not be explained by the environmental and climatic factors conventionally ascribed to melioidosis. PMID- 29260680 TI - Whole-Genome Analysis of Recurrent Staphylococcus aureus t571/ST398 Infection in Farmer, Iowa, USA. AB - Staphylococcus aureus strain sequence type (ST) 398 has emerged during the last decade, largely among persons who have contact with swine or other livestock. Although colonization with ST398 is common in livestock workers, infections are not frequently documented. We report recurrent ST398-IIa infection in an Iowa farmer in contact with swine and cattle. PMID- 29260681 TI - Changing Geographic Patterns and Risk Factors for Avian Influenza A(H7N9) Infections in Humans, China. AB - The fifth epidemic wave of avian influenza A(H7N9) virus in China during 2016 2017 demonstrated a geographic range expansion and caused more human cases than any previous wave. The factors that may explain the recent range expansion and surge in incidence remain unknown. We investigated the effect of anthropogenic, poultry, and wetland variables on all epidemic waves. Poultry predictor variables became much more important in the last 2 epidemic waves than they were previously, supporting the assumption of much wider H7N9 transmission in the chicken reservoir. We show that the future range expansion of H7N9 to northern China may increase the risk of H7N9 epidemic peaks coinciding in time and space with those of seasonal influenza, leading to a higher risk of reassortments than before, although the risk is still low so far. PMID- 29260682 TI - Antimicrobial Drug Resistance in Blood Culture Isolates at a Tertiary Hospital, Uganda. AB - We summarize antimicrobial drug resistance (AMR) patterns from blood cultures at a tertiary hospital in Uganda. High rates of resistance to first-line antibiotic drugs were observed among Staphylococcus aureus and gram-negative organisms. Microbiology services with susceptibility testing should be strengthened to support standardized reporting of AMR data in sub-Saharan Africa. PMID- 29260683 TI - Increasing Virulence in Leprosy Indicated by Global Mycobacterium spp. PMID- 29260684 TI - Increasing Number of Scarlet Fever Cases, South Korea, 2011-2016. AB - The increasing number of reported scarlet fever cases during 2011-2016 in the National Notifiable Infectious Disease database in South Korea occurred because of increased overall reporting and expanded reporting criteria rather than because of increasing scarlet fever incidence. Further increases are anticipated because of other expansions in reporting requirements. PMID- 29260685 TI - Dengue Fever in Burkina Faso, 2016. AB - We report 1,327 probable cases of dengue in Burkina Faso in 2016. Of 35 serum samples tested by a trioplex test, 19 were confirmed dengue virus (DENV) positive: 11 DENV-2, 6 DENV-3, 2 nontypeable, and 1 DENV-2/DENV-3 co-infection. Molecular testing should be conducted to correctly identify causative agents in this complex infectious disease landscape. PMID- 29260686 TI - Characterization of a Feline Influenza A(H7N2) Virus. AB - During December 2016-February 2017, influenza A viruses of the H7N2 subtype infected ~500 cats in animal shelters in New York, NY, USA, indicating virus transmission among cats. A veterinarian who treated the animals also became infected with feline influenza A(H7N2) virus and experienced respiratory symptoms. To understand the pathogenicity and transmissibility of these feline H7N2 viruses in mammals, we characterized them in vitro and in vivo. Feline H7N2 subtype viruses replicated in the respiratory organs of mice, ferrets, and cats without causing severe lesions. Direct contact transmission of feline H7N2 subtype viruses was detected in ferrets and cats; in cats, exposed animals were also infected via respiratory droplet transmission. These results suggest that the feline H7N2 subtype viruses could spread among cats and also infect humans. Outbreaks of the feline H7N2 viruses could, therefore, pose a risk to public health. PMID- 29260687 TI - Sensitivity and Specificity of Suspected Case Definition Used during West Africa Ebola Epidemic. AB - Rapid early detection and control of Ebola virus disease (EVD) is contingent on accurate case definitions. Using an epidemic surveillance dataset from Guinea, we analyzed an EVD case definition developed by the World Health Organization (WHO) and used in Guinea. We used the surveillance dataset (March-October 2014; n = 2,847 persons) to identify patients who satisfied or did not satisfy case definition criteria. Laboratory confirmation determined cases from noncases, and we calculated sensitivity, specificity and predictive values. The sensitivity of the defintion was 68.9%, and the specificity of the definition was 49.6%. The presence of epidemiologic risk factors (i.e., recent contact with a known or suspected EVD case-patient) had the highest sensitivity (74.7%), and unexplained deaths had the highest specificity (92.8%). Results for case definition analyses were statistically significant (p<0.05 by chi2 test). Multiple components of the EVD case definition used in Guinea contributed to improved overall sensitivity and specificity. PMID- 29260688 TI - Geogenomic Segregation and Temporal Trends of Human Pathogenic Escherichia coli O157:H7, Washington, USA, 2005-20141. AB - The often-noted and persistent increased incidence of Escherichia coli O157:H7 infections in rural areas is not well understood. We used a cohort of E. coli O157:H7 cases reported in Washington, USA, during 2005-2014, along with phylogenomic characterization of the infecting isolates, to identify geographic segregation of and temporal trends in specific phylogenetic lineages of E. coli O157:H7. Kernel estimation and generalized additive models demonstrated that pathogen lineages were spatially segregated during the period of analysis and identified a focus of segregation spanning multiple, predominantly rural, counties for each of the main clinical lineages, Ib, IIa, and IIb. These results suggest the existence of local reservoirs from which humans are infected. We also noted a secular increase in the proportion of lineage IIa and IIb isolates. Spatial segregation by phylogenetic lineage offers the potential to identify local reservoirs and intervene to prevent continued transmission. PMID- 29260691 TI - [Fast-track hip arthroplasty]. AB - Fast-track surgery implies a coordinated perioperative approach aimed at reducing surgical stress and facilitating post-operative recovery. The fast-track programme has reduced post-operative length of stay and has led to shorter convalescence with more rapid functional recovery and decreased morbidity and mortality in total hip arthroplasty. It should now be a standard total hip arthroplasty patient pathway, but fine tuning of the multiple factors in the fast track pathway is still needed in patients with special needs or high comorbidity burden. PMID- 29260689 TI - Drug-Resistant Polymorphisms and Copy Numbers in Plasmodium falciparum, Mozambique, 2015. AB - One of the fundamental steps toward malaria control is the use of antimalarial drugs. The success of antimalarial treatment can be affected by the presence of drug-resistant populations of Plasmodium falciparum. To assess resistance, we used molecular methods to examine 351 P. falciparum isolates collected from 4 sentinel sites in Mozambique for K13, pfmdr1, pfcrt, and pfdhps polymorphisms and for plasmepsin2 (pfpm2) and pfmdr1 copy numbers. We found multiple copies of pfpm2 in 1.1% of isolates. All isolates carried K13 wild-type alleles (3D7-like), except 4 novel polymorphisms (Leu619Leu, Phe656Ile, Val666Val, Gly690Gly). Prevalence of isolates with pfcrt mutant (K76T) allele was low (2.3%). Prevalence of isolates with pfdhps mutant alleles (A437G and K540E) was >80%, indicating persistence of sulfadoxine/pyrimethamine resistance; however, markers of artemisinin were absent, and markers of piperaquine resistance were low. Piperaquine resistance isolates may spread in Mozambique as dihydroartemisinin/piperaquine drug pressure increases. PMID- 29260690 TI - Emergence of Vaccine-Derived Polioviruses during Ebola Virus Disease Outbreak, Guinea, 2014-2015. AB - During the 2014-2015 outbreak of Ebola virus disease in Guinea, 13 type 2 circulating vaccine-derived polioviruses (cVDPVs) were isolated from 6 polio patients and 7 healthy contacts. To clarify the genetic properties of cVDPVs and their emergence, we combined epidemiologic and virologic data for polio cases in Guinea. Deviation of public health resources to the Ebola outbreak disrupted polio vaccination programs and surveillance activities, which fueled the spread of neurovirulent VDPVs in an area of low vaccination coverage and immunity. Genetic properties of cVDPVs were consistent with their capacity to cause paralytic disease in humans and capacity for sustained person-to-person transmission. Circulation ceased when coverage of oral polio vaccine increased. A polio outbreak in the context of the Ebola virus disease outbreak highlights the need to consider risks for polio emergence and spread during complex emergencies and urges awareness of the challenges in polio surveillance, vaccination, and diagnosis. PMID- 29260692 TI - [Faecal impaction in elderly patients is a potential severe condition]. AB - This case report presents an old hemiparetic male admitted to hospital from nursing home due to dark-coloured emesis. Transdermal buprenorphine 5 mcg/h had been instigated without laxatives in the preceding month. Upon arrival, an enlarged tense abdomen was found. A CT-scan dem-on-strated a 19 cm wide faecal colon impaction. Limited effect of enemas and endoscopic disimpaction resulted in surgery. The patient died shortly after discharge. The case stresses the prevention of constipation when using opioids; in particular in immobilized patients. PMID- 29260693 TI - [Chylothorax]. AB - Chylothorax is a rare condition caused by obstruction or disruption of the lymphatic branches draining the lower body and gastrointestinal tract. Chylothorax is characterized by the presence of lymphatic fluid with triglycerides and chylomicrons in the pleural cavity. The diagnosis is confirmed, when the level of triglycerides is above 1.24 mmol/l (i.e. 110 mg/dl). Aetiologically, chylothorax can be divided into traumatic or non-traumatic, and this separation is of pathophysiological importance, since the treatment should be individualized aiming at the underlying cause of the condition. PMID- 29260694 TI - [Inattentional blindness in the diagnostic process]. AB - When engaged in a demanding task of visual perception we tend to become blind to stimuli, which are not part of our primary task - a bias known as inattentional blindness. This article studies inattentional blindness in radiologists' interpretation of scans. Furthermore, it is discussed, how attention - being a limited resource - is distributed in the diagnostic process. Does focus on one diagnosis make us blind to findings supporting a differential diagnosis? Does focus on typing patient data into electronic health records draw attention away from the general clinical view of the patient? PMID- 29260695 TI - [Jaundice and liver injury with cholestatic pattern after treatment with Metoprololsuccinat]. AB - Drug-induced liver injury is a well-known adverse event to numerous medications with clinical presentations from asymptomatic liver enzyme elevation to liver failure. However, liver injury after administration with metoprolol is not common, and only few case reports have been published. This is a case report of an 80-year-old woman with liver injury with cholestatic pattern and jaundice after two months of treatment with Metoprololsuccinat. With no evidence of other disease, liver function normalized in the following months after discontinuation of Metoprololsuccinat. PMID- 29260696 TI - ? PMID- 29260697 TI - [Ankle dislocation without malleolar fracture]. AB - Ankle dislocation without malleolar fracture is rarely reported in the literature. This case report presents a 19-year-old man with a right ankle dislocation sustained during a handball game. Reduction was performed in an emergency department, and the following X-ray and MRI revealed no fracture. Given the ankle stability a Walker orthosis was applied. Upon review at two and a half weeks the patient did not wear the orthosis any longer, was found to have good function, and was fully weight-bearing. To the best of our knowledge, no such case has previously been reported in the literature. PMID- 29260698 TI - [Abdominal cocoon syndrome in an eigth-year-old girl caused acute bowel obstruction]. AB - This case report describes an eight-year-old girl who was admitted under the suspicion of gastroenteritis. The physical examination revealed symptoms of acute bowel obstruction, which was confirmed by abdominal CT scan. Explorative laparotomy showed a fibrotic membrane encapsulating the small intestine causing obstruction and ischaemia, and the perioperative diagnosis was abdominal cocoon syndrome. Two metres of the small intestine, excessive peritoneal membrane and the appendix was resected and an ileostomy was performed. The patient recovered with antibiotics, fluid therapy and parenteral nutrition. PMID- 29260699 TI - [Functional neurological movement disorders]. AB - Functional movement disorders include motor dysfunctions which are not explained by relevant neurological examination. The prevalence of the disorders is relatively high (10-15%) within an ordinary neurological patient group. Untreated, prognosis for the conditions is poor, and neurological imaging has not yet provided explanatory hypotheses. Treatment studies are sparse, but a heterogenous group of studies of intense, multidisciplinary treatment programmes all point toward good and promising treatment effects. This is not reflected in the actual treatment capacity in Denmark. PMID- 29260700 TI - [Slipped capital femoral epiphysis is diagnosed too late]. AB - Slipped capital femoral epiphysis (SCFE) is a serious orthopaedic hip disease in the adolescent population. It has a prevalence of 10.8 per 100.000 children and usually occurs in children 9-16 years of age. Despite focus on delay of the diagnosis, no improvements have been made. An adolescent complaining of stress related pain in the hip, groin, thigh or knee should be suspected of having SCFE, until an X-ray has excluded this diagnosis. Delayed diagnosis may have serious consequences in terms of further displacement of the femoral head and risk of increased avascular necrosis. PMID- 29260701 TI - [Treatment of gamma-hydroxybutyrate withdrawal]. AB - Gamma-hydroxybutyrate (GHB) is a drug of abuse, for which physical addiction develops quickly. GHB withdrawal can develop into a life-threatening condition and has previously been treated mainly with benzodiazepines. These have not always proven effective, leading to long hospitalizations in intensive care units. Based on successful Dutch treatment results for using GHB to treat GHB withdrawal symptoms, we propose to implement a similar method in Denmark. The method requires an interdisciplinary effort for which The Danish Poison Information Centre should be consulted for expertise. PMID- 29260702 TI - [Medical doctors' surgical abilities measured by means of a surgical simulator]. AB - INTRODUCTION: The aim of the study was to test the surgical abilities between orthopaedic surgeons and anaesthetists on a surgical simulator intended for children. METHODS: The study was a prospective comparative study with 31 consultant or specialist grade medical doctors: 15 orthopaedic surgeons and 16 anaesthetists. The speed and failure rate when removing foreign bodies on a surgical simulator was measured. RESULTS: There was no statistically significant difference in speed and failure rate between orthopaedic surgeons and anaesthetists, when they were working on the simulator. Anaesthetists demonstrated statistically significant more body movement and more use of foul language doing the simulation, and they were more willing to read the written instruction but less likely to follow it. CONCLUSION: Anaesthetists may be just as handy as orthopaedic surgeons but should be given more physical and verbal space in the operation room. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29260703 TI - [A randomized, single-blinded study of the effect of intake of repair beer during a hangover]. AB - We conducted a randomized, single-blinded study of the effect of alcohol intake during a hangover. We measured cardiovascular parameters, and the participants filled out a series of questionnaires regarding their well-being. We found, that an intake of five beers led to a significant decrease in systolic blood pressure, heart rate and self-reported feeling of palpitations. However, the self-reported sense of well-being did not improve. In addition, we found that the risk of brain freeze increased, as the beer's temperature fell. PMID- 29260704 TI - [The dilemma of Danish Christmas lunches]. AB - We investigated the impact of food ingestion, water intake, sleep and exercise on the elimination of ethanol, and self-assessed ability to drive a car. In a cross over design, four fasted healthy participants each underwent one day of oral ethanol intake followed by one of the abovementioned interventions and one day of oral ethanol intake followed by bed rest (control day). The elimination rate of ethanol was minimally affected (numerically it was increased by food ingestion and water intake, reduced by exercise and unchanged by sleep) and self-assessed driving abilities were associated with great variability. PMID- 29260705 TI - [The history of urine analysis]. AB - The history of urine analysis spreads over 6,000 years. This review highlights the most important people and events during that period. PMID- 29260706 TI - [Investigation of perioperative musical preferences during elective surgery]. AB - The purpose of this study was to investigate the perioperative musical preferences among patients and staff in the eye department of a university teaching hospital using a visual analogue scale questionnaire. Thirty patients and relatives from the theatre waiting room and 20 members of staff were included. The responders answered questions regarding age, diagnosis, preoperative anxiety, effect of music on anxiety, effect of music on surgical performance and preference for specific genres of music. Overall, the preferred genre of music in both the waiting-room group and in the staff group was Christmas music, provided this was in December. PMID- 29260707 TI - [Can othopaedic surgeons accelerate time, or does the enthusiasm for alcohol rub just decrease by age?] AB - Senior surgeons can execute a full surgical hand antisepsis in no time. This could be due to a changed perception of time with age. This cross-sectional study secretly timed orthopaedic surgeons during alcohol rub, investigated their perception of 120 see and attitude towards hand antisepsis. Surgeons under 50 years of age used significantly longer time on alcohol rub. No significant difference in perception of neither time nor attitude towards surgical hand antisepsis were found between age groups. Surgeons are not affected by mental aging but seem to be able to accelerate time. Surgeons are aware of standard guidelines and follow them. This study presents new findings adding to the mythic nature of the orthopaedic surgeon. PMID- 29260708 TI - [The Epic healthcare system in Denmark]. AB - In 2016 the first Danish hospitals adopted "Sundhedsplatformen", the Danish version of the Epic electronic health record. There has been much discussion about the perceived shortcomings of Sundhedsplatformen. This article reviews documents, that the introduction of electronic health records is associated with an increase in time spent on charting and an increase in errors. Even after several years of working with electronic health records physicians may consider themselves less than proficient in the use of the electronic health record. Physician dissatisfaction increases the risk of burnout, and work-related stress is linked to increased sympathetic tone and negative physiological effects, so stress management is important. PMID- 29260709 TI - Correction: The large-scale organization of shape processing in the ventral and dorsal pathways. PMID- 29260712 TI - In vitro hydrodynamic and acute clinical performance of a novel self-expanding transcatheter heart valve in various surgical bioprostheses. PMID- 29260710 TI - Conserved noncoding transcription and core promoter regulatory code in early Drosophila development. AB - Multicellular development is driven by regulatory programs that orchestrate the transcription of protein-coding and noncoding genes. To decipher this genomic regulatory code, and to investigate the developmental relevance of noncoding transcription, we compared genome-wide promoter activity throughout embryogenesis in 5 Drosophila species. Core promoters, generally not thought to play a significant regulatory role, in fact impart restrictions on the developmental timing of gene expression on a global scale. We propose a hierarchical regulatory model in which core promoters define broad windows of opportunity for expression, by defining a range of transcription factors from which they can receive regulatory inputs. This two-tiered mechanism globally orchestrates developmental gene expression, including extremely widespread noncoding transcription. The sequence and expression specificity of noncoding RNA promoters are evolutionarily conserved, implying biological relevance. Overall, this work introduces a hierarchical model for developmental gene regulation, and reveals a major role for noncoding transcription in animal development. PMID- 29260711 TI - Inferring genetic interactions from comparative fitness data. AB - Darwinian fitness is a central concept in evolutionary biology. In practice, however, it is hardly possible to measure fitness for all genotypes in a natural population. Here, we present quantitative tools to make inferences about epistatic gene interactions when the fitness landscape is only incompletely determined due to imprecise measurements or missing observations. We demonstrate that genetic interactions can often be inferred from fitness rank orders, where all genotypes are ordered according to fitness, and even from partial fitness orders. We provide a complete characterization of rank orders that imply higher order epistasis. Our theory applies to all common types of gene interactions and facilitates comprehensive investigations of diverse genetic interactions. We analyzed various genetic systems comprising HIV-1, the malaria-causing parasite Plasmodium vivax, the fungus Aspergillus niger, and the TEM-family of beta lactamase associated with antibiotic resistance. For all systems, our approach revealed higher order interactions among mutations. PMID- 29260713 TI - Correlates of non-target vessel-related adverse events in patients with ST segment elevation myocardial infarction: insights from five-year follow-up of the EXAMINATION trial. AB - AIMS: The aim of this substudy was to determine the five-year correlates of non TV-related adverse events (AE) in STEMI patients included in the EXAMINATION trial. METHODS AND RESULTS: The EXAMINATION trial randomised 1,498 STEMI patients to bare metal or everolimus-eluting stent implantation. In this substudy, patients were analysed according to non-TV-related AE, defined as the composite of either non-TV revascularisation (non-TVR) or non-TV-related myocardial infarction (MI). At five-year follow-up, 125 patients (8.3%) exhibited 136 non-TV related AE (124 [8.3%] non-TVR, 12 [0.8%] non-TV-related MI), accounting for 47.1% of 289 non-fatal cardiac events overall. These patients had a higher incidence of diabetes mellitus (p<0.001), arterial hypertension (p=0.032), previous MI (p=0.073), multivessel disease (p<0.001), and incomplete revascularisation (p=0.049), and a lower rate of ST-segment resolution >70% (p=0.042) as compared to the rest. At Cox analysis, previous MI (HR 1.872, 95% CI: 1.004-3.489; p=0.048), incomplete revascularisation (HR 1.746, 95% CI: 1.029 2.963; p=0.039) and diabetes (HR 1.942, 95% CI: 1.292-2.919; p=0.001) were independent correlates of non-TV-related AE. CONCLUSIONS: In STEMI patients undergoing primary percutaneous coronary intervention, previous MI, incomplete revascularisation and diabetes resulted in being independent correlates of five year non-TV-related AE. PMID- 29260714 TI - Fallout from the ORBITA trial - is angioplasty in a spin? PMID- 29260715 TI - A new hope - low permanent pacemaker rates with selfexpanding transcatheter heart valves. PMID- 29260716 TI - Data from real-world registries: can it guide development of the bioresorbable scaffolds of tomorrow? PMID- 29260717 TI - Sorting out coronary stents, as time goes by. PMID- 29260718 TI - Residual plaque prolapse with novel dual-layer carotid stents: is it mesh-covered or not? PMID- 29260719 TI - When will acute stroke interventions be as widely available as primary PCI? PMID- 29260721 TI - Propensity-matched comparison of percutaneous and surgical cut-down approaches in transfemoral transcatheter aortic valve implantation using a balloon-expandable valve. Moving to the percutaneous approach. PMID- 29260722 TI - How should I treat a coronary artery to pulmonary artery fistula at an acute stent thrombosis site? PMID- 29260723 TI - Compare and contrast tricuspid and mitral valve anatomy: interventional perspectives for transcatheter tricuspid valve therapies. AB - Moving transcatheter valve intervention towards atrioventricular (AV) valves implies increasing complexity. Some of the knowledge that has been generated during the development of mitral devices can be applied to the tricuspid valve (TV). A deep understanding of the peculiar anatomy of the TV and of the right heart chambers, with differences and similarities between the two AV valves, is fundamental to overcoming the specific challenges related to transcatheter TV therapies. The aim of this report is to explore similarities and differences between the mitral and tricuspid valve apparatus, and their interventional implications. PMID- 29260724 TI - Layer Structured Bismuth Selenides of Bi2Se3 and Bi3Se4 for High Energy and Flexible All-Solid-State Micro Supercapacitors. AB - Bismuth selenides (Bi2Se3 and Bi3Se4), both of which have the layered rhombohedral crystal structure, and found to be useful as electrode materials for supercapacitor application in this work. Bi2Se3 nanoplates as electrode material exhibit much better performance than that of Bi3Se4 nanoparticles in liquid electrolyte system (6 M KOH), which delivers a higher specific capacitance (272.9 F/g) than that of Bi3Se4 (193.6 F/g) at 5 mV/s. This result would may be attributed to that Bi2Se3 nanoplates possess more active electrochemical surfaces for the reversible surface redox reactions owing to its planar quintuple stacked layers (septuple layers for Bi3Se4). For the demand of electronic skin, we used a novel flexible annular interdigital structure electrode applying for all-solid state micro-supercapacitors (AMSCs). Bi2Se3 AMSCs device delivers a much more excellent supercapacitor performance, exhibits a large stack capacitance 89.5 F/cm3 (Bi3Se4: 79.1 F/cm3) at 20 mV/s, a high energy density 17.9 mWh/cm3 and high power density 18.9 W/cm3. The bismuth selenides also exhibit good cycle stability, retention 95.5% (90.3%) after 1000 c for Bi2Se3 (Bi3Se4). Obviously, Bi2Se3 nanoplates can be promising electrode materials for flexible annular interdigital all-solid-sate supercapacitor. PMID- 29260725 TI - Sensitive detection of hydroquinone using exfoliated graphene-Au/glassy carbon modified electrode. AB - Graphene nanosheets (EGr) were electrochemically prepared through one-step exfoliation of a graphite rod in a mixture of H2SO4:HNO3 (3:1) at low bias (4 V). Subsequently, gold nanoparticles were attached to the graphene surface (EGr-Au) by the reduction of the metal precursor (HAuCl4) in aqueous solution containing dispersed graphene sheets. According to the XRD investigation, the synthesized material consists of a mixture of few-layer (86%) and multi-layer (14%) graphene. The interlayer distance was found to be in the range of 0.466-0.342 nm, which is larger than the interlayer distance in graphite (0.335 nm). The average size of gold nanoparticles in the EGr-Au sample was 24 nm, in excellent agreement with the TEM results. The synthesized material was then employed to modify a glassy carbon (GC) substrate, in order to obtain a modified electrode (GC/EGr-Au). Next, the electrochemical behavior of hydroquinone (HQ) in the presence and absence of interfering species, catechol (CAT) and bisphenol A (BPA) was studied and the corresponding calibration curves were plotted. Thus, in solutions without interfering species, the GC/EGr-Au electrode has a wide linear range (3 * 10-7-10 4 M), high sensitivity (0.089 A M-1) and low detection limit (LOD = 10-7 M; S/N = 3). The presence of either catechol or bisphenol A leads to the increase of LOD to 2 * 10-7 M, and in addition changes the electrode sensitivity, up to 0.146 A M 1. PMID- 29260726 TI - Role of special cross-links in structure formation of bacterial DNA polymer. AB - Using data from contact maps of the DNA-polymer of Escherichia coli (E. Coli) (at kilobase pair resolution) as an input to our model, we introduce cross-links between monomers in a bead-spring model of a ring polymer at very specific points along the chain. Via suitable Monte Carlo simulations, we show that the presence of these cross-links leads to a particular organization of the chain at large (micron) length scales of the DNA. We also investigate the structure of a ring polymer with an equal number of cross-links at random positions along the chain. We find that though the polymer does get organized at the large length scales, the nature of the organization is quite different from the organization observed with cross-links at specific biologically determined positions. We used the contact map of E. Coli bacteria which has around 4.6 million base pairs in a single circular chromosome. In our coarse-grained flexible ring polymer model, we used 4642 monomer beads and observed that around 80 cross-links are enough to induce the large-scale organization of the molecule accounting for statistical fluctuations caused by thermal energy. The length of a DNA chain even of a simple bacterial cell such as E. Coli is much longer than typical proteins, hence we avoided methods used to tackle protein folding problems. We define new suitable quantities to identify the large scale structure of a polymer chain with a few cross-links. PMID- 29260727 TI - Dosimetric impact of dual-energy CT tissue segmentation for low-energy prostate brachytherapy: a Monte Carlo study. AB - The purpose of this study is to evaluate the impact of a novel tissue characterization method using dual-energy over single-energy computed tomography (DECT and SECT) on Monte Carlo (MC) dose calculations for low-dose rate (LDR) prostate brachytherapy performed in a patient like geometry. A virtual patient geometry is created using contours from a real patient pelvis CT scan, where known elemental compositions and varying densities are overwritten in each voxel. A second phantom is made with additional calcifications. Both phantoms are the ground truth with which all results are compared. Simulated CT images are generated from them using attenuation coefficients taken from the XCOM database with a 100 kVp spectrum for SECT and 80 and 140Sn kVp for DECT. Tissue segmentation for Monte Carlo dose calculation is made using a stoichiometric calibration method for the simulated SECT images. For the DECT images, Bayesian eigentissue decomposition is used. A LDR prostate brachytherapy plan is defined with 125I sources and then calculated using the EGSnrc user-code Brachydose for each case. Dose distributions and dose-volume histograms (DVH) are compared to ground truth to assess the accuracy of tissue segmentation. For noiseless images, DECT-based tissue segmentation outperforms the SECT procedure with a root mean square error (RMS) on relative errors on dose distributions respectively of 2.39% versus 7.77%, and provides DVHs closest to the reference DVHs for all tissues. For a medium level of CT noise, Bayesian eigentissue decomposition still performs better on the overall dose calculation as the RMS error is found to be of 7.83% compared to 9.15% for SECT. Both methods give a similar DVH for the prostate while the DECT segmentation remains more accurate for organs at risk and in presence of calcifications, with less than 5% of RMS errors within the calcifications versus up to 154% for SECT. In a patient-like geometry, DECT-based tissue segmentation provides dose distributions with the highest accuracy and the least bias compared to SECT. When imaging noise is considered, benefits of DECT are noticeable if important calcifications are found within the prostate. PMID- 29260728 TI - Tunable photovoltaic performance of preferentially oriented rutile TiO2 nanorod photoanodes based dye sensitized solar cells with quasi state electrolyte. AB - Photoanodes made of highly oriented TiO2 nanorod arrays with different aspect ratios were synthesized via one-step hydrothermal technique. Preferentially oriented single crystalline rutile TiO2 was confirmed by the single peak in XRD pattern (2theta=63o, (0 0 2)). FESEM image evidence the growth of an array of nanorods having different geometry with respect to reaction time and solution refreshment rate. The length, diameter and aspect ratio of the nanorods increased with reaction time as 4 hours (1.98 MUm, 121 nm, 15.32), 8 hours (4 MUm, 185 nm, 22.70), 12 hours (5.6 MUm, 242 nm, 27.24) and 16 hours (8 MUm, 254 nm, 38.02) respectively. Unlike conventional Dye-Sensitized Solar Cell (DSSC) with a liquid electrolyte, DSSC were fabricated here using 1D rutile TiO2 nanorods based photoanodes, N719 dye and quasi-state electrolyte. The charge transport properties were investigated from current-voltage curves and fitted using one diode model. Interestingly photovoltaic performance of DSSCs increased exponentially with the length of the nanorod and is attributed to the higher surface to volume ratio, more dye anchoring, and channelized electron transport. Higher photovoltaic performance (Jsc=5.99 mA/cm2, Voc=750 mV, eta=3.08%) was observed with photoanodes (16 hours) made of densely packed longest TiO2 nanorods (8 um, 254 nm). PMID- 29260729 TI - Characterization of the first RF coil dedicated to 1.5 T MR guided radiotherapy. AB - The purpose of this study is to investigate the attenuation characteristics of a novel radiofrequency (RF) coil, which is the first coil that is solely dedicated to MR guided radiotherapy with a 1.5 T MR-linac. Additionally, we investigated the impact of the treatment beam on the MRI performance of this RF coil. First, the attenuation characteristics of the RF coil were characterized. Second, we investigated the impact of the treatment beam on the MRI performance of the RF coil. We additionally demonstrated the ability of the anterior coil to attenuate returning electrons and thereby reducing the dose to the skin at the distal side of the treatment beam. Intensity modulated radiation therapy simulation of a clinically viable treatment plan for spinal bone metastasis shows a decrease of the dose to the planned tumor volume of 1.8% as a result of the MR coil around the patient. Ionization chamber and film measurements show that the anterior and posterior coil attenuate the beam homogeneously by 0.4% and 2.2%, respectively. The impact of the radiation resulted in a slight drop of the time-course signal to-noise ratio and was dependent on imaging parameters. However, we could not observe any image artifacts resulting from this irradiation in any situation. In conclusion, the investigated MR-coil can be utilized for treatments with the 1.5 T-linac system. However, there is still room for improvement when considering both the dosimetric and imaging performance of the coil. PMID- 29260730 TI - Measurement of effective detective quantum efficiency for a photon counting scanning mammography system and comparison with two flat panel full-field digital mammography systems. AB - Effective detective quantum efficiency (eDQE) describes the resolution and noise properties of an imaging system along with scatter and primary transmission, all measured under clinically appropriate conditions. Effective dose efficiency (eDE) is the eDQE normalised to mean glandular dose and has been proposed as a useful metric for the optimisation of clinical imaging systems. The aim of this study was to develop a methodology for measuring eDQE and eDE on a Philips microdose mammography (MDM) L30 photon counting scanning system, and to compare performance with two conventional flat panel systems. A custom made lead-blocker was manufactured to enable the accurate determination of dose measurements, and modulation transfer functions were determined free-in-air at heights of 2, 4 and 6 cm above the breast support platform. eDQE were calculated for a Philips MDM L30, Hologic Dimensions and Siemens Inspiration digital mammography system for 2, 4 and 6 cm thick poly(methyl methacrylate) (PMMA). The beam qualities (target/filter and kilovoltage) assessed were those selected by the automatic exposure control, and anti-scatter grids were used where available. Measurements of eDQE demonstrate significant differences in performance between the slit- and scan-directions for the photon counting imaging system. MTF has been shown to be the limiting factor in the scan-direction, which results in a rapid fall in eDQE at mid-to-high spatial frequencies. A comparison with two flat panel mammography systems demonstrates that this may limit image quality for small details, such as micro-calcifications, which correlates with a more conventional image quality assessment with the CDMAM phantom. eDE has shown the scanning photon counting system offers superior performance for low spatial frequencies, which will be important for the detection of large low contrast masses. Both eDQE and eDE are proposed as useful metrics that should enable optimisation of the Philips MDM L30. PMID- 29260731 TI - Four-point probe measurements using current probes with voltage feedback to measure electric potentials. AB - We present a four-point probe resistance measurement technique which uses four equivalent current measuring units, resulting in minimal hardware requirements and corresponding sources of noise. Local sample potentials are measured by a software feedback loop which adjusts the corresponding tip voltage such that no current flows to the sample. The resulting tip voltage is then equivalent to the sample potential at the tip position. We implement this measurement method into a multi-tip scanning tunneling microscope setup such that potentials can also be measured in tunneling contact, allowing in principle truly non-invasive four probe measurements. The resulting measurement capabilities are demonstrated for [Formula: see text] and [Formula: see text] samples. PMID- 29260732 TI - Thermoelectric properties of nanocrystalline Sb2Te3 thin films: experimental evaluation and first-principles calculation, addressing effect of crystal grain size. AB - The effect of crystal grain size on the thermoelectric properties of nanocrystalline antimony telluride (Sb2Te3) thin films was investigated by experiments and first-principles studies using a developed relaxation time approximation. The Sb2Te3 thin films were deposited on glass substrates using radio-frequency magnetron sputtering. To change the crystal grain size of the Sb2Te3 thin films, thermal annealing was performed at different temperatures. The crystal grain size, lattice parameter, and crystal orientation of the thin films were estimated using XRD patterns. The carrier concentration and in-plane thermoelectric properties of the thin films were measured at room temperature. A theoretical analysis was performed using a first-principles study based on density functional theory. The electronic band structures of Sb2Te3 were calculated using different lattice parameters, and the thermoelectric properties were predicted based on the semi-classical Boltzmann transport equation in the relaxation time approximation. In particular, we introduced the effect of carrier scattering at the grain boundaries into the relaxation time approximation by estimating the group velocities from the electronic band structures. Finally, the experimentally measured thermoelectric properties were compared with those obtained by calculation. As a result, the calculated thermoelectric properties were found to be in good agreement with the experimental results. Therefore, we can conclude that introducing the effect of carrier scattering at the grain boundaries into the relaxation time approximation contributes to enhance the accuracy of a first-principles calculation relating to nanocrystalline materials. PMID- 29260733 TI - p-n junction induced electron injection type transparent photosensitive film of Cu2O/carbon quantum dots/ZnO. AB - An electron injection type transparent photosensitive Cu2O/carbon quantum dot (C QD)/ZnO p-n junction film was prepared by a simple route in which, successively, the ZnO film was prepared by a sputtering process, the C QDs and Cu2O were prepared by hydrothermal synthetic and chemical methods, then the C QDs and Cu2O were introduced onto the surface of the ZnO film. The results indicated that the C QDs and Cu2O were well combined with the ZnO film. The transparency and photosensitivity of this film were investigated, and exhibited an obvious photosensitive enhancement compared with those of the unmodified film. Through analysis, this enhancement of the photoconductivity could be attributed to the remarkable Cu2O/ZnO p-n junction and C QDs with unique up-converted photoluminescence. PMID- 29260734 TI - Robust lanthanide emitters in polyelectrolyte thin films for photonic applications. AB - Trivalent lanthanides provide stable emission sources at wavelengths spanning the ultraviolet through the near infrared with uses in telecommunications, lighting, and biological sensing and imaging. We describe a method for incorporating an organometallic lanthanide complex within polyelectrolyte multilayers, producing uniform, optically active thin films on a variety of substrates. These films demonstrate excellent emission with narrow linewidths, stable over a period of months, even when bound to metal substrates. Utilizing different lanthanides such as europium and terbium, we are able to easily tune the resulting wavelength of emission of the thin film. These results demonstrate the suitability of this platform as a thin film emitter source for a variety of photonic applications such as waveguides, optical cavities, and sensors. PMID- 29260736 TI - Fe and Co NMR studies of magnetoelectric Co2 Y-type hexaferrite BSCFAO. AB - The Fe3+ and Co2+ NMR spectra for Ba0.3Sr1.7Co2 (Fe0.96Al0.04)12O22 (BSCFAO) and Ba0.3Sr1.7Co2Fe12O22 (BSCFO) were obtained in a zero magnetic field at a low temperature. We observed change in the enhancement effect of the NMR signals depending on the setting field, which was varied when applied along the b-axis and then turned off before the measurement was taken. The experimental results indicate that the magnetic structure changes from an alternating longitudinal cone to a transverse cone when the setting field is 250 mT. They also show that the spins of Co2+ ions together with those of Fe3+ ions constitute a part of the overall magnetic structure and that the substitution of Al3+ for Fe3+ weakens the magnetic anisotropy within the easy plane. From a comparison of the enhancement factors of the Fe3+ NMR obtained with the RF pulse applied along the a-axis and the c-axis, we realized that the magnetic easy plane anisotropy is approximately 16 times greater than the anisotropy within the easy plane. No changes of the NMR spectra were observed under an electric field of 1.2 MV/m. PMID- 29260735 TI - Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery. AB - Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet's sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using 1/4 dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets. PMID- 29260737 TI - XPS study of graphene oxide reduction induced by (100) and (111)-oriented Si substrates. AB - The reduction of graphene oxide (GO) has been extensively studied in literature in order to let GO partially recover the properties of graphene. Most of the techniques proposed to reduce GO are based on high temperature annealing or chemical reduction. A new procedure, based on the direct reduction of GO by etched Si substrate, was recently proposed in literature. In the present work, we accurately investigated the Si-GO interaction with x-ray photoelectron spectroscopy. In order to avoid external substrate oxidation factors we used EtOH as the GO solvent instead of water, and thermal annealing was carried out in UHV. We investigated the effect of Si(100), Si(111) and Au substrates on GO, to probe the role played by both the substrate composition and substrate orientation during the reduction process. A similar degree of GO reduction was observed for all samples but only after thermal annealing, ruling out the direct reduction effect of the substrate. PMID- 29260738 TI - Enhanced energy density and thermal conductivity in poly(fluorovinylidene-co hexafluoropropylene) nanocomposites incorporated with boron nitride nanosheets exfoliated under assistance of hyperbranched polyethylene. AB - Polymer dielectric film with a large dielectric constant, high energy density and enhanced thermal conductivity are of significance for the development of impulse capacitors. However, the fabrication of polymer dielectrics combining high energy density and thermal conductivity is still a challenge at the moment. Here we demonstrate the facile exfoliation of hexagonal boron nitride nanosheets (BNNSs) in common organic solvents under sonication with the assistance of hyperbranched polyethylene (HBPE). The noncovalent CH-pi interactions between the nanosheets and HBPE ensure the dispersion of BNNSs in organic solvents with high concentrations, because of the highly branched chain structure of HBPE. Subsequently, the resultant BNNSs with a few defects are distributed uniformly in the poly(fluorovinylidene-co-hexafluoropropylene) (P(VDF-HFP)) nanocomposite films prepared via simple solution casting. The BNNS/P(VDF-HFP) nanocomposite exhibits outstanding dielectric properties, high energy density and high thermal conductivity. The dielectric constant of the 0.5 wt% nanocomposite film is 35.5 at 100 Hz with an energy density of 5.6 J cm-3 at 325 MV m-1 and a high charge discharge efficiency of 79% due to the depression of the charge injection and chemical species ionization in a high field. Moreover, a thermal conductivity of 1.0 wt% nanocomposite film reaches 0.91 W.m-1 . K-1, which is 3.13 times higher than that of the fluoropolymer matrix. With dipole accumulation and orientation in the interfacial zone, lightweight, flexible BNNS/P(VDF-HFP) nanocomposite films with high charge-discharge performance and thermal conductivity, exhibit promising applications in relatively high-temperature electronics and energy storage devices. PMID- 29260739 TI - Emitting color tunable carbon dots by adjusting solvent towards light-emitting devices. AB - Carbon dots (CDs), one of the most significant classes of carbon-based nanophosphors, have attracted extensive attention in recent years. However, few attempts have been reported for realizing CDs with tunable emissions, especially for obtaining the red-light emissions with high photoluminescence quantum yields. Herein, we synthesized CDs with different chromatic blue, green and red emissions by facilely changing the reaction solvent during hydrothermal conditions. The photoluminescence quantum yields of 34%, 19% and 47% for the blue, green and red emissions, respectively, were achieved. Furthermore, the solid-state CD/PVA composite films were constructed through mixing the CDs with PVA polymer, in which the self-quenching of photoluminescence of CDs had been successfully avoided benefiting from the formation of hydrogen bonds between the CDs and PVA molecules. Finally, the warm white light emitting diode (WLED) was fabricated by integrating CD/PVA film on a UV-LED chip. The WLED exhibited the Commission International de l'Eclairage coordinates (CIE) of (0.38, 0.34), correlated color temperature of 3913 K and color rendering index of 91, respectively, which were comparable with the commercial WLEDs. PMID- 29260740 TI - [Hepatitis C can be cured: will hepatitis B become next?] AB - Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called 'functional cure' is a very rare event. Moreover, 'complete cure' when the virus is entirely eliminated from the body is not possible due to a persistent form of covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) in hepatocytes refractory to modern antivirals. Today, there is a plethora of new promising medications being at different stages of development that target different steps of viral life cycle, including inhibitors of interaction between HBV and its entry receptor NTCP, inhibitors of HBV cccDNA, inhibitors of nucleocapsid assembly, technologies of genome editing (TALENs, CRISPR/Cas etc) and RNA-interference. In addition to direct acting antivirals, there is a number of approaches aimed at enhancement of the innate and adaptive immune responses. In experimental conditions, some of these approaches or their combinations help to achieve functional cure. However, complete elimination of the virus is possible only using technologies of genome editing, capable of specific cccDNA degradation. Nuclease systems are currently at their early stages of development, and there is a long way to prove their efficacy and safety. Nevertheless, highly promising results of the recent years leave no doubt that CRISPR/Cas systems and similar technologies can become the basis of CHB therapy. PMID- 29260741 TI - [Lymphocyte subpopulations, levels of interferon, and expression of their receptors in patients with chronic hepatitis B and C: Correlation with the species of viruses and the degree of liver fibrosis]. AB - AIM: To determine whether there is a correlation of the composition of circulating lymphocyte subpopulations, the serum concentrations of interferon (IFN)-alpha, IFN-gamma, and IFN-lambda3, and the lymphocyte expression of types I and II IFN receptors with the species of a disease pathogen and the degree of liver fibrosis (LF) in patients with chronic hepatitis B (CHB) and in those with chronic hepatitis C (CHC). SUBJECTS AND METHODS: The investigation enrolled 44 patients with CHC, 9 patients with CHB, and 13 clinically healthy donors. The degree of LF in the patients was determined using transient elastography. The composition of peripheral blood lymphocyte subpopulations was examined; the concentrations of IFN-alpha, IFN-gamma, and IL-28B were estimated. RESULTS: Lymphocyte counts were higher in patients with CHC and in those with CHB than those in healthy donors; and the number of neutrophils was lower. There were no differences between the groups in the composition of lymphocyte subpopulations with the exception of the number of CD3+CD4+ cells, which in patients with CHC was larger than in those with CHB. In CHC and CHB patients, the counts of CD118+ lymphocytes were higher than those in healthy donors. Patients with CHB and those with CHC did not differ between themselves and from healthy donors in the expression of CD119 on the lymphocytes. In CHC patients, the relative CD119+ cell counts were higher between CD4+ lymphocytes than those in healthy donors. The serum levels of IFN-alpha and IFN-gamma in CHC and CHB patients were similar, but higher in healthy donors. The concentration of IL-28B genotype in patients with CHC was twice as high as in those with CHB, but the differences were statistically insignificant. The number of lymphocytes increased with the progression of fibrosis; that of neutrophils decreased. There was an inverse relationship between platelet counts and LF severity. Multiple comparisons of the clusters of patients with different degrees of LF revealed no differences in the number of major lymphocyte subpopulations. However, the number of CD3+CD16+CD56+ natural killer-like T (NKT) cells correlated with fibrosis severity. Patients with different degrees of LF showed no differences in the proportion of CD118- and CD119 cells between lymphocytes and in the serum levels of IFN-alpha, IFN gamma, and IL-28B levels. Patients with grade IV LF displayed a higher proportion of CD4+CD119+ lymphocytes between CD45+ cells than did those with grade III LF. CONCLUSION: Several new clinical and laboratory trends were identified and the nature and extent of previously described hematological and immunological changes were clarified in CHC or CHB patients with various degrees of LF. Some indicators may be used as additional criteria for the prognosis of the above forms of hepatitis, and a number of newly described facts suggest that it is necessary to revise the protective/phlogogenic value of types I, II, and III IFNs in chronic viral hepatitis C and B. PMID- 29260742 TI - [Overexpression of DNA-methyltransferases in persistency of cccDNA pool in chronic hepatitis B]. AB - AIM: To define the role of DNA-methyltransferases of type 1 and type 3A in hepatitis B viral cycle. MATERIAL AND METHODS: Human hepatoma cells HepG2 with stable expression of 1.1-mer HBV genome were transfected with vectors encoding DNA-methyltransferase 1 (DNMT1), DNA-methyltransferase 3A (DNMT3A) or were co transfected with these vectors. Total HBV DNA copy number, relative expression of pregenomic RNA (pgRNA), S-protein-encoding RNA (S-RNA) and cccDNA were analyzed by quantitative and semi-quantitative real-time PCR-analysis with TaqMan probes for assessment of DNMTs-mediated effects on HBV. RESULTS: DNMT1 and DNMT3A suppress HBV transcription and replication, though to different magnitude. cccDNA pool is enlarged statistically significantly ~2-fold (P<0.005) after transfection of DNMT3A, but is unaltered under DNMT1 treatment. CONCLUSION: DNMT3A regulates the size of cccDNA pool and is important for persistency of HBV infection. PMID- 29260743 TI - [Impact of current approaches to laboratory screening of donated blood and its components on hepatitis B virus infection in patients with blood system diseases]. AB - AIM: To evaluate the detection rate of markers for hepatitis B virus (HBV) in the blood samples taken from patients with blood system diseases, by applying the current approaches to examining donated blood and its components for markers of viral infections. MATERIAL AND METHODS: The investigation included blood samples from patients with blood system diseases (n=364) and donors (n=5,011). The results of laboratory screening of donated blood samples (n=13,081) were retrospectively analyzed. Commercial kits of reagents were used for immunochemical assay and polymerase chain reaction. RESULTS: Patients with blood system diseases were recorded to have markers of active HBV infection in 12.6% of cases, anti-HBc in 31.3%, and anti-HBs in 37.6%. A retrospective analysis of the results of screening donated blood samples showed the presence of markers for active HBV infection in 0.28% of cases. A prospective examination of blood donors revealed markers of HBV infection in 4.83% of cases, including those of active forms in 0.54% and anti-HBc in 4.79%. The markers of active HBV infection in donors were only anti-HBc IgM in 0.42% of cases. The blood samples from donors with an anti-HBs titer of >200 mIU/ml contained anti-HBc IgM in 10.5%. CONCLUSION: In the last 5-7 years, the detection rate of markers of HBV infection in the blood samples of patients with blood system diseases have remained at a high level. Screening for decreed markers fails to identify people with inapparent infections among the donors. Even high anti-HBs concentrations in the donated blood may be a risk for HBV transmission by transfusion to a recipient. PMID- 29260744 TI - [Clinical presentation of Ixodes tick-borne borreliosis caused by Borrelia miyamotoi in the context of an immune response to the pathogen]. AB - : Ixodes tick-borne borreliosis caused by Borrelia miyamotoi (ITBB-BM) is a previously unknown infectious disease discovered in Russia. AIM: The present study continues the investigation of the clinical features of ITBB-BM in the context of an immune system-pathogen interaction. SUBJECTS AND METHODS: The study enrolled 117 patients with ITBB-BM and a comparison group of 71 patients with Lyme disease (LD) that is ITBB with erythema migrans. All the patients were treated at the New Hospital, Yekateringburg. More than 100 clinical, epidemiological and laboratory parameters were obtained from each patient's medical history and included in the general database. A subset of patients hospitalized in 2015 and 2016 underwent additional laboratory examinations. Namely, the levels of B. miyamotoi-specific IgM and IgG antibodies were measured by the protein microarray containing GlpQ protein and four variable major proteins (VMPs): Vlp15/16, Vlp18, Vsp1, and Vlp5. The blood concentration of Borrelia was estimated by quantitative real-time PCR. RESULTS: In contrast to LD, first of all (p<0.001) the following clinical features were typical for ITBB-BM: the absence of erythema migrans (in 95% of patients), fever (93%), fatigue (96%), headache (82%), chill (41%), nausea (28%), lymphopenia (56%), thrombocytopenia (46%), the abnormal levels of alanine aminotransferase (54%) and C-reactive protein (98%), proteinuria (61%). Given the set of these indicators, the course of ITBB-BM was more severe in approximately 70% of patients. At admission, only 13% and 38% of patients had antibodies to GlpQ and VMPs, respectively; at discharge, antibodies to GlpQ and VMPs were detected in 88% of patients. There was no statistically significant association of the antibody response with individual clinical manifestations and laboratory parameters of the disease. However, patients with more severe ITBB-BM produced less IgM antibodies to VMPs and GlpQ at the time of discharge. CONCLUSION: ITBB-BM is a moderate systemic disease accompanied by the production of specific antibodies in virtually all patients. PMID- 29260745 TI - [Molecular epidemiological analysis of HIV-1 variants circulating in Russia in 1987-2015]. AB - AIM: To simultaneously analyze HIV-1 samples from all Russian regions to characterize the epidemiology of HIV infection in the country as a whole. SUBJECTS AND METHODS: The most extensive study was conducted to examine nucleotide sequences of the pol gene of HIV-1 samples isolated from HIV-positive persons in different regions of Russia, with the diagnosis date being fixed during 1987-2015. The nucleotide sequences of the HIV-1 genome were analyzed using computer programs and on-line applications to identify a virus subtype and new recombinant forms. RESULTS: The nucleotide sequences of the pol gene were analyzed in 1697 HIV-1 samples and the findings were that the genetic variant subtype A1 (IDU-A) was dominant throughout the entire territory of Russia (in more than 80% of all infection cases). Other virus variants circulating in Russia were analyzed; the phenomenon of the higher distribution of the recombinant form CRF63/02A in Siberia, which had been previously described in the literature, was also confirmed. Four new recombinant forms generated by the virus subtype A1 (IDU A) and B and two AG recombinant forms were found. There was a larger genetic distance between the viruses of IDU-A variant circulating among the injecting drug users and those infected through heterosexual contact, as well as a change in the viruses of subtype G that caused the outbreak in the south of the country over time in 1988-1989. CONCLUSION: The findings demonstrate continuous HIV-1 genetic variability and recombination over time in Russia, as well as increased genetic diversity with higher HIV infection rates in the population. PMID- 29260746 TI - [The spectrum of primary drug resistance of Mycobacterium tuberculosis in patients with tuberculosis in relation to human immunodeficiency virus status]. AB - AIM: To estimate the detection rate and spectrum of primary drug resistance of Mycobacterium tuberculosis (MBT) in patients with tuberculosis (TB) in relation to their human immunodeficiency virus (HIV) status in a region with high HIV infection rates (the Perm Territory) and to compare of drug-resistant MBT (DR MBT) in patients with HIV/TB co-infection, by using phenotypic and molecular genetic testing (MGT) methods. SUBJECTS AND METHODS: The results of sputum bacteriological examination were analyzed in 178 HIV-infected patients and 354 non-HIV-infected individuals with a TB diagnosis made in the period July 1, 2014 to August 1, 2015. The diagnostic algorithm for all patients involved a duplicate sputum test for MBT by two techniques: fluorescence microscopy (FM) and inoculation into the Levenstein-Jensen dense culture medium. In patients with HIV/TB, the bacteriological examination was complemented with two more methods: detection of MBT DNA by a real-time polymerase chain reaction assay using the AmpliTube-RV system (Synthol, Russia); and inoculation into the Middlebrook liquid nutrient medium, by applying the automated BACTEC MGIT 960 system. RESULTS: In patients with HIV/TB, the sensitivity of FM proved to be lower than in those with TB (24.2 and 32.8%, respectively; p<0.05) and that of inoculations into the dense culture medium was comparable regardless of HIV status (60.7 and 57.1%, respectively; p>0.05). The primary drug resistance of MBT in patients with HIV-TB was higher than that in HIV-negative individuals (60.2 and 41.6%, respectively; p<0.05). The phenotypic method (inoculation into the Levenstein Jensen culture medium) and MGT revealed their agreement for the resistance of MBT to rifampicin (the most clinically significant drug in the choice of treatment policy) in 88.5% of the patients with HIV/TB. CONCLUSION: In patients with HIV/TB, the sensitivity of FM for detecting acid-resistant mycobacteria was lower than in those with TB and that of inoculations into the dense medium was comparable regardless of HIV status. PMID- 29260747 TI - [Identification of Shiga toxin in patients with acute intestinal infections in the presence of mono- and mixed-O-antigens of pathogens]. AB - AIM: To investigate the time course of changes in the detection rates and levels of Shiga toxin antigen (STA) in their stool and middle-molecule circulating immune complexes (CICs) containing IgG (IgG CIC) in patients with acute intestinal infections (AIIs) in the presence of the body's circulation of mono- and mixed-LPS/O-antigens of intestinal pathogens. SUBJECTS AND METHODS: A total of 147 patients aged 15 to 55 years who had been hospitalized with AIIs were examined. The diagnosis was bacteriologically verified in 19% of the patients; in the others, it was confirmed by the detection of LPS/O-antigens of Shigella, Salmonella, Yersinia, and Campylobacter in their stool by means of the reaction of coagglutination (RCA) on glass slides. Plates for RCA displayed STA in the fecal and IgG CIC samples. RESULTS: Mono- and mixed infections were detected in 32 and 68%, respectively. The RCA plates exhibited STA in 25.2% of the fecal samples and in 90.5% of the IgG CIC ones from patients with AIIs and did not in those from donors. In monoinfection, the detection rates and levels of STA in the feces became lower in the course of the disease and remained unchanged in IgG CIC and the levels of STA also decreased in the feces, but increased in IgG CIC in mixed infection. CONCLUSION: In 25.2% of the patients with early AIIs, their stools show free STA; its detection rate and levels are significantly higher in mixed infections than those in monoinfection. The level of STA in serum IgG CIC was significantly higher in mixed infection, suggesting an active immune response to the pathogen. Given that the Shiga toxin-producing strains are present in patients with AIIs, caution should be exercised in the choice of an antibacterial drug to prevent horizontal gene transfer and to enhance toxin production and the body's intoxication. One of the advantages of RCA is the possibility of rapidly changing the spectrum of test systems, depending on the region of their application and the epidemiological situation. PMID- 29260748 TI - [Necrotizing sarcoid granulomatosis with clinical presentations of recurrent acute abdomen. Case report and literature review]. AB - The authors have described the world's first case of necrotizing sarcoid granulomatosis (NSG) in a 22-year-old woman with the clinical presentations of acute abdomen, which are associated with abdominal lymph nodal infiltration and necrosis, obvious constitutional disturbances (fever, nocturnal sweats, and significant weight loss), high inflammatory activity (anemia, leukocytosis, high erythrocyte sedimentation rates and C-reactive protein levels), the gradual appearance of splenic and hepatic necrotic foci, and infiltration into the lung and lacrimal glands with the development of unilateral uveitis. The patient underwent five surgical interventions, several needle biopsies for recurrent abdominal syndrome, and long-term antibiotic treatment for presumed sepsis, which had caused drug-induced hepatitis. Bacteriological examination of blood, puncture samples, and removed abdominal cavity tissues, serological tests, and immunomorphogical study of biopsy samples and removed tissues yielded negative results for the presence of bacterial, fungal, and tuberculosis infections. NSG was diagnosed on the basis of the systemic nature of the lesion, the presence of granulomas with severe abdominal lymph nodal necrosis and necrotizing granulomatous/lymphocytic vasculitis in the mesentery and removed spleen, as well as the absence of granulomas in the spleen, appendix, and biopsy materials of the liver, colonic mucosa, and parotid gland. Fludarabine therapy was first used in world practice due to the inefficient treatment with high-dose glucocorticoids and cyclophosphamide and to a disease relapse when reducing their doses. The paper gives a detailed review of the literature on the clinical, laboratory, radiological, and morphological manifestations of the disease, which allow the differential diagnosis of NSG with different variants of granulomatous lesions. Based on the 5-year follow-up of the patient and on the analysis of clinical, laboratory, radiological, and morphological changes, the authors uphold the concept that the disease is an independent nosological entity: necrotizing angiitis with sarcoid reactions, rather than the entity of nodular or classic sarcoidosis. PMID- 29260749 TI - [Difficulties in the diagnosis of diarrhea-associated hemolytic uremic syndrome in adults]. AB - Hemolytic uremic syndrome (HUS) is a rare, but menacing condition registered mainly in children. The paper gives a detailed description and analysis of a clinical case of HUS with a favorable outcome in an adult woman who developed the syndrome in the presence of bloody diarrhea. It considers an update on the etiology, pathogenesis, and clinical features of HUS associated with diarrheal syndrome and discusses differential diagnostic features, diagnostic problems, and characteristics of management tactics for patients. PMID- 29260750 TI - [The virus-immune hypothesis for cardiac dilatation]. AB - The paper gives an update on the pathogenetic role of viral infection and immune mechanisms in the development of cardiac dilatation at the cellular, ultrastructural, and molecular levels. Particular attention is given to the discussion of the possible role of herpesvirus infection in the mechanisms of cardiomyocyte damage with the direct or indirect impact of viral infection through immunoinflammatory responses. Data on the protective and damaging action of a number of cytokines in the immunopathogenesis of viral myocarditis are considered. PMID- 29260751 TI - [Clinical efficacy of the immunomodulatory agent cycloferon (tablets) in viral respiratory infections: Results of a systematic review and meta-analysis]. AB - The authors carried out a systematic review and subsequent meta-analysis of randomized clinical trials evaluating the efficacy of the immunomodulator agent cycloferon as tablets in adults and children with viral respiratory diseases. A total estimate of its clinical efficacy was obtained in terms of compared heterogeneous groups and response variables. The data published in 16 articles were used to calculate the formal parameters of the clinical efficacy of cycloferon (increased absolute and relative benefits, odds ratio (OR); the number of patients needed to be additionally treated with cycloferon to achieve a favorable outcome or to prevent a poor outcome in one patient, etc.). High heterogeneity hampered the unequivocal interpretation of results; however, combining the compared homogeneous groups in the meta-analysis (with adjustments for fixed and random effects) increased the statistical power of the investigation. In children aged 6 to 18 years, the OR for the positive effect of the drug (no new cases after its preventive administration) was 5.3 (95% confidence interval (CI), 4.8-5.9), heterogeneity test, chi2 = 249.5; p=0.000...; I2 = 94.8% (95% CI, 92.7-96.3%). This suggested the heterogeneity of clinical trial data and extrapolated this estimate to medical practice. The use of cycloferon in adults to treat acute respiratory viral infection enhanced their chances of enduring the disease in a mild form and avoiding serious complications: the OR for positive outcomes was 9.7 (95% CI, 7.0-13.0), while the effect was more homogeneous than in children (heterogeneity test, chi2 = 7.4; p=0.061...; I2 = 59.4% (95% CI, 0-86.5). Thus, the use of cycloferon to treat and prevent acute viral respiratory infections showed a more than 5-fold increase in the probability of avoiding the disease or enduring the latter in a mild form. PMID- 29260752 TI - [Safety of the Russian antiviral drug Kagocel]. AB - The review gives summarized information on the preclinical data and clinical trials evaluating the safety of the antiviral drug Kagocel. It notes that the manufacturer of the drug pay special attention to the control of its impurity content. There is information on the development and validation of highly sensitive and specific high-performance liquid chromatography procedures, the application of which can guarantee that free gossypol impurities are absent in the drug. The results of preclinical toxicity study of Kagocel in experiments on laboratory animals are briefly reviewed; particular attention is paid to the investigation of the drug's safety for the reproductive system of immature animals. It is noted that evaluation of the total toxic properties of Kagocel has revealed no signs of intoxication. Investigations of the reproductive toxicity of Kagocel have showed no effect on spermatogenesis. A set of experimental studies of the long-term effects of the use of Kagocel in different regimens has confirmed that the drug has no negative effect on the reproductive organs in the offspring of experimental rats and on its development. Many clinical trials, including those with participation of children aged 2 years or older, have provided important data on drug safety. The results given in the review lead to the conclusion that the use of the antiviral drug Kagocel in both general and pediatric practice is proven safe. PMID- 29260753 TI - [Clinical and epidemiological features of visceral leishmaniasis in the Republic of Crimea]. AB - The paper analyzes official statistical data, as well as visceral leishmaniasis (VL) cases who have visited the Clinical Center, I.M. Sechenov First Moscow State Medical University, and the results of parasitological studies of the materials submitted to the Reference Center for Monitoring of Leishmaniasis, E.I. Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases. Account is taken of the observations made by the Central Research Institute of Epidemiology, Russian Federal Service for Supervision of Consumer Rights Protection and Human Welfare, and of the literature data available in Russian and foreign (Ukraine) scientific journals and monographs. During the period of 1932 to 2015, a total of 14 VL cases acquired in the Crimea were notified, of which there were 4 cases of VL concurrent with HIV infection. The majority of infections occurred in the eastern part of the peninsula. Given that many areas of Crimea have the status of recreation and annually receive millions of vacationists, it is necessary to conduct a more in-depth study of all aspects of this infection. PMID- 29260754 TI - [Evolution of laboratory markers for systemic bacterial infections]. AB - The paper reviews the data available in the literature on existing laboratory markers for systemic bacterial infection, among which C-reactive protein, proinflammatory cytokines, procalcitonin test, and presepsin receive primary emphasis. PMID- 29260755 TI - [Schnitzler syndrome: A review of literature, the authors' observation, and experience with the interleukin-1 inhibitor canakinumab]. AB - The paper reviews the publications dealing with Schnitzler syndrome, a rare autoinflammatory disease, and describes the authors' own clinical observation. It describes the first Russian experience in successfully using the interleukin-1 inhibitor canakinumab to treat this disease. PMID- 29260756 TI - [Optimization of reparative dentinogenesis in experimental osteoporosis]. AB - The aim of the study was to assess histochemical changes of the dental pulp in direct pulp capping/experimental osteoporosis animal model. The study was performed on 20 two-year sheep with simulated acute pulpitis divided in 2 groups: main (15 animals/120 teeth) and control (5 animals/40 teeth). Direct pulp capping in the main group included tissue-engineered structure composed of a hydrogel PuraMatrix/3DM with ectomesenchymal stem cells immobilized on collagen sponge. In the control group collagen sponges with hydrocortisone furatsilin, chondroitin sulfate, anaesthesinum were used for the same purpose. Dentinal bridge formation was much slower in controls than in the main group. Developed tissue-engineered design optimizes each stage of the healing process by protecting the pulp from infection, reduction of exudation, hemostatic effect and in long term contributes to a significant acceleration of the formation of the dentinal bridge. PMID- 29260757 TI - [Spectrophotometric method for objective focal enamel demineralization diagnostics]. AB - The article presents the results of spectrophotometric tooth enamel scanning. Research was conducted in vitro on extracted teeth. Numeric color parameters measurements were made by VITA EasyShade spectrophotometer after the 37% phosphoric acid enamel conditioning, that was made for an artificial tooth enamel demineralization reconstruction. Then transverse section of this enamel part was evaluated by scanning electronic microscopy. The scale of enamel demineralization depth in mm/microns and its' lightness parameter compliance was created. PMID- 29260758 TI - [Regeneration of dental pulp tissue using pulpal autologous mesenchymal stem cells and platelet-rich plasma]. AB - Regeneration of pulp and dentin could be important in operative dentistry as a method to save teeth. Currently cell population from dental pulp of deciduous and permanent teeth of humans and laboratory animals are isolated and characterized. The paper presents a study on pulp regeneration using autologous mesenchymal stromal cells from pulp of molars in combination with fibrin clot, transplanted in pulp chamber of miniature pigs after pulp removal. The results proved that transplantation of autologous multipotent stromal cells of dental pulp in combination with autologous platelet-rich plasma in pulp chamber of miniature pigs after pulp removal leads to pulp restoration and reparative dentinogenesis with dentinal bridge formation on the 30th day. However, the completion of regeneration also results in a decrease in the pulp chamber volume due to the neodentin bedding. Tissue regeneration of dental pulp by direct pulp capping in the absence of inflammatory processes is a promising direction of the use of cellular technologies. PMID- 29260759 TI - [The dinamics of preventive dental visits in mandatory health insurance system]. AB - The analysis on the current standards of the amount of Medical care provided for dental diseases treatment in Russia within mandatory health insurance program has been made. The study revealed more than 80-fold difference in the number of visits for one insured patient in different regions of Russian Federation. The annual increase in financial expenses covering dental visits for prophylactic purposes is identified. It is recommended that the Federal Fund of Mandatory Health Insurance to state a clear definition to the term 'Dental visit for prophylactic purposes', while the territorial funds should strengthen the requirements for approved reporting forms submition. PMID- 29260760 TI - [Gender-related preferences in the choice of methods for aesthetic and functional rehabilitation in dentistry]. AB - The aim of the study was to assess gender-related preferences in the choice of oral rehabilitation methods. The study involved 225 patients aged 16-75. The analysis included patients survey and the assessment of actual procedures received during one year follow-up. The study revealed women to be more attentive to oral health issues resulting in more regular appointments and better compliance. Dental treatment before planned pregnancy was, however, completed in only half of the patients. When choosing materials and constructions for oral rehabilitation the leading criteria for men were 'quality' and 'safety', while women chose 'esthetics' and 'quality'. Both genders would like to have their teeth 'whiter' but women undergo bleaching procedures more often. The dentists need to consider the revealed gender-related features for planning of prevention, treatment and full oral rehabilitation. PMID- 29260761 TI - [Mineral composition of mixed saliva in patients with dental fluorosis]. AB - The aim of the study was to assess the mineral composition of mixed saliva in dental fluorosis patients undergoing treatment with microabrasion and bleaching. The study included 60 patients aged 18-35 years with various forms of dental fluorosis. Group 1 included 40 patients in which enamel microabrasion was performed, group 2 - 20 patients with microabrasion and bleaching. Mixed saliva composition was analyzed with Olimpus automatic analyzing device. Dental fluorosis treatment in both groups resulted in saliva mineral composition changed associated with enamel demineralization which proves the necessity for calcium and phosphate containing compositions in these treatment groups. PMID- 29260762 TI - [Radiographic manifestations variants of odontogenic inflammatory destructive lesions in lower molars]. AB - The analysis and comparison of clinical and radiographic manifestations of odontogenic destructive processes in the area of molars of the lower jaw 54 patients, treated at the outpatient department of surgical dentistry CRID and MS. Set the main features of clinical manifestations depending on the distribution of the destructive process of the bone. PMID- 29260763 TI - [Optimization of wound healing by correction of the oral microbiota at the stage of surgical treatment of tongue cancer]. AB - Post-resection wound healing, oral microbiota composition and saliva lysozyme activity were assessed in 36 patients with tongue carcinoma before and after surgery with the local application of 2% solution of acid-diluted chitosan in the postoperative period. The microbiocenosis of the oral cavity before treatment in cancer patients was represented by conditionally pathogenic and pathogenic bacteria, whose number is more than 4 lg CFU/cm2, indicating dysbiosis; the lysozyme level was reduced, accounting for 25.4+/-8.5 ug/ml. After the radical hemi-glossectomy the reduction in the frequency and quantity of conditionally pathogenic and pathogenic microorganisms was statistically determined, as well as an increase in the level of lysozyme of saliva on the 10 day of treatment. Patients receiving local treatment with chitosan showed an increasing number of normal microbiota in 1,5-2 times, and the level of lysozyme in 8 times (amounted to 202.87+/-56.85 ug/ml). PMID- 29260764 TI - [Analysis of the color changes in teeth at different depths preparation]. AB - Spectrophotometric analysis of the extract and intact teeth revealed the color characteristic of teeth ranged from the cervical area to the cutting edge, as well as by preparation of dental hard tissue to 0.3 mm, 0.6 mm, 0.9 mm depth. Lightness increased as preparation approached dentine. The intensity of the Lightness was more pronounced in the cervical region which is associated with a thin layer of enamel performing the lens function. It is found that Hue values weakly depend on the depth and location of the preparation, the tooth reflecting a relatively constant range of visible wavelengths. During preparation of the hard tissue at different depths the color difference deltaE* was greater than 2.6 meaning that the color must be registered before and after preparation. PMID- 29260765 TI - [Somatic pathology as a negative factor of enamel resistance of the permanent teeth]. AB - According to a survey of 292 children of 7, 12 and 15 years from Lviv it was assessed the resistance of enamel of permanent teeth by various somatic diseases. Caries susceptible enamel was most frequently revealed in children with gastrointestinal diseases and allergic diseases (66.67+/-12.17 and 83.33+/ 10.76%, respectively), as well as endocrine disorders (55.00+/-7.87%). In children with musculoskeletal system diseases caries resistant and conditionally caries resistant enamel (23.08+/-8.26 and 26.92+/-8.70%) was seen two times less than caries susceptible enamel (50.00+/-9.81%, p1<0.001, p2<0,001). The findings suggest that the somatic pathology reduced structural and functional resistance of enamel, which leads to lower resistance of dental hard tissues under the influence of cariogenic factors. PMID- 29260766 TI - [Mathematical-cartographic modeling and forecasting of caries and acute apical periodontitis incidence in pediatric population]. AB - The paper presents the results of mathematical-cartographic simulation study of the incidence of caries and acute apical periodontitis in pediatric population of Belgorod region. The Borisov district was found to be the most unfavorable area of the region with the highest incidence of the diseases. The forecast indicates an increase in the incidence of caries in children by 181.1 cases and acute apical periodontitis by 15.00 cases per 1.000 children annually in the coming years. The incidence of acute apical periodontitis is influenced by the excess of maximum permissible concentration of phenol and soot in atmospheric air, forming a homogenous cluster. PMID- 29260767 TI - [Urgent cardiovascular conditions in dental practice]. AB - Cardiovascular diseases rank first in disease patterns and their prevalence increases in most countrie, including Russian Federation. The paper presents guidelines for approaches prevention of urgent cardiovascular conditions and measures to provide first medical aid which will help avoid the negative effects in the acute clinical situations. PMID- 29260768 TI - [Prevalence of DNA viruses in maxillofacial area of HIV-infected]. AB - DNA viruses have high oncogenic risk viruses; they cause emergence of Kaposi sarcoma, Lymphoma, Squamous cell carcinoma. HIV immunodeficiency promotes increase in frequency of such tumors. Etiotropic therapy of HIV patients considerably reduces prevalence of DNA viruses and a viral malignization. PMID- 29260769 TI - [Status and problems of postgraduate dental education]. PMID- 29260771 TI - [A word to the readers]. PMID- 29260772 TI - [Department of Otorhinolaryngology at the Academician E.A. Vagner Perm State Medical University]. AB - The present article was designed to describe the history of the Department of Otorhinolaryngology based at the Academician E.A. Vagner Perm State Medical University and overview its research, educational, and therapeutic activities. PMID- 29260770 TI - [The prospects of hydrogels usage as a basis for curable osteoplastic materials]. AB - The article deals with the main types of the polymers used in hydrogel preparation. Their biological, physical and chemical properties was compared. Ways of polymers hardening and prospects of medical application were considered. The prospect of use of chitosan hydrogels activated by osteoinductors as a material for bone augmentation were concluded. PMID- 29260774 TI - [The differential approach to the surgical treatment of pathologies of the frontal sinus]. AB - The surgical intervention for the management of frontal sinusitis is required in a large fraction of patients presenting with this condition. The treatment of choice for the pathology in question is endoscopic endonasal frontotomy. Whenever the endoscopic technique is impossible to employ, the surgeon has to resort to an extranasal operation on the frontal sinus. The indications for the application of such strategy include the pathological conditions complicated by the intracranial and orbital processes, the presence of large benign tumours, recurrent post surgical purulent sinusitis and traumatic frontal sinusitis. For the preservation of the functionally competent frontal sinus during extranasal frontotomy, a frontonasal fistula with all bony walls and maximally spared mucous membrane can be created. In order to remove an osteotoma from the frontal sinus, we applied the osteoplastic approach with the formation of the osteo-periosteal flap from the frontal wall of the sinus. In those cases when it was impossible to restore the frontal sinus and there was a closed bone cavity undergoing purulent inflammation we practiced obliteration of the cavity with the use of a porous carbon implant. PMID- 29260773 TI - [The clinical and microbiological characteristics of oropharyngeal candidiasis in the HIV-infected patients at the late stages of the disease]. AB - Oropharyngeal candidiasis in 512 HIV-infected patients at the late stages of the disease was studied with special reference to the clinical and microbiological characteristics of this condition. The diagnosis was established based on the results of the clinical and microbiological examination of the patients including investigation of the tissue samples taken from the oral cavity and the throat with the use of the device specially developed for this purpose. It was shown that the disease existed in various clinical forms the most common of which were monocomponent pathology represented by pseudomembranous candidiasis in 37.5+/ 2.14% of the patients, the two-component mixed form (pseudomembranous candidiasis with concomitant angular chelitis) diagnosed in 27.5+/-1.97% cases, and the ternary form (the combination of pseudomembranous candidiasis, acute atrophic process, and angular chelitis) documented in 11.9+/-1.43% patients. The main clinical features of the disease included the combination of its various forms, multiple localization of the pathological process, and its polymorphous manifestations. Changes in the clinical course of oropharyngeal candidiasis associated with the progression of HIV from the 4A to the 4B stage were detected for the first time. They were shown to be accompanied by variations in the species composition and concentration of fungal flora in the crypts of the palatine tonsils and its sensitivity to fluconazole therapy. PMID- 29260775 TI - [The state of the serotonin system in the patients presenting with chronic polypous rhinosinusitis]. AB - This article presents the results of the study designed to determine the concentration of the neuromediator serotonin in the blood serum and tissue homogenates prepared from the polypous tissue harvested in the patients presenting with chronic polypous rhinosinusitis (CPR). The study included 51 patients with this pathology while 11 patients with chronic maxillary rhinosinusitis (CMR) and deflection of the nasal septum (DNS) made up the group of comparison. The serum serotonin levels were measured and compared in the patients of the main and both control groups. The results obtained give evidence of the significant inverse correlation between serotonin levels in the sera and tissue homogenates on the one hand and the history of allergic diseases in individual patients on the other hand. PMID- 29260776 TI - [The possibilities for the restoration of the laryngeal function: the current state-of-the-art]. AB - The restoration of the functional competence of the larynx following bilateral laryngeal nerve damage and vocal fold paralysis is a serious challenge for the surgeon that has thus far no satisfactory solution. Physiological re-innervation that occurs naturally with time is non-selective and, in the majority of the cases, leads to synkinesis. Laryngeal pacing achieved with the application of the implantable microchips appears to be a promising approach. The animal experiments have demonstrated the possibility of successful restoration of all the functions of the larynx by means of laryngeal pacing but simultaneously revealed a number of technical issues that have to be addressed if the further progress in this field is to be achieved including the choice of the proper materials for implantation, solution of problems pertaining to the neuromuscular mapping during pacer implantation, etc.). The results of the first prospective clinical trial involving the human patients gave evidence suggesting that the laryngeal electrostimulation technology is both safe and efficient. Nevertheless, further investigations and modification of the method are needed before it can be recommended for the wider application in the routine clinical practice. PMID- 29260777 TI - [Sanation of petrous bone cholesteatoma in the otosurgical practice]. AB - The present article reports the clinical cases of the surgical intervention on 20 patients presenting with petrous bone cholesteatoma. We have identified several clinical variants of petrous bone cholesteatoma based on the results of multispiral computed tomography (MSCT) of the temporal bones and categorized them into the following types in accordance with the classification proposed by Moffat Smith an M. Sanna for this pathological condition: supralabyrinthine (n=8), supralabyrinthine-apical (n=2), infralabyrinthine (n=3), infralabyrinthine-apical (n=5), massive (n=1), and massive - apical (n=1). The surgical sanation of petrous bone cholesteatoma was performed in all the 20 patients in the absence of the pronounced bone destruction in the walls of the temporal bone pyramid and of the subdural expansion of cholesteatoma. In all the cases, the trepanation cavity remained open till its complete epidermization. The follow up period was around 3 years in duration on the average. The post-surgical analysis of the clinical conditions of each of the 20 patients was performed with special reference to the surgical technique applied for the removal of petrous bone cholesteatoma and the final outcome of the radical treatment. PMID- 29260778 TI - [The application of stapedoplasty for the treatment of hearing loss in the patients suffering from obliterative otosclerosis]. AB - This article presents the results of analysis of the data obtained during the examination and the surgical treatment of the patients presenting with the obliterative form of otosclerosis and suffering from hearing impairment with special reference to the intraoperative findings, technical aspects of stapedoplasty, and its effectiveness. A total of 14 patients (17 ears) were recruited for the participation in the present study including 10 women at the mean age of 38.8+/-6.2 years and 4 men (mean age 44.8+/-3.9 years). The duration of the hearing loss in the period preceding the surgical treatment in 7 (50%) patients was more than 8 years. According to the results of tonal threshold audiometry (TTA), the mean bone conduction (BC) threshold for conductive hearing loss in the frequency range from 0.5 to 4.0 kHz was 24.9+/-8.1 dB with the mean bone air gap (BAG) equaling 38+/-5.1 dB. Computed tomography (CT) of the temporal bones revealed grade 1 obliterative otosclerosis in 4 patients, grade II of the same condition in 6 patients, and grade III in 7 ones. These findings were confirmed intraoperatively. In 15 cases, stapedostomy was carried out with the use of the non-contact CO2 laser-based system, in the remaining cases a microdrill was employed. Five patients underwent laser-assisted piston stapedoplasty while in 11 others the stapes prosthesis was placed on the autovein. One patient was treated by the same method with the use of the autocartilaginous prosthesis. The functionally acceptable results within 1 year after the surgical intervention were obtained in all the treated patients with the mean bone air gap equaling 13.2+/-3.4 dB. The best outcome (the reduction of the BC threshold and BAG by 7 dB and 25.9 db on the average respectively within 1 year after surgery was achieved in the patients with grade III obliterative otosclerosis. PMID- 29260779 TI - [The relationship between the parameters of evoked otoacoustical emission and tympanometry in the children born with the extremely low body weight]. AB - The objective of the present study was to elucidate correlation between the parameters of evoked otoacoustical emission at the distorsion product otoacoustic emissionen frequency (DPOAE) and the results of tympoanometry performed at the probe tone frequencies of 226 Hz and 1 kHz in the children born with the extremely low body weight. The results of the study give evidence of the moderate correlation dependence between the strength of the cochlear acoustic response at DPOAE and the cohlear response amplitude at the frequencies of 2 kHz and 6 kHz from TTP (r=0.3; p=0.000) obtained at the tympanometry probe tone frequency of 1 kHz. The correlation between the magnitude of the acoustic response of the cochlea, the amplitude of this response at the frequencies of 2 kHz and 6 kHz, the width of the tympanograms, and their static compliance obtained in the studies at the tympanometry probe tone frequency of 1,000 Hz (r=0.3-0.5; p=0.001) was documented in the infants at the age of 6 months and 1 year. PMID- 29260780 TI - [The results of bilateral cochlear implantation in the children who survived meningitis]. AB - The objective of the present study was the prospective analysis of the results of bilateral cochlear implantation (CI) in the children presenting with bilateral ossification of the cochlea after they had survived meningitis. A total of 15 patients underwent the surgical intervention. In those exhibiting bilateral ossification of the basal cochlear helix over the 5 mm segment (up to first bend of the cochlear turn) and partial ossification of the second helix (in 6 children), the affected portions were removed with the placement of two choleostomies, the lower one (from the ossified membrane of the cochlear window) and the upper one (toward the second helix). Activation of the speech processors of the CI systems was carried out within 4-6 weeks after surgery. The hearing abilities of the children were evaluated in accordance with the 'Estimation of the auditory perception categories', 'Estimation of the child's apprehension capacity', and 'Analysis of speech intelligibility rating' guidelines. In all the children with ossification over less than 5 mm of the basal cochlear helix, it proved possible to introduce the whole intracochlear electrode grid whereas only half of the electrode array was implanted in the cases of overall ossification of the basal helix. The first results obtained by telemetry and surdopedagogical testing gave evidence of the possibility of identifying various sources of non verbal and speech stimuli in all the treated children at a small (up to 3 meters) distance. PMID- 29260781 TI - [The substantiation for simultaneous rhinoplasty and correction of the intranasal structures in the patients presenting with the combination of pathology of the nasal cavity and disfigurement of the shape of the nose]. AB - The objective of the present work was to evaluate the effectiveness of rhinoplasty performed in the combination with the correction of the intranasal structures. The study included the comparison of intra- and post-operative characteristics of rhinoplasty carried out with and without correction of the intranasal structures in 374 patients presenting with the combination of pathology of the nasal cavity and disfigurement of the shape of the nose. It was shown that the simultaneous surgical interventions are not accompanied by a significant increase in the frequency of intra- and post-operative complications in comparison with rhinoplastic surgery alone; nor do they require additional time expenditures. At the same time, the absence or the inadequate performance of septoplasty and/or the correction of the inferior turbinated bone during rhinoplasty in the patients presenting with the combination of pathology of the nasal cavity and disfigurement of the shape of the nose is fraught with the poor aesthetic outcome of the treatment and persistent disturbances of the respiratory function. PMID- 29260782 TI - [The prevalence and risk factors of allergic rhinitis among the children of the preschool age]. AB - The objective of the present work was to estimate the prevalence and risk factors of the development of allergic rhinitis among the children at the age from 3 to 6 years. The cross-sectional study was carried out in five cities of the Altai region during the period from 2015 to 2016. The prevalence of allergic rhinitis was evaluated with the use of the Russian language version of the ISAAC questionnaire filled up by the parents of the children. A child whose parents answered in the affirmative to the question 'Did your child have the runny nose, nasal congestion, and/or sneezing in the absence of cold symptoms and acute viral infection during the last 12 months?' were considered to be suffering from active allergic rhinitis (AAR). The risk factors for the development of this condition were identified with the use of an additional questionnaire. A total of 3205 filled questionnaires were available for the analysis. Based on the data obtained, the prevalence of active allergic rhinitis among the study population was estimated at 18.0% (n=577). 243 (42.1%) of these children presented with the symptoms of conjunctivitis. Therefore, the prevalence of active allergic rhinoconjunctivitis (ARC appears to be 7.5% (n=243). In fact, the medically verified diagnosis of allergic rhinitis was established only in 6.4% (n=204) children of the 577 ones having AAR. The family history of allergic rhinitis was shown to increase the risk of development of AAR by 2.6 times (OR=2.63 , 95%; CI=2.16-3.19; p<0.01) and that of ARC by 2.8 times (OR=2.85, 95%; CI=2.16-3.75; p<0.01). Masculine gender was found to increase the risk of development of both AAR an ARC by 1.3 times (OR=1.35, 95%; CI=1.01-1.37; p<0.05) and (OR=1.35, 95%; CI=1.03-1.76; p<0.05) respectively. The actual prevalence of active allergic rhinitis was significantly higher than the frequency of the medically verified diagnoses of this condition. It is concluded that the family history of allergic diseases and the masculine gender considerably increase the risk of development of both AAR and AFC. PMID- 29260783 TI - [Possibilities of azelastine in the treatment of chronic rhinitis]. AB - There is considered modern classification of rhinitis and the accents in diagnostic and therapeutic approaches to patients with this disease are indicated, as well as the possibilities of using topical intranasal antihistamines in the treatment of allergic, vasomotor and medicamentous rhinitis. PMID- 29260784 TI - [The role of local immunotherapy in the treatment of the patients presenting with virus-associated allergic rhinitis]. AB - The objective of the present study was to evaluate the clinical effectiveness of intranasal immunotherapy with the use of sycloferon in the patients presenting with seasonal virus-associated allergic rhinitis during the period of pollination. The results of the treatment of 50 patients with virus-associated allergic rhinitis (i.e. those allergic to the sagebrush pollen) were analyzed. The patients were divided into two groups depending on the therapeutic modality being used. Those comprising the main group (21 patients) received immunotherapy with sycloferon in addition to allergen-specific immunotherapy (by sublingual administration). A cycloferon solution in the physiological saline (2:1) at a concentration of 125 mg/ml was applied to the intranasal mucous membrane with the use of a nebulizer. The inhalation was performed every other day as a course of 10 procedures at a total cycloferon dose of 1250 mg. The control group was composed of 29 patients given sublingual allergen-specific immunotherapy alone. The study included the evaluation of the patients' quality of life in accordance with the adapted and modified RQLQ questionnaire. In addition, the demand for other relevant medications following the course of intranasal immunotherapy was determined by analyzing the data extracted from the self-monitoring diaries and questionnaires. The study has shown that the inclusion of sycloferon therapy in the scheme for the management of the patients presenting with virus-associated allergic rhinitis during the period of pollination enhanced the effectiveness of the treatment as assessed from the improvement of the patients' quality of life that correlated with the reduction in the severity of rhino-conjunctival manifestations of the disease (r= -0.4, p<0.05). It is concluded that the intranasal administration of the immunomodulator sycloferon has resulted in a significant decrease of requirements for chromones (p<0.001) and antihistamines (p<0.05) among the patients suffering from allergic rhinitis. PMID- 29260785 TI - [Allergic rhinitis among the children of the Republic of Sakha (Yakutiya)]. AB - The objective of the present study was to elucidate dynamics of primary allergic rhinitis (AR) morbidity in the children population of the Republic of Sakha (Yakutiya) from the statistical materials of the Yakutian Republican Information and Analytical Centre available for the period from 2008 to 2014 in the combination with the results of allergological testing based at the National Centre of Medicine, Yakutsk, that involved 100 schoolchildren presenting with allergic rhinitis who resided in the northern regions of the Republic. The results of the study give evidence of the increasing primary allergic rhinitis morbidity rate among the population of the children and adolescents during the recent years. It is concluded that the regional programs for the prevention and early diagnostics of primary allergic rhinitis need to be elaborated and introduced in the practical work of healthcare facilities over the territory of the Republic. PMID- 29260786 TI - [The use of fenspiride for the combined treatment of exacerbation of chronic laryngitis]. AB - The present study was carried out based at the Department of Otorhinolaryngology of I.P. Pavlov First State Medical University of Saint-Petersburg. The objective of this work was to elucidate the efficacy and safety of fenspiride therapy for the treatment of exacerbation of chronic laryngitis associated with an acute respiratory infection. The patients comprising the main group received fenspiride (Eurespal, 'Servier', France) at the standard dose in addition to the conventional therapy with the use of antibiotics, inhalation, and voice rest. The patients in the group of comparison were treated following the conventional protocol without fenspiride. The clinical symptoms evaluated based on the scoring system, the results of videolaryngoscopy, and computer-assisted analysis of the voice were compared before and after treatment in the patients of both groups. The results of the study have confirmed the high effectiveness and safety of fenspiride therapy of exacerbation of chronic laryngitis. PMID- 29260787 TI - [The observation, diagnostics, and treatment of a patient presenting with a vascular branched tumour of the external ear]. AB - This article describes the observation of a clinical case of a vascular branched tumour (hemangioma) of the external ear with special reference to the clinical features and diagnostics of this condition and the methods for its surgical treatment. PMID- 29260788 TI - [Septic thrombus of the cavernous sinus]. AB - The present review was designed to represent modern views of the problem of etiopathogenesis, clinical features, diagnostics, and treatment of septic thrombus of the cavernous sinus with special reference to the currently available methods for the detection and management of this condition. PMID- 29260789 TI - [The modern view of the radiodiagnostic methods applied for determining the position of the electrode array in cochlear implantation surgery]. AB - The objective of the present work was to overview the currently available literature publications dealing with the radiodiagnostic techniques applied to evaluate the position of the electrode array used for the purpose of cochlear implantation surgery including both the conventional methods and the recently proposed approaches. It is shown that the intraoperative control guarantees the timely identification of the possible complications and should meet both the safety criteria and the requirements for obtaining high-quality images and intraoperative usability of the surgical instruments being employed. Moreover, the intraoperative monitoring can be exercised under control of fluoroscopy as well as with the use of the portable computed radiography scanners and navigation systems. The postoperative monitoring is carried out with the use of transorbital X ray visualization, multi-slice computed tomography, cone beam computed tomography, and digital tomosynthesis. Each of the listed methods has specific advantages and disadvantages, but there is yet neither a universally recognized systematic approach to the assessment of their effectiveness nor the generally acceptable criteria for the evaluation of the image quality. PMID- 29260790 TI - [The peculiar features and significance of the psycho-emotional status of the patient in the context of functional and aesthetic rhinosurgery]. AB - The objective of the present study was to summarize the literature data concerning the peculiar features of the psycho-emotional status of the patients presenting with nasal deformities and the importance of its evaluation for the preparation for the surgical rhinoplastic intervention. We present the results of analysis of the materials pertinent to the history and the current state of the psychological aspects of rhinoplasty, the importance of the development and application of the diagnostic tools for the evaluation of the psycho-emotional status of the patients presenting with deformations of the external nose. It is concluded that the disregard of the psycho-emotional status of the patients by a thonosurgeon and the resulting mistakes in determining indications for the surgical intervention can be the causes accounting for the patient's dissatisfaction with the outcome of even an ideally performed operation. PMID- 29260791 TI - [The clinical classification of acute otitis media with special reference to tympanometry]. AB - We have developed a new clinical classification of acute otitis media (AOM) based on the previously proposed classifications of V.T. Palchun with co-workers (1997) and J. Jeger (1970) in which the letter near the stage of the pathological process roughly corresponds to the type of the tympanogram as follows: stage I (acute tubootitis): A, B, C; stage II (acute catarrhal otitis media): A, B, C; stage III (acute purulent otitis media, perforation stage); stage IV (acute purulent otitis media, post-perforation stage); stage V (resolution of otitis media): A - convalescence or recovery, B1 - exudate present in the tympanic cavity; B2 - persisting perforation; C - block of the auditory tube, O - the development of complications. This classification implies the necessity of tympanometry at the stage of diagnostics of AOM although it is not mandatory because the detection of exudate as a result of paracentesis at any of the stages of otitis media will allow to designate the stage of otitis either by letter A, B or C. The application of the new classification described in this article permits to more accurately than before determine the character of the pathological process in the middle ear during the course of acute otitis media which is of special importance in the clinical pediatric practice for the timely and adequate treatment of the children. PMID- 29260793 TI - Corrigendum: Structures and biological activities of novel 4'-acetylated analogs of chrysomycins A and B. AB - This corrects the article DOI: 10.1038/ja.2017.99. PMID- 29260792 TI - A Novel Role for Oligodendrocyte Precursor Cells (OPCs) and Sox10 in Mediating Cellular and Behavioral Responses to Heroin. AB - Opiate abuse and addiction have become a worldwide epidemic with great societal and financial burdens, highlighting a critical need to understand the neurobiology of opiate addiction. Although several studies have focused on drug dependent changes in neurons, the role of glia in opiate addiction remains largely unstudied. RNA sequencing pathway analysis from the prefrontal cortex (PFC) of male rats revealed changes in several genes associated with oligodendrocyte differentiation and maturation following heroin self administration. Among these genes changed was Sox10, which is regulated, in part, by the chromatin remodeler BRG1/SMARCA4. To directly test the functional role of Sox10 in mediating heroin-induced behavioral plasticity, we selectively overexpressed Sox10 and BRG1 in the PFC. Overexpression of either Sox10 or BRG1 decreased the motivation to obtain heroin infusions in a progressive ratio test without altering the acquisition or maintenance of heroin self-administration. These data demonstrate a critical, and perhaps compensatory, role of Sox10 and BRG1 in oligodendrocytes in regulating the motivation for heroin. PMID- 29260794 TI - Winners of the 2016 JA Medals for excellence. PMID- 29260796 TI - 3.7 billion year old biogenic remains. AB - 3.7 Billion year old inclusions inside garnet crystals contain 13C depleted carbonaceous material consistent with biogenic origin. Additional evidence in the form of the other elements of life mainly O, N and P were found to be structural bound to this material by using a new technique, AFM-IR. Here we show additional evidence that support our claim. By overlaying maps generated by the AFM-IR we show how the location of 100's of nm sized contiguous domains of nitrile and possibly phosphonate overlap inside the inclusion. This shows that O, N and P are not only co-localized to the same inclusion but they are co-localized to the same patch of carbonaceous material inside the inclusion. They therefore provide spatial characterization for potentially the oldest biogenic remains in Earth's geological record and corroborates earlier claims2 for the biogenic origins of carbon in Isua metasediments. PMID- 29260797 TI - Entrained delta oscillations reflect the subjective tracking of time. AB - The ability to precisely anticipate the timing of upcoming events at the time scale of seconds is essential to predict objects' trajectories or to select relevant sensory information. What neurophysiological mechanism underlies the temporal precision in anticipating the occurrence of events? In a recent article,1 we demonstrated that the sensori-motor system predictively controls neural oscillations in time to optimize sensory selection. However, whether and how the same oscillatory processes can be used to keep track of elapsing time and evaluate short durations remains unclear. Here, we aim at testing the hypothesis that the brain tracks durations by converting (external, objective) elapsing time into an (internal, subjective) oscillatory phase-angle. To test this, we measured magnetoencephalographic oscillatory activity while participants performed a delayed-target detection task. In the delayed condition, we observe that trials that are perceived as longer are associated with faster delta-band oscillations. This suggests that the subjective indexing of time is reflected in the range of phase-angles covered by delta oscillations during the pre-stimulus period. This result provides new insights into how we predict and evaluate temporal structure and support models in which the active entrainment of sensori-motor oscillatory dynamics is exploited to track elapsing time. PMID- 29260798 TI - Potential for intermittent stimulation of nucleus basalis of Meynert to impact treatment of alzheimer's disease. AB - The brain's cholinergic arousal pathways decline in parallel with the brain's executive functions in aging and Alzheimer's Disease. The frontline and currently most effective approach to treating Alzheimer's disease is the administration of cholinesterase inhibitors, which, in a dose dependent manner, improve the symptoms of cognitive decline over the first months of treatment before further decline occurs. We recently showed that intermittent deep brain stimulation of the nucleus basalis of Meynert improves working memory function in young adult monkeys, and that this improvement depended on cholinergic function. Within minutes, the monkeys' ability to remember stimuli over a delay period improved. Over months, the monkeys performed the working memory task better even in the absence of stimulation. Here, we show historical data from our monkey colony in which more than two dozen animals have performed the same behavioral task to asymptotic performance levels. Using a distribution based on our historical data, we estimate that the monkeys receiving intermittent stimulation leapt over the performance level of 32-44 percent of peer animals in the first several months after stimulation was initiated. Implications for a parallel increase in cognitive function for early Alzheimer's patients are discussed. PMID- 29260799 TI - Novel directions in molecular systems design: The case of light-transducing synthetic cells. AB - Important progresses have been achieved in the past years in the field of bottom up synthetic biology, especially aiming at constructing cell-like systems based on lipid vesicles (liposomes) entrapping both biomolecules or synthetic compounds. These "synthetic cells" mimic the behaviour of biological cells but are constituted by a minimal number of components. One key aspect related to this research is the energetic needs of synthetic cells. Up to now, high-energy compounds have been given in order to drive biochemical reactions inside the vesicle lumen. In order to be autonomous, synthetic cells must produce their own biochemical energy from available energy sources. At this aim we started a long term research program focused on the construction of photoautotrophic synthetic cells, starting with the reconstitution, in active and highly oriented form, of the photosynthetic reaction centre in giant lipid vesicles (Altamura et al., PNAS 2017, 114, 3837-3842). Here we comment this first milestone by showing the synthetic biology context wherein it is developed, the future steps, and the experimental approach that might allow such an achievement. PMID- 29260800 TI - Saving the injured: Evolution and mechanisms. AB - Rescue behavior focused on injured individuals has rarely been observed in animals. These observations though are from very different taxa's: birds, mammals and social insects. Here we discuss likely antecedents to rescue behaviors in ants, like social carrying and alarm pheromones. We then compare similarities and preconditions necessary for rescue behavior focused on injured individuals to evolve across taxa's: a high value of individuals, a high injury risk and social interaction. Ultimately we argue that a similar problem, how to rescue injured group members, has led to different mechanisms to save injured individuals across different taxa. PMID- 29260801 TI - Light-dark decision making in snails: Do preceding light conditions matter? AB - We have recently demonstrated that preceding motor activity can facilitate decision-making not only in humans and mammals but also in molluscs.5 In the behavioral paradigm used, snails Lymnaea stagnalis were removed from their natural environment (water) and placed in a dry, asymmetrically lit arena from which they had to decide which way to go in order to reach an aquatic environment. One possible explanation of the observed effects of preceding motor activity was that it could affect the snail's memory of light conditions that corresponded to its previous aquatic habitat. Here we report experimental results discarding this hypothesis. We suggest that preceding intense locomotion is likely to facilitate decision-making by increasing the level of confidence. PMID- 29260802 TI - First, do no harm. AB - Conservation agencies charged with care of threatened plant species should be governed by the concepts that conservation actions should do no harm. Adaptive management research progresses in imperfect situations due to incomplete knowledge. Interpreting new experimental or observational evidence for inclusion in conservation plans should first consider the big picture by identifying collateral quandaries before scaling up the approach to large-scale implementation. We discuss a case study of Cycas micronesica conservation activities on the island of Guam. The use of large stem cuttings has been shown to be a viable approach for rescuing trees from planned construction sites. However, this artificial means of producing transplants exhibits shortcomings, some of which may add new threats to the existing plant population. Moreover, devoting funds for use of the new technique in tree rescue projects does not address the primary threats that have led to listing under the United States Endangered Species Act (ESA). Transplanted trees will likely succumb to those ubiquitous threats shortly after the completion of a successful rescue project. Alternatively, investing conservation funds into mitigation of the primary threats could lead to removal of the species from the ESA. PMID- 29260803 TI - Caries Excavation - How do you do it? PMID- 29260804 TI - Surface Characterization of a Glass Fiber Post after Nonthermal Plasma Treatment with Hexamethyldisiloxane. AB - PURPOSE: To characterize the surface of glass fiber posts (GFP) after different surface treatments and evaluate which method incorporates higher amounts of silicon (Si) particles, as well as to evaluate the bond strength at the post/ composite-cement interface with four different surface treatments of glass fiber posts luted with composite cement. MATERIALS AND METHODS: Twelve glass fiber posts were obtained from the manufacturer. The posts were randomly distributed into four groups (n = 3): Co (control), no surface treatment; S, 70% alcohol and silane (60 s); HF + S, 10% hydrofluoric acid gel (60 s) and silane (60 s); NTP, nonthermal plasma of hexamethyldisiloxane (HMDSO) associated with argon (30 min). The surface of each GFP was characterized through scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). Forty GFPs were randomly divided into 4 groups according the surface treatments (n = 10) and cemented with one composite cement (Rely X U200) into artificial canine teeth. The specimens were placed in a universal testing machine and subjected to tensile testing until failure occurred. Statistical analysis of the atomic percentage and bond strength was performed using ANOVA, followed by the post-hoc Tukey test (p = 0.05). RESULTS: EDS graphics showed that the NTP group had a higher Si atomic percentage (at%) than the other groups (p < 0.001). The HF + S group had a higher Si at% than did the Co and S groups. SEM images illustrated that the surfaces of the GFPs were variously modified after different treatments. The NTP group incorporated higher Si levels on the GFP surface and yielded the highest bond strengths (p < 0.005) compared to the other tested groups. CONCLUSION: Treatment with HMDSO + Ar plasma (NTP) incorporated higher Si levels on the surface of the GFPs without inducing critical defects. NTP treatment promoted better bond strength results when compared to the other tested group when GFPs were cemented with composite cement. PMID- 29260805 TI - Charge distribution and conformational stability effects of organic structure directing agents on zeolite synthesis. AB - While the use of the so-called organic structure-directing agents (OSDAs) is no stranger to zeolite synthesis at all, the effects of their charge distribution and conformational stability on the phase selectivity of the crystallization remain elusive. To systematically investigate these effects, we have prepared a series of imidazolium and pyrazolium derivatives with the same geometric shape but different positions of nitrogen atoms in the five-membered heterocyclic aromatic ring and used them as OSDAs for the synthesis of zeolites with pure silica composition. Meaningful differences in the zeolite product were observed. PMID- 29260806 TI - Approaching monocoordination at a silver(i) cation. AB - The recently reported bulky N-heterocyclic carbene ITr (ITr = [(HCNCPh3)2C:]) was found to stabilize low-coordinate Ag(i) environments. These electrophilic species were crystallographically identified as the weak solvates [(ITr)Ag(sol)]+ (sol = PhF, MesH or CH2Cl2) and as a solvent-free dimer [(ITr)Ag]22+. The highly electrophilic nature of the [(ITr)Ag]+ cation was further demonstrated by the calculation of a very high methyl ion affinity (MIA) and the synthesis of [(ITr)Ag(PCO)] which features substantial side-on electron donation from a P-C pi bond to Ag. PMID- 29260807 TI - Gold nanoparticle core-europium(iii) chelate fluorophore-doped silica shell hybrid nanocomposites for the lateral flow immunoassay of human thyroid stimulating hormone with a dual signal readout. AB - Hybrid nanocomposite particles composed of a gold core coated with a europium(iii)-chelate fluorophore-doped silica shell (AuNPs@SiO2-Eu3+) have been synthesized and applied as antibody labels in lateral flow immunoassay (LFIA) devices for the determination of human thyroid stimulating hormone (hTSH). Labeling of monoclonal anti-hTSH antibodies with AuNPs@SiO2-Eu3+ nanocomposites allows for both colorimetric and fluorometric observation of assay results on LFIA devices, relying on visible light absorption due to the localized surface plasmon resonance of the Au-core and the fluorescence emission of the Eu(iii) chelate-modified shell under UV hand lamp irradiation (365 nm), respectively. The possibility for a dual signal readout provides an attractive alternative for LFIAs: instantaneous naked eye observation of the AuNP colorimetric signal as in conventional LFIAs for hypothyroidism detection, and more sensitive fluorescence detection to assess hyperthyroidism. The limits of detection (LOD) for naked eye observation of LFIA devices are 5 MUIU mL-1 and 0.1 MUIU mL-1 for the colorimetric and fluorimetric detection, respectively. Using the fluorescence detection scheme in combination with a smartphone and digital color analysis, a quantitative linear relationship between the red intensity and the logarithmic concentration of hTSH was observed (R2 = 0.988) with an LOD of 0.02 MUIU mL-1. Finally, LFIA devices were effectively applied for detecting hTSH in spiked diluted human serum with recovery values between 100-116%. PMID- 29260808 TI - Bioinspired design of a hybrid bifunctional enzymatic/organic electrocatalyst for site selective alcohol oxidation. AB - This work combines the thermostable alcohol dehydrogenase D (AdhD) from Pyrococcus furiosus and the organic electrocatalyst TEMPO to create a bifunctional catalyst that selectively oxidizes primary and secondary alcohols. The active sites function independently, can be switched on by changing reaction conditions, and can selectively oxidize a mixture of 1- and 2-butanol. The NAD+ dependent enzyme catalyses the secondary alcohol oxidation at a rate 3-fold faster than the primary alcohol, while the covalently attached 4-glycidyl-TEMPO oxidizes 1-butanol and has negligible activity toward 2-butanol. This hybrid catalytic approach has potential value for selective alcohol oxidations as well as other electrochemical and enzymatic multistep processes in energy conversion and chemical synthesis. PMID- 29260809 TI - Thiomolybdate [Mo3S13]2- nanocluster: a molecular mimic of MoS2 active sites for highly efficient photocatalytic hydrogen evolution. AB - Thiomolybdate [Mo3S13]2- nanoclusters, as a molecular mimic of MoS2 edge sites, showed high efficiency in catalyzing photochemical H2 evolution from a molecular system of Ru(bpy)3Cl2-ascorbic acid (H2A) under visible light irradiation (>=420 nm), providing a turnover number of 1570 and an initial turnover frequency of 335 h-1 for H2 evolution based on the [Mo3S13]2- catalyst. PMID- 29260810 TI - Tertiary dynamics of human adult hemoglobin fixed in R and T quaternary structures. AB - Protein dynamics of human adult hemoglobin and its mutants restricted in R and T quaternary states following ligand photolysis were studied by time-resolved resonance Raman spectroscopy. In the time-resolved spectra, we observed spectral changes of in-plane stretching modes of heme and the iron-histidine stretching mode of the Fe-His bond for all the hemoglobin samples. The betaD99N mutant, which adopts the R state in both the ligand-bound and the deoxy forms, showed similar temporal behaviors in time-resolved resonance Raman spectra as wild-type recombinant hemoglobin until 10 MUs, consistent with the fact that the mutant undergoes only the tertiary structural changes in the R state. The betaN102T mutant, which adopts the T state in both the ligand-bound and the deoxy forms, showed much slower tertiary structural changes, suggesting that the EF helical motion is decelerated by the change of the intersubunit interactions. The present data indicate that the allosteric kinetic response between the interhelical hydrogen bonds of the EF helices and the intersubunit hydrogen bonds is bidirectional. The implications of these results for understanding the allosteric pathway of Hb are discussed in detail. PMID- 29260811 TI - The aggregation of an alkyl-C60 derivative as a function of concentration, temperature and solvent type. AB - Contrast-variation small-angle neutron scattering (CV-SANS), small-angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR) measurements of diffusion and isothermal titration calorimetry (ITC) are used to gain insight into the aggregation of an alkyl-C60 derivative, molecule 1, in n-hexane, n-decane and toluene as a function of concentration and temperature. Results point to an associative mechanism of aggregation similar to other commonly associating molecules, including non-ionic surfactants or asphaltenes in non-aqueous solvents. Little aggregation is detected in toluene, but small micelle-like structures form in n-alkane solvents, which have a C60-rich core and alkyl-rich shell. The greatest aggregation extent is found in n-hexane, and at 0.1 M the micelles of 1 comprise around 6 molecules at 25 degrees C. These micelles become smaller when the concentration is lowered, or if the solvent is changed to n decane. The solution structure is also affected by temperature, with a slightly larger aggregation extent at 10 degrees C than at 25 degrees C. At higher concentrations, for example in solutions of 1 above 0.3 M in n-decane, a bicontinuous network becomes apparent. Overall, these findings aid our understanding of the factors driving the assembly of alkyl-pi-conjugated hydrophobic amphiphiles such as 1 in solution and thereby represent a step towards the ultimate goal of exploiting this phenomenon to form materials with well-defined order. PMID- 29260812 TI - The hydrolysis of epoxides catalyzed by inorganic ammonium salts in water: kinetic evidence for hydrogen bond catalysis. AB - Naturally-occurring inorganic ammonium ions have been recently reported as efficient catalysts for some organic reactions in water, which contributes to the understanding of the chemistry in some natural environments (soils, seawater, atmospheric aerosols, ...) and biological systems, and is also potentially interesting for green chemistry as many of their salts are cheap and non-toxic. In this work, the effect of NH4+ ions on the hydrolysis of small epoxides in water was studied kinetically. The presence of NH4+ increased the hydrolysis rate by a factor of 6 to 25 compared to pure water and these catalytic effects were shown not to result from other ions, counter-ions or from acid or base catalysis, general or specific. The small amounts of amino alcohols produced in the reactions were identified as the actual catalysts by obtaining a strong acceleration of the reactions when adding these compounds directly to the epoxides in water. Replacing the amino alcohols by other strong hydrogen-bond donors, such as trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) gave the same results, demonstrating that the kinetics of these reactions was driven by hydrogen-bond catalysis. Because of the presence of many hydrogen-bond donors in natural environments (for instance amines and hydroxy-containing compounds), hydrogen-bond catalysis is likely to contribute to many reaction rates in these environments. PMID- 29260813 TI - Constructing a novel strategy for controllable synthesis of corrosion resistant Ti3+ self-doped titanium-silicon materials with efficient hydrogen evolution activity from simulated seawater. AB - Exploiting solar power for hydrogen production from seawater is a great challenge owing to the corrosive properties of seawater and inadequate visible-light conversion capabilities. Here we report an uncomplicated post-processing method to construct Ti3+ self-doped titanium-silicon material with corrosion resistance. This is a new experimental method to regulate the electrical, optical, and photocatalytic performances of titanium-containing photocatalysts in a controlled way. Moreover, we demonstrate that Ti-O-Si materials with different calcination temperatures can serve as a highly efficient and convenient catalyst for photogeneration of hydrogen from water and simulated seawater. Consequently, the optimized Ti-O-Si (400) sample exhibits impressive enhancement in the photocatalytic hydrogen evolution performance, by nearly 10.0 and 43.1 times compared with TiO2 nanoparticles in water and simulated seawater. The Ti-O-Si (400) with substantial Ti3+ and oxygen vacancies exhibits an excellent photocatalytic H2 production performance due to the improved separation and transmission of the photogenerated electron-hole, the extended visible light response, and corrosion resistance. Our work opens a new door to engineering the intrinsic properties of the titanium-containing materials. PMID- 29260814 TI - TiS3 sheet based van der Waals heterostructures with a tunable Schottky barrier. AB - Monolayer titanium trisulfide (TiS3), synthesized recently through exfoliation [Adv. Mater., 2015, 27, 2595], has emerged as a new 2D material with outstanding electronic and optical properties. Here, using first-principles calculations we show for the first time the great potential of the TiS3 monolayer as a channel material when in contact with graphene and other 2D metallic materials to form van der Waals (vdW) heterostructures, where the intrinsic properties of both the TiS3 monolayer and the 2D materials are preserved, different from the conventional 3D metal/TiS3 semiconductor heterojunction [Nanoscale, 2017, 9, 2068]. Moreover, the TiS3 monolayer forms an n-type Schottky barrier (Phie) when in contact with graphene, exhibiting a tunneling barrier and a negative band bending at the lateral interface; the Schottky barrier character can also be changed from n-type to p-type by doping graphene with boron atoms or replacing graphene with other high-work-function 2D metals, while a Schottky-barrier-free contact can be realized by doping graphene with nitrogen atoms, thus providing a solution to the contact-resistance problem in 2D electronics. PMID- 29260815 TI - The important role of salivary alpha-amylase in the gastric digestion of wheat bread starch. AB - The role of salivary alpha-amylase (HSA) in starch digestion is often overlooked in favour of that of pancreatic alpha-amylase due to the short duration of the oral phase. Although it is generally accepted that the amylase of salivary origin can continue to be active in the stomach, studies ascertaining its contribution are lacking. This study aimed to address this issue by coupling in vitro oral processing with an in vitro dynamic system that mimicked different postprandial gastric pH reduction kinetics observed in vivo following a snack- or lunch-type meal. The digestion of both starch and protein from wheat bread as well as the interplay between the two processes were studied. We have observed that the amylolytic activity of saliva plays a preponderant role hydrolysing up to 80% of bread starch in the first 30 min of gastric digestion. Amylolysis evolved exponentially and nearly superimposing curves were obtained regardless of the acidification profiles, revealing its high efficiency. PMID- 29260816 TI - The mechanism of electrochemical reduction of hydrogen peroxide on silver nanoparticles. AB - The reduction of hydrogen peroxide on a silver nanoparticle modified boron doped diamond electrode in a neutral solution is shown to proceed through a CE mechanism. Hydrogen peroxide undergoes a disproportionation reaction to form oxygen (and water) on the silver surface, creating a diffusion layer of oxygen, which, at a sufficiently biased electrode, is then reduced to hydrogen peroxide. Voltammetry and a full mechanistic simulation are undertaken to confirm the mechanism, showing at short times a dependence of the reductive signal on waiting time prior to voltammetric analysis reflecting the extent of the disproportionation step which occurs prior to voltammetric analysis. PMID- 29260817 TI - Novel highly efficient single-component multi-peak emitting aluminosilicate phosphors co-activated with Ce3+, Tb3+ and Eu2+: luminescence properties, tunable color, and thermal properties. AB - A series of emission-tunable Ce3+/Tb3+/Eu2+ doped Ca2(Mg0.75Al0.25)(Si1.75Al0.25)O7 (denoted as CMAS) phosphors have been synthesized via a high temperature solid-state reaction method. The luminescence properties, color tuning, quantum yields (QYs), energy transfer of Ce3+ to Tb3+/Eu2+, thermal stability, performance of LED devices and ratiometric temperature sensing application have been systematically investigated, respectively. Importantly, through the study of thermal stability, we found that Ce3+ and Tb3+ co-doped samples were suitable for WLED applications, while Ce3+ and Eu2+ co-doped samples were suitable for temperature sensing applications. Due to the energy transfer, Ce3+/Tb3+ co-doped samples had high luminous efficiency and the quantum efficiency of more than 80% could be achieved. Their emission colors can modulate from blue to green. In addition, on the basis of the evaluation of the as-fabricated white LED lamps via selecting the corresponding phosphors, the CCT can reach 4275 K and the CRI can increase to 86.8, indicating that this series of phosphors can act as potential color-tunable phosphors for possible applications in ultraviolet light based white LEDs. Importantly, it is found that the fluorescence intensity ratio of CMAS : 5%Ce3+,0.5%Eu2+ displays linear correlation with temperature in a wide range of 253-373 K with a high sensitivity of 2.49% K-1, indicating that it could be a good candidate for ratiometric optical thermometry. PMID- 29260818 TI - Synthesis and structural characterization of alkali metal arsinoamides. AB - The aminoarsane Mes2AsN(H)Ph was prepared from Mes2AsCl and aniline in good yields. Deprotonation of Mes2AsN(H)Ph with suitable alkali metal bases resulted in the corresponding alkali metal derivatives. Thus, reaction of Mes2AsN(H)Ph with nBuLi, NaN(SiMe3)2, or KH gave the metal complexes [(Mes2AsNPh){Li(OEt2)2}], [(Mes2AsNPh){Na(OEt2)}]2, and [(Mes2AsNPh){K(THF)}]2. These are the first metal complexes ligated by an arsinoamide. All solid-state structures were established by single crystal X-ray diffraction. The lithium compounds form a monomer in the solid-state, whereas the sodium and the potassium derivatives are dimers. In the dimeric compounds intra- and intermolecular pi-interaction of the aromatic rings with the metal atoms is observed. PMID- 29260823 TI - Geometric frustration and compatibility conditions for two-dimensional director fields. AB - Bent core (or banana shaped) liquid-crystal-forming-molecules locally favor an ordered state of zero splay and constant bend. Such a state, however, cannot be realized in the plane and the resulting liquid-crystalline phase is frustrated and must exhibit some compromise of these two mutually contradicting local intrinsic tendencies. This constitutes one of the most well-studied examples in which the intrinsic geometry of the constituents of a material gives rise to a geometrically frustrated assembly. Such geometric frustration is not only natural and ubiquitous but also leads to a striking variety of morphologies of ground states and exotic response properties. In this work we establish the necessary and sufficient conditions for two scalar functions, s and b to describe the splay and bend of a director field in the plane. We generalize these compatibility conditions for geometries with non-vanishing constant Gaussian curvature, and provide a reconstruction formula for the director field depending only on the splay and bend fields and their derivatives. Finally, we discuss optimal compromises for simple incompatible cases where the locally preferred values of the splay and bend cannot be simultaneously achieved. PMID- 29260827 TI - Multifunctional Cu-Ag2S nanoparticles with high photothermal conversion efficiency for photoacoustic imaging-guided photothermal therapy in vivo. AB - Photothermal therapy (PTT) has attracted increasing interest and become widely used in cancer therapy owing to its noninvasiveness and low level of systemic adverse effects. However, there is an urgent need to develop biocompatible and multifunctional PTT agents with high photothermal conversion efficiency. Herein, biocompatible Cu-Ag2S/PVP nanoparticles (NPs) with strong near-infrared absorption and high photothermal conversion efficiency were successfully synthesized for high-performance photoacoustic (PA) imaging-guided PTT in vivo. The novel Cu-Ag2S/PVP NPs feature high photothermal conversion efficiency (58.2%) under 808 nm light irradiation, noticeably higher than those of most reported PTT agents. Because of their good dispersibility, Cu-Ag2S/PVP NPs passively accumulate within tumors via the enhanced permeability and retention effect, which can be confirmed by PA imaging, photothermal performance, and biodistribution in vivo. Furthermore, Cu-Ag2S/PVP NPs are thoroughly cleared through feces and urine within seven days, indicating a high level of biosafety for further potential clinical translation. PMID- 29260828 TI - Stereocontrolled glycoside synthesis by activation of glycosyl sulfone donors with scandium(iii) triflate. AB - The activation of aryl glycosyl sulfone donors has been achieved using scandium(iii) triflate and has led to the selective preparation of alpha mannosides resulting from a post-glycosylation anomerization. PMID- 29260829 TI - Capillary flow and mechanical buckling in a growing annular bacterial colony. AB - A growing bacterial colony is a dense suspension of an increasing number of cells capable of individual as well as collective motion. After inoculating Pseudomonas aeruginosa over an annular area on an agar plate, we observe the growth and spread of the bacterial population, and model the process by considering the physical effects that account for the features observed. Over a course of 10-12 hours, the majority of bacteria migrate to and accumulate at the edges. We model the capillary flow induced by imbalanced evaporation flux as the cause for the accumulation, much like the well-known coffee stain phenomenon. Simultaneously, periodic buckles or protrusions occur at the inner edge. These buckles indicate that the crowding bacteria produce a jam, transforming the densely packed population at the inner edge to a solid state. The continued bacterial growth produces buckles. Subsequently, a ring of packed bacteria behind the inner edge detach from it and break into pieces, forming bacterial droplets. These droplets slowly coalesce while they continually grow and collectively surf on the agar surface in the region where the colony had previously spread over. Our study shows a clear example of how fluid dynamics and elasto-mechanics together govern the bacterial colony pattern evolution. PMID- 29260830 TI - Synthesis of thiazolidine-thiones, imino-thiazolidines and oxazolidines via the base promoted cyclisation of epoxy-sulfonamides and heterocumulenes. AB - Epoxy-sulfonamides react with heterocumulenes (carbon disulfide/isothiocyanates/isocyanates) in the presence of a base to afford ring expansion products in good to high yields with excellent regioselectivity. N-(2 Bromoethyl)-sulfonamides can also be employed as substrates. This reaction proceeds through a 5-exo-tet pathway without forming aziridine intermediates. PMID- 29260831 TI - Comparative stability, toxicity and anti-leishmanial activity of triphenyl antimony(v) and bismuth(v) alpha-hydroxy carboxylato complexes. AB - A series of triphenyl Sb(v) and Bi(v) alpha-hydroxy carboxylato complexes of the general formula [MPh3(O2CROH)2] and [MPh3(O2CRO)] have been successfully synthesised and characterised, and subsequently assayed for their comparative activity towards Leishmania parasites and human fibroblast cells. Four complexes are novel; [SbPh3Gly], [BiPh3(GlyH)2], [SbPh3(R-ManH)2] and [SbPh3(S-ManH)2], and have been structurally characterised through X-ray diffraction. These were combined in the study with the known complexes; ([SbPh3(R-Man)], [SbPh3(S-Man)], [BiPh3(R-ManH)2], [BiPh3(R-ManH)2], [SbPh3(BenzH)2], [BiPh3(BenzH)2], for which the crystal structures of [BiPh3(S-ManH)2] and [BiPh3(R-Man)2] have now been authenticated (GlyH2 = glycolic acid, R/S-ManH2 = mandelic acid, BenzH2 = benzilic acid). The complexes adopt a typical bipyramidal 7-coordinate geometry with the phenyl rings occupying the equatorial plane, and the ligands on the axial. In contrast to previous studies the Bi(v) compounds show a relatively high degree of stability in DMEM culture media. Promastigote and human fibroblast cell assays showed the Bi(v) analogues to be non-selectively toxic with a respective IC50 range of 3.58-6.33 MUM and 5.83-7.01 MUM. In contrast, the Sb(v) analogues provided much greater selectivity (promastigotes 12.5-20.7; fibroblasts 72.8 >=100 MUM). Assessment of the Sb(v) complexes against amastigotes at 10 MUM showed them to be effective with % infection values ranging from 9.5 +/- 0.5-30 +/- 1.3. PMID- 29260832 TI - 3D interconnected porous carbon nanosheets/carbon nanotubes as a polysulfide reservoir for high performance lithium-sulfur batteries. AB - Carbon materials have attracted considerable attention as the hosts for lithium sulfur batteries, especially the 3D structural carbon matrix. Herein, novel 3D interconnected porous carbon nanosheets/carbon nanotubes (denoted as PC/CNT) as a polysulfide reservoir are synthesized by a simple one-pot pyrolysis method. In the designed hybrid carbon matrix, porous carbon nanosheets exhibit hierarchical porous structures for high sulfur loading and effectively strengthen the physical confinement to trap soluble polysulfides, while carbon nanotubes provide a highly robust conductive pathway which can facilitate electron transport and maintain structural integrity. Moreover, the 3D interconnected structure combining 1D carbon nanotubes and 2D porous carbon nanosheets is beneficial for rapid electrical/ionic transport and favorable electrolyte infiltration. As a result, the S-PC/CNT composite exhibits outstanding electrochemical performance, with a high active-sulfur utilization, high specific capacity (1485.4, 1300.3 and 1138 mA h g-1 at 0.5, 1 and 2 C, respectively), superior cycling stability (only 0.1% capacity decay per cycle over 400 cycles at 2 C) and excellent rate capability (the reversible capacity of 749 mA h g-1 even at 4 C). PMID- 29260835 TI - Contribution of DNA repair xeroderma pigmentosum group D genotypes to pancreatic cancer risk in the Chinese Han population. AB - This study aimed to determine the association between the polymorphisms and haplotypes in the xeroderma pigmentosum group D (XPD) gene and the risk of pancreatic cancer in the Chinese Han population. SNaPshot was used for genotyping six SNP sites of the XPD gene. Comparisons of the correlations between different genotypes in combination with smoking and the susceptibility to pancreatic cancer were performed. Individual pancreatic cancer risk in patients who carry mutant C alleles (AC, CC, and AC+CC) at rs13181 increased (p < 0.05). Taking non-smoking individuals who carry the AA genotype as a reference, and non-smoking individuals who carry mutant allele C (AC+CC), the risk of pancreatic cancer increased by 3.343 times in individuals who smoked >= 20 cigarettes daily, 3.309 times in individuals who smoked >= 14 packs per year, 5.011 times in individuals who smoked >= 24 packs per year, and 4.013 times in the individuals who smoked >= 37 packs per year (P < 0.05). In addition, haplotype analysis revealed that haplotype AGG, which comprised rs13181, rs3916874 and rs238415, was associated with a 1.401-fold increase in pancreatic cancer risk (p < 0.05). We conclude that the polymorphism of XPD Lys751Gln (rs13181) in combination with smoking contributes to increased risk of pancreatic cancer in the Chinese Han population. Haplotype AGG might be a susceptibility haplotype for pancreatic cancer. PMID- 29260836 TI - Responsiveness of performance-based outcome measures for mobility, balance, muscle strength and manual dexterity in adults with myotonic dystrophy type 1. AB - OBJECTIVE: To assess changes and responsiveness in outcome measures of mobility, balance, muscle strength and manual dexterity in adults with myotonic dystrophy type 1. DESIGN: A 9-year longitudinal study conducted with 113 patients. METHODS: The responsiveness of the Timed Up and Go test, Berg Balance Scale, quantitative muscle testing, grip and pinch-grip strength, and Purdue Pegboard Test was assessed using criterion and construct approaches. Patient-reported perceived changes (worse/stable) in balance, walking, lower-limb weakness, stair-climbing and hand weakness were used as criteria. Predefined hypotheses about expected area under the receiver operating characteristic curves (criterion approach) and correlations between relative changes (construct approach) were explored. RESULTS: The direction and magnitude of median changes in outcome measures corresponded with patient-reported changes. Median changes in the Timed Up and Go test, grip strength, pinch-grip strength and Purdue Pegboard Test did not, in general, exceed known measurement errors. Most criterion (72%) and construct (70%) approach hypotheses were supported. Promising responsiveness was found for outcome measures of mobility, balance and muscle strength. Grip strength and manual dexterity measures showed poorer responsiveness. CONCLUSION: The performance-based outcome measures captured changes over the 9-year period and responsiveness was promising. Knowledge of measurement errors is needed to interpret the meaning of these longitudinal changes. PMID- 29260837 TI - The challenges of describing rehabilitation services: A discussion paper. AB - To apply the Classification of Service Organization in Rehabilitation (ICSO-R) classification of services to different target groups, include the user perspective, identify missing categories, and propose standardized descriptors for the categories from a Norwegian perspective. Expert-based consensus conferences with user involvement. Health professionals, stakeholders and users. Participants were divided into 5 panels, which applied the ICSO-R to describe the habilitation and rehabilitation services provided to children with cerebral palsy and people with Huntington's disease, acquired brain injuries (traumatic brain injuries and stroke) and painful musculoskeletal conditions. Based on the Problem/Population, Intervention, Comparison, Outcome (PICO) framework, the services were described according to the ICSO-R. Missing categories were identified. The ICSO-R was found to be feasible and applicable for describing a variety of services provided to different target groups in Norway, but the user perspective was lacking, categories were missing, and a need for standardized description of the categories was identified. The present work supports the need to produce an updated version of the ICSO-R and to encourage national and international discussion of the framework. The ICSO-R has the potential to become a tool for the standardized assessment of rehabilitation services. For such purposes, more standardized descriptions of subcategories are necessary. PMID- 29260838 TI - Medical Devices; General Hospital and Personal Use Devices; Classification of the Image Processing Device for Estimation of External Blood Loss. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the image processing device for estimation of external blood loss into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the image processing device for estimation of external blood loss' classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29260839 TI - Safety and Effectiveness of Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use. Final rule. AB - The Food and Drug Administration (FDA, the Agency, or we) is issuing this final rule establishing that certain active ingredients used in nonprescription (also known as over-the-counter or OTC) antiseptic products intended for use by health care professionals in a hospital setting or other health care situations outside the hospital are not generally recognized as safe and effective (GRAS/GRAE). FDA is issuing this final rule after considering the recommendations of the Nonprescription Drugs Advisory Committee (NDAC); public comments on the Agency's notices of proposed rulemaking; and all data and information on OTC health care antiseptic products that have come to the Agency's attention. This final rule finalizes the 1994 tentative final monograph (TFM) for OTC health care antiseptic drug products that published in the Federal Register of June 17, 1994 (the 1994 TFM) as amended by the proposed rule published in the Federal Register (FR) of May 1, 2015 (2015 Health Care Antiseptic Proposed Rule (PR)). PMID- 29260840 TI - Editorial. PMID- 29260841 TI - EMPLOYER CAMPAIGN TO DEREGULATE WORKING HOURS. AB - Over the past five years the ANMF has been resisting a concerted campaign by aged care employers to remove important protections that give part time employees a level of predictability in their hours and days on which they are required to work. PMID- 29260842 TI - Interfacial Synthesis of Conjugated Two-Dimensional N-Graphdiyne. AB - We explored the interfacial synthesis of 2D N-graphdiyne films at the gas/liquid and liquid/liquid interfaces. Triazine- or pyrazine-based monomers containing ethynyl group were polymerized through the Glaser coupling reactions at interfaces. Several layered, highly ordered and conjugated 2D N-graphdiyne were obtained. Their structures were characterized by TEM, SEM, AFM, XPS, and Raman spectra. Thin films with minimum thickness of 4 nm could be prepared. PMID- 29260843 TI - Hyperthemia-Promoted Cytosolic and Nuclear Delivery of Copper/Carbon Quantum Dot Crosslinked Nanosheets: Multimodal Imaging-Guided Photothermal Cancer Therapy. AB - Copper-containing nanomaterials have been applied in various fields because of their appealing physical, chemical, and biomedical properties/functions. Herein, for the first time, a facile, room-temperature, and one-pot method of simply mixing copper ions and sulfur-doped carbon dots (CDs) is developed for the synthesis of copper/carbon quantum dot (or CD)-crosslinked nanosheets (CuCD NSs). The thus-obtained CuCD NSs with the size of 20-30 nm had a high photothermal conversion efficiency of 41.3% and good photothermal stability. Especially, after coating with thiol-polyethylene glycol and fluorescent molecules, the resultant CuCD NSs could selectively target tumor tissues and realize multimodal (photoacoustic, photothermal, and fluorescence) imaging-guided cancer therapy. More importantly, our CuCD NSs exhibited laser-triggered cytosolic delivery, lysosomal escape, and nuclear-targeting properties, which greatly enhanced their therapeutic efficacy. The significantly enhanced tumor accumulation of CuCD NSs after in situ tumor-site laser irradiation was also observed in in vivo experiments. These in vitro and in vivo events occurring during the continuous laser irradiation have not been observed. Overall, this work develops a CD assisted synthetic method of photothermal nanoagents for triple-modal imaging guided phototherapy and deepens our understanding of the action mechanism of photothermal therapy, which will promote the development of nanomedicine and beyond. PMID- 29260844 TI - Cross-Linked and Biodegradable Polymeric System as a Safe Magnetic Resonance Imaging Contrast Agent. AB - Owing to the low efficacy of clinically used small-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) agents, we designed and explored biodegradable macromolecular conjugates as MRI contrast agents. The linear polymeric structure and core-cross-linked formulation possessed different characteristics and features, so we prepared and comparatively studied the two kinds of Gd-based N-(2 hydroxypropyl) methacrylamide (HPMA) polymeric systems (the core-cross-linked pHPMA-DOTA-Gd and the linear one) using the clinical agent diethylene-triamine pentaacetic acid-Gd(III) (DTPA-Gd) as a control. This study was aimed to find the optimal polymeric formulation as a biocompatible and efficient MRI contrast agent. The high molecular weight (MW, 181 kDa) and core-cross-linked copolymer was obtained via the cross-linked block linear copolymer and could be degraded to low-MW segments (29 kDa) in the presence of glutathione (GSH) and cleaned from the body. Both core-cross-linked and linear pHPMA-DOTA-Gd copolymers displayed 2 3-fold increased relaxivity (r1 value) than that of DTPA-Gd. Animal studies demonstrated that two kinds of macromolecular systems led to much longer blood circulation time, higher tumor accumulation, and much higher signal intensity compared with the linear and clinical ones. Finally, in vivo and in vitro toxicity studies indicated that the two macromolecular agents had great biocompatibility. Therefore, we performed preliminary but important studies on the Gd-based HPMA polymeric systems as biocompatible and efficient MRI contrast agents and found that the biodegradable core-cross-linked pHPMA-DOTA-Gd copolymer might have greater benefits for the foreground. PMID- 29260845 TI - Hierarchically Porous Graphene/ZIF-8 Hybrid Aerogel: Preparation, CO2 Uptake Capacity, and Mechanical Property. AB - A hierarchical zeolitic imidazole framework (ZIF) combining a micropore with a mesoporous structure is desirable to enhance mass transport and gives rise to novel applications. Here, hierarchically porous graphene/ZIF-8 hybrid aerogel (GZAn) materials were successfully prepared by a two-step reduction strategy and a layer-by-layer assembly method. To avoid a tedious dry step and the use of an energy-consuming freeze-drying technology, a reduced graphene oxide hydrogel with different reduction degrees was chosen as a template to grow ZIF-8 crystals in situ. The parameter of density and elemental analysis was adopted to calculate the amount of ZIF-8 in GZAn materials for different assembly cycles. The distribution of micropores and mesopores of GZAn materials was controlled by changing the loading of ZIFs in GZAn materials. Furthermore, GZA8 materials showed enhanced CO2 uptake capacity (0.99 mmol g-1, 298 K, 1 bar) than pure ZIF-s crystals and pure graphene aerogels, showing an excellent synergistic effect of hierarchical pore structures. Meanwhile, with the increase of ZIF-8 loading, the mechanical robustness of GZAn was uplifted obviously. This work provides an efficient method to prepare hierarchically porous ZIFs-based materials with good CO2 uptake capacity and tunable mechanical robustness. PMID- 29260846 TI - Soft Particles of Gemini Surfactant/Conjugated Polymer for Enhanced Anticancer Activity of Chemotherapeutics. AB - In this work, we developed a kind of novel nontoxic soft particle self-assembled by gemini surfactant (SDHC) and conjugated polymer (PMNT). The soft particle shows strong ability in incorporating into cell membrane, and alters the membrane permeability, especially under light irradiation. The anticancer activities of doxorubicin (DOX) were enhanced 6-9 times after cancer cells were treated with the soft particles under light irradiation. The cell viabilities of three kinds of cancer cells testify that this effect of the soft particles on chemotherapy is universal. This work provides a new strategy to enhance the anticancer activities of drugs. PMID- 29260847 TI - Manipulating the Defect Structure (VO) of In2O3 Nanoparticles for Enhancement of Formaldehyde Detection. AB - Because defects such as oxygen vacancies (VO) can affect the properties of nanomaterials, investigating the defect structure-function relationship are attracting intense attention. However, it remains an enormous challenge to the synthesis of nanomaterials with high sensing performance by manipulating VO because understanding the role of surface or bulk VO on the sensing properties of metal oxides is still missing. Herein, In2O3 nanoparticles with different contents of surface and bulk VO were obtained by hydrogen reduction treatment, and the role of surface or bulk VO on the sensing properties of In2O3 was investigated. The X-ray diffraction, ultraviolet-visible spectrophotometer, electron paramagnetic resonance, photoluminescence, Raman, X-ray photoelectron spectroscopy, Hall analysis, and the sensing results indicate that bulk VO can decrease the band gap and energy barrier and increase the carrier mobility, hence facilitating the formation of chemisorbed oxygen and enhancing the sensing response. Benefiting from bulk VO, In2O3-H10 exhibits the highest response, good selectivity, and stability for formaldehyde detection. However, surface VO does not contribute to the improvement of formaldehyde-sensing performance, and the black In2O3-H30 with the highest content of surface VO exhibits the lowest response. Our work provides a novel strategy for the synthesis of nanomaterials with high sensing performance by manipulating VO. PMID- 29260848 TI - Transition-Metal Complexes Featuring Dianionic Heavy Group 14 Element Aromatic Ligands. AB - The synthesis of dilithio-stannoles and -plumboles, dianionic aromatic compounds containing tin and lead atoms in their pi-skeletons, opened a new field of transition-metal chemistry. Since the discovery of ferrocene (Cp2Fe), which is composed of anionic aromatic ligands (Cp: cyclopentadienyl) and Fe(II), ferrocene type sandwich complexes have long played important roles in many fields of chemistry. During the last few decades, the electronic and structural properties of the Cp ligand have been modified by introducing electron-donating, electron withdrawing, and sterically encumbered substituents on the skeletal carbon atoms to obtain desirable properties of the resulting sandwich complexes. In terms of modifying the Cp ligand, we focused our attention on introducing a heavy group 14 atom into the pi-skeleton. This idea was originally inspired by a question of whether or not aromaticity was retained after the replacement of a skeletal carbon atom by a heavy group 14 atom. After we succeeded in the synthesis of aromatic dilithio-stannoles and -plumboles, revealing that the concept of conventional aromaticity was expanded to lead-containing pi-systems, we undertook the present project on applying these dianionic aromatic heavy Cp analogues as ligands for transition-metal complexes. The combination of a stannole and Cp*Ru units accomplished the creation of a neutral triple-decker complex and an anionic ruthenocene, which was not be accessible using Cp and its related ligands that are composed of only carbon atoms. The anionic ruthenocene reacted with electrophiles to afford ruthenocene-type sandwich complexes, and the structures of the stannole skeletons were highly dependent on the substituents on the tin atoms, in sharp contrast to the planar Cp ligand. The dianionic plumbole ligand was also found to function as an eta5-coordinating ligand in an anionic ruthenocene, which is noteworthy in terms of incorporating the heaviest group 14 atom into a pi-ligand to produce a ferrocene-type sandwich complex. The anionic ruthenocene bearing the plumbole ligand reacted with electrophiles to afford ruthenocene-type plumbole complexes, which have oxidation potentials lower than those of the corresponding tin analogues, demonstrating the effect of introduction of a lead atom heavier than a tin atom. In the reactions of dilithiostannoles with group 4 metals, the resulting complexes were found to have exotic electronic structures that cannot be constructed by the Cp ligand. The transition-metal complexes derived from dilithio-stannoles and -plumbole therefore exhibit remarkable differences as well as similarities to the traditional Cp-based transition-metal complexes. These results spotlight the introduction of heavy group 14 atoms into carbon-based pi-skeletons, which can perturb the electronic properties of conventional transition-metal complexes and open a new chemistry of transition-metal complexes. PMID- 29260849 TI - Horner Syndrome: A Clinical Review. AB - Horner syndrome results from an interruption of the oculosympathetic pathway. Patients with Horner syndrome present with a slightly droopy upper lid and a smaller pupil on the affected side; less commonly, there is a deficiency of sweating over the brow or face on the affected side. This condition does not usually cause vision problems or other significant symptoms, but is important as a warning sign that the oculosympathetic pathway has been interrupted, potentially with serious and even life-threatening processes. The oculosympathetic pathway has a long and circuitous course, beginning in the brain and traveling down the spinal cord to exit in the chest, then up the neck and into the orbit. Therefore, this syndrome with unimpressive clinical findings and insignificant symptoms may be a sign of serious pathology in the head, chest, or neck. This clinical review discusses how to identify the signs, confirm the diagnosis, and evaluate the many causes of Horner syndrome. PMID- 29260850 TI - Langmuir-Blodgett Nanoassemblies of the MoS2-Au Composite at the Air-Water Interface for Dengue Detection. AB - We report Langmuir-Blodgett (LB) films of molybdenum disulphide (MoS2) and gold nanoparticles (AuNP) composite being utilized as a biosensing platform for dengue detection. The LB films of the MoS2-AuNP composite have been transferred from the air-water interface to the indium tin oxide-coated glass substrate under optimized conditions. Further, antibodies specific to dengue NS1 antigen were immobilized onto these LB films. The fabricated immunosensor has been explored for NS1 antigen detection in standard samples as well as in spiked sera samples using electrochemical impedance spectroscopy. The NS1 antigen is present in the blood of infected persons from day one of the onset of clinical symptoms in primary dengue infection. The limit of detection for the standard and the spiked samples is found to be 1.67 and 1.19 ng mL-1, respectively, which is suitable for clinical applications, as NS1 antigen levels in patient's sera range from 0.04 to 2 MUg mL-1 in primary infection and from 0.01 to 2 MUg mL-1 in secondary infection. PMID- 29260851 TI - Structure/Property Relations in "Giant" Semiconductor Nanocrystals: Opportunities in Photonics and Electronics. AB - Semiconductor nanocrystals exhibit size-tunable absorption and emission ranging from the ultraviolet (UV) to the near-infrared (NIR) spectral range, high absorption coefficient, and high photoluminescence quantum yield. Effective surface passivation of these so-called quantum dots (QDs) may be achieved by growing a shell of another semiconductor material. The resulting core/shell QDs can be considered as a model system to study and optimize structure/property relations. A special case consists in growing thick shells (1.5 up to few tens of nanometers) to produce "giant" QDs (g-QDs). Tailoring the chemical composition and structure of CdSe/CdS and PbS/CdS g-QDs is a promising approach to widen the spectral separation of absorption and emission spectra (i.e., the Stokes shift), improve the isolation of photogenerated carriers from surface defects and enhance charge carrier lifetime and mobility. However, most stable systems are limited by a thick CdS shell, which strongly absorbs radiation below 500 nm, covering the UV and part of the visible range. Modification of the interfacial region between the core and shell of g-QDs or tuning their doping with narrow band gap semiconductors are effective approaches to circumvent this challenge. In addition, the synthesis of g-QDs composed of environmentally friendly elements (e.g., CuInSe2/CuInS2) represents an alternative to extend their absorption into the NIR range. Additionally, the band gap and band alignment of g-QDs can be engineered by proper selection of the constituents according to their band edge positions and by tuning their stoichiometry during wet chemical synthesis. In most cases, the quasi-type II localization regime of electrons and holes is achieved. In this type of g-QDs, electrons can leak into the shell region, while the holes remain confined within the core region. This electron-hole spatial distribution is advantageous for optoelectronic devices, resulting in efficient electron-hole separation while maintaining good stability. This Account provides an overview of emerging engineering strategies that can be adopted to optimize structure/property relations in colloidal g-QDs for efficient photon management or charge separation/transfer. In particular, we focus on our recent contributions to this rapidly expanding field of research. We summarize the design and synthesis of a variety of colloidal g-QDs with the aim of tuning the optical properties, such as absorption/emission in a wide region of the solar spectrum, which allows enlargement of their Stokes shift. We also describe the band alignment within these systems, charge carrier dynamics, and charge transfer from g-QDs into semiconducting oxides. We show how these tailored g-QDs may be used as active components in luminescent solar concentrators, photoelectrochemical cells for hydrogen generation, QD-sensitized solar cells and optical nanothermometers. In each case, we aim at providing insights on structure/property relationships and on how to optimize them toward improving device performance. Finally, we describe perspectives for future work, sketching new directions and opportunities in this field of research at the intersection between chemistry, physics, materials science and engineering. PMID- 29260852 TI - Targeting the Prion-like Aggregation of Mutant p53 to Combat Cancer. AB - Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties. Within the context of p53 aggregation and the search for ways to avert it, this review emphasizes discoveries, approaches, and research from our laboratory and others. Although its standard functions are strongly connected to tumor suppression, p53 mutants and aggregates are involved in cancer progression. p53 aggregates are heterogeneous assemblies composed of amorphous aggregates, oligomers, and amyloid-like fibrils. Evidence of these structures in tumor tissues, the in vitro capability for p53 mutants to coaggregate with wt protein, and the detection of cell-to-cell transmission indicate that cancer has the basic characteristics of prion and prion-like diseases. Various approaches aim to restore p53 functions in cancer. Methods include the use of small-molecule and peptide stabilizers of mutant p53, zinc administration, gene therapy, alkylating and DNA intercalators, and blockage of p53-MDM2 interaction. A primary challenge in developing small-molecule inhibitors of p53 aggregation is the large number of p53 mutations. Another issue is the inability to recover p53 function by dissociating mature fibrils. Consequently, efforts have emerged to target the intermediate species of the aggregation reaction. Phi-value analysis has been used to characterize the kinetics of the early phases of p53 aggregation. Our experiments using high hydrostatic pressure (HHP) and chemical denaturants have helped to clarify excited conformers of p53 that are prone to aggregation. Molecular dynamics (MD) and phasor analysis of single Trp fluorescence signals point toward the presence of preamyloidogenic conformations of p53, which are not observed for p63 or p73. Exploring the features of competent preamyloidogenic states of wt and different p53 mutants may provide a framework for designing personalized drugs for the restoration of p53 function. Protection of backbone hydrogen bonds (BHBs) has been shown to be an important factor for the stability of amyloidogenic proteins and was employed to identify and stabilize the structural defect resulting from the p53 Y220C mutation. Using MD simulations, we compared BHB protection factors between p53 family members to determine the donor acceptor pairs in p53 that exhibit lower protection. The identification of structurally vulnerable sites in p53 should provide new insights into rational designs that can rapidly be screened using our experimental methodology. Through continued and combined efforts, the outlook is positive for the development of strategies for regulating p53 amyloid transformation. PMID- 29260853 TI - Liquid Chromatography Separation and Mass Spectrometry Detection of Silver Lipoate Ag29(LA)12 Nanoclusters: Evidence of Isomerism in the Solution Phase. AB - Evidence for the existence of condensed-phase isomers of silver-lipoate clusters, Ag29(LA)12, where LA = (R)-alpha lipoic acid, was obtained by reversed-phase ion pair liquid chromatography with in-line UV-vis and electrospray ionization (ESI) MS detection. All components of a raw mixture were separated according to surface chemistry and increasing size via reversed-phase gradient HPLC methods and identified by their corresponding m/z ratio by ESI in the negative ionization mode. Aqueous and methanol mobile-phase mixtures, each containing 400 mM hexafluoroisopropanol (HFIP)-15 mM triethylamine (TEA), were employed to facilitate the interaction between the clusters and stationary phase via formation of ion-pairs. TEA-HFIP (triethylammonium-hexafluoroisopropoxide) had been shown to provide superior chromatographic peak shape and mass spectral signal compared with alternative modifiers such as TEAA (triethylammonium acetate) for analysis of oligonucleotide samples. Liquid chromatographic separation prior to mass spectrometry detection facilitated sample analysis by production of simplified mass spectra for each eluting cluster species and provided insight into the existence of at least two major solution-phase isomers of Ag29(LA)12. UV-vis detection in-line with ESI analysis provided independent confirmation of the existence of the isomers and their similar electronic structure as judged from their identical optical spectra in the 300-500 nm range. [Diastereomerism provides a possible interpretation for the near-equal abundance of the two forms, based on a structurally defined nonaqueous homologue.]. PMID- 29260854 TI - Electric Field Stiffening Effect in c-Oriented Aluminum Nitride Piezoelectric Thin Films. AB - Aluminum nitride offers unique material advantages for the realization of ultrahigh-frequency acoustic devices attributed to its high ratio of stiffness to density, compatibility with harsh environments, and superior thermal properties. Although, to date, aluminum nitride thin films have been widely investigated regarding their electrical and mechanical characteristics under alternating small signal excitation, their ultrathin nature under large bias may also provide novel and useful properties. Here, we present a comprehensive investigation of electric field stiffening effect in c-oriented aluminum nitride piezoelectric thin films. By analyzing resonance characteristics in a 2.5 GHz aluminum nitride-based film bulk acoustic resonator, we demonstrate an up to 10% linear variation in the equivalent stiffness of aluminum nitride piezoelectric thin films when an electric field was applied from -150 to 150 MV/m along the c-axis. Moreover, for the first time, an atomic interaction mechanism is proposed to reveal the nature of electric field stiffening effect, suggesting that the nonlinear variation of the interatomic force induced by electric field modulation is the intrinsic reason for this phenomenon in aluminum nitride piezoelectric thin films. Our work provides vital experimental data and effective theoretical foundation for electric field stiffening effect in aluminum nitride piezoelectric thin films, indicating the huge potential in tunable ultrahigh-frequency microwave devices. PMID- 29260855 TI - Cellulose-Based Sensor Containing Phenanthroline for the Highly Selective and Rapid Detection of Fe2+ Ions with Naked Eye and Fluorescent Dual Modes. AB - Iron ions play a vital role in many biological processes, and their concentrations are responsible for human health. Therefore, it is essential to detect the concentration of iron ions by a rapid, accurate, highly selective, and practical method. Herein, we have synthesized a cellulose-based fluorescent sensor (Phen-MDI-CA) for the highly selective and rapid detection of Fe2+ ions via chemically bonding 1,10-phenanthroline-5-amine (Phen) onto cellulose acetate (CA) using 4,4'-methylene diphenyl diisocyanate (MDI) as a cross-linker. Benefiting from the anchoring and diluting effect of a cellulose skeleton, the resultant Phen-MDI-CA displays excellent fluorescence properties in both solution and solid state. More interestingly, a cellulose-based polymer chain significantly improves the sensitivity of phenanthroline to Fe2+ ions. Upon meeting Fe2+ ions, a red, insoluble, and nonfluorescent Fe-(Phen-MDI-CA) complex appears immediately; thus, Phen-MDI-CA can work as a multimode chromogenic sensor for the highly selective, sensitive, and rapid detection of Fe2+ ions. In the instrument-free visual mode, the detection limit for Fe2+ ions is 50 ppb, and in fluorescence mode, the detection limit is 2.6 ppb. To our knowledge, this is the first time that such a low detection limit for Fe2+ ions in aqueous media has been observed by the naked eye. In addition, Phen-MDI-CA has good solubility and processability in common organic solvents, which facilitates its use in different material forms, e.g., printing ink, coating, and film. Therefore, the Fe2+ responsive and chromogenic Phen-MDI-CA exhibits a huge potential in the detection and extraction of Fe2+ ions. PMID- 29260856 TI - Acinetobacter baumannii OmpA Is a Selective Antibiotic Permeant Porin. AB - OmpAAb is a conserved, abundantly expressed outer membrane porin in Acinetobacter baumannii whose presumed role in antibiotic permeation has not been clearly demonstrated. In this report, we use a titratable heterologous expression system to express OmpAAb in isolation and demonstrate selective passage of small molecule antibiotics through OmpAAb. ETX2514, a recently discovered broad spectrum beta-lactamase inhibitor, in combination with sulbactam, is currently in clinical testing for the treatment of drug-resistant A. baumannii infections. We demonstrate that ETX2514 permeates OmpAAb and potentiates the activity of sulbactam in an OmpAAb-dependent manner. In addition, we show that small modifications in the structure of ETX2514 differentially affect its passage through OmpAAb, revealing unique structure-porin-permeation relationships. Finally, we confirm the contribution of OmpAAb to bacterial fitness using a murine thigh model of A. baumannii infection. These results, combined with the high sequence homology of OmpA across Acinetobacter spp., suggest that optimization of antibiotic entry through OmpAAb may prove to be a feasible medicinal chemistry design strategy for future antibacterial discovery efforts. PMID- 29260857 TI - Clarification of Solvent Effects on Discharge Products in Li-O2 Batteries through a Titration Method. AB - As a substitute for the current lithium-ion batteries, rechargeable lithium oxygen batteries have attracted much attention because of their theoretically high energy density, but many challenges continue to exist. For the development of these batteries, understanding and controlling the main discharge product Li2O2 (lithium peroxide) are of paramount importance. Here, we comparatively analyzed the amount of Li2O2 in the cathodes discharged at various discharge capacities and current densities in dimethyl sulfoxide (DMSO) and tetraethylene glycol dimethyl ether (TEGDME) solvents. The precise assessment entailed revisiting and revising the UV-vis titration analysis. The amount of Li2O2 electrochemically formed in DMSO was less than that formed in TEGDME at the same capacity and even at a much higher full discharge capacity in DMSO than in TEGDME. On the basis of our analytical experimental results, this unexpected result was ascribed to the presence of soluble LiO2-like intermediates that remained in the DMSO solvent and the chemical transformation of Li2O2 to LiOH, both of which originated from the inherent properties of the DMSO solvent. PMID- 29260858 TI - Methodology for the Validation of Isotopic Analyses by Mass Spectrometry in Stable-Isotope Labeling Experiments. AB - Stable-isotope labeling experiments (ILEs) are widely used to investigate the topology and operation of metabolic networks. The quality of isotopic data collected in ILEs is of utmost importance to ensure reliable biological interpretations, but current evaluation approaches are limited due to a lack of suitable reference material and relevant evaluation criteria. In this work, we present a complete methodology to evaluate mass spectrometry (MS) methods used for quantitative isotopic studies of metabolic systems. This methodology, based on a biological sample containing metabolites with controlled labeling patterns, exploits different quality metrics specific to isotopic analyses (accuracy and precision of isotopologue masses, abundances, and mass shifts and isotopic working range). We applied this methodology to evaluate a novel LC-MS method for the analysis of amino acids, which was tested on high resolution (Orbitrap operating in full scan mode) and low resolution (triple quadrupole operating in multiple reaction monitoring mode) mass spectrometers. Results show excellent accuracy and precision over a large working range and revealed matrix-specific as well as mode-specific characteristics. The proposed methodology can identify reliable (and unreliable) isotopic data in an easy and straightforward way and efficiently supports the identification of sources of systematic biases as well as of the main factors that influence the overall accuracy and precision of measurements. This approach is generic and can be used to validate isotopic analyses on different matrices, analytical platforms, labeled elements, or classes of metabolites. It is expected to strengthen the reliability of isotopic measurements and thereby the biological value of ILEs. PMID- 29260859 TI - Inner Filter Effect-Based Sensor for Horseradish Peroxidase and Its Application to Fluorescence Immunoassay. AB - Being an important model peroxidase, horseradish peroxidase (HRP) has been thoroughly understood, and the detection of HRP is not only directly related to peroxidase-triggered catalytic process, but also linked to the development of HRP based enzyme-linked immunosorbent assay (ELISA). Herein, we have reported an unconventional fluorescent sensor for convenient assay of HRP activity based on the HRP-catalyzed specific conversion of p-phenylenediamine (PPD) into chromogenic PPDox with H2O2 as the oxidizing agent, accompanied by the fluorescence quenching effect on fluorescein. By combining UV-vis absorption spectrum, isothermal titration calorimetry, and fluorescence lifetime analysis, we have confirmed the inner filter effect as a main quenching mechanism in our proposed fluorescent assay. According to the intrinsic sensitivity of fluorescent sensor and high selectivity, our PPD/fluorescein-based sensing system can be utilized for real-time monitoring of the HRP activity in real biological samples. Furthermore, the unambiguous response mechanism and excellent sensing performance encourage us to extend such HRP assay into the HRP-based fluorescent ELISA, which has a broad prospect of application in fluorescent diagnosis of hepatocellular carcinoma (HCC) by sensing alpha-fetoprotein, the well-known serologic HCC marker. PMID- 29260860 TI - Atmospheric-Pressure Dielectric Barrier Discharge as an Elemental Ion Source for Gas Chromatographic Analysis of Organochlorines. AB - Atmospheric-pressure dielectric barrier discharge (AP-DBD) plasma has emerged in recent years as a versatile plasma for molecular ionization and elemental spectroscopy. However, its capabilities as an elemental ion source have been less explored, partly because of difficulties in the detection of positive elemental ions from this low-gas-temperature plasma. In this work, we investigate the detection of negative elemental ions to enable elemental mass spectrometry (MS) using AP-DBD. A gas chromatograph is coupled to a helium AP-DBD apparatus and positioned in front of an atmospheric-pressure-sampling mass spectrometer with no modifications to the ion sampling interface. We demonstrate that Cl- ions are detected with a compound-independent efficiency, enabling elemental quantification of organochlorines. Further, addition of oxygen at low concentration (11 ppm, v/v) to the helium plasma improves the analytical performance by reducing postcolumn peak broadening, whereas high oxygen concentrations (>110 ppm, v/v) lead to loss of the compound-independent response. The optimized GC-AP-DBD-MS setup shows close to 2 orders of magnitude of linearity for its compound-independent Cl response and offers detection limits of 0.5-1 pg of Cl on column (0.6 pg/s), suitable for analysis of organochlorines in food samples. We demonstrate this capability by analyzing orange juice spiked with pesticides at 9 MUg/L and a single internal standard. Importantly, we demonstrate that a quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction followed by GC-AP-DBD-MS quantification using the single standard provides acceptable recoveries (80-120%). These results highlight uniform QuEChERS extraction of a range of compounds and the compound-independent response of AP-DBD for Cl, making the combination of the two methods desirable for the rapid quantification of organochlorines. Furthermore, we discuss ionization matrix effects in AP-DBD for chlorine detection and offer strategies to flag matrix-impacted analytes. These results suggest that AP-DBD has the potential to become a unified ion source for both elemental quantification and molecular identification of GC eluents on a single MS platform. PMID- 29260861 TI - Whole-Cell Pseudomonas aeruginosa Localized Surface Plasmon Resonance Aptasensor. AB - The detection of whole-cell Pseudomonas aeruginosa presents an intriguing challenge with direct applications in health care and the prevention of nosocomial infection. To address this problem, a localized surface plasmon resonance (LSPR) based sensing platform was developed to detect whole-cell Pseudomonas aeruginosa strain PAO1 using a surface-confined aptamer as an affinity reagent. Nanosphere lithography (NSL) was used to fabricate a sensor surface containing a hexagonal array of Au nanotriangles. The sensor surface was subsequently modified with biotinylated polyethylene glycol (Bt-PEG) thiol/PEG thiol (1:3), neutravidin, and biotinylated aptamer in a sandwich format. The 1:3 (v/v) ratio of Bt-PEG thiol/PEG thiol was specifically chosen to maximize PAO1 binding while minimizing nonspecific adsorption and steric hindrance. In contrast to prior whole-cell LSPR work, the LSPR wavelength shift was shown to be linearly related to bacterial concentration over the range of 10-103 cfu mL-1. This LSPR sensing platform is rapid (~3 h for detection), sensitive (down to the level of a single bacterium), selective for detection of Pseudomonas strain PAO1 over other strains, and exhibits a clinically relevant dynamic range and excellent shelf life (>=2 months) when stored at ambient conditions. This versatile LSPR sensing platform should be extendable to a wide range of supermolecular analytes, including both bacteria and viruses, by switching affinity reagents, and it has potential to be used in point-of-care and field-based applications. PMID- 29260862 TI - An Online Four-Dimensional HIC*SEC-IM*MS Methodology for Proof-of-Concept Characterization of Antibody Drug Conjugates. AB - There are currently two main techniques allowing the analytical characterization of interchain cysteine-linked antibody drug conjugates (ADCs) under native conditions, namely, hydrophobic interaction chromatography (HIC) and native mass spectrometry (MS). HIC is a chromatographic technique allowing the evaluation of drug load profile and calculation of average drug-to-antibody ratio (DAR) in quality control laboratories. Native MS offers structural insights into multiple ADC critical quality attributes, thanks to accurate mass measurement. However, both techniques can lead to misinterpretations or incomplete characterization when used as standalone methods. Online coupling of both techniques can thus potentially be of great interest, but the presence of large amounts of nonvolatile salts in HIC mobile phases makes it not easily directly compatible with native MS. Here, we present an innovative multidimensional analytical approach combining comprehensive online two-dimensional (2D)-chromatography that consists of HIC and size-exclusion chromatography (SEC), to ion mobility and mass spectrometry (IM-MS) for performing analytical characterization of ADCs under nondenaturing conditions. This setup enabled comprehensive and streamlined characterization of both native and forced degraded ADC samples. The proposed 4D methodology might be more generally adapted for online all-in-one HIC*SEC-IM*MS analysis of single proteins or analysis of protein complexes in nondenaturing conditions. PMID- 29260863 TI - Effects of Chloride Ions on Dissolution, ROS Generation, and Toxicity of Silver Nanoparticles under UV Irradiation. AB - This work investigates the effect of chloride ion (Cl-) on dissolution, reactive oxygen species (ROS) generation, and toxicity of citrate-coated silver nanoparticles (AgNPs) under UV irradiation. The dissolution rate was decreased by 0.01 M Cl- due to AgCl passivation on the AgNP surface. By contrast, high concentrations of Cl- (0.1 or 0.5 M) promoted dissolution due to the formation of soluble Ag-Cl complexes (AgCl x1- x). The generation of O2*- in the AgNPs/Cl-/UV system was promoted by 0.01 M Cl-, whereas it was retarded by 0.1 or 0.5 M Cl-, which was probably because the aggregation of AgNPs at high ionic strength reduced the nanoparticles' surface areas for radical formation. Additionally, Cl- contributed to *OH generation in the AgNPs/Cl-/UV system, in which the produced *OH concentrations increased with increasing Cl- concentrations. The reduction reaction between silver ions and O2*- resulted in lower dissolution rates of AgNPs/Cl- mixtures under UV irradiation than those in the dark. The phototoxicity of AgNPs toward E. coli with different concentrations of Cl- followed the order of 0.5 M > 0 M > 0.1 M > 0.01 M. Both ROS and dissolved Ag played significant role in the phototoxicity of AgNPs. This work demonstrates the potential importance of anions in the fate and biological impact of AgNPs. PMID- 29260864 TI - AQuA: An Automated Quantification Algorithm for High-Throughput NMR-Based Metabolomics and Its Application in Human Plasma. AB - A key limiting step for high-throughput NMR-based metabolomics is the lack of rapid and accurate tools for absolute quantification of many metabolites. We developed, implemented, and evaluated an algorithm, AQuA (Automated Quantification Algorithm), for targeted metabolite quantification from complex 1H NMR spectra. AQuA operates based on spectral data extracted from a library consisting of one standard calibration spectrum for each metabolite. It uses one preselected NMR signal per metabolite for determining absolute concentrations and does so by effectively accounting for interferences caused by other metabolites. AQuA was implemented and evaluated using experimental NMR spectra from human plasma. The accuracy of AQuA was tested and confirmed in comparison with a manual spectral fitting approach using the ChenomX software, in which 61 out of 67 metabolites quantified in 30 human plasma spectra showed a goodness-of-fit (r2) close to or exceeding 0.9 between the two approaches. In addition, three quality indicators generated by AQuA, namely, occurrence, interference, and positional deviation, were studied. These quality indicators permit evaluation of the results each time the algorithm is operated. The efficiency was tested and confirmed by implementing AQuA for quantification of 67 metabolites in a large data set comprising 1342 experimental spectra from human plasma, in which the whole computation took less than 1 s. PMID- 29260865 TI - Structure Transformation and Cerium-Substituted Optical Response across the Carbonitridosilicate Solid Solution (LadeltaY1-delta)2Si4N6C (delta = 0-0.5). AB - Following an investigation proving La2Si4N6C crystallizes in a monoclinic space group, isostructural to Y2Si4N6C, the reportedly hexagonal (La0.5Y0.5)2Si4N6C was reinvestigated to examine the apparent crystal structure change across the solid solution. Initially, calculating the electronic structure and phonon density of states of (La0.5Y0.5)2Si4N6C in the P63mc space group revealed an imaginary phonon mode, which is indicative of a structural instability. Displacing the atoms along the pathway of the imaginary vibration led to a previously unreported space group for carbonitridosilicates, trigonal P31c. The assignment of the trigonal space group was subsequently confirmed by synthesizing (La0.5Y0.5)2Si4N6C using high-temperature, solid state synthesis and analyzing the crystal structure with high-resolution synchrotron X-ray powder diffraction. Preparing the solid solution, (LadeltaY1-delta)1.98Ce0.02Si4N6C (delta = 0-0.5), showed that the crystal structure changes from the monoclinic to the trigonal space group at delta ~ 0.25. Finally, substituting Ce3+ in the crystal structure to investigate the optical response via steady-state luminescent and photoluminescent quantum yield measurements reveals severe luminescent quenching with increasing La3+ content, due to a combination of absorption of luminescence by the host structure and thermal quenching. These results display the virtue of combining computational and experimental techniques to solve inorganic crystal structures and assess potential phosphor hosts. PMID- 29260866 TI - Correction to "Photocatalytic Conversion of Nitrogen to Ammonia with Water on Surface Oxygen Vacancies of Titanium Dioxide". PMID- 29260867 TI - Mobile Affinity Sorbent Chromatography. AB - The objective in routine analyses is generally to determine a small number of analytes. With samples containing ~103 or more components there will be insufficient peak capacity to resolve analytes from nonanalytes. This issue was addressed herein through a new type of separation mechanism in which small groups of targeted analytes are bound with high affinity to a soluble analyte sequestering transport phase (ASTP) composed of a ~25 nm Stokes radius hydrophilic polymer core (HPC). When introduced into a 30 nm pore diameter size exclusion chromatography (SEC) column, ASTP/analyte complexes elute within minutes, together, unretained, and relatively pure in the first chromatographic peak. Nonanalytes, in contrast, enter pore matrices of the packing material, are retarded in elution velocity, and are eluted later, separated from analytes. Fabrication of ASTPs was achieved by covalently coupling an antibody or some other affinity selector to a high molecular weight HPC. Beyond sequestering analytes, the function of ASTPs is to act as a molecular weight shifting agent, conveying an effective molecular weight to analytes that is much larger than that of nonanalytes and causing them to elute in the SEC void volume. This mode of separation is referred to as mobile affinity sorbent chromatography (MASC). Subsequent to their purification, ASTP/analyte complexes were detected by fluorescence spectrometry. PMID- 29260869 TI - New Ligand Design Provides Delocalization and Promotes Strong Absorption throughout the Visible Region in a Ru(II) Complex. AB - The new Ru(II)-anthraquinone complex [Ru(bpy)2(qdpq)](PF6)2 (Ru-qdpq; bpy = 2,2' bipyridine; qdpq = 2,3-di(2-pyridyl)naphtho[2,3-f]quinoxaline-7,12-quinone) possesses a strong 1MLCT Ru -> qdpq absorption with a maximum at 546 nm that tails into the near-IR and is significantly red-shifted relative to that of the related complex [Ru(bpy)2(qdppz)](PF6)2 (Ru-qdppz; qdppz = naphtho[2,3 a]dipyrido[3,2-h:2',3'-f]phenazine-5,18-dione), with lambdamax = 450 nm. Ru-qdppz possesses electronically isolated proximal and distal qdppz-based excited states; the former is initially generated and decays to the latter, which repopulates the ground state with tau = 362 ps. In contrast, excitation of Ru-qdpq results in the population of a relatively long-lived (tau = 19 ns) Ru(dpi) -> qdpq(pi*) 3MLCT excited state where the promoted electron is delocalized throughout the qdpq ligand. Ultrafast spectroscopy, used together with steady-state absorption, electrochemistry, and DFT calculations, indicates that the unique coordination modes of the qdpq and qdppz ligands impart substantially different electronic communication throughout the quinone-containing ligand, affecting the excited state and electron transfer properties of these molecules. These observations create a pathway to synthesize complexes with red-shifted absorptions that possess long-lived, redox-active excited states that are useful for various applications, including solar energy conversion and photochemotherapy. PMID- 29260868 TI - Migratory Insertion of Carbenes into Au(III)-C Bonds. AB - Migratory insertion of carbon-based species into transition-metal-carbon bonds is a mechanistic manifold of vast significance: it underlies the Fischer-Tropsch process, Mizoroki-Heck reaction, Ziegler-Natta and analogous late-transition metal-catalyzed olefin polymerizations, and a number of carbonylative methods for the synthesis of ketones and esters, among others. Although this type of reactivity is well-precedented for most transition metals, gold constitutes a notable exception, with virtually no well-characterized examples known to date. Yet, the complementary reactivity of gold to numerous other transition metals would offer new synthetic opportunities for migratory insertion of carbon-based species into gold-carbon bonds. Here we report the discovery of well-defined Au(III) complexes that participate in rapid migratory insertion of carbenes derived from silyl- or carbonyl-stabilized diazoalkanes into Au-C bonds at temperatures >= -40 degrees C. Through a combined theoretical and experimental approach, key kinetic, thermodynamic, and structural details of this reaction manifold were elucidated. This study paves the way for homogeneous gold-catalyzed processes incorporating carbene migratory insertion steps. PMID- 29260870 TI - Reversible Lysine Derivatization Enabling Improved Arg-C Digestion, a Highly Specific Arg-C Digestion Using Trypsin. AB - The bottom-up proteomics approach has become an important strategy in diverse areas of biological research, and the enzymatic digestion is essential for this technology. Endopeptidase Arg-C catalyzing the hydrolytic cleavage of peptide bonds C-terminal to arginine could be an important protease in bottom-up proteomics. However, it has been seldom applied due to its low specificity and high cost. In this report, the reversible amine derivatization method (citraconylation and decitraconylation) was introduced and optimized toward a real Arg-C digestion using trypsin. Combination of the reversible derivatization and trypsin digestion (termed iArg-C digestion for improved Arg-C digestion) resulted in 64.2% more peptide identification (11 925 +/- 199 vs 7262 +/- 59) and significantly higher cleavage specificity (95.6% vs 73.6%) than the conventional Arg-C digestion. Comparison of iArg-C digestion with the widely used trypsin and Lys-C digestion revealed that iArg-C performed slightly better than Lys-C although not comparable to trypsin. Therefore, the well-established iArg-C digestion method is a promising approach for proteomics studies and could be used as the prior alternative digestion method to trypsin digestion in order to achieve higher proteome coverage. Data are available via ProteomeXchange with identifier PXD007994. PMID- 29260871 TI - Detecting Mechanochemical Atropisomerization within an STM Break Junction. AB - We have employed the scanning tunneling microscope break-junction technique to investigate the single-molecule conductance of a family of 5,15-diaryl porphyrins bearing thioacetyl (SAc) or methylsulfide (SMe) binding groups at the ortho position of the phenyl rings (S2 compounds). These ortho substituents lead to two atropisomers, cis and trans, for each compound, which do not interconvert in solution under ambient conditions; even at high temperatures, isomerization takes several hours (half-life 15 h at 140 degrees C for SAc in C2Cl4D2). All the S2 compounds exhibit two conductance groups, and comparison with a monothiolated (S1) compound shows the higher group arises from a direct Au-porphyrin interaction. The lower conductance group is associated with the S-to-S pathway. When the binding group is SMe, the difference in junction length distribution reflects the difference in S-S distance (0.3 nm) between the two isomers. In the case of SAc, there are no significant differences between the plateau length distributions of the two isomers, and both show maximal stretching distances well exceeding their calculated junction lengths. Contact deformation accounts for part of the extra length, but the results indicate that cis-to-trans conversion takes place in the junction for the cis isomer. The barrier to atropisomerization is lower than the strength of the thiolate Au-S and Au-Au bonds, but higher than that of the Au-SMe bond, which explains why the strain in the junction only induces isomerization in the SAc compound. PMID- 29260872 TI - Oxygen Atom Transfer to Cationic PCPNi(II) Complexes Using Amine-N-Oxides. AB - Three PCsp3P pincer ligands differing in the aryl group linking the phosphine arms with the anchoring carbon donor were used to support square planar Ni(II) bromide complexes 1-3Br. Exchange of the coordinating bromide anion for the more weakly coordinating triflate (OTf) or hexafluoroantimonate (SbF6) anions was accomplished by treatment with AgX or TlX salts to give compounds 1-3X; compounds 1OTf, 1SbF6, 2Br, 2OTf, 3Br, and 3SbF6 were all characterized by X-ray crystallography. The reactions of these Ni(II) compounds with the amine-N-oxide oxygen atom transfer agents ONMe3 and ONMePh2 were explored. For ONMe3, reactions with 2 equiv gave products in which one arm of the pincer ligand was oxidized to a P?O unit, with the other amine-N-oxide ligated to the Ni(II) center, forming products 5-6X; compounds 4OTf, 5OTf, and 6SbF6 were characterized crystallographically. Transient amine-N-oxide adducts prior to ligand oxidation were observed in some reactions. For the more effective O atom donor ONMePh2, reactions were very rapid and a second oxidation of the remaining phosphine arm was observed, producing a Ni(II) species with an OCO pincer ligand (7SbF6). All compounds were fully characterized. Experiments aimed at trapping transient Ni(IV) oxo intermediates (with cyclohexadiene, KH, and various Lewis acids) indicated that such species were not involved in the reaction. This was supported by density functional theory (DFT) computations at the B3PW91 level, which indicated that direct O atom insertion into the Ni-P bonds without the intermediacy of a Ni oxo species was the low-energy pathway. PMID- 29260873 TI - Topological Evidence of Previously Overlooked Ni+1-H...Ni H-Bonds and Their Contribution to Protein Structure and Stability. AB - Hydrogen-bonds (H-bonds) between backbone N-H donors and CO acceptors are central to our understanding of protein structure and stability. However, while interactions between backbone N atoms and the N-H of the following residue are also common, they have been ignored as potential H-bonds due to their bent geometry and the assumption that the amide N is a poor H-bond acceptor. Recently, we reported indirect experimental evidence that these interactions constitute functional H-bonds. We now report a combined atoms in molecules and noncovalent interaction theoretical analysis of electron density that unambiguously supports the characterization of these interactions as H-bonds. The calculations further suggest that the Ni+1-H...Ni H-bonds are largely electrostatic in nature and, importantly, that they make a significant contribution to stability. Thus, given their apparently frequent occurrence, Ni+1-H...Ni H-bonds likely make critical, but previously unrecognized, contributions to protein structure and function. PMID- 29260874 TI - Theoretical Study of pKa Values for Trivalent Rare-Earth Metal Cations in Aqueous Solution. AB - Molecular acidity of trivalent rare-earth metal cations in aqueous solution is an important factor dedicated to the efficiency of their extraction and separation processes. In this work, the aqueous acidity of these metal ions has been quantitatively investigated using a few theoretical approaches. Our computational results expressed in terms of pKa values agree well with the tetrad effect of trivalent rare-earth ions extensively reported in the extraction and separation of these elements. Strong linear relationships have been observed between the acidity and quantum electronic descriptors such as the molecular electrostatic potential on the acidic nucleus and the sum of the valence natural atomic orbitals energies of the dissociating proton. Making use of the predicted pKa values, we have also predicted the major ionic forms of these species in the aqueous environment with different pH values, which can be employed to rationalize the behavior difference of different rare-earth metal cations during the extraction process. Our present results should provide needed insights not only for the qualitatively understanding about the extraction and separation between yttrium and lanthanide elements but also for the prediction of novel and more efficient rare-earth metal extractants in the future. PMID- 29260875 TI - Ionic-Electronic Ambipolar Transport in Metal Halide Perovskites: Can Electronic Conductivity Limit Ionic Diffusion? AB - Ambipolar transport describes the nonequilibrium, coupled motion of positively and negatively charged particles to ensure that internal electric fields remain small. It is commonly invoked in the semiconductor community where the motion of excess electrons and holes drift and diffuse together. However, the concept of ambipolar transport is not limited to semiconductor physics. Materials scientists working on ion conducting ceramics understand ambipolar transport dictates the coupled diffusion of ions and the rate is limited by the ion with the lowest diffusion coefficient. In this Perspective, we review a third application of ambipolar transport relevant to mixed ionic-electronic conducting materials for which the motion of ions is expected to be coupled to electronic carriers. In this unique situation, the ambipolar diffusion model has been successful at explaining the photoenhanced diffusion of metal ions in chalcogenide glasses and other properties of materials. Recent examples of photoenhanced phenomena in metal halide perovskites are discussed and indicate that mixed ionic-electronic ambipolar transport is similarly important for a deep understanding of these emerging materials. PMID- 29260876 TI - Hydrophosphonodifluoromethylation of Alkenes via Thiyl-Radical/Photoredox Catalysis. AB - Visible-light-induced catalytic hydrophosphonodifluoromethylation of mono- and disubstituted alkenes using bromodifluoromethanephosphonate with a Hantzsch ester as the terminal reductant is reported. The combination of thiyl-radical catalysis with photoredox catalysis is important for achieving good chemoselectivity and high yields. PMID- 29260877 TI - Synthetic Studies on Presporolide, a Putative Enediyne Precursor of Sporolides. AB - A synthesis of the core framework of presporolide, which possesses both a strained bicyclo[7.3.0]dodecadiyne moiety and a distinctive macrolactone structure, is reported. This synthesis features: (i) a Cu-mediated O-arylation of a hindered tertiary alcohol using triarylbismuth reagent; (ii) stereoselective construction of the strained nine-membered diyne ring; and (iii) atroposelective formation of the macrolactone. PMID- 29260878 TI - Strategical Designing of Donor-Acceptor-Donor Based Organic Molecules for Tuning Their Linear Optical Properties. AB - Low-energy linear absorption spectrum of a series of 48 donor-acceptor-donor (D-A D) scheme based thiophone-benzo(bis-)X-diazole molecules with X = O, S, Se, or Te are calculated using time dependent density functional theory in order to propose strategical design of molecules that can efficiently absorb light in the infrared and visible region of the solar spectrum. Our study establishes that optical properties of the D-A-D based organic molecules significantly depend on the donor to-acceptor (D/A) ratio and the strength of the acceptor moiety. Thus, by choice of a suitable D/A ratio and type of the acceptor moiety, the linear absorption spectrum can be largely shifted, in general, while the optical gap can be engineered over a wide energy range of ~0.2-2.3 eV, in particular. It is also noticed that the increase in acceptor units (i.e., when D/A <= 1) leads to increase in steric hindrance in between them. This, in turn, disrupts the effective conjugation length and increases the optical gap. However, this effect is found to dominate strongly in the bis-configurations of the molecules as compared to the nonbis compositions. In order to reduce this effect for rational designing of effective D-A-D type chromophores with less steric hindrance, the role of pi-conjugated ethylene (-CH?CH-) linkage/spacer between the A-A units is explored further. Here, it is found that introduction of such linkage substantially decreases the steric hindrance and, thereby, the optical gap as well. Besides this, our study also highlights and explains the impact of the acceptor moiety in improving the absorption capabilities of these molecules in the low-energy region. PMID- 29260879 TI - Kinetics of the Strain-Promoted Oxidation-Controlled Cycloalkyne-1,2-quinone Cycloaddition: Experimental and Theoretical Studies. AB - Stimulated by its success in both bioconjugation and surface modification, we studied the strain-promoted oxidation-controlled cycloalkyne-1,2-quinone cycloaddition (SPOCQ) in three ways. First, the second-order rate constants and activation parameters (DeltaH?) were determined of various cyclooctynes reacting with 4-tert-butyl-1,2-quinone in a SPOCQ reaction, yielding values for DeltaH? of 4.5, 7.3, and 12.1 kcal/mol, for bicyclo[6.1.0]non-4-yne (BCN), cyclooctyne (OCT), and dibenzoazacyclooctyne (DIBAC), respectively. Second, their reaction paths were investigated in detail by a range of quantum mechanical calculations. Single-configuration theoretical methods, like various DFT and a range of MP2 based methods, typically overestimate this barrier by 3-8 kcal/mol (after inclusion of zero-point energy, thermal, and solvation corrections), whereas MP2 itself underestimates the barrier significantly. Only dispersion-corrected DFT methods like B97D (yielding 4.9, 6.4, and 12.1 kcal/mol for these three reactions) and high-level CCSD(T) and multireference multiconfiguration AQCC ab initio approaches (both yielding 8.2 kcal/mol for BCN) give good approximations of experimental data. Finally, the multireference methods show that the radical character in the TS is rather small, thus rationalizing the use of single reference methods like B97D and SCS-MP2 as intrinsically valid approaches. PMID- 29260880 TI - Comparison of two-dimensional fast spin echo T2 weighted sequences and three dimensional volume isotropic T2 weighted fast spin echo (VISTA) MRI in the evaluation of triangular fibrocartilage of the wrist. AB - OBJECTIVE: To compare image quality of three-dimensional volume isotropic T2 weighted fast spin echo (3D VISTA) and two-dimensional (2D) T2 weighted images (T2WI) for evaluation of triangular fibrocartilage (TFC) and to investigate whether 3D VISTA can replace 2D T2 WI in evaluating TFC injury. METHODS: This retrospective study included 69 patients who received wrist MRIs using both 2D T2 WI and 3D VISTA techniques for assessment of wrist pathology, including TFC injury. Two radiologists measured the signal-to-noise ratio (SNR) and the contrast-to-noise ratio (CNR) of the two sequences. The anatomical identification score and diagnostic performance were independently assessed by two interpreters. The diagnostic abilities of 3D VISTA and 2D T2 WI were analysed by sensitivity, specificity and accuracy for diagnosing TFC injury using surgically or clinically confirmed diagnostic reference standards. RESULTS: 17 cases (25%) were classified as having TFC injury. 2 cases (12%) were diagnosed surgically, and 15 cases (88%) were diagnosed by physical examination. 52 cases (75%) were diagnosed as having intact TFC. 8 of these cases (15%) were surgically confirmed, while the others were diagnosed by physical examination and clinical findings. The 3D VISTA images had significantly higher SNR and CNR values for the TFC than 2D T2 WI images. The scores of 3D VISTA's total length, full width and sharpness were similar to those of 2D T2 WI. We were unable to find a significant difference between 3D VISTA and 2D T2 WI in the ability to diagnose TFC injury. CONCLUSION: 3D VISTA image quality is similar to that of 2D T2 WI for TFC evaluation and is also excellent for tissue contrast. 3D VISTA can replace 2D images in TFC injury assessment. Advances in knowledge: 3D VISTA image quality is similar to that of 2D T2 WI for TFC evaluation and is also excellent for tissue contrast. 3D VISTA can replace 2D images in TFC injury assessment. PMID- 29260881 TI - Cardiovascular and Neuropsychiatric Events after Varenicline Use for Smoking Cessation. AB - RATIONALE: Varenicline aids in smoking cessation but has also been associated with serious adverse events. OBJECTIVES: The aim of this study was to determine the risks of cardiovascular and neuropsychiatric events after varenicline receipt in a real-world setting. METHODS: A population-based, self-controlled risk interval study using linked universal health administrative data from the diverse, multicultural population of Ontario, Canada, was conducted. In two separate analyses, new varenicline users between September 1, 2011 and February 15, 2014 were observed from 1 year before to 1 year after varenicline receipt. The relative incidences of cardiovascular and neuropsychiatric hospitalizations and emergency department visits in the 12 weeks after varenicline receipt (the risk interval) compared with the remaining observation period (the control interval) were estimated in two separate fixed-effect conditional Poisson regressions. Sensitivity analyses tested the robustness of the results. MEASUREMENTS AND MAIN RESULTS: Among 56,851 new users of varenicline, 6,317 cardiovascular and 10,041 neuropsychiatric hospitalizations and emergency department visits occurred from 1 year before to 1 year after receipt. The incidence of cardiovascular events was 34% higher in the risk compared with the control interval (relative incidence, 1.34; 95% confidence interval, 1.25-1.44). Findings were consistent in sensitivity analyses, most notably in those without any history of previous cardiovascular disease. The relative incidence of neuropsychiatric events was marginally significant in the primary (relative incidence, 1.06; 95% confidence interval, 1.00-1.13) but not all sensitivity analyses. CONCLUSIONS: Varenicline appears to be associated with an increased risk of cardiovascular but not neuropsychiatric events. PMID- 29260882 TI - Histogram analysis of apparent diffusion coefficient maps for assessing thymic epithelial tumours: correlation with world health organization classification and clinical staging. AB - OBJECTIVE: To investigate the value of apparent diffusion coefficients (ADCs) histogram analysis for assessing World Health Organization (WHO) pathological classification and Masaoka clinical stages of thymic epithelial tumours. METHODS: 37 patients with histologically confirmed thymic epithelial tumours were enrolled. ADC measurements were performed using hot-spot ROI (ADCHS-ROI) and histogram-based approach. ADC histogram parameters included mean ADC (ADCmean), median ADC (ADCmedian), 10 and 90 percentile of ADC (ADC10 and ADC90), kurtosis and skewness. One-way ANOVA, independent-sample t-test, and receiver operating characteristic were used for statistical analyses. RESULTS: There were significant differences in ADCmean, ADCmedian, ADC10, ADC90 and ADCHS-ROI among low-risk thymoma (type A, AB, B1; n = 14), high-risk thymoma (type B2, B3; n = 9) and thymic carcinoma (type C, n = 14) groups (all p-values <0.05), while no significant difference in skewness (p = 0.181) and kurtosis (p = 0.088). ADC10 showed best differentiating ability (cut-off value, <=0.689 * 10-3 mm2 s-1; AUC, 0.957; sensitivity, 95.65%; specificity, 92.86%) for discriminating low-risk thymoma from high-risk thymoma and thymic carcinoma. Advanced Masaoka stages (Stage III and IV; n = 24) tumours showed significant lower ADC parameters and higher kurtosis than early Masaoka stage (Stage I and II; n = 13) tumours (all p values <0.05), while no significant difference on skewness (p = 0.063). ADC10 showed best differentiating ability (cut-off value, <=0.689 * 10-3 mm2 s-1; AUC, 0.913; sensitivity, 91.30%; specificity, 85.71%) for discriminating advanced and early Masaoka stage epithelial tumours. CONCLUSION: ADC histogram analysis may assist in assessing the WHO pathological classification and Masaoka clinical stages of thymic epithelial tumours. Advances in knowledge: 1. ADC histogram analysis could help to assess WHO pathological classification of thymic epithelial tumours. 2. ADC histogram analysis could help to evaluate Masaoka clinical stages of thymic epithelial tumours. 3. ADC10 might be a promising imaging biomarker for assessing and characterizing thymic epithelial tumours. PMID- 29260883 TI - The Quality of Life of Children Under Chiropractic Care Using PROMIS-25: Results from a Practice-Based Research Network. AB - OBJECTIVES: To characterize pediatric chiropractic and assess pediatric quality of life (QoL). DESIGN: A prospective cohort. Setting/Locations: Individual offices within a practice-based research network located throughout the United States. SUBJECTS: A convenience sample of children (8-17 years) under chiropractic care and their parents. EXPOSURE: Chiropractic spinal adjustments and adjunctive therapies. OUTCOME MEASURES: Survey instrument measuring sociodemographic information and correlates from the clinical encounter along with the Patient Reported Outcomes Measurement Information System (PROMIS)-25 to measure QoL (i.e., depression, anxiety, and pain interference). Sociodemographic and clinical correlates were analyzed using descriptive statistics (i.e., frequencies/percentages, means, and standard deviations). The PROMIS-25 data were analyzed using scoring manuals, converting raw scores to T score metric (mean = 50; SD = 10). A generalized linear mixed model was utilized to examine covariates (i.e., sex, number of visits, and motivation for care) that may have played an important role on the PROMIS outcome. RESULTS: The original data set consisted of 915 parent-child dyads. After data cleaning, a total of 881 parents (747 females, 134 males; mean age = 42.03 years) and 881 children (467 females and 414 males; mean age = 12.49 years) comprised this study population. The parents were highly educated and presented their child for mainly wellness care. The mean number of days and patient visits from baseline to comparative QoL measures was 38.12 days and 2.74 (SD = 2.61), respectively. After controlling for the effects of motivation for care, patient visits, duration of complaint, sex, and pain rating, significant differences were observed in the probability of experiencing problems (vs. no reported problems) across all QoL domains (Wald = 82.897, df = 4, p < 0.05). Post hoc comparisons demonstrated the children were less likely to report any symptoms of depression (Wald = 6.1474, df = 1, p < 0.05), anxiety (Wald = 20.603, df = 1, p < 0.05), fatigue (Wald = 22.191, df = 1, p < 0.05), and pain interference (Wald = 47.422, df = 1, p < 0.05) after a trial of chiropractic care. CONCLUSIONS: The QoL of children improved with chiropractic care as measured by PROMIS. PMID- 29260884 TI - Engagement of stakeholders in the development of a Theory of Change for handwashing and sanitation behaviour change. AB - A Theory of Change (ToC) is an approach to map programmes aimed at inducing change in a specific context, with the goal of increasing their impact. We applied this approach to the specific case of handwashing and sanitation practices in low- and middle-income countries and developed a ToC as part of a systematic review exercise. Different existing sources of information were used to inform the initial draft of the ToC. In addition, stakeholder involvement occurred and peer review took place. Our stakeholders included methodological (ToC/quantitative and qualitative research) and content experts (WASH (Water, Sanitation, Hygiene)/behaviour change), as well as end-users/practitioners, policy-makers and donors. In conclusion, the development of a ToC, and the involvement of stakeholders in its development, was critical in terms of understanding the context in which the promotional programmes are being implemented. We recommend ToC developers to work with stakeholders to create a ToC relevant for practice. PMID- 29260885 TI - Long-Length Fiber Optic Near-Infrared (NIR) Spectroscopy Probes for On-Line Quality Control of Processed Land Animal Proteins. AB - This research was conducted using a spectral database comprising 346 samples of processed animal proteins (PAPs) with a range of compositions, analyzed using a Fourier transform near-infrared spectroscopy multichannel instrument (Matrix-F, Bruker Optics) coupled to a 100 m fiber optic cable. Using both its static and dynamic operating modes (on a conveyor belt), simulating the movement of the product in the plant, the predictive capabilities of both modes of analysis were assessed and compared, for the purposes of predicting moisture, protein, and ashes. The results show that both exhibit highly similar degrees of precision and accuracy for predicting these parameters. This research provides a foundation of scientific-technical knowledge, hitherto unknown, regarding the "on-line" incorporation of an instrument (equipped with a 100 m fiber optic cable) into a processing plant of by-products of animal origin. PMID- 29260886 TI - Sleep disturbance in patients with an implantable cardioverter defibrillator: Prevalence, predictors and impact on health status. AB - BACKGROUND: Sleep disturbances are highly prevalent in patients with cardiac diseases and associated with poor health outcomes. However, little is known about sleep disturbance in patients with an implantable cardioverter defibrillator. AIMS: We examined the prevalence and predictors of sleep disturbance and the impact on perceived health status in a Dutch cohort of implantable cardioverter defibrillator patients. METHODS: Patients ( n=195) enrolled in the Web-based distress program for implantable cardioverter defibrillator patients (WEBCARE) trial completed questionnaires at the time of implantable cardioverter defibrillator implantation, three, six and 12 months afterwards. Sleep disturbance was assessed with the corresponding item #3 of the Patient Health Questionnaire 9. RESULTS: At baseline, 67% ( n=130) reported sleep disturbance (cut off >=1). One year later, the prevalence was 57% ( n=112). Younger age (odds ratio=0.96, 95% confidence interval 0.92-0.99; p=0.012) and high negative affectivity/low social inhibition (odds ratio=4.47, 95% confidence interval 1.52 13.17; p=0.007) were associated with sleep disturbance at 12 months in adjusted analyses. Sleep disturbance was not associated with health status at 12 months. Charlson Comorbidity Index, anxiety, Type D personality and high negative affectivity/low social inhibition were associated with impaired health status at follow-up. CONCLUSIONS: Sleep disturbance was highly prevalent in patients with an implantable cardioverter defibrillator. Younger age and high negative affectivity predicted sleep disturbance 12 months post-implantation independent of other demographic, clinical, intervention and psychological covariates. Sleep disturbance was not associated with impaired health status at the 12-month follow up. PMID- 29260887 TI - Is Child Abuse Associated with Adolescent Obesity? A Population Cohort Study. AB - BACKGROUND: Child abuse is associated with obesity in adulthood through multiple mechanisms. However, little is known about the relationship between abuse and obesity during adolescence. The aim of this study was to investigate, using a birth cohort, whether there is an association between child abuse and overweight or obesity in adolescence. METHODS: This study utilizes data from the Avon Longitudinal Study of Parents and Children, a prospective cohort study based in South West England. Using data from the 4205 children with complete data at 13 and 16 years, we analyzed body mass index (BMI) and anonymous parental report of abuse. Abuse was categorized as emotional, physical, or sexual. A sub-sample of 3429 had BMI recorded at 18 years, enabling a longitudinal analysis of BMI trajectories. RESULTS: Using linear and logistic regression analysis, adjusting for sex and family adversity, no association was found between child abuse and BMI, BMI Z-scores, overweight, or obesity, at 13 or 16 years, with all confidence intervals straddling the null. There was weak evidence of a negative association between physical and emotional abuse and BMI trajectories between 13 and 18 years. CONCLUSIONS: No relationship was found between child abuse and adolescent obesity in this cohort. This challenges the assumption that adolescent obesity is linked to previous child abuse, as demonstrated for obesity in adult life. A further longitudinal study utilizing both parental and child reports with data record linkage, to improve reporting of abuse, and including neglect as an abuse category, would be desirable. PMID- 29260888 TI - Perceived control and health-related quality of life in heart transplant recipients. AB - BACKGROUND: Perceived control has been associated with improved mental health and health-related quality of life (HRQOL) in cardiac populations. However, this concept has not been well-studied in heart transplant groups. AIMS: We examine the relationship of perceived control to symptoms of anxiety and depression and HRQOL after transplant. We also examine the extent to which anxiety and depressive symptoms mediate the relationship between perceived control and HRQOL. METHODS: Our cross-sectional analysis included 113 adult heart transplant patients from the NEW HEART study. High versus low perceived control groups were determined by median split for chi-square and t-test analyses. Hierarchical multiple linear regression models were used to examine the influence of perceived control on symptoms of depression and anxiety and HRQOL. Mediation analyses included Baron and Kenny's four-step regression approach and Preacher and Hayes' bootstrapping technique to test the indirect effect of perceived control on HRQOL. RESULTS: Heart transplant patients who reported lower perceived control were more likely to be female ( p=0.003), and had significantly more depressive symptoms ( p<0.001) and anxiety ( p<0.001), and lower HRQOL ( p<0.001) than those with higher perceived control. Perceived control was a significant predictor in regression models of depressive and anxiety symptoms and HRQOL. In mediation analyses, depressive and anxiety symptoms mediated the effect of perceived control on HRQOL. CONCLUSION: Perceived control is associated with improved depressive and anxiety symptoms and HRQOL after transplant. The relationship between perceived control and HRQOL is mediated by depressive and anxiety symptoms. Future interventions should target perceived control to improve overall HRQOL. PMID- 29260889 TI - Doctor-patient relationship and quality of life in Irritable Bowel Syndrome: an exploratory study of the potential mediating role of illness perceptions and acceptance. AB - Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder characterised by unpredictable bowel symptoms. These can be difficult to manage, consequently impacting quality of life (QoL). In addition, a strained doctor patient relationship is independently reported in the qualitative literature. Given the doctor is often the first port of call for people with IBS, a difficult relationship may influence subsequent IBS management. Research suggests illness perceptions are important in determining IBS outcomes in therapy; however, their association with doctor-patient relationship and QoL is yet to be investigated. This exploratory study aimed to investigate the association between these constructs in IBS, as well as potential mediation by illness perceptions. Online questionnaires measuring doctor-patient relationship, illness perceptions, acceptance and QoL, were completed by 167 participants who reported an IBS diagnosis (144 female, mean age = 44.22 years, SD = 15.91 years). Bootstrapped pathway analysis was used to model the relationship and mediation effects. There was a significant positive correlation between patient-doctor relationship and QoL, r = .258, n = 167, p = .001. There was a significant indirect effect between doctor-patient relationship and QoL through illness coherence and acceptance (bootstrapped estimate = .058, 95%CI Lower-Upper = .02, .095, p = .002). No other indirect effects were observed in combination with good fit indices for the other illness perceptions. Findings suggest a doctor-patient relationship which fosters mutual understanding and helps patients make sense of symptoms, increases their ability to manage their IBS in a psychologically flexible manner, subsequently helping them maintain their QoL. PMID- 29260890 TI - Applicability of the Ben-Tovim Walker Body Attitude Questionnaire in Moslem women. AB - There are some valuable questionnaires to assess the body attitude but applicability of those in Moslem women is unknown and the aim of this study was assessment of the validity and reliability of the Iranian-translated versions of the Ben-Tovim Walker Body Attitudes Questionnaire (BAQ) in Iranian women. The BAQ 44 item was administered to 304 healthy non-pregnant Iranian women. A confirmatory factor analysis was carried out. The internal consistency reliability and Inter-correlations of the BAQ subscales and concurrent validity were assessed. The results showed that 9 out of 44 items had insignificant regression weights on the respective factors that further were nominated to deletion. The 6-factor model has an acceptable fit with the data. The internal consistency was .91 for all scale of 35-item BAQ. The coefficient of repeatability (ICC) respectively were .78, .77, .89, .94, .86 and .79 for attractiveness, disparagement, feeling fat, salience of weight/shape, lower body fat and strength and fitness. Results showed that the 6-factor model the 35-item questionnaire is appropriate for evaluating body attitude in Moslem women. PMID- 29260891 TI - TNF-alpha antagonism with etanercept enhances penile NOS expression, cavernosal reactivity, and testosterone levels in aged rats. AB - Erectile dysfunction (ED) has been reported to be associated with inflammation. This study investigated the effects of tumor necrosis factor alpha (TNF-alpha) inhibitor etanercept on penile neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) expressions, testosterone concentrations, neurogenic and endothelium-dependent relaxations of corpus cavernosum (CC), and circulating and cavernosal levels of inflammatory markers in aged rats. Animals were separated into control, aged, and etanercept-treated aged groups. Aged rats displayed significantly increased serum and cavernosal TNF alpha, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule (ICAM-1) levels, and decreased penile nNOS and eNOS expressions and serum testosterone levels compared with controls. In etanercept-treated aged group, NOS expressions were similar to that of the control group. The circulating and cavernosal concentrations of TNF-alpha, CRP, MCP-1, ICAM-1, and testosterone were also normalized by etanercept. Neurogenic and endothelium-dependent relaxant responses significantly decreased in aged rats and etanercept treatment markedly improved these relaxation responses. Our findings indicate that aging decreases penile NOS expression, neurogenic and endothelium-dependent relaxations of CC, and also suppresses serum testosterone levels by inducing inflammatory response that may contribute to the development of ED. TNF-alpha antagonism may be a novel strategy to treat aging-associated ED. PMID- 29260893 TI - Accuracy of coronary artery calcium scoring with tube current reduction by 75%, using an adaptive iterative reconstruction algorithm. AB - OBJECTIVE: To assess the accuracy of an iterative reconstruction (IR) technique for coronary artery calcium scoring with reduced radiation dose. METHODS: 163 consecutive patients underwent twofold scanning by 320-row detector CT at 120 kVp. A low-dose scan at 25% tube current but with standard scan length (14 cm) was followed by a standard dose scan with routine tube current but reduced scan length (10 cm). Reduced dose images were constructed using filtered back projection (FBP) and IR (adaptive iterative dose reduction in three dimensions). The standard dose scan reconstructed with FBP served as the gold standard for comparisons. Image noise and Agatston coronary calcium scores were determined and compared between the groups. RESULTS: Compared with FBP at standard dose, noise at reduced dose increased markedly with FBP but remained low with IR. Mean Agatston score with FBP at reduced dose showed a significant increase as compared with FBP at standard dose. No significant difference was observed when applying IR at reduced dose. At reduced dose, 38 (23.3%) patients were reassigned to a different cardiovascular risk category with FBP but only 8 (4.9%) with IR. Out of 47 patients with a zero Agatston score, 15 patients (31.9%) were false-positive with FBP at reduced dose, but no false positives were found with IR. CONCLUSION: IR allows accurate coronary artery calcium scoring with a radiation dose reduced by 75%. Advances in knowledge: The application of adaptive iterative dose reduction in three dimensions allows the maintenance of accurate Agatston scores and risk stratification at significantly reduced tube current, thus reducing the patient's exposure to ionizing radiation. PMID- 29260894 TI - The Use of the Patient Reported Outcomes Measurement Information System and the RAND VSQ9 to Measure the Quality of Life and Visit-Specific Satisfaction of Pregnant Patients Under Chiropractic Care Utilizing the Webster Technique. AB - OBJECTIVE: To quantify the quality of life (QoL) and visit-specific satisfaction of pregnant women. DESIGN: A prospective cohort within a practice-based research network (PBRN). Setting/Locations: Individual chiropractic offices. SUBJECTS: Pregnant women (age >=18 years) attending chiropractic care. INTERVENTION(S): Chiropractic care (i.e., The Webster Technique, spinal adjustments, and adjunctive therapies). MAIN OUTCOME MEASURES: The RAND VSQ9 to measure visit specific satisfaction and the Patient Reported Outcomes Measurement Information System (PROMIS(r))-29 to measure QoL. RESULTS: A convenience sample of 343 pregnant patients (average age = 30.96 years) comprised their study population. They were highly educated with 75% attaining a 2-year associate's degree or higher. The pregnant patients presented for chiropractic care with a mean week of gestation of 25.67 weeks (median = 28 weeks; range = 0-42 weeks) and parity (i.e., the number of live births) of 0.92 live births (median = 1; range = 0-6). From baseline (i.e., at study entrance with minimum first visit) and comparative (i.e., following a course of chiropractic care), the VSQ9 measurements revealed increasingly high satisfaction on the part of the subjects (i.e., the mean difference of baseline minus comparative measures = -0.7322; p < 0.005). The median number of visits (i.e., visits attended) at baseline and comparative measures was 1.00 (standard deviation [SD] = 22.69) and 3.30 (SD = 22.71), respectively. Across outcomes, QoL improved from baseline to comparative measurement after holding constant for visit number and time lapse, trimester of pregnancy, and care provider type. There was a reduction in mean T scores associated with fatigue (p < 0.05), pain interference (p < 0.05), sleep disturbance (p < 0.05), and an improvement in satisfaction with social roles (p < 0.05). A significant decrease was also found with pain interference (p < 0.05). No evidence was found that anxiety (p = 0.1404) or depression (p = 0.8785) changed. CONCLUSION: A PBRN study was successfully implemented among chiropractors to find pregnant patients highly satisfied and their QoL scores improving with care beyond chance. PMID- 29260895 TI - Surgical personae. PMID- 29260896 TI - The surgical personality: does it exist? AB - Introduction This study aims to answer the question of whether surgeons have different personalities to non-surgeons. Methods Members of the Royal College of Surgeons of England were sent an email survey containing 50 standard questions from the Five Factor personality assessment, which scores each respondent in five key personality traits (conscientiousness, agreeableness, neuroticism, openness, extroversion). Results were analysed and compared with a population-level data set from a survey conducted by the BBC. Results Five hundred and ninety-nine surgeons completed the survey. Analysis showed that surgeons scored significantly higher for conscientiousness, agreeableness, openness and neuroticism than non surgeons (P < 0.05). Further analysis showed that female surgeons scored higher in openness and extroversion relative to the population average and that surgeons become more prone to neuroticism than non-surgeons as they age. Conclusions The results support the notion of a surgical personality, as well as indicating that female surgeons have significantly different personality profiles from male surgeons, and that age affects surgeons' personalities in different ways to non surgeons. PMID- 29260897 TI - Coccydynia - could age, trauma and body mass index be independent prognostic factors for outcomes of intervention? AB - Introduction The aetiology of coccydynia can be multifactorial, with several associated factors such as obesity, female gender and low mood. The long-term results of operative interventions, such as manipulation under anaesthesia and coccygectomy are variable, ranging from 63-90%. Materials and methods Our aim was to identify whether age, trauma and body mass index (BMI) were independent prognostic factors in coccydynia treatment. All patients who presented to the Royal Derby Hospital with a primary diagnosis of coccydynia between January 2011 and January 2015 who had injections, manipulation under anaesthesia or coccygectomy were included. We used patient-reported satisfaction score as the primary outcome measure. We hypothesised that patients with preceding history of trauma and with high BMI (> 25) would be less satisfied. We divided patient BMI into four groups, following World Health Organization guidelines: group A (18.5 24.9), group B (25-29.9), group C (30-39.9) and group D (> 40). Results A total of 748 patients were diagnosed with coccydynia. Of these, 201 patients had 381 injections, 40 had 98 manipulations under anaesthesia and 9 had coccygectomy. Mean age was 46.4 years; 26% of patients had trauma to the coccyx. The mean time to follow-up was 7.3 months. We found a statistically significant difference (P = 0.03) between satisfaction scores in groups B and D. Patients who had trauma improved significantly (P = 0.04). The odds ratio calculation of coccygectomy and BMI revealed a higher risk of coccygectomy in Group A. Discussion This is the first study to establish BMI and trauma as independent prognostic factors for coccydynia treatment. Our hypothesis that patients with higher BMI would have lower satisfaction levels has been proven true. PMID- 29260899 TI - Ascorbate-conjugated nanoparticles for promoted oral delivery of therapeutic drugs via sodium-dependent vitamin C transporter 1 (SVCT1). PMID- 29260900 TI - Trends in dextromethorphan cough and cold products: 2000-2015 National Poison Data System intentional abuse exposure calls. AB - CONTEXT: Recent restrictions in access to and availability of dextromethorphan (DXM) cough and cold medications may correlate with changes in abuse exposures. OBJECTIVE: To extend and update existing knowledge about DXM abuse, we describe recent trends and patterns of calls to poison control centers involving DXM abuse, by demographics, geography, common brands, and medical outcomes. METHODS: We utilized data from the National Poison Data System (NPDS) maintained by the American Association of Poison Control Centers (AAPCC), which captures data on calls to U.S. poison centers on a near real-time basis. We analyzed demographic, geographic, brand and medical outcome data for single-substance DXM cough and cold product intentional abuse exposure calls in multiple age groups reported to NPDS from 2000 to 2015. RESULTS: The annual rate of single-substance DXM intentional abuse calls tripled from 2000 to 2006 and subsequently plateaued from 2006 to 2015. The highest abuse call rate was observed among adolescents 14-17 years old, where the mean annual number of calls was 1761 per year, corresponding to an annual rate of 103.6 calls per million population. From 2006 to 2015, the rate for single-substance DXM abuse calls among adolescents 14-17 years decreased by 56.3%, from 143.8 to 80.9 calls per million population. CONCLUSION: DXM intentional abuse exposure call rates have declined among adolescents 14-17 years, since their peak in 2006. The observed decline in DXM abuse call rates corresponds to a period of growing public health efforts to curtail the abuse of over-the-counter (OTC) DXM containing products, particularly among adolescents. Further evaluation of state-level sales and abuse trends among adolescents would be valuable to better understand how restricted availability of OTC DXM cough and cold products and other efforts may affect abuse rates. PMID- 29260901 TI - Development and physicochemical, toxicity and immunogenicity assessments of recombinant hepatitis B surface antigen (rHBsAg) entrapped in chitosan and mannosylated chitosan nanoparticles: as a novel vaccine delivery system and adjuvant. AB - In this study chitosan nanoparticles (CS NPs) and mannosylated chitosan nanoparticles (MCH NPs) loaded with recombinant hepatitis B surface antigen (rHBsAg) was synthesized as a vaccine delivery system and assessed toxically and immunologically. The physicochemical properties of the nanoparticles (NPs) were determined by methods including scanning electron microscope (SEM) and dynamic light scattering (DLS). The morphology of the NPs was semi spherical and the average diameter of the loaded CS and MCH NPs was found to be 189 and 239 nm, respectively. The release studies showed that after the initial burst, both of the loaded NPs provided a continuous and slow release of the antigens. 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed concentration and time dependent toxicity profile for both formulations, but rHBsAg loaded CS nanoparticle showed higher toxicity due to smaller particle size and larger zeta potential. Abnormal toxicity test (ATT) results showed no signs of toxicity in mice and guinea-pigs treated with loaded MCHNPs. Stability test for six months showed acceptable changes in size, surface charge, and antigenicity for loaded MCH nanoparticles. Finally, in vivo immunogenicity study revealed greater adjuvant capability of MCH nanoparticles than others formulations. Our results showed MCH NPs can be used as a controlled and targeted vaccine delivery system. PMID- 29260902 TI - Correction to: El-Housiny et al., Fluconazole-loaded solid lipid nanoparticles topical gel for treatment of pityriasis versicolor: formulation and clinical study. PMID- 29260903 TI - Antibiotic Resistance Profiling, Analysis of Virulence Aspects and Molecular Genotyping of Staphylococcus aureus Isolated in Sicily, Italy. AB - Staphylococcus aureus is the major cause of foodborne diseases worldwide. In this retrospective study, 84 S. aureus strains were characterized. The collection comprises 78 strains isolated during 1998 and 2014 from dairy products and tissue samples from livestock bred for dairy production in Sicily. One isolate was obtained from a pet (dog), one from an exotic animal (a circus elephant), and four human isolates were obtained during a severe food poisoning outbreak that occurred in Sicily in 2015. All the strains were characterized by pulsed-field gel electrophoresis (PFGE), for antibiotic resistance and presence of toxin genes. PFGE results showed 10 different pulsotypes, with three relatively frequent and three unique. The antibiotic resistance profiling showed that penicillin G (35.7%) and tetracycline (20.2%) resistance is largely spread. Most isolates contained at least one toxin gene making them a potential threat for public health. Enterotoxin sec gene was observed in 28.6% and seg in 23.8% of the strains, respectively; the human isolates were the only ones to concurrently harbor both seg and sei genes. In addition, 24 isolates were randomly selected and analyzed by multilocus sequence typing. Interestingly, the analysis showed the presence of 12 sequence types (STs), of which 6 were novel. One of them, ST700, was detected in 29% of the isolates and was found to be spread throughout Sicily. ST700 has been present in the island for almost 16 years (1998-2014) and it shows no host preference since it was isolated from different ruminant species. Four human isolates shared both the pulsotype (PT10) and the sequence type (ST9), as well as the virulence genes (seg-sei); this observation suggests that the isolates originated from a single clone, although they were obtained from two different individuals. PMID- 29260904 TI - Ulipristal acetate for the management of acute heavy menstrual bleeding without fibroids. AB - Heavy menstrual bleeding is a common condition among women of childbearing age. Although hysterectomy was the usual approach in acute cases in the past, other minimally invasive therapies or pharmacological alternatives, such as the levonorgestrel intrauterine device have shown to be highly effective. This case report presents the case of a pluripathological patient with acute heavy menstrual bleeding and severe anemia, who was successfully managed with ulipristal acetate, a selective progesterone receptor modulator. Bleeding control was achieved in 6 d without side effects, avoiding the need for surgery. This report suggests that ulipristal acetate could be useful in the treatment of acute uterine bleeding even in a structurally normal uterus without fibroids. PMID- 29260905 TI - LncRNA TSIX promotes osteoblast apoptosis in particle-induced osteolysis by down regulating miR-30a-5p. AB - OBJECTIVE: This study aims to investigate the role of TSIX/miR-30a-5p axis in particle-induced osteolysis (PIO). METHOD: PIO mouse model was established by the implantation of Co-Cr-Mo metal particles (CoPs). MC3T3-E1 cells received CoPs stimulation. Bone mineral density (BMD) in the skull was detected to evaluate PIO development. The expression of TSIX and miR-30a-5p was detected by using qRT-PCR. Osteoblast apoptosis was measured using flow cytometry. RNA pull-down was used to verify the regulatory relationship between TSIX and miR-30a-5p. RESULT: The results showed that BMD of the skull in PIO mice was significantly decreased compared with control mice, which indicated that the PIO model was established successfully. Moreover, CoPs could up-regulate TSIX level, down-regulate miR-30a 5p expression, and promote osteoblast apoptosis in vivo and in vitro. The results also found that TSIX negatively regulated miR-30a-5p expression, and knockdown of TSIX inhibited Runx2 expression. As expected, miR-30a-5p inhibitor could reverse the inhibition of si-TSIX on osteoblast apoptosis. CONCLUSION: TSIX played a pivotal role in PIO development by negatively regulating miR-30a-5p. PMID- 29260906 TI - Gender differences in sleep habits and quality and daytime sleepiness in elementary and high school teachers. AB - The extensive workload of teachers inside and outside the classroom may contribute to sleep problems. Such problems may occur more frequently in women due to the combination of professional demands, domestic tasks, and their relatively greater sleep needs compared to men. The objective of this cross sectional study was to evaluate the influence of gender on sleep habits and quality, and daytime sleepiness in a sample of 243 teachers (77 men and 166 women) using questionnaires. Linear regression models were used to examine the effect of gender on sleep measures; the unadjusted model considered only gender and the adjusted model considered chronotype and work characteristics as potential confounders. Bedtimes of women were significantly earlier than men during the week, but not on weekends, in the unadjusted and adjusted models. Time in bed was longer for women throughout the week and weekend in the unadjusted model. However, in the adjusted model, this statistical significance disappeared, and longer time in bed during the week was associated with teaching in one shift and for both levels of education. In addition, the female gender was associated with higher sleepiness scores compared to males in both models, and worse sleep quality in the adjusted model. Also, sleep quality was worse in subjects working in three shifts and in both types of schools (public and private). The tendency to eveningness was associated with later bedtimes and wake up times during both week days and weekends, higher irregularity of bedtimes and wake up times, and higher sleepiness scores in the adjusted model. Therefore, we suggest that female teachers do not fulfill their sleep needs and show higher levels of diurnal sleepiness and poor sleep quality that can be modulated by chronotype and some work characteristics. More studies are needed to evaluate the role of double workload on this pattern. PMID- 29260907 TI - Morning bright light exposure has no influence on self-chosen exercise intensity and mood in overweight individuals - A randomized controlled trial. AB - : Overweight is a worldwide increasing public health issue. Physical exercise is a useful countermeasure. Overweight individuals choose rather low exercise intensities, but especially high exercise intensities lead to higher energy expenditure and show beneficial health effects compared to lower exercise intensities. However, especially in the morning higher exercise intensities are likely to be avoided due to higher subjective effort. Bright light exposure has shown to increase maximum performance. The aim of this study was to investigate if bright light exposure can also increase self-chosen exercise intensity. We hypothesized that morning bright light exposure increases self-chosen exercise intensity of subsequent exercise through increased mood and reduced sleepiness in overweight individuals. In this randomized controlled single-blind parallel group design, 26 overweight individuals (11 males, 15 females; age 25 +/- 5.7 years; body mass index 28.9 +/- 2.1 kg/m2) underwent three measurement appointments. On the first appointment, subjects performed a cardiopulmonary exercise test to measure maximum oxygen uptake (VO2max). Two days later a 30-min exercise session with self-chosen exercise intensity was performed for familiarization. Then subjects were randomly allocated to bright light (~4400 lx) or a control light (~230 lx) condition. Three to seven days later, subjects were exposed to light for 30 min starting at 8:00 am, immediately followed by a 30-min exercise session with persisting light exposure. Multidimensional mood questionnaires were filled out before and after the light exposure and after the exercise session. The primary outcome was the mean power output during the exercise session and the secondary outcome the rating on the three domains (i.e. good-bad; awake-tired; calm-nervous) of the multidimensional mood questionnaire. Mean power output during the exercise session was 92 +/- 19 W in bright light and 80 +/- 37 W in control light, respectively. In the multivariate analysis adjusted for VO2max, the mean power output during the exercise session was 8.5 W higher (95% confidence interval -12.7, 29.7; p = 0.416) for participants in bright light compared to control light. There were no significant differences between the groups for any of the three domains of the questionnaire at any time point. This is in contrast to longer lasting intervention studies that show positive influences on mood and suggests that bright light therapy requires repetitive sessions to improve mood in overweight individuals. In conclusion bright light exposure does not acutely increase self-chosen exercise intensity or improve mood in a 30-min exercise session starting at 08:30. However, regarding the fact that overweight is a worldwide and rapidly increasing public health issue even small increases in exercise intensity may be relevant. The trend toward superiority of bright light over control light implicates that further studies may be conducted in a larger scale. ABBREVIATIONS: VO2max: maximum oxygen uptake; 95% CI: 95% confidence interval; SD: standard deviation. PMID- 29260908 TI - Chemical investigation of metabolites produced by an endophytic fungi Phialemonium curvatum from the leaves of Passiflora edulis. AB - Phialemonium curvatum, an endophytic fungus isolated from the leaves of Passiflora edulis was cultured in potato dextrose broth (PDB) media and chromatographic separation of the EtOAc extract of the broth and mycelium led to the isolation of 4-hydroxybenzoic acid (1), 3-indole acetic acid (2), solaniol (3), uracil (4), uridine (5) and glycerol (6). Compound 2 showed a weak antifungal activity against Cladosporium cladosporioides. This is the first report of the isolation of the endophytic fungus P. curvatum from P. edulis and complete 13CNMR assignments of 3. PMID- 29260909 TI - Endoscopic neuroendoscopy using a novel ventricular access port. AB - BACKGROUND: Hydrocephalus remains an important aspect of neurosurgical care and in select circumstances, the endoscopic third ventriculostomy (ETV) continues to remain an important treatment. In our initial experience of ETV using the commercially available plastic ventricular ports we found them both restrictive and expensive. Following this experience, we developed a stainless steel ventricular access port (VAP). We present our novel method of access involving this non-disposable ventricular port. METHOD: We have developed a series of custom-made, 316-grade stainless steel VAPs designed specifically for our ventricular endoscopes. Following a standard Burr-hole, cannulation of the lateral ventricle is performed inserting this port and removing the trocar allowing free access using a standard ventriculoscope without the requirement for disposable plastic ports. Since 2008 our unit has used a standard method of ventricular access using this device. We present our long-term experience of cases of endoscopic ventriculoscopy and ventriculostomy using this method of ventricular access. RESULTS: From December 2008 to January 2016, 56 patients underwent an endoscopic third ventriculostomy using the stainless steel ventricular port. Two 2 patients (3.6%) had a recorded complication in the form of minor self-limiting intraventricular haemorrhage. No cases of infection or mortality were noted in this patient series. CONCLUSION: We demonstrate our long term experience with a non-disposable VAP for ventricular access. This method remains safe with results that are comparable to published series. We suggest this method may be a less expensive and safe alternative to standard disposable methods of ventricular access. PMID- 29260910 TI - The Association Between the FTO rs9939609 Variant and Malignant Pleural Mesothelioma Risk: A Case-Control Study. AB - AIMS: Despite the established link between malignant pleural mesothelioma (MPM) and asbestos exposure, genetic risk factors may play a key role in MPM pathogenesis. The rs9939609 polymorphism in the FTO gene has recently been implicated as a risk factor for some types of cancer, such as breast, pancreatic, and prostate cancers. FTO variation is associated with altered adipocytokine expression and oxidative stress inflammation, which may influence asbestos mediated-carcinogenesis. This is the first study to investigate a possible association between this polymorphism and MPM risk. MATERIALS AND METHODS: FTO rs9939609 (T >A) genotypes were screened using a TaqMan(r) Genotyping Assay in a total of 235 Egyptian subjects (86 MPM patients versus 149 controls). The chi square test and logistic regression were used to evaluate the association between the candidate variant and MPM risk using a case-control design. RESULTS: In the additive genetic model, the AT and AA genotypes were associated with a 2.48-fold (95% confidence intervals [CI] = 1.04-5.92, p = 0.04) and a 3.46-fold (95% CI = 0.99-12.01, p = 0.051) increase in the odds of developing MPM, respectively, when compared to the TT genotype after adjustment for body mass index, age, and gender. Additionally, in the dominant genetic model AT/AA genotypes were associated with a 2.63-fold increase in the odds of developing MPM (95% CI = 1.13 6.12, p = 0.025). CONCLUSIONS: The present study shows for the first time that rs9939609 polymorphism in the FTO gene may be a genetic risk factor for MPM. This study highlights the association of this genetic polymorphism with cancer susceptibility, and therefore, it should be investigated in various other populations, in relation to different types of cancer, and with larger sample sizes. PMID- 29260911 TI - A retrospective investigation of the relationship between baseline covariates and rate of ALSFRS-R decline in ALS clinical trials. AB - The revised ALS functional rating scale (ALSFRS-R) is a longitudinal measure of global function commonly used to assess progression of amyotrophic lateral sclerosis (ALS), and as an endpoint in ALS clinical trials. Understanding how baseline covariates affect the rate of functional decline in ALS offers valuable information to clinical trialists. We used a mixed modeling approach in a retrospective study of the pooled resource open-Access ALS clinical trials database to elucidate the associations between baseline covariates and the rate of ALSFRS-R decline over time. In a cohort of 3203 patients followed for an average of 337 days, older age at disease onset (p < 0.001), less time since disease onset (p < 0.001), and bulbar site of onset (p < 0.001) were associated with a significantly faster decline of the ALSFRS-R, while sex did not have a statistically significant effect (p = 0.82). Selective inclusion of 'age at disease onset' and 'time since disease onset' as covariates provided the best tradeoff between model fit and model precision. The effect of bulbar onset on rate of disease progression was primarily due to accelerated decline in the bulbar subscale of the ALSFRS-R. These findings, which are novel in the clinical trial time frame, contribute to the understanding of disease trajectory in ALS and can be used to guide future design and analysis of clinical trials. PMID- 29260913 TI - Invited Brief Commentary on the Article "Breast Cancer Association with Cytomegalo Virus - a Tertiary Center Case-Control Study" Is Cytomegalo Virus a Breast Cancer Etiologic Risk Factor? PMID- 29260912 TI - Improvement of chemosensitivity and inhibition of migration via targeting tumor epithelial-to-mesenchymal transition cells by ADH-1-modified liposomes. AB - How to overcome drug resistance and prevent tumor metastasis is key to the success of malignant tumor therapy. In this paper, ADH-1 peptide-modified liposomes (A-LP) have been successfully constructed for restoring chemosensitivity and suppressing cancer cell migration. With a particle size of about 90 nm, this functionalized nanocarrier was loaded with fluorescent probe or paclitaxel (PTX). Cellular uptake studies showed that A-LP facilitated the delivery of anticancer drug to tumor cells undergoing EMT. Interestingly, this nanocarrier enhanced chemosensitivity by assessing the cell activity using CCK-8 assay. Further, the results of Wound scratch assay and Transwell migration assay showed the inhibition effect of this nanocarrier on tumor cell migration. Moreover, this nanocarrier exhibited significant tumor-targeting ability and anti tumor efficacy in vivo. Collectively, A-LP might be a novel targeted drug delivery system to enhance the efficacy of chemotherapy and prevent tumor metastasis. PMID- 29260914 TI - Coping and suicide risk in high risk psychiatric patients. AB - BACKGROUND: A dysfunctional use of coping strategies has repeatedly been linked to suicidal behaviour in non-psychiatric populations. However, data regarding association between coping strategies and suicidal behaviour in psychiatric populations are limited. AIMS: The aim of the study was to investigate the possible relationship between self-reported suicide risk, suicidal ideation and coping strategies in three psychiatric cohorts. METHOD: Three cohorts of psychiatric patients were involved in the study; recent suicide attempters (n = 55), suicide attempters at follow-up 12 years after a suicide attempt (n = 38) and patients with ongoing depression without attempted suicide (n = 72). Patients filled in the self-rating version of The Suicide Assessment Scale (SUAS-S) from which items no. 17-20 addressing current suicidal ideation were extracted. To investigate coping strategies, the Coping Orientation of Problem Experience Inventory (COPE) was used. RESULTS: In all cohorts, regression analyses showed that only avoidant coping was significantly correlated with the scores of SUAS-S adjusted for covariates. The items no. 17-20 correlated significantly to avoidant coping but not with other coping strategies in all cohorts. CONCLUSION: The results of this study indicate that among coping strategies only avoidant coping may be associated with suicide risk in psychiatric patients independently of history of attempted suicide. PMID- 29260915 TI - (off)Targeting UPR signaling: the race toward intervening ER proteostasis. PMID- 29260916 TI - Eudragit S100 coated microsponges for Colon targeting of prednisolone. AB - CONTEXT: Microsponge is a novel approach for targeting the drug to the colon for the management of colon ailments such as inflammatory bowel disease. OBJECTIVE: Prednisolone loaded microsponges (PLMs) were prepared and coated with Eudragit S 100 (ES) and evaluated for colon-specific drug delivery. MATERIALS AND METHODS: PLMs were prepared using quasi emulsion solvent diffusion technique using ethyl cellulose, triethylcitrate (1% v/v, plasticizer) and polyvinyl alcohol (Mol. Wt. 72 kDa, emulsifying agent). The developed microsponges were compressed into tablets via direct compression technique using sodium carboxymethyl cellulose (Na CMC) and magnesium stearate as super-disintegrant and lubricant, respectively. The tablets were then coated with ES to provide protection against harsh gastric environment and manifest colon-specific drug release. RESULTS: PLMs were found to be nano-porous spherical microstructures with size around 35 um and 86% drug encapsulation efficiency. Finally, they were compressed into tablets which were coated with Eudragit S 100 In vitro drug release from ES coated tablets was carried out at various simulated gastrointestinal fluids i.e. 1 hr in SGF (pH 1.2), 2 to 3 h in SIF (pH 4.6), 4-5 h in SIF (pH 6.8), and 6-24 h in SCF (pH 7.4) and the results showed the biphasic release pattern indicating prolonged release for about 24 h. DISCUSSION AND CONCLUSION: In vitro drug release studies revealed that drug starts releasing after 5 h by the time PLMs may enter into the proximal colon. Hence maximum amount of drug could be released in the colon that may result in reduction in dose and dose frequency as well as side effects of drug as observed with the conventional dosage form of prednisolone. PMID- 29260917 TI - How have our clocks evolved? Adaptive and demographic history of the out-of African dispersal told by polymorphic loci in circadian genes. AB - The mechanism of the molecular circadian clocks is currently understood as a transcription/translation feedback loop involving more than ten genes. Genetic variation at some of loci in these genes has been shaped by adaptation to environmental factors. In particular, latitudinal clines in allele frequency were documented in several animal species, but the contradictory conclusions were drawn from the results of rare human studies. Here we tested whether the out-of African dispersal of human populations to higher latitudes of the Eurasian continent was associated with latitude-dependent shifts in allele frequency at polymorphic loci in genes of three (reference, circadian and skin pigmentation) groups. In order to detect the genetics-based signatures left by latitude-driven adaptation and to distinguish them from the confounding effects of population demographic history, we analyzed allele frequencies in 1594 individuals from 5 African and 11 Eurasian populations of the 1000 Genomes Project Phase 3. Up to 80 polymorphisms with global minor allele frequency > 0.2 were sampled from each of 36 genes (1665 polymorphisms in total). As expected, percentage of polymorphisms demonstrating both significantly enlarged differentiation of Eurasian populations on allele frequency and significant correlation between latitude and allele frequency was significantly higher in pigmentation genes compared to circadian genes and in circadian genes compared to reference genes. We also showed that the latitude-driven adaptation can be separated from genetic consequences of demographic perturbations by comparison of results obtained for the whole set of 16 African and Eurasian populations with results for only Eurasian populations that share the common demographic history. The revealed latitudinal clines in allele frequency seemed to be shaped by polygenic selection occurring by small allele frequency shifts spread across many loci in circadian and non-circadian genes. The present results provided a rationale for necessity to facilitate candidate gene studies by prioritizing genetic markers of chronotype. PMID- 29260918 TI - Combination of doxorubicin with harmine-loaded liposomes exerting synergistic antitumor efficacy. AB - CONTEXT: Long-circulation (PEGLip), pH-sensitive (PEOzLip), and active targeted liposomes (PEG-TATLip)-loading doxorubicin (DOX) and harmine (HM) were prepared. Their physicochemical properties and antitumor effect were investigated. OBJECTIVES: The aims of the present study were to evaluate synergistic antitumor efficacy. MATERIALS AND METHODS: Liposomes were prepared by using thin-film dispersion, active drug-loading and target post-insertion method. Subsequently physiochemical properties including particle size distribution, zeta potential, entrapment efficiency (EE), drug-loading content and in-vitro release were determined. Besides, the in vitro cytotoxicity of free drugs and drug-loaded liposomes was explored by using a Sulforhodamine-B Staining assay and the combination index values (CI Value) were calculated. Finally, the cellular uptake experiments by MCF-7cells were carried out via flow cytometry. RESULTS AND DISCUSSION: All liposomes enhanced the antitumor effect significantly compared to free drugs. Among liposomes, PEG-TATLip enhanced the antitumor effect significantly compared to others. DOX and HM had moderate synergism with CI Value 0.85 for free drugs, 0.81 for PEGLip, 0.72 for PEOzLip, and 0.84 for PEG-TATLip respectively when the weight ratio of two drugs was 1:2. Moreover, the similarity between DOX and HM such as physicochemical properties, in vitro release modes and in vitro uptake kinetics characteristics when they were in the same formulations proved it possible for them to be delivered together. CONCLUSION: Active targeting liposomes were the most effective delivery system as compared with pH sensitive and long circulation liposomes. Additionally, DOX and HM could be co delivered in liposomes and they could play moderate synergism effect in antitumor efficacy. PMID- 29260920 TI - Potent Hemostatic Efficacy of a Novel Recombinant Fibrin Sealant Patch (KTF-374) in Rabbit Bleeding Models. AB - PURPOSE: Fibrin sealants are used for hemostasis during surgery. Commercially available fibrin sealants are made of materials of human or animal origin. We developed a novel recombinant fibrin sealant patch (KTF-374) that has thin and flexible properties. This study evaluated the hemostatic efficacy of KTF-374 for various patterns of bleeding in rabbits, as compared with that of the existing fibrin-coated collagen fleece (FCCF). MATERIALS AND METHODS: Test hemostats used were KTF-374 and FCCF. Laparotomy was performed under general anesthesia in rabbits. We created wounds in the liver, caudal vena cava, and ventral aorta under anticoagulating conditions with heparin. Test hemostats were then applied to the wound site and compressed manually for 3 min. Hemostatic efficacy was evaluated with the success rate of hemostasis at 3 min. RESULTS: In all bleeding models, the success rate of hemostasis was significantly higher with KTF-374 than FCCF. The hemostatic success rate of KTF-374 and FCCF was 100% vs. 25% (p = .007) in the partial hepatectomy model (n = 8); 100% vs. 12.5% (p = .001) in the caudal vena cava resection model (n = 8); and 100% vs. 25% (p = .004) in the ventral aortic puncture model (n = 8). The wound site could clearly be recognized through the patch after the application of KTF-374 but not FCCF. CONCLUSIONS: These results suggest that KTF-374 possesses more potent hemostatic properties than FCCF for various patterns of bleeding. KTF-374 is a promising hemostat due to its potent efficacy and good visibility of the wound site through the patch. PMID- 29260919 TI - The development of PARP as a successful target for cancer therapy. AB - INTRODUCTION: PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings. Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents. PMID- 29260921 TI - High sensitivity troponins in contemporary cardiology practice: are we turning a corner? AB - INTRODUCTION: Troponin is considered to be the gold standard biomarker for ruling out MI. There has been a drive to improve the diagnostic speed, and as such the high sensitivity cardiac troponin (hs-cTn) assays have been introduced into clinical practice and are now part of international guidelines. Their novel value in clinical practice more generally is becoming apparent. Areas covered: In this review we will evaluate the evidence for the use of hs-cTn assays in clinical practice, the issues with the assay and how the hs-cTn can be utilized in the future as a biomarker of cardiovascular risk. Expert commentary: The use of the hs-cTn assays as a 'rule out' test for MI is compelling, as a 'rule in' there are significant issues relating the specificity of the assay for MI. The future of the assay may lie in population screening and risk modeling. PMID- 29260922 TI - Comparing Chinese and European American mental health decision making. AB - BACKGROUND: Shared decision making (SDM) tends to reflect more Western values of individualism and empowerment, values that may be foreign to East Asian healthcare preferences for collectivism and family involvement: family centered decision making (FCDM). AIMS: To show that Chinese will be more likely to believe FCDM would be more pleasing for them if they were the patient. Conversely, European Americans will respond more favorably to SDM. To examine effects of Western acculturation on FCDM compared to SDM. METHOD: In this study, preferences for FCDM versus SDM and doctor-led decision making (DrDM) were examined in a vignette study completed online by European Americans (n = 298) and Chinese (n = 327). Research participants read a vignette about Lily (a depression patient) presenting with symptoms of depression. After reading the vignette, participants completed items representing two sets of outcomes: three perceptions of impact on Lily and how participants might respond for themselves in a similar decision making situation. RESULTS: Chinese rated FCDM greater than European and Chinese Americans. Chinese Americans mostly responded similar to European Americans and not Chinese. CONCLUSION: European Americans prefer SDM more for mental health services. Chinese value FCDM more than European Americans. Preferences of Chinese living in America seem to parallel European Americans. PMID- 29260923 TI - Exploring engagement in a virtual community of practice in pediatric rehabilitation: who are non-users, lurkers, and posters? AB - PURPOSE: Communities of practice are increasingly recognized in rehabilitation as useful knowledge transfer tools; however, little is known about their users. This exploratory study describes the characteristics of participants and non participants invited to engage in a pediatric rehabilitation virtual community of practice. In addition, we explored virtual community of practice utilization behaviors, engagement predictors, and the impact of strategies designed to foster engagement. MATERIALS AND METHODS: Participants' demographics including information-seeking style and organization e-readiness, as well as online platform frequency of use data were collected and analyzed using descriptive, comparative, and predictive statistics. RESULTS: Seventy-four percent of those invited used the virtual community of practice. Users had less years of experience in pediatric rehabilitation than non-users. Among the users, 71% were classified as "lurkers," who engaged through reading content only; while 29% were classified as "posters," editing online content. Predictive factors were not uncovered, however an increased number of forum visits correlated with being a poster, a non-information seeker, an employee of an organization demonstrating e readiness, and regularly working with children with the virtual community of practice specific condition. User-engagement strategies increased visits to the forum. CONCLUSIONS: These findings will assist rehabilitation leaders in leveraging rehabilitation-specific virtual community of practice to improve knowledge transfer and practice in pediatric rehabilitation and disability management. Implications for Rehabilitation Communities of practice are increasingly recognized as useful knowledge transfer tools for rehabilitation professionals and are made more accessible thanks to virtual technologies. Our virtual community of practice was found to be optimized in health care organizations with an electronic culture, when the topic area had daily relevance to its target audience, and was particularly beneficial for those who have limited years of experience in pediatric rehabilitation. A strongly committed, selected leadership team with the technological skills, content expertise, and designated time to maintain the site and to nurture discussion was deemed vital in fostering knowledge exchange in this context. User-focused engagement strategies showed promise in increasing visits to the virtual community of practice. Our study supports the importance of multi-pronged approaches in enhancing health care professional knowledge and skills Findings from this study will assist rehabilitation leaders in optimally leveraging rehabilitation specific virtual community of practice to improve knowledge transfer in pediatric rehabilitation and disability management. PMID- 29260924 TI - Pharmacokinetic drug evaluation of exenatide for the treatment of type 2 diabetes. AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor analogs are a group of therapeutic agents which mimic endogenous GLP-1, exerting their effect by the stimulation of the GLP-1 receptor with a wide distribution. Its activation increases insulin releasing dependent on blood glucose levels, suppression of glucagon secretion and a reduction of hepatic glucose output. It delays gastric emptying and increases satiety. Exenatide is the synthetic version of exendin-4, a natural peptide with similar properties to human GLP-1. There are two pharmaceutical forms, for subcutaneous injection: twice daily and once weekly. Clinical practice guidelines recommend them because of a high efficacy reducing hyperglycemia, low risk of hypoglycemia and a significative weight loss effect. Gastrointestinal adverse events are the most common beside injection site related. Their cost is the main limitation to use. Areas covered: We review the recent literature investigating the pharmacokinetics and pharmacodynamics and efficacy-safety studies of exenatide twice daily and once weekly in type 2 diabetes Expert opinion: GLP-1 receptor analogs are now positioned as an effective and safe drug for the treatment of type 2 diabetes. Exenatide significally reduces HbA1c and fasting plasma glucose. Additionally, it produces moderate weight loss and decreases blood pressure. One weekly formulation may improve compliance while cost is still a limitation. EXSCEL trial has shown that, despite cardiovascular safety, exenatide do not exhibits cardiovascular benefits. PMID- 29260926 TI - Psychometric evaluation of Turkish version of the Perceived Stress Scale with Turkish college students. AB - BACKGROUND: The Turkish version of the Perceived Stress Scale (T-PSS-10) measures the extent to which situations in one's life are appraised as stressful. AIMS: The purpose of this study was to evaluate the measurement structure of T-PSS-10. METHOD: Two-hundred and thirty-five Turkish university students (93 men and 142 women) completed the T-PSS-10, the Patient Health Questionnaire-9 (PHQ-9), the General Anxiety Disorder 7-Item Scale (GAD-7), and the Inventory of Common Problems (ICP). RESULTS: Confirmatory factor analysis results indicated that a one-factor model did not fit the data, whereas a two-factor correlated model (stress related self-efficacy beliefs, stress related feelings of helplessness) provided a better fit between the model and the data. Significant moderate correlations were found for the stress-related self-efficacy beliefs and stress related feelings of helplessness factors with depression, anxiety, academic difficulty, relationship problems and health problems. The internal consistency reliability coefficients for the stress-related self-efficacy beliefs and stress related feelings of helplessness factors were 0.68 and 0.85, respectively. CONCLUSIONS: This study provided support for the reliability and validity of T PSS-10 suggesting that it can be used as a screening instrument by health professionals working with Turkish college students. PMID- 29260925 TI - Effective management strategies for patients with marginal zone lymphoma. AB - Marginal zone lymphoma (MZL) is an uncommon indolent lymphoma classified into subtypes based on primary site of involvement: splenic, nodal and extranodal. MZLs' relative rarity has largely precluded adoption of a standard management strategy. Here, we provide an overview of the epidemiology, clinical behavior and therapeutic approaches for each subtype. Biologic insights into lymphomagenesis have identified B-cell receptor signaling as a rational therapeutic target. Recent clinical data suggest that novel agents targeting this pathway, including the Bruton's tyrosine kinase inhibitor, ibrutinib, show significant promise in treatment of relapsed MZL. More work is needed to evaluate these agents' activity in the front-line setting, possible combination regimens and the impact of resistance to B-cell receptor-targeted agents in order to optimize therapy in MZL. PMID- 29260927 TI - Substrain- and sex-dependent differences in stroke vulnerability in C57BL/6 mice. AB - The C57BL/6 mouse strain is represented by distinct substrains, increasingly recognized to differ genetically and phenotypically. The current study compared stroke vulnerability among C57BL/6 J (J), C57BL/6JEiJ (JEiJ), C57BL/6ByJ (ByJ), C57BL/6NCrl (NCrl), C57BL/6NJ (NJ) and C57BL/6NTac (NTac) substrains, using a model of permanent distal middle cerebral artery and common carotid artery occlusion. Mean infarct volume was nearly two-fold smaller in J, JEiJ and ByJ substrains relative to NCrl, NJ and NTac (N-lineage) mice. This identifies a previously unrecognized confound in stroke studies involving genetically modified strain comparisons if control substrain background were not rigorously matched. Mean infarct size was smaller in females of J and ByJ substrains than in the corresponding males, but there was no sex difference for NCrl and NJ mice. A higher proportion of small infarcts in J and ByJ substrains was largely responsible for both substrain- and sex-dependent differences. These could not be straightforwardly explained by variations in posterior communicating artery patency, MCA anatomy or acute penumbral blood flow deficits. Their larger and more homogeneously distributed infarcts, together with their established use as the common background for many genetically modified strains, may make N-lineage C57BL/6 substrains the preferred choice for future studies in experimental stroke. PMID- 29260929 TI - Switching basal insulins in type 2 diabetes: practical recommendations for health care providers. AB - Basal insulin remains the mainstay of treatment of type 2 diabetes when diet changes and exercise in combination with oral drugs and other injectable agents are not sufficient to control hyperglycemia. Insulin therapy should be individualized, and several factors influence the choice of basal insulin; these include pharmacological properties, patient preferences, and lifestyle, as well as health insurance plan formularies. The recent availability of basal insulin formulations with longer durations of action has provided further dosing flexibility; however, patients may need to switch agents throughout therapy for a variety of personal, clinical, or economic reasons. Although a unit-to-unit switching approach is usually recommended, this conversion strategy may not be appropriate for all patients and types of insulin. Glycemic control and risk of hypoglycemia must be closely monitored by health care providers during the switching process. In addition, individual changes in care and formulary coverage need to be adequately addressed in order to enable a smooth transition with optimal outcomes. PMID- 29260930 TI - The mechanisms underpinning peer support: a literature review. AB - BACKGROUND: The employment of Peer Support Workers, who themselves have experience of significant emotional distress, can promote recovery at an individual and organisational level. While research examining the benefits of peer support within mental health services continues to grow, an understanding of how, and through what processes, these benefits are reached remains under developed. AIMS: To review the published research literature relating to the process of peer support and its underpinning mechanisms to better understand how and why it works. METHOD: A scoping review of published literature identified studies relating to peer support mechanisms, processes and relationships. Studies were summarised and findings analysed. RESULTS: Five mechanisms were found to underpin peer support relationships (lived experience, love labour, the liminal position of the peer worker, strengths-focussed social and practical support, and the helper role). CONCLUSIONS: The identified mechanisms can underpin both the success and difficulties associated with peer support relationships. Further research should review a broader range of literature and clarify how these mechanisms contribute to peer support in different contexts. PMID- 29260928 TI - Contribution of sonicate-fluid cultures and broad-range PCR to microbiological diagnosis in vascular graft infections. AB - BACKGROUND: Vascular graft infections (VGI) are associated with considerable morbidity and mortality, and antimicrobial treatment is an important adjunct to surgical treatment. While microbial aetiology of VGI is often difficult to determine, other techniques such as sonication of implanted material may be used to enhance the recovery of biofilm-associated organisms. METHODS: We performed a retrospective analysis of 22 consecutive patients treated for VGI at University Medical Centre Ljubljana from May 2011 through January 2015. Explanted vascular grafts were flooded with sterile Ringer solution, sonicated for 1 min at a frequency of 40 kHz and inoculated on solid and liquid culture media. Aerobic and anaerobic cultures were performed, incubated for 14 days and any significant bacterial growth was quantitatively evaluated. Additionally, broad-range PCR from sonicate fluid was performed. Microbiological results were compared with the results of preoperatively taken blood cultures and the results of intraoperative tissue cultures (material from peri-graft collection). RESULTS: Identification of the causative organism (irrespective of the method) was achieved in 95.8%. Preoperative blood cultures were positive in 35.3%, intraoperative tissue cultures in 31.8%, sonicate fluid culture in 79.2%, while broad-range PCR from sonicate fluid was positive in 66.7%. In 37.5% the pathogen detected in sonicate fluid culture or broad-range PCR was the only positive microbiological result. CONCLUSIONS: Sonicate fluid culture and broad-range PCR from explanted vascular grafts may contribute to optimization of antimicrobial treatment. Optimal timing of antibiotic therapy before explantation should be further assessed to improve diagnostic yield. PMID- 29260932 TI - Data Lacking on Eye Injuries. PMID- 29260933 TI - letters. PMID- 29260934 TI - What Should Athletes Eat? Unmixing Folly and Facts. PMID- 29260935 TI - How 'Tilting Pelvis' Habits Hamper Skiers on Turns. PMID- 29260931 TI - Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition. AB - Endothelial-mesenchymal transition (EndoMT) is associated with damage to blood brain barrier (BBB) integrity. Circular RNAs (circRNAs) are highly expressed in the brain and are involved in brain diseases; however, whether circRNAs regulate the EndoMT in the brain remains unknown. Our study demonstrated that circHECW2 regulated the EndoMT by directly binding to MIR30D, a significantly downregulated miRNA from miRNA profiling, which subsequently caused an increased expression of ATG5. These findings shed new light on the understanding of the noncanonical role of ATG5 in the EndoMT induced by methamphetamine (Meth) or lipopolysaccharide (LPS). The in vivo relevance was confirmed as microinjection of circHecw2 siRNA lentivirus into the mouse hippocampus suppressed the EndoMT induced by LPS. These findings provide novel insights regarding the contribution of circHECW2 to the nonautophagic role of ATG5 in the EndoMT process in the context of drug abuse and the broad range of neuroinflammatory disorders. PMID- 29260937 TI - Dr. Barnard: The Key Is Heredity, Not Exercise. PMID- 29260936 TI - a need to know. PMID- 29260938 TI - Warning: Watching Can Be Hazardous to Your Health. PMID- 29260939 TI - action arena. PMID- 29260940 TI - lockerroom. PMID- 29260942 TI - winners and losers. PMID- 29260941 TI - sportspages. PMID- 29260944 TI - Let's Play Hockey With Finesse - not Fists. PMID- 29260943 TI - Distance Bicycling May Cause Ischemic Neuropathy of Penis. PMID- 29260946 TI - Looking at Eye Care in Athletes. PMID- 29260945 TI - The Short-Leg Syndrome. PMID- 29260947 TI - Helping Hockey Players Avoid Groin Pulls. PMID- 29260948 TI - Keeping a Healthy Skin on Skis - How to Do It. PMID- 29260949 TI - Spike Your Exercise Proaram With Volleyball. PMID- 29260950 TI - Dose painting of prostate cancer based on Gleason score correlations with apparent diffusion coefficients. AB - BACKGROUND: Gleason scores for prostate cancer correlates with an increased recurrence risk after radiotherapy (RT). Furthermore, higher Gleason scores correlates with decreasing apparent diffusion coefficient (ADC) data from diffusion weighted MRI (DWI-MRI). Based on these observations, we present a formalism for dose painting prescriptions of prostate volumes based on ADC images mapped to Gleason score driven dose-responses. METHODS: The Gleason score driven dose-responses were derived from a learning data set consisting of pre-RT biopsy data and post-RT outcomes for 122 patients treated with a homogeneous dose to the prostate. For a test data set of 18 prostate cancer patients with pre-RT ADC images, we mapped the ADC data to the Gleason driven dose-responses by using probability distributions constructed from published Gleason score correlations with ADC data. We used the Gleason driven dose-responses to optimize dose painting prescriptions that maximize the tumor control probability (TCP) with equal average dose as for the learning sets homogeneous treatment dose. RESULTS: The dose painting prescriptions increased the estimated TCP compared to the homogeneous dose by 0-51% for the learning set and by 4-30% for the test set. The potential for individual TCP gains with dose painting correlated with increasing Gleason score spread and larger prostate volumes. The TCP gains were also found to be larger for patients with a low expected TCP for the homogeneous dose prescription. CONCLUSIONS: We have from retrospective treatment data demonstrated a formalism that yield ADC driven dose painting prescriptions for prostate volumes that potentially can yield significant TCP increases without increasing dose burdens as compared to a homogeneous treatment dose. This motivates further development of the approach to consider more accurate ADC to Gleason mappings, issues with delivery robustness of heterogeneous dose distributions, and patient selection criteria for design of clinical trials. PMID- 29260951 TI - "Ulnar artery pseudoaneurysm and compartment syndrome formation after snake bite to the left forearm" by Lan Pin et al., Clin Toxicol (Phila) 2017 Nov. 10. PMID- 29260952 TI - Difluprednate 0.05% versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: Pooled Efficacy Analysis of Two Phase 3 Studies. AB - PURPOSE: To analyse pooled data from 2 similar phase 3 noninferiority studies comparing difluprednate 0.05% versus prednisolone acetate 1% in patients with endogenous anterior uveitis. METHODS: Patients received difluprednate alternating with vehicle or prednisolone acetate for 14 days (8 drops/day in both groups), followed by tapering from day 14 to 28. All patients were observed until day 42. RESULTS: More patients on difluprednate than on prednisolone acetate were cleared of anterior chamber cells on day twenty one (71.3% vs 54.7%; p = 0.02); results were similar at the other time points. Treatment withdrawals were higher with prednisolone acetate than difluprednate (19.8% vs 7.4%; log-rank p = 0.02). Study discontinuation due to lack of efficacy was also higher with prednisolone acetate than difluprednate (14.0% vs 0%; p = 0.0002 [pre-specified exploratory analysis]). CONCLUSIONS: More difluprednate-treated eyes were quiet following 21 days of treatment, and difluprednate-treated patients were much less likely to be withdrawn from the study because of treatment failure. PMID- 29260953 TI - Syndesmosis Ankle Sprains. AB - In brief Syndesmosis ankle sprains, though potentially disabling, often appear benign initially. These sprains are characterized by a rotational mechanism of injury, long recovery, and, frequently, heterotopic ossification. Diagnosis and grading are based on physical exam findings and imaging studies. Treatment ranges from aggressive functional rehabilitation to surgical stabilization. Long-term results can be good if the ankle mortise is anatomically reduced and a synostosis between the tibia and fibula does not form. PMID- 29260954 TI - Rhythm Abnormalities in a Young Executive. PMID- 29260955 TI - Resolving Inflammation in Active Patients. AB - In brief Inflammation is part of the body's Physiologic repair mechanism, but it doesn't always lead to healing. Optimal inflammation control typically involves a combination of suitable physical modalities and drug therapy. Although modalities such as ultrasound may have a role in managing inflammation, the standbys of ice, heat, and nonsteroidal drugs often work effectively. PMID- 29260956 TI - Decreased Testosterone and Libido With Severe Weight Loss. AB - In brief A college wrestler's weight, body brief fat, and hormone levels were measured during 2 years of competition. Marked weight loss during the initial season was associated with lower serum levels of testosterone and several other hormones, as well as a decrease in reported sexual activity. All values returned to normal after the season. The following year, with less weight loss, the wrestler had only a transient decrease in testosterone and prolactin and reported no decline in sexual activity. Body fat greater than 5% seemed essential to maintaining normal endocrine function. PMID- 29260958 TI - Keep Your Shoulders in the 'Safe Zone'. PMID- 29260957 TI - How I Manage Hip and Pelvis Injuries in Adolescents. AB - In brief Injuries to the adolescent hip and pelvis need not be disabling. A high index of suspicion when adolescents complain of pain, an accurate diagnosis, and appropriate treatment will lead to a fairly rapid return to full activity. PMID- 29260959 TI - QuikQuiz. PMID- 29260960 TI - Pearls. PMID- 29260961 TI - Discover the Wonders of Bread. PMID- 29260962 TI - Farewell to a Friend. PMID- 29260963 TI - Cumulative trauma, gender discrimination and mental health in women: mediating role of self-esteem. AB - BACKGROUND: Evidence suggests that women show symptoms of trauma-related symptoms more often than men. Gender discrimination is also associated with the severity of symptoms in women. AIMS: This study explored the relations among cumulative trauma, gender discrimination and mental health in women with a mediating role of self-esteem and emotion regulation. Two types of gender discrimination were taken into account: discrimination by parents and in the social context. Cumulative trauma over the lifetime was assessed, as well as three types of symptoms: internalising, externalising, psychoticism. METHODS: A total of 277 females from Poland participated in the study. It was hypothesised that gender discrimination and cumulative trauma would be positively related to symptoms and that lowered self-esteem mediates these relations. RESULTS: Hypotheses received partial confirmation, as both gender discrimination and cumulative trauma have been shown to be related to three types of symptoms. Self-esteem was a partial mediator between gender discrimination in the social context and symptoms. It was also demonstrated that emotion suppression is a partial mediator between cumulative trauma and symptoms. CONCLUSIONS: It has been demonstrated that socio-cultural factors, such as gender discrimination, play an important role in psychiatric symptoms development. PMID- 29260964 TI - Focusing the Diagnosis of Shoulder Pain. AB - In brief Whether shoulder pain stems from acute or overuse injury, a practical, methodical evaluation is essential for diagnosing the underlying cause and prescribing treatment. Systematic shoulder evaluation first addresses the broad categories of shoulder pain- impingement and instability- before focusing on more specific causes, such as nerve involvement. A detailed, refined assessment can help minimize reliance on radiologic tests. PMID- 29260965 TI - Chest Pain in Active Young People. AB - In brief Chest pain in children and adolescents is usually benign and noncardiac, unlike that in adults. Some of the more common causes are activity related, such as chest wall trauma and exercise-induced asthma. A careful history and physical examination will often provide a diagnosis, though about one third of causes are idiopathic. Most patients will not require extensive testing or referral. Education and reassurance are essential for relieving patient and parent anxiety. PMID- 29260966 TI - Reducing a Finger Dislocation. AB - A football player's little finger became dislocated at the metacarpophalangeal joint and could not be reduced using closed techniques. While preparations for open reduction were being made, the patient, a veteran of many dislocated and jammed fingers, offered his own solution. PMID- 29260967 TI - Exercise-Related Skin Infection. AB - In Brief Bacterial skin infections can be unpleasant side effects of exercise; among them are impetigo, folliculitis, cellulitis, and pitted keratolysis. Instituting the right combination of topical treatments and, when needed, systemic therapy can make a patient's skin safe for activity. PMID- 29260969 TI - QuikQuiz. PMID- 29260968 TI - Diagnosing Suprascapular Neuropathy. AB - In brief In this case study, a male weight lifter's severe suprascapular neuropathy led to denervation and muscle atrophy, temporarily forcing him to stop training. Manual and electro- diagnostic testing was used to determine the exact site of this nerve injury of the shoulder. Treatment emphasized range-of-motion exercises, galvanic stimulation, anti-inflammatories, and avoidance of stretch. Physicians and athletic trainers need to be aware that weight training, especially when it is unsupervised, poses a risk of serious nerve injury. PMID- 29260970 TI - A Boost From Juice? PMID- 29260971 TI - Do Gatekeepers Practice Sports Medicine? PMID- 29260972 TI - Immunization Strategies for Active Adults. AB - Healthy, active adults are often overlooked when it comes to simple disease prevention practices like vaccination. Yet when compared to inactive adults, some recreational athletes face a higher risk of exposure to diseases, such as hepatitis B, tetanus, and influenza, often without realizing it. Physicians need to identify patients at risk and help them understand that "getting your shots" can be as important on the court as it is off. PMID- 29260974 TI - Making a Splash. PMID- 29260973 TI - Pearls. PMID- 29260976 TI - Scanning Sports. PMID- 29260977 TI - Pex3 and Atg37 compete to regulate the interaction between the pexophagy receptor, Atg30, and the Hrr25 kinase. AB - Macroautophagy/autophagy is a highly conserved process in which subcellular components destined for degradation are sequestered within autophagosomes. The selectivity of autophagy is determined by autophagy receptors, such as Pichia pastoris Atg30 (autophagy-related 30), which controls the selective degradation of peroxisomes (pexophagy) through the assembly of a receptor-protein complex (RPC). Previously, we proved that the peroxisomal acyl-CoA-binding protein, Atg37, and the highly conserved peroxin, Pex3, are required for RPC formation and efficient pexophagy. Here, we describe how Atg37 and Pex3 regulate the assembly and activation of the pexophagic RPC. We demonstrate that Atg30 requires both Atg37 and Pex3 to recruit Atg8 and Atg11 to the pexophagic RPC, because Atg37 depends on Pex3 for its localization at the peroxisomal membrane. We establish that due to close proximity of Atg37- and Pex3-binding sites in the middle domain of Atg30, the binding of these proteins to Atg30 is mutually exclusive within this region. We also show that direct binding of Pex3 and Atg37 to Atg30 regulates its phosphorylation by the Hrr25 kinase, negatively and positively, respectively. Based on these results we present a model that clarifies the assembly and activation of the pexophagic RPC through the phosphoregulation of Atg30. PMID- 29260978 TI - DNA hypermethylation as a predictor of extramural vascular invasion (EMVI) in rectal cancer. AB - PURPOSE: DNA hypermethylation in gene promoter regions (CpG islands) is emerging as an important pathway in colorectal cancer tumourigenesis. Whilst genetic mutations have been associated with extramural vascular invasion (EMVI) in rectal cancer, no such association has yet been made with epigenetic factors. METHODS: 100 consecutive neoadjuvant-naive patients undergoing curative surgery for rectal were classified according to the presence or absence of EMVI on histopathological examination. DNA was extracted from tumours and subjected to bisulfite conversion and methylation-specific PCR to determine CIMP status (high, intermediate, or low; according to a validated panel of 8 genes). CIMP status was correlated with EMVI status, histopathological, clinical, and demographic variables, in addition to overall (OS) and disease free (DFS) survival. RESULTS: 51 patients were characterised as CIMP-low, 48 CIMP-intermediate, and one patient CIMP-high. EMVI positivity was associated with CIMP-intermediate epigenotype (p < 0.001). Patients with EMVI-positive tumours were found to have significantly more advanced disease by pT, pN, and pAJCC categorisation (p = 0.002, p < 0.001, and = p < 0.001, respectively). EMVI-positivity was significantly associated with the requirement for adjuvant chemotherapy (p < 0.001), and worse DFS but not OS (p = 0.012 and p = 0.052). CONCLUSIONS: Given the association between CIMP intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients' cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer. PMID- 29260979 TI - HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer. AB - HSPA5/GRP78/BiP plays an important role in cell survival or tumor progression. For these reasons, HSPA5 is an emerging therapeutic target in cancer development. Here we report that HSPA5 contributes to head and neck cancer (HNC) survival via maintenance of lysosomal activity; however, a nonthermal plasma (NTP, considered as a next-generation cancer therapy)-treated solution (NTS) inhibits HNC progression through HSPA5-dependent alteration of lysosomal activity. HSPA5 prevents NTS-induced lysosome inhibition through lysosomal-related proteins or regulation of gene expression. However, NTS-induced MUL1/MULAN/GIDE/MAPL (mitochondrial ubiquitin ligase activator of NFKB 1) leads to downregulation of HSPA5 via K48-linked ubiquitination at the lysine 446 (K446) residue. MUL1 knockdown hinders NTS-induced lysosome inhibition or cytotoxicity through the reduction of HSPA5 ubiquitination in HNC cells. While MUL1 was suppressed, HSPA5 was overexpressed in tissues of HNC patients. NTS strongly inhibited HNC progression via alterations of expression of MUL1 and HSPA5, in vivo in a xenograft model. However, NTS did not induce inhibition of tumor progression or HSPA5 reduction in MUL1 knockout (KO) HNC cells which were generated by CRISPR/Cas9 system. The data provide compelling evidence to support the idea that the regulation of the MUL1-HSPA5 axis can be a novel strategy for the treatment of HNC. PMID- 29260981 TI - A Conjunctival Retractor during Strabismus Surgery. AB - The use of a conjunctival retractor that expands a small incision in the conjunctiva/Tenon's capsule facilitated the performance of strabismus surgery through a fornix incision. A wide field of exposure revealed the entire area of the muscle insertion. While there is a risk of conjunctival tearing in elderly patients, the use of the retractor is valuable. PMID- 29260982 TI - Philadelphia Sportsmedicine: Doing it Torg's Way. AB - The University of Pennsylvania held a lucrative carrot out to Joseph S. Torg, MD, and its new Sports Medicine Clinic is already reaping the benefits of his extensive energies. PMID- 29260980 TI - Baohuoside-I suppresses cell proliferation and migration by up-regulating miR-144 in melanoma. AB - CONTEXT: Baohuoside-I was reported to induce apoptosis in non-small-cell lung cancer and inhibit the growth of multiple myeloma cells. The antitumour potential of baohuoside-I has not been demonstrated in melanoma yet. OBJECTIVE: To investigate the potential antitumour activity of baohuoside-I against melanoma and elucidate its underlying molecular mechanism. MATERIALS AND METHODS: Cell viability was evaluated by MTT assay. The malignant invasion capacity was measured with trans-well assay. The relative expression change of microRNAs was profiled with microarray. TargetScan was utilized for prediction of target gene of miR-144. Regulatory effect of miR-144 on SMAD1 was determined by dual luciferase reporter assay. Endogenous SMAD1 protein in response to ectopic expression of miR-144 was determined by immunoblotting. Xenograft mice were employed to evaluate antitumour potential of baohuoside-I (25 mg/kg by tail intravenous injection every two days) in vivo. RESULTS: Baohuoside-I significantly inhibited proliferation (45 +/- 4% reduction in M14 and 35 +/- 3% reduction in MV3 at 24 h) and migration (70 +/- 4% reduction in M14 and 72 +/- 3% reduction in MV3) in melanoma cells. Mechanistically, baohuoside-I up-regulated miR-144 expression levels (3 +/- 0.2-fold). Silence of miR-144 reversed the inhibition of baohuoside-I in melanoma. We have identified that SMAD1 was the novel target of miR-144. Moreover, baohuoside-I suppressed melanoma in vivo (52 +/- 8% reduction in xenograft tumour size at day 20). CONCLUSIONS: Our data suggested significant antitumour potential of baohuoside-I against melanoma both in vitro and in vivo, which warrants further laboratory investigation and clinical trial. PMID- 29260984 TI - scanning sports. PMID- 29260983 TI - Another Angle on Shoes. AB - Manufacturing defects in a shoe's forefoot often go undetected, but can cause gait changes leading to injury. PMID- 29260985 TI - A World Beyond Health. PMID- 29260987 TI - Daily Physical Education. PMID- 29260986 TI - Modified Low-Dye Strapping. PMID- 29260988 TI - What Do Stress Tests Show? AB - The exercise test helps evaluate cardiovascular function in athletes and diagnose disease, but it must be interpreted in conjunction with other clinical findings. PMID- 29260989 TI - The Physician's Role in School Sports Programs. AB - The author takes a careful and critical look at the consequences of the unending problem of inadequate medical coverage for school sports programs. PMID- 29260990 TI - Spondylolysis in Athletes. AB - The high occurrence of spondylolysis in these athletes suggests that certain sports actions predispose athletes to fractures in the neural arches of the lumbar vertebrae. PMID- 29260991 TI - Improving the Physical Fitness of Executives. AB - A weekend program taught these men how to improve their fitness levels without close supervision and within busy work schedules. PMID- 29260992 TI - Sportsmedicine Directory. PMID- 29260993 TI - Touch Football: A Friendly Game? AB - Although touch football is not as dangerous as tackle, the authors found a high rate of injury and a long recovery period. PMID- 29260994 TI - a need to know. PMID- 29260995 TI - Profiles of Super Senior Tennis Players. AB - These upper middle-class senior citizens play tennis to stay healthy and to enjoy life, but their experience doesn't necessarily apply to the rest of society. PMID- 29260996 TI - brief reports. PMID- 29260997 TI - Ten Most Asked Questions About Exercise. PMID- 29260998 TI - Walking for Fitness: Slow but Sure. AB - A walking program may be the best option for out-of-shape adults just starting a fitness program. It's safe, convenient, and it definitely exerts a training effect. PMID- 29261000 TI - Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review. AB - Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC. PMID- 29261001 TI - Regulation of autophagic proteolysis by the N-recognin SQSTM1/p62 of the N-end rule pathway. AB - In macroautophagy/autophagy, cargoes are collected by specific receptors, such as SQSTM1/p62 (sequestosome 1), and delivered to phagophores for lysosomal degradation. To date, little is known about how cells modulate SQSTM1 activity and autophagosome biogenesis in response to accumulating cargoes. In this study, we show that SQSTM1 is an N-recognin whose ZZ domain binds N-terminal arginine (Nt-Arg) and other N-degrons (Nt-Lys, Nt-His, Nt-Trp, Nt-Phe, and Nt-Tyr) of the N-end rule pathway. The substrates of SQSTM1 include the endoplasmic reticulum (ER)-residing chaperone HSPA5/GRP78/BiP. Upon N-end rule interaction with the Nt Arg of arginylated HSPA5 (R-HSPA5), SQSTM1 undergoes self-polymerization via disulfide bonds of Cys residues including Cys113, facilitating cargo collection. In parallel, Nt-Arg-bound SQSTM1 acts as an inducer of autophagosome biogenesis and autophagic flux. Through this dual regulatory mechanism, SQSTM1 plays a key role in the crosstalk between the ubiquitin (Ub)-proteasome system (UPS) and autophagy. Based on these results, we employed 3D-modeling of SQSTM1 and a virtual chemical library to develop small molecule ligands to the ZZ domain of SQSTM1. These autophagy inducers accelerated the autophagic removal of mutant HTT (huntingtin) aggregates. We suggest that SQSTM1 can be exploited as a novel drug target to modulate autophagic processes in pathophysiological conditions. PMID- 29261002 TI - Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer. AB - Topoisomerase 1 (TOPO-1) and carboxylesterase 2 (CES-2) are found to play crucial roles in the pathogenesis of various cancers. The prognostic role of TOPO-1 and CES-2 in patients with metastatic colorectal cancer (mCRC) who underwent irinotecan chemotherapy was largely unknown. In the current study, we assessed the expression of TOPO-1 and CES-2 in mCRC and analyzed its potential relevance to irinotecan based therapy. A total of 98 patients with mCRC were included in this study. The expression of TOPO-1 and CES-2 in mCRC tissues was evaluated by immunohistochemistry. For TOPO-1, 46 patients showed high expression and 52 patients showed low expression. For CES-2, 53 patients showed high expression and 45 patients showed low expression. The correlation between TOPO-1 or CES-2 expression and clinicopathological characteristics of mCRC patients was analyzed. Neither TOPO-1 nor CES-2 had significant correlation with age, gender, tumor site, tumor grade and metastatic sites in mCRC patients. However, high expression of CES-2 but not TOP-1 was positively correlated with better curative effect. Kaplan-Meier and log-rank test were applied to assess the correlation between progression-free survival (PFS)/overall survival (OS) and TOPO-1 or CES-2 expression in mCRC patients. High expression of TOPO-1 and CES-2 are correlated with longer PFS and OS. In summary, our findings suggest that TOPO-1 and CES-2 may play important roles irinotecan sensitivity in mCRC patients. Evaluation of expression of TOPO-1 and CES-2 may provide preliminary clinical evidence for the management of irinotecan-based therapy in mCRC patients. PMID- 29261003 TI - Yeast mating: Ceramide acyl chain length matters? PMID- 29261005 TI - Efficacy and safety of apatinib monotherapy in advanced bone and soft tissue sarcoma: An observational study. AB - Sarcomas are rare but malignant tumors with high risks of local recurrence and distant metastasis. Anti-angiogenic therapy is a potential strategy against un controlled and not-organized tumor angiogenesis. We aimed to assess the safety and efficacy of apatinib, an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, in patients with advanced sarcoma. Thirty one patients who received initial apatinib between September 2015 and August 2016 were retrospectively reviewed. Among them, 19 (61.3%) patients were heavily pretreated with two or more lines of cytotoxic chemotherapy. Apatinib was given at a start-dose of 425 mg qd. During therapy, 9 (29.0%) patients required dose interruption and 7 (22.6%) needed dose reduction, and the mean dosage of apatinib was 372.9 +/- 68.4 mg/day. In the study cohort, one patient was treated as adjunctive therapy and 6 patients stopped treatment before radiographic response assessment. Thus, 24 patients were eligible for tumor response evaluation. The objective response rate was 33.3% and clinical benefit rate was as high as 75.0%. The progression free survival was 4.25 (95% confidence interval [CI], 2.22-5.11) months, whereas the overall survival was 9.43 (95% CI, 6.64-18.72) months. Compared with other histological subtypes, leiomyosarcoma did not show significant survival benefits. Most of the adverse events (AEs) were at grade 1 or 2. The main grade 3 AEs were hypertension (6.5%), hand foot skin reaction (6.5%), and diarrhea (3.2%). In conclusion, apatinib showed promising efficacy and acceptable safety profile in metastatic or recurrent sarcoma, giving rationale clinical evidence to conduct clinical trials. PMID- 29261006 TI - Feeding Obese Diabetic Mice a Genistein Diet Induces Thermogenic and Metabolic Change. AB - Obesity is associated with elevated plasma levels of glucocorticoids and reduced levels of thyroid hormones, both known to effect food intake and energy expenditure. Furthermore, tissue specific glucocorticoid metabolism is altered in obesity, increasing insulin resistance and cardiometabolic risk. The goal of this study was to examine whether these metabolic disturbances can be prevented with the isoflavone genistein in the ob/ob mouse, a model that resembles the phenotype in human obesity. Male ob/ob mice, aged 5 weeks, were fed either a genistein-rich diet (600 mg/kg) or a genistein-free diet for 4 weeks. ob/ob mice weighed 70% more than lean controls. While there was no effect of genistein on body weight, food consumption during weeks 3 and 4 was significantly increased in genistein fed mice. This was associated with increases in body temperature and plasma levels of triiodothyronine (T3), suggesting a thermogenic effect. The hypercorticosteronism observed in the ob/ob mouse was reduced with genistein treatment. This effect was accompanied by a decrease in protein expression of renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) without changes in hepatic 11beta-HSD1. Our results suggest that a diet containing genistein can have beneficial effects on energy expenditure, T3 production, and corticosterone status in the ob/ob mouse model of obesity. PMID- 29261007 TI - Stress and coping strategies among nursing students: an international study. AB - BACKGROUND: Mounting literature on stress and coping in nursing students are available; however, most of the findings are confined to a single cultural group. AIMS: This study was conducted to determine the level of stress, its sources and coping strategies among nursing students from three countries: Greece, the Philippines and Nigeria. METHODS: Using a descriptive, comparative research design, 547 nursing students (161 Greek nursing students, 153 Filipino nursing students, 233 Nigerian nursing students) participated in the study from August 2015 to April 2016. Two standardized instruments were used, the Perceived Stress Scale (PSS) and the Coping Behavior Inventory (CBI). RESULTS: Findings revealed that the degree of stress and the type of stressors and coping styles utilized by nursing students differ according to the country of origin. The year of study predicted overall stress (beta = -0.149, p < 0.001) while advanced age predicted overall coping (beta = 0.008, p = 0.037) in the nursing students. CONCLUSIONS: Strengthening nursing students' positive coping skills may be helpful for them to effectively deal with various stressors during their educational experiences while maximizing learning. Implementing empirically tested approaches maybe useful to prevent the recurrence of stress and lessen its impact such as stress management counseling, counseling programs, establishing peer and family support systems, and formulating hospital policies that will support nursing students. PMID- 29261004 TI - Exploring and exploiting the connection between mitochondria and the virulence of human pathogenic fungi. AB - Mitochondria are best known for their role in the production of ATP; however, recent research implicates other mitochondrial functions in the virulence of human pathogenic fungi. Inhibitors of mitochondrial succinate dehydrogenase or the electron transport chain are successfully used to combat plant pathogenic fungi, but similar inhibition of mitochondrial functions has not been pursued for applications in medical mycology. Advances in understanding mitochondrial function relevant to human pathogenic fungi are in four major directions: 1) the role of mitochondrial morphology in virulence, 2) mitochondrial genetics, with a focus on mitochondrial DNA recombination and mitochondrial inheritance 3) the role of mitochondria in drug resistance, and 4) the interaction of mitochondria with other organelles. Collectively, despite the similarities in mitochondrial functions between fungi and animals, this organelle is currently an under explored potential target to treat medical mycoses. Future research could define and then exploit those mitochondrial components best suited as drug targets. PMID- 29261009 TI - Small change, big effect: Taking RAS by the tail through suppression of post prenylation carboxylmethylation. AB - Mutant RAS isoforms are the most common oncogenes affecting human cancers. After decades of effort in developing drugs targeting oncogenic RAS-driven cancers, we are still charting an unclear path. Despite recent developments exemplified by KRAS (G12C) inhibitors, direct targeting of mutant RAS remains a difficult endeavor. Inhibiting RAS function by targeting its post-translational prenylation processing has remained an important approach, especially with recent progress on the study of isoprenylcysteine carboxylmethyltransferase (ICMT), the unique enzyme for the last step of prenylation processing of RAS isoforms and other substrates. Inhibition of ICMT has shown efficacy both in vitro and in vivo in RAS-mutant cancer models. We will discuss the roles of RAS family of proteins in human cancers and the impact of post-prenylation carboxylmethylation on RAS driven tumorigenesis. In addition, we will review what is known of the molecular and cellular impact of ICMT inhibition on cancer cells that underlie its anti proliferative and pro-apoptosis efficacy. PMID- 29261008 TI - The Medicinal Mushroom, Grifola gargal, Ameliorates Allergic Bronchial Asthma. AB - Grifola gargal Singer, a medicinal mushroom, has been found to be effective for the prevention and treatment of various chronic inflammatory diseases. However, the effects of G. gargal on allergic diseases are unknown. The present study investigated the effect of G. gargal extract on allergic bronchial asthma. Asthma was induced in mice by ovalbumin sensitization and inhalation. The grade of asthma was compared between mice fed with chow containing G. gargal extract and mice given standard chow. The human mast cell and eosinophilic cell lines were used for in vitro studies. G. gargal extract significantly reduced airway hyperresponsiveness, lung eosinophilic infiltration, lung interleukin (IL)-13 expression, and plasma IgE level and significantly increased IL-10 plasma levels compared to untreated control mice. Spleen regulatory T cells were significantly increased in mice treated with the G. gargal extract compared with untreated control mice. G. gargal extract significantly suppressed expression of cytokines in mast cells and eosinophils compared with control cells. Overall, these observations show that G. gargal extract augments the lung population of regulatory T cells and ameliorates allergic inflammation and airway hyperresponsiveness in mice with allergic bronchial asthma, suggesting the potential therapeutic benefit of G. gargal extract in allergic diseases. PMID- 29261010 TI - Effect of Chlorogenic Acid Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance. AB - Chlorogenic acid has been described as a novel polyphenol with metabolic effects on glucose homeostasis. The aim of this study was to evaluate the effect of chlorogenic acid administration on glycemic control, insulin secretion, and insulin sensitivity in patients with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled clinical trial was performed in 30 patients with IGT; 15 patients randomly assigned to oral chlorogenic acid received 400 mg three times per day for 12 weeks, and the other 15 patients received placebo in the same way. Before and after the intervention, anthropometric and metabolic measurements, including fasting plasma glucose (FPG), glycated hemoglobin A1c, and a lipid profile, were performed. Area under the curve of glucose and insulin as well as the insulinogenic, Stumvoll, and Matsuda indices were calculated. Wilcoxon, Mann-Whitney U, and chi-square tests were performed, and P <= .05 was considered statistically significant. There were significant decreases in FPG (5.7 +/- 0.4 vs. 5.5 +/- 0.4 mmol/L, P = .002), insulinogenic index (0.71 +/- 0.25 vs. 0.63 +/- 0.25, P = .028), body weight, body mass index, waist circumference, triglycerides, total cholesterol, low density lipoprotein cholesterol, and very low-density lipoprotein levels in the chlorogenic acid group, with an increment in the Matsuda index (1.98 +/- 0.88 vs. 2.30 +/- 1.23, P = .002). There were no significant differences in the placebo group. In conclusion, chlorogenic acid administration in patients with IGT decreased FPG and insulin secretion, while increasing insulin sensitivity and improving both anthropometric evaluations and the lipid profile. PMID- 29261011 TI - Multiple CsrA Proteins Control Key Virulence Traits in Pseudomonas syringae pv. tomato DC3000. AB - The phytopathogenic bacterium Pseudomonas syringae pv. tomato DC3000 has a complex Gac-rsm global regulatory pathway that controls virulence, motility, production of secondary metabolites, carbon metabolism, and quorum sensing. However, despite the fact that components of this pathway are known, their physiological roles have not yet been established. Regarding the CsrA/RsmA type proteins, five paralogs, three of which are well conserved within the Pseudomonas genus (csrA1, csrA2, and csrA3), have been found in the DC3000 genome. To decipher their function, mutants lacking the three most conserved CsrA proteins have been constructed and their physiological outcomes examined. We show that they exert nonredundant functions and demonstrate that CsrA3 and, to a lesser extent, CsrA2 but not CsrA1 alter the expression of genes involved in a variety of pathways and systems important for motility, exopolysaccharide synthesis, growth, and virulence. Particularly, alginate synthesis, syringafactin production, and virulence are considerably de-repressed in a csrA3 mutant, whereas growth in planta is impaired. We propose that the linkage of growth and symptom development is under the control of CsrA3, which functions as a pivotal regulator of the DC3000 life cycle, repressing virulence traits and promoting cell division in response to environmental cues. PMID- 29261012 TI - The association of anxiety, depression, and worry symptoms on cognitive performance in older adults. AB - Emerging research suggests that a relationship exists between the cognitive aspects of anxiety (e.g. worry) and cognitive decline in older adults. The current study examined the association between anxiety, depressive, and worry symptoms on cognitive performance. Participants were 156 older adults enrolled in the Nathan Kline Institute-Rockland Sample Study (NKI-RS). Hierarchical linear regression analysis was used to determine the unique associations of anxiety, depressive, and worry symptoms on cognitive performance as measured by the Penn Computerized Neurocognitive Battery (Penn CNB), the Delis-Kaplan Executive Function System (D-KEFS), and the Rey Auditory Verbal Learning Test (RAVLT). Worry symptoms were a significant predictor of Penn CNB social cognition, complex cognition, executive function, and episodic memory performance as well as RAVLT immediate and short-delay recall, but not of D-KEFS performance or RAVLT long delay recall. In contrast, anxiety and depressive symptoms had few unique associations with cognitive performance. Given that worry symptoms have a negative impact on many aspects of neurocognitive performance, they may have utility in predicting and preventing cognitive decline in older adults. PMID- 29261013 TI - Performance of Different Methods for Detection of Incipient Occlusal Caries Lesions: An In Vitro Study. AB - OBJECTIVE: The aim of this in vitro study was to evaluate the diagnostic performance of visual inspection (VI), laser fluorescence (LF pen), fluorescence camera (FC), and alternating current impedance spectroscopy technique (ACIST) for detection of incipient occlusal caries lesions. Histology was used as the gold standard to determine the interexaminer reliability of the methods, among three examiners with different levels of experiences (Examiner 1: 5 years; examiner 2: 10 years; and examiner 3: 25 years). MATERIALS AND METHODS: One hundred two molar teeth were selected. The occlusal surfaces of teeth were evaluated with VI, LF pen, FC, and ACIST devices independently by three examiners. Diagnostic performances of methods were evaluated with binormal receiver-operating characteristics analysis. Interexaminer agreement of detection methods was assessed using Cohen's kappa coefficient values (p < 0.001). RESULTS: Incipient enamel lesions were determined more successfully with VI by all examiners. All detection methods were presented with statistically acceptable interexaminer agreement (p < 0.001). For D2 and D3 thresholds, FC for examiner 1, VI for examiner 2, and both VI and FC for examiner 3 demonstrated statistically high sensitivity and specificity (p < 0.05). CONCLUSIONS: It can be concluded that diagnostic performance of the methods was insufficient for detecting incipient occlusal caries lesions by itself. Performance can be improved by using them with VI as a traditional caries detection method. PMID- 29261016 TI - eMD letter from the editor. PMID- 29261017 TI - Managed Care Harnesses the Web. PMID- 29261014 TI - Selective improvement of pulmonary arterial hypertension with a dual ETA/ETB receptors antagonist in the apolipoprotein E-/- model of PAH and atherosclerosis. AB - Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET 1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE-/- mice with macitentan, a dual ETA/ETB receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE-/- mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ETA/ETB antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE-/- mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ETA/ETB receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis. PMID- 29261018 TI - VR Technology. PMID- 29261019 TI - The New Black Bag. PMID- 29261020 TI - Saved by the Network. PMID- 29261021 TI - Dances with Data. AB - Meanwhile, everyone's talking about outcomes management tools. These are totally irrelevant in the absence of an electronic medical record. PMID- 29261022 TI - "Is the Doctor In?" PMID- 29261023 TI - Virtual CME. PMID- 29261024 TI - Toward patient-centered outcomes for cognitive evaluations: the perspective of those affected by Parkinson's disease. AB - OBJECTIVE: Patient-centered outcomes research is predicated on the idea that the opinions, attitudes, and preferences of patients should help inform study design and interpretation. To date, little is known about what defines patient-centered outcomes from cognitive evaluations. The current evaluation sought to explore this issue in persons with Parkinson's disease (PwPD) and their care partners (CP). METHOD: Focus groups of 22 PwPD/CP dyads were conducted to identify potential consumer oriented endpoints from cognitive evaluations. These endpoints were utilized to create a Patient-Centered Cognitive Assessment Outcomes Scale, which was administered to a different group of 50 PwPD/CP dyads who rated the importance of each outcome and identified their top three priority outcomes. RESULTS: Three themes emerged from the focus groups: improved knowledge, advice, and planning. Both PwPD and CP rated items in all three domains as being very important outcomes. Priorities for outcomes in both groups favored treatment planning information slightly above knowledge based outcomes. CONCLUSIONS: The PwPD and CP identified improved knowledge, advice for daily activities, and knowledge they could use to plan for future eventualities as very important. This information can be used as a framework for future studies aimed at demonstrating patient-centered outcomes from neuropsychological evaluations. Implications for future research are discussed. PMID- 29261025 TI - Free-Ranging Synanthropic Birds (Ardea alba and Columba livia domestica) as Carriers of Salmonella spp. and Diarrheagenic Escherichia coli in the Vicinity of an Urban Zoo. AB - The presence of free-ranging urban birds is a risk factor for transmitting pathogens to captive animals and humans alike, including Salmonella spp. and diarrheagenic Escherichia coli. Cloacal swabs from 156 synanthropic Great egrets (Ardea alba) and feral pigeons (Columba livia domestica) that inhabit the surroundings of an urban zoo were processed for the identification of Salmonella spp. and diarrheagenic E. coli pathotypes. Bacterial species identification and genotypic characterization employed the matrix-assisted laser desorption ionization-time of flight mass spectrometry and PCR techniques, respectively, comparing their phylogenetic profiles through amplified fragment length polymorphism (AFLP) analysis. A total of 11 birds were positive for Salmonella Typhimurium (7%) and 9 individuals (5.8%) for diarrheagenic E. coli (enteropathogenic E. coli/Shiga-toxin producing E. coli [EPEC/STEC]) strains. S. Typhimurium strains presented highly similar AFLP profiles (85-100%), whereas EPEC/STEC strains showed more polymorphism. The results show free-ranging birds as carriers for both microorganisms in a zoo environment in Brazil for the first time and suggest these species as possible sources of infection to other animals as well as exposing personnel and visitors to potential zoonotic microorganisms. The presence of carriers highlights the importance of a surveillance system and the need for preventive measures to avoid attracting growing number of synanthropic avian species. PMID- 29261026 TI - Improved Procedure for Induction of the Androgenetic Doubled Haploids in Zebrafish. AB - Androgenesis is useful for induction of doubled haploids from male genetic resources and contributes to the restoration of individuals from cryopreserved sperm. Here, we determined the suitable conditions for egg in vitro preservation and the suitable dose of UV irradiation for genetic inactivation of the egg nucleus, and established an improved procedure for induction of androgenetic doubled haploids in zebrafish. The suitable solution for egg preservation was evaluated by the fertilization rate using different types of solutions or conditions. Hank's solution with 0.5% bovine serum albumin (pH8.0) was suitable for the preservation of zebrafish eggs. In addition, we discovered an improvement of fertilization rates by temporal preservation of ovulated eggs in the suitable solution. UV irradiation of eggs at 50-75 mJ/cm2 induced haploid embryos. Microsatellite genotyping using eight loci revealed the paternity and homozygosity of the putative androgenetic doubled haploids. The yield rate of androgenetic doubled haploids, which were induced by UV irradiation and heat shock, ranged from 0.4% to 10.7%. PMID- 29261027 TI - Micro-RNA149 confers taxane resistance to malignant mesothelioma cells via regulation of P-glycoprotein expression. AB - Multidrug resistance (MDR) represents a major hindrance to the efficacy of cancer chemotherapeutics. While surgical resection, radiation, and chemotherapy can be used to reduce tumor size, the subsequent appearance of drug resistant cells is a frequent problem. One of the main contributors to the development of MDR is increased expression of multi-drug resistant protein 1 (MDR1), also known as P glycoprotein (P-gp). P-gp is a membrane-associated efflux pump that can efficiently remove internalized taxane-base chemotherapeutics thus preventing drug accumulation and maintaining cellular viability. Consequently, investigation into the molecular mechanisms responsible for regulation of P-gp expression is necessary to facilitate treatment of MDR tumors. Using molecular and biochemical approaches, we identified that the micro-RNA, miRNA149, contributes to the development of MDR within malignant mesothelioma cells by regulating the expression of MDR1. PMID- 29261030 TI - An extension of the fuzzy improved risk graph and fuzzy analytical hierarchy process for determination of chemical complex safety integrity levels. AB - The risk graph (RG) is widely used to evaluate the safety integrity level (SIL) of safety instrument systems (SIS). However, subjective opinion-based conventional RGs cannot provide successful results for the problems of risk parameters, such as shortages or lack of data; hence, the output of a conventional approach lacks sufficient reliability. We introduced the fuzzy improved risk graph (FIRG), an extension of fuzzy set theory, to deal with possible ambiguities during SIL study and increase the reliability of conventional RGs. In the present study, the levels of consequences defined as linguistic terms were converted into qualitative intervals; therefore, by correlating the proposed approach with experts' opinions and attributing weight factors, a desired SIL value was obtained. The output of this new approach can be compared directly with quantitative risk assessment techniques to improve the safety performance of industrial systems. PMID- 29261031 TI - Alterations of emotional reactivity following righttemporal lobectomy. AB - To learn if a right temporal lobectomy altered a patient's autonomic and cognitive responses to aversive and appetitive pictures, we investigated a man whose right anterior temporal lobe and amygdala had been resected to remove an arteriovenous malformation. This patient revealed unusually low self-reports of arousal with a lack of heightened skin conductance responses to aversive pictures. For pleasant pictures, his self-reports of arousal and his physiological responses were similar to healthy men. This patient's responses are consistent with a bivalent model of emotional processing, with a right temporal lobectomy compromising the activation of his defensive action response system. PMID- 29261029 TI - Injured lung endothelium: mechanisms of self-repair and agonist-assisted recovery (2017 Grover Conference Series). AB - The lung endothelium is vulnerable to both exogenous and endogenous insults, so a properly coordinated efficient repair system is essential for the timely recovery of the lung after injury. The agents that cause endothelial injury and dysfunction fall into a broad range from mechanical forces such as pathological cyclic stretch and shear stress to bacterial pathogens and their virulent components, vasoactive agonists including thrombin and histamine, metabolic causes including high glucose and oxidized low-density lipoprotein (OxLDL), circulating microparticles, and inflammatory cytokines. The repair mechanisms employed by endothelial cells (EC) can be broadly categorized into three groups: (1) intrinsic mechanism of recovery regulated by the cross-talk between small GTPases as exemplified by Rap1-mediated EC barrier recovery from Rho-mediated thrombin-induced EC hyperpermeability; (2) agonist-assisted recovery facilitated by the activation of Rac and Rap1 with subsequent inhibition of Rho signaling as observed with many barrier protective agonists including oxidized phospholipids, sphingosine 1-phosphate, prostacyclins, and hepatocyte growth factor; and (3) self-recovery of EC by the secretion of growth factors and other pro-survival bioactive compounds including anti-inflammatory molecules such as lipoxins during the resolution of inflammation. In this review, we will discuss the molecular and cellular mechanisms of pulmonary endothelium repair that is critical for the recovery from various forms of lung injuries. PMID- 29261033 TI - Changes in User Perceptions of a Telemedicine System Over Time: From Initial Implementation to Everyday Use. AB - BACKGROUND: Benefits associated with telemedicine are contingent upon positive user perceptions. Despite this, research on user perceptions of telemedicine remains limited. INTRODUCTION: Usability approaches offer a robust way to assess user perceptions, but have rarely been applied in telemedicine. In this study, a usability approach was employed to examine how user perceptions toward a telemedicine system changed over the course of everyday use. MATERIALS AND METHODS: A telemedicine system was introduced to a hospital in the home service. Ten mobile nurses completed the System Usability Scale (SUS) after initial use, then again after 18 months of everyday use. Results were compared. Analysis included Bangor et al.'s (2009) adjective rating scale. RESULTS: The initial SUS mean was 83 (standard deviation [SD] = 7.98), indicating "excellent" usability. After 18 months, the SUS mean was 64.38, indicating "OK" usability (SD = 14.25, p < 0.05, 95% confidence interval [CI]). Over time, users had lower desire to use the system frequently (p < 0.05, 95% CI), found it more complex (p < 0.05, 95% CI), and perceived greater inconsistency in its design (p < 0.05, 95% CI). DISCUSSION: Considered with existing evidence, our usability findings indicate that a temporary period of positive user perceptions occurs when new telemedicine systems are used for the first few months. This fades with everyday use, with design inconsistency and perceived complexity becoming more noticeable. Although other factors such as user satisfaction and efficiency may also contribute, further studies are needed for confirmation. CONCLUSIONS: User perceptions of telemedicine vary with time. To help maximize the benefits and longevity of telemedicine systems, responding to intermittent user appraisal is desirable. PMID- 29261032 TI - A Novel, Low-Cost Anesthesia and Injection System for Zebrafish Researchers. AB - In this study, we designed and developed a novel low-cost system for anesthetizing and injecting adult zebrafish. The system utilizes a gradual cooling method for the anesthesia and maintains the fish in a stable anesthetic plane, as well as stabilizes the animal so that intraperitoneal injections can be consistently performed. It is a system that any laboratory with access to a workshop can build for their group. Moreover, it is a safe system for researchers, as well as a reliable one for repeated experiments since multiple fish can be injected quickly and there is little physical contact necessary between the investigator and the animal. This will likely reduce any unnecessary stress in the fish, as compared with manual methods of injection. Finally, the system is adaptable so that as the investigators' procedural needs change due to different research questions, that is, gradual rewarming or something of that nature, it could be modified. PMID- 29261034 TI - MCM interference during licensing of DNA replication in Xenopus egg extracts Possible Role of a C-terminal region of MCM3. AB - The minichromosome maintenance (MCM) complex, consisting of six subunits, Mcm2-7, is loaded onto replication origins through loading factors (origin recognition complex [ORC], Cdc6, and Cdt1) and forms an MCM double hexamer that licenses the initiation of DNA replication. Previous studies with Xenopus egg extracts showed that loading factors, especially Cdc6, dissociate from chromatin on MCM loading, but the molecular mechanism and physiological significance remain largely unknown. Using a cell-free system for MCM loading onto plasmid DNA in Xenopus egg extracts, we found that MCM loaded onto DNA prevents DNA binding of the loading factors ORC, Cdc6, and Cdt1. We further report that a peptide of the C-terminal region of MCM3 (MCM3-C), previously implicated in the initial association with ORC/Cdc6 in budding yeast, prevents ORC/Cdc6/Cdt1 binding to DNA in the absence of MCM loading. ATP-gamma-S suppresses inhibitory activities of both the MCM loaded onto DNA and the MCM3-C peptide. Other soluble factors in the extract, but neither MCM nor Cdt1, are required for the activity. Conservation of the amino acid sequences of MCM3-C and its activity in vertebrates implies a novel negative autoregulatory mechanism that interferes with MCM loading in the vicinity of licensed origins to ensure proper origin licensing. PMID- 29261036 TI - Communication with Orthopedic Trauma Patients via an Automated Mobile Phone Messaging Robot. AB - BACKGROUND: Communication with orthopedic trauma patients is traditionally problematic with low response rates (RRs). The purpose of this investigation was to (1) evaluate the feasibility of communicating with orthopedic trauma patients postoperatively, utilizing an automated mobile phone messaging platform; and (2) assess the first 2 weeks of postoperative patient-reported pain and opioid use after lower extremity orthopedic trauma procedures. MATERIALS AND METHODS: This was a prospective investigation at a Level 1 trauma center in the United States. Adult patients who were capable of mobile phone messaging and were undergoing common, lower extremity orthopedic trauma procedures were enrolled in the study. Patients received a daily mobile phone message protocol inquiring about their current pain level and amount of opioid medication they had taken in the past 24 h starting on postoperative day (POD) 3 and continuing through POD 17. Our analysis considered (1) Patient completion rate of mobile phone questions, (2) Patient-reported pain level (0-10 scale), and (3) Number and percentage of daily prescribed opioid medication patients reported taking. RESULTS: Twenty-five patients were enrolled in this investigation. Patients responded to 87.5% of the pain and opioid medication inquiries they received over the 2-week study period. There were no differences in RRs by patient age, sex, or educational attainment. Patient-reported pain decreased over the initial 2-week study period from an average of 4.9 +/- 1.7 on POD 3 to 3 +/- 2.2 on POD 16-17. Patients took an average of 68% of their maximum daily narcotic prescription on POD 3 compared with 35% of their prescribed pain medication on POD 16-17. CONCLUSIONS: We found that in orthopedic trauma patients, an automated mobile phone messaging platform elicited a high patient RR that improved upon prior methods in the literature. This method may be used to reliably obtain pain and medication utilization data after trauma procedures. PMID- 29261028 TI - The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series). AB - The pulmonary vasculature plays an important role in many lung pathologies, such as pulmonary arterial hypertension, primary graft dysfunction of lung transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects of numerous drugs that have been trialed or approved. High doses of drugs targeting the pulmonary vasculature are needed due to the lack of specific affinity of therapeutic compounds to the vasculature. To overcome this problem, the field of targeted drug delivery aims to target drugs to the pulmonary endothelial cells, especially those in pathological regions. The field uses a variety of drug delivery systems (DDSs), ranging from nano-scale drug carriers, such as liposomes, to methods of conjugating drugs to affinity moieites, such as antibodies. These DDSs can deliver small molecule drugs, protein therapeutics, and imaging agents. Here we review targeted drug delivery to the pulmonary endothelium for the treatment of pulmonary diseases. Cautionary notes are made of the risk-benefit ratio and safety-parameters one should keep in mind when developing a translational therapeutic. PMID- 29261035 TI - Zebrafish Axenic Larvae Colonization with Human Intestinal Microbiota. AB - The human intestine hosts a vast and complex microbial community that is vital for maintaining several functions related with host health. The processes that determine the gut microbiome composition are poorly understood, being the interaction between species, the external environment, and the relationship with the host the most feasible. Animal models offer the opportunity to understand the interactions between the host and the microbiota. There are different gnotobiotic mice or rat models colonized with the human microbiota, however, to our knowledge, there are no reports on the colonization of germ-free zebrafish with a complex human intestinal microbiota. In the present study, we have successfully colonized 5 days postfertilization germ-free zebrafish larvae with the human intestinal microbiota previously extracted from a donor and analyzed by high throughput sequencing the composition of the transferred microbial communities that established inside the zebrafish gut. Thus, we describe for first time which human bacteria phylotypes are able to colonize the zebrafish digestive tract. Species with relevant interest because of their linkage to dysbiosis in different human diseases, such as Akkermansia muciniphila, Eubacterium rectale, Faecalibacterium prausnitzii, Prevotella spp., or Roseburia spp. have been successfully transferred inside the zebrafish digestive tract. PMID- 29261037 TI - How Surgeons Deal with Complications. PMID- 29261038 TI - Emotion, health decision making, and health behaviour. PMID- 29261040 TI - Fluorescent nanoparticles present in Coca-Cola and Pepsi-Cola: physiochemical properties, cytotoxicity, biodistribution and digestion studies. AB - Foodborne nanoparticles (NPs) have drawn great attention due to human health concerns. This study reports the detection of the presence of fluorescent NPs, about 5 nm, in two of the most popular beverages, Coca-Cola (Coke) and Pepsi-Cola (Pepsi). The NPs contain H, C and O, three elements with a tunable emission and with a quantum yield of 3.3 and 4.3% for Coke and Pepsi, respectively. The presence of sp3-hybridized carbon atoms of alcohols and ethers bonds was confirmed by NMR analysis. The NPs can be taken up by living cells and accumulate within cell membrane and cytoplasm. Evaluation of the acute toxicity of the NPs revealed that the BALB/c mice appeared healthy after administration of a single dose of 2 g kg-1 body weight. Analysis of glutamate pyruvate transaminase (GPT), glutamic oxaloacetic transaminase (GOT), urea and creatinine showed that there were statistically, but not biologically, significant differences in some of these biochemical parameters between the test and control groups. No obvious organ damage or apparent histopathological abnormality was observed in the tested mice. The biodistribution study in major organs indicated that the NPs were easily accumulated in the digestive tract, and they were able to cross the blood brain barrier and dispersed in the brain. In vitro digestion of the NPs showed a significant fluorescence quenching of the NPs. This work represents the first report of foodborne fluorescent NPs present in Coke and Pepsi, and provides valuable insights into physicochemical properties of these NPs and their toxicity characteristics both in vitro and in vivo. PMID- 29261041 TI - letter. PMID- 29261039 TI - Protective role of FKBP51 in calcium entry-induced endothelial barrier disruption. AB - Pulmonary artery endothelial cells (PAECs) express a cation current, ISOC (store operated calcium entry current), which when activated permits calcium entry leading to inter-endothelial cell gap formation. The large molecular weight immunophilin FKBP51 inhibits ISOC but not other calcium entry pathways in PAECs. However, it is unknown whether FKBP51-mediated inhibition of ISOC is sufficient to protect the endothelial barrier from calcium entry-induced disruption. The major objective of this study was to determine whether FKBP51-mediated inhibition of ISOC leads to decreased calcium entry-induced inter-endothelial gap formation and thus preservation of the endothelial barrier. Here, we measured the effects of thapsigargin-induced ISOC on the endothelial barrier in control and FKBP51 overexpressing PAECs. FKBP51 overexpression decreased actin stress fiber and inter-endothelial cell gap formation in addition to attenuating the decrease in resistance observed with control cells using electric cell-substrate impedance sensing. Finally, the thapsigargin-induced increase in dextran flux was abolished in FKBP51 overexpressing PAECs. We then measured endothelial permeability in perfused lungs of FKBP51 knockout (FKBP51-/-) mice and observed increased calcium entry-induced permeability compared to wild-type mice. To begin to dissect the mechanism underlying the FKBP51-mediated inhibition of ISOC, a second goal of this study was to determine the role of the microtubule network. We observed that FKBP51 overexpressing PAECs exhibited increased microtubule polymerization that is critical for inhibition of ISOC by FKBP51. Overall, we have identified FKBP51 as a novel regulator of endothelial barrier integrity, and these findings are significant as they reveal a protective mechanism for endothelium against calcium entry-induced disruption. PMID- 29261042 TI - brief reports. PMID- 29261043 TI - a need to know. PMID- 29261044 TI - Cricket Injuries: Fast Pitches Change the Gentleman's Sport. AB - Two signs of a changing game are chest protectors hidden beneath traditional team sweaters and metal batting helmets. PMID- 29261046 TI - Football Injury and Equipment Update. PMID- 29261049 TI - names and faces. PMID- 29261047 TI - Cyclo-Cross Racing: A Two-Wheeled Steeplechase. AB - Cyclo-cross racing requires significant upper body strength and cardiovascular conditioning. But injuries are usually minor in this grueling sport. PMID- 29261051 TI - scanning sports. PMID- 29261050 TI - Ultrasonic Phonophoresis. PMID- 29261052 TI - [Formula: see text]O2max: A Measure of Fitness. PMID- 29261053 TI - Mountaineering and Rock-Climbing Accidents. AB - In brief There were 71,655 rock climbers and mountaineers in the Grand Teton National Park from 1970 to 1980, and there were 144 accidents and 30 deaths. Because all climbers are required to register with park officials before climbing, accurate incidence rates can be determined. There were two accidents per 1,000 climbers per year, and this rate remained stable over the ten-year study period although the number of climbers increased. Characteristics associated with accidents included being the lead climber, ascending very steep rock, being inexperienced, and making errors in judgments. Fatal accidents appeared to be associated with travel on snow. PMID- 29261054 TI - Perthes Disease: Returning Children to Sports. AB - In brief The authors provide guidelines for returning children with Perthes disease to sporting activities. They suggest maintenance of hip motion and containment of the femoral head in the acetabulum until the extent of the femoral epiphyseal necrosis can be determined. Swimming and adaptive physical therapy help regain the motion and strengthen the hip abductor muscles. Abduction brace therapy is continued in patients with a risk of femoral head deformity until reossification of the necrotic femoral head begins. Surgical containment, as an alternative to brace therapy, is recommended when an orthosis is not socially tolerated. Once reossification of the femoral head occurs, the patient may begin full activity, but osteochondritis dissecans with an osteocartilaginous loose body should be considered if catching or locking of the hip joint occurs. PMID- 29261055 TI - My Character, My Art. PMID- 29261056 TI - Dealing With Catastrophic injuries. PMID- 29261057 TI - Martial Arts Injuries. AB - In brief A large survey of martial arts athletes was conducted, and 24, 112 injuries were identified. The areas most commonly injured were the thighs, legs, and digits. Contusions, sprains, and strains were the most common types of injuries. Most injuries occurred in less experienced people, and the number of injuries decreased as expertise and training increased. Only 47 serious injuries were recorded, a rate of 1 in 500 injuries. Most serious injuries, especially head injuries, occurred while sparring and in tournaments. Less than half the injuries that occur during tournaments are brought to the attending physician. This may be because the injuries were minor or because of tournament psychology. PMID- 29261058 TI - Sleep Disturbances at High Altitude. AB - In brief Sleep disturbances at high altitude may be caused by simple physical discomforts but may also be a symptom of acute mountain sickness (AMS). Nevertheless, restful sleep is necessary to perform work optimally the next day. Acclimatization is the best way to prevent AMS, but if drugs are used to promote sleep, acetazolamide is the drug of choice. During tests on Mt. Logan, all subjects said they slept better and had less morning headache after using acetazolamide. The amount of Cheyne-Stokes breathing was reduced, arterial oxygen saturation was improved, and there was no profound hypoxemia. Traditional sedatives are often used but should be used with caution because they can worsen sleep hypoxia, impair judgment and coordination the next day, and turn a climb into a life-threatening situation. PMID- 29261059 TI - Cardiovascular Complications of Recreational Physical Activity. AB - In brief To evaluate the incidence of major cardiovascular complications (CVCs) during recreational activity the authors conducted a five-year retrospective survey of fatal and nonfatal CVCs that occurred in community recreation centers during or immediately after exercise. Forty-eight facilities reported 30 nonfatal and 38 fatal CVCs. Although most (57%) occurred during court games and jogging, the data are insufficient to infer any increased relative risk during these activities. There was one nonfatal and one fatal event every 1,124,200 and 887,526 hours of participation, respectively. These data suggest a small acute risk of CVC in the general public during recreational activity. PMID- 29261060 TI - A Physiological Profile of Four Wheelchair Marathon Racers. AB - In brief A profile of four wheelchair marathon racers (WMRs) is presented including an athletic history, dietary habits, maximal oxygen uptake, and average race pace oxygen uptake (Vo2) values. These values were compared with those of able-bodied marathon runners matched for age and race time. The WMRs had lower Vo2 max, maximal heart rates, and higher respiratory exchange ratios, and they used a higher percentage of their Vo2 max and maximal heart rate at race pace. The authors suggest that a high degree of training is required to perform the grueling marathon. PMID- 29261061 TI - Monitoring Cardiac Patients: How Much Is Enough? AB - In brief ECG monitoring is generally recommended for patients in cardiac rehabilitation, but the optimal amount of monitoring is uncertain. This article reviews several questions regarding this issue. The authors conclude that monitoring during exercise testing is necessary to determine an appropriate exercise prescription for all cardiac patients, but additional monitoring is not indicated during upper extremity as opposed to lower extremity exercise. They also believe that all patients entering exercise programs soon after hospital discharge should be monitored for at least seven weeks, and preferably 12. Periodic monitoring is useful for recognizing potential problems and evaluating long-term medication effectiveness. PMID- 29261062 TI - Plasma Mineral Levels in Marathon Runners During a 20-Day Road Race. AB - In brief Sports nutritionists generally think an athlete's increased mineral requirements can be satisfied by a greater but well-balanced caloric intake. This study supports that concept, demonstrating that 12 male runners who consumed an unrestricted, isocaloric diet maintained normal plasma mineral levels without using mineral supplements during a 500-km (312-mile) road race. None of the nine minerals tested (calcium, phosphorus, sodium, potassium, chloride, magnesium, iron, copper, and zinc) showed tendencies to become persistently reduced over the 20-day period. PMID- 29261063 TI - Junior Olympics: Sports Medicine Health and Safety Recommendations. AB - In brief The sports medicine unit at Wake Forest University organized medical and paramedical personnel to care for the medical needs of 1,800 athletes competing in the 1981 Junior Olympic Games. Based on these experiences, the unit offers recommendations for sports medicine care at future large-scale sports competitions of an intensive short duration, including physician coverage at all competitive wrestling, judo, and boxing events; separation of throwing and running events in track-and-field competition; and communication among H all medical, ambulance, and security personnel. In addition, at least 20 certified athletic trainers are needed for events of this size. PMID- 29261064 TI - Sports Medicine in China: A Group Philosophy of Fitness. AB - Fitness is an important part of building health in this country of over a billion citizens. PMID- 29261065 TI - Ed Hixson: The World Is His Niche. AB - You can take Ed Hixson out of Lake Placid, but you can't take Lake Placid out of Hixson. PMID- 29261066 TI - Training Swimmers: How Coaches Get Results. AB - Swimming training techniques are in an evolutionary stage, and coaches need access to information that will help them decide which techniques are effective and safe. PMID- 29261068 TI - Expression of a T39N mutant Rab32 protein arrests mitochondria movement within neurites of differentiated SH-SY5Y cells. AB - We have shown that multiple sclerosis (MS) and endoplasmic reticulum (ER) stress induce Rab32, an ER/mitochondria-localized small GTPase. High levels of both dominant-active (Q85L) or dominant-inactive (T39N) Rab32 are toxic to neurons. While Rab32Q85L interacts with its effector Drp1 to promote mitochondria fission, it is unclear how Rab32T39N could result as toxic to neurons. Given the perinuclear clustering of mitochondria observed upon transfection of inactive Rab32, we hypothesized Rab32T39N could stall mitochondria within neurites. The movement of mitochondria depends on kinesin-binding Miro proteins. High cytosolic [Ca2+] is bound by an EF hand motif within Miro proteins, resulting in mitochondrial arrest. Consistent with increased cytosolic [Ca2+], expression of Rab32T39N arrests mitochondria movement within neurites. PMID- 29261067 TI - Take a Hike: Switzerland's Summer Challenge. AB - Switzerland in the summer is truly a hiker's paradise, with scenery ranging from mountain meadows to palm trees to the longest glacier in Europe. PMID- 29261070 TI - brief reports. PMID- 29261069 TI - Evaluating Menstrual Irregularity in Athletes. PMID- 29261071 TI - Project Pelion: A Challenge for the Disabled. AB - Eleven disabled climbers set out in July 1981 to show others, disabled and nondisabled, that severe handicaps could not prevent them from climbing Washington's Mt. Rainier. PMID- 29261072 TI - Take the Whole Idea. PMID- 29261073 TI - Noel D. Nequin: Crusading for Road-Race Safety. AB - Chicago cardiologist Noel Nequin may be better known for organizing road races than for his work with cardiac rehabilitation patients. PMID- 29261074 TI - The Barrier Islands of South Carolina. AB - Three islands off the coast of Charleston-Kiawah, Seabrook, and Isle of Palms have recently emerged as year-round resort areas whose towering dunes, rough marshes, and brisk sea breezes make them a compelling attraction for golfers and tennis players. PMID- 29261075 TI - Intensity of Old-Timer Hockey Play. AB - In brief Twelve men (mean age 32 years) from six recreational hockey leagues in the Montreal area were measured for heart rate during league old-timer hockey games. The games were divided into six activities, including recovery on the bench, according to intensity of play so that heart rates could be matched to different parts of the game. Mean heart rate during hockey play was 161 beats-min 1, and 85% intensity (Karvonen method). Because this represents strenuous activity, communities should encourage physically unfit men to improve their fitness before playing old-timer hockey. PMID- 29261076 TI - Cold-Weather Clothing for Comfort or Heat Conservation. AB - In brief Analyses of core and peripheral temperatures in young men and women dressed in cold-weather clothing at various levels of cold indicate that the distribution of thermal insulation over the body can complement or confuse physiological heat conservation mechanisms. For short exposures, heavily insulating the hands and feet prevents cold discomfort. However, overinsulating the hands and feet for longer exposures may result in a decreased core temperature and shivering. More thermal insulation over the torso than the hands and feet complements physiological heat conservation mechanisms and maintains core temperature. PMID- 29261077 TI - scanning sports. PMID- 29261078 TI - ICE for Immediate Care of Injuries. PMID- 29261079 TI - Ski Binding Biomechanics. AB - In brief The binding is the most important factor for causing or preventing skiing injuries. Its function is to hold the ski during normal maneuvers but release it when injury-producing loads are encountered. Binding-related injuries are usually due to improper design, installation, adjustment, and maintenance. Advanced skiers who want to avoid inadvertent release can use two-mode release bindings, but beginners should use multimode bindings. Before skiing, skiers should make sure their bindings release in all directions without causing pain. Equipment should be up to date and functionally tested by a qualified shop mechanic. PMID- 29261080 TI - Preparing for a Winter Backpacking Trip. PMID- 29261081 TI - Strength Testing After Jaw Repositioning With a Mandibular Orthopedic Appliance. AB - In brief More athletes are using mandibular orthopedic repositioning appliances (MORAs), and many have claimed they cause surprising performance improvements. However, most research on this subject has suffered from serious design problems. In this double-blind experiment, control, experimental, and placebo groups of college students were tested for left and right maximal grip strength and endurance, maximal quadriceps and hamstring dynamic strength, and maximal quadriceps and hamstring static strength. Statistical analysis of the results showed that the devices did not increase the strength of the muscle groups measured or the muscular endurance of the hand. PMID- 29261082 TI - letters. PMID- 29261083 TI - Endorphins and Exercise: A Puzzling Relationship. AB - Increased blood levels of endorphins after exercise have been cited to explain everything from runners' high to reduced pain perception, but little is known about these recently isolated substances or their functions. PMID- 29261084 TI - a need to know. PMID- 29261085 TI - Athletic Performance in Children With Cardiovascular Problems. AB - In brief The effects of physical training include cardiovascular and specific muscle adaptation, decreased resting heart rate, and increased cardiac size, stroke volume, maximum cardiac output, blood volume, vagal tone, and maximum breathing capacity. Young athletes with heart disease can generally participate in sports, but there is a wide spectrum of ability among them. The treadmill exercise test should be used to establish exercise norms. Children with severe mitral stenosis, aortic stenosis, idiopathic hypertrophic subaortic stenosis, active myocarditis, pulmonary hypertension, and significant arrhythmias should not participate in strenuous sports. Others with cardiac problems should be encouraged to participate for enjoyment rather than winning. PMID- 29261086 TI - Physiological Effects of Power Volleyball. AB - In brief The six collegiate male volleyball players in this study had moderate aerobic capacity (56 ml.kg-1.min-1) and predominantly fast twitch fiber distribution (57%) in the vastus lateralis muscle. Prolonged volleyball play resulted in a greater depletion of glycogen in slow twitch fibers than in fast twitch and no hint of anaerobic fatigue. These results suggest that in spite of the apparent explosive activity of volleyball, the overall intensity is probably mild to moderate and therefore aerobic endurance may be critical to performance. PMID- 29261088 TI - Cognitive and gait decrements among non-demented older adults with Type 2 diabetes or hypertension: a systematic review. AB - OBJECTIVE: Older adults with Type 2 diabetes (DM2) and hypertension (HTN) often experience cognitive weaknesses. Growing evidence suggests that such weaknesses place patients at risk for gait disturbance and falls. The current systematic review evaluated (a) the impact of DM2 and HTN on cognition and gait and (b) the association between cognition and gait in the context of DM2 and HTN. METHODS: PubMed was searched to identify studies published in English before 15 April 2017 that evaluated both cognition and gait among non-demented older adults either as a function of DM2 or HTN status or as a function of continuous variables that indicate disease severity and/or management (e.g. blood pressure, HbA1C). Risk of bias was assessed by examining the method of verifying HTN/DM2 and excluding dementia as well as included covariates. RESULTS: In the majority of studies reviewed (n = 17), both DM2 and HTN status were associated with poorer cognitive and/or gait functioning (8 out of 10 studies). In addition, in 10 out of 11 studies cognition was reliably associated with gait. For continuous variables, higher systolic blood pressure (measured with ambulatory methods) was consistently related to poorer cognition and slower gait, but other continuous variables (e.g. HbA1C) were studied inconsistently with inconclusive results. CONCLUSIONS: Cognitive and gait decrements are not only common in the context of HTN and DM2, but also are related to each other. This suggests that clinical neuropsychologists should address cognitive contributions to gait disturbance and falls in their clinical work and research with these patient populations. PMID- 29261090 TI - Outcomes of Adolescent and Young Adults Receiving High Ligation and Mesh Repairs: A 16-Year Experience. AB - INTRODUCTION: Interestingly, the pediatric and adult surgeons perform vastly different operations in similar patient populations. Little is known about long term recurrence and quality of life (QOL) in adolescents and young adults undergoing inguinal hernia repair. We evaluated long-term patient-centered outcomes in this population to determine the optimal operative approach. METHODS: The medical records of patients 12-25 years old at the time of a primary inguinal hernia repair at our institution from 2000 to 2016 were retrospectively reviewed. Patients then completed a phone survey of their postoperative courses and QOL. Outcomes of high ligation performed by pediatric surgeons were compared to those of mesh repairs by adult general surgeons. The primary outcome was recurrence. Secondary outcomes included time to recurrence, postoperative complications, and patient-centered outcomes. A Cox regression analysis was used to determine associations for recurrence. RESULTS: Of 213 patients identified, 143 (67.1%) were repaired by adult surgeons and 70 (32.9%) repaired by pediatric surgeons. Overall recurrence rate for the entire cohort was 5.7% with a median time to recurrence of 3.5 years (interquartile range 120-2155 days). High ligation and mesh repairs had similar rates of recurrence (6.3 versus 5.8, P = .57) and postoperative complications (17% versus 16%, P = .45). 101/213 (47%) patients completed the phone survey. Of those surveyed, 20% reported postoperative pain, 10% had residual numbness and tingling, and 10% of patients complained of intermittent bulging. Overall, a survey comparison showed no differences among subgroups. CONCLUSIONS: In adolescents and young adults, the long-term recurrence rate after inguinal hernia repair is ~6% with time to recurrence approaching 4 years. Outcomes of high ligation and mesh repair are similar, highlighting the need for individualized approaches for this unique population. PMID- 29261089 TI - The Collaborative Ocular Tuberculosis Study (COTS)-1 Report 3: Polymerase Chain Reaction in the Diagnosis and Management of Tubercular Uveitis: Global Trends. AB - PURPOSE: To analyze the role of polymerase chain reaction (PCR) of ocular fluids in management of tubercular (TB) anterior, intermediate, posterior, and panuveitis. METHODS: In Collaborative Ocular Tuberculosis Study (COTS)-1 (25 centers, n = 962), patients with TB-related uveitis were included. 59 patients undergoing PCR of intraocular fluids (18 females; 53 Asian Indians) were included. RESULTS: 59 (6.13%) of COTS-1 underwent PCR analysis. PCR was positive for Mycobacterium TB in 33 patients (23 males; all Asian Indians). 26 patients were PCR negative (18 males). Eight patients with negative PCR had systemic TB. Anti-TB therapy was given in 18 negative and 31 PCR cases. At 1-year follow-up, five patients with positive PCR (15.15%) and three with negative PCR (11.54%) had persistence/worsening of inflammation. CONCLUSIONS: Data from COTS-1 suggest that PCR is not commonly done for diagnosing intraocular TB and positive/negative results may not influence management or treatment outcomes in the real world scenario. PMID- 29261092 TI - Recognition of Azole-Resistant Aspergillosis by Physicians Specializing in Infectious Diseases, United States. AB - Infections caused by pan-azole-resistant Aspergillus fumigatus strains have emerged in Europe and recently in the United States. Physicians specializing in infectious diseases reported observing pan-azole-resistant infections and low rates of susceptibility testing, suggesting the need for wider-scale testing. PMID- 29261091 TI - Association of Enterococcus spp. with Severe Combat Extremity Injury, Intensive Care, and Polymicrobial Wound Infection. AB - BACKGROUND: Combat-related extremity wound infections can complicate the recovery of injured military personnel. The Enterococcus genus contains both commensal and pathogenic bacteria found in many combat wounds. We describe the patient population susceptible to Enterococcus infection, the characteristics of Enterococcus spp. isolated from combat-related wounds, and the microbiological profile of Enterococcus-positive wounds. METHODS: Patient and culture data were obtained from the Trauma Infectious Disease Outcomes Study. Subjects were divided into a case group with enterococcal extremity wound infections and a comparator group with wound infections caused by other micro-organisms. RESULTS: Case and comparator subjects had similar patterns of injury and infection. Case subjects had higher Injury Severity Scores (33 vs. 30; p < 0.001), longer hospitalization at U.S. facilities (55 vs. 40 days; p = 0.004), and required more large-volume blood transfusions (>20 units) within 24 h post-injury (53% vs. 30%; p < 0.001). Approximately 60% of case subjects had three or more infections, and 91% had one or more polymicrobial infections, compared with 43% and 50%, respectively, in the comparator group. The thigh was the most common site of Enterococcus spp. isolation, contributing 50% of isolates. Enterococcus faecium was the predominant species isolated from case-group infections overall (66%), as well as in polymicrobial infections (74%). Frequent co-colonizing microbes in polymicrobial wound infections with Enterococcus were other ESKAPE pathogens (64%) (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae [and Escherichia coli], Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) and fungi (35%). CONCLUSIONS: The specific pathogenicity of Enterococcus relative to other pathogens in polymicrobial wounds is unknown. Identifying strain-specific outcomes and investigating the interactions of Enterococcus strains with other wound pathogens could provide additional tools and strategies for infection mitigation in combat-related wounds. PMID- 29261093 TI - Two-Center Evaluation of Disinfectant Efficacy against Ebola Virus in Clinical and Laboratory Matrices. AB - Ebola virus (EBOV) in body fluids poses risk for virus transmission. However, there are limited experimental data for such matrices on the disinfectant efficacy against EBOV. We evaluated the effectiveness of disinfectants against EBOV in blood on surfaces. Only 5% peracetic acid consistently reduced EBOV titers in dried blood to the assay limit of quantification. PMID- 29261094 TI - Postmortem Findings in Patient with Guillain-Barre Syndrome and Zika Virus Infection. AB - Postmortem examination results of a patient with Guillain-Barre syndrome and confirmed Zika virus infection revealed demyelination of the sciatic and cranial IV nerves, providing evidence of the acute demyelinating inflammatory polyneuropathy Guillain-Barre syndrome variant. Lack of evidence of Zika virus in nervous tissue suggests that pathophysiology was antibody mediated without neurotropism. PMID- 29261095 TI - Phonon-driven electron scattering and magnetothermoelectric effect in two dimensional tin selenide. AB - The bulk tin selenide (SnSe) is the best thermoelectric material currently with the highest figure-of-merit due to strong phonon-phonon interactions. We investigate the effect of electron-phonon coupling (EPC) on the transport properties of a two-dimensional (2D) SnSe sheet. We demonstrate that EPC plays a key role in the scattering rate when the constant relaxation time approximation is deficient. The EPC strength is especially large in contrast to that of pristine graphene. The scattering rate depends sensitively on the system temperatures and the carrier densities when the Fermi energy approaches the band edge. We also investigate the magnetothermoelectric effect of the 2D SnSe. It is found that at low temperatures there is enormous magnetoelectrical resistivity and magnetothermal resistivity above 200%, suggesting possible potential applications in device design. Our results agree qualitatively well with the experimental data. PMID- 29261096 TI - Novel design of honeybee-inspired needles for percutaneous procedure. AB - The focus of this paper is to present new designs of innovative bioinspired needles to be used during percutaneous procedures. Insect stingers have been known to easily penetrate soft tissues. Bioinspired needles mimicking the barbs in a honeybee stinger were developed for a smaller insertion force, which can provide a less invasive procedure. Decreasing the insertion force will decrease the tissue deformation, which is essential for more accurate targeting. In this study, some design parameters, in particular, barb shape and geometry (i.e. front angle, back angle, and height) were defined, and their effects on the insertion force were investigated. Three-dimensional printing technology was used to manufacture bioinspired needles. A specially-designed insertion test setup using tissue mimicking polyvinyl chloride (PVC) gels was developed to measure the insertion and extraction forces. The barb design parameters were then experimentally modified through detailed experimental procedures to further reduce the insertion force. Different scales of the barbed needles were designed and used to explore the size-scale effect on the insertion force. To further investigate the efficacy of the proposed needle design in real surgeries, preliminary ex vivo insertion tests into bovine liver tissue were performed. Our results show that the insertion force of the needles in different scales decreased by 21-35% in PVC gel insertion tests, and by 46% in bovine liver tissue insertion tests. PMID- 29261097 TI - Polymer architecture of magnetic gels: a review. AB - In this review article, we provide an introduction to ferrogels, i.e. polymeric gels with embedded magnetic particles. Due to the interplay between magnetic and elastic properties of these materials, they are promising candidates for engineering and biomedical applications such as actuation and controlled drug release. Particular emphasis will be put on the polymer architecture of magnetic gels since it controls the degrees of freedom of the magnetic particles in the gel, and it is important for the particle-polymer coupling determining the mechanisms available for the gel deformation in magnetic fields. We report on the different polymer architectures that have been realized so far, and provide an overview of synthesis strategies and experimental techniques for the characterization of these materials. We further focus on theoretical and simulational studies carried out on magnetic gels, and highlight their contributions towards understanding the influence of the gels' polymer architecture. PMID- 29261098 TI - Contribution of interventional cardiology to the collective dose in Spain. AB - INTRODUCTION AND OBJECTIVES: To estimate the contribution of interventional cardiology (IC) to the collective dose in Spain. METHODS: Using the information on frequencies of examinations sourced from the Spanish Society of Cardiology and the patient dose values obtained by the national DOCCACI programme. RESULTS: The fraction of the collective dose per million inhabitants derived from IC was 34 man-Sv (a total of 1600 man-Sv in Spain with 46.5 million inhabitants). The contribution of the IC derived from the medical use of x-rays in Spain resulted in 0.66% of the procedures and 4% of the x-ray collective dose. CONCLUSIONS: Even if this collective radiation dose may seem moderate, at an individual level this medical practice delivers the greatest doses and, therefore, optimisation remains of paramount importance. PMID- 29261099 TI - Body stiffness in orthogonal directions oppositely affects worm-like robot turning and straight-line locomotion. AB - Earthworms locomote using traveling waves of segment contraction and expansion, which when symmetric result in straight-line locomotion and when biased result in turning. The mechanics of the soft body permit a large range of possible body shapes which both comply with the environment and contribute to directed locomotion. Inspired by earthworms, our new platform Compliant Modular Mesh Worm robot with Steering (CMMWorm-S) has been developed to study this type of locomotion. Compared with our previous robots, CMMWorm-S is capable of an entirely new movement (turning) using two actuated degrees of freedom per segment (a total of 12 motors). The modularity of the mesh, composed of 3D printed rigid pieces and flexible tubes, allows for the interchange of components to vary the stiffness of the robot. On this robotic platform, we show that locomotion efficiency is sensitive to body stiffness. In particular, greater bending stiffness improves turning locomotion, whereas greater circumferential stiffness speeds straight-line locomotion. The data presented demonstrate the contribution of each component towards the longitudinal, circumferential and bending stiffness of mesh-based robots. These analyses can help in the development of design criteria useful for future soft robotic peristaltic devices. PMID- 29261100 TI - Institutional computed tomography diagnostic reference levels based on water equivalent diameter and size-specific dose estimates. AB - Size-specific institutional diagnostic reference levels (DRLs) were generated for chest and abdominopelvic computed tomography (CT) based on size-specific dose estimates (SSDEs) and depending on patients' water-equivalent diameter (Dw). 1690 CT examinations were included in the IRB-approved retrospective study. SSDEs based on the mean water-equivalent diameter of the entire scan volume were calculated automatically. SSDEs were analyzed for different patient sizes and institutional DRLs (iDRLS; 75% percentiles) based on Dw and SSDEs were generated. iDRLs were compared to the national DRLs. Mean volumetric computed tomography dose index (CTDIvol), Dw and SSDEs for all 1690 CT examinations were 7.2 +/- 4.0 mGy (0.84-47.9 mGy), 29.0 +/- 3.4 cm and 8.5 +/- 3.8 mGy (1.2-37.7 mGy), respectively. Overall, the mean SSDEs of all CT examinations were higher than the CTDIvol in chest CT, abdominopelvic CT and upper abdominal CT, respectively (p < 0.001 for all). There was a strong linear correlation between Dw and SSDEs in chest (R2 = 0.66), abdominopelvic (R2 = 0.98) and upper abdominal CT (R2 = 0.96) allowing for the implementation of size-specific institutional DRLs based on SSDEs and patients' Dw. We generated size-specific, Dw-dependent institutional DRLs based on SSDEs, which allow for easier and more comprehensive analyses of CT radiation exposure. Our results indicate that implementation of SSDEs into national DRLs may be beneficial. PMID- 29261101 TI - Differential Expression of VvLOXA Diversifies C6 Volatile Profiles in Some Vitis vinifera Table Grape Cultivars. AB - C6 volatiles are synthesized through lipoxygenase-hydroperoxide lyase (LOX-HPL) pathway and these volatiles play important roles in the aromatic quality of grape berries. This study investigated the evolution of both C6 volatiles and the key genes in the LOX-HPL pathway in different table grape cultivars during the berry development period, and further assessed the correlation between the accumulation of C6 volatiles and the expression of these genes in these cultivars. Results showed that hexanal, (E)-2-hexenal, (E)-2-hexen-1-ol and (Z)-3-hexen-1-ol were found to be the dominant C6 volatiles in these ripened grape cultivars under two consecutive vintages, and their flavor notes were incorporated in the overall aroma of these cultivars. The cultivar "Xiangfei" showed the most abundant level of C6 aldehydes and C6 acid, whereas the cultivar "Tamina" and "Moldova" possessed the highest C6 alcohol content. The "Muscat of Alexandria" cultivar was found to contain the highest level of C6 esters. C6 volatiles were grouped into three evolutionary patterns in these cultivars during berry development, and their evolution was consistent with the evolution of the LOX-HPL pathway genes' expression. Pearson's correlation analysis indicated that the LOX-HPL-pathway related genes were correlated to the accumulation of C6 volatiles in these cultivars, and VvLOXA appeared to be an important gene that regulated the synthesis of all C6 volatiles. PMID- 29261102 TI - Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies. AB - The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance. In the present work, a chemical library of 250 compounds was evaluated to determine their inhibition capability on the protein PTP1B. Ten molecules inhibited over the 50% of the activity of the PTP1B, the three most potent molecules were selected for its characterization, reporting Ki values of 5.2, 4.2 and 41.3 uM, for compounds 1, 2, and 3, respectively. Docking and molecular dynamics studies revealed that the three inhibitors made interactions with residues at the secondary binding site to phosphate, exclusive for PTP1B. The data reported here support these compounds as hits for the design more potent and selective inhibitors against PTP1B in the search of new antidiabetic treatment. PMID- 29261103 TI - Calli Essential Oils Synergize with Lawsone against Multidrug Resistant Pathogens. AB - The fast development of multi-drug resistant (MDR) organisms increasingly threatens global health and well-being. Plant natural products have been known for centuries as alternative medicines that can possess pharmacological characteristics, including antimicrobial activities. The antimicrobial activities of essential oil (Calli oil) extracted from the Calligonum comosum plant by hydro steam distillation was tested either alone or when combined with lawsone, a henna plant naphthoquinone, against MDR microbes. Lawsone showed significant antimicrobial activities against MDR pathogens in the range of 200-300 ug/mL. Furthermore, Calli oil showed significant antimicrobial activities against MDR bacteria in the range of 180-200 ug/mL, Candida at 220-240 ug/mL and spore forming Rhizopus fungus at 250 ug/mL. Calli oil's inhibition effect on Rhizopus, the major cause of the lethal infection mucormycosis, stands for 72 h, followed by an extended irreversible white sporulation effect. The combination of Calli oil with lawsone enhanced the antimicrobial activities of each individual alone by at least three-fold, while incorporation of both natural products in a liposome reduced their toxicity by four- to eight-fold, while maintaining the augmented efficacy of the combination treatment. We map the antimicrobial activity of Calli oil to its major component, a benzaldehyde derivative. The findings from this study demonstrate that formulations containing essential oils have the potential in the future to overcome antimicrobial resistance. PMID- 29261105 TI - Liposomal Circular Dichroism (L-CD) of Arenoyl Derivatives of Sphingolipids. Amplification of Cotton Effects in Ordered Lipid Bilayers. AB - Liposomal circular dichroism (L-CD) of acyclic amino alcohols exhibit amplification of Cotton effects when measured in highly uniform, unilamellar liposomes. The effect is likely due to intermolecular associations-H-aggregates that self-assemble spontaneously within the lipid bilayer, and persists over long time scales. L-CD spectra of N,O,O'-tri-(6'methoxy-2'-naphthoyl)-d-erythro sphingosine, or the corresponding dihydro-derivative (sphinganine), shows ~10 fold amplification of magnitudes of Cotton effects over conventional CD spectra recorded in isotropic solution. PMID- 29261106 TI - Structure and Optical Properties of Titania-PDMS Hybrid Nanocomposites Prepared by In Situ Non-Aqueous Synthesis. AB - Organic-inorganic hybrid materials are attractive due to the combination of properties from the two distinct types of materials. In this work, transparent titania-polydimethylsiloxane hybrid materials with up to 15.5 vol. % TiO2 content were prepared by an in situ non-aqueous method using titanium (IV) isopropoxide and hydroxy-terminated polydimethylsiloxane as precursors. Spectroscopy (Fourier transform infrared, Raman, Ultraviolet-visible, ellipsometry) and small-angle X ray scattering analysis allowed to describe in detail the structure and the optical properties of the nanocomposites. Titanium alkoxide was successfully used as a cross-linker and titania-like nanodomains with an average size of approximately 4 nm were shown to form during the process. The resulting hybrid nanocomposites exhibit high transparency and tunable refractive index from 1.42 up to 1.56, depending on the titania content. PMID- 29261104 TI - Biology of Porcine Parvovirus (Ungulate parvovirus 1). AB - Porcine parvovirus (PPV) is among the most important infectious agents causing infertility in pigs. Until recently, it was thought that the virus had low genetic variance, and that prevention of its harmful effect on pig fertility could be well-controlled by vaccination. However, at the beginning of the third millennium, field observations raised concerns about the effectiveness of the available vaccines against newly emerging strains. Subsequent investigations radically changed our view on the evolution and immunology of PPV, revealing that the virus is much more diverse than it was earlier anticipated, and that some of the "new" highly virulent isolates cannot be neutralized effectively by antisera raised against "old" PPV vaccine strains. These findings revitalized PPV research that led to significant advancements in the understanding of early and late viral processes during PPV infection. Our review summarizes the recent results of PPV research and aims to give a comprehensive update on the present understanding of PPV biology. PMID- 29261107 TI - Genome-Wide Identification, Evolutionary and Expression Analyses of the GALACTINOL SYNTHASE Gene Family in Rapeseed and Tobacco. AB - Galactinol synthase (GolS) is a key enzyme in raffinose family oligosaccharide (RFO) biosynthesis. The finding that GolS accumulates in plants exposed to abiotic stresses indicates RFOs function in environmental adaptation. However, the evolutionary relationships and biological functions of GolS family in rapeseed (Brassica napus) and tobacco (Nicotiana tabacum) remain unclear. In this study, we identified 20 BnGolS and 9 NtGolS genes. Subcellular localization predictions showed that most of the proteins are localized to the cytoplasm. Phylogenetic analysis identified a lost event of an ancient GolS copy in the Solanaceae and an ancient duplication event leading to evolution of GolS4/7 in the Brassicaceae. The three-dimensional structures of two GolS proteins were conserved, with an important DxD motif for binding to UDP-galactose (uridine diphosphate-galactose) and inositol. Expression profile analysis indicated that BnGolS and NtGolS genes were expressed in most tissues and highly expressed in one or two specific tissues. Hormone treatments strongly induced the expression of most BnGolS genes and homologous genes in the same subfamilies exhibited divergent-induced expression. Our study provides a comprehensive evolutionary analysis of GolS genes among the Brassicaceae and Solanaceae as well as an insight into the biological function of GolS genes in hormone response in plants. PMID- 29261108 TI - Activation of Recombinantly Expressed l-Amino Acid Oxidase from Rhizoctonia solani by Sodium Dodecyl Sulfate. AB - l-Amino acid oxidases (l-AAO) catalyze the oxidative deamination of l-amino acids to the corresponding alpha-keto acids. The non-covalently bound cofactor FAD is reoxidized by oxygen under formation of hydrogen peroxide. We expressed an active l-AAO from the fungus Rhizoctonia solani as a fusion protein in E. coli. Treatment with small amounts of the detergent sodium dodecyl sulfate (SDS) stimulated the activity of the enzyme strongly. Here, we investigated whether other detergents and amphiphilic molecules activate 9His-rsLAAO1. We found that 9His-rsLAAO1 was also activated by sodium tetradecyl sulfate. Other detergents and fatty acids were not effective. Moreover, effects of SDS on the oligomerization state and the protein structure were analyzed. Native and SDS activated 9His-rsLAAO1 behaved as dimers by size-exclusion chromatography. SDS treatment induced an increase in hydrodynamic radius as observed by size exclusion chromatography and dynamic light scattering. The activated enzyme showed accelerated thermal inactivation and an exposure of additional protease sites. Changes in tryptophan fluorescence point to a more hydrophilic environment. Moreover, FAD fluorescence increased and a lower concentration of sulfites was sufficient to form adducts with FAD. Taken together, these data point towards a more open conformation of SDS-activated l-amino acid oxidase facilitating access to the active site. PMID- 29261111 TI - Computer Simulations of Lipid Nanoparticles. AB - Lipid nanoparticles (LNP) are promising soft matter nanomaterials for drug delivery applications. In spite of their interest, little is known about the supramolecular organization of the components of these self-assembled nanoparticles. Here, we present a molecular dynamics simulation study, employing the Martini coarse-grain forcefield, of self-assembled LNPs made by tripalmitin lipid in water. We also study the adsorption of Tween 20 surfactant as a protective layer on top of the LNP. We show that, at 310 K (the temperature of interest in biological applications), the structure of the lipid nanoparticles is similar to that of a liquid droplet, in which the lipids show no nanostructuration and have high mobility. We show that, for large enough nanoparticles, the hydrophilic headgroups develop an interior surface in the NP core that stores liquid water. The surfactant is shown to organize in an inhomogeneous way at the LNP surface, with patches with high surfactant concentrations and surface patches not covered by surfactant. PMID- 29261109 TI - omega-3 Long Chain Polyunsaturated Fatty Acids as Sensitizing Agents and Multidrug Resistance Revertants in Cancer Therapy. AB - Chemotherapy efficacy is strictly limited by the resistance of cancer cells. The omega-3 long chain polyunsaturated fatty acids (omega-3 LCPUFAs) are considered chemosensitizing agents and revertants of multidrug resistance by pleiotropic, but not still well elucidated, mechanisms. Nowadays, it is accepted that alteration in gene expression, modulation of cellular proliferation and differentiation, induction of apoptosis, generation of reactive oxygen species, and lipid peroxidation are involved in omega-3 LCPUFA chemosensitizing effects. A crucial mechanism in the control of cell drug uptake and efflux is related to omega-3 LCPUFA influence on membrane lipid composition. The incorporation of docosahexaenoic acid in the lipid rafts produces significant changes in their physical-chemical properties affecting content and functions of transmembrane proteins, such as growth factors, receptors and ATP-binding cassette transporters. Of note, omega-3 LCPUFAs often alter the lipid compositions more in chemoresistant cells than in chemosensitive cells, suggesting a potential adjuvant role in the treatment of drug resistant cancers. PMID- 29261112 TI - Optimization Technology of the LHS-1 Strain for Degrading Gallnut Water Extract and Appraisal of Benzene Ring Derivatives from Fermented Gallnut Water Extract Pyrolysis by Py-GC/MS. AB - Gallnut water extract (GWE) enriches 80~90% of gallnut tannic acid (TA). In order to study the biodegradation of GWE into gallic acid (GA), the LHS-1 strain, a variant of Aspergillus niger, was chosen to determine the optimal degradation parameters for maximum production of GA by the response surface method. Pyrolysis gas chromatography-mass spectrometry (Py-GC/MS) was first applied to appraise benzene ring derivatives of fermented GWE (FGWE) pyrolysis by comparison with the pyrolytic products of a tannic acid standard sample (TAS) and GWE. The results showed that optimum conditions were at 31 degrees C and pH of 5, with a 50-h incubation period and 0.1 g.L-1 of TA as substrate. The maximum yields of GA and tannase were 63~65 mg.mL-1 and 1.17 U.mL-1, respectively. Over 20 kinds of compounds were identified as linear hydrocarbons and benzene ring derivatives based on GA and glucose. The key benzene ring derivatives were 3,4,5 trimethoxybenzoic acid methyl ester, 3-methoxy-1,2-benzenediol, and 4-hydroxy-3,5 dimethoxy-benzoic acid hydrazide. PMID- 29261110 TI - Recent Development of Prebiotic Research-Statement from an Expert Workshop. AB - A dietary prebiotic is defined as 'a substrate that is selectively utilized by host microorganisms conferring a health benefit'. Although this definition evolved concomitantly with the knowledge and technological developments that accrued in the last twenty years, what qualifies as prebiotic continues to be a matter of debate. In this statement, we report the outcome of a workshop where academic experts working in the field of prebiotic research met with scientists from industry. The workshop covered three main topics: (i) evolution of the prebiotic concept/definition; (ii) the gut modeling in vitro technology PolyFermS to study prebiotic effects; and (iii) the potential novel microbiome-modulating effects associated with vitamins. The future of prebiotic research is very promising. Indeed, the technological developments observed in recent years provide scientists with powerful tools to investigate the complex ecosystem of gut microbiota. Combining multiple in vitro approaches with in vivo studies is key to understanding the mechanisms of action of prebiotics consumption and their potential beneficial effects on the host. PMID- 29261113 TI - Enhancing Time Synchronization Support in Wireless Sensor Networks. AB - With the emerging Internet of Things (IoT) technology becoming reality, a number of applications are being proposed. Several of these applications are highly dependent on wireless sensor networks (WSN) to acquire data from the surrounding environment. In order to be really useful for most of applications, the acquired data must be coherent in terms of the time in which they are acquired, which implies that the entire sensor network presents a certain level of time synchronization. Moreover, to efficiently exchange and forward data, many communication protocols used in WSN rely also on time synchronization among the sensor nodes. Observing the importance in complying with this need for time synchronization, this work focuses on the second synchronization problem, proposing, implementing and testing a time synchronization service for low-power WSN using low frequency real-time clocks in each node. To implement this service, three algorithms based on different strategies are proposed: one based on an auto correction approach, the second based on a prediction mechanism, while the third uses an analytical correction mechanism. Their goal is the same, i.e., to make the clocks of the sensor nodes converge as quickly as possible and then to keep them most similar as possible. This goal comes along with the requirement to keep low energy consumption. Differently from other works in the literature, the proposal here is independent of any specific protocol, i.e., it may be adapted to be used in different protocols. Moreover, it explores the minimum number of synchronization messages by means of a smart clock update strategy, allowing the trade-off between the desired level of synchronization and the associated energy consumption. Experimental results, which includes data acquired from simulations and testbed deployments, provide evidence of the success in meeting this goal, as well as providing means to compare these three approaches considering the best synchronization results and their costs in terms of energy consumption. PMID- 29261114 TI - School Collective Efficacy and Bullying Behaviour: A Multilevel Study. AB - As with other forms of violent behaviour, bullying is the result of multiple influences acting on different societal levels. Yet the majority of studies on bullying focus primarily on the characteristics of individual bullies and bullied. Fewer studies have explored how the characteristics of central contexts in young people's lives are related to bullying behaviour over and above the influence of individual-level characteristics. This study explores how teacher rated school collective efficacy is related to student-reported bullying behaviour (traditional and cyberbullying victimization and perpetration). A central focus is to explore if school collective efficacy is related similarly to both traditional bullying and cyberbullying. Analyses are based on combined information from two independent data collections conducted in 2016 among 11th grade students (n = 6067) and teachers (n = 1251) in 58 upper secondary schools in Stockholm. The statistical method used is multilevel modelling, estimating two level binary logistic regression models. The results demonstrate statistically significant between-school differences in all outcomes, except traditional bullying perpetration. Strong school collective efficacy is related to less traditional bullying perpetration and less cyberbullying victimization and perpetration, indicating that collective norm regulation and school social cohesion may contribute to reducing the occurrence of bullying. PMID- 29261115 TI - Using Human iPSC-Derived Neurons to Uncover Activity-Dependent Non-Coding RNAs. AB - Humans are arguably the most complex organisms present on Earth with their ability to imagine, create, and problem solve. As underlying mechanisms enabling these capacities reside in the brain, it is not surprising that the brain has undergone an extraordinary increase in size and complexity within the last few million years. Human induced pluripotent stem cells (hiPSCs) can be differentiated into many cell types that were virtually inaccessible historically, such as neurons. Here, we used hiPSC-derived neurons to investigate the cellular response to activation at the transcript level. Neuronal activation was performed with potassium chloride (KCl) and its effects were assessed by RNA sequencing. Our results revealed the involvement of long non-coding RNAs and human-specific genetic variants in response to neuronal activation and help validate hiPSCs as a valuable resource for the study of human neuronal networks. In summary, we find that genes affected by KCl-triggered activation are implicated in pathways that drive cell proliferation, differentiation, and the emergence of specialized morphological features. Interestingly, non-coding RNAs of various classes are amongst the most highly expressed genes in activated hiPSC derived neurons, thus suggesting these play crucial roles in neural pathways and may significantly contribute to the unique functioning of the human brain. PMID- 29261116 TI - Is Job Control a Double-Edged Sword? A Cross-Lagged Panel Study on the Interplay of Quantitative Workload, Emotional Dissonance, and Job Control on Emotional Exhaustion. AB - Previous meta-analytic findings have provided ambiguous evidence on job control as a buffering moderator of the adverse impact of job demands on psychological well-being. To disentangle these mixed findings, we examine the moderating effect of job control on the adverse effects of quantitative workload and emotional dissonance as distinct work-related demands on emotional exhaustion over time. Drawing on the job demands-control model, the limited strength model of self control, and the matching principle we propose that job control can facilitate coping with work-related demands but at the same time may also require employees' self-control. Consequently, we argue that job control buffers the adverse effects of quantitative workload while it reinforces the adverse effects of emotional dissonance, which also necessitates self-control. We examine the proposed relations among employees from an energy supplying company (N = 139) in a cross lagged panel study with a six-month time lag. Our results demonstrate a mix of causal and reciprocal effects of job characteristics on emotional exhaustion over time. Furthermore, as suggested, our data provides evidence for contrasting moderating effects of job control. That is, job control buffers the adverse effects of quantitative workload while it reinforces the adverse effects of emotional dissonance on emotional exhaustion. PMID- 29261117 TI - A Water Cluster Conduit in Crystal. AB - The crystal structure of compound (1), [CuCl(phen)(H2NCH2COO)]?4H2O, reveals an unusual hydrogen-bond water cluster aggregate T6(2)6(2). Four water molecules in (1) form an isolated water cluster, [(H2O)14]n, resembling a "phenanthro [1,2]phenanthrene polymer structure shape" along the ac plane. The two face-face parallel [(H2O)14]n planes are bridged by Cl atoms in [CuCl(phen) (H2NCH2COO)] with a strong O-H???Cl hydrogen bond to form a water cluster conduit. PMID- 29261118 TI - An Easy-Made, Economical and Efficient Carbon-Doped Amorphous TiO2 Photocatalyst Obtained by Microwave Assisted Synthesis for the Degradation of Rhodamine B. AB - The search for novel materials and the development of improved processes for water purification have attracted the interest of researchers worldwide and the use of titanium dioxide in photocatalytic processes for the degradation of organic pollutants contained in water has been one of the benchmarks. Compared to crystalline titanium dioxide (cTiO2), the amorphous material has the advantages of having a higher adsorption capacity and being easier to dope with metal and non-metal elements. In this work, we take advantage of these two features to improve its photocatalytic properties in the degradation of Rhodamine B. The structural characterization by XRD analysis gives evidence of its amorphous nature and the SEM micrographs portray the disc morphology of 300 nm in diameter with heterogeneous grain boundaries. The degradation of Rhodamine B tests with the amorphous TiO2 using visible light confirm its improved catalytic activity compared to that of a commercial product, Degussa P25, which is a well-known crystalline material. PMID- 29261119 TI - An Exploration of Industry Expert Perception of Equine Welfare Using Vignettes. AB - As part of a larger Delphi survey project, equine professionals (n = 14) were presented with twelve short scenarios in which a horse's welfare could be compromised. They were asked to rank each scenario (with 0 indicating no welfare concerns and 5 indicating a situation where immediate intervention was necessary), provide justification for their ranking, and give examples of what might have been the motivation behind the scenario. The wide range within vignette scores demonstrated the diversity of opinion even among a relatively small group of equine professionals. Qualitative analysis of responses to vignettes suggested that respondents typically ranked situations higher if they had a longer duration and the potential for greater or longer-lasting consequences (e.g., serious injury). Respondents were also the most sensitive to situations in which the horse's physical well-being (e.g., painful experience) was, or could be, compromised. Financial reasons, ignorance, and human convenience were also areas discussed as potential motivators by survey respondents. Overall, responses from the vignettes allowed for a picture of welfare perception based on personal values. PMID- 29261120 TI - High-Throughput RNA-Seq Data Analysis of the Single Nucleotide Polymorphisms (SNPs) and Zygomorphic Flower Development in Pea (Pisum sativum L.). AB - Pea (Pisum sativum L.) is a model plant that has been used in classical genetics and organ development studies. However, its large and complex genome has hindered research investigations in pea. Here, we generated transcriptomes from different tissues or organs of three pea accessions using next-generation sequencing to assess single nucleotide polymorphisms (SNPs), and further investigated petal differentially expressed genes to elucidate the mechanisms regulating floral zygomorphy. Eighteen samples were sequenced, which yielded a total of 617 million clean reads, and de novo assembly resulted in 87,137 unigenes. A total of 9044 high-quality SNPs were obtained among the three accessions, and a consensus map was constructed. We further discovered several dorsoventral asymmetrically expressed genes that were confirmed by qRT-PCR among different petals, including previously reported three CYC-like proliferating cell factor (TCP) genes. One MADS-box gene was highly expressed in dorsal petals, and several MYB factors were predominantly expressed among dorsal, lateral, and/or ventral petals, together with a ventrally expressed TCP gene. In sum, our comprehensive database complements the existing resources for comparative genetic mapping and facilitates future investigations in legume zygomorphic flower development. PMID- 29261121 TI - Six-Year Retrospective Review of Hospital Data on Antimicrobial Resistance Profile of Staphylococcus aureus Isolated from Skin Infections from a Single Institution in Greece. AB - Objective: To determine the prevalence of resistant strains of Staphylococcus aureus (S. aureus) isolated from Skin and soft tissue infections (SSTI) to various antibiotics. Material and Methods: All culture-positive results for S. aureus from swabs taken from patients presenting at one Greek hospital with a skin infection between the years 2010-2015 were examined retrospectively. Bacterial cultures, identification of S. aureus and antimicrobial susceptibility testing were performed using the disk diffusion method according to Clinical and Laboratory Standards Institute (CLSI) guidelines and European Committee on Antimicrobial testing (EUCAST) breakpoints. EUCAST breakpoints were applied if no CLSI were available. Results: Of 2069 S. aureus isolates identified, 1845 (88%) were resistant to one or more antibiotics. The highest resistance was observed for benzylpenicillin (71.9%), followed by erythromycin (34.3%). Resistant strains to cefoxitin defined as MRSA (methicillin-resistant S. aureus) represented 21% of total isolates. Interestingly, resistance to fusidic acid was 22.9% and to mupirocin as high as 12.7%. Low rates were observed for minocycline, rifampicin and trimethoprim/sulfamethoxazole (SXT). Resistance to antibiotics remained relatively stable throughout the six-year period, with the exception of cefoxitin, fusidic acid and SXT. A high percentage of MRSA strains were resistant to erythromycin (60%), fusidic acid (46%), clindamycin (38%) and tetracycline (35.5%). Conclusions: Special attention is required in prescribing appropriate antibiotic therapeutic regimens, particularly for MRSA. These data on the susceptibility of S. aureus may be useful for guiding antibiotic treatment. PMID- 29261123 TI - Electrospun PVA/Bentonite Nanocomposites Mats for Drug Delivery. AB - Electrospun mats and films of polyvinyl alcohol (PVA) hydrogel are produced for drug delivery. To provide mechanical consistency to the gel a reinforcement by nanoclays is introduced in the polymer matrix. Four different suspensions of nanoparticles in the polymer solution are prepared in an adequate solvent. These suspensions are subjected to an electrospinning process to produce the nanofiber mat, while films are produced by casting. The influence of the process parameters over the nanofibers microstructure is analyzed by scanning electron microscopy (SEM). The effectiveness of nanoclay encapsulation in the nanocomposites is tested by a thermogravimetric analysis. A crosslinking reaction in solution is carried out to prevent the dissolution of the nanocomposites in aqueous media. A model protein (bovine serum albumin, BSA) is absorbed in the nanocomposites to characterize the release kinetics in phosphate-buffered saline (PBS). PMID- 29261122 TI - Association between Cesarean Section and Weight Status in Chinese Children and Adolescents: A National Survey. AB - Previous research on the association between cesarean section (CS) and childhood obesity has yielded inconsistent findings. This study assessed the secular trend of CS and explored the relationship between CS and the risks of overweight and obesity in Chinese children and adolescents. Data came from a national multicenter school-based study conducted in seven provinces of China in 2013. Covariate data including weight, height and delivery mode were extracted. Poisson regression was applied to determine the risk ratios (RRs) and 95% confidence intervals (CIs) for the risks of overweight and obesity associated with the delivery mode. A total of 18,780 (41.2%) subjects were born by CS between 1997 and 2006. The rate of CS increased from 27.2% in 1997 to 54.1% in 2006. After adjusting for major confounders, the RRs (95% CI) of overweight and obesity among subjects born by CS were 1.21 (1.15 to 1.27) and 1.51 (1.42 to 1.61), respectively. Similar results were observed in different subgroups stratified by sex, age, and region. In summary, the CS rate increased sharply in China between 1997 and 2006. CS was associated with increased risks of overweight and obesity in offspring after accounting for major confounding factors. PMID- 29261124 TI - Labdane-Type Diterpenes, Galangalditerpenes A-C, with Melanogenesis Inhibitory Activity from the Fruit of Alpinia galanga. AB - In our continuing study of biologically active natural products from the fruit of Alpinia galanga (Zingiberaceae), we newly isolated three new labdane-type diterpenes, termed galangalditerpenes A-C (1-3), along with four known sesquiterpenes (4-7) and two diterpenes (8 and 9). The stereostructures of 1-3 were elucidated on the basis of their spectroscopic properties. The melanogenesis inhibitory activities in theophylline-stimulated murine B16 melanoma 4A5 cells of these isolates, including the new diterpenes (1-3, IC50 = 4.4, 8.6, and 4.6 MUM, respectively), were found to be more than 6-87-fold higher than that of arbutin (174 MUM), a commercially available positive control. PMID- 29261125 TI - Rheological Characterization as an Alternative Method to Indentation for Determining the Setting Time of Restorative and Endodontic Cements. AB - This study explored an alternative approach using rheology to assess setting time. The following cements were tested: ProRoot(r) MTA (Dentsply, Tulsa, OK, USA), Biodentine(r) (Septodont, Saint Maur des Fosses, France), Fuji VII(r), FujiVII(r) EP, and Fuji IX(r) (from GC Corporation, Tokyo, Japan), RealSeal SETM Sealer (SybronEndo, Amersfoort, The Netherlands), AH 26(r) and AH Plus (both from Dentsply DeTrey, Konstanz, Germany). Freshly mixed cements were placed into a strain-controlled rheometer (1 rad.s-1 with an applied strain of 0.01%). From measurements of elastic modulus over time, the time taken to reach 90% of the plateau elastic modulus (designated as the setting time) was determined for each cement. In increasing order, the setting times were as follows: Fuji VII EP 3.3 min, Fuji VII 3.6 min, Fuji IX 3.7 min, ProRoot MTA 5.1 min, Biodentine 15.9 min, RealSeal 22.2 min, AH Plus 5933 min, and AH 26 5067 min. However, ProRoot MTA did not yield reliable results. The time to reach the 90% plateau elastic modulus correlates well with the setting time of glass ionomer cements and Biodentine. Using this approach gives much longer setting times for endodontic sealers than previously recognized. PMID- 29261126 TI - Remotely Exploring Deeper-Into-Matter by Non-Contact Detection of Audible Transients Excited by Laser Radiation. AB - An acoustic spectroscopic approach to detect contents within different packaging, with substantially wider applicability than other currently available subsurface spectroscopies, is presented. A frequency-doubled Nd:YAG (neodymium-doped yttrium aluminum garnet) pulsed laser (13 ns pulse length) operated at 1 Hz was used to generate the sound field of a two-component system at a distance of 50 cm. The acoustic emission was captured using a unidirectional microphone and analyzed in the frequency domain. The focused laser pulse hitting the system, with intensity above that necessary to ablate the irradiated surface, transferred an impulsive force which led the structure to vibrate. Acoustic airborne transients were directly radiated by the vibrating elastic structure of the outer component that excited the surrounding air in contact with. However, under boundary conditions, sound field is modulated by the inner component that modified the dynamical integrity of the system. Thus, the resulting frequency spectra are useful indicators of the concealed content that influences the contributions originating from the wall of the container. High-quality acoustic spectra could be recorded from a gas (air), liquid (water), and solid (sand) placed inside opaque chemical resistant polypropylene and stainless steel sample containers. Discussion about effects of laser excitation energy and sampling position on the acoustic emission events is reported. Acoustic spectroscopy may complement the other subsurface alternative spectroscopies, severely limited by their inherent optical requirements for numerous detection scenarios. PMID- 29261127 TI - Structural Characterization and Association of Ovine Dickkopf-1 Gene with Wool Production and Quality Traits in Chinese Merino. AB - Dickkopf-1 (DKK1) is an inhibitor of canonical Wnt signaling pathway and regulates hair follicle morphogenesis and cycling. To investigate the potential involvement of DKK1 in wool production and quality traits, we characterized the genomic structure of ovine DKK1, performed polymorphism detection and association analysis of ovine DKK1 with wool production and quality traits in Chinese Merino. Our results showed that ovine DKK1 consists of four exons and three introns, which encodes a protein of 262 amino acids. The coding sequence of ovine DKK1 and its deduced amino acid sequence were highly conserved in mammals. Eleven single nucleotide polymorphisms (SNPs) were identified within the ovine DKK1 genomic region. Gene-wide association analysis showed that SNP5 was significantly associated with mean fiber diameter (MFD) in the B (selected for long wool fiber and high-quality wool), PW (selected for high reproductive capacity, high clean wool yield and high-quality wool) and U (selected for long wool fiber with good uniformity, high wool yield and lower fiber diameter) strains (p < 4.55 * 10-3 = 0.05/11). Single Nucleotide Polymorphisms wide association analysis showed that SNP8 was significantly associated with MFD in A strain and fleece weight in A (selected for large body size), PM (selected for large body size, high reproductive capacity and high meat yield) and SF (selected for mean fiber diameter less than 18 MUm and wool fiber length between 5 and 9 cm) strains (p < 0.05), SNP9 was significantly associated with curvature in B and U strains (p < 0.05) and SNP10 was significantly associated with coefficient of variation of fiber diameter in A, PW and PM strains and standard deviation of fiber diameter in A and PM strains (p < 0.05). The haplotypes derived from these 11 identified SNPs were significantly associated with MFD (p < 0.05). In conclusion, our results suggest that DKK1 may be a major gene controlling wool production and quality traits, also the identified SNPs (SNPs5, 8, 9 and 10) might be used as potential molecular markers for improving sheep wool production and quality in sheep breeding. PMID- 29261128 TI - Hard Chrome-Coated and Fullerene-Doped Metal Surfaces in Orthopedic Bearings. AB - Metal-on-metal bearings for total hip replacements have been introduced as an alternative to polyethylene in young and more active patients. These have, however, been shown to be prone to implant malpositioning and have been limited by some specific design features. In that context, coatings present an option to increase wear resistance by keeping the high fracture strength of the metal substrate. A custom-made electroplating setup was designed for the coating of CoCr substrates using (a) an industrial standard chromium electrolyte; (b) a custom-made hexavalent chromium (Cr6+) electrolyte with a reduced chromium trioxide (CrO3) content, both without solid additives and (c) with the addition of fullerene (C60) nanoparticles; and (d) a trivalent chromium (Cr3+) electrolyte with C60 addition. All coatings showed an increase in microhardness compared with the metal substrate. Trivalent coatings were thinner (10 um) than the hexavalent coatings (23-40 um) and resulted in increased roughness and crack density. Wear was found to be reduced for the hexavalent chromium coatings by 70-84% compared with the CoCr-CoCr reference bearing while the trivalent chromium coating even increased wear by more than 300%. The addition of fullerenes to the electrolyte did not show any further tribological effect. PMID- 29261129 TI - Lym-1 Chimeric Antigen Receptor T Cells Exhibit Potent Anti-Tumor Effects against B-Cell Lymphoma. AB - T cells expressing chimeric antigen receptors (CARs) recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR) on the surface of human B cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo. Human T cells from healthy donors were transduced to express a Lym-1 CAR, and assessed for epitope-driven function in culture and towards Raji xenografts in NOD-scidIL2Rgammanull (NSG) mice. Lym-1 CAR T cells exhibited epitope-driven activation and lytic function against human B-cell lymphoma cell lines in culture and mediated complete regression of Raji/Luciferase-Green fluorescent protein (Raji/Luc-GFP) in NSG mice with similar or better reactivity than CD19 CAR T cells. Lym-1 CAR transduction of T cells is a promising immunotherapy for patients with Lym-1 epitope positive B-cell malignancies. PMID- 29261131 TI - Histology of Non-Melanoma Skin Cancers: An Update. AB - Non-melanoma skin cancer (NMSC) is the most frequently diagnosed cancer in humans. Several different non-melanoma skin cancers have been reported in the literature, with several histologic variants that frequently cause important differential diagnoses with other cutaneous tumors basal cell carcinoma (BCC) is the most common malignant skin tumor, with different histologic variants that are associated with a greater or less aggressive behavior and that usually may be confused with other primitive skin tumors. Actinic keratosis, Bowen's disease, keratoacanthoma, and invasive squamous cell carcinoma (SCC) correspond to the other line of NMSC, that may have only local tumoral behavior, easy to treat and with local management (as in the case of actinic keratosis (AK), Bowen's disease, and keratoacanthoma) or a more aggressive behavior with a potential metastatic spread, as in case of invasive SCC. Therefore, histopathology serves as the gold standard during daily clinical practice, in order to improve the therapeutical approaches to patients with NMSC and to understand the distinct histopathological features of NMSC. Here, we reported the main pathological features of different non-melanoma skin cancers. PMID- 29261130 TI - Nrf2, the Master Regulator of Anti-Oxidative Responses. AB - Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2). Stabilized following oxidative stress, Nrf2 induces the expression of antioxidants as well as cytoprotective genes, which provoke an anti-inflammatory expression profile, and is crucial for the initiation of healing. In view of this fundamental modulatory role, it is clear that both hyper or hypoactivation of Nrf2 contribute to the onset of chronic diseases. Understanding the tight regulation of Nrf2 expression/activation and its interaction with signaling pathways, known to affect inflammatory processes, will facilitate development of therapeutic approaches to prevent Nrf2 dysregulation and ameliorate chronic inflammatory diseases. We discuss in this review the principle mechanisms of Nrf2 regulation with a focus on inflammation and autophagy, extending the role of dysregulated Nrf2 to chronic diseases and tumor development. PMID- 29261135 TI - Optimal Rate Schedules with Data Sharing in Energy Harvesting Communication Systems. AB - Despite the abundant research on energy-efficient rate scheduling polices in energy harvesting communication systems, few works have exploited data sharing among multiple applications to further enhance the energy utilization efficiency, considering that the harvested energy from environments is limited and unstable. In this paper, to overcome the energy shortage of wireless devices at transmitting data to a platform running multiple applications/requesters, we design rate scheduling policies to respond to data requests as soon as possible by encouraging data sharing among data requests and reducing the redundancy. We formulate the problem as a transmission completion time minimization problem under constraints of dynamical data requests and energy arrivals. We develop offline and online algorithms to solve this problem. For the offline setting, we discover the relationship between two problems: the completion time minimization problem and the energy consumption minimization problem with a given completion time. We first derive the optimal algorithm for the min-energy problem and then adopt it as a building block to compute the optimal solution for the min completion-time problem. For the online setting without future information, we develop an event-driven online algorithm to complete the transmission as soon as possible. Simulation results validate the efficiency of the proposed algorithm. PMID- 29261134 TI - Fluorescence-Free Biosensor Methods in Detection of Food Pathogens with a Special Focus on Listeria monocytogenes. AB - Food pathogens contaminate food products that allow their growth on the shelf and also under refrigerated conditions. Therefore, it is of utmost importance to lower the limit of detection (LOD) of the method used and to obtain the results within hours to few days. Biosensor methods exploit the available technologies to individuate and provide an approximate quantification of the bacteria present in a sample. The main bottleneck of these methods depends on the aspecific binding to the surfaces and on a change in sensitivity when bacteria are in a complex food matrix with respect to bacteria in a liquid food sample. In this review, we introduce surface plasmon resonance (SPR), new advancements in SPR techniques, and electrochemical impedance spectroscopy (EIS), as fluorescence-free biosensing technologies for detection of L. monocytogenes in foods. The application of the two methods has facilitated L. monocytogenes detection with LOD of 1 log CFU/mL. Further advancements are envisaged through the combination of biosensor methods with immunoseparation of bacteria from larger volumes, application of lab-on-chip technologies, and EIS sensing methods for multiplex pathogen detection. Validation efforts are being conducted to demonstrate the robustness of detection, reproducibility and variability in multi-site installations. PMID- 29261133 TI - EEG Dynamics of a Go/Nogo Task in Children with ADHD. AB - BACKGROUND: Studies investigating event-related potential (ERP) evoked in a Cue Go/NoGo paradigm have shown lower frontal N1, N2 and central P3 in children with attention-deficit/hyperactivity disorder (ADHD) compared to typically developing children (TDC). However, the electroencephalographic (EEG) dynamics underlying these ERPs remain largely unexplored in ADHD. METHODS: We investigate the event related spectral perturbation and inter-trial coherence linked to the ERP triggered by visual Cue-Go/NoGo stimuli, in 14 children (7 ADHD and 7 TDC) aged 8 to 12 years. RESULTS: Compared to TDC, the EEG dynamics of children with ADHD showed a lower theta-alpha ITC concomitant to lower occipito-parietal P1-N2 and frontal N1-P2 potentials in response to Cue, Go and Nogo stimuli; an upper alpha power preceding lower central Go-P3; a lower theta-alpha power and ITC were coupled to a lower frontal Nogo-N3; a lower low-gamma power overall scalp at 300 ms after Go and Nogo stimuli. CONCLUSION: These findings suggest impaired ability in children with ADHD to conserve the brain oscillations phase associated with stimulus processing. This physiological trait might serve as a target for therapeutic intervention or be used as monitoring of their effects. PMID- 29261136 TI - Location Accuracy of INS/Gravity-Integrated Navigation System on the Basis of Ocean Experiment and Simulation. AB - An experiment comparing the location accuracy of gravity matching-aided navigation in the ocean and simulation is very important to evaluate the feasibility and the performance of an INS/gravity-integrated navigation system (IGNS) in underwater navigation. Based on a 1' * 1' marine gravity anomaly reference map and multi-model adaptive Kalman filtering algorithm, a matching location experiment of IGNS was conducted using data obtained using marine gravimeter. The location accuracy under actual ocean conditions was 2.83 nautical miles (n miles). Several groups of simulated data of marine gravity anomalies were obtained by establishing normally distributed random error N ( u , sigma 2 ) with varying mean u and noise variance sigma 2 . Thereafter, the matching location of IGNS was simulated. The results show that the changes in u had little effect on the location accuracy. However, an increase in sigma 2 resulted in a significant decrease in the location accuracy. A comparison between the actual ocean experiment and the simulation along the same route demonstrated the effectiveness of the proposed simulation method and quantitative analysis results. In addition, given the gravimeter (1-2 mGal accuracy) and the reference map (resolution 1' * 1'; accuracy 3-8 mGal), location accuracy of IGNS was up to reach ~1.0-3.0 n miles in the South China Sea. PMID- 29261132 TI - Molecular Determinants of Malignant Brain Cancers: From Intracellular Alterations to Invasion Mediated by Extracellular Vesicles. AB - Malignant glioma cells invade the surrounding brain parenchyma, by migrating along the blood vessels, thus promoting cancer growth. The biological bases of these activities are grounded in profound alterations of the metabolism and the structural organization of the cells, which consequently acquire the ability to modify the surrounding microenvironment, by altering the extracellular matrix and affecting the properties of the other cells present in the brain, such as normal glial-, endothelial- and immune-cells. Most of the effects on the surrounding environment are probably exerted through the release of a variety of extracellular vesicles (EVs), which contain many different classes of molecules, from genetic material to defined species of lipids and enzymes. EV-associated molecules can be either released into the extracellular matrix (ECM) and/or transferred to neighboring cells: as a consequence, both deep modifications of the recipient cell phenotype and digestion of ECM components are obtained, thus causing cancer propagation, as well as a general brain dysfunction. In this review, we first analyze the main intracellular and extracellular transformations required for glioma cell invasion into the brain parenchyma; then we discuss how these events may be attributed, at least in part, to EVs that, like the pawns of a dramatic chess game with cancer, open the way to the tumor cells themselves. PMID- 29261138 TI - Was the Watchmaker Blind? Or Was She One-Eyed? AB - The question whether evolution is blind is usually presented as a choice between no goals at all ('the blind watchmaker') and long-term goals which would be external to the organism, for example in the form of special creation or intelligent design. The arguments either way do not address the question whether there are short-term goals within rather than external to organisms. Organisms and their interacting populations have evolved mechanisms by which they can harness blind stochasticity and so generate rapid functional responses to environmental challenges. They can achieve this by re-organising their genomes and/or their regulatory networks. Epigenetic as well as DNA changes are involved. Evolution may have no foresight, but it is at least partially directed by organisms themselves and by the populations of which they form part. Similar arguments support partial direction in the evolution of behavior. PMID- 29261139 TI - Ovsiankina's Great Relief: How Supplemental Work during the Weekend May Contribute to Recovery in the Face of Unfinished Tasks. AB - Unfinished tasks have been identified as a significant job stressor that impairs employee recovery after work. Classic experimental research by Ovsiankina has shown that people tend to resume yet unfinished tasks to satisfy their need for closure. We apply this notion to current working life and examine supplemental work after hours as a means to achieve peace of mind. We investigate how progress towards goal accomplishment through supplemental work may facilitate recovery in terms of psychological detachment, relaxation, autonomy, and mastery experiences. We conducted a week-level diary study among 83 employees over a period of 14 consecutive weeks, which yielded 575 observations in total and 214 matched observations of unfinished tasks, supplemental work during the weekend, progress, and recovery experiences. Unfinished tasks were assessed on Friday. Supplemental work and recovery experiences were assessed on Monday. Multilevel modeling analyses provide evidence that unfinished tasks at the end of the work week are associated with lower levels of detachment at the intraindividual level, tend to relate to lower relaxation, but are unrelated to autonomy and mastery. Progress towards finishing tasks during the weekend alleviates the detrimental effects of unfinished tasks on both kinds of recovery experiences. Supplemental work is negatively linked to detachment, but largely unrelated to the other recovery experiences. PMID- 29261140 TI - Zinc Ion Removal on Hybrid Pectin-Based Beads Containing Modified Poly(Methyl Methacrylate) Waste. AB - A new hybrid sorbent in the form of round beads containing modified poly(methyl methacrylate) (PMMA) waste immobilized in pectin and crosslinked with calcium ions was prepared. A previously obtained and characterized powdered poly(methyl methacrylate)-based sorbent was used. Batch and column studies on the new material's sorption-desorption properties were performed. Two kinetic models (pseudo-first- and pseudo-second-order) and three isotherms (Langmuir, Langmuir bisite and Freundlich) were used to describe the results. Breakthrough and elution curves were also obtained. Nitric, hydrochloric, and sulfuric acid of various concentrations were used in the desorption studies. Higher sorption affinity of zinc(II) ions to hybrid sorbent than to pectin alone, reflected by higher values of the Langmuir and Freundlich model parameters, was observed. The maximum sorption capacities, calculated based on the best-fitted models, were 50.2 mg/g (Langmuir bisite) and 42.2 mg/g (Langmuir) for hybrid and only pectin beads, respectively. The stripping of Zn ions using 0.1 M solutions of mineral acids was similarly effective in the case of both sorbents. The mass balance calculated for the column studies showed about 100% recovery of zinc in a sorption-desorption cycle. By applying the hybrid sorbent under the studied conditions it is possible to purify Zn in water to the level permitted by law and concentrate Zn(II) ions by about 60 times. PMID- 29261137 TI - TRANSPARENT TESTA GLABRA 1-Dependent Regulation of Flavonoid Biosynthesis. AB - The flavonoid composition of various tissues throughout plant development is of biological relevance and particular interest for breeding. Arabidopsis thaliana TRANSPARENT TESTA GLABRA 1 (AtTTG1) is an essential regulator of late structural genes in flavonoid biosynthesis. Here, we provide a review of the regulation of the pathway's core enzymes through AtTTG1-containing R2R3-MYELOBLASTOSIS-basic HELIX-LOOP-HELIX-WD40 repeat (MBW(AtTTG1)) complexes embedded in an evolutionary context. We present a comprehensive collection of A. thalianattg1 mutants and AtTTG1 orthologs. A plethora of MBW(AtTTG1) mechanisms in regulating the five major TTG1-dependent traits is highlighted. PMID- 29261141 TI - Evaluation of the Expression of Amine Oxidase Proteins in Breast Cancer. AB - We aimed to evaluate the expression of amine oxidase proteins in breast cancer and their clinical implications. We performed immunohistochemical staining of amine oxidase proteins (LOX, lysyl oxidase, AOC3, amine oxidase, MAOA, monoamine oxidase A, MAOB, monoamine oxidase B). Based on their hormone receptors, such as estrogen receptor (ER) and progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 immunohistochemical staining, breast cancer was divided into four molecular subtypes: luminal A, luminal B, HER-2 type, and triple-negative breast cancer (TNBC). Luminal A was observed in 380 cases (49.4%), luminal B in 224 (29.1%), HER-2 type in 68 (8.8%), and TNBC in 98 (12.7%). Stromal AOC3, MAO-A, and MAO-B expression varied according to molecular subtypes. Stromal AOC3 expression was high in luminal B and HER-2 type and MAO-A expression was high in luminal A and luminal B (p < 0.001). MAO-B expression was higher in TNBC than in other subtypes (p = 0.020). LOX positivity was associated with high histological grade (p < 0.001) and high Ki-67 labeling index (LI) (p = 0.009), and stromal AOC3 positivity was associated with high histological grade (p = 0.001), high Ki-67 LI (p < 0.001), and HER-2 positivity (p = 0.002). MAO-A positivity was related to low histological grade (p < 0.001), ER positivity, PR positivity (p < 0.001), and low Ki-67 LI (p < 0.001). In univariate analysis, MAO A positivity was related to short disease-free survival in HER-2 type (p = 0.013), AOC3 negativity was related to short disease-free survival and overall survival in ER-positive breast cancer, PR-positive breast cancer, HER-2-negative breast cancer, and lymph node metastasis. In conclusion, the expression of amine oxidase proteins varies depending on the molecular subtype of breast cancer. Stromal AOC3 expression was high in luminal B and HER-2 type, and MAO-A expression was high in luminal A and luminal B. PMID- 29261142 TI - Microbial Inhibition of Fusarium Pathogens and Biological Modification of Trichothecenes in Cereal Grains. AB - Fungi of the genus Fusarium infect cereal crops during the growing season and cause head blight and other diseases. Their toxic secondary metabolites (mycotoxins) contaminate grains. Several dozen toxic compounds produced by fungal pathogens have been identified to date. Type B trichothecenes-deoxynivalenol, its acetyl derivatives and nivalenol (produced mainly by F. graminearum and F. culmorum)-are most commonly detected in cereal grains. "T-2 toxin" (produced by, among others, F. sporotrichioides) belongs to type-A trichothecenes which are more toxic than other trichothecenes. Antagonistic bacteria and fungi can affect pathogens of the genus Fusarium via different modes of action: direct (mycoparasitism or hyperparasitism), mixed-path (antibiotic secretion, production of lytic enzymes) and indirect (induction of host defense responses). Microbial modification of trichothecenes involves acetylation, deacetylation, oxidation, de epoxidation, and epimerization, and it lowers the pathogenic potential of fungi of the genus Fusarium. Other modifing mechanisms described in the paper involve the physical adsorption of mycotoxins in bacterial cells and the conjugation of mycotoxins to glucose and other compounds in plant and fungal cells. The development of several patents supports the commercialization and wider application of microorganisms biodegrading mycotoxins in grains and, consequently, in feed additives. PMID- 29261143 TI - SlbZIP38, a Tomato bZIP Family Gene Downregulated by Abscisic Acid, Is a Negative Regulator of Drought and Salt Stress Tolerance. AB - The basic leucine zipper (bZIP) transcription factors have crucial roles in plant stress responses. In this study, the bZIP family gene SlbZIP38 (GenBank accession No: XM004239373) was isolated from a tomato (Solanum lycopersicum cv. Ailsa Craig) mature leaf cDNA library. The DNA sequence of SlbZIP38 encodes a protein of 484 amino acids, including a highly conserved bZIP DNA-binding domain in the C terminal region. We found that SlbZIP38 was differentially expressed in various organs of the tomato plant and was downregulated by drought, salt stress, and abscisic acid (ABA). However, overexpression of SlbZIP38 significantly decreased drought and salt stress tolerance in tomatoes (Ailsa Craig). The findings that SlbZIP38 overexpression reduced the chlorophyll and free proline content in leaves but increased the malondialdehyde content may explain the reduced drought and salt tolerance observed in these lines. These results suggest that SlbZIP38 is a negative regulator of drought and salt resistance that acts by modulating ABA signaling. PMID- 29261145 TI - Maternal Exposure to Air Pollutants and Risk of Gestational Diabetes Mellitus in Taiwan. AB - Mounting evidence has shown an increased risk of gestational diabetes mellitus (GDM) in association with elevated exposure to air pollution. However, limited evidence is available concerning the effect of specific air pollutant(s) on GDM incidence. We conducted this case-control study on 6717 mothers with GDM diagnosed in 2006-2013 and 6717 age- and year of delivery-matched controls to further address the risk of GDM in relation to specific air pollutant. Both cases and controls were selected from a cohort of 1-million beneficiaries of Taiwan's National Health Insurance program registered in 2005. Maternal exposures to mean daily air pollutant concentration, derived from 76 fixed air quality monitoring stations within the 12-week period prior to pregnancy and during the 1st and 2nd trimesters, were assessed by the spatial analyst method (i.e., ordinary kriging) with the ArcGIS software. After controlling for potential confounders and other air pollutants, an increase in pre-pregnancy exposure of 1 inter-quartile range (IQR) for PM2.5 and SO2 was found to associate with a significantly elevated odds ratio (OR) of GDM at 1.10 (95% confidence interval (CI) 1.03-1.18 and 1.37 (95% CI 1.30-1.45), respectively. Exposures to PM2.5 and SO2 during the 1st and 2nd trimesters were also associated with significantly increased ORs, which were 1.09 (95% CI 1.02-1.17) and 1.07 (95% CI 1.01-1.14) for PM2.5, and 1.37 (95% CI 1.30 1.45) and 1.38 (95% CI 1.31-1.46) for SO2. It was concluded that higher pre- and post-pregnancy exposures to PM2.5 and SO2 for mothers were associated with a significantly but modestly elevated risk of GDM. PMID- 29261144 TI - PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple Negative Breast Cancer. AB - Triple negative breast cancer (TNBC), is defined as a type of tumor lacking the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The ER, PR and HER2 are usually the molecular therapeutic targets for breast cancers, but they are ineffective for TNBC because of their negative expressions, so chemotherapy is currently the main treatment strategy in TNBC. However, drug resistance remains a major impediment to TNBC chemotherapeutic treatment. Recently, the protein phosphatase 2A (PP2A) has been found to regulate the phosphorylation of some substrates involved in the relevant target of TNBC, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may be the effective therapeutic strategies or influence drug sensitivity to TNBCs. Furthermore, PP2A has also been found that could induce ER re expression in ER-negative breast cancer cells, and which suggests PP2A could promote the sensitivity of tamoxifen to TNBCs as a resistance reversal agent. In this review, we will summarize the potential therapeutic value of PP2A as the main node in developing targeting agents, disrupting resistance or restoring drug sensitivity in TNBC. PMID- 29261146 TI - Peripheral Endocannabinoid Responses to Hedonic Eating in Binge-Eating Disorder. AB - Reward mechanisms are likely implicated in the pathophysiology of binge-eating behaviour, which is a key symptom of binge-eating disorder (BED). Since endocannabinoids modulate food-related reward, we aimed to investigate the responses of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) to hedonic eating in patients with BED. Peripheral levels of AEA and 2-AG were measured in 7 obese BED patients before and after eating favorite (hedonic eating) and non-favorite (non-hedonic eating) foods. We found that plasma levels of AEA progressively decreased after eating the non-favorite food and significantly increased after eating the favorite food, whereas plasma levels of 2-AG did not differ significantly between the two test conditions, although they showed a trend toward significantly different time patterns. The changes in peripheral AEA levels were positively correlated to the subjects' sensations of the urge to eat and the pleasantness while eating the presented food, while changes in peripheral 2-AG levels were positively correlated to the subjects' sensation of the pleasantness while eating the presented food and to the amount of food they would eat. These results suggest the occurrence of distinctive responses of endocannabinoids to food-related reward in BED. The relevance of such findings to the pathophysiology of BED remains to be elucidated. PMID- 29261147 TI - Leptin Stimulates Prolactin mRNA Expression in the Goldfish Pituitary through a Combination of the PI3K/Akt/mTOR, MKK3/6/p38MAPK and MEK1/2/ERK1/2 Signalling Pathways. AB - Leptin actions at the pituitary level have been extensively investigated in mammalian species, but remain insufficiently characterized in lower vertebrates, especially in teleost fish. Prolactin (PRL) is a pituitary hormone of central importance to osmoregulation in fish. Using goldfish as a model, we examined the global and brain-pituitary distribution of a leptin receptor (lepR) and examined the relationship between expression of lepR and major pituitary hormones in different pituitary regions. The effects of recombinant goldfish leptin-AI and leptin-AII on PRL mRNA expression in the pituitary were further analysed, and the mechanisms underlying signal transduction for leptin-induced PRL expression were determined by pharmacological approaches. Our results showed that goldfish lepR is abundantly expressed in the brain-pituitary regions, with highly overlapping PRL transcripts within the pituitary. Recombinant goldfish leptin-AI and leptin AII proteins could stimulate PRL mRNA expression in dose- and time-dependent manners in the goldfish pituitary, by both intraperitoneal injection and primary cell incubation approaches. Moreover, the PI3K/Akt/mTOR, MKK3/6/p38MAPK, and MEK1/2/ERK1/2-but not JAK2/STAT 1, 3 and 5 cascades-were involved in leptin induced PRL mRNA expression in the goldfish pituitary. PMID- 29261148 TI - Advances in Brain Tumor Surgery for Glioblastoma in Adults. AB - Glioblastoma (GBM) is the most common primary intracranial neoplasia, and is characterized by its extremely poor prognosis. Despite maximum surgery, chemotherapy, and radiation, the histological heterogeneity of GBM makes total eradication impossible, due to residual cancer cells invading the parenchyma, which is not otherwise seen in radiographic images. Even with gross total resection, the heterogeneity and the dormant nature of brain tumor initiating cells allow for therapeutic evasion, contributing to its recurrence and malignant progression, and severely impacting survival. Visual delimitation of the tumor's margins with common surgical techniques is a challenge faced by many surgeons. In an attempt to achieve optimal safe resection, advances in approaches allowing intraoperative analysis of cancer and non-cancer tissue have been developed and applied in humans resulting in improved outcomes. In addition, functional paradigms based on stimulation techniques to map the brain's electrical activity have optimized glioma resection in eloquent areas such as the Broca's, Wernike's and perirolandic areas. In this review, we will elaborate on the current standard therapy for newly diagnosed and recurrent glioblastoma with a focus on surgical approaches. We will describe current technologies used for glioma resection, such as awake craniotomy, fluorescence guided surgery, laser interstitial thermal therapy and intraoperative mass spectrometry. Additionally, we will describe a newly developed tool that has shown promising results in preclinical experiments for brain cancer: optical coherence tomography. PMID- 29261149 TI - Evaluation of Biosynthesis, Accumulation and Antioxidant Activityof Vitamin E in Sweet Corn (Zea mays L.) during Kernel Development. AB - Sweet corn kernels were used in this research to study the dynamics of vitamin E, by evaluatingthe expression levels of genes involved in vitamin E synthesis, the accumulation of vitamin E, and the antioxidant activity during the different stage of kernel development. Results showed that expression levels of ZmHPT and ZmTC genes increased, whereas ZmTMT gene dramatically decreased during kernel development. The contents of all the types of vitamin E in sweet corn had a significant upward increase during kernel development, and reached the highest level at 30 days after pollination (DAP). Amongst the eight isomers of vitamin E, the content of gamma-tocotrienol was the highest, and increased by 14.9 folds, followed by alpha-tocopherolwith an increase of 22 folds, and thecontents of isomers gamma-tocopherol, alpha-tocotrienol, delta-tocopherol,delta-tocotrienol, and beta-tocopherol were also followed during kernel development. The antioxidant activity of sweet corn during kernel development was increased, and was up to 101.8 +/- 22.3 MUmol of alpha-tocopherol equivlent/100 g in fresh weight (FW) at 30 DAP. There was a positive correlation between vitamin E contents and antioxidant activity in sweet corn during the kernel development, and a negative correlation between the expressions of ZmTMT gene and vitamin E contents. These results revealed the relations amongst the content of vitamin E isomers and the gene expression, vitamin E accumulation, and antioxidant activity. The study can provide a harvesting strategy for vitamin E bio-fortification in sweet corn. PMID- 29261150 TI - Thermal and Antioxidant Properties of Polysaccharides Sequentially Extracted from Mulberry Leaves (Morus alba L.). AB - Polysaccharides from natural plant products are gaining considerable attention due to their multi-faceted health effects, as well their functional applications in food production. We reported the sequential extraction of mulberry leaf polysaccharides (MLPs) with hot buffer (HBSS), chelating agent (CHSS), dilute alkali (DASS) and concentrated alkali (CASS), in order to obtain polysaccharide fractions. Monosaccharide analysis proved that galactose (27.07%) and arabinose (25.99%) were the major sugars in HBSS, whereas arabinose (30.55%) was the major sugar in CHSS, and glucose was the major sugar in DASS (24.96%) and CASS (27.51%). The molecular weights of the polysaccharide fractions were 7.812 * 103 (HBSS), 3.279 * 103 (CHSS), 6.912 * 103 (DASS), and 1.408 * 103 kDa (CASS). HBSS and CASS showed the largest peak temperature and the highest endothermic enthalpy, respectively. Different antioxidant assays showed that the MLPs possessed appreciable antioxidant activities in a dose-dependent manner. At 5 mg/mL, HBSS and DASS possessed the largest 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging activity (96.82%). HBSS exhibited the highest reducing power, and DASS rendered the strongest ABTS radical scavenging activity (99.69%). CHSS performed the best hydroxyl radical scavenging activity (64.22%) and Fe2+ chelating ability (96.36%). Our results suggested that MLPs could be a promising source of natural antioxidants for use in the food, pharmaceutical, and cosmetic industries. PMID- 29261151 TI - Iron Overload and Chelation Therapy in Non-Transfusion Dependent Thalassemia. AB - Iron overload (IOL) due to increased intestinal iron absorption constitutes a major clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), which is a cumulative process with advancing age. Current models for iron metabolism in patients with NTDT suggest that suppression of serum hepcidin leads to an increase in iron absorption and subsequent release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The consequences of IOL in patients with NTDT are multiple and multifactorial. Accurate and reliable methods of diagnosis and monitoring of body iron levels are essential, and the method of choice for measuring iron accumulation will depend on the patient's needs and on the available facilities. Iron chelation therapy (ICT) remains the backbone of NTDT management and is one of the most effective and practical ways of decreasing morbidity and mortality. The aim of this review is to describe the mechanism of IOL in NTDT, and the clinical complications that can develop as a result, in addition to the current and future therapeutic options available for the management of IOL in NTDT. PMID- 29261152 TI - Increasing Antioxidant Activity and Protein Digestibility in Phaseolus vulgaris and Avena sativa by Fermentation with the Pleurotus ostreatus Fungus. AB - The aim of the research was to determine the impact of fermentation with Pleurotus ostreatus on kidney beans, black beans, and oats. The results indicate that the fungus has a positive effect on the substrates when compared to the controls. The antioxidant activity (39.5% on kidney beans and 225% on oats in relation to the controls) and content of total polyphenols (kidney beans three times higher regarding the controls) increased significantly by the presence of the fungus mycelium, even after simulated digestion. There was a significant increase in protein digestibility (from 39.99 to 48.13% in black beans, 44.06 to 69.01% in kidney beans, and 63.25 to 70.01% in oats) and a decrease of antinutrient tannins (from 65.21 to 22.07 mg in black beans, 35.54 to 23.37 in kidney beans, and 55.67 to 28.11 in oats) as well as an increase in the contents of some essential amino acids. Overall, this fermentation treatment with Pleurotus ostreatus improved the nutritional quality of cereals and legumes, making them potential ingredients for the elaboration and/or fortification of foods for human nutrition. PMID- 29261153 TI - Protective Effects of Ambient Ozone on Incidence and Outcomes of Ischemic Stroke in Changzhou, China: A Time-Series Study. AB - The potential beneficial effect of ozone (O3) on stroke had been identified experimentally and clinically, but these effects remain controversial in population-based studies. This study aimed to explore the epidemiological association between O3 and risk of ischemic stroke. Ischemic stroke related health data and air pollution data were obtained from the Center for Disease Control and Prevention and Environmental Monitoring Center in Changzhou between 2015 and 2016, respectively. The associations between the short-term exposure to O3 and daily ischemic stroke onsets and deaths were examined based on time-series generalized additive Poisson model. During the study period, daily ischemic stroke onsets and deaths decreased 0.340% (95% confidence interval (CI) -0.559% to -0.120%) and 0.697% (95% CI -1.103% to -0.290%) with an interquartile range (IQR) (41.1 ug/m3) increase in levels of ambient O3, respectively. The protective effects of O3 were more significant in men and elders and in the cool season than those in women and young people and in the warm season, respectively. The negative association was independent of PM2.5, PM10, SO2, NO2 or CO exposure. Acute O3 exposure was associated with decreased risk of ischemic stroke. These findings will help provide new insights into the relationship between ischemic stroke and ambient O3 concentrations. PMID- 29261154 TI - The Role of PAR2 in TGF-beta1-Induced ERK Activation and Cell Motility. AB - BACKGROUND: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD mediated signaling and cell migration by transforming growth factor (TGF)-beta1. However, it is not known whether activation of non-SMAD TGF-beta signaling (e.g., RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) signaling) is required for cell migration and whether it is also dependent on PAR2. METHODS: RNA interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation to detect a PAR2-ALK5 physical interaction. RESULTS: Inhibition of ERK signaling with the MEK inhibitor U0126 blunted the ability of TGF-beta1 to induce migration in pancreatic cancer Panc1 cells. ERK activation in response to PAR2 agonistic peptide (PAR2-AP) was strong and rapid, while it was moderate and delayed in response to TGF-beta1. Basal and TGF-beta1-dependent ERK, but not SMAD activation, was blocked by U0126 in Panc1 and other cell types indicating that ERK activation is downstream or independent of SMAD signaling. Moreover, cellular depletion of PAR2 in HaCaT cells strongly inhibited TGF-beta1-induced ERK activation, while the biased PAR2 agonist GB88 at 10 and 100 uM potentiated TGF-beta1-dependent ERK activation and cell migration. Finally, we provide evidence for a physical interaction between PAR2 and ALK5. Our data show that both PAR2-AP- and TGF-beta1-induced cell migration depend on ERK activation, that PAR2 expression is crucial for TGF-beta1-induced ERK activation, and that the functional cooperation of PAR2 and TGF-beta1 involves a physical interaction between PAR2 and ALK5. PMID- 29261155 TI - UPLC Quantitative Analysis of Multi-Components by Single Marker and Quality Evaluation of Polygala tenuifolia Wild. Extracts. AB - The quality control of Polygala tenuifolia Wild. is a major challenge in its clinical application. In this paper, a new strategy for the quality evaluation of P. tenuifolia extracts was verified through reverse-phase ultra-performance liquid chromatography (UPLC). The quantitative analysis of multi-components by a single marker (QAMS) was conducted with 3,6'-disinapoyl sucrose as an internal reference substance. Eight components (i.e., sibiricose A5, sibiricose A6, glomeratose A, tenuifoliside A, tenuifoliside B, tenuifoliside C, sibiricaxanthone B, and polygalaxanthone III) were determined based on the relative correction factors. The concentrations of these components were also determined by applying a conventional external standard method. The cosine value confirmed the consistency of the two methods (cosine ratio value >0.999920). Hierarchical cluster analysis, radar plots, and discriminant analysis were performed to classify 23 batches of P. tenuifolia extracts from Shanxi, Hebei, and Shaanxi in China. Results revealed that QAMS combined with radar plots and multivariate data analysis could accurately measure and clearly distinguish the different quality samples of P. tenuifolia. Hence, QAMS is a feasible and promising method for the quality control of P. tenuifolia. PMID- 29261156 TI - Adsorption of Cd (II) on Modified Granular Activated Carbons: Isotherm and Column Study. AB - In this work, equilibrium and dynamic adsorption tests of cadmium Cd (II) on activated carbons derived from different oxidation treatments (with either HNO3, H2O2, or NaOCl, corresponding to GACoxN, GACoxP, and GACoxCl samples) are presented. The oxidation treatments determined an increase in the surface functional groups (mainly the acidic ones) and a decrease in the pHPZC (except for the GACoxCl sample). A slight alteration of the textural parameters was also observed, which was more significant for the GACoxCl sample, in terms of a decrease of both Brunauer-Emmett-Teller (BET) surface area and micropore volume. Adsorption isotherms were determined for all the adsorbents and a significant increase in the adsorption performances of the oxidized samples with respect to the parent material was observed. The performances ranking was GACoxCl > GACoxP > GACoxN > GAC, likely due to the chemical surface properties of the adsorbents. Dynamic tests in a fixed bed column were carried out in terms of breakthrough curves at constant Cd inlet concentration and flow rate. GACoxCl and GACoxN showed a significantly higher value of the breakpoint time, likely due to the higher adsorption capacity. Finally, the dynamic tests were analyzed in light of a kinetic model. In the adopted experimental conditions, the results showed that mass transfer is controlled by internal pore diffusion, in which surface diffusion plays a major role. PMID- 29261157 TI - A Large-Scale Multi-Hop Localization Algorithm Based on Regularized Extreme Learning for Wireless Networks. AB - A novel large-scale multi-hop localization algorithm based on regularized extreme learning is proposed in this paper. The large-scale multi-hop localization problem is formulated as a learning problem. Unlike other similar localization algorithms, the proposed algorithm overcomes the shortcoming of the traditional algorithms which are only applicable to an isotropic network, therefore has a strong adaptability to the complex deployment environment. The proposed algorithm is composed of three stages: data acquisition, modeling and location estimation. In data acquisition stage, the training information between nodes of the given network is collected. In modeling stage, the model among the hop-counts and the physical distances between nodes is constructed using regularized extreme learning. In location estimation stage, each node finds its specific location in a distributed manner. Theoretical analysis and several experiments show that the proposed algorithm can adapt to the different topological environments with low computational cost. Furthermore, high accuracy can be achieved by this method without setting complex parameters. PMID- 29261158 TI - Real-Time Measurements and Characterization of Airborne Particulate Matter from a Primary Silicon Carbide Production Plant. AB - Airborne particulate matter in the silicon carbide (SiC) industry is a known health hazard. The aims of this study were to elucidate whether the particulate matter generated inside the Acheson furnace during active operation is representative of the overall particulate matter in the furnace hall, and whether the Acheson furnaces are the main sources of ultrafine particles (UFP) in primary SiC production. The number concentration of ultrafine particles was evaluated using an Electrical Low Pressure Impactor (ELPITM, Dekati Ltd., Tampere, Finland), a Fast Mobility Particle Sizer (FMPSTM, TSI, Shoreview, MN, USA) and a Condensation Particle Counter (CPC, TSI, Shoreview, MN, USA). The results are discussed in terms of particle number concentration, particle size distribution and are also characterized by means of electron microscopy (TEM/SEM). Two locations were investigated; the industrial Acheson process furnace hall and a pilot furnace hall; both of which represent an active operating furnace. The geometric mean of the particle number concentration in the Acheson process furnace hall was 7.7 * 104 particles/cm3 for the UFP fraction and 1.0 * 105 particles/cm3 for the submicrometre fraction. Particulate matter collected at the two sites was analysed by electron microscopy. The PM from the Acheson process furnace hall is dominated by carbonaceous particles while the samples collected near the pilot furnace are primarily rich in silicon. PMID- 29261159 TI - A Rare Case of Pure Erythroid Sarcoma in a Pediatric Patient: Case Report and Literature Review. AB - We describe an exceptional case of erythroid sarcoma in a pediatric patient as a growing orbital mass with no evidence of morphologic bone marrow involvement, who was finally diagnosed of pure erythroid sarcoma based on histopathology and flow cytometry criteria. We discuss the contribution of standardized eight-color flow cytometry as a rapid and reliable diagnostic method. The use of normal bone marrow databases allowed us to identify small aberrant populations in bone marrow and later confirm the diagnosis in the neoplastic tissue. PMID- 29261160 TI - Smoothed Body Composition Percentiles Curves for Mexican Children Aged 6 to 12 Years. AB - Overweight children and childhood obesity are a public health problem in Mexico. Obesity is traditionally assessed using body mass index (BMI), but an excess of adiposity does not necessarily reflect a high BMI. Thus, body composition indexes are a better alternative. Our objective was to generate body composition percentile curves in children from Mexico City. A total of 2026 boys and 1488 girls aged 6 to 12 years old were studied in Mexico City. Body weight, height, and BMI calculation were measured. Total body fat percentage (TBFP) was derived from the skinfold thicknesses, and fat mass (FMI) and free fat mass indexes (FFMI) were calculated. Finally, age- and gender-specific smoothed percentile curves were generated with Cole's Lambda, Mu, and Sigma (LMS) method. In general, height, weight, waist circumference (WC), and TBFP were higher in boys, but FFM was higher in girls. TBFP appeared to increase significantly between ages 8 and 9 in boys (+2.9%) and between ages 10 and 11 in girls (+1.2%). In contrast, FFM% decreased noticeably between ages 8 and 9 until 12 years old in boys and girls. FMI values peaked in boys at age 12 (P97 = 14.1 kg/m2) and in girls at age 11 (P97 = 8.8 kg/m2). FFMI percentiles increase at a steady state reaching a peak at age 12 in boys and girls. Smoothed body composition percentiles showed a different pattern in boys and girls. The use of TBFP, FMI, and FFMI along with BMI provides valuable information in epidemiological, nutritional, and clinical research. PMID- 29261161 TI - Quantitative and Sensitive Detection of Chloramphenicol by Surface-Enhanced Raman Scattering. AB - We used surface-enhanced Raman scattering (SERS) for the quantitative and sensitive detection of chloramphenicol (CAP). Using 30 nm colloidal Au nanoparticles (NPs), a low detection limit for CAP of 10-8 M was obtained. The characteristic Raman peak of CAP centered at 1344 cm-1 was used for the rapid quantitative detection of CAP in three different types of CAP eye drops, and the accuracy of the measurement result was verified by high-performance liquid chromatography (HPLC). The experimental results reveal that the SERS technique based on colloidal Au NPs is accurate and sensitive, and can be used for the rapid detection of various antibiotics. PMID- 29261162 TI - Food-Borne Outbreak Investigation and Molecular Typing: High Diversity of Staphylococcus aureus Strains and Importance of Toxin Detection. AB - Staphylococcus aureus is an important aetiological agent of food intoxications in the European Union as it can cause gastro-enteritis through the production of various staphylococcal enterotoxins (SEs) in foods. Reported enterotoxin dose levels causing food-borne illness are scarce and varying. Three food poisoning outbreaks due to enterotoxin-producing S. aureus strains which occurred in 2013 in Belgium are described. The outbreaks occurred in an elderly home, at a barbecue event and in a kindergarten and involved 28, 18, and six cases, respectively. Various food leftovers contained coagulase positive staphylococci (CPS). Low levels of staphylococcal enterotoxins ranging between 0.015 ng/g and 0.019 ng/g for enterotoxin A (SEA), and corresponding to 0.132 ng/g for SEC were quantified in the food leftovers for two of the reported outbreaks. Molecular typing of human and food isolates using pulsed-field gel electrophoresis (PFGE) and enterotoxin gene typing, confirmed the link between patients and the suspected foodstuffs. This also demonstrated the high diversity of CPS isolates both in the cases and in healthy persons carrying enterotoxin genes encoding emetic SEs for which no detection methods currently exist. For one outbreak, the investigation pointed out to the food handler who transmitted the outbreak strain to the food. Tools to improve staphylococcal food poisoning (SFP) investigations are presented. PMID- 29261164 TI - Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway. AB - The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN gamma) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4+ T cells and antigen-presenting cells (APCs) in IL-18Ralpha knockout (KO) mice and wild-type (WT) mice after LPS injection. In the acute advanced phase, the IL-18Ralpha KO mice showed a higher survival rate and a suppressed increase of blood urea nitrogen, increased levels of proinflammatory cytokines such as IFN-gamma and IL 18, the infiltration of CD4+ T cells and the expression of kidney injury molecule 1 as an AKI marker. In that phase, the renal mRNA expression of the M1 macrophage phenotype and C-C chemokine receptor type 7 as the maturation marker of dendritic cells (DCs) was also significantly decreased in the IL-18Ralpha KO mice, although there were small numbers of F4/80+ cells and DCs in the kidney. Conversely, there were no significant differences in the expressions of mRNA and protein TLR4 after LPS injection between the WT and IL-18Ralpha KO groups. Our results demonstrated that the IL-18Ralpha-mediated signaling pathway plays critical roles in CD4+ T cells and APCs and responded more quickly to IFN-gamma and IL-18 than TLR4 stimulation in the pathogenesis of LPS-induced AKI. PMID- 29261165 TI - Anomalous Behavior of Hyaluronan Crosslinking Due to the Presence of Excess Phospholipids in the Articular Cartilage System of Osteoarthritis. AB - Lubrication of articular cartilage is a complex multiscale phenomenon in synovial joint organ systems. In these systems, synovial fluid properties result from synergistic interactions between a variety of molecular constituent. Two molecular classes in particular are of importance in understanding lubrication mechanisms: hyaluronic acid and phospholipids. The purpose of this study is to evaluate interactions between hyaluronic acid and phospholipids at various functionality levels during normal and pathological synovial fluid conditions. Molecular dynamic simulations of hyaluronic acid and phospholipids complexes were performed with the concentration of hyaluronic acid set at a constant value for two organizational forms, extended (normal) and coiled (pathologic). The results demonstrated that phospholipids affect the crosslinking mechanisms of hyaluronic acid significantly and the influence is higher during pathological conditions. During normal conditions, hyaluronic acid and phospholipid interactions seem to have no competing mechanism to that of the interaction between hyaluronic acid to hyaluronic acid. On the other hand, the structures formed under pathologic conditions were highly affected by phospholipid concentration. PMID- 29261166 TI - Ancient DNA Resolves the History of Tetragnatha (Araneae, Tetragnathidae) Spiders on Rapa Nui. AB - Rapa Nui is one of the most remote islands in the world. As a young island, its biota is a consequence of both natural dispersals over the last ~1 million years and recent human introductions. It therefore provides an opportunity to study a unique community assemblage. Here, we extract DNA from museum-preserved and newly field-collected spiders from the genus Tetragnatha to explore their history on Rapa Nui. Using an optimized protocol to recover ancient DNA from museum preserved spiders, we sequence and assemble partial mitochondrial genomes from nine Tetragnatha species, two of which were found on Rapa Nui, and estimate the evolutionary relationships between these and other Tetragnatha species. Our phylogeny shows that the two Rapa Nui species are not closely related. One, the possibly extinct, T. paschae, is nested within a circumtropical species complex (T. nitens), and the other (Tetragnatha sp. Rapa Nui) appears to be a recent human introduction. Our results highlight the power of ancient DNA approaches in identifying cryptic and rare species, which can contribute to our understanding of the global distribution of biodiversity in all taxonomic lineages. PMID- 29261167 TI - A Wearable Textile 2D Touchpad Sensor Based on Screen-Printing Technology. AB - Among many of the designs used in the detection of 2D gestures for portable technology, the touchpad is one of the most complex and with more functions to implement. Its development has undergone a great push due to its use in displays, but it is not widely used with other technologies. Its application on textiles could allow a wide range of applications in the field of medicine, sports, etc. Obtaining a flexible, robust touchpad with good response and low cost is one of the objectives of this work. A textile touchpad based on a diamond pattern design using screen printing technology has been developed. This technology is widely used in the textile industry and therefore does not require heavy investments. The developed prototypes were analyzed using a particular controller for projected capacitive technologies (pro-cap), which is the most used in gesture detection. Two different designs were used to obtain the best configuration, obtaining a good result in both cases. PMID- 29261168 TI - Modulation of the Selectivity in Anions Recognition Processes by Combining Hydrogen- and Halogen-Bonding Interactions. AB - Most of the halogen bonding receptors for anions described use halogen bonding binding sites solely in the anion recognition process; only a few examples report the study of anion receptors in which the halogen bonding interaction has been used in combination with any other non-covalent interaction. With the aims to extend the knowledge in the behaviour of this kind of mixed receptors, we report here the synthesis and the anion recognition and sensing properties of a new halogen- and hydrogen- bonding receptor which binds anions by the cooperation of both non-covalent interactions. Fluorescence studies showed that the behaviour observed in the anion recognition sensing is similar to the one previously described for the halogen analogue and is quite different to the hydrogen one. On the other hand, the association constants obtained by 1H-NMR data demonstrate that the mixed halogen- and hydrogen-bonding receptor is more selective for SO42- anion than the halogen or hydrogen analogues. PMID- 29261169 TI - Access to New Cytotoxic Quinone-Amino Acid Conjugates Linked through A Vinylic Spacer from 2-Acylnaphthoquinones and Methyl 3-Aminocrotonate. AB - The reaction of 2-acetyl- and 2-benzoyl-1,4-naphthoquinone with (Z)-methyl 3 (hydroxymethyl)aminocrotonate proceeds through a formal [3+3] process to yield the corresponding 1,2-dihydrobenzisoquinolinequinones in 63% and 72% yield, respectively. The reactions of 2-acyl-1,4-naphthoquinone with enaminones, derived from diverse l- and d-amino acid methyl esters, produced the corresponding naphthoquinone amino acids conjugates bonded through a vinyl spacer in the yields range 40-71%. The presence of not-separable isomers of the naphthoquinone amino acids conjugates in the 1H- and 13C-NMR spectra is explained by the existence of conformational isomers generated by hindered rotation of the substituent bonded to the quinone double bond. These new naphthoquinone amino acids conjugates were screened in vitro on normal and cancer cell lines and showed moderate cytotoxic activities. PMID- 29261163 TI - Biotechnological and Pharmacological Applications of Biotoxins and Other Bioactive Molecules from Dinoflagellates. AB - The long-lasting interest in bioactive molecules (namely toxins) produced by (microalga) dinoflagellates has risen in recent years. Exhibiting wide diversity and complexity, said compounds are well-recognized for their biological features, with great potential for use as pharmaceutical therapies and biological research probes. Unfortunately, provision of those compounds is still far from sufficient, especially in view of an increasing demand for preclinical testing. Despite the difficulties to establish dinoflagellate cultures and obtain reasonable productivities of such compounds, intensive research has permitted a number of advances in the field. This paper accordingly reviews the characteristics of some of the most important biotoxins (and other bioactive substances) produced by dinoflagellates. It also presents and discusses (to some length) the main advances pertaining to dinoflagellate production, from bench to large scale-with an emphasis on material published since the latest review available on the subject. Such advances encompass improvements in nutrient formulation and light supply as major operational conditions; they have permitted adaptation of classical designs, and aided the development of novel configurations for dinoflagellate growth-even though shearing-related issues remain a major challenge. PMID- 29261170 TI - An Architecture Providing Depolarization Ratio Capability for a Multi-Wavelength Raman Lidar: Implementation and First Measurements. AB - A new architecture for the measurement of depolarization produced by atmospheric aerosols with a Raman lidar is presented. The system uses two different telescopes: one for depolarization measurements and another for total-power measurements. The system architecture and principle of operation are described. The first experimental results are also presented, corresponding to a collection of atmospheric conditions over the city of Barcelona. PMID- 29261172 TI - Out-of-Focus Projector Calibration Method with Distortion Correction on the Projection Plane in the Structured Light Three-Dimensional Measurement System. AB - The three-dimensional measurement system with a binary defocusing technique is widely applied in diverse fields. The measurement accuracy is mainly determined by out-of-focus projector calibration accuracy. In this paper, a high-precision out-of-focus projector calibration method that is based on distortion correction on the projection plane and nonlinear optimization algorithm is proposed. To this end, the paper experimentally presents the principle that the projector has noticeable distortions outside its focus plane. In terms of this principle, the proposed method uses a high-order radial and tangential lens distortion representation on the projection plane to correct the calibration residuals caused by projection distortion. The final accuracy parameters of out-of-focus projector were obtained using a nonlinear optimization algorithm with good initial values, which were provided by coarsely calibrating the parameters of the out-of-focus projector on the focal and projection planes. Finally, the experimental results demonstrated that the proposed method can accuracy calibrate an out-of-focus projector, regardless of the amount of defocusing. PMID- 29261174 TI - School liaison program supporting children with neurofibromatosis type 1: a model of care for children with chronic disease. PMID- 29261173 TI - The who, what, and why of research participants' intentions to request a broad range of secondary findings in a diagnostic genomic sequencing study. AB - PURPOSE: In a diagnostic exome sequencing study (the North Carolina Clinical Genomic Evaluation by Next-Generation Exome Sequencing project, NCGENES), we investigated adult patients' intentions to request six categories of secondary findings (SFs) with low or no medical actionability and correlates of their intentions. METHODS: At enrollment, eligible participants (n = 152) completed measures assessing their sociodemographic, clinical, and literacy-related characteristics. Prior to and during an in-person diagnostic result disclosure visit, they received education about categories of SFs they could request. Immediately after receiving education at the visit, participants completed measures of intention to learn SFs, interest in each category, and anticipated regret for learning and not learning each category. RESULTS: Seventy-eight percent of participants intended to learn at least some SFs. Logistic regressions examined their intention to learn any or all of these findings (versus none) and interest in each of the six individual categories (yes/no). Results revealed little association between intentions and sociodemographic, clinical, or literacy related factors. Across outcomes, participants who anticipated regret for learning SFs reported weaker intention to learn them (odds ratios (ORs) from 0.47 to 0.71), and participants who anticipated regret for not learning these findings reported stronger intention to learn them (OR 1.61-2.22). CONCLUSION: Intentions to request SFs with low or no medical actionability may be strongly influenced by participants' desire to avoid regret. PMID- 29261175 TI - Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency. AB - PURPOSE: Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases. METHODS: To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed. RESULTS: We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype. CONCLUSION: These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD. PMID- 29261171 TI - Fluorescence Sensing Using DNA Aptamers in Cancer Research and Clinical Diagnostics. AB - Among the various advantages of aptamers over antibodies, remarkable is their ability to tolerate a large number of chemical modifications within their backbone or at the termini without losing significant activity. Indeed, aptamers can be easily equipped with a wide variety of reporter groups or coupled to different carriers, nanoparticles, or other biomolecules, thus producing valuable molecular recognition tools effective for diagnostic and therapeutic purposes. This review reports an updated overview on fluorescent DNA aptamers, designed to recognize significant cancer biomarkers both in soluble or membrane-bound form. In many examples, the aptamer secondary structure switches induced by target recognition are suitably translated in a detectable fluorescent signal using either fluorescently-labelled or label-free aptamers. The fluorescence emission changes, producing an enhancement ("signal-on") or a quenching ("signal-off") effect, directly reflect the extent of the binding, thereby allowing for quantitative determination of the target in bioanalytical assays. Furthermore, several aptamers conjugated to fluorescent probes proved to be effective for applications in tumour diagnosis and intraoperative surgery, producing tumour type specific, non-invasive in vivo imaging tools for cancer pre- and post treatment assessment. PMID- 29261176 TI - "Not pathogenic until proven otherwise": perspectives of UK clinical genomics professionals toward secondary findings in context of a Genomic Medicine Multidisciplinary Team and the 100,000 Genomes Project. AB - PurposeApproaches to secondary findings in genome sequencing (GS) are unresolved. In the United Kingdom, GS is now routinely available through the 100,000 Genomes Project, which offers participants feedback of limited secondary findings.MethodsIn Oxford, a Genomic Medicine Multidisciplinary Team (GM-MDT) governs local access to GS, and reviews findings. Semistructured interviews were conducted with 19 GM-MDT members to explore perspectives on secondary findings.ResultsWhile enthusiastic about GS for diagnosing rare disease, members question the rationale for genome screening largely because of lack of evidence for clinical utility and limited justification for use of resources. Members' views are drawn from diverse experiences; they feel a strong sense of responsibility to act in participants' best interests. The capacity to return limited secondary findings should be enabled, but members favor a cautious approach that is responsive to accumulating evidence. Informed participant choice is considered critical, yet challenging. Discrimination of variants is considered essential, and requiring of specialist input and consensus. Multiple areas requiring enhanced engagement and education are identified, i.e., for patients, the public, and health-care professionals; at present, mainstreaming of genomics may be premature.ConclusionUK experts believe that evidence to inform policy toward secondary findings is lacking, arguing for caution. PMID- 29261179 TI - Corrigendum: What are people willing to pay for whole-genome sequencing information, and who decides what they receive? AB - This corrects the article DOI: 10.1038/gim.2016.61. PMID- 29261177 TI - Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. AB - PurposeTo describe our experience of offering simultaneous genetic carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA).MethodsCarrier screening is offered through general practice, obstetrics, fertility, and genetics settings before or in early pregnancy. Carriers are offered genetic counseling with prenatal/preimplantation genetic diagnosis available to those at increased risk.ResultsScreening of 12,000 individuals revealed 610 carriers (5.08%; 1 in 20): 342 CF, 35 FXS, 241 SMA (8 carriers of 2 conditions), approximately 88% of whom had no family history. At least 94% of CF and SMA carriers' partners were tested. Fifty couples (0.42%; 1 in 240) were at increased risk of having a child with one of the conditions (14 CF, 35 FXS, and 1 SMA) with 32 pregnant at the time of testing. Of these, 26 opted for prenatal diagnosis revealing 7 pregnancies affected (4 CF, 2 FXS, 1 SMA).ConclusionThe combined affected pregnancy rate is comparable to the population risk for Down syndrome, emphasizing the need to routinely offer carrier screening. The availability of appropriate genetic counseling support and a collaborative approach between laboratory teams, genetics services, health professionals offering screening, and support organizations is essential. PMID- 29261178 TI - Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG). AB - Disclaimer: These ACMG Standards and Guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these Standards and Guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Galactosemias are inherited disorders of galactose metabolism due to deficiency in one of the three enzymes involved in the Leloir pathway: galactose-1-phosphate uridyltransferase, galactokinase, and uridine diphosphate (UDP)-galactose-4'-epimerase. Galactose-1 phosphate uridyltransferase deficiency, or classic galactosemia, is the most frequent and the most severe of the three enzyme deficiencies; it is characterized by failure to thrive, liver failure, susceptibility to sepsis, and death, if untreated. Newborn screening for classic galactosemia has been implemented in all of the United States, while screening for galactokinase deficiency and UDP-galactose-4'-epimerase deficiency is not universal. Early identification and treatment of galactosemia leads to improved outcome. This document reviews the laboratory methods and best practices for the diagnosis of galactosemia. PMID- 29261180 TI - Preemptive pharmacogenetic testing: exploring the knowledge and perspectives of US payers. AB - PurposePreemptive pharmacogenetic testing aims to optimize medication use by having genetic information at the point of prescribing. Payers' decisions influence implementation of this technology. We investigated US payers' knowledge, awareness, and perspectives on preemptive pharmacogenetic testing.MethodsA qualitative study was conducted using semistructured interviews. Participants were screened for eligibility through an online survey. A blended inductive and deductive approach was used to analyze the transcripts. Two authors conducted an iterative reading process to code and categorize the data.ResultsMedical or pharmacy directors from 14 payer organizations covering 122 million US lives were interviewed. Three concept domains and ten dimensions were developed. Key findings include clinical utility concerns and limited exposure to preemptive germ-line testing, continued preference for outcomes from randomized controlled trials, interest in guideline development, importance of demonstrating an impact on clinical decision making, concerns of downstream costs and benefit predictability, and the impact of public stakeholders such as the Food and Drug Administration and Centers for Medicare and Medicaid Services.ConclusionBoth barriers and potential facilitators exist to developing cohesive reimbursement policy for pharmacogenetics, and there are unique challenges for the preemptive testing model. Prospective outcome studies, more precisely defining target populations, and predictive economic models are important considerations for future research.GENETICS in MEDICINE advance online publication, 26 October 2017; doi:10.1038/gim.2017.181. PMID- 29261181 TI - Beware the laboratory report: discrepancy in variant classification on reproductive carrier screening. PMID- 29261182 TI - Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development. AB - PURPOSE: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases. METHODS: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-beta (ER-beta) was performed in an 8-week-old human male embryo. RESULTS: We identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA binding domain of ER-beta, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER beta, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-beta immunostaining was positive in the developing intestine and eyes. CONCLUSION: Our study supports a role for ESR2 as a novel candidate gene for 46,XY DSD. PMID- 29261183 TI - Revisiting mitochondrial diagnostic criteria in the new era of genomics. AB - PurposeDiagnosing primary mitochondrial diseases (MDs) is challenging in clinical practice. The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying MD and the need for a muscle biopsy. In this new genetic era with next-generation sequencing in routine practice, we aim to validate the diagnostic value of MDC.MethodsWe retrospectively studied MDC in a multicenter cohort of genetically confirmed primary MD patients.ResultsWe studied 136 patients (61 male, 91 nuclear DNA (nDNA) mutations). Forty-five patients (33%) had probable MD and 69 (51%) had definite MD according to the MDC. A muscle biopsy was performed in 63 patients (47%). Patients with nDNA mutations versus mitochondrial DNA mutations were younger (6.4 +/- 9.7 versus 19.5 +/- 17.3 y) and had higher MDC (7.07 +/- 1.12/8 versus 5.69 +/- 1.94/8). At a cutoff of 6.5/8, the sensitivity to diagnose patients with nDNA mutations is 72.5% with a positive predictive value of 69.5%. In the nDNA mutation group, whole-exome sequencing could diagnose patients with lower scores (MDC (6.84 +/- 1.51/8) compared to Sanger sequencing MDC (7.44 +/- 1.13/8, P = 0.025)). Moreover 7/8 patients diagnosed with possible MD by MDC were diagnosed by whole-exome sequencing.ConclusionMDC remain very useful in the clinical diagnosis of MD, in interpreting whole-exome results and deciding on the need for performing muscle biopsy. PMID- 29261184 TI - Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. AB - PurposeFamilial hypercholesterolemia (FH) is an autosomal disorder of lipid metabolism presenting with increased cardiovascular risk. Although more than 1,700 variants have been associated with FH, the great majority have not been functionally proved to affect the low-density lipoprotein receptor cycle. We aimed to classify all described variants associated with FH and to establish the proportion of variants that lack evidence to support their pathogenicity.MethodsWe followed American College of Medical Genetics and Genomics (ACMG) guidelines for the classification, and collected information from a variety of databases and individual reports. A worldwide overview of publicly available FH variants was also performed.ResultsA total of 2,104 unique variants were identified as being associated with FH, but only 166 variants have been proven by complete in vitro functional studies to be causative of disease. Additionally, applying the ACMG guidelines, 1,097 variants were considered pathogenic or likely pathogenic. Only seven variants were found in all five continents.ConclusionThe lack of functional evidence for about 85% of all variants found in FH patients can compromise FH diagnosis and patient prognosis. ACMG classification improves variant interpretation, but functional studies are necessary to understand the effect of about 40% of all variants reported. Nevertheless, ACMG guidelines need to be adapted to FH for a better diagnosis. PMID- 29261185 TI - Unmet needs in human genomic variant interpretation. PMID- 29261186 TI - Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis. AB - PURPOSE: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. METHODS: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. RESULTS: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. CONCLUSION: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges of WES in prenatal diagnosis. PMID- 29261187 TI - Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants. AB - PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient participants and their clinicians. We queried patient-participants' electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient-participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient-participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer including a stage 1C fallopian tube cancer-via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility. PMID- 29261189 TI - RET somatic mutations are underrecognized in Hirschsprung disease. AB - PURPOSE: We aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk. METHODS: Targeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation. RESULTS: We identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35-44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1-28%). CONCLUSION: Somatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families. PMID- 29261188 TI - Novel copy-number variations in pharmacogenes contribute to interindividual differences in drug pharmacokinetics. AB - PurposeVariability in pharmacokinetics and drug response is shaped by single nucleotide variants (SNVs) as well as copy-number variants (CNVs) in genes with importance for drug absorption, distribution, metabolism, and excretion (ADME). While SNVs have been extensively studied, a systematic assessment of the CNV landscape in ADME genes is lacking.MethodsWe integrated data from 2,504 whole genomes from the 1000 Genomes Project and 59,898 exomes from the Exome Aggregation Consortium to identify CNVs in 208 relevant pharmacogenes.ResultsWe describe novel exonic deletions and duplications in 201 (97%) of the pharmacogenes analyzed. The deletions are population-specific and frequencies range from singletons up to 1%, accounting for >5% of all loss-of-function alleles in up to 42% of the genes studied. We experimentally confirmed novel deletions in CYP2C19, CYP4F2, and SLCO1B3 by Sanger sequencing and validated their allelic frequencies in selected populations.ConclusionCNVs are an additional source of pharmacogenetic variability with important implications for drug response and personalized therapy. This, together with the important contribution of rare alleles to the variability of pharmacogenes, emphasizes the necessity of comprehensive next-generation sequencing-based genotype identification for an accurate prediction of the genetic variability of drug pharmacokinetics. PMID- 29261190 TI - Optimal Duration of Antiplatelet Therapy Following Acute Coronary Syndrome. AB - This newsletter provides an overview of the available data pertaining to the optimal duration of dual antiplatelet therapy following an acute coronary syndrome, with a focus on individualized treatment plans to optimize patient outcomes. PMID- 29261191 TI - Stimuli-responsively porating gels by condensation. AB - A polyurethane (PU) resin derived from glycerol and hexamethylene diisocyanate and an imidazolium bromide ionic liquid chain terminator yield a stimuli responsive resin that reversibly porates as a solvation response. PMID- 29261192 TI - First-principles study on the atomistic corrosion processes of iron. AB - The corrosion of iron presents an important scientific problem and a serious economic issue. It is also one of the most important subjects in materials science because it is basically an electrochemical process and closely related to other topics such as the electrocatalysis of the oxygen reduction reaction. So far, many studies have been conducted to address the corrosion of iron, a very complicated process that occurs when iron is exposed to oxygen and water. An important question is, at which site of the iron surface the corrosion starts and how it results in the final stage of the corrosion. In the present study, as an example of superficial defects, Fe dimers sticking out of Fe(100) surfaces are considered in order to understand the iron corrosion process from first principles using density functional theory. We found that the Fe dimers spontaneously react with O2 and H2O to form Fe2(OH)4 + 4OH-. Here, it is interesting to note that the Fe dimer plays the role of a water splitting catalyst, because the space above it is always vacant and can accept oxygen molecules many times for reacting with the surrounding water molecules. Then, if the Fe2(OH)4 molecules are detached from the surface, they react with O2 to form Fe2O(OH)4 without an activation barrier, and, in turn, the Fe2O(OH)4 and H2O molecules react to form Fe2(OH)6 complexes with an activation energy of 0.653 eV. If these complexes further dissociate into Fe(OH)3 molecules, they react with each other to form Fe2O3.2H2O with an activation energy of 0.377 eV. This work may provide useful information on possible iron corrosion processes by water in the air. PMID- 29261193 TI - Source-to-exposure assessment with the Pangea multi-scale framework - case study in Australia. AB - Effective planning of airshed pollution mitigation is often constrained by a lack of integrative analysis able to relate the relevant emitters to the receptor populations at risk. Both emitter and receptor perspectives are therefore needed to consistently inform emission and exposure reduction measures. This paper aims to extend the Pangea spatial multi-scale multimedia framework to evaluate source to-receptor relationships of industrial sources of organic pollutants in Australia. Pangea solves a large compartmental system in parallel by block to determine arrays of masses at steady-state for 100 000+ compartments and 4000+ emission scenarios, and further computes population exposure by inhalation and ingestion. From an emitter perspective, radial spatial distributions of population intakes show high spatial variation in intake fractions from 0.68 to 33 ppm for benzene, and from 0.006 to 9.5 ppm for formaldehyde, contrasting urban, rural, desert, and sea source locations. Extending analyses to the receptor perspective, population exposures from the combined emissions of 4101 Australian point sources are more extended for benzene that travels over longer distances, versus formaldehyde that has a more local impact. Decomposing exposure per industrial sector shows petroleum and steel industry as the highest contributing industrial sectors for benzene, whereas the electricity sector and petroleum refining contribute most to formaldehyde exposures. The source apportionment identifies the main sources contributing to exposure at five locations. Overall, this paper demonstrates high interest in addressing exposures from both an emitter perspective well-suited to inform product oriented approaches such as LCA, and from a receptor perspective for health risk mitigation. PMID- 29261194 TI - Calcium-based biomaterials for diagnosis, treatment, and theranostics. AB - Calcium-based (CaXs) biomaterials including calcium phosphates, calcium carbonates, calcium silicate and calcium fluoride have been widely utilized in the biomedical field owing to their excellent biocompatibility and biodegradability. In recent years, CaXs biomaterials have been strategically integrated with imaging contrast agents and therapeutic agents for various molecular imaging modalities including fluorescence imaging, magnetic resonance imaging, ultrasound imaging or multimodal imaging, as well as for various therapeutic approaches including chemotherapy, gene therapy, hyperthermia therapy, photodynamic therapy, radiation therapy, or combination therapy, even imaging-guided therapy. Compared with other inorganic biomaterials such as silica , carbon-, and gold-based biomaterials, CaXs biomaterials can dissolve into nontoxic ions and participate in the normal metabolism of organisms. Thus, they offer safer clinical solutions for disease theranostics. This review focuses on the state-of-the-art progress in CaXs biomaterials, which covers from their categories, characteristics and preparation methods to their bioapplications including diagnosis, treatment, and theranostics. Moreover, the current trends and key problems as well as the future prospects and challenges of CaXs biomaterials are also discussed at the end. PMID- 29261195 TI - Electrophoretic deposition of ordered mesoporous carbon nitride on a stainless steel wire as a high-performance solid phase microextraction coating. AB - An electrophoretic deposition approach was developed to fabricate a robust ordered mesoporous carbon nitride (MCN) coating for solid-phase microextraction. The large surface area, uniform pore diameter, in-built N-rich functional groups, and electron delocalization properties of MCN make it a promising adsorbent for SPME by pi-pi, hydrogen bonding and hydrophobic interactions between analytes and MCN. PMID- 29261196 TI - Single source precursor driven phase selective synthesis of Au-CuGaS2 heteronanostructures: an observation of plasmon enhanced photocurrent efficiency. AB - The design of new functional metal-semiconductor heteronanostructures with improved photovoltaic efficiencies has drawn significant attention because of their unprecedented properties and potential applications. Herein, we report a phase selective synthesis of ternary CuGaS2 (wurtzite and tetragonal) by simple solution based thermal decomposition of a new binuclear single molecular precursor [Ga(acda)3Cu(PPh3)2]NO3 (acda = 2-aminocyclopentene-1-dithiocarboxylic acid, PPh3 = triphenylphosphine) where the phase selectivity has been achieved easily by changing the combination of surface active agents. Furthermore, we have extended our approach to develop a well-controlled synthetic strategy for the preparation of a Au-CuGaS2 heteronanocomposite with both the phases. A detailed microscopic study reveals that during heterostructure synthesis, an epitaxial junction has been formed at the interface of ternary CuGaS2 and metallic Au. To find out the influence of this epitaxial connectivity on the properties, we have studied the photocurrent and photoresponse behavior of the material and compared them with that of bare CuGaS2. For both the wurtzite and tetragonal phases, the Au-CuGaS2 twin structure exhibits a plasmon enhanced superior charge transport ability and an abruptly high photocurrent density compared to that of pure CuGaS2. Due to efficient charge separation by strong plasmon-exciton coupling at the interface, Au-CuGaS2 can be used as a potential candidate for photoelectrochemical applications. PMID- 29261197 TI - Stability of mixed-oxide titanosilicates: dependency on size and composition from nanocluster to bulk. AB - Nanostructured titanosilicate materials based upon interfacing nano-TiO2 with nano-SiO2 have drawn much attention due to their huge potential for applications in a diverse range of important fields including gas sensing, (photo)catalysis, solar cells, photonics/optical components, tailored multi-(bio)functional supports and self-cleaning coatings. In each case it is the specific mixed combination of the two SiO2 and TiO2 nanophases that determines the unique properties of the final nanomaterial. In the bulk, stoichiometric mixing of TiO2 with SiO2 is limited by formation of segregated TiO2 nanoparticles or metastable glassy phases and more controlled disperse crystalline mixings only occur at small fractions of TiO2 (<15 wt%). In order to more fully understand the stability of nano-SiO2 and nano-TiO2 combinations with respect to composition and size, we employ accurate all-electron density functional calculations to evaluate the mixing energy in (TixSi1-xO2)n nanoclusters with a range of sizes (n = 2-24) having different titania molar fractions (x = 0-1). We derive all nanoclusters from a dedicated global optimisation procedure to help ensure that they are the most energetically stable structures for their size and composition. We also consider a selection of representative intimately mixed crystalline solid phase (TixSi1-xO2)bulk systems for comparison. In agreement with experiment, we find that homogeneous mixing of SiO2 and TiO2 in bulk crystalline phases is energetically unfavourable. Conversely, we find that SiO2-TiO2 mixing is energetically favoured in small (TixSi1-xO2)n nanoclusters. Following the evolution of mixing energy with nanocluster size and composition we find that mixing is most favoured in nanoclusters with a diameter of 1 nm with TiO2 molar fractions between 0.3-0.5. Thereafter, mixed nanoclusters with increasing size have progressively less negative mixing energies up to diameters of approximately 1.5 nm. We propose some chemical-structural principles to help rationale this energetically favourable nanoscale mixing. As a guide for experimentalists to observe and characterize these mixed nano-species we also provide two measurable signatures of mixing based on their unique vibrational and structural characteristics. PMID- 29261198 TI - Hot excitons are responsible for increasing photoluminescence blinking activity in single lead sulfide/cadmium sulfide nanocrystals. AB - The kinetics of photoluminescence blinking for isolated PbS/CdS nanocrystals changes with the photon excitation energy, with PL blinking increasing in frequency and changing from a two-state to a multistate on/off switching when the excitation energy changes from 1Sh-1Se (~1.4 eV) to 1Ph-1Pe (~2.4 eV). This increase in PL blinking activity with increased photon excitation energy is reasoned in terms of the formation of hot excitons leading to emission from both the band edge state and defect states, with defect states connected to traps that are otherwise inaccessible following low photon energy excitation at the band edge. PMID- 29261199 TI - An enhanced low-frequency vibration ZnO nanorod-based tuning fork piezoelectric nanogenerator. AB - In this paper, a piezoelectric nanogenerator (PENG) based on a tuning fork-shaped cantilever was designed and fabricated, aiming at harvesting low frequency vibration energy in the environment. In the PENG, a tuning fork-shaped elastic beam combined with ZnO nanorods (NRs), instead of conventional rectangular cantilever beams, was adopted to extract vibration energy. Benefiting from the high flexibility and the controllable shape of the substrate, this PENG was extremely sensitive to vibration and can harvest weak vibration energy at a low frequency. Moreover, a series of simulation models were established to compare the performance of the PENG with that of different shapes. On this basis, the experimental results further verify that this designed energy harvester could operate at a low frequency which was about 13 Hz. The peak output voltage and current could respectively reach about 160 mV and 11 nA, and a maximum instantaneous peak power of 0.92 MUW cm-3 across a matched load of 9 MOmega was obtained. Evidently, this newly designed PENG could harvest vibration energy at a lower frequency, which will contribute to broaden the application range of the PENG in energy harvesting and self-powered systems. PMID- 29261200 TI - Diamondoid architectures from halogen-bonded halides. AB - The reactions between a tetrahedrally-shaped tecton, tetrakis(4 (iodoethynyl)phenyl)methane, and tetraphenylphosphonium halides readily afford interpenetrated and densely packed diamondoid architectures sustained by C-IX- (X = chloride, bromide, iodide) interactions. In all these halogen-bonded networks, the halide anions act as four-connecting nodes, while the tetraphenylphosphonium cations provide essential templating information and structural support. PMID- 29261201 TI - Two-dimensional electronic spectroscopy of anharmonic molecular potentials. AB - Two-dimensional electronic spectroscopy (2DES) is a powerful tool in the study of coupled electron-phonon dynamics, yet very little is known about how nonlinearities in the electron-phonon coupling, arising from anharmonicities in the nuclear potentials, affect the spectra. These become especially relevant when the coupling is strong. From the linear spectroscopies, anharmonicities are known to give structure to the zero-phonon line and to break mirror-symmetry between absorption and emission, but the 2D analogues of these effects have not been identified. Using a simple two-level model where the electronic states are described by (displaced) harmonic oscillators with differing curvatures or displaced Morse oscillators, we find that the zero-phonon line shape is essentially transferred to the diagonal in 2DES spectra, and that anharmonicities break a horizontal mirror-symmetry in the infinite waiting time limit. We also identify anharmonic effects that are only present in 2DES spectra: twisting of cross-peaks stemming from stimulated emission signals; and oscillation period mismatch between ground state bleach and stimulated emission (for harmonic oscillators with differing curvatures), or inherently chaotic oscillations (for Morse oscillators). Our findings will facilitate an improved understanding of 2DES spectra and aid the interpretation of signals that are more realistic than those arising from simple models. PMID- 29261202 TI - Fluorescence-enhanced bio-detection platforms obtained through controlled "step by-step" clustering of silver nanoparticles. AB - Metal nanoparticle coatings are widely employed as fluorescence-enhanced platforms for high-throughput biological detection; however, complex manufacturing technologies and stringent fabrication procedures hinder their development for use in bioassays. Here, we present the preparation of fluorescence-based bioassay platforms using spray-assisted step-by-step assembly of silver nanoparticles (Ag NPs) and poly(diallyldimethylammonium chloride) (PDDA). This approach allowed us to control the density and the degree of aggregation of Ag NPs on large surfaces which are prerequisites for the development of bioassay platforms with a substantial fluorescence enhancement. After one assembly cycle (1-Ag platform) the adsorbed particles are not forming aggregates or ones composed of very few particles which, as expected, led to poor fluorescence enhancement (1.1) for cyanine 5. Further assembly steps induce the clustering of Ag NPs by multiple electrostatic interactions between PDDA and Ag NPs and thus increase the number of nanoparticles per aggregate in a controlled way. We observed that the nanoparticle island growth takes place first mainly in the plane (2D) and then in the plane and in the third dimension and that the aggregate morphology (2D versus 3D) strongly affects the plasmonic fluorescence enhancement of the fluorescent dye. A substantial fluorescence enhancement (12.3) was measured for a Ag NP platform obtained after twelve assembly cycles. This result is within the ballpark of values reported in the literature for bioassay platforms using metal nanoparticles and opens the route towards the preparation of fluorescence-based bioassay platforms on the large scale. PMID- 29261203 TI - An overview and recent progress in the chemistry of uranium extraction from seawater. AB - This review provides a brief background on the extraction of uranium from seawater as well as recent work by the United States Department of Energy on this project. The world's oceans contain uranium at 3 parts per billion, and despite this low concentration, there has been historical interest in harvesting it, mainly in Japan in the 1980s and the United States in this decade. Improvements in materials, chemistry, and deployment methods have all been made, with the ultimate goal of lower cost. This has been partially realized, dropping from approximately $2000 per kg U3O8 extracted in 1984 to $500 per kg today, although this is not yet competitive with terrestrial uranium. This technology may become cost-competitive if the cost of land-based uranium rises, especially if seawater extraction technology is improved further. The coordination chemistry aspects of the project are described in more detail, exploring the functional groups that are present on typical polymer sorbents as well as small-molecule analogues of these ligands. Selectivity for uranium over other metals, particularly vanadium, remains problematic, and techniques to both quantify binding strength and selectivity in order to overcome this issue are essential for future cost improvements. PMID- 29261204 TI - Nanomolar-level selective dual channel sensing of Cu2+ and CN- from an aqueous medium by an opto-electronic chemoreceptor. AB - A dual-channel chromogenic and fluorogenic fused-aromatic-system-based chemoreceptor (2-(benzo[d]thiazol-2-yl)-1-((pyren-8-yl)methylene)hydrazine) (TyM) was designed for ditopic sensitivity towards heavy and transition metal ions (HTMs), such as Cu2+, in an aqueous medium and lethal CN- in a semi-aqueous medium. The chemoreceptor displayed proclivity towards the targeted analytes with a distinct optical response (yellow to colourless in the case of Cu2+ and yellow to bright red for CN-). TyM formed a 2 : 1 adduct with Cu2+ with a detection limit of 40 nM. A 1 : 1 binding stoichiometry was confirmed with the chemoreceptor TyM with CN- in sub-nano molar limit of detection. In addition to sophisticated spectroscopic analysis, such as UV-vis, fluorescence, FTIR, 1H-NMR, 13C-NMR, ESI-MS, and HRMS, the plausible mechanistic course of sensing was also established from a theoretical perspective. The reversible UV-vis response of the chemoreceptor TyM towards CN- and H+ can mimic different molecular logic functions and therefore can be exploited for designing several complex electronic circuits principally based on Boolean Algebra. In vitro fluorescence imaging in male microspores of seed plants (Bohonia Nigalandra) and Monilia Albicans (diploid fungus) with TyM and Cu2+ confirmed the permeability of the chemoreceptor TyM at the cellular level as well as its ability to investigate transition metals, such as Cu2+, in biological samples. PMID- 29261205 TI - Dynamical decoupling of nitroxides in o-terphenyl: a study of temperature, deuteration and concentration effects. AB - We have characterized the temperature dependent transverse relaxation for 100 MUM protonated and deuterated nitroxides in both protonated and deuterated o terphenyl (OTP and dOTP) in distinct temperature regimes between 10 K and room temperature (RT). The choice of sample compositions allowed for a clear separation into slow and fast relaxation contributions based on a sum of two stretched exponential (SSE) parameterization between 10 and 60 K, and likewise at RT. The slow contribution is purely matrix dependent, while the fast process is determined by an interplay between a molecule and a matrix. Our systematic study of dynamical decoupling (DD) as a function of temperature (at 40, 80 K and RT), spin concentration, deuteration of nitroxide and/or OTP matrix and DD scheme for 1 to 5 refocusing pulses reveals that DD significantly prolongs phase memory times with respect to Hahn echo relaxation at 40 K, which we discuss in an SSE framework. At 80 K and RT, where (intra)molecular motions dominate relaxation, DD does not preserve electron spin coherence independent of the sample composition. Instead, we report a matrix nuclei dependent performance of the applied DD scheme at 40 K with Uhrig outperforming Carr-Purcell DD in OTP, and vice versa for a dOTP matrix. PMID- 29261206 TI - Base-catalyzed thio-lactamization of 2-(1-arylvinyl)anilines with CS2 for the synthesis of quinoline-2-thiones. AB - Here we show that the base-catalyzed thio-lactamization of 2-(1 arylvinyl)anilines with CS2 is a powerful methodology to synthesize quinoline-2 thiones. This thio-lactamization uses inexpensive and versatile 2-(1 arylvinyl)anilines, which are easily available from the reaction of amines and alkynes. Compared to the known strategy in the literature, this method features the advantages like a short synthesis step and easily available starting materials. PMID- 29261207 TI - Coarse-grained molecular dynamics simulation of activated penetrant transport in glassy polymers. AB - Membrane separations of gas mixtures strive to maximize the permeability of a desired species while keeping out undesired ones. Permeability vs. selectivity data from many polymer membranes for a given gas pair with diameters dA and dB are typically collected in a "Robeson plot"', and are bound from above by a line with a slope lambda = (dB/dA)2 - 1. A microscopic understanding of this relationship, especially lambda, is still missing. We perform molecular dynamics simulations of penetrant diffusion using three different coarse-grained polymer models over a wide range of penetrant sizes, temperatures, and monomer densities. The empirically relevant lambda = (dB/dA)2 - 1 is only found for polymers that are either supercooled liquids with caged segmental dynamics or glasses and when the penetrant size is approximately half the Kuhn length of the chains, for which the penetrant diffusion is an activated process. PMID- 29261208 TI - Realization of a stable, monodisperse water-in-oil droplet system with micro scale and nano-scale confinement for tandem microscopy and diffusion NMR studies. AB - In this work we generate stable and monodisperse water-in-oil emulsions using a co-flowing geometry that produced droplet sizes between 13 MUm and 250 MUm. The drops survived transfer to NMR tubes and were stable for at least 26 hours, enabling the performance of pulsed-field-gradient NMR experiments in addition to microscopy. The drops sizes achieved as a function of flow rate agree well with a simple model for droplet generation: this yields a precise measure of the interfacial tension. The design of a cell mimetic environment with nano-scale confinement has also been demonstrated with diffusion measurements on macromolecules (PEG and Ficoll70) within droplets that are further structured internally using agarose gel networks. Containing the agarose gel in droplets appears to provide very reproducible and homogeneous network environments, enabling quantitative agreement of Ficoll70 dynamics with a theoretical model, with no fit parameters, and, with PEG, yielding a systematic polymer-size dependent slowing down in the network. This is in contrast with bulk agarose, where identical macromolecular diffusion measurements indicate the presence of heterogeneities with water pockets. PMID- 29261209 TI - Synthesis of trifluoroalkyl or difluoroalkyl phenanthridine derivatives via cascade reaction using an intramolecular cyano group as a radical acceptor under photoredox catalysis. AB - In the presence of Ru(phen)3Cl2 or fac-Ir(ppy)3 under visible-light irradiation, the addition of fluorinated radicals to N-arylacrylamides followed by an intramolecular cyano group insertion cascade cyclization process produced trifluoroalkyl or difluoroalkyl phenanthridine derivatives in moderate to good yields. Three easily available fluoroalkylated reagents CF3SO2Cl, BrCF2CO2Et and BrCF2PO(OEt)2 were used as the sources of fluorinated radicals. PMID- 29261210 TI - Lipophilic polyelectrolyte gel derived from phosphonium borate can absorb a wide range of organic solvents. AB - Herein, we demonstrate a polyelectrolyte gel which can absorb a wide range of organic solvents from dimethylsulfoxide (DMSO, permittivity: epsilon = 47.0) to tetrahydrofuran (epsilon = 5.6). The gel consists of polystyrene chains with small amounts (~5 mol%) of lipophilic electrolytes derived from triphenylphosphonium tetraaryl borate. The swelling ability of the polyelectrolyte gel was higher than that of the alkyl ammonium tetraaryl borate previously reported by us, and this is attributed to the higher compatibility with organic solvents, as well as the higher dissociating ability, of the triphenyl phosphonium salt. The role of the ionic moieties was additionally confirmed by post modification of the polyelectrolyte gel via a conventional Wittig reaction, resulting in a nonionic gel. Our findings introduced here will lead to a clear-cut molecular design for polyelectrolyte gels which absorb all solvents. PMID- 29261211 TI - Thermo-responsive gels based on supramolecular assembly of an amidoamine and citric acid. AB - In this work, we report the formation of a novel, aqueous-based thermo responsive, supramolecular gelling system prepared by a convenient and efficient self-assembly of a long-chain amino-amide and citric acid. To determine the viscosity behavior and to gain insights into the gelation mechanism, a complementary combination of techniques, including Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic light scattering (DLS), and sinusoidal oscillatory tests, were used. The supramolecular gelator exhibited remarkably reversible sol-gel transitions induced by temperature at 76 degrees C. At a concentration of 5 wt%, the zero-frequency viscosity of the supramolecular system increased by about four orders of magnitude (from 4.2 to 12 563 Pa s) by changing the temperature from 23 degrees C to 76 degrees C. The viscous nature of the supramolecular gel could be preserved up to 90 degrees C. The synergistic combination of the hydrogen bonding between amino and carboxylic acid groups and the electrostatic interactions arising from the protonation of the amino-group and the deprotonation of carboxylic acid groups enhanced at higher temperatures is presumably responsible for the thermo-responsive behavior. We anticipate that these supramolecular gelators can be beneficial in various applications such as hydrogel scaffolds for regenerative medicine, personal care products and cosmetics, and enhanced oil recovery as viscosity modifiers. PMID- 29261212 TI - A new model linking elastic properties and ionic conductivity of mixed network former glasses. AB - Glasses are promising candidate materials for all-solid-state electrolytes for rechargeable batteries due to their outstanding mechanical stability, wide electrochemical stability range, and open structure for potentially high conductivity. Mechanical stiffness and ionic conductivity are two key parameters for solid-state electrolytes. In this study, we investigate two mixed-network former glass systems, sodium borosilicate 0.2Na2O + 0.8[xBO1.5 + (1 - x)SiO2] and sodium borogermanate 0.2Na2O + 0.8[xBO1.5 + (1 - x)GeO2] glasses. With mixed network formers, the structure of the network changes while the network modifier mole fraction is kept constant, i.e., x = 0.2, which allows us to analyze the effect of the network structure on various properties, including ionic conductivity and elastic properties. Besides the non-linear, non-additive mixed glass former effect, we find that the longitudinal, shear and Young's moduli depend on the combined number density of tetrahedrally and octahedrally coordinated network former elements. These units provide connectivity in three dimensions, which is required for the networks to exhibit restoring forces in response to isotropic and shear deformations. Moreover, the activation energy for modifier cation, Na+, migration is strongly correlated with the bulk modulus, suggesting that the elastic strain energy associated with the passageway dilation for the sodium ions is governed by the bulk modulus of the glass. The detailed analysis provided here gives an estimate for the number of atoms in the vicinity of the migrating cation that are affected by elastic deformation during the activated process. The larger this number and the more compliant the glass network, the lower is the activation energy for the cation jump. PMID- 29261213 TI - Journal of Prevention of Alzheimer's Disease (JPAD): Building a "Fleet" Against Alzheimer's Disease. PMID- 29261214 TI - Multi-Domain Prevention for a Multi-Factorial Disease. PMID- 29261215 TI - Is Alzheimer's Disease Drug Development Broken? What Must Be Improved? PMID- 29261217 TI - High Alzheimer's Disease Study Complexity - Low Success Rate. PMID- 29261216 TI - Is Alzheimer's Disease Drug Development Broken? What Must Be Improved. PMID- 29261218 TI - The Timecourse of Global Cognitive Gains from Supervised Computer-Assisted Cognitive Training: A Randomised, Active-Controlled Trial in Elderly with Multiple Dementia Risk Factors. AB - BACKGROUND: Home-based computerised cognitive training (CCT) is ineffective at enhancing global cognition, a key marker of cognitive ageing. OBJECTIVES: To test the effectiveness of supervised, group-based, multidomain CCT on global cognition in older adults and to characterise the dose-response relationship during and after training. DESIGN: A randomised, double-blind, longitudinal, active controlled trial. SETTING: Community-based training centre in Sydney, Australia Participants: Eighty nondemented community-dwelling older adults (mean age = 72.1, 68.8% females) with multiple dementia risk factors but no major neuropsychiatric or sensory disorder. Of the 80 participants admitted to the study, 65 completed post-training assessment and 55 were followed up one year after training cessation. INTERVENTIONS: Thirty-six group-based sessions over three months of either CCT targeting memory, speed, attention, language and reasoning tasks, or active control training comprising audiovisual educational exercises. MEASUREMENTS: Primary outcome was change from baseline in global cognition as defined by a composite score of memory, speed and executive function. Secondary outcome was 15-month change in Bayer Activities of Daily Living from baseline to one year post-training. RESULTS: Intention-to-treat analyses revealed significant effects on global cognition in the cognitive training group compared to active control after three weeks of training (ES = 0.33, P=.039) that increased after 3 months of training (ES = 0.49, P=.003) and persisted three months after training cessation (ES = 0.30, P=0.023). Significant and durable improvements were also noted in memory and processing speed. Dose response characteristics differed among cognitive domains. Training effects waned gradually but residual gains were noted twelve months post-training. No significant effects on activities of daily living were noted and there were no adverse effects. CONCLUSIONS: In older adults with multiple dementia risk factors, group-based CCT is a safe and effective intervention for enhancing overall cognition, memory and processing speed. Dose-response relationships vary for each cognitive domain, vital information for clinical and community implementation and further trial design. PMID- 29261219 TI - Is Alzheimer's Disease Drug Development Broken? What Must Be Improved. AB - During the decade from 2002 to 2012, 99.6% of the 244 agents tested for efficacy in slowing the progression of Alzheimer's' disease (AD) failed to achieve their primary endpoints. At a CTAD symposium on November 14, 2013, in San Diego, USA, an international group of AD researchers met to discuss the evolution of trials over the past 10 years and proposed a number of changes intended to streamline and enhance the efficiency of clinical trials. Approximately 1,031 AD trials were conducted between 2000 and 2012. The number of patients per trial site tended to decrease over time necessitating a larger number of sites. The use of biomarkers for enrichment purposes, or as measures of target engagement or surrogate outcomes, results in higher screen failure and drop-out rates, adding to trial duration and/or costs. Present disease modifying AD trials ask for increasing logistical and technical requirements, necessitating the creation of highly specialized trial facilities and limiting the participation of smaller sites. Due to heavy administrative and regulatory task, only about 13% of the team's time is used for the essential recruitment. Proposals and perspectives: Strategies suggested to improve the efficiency of recruitment include establishing "ready to go cohorts" in advance of trials using biomarkers and clinical measures. Simplification and harmonization of administrative procedures, including harmonization of certification procedures, are urgently needed. Alternative approaches, such as using the Internet to screen volunteers for possible inclusion needs to be evaluated. The AD drug development enterprise from discovery through clinical trials requires re-examination and re-organization if new drugs are to be delivered to patients in a timely way. PMID- 29261220 TI - Inter-Species Glia Differences: Implications for Successful Translation of Transgenic Rodent Alzheimer's Disease Model Treatment Using Bexarotene. AB - Despite a multitude of efficacious treatments for the cognitive symptoms and pathology in transgenic mouse models of Alzheimer's disease (AD), success in human trials has been elusive. Rodent-human brain dissimilarities may help explain failures of past human trials and improve outcomes of future ones. This review highlights the essential role of the human brain's exceptional myelination in achieving and maintaining optimal brain functions, as well as underlying its vulnerability to age-related myelin breakdown and the degenerative brain diseases that process can trigger. This alternative myelin-centered perspective is used herein to help explain key disconnects in the existing treatment literature by focusing on recent reports on brain effects of bexarotene, the only marketed retinoid X receptor (RXR) agonist. The myelin perspective exposes significant yet underexplored opportunities for novel treatment and prevention interventions that have the potential to considerably reduce the tremendous burden of degenerative brain diseases. PMID- 29261221 TI - Prevention: How the Paradigm Is Shifting. PMID- 29261222 TI - Hospitalization for ambulatory care sensitive conditions among urban Metis adults. AB - BACKGROUND: Hospitalizations for ambulatory care sensitive conditions (ACSCs) are potentially preventable, but may be required if these conditions are not managed well. National-level information about ACSC hospitalizations is available for Canada, but not for Aboriginal groups. This study describes ACSC hospitalizations among urban Metis adults relative to their non-Aboriginal counterparts. DATA AND METHODS: The 2006/2007-to-2008/2009 Discharge Abstract Database, which contains hospitalization records from all acute care facilities (excluding Quebec), was linked to the 2006 Census to obtain Aboriginal identity information. Age standardized ACSC hospitalization rates (ASHRs) per 100,000 population and rate ratios were calculated for Metis aged 18 to 74 relative to non-Aboriginal people of the same ages. Odds of ACSC hospitalizations were estimated using logistic regression models, adjusting for demographic, geographic, and socioeconomic characteristics. RESULTS: The ASHR for ACSCs among urban Metis adults was twice that among non-Aboriginal adults (393 versus 184 per 100,000 population). Even when demographic, geographic, and socioeconomic characteristics were taken into account, Metis had higher odds of ACSC hospitalizations overall (OR 1.5). Most commonly, these hospitalizations were for diabetes (OR 1.8) or chronic obstructive pulmonary disease (OR 1.5). Modelled factors partly reduced differences between Metis and non-Aboriginal adults, but variations between the groups remained after all adjustments. INTERPRETATION: Rates of ACSC hospitalizations were higher among Metis than among non-Aboriginal adults who lived in urban areas. Further research using other data sources is warranted to assess the roles of factors not available for this analysis, such as primary care, co-morbidity, and health behaviours. PMID- 29261223 TI - Family networks and health among Metis aged 45 or older. AB - BACKGROUND: Social networks are important for promoting and maintaining health and well-being. Social networks, including family and friendship ties, are sources of emotional, practical and other support that enhance social participation and help combat isolation and loneliness. Aboriginal seniors have been identified as a population at risk of social isolation. DATA AND METHODS: The data are from the 2012 Aboriginal Peoples Survey, a national survey of First Nations people living off reserve, Metis, and Inuit. Frequencies, cross tabulations, and logistic regression models were used to look at family networks and self-perceived general and mental health among Metis aged 45 or older. RESULTS: An estimated 48% of Metis men and 60% of Metis women aged 45 or older had strong family networks. Older age, lower education, and non-participation in the labour force were associated with strong networks. Metis men and women with strong family networks had higher odds than did those with weak networks of reporting positive mental health, even when potential confounders were taken into account. Among Metis men, a relationship between strong family networks and positive general health was also observed. DISCUSSION: Strong family networks are associated with positive self-perceived general and mental health among Metis adults. In addition to individual behaviours, family well-being is important for general health promotion. PMID- 29261224 TI - Mitochondrial sirtuins in the rat adrenal gland: location within the glands of males and females, hormonal and developmental regulation of gene expressions. AB - INTRODUCTION: Sirtuins are NAD dependent class III histone deacetylases. In adrenal cortex mitochondria are able to transform - via nicotinamide nucleotide transhydrogenase (NNT) - NAD into NADPH, which is required for steroidogenesis. These findings suggest that sirtuins expressed in mitochondria, Sirt3, Sirt4 and Sirt5, may be associated with adrenal steroidogenesis. Therefore, the purpose of this study was to characterize the expression of mitochondrial sirtuins (Sirt3-5) in individual compartments of rat adrenal cortex, their developmental regulation and to demonstrate whether their expression is dependent on adrenocorticotrophic hormone (ACTH) and Nampt (nicotinamide phosphoribosyltransferase also known as visfatin/PBEF), the rate-limiting enzyme in the regulation of mammalian NAD synthesis. MATERIAL AND METHODS: Studies were performed on rat adrenal glands or on primary culture of rat adrenocortical cells. Expression of mitochondrial sirtuins (Sirt3-5) was evaluated by Affymetrix microarray system or QPCR. The bulk of data were extracted from our earlier experiments which have been reanalyzed in regard to Sirt3-5 mRNAs expression levels and - if necessary - validated by QPCR. RESULTS: Sirt3-5 were expressed throughout the rat adrenal, with the highest expression level of Sirt5. The level of expression of all sirtuins is higher in the zona glomerulosa (ZG) and zona fasciculata/reticularis (ZF/R) than in the adrenal medulla. Sirt3 and Sirt5 expression levels were similar in adult male and female rats, while Sirt4 expression level was higher in females. As revealed by analysis of the available open database, no significant changes in Sirt3-5 expression levels in whole adrenal glands were observed up to week 104 of life of both male and female rats. Moreover, 60 min after intraperitoneal ACTH injection the expression level of Sirt3 in the en-tire gland was elevated while Sirt5 expression level lowered. On the other hand, chronic ACTH infusion (48 h) did not change expression of studied sirtuins. In cultured cells, ACTH greatly increased the expression levels of the Sirt4 and Sirt5. In cultured cells, Fk866 - a highly specific competitive inhibitor of Nampt - reduced expression level of Sirt5 only. In enucleation-induced regenerating rat adrenal, the expression levels of all studied sirtuins were significantly reduced in relation to the control group. Finally, in primary rat adrenal culture the FCS depletion elevates the Sirt3 and Sirt4 expression levels and downregulates Sirt5 expression. CONCLUSIONS: Sirt3-5 are expressed throughout the rat adrenal, with the highest expression levels in adrenal cortex. Performed experiments (ACTH stimulation, FCS depletion, regeneration) suggest that in the adrenal cortex, the mitochondrial Sirt5 is the primary mitochondrial sirtuin involved in regulating the biological activity of adrenocortical cells. Our results also suggest that normal levels of intracellular Nampt (iNampt) enzymatic activity are required to maintain normal (control) levels of Sirt5 mRNA in cultured cells. PMID- 29261225 TI - In Vitro Validation of miRNA-Mediated Gene Expression Linked to Drug Metabolism. AB - Pharmacogenomic approaches used to investigate how genes affect drug responses are critical for designing personalized therapies aimed at maximizing efficacy and minimizing adverse effects. Drug efficacy is often dependent on the sequence and expression levels of drug target genes or those involved in the metabolism and transport of the therapeutic agent. Expression of these genes, in turn, is negatively regulated by small noncoding miRNAs. The levels of miRNAs in bodily fluids have been studied extensively as potential diagnostic and prognostic biomarkers. Studies have shown that miRNAs regulate multiple genes and sequence homology is used to predict which genes are subject to regulation by a particular miRNA. Once a gene is identified as a potential target for an miRNA of interest, experiments are undertaken to confirm that the miRNA interacts with the target gene and can alter its level of expression and/or its activity. For example, the differential expression of miRNAs in whole blood obtained from good and poor responders to ketamine has been reported both prior to, and following treatment for complex regional pain syndrome. In this case, hsa-miR-548d-5p was significantly lower in poor responders relative to good responders. This miRNA was predicted to target UDP-glucuronyl transferase 1A1 (UGT1A1), a key drug metabolizing enzyme. Described in this unit are protocols used to confirm miR 548d-5p-mediated UGT1A1 regulation. The approaches described can be employed broadly for the validation of miRNA-mediated negative regulation of any gene. Determining miRNA-mediated regulation of enzymes and transporters affecting drug metabolism is a critical step in designing personalized therapy and for understanding the mechanisms responsible for variations in the responses to therapeutic agents. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261226 TI - In Vitro Assays for the Functional Characterization of the Dopamine Transporter (DAT). AB - Detailed in this unit are protocols for studying the in vitro uptake of dopamine (DA) as a means for defining the functional characteristics of dopamine transporters. All assays are performed using commercially available cell lines that transiently express the transporter under investigation. The three main assays provided are: a kinetic assay to calculate the affinity (KM ) and maximal velocity (Vmax ) of radiolabeled DA uptake into cells; concentration-response assays to measure the potencies (IC50 /Ki values) of test compounds as transport inhibitors; and an efflux assay to assess the ability and potency (EC50 ) of a ligand to elicit reverse transport of DA accumulated in the cell. Although the methods are described using DAT and its ligands, the same procedure can be employed for studying serotonin and norepinephrine transporters as well. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261227 TI - Overview of microRNA Modulation in Analgesic Research. AB - MicroRNA(miRNA)-mediated gene regulation underlies cellular processes, playing an important role in homeostasis and diseases. The expression and function of miRNAs are altered by various pharmacological agents, with differences in the endogenous levels of miRNAs influencing drug efficacy and toxicity. Thus, miRNA levels could be a biomarker for predicting treatment response, efficacy, and safety. In addition, elucidating the mechanistic significance of miRNA alterations can aid in the identification of therapeutic targets and patient selection, and guide personalized therapy. Discussed in this overview are the properties of miRNA, their modulation, and the ways to measure them. The effects of different classes of analgesics, including opioid and non-opioid, are described as examples of drug induced modifications of miRNA, with a discussion on how measurement of miRNA levels in patients receiving analgesic therapy can assist in maximizing effectiveness while minimizing the untoward responses to this drug class. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261229 TI - In Vitro Histone Acetylation Assay. AB - Acetylation is a core cellular process involved in maintaining genomic integrity, gene regulation, and metabolism. Histone acetyltransferases (HATs) are an enzyme family that regulates these processes by catalyzing the transfer of an acetyl moiety onto target proteins. Perturbations of cellular acetylation profiles have been associated with a variety of disease states, including cancer. Changes in acetylation profiles can be achieved by mechanisms associated with acetyltransferases, such as gene down-regulation or alterations in the activity of key acetyltransferase enzymes. An important set of tools for quantifying enzyme activity are in vitro histone acetylation assays, using either endogenous or tagged overexpressed proteins. Detailed in this unit is an in vitro acetylation assay used to quantify HAT activity. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261228 TI - Overview of Monoamine Transporters. AB - The dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters, which are collectively referred to as monoamine transporters (MATs), play significant roles in regulating the neuronal response to these neurotransmitters. MATs terminate the action of these neurotransmitters by translocating them from the synaptic space into the presynaptic neurons. These three transmitters are responsible for controlling a number of physiological, emotional, and behavioral functions, with their transporters being the site of action of drugs employed for the treatment of a variety of conditions, including depression, anxiety, ADHD, schizophrenia, and psychostimulant abuse. Provided in this unit is information on the localization and regulation of MATs and the structural components of these proteins most responsible for the translocation process. Also included is a brief description of the evolution of ligands that interact with these transporters, as well as current theories concerning the pharmacological effects of substances that interact with these sites, including the molecular mechanisms of action of uptake inhibitors and allosteric modulators. Data relating to the presence, structure, and functions of allosteric modulators are included as well. The aim of this review is to provide background information on MATs to those who are new to this field, with a focus on the therapeutic potential of compounds that interact with these substrate transport sites. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261230 TI - Assessing Sociability, Social Memory, and Pup Retrieval in Mice. AB - Adaptive social behavior is important in mammals, both for the well-being of the individual and for the thriving of the species. Dysfunctions in social behavior occur in many neurodevelopmental and psychiatric diseases, and research into the genetic components of disease-relevant social deficits can open up new avenues for understanding the underlying biological mechanisms and therapeutic interventions. Genetically modified mouse models are particularly useful in this respect, and robust experimental protocols are needed to reliably assess relevant social behavior phenotypes. Here we describe in detail three protocols to quantitatively measure sociability, one of the most frequently investigated social behavior phenotypes in mice, using a three-chamber sociability test. These protocols can be extended to also assess social memory. In addition, we provide a detailed protocol on pup retrieval, which is a particularly robust maternal behavior amenable to various scientific questions. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261231 TI - The Study of Host Immune Responses Elicited by the Model Murine Hookworms Nippostrongylus brasiliensis and Heligmosomoides polygyrus. AB - Hookworm infections (Necator americanus or Ancylostoma duodenale) represent a major neglected tropical disease, affecting approximately 700 million people worldwide, and can cause severe morbidity due to the need for these worms to feed on host blood. N. brasiliensis and H. polygrus, both rodent parasites, are the two most commonly employed laboratory models of experimental hookworm infection. Both parasites evoke type 2 immune responses, and their use has been instrumental in generating fundamental insight into the molecular mechanisms of type-2 immunity and for understanding how the immune response can control parasite numbers. Here we provide a complete set of methods by which to investigate the natural progression of infection and the host immunological responses in the lung and intestine of H. polygyrus- and N. brasiliensis-infected mice. Detailed information is included about the most important parasitological and immunological measurements to perform at each time point. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261232 TI - A Mouse Model of West Nile Virus Infection. AB - The use of a mouse model to study the breadth of symptoms and disease severity seen in human West Nile virus (WNV) infection can provide insight into the kinetics of the immune response and the specific pathways responsible for control of WNV infection and viral clearance. Here, we provide protocols for performing WNV infection of mice, as well as complete immunophenotyping analysis of the cellular immune response to infection in both the periphery and the central nervous system in a mouse model of WNV infection. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261233 TI - Evaluation of the Estrous Cycle, Reproductive Tract, and Mammary Gland in Female Mice. AB - Evaluation of the female reproductive system is an important part of basic reproductive biology research, toxicology testing, and mutant mouse phenotype assessment. The female reproductive system is dynamic and the onset of puberty and the normal changes observed during estrous cyclicity can create challenges for an investigator. Experimental work in the female mouse requires an understanding of the potential impact of the estrous cycle and tracking normal changes throughout the cycle allows for control of this key variable. The estrous cycle can be evaluated using vaginal cytology, which provides the researcher a daily assessment of the entire reproductive endocrine axis and allows for samples to be collected at precise times within the cycle. These protocols describe the basic approach to evaluating the onset of cyclicity, tracking the normal cycle, and collection and microscopic evaluation of the reproductive system and mammary gland in the mouse. (c) 2017 by John Wiley & Sons, Inc. PMID- 29261234 TI - PACIFIC POWER. NURSING PARTNERSHIPS ACROSS THE BLUE CONTINENT. AB - Since it was first formed 35 years ago, the South Pacific Nurses Forum has been working to improve cross-cultural understanding and regional cooperation in nursing. Despite overwhelming health challenges in the Pacific, nurses and midwives are banding together to strive for universal access to quality healthcare, writes Karen Keast. PMID- 29261235 TI - MIDWIFE BLOSSOMS INTO AFL STAR. PMID- 29261236 TI - COMMUNICATION IS KEY. AB - Nursing is a career with an ever changing landscape of opportunities and difficulties. We work hard to stay at the forefront of modern medicine and healthcare practice. PMID- 29261237 TI - ETHICS, EVIDENCE AND THE ANTI-VACCINATION DEBATE. AB - On 11 October 2016 the Nursing and Midwifery Board of Australia (NMBA) released a position statement on 'Nurses, midwives and vaccination' (www.nursingmidwiferyboard. gov.au/News/2016-10-11-position-statement vaccination.aspx). PMID- 29261238 TI - Expanding the "safe harbor" in high-deductible health plans: better coverage and lower healthcare costs. AB - Amending regulations to expand the "safe harbor" by allowing predeductible coverage of high-value services and medications for chronic diseases would provide Americans a plan option that better meets their clinical and financial needs. PMID- 29261239 TI - Chronic disease outcomes from primary care population health program implementation. AB - OBJECTIVES: We implemented a health information technology-enabled population health management program for chronic disease management in academic hospital affiliated primary care practices, then compared quality-of-care outcome measures among practices assigned a central population health coordinator (PHC) and those not assigned a PHC. STUDY DESIGN: Quasi-experimental. METHODS: Central PHCs were nonrandomly assigned to 8 of 18 practices. They met with physicians, managed lists of patients not at goal in chronic disease registries, and performed administrative tasks. In non-PHC practices, existing staff remained responsible for these tasks. The primary outcome was difference-in-differences over the 6 month follow-up period between PHC and non-PHC practices for outcome measures for diabetes (low-density lipoprotein cholesterol [LDL-C], glycated hemoglobin [A1C], and blood pressure [BP] goal attainment), cardiovascular disease (LDL-C goal attainment), and hypertension (BP goal attainment). Secondary outcomes included process measures only (obtaining LDL-C, A1C, and BP readings) and cancer screening test completion. RESULTS: The difference in the percentage point (PP) increase in outcome measures over follow-up was greater in PHC practices than non PHC practices for all measures among patients with diabetes (LDL-C, 4.6 PP; A1C, 4.8 PP; BP, 4.7 PP), cardiovascular disease (LDL-C, 3.3 PP), and hypertension (BP, 2.3 PP) (adjusted P all <.001). Changes in cancer screening outcomes, which were not a focus of PHC efforts, were similar between PHC and non-PHC practices. CONCLUSIONS: Use of central PHCs led to greater improvement in short-term chronic disease outcome measures compared with patients in practices not assigned a central PHC. PMID- 29261241 TI - Insurance switching and mismatch between the costs and benefits of new technologies. AB - OBJECTIVES: Many therapies have immediate costs but delayed benefits. Recent and anticipated transformative therapies may exacerbate these challenges. This study explored whether disconnects between short-term budget impacts and long-term costs and benefits, and among impacts on initial payers, downstream payers, and society, are expected for a range of such therapies and whether they are likely consistent or variable, with implications for potential policy responses. STUDY DESIGN: Modeling. METHODS: We modeled the impacts of 5 hypothetical therapies affecting different patient types: curative gene therapy for a childhood disorder, highly effective hepatitis C virus therapy, disease-modifying Alzheimer disease therapy, and cardiovascular disease therapy for both rare genetic and higher-risk prior cardiovascular event populations. We constructed disease specific models, modifying best-available Markov analysis estimates for standard of-care state transition rates, utilities, and costs. We disaggregated total healthcare impacts into impacts on initial versus downstream payers, dividing payers into 3 types: commercial insurers, Medicaid, and Medicare. RESULTS: Although we found gaps between the impacts on initial and downstream payers in all examples, some substantial, the magnitude and reasons vary. CONCLUSIONS: As scientific advances generate transformative therapies with substantial structural disconnects between "who pays" and "who benefits," creative approaches may be needed by manufacturers, payers, and others to ensure appropriate access to cost effective therapies, adequate economic incentives for future development, and sustainable payer economics. Mechanisms may amortize high up-front costs over time, provide for transfers among payers, or a combination. Our research suggests that approaches should be tailored to specific disease and therapy characteristics to be effective. PMID- 29261240 TI - Impact of consumer-directed health plans on low-value healthcare. AB - OBJECTIVES: To assess the impact of consumer-directed health plan (CDHP) enrollment on low-value healthcare spending. STUDY DESIGN: We performed a quasi experimental analysis using insurance claims data from 376,091 patients aged 18 to 63 years continuously enrolled in a plan from a large national commercial insurer from 2011 to 2013. We measured spending on 26 low-value healthcare services that offer unclear or no clinical benefit. METHODS: Employing a difference-in-differences approach, we compared the change in spending on low value services for patients switching from a traditional health plan to a CDHP with the change in spending on low-value services for matched patients remaining in a traditional plan. RESULTS: Switching to a CDHP was associated with a $231.60 reduction in annual outpatient spending (95% CI, -$341.65 to -$121.53); however, no significant reductions were observed in annual spending on the 26 low-value services (--$3.64; 95% CI, -$9.60 to $2.31) or on these low-value services relative to overall outpatient spending (-$7.86 per $10,000 in outpatient spending; 95% CI, -$18.43 to $2.72). Similarly, a small reduction was noted for low-value spending on imaging (-$1.76; 95% CI, -$3.39 to -$0.14), but not relative to overall imaging spending, and no significant reductions were noted in low-value laboratory spending. CONCLUSIONS: CDHPs in their current form may represent too blunt an instrument to specifically curtail low-value healthcare spending. PMID- 29261242 TI - ED-based care coordination reduces costs for frequent ED users. AB - OBJECTIVES: We evaluated a pilot quality improvement intervention implemented in an urban academic medical center emergency department (ED) to improve care coordination and reduce ED visits and hospitalizations among frequent ED users. STUDY DESIGN: Randomized controlled trial. METHODS: We identified the most frequent ED users in both the 30 days prior to the intervention and the 12 months prior to the intervention. We randomized the top 72 patients to receive either our pilot intervention or usual care. The intervention consisted of a community health worker who assisted patients with navigating care and identifying unmet social needs and an ED-based clinical team that developed interdisciplinary acute care plans for eligible patients. After 7 months, we analyzed ED visits, hospitalizations, and costs for the intervention and control groups. RESULTS: We randomized 72 patients to the intervention (n = 36) and control (n = 36) groups. Patients randomized to the intervention group had 35% fewer ED visits (P = .10) and 31% fewer admissions from the ED (P = .20) compared with the control group. Average ED direct costs per patient were 15% lower and average inpatient direct costs per patient were 8% lower for intervention patients compared with control patients. CONCLUSIONS: ED-based care coordination is a promising approach to reduce ED use and hospitalizations among frequent ED users. Our program also demonstrated a decrease in costs per patient. Future efforts to promote population health and control costs may benefit from incorporating similar programs into acute care delivery systems. PMID- 29261243 TI - DO AGED CARE NURSES PERCEIVE MORE PROFIT EQUALS LESS AUTONOMY? AB - The number of Australians aged 85 years and over is projected to double by 2032 with an additional 82,000 residential care places required by 2025 (Sudholz 2016). PMID- 29261244 TI - WOUND INFECTION IN CLINICAL PRACTICE UPDATE. PMID- 29261245 TI - Evaluation of the Quality Blue Primary Care program on health outcomes. AB - OBJECTIVES: This study aimed to investigate the role of the Quality Blue Primary Care (QBPC) program on healthcare utilization and overall cost among the beneficiaries of Blue Cross and Blue Shield of Louisiana (BCBSLA). STUDY DESIGN: Retrospective observational cohort study using claims data from adults residing in QBPC-implemented regions continuously enrolled through BCBSLA from June 2012 to December 2014 (N = 89,034). METHODS: Controlling for age, gender, and risk score by propensity score weighting, inpatient, outpatient, and corresponding medical expenditures were each compared between the QBPC group and the control group using a difference-in-differences regression model. RESULTS: Average total cost increased in both the QBPC and control groups in 2014, but the increase was significantly less in the intervention group-a difference of $27.09 per member per month (PMPM) (P <=.001). Savings in total cost were derived largely from a decrease in hospitalizations-a difference of $18.85 PMPM (P = .0023). Furthermore, savings were associated with shifts in healthcare utilization by the intervention group toward proactive management, including increased primary care physician visits (P = .0106) and higher screening rates for diabetes (P = .0019). Inpatient admissions also decreased in the QBPC group, most significantly among those with chronic conditions (P <.05). Conversely, an unexpected increase was observed in emergency department visits. CONCLUSIONS: The QBPC program was associated with a shift in primary care delivery and reductions in overall cost. Savings were achieved largely through reductions in hospitalization costs. PMID- 29261246 TI - Impact of statin guidelines on statin utilization and costs in an employer-based primary care clinic. AB - OBJECTIVES: The purpose of this study was to describe statin utilization and costs in an employer-based patient cohort by comparing actual practice and assumed adoption of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) or 2016 US Preventive Services Task Force (USPSTF) statin recommendations versus the guidelines described in 2001 (and supplemented in 2004) in the Third Report of the National Cholesterol Education Program's Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII). STUDY DESIGN: Descriptive cohort analysis included patients treated in an employer-based primary care clinic between January 2012 and April 2014. METHODS: ATPIII, ACC/AHA, and USPSTF recommendations were retrospectively applied at the patient level based on lipid levels and statin prescribing data collected from a health risk assessment and electronic health record. Actual statin prescribing was compared with prescribing predicted by guideline recommendations. Costs for each strategy were estimated using employer pharmacy claims data. RESULTS: The study included 555 patients, of whom 112 (20.2%) were treated with a statin at baseline. ATPIII and ACC/AHA recommended statin use in 284 (51.2%) and 279 (50.3%) patients, respectively. Within the subgroup of 479 primary prevention patients, ACC/AHA recommended statin use in 203 (42.4%) versus USPSTF, which recommended statin use in 91 (19.0%). The 90-day cost per patient was similar to baseline with implementation of ATPIII or ACC/AHA recommendations, excluding use of brand name-only high-intensity statins, and costs could be reduced slightly with implementation of USPSTF guidelines. CONCLUSIONS: Despite differences in ATPIII, ACC/AHA, and USPSTF guidelines, application of any of these statin recommendations would result in optimized statin utilization and fairly neutral effects on cost in this real-world employer-based population. PMID- 29261247 TI - Reduction of emergency department use in people with disabilities. AB - OBJECTIVES: To examine emergency department (ED) use by individuals with disabilities in safety-net clinics that have adopted the patient-centered medical home (PCMH) model. STUDY DESIGN: This is a retrospective matched cohort study. Prior to matching, we identified 2269 nonelderly Medicaid beneficiaries with disabilities from a Los Angeles Medicaid managed care plan in PCMH clinics and 21,897 in non-PCMH clinics. METHODS: To minimize self-selection bias from clinics and individuals, we created 3 comparison groups through a series of propensity score matching schemes that included matching clinics with similar health service utilization per patient and matching individuals with similar demographic characteristics and underlying health conditions. Rates of having at least 1 ED visit per year and excess ED use (defined as >=2 ED visits per year) were compared across beneficiaries who received care from PCMH clinics and matched comparisons using logistic regression analyses. RESULTS: After matching on clinic and individual-level characteristics, the adjusted odds ratio (OR) of excess ED use was 25% to 33% lower (P <.05) in the PCMH group compared with the non-PCMH group. When limiting the study population to patients with at least 1 office visit, the OR of having at least 1 ED visit decreased by 21% (P <.05) for the PCMH group. Similarly, the OR of having excess ED use decreased by 38% (P <.05) for the PCMH group. CONCLUSIONS: Our study highlights that the adoption of the PCMH model in safety-net clinics was associated with reduced ED use in Medicaid beneficiaries with disabilities. PMID- 29261248 TI - Investigating the impact of intervention refusal on hospital readmission. AB - OBJECTIVES: To identify characteristics and readmission risks associated with opting out of a social work-driven transition intervention. STUDY DESIGN: Secondary data analysis of a randomized controlled pilot study at a large nonprofit urban community hospital. METHODS: Hospitalized English-speaking, cognitively intact adults 65 years or older with expected discharge back to the community were eligible for enrollment. Additionally, patients met at least 1 of the 3 criteria: 1) 75 years or older, 2) taking 5 or more medications, or 3) had 1 or more prior inpatient stays or emergency department visits in the previous 6 months. The transition intervention consisted of up to 2 in-home visits (the first occurring within 48 hours after discharge) and up to 4 telephone follow-up calls (for a maximum of 6 total contacts) by a transition social worker. This study analyzed participants randomized to the intervention arm on measures including demographics, medical diagnoses, presence of advance directive, and all cause 30-day hospital readmissions. RESULTS: Of the 90 patients randomized to the Social Work Intervention Focused on Transitions intervention group, 10% were readmitted within 30 days and nearly one-third refused (ie, opted out of) the home visit component of the intervention. Multivariate analyses revealed that those opting out of the intervention had 3 times greater odds of having a respiratory condition compared with intervention recipients (odds ratio [OR], 3.10; 95% CI, 1.09-8.80; P = .034). Additionally, opting out of the intervention (OR, 6.75; 95% CI, 1.05-43.52; P = .045) and having a diagnosis of cancer (OR, 29.59; 95% CI, 2.01-435.45; P = .014) significantly predicted readmission. CONCLUSIONS: Findings suggest that some at-risk patients may not be receptive to services and programs aimed at improving care transitions, resulting in a higher risk for readmission. PMID- 29261249 TI - Real-world economic value of a 21-gene assay in early-stage breast cancer. AB - OBJECTIVES: Value-based payment reforms shift cost-containment responsibilities to the physician. Although gene expression profiling (GEP) utilizing a 21-gene panel among patients with early-stage, axillary lymph node-negative, hormone receptor-positive, HER2/neu oncogene-negative breast cancer is able to identify a cohort that may achieve excellent outcomes without adjuvant chemotherapy, high up front costs (list price, $4175) could dissuade usage. STUDY DESIGN: Retrospective review of consecutive patients with breast cancer treated at a single cancer center. METHODS: Chart review of 227 patients 70 years or younger with outpatient costs (ie, drug average sales price, reagent costs, physician charges) during first 6 months of treatment. RESULTS: Of these patients, 68% underwent GEP, with 52%, 43%, and 5% having low, intermediate, and high recurrence risk scores, respectively. Adjuvant chemotherapy was utilized less in genomically profiled cohorts (19% vs 29%; P = .08) and was consistent with recommendations of the recurrence scores. The mean 6-month outpatient costs were $24,955 with adjuvant chemotherapy and $2654 with hormonal therapy. Patients with stage II cancer undergoing GEP received adjuvant chemotherapy at a lower frequency (28.6% vs 86.7%), but patients with stage I cancer who underwent testing were slightly more likely to receive chemotherapy (15.8% vs 14%) because the test identified patients with higher-risk tumors. Universal GEP testing of patients with stage II cancer would have resulted in net savings of $11,494 per patient inclusive of test cost; stage I testing would have increased costs by $4505. Similar trends for grade 2/3 tumors (-$2394) and grade 1 tumors (+$6047) were noted. CONCLUSIONS: Universal GEP testing of women 70 years or younger with stage II or grade 2/3 lymph node-negative breast cancers would result in lower outpatient costs, inclusive of the diagnostic test, within the first 6-month episode of care. PMID- 29261250 TI - Trends in bisphosphonate initiation within an integrated healthcare delivery system. AB - In the setting of changing temporal trends in the management of osteoporosis, we examined how select characteristics of new oral bisphosphonate (BP) initiators changed over time among 94,073 women within a large, integrated healthcare organization during the period 2004 to 2012. In the earlier era (2004-2007), approximately half of women younger than 65 years initiating BP therapy (47%-54%) had osteoporosis by bone mineral density (BMD) criteria, but this proportion increased sharply in the later era (2008-2012), with 55% to 81% having osteoporosis. This trend was not evident in older women (>=65 years). The proportion of younger women with prior fracture increased from 15% in 2008 to 32% in 2012, after remaining relatively stable (10%-15%) during the earlier era. Again, this trend was not observed among older women. Thus, among women younger than 65 years, we observed a marked temporal shift in initiation of BP treatment toward women at high risk (including those with prior fracture and those with osteoporosis by BMD testing) and away from those at lower risk (such as those with osteopenia and/or no prior fracture). PMID- 29261251 TI - INFECTION PREVENTION: PERIPHERAL INTRAVENOUS CATHETER ASSESSMENT AND CARE. AB - Peripheral intravenous catheters are the most common device in hospital patients, but they do come with infection risks. Awareness of the complications and regular assessment can reduce risks and improve patient outcomes. PMID- 29261252 TI - Production of biodiesel from soybean oil biomass as renewable energy source. AB - Transesterification of vegetable oils with short-chain alcohols is used to produce biodiesel. In the present study, crude soybean oil was investigated on the basis of three principal variables, such as optimum reaction temperature (60?C), the amount of catalyst concentration from 0.5, 1.0, 1.5, 2.0 and 2.5%? and molar ratio of methanol 1:1, 1:2, 1:3, 1:4, 1:5 and 1:6, respectively affecting yield of biodiesel. Under optimum condition, at molar ratio 1:6 in the presence of 0.5% NaOH and 60 degrees C reaction temperature and 350 rpm approximately 99.1% biodiesel yield was obtained. PMID- 29261253 TI - Bee diversity assemblage on pigeon pea, Cajanus cajan along habitat gradient. AB - The regional bee diversity was investigated on pigeon pea in three agroclimatic zones of Punjab state in northern India. Of the total nine species recorded, population of Megachilids, in particular, was significantly higher in all the three zones. Appraisal of diversity metrics revealed highest bee community diversity in Sub-mountain Undulating zone, followed by Central Plain zone, while least diversity was noted in Western zone, which highlighted the effect of habitat on species richness and abundance. Diurnal variations were evident with the most diverse bee communities recorded at 11:00 hr, followed by at 14:00 and 08:00 hr, with the lowest community diversity at 17:00 hr. The relative abundance of bee species was highly in favour of non-Apis species than Apis species. The results obtained can be used in the application of risk management through planned plant protection measures, study of plant-pollinator interactions along with conservation and augmentation of bee species. PMID- 29261254 TI - A comparison of mango seed kernel powder, mango leaf powder and Manilkara zapota seed powder for decolorization of methylene blue dye and antimicrobial activity. AB - The waste mango seed generated from mango pulp industry in India is a major problem in handling the waste and hence, conversion of mango seed kernel. Mango seeds were collected and processed for oil extraction. Decolorization of methylene blue was achieved by mango seed kernel powder, mango leaf powder and Manilkara zapota seed powder. Higher efficiency was attained in mango seed kernel powder when compared to mango leaf powder and Manilkara zapota seed powder. A 60 to 95 % of removal efficiency was achieved by varying concentration. Effect of pH, dye concentration, adsorbent dosage and temperature were studied. Mango seed kernel powder is a better option that can be used as an adsorbent for the removal of methylene blue and basic red dye from its aqueous solutions. PMID- 29261255 TI - Genetic diversity analysis of fungal pathogen Bipolaris sorghicola infecting Sorghum bicolor in India. AB - Bipolaris sorghicola (Lefebvre and Sherwin) is a well known and economically important seed-borne pathogen with the specific species of sorghum (Sorghum bicolor [L] Moench) as host. Thirty-two strains were obtained from different geographical area of sorghum growing places in India. Molecular characterization using three marker systems i.e., universal rice primers (URP), inter simple sequence repeat (ISSR) and random amplified polymorphic DNA (RAPD) was carried out. Molecular marker work revealed differences along with geographical origin clustering of various B. sorghicola strains which could not be revealed through conventional method of characterization. Out of 13 URPs, 20 ISSR and 50 RAPD primers screened, 8 primers each from URP and ISSR, and 10 primers from RAPD marker were found to result in reproducible banding pattern. One hundred per cent of polymorphic bands was recorded in all three molecular markers. Total number of bands was recorded 1986 with average of 248.25 in URP marker, and 2026 bands with average of 253.25 in ISSR marker and 2158 bands with average of 215.80 in RAPD markers. Maximum heterozygosity (Hn) was revealed by URP 17R (0.40), ISSR 10 (0.41) and RAPD marker OPC-5 (0.34). The polymorphism information content (PIC) values ranged between 5.89 to 8.28 in URP, 4.57 to 8.79 in ISSR and 4.44 to 9.64 in RAPD marker profiles. Maximum cophenetic correlation was found in URP (r = 0.910) followed by ISSR (r = 0.904) and RAPD (r = 0.870). The combined analysis of all three marker systems showed high cophenetic correlation (r = 0.911), which indicated a very good fit of the data for genetic diversity analysis. To best of our knowledge, this is a first report of genetic characterization of B. sorghicola. Hence, combined use of three marker systems would be more sensitive and reliable in characterizing genetic variability in B. sorghicola strains. PMID- 29261256 TI - The effects of dusts of bartin cement factory on Taurus Cedar (Cedru libani A Rich.) seeds' germination. AB - The present study effects of pollutant particles from Bartin Cement Factory on development of seeds and leaves of Taurus Cedar (Cedrus libani Rich.) which in plantation area around the factory were examined. For this purpose, seeds were collected from sampling trees located 200m, 400m, 600m, 800m and 1000m (control) and germination percentage of seeds, and total chlorophyll content of seedlings were determined. Moreover, in the present study, the air movement around Bartin Cement Factory and level of pollutants in sampling areas were also determined. The directions of the prevailing winds around the cement factory were North, and Northwest. From the aspect of pollutant material level, the array of sampling areas was SP1>SP2>SP3>SP4>C. On the other hand, evaluating the results of mean seed germination percentages, a significant difference (P<0.01) was noted between control and seeds of Taurus Cedar at various distances from are pollutant source. From the aspect of the power of seeds collected with 3 repetitions from Taurus Cedars located at various distances, it a significant difference (P<0.01) was found between the control and experimental groups. Accordingly, from both the aspects of mean germination percentage and seed power, an apparent increase was observed from 400 m distance. On the other hand, as the distance from cement factory increased, total chlorophyll content in Taurus Cedar seedlings increases significantly. Results of bilateral regression analysis evaluated exponential relationship at level 97% between these 2 variables. PMID- 29261257 TI - Contamination of vegetation growing on soils and substrates in the unhygienic region of Central Spis (Slovakia) polluted by heavy metals. AB - The present paper aims at clarifying the long-term impact of mining activities on the contamination of biotic components of the environment. The research was conducted in during 2011-2014 at selected locations of the cadastral territory of former mining towns of Central Spis (Slovakia) with different ecosystems of permanent grassland, mine waste sites and bankside vegetation. The results of the analysis showed that considerably dominant species at contaminated locations such as Betula pendula, Silene vulgaris, Geranium sylvaticum, Petasites hybridus, Mentha longifolia could absorb high quantities of heavy metals. The observed contents of heavy metals, especially zinc, copper and mercury in plants significantly exceeded the threshold values determined by law. The highest contamination as compared to the threshold values was found in young plants of Betula pendula in the Slovinky tailing pond site, in which zinc content exceeded the threshold value 852 times. Excess of copper content also exceeded the threshold value 271 times. The highest concentration of mercury in all of the surveyed sites was observed in dry matter of Betula pendula in the area of heap in the Por?c Valley, where threshold value was 184 times higher. Statistically significant locations similar in relation to the characteristic species and monitored heavy metals was recorded on the locations of tailing pond and heap as the most important centres of contamination with the following dominant species Betula pendula, Pinus silvestris and Agrostis capilaris. PMID- 29261270 TI - Chemical content and antimicrobial properties of three different extracts of Mentha pulegium leaves from Mugla Region, Turkey. AB - The extract of ethanol, methanol and DMSO of pennyroyal leaves from Mugla Region (Turkey) were tested for antimicrobial activity against eleven bacterial and one yeast strain by disc diffusion method. Among the extracts assayed, the methanol extract of pennyroyal leaves exhibited significant antimicrobial activity against Salmonella typhimurium and Staphylococcus aureus with 20 mm diameter inhibition zone. The DMSO extract of pennyroyal leaves displayed significant activity against S.aureus (19 mm) and Bacillus subtilis (21mm) showing inhibition zone of 19 mm and 21 mm diameter, while the ethanolic extract showed significant antimicrobial activity against S.aureus (17mm) and Klebsiella pneumoniae (20mm) inhibition zones.? On comparint the MIC value of ethanol, methanol and DMSO leaf extract, methanolic extract of pennyroyal presented best activity (MIC 8 mg ml-1) against S. typhimurium CCM 583 and S.aureus ATCC 6538/P. Analyses of GC/MS determined eleven compounds viz., neophytadiene (69.95%), Pulejon 7.85%, Pinane 4.81%, Bicyclo (3.1.1 Heptane 2.6.6.6 trimethyl) 4.68%. In conclusion, methanolic extracts of M. pulegium showed antimicrobial activity because of high neophytadiene content. PMID- 29261272 TI - MACRA +Mips = SGR PMID- 29261271 TI - Managing dislocations of the hip, knee, and ankle in the emergency department [digest]. AB - Dislocation of the major joints of the lower extremities--hip, knee, and ankle- can occur due to motor-vehicle crashes, falls, and sports injuries. Hip dislocations are the most common, and they require emergent management to prevent avascular necrosis of the femoral head. Knee dislocations are uncommon but potentially dangerous injuries that can result in amputation due to the potential for missed secondary injury, especially if they are reduced spontaneously. Isolated ankle dislocations are relatively rare, as most ankle dislocations involve an associated fracture. This review presents an algorithmic approach to management that ensures that pain relief, imaging, reduction, vascular monitoring, and emergent orthopedic consultation are carried out in a timely fashion. [Points & Pearls is a digest of Emergency Medicine Practice.]. PMID- 29261273 TI - President's Page. PMID- 29261274 TI - Microwave-Irradiation-Assisted Combustion toward Modified Graphite as Lithium Ion Battery Anode. AB - A rapid method to high-yield synthesis of modified graphite by microwave irradiation of partially oxidized graphite (oxidized by H2SO4 and KMnO4) is reported. During the microwave irradiation, electrical arc induced flame combustion of Mn2O7 and vaporization and decomposition of H2SO4 to form O2 and SO2, which helped to decompose graphite within 30 s. The modified graphite boosts its ability to support the intercalation and diffusion of Li+ ions. As an anode material for lithium ion batteries, the modified graphite displays high reversible capacity of 373 mA.h/g, approaching the theoretical value of 372 mA.h/g. Long cycling performance of 410 charge-discharge cycles shows the capacity is retained at 370 mA.h/g, demonstrating superior stability. The improved cycling stability is attributed to the formation of a stable solid electrolyte interface film with the help of in situ formed S-based compounds on a graphite sheet. This work demonstrated a simple and effective method to alter carbon structures for improving energy storage ability. PMID- 29261275 TI - Enhancing the Output Charge Density of TENG via Building Longitudinal Paths of Electrostatic Charges in the Contacting Layers. AB - The surface charge density of the tribolayer is the most parameter for developing a high performance triboelectric nanogenerator (TENG). Most previous works focused on the surface structural/chemical modification. Nevertheless, the internal space of the tribolayer and its mechanism exploration were less investigated. Herein, in this work, internal-space-charge zones are built through imbedding ravines and gullies in criss-crossed gold layers in the near-surface of the tribolayer, which leads to the high output performance of TENG. As experimental results manifest, the transfer charge density of gold-PDMS TENG (G TENG) reaches 168 MUC m-2. Through theoretical analyses, it is determined that gold layers act as the passageways and traps of the triboelectric charges when the charges drift to the internal space of the tribomaterial. Moreover, the transport and storage process of triboelectric charges in the frictional layer are investigated comprehensively by quantum mechanics for the first time. The calculation method of the output current of TENG is proposed, and the theoretical calculation results coincide with the test results well. The results verify the application of the theoretical model and help with the construction and development of the theoretical system of TENG. Meanwhile, the relative results can be directly attained by this new theoretical model, and it is possible to make full use of the theoretical analysis to achieve a better performance for TENG. This study paves an easy and novel way for enhancing the charge density of the tribolayer by internal space construction and a new underlying theoretical model. PMID- 29261276 TI - MoS2 Quantum Dot Growth Induced by S Vacancies in a ZnIn2S4 Monolayer: Atomic Level Heterostructure for Photocatalytic Hydrogen Production. AB - It is highly demanded to steer the charge flow in photocatalysts for efficient photocatalytic hydrogen reactions (PHRs). In this study, we developed a smart strategy to position MoS2 quantum dots (QDs) at the S vacancies on a Zn facet in monolayered ZnIn2S4 (Vs-M-ZnIn2S4) to craft a two-dimensional (2D) atomic-level heterostructure (MoS2QDs@Vs-M-ZnIn2S4). The electronic structure calculations indicated that the positive charge density of the Zn atom around the sulfur vacancy (Vs) was more intensive than other Zn atoms. The Vs confined in monolayered ZnIn2S4 established an important link between the electronic manipulation and activities of ZnIn2S4. The Vs acted as electron traps, prevented vertical transmission of electrons, and enriched electrons onto the Zn facet. The Vs-induced atomic-level heterostructure sewed up vacancy structures of Vs-M ZnIn2S4, resulting in a highly efficient interface with low edge contact resistance. Photogenerated electrons could quickly migrate to MoS2QDs through the intimate Zn-S bond interfaces. As a result, MoS2QDs@Vs-M-ZnIn2S4 showed a high PHR activity of 6.884 mmol g-1 h-1, which was 11 times higher than 0.623 mmol g-1 h-1 for bulk ZnIn2S4, and the apparent quantum efficiency reached as high as 63.87% (420 nm). This work provides a prototype material for looking into the role of vacancies between electronic structures and activities in 2D photocatalytic materials and gives insights into PHR systems at the atomic level. PMID- 29261277 TI - AIEgen-Functionalized Mesoporous Silica Gated by Cyclodextrin-Modified CuS for Cell Imaging and Chemo-Photothermal Cancer Therapy. AB - A novel multifunctional drug delivery system has been constructed by assembling per-6-thio-beta-cyclodextrin-modified ultrasmall CuS nanoparticles (CD-CuS) onto fluorescent AIEgen-containing mesoporous silica nanoparticles (FMSN). The CD-CuS nanoparticles are anchored on the surface of benzimidazole-grafted FMSN, acting as a gatekeeper and photothermal agent. The prepared blue-emitting nanocomposite (FMSN@CuS) exhibits good biocompatibility and cell imaging capability. Anticancer drug doxorubicin hydrochloride (DOX) molecules are loaded into FMSN@CuS, and zero prerelease at physiological pH (7.4) and on-demand drug release at an acidic environment can be achieved due to the pH-responsive gate-opening of CD-CuS only at an acidic condition. The FMSN@CuS nanocomposite can generate obvious thermal effect after the exposure of 808 nm laser, which can also accelerate the DOX release. Meanwhile, the fluorescence intensity of DOX-loaded FMSN@CuS increases with the release of DOX, and the intracellular drug release process can be tracked according to the change of luminescence intensity. More importantly, DOX loaded FMSN@CuS displays efficient anticancer effects in vitro upon 808 nm laser irradiation, demonstrating a good synergistic therapeutic effect via combining enhanced chemotherapy and photothermal therapy. PMID- 29261278 TI - Highly Enhanced Third-Harmonic Generation in 2D Perovskites at Excitonic Resonances. AB - Two-dimensional hybrid organic-inorganic Ruddlesden-Popper perovskites (RPPs) have attracted considerable attention due to their rich photonic and optoelectronic properties. The natural multi-quantum-well structure of 2D RPPs has been predicted to exhibit a large third-order nonlinearity. However, nonlinear optical studies on 2D RPPs have previously been conducted only on bulk polycrystalline samples, in which only weak third-harmonic generation (THG) has been observed. Here, we perform parametric nonlinear optical characterization of 2D perovskite nanosheets mechanically exfoliated from four different lead halide RPP single crystals, from which we observe ultrastrong THG with a maximum effective third-order susceptibility (chi(3)) of 1.12 * 10-17 m2 V-2. A maximum conversion efficiency of 0.006% is attained, which is more than 5 orders of magnitude higher than previously reported values for 2D materials. The THG emission is resonantly enhanced at the excitonic band gap energy of the 2D RPP crystals and can be tuned from violet to red by selecting the RPP homologue with the requisite resonance. Due to signal depletion effects and phase-matching conditions, the strongest nonlinear response is achieved for thicknesses less than 100 nm. PMID- 29261279 TI - Local Electronic Structure of a Single-Layer Porphyrin-Containing Covalent Organic Framework. AB - We have characterized the local electronic structure of a porphyrin-containing single-layer covalent organic framework (COF) exhibiting a square lattice. The COF monolayer was obtained by the deposition of 2,5-dimethoxybenzene-1,4 dicarboxaldehyde (DMA) and 5,10,15,20-tetrakis(4-aminophenyl) porphyrin (TAPP) onto a Au(111) surface in ultrahigh vacuum followed by annealing to facilitate Schiff-base condensations between monomers. Scanning tunneling spectroscopy (STS) experiments conducted on isolated TAPP precursor molecules and the covalently linked COF networks yield similar transport (HOMO-LUMO) gaps of 1.85 +/- 0.05 eV and 1.98 +/- 0.04 eV, respectively. The COF orbital energy alignment, however, undergoes a significant downward shift compared to isolated TAPP molecules due to the electron-withdrawing nature of the imine bond formed during COF synthesis. Direct imaging of the COF local density of states (LDOS) via dI/dV mapping reveals that the COF HOMO and LUMO states are localized mainly on the porphyrin cores and that the HOMO displays reduced symmetry. DFT calculations reproduce the imine-induced negative shift in orbital energies and reveal that the origin of the reduced COF wave function symmetry is a saddle-like structure adopted by the porphyrin macrocycle due to its interactions with the Au(111) substrate. PMID- 29261280 TI - Mesoporous Silica-Supported Nanostructured PdO/CeO2 Catalysts for Low-Temperature Methane Oxidation. AB - Nanostructured PdO/CeO2 supported on mesoporous SBA-15 silica was synthesized using a combination of incipient wetness impregnation and surface-assisted reduction. After calcination, the materials showed good activity as catalysts for the low-temperature oxidation of methane, with a sample having 5 wt % Pd loading showing 50% conversion to CO2 at ~290 degrees C and complete conversion below 360 degrees C. The stability of catalysts in the presence of water was studied. The formation of Pd(0) during the methane oxidation reaction increases the oxygen vacancies on the surface of catalysts, improving the catalytic activity. PMID- 29261281 TI - Coating Metal Nanoparticle Surfaces with Small Organic Molecules Can Reduce Nonspecific Cell Uptake. AB - Elucidation of mechanisms of uptake of nanoparticles by cells and methods to prevent this uptake is essential for many applications of nanoparticles. Most recent studies have focused on the role of proteins that coat nanoparticles and have employed PEGylation, particularly dense coatings of PEG, to reduce protein opsonization and cell uptake. Here we show that small molecule coatings on metallic nanoparticles can markedly reduce cell uptake for very sparsely PEGylated nanoparticles. Similar results were obtained in media with and without proteins, suggesting that protein opsonization is not the primary driver of this phenomenon. The reduction in cell uptake is proportional to the degree of surface coverage by the small molecules. Probing cell uptake pathways using inhibitors suggested that the primary role of increased surface coverage is to reduce nanoparticles' interactions with the scavenger receptors. This work highlights an under-investigated mechanism of cell uptake that may have played a role in many other studies and also suggests that a wide variety of molecules can be used alongside PEGylation to stably passivate nanoparticle surfaces for low cell uptake. PMID- 29261282 TI - Achieving Multicolor Long-Lived Luminescence in Dye-Encapsulated Metal-Organic Frameworks and Its Application to Anticounterfeiting Stamps. AB - Long-lived luminescent metal-organic frameworks (MOFs) have attracted much attention due to their structural tunability and potential applications in sensing, biological imaging, security systems, and logical gates. Currently, the long-lived luminescence emission of such inorganic-organic hybrids is dominantly confined to short-wavelength regions. The long-wavelength long-lived luminescence emission, however, has been rarely reported for MOFs. In this work, a series of structurally stable long-wavelength long-lived luminescent MOFs have been successfully synthesized by encapsulating different dyes into the green phosphorescent MOFs Cd(m-BDC)(BIM). The multicolor long-wavelength long-lived luminescence emissions (ranging from green to red) in dye-encapsulated MOFs are achieved by the MOF-to-dye phosphorescence energy transfer. Furthermore, the promising optical properties of these novel long-lived luminescent MOFs allow them to be used as ink pads for advanced anticounterfeiting stamps. Therefore, this work not only offers a facile way to develop new types of multicolor long lived luminescent materials but also provides a reference for the development of advanced long-lived luminescent anticounterfeiting materials. PMID- 29261283 TI - Transparent and Self-Powered Multistage Sensation Matrix for Mechanosensation Application. AB - Electronic skin based on a multimodal sensing array is ready to detect various stimuli in different categories by utilizing highly sensitive materials, sophisticated geometry designs, and integration of multifunctional sensors. However, it is still difficult to distinguish multiple and complex mechanical stimuli in a local position by conventional multimodal E-skin, which is significantly important in the signals' feedback of robotic fine motions and human-machine interactions. Here, we present a transparent, flexible, and self powered multistage sensation matrix based on piezoelectric nanogenerators constructed in a crossbar design. Each sensor cell in the matrix comprises a layer of piezoelectric polymer sandwiched between two graphene electrodes. The simple lamination design allows sequential multistage sensation in one sensing cell, including compressive/tensile strain and detaching/releasing area. Further structure engineering on PDMS substrate allows the sensor cell to be highly sensitive to the applied pressures, representing the minimum sensing pressure below 800 Pa. As the basic combinations of compressive/tensile strains or detaching/releasing represent individual output signals, the proposed multistage sensors are capable of decoding to distinguish external complex motions. The proposed self-powering multistage sensation matrix can be used universally as an autonomous invisible sensory system to detect complex motions of the human body in local position, which has promising potential in movement monitoring, human computer interaction, humanoid robots, and E-skins. PMID- 29261284 TI - A Novel Electron Microscopic Characterization of Core/Shell Nanobiostimulator Against Parasitic Plants. AB - Nanoencapsulation has proven to be an efficient route to increase significantly the solubility and bioavailability of organic compounds. This aspect of nanotechnology is illustrated for the case of phthalimide-lactone (PL), a recently synthesized strigolactone mimic whose very limited solubility in water, as a free chemical, precludes its practical use as an agrochemical in the fight against parasitic plants. Pluronic F-127 (P127) nanoparticles functionalized with PL have been synthesized and embedded in a polymeric matrix of poly(vinyl alcohol) (PVA). Low-voltage and medium voltage imaging and spectroscopic scanning electron microscopy (S(T)EM) techniques were combined to confirm the synthesis of multicore nanoparticles that were rich in nitrogen, a finding that is due to the successful encapsulation of PL. This PL@P127/PVA nanobiostimulator formulation has an impressive solubility in water, that is, 27 times higher than that of pure phthalimide-lactone. Also critical from the functional point of view, comparative bioassays clearly showed that the intrinsic stimulatory activity of this agrochemical is fully maintained in the nanoencapsulated formulation. PMID- 29261285 TI - Unusual Performance Increase in Polymer Solar Cells by Cooling a Hot Donor/Acceptor Ink in a Good Solvent. AB - Post processing is widely used to improve the photovoltaic performance of organic solar cells. However, high-temperature and long-time release of halogenated solvents are incompatible with future printing manufacturing. Inspired by the dependence of donor/acceptor optical properties on "ink" temperature, we designed a study to test its effect on photovoltaic performance. We utilize the newly reported nonfullerene ink, poly[(2,6-(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl) benzo[1,2-b:4,5-b']dithiophene))-alt-(5,5-(1',3'-di-2-thienyl-5',7'-bis(2 ethylhexyl)benzo[1',2'-c:4',5'-c']dithiophene-4,8-dione))]/3,9-bis(2-methylene-(3 (1,1-dicyanomethylene)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3 d:2',3'-d']-s-indaceno[1,2-b:5,6-b']dithiophene as a model system, and find that device performance can be improved by heating and then cooling the ink in a specific temperature range. Careful analysis reveals that device improvement comes from the optimized phase miscibility and has a negligible effect on charge transport properties. We further propose that heating and cooling the ink optimizes the phase formation time, phase distribution, and interphase diffusion in the blend films. Finally, the general nature of this process is demonstrated using a more typical polymer/fullerene system. These findings are important because this effect could potentially lead to progress in organic solar cell manufacturing. PMID- 29261287 TI - Plexcitons: The Role of Oscillator Strengths and Spectral Widths in Determining Strong Coupling. AB - Strong coupling interactions between plasmon and exciton-based excitations have been proposed to be useful in the design of optoelectronic systems. However, the role of various optical parameters dictating the plasmon-exciton (plexciton) interactions is less understood. Herein, we propose an inequality for achieving strong coupling between plasmons and excitons through appropriate variation of their oscillator strengths and spectral widths. These aspects are found to be consistent with experiments on two sets of free-standing plexcitonic systems obtained by (i) linking fluorescein isothiocyanate on Ag nanoparticles of varying sizes through silane coupling and (ii) electrostatic binding of cyanine dyes on polystyrenesulfonate-coated Au nanorods of varying aspect ratios. Being covalently linked on Ag nanoparticles, fluorescein isothiocyanate remains in monomeric state, and its high oscillator strength and narrow spectral width enable us to approach the strong coupling limit. In contrast, in the presence of polystyrenesulfonate, monomeric forms of cyanine dyes exist in equilibrium with their aggregates: Coupling is not observed for monomers and H-aggregates whose optical parameters are unfavorable. The large aggregation number, narrow spectral width, and extremely high oscillator strength of J-aggregates of cyanines permit effective delocalization of excitons along the linear assembly of chromophores, which in turn leads to efficient coupling with the plasmons. Further, the results obtained from experiments and theoretical models are jointly employed to describe the plexcitonic states, estimate the coupling strengths, and rationalize the dispersion curves. The experimental results and the theoretical analysis presented here portray a way forward to the rational design of plexcitonic systems attaining the strong coupling limits. PMID- 29261286 TI - CRISPR Approaches to Small Molecule Target Identification. AB - A long-standing challenge in drug development is the identification of the mechanisms of action of small molecules with therapeutic potential. A number of methods have been developed to address this challenge, each with inherent strengths and limitations. We here provide a brief review of these methods with a focus on chemical-genetic methods that are based on systematically profiling the effects of genetic perturbations on drug sensitivity. In particular, application of these methods to mammalian systems has been facilitated by the recent advent of CRISPR-based approaches, which enable one to readily repress, induce, or delete a given gene and determine the resulting effects on drug sensitivity. PMID- 29261288 TI - Optimization of the Pore Structure of Biomass-Based Carbons in Relation to Their Use for CO2 Capture under Low- and High-Pressure Regimes. AB - A versatile chemical activation approach for the fabrication of sustainable porous carbons with a pore network tunable from micro- to hierarchical micro /mesoporous is hereby presented. It is based on the use of a less corrosive and less toxic chemical, i.e., potassium oxalate, rather than the widely used KOH. The fabrication procedure is exemplified for glucose as precursor, although it can be extended to other biomass derivatives (saccharides) with similar results. When potassium oxalate alone is used as activating agent, highly microporous carbons are obtained (SBET ~ 1300-1700 m2 g-1). When a melamine-mediated activation process is used, hierarchical micro-/mesoporous carbons with surface areas as large as 3500 m2 g-1 are obtained. The microporous carbons are excellent adsorbents for CO2 capture at low pressure and room temperature, able to adsorb 4.2-4.5 mmol CO2 g-1 at 1 bar and 1.1-1.4 mmol CO2 g-1 at 0.15 bar. However, the micro-/mesoporous carbons provide record-high room temperature CO2 uptakes at 30 bar of 32-33 mmol g-1 CO2 and 44-49 mmol g-1 CO2 at 50 bar. The findings demonstrate the key relevance of pore size in CO2 capture, with narrow micropores having the leading role at pressures <1 bar and supermicropores/small mesopores at high pressures. In this regard, the fabrication strategy presented here allows fine-tuning of the pore network to maximize both the overall CO2 uptake and the working capacity at any target pressure. PMID- 29261289 TI - Wavelength-Dependent Damage to Adenoviral Proteins Across the Germicidal UV Spectrum. AB - Adenovirus, a waterborne pathogen responsible for causing bronchitis, pneumonia, and gastrointestinal infections, is highly resistant to UV disinfection and therefore drives the virus disinfection regulations set by the U.S. Environmental Protection Agency. Polychromatic UV irradiation has been shown to be more effective at inactivating adenovirus and other viruses than traditional monochromatic irradiation emitted at 254 nm; the enhanced efficacy has been attributed to UV-induced damage to viral proteins. This research shows UV-induced damage to adenoviral proteins across the germicidal UV spectrum at wavelength intervals between 200 and 300 nm. A deuterium lamp with bandpass filters and UV light-emitting diodes (UV LEDs) isolated wavelengths in approximate 10 nm intervals. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and image densitometry were used to detect signatures for the hexon, penton, fiber, minor capsid, and core proteins. The greatest loss of protein signature, indicating damage to viral proteins, occurred below 240 nm. Hexon and penton proteins exposed to a dose of 28 mJ/cm2 emitted at 214 nm were approximately 4 times as sensitive and fiber proteins approximately 3 times as sensitive as those exposed to a dose of 50 mJ/cm2 emitted at 254 nm. At 220 nm, a dose of 38 mJ/cm2 reduced the hexon and penton protein quantities to approximately 33% and 31% of the original amounts, respectively. In contrast, a much higher dose of 400 mJ/cm2 emitted at 261 and 278 nm reduced the original protein quantity to between 66-89% and 80-93%, respectively. No significant damage was seen with a dose of 400 mJ/cm2 at 254 nm. This research directly correlates enhanced inactivation at low wavelengths with adenoviral protein damage at those wavelengths, adding fundamental insight into the mechanisms of inactivation of polychromatic germicidal UV irradiation for improving UV water disinfection. PMID- 29261290 TI - Ratiometric Method for Rapid Monitoring of Biological Processes Using Bioresponsive MRI Contrast Agents. AB - Bioresponsive magnetic resonance imaging (MRI) contrast agents hold great potential for noninvasive tracking of essential biological processes. Consequently, a number of MR sensors for several imaging protocols have been developed, attempting to produce the maximal signal difference for a given event. Here we introduce an approach which could substantially improve the detection of physiological events with fast kinetics. We developed a nanosized, calcium sensitive dendrimeric probe that changes longitudinal and transverse relaxation times with different magnitudes. The change in their ratio is rapidly recorded by means of a balanced steady-state free precession (bSSFP) imaging protocol. The employed methodology results in an almost four times greater signal gain per unit of time as compared to conventional T1-weighted imaging with small sized contrast agents. Furthermore, it is suitable for high resolution functional MRI at high magnetic fields. This methodology could evolve into a valuable tool for rapid monitoring of various biological events. PMID- 29261291 TI - Structures of the L27 Domain of Disc Large Homologue 1 Protein Illustrate a Self Assembly Module. AB - Disc large 1 (Dlg1) proteins, members of the MAGUK protein family, are linked to cell polarity via their participation in multiprotein assemblies. At their N termini, Dlg1 proteins contain a L27 domain. Typically, the L27 domains participate in the formation of obligate hetero-oligomers with the L27 domains from their cognate partners. Among the MAGUKs, Dlg1 proteins exist as homo oligomers, and the oligomerization is solely dependent on the L27 domain. Here we provide biochemical and structural evidence of homodimerization via the L27 domain of Dlg1 from Drosophila melanogaster. The structure reveals that the core of the dimer is formed by a distinctive six-helix assembly, involving all three conserved helices from each subunit (monomer). The homodimer interface is extended by the C-terminal tail of the L27 domain of Dlg1, which forms a two stranded antiparallel beta-sheet. The structure reconciles and provides a structural context for a large body of available mutational data. From our analyses, we conclude that the observed L27 homodimerization is most likely a feature unique to the Dlg1 orthologs within the MAGUK family. PMID- 29261292 TI - Haloacetic Acid Water Disinfection Byproducts Affect Pyruvate Dehydrogenase Activity and Disrupt Cellular Metabolism. AB - The disinfection of drinking water has been a major public health achievement. However, haloacetic acids (HAAs), generated as byproducts of water disinfection, are cytotoxic, genotoxic, mutagenic, carcinogenic, and teratogenic. Previous studies of monoHAA-induced genotoxicity and cell stress demonstrated that the toxicity was due to inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), leading to disruption of cellular metabolism and energy homeostasis. DiHAAs and triHAAs are also produced during water disinfection, and whether they share mechanisms of action with monoHAAs is unknown. In this study, we evaluated the effects of mono-, di-, and tri-HAAs on cellular GAPDH enzyme kinetics, cellular ATP levels, and pyruvate dehydrogenase complex (PDC) activity. Here, treatments conducted in Chinese hamster ovary (CHO) cells revealed differences among mono-, di-, and triHAAs in their molecular targets. The monoHAAs, iodoacetic acid and bromoacetic acid, were the strongest inhibitors of GAPDH and greatly reduced cellular ATP levels. Chloroacetic acid, diHAAs, and triHAAs were weaker inhibitors of GAPDH and some increased the levels of cellular ATP. HAAs also affected PDC activity, with most HAAs activating PDC. The primary finding of this work is that mono- versus multi-HAAs address different molecular targets, and the results are generally consistent with a model in which monoHAAs activate the PDC through GAPDH inhibition-mediated disruption in cellular metabolites, including altering ATP-to-ADP and NADH-to-NAD ratios. The monoHAA-mediated reduction in cellular metabolites results in accelerated PDC activity by way of metabolite-ratio-dependent PDC regulation. DiHAAs and triHAAs are weaker inhibitors of GAPDH, but many also increase cellular ATP levels, and we suggest that they increase PDC activity by inhibiting pyruvate dehydrogenase kinase. PMID- 29261293 TI - Biodegradable PBAT/PLA Blend with Bioactive MCPA-PHBV Conjugate Suppresses Weed Growth. AB - The herbicide 2-methyl-4-chlorophenoxyacetic acid (MCPA) conjugated with poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) was prepared via a melt transesterification route. The resultant bioactive oligomer was then mixed with a blend of polylactide (PLA) and poly(butylene adipate-co-terephthalate) (PBAT) with different loadings to manufacture films to be used as a bioactive, biodegradable mulch to deliver the herbicide to target broadleaf weed species. The biological targeting of the MCPA-PHBV conjugate in the mulch film was investigated under glasshouse conditions using faba bean (Vicia faba) as a selective (nontarget) model crop species having broadleaf morphology. The presence of the MCPA-PHBV conjugate in the biodegradable PBTA/PLA blend was shown to completely suppress the growth of broadleaf weed species while displaying only a mild effect on the growth of the model crop. The degradation of the mulch film under glasshouse conditions was quite slow. The release of the MCPA-PHBV during this process was detected using NMR, GPC, EDS, and DSC analyses, indicating that the majority of the MCPA diffused out after MCPA-PHBV conjugate bond scission. These data provide a strong "proof of concept" and show that this biodegradable, bioactive film is a good candidate for future field applications and may be of wide agricultural applicability. PMID- 29261294 TI - Characterization and Photodegradation of Polybrominated Diphenyl Ethers in Car Seat Fabrics from End-of-Life Vehicles. AB - In this study, we examined the photodegradation of decabromodiphenyl ether (BDE 209) on the surface of car seat covers from end-of-life vehicles (ELVs). Samples were collected at two car dismantling facilities in Sweden and cover car models from 1989 to 1998. The content of polybrominated diphenyl ethers (PBDEs) in nine real samples (fabric and polyurethane foam) was first characterized. Fabric samples that did not contain BDE-209 were then spiked with BDE-209 and irradiated in the laboratory and under sunlight. Photoproducts were identified using high performance liquid chromatography coupled to electrospray ionization mass spectrometer (HPLC-ESI-Orbitrap-MS), whereas volatile products were analyzed by gas chromatography-mass spectrometry (GC-MS). Similar photodegradation rates and oxidation products were observed in fabric samples irradiated in the laboratory and those collected from ELVs. Estimated half-life of BDE-209 on fabric inside vehicles ranged from 3 to 6 years. Thirteen major photoproducts were identified as lower brominated products, hydroxylated BDEs, brominated and hydroxylated dibenzofurans (PBDFs) and dioxins (PBDDs). Furthermore, several photoproducts were found to be transferable into water, particularly bromophenols and hydroxylated BDEs, and others into gas phase, such as bromomethanol and 1,2 dibromoethane. This should be taken into consideration for better estimating exposure to PBDEs and to develop strategies for ELV recycling. PMID- 29261295 TI - pH-Induced Linkage Isomerism of Pd(II) Complexes: A Pathway to Air- and Water Stable Suzuki-Miyaura-Reaction Catalysts. AB - The Pd(II) complexes of the ambidentate pyridyldiketones 2,2-dimethyl-5-(3- or 4 pyridyl)pentane-3,5-dione are readily prepared in their linkage isomeric forms by the appropriate pH control during syntheses. The isolated diketonate- or pyridine bound species can be interconverted with essentially 100% efficiency by treatment with an acid or base, respectively. Under the normal basic conditions for a Suzuki-Miyaura coupling, only the diketonate forms are present and act as very efficient catalysts for this reaction. The dynamic nature of the presented complexes allows the catalytic process to be quenched and reactivated at any stage without the risk of losing the catalyst's activity. PMID- 29261296 TI - Combining the Single-Atom Engineering and Ligand-Exchange Strategies: Obtaining the Single-Heteroatom-Doped Au16Ag1(S-Adm)13 Nanocluster with Atomically Precise Structure. AB - Obtaining cognate single-heteroatom doping is highly desirable but least feasible in the research of nanoclusters (NCs). In this work, we reported a new Au16Ag1(S Adm)13 NC, which is synthesized by the combination of single-atom engineering and ligand-exchange strategies. This new NC is so far the smallest crystallographically characterized Au-based NC protected by thiolate. The Au16Ag1(S-Adm)13 exhibited a tristratified Au3-Au2Ag1-Au1 kernel capped by staple like motifs including one dimer and two tetramers. In stark contrast to the size growth from Au18(S-C6H11)14 to Au21(S-Adm)15 via just the ligand-exchange method, combining single Ag doping on Au18(S-C6H11)14 resulted in the size-decrease from Au17Ag1(S-C6H11)14 to Au16Ag1(S-Adm)13. DFT calculations were performed to both homogold Au18 and single-heteroatom-doped Au17Ag1 to explain the opposite results under the same ligand-exchange reaction. Our work is expected to inspire the synthesis of new cognate single-atom-doped NCs by combining single-atom engineering and ligand-exchange strategies and also shed light on extensive understanding of the metal synergism effect in the NC range. PMID- 29261297 TI - Synthesis and Evaluation of Doxorubicin-Loaded Gold Nanoparticles for Tumor Targeted Drug Delivery. AB - Doxorubicin is an effective and widely used cancer chemotherapeutic agent, but its application is greatly compromised by its cumulative dose-dependent side effect of cardiotoxicity. A gold nanoparticle-based drug delivery system has been designed to overcome this limitation. Five novel thiolated doxorubicin analogs were synthesized and their biological activities evaluated. Two of these analogs and PEG stabilizing ligands were then conjugated to gold nanoparticles, and the resulting Au-Dox constructs were evaluated. The results show that release of native drug can be achieved by the action of reducing agents such as glutathione or under acidic conditions, but reductive drug release gave the cleanest drug release. Gold nanoparticles (Au-Dox) were prepared with different loadings of PEG and doxorubicin, and one formulation was evaluated for mammalian stability and toxicity. Plasma levels of doxorubicin in mice treated with Au-Dox were significantly lower than in mice treated with the same amount of doxorubicin, indicating that the construct is stable under physiological conditions. Treatment of mice with Au-Dox gave no histopathologically observable differences from mice treated with saline, while mice treated with an equivalent dose of doxorubicin showed significant histopathologically observable lesions. PMID- 29261298 TI - How To Tune the Gene Delivery and Biocompatibility of Poly(2-(4-aminobutyl)-2 oxazoline) by Self- and Coassembly. AB - Despite their promising potential in gene transfection, the toxicity and limited efficiency of cationic polymers as nonviral vectors are major obstacles for their broader application. The large amount of cationic charges, for example, in poly(ethylene imine) (PEI) is known to be advantageous in terms of their transfection efficiency but goes hand-in-hand with a high toxicity. Consequently, an efficient shielding of the charges is required to minimize toxic effects. In this study, we use a simple mixed-micelle approach to optimize the required charge density for efficient DNA complex formation and to minimize toxicity by using a biocompatible polymer. In detail, we coassembled mixed poly(2-oxazoline) nanostructures ( d ~ 100 nm) consisting of a hydrophobic-cationic block copolymer (P(NonOx52- b-AmOx184)) and a hydrophobic-hydrophilic stealth block copolymer (P(EtOx155- b-NonOx76) in ratios of 0, 20, 40, 60, 80, and 100 wt % P(NonOx52- b AmOx184). All micelles with cationic polymers exhibited a very good DNA binding efficiency and dissociation ability, while the bio- and hemocompatibility improved with increasing EtOx content. Analytics via confocal laser scanning microscopy and flow cytometry showed an enhanced cellular uptake, transfection ability, and biocompatibility of all prepared micelleplexes compared to AmOx homopolymers. Micelleplexes with 80 or 100 wt % revealed a similar transfection efficiency as PEI, while the cell viability was significantly higher (80 to 90% compared to 60% for PEI). PMID- 29261299 TI - Two-Dimensional Holey Nanoarchitectures Created by Confined Self-Assembly of Nanoparticles via Block Copolymers: From Synthesis to Energy Storage Property. AB - Advances in liquid-phase exfoliation and surfactant-directed anisotropic growth of two-dimensional (2D) nanosheets have enabled their rapid development. However, it remains challenging to develop assembly strategies that lead to the construction of 2D nanomaterials with well-defined geometry and functional nanoarchitectures that are tailored to specific applications. Here we report a facile self-assembly method leading to the controlled synthesis of 2D transition metal oxide (TMO) nanosheets containing a high density of holes. We utilize graphene oxide sheets as a sacrificial template and Pluronic copolymers as surfactants. By using ZnFe2O4 (ZFO) nanoparticles as a model material, we demonstrate that by tuning the molecular weight of the Pluronic copolymers we can incorporate the ZFO particles and tune the size of the holes in the sheets. The resulting 2D ZFO nanosheets offer synergistic characteristics including increased electrochemically active surface areas, shortened ion diffusion paths, and strong inherent mechanical properties, leading to enhanced lithium-ion storage properties. Postcycling characterization confirms that the samples maintain structural integrity after electrochemical cycling. Our findings demonstrate that this template-assisted self-assembly method is a useful bottom-up route for controlled synthesis of 2D nanoarchitectures, and these holey 2D nanoarchitectures are promising for improving the electrochemical performance of next-generation lithium-ion batteries. PMID- 29261300 TI - Dimeric Structure of the Blue Light Sensor Protein Photozipper in the Active State. AB - The light oxygen voltage-sensing (LOV) domain plays a crucial role in blue light (BL) sensing in plants and microorganisms. LOV domains are usually associated with the effector domains and regulate the activities of effector domains in a BL dependent manner. Photozipper (PZ) is monomeric in the dark state. BL induces reversible dimerization of PZ and subsequently increases its affinity for the target DNA sequence. In this study, we report the analyses of PZ by pulsed electron-electron double resonance (PELDOR). The neutral flavin radical was formed by BL illumination in the presence of dithiothreitol in the LOV-C254S (without the bZIP domain) and PZ-C254S mutants, where the cysteine residue responsible for adduct formation was replaced with serine. The magnetic dipole interactions of 3 MHz between the neutral radicals were detected in both LOV C254S and PZ-C254S, indicating that these mutants are dimeric in the radical state. The PELDOR simulation showed that the distance between the radical pair is close to that estimated from the dimeric crystal structure in the "light state" [Heintz, U., and Schlichting, I. (2016) eLife 5, e11860], suggesting that in the radical state, LOV domains in PZ-C254S form a dimer similar to that of LOV-C254S, which lacks the bZIP domain. PMID- 29261302 TI - Trophic Transfer and Accumulation of Multiwalled Carbon Nanotubes in the Presence of Copper Ions in Daphnia magna and Fathead Minnow (Pimephales promelas). AB - The increase in use of nanomaterials such as multiwalled carbon nanotubes (MWCNTs) presents a need to study their interactions with the environment. Trophic transfer was measured between Daphnia magna and Pimephales promelas (fathead minnow, FHM) exposed to MWCNTs with different outer diameter (OD) sizes (MWCNT1 = 8-15 nm OD and MWCNT2 = 20-30 nm OD) in the presence and absence of copper. Pristine FHM were fed D. magna, previously exposed for 3 d to MWCNT1 or MWCNT2 (0.1 mg/L) and copper (0.01 mg/L), for 7 d. D. magna bioaccumulated less MWCNT1 (0.02 MUg/g) than MWCNT2 (0.06 MUg/g), whereas FHM accumulated more MWCNT1 (0.81 MUg/g) than MWCNT2 (0.04 MUg/g). In the presence of copper, MWCNT bioaccumulation showed an opposite trend. Mostly MWCNT1 (0.03 MUg/g) bioaccumulated in D. magna, however less MWCNT1 (0.21 MUg/g) than MWCNT2 (0.32 MUg/g) bioaccumulated in FHM. Bioaccumulation factors were higher for MWCNT1s than MWCNT2. However, an opposite trend was observed when copper was added. Plasma metallothionein-2 was measured among treatments; however concentrations were not statistically different from the control. This study demonstrates that trophic transfer of MWCNTs is possible in the aquatic environment and further exploration with mixtures can strengthen the understanding of MWCNT environmental behavior. PMID- 29261303 TI - Toxic Effects of Bisphenol S Showing Immunomodulation in Fish Macrophages. AB - Bisphenol S (BPS), a structural analogue of bisphenol A (BPA), has been increasingly used as a common replacement of BPA due to health concerns regarding the former. However, mounting evidence suggests that BPS has similar endocrine disrupting effects as BPA, and likewise, its presence in the environment may pose considerable risks to ecosystems and human health. Using fish primary macrophages (fpMQs), we here evaluated the immunomodulatory effects of BPS and its mechanisms of action associated with estrogen receptors (ERs). Following BPS exposure at environmentally relevant concentrations from 0.1 to 1000 MUg/L, we observed approximate concentration-dependent increases in nitric oxide and reactive oxygen species generation and total antioxidant capacity as well as the gene expression of inflammatory cytokines in fpMQs. BPS impaired phagocytic capability but enhanced fpMQ activation levels in response to lipopolysaccharide stimulation and promoted apoptosis, indicating an impact on cell functions. At a concentration of 100 MUg/L, BPS and BPA showed comparable pro-inflammatory potential with both up regulating the production of free radicals and cytokine expression; however, BPS had no significant potency with regards to inducing lipid peroxidation and apoptosis, different from BPA's effects. Moreover, BPS induced both eralpha and erbeta2 expression in fpMQs, whereas BPA induced only eralpha expression. This study demonstrates that, similarly to BPA, exposure to low doses of BPS significantly disturbs the immune response of fpMQs in vitro and first reveals overlapping but different roles of ERs in response to BPS and BPA. PMID- 29261301 TI - Redox-Inactive Peptide Disrupting Trx1-Ask1 Interaction for Selective Activation of Stress Signaling. AB - Thioredoxin 1 (Trx1) and glutaredoxin 1 (Grx1) are two ubiquitous redox enzymes that are central for redox homeostasis but also are implicated in many other processes, including stress sensing, inflammation, and apoptosis. In addition to their enzymatic redox activity, a growing body of evidence shows that Trx1 and Grx1 play regulatory roles via protein-protein interactions with specific proteins, including Ask1. The currently available inhibitors of Trx1 and Grx1 are thiol-reactive electrophiles or disulfides that may suffer from low selectivity because of their thiol reactivity. In this report, we used a phage peptide library to identify a 7-mer peptide, 2GTP1, that binds to both Trx1 and Grx1. We further showed that a cell-permeable derivative of 2GTP1, TAT-2GTP1, disrupts the Trx1-Ask1 interaction, which induces Ask1 phosphorylation with subsequent activation of JNK, stabilization of p53, and reduced viability of cancer cells. Notably, as opposed to a disulfide-derived Trx1 inhibitor (PX-12), TAT-2GTP1 was selective for activating the Ask1 pathway without affecting other stress signaling pathways, such as endoplasmic reticulum stress and AMPK activation. Overall, 2GTP1 will serve as a useful probe for investigating protein interactions of Trx1. PMID- 29261304 TI - Ring and Linear Copolymer Blends under Confinement. AB - The behavior of dense mixtures of two topologically different diblock copolymer (CP) chains, viz., linear (L)-CP and ring (R)-CP of the same molecular weight, which form lamellae is studied under confinement by two nonselective substrates. The effect of varying interaction strength between L-CP and R-CP from purely repulsive (demixed state) to weakly attractive (mixed state) on the morphology, domain size, chain conformations, and distribution of chains in the film is investigated. In the demixed state, collective structure factor S(q) shows a split of the predominant peak indicating the presence of two dominant length scales, while there is only one predominant peak in the mixed state, and hence a lamellar structure with single domain size. We show that the peak position q* of S(q) can be varied with the L/R interaction strength and thus allows one to control domain size by tuning L/R interaction strength without altering the chain size. We further characterize the chain size and illustrate that this domain size variation is a consequence of the variation in the size of L-CPs. Furthermore, results on the average instantaneous shape of R/L-CP reveal that their shapes are very different both in bulk and near the substrate, and R-CP assumes an oblate shape near the substrate. This shape/size difference leads to the segregation of R-CPs near the polymer-substrate interface and hence a relatively higher density of R-CPs at the interface. PMID- 29261305 TI - Solvent-Mediated Interactions Close to the Fisher-Widom Line. AB - The effective interactions between two hard spheres mediated by a square-well fluid is studied within the framework of classical density functional theory. The main focus of this study is the behavior of the effective interactions in the supercritical regime close to the Fisher-Widom line, where the decay of the bulk correlations of the solvent changes from monotonic to oscillatory, and close to the Widom line, which is the locus of (local) maxima in the bulk correlation length. The effective interactions are calculated by employing the potential distribution theorem. PMID- 29261306 TI - Control of Chain Walking by Weak Neighboring Group Interactions in Unsymmetrical Catalysts. AB - A combined theoretical and experimental study shows how weak attractive interactions of a neighboring group can strongly promote chain walking and chain transfer. This accounts for the previously observed very different microstructures obtained in ethylene polymerization by [kappa2-N,O-{2,6-(3',5' R2C6H3)2C6H3-N?C(H)-(3,5-X,Y-2-O-C6H2)}NiCH3(pyridine)], namely hyperbranched oligomers for remote substituents R = CH3 versus high-molecular-weight polyethylene for R = CF3. From a full mechanistic consideration, the alkyl olefin complex with the growing chain cis to the salicylaldiminato oxygen donor is identified as the key species. Alternative to ethylene chain growth by insertion in this species, decoordination of the monomer to form a cis beta-agostic complex provides an entry into branching and chain-transfer pathways. This release of monomer is promoted and made competitive by a weak eta2-coordination of the distal aryl rings to the metal center, operative only for the case of sufficiently electron-rich aryls. This concept for controlling chain walking is underlined by catalysts with other weakly coordinating furan and thiophene motifs, which afford highly branched oligomers with >120 branches per 1000 carbon atoms. PMID- 29261307 TI - Aminocatalyzed Synthesis of Enantioenriched Phenalene Skeletons through a Friedel Crafts/Cyclization Strategy. AB - A series of enantioenriched phenalene-derived compounds were accessed by a Friedel-Crafts/cyclization strategy. Starting from alpha,beta-unsaturated aldehydes and 2-naphthol derivatives, high levels of enantioselectivity were obtained through iminium-enamine catalysis. The catalytic system composed of a diphenylprolinol silyl ether organocatalyst and triethylamine as a base was applied to a combination of diversely functionalized substrates. The obtained phenalene-derived architectures are promising building blocks for reaching natural products and exhibit fluorescence properties. PMID- 29261308 TI - alpha-C-H Alkylation of Methyl Sulfides with Alkenes by a Scandium Catalyst. AB - The C-H addition of sulfides to alkenes is an atom-efficient route for the functionalization and modification of sulfide compounds through C-C bond formation, but this transformation is highly challenging. We report here the regioselective alpha-C(sp3)-H addition of a wide range of methyl sulfides to a variety of olefins and dienes by a half-sandwich scandium catalyst. This protocol provides a unique route for the synthesis of diverse sulfide derivatives through C-C bond formation at a sulfur-adjacent carbon atom in a 100% atom efficient fashion. PMID- 29261310 TI - Oxygenated N-Acyl Alanine Methyl Esters (NAMEs) from the Marine Bacterium Roseovarius tolerans EL-164. AB - The marine bacterium Roseovarius tolerans EL-164 (Rhodobacteraceae) can produce unique N-acylalanine methyl esters (NAMEs) besides strucutrally related N acylhomoserine lactones (AHLs), bacterial signaling compounds widespread in the Rhodobacteraceae. The structures of two unprecedented NAMEs carrying a rare terminally oxidized acyl chain are reported here. The compounds (Z)-N-16 hydroxyhexadec-9-enoyl-l-alanine methyl ester (Z9-16-OH-C16:1-NAME, 3) and (Z)-N 15-carboxypentadec-9-enoyl-l-alanine methyl ester (16COOH-C16:1-NAME, 4) were isolated, and the structures were determined by NMR and MS experiments. Both compounds were synthesized to prove assignments and to test their biological activity. Finally, non-natural, structurally related Z9-3-OH-C16:1-NAME (18) was synthesized to investigate the mass spectroscopy of structurally related NAMEs. Compound 3 showed moderate antibacterial activity against microorganisms such as Bacillus, Streptococcus, Micrococcus, or Mucor strains. In contrast to AHLs, quorum-sensing or quorum-quenching activity was not observed. PMID- 29261309 TI - Bioinspired Heterogeneous Ion Pump Membranes: Unidirectional Selective Pumping and Controllable Gating Properties Stemming from Asymmetric Ionic Group Distribution. AB - The creation of an artificial solid-state ion pump that mimics the delicate ion transport behaviors of a biological protein-based ion pump is drawing more and more research attention due to its potential applications in energy conversion, biosensor, and desalination. However, the reported bioinspired double-gated ion pump systems are generally very primary and can only realize nonselective ion pumping functions with no directionality and uncontrollable ion gating functions, which are far from their biological counterparts. To make the bioinspired device "smart" in a real sense, the implementation of high-level selectivity and directionality in the ion pumping process, while achieving great controllability in the ion gating process, is a necessity. Here, we developed a bioinspired heterogeneous ion pump membrane by combining block copolymer membrane sacrificial coating and plasma grafting technique. The system has unidirectional selective ion pumping and controllable ion gating properties. The introduction of asymmetric ionic group distribution is the key reason for its novel transport behaviors. Such a heterogeneous ion pump could not only provide a basic platform that potentially sparks further efforts to simulate the smart ion transport processes in living bodies but also promote the application of artificial nanofluidic devices in energy conversion, water treatment, and biosensing. PMID- 29261311 TI - Laser-Ablated U Atom Reactions with (CN)2 to Form UNC, U(NC)2, and U(NC)4: Matrix Infrared Spectra and Quantum Chemical Calculations. AB - Laser-ablated U atoms react with (CN)2 in excess argon and neon during codeposition at 4 K to form UNC, U(NC)2, and U(NC)4 as the major uranium-bearing products, which are identified from their matrix infrared spectra using cyanogen substituted with 13C and 15N and from quantum chemical calculations. The 12/13CN and C14/15N isotopic frequency ratios computed for the U(NC)1,2,4 molecules agree better with the observed values than those calculated for the U(CN)1,2,4 isomers. Multiplets using mixed isotopic cyanogens reveal the stoichiometries of these products, and the band positions and quantum chemical calculations confirm the isocyanide bonding arrangements, which are 14 and 51 kJ/mol more stable than the cyanide isomers for UNC and U(NC)2, respectively, and 62 kJ/mol for U(NC)4 in the isolated gas phase at the CCSD(T)/CBS level. The studies further demonstrate that the isocyano nitrogen is a better pi donor, so it interacts with U(VI) better than carbon. Although the higher isocyanides are more stable than the corresponding cyanides, U(NC)5 and U(NC)6 were not observed here most likely because unfavorable or endothermic routes are required for their production from U(NC)4. The computed U-NC bond dissociation energies decrease from 581 kJ/mol for 4[UNC] to 168 kJ/mol for 1[U(NC)6 ]. The ionic nature of U(NC)n decreases as the number of isocyano groups increases. PMID- 29261312 TI - Rearranged Phloroglucinol-Monoterpenoid Adducts from Callistemon rigidus. AB - Callisretones A (1) and B (2), two rearranged phloroglucinol-monoterpenoid adducts featuring an unprecedented isopropylcyclopenta[b]benzofuran backbone, together with their postulated biosynthetic precursors (3-9), were isolated from Callistemon rigidus. The previously assigned absolute configurations of viminalins H (7), L (8), and N (9) were revised and unequivocally established by X-ray diffraction data. A putative biosynthetic pathway toward callisretones A and B involving the rearrangement of the terpenoid motif is proposed. In addition, 1 and 2 showed inhibitory effects on nitric oxide production with IC50 values of 15.3 +/- 1.0 and 17.7 +/- 1.1 MUM, respectively. PMID- 29261313 TI - Reveal and Control of Chiral Cathodoluminescence at Subnanoscale. AB - Circularly polarized light is crucial for the modern physics research. Highly integrated nanophotonic device further requires the control of circularly polarized light at subnanoscale. Here, we report the tuning of chiral cathodoluminescence (CL) on single Au nanostructure under electron stimulation. The detected CL helicity is found ultrasensitive with the electron impinging position on the structure, and a helicity switch is achieved within a 1.86 nm electron-beam movement, which is applied to construct ternary notation sequence. The proposed configuration provides a delicate platform for the CL helicity control, which opens a way for the future chiral applications at subnanoscale like information coding and quantum communication. PMID- 29261314 TI - Dynamically Cross-Linked Self-Assembled Thermoresponsive Microgels with Homogeneous Internal Structures. AB - The internal morphology of temperature-responsive degradable poly(N isopropylacrylamide) (PNIPAM) microgels formed via an aqueous self-assembly process based on hydrazide and aldehyde-functionalized PNIPAM oligomers is investigated. A combination of surface force measurements, small angle neutron scattering (SANS), and ultrasmall angle neutron scattering (USANS) was used to demonstrate that the self-assembled microgels have a homogeneously cross-linked internal structure. This result is surprising given the sequential addition process used to fabricate the microgels, which was expected to result in a densely cross-linked shell-diffuse core structure. The homogeneous internal structure identified is also significantly different than conventional microgels prepared via precipitation polymerization, which typically exhibit a diffuse shell-dense core structure. The homogeneous structure is hypothesized to result from the dynamic nature of the hydrazone cross-linking chemistry used to couple with the assembly conditions chosen that promote polymer interdiffusion. The lack of an internal cross-linking gradient within these degradable and monodisperse microgels is expected to facilitate more consistent drug release over time, improved optical properties, and other potential application benefits. PMID- 29261315 TI - Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines via K2S2O8 Mediated Oxidative Radical Decarboxylation of Uronic Acids. AB - We have developed an efficient protocol for the synthesis of C-glycosylated phenanthridines. Tetrafuranos-4-yl and pentapyranos-5-yl radicals, generated from K2S2O8-mediated oxidative decarboxylation of furan- and pyranuronic acids, undergo attack to 2-isocyanodiphenyls and ensuing homolytic aromatic substitution to provide diverse C-glycosylated phenanthridines in satisfactory yields without resort to transition metals. This reaction tolerates various functional groups, and enables ready synthesis of complex oligosaccharide-based phenanthridines. The C-glycosylated phenanthridine derived from beta-cyclodextrin has been prepared, which might be potential in medicinal and biological chemistry due to its flexible conformation. PMID- 29261317 TI - Rhodium-Catalyzed Homocoupling of gamma-Alkylated tert-Propargylic Alcohols. AB - An unprecedented rhodium-catalyzed homocoupling reaction of gamma-alkylated tert propargylic alcohols is reported, and 2-alkynylated buta-1,3-diene or 2 alkynylated hexa-1,3,5-triene are generated selectively. Multiple beta eliminations, including sequential beta-carbon, beta-hydrogen, and beta-oxygen eliminations from the corresponding rhodium intermediates, are assumed to be involved during the reaction process. PMID- 29261318 TI - Organocatalytic Asymmetric Formal [4 + 2] Cycloaddition of in Situ Oxidation Generated ortho-Quinone Methides and Aldehydes. AB - An unprecedented chiral secondary amine-catalyzed formal [4 + 2] annulation of aldehydes and oxidation-generated beta-unsubstituted o-QMs is reported. This asymmetric protocol allows direct functionalization of the benzylic C-H bonds and furnishes [4 + 2] cycloadducts, chromanols, with excellent enantioselectivity and in up to 92% yield. The usability of this approach was further demonstrated by the enantioselective synthesis of anticancer Rhinacanthins derivative NKPLS8. PMID- 29261316 TI - Omics-Based Platform for Studying Chemical Toxicity Using Stem Cells. AB - The new strategy for chemical toxicity testing and modeling is to use in vitro human cell-based assays in conjunction with quantitative high-throughput screening (qHTS) technology, to identify molecular mechanisms and predict in vivo responses. Stem cells are more physiologically relevant than immortalized cell lines because of their unique proliferation and differentiation potentials. We established a robust two stem cells-two lineages assay system, encompassing human mesenchymal stem cells (hMSCs) along osteogenesis and human induced pluripotent stem cells (hiPSCs) along hepatogenesis. We performed qHTS phenotypic screening of LOPAC1280 and identified 38 preliminary hits for hMSCs. This was followed by validation of a selected number of hits and determination of their IC50 values and mechanistic studies of idarubicin and cantharidin treatments using proteomics and bioinformatics. In general, hiPSCs were more sensitive than hMSCs to chemicals, and differentiated progenies were less sensitive than their progenitors. We showed that chemical toxicity depends on both stem cell types and their differentiation stages. Proteomics identified and quantified over 3000 proteins for both stem cells. Bioinformatics identified apoptosis and G2/M as the top pathways conferring idarubicin toxicity. Our Omics-based assays of stem cells provide mechanistic insights into chemical toxicity and may help prioritize chemicals for in-depth toxicological evaluations. PMID- 29261319 TI - Facile Deposition of Manganese Dioxide to Albumin-Bound Paclitaxel Nanoparticles for Modulation of Hypoxic Tumor Microenvironment To Improve Chemoradiation Therapy. AB - Tumor microenvironment with hypoxia and excess hydrogen peroxide (H2O2) tremendously limits the effect of chemoradiation therapy of colorectal cancer. For the first time, we developed a facile method to deposit manganese dioxide (MnO2) on the surface of albumin bound paclitaxel nanoparticles (ANPs-PTX) to obtain MnO2-functioned ANPs-PTX (MANPs-PTX). In the tumor microenvironment, MANPs PTX could consume excess hydrogen peroxide (H2O2) to produce abundant oxygen for tumor oxygenation and improve chemoradiation therapy. Meanwhile, the released Mn2+ from MANPs-PTX had excellent T1 magnetic resonance imaging (MRI) performances for tumor detection. Notably, the obtained MANPs-PTX would be a promising theranostic agent and have potential clinical application prospects. PMID- 29261320 TI - Charged Surface-Active Impurities at Nanomolar Concentration Induce Jones-Ray Effect. AB - The electrolyte surface tension exhibits a characteristic minimum around a salt concentration of 1 mM for all ion types, known as the Jones-Ray effect. We show that a consistent description of the experimental surface tension of salts, bases, and acids is possible by assuming charged impurities in the water with a surface affinity typical for surfactants. Comparison with experimental data yields an impurity concentration in the nanomolar range, well below the typical experimental detection limit. Our modeling reveals salt-screening enhanced impurity adsorption as the mechanism behind the Jones-Ray effect: for very low salt concentration added salt screens the electrostatic repulsion between impurities at the surface, which dramatically increases impurity adsorption and thereby reduces the surface tension. PMID- 29261321 TI - Dynamic Formation of Imidazolidino Boronate Enables Design of Cysteine-Responsive Peptides. AB - We describe the dynamic and chemoselective conjugation between 2 formylphenylboronic acid and l-2,3-diaminopropionic acid yielding an imidazolidino boronate (IzB) complex. The IzB complex formation readily proceeds in biological milieu with little interference by common biomolecules except cysteine. We demonstrate the potential of this reversible conjugation for biological applications by creating "smart" peptides that specifically respond to cysteine in complex biological media. Specifically, the design and characterization of a fluorogenic sensor of cysteine is described. PMID- 29261322 TI - LSPR Tuning from 470 to 800 nm and Improved Stability of Au-Ag Nanoparticles Formed by Gold Deposition and Rebuilding in the Presence of Poly(styrenesulfonate). AB - Stability and precise control over functional properties of metal nanoparticles remain a challenge for the realization of prospective applications. Our described process of shell formation and rebuilding can address both these challenges. Template silver nanoparticles (AgNPs) stabilized by poly(styrenesulfonate) are first transformed with gold deposition, after which the resulting shell rebuilds with the replaced silver. The shell formation and rebuilding are accompanied by large shifts in localized surface plasmon resonance (LSPR) peak position, which enables LSPR tuning in a range from 470 to 800 nm. Furthermore, chemical stability of Au-AgNPs is significantly improved compared to AgNPs due to gold stability. Silver templates of different shapes and sizes were demonstrated to transform to AuAg composite NPs to further extend the accessible LSPR range tuning. Stabilization of template AgNPs with poly(styrenesulfonate), in contrast to commonly used poly(vinylpyrrolidone), was found to be a key factor for shell rebuilding. The developed Au-AgNPs were shown to be advantageous for surface plasmon resonance (SPR) detection and surface-enhanced Raman spectroscopy (SERS) owing to their tunable LSPR and enhanced stability. PMID- 29261323 TI - Iron-Catalyzed Synthesis of Tetrahydronaphthalenes via 3,4-Dihydro-2H-pyran Intermediates. AB - The development of an iron(III)-catalyzed synthetic strategy toward functionalized tetrahydronaphthalenes is described. This approach is characterized by its operational simplicity and is distinct from currently available procedures that rely on [4 + 2]-cycloadditions. Our strategy takes advantage of the divergent reactivity observed for simple aryl ketone precursors to gain exclusive access to tetrahydronaphthalene products (23 examples). Detailed mechanistic investigations identified pyrans as reactive intermediates that afford the desired tetrahydronaphthalenes in high yields upon iron(III) catalyzed Friedel-Crafts alkylation. PMID- 29261324 TI - Designer Neural Networks with Embedded Semiconductor Microtube Arrays. AB - Here we present a designer's approach to building cellular neuronal networks based on a biocompatible negative photoresist with embedded coaxial feedthroughs made of semiconductor microtubes. The diameter of the microtubes is tailored and adjusted to the diameter of cerebellum axons having a diameter of 2-3 MUm. The microtubes as well as the SU-8 layer serve as a topographical cue to the axons. Apart from the topographical guidance, we also employ chemical guidance cues enhancing neuron growth at designed spots. Therefore, the amino acid poly-l lysine is printed in droplets of pl volume in the front of the tube entrances. Our artificial neuronal network has an extremely high yield of 85% of the somas settled at the desired locations. We complete this by basic patch-clamp measurements on single cells within the neuronal network. PMID- 29261325 TI - Visible-Light-Promoted Tandem Annulation of N-(o-Ethynylaryl)acrylamides with CH2Cl2. AB - A novel tandem annulation of N-(o-ethynylaryl)acrylamides, with CH2Cl2 as a one carbon unit, for the divergent synthesis of cyclopenta[c]quinolin-4(5H)-ones and benzo[j]phenanthridin-6(5H)-ones, which relies on the substitution effect of the 2 position of the acrylamide moiety, is described. Promoted by the visible-light photoredox catalysis, this reaction allows the formation of multiple chemical bonds through multiple C-Cl/C-H functionalization and [2 + 2 + 1] annulation cascades. PMID- 29261326 TI - Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity. AB - Brown adipose tissue (BAT) plays an important role in lipid and glucose metabolism in rodents and possibly also in humans. Identification of genes responsible for BAT function would shed light on underlying pathophysiological mechanisms of metabolic disturbances. Recent linkage analysis in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), identified two closely linked quantitative trait loci (QTL) associated with glucose oxidation and glucose incorporation into BAT lipids in the vicinity of Wars2 (tryptophanyl tRNA synthetase 2 (mitochondrial)) gene on chromosome 2. The SHR harbors L53F WARS2 protein variant that was associated with reduced angiogenesis and Wars2 thus represents a prominent positional candidate gene. In the current study, we validated this candidate as a quantitative trait gene (QTG) using transgenic rescue experiment. SHR-Wars2 transgenic rats with wild type Wars2 gene when compared to SHR, showed more efficient mitochondrial proteosynthesis and increased mitochondrial respiration, which was associated with increased glucose oxidation and incorporation into BAT lipids, and with reduced weight of visceral fat. Correlation analyses in RI strains showed that increased activity of BAT was associated with amelioration of insulin resistance in muscle and white adipose tissue. In summary, these results demonstrate important role of Wars2 gene in regulating BAT function and consequently lipid and glucose metabolism. PMID- 29261327 TI - Ovarian steroid hormone secretion activity examined after supplementation of green tea extract. AB - This study aimed at examining the secretion activity of steroid hormones progesterone and 17beta-estradiol by porcine ovarian granulosa cells after addition of green tea extract. Granulosa cells were incubated with green tea extract (at doses of 0.01, 0.1, 1, 10 and 100 microg.ml(-1). Another set of cells were incubated with green tea extract at the above doses along with additional supplementation of follicle stimulating hormone (FSH) at 10 microg.ml(-1). Release of hormones by granulosa cells was assessed by EIA after 24 h exposure. Secretion of steroid hormones was not affected either by green tea extract alone or after FSH supplementation with green tea extract. Results indicate that ovarian steroidogenesis is not affected by green tea under conditions used in the experiment. PMID- 29261328 TI - "I Want to Feel Like a Full Man": Conceptualizing Gay, Bisexual, and Heterosexual Men's Sexual Difficulties. AB - Current understandings of sexual difficulties originate from a model that is based on the study of heterosexual men and women. Most research has focused on sexual difficulties experienced by heterosexual men incapable of engaging in vaginal penetration. To better understand men's perceptions and experiences of sexual difficulties, seven focus groups and 29 individual interviews were conducted with gay (n = 22), bisexual (n = 5), and heterosexual (n = 25) men. In addition, the extent to which difficulties reported by gay and bisexual men differ from heterosexual men was explored. Data were analyzed using thematic analysis applying an inductive approach. Two intercorrelated conceptualizations were identified: penis function (themes: medicalization, masculine identity, psychological consequences, coping mechanisms) and pain (themes: penile pain, pain during receptive anal sex). For the most part, gay, bisexual, and heterosexual men reported similar sexual difficulties; differences were evident regarding alternative masculinity, penis size competition, and pain during receptive anal sex. The results of this study demonstrate the complexity of men's sexual difficulties and the important role of sociocultural, interpersonal, and psychological factors. Limitations and suggested directions for future research are outlined. PMID- 29261330 TI - Corrections to: How Journalists Characterize Health Inequalities and Redefine Solutions for Native American Audiences. PMID- 29261329 TI - The impact of stepfamily relationship quality on emerging adult non-medical use of prescription drugs. AB - BACKGROUND: Emerging adults aged 18 to 25 are most at-risk for non-medical use of prescription drugs (NMUPD). While the literature dedicated to emerging-adult NMUPD has explored risk and protective factors at an individual level, much less is known regarding how interpersonal and familial factors relate to NMUPD. Because interpersonal bonds can have a significant impact on behavior, familial factors may be important predictors of NMUPD among emerging adults. OBJECTIVES: Inasmuch as growing up in a stepfamily is increasingly common for children, this study aimed to determine whether perceived stepfamily quality within three stepfamily subsystems - child-biological parent, child-stepparent, and child stepsibling - decreased the likelihood of NMUPD in emerging adulthood. METHODS: Data came from the Stepfamily Experiences Project (STEP), a retrospective survey examining emerging adults' perceptions of their stepfamily life in 2013. A national quota sampling strategy was used, and the final sample consisted of 902 emerging adults (54.1% female). A structural equation model was constructed, with regression paths from each latent construct predicting the ordinal dependent variable, NMUPD. RESULTS: Increased retrospective biological parent relationship quality in childhood significantly decreased the likelihood of intensifying NMUPD in emerging adulthood (e.g. moving from the "None" category to the "Once a month or less" category). However, stepparent and stepsibling relationship quality did not influence NMUPD. CONCLUSION: Findings underscore the importance of the preservation of the child-biological parent relationship within a stepfamily context, and encourage further research on the impact familial systems and subsystems may have on NMUPD. PMID- 29261331 TI - Two new monoterpenoid indole alkaloids from the leaves and twigs of Ochrosia borbonica. AB - Two new monoterpenoid indole alkaloids, ochrobonines A (1) and B (2), together with five known compounds (3-7), were isolated from the leaves and twigs of Ochrosia borbonica. Their structures were determined by spectroscopic method, and the absolute configuration of compound 3 was first established by single-crystal X-ray diffraction. Compounds 1 and 2 represent a rare class of monoterpenoid indole alkaloids that with a 2-[1-(3-ethylpiperidin-4-yl)vinyl]-3-methyl-1H indole skeleton. PMID- 29261332 TI - Nanomedicine for immunosuppressive therapy: achievements in pre-clinical and clinical research. AB - INTRODUCTION: Immunosuppression is the mainstay therapy in organ transplantation and autoimmune diseases. The effective clinical application of immunosuppressive agents has suffered from the emergence of systemic immunosuppression and/or individual drug side effects. Nanotechnology approaches may be used to modify the mentioned shortcomings by enhancing the delivery of immunosuppressants to target cells of the immune system, thus reducing the required dose for function, and/or reducing drug distribution to non-target tissues. Areas covered: We provide an overview on the development of nanotechnology products for the most commonly used immunosuppressive agents. At first, the rationale for the use of nanoparticles as means for immunosuppressive therapy is discussed. This is followed by a review of major accomplishments in this area, particularly in preclinical in vivo studies. Expert opinion: The results of research conducted in this area to date, points to a great promise for nano-medicine in increasing the bioavailability, reducing the toxicity, and/or potentiating the activity of immunosuppressive agents. It is, therefore, safe to speculate the more rapid translation of nanotechnologyin clinical immunosuppressive therapy in the near future providing to the overcoming of hurdles associated with nano-drug delivery such as high cost, inadequate reproducibility and potential safety concerns of the delivery systems themselves. PMID- 29261333 TI - Chemical and physical pretreatments of fruits and vegetables: Effects on drying characteristics and quality attributes - a comprehensive review. AB - Pretreatment is widely used before drying of agro-products to inactivate enzymes, enhance drying process and improve quality of dried products. In current work, the influence of various pretreatments on drying characteristics and quality attributes of fruits and vegetables is summarized. They include chemical solution (hyperosmotic, alkali, sulfite and acid, etc.) and gas (sulfur dioxide, carbon dioxide and ozone) treatments, thermal blanching (hot water, steam, super heated steam impingement, ohmic and microwave heating, etc), and non-thermal process (ultrasound, freezing, pulsed electric field, and high hydrostatic pressure, etc). Chemical pretreatments effectively enhance drying kinetics, meanwhile, it causes soluble nutrients losing, trigger food safety issues by chemical residual. Conventional hot water blanching has significant effect on inactivating various undesirable enzymatic reactions, destroying microorganisms, and softening the texture, as well as facilitating drying rate. However, it induces undesirable quality of products, e.g., loss of texture, soluble nutrients, pigment and aroma. Novel blanching treatments, such as high-humidity hot air impingement blanching, microwave and ohmic heat blanching can reduce the nutrition loss and are more efficient. Non-thermal technologies can be a better alternative to thermal blanching to overcome these drawbacks, and more fundamental researches are needed for better design and scale up. PMID- 29261334 TI - Respiratory motion correction for free-breathing 3D abdominal MRI using CNN-based image registration: a feasibility study. AB - OBJECTIVE: Free-breathing abdomen imaging requires non-rigid motion registration of unavoidable respiratory motion in three-dimensional undersampled data sets. In this work, we introduce an image registration method based on the convolutional neural network (CNN) to obtain motion-free abdominal images throughout the respiratory cycle. METHODS: Abdominal data were acquired from 10 volunteers using a 1.5 T MRI system. The respiratory signal was extracted from the central-space spokes, and the acquired data were reordered in three bins according to the corresponding breathing signal. Retrospective image reconstruction of the three near-motion free respiratory phases was performed using non-Cartesian iterative SENSE reconstruction. Then, we trained a CNN to analyse the spatial transform among the different bins. This network could generate the displacement vector field and be applied to perform registration on unseen image pairs. To demonstrate the feasibility of this registration method, we compared the performance of three different registration approaches for accurate image fusion of three bins: non-motion corrected (NMC), local affine registration method (LREG) and CNN. RESULTS: Visualization of coronal images indicated that LREG had caused broken blood vessels, while the vessels of the CNN were sharper and more consecutive. As shown in the sagittal view, compared to NMC and CNN, distorted and blurred liver contours were caused by LREG. At the same time, zoom-in axial images presented that the vessels were delineated more clearly by CNN than LREG. The statistical results of the signal-to-noise ratio, visual score, vessel sharpness and registration time over all volunteers were compared among the NMC, LREG and CNN approaches. The SNR indicated that the CNN acquired the best image quality (207.42 A+/- 96.73), which was better than NMC (116.67 A+/- 44.70) and LREG (187.93 A+/- 96.68). The image visual score agreed with SNR, marking CNN (3.85 A+/- 0.12) as the best, followed by LREG (3.43 A+/- 0.13) and NMC (2.55 A+/ 0.09). A vessel sharpness assessment yielded similar values between the CNN (0.81 A+/- 0.03) and LREG (0.80 A+/- 0.04), differentiating them from the NMC (0.78 A+/- 0.06). When compared with the LREG-based reconstruction, the CNN-based reconstruction reduces the registration time from 1 h to 1 min. CONCLUSION: Our preliminary results demonstrate the feasibility of the CNN-based approach, and this scheme outperforms the NMC- and LREG-based methods. Advances in knowledge: This method reduces the registration time from ~1 h to ~1 min, which has promising prospects for clinical use. To the best of our knowledge, this study shows the first convolutional neural network-based registration method to be applied in abdominal images. PMID- 29261335 TI - Development of a Checklist for Assessing Good Hygiene Practices of Fresh-Cut Fruits and Vegetables Using Focus Group Interviews. AB - This study aimed to develop a checklist for good hygiene practices (GHP) for raw material of vegetable origin using the focus groups (FGs) approach (n = 4). The final checklist for commercialization of horticultural products totaled 28 questions divided into six blocks, namely: water supply; hygiene, health, and training; waste control; control of pests; packaging and traceability; and hygiene of facilities and equipment. The FG methodology was efficient to elaborate a participatory and objective checklist, based on minimum hygiene requirements, serving as a tool for diagnosis, planning, and training in GHP of fresh vegetables, besides contributing to raise awareness of the consumers' food safety. The FG methodology provided useful information to establish the final checklist for GHP, with easy application, according to the previous participants' perception and experience. PMID- 29261336 TI - Health care access, concentrated poverty, and pediatric asthma hospital care use in California's San Joaquin Valley: A multilevel approach. AB - BACKGROUND: California's San Joaquin Valley is a region with a history of poverty, low health care access, and high rates of pediatric asthma. It is important to understand the potential barriers to care that challenge vulnerable populations. OBJECTIVE: The objective was to describe pediatric asthma-related utilization patterns in the emergency department (ED) and hospital by insurance coverage as well as to identify contributing individual-level indicators (age, sex, race/ethnicity, and insurance coverage) and neighborhood-level indicators of health care access. METHODS: This was a retrospective study based on secondary data from California hospital and ED records 2007-2012. Children who used services for asthma-related conditions, were aged 0-14 years, Hispanic or non Hispanic white, and resided in the San Joaquin Valley were included in the analysis. Poisson multilevel modeling was used to control for individual- and neighborhood-level factors. RESULTS: The effect of insurance coverage on asthma ED visits and hospitalizations was modified by the neighborhood-level percentage of concentrated poverty (RR = 1.01, 95% CI = 1.01-1.02; RR = 1.03, 95% CI = 1.02 1.04, respectively). The effect of insurance coverage on asthma hospitalizations was completely explained by the neighborhood-level percentage of concentrated poverty. CONCLUSIONS: Observed effects of insurance coverage on hospital care use were significantly modified by neighborhood-level measures of health care access and concentrated poverty. This suggests not only an overall greater risk for poor children on Medi-Cal, but also a greater vulnerability or response to neighborhood social factors such as socioeconomic status, community cohesiveness, crime, and racial/ethnic segregation. PMID- 29261337 TI - Current and emerging imaging techniques in the diagnosis and assessment of pulmonary hypertension. AB - INTRODUCTION: Pulmonary hypertension (PH) is a challenging condition to diagnose and treat. Over the last two decades, there have been significant advances in therapeutic approaches and imaging technologies. Current guidelines emphasize the importance of cardiac catheterization; however, the increasing availability of non-invasive imaging has the potential to improve diagnostic rates, whilst providing additional information on patient phenotypes. Areas covered: This review discusses the role of imaging in the diagnosis, prognostic assessment and follow-up of patients with PH. Imaging methods, ranging from established investigations (chest radiography, echocardiography, nuclear medicine and computerized tomography (CT)), to emerging modalities (dual energy CT, magnetic resonance imaging (MRI), optical coherence tomography and positron emission tomography (PET)) are reviewed. The value and limitations of the clinical utility of these imaging modalities and their potential clinical application are reviewed. Expert commentary: Imaging plays a key role in the diagnosis and classification of pulmonary hypertension. It also provides valuable prognostic information and emerging evidence supports a role for serial assessments. The authors anticipate an increasing role for imaging in the pulmonary hypertension clinic. This will reduce the need for invasive investigations, whilst providing valuable insights that will improve our understanding of disease facilitate a more targeted approach to treatment. PMID- 29261338 TI - Caenorhabditis elegans: A Convenient In Vivo Model for Assessing the Impact of Food Bioactive Compounds on Obesity, Aging, and Alzheimer's Disease. AB - Caenorhabditis elegans is a small free-living nematode that lives in temperate soil environments. It has been widely employed as an animal model in research involving obesity, aging, and neurodegenerative diseases, including Alzheimer's disease, because of its various advantages, such as small size, large number of progeny, completely sequenced genome, and short life span, over traditional animal models of vertebrates. These benefits contribute to an ideal research model organism. In this review, we provide an introduction to C. elegans and its applications in obesity, aging, and Alzheimer's disease studies, with the aim of stimulating scientists to use C. elegans as an experimental model in various fields of research. PMID- 29261339 TI - Effects of a Mindfulness Task on Women's Sexual Response. AB - Mindfulness-based interventions are effective at improving symptoms of sexual dysfunction in women. The mechanisms by which mindfulness improves sexual function are less clear. The main objective of our study was to investigate the impact of a mindfulness task on sexual response in women. Forty-one women (mean age = 27.2, SD = 5.6) participated in two laboratory sessions that each included two erotic films and one attention task that were presented in counterbalanced order. Both attention tasks consisted of a six-minute audio recording of either a modified body scan, focusing on genital arousal sensations (mindfulness condition), or a visualization exercise. Subjective and genital sexual arousal were measured continuously during stimulus presentation. The mindfulness task led to greater subjective and lower genital arousal. The agreement of subjective and genital sexual arousal (i.e., concordance) was greater in the mindfulness condition. Trait mindfulness was related to lower sexual arousal but also greater sexual concordance in women. Mindfulness-based interventions that encourage women to focus on physical arousal sensations in the here and now may be associated with women's improved sexual function by enhancing feelings of sexual arousal during sexual activity and by increasing concordance between subjective and genital sexual arousal. PMID- 29261340 TI - Role of Tribulus terrestris in Male Infertility: Is It Real or Fiction? AB - Tribulus terrestris is an annual herb of the Zygophyllaceae family and is commonly known as Gokshur, Gokharu, or puncturevine. Flavonoids, alkaloids, saponins, lignin, amides, and glycosides are the main active phytoconstituents of this plant. Infertility is defined by the failure to conceive a child after one year or more of regular unprotected sexual intercourse. Infertility affects society at large and has a negative impact on the social and emotional aspects of the patient. This in-depth review presents several studies that evaluate the role of Tribulus terrestris in a chronological order to help us better understand the exact mechanism by which this herbal medicine acts in male infertility. In conclusion, the exact role of Tribulus terrestris in male infertility is still controversial and needs future double-blind placebo-controlled studies that deploy larger cohorts. PMID- 29261341 TI - Benefit requirements for substance use disorder treatment in state health insurance exchanges. AB - BACKGROUND: Established in 2014, state health insurance exchanges have greatly expanded substance use disorder (SUD) treatment coverage in the United States as qualified health plans (QHPs) within the exchanges are required to conform to parity provisions laid out by the Affordable Care Act and the Mental Health Parity and Addiction Equity Act (MHPAEA). Coverage improvements, however, have not been even as states have wide discretion over how they meet these regulations. OBJECTIVE: How states regulate SUD treatment benefits offered by QHPs has implications for the accessibility and quality of care. In this study, we assessed the extent to which state insurance departments regulate the types of SUD services and medications plans must provide, as well as their use of utilization controls. METHODS: Data were collected as part of the National Drug Abuse Treatment System Survey, a nationally-representative, longitudinal study of substance use disorder treatment. Data were obtained from state Departments of Insurance via a 15-minute internet-based survey. RESULTS: States varied widely in regulations on QHPs' administration of SUD treatment benefits. Some states required plans to cover all 11 SUD treatment services and medications we assessed in the study, whereas others did not require plans to cover anything at all. Nearly all states allowed the plans to employ utilization controls, but reported little guidance regarding how they should be used. CONCLUSION: Although some states have taken full advantage of the health insurance exchanges to increase access to SUD treatment, others seem to have done the bare minimum required by the ACA. By not requiring coverage for the entire SUD continuum of care, states are hindering client access to appropriate types of care necessary for recovery. PMID- 29261342 TI - The Prevalence and Gratification of Nude Self-Presentation of Men Who Have Sex with Men in Online-Dating Environments: Attracting Attention, Empowerment, and Self-Verification. AB - This study builds on research about the importance of body presentation among men who have sex with men (MSM) by exploring the phenomenon of nude body presentation in online dating environments. In a quantitative survey of N = 9,235 MSM users of a gay online dating site (ODS) in Germany, the prevalence of nude pictures and gratifications sought while displaying them were investigated. About two-thirds of the participants declared that they use nude pictures in their dating profiles, with only small differences in prevalence between members of different ages, education levels, and sexual orientation. Furthermore, the results indicate that the use of nudity is driven by three underlying gratifications: (1) Attracting attention, meaning that nudity is used to accelerate sexual outcomes from online dating use; (2) empowerment, meaning that nudity online serves as an environment for otherwise and elsewhere inhibited forms of body presentation; and (3) self-verification, whereby nudity is used as a means of receiving affirmation from others. Regression analyses are used to investigate associations of these gratifications with sociodemographics and online dating behavior. Findings are discussed in relation to earlier research on self-presentation as well as theories of body importance among gay men. While earlier research has mainly focused on the negative implications of body presentation (e.g., self objectification; reinforcing standards of beauty), the findings of this study hint that ODS may provide a platform for acts of nude body presentation that are not possible elsewhere and are thus accompanied by empowerment and self verification. PMID- 29261343 TI - Long-Term Hypoxic Tolerance in Murine Cornea. AB - : Kosaku, Kazuhiro, Tomonori Harada, Toyoharu Jike, Isao Tsuboi, and Shin Aizawa. Long-term hypoxic tolerance in murine cornea. High Alt Med Biol 19:35-41, 2018. AIMS: The cornea is believed to be an exceedingly sensitive organ to decreases in atmospheric oxygen concentrations. Previous corneal studies have shown the hypoxic tolerance of the cornea during short-term and local hypoxic exposure. This study investigated the tolerance of the cornea during long-term and systemic hypoxia. METHODS AND RESULTS: Mice were bred under normobaric normoxia or hypoxia (10% oxygen concentration) conditions for 140 days. The layer structure, surface microvilli, and glycogen granules in the corneal epithelium were examined on day 2 and on day 140. The layer and surface structures of the corneal epithelium were normally maintained during the long-term hypoxia. Hypoxic stress caused a decrease in the glycogen granules in the corneal epithelial cells. CONCLUSIONS: Maintenance of normal structures during long-term hypoxia suggests that the cornea has a high tolerance for hypoxic stress. The quantity of glycogen in corneal epithelial cells is considered an index of corneal hypoxia resistance. PMID- 29261345 TI - Suaeglaucin A, a new coumaronochromone from Suaeda glauca. AB - A new isoflavane, suaeglaucin A (1), which was isolated from the herb of Suaeda glauca (Bunge) Bunge, was elucidated as 5,6,8-trimethoxy-7- hydroxycoumaronochromone based on its MS and 1D and 2D NMR spectroscopic data. The structure of compound 1 was confirmed by X-ray crystallographic analysis. Five known compounds (2-6) were also isolated. All compounds were isolated for the first time from Chenopodiaceae. We found that compounds 2 and 4 possessed moderate antioxidant activity. PMID- 29261344 TI - Patterns of simultaneous and concurrent alcohol and marijuana use among adolescents. AB - BACKGROUND: Alcohol and marijuana are the most commonly used substances among adolescents but little is known about patterns of co-use. OBJECTIVES: This study examined patterns of concurrent (not overlapping) and simultaneous (overlapping) use of alcohol and marijuana among adolescents. METHODS: Data from US-national samples of 12th graders (N = 84,805, 48.4% female) who participated in the Monitoring the Future study from 1976 to 2016 and who used alcohol and/or marijuana in the past 12 months were used to identify latent classes of alcohol use, marijuana use, and simultaneous alcohol and marijuana (SAM) use. RESULTS: A four-class solution indicated four patterns of use among adolescents: (1) Simultaneous alcohol and marijuana (SAM) use with binge drinking and recent marijuana use (SAM-Heavier Use; 11.2%); (2) SAM use without binge drinking and with recent marijuana use (SAM-Lighter Use; 21.6%); (3) Marijuana use and alcohol use but no SAM use (Concurrent Use; 10.7%); and (4) Alcohol use but no marijuana or SAM use (Alcohol-Only Use; 56.4%). Membership in either SAM use class was associated with a higher likelihood of truancy, evenings out, and use of illicit drugs other than marijuana. SAM-Heavier Use, compared to SAM-Lighter Use, class members were more likely to report these behaviors and be male, and less likely to have college plans. CONCLUSIONS: Among 12th graders who use both alcohol and marijuana, the majority use simultaneously, although not all use heavily. Given the recognized increased public health risks associated with simultaneous use, adolescent prevention programming should include focus on particular risks of simultaneous use. PMID- 29261346 TI - Using the theoretical domains framework to identify barriers and enablers to pediatric asthma management in primary care settings. AB - OBJECTIVES: This study aimed to apply a theory-based approach to identify barriers and enablers to implementing the Alberta Primary Care Asthma Pediatric Pathway (PCAPP) into clinical practice. Phase 1 included an assessment of assumptions underlying the intervention from the perspectives of the developers. Phase 2 determined the perceived barriers and enablers for: 1) primary care physicians' prescribing practices, 2) allied health care professionals' provision of asthma education to parents, and 3) children and parents' adherence to their treatment plans. METHODS: Interviews were conducted with 35 individuals who reside in Alberta, Canada. Phase 1 included three developers. Phase 2 included 11 primary care physicians, 10 allied health care professionals, and 11 parents of children with asthma. Phase 2 interviews were based on the 14 domains of the Theoretical Domains Framework (TDF). Transcribed interviews were analyzed using a directed content analysis. Key assumptions by the developers about the intervention, and beliefs by others about the barriers and enablers of the targeted behaviors were identified. RESULTS: Eight TDF domains mapped onto the assumptions of the pathway as described by the intervention developers. Interviews with health care professionals and parents identified nine TDF domains that influenced the targeted behaviors: knowledge, skills, beliefs about capabilities, social/professional role and identity, beliefs about consequences, environmental context and resources, behavioral regulation, social influences, and emotions. CONCLUSIONS: Barriers and enablers perceived by health care professionals and parents that influenced asthma management will inform the optimization of the PCAPP prior to its evaluation. PMID- 29261347 TI - Common First-Pass CT Angiography Findings Associated With Rapid Growth Rate in Abdominal Aorta Aneurysms Between 3 and 5 cm in Largest Diameter. AB - OBJECTIVE: The purpose of this study was to describe CT angiography (CTA) findings of lumen contrast heterogeneity and intraluminal thrombus volume and to evaluate their relationship with rapid aneurysm growth in patients with abdominal aortic aneurysms (AAA) between 3 and 5 cm. MATERIALS AND METHODS: This institutional review board-approved and HIPAA-compliant single-center retrospective study included CTA studies obtained between January 2004 and December 2014 in 140 patients with AAA (101 men, 39 women; mean age +/- SD, 70 +/ 9 years old; age range, 22-87 years old). Standardized measurements for aneurysm intraluminal thrombus volume and a relatively new metric termed "lumen contrast heterogeneity" were obtained from the CTA images. AAA growth rate data were acquired from all subsequent cross-sectional studies. The association between the imaging findings and rapid aneurysm growth (> 0.4 cm/y) was evaluated using multivariate logistic regression. Patient comorbidities and medications were added to the regression model to assess for further associations with rapid growth rate. RESULTS: Using a baseline logistic regression model, lumen contrast heterogeneity (odds ratio [OR], 1.16; 95% CI, 1.05-1.32), intraluminal thrombus volume (OR, 2.15; 95% CI, 1.26-3.86), and maximum AAA diameter (OR, 1.69; 95% CI, 1.03-2.84) were independently associated with increased likelihood of rapid aneurysm growth. None of the patient comorbidities or medications were significantly associated with the outcome when added to the baseline model. CONCLUSION: Both intraluminal thrombus and lumen contrast heterogeneity are seen on AAA CTA studies and can be quantified; both of these metrics are independently associated with rapid growth rate and should be recognized by radiologists evaluating patients with AAA during surveillance. PMID- 29261349 TI - Screening for Lung Cancer: Lexicon for Communicating With Health Care Providers. AB - OBJECTIVE: The effectiveness of lung cancer screening with low-dose CT (LDCT) has been shown by multiple clinical trials, particularly the National Lung Screening Trial. Accurate communication of LDCT results to health care providers is critical to optimal patient care. CONCLUSION: The Lung CT Screening Reporting and Data System (Lung-RADS), a structured decision-oriented reporting system designed to minimize the rate of false-positive results and developed by the American College of Radiology, is recommended for use with all LDCT examinations. PMID- 29261350 TI - Screening for Lung Cancer: Effective Recruitment Methods. AB - OBJECTIVE: The U.S. Preventive Services Task Force recommendation and Centers for Medicare & Medicaid Services coverage decision have created a favorable environment for implementation of clinical population-wide lung cancer screening. The purpose of this article is to describe effective recruitment methods for clinical lung cancer screening programs, with a focus on addressing barriers to screening for socioeconomically disadvantaged communities. CONCLUSION: Large scale recruitment of high-risk individuals into screening programs across the country is essential to significantly decrease the mortality associated with lung cancer. Recruitment strategies must also be tailored to minority and underserved communities, because they are at the highest risk for developing lung cancer. PMID- 29261348 TI - MRI Features and IDH Mutational Status of Grade II Diffuse Gliomas: Impact on Diagnosis and Prognosis. AB - OBJECTIVE: Grade II diffuse gliomas (DGs) with isocitrate dehydrogenase (IDH) mutations are associated with better prognosis than their IDH wild-type counterparts. We sought to determine the MRI characteristics associated with IDH mutational status and ascertain whether MRI considered in combination with IDH mutational status can better predict the clinical outcomes of grade II DGs. MATERIALS AND METHODS: Preoperative MRI examinations were retrospectively studied for qualitative tumor characteristics, including location, extent, cortical involvement, margin sharpness, cystic component, mineralization or hemorrhage, and contrast enhancement. Quantitative diffusion and perfusion metrics were also assessed. Logistic regression and ROC analyses were used to evaluate the relationship between MRI features and IDH mutational status. The association between IDH mutational status, 1p19q codeletion, MRI features, extent of resection, and clinical outcomes was assessed by Kaplan-Meier and Cox proportional hazards models. RESULTS: Of 100 grade II DGs, 78 were IDH mutant and 22 were IDH wild type. IDH wild-type tumors were associated with older age, multifocality, brainstem involvement, lack of cystic change, and a lower apparent diffusion coefficient (ADC). Multivariable regression showed that age older than 45 years as well as low minimum ADC (ADCmin), mean ADC, and maximum ADC values were independently associated with IDH mutational status. Of these, an ADCmin threshold of 0.9 * 10-3 mm2/s or less provided the greatest sensitivity and specificity (91% and 76%, respectively) in defining IDH wild-type grade II DGs. Combining low ADCmin with IDH wild-type status conferred worse outcomes than did IDH wild-type status alone. CONCLUSION: IDH wild-type grade II DGs are associated with a lower ADC and poor clinical outcomes. Combining IDH mutational status and ADC may allow more accurate prediction of clinical outcomes for patients with grade II DGs. PMID- 29261351 TI - Clinical Value of CT Colonography Versus Preoperative Colonoscopy in the Surgical Management of Occlusive Colorectal Cancer. AB - OBJECTIVE: CT colonography (CTC) has been recognized as a complementary approach to evaluating the entire colon after incomplete colonoscopy (IC) in patients with occlusive colorectal cancer (CRC). The objective of this study is to evaluate changes in preoperative surgical planning after CTC is performed for patients with occlusive CRC and IC in an oncologic hospital. MATERIALS AND METHODS: This retrospective study included 65 consecutive patients with occlusive CRC who underwent CTC after IC at our institution from February 2000 to April 2016. CTC examinations and radiology reports were reviewed by an abdominal radiologist. Clinical information was obtained from a review of the electronic medical record. RESULTS: CTC contributed to a change in the initial surgical plan of the surgeon for 14 of 65 patients (21.5%). In these 14 patients, CTC detected five synchronous proximal colon polyps (35.7%), five synchronous proximal cancers (35.7%), two imprecise CRC locations (14.3%), one case of proximal colon ischemia (7.1%), and one instance of tumor infiltration of the urinary bladder (7.1%). All CTC findings were confirmed at surgery, and all proximal colon polyps were subsequently confirmed to be advanced adenomas. CONCLUSION: The preoperative CTC findings optimized the surgical management plan for 21.5% of patients with occlusive CRC and IC. PMID- 29261352 TI - Incrementally Expandable Transjugular Intrahepatic Portosystemic Shunts: Single Center Experience. AB - OBJECTIVE: The purpose of this study is to investigate the long-term safety and efficacy of a small-diameter expandable transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension. MATERIALS AND METHODS: This single-center retrospective study included 28 patients (12 women and 16 men; mean age, 56.9 years) who underwent small-diameter expandable TIPS creation between 2008 and 2010 for refractory ascites (n = 15; mean [+/- SD] model for end stage liver disease [MELD] score, 15.5 +/- 5.3) or gastrointestinal variceal bleeding (n = 13; mean MELD score, 15.2 +/- 8.4). An expandable TIPS was created by deploying a covered stent inside a balloon expandable stent. For patients with recurrent symptoms, TIPS adjustment was made by balloon expandable stent balloon dilation. The TIPS diameter was defined as the diameter of the final angioplasty balloon. TIPS patency and efficacy and the rate of post-TIPS hepatic encephalopathy were evaluated. RESULTS: The median diameter of the initial TIPS was 8 mm in the group with variceal bleeding compared with 6 mm in the group with ascites (p = 0.003). The primary patency rate at 1 and 5 years was 90.8% and 73.3%, respectively. Eighty percent of patients with ascites required no or less frequent large-volume paracentesis. The clinical success rate for patients with acute variceal bleeding was 92.3%. Six patients with ascites (initial TIPS diameter, 6 mm) and two patients with variceal bleeding (initial diameter, 6 mm and 8 mm) required subsequent TIPS adjustment. Of the 22 patients with no prior history of enecphalophy, seven patients (31.8%) experienced new hepatic encephalopathy within 90 days. CONCLUSION: A small-diameter expandable TIPS is technically feasible and safe, with efficacy falling within the range of that of conventional TIPS. This technique offers the possibility of individualizing the degree of portal decompression. PMID- 29261353 TI - Reference Values for Central Airway Dimensions on CT Images of Children and Adolescents. AB - OBJECTIVE: The purpose of this study was to acquire normative data on central airway dimensions on chest CT scans in the pediatric population. MATERIALS AND METHODS: Chest CT findings reported as normal by a radiologist were collected retrospectively at 10 international centers. An experienced and independent thoracic radiologist reevaluated all CT scans for image quality and for normal findings. Semiautomated image analysis was performed to measure dimensions of the trachea and right and left main bronchi at inspiration. Intrathoracic tracheal length was measured from carina to thorax inlet. Cross-sectional area and short and long axes were measured perpendicular to the longitudinal airway axis starting from the carina every centimeter upward for the trachea and every 0.5 cm downward for the main bronchi. The effects on airway diameters of age, sex, intrathoracic tracheal length, and distance from the carina were investigated by use of mixed-effects models analysis. RESULTS: Among 1160 CT scans collected, 388 were evaluated as normal by the independent radiologist with sufficient image quality and adequate inspiratory volume level. Central airways were successfully semiautomatically analyzed in 294 of 388 CT studies. Age, sex, intrathoracic tracheal length, and distance from carina were all significant predictors in the models for tracheal and right and left main bronchial diameters (p < 0.001). The central airway dimensions increased with age up to 20 years, and dimensions were larger in male than in female adolescents. CONCLUSION: Normative data were determined for the central airways of children and adolescents. Central airway dimensions depended on distance from the carina and on intrathoracic tracheal length. PMID- 29261355 TI - Practical Updates on Gastrointestinal Pathology From the CAMP 2017 Conference. PMID- 29261354 TI - Prospective Comparison of Standard- Versus Low-Radiation-Dose CT Enterography for the Quantitative Assessment of Crohn Disease. AB - OBJECTIVE: CT enterography (CTE) is sensitive and specific for active inflammatory changes of Crohn disease (CD), but its use has been limited by exposure to ionizing radiation. The objective of this study is to show the noninferiority of a model-based iterative reconstruction (MBIR) technique using lower radiation doses compared with standard-dose CTE in the assessment of CD. SUBJECTS AND METHODS: Patients referred to a hospital radiology department for CTE for the evaluation of CD underwent both a standard examination (used to generate filtered back-projection and adaptive statistical iterative reconstruction [ASIR] images) and low-dose MBIR CTE performed in a random sequence on the same day. Images were reviewed by two radiologists for signs of small-bowel CD. Radiologic findings obtained using ASIR and clinical assessments of disease activity served as the reference standard for comparison with low-dose CTE findings. RESULTS: A total of 163 patients, 92 (56.4%) of whom had active disease, underwent CTE. MBIR was found to be noninferior to the two standard-dose techniques, with no significant differences noted between the three types of images when compared with the clinical reference standard. As compared with the radiologic standard of ASIR, the very-low-dose scans had a high degree of accuracy, with sensitivity ranging from 0.85 to 0.94 and specificity ranging from 0.84 to 0.97 depending on the reader. A significant reduction in radiation exposure was noted with MBIR (mean [+/- SD] reduction, 3.30 +/- 3.17 mSv) versus standard-dose imaging (7.16 +/- 4.61 mSv; p < 0.001). CONCLUSION: Low-dose CTE using MBIR is sensitive and specific for the detection of active inflammatory changes of CD while utilizing radiation doses substantially lower than those associated with standard techniques. PMID- 29261357 TI - JPA at Volume 100. PMID- 29261358 TI - Society for Personality Assessment/Journal of Personality Assessment: A History. PMID- 29261359 TI - Mapping AcroQoL scores to EQ-5D to obtain utility values for patients with acromegaly. AB - AIMS: To estimate a preference-based single index for the disease-specific instrument (AcroQoL) by mapping it onto the EQ-5D to assist in future economic evaluations. MATERIALS AND METHODS: A sample of 245 acromegaly patients with AcroQoL and EQ-5D scores was obtained from three previously published European studies. The sample was split into two: one sub-sample to construct the model (algorithm construction sample, n = 184), and the other one to confirm it (validation sample, n = 61). Various multiple regression models including two part model, tobit model, and generalized additive models were tested and/or evaluated for predictive ability, consistency of estimated coefficients, normality of prediction errors, and simplicity. RESULTS: Across these studies, mean age was 50-60 years and the proportion of males was 36-59%. At overall level the percentage of patients with controlled disease was 37.4%. Mean (SD) scores for AcroQoL Global Score and EQ-5D utility were 62.3 (18.5) and 0.71 (0.28), respectively. The best model for predicting EQ-5D was a generalized regression model that included the Physical Dimension summary score and categories from questions 9 and 14 as independent variables (Adj. R2 = 0.56, with mean absolute error of 0.0128 in the confirmatory sample). Observed and predicted utilities were strongly correlated (Spearman r = 0.73, p < .001) and paired t-Student test revealed non-significant differences between means (p > .05). Estimated utility scores showed a minimum error of <=10% in 45% of patients; however, error increased in patients with an observed utility score under 0.2. The model's predictive ability was confirmed in the validation cohort. LIMITATIONS AND CONCLUSIONS: A mapping algorithm was developed for mapping of AcroQoL to EQ-5D, using patient level data from three previously published studies, and including validation in the confirmatory sub-sample. Mean (SD) utilities index in this study population was estimated as 0.71 (0.28). Additional research may be needed to test this mapping algorithm in other acromegaly populations. PMID- 29261360 TI - Precision Medicine: Functional Advancements. AB - Precision medicine was conceptualized on the strength of genomic sequence analysis. High-throughput functional metrics have enhanced sequence interpretation and clinical precision. These technologies include metabolomics, magnetic resonance imaging, and I rhythm (cardiac monitoring), among others. These technologies are discussed and placed in clinical context for the medical specialties of internal medicine, pediatrics, obstetrics, and gynecology. Publications in these fields support the concept of a higher level of precision in identifying disease risk. Precise disease risk identification has the potential to enable intervention with greater specificity, resulting in disease prevention-an important goal of precision medicine. PMID- 29261361 TI - Voluntary termination of pregnancy: An opportunity for Measles, Mumps and Rubella vaccination in an Italian healthcare local unit. AB - In Italy, the National Plan for the Elimination of Measles and Congenital Rubella 2010-15 suggests offering Measles, Mumps and Rubella (MMR) vaccination to susceptible women who underwent voluntary termination of pregnancy (VTP) In Rome, S. Eugenio Hospital is one of the structures where VTP is practised in an Operative Unit called "Family Planning" The primary goal of this study was to estimate the prevalence of susceptibility to rubella, using IgG and IgM immunoassays, among women accessing VTP and to offering MMR vaccination to susceptible women. Secondarily, this study evaluated acceptance of the vaccination offer From 2013 to 2015, data were collected from 1513 voluntary termination of pregnancy (VTP) cases The results show a significant increase of 5 percent in susceptibility prevalence in the target group from 13.6% in 2013 and 2014 to 18.4% in 2015 The association between rubella susceptibility and age was statistically significant (p<0.01) Throughout the entire period, acceptance of the vaccine proposal was 19% (45/232) among susceptible women; 58% (135/232) refused the vaccine and 23% (52/232) took time to think about it This study shows an increase of 5 percent in the prevalence of rubella susceptibility over two years. This result is worrying, even considering the short span of the data collection The rate of acceptance of vaccination is unsatisfactory considering the possibility of future pregnancies This issue deserves continued action, which, going forward, might transform a "project" into a shared strategy as part of a wider network with the goal of aligning Italy with international recommendations. PMID- 29261362 TI - Rewiring to Regain Function in Patients with Spastic Hemiplegia. PMID- 29261363 TI - The Regulatory Accountability Act of 2017 - Implications for FDA Regulation and Public Health. PMID- 29261364 TI - TP53 codon 72 polymorphism and the risk of glaucoma in a north Indian cohort: A genetic association study. AB - BACKGROUND: The TP53 codon 72 Proline-Arginine polymorphism (TP53 P72R) is the most widely studied candidate among those evaluated for a putative association between impaired apoptosis and glaucoma. Considering the earlier findings about enhanced apoptotic potential by the Arg variant of TP53 P72R and the conflicting results about its association with glaucoma, we initiated a hospital-based case control association study in a north Indian cohort to investigate the association of TP53 P72R with glaucoma. MATERIALS AND METHODS: We examined the status of TP53 P72R in 139 cases of primary open angle glaucoma (POAG) and in 111 cases of primary angle closure glaucoma (PACG) with respect to 218 controls using the polymerase chain reaction-restriction fragment length polymorphism method. Logistic regression analysis including age and gender as covariates was carried out to test the association of the polymorphism with overall glaucoma, POAG, and PACG cases. RESULTS: We observed significant differences between the genotypic distributions of combined glaucoma cases and controls in the recessive model. POAG cases with respect to controls did not exhibit any significant differences in the genotypic distributions. In contrast, the genotypic distributions as per the additive and recessive models in PACG cases were significantly different from those in controls. The two models suggested an increased risk of PACG in the Arg homozygotes of the investigated cohort. CONCLUSIONS: Ours is the first study demonstrating the association of TP53 P72R with the risk of PACG. It emphasizes that apart from narrow anterior chamber angle, impaired apoptotic mechanisms could also be an important contributor toward PACG. PMID- 29261366 TI - Round Table: Charting the Factors of Fatness. PMID- 29261365 TI - Stalking the Vulnerable Epiphysis. PMID- 29261367 TI - High-Powered Rifle Shooting: A Solitary Sport. PMID- 29261368 TI - Hydroplaners' Doctors Keep A Full Kit - and Crossed Fingers. PMID- 29261369 TI - sIndians Stretch for Strength. PMID- 29261370 TI - Those Viral Skin Infections Can Run Wild. PMID- 29261371 TI - Heat Peril in Distance Runs Spurs ACSM Guideline Alert. PMID- 29261373 TI - The Abuses of Orthotics in Sports Medicine. PMID- 29261372 TI - Why Should We Exercise? PMID- 29261374 TI - Unseen Hazards Injure Minibikers. PMID- 29261376 TI - sportspages. PMID- 29261375 TI - Weight Loss Camps: The Pounds Come Off, But Then What? PMID- 29261377 TI - The Heart of the Matter. PMID- 29261379 TI - One Man's Way Into Sports Medicine. PMID- 29261378 TI - When Wrestlers Fast. PMID- 29261380 TI - letters. PMID- 29261381 TI - scanning sports. PMID- 29261383 TI - Strength Imbalance and Knee Injury. PMID- 29261382 TI - Cross-Country Ski Injuries. AB - Although Nordic skiing is generally considered safe, it is not without risk. Most injuries are to the upper body, but Dr. Lyons reports some severe lower extremity injuries. PMID- 29261384 TI - Exercise and HDL Cholesterol in Middle-Aged Men. AB - Raising high-density lipoprotein levels with exercise seems to protect against coronary heart disease. Dr. Hartung attempts to show how much exercise is necessary. PMID- 29261385 TI - Resined Fiberglass Cast for Carpal Navicular Fractures. AB - An easily applied resined fiberglass navicular cast remains firm when patients engage in normal activities, including bathing, and because it is porous, their skin stays dry. PMID- 29261386 TI - editor's notes. PMID- 29261387 TI - Exercise-Induced Anaphylaxis. AB - Sportsmedicine personnel should be able to differentiate this syndrome from other exertional reactions. PMID- 29261388 TI - letters. PMID- 29261389 TI - Case Report: Rehabilitation After Heat Stroke. AB - Enzyme levels, a graduated running program, and stress tests played important roles in the rehabilitation of a heat stroke victim. PMID- 29261390 TI - brief reports. PMID- 29261391 TI - Head Trauma in Football Players with Infectious Mononucleosis. AB - Are football players who have infectious mononucleosis more susceptible to cerebral disorders from minor head trauma? The authors discuss three case reports. PMID- 29261393 TI - Lake Placid Prepares for Winter Olympics. AB - A tiny town tucked in the mountains seems an unlikely candidate for an international sports event, especially when it is far removed from medical facilities. Dr. Hixson describes how the challenge was met. PMID- 29261394 TI - a need to know. PMID- 29261395 TI - Physical Education: Integrating the Handicapped. AB - Schools are gearing up to improve physical education for handicapped children. Teachers and administrators will need doctors' help for success. PMID- 29261396 TI - A Foolish and Passionate Runner. PMID- 29261397 TI - A 'Crash Course' in Sportsmedicine. AB - The wide variety of services offered by the Sports Medicine Clinic of Seattle parallels the different disciplines in the specialty. The completion of its first fellowship adds a new dimension. PMID- 29261399 TI - The Female Athlete in Long-Distance Running. PMID- 29261398 TI - Olympic Drug Abuse. PMID- 29261400 TI - The Muscle Biopsy: Still a Research Tool. AB - Needle biopsies show relationships between some characteristics of skeletal muscle fibers and athletic performance, but the present data don't establish any of them as predictors of athletic success. PMID- 29261401 TI - Prevalence of and Comorbid Health Conditions Associated With Pediatric Prescription Opioid Use in the US. AB - Prescription opioids are among the most effective analgesics to treat moderate to severe pain; however, little is known about the use of prescription opioids in children, particularly those receiving an extended-release formulation for the treatment of chronic pain. In this retrospective study, the authors determined the prevalence of prescription opioid use among 7-17-year-old children and associated comorbid health conditions from 2010 to 2013 using Truven Health MarketScan (MarketScan) and Optum Clinformatics DataMart (Optum). The primary end points were prevalence of using any prescription opioids, using only prescription short-acting opioids (SAOs), and at least one prescription of a long-acting opioid (LAO). The prevalence of prescription opioid use among children is non negligible and has been trending downwards: 6.90% in 2010 and 5.93% in 2013 using MarketScan and a similar trend using Optum: 5.47% in 2010 and 4.51% in 2013. Very few children had claims for LAOs, with only 0.04% (4979 children) in MarketScan and 0.03% (1117 children) in Optum. Given the very small number of children, primarily in the 12-17 age group, who are prescribed LAOs, there is a need to focus on a better understanding of the patterns of SAO use in children. PMID- 29261402 TI - Oral Versus Nasal High-Flow Bronchodilator Inhalation in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Nasal high flow (NHF) alters breathing patterns, stabilizes fraction of inspired oxygen (FiO2) during respiratory distress, helps to keep up hemostasis in the airways, and washes out the upper airways. Particularly the support of inspiratory flow and decrease in functional dead space are interesting mechanisms of action with regard to aerosol delivery. Several laboratory investigations have studied aerosol delivery via the nasal route by using NHF, whereas clinical benefits are poorly evaluated. METHODS: Thirty patients with stable chronic obstructive pulmonary disease Gold D were recruited. In a randomized order, they inhaled a salbutamol 2.5 mg/ipratropium bromide 500 MUg solution oral or NHF adapted on the second study day. A jet nebulizer was used as aerosol delivery device. The chosen flow rate was 35 L/min. RESULTS: Four patients refused to repeat the procedure, for example, for inconvenience or fear of delayed discharge, and were not included in the intention-to-treat analysis. All remaining patients tolerated both inhalation systems well. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), airway resistance (Rtot), and residual volume (RV) were significantly altered after bronchodilator inhalation with each of the both devices. The two different ways of combined bronchodilator inhalation resulted in very comparable changes in FVC, FEV1, relative 1 second-capacity (FEV1%FVC), Rtot, total lung capacity (TLC), RV, and residual volume expressed as percent of TLC (RV%TLC). However, in between devices, no difference was observed on comparing the postinhalational measurements of FVC, FEV1, Rtot, and RV. CONCLUSIONS: We conclude from this proof of-principle kind of study that inhalation of combined bronchodilators adapted to an NHF device is similarly effective to inhalation with a standard oral aerosol nebulizer. (Clinical Trails NCT02885103). PMID- 29261403 TI - Plague in Madagascar - A Tragic Opportunity for Improving Public Health. PMID- 29261404 TI - Hypothalamic GRP78, a new target against obesity? AB - The chaperone GRP78 (glucose related protein 78), also called BiP (binding immunoglobulin protein) is a key regulator of endoplasmic reticulum (ER) stress. We recently described that over-expression of GRP78 specifically in the ventromedial nucleus of the hypothalamus (VMH) releases hypothalamic ER stress in rodent obese models leading to weight loss, reduced hepatic steatosis and improved insulin and leptin sensitivity. The action of GRP78 is mediated by a feeding-independent mechanism involving increased sympathetic tone, augmented brown adipose tissue (BAT) thermogenesis and induction browning of white adipose tissue (WAT). PMID- 29261405 TI - Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug Resistant Pseudomonas aeruginosa Clinical Isolates. AB - Pseudomonas aeruginosa, a Gram-negative bacterium, is a member of the ESKAPE pathogens and one of the leading causes of healthcare-associated infections worldwide. Aminoglycosides (AGs) are recognized for their efficacy against P. aeruginosa. The most common resistance mechanism against AGs is the acquisition of AG-modifying enzymes (AMEs) by the bacteria, including AG N-acetyltransferases (AACs), AG O-phosphotransferases (APHs), and AG O-nucleotidyltransferases (ANTs). In this study, we obtained 122 multidrug-resistant P. aeruginosa clinical isolates and evaluated the antibacterial effects of six AGs and two carbapenems alone against all clinical isolates, and in combination against eight selected strains. We further probed for four representatives of the most common AME genes [aac(6')-Ib, aac(3)-IV, ant(2")-Ia, and aph(3')-Ia] by polymerase chain reaction (PCR) and compared the AME patterns of these 122 clinical isolates to their antibiotic resistance profile. Among the diverse antibiotics resistance profile displayed by these clinical isolates, we found correlations between the resistance to various AGs as well as between the resistance to one AG and the resistance to carbapenems. PCR results revealed that the presence of aac(6')-Ib renders these isolates more resistant to a variety of antibiotics. The correlation between resistance to various AGs and carbapenems partially reflects the complex resistance strategies adapted in these pathogens and encourages the development of strategic treatment for each P. aeruginosa infection by considering the genetic information of each isolated bacteria. PMID- 29261407 TI - Adolescent Waterpipe Use is Associated with Greater Body Weight: The Irbid-TRY. AB - BACKGROUND: Adult waterpipe smokers are at increased risk of obesity. However, it is unclear if adolescents, who are at the epicenter of the global waterpipe epidemic, are at similar risk. OBJECTIVE: Therefore, the current study examined the waterpipe smoking relationship with obesity among adolescents. METHODS: A sample of 2,313 boys and girls in grades 7-10 were surveyed about waterpipe and cigarette use in Jordan. Weight, body mass index (BMI), waist circumference, waist-to-hip ratio, and waist-to-height ratio were measured. Obesity indices were assessed as a function of smoking status (never used tobacco, current waterpipe only, current cigarettes only, and current dual smoking) as well as frequency of use of each tobacco product. RESULTS: About 51.5% of adolescents smoked waterpipe whereas 29.8% were overweight/obese. Students who smoked waterpipe weekly had twofold greater odds of being obese than never-smokers (OR = 2.14; 95% CI = 1.08 4.21). Approximately 12% of students currently smoked waterpipe but not cigarettes, 2% smoked cigarettes but not waterpipe, and 11% smoked both. Body weight and age- and gender-specific BMI were greater for waterpipe and dual users compared to never users, especially for dual vs. never users (58.6 +/-.8 vs. 55.6 +/-.4 and.48 +/-.07 vs..29 +/-.03, respectively; p <.005). CONCLUSIONS: For dual users, greater frequency of tobacco use was associated with greater weight and BMI. Waterpipe and dual use is associated with greater obesity, BMI, and body weight among Jordanian adolescents. Given the rising epidemics of both tobacco use and obesity among Middle Eastern adolescents, the clustering of these risk factors warrants public health action. PMID- 29261408 TI - Big Data in Public Health: Terminology, Machine Learning, and Privacy. AB - The digital world is generating data at a staggering and still increasing rate. While these "big data" have unlocked novel opportunities to understand public health, they hold still greater potential for research and practice. This review explores several key issues that have arisen around big data. First, we propose a taxonomy of sources of big data to clarify terminology and identify threads common across some subtypes of big data. Next, we consider common public health research and practice uses for big data, including surveillance, hypothesis generating research, and causal inference, while exploring the role that machine learning may play in each use. We then consider the ethical implications of the big data revolution with particular emphasis on maintaining appropriate care for privacy in a world in which technology is rapidly changing social norms regarding the need for (and even the meaning of) privacy. Finally, we make suggestions regarding structuring teams and training to succeed in working with big data in research and practice. PMID- 29261406 TI - Effectiveness and practical uses of 23-valent pneumococcal polysaccharide vaccine in healthy and special populations. AB - Streptococcus pneumonia (S. pneumoniae) is responsible for significant morbidity and mortality throughout the world. The 23-valent pneumococcal polysaccharide vaccines (PPV23) have been widely used for many years, but challenges are remaining in some respects, especially for its effectiveness among high-risk populations and older adults. This review aims to summarize recent clinical trials and studies of PPV23 vaccination among healthy people >= 2 years of age and those with high-risk conditions such as pregnant women, individuals with immunocompromising diseases and other chronic conditions, and provide health officials in China and other developing countries a comprehensive understanding of the current vaccination strategies for PPV23 and for the combined use of PPV23 and pneumococcal conjugate vaccines (PCVs) in adults. PMID- 29261409 TI - Cell Biology of T Cell Receptor Expression and Regulation. AB - T cell receptors (TCRs) are protein complexes formed by six different polypeptides. In most T cells, TCRs are composed of alphabeta subunits displaying immunoglobulin-like variable domains that recognize peptide antigens associated with major histocompatibility complex molecules expressed on the surface of antigen-presenting cells. TCRalphabeta subunits are associated with the CD3 complex formed by the gamma, delta, epsilon, and zeta subunits, which are invariable and ensure signal transduction. Here, we review how the expression and function of TCR complexes are orchestrated by several fine-tuned cellular processes that encompass (a) synthesis of the subunits and their correct assembly and expression at the plasma membrane as a single functional complex, (b) TCR membrane localization and dynamics at the plasma membrane and in endosomal compartments, (c) TCR signal transduction leading to T cell activation, and (d) TCR degradation. These processes balance each other to ensure efficient T cell responses to a variety of antigenic stimuli while preventing autoimmunity. PMID- 29261412 TI - Football Injury Update-1979 Season. AB - Improved conditioning, rule changes, and a helmet standard helped reduce football fatalities to an all-time low in 1979. PMID- 29261411 TI - Why Genetic Effects of Radiation are Observed in Mice but not in Humans. AB - Genetic effects from radiation have been observed in a number of species to date. However, observations in humans are nearly nonexistent. In this review, possible reasons for the paucity of positive observations in humans are discussed. Briefly, it appears likely that radiation sensitivity for the induction of mutations varies among different genes, and that the specific genes that were used in the past with the specific locus test utilizing millions of mice may have simply been very responsive to radiation. In support of this notion, recent studies targeting the whole genome to detect copy number variations (deletions and duplications) in offspring derived from irradiated spermatogonia indicated that the mutation induction rate per genome is surprisingly lower than what would have been expected from previous results with specific locus tests, even in the mouse. This finding leads us to speculate that the lack of evidence for the induction of germline mutations in humans is not due to any kind of species differences between humans and mice, but rather to the lack of highly responsive genes in humans, which could be used for effective mutation screening purposes. Examples of such responsive genes are the mouse coat color genes, but in human studies many more genes with higher response rates are required because the number of offspring examined and the radiation doses received are smaller than in mouse studies. Unfortunately, such genes have not yet been found in humans. These results suggest that radiation probably induces germline mutations in humans but that the mutation induction rate is likely to be much lower than has been estimated from past specific locus studies in mice. Whole genome sequencing studies will likely shed light on this point in the near future. PMID- 29261410 TI - Cross Talk between Radiation and Immunotherapy: The Twain Shall Meet. AB - There has been increased interest in the immune stimulatory properties of ionizing radiation based on several preclinical models and recently completed clinical studies performed in combination with checkpoint inhibitors. This is a paradigm shift in that it considers the role of radiation beyond its direct cytotoxic effects, however, the factors that promote or limit radiation-induced immunogenicity are still unclear. Here we review the role of radiation in modulating the various aspects of the tumor immune microenvironment and discuss in particular the direct effects of radiation on the DNA damage response and its immediate consequences to neighboring cells. The latter "danger response" in particular can enhance recruitment of dendritic and macrophage cells to the tumor microenvironment, which in turn can activate or diminish subsequent T-cell priming. Identification of the critical factors that modulate the interaction between radiation-induced cell damage and the immune system will allow for rational combinational therapy design and the development of biomarkers that predict effective immune responses. PMID- 29261415 TI - Evaluation of Sports Bras. AB - All sports bras are designed to minimize breast movement and discomfort during strenuous activity, but some do a better job than others. PMID- 29261414 TI - Injuries in Karate. AB - Protective equipment and enlightened attitudes could help prevent most karate injuries. PMID- 29261413 TI - Energy Metabolism in Diabetic Distance Runners. AB - The authors discuss chronic effects of serious endurance training on the management of diabetes and recommend ways of adjusting insulin administration to accommodate training schedules. PMID- 29261416 TI - Helmet Reconditioning: Does NOCSAE Ensure Safety? AB - NOCSAE standards certify that reconditioned football helmets can withstand impact during games, but critics question whether the helmets are safe. PMID- 29261417 TI - letters. PMID- 29261418 TI - Walking for Rehabilitation: The First Step. AB - Walking can be a positive approach for patients in rehabilitation programs. They can condition themselves, lose weight, and relieve stress without risking musculoskeletal problems. PMID- 29261421 TI - brief reports. PMID- 29261420 TI - a need to know. PMID- 29261422 TI - Removing Football Helmets Safely. PMID- 29261423 TI - scanning sports. PMID- 29261424 TI - Psychosocial Boredom. PMID- 29261425 TI - Selective Perception at Work. PMID- 29261426 TI - Examination of the Acutely Injured Knee. AB - Diagnosing an acute ligament tear is difficult for physicians who don't regularly deal with the knee. This article outlines the procedures for differentiating treatable injuries from those requiring more specialized care. PMID- 29261427 TI - Addiction Vulnerability: Exploring Relationships Among Cigarette Smoking, Substance Misuse, and Early Psychosis. AB - OBJECTIVE: Smoking rates in adolescents at risk for psychosis are significantly greater than in those who are not at risk. Recent research suggests that cigarette smoking in adolescence may be a potential marker of transition to psychosis, although the exact relationship between the two remains unclear. Our aim was to examine whether tobacco smoking is a potential marker of transition to psychosis or subsequent episodes of psychosis, independently of other substance use, or alternatively whether smoking is essentially a general marker of later mental illness episodes. METHODS: This substudy was conducted as part of an audit of a specialized early psychosis community mental health service, the Psychological Assistance Service (PAS). A multilayered audit over 10 years (January 1997 to December 2007) of PAS presentations was conducted (N = 1997), which documented baseline sociodemographic and clinical characteristics and subsequent illness episodes and service usage. Among clients with baseline smoking status information (n = 421, mean age = 18.3 years), this study examined predictors of transition to or subsequent episodes of psychosis, substance misuse, and affective disorder. RESULTS: A recent psychosis episode at baseline and receiving ongoing treatment from PAS predicted transition to or subsequent psychosis episodes; however, baseline ultra-high-risk status was not predictive. In addition, baseline smoking/substance misuse status was a significant predictor, with smokers being twice as likely to experience a subsequent episode of psychosis, even after controlling for other baseline comorbidity. Baseline smoking status also independently predicted subsequent substance misuse episodes, but not subsequent affective disorder. Among clients experiencing post-PAS comorbid substance misuse and psychosis, the majority (80.3%) reported smoking at baseline. CONCLUSIONS: Smoking status at service presentation appeared to function as a general proxy for addiction vulnerability among young help seekers and thereby as a potential marker for the development of severe mental illness (including psychosis) and associated health problems. Routine evaluations of presenting problems need to incorporate comprehensive assessments of early substance misuse and tobacco smoking. Adjunctive lifestyle interventions promoting smoking cessation, physical health, and well-being need to be offered in conjunction with conventional mental health interventions tailored to key presenting problems, recovery, and psychological strengthening. PMID- 29261428 TI - First Characterization of PAH-degrading bacteria from Rio de la Plata and high resolution melting: an encouraging step toward bioremediation. AB - The Rio de la Plata, one of the most important estuarine environments in South America that sustains valuable fisheries, is affected by PAH contamination associated with oil industry and port activities. A total of 95 bacteria with potential to degrade phenanthrene were obtained from water samples using traditional culture methods. PCR-RFLP analysis of 16S rDNA partial fragments was used as a screening tool for reducing the number of isolates during diversity studies, obtaining 42 strains with different fingerprint patterns. Phylogenetic analysis indicated that they were affiliated to 19 different genera of Gamma- and Alpha-Proteobacteria, and Actinobacteria. Some of them showed an efficient phenanthrene degradation by HPLC (between 83% and 97%) and surfactant production (between 40% and 55%). They could be an alternative for microbial selection in the degradation of PAHs in this estuarine system. In order to detect and monitor PAH-degrading bacteria in this highly productive area, rDNA amplicons of the 33 isolates, produced by PCR real time, were tested by the high-resolution melting (HRM) technique. After analyzing the generated melting curves, it was possible to accurately distinguish nine patterns corresponding to eight different genera. HRM analysis allowed a differentiation at the species level for genera Pseudomonas, Halomonas and Vibrio. The implementation of this method as a fast and sensitive scanning approach to identify PAH-degrading bacteria, avoiding the sequencing step, would mean an advance in bioremediation technologies. PMID- 29261430 TI - Investigating the Effects of Mass Media Exposure on the Uptake of Preventive Measures by Hong Kong Residents during the 2015 MERS Outbreak: The Mediating Role of Interpersonal Communication and the Perception of Concern. AB - In 2015, South Korea experienced the largest outbreak to date of the Middle East Respiratory Syndrome (MERS-CoV) outside the Middle East. Fears related to a potential spread of the disease led to an increased alert level as well as heightened media coverage in the neighboring Hong Kong. A cross-sectional survey (N = 533) among residents of Hong Kong was conducted to assess the relationships between the effects of outbreak-related mass media coverage, interpersonal communication, the perceived level of concern in one's close environment, and the uptake of preventive measures. A serial multiple mediator model finds that interpersonal communication and higher perceived concern indirectly influence the effects of media coverage on the engagement in preventive actions. These results expand previous research on the mediating role of interpersonal communication and support assumptions about a modified two-step flow of communication in the context of a public health emergency. PMID- 29261429 TI - Baseline Intraocular Pressure Is Associated With Subjective Sensitivity to Physical Exertion in Young Males. AB - PURPOSE: The purposes of this study were to (a) investigate the effect of physical effort (cycling for 60 min at 60 +/- 5% of individually computed reserve heart-rate capacity), combined with 2 different levels of cognitive demand (2 back, oddball), on intraocular pressure (IOP) and subjective judgments of perceived exertion (ratings of perceived exertion [RPE]), affect (Affective Valence subscale of the Self-Assessment Manikin [SAM]), and mental workload (National Aeronautics and Space Administration Task Load Index [NASA-TLX]); and (b) ascertain whether baseline IOP, measured before exercise, is associated with individual differences in subjective assessments of effort and affective response during exercise. METHOD: Seventeen participants (Mage = 23.28 +/- 2.37 years) performed 2 physical/cognitive dual tasks, matched in physical demand but with different mental requirements (2-back, oddball). We assessed IOP before exercise, after 2 min of active recovery, and after 15 min of passive recovery, and we also collected RPE and SAM measures during the sessions (28 measurement points). We used NASA-TLX and cognitive performance as checks of the mental manipulation. RESULTS: (a) Intraocular pressure increased after concomitant physical/mental effort, with the effect reaching statistical significance after the 2-back task (p = .002, d = 0.35) but not after the oddball condition (p = .092, d = 0.29). (b) Baseline IOP was associated with subjective sensitivity to effort and showed statistical significance for the oddball condition (p = .03, np2 = .622) but not for the 2-back task (F < 1). CONCLUSIONS: Results suggest a relationship between IOP and physical/cognitive effort, which could have implications for the management of glaucoma. Additionally, a rapid measure of IOP could be used as a marker of individual effort sensitivity in applied settings. PMID- 29261431 TI - Correction to: Peer-Reviewed Symposia. PMID- 29261432 TI - Entering the Field of Physical Education: The Journey of Fifteen First-Year Teachers. AB - PURPOSE: Given the significant challenges facing today's physical educators, the purpose of this study was to examine the expectations of induction teachers and identify the factors in both their personal and organizational environments enhanced or constrained their assimilation into the field during their 1st year. METHOD: Using occupational socialization theory as a guide, data from demographic surveys and a series of formal interviews with participants at the beginning, middle, and end of the school year were inductively analyzed for theme development. RESULTS: Results revealed positive acculturation experiences and unity regarding the purpose of physical education as preparing students to be fit for a lifetime. Barriers were noted to be family and personal crises, role conflict, isolation, marginalization, issues with classroom management and discipline, and difficulties in developing positive relationships with stakeholders. Enhancers were identified as positive interactions and rapport with students, colleagues, and administrators and favorable individual dispositions. CONCLUSION: Implications indicate a need for purposeful physical education teacher education training to proactively address these barriers during professional preparation as well as the creation of additional support systems for beginning teachers. PMID- 29261433 TI - Forgiveness and Suicidal Behavior: Cynicism and Psychache as Serial Mediators. AB - Research is burgeoning regarding the beneficial association of forgiveness with numerous health-related outcomes; however, its particular relationship to suicidal behavior has received relatively little attention. Both cynicism and psychache, or agonizing psychological pain, have displayed deleterious associations with suicidal behavior, but have rarely been incorporated into more comprehensive models of suicidal behavior. Consistent with the recent development of a theoretical model regarding the forgiveness-suicidal behavior association, the present study utilized an undergraduate sample of college students (N = 312) to test a mediation-based model of the cross-sectional association of forgiveness with suicidal behavior, as serially mediated by cynicism and psychache. Dispositional forgiveness of self and forgiveness of uncontrollable situations were each indirectly associated with less suicidal behavior via less psychache. Also, dispositional forgiveness of others was indirectly associated with less suicidal behavior via less cynicism and less psychache, in a serial fashion. The present results are consistent with the extent literature on the forgiveness suicidal behavior association, cynicism, and psychache, and pending future studies, may be utilized to inform further treatment efforts for individuals at a high risk of attempting suicide. PMID- 29261434 TI - Family conflict and future concerns: Opportunities for social workers to better support Chinese immigrant caregiver employees. AB - This paper explores the experiences of Chinese immigrant caregiver employees (CEs) residing in Southern Ontario, Canada. Qualitative analysis of participant interviews with thirteen Mandarin Chinese immigrant CEs revealed family conflicts due to cultural differences and an intergenerational gap between CEs and their care recipients. CEs also had future concerns in regards to their own health and the lack of long-term care facilities that offer cultural services for immigrant seniors. These findings provide an opportunity for social workers to collaborate with other service providers to provide ethno-specific and culturally sensitive health, community. and employment services to immigrant ethnic minority CEs. PMID- 29261435 TI - Understanding Q Fever Risk to Humans in Minnesota Through the Analysis of Spatiotemporal Trends. AB - Q fever is a widely distributed, yet, neglected zoonotic disease, for which domestic ruminants are considered the main reservoirs in some countries. There are still many gaps in our knowledge of its epidemiology, and the source of sporadic cases is often not determined. In this study, we show how Q fever surveillance data in combination with information routinely collected by government agencies in Minnesota during 1997 to 2015 can be used to characterize patterns of occurrence of Q fever illnesses and detect variables potentially associated with increased human illness. Cluster analysis and Bayesian spatial regression modeling revealed the presence of areas in Southern Minnesota at higher risk of Q fever. The number of sheep flocks at the county level helped to explain the observed number of human cases, while no association with the cattle or goat population was observed. Our results provide information about the heterogeneous spatial distribution of risk of Q fever in Minnesota. PMID- 29261436 TI - A qualitative exploration of veteran and family perspectives on medical foster homes. AB - Since 2008, the Veterans Health Administration Medical Foster Home (MFH) program has served as an alternative to nursing home care for Veterans. As part of a larger national research study, 55 in-person interviews with 62 Veterans and/or their families were conducted to identify reasons for selecting or declining MFH placement. Enrollment was attributed to: a need for increased care and a preference for highly individualized care oversight and family-oriented settings. Reasons for declining placement included: costs, location of MFHs, lack of readiness of family or Veteran to move, and level of confidence that MFHs would meet care needs. Experiences and perspectives regarding advantages and challenges of the MFH program are also described. PMID- 29261437 TI - Recovery Responses to Maximal Exercise in Healthy-Weight Children and Children With Obesity. AB - PURPOSE: The purpose of this study was to examine differences in heart rate recovery (HRRec) and oxygen consumption recovery (VO2 recovery) between young healthy-weight children and children with obesity following a maximal volitional graded exercise test (GXTmax). METHOD: Twenty healthy-weight children and 13 children with obesity completed body composition testing and performed a GXTmax. Immediately after the GXTmax, HRRec and VO2 recovery were measured each minute for 5 consecutive minutes. RESULTS: There were no statistically significant group differences in HRRec for the 5 min following maximal exercise, Wilks's Lambda = .885, F(4, 28) = 0.911, p = .471, between the healthy-weight children and children with obesity despite statistically significant differences in body fat percentage (BF%; healthy-weight children, 18.5 +/- 6.1%; children with obesity, 41.1 +/- 6.9%, p < .001) and aerobic capacity relative to body mass (VO2 peak; healthy-weight children, 46.8 +/- 8.2 mL/kg/min; children with obesity, 31.9 +/- 4.7 mL/kg/min, p < .001). There were statistically significant differences in VO2 recovery for the 5 min following exercise, Wilks's Lambda = .676, F(4, 26) = 3.117, p = .032. There were no statistically significant correlations between HRRec and body mass index (BMI), BF%, VO2peak, or physical activity. CONCLUSIONS: In a healthy pediatric population, obesity alone does not seem to significantly impact HRRec, and because HRRec was not related to obesity status, BMI, or BF%, it should not be used as the sole indicator of aerobic capacity or health status in children. Using more than one recovery variable (i.e., HRRec and VO2 recovery) may provide greater insight into cardiorespiratory fitness in this population. PMID- 29261438 TI - Anticipated suicidal ideation among female injecting drug users who are sex workers of negative or unknown HIV status in China. AB - In China, female injection drug users who are also sex workers (IDUFSW) have a high prevalence of HIV and low prevalence of HIV testing. They are concerned about HIV infection and may be subjected to the risk of suicidal ideation if they become infected, due to stress and discrimination. During 2005-2006, we recruited 199 IDUFSW who self-reported negative/unknown HIV sero-status in Dazhou, Sichuan, China, to investigate the prevalence of and factors associated with suicidal ideation if they became HIV positive. Among the participants, 40.7% responded affirmatively to the question "Whether you would commit suicide if you were infected with HIV in the future?" In multivariate analyses, hatred toward oneself, perception of dying within 2-3 years, perceived nonavailability of HIV related treatment, inability to cope with HIV-related trauma, and inclination to leave one's family if one contracted HIV were significant factors related to anticipated suicidal ideation under the hypothetical situation of HIV infection. The odds ratios (OR) ranged from 2.38 to 10.36 (p < .05). These findings can facilitate the planning of primary suicidal prevention services targeting high risk, non-HIV-positive IDUFSW. Such programs may enhance psychosocial support, empowerment, cultivation of positive coping strategies, and perceived accessibility to treatment, and be integrated with HIV testing. PMID- 29261440 TI - Association of Patient Out-of-Pocket Costs With Prescription Abandonment and Delay in Fills of Novel Oral Anticancer Agents. AB - Purpose The number of novel oral anticancer agents is increasing, but financial barriers may limit access. We examined associations between out-of-pocket (OOP) costs and reduced and/or delayed treatment initiation. Methods This retrospective claims-based study used 2014 to 2015 data from a large, proprietary, integrated database and included Medicare and commercial insurance enrollees with a new, adjudicated prescription for any of 38 oral anticancer agents. We examined rates of claim reversal (failure to purchase approved prescription), delayed initiation (reversal with subsequent fill of same agent within 90 days after adjudication), and abandonment (reversal with no fill of same agent within 90 days after adjudication) for the index oral anticancer agent. We also examined whether patients filled any alternate oral, injectable, or infusible anticancer agent within 90 days. Logistic regressions controlled for sociodemographic, clinical, and treatment characteristics to estimate adjusted rates. Results Among the final sample (N = 38,111), risk-adjusted rates of claim reversal ranged from 13% to 67%, increasing with higher OOP costs. Although the abandonment rate was 18% overall, risk-adjusted rates were higher in greater OOP cost categories (10.0% for <= $10 group v 13.5% for $50.01 to $100 group, 31.7% for $100.01 to $500 group, 41.0% for $500.01 to $2,000 group, and 49.4% for > $2,000 group; P < .001 compared with <= $10 group). Rates remained similar after accounting for use of alternate oral, injectable, or infusible anticancer agents. Delayed initiation was also more frequent for higher OOP cost categories (3% in <= $10 group v 18% in > $2,000 group; P < .001). Sensitivity and subgroup analyses by insurance type, pharmacy type, sex, and indication identified similar associations. Conclusion Higher OOP costs were associated with higher rates of oral prescription abandonment and delayed initiation across cancers. Fiscally sustainable strategies are needed to improve patient access to cancer medications. PMID- 29261441 TI - Challenges Interpreting Chemoprevention Studies Using Observational Data. PMID- 29261439 TI - Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. AB - Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline >= 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes. PMID- 29261443 TI - Reply to M. Nayan et al. PMID- 29261442 TI - Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel. AB - Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA <= 0.2, > 0.2 to 4, and > 4 ng/mL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA <= 0.2 ng/mL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P <= .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached <= 0.2 ng/mL compared with > 4 ng/mL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA <= 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA <= 0.2 ng/mL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA <= 0.2 ng/mL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA <= 0.2 ng/mL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival. PMID- 29261444 TI - Rickettsia sp. Strain NOD Infecting Ticks ( Amblyomma nodosum) in an Endemic Area of Spotted Fever in Brazil. AB - Amblyomma nodosum ticks were collected from one collared anteater ( Tamandua tetradactyla) in the Caatinga biome, Brazil. From one sample, we isolated a Rickettsia sp. that was phylogenetically close to Rickettsia sp. strain NOD, with 99.9, 100.0, and 99.8% identity for gltA, htrA, and ompA genes, respectively. PMID- 29261445 TI - Infestation by Chiggers ( Hannemania sp.) of Miranda's White-lipped Frog ( Leptodactylus macrosternum) from a Semiarid, Neotropic Region of Brazil. AB - We identified Miranda's white-lipped frog ( Leptodactylus macrosternum) as a new host for chiggers ( Hannemania sp.). A total of 57 larvae of Hannemania sp. were found on 31 frogs examined from a semiarid region of northeastern Brazil. PMID- 29261446 TI - MORTALITY TRENDS IN NORTHERN SEA OTTERS ( ENHYDRA LUTRIS KENYONI) COLLECTED FROM THE COASTS OF WASHINGTON AND OREGON, USA (2002-15). AB - During 2002-15 we examined the causes of mortality in a population of northern sea otters ( Enhydra lutris kenyoni). Beachcast sea otters were collected primarily from the US coast of Washington. Although there are no permanent sea otter residents in Oregon, several beachcast otters were collected from the Oregon coast. Infectious diseases were the primary cause of death (56%) for otters we examined. Sarcocystosis was the leading infectious cause of death (54%) and was observed throughout the study period. Some infectious diseases, such as morbilliviral encephalitis and leptospirosis, were documented for a limited number of years and then not detected again despite continued testing for these pathogens in necropsied animals. Trauma was the second most common cause of death (14%) during the study period. The continued stable growth of the Washington population of otters suggests they are able to tolerate current mortality rates. PMID- 29261447 TI - Serologic Surveillance of Wild and Pen-reared Ring-necked Pheasants ( Phasianus colchicus) as a Method of Understanding Disease Reservoirs. AB - We investigated exposure to infectious diseases in wild ( n=33) and pen-reared ( n=12) Ring-necked Pheasants ( Phasianus colchicus) in the Central Valley of California, US during 2014 and 2015. Serologic tests were positive for antibodies against hemorrhagic enteritis, infectious bursal disease, and Newcastle disease viruses in both wild and pen-reared pheasants. PMID- 29261449 TI - Using social autopsy to understand maternal, newborn, and child mortality in low resource settings: a systematic review of the literature. AB - BACKGROUND: Social, cultural, and behavioral factors are often potent upstream contributors to maternal, neonatal, and child mortality, especially in low- and middle-income countries (LMICs). Social autopsy is one method of identifying the impact of such factors, yet it is unclear how social autopsy methods are being used in LMICs. OBJECTIVE: This study aimed to identify the most common social autopsy instruments, describe overarching findings across populations and geography, and identify gaps in the existing social autopsy literature. METHODS: A systematic search of the peer-reviewed literature from 2005 to 2016 was conducted. Studies were included if they were conducted in an LMIC, focused on maternal/neonatal/infant/child health, reported on the results of original research, and explicitly mentioned the use of a social autopsy tool. RESULTS: Sixteen articles out of 1950 citations were included, representing research conducted in 11 countries. Five different tools were described, with two primary conceptual frameworks used to guide analysis: Pathway to Survival and Three Delays models. Studies varied in methods for identifying deaths, and recall periods for respondents ranged from 6 weeks to 5+ years. Across studies, recognition of danger signs appeared to be high, while subsequent care-seeking was inconsistent. Cost, distance to facility, and transportation issues were frequently cited barriers to care-seeking, however, additional barriers were reported that varied by location. Gaps in the social autopsy literature include the lack of: harmonized tools and analytical methods that allow for cross-study comparisons, discussion of complexity of decision making for care seeking, qualitative narratives that address inconsistencies in responses, and the explicit inclusion of perspectives from husbands and fathers. CONCLUSION: Despite the nascence of the field, research across 11 countries has included social autopsy methods, using a variety of tools, sampling methods, and analytical frameworks to determine how social factors impact maternal, neonatal, and child health outcomes. PMID- 29261450 TI - Coverage of routine reporting on malaria parasitological testing in Kenya, 2015 2016. AB - BACKGROUND: Following the launch of District Health Information System 2 across facilities in Kenya, more health facilities are now capable of carrying out malaria parasitological testing and reporting data as part of routine health information systems, improving the potential value of routine data for accurate and timely tracking of rapidly changing disease epidemiology at fine spatial resolutions. OBJECTIVES: This study evaluates the current coverage and completeness of reported malaria parasitological testing data in DHIS2 specifically looking at patterns in geographic coverage of public health facilities in Kenya. METHODS: Monthly facility level data on malaria parasitological testing were extracted from Kenya DHIS2 between November 2015 and October 2016. DHIS2 public facilities were matched to a geo-coded master facility list to obtain coordinates. Coverage was defined as the geographic distribution of facilities reporting any data by region. Completeness of reporting was defined as the percentage of facilities reporting any data for the whole 12-month period or for 3, 6 and 9 months. RESULTS: Public health facilities were 5,933 (59%) of 10,090 extracted. Fifty-nine per Cent of the public facilities did not report any data while 36, 29 and 22% facilities had data reported at least 3, 6 and 9 months, respectively. Only 8% of public facilities had data reported for every month. There were proportionately more hospitals (86%) than health centres (76%) and dispensaries/clinics (30%) reporting. There were significant geographic variations in reporting rates. Counties along the malaria endemic coast had the lowest reporting rate with only 1% of facilities reporting consistently for 12 months. CONCLUSION: Current coverage and completeness of reporting of malaria parasitological diagnosis across Kenya's public health system remains poor. The usefulness of routine data to improve our understanding of sub-national heterogeneity across Kenya would require significant improvements to the consistency and coverage of data captured by DHIS2. PMID- 29261451 TI - Predictors of stillbirths in Bangladesh: evidence from the 2004-2014 nation-wide household surveys. AB - BACKGROUND: Globally, stillbirth remains a significant public health issue, particularly in developing countries such as Bangladesh. OBJECTIVE: This study aimed to investigate the potential predictors of stillbirths in Bangladesh over a ten-year period. METHODS: The Bangladesh Demographic and Health Surveys data for the years 2004, 2007, 2011 and 2014 (n = 29,094) were used for the study to investigate the predictors of stillbirths. Stillbirth was examined against a set of community, socio-economic and child characteristics, using a multivariable logistic regression model that adjusted for cluster and sampling variability. RESULTS: The pooled rate of stillbirth in Bangladesh was 28 in 1000 births (95% CI: 22, 34). Stillbirth rates were higher in rural compared to urban areas in Bangladesh. Mothers who had a secondary or higher level of education (OR = 0.59, 95%CI: 0.43-0.82, P = 0.002) and those with primary education (OR = 0.66, 95%CI: 0.55-0.80, P < 0.001) were less likely to experience stillbirths compared to mothers with no education. Mothers with more than two children were significantly less likely to have stillbirths compared to mothers with one child. Those from poor households reported increased odds of stillbirth compared to those from rich households. CONCLUSION: Our analysis indicated that no maternal education, primiparity and poor household were predictors of stillbirths in Bangladesh. A collaborative effort is needed to reduce stillbirth rates among these high-risk groups in Bangladesh, with the socio-economic and health-related Sustainable Development Goals providing a critical vehicle for the co-ordination of this work. PMID- 29261453 TI - Impairment of functioning and substance use in a Latino population. AB - This study investigated the association of academic outcomes, romantic relationships, and substance use (tobacco, marijuana, cocaine) with alcohol dependence in a sample of Latino (N = 1,143) college students. Secondary data analysis was conducted on measures of grade point average in college, relationship satisfaction, drug use, and alcohol dependence. Latino college students who reported alcohol dependency had significant relational dissatisfaction and poor academic outcomes. Thus, lower grade point average and relationship dissatisfaction were associated with alcohol dependence. By focusing specifically on a Mexican American population, this study adds important information to current research regarding the commonality and differences across cultural groups regarding drug use and dependence and further clarifies the risk factors associated with substance use and dependency in a population that is vulnerable for at-risk behaviors. This study also offers insight into potential targets of treatment and intervention for this cultural group. PMID- 29261452 TI - Attitudes towards mental health and the integration of mental health services into primary health care: a cross-sectional survey among health-care workers in Lvea Em District, Cambodia. AB - BACKGROUND: Cambodia is a country where the resources for treating mental health disorders are far from sufficient. One strategy to narrow the treatment gap is to integrate mental health into primary health care (PHC). Understanding the knowledge and attitudes towards mental health integration that health-care workers have is important for assessing the challenges and opportunities when planning a potential integration project. OBJECTIVE: The aim of this study was to assess these basic conditions in Lvea Em District, Cambodia. DESIGN: A structured self-reporting questionnaire regarding attitudes and knowledge about mental health and its integration into PHC was collected from 75 health-care workers in Lvea Em District, Cambodia in October 2015. Firstly, descriptive analyses were carried out, and secondly, linear regression analyses to assess the relationship between attitudes and socio-demographic variables were conducted. RESULTS: There was clear support towards integrating mental health services into PHC among these participants as 81.3% were interested in personally delivering mental health care at their units. Respondents who reported having received some kind of mental health-care training tended to have a more positive attitude towards mentally ill people (p = 0.005) and those who thought there was a high need for mental health care had a more favourable attitude towards the integration of mental health services (p = 0.007). CONCLUSIONS: The most important finding from this survey was the willingness and the acceptance of the need for integration of mental health care. This enhances the feasibility of integrating mental health services at the PHC level. Improving the competence of mental health care in these settings will likely help to reduce the treatment gap for mental, neurological and substance use disorders in Cambodia. PMID- 29261454 TI - Development of an Inline Dry Powder Inhaler That Requires Low Air Volume. AB - BACKGROUND: Inline dry powder inhalers (DPIs) are actuated by an external air source and have distinct advantages for delivering aerosols to infants and children, and to individuals with compromised lung function or who require ventilator support. However, current inline DPIs either perform poorly, are difficult to operate, and/or require large volumes (~1 L) of air. The objective of this study was to develop and characterize a new inline DPI for aerosolizing spray-dried formulations with powder masses of 10 mg and higher using a dispersion air volume of 10 mL per actuation that is easy to load (capsule-based) and operate. METHODS: Primary features of the new low air volume (LV) DPIs are fixed hollow capillaries that both pierce the capsule and provide a continuous flow path for air and aerosol passing through the device. Two different configurations were evaluated, which were a straight-through (ST) device, with the inlet and outlet capillaries on opposite ends of the capsule, and a single sided (SS) device, with both the inlet and outlet capillaries on the same side of the capsule. The devices were operated with five actuations of a 10 mL air syringe using an albuterol sulfate (AS) excipient-enhanced growth (EEG) formulation. Device emptying and aerosol characteristics were evaluated for multiple device outlet configurations. RESULTS: Each device had specific advantages. The best case ST device produced the smallest aerosol [mean mass median aerodynamic diameter (MMAD) = 1.57 MUm; fine particle fraction <5 MUm (FPF<5MUm) = 95.2%)] but the mean emitted dose (ED) was 61.9%. The best case SS device improved ED (84.8%), but produced a larger aerosol (MMAD = 2.13 MUm; FPF<5MUm = 89.3%) that was marginally higher than the initial deaggregation target. CONCLUSIONS: The new LV-DPIs produced an acceptable high-quality aerosol with only 10 mL of dispersion air per actuation and were easy to load and operate. This performance should enable application in high and low flow mechanical ventilation systems and high efficiency lung delivery to both infants and children. PMID- 29261455 TI - Notice of Withdrawal: MR Imaging and Gadolinium: Reassessing the Risk of Nephrogenic Systemic Fibrosis in Patients with Severe Renal Disease. AB - This editorial has been withdrawn from publication by the authors in conjunction with the withdrawal of the highlighted manuscript (see https://doi.org/10.1148/radiol.2017170102). PMID- 29261456 TI - Diagnostic Ability of CT to Help Differentiate Stenosis of 30% in Patients with Atrial Fibrillation. PMID- 29261457 TI - Erik Boijsen, PhD. PMID- 29261458 TI - James G. Kereiakes, PhD. PMID- 29261461 TI - An Imaging Glimpse into the Autistic Brain. PMID- 29261459 TI - Abbreviated Biparametric Prostate MR Imaging: Is It Really an Alternative to Multiparametric MR Imaging? PMID- 29261462 TI - Contrast Media for Coronary CT Angiography: Should an Iso-osmolar Agent Be Used? PMID- 29261463 TI - Increased Rather than Decreased Small Vessel Pulsatility in Patients with Progressing Cerebral White Matter Hyperintensities. PMID- 29261464 TI - Frederick J. Bonte, MD. PMID- 29261465 TI - John Rousseau Thornbury, MD. PMID- 29261466 TI - Case 249: Intramuscular Mycetoma. AB - History A 21-year-old man presented with swelling of the medial aspect of the left thigh of 1-month duration. There was no history of fever or penetrating injury in the left thigh. The patient had undergone renal transplantation 7 years earlier and had been taking immunosuppressants since transplantation. He had undergone two surgeries at the same site in the medial aspect of the left thigh in the past 3 years for a similar problem. At physical examination, there was swelling in the medial aspect of the left thigh, with mild tenderness. A surgical scar was noted anterior to the swelling ( Fig 1 ). No redness or discharging sinus was present. Laboratory results were as follows: hemoglobin level, 11.3 g/dL (normal range, 13.8-17.2 g/dL); white blood cell count, 9.7 * 109/L (normal range, [4-11] * 109/L); neutrophil, 75% (normal range, 48%-77%); lymphocyte, 22% (normal range, 10%-24%); eosinophil, 1% (normal range, 0.3%- 7%); monocyte, 1% (normal range, 0.6%-10%); serum creatinine level, 1.3 mg/dL (114.9 MUmol/L) (normal range, 0.5-1.6 mg/dL [44.2-141.4 MUmol/L]); and serum glucose (random) level, 82 mg/dL (4.5 mmol/L) (normal range, 79-140 mg/dL [4.4-7.8 mmol/L]). Radiography of the left thigh showed soft-tissue swelling in the medial aspect of the left thigh, without underlying bone involvement (not shown). Ultrasonography (US) and magnetic resonance (MR) imaging of the left thigh were performed. [Figure: see text]. PMID- 29261468 TI - Can Dual-Energy CT Challenge MR Imaging in the Diagnosis of Focal Infiltrative Bone Marrow Lesions? PMID- 29261469 TI - The Use and Pitfalls of Intracranial Vessel Wall Imaging: How We Do It. AB - Intracranial vessel wall magnetic resonance (MR) imaging has gained much attention in the past decade and has become part of state-of-the-art MR imaging protocols to assist in diagnosing the cause of ischemic stroke. With intracranial vessel wall imaging, vessel wall characteristics have tentatively been described for atherosclerosis, vasculitis, dissections, Moyamoya disease, and aneurysms. With the increasing demand and subsequently increased use of intracranial vessel wall imaging in clinical practice, radiologists should be aware of the choices in imaging parameters and how they affect image quality, the clinical indications, methods of assessment, and limitations in the interpretation of these images. In this How I do It article, the authors will discuss the technical requirements and considerations for vessel wall image acquisition in general, describe their own vessel wall imaging protocol at 3 T and 7 T, show a step-by-step basic assessment of intracranial vessel wall imaging as performed at their institution-including commonly encountered artifacts and pitfalls-and summarize the commonly reported imaging characteristics of various intracranial vessel wall diseases for direct clinical applicability. Finally, future technical and clinical considerations for full implementation of intracranial vessel wall imaging in clinical practice, including the need for histologic validation and acquisition time reduction, will be discussed. PMID- 29261470 TI - Science to Practice: Can Functional MR Imaging Be Useful in the Evaluation of Cardiorenal Syndrome? AB - Functional magnetic resonance (MR) imaging of the kidneys has gained interest recently, especially in the detection of early changes in acute kidney injury or to predict progression of chronic kidney disease (CKD). The application of these methods to cardiorenal syndrome (CRS) is novel. CRS is widely accepted as a complex clinical problem routinely faced by clinicians. In this issue, Chang et al ( 1 ) present their preliminary experience applying blood oxygen level dependent (BOLD) MR imaging to the kidneys in mice with experimental myocardial infarction. They showed that R2* in the kidney increases after induced myocardial infarction and that the response was higher in animals with larger infarcts and over time. The authors also for the first time correlated the BOLD MR imaging findings against hypoxia-inducible factor-1alpha (HIF-1alpha) expression, an independent marker of renal hypoxia. In addition, they showed evidence for renal injury by using a kidney injury marker, kidney injury molecule-1 (KIM-1). The results of their study support the use of renal BOLD MR imaging in subjects with heart failure, in whom the risk of subsequent renal ischemia and/or hypoxia is known to exist. These results, along with those of other recent reports ( 2 ), suggest that functional imaging methods could play a key role in evaluating changes in both the primary and secondary organs involved in complex disease processes such as CRS. Availability of such methods could facilitate translation to the clinic and improve the mechanistic understanding of the complicated and interrelated pathophysiology. PMID- 29261471 TI - Using Computer Analysis to Predict Likelihood of Cancer in Lung Nodules. PMID- 29261472 TI - Case 253. PMID- 29261473 TI - Editor's Note: January 2018. PMID- 29261474 TI - Vijay M. Rao, MD, President, Radiological Society of North America, 2018. PMID- 29261475 TI - Do Tumor Shrinkage Patterns at Breast MR Imaging Predict Survival? PMID- 29261476 TI - User Experience of an Innovative Mobile Health Program to Assist in Insulin Dose Adjustment: Outcomes of a Proof-Of-Concept Trial. AB - BACKGROUND: Many patients with diabetes require insulin therapy to achieve optimal glycemic control. Initiation and titration of insulin often require an insulin dose adjustment (IDA) program, involving frequent exchange of blood glucose levels (BGLs) and insulin prescription advice between the patient and healthcare team. This process is time consuming with logistical barriers. OBJECTIVE: To develop an innovative mobile health (m-Health) mobile-based IDA program (mIDA) and evaluate the user adherence and experience through a proof-of concept trial. METHODS: In the program, an m-Health system was designed to be integrated within a clinical IDA service, comprising a Bluetooth-enabled glucose meter, smartphone application, and clinician portal. Insulin-requiring patients with type-2 diabetes mellitus and stable BGL were recruited to use the m-Health system to record and exchange BGL entries, insulin dosages, and clinical messages for 2 weeks. The user experience was evaluated by a Likert scale questionnaire. RESULTS: Nine participants, aged 58 +/- 14 years (mean +/- SD), completed the trial with average daily records of 3.1 BGL entries and 1.2 insulin dosage entries. The participants recognized the potential value of the clinical messages. They felt confident about managing their diabetes and were positive regarding ease of use and family support of the system, but disagreed that there were no technical issues. Finally, they were satisfied with the program and would continue to use it if possible. CONCLUSIONS: The m-Health system for IDA showed promising levels of adherence, usability, perception of usefulness, and satisfaction. Further research is required to assess the feasibility and cost effectiveness of using this system in outpatient settings. PMID- 29261477 TI - Legalized marijuana: Language-associated knowledge of laws and risk perceptions among Latinos. AB - This study examines the extent to which knowledge of recreational marijuana laws, health effects, and perceptions of risk for marijuana use differ between Spanish- and English-speaking Latino survey respondents from a registry of Colorado adults. Spanish-speaking Latino respondents (n = 47) had less accurate knowledge of laws permitting use of marijuana than English-speaking Latino respondents (n = 154), while reporting greater agreement with negative health effects and higher perception of risk associated with marijuana use. The results suggest that efforts to communicate health and informational messaging to the public about legalized marijuana should consider linguistic variations when tailoring campaigns for Latino audiences. PMID- 29261478 TI - A Common Force-Sharing Pattern in Joint Action That Consists of Four People. AB - The authors examined the force-sharing patterns in a joint action performed by a group of two, three, or four people compared with a solo action. In the joint actions, 28 participants produced periodic isometric forces such that the sum of forces they produced cycled between 5% and 10% maximum voluntary contraction with the right hand at 1 Hz. In both the three- and four-person tasks, the correlation between forces produced by two of the three or four participants was negative, and the remaining one or two participants produced intermediate forces. The errors of force and interval and force variabilities were smaller in four- and three-people groups than individuals. Four- and three-people groups thus performed better than individuals. PMID- 29261479 TI - Managing patients with oncologic complications in the emergency department. AB - As the prevalence of cancer continues to increase in the general population and improvements in cancer treatment prolong survival, the incidence of patients presenting to the emergency department with oncologic complications will, similarly, continue to rise. This issue reviews 3 of the more common presentations of oncology patients to the emergency department: metastatic spinal cord compression, tumor lysis syndrome, and febrile neutropenia. Signs and symptoms of these conditions can be varied and nonspecific, and may be related to the malignancy itself or to an adverse effect of the cancer treatment. Timely evidence-based decisions in the emergency department regarding diagnostic testing, medications, and arrangement of disposition and oncology follow-up can significantly improve a cancer patient's quality of life. PMID- 29261480 TI - Best practices in managing child and adolescent behavioral health emergencies. AB - Behavioral health emergencies most commonly present as depression, suicidal behavior, aggression, and severe disorganization. Emergency clinicians should avoid relying solely on past medical history or previous psychiatric diagnoses that might prematurely rule out medical pathologies. Treatments for behavioral health emergencies consist of de-escalation interventions aimed at preventing agitation, aggression, and harm. This issue reviews medical pathologies and underlying causes that can result in psychiatric presentations and summarizes evidence-based practices to evaluate, manage, and refer patients with behavioral health emergencies. PMID- 29261482 TI - [Women in biological sciences and medical research: let's break the glass ceiling!] PMID- 29261481 TI - Genetic structure of Trypanosoma congolense "forest type" circulating in domestic animals and tsetse flies in the South-West region of Cameroon. AB - Despite the economic impact of trypanosome infections, few investigations have been undertaken on the population genetics and transmission dynamics of animal trypanosomes. In this study, microsatellite markers were used to investigate the population genetics of Trypanosoma congolense "forest type", with the ultimate goal of understanding its transmission dynamics between tsetse flies and domestic animals. Blood samples were collected from pigs, sheep, goats and dogs in five villages in Fontem, South-West region of Cameroon. In these villages, tsetse were captured, dissected and their mid-guts collected. DNA was extracted from blood and tsetse mid-guts and specific primers were used to identify T. congolense "forest type". All positive samples were genetically characterized with seven microsatellite markers. Genetic analyses were performed on samples showing single infections of T. congolense "forest type". Of the 299 blood samples, 137 (46%) were infected by T. congolense "forest type". About 3% (54/1596) of tsetse fly mid-guts were infected by T. congolense "forest type". Of 182 samples with T. congolense "forest type", 52 were excluded from the genetic analysis. The genetic analysis on the 130 remaining samples revealed polymorphism within and between subpopulations of the target trypanosome. The dendrogram of genetic similarities was subdivided into two clusters and three sub-clusters, indicating one major and several minor genotypes of T. congolense "forest type" in tsetse and domestic animals. The low FSTvalues suggest low genetic differentiation and no sub structuration within subpopulations. The same T. congolense genotypes appear to circulate in tsetse and domestic animals. PMID- 29261483 TI - [Invadopodia regulation: a new function for p27 in cellular invasion]. PMID- 29261484 TI - [Measure of the biomechanical degradation of a DNA fiber under the influence of therapeutic X-rays]. PMID- 29261485 TI - [Four little days to define adult height]. PMID- 29261486 TI - [The hidden face of the lung: a platelet factory and a blood progenitors reservoir]. PMID- 29261487 TI - [Mathematic modeling: a tool for investigation of bacterial interactions in biofilms]. PMID- 29261488 TI - [Impact of the evolution of mammalian intestinal microbiotas on human health]. PMID- 29261489 TI - [Quadruplex-DNA: structures, functions and detection]. PMID- 29261490 TI - [Exome and transcriptome sequencing as complementary approaches for disease gene identification]. PMID- 29261491 TI - [Bipolar disorder: advances in the prediction of lithium response and development of new therapies using induced pluripotent stem cells]. PMID- 29261492 TI - [A rejuvenation for yeast telomerase]. PMID- 29261493 TI - [Mathematical modeling: an essential tool for the study of therapeutic targeting in solid tumors]. AB - Recent progress in biology has made the study of the medical treatment of cancer more effective, but it has also revealed the large complexity of carcinogenesis and cell signaling. For many types of cancer, several therapeutic targets are known and in some cases drugs against these targets exist. Unfortunately, the target proteins often work in networks, resulting in functional adaptation and the development of resilience/resistance to medical treatment. The use of mathematical modeling makes it possible to carry out system-level analyses for improved study of therapeutic targeting in solid tumours. We present the main types of mathematical models used in cancer research and we provide examples illustrating the relevance of these approaches in molecular oncobiology. PMID- 29261494 TI - [G-quadruplex: key controllers of human genome duplication]. AB - The correct duplication of the human genome is under the control of a spatiotemporal program that determines where and when replication forks start. This regulation thus mainly operates on replication start sites named replication origins. During the S-phase, about 50 000 origins fire in one human cell. However, the normal or perturbed progression of replication forks also strongly impacts on replication. Recently, several studies have put forward the role of a noncanonical DNA structure, the G-quadruplex, in the control of genome duplication. In this review, we describe the major impact of this structure on starting points and on the progression of replication forks. PMID- 29261495 TI - [Astrocytes and microglia: active players in synaptic plasticity]. AB - Synaptic plasticity consists in a change in structure and composition of presynaptic and postsynaptic compartments. For a long time, synaptic plasticity had been thought as a neuronal mechanism only under the control of neural network activity. However, recently, with the growing knowledge about glial physiology, plasticity has been reviewed as a mechanism influenced by the synaptic environment. Thus, it appears that astrocytes and microglia modulate these mechanisms modifying neural environment by clearance of neurotransmitters, releasing essential factors and modulating inflammation. Moreover, glia can change its own activity and the expression pattern of many factors that modulate synaptic plasticity according to the environment. Hence, these populations of "non-neuronal" cells in the central nervous system seem to be active players in synaptic plasticity. This review discusses how glia modulates synaptic plasticity focusing on long-term potentiation and depression, and questions the role of the signaling processes between astrocytes and microglia in these mechanisms. PMID- 29261496 TI - [New perspectives on preeclampsia]. AB - Preeclampsia is a major, frequent and potentially severe condition of pregnancy, characterized by severe hypertension and proteinuria. In this review, we describe recent advances in understanding the pathology, and discuss the long-term impacts on maternal vascular health. Next, we describe the genetic, epigenetic and immunological basis of preeclampsia. We describe the links between preeclampsia and oxidative stress in placental (trophoblast) and endothelial cells. We mention cellular and animal models commonly used to decipher modified pathophysiological pathways in a preeclamptic pregnancy compared to a normal pregnancy. Finally, we discuss the therapeutic options, readily available or in development, to improve the monitoring of pregnancies, the health of patients and that of children born from preeclamptic pregnancies. PMID- 29261497 TI - [Studying episodic memory : dogs as a biological model ?] AB - The ability to remember past events in all of their dimensions (what? where? when? i.e. autobiographic/episodic memory) is highly adaptive. Conversely, individuals who do not have such ability are less likely to benefit from recognizing situations similar to previous ones, e.g. to avoid being defeated several times. We will present the different types of memory and their ontogeny, focusing on those that are found in dogs. We will then describe more precisely the episodic memory, i.e. remembering events or actions from others, and their location and the time of the events and will present to which degree such a skill is found in dogs. We will show that, even if dogs are a social species whose specificities should reveal the existence of an episodic-like memory, dogs remember who and what happened but no study evidenced yet that they remember the precise time it was done. Further studies are thus needed, especially as dogs represent a relevant biological model for comparative cognition to study the ontogeny or senescence of non verbal episodic memory. PMID- 29261498 TI - [The sharing of medical coverage and additional health insurances: the defects of a mixed system]. PMID- 29261499 TI - [The necessary ethical questioning regarding the caring relationship in dental telemedicine]. AB - Technological innovations in the fields of medical imaging and communication have enabled the rise of dental telemedecine. By transforming the usual caring relationship, dental telemedicine virtualizes the medical procedure and generates a mutation of the classical relational model that rearticulates the relationship between the dentist and the patient. It introduces a positive lever that must stay up to the appraisal of the benefit-risk equation, that an ethical questioning will help to evaluate for every patient. Dental telemedicine must be understood as a mean, and not as an end. It must not be fantasized as a universal dental care model. It seems to be recommanded to investigate systematically the technological innovations and the development of protocols thanks to ethical guidelines in order to evaluate a priori and a posteriori any kind of progress that might be considered. PMID- 29261500 TI - [The resolution revolution in cryo-electron microscopy]. PMID- 29261501 TI - [The expert patients in the fight against AIDS in the Cambodia]. PMID- 29261502 TI - [A pragmatic approach to managing expensive therapies]. AB - Inflated drug prices necessarily raise the issue of rational allocation of health care resources. The system operated by the NICE agency in the UK attempts to do this by calculating the cost per quality-adjusted life year gained (QALY) and recommending funding only for drugs whose cost per QALY falls under a certain threshold. The whole process is documented in detail and easily accessible, and often results in significant discounts on drug prices. Given that some kind of rationing of health care is inevitable, the rational and transparent process followed by NICE has a number of positive features. PMID- 29261503 TI - Impact of Family Planning and Business Trainings on Private-Sector Health Care Providers in Nigeria. AB - CONTEXT: Private health care providers are an important source of modern contraceptives in Sub-Saharan Africa, yet they face many challenges that might be addressed through targeted training. METHODS: This study measures the impact of a package of trainings and supportive supervision activities targeted to private health care providers in Lagos State, Nigeria, on outcomes including range of contraceptive methods offered, providers' knowledge and quality of counseling, recordkeeping practices, access to credit and revenue. A total of 965 health care facilities were randomly assigned to treatment and control groups. Facilities in the treatment group-but not those in the control group-were offered a training package that included a contraceptive technology update and interventions to improve counseling and clinical skills and business practices. Multivariate regression analysis of data collected through facility and mystery client surveys was used to estimate effects. RESULTS: The training program had a positive effect on the range of contraceptive methods offered, with facilities in the treatment group providing more methods than facilities in the control group. The training program also had a positive impact on the quality of counseling services, especially on the range of contraceptive methods discussed by providers, their interpersonal skills and overall knowledge. Facilities in the treatment group were more likely than facilities in the control group to have good recordkeeping practices and to have obtained loans. No effect was found on revenue generation. CONCLUSION: Targeted training programs can be effective tools to improve the provision of family planning services through private providers. PMID- 29261504 TI - Service Delivery Correlates of Choosing Short-Acting Contraceptives at the Time of Uterine Evacuation in Bangladesh. AB - CONTEXT: The World Health Organization recommends that contraceptives be offered on the day of a uterine evacuation procedure (i.e., induced abortion or postabortion care for an incomplete abortion). Short-acting methods can be initiated on the day of the uterine evacuation, regardless of procedure type. METHODS: Survey data from a facility-based sample of 479 Bangladeshi women aged 18-49 who did not intend to become pregnant in the four months following their uterine evacuation were used to examine women's choice of short-acting contraceptive methods (pill, condoms or injectable). Service delivery correlates of contraceptive choice were identified using sequential logistic regression models. RESULTS: Seventy-three percent of women chose a short-acting contraceptive method on the day of their uterine evacuation. The odds that a woman chose a short-acting method, rather than no method, were lower among those who had had a medication abortion (odds ratio, 0.1) or dilatation and curettage (0.3) than among those who had had a vacuum aspiration. The likelihood that a woman chose a specific type of short-acting method varied according to the type of uterine evacuation she had had, the facility level and the governmental or nongovernmental entity that managed the facility. CONCLUSIONS: Uterine evacuation service delivery characteristics may act as barriers to women's choosing a contraceptive method following an abortion. Training and monitoring providers may help ensure that all uterine evacuation clients have access to the full range of contraceptive information and services and that their choices, rather than service delivery factors, drive postabortion contraceptive use. PMID- 29261505 TI - The Role of Public-Sector Family Planning Programs in Meeting the Demand for Contraception in Sub-Saharan Africa. AB - CONTEXT: Commonly used indicators of contraceptive behavior in a population modern contraceptive prevalence (mCPR), unmet need for contraception, demand for contraception and demand satisfied-are not well-suited for evaluating the progress made by government family planning programs in helping women and men achieve their reproductive goals. METHODS: Trends in these measures in 26 Sub Saharan African countries between 1990 and 2014 were examined. Trends in a proposed new indicator, the public-sector family planning program impact score (PFPI), and its relationship to mCPR and the family planning effort score were also assessed. Case studies were used to review public family planning program development and implementation in four countries (Nigeria, Ethiopia, Rwanda and Kenya). RESULTS: The four commonly used indicators capture the extent to which women use family planning and to which demand is satisfied, but shed no direct light on the role of family planning programs. PFPI provides evidence that can be used to hold governments accountable for meeting the demand for family planning, and was closely related to policy developments in the four case-study countries. CONCLUSIONS: PFPI provides a useful addition to the indicators currently used to assess progress in reproductive health and family planning programs. PMID- 29261506 TI - Men's Roles in Women's Abortion Trajectories in Urban Zambia. AB - CONTEXT: Given that maternal morbidity and mortality from unsafe abortion persist, especially in Africa, there is a pressing need to understand the abortion decision-making process. However, little is known about men's influence on and involvement in women's abortion decision making and care seeking. METHODS: A qualitative study was conducted at the largest public provider of abortion related care in Zambia. Thematic framework analysis was used to categorize and synthesize data from in-depth interviews conducted in 2013 with 71 women who received a safe abortion and 41 who received care following an incomplete (unsafe) abortion. RESULTS: Men influenced whether women sought a safe or unsafe abortion; their actions, lack of action and anticipated actions-negative and positive-reflected broader gender inequities. Abandonment by men, and the desire to avoid disclosing pregnancy to men because of fear of their reactions or interference, were important influences on some women's decision to seek abortion, on the secrecy and urgency with which abortion was pursued and on the level of risk assumed. However, other women discussed men's positive influences on their abortion care seeking. In this setting of low awareness of the legality and availability of abortion, some men used their greater social and economic resources to facilitate safe abortion by providing information and paying for care. CONCLUSIONS: Increasing knowledge about the legality and availability of safe abortion is vital not only among sexually active women, but also among those they confide in, including men. PMID- 29261507 TI - Longitudinal Evaluation of the Tupange Urban Family Planning Program in Kenya. AB - CONTEXT: Levels of fertility and contraceptive use have long fluctuated in Kenya. The multicomponent Tupange program, part of the Urban Reproductive Health Initiative, was initiated in 2011 to increase use of modern family planning methods. METHODS: Women aged 15-49 in the five Kenyan cities where Tupange was implemented were interviewed in 2010 and reinterviewed in 2014 to obtain information on their contraceptive use and exposure to components of the Tupange program. Fixed-effects models were estimated to identify associations between program exposure and use of modern family planning methods. Analyses were performed to determine the relative cost-effectiveness of program components. RESULTS: During the four-year follow-up period, the proportion of women using modern contraceptives increased from 45% to 52%, and the proportion of users who were using long-acting or permanent methods rose from 6% to 19%. The fixed effects model indicated that modern method use was associated with having heard Tupange-related local radio programming and marginally associated with having discussed family planning with a community health worker (CHW); among women who were unmarried or did not give birth during the study period, modern method use was associated with living near program facilities. Local radio programming was the most cost-effective program component, followed by proximity to Tupange facilities and discussions with CHWs. CONCLUSIONS: Urban reproductive health programs seeking to increase use of modern family planning methods in Kenya and other Sub-Saharan African settings should consider multicomponent approaches that include CHW activities, local radio programming and improvements to the supply environment. PMID- 29261509 TI - Addendum of: Fall Detection in Individuals With Lower Limb Amputations Using Mobile Phones: Machine Learning Enhances Robustness for Real-World Applications. AB - [This corrects the article DOI: 10.2196/mhealth.8201.]. PMID- 29261510 TI - Reference Correction to: Making Air Pollution Visible: A Tool for Promoting Environmental Health Literacy. AB - [This corrects the article DOI: 10.2196/publichealth.7492.]. PMID- 29261512 TI - LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells. AB - We investigated thoroughly the effect of lncRNA PART1 on prostate cancer cells proliferation and apoptosis, through regulating toll-like receptor (TLR) pathways. LncRNA PART1 expression was also examined by quantitative real-time polymerase chain reactions (qRT-PCR) in human tissues and the cells lines LNCaP and PC3. After transfection with si-PART1 or control constructs, the cell viability was measured by MTS and colony formation assays. In addition, the apoptosis rate of the prostate cancer cells was validated by TUNEL staining. Relationships between lncRNA PART1 expression and TLR pathway genes were demonstrated by qRT-PCR and Western blotting. High levels of lncRNA PART1 expression were correlated with advanced cancer stage and predication of poor survival. LncRNA PART1 levels was increased in PCa cells treated with 5alpha dihydrotestosterone (DHT), confirming PART1 was directly induced by androgen. Moreover, down-regulation of lncRNA PART1 inhibited prostate cancer cell proliferation and accelerated cell apoptosis. In addition, lncRNA PART1 induced downstream genes expression in TLR pathways including TLR3, TNFSF10 and CXCL13 to further influence prostate cancer cells, indicating its carcinogenesis on prostate cancer. LncRNA PART1 promoted cell proliferation ability and apoptosis via the inhibition of TLR pathways in prostate cancer. LncRNA PART1 could hence be considered as a new target in the treatment of prostate cancer. PMID- 29261511 TI - Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders. AB - Neurological diseases like Alzheimer's disease, epilepsy, parkinsonism, depression, Huntington's disease and amyotrophic lateral sclerosis prevailing globally are considered to be deeply influenced by oxidative stress-based changes in the biochemical settings of the organs. The excess oxygen concentration triggers the production of reactive oxygen species, and even the intrinsic antioxidant enzyme system, i.e. SOD, CAT and GSHPx, fails to manage their levels and keep them under desirable limits. This consequently leads to oxidation of protein, lipids and nucleic acids in the brain resulting in apoptosis, proteopathy, proteasomes and mitochondrion dysfunction, glial cell activation as well as neuroinflammation. The present exploration deals with the evidence-based mechanism of oxidative stress towards development of key neurological diseases along with the involved biomechanistics and biomaterials. PMID- 29261513 TI - High-content hydrogen water-induced downregulation of miR-136 alleviates non alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3. AB - This study was aimed to investigate the potential regulatory mechanism of high content hydrogen water (HHW) in non-alcoholic fatty liver disease (NAFLD). A high fat diet (HFD)-induced NAFLD mice model and cellular model were prepared. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total cholesterol (TCH) and triglycerides (TG) were measured. The expression levels of representative five microRNA (miRNAs) (miR-103, miR-488, miR-136, miR-505 and miR 148a) in liver tissues were determined by quantitative real-time PCR (qRT-PCR). The target of miR-136 was validated by RNA immunoprecipitation (RIP) and pull down assay. MiR-136, MEG3 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression levels following cell treatment were detected in hepatocytes using qRT PCR and Western blotting. Moreover, cell viability and TG content were conducted. MiR-136 was downregulated, MEG3 as well as Nrf2 was upregulated and serum lipid level was reduced in NAFLD mice model after HHW treatment, which exerted the same effect in cellular model. RIP and RNA pull-down assay confirmed that MEG2 was a downstream target of miR-136. What's more, HHW ameliorated lipid accumulation by regulating miR-136/MEG3/Nrf2 axis in vitro and in vivo. Hence, HHW alleviated NAFLD by downregulation of miR-136 through mediating Nrf2 via targeting MEG3. PMID- 29261515 TI - Integrative Approach to Psoriasis Vulgaris. AB - In this article, we present a literature review of the most popular and commonly used therapeutic procedures belonging to complementary and alternative medicine, which is part of the modern concept of integrative medicine, used in the treatment of psoriasis. Psoriasis is a chronic, systemic, inflammatory disease wherein skin changes are the most visible sign. It occurs in approximately 1% to 3% of the world population, and the National Psoriasis Foundation of the United States estimates the number of patients in the whole world at about 125 million. Psoriasis primarily affects the skin, burdening patients with inflamed, pruritic, and sometimes painful lesions covered with whitish scales that last for years. Because of its prevalence in the general population, diversity of the clinical picture (from minimal and localized lesions without subjective symptoms to life threatening conditions), and disease duration (practically a lifetime), psoriasis is a disease that has become a focus of modern medicine, and therapeutic options for the treatment of psoriasis are currently very numerous and diverse. Conventional treatment of psoriasis is guided by the so-called principle of "steps," where treatment options are applied according to the severity of illness assessed by a physician. Apart from the official therapy for psoriasis, as it is defined and understood in modern developed societies, there exists in parallel a great number of traditional, complementary, and alternative psoriasis treatments, which are based on the beliefs, experiences, and theories inherent to different cultures; in this article, we have analyzed the literature related to some of these procedures. PMID- 29261514 TI - Association of prothrombotic adipokine (plasminogen activator inhibitor-1) with TSH in metabolic syndrome: a case control study. AB - Background Metabolic syndrome (MetS) involves a cluster of cardiovascular risk factors, including abnormal lipids, insulin resistance and hypertension. The aim of the present study is to investigate associations between thyroid profile and the pro-thrombotic mediator, plasminogen activator inhibitor-1 (PAI-1), in MetS and identify associated biochemical markers. Materials and methods The present study was a case control study and consisted of 50 diagnosed cases of MetS and 50 healthy volunteers as controls. MetS cases were further divided into two groups based on the presence and absence of subclinical hypothyroidism (SCH). Data collected included demographic profile, clinical history and routine lab investigation. Special investigations included the thyroid function test and serum PAI-1 levels. Results The mean serum thyroid-stimulating hormone (TSH) levels were significantly higher in MetS cases as compared to controls (5.7 +/- 1.2 mIU/L vs. 2.3 +/- 1.6 mIU/L, p < 0.0001), although the mean triiodothyronine (T3) and thyroxine (T4) levels were comparable in two groups. The mean levels of serum PAI-1 were significantly higher in MetS cases as compared to controls(231 +/- 87 ng/mL vs. 185 +/- 96 ng/mL, p = 0.013). TSH and PAI-1 levels were positively correlated with various markers of MetS and negatively correlated with high-density lipoprotein (HDL). Conclusion The present study points towards the presence of thyroid dysfunction, in the form of subclinical hypothyroidism (SCH), in cases of MetS. In the presence of thyroid dysfunction, abnormal adipocytes may release adipokines, such as PAI-1, which lead to increased risk of thrombotic episodes in these patients. Hence, SCH should be appropriately managed. PMID- 29261516 TI - Neonatal Neuroprotection: Bringing Best Practice to the Bedside in the NICU. AB - Preterm birth interrupts the precise process of fetal maturation, forcing critical neurologic growth to continue within the Neonatal Intensive Care Unit (NICU). Concern for the impact of the NICU experience on the developing brain led to a unit-based Quality Improvement (QI) project to promote best outcomes for our graduates. The objective was to implement a standard of care for neonatal neuroprotection in a large urban tertiary center. A multidisciplinary committee researched and developed the Neonatal Neuroprotective Best Practice Guidelines to identify optimal interventions, as well as provide physiologic rationales to reinforce importance of these practices. An educational initiative accompanied release of this document to support consistency in clinical practice and to stress the critical role that every caregiver played in a child's outcome. As the Best Practice Guidelines encompassed virtually all aspects of caregiving in the NICU, it was impractical to measure the impact of such a broad range of interventions in a methodical manner. The full effect of these interventions will not likely be evident until NICU graduates have grown into childhood and adolescence. These constraints limited the scope of this QI project to the practicalities of identifying neuroprotective best practice and bringing it to the bedside. When combined with evidence-based medical and nursing care, neuroprotective care represents the best means of facilitating normal development and minimizing disability for our NICU graduates. PMID- 29261517 TI - Treatment Approach to Severe Microgenia Cases: Combined Use of Osseous and Implant Genioplasty. AB - INTRODUCTION: As well as the chin is an important esthetic unit of the facial structure, it is also the region having a key role in the appearance of the face. Correction of cosmetic and functional deformities that may occur in this region because of serious hypoplasia (microgenia) is performed by chin augmentation. Chin augmentation is most frequently performed via implant or osseous genioplasty in the literature. Both 2 techniques have their own advantages and disadvantages. In the literature, various studies comparing these 2 techniques and their long term results are present, but in some severe microgenia cases, these techniques can be insufficient only for augmentation. In such cases, combined use of implant and osseous genioplasty techniques can come up and data and experiences regarding such combined uses are limited in the literature. In our study, we aim to report our experiences and long-term results regarding 3 cases to whom chin augmentation combined with implant and osseous method is applied because of serious chin hypoplasia (microgenia). METHOD: Three patients to whom chin augmentation combined with osseous and implant genioplasty was applied because of severe microgenia between 2011 and 2016 are included in our study. Before the chin restoration, orthognathic surgery or maxillomandibular distraction applications owing to existing obstructive sleep apnea, malocclusion, or facial asymmetry, are performed in the patients. In preoperative period, chin augmentation amount required is planned for all the patients via cephalometric analysis and the operations of all the patients are performed under general anesthesia via intraoral access. RESULTS: Among 3 patients, 2 were male and 1 was female and their mean age was 27.3 years (22-33). In all the patients, primarily horizontal subapical sliding osteotomy was performed and advancement was performed. After osteotomy, mean 8-mm osseous advancement was obtained and Medpor implant was placed in the chin at the same session for additional augmentation. Mean advancement amount obtained by the Medpor implants was 9 mm. A total average of 17-mm augmentation was obtained in the patients via osseous and implant genioplasty. The reflection of this advancement amount on the soft tissue was measured as 13 mm. Mean follow-up period is 24 months and the patients did not encounter with a major complication in the postoperative period. In the postoperative period, early-period band application was performed at the chin of the patients to reduce edema and to support immobilization. CONCLUSIONS: Chin contour is an important part of facial aesthetics and osseous genioplasty is the ideal treatment option for the correction of most chin deformities. However, in some serious microgenia cases, osseous genioplasty may be insufficient to correct the existing deformity. In such cases, it is seen that the combined correction procedures to be applied together with the implant use can be applicable in terms of the safety and its long-term results. PMID- 29261518 TI - Surgical Treatment of Unicoronal Synostosis: A Simplified Technique without Orbital Osteotomy. AB - BACKGROUND: Although referrals for nonsyndromic frontal plagiocephaly have been increased during the past several years, successful surgical repair of unicoronal synostosis (UCS) remains a challenge for craniofacial surgeons. Most surgical techniques followed to correct supraorbital rim elevation and temporal constrictions are being noticed less and often require a secondary revision. But this new technique consists of correcting the affected ipsilateral frontal, temporal, and superior orbital rim areas in the first operation. METHODS: From 1995 to 2016, a total of 154 cases of UCS were operated by first author. A total of 91 patients were operated with standard technique, whereas the new technique was applied on 63. Whitaker scoring system was used for evaluation of patients after surgery. RESULTS: Data analysis shows a significant difference between 2 operation techniques results (P = 0.007). None of the patients from the new technique group required revision surgery. CONLUSIONS: We believe that our new technique have less invasive osteotomy on the frontal bone and no manipulation of the orbital bone, so provide sufficient bone graft and is applicable even for younger patients (<6 months). PMID- 29261520 TI - Inferior Parietal Cortex Hypoperfusion is the Most Specific Imaging Marker for AD Patients With Positive CSF Biomarker Assays in a Memory Clinic in France. AB - The diagnostic accuracy of hexamethylpropyleneamine oxime (HMPAo) single-photon emission computed tomography (SPECT) in Alzheimer disease (AD) remains undetermined in a "real-life" clinical population. The objective was to determine the HMPAo SPECT hypoperfusion pattern in cognitively impaired patients with positive CSF AD biomarker and to evaluate its diagnostic accuracy. This study included 120 patients referred to a university memory clinic assessed using HMPAo SPECT, MRI, and CSF biomarkers. Three biomarker signatures suggestive of AD were analyzed (1, Abeta1-42; 2, Abeta1-42+t-tau and/or p-tau; 3, Abeta1-42/p-tau). The clinical diagnoses were possible AD (n=29) or other causes of cognitive impairment (n=91). All CSF AD signatures were significantly (1, P=0.004; 2, P=0.017; 3, P=0.024) associated with the difference between inferior parietal perfusion and lateral dorsal frontal cortex perfusion. The hypoperfusion pattern discriminated between patients with positive CSF AD biomarkers and those with other cognitive impairments with a sensitivity of 67% to 71% and a specificity of 63% to 65% and a greatest negative predictive value (NPV) of 90%. Inferior parietal cortex hypoperfusion was the most sensitive and specific feature in AD patients diagnosed using clinical and CSF biomarker criteria. This hypoperfusion pattern was associated with an NPV of 90% and therefore discriminated sharply between AD and other cognitive disorders. PMID- 29261519 TI - Diabetic Retinopathy and Dementia in Type 1 Diabetes. AB - OBJECTIVE: Retinopathy impacts over one-third of those with diabetes mellitus and is associated with impaired cognitive performance and cerebrovascular lesions in middle-aged adults with type 1 diabetes. However, the association between diabetic retinopathy (DR) and risk of dementia in type 1 diabetes is unknown. We investigated the association between DR and incident dementia in a large, elderly population with type 1 diabetes. METHODS: A cohort of 3742 patients with type 1 diabetes aged 50 years and above was followed from January 1, 1996 to September 30, 2015 for incident dementia. DR diagnoses were identified from electronic medical records. Age as timescale Cox proportional hazard models evaluated associations between time-updated DR and dementia risk. Models were adjusted for demographics, severe glycemic events, glycosylated hemoglobin, and vascular comorbidities. RESULTS: Among 3742 patients with type 1 diabetes (47% female, 21% nonwhite), 182 (5%) were diagnosed with dementia during a mean follow-up of 6.2 years. No significant association was found between DR and incident dementia in the main analyses [adjusted Hazard Ratio=1.12; 95% confidence interval, 0.82 1.54), nor among subgroup restricted to those aged 60 years and above or 70 years and above. CONCLUSIONS: DR was not associated with risk of dementia, suggesting that pathophysiological processes underlying dementia may be different in type 1 versus type 2 diabetes. PMID- 29261521 TI - Quantitative analysis of intraventricular flow-energetics and vortex in ischaemic hearts. AB - OBJECTIVE: This study investigated the intraventricular flow dynamics in ischaemic heart disease patients. PATIENTS AND METHODS: Fourteen patients with normal ejection fraction and 16 patients with reduced ejection fraction were compared with 20 healthy individuals. Phase-contrast MRI was used to assess intraventricular flow variables and speckle-tracking echocardiography to assess myocardial strain and left ventricular (LV) dyssynchrony. Infarct size was acquired using delayed-enhancement MRI. RESULTS: The results obtained showed no significant differences in intraventricular flow variables between the healthy group and the patients with normal ejection fraction group, whereas considerable reductions in kinetic energy (KE) fluctuation index, E' (P<0.001) and vortex KE (P=0.003) were found in the patients with reduced ejection fraction group. In multivariate analysis, only vortex KE and infarct size were significantly related to LV ejection fraction (P<0.001); furthermore, vortex KE was correlated negatively with energy dissipation, energy dissipation index (r=-0.44, P=0.021). CONCLUSION: This study highlights that flow energetic indices have limited applicability as early predictors of LV progressive dysfunction, whereas vortex KE could be an alternative to LV performance. PMID- 29261523 TI - A British Perspective on the American College of Surgeons Conversation About Firearm Safety. PMID- 29261522 TI - Along for the Ride?: Surgeon Participation in Accountable Care Organizations. PMID- 29261525 TI - Pylorus Resection Does Not Reduce Delayed Gastric Emptying After Partial Pancreatoduodenectomy: A Blinded Randomized Controlled Trial. PMID- 29261524 TI - Core Set of Patient-reported Outcomes in Pancreatic Cancer (COPRAC): An International Delphi Study Among Patients and Health Care Providers. AB - OBJECTIVE: To establish an international core set of patient-reported outcomes (PROs) selected by both patients and healthcare providers (HCPs) from the United States (US), Europe, and Asia. SUMMARY BACKGROUND DATA: PROs are increasingly recognized in pancreatic cancer studies. There is no consensus on which of the many available PROs are most important. METHODS: A multicenter Delphi study among patients with pancreatic cancer (curative- and palliative-setting) and HCPs in 6 pancreatic centers in the US (Baltimore, Boston), Europe (Amsterdam, Verona), and Asia (Mumbai, Seoul) was performed. In round 1, participants rated the importance of 56 PROs on a 1 to 9 Likert scale. PROs rated as very important (scores 7-9) by the majority (>=80%) of curative- and/or palliative-patients as well as HCPs were included in the core set. PROs not fulfilling these criteria were presented again in round 2, together with feedback on individual and group ratings. Remaining PROs were ranked based on the importance ratings. RESULTS: In total 731 patients and HCPs were invited, 501 completed round 1, and 420 completed both rounds. This included 204 patients in curative-setting, 74 patients in palliative-setting, and 142 HCPs. After 2 rounds, 8 PROs were included in the core set: general quality of life, general health, physical ability, ability to work/do usual activities, fear of recurrence, satisfaction with services/care organization, abdominal complaints, and relationship with partner/family. CONCLUSIONS: This international Delphi study among patients and HCPs established a core set of PROs in pancreatic cancer, which should facilitate the design of future pancreatic cancer trials and outcomes research. PMID- 29261526 TI - Response: Hidden Costs of Hospitalization After Firearm Injury. PMID- 29261527 TI - Preoperative Evaluation Is Not Predictive of Transpyloric Feeding Conversion in Gastrostomy-dependent Pediatric Patients. AB - OBJECTIVES: Limited literature exists as to whether preoperative gastrostomy (GT) evaluation may predict which patients will go onto require gastrojejunostomy (GJ) tube feeding. The goal of this study was to compare the preoperative evaluations between patients maintained on GT feeds versus patients who required conversion to GJ feeds. METHODS: We identified patients at Boston Children's Hospital who underwent GT tube placement and required GJ feeding between 2006 and 2012. GT patients were matched according to age, neurologic, and cardiac status with GJ converted patients. Preoperative characteristics, rates of total hospitalizations, and respiratory-related admissions were reviewed. RESULTS: A total of 79 GJ patients (median interquartile range (IQR): age 15 (4.3, 55.7) months; weight 8.8 (4.6, 14.5) kg) were matched with 79 GT patients (median (IQR): age 14.6 (4.7, 55.7) months; weight 8.5 (5, 13.6) kg). Median time from GT to GJ conversion was 8 (IQR 3, 16) months. Both groups had similar rates of successful preoperative nasogastric feeding trials (GT (84.5%) versus GJ (83.1%), P = 1.0), upper gastrointestinal series (GT (89.1%) versus GJ (93.2%), P = 0.73), abnormal videofluoroscopic swallow studies (GT (53.8%) versus GJ (62.2%), P = 0.4), and completion of gastric emptying studies (GT (10.1%) versus GJ (5.1%), P = 0.22). No differences were seen in preoperative hospitalization rates (P = 0.25), respiratory admissions (P = 0.36), although GJ patients had a mean reduction in the number of hospitalization of -1.5 +/- 0.5 days, P < 0.001, after conversion. CONCLUSIONS: No differences in preoperative patient characteristics or diagnostic evaluations were seen in GT fed versus GJ converted patients. GJ patients did experience an overall decrease in total admissions after GJ conversion. PMID- 29261528 TI - Clinical Presentation and Outcomes of Diagnostic Endoscopy in Newly Presenting Children With Gastrointestinal Symptoms. AB - OBJECTIVES: Paediatric endoscopy is an important diagnostic tool; however, there is little published data to guide clinicians in selecting patients for endoscopy. This study aimed to evaluate a single centre's experience of newly presenting children focusing on presenting symptoms, investigations, and diagnostic yield. METHODS: Clinical factors and endoscopic plus histological findings over a 6 month period were assessed. Only first diagnostic endoscopies were included. All biopsies were reviewed in a weekly histopathology multidisciplinary team meeting with a final agreed outcome. Abnormal histology was used as the criterion standard for reporting abnormality. RESULTS: A total of 218 endoscopies were reviewed in 164 children. Approximately 65% were histologically normal (49% of children had macroscopically and histologically normal findings). Macroscopic and histological abnormalities (respectively) were 44% and 28% of oesophagogastroduodenoscopy (OGD) patients, 25% and 25% of colonoscopy alone, and 53% and 53% of those undergoing both OGD and colonoscopy (OGD&Col). For OGD-only patients, excluding those with raised anti-tissue transglutaminase antibodies, vomiting led to the highest rate of abnormal histology (22%). For colonoscopy only and OGD&Col patients, per rectum bleeding led to the highest rates of abnormal histology (14% and 29%, respectively), after excluding those with laboratory abnormalities (anaemia and raised erythrocyte sedimentation rate) suggestive of inflammatory bowel disease. CONCLUSIONS: This study showed that half of all first diagnostic endoscopies in our unit had neither macroscopic nor histological abnormalities. There was discrepancy between macroscopic abnormalities and histological findings in OGD. Prospective studies are needed to develop guidelines in appropriately predicting abnormality and selecting patients for endoscopy. PMID- 29261529 TI - Non-cirrhotic Portal Fibrosis in a Young Girl. PMID- 29261530 TI - CFTR Protein Function Modulation Therapy Is Finally Targeting Cystic Fibrosis related Gastrointestinal Disease. PMID- 29261531 TI - Impact of Contrast Media Concentration on Low-Kilovolt Computed Tomography Angiography: A Systematic Preclinical Approach. AB - OBJECTIVES: Low peak kilovoltage (kVp) protocols in computed tomography angiography (CTA) demand a review of contrast media (CM) administration practices. The aim of this study was to systematically evaluate different iodine concentrations of CM in a porcine model. MATERIALS AND METHODS: Dynamic 70 kVp CTA was performed on 7 pigs using a third-generation dual-source CT system. Three CM injection protocols (A-C) with an identical total iodine dose and iodine delivery rate (150 mg I/kg, 12 s, 0.75 g I/s) differed in iodine concentration and flow rate (protocol A: 400 mg I/mL, 1.9 mL/s; B: 300 mg I/mL, 2.5 mL/s; C: 150 mg I/mL, 5 mL/s). All protocols were applied in a randomized order and compared intraindividually. Arterial enhancement at different locations in the pulmonary artery, the aorta, and aortic branches was measured over time. Time attenuation curves, peak enhancement, time to peak, and bolus tracking delay times needed for static CTA were calculated. The reproducibility of optimal parameters was tested in single-phase CTA. RESULTS: The heart rates of the pigs were comparable for all protocols (P > 0.7). The injection pressure was significantly higher for protocol A (64 +/- 5 psi) and protocol C (55 +/- 3 psi) compared with protocol B (39 +/- 2 psi) (P < 0.001). Average arterial peak enhancement in the dynamic scans was 359 +/- 51 HU (protocol A), 382 +/- 36 HU (B), and 382 +/- 60 HU (C) (A compared with B and C: P < 0.01; B compared with C: P = 0.995). Time to peak enhancement decreased with increasing injection rate. The delay time for bolus tracking depended on the injection rate as well and was highest for protocol A (4.7 seconds) and lowest for protocol C (3.9 seconds) (P = 0.038). The peak enhancement values of the dynamic scans highly correlated with those of the single-phase CTA scans. CONCLUSIONS: In 70 kVp CTA, 300 mg I/mL iodine concentrations showed to be superior to high-concentration CM when keeping the iodine delivery rate constant. Besides, iodine concentrations as low as 150 mg I/mL can be administered without compromising vascular enhancement. This opens up new possibilities in CM administration. PMID- 29261532 TI - T2 Mapping for Noninvasive Assessment of Interstitial Edema in Acute Cardiac Allograft Rejection in a Mouse Model of Heterotopic Heart Transplantation. AB - OBJECTIVES: Heart transplantation (HTX) in mice is used to characterize gene deficient mice and to test new treatment strategies. The purpose was to establish noninvasive magnetic resonance imaging techniques in mice to monitor pathophysiological changes of the allograft during rejection. MATERIALS AND METHODS: Magnetic resonance imaging was performed at baseline and days 1 and 6 after isogenic (n = 10, C57BL/6) and allogenic (n = 12, C57BL/6 to BALB/c) heterotopic HTX on a 7 T small animal scanner. Respiratory- and electrocardiogram gated multislice multi-echo spin echo sequences were acquired, and parameter maps of T2 relaxation time were generated. T2 times in septal, anterior, lateral, and posterior myocardial segments as well as global T2 times were calculated and compared between groups. At day 7 animals were sacrificed and graft pathology was assessed by semiquantitative regional analysis and correlated with magnetic resonance imaging results. RESULTS: Myocardial T2 relaxation time was significantly increased in allogenic (33.4 +/- 0.1 ms) and isogenic cardiac grafts (31.8 +/- 1.8 ms) on day 1 after HTX compared with healthy donor hearts at baseline (23.1 +/- 0.3 ms, P < 0.001). Until day 6 after HTX, myocardial T2 further increased markedly in allografts but not in isografts (43.4 +/- 1.9 vs 31.2 +/- 1.1 ms, P < 0.001). Mean segmental T2 values as well as mean global T2 values in allogenic compared with isogenic cardiac grafts on day 6 were significantly higher (P < 0.01). Histologically, isogenic grafts were almost normal besides small focal leukocyte infiltrates and signs of interstitial edema, most likely due to ischemia reperfusion injury (histological sum score, 0.9 +/- 0.4). In allogenic HTX, histology revealed severe inflammation and tissue edema representing allograft rejection with increased histological scores (5.3 +/- 0.7, P < 0.001). Higher histological scores of rejection were significantly associated with increased T2 times on a segmental and a global level. CONCLUSIONS: We could show that T2 mapping is a suitable noninvasive imaging method to monitor global and regional HTX pathologies in experimental heart transplantation in mice. Progressive prolongation of T2 time was significantly associated with pathological signs of rejection. PMID- 29261534 TI - Second-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist: Effect of Inpatient Rehabilitation vs a Monitored Home-Based Program on Mobility in Patients With Total Knee Arthroplasty: The HIHO Randomized Clinical Trial. PMID- 29261533 TI - Intra-articular Triamcinolone Versus Hyaluronate Injections for Low Back Pain With Symptoms Suggestive of Lumbar Zygapophyseal Joint Arthropathy: A Pragmatic, Double-Blind Randomized Controlled Trial. AB - OBJECTIVE: The aim of the study was to compare hyaluronate with triamcinolone injections in treating chronic low back pain suggestive of lumbar zygopophyseal joint arthropathy. DESIGN: This was a prospective, double-blind, randomized controlled trial. Thirty subjects were randomly assigned to receive bilateral L3 S1 lumbar zygopophyseal joint injections with triamcinolone (KA) or Synvisc-One (HA). Pain (visual analog scale) and Pain Disability Questionnaire scores at 1, 3, and 6 mos were evaluated. RESULTS: No significant intergroup differences (P > 0.05) in outcomes were noted in the 30 recruited subjects. For KA/HA (baseline; 1 mo; 3 mos; 6 mos), visual analog scale scores were the following: 70 (15)/74 (10); 58 (29)/45 (25); 58 (29)/56 (25); and 59 (28)/63 (24), respectively. Pain Disability Questionnaire scores were the following: 100 (23)/102 (28); 77 (30)/74 (34); 87 (26)/74 (36); and 96 (25)/79 (25). Overall percent improvement at 6 mos for KA was 51 (35) and for HA was 42 (33) (P = 0.51). Synvisc-One group visual analog scale scores improved significantly (70 [20]-45 [25] at 1 mo, P = 0.008). Pain Disability Questionnaire scores improved at 1 mo (100 [23]-77 [30], P = 0.009) in the KA group and at all time points in the HA group (102 [28]-74 [34] at 1 mo, P = 0.002; 74 [36] at 3 mos, P = 0.037; 79 at 6 mos [median = 52-99.5], P < 0.001). Medians and quartiles were used in statistical analysis when data did not pass normality. CONCLUSIONS: Patients with chronic low back pain suggestive of lumbar lumbar zygopophyseal joint arthropathy responded similarly to triamcinolone or hyaluronate injections. Synvisc-One group showed significant short- and long-term functional improvement and short-term pain improvement; KA group showed only significant short-term functional benefit and no significant short- or long-term pain improvement. PMID- 29261535 TI - Limbic and Basal Ganglia Neuroanatomical Correlates of Gait and Executive Function: Older Adults With Mild Cognitive Impairment and Intact Cognition. AB - OBJECTIVE: This study aimed to examine differences in spatiotemporal gait parameters between older adults with amnestic mild cognitive impairment and normal cognition and to examine limbic and basal ganglia neural correlates of gait and executive function in older adults without dementia. DESIGN: This was a cross-sectional study of 46 community-dwelling older adults, ages 70-95 yrs, with amnestic mild cognitive impairment (n = 23) and normal cognition (n = 23). Structural magnetic resonance imaging was used to attain volumetric measures of limbic and basal ganglia structures. Quantitative motion analysis was used to measure spatiotemporal parameters of gait. The Trail Making Test was used to assess executive function. RESULTS: During fast-paced walking, older adults with amnestic mild cognitive impairment demonstrated significantly slower gait speed and shorter stride length compared with older adults with normal cognition. Stride length was positively correlated with hippocampal, anterior cingulate, and nucleus accumbens volumes (P < 0.05). Executive function was positively correlated with hippocampal, anterior cingulate, and posterior cingulate volumes (P < 0.05). CONCLUSIONS: Compared with older adults with normal cognition, those with amnestic mild cognitive impairment demonstrated slower gait speed and shorter stride length, during fast-paced walking, and lower executive function. Hippocampal and anterior cingulate volumes demonstrated moderate positive correlation with both gait and executive function, after adjusting for age. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) discuss gait performance and cognitive function in older adults with amnestic mild cognitive impairment versus normal cognition, (2) discuss neurocorrelates of gait and executive function in older adults without dementia, and (3) recognize the importance of assessing gait speed and cognitive function in the clinical management of older adults at risk for dementia. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 29261536 TI - Sleeping, TV, Cognitively Stimulating Activities, Physical Activity, and Attention-Deficit Hyperactivity Disorder Symptom Incidence in Children: A Prospective Study. AB - OBJECTIVE: To analyze associations between time spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity, all at 4 years, and (1) attention-deficit/hyperactivity disorder (ADHD) symptoms and (2) behavior problems, both assessed at 7 years, in ADHD-free children at baseline. METHOD: In total, 817 participants of the Infancia y Medio Ambiente birth cohort, without ADHD at baseline, were included. At the 4-year follow-up, parents reported the time that their children spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity. At the 7-year follow-up, parents completed the Conners' Parent Rating Scales and the Strengths and Difficulties Questionnaire, which measure ADHD symptoms and behavior problems, respectively. Negative binomial regression models were used to assess associations between the activities at 4 years and ADHD symptoms and behavior problems at 7 years. RESULTS: Children (48% girls) spent a median (p25-p75) of 10 (10-11) hours per day sleeping, 1.5 (0.9-2) hours per day watching TV, 1.4 (0.9-1.9) hours per day engaging in cognitively stimulating activities, and 1.5 (0.4-2.3) hours per day engaging in physical activity. Longer sleep duration (>10 hours per day) was associated with a lower ADHD symptom score (adjusted incidence rate ratio = 0.97, 95% confidence interval, 0.95-1.00). Longer time spent in cognitively stimulating activities (>1 hours per day) was associated with lower scores of both ADHD symptoms (0.96, 0.94-0.98) and behavior problems (0.89, 0.83-0.97). Time spent watching TV and engaging in physical activity were not associated with either outcomes. CONCLUSION: A shorter sleep duration and less time spent in cognitively stimulating activities were associated with an increased risk of developing ADHD symptoms and behavior problems. PMID- 29261537 TI - Work-family culture within hospitals: An interdepartmental analysis of employee engagement and retention. AB - BACKGROUND: Helping employees balance their work and family needs is increasingly pivotal for attracting, engaging, and retaining key talent in health care. Yet, emerging theory and anecdotal evidence suggest that, within organizations, there is considerable variation between departments or units regarding how employees' lives outside work are supported. Despite top management's efforts to develop a unified organizational work-family culture, departments have a tendency to take on their own culture, norms, and traditions such that some are more supportive than others. PURPOSE: We investigate whether more positive work-family cultures improve functioning within hospital departments. METHODOLOGY/APPROACH: We surveyed 680 hospital employees nested within 60 departments at a hospital located in the southeastern United States. RESULTS: Departments with a more (vs. less) positive work-family culture tend to have higher levels of (a) employee engagement, (b) pride in their organization, (c) confidence in management and leadership, and (d) intention to remain with the organization. Our analyses were robust when splitting the sample between clinical (e.g., nurses and physicians) and nonclinical (e.g., office, clerical, and support services) roles. CONCLUSION: Our study sheds further light on the importance of a positive work-family culture within hospitals. The key to instilling a positive, organization-wide work-family culture may be through a department-by-department focus. PRACTICE IMPLICATIONS: Benefits of positive work-family cultures within departments can extend beyond job-related attitudes and can potentially enhance recruitment strategies, improve a hospital's external image to the public, and lead to improvements in patient care and more positive patient experiences. PMID- 29261538 TI - The Current Use of United States Medical Licensing Examination Step 1 Scores: Holistic Admissions and Student Well-Being Are in the Balance. AB - United States Medical Licensing Examination Step 1 scores increasingly are being used by graduate medical education programs to "screen out" applicants to invite for an interview; medical students with scores below a certain (usually unpublished) point are not considered for an interview. Conversely, many students are extended an interview invitation based solely on their Step 1 scores, prior to the release of their Medical Student Performance Evaluation. In this Invited Commentary, the author discusses why this practice has gained popularity as well as the unintended effects it has had in multiple domains-holistic undergraduate medical education admissions practices, student well-being, and medical school curricula. Possible solutions are considered, including a pass/fail reporting structure, a national basic science curriculum, and better alignment between undergraduate and graduate medical education admissions processes and values. Through collaborative work between the Association of American Medical Colleges, the National Board of Medical Examiners, the Accreditation Council for Graduate Medical Education, and medical educators, an alternative, more holistic standardized metric by which to compare students' applications should be developed. PMID- 29261539 TI - The ASPIRE-to-Excellence Program: A Global Effort to Improve the Quality of Medical Education. AB - Publications and organizations ranking medical schools rely heavily on schools' research-oriented and grant-success data because those are the publicly available data. To address the vacuum of evidence for medical education quality, in 2012 the Association for Medical Education in Europe (AMEE) introduced an initiative entitled A Schools Programme for International Recognition of Excellence in Education (ASPIRE) awards. ASPIRE panels of international experts in specific areas of medical education have developed internationally peer-based criteria to benchmark excellence in social accountability, student engagement, student assessment, faculty development, and simulation; they plan to publish criteria on curriculum design and development in 2018. Schools are encouraged to use ASPIRE criteria to challenge themselves and, for a fee, may submit evidence that they have met the criteria for excellence in one or more of the five areas. The international panels then judge the evidence submitted by the school and determine whether an award of excellence is merited.The authors share lessons learned from five years of program experience. Of the 88 schools submitting evidence, 38 have been recognized for their excellence in one of the ASPIRE topic areas. As the number of representatives from the schools that are awarded ASPIRE recognition continues to increase and those individuals find new ways to contribute, hopes are high for this program. Challenges remain in how to better define excellence in low-resources settings, what new areas to take on, and how to keep infrastructure costs down. However, as an example of continuing global interaction for quality improvement, optimism prevails. PMID- 29261541 TI - The Medical School Admissions Process and Meeting the Public's Health Care Needs: Never the Twain Shall Meet? AB - Medical schools typically assess how good their selection process is using metrics such as students' assessment performance and the success of alumni on later indicators of academic ability and clinical competence, such as Royal College of Physicians or specialty board examinations. Addressing global issues with the maldistribution of doctors and increasing numbers of new medical school graduates choosing not to work in a clinical context requires different measurements of medical school admissions processes, like those related to graduates' career outcomes (e.g., working in underserved regions and/or working in certain specialties). This shift in focus is not straightforward. Medical education is a complex social system where, intentionally or not, medical schools focus on reproducing cultural, historical, and social norms. Simple solutions are often proposed, but they are insufficient to address these complex drivers. Instead, it is time to step back and think very differently about medical school admissions. In this Invited Commentary, the author proposes new solutions to address these issues, including bringing into the medical school selection process the perspectives of other key stakeholders; increasing collaboration and dialogue across these stakeholder groups; changing the performance metrics by which medical schools are assessed in the global education marketplace; and developing and evaluating new selection processes and tools. Medical schools must engage more reflectively and collaboratively in debates about how to align medical school admissions and meeting the health care needs of the public. PMID- 29261540 TI - Looking Back to Move Forward: First-Year Medical Students' Meta-Reflections on Their Narrative Portfolio Writings. AB - The day-to-day rigors of medical education often preclude learners from gaining a longitudinal perspective on who they are becoming. Furthermore, the current focus on competencies, coupled with concerning rates of trainee burnout and a decline in empathy, have fueled the search for pedagogic tools to foster students' reflective capacity. In response, many scholars have looked to the tradition of narrative medicine to foster "reflective spaces" wherein holistic professional identity construction can be supported. This article focuses on the rationale, content, and early analysis of the reflective space created by the narrative medicine-centered portfolio at the Columbia University Vagelos College of Physicians and Surgeons. In January 2015, the authors investigated learning outcomes derived from students' "Signature Reflections," end-of-semester meta reflections on their previous portfolio work. The authors analyzed the Signature Reflections of 97 (of 132) first-year medical students using a constant comparative process. This iterative approach allowed researchers to identify themes within students' writings and interpret the data. The authors identified two overarching interpretive themes-recognition and grappling-and six subthemes. Recognition included comments about self-awareness and empathy. Grappling encompassed the subthemes of internal change, dichotomies, wonder and questioning, and anxiety. Based on the authors' analyses, the Signature Reflection seems to provide a structured framework that encourages students' reflective capacity and the construction of holistic professional identity. Other medical educators may adopt meta-reflection, within the reflective space of a writing portfolio, to encourage students' acquisition of a longitudinal perspective on who they are becoming and how they are constructing their professional identity. PMID- 29261542 TI - Extracorporeal Membrane Oxygenation Appropriateness: An Interdisciplinary Consensus-Based Approach. AB - We describe a quality improvement initiative aimed at achieving interdisciplinary consensus about the appropriate delivery of extracorporeal membrane oxygenation (ECMO). Interdisciplinary rounds were implemented for all patients on ECMO and addressed whether care was consistent with a patient's minimally acceptable outcome, maximally acceptable burden, and relative likelihood of achieving either. The rounding process was associated with decreased days on venoarterial ECMO, from a median of 6 days in 2014 (first quartile [Q1]-third quartile [Q3], 3 10) to 5 days in 2015 (Q1-Q3, 2.5-8) and in 2016 (Q1-Q3, 1-8). Our statistical methods do not allow us to conclude that this change was due to our intervention, and it is possible that the observed decreases would have occurred whether or not the rounding process was implemented. PMID- 29261543 TI - Endotracheal Tube Connector: Holding Breaths! PMID- 29261544 TI - Mu-Opioid Receptors in Ganglia, But Not in Muscle, Mediate Peripheral Analgesia in Rat Muscle Pain. AB - BACKGROUND: Previous studies have demonstrated the participation of peripheral MU opioid receptors (MOR) in the antinociceptive effect of systemically administered morphine and loperamide in an orofacial muscle pain model, induced by hypertonic saline, but not in a spinally innervated one, in rats. In this study, we determine whether this peripheral antinociceptive effect is due to the activation of MOR localized in the muscle, ganglia, or both. METHODS: To determine the local antinociceptive effect of morphine and loperamide, 2 models of acute muscle pain (trigeminal and spinal) were used. Also, to study the MOR expression, protein quantification was performed in the trigeminal and spinal ganglia, and in the muscles. RESULTS: The behavioral results show that the intramuscular injection of morphine and loperamide did not exert an antinociceptive effect in either muscle (morphine: P = .63, loperamide: P = .9). On the other hand, MOR expression was found in the ganglia but not in the muscles. This expression was on average 44% higher (95% confidence interval, 33.3-53.9) in the trigeminal ganglia than in the spinal one. CONCLUSIONS: The peripheral antinociceptive effect of systemically administered opioids may be due to the activation of MOR in ganglia. The greater expression of MOR in trigeminal ganglia could explain the higher antinociceptive effect of opioids in orofacial muscle pain than in spinal muscle pain. Therefore, peripheral opioids could represent a promising approach for the treatment of orofacial pain. PMID- 29261545 TI - The Effect of High-Frequency, Structured Expert Feedback on the Learning Curves of Basic Interventional Ultrasound Skills Applied to Regional Anesthesia. AB - BACKGROUND: Proficiency in needle-to-ultrasound beam alignment and accurate approach to structures are pivotal for ultrasound-guided regional anesthesia. This study evaluated the effects of high-frequency, structured expert feedback on simulation training of such abilities. METHODS: Forty-two subjects randomly allocated as controls or intervention participated in two 25-trial experiments. Experiment 1 consisted of inserting a needle into a bovine muscular phantom parallel to the ultrasound beam while maintaining full imaging of the needle. In experiment 2, the needle aimed to contact a target inside the phantom. Intervention subjects received structured feedback between trials. Controls received a global critique after completing the trials. The slopes of the learning curves derived from the sequences of successes and failures were compared. Change-point analyses identified the start and the end of learning in trial sequences. The number of trials associated with learning, the number of technical errors, and the duration of training sessions were compared between intervention and controls. RESULTS: In experiment 1, learning curves departed from 73% (controls) and 76% (intervention) success rates; slopes (standard error) were 0.79% (0.02%) and 0.71% (0.04), respectively, with mean absolute difference of 0.18% (95% confidence interval [CI], 0.17%-0.19%; P = 0). Intervention subjects' learning curves were shorter and steeper than those of controls. In experiment 2, the learning curves departed from 43% (controls) and 80% (intervention) success rates; slopes (standard error) were 1.06% (0.02%) and 0.42% (0.03%), respectively, with a mean difference of 0.65% (95% CI, 0.64% 0.66%; P = 0). Feedback was associated with a greater number of trials associated with learning in both experiment 1 (mean difference, 1.55 trials; 95% CI, 0.15-3 trials; P = 0) and experiment 2 (mean difference, 4.25 trials; 95% CI, 1.47-7.03 trials; P = 0) and a lower number of technical errors per trial in experiments 1 (mean difference, 0.19; 95% CI, 0.07-0.30; P = .02) and 2 (mean difference, 0.58; 95% CI, 0.45-0.70; P = 0), but longer training sessions in both experiments 1 (mean difference, 9.2 minutes; 95% CI, 4.15-14.24 minutes; P = .01) and 2 (mean difference, 7.4 minutes; 95% CI, 1.17-13.59 minutes; P = .02). CONCLUSIONS: High frequency, structured expert feedback compared favorably to self-directed learning, being associated with shorter learning curves, smaller number of technical errors, and longer duration of in-training improvement, but increased duration of the training sessions. PMID- 29261546 TI - Why a Proactive Perioperative Medicine Policy Is Crucial for a Sustainable Population Health Strategy. PMID- 29261547 TI - Intravenous Iron for Treatment of Anemia in the 3 Perisurgical Phases: A Review and Analysis of the Current Literature. AB - Anemia is a common comorbidity throughout the entire hospital stay. Treatment options include intravenous (IV) iron, oral iron, erythropoietin, and red blood cell (RBC) transfusions. IV iron has gained in popularity with the implementation of patient blood management programs. A variety of studies have been performed to investigate the use of IV iron in preoperative, perioperative, and postoperative settings. An objective review on these studies has yet to be performed. The current narrative review provides an overview of trials investigating IV iron use in the preoperative, perioperative, and postoperative settings. We performed a literature research of English articles published between 1964 and March 2017 in Pubmed including Medline and The Cochrane Library. Only studies with a control group were included. The final review includes 20 randomized controlled trials (RCTs), 7 observational trials, and 5 retrospective studies. Measured outcomes included hemoglobin (Hb) levels, reticulocyte counts, and/or RBC concentrates. Meta-analyses of RCTs using IV iron administration before surgery led to an increase in Hb levels, a reduction of RBC use, and an improvement in patient outcome. Only a few studies investigated the use of IV iron in the perioperative setting. These studies recommended the use of perioperative IV iron in cases of severe anemia in orthopedic surgery but not in all types of surgery. Published RCTs in the postoperative setting have shown positive effects of IV iron on Hb levels, length of hospital stay, and transfusion requirements. Some studies demonstrated an increase of Hb of 0.5-1 g/dL over 4 weeks postoperatively, but the clinical relevance and effect of this increase on an improvement of patient's long-term outcomes are uncertain. To summarize, the evidence to use IV iron is strongest in the preoperative setting, while it remains an individual treatment decision to administer IV iron perioperatively or postoperatively. PMID- 29261548 TI - Prospective Observational Study of Intraoperative Anesthetic Events in District Hospitals in Namibia. AB - BACKGROUND: Access to safe surgery and anesthesia care is grossly inadequate in low- and middle-income countries, with a shortage of anesthesia providers contributing to this crisis. In Namibia, medical officers typically receive no >3 months of informal training in anesthesia. This study sought to determine the prevalence, currently unknown, of intraoperative adverse anesthetic events in this setting. Further, we assessed surgical volume, complications, and mortality outcomes at the district hospital level. METHODS: This was a prospective observational study over 7 months involving 4 district hospitals from geographically separate and diverse areas of Namibia. A standardized protocol was used to record adverse anesthetic events during surgery, surgical volume, and complications including mortality. RESULTS: A total of 737 surgical procedures were performed during the study period. There was a 10% prevalence of adverse anesthetic events intraoperatively. Of these, 70% were related to hypotension and 17% due to hypoxia and/or difficult/failed intubation. Ninety-eight percent of patients were classed as low risk (American Society of Anesthesiologists I or II). Seventy-two percent of the surgical workload was in obstetrics and gynecology, with over half being for urgent obstetrics. Perioperative mortality rate was 1.4/1000, with an overall surgical complication rate of 1.6% and a surgical infection rate of 0.8%. CONCLUSIONS: We found a 10% prevalence of adverse anesthetic events intraoperatively when anesthesia was administered by medical officers with no >3 months of informal training in this low-resource environment. The patients were considered low risk by the medical officers responsible for the anesthesia, yet these events had the potential to lead to patient harm. PMID- 29261549 TI - Continuous Noninvasive Arterial Pressure Monitoring Using the Vascular Unloading Technique (CNAP System) in Obese Patients During Laparoscopic Bariatric Operations. AB - BACKGROUND: Increasing rates of obesity create new challenges for hemodynamic monitoring in the perioperative phase. Continuous monitoring of arterial pressure (AP) is important in severely obese patients who are at particular risk for cardiovascular complications. Innovative technologies for continuous noninvasive AP monitoring are now available. In this study, we aimed to compare continuous noninvasive AP measurements using the vascular unloading technique (CNAP system; CNSystems, Graz, Austria) compared with invasive AP measurements (radial arterial catheter) in severely obese patients during laparoscopic bariatric surgery. METHODS: In 29 severely obese patients (mean body mass index 48.1 kg/m), we simultaneously recorded noninvasive and invasive AP measurements over a period of 45 minutes and averaged the measurements using 10-second episodes. We compared noninvasive (test method) and invasive (reference method) AP measurements using Bland-Altman analysis and 4-quadrant plot/concordance analysis (2-minute interval). RESULTS: We observed a mean of the differences (+/-SD, 95% limits of agreement) between the AP values obtained by the CNAP system and the invasively assessed AP values of 7.9 mm Hg (+/-9.6 mm Hg, -11.2 to 27.0 mm Hg) for mean AP, 4.8 mm Hg (+/-15.8 mm Hg, -26.5 to 36.0 mm Hg) for systolic AP, and 9.5 mm Hg (+/ 10.3 mm Hg, -10.9 to 29.9 mm Hg) for diastolic AP, respectively. The concordance rate was 97.5% for mean AP, 95.0% for systolic AP, and 96.7% for diastolic AP, respectively. CONCLUSIONS: In the setting of laparoscopic bariatric surgery, continuous noninvasive AP monitoring with the CNAP system showed good trending capabilities compared with continuous invasive AP measurements obtained with a radial arterial catheter. However, absolute CNAP- and arterial catheter-derived AP values were not interchangeable. PMID- 29261550 TI - Misaligned Feeding May Aggravate Pain by Disruption of Sleep-Awake Rhythm. AB - BACKGROUND: Increasing evidence suggests that patients with eating disorders are more likely to develop chronic pain. A misaligned diet has been reported to disrupt the sleep-awake rhythms. Combined with our previous investigation on circadian pain, we aimed to investigate the role of misaligned diet in the pain sensitivity and the underlying mechanisms. METHODS: Two-month-old C57BL/6J male mice were administered chronic constriction injury (CCI) surgery to establish neuropathic pain models. CCI mice were randomized to scheduled food access throughout the whole day (CCI-free), during the daytime (CCI-misaligned), and at night (CCI-aligned), respectively. The paw withdrawal mechanical threshold, indicating pain behavior, was measured by Von Frey. The gross motor activity pattern indicating the sleep-awake rhythm was monitored by Mini-Mitter. Melatonin (Mel) was administered to ameliorate the sleep-awake rhythm (CCI-free + Mel and CCI-misaligned + Mel). The expressions of circadian pain-related proteins were detected by quantitative polymerase chain reaction and western blot. The primary outcome is the pain threshold and the secondary outcome is the sleep-awake rhythm. RESULTS: Misaligned diet during the peri-CCI surgery period significantly decreased the paw withdrawal mechanical threshold compared with the CCI-free mice (day 14: 0.40 +/- 0.09 vs 0.64 +/- 0.15; P = .03;) and altered the sleep-awake rhythm. Mel pretreatment alleviated the increased pain (day 14, CCI-misaligned + Mel versus CCI-misaligned: day 14: 0.60 +/- 0.13 vs 0.35 +/- 0.12; P = .022) and the disrupted sleep-awake rhythm caused by misaligned feeding. The mRNA levels of N-methyl-D-aspartate receptor subtype 2B (NR2B), Ca/calmodulin-dependent protein kinase II (CaMKII), and cyclic adenosine monophosphate-response element binding protein (CREB) in the spinal dorsal horn increased in CCI-misaligned mice compared with the CCI-free mice. The phosphor-NR2B, phosphor-CaMKII, and phosphor CREB also increased in CCI-misaligned mice compared with the CCI-free mice. However, the expressions of NR2B, CaMKII, and CREB were decreased in CCI misaligned + Mel mice compared to CCI-misaligned mice at both transcriptional and translational levels. CONCLUSIONS: Misaligned diet might aggravate pain sensitivity through the disruption of the sleep-awake cycle, which could be recovered by Mel. NR2B-CaMKII-CREB may participate in the disruption of sleep awake rhythm-mediated pain aggravation. PMID- 29261552 TI - Another Historic Step Forward. PMID- 29261551 TI - Maximum allowable contrast dose and prevention of acute kidney injury following cardiovascular procedures. AB - PURPOSE OF REVIEW: Contrast-induced acute kidney injury (CI-AKI) is a serious complication. Although nonmodifiable and modifiable risk factors have been thoroughly characterized, the utility of the maximal allowable contrast dose (MACD) has not received adequate attention. The focus of this review is to provide a critical appraisal of this modifiable risk factor. RECENT FINDINGS: Several retrospective and prospective cohort studies have demonstrated that the incidence of CI-AKI among patients receiving contrast media in volumes exceeding the MACD is consistently higher compared with those who do not exceed the MACD (an average of 24 vs. 6%). Furthermore, the MACD is independent predictor of CI AKI and other adverse events. A two-step algorithm incorporating the determination of the MACD and the contrast volume to eGFR ratio prior to a planned cardiovascular procedure is a sound approach to minimize contrast volume and prevent CI-AKI. SUMMARY: Prevention of CI-AKI must remain a clinical priority. Intraprocedural preventive measures should include a priori calculation of the MACD and contrast volume to eGFR ratio to limit contrast volume. Other measures may include the adoption of the transradial approach, the use of automated contrast injectors and small catheters to limit contrast volume, the use of low-osmolar contrast agents, and if necessary the use of staged procedures. We call for the system-wide implementation of evidence-based care bundles to prevent CI-AKI. PMID- 29261553 TI - Local Modalities for Preventing Surgical Site Infections: An Evidence-based Review. AB - Surgical site infections remain a dreaded complication of orthopaedic surgery, affecting both patient economics and quality of life. It is important to note that infections are multifactorial, involving both surgical and patient factors. To decrease the occurrence of infections, surgeons frequently use local modalities, such as methicillin-resistant Staphylococcus aureus screening; preoperative bathing; intraoperative povidone-iodine lavage; and application of vancomycin powder, silver-impregnated dressings, and incisional negative-pressure wound therapy. These modalities can be applied individually or in concert to reduce the incidence of surgical site infections. Despite their frequent use, however, these interventions have limited support in the literature. PMID- 29261554 TI - The Utility of Biologics, Osteotomy, and Cartilage Restoration in the Knee. AB - The management of complex cartilage and meniscal pathology in young, athletic patients is extremely challenging. Joint preservation surgery is most difficult in patients with concomitant knee pathologies, including cartilage defects, meniscal deficiency, malalignment, and/or ligamentous insufficiency. Clinical decision making for these patients is further complicated by articular cartilage lesions, which often are incidental findings; therefore, treatment decisions must be based on the confirmed contribution of articular cartilage lesions to symptomatology. Surgical management of any of the aforementioned knee pathologies that is performed in isolation typically results in acceptable patient outcomes; however, concomitant procedures for the management of concomitant knee pathologies often are essential to the success of any single procedure. The use of biologic therapy as an alternative to or to augment more conventional surgical management has increased in popularity in the past decade, and indications for biologic therapy continue to evolve. Orthopaedic surgeons should understand knee joint preservation techniques, including biologic and reconstructive approaches in young, high-demand patients. PMID- 29261555 TI - TREATMENT OF IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS (IRVAN) WITH PHOTOCOAGULATION IN COMBINATION WITH SYSTEMIC IMMUNOSUPPRESSION. AB - BACKGROUND: Idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome is a very rare primary retinal vasculitis. It seems to evolve in stages, where there is initially a florid vasculitis associated with aneurysm formation. Neuroretinitis and macula edema are common features. Subsequently, retinal ischemia ensues, leading to neovascularization. If untreated, further sight threatening complications occur, including traction retinal detachment and secondary glaucoma. METHODS AND RESULTS: Here, we describe a patient with early idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome, who was treated with a combination of systemic immunosuppression and localized photocoagulation. There was substantial regression of the aneurysms and improvement of the macular edema. Treatment of the disorder should be based on the clinical stage and complications of the disorder. CONCLUSIONS: As shown here, a multidisciplinary approach can be very helpful in managing patients with this severe sight-threatening disorder. PMID- 29261556 TI - MACULAR BURN DURING AN ATTEMPTED YAG LASER CAPSULOTOMY BY INADVERTENT USE OF SELECTIVE LASER TRABECULOPLASTY MODE OF A DUAL-MODE LASER. AB - PURPOSE: To present a case of a patient who suffered a macular burn after an attempted YAG laser capsulotomy because of the inadvertent use of the selective laser trabeculoplasty mode of a dual-mode laser. METHOD: Case report. RESULTS: A 62-year-old man with slight opacification of the posterior capsule noted sudden central vision loss immediately after an attempted YAG laser capsulotomy. The selective laser trabeculoplasty mode of a dual-mode laser had inadvertently been used. Color photographs, fluorescein angiography, and spectral domain optical coherence tomography revealed a laser burn in the macula. The patient's central vision was impaired. CONCLUSION: Inadvertent selection of the selective laser trabeculoplasty mode when attempting to perform a YAG laser capsulotomy with a dual-mode laser may cause a macular burn with impairment of central vision. We encourage all users of dual-mode lasers to actively choose and verify the appropriate settings to minimize the risk of inadvertent retinal damage. PMID- 29261557 TI - Simple noninvasive tests for the detection of advanced liver fibrosis in patients with chronic hepatitis B. PMID- 29261559 TI - Reply. PMID- 29261560 TI - The Effect of Foot Exercises on Wound Healing in Type 2 Diabetic Patients With a Foot Ulcer. AB - PURPOSE: The purpose of this study was to investigate the effect of foot exercises on wound healing in type 2 diabetic patients with a diabetic foot ulcer. DESIGN: Prospective, randomized controlled study. SUBJECT AND SETTINGS: Sixty-five patients from an outpatient clinic with grade 1 or 2 ulcers (Wagner classification) who met study criteria agreed to participate; 60 patients completed the study and were included in the final analysis. Subjects were followed up between February 2014 and June 2015. METHODS: Subjects were recruited by the researchers in the clinics where they received treatment. Subjects were randomly allocated to either the control or intervention group. Data were collected using investigator-developed forms: patient information form and the diabetic foot exercises log. Patients in the intervention group received standard wound care and performed daily foot exercises for 12 weeks; the control group received standard wound care but no exercises. The ulcers of the patients in both the intervention and control groups were examined and measured at the 4th, 8th, and 12th weeks. The groups were compared in terms of the ulcer size and depth. To analyze and compare the data, frequency distribution, mean (standard deviation), variance analysis, and the independent samples t test and the chi test were used. RESULTS: The mean ulcer areas were 12.63 (14.43), 6.91 (5.44), 4.30 (3.70), and 3.29 (3.80) cm (P < .05) in the study intervention group, and 24.67 (20.70), 24.75 (20.84), 20.33 (20.79), and 18.52 (21.49) cm in the control group in the 4th, 8th, and 12th weeks, respectively. Significant differences were found between diabetic foot ulcer sizes in the study intervention group in the 4th and 12th weeks compared to beginning baseline (P <= .05). However, only the 12th week was different from the beginning in the control group (P = .000). The mean depths of the ulcers were 0.56 (0.85), 0.42 (0.68), 0.36 (0.50), and 0.28 (0.38) cm in the study intervention group (P < .05) and 0.61 (0.84), 0.82 (1.07), 0.83 (1.21), and 0.80 (1.26) cm in the control group, respectively, at the baseline, and at the 4th, 8th, and 12th weeks, respectively (P = .000). CONCLUSION: The ulcer areas decreased significantly in the study intervention group compared to the control group during the 3 follow-up measurements. An important finding in this study was the DFU area decreased more in those who exercised more. Findings suggests foot exercises should be included in the treatment plan when managing patients with diabetic foot ulcers. PMID- 29261562 TI - Mechanisms of attentional selection bias for threatening emotions of anger and disgust in individuals with high-trait anxiety. AB - There are still some controversies that attentional bias to negative emotions in individuals with high-trait anxiety (HTA), as compare with those with low-trait anxiety (LTA), occurs in the engagement or disengagement facet of attentional selectivity and whether this attentional bias is affected by negative emotional types. In this study, we explored the different attentional selectivity mechanisms for threatening emotions of anger and disgust between individuals with HTA and LTA using the variant attentional-probe paradigm. The results showed that under the engagement condition, the HTA group's attentional bias index of the anger mood was negative and was significantly less than the disgusting mood (positive) and that the P1 was smaller with angry faces as compared with neutral faces, which was separate from the results of the disgusted faces, having a significant difference with neutral faces on P1 component. In the LTA group, under the disengagement condition, the attentional bias index of the disgusting mood was significantly bigger than the attentional bias index of the anger mood. Moreover, the P1 of the disgusted faces was significantly bigger than the P1 of the angry faces. The topographical maps were also made to reveal the different neural underpinnings. The results suggested that there were different mechanisms of selective attentional bias for threatening emotions of anger and disgust in individuals with HTA. HTA individuals were characterized by facilitated attentional engagement with angry faces and impaired attentional engagement with disgusted faces. LTA individuals had different neural underpinnings and had impaired attentional disengagement with disgusted faces. PMID- 29261561 TI - Preterm Stress Behaviors, Autonomic Indices, and Maternal Perceptions of Infant Colic. AB - BACKGROUND: While biological and behavioral stress response systems are intact in early gestation, preterm infants' behaviors are often more subtle and difficult to interpret compared with full-term infants. They are also more vulnerable for regulatory issues (ie, colic) that are known to impact caregiver-infant interactions. Biobehavioral measures such as behavioral responsivity and heart rate variability (HRV), particularly cardiac vagal tone, may help elucidate preterm infants' stress/regulatory systems. PURPOSE: To test the hypotheses that preterm infants' consoling behaviors and high-frequency (HF) HRV in the first week of life are significantly associated and they are inverse correlates of future colic risk. METHODS/SEARCH STRATEGY: Thirty preterm (mean +/- SE = 32.7 +/ 0.3 weeks postmenstrual age [PMA]) infants underwent direct NIDCAP (Newborn Individualized Development and Assessment Program) observation during routine care and had HRV measurements during their first week postbirth. Sixty-three percent of mothers completed the Infant Colic Scale at 6 to 8 weeks adjusted postnatal age. Nonparametric tests were used to determine associations among behaviors, HRV, and maternal perceptions of infant colic. FINDINGS/RESULTS: Self consoling behaviors were positively associated with HF-HRV (vagal tone). In addition, stress behaviors were positively associated with low-frequency/high frequency HRV (sympathetic dominance). Infants who displayed more stress behaviors also demonstrated more self-consoling behaviors. No significant associations were found with colic. IMPLICATIONS FOR PRACTICE: HF-HRV provides information on the infant's capacity to modulate stress and is a useful, noninvasive measure when behaviors are more difficult to discern. IMPLICATIONS FOR RESEARCH: Further study in a larger sample is needed to determine whether behavioral stress measures and HF-HRV may be useful to determine colic risk. PMID- 29261563 TI - Pediatric In-Hospital Cardiac Arrest Secondary to Acute Pulmonary Embolism. AB - OBJECTIVES: Pulmonary embolism is a rarely reported and potentially treatable cause of cardiac arrest in children and adolescents. The objective of this case series is to describe the course of five adolescent patients with in-hospital cardiac arrest secondary to pulmonary embolism. DESIGN: Case series. SETTING: Single, large academic children's hospital. PATIENTS: All patients under the age of 18 years (n = 5) who experienced an in-hospital cardiac arrest due to apparent pulmonary embolism from August 1, 2013, to July 31, 2017. INTERVENTIONS: All five patients received systemic thrombolytic therapy (IV tissue plasminogen activator) during cardiac arrest or periarrest during ongoing resuscitation efforts. MEASUREMENTS AND MAIN RESULTS: Five adolescent patients, 15-17 years old, were treated for pulmonary embolism-related cardiac arrests during the study period. These accounted for 6.3% of all children and 25% of adolescents (12-17 yr old) receiving at least 5 minutes of in-hospital cardiopulmonary resuscitation during the study period. All five had venous thromboembolism risk factors. Two patients had known, extensive venous thrombi at the time of cardiac arrest, and one was undergoing angiography at the time of arrest. The diagnoses of pulmonary embolism were based on clinical suspicion, bedside echocardiography (n = 4), and low end tidal CO2 levels relative to arterial CO2 values (n = 5). IV tissue plasminogen activator was administered during cardiopulmonary resuscitation in three patients and after the return of spontaneous circulation, in the setting of severe hemodynamic instability, in the other two patients. Four of five patients were successfully resuscitated and survived to hospital discharge. CONCLUSIONS: Pulmonary embolism was recognized as the etiology of multiple adolescent cardiac arrests in this single-center series and may be more common than previously reported. Recognition, high-quality cardiopulmonary resuscitation, and treatment with thrombolytic therapy resulted in survival in four of five patients. PMID- 29261564 TI - Long-Term Return to Functional Baseline After Mechanical Ventilation in the ICU. AB - OBJECTIVE: Predictors of long-term functional impairment in acute respiratory failure of all causes are poorly understood. Our objective was to assess the frequency and predictors of long-term functional impairment or death after invasive mechanical ventilation for acute respiratory failure of all causes. DESIGN: Population-based, observational cohort study. SETTING: Eight adult ICUs of a single center. PATIENTS: All adult patients from Olmsted County, Minnesota, without baseline functional impairment who received mechanical ventilation in ICUs for acute respiratory failure of all causes from 2005 through 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 743 patients without baseline functional impairment received mechanical ventilation in the ICU. At 1- and 5-year follow-up, the rates of survival with return to baseline functional ability were 61% (366/597) and 53% (356/669). Among 71 patients with new functional impairment at 1 year, 55% (39/71) had recovered and were alive without functional impairment at 5 years. Factors predictive of new functional impairment or death at 1 year were age, comorbidities, discharge to other than home, mechanical ventilation of 7 days or longer, and stroke. Of factors known at the time of intubation, the following are predictive of new functional impairment or death: age, comorbidities, nonsurgical condition, Acute Physiology and Chronic Health Evaluation III score, stroke, and sepsis. Post hoc sensitivity analyses revealed no significant change in predictor variables in patient populations when stroke was excluded or who received more than 48 hours of mechanical ventilation. CONCLUSIONS: At 1- and 5-year follow-up, many patients who received mechanical ventilation for acute respiratory failure from all causes are no longer alive or have new moderate-to-severe functional impairment. Functional recovery between year 1 and year 5 is possible and common. Sepsis, stroke, illness severity, age, and comorbidities predict long-term functional outcome at intubation. PMID- 29261565 TI - Oxygen Exposure Resulting in Arterial Oxygen Tensions Above the Protocol Goal Was Associated With Worse Clinical Outcomes in Acute Respiratory Distress Syndrome. AB - OBJECTIVES: High fractions of inspired oxygen may augment lung damage to exacerbate lung injury in patients with acute respiratory distress syndrome. Participants enrolled in Acute Respiratory Distress Syndrome Network trials had a goal partial pressure of oxygen in arterial blood range of 55-80 mm Hg, yet the effect of oxygen exposure above this arterial oxygen tension range on clinical outcomes is unknown. We sought to determine if oxygen exposure that resulted in a partial pressure of oxygen in arterial blood above goal (> 80 mm Hg) was associated with worse outcomes in patients with acute respiratory distress syndrome. DESIGN: Longitudinal analysis of data collected in these trials. SETTING: Ten clinical trials conducted at Acute Respiratory Distress Syndrome Network hospitals between 1996 and 2013. SUBJECTS: Critically ill patients with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined above goal oxygen exposure as the difference between the fraction of inspired oxygen and 0.5 whenever the fraction of inspired oxygen was above 0.5 and when the partial pressure of oxygen in arterial blood was above 80 mm Hg. We then summed above goal oxygen exposures in the first five days to calculate a cumulative above goal oxygen exposure. We determined the effect of a cumulative 5-day above goal oxygen exposure on mortality prior to discharge home at 90 days. Among 2,994 participants (mean age, 51.3 yr; 54% male) with a study entry partial pressure of oxygen in arterial blood/fraction of inspired oxygen that met acute respiratory distress syndrome criteria, average cumulative above goal oxygen exposure was 0.24 fraction of inspired oxygen-days (interquartile range, 0-0.38). Participants with above goal oxygen exposure were more likely to die (adjusted interquartile range odds ratio, 1.20; 95% CI, 1.11-1.31) and have lower ventilator-free days (adjusted interquartile range mean difference of 0.83; 95% CI, -1.18 to -0.48) and lower hospital-free days (adjusted interquartile range mean difference of -1.38; 95% CI, -2.09 to -0.68). We observed a dose-response relationship between the cumulative above goal oxygen exposure and worsened clinical outcomes for participants with mild, moderate, or severe acute respiratory distress syndrome, suggesting that the observed relationship is not primarily influenced by severity of illness. CONCLUSIONS: Oxygen exposure resulting in arterial oxygen tensions above the protocol goal occurred frequently and was associated with worse clinical outcomes at all levels of acute respiratory distress syndrome severity. PMID- 29261566 TI - Cardiac Arrest and Mortality Related to Intubation Procedure in Critically Ill Adult Patients: A Multicenter Cohort Study. AB - OBJECTIVES: To determine the prevalence of and risk factors for cardiac arrest during intubation in ICU, as well as the association of ICU intubation-related cardiac arrest with 28-day mortality. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Sixty-four French ICUs. PATIENTS: Critically ill patients requiring intubation in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the 1,847 intubation procedures included, 49 cardiac arrests (2.7%) occurred, including 14 without return of spontaneous circulation (28.6%) and 35 with return of spontaneous circulation (71.4%). In multivariate analysis, the main predictors of intubation-related cardiac arrest were arterial hypotension (systolic blood pressure < 90 mm Hg) prior to intubation (odds ratio = 3.406 [1.797-6.454]; p = 0.0002), hypoxemia prior to intubation (odds ratio = 3.991 [2.101-7.583]; p < 0.0001), absence of preoxygenation (odds ratio = 3.584 [1.287-9.985]; p = 0.0146), overweight/obesity (body mass index > 25 kg/m; odds ratio = 2.005 [1.017-3.951]; p = 0.0445), and age more than 75 years old (odds ratio = 2.251 [1.080-4.678]; p = 0.0297). Overall 28-day mortality rate was 31.2% (577/1,847) and was significantly higher in patients who experienced intubation-related cardiac arrest than in noncardiac arrest patients (73.5% vs 30.1%; p < 0.001). After multivariate analysis, intubation-related cardiac arrest was an independent risk factor for 28-day mortality (hazard ratio = 3.9 [2.4-6.3]; p < 0.0001). CONCLUSIONS: ICU intubation related cardiac arrest occurs in one of 40 procedures with high immediate and 28 day mortality. We identified five independent risk factors for cardiac arrest, three of which are modifiable, possibly to decrease intubation-related cardiac arrest prevalence and 28-day ICU mortality. PMID- 29261567 TI - Association Between Partial Pressure of Arterial Carbon Dioxide and Survival to Hospital Discharge Among Patients Diagnosed With Sepsis in the Emergency Department. AB - OBJECTIVE: The objective of this study was to test the association between the partial pressure of arterial carbon dioxide and survival to hospital discharge among mechanically ventilated patients diagnosed with sepsis in the emergency department. DESIGN: Retrospective cohort study of a single center trial registry. SETTING: Academic medical center. PATIENTS: Mechanically ventilated emergency department patients. INCLUSION CRITERIA: age 18 years and older, diagnosed with sepsis in the emergency department, and mechanical ventilation initiated in the emergency department. INTERVENTIONS: Arterial blood gases obtained after initiation of mechanical ventilation were analyzed. The primary outcome was survival to hospital discharge. We tested the association between partial pressure of arterial carbon dioxide and survival using multivariable logistic regression adjusting for potential confounders. Sensitivity analyses, including propensity score matching were also performed. MEASUREMENTS AND MAIN RESULTS: Six hundred subjects were included, and 429 (72%) survived to hospital discharge. The median (interquartile range) partial pressure of arterial carbon dioxide was 42 (34-53) mm Hg for the entire cohort and 44 (35-57) and 39 (31-45) mm Hg among survivors and nonsurvivors, respectively (p < 0.0001 Wilcox rank-sum test). On multivariable analysis, a 1 mm Hg rise in partial pressure of arterial carbon dioxide was associated with a 3% increase in odds of survival (adjusted odds ratio, 1.03; 95% CI, 1.01-1.04) after adjusting for tidal volume and other potential confounders. These results remained significant on all sensitivity analyses. CONCLUSION: In this sample of mechanically ventilated sepsis patients, we found an association between increasing levels of partial pressure of arterial carbon dioxide and survival to hospital discharge. These findings justify future studies to determine the optimal target partial pressure of arterial carbon dioxide range for mechanically ventilated sepsis patients. PMID- 29261568 TI - Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis. AB - OBJECTIVE: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis. DESIGN: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). SETTING: Forty ICUs in Italy. PATIENTS: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 * 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 * 10/L who developed thrombocytopenia (<= 50 * 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 * 10/L (n = 95). INTERVENTIONS: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1. MEASUREMENTS AND MAIN RESULTS: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality. CONCLUSIONS: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis. PMID- 29261569 TI - The Cumulative Partial Pressure of Arterial Oxygen Is Associated With Neurological Outcomes After Cardiac Arrest Treated With Targeted Temperature Management. AB - OBJECTIVE: Hyperoxia could lead to a worse outcome after cardiac arrest. The aim of this study was to investigate the relationship between the cumulative partial pressure of arterial oxygen (PaO2) and neurological outcomes after cardiac arrest treated with targeted temperature management. DESIGN: Retrospective analysis of a prospective cohort. SETTING: An academic tertiary care hospital. PATIENTS: A total of 187 consecutive patients treated with targeted temperature management after cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The area under the curve of PaO2 for different cutoff values of hyperoxia (>= 100, >= 150, >= 200, >= 250, and >= 300 mm Hg) with different time intervals (0-24, 0-6, and 6-24 hr after return of spontaneous circulation) was calculated for each patient using the trapezoidal method. The primary outcome was the neurologic outcome, as defined by the cerebral performance category, at 6 months after cardiac arrest. Of 187 subjects, 77 (41%) had a good neurologic outcome at 6 months after cardiac arrest. The median age was 54 (43-69) years, and 128 (68%) were male. The area under the curve of PaO2 with cutoff values of greater than or equal to 200, greater than or equal to 250, and greater than or equal to 300 was higher in the poor outcome group at 0-6 and 0-24 hours. The adjusted odds ratios of area under the curve of PaO2 greater than or equal to 200 mm Hg were 1.659 (95% CI, 1.194-2.305) for 0-24 hours after return of spontaneous circulation and 1.548 (95% CI, 1.086-2.208) for 0-6 hours after return of spontaneous circulation. With a higher cumulative exposure to oxygen tension, we found significant increasing trends in the adjusted odds ratio for poor neurologic outcomes. CONCLUSION: In a new method for PaO2 analysis, cumulative exposure to hyperoxia was associated with neurologic outcomes in a dose-dependent manner. Greater attention to oxygen supply during the first 6 hours appears to be important for outcome after cardiac arrest. PMID- 29261570 TI - Quality of life patient-reported outcomes for locally advanced cutaneous melanoma. AB - Locally advanced cutaneous melanoma has marked quality-of-life implications; however, the patient experience of symptom management and subsequent impact on quality of life has not been well described. This study aims to address the impact on patients of advanced cutaneous melanoma through qualitative interviews. Adults with stage IIIB, IIIC, or IV (M1a) cutaneous melanoma were recruited from two cancer centers in the USA and one in Australia. Telephone interviews were conducted to assess how locoregionally advanced cutaneous melanoma impacted everyday life. Interviews were recorded, transcribed, and coded for qualitative analysis. Twenty-two melanoma patients were interviewed, mean age 69.7 years (range: 52-83), 64% male. The study included stage IIIB (36%), stage IIIC (59%), and stage IV M1a (5%) patients. Emotional health/self-perception issues were the most commonly identified (41% of patient impact expressions), including worry, concern, embarrassment, self-consciousness, fear, and thoughts of death. Limitations of lifestyle and activities were also identified (28% of expressions) including leisure and social activities, physical functioning, general functioning, and personal care. Coping strategies such as modified clothing choices, increased use of pain and/or anti-inflammatory medications, and avoidance/protection from the sun represented 20% of all impact expressions. Ratings of the degree of difficulty patients experienced (using an 11-point numerical rating scale) ranged from 0.0 to 10.0 (mean 5.7, SD 2.9). Condition related and treatment-related factors were well characterized in patients with locally advanced cutaneous melanoma. This provides a strong foundation for assessment of how cutaneous melanoma impacts quality of life. PMID- 29261571 TI - Factors Influencing Acceptability and Perceived Impacts of a Mandatory ePortfolio Implemented by an Occupational Therapy Regulatory Organization. AB - INTRODUCTION: The use of ePortfolios has been implemented in several regulatory organizations to encourage clinicians' engagement in continuing professional development (CPD). However, their use has achieved mixed success, and multiple personal and contextual factors can influence their impacts on practice change. The aim of this study was to identify which factors influence the acceptability and perceived impacts of an ePortfolio implemented by an occupational therapy regulatory organization in one Canadian province. METHOD: A cross-sectional online survey design was used. The survey was sent to registered occupational therapists in Quebec. Multiple regression analyses were conducted to identify factors influencing acceptability and outcomes: ease of use, satisfaction, impact on implementation of the CPD plan, and competence improvement. RESULTS: The survey was fully completed by 546 participants. Factors significantly influencing the ePortfolio acceptability and perceived impacts were attitude toward and familiarity with the portfolio, confidence in reflective skills, engagement in the CPD plan, and desire for feedback. Time spent completing the ePortfolio and the fact of completing it in teams were negatively associated with the outcomes. DISCUSSION: Shaping more favorable user attitudes, helping users recognize and experience the tool's benefits for their practice, and fostering confidence in their reflective skills are important factors that can be addressed to improve ePortfolio acceptability and outcomes. Contextual factors, such as time spent completing the ePortfolio and completing it in teams, seem to reflect greater difficulty with using the tool. Study findings can contribute to improving ePortfolio implementation in the CPD context. PMID- 29261572 TI - Gastrointestinal Bleeding in Patients with HeartWare Ventricular Assist Device: Does the Activation of the Lavare Cycle Make a Difference? AB - We aimed to investigate the prevalence of gastrointestinal bleeding (GIB) events in patients supported with HeartWare ventricular assist device (VAD) and activated lavare cycle. Thirty-two GIB events were documented in 22 patients (21%) after median support duration of 22 days (IQR: 11-157 days). There were 13 patients with early episodes of GIB. Meanwhile, 17 GIB events were documented in 9 patients after a median support duration of 174 days (IQR 25-736 days) (late bleeders), accounting for 0.18 events per patient's years. The GIB events appear to be a frequent complication in patients with HeartWare VAD regardless of the lavare cycle. PMID- 29261573 TI - From a Silver Lining to the Silver Anniversary: 25 Years of the Journal of Bronchology and Interventional Pulmonology. PMID- 29261574 TI - Lobar Airway Stents: Proceed With Caution. PMID- 29261575 TI - Executive Summary of Training and Competence Standards for the Interventional Pulmonology Master Program in Italy. PMID- 29261576 TI - Diagnostic Accuracy of Mediastinal Lymph Node Staging Techniques in the Preoperative Assessment of Nonsmall Cell Lung Cancer Patients. AB - BACKGROUND: Nonsmall cell lung cancer (NSCLC) treatment is based on an accurate staging. Mediastinal lymph nodes staging has a critical impact on treatment management. METHODS: The objective was to assess the current accuracy of preoperative tools for predicting mediastinal and hilar lymph nodes staging with NSCLC. Retrospective analysis of 997 biopsy-proven NSCLC patients treated at a single academic medical center between January 2006 and April 2012. Mediastinal lymph nodes were evaluated with preoperatively with: computed tomography (CT), positron emission tomography (PET), endobronchial ultrasound-guided fine needle aspiration, and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Results are compared with pathologic surgical biopsy. RESULTS: A total of 217 cervical mediastinoscopies, 15 anterior mediastinotomies, and 952 surgical lymphadenectomies were performed. The sensitivity of CT scan for mediastinal lymph nodes detection was 18.9% and PET-CT scan was 33.8%. Specificities were 94.9% and 93.8%, respectively. For hilar lymph nodes detection, CT was less sensitive (17.0% vs. 39.7%); however, more specific (94.7% vs. 80.3%) than PET CT. Endobronchial ultrasound-guided fine needle aspiration (72.7% sensitivity and 100% specificity) and endoscopic ultrasound-guided fine needle aspiration (51.9% sensitivity and 100% specificity) both demonstrated superior results. CONCLUSIONS: The majority of biopsy-proven mediastinal lymph nodes metastases are not associated with positive results on preoperative CT or PET. CT and PET have low positive predictive value for mediastinal lymph node. This study supports the routine utilization of invasive mediastinal lymph nodes staging in NSCLC, especially for patients with tumors of >4 cm diameter, regardless of CT or PET-CT results. PMID- 29261577 TI - Description of Particle Size, Distribution, and Behavior of Talc Preparations Commercially Available Within the United States. AB - BACKGROUND: Widespread use of talc pleurodesis remains controversial for many providers concerned by adverse events such as respiratory failure, which are sometimes fatal. Particle talc size has been implicated in these adverse effects, mainly on the basis of animal studies utilizing large amounts of talc or in observational studies performed on different continents with different talc preparations and doses. Our aim was to determine the particle size and distribution of only the commercially available US-talc preparations and whether the fluid content can affect this distribution. METHODS: Commercially available US talc was evaluated under scanning electron microscopy and dynamic light scattering (DLS). Distribution of talc particle size was obtained in saline and various protein-based solutions. RESULTS: Talc particle size by DLS was performed with commercially available Sterile Talc Powder and Sclerosol Intrapleural Aerosol. Sterile Talc Powder demonstrated a median diameter of 26.57 MUm with a range of particle sizes from 0.399 MUm to 100.237 MUm. Sclerosol demonstrated a median diameter of 24.49 MUm with a range of particle sizes from 0.224 MUm to 100.237 MUm. The exposure of talc to a protein rich environment (bovine serum albumin and human pleural fluid) led to the development of measureable, new, larger aggregated particle (>100 MUm). CONCLUSIONS: Currently available US talc seems to have size characteristics similar to previous described "graded" talc preparations. The exposure of talc to a protein rich environment seems to modify the overall distribution of talc particle size when examined by DLS. PMID- 29261578 TI - Cryobiopsy of the Pleura: An Improved Diagnostic Tool. AB - BACKGROUND: Medical thoracoscopy (rigid and semirigid pleuroscopy) has revolutionized the approach to the diagnosis of pleural disease by offering a very high diagnostic yield. Rigid pleuroscopy offers the advantages of therapeutic intervention and larger biopsy specimens, whereas semirigid pleuroscopy using a standard biopsy forceps yields smaller and more superficial pleural samples. Cryobiopsy through semirigid pleuroscope in anecdotal studies has been used to overcome these disadvantages. We compared the safety and efficacy of cryobiopsy with conventional forceps biopsy in terms of the specimen size and diagnostic yield. METHODS: We analyzed data of 139 (87 cryobiopsies and 52 forceps biopsies) patients with undiagnosed pleural effusion who underwent pleuroscopy using a semirigid pleuroscope. A cryoprobe (ERBE, 2.4 mm) was passed through the working channel of the semirigid pleuroscope, the target area of parietal pleura was frozen for an average freezing time of 8 seconds, then the semirigid pleuroscope along with the probe was forcibly withdrawn en bloc avulsing the frozen parietal pleura. Two to 3 samples were taken from each patient. RESULTS: The diagnostic yield was 99% with cryobiopsy and 96% with forceps biopsy. The average specimen size through cryoprobe (13.2+/-6.7; range, 7 to 35 mm) was significantly larger than with the conventional forceps (6.8+/-3.3; range, 2 to 15 mm) (P<0.001), and no major complications were noted. CONCLUSION: Cryobiopsy of the parietal pleura through the semirigid pleuroscope is a safe procedure with a very high diagnostic yield. PMID- 29261579 TI - Endoscopic Lung Volume Reduction in COPD: Improvements in Gas Transfer Capacity Are Associated With Improvements in Ventilation and Perfusion Matching. AB - BACKGROUND: Endoscopic lung volume reduction (ELVR) has been shown to improve lung function, quality of life, and exercise tolerance in patients with severe heterogeneous emphysema. Our study aims to determine the effect of ELVR on gas transfer capacity corrected for alveolar volume (KCO) and investigate the relationship between KCO and ventilation and perfusion (VQ) matching. We speculate on possible mechanisms for the observed changes METHODS:: Patients with severe chronic obstructive pulmonary disease were prospectively recruited and underwent unilateral upper lobe ELVR between 2012 and 2014. Each had respiratory function test and differential VQ scans at baseline, 1-, 3-, and 12-month post ELVR. RESULTS: In total, 11 patients had 3 sets of respiratory function test (at baseline, 1, and 3 mo), whereas 7 had 4 sets (at baseline, 1, 3, and 12 mo). KCO improved by 10.3 (+/-7.5)% at 1 month (P=NS) and 39.8 (+/-15.4)% at 12 months (P<0.05). VQ of the nontargeted lung increased by 12.8 (+/-5.6)% and 7.9 (+/ 2.3)%, respectively at 1 month, whereas those of the targeted lung both decreased (P<0.05). At 3 and 12 months, the VQ changes were similar to those at 1 month, though some were not statistically significant. CONCLUSIONS: ELVR results in improved KCO for at least 12 months. This may be explained by the VQ redistribution to the nontargeted and less emphysematous lung with improved VQ matching. PMID- 29261580 TI - Ehlers-Danlos Syndrome Type IVB and Tracheobronchomegaly. AB - Tracheobronchomegaly (TBM) is a rare disease of unknown etiology, characterized by dilatation of the trachea and main bronchi. Despite its rarity, TBM has been reported to accompany several conditions, particularly Ehlers-Danlos syndrome. Herein, we report on a 15-year-old patient who was diagnosed with TBM on the basis of radiologic and endoscopic findings and with Ehlers-Danlos syndrome type IVB presenting with marfanoid features, severe kyphoscoliosis, increased skin elasticity, and ongoing hypotonia since the neonatal period. PMID- 29261581 TI - Risk of Jaw Dislocation With Prolonged Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. PMID- 29261582 TI - Efficacy of Endobronchial Ultrasound-Transbronchial Needle Aspiration Virtual Reality Simulator Training. PMID- 29261583 TI - EUS-B-guided Biopsies of Lung Tumors. PMID- 29261584 TI - Endoscopic Lung Volume Reduction by Endobronchial Coils: First Report From Latin America. PMID- 29261585 TI - Cost-Effectiveness of Disposable Bronchoscopes: Needs Comparison with Fiberoptic Bronchoscopes too. PMID- 29261586 TI - Reply: Cost-Effectiveness of Disposable Bronchoscopes: Needs Comparison with Fiberoptic Bronchoscopes too. PMID- 29261587 TI - Endobronchial Valve Migration Secondary to Changes in Bronchial Diameter After the Initial Treatment. PMID- 29261588 TI - Bronchoscopic Management of Central Airway Obstruction Secondary to Rheumatoid Arthritis. PMID- 29261589 TI - Transbronchial Lung Cryobiopsy With 2 Bronchoscopes: nec novum nec magna. PMID- 29261590 TI - USE OF OPEN AND ENDOVASCULAR SURGICAL TECHNIQUES TO MANAGE VASCULAR INJURIES IN THE TRAUMA SETTING: A REVIEW OF THE AAST PROOVIT REGISTRY. AB - INTRODUCTION: Vascular trauma data have been submitted to the American Association for the Surgery of Trauma PROspective Observational Vascular Injury Trial (PROOVIT) database since 2013. We present data to describe current use of endovascular surgery in vascular trauma. METHODS: Registry data from March 2013 to December 2016 were reviewed. All trauma patients who had an injury to a named artery, except the forearm and lower leg, were included. Arteries were grouped into anatomic regions and by compressible and non-compressible region for analysis. This review focused on patients with non-compressible transection, partial transection, or flow limiting defect injuries. Bivariate and multivariate analyses were used to assess the relationships between study variables. RESULTS: 1143 patients from 22 institutions were included. Median age was 32 years (interquartile range IQR 23-48) and 76% (n=871) were male. Mechanisms of injury were 49% (n=561) blunt, 41% (n=464) penetrating, and 1.8% (n=21) of mixed aetiology. Gunshot wounds accounted for 73% (n=341) of all penetrating injuries. Endovascular techniques were used least often in limb trauma and most commonly in patients with blunt injuries to more than one region. Penetrating wounds to any region were preferentially treated with open surgery (74%, n=341/459). The most common indication for endovascular treatment was blunt non-compressible torso injuries (NCTI). These patients had higher injury severity scores and longer associated hospital stays, but required less packed red blood cells (PRBC), and had lower in hospital mortality than those treated with open surgery. On multivariate analysis, admission low hemoglobin concentration and abdominal injury were independent predictors of mortality. CONCLUSIONS: Our review of PROOVIT registry data demonstrates a high utilization of endovascular therapy among severely injured blunt trauma patients primarily with non-compressible torso hemorrhage. This is associated with decreased need for blood transfusion and improved survival despite longer length of stay. LEVEL OF EVIDENCE: III, Therapeutic/care management. PMID- 29261591 TI - Examining racial disparities in the time to withdrawal of life-sustaining treatment in trauma. AB - BACKGROUND: Racial disparities in medical treatment for seriously injured patients across the spectrum of care are well established, but racial disparities in end of life decision making practices have not been well described. When time from admission to time to withdrawal of life-sustaining treatment (WLST) increases, so does the potential for ineffective care, health care resource loss, and patient and family suffering. We sought to determine the existence and extent of racial disparities in late WLST after severe injury. METHODS: We queried the American College of Surgeons' Trauma Quality Improvement Program (2013-2016) for all severely injured patients (Injury Severity Score, > 15; age, > 16 years) with a WLST order longer than 24 hours after admission. We defined late WLST as care withdrawn at a time interval beyond the 75th percentile for the entire cohort. Univariate and multivariate analyses were performed using descriptive statistics, and t tests and chi tests where appropriate. Multivariable regression analysis was performed with random effects to account for institutional-level clustering using late WLST as the primary outcome and race as the primary predictor of interest. RESULTS: A total of 13,054 patients from 393 centers were included in the analysis. Median time to WLST was 5.4 days (interquartile range, 2.6-10.3). In our unadjusted analysis, African-American patients (10.1% vs. 7.1%, p < 0.001) and Hispanic patients (7.8% vs. 6.8%, p < 0.001) were more likely to have late WLST as compared to early WLST. After adjustment for patient, injury, and institutional characteristics, African-American (odds ratio, 1.42; 95% confidence interval, 1.21-1.67) and Hispanic (odds ratio, 1.23; 95% confidence interval, 1.04-1.46) race were significant predictors of late WLST. CONCLUSION: African American and Hispanic race are both significant predictors of late WLST. These findings might be due to patient preference or medical decision making, but speak to the value in assuring a high standard related to identifying goals of care in a culturally sensitive manner. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 29261592 TI - Whole blood and Hextend: Bookends of modern tactical combat casualty care field resuscitation and starting point for multifunctional resuscitation fluid development. AB - BACKGROUND: Hemorrhage is the leading cause of preventable death in traumatically injured civilian and military populations. Prehospital resuscitation largely relies on crystalloid and colloid intravascular expansion, as whole blood and component blood therapy are logistically arduous. In this experiment, we evaluated the bookends of Tactical Combat Casualty Care Guidelines recommendations of prehospital resuscitation with Hextend and whole blood in a controlled hemorrhagic shock model within non-human primates, as means of a multifunctional resuscitative fluid development. METHODS: In the nonhuman primate, a multiple injuries model was used, consisting of a musculoskeletal injury (femur fracture), soft tissue injury (15-cm laparotomy), and controlled hemorrhage to a mean arterial pressure of 20 mm Hg, demarcating the beginning of the shock period. Animals were randomized to prehospital interventions of whole blood or Hextend at T = 0 minutes, and at T = 90 minutes definitive surgical interventions and balanced sanguineous damage control resuscitation could be implemented. All animals were euthanized at T = 480 minutes. Data are expressed as mean +/- SEM; significance, p < 0.05. RESULTS: No significant differences in survival (83% vs. 100%; p = 0.3), tissue perfusion (EtCO2 and StO2) or endpoints of resuscitation (base deficit, lactate, pH) between Hextend and whole blood were identified. Second, whole blood compared with Hextend demonstrated significantly earlier normalization of clot formation time, maximal clot firmness, and alpha angle. CONCLUSION: A future multifunctional resuscitative fluid including an asanguineous, oncotic, non-oxygen-carrying component to facilitate intravascular volume expansion, and a component with synthetic coagulation factors and fibrinogen to deter coagulopathy may show equivalence to whole blood. LEVEL OF EVIDENCE: N/A: Study type: translational animal model. PMID- 29261593 TI - Nonoperative management of abdominal solid-organ injuries following blunt trauma in adults: Results from an International Consensus Conference. PMID- 29261595 TI - Occipital Nerve Stimulation Effectively Controls Refractory Seizures: A Case Report. PMID- 29261596 TI - Anterior Suprascapular Nerve Block or Low-Volume Supraclavicular Nerve Block? PMID- 29261597 TI - Reply to Dr Dillane. PMID- 29261598 TI - Anterior Suprascapular Nerve Block Versus Interscalene Brachial Plexus Block for Shoulder Surgery in the Outpatient Setting. PMID- 29261599 TI - Reply to Dr Zhou et al. PMID- 29261600 TI - Three-Dimensional Thoracic Epidural Educational Model. PMID- 29261601 TI - Erector Spinae Plane Blocks Provide Analgesia for Breast and Axillary Surgery: A Series of 3 Cases. PMID- 29261602 TI - Pediatric Eye Blocks: Threading the Needle. PMID- 29261603 TI - Reply to Drs Palte and Gayer. PMID- 29261604 TI - Route of Administration Affects Outcomes of Dexamethasone as an Adjuvant for Peripheral Nerve Blocks. PMID- 29261605 TI - Reply to Dr Pan: Caution Is Warranted Before Off-label Use of Nerve Block Adjuvants With Marginal Benefit. PMID- 29261606 TI - Ultrasound-Guided Regional Anesthesia and Standard of Care. PMID- 29261607 TI - Reply to Dr Hardman et al. PMID- 29261608 TI - Focused Cardiac Ultrasound: Limitations and Source of Interpretation Errors. PMID- 29261609 TI - Reply to Drs Saranteas and Panou. PMID- 29261611 TI - The Power of Questions. PMID- 29261612 TI - Want Your Graduates to Succeed? Teach Them to Think! PMID- 29261613 TI - Two-Year Institution Part-Time Nurse Faculty Experiences During Role Transition and Identity Development: A Phenomenological Study. AB - AIM: This study explored two-year institution part-time nurse faculty's perceptions of their experiences during their role transitions from nurses in clinical practice to part-time clinical instructors. BACKGROUND: Part-time nurse faculty enter academia as expert clinicians, but most have little or no training in the pedagogy of effective student learning. METHOD: A phenomenological study was used to explore the faculty role transition experiences. RESULTS: Findings support the proposition that six participants transitioned from their expert clinician to instructor identities; however, two continue in the process. Critical to this process are relationships with individuals in their environments, past and present experiences, the incentive to learn to be better instructors, and the importance of support and training. CONCLUSION: A model emerged, Process of Role Transition and Professional Identity Formation for Part Time Clinical Instructors at Two-Year Institutions, that is potentially useful for administrators in developing individualized orientation and professional development programs. PMID- 29261614 TI - Live Continuing Education Program for Adjunct Clinical Nursing Faculty. AB - AIM: The aim of the study was to evaluate a mentorship program for adjunct clinical faculty. BACKGROUND: The nursing faculty shortage has been cited as the primary reason for decreased student enrollments. Clinical adjuncts hired to teach to fill this shortage need a competency-based orientation and formal mentorship. METHOD: We piloted a live version of our previously online continuing education program for adjunct clinical faculty. The live program of eight modules based on three nursing competencies provided core knowledge and guidance in applying nursing education principles in clinical settings. RESULTS: A convenience sample of 84 faculty members, including experienced faculty from three nursing programs, provided feedback on the program. Overall feedback was positive, but participants indicated a need for more continuing education, mentorship, and faculty development. CONCLUSION: The program will continue to be offered to clinical faculty regionally with additional qualitative and quantitative evaluation. PMID- 29261615 TI - Reflections on Online Education and Regulations. PMID- 29261617 TI - Student Perceptions of Clinical Instructor Characteristics Affecting Clinical Experiences. PMID- 29261616 TI - What Our Readers and Authors Say About Nursing Education Perspectives. PMID- 29261618 TI - Metastasized 18F-DCFPyL-Negative Prostatic Adenocarcinoma Without Neuroendocrine Differentiation. AB - A 76-year-old man with histopathologically proven prostate cancer (initial prostate-specific antigen 110 ng/mL, Gleason 3 + 4 = 7) received F-DCFPyL PET/CT for initial staging. Both the primary tumor and pathologically enlarged pelvic lymph nodes showed no increased F-DCFPyL uptake. Subsequent histopathologic lymph node biopsy revealed prostate cancer metastasis. Prostate-specific membrane antigen tracers, such as F-DCFPyL, are promising radiopharmaceuticals for prostate cancer imaging. False-negative prostate-specific membrane antigen PET/CT findings have been reported earlier for prostate tumors with neuroendocrine differentiation. However, this report presents false-negative F-DCFPyL PET findings of an adenocarcinoma of the prostate without neuroendocrine differentiation. PMID- 29261619 TI - Discordant Findings on 18F-NaF and 99mTc-HDP Bone Scans in a Patient With ATTR Cardiac Amyloidosis. AB - Cardiac amyloidosis is an important cause of restrictive cardiomyopathy and congestive heart failure. Bone scintigraphy with [Tc]hydroxymethylene diphosphonate (Tc-HDP) and [F]sodium fluoride (F-NaF) have been investigated in the noninvasive diagnosis of transthyretin (ATTR)-related cardiac amyloidosis. We present a case of a 76-year-old man with metastatic prostate cancer who underwent Tc-HDP bone scintigraphy with an incidental finding of diffuse left ventricular abnormal uptake suggesting ATTR cardiac amyloidosis. Review of previous imaging showed a negative F-NaF PET/CT study. This example suggests that the mechanism of uptake of Tc-HDP and F-NaF may differ in patients with ATTR cardiac amyloidosis. PMID- 29261620 TI - 68Ga-PSMA Avid Primary Adenocarcinoma of the Lung With Complementary Low 18F-FDG Uptake. AB - Ga-PSMA PET/CT scan on a 70-year-old man with recently diagnosed prostate cancer revealed a spiculating nodule in the apex of the left lung with intense Ga-PSMA uptake. The nodule had no pathological F-FDG uptake and turned out to be a primary adenocarcinoma of the lung. Cases with complementary pattern of uptake in F-FDG and Ga-PSMA in metastatic clear cell renal carcinoma and in well differentiated hepatocellular carcinoma have previously been reported; however, this case illustrates that this unusual pattern can also be present in primary lung cancer. PMID- 29261621 TI - Dynamic Adaptation of Tumor Immune Response With Nivolumab Demonstrated by 18F FDG PET/CT. AB - A 61-year-old woman with lung adenocarcinoma failed first-line treatment and was placed on immunotherapy with nivolumab. FDG-PET/CT before immunotherapy showed metastases to thoracic nodes, liver, adrenal gland, and skeleton. Seven weeks after starting nivolumab, FDG-PET/CT showed mild residual activity in thoracic nodes and otherwise complete response. After 15 weeks, enlarged and FDG-avid axillary lymphadenopathy and worsening supraclavicular lymphadenopathy developed. After 20 weeks, FDG-PET/CT demonstrated marked improvement of axillary and supraclavicular lymphadenopathy. This case demonstrates that later progression of disease can still respond to continuing immunotherapy, hypothetically because of dynamic adaptations in the tug-of-war between the immunotherapy-augmented immune system and tumor. PMID- 29261622 TI - 18FDG-PET/CT for the Visualization of Inflammatory Component of Radiation-Induced Lung Injury After Stereotactic Radiotherapy. AB - Visualization and metabolic analysis of acute inflammation in the lung parenchyma plays a crucial role for the prediction and diagnosis of radiation-induced lung injury and is particularly important in medically inoperable patients because of a priori very limited pulmonary function. This case confirms that a radiation induced lung injury is accompanied by acute inflammatory reaction in the lung parenchyma irradiated with a total dose of 12-40 Gy. This well-defined inflammation component could be exactly characterized with FDG-PET/CT. PMID- 29261623 TI - Microglial Activation on 11C-CB184 PET in a Patient With Cerebellar Ataxia Associated With HIV Infection. AB - A 63-year-old man complaining of prolonged imbalance underwent C-CB184 PET to assess microglial activation 3 years after being diagnosed with cerebellar ataxia associated with HIV infection. C-CB184 images revealed significant cerebellar uptake where MRI signal abnormalities were observed at disease onset, although these abnormalities had mostly disappeared at the time of C-CB184 PET. Microglia are believed to be a long-term reservoir for HIV infection, causing persistent immune activation (ie, chronic inflammation). Hence, in this case, increased C CB184 binding may reflect persistent microglial activation along with HIV persistence in the cerebellum. However, further pathological investigations are desired to validate C-CB184 PET. PMID- 29261624 TI - Hyperparathyroidism Caused by Coexisting Parathyroid Hyperplasia and Ectopic Parathyroid Adenomas. AB - Tc sestamibi parathyroid scan was performed in a 35-year-old man with chronic renal failure to evaluate the cause of increased serum parathyroid hormone. Both early and delayed images showed intense activity overlapping the left upper pole of the thyroid, which was proven to be nodular parathyroid hyperplasia after parathyroidectomy. However, the levels of serum parathyroid hormone remained elevated postsurgically. A repeat sestamibi study revealed abnormal activity in the left upper mediastinum, which could also be subtly seen on initial sestamibi study. A retrosternal lesion was resected, which was confirmed as an ectopic parathyroid adenoma by pathological examination. PMID- 29261625 TI - Increased Methylene Diphosphonate Uptake in the Rectus Abdominis After Strenuous Exercise. AB - A 28-year-old man with papillary thyroid cancer underwent bone scintigraphy to assess possible osseous metastasis. He had vigorous workouts 5 days prior, which involved pectorals, rectus abdominis, quadriceps, and glutei. However, the images only showed increased activity in the rectus abdominis, whereas other involved muscles had no obvious uptake. No lesion in the bone was identified. PMID- 29261626 TI - 18F-FDG PET/CT in Diagnostic and Prognostic Evaluation of Patients With Suspected Recurrence of Chondrosarcoma. AB - PURPOSE: The aim of the study was to analyze the diagnostic and prognostic utility of F-FDG PET/CT to predict the disease-specific survival (DSS) with FDG uptake and tumor grade in recurrent chondrosarcoma. METHODS: Retrospective analysis of FDG PET/CT findings in 31 previously treated patients (46 studies) with mean follow-up period of 40.7 +/- 23.9 months (range, 3-77 months) from the date of first PET/CT study was done. Kaplan-Meier DSS analysis was made with respect to tumor grade, FDG uptake at the recurrent primary sites, and a combination of grade and FDG uptake as parameters. RESULTS: Recurrence (local and distant) was shown in 28 (60.8%) of 46 FDG PET/CT studies with sensitivity and specificity of 88.9% and 78.9%, respectively. The median SUVmax at the recurrent primary sites differed significantly (P = 0.008) among 3 tumor grade groups, with higher median SUVmax in higher grades. There was significant difference in median SUVmax among different grade groups except between grade II and grade III. Recurrent primary site SUVmax cutoff at 6.15 derived from the receiver operating characteristic curve yielded significant difference (P < 0.001) in mean DSS time. Significant difference in survival was noted between 3 different tumor grade groups (P = 0.016). The combination of SUVmax and grade improved the survival prediction than with grade alone. CONCLUSIONS: In recurrent chondrosarcoma, the recurrent primary site FDG uptake and grade were found to be reliable prognostic factors with respect to DSS. PET/CT in recurrence setting has the potential to predict tumor grade and survival and may assist in clinical management. PMID- 29261627 TI - Incidental Detection of Medullary Thyroid Carcinoma by 68Ga-DOTATATE PET/CT in a Patient With Neuroendocrine Tumor Liver Metastases. AB - Ga-DOTATATE, a positron-emitting somatostatin analog, has been approved by the Food and Drug Administration for imaging neuroendocrine tumors (NETs). The presence of a second primary malignancy is common in NETs; however, synchronous primary malignancy in the thyroid has rarely been reported. The value of Ga DOTATATE in medullary thyroid cancer is being investigated and is currently recommended for use when treatment with somatostatin analogs is an option. We present a 55-year-old man with abdominal pain associated with well-differentiated NET liver metastases and incidental medullary thyroid carcinoma demonstrated on a Ga-DOTATATE PET/CT. PMID- 29261628 TI - Subacute Cerebellar Infarction With Uptake on 68Ga-Prostate-Specific Membrane Antigen PET/CT. AB - We report a case of subacute cerebellar infarction mimicking metastasis on prostate-specific membrane antigen (PSMA) PET/CT. A 77-year-old man with prostate cancer treated with androgen deprivation therapy and radiotherapy with rising prostate-specific antigen was referred for Ga-PSMA PET/CT. Apart from PSMA expressing tumor of the left prostate, PSMA PET/CT demonstrated radiotracer uptake in the right cerebellar hemisphere, corresponding to a site of subacute infarction demonstrated on an MRI of the brain performed 35 days previously. As cerebellar infarcts are considerably less common than cerebral infarcts, they may not be anticipated as a potential cause for false-positive radiotracer uptake on PSMA PET. PMID- 29261629 TI - False-Positive Heat-Damaged RBC Scan for Splenosis: Case of Retroperitoneal Extramedullary Hematopoiesis. AB - Extramedullary hematopoiesis (EMH) is a well-known compensatory response to severe anemia, most commonly due to a chronic hemolytic anemia such as thalassemia or sickle cell disease. We present a case of a 72-year-old man with autoimmune hemolytic anemia refractory to steroids and splenectomy. An incidental retroperitoneal mass on CT was suggestive of ectopic splenic tissue. However, an alternative diagnosis of EMH was considered, given an atypical appearance on heat damaged Tc-RBC scan, and was confirmed with biopsy. The case report illustrates the imaging characteristics of EMH, widely known to have increased activity on Tc sulfur colloid scans. PMID- 29261630 TI - 18F-FDG PET/CT and MRI in Necrotizing Autoimmune Myopathy: "The Scarface Sign". AB - Necrotizing autoimmune myopathy (NAM) is a relatively newly recognized subgroup of idiopathic inflammatory myopathies. The common histopathologic features are myocyte necrosis without significant inflammation. Necrotizing autoimmune myopathy can be associated with connective tissue disorders but can also be triggered by viral infections such as human immunodeficiency virus or malignancy, be statin-induced NAM, or be idiopathic. Here, the authors present the case of a 58-year-old man who was referred to our PET unit for a suspected paraneoplastic syndrome in a context of NAM. Complementary contrast-enhanced CT and 3 dimensional T1-weighted MRI were carried out subsequently in order to resolve the PET/CT abnormalities. PMID- 29261631 TI - Ventriculopleural Shunt Dysfunction Due to a Loculated Pleural Collection Demonstrated on SPECT/CT Imaging. AB - A 35-year-old woman presented with increasing drowsiness on a background of childhood meningitis and hydrocephalus managed with a ventriculopleural shunt. Her cerebral CT and chest radiograph were unchanged from previous imaging and did not identify significant pathology. Because of clinical suspicion of cerebrospinal fluid shunt dysfunction, she was referred for a cerebrospinal fluid shunt study, which demonstrated tracer accumulation within a loculated pleural collection in the left costophrenic recess. PMID- 29261632 TI - Primary Aspergillosis of the Sphenoid Sinus Observed on Bone SPECT/CT. AB - The bone SPECT/CT allows for precise anatomic delineation of bone activity, which can be valuable for diagnosis of nonmalignant bone diseases. We report an extremely rare case of sphenoid sinus aspergillosis, observed on bone SPECT/CT imaging, as an isolated disease in an immunocompetent individual. A 58-year-old woman with a history of plantar fasciitis was assessed for infection in the tarsal bones. Planar bone scan image revealed incidental focal lesion in skull base, which was considered to be the left sphenoid sinusitis by the bone SPECT/CT scan. PMID- 29261633 TI - Quality and Safety in Health Care, Part XXXVI: Anticoagulation Therapy, Atrial Fibrillation, and Fellow Training PINNACLE Studies. AB - There have been numerous publications in the scientific literature based on data from the PINNACLE Registry. The current article includes PINNACLE studies on cardiology outpatients regarding anticoagulation therapy, the relationship between weight loss and atrial fibrillation, and the usefulness of the registry information for training cardiac fellows. PMID- 29261634 TI - Quality and Safety in Health Care, Part XXXVII: More PINNACLE Registry Studies. AB - Studies based on PINNACLE registry data include the management of high blood pressure, relationship of socioeconomic status and prescription practices, eligibility for medication therapy management programs, relationship of patient volume to adherence to guidelines, and relationship between quality and the type of provider. This article summarizes studies on all of those topics. PMID- 29261635 TI - Cerebral Abscesses and Osteomyelitis Caused by Fish Bone Impaction on FDG PET/CT Imaging. AB - A 50-year-old woman complained postprandial vomiting for 5 days and drowsiness for 3 days. Possible central nervous pathology was suspected clinically. Brain MRI suggested likely brain metastases. For this reason, FDG PET/CT was performed to search the primary malignancy. The images showed abnormal activity not only in the brain, but also in the retropharyngeal region and in the thoracic vertebral body. The lesions were eventually confirmed as infection caused by fish bone impaction that occurred 1 month earlier. PMID- 29261636 TI - Prognostic Value of 99mTc-Sestamibi Parathyroid Scintigraphy in Predicting Future Surgical Eligibility in Patients With Asymptomatic Primary Hyperparathyroidism. AB - PURPOSE: Patients with asymptomatic primary hyperparathyroidism might have a positive Tc-sestamibi parathyroid but do not meet criteria for surgical resection when the disease is diagnosed. However, many of these asymptomatic patients will become symptomatic or meet criteria for surgery later on. The aim of this study was to determine whether a positive sestamibi scan can precede future surgical eligibility in these patients. METHODS: This retrospective study reviewed the records of 94 asymptomatic patients who had hyperparathyroidism and underwent Tc sestamibi study with SPECT/CT imaging. Among them, 35 patients, including 12 with positive and 23 with negative sestamibi parathyroid scan, did not meet the criteria for surgery at the time of imaging, and follow-up record for at least 1 year was assessed on these patients. The imaging findings and the eligibility for surgery at the end of the follow-up were compared. RESULTS: With a median follow up of 2.4 years (range, 1-4 years), among all 35 patients who were initially not eligible for surgery, 6 of 12 patients with a positive sestamibi scan became eligible for surgery, whereas 20 of 23 patients with negative scans remained ineligible for surgery. CONCLUSIONS: Positive parathyroid SPECT/CT predicted a higher possibility of meeting surgical criteria over time in asymptomatic hyperparathyroidism patients who are not surgery eligible at the time of presentation. PMID- 29261637 TI - Amino Acid PET Imaging of the Early Metabolic Response During Tumor-Treating Fields (TTFields) Therapy in Recurrent Glioblastoma. AB - Tumor-treating fields (TTFields) therapy is a relatively new treatment approach for malignant gliomas. We evaluated if amino acid PET can detect an objective metabolic response to TTFields therapy in recurrent glioblastomas. PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) before and 2 to 3 months after the start of TTFields treatment showed an interval decrease of tryptophan uptake in the whole tumor (2 patients) or in a portion of the tumor (1 patient). These data demonstrate that TTFields therapy can induce an early metabolic response in recurrent glioblastoma, and this treatment response can be detected by amino acid PET. PMID- 29261638 TI - Orbital Metastasis: Rare Initial Presentation of an Occult Gall Bladder Carcinoma. AB - Orbital metastases are known to arise from primary breast carcinoma followed by prostate, malignant melanoma, and lung carcinoma. We report a case of orbital metastasis as the initial presentation of an occult primary gall bladder carcinoma. The FDG PET/CT helped in localizing the occult distant primary site, which previously escaped detection, and also enabled the evaluation of orbital metastasis. PMID- 29261639 TI - Active Leprosy Neuritis Detected on FDG PET/CT. AB - Uses of FDG PET/CT have been previously documented in multiple series in peripheral nerve pathologies, including neurolymphomatosis, peripheral nerve sheath tumor, and plexopathies. We present the case of a 24-year-old man with leprosy neuritis who underwent FDG PET/CT. We suggest that FDG PET/CT can be used as an adjunct tool to monitor neuritis in leprosy patients. PMID- 29261640 TI - The Added Value of Dynamic 18F-Florbetapir PET in the Assessment of Dementia With Lewy Bodies. AB - Dementia with Lewy bodies (DLB) is the most common cause of dementia after Alzheimer disease. It is often underdiagnosed because of the overlapping with Alzheimer disease symptoms. We report the F-FDG and F-florbetapir dynamic PET images (early and delay phases) of an 83-year-old woman with cognitive impairment associated with visual hallucinations and parkinsonism due to probable DLB. This image highlights that the early phases of F-florbetapir may reflect regional cerebral perfusion with a pattern very similar to that of regional glucose metabolism in DLB. PMID- 29261641 TI - Analysis of Factors Influencing Mayo Adhesive Probability Score in Partial Nephrectomy. AB - BACKGROUND To retrospectively explore the factors influencing Mayo Adhesive Probability (MAP) score in the setting of partial nephrectomy. MATERIAL AND METHODS Data of 93 consecutive patients who underwent laparoscopic and open partial nephrectomy from September 2015 to June 2016 were collected and analyzed retrospectively. Preoperative radiological elements were independently assessed by 2 readers. Ordinal logistic regression analyses were performed to evaluate radiological and clinicopathologic influencing factors of MAP score. RESULTS On univariate analysis, MAP score was associated with male sex, older age, higher body mass index (BMI), history of hypertension and diabetes mellitus, and perirenal fat thickness (posterolateral, lateral, anterior, anterolateral, and medial). On multivariate analysis, only posterolateral perirenal fat thickness (odds ratio [OR]=0.88 [0.82-0.95], p=0.001), medial perirenal fat thickness (OR=0.90 [0.83-0.98], p=0.01), and history of diabetes mellitus (OR=5.42 [1.74 16.86], p=0.004) remained statistically significant. Tumor type (malignant vs. benign) was not statistically different. In patients with renal cell carcinoma (RCC), there was no difference in tumor stage or grade. CONCLUSIONS MAP score is significantly correlated with some preoperative factors such as posterolateral and medial perirenal fat thickness and diabetes mellitus. A new radioclinical scoring system including these patient-specific factors may become a better predictive tool than MAP score alone. PMID- 29261642 TI - Structure of the mechanically activated ion channel Piezo1. AB - Piezo1 and Piezo2 are mechanically activated ion channels that mediate touch perception, proprioception and vascular development. Piezo proteins are distinct from other ion channels and their structure remains poorly defined, which impedes detailed study of their gating and ion permeation properties. Here we report a high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer. The detergent-solubilized complex adopts a three-bladed propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-transmembrane helical bundles that we term Piezo repeats. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically. The structure provides a foundation to dissect further how Piezo channels are regulated by mechanical force. PMID- 29261643 TI - A mildly relativistic wide-angle outflow in the neutron-star merger event GW170817. AB - GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 40 megaparsecs. It has been proposed that the observed gamma-ray, X-ray and radio emission is due to an ultra relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-gamma-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed gamma-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the gamma-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and gamma-ray transients in the local Universe. PMID- 29261644 TI - Age-related changes in baroreflex sensitivity and cardiac autonomic tone in children mirrored by regional brain gray matter volume trajectories. AB - BackgroundThe baroreflex and central autonomic brain regions together control the cardiovascular system. Baroreflex sensitivity (BRS) decreases with age in adults. Age-related changes in brain regions for cardiovascular control in children are unknown. We studied age-related changes in BRS, cardiac autonomic tone, and gray matter volume (GMV) of brain regions associated with cardiovascular control.MethodsBeat-to-beat blood pressure and heart rate (HR) were recorded in 49 children (6-14 years old). Spontaneous BRS was calculated by the sequence method. Cardiac autonomic tone was measured by spectral analysis of HR variability. GMV was measured using voxel-based morphometryin 112 healthy children (5-18 years old).ResultsAge-related changes in BRS were significantly different in children <10 years and >=10 years. Age-related changes in GMV in regions of interest (ROI) were also significantly different between children <10 and >=10 years and between children <11 and >=11 years. However, age-related changes in cardiac autonomic tone were progressive.ConclusionsSignificant changes in BRS trajectories between <10 and >=10 years may be associated with similar age related changes of GMV in brain ROI. This new knowledge will guide future studies examining whether childhood cardiovascular disruption manifests as deviated maturation trajectories of specific brain regions. PMID- 29261645 TI - Fetal somatic growth trajectory differs by type of congenital heart disease. AB - BackgroundThe growth trajectories of common measurements, including estimated fetal weight (EFW), head circumference (HC), and abdominal circumference (AC), in fetuses with congenital heart disease (CHD) have not been described for different cardiac lesions. We hypothesized that (i) fetuses with CHD have differential growth in utero, and (ii) different categories of CHD demonstrate different in utero growth curves.MethodsWe performed a retrospective observational cohort study of pregnancies with known fetal CHD seen from January 2000 to June 2013. For analysis, the infants were divided into single ventricle (SV), biventricular conotruncal, d-transposition of great arteries (d-TGA), biventricular septal defects (SD; including atrial, ventricular, and atrioventricular SD), and all others (Other).ResultsA total of 194 newborns met inclusion criteria. There was significant differential growth of EFW in all CHD types, except d-TGA, starting with low z-scores before 25 weeks gestation, improving toward normal around 30-32 weeks gestation, and then again differential growth with advancing gestation. SV and SD groups had significant differential growth of HC starting early in gestation and linearly progressing negative z-scores with advancing gestation.ConclusionWe observed differences in the fetal growth curves throughout gestation for the major categories of CHD, including significant differential growth in even "simple" CHD, such as SD. PMID- 29261646 TI - A conserved maternal-specific repressive domain in Zelda revealed by Cas9 mediated mutagenesis in Drosophila melanogaster. AB - In nearly all metazoans, the earliest stages of development are controlled by maternally deposited mRNAs and proteins. The zygotic genome becomes transcriptionally active hours after fertilization. Transcriptional activation during this maternal-to-zygotic transition (MZT) is tightly coordinated with the degradation of maternally provided mRNAs. In Drosophila melanogaster, the transcription factor Zelda plays an essential role in widespread activation of the zygotic genome. While Zelda expression is required both maternally and zygotically, the mechanisms by which it functions to remodel the embryonic genome and prepare the embryo for development remain unclear. Using Cas9-mediated genome editing to generate targeted mutations in the endogenous zelda locus, we determined the functional relevance of protein domains conserved amongst Zelda orthologs. We showed that neither a conserved N-terminal zinc finger nor an acidic patch were required for activity. Similarly, a previously identified splice isoform of zelda is dispensable for viability. By contrast, we identified a highly conserved zinc-finger domain that is essential for the maternal, but not zygotic functions of Zelda. Animals homozygous for mutations in this domain survived to adulthood, but embryos inheriting these loss-of-function alleles from their mothers died late in embryogenesis. These mutations did not interfere with the capacity of Zelda to activate transcription in cell culture. Unexpectedly, these mutations generated a hyperactive form of the protein and enhanced Zelda dependent gene expression. These data have defined a protein domain critical for controlling Zelda activity during the MZT, but dispensable for its roles later in development, for the first time separating the maternal and zygotic requirements for Zelda. This demonstrates that highly regulated levels of Zelda activity are required for establishing the developmental program during the MZT. We propose that tightly regulated gene expression is essential to navigate the MZT and that failure to precisely execute this developmental program leads to embryonic lethality. PMID- 29261647 TI - The detection of cryptic Plasmodium infection among villagers in Attapeu province, Lao PDR. AB - BACKGROUND: Although the malaria burden in the Lao PDR has gradually decreased, the elimination of malaria by 2030 presents many challenges. Microscopy and malaria rapid diagnostic tests (RDTs) are used to diagnose malaria in the Lao PDR; however, some studies have reported the prevalence of sub-microscopic Plasmodium infections or asymptomatic Plasmodium carriers in endemic areas. Thus, highly sensitive detection methods are needed to understand the precise malaria situation in these areas. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional malaria field survey was conducted in 3 highly endemic malaria districts (Xaysetha, Sanamxay, Phouvong) in Attapeu province, Lao PDR in 2015, to investigate the precise malaria endemicity in the area; 719 volunteers from these villages participated in the survey. Microscopy, RDTs and a real-time nested PCR were used to detect Plasmodium infections and their results were compared. A questionnaire survey of all participants was also conducted to estimate risk factors of Plasmodium infection. Numbers of infections detected by the three methods were microscopy: P. falciparum (n = 1), P. vivax (n = 2); RDTs: P. falciparum (n = 2), P. vivax (n = 3); PCR: Plasmodium (n = 47; P. falciparum [n = 4], P. vivax [n = 41], mixed infection [n = 2]; 6.5%, 47/719). Using PCR as a reference, the sensitivity and specificity of microscopy were 33.3% and 100.0%, respectively, for detecting P. falciparum infection, and 7.0% and 100.0%, for detecting P. vivax infection. Among the 47 participants with parasitemia, only one had a fever (>=37.5 degrees C) and 31 (66.0%) were adult males. Risk factors of Plasmodium infection were males and soldiers, whereas a risk factor of asymptomatic Plasmodium infection was a history of >=3 malaria episodes. CONCLUSIONS/SIGNIFICANCE: There were many asymptomatic Plasmodium carriers in the study areas of Attapeu province in 2015. Adult males, probably soldiers, were at high risk for malaria infection. P. vivax, the dominant species, accounted for 87.2% of the Plasmodium infections among the participants. To achieve malaria elimination in the Lao PDR, highly sensitive diagnostic tests, including PCR based diagnostic methods should be used, and plans targeting high-risk populations and elimination of P. vivax should be designed and implemented. PMID- 29261649 TI - Cost-effectiveness analysis of diarrhoea management approaches in Nigeria: A decision analytical model. AB - BACKGROUND: Diarrhoea is a leading cause of death in Nigerian children under 5 years. Implementing the most cost-effective approach to diarrhoea management in Nigeria will help optimize health care resources allocation. This study evaluated the cost-effectiveness of various approaches to diarrhoea management namely: the 'no treatment' approach (NT); the preventive approach with rotavirus vaccine; the integrated management of childhood illness for diarrhoea approach (IMCI); and rotavirus vaccine plus integrated management of childhood illness for diarrhoea approach (rotavirus vaccine + IMCI). METHODS: Markov cohort model conducted from the payer's perspective was used to calculate the cost-effectiveness of the four interventions. The markov model simulated a life cycle of 260 weeks for 33 million children under five years at risk of having diarrhoea (well state). Disability adjusted life years (DALYs) averted was used to quantify clinical outcome. Incremental cost-effectiveness ratio (ICER) served as measure of cost effectiveness. RESULTS: Based on cost-effectiveness threshold of $2,177.99 (i.e. representing Nigerian GDP/capita), all the approaches were very cost-effective but rotavirus vaccine approach was dominated. While IMCI has the lowest ICER of $4.6/DALY averted, the addition of rotavirus vaccine was cost-effective with an ICER of $80.1/DALY averted. Rotavirus vaccine alone was less efficient in optimizing health care resource allocation. CONCLUSION: Rotavirus vaccine + IMCI approach was the most cost-effective approach to childhood diarrhoea management. Its awareness and practice should be promoted in Nigeria. Addition of rotavirus vaccine should be considered for inclusion in the national programme of immunization. Although our findings suggest that addition of rotavirus vaccine to IMCI for diarrhoea is cost-effective, there may be need for further vaccine demonstration studies or real life studies to establish the cost-effectiveness of the vaccine in Nigeria. PMID- 29261650 TI - Self-organizing spots get under your skin. AB - Sixty-five years after Turing first revealed the potential of systems with local activation and long-range inhibition to generate pattern, we have only recently begun to identify the biological elements that operate at many scales to generate periodic patterns in nature. In this Primer, we first review the theoretical framework provided by Turing, Meinhardt, and others that suggests how periodic patterns could self-organize in developing animals. This Primer was developed to provide context for recent studies that reveal how diverse molecular, cellular, and physical mechanisms contribute to the establishment of the periodic pattern of hair or feather buds in the developing skin. From an initial emphasis on trying to disambiguate which specific mechanism plays a primary role in hair or feather bud development, we are beginning to discover that multiple mechanisms may, in at least some contexts, operate together. While the emergence of the diverse mechanisms underlying pattern formation in specific biological contexts probably reflects the contingencies of evolutionary history, an intriguing possibility is that these mechanisms interact and reinforce each other, producing emergent systems that are more robust. PMID- 29261648 TI - Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element. AB - Cohesin is crucial for genome stability, cell division, transcription and chromatin organization. Its functions critically depend on NIPBL, the cohesin loader protein that is found to be mutated in >60% of the cases of Cornelia de Lange syndrome (CdLS). Other mutations are described in the cohesin subunits SMC1A, RAD21, SMC3 and the HDAC8 protein. In 25-30% of CdLS cases no mutation in the known CdLS genes is detected. Until now, functional elements in the noncoding genome were not characterized in the molecular etiology of CdLS and therefore are excluded from mutation screening, although the impact of such mutations has now been recognized for a wide range of diseases. We have identified different elements of the noncoding genome involved in regulation of the NIPBL gene. NIPBL AS1 is a long non-coding RNA transcribed upstream and antisense to NIPBL. By knockdown and transcription blocking experiments, we could show that not the NIPBL-AS1 gene product, but its actual transcription is important to regulate NIPBL expression levels. This reveals a possibility to boost the transcriptional activity of the NIPBL gene by interfering with the NIPBL-AS1 lncRNA. Further, we have identified a novel distal enhancer regulating both NIPBL and NIPBL-AS1. Deletion of the enhancer using CRISPR genome editing in HEK293T cells reduces expression of NIPBL, NIPBL-AS1 as well as genes found to be dysregulated in CdLS. PMID- 29261651 TI - Long-lived CD8+ T cell responses following Crimean-Congo haemorrhagic fever virus infection. AB - Crimean-Congo haemorrhagic fever virus (CCHFV) is a member of the Orthonairovirus genus of the Nairoviridae family and is associated with haemorrhagic fever in humans. Although T lymphocyte responses are known to play a role in protection from and clearance of viral infections, specific T cell epitopes have yet to be identified for CCHFV following infection. A panel of overlapping peptides covering the CCHFV nucleoprotein and the structural glycoproteins, GN and GC, were screened by ELISpot assay to detect interferon gamma (IFN-gamma) production in vitro by peripheral blood mononuclear cells from eleven survivors with previous laboratory confirmed CCHFV infection. Reactive peptides were located predominantly on the nucleoprotein, with only one survivor reacting to two peptides from the glycoprotein GC. No single epitope was immunodominant, however all but one survivor showed reactivity to at least one T cell epitope. The responses were present at high frequency and detectable several years after the acute infection despite the absence of continued antigenic stimulation. T cell depletion studies confirmed that IFN-gamma production as detected using the ELISpot assay was mediated chiefly by CD8+ T cells. This is the first description of CD8+ T cell epitopic regions for CCHFV and provides confirmation of long-lived T cell responses in survivors of CCHFV infection. PMID- 29261652 TI - Proteolytic systems' expression during myogenesis and transcriptional regulation by amino acids in gilthead sea bream cultured muscle cells. AB - Proteolytic systems exert an important role in vertebrate muscle controlling protein turnover, recycling of amino acids (AA) or its use for energy production, as well as other functions like myogenesis. In fish, proteolytic systems are crucial for the relatively high muscle somatic index they possess, and because protein is the most important dietary component. Thus in this study, the molecular profile of proteolytic markers (calpains, cathepsins and ubiquitin proteasome system (UbP) members) were analyzed during gilthead sea bream (Sparus aurata) myogenesis in vitro and under different AA treatments. The gene expression of calpains (capn1, capn3 and capns1b) decreased progressively during myogenesis together with the proteasome member n3; whereas capn2, capns1a, capns1b and ubiquitin (ub) remained stable. Contrarily, the cathepsin D (ctsd) paralogs and E3 ubiquitin ligases mafbx and murf1, showed a significant peak in gene expression at day 8 of culture that slightly decreased afterwards. Moreover, the protein expression analyzed for selected molecules presented in general the same profile of the mRNA levels, which was confirmed by correlation analysis. These data suggest that calpains seem to be more important during proliferation, while cathepsins and the UbP system appear to be required for myogenic differentiation. Concerning the transcriptional regulation by AA, the recovery of their levels after a short starvation period did not show effects on cathepsins expression, whereas it down-regulated the expression of capn3, capns1b, mafbx, murf1 and up-regulated n3. With regards to AA deficiencies, the major changes occurred at day 2, when leucine limitation suppressed ctsb and ctsl expression. Besides at the same time, both leucine and lysine deficiencies increased the expression of mafbx and murf1 and decreased that of n3. Overall, the opposite nutritional regulation observed, especially for the UbP members, points out an efficient and complementary role of these factors that could be useful in gilthead sea bream diets optimization. PMID- 29261653 TI - Key scientific issues in developing drinking water guidelines for perfluoroalkyl acids: Contaminants of emerging concern. AB - Perfluoroalkyl acids (PFAAs), a group of synthetic organic chemicals with industrial and commercial uses, are of current concern because of increasing awareness of their presence in drinking water and their potential to cause adverse health effects. PFAAs are distinctive among persistent, bioaccumulative, and toxic (PBT) contaminants because they are water soluble and do not break down in the environment. This commentary discusses scientific and risk assessment issues that impact the development of drinking water guidelines for PFAAs, including choice of toxicological endpoints, uncertainty factors, and exposure assumptions used as their basis. In experimental animals, PFAAs cause toxicity to the liver, the immune, endocrine, and male reproductive systems, and the developing fetus and neonate. Low-dose effects include persistent delays in mammary gland development (perfluorooctanoic acid; PFOA) and suppression of immune response (perfluorooctane sulfonate; PFOS). In humans, even general population level exposures to some PFAAs are associated with health effects such as increased serum lipids and liver enzymes, decreased vaccine response, and decreased birth weight. Ongoing exposures to even relatively low drinking water concentrations of long-chain PFAAs substantially increase human body burdens, which remain elevated for many years after exposure ends. Notably, infants are a sensitive subpopulation for PFAA's developmental effects and receive higher exposures than adults from the same drinking water source. This information, as well as emerging data from future studies, should be considered in the development of health-protective and scientifically sound guidelines for PFAAs in drinking water. PMID- 29261654 TI - Correction: Reading wild minds: A computational assay of Theory of Mind sophistication across seven primate species. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005833.]. PMID- 29261655 TI - Cell salvage and donor blood transfusion during cesarean section: A pragmatic, multicentre randomised controlled trial (SALVO). AB - BACKGROUND: Excessive haemorrhage at cesarean section requires donor (allogeneic) blood transfusion. Cell salvage may reduce this requirement. METHODS AND FINDINGS: We conducted a pragmatic randomised controlled trial (at 26 obstetric units; participants recruited from 4 June 2013 to 17 April 2016) of routine cell salvage use (intervention) versus current standard of care without routine salvage use (control) in cesarean section among women at risk of haemorrhage. Randomisation was stratified, using random permuted blocks of variable sizes. In an intention-to-treat analysis, we used multivariable models, adjusting for stratification variables and prognostic factors identified a priori, to compare rates of donor blood transfusion (primary outcome) and fetomaternal haemorrhage >=2 ml in RhD-negative women with RhD-positive babies (a secondary outcome) between groups. Among 3,028 women randomised (2,990 analysed), 95.6% of 1,498 assigned to intervention had cell salvage deployed (50.8% had salvaged blood returned; mean 259.9 ml) versus 3.9% of 1,492 assigned to control. Donor blood transfusion rate was 3.5% in the control group versus 2.5% in the intervention group (adjusted odds ratio [OR] 0.65, 95% confidence interval [CI] 0.42 to 1.01, p = 0.056; adjusted risk difference -1.03, 95% CI -2.13 to 0.06). In a planned subgroup analysis, the transfusion rate was 4.6% in women assigned to control versus 3.0% in the intervention group among emergency cesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 2.2% versus 1.8% among elective cesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46). No case of amniotic fluid embolism was observed. The rate of fetomaternal haemorrhage was higher with the intervention (10.5% in the control group versus 25.6% in the intervention group, adjusted OR 5.63, 95% CI 1.43 to 22.14, p = 0.013). We are unable to comment on long-term antibody sensitisation effects. CONCLUSIONS: The overall reduction observed in donor blood transfusion associated with the routine use of cell salvage during cesarean section was not statistically significant. TRIAL REGISTRATION: This trial was prospectively registered on ISRCTN as trial number 66118656 and can be viewed on http://www.isrctn.com/ISRCTN66118656. PMID- 29261656 TI - Nicotinic alpha 7 receptor agonists EVP-6124 and BMS-933043, attenuate scopolamine-induced deficits in visuo-spatial paired associates learning. AB - Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR alpha7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR alpha7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR alpha7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS 933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR alpha7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR alpha7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task. PMID- 29261657 TI - Why do physicians prescribe dialysis? A prospective questionnaire study. AB - INTRODUCTION: The incidence of unplanned dialysis initiation (DI) with consequent increased comorbidity, mortality and reduced modality choice remains high, but the optimal timing of dialysis initiation (DI) remains controversial, and there is a lack of studies of specific reasons for DI. We investigated why and when physicians prescribe dialysis and hypothesized that physician motivation for DI is an independent factor which may have clinical consequences. METHODS: In the Peridialysis study, an ongoing multicenter prospective study assessing the causes and timing of DI and consequences of unplanned dialysis, physicians in 11 hospitals were asked to describe their primary, secondary and further reasons for prescribing DI. The stated reasons for DI were analyzed in relation to clinical and biochemical data at DI, and characteristics of physicians. RESULTS: In 446 patients (median age 67 years; 38% females; diabetes 25.6%), DI was prescribed by 84 doctors who stated 23 different primary reasons for DI. The primary indication was clinical in 63% and biochemical in 37%; 23% started for life-threatening conditions. Reduced renal function accounted for only 19% of primary reasons for DI but was a primary or contributing reason in 69%. The eGFR at DI was 7.2 +/-3.4 ml/min/1.73 m2, but varied according to comorbidity and cause of DI. Patients with cachexia, anorexia and pulmonary stasis (34% with heart failure) had the highest eGFR (8.2-9.8 ml/min/1.73 m2), and those with edema, "low GFR", and acidosis, the lowest (4.6-6.1 ml/min/1.73 m2). Patients with multiple comorbidity including diabetes started at a high eGFR (8.7 ml/min/1.73 m2). Physician experience played a role in dialysis prescription. Non-specialists were more likely to prescribe dialysis for life-threatening conditions, while older and more experienced physicians were more likely to start dialysis for clinical reasons, and at a lower eGFR. Female doctors started dialysis at a higher eGFR than males (8.0 vs. 7.1 ml/min/1.73 m2). CONCLUSIONS: DI was prescribed mainly based on clinical reasons in accordance with current recommendations while low renal function accounted for only 19% of primary reasons for DI. There are considerable differences in physicians' stated motivations for DI, related to their age, clinical experience and interpretation of biochemical variables. These differences may be an independent factor in the clinical treatment of patients, with consequences for the risk of unplanned DI. PMID- 29261658 TI - SYN023, a novel humanized monoclonal antibody cocktail, for post-exposure prophylaxis of rabies. AB - Rabies is a neglected zoonotic disease that is preventable in humans by appropriate post-exposure prophylaxis (PEP). However, current PEP relies on polyclonal immune globulin products purified from pooled human (HRIG) or equine (ERIG) plasma that are either in chronic shortage or in association with safety concerns. Here, we present the development of an antibody cocktail, SYN023, made of two novel monoclonal antibodies (MAb) CTB011 and CTB012 that could serve as safer and more cost-effective alternatives to the current RIG products. Both CTB011 and CTB012 are humanized MAbs that bind to non-overlapping epitopes on the rabies virus (RABV) glycoprotein (G) with sub-nanomolar affinities. Sequence analysis revealed that many of the critical residues in binding are highly conserved across different species of lyssaviruses. When combined at a 1:1 ratio, CTB011/CTB012 exhibited neutralization capabilities equivalent or superior to HRIG against 10 North American street RABV isolates in vitro and 15 prevalent Chinese RABV strains in animal models. Finally, SYN023, at a dosage of 0.03 mg/kg, was able to offer the same degree of protection as standard HRIG administration (20 IU/kg) in Syrian hamsters challenged with a highly virulent bat (Tadarida brasiliensis) RABV variant. Taken together, the high-potency and broad-spectrum neutralization demonstrated by SYN023 make it an effective candidate for human rabies PEP consideration. PMID- 29261659 TI - Assessment of MALDI-TOF mass spectrometry for filariae detection in Aedes aegypti mosquitoes. AB - Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) is an emerging tool for routine identification of bacteria, archaea and fungi. It has also been recently applied as an accurate approach for arthropod identification. Preliminary studies have shown that the MALDI-TOF MS was able to differentiate whether ticks and mosquitoes were infected or not with some bacteria and Plasmodium parasites, respectively. The aim of the present study was to test the efficiency of MALDI-TOF MS tool in distinguishing protein profiles between uninfected mosquitoes from specimens infected by filarioid helminths. Aedes aegypti mosquitoes were engorged on microfilaremic blood infected with Dirofilaria immitis, Brugia malayi or Brugia pahangi. Fifteen days post-infective blood feeding, a total of 534 mosquitoes were killed by freezing. To assess mass spectra (MS) profile changes following filariae infections, one compartment (legs, thorax, head or thorax and head) per mosquito was submitted for MALDI-TOF MS analysis; the remaining body parts were used to establish filariae infectious status by real-time qPCR. A database of reference MS, based on the mass profiles of at least two individual mosquitoes per compartment, was created. Subsequently, the remaining compartment spectra (N = 350) from Ae. aegypti infected or not infected by filariae were blind tested against the spectral database. In total, 37 discriminating peak masses ranging from 2062 to 14869 daltons were identified, of which 17, 11, 12 and 7 peak masses were for legs, thorax, thorax-head and head respectively. Two peak masses (4073 and 8847 Da) were specific to spectra from Ae. aegypti infected with filariae, regardless of nematode species or mosquito compartment. The thorax-head part provided better classification with a specificity of 94.1% and sensitivity of 86.6, 71.4 and 68.7% of D. immitis, B. malayi and B. pahangi respectively. This study presents the potential of MALDI-TOF MS as a reliable tool for differentiating non-infected and filariae-infected Ae. aegypti mosquitoes. Considering that the results might vary in other mosquito species, further studies are needed to consolidate the obtained preliminary results before applying this tool in entomological surveillance as a fast mass screening method of filariosis vectors in endemic areas. PMID- 29261660 TI - Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7. AB - PURPOSE: To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype-phenotype analysis. METHODS: Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype-phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. RESULTS: Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E 02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype-phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (beta = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (beta = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (beta = -2.16 and -2.82 MUm, P = 4.68E-02 and 2.40E 02, additive and recessive model, respectively) and increased optic nerve head blood flow (beta = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (beta = 0.03 mm3, P = 4.60E-02) and mean cup depth (beta = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (beta = -0.87 dB, P = 2.44E-02; dominant model). CONCLUSION: The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG. PMID- 29261661 TI - Individual co-variation between viral RNA load and gene expression reveals novel host factors during early dengue virus infection of the Aedes aegypti midgut. AB - Dengue virus (DENV) causes more human infections than any other mosquito-borne virus. The current lack of antiviral strategies has prompted genome-wide screens for host genes that are required for DENV infectivity. Earlier transcriptomic studies that identified DENV host factors in the primary vector Aedes aegypti used inbred laboratory colonies and/or pools of mosquitoes that erase individual variation. Here, we performed transcriptome sequencing on individual midguts in a field-derived Ae. aegypti population to identify new candidate host factors modulating DENV replication. We analyzed the transcriptomic data using an approach that accounts for individual co-variation between viral RNA load and gene expression. This approach generates a prediction about the agonist or antagonist effect of candidate genes on DENV replication based on the sign of the correlation between gene expression and viral RNA load. Using this method, we identified 39 candidate genes that went undetected by conventional pairwise comparison of gene expression levels between DENV-infected midguts and uninfected controls. Only four candidate genes were detected by both methods, emphasizing their complementarity. We demonstrated the value of our approach by functional validation of a candidate agonist gene encoding a sterol regulatory element binding protein (SREBP), which was identified by correlation analysis but not by pairwise comparison. We confirmed that SREBP promotes DENV infection in the midgut by RNAi-mediated gene knockdown in vivo. We suggest that our approach for transcriptomic analysis can empower genome-wide screens for potential agonist or antagonist factors by leveraging inter-individual variation in gene expression. More generally, this method is applicable to a wide range of phenotypic traits displaying inter-individual variation. PMID- 29261662 TI - Improving resolution of dynamic communities in human brain networks through targeted node removal. AB - Current approaches to dynamic community detection in complex networks can fail to identify multi-scale community structure, or to resolve key features of community dynamics. We propose a targeted node removal technique to improve the resolution of community detection. Using synthetic oscillator networks with well-defined "ground truth" communities, we quantify the community detection performance of a common modularity maximization algorithm. We show that the performance of the algorithm on communities of a given size deteriorates when these communities are embedded in multi-scale networks with communities of different sizes, compared to the performance in a single-scale network. We demonstrate that targeted node removal during community detection improves performance on multi-scale networks, particularly when removing the most functionally cohesive nodes. Applying this approach to network neuroscience, we compare dynamic functional brain networks derived from fMRI data taken during both repetitive single-task and varied multi task experiments. After the removal of regions in visual cortex, the most coherent functional brain area during the tasks, community detection is better able to resolve known functional brain systems into communities. In addition, node removal enables the algorithm to distinguish clear differences in brain network dynamics between these experiments, revealing task-switching behavior that was not identified with the visual regions present in the network. These results indicate that targeted node removal can improve spatial and temporal resolution in community detection, and they demonstrate a promising approach for comparison of network dynamics between neuroscientific data sets with different resolution parameters. PMID- 29261663 TI - Comparative study of impaction and sedimentation in an aerosol chamber using defined fungal spore and bacterial concentrations. AB - Biocontamination control is a very significant part of the manufacturing process of sterile drugs. Sterility is frequently monitored by active or passive air sampling measurements, but there are no specific rules as to how this is to be done. This study tested air sampling methods of active impaction and passive sedimentation under standardized conditions. Aspergillus niger (A. niger) and Staphylococcus aureus (S. aureus) were selected in this experiment to examine parallels, correlations and differences between the two methods. The results show that the number of colony forming units per plate (CFU/plate) was higher for A. niger in the active method, whereas for S. aureus it was higher in the sedimentation method. A high correlation coefficient was found between the impaction and sedimentation methods for A. niger. For S. aureus, depending on the culture media used and the time for passive air sampling, a larger number of CFU/plate was found than in active air sampling. This study concludes that active and passive air sampling can be used for monitoring the air in clean rooms. For fungal spore detection, the impaction is more efficient, as it is possible to sample a higher volume of air in a shorter period of time, whereas the optimal measurement methods for S. aureus depend on a number of factors. PMID- 29261665 TI - Molecular recognition and packing frustration in a helical protein. AB - Biomolecular recognition entails attractive forces for the functional native states and discrimination against potential nonnative interactions that favor alternate stable configurations. The challenge posed by the competition of nonnative stabilization against native-centric forces is conceptualized as frustration. Experiment indicates that frustration is often minimal in evolved biological systems although nonnative possibilities are intuitively abundant. Much of the physical basis of minimal frustration in protein folding thus remains to be elucidated. Here we make progress by studying the colicin immunity protein Im9. To assess the energetic favorability of nonnative versus native interactions, we compute free energies of association of various combinations of the four helices in Im9 (referred to as H1, H2, H3, and H4) by extensive explicit water molecular dynamics simulations (total simulated time > 300 MUs), focusing primarily on the pairs with the largest native contact surfaces, H1-H2 and H1-H4. Frustration is detected in H1-H2 packing in that a nonnative packing orientation is significantly stabilized relative to native, whereas such a prominent nonnative effect is not observed for H1-H4 packing. However, in contrast to the favored nonnative H1-H2 packing in isolation, the native H1-H2 packing orientation is stabilized by H3 and loop residues surrounding H4. Taken together, these results showcase the contextual nature of molecular recognition, and suggest further that nonnative effects in H1-H2 packing may be largely avoided by the experimentally inferred Im9 folding transition state with native packing most developed at the H1-H4 rather than the H1-H2 interface. PMID- 29261664 TI - Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2. AB - Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc. Pharmacological, biochemical and cell biological experiments further indicate this toxic effect involves casein kinase 2 (CK2) activation, providing a molecular basis for the toxic effect of PrPc on FAT. CK2 was found to phosphorylate and inhibit light chain subunits of the major motor protein conventional kinesin. Collectively, these findings suggest CK2 as a novel therapeutic target to prevent the gradual loss of neuronal connectivity that characterizes prion diseases. PMID- 29261666 TI - A longitudinal study of the associations of children's body mass index and physical activity with blood pressure. AB - Childhood blood pressure is a marker of cardiovascular disease risk in later life. We examined how body mass index (BMI) and physical activity, and changes in these, are associated with blood pressure in primary school-aged children. Data are from 1223 children aged 9 years (Year 4) in Bristol, UK, 685 of whom had been assessed at 6 years (Year 1). Child height and weight were measured, and children wore accelerometers for five days, from which average counts per minute, and moderate-to-vigorous-intensity physical activity and sedentary minutes per day were derived. At age 9 years, blood pressure was measured. Multiple imputation of missing data and adjusted linear regression models were used to examine associations. Child BMI at 9 years was cross-sectionally associated with higher systolic (SBP) and diastolic (DBP) blood pressure (mean difference [95% CI]: 1.10 [0.34, 1.87] mmHg and 0.86 [0.13, 1.60] mmHg, respectively, per SD of BMI). Prospective associations of BMI at age 6 with blood pressure at age 9 were consistent with these cross-sectional associations. However, change in BMI between 6 and 9 years was not strongly associated with subsequent SBP or DBP (0.68 [-0.61, 1.98] mmHg and 1.23 [-0.09, 2.54] mmHg, respectively). There was little evidence that physical activity or sedentary time were associated with blood pressure in either cross-sectional or prospective analyses. Greater childhood BMI is associated with higher blood pressure, and this association persists over several years. Prevention of excessive bodyweight from early childhood may be important in stemming the development of cardiovascular risk. PMID- 29261667 TI - Increased lipid availability for three days reduces whole body glucose uptake, impairs muscle mitochondrial function and initiates opposing effects on PGC 1alpha promoter methylation in healthy subjects. AB - AIMS: FFA and FFA metabolites cause insulin resistance and impair beta cell function. The goal of our research was to examine whether elevation of plasma FFA impairs mitochondrial function and alters PGC-1alpha promoter methylation. METHODS: In this uncontrolled, change from baseline study design, insulin sensitivity and glucose-stimulated insulin secretion were measured in 9 normal glucose tolerant subjects before and after 3 day lipid infusion to elevate plasma FFA concentration. Vastus lateralis muscle biopsies were obtained and mitochondrial function, PGC-1alpha expression, and PGC-1alpha promoter methylation were quantitated. RESULTS: Increased plasma FFA (440+/-93 MUmol/Lto 997+/-242 MUM, p<0.001) decreased insulin-stimulated total glucose disposal (TGD) by 25% (p = 0.008), impaired suppression of endogenous glucose production (p = 0.01), and reduced mitochondrial ATP synthesis with complex 1 (34%, p<0.05) and complex 2 (30%, p<0.05) substrates. Lipid infusion had no effect on muscle PGC 1alpha RNA expression, total methylation or non-CpG methylation, but methylation of the alternative PGC-1alpha promoter decreased (1.30+/-0.30 to 0.84+/-0.15% methylated residues/patient*strand, p = 0.055). Within PGC-1alpha promoter there was demethylation of CpT residues (0.72+/-0.16 vs. 0.28+/-0.10 methylated residues/patient*strand) (p = 0.002), which was inversely correlated with PGC 1alpha mRNA expression (r = -0.94, p<0.0001) and ATP synthesis with complex 1 (r = -0.80, p<0.01) and complex 2 (r = -0.69, p<0.05) substrates. Lipid infusion increased DNMT-3B (methyltransferase associated with PGC-1alpha promoter non-CpG methylation) mRNA expression (0.87 +/- 0.09 to 1.62 +/- 0.22 arbitrary units, p = 0.005), which correlated inversely with CpT demethylation (r = 0.67, p<0.05). CONCLUSION/INTERPRETATION: Physiologic plasma FFA elevation in NGT individuals has opposing effects on PGC-1alpha non-CpG residue methylation (CpT demethylation and increased DNMT-3B expression), which is correlated with changes in PGC-1alpha expression and skeletal muscle mitochondrial function. PMID- 29261668 TI - The looks matter; aggression escalation from changes on phenotypic appearance in the domestic fowl. AB - Domestic fowl in small groups are assumed to establish hierarchical systems based on individual recognition. Conversely, interactions in large groups are modulated by badges of status. Previous studies suggested that birds differing in phenotypic appearance (PA) became targets for aggression, possibly mistaking altered PA for badges of status. We evaluated the impact of altering PA on 0, 30, 50, 70 or 100% of the birds' house at three experimental group sizes (GS). Tested GS were 10, 20 or 40 (8 birds/m2, 3 pens/GSxPA, 45 total). Thus, for each GS we had groups initially homogenous (100U, U = Unmarked; 100M, M = Marked), or heterogeneous M and U phenotypes coexisting in different proportions: 30M/70U, 50M/50U, and 70M/30U, remaining unchanged until 33 weeks of age. Then, homogeneous groups (100U and 100M) were sequentially altered by marking or unmarking 30, 50 and 70% of birds at 34, 38 and 44 weeks, respectively. Aggressive interactions were observed before applying changes at 27-28 weeks (T0), and after each sequential PA change on week 35-36 (T1), 39-40 (T2) and 45 46 (T3). Frequency of aggressive interactions in altered groups at T1, T2, and T3 were compared with non-altered heterogeneous controls. Results indicate no differences across initial PA and GS treatments (T0; P>0.05). However, aggression escalation was observed at T1 immediately after the first PA manipulation (Tukey P<0.05 altered vs controls). Aggression in altered groups remained high at T2 when compared to controls (Tukey, P<0.05), although by T3 interactions declined to almost initial levels (Tukey, P>0.05 altered vs controls). Aggressive interactions at T1 and T2 were predominantly directed from un-altered towards recently altered birds, irrespectively of their initial phenotype and of the GS. These results demonstrate that a sudden change in PA affects group dynamics. Altered birds were exposed to escalated aggression even in small groups, where individual recognition was presumed. PMID- 29261669 TI - Patients with MDR-TB on domiciliary care in programmatic settings in Myanmar: Effect of a support package on preventing early deaths. AB - BACKGROUND: The community-based MDR-TB care (CBMDR-TBC) project was implemented in 2015 by The Union in collaboration with national TB programme (NTP) in 33 townships of upper Myanmar to improve treatment outcomes among patients with MDR TB registered under NTP. They received community-based support through the project staff, in addition to the routine domiciliary care provided by NTP staff. Each project township had a project nurse exclusively for MDR-TB and a community volunteer who provided evening directly observed therapy (in addition to morning directly observed therapy by NTP). OBJECTIVES: To determine the effect of CBMDR TBC project on death and unfavourable outcomes during the intensive phase of MDR TB treatment. METHODS: In this cohort study involving record review, all patients diagnosed with MDR-TB between January 2015 and June 2016 in project townships and initiated on treatment till 31 Dec 2016 were included. CBMDR-TBC status was categorized as "receiving support" if project initiation in patient's township was before treatment initiation, "receiving partial support" if project initiation was after treatment initiation, and "not receiving support" if project initiation was after intensive phase treatment outcome declaration. Time to event analysis (censored on 10 April 2017) and cox regression was done. RESULTS: Of 261 patients initiated on treatment, death and unfavourable outcomes were accounted for 13% and 21% among "receiving support (n = 163)", 3% and 24% among "receiving partial support (n = 75)" and 13% and 26% among "not receiving support (n = 23)" respectively. After adjusting for other potential confounders, the association between CBMDR-TBC and unfavourable outcomes was not statistically significant. However, when compared to "not receiving support", those "receiving support" and "receiving partial support" had 20% [aHR (0.95 CI: 0.8 (0.2-3.1)] and 90% lower hazard [aHR (0.95 CI: 0.1 (0.02-0.9)] of death, respectively. This was intriguing. Implementation of CBMDR-TBC coincided with implementation of decentralized MDR-TB centers at district level. Hence, patients that would have generally not accessed MDR-TB treatment before decentralization also started receiving treatment and were also included under CBMDR-TBC "received support" group. These patients could possibly be expected to sicker at treatment initiation than patients in other CBMDR-TBC groups. This could be the possible reason for nullifying the effect of CBMDR-TBC in "receiving support" group and therefore similar survival was found when compared to "not receiving support". CONCLUSION: CBMDR-TBC may prevent early deaths and has a scope for expansion to other townships of Myanmar and implications for NTPs globally. However, future studies should consider including data on extent of sickness at treatment initiation and patient level support received under CBMDR-TBC. PMID- 29261671 TI - Tragedy of the commons in the chemostat. AB - We present a proof of principle for the phenomenon of the tragedy of the commons that is at the center of many theories on the evolution of cooperation. Whereas the tragedy is commonly set in a game theoretical context, and attributed to an underlying Prisoner's Dilemma, we take an alternative approach based on basic mechanistic principles of species growth that does not rely on the specification of payoffs which may be difficult to determine in practice. We establish the tragedy in the context of a general chemostat model with two species, the cooperator and the cheater. Both species have the same growth rate function and yield constant, but the cooperator allocates a portion of the nutrient uptake towards the production of a public good -the "Commons" in the Tragedy- which is needed to digest the externally supplied nutrient. The cheater on the other hand does not produce this enzyme, and allocates all nutrient uptake towards its own growth. We prove that when the cheater is present initially, both the cooperator and the cheater will eventually go extinct, hereby confirming the occurrence of the tragedy. We also show that without the cheater, the cooperator can survive indefinitely, provided that at least a low level of public good or processed nutrient is available initially. Our results provide a predictive framework for the analysis of cooperator-cheater dynamics in a powerful model system of experimental evolution. PMID- 29261670 TI - Human intrahepatic ILC2 are IL-13positive amphiregulinpositive and their frequency correlates with model of end stage liver disease score. AB - INTRODUCTION: Innate lymphoid cells (ILC) have been implicated in the initiation of inflammation and fibrosis in mice. However, ILC have not been characterized in inflamed human liver tissue. METHODS: Human intrahepatic lymphocytes were isolated by mechanical digestion and phenotyped by flow cytometry. Conditioned medium from cultures of primary human biliary epithelial cells, stellate cells, fibroblasts and inflamed human liver tissue was used to model the effects of the inflammatory liver environment of ILC phenotype and function. RESULTS: All three ILC subsets were present in the human liver, with the ILC1 (CRTH2negCD117neg) subset constituting around 70% of intrahepatic ILCs. Both NCRpos (NKp44+) and NCRneg ILC3 (CRTH2negCD117pos) subsets were also detected. ILC2 (CRTH2pos) frequency correlated with disease severity measured by model of end stage liver disease (MELD) scoring leading us to study this subset in more detail. ILC2 displayed a tissue resident CD69+ CD161++ phenotype and expressed chemokine receptor CCR6 allowing them to respond to CCL20 secreted by cholangiocytes and stellate cells. ILC2 expressed integrins VLA-5 and VLA-6 and the IL-2 and IL-7 cytokine receptors CD25 and CD127 although IL-2 and IL-7 were barely detectable in inflamed liver tissue. Although biliary epithelial cells secrete IL-33, intrahepatic ILC2 had low expression of the ST2 receptor. Intrahepatic ILC2 secreted the immunoregulatory and repair cytokines IL-13 and amphiregulin. CONCLUSIONS: Intrahepatic ILC2 express receptors allowing them to be recruited to bile ducts in inflamed portal tracts. Their frequencies increased with worsening liver function. Their secretion of IL-13 and amphiregulin suggests they may be recruited to promote resolution and repair and thereby they may contribute to ongoing fibrogenesis in liver disease. PMID- 29261672 TI - Habitat risk assessment for regional ocean planning in the U.S. Northeast and Mid Atlantic. AB - Coastal habitats provide important benefits to people, including habitat for species targeted by fisheries and opportunities for tourism and recreation. Yet, such human activities also can imperil these habitats and undermine the ecosystem services they provide to people. Cumulative risk assessment provides an analytical framework for synthesizing the influence of multiple stressors across habitats and decision-support for balancing human uses and ecosystem health. To explore cumulative risk to habitats in the U.S. Northeast and Mid-Atlantic Ocean Planning regions, we apply the open-source InVEST Habitat Risk Assessment model to 13 habitats and 31 stressors in an exposure-consequence framework. In doing so, we advance the science priorities of EBM and both regional planning bodies by synthesizing the wealth of available data to improve our understanding of human uses and how they affect marine resources. We find that risk to ecosystems is greatest first, along the coast, where a large number of stressors occur in close proximity and secondly, along the continental shelf, where fewer, higher consequence activities occur. Habitats at greatest risk include soft and hard bottom nearshore areas, tidal flats, soft-bottom shelf habitat, and rocky intertidal zones-with the degree of risk varying spatially. Across all habitats, our results indicate that rising sea surface temperatures, commercial fishing, and shipping consistently and disproportionally contribute to risk. Further, our findings suggest that management in the nearshore will require simultaneously addressing the temporal and spatial overlap as well as intensity of multiple human activities and that management in the offshore requires more targeted efforts to reduce exposure from specific threats. We offer a transparent, generalizable approach to evaluating cumulative risk to multiple habitats and illustrate the spatially heterogeneous nature of impacts along the eastern Atlantic coast and the importance of spatial scale in estimating such impacts. These results offer a valuable decision-support tool by helping to constrain the decision space, focus attention on habitats and locations at the greatest risk, and highlight effect management strategies. PMID- 29261673 TI - We are what we eat: Regulatory gaps in the United States that put our health at risk. AB - The American diet has changed dramatically since 1958, when Congress gave the United States Food and Drug Administration (FDA) the authority to ensure the safety of chemicals in food. Since then, thousands of chemicals have entered the food system. Yet their long-term, chronic effects have been woefully understudied, their health risks inadequately assessed. The FDA has been sluggish in considering scientific knowledge about the impact of exposures-particularly at low levels and during susceptible developmental stages. The agency's failure to adequately account for the risks of perchlorate-a well-characterized endocrine disrupting chemical-to vulnerable populations is representative of systemic problems plaguing the regulation of chemicals in food. Today, we are faced with a regulatory system that, weakened by decades of limited resources, has fallen short of fully enforcing its mandates. The FDA's inability to effectively manage the safety of hundreds of chemicals is putting our children's health at risk. PMID- 29261674 TI - Mitochondrial haplogroups in patients with rheumatoid arthritis: No association with disease and disease manifestations. AB - OBJECTIVE: To describe the distribution of specific mitochondrial DNA (mtDNA) haplogroups (hgs) in a cohort of patients with rheumatoid arthritis (RA). METHODS: Two-hundred nineteen consecutive patients with RA had mtDNA isolated from their blood, sequenced and haplotyped. Patients were diagnosed according to the American College of Rheumatology (ACR)/European league against Rheumatism (EULAR) criteria. Demographic and clinical data were retrieved from the Danish nationwide database (DANBIO). Logistic regression analyses were performed to test for associations. RESULTS: One-hundred eighty-four patients were eligible for analysis. Haplogroup frequencies were: H (n = 88; 47.8%), U (n = 37; 20.1%), T (n = 22; 12.0%), J (n = 16; 8.7%), K (n = 11; 5.9%), HV (n = 6; 3.3%) and V (n = 4; 2.2%). The distribution of individual hgs was identical to the background population. Radiographic erosions were significantly associated with hg clusters JT (OR = 2.37, 95% confidence interval (CI): 1.07-5.53, p = 0.038). Significantly fewer patients from hg cluster JT received biological treatment (OR = 0.17, 95% CI: 0.03-0.87, p = 0.038). Albeit, none of these associations were significant when corrected for multiple tests. CONCLUSION: There was no significant association between mtDNA hgs and presence of RA or disease manifestations. There was an, albeit insignificant, overrepresentation of patients with hg JT among patients with erosive disease; however, slightly fewer patients in the JT group were treated with biological drugs. PMID- 29261675 TI - The limited prognostic role of echocardiograms in short-term follow-up after acute decompensated heart failure: An analysis of the Korean Heart Failure (KorHF) Registry. AB - BACKGROUND: The prognostic values of the left ventricular ejection fraction (LVEF) and end-diastolic dimension (LVEDD) have primarily been shown among patients with chronic heart failure (HF), with little representation of patients with acute HF (AHF). Therefore, we investigated the value of these echocardiographic parameters in predicting clinical outcomes among patients in the Korean Heart Failure (KorHF) Registry. METHODS: The KorHF Registry consists of 3,200 patients who were hospitalized with AHF from 2005 to 2009. The Kaplan Meier method was used to estimate survival and readmission, and differences were assessed using the log-rank test. Predictors of survival were identified using univariate and multivariate Cox proportional hazards regression analyses. RESULTS: Echocardiograms from 2,910 of the 3,200 patients (90.9%) were evaluated. The median LVEF and LVEDD (37% and 56 mm, respectively) were used as cut-offs for the binary transformation of each parameter. The cumulative death-free survival rates for all patients did not significantly differ based on LVEF or LVEDD quartiles; however, an LVEF greater than the median was associated with a better prognosis in ischemic HF patients (log-rank test; p = 0.039). Among ischemic HF patients, LVEF (dichotomized) was a significant predictor of death in a Cox model after adjusting for a history of HF, age, systolic blood pressure (SBP), serum sodium, sex, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), acute myocardial infarction (AMI), atrial fibrillation (Af) and anemia (hazard ratio (HR) 1.475, 95% confidence interval (CI) 1.099-1.979, p = 0.010). The cumulative readmission-free survival rates significantly differed among ischemic HF patients only when based on LVEDD quartiles (log-rank test; p = 0.001). In multivariate Cox proportional hazards regression analyses, LVEDD (dichotomized) remained a significant variable only among patients with ischemic HF after adjusting for sex, age, AMI, DM, COPD, serum sodium, SBP, blood urea nitrogen (BUN) and anemia (HR 1.401, 95% CI 1.067 1.841, p = 0.015). CONCLUSIONS: Among ischemic AHF patients in the KorHF Registry, LVEF is associated with mortality, whereas LVEDD is only associated with readmission in a binary transformed form. PMID- 29261676 TI - Parenting style and family type, but not child temperament, are associated with television viewing time in children at two years of age. AB - OBJECTIVES: Despite the American Academy of Pediatrics (AAP) recommending that electronic media be avoided in children under two years of age, screen use is common in infants and toddlers. The aims of this study were to determine how parenting style, infant temperament, and family type are associated with television viewing in two-year-old children. STUDY DESIGN: Participants were from the Prevention of Overweight in Infancy (POI) randomized controlled trial (n = 802) (Dunedin, New Zealand). Demographic information was collected at baseline (late pregnancy), and television and other screen time assessed by questionnaire at 24 months of age. Parenting style (Parenting Practices Questionnaire), infant temperament (Colorado Childhood Temperament Inventory), and family type (7 categories) were reported by both parents. RESULTS: Data were available for 487 participants (61% of the original participants). Median television viewing was relatively low at 21 minutes per day, or 30 minutes in those watching television (82%). Children who watched television played with mobile phones (12% of children) or iPads/tablets (22% of children) more frequently than children who did not (6% of children). In terms of parenting style, children of more authoritarian mothers (beta = 17, 95% CI: 6-27 minutes), more authoritarian partners (beta = 14, 95% CI: 2-26 minutes), or more permissive mothers (beta = 10, 95% CI: 3-17 minutes) watched significantly more television. No significant relationships were observed between child temperament and time watching television after adjustment for confounding variables. Children from "active" families (as rated by partners) watched 29 minutes less television each day (P = 0.002). CONCLUSIONS: Parenting style and family type were associated with television viewing time in young children, whereas child temperament was not. PMID- 29261677 TI - Increased soluble IL-7 receptor concentrations associate with improved IL-7 therapy outcomes in SIV-infected ART-treated Rhesus macaques. AB - The use of interleukin-7 (IL-7) as an immunorestorative therapeutic has proven effective in HIV infection, cancer and bone marrow transplantation. Mediating its activity through membrane-bound IL-7 receptor alpha (mCD127), IL-7 therapy increases T-cell numbers and survival. A soluble form, sCD127, is found in plasma, and we have previously identified increased plasma sCD127 concentrations in HIV infection. Furthermore, patients with high sCD127 exhibited the best viral control, implicating a role for IL-7 or sCD127 directly in improved virologic/immunologic outcomes. The role of the cytokine IL-7 in elevating sCD127 levels was addressed here through assessment of retrospective samples obtained from SIV-infected antiretroviral (ART)-treated Rhesus macaques. IL-7 was administered in clustered weekly doses, allowing for an assessment prior, during and following IL-7 administration. The levels of sCD127 remained relatively unchanged during both early SIV infection and following initiation of ART. However, treatment with IL-7 increased sCD127 concentrations in most animals, transiently or persistently, paralleling increased T-cell numbers, correlating significantly with CD8+ T-cell levels. In addition, proliferating CD4+ or CD8+ T cells (measured by Ki67) increased in association with elevated sCD127 concentrations. Finally, a high concentration of sCD127 in IL7-treated animals was associated with increased retention of T-cells (measured by BrDU). In addition, a lack, or loss of viral control was associated with more pronounced and frequent elevations in plasma sCD127 concentrations with IL-7 therapy. In summary, plasma sCD127 levels in SIV-infected ART-treated macaques was associated with therapeutic IL-7 administration, with higher sCD127 levels in macaques demonstrating the best T-cell responses. This study furthers our knowledge regarding the interrelationship between increased IL-7 levels and elevated sCD127 levels that may have implications for future IL-7 immunotherapeutic approaches in HIV-infected patients. PMID- 29261678 TI - Empirical analysis of vegetation dynamics and the possibility of a catastrophic desertification transition. AB - The process of desertification in the semi-arid climatic zone is considered by many as a catastrophic regime shift, since the positive feedback of vegetation density on growth rates yields a system that admits alternative steady states. Some support to this idea comes from the analysis of static patterns, where peaks of the vegetation density histogram were associated with these alternative states. Here we present a large-scale empirical study of vegetation dynamics, aimed at identifying and quantifying directly the effects of positive feedback. To do that, we have analyzed vegetation density across 2.5 * 106 km2 of the African Sahel region, with spatial resolution of 30 * 30 meters, using three consecutive snapshots. The results are mixed. The local vegetation density (measured at a single pixel) moves towards the average of the corresponding rainfall line, indicating a purely negative feedback. On the other hand, the chance of spatial clusters (of many "green" pixels) to expand in the next census is growing with their size, suggesting some positive feedback. We show that these apparently contradicting results emerge naturally in a model with positive feedback and strong demographic stochasticity, a model that allows for a catastrophic shift only in a certain range of parameters. Static patterns, like the double peak in the histogram of vegetation density, are shown to vary between censuses, with no apparent correlation with the actual dynamical features. Our work emphasizes the importance of dynamic response patterns as indicators of the state of the system, while the usefulness of static modality features appears to be quite limited. PMID- 29261680 TI - Determinants of stunting among children aged 6-59 months at Kindo Didaye woreda, Wolaita Zone, Southern Ethiopia: Unmatched case control study. AB - BACKGROUND: Stunting is a well-established risk marker of poor child development. Globally in 2017, 155 million children under 5 were estimated to be stunted. While different activities are being done to reduce the burden of stunted growth, the problem is overwhelming in Africa; it was increased by 24%. Therefore, identifying determinants of stunting among children aged 6-59 would help to set priorities for action and to the design of stunting reduction plan at a grassroots level. METHODS: The unmatched case-control study was conducted in randomly selected 8 rural kebeles of Kindo Didaye woreda, Ethiopia from February to April, 2016 to identify the determinants of stunting among children aged 6-59 months. The sampling frame was identified by enumeration of 6-59 months of age children in the entire households of the study area. From which 155 as cases and 310 as controls were chosen using anthropometric measurement based on the median of WHO 2006 reference population. The anthropometric data were analyzed by WHO Anthro 2010 software to generate Z-score values. Odds Ratio along with 95% confidence interval was estimated to identify determinants of stunting using the multivariable logistic regression. RESULTS: Drinking water from unsafe source (AOR = 7.06, 95% CI; 4.40-20.42),occasionally eating animal source food (AOR = 0.51, 95% CI; 0.02-0.68), ARI in the past two weeks (AOR = 3.04, (95% CI; 1.04 13.35), late initiation of breastfeeding after one hours after birth (AOR = 5.16, 95% CI; 2.24-15.90) and lack of vaccination (AOR = 6.38, 95% CI; 2.54-17.10)were significantly associated with stunting. CONCLUSIONS: Factors like exposure to diarrhea disease, exposure to acute respiratory infection, late initiation of breast milk after child breath, squeeze out of 1st breast milk, lack of vaccination, animal source of food, and unsafe source of water for drinking could be used to set priorities for action and to the design of Kindo Didaye woreda plan for stunting reduction down to grassroots level. Therefore, zonal health department and Kindo Didaye woreda health office should promote the importance of colostrums feeding. Drinking water should be decontaminated. Expansion of vaccination program to enhance herd immunity at the community level is important. PMID- 29261679 TI - Distinct impacts of sleep-disordered breathing on glycemic variability in patients with and without diabetes mellitus. AB - BACKGROUND: Sleep-disordered breathing (SDB) is highly prevalent in patients with diabetes mellitus (DM) and heart failure (HF) and contributes to poor cardiovascular outcomes. Enlarged glycemic variability (GV) is a risk factor of cardiac events independently of average blood glucose level, but the influence of SDB on GV is uncertain. In this study, we examined whether the impact of SDB on GV is modified by the presence of DM with or without HF. METHODS AND RESULTS: Two hundred three patients (67.5+/-14.1 [SD] years old, 132 males) who were admitted to our institute for examination or treatment of DM and/or HF underwent continuous glucose monitoring and polysomnography. Both HbA1c (8.0+/-2.0 vs. 5.7+/-0.4%) and mean amplitude of glycemic excursion (MAGE, median: 95.5 vs. 63.5 mg/dl) were significantly higher in a DM group (n = 100) than in a non-DM group (n = 103), but apnea-hypopnea index (AHI: 29.0+/-22.7 vs. 29.3+/-21.5) was similar in the two groups. AHI was correlated with log MAGE in the non-DM group but not in the DM group, and multivariate regression analysis revealed that AHI was an independent variable for log MAGE in the non-DM group but not in the DM group. We then divided the non-DM patients into two subgroups according to BNP level (100 pg/ml). AHI was positively correlated with log MAGE (r = 0.74, p<0.001) in the non-DM low-BNP subgroup, but such a correlation was not found in the non-DM high-BNP subgroup. Continuous positive airway pressure (CPAP) reduced MAGE from 75.3 to 53.0 mg/dl in the non-DM group but did not reduce MAGE in the DM group. CONCLUSION: Severity of SDB was associated with higher GV, but DM as well as HF diminished the contribution of SDB to GV. Treatment with CPAP was effective for reduction of GV only in patients without DM. PMID- 29261681 TI - Decreased expression of lethal giant larvae causes ovarian follicle cell outgrowth in the Drosophila Scutoid mutant. AB - Snail, a zinc-finger transcription factor, controls the process of epithelial mesenchymal transition, and ectopic expression of this protein may produce cells with stem cell properties. Because the effect of Snail expression in ovarian epithelial cells remains unclear, we generated Drosophila ovarian follicle stem cells (FSCs) with homozygous Scutoid (Sco) mutation. The Sco mutation is a reciprocal transposition that is known to induce ectopic Snail activity. We found that Sco mutant FSCs showed excess proliferation and high competitiveness for niche occupancy, and the descendants of this lineage formed outgrowths that failed to enter the endocycle. Surprisingly, such phenotypes were not rescued by suppressing Snail expression, but were completely restored by supplying Lethal giant larvae (Lgl). The lgl allele is a cell polarity gene that is often mutated in the genome. Importantly, Sco mutants survived in a complementation test with lgl. This result was probably obtained because the Sco-associated lgl allele appears to diminish, but not ablate lgl expression. While our data do not rule out the possibility that the Sco mutation disrupts a regulator of lgl transcription, our results strongly suggest that the phenotypes we found in Sco mutants are more closely associated with the lgl allele than ectopic Snail activity. PMID- 29261682 TI - Religion, a social determinant of mortality? A 10-year follow-up of the Health and Retirement Study. AB - The social determinants of health framework has brought a recognition of the primary importance of social forces in determining population health. Research using this framework to understand the health and mortality impact of social, economic, and political conditions, however, has rarely included religious institutions and ties. We investigate a well-measured set of social and economic determinants along with several measures of religious participation as predictors of adult mortality. Respondents (N = 18,370) aged 50 and older to the Health and Retirement Study were interviewed in 2004 and followed for all-cause mortality to 2014. Exposure variables were religious attendance, importance, and affiliation. Other social determinants of health included gender, race/ethnicity, education, household income, and net worth measured at baseline. Confounders included physical and mental health. Health behaviors and social ties were included as potential explanatory variables. Cox proportional hazards regressions were adjusted for complex sample design. After adjustment for confounders, attendance at religious services had a dose-response relationship with mortality, such that respondents who attended frequently had a 40% lower hazard of mortality (HR = 0.60, 95% CI 0.53-0.68) compared with those who never attended. Those for whom religion was "very important" had a 4% higher hazard (HR = 1.04, 95% CI 1.01 1.07); religious affiliation was not associated with risk of mortality. Higher income and net worth were associated with a reduced hazard of mortality as were female gender, Latino ethnicity, and native birth. Religious participation is multi-faceted and shows both lower and higher hazards of mortality in an adult US sample in the context of a comprehensive set of other social and economic determinants of health. PMID- 29261683 TI - Reasons for low uptake of referrals to ear and hearing services for children in Malawi. AB - BACKGROUND: Early detection and appropriate intervention for children with hearing impairment is important for maximizing functioning and quality of life. The lack of ear and hearing services in low income countries is a significant challenge, however, evidence suggests that even where such services are available, and children are referred to them, uptake is low. The aim of this study was to assess uptake of and barriers to referrals to ear and hearing services for children in Thyolo District, Malawi. METHODS: This was a mixed methods study. A survey was conducted with 170 caregivers of children who were referred for ear and hearing services during community-based screening camps to assess whether they had attended their referral and reasons for non-attendance. Semi-structured interviews were conducted with 23 caregivers of children who did not take up their referral to explore in-depth the reasons for non-uptake. In addition, 15 stakeholders were interviewed. Thematic analysis of the interview data was conducted and emerging trends were analysed. RESULTS: Referral uptake was very low with only 5 out of 150 (3%) children attending. Seven main interacting themes for non-uptake of referral were identified in the semi structured interviews: location of the hospital, lack of transport, other indirect costs of seeking care, fear and uncertainty about the referral hospital, procedural problems within the camps, awareness and understanding of hearing loss, and lack of visibility and availability of services. CONCLUSION: This study has highlighted a range of interacting challenges faced by families in accessing ear and hearing services in this setting. Understanding these context specific barriers to non-uptake of ear and hearing services is important for designing appropriate interventions to increase uptake. PMID- 29261685 TI - Mortality reductions due to mammography screening: Contemporary population-based data. AB - Our objective was to compare breast cancer mortality in two regions of the Republic of Ireland that introduced a screening programme eight years apart, and to estimate the steady-state mortality deficits the programme will produce. We carried out age- and year-matched between-region comparison of breast cancer mortality rates, and of incidence rates of stage 2-4 breast cancer, in the eligible cohorts. The regions comprised counties that, beginning in early 2000 (region 1) and late 2007 (region 2), invited women aged 50-64 to biennial mammography screening. The data were supplied by the National Cancer Registry, Central Statistics Office. As impact measures, we used age-and-year-matched mortality (from breast cancers diagnosed from 2000 onwards), rate ratios and incidence rate ratios in the compared regions from 2000 to 2013. Ratios were adjusted for between-region differences in background rates. In cohorts too old to be invited, death rates in regions 1 and 2 were 702 per 0.91 and 727 per 0.90 million women-years respectively (Ratio 0.96). In the eligible cohorts, they were 1027 per 2.9 and 1095 per 2.67 (Ratio 0.88). Thus, rates in cohorts that could have benefitted were 9% lower in region 1 than region 2: (95%CI: -20%, +4%). The incidence rates of stage 2-4 breast cancer were 7% lower in region 2 than region 1 over the entire 14 year period, and 20% lower in 2007, i.e., before the screening in region 2 began to narrow the difference. Since mortality reductions due to screening only manifest after several years, the full impact of screening has not yet been realized in region 1. The lower rate observed in that region is a conservative estimate of the steady state benefit. Additional deaths would have been averted had screening continued beyond age 64. PMID- 29261684 TI - Neural mechanisms underlying sensitivity to reverse-phi motion in the fly. AB - Optical illusions provide powerful tools for mapping the algorithms and circuits that underlie visual processing, revealing structure through atypical function. Of particular note in the study of motion detection has been the reverse-phi illusion. When contrast reversals accompany discrete movement, detected direction tends to invert. This occurs across a wide range of organisms, spanning humans and invertebrates. Here, we map an algorithmic account of the phenomenon onto neural circuitry in the fruit fly Drosophila melanogaster. Through targeted silencing experiments in tethered walking flies as well as electrophysiology and calcium imaging, we demonstrate that ON- or OFF-selective local motion detector cells T4 and T5 are sensitive to certain interactions between ON and OFF. A biologically plausible detector model accounts for subtle features of this particular form of illusory motion reversal, like the re-inversion of turning responses occurring at extreme stimulus velocities. In light of comparable circuit architecture in the mammalian retina, we suggest that similar mechanisms may apply even to human psychophysics. PMID- 29261686 TI - Evolution of language: An empirical study at eBay Big Data Lab. AB - The evolutionary theory of language predicts that a language will tend towards fewer synonyms for a given object. We subject this and related predictions to empirical tests, using data from the eBay Big Data Lab which let us access all records of the words used by eBay vendors in their item titles, and by consumers in their searches. We find support for the predictions of the evolutionary theory of language. In particular, the mapping from object to words sharpens over time on both sides of the market, i.e. among consumers and among vendors. In addition, the word mappings used on the two sides of the market become more similar over time. Our research contributes to the literature on language evolution by reporting results of a truly unique large-scale empirical study. PMID- 29261687 TI - Engagement of vulnerable youths using internet platforms. AB - AIM: The aim of this study was to explore the online distress and help-seeking behavior of youths in Hong Kong. METHODS: A cross-sectional telephone-based survey was conducted among 1,010 young people in Hong Kong. Logistic regression analysis was then performed to identify the factors associated with those who reported expressing emotional distress online and the differences in help-seeking behavior among four groups of youths: (1) the non-distressed (reference) group; (2) "Did not seek help" group; (3) "Seek informal help" group; and (4) "Seek formal help" group. RESULTS: The seeking of help and expression of distress online were found to be associated with a higher lifetime prevalence of suicidal ideation. The "Seek formal help" and "Did not seek help" groups had a similar risk profile, including a higher prevalence of suicidal ideation, non-suicidal self-injury, unsafe sex, and being bullied. The "Seek informal help" group was more likely to express distress online, which indicates that this population of youths may be accessible to professional identification. Approximately 20% of the distressed youths surveyed had not sought help despite expressing their distress online. IMPLICATION: The study's results indicate that helping professionals have opportunities to develop strategic engagement methods that make use of social media to help distressed youths. PMID- 29261688 TI - A new tropical Oligocene dolphin from Montanita/Olon, Santa Elena, Ecuador. AB - A new small probable Oligocene dolphin from Ecuador represents a new genus and species, Urkudelphis chawpipacha. The new taxon is known from a single juvenile skull and earbones; it differs from other archaic dolphins in features including widely exposed frontals at the vertex, a dorsally wide open vomer at the mesorostral groove, and a strongly projected and pointed lateral tuberosity of the periotic. Phylogenetic analysis places it toward the base of the largely extinct clade Platanistoidea. The fossil is one of a few records of tropical fossil dolphins. PMID- 29261689 TI - An improved wrapper-based feature selection method for machinery fault diagnosis. AB - A major issue of machinery fault diagnosis using vibration signals is that it is over-reliant on personnel knowledge and experience in interpreting the signal. Thus, machine learning has been adapted for machinery fault diagnosis. The quantity and quality of the input features, however, influence the fault classification performance. Feature selection plays a vital role in selecting the most representative feature subset for the machine learning algorithm. In contrast, the trade-off relationship between capability when selecting the best feature subset and computational effort is inevitable in the wrapper-based feature selection (WFS) method. This paper proposes an improved WFS technique before integration with a support vector machine (SVM) model classifier as a complete fault diagnosis system for a rolling element bearing case study. The bearing vibration dataset made available by the Case Western Reserve University Bearing Data Centre was executed using the proposed WFS and its performance has been analysed and discussed. The results reveal that the proposed WFS secures the best feature subset with a lower computational effort by eliminating the redundancy of re-evaluation. The proposed WFS has therefore been found to be capable and efficient to carry out feature selection tasks. PMID- 29261690 TI - Fisher's exact approach for post hoc analysis of a chi-squared test. AB - This research is motivated by one of our survey studies to assess the potential influence of introducing zebra mussels to the Lake Mead National Recreation Area, Nevada. One research question in this study is to investigate the association between the boating activity type and the awareness of zebra mussels. A chi squared test is often used for testing independence between two factors with nominal levels. When the null hypothesis of independence between two factors is rejected, we are often left wondering where does the significance come from. Cell residuals, including standardized residuals and adjusted residuals, are traditionally used in testing for cell significance, which is often known as a post hoc test after a statistically significant chi-squared test. In practice, the limiting distributions of these residuals are utilized for statistical inference. However, they may lead to different conclusions based on the calculated p-values, and their p-values could be over- o6r under-estimated due to the unsatisfactory performance of asymptotic approaches with regards to type I error control. In this article, we propose new exact p-values by using Fisher's approach based on three commonly used test statistics to order the sample space. We theoretically prove that the proposed new exact p-values based on these test statistics are the same. Based on our extensive simulation studies, we show that the existing asymptotic approach based on adjusted residual is often more likely to reject the null hypothesis as compared to the exact approach due to the inflated family-wise error rates as observed. We would recommend the proposed exact p-value for use in practice as a valuable post hoc analysis technique for chi-squared analysis. PMID- 29261691 TI - Do experiences and perceptions about quality of care differ among social groups in Nepal? : A study of maternal healthcare experiences of women with and without disabilities, and Dalit and non-Dalit women. AB - BACKGROUND: Suboptimal quality of care and disparities in services by healthcare providers are often reported in Nepal. Experience and perceptions about quality of care may differ according to women's socio-cultural background, individual characteristics, their exposure and expectations. This study aimed to compare perceptions of the quality of maternal healthcare services between two groups that are consistently considered vulnerable, women with disabilities from both the non-Dalit population and Dalit population and their peers without disabilities from both non-Dalit and Dalit communities. METHODS: A cross sectional survey was conducted among 343 total women that included women with disabilities, Dalits and non-Dalits. Women were recruited for interview, who were aged 15-49 years, had been pregnant within the last five years and who had used maternal care services in one of the public health facilities of Rupandehi district. A 20-item, Likert-type scale with four sub-scales or dimensions: 'Health Facility', 'Healthcare Delivery', 'Inter-personal' and 'Access to Care' was used to measure women's perceptions of quality of care. Chi-square test and t test were used to compare groups and to assess differences in perceptions; and linear regression was applied to assess confounding effects of socio-demographic factors. The mean score was compared for each item and separately for each dimension. RESULTS: All groups, women with disabilities and women without disabilities, Dalit and non-Dalit rated their perceptions and experiences of quality of care lowly in a number of items. While perceived quality of care between women with disabilities and without disabilities in the 'Health Facility' dimension and associated items, was found to differ (p<0.05), this difference was linked to disability status, but was not linked to caste differences. For example, differences in mean scores relating to 'Cleanliness and Facilities', 'Open and Friendliness' and 'Compassion and Kindness' were highly significant (p<0.001), with women with disabilities rating these as better than women without disabilities. On the other hand, women without disabilities rated the 'Availability of cash Incentives' more highly (p<0.01). No significant differences were found between Dalit and non-Dalit women in perceived quality of care, except in relation to 'Cleanliness and facilities', which Dalit women rated lower than non-Dalits (p<0.05). CONCLUSIONS: Perceptions about the quality of care differed significantly by disability status but not by caste. All groups rated the quality of healthcare delivery, interpersonal and personal factors as well as access to services 'low.' Poor service user experiences and perceptions of quality of care undermine opportunities to translate increased healthcare coverage into improved access and outcomes. Greater attention is required by policy makers, health planners and providers to the improvement of quality of care in health facilities. PMID- 29261692 TI - Grapevine Botryosphaeria dieback fungi have specific aggressiveness factor repertory involved in wood decay and stilbene metabolization. AB - Grapevine trunk diseases: Eutypa dieback, esca and Botryosphaeria dieback, which incidence has increased recently, are associated with several symptoms finally leading to the plant death. In the absence of efficient treatments, these diseases are a major problem for the viticulture; however, the factors involved in disease progression are not still fully identified. In order to get a better understanding of Botryosphaeria dieback development in grapevine, we have investigated different factors involved in Botryosphaeriaceae fungi aggressiveness. We first evaluated the activity of the wood-degrading enzymes of different isolates of Neofusicoccum parvum and Diplodia seriata, two major fungi associated with Botryosphaeria dieback. We further examinated the ability of these fungi to metabolize major grapevine phytoalexins: resveratrol and delta viniferin. Our results demonstrate that Botryosphaeriaceae were characterized by differential wood decay enzymatic activities and have the capacity to rapidly degrade stilbenes. N. parvum is able to degrade parietal polysaccharides, whereas D. seriata has a better capacity to degrade lignin. Growth of both fungi exhibited a low sensitivity to resveratrol, whereas delta-viniferin has a fungistatic effect, especially on N. parvum Bourgogne S-116. We further show that Botryosphaeriaceae are able to metabolize rapidly resveratrol and delta viniferin. The best stilbene metabolizing activity was measured for D. seriata. In conclusion, the different Botryosphaeriaceae isolates are characterized by a specific aggressiveness repertory. Wood and phenolic compound decay enzymatic activities could enable Botryosphaeriaceae to bypass chemical and physical barriers of the grapevine plant. The specific signature of Botryosphaeriaceae aggressiveness factors could explain the importance of fungi complexes in synergistic activity in order to fully colonize the host. PMID- 29261693 TI - Ex-vivo quantitative susceptibility mapping of human brain hemispheres. AB - Ex-vivo brain quantitative susceptibility mapping (QSM) allows investigation of brain characteristics at essentially the same point in time as histopathologic examination, and therefore has the potential to become an important tool for determining the role of QSM as a diagnostic and monitoring tool of age-related neuropathologies. In order to be able to translate the ex-vivo QSM findings to in vivo, it is crucial to understand the effects of death and chemical fixation on brain magnetic susceptibility measurements collected ex-vivo. Thus, the objective of this work was twofold: a) to assess the behavior of magnetic susceptibility in both gray and white matter of human brain hemispheres as a function of time postmortem, and b) to establish the relationship between in-vivo and ex-vivo gray matter susceptibility measurements on the same hemispheres. Five brain hemispheres from community-dwelling older adults were imaged ex-vivo with QSM on a weekly basis for six weeks postmortem, and the longitudinal behavior of ex-vivo magnetic susceptibility in both gray and white matter was assessed. The relationship between in-vivo and ex-vivo gray matter susceptibility measurements was investigated using QSM data from eleven older adults imaged both antemortem and postmortem. No systematic change in ex-vivo magnetic susceptibility of gray or white matter was observed over time postmortem. Additionally, it was demonstrated that, gray matter magnetic susceptibility measured ex-vivo may be well modeled as a linear function of susceptibility measured in-vivo. In conclusion, magnetic susceptibility in gray and white matter measured ex-vivo with QSM does not systematically change in the first six weeks after death. This information is important for future cross-sectional ex-vivo QSM studies of hemispheres imaged at different postmortem intervals. Furthermore, the linear relationship between in-vivo and ex-vivo gray matter magnetic susceptibility suggests that ex-vivo QSM captures information linked to antemortem gray matter magnetic susceptibility, which is important for translation of ex-vivo QSM findings to in-vivo. PMID- 29261694 TI - Widespread local chronic stressors in Caribbean coastal habitats. AB - Coastal ecosystems and the livelihoods they support are threatened by stressors acting at global and local scales. Here we used the data produced by the Caribbean Coastal Marine Productivity program (CARICOMP), the longest, largest monitoring program in the wider Caribbean, to evidence local-scale (decreases in water quality) and global-scale (increases in temperature) stressors across the basin. Trend analyses showed that visibility decreased at 42% of the stations, indicating that local-scale chronic stressors are widespread. On the other hand, only 18% of the stations showed increases in water temperature that would be expected from global warming, partially reflecting the limits in detecting trends due to inherent natural variability of temperature data. Decreases in visibility were associated with increased human density. However, this link can be decoupled by environmental factors, with conditions that increase the flush of water, dampening the effects of human influence. Besides documenting environmental stressors throughout the basin, our results can be used to inform future monitoring programs, if the desire is to identify stations that provide early warning signals of anthropogenic impacts. All CARICOMP environmental data are now available, providing an invaluable baseline that can be used to strengthen research, conservation, and management of coastal ecosystems in the Caribbean basin. PMID- 29261695 TI - Comparing the self-perceived quality of life of multimorbid patients and the general population using the EQ-5D-3L. AB - OBJECTIVES: To assess and compare the self-perceived Health Related Quality of Life (HRQoL) of multimorbid patients and the general population using health utilities (HU) and visual analogue scale (VAS) methods. METHODS: We analyzed data (n = 888) from a national, cross-sectional Swiss study of multimorbid patients recruited in primary care settings. Self-perceived HRQoL was assessed using the EQ-5D-3L instrument, composed of 1) a questionnaire on the five dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (EQ-5D dimensions), and 2) a 0-100 (0 = worst- and 100 = best-imaginable health status) VAS. We described the EQ-5D dimensions and VAS and computed HU using a standard pan-European value set. HU and VAS are the two components of the overall HRQoL assessment. We examined the proportions of multimorbid patients reporting problems (moderate/severe) in each EQ-5D dimension, corresponding proportions without problems, and mean HU and VAS values across patient characteristics. To test differences between subgroups, we used chi-square tests for dichotomous outcomes and T-tests (ANOVA if more than two groups) for continuous outcomes. Finally, we compared observed and predicted HU and VAS values. RESULTS: All 888 participants answered every EQ-5D item. Mean (SD) HU and VAS values were 0.70 (0.18) and 63.2 (19.2), respectively. HU and VAS were considerably and significantly lower in multimorbid patients than in the general population and were also lower in multimorbid patients below 60 years old and in women. Differences between observed and predicted means (SD) were -0.07 (0.18) for HU and -11.8 (20.3) for VAS. CONCLUSIONS: Self-perceived HRQoL is considerably and significantly affected by multimorbidity. More attention should be given to developing interventions that improve the HRQoL of multimorbid patients, particularly women and those aged below 60 years old. PMID- 29261696 TI - Estimating outflow facility through pressure dependent pathways of the human eye. AB - We develop and test a new theory for pressure dependent outflow from the eye. The theory comprises three main parameters: (i) a constant hydraulic conductivity, (ii) an exponential decay constant and (iii) a no-flow intraocular pressure, from which the total pressure dependent outflow, average outflow facilities and local outflow facilities for the whole eye may be evaluated. We use a new notation to specify precisely the meaning of model parameters and so model outputs. Drawing on a range of published data, we apply the theory to animal eyes, enucleated eyes and in vivo human eyes, and demonstrate how to evaluate model parameters. It is shown that the theory can fit high quality experimental data remarkably well. The new theory predicts that outflow facilities and total pressure dependent outflow for the whole eye are more than twice as large as estimates based on the Goldman equation and fluorometric analysis of anterior aqueous outflow. It appears likely that this discrepancy can be largely explained by pseudofacility and aqueous flow through the retinal pigmented epithelium, while any residual discrepancy may be due to pathological processes in aged eyes. The model predicts that if the hydraulic conductivity is too small, or the exponential decay constant is too large, then intraocular eye pressure may become unstable when subjected to normal circadian changes in aqueous production. The model also predicts relationships between variables that may be helpful when planning future experiments, and the model generates many novel testable hypotheses. With additional research, the analysis described here may find application in the differential diagnosis, prognosis and monitoring of glaucoma. PMID- 29261697 TI - Microbial cells can cooperate to resist high-level chronic ionizing radiation. AB - Understanding chronic ionizing radiation (CIR) effects is of utmost importance to protecting human health and the environment. Diverse bacteria and fungi inhabiting extremely radioactive waste and disaster sites (e.g. Hanford, Chernobyl, Fukushima) represent new targets of CIR research. We show that many microorganisms can grow under intense gamma-CIR dose rates of 13-126 Gy/h, with fungi identified as a particularly CIR-resistant group of eukaryotes: among 145 phylogenetically diverse strains tested, 78 grew under 36 Gy/h. Importantly, we demonstrate that CIR resistance can depend on cell concentration and that certain resistant microbial cells protect their neighbors (not only conspecifics, but even radiosensitive species from a different phylum), from high-level CIR. We apply a mechanistically-motivated mathematical model of CIR effects, based on accumulation/removal kinetics of reactive oxygen species (ROS) and antioxidants, in bacteria (3 Escherichia coli strains and Deinococcus radiodurans) and in fungi (Candida parapsilosis, Kazachstania exigua, Pichia kudriavzevii, Rhodotorula lysinophila, Saccharomyces cerevisiae, and Trichosporon mucoides). We also show that correlations between responses to CIR and acute ionizing radiation (AIR) among studied microorganisms are weak. For example, in D. radiodurans, the best molecular correlate for CIR resistance is the antioxidant enzyme catalase, which is dispensable for AIR resistance; and numerous CIR-resistant fungi are not AIR resistant. Our experimental findings and quantitative modeling thus demonstrate the importance of investigating CIR responses directly, rather than extrapolating from AIR. Protection of radiosensitive cell-types by radioresistant ones under high-level CIR is a potentially important new tool for bioremediation of radioactive sites and development of CIR-resistant microbiota as radioprotectors. PMID- 29261698 TI - Effects of transportation, relocation, and acclimation on phenotypes and functional characteristics of peripheral blood lymphocytes in rhesus monkeys (Macaca mulatta). AB - Nonhuman primates from domestic sources constitute a small, but critical, proportion of animals studied in research laboratories. Many of these nonhuman primates are raised at one facility and subsequently transported/relocated to another facility for research purposes. We examined the effects of transport, relocation, and acclimation on the phenotype and function of peripheral blood mononuclear cells (PBMCs) in a group of rhesus monkeys that were transported by road for approximately 21 hours from one facility to another. Using a panel of human antibodies and a set of standardized human immune assays, we evaluated the phenotype of lymphocyte subsets by flow, mitogen-specific immune responses of PBMCs in vitro, and levels of circulating cytokines and cortisol in plasma at various time points including immediately before transport, immediately upon arrival, and after approximately 30 days of acclimation. Analyses of blood samples revealed that CD3+ T-cell and CD20+ B-cell populations had decreased significantly immediately after relocation but had recovered within 30 days after arrival at the new facility. Similarly, circulating cortisol and cytokine levels in plasma were significantly higher immediately after relocation; and by the 30 day time point, these differences were no longer significant. However, immune assays of PBMCs indicated that mitogen-specific responses for proliferation, interferon gamma (IFN-gamma), and perforin were significantly higher after relocation and 30 days of acclimation. These findings have implications on the research participation of transported and relocated nonhuman primates in immunologic research studies, suggesting that 30 days is not sufficient to ensure return to baseline immune homeostasis. These data should be considered when planning research studies in order to minimize potential confounding factors associated with relocation and to maximize study validity. PMID- 29261699 TI - Sugary drinks taxation, projected consumption and fiscal revenues in Colombia: Evidence from a QUAIDS model. AB - The global shift towards diets high in sugar-sweetened beverages (SSBs) is linked to higher prevalence of obesity, diabetes and most other non-communicable diseases. In Colombia, one out of every two people was overweight or obese by 2010. This study estimates price-elasticities from a Quadratic Almost Ideal Demand System model, using the 2006-2007 Colombian Income and Expenditure survey. The food groups that were jointly considered were: unsweetened unflavored milks; coffee and tea; sugar sweetened beverages (SSBs); sweets and candies (including sugar); dairy products; meats and animal-based products; grains based staples; fruits and vegetables; and condiments and snacks. We take into account the high proportion of households not purchasing specific food and beverage groups (censored data) and endogeneity on both prices (as unit values) and total expenditure. Unhealthy beverages are price-elastic (-1.61 for SSBs) meaning that the change in consumption is proportionally larger with respect to a change in price. Also, there is a high complementarity among SSBs and major food groups (grains, meats and fruits and vegetables). In Colombia, the design of a meaningful tax to influence healthier diets is a next critical step. This study also shows that a tax of 20% on SSBs should prove to be effective, and can yield revenues of about 1% of the Colombian government's total annual fiscal revenue, which can potentially be directed towards public health promotion and investments. PMID- 29261700 TI - Effect of feeding rumen-protected methionine on productive and reproductive performance of dairy cows. AB - The objectives of this study were to evaluate the effects of daily top-dressing (individually feeding on the top of the total mixed ration) with rumen-protected methionine (RPM) from 30 +/- 3 until 126 +/- 3 Days in milk on productive and reproductive performance in lactating dairy cows. A total of 309 lactating dairy Holstein cows (138 primiparous and 171 multiparous) were randomly assigned to treatment diets containing either RPM (21.2 g of RPM + 38.8 g of dried distillers grain; 2.34% Methionine [Met] of metabolizable protein [MP]) or Control (CON; 60 g of dried distillers grain; 1.87% Met of MP). Plasma amino acids were evaluated at the time of artificial insemination (AI) and near pregnancy diagnosis. Milk production and milk composition were evaluated monthly. Pregnancy was diagnosed on Day 28 (by Pregnancy-specific protein B [PSPB]), 32, 47, and 61 (by ultrasound) and sizes of embryonic and amniotic vesicle were determined by ultrasound on Day 33 after AI. Feeding RPM increased plasma Met at 6, 9, 12, and 18 hours after top-dressing with a peak at 12 hours (52.4 vs 26.0 MUM; P < 0.001) and returned to basal by 24 hours. Cows fed RPM had a small increase in milk protein percentage (3.08 vs 3.00%; P = 0.04) with no differences on milk yield and milk protein yield. Additionally, in multiparous cows, RPM feeding increased milk protein (3.03 vs 2.95%; P = 0.05) and fat (3.45 vs 3.14%; P = 0.01) percentages, although no effects were observed in primiparous cows. In multiparous cows fed RPM, pregnancy loss was lower between Days 28 to 61 (19.6 [10/51] vs. 6.1% [3/49]; P = 0.03) or between Days 32 to 61 (8.9 [4/45] vs. 0 [0/0] %; P = 0.03), although, there was no effect of treatment on pregnancy loss in primiparous cows. Consistent with data on pregnancy loss, RPM feeding increased embryonic abdominal diameter (P = 0.01) and volume (P = 0.009) and amniotic vesicle volume (P = 0.04) on Day 33 of pregnancy in multiparous cows but had no effect on embryonic size in primiparous cows. Thus, the increase in plasma Met concentrations after feeding RPM was sufficient to produce a small increase in milk protein percentage and to improve embryonic size and pregnancy maintenance in multiparous cows. Further studies are needed to confirm these responses and understand the biological mechanisms that underlie these responses as well as the timing and concentrations of circulating Met that are needed to produce this effect. PMID- 29261701 TI - PEGylation of zinc nanoparticles amplifies their ability to enhance olfactory responses to odorant. AB - Olfactory responses are intensely enhanced with the addition of endogenous and engineered primarily-elemental small zinc nanoparticles (NPs). With aging, oxidation of these Zn nanoparticles eliminated the observed enhancement. The design of a polyethylene glycol coating to meet storage requirements of engineered zinc nanoparticles is evaluated to achieve maximal olfactory benefit. The zinc nanoparticles were covered with 1000 g/mol or 400 g/mol molecular weight polyethylene glycol (PEG). Non-PEGylated and PEGylated zinc nanoparticles were tested by electroolfactogram with isolated rat olfactory epithelium and odorant responses evoked by the mixture of eugenol, ethyl butyrate and (+/-) carvone after storage at 278 K (5 oC), 303 K (30 oC) and 323 K (50 oC). The particles were analyzed by atomic force microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and laser Doppler velocimetry. Our data indicate that stored ZnPEG400 nanoparticles maintain physiologically-consistent olfactory enhancement for over 300 days. These engineered Nanoparticles support future applications in olfactory research, sensitive detection, and medicine. PMID- 29261702 TI - Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells. AB - OBJECTIVES: Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB proficient TNBC models. In addition, recent studies reported that anti-androgen therapy shows preclinical efficacy in androgen-receptor (AR)-positive TNBC cells. Here we examined the effect of palbociclib in combination with an anti-androgen enzalutamide in TNBC cells. METHOD: MDA-MB-453, BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Protein expressions were assessed by Western blot analysis. Cytostatic effect was examined by MTT assay. Cell cycle and apoptosis were examined by flow cytometry. RESULTS: Palbociclib showed inhibitory effect in RB-proficient TNBC cells, and enzalutamide inhibited cell viability in AR-positive TNBC cells. Enzalutamide treatment could enhance the palbociclib-induced cytostatic effect in AR-positive/RB-proficient TNBC cells. In addition, palbociclib-mediated G1 arrest in AR-positive/RB-proficient TNBC cells was attenuated by RB knockdown. CONCLUSION: Our study provided a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists. PMID- 29261703 TI - Transhumeral loading during advanced upper extremity activities of daily living. AB - Percutaneous osseointegrated (OI) implants for direct skeletal attachment of upper extremity prosthetics represent an alternative to traditional socket suspension that may yield improved patient function and satisfaction. This is especially true in high-level, transhumeral amputees where prosthetic fitting is challenging and abandonment rates remain high. However, maintaining mechanical integrity of the bone-implant interface is crucial for safe clinical introduction of this technology. The collection of population data on the transhumeral loading environment will aid in the design of compliance and overload protection devices that mitigate the risk of periprosthetic fracture. We collected marker-based upper extremity kinematic data from non-amputee volunteers during advanced activities of daily living (AADLs) that applied dynamic loading to the humerus. Inverse dynamic analysis was applied to calculate the axial force, bending and torsional moments at three virtual amputation levels representing 25, 50, and 75% residual humeral length. The influences of amputation level, elbow flexion constraint, gender and anthropometric scaling were assessed. Results indicate that the proximal (25%) amputation level experienced significantly higher axial forces and bending moments across all subjects when compared to distal amputation levels (p<=0.030). Constraining elbow flexion had a limited influence on peak transhumeral loads. Male subjects experienced higher axial forces during all evaluated activities (p<=0.023). Peak axial force for all activities occurred during jumping jacks (174.5N). Peak bending (57.6Nm) and torsional (57.2Nm) moments occurred during jumping jacks and rapid internal humeral rotation, respectively. Calculated loads fall within the range of implant fixation failure loads reported in cadaveric investigations of humeral stem fixation; indicating that periprosthetic fracture may occur during non-contact AADLs. These kinematic data, collected over a range of AADLs, will aid in the development of overload protection devices and appropriate post-operative rehabilitation protocols that balance return to an active lifestyle with patient safety. PMID- 29261704 TI - A participatory approach to elucidate the consequences of land invasions on REDD+ initiatives: A case study with Indigenous communities in Panama. AB - Land tenure and tenure security are among the most important factors determining the viability and success of Reducing Emissions from Deforestation and Forest Degradation (REDD+) initiatives. The premise of the present paper is that territorial conflicts lead to forest loss and compromise the successful implementation of REDD+. Within this context, the main objectives of this paper are to (i) document, relying on participatory methods, the extent to which land conflicts drive deforestation and (ii) reflect on the legal context of REDD+ examining if, from an Indigenous perspective, it offers tools to resolve such conflicts. We used the Upper Bayano Watershed in eastern Panama as a case study of complex land tenure dynamics, and their effects on forest conservation in the context of REDD+. Combining a range of participatory methods including participatory mapping and forest carbon stock assessment, we estimated the consequences of land invasions on forest carbon stocks. Our analysis shows that invasions of Indigenous territories amounted to 27.6% of the total deforestation for the period of 2001-2014. The situation is of paramount concern in the Embera territory of Maje where 95.4% of total deforestation was caused by colonist invaders. Using and validating the maps made freely available by the Global Forest Change initiative of the University of Maryland, we then developed a reference level for the watershed and carried out a back of the envelop estimation of likely REDD+ revenue, showing its potential to bring much needed income to Indigenous communities striving to protect their forest estate. Our analysis of current legislation in Panama highlights confusion and important legal voids and emphasizes the strong links between land tenure, carbon ownership, and territorial invasions. The options and shortcoming of implementing REDD+ in Indigenous territories is discussed in the conclusion taking our legal review into account. PMID- 29261705 TI - Mixed methods inquiry into traditional healers' treatment of mental, neurological and substance abuse disorders in rural South Africa. AB - BACKGROUND: Traditional healers are acceptable and highly accessible health practitioners throughout sub-Saharan Africa. Patients in South Africa often seek concurrent traditional and allopathic treatment leading to medical pluralism. METHODS & FINDINGS: We studied the cause of five traditional illnesses known locally as "Mavabyi ya nhloko" (sickness of the head), by conducting 27 in-depth interviews and 133 surveys with a randomly selected sample of traditional healers living and working in rural, northeastern South Africa. These interviews were carried out to identify treatment practices of mental, neurological, and substance abuse (MNS) disorders. Participating healers were primarily female (77%), older in age (median: 58.0 years; interquartile range [IQR]: 50-67), had very little formal education (median: 3.7 years; IQR: 3.2-4.2), and had practiced traditional medicine for many years (median: 17 years; IQR: 9.5-30). Healers reported having the ability to successfully treat: seizure disorders (47%), patients who have lost touch with reality (47%), paralysis on one side of the body (59%), and substance abuse (21%). Female healers reported a lower odds of treating seizure disorders (Odds Ratio (OR):0.47), patients who had lost touch with reality (OR:0.26; p-value<0.05), paralysis of one side of the body (OR:0.36), and substance abuse (OR:0.36) versus males. Each additional year of education received was found to be associated with lower odds, ranging from 0.13 0.27, of treating these symptoms. Each additional patient seen by healers in the past week was associated with roughly 1.10 higher odds of treating seizure disorders, patients who have lost touch with reality, paralysis of one side of the body, and substance abuse. Healers charged a median of 500 South African Rand (~US$35) to treat substance abuse, 1000 Rand (~US$70) for seizure disorders or paralysis of one side of the body, and 1500 Rand (~US$105) for patients who have lost touch with reality. CONCLUSIONS: While not all healers elect to treat MNS disorders, many continue to do so, delaying allopathic health services to acutely ill patients. PMID- 29261706 TI - Place matters: A longitudinal analysis measuring the association between neighbourhood walkability and walking by age group and population center size in Canada. AB - This study examined the influence of walkability on walking behaviour and assessed whether associations varied according to life-stage and population center (PC) size. Walkability scores were obtained for the six-digit postal codes of residential neighbourhoods of 11,200 Canadians, who participated in biennial assessments of the National Population Health Survey from 1994 to 2010. Participants were stratified by age-group. Mixed-effects logistic regression models were used to estimate the influence of cumulative exposure to neighborhood walkability on utilitarian and exercise walking by PC size and life-stage. Associations of neighbourhood walkability with utilitarian and exercise walking varied according to age-group and PC size. Exposure to high walkable neighborhoods was associated with utilitarian walking in younger and older adults in all PC sizes, except for older adults living in a medium PC. Living in a highly walkable neighborhood in a large PC was associated with walking for exercise in younger (OR: 1.42; 95%CI: 1.20-1.67) and older adults (OR: 2.09; 95%CI: 1.51-2.89). Living in highly walkable neighbourhood in a medium PC was associated with walking for exercise in older adults (OR: 1.62; 95%CI: 1.15 2.29). These results emphasize the need to consider the size and nature of every community, and the age-group of a population when implementing strategies to promote walking. PMID- 29261707 TI - Field evaluation of HIV point-of-care testing for early infant diagnosis in Cape Town, South Africa. AB - BACKGROUND: Early infant HIV diagnosis (EID) coverage and uptake remains challenging. Point-of-care (POC) testing may improve access and turn-around times, but, while several POC technologies are in development there are few data on their implementation in the field. METHODS: We conducted an implementation study of the Alere q Detect POC system for EID at two public sector health facilities in Cape Town. HIV-exposed neonates undergoing routine EID testing at a large maternity hospital and a primary care clinic received both laboratory-based HIV PCR testing per local protocols and a POC test. We analysed the performance of POC versus laboratory testing, and conducted semi-structured interviews with providers to assess acceptability and implementation issues. RESULTS: Overall 478 specimens were taken: 311 tests were performed at the obstetric hospital (median child age, 1 days) and 167 six-week tests in primary care (median child age, 42 days). 9.0% of all tests resulted in an error with no differences by site; most errors resolved with retesting. POC was more sensitive (100%; lower 95% CI, 39.8%) and specific (100%, lower 95% CI, 98%) among older children tested in primary care compared with birth testing in hospital (90.0%, 95% CI, 55.5-99.8% and 100.0%, lower 95% CI, 98.4%, respectively). Negative predictive value was high (>99%) at both sites. In interviews, providers felt the device was simple to use and facilitated decision-making in the management of infants. However, many wanted clarity on the cause of errors on the POC device to help guide repeat testing. CONCLUSIONS: POC EID testing performs well in field implementation in health care facilities and appears highly acceptable to health care providers. PMID- 29261708 TI - Delayed processing of global shape information in developmental prosopagnosia. AB - There is accumulating evidence suggesting that a central deficit in developmental prosopagnosia (DP), a disorder characterized by profound and lifelong difficulties with face recognition, concerns impaired holistic processing. Some of this evidence comes from studies using Navon's paradigm where individuals with DP show a greater local or reduced global bias compared with controls. However, it has not been established what gives rise to this altered processing bias. Is it a reduced global precedence effect, changes in susceptibility to interference effects or both? By analyzing the performance of 10 individuals with DP in Navon's paradigm we find evidence of a reduced global precedence effect: The DPs are slower than controls to process global but not local shape information. Importantly, and in contrast to previous studies, we demonstrate that the DPs perform normally in a comprehensive test of visual attention, showing normal: visual short-term memory capacity, speed of visual processing, efficiency of top down selectivity, and allocation of attentional resources. Hence, we conclude that the reduced global precedence effect reflects a perceptual rather than an attentional deficit. We further show that this reduced global precedence effect correlates both with the DPs' face recognition abilities, as well as their ability to recognize degraded (non-face) objects. We suggest that the DPs' impaired performance in all three domains (Navon, face and object recognition) may be related to the same dysfunction; delayed derivation of global relative to local shape information. PMID- 29261709 TI - Feasibility of large-scale deployment of multiple wearable sensors in Parkinson's disease. AB - Wearable devices can capture objective day-to-day data about Parkinson's Disease (PD). This study aims to assess the feasibility of implementing wearable technology to collect data from multiple sensors during the daily lives of PD patients. The Parkinson@home study is an observational, two-cohort (North America, NAM; The Netherlands, NL) study. To recruit participants, different strategies were used between sites. Main enrolment criteria were self-reported diagnosis of PD, possession of a smartphone and age>=18 years. Participants used the Fox Wearable Companion app on a smartwatch and smartphone for a minimum of 6 weeks (NAM) or 13 weeks (NL). Sensor-derived measures estimated information about movement. Additionally, medication intake and symptoms were collected via self reports in the app. A total of 953 participants were included (NL: 304, NAM: 649). Enrolment rate was 88% in the NL (n = 304) and 51% (n = 649) in NAM. Overall, 84% (n = 805) of participants contributed sensor data. Participants were compliant for 68% (16.3 hours/participant/day) of the study period in NL and for 62% (14.8 hours/participant/day) in NAM. Daily accelerometer data collection decreased 23% in the NL after 13 weeks, and 27% in NAM after 6 weeks. Data contribution was not affected by demographics, clinical characteristics or attitude towards technology, but was by the platform usability score in the NL (chi2 (2) = 32.014, p<0.001), and self-reported depression in NAM (chi2(2) = 6.397, p = .04). The Parkinson@home study shows that it is feasible to collect objective data using multiple wearable sensors in PD during daily life in a large cohort. PMID- 29261710 TI - Vector similarity measures of hesitant fuzzy linguistic term sets and their applications. AB - In decision making, similarity measure and distance between two objects are crucial to be able to determine the relationship between those objects. Many researchers have received much attention for their research on this subject. In this study, we propose two novel similarity measures between hesitant fuzzy linguistic term sets (HFLTSs). In addition, two extensions of Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) are proposed in the hesitant fuzzy linguistic environments. Furthermore, an example of an application concerning traditional Chinese medical diagnosis and an MCDM problem have been given to illustrate the applicability and validation of these similarity measures of HFLTSs. Furthermore, the results of examples demonstrate that the Dice and Jaccard similarity measures are more reasonable than the cosine similarity measure with respect to HFLTSs. PMID- 29261711 TI - Efficient visible light photocatalysis of benzene, toluene, ethylbenzene and xylene (BTEX) in aqueous solutions using supported zinc oxide nanorods. AB - Benzene, toluene, ethylbenzene and xylenes (BTEX) are some of the common environmental pollutants originating mainly from oil and gas industries, which are toxic to human as well as other living organisms in the ecosystem. Here we investigate photocatalytic degradation of BTEX under visible light irradiation using supported zinc oxide (ZnO) nanorods grown on glass substrates using a microwave assisted hydrothermal method. ZnO nanorods were characterized by electron microscopy, X-ray diffraction (XRD), specific surface area, UV/visible absorption and photoluminescence spectroscopy. Visible light photocatalytic degradation products of BTEX are studied for individual components using gas chromatograph/mass spectrometer (GC/MS). ZnO nanorods with significant amount of electronic defect states, due to the fast crystallization of the nanorods under microwave irradiation, exhibited efficient degradation of BTEX under visible light, degrading more than 80% of the individual BTEX components in 180 minutes. Effect of initial concentration of BTEX as individual components is also probed and the photocatalytic activity of the ZnO nanorods in different conditions is explored. Formation of intermediate byproducts such as phenol, benzyl alcohol, benzaldehyde and benzoic acid were confirmed by our HPLC analysis which could be due to the photocatalytic degradation of BTEX. Carbon dioxide was evaluated and showed an increasing pattern over time indicating the mineralization process confirming the conversion of toxic organic compounds into benign products. PMID- 29261712 TI - Mouse decellularised liver scaffold improves human embryonic and induced pluripotent stem cells differentiation into hepatocyte-like cells. AB - Liver transplantation is the definitive treatment of liver failure but donor organ shortage limits its availability. Stem cells are highly expandable and have the potential to differentiate into any specialist cell. Use of patient-derived induced Pluripotent Stem Cells (hiPSCs) has the additional advantage for organ regeneration therapies by removing the need for immunosuppression. We compared hepatocyte differentiation of human embryonic stem cells (hESCs) and hiPSCs in a mouse decellularised liver scaffold (3D) with standard in vitro protocol (2D). Mouse livers were decellularised preserving micro-architecture, blood vessel network and extracellular matrix. hESCs and hiPSCs were primed towards the definitive endoderm. Cells were then seeded either in 3D or 2D cultures and the hepatocyte differentiation was continued. Both hESCs and hiPSCs differentiated more efficiently in 3D than in 2D, with higher and earlier expression of mature hepatocyte marker albumin, lipid and glycogen synthesis associated with a decrease in expression of fetal hepatocyte marker alpha-fetoprotein. Thus we conclude that stem cell hepatocyte differentiation in 3D culture promotes faster cell maturation. This finding suggests that optimised 3D protocols could allow generation of mature liver cells not achieved so far in standard 2D conditions and lead to improvement in cell models of liver disease and regenerative medicine applications. PMID- 29261713 TI - Targeted next-generation sequencing provides novel clues for associated epilepsy and cardiac conduction disorder/SUDEP. AB - Sudden unexpected death in epilepsy is an unpredicted condition in patients with a diagnosis of epilepsy, and autopsy does not conclusively identify cause of death. Although the pathophysiological mechanisms that underlie this entity remain unknown, the fact that epilepsy can affect cardiac function is not surprising. The genetic factors involving ion channels co-expressed in the heart and brain and other candidate genes have been previously described. In the present study, 20 epilepsy patients with personal or family history of heart rhythm disturbance/cardiac arrhythmias/sudden death were sequenced using a custom re-sequencing panel. Twenty-six relatives were genetically analysed to ascertain the family segregation in ten individuals. Four subjects revealed variants with positive genotype-phenotype segregation: four missense variants in the CDKL5, CNTNAP2, GRIN2A and ADGRV1 genes and one copy number variant in KCNQ1. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts, and the evaluation of the potential pathogenic role in the cardio-cerebral mechanisms requires in vivo/in vitro studies. In addition to family segregation, evaluation of the potential pathogenic roles of these variants in cardio-cerebral mechanisms by in vivo/in vitro studies should also be performed. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts. PMID- 29261714 TI - High association of Cryptosporidium spp. infection with colon adenocarcinoma in Lebanese patients. AB - BACKGROUND: The association between Cryptosporidium and human colon cancer has been reported in different populations. However, this association has not been well studied. In order to add new strong arguments for a probable link between cryptosporidiosis and colon human cancer, the aim of this study was to determine prevalence and to identify species of Cryptosporidium among Lebanese patients. METHODOLOGY AND PRINCIPAL FINDINGS: Overall, 218 digestive biopsies were collected in Tripoli, Lebanon, from three groups of patients: (i) patients with recently diagnosed colon intraepithelial neoplasia/adenocarcinoma before any treatment (n = 72); (ii) patients with recently diagnosed stomach intraepithelial neoplasia/adenocarcinoma before any treatment (n = 21); and (iii) patients without digestive intraepithelial neoplasia/adenocarcinoma but with persistent digestive symptoms (n = 125). DNA extraction was performed from paraffin-embedded tissue. The presence of the parasite in tissues was confirmed by PCR, microscopic observation and immunofluorescence analysis. We identified a high rate (21%) of Cryptosporidium presence in biopsies from Lebanese patients with recently diagnosed colonic neoplasia/adenocarcinoma before any treatment. This prevalence was significantly higher compared to 7% of Cryptosporidium prevalence among patients without colon neoplasia but with persistent gastrointestinal symptoms (OR: 4, CI: 1.65-9.6, P = 0.001). When the comparison was done against normal biopsies, the risk of infection increased 11-fold in the group of patients with colon adenocarcinoma (OR: 11.315, CI: 1.44-89.02, P = 0.003). CONCLUSIONS: This is the first study performed in Lebanon reporting the prevalence of Cryptosporidium among patients with digestive cancer. These results show that Cryptosporidium is strongly associated with human colon cancer being maybe a potential etiological agent of this disease. PMID- 29261715 TI - Gender-specific differences in the incidence of microalbuminuria in metabolic syndrome patients after treatment with fimasartan: The K-MetS study. AB - BACKGROUND: The effect of resolving metabolic syndrome on target organ damage in hypertensive patients is not well described. We evaluated whether treating metabolic syndrome (MetS) with an angiotensin receptor blocker subsequently reduced microalbuminuria in the K-MetS cohort. METHODS: Among 10,601 total metabolic syndrome patients, 3,250 (52.2% male, 56.2+/-10.0 years) with sufficient data on five specific metabolic components were included in this study. Patients were divided into four groups based on MetS status at baseline and 3 months. All patients received an angiotensin receptor blocker, fimasartan, for these 3 months; thereafter, treatment was modified at the discretion of each patient's physician. Microalbuminuria and the albumin/creatine ratio were evaluated as a proxy of organ damage. RESULTS: Blood pressure and waist circumference decreased from baseline to 3 months and 1 year. The average albumin/creatinine ratio significantly improved during the first three months of the study from 36.0+/-147.4 to 21.0+/-74.9 mg/g (p<0.05) and was persistently high in patients with MetS at baseline and 3 months versus other groups. Women in comparison with men showed significantly lower ACR among patients with newly developed MetS at 3-month. CONCLUSIONS: Treatment of hypertensive patients for one year with the angiotensin receptor blocker fimasartan significantly reduced the albumin/creatine ratio, irrespective of whether the patient had MetS; however, the albumin/creatinine ratio was significantly higher in patents with persistent or newly developed MetS compared to patients without MetS. Additionally, these findings were more prominent in women than in men. PMID- 29261716 TI - Temporal trends of antithrombotic therapy for stroke prevention in Korean patients with non-valvular atrial fibrillation in the era of non-vitamin K antagonist oral anticoagulants: A nationwide population-based study. AB - BACKGROUND: Following their introduction, the non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly prescribed in Asia for stroke prevention in patients with non-valvular atrial fibrillation (AF). Few contemporary data are available on temporal trends in antithrombotic therapy use in Asian countries, in the era of NOACs. METHODS AND RESULTS: Using the National Health Insurance Service database of the entire Korean adult AF population, the use of aspirin, vitamin K antagonist, and NOACs between 2008 and 2015 were analyzed (n = 276,246 in 2015). Most of the included cohort had CHA2DS2-VASc score >= 2 (78.2% in 2008 and 83.2% in 2015), yet approximately 17% were prescribed no antithrombotic therapy throughout the study period. Aspirin prescription consistently decreased (from 48.2% to 31.5%) over time, while OAC prescription significantly increased from 34.7% to 50.6%. NOAC prescriptions accounted for 50% of total OAC prescription in 2015. Similar trends in antithrombotic therapy were found both in men and in women, but women were more likely to be undertreated with OAC. Female gender, presence of vascular disease and prior intracranial hemorrhage were associated with OAC underuse. CONCLUSIONS: Between 2008 and 2015, a greater proportion of AF patients received OAC treatment with increasing NOAC prescription trends in the recent 3 years. A substantial proportion (approx. 50%) of Korean patients with AF still remain undertreated. PMID- 29261718 TI - Mapping QTLs for grain yield components in wheat under heat stress. AB - The current perspective of increasing global temperature makes heat stress as a major threat to wheat production worldwide. In order to identify quantitative trait loci (QTLs) associated with heat tolerance, 251 recombinant inbred lines (RILs) derived from a cross between HD2808 (heat tolerant) and HUW510 (heat susceptible) were evaluated under timely sown (normal) and late sown (heat stress) conditions for two consecutive crop seasons; 2013-14 and 2014-15. Grain yield (GY) and its components namely, grain weight/spike (GWS), grain number/spike (GNS), thousand grain weight (TGW), grain filling rate (GFR) and grain filling duration (GFD) were recorded for both conditions and years. The data collected for both timely and late sown conditions and heat susceptibility index (HSI) of these traits were used as phenotypic data for QTL identification. The frequency distribution of HSI for all the studied traits was continuous during both the years and also included transgressive segregants. Composite interval mapping identified total 24 QTLs viz., 9 (timely sown traits), 6 (late sown traits) and 9 (HSI of traits) mapped on linkage groups 2A, 2B, and 6D during both the crop seasons 2013-14 and 2014-15. The QTLs were detected for GWS (6), GNS (6), GFR (4), TGW (3), GY (3) and GFD (2). The LOD score of identified QTLs varied from 3.03 (Qtgns.iiwbr-6D) to 21.01 (Qhsitgw.iiwbr-2A) during 2014-15, explaining 11.2 and 30.6% phenotypic variance, respectively. Maximum no of QTLs were detected in chromosome 2A followed by 6D and 2B. All the QTL detected under late sown and HSI traits were identified on chromosome 2A except for QTLs associated with GFD. Fifteen out of 17 QTL detected on chromosome 2A were clustered within the marker interval between gwm448 and wmc296 and showed tight linkage with gwm122 and these were localized in 49-52 cM region of Somers consensus map of chromosome 2A i.e. within 18-59.56 cM region of chromosome 2A where no QTL related to heat stress were reported earlier. Besides, three consistent QTLs, Qgws.iiwbr-2A, Qgns.iiwbr-2A and Qgns.iiwbr-2A were also detected in all the environments in this region. The nearest QTL detected in earlier studies, QFv/Fm.cgb-2A was approximately 6cM below the presently identified QTLs region, respectively Additionally, QTLs for physiological and phenological traits and plant height under late sown and HSI of these traits were also detected on chromosome 2A. QTL for HSI of plant height and physiological maturity were located in the same genomic region of chromosome 2Awhereas QTLs for physiological and phonological traits under late sown were located 8cM and 33.5 cM below the genomic location associated with grain traits, respectively in consensus map of Somers. This QTL hot-spot region with consistent QTLs could be used to improve heat tolerance after validation. PMID- 29261717 TI - Probing the putative alpha7 nAChR/NMDAR complex in human and murine cortex and hippocampus: Different degrees of complex formation in healthy and Alzheimer brain tissue. AB - alpha7 nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartate receptors (NMDARs) are key mediators of central cholinergic and glutamatergic neurotransmission, respectively. In addition to numerous well-established functional interactions between alpha7 nAChRs and NMDARs, the two receptors have been proposed to form a multimeric complex, and in the present study we have investigated this putative alpha7 nAChR/NMDAR assembly in human and murine brain tissues. By alpha-bungarotoxin (BGT) affinity purification, alpha7 and NMDAR subunits were co-purified from human and murine cortical and hippocampal homogenates, substantiating the notion that the receptors are parts of a multimeric complex in the human and rodent brain. Interestingly, the ratios between GluN1 and alpha7 levels in BGT pull-downs from cortical homogenates from Alzheimer's disease (AD) brains were significantly lower than those in pull-downs from non-AD controls, indicating a reduced degree of alpha7 nAChR/NMDAR complex formation in the diseased tissue. A similar difference in GluN1/alpha7 ratios was observed between pull-downs from cortical homogenates from adult 3xTg-AD and age matched wild type (WT) mice, whereas the GluN1/alpha7 ratios determined in pull downs from young 3xTg-AD and age-matched WT mice did not differ significantly. The observation that pretreatment with oligomeric amyloid-beta1-42 reduced GluN1/alpha7 ratios in BGT pull-downs from human cortical homogenate in a concentration-dependent manner provided a plausible molecular mechanism for this observed reduction. In conclusion, while it will be important to further challenge the existence of the putative alpha7 nAChR/NMDAR complex in future studies applying other methodologies than biochemical assays and to investigate the functional implications of this complex for cholinergic and glutamatergic neurotransmission, this work supports the formation of the complex and presents new insights into its regulation in healthy and diseased brain tissue. PMID- 29261719 TI - Improving vehicle tracking rate and speed estimation in dusty and snowy weather conditions with a vibrating camera. AB - Traffic surveillance systems are interesting to many researchers to improve the traffic control and reduce the risk caused by accidents. In this area, many published works are only concerned about vehicle detection in normal conditions. The camera may vibrate due to wind or bridge movement. Detection and tracking of vehicles is a very difficult task when we have bad weather conditions in winter (snowy, rainy, windy, etc.), dusty weather in arid and semi-arid regions, at night, etc. Also, it is very important to consider speed of vehicles in the complicated weather condition. In this paper, we improved our method to track and count vehicles in dusty weather with vibrating camera. For this purpose, we used a background subtraction based strategy mixed with an extra processing to segment vehicles. In this paper, the extra processing included the analysis of the headlight size, location, and area. In our work, tracking was done between consecutive frames via a generalized particle filter to detect the vehicle and pair the headlights using the connected component analysis. So, vehicle counting was performed based on the pairing result, with Centroid of each blob we calculated distance between two frames by simple formula and hence dividing it by the time between two frames obtained from the video. Our proposed method was tested on several video surveillance records in different conditions such as dusty or foggy weather, vibrating camera, and in roads with medium-level traffic volumes. The results showed that the new proposed method performed better than our previously published method and other methods, including the Kalman filter or Gaussian model, in different traffic conditions. PMID- 29261720 TI - A mutant of phosphomannomutase1 retains full enzymatic activity, but is not activated by IMP: Possible implications for the disease PMM2-CDG. AB - The most frequent disorder of glycosylation, PMM2-CDG, is caused by a deficiency of phosphomannomutase activity. In humans two paralogous enzymes exist, both of them require mannose 1,6-bis-phosphate or glucose 1,6-bis-phosphate as activators, but only phospho-mannomutase1 hydrolyzes bis-phosphate hexoses. Mutations in the gene encoding phosphomannomutase2 are responsible for PMM2-CDG. Although not directly causative of the disease, the role of the paralogous enzyme in the disease should be clarified. Phosphomannomutase1 could have a beneficial effect, contributing to mannose 6-phosphate isomerization, or a detrimental effect, hydrolyzing the bis-phosphate hexose activator. A pivotal role in regulating mannose-1phosphate production and ultimately protein glycosylation might be played by inosine monophosphate that enhances the phosphatase activity of phosphomannomutase1. In this paper we analyzed human phosphomannomutases by conventional enzymatic assays as well as by novel techniques such as 31P-NMR and thermal shift assay. We characterized a triple mutant of phospomannomutase1 that retains mutase and phosphatase activity, but is unable to bind inosine monophosphate. PMID- 29261721 TI - The multistep road to ventilator-associated lung abscess: A retrospective study of S.aureus ventilator-associated pneumonia. AB - OBJECT: We observed some cases of lung abscess (LA) in ICU patients suffering S.aureus ventilator-associated pneumonia (S.aureus-VAP). We aimed to assess which of the host and/or bacteria-related features are associated with LA. METHODS: We conducted a retrospective study from January 2009 to July 2013 in a trauma surgical ICU within a teaching hospital. All adult patients presenting with S.aureus-VAP were included. We compared two groups of patients according to the formation or not of LA concomitantly to S.aureus-VAP. RESULTS: Seventy-nine S.aureus-VAP patients, predominantly males (85%) of rather young age (mean [SD]: 35yr [21-64]) with severe trauma (initial Simplified Acute Score II = 42 [32-52]) related-ICU admission, were included. Among them, 10 (14%) developed LA. Patient's characteristics significantly associated with LA development were: a younger age (p = 0.003), road traffic accidents admission (p = 0.017), head injury (p = 0.002), lower Glasgow Coma Scale (p = 0.009), blunt chest trauma (p = 0.01) pneumothorax (p = 0.01) and lung contusions (p = 0.002). No microbiological factors were significantly associated with LA formation. Abscesses were mostly bilateral, >=5 cm of diameter and with a posterior location. CONCLUSIONS: Our results do not favor a specific virulence of S.aureus, but rather highlight the role of multiple insults to the lung, promoting LA formation. Despite a similar severity score, patients with LA had more serious trauma, combining severe both chest and head insults. PMID- 29261722 TI - Multifactorial genetic divergence processes drive the onset of speciation in an Amazonian fish. AB - Understanding the processes that drive population genetic divergence in the Amazon is challenging because of the vast scale, the environmental richness and the outstanding biodiversity of the region. We addressed this issue by determining the genetic structure of the widespread Amazonian common sardine fish Triportheus albus (Characidae). We then examined the influence, on this species, of all previously proposed population-structuring factors, including isolation-by distance, isolation-by-barrier (the Teotonio Falls) and isolation-by-environment using variables that describe floodplain and water characteristics. The population genetics analyses revealed an unusually strong structure with three geographical groups: Negro/Tapajos rivers, Lower Madeira/Central Amazon, and Upper Madeira. Distance-based redundancy analyses showed that the optimal model for explaining the extreme genetic structure contains all proposed structuring factors and accounts for up to 70% of the genetic structure. We further quantified the contribution of each factor via a variance-partitioning analysis. Our results demonstrate that multiple factors, often proposed as individual drivers of population divergence, have acted in conjunction to divide T. albus into three genetic lineages. Because the conjunction of multiple long-standing population-structuring processes may lead to population reproductive isolation, that is, the onset of speciation, we suggest that the multifactorial population structuring processes highlighted in this study could account for the high speciation rate characterising the Amazon Basin. PMID- 29261723 TI - Shifting the boundaries for early caffeine initiation in neonatal practice: Results of a prospective, multicenter study on very preterm infants with respiratory distress syndrome. AB - BACKGROUND: There is growing evidence that supports the benefits of early use of caffeine in preterm neonates with RDS; however, no formal recommendations specifying the exact timing of therapy initiation have been provided. OBJECTIVES: We compared neonatal outcomes in infants receiving early (initial dose on the 1st day of life) and late (initial dose on day 2+ of life) caffeine therapy. METHODS: Using data from a prospective, cohort study, we identified 986 infants <=32 weeks' gestation with RDS and assessed the timing of caffeine therapy initiation, need for ventilatory support, mortality and incidence of typical complications of prematurity. To adjust for baseline severity, the early and late caffeine groups were propensity score (PS) matched to 286 infants (1:1). Clinical outcomes were compared between the PS-matched groups. RESULTS: Early treatment with caffeine citrate was associated with a significantly reduced need for invasive ventilation (71.3% vs 83.2%; P = 0.0165) and total duration of mechanical ventilation (mean 5 +/- 11.1 days vs 10.8 +/- 14.6 days; P = 0.0000) and significantly lower odds of intraventricular hemorrhage (IVH) (OR 0.4827; 95% CI 0.2999-0.7787) and patent ductus arteriosus (PDA) (OR 0.5686; 95% CI 0.3395-0.9523). The incidence of bronchopulmonary dysplasia (BPD) (36.4% vs 45.8%) and rates of moderate and severe BPD were not significantly different between the two groups. The mortality rates were comparable between the two groups (8.6% vs 8.5%, P = ns). CONCLUSION: Early caffeine initiation was associated with a decreased need for invasive ventilatory support and lower incidence of IVH and PDA. PMID- 29261724 TI - Incidence of inflammatory breast cancer in patients with clinical inflammatory breast symptoms. AB - BACKGROUND: To describe a large cohort of women with non-puerperal inflammatory breast and to identify characteristics of inflammatory breast cancer. METHODS: All patients consulting for inflammatory breast syndrome in the breast unit of our tertiary University hospital between September 2013 and December 2015 were prospectively included. We excluded women who were pregnant or in the postpartum period. Patients underwent systematic clinical examination and imaging (breast ultrasonography and mammography). A biopsy was performed if the clinician suspected a malignant lesion of the breast. Clinicopathologic and radiologic data were registered. Statistics were performed using R (3.0.2 version) software. RESULTS: Among the 76 patients screened and included, 38 (50%) had a malignant lesion at final diagnosis, 21 (27.6%) were diagnosed with infectious disease and 17 (22.4%) with inflammatory disease of the breast. When compared to patients with benign disease, patients with a malignant lesion were significantly older (p = 0.022, CI95% 1.78-14.7), had a significantly bigger palpable mass (p<0.001, CI 95% 22.8-58.9), were more likely to have skin thickening (p = 0.05) and had more suspicious lymph nodes at clinical examination (p<0.001, CI 95% 2.72-65.3). Precise limits on ultrasonography were significantly associated with benign lesions. The presence of a mass (p = 0.04), micro calcifications (p = 0.04) or of focal asymmetry (p<0.001, CI95% 1.3-618) on mammography was significantly associated with malignant disease. CONCLUSION: Inflammatory breast cancer was common in our cohort of women consulting for inflammatory breast syndrome. Identifying these patients with high-risk malignancy is crucial in the management of an inflammatory breast. PMID- 29261725 TI - BatchMap: A parallel implementation of the OneMap R package for fast computation of F1 linkage maps in outcrossing species. AB - With the rapid advancement of high throughput sequencing, large numbers of genetic markers can be readily and cheaply acquired, but most current software packages for genetic map construction cannot handle such dense input. Modern computer architectures and server farms represent untapped resources that can be used to enable higher marker densities to be processed in tractable time. Here we present a pipeline using a modified version of OneMap that parallelizes over bottleneck functions and achieves substantial speedups for producing a high density linkage map (N = 20,000). Using simulated data we show that the outcome is as accurate as the traditional pipeline. We further demonstrate that there is a direct relationship between the number of markers used and the level of deviation between true and estimated order, which in turn impacts the final size of a genetic map. PMID- 29261726 TI - Statin use is associated with improved survival in ovarian cancer: A retrospective population-based study. AB - BACKGROUND: Preclinical in vitro and in vivo studies suggest that statins could exhibit anticancer properties in ovarian cancer. Similar effects have also been reported in observational studies but their results remain inconsistent and could be impaired by methodological limitations. This study aimed to investigate whether statin use is associated with improved survival in ovarian cancer patients at the Belgian population-level. METHODS: All patients with invasive epithelial ovarian cancer diagnosed between 2004 and 2012 were identified from the Belgian Cancer Registry. Vital statuses were obtained from the Crossroads Bank for Social Security and ovarian cancer-specific deaths were identified from death certificates provided by regional administrations. Information on cancer treatments and statin use were retrieved from health insurance databases. Statin use was modelled as a time-varying covariate in Cox regression models to calculate adjusted hazards ratios (HR) and 95% confidence intervals (95%CI) for the association between postdiagnostic exposure to statins and overall- or ovarian cancer-specific mortality within three years after diagnosis. Adjustments were made for age at diagnosis, year of diagnosis, comorbidities, cancer stage, and cancer treatments. RESULTS: A total of 5,416 patients with epithelial ovarian cancer met the inclusion criteria. Of these 1,255 (23%) had at least one statin prescription within three years after diagnosis. Postdiagnostic use of statins was associated with a reduced risk of overall mortality (adjusted HR = 0.81, 95%CI:0.72-0.90, p<0.001). In analyses by statin type, this association was only significant for simvastatin (adjusted HR = 0.86, 95%CI:0.74-0.99, p = 0.05) or rosuvastatin (adjusted HR = 0.71, 95%CI:0.55-0.92, p = 0.01). In subgroup analyses by statin prediagnostic use, the protective association for postdiagnostic statin use was only observed in patients who were also using statins before diagnosis (adjusted HR = 0.73, 95%CI:0.64-0.83, p<0.001). Similar results were observed for ovarian cancer-specific mortality. CONCLUSION: In this large nation-wide cohort of ovarian cancer patients postdiagnostic use of statins was associated with improved survival. PMID- 29261727 TI - PARS risk charts: A 10-year study of risk assessment for cardiovascular diseases in Eastern Mediterranean Region. AB - This study was designed to develop a risk assessment chart for the clinical management and prevention of the risk of cardiovascular disease (CVD) in Iranian population, which is vital for developing national prevention programs. The Isfahan Cohort Study (ICS) is a population-based prospective study of 6504 Iranian adults >=35 years old, followed-up for ten years, from 2001 to 2010. Behavioral and cardiometabolic risk factors were examined every five years, while biennial follow-ups for the occurrence of the events was performed by phone calls or by verbal autopsy. Among these participants, 5432 (2784 women, 51.3%) were CVD free at baseline examination and had at least one follow-up. Cox proportional hazard regression was used to predict the risk of ischemic CVD events, including sudden cardiac death due to unstable angina, myocardial infarction, and stroke. The model fit statistics such as area under the receiver-operating characteristic (AUROC), calibration chi-square and the overall bias were used to assess the model performance. We also tested the Framingham model for comparison. Seven hundred and five CVD events occurred during 49452.8 person-years of follow-up. The event probabilities were calculated and presented color-coded on each gender specific PARS chart. The AUROC and Harrell's C indices were 0.74 (95% CI, 0.72 0.76) and 0.73, respectively. In the calibration, the Nam-D'Agostino chi2 was 10.82 (p = 0.29). The overall bias of the proposed model was 95.60%. PARS model was also internally validated using cross-validation. The Android app and the Web based risk assessment tool were also developed as to have an impact on public health. In comparison, the refitted and recalibrated Framingham models, estimated the CVD incidence with the overall bias of 149.60% and 128.23% for men, and 222.70% and 176.07% for women, respectively. In conclusion, the PARS risk assessment chart is a simple, accurate, and well-calibrated tool for predicting a 10-year risk of CVD occurrence in Iranian population and can be used in an attempt to develop national guidelines for the CVD management. PMID- 29261728 TI - Using thermal scanning assays to test protein-protein interactions of inner-ear cadherins. AB - Protein-protein interactions play a crucial role in biological processes such as cell-cell adhesion, immune system-pathogen interactions, and sensory perception. Understanding the structural determinants of protein-protein complex formation and obtaining quantitative estimates of their dissociation constant (KD) are essential for the study of these interactions and for the discovery of new therapeutics. At the same time, it is equally important to characterize protein protein interactions in a high-throughput fashion. Here, we use a modified thermal scanning assay to test interactions of wild type (WT) and mutant variants of N-terminal fragments (EC1+2) of cadherin-23 and protocadherin-15, two proteins essential for inner-ear mechanotransduction. An environmentally sensitive fluorescent dye (SYPRO orange) is used to monitor melting temperature (Tm) shifts of protocadherin-15 EC1+2 (pcdh15) in the presence of increasing concentrations of cadherin-23 EC1+2 (cdh23). These Tm shifts are absent when we use proteins containing deafness-related missense mutations known to disrupt cdh23 binding to pcdh15, and are increased for some rationally designed mutants expected to enhance binding. In addition, surface plasmon resonance binding experiments were used to test if the Tm shifts correlated with changes in binding affinity. We used this approach to find a double mutation (cdh23(T15E)- pcdh15(G16D)) that enhances binding affinity of the cadherin complex by 1.98 kJ/mol, roughly two fold that of the WT complex. We suggest that the thermal scanning methodology can be used in high-throughput format to quickly compare binding affinities (KD from nM up to 100 MUM) for some heterodimeric protein complexes and to screen small molecule libraries to find protein-protein interaction inhibitors and enhancers. PMID- 29261729 TI - Nucleases as a barrier to gene silencing in the cotton boll weevil, Anthonomus grandis. AB - RNA interference (RNAi) approaches have been applied as a biotechnological tool for controlling plant insect pests via selective gene down regulation. However, the inefficiency of RNAi mechanism in insects is associated with several barriers, including dsRNA delivery and uptake by the cell, dsRNA interaction with the cellular membrane receptor and dsRNA exposure to insect gut nucleases during feeding. The cotton boll weevil (Anthonomus grandis) is a coleopteran in which RNAi-mediated gene silencing does not function efficiently through dsRNA feeding, and the factors involved in the mechanism remain unknown. Herein, we identified three nucleases in the cotton boll weevil transcriptome denoted AgraNuc1, AgraNuc2, and AgraNuc3, and the influences of these nucleases on the gene silencing of A. grandis chitin synthase II (AgraChSII) were evaluated through oral dsRNA feeding trials. A phylogenetic analysis showed that all three nucleases share high similarity with the DNA/RNA non-specific endonuclease family of other insects. These nucleases were found to be mainly expressed in the posterior midgut region of the insect. Two days after nuclease RNAi-mediated gene silencing, dsRNA degradation by the gut juice was substantially reduced. Notably, after nucleases gene silencing, the orally delivered dsRNA against the AgraChSII gene resulted in improved gene silencing efficiency when compared to the control (non-silenced nucleases). The data presented here demonstrates that A. grandis midgut nucleases are effectively one of the main barriers to dsRNA delivery and emphasize the need to develop novel RNAi delivery strategies focusing on protecting the dsRNA from gut nucleases and enhancing its oral delivery and uptake to crop insect pests. PMID- 29261730 TI - aCNViewer: Comprehensive genome-wide visualization of absolute copy number and copy neutral variations. AB - MOTIVATION: Copy number variations (CNV) include net gains or losses of part or whole chromosomal regions. They differ from copy neutral loss of heterozygosity (cn-LOH) events which do not induce any net change in the copy number and are often associated with uniparental disomy. These phenomena have long been reported to be associated with diseases and particularly in cancer. Losses/gains of genomic regions are often correlated with lower/higher gene expression. On the other hand, loss of heterozygosity (LOH) and cn-LOH are common events in cancer and may be associated with the loss of a functional tumor suppressor gene. Therefore, identifying recurrent CNV and cn-LOH events can be important as they may highlight common biological components and give insights into the development or mechanisms of a disease. However, no currently available tools allow a comprehensive whole-genome visualization of recurrent CNVs and cn-LOH in groups of samples providing absolute quantification of the aberrations leading to the loss of potentially important information. RESULTS: To overcome these limitations, we developed aCNViewer (Absolute CNV Viewer), a visualization tool for absolute CNVs and cn-LOH across a group of samples. aCNViewer proposes three graphical representations: dendrograms, bi-dimensional heatmaps showing chromosomal regions sharing similar abnormality patterns, and quantitative stacked histograms facilitating the identification of recurrent absolute CNVs and cn-LOH. We illustrated aCNViewer using publically available hepatocellular carcinomas (HCCs) Affymetrix SNP Array data (Fig 1A). Regions 1q and 8q present a similar percentage of total gains but significantly different copy number gain categories (p-value of 0.0103 with a Fisher exact test), validated by another cohort of HCCs (p-value of 5.6e-7) (Fig 2B). AVAILABILITY AND IMPLEMENTATION: aCNViewer is implemented in python and R and is available with a GNU GPLv3 license on GitHub https://github.com/FJD-CEPH/aCNViewer and Docker https://hub.docker.com/r/fjdceph/acnviewer/. CONTACT: aCNViewer@cephb.fr. PMID- 29261731 TI - Time course of adiponectin and its relationship to psychological aspects in patients with anorexia nervosa during inpatient treatment. AB - OBJECTIVE: The protein hormone adiponectin promotes metabolic and psychological health. The aim of the study was to track changes in adiponectin levels in response to weight gain and to assess associations between adiponectin and psychological aspects in patients with anorexia nervosa (AN). METHODS: To investigate if adiponectin levels depend on AN severity, data were assessed from 11 inpatients with a very low body mass index (BMI) and a high chronicity (high severity group; HSS), and nine with less severe symptoms (LSS). During the course of treatment, serum adiponectin concentrations were assessed on a weekly basis along with BMI. Psychological variables (i.e., depression, anxiety, stress, and AN-specific symptoms) were obtained by means of electronic diaries. Longitudinal regressions and correlations were calculated to evaluate the temporal course of adiponectin and its relationship with psychological self-ratings. RESULTS: At the beginning adiponectin was not increased in HSS patients (p = .56), and only marginally elevated in LSS patients (p = 0.07) compared with controls. In HSS patients, adiponectin increased along with BMI during the first treatment phase (i.e., when the BMI of patients was below 16 kg/m2) and thereafter decreased with further weight gain. In LSS patients, adiponectin was not associated with BMI increase. Furthermore, adiponectin was strongly negatively correlated with psychological self-ratings when the BMI of patients was above 16 kg/m2, i.e., higher levels of adiponectin were related to lower ratings of depression, anxiety, and AN-specific symptoms. DISCUSSION: The study connects previous varying results by indicating that the course of adiponectin is dependent on BMI and symptom severity. Similarly, associations of adiponectin and psychological health depended on BMI. PMID- 29261732 TI - Molecular analysis of stomach contents reveals important grass seeds in the winter diet of Baird's and Grasshopper sparrows, two declining grassland bird species. AB - We analyzed the diet of Baird's Sparrow (Ammodramus bairdii) and Grasshopper Sparrow (A. savannarum) in three different sites and sampling periods across the Chihuahuan Desert in northern Mexico. DNA from seeds in regurgitated stomach contents was sequenced using NGS technology and identified with a barcoding approach using the P6 loop of the trnL intron as genetic marker. During each sampling period, we collected random soil samples to estimate seed availability in the soil seed bank. Due to the variability and size of the genetic marker, the resolution was limited to a family level resolution for taxonomic classification of seeds, but in several cases a genus level was achieved. Diets contained a high diversity of seeds but were dominated by a limited number of genera/families. Seeds from Panicoideae (from the genera Panicum, Setaria, Eriochloa, Botriochloa, and Hackelochloa) contributed for the largest part to the diets (53 +/- 19%), followed by Bouteloua (10 +/- 12%). Depending on the site and sampling period, other important seeds in the diets were Eragrostideae, Pleuraphis, Asteraceae, Verbena, and Amaranthus. The most abundant seeds were not always preferred. Aristida and Chloris were common in the soil seed bank but these seeds were avoided by both bird species. Baird's and Grasshopper sparrows did not differ in seed preferences. This work highlights the importance of range management practices that favor seed production of Panicoideae and Bouteloua grasses to enhance winter habitat use and survival of Baird's and Grasshopper sparrows in the Chihuahuan Desert. PMID- 29261733 TI - Genetic structure and diversity of Nodularia douglasiae (Bivalvia: Unionida) from the middle and lower Yangtze River drainage. AB - The Yangtze River drainage in China is among the most species rich rivers for freshwater mussels (order Unionida) on Earth with at least 68 species known. The freshwater mussels of the Yangtze River face a variety of threats with indications that species are declining in abundance and area of occupancy. This study represents the first analyses of the genetic structure and diversity for the common and widespread freshwater mussel Nodularia douglasiae based on microsatellite DNA genotypes and mitochondrial DNA sequences. Phylogenetic analysis a fragment of the COI mitochondrial gene indicated that N. douglasiae collected from across the middle and lower Yangtze River drainage are monophyletic with N. douglasiae from Japan, Russia, and South Korea. The results of the analysis of both the mtDNA and microsatellite datasets indicated that the seven collection locations of N. douglasiae in the middle and lower Yangtze River drainage showed high genetic diversity, significant genetic differentiation and genetic structure, and stable population dynamics over time. Moreover, we found that the connections among tributaries rivers and lakes in the Yangtze River drainage were important in maintaining gene flow among locations that N. douglasiae inhabits. An understanding of the genetic structure and diversity of a widespread species like N. douglasiae could be used as a surrogate to better understand the populations of other freshwater mussel species that are more rare in the Yangtze River drainage. At the same time, these results could provide a basis for the protection of genetic diversity and management of unionid mussels diversity and other aquatic organisms in the system. PMID- 29261734 TI - Differences in reward processing between putative cell types in primate prefrontal cortex. AB - Single-unit studies in monkeys have demonstrated that neurons in the prefrontal cortex predict the reward type, reward amount or reward availability associated with a stimulus. To examine contributions of pyramidal cells and interneurons in reward processing, single-unit activity was extracellularly recorded in prefrontal cortices of four monkeys performing a reward prediction task. Based on their shapes of spike waveforms, prefrontal neurons were classified into broad spike and narrow-spike units that represented putative pyramidal cells and interneurons, respectively. We mainly observed that narrow-spike neurons showed higher firing rates but less bursty discharges than did broad-spike neurons. Both narrow-spike and broad-spike cells selectively responded to the stimulus, reward and their interaction, and the proportions of each type of selective neurons were similar between the two cell classes. Moreover, the two types of cells displayed equal reliability of reward or stimulus discrimination. Furthermore, we found that broad-spike and narrow-spike cells showed distinct mechanisms for encoding reward or stimulus information. Broad-spike neurons raised their firing rate relative to the baseline rate to represent the preferred reward or stimulus information, whereas narrow-spike neurons inhibited their firing rate lower than the baseline rate to encode the non-preferred reward or stimulus information. Our results suggest that narrow-spike and broad-spike cells were equally involved in reward and stimulus processing in the prefrontal cortex. They utilized a binary strategy to complementarily represent reward or stimulus information, which was consistent with the task structure in which the monkeys were required to remember two reward conditions and two visual stimuli. PMID- 29261735 TI - Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock induced arterial dysfunction in rats. AB - INTRODUCTION: Long chain n-3 fatty acid supplementation may modulate septic shock induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction. METHODS: In a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments. RESULTS: We have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6+/-12.0 and 3.7+/-8.0 MUg/kg/min respectively versus 17.4+/-19.3 MUg/kg/min in D5 group, p<0.05) and DHA infusion significantly improved contractile response to phenylephrine through nitric oxide pathway inhibition. DHA moreover significantly reduced vascular oxidative stress and nitric oxide production, phosphorylated IkappaB expression and vasodilative prostaglandin production. DHA also significantly decreased polyunsaturated fatty acid pro-inflammatory mediators and significantly increased several anti inflammatory metabolites. CONCLUSIONS: DHA infusion in septic rats improved hemodynamic dysfunction through decreased vascular oxidative stress and inflammation, while EPA infusion did not have beneficial effects. PMID- 29261736 TI - Randomized clinical trial to evaluate the effect of fecal microbiota transplant for initial Clostridium difficile infection in intestinal microbiome. AB - OBJECTIVE: The aim of this study was to evaluate the impact of fecal donor unrelated donor mix (FMT-FURM) transplantation as first-line therapy for C. difficile infection (CDI) in intestinal microbiome. METHODS: We designed an open, two-arm pilot study with oral vancomycin (250mg every 6 h for 10-14 days) or FMT FURM as treatments for the first CDI episode in hospitalized adult patients in Hospital Universitario "Dr. Jose Eleuterio Gonzalez". Patients were randomized by a closed envelope method in a 1: 1 ratio to either oral vancomycin or FMT-FURM. CDI resolution was considered when there was a reduction on the Bristol scale of at least 2 points, a reduction of at least 50% in the number of bowel movements, absence of fever, and resolution of abdominal pain (at least two criteria). From each patient, a fecal sample was obtained at days 0, 3, and 7 after treatment. Specimens were cultured to isolate C. difficile, and isolates were characterized by PCR. Susceptibility testing of isolates was performed using the agar dilution method. Fecal samples and FMT-FURM were analyzed by 16S rRNA sequencing. RESULTS: We included 19 patients; 10 in the vancomycin arm and 9 in the FMT-FURM arm. However, one of the patients in the vancomycin arm and two patients in the FMT FURM arm were eliminated. Symptoms resolved in 8/9 patients (88.9%) in the vancomycin group, while symptoms resolved in 4/7 patients (57.1%) after the first FMT-FURM dose (P = 0.26) and in 5/7 patients (71.4%) after the second dose (P = 0.55). During the study, no adverse effects attributable to FMT-FURM were observed in patients. Twelve isolates were recovered, most isolates carried tcdB, tcdA, cdtA, and cdtB, with an 18-bp deletion in tcdC. All isolates were resistant to ciprofloxacin and moxifloxacin but susceptible to metronidazole, linezolid, fidaxomicin, and tetracycline. In the FMT-FURM group, the bacterial composition was dominated by Firmicutes, Bacteroidetes, and Proteobacteria at all-time points and the microbiota were remarkably stable over time. The vancomycin group showed a very different pattern of the microbial composition when comparing to the FMT FURM group over time. CONCLUSION: The results of this preliminary study showed that FMT-FURM for initial CDI is associated with specific bacterial communities that do not resemble the donors' sample. PMID- 29261737 TI - Comparative efficacy of two different topical povidone-iodine 5% regimens in reducing conjunctival bacterial flora: A randomized parallel double-masked clinical trial. AB - INTRODUCTION: The increasing prevalence of multi-resistant bacteria is a major public health concern. Infections acquired during ophthalmic surgery are devastating. The purpose of the current study is to compare the proportion of eyes with negative bacterial cultures on all tested media after 1 versus 3 sequential drops of povidone-iodine (PI) 5% into the inferior conjunctival fornix. METHODS: Patients were randomly assigned to receive 1 (PI group) drop (at time 28 minutes) or 3 (PI plus group) sequential drops (at time 0, 20 minutes and 28 minutes) of PI 5% into the inferior conjunctival sac of one randomly selected eye. A swab culture was obtained from the inferior conjunctival fornix 5 minutes before and 30 minutes after time 0. Central corneal thickness (CCT) was measured shortly before time 0 and shortly after time 30. Conjunctival swabs were incubated aerobically in enriched Thioglycolate liquid medium (meat broth) and in three solid culture media (chocolate agar, trypticase soy agar with 5% sheep blood, and Sabouraud agar). RESULTS: There was no significant difference in the proportion of negative cultures after intervention between groups (p = 0.1638). Also in the PI group (n = 59), the proportion of eyes with negative cultures after PI (79.7%) did not differ significantly from baseline (76.3%; p = 0.7539). However in the PI plus group (n = 61), the proportion of eyes with all negative cultures after PI (85.3%) was significantly higher than before PI (70.5%) (p = 0.0177). There was no significant difference in mean CCT before and after the intervention in both groups. CONCLUSION: Instillation of 3 sequential drops of PI was associated with a significant increase in the proportion of eyes with all negative cultures, while instillation of a single drop of PI was not associated with a significant increase in the proportion of negative cultures. Further study is warranted to determine whether the difference between the PI administration regimens is also associated with differences in the rates of postoperative ocular infections. PMID- 29261738 TI - Toxoplasmosis - Awareness and knowledge among medical doctors in Nigeria. AB - Toxoplasma gondii is a zoonotic parasite causing high disease burden worldwide. A One Health approach is needed to understand, prevent, and control toxoplasmosis, while knowledge gaps in the One Health aspects have been identified among medical professionals in earlier studies. As a One Health collaboration between veterinary and medical fields, we surveyed the knowledge on toxoplasmosis among medical doctors in Nigeria. The knowledge questions, which the participants answered without consulting literature and colleagues, covered epidemiological One Health aspects as well as clinical interspecialty aspects of T. gondii infections. Altogether 522 medical doctors from four tertiary hospitals completed the questionnaire. The mean number of correct answers in the knowledge questions was 7.5, and 8.4% of the participants selected at least 12 of the 17 correct answers. The proportion of medical doctors scoring such a high score was significantly higher among those who reported having seen a case of clinical toxoplasmosis than in those who did not. While 62% of the medical doctors participating in our study knew that cats can shed T. gondii in their feces, 36% incorrectly suggested that humans could do that too. That T. gondii infection can be meatborne was known by 69%, but that it can be also waterborne only by 28% of the medical doctors participating in our study. Most of the medical doctors, 78%, knew that clinical toxoplasmosis may involve the central nervous system, while only 37% answered that it can involve the eyes. Our results suggested knowledge gaps, which need to be addressed in Continuous Medical Education. The identified gaps included both intersectoral One Health aspects and interspecialty aspects: For prevention and management of toxoplasmosis, knowing the main transmission routes and that the parasite can affect several organs is relevant. PMID- 29261739 TI - Relation between cost of drug treatment and body mass index in people with type 2 diabetes in Latin America. AB - AIMS: Despite the frequent association of obesity with type 2 diabetes (T2D), the effect of the former on the cost of drug treatment of the latest has not been specifically addressed. We studied the association of overweight/obesity on the cost of drug treatment of hyperglycemia, hypertension and dyslipidemia in a population with T2D. METHODS: This observational study utilized data from the QUALIDIAB database on 3,099 T2D patients seen in Diabetes Centers in Argentina, Chile, Colombia, Peru, and Venezuela. Data were grouped according to body mass index (BMI) as Normal (18.5<=BMI<25), Overweight (25<=BMI<30), and Obese (BMI>=30). Thereafter, we assessed clinical and metabolic data and cost of drug treatment in each category. Statistical analyses included group comparisons for continuous variables (parametric or non-parametric tests), Chi-square tests for differences between proportions, and multivariable regression analysis to assess the association between BMI and monthly cost of drug treatment. RESULTS: Although all groups showed comparable degree of glycometabolic control (FBG, HbA1c), we found significant differences in other metabolic control indicators. Total cost of drug treatment of hyperglycemia and associated cardiovascular risk factors (CVRF) increased significantly (p<0.001) with increment of BMI. Hyperglycemia treatment cost showed a significant increase concordant with BMI whereas hypertension and dyslipidemia did not. Despite different values and percentages of increase, this growing cost profile was reproduced in every participating country. BMI significantly and independently affected hyperglycemia treatment cost. CONCLUSIONS: Our study shows for the first time that BMI significantly increases total expenditure on drugs for T2D and its associated CVRF treatment in Latin America. PMID- 29261740 TI - Percolation in protein sequence space. AB - The currently known protein sequences are not distributed equally in sequence space, but cluster into families. Analyzing the cluster size distribution gives a glimpse of the large and unknown extant protein sequence space, which has been explored during evolution. For six protein superfamilies with different fold and function, the cluster size distributions followed a power law with slopes between 2.4 and 3.3, which represent upper limits to the cluster distribution of extant sequences. The power law distribution of cluster sizes is in accordance with percolation theory and strongly supports connectedness of extant sequence space. Percolation of extant sequence space has three major consequences: (1) It transforms our view of sequence space as a highly connected network where each sequence has multiple neighbors, and each pair of sequences is connected by many different paths. A high degree of connectedness is a necessary condition of efficient evolution, because it overcomes the possible blockage by sign epistasis and reciprocal sign epistasis. (2) The Fisher exponent is an indicator of connectedness and saturation of sequence space of each protein superfamily. (3) All clusters are expected to be connected by extant sequences that become apparent as a higher portion of extant sequence space becomes known. Being linked to biochemically distinct homologous families, bridging sequences are promising enzyme candidates for applications in biotechnology because they are expected to have substrate ambiguity or catalytic promiscuity. PMID- 29261741 TI - Transcriptome analysis of filling stage seeds among three buckwheat species with emphasis on rutin accumulation. AB - Buckwheat is an important minor crop with pharmaceutical functions due to rutin enrichment in the seed. Seeds of common buckwheat cultivars (Fagopyrum esculentum, Fes) usually have much lower rutin content than tartary buckwheat (F. tartaricum, Ft). We previously found a wild species of common buckwheat (F. esculentum ssp. ancestrale, Fea), with seeds that are high in rutin, similar to Ft. In the present study, we investigated the mechanism by which rutin production varies among different buckwheat cultivars, Fea, a Ft variety (Xide) and a Fes variety (No.2 Pingqiao) using RNA sequencing of filling stage seeds. Sequencing data generated approximately 43.78-Gb of clean bases, all these data were pooled together and assembled 180,568 transcripts, and 109,952 unigenes. We established seed gene expression profiles of each buckwheat sample and assessed genes involved in flavonoid biosynthesis, storage proteins production, CYP450 family, starch and sucrose metabolism, and transcription factors. Differentially expressed genes between Fea and Fes were further analyzed due to their close relationship than with Ft. Expression levels of flavonoid biosynthesis gene FLS1 (Flavonol synthase 1) were similar in Fea and Ft, and much higher than in Fes, which was validated by qRT-PCR. This suggests that FLS1 transcript levels may be associated with rutin accumulation in filling stage seeds of buckwheat species. Further, we explored transcription factors by iTAK, and multiple gene families were identified as being involved in the coordinate regulation of metabolism and development. Our extensive transcriptomic data sets provide a complete description of metabolically related genes that are differentially expressed in filling stage buckwheat seeds and suggests that FLS1 is a key controller of rutin synthesis in buckwheat species. FLS1 can effectively convert dihydroflavonoids into flavonol products. These findings provide a basis for further studies of flavonoid biosynthesis in buckwheat breeding to help accelerate flavonoid metabolic engineering that would increase rutin content in cultivars of common buckwheat. PMID- 29261742 TI - In vitro dynamic model simulating the digestive tract of 6-month-old infants. AB - BACKGROUND: In vivo assays cannot always be conducted because of ethical reasons, technical constraints or costs, but a better understanding of the digestive process, especially in infants, could be of great help in preventing food-related pathologies and in developing new formulas with health benefits. In this context, in vitro dynamic systems to simulate human digestion and, in particular, infant digestion could become increasingly valuable. OBJECTIVE: To simulate the digestive process through the use of a dynamic model of the infant gastroenteric apparatus to study the digestibility of starch-based infant foods. DESIGN: Using M.I.D.A (Model of an Infant Digestive Apparatus), the oral, gastric and intestinal digestibility of two starch-based products were measured: 1) rice starch mixed with distilled water and treated using two different sterilization methods (the classical method with a holding temperature of 121 degrees C for 37 min and the HTST method with a holding temperature of 137 degrees C for 70 sec) and 2) a rice cream with (premium product) or without (basic product) an aliquot of rice flour fermented by Lactobacillus paracasei CBA L74. After the digestion the foods were analyzed for the starch concentration, the amount of D-glucose released and the percentage of hydrolyzed starch. RESULTS: An in vitro dynamic system, which was referred to as M.I.D.A., was obtained. Using this system, the starch digestion occurred only during the oral and intestinal phase, as expected. The D-glucose released during the intestinal phase was different between the classical and HTST methods (0.795 grams for the HTST versus 0.512 for the classical product). The same analysis was performed for the basic and premium products. In this case, the premium product had a significant difference in terms of the starch hydrolysis percentage during the entire process. CONCLUSIONS: The M.I.D.A. system was able to digest simple starches and a more complex food in the correct compartments. In this study, better digestibility of the premium product was revealed. PMID- 29261744 TI - Energy homeostasis in leptin deficient Lepob/ob mice. AB - Maintenance of reduced body weight is associated both with reduced energy expenditure per unit metabolic mass and increased hunger in mice and humans. Lowered circulating leptin concentration, due to decreased fat mass, provides a primary signal for this response. However, leptin deficient (Lepob/ob) mice (and leptin receptor deficient Zucker rats) reduce energy expenditure following weight reduction by a necessarily non-leptin dependent mechanisms. To identify these mechanisms, Lepob/ob mice were fed ad libitum (AL group; n = 21) or restricted to 3 kilocalories of chow per day (CR group, n = 21). After losing 20% of initial weight (in approximately 2 weeks), the CR mice were stabilized at 80% of initial body weight for two weeks by titrated refeeding, and then released from food restriction. CR mice conserved energy (-17% below predicted based on body mass and composition during the day; -52% at night); and, when released to ad libitum feeding, CR mice regained fat and lean mass (to AL levels) within 5 weeks. CR mice did so while their ad libitum caloric intake was equal to that of the AL animals. While calorically restricted, the CR mice had a significantly lower respiratory exchange ratio (RER = 0.89) compared to AL (0.94); after release to ad libitum feeding, RER was significantly higher (1.03) than in the AL group (0.93), consistent with their anabolic state. These results confirm that, in congenitally leptin deficient animals, leptin is not required for compensatory reduction in energy expenditure accompanying weight loss, but suggest that the hyperphagia of the weight-reduced state is leptin-dependent. PMID- 29261743 TI - A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats. AB - Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2 chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1beta levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation. PMID- 29261745 TI - Protonema of the moss Funaria hygrometrica can function as a lead (Pb) adsorbent. AB - Water contamination by heavy metals from industrial activities is a serious environmental concern. To mitigate heavy metal toxicity and to recover heavy metals for recycling, biomaterials used in phytoremediation and bio-sorbent filtration have recently drawn renewed attention. The filamentous protonemal cells of the moss Funaria hygrometrica can hyperaccumulate lead (Pb) up to 74% of their dry weight when exposed to solutions containing divalent Pb. Energy dispersive X-ray spectroscopy revealed that Pb is localized to the cell walls, endoplasmic reticulum-like membrane structures, and chloroplast thylakoids, suggesting that multiple Pb retention mechanisms are operating in living F. hygrometrica. The main Pb-accumulating compartment was the cell wall, and prepared cell-wall fractions could also adsorb Pb. Nuclear magnetic resonance analysis showed that polysaccharides composed of polygalacturonic acid and cellulose probably serve as the most effective Pb-binding components. The adsorption abilities were retained throughout a wide range of pH values, and bound Pb was not desorbed under conditions of high ionic strength. In addition, the moss is highly tolerant to Pb. These results suggest that the moss F. hygrometrica could be a useful tool for the mitigation of Pb-toxicity in wastewater. PMID- 29261746 TI - Piriformospora indica promotes early flowering in Arabidopsis through regulation of the photoperiod and gibberellin pathways. AB - Flowering in plants is synchronized by both environmental cues and internal regulatory factors. Previous studies have shown that the endophytic fungus Piriformospora indica promotes the growth and early flowering in Coleus forskohlii (a medicinal plant) and Arabidopsis. To further dissect the impact of P. indica on pathways responsible for flowering time in Arabidopsis, we co cultivated Arabidopsis with P. indica and used RT-qPCR to analyze the main gene regulation networks involved in flowering. Our results revealed that the symbiotic interaction of Arabidopsis with P. indica promotes early flower development and the number of siliques. In addition, expression of the core flowering regulatory gene FLOWERING LOCUS T (FT), of genes controlling the photoperiod [CRYPTOCHROMES (CRY1, CRY2) and PHYTOCHROME B (PHYB)] and those related to gibberellin (GA) functions (RGA1, AGL24, GA3, and MYB5) were induced by the fungus, while key genes controlling the age and autonomous pathways remained unchanged. Moreover, early flowering promotion conferred by P. indica was promoted by exogenous GA and inhabited by GA inhibitor, and this effect could be observed under long day and neutral day photoperiod. Therefore, our data suggested that P. indica promotes early flowering in Arabidopsis likely through photoperiod and GA rather than age or the autonomous pathway. PMID- 29261747 TI - Sex-specific reference intervals of hematologic and biochemical analytes in Sprague-Dawley rats using the nonparametric rank percentile method. AB - BACKGROUND: Hematologic and biochemical analytes of Sprague-Dawley rats are commonly used to determine effects that were induced by treatment and to evaluate organ dysfunction in toxicological safety assessments, but reference intervals have not been well established for these analytes. Reference intervals as presently defined for these analytes in Sprague-Dawley rats have not used internationally recommended statistical method nor stratified by sex. Thus, we aimed to establish sex-specific reference intervals for hematologic and biochemical parameters in Sprague-Dawley rats according to Clinical and Laboratory Standards Institute C28-A3 and American Society for Veterinary Clinical Pathology guideline. METHODS: Hematology and biochemistry blood samples were collected from 500 healthy Sprague-Dawley rats (250 males and 250 females) in the control groups. We measured 24 hematologic analytes with the Sysmex XT 2100i analyzer, 9 biochemical analytes with the Olympus AU400 analyzer. We then determined statistically relevant sex partitions and calculated reference intervals, including corresponding 90% confidence intervals, using nonparametric rank percentile method. RESULTS: We observed that most hematologic and biochemical analytes of Sprague-Dawley rats were significantly influenced by sex. Males had higher hemoglobin, hematocrit, red blood cell count, red cell distribution width, mean corpuscular volume, mean corpuscular hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, percentage of neutrophils, percentage of monocytes, alanine aminotransferase, aspartate aminotransferase, and triglycerides compared to females. Females had higher mean corpuscular hemoglobin concentration, plateletcrit, platelet count, eosinophils, percentage of lymphocytes, percentage of eosinophils, creatinine, glucose, total cholesterol and urea compared to males. Sex partition was required for most hematologic and biochemical analytes in Sprague-Dawley rats. We established sex-specific reference intervals, including corresponding 90% confidence intervals, for Sprague-Dawley rats. CONCLUSIONS: Understanding the significant discrepancies in hematologic and biochemical analytes between male and female Sprague-Dawley rats provides important insight into physiological effects in test rats. Establishment of locally sex-specific reference intervals allows a more precise evaluation of animal quality and experimental results of Sprague-Dawley rats in our toxicology safety assessment. PMID- 29261748 TI - Children's emotional experience two years after an earthquake: An exploration of knowledge of earthquakes and associated emotions. AB - OBJECTIVES: We explored whether and how the exposure to a natural disaster such as the 2012 Emilia Romagna earthquake affected the development of children's emotional competence in terms of understanding, regulating, and expressing emotions, after two years, when compared with a control group not exposed to the earthquake. We also examined the role of class level and gender. METHOD: The sample included two groups of children (n = 127) attending primary school: The experimental group (n = 65) experienced the 2012 Emilia Romagna earthquake, while the control group (n = 62) did not. The data collection took place two years after the earthquake, when children were seven or ten-year-olds. Beyond assessing the children's understanding of emotions and regulating abilities with standardized instruments, we employed semi-structured interviews to explore their knowledge of earthquakes and associated emotions, and a structured task on the intensity of some target emotions. RESULTS: We applied Generalized Linear Mixed Models. Exposure to the earthquake did not influence the understanding and regulation of emotions. The understanding of emotions varied according to class level and gender. Knowledge of earthquakes, emotional language, and emotions associated with earthquakes were, respectively, more complex, frequent, and intense for children who had experienced the earthquake, and at increasing ages. CONCLUSIONS: Our data extend the generalizability of theoretical models on children's psychological functioning following disasters, such as the dose response model and the organizational-developmental model for child resilience, and provide further knowledge on children's emotional resources related to natural disasters, as a basis for planning educational prevention programs. PMID- 29261749 TI - Influence of riverine input on the growth of Glycymeris glycymeris in the Bay of Brest, North-West France. AB - A crossdated, replicated, chronology of 114 years (1901-2014) was developed from internal growth increments in the shells of Glycymeris glycymeris samples collected monthly from the Bay of Brest, France. Bivalve sampling was undertaken between 2014 and 2015 using a dredge. In total 401 live specimens and 243 articulated paired valves from dead specimens were collected, of which 38 individuals were used to build the chronology. Chronology strength, assessed as the Expressed Population Signal, was above 0.7 throughout, falling below the generally accepted threshold of 0.85 before 1975 because of reduced sample depth. Significant positive correlations were identified between the shell growth and the annual averages of rainfall (1975-2008; r = 0.34) and inflow from the river Elorn (1989-2009; r = 0.60). A significant negative correlation was identified between shell growth and the annual average salinity (1998-2014; r = -0.62). Analysis of the monthly averages indicates that these correlations are associated with the winter months (November-February) preceding the G. glycymeris growth season suggesting that winter conditions predispose the benthic environment for later shell growth. Concentration of suspended particulate matter within the river in February is also positively correlated with shell growth, leading to the conclusion that food availability is also important to the growth of G. glycymeris in the Bay of Brest. With the addition of principle components analysis, we were able to determine that inflow from the River Elorn, nitrite levels and salinity were the fundamental drivers of G. glycymeris growth and that these environmental parameters were all linked. PMID- 29261750 TI - Effect of optical correction on subfoveal choroidal thickness in children with anisohypermetropic amblyopia. AB - The purpose of this study was to determine the effect of optical correction on the best-corrected visual acuity (BCVA) and subfoveal choroidal thickness (CT) in the eyes of children with anisohypermetropic amblyopia. Twenty-four anisohypermetropic amblyopic eyes and their fellow eyes of 24 patients and twenty three eyes of 23 age-matched control children were studied. After one year of optical correction, the BCVA in the anisohypermetropic amblyopic eyes was significantly improved. Before the treatment, the mean subfoveal CT in the amblyopic eyes was 351.9 +/- 59.4 MUm which was significantly thicker than that of control eyes at 302.4 +/- 63.2 MUm. After the treatment, the amount of change in the subfoveal CT in the amblyopic and fellow eyes was greater than that in the control eyes. The amblyopic and fellow eyes with thicker choroids had a greater thinning of the choroid whereas eyes with thinner choroids had a greater thickening of the choroid. We conclude that wearing corrective lenses improves the visual acuity, and induces changes of the subfoveal CT in eyes with anisohypermetropic amblyopia. PMID- 29261751 TI - eGARD: Extracting associations between genomic anomalies and drug responses from text. AB - Tumor molecular profiling plays an integral role in identifying genomic anomalies which may help in personalizing cancer treatments, improving patient outcomes and minimizing risks associated with different therapies. However, critical information regarding the evidence of clinical utility of such anomalies is largely buried in biomedical literature. It is becoming prohibitive for biocurators, clinical researchers and oncologists to keep up with the rapidly growing volume and breadth of information, especially those that describe therapeutic implications of biomarkers and therefore relevant for treatment selection. In an effort to improve and speed up the process of manually reviewing and extracting relevant information from literature, we have developed a natural language processing (NLP)-based text mining (TM) system called eGARD (extracting Genomic Anomalies association with Response to Drugs). This system relies on the syntactic nature of sentences coupled with various textual features to extract relations between genomic anomalies and drug response from MEDLINE abstracts. Our system achieved high precision, recall and F-measure of up to 0.95, 0.86 and 0.90, respectively, on annotated evaluation datasets created in-house and obtained externally from PharmGKB. Additionally, the system extracted information that helps determine the confidence level of extraction to support prioritization of curation. Such a system will enable clinical researchers to explore the use of published markers to stratify patients upfront for 'best-fit' therapies and readily generate hypotheses for new clinical trials. PMID- 29261752 TI - A comparison of health-related quality of life (HRQoL) across four systemic autoimmune rheumatic diseases (SARDs). AB - OBJECTIVES: To compare physical and mental health-related quality of life (HRQoL) across four systemic autoimmune rheumatic diseases (SARD). METHODS: Incident subjects enrolled in four SARD cohorts, namely systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA) and idiopathic inflammatory myopathies (IIM) were studied. The outcomes of interest were baseline Short Form Health Survey physical (PCS) and mental (MCS) component summary scores. Multivariate analysis was conducted to determine whether PCS and MCS scores differed across SARD type. RESULTS: The study included 118 SLE (93% women, mean age 36 years), 108 SSc (79% women, mean age 55), 64 RA (63% women, mean age 58) and 25 IIM (68% women, mean age 49) subjects. Mean PCS scores were 38.9 +/- 12.2 in SLE, 37.1 +/- 13.3 in RA, 35.0 +/- 13.6 in SSc and 28.0 +/- 15.4 in IIM. Mean MCS scores were 45.0 +/- 13.3 in RA, 44.4 +/- 14.7 in SSc, 40.1 +/- 14.3 in SLE and 33.6 +/- 18.7 in IIM. SARD type was an independent predictor of HRQoL with, in some cases, the magnitude of the differences reaching one standard deviation (IIM worse PCS scores compared to SLE (beta -12.23 [95% CI -18.11, 6.36; p<0.001]); IIM worse MCS scores compared to SSc (beta -11.05 [95% CI 17.53, -4.58; p = 0.001]) and RA (beta -11.72 [95% CI -18.62, -4.81; p = 0.001]). CONCLUSIONS: Cross-SARD research provides a novel approach to gain greater understanding of commonalities and differences across rheumatic diseases. The differences observed warrant further research into correlates and trajectories over time. PMID- 29261753 TI - Prevalence and molecular characterization of Giardia intestinalis in racehorses from the Sichuan province of southwestern China. AB - Giardia intestinalis, a cosmopolitan zoonotic parasite, is one of the most common causes of protozoal diarrhea in both humans and animals worldwide. Although G. intestinalis has been detected in many animals, information regarding its prevalence and genotype in Chinese racehorses is scarce. In the present study, we investigated the prevalence of G. intestinalis in racehorses and performed molecular characterization of the pathogen to assess its zoonotic potential. Two hundred and sixty-four racehorse fecal samples from six equestrian clubs located in different regions of the Sichuan province of southwestern China were examined. Nested polymerase chain reaction (PCR) analysis of the gene encoding triose phosphate isomerase (tpi) showed the prevalence of G. intestinalis to be 8.3% (22/264), and the prevalence in different clubs varied from 3.6% to 13.5%. Three assemblages were identified in the successfully sequenced samples, including the potentially zoonotic assemblages A (n = 5) and B (n = 14), the mouse-specific assemblage G (n = 3), and a mixed A and B assemblage. Sequence analysis of tpi, glutamate dehydrogenase (gdh), and beta giardin (bg) loci revealed that the majority of sequences isolated from assemblage A were identical to the subtype AIV and assemblage B isolates showed variability among the nucleotide sequences of the subtype BIV. Using the nomenclature for the multilocus genotype (MLG) model, one each of multilocus genotypes A (MLG1) and B (MLG2) were identified, with MLG2 being a novel genotype. To the best of our knowledge, this is the first study to investigate G. intestinalis in Chinese racehorses. The presence of both animal and human assemblages of G. intestinalis in racehorses indicated that these animals might constitute a potential zoonotic risk to human beings. PMID- 29261754 TI - Multiple attribute decision making model and application to food safety risk evaluation. AB - Decision making for supermarket food purchase decisions are characterized by network relationships. This paper analyzed factors that influence supermarket food selection and proposes a supplier evaluation index system based on the whole process of food production. The author established the intuitive interval value fuzzy set evaluation model based on characteristics of the network relationship among decision makers, and validated for a multiple attribute decision making case study. Thus, the proposed model provides a reliable, accurate method for multiple attribute decision making. PMID- 29261755 TI - Interaction between environment, nutrient-derived metabolites and immunity: A possible role in malaria susceptibility/resistance in Fulani and Dogon of Mali. AB - The role of some nutrient-derived metabolites on the innate and adaptive immune responses is now established. Global research approach investigating the interplay between environment, lifestyle and the host's immune responses is crucial in the understanding of malaria susceptibility. Advanced Glycation end products (AGE), which are food-derived metabolites result from the link between reducing sugar and amino group of proteins, lipids or nucleic acids. The level of exposure to AGEs varies depending on the type of diet. The dysfunction of the immune system induced by AGE and the cellular receptors for AGEs (RAGE) in susceptibility to bacterial infection has been described. But no study has yet explored their role in susceptibility to malaria. Therefore, we aimed to evaluate systemic AGE and RAGE gene polymorphism in two sympatric populations with previously described difference of susceptibility to malaria. We measured by ELISA the plasma levels of AGEs, and their soluble receptors (sRAGE) from 170 volunteers (68 Fulani and 102 Dogon). We also determined by real-time quantitative PCR the expression of RAGE, and the -374 T/A, -429 T/C polymorphisms and 63 bp deletion by fragment length restriction polymorphism. The prevalence rate of Plasmodium in Fulani and Dogon were respectively 42.64% and 51.30% for P. falciparum, 5.88% and 6.5% for P. malariae, 0% and 2.6% for P. ovale. The average AGE was 12.65 MUg/ml, and 496.48pg/ml for sRAGE. Highest levels of sRAGE were observed in Fulani (563,07pg/ml, 95% CI [547.81-580.13] vs 465.68pg/ml, 95% CI [331.19-467.51]) for Dogon, p = 0.00001. Fulani had the lowest mean of AGE (10.21MUg/ml, 95% CI [8.02-10.92]) compared to Dogon (16.88MUg/ml, 95% CI [13.92 17.96]; p = 0.00001. RAGE was more expressed in Dogon than Fulani (0.08 vs 0.04), P = 0.08. The -374A polymorphism vas more frequent in Fulani (32%) compared to Dogon (20%). The chronic exposure to dietary AGE could lead to immune responses impairment and polymorphism with implications in malaria susceptibility. More studies are necessary to better investigate this hypothesis. PMID- 29261756 TI - RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling. AB - Retinoblastoma (RB) is an inherited childhood ocular cancer caused by mutations in the tumor suppressor RB1 gene. Identification of RB1 mutations is essential to assess the risk of developing retinoblastoma in the patients' relatives. Retinoblastoma is a potentially curable cancer and an early diagnosis is critical for survival and eye preservation. Unilateral retinoblastoma is mostly non heritable and results from two somatic mutations whereas bilateral retinoblastoma is heritable and results from one germline and one somatic mutation, both have high penetrance, 90%. The purpose of this study was to identify causative RB1 mutations in RB patients with different clinical presentations. A comprehensive approach was used to study a cohort of 34 patients with unilateral, bilateral and trilateral retinoblastoma. Blood and tumor DNA was analyzed by sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Validation of an insertion mutation was performed by cloning the PCR product. Most of the patients in our cohort had unilateral RB, eight patients had bilateral RB and one patient had a trilateral tumor with ocular and suprasellar/sellar locations. Other tumors in addition to retinoblastoma were also found in the affected families. One patient had two syndromes, retinoblastoma and schwannomatosis, and another RB patient had a father with a retinoma. Five out of the 25 unilateral RB patients carried germinal mutations (20%), which were mostly missense mutations. The bilateral and trilateral patients carried splice-site, nonsense and frameshift mutations as well as a whole RB1 gene deletion. Missense mutations were associated with mild phenotype: unilateral retinoblastoma, retinoma or no tumor. In this study we identified causative RB1 mutations in most bilateral RB patients and in some unilateral RB patients, including five novel mutations. These data are crucial for genetic counseling and confirm the need to perform complete genetic screening for RB1 mutations in both constitutional and tumor tissues. PMID- 29261757 TI - Examining public knowledge and preferences for adult preventive services coverage. AB - INTRODUCTION: To examine (1) what individuals know about the existing adult preventive service coverage provisions of the Affordable Care Act (ACA), and (2) which preventive services individuals think should be covered without cost sharing. METHODS: An online panel from Survey Monkey was used to obtain a sample of 2,990 adults age 18 and older in March 2015, analyzed 2015-2017. A 17-item survey instrument was designed and used to evaluate respondents' knowledge of the adult preventive services provision of the ACA. Additionally, we asked whether various preventive services should be covered. The data include age, sex, race/ethnicity, and educational attainment as well as measures of political ideology, previous insurance status, the number of chronic conditions, and usual source of care. RESULTS: Respondents correctly answered 38.6% of the questions about existing coverage under the ACA, while on average respondents thought 12.1 of 15 preventive services should be covered (SD 3.5). Respondents were more knowledgeable about coverage for routine screenings, such as blood pressure (63.4% correct) than potentially stigmatizing screenings, such as for alcohol misuse (28.8% correct). Blood pressure screening received the highest support of coverage (89.8%) while coverage of gym memberships received the lowest support (59.4%). Individuals with conservative ideologies thought fewer services on average should be covered, but the difference was small-around one service less than those with liberal ideologies. CONCLUSIONS: Overwhelmingly, individuals think that most preventive services should be covered without cost sharing. Despite several years of coverage for preventive services, there is still confusion and lack of knowledge about which services are covered. PMID- 29261758 TI - Numerical calculation of boundary layers and wake characteristics of high-speed trains with different lengths. AB - Trains with different numbers of cars running in the open air were simulated using the delayed detached-eddy simulation (DDES). The numbers of cars included in the simulation are 3, 4, 5 and 8. The aim of this study was to investigate how train length influences the boundary layer, the wake flow, the surface pressure, the aerodynamic drag and the friction drag. To certify the accuracy of the mesh and methods, the drag coefficients from numerical simulation of trains with 3 cars were compared with those from the wind tunnel test, and agreement was obtained. The results show that the boundary layer is thicker and the wake vortices are less symmetric as the train length increases. As a result, train length greatly affects pressure. The upper surface pressure of the tail car reduced by 2.9%, the side surface pressure of the tail car reduced by 8.3% and the underneath surface pressure of the tail car reduced by 19.7% in trains that included 3 cars to those including 8 cars. In addition, train length also has a significant effect on the friction drag coefficient and the drag coefficient. The friction drag coefficient of each car in a configuration decreases along the length of the train. In a comparison between trains consisting of 3 cars to those consisting of 8 cars, the friction drag coefficient of the tail car reduced by 8.6% and the drag coefficient of the tail car reduced by 3.7%. PMID- 29261759 TI - Implementation of biological variation-based analytical performance specifications in the laboratory: Stringent evaluation of Improvacutor blood collection tubes. AB - Recently, because the quality of laboratory analyses has increased along with the need for quality improvement, several external quality control bodies have adapted performance specifications using the Desirable Biological Variation Database, termed "Ricos goals"; these criteria are more stringent than those presented in CLIA 88. In this study, we aimed to validate newly introduced serum separator tubes, Improvacutor, for routine clinical chemistry testing in accordance with Ricos goals and CLIA 88. Blood samples were collected from 100 volunteers into three types of serum vacuum tubes: Greiner Vacuette, Becton Dickinson (BD) Vacutainer, and Improve Improvacutor. The samples were subjected to 16 routine chemistry tests using a TBA-200fr NEO chemistry autoanalyzer. In the comparison analysis, all 16 test results were acceptable according to CLIA 88. However, in the comparison of Improve and BD tubes, creatinine showed 4.31% (+0.08 MUmol/L) bias. This slightly exceeded the Desirable Specification for Inaccuracy Ricos limit of +/-3.96%, but still satisfied the CLIS88 limit of +/ 26.52 MUmol/L. The remaining 15 analytes performed acceptably according to the Desirable Specifications of Ricos. The correlation coefficient of 12 analytes was greater than 0.95 in Passing-Bablok regression analysis among the three tubes, but was lower for four analytes: calcium, sodium, potassium, and chloride. In the stability assay, only potassium tested in the Greiner tube revealed a larger positive bias (2.18%) than the Ricos Desirable Specification for Inaccuracy based on biologic variation (1.8%). The BD tube also showed a positive bias of 1.74%, whereas the new Improve tube showed the smallest positive bias of 1.17% in potassium level after 72 h storage. Thus, the results of this study demonstrate that recently introduced analytical performance specifications based on components of biological variation (Rico's goal) could be extended to criterion for performance evaluation and applied. PMID- 29261760 TI - Identifying maternal and infant factors associated with newborn size in rural Bangladesh by partial least squares (PLS) regression analysis. AB - Birth weight, length and circumferences of the head, chest and arm are key measures of newborn size and health in developing countries. We assessed maternal socio-demographic factors associated with multiple measures of newborn size in a large rural population in Bangladesh using partial least squares (PLS) regression method. PLS regression, combining features from principal component analysis and multiple linear regression, is a multivariate technique with an ability to handle multicollinearity while simultaneously handling multiple dependent variables. We analyzed maternal and infant data from singletons (n = 14,506) born during a double-masked, cluster-randomized, placebo-controlled maternal vitamin A or beta carotene supplementation trial in rural northwest Bangladesh. PLS regression results identified numerous maternal factors (parity, age, early pregnancy MUAC, living standard index, years of education, number of antenatal care visits, preterm delivery and infant sex) significantly (p<0.001) associated with newborn size. Among them, preterm delivery had the largest negative influence on newborn size (Standardized beta = -0.29 - -0.19; p<0.001). Scatter plots of the scores of first two PLS components also revealed an interaction between newborn sex and preterm delivery on birth size. PLS regression was found to be more parsimonious than both ordinary least squares regression and principal component regression. It also provided more stable estimates than the ordinary least squares regression and provided the effect measure of the covariates with greater accuracy as it accounts for the correlation among the covariates and outcomes. Therefore, PLS regression is recommended when either there are multiple outcome measurements in the same study, or the covariates are correlated, or both situations exist in a dataset. PMID- 29261761 TI - Early detection of Mycobacterium avium subsp. paratuberculosis infection in cattle with multiplex-bead based immunoassays. AB - Johne's Disease (JD), caused by Mycobacterium avium subspecies paratuberculosis (MAP), results in significant economic loss to livestock production. The early detection of MAP infection in animals with extant serological assays has remained challenging due to the low sensitivity of commercially available ELISA tests, a fact that has hampered the development of effective JD control programs. Our recent protein microarray-based studies identified several promising candidate antigens that are immunogenic during different stages of MAP infection. To evaluate these antigens for use in diagnostic assays and reliably identify animals with MAP infection, a multiplex (Luminex(r)) assay was developed using color-coded flourescent beads coupled to 6 MAP recombinant proteins and applied to screen 180 serum and 90 milk samples from cows at different stages of MAP infection including negative (NL), fecal test positive/ELISA negative (F+E-), and fecal positive/ELISA positive (F+E+). The results show that while serum antibody reactivities to each of the 6 antigens were highest in F+E+ group, antibody reactivity to three of the six antigens were identified in the F+E- group, suggesting that these three antigens are expressed and provoke antibody responses during the early infection stages with MAP. Further, antibodies against all six antigens were elevated in milk samples from both the F+E- and F+E+ groups in comparison to the NL group (p<0.01). Taken together, the results of our investigation suggest that multiplex bead-based assays are able to reliably identify MAP infection, even during early stages when antibody responses in animals are undetectable with widely used commercial ELISA tests. PMID- 29261762 TI - "The mosquitoes that destroy your face". Social impact of Cutaneous Leishmaniasis in South-eastern Morocco, A qualitative study. AB - OBJECTIVE: To document the psychosocial burden of Cutaneous Leishmaniasis (CL) in rural communities in Southeastern Morocco. METHOD: Between March and April 2015, we conducted qualitative research in communities exposed to Leishmania major or L. tropica in Errachidia and Tinghir provinces. Twenty-eight focus groups discussions (FGDs) were realized, with a stratification by gender and tradition of medicine (users of folk versus professional medicine). Data were analyzed using content analysis. RESULTS: This rural population most exposed to CL in Morocco lacks access to health care in general and clearly points out there are other major public health issues that need to be resolved. Nonetheless, respondents consider the impact of CL lesions and scars as important and similar to that of burn scar tissue. Young women with CL scars in the face are stigmatized and will often be rejected for marriage in these communities. People usually try a long list of folk remedies on the active lesions, but none was felt adequate. There was a clear demand for better treatment as well as for treatment of the scars. CONCLUSIONS: The psycho-social impact of CL due to L.major and L.tropica is substantial, especially for young single women with facial scars. These generate social and self-stigma and diminish their marriage prospects. CL is well known, but not considered as a major health priority by these poor rural communities in South-eastern Morocco where gender discrimination is still an issue and access to basic health care is as neglected as CL. Early CL diagnosis and new treatment options with better skin outcomes are urgently needed. PMID- 29261763 TI - DNA content analysis allows discrimination between Trypanosoma cruzi and Trypanosoma rangeli. AB - Trypanosoma cruzi, a human protozoan parasite, is the causative agent of Chagas disease. Currently the species is divided into six taxonomic groups. The genome of the CL Brener clone has been estimated to be 106.4-110.7 Mb, and DNA content analyses revealed that it is a diploid hybrid clone. Trypanosoma rangeli is a hemoflagellate that has the same reservoirs and vectors as T. cruzi; however, it is non-pathogenic to vertebrate hosts. The haploid genome of T. rangeli was previously estimated to be 24 Mb. The parasitic strains of T. rangeli are divided into KP1(+) and KP1(-). Thus, the objective of this study was to investigate the DNA content in different strains of T. cruzi and T. rangeli by flow cytometry. All T. cruzi and T. rangeli strains yielded cell cycle profiles with clearly identifiable G1-0 (2n) and G2-M (4n) peaks. T. cruzi and T. rangeli genome sizes were estimated using the clone CL Brener and the Leishmania major CC1 as reference cell lines because their genome sequences have been previously determined. The DNA content of T. cruzi strains ranged from 87,41 to 108,16 Mb, and the DNA content of T. rangeli strains ranged from 63,25 Mb to 68,66 Mb. No differences in DNA content were observed between KP1(+) and KP1(-) T. rangeli strains. Cultures containing mixtures of the epimastigote forms of T. cruzi and T. rangeli strains resulted in cell cycle profiles with distinct G1 peaks for strains of each species. These results demonstrate that DNA content analysis by flow cytometry is a reliable technique for discrimination between T. cruzi and T. rangeli isolated from different hosts. PMID- 29261764 TI - Pyoderma outbreak among kindergarten families: Association with a Panton Valentine leukocidin (PVL)-producing S. aureus strain. AB - OBJECTIVES: We report on an outbreak of skin and soft tissue infections (SSTI) among kindergarten families. We analyzed the transmission route and aimed to control the outbreak. METHODS: The transmission route was investigated by nasal screening for Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus (PVL-SA), subsequent microbiological investigation including whole genome sequencing and a questionnaire-based analysis of epidemiological information. The control measures included distribution of outbreak information to all individuals at risk and implementation of a Staphylococcus aureus decontamination protocol. RESULTS: Individuals from 7 of 19 families were either colonized or showed signs of SSTI such as massive abscesses or eye lid infections. We found 10 PVL-SA isolates in 9 individuals. In the WGS-analysis all isolates were found identical with a maximum of 17 allele difference. The clones were methicillin-susceptible but cotrimoxazole resistant. In comparison to PVL-SAs from an international strain collection, the outbreak clone showed close genetical relatedness to PVL SAs from a non-European country. The questionnaire results showed frequent travels of one family to this area. The results also demonstrated likely transmission via direct contact between families. After initiation of Staphylococcus aureus decontamination no further case was detected. CONCLUSIONS: Our outbreak investigation showed the introduction of a PVL-SA strain into a kindergarten likely as a result of international travel and further transmission by direct contact. The implementation of a Staphylococcus aureus decontamination protocol was able to control the outbreak. PMID- 29261765 TI - The gene encoding the insulin-like androgenic gland hormone in an all-female parthenogenetic crayfish. AB - Male sexual differentiation in crustaceans is controlled by the androgenic gland (AG), a unique male endocrine organ that, in decapods, is located at the base of the 5th pereiopod. In these animals, the insulin-like androgenic gland hormone (IAG) is the major factor secreted from the AG to induce masculinization and maintain male characteristics. It has, however, recently been proposed that this hormone also plays a role in growth and ovarian development in females. In this study, we tested such a possibility by searching for the IAG gene in the marbled crayfish, a parthenogenetic animal that reproduces asexually to form an all female genetic clone. Based on the phylogenetic relationship between the marbled crayfish and Procambarus fallax, a gonochoristic species of the same North American Cambaridae family, we searched for the IAG gene in the marbled crayfish and then fully sequenced it. The open reading frame of the gene was found to be completely identical in the two species, and their introns shared over 94% identity. It was also found that, in addition to its expression at the base of the 5th pereiopod and in the testes of male P. fallax crayfish, IAG was expressed in the muscle tissue of P. fallax males and females and even of the parthenogenetic marbled crayfish. These findings provide new insight into possible functions of IAG, in addition to its role as a masculinization-inducing factor, and also constitute the basis for a discussion of the evolutionary relationship between the above two species. PMID- 29261766 TI - Characteristics of Aedes aegypti adult mosquitoes in rural and urban areas of western and coastal Kenya. AB - Aedes aegypti is the main vector for yellow fever, dengue, chikungunya and Zika viruses. Recent outbreaks of dengue and chikungunya have been reported in Kenya. Presence and abundance of this vector is associated with the risk for the occurrence and transmission of these diseases. This study aimed to characterize the presence and abundance of Ae. aegypti adult mosquitoes from rural and urban sites in western and coastal regions of Kenya. Presence and abundance of Ae. aegypti adult mosquitoes were determined indoors and outdoors in two western (urban Kisumu and rural Chulaimbo) and two coastal (urban Ukunda and rural Msambweni) sites in Kenya. Sampling was performed using quarterly human landing catches, monthly Prokopack automated aspirators and monthly Biogents-sentinel traps. A total of 2,229 adult Ae. aegypti mosquitoes were collected: 785 (35.2%) by human landing catches, 459 (20.6%) by Prokopack aspiration and 985 (44.2%) by Biogents-sentinel traps. About three times as many Ae. aegypti mosquitoes were collected in urban than rural sites (1,650 versus 579). Comparable numbers were collected in western (1,196) and coastal (1,033) sites. Over 80% were collected outdoors through human landing catches and Prokopack aspiration. The probability of collecting Ae. aegypti mosquitoes by human landing catches was significantly higher in the afternoon than morning hours (P<0.001), outdoors than indoors (P<0.001) and in urban than rural sites (P = 0.008). Significantly more Ae. aegypti mosquitoes were collected using Prokopack aspiration outdoors than indoors (P<0.001) and in urban than rural areas (P<0.001). Significantly more mosquitoes were collected using Biogents-sentinel traps in urban than rural areas (P = 0.008) and in western than coastal sites (P = 0.006). The probability of exposure to Ae. aegypti bites was highest in urban areas, outdoors and in the afternoon hours. These characteristics have major implications for the possible transmission of arboviral diseases and for the planning of surveillance and control programs. PMID- 29261767 TI - The role of gender in social network organization. AB - The digital traces we leave behind when engaging with the modern world offer an interesting lens through which we study behavioral patterns as expression of gender. Although gender differentiation has been observed in a number of settings, the majority of studies focus on a single data stream in isolation. Here we use a dataset of high resolution data collected using mobile phones, as well as detailed questionnaires, to study gender differences in a large cohort. We consider mobility behavior and individual personality traits among a group of more than 800 university students. We also investigate interactions among them expressed via person-to-person contacts, interactions on online social networks, and telecommunication. Thus, we are able to study the differences between male and female behavior captured through a multitude of channels for a single cohort. We find that while the two genders are similar in a number of aspects, there are robust deviations that include multiple facets of social interactions, suggesting the existence of inherent behavioral differences. Finally, we quantify how aspects of an individual's characteristics and social behavior reveals their gender by posing it as a classification problem. We ask: How well can we distinguish between male and female study participants based on behavior alone? Which behavioral features are most predictive? PMID- 29261768 TI - The longest diameter of tumor as a parameter of endoscopic resection in early gastric cancer: In comparison with tumor area. AB - BACKGROUND AND AIM: Tumor burden is important to predict clinical behaviors of cancer such as lymph node metastasis (LNM). Tumor size has been used as a parameter of tumor burden such as indication of endoscopic resection in early gastric cancer (EGC) to predict LNM. Thus, we aimed to investigate whether tumor area can be more helpful to predict clinical behaviors than longest diameter of tumor in EGC. PATIENTS AND METHODS: 3,059 patients who underwent gastrectomy for EGC were reviewed retrospectively. Tumor area was calculated by multiplying long and short diameter of the tumor in surgical specimen. Longest diameter means maximal longitudinal diameter of tumor in specimen. Clinicopathologic features were compared between longest diameter and area using area under receiver operating characteristic (AUROC) curves. RESULTS: Longest diameter and area of tumor showed a strong correlation (correlation coefficient 0.859, p<0.01). The cutoff value for prediction of LNM was 20 mm of longest diameter of tumor and 270 mm2 of tumor area. There was no significant difference between longest diameter and area for prediction of LNM (AUC 0.850 vs. 0.848, respectively). In differentiated-type EGC and undifferentiated-type EGC, there was no significant difference between longest diameter and area for prediction of LNM. Among mucosal or submucosal cancer prediction value of LNM between longest diameter and area was not significantly different. CONCLUSION: Tumor area may not be more helpful to predict LNM than longest diameter in EGC. Therefore, the longest diameter of tumor may be sufficient as an indicator of tumor burden in EGC. PMID- 29261769 TI - Optimal endobronchial tool sizes for targeting lung lesions based on 3D modeling. AB - BACKGROUND: For patients with suspicious lung lesions found on chest x-ray or CT, endo/trans- bronchial biopsy of the lung is the preferred method for obtaining a diagnosis. With the addition of new screening programs, a higher number of patients will require diagnostic biopsy which will prove even more challenging due to the small size of lesions found with screening. There are many endobronchial tools available on the market today and a wide range of new tools under investigation to improve diagnostic yield. However, there is little information available about the optimal tool size required to reach the majority of lesions, especially peripheral ones. In this manuscript we investigate the percentage of lesions that can be reached for various diameter tools if the tools remain inside the airways (i.e. endobronchial biopsy) and the distance a tool must travel "off-road" (or outside of the airways) to reach all lesions. METHODS AND FINDINGS: To further understand the distribution of lung lesions with respect to airway sizes and distances from the airways, six 3D models of the lung were generated. The airways were modeled at two different respiratory phases (inspiration and expiration). Three sets of 1,000 lesions were randomly distributed throughout the lung for each respiratory phase. The simulations showed that the percentage of reachable lesions decreases with increasing tool diameter and decreasing lesion diameter. A 1mm diameter tool will reach <25% of 1cm lesions if it remains inside the airways. To reach all 1cm lesions this 1mm tool would have to navigate through the parenchyma up to 8.5mm. CT scans of 21 patient lesions confirm these results reasonably well. CONCLUSIONS: The smaller the tool diameter the more likely it will be able to reach a lung lesion, whether it be for diagnostic biopsy, ablation, or resection. However, even a 1mm tool is not small enough to reach the majority of small (1-2cm) lesions. Therefore, it is necessary for endobronchial tools to be able to navigate through the parenchyma to reach the majority of lesions. PMID- 29261770 TI - Tentacle extract from the jellyfish Cyanea capillata increases proliferation and migration of human umbilical vein endothelial cells through the ERK1/2 signaling pathway. AB - Wound healing is a complex biological process, and current research finds that jellyfish have a great capacity for promoting growth and healing. However, the underlying mechanisms remain unclear. Thus, this study was conducted to investigate the molecular mechanisms and effects of a tentacle extract (TE) from the jellyfish Cyanea capillata (C. capillata) on cell proliferation and migration in human umbilical vein endothelial cells (HUVECs). First, our results showed that TE at the concentration of 1 MUg/ml could promote cell proliferation over various durations, induce a transition of the cells from the G1-phase to the S/G2 phase of the cell cycle, and increase the expression of cell cycle proteins (CyclinB1 and CyclinD1). Second, we found that TE could activate the PI3K/Akt, ERK1/2 and JNK MAPK signaling pathways but not the NF-kappaB signaling pathway or the apoptosis signaling cascade. Finally, we demonstrated that the TE-induced expression of cell cycle proteins was decreased by ERK1/2 inhibitor PD98059 but not by PI3K inhibitor LY294002 or JNK inhibitor SP600125. Similarly, the TE enhanced migration ability of HUVECs was also markedly attenuated by PD98059. Taken together, our findings indicate that TE-induced proliferation and migration in HUVECs mainly occurred through the ERK1/2 MAPK signaling pathway. These results are instructively important for further research on the isolation and purification of growth-promoting factors from C. capillata and are hopeful as a means to improve human wound repair in unfavorable conditions. PMID- 29261771 TI - Endotheliopathy is associated with higher levels of cell-free DNA following major trauma: A prospective observational study. AB - BACKGROUND: Cell free deoxyribonucleic acid (cfDNA) has been proposed as a biomarker of secondary complications following trauma. Raised thrombomodulin and syndecan-1 levels have been used to indicate endotheliopathy, and are associated with inflammation, coagulopathy, and mortality. The current study aimed to analyse the association between cfDNA and biomarkers of endotheliopathy in a cohort of trauma patients, and whether raised levels of cfDNA were associated with poorer clinical outcomes. METHODS: Serum thrombomodulin and syndecan-1 were used as biomarkers of endotheliopathy and compared to plasma cfDNA in trauma patients from two prospective longitudinal observational studies. Cohort A (n = 105) had a predicted injury severity score (ISS) >8, and had blood sampled within 1h of injury and at 4-12h. Cohort B (n = 17) had evidence of haemorrhagic shock, and had blood sampled at a median time of 3.5h after injury. Relationships between biomarkers were tested using multivariable linear regression models that included the covariates of gender, age, ISS, Glasgow Coma Scale, lactate, systolic blood pressure, and heart rate. A model was fitted to investigate whether changes in cfDNA were associated with similar changes in endothelial biomarkers. RESULTS: The mean age was 41 (SD 19), and the median ISS was 25 (IQR 12-34). There was a significant association between cfDNA levels and both syndecan-1 and thrombomodulin levels (both p<0.001). This was independent of all covariates except for ISS, which significantly correlated with cfDNA levels. 50 ng/ml change in syndecan-1 and 1 ng/ml change in thrombomodulin corresponded to 15% and 20% increases in cfDNA levels respectively (both p<0.001). Patients who died had significantly higher prehospital and in-hospital cfDNA levels (both p<0.05). CONCLUSIONS: Raised cfDNA levels are associated with markers of endotheliopathy following trauma, and are associated with mortality. This relationship is present within the first hour of injury, and a change in one biomarker level is reflected by similar changes in the others. These findings are in keeping with the hypothesis that circulating DNA and endothelial injury share a common pathway following trauma. PMID- 29261772 TI - A real-time PCR method for quantification of the total and major variant strains of the deformed wing virus. AB - European honey bees (Apis mellifera) are critically important to global food production by virtue of their pollination services but are severely threatened by deformed wing virus (DWV) especially in the presence of the external parasite Varroa destructor. DWV exists as many viral strains with the two major variants (DWV-A and DWV-B) varying in virulence. A single plasmid standard was constructed containing three sections for the specific determination of DWV-A (VP2 capsid region), DWV-B (IRES) and a conserved region suitable for total DWV (helicase region). The assays were confirmed as specific and discriminatory with limits of detections of 25, 25 and 50 genome equivalents for DWV-A, DWV-B and total-DWV, respectively. The methods were successfully tested on Apis mellifera and V. destructor samples with varying DWV profiles. The new method determined a more accurate total DWV titre in samples with substantial DWV-B than the method currently described in the COLOSS Beebook. The proposed assays could be utilized for the screening of large quantities of bee material for both a total DWV load overview along with more detailed investigations into DWV-A and DWV-B profiles. PMID- 29261773 TI - Classification of optic disc shape in glaucoma using machine learning based on quantified ocular parameters. AB - PURPOSE: This study aimed to develop a machine learning-based algorithm for objective classification of the optic disc in patients with open-angle glaucoma (OAG), using quantitative parameters obtained from ophthalmic examination instruments. METHODS: This study enrolled 163 eyes of 105 OAG patients (age: 62.3 +/- 12.6, mean deviation of Humphrey field analyzer: -8.9 +/- 7.5 dB). The eyes were classified into Nicolela's 4 optic disc types by 3 glaucoma specialists. Randomly, 114 eyes were selected for training data and 49 for test data. A neural network (NN) was trained with the training data and evaluated with the test data. We used 91 types of quantitative data, including 7 patient background characteristics, 48 quantified OCT (swept-source OCT; DRI OCT Atlantis, Topcon) values, including optic disc topography and circumpapillary retinal nerve fiber layer thickness (cpRNFLT), and 36 blood flow parameters from laser speckle flowgraphy, to build the machine learning classification model. To extract the important features among 91 parameters, minimum redundancy maximum relevance and a genetic feature selection were used. RESULTS: The validated accuracy against test data for the NN was 87.8% (Cohen's Kappa = 0.83). The important features in the NN were horizontal disc angle, spherical equivalent, cup area, age, 6-sector superotemporal cpRNFLT, average cup depth, average nasal rim disc ratio, maximum cup depth, and superior-quadrant cpRNFLT. CONCLUSION: The proposed machine learning system has proved to be good identifiers for different disc types with high accuracy. Additionally, the calculated confidence levels reported here should be very helpful for OAG care. PMID- 29261774 TI - Aging and decreased glomerular filtration rate: An elderly population-based study. AB - BACKGROUND: Although a reduced glomerular filtration rate (GFR) in old people has been attributed to physiologic aging, it may be associated with kidney disease or superimposed comorbidities. This study aims to assess the prevalence of decreased GFR in a geriatric population in a developing country and its prevalence in the absence of simultaneous diseases. STUDY DESIGN AND METHODS: This is a cross sectional study of data from the Saude, Bem-Estar e Envelhecimento cohort study (SABE study[Health, Well-Being and Aging]), a multiple cohorts study. A multistage cluster sample composed of 1,253 individuals representative of 1,249,388 inhabitants of Sao Paulo city aged >=60 years in 2010 was analyzed. The participants answered a survey on socio-demographic factors and health, had blood pressure measured and urine and blood samples collected. GFR was estimated and defined as decreased when <60 mL/min/1.73m2. Kidney damage was defined as dipstick-positive hematuria or urinary protein:creatinine > 0.20 g/g. RESULTS: The prevalence of GFR <60 mL/min/1.73m2 was 19.3%. Individuals with GFR <60 mL/min/1.73m2 were older (75+/-1 versus 69+/-1 years, p<0.001), had lower schooling (18 versus 30% with complete 8-year basic cycle, p = 0.010), and higher prevalence of hypertension (82 versus 63%, p<0.001), diabetes (34 versus 26%, p = 0.021), cardiovascular disease (43 versus 24%, p<0.001) and kidney damage (35% versus 15%, p<0.001). Only 0.7% of the entire studied population had GFR <60 mL/min/1.73m2 without simultaneous diseases or kidney damage. Among the individuals with GFR <60 mL/min/1.73m2, 3.5% had neither renal damage nor associated comorbidities, whereas among those with GFR >=60 mL/min/1.73m2, 11.0% had none of these conditions. Logistic regression showed that older age, cardiovascular disease and hypertension were associated with GFR<60 mL/min/1.73m2. CONCLUSIONS: Decreased GFR was highly prevalent among the geriatric population in a megalopolis of a developing country. It was rarely present without simultaneous chronic comorbidities or kidney damage. PMID- 29261775 TI - Nest signature changes throughout colony cycle and after social parasite invasion in social wasps. AB - Social insects recognize their nestmates by means of a cuticular hydrocarbon signature shared by colony members, but how nest signature changes across time has been rarely tested in longitudinal studies and in the field. In social wasps, the chemical signature is also deposited on the nest surface, where it is used by newly emerged wasps as a reference to learn their colony odor. Here, we investigate the temporal variations of the chemical signature that wasps have deposited on their nests. We followed the fate of the colonies of the social paper wasp Polistes biglumis in their natural environment from colony foundation to decline. Because some colonies were invaded by the social parasite Polistes atrimandibularis, we also tested the effects of social parasites on the nest signature. We observed that, as the season progresses, the nest signature changed; the overall abundance of hydrocarbons as well as the proportion of longer-chain and branched hydrocarbons increased. Where present, social parasites altered the host-nest signature qualitatively (adding parasite-specific alkenes) and quantitatively (by interfering with the increase in overall hydrocarbon abundance). Our results show that 1) colony odor is highly dynamic both in colonies controlled by legitimate foundresses and in those controlled by social parasites; 2) emerged offspring contribute little to colony signature, if at all, in comparison to foundresses; and 3) social parasites, that later mimic host signature, initially mark host nests with species-specific hydrocarbons. This study implies that important updating of the neural template used in nestmate recognition should occur in social insects. PMID- 29261776 TI - Calculating the Malliavin derivative of some stochastic mechanics problems. AB - The Malliavin calculus is an extension of the classical calculus of variations from deterministic functions to stochastic processes. In this paper we aim to show in a practical and didactic way how to calculate the Malliavin derivative, the derivative of the expectation of a quantity of interest of a model with respect to its underlying stochastic parameters, for four problems found in mechanics. The non-intrusive approach uses the Malliavin Weight Sampling (MWS) method in conjunction with a standard Monte Carlo method. The models are expressed as ODEs or PDEs and discretised using the finite difference or finite element methods. Specifically, we consider stochastic extensions of; a 1D Kelvin Voigt viscoelastic model discretised with finite differences, a 1D linear elastic bar, a hyperelastic bar undergoing buckling, and incompressible Navier-Stokes flow around a cylinder, all discretised with finite elements. A further contribution of this paper is an extension of the MWS method to the more difficult case of non-Gaussian random variables and the calculation of second order derivatives. We provide open-source code for the numerical examples in this paper. PMID- 29261777 TI - Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation. AB - Self-extracellular RNA (eRNA), released from stressed or injured cells upon various pathological situations such as ischemia-reperfusion-injury, has been shown to act as an alarmin by inducing procoagulatory and proinflammatory responses. In particular, M1-polarization of macrophages by eRNA resulted in the expression and release of a variety of cytokines, including tumor necrosis factor (TNF)-alpha or interleukin-6 (IL-6). The present study now investigates in which way self-eRNA may influence the response of macrophages towards various Toll-like receptor (TLR)-agonists. Isolated agonists of TLR2 (Pam2CSK4), TLR3 (PolyIC), TLR4 (LPS), or TLR7 (R848) induced the release of TNF-alpha in a concentration dependent manner in murine macrophages, differentiated from bone marrow-derived stem cells by mouse colony stimulating factor. Here, the presence of eRNA shifted the dose-response curve for Pam2CSK4 (Pam) considerably to the left, indicating that eRNA synergistically enhanced the cytokine liberation from macrophages even at very low Pam-levels. The synergistic activation of TLR2 by eRNA/Pam was duplicated by other TLR2-agonists such as FSL-1 or Pam3CSK4. In contrast, for TLR4-agonists such as LPS a synergistic effect of eRNA was much weaker, and was not existent for TLR3-, or TLR7-agonists. The synergistic eRNA/Pam action was dependent on the NFkappaB-signaling pathway as well as on p38MAP- and MEK1/ERK kinases and was prevented by predigestion of eRNA with RNase1 or by antibodies against TLR2. Thus, the presence of self-eRNA as alarming molecule sensitizes innate immune responses towards pathogen-associated molecular patterns (PAMPs) in a synergistic way and may thereby contribute to the differentiated outcome of inflammatory responses. PMID- 29261778 TI - Functional implications of hexameric assembly of RraA proteins from Vibrio vulnificus. AB - RNase E has a pivotal role in the degradation and processing of RNAs in Escherichia coli, and protein inhibitors RraA and RraB control its enzymatic activity. The halophilic pathogenic bacterium Vibrio vulnificus also expresses orthologs of RNase E and RraA-RNase EV, RraAV1, and RraAV2 (herein renamed as VvRNase E, VvRraA1, and VvRraA2). A previous study showed that VvRraA1 actively inhibits the ribonucleolytic activity of VvRNase E by interacting with the C terminal region of VvRNase E. However, the molecular mechanism underlying the effect of VvRraA1 on the ribonucleolytic activity of VvRNase E has not yet been elucidated. In this study, we report that the oligomer formation of VvRraA proteins affects binding efficiency to VvRNase E as well as inhibitory activity on VvRNase E action. The hexameric structure of VvRraA1 was converted to lower oligomeric forms when the Cys 9 residue was substituted with an Asp residue (VvRraA1-C9D), showing decreased inhibitory activity of VvRraA1 on VvRNase E in vivo. These results indicated that the intermolecular disulfide linkage contributed critically to the hexamerization of VvRraA1 for its proper function. On the contrary, the VvRraA2 that existed in a trimeric state did not bind to or inhibit VvRNase E. An in vitro cleavage assay further showed the reduced inhibitory effect of VvRraA-C9D on VvRNase E activity compared to wild-type VvRraA1. These findings provide insight into how VvRraA proteins can regulate VvRNase E action on its substrate RNA in V. vulnificus. In addition, based on structural and functional comparison of RraA homologs, we suggest that hexameric assembly of RraA homologs may well be required for their action on RNase E-like proteins. PMID- 29261779 TI - Median regression spline modeling of longitudinal FEV1 measurements in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients. AB - RATIONALE: Clinical phenotyping, therapeutic investigations as well as genomic, airway secretion metabolomic and metagenomic investigations can benefit from robust, nonlinear modeling of FEV1 in individual subjects. We demonstrate the utility of measuring FEV1 dynamics in representative cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) populations. METHODS: Individual FEV1 data from CF and COPD subjects were modeled by estimating median regression splines and their predicted first and second derivatives. Classes were created from variables that capture the dynamics of these curves in both cohorts. RESULTS: Nine FEV1 dynamic variables were identified from the splines and their predicted derivatives in individuals with CF (n = 177) and COPD (n = 374). Three FEV1 dynamic classes (i.e. stable, intermediate and hypervariable) were generated and described using these variables from both cohorts. In the CF cohort, the FEV1 hypervariable class (HV) was associated with a clinically unstable, female dominated phenotypes while stable FEV1 class (S) individuals were highly associated with the male-dominated milder clinical phenotype. In the COPD cohort, associations were found between the FEV1 dynamic classes, the COPD GOLD grades, with exacerbation frequency and symptoms. CONCLUSION: Nonlinear modeling of FEV1 with splines provides new insights and is useful in characterizing CF and COPD clinical phenotypes. PMID- 29261780 TI - Ectomycorrhizal fungal communities in endangered Pinus amamiana forests. AB - Interactions between trees and ectomycorrhizal (ECM) fungi are critical for the growth and survival of both partners. However, ECM symbiosis in endangered trees has hardly been explored, complicating conservation efforts. Here, we evaluated resident ECM roots and soil spore banks of ECM fungi from endangered Pinus amamiana forests on Yakushima and Tanegashima Islands, Kagoshima Prefecture, Japan. Soil samples were collected from remaining four forests in the two islands. The resident ECM roots in soil samples were subjected to molecular identification. Soil spore banks of ECM fungi were analyzed via bioassays using a range of host seedlings (P. amamiana, P. parviflora, P. densiflora and Castanopsis sieboldii) for 6-8 months. In all remaining P. amamiana forests, we discovered a new Rhizopogon species (Rhizopogon sp.1), the sequence of which has no match amoung numerous Rhizopogon sequences deposited in the international sequence database. Host identification of the resident ECM roots confirmed that Rhizopogon sp.1 was associated only with P. amamiana. Rhizopogon sp.1 was far more dominant in soil spore banks than in resident ECM roots, and its presence was confirmed in nearly all soil samples examined across the major remaining populations. While Rhizopogon sp.1 did not completely lose compatibility to other pine species, its infection rate in the bioassays was highest in the original host, P. amamiana, the performance of which was improved by the infection. These results indicate that Rhizopogon sp.1 is very likely to have a close ecological relationship with endangered P. amamiana, probably due to a long co-evolutionary period on isolated islands, and to play the key role in seedling establishment after disturbance. We may need to identify and utilize such key ECM fungi to conserve endangered trees practically. PMID- 29261781 TI - Accurate and fast feature selection workflow for high-dimensional omics data. AB - We are moving into the age of 'Big Data' in biomedical research and bioinformatics. This trend could be encapsulated in this simple formula: D = S * F, where the volume of data generated (D) increases in both dimensions: the number of samples (S) and the number of sample features (F). Frequently, a typical omics classification includes redundant and irrelevant features (e.g. genes or proteins) that can result in long computation times; decrease of the model performance and the selection of suboptimal features (genes and proteins) after the classification/regression step. Multiple algorithms and reviews has been published to describe all the existing methods for feature selection, their strengths and weakness. However, the selection of the correct FS algorithm and strategy constitutes an enormous challenge. Despite the number and diversity of algorithms available, the proper choice of an approach for facing a specific problem often falls in a 'grey zone'. In this study, we select a subset of FS methods to develop an efficient workflow and an R package for bioinformatics machine learning problems. We cover relevant issues concerning FS, ranging from domain's problems to algorithm solutions and computational tools. Finally, we use seven different proteomics and gene expression datasets to evaluate the workflow and guide the FS process. PMID- 29261782 TI - Validation of a smartphone app to map social networks of proximity. AB - Social network analysis is a prominent approach to investigate interpersonal relationships. Most studies use self-report data to quantify the connections between participants and construct social networks. In recent years smartphones have been used as an alternative to map networks by assessing the proximity between participants based on Bluetooth and GPS data. While most studies have handed out specially programmed smartphones to study participants, we developed an application for iOS and Android to collect Bluetooth data from participants' own smartphones. In this study, we compared the networks estimated with the smartphone app to those obtained from sociometric badges and self-report data. Participants (n = 21) installed the app on their phone and wore a sociometric badge during office hours. Proximity data was collected for 4 weeks. A contingency table revealed a significant association between proximity data (phi = 0.17, p<0.0001), but the marginal odds were higher for the app (8.6%) than for the badges (1.3%), indicating that dyads were more often detected by the app. We then compared the networks that were estimated using the proximity and self report data. All three networks were significantly correlated, although the correlation with self-reported data was lower for the app (rho = 0.25) than for badges (rho = 0.67). The scanning rates of the app varied considerably between devices and was lower on iOS than on Android. The association between the app and the badges increased when the network was estimated between participants whose app recorded more regularly. These findings suggest that the accuracy of proximity networks can be further improved by reducing missing data and restricting the interpersonal distance at which interactions are detected. PMID- 29261784 TI - Correction: Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats. AB - [This corrects the article DOI: 10.1371/journal.pone.0181122.]. PMID- 29261783 TI - Somatic instability of the expanded GAA repeats in Friedreich's ataxia. AB - Friedreich's ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA repeats in intron 1. FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression. Herein, we determined the extent of somatic instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate differences in the lengths of the expanded GAAs among different tissues, with significantly longer GAA tracts detected in heart and pancreas than in other tissues. The expansion bias detected in heart and pancreas may contribute to disease onset and progression, making the mechanism of somatic instability an important target for therapy. Additionally, we detected significant differences in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16 FRDA patients, with longer GAA tracts present in the lymphocytes. This result urges caution in direct comparisons of data obtained in these frequently used FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7-9 years and demonstrated progressive expansions of the GAAs with maximum gain of approximately 9 repeats per year. Continuous GAA expansions throughout the patient's lifespan, as observed in FRDA lymphocytes, should be considered in clinical trial designs and data interpretation. PMID- 29261785 TI - Correction: MicroRNA Profiling of the Effect of the Heptapeptide Angiotensin-(1 7) in A549 Lung Tumor Cells Reveals a Role for miRNA149-3p in Cellular Migration Processes. AB - [This corrects the article DOI: 10.1371/journal.pone.0162094.]. PMID- 29261788 TI - Correction: Diabetes risks and outcomes in chronic obstructive pulmonary disease patients: Two nationwide population-based retrospective cohort studies. AB - [This corrects the article DOI: 10.1371/journal.pone.0181815.]. PMID- 29261786 TI - RESUME: Turning an SWI acquisition into a fast qMRI protocol. AB - Susceptibility Weighted Imaging (SWI) is a common MRI technique that exploits the magnetic susceptibility differences between the tissues to provide valuable image contrasts, both in research and clinical contexts. However, despite its increased clinical use, SWI is not intrinsically suitable for quantitation purposes. Conversely, quantitative Magnetic Resonance Imaging (qMRI) provides a way to disentangle the sources of common MR image contrasts (e.g. proton density, T1, etc.) and to measure physical parameters intrinsically related to tissue microstructure. Unfortunately, the poor signal-to-noise ratio and resolution, coupled with the long imaging time of most qMRI strategies, have hindered the integration of quantitative imaging into clinical protocols. Here we present the RElaxometry and SUsceptibility Mapping Expedient (RESUME) to show that the standard acquisition leading to a clinical SWI dataset can be easily turned into a thorough qMRI protocol at the cost of a further 50% of the SWI scan time. The R1, [Formula: see text], proton density and magnetic susceptibility maps provided by the RESUME scheme alongside the SWI reconstruction exhibit high reproducibility and accuracy, and a submillimeter resolution is proven to be compatible with a total scan time of 7 minutes. PMID- 29261787 TI - A review of the early stages and host plants of the genera Eumerus and Merodon (Diptera: Syrphidae), with new data on four species. AB - The genera Eumerus and Merodon (Diptera: Syrphidae) have a high taxonomic diversity (300+ species altogether), but life histories of most species are unknown. In addition, these hoverfly genera are recognised to be pests (ornamental plants and vegetable crops). In this paper, early stages of four hoverfly species are described, Eumerus hungaricus Szilady, 1940, Eumerus nudus Loew, 1848 and Merodon geniculatus Strobl, 1909, from Spain, and Eumerus strigatus Walker, 1859, from California, USA. Larvae of E. nudus were obtained from swollen roots of Asphodelus cerasiferus J. Gay. Larvae of E. hungaricus were found in bulbs of Narcissus confusus Pugsley. The host plant of the examined specimen of Eumerus strigatus is unknown. Larvae of M. geniculatus were reared from bulbs of different species of Narcissus L. Scanning electron microscope imaging was used to study and illustrate the anterior respiratory processes, pupal spiracles and posterior respiratory processes of the new early stages. A compilation of all available information on the early stages and host plants of Eumerus (21 spp.) and Merodon (15 spp) is provided, as well as an identification key to all known larvae/puparia of these genera. Eumerus elavarensis Seguy, 1961 is proposed as a new synonym of E. hungaricus and first data of this species are reported from Austria, Bulgaria, Spain and Turkey. In Eumerus, larvae are alleged to rely on the previous presence of decay organisms, but in the larvae of E. nudus the sclerotisation and size of the mandibular hooks suggest that this larva can generate decay from intact plant tissue. PMID- 29261789 TI - Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers. AB - BACKGROUND: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues. METHODS: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors. RESULT: Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients. CONCLUSION: This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease. PMID- 29261790 TI - Comparison of tolerance to sunlight between spatially distant and genetically different strains of Lymantria dispar nucleopolyhedrovirus. AB - Baculoviruses are a family of insect-specific pathogenic viruses can persist outside for long periods through the formation of occlusion bodies. In spite of this ability, the UV of sunlight is an essential factor that limits the survival of baculoviruses outside the host. In the current study, we compared the UV tolerance of two strains of Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV), which were isolated in spatially different regions (LdMNPV-27/0 in Western Siberia (Russia) and LdMNPV-45/0 in North America (USA)) and dramatically differ in their potency. We exposed the studied strains to sunlight in an open area for 0.25, 0.5, 1, and 2 hours and later perorally inoculated host larvae with the same doses of virus (5x105) and with doses leading to same effect (LD90). We observed that strain LdMNPV-45/0, which previously showed high virulence against L. dispar larvae, was more sensitive to UV irradiation (estimated as the relative rate of inactivation (r, h -1) and as the half-life of the virus (tau1/2, h)) compared to LdMNPV-27/0. Exposure to sunlight induced a significant delay of LdMNPV-45/0-induced pathogenesis already after 0.25 h of sunlight exposure, while for LdMNPV-27/0 this delay was occurred only after 2 h exposure in spite of used concentrations. We also compared the sequences of the main structural proteins of the studied strains as UV light contributes not only to genome damage in viruses but also to structural protein damage. The most prominent genetic difference between the structural proteins of the strains was related to the loss of the virus enhancin factor-1 (vef-1) gene in the LdMNPV 27/0 strain. Thus initially highly potent viral strain (such as LdMNPV-45/0) is not recommend to use in the regions (or forest stand density) with high UV load. The role of virus enhancin factor-1 in baculovirus tolerance to UV needs for following studies. PMID- 29261791 TI - Distribution of Legionella and bacterial community composition among regionally diverse US cooling towers. AB - Cooling towers (CTs) are a leading source of outbreaks of Legionnaires' disease (LD), a severe form of pneumonia caused by inhalation of aerosols containing Legionella bacteria. Accordingly, proper maintenance of CTs is vital for the prevention of LD. The aim of this study was to determine the distribution of Legionella in a subset of regionally diverse US CTs and characterize the associated microbial communities. Between July and September of 2016, we obtained aliquots from water samples collected for routine Legionella testing from 196 CTs located in eight of the nine continental US climate regions. After screening for Legionella by PCR, positive samples were cultured and the resulting Legionella isolates were further characterized. Overall, 84% (164) were PCR-positive, including samples from every region studied. Of the PCR-positive samples, Legionella spp were isolated from 47% (78), L. pneumophila was isolated from 32% (53), and L. pneumophila serogroup 1 (Lp1) was isolated from 24% (40). Overall, 144 unique Legionella isolates were identified; 53% (76) of these were Legionella pneumophila. Of the 76 L. pneumophila isolates, 51% (39) were Lp1. Legionella were isolated from CTs in seven of the eight US regions examined. 16S rRNA amplicon sequencing was used to compare the bacterial communities of CT waters with and without detectable Legionella as well as the microbiomes of waters from different climate regions. Interestingly, the microbial communities were homogenous across climate regions. When a subset of seven CTs sampled in April and July were compared, there was no association with changes in corresponding CT microbiomes over time in the samples that became culture-positive for Legionella. Legionella species and Lp1 were detected frequently among the samples examined in this first large-scale study of Legionella in US CTs. Our findings highlight that, under the right conditions, there is the potential for CT-related LD outbreaks to occur throughout the US. PMID- 29261792 TI - Prevalence and risk factors for postoperative stress-related cardiomyopathy in adults. AB - Stress-related cardiomyopathy can develop during the postoperative period due to surgery-related stress factors. However, the prevalence and risk factors for this condition are not yet known. During a retrospective, observational study, patients older than 19 years who underwent procedures from January 2011 to December 2015 at a tertiary hospital were included. The main aim was to identify the prevalence and related risk factors for postoperative stress-related cardiomyopathy. To estimate the incidence per risk factor, univariate and multivariate Poisson regression analyses were performed. During the 5-year period, 95,840 patients older than 19 years underwent 125,314 procedures, and the prevalence of postoperative stress-related cardiomyopathy was 17.74 per 100,000 (95% confidence interval, 9.31-26.17), with an in-hospital mortality of 23.5%. As a result, three risk factors were significantly associated: preoperative American Society of Anesthesiologists classification (incidence rate ratio, 5.901 for American Society of Anesthesiologists class 1-2 [ref] versus 3-6; 95% confidence interval,1.289-27.002; P = 0.022); preoperative body mass index (incidence rate ratio, 1.247 for increases of 18.5 [ref] to 30; 95% confidence interval, 1.067 1.458; P = 0.006); and preoperative serum sodium (incidence rate ratio, 0.830 for each increase of 10 mmol/L from 130; 95% confidence interval, 0.731-0.942; P = 0.004). The incidence rate ratio for age for each increase of 10 years from 50 years was 1.057, but it was not statistically significant (P = 0.064). Our study found that the prevalence of postoperative stress-related cardiomyopathy was 17.74 patients per 100,000 adult patients over the course of 5 years, with four cases of in-hospital mortality. Factors that increased the risk of postoperative stress-related cardiomyopathy included higher American Society of Anesthesiologists class (>=3), preoperative hyponatremia, and higher preoperative body mass index. PMID- 29261794 TI - Correction: Metric-based vs peer-reviewed evaluation of a research output: Lesson learnt from UK's national research assessment exercise. AB - [This corrects the article DOI: 10.1371/journal.pone.0179722.]. PMID- 29261793 TI - Association between serum aluminum levels and cardiothoracic ratio in patients on chronic hemodialysis. AB - The cardiothoracic ratio (CTR) and serum aluminum levels are both associated with mortality in hemodialysis patients. However, limited data regarding the association between serum aluminum levels and the CTR have been published to date. Therefore, we aimed to elucidate this association in patients on chronic hemodialysis (CHD). We investigated the association between the serum aluminum level and the CTR in CHD in a retrospective cross-sectional study of 547 Taiwanese patients on CHD. The mean age of patients was 62.5+/-13.2 years, with a mean hemodialysis time of 7.1+/-5.2 years. Among the patients, 36.9% were diabetic and 47.9% were male. After natural logarithmic transformation (ln(aluminum)), the serum aluminum level exhibited an independent and linear relationship with the CTR (beta: 1.40, 95% confidence interval (CI), 0.6-2.2). A high serum aluminum level (>=6 ng/dL) was significantly associated with a CTR >0.5 in the crude analysis (odds ratio (OR): 2.15, 95% CI, 1.52-3.04) and remained significant after multivariable adjustment (OR: 2.45, 95% CI, 1.63 3.67). Moreover, the ln(aluminum) value was significantly associated with a CTR >0.5 (OR: 1.71, 95%CI, 1.28-2.29) in multivariable analysis, indicating a dose effect of aluminum on cardiomegaly. In conclusion, the serum aluminum level was independently associated with cardiac remodeling (elevated CTR) in patients on CHD. PMID- 29261795 TI - Ecological structure and function in a restored versus natural salt marsh. AB - Habitat reconstruction is commonly employed to restore degraded estuarine habitats and lost ecological functions. In this study, we use a combination of stable isotope analyses and macrofauna community analysis to compare the ecological structure and function between a recently constructed Spartina alterniflora salt marsh and a natural reference habitat over a 2-year period. The restored marsh was successful in providing habitat for economically and ecologically important macrofauna taxa; supporting similar or greater density, biomass, and species richness to the natural reference during all but one sampling period. Stable isotope analyses revealed that communities from the natural and the restored marshes relied on a similar diversity of food resources and that decapods had similar trophic levels. However, some generalist consumers (Palaemonetes spp. and Penaeus aztecus) were more 13C-enriched in the natural marsh, indicating a greater use of macrophyte derived organic matter relative to restored marsh counterparts. This difference was attributed to the higher quantities of macrophyte detritus and organic carbon in natural marsh sediments. Reduced marsh flooding frequency was associated with a reduction in macrofaunal biomass and decapod trophic levels. The restored marsh edge occurred at lower elevations than natural marsh edge, apparently due to reduced fetch and wind-wave exposure provided by the protective berm structures. The lower elevation of the restored marsh edge mitigated negative impacts in sampling periods with low tidal elevations that affected the natural marsh. The results of this study highlight the importance of considering sediment characteristics and elevation in salt marsh constructions. PMID- 29261796 TI - High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features. AB - BACKGROUND: High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. METHODS: Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test. RESULTS: Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3 57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2). CONCLUSION: In patients with mRCC with sarcomatoid features, use of HD IL-2 was associated with a modest ORR and a higher survival compared to historical controls (patients with mRCC and sarcomatoid features). Thus, HD IL-2 may have a role in treating selected patients with mRCC with sarcomatoid features. PMID- 29261797 TI - Correction: Identifying Optimal Vaccination Strategies for Serogroup A Neisseria meningitidis Conjugate Vaccine in the African Meningitis Belt. AB - [This corrects the article DOI: 10.1371/journal.pone.0063605.]. PMID- 29261799 TI - Correction: De novo assembly and analysis of the transcriptome of Rumex patientia L. during cold stress. AB - [This corrects the article DOI: 10.1371/journal.pone.0186470.]. PMID- 29261798 TI - Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: A systematic review and meta-analysis of preclinical studies. AB - INTRODUCTION: Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating neurologic condition with high mortality rates and long-term complications for surviving infants. Mesenchymal stem/stromal cells (MSCs) have emerged as novel therapeutic agents with promising results in experimental studies of HIE. The purpose of this study is to (a) methodically review the current preclinical literature describing MSC therapy in animal models of HIE, (b) quantify the effect size in regards to functional neurologic outcome, and (c) identify research gaps/limitations that should be addressed prior to future preclinical and clinical studies. METHODS: Adhering to the Systematic Review Protocol for Animal Intervention Studies, a systematic search of English articles was performed. Eligible studies were identified and data regarding study characteristics and outcome measures was extracted. After quality assessment, meta-analysis and meta-regression were performed to generate random effect size using standardized mean difference (SMD). Funnel plots and Egger's tests were utilized to evaluate for the presence of publication bias. RESULTS: A total of 19 studies met inclusion in the current systematic review. Meta-analysis revealed that MSCs have a significant positive effect on neurobehavioral outcome following HIE injury. Sensorimotor function was improved by 2.25 SMD (95% CI; 2.04-2.46) in cylinder rearing and 2.97 SMD (95% CI; 2.56-3.38) in rotarod. Likewise, cognitive function was improved by 2.76 SMD (95% CI; 2.53-2.98) on the water maze and 2.97 SMD (95% CI; 2.58-3.35) in object recognition. Stratification demonstrated an increased effect size depending on various study characteristics. CONCLUSIONS: Overall, these results suggest a promising role for MSCs in preclinical studies of HIE. MSC treatment demonstrates improved functional outcomes that are encouraging for future translational studies. While risk of bias and heterogeneity limited the strength of our meta-analysis, our results are consistent with those seen in this field of research. PMID- 29261801 TI - Correction: Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway. AB - [This corrects the article DOI: 10.1371/journal.pone.0180244.]. PMID- 29261800 TI - Species-specific functions of Epstein-Barr virus nuclear antigen 2 (EBNA2) reveal dual roles for initiation and maintenance of B cell immortalization. AB - Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCV) from non-human primates infect B cells, transform their growth to facilitate life-long viral persistence in the host, and contribute to B cell oncogenesis. Co-evolution of LCV with their primate hosts has led to species-specificity so that LCVs preferentially immortalize B cells from their natural host in vitro. We investigated whether the master regulator of transcription, EBV nuclear antigen 2 (EBNA2), is involved in LCV species-specificity. Using recombinant EBVs, we show that EBNA2 orthologues of LCV isolated from chimpanzees, baboons, cynomolgus or rhesus macaques cannot replace EBV EBNA2 for the immortalization of human B cells. Thus, LCV species-specificity is functionally linked to viral proteins expressed during latent, growth-transforming infection. In addition, we identified three independent domains within EBNA2 that act through species specific mechanisms. Importantly, the EBNA2 orthologues and species-specific EBNA2 domains separate unique roles for EBNA2 in the initiation of B cell immortalization from those responsible for maintaining the immortalized state. Investigating LCV species-specificity provides a novel approach to identify critical steps underlying EBV-induced B cell growth transformation, persistent infection, and oncogenesis. PMID- 29261803 TI - Correction: Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway. AB - [This corrects the article DOI: 10.1371/journal.pone.0187294.]. PMID- 29261802 TI - Two classes of protective antibodies against Pseudorabies virus variant glycoprotein B: Implications for vaccine design. AB - Pseudorabies virus (PRV) belongs to the Herpesviridae family, and is an important veterinary pathogen. Highly pathogenic PRV variants have caused severe epidemics in China since 2011, causing huge economic losses. To tackle the epidemics, we identified a panel of mouse monoclonal antibodies (mAbs) against PRV glycoprotein B (gB) that effectively block PRV infection. Among these 15 mAbs, fourteen of them block PRV entry in a complement-dependent manner. The remaining one, 1H1 mAb, however can directly neutralize the virus independent of complement and displays broad-spectrum neutralizing activities. We further determined the crystal structure of PRV gB and mapped the epitopes of these antibodies on the structure. Interestingly, all the complement-dependent neutralizing antibodies bind gB at the crown region (domain IV). In contrast, the epitope of 1H1 mAb is located at the bottom of domain I, which includes the fusion loops, indicating 1H1 mAb might neutralize the virus by interfering with the membrane fusion process. Our studies demonstrate that gB contains multiple B-cell epitopes in its crown and base regions and that antibodies targeting different epitopes block virus infection through different mechanisms. These findings would provide important clues for antiviral drug design and vaccine development. PMID- 29261804 TI - Correction: Reconstructing Asian faunal introductions to eastern Africa from multi-proxy biomolecular and archaeological datasets. AB - [This corrects the article DOI: 10.1371/journal.pone.0182565.]. PMID- 29261805 TI - Species traits modify the species-area relationship in ground-beetle (Coleoptera: Carabidae) assemblages on islands in a boreal lake. AB - Life-history traits influence colonization, persistence, and extinction of species on islands and are important aspects of theories predicting the geographical distribution and evolution of species. We used data collected from a large freshwater lake (1,413 km2) in central Canada to test the effects of island area and isolation on species richness and abundance of carabid beetles as a function of body size, wing length, and breeding season. A total of 10,018 individual beetles from 37 species were collected during the frost-free period of 2013 using transects of pitfall traps on 30 forested islands ranging in area from 0.2 to 980.7 ha. Life-history traits improved the predictive ability and significantly modified the shape of species-area and abundance-area curves. Abundance and richness of small-bodied (< 13.9 mm), macropterous (winged), and spring-breeding species decreased with island area and increased with isolation. In contrast, richness and abundance of larger-bodied (> 14.0 mm) and flightless species increased with area, but not isolation. Body size of female Carabus taedatus Fabricius, the largest-bodied species, was positively related to island area, while body size on the adjacent mainland was most similar to that on smaller islands. Overall, species with large body size and low dispersal ability, as indicated by flightlessness, were most sensitive to reductions in area. We suggest that large-bodied, flightless species are rare on small islands because habitat is less suitable for them and immigration rates are lower because they depend on freshwater drift for dispersal to islands. PMID- 29261806 TI - Main and epistatic QTL analyses for Sclerotinia Head Rot resistance in sunflower. AB - Sclerotinia Head Rot (SHR), a disease caused by Sclerotinia sclerotiorum, is one of the most limiting factors in sunflower production. In this study, we identified genomic loci associated with resistance to SHR to support the development of assisted breeding strategies. We genotyped 114 Recombinant Inbred Lines (RILs) along with their parental lines (PAC2 -partially resistant-and RHA266 -susceptible-) by using a 384 single nucleotide polymorphism (SNP) Illumina Oligo Pool Assay to saturate a sunflower genetic map. Subsequently, we tested these lines for SHR resistance using assisted inoculations with S. sclerotiorum ascospores. We also conducted a randomized complete-block assays with three replicates to visually score disease incidence (DI), disease severity (DS), disease intensity (DInt) and incubation period (IP) through four field trials (2010-2014). We finally assessed main effect quantitative trait loci (M QTLs) and epistatic QTLs (E-QTLs) by composite interval mapping (CIM) and mixed model-based composite interval mapping (MCIM), respectively. As a result of this study, the improved map incorporates 61 new SNPs over candidate genes. We detected a broad range of narrow sense heritability (h2) values (1.86-59.9%) as well as 36 M-QTLs and 13 E-QTLs along 14 linkage groups (LGs). On LG1, LG10, and LG15, we repeatedly detected QTLs across field trials; which emphasizes their putative effectiveness against SHR. In all selected variables, most of the identified QTLs showed high determination coefficients, associated with moderate to high heritability values. Using markers shared with previous Sclerotinia resistance studies, we compared the QTL locations in LG1, LG2, LG8, LG10, LG11, LG15 and LG16. This study constitutes the largest report of QTLs for SHR resistance in sunflower. Further studies focusing on the regions in LG1, LG10, and LG15 harboring the detected QTLs are necessary to identify causal alleles and contribute to unraveling the complex genetic basis governing the resistance. PMID- 29261808 TI - Correction: Perinatal outcomes after induced termination of pregnancy by methods: A nationwide register-based study of first births in Finland 1996-2013. AB - [This corrects the article DOI: 10.1371/journal.pone.0184078.]. PMID- 29261807 TI - Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein. AB - RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics. A subsequent mass spectrometric analysis of L protein pulldowns from infected human cells revealed a comprehensive network of interacting host proteins. The obtained LCMV L protein interactome was bioinformatically integrated with known host protein interactors of RdRps from other RNA viruses, emphasizing interconnected modules of human proteins. Functional characterization of selected interactors highlighted proviral (DDX3X) as well as antiviral (NKRF, TRIM21) host factors. To corroborate these findings, we infected Trim21-/- mice with LCMV and found impaired virus control in chronic infection. These results provide insights into the complex interactions of the arenavirus LCMV and other viral RdRps with the host proteome and contribute to a better molecular understanding of how chronic viruses interact with their host. PMID- 29261809 TI - Correction: Diffusion weighted imaging in patients with rectal cancer: Comparison between Gaussian and non-Gaussian models. AB - [This corrects the article DOI: 10.1371/journal.pone.0184197.]. PMID- 29261811 TI - Correction: Macrophages, but not neutrophils, are critical for proliferation of Burkholderia cenocepacia and ensuing host-damaging inflammation. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006437.]. PMID- 29261810 TI - Whole genome microarray analysis of neural progenitor C17.2 cells during differentiation and validation of 30 neural mRNA biomarkers for estimation of developmental neurotoxicity. AB - Despite its high relevance, developmental neurotoxicity (DNT) is one of the least studied forms of toxicity. Current guidelines for DNT testing are based on in vivo testing and they require extensive resources. Transcriptomic approaches using relevant in vitro models have been suggested as a useful tool for identifying possible DNT-generating compounds. In this study, we performed whole genome microarray analysis on the murine progenitor cell line C17.2 following 5 and 10 days of differentiation. We identified 30 genes that are strongly associated with neural differentiation. The C17.2 cell line can be differentiated into a co-culture of both neurons and neuroglial cells, giving a more relevant picture of the brain than using neuronal cells alone. Among the most highly upregulated genes were genes involved in neurogenesis (CHRDL1), axonal guidance (BMP4), neuronal connectivity (PLXDC2), axonogenesis (RTN4R) and astrocyte differentiation (S100B). The 30 biomarkers were further validated by exposure to non-cytotoxic concentrations of two DNT-inducing compounds (valproic acid and methylmercury) and one neurotoxic chemical possessing a possible DNT activity (acrylamide). Twenty-eight of the 30 biomarkers were altered by at least one of the neurotoxic substances, proving the importance of these biomarkers during differentiation. These results suggest that gene expression profiling using a predefined set of biomarkers could be used as a sensitive tool for initial DNT screening of chemicals. Using a predefined set of mRNA biomarkers, instead of the whole genome, makes this model affordable and high-throughput. The use of such models could help speed up the initial screening of substances, possibly indicating alerts that need to be further studied in more sophisticated models. PMID- 29261812 TI - Correction: Group elicitations yield more consistent, yet more uncertain experts in understanding risks to ecosystem services in New Zealand bays. AB - [This corrects the article DOI: 10.1371/journal.pone.0182233.]. PMID- 29261813 TI - Correction: Sanitation practices and perceptions in Kakuma refugee camp, Kenya: Comparing the status quo with a novel service-based approach. AB - [This corrects the article DOI: 10.1371/journal.pone.0180864.]. PMID- 29261814 TI - Correction: Parametric studies of metabolic cooperativity in Escherichia coli colonies: Strain and geometric confinement effects. AB - [This corrects the article DOI: 10.1371/journal.pone.0182570.]. PMID- 29261816 TI - Improving Quality of Care for Seriously Ill Patients: Opportunities for Hospitalists. AB - As the shift to value-based payment accelerates, hospitals are under increasing pressure to deliver high-quality, efficient services. Palliative care approaches improve quality of life and family well-being, and in doing so, reduce resource utilization and costs. Hospitalists frequently provide palliative care interventions to their patients, including pain and symptom management and engaging in conversations with patients and families about the realities of their illness and treatment plans that align with their priorities. Hospitalists are ideally positioned to identify patients who could most benefit from palliative care approaches and often refer the most complex cases to specialty palliative care teams. Though hospitalists are frequently called upon to provide palliative care, most lack formal training in these skills, which have not typically been included in medical education. Additional training in communication, safe and effective symptom management, and other palliative care knowledge and skills are available in both in-person and online formats. PMID- 29261815 TI - Knockdown of myeloid cell hypoxia-inducible factor-1alpha ameliorates the acute pathology in DSS-induced colitis. AB - Inflammation and hypoxia are hallmarks of inflammatory bowel disease. Low oxygen levels activate hypoxia-inducible factors as central transcriptional regulators of cellular responses to hypoxia, particularly in myeloid cells where hypoxia inducible factors control immune cell function and survival. Still, the role of myeloid hypoxia-inducible factor-1 during inflammatory bowel disease remains poorly defined. We therefore investigated the role of hypoxia-inducible factor-1 for myeloid cell function and immune response during colitis. Experimental colitis was induced by administration of 2.5% dextran sulfate sodium to mice with a conditional knockout of hypoxia-inducible factor-1alpha in myeloid cells and their wild type siblings. Murine colon tissue was examined by histologic analysis, immunohistochemistry, and quantitative polymerase chain reaction. Induction of experimental colitis increased levels of hypoxia and accumulation of hypoxia-inducible factor-1alpha positive cells in colon tissue of both treated groups. Myeloid hypoxia-inducible factor-1alpha knockout reduced weight loss and disease activity index when compared to wild type mice. Knockout mice displayed less infiltration of macrophages into intestinal mucosa and reduced mRNA expression of markers for dendritic cells and interleukin-17 secreting T helper cells. Expression of inflammatory and anti-inflammatory cytokines also showed a reduced and delayed induction in myeloid hypoxia-inducible factor-1alpha knockout mice. Our results show a disease promoting role of myeloid hypoxia-inducible factor-1 during intestinal inflammation. This might result from a hypoxia inducible factor-1 dependent increase in pro-inflammatory interleukin-17 secreting T helper cells in the absence of obvious changes in regulatory T cells. In contrast, knockout mice appear to shift the balance to anti-inflammatory signals and cells resulting in milder intestinal inflammation. PMID- 29261817 TI - Near and Far. AB - BACKGROUND: OBJECTIVE: DESIGN, SETTING, PATIENTS: INTERVENTION: MEASUREMENTS: CONCLUSIONS: PMID- 29261818 TI - Update in Hospital Palliative Care: Symptom Management, Communication, Caregiver Outcomes, and Moral Distress. AB - BACKGROUND: Updated knowledge of the palliative care (PC) literature is needed to maintain competency and best address the PC needs of hospitalized patients. We critiqued the recent PC literature with the highest potential to impact hospital practice. METHODS: We reviewed articles published between January 2016 and December 2016, which were identified through a handsearch of leading journals and a MEDLINE search. The final 9 articles selected were determined by consensus based on scientific rigor, relevance to hospital medicine, and impact on practice. RESULTS: Key findings include the following: scheduled antipsychotics were inferior to a placebo for nonterminal delirium; a low-dose morphine was superior to a weak opioid for moderate cancer pain; methadone as a coanalgesic improved high-intensity cancer pain; many hospitalized patients on comfort care still receive antimicrobials; video decision aids improved the rates of advance care planning (ACP) and hospice use and decreased costs; standardized, PC-led intervention did not improve psychological outcomes in families of patients with a chronic critical illness; caregivers of patients surviving a prolonged critical illness experienced high and persistent rates of depression; people with non normative sexuality or gender faced additional stressors with partner loss; and physician trainees experienced significant moral distress with futile treatments. CONCLUSIONS: Recent research provides important guidance for clinicians caring for hospitalized patients with serious illnesses, including symptom management, ACP, moral distress, and outcomes of critical illness. PMID- 29261821 TI - A Call to Action for Treatment of Comorbid Tobacco and Alcohol Dependence. PMID- 29261820 TI - A Method for Attributing Patient-Level Metrics to Rotating Providers in an Inpatient Setting. AB - BACKGROUND: Individual provider performance drives group metrics, and increasingly, individual providers are held accountable for these metrics. However, appropriate attribution can be challenging, particularly when multiple providers care for a single patient. OBJECTIVE: We sought to develop and operationalize individual provider scorecards that fairly attribute patient-level metrics, such as length of stay and patient satisfaction, to individual hospitalists involved in each patient's care. DESIGN: Using patients cared for by hospitalists from July 2010 through June 2014, we linked billing data across each hospitalization to assign "ownership" of patient care based on the type, timing, and number of charges associated with each hospitalization (referred to as "provider day weighted "). These metrics were presented to providers via a dashboard that was updated quarterly with their performance (relative to their peers). For the purposes of this article, we compared the method we used to the traditional method of attribution, in which an entire hospitalization is attributed to 1 provider, based on the attending of record as labeled in the administrative data. RESULTS: Provider performance in the 2 methods was concordant 56% to 75% of the time for top half versus bottom half performance (which would be expected to occur by chance 50% of the time). While provider percentile differences between the 2 methods were modest for most providers, there were some providers for whom the methods yielded dramatically different results for 1 or more metrics. CONCLUSION: We found potentially meaningful discrepancies in how well providers scored (relative to their peers) based on the method used for attribution. We demonstrate that it is possible to generate meaningful provider-level metrics from administrative data by using billing data even when multiple providers care for 1 patient over the course of a hospitalization. PMID- 29261819 TI - Inpatient Portals for Hospitalized Patients and Caregivers: A Systematic Review. AB - Patient portals, web-based personal health records linked to electronic health records (EHRs), provide patients access to their healthcare information and facilitate communication with providers. Growing evidence supports portal use in ambulatory settings; however, only recently have portals been used with hospitalized patients. Our objective was to review the literature evaluating the design, use, and impact of inpatient portals, which are patient portals designed to give hospitalized patients and caregivers inpatient EHR clinical information for the purpose of engaging them in hospital care. Literature was reviewed from 2006 to 2017 in PubMed, Web of Science, CINALPlus, Cochrane, and Scopus to identify English language studies evaluating patient portals, engagement, and inpatient care. Data were analyzed considering the following 3 themes: inpatient portal design, use and usability, and impact. Of 731 studies, 17 were included, 9 of which were published after 2015. Most studies were qualitative with small samples focusing on inpatient portal design; 1 nonrandomized trial was identified. Studies described hospitalized patients' and caregivers' information needs and design recommendations. Most patient and caregiver participants in included studies were interested in using an inpatient portal, used it when offered, and found it easy to use and/or useful. Evidence supporting the role of inpatient portals in improving patient and caregiver engagement, knowledge, communication, and care quality and safety is limited. Included studies indicated providers had concerns about using inpatient portals; however, the extent to which these concerns have been realized remains unclear. Inpatient portal research is emerging. Further investigation is needed to optimally design inpatient portals to maximize potential benefits for hospitalized patients and caregivers while minimizing unintended consequences for healthcare teams. PMID- 29261822 TI - Structural Competency and Psychiatry. PMID- 29261823 TI - Association of Surgical Volume With Perioperative Outcomes for Esophagomyotomy for Esophageal Achalasia. PMID- 29261825 TI - Age at Diagnosis as a Relative Contraindication for Intervention in Facial Nonmelanoma Skin Cancer. PMID- 29261824 TI - Effect of Varenicline Combined With Medical Management on Alcohol Use Disorder With Comorbid Cigarette Smoking: A Randomized Clinical Trial. AB - Importance: Individuals with alcohol use disorder have high rates of cigarette smoking. Varenicline tartrate, an approved treatment for smoking cessation, may reduce both drinking and smoking. Objectives: To test the efficacy of varenicline with medical management for patients with alcohol use disorder and comorbid smoking seeking alcohol treatment, and to evaluate the secondary effects on smoking abstinence. Design, Setting, and Participants: This phase 2, randomized, double-blind, parallel group, placebo-controlled trial was conducted at 2 outpatient clinics from September 19, 2012, to August 31, 2015. Eligible participants met alcohol-dependence criteria and reported heavy drinking (>=5 drinks for men and >=4 drinks for women) 2 or more times per week and smoking 2 or more times per week; 131 participants were randomized to either varenicline or placebo stratified by sex and site. All analyses were of the intention-to-treat type. Data analysis was conducted from February 5, 2016, to September 29, 2017. Interventions: Varenicline tartrate, 1 mg twice daily, and matching placebo pills for 16 weeks. Medical management emphasized medication adherence for 4 weeks followed by support for changing drinking. Main Outcomes and Measures: Percentage of heavy drinking days (PHDD) weeks 9 to 16, no heavy drinking days (NHDD) weeks 9 to 16, and prolonged smoking abstinence weeks 13 to 16. Results: Of 131 participants, 39 (29.8%) were women and 92 (70.2%) were men, the mean (SD) age was 42.7 (11.7) years, and the race/ethnicity self-identified by most respondents was black (69 [52.7%]). Sixty-four participants were randomized to receive varenicline, and 67 to receive placebo. Mean change in PHDD between varenicline and placebo across sex and site was not significantly different. However, a significant treatment by sex by time interaction for PHDD (F1,106 = 4.66; P = .03) revealed that varenicline compared with placebo resulted in a larger decrease in log-transformed PHDD in men (least square [LS] mean difference in change from baseline, 0.54; 95% CI, -0.09 to 1.18; P = .09; Cohen d = 0.45) but a smaller decrease in women (LS mean difference, -0.69; 95% CI, -1.63 to 0.25; P = .15; Cohen d = -0.53). Thirteen of 45 men (29%) had NHDD taking varenicline compared with 3 of 47 men (6%) taking placebo (Cohen h = 0.64; 95% CI, 0.22 1.03), whereas 1 of 19 women (5%) had NHDD compared with 5 of 20 women (25%) taking placebo (Cohen h = -0.60; 95% CI, -1.21 to 0.04). Taking varenicline, 8 of 64 participants (13%) achieved prolonged smoking abstinence; no one (0 of 67) quit smoking taking placebo (P = .003; Cohen h = 0.72; 95% CI, 0.38-1.07). Conclusions and Relevance: Varenicline with medical management resulted in decreased heavy drinking among men and increased smoking abstinence in the overall sample. Varenicline could be considered to promote improvements in men with these dual behavioral health risks. Trial Registration: clinicaltrials.gov Identifier: NCT01553136. PMID- 29261827 TI - From Cultural to Structural Competency-Training Psychiatry Residents to Act on Social Determinants of Health and Institutional Racism. PMID- 29261826 TI - Communication About the Probability of Cancer in Indeterminate Pulmonary Nodules. AB - Importance: Clinical guidelines recommend that clinicians estimate the probability of malignancy for patients with indeterminate pulmonary nodules (IPNs) larger than 8 mm. Adherence to these guidelines is unknown. Objectives: To determine whether clinicians document the probability of malignancy in high-risk IPNs and to compare these quantitative or qualitative predictions with the validated Mayo Clinic Model. Design, Setting, and Participants: Single institution, retrospective cohort study of patients from a tertiary care Department of Veterans Affairs hospital from January 1, 2003, through December 31, 2015. Cohort 1 included 291 veterans undergoing surgical resection of known or suspected lung cancer from January 1, 2003, through December 31, 2015. Cohort 2 included a random sample of 239 veterans undergoing inpatient or outpatient pulmonary evaluation of IPNs at the hospital from January 1, 2003, through December 31, 2012. Exposures: Clinician documentation of the quantitative or qualitative probability of malignancy. Main Outcomes and Measures: Documentation from pulmonary and/or thoracic surgery clinicians as well as information from multidisciplinary tumor board presentations was reviewed. Any documented quantitative or qualitative predictions of malignancy were extracted and summarized using descriptive statistics. Clinicians' predictions were compared with risk estimates from the Mayo Clinic Model. Results: Of 291 patients in cohort 1, 282 (96.9%) were men; mean (SD) age was 64.6 (9.0) years. Of 239 patients in cohort 2, 233 (97.5%) were men; mean (SD) age was 65.5 (10.8) years. Cancer prevalence was 258 of 291 cases (88.7%) in cohort 1 and 110 of 225 patients with a definitive diagnosis (48.9%) in cohort 2. Only 13 patients (4.5%) in cohort 1 and 3 (1.3%) in cohort 2 had a documented quantitative prediction of malignancy prior to tissue diagnosis. Of the remaining patients, 217 of 278 (78.1%) in cohort 1 and 149 of 236 (63.1%) in cohort 2 had qualitative statements of cancer risk. In cohort 2, 23 of 79 patients (29.1%) without any documented malignancy risk statements had a final diagnosis of cancer. Qualitative risk statements were distributed among 32 broad categories. The most frequently used statements aligned well with Mayo Clinic Model predictions for cohort 1 compared with cohort 2. The median Mayo Clinic Model-predicted probability of cancer was 68.7% (range, 2.4%-100.0%). Qualitative risk statements roughly aligned with Mayo predictions. Conclusions and Relevance: Clinicians rarely provide quantitative documentation of cancer probability for high-risk IPNs, even among patients drawn from a broad range of cancer probabilities. Qualitative statements of cancer risk in current practice are imprecise and highly variable. A standard scale that correlates with predicted cancer risk for IPNs should be used to communicate with patients and other clinicians. PMID- 29261828 TI - Scattered Hypopigmented, Atrophic, and Folliculocentric Papules on the Trunk. PMID- 29261830 TI - What This Computer Needs Is a Physician: Humanism and Artificial Intelligence. PMID- 29261829 TI - Association Between Medicare Expenditure Growth and Mortality Rates in Patients With Acute Myocardial Infarction: A Comparison From 1999 Through 2014. AB - Importance: Many studies have considered the association between Medicare spending and health outcomes at a point in time; few have considered the association between the long-term growth in spending and outcomes. Objective: To assess whether components of growth in Medicare expenditures are associated with mortality rates between January 1, 1999, and June 30, 2014, for beneficiaries hospitalized for acute myocardial infarction. Design, Setting, and Participants: Cross-sectional analysis of a random 20% sample of fee-for-service Medicare beneficiaries from January 1, 1999, through December 31, 2000 (n=72 473) and January 1, 2004, through December 31, 2004 (n=38 248), and 100% sample from January 1, 2008, through December 31, 2008 (n=159 558) and January 1, 2013, through June 30, 2014 (n=209 614) admitted with acute myocardial infarction to 1220 hospitals. Main Outcomes and Measures: Primary exposure measures include the growth of 180-day expenditure components (eg, inpatient, physician, and postacute care) and early percutaneous coronary intervention by hospitals adjusted for price differences and inflation. The primary outcome is the risk-adjusted 180-day case fatality rate. Results: Patients in each of the years 2004, 2008, and 2013 2014 (relative to those in 1999-2000) were qualitatively of equivalent age, less likely to be white or female, and more likely to be diabetic (all P < .001). Adjusted expenditures per patient increased 13.9% from January 1, 1999, through December 31, 2000, and January 1, 2013, through June 30, 2014, but declined 0.5% between 2008 and 2013-2014. Mean (SD) expenditures in the 5.0% of hospitals (n = 61) with the most rapid expenditure growth between 1999-2000 and 2013-2014 increased by 44.1% ($12 828 [$2315]); for the 5.0% of hospitals with the slowest expenditure growth (n = 61), mean expenditures decreased by 18.7% (-$7384 [$4141]; 95% CI, $8177-$6496). The growth in early percutaneous coronary intervention exhibited a negative association with 180-day case fatality. Spending on cardiac procedures was positively associated with 180-day mortality, while postacute care spending exhibited moderate cost-effectiveness ($455 000 per life saved after 180 days; 95% CI, $323 000-$833 000). Beyond spending on noncardiac procedures, growth in other components of spending was not associated with health improvements. Conclusions and Relevance: Health improvements for patients with acute myocardial infarction varied across hospitals and were associated with the diffusion of cost-effective care, such as early percutaneous coronary intervention and, to a lesser extent, postacute care, rather than overall expenditure growth. Interventions designed to promote hospital adoption of cost-effective care could improve patient outcomes and, if accompanied by cuts in cost-ineffective care (inside and outside of the hospital setting), also reduce expenditures. PMID- 29261831 TI - Evaluation of Early Allograft Function Using the Liver Graft Assessment Following Transplantation Risk Score Model. AB - Importance: Early allograft dysfunction (EAD) following a liver transplant (LT) unequivocally portends adverse graft and patient outcomes, but a widely accepted classification or grading system is lacking. Objective: To develop a model for individualized risk estimation of graft failure after LT and then compare the model's prognostic performance with the existing binary EAD definition (bilirubin level of >=10 mg/dL on postoperative day 7, international normalized ratio of >=1.6 on postoperative day 7, or aspartate aminotransferase or alanine aminotransferase level of >2000 U/L within the first 7 days) and the Model for Early Allograft Function (MEAF) score. Design, Setting, and Participants: This retrospective single-center analysis used a transplant database to identify all adult patients who underwent a primary LT and had data on 10 days of post-LT laboratory variables at the Dumont-UCLA Transplant Center of the David Geffen School of Medicine at UCLA between February 1, 2002, and June 30, 2015. Data collection took place from January 4, 2016, to June 30, 2016. Data analysis was conducted from July 1, 2016, to August 30, 2017. Main Outcomes and Measures: Three-month graft failure-free survival. Results: Of 2021 patients who underwent primary LT over the study period, 2008 (99.4%) had available perioperative data and were included in the analysis. The median (interquartile range [IQR]) age of recipients was 56 (49-62) years, and 1294 recipients (64.4%) were men. Overall survival and graft-failure-free survival rates were 83% and 81% at year 1, 74% and 71% at year 3, and 69% and 65% at year 5, with an 11.1% (222 recipients) incidence of 3-month graft failure or death. Multivariate factors associated with 3-month graft failure-free survival included post-LT aspartate aminotransferase level, international normalized ratio, bilirubin level, and platelet count, measures of which were used to calculate the Liver Graft Assessment Following Transplantation (L-GrAFT) risk score. The L-GrAFT model had an excellent C statistic of 0.85, with a significantly superior discrimination of 3-month graft failure-free survival compared with the existing EAD definition (C statistic, 0.68; P < .001) and the MEAF score (C statistic, 0.70; P < .001). Compared with patients with lower L-GrAFT risk, LT recipients in the highest 10th percentile of L-GrAFT scores had higher Model for End-Stage Liver Disease scores (median [IQR], 34 [26-40] vs 31 [25-38]; P = .005); greater need for pretransplant hospitalization (56.8% vs 44.8%; P = .003), renal replacement therapy (42.9% vs 30.5%; P < .001), mechanical ventilation (35.8% vs 18.1%; P < .001), and vasopressors (22.9% vs 11.0%; P < .001); longer cold ischemia times (median [IQR], 436 [311-539] vs 401 [302-506] minutes; P = .04); greater intraoperative blood transfusions (median [IQR], 17 [10-26] vs 10 [6-17] units of packed red blood cells; P < .001); and older donors (median [IQR] age, 47 [28-56] vs 41 [25 52] years; P < .001). Conclusions and Relevance: The L-GrAFT risk score allows a highly accurate, individualized risk estimation of 3-month graft failure following LT that is more accurate than existing EAD and MEAF scores. Multicenter validation may allow for the adoption of the L-GrAFT as a tool for evaluating the need for a retransplant, for establishing standardized grading of early allograft function across transplant centers, and as a highly accurate clinical end point in translational studies aiming to mitigate ischemia or reperfusion injury by modulating donor quality and recipient factors. PMID- 29261832 TI - Using Clinical Registries to Enhance Implementation Research. PMID- 29261833 TI - Stevens-Johnson Syndrome During Pregnancy: Case Report of a Newborn Treated With the Culprit Drug. PMID- 29261834 TI - Understanding How to Improve Quality and Value for Patients With Acute Myocardial Infarction. PMID- 29261835 TI - Comparison of Tumor Classifications for Cutaneous Squamous Cell Carcinoma of the Head and Neck in the 7th vs 8th Edition of the AJCC Cancer Staging Manual. AB - Importance: Previous studies have shown that the AJCC Cancer Staging Manual, 7th edition (AJCC 7), tumor classification for cutaneous squamous cell carcinoma (CSCC) failed to accurately stratify disease-related outcomes. The recently released 8th edition (AJCC 8) features a revised tumor classification for only head and neck CSCC (HNCSCC). Objective: To compare AJCC 7 and AJCC 8 tumor classifications for HNCSCC and to validate AJCC 8. Design, Setting, and Participants: This was a 10-year retrospective cohort study (2000-2009) at an academic tertiary care center reviewing 680 primary HNCSCC tumors in 459 patients. Main Outcomes and Measures: Primary HNCSCC tumors were reviewed for disease-related outcomes (DROs): local recurrence (LR), nodal metastasis (NM), and disease-specific death (DSD). Tumors were stratified by AJCC 7 and AJCC 8 tumor classification. Distinctiveness (outcome differences between categories), homogeneity (outcome similarity within categories), and monotonicity (outcome worsening with increasing categories) were assessed for both classifications. Results: Most of the 459 patients were white (451 [98.3%]) and male (312 [68.0%]). AJCC 8 high tumor categories (T3/T4) accounted for 121 (17.8%) of total cases but 50 of 71 DROs (70.4%) (22 of 34 of LRs [64.7%], 17 of 24 NMs [70.8%], and 11 of 13 of DSDs [84.6%]). This was a significant improvement over AJCC 7, where only 12 of 71 DROs (16.9%) (4 of 34 LRs [11.8%], 3 of 24 NMs [12.5%], and 5 of 13 DSDs [38.5%]) occurred in T3/T4 categories. However, AJCC 8 T2 and T3 were indistinct, with overlapping 95% CIs for 10-year cumulative incidences of LR, NM, and DSD. The 10-year cumulative incidence of DROs in the 119 AJCC 8 T3 cases were 19.7% (95% CI, 13.0%-29.7%) for LR, 14.1% (95% CI, 9.7%-20.7%) for NM, and 9.3% (95% CI, 6.8%-14.0% for DSD). Conclusions and Relevance: AJCC 8 demonstrates superior homogeneity and monotonicity compared with AJCC 7. It now may be possible for AJCC 8 HNCSCC T2, T3, and T4 cases to be recorded and tracked by tumor registries because they represented a 23.1% subset in this study, which includes nearly all poor outcomes (85.9%). Further work is needed to validate AJCC 8 with population-level data and to compare AJCC 8 performance against alternative tumor classifications. PMID- 29261836 TI - Right Lower Quadrant Pain in Early Pregnancy. PMID- 29261837 TI - Error in Abstract. PMID- 29261839 TI - Advocacy as Key to Structural Competency in Psychiatry. PMID- 29261840 TI - Herpes Zoster Rates in a Large Cohort of Patients With Systemically Treated Psoriasis. PMID- 29261838 TI - Association of an Enhanced Recovery Pilot With Length of Stay in the National Surgical Quality Improvement Program. AB - Importance: Enhanced recovery protocols (ERPs) are standardized care plans of best practices that can decrease morbidity and length of stay (LOS). However, many hospitals need help with implementation. The Enhanced Recovery in National Surgical Quality Improvement Program (ERIN) pilot was designed to support ERP implementation. Objective: To evaluate the association of the ERIN pilot with LOS after colectomy. Design, Setting, and Participants: Using a difference-in differences design, pilot LOS before and after ERP implementation was compared with matched controls in a hierarchical model, adjusting for case mix and random effects of hospitals and matched pairs. The setting was 15 hospitals of varied size and academic status from the National Surgical Quality Improvement Program. Preimplementation and postimplementation colectomy cases (July 1, 2013, to December 31, 2015) were collected using novel ERIN variables. Emergency and septic cases were excluded. A propensity score match identified a 2:1 control cohort of patients undergoing colectomy at non-ERIN hospitals. Interventions: Pilot hospitals developed and implemented ERPs that included expert guidance, multidisciplinary teams, data audits, and opportunities for collaboration. Main Outcomes and Measures: The primary outcome was LOS, and the secondary outcome was serious morbidity or mortality composite. Results: There were 4975 colectomies performed by 15 ERIN pilot hospitals (3437 before implementation and 1538 after implementation) compared with a control cohort of 9950 colectomies (4726 before implementation and 5224 after implementation). The mean LOS decreased by 1.7 days in the pilot (6.9 [interquartile range (IQR), 4-8] days before implementation vs 5.2 [IQR, 3-6] days after implementation, P < .001) compared with 0.4 day in controls (6.4 [IQR, 4-7] days before implementation vs 6.0 [IQR, 3-7] days after implementation, P < .001). Readmission did not differ pre-post for the pilot or controls. Serious morbidity or mortality decreased for pilot participants (485 [14.1%] before implementation vs 162 [10.5%] after implementation, P < .001), with no difference in controls, and remained significant after risk adjustment (adjusted odds ratio, 0.76; 95% CI, 0.60-0.96). After adjusting for differences in case mix and for clustering in hospitals and matched pairs, the adjusted difference-in-differences model demonstrated a decrease in LOS by 1.1 days in the pilot over controls (P < .001). Conclusions and Relevance: Participating ERIN pilot hospitals achieved shorter LOS and decreased complications after elective colectomy, without increasing readmissions. The ability to implement ERPs across hospitals of varied size and resources is essential. Lessons from the ERIN pilot may inform efforts to scale this effective and evidence-based intervention. PMID- 29261841 TI - A Woman in Her Late 50s With Palpitations and Light-headedness. PMID- 29261842 TI - Determinants of Failure in Hepatic Transplant. PMID- 29261843 TI - Using Network Oriented Research Assistant (NORA) Technology to Compare Digital Photographic With In-Person Assessment of Acne Vulgaris. AB - Importance: Teledermatology has undergone exponential growth in the past 2 decades. Many technological innovations are becoming available without necessarily undergoing validation studies for specific dermatologic applications. Objective: To determine whether patient-taken photographs of acne using Network Oriented Research Assistant (NORA) result in similar lesion counts and Investigator's Global Assessment (IGA) findings compared with in-person examination findings. Design, Setting, and Participants: This pilot reliability study enrolled consecutive patients with acne vulgaris from a single general dermatology practice in Los Angeles, California, who were able to use NORA on an iPhone 6 to take self-photographs. Patients were enrolled from January 1 through March 31, 2016. Each individual underwent in-person and digital evaluation of his or her acne by the same dermatologist. A period of at least 1 week separated the in-person and digital assessments of acne. Interventions: All participants were trained on how to use NORA on the iPhone 6 and take photographs of their face with the rear-facing camera. Main Outcomes and Measures: Reliability of patient taken photographs with NORA for acne evaluation compared with in-person examination findings. Acne assessment measures included lesion count (total, inflammatory, noninflammatory, and cystic) and IGA for acne severity. Results: A total of 69 patients (37 male [54%] and 32 female [46%]; mean [SD] age, 22.7 [7.7] years) enrolled in the study. The intraclass correlation coefficients of in person and photograph-based acne evaluations indicated strong agreement. The intraclass correlation coefficient for total lesion count was 0.81; for the IGA, 0.75. Inflammatory lesion count, noninflammatory lesion count, and cyst count had intraclass correlation coefficients of 0.72, 0.72, and 0.82, respectively. Conclusions and Relevance: This study found agreement between acne evaluations performed in person and from self-photographs with NORA. As a reliable telehealth technology for acne, NORA can be used as a teledermatology platform for dermatology research and can increase access to dermatologic care. PMID- 29261845 TI - Evaluation of Ganglion Cell-Inner Plexiform Layer Thinning in Eyes With Optic Disc Hemorrhage: A Trend-Based Progression Analysis. AB - Purpose: To evaluate the rate of change in ganglion cell-inner plexiform layer (GCIPL) thickness measured by optical coherence tomography (OCT) using a trend based approach in early-stage glaucomatous eyes with disc hemorrhage (DH) and to compare the GCIPL thinning rate with that in glaucomatous eyes without DH. Methods: This prospective observational study included 46 patients with early stage open-angle glaucoma and DH who underwent serial spectral-domain OCT measurements for at least 30 months. The GCIPL thinning rate was determined in the global, superior, or inferior hemiretinas and in six macular sectors by linear regression and was compared between glaucomatous eyes with DH and fellow glaucomatous eyes without DH and between glaucomatous eyes with DH and non-DH glaucomatous control eyes. Results: The GCIPL thinning rate (mean +/- standard deviation) was significantly more rapid in glaucomatous eyes with DH than in fellow eyes without DH in the inferior hemiretina (-1.07 +/- 0.75 vs. -0.44 +/- 0.54 MUm/y, P = 0.001), inferotemporal sector (-1.13 +/- 1.00 vs. -0.61 +/- 0.66 MUm/y, P = 0.028), and inferior sector (-1.33 +/- 0.79 vs. -0.42 +/- 0.78 MUm/y, P < 0.001). The GCIPL thinning rate was significantly more rapid in glaucomatous eyes with DH than in glaucomatous controls without DH in the global area (-0.78 +/- 0.85 vs. -0.32 +/- 0.48 MUm/y, P = 0.002), the inferior hemiretina (-1.00 +/- 0.94 vs. -0.37 +/- 0.67 MUm/y, P < 0.001), and the inferotemporal sector (-1.31 +/- 1.07 vs. -0.34 +/- 0.75 MUm/y, P < 0.001). Conclusions: The GCIPL thinning rate on OCT was significantly more rapid in glaucomatous eyes with DH than in fellow glaucomatous eyes without DH or glaucomatous control eyes without DH. DH could be associated with progression of glaucoma in terms of GCIPL thinning. PMID- 29261844 TI - Crosstalk Between Histone and DNA Methylation in Regulation of Retinal Matrix Metalloproteinase-9 in Diabetes. AB - Purpose: Diabetes activates matrix metalloproteinase-9 (MMP-9), and MMP-9 via damaging retinal mitochondria, activates capillary cell apoptosis. MMP-9 promoter has binding sites for many transcription factors, and in diabetes its promoter undergoes epigenetic modifications, including histone modifications and DNA methylation. Enhancer of Zeste homolog 2 (Ezh2), which catalyzes dimethylation/trimethylation of histone 3 lysine 27 (H3K27me2 and me3), is also associated with DNA methylation. Our aim was to investigate link(s) between histone and DNA modifications in the regulation of MMP-9. Methods: Using human retinal endothelial cells, and also retinal microvessels from diabetic rats, effect of hyperglycemia on H3K27me3, and recruitment of Ezh2 at the MMP-9 promoter were quantified by chromatin-immunoprecipitation technique. Role of H3K27 trimethylation in regulating DNA methylation-transcription of MMP-9 was determined by regulating Ezh2 by its specific siRNA and also a pharmacologic inhibitor. Results: Hyperglycemia elevated H3K27me3 levels and the recruitment of Ezh2 at the MMP-9 promoter, and increased the enzyme activity of Ezh2. Inhibition of Ezh2 attenuated recruitment of both DNA methylating (Dnmt1) and hydroxymethylating (Tet2) enzymes and 5 hydroxymethyl cytosine at the same region of the MMP-9 promoter, and prevented increase in MMP-9 transcription and mitochondrial damage. Conclusions: Activation of Ezh2 in diabetes, via trimethylation of H3K27, facilitates recruitment of the enzymes responsible for regulation of DNA methylation of the MMP-9 promoter, resulting in its transcriptional activation. Thus, a close crosstalk between H3K27 trimethylation and DNA methylation in diabetes plays a critical role in the maintenance of cellular epigenetic integrity of MMP-9. PMID- 29261846 TI - Intraocular Pressure Course During the Femtosecond Laser-Assisted Cataract Surgery in Porcine Cadaver Eyes. AB - Purpose: Femtosecond laser-assisted cataract surgery (FLACS) is an increasingly common procedure. Most laser systems require corneal applanation and thereby increase intraocular pressure (IOP). The purpose of the present study was to evaluate the IOP changes that occur during the FLACS procedure performed using the Catalys femtosecond laser system. Methods: IOP was measured by direct cannulation of the vitreous body of porcine cadaver eyes (N = 20). By inserting a second cannula connected to a water column, all the eyes were set to a baseline IOP of 20 mm Hg. The eyes were lifted by custom-made stands to achieve the appropriate height and position under the Catalys system. The standard FLACS procedure was performed using varying fragmentation times to assess the influence of tissue fragmentation times on IOP peaks. Results: We identified significant IOP elevations from baseline IOP levels during all steps of the FLACS procedure (baseline: 20.28 +/- 1.32 mm Hg; vacuum: 34.48 +/- 4.21 mm Hg; capture: 47.90 +/- 13.02 mm Hg; lock: 48.41 +/- 9.04 mm Hg; analysis: 47.15 +/- 5.97 mm Hg; capsulotomy: 45.74 +/- 6.52 mm Hg; fragmentation: 48.41 +/- 6.80 mm Hg; end: 17.81 +/- 1.61 mm Hg; all P < 0.001). Furthermore, the tissue fragmentation time had a significant effect on the peak IOP values detected (R = 0.62, P = 0.04, n = 9). Conclusions: The present study reveals significant IOP increases during FLACS procedures carried out using the Catalys system. PMID- 29261853 TI - Metal-free materials for fixed prosthodontic restorations. AB - BACKGROUND: Fixed prosthodontic treatment (crowns, fixed dental prostheses (FDPs), complete arch prostheses) involves the use of several different materials to replace missing tooth structure. Traditionally full metal or metal frameworks veneered with ceramic (metal-ceramic (MC)) have been used. In recent years several different metal-free systems have become available to clinicians and patients. In general, metal-free restorations should allow practitioners to better reproduce natural tooth colour, avoiding shortcomings of MC restorations. The comparative in service clinical performance of fixed prosthodontic treatments of different materials is unclear. OBJECTIVES: To assess the effects of metal free materials for prosthodontic restorations compared to metal-ceramic or other conventional all-metal materials. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (searched 3 May 2017), Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched 3 May 2017), MEDLINE Ovid (1946 to 3 May 2017), and Embase Ovid (1980 to 3 May 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials (searched 3 May 2017). No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which the clinical performance of metal-free fixed prosthodontic restorations was compared with metal-ceramic (MC) or other conventional restorations in adult patients requiring prosthodontic treatment. RCTs in which the clinical performance of different kinds of metal-free systems were compared among themselves were also considered. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted independently and in duplicate. Trial authors were contacted for missing information. Available results for the outcomes of interest of the systematic review of the studies included were tabulated as they could not be included in a formal meta-analysis. MAIN RESULTS: Nine trials involving a total of 448 participants were included. We judged two trials to be at unclear risk of bias and seven to be at high risk of bias. The majority of items of risk of bias were evaluated to be at unclear or high risk level in more than 50% of the included trials. Each trial except two was addressing a different type of intervention. All evidence was rated as being of very low quality due to problems with risk of bias and imprecision of results, the latter being due to very small sample sizes, low event rates, 95% confidence intervals including the possibility of benefit for both the test and control groups, or combinations of these problems. This means that we are very uncertain about all of the results presented in this review.One trial compared metal-free single crowns (full contour zirconia) to cast gold single crowns in 224 participants and found insufficient evidence of a difference in failure rate after one year, but after five years there was some evidence of a benefit for the gold crowns. There was insufficient evidence of a difference for crown complications at either time of assessment.One trial compared three-unit metal free FDPs (lithium disilicate) to three-unit metal-ceramic FDPs in 37 participants. There was insufficient evidence of a difference in bridge failure at one and six years, but some evidence of a benefit for the lithium disilicate group in terms of bridge complications at six years. One trial compared zirconia ceramic FDPs to metal-ceramic FDPs in 34 participants but found insufficient evidence of a difference in bridge failures (i.e. no failures in either treatment group), bridge complications or patients' aesthetic evaluation at any time of assessment up to three years.One trial compared metal-free cantilevered FDPs to metal-ceramic cantilevered FDPs in 21 participants. There was insufficient evidence of a difference for any primary outcome: bridge failures (i.e. no failures in either treatment group), bridge complications, or patients' aesthetic evaluation at any time of assessment up to three years.One trial compared metal free implant-supported screw retained single crowns (zirconia veneered with feldspathic ceramic) to metal-ceramic implant-supported screw-retained single crowns in 20 participants. There was insufficient evidence of a difference for any primary outcome: crown failures (i.e. no failures in either treatment group), crown complications, or satisfaction/aesthetic evaluation at any time of assessment up to two years.Two trials compared metal-free implant abutments (zirconia) to metal implant abutments both supporting single crowns in 50 participants. There was insufficient evidence of a difference in abutment failure at one year.One trial compared metal-free implant-supported FDPs made of two different types of zirconia ceramic in 18 participants. There was insufficient evidence of a difference in failures at any time of assessment up to 10 years (i.e. no failures in either treatment group). There was some evidence of a benefit for the zirconia-toughened alumina group in terms of complications (chipping).One trial compared metal-free tooth-supported FDPs made with two different veneering techniques (pressed versus layered) in 40 participants. There was insufficient evidence of a difference for failures (i.e. no failures in either treatment group) or complications at any time of assessment up to three years. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the effectiveness of metal-free materials for fixed prosthodontic treatment over metal-ceramic or other type of standard restorations. The overall quality of existing evidence was very low, therefore great caution should be exercised when generalising the results of the included trials. Until more evidence becomes available clinicians should continue to base decisions on which material to use for fixed prosthodontic treatment on their own clinical experience, whilst taking into consideration the individual circumstances and preferences of their patients. There is urgent need of properly designed RCTs. PMID- 29261854 TI - Clinical Question: In congestive heart failure patients with preserved ejection fraction, does spironolactone improve cardiac outcomes? AB - Answer: No. A randomized controlled trial of patients with heart failure and an ejection fraction > 45% showed that spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Level of Evidence for the Answer: ALimits: English, Adults, Randomized Controlled Trials, Meta-analysis, and Systematic review. Date Search Was Conducted: December 2015. Inclusion criteria: All randomized controlled trials, meta-analyses, and systematic reviews in patients with congestive heart failure with preserved ejection fractions, who were taking spironolactone, and published in the past 5 years. Exclusion criteria:; Age less than eighteen years, Eplerenone . PMID- 29262249 TI - Atom-Centered Potentials with Dispersion-Corrected Minimal-Basis-Set Hartree Fock: An Efficient and Accurate Computational Approach for Large Molecular Systems. AB - We present a computational methodology based on atom-centered potentials (ACPs) for the efficient and accurate structural modeling of large molecular systems. ACPs are atom-centered one-electron potentials that have the same functional form as effective-core potentials. In recent works, we showed that ACPs can be used to produce a correction to the ground-state wave function and electronic energy to alleviate shortcomings in the underlying model chemistry. In this work, we present ACPs for H, C, N, and O atoms that are specifically designed to predict accurate non-covalent binding energies and inter- and intramolecular geometries when combined with dispersion-corrected Hartree-Fock (HF-D3) and a minimal basis set (scaled MINI or MINIs). For example, the combined HF-D3/MINIs-ACP method demonstrates excellent performance, with mean absolute errors of 0.36 and 0.28 kcal/mol for the S22x5 and S66x8 benchmark sets, respectively, relative to highly correlated complete-basis-set data. The application of ACPs results in a significant decrease in error compared to uncorrected HF-D3/MINIs for all benchmark sets examined. In addition, HF-D3/MINIs-ACP, has a cost only slightly higher than a minimal-basis-set HF calculation and can be used with any electronic structure program for molecular quantum chemistry that uses Gaussian basis sets and effective-core potentials. PMID- 29261847 TI - TSC1 Mutations in Keratoconus Patients With or Without Tuberous Sclerosis. AB - Purpose: To test candidate genes TSC1 and TSC2 in a family affected by tuberous sclerosis complex (TSC) where proband was also diagnosed with bilateral keratoconus (KC) and to test the hypothesis that defects in the same gene may lead to a nonsyndromic KC. Methods: Next-generation sequencing of TSC1 and TSC2 genes was performed in a proband affected by TSC and KC. Identified mutation was confirmed by Sanger DNA sequencing. Whole exome sequencing (WES) was performed in patients with nonsyndromic KC. Sanger DNA sequencing was used to confirm WES results and to screen additional patients. RT-PCR was used to investigate TSC1 expression in seven normal human corneas and eight corneas from patients with KC. Various in silico tools were employed to model functional consequences of identified mutations. Results: A heterozygous nonsense TSC1 mutation g.132902703C>T (c.2293C>T, p.Gln765Ter) was identified in a patient with TSC and KC. Two heterozygous missense TSC1 variants g.132896322A>T (c.3408A>T, p.Asp1136Glu) and g.132896452G>A (c.3278G>A, p.Arg1093Gln) were identified in three patients with nonsyndromic KC. Two mutations were not present in The Genome Aggregation (GnomAD), The Exome Aggregation (ExAC), and 1000 Genomes (1000G) databases, while the third one was present in GnomAD and 1000G with minor allele frequencies (MAF) of 0.00001 and 0.0002, respectively. We found TSC1 expressed in normal corneas and KC corneas, albeit with various levels. Conclusions: Here for the first time we found TSC1 gene to be involved in bilateral KC and TSC as well as with nonsyndromic KC, supporting the hypothesis that diverse germline mutations of the same gene can cause genetic disorders with overlapping clinical features. PMID- 29262250 TI - Chaoborus spp. Transport CH4 from the Sediments to the Surface Waters of a Eutrophic Reservoir, But Their Contribution to Water Column CH4 Concentrations and Diffusive Efflux Is Minor. AB - Chaoborus spp. (midge larvae) live in the anoxic sediments and hypolimnia of freshwater lakes and reservoirs during the day and migrate to the surface waters at night to feed on plankton. It has recently been proposed that Chaoborus take up methane (CH4) from the sediments in their tracheal gas sacs, use this acquired buoyancy to ascend into the surface waters, and then release the CH4, thereby serving as a CH4 "pump" to the atmosphere. We tested this hypothesis using diel surveys and seasonal monitoring, as well as incubations of Chaoborus to measure CH4 transport in their gas sacs at different depths and times in a eutrophic reservoir. We found that Chaoborus transported CH4 from the hypolimnion to the lower epilimnion at dusk, but the overall rate of CH4 transport was minor, and incubations revealed substantial variability in CH4 transport over space and time. We calculated that Chaoborus transport ~0.1 mmol CH4 m-2 yr-1 to the epilimnion in our study reservoir, a very low proportion (<1%) of total CH4 diffusive flux during the summer stratified period. Our data further indicate that CH4 transport by Chaoborus is sensitive to water column mixing, Chaoborus density, and Chaoborus species identity. PMID- 29262251 TI - Hierarchically Designed 3D Holey C2N Aerogels as Bifunctional Oxygen Electrodes for Flexible and Rechargeable Zn-Air Batteries. AB - The future of electrochemical energy storage spotlights on the designed formation of highly efficient and robust bifunctional oxygen electrocatalysts that facilitate advanced rechargeable metal-air batteries. We introduce a scalable facile strategy for the construction of a hierarchical three-dimensional sulfur modulated holey C2N aerogels (S-C2NA) as bifunctional catalysts for Zn-air and Li O2 batteries. The S-C2NA exhibited ultrahigh surface area (~1943 m2 g-1) and superb electrocatalytic activities with lowest reversible oxygen electrode index ~0.65 V, outperforms the highly active bifunctional and commercial (Pt/C and RuO2) catalysts. Density functional theory and experimental results reveal that the favorable electronic structure and atomic coordination of holey C-N skeleton enable the reversible oxygen reactions. The resulting Zn-air batteries with liquid electrolytes and the solid-state batteries with S-C2NA air cathodes exhibit superb energy densities (958 and 862 Wh kg-1), low charge-discharge polarizations, excellent reversibility, and ultralong cycling lives (750 and 460 h) than the commercial Pt/C+RuO2 catalysts, respectively. Notably, Li-O2 batteries with S-C2NA demonstrated an outstanding specific capacity of ~648.7 mA h g-1 and reversible charge-discharge potentials over 200 cycles, illustrating great potential for commercial next-generation rechargeable power sources of flexible electronics. PMID- 29262252 TI - Phase-Controlled Growth of One-Dimensional Mo6Te6 Nanowires and Two-Dimensional MoTe2 Ultrathin Films Heterostructures. AB - Controllable synthesizing of one-dimensional-two-dimensional (1D-2D) heterostructures and tuning their atomic and electronic structures is nowadays of particular interest due to the extraordinary properties and potential applications. Here, we demonstrate the temperature-induced phase-controlled growth of 1D Mo6Te6-2D MoTe2 heterostructures via molecular beam epitaxy. In situ scanning tunneling microscopy study shows 2D ultrathin films are synthesized at low temperature range, while 1D nanowires gradually arise and dominate as temperature increasing. X-ray photoelectron spectroscopy confirms the good stoichiometry and scanning tunneling spectroscopy reveals the semimetallic property of grown Mo6Te6 nanowires. Through in situ annealing, a phase transition from 2D MoTe2 to 1D Mo6Te6 is induced, thus forming a semimetal-semiconductor junction in atomic level. An upward band bending of 2H-MoTe2 is caused by lateral hole injection from Mo6Te6. The work suggests a new route to synthesize 1D semimetallic transition metal chalcogenide nanowires, which could serve as ultrasmall conducting building blocks and enable band engineering in future 1D-2D heterostructure devices. PMID- 29262253 TI - Single-Droplet Multiplex Bioassay on a Robust and Stretchable Extreme Wetting Substrate through Vacuum-Based Droplet Manipulation. AB - Herein, a droplet manipulation system with a superamphiphobic (SPO) superamphiphilic (SPI) patterned polydimethylsiloxane (PDMS) substrate is developed for a multiplex bioassay from single-droplet samples. The SPO substrate is fabricated by sequential spraying of adhesive and fluorinated silica nanoparticles onto a PDMS substrate. It is subsequently subjected to oxygen plasma with a patterned mask to form SPI patterns. The SPO layer exhibits extreme liquid repellency with a high contact angle (>150 degrees ) toward low surface tension and viscous biofluidic droplets (e.g., ethylene glycol, blood, dimethyl sulfoxide, and alginate hydrogel). In contrast, the SPI exhibits liquid adhesion with a near zero contact angle. Using the droplet manipulation system, various liquid droplets can be precisely manipulated and dispensed onto the predefined SPI patterns on the SPO PDMS substrate. This system enables a multiplex colorimetric bioassay, capable of detecting multiple analytes, including glucose, uric acid, and lactate, from a single sample droplet. In addition, the detection of glucose concentrations in a plasma droplet of diabetic and healthy mice are performed to demonstrate the feasibility of the proposed system for efficient clinical diagnostic applications. PMID- 29262254 TI - Enantioselective Synthesis of Chiral alpha-Thio-Quaternary Stereogenic Centers via Phase-Transfer-Catalyzed alpha-Alkylation of alpha-Acylthiomalonates. AB - An efficient synthetic method for establishing chiral alpha-thio-alpha-quaternary stereogenic center was successfully developed. The enantioselective alpha alkylation of alpha-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, -20 degrees C, and (S,S)-3,4,5-trifluorophenyl-NAS bromide] provided the corresponding alpha-acylthio-alpha-alkylmalonates in high chemical yields (up to 99%) and high optical yields (up to 98% ee). PMID- 29262255 TI - The Role of Interfacial Water in Protein-Ligand Binding: Insights from the Indirect Solvent Mediated Potential of Mean Force. AB - Classical density functional theory (DFT) can be used to relate the thermodynamic properties of solutions to the indirect solvent mediated part of the solute solvent potential of mean force (PMF). Standard, but powerful numerical methods can be used to estimate the solute-solvent PMF from which the indirect part can be extracted. In this work we show how knowledge of the direct and indirect parts of the solute-solvent PMF for water at the interface of a protein receptor can be used to gain insights about how to design tighter binding ligands. As we show, the indirect part of the solute-solvent PMF is equal to the sum of the 1-body (energy + entropy) terms in the inhomogeneous solvation theory (IST) expansion of the solvation free energy. To illustrate the effect of displacing interfacial water molecules with particular direct/indirect PMF signatures on the binding of ligands, we carry out simulations of protein binding with several pairs of congeneric ligands. We show that interfacial water locations that contribute favorably or unfavorably at the 1-body level (energy + entropy) to the solvation free energy of the solute can be targeted as part of the ligand design process. Water locations where the indirect PMF is larger in magnitude provide better targets for displacement when adding a functional group to a ligand core. PMID- 29262256 TI - Macrocyclization of Interferon-Poly(alpha-amino acid) Conjugates Significantly Improves the Tumor Retention, Penetration, and Antitumor Efficacy. AB - Cyclization and polymer conjugation are two commonly used approaches for enhancing the pharmacological properties of protein drugs. However, cyclization of parental proteins often only affords a modest improvement in biochemical or cell-based in vitro assays. Moreover, very few studies have included a systematic pharmacological evaluation of cyclized protein-based therapeutics in live animals. On the other hand, polymer-conjugated proteins have longer circulation half-lives but usually show poor tumor penetration and suboptimal pharmacodynamics due to increased steric hindrance. We herein report the generation of a head-to-tail interferon-poly(alpha-amino acid) macrocycle conjugate circ-P(EG3Glu)20-IFN by combining the aforementioned two approaches. We then compared the antitumor pharmacological activity of this macrocycle conjugate against its linear counterparts, N-P(EG3Glu)20-IFN, C-IFN-P(EG3Glu)20, and C-IFN PEG. Our results found circ-P(EG3Glu)20-IFN to show considerably greater stability, binding affinity, and in vitro antiproliferative activity toward OVCAR3 cells than the three linear conjugates. More importantly, circ-P(EG3Glu)20 IFN exhibited longer circulation half-life, remarkably higher tumor retention, and deeper tumor penetration in vivo. As a result, administration of the macrocyclic conjugate could effectively inhibit tumor progression and extend survival in mice bearing established xenograft human OVCAR3 or SKOV3 tumors without causing severe paraneoplastic syndromes. Taken together, our study provided until now the most relevant experimental evidence in strong support of the in vivo benefit of macrocyclization of protein-polymer conjugates and for its application in next-generation therapeutics. PMID- 29262257 TI - Insights into Mollusk Shell Formation: Interlamellar and Lamellar-Specific Nacre Protein Hydrogels Differ in Ion Interaction Signatures. AB - In the mollusk shell nacre layer, there exist hydrogelator proteomes that play important roles in the formation of the mineral phase. Two of these proteomes, the intracrystalline and the framework, reside in the interior and exterior, respectively, of the nacre tablets. To date there is no clear evidence of what distinguishes an intracrystalline protein from a framework protein regarding the nucleation process. Using Eu(III), phosphate anions, and recombinant versions of the intracrystalline protein, AP7 and the framework protein, n16.3 we probed each protein hydrogel for its interactions with these model ions. Fluorescence spectroscopy of Eu(III) interactions with both protein hydrogels revealed that r AP7 exhibited enhanced effects on Eu(III) fluorescence compared to r-n16.3, and, 31P NMR experiments demonstrated that r-AP7 had a more significant impact on phosphate anions compared to r-n16.3. Thus, r-AP7 was found to be more of an ion "disruptor" than r-n16.3. Interestingly, these findings correlate with the particle size distributions and internal structure of the hydrogel particles themselves, suggesting that the physical and chemical properties of the hydrogels dictate hydrogel-ion interactions. In conclusion, we confirm that hydrogelator proteomes possess distinguishable ion interaction properties that may impact the nucleation processes in these regions and control the overall formation of mesoscale nacre tablets. PMID- 29262259 TI - DELPHIning Diagnostic Criteria for Chronic Hypersensitivity Pneumonitis. PMID- 29262260 TI - Breaking the In Vitro Barrier in Respiratory Medicine. Engineered Microphysiological Systems for Chronic Obstructive Pulmonary Disease and Beyond. PMID- 29262258 TI - Aqueous Superparamagnetic Magnetite Dispersions with Ultrahigh Initial Magnetic Susceptibilities. AB - Superparamagnetic nanoparticles with a high initial magnetic susceptibility chio are of great interest in a wide variety of chemical, biomedical, electronic, and subsurface energy applications. In order to achieve the theoretically predicted increase in chio with the cube of the magnetic diameter, new synthetic techniques are needed to control the crystal structure, particularly for magnetite nanoparticles larger than 10 nm. Aqueous magnetite dispersions (Fe3O4) with a chio of 3.3 (dimensionless SI units) at 1.9 vol %, over 3- to 5-fold greater than those reported previously, were produced in a one-pot synthesis at 210 degrees C and ambient pressure via thermal decomposition of Fe(II) acetate in triethylene glycol (TEG). The rapid nucleation and focused growth with an unusually high precursor-to-solvent molar ratio of 1:12 led to primary particles with a volume average diameter of 16 nm and low polydispersity according to TEM. The morphology was a mixture of stoichiometric and substoichiometric magnetite according to X ray diffraction (XRD) and Mossbauer spectroscopy. The increase in chio with the cube of magnetic diameter as well as a saturation magnetization approaching the theoretical limit may be attributed to the highly crystalline structure and very small nonmagnetic layer (~1 nm) with disordered spin orientation on the surface. PMID- 29262262 TI - The Clean Air Act: Substantial Success and the Challenges Ahead. PMID- 29262261 TI - Float Like Bacilli, STING Like a B: Type I Interferons in Tuberculosis. PMID- 29262263 TI - Reply: Chronic Obstructive Pulmonary Disease: Defining the Indefinable. PMID- 29262265 TI - Taking Another Look at Ambient Coarse Particles. PMID- 29262264 TI - PDE8 Is Expressed in Human Airway Smooth Muscle and Selectively Regulates cAMP Signaling by beta2-Adrenergic Receptors and Adenylyl Cyclase 6. AB - Two cAMP signaling compartments centered on adenylyl cyclase (AC) exist in human airway smooth muscle (HASM) cells, one containing beta2-adrenergic receptor AC6 and another containing E prostanoid receptor AC2. We hypothesized that different PDE isozymes selectively regulate cAMP signaling in each compartment. According to RNA-sequencing data, 18 of 24 PDE genes were expressed in primary HASM cells derived from age- and sex-matched donors with and without asthma. PDE8A was the third most abundant of the cAMP-degrading PDE genes, after PDE4A and PDE1A. Knockdown of PDE8A using shRNA evoked twofold greater cAMP responses to 1 MUM forskolin in the presence of 3-isobutyl-1-methylxanthine. Overexpression of AC2 did not alter this response, but overexpression of AC6 increased cAMP responses an additional 80%. We examined cAMP dynamics in live HASM cells using a fluorescence sensor. PF-04957325, a PDE8-selective inhibitor, increased basal cAMP concentrations by itself, indicating a significant basal level of cAMP synthesis. In the presence of an AC inhibitor to reduce basal signaling, PF 04957325 accelerated cAMP production and increased the inhibition of cell proliferation induced by isoproterenol, but it had no effect on cAMP concentrations or cell proliferation regulated by prostaglandin E2. Lipid raft fractionation of HASM cells revealed PDE8A immunoreactivity in buoyant fractions containing caveolin-1 and AC5/6 immunoreactivity. Thus, PDE8 is expressed in lipid rafts of HASM cells, where it specifically regulates beta2-adrenergic receptor AC6 signaling without effects on signaling by the E prostanoid receptors 2/4-AC2 complex. In airway diseases such as asthma and chronic obstructive pulmonary disease, PDE8 may represent a novel therapeutic target to modulate HASM responsiveness and airway remodeling. PMID- 29262267 TI - Tobacco Smoking Is a Medical Problem. We Ought to Treat It Like One. PMID- 29262266 TI - Effect of a short-term physical activity intervention on liver fat content in obese children. AB - Nonalcoholic fatty liver disease is the most common chronic liver disease and can present with advanced fibrosis or nonalcoholic steatohepatitis. The purpose of this study was to investigate the effect of a 7-day intense physical activity intervention on liver fat content in children with obesity. Fifty-seven obese children (mean body mass index: 26.5 +/- 3.2 kg/m2; mean age: 12.0 +/- 0.8 years) participated in a 7-day physical activity program. All participants were housed together, and their food intake and energy expenditure were strictly controlled. Anthropometric measurements, abdominal computerized tomography scans, and blood analyses were conducted at baseline and post-intervention. Participants lost weight by 2.53 +/- 0.85 kg on average (61.0 +/- 9.8 vs. 58.5 +/- 9.5 kg, p < 0.05), fat mass (16.7 +/- 5.1 vs. 15.7 +/- 4.9 kg, p < 0.05), and serum insulin (13.7 +/- 6.7 vs. 3.5 +/- 2.0 MUU/mL, p < 0.05). However, liver fat content was increased, presented as liver-to-spleen ratio (LSR) where lower LSR represents higher liver fat content. The intervention increased aspartate transaminase level (29.42 +/- 6.78 IU/L vs. 33.50 +/- 9.60 IU/L, p < 0.001). The change in liver fat content was not associated with the change in fasting insulin and liver enzymes. Short-term intense physical activity increased liver fat content independent of change in fasting insulin level and liver enzymes. This is the first human study to report increased liver fat content after physical activity-induced rapid weight loss. PMID- 29262268 TI - Chronic Obstructive Pulmonary Disease: Defining the Indefinable. PMID- 29262269 TI - Drug development and acute gastrointestinal infections. PMID- 29262270 TI - Adolescent Pregnancy Outcomes Among Sisters and Mothers: A Population-Based Retrospective Cohort Study Using Linkable Administrative Data. AB - OBJECTIVES: Female family members affect both the likelihood of adolescent pregnancy and the outcome of that pregnancy. We examined the degree to which an older sister's adolescent reproductive outcomes affect her younger sister's reproductive behavior, and whether relationships in adolescent pregnancy among sisters born to adolescent mothers differ from those born to nonadolescent mothers. METHODS: We followed a birth cohort in Manitoba, Ontario, Canada, to age 20 using linkable administrative databases housed at the Manitoba Centre for Health Policy. The cohort consisted of 12 391 girls born in Manitoba between April 1, 1984, and March 31, 1996, who had 1 older sister. We used logistic regression models to examine the relationships among familial adolescent pregnancy outcomes. RESULTS: Compared with adolescent girls whose older sister did not have an adolescent pregnancy, adolescent girls whose older sister had an adolescent pregnancy were more likely to have a pregnancy (adjusted odds ratio [aOR] = 2.57), regardless of whether that pregnancy was completed (aOR = 2.56) or terminated (aOR = 2.59). Relationships in adolescent pregnancy among sisters were much stronger for those born to nonadolescent mothers (aOR = 3.16 [older sister completed adolescent pregnancy] and 3.18 [older sister terminated adolescent pregnancy]) than to adolescent mothers (aOR = 1.65 [older sister completed adolescent pregnancy] and 1.77 [older sister terminated adolescent pregnancy]). For younger sisters having an adolescent pregnancy, the odds of her completing the pregnancy were reduced if her older sister had terminated an adolescent pregnancy and her mother had not been an adolescent mother (aOR = 0.38). CONCLUSIONS: Younger sisters of adolescents who had a pregnancy may benefit from targeted interventions to reduce their likelihood of adolescent pregnancies. PMID- 29262271 TI - Trial of Contralateral Seventh Cervical Nerve Transfer for Spastic Arm Paralysis. AB - BACKGROUND: Spastic limb paralysis due to injury to a cerebral hemisphere can cause long-term disability. We investigated the effect of grafting the contralateral C7 nerve from the nonparalyzed side to the paralyzed side in patients with spastic arm paralysis due to chronic cerebral injury. METHODS: We randomly assigned 36 patients who had had unilateral arm paralysis for more than 5 years to undergo C7 nerve transfer plus rehabilitation (18 patients) or to undergo rehabilitation alone (18 patients). The primary outcome was the change from baseline to month 12 in the total score on the Fugl-Meyer upper-extremity scale (scores range from 0 to 66, with higher scores indicating better function). Results The mean increase in Fugl-Meyer score in the paralyzed arm was 17.7 in the surgery group and 2.6 in the control group (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001). With regard to improvements in spasticity as measured on the Modified Ashworth Scale (an assessment of five joints, each scored from 0 to 5, with higher scores indicating more spasticity), the smallest between-group difference was in the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unit improvement, a 1-unit improvement, or no change, respectively, as compared with 1, 6, and 7 patients in the control group (P=0.02). Transcranial magnetic stimulation and functional imaging showed connectivity between the ipsilateral hemisphere and the paralyzed arm. There were no significant differences from baseline to month 12 in power, tactile threshold, or two-point discrimination in the hand on the side of the donor graft. RESULTS: The mean increase in Fugl-Meyer score in the paralyzed arm was 17.7 in the surgery group and 2.6 in the control group (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001). With regard to improvements in spasticity as measured on the Modified Ashworth Scale (an assessment of five joints, each scored from 0 to 5, with higher scores indicating more spasticity), the smallest between-group difference was in the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unit improvement, a 1-unit improvement, or no change, respectively, as compared with 1, 6, and 7 patients in the control group (P=0.02). Transcranial magnetic stimulation and functional imaging showed connectivity between the ipsilateral hemisphere and the paralyzed arm. There were no significant differences from baseline to month 12 in power, tactile threshold, or two-point discrimination in the hand on the side of the donor graft. CONCLUSIONS: In this single-center trial involving patients who had had unilateral arm paralysis due to chronic cerebral injury for more than 5 years, transfer of the C7 nerve from the nonparalyzed side to the side of the arm that was paralyzed was associated with a greater improvement in function and reduction of spasticity than rehabilitation alone over a period of 12 months. Physiological connectivity developed between the ipsilateral cerebral hemisphere and the paralyzed hand. (Funded by the National Natural Science Foundation of China and others; Chinese Clinical Trial Registry number, 13004466 .). PMID- 29262272 TI - Effects of carbohydrate mouth rinse and caffeine on high-intensity interval running in a fed state. AB - The current study aims to identify if mouth rinsing with a 6% carbohydrate mouth rinse (CMR) solution and mouth rinsing and ingestion of caffeine (CMR+CAFF) can affect exercise performance during steady-state (SS) running and high-intensity intervals (HIIT) in comparison with a 0% control solution (PLA) when in a fed state. Eight recreationally trained males completed 3 trials (CMR, CMR+CAFF, and PLA) of 45 min SS running and an HIIT protocol (90% peak treadmill velocity) until fatigue in a double blinded, repeated-measures study. Participants ingested a capsule of either CAFF or PLA before and after SS. Participants received a 25 mL bolus of carbohydrate solution (CMR and CMR+CAFF trials) or taste-matched PLA (PLA trial) prior to HIIT protocol and after every second effort. Heart rate and lactate responses were recorded throughout the SS and HIIT protocol. CMR+CAFF was significantly different when compared with PLA (p = 0.001; Cohens d = 1.34) and CMR (p = 0.031; Cohens d = 0.87) in relation to distance covered before fatigue. Although there was no significant difference between CMR and PLA, there was a small benefit for CMR (p = 0.218; Cohens d = 0.46). Results indicate that CMR and ingestion of CAFF leads to improvements in performance during interval sessions while participants were in a fed state. These findings indicate that the regular use of CMR can decrease the risk of gastrointestinal distress reported by athletes, which can be applicable to athletes in a real-world setting. PMID- 29262274 TI - Hearing Loss in Adults. PMID- 29262273 TI - Dietary supplementation with Allium hirtifolium and/or Astragalus hamosus improved memory and reduced neuro-inflammation in the rat model of Alzheimer's disease. AB - Allium hirtifolium Boiss and Astragalus hamosus L. are mentioned in Iranian traditional medicine documentation as therapy for a kind of dementia with the features and symptoms similar to those of Alzheimer's disease (AD). In the present study, the effects of these herbs on neuro-inflammation and memory have been evaluated as new therapies in amyloid beta (Abeta)-induced memory impairment model. Separate groups of rats were fed with A. hirtifolium or A. hamosus extract (both 100 mg/(kg.day)-1) started 1 week before stereotaxic surgery to 24 h before behavioral testing (totally, for 16 successive days). The effects of oral administration of mentioned extracts on the memory and neuro-inflammation were assessed in the Abeta-injected rats. The results of this study showed that oral administration of both A. hirtifolium and A. hamosus improved the memory, examined by using Y-maze test and shuttle box apparatus. Also, Western blotting analysis of cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor-alpha showed that these herbs have ameliorating effects against the neuro-inflammation caused by Abeta. These findings suggest that the use of A. hirtifolium and A. hamosus as herbal therapy may be suitable for decreasing AD-related symptoms and treatment of other neurodegenerative disorders. PMID- 29262275 TI - Tumor Mutational Burden and Response Rate to PD-1 Inhibition. PMID- 29262277 TI - Putting the Patient Back Together - Social Medicine, Network Medicine, and the Limits of Reductionism. PMID- 29262276 TI - Endoscopic Treatment versus Shunting for Infant Hydrocephalus in Uganda. AB - BACKGROUND: Postinfectious hydrocephalus in infants is a major health problem in sub-Saharan Africa. The conventional treatment is ventriculoperitoneal shunting, but surgeons are usually not immediately available to revise shunts when they fail. Endoscopic third ventriculostomy with choroid plexus cauterization (ETV CPC) is an alternative treatment that is less subject to late failure but is also less likely than shunting to result in a reduction in ventricular size that might facilitate better brain growth and cognitive outcomes. METHODS: We conducted a randomized trial to evaluate cognitive outcomes after ETV-CPC versus ventriculoperitoneal shunting in Ugandan infants with postinfectious hydrocephalus. The primary outcome was the Bayley Scales of Infant Development, Third Edition (BSID-3), cognitive scaled score 12 months after surgery (scores range from 1 to 19, with higher scores indicating better performance). The secondary outcomes were BSID-3 motor and language scores, treatment failure (defined as treatment-related death or the need for repeat surgery), and brain volume measured on computed tomography. RESULTS: A total of 100 infants were enrolled; 51 were randomly assigned to undergo ETV-CPC, and 49 were assigned to undergo ventriculoperitoneal shunting. The median BSID-3 cognitive scores at 12 months did not differ significantly between the treatment groups (a score of 4 for ETV-CPC and 2 for ventriculoperitoneal shunting; Hodges-Lehmann estimated difference, 0; 95% confidence interval [CI], -2 to 0; P=0.35). There was no significant difference between the ETV-CPC group and the ventriculoperitoneal shunt group in BSID-3 motor or language scores, rates of treatment failure (35% and 24%, respectively; hazard ratio, 0.7; 95% CI, 0.3 to 1.5; P=0.24), or brain volume (z score, -2.4 and -2.1, respectively; estimated difference, 0.3; 95% CI, 0.3 to 1.0; P=0.12). CONCLUSIONS: This single-center study involving Ugandan infants with postinfectious hydrocephalus showed no significant difference between endoscopic ETV-CPC and ventriculoperitoneal shunting with regard to cognitive outcomes at 12 months. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01936272 .). PMID- 29262278 TI - The Timing of Cord Clamping for Preterm Infants. PMID- 29262279 TI - Nivolumab and Ipilimumab in Advanced Melanoma. PMID- 29262280 TI - Clinical Diagnosis of Hidradenitis Suppurativa. PMID- 29262281 TI - Case 39-2017. A 41-Year-Old Woman with Recurrent Chest Pain. PMID- 29262282 TI - Hospital-Readmission Risk - Isolating Hospital Effects. PMID- 29262283 TI - Signatures of DNA-Repair Deficiencies in Breast Cancer. PMID- 29262284 TI - A Randomized Trial of Intensive versus Standard Blood-Pressure Control. PMID- 29262285 TI - Melanoma Metastatic to the Duodenum. PMID- 29262286 TI - Once-Weekly Exenatide and Cardiovascular Outcomes in Type 2 Diabetes. PMID- 29262287 TI - Evidence-Based Health Policy. PMID- 29262288 TI - Demonstration of the Use of Remote Temperature Monitoring Devices in Vaccine Refrigerators in Haiti. AB - After the 2010 earthquake, Haiti committed to introducing 4 new antigens into its routine immunization schedule, which required improving its cold chain (ie, temperature-controlled supply chain) and increasing vaccine storage capacity by installing new refrigerators. We tested the feasibility of using remote temperature monitoring devices (RTMDs) in Haiti in a sample of vaccine refrigerators fueled by solar panels, propane gas, or electricity. We analyzed data from 16 RTMDs monitoring 24 refrigerators in 15 sites from March through August 2014. Although 5 of the 16 RTMDs exhibited intermittent data gaps, we identified typical temperature patterns consistent with refrigerator door opening and closing, propane depletion, thermostat insufficiency, and overstocking. Actual start-up, annual maintenance, and annual electricity costs for using RTMDs were $686, $179, and $9 per refrigerator, respectively. In Haiti, RTMD use was feasible. RTMDs could be prioritized for use with existing refrigerators with high volumes of vaccines and new refrigerators to certify their functionality before use. Vaccine vial monitors could provide additional useful information about cumulative heat exposure and possible vaccine denaturation. PMID- 29262289 TI - Excess Clinical Comorbidity Among HIV-Infected Patients Accessing Primary Care in US Community Health Centers. AB - OBJECTIVES: As the life expectancy of people infected with human immunodeficiency virus (HIV) infection has increased, the spectrum of illness has evolved. We evaluated whether people living with HIV accessing primary care in US community health centers had higher morbidity compared with HIV-uninfected patients receiving care at the same sites. METHODS: We compared data from electronic health records for 12 837 HIV-infected and 227 012 HIV-uninfected patients to evaluate the relative prevalence of diabetes mellitus, hypertension, chronic kidney disease, dyslipidemia, and malignancies by HIV serostatus. We used multivariable logistic regression to evaluate differences. Participants were patients aged >=18 who were followed for >=3 years (from January 2006 to December 2016) in 1 of 17 community health centers belonging to the Community Health Applied Research Network. RESULTS: Nearly two-thirds of HIV-infected and HIV uninfected patients lived in poverty. Compared with HIV-uninfected patients, HIV infected patients were significantly more likely to be diagnosed and/or treated for diabetes (odds ratio [OR] = 1.18; 95% confidence interval [CI], 1.22-1.41), hypertension (OR = 1.38; 95% CI, 1.31-1.46), dyslipidemia (OR = 2.30; 95% CI, 2.17-2.43), chronic kidney disease (OR = 4.75; 95% CI, 4.23-5.34), lymphomas (OR = 4.02; 95% CI, 2.86-5.67), cancers related to human papillomavirus (OR = 5.05; 95% CI, 3.77-6.78), or other cancers (OR = 1.25; 95% CI, 1.10-1.42). The prevalence of stroke was higher among HIV-infected patients (OR = 1.32; 95% CI, 1.06-1.63) than among HIV-uninfected patients, but the prevalence of myocardial infarction or coronary artery disease did not differ between the 2 groups. CONCLUSIONS: As HIV-infected patients live longer, the increasing burden of noncommunicable diseases may complicate their clinical management, requiring primary care providers to be trained in chronic disease management for this population. PMID- 29262291 TI - Diagnosis of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Mycoplasma genitalium: an observational study of testing patterns, prevalence and co-infection rates in northern New Zealand. AB - : Background This study sought to determine community prevalence, epidemiology and testing patterns for sexually transmissible infections (STI) in northern New Zealand. METHODS: A total of 2643 samples submitted for STI testing between 26 November 2015 and 7 December 2015 underwent analysis by Aptima Combo 2 (Hologic, San Diego, CA, USA), Trichomonas vaginalis (TV), and Mycoplasma genitalium (MG) assays. Results were analysed by patient demographics. RESULTS: Four hundred and eleven pathogens were detected from 359 patients, with Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), TV, and MG detected in 178 (6.7%), 19 (0.7%), 80 (3%) and 134 (5.1%) samples respectively. With the exception of TV, STI prevalence was highest in people <25 years of age. Infection was more common in men for NG (odds ratio (OR) 5.05, P<0.001) and CT (OR 2.72, P<0.001). Maori and Pacific ethnicity were associated with increased risk of MG (OR 1.82, P=0.006,) TV (OR 6.1, P<0.001) and CT (OR 3.31, P<0.001) infection, and TV and NG infections were more prevalent as social deprivation increased. A mismatch between testing rates and prevalence of infection was seen, with fewer tests performed for males (OR 0.2, P<0.001) than females and no difference in testing of Maori and Pacific men (3064/100000) compared with men of European background (3181/100000, OR 0.96, P=0.76), despite an increased risk of disease. CONCLUSIONS: There are disparately low testing rates for STIs in certain high risk groups in northern New Zealand. PMID- 29262290 TI - Collection of Data on Race, Ethnicity, Language, and Nativity by US Public Health Surveillance and Monitoring Systems: Gaps and Opportunities. AB - OBJECTIVE: Despite increasing diversity in the US population, substantial gaps in collecting data on race, ethnicity, primary language, and nativity indicators persist in public health surveillance and monitoring systems. In addition, few systems provide questionnaires in foreign languages for inclusion of non-English speakers. We assessed (1) the extent of data collected on race, ethnicity, primary language, and nativity indicators (ie, place of birth, immigration status, and years in the United States) and (2) the use of data-collection instruments in non-English languages among Centers for Disease Control and Prevention (CDC)-supported public health surveillance and monitoring systems in the United States. METHODS: We identified CDC-supported surveillance and health monitoring systems in place from 2010 through 2013 by searching CDC websites and other federal websites. For each system, we assessed its website, documentation, and publications for evidence of the variables of interest and use of data collection instruments in non-English languages. We requested missing information from CDC program officials, as needed. RESULTS: Of 125 data systems, 100 (80%) collected data on race and ethnicity, 2 more collected data on ethnicity but not race, 26 (21%) collected data on racial/ethnic subcategories, 40 (32%) collected data on place of birth, 21 (17%) collected data on years in the United States, 14 (11%) collected data on immigration status, 13 (10%) collected data on primary language, and 29 (23%) used non-English data-collection instruments. Population based surveys and disease registries more often collected data on detailed variables than did case-based, administrative, and multiple-source systems. CONCLUSIONS: More complete and accurate data on race, ethnicity, primary language, and nativity can improve the quality, representativeness, and usefulness of public health surveillance and monitoring systems to plan and evaluate targeted public health interventions to eliminate health disparities. PMID- 29262293 TI - Verification and large scale clinical evaluation of a national standard protocol for Salmonella spp./Shigella spp. screening using real-time PCR combined with guided culture. AB - Salmonella spp./Shigella spp. are often associated with food poisoning and fecal oral transmission of acute gastroenteritis that requires strict monitoring, especially among people who would handle food and water. In 2014, the National Health and Family Planning Commission of the P. R. China issued a national standard protocol (recommendatory) for the screening of Salmonella spp./Shigella spp.. However, its performance has not been fully studied. Whether it was suitable for use in our laboratory was still unknown. In the current study, the new protocol was first verified by various experiments and then its clinical performance was evaluated in about 20,000 stool samples over a three-year period. Verification results showed that the new protocol was highly specific and reproducible. Sensitivity (as defined as the lower limit of detection) of the new protocol at the PCR step was 103CFU/mL and 101CFU/mL for Salmonella spp. and Shigella spp., while that at the guided culture step was 104CFU/mL and 103CFU/mL, respectively. The large scale clinical evaluation indicated that the new protocol could increase the positivity rate by two fold and decrease the workload/median turnaround time significantly. In conclusion, the protocol was verified and evaluated and was proven to be a valuable platform for the rapid, specific, sensitive and high-throughput screening of Salmonella spp./Shigella spp. PMID- 29262292 TI - Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal dominant leukodystrophy (ADLD). AB - Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disease caused by overexpression of lamin B1, a nuclear lamina filament. Early autonomic dysfunction involving the cardiovascular system before progressive somatic motor dysfunction is a striking feature of most cases of ADLD. In the Plp FLAG-LMNB1 transgenic mouse model, lamin B1 overexpression in oligodendrocytes elicits somatic motor dysfunction and neuropathology akin to ADLD. Here, we investigate whether Plp-FLAG-LMNB1 mice also develop autonomic cardiovascular dysfunction before or after somatic motor dysfunction. We find that Plp-FLAG LMNB1 mice have preserved cardiovascular responses to changes in wake-sleep state and ambient temperature and normal indexes of autonomic modulation at 37-42weeks of age despite a progressive somatic motor dysfunction, which includes impairments of walking ability (the ability to walk on a narrow path was impaired in 80% of mice at 34-38weeks of age) and subtle breathing derangements. Only late in the development of the disease phenotype did Plp-FLAG-LMNB1 mice develop a structural deficit of sympathetic noradrenergic fibers, with a 38% decrease in fiber profiles in the kidneys at 44-47weeks of age. We demonstrate that while the Plp-FLAG-LMNB1 mouse model recapitulates the age-dependent motor dysfunction of ADLD, it does not show signs of early autonomic cardiovascular dysfunction, raising the possibility that oligodendrocyte dysfunction may not be sufficient to cause the full spectrum of clinical features present in ADLD. PMID- 29262294 TI - Mechanistic understanding of insulin receptor modulation: Implications for the development of anti-diabetic drugs. AB - The insulin receptor is an important regulator of metabolic processes in the body, and in particular of glucose homeostasis, including glucose uptake into peripheral tissues. Thus, insulin administration is an effective treatment for diabetes, which is characterized by chronic elevation of blood glucose. However, insulin is not only a metabolic regulator, but also functions as a growth hormone. Accordingly, studies of long-term insulin administration and of the hyperinsulinemia associated with type 2 diabetes have raised concerns about possible increases in the risks of cancer and atherosclerosis, due to excessive stimulation of cell proliferation. Interestingly, some insulin receptor ligands that have been developed based on a peptide, an antibody, and an aptamer selectively have metabolic effects exerted through the insulin receptor but do not cause significant cellular proliferation. Although these ligands therefore have potential as anti-diabetic drugs for advanced diabetes care, the mechanism whereby they specifically activate the insulin receptor is still unclear. Recently, studies of the structure of the insulin receptor have progressed considerably, and have provided further mechanistic understanding of insulin receptor activation. Based on this progress, we propose a mechanistic model of this specificity and discuss the potential for the development of novel anti diabetic drugs that would not have the adverse effects caused by excessive mitogenic action. PMID- 29262296 TI - Electroactive biomaterials: Vehicles for controlled delivery of therapeutic agents for drug delivery and tissue regeneration. AB - Electrical stimulation for delivery of biochemical agents such as genes, proteins and RNA molecules amongst others, holds great potential for controlled therapeutic delivery and in promoting tissue regeneration. Electroactive biomaterials have the capability of delivering these agents in a localized, controlled, responsive and efficient manner. These systems have also been combined for the delivery of both physical and biochemical cues and can be programmed to achieve enhanced effects on healing by establishing control over the microenvironment. This review focuses on current state-of-the-art research in electroactive-based materials towards the delivery of drugs and other therapeutic signalling agents for wound care treatment. Future directions and current challenges for developing effective electroactive approach based therapies for wound care are discussed. PMID- 29262297 TI - Antiallodynic and antihyperalgesic activity of new 3,3-diphenyl-propionamides with anticonvulsant activity in models of pain in mice. AB - Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. The aim of the present experiments was to examine analgesic activity of three new 3,3-diphenyl-propionamides, which had previously demonstrated anticonvulsant activity in the MES (maximal electroshock seizure), scPTZ (subcutaneous pentylenetetrazole) and/or 6Hz (psychomotor seizure) tests in mice. Antinociceptive activity was examined in mouse models of acute pain (the hot plate test) and tonic pain (the formalin test) in mice. Antiallodynic and antihyperalgesic activity was estimated in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin-induced model of painful diabetic neuropathy in mice. Considering the drug safety evaluation, the influence on locomotor activity was checked. Moreover, using in vitro methods, selected compound was tested for potential hepatotoxicity on human hepatocellular carcinoma cell line and for metabolic stability. To determine the plausible mechanism of anticonvulsant and antinociceptive action, in vitro binding and functional assays were carried out. Among tested molecules two of them JOA 122 (3p) and JOA 123 (3q) revealed significant antinociceptive activity in the model of tonic pain - the formalin test and neuropathic pain models - the oxaliplatin and streptozotocin-induced peripheral neuropathy. In the binding studies JOA 122 (3p) revealed the high affinity to voltage-gated sodium channels (Nav1.2), as well as for 5-HT1A receptors. Metabolism studies in mouse liver microsomes showed a low metabolic stability of this compound. PMID- 29262298 TI - Omission P3 after voluntary action indexes the formation of action-driven prediction. AB - When humans frequently experience a certain sensory effect after a certain action, a bidirectional association between neural representations of the action and the sensory effect is rapidly acquired, which enables action-driven prediction of the sensory effect. The present study aimed to test whether or not omission P3, an event-related brain potential (ERP) elicited by the sudden omission of a sensory effect, is sensitive to the formation of action-driven prediction. For this purpose, we examined how omission P3 is affected by the number of possible visual effects. In four separate blocks (1-, 2-, 4-, and 8 stimulus blocks), participants successively pressed a right button at an interval of about 1s. In all blocks, each button press triggered a bar on a display (a bar with square edges, 85%; a bar with round edges, 5%), but occasionally did not (sudden omission of a visual effect, 10%). Participants were required to press a left button when a bar with round edges appeared. In the 1-stimulus block, the orientation of the bar was fixed throughout the block; in the 2-, 4-, and 8 stimulus blocks, the orientation was randomly varied among two, four, and eight possibilities, respectively. Omission P3 in the 1-stimulus block was greater than those in the 2-, 4-, and 8-stimulus blocks; there were no significant differences among the 2-, 4-, and 8-stimulus blocks. This binary pattern nicely fits the limitation in the acquisition of action-effect association; although an association between an action and one visual effect is easily acquired, associations between an action and two or more visual effects cannot be acquired concurrently. Taken together, the present results suggest that omission P3 is highly sensitive to the formation of action-driven prediction. PMID- 29262299 TI - ATPase N-ethylmaleimide-sensitive Fusion Protein: A Novel Key Player for Causing Spontaneous Network Excitation in Human Temporal Lobe Epilepsy. AB - The molecular basis for onset, maintenance and propagation of excitation along neuronal networks in epilepsy is still poorly understood. Besides different neurotransmitter receptors that control signal transfer at the synapse, one key regulator involved in all of these processes is the ATPase N-ethylmaleimide sensitive fusion protein (NSF). Therefore, we analyzed receptor subunits and NSF levels in tissues from the medial temporal gyrus (MTG) of patients with pharmaco resistant focal temporal lobe epilepsy resected during epilepsy surgery and autopsy controls. The resected tissues were further characterized by field potential recordings into tissues with and without spontaneous sharp wave activity. We detected increased levels of NSF, NMDA 1.1, 2A and GABAAgamma2 receptor subunits associated with spontaneous sharp wave spiking activity. We further identified correlations between NSF, AMPA receptor subunit, metabotropic glutamate receptor and adenosine 1 receptor levels in the spontaneous sharp wave spiking tissues. Our findings suggest that NSF plays a key role in controlling spontaneous network excitation in epilepsy by two mechanisms of action: (1) directly via controlling transmitter release at the presynaptic side, and (2) indirectly via altering the function of possible receptor crosstalk and directing/integrating specific receptor compounds through/into the postsynaptic membrane. PMID- 29262300 TI - Helicoverpa-inducible Thioredoxin h from Cicer arietinum: structural modeling and potential targets. AB - Thioredoxins are small and universal proteins, which are involved in the cell redox regulation. In plants, they participate in a broad range of biochemical processes like self-incompatibility, seed germination, pathogen & pest defense and oxidative stress tolerance. The h-type of thioredoxin (Trx-h) protein represents the largest Trx family. Herein, we characterized the Helicoverpa - inducible Trx h from an important legume, Cicer arietinum, CaHaTrx-h, 'CGFS' type Trxs, which encodes for a 113 amino acids long protein and possess characteristic motifs "FLKVDVDE" and "VVDFTASWCGPCRFIAPIL" and 73% sequence identity with AtTrx h. Homology modeling and simulation of the target showed that the extended beta sheet regions remain stable during the simulation while the helical regions fluctuate between alpha and 3-10 helical forms and highlights the flexibility of helix2-helix3 and terminal regions probably to accommodate an approaching protein target and facilitate their interaction. During the simulation, the structure exists in five energy minima clusters with biggest cluster size belonging to 20 25 ns time frames. PR-5 and Mannitol Dehydrogenase were nominated as potential targets and share close interaction with CaHaTrx-h via disulfide bond reduction. The study is an effort in the direction of understanding stress-related mechanisms in crop plants to overcome losses in agricultural yield. PMID- 29262301 TI - Drug nanocrystals - Versatile option for formulation of poorly soluble materials. AB - Poor solubility of drug compounds is a great issue in drug industry today and decreasing particle size is one efficient and simple way to overcome this challenge. Drug nanocrystals are solid nanosized drug particles, which are covered by a stabilizer layer. In nanoscale many physical properties, like compound solubility, are different from the solubility of bulk material, and due to this drug nanocrystals can reach supersaturation as compared to thermodynamic solubility. The most important effect of the smaller particle size is that dissolution rate is highly enhanced mainly due to the increased surface area. In this review the most important properties of nanocrystalline drug compounds are presented, with multiple examples of the development and characterization of nanocrystalline drug formulations. PMID- 29262295 TI - Potential for therapeutic targeting of AKAP signaling complexes in nervous system disorders. AB - A common feature of neurological and neuropsychiatric disorders is a breakdown in the integrity of intracellular signal transduction pathways. Dysregulation of ion channels and receptors in the cell membrane and the enzymatic mediators that link them to intracellular effectors can lead to synaptic dysfunction and neuronal death. However, therapeutic targeting of these ubiquitous signaling elements can lead to off-target side effects due to their widespread expression in multiple systems of the body. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that compartmentalize a diverse range of receptor and effector proteins to streamline signaling within nanodomain signalosomes. A number of essential neurological processes are known to critically depend on AKAP directed signaling and an understanding of the role AKAPs play in nervous system disorders has emerged in recent years. Selective targeting of AKAP protein protein interactions may be a means to uncouple pathologically active signaling pathways in neurological disorders with a greater degree of specificity. In this review we will discuss the role of AKAPs in both regulating normal nervous system function and dysfunction associated with disease, and the potential for therapeutic targeting of AKAP signaling complexes. PMID- 29262302 TI - Milling induced amorphisation and recrystallization of alpha-lactose monohydrate. AB - Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the alpha-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed alpha-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between unprocessed alpha-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spray dried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low water glass transition. PMID- 29262303 TI - Double training downshifts the threshold vs. noise contrast (TvC) functions with perceptual learning and transfer. AB - Location specific perceptual learning can transfer to a new location if the new location is trained with a secondary task that by itself does not impact the performance of the primary learning task (double training). Learning may also transfer to other locations when double training is performed at the same location. Here we investigated the mechanisms underlying double-training enabled learning and transfer with an external noise paradigm. Specifically, we measured the Vernier thresholds at various external noise contrasts before and after double training. Double training mainly vertically downshifts the TvC functions at the training and transfer locations, which may be interpreted as improved sampling efficiency in a linear amplifier model or a combination of internal noise reduction and external noise exclusion in a perceptual template model at both locations. The change of the TvC functions appears to be a high-level process that can be remapped from a training location to a new location after double training. PMID- 29262304 TI - Effects of central and peripheral cueing on perceptual and saccade performance. AB - Previous research on the spatiotemporal dynamics of exogenous and endogenous attentional allocation during saccade preparation yielded conflicting results. We hypothesize that this can be explained by the cueing type used to orient attention in a perceptual task. We investigated the time-course of attentional allocation as a function of cueing type (central vs peripheral), spatial congruency of the cued perceptual and saccade task locations, and cue validity in a dual-task paradigm. Participants performed a visual discrimination task during saccade preparation. We found that central and peripheral cues differentially affected the time-course of attentional allocation depending on spatial congruency and cue validity. Peripheral cues quickly and transiently oriented attention to the cued location. In the congruent condition, attention was maintained by the pre-saccadic attention shift, but declined in the spatially incongruent condition. Central cues slowly oriented attention to the cued location. In the congruent condition, attention was boosted by the pre-saccadic attention shift compared to a slower increase in the spatially incongruent condition. The pre-saccadic attention shift - the automatic and obligatory shift of attention to the saccade target - observed in the invalid spatially incongruent condition was not differentially affected by the cueing type orienting attention away from it. Our results suggest that exogenous and endogenous attention is dynamically and flexibly allocated to cued locations during saccade preparation while pre-saccadic attentional resources are progressively shifted to the saccade target irrespective of the cueing type. We argue that attentional selection for perception represents a partially independent process in contrast to the pre-saccadic attention shift. PMID- 29262305 TI - Effect of dentin hypersensitivity treatment on oral health related quality of life - A systematic review and meta-analysis. AB - OBJECTIVE: This study aimed to evaluate if in patients with dentin hypersensitivity (DH), the DH treatments are able to improve individuals' oral health related quality of life (OHRQoL). DATA AND SOURCES: A systematic review was performed based on PRISMA guidelines (PROSPERO CRD42016050864). Clinical trials reporting OHRQoL before and after DH treatment were included. The search was performed in the PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, LILACS, EMBASE and Scielo databases until May 2017. Hand searches and grey literature were included. Three researches independently selected the studies, extracted data, and assessed the methodological quality. The risk of bias was estimated based on the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analysis was performed by I2 test. The quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). STUDY SELECTION: Six clinical trials were included. DH was assessed by evaporative, cold, and tactile stimuli. OHRQoL was evaluated by OHIP-14 and DHEQ questionnaires. In-home and in-office desensitizing agents for DH treatment were used. The revised studies reported statistically significant reduction of DH and significant improvement in quality of life after treatment (p<0.05). Two studies were judged as high risk of bias. The studies presented high heterogeneity (I2=0.8407). The evidence was very low to moderate. CONCLUSIONS: The studies indicated decreasing of DH and improving of OHRQoL after DH treatment, although, they presented low to moderate methodological quality. CLINICAL SIGNIFICANCE: The Oral Health Relate Quality of Life of whom complaint of DH can be improved after DH treatment. PMID- 29262306 TI - Complete mitochondrial genome of Odontobutis haifengensis (Perciformes, Odontobutiae): A unique rearrangement of tRNAs and additional non-coding regions identified in the genus Odontobutis. AB - Herein, the complete mitochondrial genome of Odontobutis haifengensis was sequenced for the first time. The O. haifengensis mitogenome was 17,016bp in length and included 13 protein-coding genes, 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and a control region (CR). The genome organization, base composition, codon usage, and gene rearrangement was similar to other Odontobutis species. Furthermore, a tRNA gene rearrangement within the SLH cluster was found to be identical to other Odontobutis species. Moreover, the gene order and the positions of additional intergenic non-coding regions suggests that the observed unique gene rearrangement resulted from a tandem duplication and random loss of large-scale gene regions. Additionally, phylogenetic analysis showed that Odontobutis species form a monophyletic clade due to the conserved mitochondrial gene rearrangement. This study provides useful information that aids in a better understanding of mitogenomic diversity and evolutionary patterns of Odontobutidae species. PMID- 29262307 TI - Concurrent validation of the OMNI-Resistance Exercise Scale of perceived exertion with elastic bands in the elderly. AB - PURPOSE: To examine the concurrent validity of the OMNI-Resistance Exercise Scale of perceived exertion using elastic bands in elder population. METHODS: Twenty six participants performed three separate sets of 15 repetitions (low- medium- and high-intensity) for 4 different exercises (2 for the upper-limb and 2 for the lower limb), over two different testing sessions. The criterion variables were heart rate and applied force (average and maximum). In addition to these dependent variables, the active muscle and overall body OMNI-RES for elastic bands scores were collected at the end of each repetition. RESULTS: Significant differences in heart rate, applied force and OMNI-RES scores between the low- and high-intensity sets were observed. For all the four exercises, high intensity sets elicited higher heart rate, applied force, and RPE compared to the medium and the low overloads. Intraclass correlation coefficient was 0.79 in heart rate and ranged 0.69-0.80 in OMNI-RES Scale and 0.76-0.86 for the applied force. CONCLUSION: A strong positive and linear relationship was observed between the rating of perceived exertion and both heart rate and applied force. The OMNI-RES scale with elastic bands demonstrated to be a valid method for assessing the perceived exertion during resistance exercises and consequently represent a useful tool for prescribing exercise intensity to the elderly. PMID- 29262308 TI - Multiple-modality exercise and mind-motor training to improve mobility in older adults: A randomized controlled trial. AB - OBJECTIVE: To investigate the effects of multiple-modality exercise with or without additional mind-motor training on mobility outcomes in older adults with subjective cognitive complaints. METHODS: This was a 24-week randomized controlled trial with a 28-week no-contact follow-up. Community-dwelling older adults underwent a thrice -weekly, Multiple-Modality exercise and Mind-Motor (M4) training or Multiple-Modality (M2) exercise with an active control intervention (balance, range of motion and breathing exercises). Study outcomes included differences between groups at 24weeks and after the no-contact follow-up (i.e., 52weeks) in usual and dual-task (DT, i.e., serial sevens [S7] and phonemic verbal fluency [VF] tasks) gait velocity, step length and cycle time variability, as well as DT cognitive accuracy. RESULTS: 127 participants (mean age 67.5 [7.3] years, 71% women) were randomized to either M2 (n=64) or M4 (n=63) groups. Participants were assessed at baseline, intervention endpoint (24weeks), and study endpoint (52weeks). At 24weeks, the M2 group demonstrated greater improvements in usual gait velocity, usual step length, and DT gait velocity (VF) compared to the M4 group, and no between- or within-group changes in DT accuracy were observed. At 52weeks, the M2 group retained the gains in gait velocity and step length, whereas the M4 group demonstrated trends for improvement (p=0.052) in DT cognitive accuracy (VF). CONCLUSIONS: Our results suggest that additional mind-motor training was not effective to improve mobility outcomes. In fact, participants in the active control group experienced greater benefits as a result of the intervention. PMID- 29262309 TI - LRP1: A chameleon receptor of lung inflammation and repair. AB - The lung displays a remarkable capability to regenerate following injury. Considerable effort has been made thus far to understand the cardinal processes underpinning inflammation and reconstruction of lung tissue. However, the factors determining the resolution or persistence of inflammation and efficient wound healing or aberrant remodeling remain largely unknown. Low density lipoprotein receptor-related protein 1 (LRP1) is an endocytic/signaling cell surface receptor which controls cellular and molecular mechanisms driving the physiological and pathological inflammatory reactions and tissue remodeling in several organs. In this review, we will discuss the impact of LRP1 on the consecutive steps of the inflammatory response and its role in the balanced tissue repair and aberrant remodeling in the lung. PMID- 29262310 TI - Binding of cholera toxin B subunit to intestinal epithelial cells. AB - We have prepared 125I-labeled cholera toxin B subunit (125I-labeled CT-B, a specific activity of 98Ci/mmol) and found that it binds to rat IEC-6 and human Caco-2 intestinal epithelial cells with high affinity (Kd 3.6 and 3.7nM, respectively). The binding of labeled protein was completely inhibited by unlabeled thymosin-alpha1 (TM-alpha1), interferon-alpha2 (IFN-alpha2), and the synthetic peptide LKEKK that corresponds to residues 16-20 in TM-alpha1 and 131 135 in IFN-alpha2, but was not inhibited by the synthetic peptide KKEKL with inverted amino acid sequence (Ki>10MUM). Thus, TM-alpha1, IFN-alpha2, and the peptide: LKEKK bind with high affinity and specificity to the cholera toxin receptor on IEC-6 and Caco-2 cells. It was found that CT-B and the peptide: LKEKK at concentrations of 10-1000nM increased in a dose-dependent manner the nitric oxide production and the soluble guanylate cyclase activity in IEC-6 and Caco-2 cells. PMID- 29262311 TI - Cytotoxicity of demalonyl thyrsiflorin A, a semisynthetic labdane-derived diterpenoid, to melanoma cells. AB - Diterpenes are compounds with complex structure and due to their unique carbon skeleton and interesting biological activities, have been the focus of continuous studies for the development of new anticancer agents. The plants of the genus Calceolaria (Scrophulariaceae family), native of South America have also yielded several new diterpenes with the scopadulane skeleton, such as thyrsiflorin A. The present study was undertaken to investigate the effect of the semisynthetic compound, demalonyl thyrsiflorin A on human melanoma cells. In A375 cells compound demalonyl thyrsiflorin A showed a clear dose-response relationship in the range of 6.25-50MUM concentrations. In addition, we demonstrated an apoptotic response after treatment of cancer cells with this semisynthetic phenolic labdane diterpene at 6.25 and 12.5MUM concentrations that probably involves the reduction of Hsp70 expression and reactive oxygen species production. Alternatively, the inhibition of the caspase cascade at higher concentrations, 25 and 50MUM, correlated with additional reactive oxygen species increase, probably switched the mode of demalonyl thyrsiflorin A-induced cell death from apoptosis to necrosis. PMID- 29262312 TI - Effects of daily exposure to saccharin sodium and rebaudioside A on the ovarian cycle and steroidogenesis in rats. AB - Saccharin sodium and rebaudioside A are widely used as non-caloric sweeteners in our daily life; however, the impacts and regulatory mechanisms of such sweeteners on reproduction remain unclear. In the present study, we used rats as animal models to evaluate the effects of daily exposure to saccharin sodium and rebaudioside A on ovarian biologic functions. Weanling rats were distributed into five experimental groups receiving normal water, 1.5 or 7.5 mM saccharin sodium solution, or 0.5 or 2.5 mM rebaudioside A solution for 48 days of exposure. The results showed an increased percentage of abnormal estrous cycles, augmented number of ovarian cysts, elevated serum progesterone levels, and increased expression of steroidogenesis-related factors in saccharin sodium-treated groups. Conversely, rebaudioside A-treated groups showed decreased serum progesterone levels. Our findings suggest that saccharin sodium exerts adverse biologic effects on ovaries, and rebaudioside A is a potential steroidogenic disruptor in female rats. PMID- 29262313 TI - Molecular Prerequisites for Diminished Cold Sensitivity in Ground Squirrels and Hamsters. AB - Thirteen-lined ground squirrels and Syrian hamsters are known for their ability to withstand cold during hibernation. We found that hibernators exhibit cold tolerance even in the active state. Imaging and electrophysiology of squirrel somatosensory neurons reveal a decrease in cold sensitivity of TRPM8-expressing cells. Characterization of squirrel and hamster TRPM8 showed that the channels are chemically activated but exhibit poor activation by cold. Cold sensitivity can be re-introduced into squirrel and hamster TRPM8 by transferring the transmembrane domain from the cold sensitive rat ortholog. The same can be achieved in squirrel TRPM8 by mutating only six amino acids. Reciprocal mutations suppress cold sensitivity of the rat ortholog, supporting functional significance of these residues. Our results suggest that ground squirrels and hamsters exhibit reduced cold sensitivity, partially due to modifications in the transmembrane domain of TRPM8. Our study reveals molecular adaptations that accompany cold tolerance in two species of mammalian hibernators. PMID- 29262314 TI - Fast Ca2+ Buffer-Dependent Reliable but Plastic Transmission at Small CNS Synapses Revealed by Direct Bouton Recording. AB - The small size of presynaptic structures and their rapid function have obscured the mechanisms underlying neurotransmission and plasticity. To dissect the function of conventional small presynaptic boutons, we performed direct recording using axon varicosities of cerebellar granule cells (GCs), a parallel-fiber bouton, in dissociated culture, in which pre- and postsynaptic paired recordings are feasible. Identification and accessibility of EGFP-labeled GC boutons allowed us to patch-clamp record presynaptic voltage-gated Ca2+ currents and membrane capacitances, together with excitatory postsynaptic currents. We find that GC boutons have 20 readily releasable vesicles, which are loosely coupled to Ca2+ channels and rapidly replenished, and that synaptic strength and short-term plasticity are tightly regulated by intracellular Ca2+ buffering. Our functional dissection of small boutons thus reveals the sophisticated design of small synapses capable of reliable but plastic outputs with limited resources. PMID- 29262315 TI - Cell-Autonomous Control of Neuronal Dendrite Expansion via the Fatty Acid Synthesis Regulator SREBP. AB - During differentiation, neurons require a high lipid supply for membrane formation as they elaborate complex dendritic morphologies. While glia-derived lipids support neuronal growth during development, the importance of cell autonomous lipid production for dendrite formation has been unclear. Using Drosophila larva dendritic arborization (da) neurons, we show that dendrite expansion relies on cell-autonomous fatty acid production. The nociceptive class four (CIV) da neurons form particularly large space-filling dendrites. We show that dendrite formation in these CIVda neurons additionally requires functional sterol regulatory element binding protein (SREBP), a crucial regulator of fatty acid production. The dendrite simplification in srebp mutant CIVda neurons is accompanied by hypersensitivity of srebp mutant larvae to noxious stimuli. Taken together, our work reveals that cell-autonomous fatty acid production is required for proper dendritic development and establishes the role of SREBP in complex neurons for dendrite elaboration and function. PMID- 29262316 TI - S-Adenosylmethionine Synthesis Is Regulated by Selective N6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1. AB - S-adenosylmethionine (SAM) is an important metabolite as a methyl-group donor in DNA and histone methylation, tuning regulation of gene expression. Appropriate intracellular SAM levels must be maintained, because methyltransferase reaction rates can be limited by SAM availability. In response to SAM depletion, MAT2A, which encodes a ubiquitous mammalian methionine adenosyltransferase isozyme, was upregulated through mRNA stabilization. SAM-depletion reduced N6-methyladenosine (m6A) in the 3' UTR of MAT2A. In vitro reactions using recombinant METTL16 revealed multiple, conserved methylation targets in the 3' UTR. Knockdown of METTL16 and the m6A reader YTHDC1 abolished SAM-responsive regulation of MAT2A. Mutations of the target adenine sites of METTL16 within the 3' UTR revealed that these m6As were redundantly required for regulation. MAT2A mRNA methylation by METTL16 is read by YTHDC1, and we suggest that this allows cells to monitor and maintain intracellular SAM levels. PMID- 29262317 TI - A Small RNA Pathway Mediates Allelic Dosage in Endosperm. AB - Balance between maternal and paternal genomes within the triploid endosperm is necessary for normal seed development. The majority of endosperm genes are expressed in a 2:1 maternal:paternal ratio, reflecting genomic DNA content. Here, we find that the 2:1 transcriptional ratio is, unexpectedly, actively regulated. In A. thaliana and A. lyrata, endosperm 24-nt small RNAs are reduced in transposable elements and enriched in genes compared with the embryo. We find an inverse relationship between the parent of origin of sRNAs and mRNAs, with genes more likely to be associated with maternally than paternally biased sRNAs. Disruption of the Pol IV sRNA pathway causes a shift toward maternal allele mRNA expression for many genes. Furthermore, paternal inheritance of an RNA Pol IV mutation is sufficient to rescue seed abortion caused by excess paternal genome dosage. Thus, RNA Pol IV mediates the transcriptional balance between maternally and paternally inherited genomes in endosperm. PMID- 29262318 TI - The Protein Trio RPK1-CaM4-RbohF Mediates Transient Superoxide Production to Trigger Age-Dependent Cell Death in Arabidopsis. AB - Reactive oxygen species (ROS) are inevitable by-products of aerobic metabolic processes, causing non-specific oxidative damage and also acting as second messengers. Superoxide is a short-lived ROS that functions in various cellular responses, including aging and cell death. However, it is unclear as to how superoxide brings about age-dependent cell death and senescence. Here, we show that the accumulation and signaling of superoxide are mediated by three Arabidopsis proteins-RPK1, CaM4, and RbohF-which trigger subsequent cellular events leading to age-dependent cell death. We demonstrate that the NADPH oxidase RbohF is responsible for RPK1-mediated transient accumulation of superoxide, SIRK kinase induction, and cell death, all of which are positively regulated by CaM4. RPK1 physically interacts with and phosphorylates CaM4, which, in turn, interacts with RbohF. Overall, we demonstrate how the protein trio governs the superoxide accumulation and signaling at the cell surface to control senescence and cell death. PMID- 29262319 TI - Citrobacter rodentium Relies on Commensals for Colonization of the Colonic Mucosa. AB - We investigated the role of commensals at the peak of infection with the colonic mouse pathogen Citrobacter rodentium. Bioluminescent and kanamycin (Kan) resistant C. rodentium persisted avirulently in the cecal lumen of mice continuously treated with Kan. A single Kan treatment was sufficient to displace C. rodentium from the colonic mucosa, a phenomenon not observed following treatment with vancomycin (Van) or metronidazole (Met). Kan, Van, and Met induce distinct dysbiosis, suggesting C. rodentium relies on specific commensals for colonic colonization. Expression of the master virulence regulator ler is induced in germ-free mice, yet C. rodentium is only seen in the cecal lumen. Moreover, in conventional mice, a single Kan treatment was sufficient to displace C. rodentium constitutively expressing Ler from the colonic mucosa. These results show that expression of virulence genes is not sufficient for colonization of the colonic mucosa and that commensals are essential for a physiological infection course. PMID- 29262320 TI - The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer. AB - DNA methylation plays crucial roles in chromatin structure and gene expression. Aberrant DNA methylation patterns, including global hypomethylation and regional hypermethylation, are associated with cancer and implicated in oncogenic events. How DNA methylation is regulated in developmental and cellular processes and dysregulated in cancer is poorly understood. Here, we show that PRMT6, a protein arginine methyltransferase responsible for asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a), negatively regulates DNA methylation and that PRMT6 upregulation contributes to global DNA hypomethylation in cancer. Mechanistically, PRMT6 overexpression impairs chromatin association of UHRF1, an accessory factor of DNMT1, resulting in passive DNA demethylation. The effect is likely due to elevated H3R2me2a, which inhibits the interaction between UHRF1 and histone H3. Our work identifies a mechanistic link between protein arginine methylation and DNA methylation, which is disrupted in cancer. PMID- 29262321 TI - BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer. AB - PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers. PMID- 29262322 TI - SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing. AB - Dysregulated alternative splicing events have been implicated in many types of cancer, but the underlying molecular mechanisms remain unclear. Here, we observe that the splicing factor SRSF1 regulates DBF4B exon6 splicing by specifically binding and promoting its inclusion. Knockdown of the exon6-containing isoform (DBF4B-FL) significantly inhibits the tumorigenic potential of colon cancer cells in vitro and in mice, and SRSF1 inactivation phenocopies DBF4B-FL depletion. DBF4B-FL and SRSF1 are required for cancer cell proliferation and for the maintenance of genomic stability. Overexpression of DBF4B-FL can protect against DNA damage induced by SRSF1 knockdown and rescues growth defects in SRSF1 depleted cells. Increased DBF4B exon6 inclusion parallels SRSF1 upregulation in clinical colorectal cancer samples. Taken together, our findings identify SRSF1 as a key regulator of DBF4B pre-mRNA splicing dysregulation in colon cancer, with possible clinical implications as candidate prognostic factors in cancer patients. PMID- 29262323 TI - Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection. AB - Immune cells are equipped with a number of receptors that recognize sterile injury and pathogens. We find that host immune cells release ATP as an inflammatory signal in response to allogeneic transplantation. ATP then acts via a feedback mechanism on the P2X7 channel to activate the NLRP3 inflammasome and subsequently process and release interleukin (IL)-18. This process is a necessary stage in the deleterious Th1 response against allotransplantation via interferon gamma production. Lack of IL-18 resulted in a decrease in graft-infiltrating CD8 cells but an increase in regulatory T cells. In human liver transplant patients undergoing progressive immunosuppressive drug withdrawal, we found that patients experiencing acute rejection had higher levels of the P2X7 receptor in circulating inflammatory monocytes compared to tolerant patients. These data suggest that the pharmacological inhibition of the P2X7 receptor or the NLRP3 inflammasome will aid in inducing transplant tolerance without complete immunoparalysis. PMID- 29262324 TI - Caspase-1 Engagement and TLR-Induced c-FLIP Expression Suppress ASC/Caspase-8 Dependent Apoptosis by Inflammasome Sensors NLRP1b and NLRC4. AB - The caspase activation and recruitment domain (CARD)-based inflammasome sensors NLRP1b and NLRC4 induce caspase-1-dependent pyroptosis independent of the inflammasome adaptor ASC. Here, we show that NLRP1b and NLRC4 trigger caspase-8 mediated apoptosis as an alternative cell death program in caspase-1-/- macrophages and intestinal epithelial organoids (IECs). The caspase-8 adaptor FADD was recruited to ASC specks, which served as cytosolic platforms for caspase 8 activation and NLRP1b/NLRC4-induced apoptosis. We further found that caspase-1 protease activity dominated over scaffolding functions in suppressing caspase-8 activation and induction of apoptosis of macrophages and IECs. Moreover, TLR induced c-FLIP expression inhibited caspase-8-mediated apoptosis downstream of ASC speck assembly, but did not affect pyroptosis induction by NLRP1b and NLRC4. Moreover, unlike during pyroptosis, NLRP1b- and NLRC4-elicited apoptosis retained alarmins and the inflammasome-matured cytokines interleukin 1beta (IL-1beta) and IL-18 intracellularly. This work identifies critical mechanisms regulating apoptosis induction by the inflammasome sensors NLRP1b and NLRC4 and suggests converting pyroptosis into apoptosis as a paradigm for suppressing inflammation. PMID- 29262325 TI - B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation. AB - Epstein-Barr virus (EBV) in tumor cells is predominately in the latent phase, but the virus can undergo lytic reactivation in response to various stimuli. However, the cellular factors that control latency and lytic replication are poorly defined. In this study, we demonstrated that a cellular factor, PIAS1, restricts EBV lytic replication. PIAS1 depletion significantly facilitated EBV reactivation, while PIAS1 reconstitution had the opposite effect. Remarkably, we found that various lytic triggers promote caspase-dependent cleavage of PIAS1 to antagonize PIAS1-mediated restriction and that caspase inhibition suppresses EBV replication through blocking PIAS1 cleavage. We further demonstrated that a cleavage-resistant PIAS1 mutant suppresses EBV replication upon B cell receptor activation. Mechanistically, we demonstrated that PIAS1 acts as an inhibitor for transcription factors involved in lytic gene expression. Collectively, these results establish PIAS1 as a key regulator of EBV lytic replication and uncover a mechanism by which EBV exploits apoptotic caspases to antagonize PIAS1-mediated restriction. PMID- 29262326 TI - HIV-Specific CD8+ T Cells Exhibit Reduced and Differentially Regulated Cytolytic Activity in Lymphoid Tissue. AB - Elimination of lymphoid tissue reservoirs is a key component of HIV eradication strategies. CD8+ T cells play a critical role in control of HIV, but their functional attributes in lymph nodes (LNs) remain unclear. Here, we show that memory, follicular CXCR5+, and HIV-specific CD8+ T cells from LNs do not manifest the properties of cytolytic CD8+ T cells. While the frequency of follicular CXCR5+ CD8+ T cells was strongly inversely associated with peripheral viremia, this association was not dependent on cytolytic CXCR5+ CD8+ T cells. Moreover, the poor cytolytic activity of LN CD8+ T cells was linked to a compartmentalized dissociation between effector programming and the transcription factor T-bet. In line with this, activation of LN CD8+ T cells only partially induced the acquisition of cytolytic functions relative to peripheral blood CD8+ T cells. These results suggest that a state of immune privilege against CD8+ T cell mediated cytolysis exists in lymphoid tissue, potentially facilitating the persistence of HIV. PMID- 29262327 TI - Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication. AB - Although dendritic cells are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with the Zika virus (ZIKV). Using highly purified myeloid dendritic cells isolated from individuals with naturally acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to healthy donors. Interestingly, we noted a remarkable downregulation of antiviral interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress interferon-dependent immune responses. In contrast, several host factors known to support ZIKV infection were strongly upregulated during natural ZIKV infection; these transcripts included AXL, the main entry receptor for ZIKV; SOCS3, a negative regulator of ISG expression; and IDO-1, a recognized inducer of regulatory T cell responses. Thus, during in vivo infection, ZIKV can transform the transcriptome of dendritic cells in favor of the virus to render these cells highly conducive to ZIKV infection. PMID- 29262328 TI - Association with Aurora-A Controls N-MYC-Dependent Promoter Escape and Pause Release of RNA Polymerase II during the Cell Cycle. AB - MYC proteins bind globally to active promoters and promote transcriptional elongation by RNA polymerase II (Pol II). To identify effector proteins that mediate this function, we performed mass spectrometry on N-MYC complexes in neuroblastoma cells. The analysis shows that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21, a subunit of cohesin. N-MYC and TFIIIC bind to overlapping sites in thousands of Pol II promoters and intergenic regions. TFIIIC promotes association of RAD21 with N-MYC target sites and is required for N-MYC-dependent promoter escape and pause release of Pol II. Aurora-A competes with binding of TFIIIC and RAD21 to N-MYC in vitro and antagonizes association of TOP2A, TFIIIC, and RAD21 with N-MYC during S phase, blocking N-MYC-dependent release of Pol II from the promoter. Inhibition of Aurora-A in S phase restores RAD21 and TFIIIC binding to chromatin and partially restores N-MYC-dependent transcriptional elongation. We propose that complex formation with Aurora-A controls N-MYC function during the cell cycle. PMID- 29262329 TI - PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression. AB - Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population. PMID- 29262330 TI - Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration. AB - The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis. In contrast, when challenged through transplantation, Hlf-deficient HSCs showed an impaired ability to reconstitute hematopoiesis and became gradually exhausted upon serial transplantation. Transcriptional profiling of Hlf-deficient HSCs revealed changes associated with enhanced cellular activation, and cell-cycle analysis demonstrated a significant reduction of quiescent HSCs. Accordingly, toxic insults targeting dividing cells completely eradicated the HSC pool in Hlf-deficient mice. In summary, our findings point to HLF as a critical regulator of HSC quiescence and as an essential factor for maintaining the HSC pool during regeneration. PMID- 29262331 TI - The LXCXE Retinoblastoma Protein-Binding Motif of FOG-2 Regulates Adipogenesis. AB - GATA transcription factors and their FOG cofactors play a key role in tissue specific development and differentiation, from worms to humans. Mammals have six GATA and two FOG factors. We recently demonstrated that interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation. We show here that the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Unlike GATA-1, which inhibits cell division, FOG-2 promotes proliferation. Mice with a knockin of a Fog2 gene bearing a mutated LXCXE pRb-binding site are resistant to obesity and display higher rates of white to-brown fat conversion. Thus, each component of the GATA/FOG complex (GATA-1 and FOG-2) is involved in pRb/E2F regulation, but these molecules have markedly different roles in the control of tissue homeostasis. PMID- 29262332 TI - Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism. AB - Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to "pull" glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism. PMID- 29262333 TI - Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. AB - Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a pseudoU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs). Intravenous (i.v.) administration of hMUT mRNA in two different mouse models of MMA resulted in a 75%-85% reduction in plasma methylmalonic acid and was associated with increased hMUT protein expression and activity in liver. Repeat dosing of hMUT mRNA reduced circulating metabolites and dramatically improved survival and weight gain. Additionally, repeat i.v. dosing did not increase markers of liver toxicity or inflammation in heterozygote MMA mice. PMID- 29262334 TI - Modulation of SF1 Neuron Activity Coordinately Regulates Both Feeding Behavior and Associated Emotional States. AB - Feeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH) regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1) neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans. PMID- 29262335 TI - ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells. AB - Membraneless RNA granules originate via phase separation events driven by multivalent interactions. As RNA is the defining component of such granules, we examined how RNA contributes to granule assembly. Expansion of hexanucleotide GGGGCC (G4C2) repeats in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). We describe a biophysical phenomenon whereby G4C2 RNA (rG4C2) promotes the phase separation of RNA granule proteins in vitro and in cells. The ability of rG4C2 to promote phase separation is dependent on repeat length and RNA structure because rG4C2 must assume a G-quadruplex conformation to promote granule assembly. We demonstrate a central role for RNA in promoting phase separations and implicate rG4C2 G-quadruplex structures in the pathogenesis of C9-ALS/FTD. PMID- 29262336 TI - Hippocampus and Entorhinal Cortex Recruit Cholinergic and NMDA Receptors Separately to Generate Hippocampal Theta Oscillations. AB - Although much progress has been made in understanding type II theta rhythm generation under urethane anesthesia, less is known about the mechanisms underlying type I theta generation during active exploration. To better understand the contributions of cholinergic and NMDA receptor activation to type I theta generation, we recorded hippocampal theta oscillations from freely moving mice with local infusion of cholinergic or NMDA receptor antagonists to either the hippocampus or the entorhinal cortex (EC). We found that cholinergic receptors in the hippocampus, but not the EC, and NMDA receptors in the EC, but not the hippocampus, are critical for open-field theta generation and Y-maze performance. We further found that muscarinic M1 receptors located on pyramidal neurons, but not interneurons, are critical for cholinergic modulation of hippocampal synapses, theta generation, and Y-maze performance. These results suggest that hippocampus and EC neurons recruit cholinergic-dependent and NMDA receptor-dependent mechanisms, respectively, to generate theta oscillations to support behavioral performance. PMID- 29262337 TI - APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development. AB - Synaptic transmission is critically dependent on synaptic vesicle (SV) recycling. Although the precise mechanisms of SV retrieval are still debated, it is widely accepted that a fundamental role is played by clathrin-mediated endocytosis, a form of endocytosis that capitalizes on the clathrin/adaptor protein complex 2 (AP2) coat and several accessory factors. Here, we show that the previously uncharacterized protein KIAA1107, predicted by bioinformatics analysis to be involved in the SV cycle, is an AP2-interacting clathrin-endocytosis protein (APache). We found that APache is highly enriched in the CNS and is associated with clathrin-coated vesicles via interaction with AP2. APache-silenced neurons exhibit a severe impairment of maturation at early developmental stages, reduced SV density, enlarged endosome-like structures, and defects in synaptic transmission, consistent with an impaired clathrin/AP2-mediated SV recycling. Our data implicate APache as an actor in the complex regulation of SV trafficking, neuronal development, and synaptic plasticity. PMID- 29262340 TI - RAS and PD-L1: A Masters' Liaison in Cancer Immune Evasion. AB - Mutant RAS is a major oncoprotein in human cancer and PD-L1 is a key driver of cancer immune evasion. In this issue of Immunity, Coelho et al. (2017) demonstrate that oncogenic RAS signaling promotes tumor immune escape by stabilizing PD-L1 mRNA. PMID- 29262339 TI - Regulation of H3K4me3 at Transcriptional Enhancers Characterizes Acquisition of Virus-Specific CD8+ T Cell-Lineage-Specific Function. AB - Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs), we mapped the dynamics of ~25,000 putative CD8+ T cell transcriptional enhancers (TEs) differentially utilized during virus-specific T cell differentiation. Interestingly, we identified a subset of dynamically regulated TEs that exhibited acquisition of a non-canonical (H3K4me3+) chromatin signature upon differentiation. This unique TE subset exhibited characteristics of poised enhancers in the naive CD8+ T cell subset and demonstrated enrichment for transcription factor binding motifs known to be important for virus-specific CD8+ T cell differentiation. These data provide insights into the establishment and maintenance of the gene transcription profiles that define each stage of virus-specific T cell differentiation. PMID- 29262338 TI - Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex. AB - The Hippo pathway controls organ size and tissue homeostasis through a kinase cascade leading from the Ste20-like kinase Hpo (MST1/2 in mammals) to the transcriptional coactivator Yki (YAP/TAZ in mammals). Whereas previous studies have uncovered positive and negative regulators of Hpo/MST, how they are integrated to maintain signaling homeostasis remains poorly understood. Here, we identify a self-restricting mechanism whereby autophosphorylation of an unstructured linker in Hpo/MST creates docking sites for the STRIPAK PP2A phosphatase complex to inactivate Hpo/MST. Mutation of the phospho-dependent docking sites in Hpo/MST or deletion of Slmap, the STRIPAK subunit recognizing these docking sites, results in constitutive activation of Hpo/MST in both Drosophila and mammalian cells. In contrast, autophosphorylation of the Hpo/MST linker at distinct sites is known to recruit Mats/MOB1 to facilitate Hippo signaling. Thus, multisite autophosphorylation of Hpo/MST linker provides an evolutionarily conserved built-in molecular platform to maintain signaling homeostasis by coupling antagonistic signaling activities. PMID- 29262341 TI - Feeling Exhausted? Tuning Irf4 Energizes Dysfunctional T Cells. AB - The regulatory mechanisms governing T cell exhaustion remain incompletely understood. Man et al. (2017) and Wu et al. (2017) report that the T cell receptor responsive transcription factor Irf4 promotes T cell exhaustion in chronic viral infection but dampens exhaustion in response to tissue allografts. PMID- 29262342 TI - The Skinny on Fat Trm Cells. AB - White adipose tissue (WAT) is exposed to pathogens that breach epithelial barriers, but the role of adipose T cells in immunity isn't clear. In this issue of Immunity, Han et al. (2017) find that WAT harbors a reservoir of memory T cells that provide antimicrobial immunity at the expense of lipid synthesis and metabolism. PMID- 29262343 TI - PTENtiating CFTR for Antimicrobial Immunity. AB - Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) that reduces Pseudomonas aeruginosa culture positivity in CF patients with unclear mechanisms. Riquelme et al. (2017) propose that improved CFTR trafficking could enhance P. aeruginosa clearance through activating the tumor suppressor PTEN. PMID- 29262344 TI - Mdr1 Saves T Cells from Bile. AB - The gut contents shape intestinal immune homeostasis, a phenomenon best documented for microbiota-immune interactions. In this issue of Immunity, Cao et al. (2017) show that bile acids trigger T cell-mediated inflammation at their site of active absorption in the ileum, unless cells are protected by the membrane transporter Mdr1. PMID- 29262345 TI - I Remember You: Epigenetic Priming in Epithelial Stem Cells. AB - Exposure to inflammatory stimuli can remodel immune cells in a way that alters their response to future insults. In a landmark paper in Nature, Elaine Fuchs and colleagues show that memory of inflammation is not restricted to the hematopoietic lineage (Naik et al., 2017). PMID- 29262346 TI - LncRNA Seduction of GOT2 Goes Viral. AB - Mechanisms of viral infection are active areas of investigation. In a recent issue of Science, Wang et al. (2017) reveal an additional function of a host encoded long non-coding RNA (lncRNA) in regulating viral expression by binding a host metabolic enzyme to enhance its catalytic activity. PMID- 29262347 TI - Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection. AB - Type-2-cell-mediated immune responses play a critical role in mediating both host resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology. PMID- 29262349 TI - Natural Killer Cells Promote Fetal Development through the Secretion of Growth Promoting Factors. AB - Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy. PMID- 29262348 TI - Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2. AB - Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies. PMID- 29262350 TI - CCR6 Defines Memory B Cell Precursors in Mouse and Human Germinal Centers, Revealing Light-Zone Location and Predominant Low Antigen Affinity. AB - Memory B cells (MBCs) and plasma cells (PCs) constitute the two cellular outputs of germinal center (GC) responses that together facilitate long-term humoral immunity. Although expression of the transcription factor BLIMP-1 identifies cells undergoing PC differentiation, no such marker exists for cells committed to the MBC lineage. Here, we report that the chemokine receptor CCR6 uniquely marks MBC precursors in both mouse and human GCs. CCR6+ GC B cells were highly enriched within the GC light zone (LZ), were the most quiescent of all GC B cells, exhibited a cell-surface phenotype and gene expression signature indicative of an MBC transition, and possessed the augmented response characteristics of MBCs. MBC precursors within the GC LZ predominantly possessed a low affinity for antigen but also included cells from within the high-affinity pool. These data indicate a fundamental dichotomy between the processes that drive MBC and PC differentiation during GC responses. PMID- 29262352 TI - Swell, or Not Too Swell: Cytokines Regulate Arterial Aneurysm Formation. PMID- 29262353 TI - Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti Bacterial Innate Immunity. PMID- 29262354 TI - Sorting Things Out: Cell Sorting during Hydra Regeneration. PMID- 29262351 TI - The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids. AB - CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis. PMID- 29262355 TI - Regulation of Contraction by the Thick Filaments in Skeletal Muscle. AB - Contraction of skeletal muscle cells is initiated by a well-known signaling pathway. An action potential in a motor nerve triggers an action potential in a muscle cell membrane, a transient increase of intracellular calcium concentration, binding of calcium to troponin in the actin-containing thin filaments, and a structural change in the thin filaments that allows myosin motors from the thick filaments to bind to actin and generate force. This calcium/thin filament mediated pathway provides the "START" signal for contraction, but it is argued that the functional response of the muscle cell, including the speed of its contraction and relaxation, adaptation to the external load, and the metabolic cost of contraction is largely determined by additional mechanisms. This review considers the role of the thick filaments in those mechanisms, and puts forward a paradigm for the control of contraction in skeletal muscle in which both the thick and thin filaments have a regulatory function. The OFF state of the thick filament is characterized by helical packing of most of the myosin head or motor domains on the thick filament surface in a conformation that makes them unavailable for actin binding or ATP hydrolysis, although a small fraction of the myosin heads are constitutively ON. The availability of the majority fraction of the myosin heads for contraction is controlled in part by the external load on the muscle, so that these heads only attach to actin and hydrolyze ATP when they are required. This phenomenon seems to be the major determinant of the well-known force-velocity relationship of muscle, and controls the metabolic cost of contraction. The regulatory state of the thick filament also seems to control the dynamics of both muscle activation and relaxation. PMID- 29262356 TI - Nanoscale Assembly of High-Mobility Group AT-Hook 2 Protein with DNA Replication Fork. AB - High mobility group AT-hook 2 (HMGA2) protein is composed of three AT-hook domains. HMGA2 expresses at high levels in both embryonic stem cells and cancer cells, where it interacts with and stabilizes replication forks (RFs), resulting in elevated cell proliferation rates. In this study, we demonstrated that HMGA2 knockdown reduces cell proliferation. To understand the features required for interaction between HMGA2 and RFs, we studied the solution structure of HMGA2, free and in complex with RFs, using an integrated host of biophysical techniques. Circular dichroism and NMR experiments confirmed the disordered state of unbound HMGA2. Dynamic light scattering and sedimentation velocity experiments demonstrated that HMGA2 and RF are monodisperse in solution, and form an equimolar complex. Small-angle x-ray scattering studies revealed that HMGA2 binds in a side-by-side orientation to RF where 3 AT-hooks act as a clamp to wrap around a distorted RF. Thus, our data provide insights into how HMGA2 interacts with stalled RFs and the function of the process. PMID- 29262357 TI - Myoglobin and alpha-Lactalbumin Form Smaller Complexes with the Biosurfactant Rhamnolipid Than with SDS. AB - Biosurfactants (BSs) attract increasing attention as sustainable alternatives to petroleum-derived surfactants. This necessitates structural insight into how BSs interact with proteins encountered by current chemical surfactants. Thus, small angle x-ray scattering (SAXS) has been used for studying the structures of complexes made of the proteins alpha-Lactalbumin (alphaLA) and myoglobin (Mb) with the biosurfactant rhamnolipid (RL). For comparison, complexes between alphaLA and the chemical surfactant sodium dodecyl sulfate (SDS) were also investigated. The SAXS data for pure RL micelles can be described by prolate core shell structures with a core radius of 7.7 A and a shell thickness of 12 A, giving an aggregation number of 11. The small core radius is attributed to RL's complex hydrophobic tail. Data for the alphaLA-RL complex agree with a 12 molecule micelle with a single protein molecule in the shell. For Mb-RL, the analysis gives complexes of two connected micelles, each containing 10 RL and one protein in the shells. alphaLA-RL and Mb-RL form surfactant-saturated complexes above 5.6 and 4.7 mM RL, respectively, leaving the remaining RL in free micelles. The SAXS data for SDS agree with oblate-shaped micelles with a core of 20 A, core eccentricity 0.7, and shell thickness of 5.45 A, with an aggregation number of 74. The alphaLA-SDS complexes contain a prolate micelle with a core radius of 11 14 A and a shell of 8-12 A with up to 3 alphaLA per particle and up to 43 SDS per alphaLA, both considerably larger than for RL. Unlike the RL-protein complexes, the number of surfactant molecules in alphaLA-SDS complexes increases with surfactant concentration, and saturate at higher surfactant concentrations than alphaLA-RL complexes. The results highlight how RL and SDS follow similar overall rules of self-assembly and interactions with proteins, but that differences in the strength of protein-surfactant interactions affect the formed structures. PMID- 29262358 TI - Allosteric Modulation of Intact gamma-Secretase Structural Dynamics. AB - As a protease complex involved in the cleavage of amyloid precursor proteins that lead to the formation of amyloid beta fibrils implicated in Alzheimer's disease, gamma-secretase is an important target for developing therapeutics against Alzheimer's disease. gamma-secretase is composed of four subunits: nicastrin (NCT) in the extracellular (EC) domain, presenilin-1 (PS1), anterior pharynx defective 1, and presenilin enhancer 2 in the transmembrane (TM) domain. NCT and PS1 play important roles in binding amyloid beta precursor proteins and modulating PS1 catalytic activity. Yet, the molecular mechanisms of coupling between substrate/modulator binding and catalytic activity remain to be elucidated. Recent determination of intact human gamma-secretase cryo-electron microscopy structure has opened the way for a detailed investigation of the structural dynamics of this complex. Our analysis, based on a membrane-coupled anisotropic network model, reveals two types of NCT motions, bending and twisting, with respect to PS1. These underlie the fluctuations between the "open" and "closed" states of the lid-like NCT with respect to a hydrophilic loop 1 (HL1) on PS1, thus allowing or blocking access of the substrate peptide (EC portion) to HL1 and to the neighboring helix TM2. In addition to this alternating access mechanism, fluctuations in the volume of the PS1 central cavity facilitate the exposure of the catalytic site for substrate cleavage. Druggability simulations show that gamma-secretase presents several hot spots for either orthosteric or allosteric inhibition of catalytic activity, consistent with experimental data. In particular, a hinge region at the interface between the EC and TM domains, near the interlobe groove of NCT, emerges as an allo-targeting site that would impact the coupling between HL1/TM2 and the catalytic pocket, opening, to our knowledge, new avenues for structure-based design of novel allosteric modulators of gamma-secretase protease activity. PMID- 29262359 TI - A Hinged Signal Peptide Hairpin Enables Tat-Dependent Protein Translocation. AB - The Tat machinery catalyzes the transport of folded proteins across the bacterial cytoplasmic membrane and the thylakoid membrane in plants. Using fluorescence quenching and cross-linking approaches, we demonstrate that the Escherichia coli TatBC complex catalyzes insertion of a pre-SufI signal peptide hairpin that penetrates about halfway across the membrane bilayer. Analysis of 512 bacterial Tat signal peptides using secondary structure prediction and docking algorithms suggest that this hairpin interaction mode is generally conserved. An internal cross-link in the signal peptide that blocks transport but does not affect binding indicates that a signal peptide conformational change is required during translocation. These results suggest, to our knowledge, a novel hairpin-hinge model in which the signal peptide hairpin unhinges during movement of the mature domain across the membrane. Thus, in addition to enabling the necessary recognition, the interaction of Tat signal peptides with the receptor complex plays a critical role in the transport process itself. PMID- 29262360 TI - Prediction of Thylakoid Lipid Binding Sites on Photosystem II. AB - The thylakoid membrane has a unique lipid composition, consisting mostly of galactolipids. These thylakoid lipids have important roles in photosynthesis. Here, we investigate to what extent these lipids bind specifically to the Photosystem II complex. To this end, we performed coarse-grain MD simulations of the Photosystem II complex embedded in a thylakoid membrane with realistic composition. Based on >85 MUs simulation time, we find that monogalactosyldiacylglycerol and sulfoquinovosyldiacylglycerol lipids are enriched in the annular shell around the protein, and form distinct binding sites. From the analysis of residue contacts, we conclude that electrostatic interactions play an important role in stabilizing these binding sites. Furthermore, we find that chlorophyll a has a prevalent role in the coordination of the lipids. In addition, we observe lipids to diffuse in and out of the plastoquinone exchange cavities, allowing exchange of cocrystallized lipids with the bulk membrane and suggesting a more open nature of the plastoquinone exchange cavity. Together, our data provide a wealth of information on protein-lipid interactions for a key protein in photosynthesis. PMID- 29262361 TI - Atomistic Insights into Structural Differences between E3 and E4 Isoforms of Apolipoprotein E. AB - Among various isoforms of Apolipoprotein E (ApoE), the E4 isoform (ApoE4) is considered to be the strongest risk factor for Alzheimer's disease, whereas the E3 isoform (ApoE3) is neutral to the disease. Interestingly, the sequence of ApoE4 differs from its wild-type ApoE3 by a single amino acid C112R in the 299 amino-acid-long sequence. Hence, the puzzle remains: how a single-amino-acid difference between the ApoE3 and ApoE4 sequences can give rise to structural dissimilarities between the two isoforms, which can potentially lead to functional differences with significant pathological consequences. The major obstacle in addressing this question has been the lack of a 3D atomistic structure of ApoE4 to date. In this work, we resolve the issue by computationally modeling a plausible atomistic 3D structure of ApoE4. Our microsecond-long atomistic simulations elucidate key structural differences between monomeric ApoE3 and ApoE4, which renders ApoE4 thermodynamically less stable, less structured, and topologically less rigid compared to ApoE3. Consistent with an experimental report of the molten globule state of ApoE4, simulations identify multiple partially folded intermediates for ApoE4, which are implicated in the stronger aggregation propensity of ApoE4. PMID- 29262362 TI - Interaction of Monomeric Interleukin-8 with CXCR1 Mapped by Proton-Detected Fast MAS Solid-State NMR. AB - The human chemokine interleukin-8 (IL-8; CXCL8) is a key mediator of innate immune and inflammatory responses. This small, soluble protein triggers a host of biological effects upon binding and activating CXCR1, a G protein-coupled receptor, located in the cell membrane of neutrophils. Here, we describe 1H detected magic angle spinning solid-state NMR studies of monomeric IL-8 (1-66) bound to full-length and truncated constructs of CXCR1 in phospholipid bilayers under physiological conditions. Cross-polarization experiments demonstrate that most backbone amide sites of IL-8 (1-66) are immobilized and that their chemical shifts are perturbed upon binding to CXCR1, demonstrating that the dynamics and environments of chemokine residues are affected by interactions with the chemokine receptor. Comparisons of spectra of IL-8 (1-66) bound to full-length CXCR1 (1-350) and to N-terminal truncated construct NT-CXCR1 (39-350) identify specific chemokine residues involved in interactions with binding sites associated with N-terminal residues (binding site-I) and extracellular loop and helical residues (binding site-II) of the receptor. Intermolecular paramagnetic relaxation enhancement broadening of IL-8 (1-66) signals results from interactions of the chemokine with CXCR1 (1-350) containing Mn2+ chelated to an unnatural amino acid assists in the characterization of the receptor-bound form of the chemokine. PMID- 29262363 TI - Phosphorylation of the IDP KID Modulates Affinity for KIX by Increasing the Lifetime of the Complex. AB - Intrinsically disordered proteins (IDPs) are known to undergo a range of posttranslational modifications, but by what mechanism do such modifications affect the binding of an IDP to its partner protein? We investigate this question using one such IDP, the kinase inducible domain (KID) of the transcription factor CREB, which interacts with the KIX domain of CREB-binding protein upon phosphorylation. As with many other IDPs, KID undergoes coupled folding and binding to form alpha-helical structure upon interacting with KIX. This single site phosphorylation plays an important role in the control of transcriptional activation in vivo. Here we show that, contrary to expectation, phosphorylation has no effect on association rates-unphosphorylated KID binds just as rapidly as pKID, the phosphorylated form-but rather, acts by increasing the lifetime of the complex. We propose that by controlling the lifetime of the bound complex of pKID:KIX via altering the dissociation rate, phosphorylation can facilitate effective control of transcription regulation. PMID- 29262364 TI - pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions. AB - Understanding the detailed mechanism of interaction of intrinsically disordered proteins with their partners is crucial to comprehend their functions in signaling and transcription. Through its interaction with KIX, the disordered pKID region of CREB protein is central in the transcription of cAMP responsive genes, including those involved in long-term memory. Numerous simulation studies have investigated these interactions. Combined with experimental results, these can provide valuable and comprehensive understanding of the mechanisms involved. Here, we probe the transition state of this interaction experimentally through analyzing the kinetic effect of mutating both interface and solvent exposed residues in pKID. We show that very few specific interactions between pKID and KIX are required in the initial binding process. Only a small number of weak interactions are formed at the transition state, including nonnative interactions, and most of the folding occurs after the initial binding event. These properties are consistent with computational results and also the majority of experimental studies of intrinsically disordered protein coupled folding and binding in other protein systems, suggesting that these may be common features. PMID- 29262365 TI - Interfacial Properties of NTAIL, an Intrinsically Disordered Protein. AB - Intrinsically disordered proteins (IDPs) lack stable secondary and tertiary structure under physiological conditions in the absence of their biological partners and thus exist as dynamic ensembles of interconverting conformers, often highly soluble in water. However, in some cases, IDPs such as the ones involved in neurodegenerative diseases can form protein aggregates and their aggregation process may be triggered by the interaction with membranes. Although the interfacial behavior of globular proteins has been extensively studied, experimental data on IDPs at the air/water (A/W) and water/lipid interfaces are scarce. We studied here the intrinsically disordered C-terminal domain of the Hendra virus nucleoprotein (NTAIL) and compared its interfacial properties to those of lysozyme that is taken as a model globular protein of similar molecular mass. Adsorption of NTAIL at the A/W interface was studied in the absence and presence of phospholipids using Langmuir films, polarization modulated-infrared reflection-absorption spectroscopy, and an automated drop tensiometer for interfacial tension and elastic modulus determination with oscillating bubbles. NTAIL showed a significant surface activity, with a higher adsorption capacity at the A/W interface and penetration into egg phosphatidylcholine monolayer compared to lysozyme. Whereas lysozyme remains folded upon compression of the protein layer at the A/W interface and shows a quasi-pure elastic behavior, NTAIL shows a much higher molecular area and forms a highly viscoelastic film with a high dilational modulus. To our knowledge, a new disorder-to-order transition is thus observed for the NTAIL protein that folds into an antiparallel beta-sheet at the A/W interface and presents strong intermolecular interactions. PMID- 29262366 TI - A Loose Relationship: Incomplete H+/Sugar Coupling in the MFS Sugar Transporter GlcP. AB - The glucose transporter from Staphylococcus epidermidis, GlcPSe, is a homolog of the human GLUT sugar transporters of the major facilitator superfamily. Together with the xylose transporter from Escherichia coli, XylEEc, the other prominent prokaryotic GLUT homolog, GlcPSe, is equipped with a conserved proton-binding site arguing for an electrogenic transport mode. However, the electrophysiological analysis of GlcPSe presented here reveals important differences between the two GLUT homologs. GlcPSe, unlike XylEEc, does not perform steady-state electrogenic transport at symmetrical pH conditions. Furthermore, when a pH gradient is applied, partially uncoupled transport modes can be generated. In contrast to other bacterial sugar transporters analyzed so far, in GlcPSe sugar binding, translocation and release are also accomplished by the deprotonated transporter. Based on these experimental results, we conclude that coupling of sugar and H+ transport is incomplete in GlcPSe. To verify the viability of the observed partially coupled GlcPSe transport modes, we propose a universal eight-state kinetic model in which any degree of coupling is realized and H+/sugar symport represents only a specific instance. Furthermore, using sequence comparison with strictly coupled XylEEc and similar sugar transporters, we identify an additional charged residue that may be essential for effective H+/sugar symport. PMID- 29262367 TI - Composition Fluctuations in Lipid Bilayers. AB - Cell membranes contain multiple lipid and protein components having heterogeneous in-plane (lateral) distribution. Nanoscale rafts are believed to play an important functional role, but their phase state-domains of coexisting phases or composition fluctuations-is unknown. As a step toward understanding lateral organization of cell membranes, we investigate the difference between nanoscale domains of coexisting phases and composition fluctuations in lipid bilayers. We simulate model lipid bilayers with the MARTINI coarse-grained force field on length scales of tens of nanometers and timescales of tens of microseconds. We use a binary and a ternary mixture: a saturated and an unsaturated lipid, or a saturated lipid, an unsaturated lipid, and cholesterol, respectively. In these mixtures, the phase behavior can be tuned from a mixed state to a coexistence of a liquid-crystalline and a gel, or a liquid-ordered and a liquid-disordered phase. Transition from a two-phase to a one-phase state is achieved by raising the temperature and adding a hybrid lipid (with a saturated and an unsaturated chain). We analyze the evolution of bilayer properties along this transition: domains of two phases transform to fluctuations with local ordering and compositional demixing. Nanoscale domains and fluctuations differ in several properties, including interleaflet overlap and boundary length. Hybrid lipids show no enrichment at the boundary, but decrease the difference between the coexisting phases by ordering the disordered phase, which could explain their role in cell membranes. PMID- 29262368 TI - Single-Molecule Imaging of Wnt3A Protein Diffusion on Living Cell Membranes. AB - Wnt proteins are secreted, hydrophobic, lipidated proteins found in all animals that play essential roles in development and disease. Lipid modification is thought to facilitate the interaction of the protein with its receptor, Frizzled, but may also regulate the transport of Wnt protein and its localization at the cell membrane. Here, by employing single-molecule fluorescence techniques, we show that Wnt proteins associate with and diffuse on the plasma membranes of living cells in the absence of any receptor binding. We find that labeled Wnt3A transiently and dynamically associates with the membranes of Drosophila Schneider 2 cells, diffuses with Brownian kinetics on flattened membranes and on cellular protrusions, and does not transfer between cells in close contact. In S2 receptor plus (S2R+) cells, which express Frizzled receptors, membrane diffusion rate is reduced and membrane residency time is increased. These results provide direct evidence of Wnt3A interaction with living cell membranes, and represent, to our knowledge, a new system for investigating the dynamics of Wnt transport. PMID- 29262369 TI - Sarcomere Stiffness during Stretching and Shortening of Rigor Skeletal Myofibrils. AB - In this study, we measured the stiffness of skeletal muscle myofibrils in rigor. Using a custom-built atomic force microscope, myofibrils were first placed in a rigor state then stretched and shortened at different displacements (0.1-0.3 MUm per sarcomere) and nominal speeds (0.4 and 0.8 MUm/s). During stretching, the myofibril stiffness was independent of both displacement and speed (average of 987 nN/MUm). During shortening, the myofibril stiffness was independent of displacement, but dependent on speed (1234 nN/MUm at 0.4 MUm/s; 1106 nN/MUm at 0.8 MUm/s). Furthermore, the myofibril stiffness during shortening was greater than that during stretching and the difference depended on speed (31% at 0.4 MUm/s; 8% at 0.8 MUm/s). The results suggest that the myofibrils exhibit nonlinear viscoelastic properties that may be derived from myofibril filaments, similar to what has been observed in muscle fibers. PMID- 29262370 TI - Quantifying the Relationship between Single-Molecule Probes and Subunit Rotation in the Ribosome. AB - A major challenge in the study of biomolecular assemblies is to identify reaction coordinates that precisely monitor conformational rearrangements. This is central to the interpretation of single-molecule fluorescence resonance energy transfer measurements, where the observed dynamics depends on the labeling strategy. As an example, different probes of subunit rotation in the ribosome have provided qualitatively distinct descriptions. In one study, changes in fluorescence suggested that the 30S body undergoes a single rotation/back-rotation cycle during the process of mRNA-tRNA translocation. In contrast, an alternate assay implicated the presence of reversible rotation events before completing translocation. For future single-molecule experiments to unambiguously measure the relationship between subunit rotation and translocation, it is necessary to rationalize these conflicting descriptions. To this end, we have simulated hundreds of spontaneous subunit rotation events (~8 degrees ) using a residue level coarse-grained model of the ribosome. We analyzed nine different reaction coordinates and found that the apparently inconsistent measurements are likely a consequence of ribosomal flexibility. Further, we propose a metric for quantifying the degree of energetic coupling between experimentally measured degrees of freedom and subunit rotation. This analysis provides a physically grounded framework that can guide the development of more precise single-molecule techniques. PMID- 29262371 TI - Asymmetric Flows in the Intercellular Membrane during Cytokinesis. AB - Eukaryotic cells undergo shape changes during their division and growth. This involves flow of material both in the cell membrane and in the cytoskeletal layer beneath the membrane. Such flows result in redistribution of phospholipid at the cell surface and actomyosin in the cortex. Here we focus on the growth of the intercellular surface during cell division in a Caenorhabditis elegans embryo. The growth of this surface leads to the formation of a double-layer of separating membranes between the two daughter cells. The division plane typically has a circular periphery and the growth starts from the periphery as a membrane invagination, which grows radially inward like the shutter of a camera. The growth is typically not concentric, in the sense that the closing internal ring is located off-center. Cytoskeletal proteins anillin and septin have been found to be responsible for initiating and maintaining the asymmetry of ring closure but the role of possible asymmetry in the material flow into the growing membrane has not been investigated yet. Motivated by experimental evidence of such flow asymmetry, here we explore the patterns of internal ring closure in the growing membrane in response to asymmetric boundary fluxes. We highlight the importance of the flow asymmetry by showing that many of the asymmetric growth patterns observed experimentally can be reproduced by our model, which incorporates the viscous nature of the membrane and contractility of the associated cortex. PMID- 29262372 TI - Mechanical Properties of a Drosophila Larval Chordotonal Organ. AB - Proprioception is an integral part of the feedback circuit that is essential for locomotion control in all animals. Chordotonal organs perform proprioceptive and other mechanosensory functions in insects and crustaceans. The mechanical properties of these organs are believed to be adapted to the sensory functions, but had not been probed directly. We measured mechanical properties of a particular chordotonal organ-the lateral pentascolopidial (lch5) organ of Drosophila larvae-which plays a key role in proprioceptive locomotion control. We applied tension to the whole organ in situ by transverse deflection. Upon release of force, the organ displayed overdamped relaxation with two widely separated time constants, tens of milliseconds and seconds, respectively. When the muscles covering the lch5 organ were excised, the slow relaxation was absent, and the fast relaxation became faster. Interestingly, most of the strain in the stretched organ is localized in the cap cells, which account for two-thirds of the length of the entire organ, and could be stretched by ~10% without apparent damage. In laser ablation experiments we found that cap cells retracted by ~100 MUm after being severed from the neurons, indicating considerable steady-state stress and strain in these cells. Given the fact that actin as well as myosin motors are abundant in cap cells, the results point to a mechanical regulatory role of the cap cells in the lch5 organ. PMID- 29262374 TI - Direct Numerical Simulation of Cellular-Scale Blood Flow in 3D Microvascular Networks. AB - We present, to our knowledge, the first direct numerical simulation of 3D cellular-scale blood flow in physiologically realistic microvascular networks. The vascular networks are designed following in vivo images and data, and are comprised of bifurcating, merging, and winding vessels. Our model resolves the large deformation and dynamics of each individual red blood cell flowing through the networks with high fidelity, while simultaneously retaining the highly complex geometric details of the vascular architecture. To our knowledge, our simulations predict several novel and unexpected phenomena. We show that heterogeneity in hemodynamic quantities, which is a hallmark of microvascular blood flow, appears both in space and time, and that the temporal heterogeneity is more severe than its spatial counterpart. The cells are observed to frequently jam at vascular bifurcations resulting in reductions in hematocrit and flow rate in the daughter and mother vessels. We find that red blood cell jamming at vascular bifurcations results in several orders-of-magnitude increase in hemodynamic resistance, and thus provides an additional mechanism of increased in vivo blood viscosity as compared to that determined in vitro. A striking result from our simulations is negative pressure-flow correlations observed in several vessels, implying a significant deviation from Poiseuille's law. Furthermore, negative correlations between vascular resistance and hematocrit are observed in various vessels, also defying a major principle of particulate suspension flow. To our knowledge, these novel findings are absent in blood flow in straight tubes, and they underscore the importance of considering realistic physiological geometry and resolved cellular interactions in modeling microvascular hemodynamics. PMID- 29262373 TI - Two Distinct Fluorescence States of the Ligand-Induced Green Fluorescent Protein UnaG. AB - UnaG is a recently discovered ligand-induced fluorescent protein that utilizes bound bilirubin (BR) as its fluorophore. The fluorescence of the UnaG-BR complex (holoUnaG) compares in quantum efficiency to that of enhanced green fluorescent protein, but it is superior in that the fluorophore formation is instantaneous and not dependent on oxygen; hence, much attention has been paid to UnaG as a new fluorescent probe. However, many important molecular properties of fluorescent probes remain unknown, such as the association/dissociation rates of BR, which determine the stability thereof, and the dispersibility of UnaG in aqueous solutions, which influence the functions of labeled proteins. In this study, we found, in the process of investigating the association rate, that the holoUnaG takes two distinct fluorescence states, which we named holoUnaG1 and holoUnaG2. The holoUnaG1 initially forms after binding BR and then changes to the brighter holoUnaG2 by a reversible intra-molecular reaction, thereby finally reaching an equilibrium between the two states. Spectroscopic analysis indicated that the intra-molecular reaction was associated not with a chemical change of BR but with a change in the environmental conditions surrounding BR. We also revealed that the molecular brightness ratio and equilibrium population ratio of the two states (holoUnaG1/holoUnaG2) were 1:3.9 and 6:4, respectively, using photon number counting analysis. From these results, we have suggested a novel schema, to our knowledge, for the formation of the UnaG and BR complex system and have determined the various rate constants associated therein. Additionally, using analytical ultracentrifugation, we established that UnaG in the apo-state (apoUnaG) and the holoUnaG are monomeric in aqueous solution. These findings provide not only key information for the practical use of UnaG as a fluorescent probe, but also the possibility for development of a brighter UnaG mutant by genetic engineering to constitutive holoUnaG2. PMID- 29262375 TI - Physical Mechanisms Driving Cell Sorting in Hydra. AB - Cell sorting, whereby a heterogeneous cell mixture organizes into distinct tissues, is a fundamental patterning process in development. Hydra is a powerful model system for carrying out studies of cell sorting in three dimensions, because of its unique ability to regenerate after complete dissociation into individual cells. The physicists Alfred Gierer and Hans Meinhardt recognized Hydra's self-organizing properties more than 40 years ago. However, what drives cell sorting during regeneration of Hydra from cell aggregates is still debated. Differential motility and differential adhesion have been proposed as driving mechanisms, but the available experimental data are insufficient to distinguish between these two. Here, we answer this longstanding question by using transgenic Hydra expressing fluorescent proteins and a multiscale experimental and numerical approach. By quantifying the kinematics of single cell and whole aggregate behaviors, we show that no differences in cell motility exist among cell types and that sorting dynamics follow a power law with an exponent of ~0.5. Additionally, we measure the physical properties of separated tissues and quantify their viscosities and surface tensions. Based on our experimental results and numerical simulations, we conclude that tissue interfacial tensions are sufficient to explain cell sorting in aggregates of Hydra cells. Furthermore, we demonstrate that the aggregate's geometry during sorting is key to understanding the sorting dynamics and explains the exponent of the power law behavior. Our results answer the long standing question of the physical mechanisms driving cell sorting in Hydra cell aggregates. In addition, they demonstrate how powerful this organism is for biophysical studies of self organization and pattern formation. PMID- 29262376 TI - Benchmarks of Biomembrane Force Probe Spring Constant Models. PMID- 29262378 TI - Occurrence of sulfonated steroids and ovarian expression of steroid sulfatase and SULT1E1 in cyclic cows. AB - Historically sulfonated steroids were primarily considered as inactive metabolites destined for elimination. However, more recently they have been increasingly recognized as precursors for the production of bioactive steroids in target tissues and as functional molecules without preceding hydrolysis. In order to comprehensively characterize their occurrence in cyclic cows and their formation and hydrolysis in bovine ovarian steroidogenesis, ovaries from cyclic cows were screened for the expression of oestrogen sulfotransferase (SULTE1) and steroid sulfatase (STS) by Western blot and immunohistochemistry. Moreover, a broad spectrum of 13 sulfonated steroids was measured applying liquid chromatography-tandem mass spectrometry (LC-MS/MS) in blood samples collected from three cycling heifers during defined stages of the ovarian cycle and in fluid obtained from ovarian follicles of different size. SULT1E1 was undetectable in ovarian tissues. For STS only a weak immunostaining was found predominantly in granulosa cells of larger follicles. However, no specific band occurred in Western blot. In blood, concentrations of all sulfonated steroids investigated were below the limit of quantification (LOQ). In follicular fluid, only cholesterol sulfate was measured in considerable concentrations (328.3 +/- 63.8 ng/ml). However, the role of cholesterol sulfate in bovine follicular steroidogenesis remains unclear as concentrations were obviously unrelated to follicular size. The remaining sulfonated steroids investigated were undetectable or only slightly exceeded LOQ in a minor proportion of samples. The results are clearly contrary to a role of sulfonated steroids as important precursors, intermediates or products of bovine ovarian steroidogenesis. PMID- 29262377 TI - The short esophagus: Review of a neglected entity. AB - In this pictorial essay, the authors discuss etiologies, imaging findings with focus on fluoroscopy and management of the short esophagus in children and adults. PMID- 29262379 TI - Dexamethasone-induced upregulation of CaV3.2 T-type Ca2+ channels in rat cardiac myocytes. AB - Glucocorticoids are widely used to treat acute and chronic diseases. Unfortunately, their therapeutic use is associated with severe side effects. Glucocorticoids are known to regulate several ion channels in cardiac myocytes, including voltage-dependent Ca2+ channels. Low-voltage-activated T-type Ca2+ channels are expressed in ventricular myocytes during the fetal and perinatal period, but are practically absent in the adult. However, these channels can be re-expressed in adult cardiomyocytes under some pathological conditions. We have investigated the glucocorticoid regulation of T-type Ca2+ channels in rat cardiomyocytes. Molecular studies revealed that dexamethasone induces the upregulation of CaV3.2 mRNA in neonatal rat ventricular myocytes, whereas CaV3.1 mRNA is only slightly affected. Patch-clamp recordings confirmed that T-type Ca2+ channel currents were upregulated in dexamethasone treated cardiomyocytes, and the addition of 50 MUmol/L NiCl2 demonstrated that the CaV3.2 channel is responsible for this upregulation. The effect of dexamethasone on CaV3.2 is mediated by the activation and translocation to the cell nucleus of the glucocorticoid receptor (GR). We have isolated the upstream promoter of the Cacna1h gene and tested its activity in transfected ventricular myocytes. The initial in silico analysis of Cacna1h promoter revealed putative glucocorticoid response elements (GREs). Transcriptional activity assays combined with deletion analyses and chromatin immunoprecipitation assays demonstrated that GR binds to a region a GRE located in -1006/-985 bp of Cacna1h promoter. Importantly, upregulation of the CaV3.2 channel is also observed in vitro in adult rat ventricular myocytes, and in vivo in a rat model of excess of glucocorticoids. PMID- 29262380 TI - Vitamin D: Effects on human reproduction, pregnancy, and fetal well-being. AB - Pregnancy places exceptional demands on vitamin D and calcium availability; thus, their deficiencies during pregnancy threaten the woman and her fetus. Globally, vitamin D and other micronutrient deficiencies are common during pregnancy, especially in developing countries where pregnant women have less access to nutritional supplements. Vitamin D deficiency has been reported to be as high as 40% among pregnant women. As a pregnancy progresses, the requirements for vitamin D increase and thus, can worsen preexisting hypovitaminosis D. Consequently, hypovitaminosis D is increasingly associated with a higher incidence of fetal miscarriage, preeclampsia, gestational diabetes, bacterial vaginosis, and impaired fetal and childhood growth and development. This review explores the recent advances in the understanding of vitamin D and the pivotal role it plays in human reproduction, with an emphasis on pregnancy and its outcomes. Given the seriousness of the issue, there is a pressing need for clinicians to become aware of the risks associated with not identifying and correcting vitamin D deficiency. Identifying and correcting vitamin D deficiency, including safe exposure to sunlight, is particularly relevant for those who seek assistance with fertility issues or prenatal counseling, and those in the beginning of their pregnancy. The data point to a significant protective effects of vitamin D during pregnancy when the 25(OH)D serum level exceeds 30 ng/mL before pregnancy and during the first trimester and, sufficient levels are maintained throughout the pregnancy. PMID- 29262381 TI - Hydrazinylpyridine based highly selective optical sensor for aqueous source of carbonate ions: Electrochemical and DFT studies. AB - A series of new receptors PDZ1-3 based on 2-(arylidenehydrazinyl)pyridines have been designed and synthesized for the detection of biologically and environmentally important ions. The colorimetric detection of CO32- using neutral organic receptor PDZ-1 has been achieved with characteristic visual colour change from yellow to green accompanied by a large redshift of 215nm in absorption maxima. UV-Vis spectroscopic and cyclic voltammetric studies reveal the stoichiometry of binding and electrochemistry of host-guest complex formation. The binding constant was found to be 0.77*104M-2. In addition, electrochemical studies provide an insight into the stability of the complex. DFT studies performed on the PDZ-1 and PDZ-1-CO32- complex reveal the binding mechanism involved in the anion detection process. PDZ-1 is highly selective for carbonate and does not show any colorimetric response towards any other anions or cations, while PDZ-2 and PDZ-3 remain inactive in the ion detection process. The limit of detection (LOD) and limit of quantification (LOQ) of PDZ-1 for carbonate was found to be 0.11mM and 0.36mM respectively. Considerable binding constant and limit of detection make PDZ-1 to be used as a real time sensor for the detection of carbonate in environmental and biological samples. PMID- 29262382 TI - Ammonium nitrogen content is a dominant predictor of bacterial community composition in an acidic forest soil with exogenous nitrogen enrichment. AB - Soil pH is a dominant factor affecting bacterial community composition in acidic, neutral, and alkaline soils but not in severely acidic soils (pH<4.5). We conducted a nitrogen (N) addition experiment in the field in severely acidic forest soil to determine the response of the soil bacterial community and identified the dominant factor in determining community composition. Using a high throughput Illumina HiSeq sequencing platform, we found that high levels of N addition significantly decreased soil bacterial diversity and altered the composition of the soil bacterial community. The addition of nitrogen increased the relative abundance of copiotrophic taxa (Proteobacteria and Actinobacteria phyla) but decreased the relative abundance of oligotrophic taxa (Acidobacteria, Verrucomicrobia, Planctomycetes, and WD272). In particular, the relative abundance of N-cycling-related microbes (e.g., Burkholderia and Rhizomicrobium genera) also increased upon addition of N. Our correlation analysis showed that soil ammonium nitrogen concentration, rather than pH or nitrate nitrogen concentration, was a key environmental parameter determining the composition of the soil bacterial community. However, these bacterial response behaviors were observed only in the dry season and not in the wet season, indicating that high temperature and precipitation in the wet season may alleviate the impact of the addition of N on soil bacterial diversity and community composition. These results suggest that the soil bacterial community shifted to copiotrophic taxa with higher N demands under increased N addition in severely acidic forest soil. PMID- 29262383 TI - Erratum: "Sanitary Sewer Overflows and Emergency Room Visits for Gastrointestinal Illness: Analysis of Massachusetts Data, 2006-2007". AB - [This corrects the article DOI: 10.1289/EHP2048.]. PMID- 29262384 TI - [Surgery for Brain Lesions of Tuberous Sclerosis Complex]. PMID- 29262385 TI - [Experience and Solution of Complications of Vagus Nerve Stimulation Therapy in 139 Implant Patients with Medically Refractory Epilepsy]. AB - BACKGROUND: Vagus nerve stimulation(VNS)for patients with intractable epilepsy was approved by the Japan Ministry of Health, Labour and Welfare in 2010. More than 1,500 VNS systems were implanted by the end of August 2016. The aim of the present report is to describe complications we experienced at our department and consider the way to avoid them. METHODS AND PATIENTS: We retrospectively reviewed 139 consecutive patients(122 new implantations and 17 reimplantations)between December 2010 and March 2016. RESULTS: Seven patients demonstrated eight complications. Four patients experienced recurrent nerve paralysis with hoarseness and/or cough that did not require device removal. One patient experienced subsequent aspiration pneumonia. The device was removed in one case due to lead fracture and in three owing to surgical site infection(SSI). CONCLUSION: All recurrent nerve paralysis occurred just after we started VNS implantations. It was presumed that the nerve paralysis was caused by retraction around the vagus nerve. Smaller skin incision and decreased retraction of the surgical field has eliminated this complication. The incidence of infections is reported as 2.2%. Allergic reaction to the VNS device might be one of the causes for SSI in our series. Fracture of the lead was caused by revolving of the pulse generator under the skin. Tight sutures around the pocket or subpectoral placement of a pulse generator is necessary to prevent rotation of the generator depending upon the activity of each patient. This paper provides insight into complications and successful strategies for better outcomes in VNS therapy. PMID- 29262386 TI - [Development of Deep Venous Thrombosis Shortly after Neurological Surgery]. AB - Little is known about the incidence and characteristics of deep venous thrombosis(DVT)developing shortly after neurological surgery. Lower extremity venous ultrasound scanning was performed before and after surgery, and retrospective data of 157 surgical cases, including endovascular surgery(42.0%), craniotomy(28.7%), burr hole(24.2%), and shunt(3.2%), were evaluated. DVT that had not been pre-operatively observed was discovered in five cases of surgery(five patients, 3.2%)on the day following the surgery, and it was asymptomatic in all cases. One patient was diagnosed with pulmonary thromboembolism as a complication. No difference in characteristic factors was observed between the presence and absence of DVT development. In addition, DVT was detected on preoperative examinations in 10 cases of surgery(10 patients, 6.4%). On the basis of these results, ambulation on the first postoperative day is considered mostly safe. On the other hand, taking into account the increase in the number of patients with DVT and the possibility that a thrombus present in calf veins propagates toward the proximal side, pre-and post-operative screening tests should be performed more often. PMID- 29262387 TI - [Bath Plug Closure Method for Cerebrospinal Fluid Leakage by Endoscopic Endonasal Approach:Cooperative Treatment by Neurosurgeons and Otolaryngologists]. AB - Endoscopic endonasal surgery, an innovative surgical technique, is used to approach sinus lesions, lesions of the skull base, and intradural tumors. The cooperation of experienced otolaryngologists and neurosurgeons is important to achieve safe and reliable surgical results. The bath plug closure method is a treatment option for patients with cerebrospinal fluid(CSF)leakage. Although it includes dural and/or intradural procedures, surgery tends to be performed by otolaryngologists because its indications, detailed maneuvers, and pitfalls are not well recognized by neurosurgeons. We reviewed the cases of patients with CSF leakage treated by using the bath plug closure method with an endoscopic endonasal approach at our institution. Three patients were treated using the bath plug closure method. CSF leakage was caused by a meningocele in two cases and trauma in one case. No postoperative intracranial complications or recurrence of CSF leakage were observed. The bath plug closure method is an effective treatment strategy and allows neurosurgeons to gain in-depth knowledge of the treatment options for CSF leakage by using an endoscopic endonasal approach. PMID- 29262388 TI - [Ruptured Dissecting Aneurysm of the Fenestrated Vertebral Artery:A Case Report]. AB - Fenestration of a vertebral artery(VA)is a rare anomaly that has occasionally been associated with the formation of saccular aneurysms, whereas dissection of a limb of the fenestrated artery is an extremely rare occurrence. We report the case of a ruptured dissecting aneurysm of a fenestrated VA. A 56-year-old man presented with acute-onset headache followed by respiratory failure. Computed tomography(CT)revealed diffuse subarachnoid hemorrhage, and CT angiography(CTA)demonstrated fenestration of the left VA and a fusiform aneurysm of the dorsolateral limb of the fenestrated VA. CT after injection of contrast medium revealed dissection of a limb of the fenestrated VA. A comparison of the 3 dimensional digital subtraction angiogram obtained 2 days later with the initial CTA showed that the dissecting aneurysm had shrunk. Coil embolization of the dissecting limb of the fenestrated VA was achieved, and the patient was discharged without neurologic deficit. Further advancements in neuroimaging modalities will provide more opportunities to treat dissecting aneurysms of fenestrated VAs. The relevant clinical characteristics of VA fenestration and the treatment options for a dissecting aneurysm of a limb of the fenestrated VA are also discussed in this report. PMID- 29262389 TI - [Pontine Hemorrhage Suspected due to Dural Arteriovenous Fistula at the Craniocervical Junction:A Case Report]. AB - Dural arteriovenous fistulas occurring at the craniocervical junction(CCJd AVF)are uncommon; however, they demonstrate a wide range of clinical presentations. We describe the case of a patient with pontine hemorrhage suspected due to CCJd-AVF. A 68-year-old man presented to our hospital with a sudden onset of left hemiparesis. Cranial computed tomography(CT)revealed pontine and subarachnoid hemorrhage. Magnetic resonance imaging, as well as MR, CT, and left vertebral angiograms were performed and showed a CCJd-AVF in addition to a varix coincident with the hematoma cavities. The patient was successfully treated using surgical drainer clipping. A CCJd-AVF presenting concomitantly with a pontine hemorrhage is extremely rare. Careful assessment of the anatomical relationship between the skull base and the surrounding vascular structures is important to plan neurosurgical procedures for direct interruption of the draining vein. Three-dimensional CT angiography is a useful modality that facilitates visualization of complex and anomalous anatomical structures. PMID- 29262390 TI - [A Case of an Orbital Angioleiomyoma]. AB - A 70-year-old woman presented with a 4-year history of painless conjunctival congestion and proptosis of the right eye. Computed tomography and magnetic resonance imaging revealed a 48-mm lesion in the right medial orbit. As the symptoms progressed, the tumor was resected by performing fronto-orbital craniotomy. Histopathological examination revealed a vascular tumor surrounded by smooth muscle fibers and immunohistochemistry demonstrated tumor positivity for smooth muscle actin and desmin. The tumor was diagnosed as an angioleiomyoma, and no recurrence has been observed as of 5 years postoperatively. Angioleiomyomas in the orbit are extremely rare;thus, we have reported this case with reference to the literature. PMID- 29262391 TI - [Ruptured Dissecting Aneurysm of M2 Portion of the Middle Cerebral Artery:A Case Report]. AB - A 71-year-old woman presented with a sudden onset of headache and vomiting. Computed tomography(CT)showed diffuse subarachnoid hemorrhage(SAH)that was more severe on the right side. Three-dimensional CT angiography and right carotid angiography(CAG)demonstrated 2-mm microaneurysms at the middle cerebral artery(MCA)bifurcation and anterior communicating artery, with slight narrowing and dilatation of the M2 inferior trunk. Each microaneurysm was smooth, making it difficult to identify the bleeding source. Thus, surgery was postponed at the acute stage, and further investigation was planned. Repeated CAG was diagnostically unsuccessful, finding no source of the bleeding. On day 45 after the onset, exploratory craniotomy was performed to confirm the cause of the SAH. During the operation, both microaneurysms were found to be unruptured. However, the distal portion of the M2 inferior trunk was dark purplish and red and enlarged in a fusiform shape, suggesting a dissecting aneurysm. Residue of the SAH observed near the enlarged vessel identified it as the bleeding source. The enlarged vessel was wrapped with Bemsheets, and the Bemsheets was clipped to secure it. A dissecting aneurysm of the distal MCA is rare, as is the onset of bleeding. Based on a review of the literature related to dissecting aneurysms of the distal MCA, we recommend exploratory craniotomy if CT demonstrates laterality of the sylvian fissure on the SAH and CAG reveals stenosis or occlusion of the distal MCA in cases of SAH for which no bleeding source is detected. PMID- 29262392 TI - [Surgical Treatment for Traumatic Acute Subdural Hemorrhage in the Posterior Cranial Fossa:Three Cases Reports and Review of the Literature]. AB - Acute subdural hemorrhage(ASDH)in the posterior cranial fossa is rare. Extremely unfavorable outcomes are reported among cases accompanied by supratentorial hematoma, brainstem contusion, or intracerebellar contusion. We report three cases surgically evacuated several times for traumatic ASDH in the posterior cranial fossa simultaneously accompanied by supratentorial hematomas. In our three presented cases, the mean age was 72.3 years, and all patients were male. The mechanisms of injury included traffic accidents in two cases and fall in one. The median Glasgow Coma Scale score on admission was 6. On admission, the patients had traumatic ASDH in the posterior cranial fossa accompanied by supratentorial hematoma, so they first underwent external decompression or ICP sensor insertion for the supratentorial lesions. However, after their first surgery, all patients developed upward herniation, and subsequently underwent suboccipital craniotomy and evacuation of hematomas. Glasgow Outcome Scales were death in one case, persistent vegetable state in one case, and severe disability in one case. The patients with ASDH in the posterior cranial fossa accompanied by supratentorial hematoma should immediately undergo suboccipital craniotomy and supratentorial decompression simultaneously when the hematomas compress the brainstem and upward herniation develops. PMID- 29262393 TI - [Clinical Applications of Positron Emission Tomography for Neurosurgery(5)Application of Positron Emission Tomography Molecular Imaging in the Diagnosis of Dementia Diseases]. PMID- 29262394 TI - Dachengqi Decoction Attenuates Intestinal Vascular Endothelial Injury in Severe Acute Pancreatitis in Vitro and in Vivo. AB - BACKGROUND/AIMS: Dachengqi decoction (DCQD) is a well-known traditional Chinese herbal drug with strong anti-inflammatory effects. Angiopoietin-1 (Ang-1) plays a vital role in maintaining the stability and integrity of the vascular wall and prevents vascular leakage due to inflammatory mediators. Our previous work found that DCQD protects against pancreatic injury in rats with severe acute pancreatitis (SAP). This study aims to investigate the effects of DCQD on intestinal endothelial damage in both damaged human umbilical vein endothelial cells (HUVECs) and SAP rats. METHODS: HUVECs were randomly divided into four groups: control group, TNF-alpha group, TNF-alpha plus Ang-1 group (Ang-1 group), and TNF-alpha plus DCQD group (DCQD group). Cells were incubated for 6 h, 12 h, and 24 h, before collection. The treatment concentration of DCQD was decided based on a Cell Counting Kit-8 (CCK-8) assay. The monolayer permeability of the HUVECs was assessed by measuring the transendothelial electrical resistance (TEER). Apoptosis was analyzed by flow cytometry. mRNA and protein expression of aquaporin 1 (AQP-1), matrix metalloproteinase 9 (MMP9), and junctional adhesion molecule-C (JAM-C) was evaluated by RT-PCR, immunocytofluorescence, and western blot. Forty male Sprague-Dawley rats were randomized into a control group, SAP group, SAP plus Ang-1 group (Ang-1 group), and SAP plus DCQD group (DCQD group). SAP was induced by intraperitoneal injection of cerulein and lipopolysaccharide (LPS), while the control group received 0.9% saline solution. Evans blue was injected through the penile vein and the rats were then sacrificed 12 h after modeling. Levels of serum amylase, TNF-alpha, IL-1beta, IL-2, and IL-6 were determined by using ELISA. Intestinal tissue was analysed by histology, and capillary permeability in the tissues was evaluated by Evans blue extravasation assay. Protein and mRNA expression of AQP-1, MMP9, and JAM-C were assessed by immunohistofluorescence, western blot, and RT-PCR. RESULTS: DCQD reduced the permeability of HUVEC induced by TNF-alpha in vitro. Furthermore, DCQD altered the mRNA and protein levels of JAM-C, MMP9, and AQP-1 in HUVECs after TNF-alpha induction. SAP intestinal injury induced by cerulein combined with lipopolysaccharides was concomitant with increased expression of JAM-C and MMP9, and reduced expression of AQP-1 in intestinal tissue. Pretreatment with DCQD attenuated SAP intestinal injury and lowered the levels of serum amylase, TNF alpha, IL-1beta, IL-2, and IL-6 effectively. Our study demonstrated that DCQD decreased the expression of JAM-C and MMP9 and increased the expression of AQP-1 both in vitro and in vivo. CONCLUSION: DCQD can reduce capillary endothelial damage in acute pancreatitis-associated intestinal injury and the mechanism may be associated with the regulation of endothelial barrier function-associated proteins AQP-1, MMP9, and JAM-C. PMID- 29262395 TI - Salvianolic Acid A Protects Against Diabetic Nephropathy through Ameliorating Glomerular Endothelial Dysfunction via Inhibiting AGE-RAGE Signaling. AB - BACKGROUND/AIMS: Glomerular endothelium dysfunction leads to the progression of renal architectonic and functional abnormalities in early-stage diabetic nephropathy (DN). Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) are proved to play important roles in diabetic nephropathy. This study investigated the role of Salvianolic acid A (SalA) on early-stage DN and its possible underlying mechanism. METHODS: In vitro AGEs formation and breaking rate were measured to illustrate the effect of SalA on AGEs. Type 2 diabetic nephropathy rats were induced by high-fat diet and low-dose streptozocin (STZ). After eight-week treatment with SalA 1 mg/kg/day, 24h-urine protein, creatinine clearance was tested and renal structural injury was assessed by PAS and PASM staining. Primary glomerular endothelial cell permeability was evaluated after exposed to AGEs. AGEs-induced RhoA/ROCK and subsequently activated disarrange of cytoskeleton were assessed by western blot and immunofluorescence. RESULTS: Biochemical assay and histological examination demonstrated that SalA markedly reduced endothelium loss and glomerular hyperfiltration, suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced urinary albumin and ameliorated renal function. Further investigation suggested that SalA exerted its renoprotective effects through inhibiting AGE-RAGE signaling. It not only inhibited formation of AGEs and increased its breaking in vitro, but also reduced AGEs accumulation in vivo and downregulated RAGE expression. SalA restored glomerular endothelial permeability through suppressing AGEs-induced rearrangement of actin cytoskeleton via AGE-RAGE-RhoA/ ROCK pathway. Moreover, SalA attenuated oxidative stress induced by AGEs, subsequently alleviated inflammation and restored the disturbed autophagy in glomerular endothelial cell and diabetic rats via AGE-RAGE-Nox4 axis. CONCLUSION: Our study indicated that SalA restored glomerular endothelial function and alleviated renal structural deterioration through inhibiting AGE-RAGE, thus effectively ameliorated early stage diabetic nephropathy. SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy. PMID- 29262396 TI - Benzotriazole Enhances Cell Invasive Potency in Endometrial Carcinoma Through CTBP1-Mediated Epithelial-Mesenchymal Transition. AB - BACKGROUND/AIMS: Benzotriazole (BTR) and its derivatives, such as intermediates and UV stabilizers, are important man-made organic chemicals found in everyday life that have been recently identified as environmental toxins and a threat to female reproductive health. Previous studies have shown that BTR could act as a carcinogen by mimicking estrogen. Environmental estrogen mimics could promote the initiation and development of female cancers, such as endometrial carcinoma, a type of estrogenic-sensitive malignancy. However, there is little information on the relationship between BTR and endometrial carcinoma. In this study, we aimed to demonstrate the biological function of BTR in endometrial carcinoma and explored the underlying mechanism. METHODS: The CCK-8 assay was performed to detect cell viability; transwell-filter assay was used to assess cell invasion; gene microarray analysis was employed to determine gene expression patterns in response to BTR treatment; western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were carried out to detect the expression levels of BTR-related genes. RESULTS: Our data showed that BTR could induce the invasion and migration of endometrial carcinoma cells (Ishikawa and HEC-1-B). In addition, BTR increased the expression level of CTBP1, which could enhance the epithelial-mesenchymal transition (EMT) in cancer cells. Moreover, CTBP1 silencing reversed the effect of BTR on EMT progression in endometrial carcinoma cells. CONCLUSION: This study indicates that BTR could act as a carcinogen to promote the development of endometrial carcinoma mainly through CTBP1-mediated EMT, which deserves more attention. PMID- 29262397 TI - Pharmacological Management of a Heart Failure Patient with Severe Obesity. AB - Obesity is one of the commonest comorbidities in patients with heart failure, and it is associated with increased mortality risk. However, obese patients are often underrepresented in clinical trials and therefore evidence on their management remains scant. In order to expand knowledge on the management of these patients, anecdotal reports may be considered. In the present case report, we discuss the successful management of an obese patient who received sacubitril/valsartan therapy. This treatment was initiated after a 12-month period of losartan therapy, which did not provide any benefit in terms of heart function. Importantly, during this period the patient required frequent hospitalizations, with a marked decrease in quality of life. After the switch to sacubitril/valsartan, a 10% increase in left ventricular ejection fraction was observed (from 30 to 40%) over a 12-month period. Moreover, no hospitalizations were required, and the patient was able to carry on at least some of his daily activities. PMID- 29262398 TI - Characteristic MicroRNA Expression Induced by delta-Opioid Receptor Activation in the Rat Liver Under Prolonged Hypoxia. AB - BACKGROUND/AIMS: Hypoxic/ischemic injury to the liver is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ ischemic events, and delta-opioid receptor (DOR) is protective against hypoxic/ischemic injury, we asked if pharmacological activation of DOR can alter hypoxic events by regulating miRNA expression in the liver. As the first step, the present work aimed at testing the effect of DOR activation on hepatic miRNA expression in hypoxia. METHODS: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O2) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected according to TaqMan low-density array (TLDA) data and analyzed by quantitative real-time PCR. RESULTS: We found that: 1) 1-day hypoxia caused the upregulation of 9 miRNAs (miR-7a-5p, miR-10a 5p, miR-25-3p, miR-26b-5p, miR-122-5p, miR-128a-3p, miR-135b-5p, miR-145-5p, and miR-181a-5p) and the downregulation of 2 miRNAs (miR-34a-5p and miR-182); 2) 5 and 10-days hypoxia altered the expression of 4 miRNAs (miR-34c-5p, miR-184, miR 107-3p and miR192-5p); 3) DOR activation shifted the expression of 8 miRNAs (miR 122-5p, miR-146a-5p, miR-30e-5p, miR-128a-3p, miR-182, miR-192-5p miR-107-3p and miR-184) in normoxic condition; and 4) DOR activation modified hypoxia-induced changes in 6 miRNAs (miR-142-5p, miR-145-5p, miR-146a-5p, miR-204-5p, miR-34a-5p and miR-192-5p). CONCLUSION: Hypoxia significantly modifies the miRNA profile in the liver, while DOR activation can modify the hypoxic modification. Therefore, it is potentially possible to alter hypoxic/ischemic pathophysiology in the liver through DOR pharmacotherapy. PMID- 29262399 TI - Sacubitril/Valsartan in Clinical Practice: A Report of 2 Cases. AB - Following the results of the PARADIGM-HF trial, the European Society of Cardiology (ESC) guidelines recommend sacubitril/valsartan to replace ACE inhibitors in ambulatory patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal therapy and who fit trial criteria. However, the optimal use of sacubitril/valsartan in clinical practice needs further investigation. We report here the cases of 2 patients with HFrEH successfully treated with sacubitril/valsartan in our daily practice. Both subjects presented multiple comorbidities and received an implantable cardioverter defibrillator in primary prevention. In both patients, therapy with sacubitril/valsartan led to prompt (30 days) amelioration of heart function, with a corresponding decrease in NHYA class and without any relevant safety issue. PMID- 29262400 TI - Sacubitril/Valsartan: Effect on Walking Test and Physical Capability. AB - The 6-min walk test (6MWT) is a simple and inexpensive exercise test to evaluate physical functional capacity that is widely used in heart failure (HF) patients. With the 6MWT, a distance <350 m is associated with increased mortality in patients with HF, and change in walking distance >50 m is considered clinically relevant. To our knowledge, information on improvement in physical functional capacity with sacubitril/valsartan, as assessed by the 6MWT, is still scant. In our daily practice, we apply this test to all patients whenever possible; therefore, we report here the findings observed in a small series of 5 patients with HF with reduced ejection fraction after a 1-month treatment with sacubitril/valsartan at full dose. The mean distance walked on the 6MWT at baseline was 129 m (+/-64 SD), and this value increased to 436 m (+/-156) after 1 month of therapy with sacubitril/valsartan 97/103 mg b.i.d. The mean difference from baseline was 305 m (+/-110). According to these preliminary findings, in clinical practice, a 1-month therapy of sacubitril/valsartan optimized at a 97/103-mg b.i.d. dose appears to be associated with a relevant improvement in the 6MWT. PMID- 29262401 TI - CpG-Oligodeoxynucleotides Improved Irradiation-Induced Injuries by G-CSF and IL-6 Up-Regulation. AB - BACKGROUND/AIMS: This study investigated the radioprotective properties of three classes of CpG-oligodeoxynucleotides (CpG-ODNs) and the underlying mechanisms. METHODS: Mice irradiated at different doses(7Gy or 9Gy) were treated with or without ODNs(50MUg via intraperitoneal injection). Assays were performed to determine survival rate and the number of white blood cell in peripheral blood. The levels of granulocyte-colony stimulating factor(G-CSF), interleukin 6(IL-6) and interferon-alpha (IFN-alpha) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Survival rate of mice irradiated in 7Gy was increased from 50% to about 100% with ODNs pretreatment. ODNs administration increased the number of WBCs of irradiated mice. G-CSF, IL-6 and IFN-alpha levels were up regulated with ODNs treatment. CONCLUSION: All three classes of ODNs protected mice from irradiation-induced injuries. B-class ODNs exhibited the most potent radioprotective property via the up-regulation of G-CSF and IL-6. PMID- 29262402 TI - Sacubitril/Valsartan in "Field Practice" Patients with Advanced Heart Failure: A Monocentric Italian Experience. AB - Patients with advanced heart failure (HF) experience a continuous decline in quality of life and have a very poor prognosis. Moreover, due to numerous comorbidities present in these patients, transplantation and left ventricular assist devices are usually impracticable in clinical practice. In this challenging setting, administration of inotropic agents may be the only possible therapy; however, this treatment requires frequent hospitalizations. Our hypothesis is that sacubitril/valsartan, given its marked efficacy and manageability, can be safely used in clinical practice in this setting, potentially reducing hospitalizations and the need for inotropic support. We report here our experience in a small series of patients with advanced HF treated with sacubitril/valsartan. PMID- 29262403 TI - Sacubitril/Valsartan in an Elderly Patient with Heart Failure: A Case Report. AB - Sacubitril/valsartan has recently been approved for the treatment of heart failure with reduced ejection fraction. Given its recent introduction in the armamentarium for the treatment of heart failure (HF), "field-practice" evidence is required to deepen the clinical management of sacubitril/valsartan therapy. We report a relevant case of an elderly patient who achieved major clinical benefits after only 3 months of sacubitril/valsartan therapy. Importantly, in our assessment, we employed speckle tracking echocardiography (STE), a recent echocardiography technique that is non-Doppler and not angle dependent, which analyzes deformations of heart chambers from standard images and allows a fast, reliable, and reproducible assessment of heart function. After 3 months of therapy, NHYA class decreased from III to I-II and hypertension was controlled. Echocardiography examination also showed a marked improvement, with a reduction of left ventricular diameter, improved diastolic function (E = 0.39 m/s; A 0.69 m/s; E/A 0.55), normalized diastolic function index (E/E' TDI = 6.93), normalized atrial volume (63 mL), and improved atrial strain (15.44%). This case report documents the fast clinical and symptom improvement with sacubitril/valsartan in an elderly patient with HF; comprehensive echocardiographic assessment, including STE, also revealed a marked functional improvement with this compound. PMID- 29262405 TI - Management of a Multicomorbid Patient with Heart Failure. AB - The optimal use of sacubitril/valsartan in clinical practice needs further investigation, in particular for patients with multiple comorbidities, as such patients are usually poorly represented in clinical trials. To this end, well documented case reports may add further evidence to the bulk of "field practice" experience on sacubitril/valsartan. We report here the case of a patient with heart failure with reduced ejection refraction with multiple comorbidities treated with sacubitril/valsartan. Overall, sacubitril/valsartan led to a prompt (within a few months) improvement in LVEF (+15%, from 38 to 53%), without any noticeable adverse events. This therapy also allowed the patient to discontinue furosemide. PMID- 29262404 TI - Candida albicans and Early Childhood Caries: A Systematic Review and Meta Analysis. AB - Oral Candida albicans has been detected in children with early childhood caries (ECC) and has demonstrated cariogenic traits in animal models of the disease. Conversely, other studies found no positive correlation between C. albicans and caries experience in children, while suggesting it may have protective effects as a commensal organism. Thus, this study aimed to examine whether oral C. albicans is associated with ECC. Seven electronic databases were searched. The data from eligible studies were extracted, and the risk of bias was evaluated. A fixed effects model (Mantel-Haenszel estimate) was used for meta-analysis, and the summary effect measure was calculated by odds ratio (OR) and 95% confidence interval (CI). Fifteen cross-sectional studies were included for the qualitative assessment and 9 studies for meta-analysis. Twelve studies revealed higher oral C. albicans prevalence in ECC children than in caries-free children, while 2 studies indicated an equivalent prevalence. A pooled estimate, with OR = 6.51 and 95% CI = 4.94-8.57, indicated a significantly higher ECC experience in children with oral C. albicans than those without C. albicans (p < 0.01). The odds of experiencing ECC in children with C. albicans versus children without C. albicans were 5.26 for salivary, 6.69 for plaque, and 6.3 for oral swab samples. This systematic review indicates that children with oral C. albicans have >5 times higher odds of having ECC compared to those without C. albicans. Further prospective cohort studies are needed to determine whether C. albicans could be a risk factor for ECC, and whether it is dependent on different sample sources (saliva/plaque). PMID- 29262406 TI - Sacubitril/Valsartan in Clinical Practice: The Italian Experience. PMID- 29262407 TI - The Role of beta-Adrenergic Overstimulation in the Early Stages of Renal Injury. AB - BACKGROUND/AIMS: To assess the possible contribution of the beta-adrenergic overstimulation in early stages of renal injury, the present study evaluated, in rats, the effects of the beta-adrenoceptor agonist isoproterenol (ISO) on renal function and morphology, as well as the renal mRNA and protein expression of the NADPH oxidase isoform 4 (Nox 4) and subunit p22phox, endoplasmic reticulum (ER) stress, pro-inflammatory, pro-apoptotic and renin-angiotensin system (RAS) components. METHODS: Wistar rats received ISO (0.3 mg.kg-1.day-1 s.c.) or vehicle (control) for eight days. At the end of the treatment, food and water intake, urine output and body weight gain were evaluated and renal function studies were performed. Renal tissue was used for the morphological, quantitative PCR and immunohistochemical studies. RESULTS: ISO did not change metabolic parameters or urine output. However it induced a decrease in renal blood flow and an increase in the filtration fraction. These changes were accompanied by increased cortical mRNA and protein expression for the renal oxidative stress components including Nox 4 and p22phox; ER stress, pro-inflamatory, pro-apoptotic as well as RAS components. ISO also induced a significant increase in medullar renin protein expression. CONCLUSION: These findings support relevant information regarding the contribution of specific beta-adrenergic hyperactivity in early stage of renal injury, indicating the reactive oxygen species, ER stress and intrarenal RAS as important factors in this process. PMID- 29262408 TI - Phylogeography of the Mantled Howler Monkey (Alouatta palliata; Atelidae, Primates) across Its Geographical Range by Means of Mitochondrial Genetic Analyses and New Insights about the Phylogeny of Alouatta. AB - We analyzed 156 specimens of diverse howler monkey taxa (Alouatta; Atelidae, Primates) for different mitochondrial genes (5,567 base pairs), with special emphasis on A. palliata and related taxa. Our results showed no relevant differences among individuals of different putative taxa, A. p. palliata, A. p. aequatorialis, A. coibensis coibensis, and A. c. trabeata. We found no spatial differences in genetic structure of A. p. palliata throughout Costa Rica, Nicaragua, and Honduras. A. p. mexicana (genetic distance: 1.6-2.1%) was the most differentiated taxon within A. palliata. Therefore, we postulate the existence of only 2 clearly defined subspecies within A. palliata (A. p. palliata and A. p. mexicana). A. palliata and A. pigra (traditionally considered a subspecies of A. palliata) are 2 clearly differentiated species as was demonstrated by Cortes Ortiz and colleagues in 2003, with a temporal split between the 2 species around 3.6-3.7 million years ago (MYA). Our results with the Median Joining Network procedure showed that the ancestors of the cis-Andean Alouatta gave rise to the ancestors of the trans-Andean Alouatta around 6.0-6.9 MYA. As Cortes-Ortiz et al. showed, A. sara and A. macconnelli are differentiable species from A. seniculus, although the first 2 taxa were traditionally considered subspecies of A. seniculus. Our findings agree with the possibility that the ancestor of A. sara gave rise to the ancestor of A. pigra in northern South America. In turn, the ancestor of A. pigra originated the ancestor of A. palliata. Two of our results strongly support the hypothesis that the South American A. palliata (the putative A. p. aequatorialis) was the original population of this species; it has high genetic diversity and no evidence of population expansion. The Central America A. palliata is the derived population. It has low genetic diversity and there is clear evidence of population expansion. However, A. palliata and A. pigra probably migrated into Central America by 2 different routes: the Isthmus of Panama (A. palliata) and Caribbean island arch (A. pigra). Finally, the red howler monkeys from the island of Trinidad in the Caribbean Sea were not A. macconnelli (= A. s. stramineus) as Groves maintained in his influential 2001 publication on primate taxonomy. This taxon is more related to A. s. seniculus, although it formed a monophyletic clade. Future molecular and karyotypic studies will show if the Trinidad red howler monkeys should be considered as an extension of the Venezuelan taxon, A. arctoidea, as a subspecies of A. seniculus(A. s. seniculus), or, in the case of extensive chromosomal rearrangements, even a new species. PMID- 29262409 TI - Early Markers of Cardiovascular Risk in Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND/AIMS: Cardiovascular disease is the most frequent cause of morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD) patients, often before the onset of renal failure, and the pathogenetic mechanism is not yet well elucidated. The aim of the study was to identify early and noninvasive markers of cardiovascular risk in young ADPKD patients, in the early stages of disease. METHODS: A total of 26 patients with ADPKD and 24 control group, matched for age and sex, were enrolled, and we have assessed inflammatory indexes, mineral metabolism, metabolic state and markers of atherosclerosis and endothelial dysfunction (carotid intima media thickness (IMT), ankle brachial index (ABI), flow mediated dilation (FMD), renal resistive index (RRI), left ventricular mass index (LVMI)) and cardiopulmonary exercise testing (CPET), maximal O2 uptake (V'O2max), and O2 uptake at lactic acid threshold (V'O2@LT). RESULTS: The ADPKD patients compared to control group, showed a significant higher mean value of LVMI, RRI, homocysteine (Hcy), Homeostasis Model Assessment insulin resistance (HOMA-IR), serum uric acid (SUA), Cardiac-troponinT (cTnT) and intact parathyroid hormone (iPTH) (p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p=0.007, p=0.019; respectively), and a lower value of FMD and 25-hydroxyvitaminD (25-OH-VitD) (p<0.001, p<0.001) with reduced parameters of exercise tolerance, as V'O2max, V'O2max/Kg and V'O2max (% predicted) (p<0.001, p<0.001, p=0.018; respectively), and metabolic response indexes (V'O2@LT, V'O2 @LT%, V'O2@LT/Kg,) (p<0.001, p=0.14, p<0.001; respectively). Moreover, inflammatory indexes were significantly higher in ADPKD patients, and we found a positive correlation between HOMA-IR and C-reactive protein (CRP) (r=0.507, p=0.008), and a negative correlation between HOMA-IR and 25-OH-VitD (r=-0.585, p=0.002). CONCLUSION: In our study, ADPKD patients, in the early stages of disease, showed a greater insulin resistance, endothelial dysfunction, inflammation and mineral metabolism disorders, respect to control group. Moreover, these patients presented reduced tolerance to stress, and decreased anaerobic threshold to CPET. Our results indicate a major and early cardiovascular risk in ADPKD patients. Therefore early and noninvasive markers of cardiovascular risk and CPET should be carried out, in ADPKD patients, in the early stages of disease, despite the cost implication. PMID- 29262410 TI - Association Between Plasma Homocysteine and Microalbuminuria in Untreated Patients with Essential Hypertension: a Case-Control Study. AB - BACKGROUND/AIMS: Kidney function is critical for homocysteine (Hcy) clearance, and plasma Hcy levels are frequently increased in patients with renal failure. Microalbuminuria (MAU) is an important marker of early renal damage caused by hypertension. At present, there is insufficient evidence on the relationship between Hcy and microalbuminuria. METHODS: This is a 1: 2 matched, hospital-based case-control study. At initial visit, out of 1535 outpatients with no prior history of medication, 450 qualified subjects were selected based on inclusion and exclusion criteria. The concentration of Hcy in the serum was evaluated using a cyclic enzyme method. MAU was defined by a urine albumin/creatinine ratio (UACR) between 30 MUg/mg and 300 MUg/mg. RESULTS: A total of 450 patients were included in this study (150 in the MAU group and 300 in the non-MAU group). The MAU group had higher mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP), heart rate (HR) and plasma Hcy levels than did the non-MAU group. The area under the receiver operating characteristics (ROC) curves was 0.772 (95% CI: 0.724-0.819, P < 0.001) with a cut-off value of 15.0, and the sensitivity and specificity of Hcy in predicting the MAU status in hypertensive patients were 49.3% and 92.3%, respectively. Multiple logistic regression modelling suggested that patients with a higher Hcy level (> 15 umol/L) were more likely to have MAU (95% CI: 5.650-16.543, P < 0.001). The other predictive factor for MAU was 24-h mean SBP (95% CI: 0.941-0.993, P = 0.015). CONCLUSION: This matched case-control study indicates that Hcy may increase the susceptibility of essential hypertensive subjects to MAU. PMID- 29262411 TI - NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling. AB - BACKGROUND/AIMS: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. METHODS: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3-/- mice. RESULTS: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3-/- mice. Furthermore, Ang II induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3-/- mice. CONCLUSIONS: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension. PMID- 29262412 TI - Integrated Karyotyping of Woodland Strawberry (Fragaria vesca) with Oligopaint FISH Probes. AB - Chromosome identification is critical for many aspects of cytogenetic research. However, for Fragaria vesca, definite identification of individual chromosomes is almost impossible because of their small size and high similarity. Here, we demonstrate that bulked oligonucleotide (oligo) probes can be used as chromosome specific DNA markers for chromosome identification in F. vesca. Oligos specific to entire pseudochromosomes in the draft genome of F. vesca were identified and synthesized as libraries. In all, we synthesized 6 oligo libraries corresponding to 6 pseudochromosomes of F. vesca. These libraries were amplified and labeled as probes for fluorescence in situ hybridization (FISH). Two rounds of multicolor FISH analysis were sequentially conducted on the same metaphase cells with each round including 3 probe libraries, which permitted simultaneous identification of all chromosomes of F. vesca. Moreover, 45S and 5S rDNA were mapped to chromosomes 1, 2, and 7, respectively. A karyotype of metaphase chromosomes was constructed, representing the first FISH-based molecular cytogenetic karyotype of F. vesca. Our study can serve as a basis for future comparative cytogenetic research through cross-species chromosome painting using bulked oligo probes and will facilitate the application of breeding technologies that rely on the identification of chromosomes in the genus Fragaria. PMID- 29262413 TI - Angiotensin II Facilitates Matrix Metalloproteinase-9-Mediated Myosin Light Chain Kinase Degradation in Pressure Overload-Induced Cardiac Hypertrophy. AB - BACKGROUND/AIMS: Angiotensin II (Ang II) has been shown to promote cardiac remodeling during the process of hypertrophy. Myosin light chain kinase (MLCK), a specific kinase for the phosphorylation of myosin light chain 2 (MLC2), plays an important role in regulating cardiac muscle contraction and hypertrophy. However, whether Ang II could facilitate cardiac hypertrophy by altering the expression of MLCK remains unclear. This study aimed to investigate this effect and the underlying mechanisms. METHODS: Cardiac hypertrophy was induced via pressure overload in rats, which were then evaluated via histological and biochemical measurements and echocardiography. Angiotensin-converting enzyme inhibitor (ACEI) was used to inhibit Ang II. Neonatal rat cardiomyocytes were stimulated with Ang II to induce hypertrophy and were treated with a matrix metalloproteinase 9 (MMP9) inhibitor. Myocyte hypertrophy was evaluated using immunofluorescence and qRT-PCR. Degradation of recombinant human MLCK by recombinant human MMP9 was tested using a cleavage assay. The expression levels of MLCK, MLC2, phospho myosin light chain 2 (p-MLC2), myosin phosphatase 2 (MYPT2), and calmodulin (CaM) were measured using western blotting. RESULTS: ACEI improved cardiac function and remodeling and increased the levels of MLCK and p-MLC2 as well as reduced the expression of MMP9 in pressure overload-induced cardiac hypertrophy. Moreover, the MMP9 inhibitor alleviated myocyte hypertrophy and upregulated the levels of MLCK and p-MLC2 in Ang II-induced cardiomyocyte hypertrophy. Recombinant human MLCK was concentration- and time-dependently degraded by recombinant human MMP9 in vitro, and this process was prevented by the MMP9 inhibitor. CONCLUSION: Our results suggest that Ang II is involved in the degradation of MLCK in pressure overload-induced cardiac hypertrophy and that this process was mediated by MMP9. PMID- 29262414 TI - Quality of Life and Cost-Effectiveness of Cochlear Implants: A Narrative Review. AB - OBJECTIVES: To review evidence regarding the health-related quality of life (HRQoL) and cost-effectiveness of unilateral and bilateral cochlear implantation (CI) among children and adults with severe-to-profound hearing loss. STUDY DESIGN: Narrative review. METHODS: Publications related to quality of life (QoL) and costs of care in CI were acquired through searches in English-language databases. Studies were included if they had identified the HRQoL attainment, cost of care, cost-utility, or cost-effectiveness associated with CI. RESULTS: 57 studies were critically reviewed. The QoL outcome metrics used in these articles were divided into 2 categories - generic and condition specific. In studies investigating children, many reported no significant difference in QoL attainment between CI recipients and normal-hearing peers. In adults, significant improvements in QoL after implantation and higher QoL than in their nonimplanted (hearing-aided) peers were frequently reported. Studies involving an older adult cohort reported significant improvement in QoL after implantation, which was often independent of audiological performance. Overall, the calculated cost utility ratios consistently met the threshold of cost acceptance, indicating acceptable values for expenditures on CI. CONCLUSIONS: Considerable work has been done on the QoL attainment and health economic implications of CI. Unilateral CI across all age groups leads to reported sustained benefits in the recipients' overall and disease-specific QoL. With increased cost associated with bilateral CI, further study is needed to characterize its costs and benefits with respect to the recipients' health, well-being, and contributions to society. PMID- 29262415 TI - Anorexia Nervosa and First-Person Perspective: Altruism, Family System, and Body Experience. AB - Based on the case study of Jeanne, the objective of this article is to study patterns of specific subjectivity in anorexic subjects. We seek to identify, in a first-person perspective, the core vulnerability features of anorexic existence, beyond the dimension of food alone. The identification of a psychopathological structure results in a better understanding of Jeanne's clinical situation and helps formulate psychotherapeutic and prophylactic recommendations. We suggest that so-called "denial" is a psychological mechanism that should be reconsidered. Denial is not a mechanism pertaining to anorexic subjects alone, but is also a process encountered both in the patient's family and in the therapeutic environment. Anorexic denial is based on anosognosia and the refusal to see one's own thinness, while other people's denial consists in a widespread inability to perceive the altruism and intersubjective problematic on which the existence of an anorexic subject fundamentally depends. PMID- 29262416 TI - Consensus on Wound Antisepsis: Update 2018. AB - Wound antisepsis has undergone a renaissance due to the introduction of highly effective wound-compatible antimicrobial agents and the spread of multidrug resistant organisms (MDROs). However, a strict indication must be set for the application of these agents. An infected or critically colonized wound must be treated antiseptically. In addition, systemic antibiotic therapy is required in case the infection spreads. If applied preventively, the Wounds-at-Risk Score allows an assessment of the risk for infection and thus appropriateness of the indication. The content of this updated consensus recommendation still largely consists of discussing properties of octenidine dihydrochloride (OCT), polihexanide, and iodophores. The evaluations of hypochlorite, taurolidine, and silver ions have been updated. For critically colonized and infected chronic wounds as well as for burns, polihexanide is classified as the active agent of choice. The combination 0.1% OCT/phenoxyethanol (PE) solution is suitable for acute, contaminated, and traumatic wounds, including MRSA-colonized wounds due to its deep action. For chronic wounds, preparations with 0.05% OCT are preferable. For bite, stab/puncture, and gunshot wounds, polyvinylpyrrolidone (PVP)-iodine is the first choice, while polihexanide and hypochlorite are superior to PVP-iodine for the treatment of contaminated acute and chronic wounds. For the decolonization of wounds colonized or infected with MDROs, the combination of OCT/PE is preferred. For peritoneal rinsing or rinsing of other cavities with a lack of drainage potential as well as the risk of central nervous system exposure, hypochlorite is the superior active agent. Silver-sulfadiazine is classified as dispensable, while dyes, organic mercury compounds, and hydrogen peroxide alone are classified as obsolete. As promising prospects, acetic acid, the combination of negative pressure wound therapy with the instillation of antiseptics (NPWTi), and cold atmospheric plasma are also subjects of this assessment. PMID- 29262418 TI - Gastro-Oesophageal Reflux and Apnoea: Is There a Temporal Relationship? AB - BACKGROUND: Gastro-oesophageal reflux (GOR) and apnoea are common in infants; whether there is a causal relationship is controversial. OBJECTIVES: To determine whether there was a temporal relationship between GOR and apnoea, in particular, the frequency of obstructive apnoeas and if the frequency of GOR episodes correlated with apnoea frequency when maturity at testing was taken into account. METHODS: Polysomnography and pH/multichannel intraluminal impedance (MII) studies were performed. Apnoeas were classified as central, obstructive, or mixed. MII events were classified as acidic (pH <4) or weakly acidic (4 < pH < 7). Apnoea frequency in the 5-min period after a reflux event was compared to that in the 5 min period preceding the event and that in a 5-min reflux-free period (control period). RESULTS: Forty infants (median gestational age 29 [range 24-42] weeks) were assessed at a post-conceptional age of 37 (30-54) weeks. Obstructive (n = 580), central (n = 900), and mixed (n = 452) apnoeas were identified; 381 acid reflux events were detected by MII and 153 by the pH probe only. Apnoeas were not more frequent following GOR than during control periods. Both the frequency of apnoeas (p = 0.002) and GOR episodes (p = 0.01) were inversely related to post conceptional age at testing, but were not significantly correlated with each other when controlled for post-conceptional age. CONCLUSIONS: These results suggest that GOR does not cause apnoea. PMID- 29262417 TI - Antibiotic and Analgesic Prescription Patterns among Dentists or Management of Dental Pain and Infection during Endodontic Treatment. AB - OBJECTIVE: The aim of this study was to determine prescription patterns of antibiotics and analgesics among dentists in the management of dental pain and infection for medically healthy patients undergoing endodontic management. MATERIALS AND METHODS: This descriptive cross-sectional survey was based on a structured questionnaire. The questionnaire collected data on age, gender, years of experience, and the qualifications of dentists. Feedback on prescription patterns for antibiotics and analgesics was collected for a number of clinical scenarios. Participants' choices regarding the type, dose, and duration of antibiotics/analgesics were recorded. Completed questionnaires were analyzed using the Statistical Package for Social Sciences (SPSS; version 24) to determine relationships between prescription patterns, age, gender, and educational qualification. RESULTS: Of the 227 participants surveyed, 190 (83.7%) did not prescribe antibiotics for patients complaining of severe pain. There were significant associations between age and years of experience and antibiotic prescription for pain management (p = 0.035 and 0.04, respectively). Of the participants, 199 (87.7%) never prescribed antibiotics for reversible pulpitis with normal periapical area; there was a statistical significance in relation to gender (p = 0.044). Amoxicillin 500 mg was prescribed most of the time (51.5%). Diclofenac K (50 mg) was prescribed by 41% of the participants, while 39.2% of the participants very often prescribed ibuprofen (600 mg). CONCLUSION: Most dentists prescribed analgesics and antibiotics as recommended, but more education on the proper use of these medicines is needed for dentists and patients. PMID- 29262419 TI - A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD. AB - R-spondin proteins are secreted agonists of canonical WNT/beta-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease. PMID- 29262420 TI - Neoplastic Multifocal Skin Lesions: Biology, Etiology, and Targeted Therapies for Nonmelanoma Skin Cancers. AB - Neoplastic skin lesions are multifocal, diffuse skin infiltrations of particular relevance in the differential diagnosis of ulcerative, nodular, or crusting skin lesions. Nonmelanoma skin cancers (NMSCs), namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and also actinic keratosis (AK), are the most common malignant tumors in humans. BCCs do not proliferate rapidly and most of the times do not metastasize, while SCCs are more infiltrative, metastatic, and destructive. AKs are precursor lesions of cutaneous SCCs. The classical therapy of NMSCs makes use of photodynamic therapy associated with chemotherapeutics. With improved understanding of the pathological mechanisms of tumor initiation, progression, and differentiation, a case is made towards the use of targeted chemotherapy with the intent to reduce the cytotoxicity of classical treatments. The present review aims to describe the current state of the art on the knowledge of NMSC, including its risks factors, oncogenes, and skin carcinogenesis, discussing the classical therapy against new therapeutic options. PMID- 29262425 TI - Quantitative Determination of Delta9-THC, CBG, CBD, Their Acid Precursors and Five Other Neutral Cannabinoids by UHPLC-UV-MS. AB - Cannabinoids are a group of terpenophenolic compounds in the medicinal plant Cannabis sativa (Cannabaceae family). Cannabigerolic acid, Delta9 tetrahydrocannabinolic acid A, cannabidiolic acid, Delta9-tetrahydrocannabinol, cannabigerol, cannabidiol, cannabichromene, and tetrahydrocannabivarin are major metabolites in the classification of different strains of C. sativa. Degradation or artifact cannabinoids cannabinol, cannabicyclol, and Delta8 tetrahydrocannabinol are formed under the influence of heat and light during processing and storage of the plant sample. An ultrahigh-performance liquid chromatographic method coupled with photodiode array and single quadruple mass spectrometry detectors was developed and validated for quantitative determination of 11 cannabinoids in different C. sativa samples. Compounds 1: - 11: were baseline separated with an acetonitrile (with 0.05% formic acid) and water (with 0.05% formic acid) gradient at a flow rate of 0.25 mL/min on a Waters Cortec UPLC C18 column (100 mm * 2.1 mm I. D., 1.6 um). The limits of detection and limits of quantitation of the 11 cannabinoids were below 0.2 and 0.5 ug/mL, respectively. The relative standard deviation for the precision test was below 2.4%. A mixture of acetonitrile and methanol (80 : 20, v/v) was proven to be the best solvent system for the sample preparation. The recovery of all analytes was in the range of 97 - 105%. A total of 32 Cannabis samples including hashish, leaves, and flower buds were analyzed. PMID- 29262426 TI - [Correction: Medical Progress and Public Health - Results of the Working Group 4 of the Forum Future Public Health, Berlin]. PMID- 29262427 TI - Neurocritical Care and Emergency Neurology: Current Evidence and Consensus Practice. PMID- 29262428 TI - Bringing Emergency Neurology to Ambulances: Mobile Stroke Unit. AB - Ischemic stroke results from blocked arteries in the brain, with earlier thrombolysis with intravenous tissue plasminogen activator (tPA) and/or mechanical thrombectomy resulting in improved clinical outcomes. Mobile Stroke Unit (MSU) can speed up the treatment with tPA and facilitate faster triage for patients to hospitals for mechanical thrombectomy. The first registry-based MSU study in Germany demonstrated faster treatment times with tPA using a MSU, a higher proportion of patients being treated within the first "golden hour," and a suggestion of improved 3-month clinical outcomes. The first multicenter, prospective, randomized clinical trial comparing MSU versus standard care was started in 2014 after the launch of the MSU in Houston, TX, demonstrating the feasibility and safety of MSU operation in the United States, and reliability of telemedicine to evaluate stroke patients for tPA eligibility. Although conclusive evidence from clinical trials to support MSUs as being cost effective and improving clinical outcomes is still needed, there are a myriad of other clinical and research applications of MSUs that could have profound implications for managing patients with neurological emergencies. PMID- 29262429 TI - Blood Pressure Management for Acute Ischemic and Hemorrhagic Stroke: The Evidence. AB - Hypertension is the most common modifiable risk factor for stroke (both ischemic and hemorrhagic types). In the hyperacute phase, a majority of patients shows an elevated blood pressure (BP) at the time of presentation because of sympathetic hyperactivity or a physiological response to tissue ischemia. Therefore, BP may decrease spontaneously in a few hours and may drop further when complete recanalization is achieved. In stroke guidelines, an elevated BP is usually left untreated up to a systolic BP (SBP) of 220 mm Hg and a diastolic BP of 120 mm Hg. This recommendation is based on the BP level that corresponds to the upper limit of the pressure autoregulation zone above which cerebral blood flow is directly dependent on BP. However, in patients in whom administration of recombinant tissue-type plasminogen activator is indicated, BP should be controlled to a level < 185/110 mm Hg before infusion and should be maintained at levels < 180/105 mm Hg to limit the risk of intracerebral hemorrhage (ICH). In cases where endovascular thrombectomy is considered, the optimal intra- and postprocedural BP target have not yet been clearly identified. Expert opinion recommends that intraprocedural BP reduction could be associated with a risk of poor outcomes, and therefore, SBP may be reduced only to 120 to 140 mm Hg after successful reperfusion therapy. However, this recommendation is primarily based on observational studies and requires validation in prospective trials. It has been observed that in patients presenting with an ICH, there is no perihematomal penumbra noted and rapid BP reduction is generally well tolerated without a risk of neurological worsening. Multiple trials describing acute reduction of BP recommend SBP reduction only to 140 mm Hg because while there is no benefit of better functional outcomes below that level, there exists a definite risk of increased renal complications. PMID- 29262430 TI - Reversal of Oral Anticoagulants for Intracerebral Hemorrhage Patients: Best Strategies. AB - In patients with acute intracerebral hemorrhage (ICH), one of the major concerns is ongoing bleeding or ICH expansion. Anticoagulated patients are at higher risk of ongoing expansion and worse outcome. It may be that rapid anticoagulation reversal can reduce the risk of expansion and improve clinical outcome. For those taking coumarins, the best available evidence suggests that intravenous vitamin K combined with four-factor prothrombin complex concentrate (4F-PCC) is the most rapid and effective regimen to restore hemostasis. For those on dabigatran, the highest quality data available for reversal are for idarucizumab, although it is not yet clear whether patients derive clinical benefit from this reversal. In the absence or failure of idarucizumab, activated prothrombin complex concentrate (aPCC) is recommended. For those on factor Xa inhibitors, the ideal reversal agent is not clear. Many providers use 4F-PCC or aPCC, but more specific agents are in clinical trials and may soon be available. In addition, the half-lives of the non-vitamin K antagonists are relatively short compared with warfarin, and so some patients may not have a clinically relevant coagulopathy at the time of presentation. Overall, the optimal reversal agent, when one is required, is a function of which anticoagulant the patient is taking. PMID- 29262431 TI - Decompressive Craniectomy for Malignant Middle Cerebral Artery Stroke. AB - Advancements in the treatment of ischemic stroke have led to a recent decline in overall stroke mortality, but patients with hemispheric infarcts remain at high risk for death. Recent advances in the approach to this devastating disease include early identification of patients at high risk for swelling and standardized approaches to medical therapy. However, surgical decompression continues to be the most effective treatment for malignant edema from large hemispheric strokes. Patient selection in the past had been strictly limited to younger ages and the nondominant hemisphere. More recent evidence demonstrates a mortality benefit in older patients with a limited impact on morbidity. Judicious patient selection and shared, informed decision making with families remain the optimal approach for this devastating disease. PMID- 29262432 TI - Spontaneous Intraventricular Hemorrhage: When Should Intraventricular tPA Be Considered? AB - Spontaneous intracerebral hemorrhage (ICH) is the most common cause of intraventricular hemorrhage (IVH) in adults. Complicating approximately 40% of ICH cases, IVH adds to the morbidity and mortality of this often fatal form of stroke. It is also a severity factor that complicates subarachnoid hemorrhage and traumatic brain injury, along with other less common causes of intracranial bleeding. Medical and surgical interventions to date have focused on limiting ICH and IVH expansion, controlling intracranial pressure, and relieving obstructive hydrocephalus. The placement of an external ventricular drain (EVD) can achieve the latter two goals but has not demonstrated improvement in clinical outcomes beyond mortality reduction. More recently, intraventricular fibrinolysis, utilizing the EVD, has gained interest as a safe and potentially effective method to maintain catheter patency and facilitate hematoma removal. A recent phase III clinical trial evaluating the efficacy of intraventricular alteplase versus intraventricular saline showed a mortality benefit, but failed to meet the primary endpoint of significant functional improvement. However, planned subgroup analysis focusing on patients with IVH volume > 20 mL, and those with IVH removal > 85% suggest that significant functional benefits may be attainable with this therapy. The practice of intraventricular fibrinolysis for spontaneous IVH is not the standard of care; however, based on 20 years of experience, it meets thresholds as a safe intervention, and in those patients with a high burden of intraventricular blood, aggressive clearance may lead to improved quality of life in survivors of this morbid syndrome. PMID- 29262433 TI - Aneurysmal Subarachnoid Hemorrhage: Strategies for Preventing Vasospasm in the Intensive Care Unit. AB - This article addresses the intensive care unit (ICU) management of patients with aneurysmal subarachnoid hemorrhage (SAH), with an emphasis on the prevention of cerebral vasospasm and delayed cerebral ischemia (DCI), which are major contributors to morbidity and mortality. Interventions addressing various steps in the development of vasospasm have been attempted, with variable success. Enteral nimodipine remains the only approved measure to potentially prevent DCI. Since oral and intravenous administrations are limited by hypotension, direct administration via sustained-release pellets and intraventricular administration of sustained-release microparticles are being investigated. Studies of other calcium channel blockers have been disappointing. Efforts to remove blood from the subarachnoid space via cisternal irrigation, cisternal or ventricular thrombolysis, and lumbar cerebrospinal fluid drainage have met with limited and variable success, and they remain an area of active investigation. Several interventions that had early promise have failed to show benefit when studied in large trials; these include tirilazad, magnesium, statins, clazosentan, transluminal angioplasty, and hypervolemia. PMID- 29262434 TI - Future Directions for Hypothermia following Severe Traumatic Brian Injury. AB - Traumatic brain injury (TBI) is a serious health care problem on both individual and public health levels. As a major cause of death and disability in the United States, it is associated with a significant economic and public health burden. Although the evidence to support the use of induced hypothermia on neurologic outcome after cardiac arrest is well established, its use in treating TBI remains controversial. Hypothermia has the potential to mitigate some of the destructive processes that occur as part of secondary brain injury after TBI. Hypothermia can be helpful in lowering intracranial pressure, for example, but its influence on functional outcome is unclear. There is insufficient evidence to support the broad use of prophylactic hypothermia for neuroprotection after TBI. Investigators are beginning to more carefully select patients for temperature modulating therapies, in a more personalized approach. Examples include targeting immunomodulation and scaling hypothermia to achieve metabolic targets. This review will summarize the clinical evidence for the use of hypothermia to limit secondary brain injury following acute TBI. PMID- 29262435 TI - Neuroprognostication of Cardiac Arrest Patients: Outcomes of Importance. AB - During the last two decades, survival rates after cardiac arrest have increased while the fraction of patients surviving with a severe neurological disability or vegetative state has decreased in many countries. While improved survival is due to improvements in the whole "chain of survival," improved methods for prognostication of neurological outcome may be of major importance for the lower disability rates. Patients who are resuscitated and treated in intensive care will die mainly from the withdrawal of life-sustaining (WLST) therapy due to presumed poor chances of meaningful neurological recovery. To ensure high-quality decision-making and to reduce the risk of premature withdrawal of care, implementation of local protocols is crucial and should be guided by international recommendations. Despite rigorous neurological prognostication, cognitive impairment and related psychological distress and reduced participation in society will still be relevant concerns for cardiac arrest survivors. The commonly used outcome measures are not designed to provide information on these domains. Follow-up of the cardiac arrest survivor needs to consider the cardiovascular burden as an important factor to prevent cognitive difficulties and future decline. PMID- 29262436 TI - Multimodality Monitoring: Toward Improved Outcomes. AB - Multimodality monitoring provides insights into the critically ill brain-injured patient through the assessment of biochemical, physiological, and electrical data that provides insight into a patient's condition and what strategies may be available to limit further damage and improve the odds for recovery. Modalities utilized include evaluation of intracranial pressure along with cerebral perfusion pressure to determine adequate blood flow; continuous electroencephalography to protect the patient from seizures and to identify early functional manifestations of ischemia and toxicity; transcranial Doppler evaluation for bedside review of circulatory adequacy; tissue oxygen monitoring to establish that brain tissue is receiving adequate oxygen from blood flow; and microdialysis to evaluate the metabolic function of the tissue in areas of concern. These monitors provide insights regarding specific aspects of brain tissue and overall brain function in the critically ill patient. Although recommendations continue to evolve for therapeutic targets for each of these modalities, an effective clinician may use each of these modalities to evaluate patients on an individual basis to improve the outcome of each patient, tailoring management to provide the care needed for any unique clinical presentation. PMID- 29262437 TI - Ictal-Interictal Continuum: When to Worry About the Continuous Electroencephalography Pattern. AB - Continuous electroencephalography (cEEG) monitoring is an invaluable tool in the evaluation of encephalopathy and coma in critically ill patients. Marked increases in cEEG monitoring, coinciding with several societal guideline statements in the last decade, have allowed earlier detection and treatment of clearly harmful patterns, including nonconvulsive seizures (NCSz) and nonconvulsive status epilepticus (NCSE). However, it has also unmasked a range of EEG patterns of less clear clinical significance, with some more "malignant" than others given their potential association with increased neuronal stress and secondary brain injury. These patterns lay on a spectrum often referred to as the ictal-interictal continuum (IIC). To date, no definitive guidelines exist for the management of these potentially harmful EEG patterns, thus presenting a clinical dilemma for critical care physicians. Here, we review the various IIC patterns, their associated features, seizure risk, and outcomes and also propose a clinical approach to management based on the available data and expert opinion. PMID- 29262438 TI - Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression. AB - Autoimmune diseases affecting the nervous systems are a common cause of admission to the intensive care unit (ICU). Although there exist several well-described clinical syndromes, patients more commonly present with progressive neurologic dysfunction and laboratory and radiographic evidence of central nervous system (CNS) inflammation. In the critical care setting, the urgency to intervene to prevent permanent damage to the nervous system and secondary injury from the systemic manifestations of these syndromes often conflicts with diagnostic uncertainty. Furthermore, treatment is limited by current therapeutic agents that remain non-specific for individual diseases, especially for those whose pathophysiology remains unclear. Primary autoimmune, paraneoplastic, parainfectious, and iatrogenic neurologic disorders all share the common underlying pathophysiology of an adaptive immune response directed against an antigen within the nervous system. Several different mechanisms of immune dysfunction are responsible for pathogenesis within each of these categories of disease, and it is at this level of pathophysiology that the most effective and appropriate therapeutic decisions are made. In this review, we outline the basic diagnostic and therapeutic principles in the management of autoimmune diseases of the nervous system in the ICU. We approach these disorders not as lists of distinct clinical syndromes or molecular targets of autoimmunity but rather as clusters of syndromes based on these common underlying mechanisms of immune dysfunction. This approach emphasizes early intervention over precise diagnosis. As our understanding of the immune system continues to grow, this framework will allow for a more sophisticated approach to the management of patients with these complex, often devastating but frequently reversible, neurologic illnesses. PMID- 29262439 TI - Management of Cerebral Edema in Acute Liver Failure. AB - Advances in medical care of the acute liver failure patient have led to a significant reduction in mortality related to the condition. Nevertheless, cerebral edema and ensuing brain herniation remains one of the top causes of demise in acute liver failure. Controversy remains regarding the utility of invasive intracranial pressure monitoring as well as usage of novel treatment modalities including therapeutic hypothermia. This review provides a brief summary into the pathophysiology and risk factors for developing cerebral edema in the context of acute liver failure; this review particularly provides a practical focus on general management of the patient with established cerebral edema as well as specific intracranial pressure-lowering strategies. PMID- 29262440 TI - Who Is Safe to Extubate in the Neuroscience Intensive Care Unit? AB - Patients admitted to the neuroscience intensive care unit (NICU) may have respiratory compromise from either central or peripheral neurological pathology, and may hence require intubation and mechanical ventilation for very diverse reasons. Liberation from invasive ventilation, that is, extubation, at the earliest possible time is a widely accepted principle in intensive care. For this, classic extubation criteria have been established in the general critical care setting, mainly targeting pulmonary function and cooperativeness of the patient. However, classic extubation criteria have failed to predict successful extubation in many studies on NICU patients, and extubation failure (EF) rates range between ~20 and 40% in these. Not necessarily impaired consciousness, but neurological impairment of securing the airway and handling secretions (dysphagia, low pharyngeal muscle tone, weak cough, etc.) may be mainly responsible for this dilemma. Attempts have been made to identify predictors of EF or success, and to establish extubation scores for the NICU, but results have been partially controversial and the database is still weak. It is very important to have a stepwise protocol to approach extubation in the NICU patient and to be prepared for reintubation (at times in a difficult airway) and alternatives (such as tracheostomy). The particular challenges of safely extubating the NICU patient will be the focus of this review, including a suggestion for a standardized approach. PMID- 29262441 TI - Imaging in Neurocritical Care Practice. AB - The use of neuroimaging in conjunction with serial neurological examinations is a core component of modern neurocritical care practice. Although there is a growing role for other neuromonitoring techniques, the ability to quickly and accurately interpret images in the context of a patient's clinical status arguably remains the indispensable skill for neurocritical care practitioners. Due to its rapid acquisition time and excellent ability to detect intracerebral hemorrhage (ICH), cerebral edema, and signs of elevated intracranial pressure, computed tomography (CT) remains the most useful neuroimaging technique for intensive care unit (ICU) patients. An emergent head CT is obtained to inform most time-sensitive decisions that arise in the neurological ICU (NICU). CT features also figure prominently in prognostic scores for common NICU conditions such as traumatic brain injury (TBI), ICH, and subarachnoid hemorrhage (SAH). Among patients who are sufficiently stable to leave the ICU and lie flat for an extended period, magnetic resonance imaging provides much more detailed, high-contrast images which can aid in the detection of ischemia, diffuse axonal injury, and neuroprognostication. Though primarily used in neurocritical care research, nuclear medicine imaging techniques have some clinical applications, particularly in ancillary testing for brain death. Finally, as in the field of critical care as a whole, formal and point-of-care ultrasound studies are increasingly utilized in the NICU, and are an important tool in the neurointensivist's armamentarium. We review here the common applications of imaging in the neurocritical care setting. As ICU patients are frequently unstable and their risk of clinical decompensation increases substantially during transport away from the ICU, guidelines and recommendations for maximizing patient safety during transport to radiology studies are also explored. PMID- 29262442 TI - Isolated Dupuytren's contracture of the distal interphalangeal joint of the little finger. PMID- 29262443 TI - [The relationship between the recurrence of benign paroxysmal positional vertigo and the level of bone mineral as well as estrogen in postmenopausal women]. AB - Objective: To investigate the relationship between the recurrence of benign paroxysmal positional vertigo(BPPV) and the levels of bone mineral density(BMD) and estrogen in postmenopausal women. Methods: A total of 38 postmenopausal women with recurrent BPPV were recruited as study group, in the First Affiliated Hospital of Soochow University from December 2013 to June 2017. Meanwhile, 49 normal menopausal women were included as control. All patients were natural menopausal for over one year.The patients were diagnosed as BPPV based on results of Dix-Hallpike test and Roll-test, with at least two episodes of recurrent onset. In the subjects, BMD was measured by dual X-ray absorptiometry of lumbar vertebrae. Estrogen levels were obtained by testing serum estradiol (E2) levels in early morning fasting venous blood. In the present study, we compared the level of E2 and the value of BMD in two groups by SPSS 21.0. In the study group, patients with decreased BMD were divided into two groups: treatment and untreated group. The recurrence rate of BPPV was compared between the two groups within 12 months. Results: 1The averagel levels of E2 and BMD in the study group were (16.21+/-11.00)ng/L and -1.68+/-0.98) respectively, which were significantly lower than those in the control group (t value was 7.03 and 8.05 respectively, both P<0.05). The averagel levels of E2 and BMD incontrol group were(28.52+/ 6.34)ng/L and -0.18+/-0.77 respectively. 2The number of patients with decreased BMD in the study group (30 cases) was more than that in control group (6 cases), and the difference was statistically significant (P<0.05). 3 The recurrence rate of BPPV in treatment group [17.6%(3/17)] was significantly lower than that of untreated group [61.5%(8/13)], and the difference was statistically significant (P<0.05). Conclusion: Recurrent BPPV in postmenopausal women usually accompany with low levels of estrogen and BMD. Active treatment is helpful for their recurrence of BPPV. PMID- 29262444 TI - [Ryan index for detection of laryngopharyngeal reflux diseases]. AB - Objective: To explore the utility of pharyngeal pH monitoring which positive standard is Ryan index in diagnosis of laryngopharyngeal reflux disease. Methods: In a retrospective study, clinical data of 590 patients who had symptoms laryngopharyngeal reflux disease from February 2016 to March 2017 were analyzed. All patients were received electronic laryngoscopy, assessment of reflux symptom index(RSI) and reflux finding score(RFS), and pharyngeal pH monitoring. SPSS 19.0 software was used to analyze the date. Results: There were 94 patients whose Ryan index were positive(15.93%). Among the 94 patients, 70 were positive during upright, 12 during supine and 12 during both upright and supine. There were 40 patients(6.78%)with pH decline events related to symptoms, while those Ryan index were normal. There were 536(90.85%), 417(70.68%), 233(39.49%) and 117(19.83%) patients with pH<6.5, pH<6.0, pH<5.5 and pH<5.0 events respectively. The positive rate of RSI, RFS, RSI and RFS, RSI or RFS were 44.24%, 16.78%, 7.12%, 53.90% respectively. The RFS score in Ryan index positive group was higher than that in Ryan index negative group[(8.2+/-2.4) vs (4.0+/-2.9), u=5.424, P<0.05], while the RSI score in Ryan index positive group was not statistically different from that in Ryan index negative group[(11.3+/-6.2) vs (12.7+/-5.8), t=1.247, P=0.167]. Conclusions: Pharyngeal pH monitoring is an objective and non-invasive method which can reflect laryngopharyngeal reflux directly. However, with the Ryan index as a criterion for the diagnosis of laryngopharyngeal reflux disease, partial patients may be missed. Further studies are needed to obtain more accurate and objective laryngopharyngeal pH statistical index for diagnosis of laryngopharyngeal reflux disease. PMID- 29262445 TI - [Free medial thigh perforator flaps with various pedicle origins for the reconstruction of defect after buccal mucosa squamous cell carcinoma resection]. AB - Objective: To explore investigate the application of free medial thigh perforator flaps with different pedicle origins in the reconstruction of defect after radical resection of buccal mucosa squamous cell carcinoma. Methods: From January 2015 to December 2016, 32 cases with buccal mucosa squamous cell carcinoma underwent radical resection and buccal mucosa defect after surgery was reconstructed by free medial thigh perforator flap at the same stage. The patients included 32 males and 5 females, ranged in age from 36 to 71 years (45.2 years on average). According to UICC stage: T4N0M0 13 cases, T4N1M0 12 cases, T3N1M0 5 cases, T3N2M0 2 cases. The course ranged from 1 to 30 months (9.6 months on average). Results: The perforator flaps ranged from 8.0 cm*3.5 cm to 15.5 cm*6.0 cm in size, from 2.0 to 4.5 cm in thickness.The mean length of pedicles from gracilis muscle was (8.7+/-0.4) cm in 19 cases, the mean length of pedicles from adductor magnus muscle was (9.5+/-0.4) cm in 9 cases and the length of pedicles from femoral artery was (6.9+/-0.5) cm in 4 cases.All 44 perforator flaps survived uneventfully. The donor sites in the medial thigh were closed directly and healed well in all cases. Patients were followed up for 8 to 32 months with satisfied esthetic and functional results in reconstructed tongue, with no local recurrence. Only linear scars left in the donor sites, the functions of thighs were not affected. Conclusion: The free medial thigh perforator flap is an idea choice to reconstruct the defect after radical resection of buccal mucosa squamous cell carcinoma. PMID- 29262446 TI - [Diagnostic value of narrow-band imaging in detection of recurrent nasopharyngeal carcinoma]. AB - Objective: To evaluate the diagnostic value and feasibility of narrow-band imaging in detection of recurrent nasopharyngeal carcinoma (NPC). Methods: One thousand three hundred and sixty-four NPC patients who had completed NPC treatment were enrolled. All patients were followed-up with imaging, serological examination of EB virus and nasopharyngeal endoscopy(WL and NBI mode), in which (1) both white light (WL) and NBI modes were done; (2) positive endoscopic patients were given nasopharyngeal biopsy; (3) using histologic finding as criterion standard, the sensitivity, specificity, accuracy and Yonden's index of two modes were compared. Kappa index was used to evaluate the consistency between the two modes and pathological results respectively; (4) the positive rates of WL and NBI in patients with early recurrent (stage I+ II) were compared. Results: A total of 265 cases were suspected as having recurrent lesions by endoscopy in WL mode and 68 cases of them were pathologically diagnosed as having NPC; and 82 cases were suspected as having recurrent lesions by endoscopy in NBI mode and 74 cases of them were pathologically diagnosed as having NPC. The sensitivity, specificity, accuracy and Yonden's index of WL mode were 91.89%, 0, 25.09% and 0.0811, respectively, with a kappa of -0.045; the sensitivity, specificity, accuracy and Yonden's index of NBI mode were 100.00%, 95.94%, 97.05% and 0.9594, respectively. Conclusion: NBI has higher sensitivity, specificity, early diagnosis rate and Yonden's index than WL. PMID- 29262447 TI - [Application of narrow band imaging in the detection of premalignant and malignant lesions of the larynx]. AB - Objective: To evaluate the role of narrow band imaging (NBI) endoscopy in the diagnosis of laryngeal lesions. Methods: A total of 136 patients with laryngeal lesions were examined by NBI and white light (WLI) endoscopy from July 2016 to May 2017. Sensitivity, specificity, accuracy, and positive predictive value (PPV) and negative predictive value (NPV) of NBI and WLI were calculated. SPSS 20.0 software was used to analyze the data. Results: Compared to WLI, NBI showed higher sensitivity (94.9% vs 83.3%), specificity (95.6% vs 84.4%), PPV (94.9% vs 82.3%), and NPV (95.6% vs 85.4%). There was high consistency of the results etween NBI and pathology (kappa=0.904, P<0.01). However, consistency of the findings between WLI and pathology was relatively weak (kappa=0.677, P<0.01). NBI showed the higher accuracy in diagnoses of both benign lesions (especially for premalignant lesions, P<0.01) and malignant lesions (especially for high-grade intraepithelial neoplasia, P<0.05) than WLI. NBI findings correlated with the pathological results (r=0.739, P<0.01). Conclusions: NBI demonstrates higher accuracy in the detection of premalignant and malignant lesions of the larynx. PMID- 29262448 TI - [Application of functional parotidectomy via retroauricular hairline incision in the excising superficial parotid tumor]. AB - Objective: To evaluate the usefulness of retroauricular hairline incision (RAHI) in partial superficial parotidectomy (PSP) by comparison with modified Blair incision (MBI). Methods: A retrospective analysis of 64 medical records for patients with benign parotid tumors who underwent partial superficial parotidectomy was undertaken (28 were in MBI group, 36 in RAHI group). Size and location of tumors, operative time, occurrence of facial nerve paralysis and Frey's syndrome, and cosmetic outcomes were compared between RAHI and MBI groups. Results: Compared with MBI group, RAHI group showed better cosmetic results for benign parotid tumors in mean satisfaction score(P<0.001). There were no significant differences in size and location of tumors, operative time, incidence of transient or permanent facial nerve paralysis and Frey's syndrome between two groups (P>0.05). Conclusions: Partial superficial parotidectomy can be performed safely via RAHI in most cases of benign parotid tumors. Compared with MBI, RAHI for benign parotid tumorscan improve the cosmetic outcome, without increasing the operative time or operative morbidity. PMID- 29262449 TI - [Treatment analyses of 143 patients with maxillofacial and cervical venous malformations involved in isthmus faucium area]. AB - Objective: To analyze the clinical data and summarize therapeutic experiences of cervicofacial venous malformations involving isthmus faucium area. Methods: Clinical records from 143 patients with venous malformations involving isthmus faucium area treated at our hospital between January 2012 and January 2016 were reviewed. There were 70 males and 73 females. Age ranged from 1 to 52 years old, with a median age of 14.5 years. There were 19 cases with lesions involving in only 1 subanatomic area above and 124 cases with lesions involving in more than 1 subanatomic areas, including 63 cases with lesions involving in more than 2 areas. There were 50 patients presenting with additional maxillofacial and cervical lesions. Clinical symptoms included snoring (n=98), indistinct phonation (n=49), and tonsil hypertrophy more than degree II (n=19). Tracheotomy was performed in 3 patients prior to hospitalization, contigency tracheotomy during hospitalization in 10 patients, and oral trachea cannula in other patients. All therapeutic procedures, including single chemical ablation with ethanol injection (n=94), single lesion resection (n=9) and both of them (n=40), were performed under general anesthesia. Treatment remedies included mesh suture, macroglossia reduction and excision of maxillofacial and cervical lesions for patients presenting with extensive malformations extending to maxillofacial and cervical area. Tonsil resection were done in patients having tonsil venous malformations or tonsil hypertrophy more than degree II. Achauer's 4-grade criterion was applied to evaluate the treatment outcomes. SPSS 18.0 software was used to analyze the data. Results: Trachea cannula were not extubated untill 24 to 48 hours after treatment. Emergency tracheotomy was done in 2 cases after extubations because of dyspnea, and successful extubations were obtained in other cases. There were no advents of pulmonary vascular spasm or pulmonary embolism. There was significant difference between before and after operation (snore: chi(2)=105.431, ambiguous pronunciation: chi(2)=59.698, tonsil hypertrophy more than degree II: chi(2)=33.530, all P<0.01). The patients were followed-up for 1-4 years, and there were 123 cases at grade IV (complete disappear of lesions in 62 cases without recurrence), 17 at grade III , 3 at grade II, and no case at gradeI. Conclusions: Chemical ablation with ethanol injection for venous malformations involving isthmus faucium area is recommended, wheras combined remedies including injection, mesh suture, macroglossia reduction, and excision of cervicofacial lesions are suggested in treatment of extensive lesions extending to maxillofacial and cervical area. Tonsil resection should be done in patients having tonsil venous malformations or tonsil hypertrophy more than degree II, which is safe and highly effective, with good reservation of function, in the treatment of maxillofacial and cervical venous malformations involving isthmus faucium area. PMID- 29262450 TI - [Gasless endoscopic selective lateral neck dissection via an anterior chest approach for papillary thyroid carcinomas]. AB - Objective: To assess the safety and curative effect of gasless endoscopic selective lateral neck dissection (GESLND) via an anterior chest approach for papillary thyroid carcinoma (PTC). Methods: Eighteen patients with PTC(T1-2N1bM0, size<3.0 cm), having GESLND via an anterior chest approach, were included from November 2008 to December 2016. Results: GESLND via an anterior chest approach was successfully performed in all 18 PTC patients (seven male and eleven female) with 83.3% of T1 and 16.7% of T2. The mean operative time of selective lateral neck dissection was 73 min (range 51-92 min). The mean of intraoperative bleeding was 61.1 ml (range 30-120 ml). No major complications occurred except one transient hypoparathyroidism. No residual thyroid glands were detected on ultrasonography and thyroglobulin was(0.73+/-0.16)ng/ml three months postoperatively. The median of follow-up was 54.5 months (range 6-104 months). No recurrence disease was observed in any patient on ultrasonography, computer tomography, thyroglobulin or selective iodine-131 scan during the follow-up period. The cosmetic result and functional preservation was excellent, when the assessments were performed three months postoperatively. Conclusion: GESLND via an anterior chest approach is feasible and safe for selected PTCs, with superior appearance. PMID- 29262451 TI - [Experimental study on the effect of Yiqi Wenyang Decoction on nasal mucosa infiltration of NK cells in mice with allergic rhinitis]. AB - Objective: To observe the effect of Yiqi Wenyang Decoction on the infiltration and activation of NK cells in nasal mucosa of mouse model with allergic rhinitis (AR), and to explore the potential mechanism for effective intervention of AR with Yiqi Wenyang Decoction. Methods: Fourty-eight mice were randomly divided into blank group, model group, low, medium and high dose of Yiqi Wenyang Decoction group and Cetirizine group, with 8 rats in each group. After modeling of AR, the model group was filled with 0.9% sodium chloride solution. Yiqi Wenyang Decoction groups of each dose were given different concentrations of Yiqi Wenyang Decoction water extract, while the Cetirizine group was given aqueous solution of Cetirizine. The behavior, morphological changes of nasal mucosa and infiltration of NK cells in nasal mucosa were observed. The levels of IL-4 and INF-gamma in nasal lavage fluid were measured. Besides, the drug safety was observed by acute toxicity test. Results: In the respect of behavioral scoring, middle and high dose of Yiqi Wenyang Decoction group were superior to the model group (number of sneezing: q value was 7.189, 8.748, respectively; number of scratching nose: q value was 12.074, 14.560, respectively; all P<0.05). In middle and high dose of Yiqi Wenyang Decoction group, the infiltration of NK cells and nasal lavage fluid IL-4 levels were lower than those in model group (IOD: q value was 10.073, 12.322, respectively; IOD/Area: q value was 10.954, 14.073, respectively; IL-4: q value was 4.705, 6.801, respectively; all P<0.05). There was no significant difference in nasal lavage fluid of INF-gamma among each group (Fv=1.166, P>0.05). In acute toxicity test, no obvious poisoning symptoms and death occurred in mice. Conclusion: Yiqi Wenyang Decoction can control the nasal symptom, reduce the local NK cell infiltration of nasal mucosa and inhibit the expression of the 2-type cytokines released by NK cells, which may be related with the potential mechanism of effective intervention of AR with Yiqi Wenyang Decoction. PMID- 29262453 TI - [The observation of curative effect on closed reduction of nasal bone fracture under ultrasound guidance: report of 38 cases]. PMID- 29262452 TI - [Expression and correlation of Fra-1 and HMGA1 in laryngeal squamous cell carcinoma]. AB - Objective: To investigate the expressions of Fra-1 and HMGA1 in laryngeal squamous cell carcinoma and their correlation. Methods: Immunohistochemistry and reverse transcription-polymer chain reaction (RT-PCR) were used to detect the expressions of HMGA1 and Fra-1 in laryngeal squamous carcinoma tissues in 47 cases and para-carcinoma tissues in 21 cases(the First Hospital of Shijiazhuang). The relationship between the gene expressions in carcinoma tissues and clinopathological parameters such as pathological grade, clinical stage, lymph metastasis, age and anatomic site and the relevance of the two gene expressions were analyzed. SPSS 13.0 software was used to analyze the data. Results: The positive expression rates of Fra-1 and HMGA1 proteins in laryngeal squamous cancer tissue were 48.9% and 53.2%, which were respectively higher than the rates of 19.0% for Fra-1 (chi(2)=5.416, P<0.05) and of 23.8% for HMGA1 (chi(2)=5.083, P<0.05) in adjacent tissues. The expression of Fra-1 gene was correlation with pathological grade, clinical stage and lymph metastasis (t values were -1.079, 1.066 and -1.067, all P<0.05), but not with age and anatomic site (t values were 1.068 and -1.054, both P>0.05). The expression of HMGA1 gene was correlation with pathological grade, clinical stage, lymph metastasis and age (t values were 1.112, -1.065, -1.009 and -1.066, all P<0.05), but not with anatomic site (t= 1.036, P>0.05). The expressions of Fra-1 and HMGA1 gene were positively correlation (r=0.672, P<0.05). Conclusions: In laryngeal squamous cancer, Fra-1 and HMGA1 are excessive expression, with a positive correlation between the expressions of both genes. PMID- 29262454 TI - [Misdiagnosis of esophageal diverticulum caused by coins: a case report]. PMID- 29262455 TI - [Reconstruction of trachea with rotational suture after overlong tracheal resection due to papillary thyroid carcinoma involving trachea: a case report]. PMID- 29262456 TI - [Crouzon syndrome with cerebrospinal rhinorrhea: report of two cases]. PMID- 29262457 TI - [A case of hamartoma of the root tounge in a newborn]. PMID- 29262458 TI - [Diffuse hemorrhage in cervical mediastinum space hemorrhage: a case report]. PMID- 29262459 TI - [Composite hemangioendothelioma of the parotid gland: a case report]. PMID- 29262460 TI - [A case report of Kimura's disease involving the maxillofacial multiple gland]. PMID- 29262461 TI - [Advances in endoscopic treatment of congenital pyriform sinus fistula in children]. AB - Pyriform sinus fistula is a rare clinical disease, often with recurrent acute suppurative thyroiditis or neck infection in children.The traditional method treatment is complete resection of the fistula with or without hemithyroidectomy in external cervical surgical approach, but in recent years, minimally invasive endoscopic occlusion of the internal opening for the treatment of pyriform sinus fistula is performed in many hospitals, including electrocautery, chemocautery, laser cauterization, biocauterization, and suture closure. Literatures about endoscopic management of pyriform sinus fistula in children are reviewed and various surgical methods, complications and success rate are evaluated. PMID- 29262462 TI - [Progress in diagnosis and treatment of radioactive iodine-refractory differentiated thyroid carcinoma]. AB - The radioactive iodine-refractory differentiated thyroid carcinoma (RIR-DTC) is a complex process that involves multiple genetic changes and multiple signaling pathways.Radionuclide imaging, genomics and proteomics are effective to clarify the mechanism and helpful in clinical diagnosis and therapy.The treatment of RIR DTC includes the removal of distant metastases, drug therapy, external radiotherapy and radiofrequency ablation.This review mainly focuses on the pathogenesis, diagnosis and treatment of RIR-DTC. PMID- 29262463 TI - [Improve pediatrician's ability of identification, evaluation and management of children with autism spectrum disorder]. PMID- 29262464 TI - [Embrace the new era of developmental behavioral pediatrics in China]. PMID- 29262465 TI - [Think highly of the integration of developmental behavioral pediatrics and sub specialties]. PMID- 29262466 TI - [Consensus on early identification screening and early intervention for autism spectrum disorder]. PMID- 29262467 TI - [Evidence-based guideline on diagnosis and treatment of urinary tract infection(2016)]. PMID- 29262468 TI - [Interpretation of evidence-based guideline on diagnosis and treatment of urinary tract infection(2016)]. PMID- 29262469 TI - [Association between behavioral problems and gastrointestinal disorders among children with autism spectrum disorder]. AB - Objective: To investigate the relationship between gastrointestinal disorders (GID) and core symptoms or behavioral problems among the children with autism spectrum disorder (ASD) . Method: Totally 328 children with ASD and 202 normal controls were enrolled in this cross-sectional study from August 2013 to October 2016. The information about the gastrointestinal disorders, behavioral and emotional problems was collected by using questionnaires. Childhood Autism Rating Scale (CARS), Autism Behavior Checklist (ABC) were used to assess the core symptoms of the children with ASD. Neurodevelopmental status was evaluated with Gesell Developmental Scale (GDS). These variables were analyzed by using student's t-test and chi-square test. Result: The prevalence of GID was significantly higher in the children with ASD than in the normally developing children (49.4% (162/328) vs.25.7% (52/202), chi(2)=29.039, P=0.000), especially the symptoms of constipation (33.2% (109/328) vs. 13.9% (28/202)), diarrhea (9.5%(31/328) vs. 1.5% (3/202)), nausea and vomiting (9.5% (31/328) vs. 3.5% (7/202)), and foul defecation (16.5% (54/328) vs. 5.0% (10/202)) (all P<0.05). Among the ASD children, the prevalence of GID was similar between male and female (46.7% (133/285) vs. 46.5%(20/43), chi(2)=0.006, P=0.938), as well as among all age groups (chi(2)=1.907, P=0.862). There was no significant difference in scores of GDS in the ASD children with or without GID (all P>0.05). Compared with ASD children without GID (n=166), the ASD children with GID (n=162) got higher scores in the "Body and Object Use" of ABC scale ( (16.4+/-9.3) vs. (12.3+/-6.7) scores, t=2.258, P=0.028), and had more emotional problems (63.6% (103/162) vs. 49.4% (82/166), chi(2)=6.707, P=0.010). Moreover, the score of behavior problems questionnaire was higher in the ASD children with GID ( (35.3+/-16.8) vs. (16.1+/ 13.6) scores, t=5.748, P=0.000). Conclusion: Children with ASD have higher risk of GID than the normal developing children. While the stereotyped behaviors, problem behaviors and emotional problems are severer in the ASD children with GID. Hence, it is important to provide comprehensive treatment and management for these groups of children. PMID- 29262470 TI - [Sleep problems and the association with the levels of 6-sulfatoxymelatonin in children with autism spectrum disorder]. AB - Objective: To identify the prevalence of sleep problems in children with autism spectrum disorder (ASD) and to explore the association with the main melatonin metabolite, 6-sulfatoxymelatonin (6-SM). Method: This was a prospective case control study. Children with ASD were recruited from Child Development and Behavioral Research Center (CDBRC) of the Harbin Medical University and Harbin Special Education School from October 2015 to April 2017 (ASD group) . Healthy controls were selected from five kindergartens and one primary school in Harbin by the stratified cluster random sampling (control group) . The Children's Sleep Habits Questionnaire (CSHQ) was used to investigate the sleep problems of the two groups. The patients were matched in a 1?1 ratio for the age and sex, and the urine samples of case-control pairs were collected in the morning. The level of 6 SM was measured by the enzyme linked immunosorbent assay (ELISA). The student's t test was used for comparison between the ASD group and control group, and the Pearson correlation analysis was used to determine the correlation difference. Result: A total of 212 ASD children (mean (+/-SD) age was (6.0+/-2.7) years, and 181 patients (85.4%) were male), and a total of 334 healthy children(mean (+/-SD) age was (5.9+/-2.6) years, and 272 patients (81.4%) were male) were recruited. Among them, 101 matched case-control pairs completed the collection of urine samples. According to the statistical analysis, the scores of total CSHQ, bedtime resistance, sleep onset delay, sleep duration, night waking, parasomnia, sleep disordered breathing and daytime sleepiness in children with ASD were significantly higher than those in the control group (48.2+/-6.2 vs. 46.6+/-5.4, 11.4+/-2.5 vs. 10.7+/-2.8, 1.7+/-0.8 vs. 1.5+/-0.7, 4.1+/-1.4 vs. 3.7+/-1.1, 4.2+/-1.5 vs. 3.8+/-1.1, 8.5+/-1.5 vs. 8.3+/-1.4, 3.7+/-1.0 vs. 3.4+/-0.8, 11.7+/ 2.5 vs. 12.4+/-2.7, t=3.16, 3.00, 3.23, 2.76, 3.19, 1.99, 3.45,-2.72, P=0.002, 0.003, 0.001, 0.006, 0.002, 0.048, 0.001, 0.007), the level of 6-SM was significantly lower in children with ASD than that of healthy controls ((1.24+/ 0.50) vs. (1.68+/-0.63)MUg/h, t=-5.50, P<0.01), and the total CSHQ score was negatively correlated with the level of 6-SM (r=-0.50, P<0.01). Conclusion: The children with ASD were at high risk for sleep problems, and the melatonin metabolite of ASD group was abnormal compared with that of the control group. Moreover, there was a negative correlation between the severity of sleep problems and the level of 6-SM in ASD children. The results of our study indicate that the abnormal melatonin metabolism may be one of the causes of sleep problems in children with ASD. PMID- 29262471 TI - [Correlation between serum 25-hydroxyvitamin D level and core symptoms of autism spectrum disorder in children]. AB - Objective: To explore the relationship between serum 25-hydroxyvitamin D levels and core symptoms of autism spectrum disorder (ASD) in children. Method: In this cross-sectional study, ASD children 4 to 6 years of age who were diagnosed in Department of Developmental and Behavioral Pediatrics, First Hospital of Jilin university from January to May 2017 were assigned to ASD group, and children for routine growth and development assessment in Jilin province were assigned to control group. The two groups were well matched for age and sex, and none of them had received vitamin D supplementation. Serum 25-hydroxyvitamin D levels were measured by HPLC-MS/MS method. The patients of the ASD group were assessed with autism behavior checklist (ABC), childhood autism rating scale (CARS), social response scale (SRS), and autism treatment evaluation checklist (ATEC). The levels of vitamin D were divided into normal(>0.03 ng/L), insufficient (0.01-0.03 ng/L) and deficient (<0.01 ng/L). Levels of serum vitamin D between the two groups were compared by two independent sample t-test, and the difference in the percentages of normal, insufficient and deficient levels of vitamin D was tested by chi-square test, and correlations between vitamin D levels and the total scores or subscales of ABC, CARS, SRS and ATEC were analyzed by Pearson correlation analysis. Result: The 87 subjects in the ASD group included 75 males and 12 females, with a mean (+/-SD) age of (4.7+/-0.7) years. The 301 subjects in the control group included 249 males and 52 females, with a mean (+/-SD) age of (4.8+/-0.8) years. Serum vitamin D level in ASD children was significantly lower than that of the control group ( (0.021+/-0.008) vs. (0.036+/-0.016) ng/L, t= 8.17, P<0.01), and the between-group percentage difference of normal, insufficient and deficient levels of vitamin D was statistically significant (12 (14%) vs. 186 (62%) , 67 (77%) vs. 113 (37%) , 8 (9%) vs. 2 (1%) , chi(2)=72.1, P<0.01). There were negative correlations between serum vitamin D level in ASD children and total ABC score or ABC subscale scores (body behavior, self-care, language and social interaction)(r=-0.531,-0.397,-0.283,-0.248,-0.262, P=0.000, 0.000, 0.007, 0.020, 0.014). There were negative correlations between serum vitamin D level in ASD children and total CARS score and CARS subscale scores (imitation, nonverbal communication and general impression) (r=-0.352, -0.216, 0.248, -0.216, P=0.001, 0.046, 0.021, 0.046). There were negative correlations between serum vitamin D level in ASD children and SRS behavior subscale or ATEC social interaction subscale (r=-0.536, P=0.005, r=-0.400, P=0.014). Conclusion: Serum 25-hydroxyvitamin D level in children with ASD is obviously lower than that in the healthy control group, and there are negative correlations between vitamin D levels and core symptoms of ASD. Trial registration Chinese Clinical Trial Registry, ChiCTR-CCC-13004498. PMID- 29262472 TI - [Structural change of the corpus callosum fibers in toddlers with autism spectrum disorder: two-year follow-up]. AB - Objective: To conduct a follow-up investigation of structural changes of the corpus callosum fibers of toddlers (2 to 5 years of age) with autism spectrum disorder(ASD) and to explore the associations with clinical symptoms. Method: In this prospective randomized controlled study, ASD children who were diagnosed in the Child Mental Health Research Center, Nanjing Brain Hospital Affiliated to Nanjing Medical University from May 2011 to November 2012 were included in the ASD group, and developmentally delayed children were included in the control group (DD group). Diffusion tensor imaging (DTI) data from the two groups were obtained at two age levels: 2-3 years of age, and 4-5 years of age. Region of interest analysis was applied to assess characteristic values of total area and sub-regions of corpus callosum: the fraction anisotropy (FA), the mean diffusivity (MD), the radial diffusivity (RD) and the axial diffusivity (AD). All children were assessed using the Autism Diagnostic Interview-Revised (ADI-R) and Autism Treatment Evaluation Checklist (ATEC). The characteristic values of total area and sub-regions of corpus callosum of ASD group at two age levels were analyzed by paired sample t test; the characteristic values of total area and sub regions of corpus callosum of ASD group and DD group were analyzed by independent sample t test; the correlations between FA values of the total area and sub regions of corpus callosum and ADI-R or ATEC scores were analyzed by Pearson correlation analysis. Result: Forty cases meeting inclusion criteria were enrolled in ASD group, and 31 eligible cases were enrolled in the control group. Four children in the ASD group were lost to follow-up, and 5 children in the control group were lost to follow-up. Longitudinal comparison between the two age subgroups of ASD patients showed that the FA values of the total corpus callosum increased (0.499 55+/-0.027 59 vs. 0.505 83+/-0.086 64, t=4.88, P<0.05), but MD values, RD values and AD values of the total corpus callosum area decreased (0.000 89+/-0.000 03 vs. 0.000 81+/-0.000 14, 0.000 61+/-0.000 04 vs. 0.000 55+/ 0.000 09, 0.001 43+/-0.000 03 vs. 0.001 38+/-0.000 03, t=9.31, 7.90, 8.66, P<0.05 for all comparisons). In the area of corpus callosum genu, FA and AD values increased (t=5.59, 8.48, P<0.05 for both comparisons), but MD and RD values decreased (t=12.67, 11.28, P<0.05 for both comparisns). In the area of corpus callosum body, FA and RD values increased(t=5.46, 8.48, P<0.05 for both comparisons), but MD and AD values decreased (t=8.08, 6.22, P<0.05 for both comparisons). In the area of corpus callosum splenium, MD, RD and AD values decreased (t=6.81, 4.44, 5.51, P < 0.05 for all comparisons). Among the participants 2 to 3 years of age, there were no significantly differences in FA values of total area and sub-regions of corpus callosum between ASD group and the DD group (P > 0.05 for all comparisons); as compared with the DD group, ASD group had higher AD values of total area and splenium of corpus callosum (0.001 43+/ 0.000 03 vs. 0.001 40+/-0.000 04, 0.001 34+/-0.000 03 vs. 0.001 32+/-0.000 04, t=1.56, 1.14, P < 0.05 for both comparisons); ASD group had lower AD values but higher RD and MD values of corpus callosum genu (t=0.07, 0.55, 0.07, P < 0.05 for all comparisons); ASD group had lower RD values of corpus callosum body (t=0.07, P < 0.05). Among the participants 4 to 5 years of age, as compared with the DD group, ASD group had higher FA value of total corpus callosum area(0.505 83+/ 0.086 64 vs. 0.483 77+/-0.099 30, t=8.56, P < 0.05), lower RD value of total corpus callosum(0.000 55+/-0.000 09 vs. 0.000 56+/-0.000 12, t=14.44, P < 0.05), lower RD values of corpus callosum body (t=2.20, P < 0.05), higher FA values (t=3.35, P < 0.05) but lower AD values of corpus callosum splenium (t=2.20, P < 0.05). A correlation analysis between FA values of total area and sub-regions of corpus callosum and clinical variables showed that the FA values of total area and splenium of corpus callosum in ASD group at 2 to 3 years of age were negatively correlated with the scores of language skills in ATEC (r=-0.35,-0.36, P < 0.05 for both comparisons). And after two years, FA values of total corpus callosum were positively correlated with the scores of social communication in ATEC (r=0.34, P < 0.05). There was no significant correlation between FA values of sub-regions of corpus callosum and the scores of ATEC (P > 0.05 for all comparisons). There was no significant correlation between FA values of total area and sub-regions of corpus callosum and the scores of ADI-R (P > 0.05 for all comparisons). Conclusion: The fiber structure of corpus callosum was still in the process of maturing during the age of 2 to 5 years; however, compared with DD group, ASD group had more extensive structural abnormalities of the corpus callosum fibers as age increased, and the structural abnormalities had correlation with the core symptoms of ASD. Trial registration Chinese Clinical Trial Registry, ChiCTR-OPC-17011995. PMID- 29262473 TI - [Clinical challenges in the management of catecholaminergic polymorphic ventricular tachycardia in children]. AB - Objective: Catecholaminergic polymorphic ventricular tachycardia (CPVT) accounts for up to 10%-15% sudden cardiac death (SCD) in the children and young population. This study aimed to assess the current situation and challenges in CPVT clinical diagnosis. Method: A retrospective review included 11 children (7 male patients) at the First Hospital of Tsinghua University clinically diagnosed with CPVT from June 2014 to July 2017. Each patient was evaluated with detailed history, physical examination, resting 12-lead electrocardiogram(ECG), 24-h Holter, exercise stress test, Doppler echocardiography and genetic test. Result: During physical activity and/or emotional stress, ten children presented with recurrent syncope and one child presented with palpitation and chest distress. The mean age of symptom onset was 8.4 (4.0-13.7) years with a delayed diagnosis of 2.4 (0.04-5.00) years. Two children had a familial history of syncope or sudden death. Nine children were initially misdiagnosed as complex arrhythmic conditions (n=4), syncope of unknown origin (n=3), and drug-resistant epilepsy (n=2) treated with antiepileptic medication for several years. Bidirectional VT and (or) polymorphic VT were detected using Holter recording or exercise test ECG in all patients. Genetic test revealed CPVT-associated pathologic or possible pathologic mutations in nine patients. All patients were treated with beta blockers. Six patients were asymptomatic, four patients reported infrequent syncope, and one sudden death occurred during a mean follow-up of 0.97 years. Conclusion: CPVT mainly occurs in children and adolescents with recurrent syncope during physical activities and/or emotional stress. Early diagnosis of CPVT remains challenging due to delayed diagnosis or misdiagnosis. Detailed clinical history and exercise stress test improve the early diagnosis and intervention for CPVT patients. PMID- 29262474 TI - [Clinical application of electrical velocimetry in monitoring pediatric blood volume after cardiopulmonary bypass]. AB - Objective: To investigate the clinical applicability of electrical velocimetry (EV) in monitoring pediatric blood volume after cardiopulmonary bypass. Method: Between July 2016 and November 2016, 60 children with congenital heart disease were divided into EV group and traditional central venous pressure (CVP) group randomly. For EV group, the volume of fluid and vascular active medicine was adjusted according to the monitoring stroke volume variation (SVV) hemodynamic parameters. Whereas for CVP group empirical volume of fluid infusion was managed by the monitoring traditional hemodynamic parameters such as CVP, blood pressure, heart rate, urine volume and blood gas analysis.Heart rate (HR), mean artery pressure (MAP), blood lactic acid (LA), oxygenation index (PaO(2)/FiO(2)) at 2, 4 and 6 h after operation were observed and compared between two groups. Mechanical ventilation time and ICU monitoring time were also compared between two groups. Pearson correlation analysis was performed to investigate the significance of SVV and inferior vena cava expansion index (dIVC) for evaluating of reactivity capacity after surgery. Result: MAP level was significantly higher in EV group at 2, 4, and 6 h after operation [ (62+/-10) vs. (50+/-6) mmHg(1 mmHg=0.133 kPa), (68+/-11) vs.(59+/-4) mmHg, (71+/-6) vs. (63+/-8) mmHg respectively; t=5.580 9, 4.530 1, 4.308 1; P=0.001, 0.002, 0.001]. PaO(2)/FiO(2) ratio was higher in EV group than that of CVP group[ (362+/-23) vs. (310+/-43), (380+/-33) vs. (330+/ 38), (386+/-57) vs. (350+/-63.1) respectively, t=5.818 8, 5.419 2, 2.317 2; P=0.002, 0.001, 0.024]. However HR and blood lactic acid level was lower in EV group than the CVP group [(166+/-10) vs. (179+/-14)/min, (156+/-11) vs. (168+/ 16)/min, (138+/-10) vs. (149+/-13)/min respectively; t=3.930 7, 3.511 1, 3.671 5; P=0.002, 0.009, 0.005]; [7% vs. 33%, 3% vs. 20%, 0 vs. 13%, chi(2)=5.104 2,4.043 1,4.285 7, P=0.045 3, 0.044 4, 0.038 4] respectively; Mechanical ventilation time [ (4.3+/-0.7) vs. (8.2+/-0.8) h, P=0.008] and ICU monitoring time [ (16.4+/-3.2) vs. (21.2+/-2.6) h,P=0.003] was shorter in EV group than that in group CVP. Pearson correlation analysis suggested that the SVV and dIVC have significant positive correlation. Conclusion: SVV monitoring using EV could help to guide perioperative fluid management for children with congenital heart disease. Real time dynamic monitoring SVV improves liquid infusion management more timely, accurately, and avoids excessive or insufficient blood volume load which is associated with leading to organ dysfunction. PMID- 29262475 TI - [Clinical analysis of intestinal lymphangiectasia in 47 children]. AB - Objective: To analyze the clinical manifestations, diagnosis, treatment and prognosis of intestinal lymphangiectasia (IL) in children in order to improve the skills of diagnosis and treatment of IL. Method: Clinical manifestations, laboratory findings, gastroscopic findings, histopathological examinations and lymphatic radionuclide imaging assessments were analyzed retrospectively among 47 IL patients who were hospitalized in the Gastroenterology Department of Beijing Children's Hospital Affiliated to Capital Medical University from June 2007 to December 2015. All patients were followed up by telephone. According to the various causes, the patients were divided into the primary intestinal lymphangiectasia (PIL) group and secondary IL group, and their clinical manifestations were compared by t test, Rank sum test or Chi-square test. Result: In 47 IL patients, there were 38 children (81%) younger than 3 years old. There were 43 PIL patients (91%) and 4 secondary IL patients (9%). Between PIL and secondary IL, there were statistical differences in serum albumin (t=-3.950, P<0.005) , globulin(t=-2.850, P=0.007), age of onset(U=27.000, P=0.024), age at diagnosis(U=29.000, P=0.030) and course of disease(U=26.500, P=0.023), whereas there were no statistical differences in lymphocyte count, IgG, lymphatic radionuclide imaging, histopathology and gender(all P>0.05). Edema (44 cases, 94%), diarrhea (42 cases, 89%), accompanied with infection (35 cases, 74%) and ascites (30 cases, 64%) were the main clinical manifestations. In 47 IL patients, 45 patients were done gastroscopy and histopathological examinations, and there were 31 patients' histopathological examinations(69%) were positive. Forty patients were done lymphatic radionuclide imaging, and there was evidence of protein losing from gut via lymphatic radionuclide imaging in 39 patients(98%). Among 47 patients, 35 patients (74%) were followed up, 32 patients had good prognosis, 2 patient failed to show evidence of improvement, 1 patient died and no patient experienced a relapse till the end of the follow-up. In 35 patients, 28 patients were treated with medium chain triglycerides (MCT) dietary therapy, 26 patients showed improvement in symptoms, and 2 patients had no improvement. Among 35 patients with follow-up, there were 6 patients received surgical treatment, and their symptoms were improved. Conclusion: PIL are the majority of IL in children younger than 3 years old. The main clinical manifestations are edema, diarrhea, accompanied with infection and ascites. For the patients without the evidence of lymphangiectasia from duodenum histopathological examination, further consideration of lymphatic radionuclide imaging, clinical manifestations, and laboratory studies are needed to make a final diagnosis. MCT dietary therapy is the cornerstone of IL medical management. PMID- 29262476 TI - [Short stature, optic nerve atrophy and Pelger-Huet anomaly syndrome with antibody immunodeficiency and aplastic anemia: a case report and literature review]. AB - Objective: To investigate the clinical features and genetic characteristics of cases with NBAS gene defects. Method: Characteristics of clinical materials, immunological data and gene mutation of the first case in China with NBAS gene mutation were retrospectively analyzed. The related literature was searched by using search terms'NBAS'. Result: A 2-year-four-month old girl, was admitted due to 'fever and pallor for one day'. There was an intrauterine growth retardation at her fetal stage. Since her birth, she had suffered from recurrent infections and development delay was accompanied by persistent liver dysfunction. Her head circumference and height were 43.5 cm and 60 cm, respectively. She seemed pale. She had progeroid appearance with loose skin, sparse hair, proptosis and low-set ears. The cranial suture did no close and the anterior fontanel was about 6 cm*5 cm. Abdominal palpation showed that the liver was 2 cm below the right costal margin, and the spleen was 1.5 cm below the left rib. Both alanine aminotransferase(100-1 991 IU/L) and aspartate aminotransferase (191-1 367 IU/L) were persistently abnormal. Visual evoked potentials and fundus examination revealed optic nerve atrophy. Bone mineral density assessment showed osteoporosis. The IgG level was 2.0 g/L (3.41-19.6) and absolute count of CD19(+)B cells was 231.27/MUl (608.8-2 167.7) . Her hemoglobin level was 53 g/L. Bone marrow smear showed serious hypoplasia in erythroid cell. The gene sequencing results showed NBAS gene c.5741C> T, pR1914H and c.6496-6497insA, p.S2166Ffs* 2 compound heterozygous mutations. A total of 8 literatures were collected including 57 cases with NBAS gene homozygous or compound heterozygous mutation. These 57 cases were characterized by short stature(88%, 50/57) , Pelger Huet anomaly (75%, 43/57) , skeletal dysplasia (74%, 42/57), optic nerve atrophy (72%, 41/57), abnormality of liver enzymes or acute liver failure (42%,24/57), abnormalities of immune system(19%, 11/57), development delay of mental, language or sports(11%, 6/57). Other clinical manifestations such as progeroid appearance, proptosis and hypotonia were also common. NBAS gene c.5741G>A homozygous mutation accounted for 61% (35/57) cases. Conclusion: Cases with NBAS gene defects often manifests as short stature, optic nerve atrophy, Pelger-Huet anomaly, skeletal dysplasia, recurrent infections, abnormality of liver enzymes, progeroid appearance, proptosis, hypotonia and immunodeficiency. Gene sequencing analysis showed NBAS gene homozygous or compound heterozygous mutations, and homozygous mutation of c.5741G>A was most common. PMID- 29262477 TI - [Clinical analysis of four cases of anti GQ1b syndrome]. AB - Objective: To investigate the clinical manifestations, laboratory findings, treatment and outcome of anti-GQ1b antibody syndrome. Method: The clinical manifestations, laboratory examination, diagnosis, treatment and prognosis of (4 patients 4 male patients, from 4 to 12 years) with anti-GQ1b syndrome in Beijing Children's Hospital affiliated to Capital Medical University from 2015 to 2016 were retrospectively analyzed. Result: All 4 children presented with ataxia. Case 1 showed impaired speech, ptosis and weakness of arms; case 2 and 3 had external ophthalmoplegia, weakness of limbs; case 4 presented hypersomnia, irritability and hallucinations. Serum anti-GQ1b-IgG antibody was positive in all cases. Case 1-3 received lumber puncture at the course of 1-2 weeks, CSF presented albuminocytological dissociation, case 4 had CSF pleocytosis and increased protein level. Brain MRI of Case 1-2 were normal; Case 3 showed long T1 and T2 signal in cerebellar dentate nucleus, pons and corpus callosum; Case 4 showed long T1 and T2 signal in bilateral centrum semiovale, basal ganglia, external capsule, insula and cerebellum. Electromyograms of case 1-3 showed peripheral axonal lesion. All children were treated with IVIG. After treatment, condition of all patients were improved. According to the clinical manifestation, laboratory examination, and outcome after treatment, case 1 was diagnosed as anti-GQ1b antibody syndrome (Pharyngeal-Cervical-Brachial weakness overlapped with Miller Fisher syndrome), case 2 and 3 were diagnosed as anti-GQ1b antibody syndrome (Miller Fisher syndrome overlapped with Guillain Barre syndrome) and case 4 was diagnosed as anti-GQ1b antibody syndrome (acute ataxia hypersomnolence). Conclusion: When patients with the presence of prodromic infections, monophasic course, drowsiness, ataxia, ophthalmoplegia, weakness and the symptoms/signs are relatively symmetric, anti-GQ1b antibody syndrome should be considered. Anti-GQ1b antibody has important significance for diagnosis. Most children have a good prognosis. Early correct diagnosis can avoid unnecessary examinations and guide appropriate use of immunotherapy. PMID- 29262478 TI - [Clinical characteristics of thyroid hormone resistance syndrome in two cases with different subtypes]. AB - Objective: To analyze the clinical characteristics of children with two types of thyroid hormone resistance (RTH) syndrome, and to detect the variants of thyroid hormone receptor alpha(TRalpha) and TRbeta gene in children. Method: Two children with RTH were reported in regard to clinical manifestation, laboratory examination and genetic variants. Some related reports in literature were reviewed. Result: Case 1 was a girl, 10 years old, with thyroid enlargement for several days and without thyrotoxicosis. Laboratory work-up revealed that free thyroxine (FT(4)) was 65.77 pmol/L (reference 12-22) , free triiodothyronine (FT(3)) was 15.36 pmol/L (reference 3.1-6.8) and thyroid stimulating hormone (TSH) level was normal. There was a likely pathogenic missense variant detected in TRbeta gene and this patient was diagnosed with RTHbeta. Case 2 was a boy, 3 years old, with classic features of hypothyroidism(growth retardation, developmental retardation, skeletal dysplasia) but had only borderline-abnormal thyroid hormone levels. Targeted sequencing showed a de novo heterozygous nonsense variant in TRalpha gene which is a pathogenic variant and this patient been diagnosed with RTHalpha. Conclusion: Thyroid enlargement is a common clinical manifestation of RTHbeta, with laboratory work-up reveals elevated FT(4) and FT(3) levels but TSH level is normal. The clinical manifestations of RTHalpha are similar to those of hypothyroidism, but the thyroid hormone levels are almost normal. The gene sequence and the pathogenicity analysis for TRalpha and TRbeta will help to make a definitive diagnosis. PMID- 29262479 TI - [A case of infantile enterogenous sepsis caused methemoglobinemia]. PMID- 29262480 TI - [A case of disorders of 46,XY sex development cause of two novel mutations in the LHCGR gene]. PMID- 29262481 TI - [Exclusive enteral nutrition in the treatment of pediatric Crohn's disease]. PMID- 29262482 TI - [New progress in diagnosis and treatment of activated PI3Kdelta syndrome]. PMID- 29262483 TI - [Strengthen the construction of information systems to ensure the safety and effectiveness of air pollution and the health impact monitoring network]. PMID- 29262484 TI - [Epidemiological characteristics and relevant factors on the comorbidity of hyperactivity behavior and allergic diseases in preschool children]. AB - Objective: To understand the epidemiological characteristics and relevant factors on the comorbidity of hyperactivity behavior and allergic disease among preschool children in urban areas of Ma'anshan city. Methods: During April 2014 to April 2015, 91 kindergartens over 3 years old were investigated. In the investigation, 16 439 questionnaires were distributed to parents, and 15 291 valid questionnaires were collected. Conners abbreviated symptom questionnaire (brief symptom questionnaire) was filled out by parents to assess the children's hyperactive behaviors. Information of allergic disease history was reported by parents, including allergic dermatitis/eczema, food/drug allergy, allergic rhinitis and asthma. Multivariate unconditional logistic regression was used to analyze the relevant factors of comorbidity of hyperactivity behavior and allergy diseases. Results: The average age of the 15 291 children were (4.5+/-1.0) years old, among which 53.7% (8 218/15 291) were boys. The prevalence of hyperactive behaviors was 8.6%(1 317/15 291), and the comorbidity rate of hyperactivity and allergic deseases was 1.7% (258/15 291). After confounding factors including gender, age, delivery mode, father's age and pregnancy complications adjusted, poor sleep quality (OR=4.45, 95%CI: 2.85-6.94), long duration of watching TV at weekend (OR=1.39, 95%CI: 1.00-1.94) and poor eating behavior (OR=1.78, 95%CI: 1.07-2.98) were relevant factors of the comorbidity of hyperactivity and allergic diseases. Conclusion: The prevalence of comorbidity of hyperactivity behavior and allergic disease among preschool children in urban areas of Ma'anshan city was not high. Poor night sleep quality, long duration of watching TV and frequently picky eating were relevant factors of the comorbidity of hyperactive behaviors and allergic diseases. PMID- 29262485 TI - [Association between hair cortisol concentration and overweight and obesity in 6 9 years old childhood]. AB - Objective: To determine the possible relations between hair cortisol concentration (HCC) as a biomarker of chronic stress and childhood overweight and obesity. Methods: Children from grade 1 to 3 from 2 primary schools in Bengbu were invited to participate in the study; and those who suffer from mental disorders, endocrine diseases and those who took hormone drugs were excluded. Parental questionnaire was implemented to collect information on physical activity, screen time, sleep duration, sugar-beverage consumption, as well as socio-economic status. Height and weight were examined. Eligible hair samples from 1 263 children (598 boys and 665 girls) were obtained, and the cortisol content was determined. Multivariate logistic regression model analysis was recruited to examine the association between HCC quartiles and overweight and obesity among boys and girls, respectively. Results: HCC in P(50) (P(25)-P(75)) among girls and boys was separately 11.86 (10.57-13.15) and 11.71 (10.54-13.09) ug/kg (Z=-0.886, P=0.376); HCC in P(50) (P(25)-P(75)) among non-overweight, overweight and obesity boys was separately 11.62 (10.45-12.82), 12.24 (10.88 13.55) and 12.30 (10.99-13.53) ug/kg (chi(2)=8.24, P=0.016); HCC in P(50) (P(25) P(75)) among non-overweight, overweight and obesity girls was separately 11.35 (10.06-12.62), 12.07 (11.04-13.21) and 12.59 (11.12-13.63) ug/kg (chi(2)=36.16, P<0.001). After age, physical activity, screen time, sleep duration, sugared beverages and socio-economic status adjusted, compared with HCC in Q1 level, girls whose HCC in Q2, Q3 Q4 level had higher rates in overweight, with OR (95%CI) at 1.10 (1.04-3.32), 2.59 (1.51-4.45) and 3.16 (1.79-5.57), respectively. Girls with HCC in Q3 and Q4 level had higher rates in obesity, with OR (95%CI) at 2.22 (1.16-4.26) and 5.62 (3.04-10.41). Among boys, highest quartiles in HCC was risk factor for overweight, OR (95%CI) was 2.14 (1.18-3.90). Conclusion: Hair cortisol had a significant relation with overweight and obesity in 6-9 years old childhood especially among girls. PMID- 29262486 TI - [Association between elective cesarean section and infants' developmental behaviors: a cohort study]. AB - Objective: To investigate the effect of elective cesarean section (ECS) on infants' developmental behaviors. Methods: A total of 3 474 pregnant women living in Ma'anshan more than 6 months and accepting obstetric examination in Ma'anshan Maternal and Child Care Center were recruited from May 2013 to September 2014. Excluding participants with pregnancy termination (162), twin pregnancy (39), assisted delivery (14), emergency cesarean section (76) and unclear delivery mode (141), 3 042 pair of mother and infant entered the final analysis. Information of maternal basic demographic characteristics, pregnancy histories, pregnancy life style and pregnancy-related diseases were collected by using self-complied Maternal and Child Health Questionnaire. Information of infants' general condition and delivery modes were acquired from obstetric record. The Ages and Stages Questionnaires-third edition was used to assess infants' communication, gross motor, fine motor, problem solving and person-social function, which was completed at age of 6 months old and 18 months old, respectively. And multi factor non-conditional logistic regression model was used to analyze the association between ECS and infants' developmental behaviors. Results: The prevalence of ECS was 47.5% (1 443/3 042), among which ECS without medical indication and ECS with medical indication were 27.2% (826/3 042) and 20.3% (617/3 042), respectively. After maternal demographic characteristics, pregnant exposure and infants' basic information adjusted, compared to women with vaginal delivery, both ECS with medical indication and without medical indication increased the risk of a delay in gross motor on infants at 6 months old (RR (95%CI: 1.72 (1.08-2.77) and 1.87 (1.11-3.15), respectively.) ECS without indication decreased the risk of a delay in fine motor on infants at 6 months old (RR (95%CI):0.48 (0.28-0.82)), both ECS without medical indication and with medical indication had no statistically significant effect on 18 months infants' communication, gross motor, fine motor, problem solving and person-social function, the RR (95%CI) for ECS without medical indication were 0.86 (0.43 1.74), 1.55 (0.86-2.78), 0.74 (0.49-1.15), 1.10 (0.68-1.78) and 1.17 (0.66-2.08), respectively; and the RR (95%CI) for ECS with medical indication were 0.33 (0.12 1.02), 1.10 (0.55-2.21), 0.79 (0.48-1.29), 0.58 (0.29-1.13) and 1.48 (0.78-2.81), respectively. Conclusion: ECS affected motor development in infants at the age of 6 months old, and no influence was found in infants at the age of 18 months old. PMID- 29262487 TI - [The effect of pre-pregnancy weight and the increase of gestational weight on fetal growth restriction: a cohort study]. AB - Objective: To investigate the effect of pre-pregnancy weight and the increase of gestational weight on fetal growth restriction. Methods: From May 2013 to September 2014, a total of 3 474 pregnant women who took their first antenatal care and willing to undergo their prenatal care and delivery in Ma 'anshan Maternity and Child Care Centers were recruited in the cohort study. Excluding subjects without weight data before delivery (n=54), pregnancy termination (n=162), twins live births (n=39), without fetal birth weight data (n=7), 3 212 maternal-singleton pairs were enrolled for the final data analysis. Demographic information of pregnant woman, pregnancy history, disease history, height and weight were collected. In the 24(th)-28(th), 32(nd)-36(th) gestational week and childbirth, three follow-up visits were undertaken to collect data of pregnancy weight, pregnancy vomiting, gestational hypertension, gestational diabetes mellitus, newborn gender and birth weight. chi(2) test was used to compare the detection rate of fetal growth restriction in different groups. Multivariate unconditional logistic regression model and spreadsheet were used to analyze the independent and interaction effect of pre-pregnancy weight and the increase of gestational weight on fetal growth restriction. Results: The incidence of fetal growth restriction was 9.7%(311/3 212). The incidence of fetal growth restriction in pre-pregnancy underweight group was 14.9% (90/603), higher than that in normal pre-pregnancy weight group (8.7% (194/2 226)) (chi(2)=24.37, P<0.001). The incidence of fetal growth restriction in inadequate increase of gestational weight group was 17.9% (50/279), higher than the appropriate increase of weight group (11.8% (110/932)) (chi(2)=36.89, P<0.001). Multivariate unconditional logistic regression analysis showed that compared with normal pre-pregnancy weight group, pre-pregnancy underweightwas a risk factor for fetal growth restriction, with RR (95%CI) at 1.76 (1.34-2.32); Compared with the appropriate increase of gestational weight group, inadequate weight increase during pregnancy was a risk factor for fetal growth restriction, with the RR (95%CI) at 1.70 (1.17 2.48). No additive model interaction [relative excess risk of interaction, attributable proportions of interaction, the synergy index and their 95%CI were 0.75 (-2.14-3.63), 0.21 (-0.43-0.86) and 1.43 (0.45-4.53), respectively] or multiplication model interaction (RR (95%CI): 1.00 (0.44-2.29)) existed between pre-pregnancy underweight and inadequate increase of gestational weight on fetal growth restriction. Conclusion: Pre-pregnancy underweight and inadequate increase of gestational weight would increase the risk of fetal growth restriction without interaction. PMID- 29262488 TI - [Estimation of the impact of risk factors control on non-communicable diseases mortality, life expectancy and the labor force lost in China in 2030]. AB - Objective: To estimate the impact of risk factors control on non-communicable diseases (NCDs) mortality, life expectancy and the numbers of labor force lost in China in 2030. Methods: We used the results of China from Global Burden of Disease Study 2013, according to the correlation between death of NCDs and exposure of risk factors and the comparative risk assessment theory, to calculate population attributable fraction (PAF) and disaggregate deaths of NCDs into parts attributable and un-attributable. We used proportional change model to project risk factors exposure and un-attributable deaths of NCDs in 2030, then to get deaths of NCDs in 2030. Simulated scenarios according to the goals of global main NCDs risk factors control proposed by WHO were constructed to calculate the impact of risk factors control on NCDs death, life expectancy and the numbers of labor force lost. Results: If the risk factors exposure changed according to the trend of 1990 to 2013, compared to the numbers (8.499 million) and mortality rate (613.5/100 000) of NCDs in 2013, the death number (12.161 million) and mortality rate (859.2/100 000) would increase by 43.1% and 40.0% respectively in 2030, among which, ischemic stroke (increasing by 103.3% for death number and 98.8% for mortality rate) and ischemic heart disease (increasing by 85.0% for death number and 81.0% for mortality rate) would increase most quickly. If the risk factors get the goals in 2030, the NCDs deaths would reduce 2 631 thousands. If only one risk factor gets the goal, blood pressure (1 484 thousands NCDs deaths reduction), smoking (717 thousands reduction) and BMI (274 thousands reduction) would be the most important factors affecting NCDs death. Blood pressure control would have greater impact on ischemic heart disease (662 thousands reduction) and hemorrhagic stroke (449 thousands reduction). Smoking control would have the greatest effect on lung cancer (251 thousands reduction) and chronic obstructive pulmonary disease (201 thousands reduction). BMI control would have the greatest impact on ischemic heart disease (86 thousands reduction) and hypertensive heart disease (45 thousands reduction). If the risk factors exposure changed according to the trend of 1990 to 2013, in 2030, the life expectancy of Chinese population would reach to 79.0 years old, compared to 2013, increasing by 3.3 years old, the labor force at the age of 15-64 years old would loss 1.932 million. If the risk factors get the goals in 2030, life expectancy would increase to 81.7 years old and the number of labor force lost would decrease to 1.467 million. Blood pressure, smoking and BMI control would have much greater impact on life expectancy (4.9, 4.0 and 3.8 years old respectively) and labor force lost (630 thousands, 496 thousands and 440 thousands respectively). Conclusion: Risk factors control would play an important role in reducing NCD death, improving life expectancy of residents and reducing loss of labor force. Among them, the control of blood pressure raising, smoking and BMI raising would have a greater contribution to the improvement of population health status. PMID- 29262489 TI - [Rate of prevalence, awareness, treatment and control of hypertension among women at reproductive age in China in 2013]. AB - Objective: To analyze the rate of prevalence, awareness, treatment and control of hypertension among women at reproductive age (18-49 years old) in China in 2013. Methods: The analysis used data obtained from the China Chronic and non communicable disease surveillance in 2013.The surveillance included 176 534 adults aging >=18 years old, who were selected from 302 surveillance points by multi-stage cluster random sampling method. A total of 46 674 women at reproductive age (18-49 years old) were investigated. Blood pressures were measured by electronic blood pressure monitor. After being weighted according to complex sampling scheme and post-stratification, the rate of prevalence, awareness, treatment and control of hypertension were compared by different characteristics such as age, education, urban and rural areas, and geographic locations. Results: The prevalence of hypertension among women at reproductive age (18-49 years old) in China in 2013 was 13.5%. The rate in the rural areas was higher than that in urban areas (chi(2)=46.23, P<0.05), which were 14.5% and 12.3%, respectively. The prevalence in eastern, central and western geographic locations were separately 13.9%, 13.2% and 13.1%, there was no statistical difference (chi(2)=0.56, P>0.05). The hypertension prevalence in all age groups (18-24, 25-29, 30-34, 35-39, 40-44, 45-49 years old) were 6.6%, 9.2%, 9.6%, 12.0%, 17.9% and 28.3%, respectively. The prevalence of hypertension showed a rising trend with age increasing (t=12.32, P<0.05). The awareness, treatment and control rates of hypertension were separately 25.8%, 22.7% and 7.4% in women at reproductive age (18-49 years old), which were 31.6%, 28.2% and 9.4%, respectively in urban areas; and 21.3%, 18.5% and 5.9%, respectively in rural areas. The rates in urban areas were all higher than those in rural areas (chi square were separately 18.98, 21.31, and 6.80, P values <0.05). The treatment rate of hypertension was 86.8% among who had been aware of hypertension, and the treatment rate of hypertension was 31.8% among who received control of hypertension. The treatment rate among who had been aware of hypertension in eastern, central and western locations were 89.3%, 88.3% and 79.5%, respectively. The control rates in eastern, central and western locations were 8.5%, 8.1% and 4.7%, respectively. The treatment rate among who had been aware of hypertension and control rate in the eastern and central geographic locations was higher than that in western locations (chi square were separately 10.05 and 7.25, P values <0.05). Conclusion: The prevalence of hypertension in women at reproductive age (18-49 years old) was comparatively high, and the rates of awareness, treatment and control were low. The differences showed statistical significance between urban and rural areas. PMID- 29262490 TI - [Epidemiological analysis of viral hepatitis A in China, 2004-2015]. AB - Objective: To analyze the epidemiological characteristics of hepatitis A cases in China from 2004 to 2015. Methods: Data of hepatitis A were reported through national notifiable disease information reporting system, which covered the 31 provinces (Hong Kong, Macau and Taiwan excluded). The inclusion criteria was: date of illness onset was between January 1(st) 2004 and December 31(st) 2015, the status of reported card was confirmed, the case was classified as laboratory confirmed or clinical diagnosed, the disease was Hepatitis A. The information such as sex, date of birth, date of illness onset, place of residence was collected. The data was divided into three phases, 2004-2007, 2008-2011, 2012 2015, which represented the phase before expanded program on immunization (EPI), first 4 years after EPI, second 4 years after EPI. Results: From 2004 to 2015, there were totally 574 697 hepatitis A cases in China, the mean annual incidence was 3.62/100 000. The risk ratio of hepatitis A in 2015 was 0.23 when compared with 2004. Sichuan, Xinjiang and Yunnan contributed to 27.27% of the total cases in China. In 2012-2015, the incidence of western (3.46/100 000) region was significantly higher than that in central (1.21/100 000) and eastern (1.08/100 000) regions. From 2004-2015, number of cases in each age group declined greatly, with number of cases declining from 43 711 to 5 938 in the age group of 5-9 years, from 29 722 to 3 438 in 10-14, from 23 212 to 3 646 in 15-19. The number of cases declined from 24 079 to 10 304 in the age group of 0-4 (declined by 57.21%), but in 2012-2015, the incidence of 0-4 age group was still the highest, with 77.72% cases in Xinjiang and Sichuan. Famers, students and scattered children accounted for 69.95% of total cases, with student cases declined from 24.08% (2004-2007) to 8.67% (2012-2015). Conclusion: The incidence of hepatitis A in China is decreasing year by year, the risk has been decreasing to a relatively low level. However, in western regions and children under age five, the risk is still high. Precision intervention is needed for further prevention and control of hepatitis A. PMID- 29262491 TI - [Estimating the burden of influenza-associated hospitalization for cases of severe acute respiratory infection, Beijing, 2015]. AB - Objective: To estimate the influenza infection rate among severe acute respiratory infection(SARI) cases and the hospitalization rates of SARI attributable to influenza, based on two sentinel hospital surveillance databases in Beijing, 2015. Methods: Surveillance was conducted at two sentinel hospitals in Beijing in 2015. A total of 1 842 patients who admitted to the sentinel hospitals and met the definition of SARI were enrolled in the study. The respiratory tract specimens of SARI cases were collected, and sent to laboratories within 48 hours for influenza RNA detection. The catchment area of sentinel hospitals was defined by reviewing the home address of inpatients; A total of 1 491 patients were sampled and tested for influenza. The population size of catchment areas was obtained from demographic year book. We investigated the number of pneumonia patients admitted to the sentinel hospitals and other hospitals in catchment areas in 2015, and calculated the proportions of pneumonia patients that were admitted to sentinel hospitals in catchment areas. The catchment population size was calculated using the number of total population of catchment areas multiply by the proportions of pneumonia patients that were admitted at sentinel hospitals. Results: Among 1 491 patients, 13.7% (205 cases) was test positive for influenza viruses, 2 (0.9%) cases positive for influenza A (H1N1), 91 (44.6%) cases influenza A (H3N2), 1 (0.5%) case influenza B/Victoria, 111 (54.0%) cases influenza B/Yamagata. Influenza was associated with an estimated 30 (95%CI:9-51) SARI hospitalizations per 100 000 during 2015. The hospitalization rate was 243 (95%CI: 232-255), 86 (95%CI: 59-112),1(95%CI: 0-5), 8 (95%CI: 0-23) and 92 (95%CI: 16-168) SARI hospitalizations per 100 000 population for<5 years children, 5-14 years children, 15-24 years adult, 25-59 years adult and >=60 years population, respectively. The hospitalization rate of SARI attributed to influenza A and B was 14 (95%CI:4-17) and 16 (95%CI:0-23) per 100 000 population, respectively. Conclusion: The influenza positive rate among SARI cases was relatively high. The hospitalization burden of SARI attributed to influenza was the greatest in children under 5 year-old. PMID- 29262492 TI - [Comparison of colonization ability of O1 and O139 Vibrio cholerae strains on soft-shelled turtle's surface]. AB - Objective: To study the preferred colonization sites of O1 Vibrio cholerae (V.cholerae) and the colonization ability difference for O1 and O139 V. cholerae on soft-shelled turtle's surface. Methods: 8 O1 and O139 V. cholerae strains were obtained from branch of diarrheal diseases, Chinese center for disease control and prevention. 63 soft-shelled turtles weighing 150 g and 9 cm in length (diameter of calipash) were selected for use in the study. The preferred colonization sites and proliferation trend were studied by using bioluminescent imaging method. The colonization factors for O1 V. cholerae strains were studied by constructing colonization gene mutant strains (VC1897dmshA, VC1897dgbpA and VC1897dtcpA), performing competition colonization assays and analyzing the competitive indexes. After pairing off O1 and O139 strains respectively to perform 16 competition groups, the colonization difference of these two strains were studied by competition colonization assays. Results: The colonization sites by V. cholerae on soft-shelled turtles surfaces was clustered. More V. cholerae strains colonized on turtle's calipash and carapace on dorsal side and less strain colonized on ventral side. The competition colonization assays showed that colonization ability of O1 serogroup mshA mutant strains were 7.26 times lower than VC1897dlacZ. Besides, the CI value (O139/O1) of 11 out of the 16 competition groups were greater than 2 (between 2.07 and 59.84). Two groups showed values of 1.43 and 0.93 respectively and 3 groups lower than 0.7. Conclusion: The preferred colonization sites for O1 V. cholerae strains on body surface were observed.MSHA was one of the main colonization factors for its colonization. Our study suggested that in general, O139 V. cholerae strains have stronger colonization ability than O1 strains. Besides, strains isolated from soft-shelled turtles tend to have stronger colonization ability than strains isolated from patients. PMID- 29262493 TI - [Genetic characterization of rubella virus isolated in Guizhou Province from 2012 to 2015]. AB - Objective: To analyze the genetic characteristics of rubella virus isolated from 2012 to 2015 in Guizhou province. Methods: A total of 390 cases of suspected measles were collected from Guizhou measles network laboratory from 2012 to 2015 and 25 cases of rubella cases were diagnosed. Rubella virus isolation was performed using Vero/SLAM cells. The presence of rubella viral RNA was detected using Real-time RT-PCR after RNA extraction from infected tissue culture cells. Fragments of 480 bp and 633 bp nucleotides of E1 genes of the isolates were amplified by RT-PCR and the PCR products were sequenced and spliced. The phylogenetic tree was conducted based on the 739 bp nucleotide sequences of E1 genes and gene characteristic analysis was performed. Results: There were 19 cases of rubella outbreaks and 6 cases of rubella sporadic cases in 25 cases of suspected rubella cases. There were 11 males (44.0%) and 14 females (56.0%). The mean age and standard deviation were (12.3+/-3.9) years. A total of 10 rubella strains were isolated. The results of phylogenetic analysis showed that 7 strains of rubella virus isolates belonged to genotype 1E and the other belonged to genotype 2B. The nucleotide acid and amino acid homology among 7 strains 1E genotype were 99.0%-100% and 100% respectively. 2B genotype of 3 strains of nucleotide and amino acid homology were 99.4%-100% and 99.5%-100% respectively. Ten strains of rubella virus were not mutated in the E1 glycoprotein gene, Asn 177 and Asn 209 N-type glycosylation sites and E1 antigen epitopes between 213 and 285aa.Among them, 7 strains of 1E genotype had a mutation from leucine to phenylalanine in 338 amino acid, 2 strains of 2B genotype at 377 amino acids from valine to alanine. Conclusion: Rubella virus epidemic was caused by 1E and 2B genotypes in Guizhou from 2012 to 2015.Ten strains of rubella virus were highly conserved in nucleotide and amino acid sequences and there was no variation of important functional sites. PMID- 29262494 TI - [Epidemiological and etiological surveillance study of infectious diarrhea in Shanghai in 2013-2015]. AB - Objective: To analyze the pathogen spectrum and epidemiological characters of infectious diarrhea cases in Shanghai from July 2013 to June 2015. Methods: From July 2013 to June 2015, using multi-stage sampling to select 22 hospitals as adult diarrhea surveillance sentinels, and 3 district central hospitals together with Shanghai municipal children's hospital as children diarrhea surveillance sentinels. A total of 6 267 diarrhea cases were sampled. The demographic characters, main clinical manifestations and signs of cases were investigated, and stool specimens were collected to conduct the bacteria culture and virus nucleic acid detection. The difference of positive rate of bacteria and virus in different seasons, and age difference of relevant pathogens were compared. Results: Among 6 267 cases, 3 262 (52.05%) were male, and most of them were in 50 69 years group (1 999 cases, 31.90%) and 30-49 years group (1 691 cases, 26.98%). Totally, 2 783 positive specimens were detected out of 6 267 specimens with the positive rate being 44.41%. A total of 7 kinds of bacteria and 5 kinds of viruses were detected. The positive rate for bacterium was 12.61%(790 cases), mainly being vibrio parahaemolyticus (256 cases), diarrheagenic E.coli (239 cases) and salmonella (209 cases). The positive rate for virus was 31.80% (1 993 cases), mainly being norovirus (1 172 cases) and rotavirus (546 cases). The positive rates of viruses in winter of 2013 and 2014 were 57.89%(429 cases) and 62.14%(522 cases) respectively, higher than those of bacterium in the same periods which were 2.43% (18 cases) and 2.86% (24 cases) respectively. The positive rates of bacterium in summer of 2013, 2014 and 2015 were 14.56% (97 cases), 25.29%(258 cases) and 21.21% (49 cases), also higher than those of viruses in the same periods which were 7.51% (50 cases), 8.43%(86 cases) and 11.69% (27 cases) respectively, all of the above differences were statistically significant (P<0.05). The cases of 50-69 years group had the highest positive rate of pathogen, which was 47.57% (951/1 999). Secondly was those of 30-49 years group with 47.13% (797/1 691). Positive rate of pathogen for cases of 0-2 years group was 35.74% (213/596). Conclusion: The pathogen spectrumes of infectious diarrhea in Shanghai are mainly vibrio parahaemolyticus, diarrheagenic E.coli, salmonella, norovirus and rotavirus. The summer and winter season peak was obvious. Specific etiological surveillance and control strategies should be strengthened aiming at focus groups including children and the elderly in different seasons. PMID- 29262495 TI - [Antimicrobial resistance research of nontyphoidal Salmonella enteric infections in four hospitals in Shenzhen, 2012-2016]. PMID- 29262496 TI - [Safety evaluation of 10 MUg recombinant hepatitis B vaccine (saccharomyces cerecisiae yeast) based on the results of a phase of IV clinical trial]. PMID- 29262497 TI - [Retrospection and reflection on international progress of sugar-sweetened beverages tax policies]. AB - Since the invention of sugar, added sugars bring us enjoyment. As consumption continues to rise, especially the advent of sugary drinks makes it easier for people to consume added sugars, less sugars and reduced sugars have also become a of concern around the world. In recent years, in WHO and several countries, tax on sugary beverages has been designed to reduce the intake of sugar and prevent the economic costs of obesity and other diseases. This paper reviews the WHO's proposal on sugary drinks tax and the progress of sugary drinks tax in Hungary, Finland, France, Mexico, the United States, South Africa and other countries and regions. The effect of policy on sugary drinks tax was analyzed and considered. Suggestion and support for the progress of China's reduced sugars was provided in the last. PMID- 29262498 TI - [Advances on the research of the environmental risk factors of children autism]. AB - Autism spectrum disorder is a lifelong neurodevelopmental disorder, characterized by social interaction and communication impairments, accompanied by repetitive behaviors. Little is known about the causes and contributing factors for autism. It is difficult to prevent and cure, and has become a globe public health problem. With the development in the prevalence of autism, the idea how the environmental factors cause the autism, gains all attentions. Summarizing latest epidemiological studies and experimental evidence, this review is focused on the effect of environmental factors, including air pollutant, heavy metal and pesticides, and discussed the relation between environmental risk factors and autism. The results showed that risks of autism in children may increase following in prenatal exposure to air pollutants, heavy metal and pesticides. It is needed to do the research on the mechanism of environmental risk factor and autism for more prevention, treatment and control suggestions. PMID- 29262499 TI - [Comprehensive review of factors and preventions of mother to child transmission of hepatitis B virus]. AB - Mother-to-child transmission of hepatitis B virus (HBV) is one of major public health issues. Difference is found on effect of preventions of mother to child transmission of HBV such as Hepatitis B vaccine, Hepatitis B immunoglobulin and antiretroviral drugs. Based on the risks of hepatitis B virus on children, influencing factors and interventions of HBV mother-to-child transmission were explored to improve prevention mother-to-child transmission of hepatitis B and to search appropriate strategies reducing mother-to-child transmission of HBV. PMID- 29262500 TI - [The status of preventive medicine program of the National Natural Science Foundation of China in 2017]. PMID- 29262501 TI - [Analysis of basic research of hygienic toxicology in preventive medicine supported by the National Natural Science Foundation of China during 2003-2016]. PMID- 29262502 TI - [Precise therapy for lung cancer patients with rare sensitive mutations of epidermal growth factor receptor]. AB - Precise medicine is an emerging clinical therapeutic concept based on genomic and genetic information of patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is an important component of precise therapy for lung cancer patients. EGFR mutations occur mainly in exon 18 to 21, in which exon 19 deletion and exon 21 L858R point mutation that are known as sensitive mutations account for nearly 45% and 40%, respectively. Except for the above two mutations and T790M point mutation, the rest are rare mutations, including Ins19, Ins20, E709, G719, S768, L861 and some compound mutations. Some previous retrospective studies of small sample size and case reports showed that most of EGFR exon19 (Ins), exon 21 (L861), exon 18 (G719X) and exon20 (S768I) mutations were sensitive to TKIs. And although the exon 20 insertion mutation is usually predicted to the first and second generations of EGFR-TKIs resistance, some specific types are sensitive to the third generation of EGFR-TKIs. Currently, targeted drugs for Ins20 -Ap32788 mutation has entered into clinical trials. Patients with complex mutations have similar efficacy on EGFR-TKIs in comparison with those with single sensitivity mutations. In conclusion, when patients with rare sensitive mutations received EGFR-TKIs therapy, the efficacy and progression free survival time is similar to or slightly lower than those with classical sensitive mutations, whereas it is higher than those with wild-type EGFR. Compared with the first generation of EGFR-TKIs, second generation EGFR-TKIs may be more suitable for the treatment of lung cancer patients harboring rare sensitive EGFR mutations. PMID- 29262503 TI - [Effects of bone marrow stromal cells on the chemotherapeutic sensitivity of acute lymphoblastic leukemia cells]. AB - Objective: To investigate the influences of bone marrow stromal cells, components of extracellular matrix and cytokine secreted by stromal cells on the chemotherapeutic sensitivity of acute lymphoblastic leukemia cells to cytosine arabinoside (Ara-C). Methods: The co-culture model of acute lymphoblastic leukemia cell Sup-B15 and bone marrow stromal cell OP9 was constructed. Sup-B15 cells were cultured alone or co-cultured with OP9 cells, inactivated OP9 cells, the conditional medium (CM) of co-cultured OP9 cells and Sup-B15 cells, the CM of OP9 cells alone or Sup-B15 cells alone, respectively. The effects of different concentrations of Ara-C on the proliferation of each Sup-B1 cell group mentioned above were detected by cell counting kit-8 (CCK-8) method. The effects of different concentrations of Ara-C on the apoptosis of each group were detected by flow cytometry (FCM). The expressions of Bcl-2 protein in each group were detected by western blot. Results: The results of CCK-8 test showed that the inhibitory efficiency of Ara-C was in a dose-dependent manner. With different concentrations of Ara-C treatment for 48 hours, the half maximal inhibitory concentrations (IC(50)) of Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group were 0.510 and 0.339 MUg/ml, respectively, significantly higher than 0.091 MUg/ml of Sup-B15 cultured alone group (P<0.05). The IC(50) of CM of Sup-B15 and OP9 co-cultured group was 0.204 MUg/ml, significantly higher than 0.087 MUg/ml of the CM of OP9 cultured alone group (P<0.05) and 0.097 MUg/ml of the CM of Sup-B15 cultured alone group (P<0.05). The results of flow cytometry showed that with 0.10 MUg/ml Ara-C treatment for 24 hours, the early apoptotic cell percentages of Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group and Sup-B15 cultured alone group were (6.67+/-2.19) %, (8.95+/-3.04) % and (20.46+/-2.63) %, respectively. The early apoptotic cell percentages of Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group were significantly lower than that of Sup B15 cultured alone group (P<0.05). The early apoptotic cell percentages of the CM of Sup-B15 and OP9 co-cultured group, the CM of OP9 cultured alone group and the CM of Sup-B15 cultured alone group were (11.16+/-2.97)%, (22.08+/-2.71)% and (19.25+/-1.57)%, respectively, the former two of which were significantly lower than the last one (P<0.05). The results of western blot showed that the relative expression levels of Bcl-2 protein of Sup-B15 cultured alone group, Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group, the CM of Sup-B15 and OP9 co-cultured group, the CM of OP9 cultured alone group and the CM of Sup-B15 cultured alone group were 1.00+/-0.00, 1.53+/-0.03, 1.38+/-0.01, 1.26+/-0.05, 1.03+/-0.01 and 0.98+/-0.02, respectively. The expression levels of bcl-2 protein of three combined groups were significantly higher than that of Sup B15 cultured alone group (P<0.05). while no statistically significant difference was observed between the CM of OP9 cultured alone group and the CM of Sup-B15 cultured alone group (P>0.05). Conclusion: Bone marrow stromal cell OP9, the components of bone marrow extracellular matrix and cytokine secreted by stromal cells are involved in the induction of the chemotherapeutic resistance of Sup-B15 cells to Ara-C. PMID- 29262504 TI - [Expressions and clinical significances of paired box gene 2 and cyclin D1 in advanced ovarian serous carcinoma]. AB - Objective: To investigate the expressions and clinical significances of paired box gene 2 (Pax2) and cyclin D1 protein in advanced ovarian serous carcinoma. Methods: From January 2003 to December 2013, the pathologic tissues of 202 patients with advanced ovarian serous cancer (III-IV) who underwent initial cytoreductive surgery were collected. The expressions of Pax2 and cyclin D1 protein were detected by immunohistochemistry in tissue microarray. The relationships of their expressions with the clinicopathological features and prognosis of the patients were analyzed. Results: The positive rate of Pax2 protein expression of the 202 patients with ovarian serous adenocarcinoma was 24.8% (50/202) and that of cyclin D1 was 25.2% (51/202). The expressions of Pax2 and cyclin D1 were not significantly related with age, clinical stage and pathological grade of ovarian serous adenocarcinoma patients (P>0.05). The median overall survival (OS) time of Pax2-negative patients was 53 months and the progression-free survival (PFS) time was 29 months. The median OS time of Pax2 positive patients was 66 months and PFS time was 33 months, the OS of Pax2 negative patients was significant different from that of Pax2-positive patients (chi(2)=4.06, P=0.04). The median PFS time of Pax2-negative patients was not significant different from that of Pax2-positive patients (chi(2)=2.43, P=0.11). The median OS time of cyclin D1-negative patients was 62 months and PFS time was 30 months. The median OS time of cyclin D1-positive patients was 48 months and PFS time was 22 months. The median OS time of cyclin D1-negative patients was significantly different from that of cyclin D1-positive patients (chi(2)=4.71, P=0.03), while the median PFS time of cyclin D1-negative patients was marginally different from that of cyclin D1-positive patients (chi(2)=0.59, P=0.41). Multivariate analysis showed that the expression of Pax2 was an independent factor of the prognosis for patients with ovarian serous adenocarcinoma (RR=0.597, 95% CI 0.371-0.962, P<0.034). Conclusion: The expressions of Pax2 and cyclin D1 are associated with the prognosis of patients with advanced ovarian serous adenocarcinoma while Pax2 is an independent prognostic factor. PMID- 29262505 TI - [Discrimination and clinical value of plasma metabolomic profiles in multidrug resistant epithelial ovarian cancer]. AB - Objective: To explore the alteration of plasma metabolomic profiles, screen the new serum markers of multidrug resistant epithelial ovarian cancer (EOC), and investigate the mechanism. Methods: The serum of 132 cases with cisplatin resistant EOC, cisplatin-sensitive EOC, benign ovarian cyst and healthy donors were collected. Differentially plasma metabolic profiles were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The significantly different metabolites of each group were screened by using principal component analysis. Then compounds that played a key role in cisplatin resistance were identified by using nuclear magnetic resonance (NMR). The relationships between these compounds and clinical characteristics and prognosis were analyzed. Results: LC-MS/MS identified 25 800 metabolic compounds. According to the descending dimension algorithm by principal component analysis, six compounds which were the biggest contributor to grouping were identified. The identified results of NMR showed that the serum level of C16 Sphinganine was lower while Dodemorph was higher in the EOC than those of the normal control. Compared to the cisplatin sensitive group, cisplatin resistant group exhibited a specific metabolic trait characterized by upregulation of 1-Monopalmitin, Ricinoleic acid methyl ester, Polyoxyethylene (600) mono-ricinoleate/Glycidyl stearate and downregulation of Calycanthidine. The four components were all associated with fatty acid metabolism, and the combinational diagnostic sensitivity of these biomarkers for cisplatin-resistance was 86.50% and the specificity was 81.80%, the area of receiver operating characteristic (ROC) curve was 0.93. Conclusions: The metabolic signatures of normal control, benign ovarian cyst, cisplatin sensitivity and cisplatin resistance can be clearly separated from each other by LC-MS/MS technology.The combinational four biomarkers including Calycanthidine, 1-Monopalmitin, Ricinoleic acid methl ester and Polyoxyethylene (600) mono-ricinoleate/Glycidyl stearate are more sensitive and specific for the diagnosis of cisplatin resistant EOC, and may provide the potentially predict markers of chemotherapeutic response in metabolic level. The fatty acid metabolism may participate in the cisplatin resistant progression of EOC. PMID- 29262506 TI - [A new prognostic score system of hepatocellular carcinoma following hepatectomy]. AB - Objective: To establish a new scoring system based on the clinicopathological features of hepatocellular carcinoma (HCC) to predict prognosis of patients who received hepatectomy. Methods: A total of 845 HCC patients who underwent hepatectomy from 1999 to 2010 at Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively analyzed. 21 common clinical factors were selected in this analysis. Among these factors, the cut-off values of alpha-fetoprotein (AFP), alkaline phosphatase (ALP) and intraoperative blood loss were evaluated by using a receiver operating characteristic (ROC) curve analysis.The Kaplan-Meier method and Cox regression model were used to evaluate the independent risk factors associated with the prognosis of HCC patients after hepatectomy. HCC postoperatively prognostic scoring system was established according to the minimum weighted method of these independent risk factors, and divided the patients into 3 risk groups, including low-risk, intermediate-risk and high-risk group. The relapse-free survival (RFS) and overall survival (OS) were compared among these groups. Results: The univariate analysis showed that clinical symptoms, preoperative alpha-fetoprotein (AFP) level, serum alkaline phosphatase (ALP) level, tumor size, tumor number, abdominal lymph node metastasis, macrovascular invasion or tumor thrombus, extrahepatic invasion or serosa perforation, the severity of hepatic cirrhosis, intraoperative blood loss, the liver operative method, pathological tumor thrombus, intraoperative blood transfusion, perioperative blood transfusion were significantly associated with median RFS of these HCC patients (P<0.05). Alternatively, clinical symptoms, preoperative AFP level, serum ALP level, tumor size, tumor number, abdominal lymph node metastasis, macrovascular invasion or tumor thrombus, extrahepatic invasion or serosa perforation, the severity of hepatic cirrhosis, intraoperative blood loss, the liver operative method, pathological lymphocyte invasion, pathological tumor thrombus, intraoperative blood transfusion, perioperative blood transfusion were significantly associated with the median OS of these HCC patients (P<0.05). The multivariate analysis showed that AFP >=20 ng/ml, clinical symptoms, tumor diameter >=5 cm, multiple tumors, macrovascular invasion or tumor thrombus, extrahepatic invasion or serosa perforation, moderate and severe liver cirrhosis, non- anatomic resection were the independent risk factors of RFS and OS (P<0.05). The independent risk factor of RFS was intraoperative bleeding loss >=325 ml (P<0.05); The independent risk factors of OS were abdominal lymph node metastasis and pathological tumors thrombus (P<0.05). The respective weight of 11 independent factors was used to establish the scoring system (scores range from 0 to 26). In the score system, 0 to 5 points were defined as the low-risk group (286 cases), 6 to 12 points were determined as the intermediate-risk group (503 cases), more than 13 points were classified as the high-risk group (56 cases). The median RFS of the low-risk, intermediate-risk and high-risk group were 80, 27 and 6 months, respectively. The differences were statistically significant (P<0.001). The median OS of the three groups were 134, 51 and 15 months, respectively, and the differences were statistically significant (P<0.001). Conclusion: This new score system provides effective prediction of postoperative prognosis for HCC patients. PMID- 29262508 TI - [Expression and Prognostic Significance of P-IGF1R in Gastric Cancer]. PMID- 29262507 TI - [Measurement reproducibility of parameters derived from introvoxel incoherent motion diffusion-weighted MRI imaging of rectal cancer]. AB - Objective: To study the measurement reproducibility of parameters derived from introvoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI)-MRI of rectal cancer between- and within- radiologists. Methods: Clinical data of 34 patients with rectal cancer were prospective analyzed. Conventional MRI sequences, IVIM DWI-MRI with sixteen b values and dynamic contrast enhancement (DCE)-MRI sequences of rectum were acquired by GE 3.0-T MRI imager. The IVIM sequence images with b value=1000 sec/mm(2) were selected to measure the maximum axial section of tumor by a radiologist with 15 year-experiences in gastrointestinal cancer imaging.Two radiologists (radiologist 1 and radiologist 2 with 2 and 10 years of experience in gastrointestinal cancer imaging, respectively) independently draw a freehand region of interest (ROI) that contained the largest available tumor area on the selected section. Monoexponential apparent diffusion coefficient (ADC) and biexponential IVIM metrics maps and IVIM parameters were generated automatically by the software. The repeated measurement was performed at an interval of one week. The average values of each measurement were used for statistical analysis. ADC values and IVIM parameters obtained between- and within- radiologists were analyzed by Wilcoxon signed-rank test. Intraclass correlation coefficients (ICC) and Bland Altaman plots were used to analyze the parameter reproducibility of two measurements between- and within- radiologists. Results: The first and second measured ADC (*10(-3)mm(2)/s), true diffusivity (D, *10(-3)mm(2)/s), false diffusivity (D(*,) mm(2)/s) and perfusion fraction (f, %) by radiologist 1 were 0.997, 0.692, 0.043, 34.6 and 0.993, 0.691, 0.038, 32.8, respectively. The first and second measured ADC (*10(-3)mm(2)/s), D (*10(-3)mm(2)/s), D(*) (mm(2)/s), f (%) by radiologist 2 were 0.987, 0.651, 0.046, 32.8 and 0.996, 0.689,0.041, 32.7, respectively. No statistically significant differences were observed in ADC and IVIM parameters obtained between- and within- radiologists (P>0.05). The ADC values and the f values of two times were significantly correlated between- and within- radiologists. The D values were significantly correlated within a radiologist, and the correlation of D(*) values within a radiologist was significantly higher than that between radiologists. The 95% limits of agreement (LoA) of ADC values and f values were smaller than those of D values and D(*) values between- and within- radiologists. The 95% LoA of ADC values was the least, while that of D(*) values varied most.The 95% LoA of f values and D values kept steady within a radiologist, and 95% LoA of f values was slightly smaller than that of D values. The 95% LoA of IVIM parameters (ADC, D, f, D(*) values) within radiologists 2 were better than those within radiologist 1. Conclusions: The reproducibilities of ADC and f values are the best, while the reproducibility of D(*) values is relatively poorer in rectal cancer. Measurement reproducibility of parameters derived from IVIM may be improved by increasing radiologists' experiences in drawing ROI. PMID- 29262509 TI - [Efficacy of Weitan Waifu patch on the postsurgical gastroparesis syndrome of gastrointestinal cancer: a multi-center trial]. AB - Objective: To investigate the safety and efficacy of the Weitan Waifu patch on the postsurgical gastroparesis syndrome (PGS) of gastrointestinal cancer. Methods: The multi-center, double-blind, randomized controlled trial was conducted with superiority design. Patients with PGS of gastrointestinal cancer diagnosed in 4 AAA hospitals and the abdominal symptom manifested as cold syndrome by Chinese local syndrome differentiation were recruited. These patients were randomly divided into two groups according to 1?1 proportion. Placebo or Weitan Waifu patch was applied in control group or intervention group, respectively, based on the basic treatments, including nutrition support, gastrointestinal decompression, promoting gastric dynamics medicine.Two acupuncture points (Zhongwan and Shenque) were stuck with placebo in control group or patch in treatment group. The intervention course was 14 days or reached the effective standard. Results: From July 15, 2013 to Jun 3, 2015, 128 participants were recruited and 120 eligible cases were included in the full analysis set (FAS), and 60 cases in each group. 88 cases were included in the per protocol set (PPS), including 45 cases in the treatment group and 43 cases in the control group. In the FAS, the clinical effective rate in the treatment group was 68.3%, significantly superior than 41.7% of the control group (P=0.003). The medium time of effective therapy in the treatment group was 8 days, significantly shorter than 10 days in the control group (P=0.017). In the FAS, 3 adverse events occurred in the treatment group, including mild to moderate decrustation, pruritus and nausea. The incidence rate of adverse events was 5.0% (3/60) and these symptoms were spontaneously remitted after drug withdrawal. No severe adverse events were observed in the control group. There was no significant difference between these two groups (P=0.244). Conclusion: Weitan Waifu patch is a safely and effectively therapeutic method for patients with PGS (cold syndrome) of gastroenterological cancer. Trial registration: International Standard Randomized Controlled Trial Number Register, ISRCTN18291857. PMID- 29262510 TI - [A prospective pilot study of combined intra-operative radiotherapy for centrally located hepatocellular carcinomas]. AB - Objective: To carry out a prospective cohort study of combined intra-operative radiotherapy for centrally located hepatocellular carcinomas (HCC) and to observe the safety and postoperative complications. Methods: A total of 79 patients with centrally located HCC who underwent hepatectomy were divided into two groups: experimental group (combined with targeted intra-operative radiotherapy, 32 cases) and control group (single surgical operation, 47 cases). Patients in the experimental group received intra-operative electron radiotherapy after tumor resection, while patients in the control group received to intra-operative electron radiotherapy.The haemorrhagia amount and operation time during the operation, intra-operative liver function and the recovery of liver and gastrointestinal tract of patients in these two groups were compared. Results: No postoperative 30-day mortality was observed in all of the patients. The average total operation time of patients in the experimental group was (319+/-76) min, significantly longer than (233+/-76) min of the control group (P<0.001). The average aspartate transaminase (AST) level of patients in the experimental group at postoperative day 1 was 562.5 U/L, significantly higher than 347.0 U/L of control group (P=0.031). However, the average prothrombin activity levels of patients in the experimental group at postoperative day 3 and day 7 were (68.3+/ 17.9)% and (73.4+/-10.2)%, respectively, significantly lower than (78.9+/-15.9)% and (80.0+/-10.6)% of control group (both P<0.05). There were no significant differences of tumor volume, differentiation degree, satellite lesion, dorsal membrane invasion, microvascular invasion between these two groups (all P>0.05). There were no significant differences of hospital stay, ventilation time, the incidence of hepatic insufficiency, ascites, pleural effusion, infection, biliary fistula between these two groups (all P>0.05). There were no significant differences of alanine aminotransferase (ALT), albumin, total bilirubin between these two groups at postoperative day 1, 3, 5 and 7 (all of P>0.05). Conclusion: The resection of centrally located HCC combined with intra-operative radiotherapy may increase the total operation time, delay the early postoperative recovery of liver function, but it is still safe and feasible. Trial registration: National Cancer Centre /Cancer Hospital, Chinese Academy of Medical Sciences, ChiCTR-TRC 12002802. PMID- 29262511 TI - [Surgical management of elderly patients with medial wall pyriform sinus cancer]. AB - Objective: To investigate the clinical efficacy of preoperative-, postoperative radiotherapy and surgery for preserving laryngeal function in patient over 70 years of age with medial wall pyriform sinus cancer. Methods: Clinical data of 48 patients over 70 years of age with medial wall pyriform sinus cancer who received surgical treatment from January 2001 to December 2010 were retrospectively analyzed. Among them, 21 cases were given preoperative radiotherapy and surgery (R+ S). The radiation therapy dose was 45 Gy. And 14 cases' larynx is preserved. In addition, 27 cases were given postoperative radiotherapy and surgery (S+ R). The radiation therapy dose was 65 Gy. And 10 cases had preserved laryngeal function. Survival rates were analyzed by the Kaplan-Meier method. Chi-square test was used to compare complications between two groups. Results: The larynx preservation rate in R+ S group [66.7% (14/21)] was significantly higher than that in S+ R group [37.0% (10/27), P<0.05]. The complication rate and decannulation rate in R+ S group were 42.9% (9/21) and 64.3% (9/14), respectively, showing no difference compared with those in S+ R group [37.0% (10/27) and 50.0% (5/10), respectively] (all P>0.05). The complication rates of patients with and without larynx preservation were 41.7% (10/24) and 37.5% (9/24), respectively, showing no difference between two groups (P>0.05). The overall 3-years and 5-years survival rates for all patients were 54.2% (26/48) and 35.4% (17/48), respectively. There was no significant difference in survival rates between R+ S [38.1% (8/21)] group and S+ R group [33.3% (9/27), P>0.05)]. In the R+ S group, the survival rates in patients with and without larynx preservation were 40.0% (4/10) and 29.4% (5/17), respectively, showing no significant difference between two groups (P>0.05). Conclusions: It is secure and effective to choose the operation with laryngeal preservation for patient over 70 years of age with medial wall pyriform sinus cancer based on their physical conditions and the tumor extension. The preoperative- and postoperative radiotherapy have the similar effect. Preoperative radiotherapy and surgery increases the laryngeal preservation rate. PMID- 29262512 TI - [Study on the metastatic sequence of cervix lymph node in hypopharyngeal carcinoma]. AB - Objective: To investigate the metastatic sequence of cervical lymph node in hypopharyngeal carcinoma aimed at guiding neck exploration. Methods: Seventy-five serial sections of integrally dissected lateral neck specimens from 67 patients of hypophayryngeal carcinoma were histopathologically observed, and the metastatic sequence of cervical lymph node of hypophayryngeal carcinoma were analysed. Results: In 75 integrally dissected lateral neck specimens, 63 laterals were found to occur cervical lymph node metastases, the metastatic ratio was 84.0%. The analytic result of 63 dissected lateral neck specimens with positive lymph nodes showed that the metastatic lymph node ratio in descending order was level II (90.5%), level III (76.2%), level IV (41.3%), level V (15.9%), level I (7.9%) and level VI (3.2%). The metastatic ratio of lymph node between level I~VI were significantly different from each other (P<0.01). When the tumor metastasized to one cervical lymph node, this could be found in levels II or III, when metastasized to two cervical lymph nodes, these could be found in levels II, III, IV, and when metastasized to more than 5 of cervical lymph nodes, these could be found in levels II, III, IV, V, Iand VI. According to the occurring sequence, metastatic ratio and number of cervical lymph node metastasis (LNM), levels II and III were identified as the first station, level IV was the second station and levels V, I and VI were the third station of cervical LNM in hypopharyngeal carcinoma. Conclusion: The confirmation of metastatic sequence of cervical lymph node in hypophayryngeal carcinoma provides a reliable evidence for neck lymph node dissection and reference value for clinic therapy. PMID- 29262513 TI - [Calculating the Hausdorff distance based on the scripting in RayStation treatment planning system]. AB - Objective: To calculate out the Hausdorff distance based on the scripting in RayStation treatment planning system, which was then applied in measuring the deformation error of brain stem during image automatic registration between CT and MR. Methods: Scripting was edited in RayStation system (version 4.7) by using IronPython. The set of point coordinates on the contour of any two region of interest (ROI) had been found firstly, then the Hausdorff distance between the two point sets was calculated out. A graphical user interface (GUI) was designed by using XAML to acquire the visualized output of Hausdorff distance. GUI appeared when the script was run, where two ROIs was selected, then the corresponding Hausdorff distance and the running time were displayed by pressing the "Calculate" button. Results: The mean Hausdorff distance of brain stem in 20 patients with head and neck neoplasms was 1.20 cm while the mean elapsed time was 11.01s. Conclusions: Hausdorff distance of any two ROIs can be calculated out by using the developed method. GUI is designed to realize the visual interaction with RayStation system. Therefore, the RayStation system satisfies the demands of Hausdorff distance calculation in both clinical and research work. PMID- 29262514 TI - [Early diagnosis and early treatment for liver cancer in Qidong: survival of patients and effectiveness of screening]. AB - Objective: To evaluate the patients' survival and effectiveness of the live cancer screening for population at high risk for liver cancer in Qidong. Methods: According to the Expert Scheme proposed the Expert Committee of Early Detection and Early Treatment, China Cancer Foundation, diagnostical screening by using combined methods of alpha-fetoprotein and B ultrasound monitoring were carried out biannually in individuals with positive HBsAg who were screened from Qidong area. The evaluation indices of the effectiveness are task completion rate of screening, detection rate of liver cancer, early diagnosis rate, and treatment rate. The deadline of the follow-up for the surviving outcome was March 31, 2016. The life-table method was used to calculate the observed survival, and to make comparison and significant tests between survival rates in Group A (those found via repeated periodic screening) and Group B (those diagnosed without periodic screening). Results: Since 2007, 38 016 target population have been screened, and 3 703(9.74%) individuals with positive HBsAg were found. Except for 29 patients with liver cancer at the initial screening, 3 674 persons in the cohort were followed up; 268 patients with liver cancer were detected from the 33 199 person times screening, with an annual detection rate of 1.61%. Of them, 186 patients were found in Group A(1.12%), in which 149 patients were the early cases, with an early detection rate of 80.11%; 167 out of 186(89.78%) patients received treatment after diagnosis. The incidence of liver cancer in this HBsAg (+ ) cohort of 25 452 person-years was 1 052.96 per 100 000 annually, 187 cases in males(1 488.45/100 000)and 81 cases in females(628.46/100 000). The 1-, 3-, 5-, and 8-year survival of all patients with liver cancer were 64.55%, 40.50%, 32.54%, and 19.65%, respectively. The 1-, 3-, 5-, and 8-year survival rates were 77.16%, 49.04%, 38.53%, and 24.25% in Group A, and were 36.25%, 21.21%, 21.21%, and 0% in Group B, respectively, with significant differences between two groups (P<0.05). Conclusion: The findings show that screening of individuals at high risk of development of liver cancer, with semiannual AFP and B ultrasound, according to the Expert Scheme, is effective not only in increasing detection rate but also in detecting liver cancer at early stage, and in improving patients' survival as well. PMID- 29262516 TI - [Gallbladder carcinoma with tumor thrombus in the common bile duct: a case report]. PMID- 29262515 TI - [Effect of neoadjuvant chemotherapy on the overall treatment strategy in operable breast cancer]. AB - The intention of neoadjuvant chemotherapy in breast cancer is to shrink the tumors in locally advanced disease and to improve the degree of cure of operation (security). Therefore, it is expected to improve quality of life and survival for patients. Additionally, neoadjuvant chemotherapy is administered based on the observable primary tumor. Thus, the timely assessment of tumor response to chemotherapeutic drugs provides a basis for subsequent treatment. Currently, however, the treatment concept of breast cancer requires whole process management. It requires clinicians to develop the overall treatment strategy according to tumor biological information of patients, as well as timely and reasonable adjustment of the subsequent treatment based on the response to neoadjuvant chemotherapy. These are new problems arising from neoadjuvant chemotherapy. PMID- 29262517 TI - [Lateral Ventricular Chordoid Glioma in a Pediatric Patient: a Case Report]. PMID- 29262518 TI - Therapy of polycythemia vera: is it time to change? PMID- 29262519 TI - Lck activation: puzzling the pieces together. PMID- 29262520 TI - Immune control in chronic myeloid leukemia. PMID- 29262521 TI - SMX makes the cut in genome stability. PMID- 29262522 TI - Avelumab demonstrates promise in advanced NSCLC. PMID- 29262524 TI - Loss of p53-inducible long non-coding RNA LINC01021 increases chemosensitivity. AB - We have previously identified the long non-coding RNA LINC01021 as a direct p53 target (Hunten et al. Mol Cell Proteomics. 2015; 14:2609-2629). Here, we show that LINC01021 is up-regulated in colorectal cancer (CRC) cell lines upon various p53-activating treatments. The LINC01021 promoter and the p53 binding site lie within a MER61C LTR, which originated from insertion of endogenous retrovirus 1 (ERV1) sequences. Deletion of this MER61C element by a CRISPR/Cas9 approach, as well as siRNA-mediated knockdown of LINC01021 RNA significantly enhanced the sensitivity of the CRC cell line HCT116 towards the chemotherapeutic drugs doxorubicin and 5-FU, suggesting that LINC01021 is an integral part of the p53 mediated response to DNA damage. Inactivation of LINC01021 and also its ectopic expression did not affect p53 protein expression and transcriptional activity, implying that LINC01021 does not feedback to p53. Furthermore, in CRC patient samples LINC01021 expression positively correlated with a wild-type p53 associated gene expression signature. LINC01021 expression was increased in primary colorectal tumors and displayed a bimodal distribution that was particularly pronounced in the mesenchymal CMS4 consensus molecular subtype of CRCs. CMS4 tumors with low LINC01021 expression were associated with poor patient survival. Our results suggest that the genomic redistribution of ERV1-derived p53 response elements and generation of novel p53-inducible lncRNA-encoding genes was selected for during primate evolution as integral part of the cellular response to various forms of genotoxic stress. PMID- 29262525 TI - Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor alpha in a beta-amyloid protein -dependent mechanism. AB - Cyclooxygenase-2 (COX-2) has been found to be induced during the early stage of Alzheimer's disease (AD). Using mouse-derived astrocyte and APP/PS1 transgenic (Tg) mice as model systems, we firstly elucidated the mechanisms underlying COX-2 metabolic production including prostaglandin (PG)E2- and PGI2-mediated tumor necrosis factor alpha (TNF-alpha) regulation. Specifically, PGE2 accumulation in astrocyte activated the p38 and JNK/c-Jun signaling pathways via phosphorylation, resulting in TNF-alpha expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 in stimulating the production of TNF-alpha by inhibiting the activity of TNF-alpha promoter and the binding activity of AP1 on the promoter of TNF-alpha. Moreover, our data also showed that not only Abeta1-42 oligomers but also Abeta1-42 fibrils have the ability to involve in mediating the antagonistic effects of PGE2 and PGI2 on regulating the expression of TNF-alpha via a p38- and JNK/c-Jun-dependent, AP1-transactivating mechanism. Reciprocally, the production of TNF-alpha finally accelerated the deposition of beta-amyloid protein (Abeta)1-42 in beta-amyloid plaques (APs), which contribute to the cognitive decline of AD. PMID- 29262523 TI - PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1. AB - Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene. PMID- 29262526 TI - Chronic inflammation and apoptosis propagate in ischemic cerebellum and heart of non-human primates. AB - The major pathological consequences of cerebral ischemia are characterized by neurological deficits commonly ascribed to the infarcted tissue and its surrounding region, however, brain areas, as well as peripheral organs, distal from the original injury may manifest as subtle disease sequelae that can increase the risks of co-morbidities complicating the disease symptoms. To evaluate the vulnerability of the cerebellum and the heart to secondary injuries in the late stage of transient global ischemia (TGI) model in non-human primates (NHP), brain and heart tissues were collected at six months post-TGI. Unbiased stereological analyses of immunostained tissues showed significant Purkinje cells loss in lobule III and lobule IX of the TGI cerebellum relative to sham cerebellum, with corresponding upregulation of inflammatory and apoptotic cells. Similarly, TGI hearts revealed significant activation of inflammatory and apoptotic cells relative to sham hearts. Aberrant inflammation and apoptosis in the cerebellum and the heart of chronic TGI-exposed NHPs suggest distal secondary injuries manifesting both centrally and peripherally. These results advance our understanding on the sustained propagation of chronic secondary injuries after TGI, highlighting the need to develop therapeutic interventions targeting the brain, as well as the heart, in order to abrogate cerebral ischemia and its related co-morbidities. PMID- 29262527 TI - Regulatory T cells characterized by low Id3 expression are highly suppressive and accumulate during chronic infection. AB - Foxp3+ regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator Id3. Id3lo Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of Id3hi into Id3lo Treg cells and during chronic infection Id3lo Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections. PMID- 29262528 TI - Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells. AB - The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3 ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches. PMID- 29262529 TI - APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. AB - Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT;ApcMin/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT;ApcMin/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT;ApcMin/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance. PMID- 29262530 TI - Prognostic effect of adjuvant chemoradiotherapy for patients with gastric cancer: an updated evidence of randomized controlled trials. AB - The prognostic effect of chemoradiotherapy in gastric cancer has been evaluated for decades while the results are still in debate and heterogeneous. We thus comprehensively updated the evidence through systematic review and meta-analysis to evaluate chemoradiotherapy in gastric cancer to determine its effect. Pubmed, EMBASE, and Cochrane Library from the earliest possible year to April 2017 were searched. Randomised controlled trials (RCTs) that assessed the effects of combined chemoradiotherapy for patients with gastric cancer compared with that of single chemotherapy were included. The main outcome measure was 5-year overall survival (OS) and the second was disease-free survival (DFS) or recurrence-free survival (RFS). Fifteen RCTs involving 3347 patients were included into this meta analysis. Compared with single chemotherapy, the relative risk (RR) for 5-year OS for chemoradiotherapy was 1.05 (95% CI 0.88 to 1.25), with moderate heterogeneity across eligible trials (I2 = 55.7%, p = 0.016). Subgroup analyses and sensitivity analyses confirmed the consistent findings. We found that significant survival benefit for 5-year DFS/RFS for chemoradiotherapy over single chemotherapy (RR 0.89 95% CI 0.81 to 0.98) for patients with gastric cancer. This updated meta analysis does not provide strong evidence for a 5-year survival benefit of chemoradiotherapy over chemotherapy alone in patients with gastric cancer. A clear advantage of chemoradiotherapy over chemotherapy has not been established. Further larger RCTs should be conducted to determine its true effect. PMID- 29262531 TI - Mutational profile of primary breast diffuse large B-cell lymphoma. AB - Primary breast lymphoma is a rare form of extra-nodal lymphoid neoplasm. The most common histological type is the diffuse large B-cell lymphoma, which represents 60-80% of all the cases. Our study analyzes the mutational profile of the primary lymphoma of the breast through targeted massive sequencing with a panel of 38 genes in a group of 17 patients with primary breast diffuse large B-cell lymphoma. Seventy-point-five percent of the patients presented with stage IE and 29.5% with stage IIE. 44% of the cases correspond to lymphomas with germinal center phenotype and 33.3% to activated B-cell. The genes with a higher mutational frequency include PIM1 (in 50% of the analyzed samples), MYD88 (39%), CD79B, PRDM1 and CARD11 (17%), KMT2D, TNFIAP3 and CREBBP (11%). The profile of mutant genes involves mostly the NFkappaB signaling pathway. The high frequency of mutations in PIM1 compared with other lymphomas may have implications in the clinical presentation and evolution of this type of lymphoma. PMID- 29262532 TI - Unique signalling connectivity of FGFR3-TACC3 oncoprotein revealed by quantitative phosphoproteomics and differential network analysis. AB - The FGFR3-TACC3 fusion is an oncogenic driver in diverse malignancies, including bladder cancer, characterized by upregulated tyrosine kinase activity. To gain insights into distinct properties of FGFR3-TACC3 down-stream signalling, we utilised telomerase-immortalised normal human urothelial cell lines expressing either the fusion or wild-type FGFR3 (isoform IIIb) for subsequent quantitative proteomics and network analysis. Cellular lysates were chemically labelled with isobaric tandem mass tag reagents and, after phosphopeptide enrichment, liquid chromatography-high mass accuracy tandem mass spectrometry (LC-MS/MS) was used for peptide identification and quantification. Comparison of data from the two cell lines under non-stimulated and FGF1 stimulated conditions and of data representing physiological stimulation of FGFR3 identified about 200 regulated phosphosites. The identified phosphoproteins and quantified phosphosites were further analysed in the context of functional biological networks by inferring kinase-substrate interactions, mapping these to a comprehensive human signalling interaction network, filtering based on tissue-expression profiles and applying disease module detection and pathway enrichment methods. Analysis of our phosphoproteomics data using these bioinformatics methods combined into a new protocol-Disease Relevant Analysis of Genes On Networks (DRAGON)-allowed us to tease apart pathways differentially involved in FGFR3-TACC3 signalling in comparison to wild-type FGFR3 and to investigate their local phospho-signalling context. We highlight 9 pathways significantly regulated only in the cell line expressing FGFR3-TACC3 fusion and 5 pathways regulated only by stimulation of the wild-type FGFR3. Pathways differentially linked to FGFR3-TACC3 fusion include those related to chaperone activation and stress response and to regulation of TP53 expression and degradation that could contribute to development and maintenance of the cancer phenotype. PMID- 29262533 TI - High-grade ovarian serous carcinoma patients exhibit profound alterations in lipid metabolism. AB - Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3 hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications. PMID- 29262534 TI - GUCY2C maintains intestinal LGR5+ stem cells by opposing ER stress. AB - Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c-/- ) were combined with immunodetection techniques and pharmacological treatments to define the role of the GUCY2C signaling axis in supporting ISCs. ISCs were reduced in Gucy2c-/- mice, associated with loss of active Lgr5+ cells but a reciprocal increase in reserve Bmi1+ cells. GUCY2C was expressed in crypt base Lgr5+ cells in which it mediates canonical cyclic (c) GMP-dependent signaling. Endoplasmic reticulum (ER) stress, typically absent from ISCs, was elevated throughout the crypt base in Gucy2c-/- mice. The chemical chaperone tauroursodeoxycholic acid resolved this ER stress and restored the balance of ISCs, an effect mimicked by the GUCY2C effector 8Br-cGMP. Reduced ISCs in Gucy2c-/- mice was associated with greater epithelial injury and impaired regeneration following sub-lethal doses of irradiation. These observations suggest that GUCY2C provides homeostatic signals that modulate ER stress and cell vulnerability as part of the machinery contributing to the integrity of ISCs. PMID- 29262535 TI - Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers. AB - Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR's target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. We found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively - xenobiotics) and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases. PMID- 29262536 TI - Delineating the distinct role of AKT in mediating cell survival and proliferation induced by CD154 and IL-4/IL-21 in chronic lymphocytic leukemia. AB - The functional significance of AKT in chronic lymphocytic leukemia (CLL) remains unclear. Given the importance of non-malignant T cells in regulating clonal expansion in CLL, we investigated the role of AKT in T cell-mediated cytoprotection and proliferation using an established co-culture system in which primary CLL cells were incubated on a monolayer of transfected mouse fibroblasts expressing human CD40L (CD154). Stimulation of CLL cells via CD40 induced activation of AKT, which was closely associated with downregulation of its negative regulator PTEN, and protected CLL cells from killing by bendamustine. This cytoprotective effect of CD40 stimulation was prevented by a selective inhibitor of AKT. Stimulation of CLL cells with CD154 + IL-4 or IL-21 induced proliferation detected as reduced fluorescence of cells pre-stained with CFSE. AKT inhibition produced a significant, consistent reduction in proliferation induced by CD154 + IL-4 and a reduction in proliferation induced by CD154 + IL-21 in most but not all cases. In contrast, AKT inhibition had no effect on the proliferation of normal B cells induced by CD154 + IL-4 or IL-21. These findings indicate that AKT contributes in a significant way to T-cell mediated survival and proliferation signalling in CLL and support the clinical evaluation of AKT inhibitors in this disease. PMID- 29262537 TI - Efficacy and toxicity of image-guided intensity-modulated radiation therapy combined with dose-escalated brachytherapy for stage IIB cervical cancer. AB - Considering internal organ motion and tumor regression, it is controversial to use intensity-modulated radiation therapy (IMRT) in definitive radiotherapy for cervical cancer. In this study, we evaluated the efficacy and toxicity of IMRT combined with dose-escalated intracavitary brachytherapy (ICBT) for cervical cancer. In total, 373 consecutive FIGO-stage-IIB cervical cancer patients treated with IMRT combined with ICBT and concurrent chemotherapy were included in this study. A dose of 50.4 Gy in 28 fractions was delivered to the pelvis for IMRT. Weekly cone-beam computed tomography or daily megavoltage computed tomography was used for image guiding. For ICBT, 30-36 Gy in five to seven fractions were prescribed to point A. All patients received concurrent chemotherapy. The median follow-up duration was 32.5 months (range, 3.1-119.8 months). The three-year overall survival, disease-free survival and local control rates were 87.5%, 82.2% and 92.5%, respectively. Sixty patients (16.1%) experienced treatment failure, including 23 patients (6.2%) with pelvic relapse. The incidences of >=grade 3 chronic gastrointestinal and genitourinary toxicity were 2.7% and 2.4%, respectively. These findings indicate that image-guided IMRT combined with dose escalated ICBT results in good survival with acceptable toxicity in stage IIB cervical cancer patients. PMID- 29262538 TI - Alpha-ketoglutarate suppresses the NF-kappaB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway. AB - Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-kappaB)-mediated inflammatory pathway and pregnane X receptor (PXR) regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-kappaB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro. Thus dietary AKG supplementation reversed the adverse effects induced by LPS. We also found a strong inhibitory effects on the NF-kappaB-mediated inflammatory pathway, especially, in the AKG-treated intestinal tissues, LPS-induced NF-kappaB phosphorylation was inhibited and TNF-alpha was suppressed. Interestingly, AKG has potent effects in regulating the PXR and its downstream targets such as CYP3As and CYP2Bs in vivo and in vitro, although AKG is not a known PXR ligand. One potential mechanism for the up-regulation of the PXR pathway is through the down-regulation of NF-kappaB pathway which in turn de-represses the PXR-regulated target expression. Taken together, our results suggest that AKG improves intestinal immune system through modulating the interaction between PXR and NF kappaB. Our findings have important implications for the prevention and treatment of intestinal inflammatory diseases in neonates. PMID- 29262539 TI - Panax notoginseng saponins mitigate cisplatin induced nephrotoxicity by inducing mitophagy via HIF-1alpha. AB - We investigated the role of HIF-1alpha in the mitigation of cisplatin-induced nephrotoxicity by Panax notoginseng saponins (PNS) in a rat model. Serum creatinine (Scr), blood urea nitrogen (BUN) and urinary N-acetyl-beta-D glucosaminidase (NAG) levels were all elevated in cisplatin treated rats. PNS reduced Scr, BUN and NAG levels in the presence or absence of the HIF-1alpha inhibitor 2-methoxyestradiol (2ME2). PNS also reduced the high tubular injury scores, which corresponded to renal tubular damage in cisplatin-treated rats and which were exacerbated by 2ME2. Renal tissues from PNS-treated rats showed increased HIF-1alpha mRNA and nuclear localized HIF-1alpha protein. Moreover, PNS treatment increased BNIP3 mRNA as well as LC3-II, BNIP3 and Beclin-1 proteins and the LC3-II/LC3-I ratio in rat renal tissues. This suggested that PNS treatment enhanced HIF-1alpha, which in turn increased autophagy. This was confirmed in transmission electron micrographs of renal tissues that showed autophagosomes in PNS-treated renal tissues. These findings demonstrate that PNS mitigates cisplatin-induced nephrotoxicity by enhancing mitophagy via a HIF 1alpha/BNIP3/Beclin-1 signaling pathway. PMID- 29262540 TI - LincRNA FEZF1-AS1 contributes to the proliferation of LAD cells by silencing p57 expression. AB - LincRNA FEZF1-AS1 has been identified to exert oncogenic functions in various biological processes of tumorigenesis. However, the function of FEZF1-AS1 in lung adenocarcinoma still remains unclear. Our findings revealed that FEZF1-AS1 was increased in lung adenocarcinoma tissues and cell lines and high level of FEZF1 AS1 was associated with poor prognosis of lung adenocarcinoma. Functional experiments and mechanistic investigations demonstrated that knockdown of FEZF1 AS1 significantly repressed proliferation through influencing the distribution of cell cycle. Besides, we also uncovered that FEZF1-AS1 could suppress p57 expression through recruiting EZH2 and LSD1 to the promoter of p57, thus influenced the cell cycle and proliferation. Collectively, our results suggested that FEZF1-AS1 was involved in the progression of lung adenocarcinoma and might be as a potential therapy target for human lung adenocarcinoma. PMID- 29262541 TI - Sustained activation of the AKT/mTOR and MAP kinase pathways mediate resistance to the Src inhibitor, dasatinib, in thyroid cancer. AB - New targeted therapies are needed for advanced thyroid cancer. Our lab has shown that Src is a key mediator of tumorigenic processes in thyroid cancer. However, single-agent Src inhibitors have had limited efficacy in solid tumors. In order to more effectively target Src in the clinic, our lab has previously generated four thyroid cancer cell lines that are resistant to dasatinib through gradual dose escalation. We further tested two additional Src inhibitors and shown the dasatinib-resistant (DasRes) cells exhibit cross-resistance to saracatinib, but are sensitive to bosutinib, suggesting that unique off-targets of bosutinib play an important role in mediating sensitivity to bosutinib. To identify the kinases targeted by dasatinib and bosutinib, we utilized an unbiased compound centric chemical proteomics screen. We identified 33 kinases that were enriched in the bosutinib pull down. Using the STRING database to map protein-protein interactions of the unique bosutinib targets, we identified a signaling axis which included mTOR, FAK, and MEK. Inhibition of the mTOR, MEK, and Src/FAK nodes simultaneously was the most effective at reducing cell growth and survival. Overall, these studies have identified key mediators of Src inhibitor resistance, and show that targeting these signaling nodes are necessary for anti-tumor efficacy. PMID- 29262542 TI - Identification of SPOP related metabolic pathways in prostate cancer. AB - Speckle-type POZ protein (SPOP), as a cullin-based E3 ubiquitin ligase, has been identified as one of the most frequently mutated genes in prostate cancer (PCa). However, whether SPOP mutations contribute to metabolic reprogramming in PCa remains unknown. Here, integrated studies of transcriptomics and metabolomics as well as lipidomics were performed in matched PCa tumor (PCT) and adjacent non tumor (ANT) tissues, followed by correlation analysis of SPOP mutations with altered metabolic pathways in SPOP-mutated PCa patients. Interestingly, transcriptomics profiling showed that all SPOP mutations (with 16.7% frequency, 11/66) occurred at the conserved residues in the substrate binding domain of meprin and TRAF homology (MATH). The results of integrated analysis indicated that three metabolic pathways, including tricarboxylic acid (TCA) cycle, fatty acid metabolism and glycerophospholipid metabolism, exhibited obvious upregulation in SPOP-mutated PCT tissues. Furthermore, both correlation analyses based on integrated data and cBioportal revealed that FH, ELOVL2 and ACADL genes might be involved in SPOP-mutation-related upregulation of these metabolic pathways. Taken together, our study provided new insights in understanding the relationship between metabolic pathways and SPOP mutations in PCa. PMID- 29262543 TI - Treatment and survival outcomes of lobular carcinoma in situ of the breast: a SEER population based study. AB - Lobular carcinoma in situ (LCIS) represents 5.3% of in situ specimens, and is thought to carry a low risk for developing to the invasive lobular breast cancer (ILC). There is still no standard care approach for patients with LCIS. We aimed to define the impacts of surgical and radiation intervention on survival outcomes of LCIS. LCIS cases from 2004 to 2013 of the recent Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Clinicopathologic features were analyzed in 16002 patients between 2004 and 2013. Treatment modalities included no surgery (NS), lumpectomy alone (LA), lumpectomy with radiation treatment (LRT), mastectomy alone (MA) and mastectomy with radiation treatment (MRT). The overall survival (OS) was calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the variables of treatment, race, hormone receptor status, grade and age. Among 16002 patients, median follow-up was 54 months. Patients treated with LA had superior OS for NS (P = 0.001), MA (P < 0.001) and MRT P = 0.018). LRT only had superior OS for MRT (P = 0.009). There was no statistically significance between LA and LRT (P = 0.317). Improved OS was also correlated with younger age (P < 0.001), progesterone receptor positive (P = 0.001). Black patients had the worst OS (P < 0.001). There was no obvious survival difference among grade groups (P = 0.536). The LCIS patients treated with LA or LRT had better survival comparing with other groups. Considering the medical expense and the risk of radiotherapy, LA may be the most appropriate therapy for patients with LCIS. PMID- 29262544 TI - Optimization of EGFR mutation detection by the fully-automated qPCR-based Idylla system on tumor tissue from patients with non-small cell lung cancer. AB - Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lung cancer who have known EGFR mutations. Currently, patient care has to respond to several imperatives to make these inhibitors broadly available to all patients; fast and accurate detection of EGFR mutations by a sensitive and specific standardized cost-effective method, easy-to-implement in settings with limited expertise in molecular diagnostics. We evaluated the IdyllaTM EGFR Mutation Assay (Biocartis) for the detection of EGFR mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples from a series of 55 patients with lung adenocarcinoma and compared these results with those obtained by a pyrosequencing ISO-15189 accredited laboratory method. The comparison was made on both whole surgical tumor sections and on three artificially constructed small biopsies (~1 mm) from the same FFPE blocks. Cost-effectiveness and turnaround time comparison between the two methods was performed. On both whole tissue sections and on biopsy cores, the IdyllaTM and pyrosequencing had an agreement of 95% (52/55). The IdyllaTM EGFR Assay produced results faster and more cost-effective than pyrosequencing. The IdyllaTM system showed a good sensitivity and was cost-saving in our setting. Because of the easy workflow, the IdyllaTM system has the potential to expand EGFR testing to more pathology laboratories in a reliable and fast manner. PMID- 29262545 TI - Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma. AB - SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC. PMID- 29262546 TI - Neutrophil-to-lymphocyte ratio predicts survival in European patients with hepatocellular carcinoma administered sorafenib. AB - : Neutrophil-to-lymphocyte ratio (NLR) is considered a prognostic factor in patients with hepatocellular carcinoma (HCC). Our aim is to investigate the prognostic significance of NLR in patients with HCC treated with sorafenib. Results: Median follow-up time was 7 months. Patients were mostly in the intermediate (27.3%) or advanced (72.7%) BCLC stages, 38.6% had vascular invasion and 27.5% extrahepatic disease. A large proportion (38.9%) had been previously treated with TACE. Liver function was preserved: 65.8% were classed as Child A. Median overall survival was 7.7 months (95% CI: 5.8-9.6). In univariate analysis, vascular invasion (P = 0.004), ECOG-PS >= 1 (P < 0.001), high bilirubin (P < 0.001), clinical ascites (P = 0.036), BCLC stage (P = 0.004), no previous TACE (P = 0.041) and NRL >= 2.3 (P = 0.005) were predictors of poor survival. Skin toxicity (P = 0.039) or hypertension (P = 0.033) during treatment were related to better survival. In multivariate analysis NLR >= 2.3 [HR 1.72 (95% CI: 1.03 2.71)], hyperbilirubinemia [HR 3.42 (95% CI: 1.87-6.25)] and ECOG-PS >= 1 [HR 1.97 (95% CI: 1.19-3.26)] were found as independent indicators of poor overall survival. Dermatologic adverse effects were an indicator of good overall survival [HR 0.59 (95% CI: 0.38-0.92)]. Material and Methods: One hundred and fifty-four consecutive HCC patients treated with sorafenib in four different Spanish hospitals between August 2005 and October 2013 were analysed. Clinical, laboratory, and tumour features were obtained. Survival was calculated from the moment sorafenib treatment was initiated. Log-rank and Cox regression were used to analyse the ability of NLR to predict survival. Conclusions: NLR is an independent prognostic indicator for overall survival in HCC patients treated with sorafenib. PMID- 29262547 TI - Crotonoside exhibits selective post-inhibition effect in AML cells via inhibition of FLT3 and HDAC3/6. AB - Targeted therapies for the treatment of acute myeloid leukemia (AML), specifically the FLT3 inhibitors, have shown promising results. Nevertheless, it is very unlikely that inhibitors which target a single pathway will provide long term disease control. Here, we report the characterization of crotonoside, a natural product extracted from Chinese medicinal herb, Croton, for the treatment of AML via inhibition of FLT3 and HDAC3/6. In vitro, crotonoside exhibited selective inhibition in AML cells. In vivo, crotonoside treatment at 70 and 35 mg/kg/d produced significant AML tumor inhibition rates of 93.5% and 73.6%, respectively. Studies on the anti-AML mechanism of crotonoside demonstrated a significant inhibition of FLT3 signaling, cell cycle arrest in G0/G1 phase, and apoptosis. In contrast to classic FLT3 inhibitor; sunitinib, crotonoside was able to selectively suppress the expression of HDAC3 and HDAC6 without altering the expression of other HDAC isoforms. Inhibitors of HDAC3 and HDAC6; RGFP966 and HPOB, respectively, also exhibited selective inhibition in AML cells. Furthermore, we established novel signaling pathways including HDAC3/NF-kappaB p65 and HDAC6/c-Myc besides FLT3/c-Myc which are aberrantly regulated in the progression of AML. In addition, crotonoside alone or the combination of sunitinib/RFP966/HPOB exhibited a significant post-inhibition effect in AML cells by the inhibition of FLT3 and HDAC3/6. Inhibitors targeting the FLT3 and HDAC3/6 might provide a more effective treatment strategy for AML. Taken together, the present study suggests that crotonoside could be a promising candidate for the treatment of AML, and deserves further investigations. PMID- 29262548 TI - A framework for exploring associations between biomedical terms in PubMed. AB - Co-occurrence relationships in PubMed between terms accelerate the recognition of term associations. The lack of manually curated relationships in vocabularies and the rapid increase of biomedical literatures highlight the importance of co occurrence relationships. Here we proposed a framework to explore term associations based on a standard procedure that comprises multiple tools of text mining and relationship degree calculation methods. The text of PubMed were segmented into sentences by Apache OpenNLP first, and then terms of sentences were recognized by MGREP. After that two terms occurring in a common sentence were identified as a co-occurrence relationship. The relationship degree is then calculated using Normalized MEDLINE Distance (NMD) or relationship-scaled score (RSS) method. The framework was utilized in exploring associations between terms of Gene Ontology (GO) and Disease Ontology (DO) based on co-occurrence relationship. Results show that pairs of terms with more co-occurrence relationships indicate shared more semantic relationships of ontology and genes. The identified association terms based on co-occurrence relationships were applied in constructing a disease association network (DAN). The small giant component confirms with the observation that diseases in the same class have more linkage than diseases in different classes. PMID- 29262549 TI - Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand therapy. AB - Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis of and therapy for metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to measure overall-survival (OS) in mCRPC patients who received either abiraterone or enzalutamide prior to PSMA therapy. The second aim of this study was to analyse the predictors of OS according to different pre therapeutic parameters and also the responses to the first cycle of radioligand therapy (RLT) base on PSA level. Patients with mCRPC and a history of therapy with either abiraterone or enzalutamide or both, were included in this study. Different laboratory tests and pre-therapeutic parameters have been included into the analysis. One-hundred patients received a total of 347 cycles of Lu-PSMA (median: three cycles). 69 patients showed a decline in PSA two months after the first cycle, and 38 of those patients showed a PSA decline of = > 50%. The median OS was 60 weeks. In the multivariate analysis, the level of albumin, AST and haemoglobin, existence of liver metastases and a decline of > 14% in PSA level had a significant impact on overall-survival. The median OS is significantly longer in patients without hepatic involvement, with high levels of albumin and Hb and low levels of AST. A decline in PSA levels of more than 14% was the most important response parameter with regard to overall survival. PMID- 29262550 TI - Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. AB - Background: Nivolumab offers a superior survival benefit over docetaxel in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). An association between programmed cell death ligand-1 (PD-L1) expression and the efficacy of nivolumab has been reported in many studies. However, the association between the clinical parameters and efficacy of nivolumab remains unclear in advanced NSCLC patients. Results: Among 124 patients, 108 (88%) were performance status (PS) 0 to 1. PD-L1 expression was assessed in 89 patients, with 51 (57%) patients having PD-L1 positive expression. In all patients, the objective response rate (ORR) in patients with elevated CRP levels (>= 1 mg/dl) was significantly worse than those without elevated CRP levels (< 1 mg/dl) (8.3 vs 23.4%, p = 0.0180). The PS (>= 2), smoking index (< 400), CRP levels (>= 1 mg/dl) and LDH (>= 245 IU/L) were significantly associated with a shorter PFS and OS in patients treated with nivolumab. Multivariate analyses showed that the PS (>= 2), smoking index (< 400), CRP levels (>= 1 mg/dl) and LDH (>= 245 IU/L) and PD-L1 expression were significant factors associated with a longer PFS of nivolumab. Materials and Methods: We retrospectively analyzed 124 patients who received nivolumab as a subsequent treatment. The patient characteristics, laboratory data at baseline (C-reactive protein [CRP] and lactate dehydrogenase [LDH]), PD-L1 expression, nivolumab response, progression-free survival (PFS), and overall survival (OS) were evaluated. Conclusions: Clinical parameters, such as PS, serum CRP, serum LDH, and smoking status, were significantly associated with the response duration and survival in patients treated with nivolumab. PMID- 29262551 TI - The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy. AB - The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm3: untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient. PMID- 29262552 TI - Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B. AB - Abnormalities in cancer metabolism represent potential targets for cancer therapy. We have recently identified a natural compound Quambalarine B (QB), which inhibits proliferation of several leukemic cell lines followed by cell death. We have predicted ubiquinone binding sites of mitochondrial respiratory complexes as potential molecular targets of QB in leukemia cells. Hence, we tracked the effect of QB on leukemia metabolism by applying several omics and biochemical techniques. We have confirmed the inhibition of respiratory complexes by QB and found an increase in the intracellular AMP levels together with respiratory substrates. Inhibition of mitochondrial respiration by QB triggered reprogramming of leukemic cell metabolism involving disproportions in glycolytic flux, inhibition of proteins O-glycosylation, stimulation of glycine synthesis pathway, and pyruvate kinase activity, followed by an increase in pyruvate and a decrease in lactate levels. Inhibition of mitochondrial complex I by QB suppressed folate metabolism as determined by a decrease in formate production. We have also observed an increase in cellular levels of several amino acids except for aspartate, indicating the dependence of Jurkat (T-ALL) cells on aspartate synthesis. These results indicate blockade of mitochondrial complex I and II activity by QB and reduction in aspartate and folate metabolism as therapeutic targets in T-ALL cells. Anti-cancer activity of QB was also confirmed during in vivo studies, suggesting the therapeutic potential of this natural compound. PMID- 29262553 TI - Inhibition of PTEN activity aggravates cisplatin-induced acute kidney injury. AB - Cisplatin (cis-Diamminedichloroplatinum II) has been widely and effectively used in chemotherapy against tumors. Nephrotoxicity due to cisplatin is one of the most common clinical causes of acute kidney injury (AKI), which has a poor prognosis and high mortality. The signaling mechanisms underlying cisplatin induced AKI are not completely understood. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor that negatively regulates the cell survival pathway and is considered a double-edged sword in organ damage. In this study, we examined the effect that inhibiting PTEN activity in experimental models of cisplatin-induced AKI had on the degrees of AKI. Compared with vehicle mice, mice treated with bpV(pic) (specific inhibitor of PTEN) had exacerbated renal damage due to cisplatin-induced AKI. Furthermore, inhibition of PTEN activity increased cell apoptosis in the kidneys of mice induced by cisplatin. More inflammatory cytokines were activated after cisplatin treatment in mice of the bpV(pic)-treated group compared with vehicle mice, and these inflammatory cytokines may be partially derived from bone marrow cells. In addition, inhibiting PTEN activity decreased the phosphorylation of p53 in the pathogenesis of cisplatin-induced AKI. In summary, our study has demonstrated that inhibiting PTEN activity aggravates cisplatin-induced AKI via apoptosis, inflammatory reaction, and p53 signaling pathway. These results indicated that PTEN may serve as a novel therapeutic target for cisplatin-induced AKI. PMID- 29262554 TI - Cucurbitacin B and SCH772984 exhibit synergistic anti-pancreatic cancer activities by suppressing EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling. AB - Cucurbitacin B (CuB) is a natural tetracyclic triterpene product and displays antitumor activity across a wide array of cancers. In this study, we explored the anti-pancreatic cancer activity of CuB alone and in combination with SCH772984, an ERK inhibitor, in vitro and in vivo. CuB inhibited proliferation of pancreatic cancer cells by arresting them in the G2/M cell cycle phase. This was associated with inhibition of EGFR expression and activity and downstream signaling, including PI3K/Akt/mTOR and STAT3. Interestingly, ERK activity was markedly enhanced by activating AMPK signaling after 12 h of CuB treatment. SCH772984 potentiates the cytotoxic effect of CuB on pancreatic cancer cells through complementary inhibition of EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling, followed by an increase in the pro-apoptotic protein Bim and a decrease in the anti-apoptotic proteins Mcl-1, Bcl-2, Bcl-xl and survivin. Furthermore, combined therapy with CuB and SCH772984 resulted in highly significant growth inhibition of pancreatic cancer xenografts. These results may provide a basis for further development of combining CuB and ERK inhibitors to treat pancreatic cancer. PMID- 29262555 TI - A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment. AB - Production of metastasis capable precursors begins within the primary tumor. Here, we define the bidirectional interactions with stromal cells involved in promoting these precursors within BRCA1-IRIS (hereafter IRIS) overexpressing (IRISOE) TNBC tumors. We define an aggressiveness niche, functionally defined as the necrotic/hypoxic core of the tumor, in which metabolically stressed, hypoxic, and inflamed IRISOE TNBC cells secrete higher levels of cytokines, chemokines and growth factors. One cytokine; IL-1beta attracts mesenchymal stem cells (MSCs) to the niche and activates them to secrete CXCL1 that entrains IRISOE cells to secrete higher levels of CCL2 and VEGF. CCL2 attracts macrophages (TAMs) to the niche and activates them to secrete S100A8, and VEGF attracts endothelial cells (ECs) and activates them to secrete IL-8. In concert, CXCL1, S100A8 and IL-8 entrain aggressiveness in IRISOE TNBC cells within the niche. Indeed, compared to IRISOE cells alone, tumors developed by co-injecting IRISOE cells admixed with MSCs (10:1) in athymic mice were bigger and more aggressive. They contained more TAMs and ECs, expressed higher-levels of basal, epithelial to mesenchymal transition, and stemness biomarkers, quickly progressed to lymph-node or visceral metastases, and were highly sensitive to the IL-1beta inhibitor "Anakinra". Our findings supported by human data show that breast cancer patients with high levels of IL-1beta, CXCL1, CCL2, S100A8, VEGF, and IL-8 would show worse clinical outcomes. Our findings argue that this cytokine set is a diagnostic biomarker for patients who may benefit from an IRIS inhibitor-based therapy, and is a blue print for translation of approaches to combining that therapy with inhibitors of these bidirectional interactions to overcome TNBC metastasis. PMID- 29262556 TI - PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors. AB - Thyroid carcinomas are the most prevalent endocrine cancers. The BRAFV600E mutation is found in 40% of the papillary type and 25% of the anaplastic type. BRAFV600E inhibitors have shown great success in melanoma but, they have been, to date, less successful in thyroid cancer. About 50% of anaplastic thyroid carcinomas present mutations/amplification of the phosphatidylinositol 3' kinase. Here we propose to investigate if the hyper activation of that pathway could influence the response to BRAFV600E specific inhibitors. To test this, we used two mouse models of thyroid cancer. Single mutant (BRAFV600E) mice responded to BRAFV600E-specific inhibition (PLX-4720), while double mutant mice (BRAFV600E; PIK3CAH1047R) showed resistance and even signs of aggravation. This resistance was abrogated by combination with a phosphoinositide 3-kinase inhibitor. At the molecular level, we showed that this resistance was concomitant to a paradoxical activation of the MAP-Kinase pathway, which could be overturned by phosphoinositide 3-kinase inhibition in vivo in our mouse model and in vitro in human double mutant cell lines. In conclusion, we reveal a phosphoinositide 3 kinase driven, paradoxical MAP-Kinase pathway activation as mechanism for resistance to BRAFV600E specific inhibitors in a clinically relevant mouse model of thyroid cancer. PMID- 29262557 TI - Characteristic proteins in the plasma of postoperative colorectal and liver cancer patients with Yin deficiency of liver-kidney syndrome. AB - Systems biology and bioinformatics provide the feasibility for the basic research associated with "same traditional Chinese medicine (TCM) syndrome in different diseases". In this study, the plasma proteins in postoperative colorectal (PCC) and postoperative liver cancer (PLC) patients with YDLKS (Yin deficiency of liver kidney syndrome) were screened out using iTRAQ combined with LC-MS/MS technology. The results demonstrated that, KNG1, AMBP, SERPING1, etc, were all differentially expressed in both PCC and PLC patients with YDLKS, and associated closely with complement and coagulation cascades pathway. C7 and C2 were another two representative factors involving in former pathway. Further validation showed that, the C7 levels were increased significantly in PLC (P < 0.05) and PCC (P < 0.05) with YDLKS group compared to those of NS (no obvious TCM syndromes) group. The AMBP levels were down-regulated significantly in PLC with YDLKS group compared to those of PCC with YDLKS group (P < 0.05). The significant differences of SERPING1 levels (and C2 levels) were shown between YDLKS and NS in PCC (P < 0.01). There were also significant differences of C2 levels between PCC and PLC patients with YDLKS (P < 0.05). Moreover, significant differences of C2 levels were also found between PLC and PCC patients with YDLKS (P < 0.01). ROC curves indicated that, C7 and SERPING1 independently had a potential diagnostic value in distinguishing YDLKS from NS in PLC and PCC, providing the evidences for the material basis of "same TCM syndrome in different diseases" in PCC and PLC patients with YDLKS. PMID- 29262558 TI - Deletion or inhibition of soluble epoxide hydrolase protects against brain damage and reduces microglia-mediated neuroinflammation in traumatic brain injury. AB - Traumatic brain injury (TBI) induces a series of inflammatory processes that contribute to neuronal damage. The present study investigated the involvement of soluble epoxide hydrolase (sEH) in neuroinflammation and brain damage in mouse TBI and in microglial cultures. The effects of genetic deletion of sEH and treatment with an sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), on brain damage and inflammatory responses were evaluated in mice subjected to controlled cortical impact. The anti-inflammatory mechanism of sEH inhibition/deletion was investigated in vitro. TBI-induced an increase in sEH protein level in the injured cortex from 1 h to 4 days and sEH was expressed in microglia. Genetic deletion of sEH significantly attenuated functional deficits and brain damage up to 28 days post-TBI. Deletion of sEH also reduced neuronal death, apoptosis, brain edema, and BBB permeability at 1 and 4 day(s). These changes were associated with markedly reduced microglial/macrophage activation, neutrophil infiltration, matrix metalloproteinase-9 activity, inflammatory mediator expression at 1 and 4 day(s), and epoxyeicosatrienoic acid (EET) degradation at 1 and 4 day(s). Administration of AUDA attenuated brain edema, apoptosis, inflammatory mediator upregulation and EET degradation at 4 days. In primary microglial cultures, AUDA attenuated both LPS- or IFN-gamma-stimulated nitric oxide (NO) production and reduced LPS- or IFN-gamma-induced p38 MAPK and NF-kappaB signaling. Deletion of sEH also reduced IFN-gamma-induced NO production. Moreover, AUDA attenuated N2A neuronal death induced by BV2 microglial-conditioned media. Our results suggest that inhibition of sEH may be a potential therapy for TBI by modulating the cytotoxic functions of microglia. PMID- 29262559 TI - MiR-129 blocks estrogen induction of NOTCH signaling activity in breast cancer stem-like cells. AB - Stem-like cells in tumor group featured the major role in the chemotherapy resistance of breast cancer, and the reduction of stem-like cells helped to perish the tumor when receiving chemotherapy. Smaller stem cells number indicated better therapeutic effect in vitro and in clinics, but how did miR-129 and Notch signaling function in breast cancer stem-like cells (BrCSCs) were unclear yet. Through using sphere forming assay and FACS sorting, we found that miR-129 decreased the proportion of stem-like cells in breast cancer cells. Results further indicated that miR-129 degraded the Estrogen Receptor 1 (ESR1) mRNA through a post-translational manner and contributed to the decline of stem-like cells number, preventing tumor regeneration. Cyclin d1 and DICER 1 were proved to promote Let-7 maturation, and in present study, we proved that miR-129 exhibited inhibition on ESR1 and halted the cyclin d1/DICER 1 sustaining of Let-7, which consequently released the Let-7 degradation of NUMB. The restoration of suppressive NUMB by upregulating miR-129 resulted in NOTCH signaling inhibition. In conclusion, we demonstrated the negative regulation of miR-129 on NOTCH signaling activation in BrCSCs' renewal, which was achieved via continuous suppression on cyclin d1/DICER1 sustaining of Let-7 level, and eventually rescued the targeted inhibition of NUMB. The miR-129/ESR1 signaling played pivotal role in controlling DICER1/Let-7/NOTCH cascade via cyclin d1, revealing the novel mechanism of dual Let-7 in non-coding genes network. PMID- 29262560 TI - Bone marrow fibrosis in chronic myelomonocytic leukemia is associated with increased megakaryopoiesis, splenomegaly and with a shorter median time to disease progression. AB - Bone marrow (BM) fibrosis is an adverse prognostic marker in several myeloid neoplasms, particularly in myelodysplastic syndrome (MDS) with fibrosis; however, its significance in chronic myelomonoctyic leukemia (CMML) has not been evaluated. We performed a retrospective analysis to investigate the prognostic and clinicopathological features of CMML with and without BM fibrosis. The study included specimens from a total of 83 untreated CMML patients from 2 large institutions. Patients with any amount of BM fibrosis (MF-1 or higher; MF1+) had significantly shorter progression-free survival (MF1+, 28.3 months vs MF0, not reached; p = 0.001, log rank test), splenomegaly (p = 0.016), and increased BM megakaryocytes (p = 0.04) compared to patients without BM fibrosis (MF-0). No association was observed between fibrosis and peripheral blood parameters, presence of JAK2 V617F mutation, BM blasts, or overall survival. Our study demonstrates the importance of assessing BM fibrosis in CMML. Similar to MDS, the presence of BM fibrosis may identify a distinct subgroup of CMML patients (CMML F) with a more aggressive clinical course. PMID- 29262561 TI - Anti-NY-ESO-1 autoantibody may be a tumor marker for intrahepatic cholangiocarcinoma. AB - Anti-NY-ESO-1 antibody is observed in a multitude of malignancies. This study was aimed to evaluate the expression of serum anti-NY-ESO-1 antibodies and its prognostic value in intrahepatic cholangiocarcinoma. A total of 103 patients with intrahepatic cholangiocarcinoma were enrolled in the study. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the serum level of anti-NY ESO-1 antibody. Western blotting was performed to assess the NY-ESO-1 expression in tumor and adjacent tissues. The serum NY-ESO-1 antibody was detected in 18.4% of patients with intrahepatic cholangiocarcinoma, a value that was significantly higher than that in patients with chronic Hepatitis B. Serum NY-ESO-1 antibody was positively correlated with tumor differentiation, lymphatic metastasis, cTNM stage and abdominal pain. Finally, there was a higher cumulative survival rate in patients with serum NY-ESO-1 positivity than in those with serum NY-ESO-1 negativity among the patients with stage III + IV. Our data uncovered that NY-ESO 1 antibody might be a helpful tumor marker and prognostic predictor in intrahepatic cholangiocarcinoma. PMID- 29262562 TI - Characterization of plasma proteins in children of different Mycobacterium tuberculosis infection status using label-free quantitative proteomics. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is an infectious disease found worldwide. Children infected with MTB are more likely to progress to active TB (ATB); however, the molecular mechanism behind this process has long been a mystery. We employed the label-free quantitative proteomic technology to identify and characterize differences in plasma proteins between ATB and latent TB infection (LTBI) in children. To detect differences that are indicative of MTB infection, we first selected proteins whose expressions were markedly different between the ATB and LTBI groups and the control groups (inflammatory disease control (IDC) and healthy control (HC) groups). A total of 521 proteins differed (> 1.5-fold or < 0.6-fold) in the LTBI group, and 318 proteins in the ATB group when compared with the control groups. Of these, 49 overlapping proteins were differentially expressed between LTBI and ATB. Gene Ontology (GO) analysis revealed most proteins had a cellular and organelle distribution. The MTB infection status was mainly related to differences in binding, cellular and metabolic processes. XRCC4, PCF11, SEMA4A and ATP11A were selected and further verified by qPCR and western blot. At the mRNA level, the expression of XRCC4, PCF11and SEMA4A presented an increased trend in ATB group compare with LTBI. At the protein level, the expression of all these proteins by western blot in ATB/LTBI was consistent with the trends from proteomic detection. Our results provide important data for future mechanism studies and biomarker selection for MTB infection in children. PMID- 29262563 TI - Regulation of epithelial-mesenchymal transition and metastasis by TGF-beta, P bodies, and autophagy. AB - Processing bodies (P-bodies) are ribonucleoprotein complexes involved in post transcriptional mRNA metabolism that accumulate in cells exposed to various stress stimuli. The treatment of mammary epithelial cells with transforming growth factor-beta (TGF-beta), triggers epithelial-mesenchymal transition (EMT), and induces the formation of P-bodies. Ectopic expression of the transcription factor TWIST, which stimulates EMT downstream of the TGF-beta receptor, also promotes P-body formation. Removal of TGF-beta from treated cells results in the clearance of P-bodies by a process that is blocked by inhibitors of autophagy. Activators of autophagy enhance P-body clearance and block EMT. Blockage of P body formation by disruption of the gene for DDX6, a protein essential for P-body assembly, blocks EMT and prevents tumor cell metastasis in vivo. These studies suggest critical roles for P-body formation and autophagy in transitions of cancer cells between epithelial and mesenchymal phenotypes and help explain how autophagy functions to promote or suppress tumor cell growth during different stages of tumorigenesis. PMID- 29262564 TI - Plasmatic miR-210, miR-221 and miR-1233 profile: potential liquid biopsies candidates for renal cell carcinoma. AB - Renal cell carcinoma (RCC) represents a challenge for clinicians since the nonexistence of screening and monitoring tests contributes to the fact that one third of patients are diagnosed with metastatic disease and 20-40% of the remaining patients will also develop metastasis. Modern medicine is now trying to establish circulating biomolecules as the gold standard of biomarkers. Among the molecules that can be released from tumor cells we can find microRNAs. The aim of this study was to evaluate the applicability of cancer-related miR-210, miR-218, miR-221 and miR-1233 as prognostic biomarkers for RCC. Patients with higher levels of miR-210, miR-221 and miR-1233 presented a higher risk of specific death by RCC and a lower cancer-specific survival. The addition of miR-210, miR-221 and miR-1233 plasma levels information improved the capacity to predict death by cancer in 8, 4% when compared to the current variables used by clinicians. We also verified that hypoxia stimulates the release of miR-210 and miR-1233 from HKC-8, RCC-FG2 and 786-O cell lines. These results support the addition of circulating microRNAs as prognostic biomarkers for RCC. PMID- 29262565 TI - A prognostic 4-gene expression signature for patients with HER2-negative breast cancer receiving taxane and anthracycline-based chemotherapy. AB - Breast cancer is a heterogeneous group of diseases with diverse clinicopathological and molecular features. At present, chemo-resistance still poses a major obstacle to successful treatment of HER-2 negative breast cancer. Reliable biomarkers are urgently needed to accurately predict the therapeutic sensitivity and prognosis of such patients. In this study, we identified 3145 distant relapse-free survival (DRFS) associated genes in 310 patients with HER-2 negative breast cancer receiving taxane and anthracycline-based chemotherapy in the GSE25055 dataset using univariate survival analysis. Four genes (SRPK1, PCCA, PRLR and FBP1) were further selected by a robust likelihood-based survival model. A risk score model was then constructed with the regression coefficients of the four signature genes. Patients in the training set were successfully divided into high- and low-risk groups with significant differences in DRFS between the two groups. The predictive value was further validated in GSE25065 dataset and similar results were observed. Moreover, the 4-gene signature was proved to have superior prognostic power compared with several clinical signatures such as tumor size, lymph node invasion, TNM stage and PAM50 signature. Our findings indicated that the 4-gene signature was a robust prognostic marker with a good prospect of clinical application for HER-2 negative breast cancer patients receiving taxane anthracycline combination therapy. PMID- 29262566 TI - Characterization of epithelial-mesenchymal transition intermediate/hybrid phenotypes associated to resistance to EGFR inhibitors in non-small cell lung cancer cell lines. AB - Increasing evidence points to a key role played by epithelial-mesenchymal transition (EMT) in cancer progression and drug resistance. In this study, we used wet and in silico approaches to investigate whether EMT phenotypes are associated to resistance to target therapy in a non-small cell lung cancer model system harboring activating mutations of the epidermal growth factor receptor. The combination of different analysis techniques allowed us to describe intermediate/hybrid and complete EMT phenotypes respectively in HCC827- and HCC4006-derived drug-resistant human cancer cell lines. Interestingly, intermediate/hybrid EMT phenotypes, a collective cell migration and increased stem-like ability associate to resistance to the epidermal growth factor receptor inhibitor, erlotinib, in HCC827 derived cell lines. Moreover, the use of three complementary approaches for gene expression analysis supported the identification of a small EMT-related gene list, which may have otherwise been overlooked by standard stand-alone methods for gene expression analysis. PMID- 29262567 TI - HNRNPK inhibits gastric cancer cell proliferation through p53/p21/CCND1 pathway. AB - Gastric cancer (GC) is one of the most common human cancers. The molecular mechanisms underlying GC carcinogenesis and progression are still not well understood. In this study, we showed that heterogeneous nuclear ribonucleoprotein K (HNRNPK) was an effective prognostic marker for GC patients especially in early stage. Overexpression of HNRNPK can retard tumor cell proliferation and colony formation in vitro and inhibit tumor growth in vivo through p53/p21/CCND1 axis. Bioinformatics analyses indicated that HNRNPK associated genes were enriched in cell cycle and DNA replication process. Protein-protein interaction network showed that HNRNPK was physically interacted with p53, p21 and other cancer related genes. Besides, GSEA showed that HNRNPK expression was positively correlated with GAMMA radiation response and DNA repair, while negatively correlated with angiogenesis, TGF-beta and Hedgehog pathway activation. Finally, several chemicals including Glycine that may repress GC progression through upregulating HNRNPK are suggested. Our study demonstrated that HNRNPK may play as a tumor suppressor in gastric cancer and could be a potential therapeutic target for GC. PMID- 29262568 TI - Prioritizing chronic obstructive pulmonary disease (COPD) candidate genes in COPD related networks. AB - Chronic obstructive pulmonary disease (COPD) is a multi-factor disease, which could be caused by many factors, including disturbances of metabolism and protein protein interactions (PPIs). In this paper, a weighted COPD-related metabolic network and a weighted COPD-related PPI network were constructed base on COPD disease genes and functional information. Candidate genes in these weighted COPD related networks were prioritized by making use of a gene prioritization method, respectively. Literature review and functional enrichment analysis of the top 100 genes in these two networks suggested the correlation of COPD and these genes. The performance of our gene prioritization method was superior to that of ToppGene and ToppNet for genes from the COPD-related metabolic network or the COPD-related PPI network after assessing using leave-one-out cross-validation, literature validation and functional enrichment analysis. The top-ranked genes prioritized from COPD-related metabolic and PPI networks could promote the better understanding about the molecular mechanism of this disease from different perspectives. The top 100 genes in COPD-related metabolic network or COPD-related PPI network might be potential markers for the diagnosis and treatment of COPD. PMID- 29262569 TI - Evaluation of the association of UBASH3A and SYNGR1 with rheumatoid arthritis and disease activity and severity in Han Chinese. AB - Rheumatoid arthritis (RA) is a common complex autoimmune disorder. UBASH3A and SYNGR1 were identified recently as susceptibility genes for RA risk in Korean and European populations, but the genetic aetiology and pathogenesis of RA have not been fully elucidated. We designed a two-stage case-control study including 916 RA patients and 2,266 unrelated healthy controls to identify common genetic variants in UBASH3A and SYNGR1 that predispose Han Chinese individuals to RA. We also evaluated the role of associated variants in clinical manifestations of RA, which may provide clues to the mechanisms involved in the aetiology of RA. We successfully identified two SNPs, rs1893592 in UBASH3A and rs909685 in SYNGR1, as significantly associated with the disease status of RA using our two-stage strategy. The rs1893592 SNP in UBASH3A was related with DAS28, CRP level and bone erosion. In summary, our results indicate that genetic variants in UBASH3A and SYNGR1 may modify individual susceptibility to RA in the Han Chinese population and support the role of the UBASH3A gene in RA disease activity and severity. PMID- 29262570 TI - DanHong injection targets endothelin receptor type B and angiotensin II receptor type 1 in protection against cardiac hypertrophy. AB - Cardiac hypertrophy (CH) is an independent risk factor for cardiovascular diseases (CVDs). Mitigating or preventing CH is the most effective strategy for the treatment of CVDs. DanHong injection (DH) is a Chinese herbal medicine preparation (CHMP) widely used in clinical treatment of several CVDs in China. However, the direct targets and cellular mechanisms for these protective effects remain unclear. This study was designed to illustrate the direct targets of DH in protecting against CH and investigate CH molecular pathogenesis. A hypertrophic cell model was induced by endothelin-1 (ET-1) on human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Real time cellular analysis (RTCA) cardio system and high content analysis (HCA) were used to detect the changes in contractile function, morphology and protein level of hypertrophic hiPS-CMs. Agonist and antagonist assay on receptors were performed using calcium mobilization high-throughput screening (HTS). DH significantly attenuated CH by modulating myocardial contractility, suppressing cell area enlargement and down regulating ET-1-induced brain natriuretic peptide (BNP), actinin alpha 2 (ACTN2) and cardiac muscle troponin T (TNNT2) protein expression (P < 0.05). Endothelin receptor type B (ETBR) and angiotensin II receptor type 1 (AT1R) were DH direct targets, with IC50 value of 25.67 MUL/mL and 1.10 MUL/mL, respectively. Proteomics analysis showed that proteins involved in cell cycle inhibition, RNA processing, mitochondrial translation and cytoskeleton are significant regulated by DH treatment. These data revealed that ETBR and AT1R are DH direct targets on protecting against CH, providing a strategy to explore direct targets of CHMPs. PMID- 29262571 TI - Ovarian cancer variant rs2072590 is associated with HOXD1 and HOXD3 gene expression. AB - Ovarian cancer (OC) is a common cancer in women and the leading cause of deaths from gynaecological malignancies in the world. In addition to the candidate gene approach to identify OC susceptibility genes, the genome-wide association study (GWAS) methods have reported new variants that are associated with OC risk. The minor allele of rs2072590 at 2q31 was associated with an increased OC risk, and was primarily significant for serous subtype. The OC risk-associated SNP rs2072590 lies in non-coding DNA downstream of HOXD3 and upstream of HOXD1, and it tags SNPs in the HOXD3 3' UTR. We think that the non-coding rs2072590 variant may contribute to OC susceptibility by regulating the gene expression of HOXD1 and HOXD3. In order to investigate this association, we performed a bioinformatics analysis by a functional annotation of rs2072590 variant using RegulomeDB (version 1.1), HaploReg (version 4.1), and PhenoScanner (version 1.1). Using HaploReg, we identified 19 genetic variants tagged by rs2072590 variant with with r2 >= 0.8. Using RegulomeDB, we identified that three genetic variants are likely to affect TF binding + any motif + DNase Footprint + DNase peak. Other genetic variants are likely to affect TF binding + DNase peak. Using PhenoScanner (version 1.1), we identified that these 19 genetic variants could significantly regulate the expression of nearby genes, especially the HOXD1 and HOXD3 in human ovary tissue. PMID- 29262572 TI - GATA3 frameshift mutation promotes tumor growth in human luminal breast cancer cells and induces transcriptional changes seen in primary GATA3 mutant breast cancers. AB - The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. Heterozygous mutations, mostly frameshifts, are seen in 15% of estrogen receptor positive breast cancers, the subtype in which these mutations are almost exclusively found. Mouse studies have shown that Gata3 is critical for breast development and that GATA3 gene dosage affects breast tumor progression. Human patient data have shown that high Gata3 expression, a feature of luminal subtype breast cancers, is associated with a better prognosis. Although the frequency of GATA3 mutation suggests an important role in breast cancer development or progression, there is little understanding of how mutations in GATA3 affect its function in luminal breast epithelial cells and what gene expression changes result as a consequence of the mutations. Here, using gene editing, we have created two sets of isogenic human luminal breast cancer cell lines with and without a hotspot truncating GATA3 mutation. GATA3 mutation enhanced tumor growth in vivo but did not affect sensitivity to clinically used hormonal therapies or chemotherapeutic agents. We identified genes with upregulated and downregulated expression in GATA3 mutant cells, a subset of which was concordantly differentially expressed in GATA3 mutant primary luminal breast cancers. Addback of mutant GATA3 recapitulated mutation-specific gene expression changes and enhanced soft agar colony formation, suggesting a gain of function for the mutant protein. PMID- 29262573 TI - Differential expression of c-Met between primary and metastatic sites in clear cell renal cell carcinoma and its association with PD-L1 expression. AB - In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials. PMID- 29262574 TI - Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue. AB - Despite intense research, squamous cell carcinoma of the tongue remains a devastating disease with a five-year survival of around 60%. Late detection and recurrence are the main causes for poor survival. The identification of circulating factors for early diagnosis and/or prognosis of cancer is a rapidly evolving field of interest, with the hope of finding stable and reliable markers of clinical significance. The aim of this study was to evaluate circulating miRNAs and proteins as potential factors for distinguishing patients with tongue squamous cell carcinoma from healthy controls. Array-based profiling of 372 miRNAs in plasma samples showed broad variations between different patients and did not show any evidence for their use in diagnosis of tongue cancer. Although one miRNA, miR-150, was significantly down-regulated in plasma from patients compared to controls. Surprisingly, the corresponding tumor tissue showed an up regulation of miR-150. Among circulating proteins, 23 were identified as potential markers of squamous cell carcinoma of the tongue. These findings imply that circulating proteins are a more promising source of biomarkers for tongue squamous cell carcinomas than circulating miRNAs. The data also highlight that circulating markers are not always directly associated with tumor cell properties. PMID- 29262575 TI - The roles of ING5 expression in ovarian carcinogenesis and subsequent progression: a target of gene therapy. AB - Here, we found that ING5 overexpression suppressed cell viability, glucose metabolism, migration, invasion and epithelial-mesenchymal transition, and induced cell arrest, apoptosis, senescence, autophagy and fat accumulation in ovarian cancer cells. ING5-mediated chemoresistance was positively linked to apoptotic resistance and chemoresistance-related gene expression. ING5 overexpression suppressed tumor growth of ovarian cancer by decreasing proliferation, and inducing apoptosis and autophagy. ING5 mRNA level was lower in ovarian cancer than normal ovary, and borderline than benign tumors (p < 0.05), and negatively correlated with vascular invasion, lymphatic invasion and FIGO staging of ovarian cancer (p < 0.05). ING5 protein was less expressed in primary cancer than normal ovary (p < 0.05). There was a negative correlation between ING5 mRNA expression and the overall or progression-free survival time of the cancer patients with Grade 2, Grade 3, and stage I cancer (p < 0.05). Immunohistochemically, ING5 was less expressed in serous and mucinous adenocarcinoma than miscellaneous subtypes, and positively correlated with dedifferentiation and ki-67 expression of ovarian cancer (p < 0.05). These data suggested that down-regulated ING5 expression might be involved in ovarian carcinogenesis possibly by suppressing aggressive phenotypes, including proliferation, tumor growth, migration, invasion, and anti-apoptosis. PMID- 29262576 TI - IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines. AB - The recent RESORCE trial showed that treatment with Regorafenib after Sorafenib failure provided a significant improvement in overall survival in HCC patients. Preclinical and clinical trial data showed that Regorafenib is a more potent drug than Sorafenib. In this study we aimed at improving Regorafenib actions and at reducing its toxicity, by targeting parallel pathways or by combination with Vitamins K (VKs). We investigated the effects of Regorafenib administrated at low concentrations and in combination with either VK1 and/or with GSK1838705A or OSI 906, two IGF1-R inhibitors, on HCC cell growth and motility. Our results showed that both IGF1-R inhibitors potentiated the antiproliferative and pro-apoptotic effects of Regorafenib and/or VK1 in HCC cell lines. Moreover we provide evidence that the combined treatment with IG1-R antagonists and Regorafenib (and/or VK1) also caused a significant reduction and depolymerization of actin resulting in synergistic inhibition exerted on cell migration. Thus, simultaneous blocking of MAPK and PI3K/Akt cascades with IGF1-R inhibitors plus Regorafenib could represent a more potent approach for HCC treatment. PMID- 29262577 TI - The association of triglycerides and total cholesterol concentrations with newly diagnosed diabetes in adults in China. AB - Background: It has already been suggested that high abnormal blood lipid concentration is associated with hyperglycaemia. However, no data is available about the roles of triglycerides (TG) and total cholesterol (TC) levels in diabetes. Here, for the first time we investigated the roles of TG and TC levels, gender and abdominal fat in the development of newly diagnosed diabetes in China. Materials and Methods: Two population-based cross-sectional surveys were conducted from 2006 to 2009 in Qingdao, China. Newly diagnosed diabetes was defined according to FPG and/or 2 h PG criteria. The associations between diabetes and TG, and TC levels were assessed by multi-variable logistic regression models. Results: As compared with non-diabetes, the odds ratio[(95% confidence intervals), OR(95% CI)] for diabetes corresponding to hypertriglyceridemia (HTG) were 1.54 (1.01, 2.35) in men and 2.02 (1.49, 3.10) in women for TG and accompany with Hypercholesterolemia (HTC) 2.93 (1.97, 4.37) and 2.13 (1.49, 3.05) for TC, when both were fitted simultaneously in the model adjusting for age, geographic division, marital status, school years, family history of diabetes, monthly income, systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), high density lipoprotein cholesterol (HDL-C), alanine amino transferase (ALT) and gamma glutamyltransferase (GGT). Conclusions: HTG in both gender, borderline high TC and HTC in men were an independent risk factor for diabetes in this Chinese population, however, HTC was mediated through abdominal fat for diabetes in women. Our findings may help to enhance the current knowledge of diabetes patho physiology, and the associations between TG, TC level and diabetes is also clinically informative. PMID- 29262578 TI - Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice. AB - Activation of cannabinoid receptor type 2 has been shown to have anti-fibrosis function in skin and heart. However, whether activating cannabinoid receptor type 2 inhibits pulmonary fibrosis remains elusive. Lung fibroblasts and TGF-beta1 are key players in the pathogenesis of pulmonary fibrosis. In this research, we aimed to investigate the role of cannabinoid receptor type 2 in pulmonary fibrosis in vitro and in vivo. In lung fibroblasts stimulated by TGF-beta1, preincubated by cannabinoid receptor type 2 agonist JWH133 not only reduced the elevated levels of collagen I and alpha-SMA, but also inhibited fibroblasts' proliferation and migration. The dosage of JWH133 had no clear cytotoxic activity, and all these JWH133 effects were partially abrogated by cannabinoid receptor type 2 antagonist SR144528. In bleomycin-induced mice pulmonary fibrosis model, CT images of the lung tissue revealed an extensive ground-glass opacity, reticular pattern and fibrosis stranding. Notably, JWH133 treatment controlled the ongoing fibrotic process (showed by decreased lung density and fibrosis score). Meanwhile, lung histological results revealed that JWH133 treatment suppressed both the inflammatory response and extracellular collagen deposition. SR144528 may increase the pulmonary fibrosis, but no statistically significant difference was proved. Importantly, JWH133 reduced serum profibrotic cytokines levels of TGF beta1 and inhibited TGF-beta1/Smad2 pathway in vitro and in vivo. Our research indicated that activating cannabinoid receptor type 2 by a pharmacological method might be a potential strategy for pulmonary fibrosis. PMID- 29262580 TI - Solanum incanum extract (SR-T100) induces melanoma cell apoptosis and inhibits established lung metastasis. AB - Melanoma, a cancer derived from melanocytes, is one of the most chemoresistant cancers and tends to metastasize. Once it metastasizes, the prognosis is poor. Even with the recent advancement of targeted therapy and immunotherapy, the prognosis remains discouraging. SR-T100, a Solanum incanum extract, shows anticancer effects against several cancers; however, its therapeutic efficacy against melanoma and established metastasis remains unknown. In this study, we showed that SR-T100 induces apoptosis, DNA damage, and G0/G1 cell cycle arrest in murine B16 melanoma cells in vitro. In vivo, intralesional injection of SR-T100 decreased the tumor size of the regional melanoma in the foot pad. Moreover, intraperitoneal injection of SR-T100 inhibited the growth and the number of established melanoma metastases in the lungs. Our study highlights SR-T100 as a potential novel treatment for established tumors from regional and metastatic melanoma. PMID- 29262579 TI - The association of IL-17A polymorphisms with IL-17A serum levels and risk of ischemic stroke. AB - The aim of our study was to investigate the association of interleukin-17A (IL 17A) polymorphisms with IL-17A serum levels and risk of ischemic stroke (IS) in a Chinese population. 392 IS patients and 443 controls were included in this study. The polymorphisms of IL-17A gene were determined by Snapshot SNP genotyping assay and DNA sequencing. Serum IL-17A levels were measured by enzyme-linked immunosorbent assay (ELISA). We found that the G allele, GA and GG genotypes, and GA/GG vs. AA model of rs2275913 polymorphism were associated with increased risk of IS even after adjusted by clinical characters such as age, gender and diabetes (G vs. A: OR=1.27, 95% CI, 1.05~1.54, P=0.014; GA vs. AA: OR=1.72, 95% CI, 1.05~2.81, P=0.032; GG vs. AA: OR=1.99, 95% CI, 1.08~3.67, P=0.028; GA/GG vs. AA: OR=1.78, 95% CI, 1.11~2.86, P=0.017). Serum IL-17A levels were increased in IS patients compared with controls (P<0.01). Individuals carrying rs2275913 GA or GG genotype present higher serum IL-17A levels compared with the rs2275913AA genotype in the IS group (P<0.01). In conclusion, this is the first study reporting the rs2275913 polymorphism as a risk factor for IS, which may be partly explained by influencing the levels of IL-17A cytokine. PMID- 29262581 TI - Marital status and survival in patients with non-small cell lung cancer: an analysis of 70006 patients in the SEER database. AB - Marital status has been demonstrated to be related to the survival of patients in various cancer types, but the relationship in the large population of non-small cell lung cancer (NSCLC) has rarely been studied. In this study, we retrospectively extracted 70006 eligible NSCLC patients from the Surveillance, Epidemiology, and End Results (SEER) database in the period from 2004 to 2012. Marital status was categorized as married, divorced/separated, widowed, and never married. Chi-square tests were used to investigate the association between marital status and other variables. The Kaplan-Meier test was adopted to compare survival curves of different groups. Multivariate Cox regression analyses were conducted to estimate the effect of marital status on overall survival (OS) and NSCLC cause-specific survival (CSS). We further performed subgroup analyses according to TNM stage and surgery condition. The results showed that marital status was an independent prognostic factor for OS and CSS of NSCLC patients. Subgroup analyses showed that the relationship between marital status and prognosis varies according to different conditions. Widowed patients with surgery were at greater risk of death across all stages and non-surgical unmarried patients at advanced stages suffered poorer prognosis than the married. To conclude, in the NSCLC patients, married patients had advantage over the unmarried in both OS and CSS. PMID- 29262582 TI - A novel inflammation-based prognostic index for patients with esophageal squamous cell carcinoma: neutrophil lymphocyte ratio/albumin ratio. AB - Background: We initially proposed a novel inflammation-based prognostic index, named neutrophil lymphocyte ratio/albumin ratio (NLR/Alb), for predicting the postoperative survival in esophageal squamous cell carcinoma (ESCC). Materials and methods: A retrospective study of 329 cases with resectable ESCC was included. The optimal cut-off values were evaluated by X-tile program. The 5-year cancer-specific survival (CSS) was calculated by Kaplan-Meier method. Cox regression analyses were performed to evaluate the prognostic factors. Results: The optimal cut-off value was 0.1 for NLR/Alb according to the X-tile program. There was a significantly better 5-year CSS in patients with NLR/Alb <= 0.1 than patients with NLR/Alb > 0.1 (39.1% vs. 11.0%, P < 0.001). According to multivariate analyses, NLR/Alb (P = 0.001) was an independent prognostic factor. Conclusions: The NLR/Alb is a novel and usefull predictive factor in patients with ESCC. PMID- 29262583 TI - Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer. AB - Objective: Protein disulfide isomerase (PDI) is an oxidoreductase that is overexpressed in several cancers. PDI family members (PDIs) play a role in various diseases including cancer. Select PDIs were reported as useful markers in other cancers but their expression in ovarian cancer has not been thoroughly assessed. We sought to evaluate the expression of PDI, PDIA6, PDIR, ERp57, ERp72 and AGR3 in ovarian cancer patient samples and examine their prognostic significance. Methods: TMA samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of PDI family proteins using IHC. Results: We observed significant increases in PDI (p = 9.16E-36), PDIA6 (p = 5.51E-33), PDIR (p = 1.81E-12), ERp57 (p = 9.13E-07), ERp72 (p = 3.65E-22), and AGR3 (p = 4.56E-24) expression in ovarian cancers compared to normal tissues. Expression of PDI family members also increases during disease progression (p <0.001). All PDI family members are overexpressed in serous ovarian cancer (p<0.001). However, PDI, PDIA6, PDIR, ERp72 and AGR3 are more significantly overexpressed (p<0.001) than ERp57 (p<0.05) in clear cell ovarian carcinoma. Importantly, overexpression of PDI family members is associated with poor survival in ovarian cancer (p = 0.045 for PDI, p = 0.047 for PDIR, p = 0.037 for ERp57, p = 0.046 for ERp72, p = 0.040 for AGR3) with the exception of PDIA6 (p = 0.381). Conclusions: Our findings demonstrate that select PDI family members (PDI, PDIR, ERp72, ERp57 and AGR3) are potential prognostic markers for ovarian cancer. PMID- 29262584 TI - CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer. AB - Worldwide, gastric cancer is one of the most fatal cancers. Epigenetic alterations in gastric cancer play important roles in silencing of tumor suppressor genes. We previously found that CXXC finger protein 4 (CXXC4) was a novel tumor suppressor in gastric cancer. In this report, we demonstrated that CXXC4 inhibited growth of gastric cancer cells as a pro-apoptotic factor. This inhibition could be reversed by the pan-caspase inhibitor called Z-VAD-FMK. However, CXXC4 with mutations in its DNA binding domain failed to induce apoptosis. Growth differentiation factor 15 (GDF15) was identified as one of potential targets responsible for CXXC4-induced apoptosis. CXXC4 activated GDF15 transcription through enhancing the interaction of transcription factor Sp1 with GDF15 promoter. In summary, the nuclear protein CXXC4 activated apoptosis in gastric cancer through up-regulating its novel potential downstream target GDF15. GDF15 might be a promising target for clinical treatment of gastric cancer with CXXC4 deficiency. PMID- 29262585 TI - STAT3-mediated activation of miR-21 is involved in down-regulation of TIMP3 and neovascularization in the ischemic retina. AB - Retinal neovascularization (RNV) is a sight threatening complication of ischemic retinopathies with limited therapeutic options. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been shown to play a crucial role in promoting RNV. However, manipulating of STAT3 activity can cause significant adverse side effects due to its neurotrophic properties. In this study, we identified microRNA-21 (miR-21) as a downstream effector of STAT3 activity in the ischemic retinas and determined its role in promoting RNV through inhibition of its molecular target, the tissue inhibitor of matrix metalloproteinases 3 (TIMP3). Using human retinal endothelial cells (HREC) exposed to hypoxia and a mouse model of oxygen-induced retinopathy (OIR), we found that TIMP3 expression was significantly decreased at both mRNA and protein levels and this paralleled the activation of STAT3 and up-regulation of miR-21. Moreover, TIMP3 expression was restored by knockdown of STAT3 or blocking of miR 21 in HREC, thus, confirming TIMP3 as a downstream target of STAT3/miR-21 pathway. Finally, in a mouse model of OIR, blockade of miR-21 by a specific antisense (a.miR-21), halted RNV and this effect was associated with rescuing of TIMP3 expression. Our data show that miR-21 mediates STAT3 pro-angiogenic effects in the ischemic retina, thus suggesting its blockade as a potential therapy to prevent/halt RNV. PMID- 29262586 TI - Human papillomavirus type 18 E5 oncogene supports cell cycle progression and impairs epithelial differentiation by modulating growth factor receptor signalling during the virus life cycle. AB - Deregulation of proliferation and differentiation-dependent signalling pathways is a hallmark of human papillomavirus (HPV) infection. Although the manipulation of these pathways by E6 and E7 has been extensively studied, controversies surround the role of the E5 oncoprotein during a productive virus life cycle. By integrating primary keratinocytes harbouring wild type or E5 knockout HPV18 genomes with pharmacological and gain/loss of function models, this study aimed to provide molecular information about the role of E5 in epithelial proliferation and differentiation. We show that E5 contributes to cell cycle progression and unscheduled host DNA synthesis in differentiating keratinocytes. E5 function correlates with increased EGFR activation in differentiating cells and blockade of this pathway impairs differentiation-dependent cell cycle progression of HPV18 containing cells. Our findings provide a functional requirement of enhanced EGFR signalling for suprabasal cellular DNA synthesis during the virus life cycle. They also reveal an unrecognised contribution of E5 towards the impaired keratinocyte differentiation observed during a productive HPV infection. E5 suppresses a signalling axis consisting of the keratinocyte growth factor receptor (KGFR) pathway. Inhibition of this pathway compensates for the loss of E5 in knockout cells and re-instates the delay in differentiation. The negative regulation of KGFR involves suppression by the EGFR pathway. Thus our data reveal an unappreciated role for E5-mediated EGFR signalling in orchestrating the balance between proliferation and differentiation in suprabasal cells. PMID- 29262587 TI - IL-22 promotes the progression of breast cancer through regulating HOXB-AS5. AB - Interleukin-22 (IL-22) is a well-known tumor related inflammatory factor that is associated with variety of cancers. HOXB-AS5, a long non-coding RNA located in HOX gene clusters, has been elevated in breast cancer (BC) tissues. Herein, IL-22 and HOXB-AS5 were upregulated in the serum and tissues of BC patients and were associated with clinical stages. Furthermore, we also investigated the effects of IL-22-HOXB-AS5 pathway on progression of BC, and the results suggested that IL-22 and HOXB-AS5 synergistically promoted MDA-MB-231 cell growth, migration and invasion and activated the PI3K-AKT-mTOR pathway. These findings demonstrated that the IL-22-HOXB-AS5-PI3K/AKT functional axes may serve as potential molecule biomarkers for diagnosis and therapy evaluation or targeted therapeutic strategy in BC. PMID- 29262588 TI - Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors. AB - mTOR pathway activation and hypervascularity have been identified as important characteristics of pancreatic neuroendocrine tumors (pNETs). Agents targeting angiogenesis and mTOR, such as sunitinib and everolimus (RAD001), have been shown to result in progression-free survival of approximately 11 months in patients with advanced pNETs. Novel treatment is needed to extend survival. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), which is encoded by PCK2, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. PEPCK-M has been demonstrated to potentiate cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK C)-mediated gluconeogenesis and to play a critical role in the survival program initiated upon stress during metabolism in cancer cells. Elevated expression of PCK2 has been found in various tumors according to the results of The Cancer Genome Atlas project. However, the role of PEPCK-M aberration in cancers is not well understood. In the current study, we observed that 12 of 21 (57%) pNET patients had high expression of PEPCK-M in the tumors, whereas the normal islet cells had weak expression of PEPCK-M. Knockdown of PCK2 inhibited the proliferation of pNET cells and enhanced the sensitivity of pNET cells to mTOR inhibitors. Knockdown of PCK2 promoted glycolysis but reduced mitochondrial oxidative phosphorylation in pNET cells. The combination of mTOR inhibitors and an anti-glycolysis agent, 2-DG, synergistically or additively inhibited the proliferation of pNET cells, particularly for the cells with high expression of PEPCK-M. Therefore, targeting PEPCK-M or glycolysis combined with inhibiting mTOR is a potential therapeutic approach for the treatment of pNETs. PMID- 29262589 TI - ABR, a novel inducer of transcription factor C/EBPalpha, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia. AB - Active BCR related (ABR) gene deactivates ras-related C3 botulinum toxin substrate 1 (RAC1), which plays an essential role in regulating normal hematopoiesis and in leukemia. BCR gene, closely related to ABR, acts as a tumor suppressor in chronic myeloid leukemia and has overlapping functions with ABR. Evidence for a putative tumor suppressor role of ABR has been shown in several solid tumors, in which deletion of ABR is present. Our results show downregulation of ABR in AML. A block of ABR prevents myeloid differentiation and leads to repression of the myeloid transcription factor C/EBPalpha, a major regulator of myeloid differentiation and functionally impaired in leukemia. Conversely, stable overexpression of ABR enhances myeloid differentiation. Inactivation of the known ABR target RAC1 by treatment with the RAC1 inhibitor NSC23766 resulted in an increased expression of C/EBPalpha in primary AML samples and in AML cell lines U937 and MV4;11. Finally, AML patients with high ABR expression at diagnosis showed a significant longer overall survival and patients who respond to azacitidine therapy showed a significant higher ABR expression. This is the first report showing that ABR expression plays a critical role in both myelopoiesis and AML. Our data indicate the tumor suppressor potential of ABR and underline its potential role in leukemia therapeutic strategies. PMID- 29262590 TI - Human induced pluripotent stem cell-derived mesenchymal stem cells prevent adriamycin nephropathy in mice. AB - Human induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs) are emerging as attractive options for use in cell replacement therapy, but their effect in kidney diseases remains unknown. Here, we showed that intravenous injection of iPS-MSCs protect against renal function loss in both short-term and long-term models of adriamycin nephropathy (AN). In the short-term AN model, iPS MSCs conferred a substantial anti-apoptotic effect on tubular cells, associated with a downregulation of Bax and Bax/Bcl2 ratio and an upregulation of survivin expression. In vitro, conditioned medium from iPS-MSCs (iPSMSC-CM) significantly limited albumin-induced tubular apoptosis and enhanced tubular proliferation, accompanied by a reduced expression of tubular Bax and an elevated expression of Bcl2 and survivin. Oxidative stress was markedly attenuated by iPS-MSCs both in AN mice and in protein-overloaded tubular cells. In the long-term AN model, repeated injections of iPS-MSCs significantly inhibited tubulointerstitial fibrosis and reduced intrarenal deposition of collagen I, collagen IV and alphaSMA. Modulation of the hedgehog signaling pathway contributed to the anti fibrotic effect of iPS-MSCs in chronic AN. Finally, we detected that most of the infused iPS-MSCs were entrapped in the lungs. In conclusion, our data support a beneficial role of iPS-MSCs in both acute and chronic AN. PMID- 29262591 TI - Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells. AB - Anti-VEGF therapy with Bevacizumab is approved for glioblastoma treatment, however, it is known that tumors acquired resistance and eventually became even more aggressive and infiltrative after treatment. In the present study we aimed to unravel the potential cellular mechanisms of resistance to Bevacizumab in glioblastoma in vitro models. Using a panel of glioblastoma cell lines we found that Bevacizumab is able to block the secreted VEGF by the tumor cells and be internalized to the cytoplasm, inducing cytotoxicity in vitro. We further found that Bevacizumab increases the expression of hypoxic (HIF-1alpha and CAIX) and glycolytic markers (GLUT1 and MCT1), leading to higher glucose uptake and lactate production. Furthermore, we showed that part of the consumed glucose by the tumor cells can be stored as glycogen, hampering cell dead following Bevacizumab treatment. Importantly, we found that this change on the glycolytic metabolism occurs independently of hypoxia and before mitochondrial impairment or autophagy induction. Finally, the combination of Bevacizumab with glucose uptake inhibitors decreased in vivo tumor growth and angiogenesis and shift the expression of glycolytic proteins. In conclusion, we reported that Bevacizumab is able to increase the glucose metabolism on cancer cells by abrogating autocrine VEGF in vitro. Define the effects of anti-angiogenic drugs at the cellular level can allow us to discover ways to revert acquired resistance to this therapeutic approaches in the future. PMID- 29262592 TI - Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer. AB - Background: Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. Results: The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1-70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, P = 0.04). Materials and Methods: We retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed. Conclusions: There are significantly fewer TILs in brain metastases than in primary breast tumors. PMID- 29262593 TI - The shedded ectodomain of Lyve-1 expressed on M2-like tumor-associated macrophages inhibits melanoma cell proliferation. AB - Targeting immune cells that support tumor growth is an effective therapeutic strategy in tumor entities such as melanoma. M2-like tumor-associated macrophages (TAM) sustain tumor growth by secreting anti-inflammatory cytokines, proteases and growth factors. In this study, we show that a protein derived from M2-like macrophages namely the shedded ectodomain of Lyve-1 (sLyve-1) decreases human HT144 and murine B16F1 melanoma cell proliferation significantly by acting as a decoy receptor for low-molecular weight hyaluronic acid (LMW-HA) although the LMW HA/Lyve-1 interaction on lymphatic endothelial cells has been described to induce lymphangiogenesis. This is in line with our finding that the number of LYVE-1+ TAM decreases in higher human melanoma stages and that the early growth of B16 transplant tumors is enhanced in Lyve-1 knockout mice when compared to wild-type mice due to an increased melanoma cell proliferation. LYVE-1 expressing TAM are however true M2 macrophages as they co-express typical M2-markers such as CD163 and CD206. The results of the present study highlight the necessity to carefully determine the net effect particular TAM subpopulations have on tumors before establishing a treatment to target these immune cells. PMID- 29262594 TI - Multi-omics analyses of red blood cell reveal antioxidation mechanisms associated with hemolytic toxicity of gossypol. AB - Gossypol is an antiproliferative drug with limited use due to its hemolytic toxicity. In this study, accelerated hemolysis was observed in the cows treated with gossypol. Comparative metabolomics were used to gain responsive pathways in the red blood cell (RBC) to the treatment, which were crossly validated by parallel iTRAQ-based proteomic analysis and enzyme activity assay. We found that gossypol treatment appeared to considerably activate pentose phosphate pathway (PPP) with an increased key product of ribose-5-phosphate and the increased abundance and activity of several key enzymes such as 6-phosphogluconate dehydrogenase, flavin reductase, and ribose-phosphate pyrophesphokinase. Meanwhile, a decreased glycolysis metabolism was observed, as many input metabolites of glycolysis were reduced in the gossypol group, whereas its distal metabolites were unchanged, along with decreased abundance of triosephosphate isomerase and increased abundance of enzymes catalyzing several distal glycolytic steps. Oxidative reduction pathways were also remarkably affected as we found a decreased substrate of flavin reductase, glutathione disulfide, increased glutathione reductase activity, and increased abundance and activity of glutathione S-transferase with the increase of its catalytic product, cysteine. Our results demonstrated that glycolysis, PPP, and oxidative reduction pathways of RBC were all involved in RBC's response to the hemolytic toxicity of gossypol. PMID- 29262595 TI - Reversion of resistance to oxaliplatin by inhibition of p38 MAPK in colorectal cancer cell lines: involvement of the calpain / Nox1 pathway. AB - Oxaliplatin is a major treatment for metastatic colorectal cancer, however its effectiveness is greatly diminished by the development of resistances. Our previous work has shown that oxaliplatin efficacy depends on the reactive oxygen species (ROS) produced by Nox1. In this report, we investigated Nox1 involvement in the survival mechanisms of oxaliplatin resistant cell lines that we have selected. Our results show that basal ROS production by Nox1 is increased in resistant cells. Whereas the transitory Nox1-dependent production of superoxide contributes to the cytotoxicity of oxaliplatin in sensitive cells, oxaliplatin treatment of resistant cells leads to a decrease in the production of superoxide associated with an increase of H2O2 and a decreased cytotoxicity of oxaliplatin. We have shown that calpains regulate differently Nox1 according to the sensitivity of the cells to oxaliplatin. In sensitive cells, calpains inhibit Nox1 by cleaving NoxA1 leading to a transient ROS production necessary for oxaliplatin cytotoxic effects. In contrast, in resistant cells calpain activation is associated with an increase of Nox1 activity through Src kinases, inducing a strong and maintained ROS production responsible for cell survival. Using a kinomic study we have shown that this overactivation of Nox1 results in an increase of p38 MAPK activity allowing the resistant cells to escape apoptosis. Our results show that the modulation of Nox1 activity in the context of anticancer treatment remains complex. However, a strategy to maximize Nox1 activation while inhibiting the p38 MAPK-dependent escape routes appears to be an option of choice to optimize oxaliplatin efficiency. PMID- 29262596 TI - The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains. AB - Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI 1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains. PMID- 29262597 TI - Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer. AB - The mechanism of Sonic Hedgehog (Shh) pathway activation in non-small cell lung cancer (NSCLC) is poorly described. Using an antibody against the Shh C-terminal domain, we found a small population of Shh-positive (Shh+) cells in NSCLC cells. The objective of this study was to characterize these Shh+ cells. Shh+ and Shh- cells were sorted by using Fluorescence Activated Cell Sorting (FACS) on 12 commercial NSCLC cell lines. Functional analyses on sorted cells were performed with gene expression assays (qRT-PCR and microarray) and cells were treated with cytotoxic chemotherapy and a targeted inhibitor of Shh signaling (GDC0449). We used in vivo models of nude mice inoculated with Shh+ and Shh- sorted cells and drug-treated cells. Finally, we confirmed our results in fresh human NSCLC samples (n=48) paired with normal lung tissue. We found that Shh+ cells produced an uncleaved, full-length Shh protein detected on the membranes of these cells. Shh+ cells exerted a paracrine effect on Shh- cells, inducing their proliferation and migration. Shh+ cells were chemo-resistant and showed features of cancer stem cells (CSCs) in vitro and in vivo. Pharmacological inhibition of the Shh pathway suppressed their CSC features. A high percentage of Shh+ cells was associated with poor prognosis in early-stage NSCLC patients. In conclusion, we describe for the first time the presence of an abnormal membrane-bound full-length Shh protein in human cancer cells that allows the identification of CSCs in vitro and in vivo. PMID- 29262598 TI - Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model. AB - Folate impacts the genome and epigenome by feeding into one-carbon metabolism to produce critical metabolites, deoxythymidine monophosphate and s adenosylmethionine. The impact of folate exposure and intervention timing on cancer progression remains controversial. Due to polyamine metabolism's extraordinary biosynthetic flux in prostate cancer (CaP) we demonstrated androgen stimulated CaP is susceptible to dietary folate deficiency. We hypothesized dietary folate levels may also affect castration recurrent CaP. We used the CWR22 human xenograft model which recurs following androgen withdrawal. Engrafted mice were fed a folate depleted or supplemented diet beginning at androgen withdrawal, or prior to xenograft implantation. Both folate depletion and supplementation at the time of withdrawal significantly decreased recurrence incidence. Folate supplementation prior to xenograft implantation increased time to recurrence, suggesting a protective role. By contrast, folate depleted recurrent tumors exhibited transcriptional adaptive responses that maintained high polyamine levels at the expense of increased DNA damage and DNA methylation alterations. Mining of publically available data demonstrated folate related pathways are exceptionally dysregulated in human CaP, which correlated with decreased time to biochemical recurrence. These findings highlight the potential for novel therapeutic interventions that target these metabolic pathways in CaP and provide a rationale to apply such strategies alongside androgen withdrawal. PMID- 29262599 TI - Fusion of the genes ataxin 2 like, ATXN2L, and Janus kinase 2, JAK2, in cutaneous CD4 positive T-cell lymphoma. AB - Acquired mutations were recently described in cutaneous T-cell lymphomas for the JAK1, JAK3, STAT3, and STAT5B genes of the JAK-STAT pathway. In the present study, RNA-sequencing of a primary cutaneous CD4 positive T-cell lymphoma carrying a three-way t(9;13;16)(p24;q34;p11) chromosome translocation showed that JAK2 from chromosome band 9p24 was rearranged and fused to a novel partner gene, ATXN2L, from 16p11. RT-PCR together with Sanger sequencing verified the presence of the ATXN2L-JAK2 fusion transcript. The ATXN2L-JAK2 fusion gene would code for a chimeric protein containing all domains of ATXN2L and the catalytic domain of the JAK2 tyrosine kinase. The ATXN2L-JAK2 chimeric protein could lead to constitutive activation of the downstream JAK-STAT signaling pathway in a manner similar to that seen for other JAK2 fusion proteins. PMID- 29262600 TI - SAMMSON drives the self-renewal of liver tumor initiating cells through EZH2 dependent Wnt/beta-catenin activation. AB - Liver cancer is one of the most serious cancers all over the world. Liver tumor initiating cells (TICs) account for tumor initiation and metastasis. However, the regulatory mechanism of liver TICs remains unclear. Here we found long noncoding RNA SAMMSON is highly expressed in liver cancer and liver TICs. SAMMSON silenced cells show impaired self-renewal capacity, while, its overexpression induces enhanced self-renewal. SAMMSON drives the activation of Wnt/beta-catenin signaling, and thus promotes liver TIC self-renewal. SAMMSON interacts with EZH2, a core component of PRC2 complex, and inhibits the expression of CTNNBIP1 through EZH2 dependent manner. SAMMSON binds to CTNNBIP1 promoter and recruits EZH2 to CTNNBIP1 promoter. What's more, targeting liver TICs through SAMMSON, EZH2 and Wnt/beta-catenin signaling impaired liver TIC self-renewal, decreased tumor propagation and severity. Taken together, SAMMSON drives liver TIC self-renewal through EZH2-dependent Wnt/beta-catenin activation. PMID- 29262601 TI - Ruxolitinib combined with vorinostat suppresses tumor growth and alters metabolic phenotype in hematological diseases. AB - JAK-2 dysregulation plays an important role as an oncogenic driver, and is thus a promising therapeutic target in hematological malignancies. Ruxolitinib is a pyrrolo[2.3-d]pyrimidine derivative with inhibitory activity against JAK1 and JAK2, moderate activity against TYK2, and minor activity against JAK3. Vorinostat is an HDAC inhibitor that reduces JAK-2 expression, thus affecting JAK-2 mRNA expression and increasing JAK-2 proteasomal deterioration. Here we hypothesized that the combination of ruxolitinib and vorinostat could have synergistic effects against hematological disease. We tested combinations of low doses of ruxolitinib and vorinostat in 12 cell lines, and observed highly synergistic cytotoxic action in six cell lines, which was maintained for up to 120 h in the presence of stromal cells. The sensitivity of the six cell lines may be explained by the broad effects of the drug combination, which can affect various targets. Treatment with the combination of ruxolitinib and vorinostat appeared to induce a possible reversal of the Warburg effect, with associated ROS production, apoptotic events, and growth inhibition. Decreased glucose metabolism may have markedly sensitized the six more susceptible cell lines to combined treatment. Therapeutic inhibition of the JAK/STAT pathway seems to offer substantial anti tumor benefit, and combined therapy with ruxolitinib and vorinostat may represent a promising novel therapeutic modality for hematological neoplasms. PMID- 29262602 TI - Dihydroartemisinin inhibits EMT induced by platinum-based drugs via Akt-Snail pathway. AB - Artemisinin and its derivatives exhibit a high activity against a range of cancer cell types both in vitro and in vivo. In clinical practice, platinum-based anti cancer chemotherapy is widely used to treat tumors. However, a large proportion of patients receiving these treatments will relapse because of metastasis and drug resistance. The purpose of this study is to explore the combinational anti metastatic effect of platinum-based drugs and dihydroartemisinin (DHA). Both DDP and oxaliplatin (OXA) at low doses could induce epithelial-mesenchymal transition (EMT) in HCC. Meanwhile, co-administration of DHA could enhance DDP and OXA chemosensitivity in HCC and reverse drug resistance. DHA reversed the morphological changes induced by DDP or OXA and reversed the changes in EMT biomarkers induced by DDP and OXA in HCC in vitro and in vivo via AKT-Snail signaling. DHA significantly increased platinum-based drug sensitivity and suppressed EMT induced by platinum-based drugs via AKT-Snail signaling in HCC. DHA is expected to become the new adjuvant for chemotherapy. PMID- 29262603 TI - LINE-1 couples EMT programming with acquisition of oncogenic phenotypes in human bronchial epithelial cells. AB - Although several lines of evidence have established the central role of epithelial-to-mesenchymal-transition (EMT) in malignant progression of non-small cell lung cancers (NSCLCs), the molecular events connecting EMT to malignancy remain poorly understood. This study presents evidence that Long Interspersed Nuclear Element-1 (LINE-1) retrotransposon couples EMT programming with malignancy in human bronchial epithelial cells (BEAS-2B). This conclusion is supported by studies showing that: 1) activation of EMT programming by TGF-beta1 increases LINE-1 mRNAs and protein; 2) the lung carcinogen benzo(a)pyrene coregulates TGF-beta1 and LINE-1 mRNAs, with LINE-1 positioned downstream of TGF beta1 signaling; and, 3) forced expression of LINE-1 in BEAS-2B cells recapitulates EMT programming and induces malignant phenotypes and tumorigenesis in vivo. These findings identify a TGFbeta1-LINE-1 axis as a critical effector pathway that can be targeted for the development of precision therapies during malignant progression of intractable NSCLCs. PMID- 29262604 TI - Is there a difference in testosterone levels and its regulators in men carrying BRCA mutations? AB - Background: Male BRCA mutation carriers are at risk for an early onset aggressive prostate cancer. No data exist on the association of testosterone levels among these patients. We aimed to analyze testosterone and associated hormonal levels among male BRCA carriers and non-carriers. Patients and methods: Overall 87 male carriers and 43 non-carriers aged 40-70 were prospectively enrolled. Clinical data were collected and all patients were tested for total testosterone (TT), prostate specific antigen (PSA), follicle stimulating hormone (FSH), luteinizing hormone (LH), free androgen index (FAI), sex hormone binding globulin (SHBG) and prolactin. Multivariate linear regression analysis was performed to predict TT levels. Results: The median age, mean BMI, comorbidities, PSA, FSH, LH and SHBG levels in both groups were similar. However, mean TT and FAI were higher in the carriers (16.7 nmol/l vs 13.5 nmol/l, p=0.03 and 39.5 vs 34.8, p=0.05, respectively), while prolactin was significantly lower. Multivariate analysis demonstrated that while BMI was inversely correlated to TT levels in both groups, LH was a predictor only in non-carriers. Conclusions: Carriers have higher TT and FAI levels and lower prolactin levels; but LH does not predict their TT levels. Further research in a larger cohort of BRCA carriers with and without prostate cancer should be performed. PMID- 29262605 TI - Interaction and joint effect of ALT and chronic liver disease on liver cancer in type 2 diabetes patients. AB - Background: This study examined whether serum alanine transaminase (ALT) and chronic liver diseases were interactively, jointly, or independently associated with hepatocellular carcinoma (HCC) risk in type 2 diabetic patients. Materials and Methods: A retrospective cohort study was conducted in 46,369 Chinese type 2 diabetic patients, aged 30 and older, in National Diabetes Care Management Program in 2002-2004. These data were analyzed by multivariate Cox proportional hazards models. Results: Mean follow-up period was 8.20 years. Multivariate adjusted hazard ratios of HCC were 2.85 (95% confidence interval, CI: 2.45-3.31), 3.80 (3.04-4.76), and 3.89 (3.08-4.91) for patients with a level of ALT 40-80, 80 120, and >120 U/L, respectively, compared with patients with a level of ALT < 40 U/L after multivariable adjustment. Significant hazard ratios of HCC for patients with a level of ALT >= 40 U/L and alcoholic liver damage, nonalcoholic fatty liver disease, liver cirrhosis, hepatitis B virus and hepatitis C virus infection, or any one of these chronic liver diseases compared with patients with ALT level < 40 U/L and no counterpart comorbidity were observed. Significant effect modifications were observed between ALT level with liver cirrhosis and HBV. Conclusions: Results suggest significant effect modification and joint associations of ALT >= 40 U/L and chronic liver diseases. Diabetes care should provide lifestyle or treatment interventions to manage ALT level, liver cirrhosis and hepatitis B virus infection for reducing burden of HCC. PMID- 29262606 TI - Elevated serum urate is a potential factor in reduction of total bilirubin: a Mendelian randomization study. AB - Aim: A Mendelian randomization study (MRS) can be linked to a "natural" randomized controlled trial in order to avoid potential bias of observational epidemiology. We aimed to study the possible association between serum urate (SU) and total bilirubin (TBIL) using MRS. Materials and Methods: An observational epidemiological study using ordinary least squares (OLS) regression and MRS using two-stage least square (TLS) regression was conducted to assess the effect of SU on TBIL. The comparison between the OLS regression and the TLS regression was analyzed by the Durbin-Hausman test. If the p value is significant, it suggests that the OLS regression cannot evaluate the relationship between exposure and outcome, and the TLS regression is precise; while if the p value is not significant, there would be no significant difference between the two regressions. Results: A total of 3,753 subjects were analyzed. In OLS regression, there was no significant association between SU and TBIL in all subjects and subgroup analysis (all p > 0.05). However, MRS revealed a negative correlation between SU and TBIL after adjustment for confounders (beta = -0.021, p = 0.010). Further analysis was conducted in different SU subgroups, and results show that elevated SU was associated with a significant reduction in TBIL after adjustment for hyperuricemic subjects (beta = -0.053, p = 0.027). In addition, the results using the Durbin-Hausman test further confirmed a negative effect of SU on TBIL (p = 0.002 and 0.010, respectively). Conclusions: This research shows for the first time that elevated SU was a potential causal factor in the reduction of TBIL and it provides strong evidence to resolve the controversial association between SU and TBIL. PMID- 29262607 TI - Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD). AB - ZB716 is a selective estrogen receptor downregulator (SERD) with excellent oral bioavailability and superior efficacy. In this study, we investigate the in vitro and in vivo metabolism and the pharmacokinetics of ZB716 by incubation with liver microsomes, liver cytosol, and by orally dosing rodents. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem +mass spectrometry. The metabolic profile of ZB716 showed fulvestrant and ZB716 sulfone as the two major oxidative metabolites. ZB716 also underwent some degree of sulfation and glucuronidation in vitro. The major oxidative metabolites of ZB716 were found in rat plasma, feces, and urine samples. No sulfation and glucuronidation metabolites from ZB716 were found in plasma. Limited amounts of sulfate conjugates and glucuronides of ZB716 were detected in feces. The glucuronidation on 3-OH position of fulvestrant was the main metabolite found in urine, suggesting that this specific site of phase 2 metabolism is blocked in ZB716 and formation of glucuronide 3-fulvestrant must be preceded by metabolic transformation of ZB716 to fulvestrant. The pharmacokinetic study of ZB716 showed a half-life (t1/2) at 17.03 hour, the area under curve value (AUC) of 1451.82 ng/ml*h, and the maximum plasma concentration (Cmax) at 158.12 ng/mL reached at 2 h after a single dose of 10 mg/kg by oral gavage. Overall this study elucidated important metabolic characteristics of ZB716, an oral SERD that has demonstrated superior bioavailability and efficacy in preclinical studies conducted so far. PMID- 29262608 TI - "Paradoxical" findings of tumor vascularity and oxygenation in recurrent glioblastomas refractory to bevacizumab. AB - Anti-angiogenic therapy induces the apparent normalization of vascular structure, decreases microvessel density (MVD), and improves tumor oxygenation in glioblastomas (GBMs). Six initial and recurrent tumor pairs after bevacizumab (Bev) treatment were compared with GBMs from nine patients resected under neoadjuvant Bev treatment with regard to histological characteristics; MVD; MIB-1 index; and expression of vascular endothelial growth factor (VEGF) and its receptors, hypoxia markers (hypoxia-inducible factor 1 alpha, carbonic anhydrase 9), and nestin as a marker of glioma stem-like cells. In recurrent tumors post Bev treatment, while the MVD remained low compared with the paired initial tumors (pre-Bev tumors), the expression of hypoxic markers were increased and were even higher in expression compared with the paired pre-Bev tumors in three of the six cases. MIB-1 indices were similar among the initial GBMs, neoadjuvant group, and recurrent tumors post-Bev treatment. The nestin-positive cell ratio of the post Bev recurrent tumors was as high as that of the pre-Bev tumors. The expression of VEGF and VEGFR1 was increased in the post-Bev recurrent tumors in three and four cases, respectively, compared with the paired pre-Bev tumors. In the majority of Bev-refractory GBMs, tumor hypoxia was present with a paradoxical decrease in MVD. These findings suggest that re-activation of tumor angiogenesis is not initially involved in the acquisition of resistance to Bev. PMID- 29262609 TI - Autocrine hGH stimulates oncogenicity, epithelial-mesenchymal transition and cancer stem cell-like behavior in human colorectal carcinoma. AB - Tumor derived human growth hormone (hGH) has been implicated in cancer development and progression. However, the specific functional role of autocrine/paracrine hGH in colorectal cancer (CRC) remains largely to be determined. Herein, we demonstrated a crucial oncogenic role of autocrine hGH in CRC progression. Elevated hGH expression was detected in CRC compared to normal colorectal tissue, and hGH expression in CRC was positively associated with tumor size and lymph node metastasis. Forced expression of hGH stimulated cell proliferation, survival, oncogenicity and epithelial to mesenchymal transition (EMT) of CRC cells, and promoted xenograft growth and local invasion in vivo. Autocrine hGH expression in CRC cells stimulated the activation of the ERK1/2 pathway, which in turn resulted in increased transcription of the mesenchymal marker FIBRONECTIN 1 and transcriptional repression of the epithelial marker E CADHERIN. The autocrine hGH-stimulated increase in CRC cell proliferation, cell survival and EMT was abrogated upon ERK1/2 inhibition. Furthermore, autocrine hGH stimulated CRC cell migration and invasion was dependent on the ERK1/2-mediated increase in FIBRONECTIN 1 expression and decrease in E-CADHERIN expression. Forced expression of hGH also enhanced CSC-like behavior of CRC cells, as characterized by increased colonosphere formation, ALDH-positive population and CSC marker expression. Autocrine hGH-enhanced cancer stem cell (CSC)-like behavior in CRC cells was also observed to be E-CADHERIN-dependent. Thus, autocrine hGH plays a critical role in CRC progression, and inhibition of hGH could be a promising targeted therapeutic approach to limit disease progression in metastatic CRC patients. PMID- 29262610 TI - Identifying key regulating miRNAs in hepatocellular carcinomas by an omics' method. AB - The miRNAs play important regulating roles in the pathogenesis of hepatocellular carcinoma (HCC). To uncover key regulating miRNAs in HCC that were neglected by traditional analyzing methods of transcriptomics data, we proposed a novel molecular-network-based omics' (MNBO) method. With this method, we predicted HCC regulating miRNAs, and confirmed the role of a novel miR-590-3P/EED axis by a clinical study and in vitro, in vivo wet-experiments. The miR-590-3P is significantly down-regulated in HCC patients. And low level of miR-590-3P in HCC is associated with poor prognosis of patients. In HCC cell lines, the miR-590-3P suppressed cell proliferation by inhibiting the transformation G1 phase to S phases of the cell cycle. Moreover, the miR-590-3P inhibited migration and invasion of HCC cells. Further investigations indicated that miR-590-3P play its roles by inhibiting polycomb protein EED. The experiments in animal model implied miR-590-3P could be a potential therapeutic agent for HCC in the future. In conclusion, the discovery of miR-590-3P revealed the MNBO would be a useful strategy to uncover key regulating miRNAs in HCC. PMID- 29262611 TI - PARP inhibition causes premature loss of cohesion in cancer cells. AB - Poly(ADP-ribose) polymerases (PARPs) regulate various aspects of cellular function including mitotic progression. Although PARP inhibitors have been undergoing various clinical trials and the PARP1/2 inhibitor olaparib was approved as monotherapy for BRCA-mutated ovarian cancer, their mode of action in killing tumour cells is not fully understood. We investigated the effect of PARP inhibition on mitosis in cancerous (cervical, ovary, breast and osteosarcoma) and non-cancerous cells by live-cell imaging. The clinically relevant inhibitor olaparib induced strong perturbations in mitosis, including problems with chromosome alignment at the metaphase plate, anaphase delay, and premature loss of cohesion (cohesion fatigue) after a prolonged metaphase arrest, resulting in sister chromatid scattering. PARP1 and PARP2 depletion suppressed the phenotype while PARP2 overexpression enhanced it, suggesting that olaparib-bound PARP1 and PARP2 rather than the lack of catalytic activity causes this phenotype. Olaparib induced mitotic chromatid scattering was observed in various cancer cell lines with increased protein levels of PARP1 and PARP2, but not in non-cancer or cancer cell lines that expressed lower levels of PARP1 or PARP2. Interestingly, the sister chromatid scattering phenotype occurred only when olaparib was added during the S-phase preceding mitosis, suggesting that PARP1 and PARP2 entrapment at replication forks impairs sister chromatid cohesion. Clinically relevant DNA damaging agents that impair replication progression such as topoisomerase inhibitors and cisplatin were also found to induce sister chromatid scattering and metaphase plate alignment problems, suggesting that these mitotic phenotypes are a common outcome of replication perturbation. PMID- 29262612 TI - Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism. AB - We analyzed survival effects for 15 different pairs of clinically relevant anti cancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergyTM II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism. PMID- 29262613 TI - Recurrent somatic mutations of PRKAR1A in isolated cardiac myxoma. AB - Background: Cardiac myxomas are benign tumors that commonly arise within the left atria. Familial cardiac myxomas are a part of Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome caused by germline mutations in PRKAR1A. Seven percent of cardiac myxomas are associated with CNC. To date, the genetic basis of isolated cardiac myxomas (ICM), however, has not been fully elucidated. Methods: We investigated the genetic profile of ICM using whole exome sequencing (WES). Suspected mutations were confirmed using targeted sanger sequencing. To further examine the presence of PRKAR1A mutations in ICM, we performed targeted sequencing in an additional 61 ICM specimens. Results: 87.5% (7/8) of ICM harbored mutations in PRKAR1A. Three of the 8 ICM harbored biallelic somatic mutations of PRKAR1A, including c.607_610del:p.Leu203fs (pathogenic) + c.C896G:p.Ser299X (pathogenic), c.952delT:p.Leu318fs (pathogenic) + c.769-2 A>G (pathogenic) and c.178-1 G>C (pathogenic) + c. 550+1 G>C (pathogenic). Four of 8 tumors harbored monoallelic PRKAR1A mutations, including c.523_524insG:p.Tyr175_Val176delinsX (pathogenic), c.C920A:p.Ser307X (pathogenic), c.30delG:p.Glu10fs (pathogenic) and c.C289T:p.Arg97X (pathogenic). No identical variants were observed across the 8 ICM samples. Interestingly, none of these variants have been previously described in familial cardiac myxomas. In order to confirm our findings, directed sequencing of 61 ICM specimens was subsequently performed. Sixty-four percent (39/61) of ICMs tumors contained inactivating PRKAR1A mutations. Conclusion: Our findings suggest that loss-of function mutations of PRKAR1A may play a vital role in the formation of isolated cardiac myxomas. PMID- 29262614 TI - LPI-NRLMF: lncRNA-protein interaction prediction by neighborhood regularized logistic matrix factorization. AB - LncRNA-protein interactions play important roles in many important cellular processes including signaling, transcriptional regulation, and even the generation and progression of complex diseases. However, experimental methods for determining proteins bound by a specific lncRNA remain expensive, difficult and time-consuming, and only a few theoretical approaches are available for predicting potential lncRNA-protein associations. In this study, we developed a novel matrix factorization computational approach to uncover lncRNA-protein relationships, namely lncRNA-protein interactions prediction by neighborhood regularized logistic matrix factorization (LPI-NRLMF). Moreover, it is a semi supervised and does not need negative samples. As a result, new model obtained reliable performance in the leave-one-out cross validation (the AUC of 0.9025 and AUPR of 0.6924), which significantly improved the prediction performance of previous models. Furthermore, the case study demonstrated that many lncRNA protein interactions predicted by our method can be successfully confirmed by experiments. It is anticipated that LPI-NRLMF could serve as a useful resource for potential lncRNA-protein association identification. PMID- 29262615 TI - Cavin-1 regulates caveolae-mediated LDL transcytosis: crosstalk in an AMPK/eNOS/ NF-kappaB/Sp1 loop. AB - Caveolae are specialized lipid rafts structure in the cell membrane and critical for regulating endothelial functions, e.g. transcytosis of macromolecules like low density lipoprotein (LDL) etc. Specifically, the organization and functions of caveolae are mediated by structure protein (caveolin-1) and adapter protein (cavin-1). The pathogenic role of caveolin-1 is well studied; nevertheless, mechanisms whereby cavin-1 regulates signaling transduction remain poorly understood. The aim of this study was designed to explore the role of cavin-1 in caveolae-mediated LDL transcytosis across endothelial cells. We reported here that cavin-1 knockdown mediated by small interfering RNA (siRNA) caused a significant decrease of LDL transcytosis. Moreover, cavin-1 knockdown increased the activity of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide (NO). Consequently, an eNOS inhibitor, N-Nitro-L-Arginine Methyl Ester (L-NAME), not only suppressed the activity of specificity protein (Sp1) and nuclear factor kappa B (NF-kappaB), but also inhibited both activities via activating adenosine 5'-monophosphate- activated protein kinase (AMPK). In conclusion, we proposed an AMPK/eNOS/NF-kappaB/Sp1 circuit loop was formed to regulate caveolae residing proteins' expression, e.g. LDL receptor (LDLR), caveolin-1, eNOS, thereby to regulate caveolae-mediated LDL transcytosis in endothelial cells. PMID- 29262616 TI - Loss of digestive organ expansion factor (Diexf) reveals an essential role during murine embryonic development that is independent of p53. AB - Increased levels of inhibitors of the p53 tumor suppressor such as Mdm2 and Mdm4 drive tumor development and thus serve as targets for therapeutic intervention. Recently, digestive organ expansion factor (Diexf) has been identified as a novel inhibitor of p53 in zebrafish. Here, we address the potential role of Diexf as a regulator of the p53 pathway in mammals by generating Diexf knockout mice. We demonstrate that, similar to Mdm2 and Mdm4, homozygous deletion of Diexf is embryonic lethal. However, unlike in Mdm2 and Mdm4 mice, loss of p53 does not rescue this phenotype. Moreover, Diexf heterozygous animals are not sensitive to sub-lethal ionizing radiation. Thus, we conclude that Diexf is an essential developmental gene in the mouse, but is not a significant regulator of the p53 pathway during development or in response to ionizing radiation. PMID- 29262617 TI - Microtubins: a novel class of small synthetic microtubule targeting drugs that inhibit cancer cell proliferation. AB - Microtubule targeting drugs like taxanes, vinca alkaloids, and epothilones are widely-used and effective chemotherapeutic agents that target the dynamic instability of microtubules and inhibit spindle functioning. However, these drugs have limitations associated with their production, solubility, efficacy and unwanted toxicities, thus driving the need to identify novel antimitotic drugs that can be used as anticancer agents. We have discovered and characterized the Microtubins (Microtubule inhibitors), a novel class of small synthetic compounds, which target tubulin to inhibit microtubule polymerization, arrest cancer cells predominantly in mitosis, activate the spindle assembly checkpoint and trigger an apoptotic cell death. Importantly, the Microtubins do not compete for the known vinca or colchicine binding sites. Additionally, through chemical synthesis and structure-activity relationship studies, we have determined that specific modifications to the Microtubin phenyl ring can activate or inhibit its bioactivity. Combined, these data define the Microtubins as a novel class of compounds that inhibit cancer cell proliferation by perturbing microtubule polymerization and they could be used to develop novel cancer therapeutics. PMID- 29262618 TI - Overexpression of ceramide synthase 1 increases C18-ceramide and leads to lethal autophagy in human glioma. AB - Ceramide synthase 1 (CERS1) is the most highly expressed CERS in the central nervous system, and ceramide with an 18-carbon-containing fatty acid chain (C18 ceramide) in the brain plays important roles in signaling and sphingolipid development. However, the roles of CERS1 and C18-ceramide in glioma are largely unknown. In the present study, measured by electrospray ionization linear ion trap mass spectrometry, C18-ceramide was significantly lower in glioma tumor tissues compared with controls (P < 0.001), indicating that C18-ceramide might have a role in glioma. These roles were examined by reconstitution of C18 ceramide in U251 and A172 glioma cells via addition of exogenous C18-ceramide or overexpression of CERS1, which has been shown to specifically induce the generation of C18-ceramide. Overexpression of CERS1 or adding exogenous C18 ceramide inhibited cell viability and induced cell death by activating endoplasmic reticulum stress, which induced lethal autophagy and inhibited PI3K/AKT signal pathway in U251 and A172 glioma cells. Moreover, overexpression of CERS1 or adding exogenous C18-ceramide increased the sensitivity of U251 and A172 glioma cells to teniposide (VM-26). Thus, the combined therapy of CERS1/C18 ceramide and VM-26 may be a novel therapeutic strategy for the treatment of human glioma. PMID- 29262619 TI - Kv4.3 expression reverses ICa remodeling in ventricular myocytes of heart failure. AB - Background: Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent L-type calcium channel (LTCC) current (ICa) remodeling is an important contributor to the disruption of calcium homeostasis in heart failure (HF). We have reported that Kv4.3 proteins play an important role in delicate regulation of the membrane associated CaMKII activity in ventricular myocytes. Here, we investigated the effect of in vivo Kv4.3 expression on ICa in HF left ventricular (LV) myocytes. Results: Kv4.3 expression reduced overall CaMKII autophosphorylation with much greater reduction in the membrane compartmentalized CaMKII activity. ICa density in subepicardial (SEP) and subendocardial (SEN) myocytes was proportionately reduced, without changing the transmural gradient. While the time course of ICa decay was hastened, the voltage-dependence of ICa activation and inactivation, however, remained unchanged. ICa recovery from inactivation was significantly accelerated. In line with the partial inhibition of CaMKII, the frequency dependent Ca2+-induced ICa facilitation was recovered in the HF myocytes transfected with Kv4.3. Materials and Methods: Pressure-overload HF was induced by thoracic aortic banding. Kv4.3 expression was achieved by Ad-Kv4.3 injection in the LV myocardium. ICa was recorded in dissociated SEP and SEN myocytes using whole-cell patch clamp method. Conclusions: Kv4.3 expression in HF ventricle can effectively reverse ICa remodeling via inhibition of the membrane-associated CaMKII, pointing to Kv4.3 restoration as a potential therapeutic approach for the disordered calcium regulation in HF. PMID- 29262620 TI - Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O6 methylguanine DNA methyltransferase as a biomarker for response. AB - Recent advances in the treatment of neuroendocrine tumors (NET), including the combination regimen of capecitabine and temozolomide (CAPTEM), have mostly focused on grade 1 and 2 pancreatic neuroendocrine tumors (pNET). We undertook a retrospective review of 38 patients with advanced NET treated with CAPTEM, including patients with non-pancreatic tumors as well as grade 2 and 3 tumors. O6 methylguanine DNA methyltransferase (MGMT) expression was assessed as a predictive biomarker. We found that CAPTEM demonstrated activity in patients with all grades and in pNET and non-pNET. Median progression free survival (mPFS) was 13.0 months (95% CI: 5.6-17.0) and median overall survival (mOS) 29.3 months (95% CI 17.7 - 45.3). Among evaluable patients, there were 11 (38%) partial responses, 15 (52%) stable disease, and 3 (10%) progressive disease for a disease control rate of 90%. A higher rate of partial responses occurred in patients whose tumors had low levels of MGMT expression (63%) compared to intermediate-high (17%) (p=0.19). Our results show that CAPTEM therapy is active in patients with NET including in previously treated patients and in those with poorly-differentiated histology. We observed a trend towards increased response rate, median PFS, and median OS in patients whose tumors had low MGMT protein expression. PMID- 29262621 TI - Mansouramycin C kills cancer cells through reactive oxygen species production mediated by opening of mitochondrial permeability transition pore. AB - Cancer is one of the deadliest diseases in the world and the search for novel anticancer agents is urgently required. Marine-derived isoquinolinequinones have exhibited promising anticancer activities. However, the exact mechanisms of cytotoxic activities of these isoquinolinequinones are poorly characterized. In this study, we investigated the anticancer effects and molecular mechanisms of mansouramycin C (Mm C), a cytotoxic isoquinolinequinone isolated from a marine streptomycete. We demonstrated that Mm C preferentially killed cancer cells and the cytotoxic effects were mediated by reactive oxygen species (ROS) generation. Mass spectrometry based proteomic analysis of Mm C-treated A549 cells revealed that many ROS-related proteins were differentially expressed. Proteomic-profiling after Mm C treatment identified oxidative phosphorylation as the most significant changes in pathways. Analysis also revealed extensive defects in mitochondrial structure and function. Furthermore, we disclosed that Mm C-induced ROS generation was caused by opening of mitochondrial permeability transition pore. Notably, Mm C synergized with sorafenib to induce cell death in A549 cells. Hence, we propose that the marine-derived natural compound Mm C is a potent inducer of the mitochondrial permeability transition and a promising anticancer drug candidate. Moreover, molecular mechanisms of Mm C shed new light on the understanding of the cytotoxic mechanisms of marine-derived isoquinolinequiones. PMID- 29262622 TI - The WAVE3-YB1 interaction regulates cancer stem cells activity in breast cancer. AB - Resistance to therapy is the main cause of tumor recurrence and metastasis and cancer stem cells (CSCs) play a crucial role in this process, especially in triple-negative breast cancers (TNBCs). Unfortunately, no FDA-approved treatment is currently available for this subtype of BC, which explains the high rate of mortality in patients with TNBC tumors. WAVE3, a member of the WASP/WAVE actin cytoskeleton remodeling family of protein, has been established as a major driver of tumor progression and metastasis of several solid tumors, including those originating in the breast. Our recently published studies found WAVE3 to mediate the process of chemoresistance in TNBCs. The molecular mechanisms whereby WAVE3 regulates chemoresistance in TNBC tumors remains largely unknown, as does the role of WAVE3 in CSC maintenance. Here we show that WAVE3 promotes CSC self renewal and regulates transcription of CSC-specific genes, which, in part, provides a mechanistic explanation for the function of WAVE3 in chemoresistance in TNBCs. Our data show that WAVE3 is enriched in the CSC-subpopulation of TNBC cell lines. Knockout of WAVE3 via CRISPR/Cas9 significantly attenuates the CSC subpopulation and inhibits transcription of CSC transcription factors. Mechanistically, we established a link between WAVE3 and the Y-box-binding protein-1 (YB1), a transcription factor and CSC-maintenance gene. Indeed, the interaction of WAVE3 with YB1 is required for YB1 translocation to the nucleus of cancer cells, and activation of transcription of CSC-specific genes. Our findings identify a new WAVE3/YB1 signaling axis that regulates the CSC-mediated resistance to therapy and opens a new therapeutic window for TNBCs treatment. PMID- 29262624 TI - Fasudil attenuates soluble fms-like tyrosine kinase-1 (sFlt-1)-induced hypertension in pregnant mice through RhoA/ROCK pathway. AB - Preeclampsia (PE) has become the leading cause of maternal and fetal morbidity and mortality in the world, which is characterized by a systemic maternal inflammatory response associated with endothelial dysfunction, hypertension, and proteinuria. The development of PE is still barely predictable and thus challenging to prevent and manage clinically. Fasudil (FSD), the first-generation Rho/ROCK inhibitor, has been studied widely and applied in clinical practice with high safety and efficacy in treating hypertension and other cardiovascular diseases. However, few studies have focused on the effect of fasudil on preeclampsia in vivo and in vitro. Therefore, the aim of this study is to investigate the effects of fasudil on hypoxia/reoxygenation injury in vitro and its role on preeclamptic animal model. Here, we found that RhoA/ROCK pathway was significantly activated in H/R-challenged endothelial cells and in placenta and umbilical vessel of PE mice. And fasudil pre-treatment can protect vascular endothelial cells from H/R-induced apoptosis. In addition, inhibition of RhoA/ROCK pathway with fasudil can reduce the high blood pressure and urine protein levels as well as the concentration of s-Flt in peripheral and umbilical blood in a dose-dependent manner, thus resulting in prevention of the development of PE. Thus, Fasudil attenuates soluble fms-like tyrosine kinase-1 (sFlt-1) induced hypertension in pregnant mice through RhoA/ROCK pathway, which would become a potential strategy for PE therapy. PMID- 29262623 TI - Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo. AB - Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both in vitro and in vivo. We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a TH-MYCN transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of TH-MYCN transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB. PMID- 29262625 TI - Genomic variations in paired normal controls for lung adenocarcinomas. AB - Somatic genomic mutations in lung adenocarcinomas (LUADs) have been extensively dissected, but whether the counterpart normal lung tissues that are exposed to ambient air or tobacco smoke as the tumor tissues do, harbor genomic variations, remains unclear. Here, the genome of normal lung tissues and paired tumors of 11 patients with LUAD were sequenced, the genome sequences of counterpart normal controls (CNCs) and tumor tissues of 513 patients were downloaded from TCGA database and analyzed. In the initial screening, genomic alterations were identified in the "normal" lung tissues and verified by Sanger capillary sequencing. In CNCs of TCGA datasets, a mean of 0.2721 exonic variations/Mb and 5.2885 altered genes per sample were uncovered. The C:G->T:A transitions, a signature of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes in CNCs. 16 genes had a variant rate of more than 2%, and CNC variations in MUC5B, ZXDB, PLIN4, CCDC144NL, CNTNAP3B, and CCDC180 were associated with poor prognosis whereas alterations in CHD3 and KRTAP5-5 were associated with favorable clinical outcome of the patients. This study identified the genomic alterations in CNC samples of LUADs, and further highlighted the DNA damage effect of tobacco on lung epithelial cells. PMID- 29262626 TI - Pattern of p53 protein expression is predictive for survival in chemoradiotherapy naive esophageal adenocarcinoma. AB - Introduction: TP53 mutations are considered to be the driving factor in the initiation of esophageal adenocarcinoma (EAC). However, the impact of this gene and its encoded protein as a prognostic marker has not been definitely established yet. Methods: In total, 204 chemoradiotherapy (CRT)-naive patients with EAC were included for p53 protein expression evaluation by immunohistochemistry (IHC) on the resection specimens, categorized as overexpression, heterogeneous or loss of expression, and correlated with disease free survival (DFS) and overall survival (OS) using multivariable Cox regression analysis. In a subset representing all three IHC subgroups mutational status of selected candidate genes (n=33) and high throughput methylation profiling (n=16) was assessed. Results: Compared to heterogeneous p53 expression, loss and overexpression were both independently predictive for adverse DFS and OS. TP53 mutational status significantly correlated with the IHC categories (p=0.035). Most of the EAC with loss- or overexpression harbored TP53 mutations (18/20, representing nonsense and missense mutations respectively). In contrast, 6/13 EAC with heterogeneous expression were TP53 wild type, of which two demonstrated MDM4 or MDM2 amplification. Combined genomic hypomethylation and high frequency of intra-chromosomal breaks was found in a selection of EAC without p53 overexpression. Conclusion: P53 expression pattern is prognostic for DFS and OS in this historical cohort of CRT-naive EAC. P53 IHC is an informative readout for TP53 mutational status in EAC with either loss- or overexpression, but not in case of a heterogeneous p53 pattern. Different EAC pathogenesis might exist, related to p53 and other candidate gene status, DNA hypomethylation and intrachromosomal breaks. PMID- 29262627 TI - Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis. AB - Primary liver cancers represent the second leading cause of cancer-related deaths worldwide. Diverse etiological factors include chronic viral hepatitis, aflatoxin and alcohol exposure as well as aberrant liver lipid overload. Cholesterol has been identified as a key inducer of metabolic impairment, oxidative stress and promoter of cellular dysfunction. The aim of this work was to address the oxidative stress-mediated DNA damage induced by cholesterol overload, and its role in the development of hepatocellular carcinoma. C57BL/6 male mice were fed with a high cholesterol diet, followed by a single dose of N-diethylnitrosamine (DEN, 10 MUg/g, ip). Reactive oxygen species generation, DNA oxidation, antioxidant and DNA repair proteins were analyzed at different time points. Diet induced cholesterol overload caused enhanced oxidative DNA damage in the liver and was associated with a decrease in key DNA repair genes as early as 7 days. Interestingly, we found a cell survival response, induced by cholesterol, judged by a decrement in Bax to Bcl2 ratio. Importantly, N-acetyl-cysteine supplementation significantly prevented DNA oxidation damage. Furthermore, at 8 months after DEN administration, tumor growth was significantly enhanced in mice under cholesterol diet in comparison to control animals. Together, these results suggest that cholesterol overload exerts an oxidative stress-mediated effects and promotes the development of liver cancer. PMID- 29262628 TI - Predictive value of quantitative HER2, HER3 and p95HER2 levels in HER2-positive advanced breast cancer patients treated with lapatinib following progression on trastuzumab. AB - Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) approved in second line treatment of advanced or metastatic breast cancer following progression on trastuzumab-containing therapy. Biomarkers for activity of lapatinib and other TKIs are lacking. Formalin-fixed, paraffin-embedded primary tumor samples were obtained from 189 HER2-positive patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark(r) Breast Cancer Assay was used to quantify HER2 protein expression. HER3 and p95HER2 protein expression was quantified using the VeraTag(r) technology. Overall survival (OS) was inversely correlated with HER2 (HR = 1.9/log; P = 0.009) for patients with tumors above the cut-off positivity level by the HERmark assay. OS was significantly shorter for those with above median HER2 levels (HR = 1.7; P = 0.015) and trended shorter for those below the cut-off level of positivity by the HERmark assay (HR = 1.7; P = 0.057) compared to cases with moderate HER2 overexpression. The relationship between HER2 protein expression and OS was best captured with a U-shaped parabolic function (P = 0.004), with the best prognosis at moderate levels of HER2 protein overexpression. In a multivariate model including HER2, increasing p95HER2 expression was associated with longer OS (HR = 0.35/log; P = 0.027). Continuous HER3 did not significantly correlate with OS. Patients with moderately overexpressed HER2 levels and high p95HER2 expression may have best outcomes while receiving lapatinib following progression on trastuzumab. Further study is warranted to explore the predictive utility of quantitative HER2 and p95HER2 in guiding HER2-directed therapies. PMID- 29262629 TI - Long non-coding RNA ZFAS1 sponges miR-486 to promote osteosarcoma cells progression and metastasis in vitro and vivo. AB - Long noncoding RNAs (lncRNAs) have been wildly demonstrated to participate in the osteosarcoma tumorigenesis. ZFAS1 is a novel identified lncRNA, however, its role in osteosarcoma is still unclear. In present study, we utilize lncRNA microarray assay to screen the lncRNA expression profile in osteosarcoma tissue, and investigate the regulatory function of ZFAS1 in osteosarcoma. LncRNA microarray assay revealed that lncRNA ZFAS1 was significantly up-regulated in 3 pairs of osteosarcoma and adjacent non-tumor tissue, which was confirmed by RT-PCR. Furthermore, in 53 pairs of osteosarcoma patient samples, the up-regulated expression of ZFAS1 was closely related to poor prognosis. In vitro, loss-of function experiments showed that ZFAS1 knockdown significantly suppressed the proliferation, induced cycle arrest at G0/G1 phase and enhance apoptosis. In vivo, ZFAS1 knockdown inhibited the tumor growth. Bioinformatics online programs predicted that ZFAS1 sponge miR-486 at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Rescue experiments confirmed that miR-486 could reverse the functions of ZFAS1 on osteosarcoma genesis. In conclusion, our results demonstrate that ZFAS1 act as competing endogenous RNA (ceRNA) for miR-486, and act as oncogene in osteosarcoma tumorigenesis, and discover the functional regulatory pathway of ZFAS1 sponging miR-486. PMID- 29262630 TI - Deletion of resistin-like molecule-beta attenuates angiotensin II-induced abdominal aortic aneurysm. AB - In the present study, we want to test whether deletion of resistin-like molecule beta (RELMbeta) attenuates angiotensin II (Ang II)-induced formation of abdominal aortic aneurysm (AAA). RELMbeta gene expression was inhibited by siRNA both in vivo and in vitro. Apolipoprotein E-knockout (ApoE-/-) mice were randomly divided into saline, Ang II, siRNA negative control (si-NC) and siRNA RELMbeta (si RELMbeta) groups (n=15 each), and mice in the last three groups underwent Ang II infusion for 4 weeks to induce AAA. RELMbeta gene deficiency significantly decreased AAA incidence and severity, which was associated with reduced macrophage accumulation and decreased expression of proinflammatory cytokines (monocyte chemoattractant protein 1 and interleukin 6), matrix metalloproteinase 2 (MMP-2) and MMP-9 in the aortic wall. In cultured macrophages, RELMbeta deficiency blunted the response of macrophages to Ang II and downregulated the levels of proinflammatory cytokines, MMP-2 and MMP-9. Recombinant RELMbeta promoted the secretion of proinflammatory cytokines, MMP-2 and MMP-9 in macrophages and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) signaling, which was reversed with pretreatment with inhibitors of ERK1/2 and JNK. Deletion of RELMbeta attenuated Ang II-induced AAA formation in ApoE-/- mice. The inherent mechanism may involve the reduced expression of proinflammatory cytokines, MMP-2 and MMP-9, which was mediated by ERK1/2 and JNK activation. Therefore, inhibiting RELMbeta secretion may be a novel approach for anti-aneurysm treatment. PMID- 29262631 TI - Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy. AB - Purpose: To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post treatment at prostatectomy. Methods: We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. Results: Fourteen men were equally randomized (7 per arm) to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR = 1.50, 95% CI 0.26 8.69, P = 0.65). Conclusions: Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear. PMID- 29262632 TI - Inhibition of HSP90 sensitizes a novel Raf/ERK dual inhibitor CY-9d in triple negative breast cancer cells. AB - Raf and extracellular signal-regulated kinases (ERK) are both important therapeutic targets in the mitogen-activated protein kinase (MAPK) pathway, and play crucial roles in the apoptosis resistance of breast cancer cells. In the present study, cytotoxic and apoptosis-inducing activities of the Raf/ERK dual inhibitor CY-9d were found to be restricted in triple negative breast cancer (TNBC) cells compared with ER/PR-positive cells. Based on the analysis of differentially expressed proteins using a quantitative proteomic iTRAQ method and bioinformatics analysis, HSP90 was found to identify as a potential mediator between Raf and ERK in TNBC cells. Western blotting and RNA interference suggested that down-regulated IQGAP1 can attenuate the routine Raf/MEK/ERK cascade and recruit HSP90 as a bypass pathway. Simultaneous treatment with the HSP90 inhibitor and CY-9d at sub-therapeutic doses was found to produce synergistic therapeutic and apoptosis-inducing effects in TNBC cells. Moreover, CY-9d was also found to suppress breast cancer growth, inhibit the activation of Raf/ERK, and induce mitochondrial apoptosis in vivo without remarkable toxicity. These results support the combination of HSP90 and Raf/ERK inhibitors as a potential target therapeutic strategy with enhanced tumor growth suppression, downstream pathway blockade, and greater induction of apoptosis. PMID- 29262633 TI - Overexpression of miR-216b sensitizes NSCLC cells to cisplatin-induced apoptosis by targeting c-Jun. AB - Platinum-based chemotherapy is still be the standard treatment for non-small cell lung cancer (NSCLC). Recently, studies demonstrate that some kinds of microRNAs (miRNAs) are associated with chemosensitivity of NSCLC cells to platinum-based treatment. Unfortunately, cancer cells usually change their expression profile of miRNAs to form drug resistance against chemotherapy. In the present study, we focused on miR-216b to investigate whether miR-216b determined sensitivity of NSCLC cells to cisplatin. We observed that expression level of miR-216b was significantly decreased in NSCLC cell lines when they were under the cisplatin treatment. However, restore of miR-216b by transfecting with its mimics was found to increase the cytotoxicity of cisplatin to NSCLC cells. Studies on mechanisms elucidated that miR-216b targeted c-Jun in NSCLC. Overexpression of miR-216b can suppress the cisplatin-induced upregulation of c-Jun. As the downstream, overexpression of Bcl-xl induced by c-Jun/ATF2 heterodimers was inhibited in miR 216b transfected NSCLC cells. Since Bcl-xl is a key anti-apoptotic protein, we found that sensitivity of NSCLC cells to cisplatin-induced apoptosis was significantly increased because of the overexpression of miR-216b. PMID- 29262634 TI - Glucose-derived AGEs enhance human gastric cancer metastasis through RAGE/ERK/Sp1/MMP2 cascade. AB - Advanced glycation end products (AGEs) have been reported to take part in many cancer processes. Whether AGEs contribute to gastric cancer (GC) course and the underlying mechanism are still unclear. Here, glucose-derived AGEs are detected to be accumulated in tumor tissues and blood of patients with GC. As the receptor for AGEs, RAGE is highly expressed in cancer tissues, and closely associated with the depth of cancer invasion, lymph node metastasis and TNM stage. Both in vivo and in vitro treatment of AGEs accelerate the tumor invasion and metastasis, with upregualtion of RAGE, Specificity Protein 1 (Sp1), and MMP2 protein expression, as well as enhancement of MMP2 activity. Either RAGE-blocking antibody or Sp1 knockdown can partially block the AGEs-induced effects. Moreover, AGEs increased the phosphorylation of ERK, and reducing the phosphorylation level of ERK by MEK1/2 inhibitor decreased the expression of Sp1. These results indicate that accumulation of glucose-derived AGEs may act as one of potential risk factors for GC progression and promote the invasion and metastasis of gastric cancer partially through the activation of RAGE/ERK/Sp1/MMP2 pathway. PMID- 29262635 TI - Preoperative prediction of hepatocellular carcinoma with portal vein tumor thrombus based on conventional data. AB - Hepatocellular carcinoma (HCC) has a high predilection with portal vein tumor thrombosis (PVTT). However, part of the PVTT type can be found only under the microscopy, which was namely as type I0. The objective of this study was to establish a simple and inexpensive non-invasive model to predict the presentation of PVTT at HCC patients. A total of 815 HCC patients were retrospectively evaluated and randomly assigned into 2 groups: the training group (n = 408) and validation group (n = 407). A new index model, namely WgammaAL, was built to predict the presence of PVTT in the training subjects and was further validated in the validation subjects. At the optimal cutoff of 8.90, WgammaAL identified patients with a hazard ratio (HR) of 7.139 for the presence of PVTT. The area under receiver operating characteristic (AUROC) of WgammaAL was 0.795 (sensitivity: 71.9%; specificity: 78.6%) for differentiation between PVTT and non PVTT patients in the training group. The AUROC of WgammaAL in differentiating patients with PVTT type I0 from non-PVTT patients was 0.748 (sensitivity: 72.1%; specificity: 68.4%) with an HR of 5.355. In addition, WgammaAL > 8.90 was significantly associated with large tumors, multiple tumor numbers, TNM stage III IV, metastasis, and overall survival in HCC patients. The novel predictive model represents a simple and inexpensive model that can identify the presence of PVTT in HCC patients with a high degree of accuracy, with important clinical significance in the future therapeutic management of HCC patients. PMID- 29262636 TI - The significance of eosinophils in predicting the severity of acute ischemic stroke. AB - Background: Previous studies have shown that tumor-associated tissue eosinophilia have a role in various types of solid tumors. However, the relationship between eosinophil and acute ischemic stroke (AIS) is unclear. We aimed to investigate the diagnostic significance of eosinophil in AIS patients. Methods: This study included 300 AIS patients without hypereosinophilic syndrome (HES). The hematologic indices were collected from each patient, including white blood count, eosinophil count, eosinophil percentage, neutrophil count, red blood count, and platelet. The severity of AIS was estimated by national institute of health stroke scale (NIHSS). Logistic regression analyses were performed to confirm the biomarkers for NIHSS and in-hospital non-death among the cases. Moreover, receiver-operating characteristics (ROC) analyses were used to investigate the clinical performances of eosinophils and NIHSS in prediction of non-death. Results: The admission NIHSS (P<0.001) and BMI (P<0.001) were predictors to the non-death of the patients. There was a significant correlation between eosinophil counts or eosinophil percentage and NIHSS score (r= -0.451, P < 0.001; r= -0.617, P<0.001, Spearson Correlation). ROC analysis showed that eosinophil counts and eosinophil percentage could predict non-death of the patients in-hospital, with the areas under the curves (AUC) of 0.791 and 0.867, respectively. Conclusions: Our study revealed a relationship between eosinophil and NIHSS score in the patients with AIS. Eosinophils might have certain value for predicting the severity of AIS. PMID- 29262637 TI - Metformin reverses bFGF-induced epithelial-mesenchymal transition in HCC cells. AB - Metformin had exerted important inhibitory effects in multiple cancers. However, the correlation between metformin and hepatocellular carcinoma (HCC) metastasis, and the relevant mechanisms are still unclear. By quantitative proteomics analysis technique, we found metformin could suppress FGF signalling significantly. In FGF signalling basic fibroblast growth factor (bFGF) is a crucial member, it initially binds to its receptors, the complex of bFGF and receptors activate FGF signallings, and promote many cancers progressions. When treating HCC cell lines HepG2 and Huh7 with bFGF, we observed the cells exhibited epithelial mesenchymal transition (EMT) and these cells metastasis potential was enhanced dramaticlly. However, when treating with metformin and bFGF together, EMT and metastasis induced by bFGF could be inhibited in these cells. Furthermore, bFGF could activate AKT/GSK-3beta signalling, sequentially decrease the interaction between GSK-3beta and Twist1 and decrease ubiquitination of Twist1 leading to Twist1 degradation reducing. While metformin could repress the bFGF-mediated activation in AKT/GSK-3beta signalling, inhibition on interaction between GSK-3beta and Twist1, enhancement of Twist1 stability. Taken together, our findings suggested that metformin had prominent negative effects on bFGF induced EMT and metastasis in HCC cells. PMID- 29262638 TI - Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation. AB - Gastric cancer (GC) is a globally occurring malignancy that is characterized by a high mortality rate due to a high tendency to metastasize and poor prognoses. Sorcin, as known as SRI, a soluble resistance-related calcium-binding protein, plays a significant role in multidrug resistance. Sorcin is related to the migration and invasion of cancer cells. However, the mechanism remains unclear. Here, we used immunohistochemistry to confirm that the expression of sorcin in cancer tissues is higher than that in the adjacent normal tissues. The wound healing and transwell results indicate that sorcin can induce migration and invasion of GC cells. To explore the role of sorcin in GC metastasis, isobaric tags for relative and absolutely quantitation (iTRAQ) were used to examine cells with and without sorcin knockdown to identify the differentially expressed proteins (DEPs). The results were evaluated via RT-PCR and western blot to confirm the ITRAQ data. Inhibition of sorcin expression can down- regulate the expression of CTSZ, MMP2, MMP9 and p-STAT3 followed by suppression of tumor growth and metastasis. Together, we concluded that sorcin has a oncogenic activity via inducing tumor growth and metastasis, leading to development of therapeutic treatments for GC. PMID- 29262639 TI - A PiggyBac mediated approach for lactoferricin gene transfer in bovine mammary epithelial stem cells for management of bovine mastitis. AB - The antibacterial and anti-inflammatory properties of lactoferricin have been ascribed to its ability to sequester essential iron. The objective of the study was to clone bovine lactoferricin (LFcinB) gene into PiggyBac Transposon vector, expression study in the bovine mammary epithelial stem cells (bMESCs) and also to determine the antimicrobial property of recombinant LFcinB against bovine mastitis-causing organisms. The PiggyBac-LFcinB was transfected into bMESCs by electroporation and a three fold of LFcinB secretion was observed in the transfected bMESCs medium by ELISA assay. Furthermore, the assessment of antimicrobial activity against mastitis causing pathogens Staphylococcus aureus and Escherichia coli demonstrated convincing evidence to prove strong antibacterial activity of LFcinB with 14.0+/-1.0 mm and 18.0+/-1.5 mm zone of inhibition against both organisms, respectively. The present study provides the convincing evidence to suggest the potential of PiggyBac transposon system to transfer antibacterial peptide into bMESCs or cow mammary gland and also pave the way to use bovine mammary gland as the bioreactors. Simultaneously, it also suggest toward commercial utilization of LFcinB bioreactor system in pharmaceutical industry. PMID- 29262640 TI - GEJ cancers: gastric or esophageal tumors? searching for the answer according to molecular identity. AB - The 7th edition of Union for International Cancer Control (UICC) staging system moved gastroesophageal junction (GEJ) cancers from gastric to esophageal group. Since clinical management is strongly influenced by this staging system, we looked at molecular fingerprints of GEJ tumors and compared to gastric and esophageal profiles. We aimed at elucidating whether GEJ cancers cluster with gastric or esophageal groups according to mRNA and microRNA expression pattern, since this might represent tumor identity. The clinical and expression data were downloaded from The Cancer Genome Atlas (TCGA) with 395 stomach, 184 esophagus and 521 colon samples for mRNA analyses and 392 stomach, 175 esophagus and 459 colon samples for microRNA comparisons. Both Principal Component Analysis (PCA) and Heat Map plots were performed in R platform, using Log2 transformation of RPKM normalized data. Differential Expression Analysis was also performed in R, using RAW data and the DESeq2 package. The mRNAs and microRNAs were tagged as differentially expressed if they met the following criteria: i) FDR adjusted p value < 0.05; and ii) |Log2 (fold-change)| > 2. Esophagus squamous cell carcinoma (ESCC) clustered apart of the others tumors, while adenocarcinomas (AC) clustered all together according to both mRNAs and microRNAs expression patterns. The HMs of the differentially expressed mRNAs and microRNAs also demonstrated that ESCC belongs to a different group, while AC molecular signature of esophagus looks like AC of the cardia and non cardia regions. Even distal gastric cancers are quite similar to AC of the lower esophagus, demonstrating that esophagus AC relies much closer to gastric cancers than to esophagus cancers. By using robust molecular fingerprints, it was strongly demonstrated that GEJ tumors looks more like gastric cancers than esophageal cancers, despite of tumor heterogeneity. PMID- 29262641 TI - Dynamic changes in the cell membrane on three dimensional low coherent quantitative phase microscopy (3D LC-QPM) after treatment with the near infrared photoimmunotherapy. AB - Near infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer therapy that relies on the binding of a near-infrared antibody photoabsorber conjugate (APC) to a cancer cell. Subsequent exposure to NIR light selectively induces rapid necrotic cell death on target-expressing cells with minimal off-target effects. When treated with NIR-PIT, targeted cells become swollen, develop blebs and burst within minutes of light exposure. Detailed spatial and temporal morphological changes of the cellular membrane of targeted cells treated with NIR PIT have not been fully explored with state-of-the-art microscopic methods. In this study, we investigated the morphologic and kinetic effects of PIT on two types of cells, a spindle-shaped 3T3/Her cell and a spheric-shaped MDA-MB468 cell, after NIR-PIT using three-dimensional low-coherent quantitative phase microscopy (3D LC-QPM). Adhesive cells treated with NIR-PIT demonstrated region specific cell membrane rupture occurring first on the distal free edge of the cell near the site of adhesion, in a process that was independent of cell shape. The results show that the peripheral portions of the cell membrane near the site of adhesion are particularly vulnerable to the effects of NIR-PIT, likely because these sites exhibit higher baseline surface tension. PMID- 29262642 TI - Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent. AB - High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using 89Zr-labeled glembatumumab ([89Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [89Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [89Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 +/- 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [89Zr]DFO-CR011 tumor uptake in gpNMB expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [89Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [89Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC. PMID- 29262643 TI - Hepatocellular glycogenotic foci after combined intraportal pancreatic islet transplantation and knockout of the carbohydrate responsive element binding protein in diabetic mice. AB - Aims: The intraportal pancreatic islet transplantation (IPIT) model of diabetic rats is an insulin mediated model of hepatocarcinogenesis characterized by the induction of clear cell foci (CCF) of altered hepatocytes, which are pre neoplastic lesions excessively storing glycogen (glycogenosis) and exhibiting activation of the AKT/mTOR protooncogenic pathway. In this study, we transferred the IPIT model to the mouse and combined it with the knockout of the transcription factor carbohydrate responsive element binding protein (chREBP). Methods: C57BL/6J Wild-type (WT) and chREBP-knockout (chREBP-KO) mice (n = 297) were matched to 16 groups (WT/ chREBP-KO, experimental/control, streptozotocine induced diabetic/not diabetic, one/four weeks). Experimental groups received the intraportal transplantation of 70 pancreatic islets. Liver and pancreatic tissue was examined using histology, morphometry, enzyme- and immunohistochemistry and electron microscopy. Results: CCF emerged in the liver acini downstream of the transplanted islets. In comparison to WT lesions, CCF of chREBP-KO mice displayed more glycogen accumulation, reduced activity of the gluconeogenic enzyme glucose 6-phosphatase, decreased glycolysis, lipogenesis and reduced levels of the AKT/mTOR cascade members. Proliferative activity of CCF was ~two folds higher in WT mice than in chREBP-KO mice. Conclusions: The IPIT model is applicable to mice, as murine CCF resemble preneoplastic liver lesions from this hepatocarcinogenesis model in the rat in terms of morphological, metabolic and molecular alterations and proliferative activity, which is diminished after chREBP knockout. chREBP appears to be an essential component of AKT/mTOR mediated cell proliferation and the metabolic switch from a glycogenotic to lipogenic phenotype in precursor lesions of hepatocarcinogenesis. PMID- 29262644 TI - EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1 L expression in colorectal cancer liver metastasis in a cell context-dependent manner. AB - We have shown that carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L) expression in MC38 metastatic colorectal cancer (CRC) cells results in liver metastasis inhibition via CCL2 and STAT3 signaling. But other molecular mechanisms orchestrating CEACAM1-L-mediated metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced ephrin type-A receptor 2 (EPHA2) expression and activity. An EPHA2-specific inhibitor reduced EPHA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high CEACAM1 in combination with low EPHA2 expression benefited from longer time to first recurrence/metastasis compared to those with high EPHA2 expression. With the added interaction of CEACAM6, we denoted that CEACAM1 high- and EPHA2 low expressing patient samples with lower CEACAM6 expression also exhibited a longer time to first recurrence/metastasis. In HT29 human CRC cells, down-regulation of CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver metastasis through cell context-dependent EPHA2-mediated signaling. However, CEACAM1's role should be considered in the presence of other CEACAM family members. PMID- 29262645 TI - Therapeutic effects of the euglenoid ichthyotoxin, euglenophycin, in colon cancer. AB - Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and the 3rd leading cause of cancer-related mortality. The emergence of drug resistance poses a major challenge in CRC care or treatment. This can be addressed by determining cancer mechanisms, discovery of druggable targets, and development of new drugs. In search for novel agents, aquatic microorganisms offer a vastly untapped pharmacological source that can be developed for cancer therapeutics. In this study, we characterized the anti-colorectal cancer potential of euglenophycin, a microalgal toxin from Euglena sanguinea. The toxin (49.1-114.6 MUM) demonstrated cytotoxic, anti-proliferative, anti-clonogenic, and anti-migration effects against HCT116, HT29, and SW620 CRC cells. We identified G1 cell cycle arrest and cell type - dependent modulation of autophagy as mechanisms of growth inhibition. We validated euglenophycin's anti-tumorigenic activity in vivo using CRL:Nu(NCr)Foxn1nu athymic nude mouse CRC xenograft models. Intraperitoneal toxin administration (100 mg/kg; 5 days) decreased HCT116 and HT29 xenograft tumor volumes (n=10 each). Tumor inhibition was associated with reduced expression of autophagy negative regulator mechanistic target of rapamycin (mTOR) and decreased trend of serum pro-inflammatory cytokines. Together, these results provide compelling evidence that euglenophycin can be a promising anti-colorectal cancer agent targeting multiple cancer-promoting processes. Furthermore, this study supports expanding natural products drug discovery to freshwater niches as prospective sources of anti-cancer compounds. PMID- 29262646 TI - Inhibition of microRNA-218 reduces HIF-1alpha by targeting on Robo1 in mice aortic endothelial cells under intermittent hypoxia. AB - Objective: To investigate the effects of miR-218 on expression of hypoxia inducible factors 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and cell apoptosis in normal mice aortic endothelial cells under intermittent hypoxia (IH) condition. Methods: Anti-miR-218 inhibitor, miR-negative control and miR-218 mimic were used to tranfect the cells in different groups under IH condition. Both RT-PCR and Western blot were used to determine the expressions of HIF-1alpha and VEGF. Akt, p-Akt and cell apoptosis related proteins bcl-2, bax and caspase-3 and roundabout 1 (Robo1) were measured using Western blot. Cell apoptosis was evaluated by flow cytometry. Statistical analysis was performed using SPSS 18.0. Results: Expression of miR-218 was significantly up-regulated in the IH group and was significantly inhibited when cells were transfected with miR 218 inhibitor. Down regulation of miR-218 could reduce the expression of HIF 1alpha and VEGF under intermittent hypoxia condition. In cells transfected with miR-218 mimic, expression of HIF-1alpha and VEGF significantly increased compared with the control. However, when treated with LY294002, the expression of HIF 1alpha and VEGF both decreased. Apoptosis assay showed that down regulation of miR-218 could inhibit intermittent hypoxia induced cell apoptosis, decrease expression of caspase-3 and bax and increase expression of bcl-2 under intermittent hypoxia condition. At last, silencing Robo1 could significantly enhance the expression of HIF-1alpha under IH condition. Conclusion: Inhibition of miR-218 could reduce the expression of HIF-1alpha and protect against IH induced apoptosis in mice aortic endothelial cells. The effects were associated with PI3K/AKT pathway and might through targeting of Robo1. PMID- 29262647 TI - Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells. AB - Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS mediated pathway. PMID- 29262648 TI - Predicting survival time of lung cancer patients using radiomic analysis. AB - Objectives: This study investigates the prediction of Non-small cell lung cancer (NSCLC) patient survival outcomes based on radiomic texture and shape features automatically extracted from tumor image data. Materials and Methods: Retrospective analysis involves CT scans of 315 NSCLC patients from The Cancer Imaging Archive (TCIA). A total of 24 image features are computed from labeled tumor volumes of patients within groups defined using NSCLC subtype and TNM staging information. Spearman's rank correlation, Kaplan-Meier estimation and log rank tests were used to identify features related to long/short NSCLC patient survival groups. Automatic random forest classification was used to predict patient survival group from multivariate feature data. Significance is assessed at P < 0.05 following Holm-Bonferroni correction for multiple comparisons. Results: Significant correlations between radiomic features and survival were observed for four clinical groups: (group, [absolute correlation range]): (large cell carcinoma (LCC) [0.35, 0.43]), (tumor size T2, [0.31, 0.39]), (non lymph node metastasis N0, [0.3, 0.33]), (TNM stage I, [0.39, 0.48]). Significant log rank relationships between features and survival time were observed for three clinical groups: (group, hazard ratio): (LCC, 3.0), (LCC, 3.9), (T2, 2.5) and (stage I, 2.9). Automatic survival prediction performance (i.e. below/above median) is superior for combined radiomic features with age-TNM in comparison to standard TNM clinical staging information (clinical group, mean area-under-the ROC-curve (AUC)): (LCC, 75.73%), (N0, 70.33%), (T2, 70.28%) and (TNM-I, 76.17%). Conclusion: Quantitative lung CT imaging features can be used as indicators of survival, in particular for patients with large-cell-carcinoma (LCC), primary tumor-sizes (T2) and no lymph-node-metastasis (N0). PMID- 29262649 TI - ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression. AB - TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a TERT promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations. PMID- 29262650 TI - Human glioma stem-like cells induce malignant transformation of bone marrow mesenchymal stem cells by activating TERT expression. AB - We investigated whether glioma stem-like cells (GSCs) malignantly transformed bone marrow mesenchymal stem cells (tBMSCs) in the tumor microenvironment. Transplantation of enhanced green fluorescence protein (EGFP)-labeled BMSCs into irradiated athymic nude mice was followed by intracranial injection of red fluorescent protein-expressing glioma stem-like cells (SU3-RFP-GSCs). Singly cloned EGFP-BMSCs, harvested from the intracranial tumors showed TERT overexpression, high proliferation, colony formation and invasiveness in Transwell matrigel assays. Transfection of normal BMSCs with TERT (TERT-BMSCs) enhanced proliferation, colony formation and invasiveness, though these characteristics remained lower than in tBMSCs. The tBMSCs and TERT-BMSCs showed high surface expression of CD44, CD105, CD29 and CD90 and an absence of CD31, CD34, CD45, and CD11b, as in normal BMSCs. Alizarin red S and oil red O staining confirmed tBMSCs and TERT-BMSCs transdifferentiated into osteocytes and adipocytes, respectively. When normal BMSCs were indirectly co-cultured in medium from SU3-RFP-GSCs, they exhibited increased growth and proliferation, suggesting paracrine factors from GSCs induced their malignant transformation. Tumorigenicity assays in athymic nude mice showed that transplanted tBMSCs and TERT-BMSCs generated 100% and 20% subcutaneous tumors, respectively, while normal BMSCs generated no tumors. GSCs thus induce malignant transformation of BMSCs by activating TERT expression in BMSCs. PMID- 29262651 TI - High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy. AB - Despite impressive clinical activity in patients with germline BRCA1 and BRCA2 (BRCA1/2) mutant cancers, antitumor responses to poly(ADP-Ribose) polymerase (PARP) inhibitors are variable. We set out to assess the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors, its correlation with patient outcomes, and the identification of factors associated with RDR. We retrospectively reviewed all patients with advanced cancers from five early phase PARP inhibitor monotherapy trials. 113 patients (ovarian cancers 57.5%; breast cancers 23.9%) were included in this retrospective study; 46 (40.7%) patients developed RDR on PARP inhibitor monotherapy. We identified two patterns of RDR: early RDR (1st or 2nd on-treatment scans) in 69.6% of patients, and late RDR (penultimate or final scans) in 30.4% of patients. Early RDR was associated with shorter time to progression (TTP) (225 vs 367 days, HR:0.59, 95%CI 0.36-0.98; p=0.04) and overall survival (OS) (499 vs 857 days; HR:0.47, 95%CI 0.27-0.82, p=0.006). Seventy-nine (69.9%) patients had known germline BRCA1/2 mutations; 49.4% of these BRCA1/2 mutation carriers developed RDR versus 20.6% of patients with unknown or wildtype BRCA1/2 status. Harboring germline BRCA1/2 mutations was independently predictive for RDR (RR:2.93, 95% CI 1.08-7.90, p=0.03). Patients with germline BRCA1 mutations had worse TTP and OS than BRCA2 mutation carriers (212 vs 406 days, HR:0.58, 95% CI 0.36-0.94, p=0.023 and 515 vs 937 days; HR:0.49, 95% CI 0.29-0.83; p=0.007). RDR with PARP inhibitors are frequent, particularly in germline BRCA1/2 mutation carriers. These findings have clinical implications for patient outcomes and may reflect underlying intrapatient genomic heterogeneity. PMID- 29262652 TI - Radiomic analysis in contrast-enhanced CT: predict treatment response to chemoradiotherapy in esophageal carcinoma. AB - Objectives: To investigate the capability of computed-tomography (CT) radiomic features to predict the therapeutic response of Esophageal Carcinoma (EC) to chemoradiotherapy (CRT). Methods: Pretreatment contrast-enhanced CT images of 49 EC patients (33 responders, 16 nonresponders) who received with CRT were retrospectively analyzed. The region of tumor was contoured by two radiologists. A total of 214 features were extracted from the tumor region. Kruskal-Wallis test and receiver operating characteristic (ROC) analysis were performed to evaluate the capability of each feature on treatment response classification. Support vector machine (SVM) and artificial neural network (ANN) algorithms were used to build models for prediction of the treatment response. The statistical difference between the performances of the models was assessed using McNemar's test. Results: Radiomic-based classification showed significance in differentiating responders from nonresponders. Five features were found to discriminate nonresponders from responders (AUCs from 0.686 to 0.727). Considering these features, two features (Histogram2D_skewness: P = 0.015. Histogram2D_kurtosis: P = 0.039) were significant for differentiating SDs (stable disease) from PRs (partial response) and one feature (Histogram2D_skewness: P = 0.027) for differentiating SDs from CRs (complete response). Both classifiers showed potential in predicting the treatment response with higher accuracy (ANN: 0.972, SVM: 0.891). No statistically significant difference was observed in the performance of the two classifiers (P = 0.250). Conclusions: CT-based radiomic features can be used as imaging biomarkers to predict tumor response to CRT in EC patients. PMID- 29262653 TI - The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2). AB - Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized. Furthermore, we demonstrate that under growth conditions, MdmX enhances the neddylation activity of Mdm2 on p53 and is a substrate for neddylation itself. Importantly, MdmX knockdown in MCF-7 breast cancer cells resulted in diminished neddylated p53, suggesting that MdmX is important for Mdm2 mediated neddylation. Supporting this finding, the lack of MdmX in transient assays or in p53/MdmX-/- MEFs results in decreased or altered neddylation of p53 respectively; therefore, MdmX is a critical component of the Mdm2-mediated neddylating complex. c-Src is the upstream activator of this Mdm2-MdmX neddylating pathway and loss of Src signaling leads to the destabilization of MdmX that is dependent on the RING (Really Interesting New Gene) domain of MdmX. Treatment with a small molecule inhibitor of neddylation, MLN4924, results in the activation of Ataxia Telangiectasia Mutated (ATM). ATM phosphorylates Mdm2, converting Mdm2 to a ubiquitinating enzyme which leads to the destabilization of MdmX. These data show how distinct signaling pathways engage neddylating or ubiquitinating activities and impact the Mdm2-MdmX axis. PMID- 29262654 TI - Prognostic impact of multimorbidity in patients with type 2 diabetes and ST elevation myocardial infarction. AB - Introduction: There is an increasing body of evidence on the clinical importance of multimorbidity, which is defined as the coexistence of two or more chronic conditions. Type 2 diabetes (T2DM) is one of the most frequent chronic conditions. Most adults with type 2 diabetes have at least 1 coexisting chronic condition and approximately 40% have 3 or more. Prior studies have suggested that cardiovascular (CVD) and non-CVD comorbid conditions yield worse outcomes in patients hospitalized with ST-elevation myocardial infarction (STEMI). It is unclear, however, the extent to which multimorbidity has a cumulative effect on long-term risk. Therefore we have set out to determine the prognostic value of multiple comorbidity on long-term outcomes in this population of patients. Methods: A total of 277 patients with T2DM and STEMI undergoing primary percutaneous coronary intervention (PCI) were enrolled. Based on the number of comorbidities the study population was divided into two groups: group 1 (N=58) with <= 1 comorbidity and group 2 (N=219) with >= 2 comorbidities. Results: Comorbid conditions were prevalent among study participants (Figure 1). The median number of comorbidities was three. 15.9% of patients had one comorbidity and 22.0%, 34.3%, and 22.7% of patients had two, three or at least four comorbid conditions respectively. A majority of patients had at least one CVD comorbidity (6.1% of patients had none), whereas 53.1% of patients did not have any non-CVD comorbidity. During hospitalization 3 out of 58 patients (5.2%) died in group 1 and 25 of 219 patients (11.4%) died in group 2. The number of comorbid conditions was not an independent predictor of in-hospital death. During 12-month follow-up, 5 of 58 patients (8.6%) and 42 of 219 patients (19.9%) died, respectively in group 1 and 2 (P=0.05). The number of comorbid conditions proved in ROC analysis that for 12-month mortality, the prognostic value was modest, but for 12-month acute coronary syndromes the prognostic value was good. Increase in the number of comorbid conditions by one was associated with a 15% increase in the relative risk of 12-month mortality and a 41% increase in the relative risk of 12-month acute coronary syndromes (ACS). Conclusions: Comorbid conditions are highly prevalent among these groups of patients. Majority of patients have at least 2 other cardiovascular comorbidities and one or two non-cardiovascular comorbidities. In terms of long-term follow-up, multimorbidity was associated with worse outcomes. The risk of both long-term mortality and ACS increased with the increasing number of comorbidities. In summary, our findings highlight the importance of indentifying patients with multimorbidity. This, in turn, could allow for provision of better care to these high-risk and complex group of patients. PMID- 29262655 TI - Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). AB - Cancer cells reprogram their metabolism and energy production to sustain increased growth, enable metastasis and overcome resistance to cancer treatments. Although primary roles for many metabolic proteins have been identified, some are promiscuous in regards to the reaction they catalyze. To efficiently target these enzymes, a good understanding of their enzymatic function and structure, as well as knowledge regarding any substrate or catalytic promiscuity is required. Here we focus on the characterization of human 3-phosphoglycerate dehydrogenase (PHGDH). PHGDH catalyzes the NAD+-dependent conversion of 3-phosphoglycerate to phosphohydroxypyruvate, which is the first step in the de novo synthesis pathway of serine, a critical amino acid for protein and nucleic acid biosynthesis. We have investigated substrate analogues to assess whether PHGDH might possess other enzymatic roles that could explain its occasional over-expression in cancer, as well as to help with the design of specific inhibitors. We also report the crystal structure of the catalytic subunit of human PHGDH, a dimer, solved with bound cofactor in one monomer and both cofactor and L-tartrate in the second monomer. In vitro enzyme activity measurements show that the catalytic subunit of PHGDH is still active and that PHGDH activity could be significantly inhibited with adenosine 5'-diphosphoribose. PMID- 29262656 TI - Neuroprotective effects of allicin on ischemia-reperfusion brain injury. AB - Background: Ischemia-reperfusion brain injury (IRBI) is an important cause for mortality and morbidity. Studies on humans and animals showed that oxidative stress (OS) plays a crucial role in ischemic stroke with or without reperfusion. Allicin is reported to be able to attenuate OS and has neuroprotective effects on rabbits' ischemia-reperfusion spinal cord injury. Aim: To explore whether Allicin pretreatment has neuroprotective effects on IRBI in mice. Methods and results: Transient middle cerebral artery occlusion (MCAO) was conducted to induce IRBI in mice. The mice were pretreated with either Allicin (MCAOA) or normal saline in the same volume (MCAONS). Sham-operated groups [Allicin group (SOA) and normal saline group (SONS)] were also set. Blood pressure and cerebral blood flow measurements revealed comparable hemodynamics. Via brain MRI and neuronal nuclear antigen (NeuN) immune-histochemical staining, MCAOA mice had a significantly reduced stroke size than MCAONS mice (P < 0.05, n = 15). Allicin pretreatment could attenuate the OS, the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, inflammation, dysfunction of mitochondrial respiratory chain, and apoptosis (all P < 0.05, n = 15). Furthermore, Allicin also increased the activities of endogenous antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione S transferase (GST), and promoted the angiogenesis in the peri-infarct zone (all P < 0.05, n = 15). Conclusion: We showed that Allicin could protect mice from IRBI through a series of mechanisms. Allicin represents a new therapeutic direction of IRBI. PMID- 29262657 TI - hsa-miR-29c-3p regulates biological function of colorectal cancer by targeting SPARC. AB - Colorectal cancer (CRC) is the most common type of behavioral cancers, miRNAs play a critical role in cancer development and progression. In the present study, we downloaded the original data from Gene Expression Omnibus (GEO) and conduct data analysis. has-mir-29c-3p mimic, inhibitor, negative control or si-SPARC (secreted protein acidic, rich in cysteine) were transfected into HCT116 cells, respectively. Quantitative real time PCR (qRT-PCR) was used to measure has-mir 29c-3p and SPARC mRNA expressions, western blot was used to detect ACAA1 (acetyl CoA acyltransferase 1), ACOX1 (acyl-CoA oxidase 1), COL1A1(collagen, type I, alpha-1), COL1A2 (collagen, type I, alpha-2), COL4A1 (collagen, type IV, alpha 1), COL5A2 (collagen, type V, alpha-2), COL12A1 (collagen, type XII, alpha-1), CPT2 (carnitine palmitoyltransferase 2), ETHE1 (persulfide dioxygenase), HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2), SPARC, SQRDL (sulfide quinone oxidoreductase), and TST (thiosulfate sulfurtransferase) protein expression. CCK 8 and wound healing assay were employed to verify cell proliferation and migration. The luciferase reporter assay data made sure the target correlation of has-mir-29c-3p and SPARC. Firstly, we found that the expression of has-mir-29c-3p was lower in CRC tissues than in their paired corresponding non-cancerous tissues and there was significant inversed correlation between has-mir-29c-3p and SPARC. Overexpression of has-mir-29c-3p reduced cell proliferation and migration. SPARC was identified as a direct target of has-mir-29c-3p, whose silencing reduced cell proliferation and migration. These data showed that has-mir-29c-3p regulates CRC cell functions through regulating SPARC expression. Taken together, has-mir-29c 3p may function as an oncogenic miRNA targeting SPARC, targeted modulation of has mir-29c-3p expression may became a potential strategy for the treatment. PMID- 29262658 TI - Human CRL4DDB2 ubiquitin ligase preferentially regulates post-repair chromatin restoration of H3K56Ac through recruitment of histone chaperon CAF-1. AB - Acetylated histone H3 lysine 56 (H3K56Ac) diminishes in response to DNA damage but is restored following DNA repair. Here, we report that CRL4DDB2 ubiquitin ligase preferentially regulates post-repair chromatin restoration of H3K56Ac through recruitment of histone chaperon CAF-1. We show that H3K56Ac accumulates at DNA damage sites. The restoration of H3K56Ac but not H3K27Ac, H3K18Ac and H3K14Ac depends on CAF-1 function, whereas all these acetylations are mediated by CBP/p300. The CRL4DDB2 components, DDB1, DDB2 and CUL4A, are also required for maintaining the H3K56Ac and H3K9Ac level in chromatin, and for restoring H3K56Ac following induction of DNA photolesions and strand breaks. Depletion of CUL4A decreases the recruitment of CAF-1 p60 and p150 to ultraviolet radiation- and phleomycin-induced DNA damage. Neddylation inhibition renders CRL4DDB2 inactive, decreases H3K56Ac level, diminishes CAF-1 recruitment and prevents H3K56Ac restoration. Mutation in the PIP box of DDB2 compromises its capability to elevate the H3K56Ac level but does not affect XPC ubiquitination. These results demonstrated a function of CRL4DDB2 in differential regulation of histone acetylation in response to DNA damage, suggesting a novel role of CRL4DDB2 in repair-driven chromatin assembly. PMID- 29262659 TI - The microRNA miR-10b as a potentially promising biomarker to predict the prognosis of cancer patients: a meta-analysis. AB - Background: Reported studies on carcinoma have evaluated the significance of the microRNA miR-10b in the development and progression of many cancers. Increased expression of miR-10b is associated with the susceptibility to lymph node metastasis and distant metastasis in various tumors. Results: The results of the meta-analysis revealed that lymph node metastasis occurred more frequently in the patients group with high expression level of miR-10b than in the patients group with low expression level of miR-10b (OR=4.65, 95% CI: 3.40-6.37, P <0.00001, fixed-effects model). Additionally, a similar result was observed in the association between miR-10b expression and distant metastasis (OR=2.70, 95% CI: 1.79-4.08, P <0.00001, fixed-effects model). Materials and Methods: In this study, a meta-analysis, including the majority of the relevant articles, was conducted to investigate the association of the miR-10b expression level with metastasis in cancer patients. Systematic literature retrieval was performed by searching in a number of electronic databases. The meta-analysis was conducted using the RevMan 5.2 software and Stata SE12.0 software. A total of 962 patients with carcinoma from 9 studies were included in analysis. Conclusions: This meta analysis demonstrated that the overexpression of miR-10b was significantly correlated with metastasis status, and indicated the potential clinical use of miR-10b as a molecular biomarker, particularly in assessing prognosis for patients with cancers. PMID- 29262660 TI - Multicenter phase II study of apatinib treatment for metastatic gastric cancer after failure of second-line chemotherapy. AB - Apatinib is a tyrosine kinase inhibitor and vascular endothelial growth factor receptor 2 (VEGFR-2) targeted drug. A phase I clinical trial showed that this agent has antitumor activity in Chinese patients with metastatic gastric cancer (mGC). The aim of this study was to investigate the safety and efficacy of apatinib treatment in patients with mGC. This was an open-label, multicenter, single-arm study involving four institutions in China. We enrolled 42 patients from March 2015 to October 2015 who experienced tumor progression after second line chemotherapy and had no other treatment options that clearly conferred a survival benefit. Oral apatinib (850 mg daily) was administered within 30 min of eating breakfast, lunch, or dinner on days 1 through 28 of each 4-week cycle. The median progression-free survival (PFS) time and median overall survival (OS) time were 4.0 months (95% CI, 2.85-5.15) and 4.50 months (95% CI, 4.03-4.97), respectively. The disease control rate (DCR) and objective response rate (ORR) were, respectively, 78.57% and 9.52% after 2 cycles and 57.14% and 19.05% after 4 cycles. The main adverse events (AEs) were secondary hypertension, elevated aminotransferase, and hand-foot syndrome, with incidences of 35.71%, 45.24%, and 40.48%, respectively. The most common grade 3 to 4 AEs were secondary hypertension and elevated aminotransferase, with incidences of 7.14% each. Apatinib is effective and safe in heavily pretreated patients with mGC who fail to respond to two or more prior chemotherapy regimens. Toxicities were tolerable or could be clinically managed. PMID- 29262661 TI - Resting-state functional magnetic resonance imaging shows altered brain network topology in Type 2 diabetic patients without cognitive impairment. AB - We analyzed topology of brain functional networks in type 2 diabetes mellitus (T2DM) patients without mild cognitive impairment. We recruited T2DM patients without mild cognitive impairment (4 males and 8 females) and healthy control subjects (8 males and 16 females) to undergo cognitive testing and resting-state functional magnetic resonance imaging. Graph theoretical analysis of functional brain networks revealed abnormal small-world architecture in T2DM patients as compared to control subjects. The functional brain networks of T2DM patients showed increased path length, decreased global efficiency and disrupted long distance connections. Moreover, reduced nodal characteristics were distributed in the frontal, parietal and temporal lobes, while increased nodal characteristics were distributed in the frontal, occipital lobes, and basal ganglia in the T2DM patients. The disrupted topological properties correlated with cognitive performance of T2DM patients. These findings demonstrate altered topological organization of functional brain networks in T2DM patients without mild cognitive impairment. PMID- 29262662 TI - Comparison of repeated surgical resection and radiofrequency ablation for small recurrent hepatocellular carcinoma after primary resection. AB - There is controversy concerning whether radiofrequency ablation (RFA) or surgical resection (SR) is a better treatment option for recurrent HCC after resection. In Kaohsiung Veteran General Hospital, from January 2002 to September 2014, a total of 100 consecutive patients who developed recurrent HCCs with a tumor size ? 3 cm and tumor numbers ? 3 after surgical resection were enrolled. Among these patients, 57 patients received RFA and 43 patients underwent repeated SR. Baseline characteristics at the time of recurrence after hepatic resection and clinical outcomes following treatment of recurrent HCC were compared between the two groups. The baseline data of initial HCC and the first recurrence of HCC were comparable in both groups. The 1-, 3-, 5-year overall survival rates following treatment of the first recurrence of HCC were 97.6%, 82.7%, 56.4% in the repeated SR group and 98.2%, 77.2%, 52.6% in the RFA group (p = 0.69). The 1-, 3-, 5-year disease-free survival rates were 57.0%, 32.1%, 28.6% in the repeated SR group and 60.8%, 26.6%, 16.6% in the RFA group ((p = 0.89). There was a trend whereby patients who underwent repeated SR had more procedure-related morbidity than patients who underwent RFA (16% vs. 7%, p = 0.14). The median total hospital days were longer in the repeated SR group than that in the RFA group (13 vs. 5 days, p < 0.05). In the small recurrent HCCs after SR, RFA achieved similar overall survival and disease-free survival than those with repeated SR as well as having a shorter hospital stay. PMID- 29262663 TI - Sex differences in outcomes and risk factors among elderly patients with ischemic stroke. AB - We aimed to investigate the sex differences in the clinical characteristics and risk factors for adverse outcomes among elderly patients with atherosclerotic stroke. We recruited 942 consecutive patients with atherosclerotic stroke aged 75 years and older between January 2008 and December 2013 from Jiamusi University First Hospital, China. Stroke subtype, severity, risk factors, and outcomes (mortality, dependency, and recurrence) at 3 and 12 months after stroke were recorded and assessed. Mortality at 3 months after stroke was higher in men than in women. Stroke severity was an independent risk factor for mortality, dependency, and recurrence at 3 and 12 months after stroke in both men and women. However, the presence of total anterior circulation infarct and obesity protected against mortality at 3 months after stroke in men, while total anterior circulation infarct was a risk factor for dependency at 3 months after stroke in women. In women, positive associations were found between fasting plasma glucose level and mortality at 3 months after stroke and between hypertension, atrial fibrillation, and recurrence at 12 months after stroke. These findings suggest that it is crucial to control the primary risk factors individually by sex, especially regarding hypertension and atrial fibrillation management, to improve secondary prevention of stroke among the elderly and reduce the burden of stroke in China. PMID- 29262664 TI - Effect of postoperative analgesia technique on the prognosis of gastric cancer: a retrospective analysis. AB - Background: Whether regional analgesia techniques have favorable impact on prognosis after cancer surgery is unclear, and existing reports show controversial results. The aim of the present study was to evaluate and compare recurrence and mortality between patients that received either intravenous (IV) or epidural patient controlled analgesia (PCA) for pain control after curative surgery for gastric cancer. Materials and methods: Medical records of patients that underwent curative gastrectomy for gastric cancer between November 2005 and December 2010 were reviewed. Identified patients were categorized according to the use of IV or epidural PCA for postoperative analgesia. Demographic and perioperative variables including type of PCA were analyzed by univariate and multiple regression analysis to investigate any association with recurrence and mortality after surgery. Propensity score matching was done to adjust for selection bias. Results: Of the 3,799 patients included in this analysis, 374 and 3, 425 patients received IV and epidural PCAs, respectively. No difference in recurrence (HR, 1.092; 95% CI 0.859 to 1.388; P = 0.471) or mortality (HR, 0.695; 95% CI 0.429 to 1.125; P = 0.138) was identified between the use of IV and epidural PCA. Propensity score matching also showed no difference in recurrence (HR, 1.098; 95% CI 0.756 to 1.596; P = 0.623) or mortality (HR, 0.855; 95% CI 0.391 to 1.869; P = 0.695) between the two groups. Conclusions: Postoperative use of epidural analgesia was not found to be associated with reduced recurrence or mortality after curative surgery in gastric cancer patients. This finding needs to be confirmed with prospective studies in the future. PMID- 29262665 TI - Improved glycemic control with proximal intestinal bypass and weight loss following gastrectomy in non-obese diabetic gastric cancer patients. AB - Purpose: The aim of this study was to assess whether gastrectomy influences glycemic control in non-obese diabetic gastric cancer patients and to identify factors related to glucose metabolism after gastrectomy. Materials and Methods: We retrospectively analyzed changes in glucose metabolism in 238 non-obese (body mass index < 30 kg/m2) patients with type II diabetes who underwent distal gastrectomy with either gastroduodenostomy (n = 91) or gastrojejunostomy (n = 147) for stage I gastric cancer. We collected demographics, diabetes-related features, surgery-related features, and changes in glucose metabolism during follow-up. The effect of surgery on the course of diabetes was evaluated at different time points according to fasting blood glucose levels and use of diabetes-related medication. Results: Preoperatively, the mean body mass index was 24.3 +/- 2.3. Weight, body mass index and fasting blood glucose of all patients were significantly lower compared to preoperative levels at all time points. Weight loss after 6 months and the percentage of patients whose weight loss ratio was higher than 10% after one year were greater in the gastrojejunostomy group than the gastroduodenostomy group. Overall, 88 (37%) patients showed improvement in their diabetes course at one month after surgery; 152 (64%) showed improvement after 2 years. Duration of diabetes, weight loss, and reconstruction type were associated with improvement in diabetes at different time points. At 6 months and thereafter, the percentage of patients with an improved diabetes course was highest in the gastrojejunostomy plus higher than 10% weight loss group. Conclusions: Although weight loss may be associated with adverse effects of gastrectomy, postoperative weight loss in an acceptable range is a useful measure of the better glycemic control for the group of diabetic patients. Selecting gastrojejunostomy during gastrectomy and inducing acceptable weight loss after gastrectomy could be beneficial to the non-obese diabetic gastric cancer patients for improved glycemic control. PMID- 29262667 TI - Current diagnostics and treatment of fibrosarcoma -perspectives for future therapeutic targets and strategies. AB - Adult-type fibrosarcoma is a rare and highly aggressive subtype of soft tissue sarcomas. Due to the existence of other spindle-cell shaped sarcomas, its diagnosis is always one of exclusion. The likelihood of misdiagnoses between similar tumour entities is high, and often leads to inappropriate tumour treatment. We summarize here the main features of fibrosarcoma. When fibrosarcoma is appropriately diagnosed, the patient's overall prognosis is generally quite poor. Fibrosarcoma is characterized by its low sensitivity towards radio- and chemotherapy as well as by its high rate of tumour recurrences. Thus it is important to identify new methods to improve treatment of this tumour entity. We discuss some promising new directions in fibrosarcoma research, specifically focusing on more effective targeting of the tumour microenvironment. Communication between tumour cells and their surrounding stromal tissue play a crucial role in cancer progression, invasion, metastasis and chemosensitivity. The therapeutic potential of targeting the tumour microenvironment is addressed. PMID- 29262666 TI - Exploiting cancer's phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy. AB - Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or 'corrected' through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy. PMID- 29262668 TI - Testicular cancer from diagnosis to epigenetic factors. AB - Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2gamma (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs). PMID- 29262669 TI - Advances in the understanding and management of T-cell prolymphocytic leukemia. AB - T-prolymphocytic leukemia (T-PLL) is a rare T-cell neoplasm with an aggressive clinical course. Leukemic T-cells exhibit a post-thymic T-cell phenotype (Tdt-, CD1a-, CD5+, CD2+ and CD7+) and are generally CD4+/CD8-, but CD4+/CD8+ or CD8+/CD4- T-PLL have also been reported. The hallmark of T-PLL is the rearrangement of chromosome 14 involving genes for the subunits of the T-cell receptor (TCR) complex, leading to overexpression of the proto-oncogene TCL1. In addition, molecular analysis shows that T-PLL exhibits substantial mutational activation of the IL2RG-JAK1-JAK3-, STAT5B axis. T-PLL patients have a poor prognosis, due to a poor response to conventional chemotherapy. Monoclonal antibody therapy with antiCD52-alemtuzumab has considerably improved outcomes, but the responses to treatment are transient; hence, patients who achieve a response to therapy are considered for stem cell transplantation (SCT). This combined approach has extended the median survival to four years or more. Nevertheless, new approaches using well-tolerated therapies that target growth and survival signals are needed for most patients unable to receive intensive chemotherapy. PMID- 29262671 TI - Prophylactic extended-field irradiation with concurrent chemotherapy for pelvic lymph node-positive cervical cancer. AB - PURPOSE: This study aimed to evaluate whether prophylactic extended-field pelvic radiotherapy (EF-PRT) yields better results than standard whole pelvic radiotherapy (WPRT) in patients with pelvic lymph node-positive cervical cancer treated with concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: A total of 126 cases of stage IB-IVA cervical cancer that had pelvic lymph node involvement in magnetic resonance imaging and were treated with CCRT between 2000 and 2016 were reviewed. None of the patients had paraaortic lymph node (PALN) metastases. The patients were classified to two groups, namely, those treated with EF-PRT, including prophylactic para-aortic radiotherapy, and those treated only with WPRT. The median dose to the PALN area in patients treated with EF-PRT was 45 Gy. All patients received concurrent cisplatin-based chemotherapy. RESULTS: Overall, 52 and 74 patients underwent EF-PRT and WPRT, respectively. Patient characteristics and irradiated dose were not significantly different, except the dose to the para-aortic area, between the two groups. The median follow-up period was 75.5 months (range, 5 to 195 months). The 10-year cumulative recurrence rate of PALN for EF-PRT vs. WPRT was 6.9% and 10.1% (p = 0.421), respectively. The 10-year disease-free survival and overall survival for EF-PRT vs. WPRT were 69.7% vs. 66.1% (p = 0.748) and 71.7% vs. 72.3% (p = 0.845), respectively. Acute gastrointestinal complications were significantly higher in EF-PRT (n = 21; 40.4%) than WPRT (n = 26; 35.1%) (p = 0.046). Late toxicities were not significantly different in both groups. CONCLUSION: In this study, prophylactic radiotherapy for PALN does not have an additional benefit in patients with pelvic lymph node-positive cervical cancer treated with CCRT. PMID- 29262672 TI - Dosimetric comparison between modulated arc therapy and static intensity modulated radiotherapy in thoracic esophageal cancer: a single institutional experience. AB - PURPOSE: The objective of this study was to compare dosimetric characteristics of three-dimensional conformal radiotherapy (3D-CRT) and two types of intensity modulated radiotherapy (IMRT) which are step-and-shoot intensity modulated radiotherapy (s-IMRT) and modulated arc therapy (mARC) for thoracic esophageal cancer and analyze whether IMRT could reduce organ-at-risk (OAR) dose. MATERIALS AND METHODS: We performed 3D-CRT, s-IMRT, and mARC planning for ten patients with thoracic esophageal cancer. The dose-volume histogram for each plan was extracted and the mean dose and clinically significant parameters were analyzed. RESULTS: Analysis of target coverage showed that the conformity index (CI) and conformation number (CN) in mARC were superior to the other two plans (CI, p = 0.050; CN, p = 0.042). For the comparison of OAR, lung V5 was lowest in s-IMRT, followed by 3D-CRT, and mARC (p = 0.033). s-IMRT and mARC had lower values than 3D-CRT for heart V30 (p = 0.039), V40 (p = 0.040), and V50 (p = 0.032). CONCLUSION: Effective conservation of the lung and heart in thoracic esophageal cancer could be expected when using s-IMRT. The mARC was lower in lung V10, V20, and V30 than in 3D-CRT, but could not be proven superior in lung V5. In conclusion, low-dose exposure to the lung and heart were expected to be lower in s-IMRT, reducing complications such as radiation pneumonitis or heart-related toxicities. PMID- 29262670 TI - Tumor-derived exosomes in ovarian cancer - liquid biopsies for early detection and real-time monitoring of cancer progression. AB - Ovarian cancer usually has a poor prognosis because it predominantly presents as high stage disease. New approaches are required to develop more effective early detection strategies and real-time treatment response monitoring. Nano-sized extracellular vesicles (EVs, including exosomes) may provide an approach to enrich tumor biomarker detection and address this clinical need. Exosomes are membranous extracellular vesicles of approximately 100 nm in diameter that have potential to be used as biomarkers and therapeutic delivery tools for ovarian cancer. Exosomal content (proteins and miRNA) is often parent cell specific thus providing an insight or "fingerprint" of the intracellular environment. Furthermore, exosomes can aid cell-cell communication and have the ability to modify target cells by transferring their content. Additionally, via the capacity to evade the immune system and remain stable over long periods in circulation, exosomes have potential as natural drug agents. This review examines the potential role of exosomes in diagnosis, drug delivery and real-time monitoring in ovarian cancer. PMID- 29262673 TI - Saturation Mutagenesis by Efficient Free-Energy Calculation. AB - Single-point mutations in proteins can greatly influence protein stability, binding affinity, protein function or its expression per se. Here, we present accurate and efficient predictions of the free energy of mutation of amino acids. We divided the complete mutational free energy into an uncharging step, which we approximate by a third-power fitting (TPF) approach, and an annihilation step, which we approximate using the one-step perturbation (OSP) method. As a diverse set of test systems, we computed the solvation free energy of all amino acid side chain analogues and obtained an excellent agreement with thermodynamic integration (TI) data. Moreover, we calculated mutational free energies in model tripeptides and established an efficient protocol involving a single reference state. Again, the approximate methods agreed excellently with the TI references, with a root-mean-square error of only 3.6 kJ/mol over 17 mutations. Our combined TPF+OSP approach does show not only a very good agreement but also a 2-fold higher efficiency than full blown TI calculations. PMID- 29262674 TI - Visual Sensor for Sterilization of Polymer Fixtures Using Embedded Mesoporous Silicon Photonic Crystals. AB - A porous photonic crystal is integrated with a plastic medical fixture (IV connector hub) to provide a visual colorimetric sensor to indicate the presence or absence of alcohol used to sterilize the fixture. The photonic crystal is prepared in porous silicon (pSi) by electrochemical anodization of single crystal silicon, and the porosity and the stop band of the material is engineered such that the integrated device visibly changes color (green to red or blue to green) when infiltrated with alcohol. Two types of self-reporting devices are prepared and their performance compared: the first type involves heat-assisted fusion of a freestanding pSi photonic crystal to the connector end of a preformed polycarbonate hub, forming a composite where the unfilled portion of the pSi film acts as the sensor; the second involves generation of an all-polymer replica of the pSi photonic crystal by complete thermal infiltration of the pSi film and subsequent chemical dissolution of the pSi portion. Both types of sensors visibly change color when wetted with alcohol, and the color reverts to the original upon evaporation of the liquid. The sensor performance is verified using E. coli infected samples. PMID- 29262675 TI - Holding the Nucleosome Together: A Quantitative Description of the DNA-Histone Interface in Solution. AB - The nucleosome is the fundamental unit of eukaryotic genome packaging in the chromatin. In this complex, the DNA wraps around eight histone proteins to form a superhelical double helix. The resulting bending, stronger than anything observed in free DNA, raises the question of how such a distortion is stabilized by the proteic and solvent environments. In this work, the DNA-histone interface in solution was exhaustively analyzed from nucleosome structures generated by molecular dynamics. An original Voronoi tessellation technique, measuring the topology of interacting elements without any empirical or subjective adjustment, was used to characterize the interface in terms of contact area and occurrence. Our results revealed an interface more robust than previously known, combining extensive, long-lived nonelectrostatic and electrostatic interactions between DNA and both structured and unstructured histone regions. Cation accumulation makes the proximity of juxtaposed DNA gyres in the superhelix possible by shielding the strong electrostatic repulsion of the charged phosphate groups. Overall, this study provides new insights on the nucleosome cohesion, explaining how DNA distortions can be maintained in a nucleoprotein complex. PMID- 29262676 TI - Variability in Foliar Ellagitannins of Hippophae rhamnoides L. and Identification of a New Ellagitannin, Hippophaenin C. AB - Berries of common sea-buckthorn (Hippophae rhamnoides L.) are well-known and used for their bioactive components, and while there is a considerable amount of research on the leaves as well, their ellagitannins (ETs) have not been a prominent focus of research. We identified and quantified ten major hydrophilic polyphenols, all ETs, in H. rhamnoides leaves and compared their abundance between 58 plant individuals. Of these compounds, hippophaenin C was characterized as a new ellagitannin by various spectrometric methods. The total concentrations of ETs ranged from 42.5 mg g-1 dry weight (DW) to 109.1 mg g-1 DW between individual plants. Among the ETs, hippophaenin C, stachyurin, and casuarinin were on average the most abundant compounds. Sexes did not differ significantly, while cultivars showed variation in some ETs. These results suggest that H. rhamnoides leaves could be a potential and rich source of several ETs. PMID- 29262677 TI - Phospholyl(borane) Amino Acids and Peptides: Stereoselective Synthesis and Fluorescent Properties with Large Stokes Shift. AB - The synthesis of phospholyl(borane) amino acids was stereoselectively achieved by reaction of phospholide anion with iodo alpha-amino ester derived from l-aspartic acid or l-serine, followed by in situ complexation with borane. Phospholyl(borane) amino acids are easy to store and can be subjected to direct transformation into the corresponding free phospholyl, gold complex, oxide or sulfur derivatives as well as phospholinium salts, thus offering a variety of side chains. After selective deprotection of carboxylic function or amine, C- or N- peptide coupling with an alanine moiety proved the possible incorporation into peptides. Such phospholyl amino acid and peptide derivatives exhibit fluorescent properties with a large Stokes shift (160 nm) and fluorescence up to 535 nm, depending on the phosphole aromaticity and the chemical environment. These phospholyl(borane) amino acids constitute a new class of unnatural amino acids useful for structure-activities relationship studies and appear to be promising fluorophores for the development of labeled peptides. PMID- 29262678 TI - C-C Coupling on Single-Atom-Based Heterogeneous Catalyst. AB - Compared to homogeneous catalysis, heterogeneous catalysis allows for ready separation of products from the catalyst and thus reuse of the catalyst. C-C coupling is typically performed on a molecular catalyst which is mixed with reactants in liquid phase during catalysis. This homogeneous mixing at a molecular level in the same phase makes separation of the molecular catalyst extremely challenging and costly. Here we demonstrated that a TiO2-based nanoparticle catalyst anchoring singly dispersed Pd atoms (Pd1/TiO2) is selective and highly active for more than 10 Sonogashira C-C coupling reactions (R=CH + R'X -> R=R'; X = Br, I; R' = aryl or vinyl). The coupling between iodobenzene and phenylacetylene on Pd1/TiO2 exhibits a turnover rate of 51.0 diphenylacetylene molecules per anchored Pd atom per minute at 60 degrees C, with a low apparent activation barrier of 28.9 kJ/mol and no cost of catalyst separation. DFT calculations suggest that the single Pd atom bonded to surface lattice oxygen atoms of TiO2 acts as a site to dissociatively chemisorb iodobenzene to generate an intermediate phenyl, which then couples with phenylacetylenyl bound to a surface oxygen atom. This coupling of phenyl adsorbed on Pd1 and phenylacetylenyl bound to Oad of TiO2 forms the product molecule, diphenylacetylene. PMID- 29262679 TI - Isolation, Structural Elucidation, and Liquid Chromatography-Mass Spectrometry Analysis of Steroidal Glycosides from Polygonatum odoratum. AB - The rhizomes of Polygonatum odoratum represent a traditional Chinese medicine and functional food. A phytochemical investigation resulted in the isolation of eight steroidal glycosides (1-8), including two new compounds, polygonatumosides F (1) and G (2). The structures were elucidated by spectroscopic data and chemical reactions. Compound 7 showed antiproliferation activity against human hepatocellular carcinoma cell line HepG2 (IC50 of 3.2 MUM). The chemical profile and contents of steroidal glycosides of P. odoratum rhizomes collected at different dates and geographical locations were also investigated, indicating that the rational harvest of P. odoratum in spring and autumn is preferable to obtain higher levels of steroidal glycosides. Compounds 1 and 7 showed the highest contents in all P. odoratum samples and have potential to serve as chemotaxonomic and chemical markers for quality control of this important plant material. 14-Hydroxylation may be a key step for the biosynthesis of compounds 1 7. PMID- 29262680 TI - Mechanism of OmpG pH-Dependent Gating from Loop Ensemble and Single Channel Studies. AB - Outer membrane protein G (OmpG) from Escherichia coli has exhibited pH-dependent gating that can be employed by bacteria to alter the permeability of their outer membranes in response to environmental changes. We developed a computational model, Protein Topology of Zoetic Loops (Pretzel), to investigate the roles of OmpG extracellular loops implicated in gating. The key interactions predicted by our model were verified by single-channel recording data. Our results indicate that the gating equilibrium is primarily controlled by an electrostatic interaction network formed between the gating loop and charged residues in the lumen. The results shed light on the mechanism of OmpG gating and will provide a fundamental basis for the engineering of OmpG as a nanopore sensor. Our computational Pretzel model could be applied to other outer membrane proteins that contain intricate dynamic loops that are functionally important. PMID- 29262681 TI - Anomalous Dependence of the Reactivity on the Presence of Steps: Dissociation of D2 on Cu(211). AB - Stepped metal surfaces are usually assumed to exhibit an increased catalytic activity for bond cleavage of small molecules over their flat single-crystal counterparts. We present experimental and theoretical data on the dissociative adsorption of molecular hydrogen on copper that contradicts this notion. We observe hydrogen molecules to be more reactive on the flat Cu(111) than on the stepped Cu(211) surface. We suggest that this exceptional behavior is due to a geometric effect, that is, that bond cleavage on the flat surface does not occur preferentially over a top site. PMID- 29262682 TI - The Interplay between Structural Stability and Plasticity Determines Mutation Profiles and Chaperone Dependence in Protein Kinases. AB - We present a novel comparative analysis of representative protein kinases to characterize the main dynamic and energetic determinants of functional regulation shared among different families. The relationships between stability and plasticity are also used to rationalize kinase tendencies to interact with the molecular chaperone Hsp90. These questions are tackled through newly developed molecular-dynamics-based methods of analysis of internal energy and dynamics applied to a total of 37 different systems, which represent wild-type and mutated proteins, including active and inactive states. Energetic decomposition analysis is coupled to multiple structural alignments and dynamic decomposition methods and identifies, across different families, common elements that underlie fold stabilization and conformational regulation. This analysis also exposes which substructures play a key role in determining chaperone dependence. Overall, the results highlight common interaction networks that underpin kinase stabilization, are modulated by mutations (even if located at a distance), and underlie their tendencies to act as clients or nonclients of Hsp90. PMID- 29262683 TI - Cucurbit[7]uril-Directed Assembly of Colloidal Membrane and Stimuli-Responsive Microcapsules at the liquid-liquid Interface. AB - Colloidal microcapsules based on supramolecular architectures feature attractive properties and offer new opportunities in diverse areas such as delivery, sensing, and catalysis. Herein, we report a new strategy to fabricate the colloidal membrane and stimuli-responsive microcapsules by utilizing cucurbit[7]uril-mediated interfacial host-guest molecular recognition. In contrast to the traditionally used cross-linking approach, this method exploits the engineered interaction between a nanoparticle ligand and cucurbit[7]uril to tune the interfacial energy and stabilize the colloidal assembly at the interface. These capsules provide a versatile platform for simultaneous encapsulation of dual cargos. Additionally, the dynamic nature of the supramolecular interactions allows triggered release of the encapsulated cargos through the orthogonal presentation of a high affinity guest molecule. PMID- 29262684 TI - Surface-Enhanced Infrared Absorption: Pushing the Frontier for On-Chip Gas Sensing. AB - Surface-enhanced infrared absorption (SEIRA) is capable of identifying molecular fingerprints by resonant detection of infrared vibrational modes through the coupling with plasmonic modes of metallic nanostructures. However, SEIRA for on chip gas sensing is still not very successful due to the intrinsically weak light matter interaction between photons and gas molecules and the technical challenges in accumulating sufficient gas species in the vicinity of the spatially localized enhanced electric field, namely, the "hot-spots", generated through plasmonics. In this paper, we present a suspended silicon nitride (Si3N4) nanomembrane device by integrating plasmonic nanopatch gold antennas with metal-organic framework (MOF), which can largely adsorb carbon dioxide (CO2) through its nanoporous structure. Unlike conventional SEIRA sensing relying on highly localized hot spots of plasmonic nanoantennas or nanoparticles, the device reported in this paper engineered the coupled surface plasmon polaritons in the metal-Si3N4 and metal-MOF interfaces to achieve strong optical field enhancement across the entire MOF film. We successfully demonstrated on-chip gas sensing of CO2 with more than 1800* enhancement factors by combining the concentration effect from the 2.7 MUm MOF thin film and the optical field enhancement of the plasmonic nanopatch antennas. PMID- 29262685 TI - Protein Fluctuations and Cavity Changes Relationship. AB - Protein cavities and tunnels are critical for function. Ligand recognition and binding, transport, and enzyme catalysis require cavities rearrangements. Therefore, the flexibility of cavities should be guaranteed by protein vibrational dynamics. Molecular dynamics simulations provide a framework to explore conformational plasticity of protein cavities. Herein, we present a novel procedure to characterize the dynamics of protein cavities in terms of their volume gradient vector. For this purpose, we make use of algorithms for calculation of the cavity volume that result robust for numerical differentiations. Volume gradient vector is expressed in terms of principal component analysis obtained from equilibrated molecular dynamics simulations. We analyze contributions of principal component modes to the volume gradient vector according to their frequency and degree of delocalization. In all our test cases, we find that low frequency modes play a critical role together with minor contributions of high frequency modes. These modes involve concerted motions of significant fractions of the total residues lining the cavities. We make use of variations of the potential energy of a protein in the direction of the volume gradient vector as a measure of flexibility of the cavity. We show that proteins whose collective low frequency fluctuations contribute the most to changes of cavity volume exhibit more flexible cavities. PMID- 29262687 TI - Spotlights: Volume 8, Issue 24. PMID- 29262686 TI - Theoretical Study of Small Iron-Oxyhydroxide Clusters and Formation of Ferrihydrite. AB - Hydrolysis of iron compounds in water leads to the formation of Fe(III) oyxhydroxide-based minerals like ferrihydrite, which act as natural scavengers of inorganic contaminants in the environment. Though studied widely, experimental identification of these oxyhydroxides remains very difficult due to their extreme reactivity. The present study theoretically investigates the formation of Fe(III) oxyhydroxides starting from a single hydrated Fe(III) ion, modeling the formation of larger clusters gradually. The structures, formation enthalpies, and free energies of dimers, trimers, tetramers, and even larger Fe(III) oxyhydroxide clusters comprising of Fe5, Fe7, and Fe13-Keggin ions in gaseous phase and in aqueous medium (using self-consistent reaction field method) are systematically studied using density functional theory. Spontaneous formation of certain multinuclear Fe(III) oxyhydroxide clusters with clear structural signatures of ferrihydrite highlights their potential as prenucleation clusters in the course of mineralization. PMID- 29262688 TI - Challenges to uptake of cancer education resources by rural Aboriginal Health Workers: the Cancer Healing Messages flipchart experience. AB - INTRODUCTION: The Australian Aboriginal and Torres Strait Islander (Aboriginal) population has a higher age-standardised cancer mortality rate and a significantly lower 5-year survival rate for all cancers than the non-Aboriginal population. Aboriginal people from regional and remote South Australia and the Northern Territory, are often required to travel to Adelaide to access specialist cancer care services. The burden and expenses associated with transport and accommodation and cultural and linguistic factors have been identified as barriers to accessing medical treatment and health services. In collaboration with community and stakeholders, Cancer Council South Australia led the development of the Cancer Healing Messages flipchart and patient flyer to assist health professionals in explaining cancer and the cancer journey to Aboriginal cancer patients and their families. This study examined the usage, acceptability and perceived usefulness of the resources, barriers to uptake, and strategies to improve their utilisation and sustainability. METHODS: An evaluation survey was conducted among Aboriginal Health Workers (AHWs) and other health professionals working with Aboriginal clients in South Australia (n=18). Participants indicated whether they agreed that the resources are valuable, culturally appropriate, helpful for explaining aspects of cancer to Aboriginal cancer patients, and useful with regard patient outcomes, how frequently they used or would use the resources for information, and how they use the flipchart in practice. Participants were also asked to report any usage barriers. RESULTS: The resources were considered useful, valuable and culturally appropriate by almost all participants; however, there was a discrepancy between intentions to use the resources and actual uptake, which was low. The most commonly reported barriers related to appropriateness for certain patients and lack of availability of resources in some contexts. CONCLUSION: The Cancer Healing Messages flipchart and patient flyer are perceived as appropriate, valuable, and useful tools for AHWs. A long-term strategy and clear implementation plan involving education, training and promotion of the materials, is required to achieve broad reach and sustainable utilisation of the Cancer Healing Messages flipchart and patient flyer. PMID- 29262689 TI - HIV Infection and Drug Resistance with Unsupervised Use of HIV Pre-Exposure Prophylaxis. AB - Although the Centers for Disease Control and Prevention currently only recommend daily dosing of HIV pre-exposure prophylaxis (PrEP), an on-demand PrEP dosing strategy that includes doses before and after sexual activity has been shown to reduce risk for HIV acquisition in men who have sex with men. In this letter, we report a case of HIV infection and drug resistance in a patient using PrEP outside of regular clinical care, adopting a sporadic, suboptimal dosing strategy with pills he obtained from his sexual partners. This case illustrates the potential risks of PrEP use without provider monitoring to ensure safe and effective dosing and laboratory follow-up, as well as key challenges that must be addressed as nondaily PrEP use becomes more common outside of controlled research settings. PMID- 29262690 TI - Assessment of Risk Factors Associated With Hospital-Acquired Pressure Injuries and Impact on Health Care Utilization and Cost Outcomes in US Hospitals. AB - Hospital-acquired pressure injuries (HAPI) are a societal burden and considered potentially preventable. Data on risk factors and HAPI burden are important for effective prevention initiatives. This study of the 2009-2014 US Premier Healthcare Database identified HAPI risk factors and compared outcomes after matching HAPI to non-HAPI patients. The cumulative incidence of HAPI was 0.28% (47 365 HAPI among 16 967 687 total adult inpatients). Among the matched sample of 110 808 patients (27 702 HAPI), the strongest risk factors for HAPI were prior PI (odds ratio [OR] = 12.52, 95% confidence interval [CI] = 11.93-13.15), prior diabetic foot ulcer (OR = 3.43, 95% CI = 3.20-3.68), and malnutrition (OR = 3.11, 95% CI = 3.02-3.20). HAPI patients had longer adjusted length of stay (3.7 days, P < .0001), higher total hospitalization cost ($8014, P < .0001), and greater odds of readmissions through 180 days (OR = 1.60, 95% CI = 1.55-1.65). This study demonstrates how big data may help quantify HAPI burden and improve internal hospital processes by identifying high-risk patients and informing best practices for prevention. PMID- 29262691 TI - The Home Observation Measure of the Environment is associated with symptoms of ADHD and oppositionality in a CAMHS sample. AB - BACKGROUND: Severe early deprivation has a causal role in attention deficit/hyperactivity disorder (ADHD). Adversity in the home is associated with increased ADHD and oppositional symptoms in children with ADHD. We aimed to replicate this in an independent clinic sample. METHODS: A total of 247 sequential families with a child referred to child and adolescent mental health services (CAMHS) were invited to participate; 100 families completed the study. The Home Observation Measure of the Environment (HOME) assessment was completed in the family home; parents completed the Conners' Rating Scale. RESULTS: A less supportive home was associated with more symptoms of inattention ( r = .33, p = .001), hyperactivity/impulsivity ( r = -.22, p = .028) and oppositionality ( r = .48, significant at p < .000001). CONCLUSION: The HOME correlates with ADHD and oppositional symptom severity in a clinic sample; more research is required to ascertain whether this is a causal association and the direction of causation. If causal, then the modification of the home environment may be a treatment strategy for ADHD. PMID- 29262693 TI - A Randomized Controlled Trial of Multiple Versions of an Acceptance and Commitment Therapy Matrix App for Well-Being. AB - Mobile apps may be useful in teaching psychological skills in a high-frequency, low-intensity intervention. The acceptance and commitment therapy (ACT) matrix is a visual tool to help develop psychological flexibility by categorizing moment-to moment experience and is well suited to a mobile app. This pilot study tested the effects of a simple and complex version of a novel app using the ACT matrix in two distinct samples: help-seeking individuals ( n = 35) and students receiving SONA credit ( n = 63). Findings indicated no differences between app conditions and a waitlist condition in the SONA credit sample. However, in the help-seeking sample, improvements were found on well-being and valued action in participants who used the app, with greater improvements and app adoption for those using a complex version with additional skills. A mobile app based on the ACT matrix has benefits for help-seeking individuals, but supplementary features may be necessary to support consistent use and benefits. PMID- 29262694 TI - Can we afford to offer pre-exposure prophylaxis to MSM in Catalonia? Cost effectiveness analysis and budget impact assessment. AB - Pre-exposure prophylaxis (PrEP) effectiveness has been well established. This study aims to assess the cost-effectiveness of providing PrEP, estimate the number of eligible MSM, and its budget impact in Catalonia. Cost-effectiveness analysis compared costs of on daily basis and "on demand" PrEP to prevent one infection with lifetime costs of one HIV infection. We estimated the total cost of providing PrEP by estimating number of eligible MSM, and included in the budget impact assessment antiretroviral and laboratory costs. Costs were lower for the on-demand PrEP group by ?64015.1 and the incremental benefit was nearly 15 life-years and 17 quality-adjusted life-years gained. The incremental cost effectiveness ratio (ICER) was cost-effective at ?6281.62 when undiscounted PrEP was given daily. On-demand PrEP can be considered cost-saving in 20 years if the price is reduced by 90%. The number of eligible MSM in Catalonia ranges from 5,989 to 10,972. At current antiretroviral costs, the annual cost would range between ?25.3-46.7 million/year (on demand PrEP), and ?42.9-78.7 million/year (daily basis PrEP). PrEP is most cost-effective if targeted towards groups with high incidence rates of over 3%/year. Beneficial ICER depends on reducing the current price of Truvada(r) and ensuring that effectiveness is maintained at high levels. PMID- 29262692 TI - Optimization of the EC26-2A4 Epitope in the gp41 Membrane Proximal External Region Targeted by Neutralizing Antibodies from an Elite Controller. AB - The analysis of patient derived HIV neutralizing antibodies (nAbs) and their target epitopes in the viral envelope (Env) protein provides important basic information for vaccine design. In this study we optimized an epitope, EC26-2A4, that is targeted by neutralizing antibodies from an elite controller (EC26) and localizes in the membrane-proximal external region from the gp41 transmembrane protein. Due to its overlap with the epitope of the first generation broadly neutralizing monoclonal Ab (mAb) 2F5 associated with autoreactivity, we first defined the minimal core epitope reacting with antibodies from EC26 plasma, but not with mAb 2F5. The optimized minimal epitope, EC26-2A4DeltaM, was able to induce neutralizing antibodies in vaccinated mice. We further analyzed the frequency of antibodies against the EC26-2A4DeltaM peptide in HIV-positive patient sera from a treated cohort and an untreated long-term nonprogressor (LTNP) cohort. Interestingly, 27% of the LTNP sera reacted with the peptide, whereas only 9% showed reactivity in the treated cohort. Although there was no association between the presence of antibodies against the EC26-2A4DeltaM epitope and viral load or CD4 count in these patients, the CD4 nadir in the treated cohort was higher in patients positive for EC26-2A4DeltaM antibodies, in particular in patients having such antibodies at an early and a late timepoint after infection. PMID- 29262695 TI - Dextran sulphate sodium (DSS) causes intestinal histopathology and inflammatory changes consistent with increased gut leakiness in chickens. AB - 1. The clinical severity, histological changes, indicators of gut leakiness and inflammatory cytokine profiles were studied in chickens with dextran sulphate sodium (DSS)-induced intestinal inflammation. 2. The experimental groups (1.25%, 1.5% and 2.5% DSS) showed clinical signs, such as loose stools and weight loss, which increased with additional treatment days and, as expected, the effects of DSS-induced intestinal inflammation were time and dose-dependent. 3. After 10 d, histological manifestations were evident, including goblet cell depletion, mucus layer loss, significantly shorter villi and a thinner total ileal mucosa. 4. The d(-)-lactate value, which was used as a gut leakiness indicator, was significantly increased in the 2.5% DSS group. 5. Expression of the inflammatory cytokines interleukin-1Beta, tumour necrosis factor alpha and interleukin-10 in the serum significantly increased with DSS treatment. 6. This study indicates that the experimental intestinal inflammation induced by DSS is an ideal model to study the pathogenic mechanisms of intestinal inflammation in chickens and to test the efficacy of therapies. PMID- 29262696 TI - Experiences of Female and Male Medical Students With Death, Dying, and Palliative Care: One Size Does Not Fit All. AB - BACKGROUND: Medical students learn about death, dying, and palliative care (DDPC) through formal curricular offerings and informal clinical experiences; however, the lessons learned in the clinic may be at odds with the formal curriculum. Reflective writing is a means for students to "bracket" their DDPC experiences and reconcile conflicts between the formal and informal curriculum. OBJECTIVES: The aim of this study is to compare the level of reflection demonstrated in medical students' narratives on DDPC with other experiences and to examine the domains of professionalism that students perceive to be prevalent in their DDPC experiences. METHODS: Third-year medical students submitted professionalism narratives during their internal medicine clerkship. We identified a subset of narratives related to DDPC (n = 388) and randomly selected control narratives (n = 153). We assessed the level of reflection demonstrated in the narratives using a validated rubric and analyzed the professionalism domains that students identified as relevant to their experience. RESULTS: There was no difference in reflective level between DDPC and control narratives. Within the DDPC group, female students demonstrated higher reflection (2.24 +/- 0.71) than male students (2.01 +/- 0.77; P < .001). Caring, compassion and communication, and honor and integrity were prominent among DDPC narratives. More females identified caring, compassion, and communication as relevant to their DDPC experiences, whereas more males identified altruism. CONCLUSION: Males and females have different perceptions of DDPC experiences, and female students appear to be more deeply impacted. These findings can help clinical faculty engage students more effectively with this challenging topic. PMID- 29262697 TI - Vancomycin Dosing in Obese Patients: Special Considerations and Novel Dosing Strategies. AB - OBJECTIVE: To review the literature regarding vancomycin pharmacokinetics in obese patients and strategies used to improve dosing in this population. DATA SOURCES: PubMed, EMBASE (1974 to November 2017), and Google Scholar searches were conducted using the search terms vancomycin, obese, obesity, pharmacokinetics, strategy, and dosing. Additional articles were selected from reference lists of selected studies. STUDY SELECTION AND DATA EXTRACTION: Included articles were those published in English with a primary focus on vancomycin pharmacokinetic parameters in obese patients and practical vancomycin dosing strategies, clinical experiences, or challenges of dosing vancomycin in this population. DATA SYNTHESIS: Volume of distribution and clearance are the pharmacokinetic parameters that most often affect vancomycin dosing in obese patients; both are increased in this population. Challenges with dosing in obese patients include inconsistent and inadequate dosing, observations that the obese population may not be homogeneous, and reports of an increased likelihood of supratherapeutic trough concentrations. Investigators have revised and developed dosing and monitoring protocols to address these challenges. These approaches improved target trough attainment to varying degrees. CONCLUSIONS: Some of the vancomycin dosing approaches provided promising results in obese patients, but there were notable differences in methods used to develop these approaches, and sample sizes were small. Although some approaches can be considered for validation in individual institutions, further research is warranted. This may include validating approaches in larger populations with narrower obesity severity ranges, investigating target attainment in indication-specific target ranges, and evaluating the impact of different dosing weights and methods of creatinine clearance calculation. PMID- 29262698 TI - An Application for the Quantitative Analysis of Pharmaceutical Tablets Using a Rapid Switching System Between a Near-Infrared Spectrometer and a Portable Near Infrared Imaging System Equipped with Fiber Optics. AB - We present a rapid switching system between a newly developed near-infrared (NIR) spectrometer and its imaging system to select the spot size of a diffuse reflectance (DR) probe. In a previous study, we developed a portable NIR imaging system, known as D-NIRs, which has significant advantages over other systems. Its high speed, high spectral resolution, and portability are particularly useful in the process of monitoring pharmaceutical tablets. However, the spectral accuracies relating to the changes in the formulation of the pharmaceutical tablets have not been fully discussed. Therefore, we improved the rapid optical switching system and present a new model of D-NIRs (ND-NIRs) here. This system can automatically switch the optical paths of the DR and NIR imaging probes, greatly contributing to the simultaneous measurement of both the imaging and spot. The NIR spectra of the model tablets, including 0-10% ascorbic acid, were measured and simultaneous NIR images of the tablets were obtained. The predicted results using spot sizes for the DR probe of 1 and 5 mm diameter, resulted in concentrations of R2 = 0.79 and 0.94, with root mean square errors (RMSE) of 1.78 and 0.89, respectively. For tablets with a high concentration of ascorbic acid, the NIR imaging results showed inhomogeneity in concentration. However, the predicted values for the low concentration samples appeared higher than the known concentration of the tablets, although the homogeneity of the concentration was confirmed. In addition, the optimal spot size using NIR imaging data was estimated to be 5-7 mm. The results obtained in this study show that the spot size of the fiber probe, attached to a spectrometer, is important in developing a highly reliable model to determine the component concentration of a tablet. PMID- 29262699 TI - Influences on selection of assistive technology for young children in South Africa: perspectives from rehabilitation professionals. AB - : Selection of assistive technology for young children is a complex process. Within a context with limited resources, such as South Africa, research is needed to determine the factors influencing the assistive technology selection process, as these could ultimately either facilitate or hinder the availability and accessibility of affordable, adaptable, acceptable, and high quality assistive technology for this age group. METHOD: Two asynchronous online focus groups were conducted with 16 rehabilitation professionals to identify the factors they perceived to influence the selection and provision of assistive technology to young children within the South African context. DATA ANALYSIS: A process of deductive thematic analysis was followed by inductive analysis of the data. Components of the Assistive Technology Device Selection Framework were used as themes to guide the deductive analysis, followed by inductive analysis to create subthemes. DISCUSSION: The important role of the professional was highlighted in negotiating all the factors to consider in the assistive technology selection and provision process. Adaptation of the Assistive Technology Device Selection Framework is suggested in order to facilitate application to low resourced contexts, such as South Africa. Implications for rehabilitation Assistive technology selection is a complex process with factors pertaining to the users (child and family) of the assistive technology, as well as the rehabilitation professional recommending the assistive technology influencing the process. Although it may be an important factor, the availability of financial resources to purchase assistive technology is not the only determining factor in providing appropriate assistive technology to young children in contexts with limited resources. Formalized support, such as reflective supervision or mentorship programs should be facilitated and utilized by recommending professionals. Home and school visits during assessment ensure a good match between assistive technology and users within the particular context. Facilitating the availability of assistive technology for trial during assessment and/or for a period afterwards will increase the likelihood that appropriate recommendations for assistive technology are made. PMID- 29262700 TI - Early Clinically Relevant Improvement in Quality of Life and Clinical Outcomes 1 Year Postsurgery in Patients with Knee and Hip Joint Arthroplasties. AB - Objective To measure and identify the determinants of the outcomes after hip/knee arthroplasty (HA/KA) in patients with osteoarthritis during the first postsurgical year. Design In this prospective observational study, we evaluated the preoperative and postoperative (3, 6, and 12 months) outcomes of 626 patients who underwent HA (346 with median age 65 years, 59% female) or KA (280 with median age 66.5 years, 54% female) between 2008 and 2013. Generic and specific tools were used to measure health-related quality of life (HRQoL) and utility. Good outcome was defined as an improvement in WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) greater than or equal to the minimal important difference (MID). Regressions were performed to evaluate the relationship between preoperative and postoperative measures and evolution of WOMAC/good outcome. Results We observed an almost systematic improvement of all parameters for up to 12 months, but especially at the 3-month follow-up. The low number of comorbidities and the absence of postoperative complications were the common determinants of improvement of WOMAC total score after 12 months. Other parameters (background of the joint, preoperative function and length of hospital stay in KA group; place of discharge in HA group) affected the evolution of WOMAC scores. 87.09% of HA and 73.06% of KA patients experienced a good outcome. A small number of comorbidities, a worse preoperative function, a shortened hospital stay (KA only), and an absence of early postoperative complications (HA only) significantly predicted a good outcome. Conclusions Intermediate HRQoL following HA or KA improved quickly from preoperative levels for all instruments. More than 70% of patients achieved a good outcome defined as improved pain, stiffness and disability and the predictors are slightly close. PMID- 29262702 TI - Successful Return to Sport Following Distal Femoral Varus Osteotomy. AB - Objective Distal femoral varus osteotomy (DFVO) is an effective treatment for unloading valgus knee malalignment; however, there is limited evidence on the ability for patients to return to athletics following this procedure. The purpose of this study is to report the functional outcomes and rate of return to sport for athletes that underwent DFVO. Design A consecutive series of athletes that had undergone DFVO were retrospectively reviewed. Radiographs were assessed to determine preoperative and postoperative alignment. Institutional registries were used to collect preoperative and postoperative Marx Activity Scale, International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form scores, and return to sport. Results Thirteen patients (8 males, 5 females) with a mean age of 24 years (range 17-35 years) and a mean follow-up of 43 months (range 24-74 months) were included in the study. Six patients underwent medial closing wedge DFVO versus 7 patients who underwent lateral opening wedge DFVO. Nine of 13 had concomitant chondral, meniscal, or ligamentous procedures performed. The mean alignment correction was 8 degrees (range 5 degrees -13 degrees ). All patients were able to successfully return to sport at a mean of 11 months (range 9-13 months). Furthermore, all 13 patients demonstrated an improvement in both Marx Activity Scale (4-11; P < 0.01) and IKDC scores (53-89; P < 0.01) after surgery. Conclusions Correction of valgus knee malalignment through DFVO-either medial closing wedge or lateral opening wedge-can reliably result in improvement in function and return to sport. Concomitant chondral, meniscal, and ligamentous pathology should be addressed. PMID- 29262701 TI - Optimization of Extracellular Matrix Synthesis and Accumulation by Human Articular Chondrocytes in 3-Dimensional Construct with Repetitive Hydrostatic Pressure. AB - Objective The effects of hydrostatic pressure (HP) on the matrix synthesis by human articular chondrocytes have been reported elsewhere. In order to optimize the production of extracellular matrix, we aimed to clarify the effects of repetitive HP on metabolic function by human articular chondrocytes. Design The human articular chondrocytes were expanded and embedded within a collagen gel/sponge scaffold. We incubated these constructs with and without HP followed by atmospheric pressure (AP) and repeated the second HP followed by AP over 14 days. Genomic, biochemical, and histological evaluation were performed to compare the effects of each regimen on the constructs. Results The gene expressions of collagen type II and aggrecan core protein were significantly upregulated with repetitive HP regimens compared with a single HP or AP by 14 days ( P < 0.01 or 0.05). Matrix metalloptoteinase-13 (MMP-13) in AP was upregulated significantly compared to other HP regimens at day 14 ( P < 0.01). No significant difference was observed in tissue inhibitor of metalloproteinases-II. Immunohistology demonstrated that application of HP (both repetitive and single) promoted the accumulation of specific extracellular matrix and reduced a MMP-13. A single regimen of HP followed by AP significantly increased the amount of sulfated glycosaminoglycan than that of the AP, whereas repetitive HP remained similar level of that of the AP. Conclusions Repetitive HP had a greater effect on anabolic activity by chondrocytes than a single HP regimen, which will be advantageous for producing a matrix-rich cell construct. PMID- 29262703 TI - Inhibitory effects of four neonicotinoid active ingredients on acetylcholine esterase activity. AB - There is a great concern about the decline of pollinators, and neonicotinoids emerging bee disorders are assumed to play a significant role. Since changes in learning ability has been observed in honey bees exposed to some acetylcholine esterase (AChE) inhibitors, we therefore, tested in vitro the effect of four neonicotinoids on purified eel AChE. AChE activity was inhibited in a concentration-dependent manner, and calculated IC50 values for thiamethoxam (IC50 = 414 MUM) and clothianidin (IC50 = 160 MUM) were found to be much higher compared to acetamiprid (IC50 = 75.2 MUM) and thiacloprid (IC50 = 87.8 MUM). The Lineweaver-Burk reciprocal plots for acetamiprid shows unchanged Vmax and increased Km values with inhibitor concentrations, while analysis of Michaelis Menten plots shows predominantly competitive mechanism. The inhibition constant value (Ki = 24.3 MUM) indicates strong binding of the acetamiprid complex to AChE. Finally, the four tested neonicotinoids are not a uniform group regarding their blocking ability. Our results suggest a previously not established, direct AChE blocking mechanism of neonicotinoids tested, thus the neuronal AChE enzyme is likely among the direct targets of the neonicotinoid insecticides. We conclude, that these AChE inhibitory effects may also contribute to toxic effects on the whole exposed animal. PMID- 29262704 TI - Comparison of the production and chemical constituents of five Perilla frutescens (L.) Britt. accessions. AB - An open field experiment was carried out with five purple Perilla frutescens accessions (588P, GB, J3, JTD3, PS3) in 2014 and 2015. Morphological traits, production, total phenolic content (TPC), essential oil content (EOC) and composition as well as the antioxidant capacity (AOC) were investigated. Highest biomass was produced by JTD3 in both years. The antioxidant capacity and total phenolic content in the stems was lower than in the leaves in all accessions. Leaves of accession GB produced the highest AOC values (215.594 +/- 1.437 in 2014 and 86.609 +/- 3.602 mg AAE g-1 in 2015, respectively) while the strain 588P showed the lowest values (139.544 +/- 1.934 in 2014 and 38.966 +/- 4.569 mg AAE g 1 in 2015, respectively). The highest TPC values were measured by PS3 in 2014 (204.320 +/- 1.822 mg GAE g-1) and GB in 2015 (136.450 +/- mg GAE g-1). The 588P produced the highest essential oil content (1.432 ml 100 g-1 DM) while J3 had the lowest (0.144 ml 100 g-1 DM) in both years. Strong positive correlation was found between the density of glandular hairs and the essential oil content. Three accessions (588P, J3, JTD3) belong to the perillaldehyde chemotype while GB and PS3 to the dehydro elsholtzia ketone chemotype. All studied accessions can be cultivated in Hungary. For the biomass production the JTD3, while for the essential oil production the 588P can be recommended. PMID- 29262705 TI - Salinity tolerance of grafted watermelon seedlings. AB - In order to evaluate the salinity tolerance of grafted watermelon, two sets of experiments were conducted in a growing chamber where 'Esmeralda' varieties were grafted onto interspecific squash (Cucurbita maxima Duch. * Cucurbita moschata Duch.) and Lagenaria siceraria rootstocks. Both non-grafted and self-garfted plants were used for control. For salt stress, 2.85 and 4.28 mM/l substrate doses of NaCl were added with each irrigation in 2 day intervals for a duration of 23 days. Interspecific-grafted plants showed the highest salinity tolerance as plant biomass and leaf area were not decreased but improved by salinity in most cases. Furthermore, transpiration and photosynthesis activity did not decrease as much as it did in the case of other grafting combinations. Interspecific and Lagenaria rootstocks showed sodium retention, as elevation of Na+ content in the leaves of these grafting combinations was negligible compared to self-grafted and non grafted ones. Presumably abiotic stress tolerance can be enhanced by grafting per se considering measured parameters of self-grafted plants did not decrease as much as seen in non-grafted ones. PMID- 29262706 TI - In silico characterisation of novel rice transcripts differentially expressed in phosphorus dificient conditions suggests a role of these transcripts in multiple abiotic stresses. AB - Phosphorus deficiency adversely affects crop productivity. The mechanism of tolerance in plants is not well understood. The current study successfully annotated a set of highly significant (Log2 RPKM >=3) nine novel sequences up regulated in P deficient condition identified from a low P tolerant rice genotype. Sequence annotation identified two transcripts (Os01g37260 and Os02g11060) carrying known domains, F-box and WD, respectively. Multiple Expectation maximization for Motif Elicitation (MEME) revealed presence of conserved domains like D[LP][HY][CL]D[CM][DT]C[AP][DQ][IQ]C, [EH][DN]HN[HS] [ER][FY][EP]I[HN]H which might play a role in phosphorus deficiency tolerance. Analysis of the upstream regions indicated presence of stress responsive elements like E Box, ABRE, and MYBCORE suggesting regulation of the novel transcripts by DNA binding. Protein localization prediction tool suggests that these novel proteins might be targeted to nucleus, chloroplast and cell wall. Transcripts Os02g03640 and Os02g10250 revealed potential target sites for microRNA binding suggesting role of novel miRNAs in low phosphorus response. Our analysis suggests that an F-box protein, Os01g37260 (OSFBx14) might be a promising candidate gene playing a role in multiple abiotic stresses including P deficiency. PMID- 29262708 TI - In vivo screening of diterpene alkaloids using bdelloid rotifer assays. AB - The group of diterpene alkaloids contains numerous compounds with complex chemistry and diverse pharmacological activities. Beside toxicity, these compounds possess activity on the cardiovascular system, tumor cell lines and nervous system. The pharmacological properties have been described using in vitro and in vivo techniques; however, the bioactivities of many compounds have not thoroughly been studied. Here we report on the in vivo evaluation of ten diterpene alkaloids using bdelloid rotifer assays. Napelline exerted toxic effects on rotifers, while wide tolerance range was observed for other investigated compounds. Weak toxicity of songorine is supported by our experiment. Toxicological data for senbusine A, senbusine C, septentrioidine and hetisinone are reported for the first time. PMID- 29262707 TI - Hydrogen peroxide prolongs mitotic arrest in a dose dependent manner and independently of the spindle assembly checkpoint activity in Saccharomyces cerevisiae. AB - Oxidative stress and chromosome missegregation are important factors that are linked to aneuploidy. A major reason for chromosome missegragation is the inappropriate activity of the spindle assembly checkpoint (SAC), a conserved surveillance mechanism that monitors the state of kinetochore-microtubule attachments to ensure equal chromosome segregation in mitosis. SAC-activation induces a prolonged mitotic arrest. Mitosis is considered the most vulnerable cell cycle phase to several external signals, therefore increasing the time cells spent in this phase via mitotic arrest induction by SAC-activating agents is favorable for cancer therapy. Cancer cells also display elevated oxidative stress due to abnormally high production of reactive oxygen species (ROS). However, the effect of increased oxidative stress on the duration of mitotic arrest remains largely unknown. In this study, we investigated the effect of H2O2-induced oxidative stress on the mitotic arrest induced by a SAC-activating agent (nocodazole) in Saccharomyces cerevisiae. Our data suggest that oxidative stress prolongs SAC-activation induced mitotic arrest in a dose dependent manner. We, in addition, investigated the effect of H2O2 treatment on the mitotic arrest induced independently of SAC-activation by using a conditional mutant (cdc23) and showed that the effect of H2O2-induced oxidative stress on mitotic arrest is independent of the SAC activity. PMID- 29262709 TI - Chemical composition and antimicrobial activity of the commercial Origanum onites L. oil against nosocomial carbapenem resistant extended spectrum beta lactamase producer Escherichia coli isolates. AB - In recent years rapidly growing antibiotic resistance has increased interest toward natural products, especially essential oils because of their various effects. The aim of this study was to identify the chemical composition of the commercial Origanum onites essential oil (EO) and to investigate the antimicrobial activity by disc diffusion and dilution methods, against ten different ATCC strains, including eight bacteria, two yeasts and seventy-nine clinical nosocomial Escherichia coli isolates that produce extended spectrum beta lactamase (ESBL). The chemical composition of EO was analyzed by GC and GC-MS. The major compounds of the EO were determined as carvacrol (51.4%) followed by linalool (11.2%), p-cymene (8.9%) and gamma-terpinene (6.7%). O. onites EO had antimicrobial activity against all standard strains and inhibited microbial growth of ESBL positive E. coli isolates. According to our results, O. onites EO may be an alternative to synthetic drug, used in combination with other antibiotics for treatment of infection caused by multidrug resistant bacteria after testing toxic effects and irritation at preferred doses on human. PMID- 29262710 TI - Establishment of an efficient plant regeneration culture protocol and achievement of successful genetic transformation in Jatropha curcas L. AB - An efficient and reproducible protocol is described for shoot-bud regeneration and Agrobacterium tumefaciens-mediated genetic transformation of J. curcas. Treating the explants with high concentrations (5-120 mg/L) of TDZ for short durations (5-80 min) before inoculation culture increased significantly the regeneration frequency and improved the quality of the regenerated buds. The highest shoot-buds induction rate (87.35%) was achieved when petiole explants were treated with 20 mg/L TDZ solution for 20 min and inoculated on hormone-free MS medium for 30 days. Regenerated shoots of 0.5 cm or a little longer were isolated and grafted to seedling stocks of the same species, and then the grafted plantlets were planted on half-strength MS medium containing 0.1 mg/L IBA and 2 mg/L sodium nitroprusside (SNP). This grafting strategy was found to be very effective, to obtain that healthy grafted plantlets ready for acclimatization within 20 days. By the above mentioned protocol and with general Agrobacterium - mediated genetic transformation methods only 65 days were needed to obtain intact transgenic plants. PMID- 29262711 TI - Hydrogen peroxide induced oxidative damage on mechanical properties of the articular cartilage. AB - Articular cartilage has unique mechanical and physicochemical properties which are responsible for its load carrying capabilities. This work investigates the effects of hydrogen peroxide induced oxidative damage on mechanical properties of articular cartilage. Bovine articular cartilage was exposed to hydrogen peroxide for a week. Dynamic and static mechanical tests applied to calculate articular cartilage compressive modulus. We observed higher control curve slopes than that of hydrogen peroxide curves which account for lesser stiffness values in the exposed articular cartilage. For the instantaneous experiments, results were statistically significant (p = 0.01, p < 0.05). Here report that hydrogen peroxide induced oxidative damage causes reduction in the stiffness of the articular cartilage. PMID- 29262712 TI - Acetaldehyde suppresses growth, changes conidia morphology and reduces the production of adenosine 3',5'-cyclic monophosphate in a dose dependent manner in Alternaria alternata. AB - One-day-old cultures of the plant pathogenic fungus Alternaria alternata were exposed to 0%, 5% and 10% acetaldehyde mixed with distilled water. Fungal growth data showed that, overall, the 5% and the 10% acetaldehyde treatments significantly inhibited the growth of A. alternata, and that acetyldehyde also facilitated maturity and multicellularity of fungal conidia. The increase of the acetyldehyde dose also caused correlated decrease of adenosine 3',5'-cyclic monophosphate produced by A. alternata. PMID- 29262713 TI - Electro-antennographic response of Helopeltis theivora to synthetic pesticides used in tea plantations. AB - Helopeltis theivora is considered as one of the major pest in tea plantations causing considerable economic damage. Recent control strategies against this notorious polyphagous pest mainly depend on the application of insecticides. The study is focused on the antennal response of H. theivora on exposure to different insecticides using electroantenogram (EAG). The result showed that the insects perceive quinalphos as they are frequently exposed to it. The hierarchy of the EAG response of exposed and unexposed insects was quinalphos > bifenthrin > deltamethrin > thiamethoxam. PMID- 29262714 TI - Cinnamic acid and fish flour affect wheat phenolic acids and flavonoid compounds, lipid peroxidation, proline levels under salt stress. AB - To elucidate the physiological mechanism of salt stress mitigated by cinnamic acid (CA) and fish flour (FF) pretreatment, wheat was pretreated with 20, 50 and 100 ppm CA and 1 g/10 mL FF for 2 d and was then cultivated. We investigated whether exogenous CA + FF could protect wheat from salt stress and examined whether the protective effect was associated with the regulation of seed vigor, antioxidant defense systems, phenolic biosynthesis and lipid peroxidation. At 2 days exogenous CA did not influence seed vigor. Salt stress increased the phenolic biosynthesis, but the CA + FF-combined pretreatment enhanced the phenolic biosynthesis even more under salt stress and decreased lipid peroxidation to some extent, enhancing the tolerance of wheat to salt stress. PMID- 29262715 TI - How arbuscular mycorrhizal fungi influence the defense system of sunflower during different abiotic stresses. AB - The association between terrestrial plants and arbuscular mycorrhizal (AM) fungi is one of the most common and widespread mutualistic plant-fungi interaction. AM fungi are of beneficial effects on the water and nutrient uptake of plants and increase plant defense mechanisms to alleviate different stresses. The aim of this study was to determine the level of polyphenol oxidase (PPO), guaiacol peroxidase (POX) and glutathione S-transferase (GST) enzyme activities and to track the expression of glutathione S-transferase (GST) gene in plant-arbuscular mycorrhizal system under temperature- and mechanical stress conditions. Our results suggest that induced tolerance of mycorrhizal sunflower to high temperature may be attributed to the induction of GST, POX and PPO enzyme activities as well as to the elevated expression of GST. However, the degree of tolerance of the plant is significantly influenced by the age which is probably justified by the energy considerations. PMID- 29262716 TI - Perspectives of children and adolescents on the perceived determinants of physical activity during recess. AB - Promotion of healthy lifestyles in youth focuses on school-based interventions with the aim to increase physical activity (PA) during school days. Drawing on seventeen focus group discussions from three purposively selected Estonian schools, we explored factors that perceivably affect students' recess physical activity (RPA). Both inductive and deductive principles of data analysis were used to extract major and subthemes related to factors that inhibit or enhance RPA. Participants identified barriers and facilitators to recess PA as originating mainly from physical and organizational school environment. Also, unsuitable weather was described as a barrier to being active. Additionally, feelings, behavioral and normative beliefs were described as constraining or facilitating RPA. Results highlighted two culture-specific unique perceived determinants of RPA that need to be addressed during the development of school based interventions to increase PA. PMID- 29262717 TI - Family structure and children's unmet health-care needs. AB - This study assessed children's unmet health-care needs within different family types (two-parent biological/adoptive, two-parent stepfamily, and single-mother family type) using data from the 2011/2012 National Survey of Children's Health. Findings indicate that 10.4% of children in single-mother family types had unmet health-care needs compared to 8.7% of children from a two-parent stepfamily and 5.3% for those from two-parent biological/adoptive families. Further analyses revealed racial/ethnic disparities with Black children from two parent biological/adoptive families being 1.54 (95% confidence interval 1.13, 2.05) times more likely to have unmet health-care needs, while Hispanic children were less likely to have unmet health-care needs relative to their white counterparts. Children from lower income two-parent families had a higher likelihood of unmet health-care needs. The noncontinuous insurance coverage was a risk factor for increasing unmet health-care needs across all three different family types. These findings show major differences in unmet health-care needs among children living in different family structure types. It is recommended that interventions for increasing access to care need to be tailored differently across various family types in order to achieve continuous and sufficient health-care services for our children. PMID- 29262718 TI - Procrastination and predictor variables among a group of dental students in Turkey. AB - The aim of this study was to assess the prevalence of procrastination among a group of Turkish dental students and to determine the predictors and consequences of procrastination. A total number of 273 females and 179 males (aged between 18 and 28) were included in the study. Tuckman procrastination scale, Academic Life Satisfaction Scale, Concern over Mistake Scale, Poor Time Management Scale, Self Doubt Scale, Irrational Beliefs about Studying Scale, Positive and Negative Affect Schedule and Life Satisfaction Scale were used to gather data. Results indicated that 50% of participants were more likely to procrastinate their academic assignments or tasks. Procrastination score did not differ according to gender. The findings suggested that procrastinating students had a higher level of poor time management, self-doubt and irrational beliefs about studying, and poor academic performance and well-being than their non-procrastinating counterparts. Preventive strategies are necessary to overcome procrastination which affects the academic achievement, satisfaction, and well-being of dental students. PMID- 29262719 TI - Kaurenoic acid extracted from Sphagneticola trilobata reduces acetaminophen induced hepatotoxicity through inhibition of oxidative stress and pro inflammatory cytokine production in mice. AB - Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses. However, acetaminophen overdose can be fatal. Currently, the only treatment available is the N-acetyl cysteine. The diterpene kaurenoic acid (ent-kaur-16-en-19-oic acid, KA) is the major constituent of Sphagneticola trilobata (L.) Pruski. KA presents anti-inflammatory, anti nociceptive and antioxidant properties. In this study, we evaluated the efficacy of KA in a model of acetaminophen-induced hepatotoxicity. KA increased, in a dose dependent manner, the survival rate after acetaminophen overdose. KA reduced acetaminophen-induced hepatic necrosis and ALT and AST levels. KA decreased acetaminophen-induced neutrophil and macrophage recruitment, oxidative stress and the production of IL-33, TNF-alpha and IL-1beta, alongside with normalisation of IL-10 levels in the liver. Therefore, KA showed preclinical efficacy in acetaminophen-induced hepatotoxicity and lethality. PMID- 29262720 TI - Impact of host cell line choice on glycan profile. AB - Protein glycosylation is post-translational modification (PTM) which is important for pharmacokinetics and immunogenicity of recombinant glycoprotein therapeutics. As a result of variations in monosaccharide composition, glycosidic linkages and glycan branching, glycosylation introduces considerable complexity and heterogeneity to therapeutics. The host cell line used to produce the glycoprotein has a strong influence on the glycosylation because different host systems may express varying repertoire of glycosylation enzymes and transporters that contributes to specificity and heterogeneity in glycosylation profiles. In this review, we discuss the types of host cell lines currently used for recombinant therapeutic production, their glycosylation potential and the resultant impact on glycoprotein properties. In addition, we compare the reported glycosylation profiles of four recombinant glycoproteins: immunoglobulin G (IgG), coagulation factor VII (FVII), erythropoietin (EPO) and alpha-1 antitrypsin (A1AT) produced in different mammalian cells to establish the influence of mammalian host cell lines on glycosylation. PMID- 29262721 TI - BCL6 as a therapeutic target for lymphoma. AB - INTRODUCTION: B cell lymphoma 6 (BCL6) is a transcriptional repressor critical for the development and maintenance of germinal centers (GCs), which are required for generation of an effective humoral immune response. Genomic aberrations of BCL6, including mutations and translocations that occur during the GC reaction, as well as alterations of genes that regulate BCL6 expression, lead to sustained activity of BCL6, which promotes the development of GC-derived lymphomas. Since many types of B cell non-Hodgkin lymphomas (B-NHL) arise from neoplastic transformation of GC B cells and a high proportion harbor genetic lesions that deregulate BCL6 expression, inhibition of BCL6 has emerged as an attractive therapeutic strategy for lymphomas. Areas covered: This review examines the rationale for and challenges in therapeutic targeting of BCL6 in lymphomas. We describe approaches that have been used and are currently being considered for inhibition of BCL6. Expert opinion: Several BCL6 inhibiting agents, including peptidomimetics, small molecules, and natural compounds, most of which target the BTB domain of the protein at the corepressor binding site, have been developed with demonstration of anti-lymphoma activity in preclinical models. Future clinical trials will be important to investigate the efficacy of targeting BCL6 in B-NHL (and other neoplasms), particularly in combination with other therapies. PMID- 29262722 TI - Syndesmotic Injury Assessment With Lateral Imaging During Stress Testing in a Cadaveric Model. AB - BACKGROUND: External rotation, lateral, and sagittal stress tests are commonly used to diagnose syndesmotic injuries, but their efficacy remains unclear. The purpose of this study was to characterize applied stresses with fibular motion throughout the syndesmotic injury spectrum. We hypothesized that sagittal fibular motion would have greater fidelity in detecting changes in syndesmotic status compared to mortise imaging. METHODS: Syndesmotic instability was characterized using motion analysis during external rotation, lateral, and sagittal stress tests on cadaveric specimens (n = 9). A progressive syndesmotic injury was created by sectioning the tibiofibular and deltoid ligaments. Applied loads and fibular motion were synchronously measured using a force transducer and motion capture, respectively, while mortise and lateral radiographs were acquired to quantify clinical measurements. Fibular motion in response to these 3 stress tests was compared between the intact, complete lateral syndesmotic injury and lateral injury plus a completely sectioned deltoid condition. RESULTS: Stress tests performed under lateral imaging detected syndesmotic injuries with greater sensitivity than the clinical-standard mortise view. Lateral imaging was twice as sensitive to applied loads as mortise view imaging. Specifically, half as much linear force generated 2 mm of detectable syndesmotic motion. In addition, fibular motion increased linearly in response to sagittal stresses (Pearson's r [rho] = 0.91 +/- 0.1) but not lateral stresses (rho = 0.29 +/- 0.66). CONCLUSION: Stress tests using lateral imaging detected syndesmotic injuries with greater sensitivity than a typical mortise view. In addition to greater diagnostic sensitivity, reduced loads were required to detect injuries. CLINICAL RELEVANCE: Syndesmotic injuries may be better diagnosed using stress tests that are assessed using lateral imaging than standard mortise view imaging. PMID- 29262723 TI - Efficacy of Particulated Juvenile Cartilage Allograft Transplantation for Osteochondral Lesions of the Talus. AB - BACKGROUND: Particulated juvenile cartilage allograft transplantation (PJCAT) is a novel treatment option for osteochondral lesions of the talus (OLTs). It is typically employed as a salvage procedure after initial debridement and microfracture has failed as it is theorized to deliver viable hyaline cartilage. We hypothesized that PJCAT would be a safe and effective treatment option for OLTs. METHODS: This is a retrospective case-control study of patients who underwent PJCAT for the treatment of OLTs at a single academic institution. Failure of the procedure was defined as no change or worsening of symptoms and/or the need for a subsequent cartilage restoration procedure. Variables recorded included preoperative magnetic resonance imaging (MRI) area and volume, intraoperative size, etiology, lesion location, sex, age, body mass index (BMI), history of prior surgery, American Orthopaedic Foot & Ankle Society score, and foot and ankle outcome score. Fifteen patients completed a minimum of 12 months of follow-up (mean, 34.6 months). RESULTS: The failure rate of PJCAT in this series was 40% (6/15). Preoperative MRI area and intraoperative OLT size along with male sex were predictive of failure ( P < .05). Age, BMI, etiology, technique (open vs arthroscopic), history of prior surgery, and location of lesion were not predictors of failure in this limited series ( P > .05). Patients with lesions greater than 125 mm2 area had a significant increased risk of clinical failure ( P < .05). Functional outcome scores were significantly better at final follow-up in the patients who had undergone successful treatment vs those who did not. CONCLUSION: These findings demonstrate the association of preoperative MRI lesion area, intraoperative lesion size, and male sex as risk factors for failure of PJCAT setting of an already difficult to treat pathology. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29262724 TI - Nucleoside alkaloids with anti-platelet aggregation activity from the rhizomes of Ligusticum striatum. AB - Two new (1-2) and six known (3-8) nucleoside alkaloids were isolated from the rhizomes of Ligusticum striatum DC. Compounds 1 and 2 (liguadenosines A and B) were unusual N-10 substituted adenosine derivatives. Their structures were elucidated by extensive spectroscopic analyses and ECD calculation. Most of them significantly inhibited the abnormal increase in platelet aggregation induced by ADP at concentrations of 50 and 100 MUM. Particularly, the inhibitory effect of 3 was equivalent to aspirin. PMID- 29262725 TI - Does Valproic Acid/Na Valproate Suppress Auditory Startle Reflex in Patients With Epilepsy? AB - BACKGROUND AND OBJECTIVE: Auditory startle response (ASR) was normal in juvenile myoclonic epilepsy whereas it was suppressed in progressive myoclonic epilepsy. However, both groups were using valproic acid/Na valproate (VPA) in different doses. Therefore, we aimed to analyze whether VPA has an impact on ASR in a cohort of epilepsy. For this purpose, we included patients with epilepsy and analyzed ASR in patients who were using VPA. PATIENTS AND METHOD: We included 51 consecutive patients who had epilepsy and were using VPA between January 2014 and January 2016. Two control groups of 37 epilepsy patients using other antiepileptic drugs (AEDs) and of 25 healthy subjects were also constituted. All participants underwent investigations of ASR and startle response to somatosensory inputs (SSS) under similar conditions. RESULTS: An analysis of patients using VPA, not using VPA and healthy subjects revealed significantly longer latency and lower probability of orbicularis oculi (O.oc) and sternocleidomastoid responses after auditory stimulation, decreased total ASR probability and longer latency of O.oc response after somatosensory stimulation in patient groups compared with healthy subjects. Multivariate analysis showed type of AED had a role in the generation of abnormalities. VPA, carbamazepine, and multiple AED use caused suppression of ASR. Total ASR probability was decreased or O.oc latency got longer with longer duration of VPA use whereas serum VPA level at the time of investigation did not correlate with total ASR probability. DISCUSSION: Both ASR and SSS are suppressed by the effect of VPA, especially in patients using for a long period and in patients using other AEDs with VPA. Given the fact that VPA leads to long-standing synaptic changes of dopaminergic transmission, abnormalities of this network may be the more likely cause. PMID- 29262726 TI - Phytochemical analysis of non-polar solvent extracts of the Wisteria sinensis leaves. AB - A comparative study on the phytochemical composition of the n-hexane and chloroform extracts from Wisteria sinensis leaves collected in June and October is described. Continuous extraction in Soxhlet apparatus, as well as ultrasound assisted technique, was used for the preparation of the extracts. All the extracts were analysed by GC/MS method. As a result, alpha-tocopherol was identified as the main component (56%) of the extracts from October leaves, whereas, beta-sitosterol was identified as the main compound (47%) in the extracts from the June leaves. Additionally, pure alpha-tocopherol was isolated from n-hexane extract of the October leaves using column chromatography. A total of 6.25 mg of alpha-tocopherol was isolated from 1 g of dried leaves. The presence of the vitamin E in extracts from W. sinensis leaves is described here for the first time. PMID- 29262727 TI - Lymph node 8a as a prognostic marker for poorer prognosis in pancreatic and periampullary carcinoma. AB - OBJECTIVES: An investigation of patients with pancreatic carcinoma aims to identify those who will benefit from surgery. Physical examination, radiology and laboratory findings are helpful. Most prognostic markers, such as lymph node status, micro metastasis and tumour differentiation, are not preoperatively accessible. Metastatic disease in lymph node 8a (Ln8a) in patients operated for pancreatic carcinoma has been reported to be a predictor of shorter overall survival (OS). This lymph node can be assessed preoperatively through resection (possibly even with laparoscopy) and subsequent histopathology. The value of the procedure is disputed. The aim of this study is to investigate whether metastatic disease in Ln8a is a predictor of decreased OS. MATERIALS AND METHODS: In patients with suspected pancreatic or periampullary carcinoma, who were operated with pancreatoduodenectomy (PD), Ln8a was separately resected and analysed with standard and immuno-histochemical methods. Patients with or without metastasis in Ln8a were compared regarding OS. RESULTS: Between 2008 and 2011, 122 consecutive patients were eligible and 87 were resected and had LN8a analysed separately. Sixteen patients were Ln8a + and 71 were Ln8a-. Patients with Ln8a + had a significantly reduced median OS as compared to patients with Ln8a- (0.74 (95% CI 0.26-1.26) versus 5.91 years (95% CI 2.91-), p < .001). CONCLUSION: Ln8a + was associated with a marked reduction of OS, indicating a possible role in the future preoperative workup in patients with a suspicion of pancreatic cancer. PMID- 29262728 TI - Three new polyketides from fruiting bodies of the endophytic ascomycete Xylaria polymorpha. AB - The isolation of three new secondary metabolites from the fruiting body of Xylaria polymorpha is described. The new compounds are of mixed biosynthetic origin consisting of a polyketide starter, extended with a methyl orsellinate unit and terminated hydrolytically or with an amine-containing terminal unit. PMID- 29262729 TI - The peripheral blood transcriptome identifies dysregulation of inflammatory response genes in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, resulting in ovulation failure and other metabolic problems. However, the underlying mechanisms of it remain largely uncertain due to the complexity of clinical manifestations. This systemic disorder is involved in endocrine, metabolism, immune system and many organs, and few studies have explored peripheral blood transcriptome in patients with PCOS. We performed gene expression profiling of peripheral blood from 8 PCOS patients and eight healthy women with microarray. The significance analysis of microarray (SAM) software was employed to screen the differentially expressed genes (DEGs) and gene ontology (GO) was used for functional enrichment analysis. In total, 181 DEGs with fold changes >2.0 and q-values <0.05 were identified between the two groups. Among them, 149 were up-regulated and 32 down-regulated in PCOS. Unsupervised clustering of expressed genes could readily differentiate PCOS from control. More importantly, inflammatory response pathway including 14 dysregulated genes was highly enriched in PCOS. Furthermore, 10 DEGs were validated using quantitative reverse-transcription PCR (qRT-PCR) assays. Our study provides independent evidence for the involvement of systemic inflammatory response in PCOS and it may facilitate a greater understanding of this complex disease. PMID- 29262730 TI - Abuse-deterrent opioids: an update on current approaches and considerations. AB - OBJECTIVE: Abuse and misuse of prescription opioids is a significant public health concern. This review examines the strategies used to confer abuse deterrent properties on opioid abuse-deterrent formulations (ADFs), the characteristics and supporting data for each of the available ADFs, and the role of opioid ADFs as part of a comprehensive opioid risk management plan. METHODS: A PubMed search was performed for articles published within the last 10 years using the search terms "abuse deterrent opioids". Articles were limited to clinical studies and reviews focusing on United States (US) Food and Drug Administration (FDA)-approved opioid ADFs in the US. RESULTS: There are currently nine extended release and one immediate-release opioid pain medications with US FDA-approved ADF labelling. All use either physical and chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence is mounting that introduction of opioid ADFs has been associated with decreased rates of abuse and diversion of opioids in the US. CONCLUSIONS: Although not sufficient by themselves to prevent prescription opioid abuse and misuse, opioid ADFs are an important component of a healthcare provider's comprehensive opioid risk management plan (along with utilization of prescription drug monitoring programs, clinical assessment tools, urine tests, co-prescribing of naloxone to patients at risk of an overdose, access to non-pharmacological treatments and addiction/mental health resources, among others). Adoption of opioid ADFs should be considered as part of an overall public health opioid risk management plan involving all stakeholders to balance legitimate safe and effective use of opioids against misuse and abuse. PMID- 29262731 TI - A systematic review of psychoneuroimmunology-based interventions. AB - Psychoneuroimmunology-based interventions are used to attenuated disease progression and/or side effects of pharmacological treatment. This systematic review evaluates the different therapeutic and/or clinical psychoneuroimmunology based interventions associated to both psychological, neuroendocrine and immunological variables. The review was conducted for all English, Portuguese and Spanish language articles published between 2005 and 2015. Independent investigators analyzed 42 studies concerning human psychoneuroimmunology-based interventions. Decreased levels of cortisol, epinephrine and norepinephrine (stress-related hormones) were associated to interventions like yoga, meditation, tai chi, acupuncture, mindfulness, religious/spiritual practices, cognitive behavior therapy, coping and physical exercises. Moreover, those interventions were also associated to reductions in inflammatory processes and levels of pro inflammatory cytokines in cancer, HIV, depression, anxiety, wound healing, sleep disorder, cardiovascular diseases and fibromyalgia. Despite the associations between PNI variables and clinical/therapeutic interventions, only one study evidenced significant effects on a disease progression. PMID- 29262732 TI - Chk1 modulates the interaction between myosin phosphatase targeting protein 1 (MYPT1) and protein phosphatase 1cbeta (PP1cbeta). AB - Polo-like kinase 1 (Plk1) is an instrumental kinase that modulates many aspects of the cell cycle. Previous investigations have indicated that Plk1 is a target of the DNA damage response, and Plk1 inhibition is dependent on ATM/ATR and Chk1. But the exact mechanism remains elusive. In a proteomic screen to identify Chk1 interacting proteins, we found that myosin phosphatase targeting protein 1 (MYPT1) was present in the immunocomplex. MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1beta (PP1cbeta) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1 PP1cbeta interaction and subsequent Plk1 dephosphorylation. Phosphorylation of Ser20 is abolished during mitotic damage when Chk1 is inhibited. The degradation of MYPT1 is also regulated by Chk1 phosphorylation. Our results thus unveil the underlying machinery that attenuates Plk1 activity during mitotic damage through Chk1-induced phosphorylation of MYPT1. PMID- 29262733 TI - Structures and antipathogenic fungi activities of flavonoids from pathogen infected Astragalus adsurgens. AB - Healthy Astragalus adsurgens is a highly palatable forage widely cultivated in arid areas of north China, while pathogen- (Embellisia asttrgali) infected A. adsurgens is poisonous forage and often causes disastrous livestock losses. A phytochemical investigation was carried out on the E. asttrgali-infected A. adsurgens; as a result, a new compound, (2R, 3S)-7,4'-dimethoxy-2' hydroxyflavanol (1), together with nine known flavonoids was obtained. It was found that the content of most of these compounds in E. asttrgali-infected A. adsurgens was higher than that in healthy A. adsurgens. Moreover, compounds 2 and 3 exhibited weak inhibitory activity against Fusarium graminearum and E. asttrgali with EC50 over 100 MUg/mL, and showed moderate inhibitory activity against Bipolaris sorokinianum with EC50 of 39.1 and 95.0 MUg/mL. Compounds 1-4 exhibited a high degree of inhibitory activity against Curvularia lunata, with 21.73, 43.93, 45.02 and 44.51% inhibition ratio at concentration of 50 MUg/mL. PMID- 29262734 TI - Sit less and move more: perspectives of adults with multiple sclerosis. AB - PURPOSE: Multiple sclerosis is a chronic neurological disease with the highest prevalence in Canada. Replacing sedentary behavior with light activities may be a feasible approach to manage multiple sclerosis symptoms. This study explored the perspectives of adults with multiple sclerosis about sedentary behavior, physical activity and ways to change behavior. METHODS: Fifteen adults with multiple sclerosis (age 43 +/- 13 years; mean +/- standard deviation), recruited through the multiple sclerosis Clinic at the University of Alberta, Edmonton, Canada, participated in semi-structured interviews. Interview audios were transcribed verbatim and coded. NVivo software was used to facilitate the inductive process of thematic analysis. RESULTS: Balancing competing priorities between sitting and moving was the primary theme. Participants were aware of the benefits of physical activity to their overall health, and in the management of fatigue and muscle stiffness. Due to fatigue, they often chose sitting to get their energy back. Further, some barriers included perceived fear of losing balance or embarrassment while walking. Activity monitoring, accountability, educational and individualized programs were suggested strategies to motivate more movement. CONCLUSIONS: Adults with multiple sclerosis were open to the idea of replacing sitting with light activities. Motivational and educational programs are required to help them to change sedentary behavior to moving more. IMPLICATIONS FOR REHABILITATION One of the most challenging and common difficulties of multiple sclerosis is walking impairment that worsens because of multiple sclerosis progression, and is a common goal in the rehabilitation of people with multiple sclerosis. The deterioration in walking abilities is related to lower levels of physical activity and more sedentary behavior, such that adults with multiple sclerosis spend 8 to 10.5 h per day sitting. Replacing prolonged sedentary behavior with light physical activities, and incorporating education, encouragement, and self-monitoring strategies are feasible approaches to manage the symptoms of multiple sclerosis. PMID- 29262735 TI - Identification of degranulation inhibitors from rooibos (Aspalathus linearis) tea in rat basophilic leukaemia cells. AB - Quercetin, luteolin and chrysoeriol were identified from rooibos tea as degranulation inhibitors in rat basophilic leukaemia cells. The degranulation inhibitory activity of chrysoeriol was first discovered in the present study. When quercetin, luteolin and chrysoeriol were mixed in the ratio that occurs in rooibos tea extract, the mixture inhibited antigen- and calcium ionophore stimulated degranulation to the same degree as that by the whole rooibos tea extract. These findings indicate that these three flavonoids are the key factors underlying the degranulation inhibitory activity of rooibos tea. PMID- 29262736 TI - Cirrhotic patients with minimal hepatic encephalopathy have increased capacity to eliminate superoxide and peroxynitrite in lymphocytes, associated with cognitive impairment. AB - Patients with minimal hepatic encephalopathy (MHE) show increased oxidative stress in blood. We aimed to assess whether MHE patients show alterations in different types of blood cells in (a) basal reactive oxygen and nitrogen species levels; (b) capacity to metabolise these species. To assess the mechanisms involved in the altered capacity to metabolise these species we also analysed: (c) peroxynitrite formation and d) peroxynitrite reaction with biological molecules. Levels of reactive oxygen and nitrogen species were measured by flow cytometry in blood cell populations from cirrhotic patients with and without MHE and controls, under basal conditions and after adding generators of superoxide (plumbagin) or nitric oxide (NOR-1) to assess the capacity to eliminate them. Under basal conditions, MHE patients show reduced superoxide and peroxynitrite levels and increased nitric oxide (NO) and nitrotyrosine levels. In patients without MHE plumbagin strongly increases cellular superoxide, moderately peroxynitrite and reduces NO levels. In MHE patients, plumbagin increases slightly superoxide and strongly peroxynitrite levels and affects slightly NO levels. NOR-1 increases NO levels much less in patients with than without MHE. These data show that the mechanisms and the capacity to eliminate cellular superoxide, NO and peroxynitrite are enhanced in MHE patients. Superoxide elimination is enhanced through reaction with NO to form peroxynitrite which, in turn, is eliminated by enhanced reaction with biological molecules, which could contribute to cognitive impairment in MHE. The data show that basal free radical levels do not reflect the oxidative stress status in MHE. PMID- 29262737 TI - A spatial analysis of amyotrophic lateral sclerosis (ALS) cases in the United States and their proximity to multidisciplinary ALS clinics, 2013. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that typically results in death within 2-5 years of initial symptom onset. Multidisciplinary ALS clinics (MDCs) have been established to provide specialty care to people living with the disease. OBJECTIVE: To estimate the proximity of ALS prevalence cases to the nearest MDC in the US to help evaluate one aspect of access to care. METHODS: Using 2013 prevalence data from the National ALS Registry, cases were geocoded by city using geographic information system (GIS) software, along with the locations of all MDCs in operation during 2013. Case-to MDC proximity was calculated and analyzed by sex, race, and age group. RESULTS: During 2013, there were 72 MDCs in operation in 30 different states. A total of 15,633 ALS cases were geocoded and were distributed throughout all 50 states. Of these, 62.6% were male, 77.9% were white, and 76.2% were 50-79 years old. For overall case-to-MDC proximity, nearly half (44.9%) of all geocoded cases in the US lived >50 miles from an MDC, including approximately a quarter who lived >100 miles from an MDC. There was a statistically significant difference between distance to MDC by race and age group. CONCLUSIONS: The high percentage of those living more than 50 miles from the nearest specialized clinic underscores one of the many challenges of ALS. Having better access to care, whether at MDCs or through other modalities, is likely key to increasing survivability and obtaining appropriate end-of-life treatment and support for people with ALS. PMID- 29262739 TI - Robots and people with dementia: Unintended consequences and moral hazard. AB - The use of social robots in elder care is entering the mainstream as robots become more sophisticated and populations age. While there are many potential benefits to the use of social robots in care for the older people, there are ethical challenges as well. This article focuses on the societal consequences of the adoption of social robots in care for people with dementia. Making extensive use of Alasdair MacIntyre's Dependent Rational Animals to discuss issues of unintended consequences and moral hazard, we contend that in choosing to avoid the vulnerability and dependency of human existence, a society blinds itself from the animal reality of humankind. The consequence of this is that a flourishing society, in which each individual is helped to develop the virtues essential to her flourishing, becomes harder to achieve. PMID- 29262738 TI - Smoking is associated with risk for developing inflammatory bowel disease including late onset ulcerative colitis: a prospective study. AB - OBJECTIVES: Life style factors have been associated with inflammatory bowel disease (IBD) but there is a lack of data on the exposure of life styles factors before the onset of IBD. Our aim was to study the association between lifestyle factors and the development of IBD in a prospective setting. MATERIALS AND METHODS: We performed a case control study of 72 patients who later developed ulcerative colitis (UC), 26 patients who developed Crohn's disease (CD) and 427 healthy controls from the Vasterbotten intervention project matched for gender, age, year of health survey and area of residence. At recruitment, participants completed validated lifestyle questionnaires including data on alcohol intake. Information from this was used to assess the connection between lifestyle factors and later developing IBD. RESULTS: For CD and UC, the median age at diagnosis was 53 and 52 years and median time of survey was 4 and 6 years before diagnosis, respectively. Multivariate odds ratio (OR) showed an association between never smoking and not developing IBD, including both UC and CD, OR (95% CI) 0.341 (0.136-0.853) and 0.473 (0.259-0.864), respectively. Marital status, educational level, alcohol consumption, reported physical activity and use of moist smokeless tobacco (snus) did not differ between patients and controls. CONCLUSIONS: Smoking proves to be a risk factor for both CD and UC in this prospective case-control study. No association was seen for snus users, implying a non-nicotine pathogenic mechanism from combusted tobacco. PMID- 29262740 TI - Service evaluation: A grey area of research? AB - The National Health Service in the United Kingdom categorises research and research-like activities in five ways, such as 'service evaluation', 'clinical audit', 'surveillance', 'usual practice' and 'research'. Only activities classified as 'research' require review by the Research Ethics Committees. It is argued, in this position paper, that the current governance of research and research-like activities does not provide sufficient ethical oversight for projects classified as 'service evaluation'. The distinction between the categories of 'research' and 'service evaluation' can be a grey area. A considerable percentage of studies are considered as non-research and therefore not eligible to be reviewed by the Research Ethics Committee, which scrutinises research proposals rigorously to ensure they conform to established ethical standards, protecting research participants from harm, preserving their rights and providing reassurance to the public. This article explores the ethical discomfort potentially inherent in the activity currently labelled as 'service evaluation'. PMID- 29262741 TI - Liposomal co-delivery-based quantitative evaluation of chemosensitivity enhancement in breast cancer stem cells by knockdown of GRP78/CLU. AB - Resistance to chemotherapy is a key factor in the inefficacy of various forms of treatments for cancer. In the present study, chemo-resistant proteins, including glucose-regulated protein 78 (GRP78)/clusterin (CLU) targeted 1,2-dioleoyloxy-3 trimethylammoniumpropane (DOTAP) liposomes, were developed as a delivery system for co-delivery of camptothecin (CPT) and GRP78 siRNA/CLU siRNA. Their drug/gene co-deliveries were quantitatively assessed in cancer stem cells (CSC) and MCF-7 cells. DOTAP-CPT/siRNA were prepared via electrostatic interaction on GRP78 siRNA or CLU siRNA. The size and zeta-potential of liposomes and lipoplexes were measured by dynamic light scattering techniques and electrophoretic light scattering spectrophotometry. The lipoplexes formation was tested by using gel electrophoresis. Immunofluorescence analysis showed that the expression level of CLU and GRP78 were significantly elevated in CSC compared to MCF-7 cells. Transfection and drug-delivery efficiency of DOTAP-CPT/siRNA were quantitatively compared with Lipofectamine 2000. Compared to free CPT, DOTAP-CPT-siCLU delivery in CSC and MCF-7 cells increased transfection efficiency and chemo-sensitivity by 4.1- and 5.9-fold, respectively. On the other hand, DOTAP-CPT-siGRP78 delivery increased transfection efficiency and chemo sensitivity by 4.4- and 6.2-fold in CSC and MCF-7 cells, respectively, compared to free CPT. It is significant that 3 +/- 1.2-fold increase in transfection efficiency was achieved by lipofectamine. Consequently, an increase in anti-cancer/gene silencing efficacy was quantitatively observed as an effect of DOTAP-CPT/siRNA treatment, which was relatively higher than lipofectamine treatment. Conclusively, our experimental data quantitatively demonstrate that using DOTAP-CPT-siRNA specifically targeting (CSCs) chemo-resistant protein in vitro offers substantial potential for synergistic anti-cancer therapy. PMID- 29262742 TI - Efficacy and safety of voriconazole in immunocompromised patients: systematic review and meta-analysis. AB - BACKGROUND: Voriconazole is a second-generation triazole. It has excellent bioavailability and broad antifungal spectrum; thus, it is an attractive option for patients at high risk of invasive fungal infections (IFIs). Comparing efficacy and safety of voriconazole with other antifungals in prophylaxis or treatment of IFIs would be useful to draw conclusions regarding prevention and therapeutics of these infections. AIM: To assess efficacy and safety of voriconazole compared with other options as prophylaxis or treatment of IFIs in haematology-oncology patients. MATERIALS AND METHODS: A literature search was performed in MEDLINE database using the search term 'voriconazole' and completed with manual search. STUDY SELECTION: Randomized controlled trials (RCTs) comparing voriconazole with other antifungal agents or placebo. DATA EXTRACTION: Seven studies fulfilled the eligibility criteria. RESULTS: Five studies compared voriconazole to another comparator as prophylaxis of IFIs and two as treatment. Pooled results showed that voriconazole was more effective than the comparator (RR = 1.17; 95%CI = 1.01-1.34), but heterogeneity was significant (Q test 32.7; p = .00001). Sub-analysis according to prophylaxis showed RR = 1.17; 95%CI = 1.00 1.37; while as treatment, RR = 1.23; 95%CI = 0.68-2.22. Risk of adverse events was not different from that observed for the comparator (RR = 1.06, 95%CI = 0.66 1.72) though significant heterogeneity was detected (p < .01). CONCLUSIONS: Voriconazole was as effective and safe as comparators, probably better as prophylaxis than as treatment, but limitations due to variability in the sample size of studies, differences in the age of patients, and heterogeneity between studies' outcome measures indicate the need for further research. PMID- 29262743 TI - Fly on the right: Lateral preferences when choosing aircraft seats. AB - A small preference has been observed for people to choose seats on the left of aircraft when booking via an online system. Although this is consistent with pseudoneglect-the known leftward bias in perception and representation-rightward preferences have been commonly observed in seating selection tasks in other environments. Additionally, the previous research in aircraft seating was unable to dissociate a bias to one side of the screen from a bias to one side of the cabin of the aircraft. Here, we present a study in which participants were asked to select seats for a range of fictional flights. They demonstrated a preference for seats on the right of the cabin, irrespective of whether the right of the cabin appeared to either the right or the left of the screen, a preference for seats towards the front of the aircraft and a preference to favour window and aisle seats. This suggests, in contrast to previous research, that participants demonstrated a rightward lateral bias to representations of an aircraft. These results may have implications for our understanding of asymmetries in cognition as well as having potentially important practical implications for airlines. PMID- 29262744 TI - Lipoprotein(a) in clinical practice: New perspectives from basic and translational science. AB - Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS). Genetic, epidemiological and in vitro data provide strong evidence for a pathogenic role for Lp(a) in the progression of atherothrombotic disease. Despite these advancements and a race to develop new Lp(a) lowering therapies, there are still many unanswered and emerging questions about the metabolism and pathophysiology of Lp(a). New studies have drawn attention to Lp(a) as a contributor to novel pathogenic processes, yet the mechanisms underlying the contribution of Lp(a) to CVD remain enigmatic. New therapeutics show promise in lowering plasma Lp(a) levels, although the complete mechanisms of Lp(a) lowering are not fully understood. Specific agents targeted to apolipoprotein(a) (apo(a)), namely antisense oligonucleotide therapy, demonstrate potential to decrease Lp(a) to levels below the 30-50 mg/dL (75-150 nmol/L) CVD risk threshold. This therapeutic approach should aid in assessing the benefit of lowering Lp(a) in a clinical setting. PMID- 29262745 TI - Two New Species of Plagioporus (Digenea: Opecoelidae) from the Ouachita Madtom, Noturus lachneri, and the Banded Sculpin, Cottus carolinae, from Arkansas. AB - Plagioporus ictaluri n. sp. and Plagioporus carolini n. sp. are described from the intestines of the Ouachita Madtom, Noturus lachneri, and the Banded Sculpin, Cottus carolinae, respectively, from adjacent drainages in Arkansas. The new species are morphologically most similar to one another and in turn similar to Plagioporus sinitsini, Plagioporus chiliticorum, Plagioporus serratus, and Plagioporus hypentelii, but they can be distinguished from these congeners in possession of an excretory vesicle that extends anteriorly to the level of the anterior testis as opposed to 1 reaching only the posterior testis ( P. hypentelii) or 1 confined to the posttesticular space ( P. sinitsini, P. serratus, and P. chiliticorum), a feature that necessitates altering the generic diagnosis for the genus. Plagioporus ictaluri n. sp. is distinguished from Plagioporus carolini n. sp. in having tandem vs. oblique testes, a submedian to median ovary as opposed to 1 that is dextral, a ventral sucker occupying 53-71% of the body width (BW) vs. 80-92% of the BW, an oral sucker occupying 36-47% of the BW as opposed to 49-58% of the BW, and a pharynx occupying 21-26% of the BW compared to 28-36% of the BW. A Bayesian inference analysis of partial 28S rDNA sequences of the 2 new species and those of 34 opecoelids obtained from GenBank found that P. ictaluri and P. carolini formed a highly supported clade that was sister to P. chiliticorum and in turn to P. sinitsini. These 4 species are notably the only Nearctic plagioporids included in the analysis without a uterus extending to the posterior end that lack a confluent vitelline field in the posttesticular space. This study includes the first species of Plagioporus to be described from an ictalurid host and the first species in the genus to be described from a cottid east of the Rocky Mountains. PMID- 29262746 TI - How teachers can help learners build storage and retrieval strength. AB - AIM: To be an effective teacher, content expertise is necessary but alone does not guarantee optimal learning outcomes for students. In this article, the authors discuss ways in which medical teachers can shape the learning of their students and enable them to become more efficient and effective learners. METHODS: Using Bjork and Bjork's new theory of disuse as their framework, the authors discuss strategies to improve storage strength of to-be-learned information and strategies to improve retrieval strength of learned information. RESULTS: Strategies to improve storage strength include optimizing cognitive load, providing causal explanations, and giving effective feedback. Strategies to improve retrieval strength include situated cognition and various types of retrieval practice. CONCLUSIONS: Adopting these teaching strategies should hopefully help teachers improve the learning outcomes of their students, but there is still a need for further research into the science of learning and the science of instruction, including comparative effectiveness of different teaching strategies and how best to translate findings from the psychology literature into medical education. PMID- 29262747 TI - Development of an eHealth Program for Parents of Adolescents With Type 1 Diabetes. AB - Purpose The purpose of this study was to understand the experience of parenting an adolescent with type 1 diabetes (T1DM), to develop a prototype of an eHealth program for parents of adolescents with T1DM, and to evaluate the prototype content and acceptability from the perspective of parents and health care providers. Methods A multiphase method was used generating both qualitative and quantitative data at multiple time points. There were 27 parents of adolescents aged 12 to 18 years with T1DM and 16 health care providers who participated in semistructured interviews to identify parental challenges; 53 parents and 27 providers evaluated the prototype. Thematic content analysis was used to analyze interview transcripts, and descriptive statistics were used to summarize survey data. Results Challenges experienced by parents of adolescents with T1DM included understanding the developmental and hormonal changes of adolescence that affect diabetes care, feeling tension between adolescent independence and parent control, communicating without nagging or conflict, transferring diabetes care responsibility safely, dealing with feelings of stress and distress, and perceiving a lack of resources for T1DM care and insufficient personal time for self-care. In the prototype evaluation, both parents and providers found content to be relevant and provided feedback to guide the development of the full program. Conclusions Parents of adolescents with T1DM and providers expressed a need for parents to have more support in transitioning diabetes care from parent to adolescent. eHealth programs offer an ideal way to address these needs and ultimately can be linked to electronic medical records improving quality and efficiency of health care in this population. PMID- 29262748 TI - Outcomes of ICU Admission of Patients With Progressive Metastatic Gastrointestinal Cancer. AB - BACKGROUND: Data on the outcomes of intensive care unit (ICU) admissions for patients with advanced incurable chemoresistant solid tumor malignancies, and the benefits of subsequent/post-ICU anticancer treatments are limited but have end-of life and ethical implications. METHODS: An institutional database was queried to identify patients of the gastrointestinal (GI) medical oncology service of Memorial Sloan Kettering Cancer Center with >=1 ICU admission during 2014. Records were reviewed for evidence of cancer control from cancer treatment after the ICU admission. RESULTS: Twenty-eight patients who had progressed beyond at least first-line chemotherapy for metastatic GI adenocarcinoma were admitted to the ICU for sequelae of progressive clinical deterioration. The most frequent reasons for ICU admission were sepsis (39%) and acute respiratory failure (29%). Ten patients died in the ICU, 3 died during the same hospitalization after ICU discharge, and 15 were discharged from the hospital. Of these 15, the median survival from hospital discharge was 2.2 months and 6 received further chemotherapy but with no evidence of clinical benefit. Of these 6, 3 lived over 5 months but the treatment of 5 entailed recycling of previously ineffective chemotherapy agents (3) or those originally used in the adjuvant setting (2). Two of these patients received liver-directed therapy without benefit. CONCLUSIONS: Admissions to the ICU in this cancer population were associated with high morbidity and mortality and did not result in benefit from subsequent cancer treatment. These data can be used to help establish realistic expectations and care goals in previously treated patients having metastatic GI cancer with clinical deterioration. PMID- 29262749 TI - Can Dual Task Walking Improve in Parkinson's Disease After External Focus of Attention Exercise? A Single Blind Randomized Controlled Trial. AB - BACKGROUND: It may be possible to use attention-based exercise to decrease demands associated with walking in Parkinson's disease (PD), and thus improve dual task walking ability. For example, an external focus of attention (focusing on the effect of an action on the environment) may recruit automatic control processes degenerated in PD, whereas an internal focus (limb movement) may recruit conscious (nonautomatic) control processes. Thus, we aimed to investigate how externally and internally focused exercise influences dual task walking and symptom severity in PD. METHODS: Forty-seven participants with PD were randomized to either an Externally (n = 24) or Internally (n = 23) focused group and completed 33 one-hour attention-based exercise sessions over 11 weeks. In addition, 16 participants were part of a control group. Before, after, and 8 weeks following the program (pre/post/washout), gait patterns were measured during single and dual task walking (digit-monitoring task, ie, walking while counting numbers announced by an audio-track), and symptom severity (UPDRS-III) was assessed ON and OFF dopamine replacement. Pairwise comparisons (95% confidence intervals [CIs]) and repeated-measures analyses of variance were conducted. RESULTS: Pre to post: Dual task step time decreased in the external group (Delta = 0.02 seconds, CI 0.01-0.04). Dual task step length (Delta = 2.3 cm, CI 0.86-3.75) and velocity (Delta = 4.5 cm/s, CI 0.59-8.48) decreased (became worse) in the internal group. UPDRS-III scores (ON and OFF) decreased (improved) in only the External group. Pre to washout: Dual task step time ( P = .005) and percentage in double support ( P = .014) significantly decreased (improved) in both exercise groups, although only the internal group increased error on the secondary counting task (ie, more errors monitoring numbers). UPDRS-III scores in both exercise groups significantly decreased ( P = .001). CONCLUSIONS: Since dual task walking improvements were found immediately, and 8 weeks after the cessation of an externally focused exercise program, we conclude that externally focused exercise may improve on functioning of automatic control networks in PD. Internally focused exercise hindered dual tasking ability. Overall, externally focused exercise led to greater rehabilitation benefits in dual tasking and motor symptoms compared with internally focused exercise. PMID- 29262750 TI - Emotional distress and positive and negative memories from military deployment: the influence of PTSD symptoms and time. AB - During military deployment, soldiers are confronted with both negative and positive events. What is remembered and how it affects an individual is influenced by not only the perceived emotion of the event, but also the emotional state of the individual. Here we examined the most negative and most positive deployment memories from a company of 337 soldiers who were deployed together to Afghanistan. We examined how the level of emotional distress of the soldiers and the valence of the memory were related to the emotional intensity, experience of reliving, rehearsal and coherence of the memories, and how the perceived impact of these memories changed over time. We found that soldiers with higher levels of post-traumatic stress disorder (PTSD) symptoms were more affected by both their negative and positive memories, compared with soldiers with lower levels of PTSD symptoms. Emotional intensity of the most negative memory increased over time in the group with highest levels of PTSD symptoms, but dropped in the other groups. The present study adds to the literature on emotion and autobiographical memory and how this relationship interacts with an individual's present level of emotional distress and the passage of time. PMID- 29262751 TI - The effect of age and compression strength on venous leg ulcer healing. AB - Objectives The aim of the study is to compare proportions of venous leg ulcers healed in patients treated with two different sub-bandage pressure values in relation to age. Methods The study included 102 outpatients with venous leg ulcers, one group with moderate compression pressure of 35-40 mmHg and the second with high pressure >45 mmHg. Each group was divided into two subgroups according to the age (>=65 vs. <65 years). Computerized planimetry was used to measure the size of the ulcers at 6, 12, 18 and 24 weeks. Results Kaplan-Maier analysis showed high pressure leads to higher proportion of healed venous leg ulcers, compared to moderate pressure, in patients aged >=65 years (57.6% vs. 28%) and in patients <65 years (53.8% vs. 36%) (p < 0.05). Conclusion The study showed that higher compression pressure leads to higher proportions of venous leg ulcers healed, independent of age and could be safely preferred in older patients. PMID- 29262752 TI - Should re-intervention be the definitive outcome measure for varicose vein intervention? PMID- 29262753 TI - Low molecular weight polyethylenimine-grafted soybean protein gene carriers with low cytotoxicity and greatly improved transfection in vitro. AB - A series of gene carriers (SP-PEI) have been synthesized by acylation reaction between soybean protein and branched polyethylenimine with low molecular weight of 600, 1200 and 1800 Da, and designed as SP-PEI600, SP-PEI1200 and SP-PEI1800, respectively. SP-PEI could effectively condense plasmid DNA into nanoscale polyplexes with size range of 100-200 nm, and exhibited much lower cytotoxicity against 293T and SH-SY5Y cells than that of branched polyethylenimine (25 kDa). In vitro gene transfection demonstrated that SP-PEI/DNA complex displayed increased transfection against 293T and SH-SY5Y cells with the increase of the weight ratio of SP-PEI/DNA complex with or without 10% serum. At weight ratio of 24, SP-PEI1800/DNA polyplexes showed the highest transfection on SH-SY5Y cells, which was almost three folds higher than PEI (25 kDa). Furthermore, these SP PEIs/DNA polyplexes could effectively transfect 293T and SH-SY5Y cells with or without 10% serum, suggesting their excellent serum tolerance. PMID- 29262754 TI - Streptococcus anginosus group bloodstream infections in the western interior of British Columbia, Canada. AB - BACKGROUND: The epidemiology of Streptococcus anginosus group (SaG) bloodstream infections (BSI) has not been well defined in non-selected populations. The objective of this study was to determine the incidence, risk factors and outcome associated with SaG BSI. METHODS: Population-based surveillance was conducted in the western interior region of British Columbia, Canada between 1 April 2010 and 31 March 2017. RESULTS: Forty-six episodes were identified for an overall annual incidence of 3.7 per 100,000 population. The incidence increased with older age and males were at significantly higher risk (5.2 vs. 2.1 per 100,000; incidence rate ratio, 2.5; 95% confidence interval, 1.3-5.1; p = .004). Nearly one-half (22; 48%) of patients had no chronic co-morbid illness, whereas 17 (40%) had 1-2, six (13%) had 3-4 and one (2%) had 5 Charlson scores with diabetes and cancer being the most common. Predisposing factors for development of SaG BSI were identified in 30 (65%) cases. The gastro-intestinal tract was the most common focus of infection (13; 28%) followed by cardiovascular and skin/soft tissue (six cases each; 13%) and in seven (15%) cases no focus was identified. Drainage procedures were required in 21 (46%) patients of whom seven (15%) patients had percutaneous drains and 14 (30%) required surgical operations. Forty-one (89%) patients were admitted to hospital for a median hospital length stay of 11 (interquartile range, 7-18) days. The in-hospital and 30-day all cause case fatality rates were 3/41 (7%) and 4/46 (9%), respectively. CONCLUSION: SaG BSI is an important cause of morbidity and mortality. PMID- 29262755 TI - Effect of direct and indirect contact with mental illness on dangerousness and social distance. AB - BACKGROUND: This study is based on the contact hypothesis that contact with mental illness is the most effective anti-stigma strategy. AIMS: This study aims to analyze which form of contact can most effectively decrease the dangerousness and social distance associated with schizophrenia, depression and alcoholism. METHOD: In total, 573 Korean adults ( Mage = 43.71 years, standard deviation ( SD) = 13.41; 54.1% male, 45.9% female) were surveyed about randomly assigned vignettes of schizophrenia, depression and alcoholism. The participants were questioned on the dangerousness and social distance associated with the assigned vignette, as well as direct and indirect contact experience with the mental illness. Two-way analysis of variance (ANOVA) was used to determine the main effect and interaction effect that the type of mental illness and contact experience have on the two dependent variables (dangerousness and social distance). RESULTS: The findings show that the type of mental illness has a significant main effect on dangerousness and social distance, but contact type only has a significant main effect on social distance. Moreover, the two independent variables (mental illness subtype and contact experience) have an interaction effect on two dependent variables (dangerousness and social distance). Therefore, the anti-stigma effect of contact varies according to the type of mental illness. CONCLUSION: Our findings suggest that appropriate anti stigma strategies are required for each type of mental illness. Considering that opportunities for direct contact with persons with mental illness are highly limited, it is necessary to actively utilize indirect contact. PMID- 29262756 TI - Prenatal diagnosis of chromosomal polymorphisms: most commonly observed polymorphism on Chromosome 9 have associations with low PAPP-A values. AB - INTRODUCTION: To identify the prevalence and types of fetal chromosomal polymorphisms in pregnant women and to examine possible associations with screening test parameters. MATERIALS AND METHODS: Fetal chromosomal polymorphism rate was investigated in pregnant women who had been implemented for invasive prenatal test in a tertiary reference center in Thrace Region of Turkey. Fetal chromosomal polymorphisms were determined and their effects on screening tests' parameters were investigated. Possible differences in the first and second trimester screening test parameters between women; with fetal chromosomal polymorphism who had screening test results (Group 1) and those with a normal karyotype (Group 2) were evaluated. RESULTS: Fetal chromosomal polymorphism prevalence was 5.3% (n = 101). The most common polymorphisms were identified on chromosome 9, 1, and 16 [54.5% (n = 55); 8.9% (n = 9), and 6.9% (n = 7), respectively]. The most common polymorphic variant was 9qh+ (n = 23; 22.8%). Among the screening test parameters, significantly lower pregnancy-associated plasma protein-A (PAPP-A) (p = .028) and higher unconjugated estriol (uE3) (p = .019) values were found in Group 1. In patients having fetuses with polymorphic variants on chromosome 9, a significantly lower PAPP-A values were observed compared to women with other fetal polymorphic variants (p = .048) or women having fetuses with normal karyotype (p = .007). CONCLUSIONS: Lower PAPP-A and higher uE3 levels were observed in women having fetuses with chromosomal polymorphisms, which might affect screening test results. Lower PAPP-A levels were apparent in women having fetuses with polymorphism on chromosome 9. PMID- 29262757 TI - Development and Initial Validation of the Caregiver Perceptions About Communication With Clinical Team Members (CAPACITY) Measure. AB - Despite the important role that family caregivers play managing the care of persons with complex health needs, little is known about how caregivers perceive themselves to be recognized and valued by health care professionals. Our objective was to develop and validate a novel measure, the CAregiver Perceptions About Commun Ication with Clinical Team members (CAPACITY) instrument. Questions focus on perceived quality of communication with the health care team and the extent to which caregivers believe that the health care team considers their capacity and preferences in decision making. A confirmatory factor analysis supported a two-factor solution addressing communication and capacity. Internal consistency reliability was .90 for the communication domain and .93 for the capacity domain. Correlations between these two subscales and individual difference measures provided evidence of convergent and discriminant validity. The CAPACITY instrument may be a useful performance measure that quantifies the extent to which caregivers' experience person- and family-centered health care. PMID- 29262758 TI - Phase Relationship between DLMO and Sleep Onset and the Risk of Metabolic Disease among Normal Weight and Overweight/Obese Adults. AB - Circadian misalignment is hypothesized to contribute to increased diabetes and obesity among shift workers and individuals with late sleep timing. Accordingly, the goal of our study was to identify-among normal and overweight/obese adults associations between circadian timing (dim light melatonin onset; DLMO) and circadian misalignment (the interval between DLMO and sleep onset) with metabolic disease risk. This was a secondary analysis of data from a larger study. Participants ages 18 to 50 years without depression, diabetes, or shift work, with sleep duration 6.5 h or more, completed the following evaluations: 7 days of wrist actigraphy, circadian timing assessment (DLMO), and a fasting blood draw to measure glucose and insulin and calculate the Homeostatic Model of Assessment Insulin Resistance (HOMA-IR). Data were analyzed using correlation and regression analyses controlling for age, sex, DLMO, and sleep duration. Analyses were conducted for the entire sample ( n = 54) and stratified by normal weight ( n = 36) and overweight/obese groups ( n = 18). Mean age was 26.4 years (SD = 7.1 years). Average sleep duration was 436.2 min (SD = 55.1 min), DLMO was 2250h (SD = 01:31), and interval between DLMO and sleep onset was 2 h 18 min (SD = 53 min). Average BMI was 24.3 kg/m2 (SD = 4.5 kg/m2). Circadian timing and interval between DLMO and sleep onset were not associated with glucose, insulin, or HOMA IR in the main analyses. Among overweight/obese participants, a shorter interval between DLMO and sleep onset was associated with higher insulin ( B[SE] = -5.12 [2.24], p = 0.04) and HOMA-IR ( B[SE] = -1.32 [0.57], p = 0.04). Results of our multivariable model indicated that among overweight/obese participants, insulin was 5.1 pmol/L higher and HOMA was 1.3 uU/mL higher for every hour closer that sleep onset was to DLMO. The strengths of this study include the use of objective measures of circadian timing, but results should be considered hypothesis generating due to the small sample size and use of subgroup analyses. PMID- 29262759 TI - The Factors That Influence and Protect Against Power Imbalance in Covert Bullying Among Preadolescent Children at School: A Thematic Analysis. AB - In this article, the perceptions of preadolescent children (ages 9-11) regarding factors that influence and protect against power imbalance associated with covert aggression and bullying are explored. In aggression research, the term covert has been typically used to describe relational, indirect, and social acts of aggression that are hidden. These behaviors contrast with overt physical and verbal aggression. Children have previously conveyed their belief that covert aggression is harmful because adults do not see it even though children, themselves, are aware. We used focus groups to explore children's understanding of covert aggression and to identify children's experience and perception of adult support in relation to bullying. Thematic analysis supported the definition of covert aggression as that which is intentionally hidden from adults. Friendship, social exclusion, and secret from teacher were identified as factors that influence power imbalance, while support from friends and adult support protected against power imbalance. PMID- 29262760 TI - Nanofractionation Platform with Parallel Mass Spectrometry for Identification of CYP1A2 Inhibitors in Metabolic Mixtures. AB - With early assessment of inhibitory properties of drug candidates and their circulating metabolites toward cytochrome P450 enzymes, drug attrition, especially later in the drug development process, can be decreased. Here we describe the development and validation of an at-line nanofractionation platform, which was applied for screening of CYP1A2 inhibitors in Phase I metabolic mixtures. With this platform, a metabolic mixture is separated by liquid chromatography (LC), followed by parallel nanofractionation on a microtiter well plate and mass spectrometry (MS) analysis. After solvent evaporation, all metabolites present in the nanofractionated mixture are assayed utilizing a fluorescence CYP1A2 inhibition bioassay performed on the plate. Next, a bioactivity chromatogram is constructed from the bioassay results. By peak shape and retention time correlation of the bioactivity peaks with the obtained MS data, CYP1A2-bioactive inhibiting metabolites can be identified. The method correctly evaluated the potency of five CYP1A2 inhibitors. Mixtures comprising potent inhibitors of CYP1A2 or in vitro-generated metabolites of ellipticine were evaluated for their inhibitory bioactivities. In both cases, good LC separation of all compounds was achieved and bioactivity data could be accurately correlated with the parallel recorded MS data. Generation and evaluation of Phase II metabolites of hydroxylated ellipticine was also pursued. PMID- 29262761 TI - Dissolution and bandgap paradigms for predicting the toxicity of metal oxide nanoparticles in the marine environment: an in vivo study with oyster embryos. AB - Dissolution and bandgap paradigms have been proposed for predicting the ability of metal oxide nanoparticles (NPs) to induce oxidative stress in different in vitro and in vivo models. Here, we addressed the effectiveness of these paradigms in vivo and under conditions typical of the marine environment, a final sink for many NPs released through aquatic systems. We used ZnO and MnO2 NPs as models for dissolution and bandgap paradigms, respectively, and CeO2 NPs to assess reactive oxygen radical (ROS) production via Fenton-like reactions in vivo. Oyster embryos were exposed to 0.5-500 MUM of each test NP over 24 h and oxidative stress was determined as a primary toxicity pathway across successive levels of biological complexity, with arrested development as the main pathological outcome. NPs were actively ingested by oyster larvae and entered cells. Dissolution was a viable paradigm for predicting the toxicity of NPs in the marine environment, whereas the surface reactivity based paradigms (i.e. bandgap and ROS generation via Fenton-like reaction) were not supported under seawater conditions. Bio-imaging identified potential cellular storage-disposal sites of solid particles that could ameliorate the toxicological behavior of non-dissolving NPs, whilst abiotic screening of surface reactivity suggested that the adsorption-complexation of surface active sites by seawater ions could provide a valuable hypothesis to explain the quenching of the intrinsic oxidation potential of MnO2 NPs in seawater. PMID- 29262762 TI - Erratum. PMID- 29262764 TI - AVA Spring Meeting, Farnborough, UK, April 3, 2017. PMID- 29262763 TI - Immunohistochemical Characterization of Canine Oral Papillary Squamous Cell Carcinoma. AB - Recently, histologic subtypes of oral squamous cell carcinoma (SCC) corresponding to the human classification scheme have been proposed for dogs. A papillary squamous cell carcinoma subtype is characterized by dominant exophytic architectural growth with limited invasion, a lower metastatic rate, and better overall survival compared with conventional SCC. Whereas most canine oral conventional SCCs are easily diagnosed by histologic examination, the diagnosis of canine oral papillary squamous cell carcinoma (COPSCC) can be challenging since the exophytic portion lacks histologic features of malignancy and appears similar to oral nonviral papillomas. In contrast, the invasive portion of COPSCC has morphologic similarities to conventional SCC and canine acanthomatous ameloblastoma. The goals of this study were to immunophenotype these 3 entities and to potentially identify discriminating markers. A panel of 17 immunohistochemical markers was investigated in tissue microarrays that included 25 COPSCCs, 10 conventional SCCs, and 10 canine acanthomatous ameloblastomas. Additionally, COPSCCs were screened for papillomavirus as a potential cause using immunohistochemistry and in situ hybridization. COPSCC had immunophenotypical similarities with conventional SCC and acanthomatous ameloblastoma, but the combined differences in immunolabeling for AE1/AE3, 34betaE12, p63, and calretinin discriminated between the entities. Papillomavirus was not detected in any COPSCC, making a viral pathogenesis unlikely. A better understanding of the immunophenotype of COPSCC will aid in a more accurate diagnosis and potentially improve therapeutic approaches. PMID- 29262765 TI - Rosiglitazone pretreatment influences thrombin-induced anti-oxidative action via activating NQO1and gamma-GCS in rat microglial cells. AB - Objective To explore the molecular mechanism involved in rosiglitazone against secondary brain damage caused by cerebral hemorrhage, we pretreated thrombin induced microglial cells by rosiglitazone and then investigated its effect on antioxidant-related genes NQO1and gamma-GCS expression change. Methods Primary microglial cells were obtained from the brain tissue of newborn Sprague-Dawley (SD) rats and were randomly divided into three groups: the normal (control), thrombin stimulation (TH), thrombin-treated plus rosiglitazone (TH+RGZ). The expression of NQO1and gamma-GCS was measured by immunocytochemistry, real-time PCR, and western blot analysis. Results The immunocytochemistry showed that the number of NQO1and gamma-GCS stained cells in TH and TH+RGZ group increased compared to the control group. In addition, the expression of NQO1 and gamma-GCS in TH+RGZ group remarkably increased in mRNA and protein level compared to TH only group (p < 0.01). Conclusion Rosiglitazone can increase thrombin-induced microglia anti-oxidative ability by increasing NQO1and gamma-GCS expression, which can effectively reduce secondary injury after cerebral hemorrhage. PMID- 29262766 TI - Neuroanatomical and electrophysiological recovery in the contralateral intact cortex following transient focal cerebral ischemia in rats. AB - Objectives Focal cerebral ischemia may induce synaptic, electrophysiological, and metabolic dysfunction in remote areas. We have shown that the remote dendritic spine density changes and electrophysiological diaschisis in the acute and subacute stages after stroke previously. Here, we further evaluated electrophysiological outcomes and synapto-dendritic plasticity in long-term recovery in the contralateral cortex following focal cerebral ischemia. Methods Male Sprague-Dawley rats were subjected to intraluminal suture occlusion for 90 min or sham-occlusion. Somatosensory electrophysiological recordings (SSEPs) and neurobehavioral tests were recorded each day for 28 days. Postmortem brains were sectioned and subjected to Nissl staining and Golgi-Cox impregnation through a 28 day period following ischemic stroke. Results In the ipsilateral cortex, infarct size in the cortex and striatum was decreased after the subacute stage; the brains showed reduced swelling in the cortex and stratum 3 days after ischemic insults. Dendritic spine density and SSEP amplitude decreased significantly during a 28-day recovery period. In the contralateral cortex, dendritic spine density and SSEP amplitude decreased significantly for 21 days after ischemic stroke, but recovered to baseline by day 28. The deterioration of the dendritic spine (density reduction) in the ischemic cortex was observed; however, this increased neuroplasticity in the contralateral cortex in the subacute stage. Discussion Focal cerebral ischemia-reperfusion induces time-dependent reduction of dendritic spine density and electrophysiological depression in both the ipsilateral and contralateral cortices and intact brain. This neuroanatomical and electrophysiological evidence suggests that neuroplasticity and functional re organization in the contralateral cortex is possible following focal cerebral ischemia. PMID- 29262767 TI - Electric or traumatic injury? The role of histopathological investigations. AB - Analysis of wounds is crucial in forensic medicine to prove how an injury was caused. In many cases, microscopic analysis may be decisive. It is often difficult to distinguish macroscopic skin lesions resulting from electrical, mechanical and from thermal trauma where these occur simultaneously and to formulate a correct differential diagnosis. We report two cases in which the injuries found on the bodies and the manner of death raised uncertainty. An autopsy was performed. External examination of the bodies showed skin injuries that needed histopathological analysis to reconstruct the dynamics and the manner of death which has an important role in doubtful cases. PMID- 29262768 TI - Analysis of cardiovascular mortality, bleeding, vascular and cerebrovascular events in patients with atrial fibrillation vs. sinus rhythm undergoing transfemoral Transcatheter Aortic Valve Implantation (TAVR). AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been demonstrated to be an established therapy for high-risk, inoperable patients with severe symptomatic aortic valve stenosis. For patients with moderate surgical risk, TAVR is equivalent to conventional aortic valve surgery. However, atrial fibrillation (AF) is also present in many of these patients, thus requiring post-implantation oral anticoagulation therapy in addition to the inhibition of thrombocyte aggregation, which poses the risk of bleeding complications. The aim of our work was to investigate the influence of AF on mortality and the occurrence of bleeding, vascular and cerebrovascular complications related to TAVR according to the VARC-2 criteria. METHODS: Two hundred eighty-three patients who underwent TAVR between March 2010 and April 2016 were retrospectively examined. In total, 257 patients who underwent transfemoral access were included in this study. The mean patient age was 81 +/- 6 years, 54.1% of the patients were women, and 42.4% had pre-interventional AF. RESULTS: Compared to patients with sinus rhythm (SR, n = 148), patients with AF (n = 109) had an almost three-fold higher incidence of major vascular complications (AF 14.7% vs. SR 5.4%, p = 0.016) and life threatening bleeding (AF 11.9% vs. SR 4.1%, p = 0.028) during the first 30 post procedural days. However, the rate of cerebrovascular complications (AF 3.7% vs. SR 2.7%, p = 0.726) did not significantly differ between the two groups. Overall mortality was significantly higher in patients with AF during the first month (AF 8.3% vs. SR 2.0%, p = 0.032) and the first year (AF 28.4% vs. SR 15.3%; p = 0.020) following TAVR. CONCLUSION: Patients with AF had significantly more severe bleeding complications after TAVR, which were significantly related to mortality. Future prospective randomized studies must clarify the optimal anticoagulation therapy for patients with AF after TAVR. TRIAL REGISTRATION: DRKS00011798 on DRKS (Date 17.03.2017). PMID- 29262769 TI - A comprehensive analysis on preservation patterns of gene co-expression networks during Alzheimer's disease progression. AB - BACKGROUND: Alzheimer's disease (AD) is a chronic neuro-degenerative disruption of the brain which involves in large scale transcriptomic variation. The disease does not impact every regions of the brain at the same time, instead it progresses slowly involving somewhat sequential interaction with different regions. Analysis of the expression patterns of the genes in different regions of the brain influenced in AD surely contribute for a enhanced comprehension of AD pathogenesis and shed light on the early characterization of the disease. RESULTS: Here, we have proposed a framework to identify perturbation and preservation characteristics of gene expression patterns across six distinct regions of the brain ("EC", "HIP", "PC", "MTG", "SFG", and "VCX") affected in AD. Co-expression modules were discovered considering a couple of regions at once. These are then analyzed to know the preservation and perturbation characteristics. Different module preservation statistics and a rank aggregation mechanism have been adopted to detect the changes of expression patterns across brain regions. Gene ontology (GO) and pathway based analysis were also carried out to know the biological meaning of preserved and perturbed modules. CONCLUSIONS: In this article, we have extensively studied the preservation patterns of co-expressed modules in six distinct brain regions affected in AD. Some modules are emerged as the most preserved while some others are detected as perturbed between a pair of brain regions. Further investigation on the topological properties of preserved and non-preserved modules reveals a substantial association amongst "betweenness centrality" and "degree" of the involved genes. Our findings may render a deeper realization of the preservation characteristics of gene expression patterns in discrete brain regions affected by AD. PMID- 29262770 TI - Patterns of genetic variation among geographic and host-plant associated populations of the peach fruit moth Carposina sasakii (Lepidoptera: Carposinidae). AB - BACKGROUND: Populations of herbivorous insects may become genetically differentiated because of local adaptation to different hosts and climates as well as historical processes, and further genetic divergence may occur following the development of reproductive isolation among populations. Here we investigate the population genetic structure of the orchard pest peach fruit moth (PFM) Carposina sasakii (Lepidoptera: Carposinidae) in China, which shows distinct biological differences when characterized from different host plants. Genetic diversity and genetic structure were assessed among populations from seven plant hosts and nine regions using 19 microsatellite loci and a mitochondrial sequence. RESULTS: Strong genetic differentiation was found among geographical populations representing distinct geographical regions, but not in host-associated populations collected from the same area. Mantel tests based on microsatellite loci indicated an association between genetic differentiation and geographical distance, and to a lesser extent environmental differentiation. Approximate Bayesian Computation analyses supported the scenario that PFM likely originated from a southern area and dispersed northwards before the last glacial maximum during the Quaternary. CONCLUSIONS: Our analyses suggested a strong impact of geographical barriers and historical events rather than host plants on the genetic structure of the PFM; however, uncharacterized environmental factors and host plants may also play a role. Studies on adaptive shifts in this moth should take into account geographical and historical factors. PMID- 29262771 TI - Frequent attenders in late life in primary care: a systematic review of European studies. AB - BACKGROUND: High utilization of health care services is a costly phenomenon commonly observed in primary care practices. However, while frequent attendance in primary care has been broadly studied across age groups, aspects of high utilization by elderly patients have not been investigated in detail. The aim of this paper is to provide a systematic review of frequent attendance in primary care among elderly people. METHODS: We searched five databases (PubMed, PsycINFO, Web of Science, PubPsych, and Cochrane Library) for published papers addressing frequent attendance in primary health care among elderly individuals. Quality of studies was assessed using established criteria for evaluating methodological quality. RESULTS: Ten studies met inclusion criteria and were included for detailed analysis. The average number of patients frequently utilizing primary care services varied across studies from 10% to 33% of the elderly samples and subsamples. The definition of frequent attendance across studies differed substantially. The most consistent associations between frequent attendance and old age were found for presence and severity of physical illness. Results on mental disorders and frequent attendance were heterogeneous. Only a few studies have assessed frequent attendance in association with factors such as drug use, social support or sociodemographic aspects; however results were inconsistent. CONCLUSIONS: Severe ill health and the need for treatment serve as the main drivers of frequent attendance in older adults. As results were scarce and divergent, future studies are needed to provide more information on this topic. Since prior studies have offered only a snapshot of this service use behaviour, a longitudinal approach would be preferable in the future. PMID- 29262773 TI - The red distribution width and the platelet distribution width as prognostic predictors in gastric cancer. AB - BACKGROUND: Increasing attention is focused on the relationship of inflammation biomarkers with malignant tumors. The purpose of the present study was to detect whether the preoperative the red distribution width (RDW) and the platelet distribution width (PDW) can be used to distinguish patients with gastric cancer (GC) or early stage GC from the healthy controls and predict the progression and prognosis of the GC. METHODS: The RDW and PDW values of 227 patients with GC and 164 patients with early GC were retrospectively analyzed comparing with 101 healthy controls. In addition, the clinicopathological features, survival curves and prognosis of the patients with GC were compared between the high and low groups according to the RDW and PDW values. RESULTS: Significant higher RDW and lower PDW were detected in patients with GC and early GC compared to the healthy controls. A higher RDW was significantly associated with older age, a larger tumor diameter, deeper tumor infiltration, and lymph node metastasis while a lower PDW was significantly associated with male, older age, a larger tumor diameter, deeper tumor infiltration, elevated CEA and CA125. Increased RDW was significantly associated with worse overall survival (OS) and disease-free survival (DFS) for GC (P = 0.042 and P = 0.033, respectively) and early GC (P = 0.037 and P = 0.009, respectively) while decreased PDW indicated a significantly association with poor DFS for early GC (P = 0.006). Univariate and multivariate survival analysis showed that RDW and PDW can act as independent prognostic factors for DFS (P = 0.028 and P = 0.020) in patients with early GC. CONCLUSION: The preoperative RDW and PDW were simple and convenient predictive factors for the progression and prognosis of patients with GC. PMID- 29262772 TI - Mandibulate convergence in an armoured Cambrian stem chelicerate. AB - BACKGROUND: Chelicerata represents a vast clade of mostly predatory arthropods united by a distinctive body plan throughout the Phanerozoic. Their origins, however, with respect to both their ancestral morphological features and their related ecologies, are still poorly understood. In particular, it remains unclear whether their major diagnostic characters were acquired early on, and their anatomical organization rapidly constrained, or if they emerged from a stem lineage encompassing an array of structural variations, based on a more labile "panchelicerate" body plan. RESULTS: In this study, we reinvestigated the problematic middle Cambrian arthropod Habelia optata Walcott from the Burgess Shale, and found that it was a close relative of Sanctacaris uncata Briggs and Collins (in Habeliida, ord. nov.), both retrieved in our Bayesian phylogeny as stem chelicerates. Habelia possesses an exoskeleton covered in numerous spines and a bipartite telson as long as the rest of the body. Segments are arranged into three tagmata. The prosoma includes a reduced appendage possibly precursor to the chelicera, raptorial endopods connected to five pairs of outstandingly large and overlapping gnathobasic basipods, antennule-like exopods seemingly dissociated from the main limb axis, and, posteriorly, a pair of appendages morphologically similar to thoracic ones. While the head configuration of habeliidans anchors a seven-segmented prosoma as the chelicerate ground pattern, the peculiar size and arrangement of gnathobases and the presence of sensory/tactile appendages also point to an early convergence with the masticatory head of mandibulates. CONCLUSIONS: Although habeliidans illustrate the early appearance of some diagnostic chelicerate features in the evolution of euarthropods, the unique convergence of their cephalons with mandibulate anatomies suggests that these traits retained an unusual variability in these taxa. The common involvement of strong gnathal appendages across non-megacheirans Cambrian taxa also illustrates that the specialization of the head as the dedicated food-processing tagma was critical to the emergence of both lineages of extant euarthropods-Chelicerata and Mandibulata-and implies that this diversification was facilitated by the expansion of durophagous niches. PMID- 29262774 TI - The combined impact of mechanical factors on the wall stress of the human ascending aorta - a finite elements study. AB - BACKGROUND: Biomechanical factors influence stress in the aortic wall. The aim of this study was to assess how thediameter and shape of the vessel, blood pressure and longitudinal systolic aortic stretching (SAS) caused by thecontraction of the myocardium influence stress in the aortic wall. METHODS: Three computational models of the non-dilated aorta and aneurysms of the ascending aorta and aorticroot were created. Then, finite elements analyses were carried out. The models were subjected to blood pressure(120 mmHg and 160 mmHg) and longitudinal systolic aortic stretching (0 mm, 5 mm, 10 mm and 15 mm). Theinfluence of wall elasticity was examined too. RESULTS: Blood pressure had a smaller impact on the stress than the SAS. An increase in blood pressure from120 mmHgto 160 mmHg increased the peak wall stress (PWS) on average by 0.1 MPa in all models. A 5 mm SAS caused a 0.1-0.2 MPa increase in PWS in all the models. The increase in PWS caused by a 10mm and 15mmSAS was 0.2 MPa and 0.4 MPa in the non-dilated aorta, 0.2-0.3 MPa and 0.3-0.5 MPa in the aneurysm of the ascending aorta, and 0.1-0.2 MPaand 0.2-0.3 MPa in the aortic root aneurysm model, respectively. The loss of elasticity of the aneurysmal wall resulted in an increase of PWS by 0.1-0.2 MPa. CONCLUSIONS: Aortic geometry, wall stiffness, blood pressure and SAS have an impact on PWS. However, SAS had thebiggest impact on wall stress. The results of this study may be useful in future patient-specific computational modelsused to assess the risk of aortic complications. PMID- 29262775 TI - ShinyGPAS: interactive genomic prediction accuracy simulator based on deterministic formulas. AB - BACKGROUND: Deterministic formulas for the accuracy of genomic predictions highlight the relationships among prediction accuracy and potential factors influencing prediction accuracy prior to performing computationally intensive cross-validation. Visualizing such deterministic formulas in an interactive manner may lead to a better understanding of how genetic factors control prediction accuracy. RESULTS: The software to simulate deterministic formulas for genomic prediction accuracy was implemented in R and encapsulated as a web-based Shiny application. Shiny genomic prediction accuracy simulator (ShinyGPAS) simulates various deterministic formulas and delivers dynamic scatter plots of prediction accuracy versus genetic factors impacting prediction accuracy, while requiring only mouse navigation in a web browser. ShinyGPAS is available at: https://chikudaisei.shinyapps.io/shinygpas/ . CONCLUSION: ShinyGPAS is a shiny based interactive genomic prediction accuracy simulator using deterministic formulas. It can be used for interactively exploring potential factors that influence prediction accuracy in genome-enabled prediction, simulating achievable prediction accuracy prior to genotyping individuals, or supporting in-class teaching. ShinyGPAS is open source software and it is hosted online as a freely available web-based resource with an intuitive graphical user interface. PMID- 29262776 TI - Repeat Chlamydia trachomatis testing among heterosexual STI outpatient clinic visitors in the Netherlands: a longitudinal study. AB - BACKGROUND: Chlamydia infections are common in both men and women, are often asymptomatic and can cause serious complications. Repeat testing in high-risk groups is therefore indicated. In the Netherlands, guidelines on repeat chlamydia testing differ between testing facilities, and knowledge on repeat testing behaviour is limited. Here, we analyse the current repeat testing behaviour of heterosexual STI clinic visitors, and aim to identify groups for which repeat testing advice could be advantageous. METHODS: Longitudinal surveillance data from all Dutch STI outpatient clinics were used, which included all STI clinic consultations carried out among heterosexual men and women between June 2014 and December 2015. Repeat testing was defined as returning to the same STI clinic between 35 days and 12 months after initial consultation. We calculated chlamydia positivity at repeat test stratified by initial test result and time between consultations. Logistic regression analyses were used to identify predictors of repeat testing, and predictors of having a chlamydia positive repeat test. RESULTS: In total, 140,486 consultations in 75,487 women and 46,286 men were available for analyses. Overall, 15.4% of women and 11.1% of men returned to the STI clinic within the study period. Highest chlamydia positivity at repeat test was seen 3-5 months after initial positive test. Among both women and men, repeat testing was associated with non-Western ethnicity, having had more than two sex partners in the past 6 months, reporting STI symptoms, having a history of STI, and having a chlamydia positive initial test. Among repeat testers, chlamydia positive repeat test was most strongly associated with younger age, followed by a chlamydia positive initial test. CONCLUSIONS: Repeat testing most often resulted in a positive test result among young heterosexuals (<25) and heterosexuals of any age with a chlamydia infection at the initial consultation. Further efforts are needed to determine optimal repeat testing strategies. PMID- 29262777 TI - Evolutionary history of the NAM-B1 gene in wild and domesticated tetraploid wheat. AB - BACKGROUND: The NAM-B1 gene in wheat has for almost three decades been extensively studied and utilized in breeding programs because of its significant impact on grain protein and mineral content and pleiotropic effects on senescence rate and grain size. First detected in wild emmer wheat, the wild-type allele of the gene has been introgressed into durum and bread wheat. Later studies have, however, also found the presence of the wild-type allele in some domesticated subspecies. In this study we trace the evolutionary history of the NAM-B1 in tetraploid wheat species and evaluate it as a putative domestication gene. RESULTS: Genotyping of wild and landrace tetraploid accessions showed presence of only null alleles in durum. Domesticated emmer wheats contained both null alleles and the wild-type allele while wild emmers, with one exception, only carried the wild-type allele. One of the null alleles consists of a deletion that covers several 100 kb. The other null-allele, a one-basepair frame-shift insertion, likely arose among wild emmer. This allele was the target of a selective sweep, extending over several 100 kb. CONCLUSIONS: The NAM-B1 gene fulfils some criteria for being a domestication gene by encoding a trait of domestication relevance (seed size) and is here shown to have been under positive selection. The presence of both wild-type and null alleles in domesticated emmer does, however, suggest the gene to be a diversification gene in this species. Further studies of genotype-environment interactions are needed to find out under what conditions selection on different NAM-B1 alleles have been beneficial. PMID- 29262778 TI - Acute coronary syndromes occurring while driving: frequency and patient characteristics. AB - BACKGROUND: Acute coronary syndrome (ACS) may occur during any human activity, including driving. The objectives of this study were to report the frequency of ACS occurring while driving, clarify patient characteristics, and analyze the behavioral patterns of drivers who sustained ACS. METHODS: A single-center, retrospective observational study was conducted using prospectively acquired data. Among 1605 ACS patients admitted between January 2011 and December 2016, 65 (60 men/5 women) patients who sustained ACS while driving were identified. Clinical variables were compared between these 65 patients and 1540 patients who sustained ACS while performing other activities. Furthermore, multivariable regression analysis was performed to identify variables associated with ACS. RESULTS: The frequency of ACS occurring while driving was 4.0% (65/1605). Compared with patients who sustained ACS while performing other activities, those who sustained ACS while driving were significantly younger (66.2 +/- 13.0 vs. 57.5 +/- 12.2 years, p < 0.001) and more likely to smoke (34.2 vs. 60.0%, p < 0.001). Multivariable regression analysis showed that age (OR 0.961; 95% CI 0.940 0.982) and current smoking (OR 1.978; 95% CI 1.145-3.417) were associated with ACS. While 55 drivers (85%) who remained conscious after ACS could seek medical attention without causing accidents, the other 10 (15%) who sustained cardiac arrest caused accidents. CONCLUSIONS: The association between current smoking and ACS occurring while driving suggests that smoking cessation is advised for smokers who drive from the standpoint of driving safety. We expect that prospective studies be conducted to verify our findings and identify individuals at risk for ACS while driving. PMID- 29262779 TI - A rare cause of acute liver failure- a case report. AB - BACKGROUND: Acute liver failure (ALF) induced by diffuse metastatic disease has rarely been reported. CASE PRESENTATION: We present a 51-years-old woman with relevant clinical history for breast cancer. The patient was admitted in the emergency department with jaundice, dark urine and pale stools. She was on the 10th day of hormonotherapy for recurrence of breast cancer, diagnosed 7 years previously. Usual causes of acute liver failure were excluded, all drugs were stopped and the imaging studies performed were positive only for steatosis. Nonetheless, ALF progressed and the patient died 4 days later. Autopsy demonstrated a massive intrasinusoidal infiltration of the liver by breast cancer cells. CONCLUSION: We highlight a rare cause of ALF. Although uncommon, physicians should be alert for this situation as the diagnosis can be challenging and the imaging studies can remain normal. PMID- 29262780 TI - Primary pancreatic plasmacytoma: a rare case report. AB - BACKGROUND: Extramedullary plasmacytoma is a very rare tumor derived from plasma cells and found outside the bone marrow. Most have been identified in patients with the more aggressive anaplastic form of the disease. Only a few cases of primary pancreatic plasmacytoma have been reported. CASE PRESENTATION: We present a case of a 56-year-old man in whom a pancreatic mass was found incidentally. The lesion was determined to be a pancreatic plasmacytoma after distal pancreatectomy. There are no indications of clinical, laboratory or imaging findings of multiple myeloma nor any association with plasmacytoma in any other places, so the diagnosis of primary pancreatic plasmacytoma was made. CONCLUSION: Primary pancreatic plasmacytoma is rare and the diagnosis is difficult before surgery. PMID- 29262781 TI - PDE1A polymorphism contributes to the susceptibility of nephrolithiasis. AB - BACKGROUND: Previous studies have confirmed a family risk of nephrolithiasis (NL), but only 15% of all cases are associated with an identified monogenic factor. In clinical practice, our group encountered a patient with NL combined with cystic kidney disease that had 3 affected family members. No known mutations association with NL was detected in this family, and thus further investigation of the molecular cause of NL was deemed to be necessary. RESULTS: Quality analysis from the sequencing stage showed a more than 80-fold average depth and 95% coverage for each sample, and six mutations within six genes were chosen as candidate variants for further validation. Genotyping of rs182089527in the phosphodiesterase 1A (PDE1A) gene in the validation cohort indicated that the alternative allele was present in 15 patients with heterozygosity and in 1 patient with homozygosity, and exhibited significant enrichment in NL patients (Fisher's exact test, adjusted p = 0.0042) and kidney cystic patients (Fisher's exact test, adjusted p = 0.067) compared to controls. In addition, function analysis displayed a significant decrease in the protein and mRNA expression levels resulting from the rs182089527 mutant sequence compared with the wild-type sequence. Moreover, patients with this mutation displayed a high level of creatinine and urea in urinalysis. CONCLUSIONS: Our study provides genetic evidence that the rs182089527 mutation in PDE1A is involved in the development of NL and kidney cysts, which should help to improve personalized medicine for diagnosis and treatment. PMID- 29262783 TI - Hepatitis B vaccination coverage among healthcare workers at national hospital in Tanzania: how much, who and why? AB - BACKGROUND: Hepatitis B vaccination for healthcare workers (HCWs) is a key component of the WHO Hepatitis B Elimination Strategy 2016-2021. Data on current hepatitis B vaccine coverage among health care workers in Sub-Saharan Africa are scarce, but these data are vital for effective programming. We assessed the proportion of HCWs vaccinated for hepatitis B and the factors associated with adequate vaccination coverage at a national hospital in Tanzania. METHODS: A descriptive cross-sectional study was conducted among consenting healthcare workers between 30th July and 30th September 2015. Vaccination histories were obtained through self-administered questionnaires. Means and proportions were used to summarize the data. Student's t and chi-squared tests were used as appropriate. Logistic regression was used to determine the factors associated with vaccination. RESULTS: A total of 348 HCWs were interviewed, of whom 198 (56.9%) had received at least one dose of hepatitis B vaccination, while only 117 (33.6%) were fully vaccinated. About half of the 81 HCWs with partial vaccination (49.4%) had missed their subsequent vaccination appointments. Among unvaccinated HCWs, 14 (9.3%) had either HBV infection or antibodies against HBV infection upon pre-vaccination screening. However, the remaining participants were not vaccinated and did not know their immune status against HBV. Nearly all respondents (347, 99.3%) had heard about the hepatitis B viral vaccine. The following reasons for non-vaccination were given: 98 (65.3%) reported that they had not been offered the vaccine; 70 (46.7%) observed standard precautions to ensure infection prevention and 60 (41.3%) blamed a low level of awareness regarding the availability of the hepatitis B vaccine. CONCLUSION: The current vaccination coverage among practicing healthcare workers at Muhimbili National Hospital is low, despite a high level of awareness and the acceptance of the vaccine. Expedited and concerted efforts to scale vaccine uptake should include improved access to the vaccine, especially for newly recruited HCWs. The extension of the study to private healthcare settings and lower-level facilities would be useful. PMID- 29262782 TI - Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network. AB - BACKGROUND: Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome wide overview of the gene regulatory network in chondrogenesis has not been achieved. RESULTS: In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage selective genes. CONCLUSIONS: Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders. PMID- 29262784 TI - Risk of mortality associated with respiratory syncytial virus and influenza infection in adults. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection constitutes a substantial disease burden in the general population. However, the risk of death for RSV infection has been rarely evaluated with confounders or comorbidities adjusted. We aimed to evaluate whether RSV infection is associated with higher mortality than seasonal influenza after adjusting for confounders and comorbidities and the effect of oseltamivir on the mortality in patients with influenza infection. METHODS: A retrospective cohort study was conducted on adult (>=18 years) patients admitted to the emergency department and ward of a university teaching hospital for suspected viral infection during 2013-2015 (N = 3743). RSV infection was diagnosed by multiplex PCR (N = 87). Adults hospitalized for seasonal influenza during the study period were enrolled as a comparison group (n = 312). The main outcome was 20-day all-cause mortality.We used Cox proportional hazard regression analyses to calculate the relative risk of death. RESULTS: Adult patients were less likely to be diagnosed with RSV than with influenza (2.3 vs 8.3%, respectively), were older and more likely to be diagnosed with pneumonia, chronic obstructive pulmonary disease, hypoxemia, and bacterial co-infection. In patients with RSV infection, the 20-day all-cause mortality was higher than that for influenza, (18.4 vs 6.7%, respectively). RSV infection showed significantly higher risk of death compared to the seasonal influenza group, with hazard ratio, 2.32 (95% CI, 1.17-4.58). Oseltamivir had no significant effect on mortality in patients with influenza. CONCLUSIONS: RSV infection was significantly associated with a higher risk of death than seasonal influenza, adjusted for potential confounders and comorbidities. PMID- 29262785 TI - Radiation used for head and neck cancer increases virulence in Candida tropicalis isolated from a cancer patient. AB - BACKGROUND: Studies have shown that radiation from radiotherapy increases the yeast colonization of patients. However it is not clear, if such radiation alters the yeast itself. The aim of the present study was therefore to report the direct impact of gamma radiation on Candida tropicalis. METHODS: C. tropicalis was obtained from a patient with a carcinoma, a suspension of this yeast containing 2.0 * 103 colony forming units per milliliter was prepared. It was submitted to gamma radiation dosage similar to that used in the treatment of head and neck cancer. After a cumulative dose of 7200 cGy some virulence attributes of C. tropicalis, including macro and micromorphological characteristics, adhesion and biofilm abilities, murine experimental infection and phagocytosis resistance were evaluated on irradiated and non-irradiated yeasts. RESULTS: After irradiation the colony morphology of the yeast was altered from a ring format to a smooth appearance in most colonies. Scanning electron microscopy revealed notable differences in the structures of both these colonies and the yeast cells, with the loss of pseudohyphae following irradiation and an increase in extracellular matrix production. The adherence and biofilm production of the yeast was greater following irradiation, both in terms of the number of yeasts and total biomass production on several abiotic surfaces and TR146 cells. The phagocytic index of the irradiated yeasts was not statistically different; however, the presence of cellular debris was detected in the kidneys of infected animals. Mice infected with irradiated yeasts developed an infection at the site of the yeast inoculation, although systemic infection was unchanged. CONCLUSIONS: Our findings show for the first time that C. tropicalis, one of the most important yeasts from colonization, which cause fatal candidemia in cancer patients, is affected by gamma irradiation, with changes to its virulence profile. PMID- 29262786 TI - The absence of reproductive isolation between non-sister and deeply diverged mitochondrial lineages of the black-throated tit (Aegithalos concinnus) revealed by a multilocus genetic analysis in a contact zone. AB - BACKGROUND: A deep divergence of mitochondrial DNA is common in species delimitated by morphological traits. Several hypotheses can explain such variations, such as cryptic species, introgression, allopatric divergence and ancestral lineage. The black-throated tit harbors several deeply divergent mitochondrial lineages. Two lineages with 5% divergence, but having a high level of gene flow, have been detected in its subspecies, A. C. concinnus and A. c. talifuenses. In this study, we conducted a genetic analysis at a contact zone of these two lineages to identify whether these lineages either reflect a high level of intraspecific variation in mitochondrial loci or represent incipient speciation. Mitochondrial ND2 and 11 microsatellite loci were used to conduct phylogenetic and population structure analyses. RESULTS: ND2 haplotypes actually diverged into two groups within subspecies A. c. talifuenses; however, they formed a non-sister relationship when including all available GenBank ND2 sequences. Analyses of microsatellite data indicated no existing population structure and showed a pattern of isolation by distance. Individuals sampled at the contact zone were almost identified as F2 hybrids. CONCLUSIONS: Isolation for 2.4 Ma, as suggested by a previous study, appeared to be insufficient to develop robust reproductive barriers. Reproductive barriers were weak, or even absent between the divergent lineages, highlighting that incipient speciation was unlikely to be the case. Considering the results from previous studies, the divergent lineages may be better explained by secondary contact after allopatric isolation because of Pleistocene climate changes, but other hypotheses cannot be definitively ruled out because of the lack of representative samples from the other distribution region and its relatives. Considering that divergence in morphology was hardly observed and the particular split in genetics, the two subspecies might be better merged. The current findings also highlight the likely contribution of male-biased dispersal to male-biased gene flow among mitochondrial lineages; more efforts are needed to illustrate the evolutionary history of the black-throated tit. PMID- 29262787 TI - Eosinophilic granulomatosis with polyangiitis: myocardial thickening reversed by corticosteroids. AB - BACKGROUND: In 1951 Churg and Strauss first described the clinical condition now known as eosinophilic granulomatosis with polyangiitis (EGPA), characterized by asthma, nasal polyposis, rhinosinusitis, hypereosinophilia with organ infiltration, and necrotizing vasculitis. It is classified as an antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, but ANCA negativity is common and more frequently encountered in EGPA with myocardial involvement. Long-term survival has substantially improved with corticosteroid treatment but myocardial involvement is still the leading cause of death in EGPA. CASE PRESENTATION: A 53 year old man with a history of asthma and nasal polyposis presented with acute chest pain and elevated troponin; a percutaneous coronary intervention was performed. The left ventricle was described as hypertrophic. After 20 days the myocardium had markedly increased in thickness of both the right and left ventricle. Evaluation revealed hypereosinophilia in the blood and nasal mucosal tissue, which confirmed the diagnosis of EGPA. He presented with signs of active vasculitis including weight loss, tiredness, intracerebral hemorrhage, and increasing serum creatinine. After 6 days of corticosteroid treatment, the myocardium returned to its initial thickness. CONCLUSION: Rapid and marked thickening of the myocardium is not frequently reported but may occur in EGPA. Myocardial thickening in EGPA can be quickly reversed by corticosteroids, and is most likely caused by edema. PMID- 29262788 TI - Rapid and large-scale implementation of HCV treatment advances in France, 2007 2015. AB - BACKGROUND: The last decade was marked by major advances in HCV treatment with the introduction of first wave protease inhibitors (1st-wave PIs, telaprevir or boceprevir) in 2011 and second direct-acting antivirals (2nd-wave DAAs) in 2014, that followed low effective pegylated interferon alpha / ribavirin bitherapy. We estimated the number of patients initiating HCV treatment in France between 2007 and 2015 according to the type of therapy, described their demographical characteristics, and estimated how many were cured with 2nd-wave DAAs in 2014 2015. METHODS: Individual data from the national health insurance information system were analysed. HCV treatment initiation was defined as a drug reimbursement in the absence of any reimbursement for the same drug in the previous six weeks. RESULTS: Between 2007 and 2015, 72,277 patients initiated at least one HCV treatment. The annual number of patients initiating treatment decreased from 2007 (~13,300) to 2010 (~10,000). It then increased with the introduction of 1st-wave PIs (~12,500 in 2012), before decreasing again in 2013 (~8400). A marked increase followed upon the approval of 2nd-wave DAAs in 2014 (~11,600). Approximately, 8700 and 14,700 patients initiated 2nd-wave DAAs in 2014 and 2015, respectively, corresponding to an estimated 20,300 cured patients in 2014-2015. Patients initiating HCV treatment were mostly male (~65% throughout the 9-year period). Women were older than men (mean age: 55.0 vs. 48.9). Increasing age was associated with more advanced treatment. Among patients initiating 2nd-wave DAAs, the proportions of those under 40 and over 79 years old increased between 2014 and 2015, whereas the proportion of those previously treated for HCV 2007 onwards declined. CONCLUSIONS: Successive advances in HCV treatment have been rapidly and widely implemented in France. With the announcement of universal access to DAAs in mid-2016 and price reductions, access to 2nd-wave DAAs is expected to expand even more. PMID- 29262789 TI - Parental investment matters for maternal and offspring immune defense in the mouthbrooding cichlid Astatotilapia burtoni. AB - BACKGROUND: Parental care, while increasing parental fitness through offspring survival, also bears cost to the care-giving parent. Consequentially, trade offs between parental care and other vitally important traits, such as the immune system seem evident. In co-occurring phases of parental care and immunological challenges negative consequences through a resource allocation trade off on both the parental and the offspring conditions can be predicted. While the immune system reflects parental stress conditions, parental immunological investments also boost offspring survival via the transfer of immunological substances (trans generational immune priming). We investigated this relationship in the mouthbrooding East African cichlid Astotatilapia burtoni. Prior to mating, females were exposed to an immunological activation, while others remained immunologically naive. Correspondingly, the immunological status of females was either examined directly after reproduction or after mouthbrooding had ceased. Offspring from both groups were exposed to immunological challenges to assess the extent of trans-generational immune priming. As proxy for immune status, cellular immunological activity and gene expression were determined. RESULTS: Both reproducing and mouthbrooding females allocate their resources towards reproduction. While upon reproduction the innate immune system was impeded, mouthbrooding females showed an attenuation of inflammatory components. Juveniles from immune challenged mouthbrooding females showed downregulation of immune and life history candidate genes, implying a limitation of trans-generational plasticity when parents experience stress during the costly reproductive phase. CONCLUSION: Our results provide evidence that both parental investment via mouthbrooding and the rise of the immunological activity upon an immune challenge are costly traits. If applied simultaneously, not only mothers seem to be impacted in their performance, but also offspring are impeded in their ability to react upon a potentially virulent pathogen exposure. PMID- 29262790 TI - Rheumatoid factor is correlated with disease activity and inflammatory markers in antineutrophil cytoplasmic antibody-associated vasculitis. AB - BACKGROUND: Some patients with antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV. RESULTS: Forty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (n = 29) and an RF-negative subset (n = 18). The Birmingham Vasculitis Activity Score (BVAS) was higher (P = 0.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (P = 0.020 and P = 0.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (r = 0.50, P = 0.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (r = 0.41, P = 0.004), ESR (r = 0.39, P = 0.016), IgM (r = 0.36, P = 0.016) and IgG (r = 0.37, P = 0.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF positive subset than in the RF-negative subset. CONCLUSIONS: In patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV. PMID- 29262791 TI - GlycA, a marker of protein glycosylation, is related to albuminuria and estimated glomerular filtration rate: the ELSA-Brasil study. AB - BACKGROUND: Systemic inflammation has been implicated in several chronic diseases. GlycA is a new nuclear mass resonance (NMR) spectroscopy-derived biomarker of systemic inflammation that reflects protein glycosylation. We evaluated the association of GlycA with albuminuria and eGFR in the ELSA-Brasil Study. METHODS: The cross-sectional association between GlycA (automated NMR LipoProfile((r)) test spectra, LabCorp, Raleigh, NC), and overnight 12 h albuminuria and CKD-EPI eGFR was evaluated among 5050 participants. RESULTS: GlycA was higher among older, women, smokers, alcohol abstemious, obese and in those with diabetes, hypertension or dyslipidemia. In addition, both eGFR and albuminuria were associated to GlycA. In linear regression, GlycA was independently associated with log albuminuria (B 0.03; 95%CI 0.02-0.04, P < 0.0001, per 1sd increase) and inversely related to eGFR (B -0.53; 95%CI -0.99 - 0.07, P < 0.02), even after adjustments including hsCRP. In logistic regression, GlycA was independently related to the risk of A2 or A3 albuminuria (OR 1.42, 95%CI 1.27-1.57, p < 0.0001, per 1sd increase), of having an eGFR < 60 ml/min/1.73m2 (OR 1.26, 95%CI 1.12-1.41, p = 0.0003, per 1 sd) or of a combined diagnosis of both conditions (OR 1.35, 95%CI 1.23-1.46, p < 0.0001, per 1 sd). In the ROC curve, GlycA had a higher AUC in comparison to hsCRP (AUC 0.67 vs. 0.62, p = 0.06) for the association with albuminuria A2 or A3. CONCLUSIONS: The present study demonstrates that GlycA is associated with albuminuria and eGFR, independently of major risk factors for CKD progression, including (and with a stronger association than) hsCRP. GlycA should be further evaluated in CKD progression. PMID- 29262792 TI - Ultra-high b-value diffusion-weighted imaging features of the prostatic leiomyoma case report. AB - BACKGROUND: Leiomyoma of the prostate is a rare benign tumor arising from smooth muscle fibers. Most cases are incidental findings observed during pathological examinations after resection of the prostate. To the best of our knowledge, only few studies have reported the conventional magnetic resonance imaging (MRI) findings of such tumors; however, no reports have described the ultra-high b value diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) findings of prostatic leiomyomas. CASE PRESENTATION: We report MR imaging characteristics and surgical pathologic findings of a case of prostatic leiomyoma treated by robot-assisted transperitoneal laparoscopic approach. Typical MR features showed a homogeneous lesion with slightly hypointense signal compared to the skeletal muscle on T2-weighted images, and isointense signal relative to the muscle on T1-weighted images with fat suppression, which collectively demonstrate apparent homogeneous enhancement with a non-enhanced envelope. A slightly hyperintense signal compared to the skeletal muscle was observed on ultra-high b value DWI, and higher ADC values were observed as compared to the prostate cancer. CONCLUSIONS: Prostatic leiomyoma is a benign tumor. This case indicates that MRI features of prostatic leiomyoma are helpful for the differential diagnosis of prostate cancer. PMID- 29262793 TI - Takotsubo syndrome - adding pieces to a complex puzzle. AB - Takotsubo syndrome, a form of acutely decompensated heart failure, has drawn interest because of its intriguing pathophysiology and therapeutic dilemmas. In their recent work in BMC Cardiovascular Disorders, Abanador-Kamper et al. describe the therapy management in these patients and add valuable information on cardiovascular magnetic resonance imaging evolution. PMID- 29262794 TI - Risk factors for mortality among patients admitted with upper gastrointestinal bleeding at a tertiary hospital: a prospective cohort study. AB - BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common gastrointestinal emergency, which is potentially fatal. Proper management of UGIB requires risk stratification of patients which can guide the type and aggressiveness of management. The aim of this was study was identify the causes of UGIB and factors that increase the risk of mortality in these patients. METHODS: This was a prospective cohort study conducted over a period of seven months at a tertiary hospital. Adults admitted with UGIB were included in the study. Demographic data, laboratory parameters and endoscopic findings were recorded. Patients were then followed up for 60 days to identify the occurrence of mortality. Chi-square tests and cox-regression was used to determine association between risk factors and mortality in the bivariate and multivariate analysis, respectively. RESULTS: A total of 170 patients with UGIB were included. Males accounted for the majority (71.2%). Median age of the study population was 40.0 years. Chronic liver disease was present in 30.6% of study patients. The most common cause of UGIB among the 86 patients who underwent endoscopy was oesophageal varices (57%), followed by peptic ulcer disease (18%) and gastritis (10%). Mortality occurred in 57 patients (33.5%) and was significantly higher in patients with high white blood cell count (HR 2.45, p 0.011), raised serum alanine aminotransferase (HR 4.22, p 0.016), raised serum total bilirubin (HR 5.79, p 0.008) and lack of an endoscopic procedure done (HR 4.40, p <0.001). Rebleeding was reported in 12 patients (7.1%) and readmission due to UGIB in 4 patients (2.4%) CONCLUSIONS: Oesophageal varices was the most common cause of UGIB. One-third of patients admitted with upper gastrointestinal bleeding died within 60 days of admission, signifying a high burden. Rebleeding and readmission rates were low. A high WBC count, raised serum ALT, raised serum total bilirubin and a lack of endoscopy were independent predictors of mortality. These findings can be used to risk-stratify patients who may benefit from early and more aggressive management. PMID- 29262795 TI - Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial). AB - BACKGROUND: The number of bariatric interventions for morbid obesity is increasing worldwide. Rapid weight loss is a major risk factor for gallstone development. Approximately 11 % of patients who underwent Roux-en-Y gastric bypass develop symptomatic gallstone disease. Gallstone disease can lead to severe complications and often requires hospitalization and surgery. Ursodeoxycholic acid (UDCA) prevents the formation of gallstones after bariatric surgery. However, randomized controlled trials with symptomatic gallstone disease as primary endpoint have not been conducted. Currently, major guidelines make no definite statement about postoperative UDCA prophylaxis and most bariatric centers do not prescribe UDCA. METHODS: A randomized, placebo-controlled, double blind multicenter trial will be performed for which 980 patients will be included. The study population consists of consecutive patients scheduled to undergo Roux-en-Y gastric bypass or sleeve gastrectomy in three bariatric centers in the Netherlands. Patients will undergo a preoperative ultrasound and randomization will be stratified for pre-existing gallstones and for type of surgery. The intervention group will receive UDCA 900 mg once daily for six months. The placebo group will receive similar-looking placebo tablets. The primary endpoint is symptomatic gallstone disease after 24 months, defined as admission or hospital visit for symptomatic gallstone disease. Secondary endpoints consist of the development of gallstones on ultrasound at 24 months, number of cholecystectomies, side-effects of UDCA and quality of life. Furthermore, cost-effectiveness, cost-utility and budget impact analyses will be performed. DISCUSSION: The UPGRADE trial will answer the question whether UDCA reduces the incidence of symptomatic gallstone disease after Roux-en-Y gastric bypass or sleeve gastrectomy. Furthermore it will determine if treatment with UDCA is cost-effective. TRIAL REGISTRATION: Netherlands Trial Register (trialregister.nl) 6135 . Date registered: 21-Nov-2016. PMID- 29262796 TI - Malnutrition-inflammation is a risk factor for cerebral small vessel diseases and cognitive decline in peritoneal dialysis patients: a cross-sectional observational study. AB - BACKGROUND: Chronic kidney disease patients have an increased prevalence of subclinical cerebrovascular diseases. Dialysis patients have severe vascular diseases burden. The cerebral small vessel diseases (CSVD) are difficult to find by clinical assessment. The evaluation of CVSD needs MRI. Cognitive impairment is a consequence of CVSD which is diagnosed by cognitive testing. These limited the study of CVSD and cognitive function in dialysis patients. Peritoneal dialysis (PD) patients are minority of dialysis population. We know even fewer about the CVSD in this special population. METHODS: In this cross-sectional study, we enrolled 72 PD patients who received care at the Peking Union Medical College hospital peritoneal dialysis center. CSVD were assessed by brain MR images. Cognitive function was evaluated with the Chinese version of the MMSE and MoCA. RESULTS: In our PD patients, the brain MRI showed the prevalence different signs of CSVD were: lacunar infarcts 38.9%, microbleeds 36.1%, abnormal brain white matter hyperintensities (WMHs) 48.6%, and intracerebral hemorrhage 4.2%. 25% and 86.8%of our patients could be diagnosed as cognitive impairment, according to the MMSE and MoCA test, respectively. nPCR was lower in patients with a lacunar infarct or intracerebral hemorrhage, and relative to the MMSA/MoCA score; hsCRP was higher in patients with lacunar infarct or abnormal WMHs and negative relative to the MMSA/MoCA score. In logistic regression analyses, nPCR was an independent risk factor for lacunar infarcts and impaired cognitive function. The presence of lacunar infarct was an independent risk factor for cognitive function decline. CONCLUSION: We demonstrated a high prevalence of CSVD and cognitive impairment in our PD patients. Lacunar infarct was the main kind of CVSD responsible for PD patients cognitive function decline. Our novel observation also revealed an association between malnutrition-inflammation and CSVD. PMID- 29262797 TI - Etiologic spectrum and occurrence of coinfections in children hospitalized with community-acquired pneumonia. AB - BACKGROUND: Co-infections are common in childhood community acquired pneumonia (CAP). However, their etiological pattern and clinical impact remains inconclusive. METHODS: Eight hundred forty-six consecutive children with CAP were evaluated prospectively for the presence of viral and bacterial pathogens. Nasopharyngeal aspirates were examined by direct immunofluorescence assay or polymerase chain reaction (PCR) for viruses. PCR of nasopharyngeal aspirates and enzyme-linked immunosorbent assays were performed to detect M. pneumoniae. Bacteria was detected in blood, bronchoalveolar lavage specimen, or pleural fluid by culture. RESULTS: Causative pathogen was identified in 70.1% (593 of 846) of the patients. The most commonly detected pathogens were respiratory syncytial virus (RSV) (22.9%), human rhinovirus (HRV) (22.1%), M. pneumoniae (15.8%). Coinfection was identified in 34.6% (293 of 846) of the patients. The majority of these (209 [71.3%] of 293) were mixed viral-bacterial infections. Age < 6 months (odds ratio: 2.1; 95% confidence interval: 1.2-3.3) and admission of PICU (odds ratio: 12.5; 95% confidence interval: 1.6-97.4) were associated with mix infection. Patients with mix infection had a higher rate of PICU admission. CONCLUSIONS: The high mix infection burden in childhood CAP underscores a need for the enhancement of sensitive, inexpensive, and rapid diagnostics to accurately identify pneumonia pathogens. PMID- 29262798 TI - Which strategies might improve local primary healthcare in Germany? An explorative study from a local government point of view. AB - BACKGROUND: Facing rising inequities and poorer accessibility of physicians in rural areas, new healthcare delivery structures are being considered to support local healthcare in German communities. To better understand perspectives on and attitudes towards different supplementary models, we examined attitudes among local politicians in the German federal state of Lower Saxony towards the suitability of supplementary care models. METHODS: As part of a cross-sectional study, we surveyed local politicians in Lower Saxony at the local authority and district levels (n = 449) by mail questionnaire. We asked for an assessment of four potential supplementary healthcare models at the local level: the use of trained medical assistants, patients' buses, mobile physicians' offices, and telemedicine. RESULTS: The response rate was 71.0% for mayors (n = 292) and 81.6% (n = 31) for county administrators. In summary, 72.4% of respondents supported the use of trained medical assistants, 48.9% voted for patients' buses, 22.0% for mobile physicians' offices, and 13.9% for telemedicine. Except for telemedicine, the politicians' approval of the supplementary models in rural areas was higher than in urban areas. The assessment regarding the suitability of each model was not significantly connected with indicators of a positively or negatively assessed local healthcare situation. The analyses showed that the use of trained medical assistants was associated with the positive effects of division of labor and potential to relieve physicians. In contrast, there was skepticism about technical support via telemedicine, mostly due to concerns about its unsuitability for elderly people and the potential lower quality of healthcare delivery. CONCLUSION: Local politicians widely accept the use of trained medical assistants, whereas the applicability of technical solutions such as telemedicine is perceived with skepticism. Therefore, the knowledge gap between evidence for and prejudices against telemedicine needs to be addressed more effectively. Reasons for the assessments of the presented models are more likely traceable to personal views than to assessments of the actual estimated local primary care situation. PMID- 29262799 TI - Partner notification and partner treatment for chlamydia: attitude and practice of general practitioners in the Netherlands; a landscape analysis. AB - BACKGROUND: Chlamydia prevalence remains high despite scaling-up control efforts. Transmission is not effectively interrupted without partner notification (PN) and (timely) partner treatment (PT). In the Netherlands, the follow-up of partners is not standardized and may depend on GPs' time and priorities. We investigated current practice and attitude of GPs towards PN and PT to determine the potential for Patient-Initiated Partner Treatment, which is legally not supported yet. METHODS: Multiple data-sources were combined for a landscape analysis. Quantitative data on (potential) PT were obtained from prescriptions in the national pharmacy register (2004-2014) and electronic patient data from NIVEL Primary Care Database (PCD) and from STI consultations in a subgroup of sentinel practices therein. Furthermore, we collected information on current practice via two short questionnaires at a national GP conference and obtained insight into GPs' attitudes towards PN/PT in a vignette study among GPs partaking in NIVEL PCD. RESULTS: Prescription data showed Azithromycin double dosages in 1-2% of cases in the pharmacy register (37.000 per year); probable chlamydia-specific repeated prescriptions or double dosages of other antibiotics in NIVEL-PCD (115/1078) could not be interpreted as PT for chlamydia with certainty. STI consultation data revealed direct PT in 6/100 cases, via partner prescription or double doses. In the questionnaires the large majority of GPs (>95% of 1411) reported to discuss PN of current and ex-partner(s) with chlamydia patients. Direct PT was indicated as most common method by 4% of 271 GPs overall and by 12% for partners registered in the same practice. Usually, GPs leave further steps to the patients (83%), advising patients to tell partners to get tested (56%) or treated (28%). In the vignette study, 16-20% of 268 GPs indicated willingness to provide direct PT, depending on patient/partner profile, more (24-45%) if patients would have the chance to notify their partner first. CONCLUSION: GPs in the Netherlands already treat some partners of chlamydia cases directly, especially partners registered in the same practice. Follow-up of partner notification and treatment in general practice needs more attention. GPs may be open to implement PIPT more often, provided there are clear guidelines to arrange this legally and practically. PMID- 29262800 TI - Comparison of equations for estimating glomerular filtration rate in screening for chronic kidney disease in asymptomatic black Africans: a cross sectional study. AB - BACKGROUND: Several equations have been developed to estimate glomerular filtration rate (eGFR). The common equations used were derived from populations predominantly comprised of Caucasians with chronic kidney disease (CKD). Some of the equations provide a correction factor for African-Americans due to their relatively increased muscle mass and this has been extrapolated to black Africans. Studies carried out in Africa in patients with CKD suggest that using this correction factor for the black African race may not be appropriate. However, these studies were not carried out in healthy individuals and as such the extrapolation of the findings to an asymptomatic black African population is questionable. We sought to compare the proportion of asymptomatic black Africans reported as having reduced eGFR using various eGFR equations. We further compared the association between known risk factors for CKD with eGFR determined using the different equations. METHODS: We used participant and laboratory data collected as part of a global reference interval study conducted by the Committee of Reference Intervals and Decision Limits (C-RIDL) under the International Federation of Clinical Chemistry (IFCC). Serum creatinine values were used to calculate eGFR using the Cockcroft-Gault (CG), re-expressed 4 variable modified diet in renal disease (4v-MDRD), full age spectrum (FAS) and chronic kidney disease epidemiology collaboration equations (CKD-EPI). CKD classification based on eGFR was determined for every participant. RESULTS: A total of 533 participants were included comprising 273 (51.2%) females. The 4v-MDRD equation without correction for race classified the least number of participants (61.7%) as having an eGFR equivalent to CKD stage G1 compared to 93.6% for CKD-EPI with correction for race. Only age had a statistically significant linear association with eGFR across all equations after performing multiple regression analysis. The multiple correlation coefficients for CKD risk factors were higher for CKD-EPI determined eGFRs. CONCLUSIONS: This study found that eGFR determined using CKD EPI equations better correlated with a prediction model that included risk factors for CKD and classified fewer asymptomatic black Africans as having a reduced eGFR compared to 4v-MDRD, FAS and CG corrected for body surface area. PMID- 29262801 TI - A new digital denture procedure: a first practitioners appraisal. AB - BACKGROUND: Historically, the complete removable denture is the last prosthetic procedure to switch to digital techniques whose advantages are mainly observed in the laboratory stages; however, it is not possible to measure the depressibility of the oral mucosa using optical cameras, thus conventional impression techniques are still necessary. This article describes the clinical and laboratory procedure and practitioners appraisal of the first fifteen digitally designed complete removable dental prostheses. METHODS: Several systems are now available including the Wieland(r) Digital Denture(r) which offers a complete procedure. This system is composed of a five axis-milling machine combined with a laboratory scanner and a design software application. Fifteen rehabilitations were carried out using the Wieland(r) system. RESULTS: The practitioner's role is simplified by intraoral recording with a central point and a reduced number of sessions. The prosthesis laboratory requires considerable investment in learning and equipment, making it possible to obtain ideal mounting assemblies in accordance with the occluso prosthetic concept of bilateral balanced occlusion. The absence of polymerization and therefore of base deformation risks reduce the equilibration step. Finally, the creation of templates as an alternative to the assembly of teeth on wax makes it possible to functionally validate (masticatory and phonatory) the future dentures. However, this procedure still presented some limitations in terms of scanning and software scope of applications. CONCLUSION: Digital denture design software is relatively efficient and helps to standardize clinical results. However, to this date, improvements of the software are still required for a routine use. PMID- 29262802 TI - Implication of species change of Nontuberculous Mycobacteria during or after treatment. AB - BACKGROUND: Co-existence or subsequent isolation of multiple nontuberculous mycobacteria (NTM) species in same patient has been reported. However, clinical significance of these observations is unclear. The aim of this study was to determine clinical implications of changes of NTM species during or after treatment in patients with NTM lung disease. METHODS: Patients with NTM lung disease, who experienced changes of NTM species during treatment or within 2 years of treatment completion between January 1, 2009 and December 31, 2015, were included in the analysis. Demographic, clinical, microbiological, and radiographic data were reviewed and analyzed. RESULTS: During the study period, 473 patients were newly diagnosed with NTM lung disease. Treatment was started in 164 patients (34.6%). Among these 164 patients, 16 experienced changes of NTM species during or within 2 years of treatment completion. Seven showed changes from M. avium complex (MAC) to M. abscessus subspecies abscessus (MAA) and five patients displayed changes from M. abscessus subspecies massiliense (MAM) to MAC. With isolation of new NTM species, 6 out of 7 patients with change from MAC to MAA reported worsening of symptoms, whereas none of the five patients with change from MAM to MAC reported worsening of symptoms. All MAA isolated during or after treatment for MAC lung diseases showed inducible resistance to clarithromycin. CONCLUSIONS: Change of NTM species may occur during or after treatment for NTM lung disease. Especially, changes from MAC to MAA is accompanied by symptomatic and radiographic worsening as well as inducible resistance to clarithromycin. PMID- 29262804 TI - Evaluation of serum zinc levels in patients with recurrent aphthous stomatitis (RAS). AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is an ulcerative disease of the oral mucosa without a clearly defined etiology. The aim of the study was to evaluate the serum zinc levels in patients with RAS in comparison to healthy controls and to validate the association between zinc levels and the course of RAS. METHODS: Seventy-five patients with RAS and 72 controls underwent full dental examination. Serum zinc levels were determined by flame atomic absorption spectroscopy (F AAS). The results were statistically analyzed with Kruskal Wallis, Mann-Whitney, chi-square tests and the test of difference between the two rates of structure with p < 0.05 as a significance level (Statistica 10, StatSoft(r)). RESULTS: No statistically significant differences were detected in serum zinc levels between RAS patients and healthy controls. The mean serum zinc concentration was found to be 84.2 MUg/dL in RAS group and 83.9 MUd/dL in controls, within the accepted norms. Zinc deficiency was observed in 10.7% patients from the RAS group and in 6.9% controls. No significant differences in serum zinc levels were found between patients when the course of the disease was considered. CONCLUSIONS: Serum zinc concentrations did not differ significantly in RAS patients and in healthy controls and it did not influence the course of the disease. Therefore, zinc does not appear to be an important modifying factor in the development of RAS. PMID- 29262803 TI - Clinical baseline and prognostic difference of platelet lymphocyte ratio (PLR) in right-sided and let-sided colon cancers. AB - BACKGROUND: Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ with respect to their biology and genomic patterns, but inflammatory index variation did not fully investigate. This study aimed to examine the difference of inflammatory indexes and its value between RCC and LCC. METHODS: The differences of common clinicopathologic factors, inflammatory indexes including PLR (Platelet lymphocyte ratio) between LCC and RCC were analyzed in the training cohort with logistic regression model, subsequently, confirmed in validation cohort. Kaplan-Meier analysis was applied for the analysis of the survival difference distinguished by the PLR and the Nonparametric Test was adopted to demonstrate the difference of PLR variation with the standard TNM classification between RCC and LCC. RESULTS: A total of 1846 CRC patients entered the study, 744 (40.3%) patients were RCC, 1102 (59.7%) were LCC. The patients' number in both cohorts was 923. It was found that LCC patients in the training cohort significantly to be with higher CEA, adenocarcinoma, early UICC/AJCC stage, p-MMR (mismatch-repair proficient), and lower PLR, and the later four features were confirm in validation cohort. Higher PLR, the unique inflammatory index, was significantly associated with poorer OS in LCC cohort (P = 0.002) and was elevated with the TNM stage in the LCC patients (P < 0.001), however, the two relationships did not sustain in RCC patients. CONCLUSION: Expect the classical characteristics, PLR, an inexpensive and easily assessable inflammatory index was found first time to be significant differ between LCC and RCC. Further, elevated PLR associated with poor OS (overall survival) in the LCC and more common in advanced TNM stage. PMID- 29262805 TI - Arteriovenous fistulae after renal biopsy: diagnosis and outcomes using Doppler ultrasound assessment. AB - BACKGROUND: Percutaneous renal biopsy (PRB) is an important technique providing relevant information to guide diagnosis and treatment in renal disease. As an invasive procedure it has complications. Most studies up to date have analysed complications related to bleeding. We report the largest single-center experience on routine Doppler ultrasound (US) assessment post PRB, showing incidence and natural history of arteriovenous fistulae (AVF) post PRB. METHODS: We retrospectively analysed 327 consecutive adult PRB performed at Ramon Cajal University Hospital between January 2011 and December 2014. All biopsies were done under real-time US guidance by a trained nephrologist. Routine Doppler mapping and kidney US was done within 24 h post biopsy regardless of symptoms. Comorbidities, full blood count, clotting, bleeding time and blood pressure were recorded at the time of biopsy. Post biopsy protocol included vitals and urine void checked visually for haematuria. Logistic regression was used to investigate links between AVF, needle size, correcting for potential confounding variables. RESULTS: 46,5% were kidney transplants and 53,5% were native biopsies. Diagnostic material was obtained in 90,5% (142 grafts and 154 native). Forty-seven AVF's (14.37%) were identified with routine kidney Doppler mapping, 95% asymptomatic (n = 45), 28 in grafts (18.4%) and 17 natives (9.7%) (p-value 0.7). Both groups were comparable in terms of comorbidities, passes, cylinders or biopsy yield (p-value NS). 80% were <1 cm in size and 46.6% closed spontaneously in less than 30 days (range 3-151). Larger AVF's (1-2 cm) took a mean of 52 days to closure (range 13 151). Needle size was not statistically significant factor for AVF (p-value 0.71). CONCLUSIONS: Contrary to historical data published, AVF's are a common complication post PRB that can be easily missed. Routine US Doppler mapping performed by trained staff is a cost-effective, non-invasive tool to diagnose and follow up AVF's, helping to assess management. PMID- 29262806 TI - Identifying gaps in the practices of rural health extension workers in Ethiopia: a task analysis study. AB - BACKGROUND: Health extension workers (HEWs) are the frontline health workers for Ethiopia's primary health care system. The Federal Ministry of Health is seeking to upgrade and increase the number of HEWs, particularly in remote areas, and address concerns about HEWs' pre-service education and practices. The aim of this study was to identify gaps in HEWs' practices and recommend changes in their training and scope of practice. METHODS: A cross-sectional descriptive task analysis was conducted to assess the work of rural HEWs who had been in practice for six months to five years. One hundred participants were invited from 100 health posts in five regions of Ethiopia. HEWs self-reported on 62 tasks on: frequency, criticality (importance), where the task was learned, and ability to perform the task. Descriptive statistics, including frequencies and percentages, were computed for each variable. Task combinations were examined to identify tasks performed infrequently or for which HEWs are inadequately prepared. RESULTS: A total of 82 rural HEWs participated in the study. Nearly all HEWs rated every task as highly critical to individual and public health outcomes. On average, most HEWs (51.5%-57.4%) reported learning hygiene and environmental sanitation tasks, disease prevention and control tasks, family health tasks, and health education and communication tasks outside of their pre-service education, primarily through in-service and on-the-job training. Over half of HEWs reported performing certain critical tasks infrequently, including management of supplies, stocks and maintenance at the facility and management of the cold chain system. Almost all HEWs (95.7-97.2%) perceived themselves as competent and proficient in performing tasks in all program areas. CONCLUSION: HEWs were insufficiently prepared during pre-service education for all tasks that fall within their scope of practice. Many learned tasks through in-service or on-the-job training, and some tasks were not learned at all. Some tasks that are part of expected HEW practice were performed infrequently, potentially reducing the effectiveness of the Health Extension Program to provide preventive and basic curative health care services to communities. Findings should alert policy makers to the need to review HEWs' scope of practice, update pre-service education curricula and prioritize in-service training modules. PMID- 29262807 TI - A metastatic invasive mole arising from iatrogenic uterus perforation. AB - BACKGROUND: Invasive mole derives from hydatidiform mole, but its pathogenesis remains unknown. Invasive mole arising from iatrogenic uterine perforation has not been reported yet. CASE PRESENTATION: A reproductive woman was admitted because she suffered form severe abdominal pain and acute intra-abdominal hemorrhage after suction evacuation due to misdiagnosis as inevitable abortion. The patient underwent hysteroscopy and laparoscopy, by which an iatrogenic uterine perforation and omentum and pelvic peritoneum metastases were confirmed. All lesions were removed and the final pathological diagnosis was metastatic invasive mole. The patient underwent post-operative chemotherapy with methotrexate and presented a good prognosis. CONCLUSION: Invasive mole arising form iatrogenic uterine perforation displays an unusual metastatic manner other than general invasive moles. The prevention of uterine perforation should be emphasized during suction evacuation for mole pregnancy. PMID- 29262808 TI - Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes. AB - BACKGROUND: Histones undergo extensive post-translational modifications and this epigenetic regulation plays an important role in modulating transcriptional programs capable of driving cancer progression. Acetylation of histone H3K18, associated with gene activation, is enhanced by P300 and opposed by the deacetylase Sirtuin2 (SIRT2). As these enzymes represent an important target for cancer therapy, we sought to determine whether the underlying genes are altered during prostate cancer (PCa) progression. METHODS: Tissue microarrays generated from 71 radical prostatectomy patients were initially immunostained for H3K18Ac, P300 and SIRT2. Protein levels were quantified using VECTRA automation and correlated with clinicopathologic parameters. The Cancer Genome Atlas (TGCA, n = 499) and Gene Expression Omnibus (n = 504) databases were queried for expression, genomic and clinical data. Statistics were performed using SPSSv23. RESULTS: Nuclear histone H3K18Ac staining increases in primary cancer (p = 0.05) and further in metastases (p < 0.01) compared to benign on tissue arrays. P300 protein expression increases in cancer (p = 0.04) and metastases (p < 0.001). A progressive decrease in nuclear SIRT2 staining occurs comparing benign to cancer or metastases (p = 0.04 and p = 0.03 respectively). Decreased SIRT2 correlates with higher grade cancer (p = 0.02). Time to Prostate Specific Antigen (PSA) recurrence is shorter in patients exhibiting high compared to low H3K18Ac expression (350 vs. 1542 days respectively, P = 0.03). In GEO, SIRT2 mRNA levels are lower in primary and metastatic tumors (p = 0.01 and 0.001, respectively). TGCA analysis demonstrates SIRT2 deletion in 6% and increasing clinical stage, positive margins and lower PSA recurrence-free survival in patients with SIRT2 loss/deletion (p = 0.01, 0.04 and 0.04 respectively). In this dataset, a correlation between decreasing SIRT2 and increasing P300 mRNA expression occurs in tumor samples (R = -0.46). CONCLUSIONS: In multiple datasets, decreases in SIRT2 expression portend worse clinicopathologic outcomes. Alterations in SIRT2 H3K18Ac suggest altered P300 activity and identify a subset of tumors that could benefit from histone deacetylation inhibition. PMID- 29262809 TI - Using medication utilization information to develop an asthma severity classification model. AB - BACKGROUND: Claims data are currently widely used as source data in asthma studies. However, the insufficient information in claims data related to level of asthma severity may negatively impact study findings. The present study develops and validates an asthma severity classification model that uses medication utilization in Taiwan National Health Insurance claims data. METHODS: The National Health Insurance Research Database was used for the years 2006-2012 and included a total of 7221 patients newly diagnosed with asthma in 2007 for model development and in 2008 for model validation. The medication utilization of patients during the first year after the index date was used to classify level of severity, and the acute exacerbation of asthma during the second through fourth years after the index date was used as the outcome variable. Three models were developed, with subjects classified into four, three, and two groups, respectively. The area under the receiver operating characteristic curve (AUC) and the Kaplan-Meier survival curve were used to compare the performances of the classification models. RESULTS: In development data, the distribution of subjects and acute exacerbation rate among the stage 1 to stage 4 were: 62.71%, 5.54%, 22.79%, and 8.96%, and 8.17%, 9.55%, 11.97%, and 14.91%, respectively. The results also showed the higher severity groups to be more prone to being prescribed oral corticosteroids for asthma control, while lower severity groups were more likely to be prescribed short-acting medication and inhaled corticosteroid treatment. Furthermore, the results of survival analysis showed two-group classification was recommended and yield moderate performance (AUC = 0.671). In validation data, the distribution of subjects, acute exacerbation rates, and medication uses among stages were similar to those in development data, and the results of survival analysis were also the same. CONCLUSIONS: Understanding asthma severity is critical to conducting effective, scholarly research on asthma, which currently uses claims data as a primary data source. The model developed in the present study not only overcomes a gap in the current literature but also provides an opportunity to improve the validity and quality of claims-data-based asthma studies. PMID- 29262810 TI - Implementation of the Robson classification in clinical practice:Lithuania's experience. AB - BACKGROUND: To determine the cesarean section (CS) rate in Lithuania, identify the groups of women that influence it using the Robson classification and to determine the impact of implementing the use of the Robson classification on the CS rate. METHODS: The Robson classification was introduced in Lithuanian hospitals prospectively classifying all the deliveries in 2012. The overall CS rate, sizes of the Robson groups of women, CS rate in each group and contribution to the overall CS rate from each group was calculated and the results were discussed. The analysis was repeated in 2014 and the data were compared using MS EXCEL and SPSS 23.0. RESULTS: Nineteen Lithuanian hospitals participated in the study. They represented 84.1% of the deliveries (23,742 out of 28,230) in 2012 and 88.5% of the deliveries (24,653 out of 27,872) in 2014. The CS rate decreased from 26.9% (6379/23,742) in 2012 to 22.7% (5605/24,653) in 2014 (p < 0.001). The greatest contributions to the overall CS rate were made by groups 1, 2 and 5. The greatest decrease in the CS rate was detected in group 2. The absolute contribution to the overall CS rate decreased from 4.9% to 3.8%. CONCLUSION: The Robson classification can work as an audit tool to identify the groups that have the greatest impact on the CS rate. It also helps to develop a strategy focussing on the reduction of the CS rate. PMID- 29262811 TI - Nutrition and Culinary in the Kitchen Program: a randomized controlled intervention to promote cooking skills and healthy eating in university students study protocol. AB - BACKGROUND: Community-based intervention studies that aim at developing cooking skills have increased in the scientific literature and are related to healthier food practices. However, methodological limitations are observed and only a few studies have university students as the target. The university entrance period has been related to negative changes in eating habits among young people and it represents an important period for developing interventions for health promotion. This study describes the study protocol and the evaluation framework for the Nutrition and Culinary in the Kitchen program. This program aims to develop cooking skills in university students, and is based on the Cooking with a Chef program in the United States. METHODS: This ongoing, randomized controlled intervention was designed with a six month follow-up study. The intervention consisted of three-hour weekly classes during a six week period with printed materials provided. Five of the classes were hands-on cooking and one was a tour to a popular food market. There were eight primary outcome measures: changes in relation to i) accessibility and availability of fruits and vegetables; ii) cooking attitudes; iii) cooking behaviors at home; iv) cooking behaviors away from home; v) produce consumption self-efficacy; vi) self-efficacy for using basic cooking techniques; vii) self-efficacy for using fruits, vegetables, and seasonings (while cooking); and viii) knowledge of cooking terms and techniques. Secondary outcomes included changes in body mass index and in personal characteristics related to cooking. Repeated measures were collected through the application of an online self-completed survey, at baseline, after intervention and six months after intervention. A sample of 80 university students (40: intervention group; 40: control group) was estimated to detect a mean change of 1.5 points in cooking knowledge, with study power of 80%, and 95% level of confidence, plus 20% for random losses and 10% for confounding factors. The control group participants have continued with their usual activities. Data analyses will evaluate the intervention effect on changes in outcomes within and between groups, as well as explore relations with personal characteristics. DISCUSSION: This method provides new evidence about whether or not a culinary intervention targeting university students has an impact on the improvement of cooking skills and healthy eating practices. TRIAL REGISTRATION: Brazilian Clinical Trials Registry - RBR-8nwxh5 ( http://www.ensaiosclinicos.gov.br/rg/RBR 8nwxh5/ ). PMID- 29262812 TI - Isoprenaline/beta2-AR activates Plexin-A1/VEGFR2 signals via VEGF secretion in gastric cancer cells to promote tumor angiogenesis. AB - BACKGROUND: The role of stress signals in regulating gastric cancer initiation and progression is not quite clear. It is known that stress signals modulate multiple processes such as immune function, cell migration and angiogenesis. However, few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis. METHODS: Here, we used beta2 adrenergic receptor (beta2-AR) agonist isoprenaline to imitate a stress signal and demonstrated the molecular mechanism underlying stress's influence on tumor angiogenesis. RESULTS: We found that isoprenaline stimulated vascular endothelial growth factor (VEGF) secretion in gastric cancer cells and plexin-A1 expression was induced by human recombinant VEGF165 in both gastric cancer cells and vascular endothelial cells. Furthermore, interfere with plexin-A1 expression in gastric cancer cells influence HUVEC tube formation, migration and tumor growth in vivo. CONCLUSIONS: These findings suggest that isoprenaline stimulate VGEF secretion and subsequently up-regulate the expression of plexin-A1 and VEGFR2 in gastric cancer cells, which form a positive impetus to promote tumor angiogenesis. This study reveals a novel molecular mechanism that a stress signal like isoprenaline may enhance angiogenesis via activating plexin-A1/VEGFR2 signaling pathway in gastric cancer, which may be a potential target in development of an anti-angiogenic therapy for gastric cancer. PMID- 29262813 TI - Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels. AB - BACKGROUND: Aldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria. METHODS: We performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients (n = 33, creatinine clearance (CrCl) 85 (75-95) ml/min, proteinuria 3.2 (2.5-4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 +/- 10 mmol Na+/day) and low (89 +/- 8 mmol Na+/day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median. RESULTS: Lower CrCl was correlated with higher PAC during placebo as well as during ARB (beta = 1.213, P = 0.008 and beta = -1.090, P = 0.010). Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition (ACEi; lisinopril 40 mg/day), and dual RAASi (lisinopril 40 mg/day + valsartan 320 mg/day). Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median. CONCLUSIONS: In CKD patients with a standardized regular sodium intake, worse renal function is associated with a higher aldosterone, untreated and during RAASi with either ARB, ACEi, or both. Furthermore, higher aldosterone is associated with higher blood pressure, which can be treated with the combination of RAASi, HCT and dietary sodium restriction. The first study was performed before it was standard to register trials and the study was not retrospectively registered. The second study was registered in the Netherlands Trial Register on the 5th of May 2006 (NTR675). PMID- 29262814 TI - Participatory improvement of a template for informed consent documents in biobank research - study results and methodological reflections. AB - BACKGROUND: For valid informed consent, it is crucial that patients or research participants fully understand all that their consent entails. Testing and revising informed consent documents with the assistance of their addressees can improve their understandability. In this study we aimed at further developing a method for testing and improving informed consent documents with regard to readability and test-readers' understanding and reactions. METHODS: We tested, revised, and retested template informed consent documents for biobank research by means of 11 focus group interviews with members from the documents' target population. For the analysis of focus group excerpts we used qualitative content analysis. Revisions were made based on focus group feedback in an iterative process. RESULTS: Focus group participants gave substantial feedback on the original and on the revised version of the tested documents. Revisions included adding and clarifying explanations, including an info-box summarizing the main points of the text and an illustrative graphic. CONCLUSION: Our results indicate positive effects on the tested and revised informed consent documents in regard to general readability and test-readers' understanding and reactions. Participatory methods for improving informed consent should be more often applied and further evaluated for both, medical interventions and clinical research. Particular conceptual and methodological challenges need to be addressed in the future. PMID- 29262815 TI - Effectiveness of message framing on women's intention to perform cytomegalovirus prevention behaviors: a cross-sectional study. AB - BACKGROUND: The purpose of this study was to evaluate the effect of message framing on women's intention to perform cytomegalovirus (CMV) prevention behaviors involving handwashing, not sharing food and eating utensils, not kissing a child on the lips and not placing a pacifier in the mouth after it was in a child's mouth. METHODS: An online panel of women 18-40 years, who were pregnant or planning a pregnancy were randomized in a 2 * 2 factorial design to receive 1 of 4 CMV fact sheets. The fact sheets were framed as either what could be gained or be lost by following (or not) the recommendations and the likelihood of being affected by CMV (i.e., small chance or one of the most common infections in infants). The questionnaire measured CMV knowledge, participation in CMV risk or prevention behaviors, perceived severity of and susceptibly to CMV, and the perceived control over and the efficacy of recommended prevention behaviors. The dependent variable, intention to modify behavior, was an index score that ranged from 0 to 16 with higher values indicating greater intention. Linear regression was used to evaluate the association between all independent variables and overall behavioral intention. RESULTS: The sample included 840 women; 15.5% were familiar with CMV. Behavioral intention was high (M = 10.43; SD = 5.13) but did not differ across the message frames (p = 0.23). Overall, behavioral intention was predicted by CMV knowledge, message credibility, perceived severity of CMV, perceived behavioral control and response efficacy. Significant interactions with gain vs. loss frame were observed for perceived behavioral control (p = 0.03) and response efficacy (p = .003). CONCLUSIONS: Framing CMV messages by what women stand to gain or lose interacts with perceived behavioral control and response efficacy to influence behavioral intention. Perceived behavioral control and response efficacy were most predictive of behavioral intention overall regardless of frame. Messaging that focuses on these two variables, particularly for avoiding kissing a child on the lips and sharing food, cups and utensils, may result in greater gains in intention to participate in CMV prevention behaviors. PMID- 29262816 TI - The impact of healthcare reform on the efficiency of public county hospitals in China. AB - BACKGROUND: The new round of Healthcare Reform in China has implemented over 3 years since 2009, and promoted greatly the development of public county hospitals. The purpose of this study is to evaluate county hospitals efficiency before and after the healthcare reform, and further assess the reform effectiveness through the comparative analysis of the efficiency. METHODS: Data envelopment analysis (DEA) was employed to calculate the efficiency of 1105 sample hospitals which were selected from 31 provinces of China, also, Tobit regression was used to regress against those main external environmental factors. RESULTS: Our results show that the scales and amounts of service of hospitals had increased sharply, however, the efficiency was relatively low and decreased slightly from 2008 to 2012. Thirteen (1.18%) in 2008 and six (0.54%) hospitals in 2012 were defined as technically efficient, and the average scores were 0.2916 and 0.2503. The technical efficiency average score of the post-reform was significantly less than that of the pre-reform (p < 0.001), and the score of eastern region was highest and the western was lowest among three regions of China. CONCLUSIONS: It suggests the reform had not well improved county hospital efficiency although hospitals have reached a fair developing scale, and the corresponding policies and measures should be put into effect for improving efficiency, especially in the level and structure of health investment, operation and supervision mechanism of county hospitals. PMID- 29262818 TI - Association of dietary habits and parental-reported sleep tooth grinding with tooth wear in children with mixed dentition. AB - BACKGROUND: Tooth wear has a multifactorial etiology, thus it should be assessed within a multiple-variable framework. The objective of this investigation was to assess the association of dietary habits and parental-reported sleep tooth grinding (STG) with tooth wear in children with mixed dentition. METHODS: One hundred twenty-one (N = 121) subjects (mean age 9.6 years) participated in a cross-sectional study. Wear of 1637 teeth was evaluated using the screening module of the Tooth Wear Evaluation System (TWES). Parental-report of STG was evaluated by means of the Children's Sleep Habits Questionnaire (CSHQ), whilst dietary habits were investigated by means of the Health Behaviour in School-Aged Children Food-Frequency Questionnaire (HBSC-FFQ). Data were analyzed with the Spearman correlation test and ordinal-multiple-variable regression analyses. Odds Ratio (OR) and ordinal OR were obtained for the independent variables included in the models. RESULTS: Parental-report of STG is not associated with tooth wear in the mixed dentition; some dietary habits were found to be correlated with specific tooth wear patterns, but the correlation values were weak. Associations were found between dietary habits and the increase-to-increase severity of occlusal/incisal and non-occlusal/non-incisal tooth wear of some teeth (OR > 2). CONCLUSIONS: A strong correlation of dietary habits and sleep tooth grinding with tooth wear in the mixed dentition was not demonstrated. However, dietary habits showed to have effects in terms of increase-to-increase severity. PMID- 29262817 TI - Effects of Salvia miltiorrhiza extract with supplemental liquefied calcium on osteoporosis in calcium-deficient ovariectomized mice. AB - BACKGROUND: Extracts from Salvia miltiorrhiza Bunge have been used in traditional Asian medicine to treat coronary heart disease, chronic renal failure, atherosclerosis, myocardial infraction, angina pectoris, myocardial ischemia, dysmenorrheal, neurasthenic insomnia, liver fibrosis and cirrhosis. The aim of the study was to investigate the anti-RANK signal effect of the combination of S.miltiorrhiza Bunge (SME) and liquefied calcium (LCa) supplement with ovariectomized (OVX-SML) mice, a osteoporosis animal model. Results were compared to 17beta-estradiol (E2) treatment. METHODS: A total of 70 female ICR strain mice (7 weeks) were randomly divided into 10 groups with 7 mice in each group as follows: (1) sham-operated control mice (sham) received daily oral phosphate buffered-saline (PBS) of equal volumes through oral administration. (2) OVX mice received a daily oral administration of PBS (OVX). (3) OVX mice treated daily with 50 mg/kg b.w./ day of SME (4) with 100 mg/kg b.w./day of SME or (5) with 200 mg/kg b.w./day of SME via oral administration. (6) OVX mice treated daily with 50 mg/kg b.w./day of SML (7) with 100 mg/kg b.w./day of SML or (8) with 200 mg/kg b.w./day of SML via oral administration. (9) OVX mice treated daily with 10 ml/kg b.w./day of LCa (10) OVX mice received i.p. injections of 17beta-estradiol (E2) (0.1 mg/kg b.w./day) three times per week for 12 weeks. RESULTS: micro-CT analysis revealed that oral administration of SML inhibited tibial bone loss, sustained trabecular bone state, and ameliorated bone biochemical markers. In addition, SML administration compared to SEM and LCa reduced serum levels of RANKL, osteocalcin and BALP through increased serum levels of OPG and E2 in OVX mice. SML also had more beneficial effects on protection of estrogen-dependent bone loss through blocking expression of TRAF6 and NFTAc1 and produces cathepsin K and calcitonin receptor to develop osteoclast differentiation. CONCLUSION: These data suggest that S. miltiorrhiza Bunge combined with liquefied calcium supplement has an inhibitory activity in OVX mice. This result implies the possibility of a pharmacological intervention specifically directed toward a disease such as osteoporosis where decreased bone strength increases the risk of a broken bone . PMID- 29262819 TI - Health, lifestyle and employment beyond state-pension age. AB - BACKGROUND: The factors influencing one's choice to retire vary, with financial and health considerations being some of the main factors impacting or associated with people's timing of retirement. The aim of the study is to investigate the differences in current health and health-related behaviours, such as smoking, drinking and exercising, between people who kept on working beyond state-pension age and those who retired before or at state-pension age. METHODS: Data from six waves (2003, 2008-2012) of the Scottish Health Survey (SHeS) are used. Descriptive analyses were used to characterise the population. Multivariate logistic regression was undertaken to analyse the relationship between retirement groups and gender, age, deprivation, marital status, housing tenure, general health, longstanding illness, cigarette smoking status, amount of exercise and mental health, using Stata. RESULTS: Reporting poor self-rated health or having a long-standing illness was associated with increased odds of retiring before state pension age (SPA) in groups with a medium deprivation profile in almost all the survey years. For the least deprived there was little evidence of an association between poor health and extended-working-life, while significant associations were observed for the most deprived. An increasing trend was observed for both genders in the number of people extending their working life. Similar associations between reporting poorer self-rated health and extended working lives were observed for men and women. Distinct gender differences were observed for the associations with reporting poor mental health and no exercise. In the adjusted models, both were significantly associated with retiring at or before SPA in almost every year for women, whereas no significant associations were observed (except in 1 year) for men. CONCLUSIONS: This study shows an increasing trend in the number of people extending their working lives and demonstrates significant associations between health and lifestyle behaviours and employment status past SPA. The results suggest that good health - both physically and mentally - along with either a need or a want to stay in employment could be important reasons for continuing to work beyond SPA. PMID- 29262820 TI - A case report of erythroderma in a patient with borderline leprosy on reversal reaction: a result of the exacerbated reaction? AB - BACKGROUND: Erythroderma is characterized by erythema and scaling affecting more than 90% of the body surface area. Inflammatory, neoplastic and, more rarely, infectious diseases may culminate with erythroderma. Diagnosis of the underlying disorder is therefore crucial to institute the appropriate therapy. Leprosy is a chronic infectious disease that is endemic in Brazil. Here we present an unusual case of leprosy and reversal reaction causing erythroderma, and we discuss the underlying immunological mechanisms which could contribute to the generalized skin inflammation. CASE PRESENTATION: We report a case of a patient with reversal reaction (RR) in borderline borderline leprosy presenting with erythroderma and neural disabilities. Histopathology of the skin showed regular acanthosis and spongiosis in the epidermis and, in the dermis, compact epithelioid granulomas as well as grouped and isolated bacilli. This duality probably reflects the transition from an anergic/multibacillary state to a state of more effective immunity and bacillary control, typical of RR. Leprosy was successfully treated with WHO's multidrug therapy, plus prednisone for controlling the RR; the erythroderma resolved in parallel with this treatment. Immunologic studies showed in situ predominance of IFNgamma + over IL-4+ lymphocytes and of IL-17+ over Foxp3+ lymphocytes, suggesting an exacerbated Th-1/Th-17 immunoreactivity and poor Th-2 and regulatory T-cell responses. Circulating Tregs were also diminished. We hypothesize that the flare-up of anti-mycobacteria immunoreactivity that underlies RR may have triggered the intense inflammatory skin lesions that culminated with erythroderma. CONCLUSIONS: This case report highlights the importance of thorough clinical examination of erythrodermic patients in search for its etiology and suggests that an intense and probably uncontrolled leprosy RR can culminate in the development of erythroderma. PMID- 29262821 TI - Assessment of a bedside test for N-terminal pro B-type natriuretic peptide (NT proBNP) to differentiate cardiac from non-cardiac causes of pleural effusion in cats. AB - BACKGROUND: Cats with pleural effusion represent common emergencies in small animal practice. The aim of this prospective study was to investigate the diagnostic ability of a point-of-care ELISA (POC-ELISA) for the measurement of N terminal pro B-type natriuretic peptide (NT-proBNP) to differentiate cardiac from non-cardiac disease in cats with pleural effusion. The sample material for use of this rapid test was either plasma or diluted pleural effusion. Twenty cats with moderate to severe pleural effusion were prospectively recruited. The cats were grouped into two groups, with or without congestive heart failure (CHF; N-CHF), after complete work-up. Blood and effusion were collected in EDTA tubes. Plasma and pleural effusion supernatants were transferred into stabilizer tubes and frozen. POC-ELISA for NT-proBNP was performed with plasma and diluted effusion (1:1). Quantitative NT-proBNP measurement was performed in plasma and diluted and undiluted effusions. RESULTS: Six cats were assigned to the CHF group. Of the 14 cats in the N-CHF group, 6 had concurrent cardiac abnormalities that were not responsible for the effusion. For the detection of CHF, the test displayed respective sensitivities and specificities of 100% and 79% in plasma and 100% and 86% in diluted pleural fluid. Receiver operating characteristic (ROC) analysis for quantitative NT-proBNP measurement of plasma and diluted and undiluted pleural effusions displayed areas under the curve of 0.98, sensitivities of 100% and specificities of 86%. The optimum cut-off was calculated at 399 pmol/l in plasma and 229 pmol/l in the diluted effusion and 467 pmol/l in the undiluted effusion. CONCLUSIONS: POC-ELISA for NT-proBNP in both plasma and diluted pleural effusion was suitable to differentiate cardiac from non-cardiac causes of feline pleural effusion. According to our results, use of pleural effusion is feasible, but dilution of the effusion before measurement seems to improve specificity. PMID- 29262822 TI - Care delivery and compensation system changes: a case study of organizational readiness within a large dental care practice organization in the United States. AB - BACKGROUND: Dental care delivery systems in the United States are consolidating and large practice organizations are becoming more common. At the same time, greater accountability for addressing disparities in access to care is being demanded when public funds are used to pay for care. As change occurs within these new practice structures, attempts to implement change in the delivery system may be hampered by failure to understand the organizational climate or fail to prepare employees to accommodate new goals or processes. Studies of organizational behavior within oral health care are sparse and have not addressed consolidation of current delivery systems. The objective of this case study was to assess organizational readiness for implementing change in a large dental care organization consisting of staff model clinics and affiliated dental practices and test associations of readiness with workforce characteristics and work environment. METHODS: A dental care organization implemented a multifaceted quality improvement program, called PREDICT, in which community-based mobile and clinic-based dental services were integrated and the team compensated based in part on meeting performance targets. Dental care providers and supporting staff members (N = 181) were surveyed before program implementation and organizational readiness for implementing change (ORIC) was assessed by two 5-point scales: change commitment and efficacy. RESULTS: Providers and staff demonstrated high organizational readiness for change. Median change commitment was 3.8 (Interquartile range [IQR]: 3.3-4.3) and change efficacy was 3.8 (IQR: 3.0-4.2). In the adjusted regression model, change commitment was associated with organizational climate, support for methods to arrest tooth decay and was inversely related to office chaos. Change efficacy was associated with organizational climate, support for the company's mission and was inversely related to burnout. Each unit increase in the organizational climate scale predicted 0.45 and 0.8-unit increases in change commitment and change efficacy. CONCLUSIONS: The survey identified positive readiness for change and highlighted weaknesses that are important cautions for this organization and others initiating change. Future studies will examine how organizational readiness to change, workforce characteristics and work environment influenced successful implementation within this organization. PMID- 29262823 TI - Assessing the reach and effectiveness of mHealth: evidence from a reproductive health program for adolescent girls in Ghana. AB - BACKGROUND: While mobile health (mHealth) programs are increasingly used to provide health information and deliver interventions, little is known regarding the relative reach and effectiveness of these programs across sociodemographic characteristics. We use data from a recent trial of a text-messaging intervention on adolescent sexual and reproductive health (SRH) to assess the degree to which mHealth programs reach target adolescent subpopulations who may be at higher risk of poor SRH outcomes. METHODS: The study was conducted among girls aged 14-24 in 22 secondary schools in Accra, Ghana. The mHealth intervention was an interactive mobile phone quiz in which participants could win phone credit for texting correct answers to SRH questions. We use detailed data on individuals' level of engagement with the program, SRH knowledge scores, and self-reported pregnancy collected as part of the original trial to assess the extent to which engagement and program impact vary across parental education, sexual experience, SRH knowledge deficit, and parental support. RESULTS: Eighty-one percent of participants engaged with the mHealth program, with no evidence that the program disproportionally reached better-off groups. The program was effective at increasing knowledge of SRH across all strata. Higher levels of engagement were associated with higher knowledge scores up to year later. There was no significant impact of the program on self-reported pregnancy within subgroups. CONCLUSION: mHealth programs for adolescents have the potential to engage and increase SRH knowledge of adolescent girls across sociodemographic strata, including those who may be at higher risk of poor SRH outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02031575 . Registered 07 Jan 2014. PMID- 29262824 TI - Upper airway stabilization by osteopathic manipulation of the sphenopalatine ganglion versus sham manipulation in OSAS patients: a proof-of-concept, randomized, crossover, double-blind, controlled study. AB - BACKGROUND: Osteopathic manipulative treatment (OMT) of the sphenopalatine ganglion (SPG) is used empirically for the treatment of rhinitis and snoring and is thought to increase pharyngeal stability. This trial was designed to study the effects of this treatment on pharyngeal stability evaluated by critical closing pressure in obstructive sleep apnoea syndrome. METHODS: This single-centre, randomized, crossover, double-blind study compared active manipulation and sham manipulation of the SPG. Randomization was computer-generated. Patients each received one active manipulation and one sham manipulation at an interval of 21 days and were evaluated 30 min and 48 h after each session administered by a qualified osteopath. Neither the patients, nor the investigator performing the evaluations were informed about the order of the two techniques (double-blind). The primary endpoint was the percentage of responding patients presenting increased pharyngeal stability defined by a variation of critical closing pressure (Pcrit) of at least -4 cmH2O at 30 min. Secondary endpoints were the variation of Pcrit in absolute values, sleepiness and snoring. Others endpoints were lacrimation (Schirmer's test), induced pain, sensations experienced during OMT. RESULTS: Ten patients were included and nine (57 [50; 58] years, comprising 7 men, with an apnoea-hypopnoea index of 31.0 [25.5; 33.2]/h; (values are median [quartiles])) were analysed. Seven patients were analysed for the primary endpoint and nine patients were analysed for secondary endpoints. Five patients responded after active manipulation versus no patients after sham manipulation (p = 0.0209). Active manipulation induced more intense pain (p = 0.0089), increased lacrimation (ns) and more tactile, nociceptive and gustatory sensations (13 versus 1) compared to sham manipulation. No significant difference was observed for the other endpoints. CONCLUSIONS: Osteopathic manipulative treatment of the SPG may improve pharyngeal stability in obstructive sleep apnoea syndrome. This trial validates the feasibility of the randomized, controlled, double-blind methodology for evaluation of this osteopathic treatment. Studies on a larger sample size must specify the efficacy on the apnoea-hypopnoea index. TRIAL REGISTRATION: The study was retrospectively registered in the clinicaltrial.gov registry under reference NCT01193738 on 1st September 2010 (first inclusion May 19, 2010). PMID- 29262825 TI - A randomized, double-blind, prospective, placebo-controlled study of the efficacy of a diet supplemented with curcuminoids extract, hydrolyzed collagen and green tea extract in owner's dogs with osteoarthritis. AB - BACKGROUND: We have previously demonstrated that a mixture of Curcuminoids extract, hydrolyzed COllagen and green Tea extract (CCOT) inhibited inflammatory and catabolic mediator's synthesis by bovine and human chondrocytes. A randomly allocated, double-blind, prospective, placebo-controlled study was performed to evaluate the efficacy of a diet containing this CCOT mixture on dogs with naturally occurring osteoarthritis (OA). Therefore, 42 owner's dogs with OA were randomly assigned to receive for 3 months an experimental diet (control) or the same diet supplemented with CCOT. RESULTS: Ground reaction forces did not show statistical differences between groups. After 3 months of feeding, there was a significant reduction of pain at manipulation in the CCOT group, but not in the control group. The evolution for pain at manipulation depended on the diet. The three other parameters evaluated by veterinary subjective assessment (lameness, pain at palpation and joint mobility) did not show statistical differences. Concerning owner subjective assessment, pain severity score worsened in the control group but remained stable in CCOT group. The evolution for pain severity depended on the diet. No statistical difference was found for pain interference, except for the ability to rise to standing from lying down, which was significantly improved in the CCOT compared to the control group. Serum OA biomarkers did not show statistical differences. CONCLUSIONS: Objective variables measured, such as ground reaction forces and OA biomarkers, did not show statistical differences. However, indicators of pain appeared reduced in dogs receiving CCOT mixture for 3 months. The difference of evolution between groups suggests that a greater number of dogs may be necessary to reach a stronger effect on other parameters. PMID- 29262826 TI - Investigating the physiology of viable but non-culturable bacteria by microfluidics and time-lapse microscopy. AB - BACKGROUND: Clonal microbial populations often harbor rare phenotypic variants that are typically hidden within the majority of the remaining cells, but are crucial for the population's resilience to external perturbations. Persister and viable but non-culturable (VBNC) cells are two important clonal bacterial subpopulations that can survive antibiotic treatment. Both persister and VBNC cells pose a serious threat to human health. However, unlike persister cells, which quickly resume growth following drug removal, VBNC cells can remain non growing for prolonged periods of time, thus eluding detection via traditional microbiological assays. Therefore, understanding the molecular mechanisms underlying the formation of VBNC cells requires the characterization of the clonal population with single-cell resolution. A combination of microfluidics, time-lapse microscopy, and fluorescent reporter strains offers the perfect platform for investigating individual cells while manipulating their environment. METHODS: Here, we report a novel single-cell approach to investigate VBNC cells. We perform drug treatment, bacterial culturing, and live/dead staining in series by using transcriptional reporter strains and novel adaptations to the mother machine technology. Since we track each cell throughout the experiment, we are able to quantify the size, morphology and fluorescence that each VBNC cell displayed before, during and after drug treatment. RESULTS: We show that VBNC cells are not dead or dying cells but share similar phenotypic features with persister cells, suggesting a link between these two subpopulations, at least in the Escherichia coli strain under investigation. We strengthen this link by demonstrating that, before drug treatment, both persister and VBNC cells can be distinguished from the remainder of the population by their lower fluorescence when using a reporter strain for tnaC, encoding the leader peptide of the tnaCAB operon responsible for tryptophan metabolism. CONCLUSION: Our data demonstrates the suitability of our approach for studying the physiology of non-growing cells in response to external perturbations. Our approach will allow the identification of novel biomarkers for the isolation of VBNC and persister cells and will open new opportunities to map the detailed biochemical makeup of these clonal subpopulations. PMID- 29262827 TI - Examining the validity and utility of two secondary sources of food environment data against street audits in England. AB - BACKGROUND: Secondary data containing the locations of food outlets is increasingly used in nutrition and obesity research and policy. However, evidence evaluating these data is limited. This study validates two sources of secondary food environment data: Ordnance Survey Points of Interest data (POI) and food hygiene data from the Food Standards Agency (FSA), against street audits in England and appraises the utility of these data. METHODS: Audits were conducted across 52 Lower Super Output Areas in England. All streets within each Lower Super Output Area were covered to identify the name and street address of all food outlets therein. Audit-identified outlets were matched to outlets in the POI and FSA data to identify true positives (TP: outlets in both the audits and the POI/FSA data), false positives (FP: outlets in the POI/FSA data only) and false negatives (FN: outlets in the audits only). Agreement was assessed using positive predictive values (PPV: TP/(TP + FP)) and sensitivities (TP/(TP + FN)). Variations in sensitivities and PPVs across environment and outlet types were assessed using multi-level logistic regression. Proprietary classifications within the POI data were additionally used to classify outlets, and agreement between audit-derived and POI-derived classifications was assessed. RESULTS: Street audits identified 1172 outlets, compared to 1100 and 1082 for POI and FSA respectively. PPVs were statistically significantly higher for FSA (0.91, CI: 0.89-0.93) than for POI (0.86, CI: 0.84-0.88). However, sensitivity values were not different between the two datasets. Sensitivity and PPVs varied across outlet types for both datasets. Without accounting for this, POI had statistically significantly better PPVs in rural and affluent areas. After accounting for variability across outlet types, FSA had statistically significantly better sensitivity in rural areas and worse sensitivity in rural middle affluence areas (relative to deprived). Audit-derived and POI-derived classifications exhibited substantial agreement (p < 0.001; Kappa = 0.66, CI: 0.63-0.70). CONCLUSIONS: POI and FSA data have good agreement with street audits; although both datasets had geographic biases which may need to be accounted for in analyses. Use of POI proprietary classifications is an accurate method for classifying outlets, providing time savings compared to manual classification of outlets. PMID- 29262828 TI - An analysis of suicide trends in Scotland 1950-2014: comparison with England & Wales. AB - BACKGROUND: Scotland has disproportionately high rates of suicide compared with England. An analysis of trends may help reveal whether rates appear driven more by birth cohort, period or age. A 'birth cohort effect' for England & Wales has been previously reported by Gunnell et al. (B J Psych 182:164-70, 2003). This study replicates this analysis for Scotland, makes comparisons between the countries, and provides information on 'vulnerable' cohorts. METHODS: Suicide and corresponding general population data were obtained from the National Records of Scotland, 1950 to 2014. Age and gender specific mortality rates were estimated. Age, period and cohort patterns were explored graphically by trend analysis. RESULTS: A pattern was found whereby successive male birth cohorts born after 1940 experienced higher suicide rates, in increasingly younger age groups, echoing findings reported for England & Wales. Young men (aged 20-39) were found to have a marked and statistically significant increase in suicide between those in the 1960 and 1965 birth cohorts. The 1965 cohort peaked in suicide rate aged 35-39, and the subsequent 1970 cohort peaked even younger, aged 25-29; it is possible that these 1965 and 1970 cohorts are at greater mass vulnerability to suicide than earlier cohorts. This was reflected in data for England & Wales, but to a lesser extent. Suicide rates associated with male birth cohorts subsequent to 1975 were less severe, and not statistically significantly different from earlier cohorts, suggestive of an amelioration of any possible influential 'cohort' effect. Scottish female suicide rates for all age groups converged and stabilised over time. Women have not been as affected as men, with less variation in patterns by different birth cohorts and with a much less convincing corresponding pattern suggestive of a 'cohort' effect. CONCLUSIONS: Trend analysis is useful in identifying 'vulnerable' cohorts, providing opportunities to develop suicide prevention strategies addressing these cohorts as they age. PMID- 29262829 TI - Therapeutic hypothermia in patients with coagulopathy following severe traumatic brain injury. AB - BACKGROUND: Coagulopathy in traumatic brain injury (TBI) has been associated with poor neurological outcomes and higher in-hospital mortality. In general principle of trauma management, hypothermia should be prevented as it directly worsens coagulopathy. Therefore, we examined the safety of mild therapeutic hypothermia (MTH) in patients with coagulopathy following severe TBI. METHODS: We re evaluated the brain hypothermia (B-HYPO) study data based on coagulopathy and compared the Glasgow Outcome Scale scores and survival rates at 6 months using per protocol analyses. Coagulopathy was defined as an activated partial thromboplastin time (APTT) > 60 s and/or fibrin/fibrinogen degradation product levels (FDP) > 90 MUg/mL on admission. Baseline characteristics, coagulation parameters, and outcomes were compared between the control and MTH groups with or without coagulopathy. RESULTS: In patients with coagulopathy, 12 patients were allocated to the control group (35.5-37.0 degrees C) and 20 patients to the MTH group (32-34 degrees C). In patients without coagulopathy, 28 were allocated to the control group and 59 patients were allocated to the MTH group. In patients with coagulopathy, favorable neurological outcomes and survival rates were comparable between the control and MTH groups (33.3% vs. 35.0%, P = 1.00; 50.0% vs. 60.0%, P = 0.72) with no difference in complication rates. On admission, no significant differences in APTT or FDP levels were observed between the two groups; however, APTT was significantly prolonged in the MTH group compared to the control group on day 3. DISCUSSION: Based on our study, MTH did not seem to negatively affect the outcomes in patients with coagulopathy following severe TBI on admission; therefore, the present study indicates that MTH may be applicable even in patients with severe TBI and coagulopathy. CONCLUSIONS: Our study suggests that in comparison to control, MTH does not worsen the outcome of patients with coagulopathy following severe TBI. TRIAL REGISTRATION: UMIN-CTR, No. C000000231 , Registered 13 September 2005. PMID- 29262830 TI - Harmonising data on the correlates of physical activity and sedentary behaviour in young people: Methods and lessons learnt from the international Children's Accelerometry database (ICAD). AB - BACKGROUND: Large, heterogeneous datasets are required to enhance understanding of the multi-level influences on children's physical activity and sedentary behaviour. One route to achieving this is through the pooling and co-analysis of data from multiple studies. Where this approach is used, transparency of the methodology for data collation and harmonisation is essential to enable appropriate analysis and interpretation of the derived data. In this paper, we describe the acquisition, management and harmonisation of non-accelerometer data in a project to expand the International Children's Accelerometry Database (ICAD). METHOD: Following a consultation process, ICAD partners were requested to share accelerometer data and information on selected behavioural, social, environmental and health-related constructs. All data were collated into a single repository for cataloguing and harmonisation. Harmonised variables were derived iteratively, with input from the ICAD investigators and a panel of invited experts. Extensive documentation, describing the source data and harmonisation procedure, was prepared and made available through the ICAD website. RESULTS: Work to expand ICAD has increased the number of studies with longitudinal accelerometer data, and expanded the breadth of behavioural, social and environmental characteristics that can be used as exposure variables. A set of core harmonised variables, including parent education, ethnicity, school travel mode/duration and car ownership, were derived for use by the research community. Guidance documents and facilities to enable the creation of new harmonised variables were also devised and made available to ICAD users. An expanded ICAD database was made available in May 2017. CONCLUSION: The project to expand ICAD further demonstrates the feasibility of pooling data on physical activity, sedentary behaviour and potential determinants from multiple studies. Key to this process is the rigorous conduct and reporting of retrospective data harmonisation, which is essential to the appropriate analysis and interpretation of derived data. These documents, made available through the ICAD website, may also serve as a guide to others undertaking similar projects. PMID- 29262832 TI - Human Resource Information System implementation readiness in the Ethiopian health sector: a cross-sectional study. AB - BACKGROUND: Health workforce information systems in low-income countries tend to be defective with poor relationship to information sources. Human Resource Information System (HRIS) is currently in a pilot implementation phase in the Federal Ministry of Health and Regional Health Bureaus of Ethiopia. Before scaling up the implementation, it is important to understand the implementation readiness of hospitals and health departments. The aims of this study were to assess the readiness for HRIS implementation, identify associated factors, and explore the implementation challenges in public hospitals and health departments of the Amhara National Regional State, Ethiopia. METHODS: An institution-based cross-sectional study supplemented with a qualitative study was conducted from the 15th of February to the 30th of March 2016 in 19 public hospitals and health departments of the Amhara National Regional State, Ethiopia. A self-administered questionnaire was used to collect the data. The questionnaire includes items on socio-demographic characteristics and questions measuring technical, personal, and organizational factors adapted from the 32-item questionnaire of the Management Science for Health (MSH) HRIS readiness assessment tool. The data were entered and analyzed with statistical software. Descriptive statistics and bivariate and multivariable logistic regression analyses were performed. Odds ratios with 95% confidence interval were computed to identify the factors statistically associated with readiness of HRIS implementation. In-depth interviews and observation checklists were used to collect qualitative data. Thematic content analysis was used to analyze the qualitative data. RESULT: A total of 246 human resource (HR) employees and 16 key informants have been included in the study. The HR employee's level of readiness for HRIS implementation in this study was 35.8%. Employee's Internet access (AOR = 2.59, 95%CI = 1.19, 5.62), availability of separate HR section (AOR = 8.08, 95%CI = 3.69, 17.70), basic computer skills (AOR = 6.74, 95%CI = 2.75, 16.56), and fear of unemployment (AOR = 2.83, 95%CI = 1.27, 6.32) were associated with readiness of HRIS implementation. Poor logistic supply, lack of competency, poor commitment, and shortage of finance were the challenges of HRIS implementation. CONCLUSION: In this study, readiness of HRIS implementation was low. Strategies targeting to improve skills, awareness, and attitude of HR employees would facilitate the implementation process. PMID- 29262831 TI - Antimicrobials for the treatment of drug-resistant Acinetobacter baumannii pneumonia in critically ill patients: a systemic review and Bayesian network meta analysis. AB - BACKGROUND: An optimal therapy for the treatment of pneumonia caused by drug resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis. METHODS: Systematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%. RESULTS: Twenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41-0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04-0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07-0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19-0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32 0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16-0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL. CONCLUSIONS: This Bayesian network meta analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order. PMID- 29262833 TI - The role of epithelial-mesenchymal transition in the post-lung transplantation bronchiolitis obliterans. AB - BACKGROUND: Many patients who receive lung transplantation (LT) operations develop varying degrees of bronchiolitis obliterans (BO) after the surgeries. Epithelial-mesenchymal transition (EMT) is considered to be related to the process of bronchiolitis obliterans. In this study we simulated the pathological process of post-lung transplantation bronchiolitis obliterans, and explored the correlation between BO and EMT of small airway epithelial cells. METHODS: We transplanted the left lungs of F344 rats to Lewis rats by the Tri-cuff anastomosis and established the allogeneic rat left lung orthotopic transplantation model. Cyclosporine and lipopolysaccharide were administrated appropriately after the surgery. The histological structure and the expression levels of the EMT markers was observed with the methods of HE staining, Masson staining and immunohistochemistry. The analysis of enumeration data was performed using Fisher's Exact test and Spearman's rank correlation was used for the correlation analysis. RESULTS: Inflammatory cell infiltration, fibroplasia of bronchiole walls and significant lumen stenosis were found in the pulmonary mesenchyme of the transplanted lungs. The positive expression rate of E-cadherin in the transplanted lungs was 38.50% (5/13), significantly lower than that in the normal lung tissues [87.50% (7/8)] (P < 0.05), while the positive expression rate of Vimentin was 76.92% (10/13) which is significantly higher than that in the normal lung tissues [25.00% (2/8)] (P < 0.05). And a negative correlation existed between the expression levels of E-cadherin and Vimentin (r = -0.750, P < 0.01). CONCLUSIONS: In the disease model we established in this study, we found pathological changes that met BO characteristics happened in the transplanted lungs. Meanwhile, the small airway epithelial cells of transplanted lungs underwent an epithelial-mesenchymal transition, which indicated a role of EMT in the BO airway remodeling. PMID- 29262834 TI - Isoprenoids responsible for protein prenylation modulate the biological effects of statins on pancreatic cancer cells. AB - BACKGROUND: Statin treatment of hypercholesterolemia is accompanied also with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases. These include Ras proteins, prevalently mutated in pancreatic cancer. In our study, we evaluated the effect of three key intermediates of the mevalonate pathway on GFP-K-Ras protein localization and the gene expression profile in pancreatic cancer cells after exposure to individual statins. METHODS: These effects were tested on MiaPaCa-2 human pancreatic cancer cells carrying a K-Ras activating mutation (G12C) after exposure to individual statins (20 MUM). The effect of statins (atorvastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin) and mevalonate intermediates on GFP K-Ras protein translocation was analyzed using fluorescence microscopy. The changes in gene expression induced in MiaPaCa-2 cells treated with simvastatin, FPP, GGPP, and their combinations with simvastatin were examined by whole genome DNA microarray analysis. RESULTS: All tested statins efficiently inhibited K-Ras protein trafficking from cytoplasm to the cell membrane of the MiaPaCa-2 cells. The inhibitory effect of statins on GFP-K-Ras protein trafficking was partially prevented by addition of any of the mevalonate pathway's intermediates tested. Expressions of genes involved in metabolic and signaling pathways modulated by simvastatin treatment was normalized by the concurrent addition of FPP or GGPP. K Ras protein trafficking within the pancreatic cancer cells is effectively inhibited by the majority of statins; the inhibition is eliminated by isoprenoid intermediates of the mevalonate pathway. CONCLUSIONS: Our data indicate that the anticancer effects of statins observed in numerous studies to a large extent are mediated through isoprenoid intermediates of the mevalonate pathway, as they influence expression of genes involved in multiple intracellular pathways. PMID- 29262835 TI - Molecular identification of Borrelia spirochetes in questing Ixodes ricinus from northwestern Spain. AB - BACKGROUND: Ixodes ricinus, the predominant tick species in Europe, can transmit the causative agents of important human diseases such as Lyme borreliosis (LB), caused by Borrelia spirochetes. In northern Spain, LB is considered endemic; recently, a significant increase of the annual incidence of LB was reported in the northwestern (NW) region. METHODS: In order to provide information on the prevalence of Borrelia spp., pooled and individually free-living I. ricinus from NW Spain were molecularly analyzed. Positive samples were characterized at the fla and Glpq genes and the rrfA-rrlB intergenic spacer region to identify Borrelia species/genospecies. RESULTS: Borrelia burgdorferi (sensu lato) (s.l.) individual prevalence and MIR were significantly higher in adult females (32.3 and 16%) than in nymphs (18.8 and 6.2%) and adult males (15.6 and 8.4%). Five Borrelia genospecies belonging to the B. burgdorferi (s.l.) group were identified: B. garinii was predominant, followed by B. valaisiana, B. lusitaniae, B. afzelii and B. burgdorferi (sensu stricto) (s.s.). One species belonging to the tick-borne relapsing fever group (B. miyamotoi) was also found, showing low individual prevalence (1%), positive pool (0.7%) and MIR (0.1%) values. To our knowledge, this is the first citation of B. miyamotoi in free-living ticks from Spain. CONCLUSIONS: The significant prevalences of B. burgdorferi (s.l.) genospecies detected in questing ticks from NW Spain are similar to those detected in northern and central European countries and higher to those previously found in Spain. These results together with the high incidence of LB in humans and the high seroprevalence of B. burgdorferi (s.l.) in roe deer shown in other studies reveal that the northwest area is one of the most risky regions for acquiring LB in Spain. PMID- 29262836 TI - PORTAF - postoperative radiotherapy of non-small cell lung cancer: accelerated versus conventional fractionation - study protocol for a randomized controlled trial. AB - BACKGROUND: In early-stage non-small cell lung cancer (NSCLC) without affected lymph nodes detected at staging, surgical resection is still the mainstay of treatment. However, in patients with metastatic mediastinal lymph nodes (pN2) or non-radically resected primary tumors (R1/R2), postoperative radiotherapy (possibly combined with chemotherapy) is indicated. So far, investigations about time factors affecting postoperative radiotherapy have only examined the waiting time defined as interval between surgery and start of radiotherapy, but not the overall treatment time (OTT) itself. Conversely, results from trials on primary radio(chemo)therapy in NSCLC show that longer OTT correlates with significantly worse local tumor control and overall survival rates. This time factor of primary radio(chemo)therapy is thought to mainly be based on repopulation of surviving tumor cells between irradiation fractions. It remains to be elucidated if such an effect also occurs when patients with NSCLC are treated with postoperative radiotherapy after surgery (and chemotherapy). Our own retrospective data suggest an advantage of shorter OTT also for postoperative radiotherapy in this patient group. METHODS/DESIGN: This is a multicenter, prospective randomized trial investigating whether an accelerated course of postoperative radiotherapy with photons or protons (7 fractions per week, 2 Gy fractions) improves locoregional tumor control in NSCLC patients in comparison to conventional fractionation (5 fractions per week, 2 Gy fractions). Target volumes and total radiation doses will be stratified in both treatment arms based on individual risk factors. DISCUSSION: For the primary endpoint of the study we postulate an increase in local tumor control from 70% to 85% after 36 months. Secondary endpoints are overall survival of patients; local recurrence-free and distant metastases-free survival after 36 months; acute and late toxicity and quality of life for both treatment methods. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02189967 . Registered on 22 May 2014. PMID- 29262838 TI - Quality measurers of therapeutic communities for substance dependence: an international collaborative study survey in Latin America. AB - BACKGROUND: In Latin America, substance related disorders are highly prevalent and one of the treatment strategies is the Therapeutic Communities (TCs), however, in Latin America there is scarce data about this treatment strategies, their quality, drop-out rates and patient satisfaction. METHODS: Based on a previous study in 5 Latin American countries, the TCs who had a score equal or higher than 9 according to the De Leon criteria which are some fundamental items that the TCs should meet, were selected to carry out a descriptive and retrospective study of qualitative and quantitative characteristics of the TCs. RESULTS: Data from 58 TCs in 5 countries were included, with a sample of 1414 patients interviewed, of which most were single men, with no hospitalization history in a therapeutic community. Marijuana was the most commonly substance used in the 30 days prior to hospitalization, with 78% of interviewees referring alcohol consumption in the last 6 months and an average onset of psychoactive substances at 16 years of age. A 79% of the patients interviewed perceived some improvement during their stay in the TCs. The less fulfilled Quality Indicators by the TCs were "Requesting a professional qualification to former addicts that belonged to the program" and "Work as part of the therapeutic program". Among the reasons for discharge found in the database, 44% were due to therapeutic discharge with fulfillment of the treatment plan and 44% withdraws. CONCLUSION: The user satisfaction with TCs, in terms of infrastructure and quality are quite high, as the fulfillment of essential quality items, however, the follow up information to evaluate effectiveness of the treatment is poor or in some cases unknown. PMID- 29262837 TI - gammadeltaT cells but not alphabetaT cells contribute to sepsis-induced white matter injury and motor abnormalities in mice. AB - BACKGROUND: Infection and sepsis are associated with brain white matter injury in preterm infants and the subsequent development of cerebral palsy. METHODS: In the present study, we used a neonatal mouse sepsis-induced white matter injury model to determine the contribution of different T cell subsets (alphabetaT cells and gammadeltaT cells) to white matter injury and consequent behavioral changes. C57BL/6J wild-type (WT), T cell receptor (TCR) delta-deficient (Tcrd -/-, lacking gammadeltaT cells), and TCRalpha-deficient (Tcra -/-, lacking alphabetaT cells) mice were administered with lipopolysaccharide (LPS) at postnatal day (PND) 2. Brain myelination was examined at PNDs 12, 26, and 60. Motor function and anxiety like behavior were evaluated at PND 26 or 30 using DigiGait analysis and an elevated plus maze. RESULTS: White matter development was normal in Tcrd -/- and Tcralpha -/- compared to WT mice. LPS exposure induced reductions in white matter tissue volume in WT and Tcralpha -/- mice, but not in the Tcrd -/- mice, compared with the saline-treated groups. Neither LPS administration nor the T cell deficiency affected anxiety behavior in these mice as determined with the elevated plus maze. DigiGait analysis revealed motor function deficiency after LPS-induced sepsis in both WT and Tcralpha -/- mice, but no such effect was observed in Tcrd -/- mice. CONCLUSIONS: Our results suggest that gammadeltaT cells but not alphabetaT cells contribute to sepsis-induced white matter injury and subsequent motor function abnormalities in early life. Modulating the activity of gammadeltaT cells in the early stages of preterm white matter injury might represent a novel therapeutic strategy for the treatment of perinatal brain injury. PMID- 29262839 TI - Receptor of ghrelin is expressed in cutaneous neurofibromas of individuals with neurofibromatosis 1. AB - BACKGROUND: Multiple cutaneous neurofibromas are a hallmark of neurofibromatosis 1 (NF1). They begin to appear during puberty and increase in number and volume during pregnancy, suggesting a hormonal influence. Ghrelin is a hormone that acts via growth hormone secretagogue receptor (GHS-R), which is overexpressed in many neoplasms and is involved in tumorigenesis. We aimed to investigate GHS-R expression in NF1 cutaneous neurofibromas and its relationship with tumors volume, and patient's age and gender. RESULTS: Sample comprised 108 cutaneous neurofibromas (55 large and 53 small tumors) from 55 NF1 individuals. GHS-R expression was investigated by immunohistochemistry in tissue micro and macroarrays and quantified using a digital computer-assisted method. All neurofibromas expressed GHS-R, with a percentage of positive cells ranging from 4.9% to 76.1%. Large neurofibromas expressed more GHS-R than the small ones. The percentage of GHS-R-positive cells and intensity of GHS-R expression were positively correlated with neurofibromas volume. GHS-R expression was more common in female gender. CONCLUSIONS: GHS-R is expressed in cutaneous neurofibromas. Larger neurofibromas have a higher percentage of positive cells and higher GHS-R intensity. Based on our results we speculate that ghrelin may have an action on the tumorigenesis of cutaneous neurofibromas. Future studies are required to understand the role of ghrelin in the pathogenesis of NF1-associated cutaneous neurofibroma. PMID- 29262840 TI - Reptile-associated Borrelia species in the goanna tick (Bothriocroton undatum) from Sydney, Australia. AB - BACKGROUND: Knowledge on the capacity of Australian ticks to carry Borrelia species is currently limited or missing. To evaluate the potential of ticks to carry bacterial pathogens and their DNA, it is imperative to have a robust workflow that maximises recovery of bacterial DNA within ticks in order to enable accurate identification. By exploiting the bilateral anatomical symmetry of ticks, we were able to directly compare two DNA extraction methods for 16S rRNA gene diversity profiling and pathogen detection. We aimed to assess which combination of DNA extraction and 16S rRNA hypervariable region enables identification of the greatest bacterial diversity, whilst minimising bias, and providing the greatest capacity for the identification of Borrelia spp. RESULTS: We collected Australian endemic ticks (Bothriocroton undatum), isolated DNA from equal tick halves using two commercial DNA extraction methods and sequenced samples using V1-V3 and V3-V4 16S rRNA gene diversity profiling assays. Two distinct Borrelia spp. operational taxonomic units (OTUs) were detected using the V1-V3 16S rRNA hypervariable region and matching Borrelia spp. sequences were obtained using a conventional nested-PCR. The tick 16S rRNA gene diversity profile was dominated by Rickettsia spp. (98-99%), while the remaining OTUs belonged to Proteobacteria (51-81%), Actinobacteria (6-30%) and Firmicutes (2 7%). Multiple comparisons tests demonstrated biases in each of the DNA extraction kits towards different bacterial taxa. CONCLUSIONS: Two distinct Borrelia species belonging to the reptile-associated Borrelia group were identified. Our results show that the method of DNA extraction can promote bias in the final microbiota identified. We determined an optimal DNA extraction method and 16S rRNA gene diversity profile assay that maximises detection of Borrelia species. PMID- 29262841 TI - Statistical analysis plan for the 'Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage' (TICH-2) trial. AB - RATIONALE: Aside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH). METHODS AND DESIGN: TICH 2 is a pragmatic, phase III, prospective, double-blind, randomised placebo controlled trial. Two thousand adult (aged >= 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat. RESULTS: This paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year. DISCUSSION: The SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN93732214 . Registered on 17 January 2013. PMID- 29262842 TI - A multiplex marker set for microsatellite typing and sexing of sooty terns Onychoprion fuscatus. AB - OBJECTIVES: Seabirds have suffered dramatic population declines in recent decades with one such species being the sooty tern Onychoprion fuscatus. An urgent call to re-assess their conservation status has been made given that some populations, such as the one on Ascension Island, South Atlantic, have declined by over 80% in three generations. Little is known about their population genetics, which would aid conservation management through understanding ecological processes and vulnerability to environmental change. We developed a multiplex microsatellite marker set for sooty terns including sex-typing markers to assist population genetics studies. RESULTS: Fifty microsatellite loci were isolated and tested in 23 individuals from Ascension Island. Thirty-one were polymorphic and displayed between 4 and 20 alleles. Three loci were Z-linked and two autosomal loci deviated from Hardy-Weinberg equilibrium. The remaining 26 autosomal loci together with three sex-typing makers were optimised in seven polymerase chain reaction plexes. These 26 highly polymorphic markers will be useful for understanding genetic structure of the Ascension Island population and the species as a whole. Combining these with recently developed microsatellite markers isolated from Indian Ocean birds will allow for assessment of global population structure and genetic diversity. PMID- 29262843 TI - Tenuigenin protects dopaminergic neurons from inflammation via suppressing NLRP3 inflammasome activation in microglia. AB - BACKGROUND: Emerging evidence indicates that nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of PD. Tenuigenin, a major active component of Polygala tenuifolia, has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. METHODS: In the present study, the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mouse model of PD was established to explore the effect of tenuigenin on dopaminergic neurons in substantia nigra. We next activated NLRP3 inflammasome in both BV2 microglia cells and adult mice to investigate the mechanisms for the neuroprotective effect of tenuigenin. RESULTS: We demonstrated that treatment with tenuigenin increased striatal dopaminergic levels and improved motor impairment induced by MPTP. Also, tenuigenin significantly ameliorated the degeneration of dopaminergic neurons and inhibited NLRP3 inflammasome activation in substantia nigra of MPTP mouse model. We further found that tenuigenin reduced intracellular reactive oxygen species (ROS) production and suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1beta secretion in BV2 microglia cells. These data indicate that tenuigenin inhibits the activation of NLRP3 inflammasome via downregulating ROS. Correspondingly, in vivo data showed that tenuigenin attenuates microglia activation induced by lipopolysaccharide (LPS) in substantia nigra via suppressing NLRP3 inflammasome. CONCLUSIONS: Our findings reveal that tenuigenin protects dopaminergic neurons from inflammation partly through inhibition of NLRP3 inflammasome activation in microglia, and suggest the promising clinical use of tenuigenin for PD therapy. PMID- 29262844 TI - Health-related quality of life for First Nations and Caucasian women in the First Nations Bone Health Study. AB - OBJECTIVE: Studies about the health of Indigenous (i.e., original inhabitants) populations often focus on chronic diseases and risk behaviors, emphasizing physical aspects of health. Our objective was to test for differences in self reported health-related quality of life (HRQOL), which provides a multidimensional and holistic perspective on health, between First Nations (one group of Indigenous peoples) and Caucasian women. Data were from the First Nations Bone Health Study, conducted in the Canadian province of Manitoba. HRQOL was measured using the validated Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). It captures respondent's perceptions of eight health domains, as well as overall mental and physical health components. RESULTS: Analyses were conducted for 707 participants of which 47.4% were of First Nations origin. First Nations respondents had significantly lower unadjusted scores (p < 0.05) than Caucasian respondents on all SF-36 dimensions, except bodily pain and vitality. They also had significantly lower overall mental health scores. After adjusting for multiple determinants of health (e.g., age, education, substance use), differences were no longer statistically significant, except for the social functioning and role emotional domains and overall mental health component. Complex cultural factors are likely responsible for the persistent mental health inequalities experienced by First Nations women. PMID- 29262845 TI - Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. AB - BACKGROUND: Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. RESULTS: We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells. CONCLUSIONS: We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs. PMID- 29262846 TI - Reduction of the contaminant fraction of DNA obtained from an ancient giant panda bone. AB - OBJECTIVE: A key challenge in ancient DNA research is massive microbial DNA contamination from the deposition site which accumulates post mortem in the study organism's remains. Two simple and cost-effective methods to enrich the relative endogenous fraction of DNA in ancient samples involve treatment of sample powder with either bleach or Proteinase K pre-digestion prior to DNA extraction. Both approaches have yielded promising but varying results in other studies. Here, we contribute data on the performance of these methods using a comprehensive and systematic series of experiments applied to a single ancient bone fragment from a giant panda (Ailuropoda melanoleuca). RESULTS: Bleach and pre-digestion treatments increased the endogenous DNA content up to ninefold. However, the absolute amount of DNA retrieved was dramatically reduced by all treatments. We also observed reduced DNA damage patterns in pre-treated libraries compared to untreated ones, resulting in longer mean fragment lengths and reduced thymine over-representation at fragment ends. Guanine-cytosine (GC) contents of both mapped and total reads are consistent between treatments and conform to general expectations, indicating no obvious biasing effect of the applied methods. Our results therefore confirm the value of bleach and pre-digestion as tools in palaeogenomic studies, providing sufficient material is available. PMID- 29262847 TI - Systems-epigenomics inference of transcription factor activity implicates aryl hydrocarbon-receptor inactivation as a key event in lung cancer development. AB - BACKGROUND: Diverse molecular alterations associated with smoking in normal and precursor lung cancer cells have been reported, yet their role in lung cancer etiology remains unclear. A prominent example is hypomethylation of the aryl hydrocarbon-receptor repressor (AHRR) locus, which is observed in blood and squamous epithelial cells of smokers, but not in lung cancer. RESULTS: Using a novel systems-epigenomics algorithm, called SEPIRA, which leverages the power of a large RNA-sequencing expression compendium to infer regulatory activity from messenger RNA expression or DNA methylation (DNAm) profiles, we infer the landscape of binding activity of lung-specific transcription factors (TFs) in lung carcinogenesis. We show that lung-specific TFs become preferentially inactivated in lung cancer and precursor lung cancer lesions and further demonstrate that these results can be derived using only DNAm data. We identify subsets of TFs which become inactivated in precursor cells. Among these regulatory factors, we identify AHR, the aryl hydrocarbon-receptor which controls a healthy immune response in the lung epithelium and whose repressor, AHRR, has recently been implicated in smoking-mediated lung cancer. In addition, we identify FOXJ1, a TF which promotes growth of airway cilia and effective clearance of the lung airway epithelium from carcinogens. CONCLUSIONS: We identify TFs, such as AHR, which become inactivated in the earliest stages of lung cancer and which, unlike AHRR hypomethylation, are also inactivated in lung cancer itself. The novel systems-epigenomics algorithm SEPIRA will be useful to the wider epigenome-wide association study community as a means of inferring regulatory activity. PMID- 29262849 TI - Non-communicable diseases control in China and Japan. AB - China and Japan share numerous similarities other than their geographical proximity. Facing the great challenges of non-communicable diseases (NCDs), China and Japan have developed different preventive strategies and systems. While Japan has made great progress in primary prevention of NCDs through strong legislation, the 'Specific Health Check and Guidance System' and a unique licensed health professional system, China is attempting to catch up by changing its strategies in NCDs control. In this manuscript, we compared disease burden of NCDs, health care systems and preventive strategies against NCDs between China and Japan. In this light, we summarized the points that the two countries can learn from each other, and proposed recommendations for the two countries in NCDs control. PMID- 29262848 TI - Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in adult and pediatric burn patients. AB - BACKGROUND: Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. METHODS: All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. RESULTS: Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. CONCLUSION: Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation. PMID- 29262851 TI - Single-cell RNA-seq study determines the ontogeny of macrophages in glioblastomas. AB - A large-scale single-cell RNA-seq analysis of tumor-associated macrophages in gliomas has unveiled a new aspect of the complex tumor microenvironment and new biomarkers. PMID- 29262850 TI - The oncogenic role of circPVT1 in head and neck squamous cell carcinoma is mediated through the mutant p53/YAP/TEAD transcription-competent complex. AB - BACKGROUND: Circular RNAs are a class of endogenous RNAs with various functions in eukaryotic cells. Worthy of note, circular RNAs play a critical role in cancer. Currently, nothing is known about their role in head and neck squamous cell carcinoma (HNSCC). The identification of circular RNAs in HNSCC might become useful for diagnostic and therapeutic strategies in HNSCC. RESULTS: Using samples from 115 HNSCC patients, we find that circPVT1 is over-expressed in tumors compared to matched non-tumoral tissues, with particular enrichment in patients with TP53 mutations. circPVT1 up- and down-regulation determine, respectively, an increase and a reduction of the malignant phenotype in HNSCC cell lines. We show that circPVT1 expression is transcriptionally enhanced by the mut-p53/YAP/TEAD complex. circPVT1 acts as an oncogene modulating the expression of miR-497-5p and genes involved in the control of cell proliferation. CONCLUSIONS: This study shows the oncogenic role of circPVT1 in HNSCC, extending current knowledge about the role of circular RNAs in cancer. PMID- 29262852 TI - Comparison of three DNA extraction methods for the detection and quantification of GMO in Ecuadorian manufactured food. AB - OBJECTIVES: In Ecuador, food products need to be labeled if exceeded 0.9% of transgenic content in whole products. For the detection of genetically modified organisms (GMOs), three DNA extraction methods were tested in 35 food products commercialized in Ecuador. Samples with positive amplification of endogenous genes were screened for the presence of the Cauliflower mosaic virus 35S-promoter (P35S) and the nopaline synthase-terminator (Tnos). TaqManTM probes were used for determination of transgenic content of the GTS 40-3-2 and MON810 events through quantitative PCR (qPCR). RESULTS: Twenty-six processed food samples were positive for the P35S alone and eight samples for the Tnos and P35S. Absolute qPCR results indicated that eleven samples were positive for GTS 40-3-2 specific event and two for MON810 specific event. A total of nine samples for events GTS 40-3-2 and MON810 exceeded the umbral allowed of transgenic content in the whole food product with the specific events. Different food products may require different DNA extraction protocols for GMO detection through PCR. Among the three methods tested, the DNeasy mericon food kit DNA extraction method obtained higher proportion of amplified endogenous genes through PCR. Finally, event-specific GMOs were detected in food products in Ecuador. PMID- 29262853 TI - Proper training and use of ultrasonography facilitates lumbar puncture. AB - With great interest, we read the study of Line Dussourd et al. concluding that ultrasonography allows better identification of anatomical structures before performing a lumbar puncture. We cannot concur with the conclusions of the study because the authors did not visualize the conus medullaris directly, nor did they assess the individual intervertebral levels. In our commentary, we make some suggestions for improvement using ultrasound to locate the optimal site for a lumbar puncture. We do agree that neuraxial ultrasound is of great benefit for the performance of lumbar punctures. Proper training and applying the correct technique, however, is necessary for obtaining all benefits ultrasonography offers. PMID- 29262854 TI - Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders. AB - BACKGROUND: Integrating rare variation from trio family and case-control studies has successfully implicated specific genes contributing to risk of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), intellectual disability (ID), developmental disorders (DDs), and epilepsy (EPI). For schizophrenia (SCZ), however, while sets of genes have been implicated through the study of rare variation, only two risk genes have been identified. METHODS: We used hierarchical Bayesian modeling of rare-variant genetic architecture to estimate mean effect sizes and risk-gene proportions, analyzing the largest available collection of whole exome sequence data for SCZ (1,077 trios, 6,699 cases, and 13,028 controls), and data for four NDDs (ASD, ID, DD, and EPI; total 10,792 trios, and 4,058 cases and controls). RESULTS: For SCZ, we estimate there are 1,551 risk genes. There are more risk genes and they have weaker effects than for NDDs. We provide power analyses to predict the number of risk-gene discoveries as more data become available. We confirm and augment prior risk gene and gene set enrichment results for SCZ and NDDs. In particular, we detected 98 new DD risk genes at FDR < 0.05. Correlations of risk-gene posterior probabilities are high across four NDDs (rho>0.55), but low between SCZ and the NDDs (rho<0.3). An in-depth analysis of 288 NDD genes shows there is highly significant protein-protein interaction (PPI) network connectivity, and functionally distinct PPI subnetworks based on pathway enrichment, single-cell RNA-seq cell types, and multi-region developmental brain RNA-seq. CONCLUSIONS: We have extended a pipeline used in ASD studies and applied it to infer rare genetic parameters for SCZ and four NDDs ( https://github.com/hoangtn/extTADA ). We find many new DD risk genes, supported by gene set enrichment and PPI network connectivity analyses. We find greater similarity among NDDs than between NDDs and SCZ. NDD gene subnetworks are implicated in postnatally expressed presynaptic and postsynaptic genes, and for transcriptional and post-transcriptional gene regulation in prenatal neural progenitor and stem cells. PMID- 29262855 TI - Application of nanostructured lipid carriers: the prolonged protective effects for sesamol in in vitro and in vivo models of ischemic stroke via activation of PI3K signalling pathway. AB - BACKGROUND: Treatment of the ischemic stroke has remained a major healthcare challenge. The phenolic compound, sesamol, has shown promising antioxidant and neuroprotective effects, however, fast clearance may negatively affect its efficiency. This, prompted us to incorporate sesamol into the nanostructured lipid carriers (S-NLCs) and evaluate its therapeutic potential in in vitro and in vivo models of ischemic stroke. METHODS: S-NLCs formulations were prepared by high-pressure homogenization followed by physicochemical characterization, evaluation of the bioactivity of the optimal formulation in oxygen-glucose deprivation (OGD) and global cerebral ischemia/reperfusion (I/R) injury and implication of phosphatidylinositol 3-kinase (PI3K) pathway in this regard. Two- or three-way ANOVA, Mann-Whitney U test, and Student's t-test were used for data analysis. RESULTS: Formation of S-NLCs which exhibited a controlled release profile, was confirmed by scanning electron microscope and differential scanning calorimetry. 1- and 8-h OGD followed by 24 h re-oxygenation significantly reduced PC12 cell viability, increased lactate dehydrogenase activity and the number of condensed nuclei, and induced oxidative stress as revealed by increased malondialdehyde level and decreased glutathione content and superoxide dismutase and catalase activities. Sesamol (80 and 100 MUM) reduced the cytotoxicity, oxidative stress, and cellular damage only after 1-h OGD, while, S-NLCs (containing 80 and 100 MUM of sesamol) were effective at both time points. Intravenous injections of S-NLCs (20 and 25 mg/kg) into rats markedly attenuated I/R-induced neurobehavioural deficits, cellular damage, and oxidative stress, while, free sesamol failed. Pre-treatment with PI3K inhibitor, LY294002, abolished the protective effects against OGD or I/R. CONCLUSIONS: S-NLCs improve the pharmacological profile of sesamol and provide longer lasting protective effects for this phenolic phytochemical. This nanoformulation by activating PI3K pathway may serve as a promising candidate for neuroprotection against the cerebral stroke or other neurodegenerative disorders. Sesamol-loaded NLCs, a promising nanoformulation against the ischemic stroke. PMID- 29262857 TI - Trends in Demographic and Health Survey data quality: an analysis of age heaping over time in 34 countries in Sub Saharan Africa between 1987 and 2015. AB - OBJECTIVE: This paper evaluates one aspect of data quality within DHS surveys, the accuracy of age reporting as measured by age heaping. Other literature has explored this phenomenon, and this analysis build on previous work, expanding the analysis of the extent of age heaping across multiple countries, and across time. RESULTS: This paper makes a comparison of the magnitude of Whipple's index of age heaping across all Demographic and Health Surveys from 1986 to 2015 in Sub Saharan Africa. A random slope multilevel model is used to evaluate the trend in the proportion of respondents within each survey rounding their age to the nearest age with terminal digit 0 or 5. The trend in the proportion of misreported ages has remained flat, in the region of 5% of respondents misreporting their age. We find that Nigeria and Ghana have demonstrated considerable improvements in age reporting quality, but that a number of countries have considerable increases in the proportion of age misreported, most notably Mali and Ethiopia with demonstrate increases in excess of 10% points. PMID- 29262856 TI - Promoting the expansion and function of human corneal endothelial cells with an orbital adipose-derived stem cell-conditioned medium. AB - BACKGROUND: Corneal endothelial dysfunction causes severe impairment of vision. The only solution is corneal transplantation. However, this treatment is hampered by a worldwide shortage of donor corneas. New therapies may replace the conventional donor corneal transplantation alongside the developments in regenerative medicine and tissue engineering, but sufficient functional corneal endothelial cells (CECs) are essential. The aim of this study was to promote the expansion and function of human corneal endothelial cells (HCECs) in vitro and in vivo. METHODS: The phenotypes of human orbital adipose-derived stem cells (OASCs) were detected by flow cytometry and immunofluorescence. HCECs were isolated and cultured using a conditioned medium obtained from OASCs (OASC-CM) in vitro. Related cell markers of HCECs were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence. The cell counting kit-8 (CCK-8) assay and the wound healing assay were performed to evaluate the proliferation ability of the cells. The cultured HCECs were then transplanted into rabbit and monkey corneal endothelial dysfunction models by cell injection. RESULTS: CD29, CD105, CD49e, CD166, and vimentin were highly expressed in cultured human OASCs. The CEC-relative markers zonula occludens-1 (ZO-1), Na+/K+ ATPase, N-cadherin, Col8a2, and SLC4A4 were expressed in HCECs cultured by OASC CM. The HCECs were able to maintain polygonal cell morphology and good proliferative capacity. In animal experiments, corneal transparency was achieved after the injection of HCECs, which demonstrated the good repair capacity of the cells. CONCLUSIONS: The proliferation abilities of the cells were significantly enhanced, and related functional markers were strongly positive, while HCEC morphology was maintained using OASC-CM. HCECs obtained some stem cell-like properties. This preclinical study confirmed the therapeutic ability of the HCECs in vivo. Our findings demonstrated that cultured HCECs with OASC-CM might be a promising source for research and clinical treatment. PMID- 29262858 TI - Concordance between modification of diet in renal disease, chronic kidney disease epidemiology collaboration and Cockcroft-Gault equations in patients with chronic kidney disease at St. Paul's hospital millennium medical college, Addis Ababa, Ethiopia. AB - BACKGROUND: The most commonly used glomerular filtration rate estimating equations for drug dosing are Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. However there is still a concern about whether to use MDRD and CKD-EPI interchangeably with CG for drug dosage adjustment. METHODS: The study was initiated to determine the concordance between MDRD, CKD-EPI and CG equations and associated factors in patients with chronic kidney disease at Saint Paul's Hospital Millennium Medical College (SPHMMC). This was a cross sectional study which involved patient chart review and physicians self-administered questionnaire. Serum creatinine level >= 1.2 mg/dL was used as a cutoff point in pre-selection of patients. The correctness of the drug dose prescribed for the level of renal function were compared to the drug database (Lexi-Comp) available through Up-to-date version 21.2. RESULTS: Among the total of 422 patients, 249 (59%) were males. Mean age of patients was 46.09 years. The use of MDRD equation for drug dose adjustment by physicians working in the renal clinic of SPHMMC was six out of nine physicians. The Pearson correlation coefficient between the CG with MDRD and CKD-EPI equations was r = 0.94, P < 0.001 and r = 0.95, P < 0.001, respectively. The concordance between the CG with MDRD and CKD-EPI equations for FDA assigned kidney function categories was 73.7%, Kappa = 0.644 and 74.9%, Kappa = 0.659, respectively. Concordance between the CG with MDRD and CKD-EPI equations for the drug dosing recommendation was 89.6%, kappa = 0.782 and 92%, kappa = 0.834, respectively. Age > 70 years was associated with discordance between CG and MDRD equations for drug dosing recommendation whereas serum creatinine 1.2 3.5 mg/dL, weight < 61 Kg and age > 70 years were associated with discordance between the CG with MDRD and CKD-EPI equations for FDA assigned kidney function categories. However, none of the factors associated with discordance between CG and CKD-EPI for drug dosing. CONCLUSION: MDRD equation can be used interchangeably with CG equation for drug dosing recommended in all adult patients between the age of 18 and 70 years. CKD-EPI can be used interchangeably with CG in all adult Ethiopian patients with CKD. PMID- 29262859 TI - The effect of Danshen extract on lipoprotein-associated phospholipase A2 levels in patients with stable angina pectoris: study protocol for a randomized controlled trial - the DOLPHIN study. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2), a biomarker of oxidation and inflammation, has been associated with increased coronary artery disease risk. To date, very few studies have examined the Chinese herbal drug Danshen or its extract on Lp-PLA2 in patients with stable angina pectoris. In this study, we aim to investigate the effect of Danshen extract on Lp-PLA2 level in patients with stable angina. METHODS/DESIGN: This is a randomized, single blind, placebo-controlled, adaptive clinical trial. A total of 156 patients meeting the eligibility criteria will be randomly assigned to either the Danshen extract (DanshenDuofensuanyan injection and Danshen drop spill) group or the placebo group in a 1:1 ratio. Participants will then undergo treatment with DanshenDuofensuanyan injection or placebo (glucose) during hospitalization, followed by open-label Danshen drop spill (30 pills/day) in Danshen extract group for 60 days after discharge. Because this is an adaptive trial, two interim analyses are prospectively planned. These will be performed after one-third and two-thirds of the patients, respectively, have completed the trial. On the basis of the results of these interim analyses, a data monitoring committee will determine how to modify aspects of the study without undermining the validity and integrity of the trial. The primary outcome measure is the serum level of Lp-PLA2 in the Danshen extract group and the placebo group. The secondary outcomes include the proportion of patients who show a clinically significant change, which is defined as at least a 20-point improvement in angina frequency score on the Seattle Angina Questionnaire and the carotid intima-media thickness, which will be measured using ultrasound. Other secondary efficacy and safety outcomes will also be assessed. DISCUSSION: This study will provide evidence that Danshen extract is beneficial for stable angina and may establish a possible mechanism of Danshen treatment effects on cardiovascular disease. This study may also validate an objective blood test (LP-PLA2 level) for assessing the effectiveness of Danshen therapy in patients with stable angina pectoris. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02870764 . Registered on 13 August 2016. PMID- 29262860 TI - Increased CD127+ and decreased CD57+ T cell expression levels in HIV-infected patients on NRTI-sparing regimens. AB - BACKGROUND: NRTIs-sparing regimens exert favourable profiles on T-cell homeostasis associated parameters. Our aim was to analyze the effect of NRTIs sparing regimen (NRTI-sparing-cART) vs NRTIs-containing regimen (NRTI-cART), on T cell homeostasis associated parameters in naive HIV-infected patients. METHODS: Biomarkers of cell survival (CD127) and replicative senescence (CD57), were measured by multiparametric flow cytometry for T-cell phenotyping on peripheral blood mononuclear cells (PBMCs) samples just before (baseline) and after 48 weeks of undetectable viral load in patients on NRTI-sparing-cART (N = 13) and NRTI cART (N = 14). After 48 weeks a subgroup of patients (n = 5) on NRTI-cART switched to NRTI-sparing-cART for another additional 48 weeks. In vitro assays were performed on PBMCs from HIV-uninfected healthy donors exposed or not to HIV. To analyze the independent factors associated with type of cART bivariate and stepwise multivariate analysis were performed after adjusting for basal CD4+, CD8+ and nadir CD4+ T-cell counts. RESULTS: After 48 weeks of a NRTI-sparing-cART vs NRTI-cART patients have higher effector memory (EM) CD4+ CD127+ T-cell levels, lower EM CD4+ CD57+ T-cell levels, higher CD8+ CD127+ T-cell levels, lower CD8+ CD57+ T-cell levels and higher memory CD8+ T-cell levels. This effect was confirmed in the subgroup of patients who switched to NRTI-sparing-cART. In vitro assays confirmed that the deleterious effect of a NRTIs-containing regimen was due to NRTIs. CONCLUSIONS: The implementation of NRTI-sparing regimens, with a favourable profile in CD127 and CD57 T-cell expression, could benefit cART patients. These results could have potential implications in a decrease in the number of Non-AIDS events. PMID- 29262861 TI - HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma. AB - BACKGROUND: Heat shock protein 90 (HSP90) functions as a well-known onco-protein to regulate protein conformation, stability and degradation. Pyruvate kinase M2 (PKM2), a critical regulator of the metabolism, growth and metastasis of cancer cells, has been confirmed to be overexpressed in various human cancer including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the oncogenic functions of HSP90 and PKM2 overexpression in HCC remain unknown. METHODS: The expression of HSP90 and PKM2 in HCC specimens and cells were detected by immunoblotting and immunostaining. The interaction between HSP90 and PKM2 was confirmed by tandem affinity purification, co-immunoprecipitation and Glutathione S transferase (GST)-pulldown assay. RESULTS: In this study, we found that HSP90 could bind to PKM2 and subsequently increased PKM2 abundance in HCC cells. Immunohistochemistry (IHC) staining showed that HSP90 level was positively correlated with PKM2 level in HCC tissues. Mechanistically, HSP90 was found to increase the phosphorylation of PKM2 at Thr-328. Protein kinase glycogen synthase kinase-3beta (GSK-3beta) formed a protein complex with HSP90 and PKM2, and directly mediated Thr-328 phosphorylation of PKM2 induced by HSP90. Thr-328 phosphorylation was critical for maintaining PKM2 stability and its biological functions in regulating glycolysis, mitochondria respiration, proliferation and apoptosis. Functionally, we found that HSP90 promoted the glycolysis and proliferation and inhibited apoptosis of HCC cells in a PKM2 dependent manner. In vivo experiments disclosed that PKM2 was required for the promoting effects of HSP90 on the growth of HCC cells in mice. Furthermore, we demonstrated that positive expression of HSP90 and PKM2 was correlated with poor clinicopathological features including high alpha fetoprotein (AFP) level, large tumor size, portal vein tumor thrombus (PVTT) and advanced tumor-node-metastasis (TNM) stage. Furthermore, we demonstrated that positive expression of HSP90 and PKM2, and a combination of these proteins could strongly predict the poor prognosis of HCC patients. CONCLUSIONS: We suggest that HSP90 potentiates the glycolysis and proliferation, reduces the apoptosis and thus enhances the growth of HCC cells through PKM2. PMID- 29262862 TI - Selenium nanoparticles-loaded chitosan/citrate complex and its protection against oxidative stress in D-galactose-induced aging mice. AB - BACKGROUND: Selenium (Se) is an indispensable trace element required for animals and humans, and extra Se-supplement is necessary, especially for those having Se deficiency. Recently, selenium nanoparticles (SeNPs), as a special form of Se supplement, have attracted worldwide attention due to their distinguished properties and excellent bioactivities. In this present study, an eco-friendly and economic way to prepare stable SeNPs was introduced. SeNPs were synthesized in the presence of chitosan (CTS) and then embedded into chitosan/citrate gel, generating selenium nanoparticles-loaded chitosan/citrate complex (SeNPs-C/C). Additionally, the clinical potential of SeNPs-C/C was evaluated by using D galactose (D-gal)-induced aging mice model. RESULTS: SeNPs in high uniform with an average diameter of around 50 nm were synthesized in the presence of chitosan, and reversible ionic gelation between chitosan and citrate was utilized to load SeNPs. Subsphaeroidal SeNPs-C/C microspheres of 1-30 MUm were obtained by spay drying. Single SeNPs were physically separated and embedded inside SeNPs-C/C microparticles, with excellent stability and acceptable release. Acute fetal test showed SeNPs-C/C was safer than selenite, with a median lethal dose (LD50) of approximately 4-fold to 11-fold of that of selenite. Oral administration of SeNPs C/C remarkably retarded the oxidative stress of D-gal in Kunming mice by enhancing the activity of antioxidase, as evidenced by its significant protection of the growth, liver, Se retention and antioxidant bio-markers of mice against D gal. CONCLUSIONS: The design of SeNPs-C/C opens a new path for oral delivery of SeNPs with excellent stability, energy-conservation and environment-friendliness. SeNPs-C/C, as a novel supplement of Se, could be further developed to defend the aging process induced by D-gal. PMID- 29262863 TI - The efficacy and feasibility of total reconstruction versus nontotal reconstruction of the pelvic floor on short-term and long-term urinary continence rates after radical prostatectomy: a meta-analysis. AB - BACKGROUND: Recently, total pelvic floor reconstruction (TR) has been the treatment of choice for improving urinary incontinence (UI) after radical prostatectomy (RP). However, the superiority of TR with respect to urinary continence recovery following RP remains controversial. This study identified the effect of TR versus nonTR of the pelvic floor on short-term and long-term continence rates after RP. METHODS: A literature search was performed in November 2017 using the PubMed, Embase, and Web of Science databases. Only comparative research or clinical studies reporting urinary continence outcomes was included in the meta-analysis, and the quality of evidence was evaluated using the 2011 Level of Evidence for therapy research. RESULTS: We analyzed ten studies reporting urinary continence rates after RP at one or more postoperative time points (1, 2, 4, 12, 24, and 52 weeks). TR was associated with significantly better urinary continence outcomes at 1 week (OR 2.76, 95% CI 1.58-4.84, P < 0.001), 2 weeks (OR 2.57, 95% CI 1.74-3.80, P < 0.001), 4 weeks (OR 2.61, 95% CI 1.56-4.38, P < 0.001), 12 weeks (OR 4.33, 95% CI 2.01-9.33, P < 0.001), 24 weeks (OR 3.83, 95% CI 1.54-9.55, P = 0.004), 52 weeks (OR 4.10, 95% CI 1.80-9.38, P < 0.001) after RP. There was no difference in the rate of complications between the two arms (OR 0.54, 95% CI 0.19-1.54, P = 0.25). CONCLUSIONS: Compared with nonTR, TR is significantly and positively associated with a return to continence but not with complication rate in men following RP, suggesting that TR may be useful for decreasing the urinary incontinence rate after surgery. PMID- 29262865 TI - Surgical management of inverted papilloma; a single-center analysis of 247 patients with long follow-up. AB - BACKGROUND: Our aim was to review our management of inverted papilloma (IP), perform a recurrence analysis, and review the literature. METHODS: A retrospective analysis of 247 patients treated for an IP. Patients were grouped according to surgical approach, tumor presentation (primary, residual and recurrence) and Krouse-stage. RESULTS: Recurrence was observed in 20.3%, 28.6% and 35.1% (p = 0.017) of the patients who underwent endoscopic, external and combined surgery, respectively. Recurrences occurred more often in residual than primary IP (36.9% vs. 22.3%, p = 0.021). Primary endoscopic surgery had a recurrence rate of 12.5%, which was comparable to the recent literature (11.2%, 161/1433). CONCLUSIONS: The relatively high number of recurrences in this cohort is explained by the long follow-up and previous (incomplete) surgery in 61.5% of the cases. The inferior outcome of residual IP underscores the importance of having a low threshold for preoperative biopsy in unilateral and atypical sinonasal disease. PMID- 29262864 TI - Socio-cultural determinants of physical activity across the life course: a 'Determinants of Diet and Physical Activity' (DEDIPAC) umbrella systematic literature review. AB - OBJECTIVE: Regular physical activity (PA) reduces the risk of disease and premature death. Knowing factors associated with PA might help reducing the disease and economic burden caused by low activity. Studies suggest that socio cultural factors may affect PA, but systematic overviews of findings across the life course are scarce. This umbrella systematic literature review (SLR) summarizes and evaluates available evidence on socio-cultural determinants of PA in children, adolescents, and adults. METHODS: This manuscript was drafted following the recommendations of the 'Preferred Reporting Items for Systematic reviews and Meta-Analyses' (PRISMA) checklist. The MEDLINE, Web of Science, Scopus, and SPORTDiscus databases were searched for SLRs and meta-analyses (MAs) on observational studies published in English that assessed PA determinants between January 2004 and April 2016. The methodological quality was assessed and relevant information on socio-cultural determinants and any associations with PA was extracted. The available evidence was evaluated based on the importance of potential determinants and the strength of the evidence. RESULTS: Twenty SLRs and three MAs encompassing 657 eligible primary studies investigated potential socio cultural PA determinants, with predominantly moderate methodological quality. Twenty-nine potential PA determinants were identified that were primarily assessed in children and adolescents and investigated the micro-environmental home/household level. We found probable evidence that receiving encouragement from significant others and having a companion for PA were associated with higher PA in children and adolescents, and that parental marital status (living with partner) and experiencing parental modeling were not associated with PA in children. Evidence for the other potential determinants was limited, suggestive, or non-conclusive. In adults, quantitative and conclusive data were scarce. CONCLUSIONS: A substantial number of SLRs and MAs investigating potential socio cultural determinants of PA were identified. Our data suggest that receiving social support from significant others may increase PA levels in children and adolescents, whereas parental marital status is not a determinant in children. Evidence for other potential determinants was limited. This was mainly due to inconsistencies in results on potential socio-cultural determinants of PA across reviews and studies. TRIAL REGISTRATIONS: This umbrella SLR was recorded on PROSPERO (Record ID: CRD42015010616 ). PMID- 29262866 TI - Effects of a naturally occurring amino acid substitution in bovine PrP: a model for inherited prion disease in a natural host species. AB - OBJECTIVE: The most common hereditary prion disease is human Creutzfeldt-Jakob disease (CJD), associated with a mutation in the prion gene resulting in a glutamic acid to lysine substitution at position 200 (E200K) in the prion protein. Models of E200K CJD in transgenic mice have proven interesting but have limitations including inconsistencies in disease presentation, requirement for mixed species chimeric protein constructs, and the relatively short life span and time to disease onset in rodents. These factors limit research on the mechanism by which the mutation drives disease development. Therefore, our objective was to provide the first assessment of cattle carrying the homologous mutation, E211K, as a system for investigating longer-term disease mechanisms. The E211K substitution was associated with a case of bovine spongiform encephalopathy from 2006. RESULTS: We assessed the molecular properties of bovine E211K prion protein, characterized the molecular genetics of a population of cattle E211K carriers (offspring of the original EK211 cow) in relation to findings in humans, and generated preliminary evidence that the impacts of copper-induced oxidative stress may be different in cattle as compared to observations in transgenic mouse models. The cattle E211K system provides the opportunity for future analysis of physiological changes over time. PMID- 29262867 TI - Spectrum and antibiogram of bacteria isolated from patients presenting with infected wounds in a Tertiary Hospital, northern Tanzania. AB - OBJECTIVE: This study aimed to determine the spectrum and antibiogram of the isolated bacteria from patients presenting with infected wounds at Kilimanjaro Christian Medical Centre in northern Tanzania. RESULTS: Bacterial growth was observed in the vast majority of wound swabs (91.4%). Most of the bacteria isolated (62.3%) were Gram-negative rods. Staphylococcus aureus was the most common isolated organism (16%) followed by other Coliforms and Enterococcus spp. (12.5% each). Enterococcus spp. (36.4%) was the most common isolated bacteria in diabetic wounds whereas S. aureus was the most common isolated bacteria from the wounds caused by trauma (40.0%) and surgical site infection (20.6%). Resistance was high to most common antibiotics used in the hospital. PMID- 29262868 TI - Quinones are growth factors for the human gut microbiota. AB - BACKGROUND: The human gut microbiome has been linked to numerous components of health and disease. However, approximately 25% of the bacterial species in the gut remain uncultured, which limits our ability to properly understand, and exploit, the human microbiome. Previously, we found that growing environmental bacteria in situ in a diffusion chamber enables growth of uncultured species, suggesting the existence of growth factors in the natural environment not found in traditional cultivation media. One source of growth factors proved to be neighboring bacteria, and by using co-culture, we isolated previously uncultured organisms from the marine environment and identified siderophores as a major class of bacterial growth factors. Here, we employ similar co-culture techniques to grow bacteria from the human gut microbiome and identify novel growth factors. RESULTS: By testing dependence of slow-growing colonies on faster-growing neighboring bacteria in a co-culture assay, eight taxonomically diverse pairs of bacteria were identified, in which an "induced" isolate formed a gradient of growth around a cultivatable "helper." This set included two novel species Faecalibacterium sp. KLE1255-belonging to the anti-inflammatory Faecalibacterium genus-and Sutterella sp. KLE1607. While multiple helper strains were identified, Escherichia coli was also capable of promoting growth of all induced isolates. Screening a knockout library of E. coli showed that a menaquinone biosynthesis pathway was required for growth induction of Faecalibacterium sp. KLE1255 and other induced isolates. Purified menaquinones induced growth of 7/8 of the isolated strains, quinone specificity profiles for individual bacteria were identified, and genome analysis suggests an incomplete menaquinone biosynthetic capability yet the presence of anaerobic terminal reductases in the induced strains, indicating an ability to respire anaerobically. CONCLUSIONS: Our data show that menaquinones are a major class of growth factors for bacteria from the human gut microbiome. These organisms are taxonomically diverse, including members of the genus Faecalibacterium, Bacteroides, Bilophila, Gordonibacter, and Sutterella. This suggests that loss of quinone biosynthesis happened independently in many lineages of the human microbiota. Quinones can be used to improve existing bacterial growth media or modulate the human gut microbiota by encouraging the growth of important symbionts, such as Faecalibacterium species. PMID- 29262869 TI - Endometriosis-associated hydrocele of the canal of Nuck with immunohistochemical confirmation: a case report. AB - BACKGROUND: The canal of Nuck is an embryological vestige of the processus vaginalis, and presents a potential site for endometriosis seeding. Hydroceles in this region are a rare cause of inguinal swelling in females. In addition, endometriosis localized to the canal of Nuck is exceedingly rare. CASE PRESENTATION: A 44-year-old Japanese woman presented with a painful mass overlying her right pubis. She underwent surgery to completely excise the mass. During surgery, division of the external oblique aponeurosis revealed a cyst that occupied the inguinal canal and it adhered to the transverse fascia, inguinal ligament, and pubic bone. The cyst was dissected from the round ligament, and the defect in the internal inguinal ring was repaired and reinforced with mesh. On macroscopic examination, the cyst had a heterogeneous fibrous aspect with dark brown inclusions. Microscopic examination revealed that the cyst was tortuous, lined by mesothelial-like cells, and accompanied by partial subcapsular hemorrhage. Endometrium-like tissue was observed in the cystic wall. Immunohistochemical staining for podoplanin confirmed the mesothelial origin of the cyst-lining cells. The epithelial cells and stromal cells were positive for estrogen receptors. CONCLUSIONS: In this case of an endometriosis-associated hydrocele of the canal of Nuck, the mesothelial origin of the cyst-lining cells and endometriosis were confirmed by positive immunohistochemical staining for podoplanin and estrogen receptors, respectively. We determined that hydrocele resection and reinforcement of the anterior inguinal canal wall (if necessary) are appropriate treatments for this condition. PMID- 29262871 TI - Using pre- and post-survey instruments in interventions: determining the random response benchmark and its implications for measuring effectiveness. AB - OBJECTIVE: The present communication demonstrates that even if individuals are answering a pre/post survey at random, the percentage of individuals showing improvement from the pre- to the post-survey can be surprisingly high. Some simple formulas and tables are presented that will allow analysts to quickly determine the expected percentage of individuals showing improvement if participants just answered the survey at random. This benchmark percentage, in turn, defines the appropriate null hypothesis for testing if the actual percentage observed is greater than the expected random answering percentage. DESIGN: The analysis is demonstrated by testing if actual improvement in a component of the US Department of Agriculture's (USDA) Expanded Food and Nutrition Education Program is significantly different from random answering improvement. SETTING: USA. SUBJECTS: From 2011 to 2014, 364320 adults completed a standardized pre- and post-survey administered by the USDA. RESULTS: For each year, the statement that the actual number of improvements is less than the expected number if the questions were just answered at random cannot be rejected. This does not mean that the pre-/post-test survey instrument is flawed, only that the data are being inappropriately evaluated. CONCLUSIONS: Knowing the percentage of individuals showing improvement on a pre/post survey instrument when questions are randomly answered is an important benchmark number to determine in order to draw valid inferences about nutrition interventions. The results presented here should help analysts in determining this benchmark number for some common survey structures and avoid drawing faulty inferences about the effectiveness of an intervention. PMID- 29262870 TI - Integration of CT urography improves diagnostic confidence of 68Ga-PSMA-11 PET/CT in prostate cancer patients. AB - BACKGROUND: To prove the feasibility of integrating CT urography (CTU) into 68Ga PSMA-11 PET/CT and to analyze the impact of CTU on assigning focal tracer accumulation in the ureteric space to either ureteric excretion or metastatic disease concerning topographic attribution and diagnostic confidence. METHODS: Ten prostate cancer patients who underwent 68Ga-PSMA-11 PET/CT including CTU because of biochemical relapse or known metastatic disease were retrospectively analyzed. CTU consisted of an excretory phase 10 min after injection of 80 mL iodinated contrast material. Ureter opacification at CTU was evaluated using the following score: 0, 0% opacification; 1, < 50%; 2, 50-99%; 3, 100%. Topographic attribution and confidence of topographic attribution of focal tracer accumulation in the ureteric space were separately assessed for 68Ga-PSMA-11 PET/CT without and with CTU. Diagnostic confidence was evaluated using the following score: 0, < 25% confidence; 1, 26-50%; 2, 51-75%; 3, 76-100%. RESULTS: At CTU, mean ureter opacification score was 2.6 +/- 0.7. At 68Ga-PSMA-11 PET/CT without CTU, mean confidence of topographic attribution of focal tracer accumulation was 2.5 +/- 0.7 in total and 2.6 +/- 0.7 for metastatic disease. At 68Ga-PSMA-11 PET/CT with CTU, mean confidence of topographic attribution of focal areas of tracer accumulation was significantly higher with 2.9 +/- 0.2 in total and 2.7 +/- 0.9 for metastatic disease (p < 0.001). In 4 of 34 findings (12%) attribution to either ureteric excretion or metastatic disease was discrepant between 68Ga-PSMA-11 PET/CT without and with CTU (n.s). CONCLUSIONS: Integration of CTU into 68Ga-PSMA-11 PET/CT is feasible and increases diagnostic confidence of assigning focal areas of tracer accumulation in the ureteric space to either metastatic disease or ureteric excretion. PMID- 29262872 TI - Is spirituality related to survival in advanced cancer inpatients in Korea? AB - OBJECTIVE: Spirituality is what gives people meaning and purpose in life, and it has been recognized as a critical factor in patients' well-being, particularly at the ends of their lives. Studies have demonstrated relationships between spirituality and patient-reported outcomes such as quality of life and mental health. Although a number of studies have suggested that spiritual belief can be associated with mortality, the results are inconsistent. We aimed to determine whether spirituality was related to survival in advanced cancer inpatients in Korea. METHOD: For this multicenter study, we recruited adult advanced cancer inpatients who had been admitted to seven palliative care units with estimated survival of <3 months. We measured spirituality at admission using the Korean version of the Functional Assessment of Chronic Illness Therapy-Spiritual Well Being (FACIT-sp), which comprises two subscales: meaning/peace and faith. We calculated a Kaplan-Meier curve for spirituality, dichotomized at the predefined cutoffs and medians for the total scale and each of the two subscales, and performed univariate regression with a Cox proportional hazard model. Result We enrolled a total of 204 adults (mean age: 64.5 +/- 13.0; 48.5% female) in the study. The most common primary cancer diagnoses were lung (21.6%), colorectal (18.6%), and liver/biliary tract (13.0%). Median survival was 19.5 days (95% confidence interval [CI 95%]: 23.5, 30.6). Total FACIT-sp score was not related to survival time (hazard ratio [HR] = 0.981, CI 95% = 0.957, 1.007), and neither were the scores for its two subscales, meaning/peace (HR = 0.969, CI 95% = 0.932, 1.008) and faith (HR = 0.981, CI 95% = 0.938, 1.026). Significance of results Spirituality was not related to survival in advanced cancer inpatients in Korea. Plausible mechanisms merit further investigation. PMID- 29262873 TI - Prepare for Take-Off: Fasten Your Seatbelt and Keep a Magnet in Your Pocket! AB - Fainting on a plane is quite common, and stewards are used to taking care of things. Statistically, there is always a physician on board. This Letter to the Editor details a case report that deals with inappropriate pacemaker inhibition during a flight. Roche NC , Thabouillot O , Bouvier F , Paule P. Prepare for take off: fasten your seatbelt and keep a magnet in your pocket!. Prehosp Disaster Med. 2018;33(1):114-115. PMID- 29262874 TI - Manual and Automated Cleaning Are Equally Effective for the Removal of Organic Contaminants From Laparoscopic Instruments. AB - OBJECTIVE To compare the effectiveness of manual and automated methods for cleaning laparoscopic instruments. DESIGN Experimental laboratory study. METHODS We evaluated 4 methods of cleaning laparoscopic instruments: (1) manual-only cleaning and rinsing with potable tap water; (2) manual cleaning and rinsing with potable tap water, followed by ultrasonic cleaning without rinsing; (3) manual cleaning and rinsing with potable tap water followed by ultrasonic cleaning and rinsing with potable tap water; and (4) manual cleaning and rinsing with potable tap water, followed by ultrasonic cleaning and rinsing: first with potable tap water and then with sterile distilled water. Organic residues of protein, hemoglobin, and carbohydrates were evaluated using spectrophotometry. RESULTS The various cleaning methods tested did not result in statistically significant differences (P>.05) in the levels of investigated organic residues. CONCLUSIONS All cleaning and rinsing methods tested were found to be effective in reducing the levels of organic residues on laparoscopic instruments. Thus, there is no advantage gained by supplementing manual-only cleaning with automated ultrasonic cleaning, nor was there a difference between rinsing with potable tap versus sterile distilled water. Infect Control Hosp Epidemiol 2018;39:58-63. PMID- 29262875 TI - Product reformulation and nutritional improvements after new competitive food standards in schools. AB - OBJECTIVE: In 2012, Massachusetts enacted school competitive food and beverage standards similar to national Smart Snacks. These standards aim to improve the nutritional quality of competitive snacks. It was previously demonstrated that a majority of foods and beverages were compliant with the standards, but it was unknown whether food manufacturers reformulated products in response to the standards. The present study assessed whether products were reformulated after standards were implemented; the availability of reformulated products outside schools; and whether compliance with the standards improved the nutrient composition of competitive snacks. DESIGN: An observational cohort study documenting all competitive snacks sold before (2012) and after (2013 and 2014) the standards were implemented. SETTING: The sample included thirty-six school districts with both a middle and high school. RESULTS: After 2012, energy, saturated fat, Na and sugar decreased and fibre increased among all competitive foods. By 2013, 8 % of foods were reformulated, as were an additional 9 % by 2014. Nearly 15 % of reformulated foods were look-alike products that could not be purchased at supermarkets. Energy and Na in beverages decreased after 2012, in part facilitated by smaller package sizes. CONCLUSIONS: Massachusetts' law was effective in improving the nutritional content of snacks and product reformulation helped schools adhere to the law. This suggests fully implementing Smart Snacks standards may similarly improve the foods available in schools nationally. However, only some healthier reformulated foods were available outside schools. PMID- 29262876 TI - Impacts on employment, finances, and lifestyle for working age people facing an expected premature death: A systematic review. AB - : ABSTRACTObjective:The working ages (25-65 years) are a period when most people have significant work, financial, and family responsibilities. A small proportion of working age people will face an expected premature death from cancer or other life-limiting illness. Understanding the impact an expected premature death has on this population is important for informing support. The current study set out to summarize research describing the effects that facing an expected premature death has on employment, financial, and lifestyle of working age people and their families. METHOD: A systematic review using narrative synthesis approach. Four electronic databases were searched in July 2016 for peer-reviewed, English language studies focusing on the financial, employment, and lifestyle concerns of working age adults living with an advanced life-limiting illness and/or their carers and/or children. RESULTS: Fifteen quantitative and 12 qualitative studies were included. Two-thirds (n = 18) were focused on cancer. All studies identified adverse effects on workforce participation, finances, and lifestyle. Many patients were forced to work less or give up work/retire early because of symptoms and reduced functioning. In addition to treatment costs, patients and families were also faced with child care, travel, and home/car modification costs. Being younger was associated with greater employment and financial burden, whereas having children was associated with lower functional well-being. Changes in family roles were identified as challenging regardless of diagnosis, whereas maintaining normalcy and creating stability was seen as a priority by parents with advanced cancer. This review is limited by the smaller number of studies focussing on the needs of working age people with nonmalignant disease. SIGNIFICANCE OF RESULTS: Working age people facing an expected premature death and their families have significant unmet financial, employment, and lifestyle needs. Comparing and contrasting their severity, timing, and priority for people with nonmalignant conditions is required to better understand their unique needs. PMID- 29262877 TI - Improvement in Severe Orthostatic Hypotension Following Carbidopa Dose Reduction. PMID- 29262878 TI - Monitoring the changes to the nutrient composition of fast foods following the introduction of menu labelling in New South Wales, Australia: an observational study. AB - OBJECTIVE: The present study examined the energy (kilojoule) content of Australian fast-food menu items over seven years, before and after introduction of menu board labelling, to determine the impact of the introduction of the legislation. DESIGN: Analysis of the median energy contents per serving and per 100g of fast-food menu items. Change in energy content of menu items across the years surveyed and differences in energy content of standard and limited-time only menu items were analysed. SETTING: Five of Australia's largest fast food chains: Hungry Jack's, KFC, McDonald's, Oporto and Red Rooster. SUBJECTS: All standard and limited-time only menu items available at each fast-food chain, collected annually for seven years, 2009-2015. RESULTS: Although some fast-food chains/menu item categories had significant increases in the energy contents of their menus at some time points during the 7-year period, overall there were no significant or systematic decreases in energy following the introduction of menu labelling (P=0.19 by +17 kJ/100 g, P=0.83 by +8 kJ/serving). Limited-time only items were significantly higher in median energy content per 100 g than standard menu items (+74 kJ/100 g, P=0.002). CONCLUSIONS: While reformulation across the entire Australian fast-food supply has the potential to positively influence population nutrient intake, the introduction of menu labelling legislation in New South Wales, Australia did not lead to reduced energy contents across the five fast-food chains. To encourage widespread reformulation by the fast-food industry and enhance the impact of labelling legislation, the government should work with industry to set targets for reformulation of nutrient content. PMID- 29262879 TI - The role of the mussel Mytilus spp. in the transmission of ostreid herpesvirus-1 microVar. AB - The Pacific oyster Crassostrea gigas contributes significantly to global aquaculture; however, C. gigas culture has been affected by ostreid herpesvirus-1 (OsHV-1) and variants. The dynamics of how the virus maintains itself at culture sites is unclear and the role of carriers, reservoirs or hosts is unknown. Both wild and cultured mussels Mytilus spp. (Mytilus edulis, Mytilus galloprovincialis and hybrids) are commonly found at C. gigas culture sites. The objective of this study was to investigate if Mytilus spp. can harbour the virus and if viral transmission can occur between mussels and oysters. Mytilus spp. living at oyster trestles, 400-500 m higher up the shore from the trestles and up to 26 km at non culture sites were screened for OsHV-1 and variants by all the World Organization for Animal Health (OIE) recommended diagnostic methods including polymerase chain reaction (PCR), quantitative PCR (qPCR), histology, in situ hybridization and confirmation using direct sequencing. The particular primers that target OsHV-1 and variants, including OsHV-1 microVar (MUVar), were used in the PCR and qPCR. OsHV-1 MUVar was detected in wild Mytilus spp. at C. gigas culture sites and more significantly the virus was detected in mussels at non-culture sites. Cohabitation of exposed wild mussels and naive C. gigas resulted in viral transmission after 14 days, under an elevated temperature regime. These results indicate that mussels can harbour OsHV-1 MUVar; however, the impact of OsHV-1 MUVar on Mytilus spp. requires further investigation. PMID- 29262880 TI - [Metabolomics of Chronic Myelogenous Leukemia Based on GC-MS]. AB - OBJECTIVE: To investigate the metabolism characteristics, to search for potential biomarkers associated with disease and to explore related metabolic pathways by analyzing the plasma metabolic profile of patients with chronic myelogenous leukemia (CML) through metabolomies. METHODS: Twenty-six newly diagnosed CML patients in the First Affilated Hospital of Soochow University from February 2015 to April 2015, 26 allogeneic hematopoietic stem cell donors as healthy controls and 26 patients treated with tyrosine kinase inhibitors (TKI) to obtain the best efficacy as post-treatment controls were enrolled in this study. All the metabolites of plasma were extracted by Gas Chromatography-Mass Spectrometer(GC MS) to collect metabolic fingerprint. Multivariate pattern recognition analysis and t test were combined to screen out the metabolic biomarkers at different time points. The receiver operating characteristic curve analysis was used to evaluate the clinical efficacy of metabolites, and the metabolic pathway analysis was performed. RESULTS: Significantly different metabolite expression mode was found seen between CML and healthy control groups. Six changed metabolites in CML were confirmed by multivariate and variate statistical analyses. Compared with the healthy controls, the levels of tetradecanoic acid and glycerol were decreased, the lactic acid, myo-inositol, d-galactose and glycine in CML patients also increased (all VIP>1,P<0.05, AUC>0.7). The plasma metabolites in CML patients after treatment with tyrosine kinase inhibitors (TKI) showed a recovery trend toward to normal levels. The plasma metabolic pathways of CML were mainly related with galactose, pyruvate, glycerolipid, inositol phosphate and glycine, serine and threonine metabolism (all impact value>0.10). CONCLUSION: Significant changes in plasma metabolite levels were found in CML patients. Metabolomics combined with multivariate pattern recognition analysis may be a new tool to assist diagnosis. PMID- 29262881 TI - [Influence of Nucleostemin Expression Down-Regulation on PI3K/AKT/mTOR Signal Pathway in HL-60 Cells]. AB - OBJECTIVE: To explore the effect of nucleostemin(NS) RNAi on the expression of signal molecules in PI3K/AKT/mTOR pathway, a candidate of p53-independent signal pathway in the leukemia HL-60 cells. METHODS: The expression of NS was interfered by transfection of P53-deficient HL-60 cells with the recombinant lentivirus expression vector NS-RNAi-GV248. The exression of NS and signal molecules of PI3K/AKT/mTOR pathway were detected by Western blot. RESULTS: The fluorescence microscopy showed that the recombinant lentivirus vector NS-RNAi-GV248 transfected HL-60 cells successfully with a 80% transfection rate. Western blot showed that the expression of NS protein was inhibited obviously in HL-60 cells, and the expression levels of AKT, p-AKT, p70s6k and p-p70s6k were not statistically different(t1=2.31,P>0.05;t2=3.62,P>0.05;t3=1.60,P>0.05;t4=2.72,P>0.05) in comparison with control; the expression of GbetaL protein was statistically down regnlated (t=15.01,P=0.002). CONCLUSION: The changes of GbetaL protein correlats with NS knockdown. The PI3K/AKT/mTOR pathway may be one of nucleostemin p53 independent signal pathways. PMID- 29262882 TI - [Analysis of Efficacy and Related Factors of Acquired Deep Molecular Response in Chronic Myeloid Leukemia Patients Treated with TKI]. AB - OBJECTIVE: To evaluate the efficacy and related factors of acquired deep molecular response(DMR) for treating patients with chronic myeloid leukemia(CML) by using TKI. METHODS: The clinical data of 131 TKI-treated patients with CML were analyzed retrospectively. The therapeutic effects of each time-points were evaluated, and the related factors of MR4.5 were analyzed. RESULTS: The median follow up-time of 131 cases with CML was 24 months (6-120 months), among them the treatment of 30 patient was converted to nilotinib after a median of 12 months (1 69.6 months) with imatinib, and 13 patient was converted to dasatinib treatment after a median of 31.2 month (3.1-87.6 months) with imatinib. After treatment for 3, 6 and 12 month, the rate of major cytogenetic response (MCyR) was 78%, 79.4% and 95.9%, and the complete cytogenetic response (CCyR) rate was 48.8%, 66.7% and 73.5%, respectively. 60% patients obtained BCR-ABLIS<10% at 3 months, 56.3% patients obtained BCR-ABLIS<1% at 6 months, 55.2% patients obtained BCR ABLIS<0.1% at 12 months. In continued imatinib therapy group, 53 patients (60.9%) obtained MR4.5, and 33 cases (37.9%) obtained stable MR4.5. Multivariate analysis showed that sex, WBC count at the time of diagnosis and BCR-ABLIS level at 3 months were independent factors for obtaining MR4.5. The 3-month BCR-ABLIS level was an independent factor to obtain stable MR4.5. 18 cases (40.9%) in the second generation TKI group received MR4.5 and the 3-month BCR-ABLIS level was also an independent predictor for MR4.5. CONCLUSION: The excellent cytogenetic and molecular responses are observed in CML patients treated with cmatinib. Conversion to second-generation TKI therapy for patients with resistant or intolerant to imatinib also can achieve a satisfactory response and a higher rate of deeper molecular remission. The higher incidence of early molecular response predicting MR4.5 and stable MR4.5 is achieved. PMID- 29262883 TI - [Comparison of Curative Effect between Fu Fang Huang Dai Pian and Arsenic Trioxide in Treatment of 45 Patients with Acute Promyelocytic Leukaemia]. AB - OBJECTIVE: To investigate the clinical efficacy of Fu Fan Huang Dai Pian(RIF) and arsenic trioxide (ATO) regimens for treatment of children with acute promyelocytic leukemia (APL) and to explore the risk factors affecting the prognosis of patients. METHODS: The clinical data of 45 newly diagnosed APL children admitted in our hospital from January 2004 to May 2017 were analyzed retrospectively. Among 45 APL children, 25 children were treated by chemotherapetic regimen including RIF (RIF group), another 20 children were treated by chemotherapeutic regimen including ATO (ATO group). The follow-up was performed in all APL children. The prognosis and incidence of side reactions from drugs in 2 groups were compared, and the high risk factors affecting the prognosis of patients were analyzed. RESULTS: The median follow-up time was 49.8% months. In RIF group, no early death occured in 25 APL children; 5 cases did not achieve complete remission (CR) after induction therapy, CR rate was 88%. Out of 25 cases 2 caes relapsed, 3 cases died, 20 cases maintained contined CR (CCR), 2 cases failed to be followed-up. In ATO group, 2 cases suffered from early death, 5 cases did not achieve CR after induction therapy, CR rate was 90%, 2 caese relapsed and died, 15 cases maintained CCR, the follow-up failed in 1 caes. The 5 year- OS and EFS rate in all the patients were predicted as (82.2+/-6.2)% and (76.4+/-6.6)% respectively. The OS and EFS rate in RIF group were (86.1+/-7.4)% and (78.4+/-8.6)% respectively, which were significantly different from OS and EFS rate (76.4%+/-10.6%) and (74.0%+/-10.1%) respectively in ATO group (all P>0.05). As for the side reaction from drug, except for the cardiac damage (P<0.05), incidence of other side reactions was not significantly different between 2 groups (P>0.05). In addition, the 5 year-OS and EFS rates in APL children with CNSL were significantly lower than those in APL children without CNSL (all P<0.05), the 5 year OS and EFS rate in APL children did not reache M1 and with high risk were significantly lower than those in APL children reached M1 after induction therapy and with low and standerd risk (P<0.05 and P<0.05); the 5 year-OS and EFS rates did not correlate with age and sex. CONCLUSION: The Fu Fang Huang Dai Pian shows the therapeutic efficacy on APL children same as ATO, moreover, no obvious enhancement in incidence of side reactions is observed, therefore, the Fu Fang Huang Dai Pian is effective and safe for treatment of APL children. The CNSL, poor respond to treatment, high risk in clinical stratification are high risk factors affecting prognosis of patients. PMID- 29262884 TI - [Changes of Peripheral Blood Marrow-Derived Suppressor Cell Level after Chemotherapy Induction Remission by VDLP Regimen and Their Relationship with Immune System in B-ALL Children]. AB - OBJECTIVE: To investigate the changes of peripheral blood marrow-derived suppressor cell level after chemotherapy induction remission by regimen consisting of vincristine, daunorubicin, L-asparaginase and prednisone (VDLP) and to analyze their relationship with immume system in B-ALL children. METHODS: Thirty B-ALL children after induction remission by VDLP regimen from August 2015 to August 2016 were selected as B-ALL group and 30 normal healthy children were selected as control group. The peripheral blood in 2 groups was collected and detected by flow cytometry, then the ratios of CD30+ cells and CD33+ HLA-DR- marrow-derived suppressor cells, CD14+CD33+HLA-DR- marrow-derived suppressor cells and CD15+CD33+HLA-DR- marrow-derived suppressor cells were calculated, and their changes after induction remission by VDLP regimen and the relationship with immune system were analyzed. RESULTS: After treatment the ratio of CD33+ cells in peripheral blood of B-ALL group and control group was not significantly different (P> 0.05), moreover, the ratio of CD33+ cells in B-ALL group was significantly higher than that before treatment (P<0.05), while the ratios of CD33+ HLA-DR- marrow-derived suppressor cells, CD14+CD33+HLA-DR- marrow-derived suppressor cells and CD15+CD33+HLA-DR- marrow-derived suppressor cells in B-ALL group were significantly lower than those in control group (all P<0.05), but the ratios of these cells in B-ALL group were higher than those before treatment, and yet there was no statistical significance (P>0.05). CONCLUSION: The ratios of marrow derived suppressor cells in peripheral blood of B-ALL children in complete remission after treatment with VDLP regimen are higher than those before treatment, but are significantly lower than normal value, which may be related with non-complese recovery of immune system in B-ALL children after treatment. PMID- 29262885 TI - [Alteration of IFN-gamma, IL-4, IL-17 and TGF-beta levels in Serum of Patients with Chronic Lymphocytic Leukemia Treated with FCR]. AB - OBJECTIVE: To investigate the alteration and clinical significance of IFN-gamma, IL-4, IL-17 and TGF-beta levels in serum of patients with chronic lymphocytic leukemia treated with FCR. METHODS: Forty-seven CLL patients treated with FCR regimen were enrolled in CLL group, meanwhile 30 healthy persons were selected in control group. The serum levels of IFN-gamma, IL-4, IL-17 and TGF-beta were detected by ELISA in CLL group before and after treatment and in control group, then the differences of IFN-gamma, IL-4, IL-17 and TGF-beta levels as well as IFN gamma/IL-4 ratio and TGF-beta/IL-17 ratio were compared between 2 groups. RESULTS: Before treatment with PCR regimen, the IL-4, IL-17 and TGF-beta levels as well as TGF-beta/IL-17 in CLL group were higher than those in control group (P<0.05), while the IFN-gamma level and IFN-gamma/IL-4 ratio in CLL group were lower than those in control group (P<0.05); after treatment with PCR regimen, the IL-4, IL-17 and TGF-beta levels as well as TGF-beta/IL-17 ratio all significantly decreased (P<0.05), while IFN-gamma level and IFN-gamma/IL-4 ratio significantly increased (P<0.05) as compared with those before treatment, moreover, the IL-4 and IL-17 levels as well as TGF-beta/ IL-17 and IFN-gamma /IL-4 ratio were no significantly different from those in control group (P>0.05), only the IFN-gamma and TGF-beta levels were significantly diffrent from control group (P<0.05). The analysis of Binet staging (stage A, B, C) showed that along with pregression of Binet stages, the TGF-gamma/IL-17 levels as well as the IFN-gamma/IL-4 ratio in CLL group negatively correlated with Binet staging (r=-0.53), while the TGF beta/IL-17 ratio positively correlated with Binet staging (r=0.46). The analysis of grouping accoraing to therapentic efficacy fonnd that the IL-4 and IL-17 levels and IFN-gamma/IL-4 and TGF-beta/IL-17 ratios in CR and PR groups were significantly different before and after treatment (P<0.05), while those in SD and PD groups did not showed statistical difference before and after treatment (P>0.05). CONCLUSION: Along with the progression of disease, the IFN-gamma/ IL-4 ratio gradually decreases, and the TGF-beta / L-17 ratio gradually increases. The treatment with FCR regimen can overcome this tread, therefore dynamically monitoring the chages of IFN-gamma/ IL-4 and TGF-beta / L-17 ratios may contribute to guide the clinical treatment. PMID- 29262886 TI - [Relationship between High Expression of c-FLIP and Drug Resistance of Leukemia Cells]. AB - OBJECTIVE: To explore the effect of c-FLIP expression on drug resistance of Kasumi-1 leukemia cells and its mechanisms. METHODS: Tet-on inducible system was used to construct the conditional expression vector of c-FLIP by cloning the c FLIP gene into lentivirus vector pLVX-Tight-Puro, then the Kasumi-1 cells were transfected with lentivirus pLVX-Tight-Puro-c-FLIP. The expression of c-FLIP was induced by doxycycline(Dox) for different time and doses, and verified by qRT-PCR and Western blot. On the basis of the overexpression of c-FLIP, the Kasumi-1-c FLIP cells were treated with CH11 and PB in order to induce apoptosis, and the Giemsa staining was used to show the apoptotic cell morphology. RESULTS: qRT-PCR and Western blot showed the overexpression of c-FLIP, the CH11 and PB can induce Kasumi-1 cell apoptosis, while the c-FLIP overexpression weakened this effects. Western blot showed that the c-FLIP blocked the caspase-8 activation. CONCLUSION: The overexpression of c-FLIP inhibits the apoptosis caused by CH11 and PB, and leads to drug resistance in leukemia cells. PMID- 29262888 TI - [Application of Next Generation Sequencing for AML/MDS Diagnosis and Treatment]. AB - OBJECTIVE: To detect the mutations of AML/MDS- related genes by using next generation sequencing (NGS), to analyze the mutation levels of each genes in the AML/MDS and the sensitivity of NGS, and to evaluate the feasibility of gene mutations for monitoring the MRD and predicating the progression of diseases. METHODS: The specimens were collected from primary AML (68 cases) and MDS (57 cases) patients from August 2015 to June 2016 in the Harbin Institute of Hematology and Oncology. The mutations of 22 related genes were detected by using AML/MDS-NGS chips. RESULTS: TET2 gene showed the highest mutation rate in AML (55.9%) and MDS (56.1%). The gene mutations were as follows: CEBPA (11.8%), DNMT3A (7.4%), C-KIT (7.4%) and FLT3-ITD (7.4%) in AML, and U2AF1 (10.5%) and SRSF2 (10.5%) in MDS. All the genes had specific mutation sites except TP53 and CEBPA. The mutations of FLT3, C-KIT and CEBPA became negative in the 5 AML patients in remission when compared with those at primary attack, but the mutation rate of TET2 gene was not obviously changed, whereas the mutation rate of the 5 MDS patients was not significantly changed. The new gene mutations appeared in 3 MDS patients with disease progression, but the mutation rate was not changed significantly in the disease progression. The gene mutation rate still has not been changed significantly even after remission. CONCLUSION: Both AML and MDS have their own specific mutated genes and sites. Some gene mutations, such as CEBPA, can be used as an effective indicator to monitoring MRD in AML patients, but those only used for the evaluation of the disease progression and prognosis in MDS patients. PMID- 29262887 TI - [Treatment of Invasive Fungal Infection in Childhood Acute Lymphoblastic Leukemia with Amphotericin B and Voriconazole]. AB - OBJECTIVE: To study the clinical efficacy of amphotericin B and voriconazole in the treatment of invasive fungal infection in children with acute lymphoblastic leukemia(ALL) during chemotherapy. METHODS: The clinical data of 214 patients with acute lymphoblastic leukemia admitted in our hospital from March 2014 to February 2017 was retrospectively analyzed. Among them 65 patients had invasive fungal infection (IFI) during the chemotherapy period, out of them 35 patients treated with voriconazole were enrolled in group A; anather 30 patients treated with amphotericin B were enrolled in group B. The clinical factors that affected the incidence of IFI was statistically analyzed. And the efficacy and adverse reactions in children with ALL were compared after treatment for 8 weeks. RESULTS: The incidence of IFI in children with ALL in this study was 30.37%, and was related with the duration of hospitalization and the level of neutrophil deficiency (P<0.05). The total effective rates of group A and group B were 72.28% and 43.33%, respectively, their difference was statistically significant between 2 group (P<0.05). The incidence of renal function impairment, digestive dysfunction and neurotoxicity were 8.57%, 5.71% and 5.71% in children with ALL treated with voriconazole respectively, which were lower than those in children treated with amphotericin B (P<0.05). The score index of Physical health, energy state, emotion control and overall health in group A were significantly higher than those in B group, and the difference was statistically significant (P<0.05). CONCLUSION: The occurrence of IFI in children with ALL relats with the time of hospitalization and the level of neutrophils. The clinical effect of voriconazole is better, and the incidence of adverse reactions can be reduced, suggesting important clinical significance. PMID- 29262889 TI - [Value of BCL-2 and PD-L1 Combined Detection in Predicting the Prognosis of Primary Acute Leukemia]. AB - OBJECTIVE: To evaluate the clinical value of combined detection of BCL-2 and PD L1 in predicting the prognosis of newly diagnosed patients with acute leukemia (AL). METHODS: A total of 100 cases of AL in our hospital from Jan. 2013 to Sep. 2016 were enrolled in the study. The mRNA expression of BCL-2 and PD-L1 in peripheral blood of patients was detected by RT-PCR, and the prognosis of the patients was followed up. According to the follow-up results, these patients were divided into complete remission group and no remission group, the statistical analysis of different indexes predicting the prognosis was performed. RESULTS: Compared with the healthy control group, the positive rates of BCL-2 and PD-L1 in the bone marrow specimens of AL patients significantly increased (P<0.01). The BCL-2 predicting the prognosis of patients showed that the area under the curve (AUC) was 0.725(P=0.006), the diagnostic threshold was 1.550, the sensitivity(Sen) and specificity(Spe) were 72% and 84%, respectively. The single PD-L1 detection for predicting the prognosis of patients showed that AUC was 0.740 (P=0.004), diagnostic threshold was 12.500, Sen and Spe were 66.7% and 73.1%, respectively. The diagnostic index of combined detection was 77.90, which were higher than that of series detection 54.75, and higher than that of the independent diagnostic index. CONCLUSION: Detection of BCL-2 combined with PD-L1 can be used to evaluate the prognosis of patients with newly diagnosed acute leukemia, which can improve the specificity and sensitivity of the detection, and has higher clinical diagnostic value than single actection. PMID- 29262890 TI - [Curative Effect of Decitabine Combined with IAG Regimen for Senile Patients with Myelodysplastic Syndrome (MDS) Transformed Acute Myeloid Leukemia]. AB - OBJECTIVE: To investigate the curative effect and safety of decitabine combined with IAG regimen for treating senile MDS-transformed AML patients. METHODS: Two cases of senile MDS-transformed AML were treated with decitabine combined with IAG regimen (decitabine 25 mg/d,qd,ivgtt,d1-5,Idarubicin 10 mg/d,qd,ivgtt,d6,Ara C 10 mg/m2,q12h, sc,d 6-19,G-CSF 300 ug,qd,ih,d6-19). The efficacy and adverse reactions were observed in these cases. RESULTS: 1 case for 2 courses and 1 case for 1 course obtained complete remission(CR). The myelosuppression and infections due to neutropenia were the most frequent adverse effects, the severe nonhematologic toxicity, such as liver and kidney and gastrointestinal reactions, were not observed in these patients. CONCLUSION: Decitabine combined with IAG regimen is an effective for treating senile MDS-transformed AML patients. PMID- 29262891 TI - [Clinical Analysis of Deep Venous Thromboembolism in Children with Acute Lymphocytic Leukemia]. AB - OBJECTIVE: To explore clinical characteristics and outcome of deep vein thrombosis(DVT) in children with acute lymphoblastic leukemia (ALL). METHODS: A tatol of 266 patients were diagnosed as ALL from January 1, 2010 to May 31, 2016. The clinical data of 12 cases of patients with DVT were retrospectively analyzed, 183 cases diagnosed before January 1, 2015 were received chemotherapy with the scheme of SCMC-05. The other cases were treated by the scheme of CCCG. All the patients received central venous catheter. RESULTS: The DVT happened in 12 cases including 10 cases of limb DVT and 2 cases of intacranial venous sinus thrombosis. The DVT mostly occured in intermediate risk ALL patients, the infection and coagulopathy existed in most patients. They were treated with low molecular heparin(LWHP), among them 5 cases were given extubation; the thrombus disappeared in 6 cases after 1 week; the intracranial venous sinus thrombosis in 1 case did not obviously improved after 6 months of treatment. The ALL children with DVT were treated with LWHP when using L-ASP, as a result no thrombuses happened. CONCLUSION: Centralvenous catheter and chemotherapeutic drugs were the major cause of DVT. Abnormal coagulation, infection, and risk stratification are another risk factors for thrombosis. ALL children thrombosis are benefited from LWHP prevention when using L-ASP again. PMID- 29262892 TI - [Transcription Factor Pax5 Promotes B-lymphomagenesis in a Promoter-Independent Manner]. AB - OBJECTIVE: To determine whether B lymphocyte-specific transcription factor Pax5 regulates B-lympho-magenesis without direct binding to promoter. METHODS: Mouse B lymphoma cell line myc3 and 38B9 were infected with GFP- tagged retrovirus that encodes wide type or various mutant pax5 genes. After viral infection for 48 hours, the percentage of GFP positive lymphoma cells was determined by flow cytomety. The percentage of GFP positive tumor cells was further monitored every 3 days in vitro or once the tumor was formed in vivo. Both cell cycle and apoptic cell number of GFP positive lymphoma cells were analyzed using flow cytometry. RESULTS: Similar to the infection with wild type Pax5 retrovirus, infection with Pax5 mt 1-357 and Pax5 mt 304-358 that lacks of DNA binding motif can strongly increase the percentage of GFP+ B-lymphoma cells both in vitro and in vivo (P<0.01), while infection with empty viral vector migR-GFP and Pax5 mt 1-143 containing only DNA binding motif failed to increase the percentage of GFP positive tumor cells (P>0.05). Moreover, the analysis of flow cytometry demonstrated that more B-lymphoma cells infected with wild type Pax5, Pax5 mt 1 357 and Pax5 mt 304-358 retroviruses entered S and G2/M phases in comparison with those infected with empty viral vector migR-GFP and Pax5 mt 1-143. Apoptotic rates among different groups were not significantly changed. CONCLUSION: Pax5 can promote B-lymphoma cell growth both in vitro and in vivo in a promoter independent manner. This is mainly due to the accelerating of cell cycle rather than decreasing apoptosis. Our studies provide potential theory for restraing B lymphomagenesis by targeting the specific Pax5 domains. PMID- 29262893 TI - [Lymphocytic Clonal Expansion in Adult Patients with Epstein-Barr Virus Associated Lymphoproliferative Disease]. AB - OBJECTIVE: To explore the lymphocytic clonal expansion in adult patients with Epstein-Barr virus-associated lymphoproliferative diseases (EBV+LPD), and to investigate the experimental methods for EBV+LPD cells so as to provide a more objective measure for the diagnosis, classification and prognosis in the early stage of this disease. METHODS: Peripheral blood samples from 5 patients with EBV+LPD, 4 patients with adult infectious mononucleosis(IM) as negative control and 3 patients with acute NK-cell leukemia(ANKL) as positive control were collected. Prior to immunochemotherapy, viral loads and clonality were analysed by flow cytometry (FCM), T cell receptor gene rearrangement (TCR) was detected by real-time polymerase chain reaction (RT-PCR), and diversity of EB virus terminal repeat (EBV-TR) was detected by Southern blot. RESULTS: FCM showed only 1 case with clonal TCRVbeta in 5 patients with EBV+LPD, TCR clonal expansion could be detected both in patients with IM(4 of 4) and 4 patients with EBV+LPD(4 of 5), Out of patients with EBV+LPD, 1 patient displayed a monoclonal band and 2 patients showed oligoclonal bands when detecting EBV-TR by southen blot. CONCLUSION: Detecting the diversity of EBV-TR by Southern blot may be the most objective way to reflex clonal transformation of EBV+LPD, which is of great benefit to the diagnosis, classification and prognosis in the early stage of this disease. PMID- 29262894 TI - [Expression of Apoptosis-related Protein Livin and Caspase-3 in Diffuse Large B Cell Lymphoma and Its Clinical Significance]. AB - OBJECTIVE: To detect the expression levels of Livin and Caspase-3 proteins in diffuse large B cell lymphoma (DLBCL), and to explore its correlation with clinicopathological characteristics, so as to provide a reference for clinical treatment and evaluation prognosis of DLBCL. METHODS: Immunohisto-chemical staining was performed to detect the expression of Livin and Caspase-3 in the samples from 51 DLBCL patients and 20 patients with reactive hyperplasia of lymph node (RHL). The relation between Livin and Caspase-3 with the factors influencing the prognosis of DLBCL was analyzed. RESULTS: Livin+ was not expressed in the tissues of RHL, but its expression rates reached to 58.82%(30/51) in 51 cases of DLBCL(P<0.05). The expression rats of Caspase-3 in DLBCL and RHL were 25.49%(13/51) and 85.0%(17/20) respectively, and the difference was statistically significant(P<0.05). The expression level of Livin in DLBCL tissues was related with clinical stage and pathological type(P<0.01, P<0.01). The expression of Livin was not obviously related with sex, age and extranodal involvement. The expression level of Caspase-3 in DLBCL tissues was related with clinical stage (P<0.05). The expression of Caspase-3 was not obviously related with sex, age, pathological type and extranodal involvement. There was a negative correlation between Livin and Caspase-3 in DLBCL(gammas=-0.333,P=0.017). Kaplan-meier survival analysis revealed that the expressions of Livin and Caspase-3 were related stalistically significantly with the patients prognosis (P<0.01, P<0.05). CONCLUSION: Over-expression of Livin in DLBCL and DLBCL of non-GCB subtypes, and low-expression of Caspase-3 in DLBCL may play a significant role in clinical prognosis of DLBCL. PMID- 29262895 TI - [DA-EPOCH Chemotherapy Combined with G-CSF Effectively Mobilizes Autologous PBHSC in NHL Patients]. AB - OBJECTIVE: To study the effect of the DA-EPOCH chemotherapy combined with G-CSF and the CTX therapy with G-CSF on mobilizing and collecting the peripheral blood hematopoietic stem cells and the later hematopoietic recovery. METHODS: Forty patients accepted mobilization and collection of peripheral blood stem cells(PBSC) after treated by CTX+G-CSF and DA-EPOCH+G-CSF therapy respectively, and were treated by auto-transfusion after BEAM pre-regimen. The mobilization efficacy, adverse effects and hematopoietic recovery after autologous transplantation were analyzed retrospectively. RESULTS: During the CTX+G-CSF mobilization, only one patient achieved the white blood cell(WBC) at 0.8*109/L, while the others were with the lowest WBC level above 2.0*109/L. The platelet counts were all normal with the exception of 3 cases at 80*109/L. The median percentage of CD34+ cells in one period of collection was 0.99(0.35-1.30)%. The median MNC was (3.80+/-2.05)*1010. The cumulative total of mononuclear cell was (5.84+/-2.48)*108/kg, and the median CD34+ cell count was 3.84(3.91-6.5)*106/kg. During the DA-EPOCH+G-CSF mobilization, the peripheral WBC count of patients were decreased to the lowest level at (0.2-1.4)*109/L. The platelet counts were all above 40*109/L except for 1 case in which the platelet count was reduced to 8*109/L. The median percentage of CD34+ cells in one period of collection was 0.85(0.34-1.2)%. The median MNC was (3.68+/-1.56)*1010. The cumulative total of mononuclear cells was (6.01+/-2.26)*108/kg, and the median CD34+ cell count was 4.44(2.7-7.10)*106/kg. There were no statistical differences between the 2 groups in the median percentage of CD34+ cells, the median MNC, the cumulative total of mononuclear cells and the median CD34+ cell counts (P>0.05). The average acquired time for granulocyte engraftment was 10.00(9.00-11.00) days, and for platelet engraftment was 12.50(11.00-17.25) days, with no statistical difference(P>0.05). No death occurred during the process of transplantation. CONCLUSION: DA-EPOCH therapy combined with G-CSF can effectively mobilize the peripheral blood hematopoietic stem cells in NHL patients with higher safety and lower price, and proves to be worth recommending in clinical use. PMID- 29262896 TI - [Effects of Sinomenine on Proliferation and Apoptosis of MCL Jeko-1 Cell Line and Its Mechanism]. AB - OBJECTIVE: To investigate the effects of sinomenine on growth and apoptosis of MCL Jeko-1 cell line and its mechanism. METHODS: The proliferation rate of Jeko-1 cells treated by different doses of sinomenine was assayed by MTT method; and the cell apoptosis was detected by flow cytometry. The expressions of Cyclin D1, BCL 2, BAX, Caspase-3, Akt signaling pathway protein Akt, phosphorylated-Akt (p-Akt), and phosphorylated-mTOR (p-mTOR), phosphorylated- P70S6K(p-P70S6K) were determined by Western blot. RESULTS: The growth of Jeko-1 cell line was inhibited by Sinomenine. The apoptosis rates of Jeko-1 cells treated by 0, 1, 2, and 4 mmol /L of Sinomenine for 24 hours were (2.21+/-1.05) %, (11. 29+/-2.42)%, (18.79+/ 2.84) %, (31.05+/-3.52) % respectively, and with very statistically significant difference(P<0.01). The expressions of p-Akt, p-mTOR, p-P70S6K were down regulated, but total Akt expression was not changed. The expressions of cyclin D1 and BCL-2 were down-regulated, but that of BAX, and Caspase-3 were up-regulated. CONCLUSION: The sinomenine can inhibit Jeko-1 cell proliferation, which may be realized through down-regulating the phosphorylation level of p-Akt, p-mTOR, and p-P70S6K, thus inhibiting the Akt signaling pathway and promoting the cell apoptosis. PMID- 29262897 TI - [Diagnostic Value of Protocadherin 15 for NK/T Cell Lymphoma]. AB - OBJECTIVE: To explore whether PCDH15-SI is stable and accurate to diagnose NK/T cell lymphoma or not. METHODS: The paraffin-biopsiy specimens were collected from 45 cases of NK/T-cell lymphoma and 33 cases of non-NK/T-cell lymphoma in Department of pathology, West China Hospital of Sichuan University. The paraffin sections were stained by immunohistochemistry and blank controls were set up. The peripheral blood was collected from these cases of NK/T-cell lymphoma and non NK/T-cell lymphoma, as well as from the normal controls in the same hospital. The serum PCDH15 levels were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Immunohistochemistry showed that PCDH15 were expressed in biopsy specimens of both the NK/T-cell lymphoma in the experimental group and the non NK/T cell lymphoma in the control group. The expression rate in the NK/T-cell lymphoma group was higher than that in control group. The PCDH15-SI can be detected in NK/T cell lymphoma, non-NK/T cell lymphoma and the normal controls, which is higher in lymphoma patients than that in control, and the serum level was higher in the non-NK/T-cell lymphoma patients than that in the NK/T-cell lymphoma patients. Also, the serum level was higher in the patients with advanced disease than that in the patients at early stage. CONCLUSION: PCDH15 does not act as the new diagnostic marker for NK/T cell lymphoma. The serum level of PCDH15-SI may be helpful to the staging and judging therapeutic effect and prognosis for the patients with non-Hodgkin's lymphoma. PMID- 29262898 TI - [Notch1 Gene Silenced by RNAi Inhibits Oncogenicity of Myeloma Cell Line]. AB - OBJECTIVE: To investigate the effect of Notch1 gene silencing by RNA interference on oncogenicity of multiple myeloma cells in NOD/SCID mice. METHODS: Targeting silenced Notch1 gene was target-sotenced by transfection of Notch1-shRNA in multiple myeloma RPMI8226 cells of NOD/SCID mouse myeloma models, and the change of the volume and speed of oncogenicity in myeloma mouse models were evaluated after Notch1 gene silencing, and ELISA was used to detect the serum expression level of IL-6 and VEGF in the tumor-bearing mice. RESULTS: After Notch1 gene was silenced by Notch1-shRNA, the speed of tumor formation was significantly inhibited and the tumor volume was reduced in the tumor-bearing mice, as compared with the control group, and the difference was statistically significant (P<0.05). The serum level of IL-6 and VEGF in the tumor-bearing mice significantly decreased in comparison with the control group (P<0.05 ). CONCLUSION: The oncogenicity of myeloma cells in the models NOD/SCID mouse myeloma is significantly inhibited by Notch1 gene-silencing, and its mechanism may relate with the decreased secretory level of IL-6 and VEGF after Notch1 gene silencing. Notch1 gene silencing can be used as a new strategy to treat multiple myeloma. PMID- 29262899 TI - [Icaritin Reverses Multidrug Resistance of Multiple Myeloma Cell Line KM3/BTZ]. AB - OBJECTIVE: To investigate the reversing effect of icaritin on multidrug resistance of multiple myeloma cell lines KM3/BTZ and its underlying mechanism. METHODS: KM3/BTZ cells were established by a gradually ascending gradient induction of bortezomib (BTZ). The sensitivities of KM3 and KM3/BTZ cells to 7 chemotherapeutic drugs, the inhibition and reversal effects of icaritin on proliferation and drug-resistance of KM3/BTZ cells were analyzed by MTT. The apoptosis was analyzed by flow cytometry, and the expression of Par-4, HSP27 and P-gp were detected by Western blot. RESULTS: KM3/BTZ cells were not only resistant to BTZ, but also to other 6 chemotherapeutic drugs. The resistance index (RI) to BTZ was 17.84, and higher than that of other chemotherapeutic drugs. Icaritin inhibited the proliferation and induced the apoptosis of KM3/BTZ cells. The IC50 value of BTZ decreased from 0.345 ug/ml to 0.149 ug/ml, and the reversal index was 2.38 (P<0.05). The expression of Par-4 protein increased in a concentration-dependent manner, while the expression of HSP27 and P-gp were down regulated. CONCLUSION: Icaritin can inhibit cell proliferation and induce apoptosis of KM3/BTZ cells, moreover, can effectively reverse the multidrug resistance of KM3/BTZ cells. The mechanism may be related with down-regulation of HSP27 and P-gp expression, and up-regulation of Par-4 expression. PMID- 29262900 TI - [Prognostic Impact of 1q21 Amplification in Newly Diagnosed Multiple Myeloma Patients Receiving Bortezomib-Based First-Line Treatment]. AB - OBJECTIVE: To explore the amplification rate, clinical correlation and prognostic significance of 1q21 amplification in newly diagnosed patients with multiple myeloma (MM). METHODS: I-FISH was performed on purified 138+ plasma cells from 72 newly diagnosed MM patients from February 2013 to February 2016 receiving bortezomib-based chemotherapy by using probe covered 1q21 region. Cut off value is 20%. Amplification rate, clinical relevance and prognostic significance were analysed in MM patients. RESULTS: Among 72 patients, male 52, femail 20, the median age was 58(33-80).The amplification rate of 1q21 was 45.8%, the 1q21 amplification was positivly correlated with 13q14 deletion(P=0.041)and ISS III stage (P=0.002). With a median follow-up time of 17.0(3.0-40.0)months, the estimated median progression-free survival(PFS) time and overall survival(OS) time for patients with 1q21 amplification were 17.0 and 22.0 months, however, they did not reach in patients without 1q21 amplification(P=0.000, P=0.001). The multivariate analysis showed that del(17p13), 1q21 amplification and LDH>=220 U/L remained as independent risk factors for PFS and OS. CONCLUSION: 1q21 amplification is an important genetics prognosis indicator in newly diagnosed multiple myeloma patients receiving bortezomib-based first-line treatment. Bortezomib-based treatment can not improve the poor survival in patients with 1q21 amplification. PMID- 29262901 TI - [Significance of Detecting the Plasma Levels of MMP-13 in Patients with Multiple Myeloma]. AB - OBJECTIVE: To study the significance of detecting the plasma level of matrix metalloproteinase-13(MMP-13) in patients with multiple myeloma(MM) and to investigate the correlation of MMP-13 levels in MM patients with myeloma bone disease(MBD). METHODS: The plasma level of MMP-13 was quantitatively analyzed in 53 newly diagnosed MM patients and 30 healthy controls by enzyme-linked immunosorbent assay(ELISA). Imaging examination was used to determine bone damage in patients with MM. At the same time, using a dual-energy X-ray absortionmetry(DXA), the bone mineral density was examined on vertebra L2 to L4 in the anteroposterior position and the proximal left femur in 17 MM patients and 15 healthy controls. RESULTS: The plasma level of MMP-13 in MM patients was significantly higher than that in the controls(P<0.01), and the MMP-13 level in MM patients with stage III of International Staging System(ISS) was significantly higher than that in patients with stage I-II(P<0.01). The MMP-13 level in MM patients without MBD was significantly higher than that in the controls(P<0.05). According to bone disease grading, 53 patients were divided into group A(bone grade 0-2, n=18)and group B(bone grade 3-4, n=35). Compared with group A, MMP-13 level group B was enhanced significantly (P<0.01). Further analyses revealed that the level of MMP-13 negatively correlated with the bone mineral density on L2 to L4, greater trochanter and Ward's triangle(r values were -0.693, -0.575 and 0.575, respectively, P<0.05), but not correlated with left femoral neck(r= 0.339)(P>0.05). CONCLUSION: The level of MMP-13 in MM patients is significantly high, and closely relates with ISS clinical stage, degree of MBD and the bone mineral density of MM patients. MMP-13 plays an important role in the development of MBD. PMID- 29262902 TI - [Targeting Notch1 Gene Inhibits the Proliferation of Multiple Myeloma Cells]. AB - OBJECTIVE: To investigate the effects of Notch1 gene silencing on the proliferation and apoptosis of multiple myeloma cells, and to find the new targets for the treatment of multiple myeloma. METHODS: Notch1-shRNA targeted silencing Notch1 gene was transfected into multiple myeloma RPMI8226 cells, the CCK-8 and flow cytometry were used to detect the proliferation and apoptosis of myeloma cells after Notch1-shRNA transfection, the real-time fluorescence quantitative PCR was used to analyze expression level of Notch1 mRNA, and the Western blot were used to detect the expression level of Notch1 signaling pathway related protein, such as Hes-1, Jagged-1, Jagged-2, BCL-2, PTEN, AKT and P-AKT. RESULTS: The mRNA and protein expression levels of Notch1-shRNA transfected cells were significantly inhibited in the experimental group assayed by real time fluorescence quantitative PCR and Western blot, the mRNA and protein expression level were down-regulated to 66% + 0.1%, 88% + 3.4% respectively, as compared with the control group(P<0.05). CCK-8 results confirmed that the cell proliferation rate was significantly decreased in the experimental group 48 hours after transfection. Flow cytometry results showed that the cell apoptosis rate was significantly higher in the experimental group than that in the control group. The expression levels of downstream protein Hes1, p-AKT and BCL-2 were decreased, the level of PTEN increased significantly after Notch1 gene silencing. CONCLUSION: Notch1 gene silencing by transfection of Notch1-shRNA can inhibit the proliferation of myeloma cells and induce their apoptosis, and its mechanism is related to the activation of PTEN gene and p-AKT signaling. Notch1 signal can be used as a potential target for multiple myeloma therapy. PMID- 29262903 TI - [Effect of Myeloma-Derived Exosomes on Surface Activating Receptors of NK Cells]. AB - OBJECTIVE: To investigate the effect of myeloma-derived exosomes on surface activating receptors of NK cells, and to explore the mechanism of the function defect of NK cells. METHODS: The exosomes from the supernatant of multiple myeloma cell lines RPMI8226 and U266 were extracted by ultracentrifugation, and the size of them was identified under electron microscope; the human primary NK cells were extracted, and were co-cultured with the myeloma-derived exosomes (40 ug/ml), then the expression levels of surface activating receptors NKp46, NKp30 and NKG2D of NK cells at 0,1,4 and 24 hours were detected by flow cytometry. RESULTS: The exosomes showed small vesicular, sized 30-100 nm under electron microscope. The expression of surface activating receptors of NK cells declined at different degree after co-cultured with myeloma-derived exosomes. CONCLUSION: Myeloma-derived exosomes can inhibit the expression of surface activating receptors of NK cells. PMID- 29262904 TI - [Monitoring of HBsAg and Risk of HBV Infection in Patients with Multiple Myeloma]. AB - OBJECTIVE: To explore the incidence of HBsAg and the risk of HBV infection in patients with multiple myeloma (MM). METHODS: A total of 114 newly diagnosed MM patients admitted in our hospital from May 2014 to July 2016 were enrolled in MM group, 110 healthy persons were enrolled in control group. The HBsAg positive rate and HBV infection rate were compared between 2 groups; the HBV infection rate of MM patients was compared before and after chemotherapy. According to detected results, all patients were divided into HBsAg+ group and HBsAg- group, and the lever damage in 2 groups was compared before and after treatment. For HBsAg+ and HBV-DNA+ patients, the preventive antiviral treatment was performed, while for other patients the preventive antiviral treatment was not performed, then the HBV reactivation was tested in each group. RESULTS: The incidence of HBsAg+ in MM patients seem a litter higher than that in control group without statistical significance (P>0.05); the incidence and severity of HBsAg+ group were higher than those of control group before treatment, moreover the difference between 2 groups was more significant after treatment (P< 0.05). The HBsAg reactivation was not found in 4 pases with HBsAg+ who received the proventive antiviral treatment, while the HBsAg reactivation was observed in 2 cases out of 6 cases without proventive antiviral treatment; the HBsAg reactivation happened only in 1 case of HBsAg- group after treatment. The HBV infection rate in MM patients after chemotherapy was significantly enhenced as compared with infection rate before chemotherapy(P< 0.05). CONCLUSION: The HBV infection rate in MM patients is higher than that in normal persons, moreover tha HBV-reactivation may happen in patients with ocult HBV infection in process of treatment; the HBV infection correlates with MM to a certain degree. The monitoring HBsAg for MM patients contributes to evaluation of liver danage. PMID- 29262905 TI - [Establishment of BOR-Resistant U266 Cell Line and the Detection of Its Biological Activities]. AB - OBJECTIVE: To establish bortezomib (BOR)-resistant human multiple myeloma U266 cell line U266/BOR and to detect its biological characteristics. METHODS: U266 cells were constantly exposed at low dose and progressively increasing dose of BOR to establish U266/BOR, the cell morphology was observed by inverted microscopy, IC50 and resistant index were determined by MTT assay, cell growth curve was drawed and the doubling time was calculated; cell cycle distribution were analyzed by flow cytometry, and RT-PCR was used to detect the mRNA expression of resistance-related genes. RESULTS: The MM U266/BOR cell line was successfully constructed and its resistance index was up to 19.8. The both cell morphologies were not different. Compared with U266 cells, the multiplication time was postponed with the increase of G0/G1 cell ratio, and S phase was reduced. The mRNA expression of PTPROt, Beclin 1 and PTEN were reduced, and the mRNA expression of c-Maf was enhanced in U266/BOR cells; as compared with U266 cells, but the MDR1 mRNA expression was not different between U266 cells and U266 BOR cells. CONCLUSION: The BOR-resistant U266 cell line has been establiseed successfully. It provides an ideal cell model for further exploration of the mechanism for BOR resistance. PMID- 29262906 TI - [Establishment and Management of Multiple Myeloma Specimen Bank Applied for Molecular Biological Researches]. AB - OBJECTIVE: To establish a multiple myeloma specimen bank applied for molecular biological researches and to explore the methods of specimen collection, transportation, storage, quality control and the management of specimen bank. METHODS: Bone marrow and blood samples were collected from multiple myeloma patients, plasma cell sorting were operated after the separation of mononuclear cells from bone marrow specimens. The plasma cells were divided into 2 parts, one was added with proper amount of TRIzol and then kept in -80 degrees C refrigerator for subsequent RNA extraction, the other was added with proper amount of calf serum cell frozen liquid and then kept in -80 degrees C refrigerator for subsequent cryopreservation of DNA extraction after numbered respectively. Serum and plasma were separated from peripheral blood, specimens of serum and plasma were then stored at -80 degrees C refrigerator after registration. Meantime, the myeloma specimen information management system was established, managed and maintained by specially-assigned persons and continuous modification and improvement in the process of use as to facilitate the rapid collection, management, query of the effective samples and clinical data. RESULTS: A total of 244 portions plasma cells, 564 portions of serum, and 1005 portions of plasma were collected, clinical characters were documented. CONCLUSION: A multiple myeloma specimen bank have been established initially, which can provide quality samples and related clinical information for molecular biological research on multiple myeloma. PMID- 29262907 TI - [Effects of Cyclin A1 on the Proliferation of SKM-1 Cells and Its Potential Role in Myelodysplastic Syndrome]. AB - OBJECTIVE: To investigate the effects of Cyclin A1 on the proliferation of SKM-1 cells and its underlying role in myelodysplastic syndrome (MDS). METHODS: Cyclin A1 was knocked down with its small interfering RNA (siRNA). The efficiency of siRNA transfection was measured by Western blot and RT-PCR. Then the proliferation of SKM-1 cells and the expression of CDK2,RUNX1 and SRSF2 with and without knockdown of Cyclin A1 recorded and analysed respectively. RESULTS: Cyclin A1 was knocked down by siRNA after transfected for 48 h. The kncokdown of Cyclin A1 inhibited the proliferation of SKM-1 cells and down-regulated the expression of CDK2, RUNX1 and SRSF2, and these effects were at least partially mediated through RUNX1 and SRSF2 signaling pathway. CONCLUSION: Cyclin A1 plays an important role in the proliferation of SKM-1 cells. These findings provide new insights into the pathogenesis of MDS, and it may be a potential target in the treatment of MDS. PMID- 29262908 TI - [Detection of ASXL1 Mutation and CALR Mutation Coexistance in Patients with Ph Negative Myeloproliferative Neoplasm and Its Clinical Gignificance]. AB - OBJECTIVE: To explore the coexistence of ASXL1 and CALR gene mutations in patients with essential thrombocytheima (ET) and with primary myelofibrosis(PMF), and to compare the differences of clinical characteristics between ET and PMF patients carrying ASXL1 and CALR mutations, and ET and PMF patients carrying solitary gene mutation, and ET and PMF patients without any mutations. METHODS: The mutations of ASXL1 gene at exon 12, CALR gene at exon 9 and MPL gene at exon 10 in 263 essential ET patients and 29 PMF patients were detected by PCR amplification followed by direct sequencing of genomic DNA. The JAK2V617F mutations were used by allele specific PCR detection. RESULTS: 72.6%(212/292)of patients harbored at least one mutation. The incidences of ASXL1 and CALR mutations were 5.8% and 30.5%, respectively. The frequencies of JAK2V617F and MPL mutations were 39.0% and 2.4%, respectively. 5.1%(15/292) of patients had double mutations, including ASXL1 and CALR(n=11), ASXL1 and JAK2V617F(n=2), MPL and CALR(n=1) and ASXL1 and MPL(n=1). The frequency of concurrent ASXL1 and CALR mutations was found to be high. Significant difference was found on hemoglobin levels and platelet counts between CALR and ASXL1 mutations and single mutation (P<0.05),however, the difference on leukocyte counts and median age was not found. Compared with negative patients, the presence of ASXL1 and CALR mutations was found to be significantly correlative with lower hemoglobin level (P=0.045), lower leukocyte count (P=0.002) and with higher platelet counts(P=0.001), but the difference of median age was not found. CONCLUSION: The frequency of concurrent ASXL1 and CALR mutations is higher in ET patients. The coexistence of ASXL1 and CALR gene mutations significantly associated with lower hemoglobin level and higher platelet count. PMID- 29262909 TI - [Establishing the Ion Torrent PGM Sequencing Methods for the Clinical Diagnosis of MPN Patients]. AB - OBJECTIVE: To investigate the feasibility and relibility of rapidly and accurately acquiring the informations of gene mutations in MPN patients by using self-designed custom MPN mutation-related multipe-PCR primer kit and next generation Ion Torrent PGM sequencing platform. METHODS: The bone marrow samples of 10 MPN patients with JAK2V617F and/or CALR+, Ph- confirmed by sanger sequencing method were collected and were re-detected by using next generation Ion Torrent PGM sequencing method, then the consistence of results of above mentioned 2 kinds of detection methods was compared. RESULTS: In terms of JAK2V617F, MPL and CALR mutations, the results of Ion Torrent PGM sequencing were complete consistent with results of Sanger sequencing, except 52 bp deletion of CALR gene, which conld not be detected by next generation Ion Torrent PGM sequencing method in all bone marrow samples. CONCLUSION: The detection of multiple gene mutations in MPN patients by Ion Torrent PGM sequencing platform is feasible and can meet the needs of clinical testing. This method can complete detection of all 23 mutetions within 1-2 days, moreover, possesses advantages of high sensitivity, specificity, rapidity, high throughput and low cost. PMID- 29262910 TI - [Clinical Value of p15, DAPK, SOCS1 and FHIT Genes Combined Detection in the Early Diagnosis and Prognosis Evaluation of Myelodysplastic Syndrome]. AB - OBJECTIVE: To investigate the value of p15, DAPK, SOCS1 and FHIT genes combined detection in the early diagnosis and prognosis evaluation of patients with myelodysplastic syndrome(MDS). METHODS: The methylation-specific PCR (MSP) was used to detect the methylation of the above-mentioned 4 genes in 67 patients with MDS. The value of 4 gene combined detection in the early diagnosis and prognosis evaluation of patients with MDS was compared and anazlyzed. RESULTS: The methylation rates of p15, DAPK, SOCS1 and FHIT genes in 67 patients with MDS were 37.3%, 35.8%, 47.8% and 52.2%, respectively, which were significantly higher than those in control group (P<0.05). The accordance rates of p15, DAPK, SOCS1 and FHIT single detection for diagnosis of MDS were 37.3%,35.8%,47.8% and 52.2%, respectively, meanswhile the accordance rate of above-mentioned 4 gene combined detection for diagnosis of MDS was 82.1%, which was significantly higher than that of single gene detection(P<0.001). The methylation of >=2 genes in relatively high risk group was significantly higher than that in relatively low risk group (P<0.05). The median survival time of MDS patients was 18(13.3, 22.7) months; the median survival time in relatively low risk group was significantly longer than that in relatively high risk group [27(20.3,33.7) months vs 9(5.9,12.1) months] (P<0.05). The survival time of MDS patients with different risks displayed the trend of shorting feature along with increasing of methylated genes (P<0.05). CONCLUSION: The combined detection of above menthioned 4 genes can improve the accuracy of early diagnosis and prognosis evaluation for MDS patients. PMID- 29262911 TI - [Analysis of Irregular Antibody Production in Severe beta-Thalassemia Children with long-term Blood Transtusion and Its Correlation with RH Gene and Anemia Gene Mutation Site]. AB - OBJECTIVE: To analyze the prevalence of irregular antibodies in children with severe beta-thalassemia after long-term blood transfusion and its correlation with RH and anemia gene mutations site. METHODS: One hundred twenty children with severe beta-thalassemia and long-term blood transfusion were selected in our hospital, the genomic DNA was extracted and the genotype of RH factor were determined by PCR-SSP. The irregular antibodies and their types were screened and identified by the serological method, the gene types of the severe beta thalassemia were analyzed by reverse dot blot hybridization on DNA chip and PCR amplification. RESULTS: The major of RH genotypes in 120 children were Ce/Ce (59.17%) and CE/ce (25%), among them 10 children possessed the positive irregular antibodies (8.33%), out of these 10 children, the genotypes of RH factor were Ce/Ce in 6 cases, cE/cE, CE/ce, cE/ce and Ce/ce in one case; among these 10 children with positive irregular antibodies, the anemia gene mutations were IVs 11654M in 2 cases, cD4142M in 6 cases, 28M in 1 case, and CD71-72M in 1 case. CONCLUSION: Irregular antibodies produced by regular blood transfusion in children with severe beta-thalassemia may be related with RH factor and anemia gene mutation sites. PMID- 29262912 TI - [Value of CD3+CD4+ T Cell Count in Prediction of Viral Infection after Hematopoietic Stem Cell Transplantation in Patients Severe Aplastic Anemia]. AB - OBJECTIVE: To explore the value of CD3+CD4+ T cell count in prediction of viral infections after allogeneic hematopoietic stem cell transplantation(allo-HSCT) in the patients with severe aplastic anemia(SAA). METHODS: A total of 78 SAA patients with allo-HSCT in Guangzhou First People's Hospital from January 2014 to July 2016 were enrolled in this study. The absolute numbers of CD3+CD4+T cells were measured by flow cytometry at 1,2,3,6, and 12 month after allo-HSCT. According to the cell counts, the patients were divided into 3 groups: i.e. <50/ul (n=120), 50-100/ul(n=48) and >100/ul(n=123)groups. The infection incidences of human cytomegalovirus (HCMV) and Epstein-Barr virus(EBV) within 2 weeks around each time point were compared between different groups. According the counts of CD3+CD4+T cells at 3 months after-transplant, these patients were divided into 2 groups, i.e.>100/ul (n=30) and <=100/ul (n=48). The incidences and duration of HCMV and EBV infection, overall survival rate were compared between 2 groups. RESULTS: The incidences of CMV and EBV infection significantly decreased in CD3+CD4+ T cell >100/ul group as compared with <50/ul and 50-100/ul groups. At 3 months after-transplant, there was lower incidence rates of CMV disease, EBV infection, shorter durations of CMV infection and better survival in CD3+CD4+ T cell >100/ul group as compared with <=100/ul group. CONCLUSION: CD3+CD4+ T cell count is a good predictor for CMV and EBV infection after allo-HSCT in SAA patients. There are low risk of infe-ctions from CMV and EBV when CD3+CD4+ T cell count >100/ul in any time after transplant, which means lower occurrence of CMV and EBV infection and better survival when CD3+CD4+ T cell counts is >100/ul in 3 months after transplant in SAA patients. PMID- 29262913 TI - [Screening Abnormal Hemoglobin Diseases for Couples of Childbearing Age in Guangzhou City by HPLC]. AB - OBJECTIVE: To investigate the incidence and common types of abnormal hemoglobin diseases of the couples at childbearing age by using high performance liquid chromatography (HPLC) in Guangzhou city. METHODS: The couple of childbearing age in the Birth defect intervention project and Free pre pregnancy health examination were screened from October 2008 to February 2016 in Guangzhou city. The HPLC was used to detect abnormal hemoglobin; The Gap-PCR and reverse dot blot(RDB) were used to detect thalassemia gene deletions. RESULTS: The detection rate of hemoglobinopathies was 1.14% in the couples of childbearing age in Guangzhou city. 8 kinds of abnormal hemoglobin were detected: Hb E in 102 cases(17 cases with alpha thalassemia) , Hb Q-Thailand in 20 cases(18 cases with alpha thalassemia, 2 cases with alpha and beta thalassemia), Hb D-Iran in 4 cases(2 cases with alpha thalassemia, 1 case with alpha and beta thalassemia), Hb G-Honolulu in 3 cases(1 case with alpha thalassemia), Hb J-Bangkok in 2 cases(2 cases with alpha thalassemia), Hb Osu-Christiansborg in 1 case(with alpha thalassemia), Hb Hasharon in 1 case(with alpha thalassemia), Hb Koln in 1 case(with alpha thalassemia). CONCLUSION: The incidence of abnormal hemoglobin diseases in Guangzhou area has been found to be more high, 8 kinds of abnormal hemoglobin are found by HPLC, the HPLC is an effective way to screen the couples of childbearing age for beta thalassemia and hemoglobinopathies. PMID- 29262914 TI - [Expression of MicroRNA-15a in Children with Primary Immune Thrombocytopenia and Its Significance]. AB - OBJECTIVE: To analyze the expression of MicroRNA-15a (miR-15a) in children with primary immune thrombocytopenia (ITP) and its significance. METHODS: The peripheral blood monomuclear cells (PBMNC) were isolated and cultured from ITP patients and healthy volunteers. The expression level of miR-15a was measured by real-time PCR. After miR-15a mimic was transfected into PBMNC, the levels of INF gamma, IL-2, IL-4 and IL-10 were measured by ELISA. RESULTS: The expression of miR-15a was significantly decreased in PBMNC. The production of IFN-gamma and IL 2 was dramatically increased, and the level of IL-4, IL-10 was decreased in PBMNC. Moreover, the expression of miR-15a was negatively correlated with IFN gamma and IL-2, and positively with IL-4 and IL-10. Furthermore, the results showed that the overexpression of miR-15a could decrease the production of IFN gamma and IL-2, and increase the production of IL-4 and IL-10. CONCLUSION: miR 15a is significantly down-regulated in PBMNC of children with primary ITP and involved in the regulation of Th1/Th2 imbalance. It is suggested that miR-15a may be a potential therapeutic target for ITP. PMID- 29262915 TI - [Clinical Significance of Coagulation Indicators and their Correlation with Inflammatory Factors in Critical Patients with Thromboembolism]. AB - OBJECTIVE: To evaluate the levels of coagulation indicators [thrombomodulin(TM)/ thrombin-antithrombin complexes(TAT)/ alpha2-plasmin inhibitor-plasmin complexes(PIC)/ tissue plasminogen activator-inhibitor complexes(t-PAIC) /D Dimer(D-D)/fibrin degradation products(FDP)] in the critical patients with thromboembolism, analyse their correlation with inflammatory factor (procalcitonin/C reactive protein/ interleukin-6), and explore the diagnostic significance of coagulation indicators for these patients. METHODS: The serum levels of the coagulation indicators (TM/TAT/PIC/t-PAIC/D-D /FDP) and inflammatory factors (PCT/IL-6/CRP) were detected in the patient group with critical thromboembolism (n= 38) and critical patient group without thromboembolism as control (n= 81) . The correlation of coagulation indicators with inflammatory factors was analyzed. RESULTS: The values of TM/TAT/PIC/D-D/FDP in thromboembolism group were statistically significantly higher than those in control group (P<0.05). However, the t-PAIC values were not significantly different (P>0.05), and 3 inflammatory factors (PCT/CRP/IL-6) in thromboembolism patients were significantly higher than those in control group (P<0.05). The correlation analysis suggested that the correlation coefficients of TM with PCT, CRP and IL-6 were 0.288, 0.249 and 0.270, respectively (P<0.05). CONCLUSION: The critical patients with thromboembolism show an obviously higher systemic inflammatory response, and accompany with coagulation dysfunction. There is a network relationship between inflammation and coagulation, the interaction of inflammatory factors with coagulation indicators promotes thromboembolism and inflammation. PMID- 29262916 TI - [Detection of ATP Level in CD4+ T Lymphocytes and Its Clinical Significance in Allogeneic Hematopoietic Stem Cell Transplantation Recipients]. AB - OBJECTIVE: To explore the clinical value of detecting adenosine triphosphate (ATP) level in CD4+ T lymphocytes (Immuknow ATP) of patients on early stage after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The base line ATP value in CD4+ T lymphocytes in cases of hematological malignancies and the ATP level in CD4+ T lymphocytes of acute leukemia patients before allo-HSCT were detected. Allo-HSCT recipients were devided into 3 groups with different level of immunereactivity according to ATP concentraiton in month 3 (day 90+/-5) after allo-HSCT. The clinical characteristics of patients in 3 groups were analyzed. RESULTS: The mass concentration of Immuknow ATP in 15 cases of hematological malignancies before allo-HSCT ranged from 56.21-435.71 ng/ml, with a mean of 203.98+/-112.72 ng/ml. The ATP level in 46 cases after allo-HSCT ranged from 1.69-333.09 ng/ml, with a median of 41.96 ng/ml. Both 91.26 ng/ml (mean-SD) and 316.70 ng/ml (mean+SD) were used as cutoff, and 36 allo-HSCT recipients (78.3%) were assigned to low immunereactivity group, 8 recipients (17.4%) to middle group and 2 recipients (4.3%) to high group. The incidence of infection in low immunereactivity group was significantly higher than that in middle immunereactivity group (86.1% vs 50.0%)(P=0.022), and also significantly higher than that in high immunereactivity group (86.1% vs 0%)(P=0.002). There were no statistical differences in the incidences of severe infection among 3 groups. The incidence of grade II or higher acute graft versus host disease (aGVHD) in high immunereactivity group was superior to that in low immunereactivity group statistically (100% vs 13.9%)(P=0.002). Immune-mediated organ injury occurred more frequently in high immunereactivity group as compared with low and middle immunereactivity groups (100% vs 0% and vs 0%)(P=0.000; P=0.002). There were no significant differences in relapse rates of leukemia among 3 groups. The percentage of patients with increased trough blood concentration of cyclosporine A(CsA) was not significantly different among 3 groups (P=0.720). CONCLUSION: Detection of ATP level in CD4+ T lymphocytes on early stage after allo-HSCT possesses clinical significance for predicting infection, severity at aGVHD and immune-mediated organ injury. PMID- 29262917 TI - [Risk Factors of Leukemia-free Survival in Ph+ ALL Patients with Allogeneic Hematopoietic Stem Cell Transplantation]. AB - OBJECTIVE: To explore the effect of BCR-ABL gene transcripts on Leukemia-free survival (LFS) and prognosis of patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The clinical data of 107 cases of Ph+ B-ALL patients received allo-HSCT from July 2006 to November 2014 in the First Affiliated Hospital of Soochow University were collected and the relationship between the clinical characteristics and LFS after transplantation was analyzed. RESULTS: Out of 107 Ph+ ALL patients (64 males and 43 females) with a median age of 30(7 to 54)years old, 35.5% (38/107) cases relapsed after transplantation within a median time of 6.9 (1.5 to 40.7) months. A total of 39 (36.4%) cases died within a median time of 19.8 (3.6 to 83.7) months after HSCT, of which 51.3% (20/39) due to disease relapse and 25.6% (10/39) due to infection. BCR-ABL gene transcripts of 49 cases turn into negative before transplantation, of which the expected 5-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and overall survival (OS) were 26.5%, 29.5% and 41.6%, respectively. Another 49 cases still had a positive BCR-ABL gene transcripts before transplantation, of which the life expectancy of 5 year CIR, NRM and OS were 64.4%,8.9% and 48.9%, respectively. Compared with BCR-ABL positive patients, BCR ABL negative patients showed a lower CIR (P<0.001), a higher NRM (P=0.030) and a similar OS (41.6% versus 48.9%, P=0.497). Multivariate analysis showed that BCR ABL positive (P=0.016) and a disease statusphase >=CR2 (P<0.001) before HSCT were independent risk factors for LFS, while the age underwent HSCT was the principal element affecting prognosis (P<0.001). CONCLUSION: Both the relapse and infection are the main causes of death in the patients after transplantation. A disease status >=CR2 and the BCR-ABL positive before transplantation are 2 independent risk factors of LFS in the patients with Ph+ ALL after allo-HSCT. PMID- 29262918 TI - [Molecular and Genetic Mechanism of Three Cases of Para-Bombay Blood Group]. AB - OBJECTIVE: To explore molecular and genetic mechanism of 3 cases of para-Bombay blood group. METHODS: The bood samples of proband and family members were selected to identify their blood groups with conventional serologic methods, and salivary components carrying the ABH antigens were detected. The coding regions of FUT1 as well as exon 6 and 7 of the ABO gene were amplified using polymerase chain reaction(PCR), and the FUT1 gene was directly sequenced. RESULTS: All the 3 cases of proband were confirmed as para-Bombay blood group. Direct sequencing revealed h new2 (nt328G->A) and h1(nt 547 DeltaAG) in FUT1 gene of the proband 1, and FUT1 genotype was h1/h new2. However, the genotypes of his parents were H/h1 and H/h new2, which were non-Bombay individuals. The FUT1 genotypes of proband 2 and 3 were h1h2 (nt 547 DeltaAG) and h1h2 (nt 880 DeltaTT), respectively. CONCLUSION: The technology of molecular biology can be used to detect the base deletion mutations in FUT1 gene, which contributes to the analysis of molecular and genetic mechanism of para-Bombay blood group. PMID- 29262919 TI - [Gene Polymorphism 24 Rare Blood Group Antigens of 11 RBC Blood Group Systems in Manchu Population of Harbin Area in China]. AB - OBJECTIVE: The purpose of this study was to investigate the 24 kinds of antigen gene polymorphism chara-cteristics in 11 RBC blood group systems of Manchu population blood donor in Harbin Area of China, so as to better perform the clinical blood transfusion and to avoid adverse transfusion reactions. METHODS: Twenty-four antigen genes (GYPB (S/S), Duffy, Kell, Dombrock, Diego, Kidd, Scianna, Colton, Lutheran, Yt, Mur) were assessed by the polymerase chain reaction sequence specific primers (PCR-SSP) in 11 blood type systems, including Fya, Fyb; K, K; Doa, Dob; Dia, Dib; JKa, JKb; Sc1,Sc2; Coa, Cob; Lua, Lub; Yta, Ytb; Kpa, Kpb; Mur, Mur2 among 200 Manchus in Harbin. RESULTS: The gene frequency of blood type system in Harbin Manchu GYPB (S/S) was as follows: S=0.0625, s=0.9325; the gene frequency of duffy blood type system: Fya=0.0525, Fyb=0.9475; Gene frequency of Dombrock type system was as follows: Doa=0.1250, Dob=0.8750; Gene frequency of Diego type system: Dia=0.0275, Dib=0.9725; the gene frequency of Kidd blood type system: JKa=0.5650, JKb=0.4350; the gene frequency of Mur blood type system: Mur1 = 0.0050, Mur2 = 0.9950; the Kell, Scianna, Colton, Lutheran and Yt type blood type system displayed a monomorph distribution and the genotype was kkKpbKpb,Sc1Sc1,CoaCoa, LubLub, YtaYta, respectively. CONCLUSION: The distribution of GYPB(S/s),Duffy,Dombrock, Diego, Kidd and Mur blood type system in Harbin Manchu has been found to be characterized by polymorphism, and the distribution of kell, scianna, colton, lutheran and ye blood type system has been found to be characterized by oligomorphism. The gene destribution of dombrock and Kidd blood group systems is unique in Harbin Manchu. PMID- 29262920 TI - [Phenotype Types and Genetic Mutation Mechanism of Rhesus D Variant Individuals]. AB - OBJECTIVE: To explore the phenotype types and genetic mutation mechanism of Rhesus D variant individuals. METHODS: Fouty-eight peripheral blood samples of pregnancies and blood donors who had been identified as Rhesus D variant by using routine serologic methods were collected from January 2013 to October 2015 in our center. The multiple ligation-dependent probe amplification(MLPA) was used to determine the RHD after genomic DNA had been extracted from the blood sample, then the data including gene copy number variations, point mutations, deletions and hybrid fusions were analyzed by GeneMarker software. All exons of blood sample RHD were amplified via PCR and analyzed by sequencing when its MLPA results were not in accordance with serologic results. Cloning and haplotype sequencing were performed if novel allele had been found. RESULTS: Rh phenotypes of the 48 samples were typed as following: 20 cases out of 48 were CcDee(41.7%, 20/48),12 cases were ccDEe (25%,12/48), 11 cases were CCDee(22.9%, 11/48), 5 cases were CcDEe (10.4%, 5/48), respectively. The MLPA analysis showed that 38 cases possessed only 1 variant allele(RHD zygosity was Dvd), while 10 cases possessed 2 variant alleles(RHD zygosity was DvDv). In Dvd type individuals, point mutations were found in 18 cases and RHD/CE hybrid fusions were found in 20 cases. In DvDv individuals, point mutations combined with RHD/CE hybrid fusions were found in 9 cases, deletion combined with RHD/CE hybrid fusions were found in 1 case. Variant alleles analysis basing on MLPA showed that 14 cases were weak D 15 and 22 cases were RhD VI type 3, however, the variant alleles were not identified in 7 cases due to lack of detecting probes and were identified via sequencing analysis. Two novel mutations, 79-81delCTC and 689G>A were also certificated by sequencing in 2 cases. CONCLUSION: CcDee is the major Rh phenotype in RhD variants, weak D 15 and RhD VI type 3 are the main serologic type of RhD variants, point mutation and RHD/CE hybrid fusions are main molecular mechanism for RhD variant phenotype. Besides, 79-81delCTC and 689G>A are two novel alleles. PMID- 29262921 TI - [Immunoserology and RHD Genotype Analysis of DVI Type 3 Genotype Pregnant Women with Anti-D]. AB - OBJECTIVE: To performe the immuneserological and RHD Genotype analyses for DVI type 3 genotype pregnemt women with anti-D. METHODS: RhD blood type of this pregnant women was identified by common serological methods, then the blood group specific antibodies was screened and identified; the polymerase chain reaction sequence specific primer(PCR-SSP) was used to identify the pregnant women's RHD genotype; RhD blood group for the pregnant women, her spouse and daughter was genogrouped and genetically analyzed by multiplex ligation-dependent probe amplification(MLPA). The heredity of this family was analyzed finally. RESULTS: The titer of IgG anti-D in the pregnant woman serum was 1:8; the PCR-SSP showed that the 3rd to 6th exons of RHD gene were missing in the pregnant woman. the genotype of pregnant woman was identified as DVI type 3; the MLPA analysis showed that this pregnant women owned only one RHD allele with 3rd to 6th exons missed, and her genotype was identified as CDVIe/cde; her spouse was identified as CDe/CDe homozygous genotype, and her daughter as CDe/CDVIe. CONCLUSION: Accurate identification of RhD blood type is of great significance for a safe and effective clinical blood transfusion strategy, and for taking appropriate measures to prevent hemolytic disease of newborn (HDN) at women childbearing age. PMID- 29262922 TI - [Blood Test Patterns for Blood Donors after Nucleic Acid Detection in the Blood Center]. AB - OBJECTIVE: To investigate the blood test patterns for blood donors after nucleic acid detection in blood center. METHODS: The collected blood samples after voluntary blood donors first were detected by conventional ELISA, then 31981 negative samples were detected via HBV/HCV/HIV combined nucleic acid test of 6 mixed samples(22716 cases) or single samples(9265 cases) by means of Roche cobas s201 instrument. The combined detection method as follows: the blood samples were assayed by conventional nucleic acid test of 6 mixed samples, at same time, 6 mixed samples were treated with polyethylene glycol precipitation method to concentrate the virus, then the nucleic acid test of blood samples was performed; the single detection method as follows: firstly the conventional nucleic acid test of single sample was performed, then the positive reactive samples after re examination were 6-fold diluted to simulate the nucleic acid test of 6-mixed samples. The positive rate of positive samples detected by combined nucleic acid test, positive samples detected by nucleic acid test of mixed virus concentration and positive samples detected by single nucleic acid test was statistically analyzed. In addition, for HBV+ persons the serological test yet should be performed. RESULTS: In 22 716 samples detected by nucleic acid test of 6 mixed samples (MP-6-NAT) , 9 cases were HBV+(0.400/00, 9/22716); at same time, the detection of same samples by nucleic acid test of mixed sample virus concentration showed 29 cases of HBV+(1.280/00, 29/22716). In 9265 samples detected by single nucleic acid test(ID-NAT) 12 cases showed HBV+ (1.300/00, 12/9265), meanwhile the detection of these 12 samples with HBV+ by 6-fold dilution for virus concentration found only 4 samples with HBV+. In serological qualified samples, ID-NAT unqualified rate was 1.280/00, which was higher than that of MP-6-NAT(0.40/00) (chi2=8.11, P<0.05); but there was no statistical difference between unqualified rate of ID-NAT and MP-6-NAT(1.30/00 vs 1.280/00)(chi2=0.00, P>0.05). In 41 samples with HBsAg-HBV DNA+ detected by ELISA, 36 samples were confirmed to be occult HBV infective(OBI) by HBsAb, HBcAb test of ELISA; out of these 41 samples, 33 samples showed HBcAb+(91.66% of OBI), 5 might be HBV "window period" infective, moreover the HCV RNA and HIV RNA positive samples were not found. CONCLUSION: To avoid the missdiagnosis of donors with low level of virus, the nucleic acid test must be carried out after virus concentration of mixed samples when the blood test pattern of donors is nucleic acid test of mixed samples, otherwise the single nucleic acid test must be performed to obtain more high detected rate of virus nucleic acid. The HBcAb serologic test and physical examination of donors before blood donation must be enhanced on basis of serological test of HBsAg; for high risk people, the persuading no blood donation is simplest pattern. PMID- 29262923 TI - [Correlation and Consistency of Two Different Methods for Detecting Coagulation Function]. AB - OBJECTIVE: To study the correlation and consistency of the 2 different methods for detecting coagulation function. METHODS: One hundred and six inpatients of ICU and department of gastroenterology in our hospital were retrospectively analyzed. The clinical data of thromboelastography and coagulation test were collected, and the detection results of 2 different methods were statistically analyzed. RESULTS: The K, MA value and alpha-Angle in thrombelastometry significantly related with fibrinogen (r=-0.62, 0.36, 0.38, all P<0.01), and the R time significantly related with prothrombin time and activated partial thromboplastin time (r=0.31, 0.35, both P<0.01); the Kappa values of K value, MA value, alpha-Angle and fibrinogen value were 0.34, 0.46, 0.31 respectively (all P<0.05), and the chi square test values were respectively 1.12, 1.42, 0.14 (P=0.28, 0.21, 0.69); the Kappa values of R time in thrombelastometry with prothrombin time, activated partial thromboplastin time(APTT) were respectively 0.05,0.07 (P=0.88, 0.81), and the chi square tests showed that the Kappa values were respectively 19.57, 9.07 (both P<0.01). CONCLUSION: Thromboelastography and coagulation test show significant correlation, with poor consistency, so the 2 kinds of methods can not be replaced for each other, which still can not be used to better assess the risk of bleeding. PMID- 29262924 TI - [Familial Haemophagocytic Lymphohistiocytosis Occurs in A Fetus at His Third Trimester-A Case Report]. AB - OBJECTIVE: To analyze the clinical features and pathogenetic gene mutation in a fetus at his third trimester with familial haemophagocytic lymphohistiocytosis (FHL). METHODS: Target region sequencing and high-throughput sequencing were used to detect pathogenetic gene mutations for familial haemophagocytic lymphohistiocytosis in a late onset HLH fetus. Pathogenetic gene mutations of the patient and his parents were verified by Sanger dideoxy sequencing. RESULTS: A male neonate, who had right pleural effusion, hepatomegaly and splenomegaly previously revealed by fetus ultrasound, was delivered at full-term by cesarean section. His clinical presentation showed recurrent fever, tachypenea, decreased breath sounds on right side, hepatosplenomegaly etc., which were gradually aggravating Lab.tests results were as follows: WBC 9.88*109/L, Hb 91 g/L, Plt 13*109/L, ALT 18 U/L,AST 69 U/L,TBIL 207.2 umol/L, DBIL 183.5 umol/L, TG 3.05 mmol/L, Fib 0.88 g/L, Serum ferritin 3 120 ng/ml and sIL-2R 57 420 U/ml. FCM showed that CD3-CD16+CD56+ cells reached to 3.60% in the pripheral blood. Haemophagocytes were occasionally found in the bone marrow. NK/NKT stimulation test showed a severe damage of degranulation of NK cells. Sequence analysis of genomic DNA from his peripheral blood demonstrated the compound heterozygous mutations of UNC13D gene: c.2448-13 G>A in exon26 and c.1055+1 G>A in exon12, both were pathogenetic mutations. In detailed family survey, it was confirmed that the mutation c.2448-13 G>A in exon26 was inherited from his mother and c.1055+1 G>A in exon12 from his father. CONCLUSION: A rare case of familial haemophagocytic lymphohistiocytosis type 3 (FHL3) with late fetus onset who carried pathogenetic compound heterozygous mutations of UNC13D gene. Those neonates with recurrent fever, serous effusions and multiple organ failure should be screened for FHL. Identifying the pathogenic gene mutations laid the foundation of conceiving disease-free newborns. PMID- 29262925 TI - [Research Progress on Chimeric Antigen Receptor T Cells-Review]. AB - As more and more clinical trials about chimeric antigen receptor T cells (CAR-T) have been carried out successfully, the CAR-T are getting well-known. Thanks for genetic engineering, CAR-T has the tumor special antigen expressed on the surface. CAR-T therapy is the adoptive immunotheraphy for rapidly advancing tumors. This technology has made a great progress in both blood malignancies and solid tumor. However, CAR-T also meet many difficulties in the way of development. This review discusses the clinical application, challenges and developing trend of CAR-T. PMID- 29262926 TI - [Research Advance in Light Chain Escape of Multiple Myeloma -Review]. AB - More than 80% of patients with MM is present as intact monoclonal immunoglobulin (Ig). Usually, the patients with intact immunoglobulin MM (IIMM) show parallel fluctuations of their intact Ig and FLCs or BJP. In the era of novel agents, including thalidomide, lenalidomide and bortezomib, the natural disease development and classic relapse patterns have been changed, the relapse was characterized by an increase in sFLC or BJP without a corresponding increase in paraprotein level, a phenomenon termed "light chain escape", indicates a worse outcome in patients with MM. This review focuses on the mechanism, clinical significance and early diagnosis of light chain escape. PMID- 29262927 TI - [Advances in the Diagnosis and Therapy of Primary Plasma Cell Leukemia -Review]. AB - Primary plasma cell leukemia (PPCL) is an uncommon and very aggressive hematological disease, which has different cytogenetic abnormalities, special molecular and biological characteristics, compared with multiple myeloma(MM). The clinical course is unfavorable with short remissions and reduced overall survival(OS). Intensive chemotherapy regimens and bortezomib-based regimens, immunoregulatory drugs(IMiDs) as well as stem cell transplantation may be beneficial to PPCL patients. This review summarizes the recent advances of this malignant disease, including clinical and biochemical characteristics of PPCL, therapy and prognosis of PPCL, new drugs for PPCL and so on. PMID- 29262928 TI - [Research Progress on miR-125 Family in Malignant Hematologic Diseases-Review]. AB - MicroRNAs (miRNAs) are a class of endogenous non-coding single-stranded small noncoding RNAs with the length of 20 to 23 nucleotides. MicroRNA-125 (miR-125) family, which is a highly conserved miRNA family, is consist of miR-125a, miR 125b-1 and miR-125b-2. Accumulating evidence demonstrated that miR-125 can be involved in various physiological and pathological processes in vivo. Importantly, it is closely related with the tumorigenesis and tumor development, including tumor cell proliferation, apoptosis, invasion and metastasis, metabolism and immune response. In malignant hematologic diseases, it is defined either as a oncogene, or as a tumor suppressor gene, even, closely related with the drug resistance in a variety of hematologic malignancies. MiR-125 is expected to become a new therapeutic target. Newly, the research of the relationship between miR-125 family and hematologic malignancies become increasing, including leukemia, lymphoma, multiple myeloma. In this review, the relationship between miR-125 family with malignant hematologic diseases and its latest research progress are summarized. PMID- 29262929 TI - [Research Advance on Role of Umbilical Cord Mesenchymal Stem Cell in Hematopoietic Stem Cells Transplantation-Review]. AB - Hematopoietic stem cell transplantation is an important method for the treatment of hematological malignancies. The hematopoietic recovery after transplantation, graft-versus-host disease (GVHD) prevention and treatment are the key to affect transplant success. Umbilical cord mesenchymal stem cells (hUC-MSC) can improve the hematopoietic microenvironment, promote hematopoietic stem cell homing and hematopoietic recovery, support hematopoiesis. In aduition, the hUC-MSC have immune function for a variety of immune cells, can avoid and alleviate the host immune response, have a certain effect on the treatment of GVHD. This article reviews the research advances on umbilical cord mesenchymal stem cells in hematopoietic stem cell transplantation. PMID- 29262930 TI - An approach to anaemia diagnosis - concerns in primary care. PMID- 29262931 TI - HIV-positive patients in the intensive care unit. PMID- 29262932 TI - End-of-life care and organ and tissue donation in South Africa - it's time for a national policy to lead the way. PMID- 29262933 TI - The African Hospitalist Fellowship. AB - The African Paediatric Fellowship Programme is rolling out a training course for newly qualified paediatricians to equip them with the leadership skills to function in complex general paediatric settings. The care of children in Africa carries its own unique demands, from the layering effects of multiple conditions through to establishing and sustaining services under severe resource constraints. This novel training concept aims to strengthen confidence and knowledge in areas that are not priorities during standard general paediatric training. The skills gained are considered of great relevance in assisting general paediatricians to achieve their full potential in their careers. PMID- 29262934 TI - Provision of acute and elective general surgical care at a tertiary facility in the era of subspecialisation. AB - BACKGROUND: The need for an acute care and general surgical unit (ACGSU) to provide care for patients previously managed on an ad hoc basis by subspecialist units was recognised by the provincial government of the Western Cape Province, South Africa, the management of Groote Schuur Hospital (GSH) and the Department of Surgery. OBJECTIVE: To describe the resulting ACGSU and its functioning. METHODS: Data available from administrative records, patient files and operating room forms were collected in spreadsheet form for the period July 2013 - November 2016 inclusive. RESULTS: The ACGSU comprised a medical care team of four consultants and four to five trainees. A total of 7 571 patients were seen during the study period, the majority (66.1%) referred from the GSH Emergency Centre. Skin and soft-tissue infections formed the major disease complex. A total of 3 144 operative records were available. The most common procedures were wound debridement and inguinal hernia repairs. Trainees acted as primary surgeon in most cases. Complications (Clavien-Dindo grades I - V) were noted in 25.0% of patients. CONCLUSIONS: The ACGSU provides patient management that would otherwise complicate care in the subspecialist surgical units. It serves as a training ground for registrars and stands as a model for other institutions. Further research into the effect on patient care is planned. PMID- 29262935 TI - Kaposi's sarcoma: Good outcome with doxorubicin, bleomycin and vincristine sulphate (ABV) chemotherapy and highly active antiretroviral therapy. AB - There is little published information on effective treatment of Kaposi's sarcoma (KS) in children in low-income countries. We prospectively treated 12 patients with an institutional review board-approved protocol consisting of four monthly courses of doxorubicin (Adriamycin), bleomycin and vincristine sulphate (ABV), with highly active antiretroviral therapy (HAART) plus co-trimoxazole prophylaxis for those who were HIV-positive, with additional vincristine if remission was not achieved after 4 months. Maintenance HAART plus co-trimoxazole was given to all HIV-positive patients. A fine-needle aspirate and CD4+ count were done if possible, and staging was performed according to Mitsuyasu. Eight of ten HIV positive patients with stage III - IVB disease, and both HIV-negative patients with stage I disease, were in remission after 473 - 1 490 (mean 939) days. One patient died after absconding during treatment, and one died from neutropenia related pulmonary infection. ABV with or without HAART is an effective treatment option for children with KS. PMID- 29262936 TI - Protecting personal information: Implications of the Protection of Personal Information (POPI) Act for healthcare professionals. AB - Careless handling of patient information in daily medical practice can result in Health Professions Council of South Africa sanction, breach of privacy lawsuits and, in extreme cases, serious monetary penalty or even imprisonment. This review will focus on the Protection of Personal Information (POPI) Act (No. 4 of 2013) and the implications thereof for healthcare professionals in daily practice. Recommendations regarding the safeguarding of information are made. PMID- 29262937 TI - Investigating nystagmus in patients with traumatic brain injury: A systematic review (1996 - 2016). AB - BACKGROUND: Traumatic brain injury (TBI) is a health and socioeconomic concern worldwide. In patients with TBI, post-traumatic balance problems are often the result of damage to the vestibular system. Nystagmus is common in these patients, and can provide insight into the damage that has resulted from the trauma. OBJECTIVE: To present a systematic overview of published literature regarding nystagmus in patients with TBI. METHODS: Nine databases and platforms were searched during October 2016 for articles published between 1996 and 2016. Studies of any research design and published in English that focused on nystagmus in patients with TBI were considered for inclusion. A total of 110 articles were screened once duplicates had been removed, and 29 full-text articles were assessed. Eleven articles were included in the quality appraisal phase (using the McMaster tool), after which 10 articles were included in this review. RESULTS: This review describes nystagmus in 713 patients, and all articles reviewed described the type of assessment method that was used. However, the results lacked comprehensive data regarding the assessment, measurement and description of nystagmus in TBI patients, or the possible link and relationship between nystagmus and TBI. CONCLUSIONS: This systematic review indicated that: (i) there is a growing body of evidence that benign paroxysmal positional vertigo should be considered during the medical examination of all patients suffering from head trauma; (ii) all patients with TBI should undergo visual (eye movement) and vestibular examination; and (iii) future studies should include quantitative measurements of eye movements and nystagmus. PMID- 29262938 TI - Beyond clinical trials: Cross-sectional associations of combination antiretroviral therapy with reports of multiple symptoms and non-adherence among adolescents in South Africa. AB - BACKGROUND: Studies investigating symptoms associated with combination antiretroviral therapy (cART) use among adolescents in resource-limited settings are rare beyond clinical trials. Identifying adolescents at risk of non-adherence is imperative for HIV/AIDS programming and controlling the epidemic in this key population. OBJECTIVE: To examine which cART regimens were associated with reports of multiple symptoms and past-week non-adherence in a large community traced sample of HIV-positive adolescents in South Africa (SA). METHODS: A total of 1 175 HIV-positive ART-experienced adolescents aged 10 - 19 years attending 53 health facilities in the Eastern Cape Province, SA, were interviewed in 2014 - 2015. Ninety percent (n=1 059) were included in the study. Adolescents who reported no medication use and those with unclear or missing data were excluded from further analysis, resulting in a sample for analysis of n=501. Outcomes were reports of multiple symptoms (three or more symptoms in the past 6 months) and past-week ART non-adherence (<95% correct doses in the past week). Multivariable logistic regression analyses controlled for sociodemographic and HIV-related covariates in Stata 13/IC. RESULTS: Of the adolescents included, 54.3% were female. The median age was 14 (interquartile range 12 - 16) years, and 66.5% were vertically infected. The prevalence of multiple symptoms was 59.7% (95% confidence interval (CI) 55.3 - 63.9). Independent of covariates, stavudine (d4T) containing cART regimens and the fixed-dose combination of tenofovir (TDF) + emtricitabine (FTC) + efavirenz (EFV) were associated with more reports of multiple symptoms (adjusted odds ratio (aOR) 3.38; 95% CI 1.19 - 9.60 and aOR 2.67; 95% CI 1.21 - 5.88, respectively). Lopinavir/ritonavir (LPV/r)-containing regimens were associated with fewer reports of multiple symptoms (aOR 0.47; 95% CI 0.21 - 1.04). For EFV-based regimens, adolescents on d4T + lamivudine (3TC) + EFV were more likely to report multiple symptoms than those on TDF + FTC + EFV or those on abacavir (ABC) + 3TC + EFV (aOR 3.26; 95% CI 1.01 - 10.52, aOR 2.86; 95% CI 1.35 - 6.05 and aOR 1.08; 95% CI 0.64 - 1.82, respectively). However, only TDF + FTC + EFV cART was associated with lower levels of non-adherence among participants (aOR 0.44; 95% CI 0.21 - 0.93). CONCLUSIONS: Rates of multiple symptoms among HIV-positive ART-experienced adolescents were high. d4T-containing regimens and TDF + FTC + EFV were associated with more reports of multiple symptoms, whereas LPV/r-containing regimens were associated with fewer reports. However, adolescents on TDF + FTC + EFV were the most adherent subgroup. These findings support the World Health Organization-recommended discontinuation of d4T use, but also underscore the dilemma faced by clinicians when choosing between low-toxicity regimens and those that promote ART adherence, particularly among HIV-positive adolescents. PMID- 29262939 TI - Sensory integration intervention and the development of the premature infant: A controlled trial. AB - BACKGROUND: Premature infants are at risk of sensory processing difficulties and developmental delays due to an immature central nervous system and possible episodes of medical instability, discomfort, pain and stress during the first weeks or months after birth. OBJECTIVE: To investigate the effect of Ayres Sensory Integration (ASI) on the development of premature infants in the first 12 months of life. METHODS: A pre-/post-test experimental design was used to randomly divide 24 premature infants from a low socioeconomic setting in Bloemfontein, South Africa, into experimental and control groups after being matched by corrected age and gender. Developmental status was determined with the Bayley III Scales of Infant and Toddler Development, the Test of Sensory Functions in Infants and the Infant/Toddler Sensory Profile. The experimental group received 10 weeks of ASI intervention. RESULTS: ASI intervention had a positive effect on the sensory processing and development of premature infants, especially in terms of cognitive, language and motor development. CONCLUSIONS: ASI intervention at an early age enhances the developmental progress of premature infants. PMID- 29262940 TI - Extraspinal osteoarticular multidrug-resistant tuberculosis in children: A case series. AB - BACKGROUND: South Africa (SA) is known to have a high disease burden of tuberculosis (TB). Extraspinal osteoarticular multidrug-resistant tuberculosis (ESOA MDR-TB) in children has only been described in a few case reports worldwide. OBJECTIVES: To describe the epidemiology and highlight the potential problem of ESOA MDR-TB infections as seen in children from a single academic hospital in SA. METHODS: A retrospective record review was performed on all children diagnosed with ESOA TB infection at Chris Hani Baragwanath Academic Hospital, Johannesburg, between 1 January 2006 and 31 December 2015. All patients with a positive TB culture (fluid or tissue) from the surgical site of biopsy (bone or joint) and who were hospitalised were included. Organism culture and drug sensitivity testing were performed. RESULTS: Overall 19 cases of ESOA TB were identified. Areas involved included the shoulder (2 cases), elbow (2 cases), hip (7 cases), knee (4 cases), ankle (3 cases) and humerus (1 case). The mean age of the population was 7.7 (range 2.0 - 14.0) years. The mean white cell count was 11.3 (range 5 - 28.9) * 109/L, the mean C-reactive protein level 53.8 (range 1.0 364.0) mg/L and the mean erythrocyte sedimentation rate 35.5 (range 4.0 - 85.0) mm/h. Two cases (10.5%) were MDR, and a further case (5.3%) was resistant to isoniazid only. Four of 12 patients tested positive for HIV. One of the HIV positive patients was isoniazid resistant. The two positive ESOA MDR-TB cases are discussed in detail. CONCLUSIONS: These findings indicate that ESOA MDR-TB is a reality in this paediatric population (10.5%) and a high index of suspicion should be maintained, especially when cultures are negative in children with signs and symptoms of ESOA TB. The effect of HIV infection on the incidence of ESOA MDR-TB requires further study. PMID- 29262941 TI - Impact of the learning environment on career intentions of paediatric interns. AB - BACKGROUND: High childhood disease burdens in South Africa (SA) prioritise the need for careers in paediatrics. Experiences of junior doctors during internship may influence career trajectories in a direction that is discordant with national health priorities. OBJECTIVE: To explore the influence of the learning environment and demography on career intentions of SA paediatric interns. METHODS: This cross-sectional study involved sampling intern groups at the start and completion of internship in paediatrics to determine their career intentions. A validated version of the Postgraduate Hospital Educational Environmental Measure was used to measure perceptions of the learning environment (LE) in the post-paediatric internship cohort. Measures of the LE in combination with demographic factors were compared with career intentions. Associations were determined by t-tests or analysis of variance and chi2 tests. RESULTS: A total sample size of 422 was obtained from two separate cohorts, which were demographically similar except for age. Most interns (88.4%) intended to remain in SA, with 72.6% indicating an intention to practise in the public healthcare sector. There was a high intention to specialise (85.9%), and 60.2% were keen on a career that involved children. Previous educational exposure and demographic factors other than gender did not significantly influence career intentions. Perceptions of the LE significantly influenced decisions to stay in SA's public sector and to care for children. The decision to specialise, however, was not influenced by demographic variables or perceptions of the LE. CONCLUSIONS: Paediatric interns from diverse sociocultural and educational backgrounds had similar career intentions. Most interns were keen to work with children in SA's public sector. However, learning experiences during internship significantly influence these intentions and have the potential to drive young doctors away from SA, its public health service and paediatric care. Ensuring that training and support of interns are optimised is essential if SA is to align its healthcare needs with the aspirations of its future healthcare workers. PMID- 29262942 TI - Access to and utilisation of healthcare services by sex workers at truck-stop clinics in South Africa: A case study. AB - BACKGROUND: Sex worker-specific health services aim to respond to the challenges that this key population faces in accessing healthcare. These services aim to integrate primary healthcare (PHC) interventions, yet most services tend to focus on prevention of HIV and sexually transmitted infections (STIs). North Star Alliance (North Star) is a public-private partnership providing a healthcare service package in roadside wellness clinics (RWCs) to at-risk populations along transport corridors in sub-Saharan Africa. OBJECTIVES: To inform future service development for sex workers and describe North Star's contribution to healthcare provision to this population in South Africa, we describe services provided to and utilised by sex workers, and their views of these services. METHODS: Using a mixed-methods approach, we present quantitative analyses of anonymised North Star routine data for sex workers for October 2013 - September 2015, covering nine sites in seven provinces. Clinic visits were disaggregated by type of service accessed. We performed thematic analysis of 25 semi-structured interviews conducted at five clinics. RESULTS: A total of 2 794 sex workers accessed RWCs during the 2 years. Sex workers attending clinics were almost exclusively female (98.2%) and aged <40 years (83.8%). The majority were South African (83.8%), except at Musina, where the majority of clients were Zimbabwean. On average, sex workers visited the clinics 1.5 times per person. However, in most cases only one service was accessed per visit. PHC services other than for HIV and STIs were accessed more commonly than HIV-specific services and STI treatment. There was an increase in the number of services accessed over time, the figure almost doubling from 1 489 during the first year to 2 936 during the second year. Although during recruitment participants reported having had sex in exchange for goods or money during the past 3 months, not all participants self-identified as sex workers during interviews; however, all reported feeling at higher risk of poor health than the general population owing to their involvement in sex work. Participants reported satisfaction with site accessibility, location and operating hours. Sex workers accessing sites described services as being suitable and accessible, with friendly staff. CONCLUSIONS: RWCs were highly appreciated by the users, as they are suitable and accessible. The sex workers who used the clinics visited them irregularly, mostly for PHC services other than HIV and STIs. Services other than the one for which the sex worker came to the clinic rarely appeared to be offered. We recommend areas for service expansion. PMID- 29262943 TI - Vulvar cancer is not a disease of the elderly: Treatment and outcome at a tertiary referral centre in South Africa. AB - BACKGROUND: An increase in vulvar cancer in young women is attributed to infection with oncogenic human papillomavirus (HPV). South Africa (SA) has a high prevalence of HPV, and it was therefore hypothesised that women with vulvar cancer here would be younger than in high-income countries (HICs). OBJECTIVE: To describe age, cancer stage, treatment and outcome of patients with vulvar cancer at a tertiary referral centre in SA. METHODS: In a retrospective observational study, patient records of women diagnosed with vulvar cancer between 2001 and 2014 were reviewed and demographic and surgical details captured. Histology results of vulvar biopsies and resected specimens were checked for HPV changes, koilocytes and usual-type vulval intraepithelial neoplasia. Patients were restaged using the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system to allow for comparison of outcomes. Five-year disease specific survival probability curves were generated using Kaplan-Meier analysis. RESULTS: The mean age of the 180 patients in the study was 52.5 years. Those who had documented HPV changes on histological specimens had a mean age of 50.4 years. More than 50% of the patients had advanced-stage disease, and 62.7% were treated with primary surgery. Five-year disease-specific survival probabilities were similar to those reported in the literature. CONCLUSIONS: Vulvar cancer should not be regarded as a disease of the elderly in SA, as women with vulvar cancer are 10 - 15 years younger than in HICs. A large proportion of patients present with advanced-stage disease. Health professionals should be alert to vulvar lesions, especially in women with abnormal Pap smears, to reduce the morbidity and mortality of this disease. PMID- 29262944 TI - Near-miss maternal morbidity from severe haemorrhage at caesarean section: A process and structure audit of system deficiencies in South Africa. AB - BACKGROUND: A rising caesarean section rate and substandard peri-operative care are believed to be the main reasons for recent increases in maternal deaths from bleeding during and after caesarean section (BDACS) in South Africa (SA). The Donabedian model assumes that clinical outcomes are influenced by healthcare workers and the healthcare system. OBJECTIVES: To evaluate near-miss cases from BDACS with regard to health system structure (resources and facilities) and process (patient care). METHODS: A cross-sectional prospective study was conducted in greater Johannesburg, SA. Data of women who had near-miss-related BDACS were collected by means of ongoing surveillance at 13 public hospitals. The World Health Organization intervention criteria were used to identify near-miss cases. A comparison of structure and process between the healthcare facilities was conducted. RESULTS: Of 20 527 caesarean sections , there were 93 near misses and 7 maternal deaths from BDACS. Dominant risk factors for near misses were previous caesarean section (43.9%), anaemia (25.3%) and pregnancy-induced hypertension (28.6%). Eighteen women were transferred to higher levels of care, and 8 (44.4%) experienced transport delays of >1 hour. The caesarean section decision-to-incision interval (DII) was >=60 minutes in 77 of 86 women, with an average interval of 4 hours. Structural deficiencies were frequently present in district hospitals, and there were serious delays in ambulance transfer and DIIs at all levels of care. CONCLUSION: The majority of the women had risk factors for BDACS. There were major ambulance delays and lack of facilities, mostly in district hospitals. All women required life-saving interventions, but could not access appropriate care timeously. Prevention and management of BDACS require a fully functional health system. PMID- 29262945 TI - Cost awareness among healthcare professionals at a South African hospital: A cross-sectional survey. AB - BACKGROUND: Financial cost is a recognised cause of lack of access to adequate healthcare in South Africa (SA). Data describing the SA healthcare professional (HCP)'s awareness of costs are scant. Their increased awareness of healthcare costs may improve efficacy and reduce wasteful expenditure. OBJECTIVE: To assess SA HCP's knowledge of healthcare costs, identify factors that influence cost awareness, and to determine if surveyed HCPs received training related to cost management during their studies or at any stage during their practice. METHODS: This cross-sectional survey was conducted by means of a standardised questionnaire. HCPs working at a major tertiary academic hospital were asked to answer an anonymous standardised questionnaire aimed at determining their awareness of the costs of commonly requested hospital items and tests. Cost accuracy was determined by assessing the log deviation of the estimated cost from true cost, with values >0 and <0 representing overestimates and underestimates, respectively. Cost estimations were considered correct if the absolute value of the log deviation was <0.2. Participants' attitudes towards the potential impact of the availability of cost information on their practice were assessed. RESULTS: The overall cost estimation of accuracy was low (mean 0.60; standard deviation 1.99) and differed widely between items. Cheaper items were more likely to be overestimated and expensive items to be underestimated. The majority of participants indicated that cost awareness education was not part of their training or practice (84.5%) and that they would like cost information to be made readily available (92.2%). Eighty-four percent of participants were of the opinion that cost information would not negatively affect patient care. CONCLUSION: The use of percentage deviation from true cost as a method of assessing cost awareness creates a bias towards overestimation, which is more relevant for cheap items, as larger overestimates are more common for these items. We propose the use of log deviation of the estimated cost from the true cost as a method of assessing cost estimation accuracy. HCPs have a limited understanding of the costs of disposables, tests and drugs commonly used in their practice and would prefer that cost information be made readily available to them. Attention should be paid to improving cost awareness among HCPs working at SA hospitals. PMID- 29262946 TI - Development and validation of a method to estimate body weight in critically ill children using length and mid-arm circumference measurements: The PAWPER XL-MAC system. AB - BACKGROUND: Erroneous weight estimation during the management of emergency presentations in children may contribute to patient harm and poor outcomes. The PAWPER (Paediatric Advanced Weight Prediction in the Emergency Room) XL tape is an accurate length-based, habitus-modified weight estimation device, but is vulnerable to errors if subjective visual assessments of children's body habitus are incorrect or erratic. OBJECTIVE: Mid-arm circumference (MAC) has previously been used as a surrogate indicator of habitus, and the objective of this study was to determine whether MAC cut-off values could be used to predict habitus scores (HSs) to create an objective and standardised weight estimation methodology, the PAWPER XL-MAC method. METHODS: The PAWPER XL-MAC model was developed by creating MAC ranges for each HS in each weight segment of the tape. This model was validated against two samples, the National Health and Nutrition Examination Survey datasets and data from two previous PAWPER tape studies. The primary outcome measure was to achieve >70% of estimations within 10% of measured weight (PW10 >70%) and >95% within 20% of measured weight (PW20 >95%) for children aged 0 - 18 years. RESULTS: The PAWPER XL-MAC model achieved very high accuracy in the three validation datasets (PW10 79.2%, 79.0% and 81.9%) and a very low critical error rate (PW20 98.5%, 96.0% and 98.0%). This accuracy was maintained across all ages and in all habitus types, except for the severely obese. CONCLUSIONS: The PAWPER XL-MAC model proved to be a very accurate, fully objective, standardised system in this study. It has the potential to be accurate across a wide variety of populations, even when used by those not experienced in visual assessment of habitus. PMID- 29262947 TI - Endoscopy services in KwaZulu-Natal Province, South Africa, are insufficient for the burden of disease: Is patient care compromised? AB - BACKGROUND: Endoscopy services are central to the diagnosis and management of many gastrointestinal (GI) diseases. OBJECTIVE: To evaluate the adequacy of endoscopy services in the public sector hospitals of KwaZulu-Natal (KZN) Province, South Africa, in 2016. METHODS: A cross-sectional study was performed using a questionnaire completed by the clinical heads of endoscopy units in the public hospitals in KZN. RESULTS: The heads of 11 of the 12 endoscopy units responded. Two units were in tertiary-level hospitals and nine in regional hospitals. A total of 22 353 endoscopic procedures were performed annually, averaging 2 032 cases per annum per centre; they were performed by 89 endoscopists, of whom 72 (80.1%) were general surgeons. There were 0.06 registered gastroenterologists (GEs) per 100 000 population. Each endoscopist performed an average of 263 endoscopies per annum. There were 1.18 endoscopy rooms available per unit, and two units had on-site fluoroscopy available. The average waiting period for an upper endoscopy was 27 (range 7 - 60) days, for colonoscopy 29 (range 7 - 90) days and for duodenoscopy/endoscopic retrograde cholangiopancreatography 13 (range 4 - 20) days. This included patients with alarm symptoms for GI cancers. Equipment breakages interrupted most services, except for one hospital that had a service contract. Unit heads cited lack of equipment, trained staff and maintenance contracts as major shortcomings. CONCLUSIONS: Endoscopy units in KZN are not adequately equipped to deal with the endoscopy workload and services are plagued by frequent disruptions, which impact negatively on service delivery. There is a need to train more GEs. Patient care is compromised in these public hospitals. PMID- 29262948 TI - The world's first human-to-human heart transplant at Groote Schuur Hospital: 50 years later. PMID- 29262950 TI - Cardiac transplantation - the anaesthetist's view: A case report. Author: J Ozinsky. AB - Article on the first heart transplant, performed at Groote Schuur Hospital, Cape Town, on 3 December 1967. Reprinted from the SAMJ of 30 December 1967 to commemorate the 50th anniversary of the transplant. PMID- 29262951 TI - The operation: A human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. Author: C N Barnard. AB - Article on the first heart transplant, performed at Groote Schuur Hospital, Cape Town, on 3 December 1967. Reprinted from the SAMJ of 30 December 1967 to commemorate the 50th anniversary of the transplant. PMID- 29262952 TI - Acute high-altitude illness. AB - Letter by Basnyat on article by Hofmeyr et al. (Hofmeyr R, Tolken G, De Decker R. Acute high-altitude illness. S Afr J Med 2017;107(7):556-561. https://doi.org/10.7196/SAMJ.2017.v107i7.12612); and response by Hofmeyr et al. PMID- 29262953 TI - Development of the MB ChB curriculum map at the University of KwaZulu-Natal, South Africa. PMID- 29262954 TI - Human dignity and the future of the voluntary active euthanasia debate in South Africa. PMID- 29262955 TI - Lamivudine monotherapy in children and adolescents: The devil is in the detail. AB - Although expanded access to antiretroviral therapy (ART), and starting lifelong ART as soon as possible after diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother-to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential accumulation of resistance mutations, limited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF. PMID- 29262957 TI - Application opportunities of geographic information systems analysis to support achievement of the UNAIDS 90-90-90 targets in South Africa. AB - In an effort to achieve control of the HIV epidemic, 90-90-90 targets have been proposed whereby 90% of the HIV-infected population should know their status, 90% of those diagnosed should be receiving antiretroviral therapy, and 90% of those on treatment should be virologically suppressed. In this article we present approaches for using relatively simple geographic information systems (GIS) analyses of routinely available data to support HIV programme management towards achieving the 90-90-90 targets, with a focus on South Africa (SA) and other high prevalence settings in low- and middle-income countries. We present programme level GIS applications to map aggregated health data and individual-level applications to track distinct patients. We illustrate these applications using data from City of Johannesburg Region D, demonstrating that GIS has great potential to guide HIV programme operations and assist in achieving the 90-90-90 targets in SA. PMID- 29262956 TI - Prevalence and predictors of late presentation for HIV care in South Africa. AB - BACKGROUND: Many people living with HIV in South Africa (SA) are not aware of their seropositive status and are diagnosed late during the course of HIV infection. These individuals do not obtain the full benefit from available HIV care and treatment services. OBJECTIVES: To describe the prevalence of late presentation for HIV care among newly diagnosed HIV-positive individuals and evaluate sociodemographic variables associated with late presentation for HIV care in three high-burden districts of SA. METHODS: We used data abstracted from records of 8 138 newly diagnosed HIV-positive individuals in 35 clinics between 1 June 2014 and 31 March 2015 to determine the prevalence of late presentation among newly diagnosed HIV-positive individuals in selected high-prevalence health districts. Individuals were categorised as 'moderately late', 'very late' or 'extremely late' presenters based on specified criteria. Descriptive analysis was performed to measure the prevalence of late presentation, and multivariate regression analysis was conducted to identify variables independently associated with extremely late presentation. RESULTS: Overall, 79% of the newly diagnosed cases presented for HIV care late in the course of HIV infection (CD4+ count <=500 cells/uL and/or AIDS-defining illness in World Health Organization (WHO) stage III/IV), 19% presented moderately late (CD4+ count 351 - 500 cells/uL and WHO clinical stage I or II), 27% presented very late (CD4+ count 201 - 350 cells/uL or WHO clinical stage III), and 33% presented extremely late (CD4+ count <=200 cells/uL and/or WHO clinical stage IV) for HIV care. Multivariate regression analysis indicated that males, non-pregnant women, individuals aged >30 years, and those accessing care in facilities located in townships and inner cities were more likely to present late for HIV care. CONCLUSIONS: The majority of newly diagnosed HIV-positive individuals in the three high-burden districts (Gert Sibande, uThukela and City of Johannesburg) presented for HIV care late in the course of HIV infection. Interventions that encourage early presentation for HIV care should be prioritised in SA and should target males, non-pregnant women, individuals aged >30 years and those accessing care in facilities located in inner cities and urban townships. PMID- 29262958 TI - Disclosing details about the medical treatment of a deceased public figure in a book: Who should have consented to the disclosures in Mandela's Last Days? AB - A recently published book by the head of Nelson Mandela's medical team made personal disclosures about his treatment of the late president in his final years up until his death. The author claimed that he had written the book at the request of family members. This was contested by some family members and the executors of Mandela's estate, and the book was subsequently withdrawn by the publishers. The Mandela book case raises ethical and legal questions about who should consent to publication of medical information about public figures after their death. The ethical rules of conduct of the Health Professions Council of South Africa (HPCSA) state that confidential information about a deceased person should only be divulged 'with the written consent of his or her next of kin or the executor of his or her estate'. 'Next of kin' is not defined, however, and problems arise when family members and the executors are divided about giving such written consent. It is recommended that in such cases the specific order of priority for consent by relatives in the National Health Act be followed. However, conduct that is unethical under the rules of the HPCSA may not necessarily be actionable under the law. For instance, the law does not protect the confidentiality of deceased persons, and generally when people die their constitutional and common-law personality rights - including their right to privacy and confidentiality - die with them. This means that the next of kin or executors of the estates of deceased persons may not bring actions for damages on behalf of such persons for breaches of confidentiality arising after their deaths. The next of kin may, however, sue in their personal capacity if they can show that the disclosures were an unlawful invasion of their own privacy. Conversely, if the privacy of interests of the next of kin are not harmed where there has been publication without their consent, they will not be able to sue for damages. PMID- 29262959 TI - Berg adder (Bitis atropos): An unusual case of acute poisoning. AB - A 5-year-old boy presented to hospital with mild local cytotoxic and severe neurotoxic symptoms. The neurotoxic symptoms included ptosis, fixed dilated pupils and flaccid paralysis with respiratory failure. Mild hyponatraemia was also a clinical feature. After various unsuccessful treatment options were followed, the Tygerberg Poison Information Centre was contacted and a diagnosis of berg adder bite was made. Berg adder bites are uncommon and therefore not usually considered in the differential diagnosis of a patient presenting with an unexplained clinical picture. A timeous poison information helpline consultation is recommended in this situation. PMID- 29262960 TI - Impact of Xpert MTB/RIF rollout on management of tuberculosis in a South African community. AB - BACKGROUND: The Xpert MTB/RIF test shortens the time to microbiological confirmation of pulmonary tuberculosis (TB) under research conditions. OBJECTIVE: To evaluate the field impact of Xpert MTB/RIF rollout on TB diagnostic yield and time to treatment in a South African (SA) community. METHODS: We compared TB investigation outcomes for 6-month calendar periods before and after Xpert MTB/RIF rollout in a semi-rural area of SA. The proportion of adult patients who tested positive by sputum smear microscopy, liquid culture or Xpert MTB/RIF and the proportion of positive sputum smear, liquid culture or Xpert MTB/RIF tests were compared. Secondary outcomes included time to laboratory diagnosis and treatment initiation. Data were collected from the National Health Laboratory Service database and from the Western Cape Provincial Department of Health TB register. RESULTS: Regional rollout of Xpert MTB/RIF testing occurred in 2013. Of the 15 629 patients investigated in the post-rollout period, 7.9% tested positive on GeneXpert, compared with 6.4% of the 10 741 investigated in the pre-rollout period who tested positive by sputum smear microscopy (p<0.001). Median laboratory processing time was <1 day for Xpert MTB/RIF (interquartile range (IQR) 0 - 1) compared with 1 day (IQR 0 - 16) for sputum smear microscopy (p=0.001). The median time to TB treatment initiation was 4 days (IQR 2 - 8) after rollout compared with 5 days (IQR 2 - 14) before (p=0.001). CONCLUSIONS: Patients investigated for suspected pulmonary TB were more likely to be diagnosed after rollout of Xpert MTB/RIF testing, although the benefit to diagnostic yield was modest, and Xpert MTB/RIF testing was associated with a marginal improvement in time to treatment initiation. PMID- 29262961 TI - Defining the need for surgical intervention following a snakebite still relies heavily on clinical assessment: The experience in Pietermaritzburg, South Africa. AB - BACKGROUND: This audit of snakebites was undertaken to document our experience with snakebite in the western part of KwaZulu-Natal (KZN) Province, South Africa (SA). OBJECTIVE: To document our experience with snakebite in the western part of KZN, and to interrogate the data on patients who required some form of surgical intervention. METHODS: A retrospective study was undertaken at the Pietermaritzburg Metropolitan Trauma Service, Pietermaritzburg, SA. The Hybrid Electronic Medical Registry was reviewed for the 5-year period January 2012 - December 2016. All patients admitted to the service for management of snakebite were included. RESULTS: The offending snake is rarely identified, and the syndromic approach is now the mainstay of management. Most envenomations seen during the study period were cytotoxic, presenting with painful progressive swelling (PPS). We did not see any purely neurotoxic or haemotoxic envenomations. Antivenom is required for a subset of patients. The indications are essentially PPS that increases by >15 cm over an hour, PPS up to the elbow or knee after 4 hours, PPS of the whole limb after 8 hours, threatened airway, shortness of breath, associated clotting abnormalities and compartment syndrome. If no symptoms have manifested within 1 hour of a snakebite, clinically significant envenomation is unlikely to have occurred. Antivenom is associated with a high rate of anaphylaxis and should only be administered when absolutely indicated, preferably in a high-care setting under continuous monitoring. The need for surgery is less well defined. Urgent surgery is indicated for compartment syndrome of the limb, which is a potentially life- and limb-threatening condition. Its diagnosis is usually made clinically, but this is difficult in snakebites. Morbidity and cost increase dramatically once fasciotomy is required, as evidenced by much longer hospital stay. There is frequently a degree of cross over between cytotoxicity and haemotoxicity in envenomations that require fasciotomy, which means that fasciotomy may result in catastrophic bleeding and should be preceded by the administration of antivenom, especially in patients with a low platelet count or a high international normalised ratio. Physiological and biochemical markers are unhelpful in assessing the need for fasciotomy. Objective methods include measurement of compartment pressures and ultrasound. CONCLUSION: The syndromic management of snakebite is effective and safe. There is a high incidence of anaphylactic reactions to antivenom, and its administration must be closely supervised. In our area we overwhelmingly see cytotoxic snakebites with PPS. Surgery is often needed, and we need to refine our algorithms in terms of deciding on surgery. PMID- 29262962 TI - A comparison of private and public sector intensive care unit infrastructure in South Africa. AB - BACKGROUND: Intensive care units (ICUs) are designed to care for patients who are often at increased risk of acquiring healthcare-associated infections. The structure of ICUs should be optimally designed to facilitate the care of these critically ill patients, and minimise their risk of infection. National regulations (R158) were developed to govern the building and registration of private hospitals, and until recently equivalent regulations were not available for public hospitals. OBJECTIVE: To assess and compare the compliance of ICUs in the private and public sectors with the R158 regulations. METHODS: A cross sectional study design was used to assess the infrastructure of 25 private sector and 6 public sector ICUs in eThekwini Health District, KwaZulu-Natal Province, South Africa. We used the R158 checklist, which was developed by the KwaZulu Natal Department of Health Private Licensing Unit and Infection Prevention and Control Unit. The aspects covered in the R158 checklist were categorised into the design, general safety and patient services of the ICUs. RESULTS: Most of the ICUs in both sectors met the general safety requirements. There were varying levels of compliance with the design criteria. Only 7 (28.0%) and 1 (16.7%) of the private and public ICUs, respectively, had sufficient space around the beds. Twenty-two private ICUs (88.0%) and 4 public ICUs (66.7%) had isolation rooms, but only some of these isolation rooms (15 private and 2 public) had appropriate mechanical ventilation. None of the ICUs had clinical hand-wash basins in the nurse stations and dirty utility rooms. The majority of the ICUs had the required number of oxygen and electric outlets at the bedside. None of the public ICUs met the light intensity requirement over the bed area. CONCLUSIONS: Adequate spacing in ICUs is an issue in many cases. Interventions need to be put in place to ensure that ICUs meet the relevant design standards. There is an urgent need to revise the R158 regulations to reflect current best practices, particularly with regard to infection control. The same standards should be applied to ICUs in the private and public health sectors to maintain quality of care to patients. PMID- 29262963 TI - Mortality trends in the City of Cape Town between 2001 and 2013: Reducing inequities in health. AB - BACKGROUND: The City of Cape Town (CoCT), South Africa, has collected cause-of death data from death certificates for many years to monitor population health. In 2000, the CoCT and collaborators set up a local mortality surveillance system to provide timeous mortality data at subdistrict level. Initial analyses revealed large disparities in health across subdistricts and directed the implementation of public health interventions aimed at reducing these disparatities. OBJECTIVES: To describe the changes in mortality between 2001 and 2013 in health subdistricts in the CoCT. METHODS: Pooled mortality data for the periods 2001 - 2004 and 2010 2013, from a local mortality surveillance system in the CoCT, were analysed by age, gender, cause of death and health subdistrict. Age-specific mortality rates for each period were calculated and age-standardised using the world standard population, and then compared across subdistricts. RESULTS: All-cause mortality in the CoCT declined by 8% from 938 to 863 per 100 000 between 2001 - 2004 and 2010 - 2013. Mortality in males declined more than in females owing to a large reduction in male injury mortality, particularly firearm-related homicide. HIV/AIDS and tuberculosis (TB) mortality dropped by ~10% in both males and females, but there was a marked shift to older ages. Mortality in children aged <5 years dropped markedly, mostly owing to reductions in HIV/AIDS and TB mortality. Health inequities between subdistricts were reduced, with the highest burden subdistricts achieving the largest reductions in mortality. CONCLUSIONS: Local mortality surveillance provides important data for planning, implementing and evaluating targeted health interventions at small-area level. Trends in mortality over the past decade indicate some gains in health and equity, but highlight the need for multisectoral interventions to focus on HIV and TB and homicide and the emerging epidemic of non-communicable diseases. PMID- 29262964 TI - Geographical maldistribution of surgical resources in South Africa: A review of the number of hospitals, hospital beds and surgical beds. AB - BACKGROUND: The global burden of surgical disease has been studied to a limited extent. Despite the proven benefits of surgery, surgical services remain poorly resourced. Contributing to this global crisis is the critical lack of data regarding available resources. OBJECTIVE: To analyse the distribution of some resources necessary for the provision of surgical care. The distribution and number of surgical resources (number of surgical beds) relative to the general resources (number of hospitals and total number of beds) in South Africa were analysed. METHODS: All hospitals in the country, including those in the public and private sectors, were contacted, and the total number of hospitals, the level of care (district v. regional v. tertiary), the total number of hospital beds, and the number of surgical beds were determined. The data were analysed according to the provincial distribution and the public v. private sector distribution relative to the size of the population. RESULTS: A total of 544 hospitals were included in the study - 327 in the public sector and 217 in the private sector. The public sector hospitals included 257 district-, 49 regional- and 21 tertiary level hospitals. Nationally, there were 1 hospital, 187 hospital beds and 42 surgical beds per 100 000 population. Gauteng Province (GP), the Eastern Cape, KwaZulu-Natal (KZN) and the Western Cape had the most hospitals and GP had the largest number of private hospitals. GP and KZN had the largest total number of beds (n=29 181 and n=22 889, respectively) and number of surgical beds (n=7 289 and n=4 651, respectively). GP had the largest number of private surgical beds (n=4 837). There was a marked variation in the number of hospitals, total number of beds, and number of surgical beds among provinces. CONCLUSION: This study provided an estimation of the number of hospitals, total number of beds, and number of surgical beds, and showed a marked variation among provinces and between the public and private sectors. PMID- 29262965 TI - Acne in South African black adults: A retrospective study in the private sector. AB - BACKGROUND: Acne vulgaris is the most common skin disorder affecting teenagers and young adults, and is becoming increasingly common in middle-aged women. It affects all skin types and ethnic groups, but dark-skinned individuals are burdened by post-inflammatory hyperpigmentation (PIH) as a sequela. PIH causes distress in acne patients even after the inflammatory lesions have resolved. OBJECTIVE: To describe the characteristics of acne in black South African adults in the private health sector in Durban, KwaZulu-Natal Province. METHODS: A retrospective study of records of patients attending two large private dermatology clinics in central Durban, mainly catering for black patients, was performed. Data were collected for the period January - December 2014. Records with acne as a diagnosis were retrieved and analysed with regard to age, demographics, type and severity of acne, therapy, HIV status and outcomes. RESULTS: Of a total of ~3 000 charts available for the 12-month period, 242 had acne as a diagnosis and were retrieved and analysed. Of these patients, 204 (84.3%) were female and the remainder were male. The mean age was 28.5 years (under-18s were excluded from the study). Inflammatory acne was the most frequently encountered form (58.6%). Fifteen patients (6.2%) were on topical treatment only, and 226 (93.4%) were on topical plus systemic treatment. PIH was the most common sequela (81.0% of patients). CONCLUSIONS: The majority of the patients were young females with inflammatory acne, and PIH was the most common sequela. Early and vigorous treatment of acne may minimise its complications, including those seen mainly in black patients. PMID- 29262966 TI - Multimorbidity in a large district hospital: A descriptive cross-sectional study. AB - BACKGROUND: There is substantial research documenting the burden of disease globally and in the South African (SA) primary care context. Few studies address the disease profile and its implications in the SA hospital setting. OBJECTIVES: To describe the disease profile in the internal medicine department of a large district hospital, using variables related to comorbidity and patient length of stay. The study included specific exploration into the HIV/tuberculosis (TB) syndemic, the acuity of HIV disease, and lifestyle risk factors. METHODS: The sample population consisted of all consecutive admissions to the internal medicine department of a large district hospital in the Cape metropole during May 2015. A retrospective folder review and subsequent data analysis were completed. RESULTS: Hypertension, HIV, type 2 diabetes mellitus, TB and cardiac failure were the five most prevalent diseases. Extensive multimorbidity was observed, with 86.0% of patients suffering from two or more diseases concurrently. The average number of comorbidities per patient was 3.4, although no clear relationship between the number of comorbidities and length of stay was found. Of the various diseases, only TB and HIV were associated with above-average length of stay, particularly among co-infected patients and those who had defaulted from or never received antiretroviral (ARV) treatment. Compared with patients currently receiving ARVs, much higher proportions of patients who had defaulted from or never received ARV treatment had CD4+ counts <200 cells/uL. Of the lifestyle risk factors investigated, a history of excessive alcohol use and/or drug use was associated with an increased length of stay. Most patients were discharged home, with 15.7% being referred to other institutions. CONCLUSIONS: Chronic conditions, particularly HIV, TB and non-communicable diseases, represented much of the disease profile in the internal medicine department. Of the comorbidities investigated, the greatest contributor to length of stay was HIV/TB co-infection. Factors such as HIV, TB and substance use that increase length of stay cannot be impacted upon by the district hospital staff in isolation. To improve the health of communities, we require partnerships between doctors, community health providers and patients with their families. Multimorbidity was widespread, suggesting the need to include an understanding of multimorbidity, including the patient perspective, in medical education and health system reform. PMID- 29262967 TI - Hepatitis C: A South African literature review and results from a burden of disease study among a cohort of drug-using men who have sex with men in Cape Town, South Africa. AB - BACKGROUND: Hepatitis C virus (HCV) is a chronic infection of increasing importance, especially among people living with HIV/AIDS. Co-infection with HIV can accelerate progression of HCV liver disease to cirrhosis and end-stage liver failure and elevate the risk of hepatocellular carcinoma. Globally, men who have sex with men (MSM) and people who inject drugs are at increased risk of HCV infection compared with the general population. Few studies on HCV in these key populations have been done in South Africa (SA). OBJECTIVE: To describe the disease burden of HCV in drug-using MSM who attend harm-reduction services at the Anova Health Institute's Health4Men clinic in Cape Town, SA. METHODS: In 2012 - 2014, attendees of an MSM-focused harm-reduction programme were invited to participate in our study. After informed consent, participants completed a brief demographic questionnaire and underwent phlebotomy for anti-HCV antibody, hepatitis B virus (HBV) surface antigen and surface antibody testing. Participants received counselling and education with regard to their results. HIV status was extracted from the case notes of participants who had previously been tested at the study site. Data were analysed using standard statistical techniques. RESULTS: Forty-one MSM were enrolled - 11 (27.0%) tested anti-HCV antibody-positive, indicating prior exposure to HCV or chronic infection; 10/11 (91.0%) were positive for HBV surface antibodies, suggesting previous HBV exposure or vaccination; and 1 (2.0%) screened positive for HBV. Of the HCV seropositive individuals, HIV status was known in 8/11; 3/8 (37.5%) were HIV positive. CONCLUSION: We demonstrated a high burden of HCV exposure or infection among a small urban cohort of MSM who inject drugs. We recommend active screening of MSM (especially those who report drug use) for HCV, and the development of referral networks for access to treatment. PMID- 29262968 TI - Auditing stillbirths at Lower Umfolozi War Memorial Regional Hospital: A 12-month review. AB - BACKGROUND: Although the total number of stillbirths worldwide was estimated at 2.6 million in 2009, there is currently a dearth of literature on stillbirths in developing countries and rural settings, where the majority of such births occur. The 'Hands Up' Mortality and Morbidity Extraction Tool (HUMMET), developed at Lower Umfolozi War Memorial Regional Hospital (LUWMRH) in 2010, outlines a systematic approach to summarising individual cases of adverse perinatal outcomes. OBJECTIVES: To depict the HUMMET form by describing the detailed demographic and obstetric profile of patients who delivered a stillborn infant at LUWMRH, as well as risk factors associated with these stillbirths between 1 April 2014 and 31 March 2015. The findings add to a global initiative advanced by the Lancet series on stillbirths, aimed at raising awareness of stillbirth statistics in low- and middle-income countries. METHODS: A total of 310 detailed stillbirth case summaries of 305 patients were collected during the study period, representing 90% of the total number of stillborn infants delivered at LUWMRH. A retrospective audit of the HUMMET forms was conducted and the cases were further summarised in a Microsoft Excel spreadsheet that allowed for a univariate analysis of the variables. RESULTS: The stillbirth rate at LUWMRH is much higher than that at other regional hospitals owing to the number of at-risk referrals and emergency cases from surrounding clinics and district hospitals. Referrals were from local clinics (49%) and district hospitals (45%), 35% of stillbirths were due to abruptio placentae and a large proportion were associated with gestational hypertension, pre-eclampsia and/or eclampsia. Avoidable factors were predominantly a late patient response to reduced fetal movements and delays in transfer to hospital. Twenty percent of stillbirths were associated with inappropriate monitoring or management of the obstetric condition at the district hospital. CONCLUSION: The HUMMET form provides a systematic approach to analysing cases of perinatal morbidity and mortality in line with the requirements of the Perinatal Problem Identification Programme database, but provides more details on the circumstances and contributing factors. A repeat audit is recommended to determine whether interventions have been effective. PMID- 29262969 TI - Obstetric spinal hypotension: Preoperative risk factors and the development of a preliminary risk score - the PRAM score. AB - BACKGROUND: Obstetric spinal hypotension is a common and important problem during caesarean delivery. Identifying patients at risk for hypotension may guide clinical decision-making and allow timeous referral. OBJECTIVE: Using preoperative risk factors, to develop a simple scoring system to predict systolic hypotension. METHODS: This prospective, single-centre, observational study of patients undergoing elective or urgent caesarean delivery assessed body mass index, baseline heart rate, baseline mean arterial pressure (MAP), maternal age, urgency of surgery (elective v. non-elective) and preoperative haemoglobin concentration as predictors of spinal hypotension (systolic blood pressure <90 mmHg). We used empirical cut-point estimations in a logistic regression model to develop a scoring system for prediction of hypotension. RESULTS: From 504 eligible patients, preoperative heart rate (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.00 - 1.03; p=0.012), preoperative MAP (OR 0.97, 95% CI 0.95 - 0.98; p<0.001) and maternal age (OR 1.05, 95% CI 1.02 - 1.08; p=0.002) were found to be predictors of hypotension. We derived a preliminary scoring system (pulse rate >90 bpm, age >25 years, MAP <90 mmHg - the PRAM score) for the prediction of systolic hypotension following obstetric spinal anaesthesia. Patients with three factors had a 53% chance of developing hypotension, compared with the overall incidence of 30%. The PRAM score showed good discrimination, with a c-statistic of 0.626 (95% CI 0.576 - 0.676) and good calibration. CONCLUSIONS: Preoperative heart rate, preoperative MAP and maternal age were predictive of hypotension in elective and emergency caesarean delivery. The PRAM score shows promise as a simple, practical means to identify these patients preoperatively, but requires prospective validation. PMID- 29262970 TI - Gendered risk factors associated with self-harm mortality among youth in South Africa, 2006 - 2014. AB - BACKGROUND: Despite efforts to reduce self-harm mortality, death rates remain high, with almost 12% of all youth deaths in South Africa (SA) attributed to this cause. There are gendered differences in causes of death among youth, but little is known about the sex-specific risk factors. OBJECTIVE: To identify the levels and sex-specific determinants of self-harm mortality among youth in SA. METHODS: This was a cross-sectional study of SA death notification forms from 2006 to 2014. Descriptive and analytical statistical techniques were used, including cause-specific mortality rates, proportional mortality ratios and logistic regression models. RESULTS: A total of 1 122 youth (15 - 24 years of age) deaths due to self-harm causes were reported over the study period, during which rates of self-harm mortality increased. More deaths of males (n=818) than females (n=304) were reported. Almost 60% of deaths (p<0.05) were of 20 - 24-year-olds, and 46.4% (p<0.05) of those who died had a secondary education. Almost 10% of females (p<0.05) were pregnant at the time of death. Hanging was the most common type of self-harm mortality among males (79.2%) and females (49.3%). While 11.0% (n=90) of self-harm deaths of males were due to poisoning, more females used this method (39.8%, n=121). The probability of self-harm mortality for males increased according to certain provinces of residence. For females the odds were higher for those who were pregnant (odds ratio (OR) 1.3; p<0.05) and non-South African (OR 1.7; p<0.05) and had secondary education (OR 1.4; p<0.05). CONCLUSIONS: The study showed gender differentials in the determinants of self-harm mortality among youth in SA. For this reason, uniform approaches to awareness campaigns need to be altered to address the specific needs of youth. While males have higher rates than females, the prevalence of self-harm mortality in pregnant females is of concern and needs to be addressed specifically, as it relates not only to suicidal ideation and behaviour but also to youth sexual and reproductive health programmes in the country. PMID- 29262971 TI - Nutritional supplements for people being treated for active tuberculosis: A technical summary. AB - Tuberculosis and nutrition are intrinsically linked in a complex relationship. Altered metabolism and loss of appetite associated with tuberculosis may result in undernutrition, which in turn may worsen the disease or delay recovery. We highlight an updated Cochrane review assessing the effects of oral nutritional supplements in people with active tuberculosis who are receiving antituberculosis drug therapy. The review authors conducted a comprehensive search (February 2016) for all randomised controlled trials comparing any oral nutritional supplement, given for at least 4 weeks, with no nutritional intervention, placebo or dietary advice only in people receiving antituberculosis treatment. Of the 35 trials (N=8 283 participants) included, seven assessed the provision of free food or high energy supplements, six assessed multi-micronutrient supplementation, and 21 assessed single- or dual-micronutrient supplementation. There is currently insufficient evidence to indicate whether routinely providing free food or high energy supplements improves antituberculosis treatment outcomes (i.e. reduced death and increased cure rates at 6 and 12 months), but it probably improves weight gain in some settings. Plasma levels of zinc, vitamin D, vitamin E and selenium probably improve with supplementation, but currently no reliable evidence demonstrates that routine supplementation with multi-, single or dual micronutrients above the recommended daily intake has clinical benefits (i.e. reduced death, increased cure rate at 6 and 12 months, improved nutritional status) in patients receiving antituberculosis treatment. In South Africa, most provinces implement a supplementation protocol based on nutritional assessment and classification of individuals rather than on disease diagnosis or treatment status. PMID- 29262972 TI - 'Covering doctors' standing in for unavailable colleagues: What is the legal position? AB - Covering doctors are those who stand in for colleagues when the latter are unable to deal with their patients. Covering doctors who begin to issue telephonic instructions to nurses or other healthcare practitioners regarding the treatment of the patients they are covering are in the same position as any other doctors treating patients. They cannot argue that the patients they are covering only become their patients once an emergency or crisis occurs or when they see the patients for the first time, and that prior to that their function is merely to monitor the patient's progress. They also cannot rely on telephone instructions for long periods of time when the patient's health may be in danger, without seeing the patient. However, if covering doctors are found to be negligent they can still escape liability if the plaintiff cannot prove a causal link between their negligence and the harm that resulted 'beyond a reasonable doubt'. PMID- 29262973 TI - A cool ECG. AB - The electrocardiographic changes of hypothermia are discussed in this case of a man who was brought to an emergency centre with altered mental status. The main ECG signs are a shivering artefact baseline, J waves, and PR-, QRS- and QT interval prolongation. PMID- 29262974 TI - South African clinical practice guidelines: A landscape analysis. AB - BACKGROUND: South Africa (SA) is in the process of implementing National Health Insurance (NHI), which will require co-ordination of health provision across sectors and levels of care. Clinical practice guidelines (CPGs) are tools for standardising and implementing care, and are intended to influence clinical decision-making with consequences for patient outcomes, health system costs and resource use. Under NHI, CPGs will be used to guide the provision of healthcare for South Africans. It is therefore important to explore the current landscape of CPG developers and development. OBJECTIVE: To identify and describe all CPGs available in the public domain produced by SA developers for the SA context. METHODS: We conducted a cross-sectional evaluation using a two-part search process: an iterative, electronic search of grey literature and relevant websites (161 websites searched), and a systematic search for peer-reviewed literature (PubMed) after publication year 2000. CPGs were identified, and data were extracted and categorised by two independent reviewers. Any discrepancies were referred to a third reviewer. Data extracted included a description of the developer, condition, and reporting of items associated with CPG quality. RESULTS: A search conducted in May 2017 identified 285 CPGs published after January 2000. Of those, 171 had been developed in the past 5 years. Developers included the national and provincial departments of health (DoH), professional societies and associations, ad hoc collaborations of clinicians, and the Council for Medical Schemes. Topics varied by developer; DoH CPGs focused on high-burden conditions (HIV/AIDS, tuberculosis and malaria), and other developers focused on non-communicable diseases. A conflict of interest statement was included in 23% of CPGs developed by societies or clinicians, compared with 4% of DoH CPGs. CONCLUSION: Accessing CPGs was challenging and required extensive searching. SA has many contributors to CPG development from the public and private sectors and across disciplines, but there is no formal co-ordination or prioritisation of topics for CPG development. Different versions of the CPGs were identified and key quality items were poorly reported, potentially affecting the usability and credibility of those available. There was substantial variation in CPG comprehensiveness and methodological approach. Establishing a national CPG co ordinating unit responsible for developing standards for CPG development along with clinical quality standards, and supporting high-quality CPG development, is one essential step for moving forward with NHI. PMID- 29262975 TI - Opportunities to optimise colistin stewardship in hospitalised patients in South Africa: Results of a multisite utilisation audit. AB - BACKGROUND: Colistin is an old antibiotic that has been reintroduced as salvage therapy in hospitalised patients because it is frequently the only agent active against Gram-negative bacteria. Various guidelines for colistin administration have led to confusion in establishing the appropriate dose, which has potential for adverse consequences including treatment failure or toxicity. The emergence and spread of colistin resistance has been documented in South Africa (SA), but no local information exists on how and why colistin is used in hospitals, and similarly, compliance with current dosing guidelines is unknown. OBJECTIVES: To evaluate the current utilisation of colistin in SA hospitals, in order to identify stewardship opportunities that could enhance the appropriate use of this antibiotic. METHODS: Electronic patient records of adult patients on intravenous (IV) colistin therapy for >72 hours in four private hospitals were retrospectively audited over a 10-month period (1 September 2015 - 30 June 2016). The following data were recorded: patient demographics, culture and susceptibility profiles, diagnosis, and indication for use. Compliance with six colistin process measures was audited: obtaining a culture prior to initiation, administration of a loading dose, administration of the correct loading dose, adjustments to maintenance dose according to renal function, whether colistin was administered in combination with another antibiotic, and whether de-escalation following culture and sensitivity results occurred. Outcome measures included effects on renal function, overall hospital mortality, intensive care unit length of stay (LoS), and hospital LoS. RESULTS: Records of 199 patients on IV colistin were reviewed. There was 99.0% compliance with obtaining a culture prior to antibiotic therapy, 93.5% compliance with prescription of a loading dose, and 98.5% compliance regarding prescription of colistin in combination with another agent. However, overall composite compliance with the six colistin stewardship process measures was 82.0%. Non-compliance related to inappropriate loading and maintenance doses, lack of adjustment according to renal function and lack of de escalation following culture sensitivity was evident. Significantly shorter durations of treatment were noted in patients who received higher loading doses (p=0.040) and in those who received maintenance doses of 4.5 MU twice daily v. 3 MU three times daily (p=0.0027). In addition, compared with patients who survived, more patients who died received the 3 MU three times daily maintenance dose (p=0.0037; phi coefficient 0.26). CONCLUSIONS: The study identified multiple stewardship opportunities to optimise colistin therapy in hospitalised patients. Urgent implementation of a stewardship bundle to improve colistin utilisation is warranted. PMID- 29262976 TI - Self-reported alcohol use and binge drinking in South Africa: Evidence from the National Income Dynamics Study, 2014 - 2015. AB - BACKGROUND: Although the South African (SA) government has implemented alcohol control measures, alcohol consumption remains high. OBJECTIVES: To quantify the prevalence of self-reported current drinking and binge drinking in SA, and to determine important covariates. METHODS: We used the 2014 - 2015 National Income Dynamics Study, a nationally representative dataset of just over 20 000 individuals aged >=15 years. Multiple regression logit analyses were performed separately by gender for self-reported current drinkers (any amount), self reported bingers as a proportion of drinkers, and self-reported bingers as a proportion of the total population. An individual was defined as a binge drinker if he/she reported consumption of >=5 standard drinks on an average drinking day. RESULTS: Current alcohol use (any amount) in 2014 - 2015 was reported by 33.1% of the population (47.7% males, 20.2% females). Of drinkers, 43.0% reported binge drinking (48.2% males, 32.4% females). The prevalence of self-reported binge drinking as a percentage of the total population was 14.1% (22.8% males, 6.4% females). Although black African males and females were less likely than white males and females to report drinking any amount, they were more likely to report binge drinking. Coloured (mixed race) females were more likely than black African females to report drinking any amount. Males and females who professed a religious affiliation were less likely than those who did not to report drinking any alcohol. The prevalence of self-reported binge drinking was highest among males and females aged 25 - 34 years. Smoking cigarettes substantially increased the likelihood of drinking any amount and of binge drinking for both genders. CONCLUSION: In SA, one in three individuals reported drinking alcohol, while one in seven reported binge drinking on an average day on which alcohol was consumed. Strong, evidence-based policies are needed to reduce the detrimental effects of alcohol use. PMID- 29262977 TI - Prevalence of tobacco use in selected Johannesburg suburbs. AB - BACKGROUND: Tobacco smoking is estimated to kill more than 44 000 South Africans every year. Studies have shown that since the introduction of tobacco control measures, national smoking prevalence has declined in South Africa (SA). OBJECTIVE: To determine the prevalence of tobacco smoking over a 7-year period in five impoverished neighbourhoods in Johannesburg, SA. METHODS: Data were collected through the annual administration of a prestructured questionnaire to one adult respondent in preselected dwellings from 2006 to 2012. Information was collected on socioeconomic status, smoking practices and health status. RESULTS: Over the 7-year period of the analysis, smoking levels remained unchanged. The proportion of households with one or more smokers varied significantly across the five study neighbourhoods. Approximately 20% of households in Hillbrow and as many as 77% in Riverlea had a member who smoked. CONCLUSIONS: Despite a national downward trend in smoking levels, tobacco use remains high and persistent in certain vulnerable communities, requiring scaled-up action to reduce the risk of a range of tobacco-related diseases. PMID- 29262978 TI - Predictors of treatment success in smoking cessation with varenicline combined with nicotine replacement therapy v. varenicline alone. AB - BACKGROUND: Identification of the predictors of treatment success in smoking cessation may help healthcare workers to improve the effectiveness of attempts at quitting. OBJECTIVE: To identify the predictors of success in a randomised controlled trial comparing varenicline alone or in combination with nicotine replacement therapy (NRT). METHODS: A post-hoc analysis of the data of 435 subjects who participated in a 24-week, multicentre trial in South Africa was performed. Logistic regression was used to analyse the effect of age, sex, age at smoking initiation, daily cigarette consumption, nicotine dependence, and reinforcement assessment on abstinence rates at 12 and 24 weeks. Point prevalence and continuous abstinence rates were self-reported and confirmed biochemically with exhaled carbon monoxide readings. RESULTS: The significant predictors of continuous abstinence at 12 and 24 weeks on multivariate analysis were lower daily cigarette consumption (odds ratio (OR) 1.86, 95% confidence interval (CI) 1.21 - 2.87, p=0.005 and OR 1.83, 95% CI 1.12 - 2.98, p=0.02, respectively) and older age (OR 1.52, 95% CI 1.00 - 2.31, p=0.049 and OR 1.79, 95% CI 1.13 - 2.84, p=0.01, respectively). There was no difference in the predictors of success in the univariate analysis, except that older age predicted point prevalence abstinence at 12 weeks (OR 1.47, 95% CI 1.00 - 2.15, p=0.049). The findings were inconclusive for an association between abstinence and lower nicotine dependence, older age at smoking initiation and positive reinforcement. CONCLUSION: Older age and lower daily cigarette consumption are associated with a higher likelihood of abstinence in patients using varenicline, regardless of the addition of NRT. PMID- 29262979 TI - Good correlation between the Afinion AS100 analyser and the ABX Pentra 400 analyser for the measurement of glycosylated haemoglobin and lipid levels in older adults in Durban, South Africa. AB - BACKGROUND: The Afinion AS100 analyser is a small bench-top, multi-assay, point of-care (POC) analyser that is able to measure glycated haemoglobin (HbA1c) and lipid levels. OBJECTIVE: To assess performance of the Afinion analyser compared with a reference laboratory test for the measurement of HbA1c and lipid levels. METHOD: The study involved men and women enrolled in a cross-sectional study, Sexual health, HIV infection and comorbidity with non-communicable diseases among Older Persons (SHIOP), which was conducted from February to May 2016. Whole blood was drawn aseptically by a trained study nurse into a serum separator gel tube and an ethylenediaminetetra-acetic acid (EDTA) tube. The EDTA whole blood was used to measure HbA1c levels, and serum to measure total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C) and triglyceride levels. Lin's correlation coefficient was used to assess the agreement between the Afinion and ABX Pentra 400 analysers for each marker. RESULTS: A total of 435 older individuals were included in the study. The proportion of HbA1c results that were correctly classified by the Afinion analyser was 92.2%. Bland-Altman analysis and linear regression analysis showed a very good agreement (correlation concordance 0.89) between the two analysers for the measurement of HbA1c. The two-way scatter plot for TC showed a substantial correlation (0.80). However, a total of 69 cholesterol results that were within the normal range on the Pentra were misclassified as abnormal on the Afinion. The readings obtained for HDL-C levels with the Afinion were shown to be slightly overestimated when compared with the Pentra. However, correlation for HDL-C on the two analysers was 0.93, indicating an almost perfect agreement. Seventy-four LDL-C results were erroneously classified as abnormal on the Afinion but were within the normal range on the Pentra, resulting in a substantial correlation of 0.75. An excellent agreement was observed between triglyceride measurements (0.99). CONCLUSION: This study supports the use of the Afinion AS100 analyser in POC testing for the measurement of HbA1c, triglycerides and HDL-C in a South African setting. PMID- 29262980 TI - Anaemia, renal dysfunction and in-hospital outcomes in patients with heart failure in Botswana. AB - BACKGROUND: Anaemia and renal dysfunction are associated with an increased morbidity and mortality in heart failure (HF) patients. OBJECTIVE: To estimate the frequency and impact of anaemia and renal dysfunction on in-hospital outcomes in patients with HF. METHODS: A total of 193 consecutive patients with HF admitted to Princess Marina Hospital, Gaborone, Botswana, from February 2014 to February 2015, were studied. Anaemia was defined as haemoglobin <13 g/dL for men and <12 g/dL for women. Renal dysfunction was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, calculated by the simplified Modification of Diet in Renal Disease formula. The in-hospital outcomes included length of hospital stay and mortality. RESULTS: The mean (standard deviation (SD)) age was 54.2 (17.1) years and 53.9% of the patients were men. The overall median eGFR was 75.9 mL/min/1.73 m2 and renal dysfunction was detected in 60 (31.1%) patients. Renal dysfunction was associated with hypertension (p=0.01), diabetes mellitus (p=0.01) and a lower haemoglobin level (p=0.008). The mean (SD) haemoglobin was 12.0 (3.0) g/dL and 54.9% of the patients were anaemic. Microcytic, normocytic and macrocytic anaemia were found in 32.1%, 57.5% and 10.4% of patients, respectively. The mean (SD) haemoglobin level for males was significantly higher than for females (12.4 (3.3) g/dL v. 11.5 (2.5) g/dL; p=0.038). Anaemia was more common in patients with diabetes (p=0.028) and in those with increased left ventricular ejection fraction (p=0.005). Neither renal dysfunction nor anaemia was significantly associated with the length of hospital stay or in-hospital mortality. CONCLUSION: Anaemia and renal dysfunction are prevalent in HF patients, but neither was an independent predictor of length of stay or in-hospital mortality in this population. These findings indicate that HF data in developed countries may not apply to countries in sub-Saharan Africa, and call for more studies to be done in this region. PMID- 29262981 TI - Keeping our heads above water: A systematic review of fatal drowning in South Africa. AB - BACKGROUND: Drowning is defined as the process of experiencing respiratory impairment from submersion/immersion in liquid, and can have one of three outcomes - no morbidity, morbidity or mortality. The World Health Organization African region accounts for approximately 20% of global drowning, with a drowning mortality rate of 13.1 per 100 000 population. The strategic implementation of intervention programmes driven by evidence-based decisions is of prime importance in resource-limited settings such as South Africa (SA). OBJECTIVE: To review the available epidemiological data on fatal drowning in SA in order to identify gaps in the current knowledge base and priority intervention areas. METHODS: A systematic review of published literature was conducted to review the available epidemiological data describing fatal drowning in SA. In addition, an internet search for grey literature, including technical reports, describing SA fatal drowning epidemiology was conducted. RESULTS: A total of 13 published research articles and 27 reports obtained through a grey literature search met the inclusion and exclusion criteria. These 40 articles and reports covered data collection periods between 1995 and 2016, and were largely focused on urban settings. The fatal drowning burden in SA is stable at approximately 3.0 per 100 000 population, but is increasing as a proportion of all non-natural deaths. Drowning mortality rates are high in children aged <15 years, particularly in those aged <5. CONCLUSIONS: This review suggests that SA drowning prevention initiatives are currently confined to the early stages of an effective injury prevention strategy. The distribution of mortality across age groups and drowning location differs substantially between urban centres and provinces. There is therefore a need for detailed drowning surveillance to monitor national trends and identify risk factors in all SA communities. PMID- 29262982 TI - Treatment outcomes and tolerability of the revised WHO anti-tuberculosis drug dosages for children. AB - BACKGROUND: In 2010, the World Health Organization (WHO) revised the paediatric dosages of anti-tuberculosis drugs, increasing rifampicin to 15 mg/kg, isoniazid to 10 mg/kg and pyrazinamide to 35 mg/kg. We assessed treatment outcomes, safety and adherence among children treated with the new recommended dosages. METHODS: Prospective cohort of children started on anti-tuberculosis treatment in Uganda with 12 months of follow-up, including alanine aminotransferase (ALT) monitoring. Treatment intake was observed. RESULTS: Of 144 treated children, 81 were male (56.3%), 106 (73.6%) were aged <5 years, 30 (22%) had moderate to severe malnutrition and 48 (33.3%) had human immunodeficiency virus infection. Treatment outcomes were as follows: 117 (81.3%) successes, 3 (2.1%) failures, 4 (2.8%) lost to follow-up, 19 (13.2%) deaths and 1 (0.7%) transferred out. There was no relapse. Severe malnutrition (adjusted hazard ratio 8.76, 95% confidence interval [CI] 1.59-48.25) was the only predictor of death. Two serious adverse events were attributed to treatment: one case of increased ALT and one with peripheral neuropathy. Median ALT values at baseline and at weeks 2, 4 and 8 were respectively 24 (interquartile range [IQR] 16-39), 26 (IQR 18-38), 28 (IQR 21-40) and 27 (IQR 19-38) international units/l. Treatment adherence was above 85% on all visits. CONCLUSION: We confirm the good tolerability of and adherence to the new treatment recommendations. The increased risk of fatal outcome among severely malnourished children requires attention. PMID- 29262983 TI - Maternal gestational weight gain during pregnancy: prioritising the conversation. AB - Pregnancy is a critical stage of life requiring urgent attention when taking a lifespan approach to obesity prevention. Excessive gestational weight gain (GWG) is highly predictive of overweight and obesity later in life for women and their offspring. This discussion describes the challenges faced by health professionals (general practitioners, midwives, allied health) in primary care in Australia when addressing GWG, presents evidence that supports re-prioritising GWG and highlights strategies that can be used to address GWG. The revised National Health and Medical Research Council antenatal care guidelines (to be formally released in early 2018) indicate it will be the responsibility of health professionals in antenatal care to initiate conversations about GWG with women. Women are open to discussing this sensitive topic and health professionals in primary care have an opportunity to be proactive in addressing barriers that have hindered conversations about GWG in the past so that women are supported to manage their weight during pregnancy. PMID- 29262984 TI - Outpatient consultant physician service usage in Australia by specialty and state and territory. AB - Objectives To determine national service usage for initial and subsequent outpatient consultations with a consultant physician and any variation in service use patterns between states and territories relative to population.Methods An analysis was conducted of consultant physician Medicare claims data from the year 2014 for an initial (item 110) and subsequent consultation (item 116) and, for patients with multiple morbidities, initial management planning (item 132) and review (133). The analysis included 12 medical specialties representative of common adult non-surgical medical care (cardiology, endocrinology, gastroenterology, general medicine, geriatric medicine, haematology, immunology and allergy, medical oncology, nephrology, neurology, respiratory medicine and rheumatology). Main outcome measures were per-capita service use by medical speciality and by state and territory and ratio of subsequent consultations to initial consultations by medical speciality and by state and territory.Results There was marked variation in per-capita consultant physician service use across the states and territories, tending higher than average in New South Wales and Victoria, and lower than average in the Northern Territory. There was variation between and within specialties across states and territories in the ratio of subsequent consultations to initial consultations.Conclusion Significant per capita variation in consultant physician utilisation is occurring across Australia. Future studies should explore the variation in greater detail to discern whether workforce issues, access or economic barriers to care, or the possibility of over- or under-servicing in certain geographic areas is leading to this variation.What is known about the topic? There are nearly 11million initial and subsequent consultant physician consultations billed to Medicare per year, incurring nearly A$850million in Medicare benefits. Little attention has been paid to per-capita variation in rates of consultant physician service use across states and territories.What does this paper add? There is marked variation in per capita consultant physician service use across different states and territories both within and between specialties.What are the implications for practitioners? Variation in service use may be due to limitations in the healthcare workforce, access or economic barriers, or systematic over- or under-servicing. The clinical appropriateness of repeated follow-up consultations is unclear. PMID- 29262985 TI - Age differences in attitudes toward safer sex practices in heterosexual men using an Australian Internet dating service. AB - : Background This cross-sectional study investigated sexually transmissible infection (STI) knowledge, safer sex attitudes and behaviours of sexually active, heterosexual men using an Internet dating service, and explored factors associated with protective attitudes. METHODS: An anonymous online survey was sent to men who had logged onto an Internet dating service within the previous year. Factors associated with discussing STIs before sex and condom use intention with a new partner were analysed. RESULTS: In total, 2339 responses were analysed. Men had lower STI knowledge scores, lower use of condoms and greater beliefs that condoms reduced interest in sex as age increased. Younger men (aged 18-29 years) were more likely to report intentions of only having sex with a new partner if a condom was used compared with older men aged over 60 years. Predictors of having a discussion about STIs with a new partner were older age, better knowledge of STIs, greater distress at a potential diagnosis of an STI and stronger future condom use intention. Intention to only have sex with a new female partner if a condom was used was associated with higher STI knowledge, discussing STIs with a new partner and distress at a diagnosis of an STI. Men with a higher number of sexual partners in the last year were less likely to have an STI discussion with new partners or intend to use a condom with a new partner. CONCLUSIONS: Older Internet-dating, heterosexual men are vulnerable to STIs. Health promotion interventions to increase STI awareness, condom use and STI testing in older men are warranted. PMID- 29262986 TI - Thyroid replacement therapy might undermine hypothyroidism-related longevity. PMID- 29262987 TI - Discovery of orally efficacious RORgammat inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds. AB - A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORgammat) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4 (trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORgammat in a mouse PD (pharmacodynamic) model upon oral administration. PMID- 29262988 TI - Evaluation of the molecular Xpert Xpress Flu/RSV assay vs. Alere i Influenza A & B assay for rapid detection of influenza viruses. AB - A new FDA-approved Xpert Xpress Flu/RSV assay has been released for rapid influenza virus detection. We collected 134 nasopharyngeal specimens to compare the diagnostic performance of the Xpert assay and the Alere i Influenza A & B assay for influenza A and B virus detection. The Xpert assay demonstrated 100% and 96.3% sensitivity to influenza A and influenza B virus respectively. Its specificity was 100% for both viruses. The Alere i assay demonstrated slightly lower sensitivity but similar specificity to the Xpert Xpress assay. Although the Xpert assay (30 min) required longer processing time than the Alere assay (15 min), the handling procedure of the Alere assay was more complicated than the Xpert assay. As the GenXpert system has higher throughput than the Alere system, it is more suitable for hospital clinical laboratories. Overall, the new Xpert Xpress Flu/RSV assay is a reliable and useful tool for rapid influenza detection. PMID- 29262990 TI - A neuroethics round up. PMID- 29262991 TI - Advances in multiple sclerosis: from reduced relapses to remedies. PMID- 29262989 TI - Epileptic Seizure Prediction Using Big Data and Deep Learning: Toward a Mobile System. AB - BACKGROUND: Seizure prediction can increase independence and allow preventative treatment for patients with epilepsy. We present a proof-of-concept for a seizure prediction system that is accurate, fully automated, patient-specific, and tunable to an individual's needs. METHODS: Intracranial electroencephalography (iEEG) data of ten patients obtained from a seizure advisory system were analyzed as part of a pseudoprospective seizure prediction study. First, a deep learning classifier was trained to distinguish between preictal and interictal signals. Second, classifier performance was tested on held-out iEEG data from all patients and benchmarked against the performance of a random predictor. Third, the prediction system was tuned so sensitivity or time in warning could be prioritized by the patient. Finally, a demonstration of the feasibility of deployment of the prediction system onto an ultra-low power neuromorphic chip for autonomous operation on a wearable device is provided. RESULTS: The prediction system achieved mean sensitivity of 69% and mean time in warning of 27%, significantly surpassing an equivalent random predictor for all patients by 42%. CONCLUSION: This study demonstrates that deep learning in combination with neuromorphic hardware can provide the basis for a wearable, real-time, always-on, patient-specific seizure warning system with low power consumption and reliable long-term performance. PMID- 29262992 TI - Neuromuscular disorders: 2017, a year to remember. PMID- 29262993 TI - Traumatic brain injury in 2017: exploring the secrets of concussion. PMID- 29262994 TI - Pain medicine gets personal. PMID- 29262995 TI - Health implications of sleep and circadian rhythm research in 2017. PMID- 29262996 TI - Research advances in neurological infections in 2017. PMID- 29262997 TI - Stroke research in 2017: surgical progress and stem-cell advances. PMID- 29262998 TI - HERMES: a helpful messenger in the anaesthesia for thrombectomy debate? PMID- 29262999 TI - The genetic architecture of dementia with Lewy bodies is shaping up. PMID- 29263000 TI - Corrections. PMID- 29263001 TI - Corrections. PMID- 29263002 TI - Advice for those trying to find a cure for the shaking palsy. PMID- 29263003 TI - World Wide Fingers will advance dementia prevention. PMID- 29263005 TI - Raul Martinez. PMID- 29263004 TI - Neurodegeneration: the first mechanistic therapy and other progress in 2017. PMID- 29263007 TI - Headache advances in 2017: a new horizon in migraine therapy. PMID- 29263009 TI - A new classification and class 1 evidence transform clinical practice in epilepsy. PMID- 29263010 TI - High priority publications on Parkinson's disease in 2017. PMID- 29263011 TI - Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. AB - High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders. PMID- 29263008 TI - Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. AB - BACKGROUND: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. METHODS: In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. FINDINGS: This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 * 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 * 10-10), an GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 * 10-9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27 1.79; p=2.32 * 10-6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. INTERPRETATION: Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease. FUNDING: The Alzheimer's Society and the Lewy Body Society. PMID- 29263012 TI - Sinus node dysfunction masquerading as complete atrioventricular block in the setting of atrial parasystole after heart transplantation. AB - Heart transplantation is the gold standard for treatment of end stage heart failure. Atrial parasystole (AP), defined as the presence of an additional dissociated atrial pacemaker on a surface electrocardiogram, has been described to be seen after heart transplantation using biatrial surgical technique. AP may pose a challenge in diagnosing underlying rhythm disturbances in these patients. Here, we report a rare phenomenon of junctional escape rhythm with sinus node dysfunction, mimicking as complete atrioventricular block due to the presence of an AP, in a heart transplant recipient. PMID- 29263014 TI - Intracranial Complications of Sinusitis. PMID- 29263013 TI - Ultrastructural change of the subchondral bone increases the severity of cartilage damage in osteoporotic osteoarthritis of the knee in rabbits. AB - Osteoporotic osteoarthritis is a phenotype of osteoarthritis (OA) manifested as fragile and osteoporotic subchondral bone. However, the ultrastructural features of subchondral bone in osteoporosis OA have not been determined. The study was aimed to investigate the ultrastructural dynamic changes of subchondral bone in osteoporotic OA model and how the ultrastructural damage in the subchondral bone caused by osteoporosis deteriorated the cartilage damage in OA. Eighteen rabbits were equally randomized to three groups, including the control, the OA and the osteoporotic OA groups. The structural changes of cartilage were evaluated by HE and safranin-O fast green staining, the Mankin's grading system was used to assess the stage of OA progression. And microstructural or ultrastructural changes in subchondral bone were assessed by micro-computed tomography or by scanning electron microscopy. According to the changes of cartilage histopathology, the OA group was in the early pathological stage of OA while the osteoporotic OA group was in the middle stage of OA based on Mankin's grading system. In addition, the damage of cartilage surface, reduction in the number of chondrocytes and the matrix staining were more increased in the osteoporotic OA group compared to the OA group. Compared to the OA group, the subchondral bone in the microstructure and ultrastructure in the osteoporotic OA group showed more microfracture changes in trabecular bone with more destructions of the tree-like mesh. Moreover, the collagen fibers were random rough with a fewer amount of bone lacunae in subchondral cortical plate in the osteoporotic OA group compared to the OA group. These findings indicated that the subchondral bone ultrastructure in the osteoporotic OA model was characterized by the destruction of the network structure and collagen fibers. The subchondral bone ultrastructural damage caused by osteoporosis may change mechanical properties of the upper cartilage and aggravate OA cartilage. Therefore, early diagnosis and treatment of osteoporosis is of great significance to prevent early OA from further developing osteoporotic OA. PMID- 29263015 TI - The Contemporary Bacteriologic Epidemiology of Osteoarticular Infections in Children in Switzerland. AB - OBJECTIVES: To assess the contemporary bacteriologic epidemiology of pediatric osteoarticular infection with particular regard to children's ages, because Kingella kingae has gained increasing recognition as the predominant pathogen for osteoarticular infection in young children. STUDY DESIGN: Retrospective file review of enrolled children from 0 to 15 years of age, admitted to our institution from 2007 to 2015 for suspected osteoarticular infection (217 cases). Information on age, sex, the bone or joint infected, imaging studies, and laboratory data (including bacterial investigations) were collected for analysis. RESULTS: Microorganism identification was possible for 138 infected children (63.6%), through blood (cultures or polymerase chain reaction [PCR]) and/or operative samples (cultures or PCR). Thirty-one patients (14.3%) were found to both have positive blood cultures and operative samples. The results of positive bacteriology specimens identified the most common causative pathogen for osteoarticular infection as K kingae (47.8% of microbiologically confirmed osteoarticular infections of all ages, and 87.7% in children between the ages of 6 and 48 months), significantly more common than Staphylococcus aureus (35.5% of microbiologically confirmed osteoarticular infections of all ages, and 78.2% in children >4 years of age). CONCLUSIONS: Use of the appropriate PCR assays demonstrated that K kingae currently is the major bacterial cause of pediatric osteoarticular infection, especially in children <4 years of age in whom K kingae is more common than S aureus. PCR assays should be used in routine microbiologic laboratory evaluation to improve diagnostic performance. However, despite the use of molecular methods, there are many osteoarticular infections in which no microorganism is detected, which suggests that these infections may be caused by other as yet unrecognized fastidious microorganisms. PMID- 29263016 TI - Monitoring Prevention Impact of Mother-to-Child Transmission of HIV in Concentrated Epidemics With Program and Survey Data. AB - BACKGROUND: The prevention of mother-to-child transmission (PMTCT) of HIV program was introduced in Vietnam in 2005. Despite the scaling up of PMTCT programs, the rate of mother-to-child HIV transmission in Vietnam was estimated as high as 20% in 2013. OBJECTIVE: The objective of this study was to assess the outcomes of PMTCT and identified factors associated with mother-to-child transmission and infant survival using survey and program data in a high HIV burden province in Vietnam. METHODS: This community-based retrospective cohort study observed pregnant women diagnosed with HIV infection in Thai Nguyen province from October 2008 to December 2012. Data were collected through interviews using a structured questionnaire and through reviews of log books and medical charts in antenatal care and HIV clinics. Logistic regression and survival analysis were used to analyze data using Stata (StataCorp). RESULTS: A total of 172 pregnant women living with HIV were identified between 2008 and 2012. Most of these women had acquired the HIV infection from their husband (77/119, 64.7%). Significant improvement in the PMTCT program was documented, including reduction in late diagnosis of HIV for pregnant women from 62.5% in 2008 to 30% in 2012. Access to antiretrovirals (ARVs) improved, increasing from a rate of 18.2% (2008) to 70.0% (2011) for mothers and from 36.4% (2008) to 93.3% (2012) for infants. For infants, early diagnosis within 2 months of birth reached 66.7% in 2012 compared with 16.7% in 2009. Transmission rate reduced from 27.3% in 2008 to 6.7% in 2012. Late diagnosis was associated with increased risk for HIV transmission (odds ratio [OR] 14.7, 95% CI 1.8-121.4, P=.01), whereas ARV therapy for mother and infant in combination with infant formula feeding were associated with reduced risk for HIV transmission (OR 0.01, 95% CI 0.001-0.1; P<.001). Overall survival rate for HIV-exposed infants at 12 months was 97.7%. CONCLUSIONS: A combination of program and survey data measured the impact of prevention of HIV transmission from mother-to-child interventions. Significant improvement in access to the interventions was documented in Thai Nguyen province. However, factors that increased the risk of HIV transmission, such as late diagnosis, remain to be addressed. PMID- 29263018 TI - E-Cigarette Surveillance With Social Media Data: Social Bots, Emerging Topics, and Trends. AB - BACKGROUND: As e-cigarette use rapidly increases in popularity, data from online social systems (Twitter, Instagram, Google Web Search) can be used to capture and describe the social and environmental context in which individuals use, perceive, and are marketed this tobacco product. Social media data may serve as a massive focus group where people organically discuss e-cigarettes unprimed by a researcher, without instrument bias, captured in near real time and at low costs. OBJECTIVE: This study documents e-cigarette-related discussions on Twitter, describing themes of conversations and locations where Twitter users often discuss e-cigarettes, to identify priority areas for e-cigarette education campaigns. Additionally, this study demonstrates the importance of distinguishing between social bots and human users when attempting to understand public health related behaviors and attitudes. METHODS: E-cigarette-related posts on Twitter (N=6,185,153) were collected from December 24, 2016, to April 21, 2017. Techniques drawn from network science were used to determine discussions of e cigarettes by describing which hashtags co-occur (concept clusters) in a Twitter network. Posts and metadata were used to describe where geographically e cigarette-related discussions in the United States occurred. Machine learning models were used to distinguish between Twitter posts reflecting attitudes and behaviors of genuine human users from those of social bots. Odds ratios were computed from 2x2 contingency tables to detect if hashtags varied by source (social bot vs human user) using the Fisher exact test to determine statistical significance. RESULTS: Clusters found in the corpus of hashtags from human users included behaviors (eg, #vaping), vaping identity (eg, #vapelife), and vaping community (eg, #vapenation). Additional clusters included products (eg, #eliquids), dual tobacco use (eg, #hookah), and polysubstance use (eg, #marijuana). Clusters found in the corpus of hashtags from social bots included health (eg, #health), smoking cessation (eg, #quitsmoking), and new products (eg, #ismog). Social bots were significantly more likely to post hashtags that referenced smoking cessation and new products compared to human users. The volume of tweets was highest in the Mid-Atlantic (eg, Pennsylvania, New Jersey, Maryland, and New York), followed by the West Coast and Southwest (eg, California, Arizona and Nevada). CONCLUSIONS: Social media data may be used to complement and extend the surveillance of health behaviors including tobacco product use. Public health researchers could harness these data and methods to identify new products or devices. Furthermore, findings from this study demonstrate the importance of distinguishing between Twitter posts from social bots and humans when attempting to understand attitudes and behaviors. Social bots may be used to perpetuate the idea that e-cigarettes are helpful in cessation and to promote new products as they enter the marketplace. PMID- 29263017 TI - The Effect of Screen-to-Screen Versus Face-to-Face Consultation on Doctor-Patient Communication: An Experimental Study with Simulated Patients. AB - BACKGROUND: Despite the emergence of Web-based patient-provider contact, it is still unclear how the quality of Web-based doctor-patient interactions differs from face-to-face interactions. OBJECTIVE: This study aimed to examine (1) the impact of a consultation medium on doctors' and patients' communicative behavior in terms of information exchange, interpersonal relationship building, and shared decision making and (2) the mediating role of doctors' and patients' communicative behavior on satisfaction with both types of consultation medium. METHODS: Doctor-patient consultations on pelvic organ prolapse were simulated, both in a face-to-face and in a screen-to-screen (video) setting. Twelve medical interns and 6 simulated patients prepared 4 different written scenarios and were randomized to perform a total of 48 consultations. Effects of the consultations were measured by questionnaires that participants filled out directly after the consultation. RESULTS: With respect to patient-related outcomes, satisfaction, perceived information exchange, interpersonal relationship building, and perceived shared decision making showed no significant differences between face to-face and screen-to-screen consultations. Patients' attitude toward Web-based communication (b=-.249, P=.02 and patients' perceived time and attention (b=.271, P=.03) significantly predicted patients' perceived interpersonal relationship building. Patients' perceived shared decision making was positively related to their satisfaction with the consultation (b=.254, P=.005). Overall, patients experienced significantly greater shared decision making with a female doctor (mean 4.21, SD 0.49) than with a male doctor (mean 3.66 [SD 0.73]; b=.401, P=.009). Doctor-related outcomes showed no significant differences in satisfaction, perceived information exchange, interpersonal relationship building, and perceived shared decision making between the conditions. There was a positive relationship between perceived information exchange and doctors' satisfaction with the consultation (b=.533, P<.001). Furthermore, doctors' perceived interpersonal relationship building was positively related to doctors' satisfaction with the consultation (b=.331, P=.003). CONCLUSIONS: In this study, the quality of doctor-patient communication, as indicated by information exchange, interpersonal relationship building, and shared decision making, did not differ significantly between Web-based and face-to-face consultations. Doctors and simulated patients were equally satisfied with both types of consultation medium, and no differences were found in the manner in which participants perceived communicative behavior during these consultations. The findings suggest that worries about a negative impact of Web-based video consultation on the quality of patient-provider consultations seem unwarranted as they offer the same interaction quality and satisfaction level as regular face-to face consultations. PMID- 29263020 TI - Online access to GPs can offer benefits to GPs and patients. PMID- 29263021 TI - Drug shortages cost NHS L38m in November. PMID- 29263019 TI - Daily Activity Measured With Wearable Technology as a Novel Measurement of Treatment Effect in Patients With Coronary Microvascular Dysfunction: Substudy of a Randomized Controlled Crossover Trial. AB - BACKGROUND: Digital wearable devices provide a "real-world" assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. OBJECTIVE: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. METHODS: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and coronary microvascular dysfunction (CMD) with no obstructive coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. RESULTS: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ 7), a direct correlation with increased step count (r=.42, P=.02) was observed. CONCLUSIONS: We report one of the first studies to use digital wearable device determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. TRIAL REGISTRATION: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO). PMID- 29263022 TI - Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy. AB - Inflammation plays an important role in the pathogenesis of diabetic retinopathy. We have previously demonstrated the effect of cathepsin D (CD) on the mechanical disruption of retinal endothelial cell junctions and increased vasopermeability, as well as increased levels of CD in retinas of diabetic mice. Here, we have also examined the effect of CD on endothelial-pericyte interactions, as well as the effect of dipeptidyl peptidase-4 (DPP4) inhibitor on CD in endothelial-pericyte interactions in vitro and in vivo. Cocultured cells that were treated with pro-CD demonstrated a significant decrease in the expression of platelet-derived growth factor receptor-beta, a tyrosine kinase receptor that is required for pericyte cell survival; N-cadherin, the key adherens junction protein between endothelium and pericytes; and increases in the vessel destabilizing agent, angiopoietin-2. The effect was reversed in cells that were treated with DPP4 inhibitor along with pro-CD. With pro-CD treatment, there was a significant increase in the phosphorylation of the downstream signaling protein, PKC-alpha, and Ca2+/calmodulin-dependent protein kinase II in endothelial cells and pericytes, which disrupts adherens junction structure and function, and this was significantly reduced with DPP4 inhibitor treatment. Increased CD levels, vasopermeability, and alteration in junctional-related proteins were observed in the retinas of diabetic rats, which were significantly changed with DPP4 inhibitor treatment. Thus, DPP4 inhibitors may be used as potential adjuvant therapeutic agents to treat increased vascular leakage observed in patients with diabetic macular edema.-Monickaraj, F., McGuire, P., Das, A. Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy. PMID- 29263023 TI - Seven sins when interpreting statistics in sports injury science. PMID- 29263024 TI - A Delphi developed syllabus for the medical specialty of sport and exercise medicine. AB - Training in the medical specialty of sport and exercise medicine is now available in many, but not all countries. Lack of resources may be a barrier to the development of this important specialty field and the International Syllabus in Sport and Exercise Medicine Group was convened to reduce one potential barrier, the need to develop a syllabus. The group is composed of 17 sport and exercise medicine specialists residing in 12 countries (Australia, Canada, India, Ireland, Malaysia, the Netherlands, Qatar, South Africa, Sweden, Switzerland, the UK and USA). This paper presents the first phase of this project covering the domains and general learning areas of a specialist training syllabus in sport and exercise medicine. PMID- 29263025 TI - Extended Effectiveness of the Etonogestrel-Releasing Contraceptive Implant and the 20 ug Levonorgestrel-Releasing Intrauterine System for 2 Years Beyond U.S. Food and Drug Administration Product Labeling. PMID- 29263026 TI - Newborn in cardiogenic shock. AB - CLINICAL INTRODUCTION: A 2-month-old baby boy was referred to our centre due to tachycardia and acute heart failure. The ECG showed a narrow complex tachycardia with a heart rate of 300 beats per minute (Figure 1). Echocardiographically, a patent foramen ovale and a parachute mitral valve with mild regurgitation were diagnosed; cardiac function was highly impaired.heartjnl;104/6/467/F1F1F1Figure 1ECG (50 mm/s) showing the small complex tachycardia. QUESTION: Which of the following is the most likely diagnosis?Ectopic atrial tachycardiaAtrial flutterChaotic atrial tachycardiaFocal micro re-entrant tachycardiaAtrial fibrillation. PMID- 29263027 TI - The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila. AB - The Drosophila Y chromosome is a 40-Mb segment of mostly repetitive DNA; it harbors a handful of protein-coding genes and a disproportionate amount of satellite repeats, transposable elements, and multicopy DNA arrays. Intron retention (IR) is a type of alternative splicing (AS) event by which one or more introns remain within the mature transcript. IR recently emerged as a deliberate cellular mechanism to modulate gene expression levels and has been implicated in multiple biological processes. However, the extent of sex differences in IR and the contribution of the Y chromosome to the modulation of AS and IR rates has not been addressed. Here we showed pervasive IR in the fruit fly Drosophila melanogaster with thousands of novel IR events, hundreds of which displayed extensive sex bias. The data also revealed an unsuspected role for the Y chromosome in the modulation of AS and IR. The majority of sex-biased IR events introduced premature termination codons and the magnitude of sex bias was associated with gene expression differences between the sexes. Surprisingly, an extra Y chromosome in males (X^YY genotype) or the presence of a Y chromosome in females (X^XY genotype) significantly modulated IR and recapitulated natural differences in IR between the sexes. Our results highlight the significance of sex-biased IR in tuning sex differences and the role of the Y chromosome as a source of variable IR rates between the sexes. Modulation of splicing and IR rates across the genome represent new and unexpected outcomes of the Drosophila Y chromosome. PMID- 29263030 TI - BET Proteins as Targets for Anticancer Treatment. AB - Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. Over the last years, several BET inhibitors have been developed and clinically tested. Results from the first clinical trials show limited single-agent activity in a small subset of patients with hematologic malignancies and in NUT carcinoma. Adverse events have been observed and may limit treatment compliance. Here, we review the preclinical rationale for targeting BET proteins in cancer and the preliminary results from clinical trials, and outline future directions for the use of BET inhibitors as antitumor agents.Significance: BET inhibitors represent a new class of anticancer agents. Results from the first clinical trials confirm the antitumor potential of BET inhibitors, but their efficacy as single agents seems to be limited. Based on preclinical data, combination therapies with other anticancer agents and the development of a new generation of compounds may open new possibilities for targeting BET proteins as effective anticancer strategies. Cancer Discov; 8(1); 24-36. (c)2017 AACR. PMID- 29263028 TI - A Novel Sterol-Signaling Pathway Governs Azole Antifungal Drug Resistance and Hypoxic Gene Repression in Saccharomyces cerevisiae. AB - During antifungal drug treatment and hypoxia, genetic and epigenetic changes occur to maintain sterol homeostasis and cellular function. In this study, we show that SET domain-containing epigenetic factors govern drug efficacy to the medically relevant azole class of antifungal drugs. Upon this discovery, we determined that Set4 is induced when Saccharomyces cerevisiae are treated with azole drugs or grown under hypoxic conditions; two conditions that deplete cellular ergosterol and increase sterol precursors. Interestingly, Set4 induction is controlled by the sterol-sensing transcription factors, Upc2 and Ecm22 To determine the role of Set4 on gene expression under hypoxic conditions, we performed RNA-sequencing analysis and showed that Set4 is required for global changes in gene expression. Specifically, loss of Set4 led to an upregulation of nearly all ergosterol genes, including ERG11 and ERG3, suggesting that Set4 functions in gene repression. Furthermore, mass spectrometry analysis revealed that Set4 interacts with the hypoxic-specific transcriptional repressor, Hap1, where this interaction is necessary for Set4 recruitment to ergosterol gene promoters under hypoxia. Finally, an erg3Delta strain, which produces precursor sterols but lacks ergosterol, expresses Set4 under untreated aerobic conditions. Together, our data suggest that sterol precursors are needed for Set4 induction through an Upc2-mediated mechanism. Overall, this new sterol-signaling pathway governs azole antifungal drug resistance and mediates repression of sterol genes under hypoxic conditions. PMID- 29263029 TI - Fine-Scale Recombination Maps of Fungal Plant Pathogens Reveal Dynamic Recombination Landscapes and Intragenic Hotspots. AB - Meiotic recombination is an important driver of evolution. Variability in the intensity of recombination across chromosomes can affect sequence composition, nucleotide variation, and rates of adaptation. In many organisms, recombination events are concentrated within short segments termed recombination hotspots. The variation in recombination rate and positions of recombination hotspot can be studied using population genomics data and statistical methods. In this study, we conducted population genomics analyses to address the evolution of recombination in two closely related fungal plant pathogens: the prominent wheat pathogen Zymoseptoria tritici and a sister species infecting wild grasses Z. ardabiliae We specifically addressed whether recombination landscapes, including hotspot positions, are conserved in the two recently diverged species and if recombination contributes to rapid evolution of pathogenicity traits. We conducted a detailed simulation analysis to assess the performance of methods of recombination rate estimation based on patterns of linkage disequilibrium, in particular in the context of high nucleotide diversity. Our analyses reveal overall high recombination rates, a lack of suppressed recombination in centromeres, and significantly lower recombination rates on chromosomes that are known to be accessory. The comparison of the recombination landscapes of the two species reveals a strong correlation of recombination rate at the megabase scale, but little correlation at smaller scales. The recombination landscapes in both pathogen species are dominated by frequent recombination hotspots across the genome including coding regions, suggesting a strong impact of recombination on gene evolution. A significant but small fraction of these hotspots colocalize between the two species, suggesting that hotspot dynamics contribute to the overall pattern of fast evolving recombination in these species. PMID- 29263031 TI - Highlights From the 2017 Cardiovascular and Stroke Nursing Clinical Symposium. PMID- 29263033 TI - Marital Status and Outcomes in Patients With Cardiovascular Disease. AB - BACKGROUND: Being unmarried is associated with decreased survival in the general population. Whether married, divorced, separated, widowed, or never-married status affects outcomes in patients with cardiovascular disease has not been well characterized. METHODS AND RESULTS: A prospective cohort (inception period 2003 2015) of 6051 patients (mean age 63 years, 64% male, 23% black) undergoing cardiac catheterization for suspected or confirmed coronary artery disease was followed for a median of 3.7 years (interquartile range: 1.7-6.7 years). Marital status was stratified as married (n=4088) versus unmarried (n=1963), which included those who were never married (n=451), divorced or separated (n=842), or widowed (n=670). The relationship between marital status and primary outcome of cardiovascular death and myocardial infarction was examined using Cox regression models adjusted for clinical characteristics. There were 1085 (18%) deaths from all causes, 688 (11%) cardiovascular-related deaths, and 272 (4.5%) incident myocardial infarction events. Compared with married participants, being unmarried was associated with higher risk of all-cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.06-1.47), cardiovascular death (HR: 1.45; 95% CI, 1.18-1.78), and cardiovascular death or myocardial infarction (HR: 1.52; 95% CI, 1.27-1.83). Compared with married participants, the increase in cardiovascular death or myocardial infarction was similar for the participants who were divorced or separated (HR: 1.41; 95% CI, 1.10-1.81), widowed (HR: 1.71; 95% CI, 1.32 2.20), or never married (HR: 1.40; 95% CI, 0.97-2.03). The findings persisted after adjustment for medications and other socioeconomic factors. CONCLUSIONS: Marital status is independently associated with cardiovascular outcomes in patients with or at high risk of cardiovascular disease, with higher mortality in the unmarried population. The mechanisms responsible for this increased risk require further study. PMID- 29263034 TI - Helicity and Vorticity of Pulmonary Arterial Flow in Patients With Pulmonary Hypertension: Quantitative Analysis of Flow Formations. AB - BACKGROUND: Qualitative and quantitative flow hemodynamic indexes have been shown to reflect right ventricular (RV) afterload and function in pulmonary hypertension (PH). We aimed to quantify flow hemodynamic formations in pulmonary arteries using 4-dimensional flow cardiac magnetic resonance imaging and the spatial velocity derivatives helicity and vorticity in a heterogeneous PH population. METHODS AND RESULTS: Patients with PH (n=35) and controls (n=10) underwent 4-dimensional flow magnetic resonance imaging study for computation of helicity and vorticity in the main pulmonary artery (MPA), the right pulmonary artery, and the RV outflow tract. Helicity and vorticity were correlated with standard RV volumetric and functional indexes along with MPA stiffness assessed by measuring relative area change. Patients with PH had a significantly decreased helicity in the MPA (8 versus 32 m/s2; P<0.001), the right pulmonary artery (24 versus 50 m/s2; P<0.001), and the RV outflow tract-MPA unit (15 versus 42 m/s2; P<0.001). Vorticity was significantly decreased in patients with PH only in the right pulmonary artery (26 versus 45 1/s; P<0.001). Total helicity computed correlated with the cardiac magnetic resonance imaging-derived ventricular vascular coupling (-0.927; P<0.000), the RV ejection fraction (0.865; P<0.0001), cardiac output (0.581; P<0.0001), mean pulmonary arterial pressure (-0.581; P=0.0008), and relative area change measured at the MPA (0.789; P<0.0001). CONCLUSIONS: The flow hemodynamic character in patients with PH assessed via quantitative analysis is considerably different when compared with healthy and normotensive controls. A strong association between helicity in pulmonary arteries and ventricular-vascular coupling suggests a relationship between the mechanical and flow hemodynamic domains. PMID- 29263032 TI - Effect of Plant Protein on Blood Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: There is a heightened interest in plant-based diets for cardiovascular disease prevention. Although plant protein is thought to mediate such prevention through modifying blood lipids, the effect of plant protein in specific substitution for animal protein on blood lipids remains unclear. To assess the effect of this substitution on established lipid targets for cardiovascular risk reduction, we conducted a systematic review and meta-analysis of randomized controlled trials using the Grading of Recommendations Assessment, Development, and Evaluation system. METHODS AND RESULTS: MEDLINE, EMBASE, and the Cochrane Registry were searched through September 9, 2017. We included randomized controlled trials of >=3 weeks comparing the effect of plant protein in substitution for animal protein on low-density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B. Two independent reviewers extracted relevant data and assessed risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences with 95% confidence intervals. Heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). The overall quality (certainty) of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. One-hundred twelve randomized controlled trials met the eligibility criteria. Plant protein in substitution for animal protein decreased low-density lipoprotein cholesterol by 0.16 mmol/L (95% confidence interval, 0.20 to -0.12 mmol/L; P<0.00001; I2=55%; moderate-quality evidence), non-high density lipoprotein cholesterol by 0.18 mmol/L (95% confidence interval, -0.22 to -0.14 mmol/L; P<0.00001; I2=52%; moderate-quality evidence), and apolipoprotein B by 0.05 g/L (95% confidence interval, -0.06 to -0.03 g/L; P<0.00001; I2=30%; moderate-quality evidence). CONCLUSIONS: Substitution of plant protein for animal protein decreases the established lipid targets low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. More high-quality randomized trials are needed to improve our estimates. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02037321. PMID- 29263035 TI - beta-Blocker Therapy Prior to Admission for Acute Coronary Syndrome in Patients Without Heart Failure or Left Ventricular Dysfunction Improves In-Hospital and 12 Month Outcome: Results From the GULF-RACE 2 (Gulf Registry of Acute Coronary Events-2). AB - BACKGROUND: The prognostic impact of beta-blockers (BB) in acute coronary syndrome (ACS) patients without heart failure (HF) or left ventricular dysfunction is controversial, especially in the postreperfusion era. We sought to determine whether a BB therapy before admission for ACS has a favorable in hospital outcome in patients without HF, and whether they also reduce 12-month mortality if still prescribed on discharge. METHODS AND RESULTS: The GULF-RACE 2 (Gulf Registry of Acute Coronary Events-2) is a prospective multicenter study of ACS in 6 Middle Eastern countries. We studied in-hospital cardiovascular events in patients hospitalized for ACS without HF in relation to BB on admission, and 1 year mortality in relation to BB on discharge. Among the 7903 participants, 7407 did not have HF, of whom 5937 (80.15%) patients were on BB. Patients on BB tended to be older and have more comorbidities. However, they had a lower risk of in hospital mortality, mitral regurgitation, HF, cardiogenic shock, and ventricular tachycardia/ventricular fibrillation. Furthermore, 4208 patients were discharged alive and had an ejection fraction >=40%. Among those, 84.1% had a BB prescription. At 12 months, they also had a reduced risk of mortality as compared with the non-BB group. Even after correcting for confounding factors in 2 different models, in-hospital and 12-month mortality risk was still lower in the BB group. CONCLUSIONS: In this cohort of ACS, BB therapy before admission for ACS is associated with decreased in-hospital mortality and major cardiovascular events, and 1-year mortality in patients without HF or left ventricular dysfunction if still prescribed on discharge. PMID- 29263037 TI - Diagnostic Error in Medicine: Implications for Clinical Laboratory Scientists. AB - The recent interest in diagnostic error in medicine was preceded almost fifty years ago by a focus on the problem-solving strategies of the experts of that time. This focus also extended to include the development of computer-based decision support systems to aid clinicians in diagnosis. Interest in medical errors was heightened with the publication of the Institute of Medicine report To Err is Human in 2000; however, there was still a relative neglect of the problem that diagnostic error presents. This article discusses the extent and types of diagnostic error in medicine, the challenges of studying diagnostic error, and strategies to address these errors. The role of the clinical laboratory in regard to diagnostic errors in medicine is also highlighted. PMID- 29263038 TI - Elevated Expression of DLG1 Is Associated with Poor Prognosis in Patients with Colorectal Cancer. AB - AIMS AND BACKGROUND: Discs large homolog 1 (DLG1) belongs to the modular proteins Membrane Associated Guanylate Kinases (MAGUKs) and plays a major role in the formation of cell-cell junctions and cell polarity. DLG1 varies in expression and localization among malignancies. However, the clinical significance of DLG1 in the context of human colorectal cancer (CRC) remains unclear. The purpose of this study study is to determine the association of DLG1 with clinicopathological characteristics and prognosis of CRC patients. METHODS: DLG1 expression in human CRC was detected by immunohistochemical analysis and validated with mRNA data from a high-throughput sequencing TCGA datasets. The association of DLG1 expression with clinicopathological features in CRC patients was then statistically analyzed. RESULTS: Immunohistochemistry analysis found that DLG1 expression was significantly elevated in CRC tissues, compared with the expression in adjacent non-cancerous colon tissues (P=0.000). High DLG1 expression was significantly associated with advanced clinical stage (P=0.011) and enhanced tumor invasion (P=0.002). The TCGA mRNA expression data revealed that DLG1 mRNA expression was up-regulated in CRC tissues with advanced clinical stage (P=0.008), enhanced tumor invasion (P=0.042), lymph node metastasis (P=0.030), and distant metastasis (P=0.043). Kaplan-Meier survival curves revealed that CRC patients with high DLG1 levels had shorter survival (P=0.040). Furthermore, DLG1 was an independent prognostic factor for CRC patients (HR 2.202, 95% CI 1.057-4.587; P=0.035). CONCLUSIONS: These findings suggest that the increased expression of DLG1 may be predictive of an unfavorable prognosis in CRC patient and serve as a novel therapeutic target in this malignancy. PMID- 29263039 TI - Loop Electrosurgical Excision Procedure vs. Cold Knife Cone in Treatment of Cervical Intraepithelial Neoplasia: Review of 447 Cases. AB - Loop electrosurgical excision procedure (LEEP) and cold knife cone (CKC) are often used for the treatment of high-grade cervical intraepithelial lesions. LEEP is an in-office procedure with less discomfort and fewer complications than CKC. However, concerns related to LEEP include the interpretability of the resection margins, positive margins, and the tissue fragmentation. Negative for dysplasia in LEEP or CKC specimens are not uncommon, which may be associated with lesion regression or interpretation errors. 447 cases with 259 LEEP and 188 CKC were included in this study. Patients with CKC were significantly older than patients with LEEP (38 vs. 31, p=0.0001). LEEP was associated with more tissue fragmentation (45.2% vs. 8.5%, p=0.0001) and un-interpretable surgical margins than CKC (10.4% vs. 2.7%, p=0.001). LEEP and CKC had similar positive surgical margin rate. 380 cases had both in-house biopsy and LEEP/CKC (219 LEEP and 161 CKC) specimens. Twenty four cases were negative for dysplasia on the LEEP/CKC (6.3%, 24/380), and the negative rates were similar between LEEP and CKC groups (6.8% vs. 5.6%, p=0.67). Reviewing the previous biopsy or cytology of the 24 negative cases confirmed high-grade squamous intraepithelial lesion (HSIL/CIN2+) in 22 cases, and the remaining 2 cases were misinterpretations of low-grade squamous intraepithelial lesion (LSIL/CIN1) in the biopsy or cytology. The negative rate was higher in cervical cytology only group comparing to cervical biopsy confirmed CIN2+ group (10.8% vs. 5.4%), but it was not statistically significant (p=0.15). The residual/recurrent rate for cervical dysplasia was only 2.9% (11/373). PMID- 29263036 TI - Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure. AB - BACKGROUND: Congestive heart failure (CHF) is a common cardiovascular disease that is often accompanied by ventricular arrhythmias. The decrease of the slow component of the delayed rectifier potassium current (IKs) in CHF leads to action potential (AP) prolongation, and the IKs is an important contributor to the development of ventricular arrhythmias. However, the molecular mechanisms underlying ventricular arrhythmias are still unknown. METHODS AND RESULTS: Kcna2 and Kcna2 antisense RNA (Kcna2 AS) transcript expression was measured in rat cardiac tissues using quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. There was a 43% reduction in Kcna2 mRNA in the left ventricular myocardium of rats with CHF. Kcna2 knockdown in the heart decreased the IKs and prolonged APs in cardiomyocytes, consistent with the changes observed in heart failure. Conversely, Kcna2 overexpression in the heart significantly attenuated the CHF-induced decreases in the IKs, AP prolongation, and ventricular arrhythmias. Kcna2 AS was upregulated ~1.7-fold in rats with CHF and with phenylephrine-induced cardiomyocyte hypertrophy. Kcna2 AS inhibition increased the CHF-induced downregulation of Kcna2. Consequently, Kcna2 AS mitigated the decrease in the IKs and the prolongation of APs in vivo and in vitro and reduced ventricular arrhythmias, as detected using electrocardiography. CONCLUSIONS: Ventricular Kcna2 AS expression increases in rats with CHF and contributes to reduced IKs, prolonged APs, and the occurrence of ventricular arrhythmias by silencing Kcna2. Thus, Kcna2 AS may be a new target for the prevention and treatment of ventricular arrhythmias in patients with CHF. PMID- 29263040 TI - T Cell Immunoglobulin- and Mucin-Domain-Containing Molecule 3 Gene Polymorphisms and Susceptibility to Invasive Breast Cancer. AB - The T-cell immunoglobulin and mucin domain containing molecule 3 (TIM-3) gene is an important immune regulatory molecule. In fact, studies have shown that polymorphisms in the (TIM-3) gene may be associated with various cancers. The goal of this study was to investigate whether the -1516G/T, -574G/T, or +4259T/G single-nucleotide polymorphisms (SNPs) in the TIM-3 gene contribute to a genetic susceptibility to invasive breast cancer in the Han ethnicity of northern China. Genotyping of the TIM-3 -1516G/T, -574G/T and +4259T/G were performed in 301 patients with invasive breast cancer and in 151 healthy individuals via a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The results showed that the prevalence of the +4259T/G genotype and the +4259G allele were significantly increased in the breast cancer patients compared to the controls [odds ratio (OR)=7.641, 95% confidence interval (CI), 1.795 32.522, P=0.001; OR=7.317, 95%CI, 1.731-30.925, P=0.001, respectively]. The GGG haplotype had a significantly different distribution between patients and controls (OR=5.421, 95%CI, 1.263-23.275, P=0.011). In addition, the prevalence of the +4259T/G polymorphism was higher in patients with metastasis than those without metastasis (13.6% vs. 4.8%, respectively, OR=3.158, 95%CI, 1.300-7.672, P=0.011). Furthermore, results showed that the prevalence of the +4259T/G genotype was correlated with the intensity of Ki-67 by immunohistochemical staining (P=0.022). Overall, these results suggested that the +4259T/G SNP in the TIM-3 gene may play an important role as a genetic risk factor for the progression and prognosis of invasive breast cancer in these patients. in Han ethnicity of northern China. PMID- 29263041 TI - Enzyme Kinetic Assay to Measure the Activity of Tumor M2 Pyruvate Kinase in Breast Cancer Patients. AB - BACKGROUND: M2 type Pyruvate kinase (PKM2) is the key rate-limiting enzyme of glycolysis, and it mainly exists as a dimer in tumor cells. This study aims to establish an enzyme kinetic assay for serum tumor M2 pyruvate kinase (TuM2-PK), and to evaluate its diagnostic value in breast cancer. METHODS: The catalytic kinetics of Pyruvate Kinase (PK) was examined. Its allosteric regulation property and Michaelis constant were then measured. Next, the levels of TuM2-PK in serum were detected and compared with results from an enzyme-linked immunosorbent assay (ELISA). Finally, the levels of TuM2-PK among breast cancer patients, post mastectomy patients, patients with benign breast diseases, and healthy controls were compared. RESULTS: A PK kinetic assay was established in this study. The assay reaction time is 108 seconds, and the optimum pH level is 8.0. In the presence of the allosteric activator fructose 1, 6-bisphosphate (FBP), the Km of PK for phosphoenolpyruvate (PEP) is 0.15 mmol/L and the Vmax is 330 MUmol/min. The levels of TuM2-PK in serum obtained by enzyme kinetics are comparable to the ELISA results. Both assays showed that TuM2-PK in breast cancer patients was increased from stage I to IV. Importantly, TuM2-PK levels were significantly different between early and late-stage breast cancer patients (stage I and stage II vs. stage III and IV), as well as between late-stage and non-malignant patients (p<0.05). No statistical difference was found between benign breast disease patients and healthy controls. CONCLUSIONS: An enzyme kinetic assay of serum TuM2-PK was successfully established and may be useful for breast cancer diagnosis. PMID- 29263042 TI - Overexpression of HHEX in Acute Myeloid Leukemia with t(8;21)(q22;q22) Translocation. AB - BACKGROUND: The hematopoietically expressed homeobox (HHEX) is widely expressed in hematopoietic stem cells and is an essential transcription factor in embryonic development; however its role in hematopoiesis and leukemogenesis is poorly understood. We are thus exploring the association of HHEX and acute myeloid leukemia (AML). METHODS: The study included 56 AML patients and 12 normal bone marrows (NBMs). Real-time quantitative polymerase chain reaction (Q-PCR) was used to assess HHEX expression. The functional consequences of this gene were explored in the Kasumi-1 cell-line following dampened expression of HHEX. This was done by transfecting small interfering RNA (siRNA). RESULTS: Expression levels of HHEX in AML were similar to that found in controls (0.094+/-0.103 vs. 0.078+/-0.112; p=0.203), but AML with t(8;21) was more prevalent than other types of AMLs (p<0.01) or controls (p<0.05). Expression levels of HHEX in AML (non-M3) did not significantly affect overall survival (p=0.555). In vitro studies carried out in Kasumi-1 cells suggest that after decreasing HHEX, cell viability at 48 and 72 h were significantly reduced compared to controls (p<0.05). The apoptotic rate was also significantly increased at 48 and 72 h compared to controls (p<0.05). CONCLUSIONS: HHEX is expressed in multiple types of AML, with the highest levels seen in t(8;21) AML. HHEX was essential for Kasumi-1 cell proliferation and may represent a potential therapeutic target enabling against AML. PMID- 29263043 TI - Expression and Significance of Metalloproteinase and Collagen in Vaginal Wall Tissues of Patients with Pelvic Organ Prolapse. AB - PURPOSE: The purpose of this study is to investigate the roles of matrix metalloproteinases (MMPs) and collagen in female patients with pelvic organ prolapse (POP). METHODS: Sixty POP patients comprised the POP group (23 cases of grade II prolapse (POP-subgroup 1) and 37 cases of grade III-IV prolapse (POP subgroup 2)]; another 35 non-POP patients comprised the control group. Reverse transcription polymerase chain reaction and immunohistochemistry were used to detect the relative mRNA and protein expression of MMP-1, MMP-8, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), and type I and III collagen in the anterior vaginal wall tissues. RESULTS: The relative mRNA and protein expression of MMP-1 and MMP-8 in the anterior vaginal wall tissues of POP-subgroup 2 was significantly higher than those in POP-subgroup 1 and the control group (P<0.05). The relative mRNA and protein expression of TIMP-1 in POP-subgroup 2 was significantly lower than those in POP-subgroup 1 and the control group (P<0.05). Similarly, the expression of types I and III collagen was significantly lower than those in POP-subgroup 1 and the control group (P<0.05). CONCLUSIONS: Reduced expression of types I and III collagen and TIMP-1 as well as the increased expression of MMP-1 and MMP-8 in the anterior vaginal wall tissues play important roles in the onset of POP. PMID- 29263044 TI - Sp-1 Negatively Regulates miR-20b Expression in Macrophages. AB - miR-20b is a member of the miR-106a-363 gene cluster, located on the X chromosome. miR-20b regulates the expression of multiple genes in vivo and it is closely related to the occurrence and development of many diseases. These diseases include inflammatory diseases and tumor development, amongst others. However, few studies have focused on the regulation of the miR-20b gene itself. In this study, we are using the miRBase database to obtain the upstream 2000 bp sequence of the miR-20b precursor. Bio-informatics software P-MATCH 1.0 and AliBaba2 werethen used to predict transcription factor binding in the upstream region. Sp-1 was identified as one of the most probable transcription factors regulating miR-20b gene expression. After treatment with a Sp-1 siRNA, the expression of miR-20b was significantly increased in RAW264.7 cells, as well as peritoneal and alveolar macrophages. In addition, the interference with Sp-1 gene expression also reversed the decrease in miR-20b expression in RAW264.7 cells induced by TNF-alpha. These results indicate that Sp-1 negatively regulates the expression of miR-20b in macrophages. This finding suggests the potential of Sp-1 as a target for therapies in diseases that are associated with miR-20b overexpression. PMID- 29263045 TI - Evaluation of Chitotriosidase as a Marker of Inflammatory Status in Critical Limb Ischemia. AB - BACKGROUND: Chitotriosidase is an enzyme secreted by activated macrophages. This study aims to investigate the usefulness of circulating chitotriosidase activity as a marker of inflammatory status in patients with critical limb ischemia (CLI). MATERIALS AND METHODS: An observational gender-matched case-control study was conducted on patients hospitalized with the primary diagnosis of CLI, as well as a control group. The control group consisted of healthy volunteers. RESULTS: Forty-three patients were included in each group. Similar demographic characteristics (median age of 60-62 years and overweight) were observed in both groups. Chitotriosidase activity ranged from 110 nmol/ml/hr to 1530 nmol/ml/hr in the CLI group and from 30 nmol/ml/hr to 440 nmol/ml/hr in the control group; demonstrating significantly elevated values in the CLI group (p<0.001). Median plasma chitotriosidase activity was significantly elevated in smokers compared with non-smokers in both groups (p<0.05). However, this activity had higher values in CLI than in control subjects. Receiver operating characteristic (ROC) analysis was then performed in order to verify the diagnostic accuracy of chitotriosidase as an inflammatory biomarker in CLI. CONCLUSION: Circulating chitotriosidase is a test which can potentially be used for the monitoring of CLI patients without other inflammatory conditions. However, the interpretation of elevated values must take into account the inflammatory response induced by tobacco exposure. PMID- 29263006 TI - Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data. AB - BACKGROUND: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. METHODS: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. FINDINGS: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1.52, 95% CI 1.09-2.11, p=0.014) and in those who did not have GA (adjusted cOR 2.33, 95% CI 1.75-3.10, p<0.0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1.53, 95% CI 1.14-2.04, p=0.0044). The risk of bias and variability between studies was assessed to be low. INTERPRETATION: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons. FUNDING: Medtronic. PMID- 29263046 TI - Berberine Attenuates NLRP3 Inflammasome Activation in Macrophages to Reduce the Secretion of Interleukin-1beta. AB - OBJECTIVES: The purpose of this study is to evaluate whether Berberine can suppress the inflammatory response in atherosclerosis lesions and its potential associated signaling pathways and mechanism of action. METHODS: We isolated human peripheral blood mononuclear cells. After co-culturing them with ox-LDL stimulated cells, ROS was measured by its fluorescence intensity and NADPH oxidase activity was detected by the OD value from the spectrophotometer. Human peripheral blood mononuclear cells were then pretreated with different concentrations of berberine after treatment with NLRP3 activator ATP. Western blot was used to measure the releas of IL-1beta. We also used confocal microscopy to detect the nuclear import of NF-kB in macrophages. RESULTS: In this study we observed that berberine suppressed IL-1beta secretion that was induced by the activation of the NLRP3 inflammasome in macrophages. In addition, we demonstrated that berberine may possibly reduce reactive oxygen species (ROS)-dependent NLRP3 inflammasome activation. Moreover, Berberine inhibited the expression of pro-IL 1beta through inhibition of the nuclear factor kappab (NF-kappaB) pathway, which prevented the priming IL-1beta secretion. CONCLUSION: Our results suggest that berberine alleviates NLRP3 inflammation activation by reducing IL-1beta secretion from macrophages, which could be an important therapeutic target in atherosclerosis. PMID- 29263047 TI - Nicotinic Acid Receptor GPR109A Exerts Anti-Inflammatory Effects Through Inhibiting the Akt/mTOR Signaling Pathway in MIN6 Pancreatic beta cells. AB - OBJECTIVES: We found that activation of the nicotinic acid receptor GPR109A, expressed by the MIN6 murine pancreatic beta cell line, inhibits nitric oxide accumulation induced by IFN-gamma and TNF-alpha, implicating an anti-inflammatory effect of GPR109A in MIN6 cells. Nevertheless, the mechanism of its anti inflammatory effect is still unknown. In this study, we used palmitic acid to stimulate MIN6 cells to induce inflammatory cytokine production and explored the mechanism by which GPR109A exerts anti-inflammatory effects. MATERIALS AND METHODS: RT-PCR and immunocytochemical staining were used to detect the expression of GPR109A in MIN6 cells. Western blotting was used to detect the activation of the Akt/mTOR signaling pathway and expression of the inflammatory cytokine INF-gamma, in MIN6 cells, following treatments with palmitic acid and palmitic acid+nicotinic acid, or with different concentrations of nicotinic acid and 3-hydroxybutyrate. RESULTS: In MIN6 cells, GPR109A transcripts and protein are expressed and GPR109A protein is mainly located in the cell membrane and cytoplasm. Palmitic acid enhanced the phosphorylation of Akt and p70S6K and elevated the expression of IFN-gamma. Co-treatment with nicotinic acid, which is an agonist of GPR109A, inhibited the palmitic acid-induced phosphorylation of Akt, mTOR, and p70S6K, as well as the expression of IFN-gamma. CONCLUSIONS: GPR109A may inhibit inflammatory cytokine production, induced by palmitic acid, by MIN6 cells possibly via inhibiting the Akt/mTOR signaling pathway. PMID- 29263049 TI - Effect of Serum Immunoglobulins on Routine Coagulation Tests: A Comparison of Coagulation Analyzers using Mechanical and Optical Clot Detection. AB - BACKGROUND: We previously showed that the prothrombin time (PT), but not activated partial thromboplastin time (APTT), is correlated with serum immunoglobulin level in patients with plasma cell neoplasms. METHODS: To determine if the observed effect of serum immunoglobulins on PT was reagent and/or method dependent, PT and APTT were measured in plasma samples obtained from patients referred to the Myeloma Institute using mechanical (STAR Evolution; Diagnostica Stago) and optical clot detection (ACL TOP 500 analyzer; Instrumentation Laboratory) and manufacturer provided reagents. RESULTS: A total of 97 patients were included in this study. Twelve patients had abnormal coagulation test results. An isolated prolonged PT was found in 8 patients and an isolated prolonged PTT was detected in 4 patients. CONCLUSION: The PT, but not APTT, was positively correlated with serum paraprotein level and this correlation was observed regardless of the reagents and instrumentation used to assess clot time. PMID- 29263048 TI - Comparison of Two Point-of-Care CYP2C19 Genotyping Assays for Genotype-Guided Antiplatelet Therapy. AB - BACKGROUND: CYP2C19 polymorphisms contribute about 12% of the variability in the antiplatelet effect of clopidogrel, which is commonly prescribed for patients undergoing percutaneous coronary intervention. For these patients, rapid turnaround time of CYP2C19 genotyping may be critical. We validated and compared the performance of two point-of-care CYP2C19 genotype tests, Nanosphere Verigene CYP2C19 Nucleic Acid Test and Spartan RX CYP2C19 System. MATERIALS AND METHODS: Our CLIA certified Molecular Diagnostic Laboratory performed 99 Verigene tests and 108 Spartan RX CYP2C19 assays. We compared performance and genotype results between the two platforms, across runs, and among technologists. Based on our validation results, we started offering CYP2C19 genotyping using the Spartan RX CYP2C19 assay for post-percutaneous coronary intervention patients. RESULTS: Laboratory validation genotype results were consistent between both assays when the assays produced results (100% accuracy); however, the Verigene CYP2C19 had a 33% no call rate. In contrast, Spartan consistently showed accurate results. Using a newly established clinical workflow, we assayed 342 post-percutaneous coronary intervention patients with the Spartan test. Within one hour of submitting patient samples, ordering physicians were notified of any clinically significant results and provided clinical decision support. CONCLUSIONS: Every approach has its limitations, but our practice of using the Spartan RX CYP2C19 test in our acute cardiac workflow provides accurate and rapid results to guide clinical decision-making at the point-of-care. Prospective follow-up is ongoing to evaluate outcomes and effectiveness of CYP2C19 testing. PMID- 29263050 TI - A Novel Inherited Mutation of SCN8A in a Korean Family with Benign Familial Infantile Epilepsy Using Diagnostic Exome Sequencing. AB - Mutations in SCN8A, which codes for the voltage-gated sodium channel NaV1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment. Here, we report the case of an infant and her father with early onset benign familial infantile epilepsy, but without cognitive or neurological impairment. In this patient, diagnostic exome sequencing (DES) identified a heterozygous mutation (c.4427G>A; p.Gly1476Asp) in the SCN8A gene. This mutation, confirmed by Sanger sequencing, effects a highly conserved amino acid. In-silico analysis predicts that this mutation may be pathogenic. To our knowledge, this is the first clinical report on Korean benign familial infantile epilepsy with a SCN8A mutation. We were able to achieve good seizure control in our patients with sodium channel blockers. This result suggests the application of DES will be valuable for the diagnosis of patients with infantile epilepsy but no cognitive impairment. PMID- 29263051 TI - Microduplications of 10q24 Detected in Two Chinese Patients with Split-hand/foot Malformation Type 3. AB - Split hand/foot malformation (SHFM) is a congenital heterogeneous disorder with prominent limb deficiency. Seven loci have been identified to associate with SHFM, including SHFM1 to SHFM6 and SHFM/SHFLD. SHFM3 is an autosomal dominant disease, of which the pathogenesis is closely related to the genomic rearrangements at 10q24.We described two Chinese patients with the SHFM3 phenotype by high-resolution SNP array technology. We detected a 534kb microduplication at 10q24 encompassing TLX1, LBX1, BTRC and POLL, and a 600kb duplication with TLX1, LBX1, BTRC, POLL, and FBXW4 located. Sequencing analysis did not find any pathogenic mutations in genes within the region detected by SNP Array Analysis. Our findings may offer more evidence for the further mechanism research of limb-specific congenital disease and will give more precise diagnosis to SHFM3 patients. PMID- 29263052 TI - Histiocytic Sarcoma with p16-Overexpression Presenting as Uterine Cervical Mass. AB - A 67-year-old woman presented with post-menopausal bleeding. Physical examination and imaging revealed a cervical mass with extensive pelvic involvement and supraclavicular lymphadenopathy. Clinical diagnosis was stage IVB cervical carcinoma. Cervical biopsy revealed high-grade squamous intraepithelial lesion and epithelioid tumor cells in the stroma. Lymph node biopsy revealed metastasis by similar epithelioid tumor cells. The epithelioid tumor cells were positive for p16, CD68, and CD163 on immunohistochemical study. The diagnosis of histiocytic sarcoma (HS) was rendered. This case demonstrated a rare presentation of HS mimicking cervical carcinoma. Awareness of this rare entity with appropriate ancillary tests is essential for accurate diagnosis. In contrast to the previous postulation of p16-inactivation as the pathogenesis of HS, p16-overexpression might suggest a different pathway for tumorigenesis. PMID- 29263053 TI - A Novel Sex Chromosome Mosaicism 45,X/45,Y/46,XY/46,YY/47,XYY Causing Ambiguous Genitalia. AB - Sex chromosomal mosaicism has been considered as a major cause of human sexual differentiation disorders, like partial virilization and ambiguous genitalia. 45,X/46,XX, 45,X/46,XY and 46,XY/47,XXY are three most common sex chromosome mosaics associated with human ambiguous genitalia. Here, we report the case of a 3-year-old boy with ambiguous genitalia, bilateral cryptorchidism, and with an inguinal hernia. G banded cytological karyotyping and FISH analyses revealed that the patient has extremely rare and novel sex chromosome mosaic 45,X/45,Y/46,XY/46,YY/47,XYY karyotype. These cells exist in different percentages, important for phenotypic appearance of the patient. This is a first report of an unusual mosaic karyotype causing ambiguous genitalia. PMID- 29263054 TI - Well Differentiated Endometrioid Adenocarcinoma of the Endometrium with "Adenoma Malignum-Like" Pattern of Invasion: Report of Two Cases and Review of Literature. AB - Unusual variants of endometrial endometrioid adenocarcinoma can be diagnostically challenging and pose difficulties to differentiate from their benign and malignant mimickers. Here we describe an entity that has been well documented in the literature, yet little is known about true outcome due to lack of studies with a large number of cases. Diffusely infiltrative or "adenoma-malignum-like" is an uncommon pattern of invasion in endometrioid endometrial adenocarcinoma which could be confused with adenomyosis. To the best of our knowledge only 58 cases (excluding these 2 cases) have been reported up to date in the English literature. PMID- 29263055 TI - Acute Appendicitis and Mean Platelet Volume: A Systemic Review and Meta-analysis. AB - BACKGROUND: Acute appendicitis (AA) is a common condition in general surgery, often with serious consequences such as septicemia and intra-abdominal infection. Mean platelet volume (MPV) - a platelet parameter - could be an index of inflammation. We carried out the present study to perform a meta-analysis of AA and MPV. METHODS: A systematic search was conducted in databases of PubMed and Embase from 1966 to 2015. Weighted mean difference and 95% confidence interval (CI) were then calculated. Finally, statistical analysis was carried out using Stata 12.0 software. RESULTS: Of the 88 selected studies, five case-control studies met the selection criteria. These cases, comprised1416 cases of AA and 685 controls. The results showed a prominent decrease of MPV levels in patients suffering from AA, compared to the control group. (weighted mean difference, 0.64; 95% CI, -0.74 to -0.54; P=0.037). CONCLUSIONS: AA cases had a lower MPV than the controls, which supports MPV as a potential biomarker of AA. PMID- 29263056 TI - Pyrazinamide Resistance among Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates in Myanmar. PMID- 29263057 TI - Pharmacokinetic/Pharmacodynamic Determinants of Vancomycin Efficacy in Enterococcal Bacteremia. AB - While pharmacokinetic-pharmacodynamic targets for vancomycin therapy are recognized for invasive methicillin-resistant Staphylococcus aureus infections, scant data are available to guide therapy for other Gram-positive infections. A retrospective single-center cohort of patients with Enterococcus bacteremia hospitalized between 1 January 2009 and 31 May 2015 were studied. The average vancomycin AUC0-24 was computed using a Bayesian approach. The MIC was determined by gradient diffusion (Etest; bioMerieux), and the average AUC0-24/MIC value over the initial 72 h of therapy was calculated. We assessed 30-day all-cause mortality as the primary outcome. Classification and regression tree analysis (CART) was used to identify the vancomycin AUC0-24/MIC value associated with 30 day mortality. Fifty-seven patients with enterococcal bacteremia (32 E. faecium, 21 E. faecalis, and 4 other Enterococcus spp.) were studied. The median vancomycin MIC was 0.75 mg/liter (range, 0.38 to 3 mg/liter). All-cause 30-day mortality occurred in 10 of 57 patients (17.5%). A CART-derived vancomycin AUC/MICEtest value of >=389 was associated with reduced mortality (P = 0.017); failure to achieve this independently predicted 30-day mortality (odds ratio, 6.83 [95% confidence interval = 1.51 to 30.84]; P = 0.01). We found that a vancomycin AUC/MICEtest value of >=389 achieved within 72 h was associated with reduced mortality. Larger, prospective studies are warranted to verify the vancomycin pharmacodynamic targets associated with maximal clinical outcomes and acceptable safety. PMID- 29263058 TI - Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis: an Update. PMID- 29263059 TI - Impact of Homologous Resistance Mutations from Pathogenic Yeast on Saccharomyces cerevisiae Lanosterol 14alpha-Demethylase. AB - Fungal infections frequently affect immunodeficient individuals and are estimated to kill 1.35 million people per annum. Azole antifungals target the membrane bound cytochrome P450 monooxygenase lanosterol 14alpha-demethylase (CYP51; Erg11p). Mutations in CYP51 can render the widely used triazole drugs less effective. The Candida albicans CYP51 mutation G464S and the double mutation Y132F G464S (Y140F and G464S by Saccharomyces cerevisiae numbering) as well as the CYP51A G54E/R/W mutations of Aspergillus fumigatus (G73E/R/W by S. cerevisiae numbering) have been reproduced in a recombinant C-terminal hexahistidine-tagged version of S. cerevisiae CYP51 (ScErg11p6*His). Phenotypes and X-ray crystal structures were determined for the mutant enzymes. Liquid microdilution assays showed that the G464S mutation in ScErg11p6*His conferred no difference in the susceptibility of yeast to triazole drugs but in combination with the Y140F mutation gave a 4-fold reduction in susceptibility to the short-tailed triazole fluconazole. The ScErg11p6*His Y140F G464S mutant was unstable during purification and was not crystallized. The ScErg11p6*His G73E/R/W mutations conferred increased susceptibly to all triazoles tested in liquid microdilution assays. High-resolution X-ray crystal structures reveal two different conformations of the ligand itraconazole, including a previously unseen conformation, as well as interactions between the tail of this triazole and the E/W73 residue. This study shows that S. cerevisiae CYP51 adequately represents some but not all mutations in CYP51s of pathogenic fungi. Insight into the molecular mechanisms of resistance mutations in CYP51 will assist the development of inhibitors that will overcome antifungal resistance. PMID- 29263060 TI - Nitric Oxide-Mediated Induction of Dispersal in Pseudomonas aeruginosa Biofilms Is Inhibited by Flavohemoglobin Production and Is Enhanced by Imidazole. AB - The biological signal molecule nitric oxide (NO) was found to induce biofilm dispersal across a range of bacterial species, which led to its consideration for therapeutic strategies to treat biofilms and biofilm-related infections. However, biofilms are often not completely dispersed after exposure to NO. To better understand this phenomenon, we investigated the response of Pseudomonas aeruginosa biofilm cells to successive NO treatments. When biofilms were first pretreated with a low, noneffective dose of NO, a second dose of the signal molecule at a concentration usually capable of inducing dispersal did not have any effect. Amperometric analysis revealed that pretreated P. aeruginosa cells had enhanced NO-scavenging activity, and this effect was associated with the production of the flavohemoglobin Fhp. Further, quantitative real-time reverse transcription-PCR (qRT-PCR) analysis showed that fhp expression increased by over 100-fold in NO-pretreated biofilms compared to untreated biofilms. Biofilms of mutant strains harboring mutations in fhp or fhpR, encoding a NO-responsive regulator of fhp, were not affected in their dispersal response after the initial pretreatment with NO. Overall, these results suggest that FhpR can sense NO to trigger production of the flavohemoglobin Fhp and inhibit subsequent dispersal responses to NO. Finally, the addition of imidazole, which can inhibit the NO dioxygenase activity of flavohemoglobin, attenuated the prevention of dispersal after NO pretreatment and improved the dispersal response in older, starved biofilms. This study clarifies the underlying mechanisms of impaired dispersal induced by repeated NO treatments and offers a new perspective for improving the use of NO in biofilm control strategies. PMID- 29263061 TI - Effects of Renal Impairment and Hemodialysis on the Pharmacokinetics and Safety of the Glecaprevir and Pibrentasvir Combination in Hepatitis C Virus-Negative Subjects. AB - Hepatitis C virus (HCV) infection is an independent risk factor for developing chronic renal impairment and end-stage renal disease. Limited treatment options are available for HCV genotype 2, 3, 5, and 6 infections in patients with an estimated glomerular filtration rate (eGFR) of <30 ml/min. Glecaprevir and pibrentasvir are active against all six major HCV genotypes, are primarily excreted in the bile, and have minimal renal elimination. Therefore, combined treatment with these direct-acting antivirals may be useful for patients with HCV infection and chronic kidney disease. A phase 1, multicenter, open-label study evaluated the effects of renal impairment on the pharmacokinetics and safety of glecaprevir-pibrentasvir. In substudy 1, 38 subjects with stage 2 to 5 chronic kidney disease who were not on dialysis or who had normal renal function received single doses of the combination of 300 mg glecaprevir and 120 mg pibrentasvir. In substudy 2, 8 subjects requiring hemodialysis received single doses of the combination of 300 mg glecaprevir and 120 mg pibrentasvir under dialysis and nondialysis conditions. Regression analyses demonstrated increased glecaprevir and pibrentasvir plasma exposures, as determined by the area under the curve, with decreasing renal function, up to 56% and 46%, respectively, in subjects with an eGFR of <15 ml/min/1.73 m2 In dialysis-dependent subjects, glecaprevir and pibrentasvir exposures were similar (<=18% difference) when study drugs were administered before hemodialysis or on a nondialysis day. Adverse events were mostly mild, with the most common being self-limited fatigue (3 subjects). The study findings support the clinical evaluation of glecaprevir-pibrentasvir without dose adjustment in HCV-infected subjects with renal impairment. (This study has been registered at ClinicalTrials.gov under registration number NCT02442258.). PMID- 29263062 TI - Modeling the Emergence of Antibiotic Resistance in the Environment: an Analytical Solution for the Minimum Selection Concentration. AB - Environmental antibiotic risk management requires an understanding of how subinhibitory antibiotic concentrations contribute to the spread of resistance. We develop a simple model of competition between sensitive and resistant bacterial strains to predict the minimum selection concentration (MSC), the lowest level of antibiotic at which resistant bacteria are selected. We present an analytical solution for the MSC based on the routinely measured MIC, the selection coefficient (sc) that expresses fitness differences between strains, the intrinsic net growth rate, and the shape of the bacterial growth dose response curve with antibiotic or metal exposure (the Hill coefficient [kappa]). We calibrated the model by optimizing the Hill coefficient to fit previously reported experimental growth rate difference data. The model fit varied among nine compound-taxon combinations examined but predicted the experimentally observed MSC/MIC ratio well (R2 >= 0.95). The shape of the antibiotic response curve varied among compounds (0.7 <= kappa <= 10.5), with the steepest curve being found for the aminoglycosides streptomycin and kanamycin. The model was sensitive to this antibiotic response curve shape and to the sc, indicating the importance of fitness differences between strains for determining the MSC. The MSC can be >1 order of magnitude lower than the MIC, typically by the factor sckappa This study provides an initial quantitative depiction and a framework for a research agenda to examine the growing evidence of selection for resistant bacterial communities at low environmental antibiotic concentrations. PMID- 29263063 TI - Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP 1 Monocytes. AB - Linezolid, the first clinically available oxazolidinone antibiotic, causes potentially severe toxicities (myelosuppression, lactic acidosis, and neuropathies) ascribed to impairment of mitochondrial protein synthesis and consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone, shows an enhanced activity compared to linezolid but is also a more potent inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid for (i) inhibition of the expression of subunit I of cytochrome c-oxidase (CYTox I; Western blot analysis), (ii) cytochrome c-oxidase activity (biochemical assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) alteration of mitochondrial ultrastructure (electron microscopy) using HL-60 promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of modal MIC against Staphylococcus aureus) and therapeutically (Cmin - Cmax) pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h) inhibition of CYTox I expression, cytochrome c-oxidase activity, and spare respiratory capacity, with conspicuous swelling of the mitochondrial matrix and loss of their cristae. Globally, tedizolid was a more potent inhibitor than linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully reversible upon drug withdrawal. Using an alternation of exposure to and withdrawal from drug mimicking their approved schedule of administration (twice daily and once daily [qD] for linezolid and tedizolid, respectively), only partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid reversal of toxic effects upon discontinuous administration may mitigate oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its reported lower preclinical and clinical toxicity. PMID- 29263064 TI - Depot Subcutaneous Injection with Chalcone CH8-Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres as a Single-Dose Treatment of Cutaneous Leishmaniasis. AB - Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. In vitro, murine macrophages avidly phagocytosed CH8/PLGA smaller than 6 MUm without triggering oxidative mechanisms. Upon 48 h of incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular Leishmania amazonensis than to macrophages. In vivo, BALB/c were given one or three subcutaneous injections in the infected ear with 1.2 mg/kg of CH8 in free or CH8/PLGA forms, whereas controls received three CH8-equivalent doses of naked PLGA microparticles or meglumine antimoniate (Glucantime; Sanofi-Aventis). Although a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80 and 97% reductions, respectively, in relation to saline controls. Meglumine antimoniate treatment was the least effective (only 36% reduction) and the most toxic, as indicated by elevated alanine aminotransferase serum levels. Together, these findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL. PMID- 29263065 TI - Characterization of KPC-Encoding Plasmids from Enterobacteriaceae Isolated in a Czech Hospital. AB - Ten Enterobacteriaceae isolates collected in a Czech hospital carried blaKPC positive plasmids of different sizes (~30, ~45, and ~80 kb). Sequencing revealed three types of plasmids (A to C) with the Tn4401a transposon. Type A plasmids comprised an IncR backbone and a KPC-2-encoding multidrug resistance (MDR) region. Type B plasmids were derivatives of type A plasmids carrying an IncN3 like segment, while type C plasmids were IncP6 plasmids sharing the same KPC-2 encoding MDR region with type A and B plasmids. PMID- 29263066 TI - Prediction of Fluoroquinolone Susceptibility Directly from Whole-Genome Sequence Data by Using Liquid Chromatography-Tandem Mass Spectrometry To Identify Mutant Genotypes. AB - Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis, using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms for fluoroquinolone nonsusceptibility using Klebsiella pneumoniae as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography-tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole-genome sequence data were functionally important in the context of fluoroquinolone susceptibility. PMID- 29263067 TI - Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella pneumoniae Sequence Type 307 Isolates. AB - Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in Klebsiella pneumoniae sequence type 258 (ST258) blaKPC-3-harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant Klebsiella pneumoniae isolates from a patient with pancreatitis. All susceptible (n = 3) and resistant (n = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ AVI resistance first occurred through a 532G -> T blaKPC-2 point mutation in blaKPC-2 (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (<=2 MUg/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 MUg/ml) but also MEM resistance (MIC > 128 MUg/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type blaKPC-2 into a novel plasmid, an IS1 insertion upstream of ompK36, and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non-K. pneumoniae ST258 clonal backgrounds and alternative blaKPC variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment. PMID- 29263068 TI - Prostaglandin E2 Receptor Antagonist with Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus. AB - Polymicrobial intra-abdominal infections (IAI) involving Candida albicans and Staphylococcus aureus are associated with severe morbidity and mortality (~80%). Our laboratory discovered that the immunomodulatory eicosanoid prostaglandin E2 (PGE2) plays a key role in the lethal inflammatory response during polymicrobial IAI using a mouse model of infection. In studies designed to uncover key PGE2 biosynthesis/signaling components involved in the response, selective eicosanoid enzyme inhibitors and receptor antagonists were selected and prescreened for antimicrobial activity against C. albicans or S. aureus Unexpectedly, we found that the EP4 receptor antagonist L-161,982 had direct growth-inhibitory effects on S. aureusin vitro at the physiological concentration required to block the PGE2 interaction with EP4 This antimicrobial activity was observed with methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA) strains, with the MIC and minimum bactericidal concentration values for planktonic cells being 50 MUg/ml and 100 MUg/ml, respectively. In addition, L 161,982 inhibited S. aureus biofilm formation and had activity against preformed mature biofilms. More importantly, treatment of mice with L-161,982 following intraperitoneal inoculation with a lethal dose of MRSA significantly reduced the bioburden and enhanced survival. Furthermore, L-161,982 protected mice against the synergistic lethality induced by coinfection with C. albicans and S. aureus The antimicrobial activity of L-161,982 is independent of EP4 receptor inhibitory activity; an alternative EP4 receptor antagonist exerted no antimicrobial or protective effects. Taken together, these findings demonstrate that L-161,982 has potent antimicrobial activity against MRSA and may represent a significant therapeutic alternative in improving the prognosis of mono- or polymicrobial infections involving MRSA. PMID- 29263070 TI - Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects. AB - Alalevonadifloxacin (WCK 2349) is a novel l-alanine ester prodrug of levonadifloxacin that is being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin to healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM samples from 30 healthy subjects were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following oral dosing of alalevonadifloxacin (1,000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage (BAL) fluid sampling time, i.e., 2, 4, 6, 8, or 12 h after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-h interval following the first and ninth oral doses. Penetration ratios were calculated from the areas under the concentration-time curves from 0 to 12 h (AUC0-12) for plasma, ELF, and AM by using mean (and median) concentrations at each BAL sampling time. Unbound plasma concentrations (~85% plasma protein binding) were used to determine site to-plasma penetration ratios. Plasma PK parameter values for levonadifloxacin were similar after the first and ninth doses. The respective AUC0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg . h/liter, respectively. The penetration ratios for ELF and AM levonadifloxacin concentrations to unbound plasma levonadifloxacin concentrations were 7.66 and 1.58, respectively. Similar penetration ratios were observed with median concentrations. The observed plasma, ELF, and AM concentrations of levonadifloxacin support further studies of alalevonadifloxacin for treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02253342.). PMID- 29263069 TI - Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Aerosolized Colistin in a Mouse Lung Infection Model. AB - Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. In vivo time-kill experiments were carried out with three different strains of Pseudomonas aeruginosa An MBM was developed in S ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal Emax model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a >=2-log10 bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin. PMID- 29263071 TI - Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs. AB - Invasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reversing azole resistance in Candida In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity in Candida albicans Surprisingly, the majority of assayed sulfa drugs (15 of 21) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with fractional inhibitory concentration index (SigmaFIC) values ranging from <0.0312 to 0.25. Remarkably, five sulfa drugs were able to reverse azole resistance in a clinically achievable range. The structure-activity relationships (SARs) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibit Candida biofilm by 40% in vitro was confirmed. In addition, the effects of sulfa fluconazole combinations on Candida growth kinetics and efflux machinery were explored. Finally, using a Caenorhabditis elegans infection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activity in vivo, reducing Candida in infected worms by ~50% compared to the control. PMID- 29263072 TI - Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis. AB - Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 h postdose in children with tuberculosis on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method, and pharmacokinetic parameters were calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1, and CES2 SNPs were performed using validated TaqMan genotyping assays. The Kruskal-Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups and was followed by the Wilcoxon rank sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have a high frequency of implicated genotypes. Further studies in other populations are warranted. PMID- 29263073 TI - Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015. AB - The activities of ceftolozane-tazobactam and comparator agents against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States during 2013 to 2015 were evaluated. Organisms included 1,576 Pseudomonas aeruginosa and 2,362 Enterobacteriaceae isolates susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78.6%, respectively, of the P. aeruginosa isolates. Ceftolozane tazobactam inhibited 77.5 to 85.1% of isolates nonsusceptible to antipseudomonal beta-lactams and 86.6% and 71.0% of the 372 (23.6% overall) multidrug- and 155 (9.8%) extensively drug-resistant isolates tested. The activity of this combination was greater than those of other beta-lactams evaluated against P. aeruginosa groups across all U.S. census divisions. Ceftolozane-tazobactam was active against 90.6% of the Enterobacteriaceae, being less active than only meropenem (95.6% susceptible) among the beta-lactams evaluated. Against 145 Escherichia coli and Klebsiella pneumoniae isolates carrying extended-spectrum beta-lactamase (ESBL)-encoding genes without carbapenemases, ceftolozane tazobactam inhibited 82.8% of these isolates and was more active than cefepime and piperacillin-tazobactam (15.2% and 74.3% susceptible, respectively). ESBL genes included in this analysis were mainly blaCTX-M-15-like (89 isolates) and blaCTX-M-14-like (22) genes but also blaSHV (31) and blaTEM (3). Ceftolozane tazobactam also displayed activity (84.6% susceptible) against 13 isolates harboring acquired AmpC genes. All beta-lactams displayed limited activity against blaKPC-carrying isolates. Ceftolozane-tazobactam was the most active beta lactam tested against P. aeruginosa isolates from isolates that were the probable cause of pneumonia and displayed in vitro activity against Enterobacteriaceae, including isolates resistant to cephalosporins and carrying ESBL genes. PMID- 29263074 TI - Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts In Vitro Antimalarial Activity. AB - The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (~90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia. PMID- 29263075 TI - Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis. AB - AmBisome (LAmB), a liposomal formulation of amphotericin B (AmB), is a second line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with those of the deoxycholate form of AmB (DAmB; trade name Fungizone) in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 h after single intravenous (i.v.) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6, and 8). After single and multiple dosing, intralesional concentrations were 5- and 20-fold, respectively, higher than those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25, or 12.5 mg/kg (i.v.), there was a clear correlation between dose level, intralesional AmB concentration, and relative reduction in parasite load and lesion size (R2 values of >0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation. PMID- 29263076 TI - Aminoarabinosylation of Lipid A Is Critical for the Development of Colistin Resistance in Pseudomonas aeruginosa. AB - Lipid A aminoarabinosylation is invariably associated with colistin resistance in Pseudomonas aeruginosa; however, the existence of alternative aminoarabinosylation-independent colistin resistance mechanisms in this bacterium has remained elusive. By combining reverse genetics with experimental evolution assays, we demonstrate that a functional lipid A aminoarabinosylation pathway is critical for the acquisition of colistin resistance in reference and clinical P. aeruginosa isolates. This highlights lipid A aminoarabinosylation as a promising target for the design of colistin adjuvants against P. aeruginosa. PMID- 29263077 TI - Antimicrobial Activity of Dalbavancin against Staphylococcus aureus with Decreased Susceptibility to Glycopeptides, Daptomycin, and/or Linezolid from U.S. Medical Centers. AB - Dalbavancin activity was assessed against a large collection of Staphylococcus aureus isolates (n = 59,903), including isolates with decreased susceptibility to vancomycin (MIC, >=2 mg/liter; n = 1,141), daptomycin (MIC, >=2 mg/liter; n = 48), telavancin (MIC, >=0.12 mg/liter; n = 52), teicoplanin (MIC, >=4 mg/liter; n = 143), and/or linezolid (MIC, >=8 mg/liter; n = 25). Dalbavancin displayed susceptibility rates ranging from 90.4% (isolates with telavancin MIC >=0.12 mg/liter) to 100.0% (linezolid-resistant isolates) and lower MIC values than the comparators against these resistant subsets. PMID- 29263078 TI - Dramatic Increase of Amoxicillin-Induced Crystal Nephropathy Found in a Cohort Study of French Pharmacovigilance Centers. AB - An increase in amoxicillin-induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [interquartile range {IQR}, 43 to 110] mg/kg of body weight/day) in all patients, either for treating infection (n = 15) or as surgical prophylaxis (n = 30). Delay between AMX administration and AICN onset was 1 (IQR, 1 to 3) day; 30, 4, and 11 patients developed KDIGO stage 1, 2, and 3 acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 (IQR, 2 to 6) days. Precipitating factors were identified in only one-third of cases. Twelve patients required intensive care unit admission, and 8 needed renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN in the Paris RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers. PMID- 29263079 TI - Impact of Real-Time Therapeutic Drug Monitoring on the Prescription of Antibiotics in Burn Patients Requiring Admission to the Intensive Care Unit. AB - As pharmacokinetics after burn trauma are difficult to predict, we conducted a 3 year prospective, monocentric, randomized, controlled trial to determine the extent of under- and overdosing of antibiotics and further evaluate the impact of systematic therapeutic drug monitoring (TDM) with same-day real-time dose adaptation to reach and maintain antibiotic concentrations within the therapeutic range. Forty-five consecutive burn patients treated with antibiotics were prospectively screened. Forty fulfilled the inclusion criteria; after one patient refused to participate and one withdrew consent, 19 were randomly assigned to an intervention group (patients with real-time antibiotic concentration determination and subsequent adaptations) and 19 were randomly assigned to a standard-of-care group (patients with antibiotic administration at the physician's discretion without real-time TDM). Seventy-three infection episodes were analyzed. Before the intervention, only 46/82 (56%) initial trough concentrations fell within the range. There was no difference between groups in the initial trough concentrations (adjusted hazard ratio = 1.39 [95% confidence interval {CI}, 0.81 to 2.39], P = 0.227) or the time to reach the target. However, thanks to real-time dose adjustments, the trough concentrations of the intervention group remained more within the predefined range (57/77 [74.0%] versus 48/85 [56.5%]; adjusted odd ratio [OR] = 2.34 [95% CI, 1.17 to 4.81], P = 0.018), more days were spent within the target range (193 days/297 days on antibiotics [65.0%] versus 171 days/311 days in antibiotics [55.0%]; adjusted OR = 1.64 [95% CI, 1.16 to 2.32], P = 0.005), and fewer results were below the target trough concentrations (25/118 [21.2%] versus 44/126 [34.9%]; adjusted OR = 0.47 [95% CI, 0.26 to 0.87], P = 0.015). No difference in infection outcomes was observed between the study groups. Systematic TDM with same-day real-time dose adaptation was effective in reaching and maintaining therapeutic antibiotic concentrations in infected burn patients, which prevented both over- and underdosing. A larger multicentric study is needed to further evaluate the impact of this strategy on infection outcomes and the emergence of antibiotic resistance during long-term burn treatment. (This study was registered with the ClinicalTrials.gov platform under registration no. NCT01965340 on 27 September 2013.). PMID- 29263080 TI - Phase separation of BuGZ promotes Aurora A activation and spindle assembly. AB - The spindle matrix has been proposed to facilitate mitotic spindle assembly. In this issue, Huang et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201706103) show that the spindle matrix protein BuGZ is sufficient to form micron-scale compartments that recruit and activate Aurora A, a critical kinase for spindle assembly. PMID- 29263082 TI - A toolbox of anti-mouse and anti-rabbit IgG secondary nanobodies. AB - Polyclonal anti-immunoglobulin G (anti-IgG) secondary antibodies are essential tools for many molecular biology techniques and diagnostic tests. Their animal based production is, however, a major ethical problem. Here, we introduce a sustainable alternative, namely nanobodies against all mouse IgG subclasses and rabbit IgG. They can be produced at large scale in Escherichia coli and could thus make secondary antibody production in animals obsolete. Their recombinant nature allows fusion with affinity tags or reporter enzymes as well as efficient maleimide chemistry for fluorophore coupling. We demonstrate their superior performance in Western blotting, in both peroxidase- and fluorophore-linked form. Their site-specific labeling with multiple fluorophores creates bright imaging reagents for confocal and superresolution microscopy with much smaller label displacement than traditional secondary antibodies. They also enable simpler and faster immunostaining protocols, and allow multitarget localization with primary IgGs from the same species and of the same class. PMID- 29263081 TI - Opportunities for organoids as new models of aging. AB - The biology of aging is challenging to study, particularly in humans. As a result, model organisms are used to approximate the physiological context of aging in humans. However, the best model organisms remain expensive and time consuming to use. More importantly, they may not reflect directly on the process of aging in people. Human cell culture provides an alternative, but many functional signs of aging occur at the level of tissues rather than cells and are therefore not readily apparent in traditional cell culture models. Organoids have the potential to effectively balance between the strengths and weaknesses of traditional models of aging. They have sufficient complexity to capture relevant signs of aging at the molecular, cellular, and tissue levels, while presenting an experimentally tractable alternative to animal studies. Organoid systems have been developed to model many human tissues and diseases. Here we provide a perspective on the potential for organoids to serve as models for aging and describe how current organoid techniques could be applied to aging research. PMID- 29263084 TI - CORRECTION. PMID- 29263083 TI - Doctor won't see you now: changing paradigms in mountain medicine. AB - The evolution in communication and digital technologies is revolutionising the practice of medicine. A physician is now able to oversee provision of healthcare at a distance. In this paper, we argue that practice of telemedicine is an essential and evolving aspect of high altitude and expedition medicine. We acknowledge the lack of international consensus, limited legislation as well as possible reservations towards telemedical practice. Given some unique social and medical aspects of participation in remote, high altitude expeditions we propose a number of guiding principles for those involved in provision of telemedical services for such endeavours. PMID- 29263087 TI - Axis of Algae: Disruption of Basal Cell Fates in the Brown Alga Ectocarpus. PMID- 29263086 TI - Is It Ordered Correctly? Validating Genome Assemblies by Optical Mapping. AB - Long-read single-molecule sequencing, Hi-C sequencing, and improved bioinformatic tools are ushering in an era where complete genome assembly will become common for species with few or no classical genetic resources. There are no guidelines for how to proceed in such cases. Ideally, such genomes would be sequenced by two different methods so that one assembly serves as confirmation of the other; however, cost constraints make this approach unlikely. Overreliance on synteny as a means of confirming and ordering contigs will lead to compounded errors. Optical mapping is an accessible and relatively mature technology that can be used for genome assembly validation. We discuss how optical mapping can be used as a validation tool for genome assemblies and how to interpret the results. In addition, we discuss methods for using optical map data to enhance genome assemblies derived from both traditional sequence contigs and Hi-C pseudomolecules. PMID- 29263085 TI - Brassinosteroids Modulate Meristem Fate and Differentiation of Unique Inflorescence Morphology in Setaria viridis. AB - Inflorescence architecture is a key determinant of yield potential in many crops and is patterned by the organization and developmental fate of axillary meristems. In cereals, flowers and grain are borne from spikelets, which differentiate in the final iteration of axillary meristem branching. In Setaria spp, inflorescence branches terminate in either a spikelet or a sterile bristle, and these structures appear to be paired. In this work, we leverage Setaria viridis to investigate a role for the phytohormones brassinosteroids (BRs) in specifying bristle identity and maintaining spikelet meristem determinacy. We report the molecular identification and characterization of the Bristleless1 (Bsl1) locus in S. viridis, which encodes a rate-limiting enzyme in BR biosynthesis. Loss-of-function bsl1 mutants fail to initiate a bristle identity program, resulting in homeotic conversion of bristles to spikelets. In addition, spikelet meristem determinacy is altered in the mutants, which produce two florets per spikelet instead of one. Both of these phenotypes provide avenues for enhanced grain production in cereal crops. Our results indicate that the spatiotemporal restriction of BR biosynthesis at boundary domains influences meristem fate decisions during inflorescence development. The bsl1 mutants provide insight into the molecular basis underlying morphological variation in inflorescence architecture. PMID- 29263088 TI - Comprehensive, integrated approaches to suicide prevention: practical guidance. AB - BACKGROUND: Efforts in the USA during the 21st century to stem the ever-rising tide of suicide and risk-related premature deaths, such as those caused by drug intoxications, have failed. Based primarily on identifying individuals with heightened risk nearing the precipice of death, these initiatives face fundamental obstacles that cannot be overcome readily. OBJECTIVE: This paper describes the step-by-step development of a comprehensive public health approach that seeks to integrate at the community level an array of programmatic efforts, which address upstream (distal) risk factors to alter life trajectories while also involving health systems and clinical providers who care for vulnerable, distressed individuals, many of whom have attempted suicide. CONCLUSION: Preventing suicide and related self-injury morbidity and mortality, and their antecedents, will require a systemic approach that builds on a societal commitment to save lives and collective actions that bring together diverse communities, service organisations, healthcare providers and governmental agencies and political leaders. This will require frank, data-based appraisals of burden that drive planning, programme development and implementation, rigorous evaluation and a willingness to try-fail-and-try-again until the tide has been turned. PMID- 29263089 TI - What is the level of household gun ownership in urban Mexico? An estimate from the first Mexican survey on gun ownership 2017. AB - Gun violence has increased in Mexico since the mid-2000s, but little is known about patterns of gun ownership. We examine the size and composition of the privately held urban firearm stock in Mexico, motivations for ownership, and attitudes about gun laws. To this end, a household telephone survey of 1361 adults living in nine Mexican cities was conducted in the summer of 2017. We find that few urban Mexican households contain guns. Most of those who report ownership possess one gun, having purchased it recently for self-defense. Few urban Mexican citizens plan to purchase a gun in the future. Respondents are more likely to believe that crime in Mexico would increase if guns were allowed in more places (ie, workplaces and motor vehicles). Evidence suggests urban Mexico has relative low rates of firearm ownership. Few city dwellers plan on obtaining a firearm in the near future. PMID- 29263090 TI - A membrane-associated, fluorogenic reporter for mammalian phospholipase C isozymes. AB - A diverse group of cell-surface receptors, including many G protein-coupled receptors and receptor tyrosine kinases, activate phospholipase C (PLC) isozymes to hydrolyze phosphatidylinositol 4,5-bisphosphate into the second messengers diacylglycerol and 1,4,5-inositol trisphosphate. Consequently, PLCs control various cellular processes, and their aberrant regulation contributes to many diseases, including cancer, atherosclerosis, and rheumatoid arthritis. Despite the widespread importance of PLCs in human biology and disease, it has been impossible to directly monitor the real-time activation of these enzymes at membranes. To overcome this limitation, here we describe XY-69, a fluorogenic reporter that preferentially partitions into membranes and provides a selective tool for measuring the real-time activity of PLCs as either purified enzymes or in cellular lysates. Indeed, XY-69 faithfully reported the membrane-dependent activation of PLC-beta3 by Galphaq Therefore, XY-69 can replace radioactive phosphatidylinositol 4,5-bisphosphate used in conventional PLC assays and will enable high-throughput screens to identify both orthosteric and allosteric PLC inhibitors. In the future, cell-permeable variants of XY-69 represent promising candidates for reporting the activation of PLCs in live cells with high spatiotemporal resolution. PMID- 29263091 TI - Substitution of the D1-Asn87 site in photosystem II of cyanobacteria mimics the chloride-binding characteristics of spinach photosystem II. AB - Photoinduced water oxidation at the O2-evolving complex (OEC) of photosystem II (PSII) is a complex process involving a tetramanganese-calcium cluster that is surrounded by a hydrogen-bonded network of water molecules, chloride ions, and amino acid residues. Although the structure of the OEC has remained conserved over eons of evolution, significant differences in the chloride-binding characteristics exist between cyanobacteria and higher plants. An analysis of amino acid residues in and around the OEC has identified residue 87 in the D1 subunit as the only significant difference between PSII in cyanobacteria and higher plants. We substituted the D1-Asn87 residue in the cyanobacterium Synechocystis sp. PCC 6803 (wildtype) with alanine, present in higher plants, or with aspartic acid. We studied PSII core complexes purified from D1-N87A and D1 N87D variant strains to probe the function of the D1-Asn87 residue in the water oxidation mechanism. EPR spectra of the S2 state and flash-induced FTIR spectra of both D1-N87A and D1-N87D PSII core complexes exhibited characteristics similar to those of wildtype Synechocystis PSII core complexes. However, flash-induced O2 evolution studies revealed a decreased cycling efficiency of the D1-N87D variant, whereas the cycling efficiency of the D1-N87A PSII variant was similar to that of wildtype PSII. Steady-state O2-evolution activity assays revealed that substitution of the D1 residue at position 87 with alanine perturbs the chloride binding site in the proton-exit channel. These findings provide new insight into the role of the D1-Asn87 site in the water-oxidation mechanism and explain the difference in the chloride-binding properties of cyanobacterial and higher-plant PSII. PMID- 29263092 TI - Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes. AB - The transcription factor BCL11A has recently been reported to be a driving force in triple-negative breast cancer (TNBC), contributing to the maintenance of a chemoresistant breast cancer stem cell (BCSC) population. Although BCL11A was shown to suppress gamma-globin and p21 and to induce MDM2 expression in the hematopoietic system, its downstream targets in TNBC are still unclear. For its role in transcriptional repression, BCL11A was found to interact with several corepressor complexes; however, the mechanisms underlying these interactions remain unknown. Here, we reveal that BCL11A interacts with histone methyltransferase (PRC2) and histone deacetylase (NuRD and SIN3A) complexes through their common subunit, RBBP4/7. In fluorescence polarization assays, we show that BCL11A competes with histone H3 for binding to the negatively charged top face of RBBP4. To define that interaction, we solved the crystal structure of RBBP4 in complex with an N-terminal peptide of BCL11A (residues 2-16, BCL11A(2 16)). The crystal structure identifies novel interactions between BCL11A and the side of the beta-propeller of RBBP4 that are not seen with histone H3. We next show that BCL11A(2-16) pulls down RBBP4, RBBP7, and other components of PRC2, NuRD, and SIN3A from the cell lysate of the TNBC cell line SUM149. Furthermore, we demonstrate the therapeutic potential of targeting the RBBP4-BCL11A binding by showing that a BCL11A peptide can decrease aldehyde dehydrogenase-positive BCSCs and mammosphere formation capacity in SUM149. Together, our findings have uncovered a previously unidentified mechanism that BCL11A may use to recruit epigenetic complexes to regulate transcription and promote tumorigenesis. PMID- 29263093 TI - Silencing steroid receptor coactivator-1 in the nucleus of the solitary tract reduces estrogenic effects on feeding and apolipoprotein A-IV expression. AB - We previously found that 17beta-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor alpha (ERalpha), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERalpha and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females. PMID- 29263094 TI - Stand-alone ClpG disaggregase confers superior heat tolerance to bacteria. AB - AAA+ disaggregases solubilize aggregated proteins and confer heat tolerance to cells. Their disaggregation activities crucially depend on partner proteins, which target the AAA+ disaggregases to protein aggregates while concurrently stimulating their ATPase activities. Here, we report on two potent ClpG disaggregase homologs acquired through horizontal gene transfer by the species Pseudomonas aeruginosa and subsequently abundant P. aeruginosa clone C. ClpG exhibits high, stand-alone disaggregation potential without involving any partner cooperation. Specific molecular features, including high basal ATPase activity, a unique aggregate binding domain, and almost exclusive expression in stationary phase distinguish ClpG from other AAA+ disaggregases. Consequently, ClpG largely contributes to heat tolerance of P. aeruginosa primarily in stationary phase and boosts heat resistance 100-fold when expressed in Escherichia coli This qualifies ClpG as a potential persistence and virulence factor in P. aeruginosa. PMID- 29263095 TI - Lumpy species coexistence arises robustly in fluctuating resource environments. AB - The effect of life-history traits on resource competition outcomes is well understood in the context of a constant resource supply. However, almost all natural systems are subject to fluctuations of resources driven by cyclical processes such as seasonality and tidal hydrology. To understand community composition, it is therefore imperative to study the impact of resource fluctuations on interspecies competition. We adapted a well-established resource competition model to show that fluctuations in inflow concentrations of two limiting resources lead to the survival of species in clumps along the trait axis, consistent with observations of "lumpy coexistence" [Scheffer M, van Nes EH (2006) Proc Natl Acad Sci USA 103:6230-6235]. A complex dynamic pattern in the available ambient resources arose very early in the self-organization process and dictated the locations of clumps along the trait axis by creating niches that promoted the growth of species with specific traits. This dynamic pattern emerged as the combined result of fluctuations in the inflow of resources and their consumption by the most competitive species that accumulated the bulk of biomass early in assemblage organization. Clumps emerged robustly across a range of periodicities, phase differences, and amplitudes. Given the ubiquity in the real world of asynchronous fluctuations of limiting resources, our findings imply that assemblage organization in clumps should be a common feature in nature. PMID- 29263096 TI - Histone demethylase LSD1 regulates hematopoietic stem cells homeostasis and protects from death by endotoxic shock. AB - Hematopoietic stem cells (HSCs) maintain a quiescent state during homeostasis, but with acute infection, they exit the quiescent state to increase the output of immune cells, the so-called "emergency hematopoiesis." However, HSCs' response to severe infection during septic shock and the pathological impact remain poorly elucidated. Here, we report that the histone demethylase KDM1A/LSD1, serving as a critical regulator of mammalian hematopoiesis, is a negative regulator of the response to inflammation in HSCs during endotoxic shock typically observed during acute bacterial or viral infection. Inflammation-induced LSD1 deficiency results in an acute expansion of a pathological population of hyperproliferative and hyperinflammatory myeloid progenitors, resulting in a septic shock phenotype and acute death. Unexpectedly, in vivo administration of bacterial lipopolysaccharide (LPS) to wild-type mice results in acute suppression of LSD1 in HSCs with a septic shock phenotype that resembles that observed following induced deletion of LSD1 The suppression of LSD1 in HSCs is caused, at least in large part, by a cohort of inflammation-induced microRNAs. Significantly, reconstitution of mice with bone marrow progenitor cells expressing inhibitors of these inflammation induced microRNAs blocked the suppression of LSD1 in vivo following acute LPS administration and prevented mortality from endotoxic shock. Our results indicate that LSD1 activators or miRNA antagonists could serve as a therapeutic approach for life-threatening septic shock characterized by dysfunction of HSCs. PMID- 29263097 TI - Multiple Structures Disclose the Secretins' Secrets. AB - Bacterial secretins are outer membrane proteins that provide a path for secreted proteins to access the cell exterior/surface. They are one of the core components of secretion machines and are found in type II and type III secretion systems (T2SS and T3SS, respectively). The secretins comprise giant ring-shaped homo oligomers whose precise atomic organization was only recently deciphered thanks to spectacular developments in cryo-electron microscopy (cryo-EM) imaging techniques. PMID- 29263098 TI - The Ca2+ induced two-component system, CvsSR regulates the Type III secretion system and the extracytoplasmic function sigma-factor AlgU in Pseudomonas syringae pv. tomato DC3000. AB - Two-component systems (TCSs) of bacteria regulate many different aspects of the bacterial life cycle including pathogenesis. Most TCSs remain uncharacterized with no information about the signal(s) or regulatory targets and/or role in bacterial pathogenesis. Here, we characterized a TCS in the plant-pathogenic bacterium Pseudomonas syringae pv. tomato DC3000 (Pto) composed of the histidine kinase, CvsS, and the response regulator, CvsR. CvsSR is necessary for virulence of Pto, since DeltacvsS and DeltacvsR strains produced fewer symptoms and demonstrated reduced growth on multiple hosts as compared to WT. We discovered that expression of cvsSR is induced by Ca2+ concentrations found in leaf apoplastic fluid. Thus, Ca2+ can be added to the list of signals that promote pathogenesis of Pto during host colonization. Through chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) and global transcriptome analysis (RNA-seq) we discerned the CvsR regulon. CvsR directly activated expression of the type III secretion system regulators, hrpR and hrpS, that regulates Pto virulence in a type III secretion system dependent manner. CvsR also indirectly repressed transcription of the extracytoplasmic sigma factor algU and production of alginate. Phenotypic analysis determined that CvsSR inversely regulated biofilm formation, swarming motility, and cellulose production in a Ca2+-dependent manner. Overall, our results show that CvsSR is a key regulatory hub critical for interaction with host plants.Importance Pathogenic bacteria must be able to react and respond to the surrounding environment, make use of available resources, and avert or counter host immune responses. Often, these abilities rely on two-component systems (TCSs) composed of interacting proteins that modulate gene expression. We identified a TCS in the plant-pathogenic bacterium Pseudomonas syringae that responds to the presence of calcium, which is an important signal during the plant defense response. We showed that when P. syringae is grown in the presence of calcium this TCS regulates expression of disease contributing factors. Overall, our results provide a better understanding of how bacterial pathogens respond to plant signals and control systems necessary for eliciting disease. PMID- 29263099 TI - Roles of Staphylococcus aureus Mnh1 and Mnh2 Antiporters in Salt Tolerance, Alkali Tolerance, and Pathogenesis. AB - Staphylococcus aureus has three types of cation/proton antiporters. The type 3 family includes two multisubunit Na+/H+ (Mnh) antiporters, Mnh1 and Mnh2. These antiporters are clusters of seven hydrophobic membrane-bound protein subunits. Mnh antiporters play important roles in maintaining cytoplasmic pH in prokaryotes, enabling their survival under extreme environmental stress. In this study, we investigated the physiological roles and catalytic properties of Mnh1 and Mnh2 in S. aureus Both Mnh1 and Mnh2 were cloned separately into a pGEM3Z+ vector in the antiporter-deficient KNabc Escherichia coli strain. The catalytic properties of the antiporters were measured in everted (inside out) vesicles. The Mnh1 antiporter exhibited a significant exchange of Na+/H+ cations at pH 7.5. Mnh2 showed a significant exchange of both Na+/H+ and K+/H+ cations, especially at pH 8.5. Under elevated salt conditions, deletion of the mnhA1 gene resulted in a significant reduction in the growth rate of S. aureus in the range of pH 7.5 to 9. Deletion of mnhA2 had similar effects but mainly in the range of pH 8.5 to 9.5. Double deletion of mnhA1 and mnhA2 led to a severe reduction in the S. aureus growth rate mainly at pH values above 8.5. The effects of functional losses of both antiporters in S. aureus were also assessed via their support of virulence in a mouse in vivo infection model. Deletion of the mnhA1 gene led to a major loss of S. aureus virulence in mice, while deletion of mnh2 led to no change in virulence.IMPORTANCE This study focuses on the catalytic properties and physiological roles of Mnh1 and Mnh2 cation/proton antiporters in S. aureus and their contributions under different stress conditions. The Mnh1 antiporter was found to have catalytic activity for Na+/H+ antiport, and it plays a significant role in maintaining halotolerance at pH 7.5 while the Mnh2 antiporter has catalytic antiporter activities for Na+/H+ and K+/H+ that have roles in both osmotolerance and halotolerance in S. aureus Study of S. aureus with a single deletion of either mnhA1 or mnhA2 was assessed in an infection model of mice. The result shows that mnhA1, but not mnhA2, plays a major role in S. aureus virulence. PMID- 29263100 TI - Replication rapidly recovers and continues in the presence of hydroxyurea in Escherichia coli. AB - In both prokaryotes and eukaryotes, hydroxyurea is suggested to inhibit DNA replication by inactivating ribonucleotide reductase and depleting deoxyribonucleoside triphosphate pools. In this study, we show that the inhibition of replication in Escherichia coli is transient even at concentrations of 0.1 M hydroxyurea and that replication rapidly recovers and continues in its presence. The recovery of replication does not require the alternative ribonucleotide reductases, NrdEF and NrdDG, or translesion DNA polymerases, Pol II, Pol IV, or Pol V. Ribonucleotides are incorporated at higher frequencies during replication in the presence of hydroxyurea. However, these do not contribute significantly to the observed synthesis or toxicity. Hydroxyurea toxicity was only observed under conditions where the stability of hydroxyurea was compromised and byproducts, known to damage DNA directly, were allowed to accumulate. The results demonstrate that hydroxyurea is not a direct or specific inhibitor of DNA synthesis in vivo, and that the transient inhibition observed is most likely due to a general depletion of iron cofactors from enzymes when 0.1 M hydroxyurea is initially applied. Finally, the results support previous studies suggesting that hydroxyurea toxicity is mediated primarily through direct DNA damage induced by the breakdown products of hydroxyurea, rather than by inhibition of replication or depletion of deoxyribonucleotide levels in the cell.IMPORTANCE: Hydroxyurea is commonly suggested to function by inhibiting DNA replication through the inactivation of ribonucleotide reductase and depleting deoxyribonucleoside triphosphate pools. Here, we show that hydroxyurea only transiently inhibits replication in Escherichia coli before it rapidly recovers and continues in the presence of this drug. The recovery of replication does not depend on alternative ribonucleotide reductases, translesion synthesis, or RecA. Further we show that hydroxyurea toxicity is only observed after toxic intermediates that accumulate when hydroxyurea breaks down, damage DNA and induce lethality. The results demonstrate that hydroxyurea toxicity is mediated indirectly by the formation of DNA damage, rather than by an inhibition of replication or depletion of deoxyribonucleotide levels in the cell. PMID- 29263101 TI - Phyletic Distribution and Lineage-Specific Domain Architectures of Archaeal Two Component Signal Transduction Systems. AB - The two-component signal transduction (TCS) machinery is a key mechanism of sensing environmental changes in the prokaryotic world. TCS systems have been characterized thoroughly in bacteria but to a much lesser extent in archaea. Here, we provide an updated census of more than 2,000 histidine kinases and response regulators encoded in 218 complete archaeal genomes, as well as unfinished genomes available from metagenomic data. We describe the domain architectures of the archaeal TCS components, including several novel output domains, and discuss the evolution of the archaeal TCS machinery. The distribution of TCS systems in archaea is strongly biased, with high levels of abundance in haloarchaea and thaumarchaea but none detected in the sequenced genomes from the phyla Crenarchaeota, Nanoarchaeota, and Korarchaeota The archaeal sensor histidine kinases are generally similar to their well-studied bacterial counterparts but are often located in the cytoplasm and carry multiple PAS and/or GAF domains. In contrast, archaeal response regulators differ dramatically from the bacterial ones. Most archaeal genomes do not encode any of the major classes of bacterial response regulators, such as the DNA-binding transcriptional regulators of the OmpR/PhoB, NarL/FixJ, NtrC, AgrA/LytR, and ActR/PrrA families and the response regulators with GGDEF and/or EAL output domains. Instead, archaea encode multiple copies of response regulators containing either the stand-alone receiver (REC) domain or combinations of REC with PAS and/or GAF domains. Therefore, the prevailing mechanism of archaeal TCS signaling appears to be via a variety of protein-protein interactions, rather than direct transcriptional regulation.IMPORTANCE Although the Archaea represent a separate domain of life, their signaling systems have been assumed to be closely similar to the bacterial ones. A study of the domain architectures of the archaeal two-component signal transduction (TCS) machinery revealed an overall similarity of archaeal and bacterial sensory modules but substantial differences in the signal output modules. The prevailing mechanism of archaeal TCS signaling appears to involve various protein-protein interactions rather than direct transcription regulation. The complete list of histidine kinases and response regulators encoded in the analyzed archaeal genomes is available online at http://www.ncbi.nlm.nih.gov/Complete_Genomes/TCSarchaea.html. PMID- 29263102 TI - Cellular Stoichiometry of Methyl-Accepting Chemotaxis Proteins in Sinorhizobium meliloti. AB - The chemosensory system in Sinorhizobium meliloti has several important deviations from the widely studied enterobacterial paradigm. To better understand the differences between the two systems and how they are optimally tuned, we determined the cellular stoichiometry of the methyl-accepting chemotaxis proteins (MCPs) and the histidine kinase CheA in S. meliloti Quantitative immunoblotting was used to determine the total amount of MCPs and CheA per cell in S. meliloti The MCPs are present in the cell in high abundance (McpV), low abundance (IcpA, McpU, McpX, and McpW), and very low abundance (McpY and McpZ), whereas McpT was below the detection limit. The approximate cellular ratio of these three receptor groups is 300:30:1. The chemoreceptor-to-CheA ratio is 23.5:1, highly similar to that seen in Bacillus subtilis (23:1) and about 10 times higher than that in Escherichia coli (3.4:1). Different from E. coli, the high-abundance receptors in S. meliloti are lacking the carboxy-terminal NWETF pentapeptide that binds the CheR methyltransferase and CheB methylesterase. Using transcriptional lacZ fusions, we showed that chemoreceptors are positively controlled by the master regulators of motility, VisNR and Rem. In addition, FlbT, a class IIA transcriptional regulator of flagellins, also positively regulates the expression of most chemoreceptors except for McpT and McpY, identifying chemoreceptors as class III genes. Taken together, these results demonstrate that the chemosensory complex and the adaptation system in S. meliloti deviates significantly from the established enterobacterial paradigm but shares some similarities with B. subtilisIMPORTANCE The symbiotic soil bacterium Sinorhizobium meliloti is of great agricultural importance because of its nitrogen-fixing properties, which enhances growth of its plant symbiont, alfalfa. Chemotaxis provides a competitive advantage for bacteria to sense their environment and interact with their eukaryotic hosts. For a better understanding of the role of chemotaxis in these processes, detailed knowledge on the regulation and composition of the chemosensory machinery is essential. Here, we show that chemoreceptor gene expression in S. meliloti is controlled through the main transcriptional regulators of motility. Chemoreceptor abundance is much lower in S. meliloti than in Escherichia coli and Bacillus subtilis Moreover, the chemoreceptor-to-kinase CheA ratio is different from that of E. coli but similar to that of B. subtilis. PMID- 29263103 TI - Immunoproteasome Subunits Are Required for CD8+ T Cell Function and Host Resistance to Brucella abortus Infection in Mice. AB - The immunoproteasome is a specific proteasome isoform composed of three subunits, termed beta1i, beta2i, and beta5i. Its proteolytic activity enhances the quantity and quality of peptides to be presented by major histocompatibility complex class I (MHC-I) molecules to CD8+ T cells. However, the role of the combined deficiency of the three immunoproteasome subunits in protective immunity against bacterial pathogens has not been investigated. In this study, we addressed the role of the immunoproteasome during infection by Brucella abortus, an intracellular bacterium that requires CD8+ T cell responses for the control of infection. Here, we demonstrate that immunoproteasome triple-knockout (TKO) mice were more susceptible to Brucella infection. This observed susceptibility was accompanied by reduced interferon gamma (IFN-gamma) production by mouse CD4+ and CD8+ T lymphocytes. Moreover, the absence of the immunoproteasome had an impact on MHC-I surface expression and antigen presentation by dendritic cells. CD8+ T cell function, which plays a pivotal role in B. abortus immunity, also presented a partial impairment of granzyme B expression and, consequently, reduced cytotoxic activity. In conclusion, these results strongly suggest that immunoproteasome subunits are important components in host resistance to B. abortus infection by impacting both the magnitude and quality of CD8+ T cell responses. PMID- 29263104 TI - CCR2+ Inflammatory Monocytes Are Recruited to Yersinia pseudotuberculosis Pyogranulomas and Dictate Adaptive Responses at the Expense of Innate Immunity during Oral Infection. AB - Murine Ly6Chi inflammatory monocytes (IMs) require CCR2 to leave the bone marrow and enter mesenteric lymph nodes (MLNs) and other organs in response to Yersinia pseudotuberculosis infection. We are investigating how IMs, which can differentiate into CD11c+ dendritic cells (DCs), contribute to innate and adaptive immunity to Y. pseudotuberculosis Previously, we obtained evidence that IMs are important for a dominant CD8+ T cell response to the epitope YopE69-77 and host survival using intravenous infections with attenuated Y. pseudotuberculosis Here we challenged CCR2+/+ or CCR2-/- mice orally with wild type Y. pseudotuberculosis to investigate how IMs contribute to immune responses during intestinal infection. Unexpectedly, CCR2-/- mice did not have reduced survival but retained body weight better and their MLNs cleared Y. pseudotuberculosis faster and with reduced lymphadenopathy compared to controls. Enhanced bacterial clearance in CCR2-/- mice correlated with reduced numbers of IMs in spleens and increased numbers of neutrophils in livers. In situ imaging of MLNs and spleens from CCR2-GFP mice showed that green fluorescent protein positive (GFP+) IMs accumulated at the periphery of neutrophil-rich Yersinia containing pyogranulomas. GFP+ IMs colocalized with CD11c+ cells and YopE69-77 specific CD8+ T cells in MLNs, suggesting that IM-derived DCs prime adaptive responses in Yersinia pyogranulomas. Consistently, CCR2-/- mice had reduced numbers of splenic DCs, YopE69-77-specific CD8+ T cells, CD4+ T cells, and B cells in organs and lower levels of serum antibodies to Y. pseudotuberculosis antigens. Our data suggest that IMs differentiate into DCs in MLN pyogranulomas and direct adaptive responses in T cells at the expense of innate immunity during oral Y. pseudotuberculosis infection. PMID- 29263105 TI - Autoimmune-Disease-Prone NOD Mice Help To Reveal a New Genetic Locus for Reducing Pulmonary Disease Caused by Mycoplasma pulmonis. AB - Mycoplasmas are bacterial pathogens of a range of animals, including humans, and are a common cause of respiratory disease. However, the host genetic factors that affect resistance to infection or regulate the resulting pulmonary inflammation are not well defined. We and others have previously demonstrated that nonobese diabetic (NOD) mice can be used to investigate disease loci that affect bacterial infection and autoimmune diabetes. Here we show that NOD mice are more susceptible than C57BL/6 (B6) mice to infection with Mycoplasma pulmonis, a natural model of pulmonary mycoplasmosis. The lungs of infected NOD mice had higher loads of M. pulmonis and more severe inflammatory lesions. Moreover, congenic NOD mice that harbored different B6-derived chromosomal intervals enabled identification and localization of a new mycoplasmosis locus, termed Mpr2, on chromosome 13. These congenic NOD mice demonstrated that the B6 allele for Mpr2 reduced the severity of pulmonary inflammation caused by infection with M. pulmonis and that this was associated with altered cytokine and chemokine concentrations in the infected lungs. Mpr2 also colocalizes to the same genomic interval as Listr2 and Idd14, genetic loci linked to listeriosis resistance and autoimmune diabetes susceptibility, respectively, suggesting that allelic variation within these loci may affect the development of both infectious and autoimmune disease. PMID- 29263106 TI - Aspergillus fumigatus Preexposure Worsens Pathology and Improves Control of Mycobacterium abscessus Pulmonary Infection in Mice. AB - Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus, which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORgamma-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus-coinfected lungs. Our results demonstrate that A. fumigatus, an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model. PMID- 29263107 TI - The VirAB ABC Transporter Is Required for VirR Regulation of Listeria monocytogenes Virulence and Resistance to Nisin. AB - Listeria monocytogenes is a Gram-positive intracellular pathogen that causes a severe invasive disease. Upon infecting a host cell, L. monocytogenes upregulates the transcription of numerous factors necessary for productive infection. VirR is the response regulator component of a two-component regulatory system in L. monocytogenes In this report, we have identified the putative ABC transporter encoded by genes lmo1746-lmo1747 as necessary for VirR function. We have designated lmo1746-lmo1747 virAB We constructed an in-frame deletion of virAB and determined that the DeltavirAB mutant exhibited reduced transcription of VirR regulated genes. The DeltavirAB mutant also showed defects in in vitro plaque formation and in vivo virulence that were similar to those of a DeltavirR deletion mutant. Since VirR is important for innate resistance to antimicrobial agents, we determined the MICs of nisin and bacitracin for DeltavirAB bacteria. We found that VirAB expression was necessary for nisin resistance but was dispensable for resistance to bacitracin. This result suggested a VirAB independent mechanism of VirR regulation in response to bacitracin. Lastly, we found that the DeltavirR and DeltavirAB mutants had no deficiency in growth in broth culture, intracellular replication, or production of the ActA surface protein, which facilitates actin-based motility and cell-to-cell spread. However, the DeltavirR and DeltavirAB mutants produced shorter actin tails during intracellular infection, which suggested that these mutants have a reduced ability to move and spread via actin-based motility. These findings have demonstrated that L. monocytogenes VirAB functions in a pathway with VirR to regulate the expression of genes necessary for virulence and resistance to antimicrobial agents. PMID- 29263108 TI - Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae. AB - Four previously identified immunodominant B-cell epitopes, located within known virulent pneumococcal proteins CbpD, PhtD, PhtE, and ZmpB, had shown promising in vivo immunological characteristics, indicating their potential to be used as vaccine antigens. In this study, we further evaluated the opsonophagocytic activity of antibodies against these epitopes and their capacity to protect mice from pneumococcal sepsis. An opsonophagocytic killing assay (OPKA) revealed that OPKA titers of human anti-peptide antibodies against pneumococcal serotypes 1, 3, and 19A were significantly higher (P < 0.001) than those of the control sera, suggesting their functional potential against virulent clinical isolates. Data obtained from mice actively immunized with any of the selected epitope analogues or with a mixture of these (G_Mix group) showed, compared to controls, enhanced survival against the highly virulent pneumococcal serotype 3 (P < 0.001). Moreover, passive transfer of hyperimmune serum from G_Mix to naive mice also conferred protection to a lethal challenge with serotype 3, which demonstrates that the observed protection was antibody mediated. All immunized murine groups elicited gradually higher antibody titers and avidity, suggesting a maturation of immune response over time. Among the tested peptides, PhD_pep19 and PhtE_pep40 peptides, which reside within the zinc-binding domains of PhtD and PhtE proteins, exhibited superior immunological characteristics. Recently it has been shown that zinc uptake is of high importance for the virulence of Streptococcus pneumoniae; thus, our findings suggest that these epitopes deserve further evaluation as novel immunoreactive components for the development of a polysaccharide independent pneumococcal vaccine. PMID- 29263109 TI - Prevalence of IgG and Neutralizing Antibodies against Staphylococcus aureus Alpha Toxin in Healthy Human Subjects and Diverse Patient Populations. AB - Staphylococcus aureus causes an array of serious infections resulting in high morbidity and mortality worldwide. This study evaluated naturally occurring serum anti-alpha-toxin (anti-AT) antibody levels in human subjects from various age groups, individuals with S. aureus dialysis and surgical-site infections, and S. aureus-colonized versus noncolonized subjects. Anti-AT immunoglobulin G (IgG) and neutralizing antibody (NAb) levels in infants (aged <=1 year) were significantly lower than those in other populations. In comparison to adolescent, adult, and elderly populations, young children (aged 2 to 10 years) had equivalent anti-AT IgG levels but significantly lower anti-AT NAb levels. Therefore, the development of anti-AT NAbs appears to occur later than that of AT-specific IgG, suggesting a maturation of the immune response to AT. Anti-AT IgG levels were slightly higher in S. aureus-colonized subjects than in noncolonized subjects. The methicillin susceptibility status of colonizing isolates had no effect on anti-AT antibody levels in S. aureus-colonized subjects. The highest anti-AT IgG and NAb levels were observed in dialysis patients with acute S. aureus infection. Anti-AT IgG and NAb levels were well correlated in subjects aged >10 years, regardless of colonization or infection status. These data demonstrate that AT elicits a robust IgG humoral response in infants and young children that becomes stable prior to adolescence, matures into higher levels of NAbs in healthy adolescents, and becomes elevated during S. aureus infection. These findings may assist in identifying subjects and patient populations that could benefit from vaccination or immunoprophylaxis with anti-AT monoclonal antibodies. PMID- 29263110 TI - The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans. AB - Streptococcus pneumoniae is a frequent colonizer of the upper respiratory tract and a leading cause of bacterial pneumonia. The innate immune system senses pneumococcal cell wall components, toxin, and nucleic acids, which leads to production of inflammatory mediators to initiate and control antibacterial defense. Here, we show that the cGAS (cyclic GMP-AMP [cGAMP] synthase)-STING pathway mediates detection of pneumococcal DNA in mouse macrophages to primarily stimulate type I interferon (IFN) responses. Cells of human individuals carrying HAQ TMEM173, which encodes a common hypomorphic variant of STING, were largely or partly defective in inducing type I IFNs and proinflammatory cytokines upon infection. Subsequent analyses, however, revealed that STING was dispensable for restricting S. pneumoniae during acute pneumonia in mice. Moreover, explorative analyses did not find differences in the allele frequency of HAQ TMEM173 in nonvaccinated pneumococcal pneumonia patients and healthy controls or an association of HAQ TMEM173 carriage with disease severity. Together, our results indicate that the cGAS/STING pathway senses S. pneumoniae but plays no major role in antipneumococcal immunity in mice and humans. PMID- 29263111 TI - Streptococcus sanguinis Noncoding cia-Dependent Small RNAs Negatively Regulate Expression of Type IV Pilus Retraction ATPase PilT and Biofilm Formation. AB - Small noncoding RNAs (sRNAs) have been identified as important regulators of gene expression in various cellular processes. cia-dependent small RNAs (csRNAs), a group of sRNAs that are controlled by the two-component regulatory system CiaRH, are widely conserved in streptococci, but their targets have been identified only in Streptococcus pneumoniaeStreptococcus sanguinis, a pioneer colonizer of teeth and one of the most predominant bacteria in the early oral biofilm, has been shown to have six csRNAs. Using computational target prediction and the luciferase reporter assay, we identified pilT, a constituent of the type IV pilus operon, as a negative regulatory target for one of the csRNAs, namely, csRNA1-1, in S. sanguinis RNA-RNA electrophoretic mobility shift assay using a nucleotide exchange mutant of csRNA1-1 revealed that csRNA1-1 binds directly to pilT mRNA. In addition, csRNA1-1 and csRNA1-2, a putative gene duplication product of csRNA1 1 that is tandemly located in the S. sanguinis genome, negatively regulated S. sanguinis biofilm formation. These results suggest the involvement of csRNAs in the colonization step of S. sanguinis. PMID- 29263112 TI - Enterotoxigenic Escherichia coli Adhesin-Toxoid Multiepitope Fusion Antigen CFA/I/II/IV-3xSTaN12S-mnLTG192G/L211A-Derived Antibodies Inhibit Adherence of Seven Adhesins, Neutralize Enterotoxicity of LT and STa Toxins, and Protect Piglets against Diarrhea. AB - Enterotoxigenic Escherichia coli (ETEC) strains are a leading cause of children's diarrhea and travelers' diarrhea. Vaccines inducing antibodies to broadly inhibit bacterial adherence and to neutralize toxin enterotoxicity are expected to be effective against ETEC-associated diarrhea. 6*His-tagged adhesin-toxoid fusion proteins were shown to induce neutralizing antibodies to several adhesins and LT and STa toxins (X. Ruan, D. A. Sack, W. Zhang, PLoS One 10:e0121623, 2015, https://doi.org/10.1371/journal.pone.0121623). However, antibodies derived from His-tagged CFA/I/II/IV-2xSTaA14Q-dmLT or CFA/I/II/IV-2xSTaN12S-dmLT protein were less effective in neutralizing STa enterotoxicity and were not evaluated in vivo for efficacy against ETEC diarrhea. Additionally, His-tagged proteins are considered less desirable for human vaccines. In this study, we produced a tagless adhesin-toxoid MEFA (multiepitope fusion antigen) protein, enhanced anti STa immunogenicity by including a third copy of STa toxoid STaN12S, and examined antigen immunogenicity in a murine model. Moreover, we immunized pregnant pigs with the tagless adhesin-toxoid MEFA protein and evaluated passive antibody protection against STa+ or LT+ ETEC infection in a pig challenge model. Results showed that tagless adhesin-toxoid MEFA CFA/I/II/IV-3xSTaN12S-mnLTR192G/L211A induced broad antiadhesin and antitoxin antibody responses in the intraperitoneally immunized mice and the intramuscularly immunized pigs. Mouse and pig serum antibodies significantly inhibited adherence of seven colonization factor antigen (CFA) adhesins (CFA/I and CS1 to CS6) and effectively neutralized both toxins. More importantly, suckling piglets born to the immunized mothers acquired antibodies and were protected against STa+ ETEC and LT+ ETEC diarrhea. These results indicated that tagless CFA/I/II/IV-3xSTaN12S-mnLTR192G/L211A induced broadly protective antiadhesin and antitoxin antibodies and demonstrate that this adhesin-toxoid MEFA is a potential antigen for developing broadly protective ETEC vaccines. PMID- 29263113 TI - Variation in the Early Host-Pathogen Interaction of Bovine Macrophages with Divergent Mycobacterium bovis Strains in the United Kingdom. AB - Bovine tuberculosis has been an escalating animal health issue in the United Kingdom since the 1980s, even though control policies have been in place for over 60 years. The importance of the genetics of the etiological agent, Mycobacterium bovis, in the reemergence of the disease has been largely overlooked. We compared the interaction between bovine monocyte-derived macrophages (bMDM) and two M. bovis strains, AF2122/97 and G18, representing distinct genotypes currently circulating in the United Kingdom. These M. bovis strains exhibited differences in survival and growth in bMDM. Although uptake was similar, the number of viable intracellular AF2122/97 organisms increased rapidly, while G18 growth was constrained for the first 24 h. AF2122/97 infection induced a greater transcriptional response by bMDM than G18 infection with respect to the number of differentially expressed genes and the fold changes measured. AF2122/97 infection induced more bMDM cell death, with characteristics of necrosis and apoptosis, more inflammasome activation, and a greater type I interferon response than G18. In conclusion, the two investigated M. bovis strains interact in significantly different ways with the host macrophage. In contrast to the relatively silent infection by G18, AF2122/97 induces greater signaling to attract other immune cells and induces host cell death, which may promote secondary infections of naive macrophages. These differences may affect early events in the host-pathogen interaction, including granuloma development, which could in turn alter the progression of the disease. Therefore, the potential involvement of M. bovis genotypes in the reemergence of bovine tuberculosis in the United Kingdom warrants further investigation. PMID- 29263114 TI - Hemolysis during and after 21 days of head-down-tilt bed rest. AB - Hemoconcentration is observed in bed rest studies, descent from altitude, and exposure to microgravity. Hemoconcentration triggers erythrocyte losses to subsequently normalize erythrocyte concentration. The mechanisms of erythrocyte loss may involve enhanced hemolysis, but has never been measured directly in bed rest studies. Steady-state hemolysis was evaluated by measuring two heme degradation products, endogenous carbon monoxide concentration [CO] and urobilinogen in feces, in 10 healthy men, before, during, and after two campaigns of 21 days of 6 degrees head-down-tilt (HDT) bed rest. The subjects were hemoconcentrated at 10 and 21 days of bed rest: mean concentrations of hemoglobin (15.0 +/- 0.2 g/L and 14.6 +/- 0.1 g/L, respectively) and erythrocytes (5.18 +/- 0.06E6/MUL and 5.02 +/- 0.06E6/MUL, respectively) were increased compared to baseline (all Ps < 0.05). In contrast, mean hemoglobin mass (743 +/- 19 g) and number of erythrocytes (2.56 +/- 0.07E13) were decreased at 21 days of bed rest (both Ps < 0.05). Indicators of hemolysis mean [CO] (1660 +/- 49 ppb and 1624 +/- 48 ppb, respectively) and fecal urobilinogen concentration (180 +/- 23 mg/day and 199 +/- 22 mg/day, respectively) were unchanged at 10 and 21 days of bed rest compared to baseline (both Ps > 0.05). A significant decrease in [CO] (-505 ppb) was measured at day 28 after bed rest. HDT bed rest caused hemoconcentration in parallel with lower hemoglobin mass. Circulating indicators of hemolysis remained unchanged throughout bed rest supporting that enhanced hemolysis did not contribute significantly to erythrocyte loss during the hemoconcentration of bed rest. At day 28 after bed rest, decreased hemolysis accompanied the recovery of erythrocytes, a novel finding. PMID- 29263115 TI - Adiponectin attenuates profibrotic extracellular matrix remodeling following cardiac injury by up-regulating matrix metalloproteinase 9 expression in mice. AB - Adiponectin (APN) is a multifunctional adipocytokine that inhibits myocardial fibrosis, dilatation, and left ventricular (LV) dysfunction after myocardial infarction (MI). Coxsackievirus B3 (CVB3) myocarditis is associated with intense extracellular matrix (ECM) remodeling which might progress to dilated cardiomyopathy. Here, we investigated in experimental CVB3 myocarditis whether APN inhibits adverse ECM remodeling following cardiac injury by affecting matrix metalloproteinase (MMP) expression. Cardiac injury was induced by CVB3 infection in APN knockout (APN-KO) and wild-type (WT) mice. Expression and activity of MMPs was quantified by qRT-PCR and zymography, respectively. Activation of protein kinases was assessed by immunoblot. In cardiac myocytes and fibroblasts APN up regulates MMP-9 expression via activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)1/2 which function as master regulators of inflammation-induced MMP-9 expression. Correspondingly, APN further increased up-regulation of MMP-9 expression triggered by tumor necrosis factor (TNF)alpha, lipopolysaccharide (LPS) and R-848 in cardiac fibroblasts. In vivo, compared to WT mice cardiac MMP-9 activity and serum levels of carboxy-terminal telopeptide of type I collagen (ICTP) were attenuated in APN-KO mice in subacute (day 7 p.i.) CVB3 myocarditis. Moreover, on day 3 and day 7 post CVB3 infection splenic MMP-9 expression was diminished in APN-KO mice correlating with attenuated myocardial immune cell infiltration in subacute CVB3 myocarditis. These results indicate that APN attenuates adverse cardiac remodeling following cardiac injury by up-regulating MMP-9 expression in cardiac and immune cells. Thus, APN mediates intensified collagen cleavage that might explain inhibition of LV fibrosis and dysfunction. PMID- 29263116 TI - Acute resistance exercise induces Sestrin2 phosphorylation and p62 dephosphorylation in human skeletal muscle. AB - Sestrins (1, 2, 3) are a family of stress-inducible proteins capable of attenuating oxidative stress, regulating metabolism, and stimulating autophagy. Sequestosome1 (p62) is also a stress-inducible multifunctional protein acting as a signaling hub for oxidative stress and selective autophagy. It is unclear whether Sestrin and p62Ser403 are regulated acutely or chronically by resistance exercise (RE) or training (RT) in human skeletal muscle. Therefore, the acute and chronic effects of RE on Sestrin and p62 in human skeletal muscle were examined through two studies. In Study 1, nine active men (22.1 +/- 2.2 years) performed a bout of single-leg strength exercises and muscle biopsies were collected before, 2, 24, and 48 h after exercise. In Study 2, 10 active men (21.3 +/- 1.9 years) strength trained for 12 weeks (2 days per week) and biopsies were collected pre- and post-training. Acutely, 2 h postexercise, phosphorylation of p62Ser403 was downregulated, while there was a mobility shift of Sestrin2, indicative of increased phosphorylation. Forty-eight hours postexercise, the protein expression of both Sestrin1 and total p62 increased. Chronic exercise had no impact on the gene or protein expression of Sestrin2/3 or p62, but Sestrin1 protein was upregulated. These findings demonstrated an inverse relationship between Sestrin2 and p62 phosphorylation after a single bout of RE, indicating they are transiently regulated. Contrarily, 12 weeks of RT increased protein expression of Sestrin1, suggesting that despite the strong sequence homology of the Sestrin family, they are differentially regulated in response to acute RE and chronic RT. PMID- 29263117 TI - Stabilization of hypoxia inducible factor by cobalt chloride can alter renal epithelial transport. AB - Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we examined the effect of stabilized HIF 1alpha on renal epithelial permeability and directed sodium transport. This study was motivated by histological analysis of cystic kidneys showing increased expression levels of HIF-1alpha and HIF-2alpha We hypothesize that compression induced localized ischemia-hypoxia of normal epithelia near a cyst leads to local stabilization of HIF-1alpha, leading to altered transepithelial transport that encourages cyst expansion. We found that stabilized HIF-1alpha alters both transcellular and paracellular transport through renal epithelial monolayers in a manner consistent with secretory behavior, indicating localized ischemia-hypoxia may lead to altered salt and water transport through kidney epithelial monolayers. A quantity of 100 MUmol/L Cobalt chloride (CoCl2) was used acutely to stabilize HIF-1alpha in confluent cultures of mouse renal epithelia. We measured increased transepithelial permeability and decreased transepithelial resistance (TER) when HIF-1alpha was stabilized. Most interestingly, we measured a change in the direction of sodium current, most likely corresponding to abnormal secretory function, supporting our positive-feedback hypothesis. PMID- 29263118 TI - In vitro cellular models of human hepatic fatty acid metabolism: differences between Huh7 and HepG2 cell lines in human and fetal bovine culturing serum. AB - Human primary hepatocytes are the gold standard for investigating lipid metabolism in nonalcoholic fatty liver disease (NAFLD); however, due to limitations including availability and donor variability, the hepatoma cell lines Huh7 and HepG2 are commonly used. Culturing these cell lines in human serum (HS) has been reported to improve functionality; however, direct comparison of fatty acid (FA) metabolism in response to culturing in HS is lacking. The aim of this study was to compare FA metabolism between HepG2 and Huh7 cells in response to culturing in different sera. Both HepG2 and Huh7 cells were grown in media containing 11 mmol/L glucose and either 2% HS or 10% fetal bovine serum. After 3 days, insulin and insulin-like growth factor-1 signaling were measured. At 7 days, intracellular triacylglycerol (TAG) and media 3-hydroxybutyrate, TAG and apolipoprotein B were measured, as was the FA composition of intracellular TAG and phospholipids. Both cell lines demonstrated higher levels of polyunsaturated fatty acid content, increased insulin sensitivity, higher media TAG levels and increased FA oxidation when cultured in HS Notably, independent of serum type, Huh7 cells had higher intracellular TAG compared to HepG2 cells, which was in part attributable to a higher de novo lipogenesis. Our data demonstrate that intrahepatocellular FA metabolism is different between cell lines and influenced by culturing sera. As a result, when developing a physiologically-relevant model of FA metabolism that could be developed for the study of NAFLD, consideration of both parameters is required. PMID- 29263121 TI - A Novel Approach to Assessing Infants With Neonatal Abstinence Syndrome. AB - OBJECTIVES: Neonatal abstinence syndrome (NAS) is a growing problem and poses a significant burden on the health care system. The traditional Finnegan Neonatal Abstinence Scoring System (FNASS) assessment approach may lead to unnecessary opioid treatment of infants with NAS. We developed a novel assessment approach and describe its effect on the management of infants with NAS. METHODS: We retrospectively compared treatment decisions of 50 consecutive opioid-exposed infants managed on the inpatient unit at the Yale New Haven Children's Hospital. All infants had FNASS scores recorded every 2 to 6 hours but were managed by using the Eat, Sleep, Console (ESC) assessment approach. Actual treatment decisions made by using the ESC approach were compared with predicted treatment decisions based on recorded FNASS scores. The primary outcome was postnatal treatment with morphine. RESULTS: By using the ESC approach, 6 infants (12%) were treated with morphine compared with 31 infants (62%) predicted to be treated with morphine by using the FNASS approach (P < .001). The ESC approach started or increased morphine on 8 days (2.7%) compared with 76 days (25.7%) predicted by using the FNASS approach (P < .001). There were no readmissions or adverse events reported. CONCLUSIONS: Infants managed by using the ESC approach were treated with morphine significantly less frequently than they would have been by using the FNASS approach. The ESC approach is an effective method for the management of infants with NAS that limits pharmacologic treatment and may lead to substantial reductions in length of stay. PMID- 29263119 TI - Impact of acute versus repetitive moderate intensity endurance exercise on kidney injury markers. AB - Exercise may lead to kidney injury through several mechanisms. Urinary Kidney Injury Molecule-1 (uKIM1) and Neutrophil Gelatinase-Associated Lipocalin (uNGAL) are known biomarkers for acute kidney injury, but their response to repetitive exercise remains unknown. We examined the effects of a single versus repetitive bouts of exercise on markers for kidney injury in a middle-aged population. Sixty subjects (aged 29-78 years, 50% male) were included and walked 30, 40 or 50 km for three consecutive days. At baseline and after exercise day 1 and 3, a urine sample was collected to determine uNGAL and uKIM1. Furthermore, urinary cystatin C, creatinine, and osmolality were used to correct for dehydration-related changes in urinary concentration. Baseline uNGAL was 9.2 (5.2-14.7) ng/mL and increased to 20.7 (11.0-37.2) ng/mL and 14.2(8.0-26.3) ng/mL after day 1 and day 3, respectively, (P <= 0.001). Baseline uKIM1 concentration was 2.6 (1.4-6.0) ng/mL and increased to 5.2 (2.4-9.1) ng/mL (P = 0.002) after day 1, whereas uKIM1 was not different from baseline at day 3 (2.9 [1.4-6.4] ng/mL (P = 0.52)). Furthermore, both uNGAL and uKIM1 levels were higher after day 1 compared to day 3 (P < 0.01). When corrected for urinary cystatin C, creatinine, and osmolality, uNGAL demonstrated a similar response compared to the uncorrected data, whereas differences in uKIM1 between baseline, day 1 and day 3 (Ptime = 0.63) were no longer observed for cystatin C and creatinine corrected data. A single bout of prolonged exercise significantly increased uNGAL concentration, whereas no changes in uKIM1 were found. Repetitive bouts of exercise show that there is no cumulative effect of kidney injury markers. PMID- 29263120 TI - Macrophage migration inhibitory factor mediates protease-activated receptor 4 induced bladder pain through urothelial high mobility group box 1. AB - Macrophage migration inhibitory factor (MIF) mediates pain although the mechanisms are not well understood. Urothelial activation of protease activated receptor 4 (PAR4) results in urothelial MIF release, urothelial high mobility group box 1 (HMGB1) release and bladder pain in mice without bladder inflammation. All three effects are prevented by MIF inhibition while intravesical disulfide HMGB1 alone can induce bladder pain. This study utilizes genetic MIF deletion to determine whether MIF mediates PAR4-induced bladder pain and is upstream of HMGB1-induced bladder pain. Wild type (C57/BL6) and MIF knockout (KO) mice were treated with intravesical PAR4 activating peptide or disulfide HMGB1 and tested for abdominal mechanical hypersensitivity at baseline (before treatment) and 24 h after injection. Micturition parameters and bladder histology were examined after behavioral test. Real-time PCR and western blotting measured HMGB1 mRNA and protein levels in the bladders of naive wild type and MIF KO mice, while immunofluorescence measured HMGB1 protein levels in the urothelium of both strains. Intravesical PAR4 activation resulted in abdominal mechanical hypersensitivity in wild-type mice but not MIF KO mice. Intravesical disulfide HMGB1 induced abdominal mechanical hypersensitivity in both strains. Neither treatment resulted in significant changes in micturition or bladder histology in either strain. HMGB1 mRNA and protein levels were higher in MIF KO mouse bladders and the urothelium of MIF KO bladder had greater immunostaining than the wild type strain. MIF is a pivotal molecule mediating PAR4-induced bladder pain and regulating urothelial HMGB1 production and release to elicit bladder pain. PMID- 29263122 TI - Hospital Variation in Neonatal Abstinence Syndrome Incidence, Treatment Modalities, Resource Use, and Costs Across Pediatric Hospitals in the United States, 2013 to 2016. AB - BACKGROUND: The national incidence of neonatal abstinence syndrome (NAS) has increased with the opioid epidemic in the United States. The impact of pharmacologic treatment on hospital use is not well established. We examined the recent population of neonates with NAS admitted to pediatric hospitals, hospital variation in pharmacologic treatment, and the effect of treatment on resource use during neonatal hospitalization, including length of stay (LOS), readmission, and cost-of-living adjusted hospital costs. METHODS: We included inpatients discharged between January 2013 and March 2016 from hospitals in the Pediatric Health Information System. We compared neonates with NAS to those without on demographic, socioeconomic, clinical characteristics and hospital resource use. We also compared neonates with NAS on these characteristics by pharmacologic treatment. RESULTS: This analysis included 136 762 neonatal encounters from 23 hospitals. Of these, 2% had a diagnosis of NAS. Compared with other neonates, neonates with NAS had a longer LOS (18.7 vs 2.9 days; P = .004). Average costs per admission were 10 times higher for neonates with NAS ($37 584 vs $3536; P = .003). Of neonates with NAS, 70% were treated pharmacologically with wide variation in hospital rates of pharmacotherapy (range: 13%-90%). Pharmacologically-treated neonates with NAS experienced a longer LOS (22.0 vs 10.9 days; P = .004) than other neonates with NAS. Total costs for pharmacologically-treated neonates with NAS were over 2 times higher ($44 720 vs $20 708; P = .002) than neonates with NAS treated without pharmacotherapy. CONCLUSIONS: Neonates with NAS, particularly those treated pharmacologically, have lengthier, more expensive hospital stays. Significant variation in pharmacologic treatment reflects opportunities for practice standardization and substantial reductions in resource use. PMID- 29263123 TI - Neonatal Abstinence Syndrome and the Pediatric Hospitalist: 5 Years Later. PMID- 29263124 TI - Randomized Clinical Trial of Standard- Versus High-Calorie Formula for Methadone Exposed Infants: A Feasibility Study. AB - BACKGROUND: Newborns who are prenatally exposed to methadone are at risk for neonatal abstinence syndrome and the associated excess weight loss and poor weight gain. This pilot feasibility study aimed to evaluate early caloric enhancement on weight patterns among infants born to women receiving methadone maintenance therapy while pregnant. METHODS: In this double-blind pilot feasibility study, we randomly assigned infants with fetal methadone exposure to 24 or 20 kcal/oz formula from days 3 to 21. Randomization was stratified by any breastfeeding, sex of the infant, and gestational age. Eligible infants were >=35 weeks' gestation and weighed >=2200 g. Outcomes were days to weight nadir, maximum percent weight loss, days to birth weight, percentage weight change per day, and feasibility. RESULTS: A total of 49 infants were randomly assigned (22 to standard- and 27 to high-calorie formula); groups had comparable demographic characteristics. Main outcomes comparing standard- to high-calorie formula groups were not significant (days to weight nadir, 5.0 vs 4.4 days; P = .20; maximum percent weight loss, -9.4% vs -8.6%; P = .15; days to birth weight, 14.7 vs 13.6 days; P = .07); however, in longitudinal analyses (days 4 to 21), the high calorie group had a higher percent weight gained per day compared with the standard-calorie group (P <.001). There were high levels of protocol adherence, and no adverse effects were observed. CONCLUSIONS: Study findings suggest that early initiation of high-calorie formula for infants with prenatal methadone exposure may be beneficial for weight gain; evaluation in a larger study is warranted. PMID- 29263125 TI - Temperate phages as self-replicating weapons in bacterial competition. AB - Microbial communities are accompanied by a diverse array of viruses. Through infections of abundant microbes, these viruses have the potential to mediate competition within the community, effectively weakening competitive interactions and promoting coexistence. This is of particular relevance for host-associated microbial communities, because the diversity of the microbiota has been linked to host health and functioning. Here, we study the interaction between two key members of the microbiota of the freshwater metazoan Hydra vulgaris The two commensal bacteria Curvibacter sp. and Duganella sp. protect their host from fungal infections, but only if both of them are present. Coexistence of the two bacteria is thus beneficial for Hydra Intriguingly, Duganella sp. appears to be the superior competitor in vitro due to its higher growth rate when both bacteria are grown separately, but in co-culture the outcome of competition depends on the relative initial abundances of the two species. The presence of an inducible prophage in the Curvibacter sp. genome, which is able to lytically infect Duganella sp., led us to hypothesize that the phage modulates the interaction between these two key members of the Hydra microbiota. Using a mathematical model, we show that the interplay of the lysogenic life cycle of the Curvibacter phage and the lytic life cycle on Duganella sp. can explain the observed complex competitive interaction between the two bacteria. Our results highlight the importance of taking lysogeny into account for understanding microbe-virus interactions and show the complex role phages can play in promoting coexistence of their bacterial hosts. PMID- 29263127 TI - A combined three-dimensional in vitro-in silico approach to modelling bubble dynamics in decompression sickness. AB - The growth of bubbles within the body is widely believed to be the cause of decompression sickness (DCS). Dive computer algorithms that aim to prevent DCS by mathematically modelling bubble dynamics and tissue gas kinetics are challenging to validate. This is due to lack of understanding regarding the mechanism(s) leading from bubble formation to DCS. In this work, a biomimetic in vitro tissue phantom and a three-dimensional computational model, comprising a hyperelastic strain-energy density function to model tissue elasticity, were combined to investigate key areas of bubble dynamics. A sensitivity analysis indicated that the diffusion coefficient was the most influential material parameter. Comparison of computational and experimental data revealed the bubble surface's diffusion coefficient to be 30 times smaller than that in the bulk tissue and dependent on the bubble's surface area. The initial size, size distribution and proximity of bubbles within the tissue phantom were also shown to influence their subsequent dynamics highlighting the importance of modelling bubble nucleation and bubble bubble interactions in order to develop more accurate dive algorithms. PMID- 29263126 TI - The biomechanical role of the chondrocranium and sutures in a lizard cranium. AB - The role of soft tissues in skull biomechanics remains poorly understood. Not least, the chondrocranium, the portion of the braincase which persists as cartilage with varying degrees of mineralization. It also remains commonplace to overlook the biomechanical role of sutures despite evidence that they alter strain distribution. Here, we examine the role of both the sutures and the chondrocranium in the South American tegu lizard Salvator merianae We use multi body dynamics analysis (MDA) to provide realistic loading conditions for anterior and posterior unilateral biting and a detailed finite element model to examine strain magnitude and distribution. We find that strains within the chondrocranium are greatest during anterior biting and are primarily tensile; also that strain within the cranium is not greatly reduced by the presence of the chondrocranium unless it is given the same material properties as bone. This result contradicts previous suggestions that the anterior portion (the nasal septum) acts as a supporting structure. Inclusion of sutures to the cranium model not only increases overall strain magnitudes but also leads to a more complex distribution of tension and compression rather than that of a beam under sagittal bending. PMID- 29263128 TI - Ascorbic acid may not be involved in cryptochrome-based magnetoreception. AB - Seventeen years after it was originally suggested, the photoreceptor protein cryptochrome remains the most probable host for the radical pair intermediates that are thought to be the sensors in the avian magnetic compass. Although evidence in favour of this hypothesis is accumulating, the intracellular interaction partners of the sensory protein are still unknown. It has been suggested that ascorbate ions could interact with surface-exposed tryptophan radicals in photoactivated cryptochromes, and so lead to the formation of a radical pair comprised of the reduced form of the flavin adenine dinucleotide cofactor, FAD*-, and the ascorbate radical, Asc*- This species could provide a more sensitive compass than a FAD-tryptophan radical pair. In this study of Drosophila melanogaster cryptochrome and Erithacus rubecula (European robin) cryptochrome 1a, we use molecular dynamics simulations to characterize the transient encounters of ascorbate ions with tryptophan radicals in cryptochrome in order to assess the likelihood of the [FAD*- Asc*-]-pathway. It is shown that ascorbate ions are expected to bind near the tryptophan radicals for periods of a few nanoseconds. The rate at which these encounters happen is low, and it is therefore concluded that ascorbate ions are unlikely to be involved in magnetoreception if the ascorbate concentration is only of the order of 1 mM or less. PMID- 29263129 TI - Microbial metabolism directly affects trace gases in (sub) polar snowpacks. AB - Concentrations of trace gases trapped in ice are considered to develop uniquely from direct snow/atmosphere interactions at the time of contact. This assumption relies upon limited or no biological, chemical or physical transformations occurring during transition from snow to firn to ice; a process that can take decades to complete. Here, we present the first evidence of environmental alteration due to in situ microbial metabolism of trace gases (methyl halides and dimethyl sulfide) in polar snow. We collected evidence for ongoing microbial metabolism from an Arctic and an Antarctic location during different years. Methyl iodide production in the snowpack decreased significantly after exposure to enhanced UV radiation. Our results also show large variations in the production and consumption of other methyl halides, including methyl bromide and methyl chloride, used in climate interpretations. These results suggest that this long-neglected microbial activity could constitute a potential source of error in climate history interpretations, by introducing a so far unappreciated source of bias in the quantification of atmospheric-derived trace gases trapped within the polar ice caps. PMID- 29263130 TI - A sound worth saving: acoustic characteristics of a massive fish spawning aggregation. AB - Group choruses of marine animals can produce extraordinarily loud sounds that markedly elevate levels of the ambient soundscape. We investigated sound production in the Gulf corvina (Cynoscion othonopterus), a soniferous marine fish with a unique reproductive behaviour threatened by overfishing, to compare with sounds produced by other marine animals. We coupled echosounder and hydrophone surveys to estimate the magnitude of the aggregation and sounds produced during spawning. We characterized individual calls and documented changes in the soundscape generated by the presence of as many as 1.5 million corvina within a spawning aggregation spanning distances up to 27 km. We show that calls by male corvina represent the loudest sounds recorded in a marine fish, and the spatio temporal magnitude of their collective choruses are among the loudest animal sounds recorded in aquatic environments. While this wildlife spectacle is at great risk of disappearing due to overfishing, regional conservation efforts are focused on other endangered marine animals. PMID- 29263131 TI - Behavioural responses of naked mole rats to acute hypoxia and anoxia. AB - Naked mole rats (NMRs) are among the most hypoxia-tolerant mammals. Other species respond to hypoxia by either escaping the hypoxic environment or drastically decreasing behavioural activity and body temperature (Tb) to conserve energy. However, NMRs rarely leave their underground burrows, which are putatively hypoxic and thermally stable near the NMRs' preferred Tb Therefore, we asked whether NMRs are able to employ behavioural and thermoregulatory strategies in response to hypoxia despite their need to remain active and the minimal thermal scope in their burrows. We exposed NMRs to progressively deeper levels of hypoxia (from 21 to 0% O2) while measuring their behaviour and Tb Behavioural activity decreased 40-60% in hypoxia and Tb decreased slightly in moderate hypoxia (5-9%) and then further with deeper hypoxia (3% O2). However, even at 3% O2 NMRs remained somewhat active and warm, and continued to explore their environment. Remarkably, NMRs were active for greater than 90 s in acute anoxia and Tb and metabolic rate decreased rapidly. We conclude that NMRs are adapted to remain awake and functional even at the extremes of their hypoxia-tolerance. This adaptation likely reflects variable and challenging levels of environmental hypoxia in the natural habitat of this species. PMID- 29263132 TI - Genetics redraws pelagic biogeography of Calanus. AB - Planktonic copepods of the genus Calanus play a central role in North Atlantic/Arctic marine food webs. Here, using molecular markers, we redrew the distributional ranges of Calanus species inhabiting the North Atlantic and Arctic Oceans and revealed much wider and more broadly overlapping distributions than previously described. The Arctic shelf species, C. glacialis, dominated the zooplankton assemblage of many Norwegian fjords, where only C. finmarchicus has been reported previously. In these fjords, high occurrences of the Arctic species C. hyperboreus were also found. Molecular markers revealed that the most common method of species identification, prosome length, cannot reliably discriminate the species in Norwegian fjords. Differences in degree of genetic differentiation among fjord populations of the two species suggested that C. glacialis is a more permanent resident of the fjords than C. finmarchicus We found no evidence of hybridization between the species. Our results indicate a critical need for the wider use of molecular markers to reliably identify and discriminate these morphologically similar copepod species, which serve as important indicators of climate responses. PMID- 29263133 TI - miR-222 isoforms are differentially regulated by type-I interferon. AB - Endogenous microRNAs (miRNAs) often exist as multiple isoforms (known as "isomiRs") with predominant variation around their 3'-end. Increasing evidence suggests that different isomiRs of the same family can have diverse functional roles, as recently demonstrated with the example of miR-222-3p 3'-end variants. While isomiR levels from a same miRNA family can vary between tissues and cell types, change of templated isomiR stoichiometry to stimulation has not been reported to date. Relying on small RNA-sequencing analyses, we demonstrate here that miR-222-3p 3'-end variants >23 nt are specifically decreased upon interferon (IFN) beta stimulation of human fibroblasts, while shorter isoforms are spared. This length-dependent dynamic regulation of long miR-222-3p 3'-isoforms and >40 other miRNA families was confirmed in human monocyte-derived dendritic cells following infection with Salmonella Typhimurium, underlining the breadth of 3' length regulation by infection, beyond the example of miR-222-3p. We further show that stem-loop miRNA Taqman RT-qPCR exhibits selectivity between 3'-isoforms, according to their length, and that this can lead to misinterpretation of results when these isoforms are differentially regulated. Collectively, and to our knowledge, this work constitutes the first demonstration that the stoichiometry of highly abundant templated 3'-isoforms of a same miRNA family can be dynamically regulated by a stimulus. Given that such 3'-isomiRs can have different functions, our study underlines the need to consider isomiRs when investigating miRNA-based regulation. PMID- 29263135 TI - Moral case deliberation. AB - Ethical dilemmas in general are characterised by a choice between two mutually excluding options neither of which is satisfactory, because there always will be a form of moral damage. Within the context of medicine several ethics support services have been developed to support healthcare professionals in dealing with ethical dilemmas, including moral case deliberation. In this article, we describe how moral case deliberation works in daily practice, illustrated with a case example from the neurology ward. The article is meant as an introduction to moral case deliberation according to the dilemma method. We show its relevance to the clinic and the context needed to put it into practice. PMID- 29263134 TI - Auto- and cross-regulation of the hnRNPs D and DL. AB - HnRNP D, better known as AUF1, is an extensively studied protein that controls a variety of cellular pathways. Consequently, its expression has to be tightly regulated to prevent the onset of pathologies. In contrast, the cellular functions and regulation of its ubiquitously expressed paralog hnRNP DL are barely explored. Here, we present an intricate crosstalk between these two proteins. Both hnRNP D and DL are able to control their own expression by alternative splicing of cassette exons in their 3'UTRs. Exon inclusion produces mRNAs degraded by nonsense-mediated decay. Moreover, hnRNP D and DL control the expression of one another by the same mechanism. Thus, we identified two novel ways of how hnRNP D expression is controlled. The tight interconnection of expression control directly links hnRNP DL to hnRNP D-related diseases and emphasizes the importance of a systematic analysis of its cellular functions. PMID- 29263136 TI - Foetal growth restriction in mice modifies postnatal airway responsiveness in an age and sex-dependent manner. AB - Epidemiological studies demonstrate an association between intrauterine growth restriction (IUGR) and asthma; however the underlying mechanism is unknown. We investigated the impact of maternal hypoxia-induced IUGR on airway responsiveness in male and female mice during juvenility and adulthood. Pregnant BALB/c mice were housed under hypoxic conditions for gestational days 11-17.5 and then returned to normoxic conditions for the remainder of pregnancy. A control group was housed under normoxic conditions throughout pregnancy. Offspring were studied at 2 weeks (juveniles) and 8 weeks (adults), where lung volume was assessed by plethysmography, airway responsiveness to methacholine determined by the forced oscillation technique and lungs fixed for morphometry. IUGR offspring were lighter at birth, exhibited "catch-up growth" by 2 weeks, but were again lighter in adulthood. IUGR males were "hyper-responsive" at 2 weeks and "hypo-responsive" as adults, in contrast with IUGR females who were hyper-responsive in adulthood. IUGR males had increased inner and total wall thickness at 2 weeks which resolved by adulthood, while airways in IUGR females were structurally normal throughout life. There were no differences in lung volume between Control and IUGR offspring at any age. Our data demonstrate changes in airway responsiveness as a result of IUGR that could influence susceptibility to asthma development and contribute to sexual dimorphism in asthma prevalence which switches from a male dominated disease in early life to a female dominated disease in adulthood. PMID- 29263137 TI - Functional blocking of Ninjurin1 as a strategy for protecting endothelial cells in diabetes mellitus. AB - Ongoing efforts to remove pathological inflammatory stimuli are crucial for the protection of endothelial cells in diabetes. Nerve injury-induced protein 1 (Ninj1) is an adhesion molecule that not only contributes to inflammation but also regulates the apoptosis of endothelial cells. In the present study, Ninj1 was found highly expressed in endothelial cells in Type 2 diabetic mice and increased in high-glucose (HG) cultured HUVECs. Furthermore, we found that Ninj1 levels are up-regulated in endothelial cells in clinical specimens of diabetic patients when compared with nondiabetic tissues, indicating a biological correlation between Ninj1 and endothelial pathophysiology in diabetic condition. Functional blocking of Ninj1 promoted endothelial tube formation and eNOS phosphorylation in the HG condition. Additionally, blocking Ninj1 inhibited the activation of caspase-3 and increased the Bcl-2/Bax ratio, thus inhibiting HUVECs apoptosis induced by HG. HG-induced ROS overproduction, p38 MAPK and NF-kappaB activation, and the overexpression of VCAM-1, ICAM-1, MCP-1, and IL-6 genes were ameliorated after Ninj1 was blocked. Using the signaling pathway inhibitor LY294002, we found that Bcl-2 expression and eNOS phosphorylation after Ninj1 blockade were regulated via PI3K/Akt signaling pathway. The in vivo endothelial contents, alpha-SMA+PECAM-1+ vascular numbers, and blood perfusion in the hindlimb were markedly up-regulated after Ninj1 was blocked. According to our findings, functional blocking of Ninj1 shows protective effects on diabetic endothelial cells both in vitro and in vivo Thus, we consider Ninj1 to be a potential therapeutic target for preventing endothelial dysfunction in diabetes mellitus. PMID- 29263139 TI - Quick and dirty? A systematic review of the use of rapid ethnographies in healthcare organisation and delivery. AB - BACKGROUND: The ability to capture the complexities of healthcare practices and the quick turnaround of findings make rapid ethnographies appealing to the healthcare sector, where changing organisational climates and priorities require actionable findings at strategic time points. Despite methodological advancement, there continue to be challenges in the implementation of rapid ethnographies concerning sampling, the interpretation of findings and management of field research. The purpose of this review was to explore the benefits and challenges of using rapid ethnographies to inform healthcare organisation and delivery and identify areas that require improvement. METHODS: This was a systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used the Mixed Methods Appraisal Tool to assess the quality of the articles. We developed the search strategy using the Population, Intervention, Comparison, Outcomes, Settingframework and searched for peer reviewed articles in MEDLINE, CINAHL PLUS, Web of Science and ProQuest Central. We included articles that reported findings from rapid ethnographies in healthcare contexts or addressing issues related to health service use. RESULTS: 26 articles were included in the review. We found an increase in the use of rapid ethnographies in the last 20/00years. We found variability in terminology and developed a typology to clarify conceptual differences. The studies generated findings that could be used to inform policy and practice. The main limitations of the studies were: the poor quality of reporting of study designs, mainly data analysis methods, and lack of reflexivity. CONCLUSIONS: Rapid ethnographies have the potential to generate findings that can inform changes in healthcare practices in a timely manner, but greater attention needs to be paid to the reflexive interpretation of findings and the description of research methods. TRIAL REGISTRATION NUMBER: CRD42017065874. PMID- 29263140 TI - Hospital culture and clinical performance: where next? PMID- 29263138 TI - The 10-nm chromatin fiber and its relationship to interphase chromosome organization. AB - A chromosome is a single long DNA molecule assembled along its length with nucleosomes and proteins. During interphase, a mammalian chromosome exists as a highly organized supramolecular globule in the nucleus. Here, we discuss new insights into how genomic DNA is packaged and organized within interphase chromosomes. Our emphasis is on the structural principles that underlie chromosome organization, with a particular focus on the intrinsic contributions of the 10-nm chromatin fiber, but not the regular 30-nm fiber. We hypothesize that the hierarchical globular organization of an interphase chromosome is fundamentally established by the self-interacting properties of a 10-nm zig-zag array of nucleosomes, while histone post-translational modifications, histone variants, and chromatin-associated proteins serve to mold generic chromatin domains into specific structural and functional entities. PMID- 29263141 TI - GLP-1 receptor regulates cell growth through regulating IDE expression level in Abeta1-42-treated PC12 cells. AB - This study aimed to validate whether glucagon-like peptide-1 receptor (GLP-1R) / cyclic adenosine monophosphate (cAMP) / protein kinase (PKA) / insulin-degrading enzyme (IDE) signaling pathway was associated with neuronal apoptosis. We developed an animal model presenting both Alzheimer's disease (AD) and type 2 diabetes (T2D), by crossing APP/PS1 mice (AD model) with streptozotocin (STZ) treated mice (a T2D model). Neuronal apoptosis was detected by TUNEL staining and the expression levels of apoptosis-related proteins were examined by Western blotting. The viability of PC12 cells was analyzed by MTT assay and apoptosis of PC12 cells was detected by flow cytometry. The mRNA expression level was detected by qRT-PCR. T2D contributes to AD progress by prompting neuronal apoptosis and increasing expression of pro-apoptotic protein. beta-Amyloid peptide1-42 (Abeta1 42) was shown to exert effects on inhibiting cell viability and prompting cell apoptosis of PC12 cells. However, GLP-1R agonist geniposide (Gen) significantly reversed them, exerting a protective role on PC12 cells. And IDE antagonist bacitracin (Bac) markedly reversed the protective effects of Gen on Abeta1-42 treated PC12 cells. Besides, Gen significantly reversed the effects of Abeta1-42 treatment on IDE expression, and the inhibitor of cAMP/PKA signaling pathway markedly reversed the effects of Gen on IDE expression level in Abeta1-42-treated PC12 cells. In conclusion, GLP-1R regulates cell growth, at least partially, through regulating cAMP/PKA/IDE signaling pathway in Abeta1-42-treated PC12 cells. PMID- 29263142 TI - Structure and function of urea amidolyase. AB - Urea is the degradation product of a wide range of nitrogen containing bio molecules. Urea amidolyase (UA) catalyzes the conversion of urea to ammonium, the essential first step in utilizing urea as a nitrogen source. It is widely distributed in fungi, bacteria and other microorganisms, and plays an important role in nitrogen recycling in the biosphere. UA is composed of urea carboxylase (UC) and allophanate hydrolase (AH) domains, which catalyze sequential reactions. In some organisms UC and AH are encoded by separated genes. We present here structure of the Kluyveromyces lactis UA (KlUA). The structure revealed that KlUA forms a compact homo-dimer with a molecular weight of 400 kDa. Structure inspired biochemical experiments revealed the mechanism of its reaction intermediate translocation, and that the KlUA holo-enzyme formation is essential for its optimal activity. Interestingly, previous studies and ours suggest that UC and AH encoded by separated genes probably do not form a KlUA-like complex, consequently they might not catalyze the urea to ammonium conversion as efficiently. PMID- 29263143 TI - MicroRNA-638 inhibits cell growth and tubule formation by suppressing VEGFA expression in human Ewing sarcoma cells. AB - Ewing sarcoma (EWS) is a kind of aggressive tumor of bone and soft tissues, which most occurring in children and adolescents. MicroRNAs (miRNAs) perform essential function in the progression and development of EWS, while the putative role of miR-638 in EWS remains uncertain. Accordingly, we detected the expression of miR 638 and explored its putative biological effects on the malignant phenotype of EWS cells. As expected, miR-638 was significantly down-regulated in EWS cells. Moreover, overexpression of miR-638 suppressed cell growth, induced cell apoptosis, and inhibited tubule formation of EWS cells in vitro Among the putative target genes of miR-638 predicted by the miRNA target prediction tools, vascular endothelial cell growth factor A (VEGFA) attracted out attention most. The luciferase reporter assays reaffirmed that VEGFA was a targeted gene of miR 638 in EWS cells. Furthermore, miR-638 suppressed the mRNA and protein level of VEGFA, and restored the expression of VEGFA reversed the suppressed effects of miR-638 in EWS cells. Taken together, the results suggested that miR-638 might perform tumor suppressive effects in EWS, which might be mediated, at least partially, through suppressing the activity of VEGFA. PMID- 29263144 TI - Protein carbonyl concentration as a biomarker for development and mortality in sepsis-induced acute kidney injury. AB - The objective of the present study was to evaluate protein carbonyl concentration as a predictor of AKI development in patients with septic shock and of renal replacement therapy (RRT) and mortality in patients with SAKI. This was a prospective observational study of 175 consecutive patients over the age of 18 years with septic shock upon Intensive Care Unit (ICU) admission. After exclusion of 46 patients (27 due to AKI at ICU admission), a total of 129 patients were enrolled in the study. Demographic information and blood samples were taken within the first 24 h of the patient's admission to determine serum protein carbonyl concentrations. Among the patients who developed SAKI, the development of AKI was evaluated, along with mortality and need for RRT. The mean age of the patients was 63.3 +/- 15.7 years, 47% were male and 51.2% developed SAKI during ICU stay. In addition, protein carbonyl concentration was shown to be associated with SAKI. Among 66 patients with SAKI, 77% died during the ICU stay. Protein carbonyl concentration was not associated with RRT in patients with SAKI. However, the ROC curve analysis revealed that higher levels of protein carbonyl were associated with mortality in these patients. In logistic regression models, protein carbonyl level was associated with SAKI development (OR: 1.416; 95% CI: 1.247-1.609; P<0.001) and mortality when adjusted by age, gender, and APACHE II score (OR: 1.357; 95% CI: 1.147-1.605; P<0.001). In conclusion, protein carbonyl concentration is predictive of AKI development and mortality in patients with SAKI, with excellent reliability. PMID- 29263145 TI - Evaluation of efficacy and safety of Reteplase and Alteplase in the treatment of hyper-acute cerebral infarction. AB - Objective: The present study aimed to investigate the efficacy and safety of Reteplase (rPA) and Alteplase (rt-PA) in the treatment of hyper-acute cerebral infarction (CI).Methods: Six hundred and eleven patients with hyper-acute CI selected from September 2014 to September 2016 were assigned into the aspirin, rt PA, rPA, rt-PA + aspirin, and rPA + aspirin groups based on their willingness. The difference of efficacy in five groups were evaluated with National Institute of Health Stroke Scale (NIHSS), modified rankin scale (mRS), and Barthel Index (BI). Coagulation function, blood lipid, and hemodynamics were analyzed. The safety differences were compared by observing the adverse reactions.Results: Compared with the rt-PA, rPA, and aspirin groups, NIHSS score, mRS score, the incidence of non- and symptomatic cerebral hemorrhage as well as the rate of adverse reactions were decreased, while BI were increased in the rt-PA + aspirin and rPA + aspirin groups after treatment. Compared with the rt-PA and rPA groups, total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were lower, whereas the hematocrit, whole blood high shear viscosity, whole blood low shear viscosity, plasma viscosity, erythrocyte electrophoresis time, fibrinogen, erythrocyte sedimentation rate (ESR), K value in blood sedimentation equation, and the comprehensive abnormality degree of blood rheology were higher in the rt PA + aspirin and rPA + aspirin groups.Conclusion: The efficacy and safety of rt PA or rPA combined with aspirin in the treatment of hyper-acute CI were better than those of rPA or rt-PA monotherapy. PMID- 29263146 TI - The role of radical prostatectomy for the treatment of metastatic prostate cancer: a systematic review and meta-analysis. AB - The recommended therapy by EAU guidelines for metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT) with or without chemotherapy. The role of radical prostatectomy (RP) in the treatment of mPCa is still controversial. Hence, a meta-analysis was conducted by comprehensively searching the databases PubMed, EMBASE and Web of Science for the relevant studies published before September 1st, 2017. Our results successfully shed light on the relationship that RP for mPCa was associated with decreased cancer-specific mortality (CSM) (pooled HR = 0.41, 95%CI = 0.36-0.47) and enhanced overall survival (OS) (pooled HR = 0.49, 95%CI = 0.44-0.55). Subsequent stratified analysis demonstrated that no matter how RP compared with no local therapy (NLT) or radiation therapy (RT), it was linked to a lower CSM (pooled HR = 0.36, 95%CI = 0.30-0.43 and pooled HR = 0.56, 95%CI 0.43-0.73, respectively) and a higher OS (pooled HR = 0.49, 95%CI = 0.44-0.56 and pooled HR = 0.46, 95%CI 0.33-0.65, separately). When comparing different levels of Gleason score, M-stage or N-stage, our results indicated that high level of Gleason score, M-stage or N-stage was associated with increased CSM. In summary, the outcomes of the present meta-analysis demonstrated that RP for mPCa was correlated with decreased CSM and enhanced OS in eligible patients of involved studies. In addition, patients with less aggressive tumors and good general health seemed to benefit the most. Moreover, no matter compared with NLT or RT, RP showed significant superiority in OS or CSM. Upcoming prospective randomized controlled trials were warranted to provide more high-quality data. PMID- 29263147 TI - Phenylalanine regulates initiation of digestive enzyme mRNA translation in pancreatic acinar cells and tissue segments in dairy calves. AB - As new nutritional strategies for ruminant are designed to change production efficiency by improving the supply of rumen protect protein, lipid, and even starch, the digestive system must fit to utilize these increased nutrient supplies, especially the pancreas. The objective of this study was to investigate the effects of phenylalanine (Phe) on digestive enzymes synthesis or secretion and cellular signaling in pancreatic acinar (PA) cells of dairy calves. The PA cells isolated from fresh pancreas of dairy calves, and cultured in completed RIPA 1640 medium with no fetal serum but 0, 0.15 and 0.45 mM Phe at 37 degrees C in CO2 incubator for 120 min. The pancreatic tissue segments (PTS) was cut approximately 2 * 2 mm from the fresh pancreas, and incubated in oxygenated Krebs Ringer bicarbonate (KRB) buffer containing 0 or 0.35 mM Phe at 39 degrees C for 180 min, and the samples were collected every 60 min after incubation. In PA cells, Phe increased (P < 0.05) the alpha-amylase secretion and mRNA expression, the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). In PTS, the Phe increased (P < 0.05) alpha-amylase and trypsin synthesis, secretion and mRNA expression, as well as the phosphorylation of S6K1 and 4EBP1. Conclusively, these results suggested that Phe regulates the synthesis or secretion of alpha-amylase, trypsin and lipase through mRNA translation initiation factors - S6K1 and 4EBP1. PMID- 29263148 TI - Regulatory T cells constrain the TCR repertoire of antigen-stimulated conventional CD4 T cells. AB - To analyze the potential role of Tregs in controlling the TCR repertoire breadth to a non-self-antigen, a TCRbeta transgenic mouse model (EF4.1) expressing a limited, yet polyclonal naive T-cell repertoire was used. The response of EF4.1 mice to an I-Ab-associated epitope of the F-MuLV envelope protein is dominated by clones expressing a Valpha2 gene segment, thus allowing a comprehensive analysis of the TCRalpha repertoire in a relatively large cohort of mice. Control and Treg depleted EF4.1 mice were immunized, and the extent of the Valpha2-bearing, antigen-specific TCR repertoire was characterized by high-throughput sequencing and spectratyping analysis. In addition to increased clonal expansion and acquisition of effector functions, Treg depletion led to the expression of a more diverse TCR repertoire comprising several private clonotypes rarely observed in control mice or in the pre-immune repertoire. Injection of anti-CD86 antibodies in vivo led to a strong reduction in TCR diversity, suggesting that Tregs may influence TCR repertoire diversity by modulating costimulatory molecule availability. Collectively, these studies illustrate an additional mechanism whereby Tregs control the immune response to non-self-antigens. PMID- 29263149 TI - GATA6 Controls Insulin Biosynthesis and Secretion in Adult beta-Cells. AB - GATA4 and GATA6 play essential, but redundant, roles in pancreas formation in mice, and GATA6 mutations cause pancreatic agenesis in humans. GATA6 mutations have also recently been linked to adult-onset diabetes, with subclinical or no exocrine insufficiency, suggesting an important role for GATA6 in human beta-cell physiology. To investigate the role of GATA6 in the adult endocrine pancreas, we generated mice in which Gata6 is specifically inactivated in the pancreas. These mice develop glucose intolerance. Islets deficient in GATA6 activity display decreased insulin content and impaired insulin secretion. Gata6-deficient beta cells exhibit ultrastructural abnormalities, including increased immature insulin granules, swollen mitochondria, and disorganized endoplasmic reticulum. We also demonstrate that Pdx1 expression in adult beta-cells depends on GATA sites in transgenic reporter mice and that loss of GATA6 greatly affects beta-cell specific gene expression. These findings demonstrate the essential role of GATA6 in beta-cell function. PMID- 29263150 TI - Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). AB - BACKGROUND: Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM). METHODS: In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup. RESULTS: The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each P<0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, P<0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both P<0.001). In patients with DM, E/S reduced the 7-year Kaplan-Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91-1.04; Pint=0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients >=75 years of age had a 20% relative reduction in the primary end point regardless of DM (Pint=0.91), whereas patients <75 years of age with DM had greater benefit than those without (Pint=0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin (Pint =0.034). CONCLUSIONS: In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878. PMID- 29263151 TI - KRAS Oncogenic Signaling Extends beyond Cancer Cells to Orchestrate the Microenvironment. AB - KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. Despite the large investment to understand the effects of KRAS activation in cancer cells, pharmacologic targeting of KRAS or its downstream effectors has not yet been successful at the clinical level. Recent studies are now describing new mechanisms of KRAS-induced tumorigenesis by analyzing its effects on the components of the tumor microenvironment. These studies revealed that the activation of KRAS on cancer cells extends to the surrounding microenvironment, affecting the properties and functions of its constituents. Herein, we discuss the most emergent perspectives on the relationship between KRAS-mutant cancer cells and their microenvironment components. Cancer Res; 78(1); 7-14. (c)2017 AACR. PMID- 29263153 TI - Choosing Wisely Canada Students and Trainees Advocating for Resource Stewardship (STARS) campaign: a descriptive evaluation. AB - BACKGROUND: Resource stewardship is being increasingly recognized as an essential competency for physicians, but medical schools are just beginning to integrate this into education. We describe the evaluation of Choosing Wisely Canada's Students and Trainees Advocating for Resource Stewardship (STARS) campaign, a student-led campaign to advance resource stewardship education in medical schools across Canada. METHODS: We evaluated the campaign 6 months after its launch, in November 2015. STARS students were administered a telephone survey eliciting a description of the initiatives that they had implemented or planned to implement at their schools to promote resource stewardship, and exploring their perceptions of facilitators of and barriers to successful implementation of their initiatives. We used a mixed-methods approach to analyze and summarize the data. RESULTS: Twenty-seven (82%) of the 33 eligible students representing all 17 medical schools responded. In 14 schools (82%), students led various local activities (e.g., interest groups, campaign weeks) to raise awareness about resource stewardship among medical students and faculty. Students contributed to curriculum change (both planned and implemented) at 10 schools (59%). Thematic analysis revealed key program characteristics that facilitated success (e.g., pan Canadian student network, local faculty champion) as well as barriers to implementing change (e.g., complex processes to change curriculum, hierarchical nature of medical school). INTERPRETATION: This student-led campaign, with support from local faculty and Choosing Wisely Canada staff, led to awareness building activities and early curricula change at medical schools across Canada. Future plans will build on the initial momentum created by the STARS campaign to sustain and spread local initiatives. PMID- 29263152 TI - MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer. AB - The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-kappaB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205-15. (c)2017 AACR. PMID- 29263154 TI - Transsphenoidal surgery for pituitary tumours: frequency and predictors of delayed hyponatraemia and their relationship to early readmission. AB - OBJECTIVE: A major cause of readmission after transsphenoidal surgery (TSS) is delayed hyponatraemia. The purpose of this study was to identify predictors of hyponatraemia one week post surgery and predictors of 30-day readmissions for hyponatraemia. DESIGN: A retrospective cohort study including patients who had TSS performed for pituitary lesions. METHOD: The risk of readmission for hyponatraemia was assessed in consecutive patients between January 2008 and March 2016. The risk of hyponatraemia one week post surgery was assessed in patients admitted for TSS between July 2011 and March 2016. RESULTS: Of all included patients, 56/522 (10.7%) were readmitted within 30 days. Hyponatraemia was found in 14/56 (25%) of 30-day readmissions. We did not identify any predictive variable for hyponatraemia on readmission. The number of patients with hyponatraemia on the seventh post-operative day was 26/314 (8.3%). The risk of hyponatraemia one week post surgery was increased by an odds ratio of 2.40 (95% CI: 1.06-5.40) in patients with a tumour abutting the optic chiasm and by an odds ratio of 1.16 (1.04-1.31) per mmol/L decrease in sodium levels on the first post operative day. CONCLUSIONS: Hyponatraemia occurred in 25% of readmissions; however, we did not identify any predictive variable for readmission with hyponatraemia. One week post surgery, 8.9% had hyponatraemia. Tumours pressing on the optic chiasm as well as a fall in sodium levels on the first post-operative day were associated with an increased risk of hyponatraemia one week post surgery. We suggest that a day 7 serum sodium <130 nmol/L should lead to concern and the provision of patient advice. PMID- 29263155 TI - Molecular Predicators of Duodenal Familial Adenomatous Polyposis Chemoprevention: Do Chemopreventive Drugs Hit Their Presumed Molecular Targets? AB - Patients with familial adenomatous polyposis (FAP) have an increased risk of developing duodenal adenomas and adenocarcinomas. In previous trials, sulindac (a cyclooxygenase inhibitor) alone failed to significantly suppress duodenal tumorigenesis in FAP patients, but sulindac plus the tyrosine kinase inhibitor erlotinib significantly reduced duodenal polyp burden. Delker and colleagues report in this issue (beginning on page 4) on transcriptome analyses that aimed to identify the molecular targets mediating the response to sulindac-erlotinib. Their exploratory transcriptome analyses suggested that sulindac-erlotinib suppressed duodenal polyposis via inhibiting Wnt/beta-catenin, EGFR, and cyclooxygenase pathways. This perspective discusses the significance and limitations of the study. Cancer Prev Res; 11(1); 1-3. (c)2017 AACRSee related article by Delker et al., p. 4. PMID- 29263156 TI - Introduction, Cancellation, and Future Promise of Medicare Cardiac Episode Payment Models. PMID- 29263157 TI - SRC increases MYC mRNA expression in ER+ breast cancer via mRNA stabilization and inhibition of p53 function. AB - The transcription factor MYC is important in breast cancer and its mRNA is maintained at a high level even in the absence of gene amplification. The mechanism(s) underlying increased MYC mRNA expression are unknown. Here we demonstrate that MYC mRNA was stabilized upon estrogen stimulation of estrogen receptor-positive breast cancer cells, via SRC-dependent effects on a recently described RNA-binding protein DeltaN-IMP1. We also show that loss of the tumor suppressor p53 increased MYC mRNA levels, even in the absence of estrogen stimulation. However, in cells with wildtype p53, SRC acted to overcome p53 mediated inhibition of estrogen-stimulated cell cycle entry and progression. SRC thus promotes cell proliferation in two ways: stabilizing MYC mRNA and inhibiting p53 function. Since estrogen receptor-positive breast cancers typically express wild-type p53, these studies establish a rationale for p53 status to be predictive for effective SRC inhibitor treatment in this subtype of breast cancer. PMID- 29263158 TI - Clb6-Cdc28 Promotes Ribonucleotide Reductase Subcellular Redistribution during S Phase. AB - A tightly controlled cellular deoxyribonucleotide (deoxynucleoside triphosphate [dNTP]) pool is critical for maintenance of genome integrity. One mode of dNTP pool regulation is through subcellular localization of ribonucleotide reductase (RNR), the enzyme that catalyzes the rate-limiting step of dNTP biosynthesis. In Saccharomyces cerevisiae, the RNR small subunit, Rnr2-Rnr4, is localized to the nucleus, whereas the large subunit, Rnr1, is cytoplasmic. As cells enter S phase or encounter DNA damage, Rnr2-Rnr4 relocalizes to the cytoplasm to form an active holoenzyme complex with Rnr1. Although the DNA damage-induced relocalization requires the checkpoint kinases Mec1-Rad53-Dun1, the S-phase-specific redistribution does not. Here, we report that the S-phase cyclin-cyclin-dependent kinase (CDK) complex Clb6-Cdc28 controls Rnr2-Rnr4 relocalization in S phase. Rnr2 contains a consensus CDK site and exhibits Clb6-dependent phosphorylation in S phase. Deletion of CLB6 or removal of the CDK site results in an increased association of Rnr2 with its nuclear anchor Wtm1, nuclear retention of Rnr2-Rnr4, and an enhanced sensitivity to the RNR inhibitor hydroxyurea. Thus, we propose that Rnr2-Rnr4 redistribution in S phase is triggered by Clb6-Cdc28-mediated phosphorylation of Rnr2, which disrupts the Rnr2-Wtm1 interaction and promotes the release of Rnr2-Rnr4 from the nucleus. PMID- 29263160 TI - P4HB recurrent missense mutation causing Cole-Carpenter syndrome. AB - BACKGROUND: Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB. OBJECTIVES: Here, we report a 3 year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HB as reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production. METHODS: We undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here. RESULTS: The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HB variant). DISCUSSION: P4HB (Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se. CONCLUSIONS: We provide additional evidence of P4HB as a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder. PMID- 29263159 TI - Pathogenicity of a Human Laminin beta2 Mutation Revealed in Models of Alport Syndrome. AB - Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin beta2 (LAMB2), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient's nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3-/- mouse model of autosomal recessive Alport syndrome and increased proteinuria in Col4a5+/- females that exhibit a mild form of X linked Alport syndrome due to mosaic deposition of collagen alpha3alpha4alpha5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans. PMID- 29263161 TI - ImmunoMap: A Bioinformatics Tool for T-cell Repertoire Analysis. AB - Despite a dramatic increase in T-cell receptor (TCR) sequencing, few approaches biologically parse the data in a fashion that both helps yield new information about immune responses and may guide immunotherapeutic interventions. To address this issue, we developed a method, ImmunoMap, that utilizes a sequence analysis approach inspired by phylogenetics to examine TCR repertoire relatedness. ImmunoMap analysis of the CD8 T-cell response to self-antigen (Kb-TRP2) or to a model foreign antigen (Kb-SIY) in naive and tumor-bearing B6 mice showed differences in the T-cell repertoire of self- versus foreign antigen-specific responses, potentially reflecting immune pressure by the tumor, and also detected lymphoid organ-specific differences in TCR repertoires. When ImmunoMap was used to analyze clinical trial data of tumor-infiltrating lymphocytes from patients being treated with anti-PD-1, ImmunoMap, but not standard TCR sequence analyses, revealed a clinically predicative signature in pre- and posttherapy samples. Cancer Immunol Res; 6(2); 151-62. (c)2017 AACR. PMID- 29263162 TI - Plasma Alkylresorcinol Metabolite, a Biomarker of Whole-Grain Wheat and Rye Intake, and Risk of Type 2 Diabetes and Impaired Glucose Regulation in a Chinese Population. AB - OBJECTIVE: To examine the association of plasma alkylresorcinol metabolite 3-(3,5 dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, with type 2 diabetes (T2D) and impaired glucose regulation (IGR) in a Chinese population. RESEARCH DESIGN AND METHODS: A total of 1,060 newly diagnosed T2D patients, 736 newly diagnosed IGR patients, and 1,443 control subjects with normal glucose tolerance were recruited in the case-control study. Plasma DHPPA concentrations were determined by high-performance liquid chromatography-tandem mass spectroscopy. Multivariate logistic regression analysis was used to evaluate the independent association of plasma DHPPA concentrations with the likelihood of T2D and IGR. RESULTS: After adjustment for age, sex, BMI, and family history of diabetes, the odds ratios (95% CI) of T2D and IGR were 0.57 (0.45, 0.73) and 0.66 (0.50, 0.85), respectively, comparing the lowest with the highest quartile of plasma DHPPA concentrations. Further adjustment for current smoking status, current alcohol consumption, physical activity, history of hypertension, and educational level did not change the observed association materially. Similar results were also obtained in T2D and IGR groups combined. The inverse association of plasma DHPPA with T2D persisted in stratified analyses according to age, sex, BMI, current smoking status, current alcohol consumption, physical activity, family history of diabetes, and history of hypertension. CONCLUSIONS: These findings suggested that higher plasma DHPPA concentrations were associated with lower odds of T2D and IGR. Further studies are warranted to confirm these findings in prospective cohorts. PMID- 29263163 TI - Incidence of End-Stage Renal Disease in Patients With Type 1 Diabetes. AB - OBJECTIVE: To investigate how risk of end-stage renal disease (ESRD) among patients with type 1 diabetes has changed over time and further how the risk is affected by age, sex, and time period of diagnosis of diabetes. RESEARCH DESIGN AND METHODS: A cohort including all patients <30 years old diagnosed with type 1 diabetes in Finland in 1965-2011 was followed until start of renal replacement therapy, death, or end of follow-up at the end of 2013. Altogether, 29,906 patients were included. The main outcome was cumulative risk of ESRD, accounting for death as a competing risk. RESULTS: The patients were followed up for a median of 20 years. During 616,403 patient-years, 1,543 ESRD cases and 4,185 deaths were recorded. The cumulative risk of ESRD was 2.2% after 20 years and 7.0% after 30 years from the diabetes diagnosis. The relative risk of ESRD was 0.13 (95% CI 0.08-0.22) among patients diagnosed in 1995-2011 compared with those diagnosed in 1965-1979. Patients <5 years old at the time of diagnosis had the lowest risk of ESRD after diagnosis. With the cumulative risk of ESRD estimated from time of birth, the patients aged 5-9 years at diabetes diagnosis were at highest risk. CONCLUSIONS: The cumulative risk of ESRD has decreased markedly during the past five decades. This highlights the importance of modern treatment of diabetes and diabetic nephropathy. PMID- 29263164 TI - Diabetes Is Associated With Reduced Stress Hyperlactatemia in Cardiac Surgery. AB - OBJECTIVE: Hyperglycemia and hyperlactatemia are associated with increased morbidity and mortality in critical illness. We evaluated the relationship among hyperlactatemia, glycemic control, and diabetes mellitus (DM) after cardiac surgery. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study of 4,098 cardiac surgery patients treated between 2011 and 2015. Patients were stratified by DM and glucose-lowering medication history. Hyperglycemia (glucose >180 mg/dL), hypoglycemia (<70 mg/dL), and the hyperglycemic index were assessed postoperatively (48 h). The relationship between lactate and glucose levels was modeled using generalized linear regression. Mortality was analyzed using an extended Cox regression model. RESULTS: Hyperglycemia occurred in 26.0% of patients without DM (NODM), 46.5% with DM without prior drug treatment (DMNT), 62.8% on oral medication (DMOM), and 73.8% on insulin therapy (DMIT) (P < 0.0001). Hypoglycemia occurred in 6.3%, 9.1%, 8.8%, and 10.8% of NODM, DMNT, DMOM, and DMIT, respectively (P = 0.0012). The lactate levels of all patients were temporarily increased with surgery. This increase was greater in patients who also had hyperglycemia or hypoglycemia and was markedly attenuated in patients with DM. Peak lactate was 5.8 mmol/L (95% CI 5.6, 6.0) in NODM with hyperglycemia vs. 3.3 (95% CI 3.2, 3.4) without hyperglycemia; in DMNT: 4.8 (95% CI 4.4, 5.2) vs. 3.4 (95% CI 3.1, 3.6); in DMOM: 3.8 (95% CI 3.5, 4.1) vs. 2.9 (95% CI 2.7, 3.1); and in DMIT: 3.3 (95% CI 3.0, 3.5) vs. 2.7 (95% CI 2.3, 3.0). Increasing lactate levels were associated with increasing mortality; increasing glucose reduced this effect in DM but not in NODM (P = 0.0069 for three-way interaction). CONCLUSIONS: Stress hyperlactatemia is markedly attenuated in patients with DM. There is a three-way interaction among DM, stress hyperlactatemia, and stress hyperglycemia associated with mortality after cardiac surgery. PMID- 29263165 TI - In This Issue of Diabetes. PMID- 29263166 TI - Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication. AB - The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10-20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D. PMID- 29263168 TI - SCP4: A Small Nuclear Phosphatase Having a Big Effect on FoxOs in Gluconeogenesis. PMID- 29263167 TI - The Adiponectin Paradox for All-Cause and Cardiovascular Mortality. AB - Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate. PMID- 29263170 TI - Accuracy, user-friendliness and usefulness of the Cobas h232 point-of-care test for NT-proBNP in primary care. AB - AIMS: N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been shown to be useful for ruling out heart failure in primary care. In this study, we examined the accuracy of the Cobas h232 point-of-care (POC) instrument in primary care compared with an in-hospital measurement. Furthermore, we investigated the user friendliness and usefulness of the POC device. METHODS: Five general practitioner (GP) groups were asked to evaluate adult patients who were suspected of having heart failure and to test NT-proBNP with the Cobas h232. The samples were subsequently delivered to and analysed at a central hospital laboratory by the Cobas e602 using conventional transport and storage. Difference between the paired measurements was analysed using a percentage difference plot, and correlation was assessed using Passing-Bablok linear regression analysis. User friendliness and usefulness were assessed using semistructured questionnaires. RESULTS: Nineteen GPs studied 94 patients. Passing-Bablok analysis showed a slope of 1.05 (95% CI 1.00 to 1.11) (R2=0.97). The percentage difference plot showed a mean difference of 15.7% (95% CI -46.0% to -77.4%). User-friendliness and usefulness had median scores of 4 or 5 on a five-point Likert scale. Eighteen out of 19 GPs confirmed that the device influenced their clinical practice. During the study, GPs' confidence in using NT-proBNP increased significantly from a mean score of 4.4 (95% CI 3.2 to 5.6) to 7.6 out of 10 (95% CI 7.1 to 8.2). CONCLUSIONS: The Cobas h232 NT-proBNP POC test proved to be an accurate, user friendly and useful test in primary care. Nearly all participating GPs were convinced that the test could benefit clinical decision making. PMID- 29263172 TI - Advanced pulmonary arterial hypertension: mechanical support and lung transplantation. AB - The development of targeted therapies has transformed the outlook for patients with pulmonary arterial hypertension (PAH); however, some patients fail to achieve an adequate clinical response despite receiving maximal treatment. For these patients, lung transplantation remains an important therapeutic option, and recommendations for transplantation are included in the current European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension. Although lung transplantation is not without risk, overall long-term survival rates are good and substantial improvements in quality of life have been reported for lung transplant recipients. In this review, we describe the important considerations prior to, during and after transplantation, including the role of mechanical support, in patients with advanced PAH. PMID- 29263171 TI - Lung nodules: size still matters. AB - The incidence of indeterminate pulmonary nodules has risen constantly over the past few years. Determination of lung nodule malignancy is pivotal, because the early diagnosis of lung cancer could lead to a definitive intervention. According to the current international guidelines, size and growth rate represent the main indicators to determine the nature of a pulmonary nodule. However, there are some limitations in evaluating and characterising nodules when only their dimensions are taken into account. There is no single method for measuring nodules, and intrinsic errors, which can determine variations in nodule measurement and in growth assessment, do exist when performing measurements either manually or with automated or semi-automated methods. When considering subsolid nodules the presence and size of a solid component is the major determinant of malignancy and nodule management, as reported in the latest guidelines. Nevertheless, other nodule morphological characteristics have been associated with an increased risk of malignancy. In addition, the clinical context should not be overlooked in determining the probability of malignancy. Predictive models have been proposed as a potential means to overcome the limitations of a sized-based assessment of the malignancy risk for indeterminate pulmonary nodules. PMID- 29263173 TI - Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled. AB - The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets. PMID- 29263175 TI - Pulmonary arterial hypertension: tailoring treatment to risk in the current era. AB - Recent advances in the treatment of pulmonary arterial hypertension (PAH) have led to improved patient outcomes. Multiple PAH therapies are now available and optimising the use of these drugs in clinical practice is vital. In this review, we discuss the management of PAH patients in the context of current treatment guidelines and supporting clinical evidence. In clinical practice, considerable emphasis is placed on the importance of making treatment decisions guided by each patient's risk status, which should be assessed using multiple prognostic parameters. As PAH is a progressive disease, regular assessments are essential to ensure that any change in risk is detected in a timely manner and treatment is adjusted accordingly. With the availability of therapies that target three different pathogenic pathways, combination therapy is now the standard of care. For most patients, this involves dual combination therapy with agents targeting the endothelin and nitric oxide pathways. Therapies targeting the prostacyclin pathway should be added for patients receiving dual combination therapy who do not achieve a low-risk status. There is also a need for a holistic approach to treatment beyond pharmacological therapies. Implementation of all these approaches will ensure that PAH patients receive maximal benefit from currently available therapies. PMID- 29263176 TI - The changing landscape of chronic thromboembolic pulmonary hypertension management. AB - For patients with chronic thromboembolic pulmonary hypertension (CTEPH), the current standard of care involves surgical removal of fibro-thrombotic obstructions by pulmonary endarterectomy. While this approach has excellent outcomes, significant proportions of patients are not eligible for surgery or suffer from persistent/recurrent pulmonary hypertension after the procedure. The availability of balloon pulmonary angioplasty and the approval of the first medical therapy for use in CTEPH have significantly improved the outlook for patients ineligible for pulmonary endarterectomy. In this comprehensive review, we discuss the latest developments in the rapidly evolving field of CTEPH. These include improvements in imaging modalities and advances in surgical and interventional techniques, which have broadened the range of patients who may benefit from such procedures. The efficacy and safety of targeted medical therapies in CTEPH patients are also discussed, particularly the encouraging data from the recent MERIT-1 trial, which demonstrated the beneficial impact of using macitentan to treat patients with inoperable CTEPH, including those on background therapy. As the treatment options for CTEPH improve, hybrid management involving more than one intervention in the same patient may become a viable option in the near future. PMID- 29263177 TI - Pulmonary hypertension: a paradigm for rare pulmonary diseases. PMID- 29263174 TI - Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice. AB - Pulmonary hypertension (PH) is an often-fatal vascular disease of unclear molecular origins. The pulmonary vascular remodelling which occurs in PH is characterised by elevated vasomotor tone and a pro-proliferative state, ultimately leading to right ventricular dysfunction and heart failure. Guided in many respects by prior evidence from cancer biology, recent investigations have identified metabolic aberrations as crucial components of the disease process in both the pulmonary vessels and the right ventricle. Given the need for improved diagnostic and therapeutic options for PH, the development or repurposing of metabolic tracers and medications could provide an effective avenue for preventing or even reversing disease progression. In this review, we describe the metabolic mechanisms that are known to be dysregulated in PH; we explore the advancing diagnostic testing and imaging modalities that are being developed to improve diagnostic capability for this disease; and we discuss emerging drugs for PH which target these metabolic pathways. PMID- 29263178 TI - Geographical epidemiology of health and overall deprivation in England, its changes and persistence from 2004 to 2015: a longitudinal spatial population study. AB - BACKGROUND: Socioeconomic deprivation is a key determinant for health. In England, the Index of Multiple Deprivation (IMD) is a widely used composite measure of deprivation. However, little is known about its spatial clustering or persistence across time. METHODS: Data for overall IMD and its health domain were analysed for 2004-2015 at a low geographical area (average of 1500 people). Levels and temporal changes were spatially visualised for the whole of England and its 10 administrative regions. Spatial clustering was quantified using Moran's I, correlations over time were quantified using Pearson's r. RESULTS: Between 2004 and 2015 we observed a strong persistence for both overall (r=0.94) and health-related deprivation (r=0.92). At the regional level, small changes were observed over time, but with areas slowly regressing towards the mean. However, for the North East, North West and Yorkshire, where health-related deprivation was the highest, the decreasing trend in health-related deprivation reversed and we noticed increases in 2015. Results did not support our hypothesis of increasing spatial clustering over time. However, marked regional variability was observed in both aggregate deprivation outcomes. The lowest autocorrelation was seen in the North East and changed very little over time, while the South East had the highest autocorrelation at all time points. CONCLUSIONS: Overall and health-related deprivation patterns persisted in England, with large and unchanging health inequalities between the North and the South. The spatial aspect of deprivation can inform the targeting of health and social care interventions, particularly in areas with high levels of deprivation clustering. PMID- 29263179 TI - Understanding child disadvantage from a social determinants perspective. AB - BACKGROUND: Child health and developmental inequities exist in all countries. Comprehensive and robust concepts of disadvantage are fundamental to growing an evidence base that can reveal the extent of inequities in childhood, and identify modifiable leverage points for change. We conceptualise and test a multidimensional framework of child disadvantage aligned to a social determinants and bioecological perspective. METHODS: The Longitudinal Study of Australian Children is a nationally representative sample of two cohorts of Australian children, including the birth cohort of 5107 infants, which commenced in May 2004. The analysis focused on disadvantage indicators collected at age 4-5 years. Confirmatory factor analysis was used to test a theoretically informed model of disadvantage. Concurrent validity was examined through associations with academic performance at 8-9 years. RESULTS: The model comprising four latent factors of sociodemographic (10 indicators), geographical environments (three indicators), health conditions (three indicators) and risk factors (14 indicators) was found to provide a better fit for the data than alternative models. Each factor was associated with academic performance, providing evidence of concurrent validity. CONCLUSION: The study provides a theoretically informed and empirically tested framework for operationalising relative child disadvantage. Understanding and addressing inequities will be facilitated by capturing the complexity of children's experiences of disadvantage across the multiple environments in which their development unfolds. PMID- 29263180 TI - Men's health and co-residence with older generations in Russia: better or worse? AB - BACKGROUND: Previous studies show contradictory findings on the relationship between health and intergenerational living arrangements (ILAs), which may be due to variation in who selects themselves into and out of ILA. Addressing the selectivity into ILA and the health of the older generation, we assess whether there is a health-protective or health-damaging effect of ILA. We locate our study in the Russian context, where ILA is prevalent and men's health has become a public health issue. METHODS: We apply a fixed-effects logistic regression to self-rated health status of 11 546 men aged 25 years or older who participated in at least two waves in the Russian Longitudinal Monitoring Survey from 1994 to 2015. To further isolate the health effect of ILA, we observe only associations after transitioning into or out of ILA. RESULTS: A transition into co-residence with an unhealthy older generation increases men's odds of reporting poor health (OR=0.64, CI 0.44 to 0.93). A transition out of co-residence with a healthy older generation decreases men's odds of reporting fine health by 63% (OR=0.37, CI 0.28 to 0.50), whereas continuing to live with an unhealthy older generation decreases the odds by half (OR=0.49, CI 0.38 to 0.63). CONCLUSIONS: We reveal a health interlinkage between co-residing generations by finding a detrimental health effect of co-residence with an unhealthy older generation. No longer living with an older generation who was in fine health also negatively affects men's health. Future studies should address heterogeneity related to the health of older generations, unobserved time-constant characteristics of younger generations and selectivity into/out of ILA. PMID- 29263181 TI - Loss-of-Function Mutations in Calcitonin Receptor (CALCR) Identify Highly Aggressive Glioblastoma with Poor Outcome. AB - Purpose: Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole-exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways.Experimental Design: WES of different astrocytoma samples (n = 42; Indian cohort) was carried out and compared with that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines, and mouse xenograft models were used for functional characterization of calcitonin receptor (CALCR) and establish it as a therapeutic target.Results: A similar mutation spectrum between the Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective "neuroactive ligand-receptor interaction" pathway (n = 23; 9.54%) that have significantly poor prognosis (P < 0.0001). Furthermore, GBMs with mutated calcitonin receptor (CALCR) or reduced transcript levels predicted poor prognosis. Exogenously added calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss of function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro Furthermore, calcitonin inhibited patient-derived neurosphere growth and in vivo glioma tumor growth in a mouse model.Conclusions: We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM. Clin Cancer Res; 24(6); 1448-58. (c)2017 AACR. PMID- 29263183 TI - Urinary Concentrations of Polycyclic Aromatic Hydrocarbon Metabolites in Mate Drinkers in Rio Grande do Sul, Brazil. AB - Background: Consumption of mate, an infusion of the herb Ilex paraguariensis (yerba mate), is associated with increased risk of esophageal squamous cell carcinoma (ESCC), but the carcinogenic mechanism is unclear. Commercial brands of yerba mate contain high levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs), which are acquired during the traditional drying process. The purpose of this study was to characterize exposure to PAHs in mate drinkers over a wide range of mate consumption.Methods: We recruited 244 adults who answered a questionnaire and collected a fasting spot urine specimen. We quantified urinary concentrations of seven PAH metabolites and assessed associations between self reported recent mate consumption and urinary PAH metabolites by multivariate regression.Results: Recent mate consumption showed a significant dose-response association with 6 of 7 PAH metabolites in unadjusted models (Ptrend < 0.05). After adjustment for creatinine and potential confounders, concentrations of 2 naphthol, 1-hydroxyphenanthrene, and the sum of 2- and 3-hydroxyphenanthrene remained significantly associated with recent mate intake. The sum of the urinary concentrations of the phenanthrene metabolites was similar or higher among mate drinkers who did not smoke than among smokers who did not drink mateConclusions: Urinary concentrations of PAH metabolites were significantly associated with self reported amounts of recent mate intake, and drinking mate increased urinary concentrations of some PAH metabolites as much as smoking cigarettes.Impact: Drinking mate is a source of exposure to potentially carcinogenic PAHs, consistent with the hypothesis that the PAH content of mate may contribute to the increased risk of ESCC in mate drinkers. Cancer Epidemiol Biomarkers Prev; 27(3); 331-7. (c)2017 AACR. PMID- 29263182 TI - Epigenetic Reprogramming Strategies to Reverse Global Loss of 5 Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer. AB - Purpose: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation.Experimental Design: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically.Results: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease.Conclusions: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. Clin Cancer Res; 24(6); 1389-401. (c)2017 AACR. PMID- 29263184 TI - Helicobacter pylori Blood Biomarkers and Gastric Cancer Survival in China. AB - Background: Infection with Helicobacter pylori is the leading risk factor for noncardia gastric cancer, yet its influence on prognosis of gastric cancer is largely unknown. Thus, exploring the role of Helicobacter pylori (H. pylori) in survival could lead to a greater understanding of the high mortality associated with gastric cancer.Methods: Seropositivity to 15 H. pylori antigens was assessed using a multiplex assay in two prospective cohorts, the Shanghai Men's Health Study and the Shanghai Women's Health Study. Multivariable-adjusted Cox proportional hazards regression was used to examine the association between prediagnostic H. pylori antigen levels and gastric cancer-specific survival.Results: Prediagnostic levels of H. pylori serum antibodies that were previously associated with gastric cancer incidence in this population were not associated with gastric cancer survival, whether assessed in a 6-antigen panel [HR = 1.29; 95% confidence interval (CI), 0.78-2.13 for men; HR = 0.93; 95% CI, 0.57-1.52 for women], focused on CagA+H. pylori (HR = 0.73; 95% CI, 0.44-1.20 forwomen; HR = 1.27; 95% CI, 0.70-2.31 for men) or on the high-risk biomarkers of dual Omp and HP 0305 seropositivity (HR = 0.97; 95% CI, 0.72-1.30 for women; HR = 1.37; 95% CI, 0.97-1.94 for men).Conclusions: Prediagnostic H. pylori antigen levels are not associated with gastric cancer survival in East Asian populations.Impact: Identification of additional factors associated with gastric cancer survival would further our understanding of the high mortality associated with this malignancy. Cancer Epidemiol Biomarkers Prev; 27(3); 342-4. (c)2017 AACR. PMID- 29263185 TI - Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer. AB - Background: Radiation exposure is a well-documented risk factor for thyroid cancer; diagnostic imaging represents an increasing source of exposure. Germline variations in DNA repair genes could increase risk of developing thyroid cancer following diagnostic radiation exposure. No studies have directly tested for interaction between germline mutations and radiation exposure.Methods: Using data and DNA samples from a Connecticut population-based case-control study performed in 2010 to 2011, we genotyped 440 cases of incident thyroid cancer and 465 population-based controls for 296 SNPs in 52 DNA repair genes. We used multivariate unconditional logistic regression models to estimate associations between each SNP and thyroid cancer risk, as well as to directly estimate the genotype-environment interaction between each SNP and ionizing radiation.Results: Three SNPs were associated with increased risk of thyroid cancer and with thyroid microcarcinoma: HUS rs2708896, HUS rs10951937, and MGMT rs12769288. No SNPs were associated with increased risk of larger tumor (>10 mm) in the additive model. The gene-environment interaction analysis yielded 24 SNPs with Pinteraction < 0.05 for all thyroid cancer, 12 SNPs with Pinteraction < 0.05 for thyroid microcarcinoma, and 5 SNPs with Pinteraction < 0.05 for larger tumors.Conclusions: Germline variants in DNA repair genes are associated with thyroid cancer risk and are differentially associated with thyroid microcarcinoma and large tumor size. Our study provides the first evidence that germline genetic variations modify the association between diagnostic radiation and thyroid cancer risk.Impact: Thyroid microcarcinoma may represent a distinct subset of thyroid cancer. The effect of diagnostic radiation on thyroid cancer risk varies by germline polymorphism. Cancer Epidemiol Biomarkers Prev; 27(3); 285-94. (c)2017 AACR. PMID- 29263186 TI - Association between Dietary Energy Density and Risk of Breast, Endometrial, Ovarian, and Colorectal Cancer among Canadian Women. AB - Background: Dietary energy density (DED) is strongly associated with cancer associated metabolic disorders such as obesity and metabolic syndrome and may thus influence carcinogenesis. However, little is known about its association with cancer. Therefore, we investigated the association of DED with risk of breast, endometrial, ovarian, and colorectal cancers in the Canadian Study of Diet, Lifestyle, and Health.Methods: We conducted a case-cohort study that included an age-stratified subcohort of 3,120 of the 39,532 female participants who completed self-administered lifestyle and dietary questionnaires at baseline, and in whom, respectively, 922, 188, 104, and 269 incident breast, endometrial, ovarian, and colorectal cancer cases were diagnosed, respectively. We estimated HRs and 95% confidence intervals for the association of DED with risk of these cancers using Cox proportional hazards regression models modified for the case cohort design.Results: There was no statistically significant association between DED and risk of breast, endometrial, ovarian, and colorectal cancers.Conclusions: Our study suggests that DED is not independently associated with risk of breast, endometrial, ovarian, and colorectal cancers among women.Impact: Further investigation of the association between DED and risk of these cancers in larger prospective studies is warranted, as demonstration of associations may have important implications for primary prevention of these cancers. Cancer Epidemiol Biomarkers Prev; 27(3); 338-41. (c)2017 AACR. PMID- 29263187 TI - Enhancing the Infrastructure of the Atherosclerosis Risk in Communities (ARIC) Study for Cancer Epidemiology Research: ARIC Cancer. AB - Background: We describe the expansion of the Atherosclerosis Risk in Communities (ARIC) Study into a cancer cohort. In 1987 to 1989, ARIC recruited 15,792 participants 45 to 64 years old to be sex (55% female), race (27% black), and geographically diverse. ARIC has exceptional data collected during 6 clinical visits and calls every 6 months, repeated biospecimens, and linkage to Medicare claims data.Methods: We established a Cancer Coordinating Center to implement infrastructure activities, convened a Working Group for data use, leveraged ARIC staff and procedures, and developed protocols. We initiated a cancer-specific participant contact, added questions to existing contacts, obtained permission to collect medical records and tissue, abstracted records, linked with state cancer registries, and adjudicated cases and characterizing data.Results: Through 2012, we ascertained and characterized 4,743 incident invasive, first, and subsequent primary cancers among 4,107 participants and 1,660 cancer-related deaths. We generated a total cancer incidence and mortality analytic case file, and analytic case files for bladder, breast, colorectal, liver, lung, pancreas, and prostate cancer incidence, mortality, and case fatality. Adjudication of multiple data sources improved case records and identified cancers not identified via registries. From 2013 onward, we ascertain cases from self-report coupled with medical records. Additional cancer registry linkages are planned.Conclusions: Compared with starting a new cohort, expanding a cardiovascular cohort into ARIC Cancer was an efficient strategy. Our efforts yielded enhanced case files with 25 years of follow-up.Impact: Now that the cancer infrastructure is established, ARIC is contributing its unique features to modern cancer epidemiology research. Cancer Epidemiol Biomarkers Prev; 27(3); 295-305. (c)2017 AACR. PMID- 29263188 TI - Depression, Antidepressant Use, and Breast Cancer Risk in Pre- and Postmenopausal Women: A Prospective Cohort Study. AB - Background: Depression and antidepressant use is highly prevalent among U.S. women and may be related to increased breast cancer risk. However, prior studies are not in agreement regarding an increase in risk.Methods: We conducted a prospective cohort study within the Nurses' Health Study (NHS) and NHSII among females age 25 and older. Over more than 10 years of follow-up in each cohort, 4,014 incident invasive breast cancers were diagnosed. We used Cox proportional hazards regressions with updating of exposures and covariates throughout follow up to estimate HRs and 95% confidence intervals (CIs) for associations between clinical depression and antidepressant use with invasive breast cancer risk. Analyses were repeated separately for in situ disease, as well as stratified by estrogen receptor (ER) subtype and menopausal status at diagnosis.Results: No statistically significant associations were observed between clinical depression (HR for reporting >=3 times vs. 0, 1.13; 95% CI, 0.85-1.49) or antidepressant use (HR for reporting >=3 times vs. 0, 0.92; 95% CI, 0.80-1.05) and invasive breast cancer risk in multivariable analyses. Likewise, we observed no significant associations between clinical depression or antidepressant use and risk of in situ, ER+, ER-, premenopausal, or postmenopausal breast cancer.Conclusions: In the largest prospective study to date, we find no evidence that either depression or antidepressant use increase risk of breast cancer.Impact: The results of this study are reassuring in that neither depression nor antidepressant use appear to be related to subsequent breast cancer risk. Cancer Epidemiol Biomarkers Prev; 27(3); 306-14. (c)2017 AACR. PMID- 29263190 TI - In This Issue of Diabetes Care. PMID- 29263191 TI - In an Anniversary Year, Diabetes Care Takes a Selfie. PMID- 29263189 TI - Opium Use and Risk of Pancreatic Cancer: A Prospective Cohort Study. AB - Background: We examined the association between opium consumption and pancreatic cancer incidence in a large-scale prospective cohort of the general population in northeastern Iran.Methods: A total of 50,045 adults were systematically followed up (median of 7.4 years), and incident cases of pancreatic cancer were identified. Self-reported data on opium consumption was collected at baseline. Cumulative use (-year) was defined as number of nokhods (a local unit, approximately 0.2 g) of opium consumed per day multiplied by number of years consuming. Adjusted HRs and 95% confidence intervals (CIs) for the association between opium consumption and pancreatic cancer were calculated using Cox proportional hazards regression models.Results: Overall, 54 confirmed cases of pancreatic cancer were identified. Opium use of more than 81 nokhod-years (high cumulative use), compared with never use, was strongly associated with pancreatic cancer even after adjustments for multiple potential confounding factors [HR = 3.01; 95% CI, 1.25-7.26]. High cumulative consumption of opium was significantly associated with risk of pancreatic cancer after adjusting for cumulative dose of cigarette smoking [HR = 3.56; 95% CI, 1.49-8.50]. In a sensitivity analysis, we excluded participants (including 2 pancreatic cancer cases) who were recruited within the first 5 years of starting opium consumption; high cumulative use of opium was still associated with pancreatic cancer risk [HR = 2.75; 95% CI, 1.14 6.64].Conclusions: Our results showed a positive association between opium consumption and pancreatic cancer.Impact: This is the first prospective large scale study to show the association of opium consumption with pancreatic cancer as a risk factor. Cancer Epidemiol Biomarkers Prev; 27(3); 268-73. (c)2017 AACR. PMID- 29263192 TI - Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias? AB - Two recent observational studies reported a remarkably lower rate of all-cause death associated with sodium-glucose cotransporter 2 inhibitor (-SGLT2i) use in all patients with type 2 diabetes and not only those at increased cardiovascular risk. The >50% lower mortality rates reported in these studies are much greater than those found in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) randomized trials. We show that these observational studies are affected by time-related biases, including immortal time bias and time-lag bias, which tend to exaggerate the benefits observed with a drug. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study, based on 166,033 users of SGLT2i and 1,226,221 users of other glucose-lowering drugs (oGLD) identified from health care databases of six countries, was affected by immortal time bias. Indeed, the immortal time between the first oGLD prescription and the first SGLT2i prescription was omitted from the analysis, which resulted in increasing the rate of death in the oGLD group and thus producing the appearance of a lower risk of death with SGLT2i use. The Swedish study compared 10,879 SGLT2i/dipeptidyl peptidase 4 inhibitor (DPP-4i) users with 10,879 matched insulin users. Such comparisons involving second-line therapies with a third-line therapy can introduce time-lag bias, as the patients may not be at the same stage of diabetes. This bias is compounded by the fact that the users of insulin had already started their insulin before cohort entry, unlike the new users of SGLT2i. Finally, the study also introduces immortal time bias with respect to the effects of SGLT2i relative to DPP-4i. In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time-lag biases. It thus remains uncertain whether the benefit seen with empagliflozin in the EMPA-REG OUTCOME trial applies to all SGLT2i and to all patients with type 2 diabetes, not only those at increased cardiovascular risk. While observational studies can provide crucial real-world evidence for the effects of medications, they need to be carefully conducted to avoid such major time-related biases. PMID- 29263193 TI - Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. PMID- 29263196 TI - Comment on Han et al. Comparative Effectiveness of Diabetic Oral Medications Among HIV-Infected and HIV-Uninfected Veterans. Diabetes Care 2017;40:218-225. PMID- 29263197 TI - Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects. Diabetes Care 2017;40:1436-1443. PMID- 29263194 TI - Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors' Expert Forum. AB - In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date. PMID- 29263198 TI - Response to Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects. Diabetes Care 2017;40:1436-1443. PMID- 29263199 TI - The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development. AB - MicroRNAs are important regulators of local protein synthesis during neuronal development. We investigated the dynamic regulation of microRNA production and found that the majority of the microRNA-generating complex, consisting of Dicer, TRBP, and PACT, specifically associates with intracellular membranes in developing neurons. Stimulation with brain-derived neurotrophic factor (BDNF), which promotes dendritogenesis, caused the redistribution of TRBP from the endoplasmic reticulum into the cytoplasm, and its dissociation from Dicer, in a Ca2+-dependent manner. As a result, the processing of a subset of neuronal precursor microRNAs, among them the dendritically localized pre-miR16, was impaired. Decreased production of miR-16-5p, which targeted the BDNF mRNA itself, was rescued by expression of a membrane-targeted TRBP Moreover, miR-16-5p or membrane-targeted TRBP expression blocked BDNF-induced dendritogenesis, demonstrating the importance of neuronal TRBP dynamics for activity-dependent neuronal development. We propose that neurons employ specialized mechanisms to modulate local gene expression in dendrites, via the dynamic regulation of microRNA biogenesis factors at intracellular membranes of the endoplasmic reticulum, which in turn is crucial for neuronal dendrite complexity and therefore neuronal circuit formation and function. PMID- 29263200 TI - WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome. AB - WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11 null mice also exhibit early-onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin releasing hormone production. The CHH/KS-associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum. PMID- 29263201 TI - Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. AB - Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAFV600E-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAFV600E-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary. PMID- 29263202 TI - Validation of Whole-Genome Sequencing for Identification and Characterization of Shiga Toxin-Producing Escherichia coli To Produce Standardized Data To Enable Data Sharing. AB - Whole-genome sequencing (WGS) is rapidly becoming the method of choice for outbreak investigations and public health surveillance of microbial pathogens. The combination of improved cluster resolution and prediction of resistance and virulence phenotypes provided by a single tool is extremely advantageous. However, the data produced are complex, and standard bioinformatics pipelines are required to translate the output into easily interpreted epidemiologically relevant information for public health action. The main aim of this study was to validate the implementation of WGS at the Scottish Escherichia coli O157/STEC Reference Laboratory (SERL) using the Public Health England (PHE) bioinformatics pipeline to produce standardized data to enable interlaboratory comparison of results generated at two national reference laboratories. In addition, we evaluated the BioNumerics whole-genome multilocus sequence typing (wgMLST) and E. coli genotyping plug-in tools using the same data set. A panel of 150 well characterized isolates of Shiga toxin-producing E. coli (STEC) that had been sequenced and analyzed at PHE using the PHE pipeline and database (SnapperDB) was assembled to provide identification and typing data, including serotype (O:H type), sequence type (ST), virulence genes (eae and Shiga toxin [stx] subtype), and a single-nucleotide polymorphism (SNP) address. To validate the implementation of sequencing at the SERL, DNA was reextracted from the isolates and sequenced and analyzed using the PHE pipeline, which had been installed at the SERL; the output was then compared with the PHE data. The results showed a very high correlation between the data, ranging from 93% to 100%, suggesting that the standardization of WGS between our reference laboratories is possible. We also found excellent correlation between the results obtained using the PHE pipeline and BioNumerics, except for the detection of stx2a and stx2c when these subtypes are both carried by strains. PMID- 29263203 TI - Development of Zika Virus Serological Testing Strategies in New York State. AB - The recent outbreak of Zika virus (ZIKV) in the Americas has challenged diagnostic laboratory testing strategies. At the Wadsworth Center, ZIKV serological testing was performed for over 10,000 specimens, using a combination of an enzyme-linked immunosorbent assay (ELISA) for IgM antibodies (Abs) to ZIKV, a polyvalent microsphere immunoassay (MIA) to detect Abs broadly reactive with flaviviruses, and a plaque reduction neutralization test (PRNT) for further testing. Overall, 42% of patients showed serological evidence of flavivirus infection (primarily past dengue virus [DENV] infection), while 7% possessed IgM Abs to ZIKV and/or DENV. ZIKV IgM Abs typically arose within 3 to 4 days, with only one instance of duration beyond 100 days after reported symptoms. PRNT analysis of 826 IgM-positive specimens showed 7% positive neutralization to ZIKV alone, 9% to DENV alone, and 85% to both ZIKV and DENV. Thus, the extensive Ab cross-reactivity among flaviviruses significantly reduced the value of performing PRNT analysis, especially when a traditional paired serum algorithm with viral neutralization titering was used. Nevertheless, the finding of a negative ZIKV result by PRNT was invaluable for reassuring both physicians and patients. The MIA detected both IgM and IgG, which enabled us to identify patients who presented without IgM anti-ZIKV Abs but still had ZIKV-specific neutralizing Abs. On the basis of these results, a new algorithm, which included an IgM Ab capture (MAC)-ELISA to detect recent infection, a flavivirus MIA to identify patients no longer producing IgM, and a single-dilution PRNT for ZIKV exclusion and occasional discrimination of ZIKV and DENV, was implemented. PMID- 29263204 TI - Parallel Validation of Three Molecular Devices for Simultaneous Detection and Identification of Influenza A and B and Respiratory Syncytial Viruses. AB - Rapid identification of respiratory pathogens, such as influenza virus A (FluA), influenza virus B (FluB), and respiratory syncytial virus (RSV), reduces unnecessary antimicrobial use and enhances infection control practice. We performed a comparative evaluation of three molecular methods: (i) the Aries Flu A/B & RSV, (ii) the Xpert Xpress Flu/RSV, and (iii) the Cobas Flu A/B & RSV assays. The clinical performances of the three methods were evaluated using 200 remnant nasopharyngeal swab (NPS) specimens against a combined reference standard. The limits of detection (LODs) were determined using FluA, FluB, and RSV control strains with known titers. The 95% LODs were between 1.702 and 0.0003 50% tissue culture infective dose (TCID50), with no significant differences revealed among the three assays. Perfect qualitative detection agreement was obtained in the reproducibility study. The Cobas assay failed at the first run on 13 clinical specimens, resulting in an invalid rate of 6.5%. The sensitivities and specificities for all assays were 96.0 to 100.0% and 99.3 to 100% for all three viruses. For on-demand single-specimen and batched 12-specimen workflows, the test turnaround times were 115.5 and 128.8 min for the Aries assay (12 sample capacity), 34.2 and 44.2 min for the Xpress assay (16 sample capacity), and 21.0 and 254.4 min for the Cobas assay (one instrument), respectively. In summary, the Aries, Xpress, and Cobas Liat assays demonstrated excellent sensitivities and specificities for simultaneous detection and identification of FluA, FluB, and RSV from NPS specimens in cancer patients. Test turnaround time was significantly shorter on the Xpress when instrument scalability is unlimited. PMID- 29263205 TI - Genome-Based Analysis of Enterococcus faecium Bacteremia Associated with Recurrent and Mixed-Strain Infection. AB - Vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections are associated with high recurrence rates. This study used genome sequencing to accurately distinguish the frequency of relapse and reinfection in patients with recurrent E. faecium bacteremia and to investigate strain relatedness in patients with apparent VREfm and vancomycin-susceptible E. faecium (VSEfm) mixed infection. A retrospective study was performed at the Cambridge University Hospitals NHS Foundation Trust (CUH) between November 2006 and December 2012. We analyzed the genomes of 44 E. faecium isolates from 21 patients (26 VREfm isolates from 12 patients with recurrent bacteremia and 18 isolates from 9 patients with putative VREfm/VSEfm mixed infection). Phenotypic antibiotic susceptibility was determined using a Vitek2 instrument. Genomes were compared with those of a further 263 E. faecium isolates associated with bacteremia in patients at CUH over the same time period. Pairwise comparison of core genomes indicated that 10 (71%) episodes of recurrent VREfm bacteremia were due to reinfection with a new strain, with reinfection being more likely with increasing time between the two positive cultures. The majority (78%) of patients with a mixed VREfm and VSEfm infection had unrelated strains. More than half (59%) of study isolates were closely related to another isolate associated with bacteremia from CUH. This included 60% of isolates associated with reinfection, indicating acquisition in the hospital. This study provides the first high-resolution insights into recurrence and mixed infection by E. faecium and demonstrates that reinfection with a new strain, often acquired from the hospital, is a driver of recurrence. PMID- 29263207 TI - Nigrograna mackinnonii, Not Trematosphaeria grisea (syn., Madurella grisea), Is the Main Agent of Black Grain Eumycetoma in Latin America. AB - Mycetoma, a chronic and mutilating subcutaneous infection recognized by the WHO as a neglected tropical disease, has been reported in >25 countries in Africa, Asia, and South America. In Latin America, Trematosphaeria grisea is assumed to be the prevalent fungal agent. Recent molecular studies have shown that this is an environmental saprobe in Europe, where it is rarely implicated in human diseases. The aim of the present paper is to establish the identity of Latin American cases ascribed to Trematosphaeria grisea Three cases analyzed were caused by Nigrograna mackinnonii Data on an additional 21 strains in the literature revealed that N. mackinnonii rather than T. grisea is responsible for most cases of black grain eumycetoma in Latin America. PMID- 29263206 TI - Development of Envelope Protein Antigens To Serologically Differentiate Zika Virus Infection from Dengue Virus Infection. AB - Zika virus (ZIKV) is an emerging flavivirus that can cause birth defects and neurologic complications. Molecular tests are effective for diagnosing acute ZIKV infection, although the majority of infections produce no symptoms at all or present after the narrow window in which molecular diagnostics are dependable. Serology is a reliable method for detecting infections after the viremic period; however, most serological assays have limited specificity due to cross-reactive antibodies elicited by flavivirus infections. Since ZIKV and dengue virus (DENV) widely cocirculate, distinguishing ZIKV infection from DENV infection is particularly important for diagnosing individual cases or for surveillance to coordinate public health responses. Flaviviruses also elicit type-specific antibodies directed to non-cross-reactive epitopes of the infecting virus; such epitopes are attractive targets for the design of antigens for development of serological tests with greater specificity. Guided by comparative epitope modeling of the ZIKV envelope protein, we designed two recombinant antigens displaying unique antigenic regions on domain I (Z-EDI) and domain III (Z-EDIII) of the ZIKV envelope protein. Both the Z-EDI and Z-EDIII antigens consistently detected ZIKV-specific IgG in ZIKV-immune sera but not cross-reactive IgG in DENV immune sera in late convalescence (>12 weeks postinfection). In contrast, during early convalescence (2 to 12 weeks postinfection), secondary DENV-immune sera and some primary DENV-immune sera cross-reacted with the Z-EDI and Z-EDIII antigens. Analysis of sequential samples from DENV-immune individuals demonstrated that Z EDIII cross-reactivity peaked in early convalescence and declined steeply over time. The Z-EDIII antigen has much potential as a diagnostic antigen for population-level surveillance and for detecting past infections in patients. PMID- 29263208 TI - Multicenter Clinical Evaluation of the Alere i Respiratory Syncytial Virus Isothermal Nucleic Acid Amplification Assay. AB - The Alere i respiratory syncytial virus (RSV) assay is an isothermal nucleic acid amplification test capable of detecting RSV directly from respiratory specimens, with results being available in <=13 min after test initiation. The objective of this study was to evaluate the performance characteristics of the Alere i RSV assay in a point-of-care setting by using direct nasopharyngeal (NP) swab specimens (direct NP) and nasopharyngeal swab specimens eluted and transported in viral transport medium (VTM NP). The study was a prospective, multicenter, clinical trial conducted at 9 sites across the United States to evaluate the clinical performance of the Alere i RSV assay with respiratory specimens obtained from both children (age, <18 years) and older adults (age, >60 years). The performance of the Alere i RSV assay was compared with that of the reference method, the Prodesse ProFlu+ real-time reverse transcriptase PCR (RT-PCR) assay. All specimens with discrepant test results were tested further by a second FDA cleared PCR assay (the Verigene respiratory virus plus nucleic acid test; Luminex Inc., TX). A total of 554 subjects with signs and symptoms of respiratory infections were enrolled, and respiratory samples were collected in this study. In comparison with the ProFlu+ real-time RT-PCR, the overall sensitivity and specificity of Alere i RSV assay for the detection of RSV were 98.6% (95% confidence interval [CI], 94.4 to 99.7%) and 98.0% (95% CI, 95.8 to 99.1%), respectively, for direct NP and 98.6% (95% CI, 94.4 to 99.7%) and 97.8% (95% CI, 95.5 to 98.9%), respectively, for VTM NP. The Alere i RSV is a highly sensitive and specific molecular assay ideal for rapid RSV detection in patients in the point-of-care setting due to its minimal hands-on time and rapid result availability. PMID- 29263210 TI - Genetics of development time in a butterfly: predictions from optimality and a test by subspecies crossing. AB - Earlier studies on adaptive plasticity in development time and diapause regulation in the speckled wood butterfly, Pararge aegeria L., have been based on optimality models and have not considered genetics. Nevertheless, they have been successful in predicting patterns observed. From the results of these studies we predicted the genetics of larval and pupal development time, as well as of diapause control, to be polygenic and sex linked. We show that this is the case by crossing a population of the northern subspecies P. a. tircis from southern Sweden, which shows a diapause in some daylengths and is protandrous, with a population of the southern subspecies P. a. aegeria from Madeira. The latter inhabits a much less seasonal environment, develops directly at all daylengths, and is not protandrous. Offspring showed variable and intermediate larval and pupal development times when reared at daylengths inducing diapause in Swedish pure stock. Female offspring were more similar to their mothers in the reciprocal crosses, whereas development time in male offspring was not sensitive to the direction of the cross. This suggests the presence of a sex-linked modifying factor. The results show that the outcome of tests of optimality models can be used to predict genetic systems. PMID- 29263211 TI - Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor. AB - Natural killer gene complex-encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell-mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti-Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8alpha+ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g expressing activated DCs during immune responses. PMID- 29263213 TI - ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth. AB - The blockade of immune checkpoints by anti-receptor and/or anti-ligand mAb is one of the most promising approaches to cancer immunotherapy. The interaction between Ig-like transcript 3 (ILT3), a marker of tolerogenic dendritic cells, also known as LILRB4/LIR5/CD85k, and its still unidentified ligand on the surface of activated human T cells is potentially important for immune checkpoint blockade. To identify the ILT3 ligand, we generated mAb by immunizing mice with Jurkat acute T cell leukemia, which binds ILT3.Fc to its membrane. Flow cytometry, mass spectrometry, and Biacore studies demonstrated that the ILT3 ligand is a CD166/activated leukocyte cell adhesion molecule. Knockdown of CD166 in primary human T cells by nucleofection abolished the capacity of ILT3.Fc to inhibit CD4+ Th cell proliferation and to induce the generation of CD8+CD28- T suppressor cells. CD166 displays strong heterophilic interaction with CD6 and weaker homophilic CD166-CD166 cell adhesion interaction. ILT3.Fc inhibited the growth of CD166+ tumor cell lines (TCL) derived from lymphoid malignancies in vitro and in vivo. CRISPR-Cas9-based knockout of CD166 from TCL abrogated ILT3.Fc binding and its tumor-inhibitory effect. The mechanism underlying the effect of ILT3.Fc on tumor cell growth involves inhibition of the p70S6K signaling pathway. Blockade of CD166 by ILT3.Fc inhibited progression of human TCL in NOD.Cg-Prkdc Il-2rg/SzJ mice, suggesting its potential immunotherapeutic value. PMID- 29263212 TI - Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success. AB - The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-alpha, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection. PMID- 29263214 TI - Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment. AB - TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis. PMID- 29263217 TI - Resolving the dark side of therapy-driven cancer cell death. AB - In this issue of JEM, Sulciner et al. (https://doi.org/10.1084/jem.20170681) provide evidence that therapy-induced cancer cell death can, paradoxically, stimulate and accelerate the growth of surviving malignant cells by fueling tumor promoting inflammation. Resolvins, a class of lipid mediators, counteract this effect, representing an attractive target for therapeutic intervention. PMID- 29263209 TI - Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies. AB - Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies. PMID- 29263215 TI - Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage. AB - The extent of NK cell activity during the innate immune response affects downstream immune functions and, ultimately, the outcome of infectious or malignant disease. However, the mechanisms that terminate human NK cell responses have yet to be defined. When activation receptors expressed on NK cell surfaces bind to ligands on diseased cells, they initiate a signal that is propagated by a number of intracellular kinases, including Zap70 and Syk, eventually leading to NK cell activation. We assayed Zap70 and Syk content in NK cells from healthy human donors and identified a subset of NK cells with unusually low levels of these two kinases. We found that this Zap70lowSyklow subset consisted of NK cells expressing a range of surface markers, including CD56hi and CD56low NK cells. Upon in vitro stimulation with target cells, Zap70lowSyklow NK cells failed to produce IFN-gamma and lysed target cells at one third the capacity of Zap70hiSykhi NK cells. We determined two independent in vitro conditions that induce the Zap70lowSyklow phenotype in NK cells: continuous stimulation with activation beads and DNA damage. The expression of inhibitory receptors, including NKG2A and inhibitory killer Ig-like receptors (KIRs), was negatively correlated with the Zap70lowSyklow phenotype. Moreover, expression of multiple KIRs reduced the likelihood of Zap70 downregulation during continuous activation, regardless of whether NK cells had been educated through KIR-HLA interactions in vivo. Our findings show that human NK cells are able to terminate their functional activity without the aid of other immune cells through the downregulation of activation kinases. PMID- 29263216 TI - The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury. AB - The disposal of apoptotic bodies by professional phagocytes is crucial to effective inflammation resolution. Our ability to improve the disposal of apoptotic bodies by professional phagocytes is impaired by a limited understanding of the molecular mechanisms that regulate the engulfment and digestion of the efferocytic cargo. Macrophages are professional phagocytes necessary for liver inflammation, fibrosis, and resolution, switching their phenotype from proinflammatory to restorative. Using sterile liver injury models, we show that the STAT3-IL-10-IL-6 axis is a positive regulator of macrophage efferocytosis, survival, and phenotypic conversion, directly linking debris engulfment to tissue repair. PMID- 29263219 TI - Silent cerebral infarction: Not so silent after all. PMID- 29263218 TI - RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. AB - Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal-related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)-mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death. PMID- 29263220 TI - Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study. AB - OBJECTIVE: To investigate brain amyloid pathology in a dementia-risk population defined as cardiovascular risk factors, aging, and dementia risk (CAIDE) score of at least 6 but with normal cognition and to examine associations between brain amyloid load and cognitive performance and vascular risk factors. METHODS: A subgroup of 48 individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in brain 11C-Pittsburgh compound B (PiB)-PET imaging, brain MRI, and neuropsychological assessment at the beginning of the study. Lifestyle/vascular risk factors were determined as body mass index, blood pressure, total and low density lipoprotein cholesterol, and glucose homeostasis model assessment. White matter lesions were visually rated from MRIs by a semiquantitative Fazekas score. RESULTS: Twenty participants (42%) had a positive PiB-PET on visual analysis. The PiB-positive group performed worse in executive functioning tests, included more participants with APOE epsilon4 allele (50%), and showed slightly better glucose homeostasis compared to PiB-negative participants. PiB-positive and -negative participants did not differ significantly in other cognitive domain scores or other vascular risk factors. There was no significant difference in Fazekas score between the PiB groups. CONCLUSIONS: The high percentage of PiB-positive participants provides evidence of a successful recruitment process of the at-risk population in the main FINGER intervention trial. The results suggest a possible association between early brain amyloid accumulation and decline in executive functions. APOE epsilon4 was clearly associated with amyloid positivity, but no other risk factor was found to be associated with positive PiB-PET. PMID- 29263221 TI - The laser shoes: A new ambulatory device to alleviate freezing of gait in Parkinson disease. AB - OBJECTIVE: To assess, in a cross-sectional study, the feasibility and immediate efficacy of laser shoes, a new ambulatory visual cueing device with practical applicability for use in daily life, on freezing of gait (FOG) and gait measures in Parkinson disease (PD). METHODS: We tested 21 patients with PD and FOG, both "off" and "on" medication. In a controlled gait laboratory, we measured the number of FOG episodes and the percent time frozen occurring during a standardized walking protocol that included FOG provoking circumstances. Participants performed 10 trials with and 10 trials without cueing. FOG was assessed using offline video analysis by an independent rater. Gait measures were recorded in between FOG episodes with the use of accelerometry. RESULTS: Cueing using laser shoes was associated with a significant reduction in the number of FOG episodes, both "off" (45.9%) and "on" (37.7%) medication. Moreover, laser shoes significantly reduced the percent time frozen by 56.5% (95% confidence interval [CI] 32.5-85.8; p = 0.004) when "off" medication. The reduction while "on" medication was slightly smaller (51.4%, 95% CI -41.8 to 91.5; p = 0.075). These effects were paralleled by patients' positive subjective experience on laser shoes' efficacy. There were no clinically meaningful changes in the gait measures. CONCLUSIONS: These findings demonstrate the immediate efficacy of laser shoes in a controlled gait laboratory, and offer a promising intervention with potential to deliver in-home cueing for patients with FOG. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with PD, laser shoes significantly reduce FOG severity (both number and duration of FOG episodes). PMID- 29263222 TI - Nutrients and bioactives in green leafy vegetables and cognitive decline: Prospective study. AB - OBJECTIVE: To increase understanding of the biological mechanisms underlying the association, we investigated the individual relations to cognitive decline of the primary nutrients and bioactives in green leafy vegetables, including vitamin K (phylloquinone), lutein, beta-carotene, nitrate, folate, kaempferol, and alpha tocopherol. METHODS: This was a prospective study of 960 participants of the Memory and Aging Project, ages 58-99 years, who completed a food frequency questionnaire and had >=2 cognitive assessments over a mean 4.7 years. RESULTS: In a linear mixed model adjusted for age, sex, education, participation in cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green leafy vegetables was associated with slower cognitive decline; the decline rate for those in the highest quintile of intake (median 1.3 servings/d) was slower by beta = 0.05 standardized units (p = 0.0001) or the equivalent of being 11 years younger in age. Higher intakes of each of the nutrients and bioactives except beta-carotene were individually associated with slower cognitive decline. In the adjusted models, the rates for the highest vs the lowest quintiles of intake were beta = 0.02, p = 0.002 for phylloquinone; beta = 0.04, p = 0.002 for lutein; beta = 0.05, p < 0.001 for folate; beta = 0.03, p = 0.02 for alpha-tocopherol; beta = 0.04, p = 0.002 for nitrate; beta = 0.04, p = 0.003 for kaempferol; and beta = 0.02, p = 0.08 for beta-carotene. CONCLUSIONS: Consumption of approximately 1 serving per day of green leafy vegetables and foods rich in phylloquinone, lutein, nitrate, folate, alpha tocopherol, and kaempferol may help to slow cognitive decline with aging. PMID- 29263223 TI - Moyamoya-like cerebrovascular disease in a child with a novel mutation in myosin heavy chain 11. PMID- 29263225 TI - Morvan syndrome associated with CASPR2 and LGI1 antibodies in a child. PMID- 29263224 TI - Progranulin: Functions and neurologic correlations. PMID- 29263226 TI - Silent cerebral infarct definitions and full-scale IQ loss in children with sickle cell anemia. AB - OBJECTIVE: To evaluate whether application of the adult definition of silent cerebral infarct (SCI) (T2-weighted hyperintensity >=5 mm with corresponding T1 weighted hypointensity on MRI) is associated with full-scale IQ (FSIQ) loss in children with sickle cell anemia (SCA), and if so, whether this loss is greater than that of the reference pediatric definition of SCI (T2-weighted hyperintensity >=3 mm in children on MRI; change in FSIQ -5.2 points; p = 0.017; 95% confidence interval [CI] -9.48 to -0.93). METHODS: Among children with SCA screened for SCI in the Silent Cerebral Infarct Transfusion trial, ages 5-14 years, a total of 150 participants (107 with SCIs and 43 without SCIs) were administered the Wechsler Abbreviated Scale of Intelligence. A multivariable linear regression was used to model FSIQ in this population, with varying definitions of SCI independently substituted for the SCI covariate. RESULTS: The adult definition of SCI applied to 27% of the pediatric participants with SCIs and was not associated with a statistically significant change in FSIQ (unstandardized coefficient -3.9 points; p = 0.114; 95% CI -8.75 to 0.95), with predicted mean FSIQ of 92.1 and 96.0, respectively, for those with and without the adult definition of SCI. CONCLUSIONS: The adult definition of SCI may be too restrictive and was not associated with significant FSIQ decline in children with SCA. Based on these findings, we find no utility in applying the adult definition of SCI to children with SCA and recommend maintaining the current pediatric definition of SCI in this population. PMID- 29263227 TI - Simultaneous recording of cervical and ocular vestibular-evoked myogenic potentials. AB - OBJECTIVE: To increase clinical application of vestibular-evoked myogenic potentials (VEMPs) by reducing the testing time by evaluating whether a simultaneous recording of ocular and cervical VEMPs can be achieved without a loss in diagnostic sensitivity and specificity. METHODS: Simultaneous recording of ocular and cervical VEMPs on each side during monaural stimulation, bilateral simultaneous recording of ocular VEMPs and cervical VEMPs during binaural stimulation, and conventional sequential recording of ocular and cervical VEMPs on each side using air-conducted sound (500 Hz, 5-millisecond tone burst) were compared in 40 healthy participants (HPs) and 20 patients with acute vestibular neuritis. RESULTS: Either simultaneous recording during monaural and binaural stimulation effectively reduced the recording time by ~55% of that for conventional sequential recordings in both the HP and patient groups. The simultaneous recording with monaural stimulation resulted in latencies and thresholds of both VEMPs and the amplitude of cervical VEMPs similar to those found during the conventional recordings but larger ocular VEMP amplitudes (156%) in both groups. In contrast, compared to the conventional recording, simultaneous recording of each VEMP during binaural stimulation showed reduced amplitudes (31%) and increased thresholds for cervical VEMPs in both groups. CONCLUSIONS: The results of simultaneous recording of cervical and ocular VEMPs during monaural stimulation were comparable to those obtained from the conventional recording while reducing the time to record both VEMPs on each side. CLINICALTRIALSGOV IDENTIFIER: NCT03049683. PMID- 29263229 TI - Erratum for the Research Article: "The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity" by M. Wieczorek, J. Tcherkezian, C. Bernier, A. E. Prota, S. Chaaban, Y. Rolland, C. Godbout, M. A. Hancock, J. C. Arezzo, O. Ocal, C. Rocha, N. Olieric, A. Hall, H. Ding, A. Bramoulle, M. G. Annis, G. Zogopoulos, P. G. Harran, T. M. Wilkie, R. A. Brekken, P. M. Siegel, M. O. Steinmetz, G. C. Shore, G. J. Brouhard, A. Roulston. PMID- 29263228 TI - Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell-mediated TNFalpha signaling. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood. To mimic clinical HSCT, we injected human umbilical cord blood (UCB) cells at different doses and compositions into immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice. Surprisingly, higher UCB cell doses inversely correlated with stem and progenitor cell engraftment. This observation was attributable to increased donor cell-derived inflammatory signals. Donor T cell-derived tumor necrosis factor-alpha (TNFalpha) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell-derived TNFalpha in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNFalpha on transplanted cells could be decoupled from the indirect effect of alleviating graft-versus-host disease (GVHD) by interleukin-6 (IL-6) blockade. Our study demonstrates that donor immune cell-derived inflammatory signals directly influence HSC fate, and provides new clinically relevant strategies to improve engraftment efficiency during HSCT. PMID- 29263230 TI - Vaccination of dogs in an African city interrupts rabies transmission and reduces human exposure. AB - Despite the existence of effective rabies vaccines for dogs, dog-transmitted human rabies persists and has reemerged in Africa. Two consecutive dog vaccination campaigns took place in Chad in 2012 and 2013 (coverage of 71% in both years) in the capital city of N'Djamena, as previously published. We developed a deterministic model of dog-human rabies transmission fitted to weekly incidence data of rabid dogs and exposed human cases in N'Djamena. Our analysis showed that the effective reproductive number, that is, the number of new dogs infected by a rabid dog, fell to below one through November 2014. The modeled incidence of human rabies exposure fell to less than one person per million people per year. A phylodynamic estimation of the effective reproductive number from 29 canine rabies virus genetic sequences of the viral N-protein confirmed the results of the deterministic transmission model, implying that rabies transmission between dogs was interrupted for 9 months. However, new dog rabies cases appeared earlier than the transmission and phylodynamic models predicted. This may have been due to the continuous movement of rabies-exposed dogs into N'Djamena from outside the city. Our results show that canine rabies transmission to humans can be interrupted in an African city with currently available dog rabies vaccines, provided that the vaccination area includes larger adjacent regions, and local communities are informed and engaged. PMID- 29263231 TI - Human ESC-derived retinal epithelial cell sheets potentiate rescue of photoreceptor cell loss in rats with retinal degeneration. AB - Replacing defective retinal pigment epithelial (RPE) cells with those derived from human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs) is a potential strategy for treating retinal degenerative diseases. Early clinical trials have demonstrated that hESC-derived or hiPSC-derived RPE cells can be delivered safely as a suspension to the human eye. The next step is transplantation of hESC/hiPSC-derived RPE cells as cell sheets that are more physiological. We have developed a tissue-engineered product consisting of hESC derived RPE cells grown as sheets on human amniotic membrane as a biocompatible substrate. We established a surgical approach to engraft this tissue-engineered product into the subretinal space of the eyes of rats with photoreceptor cell loss. We show that transplantation of the hESC-RPE cell sheets grown on a human amniotic membrane scaffold resulted in rescue of photoreceptor cell death and improved visual acuity in rats with retinal degeneration compared to hESC-RPE cells injected as a cell suspension. These results suggest that tissue-engineered hESC-RPE cell sheets produced under good manufacturing practice conditions may be a useful approach for treating diseases of retinal degeneration. PMID- 29263234 TI - Cytokine diagnosis of pleural TB: will it stand the test of time? PMID- 29263233 TI - Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats. AB - Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS. PMID- 29263232 TI - A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. AB - Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro. We developed an in vitro cell model system composed of human monocyte-derived microglia-like (MDMi) cells that recapitulated key aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, and METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the PILRB and LRRK2 loci, the cis-eQTL was found in the MDMi cells but not in human peripheral blood monocytes, suggesting that differentiation of monocytes into microglia-like cells led to the acquisition of a cellular state that could reveal the functional consequences of certain genetic variants. We further validated the effect of risk haplotypes at the protein level for PILRB and CD33, and we confirmed that the CD33 risk haplotype altered phagocytosis by the MDMi cells. We propose that increased LRRK2 gene expression by MDMi cells could be a functional outcome of rs76904798, a single-nucleotide polymorphism in the LRKK2 locus that is associated with Parkinson's disease. PMID- 29263235 TI - Successful haematopoietic stem cell transplantation in a case of pulmonary alveolar proteinosis due to GM-CSF receptor deficiency. PMID- 29263236 TI - Gonadotropin-Releasing Hormone (GnRH) Neuron Excitability Is Regulated by Estradiol Feedback and Kisspeptin. AB - Gonadotropin-releasing hormone (GnRH) neurons produce the central output controlling fertility and are regulated by steroid feedback. A switch from estradiol negative to positive feedback initiates the GnRH surge, ultimately triggering ovulation. This occurs on a daily basis in ovariectomized, estradiol treated (OVX+E) mice; GnRH neurons are suppressed in the morning and activated in the afternoon. To test the hypotheses that estradiol and time of day signals alter GnRH neuron responsiveness to stimuli, GFP-identified GnRH neurons in brain slices from OVX+E or OVX female mice were recorded during the morning or afternoon. No differences were observed in baseline membrane potential. Current clamp revealed GnRH neurons fired more action potentials in response to current injection during positive feedback relative to all other groups, which were not different from each other despite reports of differing ionic conductances. Kisspeptin increased GnRH neuron response in cells from OVX and OVX+E mice in the morning but not afternoon. Paradoxically, excitability in kisspeptin knock-out mice was similar to the maximum observed in control mice but was unchanged by time of day or estradiol. A mathematical model applying a Markov Chain Monte Carlo method to estimate probability distributions for estradiol- and time of day dependent parameters was used to predict intrinsic properties underlying excitability changes. A single identifiable distribution of solutions accounted for similar GnRH neuron excitability in all groups other than positive feedback despite different underlying conductance properties; this was attributable to interdependence of voltage-gated potassium channel properties. In contrast, redundant solutions may explain positive feedback, perhaps indicative of the importance of this state for species survival.SIGNIFICANCE STATEMENT Infertility affects 15%-20% of couples; failure to ovulate is a common cause. Understanding how the brain controls ovulation is critical for new developments in both infertility treatment and contraception. Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for central neural control of ovulation. We studied how estradiol feedback regulates GnRH excitability, a key determinant of neural firing rate using laboratory and computational approaches. GnRH excitability is upregulated during positive feedback, perhaps driving increased neural firing rate at this time. Kisspeptin increased GnRH excitability and was essential for estradiol regulation of excitability. Modeling predicts that multiple combinations of changes to GnRH intrinsic conductances can produce the firing response in positive feedback, suggesting the brain has many ways to induce ovulation. PMID- 29263238 TI - Attention Shifts Recruit the Monkey Default Mode Network. AB - A unifying function associated with the default mode network (DMN), which is more active during rest than under active task conditions, has been difficult to define. The DMN is activated during monitoring the external world for unexpected events, as a sentinel, and when humans are engaged in high-level internally focused tasks. The existence of DMN correlates in other species, such as mice, challenge the idea that internally focused, high-level cognitive operations, such as introspection, autobiographical memory retrieval, planning the future, and predicting someone else's thoughts, are evolutionarily preserved defining properties of the DMN. A recent human study demonstrated that demanding cognitive shifts could recruit the DMN, yet it is unknown whether this holds for nonhuman species. Therefore, we tested whether large changes in cognitive context would recruit DMN regions in female and male nonhuman primates. Such changes were measured as displacements of spatial attentional weights based on internal rules of relevance (spatial shifts) compared with maintaining attentional weights at the same location (stay events). Using fMRI in macaques, we detected that a cortical network, activated during shifts, largely overlapped with the DMN. Moreover, fMRI time courses sampled from independently defined DMN foci showed significant shift selectivity during the demanding attention task. Finally, functional clustering based on independent resting state data revealed that DMN and shift regions clustered conjointly, whereas regions activated during the stay events clustered apart. We therefore propose that cognitive shifting in primates generally recruits DMN regions. This might explain a breakdown of the DMN in many neurological diseases characterized by declined cognitive flexibility.SIGNIFICANCE STATEMENT Activation of the human default mode network (DMN) can be measured with fMRI when subjects shift thoughts between high-level internally directed cognitive states, when thinking about the self, the perspective of others, when imagining future and past events, and during mind wandering. Furthermore, the DMN is activated as a sentinel, monitoring the environment for unexpected events. Arguably, these cognitive processes have in common fast and substantial changes in cognitive context. As DMN activity has also been reported in nonhuman species, we tested whether shifts in spatial attention activated the monkey DMN. Core monkey DMN and shift-selective regions shared several functional properties, indicating that cognitive shifting, in general, might constitute one of the evolutionarily preserved functions of the DMN. PMID- 29263237 TI - Selective Suppression of Local Interneuron Circuits in Human Motor Cortex Contributes to Movement Preparation. AB - Changes in neural activity occur in the motor cortex before movement, but the nature and purpose of this preparatory activity is unclear. To investigate this in the human (male and female) brain noninvasively, we used transcranial magnetic stimulation (TMS) to probe the excitability of distinct sets of excitatory inputs to corticospinal neurons during the warning period of various reaction time tasks. Using two separate methods (H-reflex conditioning and directional effects of TMS), we show that a specific set of excitatory inputs to corticospinal neurons are suppressed during motor preparation, while another set of inputs remain unaffected. To probe the behavioral relevance of this suppression, we examined whether the strength of the selective preparatory inhibition in each trial was related to reaction time. Surprisingly, the greater the amount of selective preparatory inhibition, the faster the reaction time was. This suggests that the inhibition of inputs to corticospinal neurons is not involved in preventing the release of movement but may in fact facilitate rapid reactions. Thus, selective suppression of a specific set of motor cortical neurons may be a key aspect of successful movement preparation.SIGNIFICANCE STATEMENT Movement preparation evokes substantial activity in the motor cortex despite no apparent movement. One explanation for the lack of movement is that motor cortical output in this period is gated by an inhibitory mechanism. This notion was supported by previous noninvasive TMS studies of human motor cortex indicating a reduction of corticospinal excitability. On the contrary, our data support the idea that there is a coordinated balance of activity upstream of the corticospinal output neurons. This includes a suppression of specific local circuits that supports, rather than inhibits, the rapid generation of prepared movements. Thus, the selective suppression of local circuits appears to be an essential part of successful movement preparation instead of an external control mechanism. PMID- 29263239 TI - Decoding Trans-Saccadic Memory. AB - We examine whether peripheral information at a planned saccade target affects immediate postsaccadic processing at the fovea on saccade landing. Current neuroimaging research suggests that presaccadic stimulation has a late effect on postsaccadic processing, in contrast to the early effect seen in behavioral studies. Human participants (both male and female) were instructed to saccade toward a face or a house that, on different trials, remained the same, changed, or disappeared during the saccade. We used a multivariate pattern analysis of electroencephalography data to decode face versus house processing directly after the saccade. The classifier was trained on separate trials without a saccade, where a house or face was presented at the fovea. When the saccade target remained the same across the saccade, we could reliably decode the target 123 ms after saccade offset. In contrast, when the target was changed during the saccade, the new target was decoded at a later time-point, 151 ms after saccade offset. The "same" condition advantage suggests that congruent presaccadic information facilitates processing of the postsaccadic stimulus compared with incongruent information. Finally, the saccade target could be decoded above chance even when it had been removed during the saccade, albeit with a slower time course (162 ms) and poorer signal strength. These findings indicate that information about the (peripheral) presaccadic stimulus is transferred across the saccade so that it becomes quickly available and influences processing at its expected new retinal position (the fovea).SIGNIFICANCE STATEMENT Here we provide neural evidence for early information transfer across saccades. Specifically, we examined the effect of presaccadic sensory information on the initial neuronal processing of a postsaccadic stimuli. Using electroencephalography and multivariate pattern analysis, we found the following: (1) that the identity of the presaccadic stimulus modulated the postsaccadic latency of stimulus relevant information; and (2) that a saccadic neural marker for a saccade target stimulus could be detected even when the stimulus had been removed during saccade. These results demonstrate that information about the peripheral presaccadic stimulus was transferred across the saccade and influenced processing at a new retinal position (the fovea) directly after the saccade landed. PMID- 29263240 TI - Cocaine Selectively Reorganizes Excitatory Inputs to Substantia Nigra Pars Compacta Dopamine Neurons. AB - Substantia nigra pars compacta (SNc) dopamine neurons and their targets are involved in addiction and cue-induced relapse. However, afferents onto SNc dopamine neurons themselves appear insensitive to drugs of abuse, such as cocaine, when afferents are collectively stimulated electrically. This contrasts with ventral tegmental area (VTA) dopamine neurons, whose glutamate afferents react robustly to cocaine. We used an optogenetic strategy to isolate identified SNc inputs and determine whether cocaine sensitivity in the mouse SNc circuit is conferred at the level of three glutamate afferents: dorsal raphe nucleus (DR), pedunculopontine nucleus (PPN), and subthalamic nucleus (STN). We found that excitatory afferents to SNc dopamine neurons are sensitive to cocaine in an afferent-specific manner. A single exposure to cocaine in vivo led to PPN innervated synapses reducing the AMPA-to-NMDA receptor-mediated current ratio. In contrast to work in the VTA, this was due to increased NMDA receptor function with no change in AMPA receptor function. STN synapses showed a decrease in calcium-permeable AMPA receptors after cocaine, but no change in the AMPA-to-NMDA ratio. Cocaine also increased the release probability at DR-innervated and STN innervated synapses, quantified by decreases in paired-pulse ratios. However, release probability at PPN-innervated synapses remained unaffected. By examining identified inputs, our results demonstrate a functional distribution among excitatory SNc afferent nuclei in response to cocaine, and suggest a compelling architecture for differentiation and separate parsing of inputs within the nigrostriatal system.SIGNIFICANCE STATEMENT Prior studies have established that substantia nigra pars compacta (SNc) dopamine neurons are a key node in the circuitry that drives addiction and relapse, yet cocaine apparently has no effect on electrically stimulated excitatory inputs. Our study is the first to demonstrate the functional impact of a drug of abuse on synaptic mechanisms of identified afferents to the SNc. Optogenetic dissection of inputs originating from dorsal raphe, pedunculopontine, and subthalamic nuclei were tested for synaptic modifications following in vivo cocaine exposure. Our results demonstrate that cocaine differentially induces modifications to SNc synapses depending on input origin. This presents implications for understanding dopamine processing of motivated behavior; most critically, it indicates that dopamine neurons selectively modulate signal reception processed by afferent nuclei. PMID- 29263242 TI - A Combination of Chitosan, Cellulose, and Seaweed Polysaccharide Inhibits Postoperative Intra-abdominal Adhesion in Rats. AB - Intra-abdominal adhesion is a common complication after laparotomy. Conventional therapeutic strategies still cannot safely and effectively prevent this disorder. In this study, a combination of chitosan, cellulose, and seaweed polysaccharide (thereafter referred as CCS) was developed to significantly alleviate the formation of postoperative adhesion in rats with abdominal trauma. Transforming growth factor beta1 (TGF-beta1, an important promoter of fibrosis) and its downstream factors-namely, alpha-smooth muscle actin and plasminogen activator inhibitor-1 (PAI-1)-were effectively suppressed by CCS in vivo, and as a result, the activation of tissue plasminogen activator (tPA, may generate plasmin that is a fibrinolytic factor capable of breaking down fibrin) was significantly promoted, presenting antifibrosis effects of CCS. In addition, the activity of kinases [e.g., transforming growth factor-activated kinase 1 (TAK1), c-Jun N terminal kinase (JNK)/Stress-activated Protein Kinase (SAPK), and p38] in the mitogen-activated protein kinase (MAPK) inflammation signaling pathway was also significantly suppressed by CCS in vivo, demonstrating anti-inflammatory functions of CCS. The histologic studies further confirmed the role of CCS in the inhibition of fibrosis, collagen deposition, inflammation, and vascular proliferation. These results indicate the clinical potential of CCS in the treatment of postoperative intra-abdominal adhesion. CCS may induce both antifibrosis and anti-inflammatory effects, potentially inhibiting the postoperative intra-abdominal adhesion. For antifibrosis effects, the expression of PAI-1 (a key factor for the adhesion formation) can be regulated by different TGF-beta1-associated signaling pathways, such as the Smads/p53 pathway, metalloproteinase/tissue inhibitor of matrix metalloproteinases pathway, Mitogen activated Extracellular signal-regulated Kinase (MEK)/extracellular regulated protein kinase (ERK) pathway, and Yes-associated protein/transcriptional coactivator with PDZ-binding motif pathway. Following the downregulation of PAI-1 achieved by CCS, the activation of tPA (which may generate plasmin that is a fibrinolytic factor capable of breaking down fibrin) is significantly promoted. For anti-inflammation effects, CCS may suppress the phosphorylation of classic kinases (e.g., TAK1, JNK, and p38) in the MAPK signaling pathway. In addition to the MAPK pathway, inflammatory pathways, such as Nuclear Factor-kappa-gene Binding(NF-kappaB), MEK/ERK, and Ras homologue protein/Rho associated coiled coil forming protein, are associated with the formation of intra-abdominal adhesion. Therefore, the prevention mechanisms of CCS will be further investigated in the future, with a hope of fully understanding of antiadhesion effects. PMID- 29263241 TI - Neural Mechanisms Underlying Cross-Modal Phonetic Encoding. AB - Audiovisual (AV) integration is essential for speech comprehension, especially in adverse listening situations. Divergent, but not mutually exclusive, theories have been proposed to explain the neural mechanisms underlying AV integration. One theory advocates that this process occurs via interactions between the auditory and visual cortices, as opposed to fusion of AV percepts in a multisensory integrator. Building upon this idea, we proposed that AV integration in spoken language reflects visually induced weighting of phonetic representations at the auditory cortex. EEG was recorded while male and female human subjects watched and listened to videos of a speaker uttering consonant vowel (CV) syllables /ba/ and /fa/, presented in Auditory-only, AV congruent or incongruent contexts. Subjects reported whether they heard /ba/ or /fa/. We hypothesized that vision alters phonetic encoding by dynamically weighting which phonetic representation in the auditory cortex is strengthened or weakened. That is, when subjects are presented with visual /fa/ and acoustic /ba/ and hear /fa/ (illusion-fa), the visual input strengthens the weighting of the phone /f/ representation. When subjects are presented with visual /ba/ and acoustic /fa/ and hear /ba/ (illusion-ba), the visual input weakens the weighting of the phone /f/ representation. Indeed, we found an enlarged N1 auditory evoked potential when subjects perceived illusion-ba, and a reduced N1 when they perceived illusion-fa, mirroring the N1 behavior for /ba/ and /fa/ in Auditory-only settings. These effects were especially pronounced in individuals with more robust illusory perception. These findings provide evidence that visual speech modifies phonetic encoding at the auditory cortex.SIGNIFICANCE STATEMENT The current study presents evidence that audiovisual integration in spoken language occurs when one modality (vision) acts on representations of a second modality (audition). Using the McGurk illusion, we show that visual context primes phonetic representations at the auditory cortex, altering the auditory percept, evidenced by changes in the N1 auditory evoked potential. This finding reinforces the theory that audiovisual integration occurs via visual networks influencing phonetic representations in the auditory cortex. We believe that this will lead to the generation of new hypotheses regarding cross-modal mapping, particularly whether it occurs via direct or indirect routes (e.g., via a multisensory mediator). PMID- 29263243 TI - A Potent Antagonist of Protease-Activated Receptor 2 That Inhibits Multiple Signaling Functions in Human Cancer Cells. AB - Protease-activated receptor 2 (PAR2) is a cell surface protein linked to G protein dependent and independent intracellular signaling pathways that produce a wide range of physiological responses, including those related to metabolism, inflammation, pain, and cancer. Certain proteases, peptides, and nonpeptides are known to potently activate PAR2. However, no effective potent PAR2 antagonists have been reported yet despite their anticipated therapeutic potential. This study investigates antagonism of key PAR2-dependent signaling properties and functions by the imidazopyridazine compound I-191 (4-(8-(tert-butyl)-6-(4 fluorophenyl)imidazo[1,2-b]pyridazine-2-carbonyl)-3,3-dimethylpiperazin-2-one) in cancer cells. At nanomolar concentrations, I-191 inhibited PAR2 binding of and activation by structurally distinct PAR2 agonists (trypsin, peptide, nonpeptide) in a concentration-dependent manner in cells of the human colon adenocarcinoma grade II cell line (HT29). I-191 potently attenuated multiple PAR2-mediated intracellular signaling pathways leading to Ca2+ release, extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation, Ras homologue gene family, member A (RhoA) activation, and inhibition of forskolin-induced cAMP accumulation. The mechanism of action of I-191 was investigated using binding and calcium mobilization studies in HT29 cells where I-191 was shown to be noncompetitive and a negative allosteric modulator of the agonist 2f-LIGRL-NH2 The compound alone did not activate these PAR2-mediated pathways, even at high micromolar concentrations, indicating no bias in these signaling properties. I-191 also potently inhibited PAR2-mediated downstream functional responses, including expression and secretion of inflammatory cytokines and cell apoptosis and migration, in human colon adenocarcinoma grade II cell line (HT29) and human breast adenocarcinoma cells (MDA-MB-231). These findings indicate that I-191 is a potent PAR2 antagonist that inhibits multiple PAR2-induced signaling pathways and functional responses. I-191 may be a valuable tool for characterizing PAR2 functions in cancer and in other cellular, physiological, and disease settings. PMID- 29263244 TI - Triple Angiokinase Inhibitor Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases. AB - The triple-angiokinase inhibitor nintedanib is an orally available, potent, and selective inhibitor of tumor angiogenesis by blocking the tyrosine kinase activities of vascular endothelial growth factor receptor (VEGFR) 1-3, platelet derived growth factor receptor (PDGFR)-alpha and -beta, and fibroblast growth factor receptor (FGFR) 1-3. Nintedanib has received regulatory approval as second line treatment of adenocarcinoma non-small cell lung cancer (NSCLC), in combination with docetaxel. In addition, nintedanib has been approved for the treatment of idiopathic lung fibrosis. Here we report the results from a broad kinase screen that identified additional kinases as targets for nintedanib in the low nanomolar range. Several of these kinases are known to be mutated or overexpressed and are involved in tumor development (discoidin domain receptor family, member 1 and 2, tropomyosin receptor kinase A (TRKA) and C, rearranged during transfection proto-oncogene [RET proto oncogene]), as well as in fibrotic diseases (e.g., DDRs). In tumor cell lines displaying molecular alterations in potential nintedanib targets, the inhibitor demonstrates direct antiproliferative effects: in the NSCLC cell line NCI-H1703 carrying a PDGFRalpha amplification (ampl.); the gastric cancer cell line KatoIII and the breast cancer cell line MFM223, both driven by a FGFR2 amplification; AN3CA (endometrial carcinoma) bearing a mutated FGFR2; the acute myeloid leukemia cell lines MOLM-13 and MV-4 11-B with FLT3 mutations; and the NSCLC adenocarcinoma LC-2/ad harboring a CCDC6 RET fusion. Potent kinase inhibition does not, however, strictly translate into antiproliferative activity, as demonstrated in the TRKA-dependent cell lines CUTO 3 and KM-12. Importantly, nintedanib treatment of NCI-H1703 tumor xenografts triggered effective tumor shrinkage, indicating a direct effect on the tumor cells in addition to the antiangiogenic effect on the tumor stroma. These findings will be instructive in guiding future genome-based clinical trials of nintedanib. PMID- 29263245 TI - Deciphering pathogenicity and antibiotic resistance islands in methicillin resistant Staphylococcus aureus genomes. AB - Staphylococcus aureus is a versatile pathogen that is capable of causing infections in both humans and animals. It can cause furuncles, septicaemia, pneumonia and endocarditis. Adaptation of S. aureus to the modern hospital environment has been facilitated, in part, by the horizontal acquisition of drug resistance genes, such as mecA gene that imparts resistance to methicillin. Horizontal acquisitions of islands of genes harbouring virulence and antibiotic resistance genes have made S. aureus resistant to commonly used antibiotics. To decipher genomic islands (GIs) in 22 hospital- and 9 community-associated methicillin-resistant S. aureus strains and classify a subset of GIs carrying virulence and resistance genes as pathogenicity and resistance islands respectively, we applied a host of methods for localizing genomic islands in prokaryotic genomes. Surprisingly, none of the frequently used GI prediction methods could perform well in delineating the resistance islands in the S. aureus genomes. Rather, a gene clustering procedure exploiting biases in codon usage for identifying horizontally transferred genes outperformed the current methods for GI detection, in particular in identifying the known islands in S. aureus including the SCCmec island that harbours the mecA resistance gene. The gene clustering approach also identified novel, as yet unreported islands, with many of these found to harbour virulence and/or resistance genes. These as yet unexplored islands may provide valuable information on the evolution of drug resistance in S. aureus. PMID- 29263246 TI - Cyclic nucleotide signalling in malaria parasites. AB - The cyclic nucleotides 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5' cyclic guanosine monophosphate (cGMP) are intracellular messengers found in most animal cell types. They usually mediate an extracellular stimulus to drive a change in cell function through activation of their respective cyclic nucleotide dependent protein kinases, PKA and PKG. The enzymatic components of the malaria parasite cyclic nucleotide signalling pathways have been identified, and the genetic and biochemical studies of these enzymes carried out to date are reviewed herein. What has become very clear is that cyclic nucleotides play vital roles in controlling every stage of the complex malaria parasite life cycle. Our understanding of the involvement of cyclic nucleotide signalling in orchestrating the complex biology of malaria parasites is still in its infancy, but the recent advances in our genetic tools and the increasing interest in signalling will deliver more rapid progress in the coming years. PMID- 29263247 TI - Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism. AB - Endothelial cell (EC) metabolism has lately emerged as a novel and promising therapeutic target to block vascular dysregulation associated with diseases like cancer and blinding eye disease. Glycolysis, fatty acid oxidation (FAO) and, more recently, glutamine/asparagine metabolism emerged as key regulators of EC metabolism, able to impact angiogenesis in health and disease. ECs are highly glycolytic as they require ATP and biomass for vessel sprouting. Notably, a regulator of the glycolytic pathway, 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase 3, controls vessel sprouting during the angiogenic switch and its inhibition in tumour ECs leads to vessel normalization, thereby reducing metastasis and ameliorating chemotherapy. Moreover, FAO promotes EC proliferation through DNA synthesis, and plays an essential role in lymphangiogenesis via epigenetic regulation of histone acetylation. Pathological angiogenesis was decreased upon blockade of carnitine palmitoyltransferase 1, a regulator of FAO in ECs. More recently, metabolism of glutamine, in conjunction with asparagine, was reported to maintain EC sprouting through TCA anaplerosis, redox homeostasis, mTOR activation and endoplasmic stress control. Inactivation or blockade of glutaminase 1, which hydrolyses glutamine into ammonia and glutamate, impairs angiogenesis in health and disease, while silencing of asparagine synthetase reduces vessel sprouting in vitro In this review, we summarize recent insights into EC metabolism and discuss therapeutic implications of targeting EC metabolism. PMID- 29263248 TI - Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells. AB - N-Methyl-d-aspartate receptor (NMDAR) activation is implicated in the malignant progression of many cancer types, as previously shown by the growth-inhibitory effects of NMDAR antagonists. NMDAR-mediated calcium influx and its downstream signalling depend critically, however, on the dynamics of membrane potential and ambient glutamate concentration, which are poorly characterized in cancer cells. Here, we have used low-noise whole-cell patch-clamp recording to investigate the electrophysiology of glutamate signalling in pancreatic neuroendocrine tumour (PanNET) cells derived from a genetically-engineered mouse model (GEMM) of PanNET, in which NMDAR signalling is known to promote cancer progression. Activating NMDARs caused excitation and intracellular calcium elevation, and intracellular perfusion with physiological levels of glutamate led to VGLUT dependent autocrine NMDAR activation. Necrotic cells, which are often present in rapidly-growing tumours, were shown to release endogenous cytoplasmic glutamate, and necrosis induced by mechanical rupture of the plasma membrane produced intense NMDAR activation in nearby cells. Computational modelling, based on these results, predicts that NMDARs in cancer cells can be strongly activated in the tumour microenvironment by both autocrine glutamate release and necrosis. PMID- 29263249 TI - Cadherin-7 enhances Sonic Hedgehog signalling by preventing Gli3 repressor formation during neural tube patterning. AB - Sonic Hedgehog (Shh) is a ventrally enriched morphogen controlling dorsoventral patterning of the neural tube. In the dorsal spinal cord, Gli3 protein bound to suppressor-of-fused (Sufu) is converted into Gli3 repressor (Gli3R), which inhibits Shh-target genes. Activation of Shh signalling prevents Gli3R formation, promoting neural tube ventralization. We show that cadherin-7 (Cdh7) expression in the intermediate spinal cord region is required to delimit the boundary between the ventral and the dorsal spinal cord. We demonstrate that Cdh7 functions as a receptor for Shh and enhances Shh signalling. Binding of Shh to Cdh7 promotes its aggregation on the cell membrane and association of Cdh7 with Gli3 and Sufu. These interactions prevent Gli3R formation and cause Gli3 protein degradation. We propose that Shh can act through Cdh7 to limit intracellular movement of Gli3 protein and production of Gli3R, thus eliciting more efficient activation of Gli-dependent signalling. PMID- 29263251 TI - Improving Time to Antibiotic Administration for Bone Marrow Transplant Patients With First Fever. AB - BACKGROUND AND OBJECTIVE: Timely antibiotic administration in immunocompromised patients is associated with improved outcomes. The aim of our study was to decrease the mean time to administration of antibiotics in hospitalized bone marrow transplant patients with fever from 75 to <60 minutes. METHODS: By using the Model of Improvement, we performed plan-do-study-act cycles to design, test, and implement high-reliability interventions to decrease time to antibiotics. Nursing, physician, and pharmacy interventions were successfully applied to improve timely antibiotic administration. RESULTS: The study period was from April 2014 through March of 2017. Through heightened awareness, dedicated roles and responsibilities, a standardized order set specifically used for first fever patients, notification to the pharmacy about newly febrile first fever patients through a dedicated order, the creation of a dedicated sticker ("STAT first dose antibiotic, give directly to nurse") to be printed when antibiotics were entered via the order set in the pharmacy, and prioritization of antibiotic delivery on arrival on the floor, we saw an increase in the percentage of patients receiving antibiotics within 60 minutes of documented fever from a mean of 40% to over 90%. Our mean time for antibiotic administration decreased from 75 to 45 minutes. CONCLUSIONS: Implementation of a standardized process for notifying providers of new fever in patients, prioritization of antibiotic preparation in the central pharmacy, and timely antibiotic order entry resulted in improved times to antibiotic administration in the febrile bone marrow transplant population. PMID- 29263250 TI - Two-step phosphorylation of Ana2 by Plk4 is required for the sequential loading of Ana2 and Sas6 to initiate procentriole formation. AB - The conserved process of centriole duplication requires Plk4 kinase to recruit and promote interactions between Sas6 and Sas5/Ana2/STIL (respective nomenclature of worms/flies/humans). Plk4-mediated phosphorylation of Ana2/STIL in its conserved STAN motif has been shown to promote its interaction with Sas6. However, STAN motif phosphorylation is not required for recruitment of Ana2 to the centriole. Here we show that in Drosophila, Ana2 loads onto the site of procentriole formation ahead of Sas6 in a process that also requires Plk4. However, whereas Plk4 is first recruited to multiple sites around the ring of zone II at the periphery of the centriole, Ana2 is recruited to a single site in telophase before Plk4 becomes finally restricted to this same single site. When we over-ride the auto-destruction of Plk4, it remains localized to multiple sites in the outer ring of the centriole and, if catalytically active, recruits Ana2 to these sites. Thus, it is the active form of Plk4 that promotes Ana2's recruitment to the centriole. We now show that Plk4 phosphorylates Ana2 at a site other than the STAN motif, which lies in a conserved region we term the ANST (ANa2-STil) motif. Mutation of this site, S38, to a non-phosphorylatable residue prevents the procentriole loading of Ana2 and blocks centriole duplication. Thus the initiation of procentriole formation requires Plk4 to first phosphorylate a single serine residue in the ANST motif to promote Ana2's recruitment and, secondly, to phosphorylate four residues in the STAN motif enabling Ana2 to recruit Sas6. We discuss these findings in light of the multiple Plk4 phosphorylation sites on Ana2. PMID- 29263252 TI - Delay in State Adoption of Newborn Screening Tests. PMID- 29263253 TI - Trends in Regionalization of Hospital Care for Common Pediatric Conditions. AB - OBJECTIVES: We have previously observed that hospital care for children is concentrating significantly in Massachusetts. We now extend those observations to include 4 US states and give closer attention to the management patterns of specific clinical conditions. METHODS: We used inpatient and emergency department administrative data sets from California, Florida, Massachusetts, and New York to measure transfer frequency and identify the site of care completion for >252 million hospital encounters from 2006 through 2013. We compared the concentration of pediatric care to adult care by using the Hospital Capability Index for all acute-care hospitals and quantified the regionalization of clinical conditions by using the Regionalization Index. RESULTS: The availability of hospital care was significantly more limited for children than adults in all 4 states (median Hospital Capability Index: 0.19 vs 0.74 in CA, 0.08 vs 0.79 in FL, 0.18 vs 0.69 in MA, and 0.16 vs 0.75 in NY). Between 2006 and 2011, care was concentrated for both adults and children but much more so for children. Although pediatric admissions decreased by 9.3% (from 545 330 to 494 645), interhospital transfers increased by 24.6% (from 64 285 to 80 101). The largest change in transfer rate was among children with common conditions, such as abdominal pain and asthma. CONCLUSIONS: Definitive pediatric hospital care is less available than adult care and is increasingly dependent on referral centers. This should be accounted for in public health plans, disaster preparedness, and determinations of network adequacy. PMID- 29263254 TI - Dissection of epitope-specific mechanisms of neutralization of influenza virus by intact IgG and Fab fragments. AB - The neutralizing antibody (nAb) response against the influenza virus's hemagglutinin (HA) fusion glycoprotein is important for preventing viral infection, but we lack a comprehensive understanding of the mechanisms by which these antibodies act. Here we investigated the effect of nAb binding and the role of IgG bivalency on inhibition of HA function for nAbs targeting distinct HA epitopes. HC19 targets the receptor-binding pocket at HA's distal end, while FI6v3 binds primarily to the HA2 fusion subunit towards the base of the stalk. Surprisingly, HC19 inhibited HA's ability to induce lipid mixing by preventing structural rearrangement of HA under fusion activating conditions. These results suggest that nAbs such as HC19 not only act by blocking receptor binding, but also inhibit key late-stage HA conformational changes required for fusion. Intact HC19 IgG was also shown to crosslink separate virus particles, burying large proportions of HA within aggregates where they are blocked from interacting with target membranes; Fabs yielded no such aggregation and displayed weaker neutralization than IgG, emphasizing the impact of bivalency on the ability to neutralize virus. In contrast, the stem-targeting nAb FI6v3 did not aggregate particles. The Fab was significantly less effective than IgG in preventing both membrane disruption and fusion. We infer that inter-spike crosslinking within a given particle by FI6v3 IgG may be critical to its potent neutralization, as no significant neutralization occurred with Fabs. These results demonstrate that IgG bivalency enhances HA inhibition through functionally important modes not evident in pared down Fab-soluble HA structures.IMPORTANCEThe influenza virus's hemagglutinin (HA) fusion glycoprotein mediates entry into target cells and is the primary antigenic target of neutralizing antibodies (nAbs). Our current structural understanding of mechanisms of Ab-mediated neutralization largely relies on high resolution characterization of antigen binding fragments (Fab) in complex with soluble, isolated antigen constructs by cryo-EM single particle reconstruction or X-ray crystallography. Interactions between full-length IgG and whole virions have not been well-characterized, and a gap remains in our understanding of how intact Abs neutralize virus and prevent infection. Using structural and biophysical approaches, we observed that Ab-mediated inhibition of HA function and neutralization of virus infectivity occurs by multiple coexisting mechanisms and is largely dependent on the specific epitope that is targeted and is highly dependent on the bivalent nature of IgG molecules. PMID- 29263255 TI - Simultaneous Insertion of Two Ligands in gD for Cultivation of Oncolytic Herpes Simplex Viruses in Noncancer Cells and Retargeting to Cancer Receptors. AB - Insertion of a single-chain variable-fragment antibody (scFv) to HER2 (human epidermal growth factor receptor 2) in gD, gH, or gB gives rise to herpes simplex viruses (HSVs) specifically retargeted to HER2-positive cancer cells, hence to highly specific nonattenuated oncolytic agents. Clinical-grade virus production cannot rely on cancer cells. Recently, we developed a double-retargeting strategy whereby gH carries the GCN4 peptide for retargeting to the noncancer producer Vero-GCN4R cell line and gD carries the scFv to HER2 for cancer retargeting. Here, we engineered double-retargeted recombinants, which carry both the GCN4 peptide and the scFv to HER2 in gD. Novel, more-advantageous detargeting strategies were devised so as to optimize the cultivation of the double retargeted recombinants. Nectin1 detargeting was achieved by deletion of amino acids (aa) 35 to 39, 214 to 223, or 219 to 223 and replacement of the deleted sequences with one of the two ligands. The last two deletions were not attempted before. All recombinants exhibited the double retargeting to HER2 and to the Vero GCN4R cells, as well as detargeting from the natural receptors HVEM and nectin1. Of note, some recombinants grew to higher yields than others. The best-performing recombinants carried a gD deletion as small as 5 amino acids and grew to titers similar to those exhibited by the singly retargeted R-LM113 and by the nonretargeted R-LM5. This study shows that double retargeting through insertion of two ligands in gD is feasible and, when combined with appropriate detargeting modifications, can result in recombinants highly effective in vitro and in vivoIMPORTANCE There is increasing interest in oncolytic viruses following the FDA and European Medicines Agency (EMA) approval of the oncolytic HSV OncovexGM CSF and, mainly, because they greatly boost the immune response to the tumor and can be combined with immunotherapeutic agents, particularly immune checkpoint inhibitors. A strategy to gain high cancer specificity and avoid virus attenuation is to retarget the virus tropism to cancer-specific receptors of choice. However, cultivation of retargeted oncolytics in cells expressing the cancer receptor may not be approvable by regulatory agencies. We devised a strategy for their cultivation in noncancer cells. Here, we describe a double retargeting strategy, based on the simultaneous insertion of two ligands in gD, one for retargeting to a producer, universal Vero cell derivative and one for retargeting to the HER2 cancer receptor. These insertions were combined with novel, minimally disadvantageous detargeting modifications. The current and accompanying studies indicate how to best achieve the clinical-grade cultivation of retargeted oncolytics. PMID- 29263256 TI - Cryo-EM Structure of Seneca Valley Virus Procapsid. AB - Seneca Valley Virus, like some other members of the picornaviridae, forms naturally occurring empty capsids, known as procapsids. The procapsid has the same antigenicity as the full virion, so they present an interesting possibility for the formation of stable virus-like particles. Interestingly, although SVV is a livestock pathogen, it has also been found to preferentially infect tumour cells, and is being explored for use as a therapeutic agent in the treatment of small cell lung cancers. Here we used cryo-electron microscopy to investigate the procapsid structure and describe the transition of capsid protein VP0 to the cleaved forms of VP4 and VP2. We show that the SVV receptor binds the procapsid, as evidence of its native antigenicity. In comparing the procapsid structure to that of the full virion, we also show that a cage of RNA serves to stabilize the inside surface of the virus, thereby making it more acid-stable.ImportanceViruses are extensively studied to help us understand infection and disease. One of the by-products of some virus infections are the naturally occurring empty virus capsids (containing no genome), termed procapsids, whose function remains unclear. Here we investigate the structure and formation of the procapsids of Seneca Valley Virus, to better understand how they form, what causes them to form, how they behave, and how we can make use of them. One potential benefit of this work is the modification of the procapsid to develop it for targeted in vivo delivery of therapeutics or to make a stable vaccine against SVV, which could be of great interest to the agricultural industry. PMID- 29263257 TI - Dual Ligand Insertion in gB and gD of Oncolytic Herpes Simplex Viruses for Retargeting to a Producer Vero Cell Line and to Cancer Cells. AB - Oncolytic viruses gain cancer specificity in several ways. Like the majority of viruses, they grow better in cancer cells that are defective in mounting the host response to viruses. Often, they are attenuated by deletion or mutation of virulence genes that counteract the host response or are naturally occurring oncolytic mutants. In contrast, retargeted viruses are not attenuated or deleted; their cancer specificity rests on a modified, specific tropism for cancer receptors. For herpes simplex virus (HSV)-based oncolytics, the detargeting retargeting strategies employed so far were based on genetic modifications of gD. Recently, we showed that even gH or gB can serve as retargeting tools. To enable the growth of retargeted HSVs in cells that can be used for clinical-grade virus production, a double-retargeting strategy has been developed. Here we show that several sites in the N terminus of gB are suitable to harbor the 20-amino-acid (aa)-long GCN4 peptide, which readdresses HSV tropism to Vero cells expressing the artificial GCN4 receptor and thus enables virus cultivation in the producer noncancer Vero-GCN4R cell line. The gB modifications can be combined with a minimal detargeting modification in gD, consisting in the deletion of two residues, aa 30 and 38, and replacement of aa 38 with the scFv to human epidermal growth factor receptor 2 (HER2), for retargeting to the cancer receptor. The panel of recombinants was analyzed comparatively in terms of virus growth, cell to-cell spread, cytotoxicity, and in vivo antitumor efficacy to define the best double-retargeting strategy.IMPORTANCE There is increasing interest in oncolytic viruses, following FDA and the European Medicines Agency (EMA) approval of HSV OncovexGM-CSF, and, mainly, because they greatly boost the immune response to the tumor and can be combined with immunotherapeutic agents, particularly checkpoint inhibitors. A strategy to gain cancer specificity and avoid virus attenuation is to retarget the virus tropism to cancer-specific receptors of choice. Cultivation of fully retargeted viruses is challenging, since they require cells that express the cancer receptor. We devised a strategy for their cultivation in producer noncancer Vero cell derivatives. Here, we developed a double-retargeting strategy, based on insertion of one ligand in gB for retargeting to a Vero cell derivative and of anti-HER2 ligand in gD for cancer retargeting. These modifications were combined with a minimally destructive detargeting strategy. This study and its companion paper explain the clinical-grade cultivation of retargeted oncolytic HSVs and promote their translation to the clinic. PMID- 29263258 TI - Major Histocompatibility Complex Class I (FLA-E*01801) Molecular Structure in Domestic Cats Demonstrates Species-Specific Characteristics in Presenting Viral Antigen Peptides. AB - Feline immunodeficiency virus (FIV) infection in domestic cats is the smallest usable natural model for lentiviral infection studies. FLA-E*01801 was applied to FIV AIDS vaccine research. We determined the crystal structure of FLA-E*01801 complexed with a peptide derived from FIV (gag positions 40 to 48; RMANVSTGR [RMA9]). The A pocket of the FLA-E*01801 complex plays a valuable restrictive role in peptide binding. Mutation experiments and circular-dichroism (CD) spectroscopy revealed that peptides with Asp at the first position (P1) could not bind to FLA-E*01801. The crystal structure and in vitro refolding of the mutant FLA-E*01801 complex demonstrated that Glu63 and Trp167 in the A pocket play important roles in restricting P1D. The B pocket of the FLA-E*01801 complex accommodates M/T/A/V/I/L/S residues, whereas the negatively charged F pocket prefers R/K residues. Based on the peptide binding motif, 125 FLA-E*01801 restricted FIV nonapeptides (San Diego isolate) were identified. Our results provide the structural basis for peptide presentation by the FLA-E*01801 molecule, especially A pocket restriction on peptide binding, and identify the potential cytotoxic T lymphocyte (CTL) epitope peptides of FIV presented by FLA E*01801. These results will benefit both the reasonable design of FLA-E*01801 restricted CTL epitopes and the further development of the AIDS vaccine.IMPORTANCE Feline immunodeficiency virus (FIV) is a viral pathogen in cats, and this infection is the smallest usable natural model for lentivirus infection studies. To examine how FLA I presents FIV epitope peptides, we crystallized and solved the first classic feline major histocompatibility complex class I (MHC-I) molecular structure. Surprisingly, pocket A restricts peptide binding. Trp167 blocks the left side of pocket A, causing P1D to conflict with Glu63 We also identified the FLA-E*01801 binding motif X (except D) (M/T/A/V/I/L/S)-X-X-X-X-X-X-(R/K) based on structural and biochemical experiments. We identified 125 FLA-E*01801-restricted nonapeptides from FIV. These results are valuable for developing peptide-based FIV and human immunodeficiency virus (HIV) vaccines and for studying how MHC-I molecules present peptides. PMID- 29263259 TI - The ATM and Rad3-Related (ATR) Protein Kinase Pathway Is Activated by Herpes Simplex Virus 1 and Required for Efficient Viral Replication. AB - The ATM and Rad3-related (ATR) protein kinase and its downstream effector Chk1 are key sensors and organizers of the DNA damage response (DDR) to a variety of insults. Previous studies of herpes simplex virus 1 (HSV-1) showed no evidence for activation of the ATR pathway. Here we demonstrate that both Chk1 and ATR were phosphorylated by 3 h postinfection (h.p.i.). Activation of ATR and Chk1 was observed using 4 different HSV-1 strains in multiple cell types, while a specific ATR inhibitor blocked activation. Mechanistic studies point to early viral gene expression as a key trigger for ATR activation. Both pATR and pChk1 localized to the nucleus within viral replication centers, or associated with their periphery, by 3 h.p.i. Significant levels of pATR and pChk1 were also detected in the cytoplasm, where they colocalized with ICP4 and ICP0. Proximity ligation assays confirmed that pATR and pChk1 were closely and specifically associated with ICP4 and ICP0 in both the nucleus and cytoplasm by 3 h.p.i., but not with ICP8 or ICP27, presumably in a multiprotein complex. Chemically distinct ATR and Chk1 inhibitors blocked HSV-1 replication and infectious virion production, while inhibitors of ATM, Chk2, and DNA-dependent protein kinase (DNA-PK) did not. Together our data show that HSV-1 activates the ATR pathway at early stages of infection and that ATR and Chk1 kinase activities play important roles in HSV-1 replication fitness. These findings indicate that the ATR pathway may provide insight for therapeutic approaches.IMPORTANCE Viruses have evolved complex associations with cellular DNA damage response (DDR) pathways, which sense troublesome DNA structures formed during infection. The first evidence for activation of the ATR pathway by HSV-1 is presented. ATR is activated, and its downstream target Chk1 is robustly phosphorylated, during early stages of infection. Both activated proteins are found in the nucleus associated with viral replication compartments and in the cytoplasm associated with viral proteins. We also demonstrate that both ATR and Chk1 kinase activities are important for viral replication. The findings suggest that HSV-1 activates ATR and Chk1 during early stages of infection and utilizes the enzymes to promote its own replication. The observation may be exploitable for antiviral approaches. PMID- 29263260 TI - Antagonism of the Protein Kinase R Pathway in Human Cells by Rhesus Cytomegalovirus. AB - While cytomegalovirus (CMV) infections are often limited in host range by lengthy coevolution with a single host species, a few CMVs are known to deviate from this rule. For example, rhesus macaque CMV (RhCMV), a model for human CMV (HCMV) pathogenesis and vaccine development, can replicate in human cells, as well as in rhesus cells. Both HCMV and RhCMV encode species-specific antagonists of the broadly acting host cell restriction factor protein kinase R (PKR). Although the RhCMV antagonist of PKR, rTRS1, has very limited activity against human PKR, here, we show it is essential for RhCMV replication in human cells because it prevents human PKR from phosphorylating the translation initiation factor eIF2alpha, thereby allowing continued translation and viral replication. Although rTRS1 is necessary for RhCMV replication, it is not sufficient to rescue replication of HCMV lacking its own PKR antagonists in human fibroblasts. However, overexpression of rTRS1 in human fibroblasts enabled HCMV expressing rTRS1 to replicate, indicating that elevated levels or early expression of a weak antagonist can counteract a resistant restriction factor like human PKR. Exploring potential mechanisms that might allow RhCMV to replicate in human cells revealed that RhCMV makes no less double-stranded RNA than HCMV. Rather, in human cells, RhCMV expresses rTRS1 at levels 2 to 3 times higher than those of the HCMV encoded PKR antagonists during HCMV infection. These data suggest that even a modest increase in expression of this weak PKR antagonist is sufficient to enable RhCMV replication in human cells.IMPORTANCE Rhesus macaque cytomegalovirus (RhCMV) offers a valuable model for studying congenital human cytomegalovirus (HCMV) pathogenesis and vaccine development. Therefore, it is critical to understand variations in how each virus infects and affects its host species to be able to apply insights gained from the RhCMV model to HCMV. While HCMV is capable only of infecting cells from humans and very closely related species, RhCMV displays a wider host range, including human as well as rhesus cells. RhCMV expresses an antagonist of a broadly acting antiviral factor present in all mammalian cells, and its ability to counter both the rhesus and human versions of this host factor is a key component of RhCMV's ability to cross species barriers. Here, we examine the molecular mechanisms that allow this RhCMV antagonist to function against a human restriction factor. PMID- 29263261 TI - The Host Factor AUF1 p45 Supports Flavivirus Propagation by Triggering the RNA Switch Required for Viral Genome Cyclization. AB - In previous studies, we showed that the cellular RNA-binding protein AUF1 supports the replication process of the flavivirus West Nile virus. Here we demonstrate that the protein also enables effective proliferation of dengue virus and Zika virus, indicating that AUF1 is a general flavivirus host factor. Further studies demonstrated that the AUF1 isoform p45 significantly stimulates the initiation of viral RNA replication and that the protein's RNA chaperone activity enhances the interactions of the viral 5'UAR and 3'UAR genome cyclization sequences. Most interestingly, we observed that AUF1 p45 destabilizes not only the 3'-terminal stem-loop (3'SL) but also 5'-terminal stem-loop B (SLB) of the viral genome. RNA structure analyses revealed that AUF1 p45 increases the accessibility of defined nucleotides within the 3'SL and SLB and, in this way, exposes both UAR cyclization elements. Conversely, AUF1 p45 does not modulate the fold of stem-loop A (SLA) at the immediate genomic 5' end, which is proposed to function as a promoter of the viral RNA-dependent RNA polymerase (RdRp). These findings suggest that AUF1 p45, by destabilizing specific stem-loop structures within the 5' and 3' ends of the flaviviral genome, assists genome cyclization and concurrently enables the RdRp to initiate RNA synthesis. Our study thus highlights the role of a cellular RNA-binding protein inducing a flaviviral RNA switch that is crucial for viral replication.IMPORTANCE The genus Flavivirus within the Flaviviridae family includes important human pathogens, such as dengue, West Nile, and Zika viruses. The initiation of replication of the flaviviral RNA genome requires a transformation from a linear to a cyclized form. This involves considerable structural reorganization of several RNA motifs at the genomic 5' and 3' ends. Specifically, it needs a melting of stem structures to expose complementary 5' and 3' cyclization elements to enable their annealing during cyclization. Here we show that a cellular RNA chaperone, AUF1 p45, which supports the replication of all three aforementioned flaviviruses, specifically rearranges stem structures at both ends of the viral genome and in this way permits 5'-3' interactions of cyclization elements. Thus, AUF1 p45 triggers the RNA switch in the flaviviral genome that is crucial for viral replication. These findings represent an important example of how cellular (host) factors promote the propagation of RNA viruses. PMID- 29263262 TI - Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis. AB - Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash, and encephalomyelitis. Previous studies in mice with a virulent strain (neuroadapted SINV [NSV]) of the alphavirus Sindbis virus (SINV) identified a role for Th17 cells and regulation by interleukin-10 (IL-10) in the pathogenesis of fatal encephalomyelitis (K. A. Kulcsar, V. K. Baxter, I. P. Greene, and D. E. Griffin, Proc Natl Acad Sci U S A 111:16053-16058, 2014, https://doi.org/10.1073/pnas.1418966111). To determine the role of virus virulence in generation of immune responses, we analyzed the modulatory effects of IL-10 on disease severity, virus clearance, and the CD4+ T cell response to infection with a recombinant strain of SINV of intermediate virulence (TE12). The absence of IL-10 during TE12 infection led to longer morbidity, more weight loss, higher mortality, and slower viral clearance than in wild-type mice. More severe disease and impaired virus clearance in IL-10-/- mice were associated with more Th1 cells, fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells, and B cells, and delayed production of antiviral antibody in the central nervous system (CNS) without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain.IMPORTANCE Alphaviruses cause mosquito borne outbreaks of encephalomyelitis, but determinants of outcome are incompletely understood. We analyzed the effects of the anti-inflammatory cytokine IL-10 on disease severity and virus clearance after infection with an alphavirus strain of intermediate virulence. The absence of IL-10 led to longer illness, more weight loss, more death, and slower viral clearance than in mice that produced IL-10. IL-10 influenced development of disease-causing T cells and entry into the brain of B cells producing antiviral antibody. The Th1 pathogenic cell subtype that developed in IL-10-deficient mice infected with a less virulent virus was distinct from the Th17 subtype that developed in response to a more virulent virus, indicating a role for virus strain in determining the immune response. Slow production of antibody in the nervous system led to delayed virus clearance. Therefore, both the virus strain and the host response to infection are important determinants of outcome. PMID- 29263263 TI - Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses. AB - Interferon-induced transmembrane proteins (IFITMs) are restriction factors that inhibit the infectious entry of many enveloped RNA viruses. However, we demonstrated previously that human IFITM2 and IFITM3 are essential host factors facilitating the entry of human coronavirus (HCoV) OC43. In a continuing effort to decipher the molecular mechanism underlying IFITM differential modulation of HCoV entry, we investigated the roles of structural motifs important for IFITM protein posttranslational modifications, intracellular trafficking, and oligomerization in modulating the entry of five HCoVs. We found that three distinct mutations in IFITM1 or IFITM3 converted the host restriction factors to enhance entry driven by the spike proteins of severe acute respiratory syndrome coronavirus (SARS-CoV) and/or Middle East respiratory syndrome coronavirus (MERS CoV). First, replacement of IFITM3 tyrosine 20 with either alanine or aspartic acid to mimic unphosphorylated or phosphorylated IFITM3 reduced its activity to inhibit the entry of HCoV-NL63 and -229E but enhanced the entry of SARS-CoV and MERS-CoV. Second, replacement of IFITM3 tyrosine 99 with either alanine or aspartic acid reduced its activity to inhibit the entry of HCoV-NL63 and SARS-CoV but promoted the entry of MERS-CoV. Third, deletion of the carboxyl-terminal 12 amino acid residues from IFITM1 enhanced the entry of MERS-CoV and HCoV-OC43. These findings suggest that these residues and structural motifs of IFITM proteins are key determinants for modulating the entry of HCoVs, most likely through interaction with viral and/or host cellular components at the site of viral entry to modulate the fusion of viral envelope and cellular membranes.IMPORTANCE The differential effects of IFITM proteins on the entry of HCoVs that utilize divergent entry pathways and membrane fusion mechanisms even when using the same receptor make the HCoVs a valuable system for comparative investigation of the molecular mechanisms underlying IFITM restriction or promotion of virus entry into host cells. Identification of three distinct mutations that converted IFITM1 or IFITM3 from inhibitors to enhancers of MERS CoV or SARS-CoV spike protein-mediated entry revealed key structural motifs or residues determining the biological activities of IFITM proteins. These findings have thus paved the way for further identification of viral and host factors that interact with those structural motifs of IFITM proteins to differentially modulate the infectious entry of HCoVs. PMID- 29263264 TI - Enhancing the Thermostability and Immunogenicity of a Respiratory Syncytial Virus (RSV) Live-Attenuated Vaccine by Incorporating Unique RSV Line19F Protein Residues. AB - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, and an effective vaccine is not yet available. We previously generated an RSV live-attenuated vaccine (LAV) candidate, DB1, which was attenuated by a low-fusion subgroup B F protein (BAF) and codon-deoptimized nonstructural protein genes. DB1 was immunogenic and protective in cotton rats but lacked thermostability and stability of the prefusion conformation of F compared to strains with the line19F gene. We hypothesized that substitution of unique residues from the thermostable A2-line19F strain could thermostabilize DB1 and boost its immunogenicity. We therefore substituted 4 unique line19F residues into the BAF protein of DB1 by site-directed mutagenesis and rescued the recombinant virus, DB1-QUAD. Compared to DB1, DB1-QUAD had improved thermostability at 4 degrees C and higher levels of prefusion F as measured by enzyme-linked immunosorbent assays (ELISAs). DB1-QUAD was attenuated in normal human bronchial epithelial cells, in BALB/c mice, and in cotton rats but grew to wild-type titers in Vero cells. In mice, DB1-QUAD was highly immunogenic and generated significantly higher neutralizing antibody titers to a panel of RSV A and B strains than did DB1. DB1-QUAD was also efficacious against wild-type RSV challenge in mice and cotton rats. Thus, substitution of unique line19F residues into RSV LAV DB1 enhanced vaccine thermostability, incorporation of prefusion F, and immunogenicity and generated a promising vaccine candidate that merits further investigation.IMPORTANCE We boosted the thermostability and immunogenicity of an RSV live-attenuated vaccine candidate by substituting 4 unique residues from the RSV line19F protein into the F protein of the heterologous vaccine strain DB1. The resultant vaccine candidate, DB1-QUAD, was thermostable, attenuated in vivo, highly immunogenic, and protective against RSV challenge in mice and cotton rats. PMID- 29263265 TI - Actin-dependent non-lytic rotavirus exit and infectious virus morphogenetic pathway in non-polarized cells. AB - During the late stages of rotavirus morphogenesis the surface proteins VP4 and VP7 are assembled onto the previously structured double-layered virus particles to yield a triple-layered, mature infectious virus. The current model for the assembly of the outer capsid is that it occurs within the lumen of the endoplasmic reticulum. However, it has been shown that VP4 and infectious virus associate with lipid rafts, suggesting that the final assembly of the rotavirus spike protein VP4 involves a post-endoplasmic reticulum event. In this work, we found that the actin inhibitor jasplakinolide blocks the cell egress of rotavirus from non-polarized MA104 cells at early times of infection when there is still no evidence of cell lysis. These findings are in contrast with the traditional assumption that rotavirus is released from non-polarized cells by a non-specific mechanism when the cell integrity is lost. Inspection of the virus present in the extracellular media by density flotation gradients revealed that a fraction of the released virus is associated with low-density membranous structures. Furthermore, the intracellular localization of VP4, its interaction with lipid rafts and its targeting to the cell surface were shown to be prevented by jasplakinolide, implying a role for actin in these processes. Finally, the VP4 present at the plasma membrane was shown to be incorporated into the extracellular infectious virus, suggesting the existence of a novel pathway for the assembly of the rotavirus spike protein.IMPORTANCE Rotavirus is a major etiological agent of infantile acute severe diarrhea. It is a non-enveloped virus formed by three concentric layers of protein. The early stages of rotavirus replication, including cell attachment and entry, synthesis and translation of viral mRNAs, replication of the genomic dsRNA, and the assembly of double-layered viral particles, have been widely studied. However, the mechanism involved in the later stages of infection, i.e, viral particle maturation and cell exit, have been less characterized. It has been historically assumed that rotavirus exits non-polarized cells following cell lysis. In this work, we show that the virus exits cells by a non-lytic, actin-dependent mechanism and, most importantly, we describe that VP4, the spike protein of the virus, is present on the cell surface and is incorporated into mature, infectious virus, indicating a novel pathway for the assembly of this protein. PMID- 29263266 TI - GalNAc-Specific Soybean Lectin Inhibits HIV Infection of Macrophages through Induction of Antiviral Factors. AB - Although it has been shown that some mannose-binding lectins (MBLs) exhibit significant activity against HIV infection, little is known about whether N acetylgalactosamine (GalNAc)-binding lectins have the ability to inhibit HIV infection. Here, we demonstrate that a soybean-derived lectin (SBL) with GalNAc binding affinity could potently suppress HIV infection of macrophages in a dose dependent fashion. Unlike the MBLs, which block HIV only through binding to the glycosylated envelope proteins (gp120 and gp41) of the virus, SBL inhibited HIV at multiple steps of the virus infection/replication cycle. SBL could activate the beta interferon (IFN-beta)-STAT signaling pathway, resulting in the upregulation of a number of antiviral interferon-stimulated genes (ISGs) in macrophages. In addition, SBL treatment of macrophages induced the production of C-C chemokines, which bind to HIV entry coreceptor CCR5. Deglycosylation of cell surface galactosyl moieties or presaturation of GalNAc-binding capacity could compromise SBL-mediated induction of the antiviral factors. Furthermore, SBL exerted its anti-HIV activity in the low nanomolar range with no mitogenic effect on CD4+ T cells, a major advantage in the development of SBL as a potential anti HIV agent compared with MBLs. These data indicate a necessity to further investigate SBL as an alternative and cost-effective anti-HIV natural product.IMPORTANCE Mannose-binding lectins (MBLs) can block the attachment of HIV to target cells and have been suggested as anti-HIV microbicides. However, the mitogenic effect of MBLs on CD4+ T cells limits this potential in clinical settings. Lectins with galactose (Gal)- or N-acetylgalactosamine (GalNAc)-binding specificity are another important category of carbohydrate-binding proteins (CBP). Compared to high-mannose N-linked glycans, GalNAc-type glycans present much less in HIV gp120 or gp41 glycosylation. Here, we demonstrate that GalNAc specific soybean lectin (SBL) triggers antiviral signaling via recognition of the cell surface galactosyl group of macrophages, which results in the suppression of HIV at multiple steps. More importantly, SBL has no mitogenic effect on the activation of CD4+ T cells, a major advantage in the development of Gal/GalNAc specific lectins as naturopathic anti-HIV agents. PMID- 29263267 TI - Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small Molecule Agonist of the STING Pathway. AB - The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFN induced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N-(methylcarbamoyl)-2-{[5-(4-methylphenyl) 1,3,4-oxadiazol-2-yl]sulfanyl}-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse genetics-based loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection.IMPORTANCE Due to the increase in emerging arthropod-borne viruses, such as chikungunya virus, that lack FDA-approved therapeutics and vaccines, it is important to better understand the signaling pathways that lead to clearance of virus. Here we show that C11 treatment makes human cells refractory to replication of a number of these viruses, which supports its value in increasing our understanding of the immune response and viral pathogenesis required to establish host infection. We also show that C11 depends on signaling through STING to produce antiviral type I interferon, which further supports its potential as a therapeutic drug or research tool. PMID- 29263268 TI - Naturally Occurring Frameshift Mutations in the tvb Receptor Gene Are Responsible for Decreased Susceptibility of Chicken to Infection with Avian Leukosis Virus Subgroups B, D, and E. AB - The group of highly related avian leukosis viruses (ALVs) in chickens are thought to have evolved from a common retroviral ancestor into six subgroups, A to E and J. These ALV subgroups use diverse cellular proteins encoded by four genetic loci in chickens as receptors to gain entry into host cells. Hosts exposed to ALVs might be under selective pressure to develop resistance to ALV infection. Indeed, resistance alleles have previously been identified in all four receptor loci in chickens. The tvb gene encodes a receptor, which determines the susceptibility of host cells to ALV subgroup B (ALV-B), ALV-D, and ALV-E. Here we describe the identification of two novel alleles of the tvb receptor gene, which possess independent insertions each within exon 4. The insertions resulted in frameshift mutations that reveal a premature stop codon that causes nonsense-mediated decay of the mutant mRNA and the production of truncated Tvb protein. As a result, we observed that the frameshift mutations in the tvb gene significantly lower the binding affinity of the truncated Tvb receptors for the ALV-B, ALV-D, and ALV-E envelope glycoproteins and significantly reduce susceptibility to infection by ALV-B, ALV-D and ALV-E in vitro and in vivo Taken together, these findings suggest that frameshift mutation can be a molecular mechanism of reducing susceptibility to ALV and enhance our understanding of virus-host coevolution.IMPORTANCE Avian leukosis virus (ALV) once caused devastating economic loss to the U.S. poultry industry prior the current eradication schemes in place, and it continues to cause severe calamity to the poultry industry in China and Southeast Asia, where deployment of a complete eradication scheme remains a challenge. The tvb gene encodes the cellular receptor necessary for subgroup B, D, and E ALV infection. Two tvb allelic variants that resulted from frameshift mutations have been identified in this study, which have been shown to have significantly reduced functionality in mediating subgroup B, D, and E ALV infection. Unlike the control of herpesvirus-induced diseases by vaccination, the control of avian leukosis in chickens has relied totally on virus eradication measures and host genetic resistance. This finding enriches the allelic pool of the tvb gene and expands the potential for genetic improvement of ALV resistance in varied chicken populations by selection. PMID- 29263269 TI - Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I Interferon Production by Inactivating the DNA Sensor cGAS without Affecting STING. AB - The innate immune response plays a pivotal role during human cytomegalovirus (HCMV) primary infection. Indeed, HCMV infection of primary fibroblasts rapidly triggers strong induction of type I interferons (IFN-I), accompanied by proinflammatory cytokine release. Here, we show that primary human foreskin fibroblasts (HFFs) infected with a mutant HCMV TB40/E strain unable to express UL83-encoded pp65 (v65Stop) produce significantly higher IFN-beta levels than HFFs infected with the wild-type TB40/E strain or the pp65 revertant (v65Rev), suggesting that the tegument protein pp65 may dampen IFN-beta production. To clarify the mechanisms through which pp65 inhibits IFN-beta production, we analyzed the activation of the cGAS/STING/IRF3 axis in HFFs infected with either the wild type, the revertant v65Rev, or the pp65-deficient mutant v65Stop. We found that pp65 selectively binds to cGAS and prevents its interaction with STING, thus inactivating the signaling pathway through the cGAS/STING/IRF3 axis. Consistently, addition of exogenous cGAMP to v65Rev-infected cells triggered the production of IFN-beta levels similar to those observed with v65Stop-infected cells, confirming that pp65 inactivation of IFN-beta production occurs at the cGAS level. Notably, within the first 24 h of HCMV infection, STING undergoes proteasome degradation independently of the presence or absence of pp65. Collectively, our data provide mechanistic insights into the interplay between HCMV pp65 and cGAS, leading to subsequent immune evasion by this prominent DNA virus.IMPORTANCE Primary human foreskin fibroblasts (HFFs) produce type I IFN (IFN-I) when infected with HCMV. However, we observed significantly higher IFN beta levels when HFFs were infected with HCMV that was unable to express UL83 encoded pp65 (v65Stop), suggesting that pp65 (pUL83) may constitute a viral evasion factor. This study demonstrates that the HCMV tegument protein pp65 inhibits IFN-beta production by binding and inactivating cGAS early during infection. In addition, this inhibitory activity specifically targets cGAS, since it can be bypassed via the addition of exogenous cGAMP, even in the presence of pp65. Notably, STING proteasome-mediated degradation was observed in both the presence and absence of pp65. Collectively, our data underscore the important role of the tegument protein pp65 as a critical molecular hub in HCMV's evasion strategy against the innate immune response. PMID- 29263270 TI - Identification of a Conserved Interface of Human Immunodeficiency Virus Type 1 and Feline Immunodeficiency Virus Vifs with Cullin 5. AB - Members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 [A3]) family of DNA cytidine deaminases are intrinsic restriction factors against retroviruses. In felids such as the domestic cat (Felis catus), the A3 genes encode the A3Z2, A3Z3, and A3Z2Z3 antiviral cytidine deaminases. Only A3Z3 and A3Z2Z3 inhibit viral infectivity factor (Vif)-deficient feline immunodeficiency virus (FIV). The FIV Vif protein interacts with Cullin (CUL), Elongin B (ELOB), and Elongin C (ELOC) to form an E3 ubiquitination complex to induce the degradation of feline A3s. However, the functional domains in FIV Vif for the interaction with Cullin are poorly understood. Here, we found that the expression of dominant negative CUL5 prevented the degradation of feline A3s by FIV Vif, while dominant negative CUL2 had no influence on the degradation of A3. In coimmunoprecipitation assays, FIV Vif bound to CUL5 but not CUL2. To identify the CUL5 interaction site in FIV Vif, the conserved amino acids from positions 47 to 160 of FIV Vif were mutated, but these mutations did not impair the binding of Vif to CUL5. By focusing on a potential zinc-binding motif (K175-C161-C184-C187) of FIV Vif, we found a conserved hydrophobic region (174IR175) that is important for the CUL5 interaction. Mutation of this region also impaired the FIV Vif induced degradation of feline A3s. Based on a structural model of the FIV Vif CUL5 interaction, the 52LW53 region in CUL5 was identified as mediating binding to FIV Vif. By comparing our results to the human immunodeficiency virus type 1 (HIV-1) Vif-CUL5 interaction surface (120IR121, a hydrophobic region that is localized in the zinc-binding motif), we suggest that the CUL5 interaction surface in the diverse HIV-1 and FIV Vifs is evolutionarily conserved, indicating a strong structural constraint. However, the FIV Vif-CUL5 interaction is zinc independent, which contrasts with the zinc dependence of HIV-1 Vif.IMPORTANCE Feline immunodeficiency virus (FIV), which is similar to human immunodeficiency virus type 1 (HIV-1), replicates in its natural host in T cells and macrophages that express the antiviral restriction factor APOBEC3 (A3). To escape A3s, FIV and HIV induce the degradation of these proteins by building a ubiquitin ligase complex using the viral protein Vif to connect to cellular proteins, including Cullin 5. Here, we identified the protein residues that regulate this interaction in FIV Vif and Cullin 5. While our structural model suggests that the diverse FIV and HIV-1 Vifs use conserved residues for Cullin 5 binding, FIV Vif binds Cullin 5 independently of zinc, in contrast to HIV-1 Vif. PMID- 29263271 TI - Asian elephant T cell responses to Elephant Endotheliotropic Herpesvirus (EEHV). AB - Elephant Endotheliotropic Herpesvirus (EEHV) can cause lethal hemorrhagic disease in juvenile Asian elephants, an endangered species. One hypothesis to explain this vulnerability of some juvenile elephants is that they fail to mount an effective T cell response to the virus. To our knowledge, there have been no studies of Asian elephant T cell responses to EEHV. To address this deficiency, we validated the IFN-gamma ELISpot assay for tracking antigen-directed T cell activity by monitoring rabies-specific responses in vaccinated elephants. Additionally, we generated monoclonal antibodies to Asian elephant CD4 and CD8 to facilitate phenotypic T cell profiling. Using these tools, we screened healthy elephants with a prior history of EEHV infection for reactivity against 9 EEHV proteins whose counterparts in other herpesviruses are known to induce T cell responses in their natural hosts. We identified glycoprotein B (gB) and the putative regulatory protein E40 as the most immunogenic T cell targets (IFN-gamma responses in 5 of 7 elephants) followed by the major capsid protein (MCP) (IFN gamma responses in 3 of 7 elephants). We also observed that IFN-gamma responses were largely from CD4+ T cells. We detected no activity against the predicted major immediate early (E44) and large tegument (E34) proteins- both immunodominant T cell targets in humans latently infected with cytomegalovirus. These studies have identified EEHV-specific T cells in Asian elephants for the first time, lending insight into the T cell priming that might be required to protect against EEHV disease and will guide the design of effective vaccine strategies.IMPORTANCE Endangered Asian elephants are facing many threats, including lethal hemorrhagic disease from elephant endotheliotropic herpesvirus (EEHV). EEHV usually establishes chronic, benign infections in mature Asian elephants but can be lethal to juvenile elephants in captivity and the wild. It is the leading cause of death in captive Asian elephants in North America and Europe. Despite availability of sensitive tests and protocols for treating EEHV associated illness, these measures are not always effective. The best line of defense would be a preventative vaccine. We interrogated normal healthy elephants previously infected with EEHV for T cell responses to 9 EEHV proteins predicted to induce cellular immune responses. Three proteins elicited IFN-gamma responses, suggesting their potential usefulness as vaccine candidates. Our work is the first to describe T cell responses to a member of the proposed fourth subfamily of mammalian herpesviruses, the Deltaherpesvirinae, within a host species in the clade Afrotheria. An EEHV vaccine would greatly contribute to the healthcare of Asian and African elephants that are also susceptible to this disease. PMID- 29263272 TI - RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5' Nontranslated Regions. AB - Coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71) are closely related enteroviruses that cause the same hand, foot, and mouth disease (HFMD), but neurological complications occur only very rarely in CV-A16 compared to EV-A71 infections. To elucidate host responses that may be able to explain these differences, we performed transcriptomic analysis and real-time quantitative PCR (RT-qPCR) in CV-A16-infected neuroblastoma cells (SK-N-SH), and the results showed that the radical S-adenosylmethionine domain containing 2 (RSAD2) was the highest upregulated gene in the antimicrobial pathway. Increased RSAD2 expression was correlated with reduced viral replication, while RSAD2 knockdown cells were correlated with increased replication. EV-A71 replication showed no apparent correlation to RSAD2 expressions. Absent in melanoma 2 (AIM2), which is associated with pyroptotic cell death, was upregulated in EV-A71-infected neurons but not in CV-A16 infection, suggesting that the AIM2 inflammasome played a significant role in suppressing EV-A71 replication. Chimeric viruses derived from CV-A16 and EV-A71 but containing swapped 5' nontranslated regions (5' NTRs) showed that RSAD2 expression/viral replication and AIM2 expression/viral replication patterns may be linked to the 5' NTRs of parental viruses. Differences in secondary structure of internal ribosomal entry sites within the 5' NTR may be responsible for these findings. Overall, our results suggest that CV-A16 and EV-A71 elicit different host responses to infection, which may help explain the apparent lower incidence of CV-A16-associated neurovirulence in HFMD outbreaks compared to EV-A71 infection.IMPORTANCE Although coxsackievirus A16 (CV A16) and enterovirus A17 (EV-A71) both cause hand, foot, and mouth disease, EV A71 has emerged as a leading cause of nonpolio, enteroviral fatal encephalomyelitis among young children. The significance of our research is in the identification of the possible differing and novel mechanisms of CV-A16 and EV-A71 inhibition in neuronal cells that may impact viral neuropathogenesis. We further showed that viral 5' NTRs may play significant roles in eliciting different host response mechanisms. PMID- 29263273 TI - Efficient Translation of Epstein-Barr Virus (EBV) DNA Polymerase Contributes to the Enhanced Lytic Replication Phenotype of M81 EBV. AB - Epstein-Barr virus (EBV) is linked to the development of both lymphoid and epithelial malignancies worldwide. The M81 strain of EBV, isolated from a Chinese patient with nasopharyngeal carcinoma (NPC), demonstrates spontaneous lytic replication and high-titer virus production in comparison to the prototype B95-8 EBV strain. Genetic comparisons of M81 and B95-8 EBVs were previously been performed in order to determine if the hyperlytic property of M81 is associated with sequence differences in essential lytic genes. EBV SM is an RNA-binding protein expressed during early lytic replication that is essential for virus production. We compared the functions of M81 SM and B95-8 SM and demonstrate that polymorphisms in SM do not contribute to the lytic phenotype of M81 EBV. However, the expression level of the EBV DNA polymerase protein was much higher in M81- than in B95-8-infected cells. The relative deficiency in the expression of B95-8 DNA polymerase was related to the B95-8 genome deletion, which truncates the BALF5 3' untranslated region (UTR). Similarly, the insertion of bacmid DNA into the widely used recombinant B95-8 bacmid creates an inefficient BALF5 3' UTR. We further showed that the while SM is required for and facilitates the efficient expression of both M81 and B95-8 mRNAs regardless of the 3' UTR, the BALF5 3' UTR sequence is important for BALF5 protein translation. These data indicate that the enhanced lytic replication and virus production of M81 compared to those of B95-8 are partly due to the robust translation of EBV DNA polymerase required for viral DNA replication due to a more efficient BALF5 3' UTR in M81.IMPORTANCE Epstein Barr virus (EBV) infects more than 90% of the human population, but the incidence of EBV-associated tumors varies greatly in different parts of the world. Thus, understanding the connection between genetic polymorphisms from patient isolates of EBV, gene expression phenotypes, and disease is important and may help in developing antiviral therapy. This study examines potential causes of the enhanced lytic replicative properties of M81 EBV isolated from a nasopharyngeal carcinoma (NPC) patient and provides new evidence for the role of the BALF5 gene 3' UTR sequence in DNA polymerase protein expression during lytic replication. Variation in the gene structure of the DNA polymerase gene may therefore contribute to lytic virus reactivation and pathogenesis. PMID- 29263274 TI - The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG I-Mediated Innate Immune Signaling. AB - Retinoic acid-inducible gene I (RIG-I) is a key pattern recognition receptor that senses viral RNA and interacts with the mitochondrial adaptor MAVS, triggering a signaling cascade that results in the production of type I interferons (IFNs). This signaling axis is initiated by K63-linked ubiquitination of RIG-I mediated by the E3 ubiquitin ligase TRIM25, which promotes the interaction of RIG-I with MAVS. USP15 was recently identified as an upstream regulator of TRIM25, stabilizing the enzyme through removal of degradative K48-linked polyubiquitin, ultimately promoting RIG-I-dependent cytokine responses. Here, we show that the E6 oncoprotein of human papillomavirus type 16 (HPV16) as well as of other HPV types form a complex with TRIM25 and USP15 in human cells. In the presence of E6, the K48-linked ubiquitination of TRIM25 was markedly increased, and in line with this, TRIM25 degradation was enhanced. Our results further showed that E6 inhibited the TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD dependent interaction with MAVS. HPV16 E6, but not E7, suppressed the RIG-I mediated induction of IFN-beta, chemokines, and IFN-stimulated genes (ISGs). Finally, CRISPR-Cas9 gene targeting in human keratinocytes showed that the TRIM25 RIG-I-MAVS triad is important for eliciting an antiviral immune response to HPV16 infection. Our study thus identifies a novel immune escape mechanism that is conserved among different HPV strains and further indicates that the RIG-I signaling pathway plays an important role in the innate immune response to HPV infection.IMPORTANCE Persistent infection and tumorigenesis by HPVs are known to require viral manipulation of a variety of cellular processes, including those involved in innate immune responses. Here, we show that the HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection, providing evidence that RIG-I, whose role in sensing RNA virus infections has been well characterized, also plays a crucial role in the antiviral host response to small DNA viruses of the Papillomaviridae family. PMID- 29263276 TI - Sex and genotype effects on nutrient-dependent fitness landscapes in Drosophila melanogaster. AB - The sexes perform different reproductive roles and have evolved sometimes strikingly different phenotypes. One focal point of adaptive divergence occurs in the context of diet and metabolism, and males and females of a range of species have been shown to require different nutrients to maximize their fitness. Biochemical analyses in Drosophila melanogaster have confirmed that dimorphism in dietary requirements is associated with molecular sex differences in metabolite titres. In addition, they also showed significant within-sex genetic variation in the metabolome. To date however, it is unknown whether this metabolic variation translates into differences in reproductive fitness. The answer to this question is crucial to establish whether genetic variation is selectively neutral or indicative of constraints on sex-specific physiological adaptation and optimization. Here we assay genetic variation in consumption and metabolic fitness effects by screening male and female fitness of thirty D. melanogaster genotypes across four protein-to-carbohydrate ratios. In addition to confirming sexual dimorphism in consumption and fitness, we find significant genetic variation in male and female dietary requirements. Importantly, these differences are not explained by feeding responses and probably reflect metabolic variation that, in turn, suggests the presence of genetic constraints on metabolic dimorphism. PMID- 29263275 TI - Deficiency of the IRE1alpha-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1. AB - Oncolytic virotherapy is an emerging treatment modality that uses replication competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (Togaviridae) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1alpha or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1alpha blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1alpha suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1alpha is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells.IMPORTANCE Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 in vitro and in vivo A survey of cancer tissue banks revealed that IRE1alpha, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future. PMID- 29263277 TI - Corals hosting symbiotic hydrozoans are less susceptible to predation and disease. AB - In spite of growing evidence that climate change may dramatically affect networks of interacting species, whether-and to what extent-ecological interactions can mediate species' responses to disturbances is an open question. Here we show how a largely overseen association such as that between hydrozoans and scleractinian corals could be possibly associated with a reduction in coral susceptibility to ever-increasing predator and disease outbreaks. We examined 2455 scleractinian colonies (from both Maldivian and the Saudi Arabian coral reefs) searching for non-random patterns in the occurrence of hydrozoans on corals showing signs of different health conditions (i.e. bleaching, algal overgrowth, corallivory and different coral diseases). We show that, after accounting for geographical, ecological and co-evolutionary factors, signs of disease and corallivory are significantly lower in coral colonies hosting hydrozoans than in hydrozoan-free ones. This finding has important implications for our understanding of the ecology of coral reefs, and for their conservation in the current scenario of global change, because it suggests that symbiotic hydrozoans may play an active role in protecting their scleractinian hosts from stresses induced by warming water temperatures. PMID- 29263278 TI - Balancing selection for aflatoxin in Aspergillus flavus is maintained through interference competition with, and fungivory by insects. AB - The role of microbial secondary metabolites in the ecology of the organisms that produce them remains poorly understood. Variation in aflatoxin production by Aspergillus flavus is maintained by balancing selection, but the ecological function and impact on fungal fitness of this compound are unknown. We hypothesize that balancing selection for aflatoxin production in A. flavus is driven by interaction with insects. To test this, we competed naturally occurring aflatoxigenic and non-aflatoxigenic fungal isolates against Drosophila larvae on medium containing 0-1750 ppb aflatoxin, using quantitative PCR to quantify A. flavus DNA as a proxy for fungal fitness. The addition of aflatoxin across this range resulted in a 26-fold increase in fungal fitness. With no added toxin, aflatoxigenic isolates caused higher mortality of Drosophila larvae and had slightly higher fitness than non-aflatoxigenic isolates. Additionally, aflatoxin production increased an average of 1.5-fold in the presence of a single larva and nearly threefold when the fungus was mechanically damaged. We argue that the role of aflatoxin in protection from fungivory is inextricably linked to its role in interference competition. Our results, to our knowledge, provide the first clear evidence of a fitness advantage conferred to A. flavus by aflatoxin when interacting with insects. PMID- 29263279 TI - Whole-genome resequencing reveals candidate mutations for pig prolificacy. AB - Changes in pig fertility have occurred as a result of domestication, but are not understood at the level of genetic variation. To identify variations potentially responsible for prolificacy, we sequenced the genomes of the highly prolific Taihu pig breed and four control breeds. Genes involved in embryogenesis and morphogenesis were targeted in the Taihu pig, consistent with the morphological differences observed between the Taihu pig and others during pregnancy. Additionally, excessive functional non-coding mutations have been specifically fixed or nearly fixed in the Taihu pig. We focused attention on an oestrogen response element (ERE) within the first intron of the bone morphogenetic protein receptor type-1B gene (BMPR1B) that overlaps with a known quantitative trait locus (QTL) for pig fecundity. Using 242 pigs from 30 different breeds, we confirmed that the genotype of the ERE was nearly fixed in the Taihu pig. ERE function was assessed by luciferase assays, examination of histological sections, chromatin immunoprecipitation, quantitative polymerase chain reactions, and western blots. The results suggest that the ERE may control pig prolificacy via the cis-regulation of BMPR1B expression. This study provides new insight into changes in reproductive performance and highlights the role of non-coding mutations in generating phenotypic diversity between breeds. PMID- 29263280 TI - Neonicotinoid pesticides and nutritional stress synergistically reduce survival in honey bees. AB - The honey bee is a major pollinator whose health is of global concern. Declines in bee health are related to multiple factors, including resource quality and pesticide contamination. Intensive agricultural areas with crop monocultures potentially reduce the quality and quantity of available nutrients and expose bee foragers to pesticides. However, there is, to date, no evidence for synergistic effects between pesticides and nutritional stress in animals. The neonicotinoids clothianidin (CLO) and thiamethoxam (TMX) are common systemic pesticides that are used worldwide and found in nectar and pollen. We therefore tested if nutritional stress (limited access to nectar and access to nectar with low-sugar concentrations) and sublethal, field-realistic acute exposures to two neonicotinoids (CLO and TMX at 1/5 and 1/25 of LD50) could alter bee survival, food consumption and haemolymph sugar levels. Bee survival was synergistically reduced by the combination of poor nutrition and pesticide exposure (-50%). Nutritional and pesticide stressors reduced also food consumption (-48%) and haemolymph levels of glucose (-60%) and trehalose (-27%). Our results provide the first demonstration that field-realistic nutritional stress and pesticide exposure can synergistically interact and cause significant harm to animal survival. These findings have implications for current pesticide risk assessment and pollinator protection. PMID- 29263281 TI - Arboreality constrains morphological evolution but not species diversification in vipers. AB - An increase in ecological opportunities, either through changes in the environment or acquisition of new traits, is frequently associated with an increase in species and morphological diversification. However, it is possible that certain ecological settings might prevent lineages from diversifying. Arboreality evolved multiple times in vipers, making them ideal organisms for exploring how potentially new ecological opportunities affect their morphology and speciation regimes. Arboreal snakes are frequently suggested to have a very specialized morphology, and being too large, too small, too heavy, or having short tails might be challenging for them. Using trait-evolution models, we show that arboreal vipers are evolving towards intermediate body sizes, with longer tails and more slender bodies than terrestrial vipers. Arboreality strongly constrains body size and circumference evolution in vipers, while terrestrial lineages are evolving towards a broader range of morphological variants. Trait dependent diversification models, however, suggest similar speciation rates between microhabitats. Thus, we show that arboreality might constrain morphological evolution but not necessarily affect the rates at which lineages generate new species. PMID- 29263282 TI - The perceptual shaping of anticipatory actions. AB - Humans display anticipatory motor responses to minimize the adverse effects of predictable perturbations. A widely accepted explanation for this behaviour relies on the notion of an inverse model that, learning from motor errors, anticipates corrective responses. Here, we propose and validate the alternative hypothesis that anticipatory control can be realized through a cascade of purely sensory predictions that drive the motor system, reflecting the causal sequence of the perceptual events preceding the error. We compare both hypotheses in a simulated anticipatory postural adjustment task. We observe that adaptation in the sensory domain, but not in the motor one, supports the robust and generalizable anticipatory control characteristic of biological systems. Our proposal unites the neurobiology of the cerebellum with the theory of active inference and provides a concrete implementation of its core tenets with great relevance both to our understanding of biological control systems and, possibly, to their emulation in complex artefacts. PMID- 29263283 TI - Infections on the move: how transient phases of host movement influence disease spread. AB - Animal movement impacts the spread of human and wildlife diseases, and there is significant interest in understanding the role of migrations, biological invasions and other wildlife movements in spatial infection dynamics. However, the influence of processes acting on infections during transient phases of host movement is poorly understood. We propose a conceptual framework that explicitly considers infection dynamics during transient phases of host movement to better predict infection spread through spatial host networks. Accounting for host transient movement captures key processes that occur while hosts move between locations, which together determine the rate at which hosts spread infections through networks. We review theoretical and empirical studies of host movement and infection spread, highlighting the multiple factors that impact the infection status of hosts. We then outline characteristics of hosts, parasites and the environment that influence these dynamics. Recent technological advances provide disease ecologists unprecedented ability to track the fine-scale movement of organisms. These, in conjunction with experimental testing of the factors driving infection dynamics during host movement, can inform models of infection spread based on constituent biological processes. PMID- 29263284 TI - Social class and wise reasoning about interpersonal conflicts across regions, persons and situations. AB - We propose that class is inversely related to a propensity for using wise reasoning (recognizing limits of their knowledge, consider world in flux and change, acknowledges and integrate different perspectives) in interpersonal situations, contrary to established class advantage in abstract cognition. Two studies-an online survey from regions differing in economic affluence (n = 2 145) and a representative in-lab study with stratified sampling of adults from working and middle-class backgrounds (n = 299)-tested this proposition, indicating that higher social class consistently related to lower levels of wise reasoning across different levels of analysis, including regional and individual differences, and subjective construal of specific situations. The results held across personal and standardized hypothetical situations, across self-reported and observed wise reasoning, and when controlling for fluid and crystallized cognitive abilities. Consistent with an ecological framework, class differences in wise reasoning were specific to interpersonal (versus societal) conflicts. These findings suggest that higher social class weighs individuals down by providing the ecological constraints that undermine wise reasoning about interpersonal affairs. PMID- 29263285 TI - Rabies elimination research: juxtaposing optimism, pragmatism and realism. AB - More than 100 years of research has now been conducted into the prevention, control and elimination of rabies with safe and highly efficacious vaccines developed for use in human and animal populations. Domestic dogs are a major reservoir for rabies, and although considerable advances have been made towards the elimination and control of canine rabies in many parts of the world, the disease continues to kill tens of thousands of people every year in Africa and Asia. Policy efforts are now being directed towards a global target of zero human deaths from dog-mediated rabies by 2030 and the global elimination of canine rabies. Here we demonstrate how research provides a cause for optimism as to the feasibility of these goals through strategies based around mass dog vaccination. We summarize some of the pragmatic insights generated from rabies epidemiology and dog ecology research that can improve the design of dog vaccination strategies in low- and middle-income countries and which should encourage implementation without further delay. We also highlight the need for realism in reaching the feasible, although technically more difficult and longer-term goal of global elimination of canine rabies. Finally, we discuss how research on rabies has broader relevance to the control and elimination of a suite of diseases of current concern to human and animal health, providing an exemplar of the value of a 'One Health' approach. PMID- 29263286 TI - Scale dependencies and generalism in host use shape virus prevalence. AB - Processes that generate the distribution of pathogens and their interactions with hosts are not insensitive to changes in spatial scale. Spatial scales and species traits are often selected intentionally, based on practical considerations, ignoring biases that the scale and type of observation may introduce. Specifically, these biases might change the interpretation of disease-diversity relationships that are reported as either 'dilution' or 'amplification' effects. Here, we combine field data of a host-pathogen community with empirical models to test the effects that (i) spatial scale and (ii) host range have on the relationship between plant-virus infection prevalence and diversity. We show that prevalence-diversity relationships are scale-dependent and can produce opposite effects associated with different habitats at sub-ecosystem scales. The total number of host species of each virus reflected generalism at the ecosystem scale. However, plasticity in host range resembled habitat-specific specialization and also changed model predictions. We show that habitat heterogeneity, ignored at larger (ecosystem) spatial scales, influences pathogen distributions. Hence, understanding disease distributions and the evolution of pathogens requires reconciling specific hypotheses of the study with an appropriate spatial scale, or scales, and consideration of traits, such as host range, that might strongly contribute to biotic interactions. PMID- 29263287 TI - Bathyal feasting: post-spawning squid as a source of carbon for deep-sea benthic communities. AB - In many oceanic carbon budgets there is a discrepancy between the energetic requirements of deep-sea benthic communities and the supply of organic matter. This suggests that there are unidentified and unmeasured food sources reaching the seafloor. During 11 deep-sea remotely operated vehicle (ROV) surveys in the Gulf of California, the remains (squid carcasses and hatched-out egg sheets) of 64 post-brooding squid were encountered. As many as 36 remains were encountered during a single dive. To our knowledge this is one of the largest numbers of natural food falls of medium-size deep-sea nekton described to date. Various deep sea scavengers (Ophiuroidea, Holothuroidea, Decapoda, Asteroidea, Enteropneusta) were associated with the remains. Although many of the 80 examined ROV dives did not encounter dead squids or egg sheets (n = 69), and the phenomenon may be geographically and temporally restricted, our results show that dead, sinking squid transport carbon from the water column to the seafloor in the Gulf of California. Based on food fall observations from individual dives, we estimate that annual squid carcass depositions may regionally contribute from 0.05 to 12.07 mg C m-2 d-1 to the seafloor in the areas where we observed the remains. The sinking of squid carcasses may constitute a significant but underestimated carbon vector between the water column and the seafloor worldwide, because squid populations are enormous and are regionally expanding as a result of climate change and pressure on fish stocks. In the future, standardized methods and surveys in geographical regions that have large squid populations will be important for investigating the overall contribution of squid falls to regional carbon budgets. PMID- 29263288 TI - Introducing forensic entomology in cases of suspected animal neglect. AB - Cases of arthropod-infested, abandoned or abused animals are sometimes brought to the attention of veterinarians by animal welfare authorities, with the requirement for a full postmortem examination towards criminal or civil proceedings. In these situations, entomology is an important support tool for the pathologists' investigation since the presence of arthropod life cycle stages serve as reliable forensic markers, especially for blowflies which form the first waves of activity following death. In the present study, 70 cadavers from a total of 544 referred to the Institute of Veterinary Science, University of Liverpool, between 2009 and 2014 displayed evidence of infestation. Here, the authors introduce principles of applied entomology and simplified approaches for estimating the minimum time since death, relevant in the context of routine submissions and the broad remit of individual cases. Despite often limited availability of scene of the crime and local thermal data, the interpretation of the minimum postmortem interval has nonetheless proved valuable as an adjunct to the expert pathology report. However, future developments and enhanced accuracy in this area of animal welfare require resource and training in expertise, and agreed standardisation of both laboratory and field procedures. PMID- 29263289 TI - Study of ingredients and nutrient composition of commercially available treats for dogs. AB - Forty-one dog treats were selected from the market with the aim of providing more insight into supplemental pet food composition. Thirty-two products (four biscuits, nine tender treats, two meat-based strips, five rawhides, eight chewable sticks, four dental care sticks) were analysed for proximate nutrient composition and quantification of minerals, hydroxyproline (Hyp), starch, glucose, fructose and sucrose. Labelled ingredients were often expressed as non specific categories. A treat supplied a mean of 332.0+/-39.2 kcal metabolisable energy (ME)/100 g, and the most energy-dense product was a tender treat (475.0 kcal ME/100 g). Small dogs receive the highest percentage of maintenance energy requirement when producers' feeding instructions are followed. Treat categories revealed variability in dry matter, crude protein, ash, Hyp and starch. Rawhides showed the highest Hyp content. Simple sugars were identified in most treats, and sucrose was the most prevalent. Results of the study suggest treat labelling should include more information on the ingredients used, and the varying nutrient and caloric density of treats should be considered. Specific attention should be given to the use of treats in dogs with specific ingredient sensitivities or nutrient considerations. PMID- 29263290 TI - Heightened risk of canine chocolate exposure at Christmas and Easter. PMID- 29263291 TI - Antimicrobial use in dairy cattle: 'what gets measured gets improved'. PMID- 29263293 TI - Twin photonic nanojets generated from coherent illumination of microscale sphere and cylinder. AB - Photonic nanojets, highly focused beams of light created by planar illumination of a microsphere, have been shown to produce narrow subwavelength beams over distances of several wavelengths in the near field. In this work, we investigate the generation of twin photonic nanojets through the illumination of a microsphere or cylinder from two coherent sources with relative phase shift. Under these conditions, symmetric twin nanojets separated by an intensity null can be generated. Compared to a photonic nanojet, the twin nanojets can achieve an even smaller subwavelength beam, and have the added advantage of having more complex intensity profiles that can be controlled by multiple parameters. Using both finite-difference time-domain and Mie theory models, the width, length, and intensity enhancement factor of the nanojet geometry are found to be functions of the phase, angle offsets, and particle geometry. Such twin photonic nanojets can find applications in optical trapping, manipulation, nanolithography, and enhancement of nonlinear optical properties. PMID- 29263292 TI - Quantitative analysis of antimicrobial use on British dairy farms. AB - Antimicrobial resistance has been reported to represent a growing threat to both human and animal health, and concerns have been raised around levels of antimicrobial usage (AMU) within the livestock industry. To provide a benchmark for dairy cattle AMU and identify factors associated with high AMU, data from a convenience sample of 358 dairy farms were analysed using both mass-based and dose-based metrics following standard methodologies proposed by the European Surveillance of Veterinary Antimicrobial Consumption project. Metrics calculated were mass (mg) of antimicrobial active ingredient per population correction unit (mg/PCU), defined daily doses (DDDvet) and defined course doses (DCDvet). AMU on dairy farms ranged from 0.36 to 97.79 mg/PCU, with a median and mean of 15.97 and 20.62 mg/PCU, respectively. Dose-based analysis ranged from 0.05 to 20.29 DDDvet, with a median and mean of 4.03 and 4.60 DDDvet, respectively. Multivariable analysis highlighted that usage of antibiotics via oral and footbath routes increased the odds of a farm being in the top quartile (>27.9 mg/PCU) of antimicrobial users. While dairy cattle farm AMU appeared to be lower than UK livestock average, there were a selection of outlying farms with extremely high AMU, with the top 25 per cent of farms contributing greater than 50 per cent of AMU by mass. Identification of these high use farms may enable targeted AMU reduction strategies and facilitate a significant reduction in overall dairy cattle AMU. PMID- 29263294 TI - Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation. AB - Cardiac hypertrophic remodeling during chronic hemodynamic stress is associated with a switch in preferred energy substrate from fatty acids to glucose, usually considered to be energetically favorable. The mechanistic interrelationship between altered energy metabolism, remodeling, and function remains unclear. The ROS-generating NADPH oxidase-4 (Nox4) is upregulated in the overloaded heart, where it ameliorates adverse remodeling. Here, we show that Nox4 redirects glucose metabolism away from oxidation but increases fatty acid oxidation, thereby maintaining cardiac energetics during acute or chronic stresses. The changes in glucose and fatty acid metabolism are interlinked via a Nox4-ATF4 dependent increase in the hexosamine biosynthetic pathway, which mediates the attachment of O-linked N-acetylglucosamine (O-GlcNAcylation) to the fatty acid transporter CD36 and enhances fatty acid utilization. These data uncover a potentially novel redox pathway that regulates protein O-GlcNAcylation and reprograms cardiac substrate metabolism to favorably modify adaptation to chronic stress. Our results also suggest that increased fatty acid oxidation in the chronically stressed heart may be beneficial. PMID- 29263295 TI - Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15. AB - The genome-wide activity of transcription factors (TFs) on multiple regulatory elements precludes their use as gene-specific regulators. Here we show that ectopic expression of a TF in a cell-specific context can be used to silence the expression of a specific gene as a therapeutic approach to regulate gene expression in human disease. We selected the TF Kruppel-like factor 15 (KLF15) based on its putative ability to recognize a specific DNA sequence motif present in the rhodopsin (RHO) promoter and its lack of expression in terminally differentiated rod photoreceptors (the RHO-expressing cells). Adeno-associated virus (AAV) vector-mediated ectopic expression of KLF15 in rod photoreceptors of pigs enables Rho silencing with limited genome-wide transcriptional perturbations. Suppression of a RHO mutant allele by KLF15 corrects the phenotype of a mouse model of retinitis pigmentosa with no observed toxicity. Cell-specific context conditioning of TF activity may prove a novel mode for somatic gene targeted manipulation. PMID- 29263296 TI - NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. AB - Childhood obesity is a major global concern, with over 50 million children now classified as obese. Obesity has been linked to the development of numerous chronic inflammatory diseases, including type 2 diabetes and multiple cancers. NK cells are a subset of innate effector cells, which play an important role in the regulation of adipose tissue and antitumor immunity. NK cells can spontaneously kill transformed cells and coordinate subsequent immune responses through their production of cytokines. We investigated the effect of obesity on NK cells in a cohort of obese children, compared to children with a healthy weight. We demonstrated a reduction in peripheral NK cell frequencies in childhood obesity and inverse correlations with body mass index and insulin resistance. Compared with NK cells from children with normal weight, we show increased NK cell activation and metabolism in obese children (PD-1, mTOR activation, ECAR, and mitochondrial ROS), along with a reduced capacity to respond to stimulus, ultimately leading to loss of function (proliferation and tumor lysis). Collectively we show that NK cells from obese children are activated, metabolically stressed, and losing the ability to perform their basic duties. Paired with the reduction in NK cell frequencies in childhood obesity, this suggests that the negative effect on antitumor immunity is present early in the life course of obesity and certainly many years before the development of overt malignancies. PMID- 29263297 TI - Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown etiology characterized by a compositionally and mechanically altered extracellular matrix. Poor understanding of the origin of alpha-smooth muscle actin (alpha-SMA) expressing myofibroblasts has hindered curative therapies. Though proposed as a source of myofibroblasts in mammalian tissues, identification of microvascular pericytes (PC) as contributors to alpha-SMA-expressing populations in human IPF and the mechanisms driving this accumulation remain unexplored. Here, we demonstrate enhanced detection of alpha-SMA+ cells coexpressing the PC marker neural/glial antigen 2 in the human IPF lung. Isolated human PC cultured on decellularized IPF lung matrices adopt expression of alpha-SMA, demonstrating that these cells undergo phenotypic transition in response to direct contact with the extracellular matrix (ECM) of the fibrotic human lung. Using potentially novel human lung-conjugated hydrogels with tunable mechanical properties, we decoupled PC responses to matrix composition and stiffness to show that alpha SMA+ PC accumulate in a mechanosensitive manner independent of matrix composition. PC activated with TGF-beta1 remodel the normal lung matrix, increasing tissue stiffness to facilitate the emergence of alpha-SMA+ PC via MKL 1/MTRFA mechanotranduction. Nintedanib, a tyrosine-kinase inhibitor approved for IPF treatment, restores the elastic modulus of fibrotic lung matrices to reverse the alpha-SMA+ phenotype. This work furthers our understanding of the role that microvascular PC play in the evolution of IPF, describes the creation of an ex vivo platform that advances the study of fibrosis, and presents a potentially novel mode of action for a commonly used antifibrotic therapy that has great relevance for human disease. PMID- 29263298 TI - Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects. AB - Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Delta9) increases abundance of With-No-Lysine [K] Kinase 4 (WNK4), with excessive activation of the downstream Sterile 20 (STE20)/SPS-1-related proline/alanine-rich kinase (SPAK) increasing phosphorylation of the Na+-Cl- cotransporter (NCC). CUL3-Delta9 promotes its own degradation via autoubiquitination, leading to the hypothesis that Cul3 haploinsufficiency causes FHHt. To directly test this, we generated Cul3 heterozygous mice (CUL3-Het), and Cul3 heterozygotes also expressing CUL3-Delta9 (CUL3-Het/Delta9), using an inducible renal epithelial-specific system. Endogenous CUL3 was reduced to 50% in both models, and consistent with autoubiquitination, CUL3-Delta9 protein was undetectable in CUL3-Het/Delta9 kidneys unless primary renal epithelia cells were cultured. Abundances of WNK4 and phosphorylated NCC did not differ between control and CUL3-Het mice, but they were elevated in CUL3-Het/Delta9 mice, which also displayed higher plasma [K+] and blood pressure. Abundance of phosphorylated Na+-K+-2Cl- cotransporter (NKCC2) was also increased, which may contribute to the severity of CUL3-Delta9-mediated FHHt. WNK4 and SPAK localized to puncta in NCC positive segments but not in NKCC2-positive segments, suggesting differential effects of CUL3-Delta9. These results indicate that Cul3 haploinsufficiency does not cause FHHt, but dominant effects of CUL3-Delta9 are required. PMID- 29263299 TI - Nrf2/antioxidant pathway mediates beta cell self-repair after damage by high-fat diet-induced oxidative stress. AB - Many theories have been advanced to better understand why beta cell function and structure relentlessly deteriorate during the course of type 2 diabetes (T2D). These theories include inflammation, apoptosis, replication, neogenesis, autophagy, differentiation, dedifferentiation, and decreased levels of insulin gene regulatory proteins. However, none of these have considered the possibility that endogenous self-repair of existing beta cells may be an important factor. To examine this hypothesis, we conducted studies with female Zucker diabetic fatty rats fed a high-fat diet (HFD) for 1, 2, 4, 7, 9, 18, or 28 days, followed by a return to regular chow for 2-3 weeks. Repair was defined as reversal of elevated blood glucose and of inappropriately low blood insulin levels caused by a HFD, as well as reversal of structural damage visualized by imaging studies. We observed evidence of functional beta cell damage after a 9-day exposure to a HFD and then repair after 2-3 weeks of being returned to normal chow (blood glucose [BG] = 348 +/- 30 vs. 126 +/- 3; mg/dl; days 9 vs. 23 day, P < 0.01). After 18- and 28-day exposure to a HFD, damage was more severe and repair was less evident. Insulin levels progressively diminished with 9-day exposure to a HFD; after returning to a regular diet, insulin levels rebounded toward, but did not reach, normal values. Increase in beta cell mass was 4-fold after 9 days and 3-fold after 18 days, and there was no increase after 28 days of a HFD. Increases in beta cell mass during a HFD were not different when comparing values before and after a return to regular diet within the 9-, 18-, or 28-day studies. No changes were observed in apoptosis or beta cell replication. Formation of intracellular markers of oxidative stress, intranuclear translocation of Nrf2, and formation of intracellular antioxidant proteins indicated the participation of HFD/oxidative stress induction of the Nrf2/antioxidant pathway. Flow cytometry-based assessment of beta cell volume, morphology, and insulin-specific immunoreactivity, as well as ultrastructural analysis by transmission electron microscopy, revealed that short-term exposure to a HFD produced significant changes in beta cell morphology and function that are reversible after returning to regular chow. These results suggest that a possible mechanism mediating the ability of beta cells to self repair after a short-term exposure to a HFD is the activation of the Nrf2/antioxidant pathway. PMID- 29263300 TI - Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms. AB - The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-beta. Chromatin IP assay of the PDGFR-beta promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-alpha protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-alpha lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis. PMID- 29263301 TI - Fully automated, deep learning segmentation of oxygen-induced retinopathy images. AB - Oxygen-induced retinopathy (OIR) is a widely used model to study ischemia-driven neovascularization (NV) in the retina and to serve in proof-of-concept studies in evaluating antiangiogenic drugs for ocular, as well as nonocular, diseases. The primary parameters that are analyzed in this mouse model include the percentage of retina with vaso-obliteration (VO) and NV areas. However, quantification of these two key variables comes with a great challenge due to the requirement of human experts to read the images. Human readers are costly, time-consuming, and subject to bias. Using recent advances in machine learning and computer vision, we trained deep learning neural networks using over a thousand segmentations to fully automate segmentation in OIR images. While determining the percentage area of VO, our algorithm achieved a similar range of correlation coefficients to that of expert inter-human correlation coefficients. In addition, our algorithm achieved a higher range of correlation coefficients compared with inter-expert correlation coefficients for quantification of the percentage area of neovascular tufts. In summary, we have created an open-source, fully automated pipeline for the quantification of key values of OIR images using deep learning neural networks. PMID- 29263302 TI - Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. AB - Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care. PMID- 29263303 TI - Intestinal, but not hepatic, ChREBP is required for fructose tolerance. AB - Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance. PMID- 29263304 TI - Dengue vaccine-induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies. AB - Declining levels of maternal antibodies were shown to sensitize infants born to dengue-immune mothers to severe disease during primary infection, through the process of antibody-dependent enhancement of infection (ADE). With the recent approval for human use of Sanofi-Pasteur's chimeric dengue vaccine CYD-TDV and several vaccine candidates in clinical development, the scenario of infants born to vaccinated mothers has become a reality. This raises 2 questions: will declining levels of maternal vaccine-induced antibodies cause ADE; and, will maternal antibodies interfere with vaccination efficacy in the infant? To address these questions, the above scenario was modeled in mice. Type I IFN-deficient female mice were immunized with live attenuated DENV2 PDK53, the core component of the tetravalent DENVax candidate currently under clinical development. Pups born to PDK53-immunized dams acquired maternal antibodies that strongly neutralized parental strain 16681, but not the heterologous DENV2 strain D2Y98P PP1, and instead caused ADE during primary infection with this strain. Furthermore, pups failed to seroconvert after PDK53 vaccination, owing to maternal antibody interference. However, a cross-protective multifunctional CD8+ T cell response did develop. Thus, our work advocates for the development of dengue vaccine candidates that induce protective CD8+ T cells despite the presence of enhancing, interfering maternal antibodies. PMID- 29263305 TI - Therapeutic drug repositioning using personalized proteomics of liquid biopsies. AB - BACKGROUND: In patients with limited response to conventional therapeutics, repositioning of already approved drugs can bring new, more effective options. Current drug repositioning methods, however, frequently rely on retrospective computational analyses and genetic testing - time consuming methods that delay application of repositioned drugs. Here, we show how proteomic analysis of liquid biopsies successfully guided treatment of neovascular inflammatory vitreoretinopathy (NIV), an inherited autoinflammatory disease with otherwise poor clinical outcomes. METHODS: Vitreous biopsies from NIV patients were profiled by an antibody array for expression of 200 cytokine-signaling proteins. Non-NIV controls were compared with NIV samples from various stages of disease progression. Patterns were identified by 1-way ANOVA, hierarchical clustering, and pathway analysis. Subjects treated with repositioned therapies were followed longitudinally. RESULTS: Proteomic profiles revealed molecular pathways in NIV pathologies and implicated superior and inferior targets for therapy. Anti-VEGF injections resolved vitreous hemorrhages without the need for vitrectomy surgery. Methotrexate injections reversed inflammatory cell reactions without the side effects of corticosteroids. Anti-IL-6 therapy prevented recurrent fibrosis and retinal detachment where all prior antiinflammatory interventions had failed. The cytokine array also showed that TNF-alpha levels were normal and that corticosteroid-sensitive pathways were absent in fibrotic NIV, helping explain prior failure of these conventional therapeutic approaches. CONCLUSIONS: Personalized proteomics can uncover highly personalized therapies for autoinflammatory disease that can be timed with specific pathologic activities. This precision medicine strategy can also help prevent delivery of ineffective drugs. Importantly, proteomic profiling of liquid biopsies offers an endpoint analysis that can directly guide treatment using available drugs. PMID- 29263306 TI - Computational analysis of antibody dynamics identifies recent HIV-1 infection. AB - Accurate HIV-1 incidence estimation is critical to the success of HIV-1 prevention strategies. Current assays are limited by high false recent rates (FRRs) in certain populations and a short mean duration of recent infection (MDRI). Dynamic early HIV-1 antibody response kinetics were harnessed to identify biomarkers for improved incidence assays. We conducted retrospective analyses on circulating antibodies from known recent and longstanding infections and evaluated binding and avidity measurements of Env and non-Env antigens and multiple antibody forms (i.e., IgG, IgA, IgG3, IgG4, dIgA, and IgM) in a diverse panel of 164 HIV-1-infected participants (clades A, B, C). Discriminant function analysis identified an optimal set of measurements that were subsequently evaluated in a 324-specimen blinded biomarker validation panel. These biomarkers included clade C gp140 IgG3, transmitted/founder clade C gp140 IgG4 avidity, clade B gp140 IgG4 avidity, and gp41 immunodominant region IgG avidity. MDRI was estimated at 215 day or alternatively, 267 days. FRRs in untreated and treated subjects were 5.0% and 3.6%, respectively. Thus, computational analysis of dynamic HIV-1 antibody isotype and antigen interactions during infection enabled design of a promising HIV-1 recency assay for improved cross-sectional incidence estimation. PMID- 29263307 TI - Alveolar injury and regeneration following deletion of ABCA3. AB - Adaptation to air breathing after birth is dependent upon the synthesis and secretion of pulmonary surfactant by alveolar type 2 (AT2) cells. Surfactant, a complex mixture of phospholipids and proteins, is secreted into the alveolus, where it reduces collapsing forces at the air-liquid interface to maintain lung volumes during the ventilatory cycle. ABCA3, an ATP-dependent Walker domain containing transport protein, is required for surfactant synthesis and lung function at birth. Mutations in ABCA3 cause severe surfactant deficiency and respiratory failure in newborn infants. We conditionally deleted the Abca3 gene in AT2 cells in the mature mouse lung. Loss of ABCA3 caused alveolar cell injury and respiratory failure. ABCA3-related lung dysfunction was associated with surfactant deficiency, inflammation, and alveolar-capillary leak. Extensive but incomplete deletion of ABCA3 caused alveolar injury and inflammation, and it initiated proliferation of progenitor cells, restoring ABCA3 expression, lung structure, and function. M2-like macrophages were recruited to sites of AT2 cell proliferation during the regenerative process and were present in lung tissue from patients with severe lung disease caused by mutations in ABCA3. The remarkable and selective regeneration of ABCA3-sufficient AT2 progenitor cells provides plausible approaches for future correction of ABCA3 and other genetic disorders associated with surfactant deficiency and acute interstitial lung disease. PMID- 29263308 TI - Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectories. AB - Heterogeneity within and among tumors in a metastatic cancer patient is a well established phenomenon that may confound treatment and accurate prognosis. Here, we used whole-exome sequencing to survey metastatic breast cancer tumors from 5 patients in a rapid autopsy program to construct the origin and genetic development of metastases. Metastases were obtained from 5 breast cancer patients using a rapid autopsy protocol and subjected to whole-exome sequencing. Metastases were evaluated for sharing of somatic mutations, correlation of copy number variation and loss of heterozygosity, and genetic similarity scores. Pathological features of the patients' disease were assessed by immunohistochemical analyses. Our data support a monoclonal origin of metastasis in 3 cases, but in 2 cases, metastases arose from at least 2 distinct subclones in the primary tumor. In the latter 2 cases, the primary tumor presented with mixed histologic and pathologic features, suggesting early divergent evolution within the primary tumor with maintenance of metastatic capability in multiple lineages. We used genetic and histopathological evidence to demonstrate that metastases can be derived from a single or multiple independent clones within a primary tumor. This underscores the complexity of breast cancer clonal evolution and has implications for how best to determine and implement therapies for early- and late-stage disease. PMID- 29263309 TI - C5aR1 promotes acute pyelonephritis induced by uropathogenic E. coli. AB - C5a receptor 1 (C5aR1) is a G protein-coupled receptor for C5a and also an N linked glycosylated protein. In addition to myeloid cells, C5aR1 is expressed on epithelial cells. In this study, we examined the role of C5aR1 in bacterial adhesion/colonization of renal tubular epithelium and addressed the underlying mechanisms of this role. We show that acute kidney infection was significantly reduced in mice with genetic deletion or through pharmacologic inhibition of C5aR1 following bladder inoculation with uropathogenic E. coli (UPEC). This was associated with reduced expression of terminal alpha-mannosyl residues (Man; a ligand for type 1 fimbriae of E. coli) on the luminal surface of renal tubular epithelium and reduction of early UPEC colonization in these mice. Confocal microscopy demonstrated that UPEC bind to Man on the luminal surface of renal tubular epithelium. In vitro analyses showed that C5a stimulation enhances Man expression in renal tubular epithelial cells and subsequent bacterial adhesion, which, at least in part, is dependent on TNF-alpha driven by C5aR1-mediated intracellular signaling. Our findings demonstrate a previously unknown pathogenic role for C5aR1 in acute pyelonephritis, proposing a potentially novel mechanism by which C5a/C5aR1 signaling mediates upregulation of carbohydrate ligands on renal tubules to facilitate UPEC adhesion. PMID- 29263310 TI - Eosinophils promote inducible NOS-mediated lung allograft acceptance. AB - Lungs allografts have worse long-term survival compared with other organ transplants. This is most likely due to their unique immunoregulation that may not respond to traditional immunosuppression. For example, local NO generation by inducible NOS (iNOS) is critical for lung allograft acceptance but associates with rejection of other solid organs. The source of NO in accepting lung allografts remains unknown. Here, we report that, unlike the case for other pulmonary processes in which myeloid cells control NO generation, recipient derived eosinophils play a critical and nonredundant role in iNOS-mediated lung allograft acceptance. Depletion of eosinophils reduces NO levels to that of recipients with global deletion of iNOS and leads to a costimulatory blockade resistant form of rejection. Furthermore, NO production by eosinophils depends on Th1 polarization by inflammatory mediators, such as IFN-gamma and TNF-alpha. Neutralization of such mediators abrogates eosinophil suppressive capacity. Our data point to what we believe to be a unique and previously unrecognized role of eosinophil polarization in mediating allograft tolerance and put into perspective the use of high-dose eosinophil-ablating corticosteroids after lung transplantation. PMID- 29263311 TI - Identification of ion-channel modulators that protect against aminoglycoside induced hair cell death. AB - Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red-conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem. PMID- 29263312 TI - beta-Arrestin2 mediates progression of murine primary myelofibrosis. AB - Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. beta-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, beta-arrestin2 (betaarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between betaarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor betaarr2-knockout (betaarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted betaarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of betaarr2-/- cells. In order to assess the effect of acute loss of betaarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional betaarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic betaarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that betaarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease. PMID- 29263313 TI - Disseminated Nocardiosis Associated with Treatment with Infliximab in a Patient with Ulcerative Colitis. AB - BACKGROUND Opportunistic infections may occur when patients with inflammatory bowel disease (IBD) are treated with tumor necrosis factor (TNF)-alpha inhibitors. With the increasing use of new immunosuppressant drugs, the incidence of opportunistic or atypical infections is also increasing, including with Nocardia spp. A high level of awareness of atypical infections is warranted in immunosuppressed patients. CASE REPORT A 57-year-old female African American, with a past medical history of ulcerative colitis (UC) and arthritis, was treated with infliximab and prednisone. She presented to the emergency department with acute onset of chest pain, shortness of breath, and a two-week history of a productive cough. Examination showed hypoxia, tachypnea, decreased and coarse bilateral breath sounds, and fluctuant, tender, erythematous masses on her trunk and groin. Laboratory investigations showed a leukocytosis with a left shift. She was initially treated for presumed community-acquired pneumonia (CAP). However, blood cultures grew Nocardia farcinica and treatment with trimethoprim sulfamethoxazole (TMP-SMX) was begun, which was complicated by severe symptomatic hyponatremia. Following recovery from infection and resolution of the hyponatremia, the patient was discharged to a senior care facility, but with continued treatment with TMP-SMX. CONCLUSIONS To our knowledge, this is the first case of disseminated nocardiosis associated with infliximab treatment in a patient with ulcerative colitis. As with other forms of immunosuppressive therapy, patients who are treated with infliximab should be followed closely due to the increased risk of atypical infections. When initiating antibiotic therapy, careful monitoring of possible side effects should be done. PMID- 29263314 TI - High RNA-Binding Motif Protein 3 (RBM3) Expression is Independently Associated with Prolonged Overall Survival in Intestinal-Type Gastric Cancer. AB - BACKGROUND High expression of the RNA-binding motif protein 3 (RBM3) has previously been described as a favorable clinicopathological factor in several cancers, including ovarian cancer, colorectal cancer, prostate cancer, and breast cancer. The aim of this study was to examine the prognostic implications of RBM3 expression in gastric cancer. MATERIAL AND METHODS Immunohistochemical analysis of RBM3 expression from 123 patients showed that upregulated RBM3 was mainly found in intestinal-type (n=78, case=59) cancer compared to diffuse-type (n=15, case=8) and mixed-type (n=30, case=17). There were no significant differences in RBM3 expression in subgroups of clinicopathological parameters. RBM3 expression was strongly associated with p53 but not with Ki-67. Cox univariate analysis revealed that high RBM3 expression was closely associated with prolonged overall survival time (HR 0.504, 95% CI: 0.300-0.845, P=0.009). Multivariate analysis remained supporting these associations when adjusted for age, sex, tumor size, differentiation grade, TNM stage, lymphatic invasion, and Ki-67 and p53 expression (HR 0.541, 95% CI: 0.308-0.952, P=0.033), where Lauren grade was not included. Lauren grade was the only factor with independent prognostic significance in a model adjusted for all factors. These results were confirmed by Kaplan-Meier analysis. RESULTS Therefore, together with the upregulated RBM3 expression observed in intestinal-type of Lauren grade, we suggest that upregulation of RBM3 is partially responsible for the favorable overall survival in cases with intestinal Lauren grade, which is demonstrated by the box diagram and Kaplan-Meier analysis. Our results showed that high RBM3 expression in gastric cancer is mainly found in intestinal-type of Lauren grade and is associated with longer overall survival time. CONCLUSIONS We found that RBM3 is a potential biomarker of good prognosis and deserves further validation. PMID- 29263315 TI - Author Correction: Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides. AB - The original version of this article contained an error in Fig. 5c. The label for the back series of columns was incorrectly given as '1.5 mM pH 2', rather than the correct '1.5 mM pH 7'. This has now been corrected in both the PDF and HTML versions of the article. PMID- 29263316 TI - Author Correction: Herbivores rescue diversity in warming tundra by modulating trait-dependent species losses and gains. AB - The original version of this Article contained errors in Figure 2. The dark green symbols on the scatter plot were light green, and vice versa. These errors have now been corrected in the PDF and HTML versions of the Article. PMID- 29263317 TI - Author Correction: FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2. AB - The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following: This study was in part supported by the Swiss National Foundation Grant No.: 31003A-156023 to Alessandro Sartori. PMID- 29263318 TI - The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. AB - Dopamine neurotransmission is highly dysregulated by the psychostimulant methamphetamine, a substrate for the dopamine transporter (DAT). Through interactions with DAT, methamphetamine increases extracellular dopamine levels in the brain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (sigma1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for sigma1R regulation of dopamine neurotransmission in response to methamphetamine. We found that sigma1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that sigma1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, sigma1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the sigma1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for sigma1R regulation of dopamine neurotransmission and support the sigma1R as a putative target for the treatment of methamphetamine addiction. PMID- 29263319 TI - PCH1 and PCHL promote photomorphogenesis in plants by controlling phytochrome B dark reversion. AB - Phytochrome B (phyB) is the primary red light photoreceptor in plants, and regulates both growth and development. The relative levels of phyB in the active state are determined by the light conditions, such as direct sunlight or shade, but are also affected by light-independent dark reversion. Dark reversion is a temperature-dependent thermal relaxation process, by which phyB reverts from the active to the inactive state. Here, we show that the homologous phyB-binding proteins PCH1 and PCHL suppress phyB dark reversion, resulting in plants with dramatically enhanced light sensitivity. Moreover, far-red and blue light upregulate the expression of PCH1 and PCHL in a phyB independent manner, thereby increasing the response to red light perceived by phyB. PCH1 and PCHL therefore provide a node for the molecular integration of different light qualities by regulation of phyB dark reversion, allowing plants to adapt growth and development to the ambient environment. PMID- 29263321 TI - Fundamental interplay between anionic/cationic redox governing the kinetics and thermodynamics of lithium-rich cathodes. AB - Reversible anionic redox has rejuvenated the search for high-capacity lithium-ion battery cathodes. Real-world success necessitates the holistic mastering of this electrochemistry's kinetics, thermodynamics, and stability. Here we prove oxygen redox reactivity in the archetypical lithium- and manganese-rich layered cathodes through bulk-sensitive synchrotron-based spectroscopies, and elucidate their complete anionic/cationic charge-compensation mechanism. Furthermore, via various electroanalytical methods, we answer how the anionic/cationic interplay governs application-wise important issues-namely sluggish kinetics, large hysteresis, and voltage fade-that afflict these promising cathodes despite widespread industrial and academic efforts. We find that cationic redox is kinetically fast and without hysteresis unlike sluggish anions, which furthermore show different oxidation vs. reduction potentials. Additionally, more time spent with fully oxidized oxygen promotes voltage fade. These fundamental insights about anionic redox are indispensable for improving lithium-rich cathodes. Moreover, our methodology provides guidelines for assessing the merits of existing and future anionic redox based high-energy cathodes, which are being discovered rapidly. PMID- 29263320 TI - Dynamic intramolecular regulation of the histone chaperone nucleoplasmin controls histone binding and release. AB - Nucleoplasmin (Npm) is a highly conserved histone chaperone responsible for the maternal storage and zygotic release of histones H2A/H2B. Npm contains a pentameric N-terminal core domain and an intrinsically disordered C-terminal tail domain. Though intrinsically disordered regions are common among histone chaperones, their roles in histone binding and chaperoning remain unclear. Using an NMR-based approach, here we demonstrate that the Xenopus laevis Npm tail domain controls the binding of histones at its largest acidic stretch (A2) via direct competition with both the C-terminal basic stretch and basic nuclear localization signal. NMR and small-angle X-ray scattering (SAXS) structural analyses allowed us to construct models of both the tail domain and the pentameric complex. Functional analyses demonstrate that these competitive intramolecular interactions negatively regulate Npm histone chaperone activity in vitro. Together these data establish a potentially generalizable mechanism of histone chaperone regulation via dynamic and specific intramolecular shielding of histone interaction sites. PMID- 29263323 TI - Reduced biomass burning emissions reconcile conflicting estimates of the post 2006 atmospheric methane budget. AB - Several viable but conflicting explanations have been proposed to explain the recent ~8 p.p.b. per year increase in atmospheric methane after 2006, equivalent to net emissions increase of ~25 Tg CH4 per year. A concurrent increase in atmospheric ethane implicates a fossil source; a concurrent decrease in the heavy isotope content of methane points toward a biogenic source, while other studies propose a decrease in the chemical sink (OH). Here we show that biomass burning emissions of methane decreased by 3.7 (+/-1.4) Tg CH4 per year from the 2001-2007 to the 2008-2014 time periods using satellite measurements of CO and CH4, nearly twice the decrease expected from prior estimates. After updating both the total and isotopic budgets for atmospheric methane with these revised biomass burning emissions (and assuming no change to the chemical sink), we find that fossil fuels contribute between 12-19 Tg CH4 per year to the recent atmospheric methane increase, thus reconciling the isotopic- and ethane-based results. PMID- 29263322 TI - NAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease. AB - Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can also drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Inflammasomes are broadly expressed in haematopoietic and non haematopoietic cells and can trigger numerous downstream responses including production of IL-1beta, IL-18, eicosanoids and pyroptotic cell death. Here we show a mouse model with endogenous NLRC4 inflammasome activation in Lysozyme2 + cells (monocytes, macrophages and neutrophils) in vivo exhibits a severe systemic inflammatory disease, reminiscent of human patients that carry mutant auto-active NLRC4 alleles. Interestingly, specific NLRC4 activation in Mrp8 + cells (primarily neutrophil lineage) is sufficient to cause severe inflammatory disease. Disease is ameliorated on an Asc -/- background, and can be suppressed by injections of anti-IL-1 receptor antibody. Our results provide insight into the mechanisms by which NLRC4 inflammasome activation mediates auto-inflammatory disease in vivo. PMID- 29263325 TI - Transient two-dimensional vibrational spectroscopy of an operating molecular machine. AB - Synthetic molecular machines are promising building blocks for future nanoscopic devices. However, the details of their mechanical behaviour are in many cases still largely unknown. A deeper understanding of mechanics at the molecular level is essential for the design and construction of complex nanodevices. Here, we show that transient two-dimensional infrared (T2DIR) spectroscopy makes it possible to monitor the conformational changes of a translational molecular machine during its operation. Translation of a macrocyclic ring from one station to another on a molecular thread is initiated by a UV pulse. The arrival of the shuttling macrocycle at the final station is visible from a newly appearing cross peak between these two moieties. To eliminate spectral congestion in the T2DIR spectra, we use a subtraction method applicable to many other complex molecular systems. The T2DIR spectra indicate that the macrocycle adopts a boat-like conformation at the final station, which contrasts with the chair-like conformation at the initial station. PMID- 29263324 TI - Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1. AB - Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes cap-dependent translation in polysomes, and reduces the anti proliferative effect of mTOR kinase inhibitors. Conversely, genetic and pharmacological inhibition of Snail function restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Our study reveals a critical Snail-4E-BP1 signaling axis in tumorigenesis, and provides a rationale for targeting Snail to improve mTOR-targeted therapies. PMID- 29263326 TI - Interdependent action of KH domain proteins Krr1 and Dim2 drive the 40S platform assembly. AB - Ribosome biogenesis begins in the nucleolus with the formation of 90S pre ribosomes, from which pre-40S and pre-60S particles arise that subsequently follow separate maturation pathways. Here, we show how structurally related assembly factors, the KH domain proteins Krr1 and Dim2, participate in ribosome assembly. Initially, Dim2 (Pno1) orchestrates an early step in small subunit biogenesis through its binding to a distinct region of the 90S pre-ribosome. This involves Utp1 of the UTP-B module, and Utp14, an activator of the DEAH-box helicase Dhr1 that catalyzes the removal of U3 snoRNP from the 90S. Following this dismantling reaction, the pre-40S subunit emerges, but Dim2 relocates to the pre-40S platform domain, previously occupied in the 90S by the other KH factor Krr1 through its interaction with Rps14 and the UTP-C module. Our findings show how the structurally related Krr1 and Dim2 can control stepwise ribosome assembly during the 90S-to-pre-40S subunit transition. PMID- 29263328 TI - Influence of environment on testing of hydraulic sealers. AB - In vitro material testing is undertaken by conducting a series of tests following procedures outlined in international standards. All material properties are measured in water; however biological behavior is undertaken in alternative media such as Dulbecco's modified eagle medium (DMEM) or simulated body fluid. The aim of this study was to characterize four dental root canal sealers and study their properties in different media. Four dental root canal sealers were assessed. They were characterized by a combination of techniques and the sealer properties were tested as specified by ISO 6876 (2012) and also in alternative media. The sealer biocompatibility was measured by cell function and proliferation assays of elutions. All sealers complied with ISO specifications. The material properties were effected by the type of soaking medium used and the surface micromorphology and elemental composition were dependent on the soaking solution type. Both BioRoot and MTA Fillapex showed cytotoxicity which reduced at higher dilutions. The material chemistry, presentation, environmental conditions and testing methodology used affected the sealer properties. Standards specific to sealer type are thus indicated. Furthermore the methodology used in the standard testing should be more relevant to clinical situations. PMID- 29263327 TI - Structural connections in the brain in relation to gender identity and sexual orientation. AB - Both transgenderism and homosexuality are facets of human biology, believed to derive from different sexual differentiation of the brain. The two phenomena are, however, fundamentally unalike, despite an increased prevalence of homosexuality among transgender populations. Transgenderism is associated with strong feelings of incongruence between one's physical sex and experienced gender, not reported in homosexual persons. The present study searches to find neural correlates for the respective conditions, using fractional anisotropy (FA) as a measure of white matter connections that has consistently shown sex differences. We compared FA in 40 transgender men (female birth-assigned sex) and 27 transgender women (male birth-assigned sex), with both homosexual (29 male, 30 female) and heterosexual (40 male, 40 female) cisgender controls. Previously reported sex differences in FA were reproduced in cis-heterosexual groups, but were not found among the cis homosexual groups. After controlling for sexual orientation, the transgender groups showed sex-typical FA-values. The only exception was the right inferior fronto-occipital tract, connecting parietal and frontal brain areas that mediate own body perception. Our findings suggest that the neuroanatomical signature of transgenderism is related to brain areas processing the perception of self and body ownership, whereas homosexuality seems to be associated with less cerebral sexual differentiation. PMID- 29263329 TI - Electromigration Mechanism of Failure in Flip-Chip Solder Joints Based on Discrete Void Formation. AB - In this investigation, SnAgCu and SN100C solders were electromigration (EM) tested, and the 3D laminography imaging technique was employed for in-situ observation of the microstructure evolution during testing. We found that discrete voids nucleate, grow and coalesce along the intermetallic compound/solder interface during EM testing. A systematic analysis yields quantitative information on the number, volume, and growth rate of voids, and the EM parameter of DZ*. We observe that fast intrinsic diffusion in SnAgCu solder causes void growth and coalescence, while in the SN100C solder this coalescence was not significant. To deduce the current density distribution, finite-element models were constructed on the basis of the laminography images. The discrete voids do not change the global current density distribution, but they induce the local current crowding around the voids: this local current crowding enhances the lateral void growth and coalescence. The correlation between the current density and the probability of void formation indicates that a threshold current density exists for the activation of void formation. There is a significant increase in the probability of void formation when the current density exceeds half of the maximum value. PMID- 29263330 TI - Annexin-A1 enhances breast cancer growth and migration by promoting alternative macrophage polarization in the tumour microenvironment. AB - Macrophages are potent immune cells with well-established roles in the response to stress, injury, infection and inflammation. The classically activated macrophages (M1) are induced by lipopolysaccharide (LPS) and express a wide range of pro-inflammatory genes. M2 macrophages are induced by T helper type 2 cytokines such as interleukin-4 (IL4) and express high levels of anti inflammatory and tissue repair genes. The strong association between macrophages and tumour cells as well as the high incidences of leukocyte infiltration in solid tumours have contributed to the discovery that tumour-associated macrophages (TAMs) are key to tumour progression. Here, we investigated the role of Annexin A1 (ANXA1), a well characterized immunomodulatory protein on macrophage polarization and the interaction between macrophages and breast cancer cells. Our results demonstrate that ANXA1 regulates macrophage polarization and activation. ANXA1 can act dually as an endogenous signalling molecule or as a secreted mediator which acts via its receptor, FPR2, to promote macrophage polarization. Furthermore, ANXA1 deficient mice exhibit reduced tumour growth and enhanced survival in vivo, possibly due to increased M1 macrophages within the tumor microenvironment. These results provide new insights into the molecular mechanisms of macrophage polarization with therapeutic potential to suppress breast cancer growth and metastasis. PMID- 29263331 TI - Genome-wide analysis of SSR and ILP markers in trees: diversity profiling, alternate distribution, and applications in duplication. AB - Molecular markers are efficient tools for breeding and genetic studies. However, despite their ecological and economic importance, their development and application have long been hampered. In this study, we identified 524,170 simple sequence repeat (SSR), 267,636 intron length polymorphism (ILP), and 11,872 potential intron polymorphism (PIP) markers from 16 tree species based on recently available genome sequences. Larger motifs, including hexamers and heptamers, accounted for most of the seven different types of SSR loci. Within these loci, A/T bases comprised a significantly larger proportion of sequence than G/C. SSR and ILP markers exhibited an alternative distribution pattern. Most SSRs were monomorphic markers, and the proportions of polymorphic markers were positively correlated with genome size. By verifying with all 16 tree species, 54 SSR, 418 ILP, and four PIP universal markers were obtained, and their efficiency was examined by PCR. A combination of five SSR and six ILP markers were used for the phylogenetic analysis of 30 willow samples, revealing a positive correlation between genetic diversity and geographic distance. We also found that SSRs can be used as tools for duplication analysis. Our findings provide important foundations for the development of breeding and genetic studies in tree species. PMID- 29263332 TI - Universal in vivo Textural Model for Human Skin based on Optical Coherence Tomograms. AB - Currently, diagnosis of skin diseases is based primarily on the visual pattern recognition skills and expertise of the physician observing the lesion. Even though dermatologists are trained to recognize patterns of morphology, it is still a subjective visual assessment. Tools for automated pattern recognition can provide objective information to support clinical decision-making. Noninvasive skin imaging techniques provide complementary information to the clinician. In recent years, optical coherence tomography (OCT) has become a powerful skin imaging technique. According to specific functional needs, skin architecture varies across different parts of the body, as do the textural characteristics in OCT images. There is, therefore, a critical need to systematically analyze OCT images from different body sites, to identify their significant qualitative and quantitative differences. Sixty-three optical and textural features extracted from OCT images of healthy and diseased skin are analyzed and, in conjunction with decision-theoretic approaches, used to create computational models of the diseases. We demonstrate that these models provide objective information to the clinician to assist in the diagnosis of abnormalities of cutaneous microstructure, and hence, aid in the determination of treatment. Specifically, we demonstrate the performance of this methodology on differentiating basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) from healthy tissue. PMID- 29263333 TI - Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. AB - There are few reports on hydrocortisone administration after cardiac arrest, and those that have been published included few subjects. This study aimed to evaluate the effect of hydrocortisone administration on the outcomes of patients who experienced cardiac arrest. We investigated the survival discharge rates and the length of hospital stay from cardiac arrest to discharge, stratified by use of hydrocortisone, using a Japanese health-insurance claims dataset that covers approximately 2% of the Japanese population. The study included the data of 2233 subjects who experienced either in-hospital or out-of-hospital cardiac arrest between January 2005 and May 2014. These patients were divided into two groups, based on the administration of hydrocortisone. We adjusted the baseline characteristics, medical treatment, and drug administration data of the two groups using propensity scores obtained via the inverse probability of treatment weighted method. The hydrocortisone group had a significantly higher survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60-10.98, p = 0.004). In addition, the administration of hydrocortisone was independent predictor of survival to discharge (hazard ratio: 4.6, p < 0.001). The results demonstrate a correlation between hydrocortisone administration and the high rates of survival to discharge. PMID- 29263334 TI - On the homogeneity and heterogeneity of cortical thickness profiles in Homo sapiens sapiens. AB - Cortical thickness has been investigated since the beginning of the 20th century, but we do not know how similar the cortical thickness profiles among humans are. In this study, the local similarity of cortical thickness profiles was investigated using sliding window methods. Here, we show that approximately 5% of the cortical thickness profiles are similarly expressed among humans while 45% of the cortical thickness profiles show a high level of heterogeneity. Therefore, heterogeneity is the rule, not the exception. Cortical thickness profiles of somatosensory homunculi and the anterior insula are consistent among humans, while the cortical thickness profiles of the motor homunculus are more variable. Cortical thickness profiles of homunculi that code for muscle position and skin stimulation are highly similar among humans despite large differences in sex, education, and age. This finding suggests that the structure of these cortices remains well preserved over a lifetime. Our observations possibly relativize opinions on cortical plasticity. PMID- 29263335 TI - Mediation of cellular osteogenic differentiation through daily stimulation time based on polypyrrole planar electrodes. AB - In electrical stimulation (ES), daily stimulation time means the interacting duration with cells per day, and is a vital factor for mediating cellular function. In the present study, the effect of stimulation time on osteogenic differentiation of MC3T3-E1 cells was investigated under ES on polypyrrole (Ppy) planar interdigitated electrodes (IDE). The results demonstrated that only a suitable daily stimulation time supported to obviously upregulate the expression of ALP protein and osteogenesis-related genes (ALP, Col-I, Runx2 and OCN), while a short or long daily stimulation time showed no significant outcomes. These might be attributed to the mechanism that an ES induced transient change in intracellular calcium ion concentration, which was responsible for activating calcium ion signaling pathway to enhance cellular osteogenic differentiation. A shorter daily time could lead to insufficient duration for the transient change in intracellular calcium ion concentration, and a longer daily time could give rise to cellular fatigue with no transient change. This work therefore provides new insights into the fundamental understanding of cell responses to ES and will have an impact on further designing materials to mediate cell behaviors. PMID- 29263336 TI - Enrichment of megabase-sized DNA molecules for single-molecule optical mapping and next-generation sequencing. AB - Next-generation sequencing (NGS) has caused a revolution, yet left a gap: long range genetic information from native, non-amplified DNA fragments is unavailable. It might be obtained by optical mapping of megabase-sized DNA molecules. Frequently only a specific genomic region is of interest, so here we introduce a method for selection and enrichment of megabase-sized DNA molecules intended for single-molecule optical mapping: DNA from a human cell line is digested by the NotI rare-cutting enzyme and size-selected by pulsed-field gel electrophoresis. For demonstration, more than 600 sub-megabase- to megabase-sized DNA molecules were recovered from the gel and analysed by denaturation renaturation optical mapping. Size-selected molecules from the same gel were sequenced by NGS. The optically mapped molecules and the NGS reads showed enrichment from regions defined by NotI restriction sites. We demonstrate that the unannotated genome can be characterized in a locus-specific manner via molecules partially overlapping with the annotated genome. The method is a promising tool for investigation of structural variants in enriched human genomic regions for both research and diagnostic purposes. Our enrichment method could potentially work with other genomes or target specified regions by applying other genomic editing tools, such as the CRISPR/Cas9 system. PMID- 29263337 TI - Functional and cooperative stabilization of a two-metal (Ca, Zn) center in alpha amylase derived from Flavobacteriaceae species. AB - Mesophilic alpha-amylase from Flavobacteriaceae (FSA) is evolutionary closely related to thermophilic archaeal Pyrococcus furiosus alpha-amylase (PWA), but lacks the high thermostability, despite the conservation of most residues involved in the two-metal (Ca, Zn) binding center of PWA. In this study, a disulfide bond was introduced near the two-metal binding center of FSA (designated mutant EH-CC) and this modification resulted in a slight improvement in thermostability. As expected, E204G mutations in FSA and EH-CC led to the recovery of Ca2+-binding site. Interestingly, both Ca2+- and Zn2+-dependent thermostability were significantly enhanced; 153.1% or 50.8% activities was retained after a 30-min incubation period at 50 degrees C, in the presence of Ca2+ or Zn2+. The C214S mutation, which affects Zn2+-binding, also remarkably enhanced Zn2+- and Ca2+- dependent thermostability, indicating that Ca2+- and Zn2+-binding sites function cooperatively to maintain protein stability. Furthermore, an isothermal titration calorimetry (ITC) analysis revealed a novel Zn2+-binding site in mutant EH-CC-E204G. This metal ion cooperation provides a possible method for the generation of alpha-amylases with desired thermal properties by in silico rational design and systems engineering, to generate a Zn2+-binding site adjacent to the conserved Ca2+-binding site. PMID- 29263338 TI - Cross-species transferability of EST-SSR markers developed from the transcriptome of Melilotus and their application to population genetics research. AB - Melilotus is one of the most important legume forages, but the lack of molecular markers has limited the development and utilization of Melilotus germplasm resources. In the present study, 151 M clean reads were generated from various genotypes of Melilotus albus using Illumina sequencing. A total of 19,263 potential EST-SSRs were identified from 104,358 unigene sequences. Moreover, 18,182 primer pairs were successfully designed, and 550 primer pairs were selected using criteria of base repeat type, fragment length and annealing temperature. In addition, 550 primer pairs were screened by using PCR amplification products and used to assess polymorphisms in 15 M. albus accessions. A total of 114 primer pairs were detected as being highly polymorphic, and the average polymorphism information content (PIC) value was 0.79. Furthermore, those 114 polymorphic primer pairs were used to evaluate the transferability to 18 species of the genus Melilotus, and 70 EST-SSR markers were found to be transferable among the 18 Melilotus species. According to the UPGMA dendrogram and STRUCTURE analysis, the 18 Melilotus species were classified into three clusters. This study offers a valuable resource for the genetic diversity and molecular assisted breeding of germplasm resources in the genus Melilotus. PMID- 29263339 TI - Post-Transcriptional Regulation of Hepatic DDAH1 with TNF Blockade Leads to Improved eNOS Function and Reduced Portal Pressure In Cirrhotic Rats. AB - Portal hypertension (PH) is a major cause of morbidity and mortality in chronic liver disease. Infection and inflammation play a role in potentiating PH and pro inflammatory cytokines, including TNF, are associated with severity of PH. In this study, cirrhotic bile duct ligated (BDL) rats with PH were treated with Infliximab (IFX, a monoclonal antibody against TNF) and its impact on modulation of vascular tone was assessed. BDL rats had increased TNF and NFkB compared to sham operated rats, and their reduction by IFX was associated with a reduction in portal pressure. IFX treatment also reduced hepatic oxidative stress, and biochemical markers of hepatic inflammation and injury. IFX treatment was associated with an improvement in eNOS activity and increased L-arginine/ADMA ratio and DDAH1 expression. In vitro analysis of HepG2 hepatocytes showed that DDAH1 protein expression is reduced by oxidative stress, and this is in part mediated by post-transcriptional regulation by the 3'UTR. This study supports a role for the DDAH1/ADMA axis on the effect of inflammation and oxidative stress in PH and provides insight for new therapies. PMID- 29263340 TI - Stroboscopic vision and sustained attention during coincidence-anticipation. AB - We compared coincidence-anticipation performance in normal vision and stroboscopic vision as a function of time-on-task. Participants estimated the arrival time of a real object that moved with constant acceleration (-0.7, 0, +0.7 m/s2) in a pseudo-randomised order across 4 blocks of 30 trials in both vision conditions, received in a counter-balanced order. Participants (n = 20) became more errorful (accuracy and variability) in the normal vision condition as a function of time-on-task, whereas performance was maintained in the stroboscopic vision condition. We interpret these data as showing that participants failed to maintain coincidence-anticipation performance in the normal vision condition due to monotony and attentional underload. In contrast, the stroboscopic vision condition placed a greater demand on visual-spatial memory for motion extrapolation, and thus participants did not experience the typical vigilance decrement in performance. While short-term adaptation effects from practicing in stroboscopic vision are promising, future work needs to consider for how long participants can maintain effortful processing, and whether there are negative carry-over effects from cognitive fatigue when transferring to normal vision. PMID- 29263342 TI - BIGL: Biochemically Intuitive Generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonism. AB - Clinical efficacy regularly requires the combination of drugs. For an early estimation of the clinical value of (potentially many) combinations of pharmacologic compounds during discovery, the observed combination effect is typically compared to that expected under a null model. Mechanistic accuracy of that null model is not aspired to; to the contrary, combinations that deviate favorably from the model (and thereby disprove its accuracy) are prioritized. Arguably the most popular null model is the Loewe Additivity model, which conceptually maps any assay under study to a (virtual) single-step enzymatic reaction. It is easy-to-interpret and requires no other information than the concentration-response curves of the individual compounds. However, the original Loewe model cannot accommodate concentration-response curves with different maximal responses and, by consequence, combinations of an agonist with a partial or inverse agonist. We propose an extension, named Biochemically Intuitive Generalized Loewe (BIGL), that can address different maximal responses, while preserving the biochemical underpinning and interpretability of the original Loewe model. In addition, we formulate statistical tests for detecting synergy and antagonism, which allow for detecting statistically significant greater/lesser observed combined effects than expected from the null model. Finally, we demonstrate the novel method through application to several publicly available datasets. PMID- 29263341 TI - Runx2 mediated Induction of Novel Targets ST2 and Runx3 Leads to Cooperative Regulation of Hypertrophic Differentiation in ATDC5 Chondrocytes. AB - Knowledge concerning expression and function of Suppression of Tumorigenicity 2 (ST2) in chondrocytes is at present, limited. Analysis of murine growth plates and ATDC5 chondrocytes indicated peak expression of the ST2 transmembrane receptor (ST2L) and soluble (sST2) isoforms during the hypertrophic differentiation concomitant with the expression of the hypertrophic markers Collagen X (Col X), Runx2 and MMP-13. Gain- and loss-of-function experiments in ATDC5 and primary human growth plate chondrocytes (PHCs), confirmed regulation of ST2 by the key transcription factor Runx2, indicating ST2 to be a novel Runx2 target. ST2 knock-out mice (ST2-/-) exhibited noticeable hypertrophic zone (HZ) reduction in murine growth plates, accompanied by lower expression of Col X and Osteocalcin (OSC) compared to wild-type (WT) mice. Likewise, ST2 knockdown resulted in decreased Col X expression and downregulation of OSC and Vascular Endothelial Growth Factor (VEGF) in ATDC5 cells. The ST2 suppression was also associated with upregulation of the proliferative stage markers Sox9 and Collagen II (Col II), indicating ST2 to be a new regulator of ATDC5 chondrocyte differentiation. Runx3 was, furthermore, identified as a novel Runx2 target in chondrocytes. This study suggests that Runx2 mediates ST2 and Runx3 induction to cooperatively regulate hypertrophic differentiation of ATDC5 chondrocytes. PMID- 29263343 TI - Convergent microevolution of Cryptococcus neoformans hypervirulence in the laboratory and the clinic. AB - Reference strains are a key component of laboratory research, providing a common background allowing for comparisons across a community of researchers. However, laboratory passage of these strains has been shown to lead to reduced fitness and the attenuation of virulence in some species. In this study we show the opposite in the fungal pathogen Cryptococcus neoformans, with analysis of a collection of type strain H99 subcultures revealing that the most commonly used laboratory subcultures belong to a mutant lineage of the type strain that is hypervirulent. The pleiotropic mutant phenotypes in this H99L (for "Laboratory") lineage are the result of a deletion in the gene encoding the SAGA Associated Factor Sgf29, a mutation that is also present in the widely-used H99L-derived KN99a/alpha congenic pair. At a molecular level, loss of this gene results in a reduction in histone H3K9 acetylation. Remarkably, analysis of clinical isolates identified loss of function SGF29 mutations in C. neoformans strains infecting two of fourteen patients, demonstrating not only the first example of hypervirulence in clinical C. neoformans samples, but also parallels between in vitro and in vivo microevolution for hypervirulence in this important pathogen. PMID- 29263344 TI - Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort. AB - People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings. PMID- 29263345 TI - Automated Detection of Iris Furrows and their Influence on Dynamic Iris Volume Change. AB - We introduced a new method for detecting iris surface furrows and identify its associations with dynamic changes in iris volume in healthy eyes. Swept-source optical coherence tomography was performed on 65 subjects with open angle under light and dark conditions. Iris boundaries were identified and a reconstruction of the anterior iris surface was obtained. Furrows were detected by identifying locally deep (minima) points on the iris surface and reported as furrow length in millimetres. Iris volume was quantified. Associations between furrow length and dynamic changes in iris volume were assessed using linear regression model. With pupil dilation, furrow length increased (15.84 mm) whereas iris volume decreased (-1.19 +/- 0.66 mm3). Longer furrow length was associated with larger static iris volume, as well as smaller loss of iris volume with pupil dilation (beta = -0.10, representing 0.1 mm3 less loss in iris volume per 10 mm increase in iris furrow length; P = 0.002, adjusted for age, gender and changes in pupil size). Our iris furrow length measurements are robust and intuitive. Eyes with longer furrows have larger iris volume and lose less volume during physiological pupil dilation. These findings highlight the potential for iris surface features as indicators of iris morphological behavior. PMID- 29263346 TI - MicroRNA-365 regulates IL-1beta-induced catabolic factor expression by targeting HIF-2alpha in primary chondrocytes. AB - Endothelial Per-Arnt-Sim domain protein-1/hypoxia-inducible factor-2alpha (EPAS 1/ HIF-2alpha) is a catabolic transcription factor that regulates osteoarthritis (OA)-related cartilage destruction. Here, we examined whether microRNA-365 (miR 365) affects interleukin (IL)-1beta-induced expression of catabolic factors in chondrocytes via regulation of HIF-2alpha. MiR-365 levels were significantly decreased in human OA cartilage relative to normal cartilage. Overexpression of miR-365 significantly suppressed IL-1beta-induced expression of HIF-2alpha in human articular chondrocytes. Pharmacological inhibition of various IL-1beta associated signaling pathways revealed mitogen-activated protein kinase and nuclear factor-kappaB as the primary pathways driving IL-1beta-mediated decreases in miR-365 and subsequent increase in HIF-2alpha expression. Using a luciferase reporter assay encoding the 3' untranslated region (UTR) of human HIF-2alpha mRNA, we showed that overexpression of miR-365 significantly suppressed IL-1beta induced up-regulation of HIF-2alpha. AGO2 RNA-immunoprecipitation (IP) assay demonstrated that miR-365 and HIF-2alpha mRNA were enriched in the AGO2-IP fraction in miR-365-transfected primary chondrocytes compared to miR-con transfected cells, indicating that HIF-2alpha is a target of miR-365. Furthermore, miR-365 overexpression significantly suppressed IL-1beta-induced expression of catabolic factors, including cyclooxygenase-2 and matrix metalloproteinase-1, -3 and -13, in chondrocytes. In pellet culture of primary chondrocytes miR-365 prevented IL-1beta-stimulated extracellular matrix loss and matrix metalloproteinase-13 expression. MiR-365 regulates IL-1beta-stimulated catabolic effects in human chondrocytes by modulating HIF-2alpha expression. PMID- 29263347 TI - Functional characterization of a type 2 metallothionein gene, SsMT2, from alkaline-tolerant Suaeda salsa. AB - A type 2 metallothionein gene, SsMT2, was cloned from Suaeda salsa, a salt- and alkali-tolerant plant, which is dominant species on the saline/alkali soil of northeast China. The SsMT2 gene was expressed in all organs except the flower and its expression was induced by various stresses such as CdCl2, NaCl, NaHCO3, and H2O2 treatments. SsMT2-transgenic yeast (Saccharomyces cerevisiae) and plants (Arabidopsis thaliana) showed significantly increased resistance to metal, salt and oxidant stresses. These transgenics accumulated more Cd2+, but less Na+ than their wild type counterparts. SsMT2 transgenic Arabidopsis maintained lower level of H2O2 than wild type plants did in response to the stress treatments. These results demonstrated that the SsMT2 gene plays an important role in reactive oxygen species scavenging and confers enhanced metal and oxidant tolerance to plants. PMID- 29263348 TI - STIM2 regulates both intracellular Ca2+ distribution and Ca2+ movement in skeletal myotubes. AB - Stromal interaction molecule 1 (STIM1) along with Orai1 mediates extracellular Ca2+ entry into the cytosol through a store-operated Ca2+ entry (SOCE) mechanism in various tissues including skeletal muscle. However, the role(s) of STIM2, a homolog of STIM1, in skeletal muscle has not been well addressed. The present study, first, was focused on searching for STIM2-binding proteins from among proteins mediating skeletal muscle functions. This study used a binding assay, quadrupole time-of-flight mass spectrometry, and co-immunoprecipitation assay with bona-fide STIM2- and SERCA1a-expressing rabbit skeletal muscle. The region for amino acids from 453 to 729 of STIM2 binds to sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1a (SERCA1a). Next, oxalate-supported 45Ca2+-uptake experiments and various single-myotube Ca2+ imaging experiments using STIM2 knockdown mouse primary skeletal myotubes have suggested that STIM2 attenuates SERCA1a activity during skeletal muscle contraction, which contributes to the intracellular Ca2+ distribution between the cytosol and the SR at rest. In addition, STIM2 regulates Ca2+ movement through RyR1 during skeletal muscle contraction as well as SOCE. Therefore, via regulation of SERCA1a activity, STIM2 regulates both intracellular Ca2+ distribution and Ca2+ movement in skeletal muscle, which makes it both similar to, yet different from, STIM1. PMID- 29263349 TI - Complete genome sequencing and genomic characterization of two Escherichia coli strains co-producing MCR-1 and NDM-1 from bloodstream infection. AB - We previously described the discovery of two Escherichia coli isolates (EC1002 and EC2474) co-harbouring mcr-1 and bla NDM-1 genes, which were recovered from bloodstream infection in China. More importantly, these antibiotic resistance genes were located on different plasmids and signaling the potential spread of pandrug-resistant bacteria. Here, the complete genome sequences of both isolates were determined using Pacbio RS II and Illumina HiSeq2000 systems. The genome of EC1002 consists of a 5,177,501 base pair chromosome and four circular plasmids, while the genome of EC2474 consists of a 5,013,813 base pair chromosome and three plasmids. The plasmid replicon type of pEC1002_NDM and pEC2474_NDM were identified as IncA/C2 and IncF, respectively. The genetic environment of bla NDM 1 in this study was similar to bla NDM-carrying plasmids detected in China, although the overall nucleotide identity and query coverage were variable. The plasmid replicon type of pEC1002_MCR and pEC2474_MCR were identified as IncI2 and IncHI2, respectively. Two different genetic strategies for mcr-1 gene spread were observed in this study and bla NDM-1 genes were also found transferred by two different mobile genetic elements in two plasmids. The findings of this study further support that the diversified transfer mechanisms of bla NDM-1 and mcr-1 present in Enterobacteriaceae. PMID- 29263350 TI - Evaluating single molecule detection methods for microarrays with high dynamic range for quantitative single cell analysis. AB - Single molecule microarrays have been used in quantitative proteomics, in particular, single cell analysis requiring high sensitivity and ultra-low limits of detection. In this paper, several image analysis methods are evaluated for their ability to accurately enumerate single molecules bound to a microarray spot. Crucially, protein abundance in single cells can vary significantly and may span several orders of magnitude. This poses a challenge to single molecule image analysis. In order to quantitatively assess the performance of each method, synthetic image datasets are generated with known ground truth whereby the number of single molecules varies over 5 orders of magnitude with a range of signal to noise ratios. Experiments were performed on synthetic datasets whereby the number of single molecules per spot corresponds to realistic single cell distributions whose ground truth summary statistics are known. The methods of image analysis are assessed in their ability to accurately estimate the distribution parameters. It is shown that super-resolution image analysis methods can significantly improve counting accuracy and better cope with single molecule congestion. The results highlight the challenge posed by quantitative single cell analysis and the implications to performing such analyses using microarray based approaches are discussed. PMID- 29263351 TI - Interleukin-33 modulates inflammation in endometriosis. AB - Endometriosis is a debilitating condition that is categorized by the abnormal growth of endometrial tissue outside the uterus. Although the pathogenesis of this disease remains unknown, it is well established that endometriosis patients exhibit immune dysfunction. Interleukin (IL)-33 is a danger signal that is a critical regulator of chronic inflammation. Although plasma and peritoneal fluid levels of IL-33 have been associated with deep infiltrating endometriosis, its contribution to the disease pathophysiology is unknown. We investigated the role of IL-33 in the pathology of endometriosis using patient samples, cell lines and a syngeneic mouse model. We found that endometriotic lesions produce significantly higher levels of IL-33 compared to the endometrium of healthy, fertile controls. In vitro stimulation of endometrial epithelial, endothelial and endometriotic epithelial cells with IL-33 led to the production of pro inflammatory and angiogenic cytokines. In a syngeneic mouse model of endometriosis, IL-33 injections caused systemic inflammation, which manifested as an increase in plasma pro-inflammatory cytokines compared to control mice. Furthermore, endometriotic lesions from IL-33 treated mice were highly vascularized and exhibited increased proliferation. Collectively, we provide convincing evidence that IL-33 perpetuates inflammation, angiogenesis and lesion proliferation, which are critical events in the lesion survival and progression of endometriosis. PMID- 29263352 TI - Complementation of a mutation in CpSRP43 causing partial truncation of light harvesting chlorophyll antenna in Chlorella vulgaris. AB - Photosynthesis of microalgae enables conversion of light energy into chemical energy to produce biomass and biomaterials. However, the efficiency of this process must be enhanced, and truncation of light-harvesting complex (LHC) has been suggested to improve photosynthetic efficiency. We reported an EMS-induced mutant (E5) showing partially reduced LHC in Chlorella vulgaris. We determined the mutation by sequencing the whole genome of WT and E5. Augustus gene prediction was used for determining CDS, and non-synonymous changes in E5 were screened. Among these, we found a point mutation (T to A) in a gene homologous to chloroplast signal recognition particle 43 kDa (CpSRP43). The point mutation changed the 102nd valine to glutamic acid (V102E) located in the first chromodomain. Phylogenetic analyses of CpSRP43 revealed that this amino acid was valine or isoleucine in microalgae and plants, suggesting important functions. Transformation of E5 with WT CpSRP43 showed varying degrees of complementation, which was demonstrated by partial recovery of the LHCII proteins to the WT level, and partially restored photosynthetic pigments, photosynthetic ETR, NPQ, and growth, indicating that the V102E mutation was responsible for the reduced LHC in E5. PMID- 29263353 TI - Intensive spa and exercise therapy program for returning to work for low back pain patients: a randomized controlled trial. AB - We aimed to determine whether a 5-day intensive inpatient spa and exercise therapy and educational program is more effective than usual care in improving the rate of returning to work at 1 year for patients with subacute and chronic low back pain (LBP) on sick leave for 4 to 24 weeks. We conducted a 12-month randomized controlled trial. LBP patients were assigned to 5-day spa (2 hr/day), exercise (30 min/day) and education (45 min/day) or to usual care. The primary outcome was the percentage of patients returning to work at 1 year after randomization. Secondary outcomes were pain, disability and health-related quality of life at 1 year and number of sick leave days from 6 to 12 months. The projected recruitment was not achieved. Only 88/700 (12.6%) patients planned were enrolled: 45 in the spa therapy group and 43 in the usual care group. At 1 year, returning to work was 56.3% versus 41.9% (OR 1.69 [95% CI 0.60-4.73], p = 0.32) respectively. There was no significant difference for any of the secondary outcomes. However, our study lacked power. PMID- 29263354 TI - Involvement of Innate Immune System in Late Stages of Inherited Photoreceptor Degeneration. AB - Retinitis pigmentosa (RP) is a group of inherited retinal degenerations that lead to progressive vision loss. Over 200 mutations in 60 different genes have been shown to cause RP. Given the diversity of genes and mutations that cause RP, corrective gene therapy approaches currently in development may prove both time consuming and cost-prohibitive for treatment of all forms of RP. An alternative approach is to find common biological pathways that cause retinal degeneration in various forms of RP, and identify new molecular targets. With this goal, we analyzed the retinal transcriptome of two non-allelic forms of RP in dogs, rcd1 and xlpra2, at clinically relevant advanced stages of the two diseases. Both diseases showed very similar trends in changes in gene expression compared to control normal dogs. Pathway analysis revealed upregulation of various components of the innate immune system in both diseases, including inflammasome and complement pathways. Our results show that the retinal transcriptome at advanced stages of RP is very similar to that of other retinal degenerative diseases such as age-related macular degeneration and diabetic retinopathy. Thus, drugs and therapeutics already in development for targeting these retinopathies may also prove useful for the treatment of many forms of RP. PMID- 29263355 TI - Formation of Cell Membrane Component Domains in Artificial Lipid Bilayer. AB - The lipid bilayer environment around membrane proteins strongly affects their structure and functions. Here, we aimed to study the fusion of proteoliposomes (PLs) derived from cultured cells with an artificial lipid bilayer membrane and the distribution of the PL components after the fusion. PLs, which were extracted as a crude membrane fraction from Chinese hamster ovary (CHO) cells, formed isolated domains in a supported lipid bilayer (SLB), comprising phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cholesterol (Chol), after the fusion. Observation with a fluorescence microscope and an atomic force microscope showed that the membrane fusion occurred selectively at microdomains in the PC + PE + Chol-SLB, and that almost all the components of the PL were retained in the domain. PLs derived from human embryonic kidney 293 (HEK) cells also formed isolated domains in the PC + PE + Chol-SLB, but their fusion kinetics was different from that of the CHO-PLs. We attempted to explain the mechanism of the PL-SLB fusion and the difference between CHO- and HEK-PLs, based on a kinetic model. The domains that contained the whole cell membrane components provided environments similar to that of natural cell membranes, and were thus effective for studying membrane proteins using artificial lipid bilayer membranes. PMID- 29263356 TI - Identification and expression of CAMTA genes in Populus trichocarpa under biotic and abiotic stress. AB - The calmodulin-binding transcription activators (CAMTAs) transcription factor family plays an important role in normal plant growth and development, as well as in biotic and abiotic stress resistance. In this study, we identified seven CAMTA genes across the whole genome of Populus trichocarpa and analyzed the expression patterns of PtCAMTAs in the root and leaf tissues. Promoter cis-element analysis indicated that most CAMTA genes contained stress- or phytohormone-related cis elements. Quantitative real-time reverse transcription-PCR (qRT-PCR) indicated indicated that PtCAMTAs were induced by mannitol, NaCl, cold stress, pathogenic infection with A. alternata, and phytohormone treatments with abscisic acid, salicylic acid, and methyl jasmonate. We analyzed the expression of homologous genes between P. trichocarpa and P. ussuriensis and alternative splicing forms of PtCAMTA genes under cold stress. We also performed a network interaction analysis for PtCAMTA proteins to predict their interactions and associations. The results of the present study serve as a basis for future functional studies on the Populus CAMTA family. PMID- 29263357 TI - Identification and characterization of the structure-activity relationships involved in UGT1A1 inhibition by anthraquinone and dianthrone constituents of Polygonum multiflorum. AB - The adverse effects of Polygonum (P.) multiflorum, including abnormal bilirubin metabolism, are a serious public health issue. As uridine diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1) is the only enzyme responsible for bilirubin metabolism, we investigated the inhibitory effect of a P. multiflorum extract and 10 anthraquinone and dianthrone compounds on UGT1A1 in rat liver microsomes in vitro. The P. multiflorum extract exhibited the strongest inhibitory effect on UGT1A1 activity (inhibition constant [Ki] = 0.3257 MUM, 1422 MUg of material/mL), followed by cis-emodin dianthrones (Ki = 0.8630 MUM), trans-emodin dianthrones (Ki = 1.083 MUM), emodin-8-O-glc (Ki = 3.425 MUM), and polygonumnolide C2 (Ki = 4.291 MUM). Analysis of the structure-activity relationships of these compounds suggested that the spatial orientation of the molecules and the presence of particular functional groups affect UGT1A1 inhibition. A mechanistic analysis showed that all the tested compounds docked into two of the nine active sites of UGT1A1 and suggested that hydrophobic interactions and hydrogen bonds are important for the affinity of the tested compounds for UGT1A1; moreover, their interaction energies were generally in agreement with the Ki values. These findings provide insight into adverse reactions to P. multiflorum and identify the pharmacophores involved in inhibition of UGT1A1. PMID- 29263358 TI - The importance of filamentous cyanobacteria in the development of oxygenic photogranules. AB - Microorganisms often respond to their environment by growing as densely packed communities in biofilms, flocs or granules. One major advantage of life in these aggregates is the retention of its community in an ecosystem despite flowing water. We describe here a novel type of granule dominated by filamentous and motile cyanobacteria of the order Oscillatoriales. These bacteria form a mat-like photoactive outer layer around an otherwise unconsolidated core. The spatial organization of the phototrophic layer resembles microbial mats growing on sediments but is spherical. We describe the production of these oxygenic photogranules under static batch conditions, as well as in turbulently mixed bioreactors. Photogranulation defies typically postulated requirements for granulation in biotechnology, i.e., the need for hydrodynamic shear and selective washout. Photogranulation as described here is a robust phenomenon with respect to inoculum characteristics and environmental parameters like carbon sources. A bioprocess using oxygenic photogranules is an attractive candidate for energy positive wastewater treatment as it biologically couples CO2 and O2 fluxes. As a result, the external supply of oxygen may become obsolete and otherwise released CO2 is fixed by photosynthesis for the production of an organic-rich biofeedstock as a renewable energy source. PMID- 29263359 TI - Recombinant influenza H9N2 virus with a substitution of H3 hemagglutinin transmembrane domain showed enhanced immunogenicity in mice and chicken. AB - In recent years, avian influenza virus H9N2 undergoing antigenic drift represents a threat to poultry farming as well as public health. Current vaccines are restricted to inactivated vaccine strains and their related variants. In this study, a recombinant H9N2 (H9N2-TM) strain with a replaced H3 hemagglutinin (HA) transmembrane (TM) domain was generated. Virus assembly and viral protein composition were not affected by the transmembrane domain replacement. Further, the recombinant TM-replaced H9N2-TM virus could provide better inter-clade protection in both mice and chickens against H9N2, suggesting that the H3-TM replacement could be considered as a strategy to develop efficient subtype specific H9N2 influenza vaccines. PMID- 29263360 TI - Atomistic study of the solid state inside graphene nanobubbles. AB - A two-dimensional (2D) material placed on an atomically flat substrate can lead to the formation of surface nanobubbles trapping different types of substances. In this paper graphene nanobubbles of the radius of 7-34 nm with argon atoms inside are studied using molecular dynamics (MD). All modeled graphene nanobubbles except for the smallest ones exhibit an universal shape, i.e., a constant ratio of a bubble height to its footprint radius, which is in an agreement with experimental studies and their interpretation using the elastic theory of membranes. MD simulations reveal that argon does exist in a solid close packed phase, although the internal pressure in the nanobubble is not sufficiently high for the ordinary crystallization that would occur in a bulk system. The smallest graphene bubbles with a radius of 7 nm exhibit an unusual "pancake" shape. Previously, nanobubbles with a similar pancake shape were experimentally observed in completely different systems at the interface between water and a hydrophobic surface. PMID- 29263361 TI - Supervised learning in spiking neural networks with FORCE training. AB - Populations of neurons display an extraordinary diversity in the behaviors they affect and display. Machine learning techniques have recently emerged that allow us to create networks of model neurons that display behaviors of similar complexity. Here we demonstrate the direct applicability of one such technique, the FORCE method, to spiking neural networks. We train these networks to mimic dynamical systems, classify inputs, and store discrete sequences that correspond to the notes of a song. Finally, we use FORCE training to create two biologically motivated model circuits. One is inspired by the zebra finch and successfully reproduces songbird singing. The second network is motivated by the hippocampus and is trained to store and replay a movie scene. FORCE trained networks reproduce behaviors comparable in complexity to their inspired circuits and yield information not easily obtainable with other techniques, such as behavioral responses to pharmacological manipulations and spike timing statistics. PMID- 29263362 TI - Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway. AB - Nuclear factor (erythroid-derived 2)-like 2 and its Caenorhabditis elegans ortholog, SKN-1, are transcription factors that have a pivotal role in the oxidative stress response, cellular homeostasis, and organismal lifespan. Similar to other defense systems, the NRF2-mediated stress response is compromised in aging and neurodegenerative diseases. Here, we report that the FDA approved drug hydralazine is a bona fide activator of the NRF2/SKN-1 signaling pathway. We demonstrate that hydralazine extends healthy lifespan (~25%) in wild type and tauopathy model C. elegans at least as effectively as other anti-aging compounds, such as curcumin and metformin. We show that hydralazine-mediated lifespan extension is SKN-1 dependent, with a mechanism most likely mimicking calorie restriction. Using both in vitro and in vivo models, we go on to demonstrate that hydralazine has neuroprotective properties against endogenous and exogenous stressors. Our data suggest that hydralazine may be a viable candidate for the treatment of age-related disorders. PMID- 29263364 TI - p53 and cyclin G cooperate in mediating genome stability in somatic cells of Drosophila. AB - One of the key players in genome surveillance is the tumour suppressor p53 mediating the adaptive response to a multitude of stress signals. Here we identify Cyclin G (CycG) as co-factor of p53-mediated genome stability. CycG has been shown before to be involved in double-strand break repair during meiosis. Moreover, it is also important for mediating DNA damage response in somatic tissue. Here we find it in protein complexes together with p53, and show that the two proteins interact physically in vitro and in vivo in response to ionizing irradiation. In contrast to mammals, Drosophila Cyclin G is no transcriptional target of p53. Genetic interaction data reveal that p53 activity during DNA damage response requires the presence of CycG. Morphological defects caused by overexpression of p53 are ameliorated in cycG null mutants. Moreover, using a p53 biosensor we show that p53 activity is impeded in cycG mutants. As both p53 and CycG are likewise required for DNA damage repair and longevity we propose that CycG plays a positive role in mediating p53 function in genome surveillance of Drosophila. PMID- 29263363 TI - Polarized actin and VE-cadherin dynamics regulate junctional remodelling and cell migration during sprouting angiogenesis. AB - VEGFR-2/Notch signalling regulates angiogenesis in part by driving the remodelling of endothelial cell junctions and by inducing cell migration. Here, we show that VEGF-induced polarized cell elongation increases cell perimeter and decreases the relative VE-cadherin concentration at junctions, triggering polarized formation of actin-driven junction-associated intermittent lamellipodia (JAIL) under control of the WASP/WAVE/ARP2/3 complex. JAIL allow formation of new VE-cadherin adhesion sites that are critical for cell migration and monolayer integrity. Whereas at the leading edge of the cell, large JAIL drive cell migration with supportive contraction, lateral junctions show small JAIL that allow relative cell movement. VEGFR-2 activation initiates cell elongation through dephosphorylation of junctional myosin light chain II, which leads to a local loss of tension to induce JAIL-mediated junctional remodelling. These events require both microtubules and polarized Rac activity. Together, we propose a model where polarized JAIL formation drives directed cell migration and junctional remodelling during sprouting angiogenesis. PMID- 29263365 TI - Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. AB - The epigenomic reader Brd4 is an important drug target for cancers. However, its role in cell differentiation and animal development remains largely unclear. Using two conditional knockout mouse strains and derived cells, we demonstrate that Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. Brd4 co-localizes with lineage-determining transcription factors (LDTFs) on active enhancers during differentiation. LDTFs coordinate with H3K4 mono-methyltransferases MLL3/MLL4 (KMT2C/KMT2D) and H3K27 acetyltransferases CBP/p300 to recruit Brd4 to enhancers activated during differentiation. Brd4 deletion prevents the enrichment of Mediator and RNA polymerase II transcription machinery, but not that of LDTFs, MLL3/MLL4-mediated H3K4me1, and CBP/p300 mediated H3K27ac, on enhancers. Consequently, Brd4 deletion prevents enhancer RNA production, cell identity gene induction and cell differentiation. Interestingly, Brd4 is dispensable for maintaining cell identity genes in differentiated cells. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction in differentiation. PMID- 29263367 TI - Enhancing security of incoherent optical cryptosystem by a simple position multiplexing technique and ultra-broadband illumination. AB - A position-multiplexing technique with ultra-broadband illumination is proposed to enhance the information security of an incoherent optical cryptosystem. This simplified optical encryption system only contains one diffuser acting as the random phase mask (RPM). Incoherent light coming from a plaintext passes through this nature RPM and generates the corresponding ciphertext on a camera. The proposed system effectively reduces problems of critical alignment sensitivity and coherent noise that are found in the coherent illumination. Here, the use of ultra-broadband illumination has the advantage of reducing the speckle contrast that makes the ciphertext more complex. Reduction of the ciphertext size further increases the strength of the ciphering. Using the spatial decorrelation of the speckle pattern we have demonstrated a position multiplexed based cryptosystem, where the ciphertext is the superposition of uniquely encrypted texts from various spatial positions. These unique spatial keys are utilized to decrypt the plaintext located at different spatial positions, and a complete decrypted text can be concatenated with high fidelity. Benefiting from position-multiplexing, the information of interest is scrambled together by a truly random method in a smaller ciphertext. A high performance security for an optical cryptosystem has been achieved in a simple setup with a ground glass diffuser as a nature RPM, the broadband incoherent illumination and small position-multiplexed ciphertext. PMID- 29263366 TI - Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne. AB - Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients. PMID- 29263368 TI - Controlling bottom-up rapid growth of single crystalline gallium nitride nanowires on silicon. AB - We report single crystalline gallium nitride nanowire growth from Ni and Ni-Au catalysts on silicon using hydride vapor phase epitaxy. The growth takes place rapidly; efficiency in time is higher than the conventional nanowire growth in metal-organic chemical vapor deposition and thin film growth in molecular beam epitaxy. The effects of V/III ratio and carrier gas flow on growth are discussed regarding surface polarity and sticking coefficient of molecules. The nanowires of gallium nitride exhibit excellent crystallinity with smooth and straight morphology and uniform orientation. The growth mechanism follows self-assembly from both catalysts, where Au acts as a protection from etching during growth enabling the growth of ultra-long nanowires. The photoluminescence of such nanowires are adjustable by tuning the growth parameters to achieve blue emission. The practical range of parameters for mass production of such high crystal quality and uniformity of nanowires is suggested. PMID- 29263369 TI - Modulation of fibronectin and laminin expression by Rhodium (II) citrate-coated maghemite nanoparticles in mice bearing breast tumor. AB - Degradation of cellular matrix is one of the important processes related to the progression of breast cancer. Tumor cells have the ability to exhibit necessary conditions for growth and survival, promoting degradation processes of extracellular matrix proteins, such as laminin (LN) and fibronectin (FN). In this study, we evaluated whether treatments, based on free rhodium (II) citrate (Rh2(H2cit)4), maghemite nanoparticles coated with citrate (Magh-cit) and maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2(H2cit)4), in murine metastatic breast carcinoma models can modulate the expression of laminin and fibronectin proteins. Synthesized nanoparticles were characterized using X ray diffraction, transmission electron microscopy, energy dispersive spectroscopy and dynamic light scattering. The expression of FN and LN was assessed using immunohistochemistry and western blotting. The gene expression of FN1 and LAMA1 were evaluated using real-time PCR. The FN1 and LAMA1 transcripts from the Magh Rh2(H2cit)4 treated group were 95% and 94%, respectively, lower than the control group. Significant reduction in tumor volume for animals treated with Magh Rh2(H2cit)4 was observed, of about 83%. We witnessed statistically significant reductions of FN and LN expression following treatment with Magh-Rh2(H2cit)4. We have demonstrated that the antitumor effects of Magh-Rh2(H2cit)4 and Rh2(H2cit)4 regulate the expression of FN and LN in metastatic breast tumors. PMID- 29263370 TI - Shape analysis of the basioccipital bone in Pax7-deficient mice. AB - We compared the cranial base of newborn Pax7-deficient and wildtype mice using a computational shape modeling technology called particle-based modeling (PBM). We found systematic differences in the morphology of the basiooccipital bone, including a broadening of the basioccipital bone and an antero-inferior inflection of its posterior edge in the Pax7-deficient mice. We show that the Pax7 cell lineage contributes to the basioccipital bone and that the location of the Pax7 lineage correlates with the morphology most effected by Pax7 deficiency. Our results suggest that the Pax7-deficient mouse may be a suitable model for investigating the genetic control of the location and orientation of the foramen magnum, and changes in the breadth of the basioccipital. PMID- 29263372 TI - Seabird species vary in behavioural response to drone census. AB - Unmanned aerial vehicles (UAVs) provide an opportunity to rapidly census wildlife in remote areas while removing some of the hazards. However, wildlife may respond negatively to the UAVs, thereby skewing counts. We surveyed four species of Arctic cliff-nesting seabirds (glaucous gull Larus hyperboreus, Iceland gull Larus glaucoides, common murre Uria aalge and thick-billed murre Uria lomvia) using a UAV and compared censusing techniques to ground photography. An average of 8.5% of murres flew off in response to the UAV, but >99% of those birds were non-breeders. We were unable to detect any impact of the UAV on breeding success of murres, except at a site where aerial predators were abundant and several birds lost their eggs to predators following UAV flights. Furthermore, we found little evidence for habituation by murres to the UAV. Most gulls flew off in response to the UAV, but returned to the nest within five minutes. Counts of gull nests and adults were similar between UAV and ground photography, however the UAV detected up to 52.4% more chicks because chicks were camouflaged and invisible to ground observers. UAVs provide a less hazardous and potentially more accurate method for surveying wildlife. We provide some simple recommendations for their use. PMID- 29263371 TI - Aggressive NK-cell leukemia: clinical subtypes, molecular features, and treatment outcomes. PMID- 29263374 TI - Rheumatoid arthritis: Higher disease risk in children of women with RA. PMID- 29263373 TI - Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment. AB - MiR-34a acts as tumor suppressor microRNA (miRNA) in several cancers, including multiple myeloma (MM), by controlling the expression of target proteins involved in cell cycle, differentiation and apoptosis. Here, we have investigated the combination between miR-34a and gamma-secretase inhibitor (gammaSI), Sirtinol or zoledronic acid (ZOL) in order to enhance the inhibitory action of this miRNA on its canonical targets such as Notch1 and SIRT1, and on Ras/MAPK-dependent pathways. Our data demonstrate that miR-34a synthetic mimics significantly enhance the anti-tumor activity of all the above-mentioned anti-cancer agents in RPMI 8226 MM cells. We found that gammaSI enhanced miR-34a-dependent anti-tumor effects by activating the extrinsic apoptotic pathway which could overcome the cytoprotective autophagic mechanism. Moreover, the combination between miR-34a and gammaSI increased the cell surface calreticulin (CRT) expression, that is well known for triggering anti-tumor immunological response. The combination between miR-34a and Sirtinol induced the activation of an intrinsic apoptotic pathway along with increased surface expression of CRT. Regarding ZOL, we found a powerful growth inhibition after enforced miR-34a expression, which was not likely attributable to neither apoptosis nor autophagy modulation. Based on our data, the combination of miR-34a with other anti-cancer agents appears a promising anti-MM strategy deserving further investigation. PMID- 29263375 TI - Osteoarthritis: Arthroscopy does not delay TKA for knee OA. PMID- 29263376 TI - Osteoarthritis: Arthroscopy does not delay TKA for knee OA. PMID- 29263377 TI - Systemic lupus erythematosus: Rituximab improves SLE disease activity. PMID- 29263378 TI - Engineering cell sensing and responses using a GPCR-coupled CRISPR-Cas system. AB - G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes and detect a wide array of cues in the human body. Here we describe a molecular device that couples CRISPR-dCas9 genome regulation to diverse natural and synthetic extracellular signals via GPCRs. We generate alternative architectures for fusing CRISPR to GPCRs utilizing the previously reported design, Tango, and our design, ChaCha. Mathematical modeling suggests that for the CRISPR ChaCha design, multiple dCas9 molecules can be released across the lifetime of a GPCR. The CRISPR ChaCha is dose-dependent, reversible, and can activate multiple endogenous genes simultaneously in response to extracellular ligands. We adopt the design to diverse GPCRs that sense a broad spectrum of ligands, including synthetic compounds, chemokines, mitogens, fatty acids, and hormones. This toolkit of CRISPR-coupled GPCRs provides a modular platform for rewiring diverse ligand sensing to targeted genome regulation for engineering cellular functions. PMID- 29263379 TI - Impact of grain boundaries on efficiency and stability of organic-inorganic trihalide perovskites. AB - Organic-inorganic perovskite solar cells have attracted tremendous attention because of their remarkably high power conversion efficiencies. To further improve device performance, it is imperative to obtain fundamental understandings on the photo-response and long-term stability down to the microscopic level. Here, we report the quantitative nanoscale photoconductivity imaging on two methylammonium lead triiodide thin films with different efficiencies by light stimulated microwave impedance microscopy. The microwave signals are largely uniform across grains and grain boundaries, suggesting that microstructures do not lead to strong spatial variations of the intrinsic photo-response. In contrast, the measured photoconductivity and lifetime are strongly affected by bulk properties such as the sample crystallinity. As visualized by the spatial evolution of local photoconductivity, the degradation process begins with the disintegration of grains rather than nucleation and propagation from visible boundaries between grains. Our findings provide insights to improve the electro optical properties of perovskite thin films towards large-scale commercialization. PMID- 29263380 TI - A two-dimensional ON/OFF switching device based on anisotropic interactions of atomic quantum dots on Si(100):H. AB - Controlling the properties of quantum dots at the atomic scale, such as dangling bonds, is a general motivation as they allow studying various nanoscale processes including atomic switches, charge storage, or low binding energy state interactions. Adjusting the coupling of individual silicon dangling bonds to form a 2D device having a defined function remains a challenge. Here, we exploit the anisotropic interactions between silicon dangling bonds on n-type doped Si(100):H surface to tune their hybridization. This process arises from interactions between the subsurface silicon network and dangling bonds inducing a combination of Jahn-Teller distortions and local charge ordering. A three-pointed star-shaped device prototype is designed. By changing the charge state of this device, its electronic properties are shown to switch reversibly from an ON to an OFF state via local change of its central gap. Our results provide a playground for the study of quantum information at the nanoscale. PMID- 29263382 TI - Neural coding: Investigating social spaces. PMID- 29263381 TI - Cross-boundary subsidy cascades from oil palm degrade distant tropical forests. AB - Native species that forage in farmland may increase their local abundances thereby affecting adjacent ecosystems within their landscape. We used two decades of ecological data from a protected primary rainforest in Malaysia to illutrate how subsidies from neighboring oil palm plantations triggered powerful secondary 'cascading' effects on natural habitats located >1.3 km away. We found (i) oil palm fruit drove 100-fold increases in crop-raiding native wild boar (Sus scrofa), (ii) wild boar used thousands of understory plants to construct birthing nests in the pristine forest interior, and (iii) nest building caused a 62% decline in forest tree sapling density over the 24-year study period. The long term, landscape-scale indirect effects from agriculture suggest its full ecological footprint may be larger in extent than is currently recognized. Cross boundary subsidy cascades may be widespread in both terrestrial and marine ecosystems and present significant conservation challenges. PMID- 29263383 TI - Inter-annual and decadal changes in teleconnections drive continental-scale synchronization of tree reproduction. AB - Climate teleconnections drive highly variable and synchronous seed production (masting) over large scales. Disentangling the effect of high-frequency (inter annual variation) from low-frequency (decadal trends) components of climate oscillations will improve our understanding of masting as an ecosystem process. Using century-long observations on masting (the MASTREE database) and data on the Northern Atlantic Oscillation (NAO), we show that in the last 60 years both high frequency summer and spring NAO, and low-frequency winter NAO components are highly correlated to continent-wide masting in European beech and Norway spruce. Relationships are weaker (non-stationary) in the early twentieth century. This finding improves our understanding on how climate variation affects large-scale synchronization of tree masting. Moreover, it supports the connection between proximate and ultimate causes of masting: indeed, large-scale features of atmospheric circulation coherently drive cues and resources for masting, as well as its evolutionary drivers, such as pollination efficiency, abundance of seed dispersers, and natural disturbance regimes. PMID- 29263386 TI - Contributions of changes in climatology and perturbation and the resulting nonlinearity to regional climate change. AB - Future changes in large-scale climatology and perturbation may have different impacts on regional climate change. It is important to understand the impacts of climatology and perturbation in terms of both thermodynamic and dynamic changes. Although many studies have investigated the influence of climatology changes on regional climate, the significance of perturbation changes is still debated. The nonlinear effect of these two changes is also unknown. We propose a systematic procedure that extracts the influences of three factors: changes in climatology, changes in perturbation and the resulting nonlinear effect. We then demonstrate the usefulness of the procedure, applying it to future changes in precipitation. All three factors have the same degree of influence, especially for extreme rainfall events. Thus, regional climate assessments should consider not only the climatology change but also the perturbation change and their nonlinearity. This procedure can advance interpretations of future regional climates. PMID- 29263384 TI - Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. AB - The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. We identified and accounted for a variety of technical and biological sources of variation in a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal and increased the concordance with post-mortem data sets. We predict a growing convergence between hiPSC and post mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones. PMID- 29263387 TI - Subtalar Joint Pronation and Energy Absorption Requirements During Walking are Related to Tibialis Posterior Tendinous Tissue Strain. AB - During human walking, the tibialis posterior (TP) tendon absorbs energy in early stance as the subtalar joint (STJ) pronates. However, it remains unclear whether an increase in energy absorption between individuals, possibly a result of larger STJ pronation displacement, is fulfilled by greater magnitudes of TP tendon or muscle fascicle strain. By collecting direct measurements of muscle fascicle length (ultrasound), MTU length (3D motion capture and musculoskeletal modelling), and TP muscle activation (intramuscular electromyography) we endeavoured to illustrate that the TP tendinous tissue fulfils the requirements for energy absorption at the STJ as a result of an increase in muscle force production. While a significant relationship between TP tendon strain, energy absorption at the STJ (R2 = 0.53, P = < 0.01) and STJ pronation (R2 = 0.53, P = < 0.01) was evident, we failed to find any significant associations between tendon strain and surrogate measure of TP muscle force (TP muscle activation together with ankle and subtalar joint moments). These results suggest that TP tendon compliance may explain the variance in pronation and energy absorption at the STJ. Therefore, as the tendinous tissue of the TP is accountable for the absorption of energy at the STJ it may be predisposed to strain-induced injury. PMID- 29263385 TI - The HIV co-receptor CCR5 regulates osteoclast function. AB - C-C chemokine receptor 5 (CCR5) is a co-receptor of HIV. Epidemiological findings suggest that the functional loss of CCR5 is correlated with a lower incidence of bone-destructive diseases as well as of HIV transmission. However, it is not clear whether CCR5 is involved in regulation of the function of bone cells, in addition to that of immune cells. Here we show that blockade of CCR5 using specific antibodies impairs human osteoclast function in vitro. Ccr5-deficient (Ccr5 -/- ) mice presented with dysfunctional osteoclasts and were resistant to osteoporosis induced by receptor activator of nuclear factor kappa-B ligand (RANKL), which triggers osteoporosis independently of inflammatory and immunomodulatory pathways. Furthermore, Ccr5 deficiency impairs the cellular locomotion and bone-resorption activity of osteoclasts, which is associated with the disarrangement of podosomes and adhesion complex molecules including Pyk2. Overall, the data provides evidence that CCR5 has an essential role in bone destructive conditions through the functional regulation of osteoclasts. PMID- 29263388 TI - Insulator-metal transition in substrate-independent VO2 thin film for phase change devices. AB - Vanadium has 11 oxide phases, with the binary VO2 presenting stimuli-dependent phase transitions that manifest as switchable electronic and optical features. An elevated temperature induces an insulator-to-metal transition (IMT) as the crystal reorients from a monoclinic state (insulator) to a tetragonal arrangement (metallic). This transition is accompanied by a simultaneous change in optical properties making VO2 a versatile optoelectronic material. However, its deployment in scalable devices suffers because of the requirement of specialised substrates to retain the functionality of the material. Sensitivity to oxygen concentration and larger-scale VO2 synthesis have also been standing issues in VO2 fabrication. Here, we address these major challenges in harnessing the functionality in VO2 by demonstrating an approach that enables crystalline, switchable VO2 on any substrate. Glass, silicon, and quartz are used as model platforms to show the effectiveness of the process. Temperature-dependent electrical and optical characterisation is used demonstrating three to four orders of magnitude in resistive switching, >60% chromic discrimination at infrared wavelengths, and terahertz property extraction. This capability will significantly broaden the horizon of applications that have been envisioned but remained unrealised due to the lack of ability to realise VO2 on any substrate, thereby exploiting its untapped potential. PMID- 29263390 TI - Brain hubs in lesion models: Predicting functional network topology with lesion patterns in patients. AB - Various important topological properties of healthy brain connectome have recently been identified. However, the manner in which brain lesion changes the functional network topology is unknown. We examined how critical specific brain areas are in the maintenance of network topology using multivariate support vector regression analysis on brain structural and resting-state functional imaging data in 96 patients with brain damages. Patients' cortical lesion distribution patterns could significantly predict the functional network topology and a set of regions with significant weights in the prediction models were identified as "lesion hubs". Intriguingly, we found two different types of lesion hubs, whose lesions associated with changes of network topology towards relatively different directions, being either more integrated (global) or more segregated (local), and correspond to hubs identified in healthy functional network in complex manners. Our results pose further important questions about the potential dynamics of the functional brain network after brain damage. PMID- 29263391 TI - Structure and function of the microbial consortia of activated sludge in typical municipal wastewater treatment plants in winter. AB - To better understand the relationship between the environmental variables and microbial communities of activated sludge, we took winter samples from different biological treatment units (anaerobic, oxic, etc) from the WWTP's of a number of Chinese cities. Differences in influent organic components and activated sludge microbial communities were identified by gas chromatography-mass spectrometry and high-throughput sequencing technology, respectively. Liquid nitrogen grinding pretreatment of samples was found to aid in the obtaining of a more bio diversified sample. Influent type and dissolved oxygen concentration influenced the activated sludge microbial community structure. Nitrospira, Caldilineaceae and Anaerolineaceae were highly related to domestic wastewater treatment systems, whereas Thauera was the most abundant putative refractory aromatic hydrocarbon decomposer found in industrial wastewater treatment systems. Within the influent composition, we speculate that Thauera, Macellibacteroides and Desulfomicrobium are the key functional genera of the anaerobic environment of the textile dyeing industry wastewater treatment systems, whilst Thauera and Thiobacillus are key functional microbes in fine chemical wastewater treatment systems. PMID- 29263389 TI - Midbrain circuit regulation of individual alcohol drinking behaviors in mice. AB - Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors. PMID- 29263392 TI - Morphology of travel routes and the organization of cities. AB - The city is a complex system that evolves through its inherent social and economic interactions. Mediating the movements of people and resources, urban street networks offer a spatial footprint of these activities. Of particular interest is the interplay between street structure and its functional usage. Here, we study the shape of 472,040 spatiotemporally optimized travel routes in the 92 most populated cities in the world, finding that their collective morphology exhibits a directional bias influenced by the attractive (or repulsive) forces resulting from congestion, accessibility, and travel demand. To capture this, we develop a simple geometric measure, inness, that maps this force field. In particular, cities with common inness patterns cluster together in groups that are correlated with their putative stage of urban development as measured by a series of socio-economic and infrastructural indicators, suggesting a strong connection between urban development, increasing physical connectivity, and diversity of road hierarchies. PMID- 29263394 TI - Biological characters of Trichogramma dendrolimi (Hymenoptera: Trichogrammatidae) reared in vitro versus in vivo for thirty generations. AB - Trichogramma dendrolimi which is an economically important biological control agent were reared for 30 generations on a modified artificial medium and natural host. Biological characters were assessed and compared with parasitoids reared in vivo. Pupation rate and normal adults rate of in vitro-reared parasitoids were significantly higher compared with in vivo-reared parasitoids. The adult emergence rate, number of adults produced, and fecundity of T. dendrolimi reared in vitro were lower than those reared in vivo. The percentage of females and longevity did not vary between the two rearing methods. The overall fitness of the parasitoids reared artificially from the first to the 20th generation was higher than of those reared from the 21st generation onwards. No differences were observed in the fitness parameters of parasitoids reared in vivo across any of the 30 generations. The results suggest that the modified artificial medium used in this study is suitable for the continuous rearing of T. dendrolimi for at least 20 generations, and has the potential for the mass production of these parasitoids for use in biological control. Such a substrate could be examined for use in rearing other parasitoid species that are important in biological control. PMID- 29263393 TI - Heartbeat Complexity Modulation in Bipolar Disorder during Daytime and Nighttime. AB - This study reports on the complexity modulation of heartbeat dynamics in patients affected by bipolar disorder. In particular, a multiscale entropy analysis was applied to the R-R interval series, that were derived from electrocardiographic (ECG) signals for a group of nineteen subjects comprised of eight patients and eleven healthy control subjects. They were monitored using a textile-based sensorized t-shirt during the day and overnight for a total of 47 diurnal and 27 nocturnal recordings. Patients showed three different mood states: depression, hypomania and euthymia. Results show a clear loss of complexity during depressive and hypomanic states as compared to euthymic and healthy control states. In addition, we observed that a more significant complexity modulation among healthy and pathological mood states occurs during the night. These findings suggest that bipolar disorder is associated with an enhanced sleep-related dysregulation of the Autonomic Nervous System (ANS) activity, and that heartbeat complex dynamics may serve as a viable marker of pathological conditions in mental health. PMID- 29263395 TI - Surface modifications for phase change cooling applications via crenarchaeon Sulfolobus solfataricus P2 bio-coatings. AB - Due to its high heat removal capability and exploitation of latent heat, boiling is considered to be one of the most effective cooling methods in industry. Surface structure and wettability are two factors imposing boiling phenomena. Here, we propose an effective and facile method for surface enhancement via crenarchaeon Sulfolobus Solfataricus P2 bio-coatings. The positive effects of such surfaces of bio-coatings were assessed, and enhancements in heat transfer and cooling were obtained. Visualization was also performed, and bubble dynamics of generated bubbles and vapor columns from the tested surfaces with bio-coatings are here presented. Superior performance in terms of boiling heat transfer and cooling was reached with the use of crenarchaeon Sulfolobus Solfataricus P2 coated surfaces. Thus, this study clearly demonstrates the potential of futuristic surfaces with bio-coatings to achieve substantial energy saving and efficiency. PMID- 29263396 TI - Inhaled bronchodilators and acute myocardial infarction: a nested case-control study. AB - We investigated the association between the use of inhaled bronchodilators and the risk of AMI. A nested case-control study using the nationwide insurance claims database was conducted. Overall, 11,054 AMI cases and 47,815 matched (up to 1:5) controls were identified from 1,036,119 subjects without acute major cardiovascular events in the past year. Long-acting and short-acting beta agonists (LABAs and SABAs) were associated with increase in the risk of AMI, although an inhaled corticosteroid combined with a long-acting beta-agonist was not. Long-acting muscarinic antagonists (LAMAs) in a dry powder inhaler (DPI) were significantly associated with reduced risk of AMI, while LAMAs in a soft mist inhaler (SMI) didn't decrease the risk of it. In hypertensive or diabetic patients, LAMAs in a DPI were associated with reduced risk of AMI, but LABAs were associated with increased risk. Among the beta-blocker users, the reduction of AMI risk by LAMAs was the most significant. In conclusions, inhaled beta-agonists were associated with increase in the risk of AMI, while LABAs accompanied by ICSs were not associated with increase in the risk of AMI. LAMAs in a DPI use were associated with lower risk of AMI. PMID- 29263397 TI - Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice. AB - There exists an intricate relationship between hypercholesterolemia (elevated plasma cholesterol) and brain functions. The present study aims to understand the impact of hypercholesterolemia on pathological consequences in mouse brain. A chronic mouse model of hypercholesterolemia was induced by giving high cholesterol diet for 12 weeks. The hypercholesterolemic mice developed cognitive impairment as evident from object recognition memory test. Cholesterol accumulation was observed in four discrete brain regions, such as cortex, striatum, hippocampus and substantia nigra along with significantly damaged blood brain barrier by hypercholesterolemia. The crucial finding is the loss of acetylcholinesterase activity with mitochondrial dysfunction globally in the brain of hypercholesterolemic mice, which is related to the levels of cholesterol. Moreover, the levels of hydroxyl radical were elevated in the regions of brain where the activity of mitochondrial complexes was found to be reduced. Intriguingly, elevations of inflammatory stress markers in the cholesterol-rich brain regions were observed. As cognitive impairment, diminished brain acetylcholinesterase activity, mitochondrial dysfunctions, and inflammation are the prima facie pathologies of neurodegenerative diseases, the findings impose hypercholesterolemia as potential risk factor towards brain dysfunction. PMID- 29263398 TI - Forest productivity in southwestern Europe is controlled by coupled North Atlantic and Atlantic Multidecadal Oscillations. AB - The North Atlantic Oscillation (NAO) depicts annual and decadal oscillatory modes of variability responsible for dry spells over the European continent. The NAO therefore holds a great potential to evaluate the role, as carbon sinks, of water limited forests under climate change. However, uncertainties related to inconsistent responses of long-term forest productivity to NAO have so far hampered firm conclusions on its impacts. We hypothesize that, in part, such inconsistencies might have their origin in periodical sea surface temperature anomalies in the Atlantic Ocean (i.e., Atlantic Multidecadal Oscillation, AMO). Here we show strong empirical evidence in support of this hypothesis using 120 years of periodical inventory data from Iberian pine forests. Our results point to AMO+ NAO+ and AMO-NAO- phases as being critical for forest productivity, likely due to decreased winter water balance and abnormally low winter temperatures, respectively. Our findings could be essential for the evaluation of ecosystem functioning vulnerabilities associated with increased climatic anomalies under unprecedented warming conditions in the Mediterranean. PMID- 29263399 TI - RON4L1 is a new member of the moving junction complex in Toxoplasma gondii. AB - Apicomplexa parasites, including Toxoplasma and Plasmodium species, possess a unique invasion mechanism that involves a tight apposition between the parasite and the host plasma membranes, called "moving junction" (MJ). The MJ is formed by the assembly of the microneme protein AMA1, exposed at the surface of the parasite, and the parasite rhoptry neck (RON) protein RON2, exposed at the surface of the host cell. In the host cell, RON2 is associated with three additional parasite RON proteins, RON4, RON5 and RON8. Here we describe RON4L1, an additional member of the MJ complex in Toxoplasma. RON4L1 displays some sequence similarity with RON4 and is cleaved at the C-terminal end before reaching the rhoptry neck. Upon secretion during invasion, RON4L1 is associated with MJ and targeted to the cytosolic face of the host membrane. We generated a RON4 L1 knock-out cell line and showed that it is not essential for the lytic cycle in vitro, although mutant parasites kill mice less efficiently. Similarly to RON8, RON4L1 is a coccidian-specific protein and its traffic to the MJ is not affected in absence of RON2, RON4 and RON5, suggesting the co-existence of independent MJ complexes in tachyzoite of Toxoplasma. PMID- 29263400 TI - Three classes of ligands each bind to distinct sites on the orphan G protein coupled receptor GPR84. AB - Medium chain fatty acids can activate the pro-inflammatory receptor GPR84 but so also can molecules related to 3,3'-diindolylmethane. 3,3'-Diindolylmethane and decanoic acid acted as strong positive allosteric modulators of the function of each other and analysis showed the affinity of 3,3'-diindolylmethane to be at least 100 fold higher. Methyl decanoate was not an agonist at GPR84. This implies a key role in binding for the carboxylic acid of the fatty acid. Via homology modelling we predicted and confirmed an integral role of arginine172, located in the 2nd extracellular loop, in the action of decanoic acid but not of 3,3' diindolylmethane. Exemplars from a patented series of GPR84 antagonists were able to block agonist actions of both decanoic acid and 3,3'-diindolylmethane at GPR84. However, although a radiolabelled form of a related antagonist, [3H]G9543, was able to bind with high affinity to GPR84, this was not competed for by increasing concentrations of either decanoic acid or 3,3'-diindolylmethane and was not affected adversely by mutation of arginine172. These studies identify three separable ligand binding sites within GPR84 and suggest that if medium chain fatty acids are true endogenous regulators then co-binding with a positive allosteric modulator would greatly enhance their function in physiological settings. PMID- 29263401 TI - Single-cell-based evaluation of sperm progressive motility via fluorescent assessment of mitochondria membrane potential. AB - Sperm cells progressive motility is the most important parameter involved in the fertilization process. Sperm middle piece contains mitochondria, which play a critical role in energy production and whose proper operation ensures the reproductive success. Notably, sperm progressive motility is strictly related to mitochondrial membrane potential (MMP) and consequently to mitochondrial functionality. Although previous studies presented an evaluation of mitochondrial function through MMP assessment in entire sperm cells samples, a quantitative approach at single-cell level could provide more insights in the analysis of semen quality. Here we combine laser scanning confocal microscopy and functional fluorescent staining of mitochondrial membrane to assess MMP distribution among isolated spermatozoa. We found that the sperm fluorescence value increases as a function of growing progressive motility and that such fluorescence is influenced by MMP disruptors, potentially allowing for the discrimination of different quality classes of sperm cells in heterogeneous populations. PMID- 29263403 TI - Modulating Thin Film Transistor Characteristics by Texturing the Gate Metal. AB - The development of reliable, high performance integrated circuits based on thin film transistors (TFTs) is of interest for the development of flexible electronic circuits. In this work we illustrate the modulation of TFT transconductance via the texturing of the gate metal created by the addition of a conductive pattern on top of a planar gate. Texturing results in the semiconductor-insulator interface acquiring a non-planar geometry with local variations in the radius of curvature. This influences various TFT parameters such as the subthreshold slope, gate voltage at the onset of conduction, contact resistance and gate capacitance. Specific studies are performed on textures based on periodic striations oriented along different directions. Textured TFTs showed upto +/-40% variation in transconductance depending on the texture orientation as compared to conventional planar gate TFTs. Analytical models are developed and compared with experiments. Gain boosting in common source amplifiers based on textured TFTs as compared to conventional TFTs is demonstrated. PMID- 29263402 TI - Genome-wide association study identifies a missense variant at APOA5 for coronary artery disease in Multi-Ethnic Cohorts from Southeast Asia. AB - Recent genome-wide association studies (GWAS) have identified multiple loci associated with coronary artery disease (CAD) among predominantly Europeans. However, their relevance to multi-ethnic populations from Southeast Asia is largely unknown. We performed a meta-analysis of four GWAS comprising three Chinese studies and one Malay study (Total N = 2,169 CAD cases and 7,376 controls). Top hits (P < 5 * 10-8) were further evaluated in 291 CAD cases and 1,848 controls of Asian Indians. Using all datasets, we validated recently identified loci associated with CAD. The involvement of known canonical pathways in CAD was tested by Ingenuity Pathway Analysis. We identified a missense SNP (rs2075291, G > T, G185C) in APOA5 for CAD that reached robust genome-wide significance (Meta P = 7.09 * 10-10, OR = 1.636). Conditional probability analysis indicated that the association at rs2075291 was independent of previously reported index SNP rs964184 in APOA5. We further replicated 10 loci previously identified among predominantly Europeans (P: 1.33 * 10-7-0.047). Seven pathways (P: 1.10 * 10-5-0.019) were identified. We identified a missense SNP, rs2075291, in APOA5 associated with CAD at a genome-wide significance level and provided new insights into pathways contributing to the susceptibility to CAD in the multi-ethnic populations from Southeast Asia. PMID- 29263404 TI - Identifying the ubiquitination targets of E6AP by orthogonal ubiquitin transfer. AB - E3 ubiquitin (UB) ligases are the ending modules of the E1-E2-E3 cascades that transfer UB to cellular proteins and regulate their biological functions. Identifying the substrates of an E3 holds the key to elucidate its role in cell regulation. Here, we construct an orthogonal UB transfer (OUT) cascade to identify the substrates of E6AP, a HECT E3 also known as Ube3a that is implicated in cancer and neurodevelopmental disorders. We use yeast cell surface display to engineer E6AP to exclusively transfer an affinity-tagged UB variant (xUB) to its substrate proteins. Proteomic identification of xUB-conjugated proteins in HEK293 cells affords 130 potential E6AP targets. Among them, we verify that MAPK1, CDK1, CDK4, PRMT5, beta-catenin, and UbxD8 are directly ubiquitinated by E6AP in vitro and in the cell. Our work establishes OUT as an efficient platform to profile E3 substrates and reveal the cellular circuits mediated by the E3 enzymes. PMID- 29263406 TI - Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition. AB - In the version of this article initially published, author Charan Ranganath's last name was misspelled Rangananth in the author list. Also, A. David Redish (redish@umn.edu) has been added as a corresponding author. The error has been corrected, and the corresponding author added, in the HTML and PDF versions of the article. PMID- 29263405 TI - Bio-inspired reversible underwater adhesive. AB - The design of smart surfaces with switchable adhesive properties in a wet environment has remained a challenge in adhesion science and materials engineering. Despite intense demands in various industrial applications and exciting progress in mimicking the remarkable wet adhesion through the delicate control of catechol chemistry, polyelectrolyte complex, and supramolecular architectures, the full recapitulation of nature's dynamic function is limited. Here, we show a facile approach to synthesize bioinspired adhesive, which entails the reversible, tunable, and fast regulation of the wet adhesion on diverse surfaces. The smart wet adhesive takes advantage of the host-guest molecular interaction and the adhesive nature of catechol chemistry, as well as the responsive polymer, allowing for screening and activation of the interfacial interaction simply by a local temperature trigger in an on-demand manner. Our work opens up an avenue for the rational design of bioinspired adhesives with performances even beyond nature. PMID- 29263407 TI - Author Correction: Synuclein and dopamine: the Bonnie and Clyde of Parkinson's disease. AB - In the version of this article initially published, the molecular mass of synuclein was given as 140 kDa instead of ~14 kDa. The error has been corrected in the HTML and PDF versions of the article. PMID- 29263408 TI - Reinstatement of contextual conditioned anxiety in virtual reality and the effects of transcutaneous vagus nerve stimulation in humans. AB - Since exposure therapy for anxiety disorders incorporates extinction of contextual anxiety, relapses may be due to reinstatement processes. Animal research demonstrated more stable extinction memory and less anxiety relapse due to vagus nerve stimulation (VNS). We report a valid human three-day context conditioning, extinction and return of anxiety protocol, which we used to examine effects of transcutaneous VNS (tVNS). Seventy-five healthy participants received electric stimuli (unconditioned stimuli, US) during acquisition (Day1) when guided through one virtual office (anxiety context, CTX+) but never in another (safety context, CTX-). During extinction (Day2), participants received tVNS, sham, or no stimulation and revisited both contexts without US delivery. On Day3, participants received three USs for reinstatement followed by a test phase. Successful acquisition, i.e. startle potentiation, lower valence, higher arousal, anxiety and contingency ratings in CTX+ versus CTX-, the disappearance of these effects during extinction, and successful reinstatement indicate validity of this paradigm. Interestingly, we found generalized reinstatement in startle responses and differential reinstatement in valence ratings. Altogether, our protocol serves as valid conditioning paradigm. Reinstatement effects indicate different anxiety networks underlying physiological versus verbal responses. However, tVNS did neither affect extinction nor reinstatement, which asks for validation and improvement of the stimulation protocol. PMID- 29263409 TI - A Retrospective Multicentric Study of Ewing Sarcoma Family of Tumors in Patients Older Than 50: Management and Outcome. AB - Ewing's sarcoma family of tumors (EFTs) is a group of rare and aggressive tumors. Data on EFTs in patients (pts) >= 50 years are limited and these pts are often not eligible for clinical trials. Some, but not all, studies have reported inferior outcome for older pts with EFTs. We conducted an IRB-approved retrospective analysis among centers of the French Sarcoma Group on pts diagnosed with EFTs at age >=50 between 2000 and 2012. Clinical features, treatment modality and outcomes were analyzed. Seventy-seven pts were identified, including 36 females (46.8%) and the median age at diagnosis was 56 years (range: 50-86). The primary tumor was located in soft tissue in 59 pts (76.6%). Fifty-six pts (72.7%) had localized disease, among them 49 (87.5%) received chemotherapy in addition to local therapy. Their estimated 3-yr OS and event-free survival (EFS) rates were respectively 73.3% and 62.2%. Recurrence occurred in 43 pts. The estimated 3-yr OS rate was 37% in pts with metastatic disease at presentation. EFTs in pts >=50 years are more likely to originate from soft tissue and their outcomes appear to be worse than that of younger pts treated with modern protocols. PMID- 29263410 TI - Regulation of ribonucleotide synthesis by the Pseudomonas aeruginosa two component system AlgR in response to oxidative stress. AB - Ribonucleotide reductases (RNR) catalyze the last step of deoxyribonucleotide synthesis, and are therefore essential to DNA-based life. Three forms of RNR exist: classes I, II, and III. While eukaryotic cells use only class Ia RNR, bacteria can harbor any combination of classes, granting them adaptability. The opportunistic pathogen Pseudomonas aeruginosa surprisingly encodes all three classes, allowing it to thrive in different environments. Here we study an aspect of the complex RNR regulation whose molecular mechanism has never been elucidated, the well-described induction through oxidative stress, and link it to the AlgZR two-component system, the primary regulator of the mucoid phenotype. Through bioinformatics, we identify AlgR binding locations in RNR promoters, which we characterize functionally through EMSA and physically through AFM imaging. Gene reporter assays in different growth models are used to study the AlgZR-mediated control on the RNR network under various environmental conditions and physiological states. Thereby, we show that the two-component system AlgZR, which is crucial for bacterial conversion to the mucoid phenotype associated with chronic disease, controls the RNR network and directs how the DNA synthesis pathway is modulated in mucoid and non-mucoid biofilms, allowing it to respond to oxidative stress. PMID- 29263411 TI - Tissue Tropism in Host Transcriptional Response to Members of the Bovine Respiratory Disease Complex. AB - Bovine respiratory disease (BRD) is the most common infectious disease of beef and dairy cattle and is characterized by a complex infectious etiology that includes a variety of viral and bacterial pathogens. We examined the global changes in mRNA abundance in healthy lung and lung lesions and in the lymphoid tissues bronchial lymph node, retropharyngeal lymph node, nasopharyngeal lymph node and pharyngeal tonsil collected at the peak of clinical disease from beef cattle experimentally challenged with either bovine respiratory syncytial virus, infectious bovine rhinotracheitis, bovine viral diarrhea virus, Mannheimia haemolytica or Mycoplasma bovis. We identified signatures of tissue-specific transcriptional responses indicative of tropism in the coordination of host's immune tissue responses to infection by viral or bacterial infections. Furthermore, our study shows that this tissue tropism in host transcriptional response to BRD pathogens results in the activation of different networks of response genes. The differential crosstalk among genes expressed in lymphoid tissues was predicted to be orchestrated by specific immune genes that act as 'key players' within expression networks. The results of this study serve as a basis for the development of innovative therapeutic strategies and for the selection of cattle with enhanced resistance to BRD. PMID- 29263412 TI - Peptide aptamer-modified single-walled carbon nanotube-based transistors for high performance biosensors. AB - Biosensors employing single-walled carbon nanotube field-effect transistors (SWCNT FETs) offer ultimate sensitivity. However, besides the sensitivity, a high selectivity is critically important to distinguish the true signal from interference signals in a non-controlled environment. This work presents the first demonstration of the successful integration of a novel peptide aptamer with a liquid-gated SWCNT FET to achieve highly sensitive and specific detection of Cathepsin E (CatE), a useful prognostic biomarker for cancer diagnosis. Novel peptide aptamers that specifically recognize CatE are engineered by systemic in vitro evolution. The SWCNTs were firstly grown using the thermal chemical vapor deposition (CVD) method and then were employed as a channel to fabricate a SWCNT FET device. Next, the SWCNTs were functionalized by noncovalent immobilization of the peptide aptamer using 1-pyrenebutanoic acid succinimidyl ester (PBASE) linker. The resulting FET sensors exhibited a high selectivity (no response to bovine serum albumin and cathepsin K) and label-free detection of CatE at unprecedentedly low concentrations in both phosphate-buffered saline (2.3 pM) and human serum (0.23 nM). Our results highlight the use of peptide aptamer-modified SWCNT FET sensors as a promising platform for near-patient testing and point-of care testing applications. PMID- 29263413 TI - Modeling of autophagy-related gene expression dynamics during long term fasting in European eel (Anguilla anguilla). AB - Autophagy is an evolutionary conserved cellular self-degradation process considered as a major energy mobilizing system in eukaryotes. It has long been considered as a post-translationally regulated event, and the importance of transcriptional regulation of autophagy-related genes (atg) for somatic maintenance and homeostasis during long period of stress emerged only recently. In this regard, large changes in atg transcription have been documented in several species under diverse types of prolonged catabolic situations. However, the available data primarily concern atg mRNA levels at specific times and fail to capture the dynamic relationship between transcript production over time and integrated phenotypes. Here, we present the development of a statistical model describing the dynamics of expression of several atg and lysosomal genes in European glass eel (Anguilla anguilla) during long-term fasting at two temperatures (9 degrees C and 12 degrees C) and make use of this model to infer the effect of transcripts dynamics on an integrated phenotype - here weight loss. Our analysis shows long-term non-random fluctuating atg expression dynamics and reveals for the first time a significant contribution of atg transcripts production over time to weight loss. The proposed approach thus offers a new perspective on the long-term transcriptional control of autophagy and its physiological role. PMID- 29263414 TI - Focal facial dermal dysplasia type 4: identification of novel CYP26C1 mutations in unrelated patients. AB - The focal facial dermal dysplasias (FFDDs) are a group of rare inherited developmental disorders characterized by congenital scar-like atrophic lesions in the bitemporal (FFDD1, 2, and 3) or preauricular (FFDD4) areas. FFDD4 is an autosomal-recessive trait characterized by preauricular skin defects without additional dysmorphic findings. Previously, only two CYP26C1 mutations in four unrelated patients with FFDD4 were reported. Here, we report two additional unrelated FFDD4 patients with four CYP26C1 mutations including three novel lesions: a missense mutation, c.230G>C (p.Arg77Pro), and two splice-site mutations, c.1191+1G>T (IVS5(+1)G>T) and c.1191+2insT (IVS5(+2)insT). In silico analyses predicted all three mutations as pathogenic. Compound heterozygosity was validated through parental studies. These results provide further evidence that CYP26C1 mutations are the molecular genetic basis of FFDD4. Identification of additional cases by dermatologists, pediatricians, and medical geneticists will lead to further understanding of the clinical spectrum of FFDD4 and define its molecular genetic heterogeneity. PMID- 29263415 TI - Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma. AB - The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro, to date no Grp94 selective inhibitors have been investigated in vivo. Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct Hsp90 family member holds translational promise for ocular and other diseases associated with cell stress and protein misfolding. PMID- 29263416 TI - EGCG-mediated Protection of the Membrane Disruption and Cytotoxicity Caused by the 'Active Oligomer' of alpha-Synuclein. AB - (-)-Epigallocatechin gallate (EGCG), the major component of green tea, has been re-evaluated with alpha-synuclein (alphaS), a pathological constituent of Parkinson's disease, to elaborate its therapeutic value. EGCG has been demonstrated to not only induce the off-pathway 'compact' oligomers of alphaS as suggested previously, but also drastically enhance the amyloid fibril formation of alphaS. Considering that the EGCG-induced amyloid fibrils could be a product of on-pathway SDS-sensitive 'transient' oligomers, the polyphenol effect on the transient 'active' oligomers (AOs) was investigated. By facilitating the fibril formation and thus eliminating the toxic AOs, EGCG was shown to suppress the membrane disrupting radiating amyloid fibril formation on the surface of liposomal membranes and thus protect the cells which could be readily affected by AOs. Taken together, EGCG has been suggested to exhibit its protective effect against the alphaS-mediated cytotoxicity by not only producing the off-pathway 'compact' oligomers, but also facilitating the conversion of 'active' oligomers into amyloid fibrils. PMID- 29263418 TI - Preparing Rubisco for a tune up. PMID- 29263417 TI - The activity of myeloid cell-specific VHH immunotoxins is target-, epitope-, subset- and organ dependent. AB - The central role of myeloid cells in driving autoimmune diseases and cancer has raised interest in manipulating their function or depleting them for therapeutic benefits. To achieve this, antibodies are used to antagonize differentiation, survival and polarization signals or to kill target cells, for example in the form of antibody-drug conjugates (ADC). The action of ADC in vivo can be hard to predict based on target expression pattern alone. The biology of the targeted receptor as well as its interplay with the ADC can have drastic effects on cell apoptosis versus survival. Here we investigated the efficacy of CD11b or Ly-6C/Ly 6G-specific variable fragments of camelid heavy chain-only antibodies (VHH) conjugated to Pseudomonas exotoxin A to deplete myeloid cells in vitro and in vivo. Our data highlight striking differences in cell killing in vivo, depending on the cell subset and organs targeted, but not antigen expression level or VHH affinity. We observed striking differences in depletion efficiency of monocytes versus granulocytes in mice. Despite similar binding of Ly-6C/Ly-6G-specific VHH immunotoxin to granulocytes and monocytes, granulocytes were significantly more sensitive than monocytes to immunotoxins treatment. Our results illustrate the need of early, thorough in vivo characterization of ADC candidates. PMID- 29263419 TI - Atomic structural details of a protein grafted onto gold nanoparticles. AB - The development of a methodology for the structural characterization at atomic detail of proteins conjugated to nanoparticles would be a breakthrough in nanotechnology. Solution and solid-state NMR spectroscopies are currently used to investigate molecules and peptides grafted onto nanoparticles, but the strategies used so far fall short in the application to proteins, which represent a thrilling development in theranostics. We here demonstrate the feasibility of highly-resolved multidimensional heteronuclear spectra of a large protein assembly conjugated to PEGylated gold nanoparticles. The spectra have been obtained by direct proton detection under fast MAS and allow for both a fast fingerprinting for the assessment of the preservation of the native fold and for resonance assignment. We thus demonstrate that the structural characterization and the application of the structure-based methodologies to proteins bound to gold nanoparticles is feasible and potentially extensible to other hybrid protein nanomaterials. PMID- 29263421 TI - The evolving landscape of metastatic hormone-sensitive prostate cancer: a critical review of the evidence for adding docetaxel or abiraterone to androgen deprivation. AB - BACKGROUND: Until 2015, androgen deprivation therapy (ADT) alone was the standard of-care for metastatic hormone-sensitive prostate cancer (mHSPC). In 2015, the CHAARTED and STAMPEDE-Docetaxel studies demonstrated marked survival benefit with the addition of docetaxel to ADT in the mHSPC setting, leading to a change in the standard-of-care for mHSPC. The recent LATITUDE and STAMPEDE-Abiraterone trials showed similar substantial improvement in survival with the addition of abiraterone plus prednisone to ADT in this space. METHODS: We conducted a review of the randomized phase III studies that have investigated either the addition of docetaxel or abiraterone to ADT in patients with mHSPC. RESULTS: We describe the study designs, key eligibility criteria, and key results for the CHAARTED, STAMPEDE-Docetaxel, GETUG-AFU 15, LATITUDE, and STAMPEDE-Abiraterone clinical trials. We compare the data for abiraterone/prednisone plus ADT in mHSPC with the evidence for docetaxel plus ADT in these patients. Finally, we discuss several factors that should be considered when choosing between docetaxel/ADT or abiraterone/prednisone/ADT in mHSPC. CONCLUSIONS: The management of mHSPC is evolving. Abiraterone plus prednisone in addition to ADT has emerged as an alternative standard-of-care to docetaxel plus ADT, and ongoing trials should clarify whether combination vs. sequential approaches with AR-targeting agents and taxane chemotherapy are preferred for initial management in the hormone sensitive setting. PMID- 29263420 TI - Post prostatectomy outcomes of patients with high-risk prostate cancer treated with neoadjuvant androgen blockade. AB - BACKGROUND: Patients with high-risk prostate cancer have an increased likelihood of experiencing a relapse following radical prostatectomy (RP). We previously conducted three neoadjuvant androgen-deprivation therapy (ADT) trials prior to RP in unfavorable intermediate and high-risk disease. METHODS: In this analysis, we report on the post-RP outcomes of a subset of patients enrolled on these studies. We conducted a pooled analysis of patients with available follow-up data treated on three neoadjuvant trials at three institutions. All patients received intense ADT prior to RP. The primary endpoint was time to biochemical recurrence (BCR). BCR was defined as a PSA >= 0.2 ng/mL or treatment with radiation or androgen deprivation therapy for a rising PSA < 0.2 ng/mL. RESULTS: Overall, 72 patients were included of whom the majority had a Gleason score >= 8 (n = 46, 63.9%). Following neoadjuvant therapy, 55.7% of patients (n = 39/70) had pT3 disease, 40% (n = 28) had seminal vesicle invasion, 12.9% (n = 9) had positive margins, and 11.4% (n = 8) had lymph node involvement. Overall, 11 (15.7%) had tumor measuring <= 0.5 cm, which included four patients (5.7%) with a pathologic complete response and seven (10.0%) with residual tumor measuring 0.1-0.5 cm. Compared to pretreatment clinical staging, 10 patients (14.3%) had pathologic T downstaging at RP. The median follow-up was 3.4 years. Overall, the 3-year BCR-free rate was 70% (95% CI 57%, 90%). Of the 15 patients with either residual tumor <= 0.5 cm or pathologic T downstaging, no patient experienced a recurrence. CONCLUSION: In this exploratory pooled clinical trials analysis, we highlight that neoadjuvant therapy prior to RP in unfavorable intermediate and high-risk patients may potentially have a positive impact on recurrence rates. Larger studies with longer follow-up periods are warranted to evaluate the impact of neoadjuvant hormone therapy on pathologic and long-term outcomes. PMID- 29263422 TI - Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice. AB - Hepatocellular carcinoma (HCC) has the second lowest 5-year survival rate (~16%) of all tumor types partly owing to the lack of effective therapeutic agents. Withaferin A (WA) is a bioactive molecule derived from Withania somnifera and the present study is designed to systemically investigate the anti-HCC efficacy of WA. WA inhibited growth, migration and invasion of HCC cells. Using a phospho kinase screening array, we discovered that WA increased phosphorylation of ERK and p38 in HCC. Further analyses revealed a key role of ERK leading to increased phosphorylation of p90-ribosomal S6 kinase (RSK) and a concomitant activation of ETS-like transcription factor-1(ELK1) and Death Receptor protein-5 (DR5) in HCC. Importantly, oral administration of WA effectively inhibited HepG2-xenografts and DEN-induced-HCC in C57BL/6 mice. Analyses of WA-treated HepG2-xenografts and DEN induced-HCC tumors showed elevated levels of ERK, RSK, ELK1 and DR5 along with decreased expression of Ki67. In silico analyses of HCC, utilizing published profiling studies showed an inverse correlation between DR5 and Ki67. These data showed the efficacy of WA as an effective agent for HCC inhibition and provided first in vitro and in vivo evidence supporting the key role of a novel crosstalk between WA, ERK/RSK, ELK1, and DR5 in HCC inhibition. PMID- 29263423 TI - Broadband impedance match to two-dimensional materials in the terahertz domain. AB - The coupling of an electromagnetic plane wave to a thin conductor depends on the sheet conductance of the material: a poor conductor interacts weakly with the incoming light, allowing the majority of the radiation to pass; a good conductor also does not absorb, reflecting the wave almost entirely. For suspended films, the transition from transmitter to reflector occurs when the sheet resistance is approximately the characteristic impedance of free space (Z 0 = 377 Omega). Near this point, the interaction is maximized, and the conductor absorbs strongly. Here we show that monolayer graphene, a tunable conductor, can be electrically modified to reach this transition, thereby achieving the maximum absorptive coupling across a broad range of frequencies in terahertz (THz) band. This property to be transparent or absorbing of an electromagnetic wave based on tunable electronic properties (rather than geometric structure) is expected to have numerous applications in mm wave and THz components and systems. PMID- 29263424 TI - Machine Learning for Nuclear Mechano-Morphometric Biomarkers in Cancer Diagnosis. AB - Current cancer diagnosis employs various nuclear morphometric measures. While these have allowed accurate late-stage prognosis, early diagnosis is still a major challenge. Recent evidence highlights the importance of alterations in mechanical properties of single cells and their nuclei as critical drivers for the onset of cancer. We here present a method to detect subtle changes in nuclear morphometrics at single-cell resolution by combining fluorescence imaging and deep learning. This assay includes a convolutional neural net pipeline and allows us to discriminate between normal and human breast cancer cell lines (fibrocystic and metastatic states) as well as normal and cancer cells in tissue slices with high accuracy. Further, we establish the sensitivity of our pipeline by detecting subtle alterations in normal cells when subjected to small mechano-chemical perturbations that mimic tumor microenvironments. In addition, our assay provides interpretable features that could aid pathological inspections. This pipeline opens new avenues for early disease diagnostics and drug discovery. PMID- 29263425 TI - Integrated nano-opto-electro-mechanical sensor for spectrometry and nanometrology. AB - Spectrometry is widely used for the characterization of materials, tissues, and gases, and the need for size and cost scaling is driving the development of mini and microspectrometers. While nanophotonic devices provide narrowband filtering that can be used for spectrometry, their practical application has been hampered by the difficulty of integrating tuning and read-out structures. Here, a nano opto-electro-mechanical system is presented where the three functionalities of transduction, actuation, and detection are integrated, resulting in a high resolution spectrometer with a micrometer-scale footprint. The system consists of an electromechanically tunable double-membrane photonic crystal cavity with an integrated quantum dot photodiode. Using this structure, we demonstrate a resonance modulation spectroscopy technique that provides subpicometer wavelength resolution. We show its application in the measurement of narrow gas absorption lines and in the interrogation of fiber Bragg gratings. We also explore its operation as displacement-to-photocurrent transducer, demonstrating optomechanical displacement sensing with integrated photocurrent read-out. PMID- 29263427 TI - High-efficiency terahertz devices based on cross-polarization converter. AB - Metasurface-based devices have been investigated intensively because of their attractive properties but these devices generally suffer from low efficiency. Here we demonstrate several high-efficiency terahertz (THz) devices based on cross-polarization converters that is composed of bilayer metasurface-based structures. The converter can transfer the polarization states of transmitted THz waves from the x-direction into the y-direction with an experimental conversion efficiency of 85%. This high-efficiency transfer mechanism is investigated in detail. Furthermore, this kind of devices can be fabricated easily. A THz metalens is designed and fabricated and its focusing and imaging properties are investigated experimentally. A pure phase THz hologram that can generate different images on different propagation planes is also designed and the image reconstruction capabilities of the phase holograms are demonstrated experimentally. The performance levels of all designed devices show excellent agreement between the theoretical expectations and the corresponding experimental results. This technology may pave the way towards practical applications of such metasurface devices. PMID- 29263426 TI - Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation. AB - Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/beta catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway. PMID- 29263429 TI - Calcification Propensity of Serum is Independent of Excretory Renal Function. AB - Vascular calcification is a component of cardiovascular disease, which is leading cause of death in patients with chronic kidney disease (CKD). A functional assay (T50-test) measuring the propensity of human serum to calcify associates with mortality and cardiovascular events in CKD patients. Calcification propensity is known to increase with CKD stage. We investigated whether the T50 readout is directly dependent on excretory kidney function (eGFR) or rather explained by deranged parameters of bone and mineral metabolism in the course of CKD. T50, along with markers implicated in calcification and mineral metabolism, were measured in a cross-sectional cohort of 118 patients with CKD stage 1-5. Associations of T50 with measured parameters were analysed and partial correlations performed to test to which extent the association of T50 with eGFR can be attributed to variation of these parameters. T50 correlates with eGFR, but serum levels of phosphate and calcium largely explain this association. Phosphate, magnesium, fetuin A, albumin, bicarbonate, and serum cross-laps but not Parathyroid Hormone or Fibroblast Growth Factor 23 are associated with T50 in multivariate adjusted models. These findings indicate that T50 values depend mainly on the concentration of promoters and inhibitors of calcification in serum, but not excretory kidney function. PMID- 29263428 TI - Deciphering the emergence, genetic diversity and evolution of classical swine fever virus. AB - Classical swine fever (CSF) is one of the most important infectious diseases causing significant economic losses. Its causal agent, CSF virus (CSFV), is a member of the Pestivirus genus included into the Flaviviridae family. Previous molecular epidemiology studies have revealed the CSFV diversity is divided into three main genotypes and different subgenotypes. However, the classification system for CSFV has not yet been harmonized internationally. Similarly, the phylogeny and evolutionary dynamics of CSFV remain unclear. The current study provides novel and significant insights into the origin, diversification and evolutionary process of CSFV. In addition, the best phylogenetic marker for CSFV capable of reproducing the same phylogenetic and evolutionary information as the complete viral genome is characterized. Also, a reliable cut-off to accurately classify CSFV at genotype and subgenotype levels is established. Based on the time for the most recent common ancestor (tMRCA) reconstruction and cophylogenetic analysis, it was determined that CSFV emerged around 225 years ago when the Tunisian Sheep Virus jumped from its natural host to swine. CSFV emergence was followed by a genetic expansion in three main lineages, driven by the action of positive selection pressure and functional divergence, as main natural forces. PMID- 29263430 TI - Three tandem promoters, together with IHF, regulate growth phase dependent expression of the Escherichia coli kps capsule gene cluster. AB - In this study we characterise three tandem promoters (PR1-1, PR1-2 and PR1-3) within the PR1 regulatory region of the Escherichia coli kps capsule gene cluster. Transcription from promoter PR1-2 was dependent on the activity of the upstream promoter PR1-1, which activated PR1-2 via transcription coupled DNA supercoiling. During growth at 37 degrees C a temporal pattern of transcription from all three promoters was observed with maximum transcriptional activity evident during mid-exponential phase followed by a sharp decrease in activity as the cells enter stationary phase. The growth phase dependent transcription was regulated by Integration Host Factor (IHF), which bound within the PR1 region to repress transcription from PR1-2 and PR1-3. This pattern of transcription was mirrored by growth phase dependent expression of the K1 capsule. Overall these data reveal a complex pattern of transcriptional regulation for an important virulence factor with IHF playing a role in regulating growth phase expression. PMID- 29263431 TI - Chemical and physical factors of desensitizing and/or anti-erosive toothpastes associated with lower erosive tooth wear. AB - Toothpastes have a complex formulation and their different chemical and physical factors will influence their effectiveness against erosive tooth wear (ETW). We, therefore, investigated the effect of different desensitizing and/or anti-erosive toothpastes on initial enamel erosion and abrasion, and analysed how the interplay of their chemical and physical factors influences ETW. Human enamel specimens were submitted to 5 erosion-abrasion cycles using 9 different toothpastes and an artificial saliva group, and enamel surface loss (SL) was calculated. Chemical and physical factors (pH; presence of tin; calcium, phosphate and fluoride concentrations; % weight of solid particles; wettability; and particle size) of the toothpaste slurries were then analysed and associated with the amount of SL in a multivariate model. We observed that all desensitizing and/or anti-erosive toothpastes presented different degrees of SL. Besides pH and fluoride, all other chemical and physical factors were associated with SL. The results of this experiment indicate that enamel SL occurs independent of whether the toothpastes have a desensitizing or anti-erosive claim, and that lower SL is associated with the presence of tin, higher concentration of calcium and phosphate, higher % weight of solid particles, smaller particle size, and lower wettability. PMID- 29263432 TI - Estimated Glomerular Filtration Rate, Proteinuria, and Risk of Cardiovascular Diseases and All-cause Mortality in Diabetic Population: a Community-based Cohort Study. AB - Data about associations between estimated glomerular filtration rate (eGFR) and proteinuria with cardiovascular diseases (CVDs) and all-cause mortality among diabetic population is less described. We aimed to describe these associations in Chinese diabetic population, and investigate the difference between sexes. The study was based on 8,301 diabetic participants in the Kailuan study, who was free of CVDs at baseline. We used Cox proportional hazard models to examine the associations of eGFR and proteinuria with CVDs and all-cause mortality. A stratified analysis by gender was performed. During a median follow-up of 8.05 years, 917 deaths and 813 incident CVDs occurred. Adjusted for all potential confounders, eGFR was associated with all-cause mortality, but not associated with incidence of CVDs. Compared to those with eGFR >= 90 ml/min/1.73 m2, Participants with eGFR <45 ml/min/1.73 m2 had 1.50 fold higher risk of all-cause mortality. Adjusted for all potential confounders, proteinuria was associated with risk of both CVDs and all-cause mortality. Additionally, the risk of all cause mortality by proteinuria was greater in women than that in men. Both lower eGFR and proteinuria are independent risk factors for all-cause mortality in the Chinese diabetic population. Proteinuria conferred excessive risk for CVDs, and especially in women. PMID- 29263433 TI - A Proposal to Stratify the Intermediate-Risk Thyroid Nodules According to the AACE/ACE/AME Guidelines with Ultrasound Features. AB - To propose a risk stratification system for intermediate-risk thyroid nodules (TNs) according to American Association of Clinical Endocrinologists, American College of Endocrinology and Associazione Medici Endocrinologi Medical (AACE/ACE/AME) Guideline with ultrasound (US) features. 1000 patients with 1000 nodules (902 benign nodules and 98 malignant nodules) were included. All the nodules were confirmed with either fine needle aspiration (FNA) cytology and follow-up or histology results after surgery. Univariate analysis and binary multivariate logic regression analysis were applied to analyze the possible risk US features associated with malignancy. Receiver operating characteristic curves (ROC) were drew and compared. Univariate analysis and binary multivariate logistic regression analysis showed that indeterminate hyper-echoic spot (OR = 4.544), slightly ill-defined margin (OR = 2.559), slight hyper-echogenicity (OR = 1.992) and no macro-calcification (OR = 1.921) were risk factors for the intermediate-risk thyroid nodules (TNs). A predicting model was established based on the 4 risk factors. The risk rates of malignancy were 5.7% (26/455) in Stage I, 11.0% (49/445) in Stage II, 23.1% (21/91) in Stage III, 33.3% (3/9) in Stage IV. In conclusion, for the intermediate-risk TNs, special attention should be paid to the TNs with indeterminate hyper-echoic spot, slightly ill-defined margin, slight hyper-echogenicity, or no macro-calcification. The probability of malignancy increased with the number of risk factors increasing. PMID- 29263434 TI - Robust broad spectral photodetection (UV-NIR) and ultra high responsivity investigated in nanosheets and nanowires of Bi2Te3 under harsh nano-milling conditions. AB - Due to miniaturization of device dimensions, the next generation's photodetector based devices are expected to be fabricated from robust nanostructured materials. Hence there is an utmost requirement of investigating exotic optoelectronic properties of nanodevices fabricated from new novel materials and testing their performances at harsh conditions. The recent advances on 2D layered materials indicate exciting progress on broad spectral photodetection (BSP) but still there is a great demand for fabricating ultra-high performance photodetectors made from single material sensing broad electromagnetic spectrum since the detection range 325 nm-1550 nm is not covered by the conventional Si or InGaAs photodetectors. Alternatively, Bi2Te3 is a layered material, possesses exciting optoelectronic, thermoelectric, plasmonics properties. Here we report robust photoconductivity measurements on Bi2Te3 nanosheets and nanowires demonstrating BSP from UV to NIR. The nanosheets of Bi2Te3 show the best ultra-high photoresponsivity (~74 A/W at 1550 nm). Further these nanosheets when transform into nanowires using harsh FIB milling conditions exhibit about one order enhancement in the photoresponsivity without affecting the performance of the device even after 4 months of storage at ambient conditions. An ultra-high photoresponsivity and BSP indicate exciting robust nature of topological insulator based nanodevices for optoelectronic applications. PMID- 29263435 TI - Agarose capsules as new tools for protecting denuded mouse oocytes/embryos during handling and freezing-thawing and supporting embryonic development in vivo. AB - Oocytes without a zona pellucida (ZP) often occur as a result of congenital or operational effects, but they are difficult to handle, and embryonic survival is low. Such zona-free (ZF) oocytes are therefore not used in clinics or laboratories. Furthermore, in the laboratory, removal of the ZP is often necessary for genetic manipulation by viral infection or twin production by blastomere separation, but adverse effects on development have been reported. It would therefore be extremely valuable if the embryo could be covered with a structure similar to that of the ZP. In this study, we sought to determine whether an agarose capsule could serve as a substitute for the ZP. Our results indicate that embryos derived from these agarose capsules were able to develop normally, and could be transplanted to obtain viable offspring, without having to remove the agarose capsule. Furthermore, before compaction, the agarose capsule embryos exhibited good freezing tolerance, and survival rate was extremely high compared to ZF embryos. Thus, agarose capsules represent a valuable tool for utilizing oocytes and embryos that lack a ZP, both in a clinical and livestock setting. PMID- 29263437 TI - Extension for Community Healthcare Outcomes (ECHO): a new model for community health worker training and support. AB - More than 50,000 community health workers (CHWs) are employed in the United States (US), a country with no national accreditation or certification program. In the US, CHWs are trained, formally and/or on-the-job, and rarely is long-term mentoring included. We developed a CHW training program using the Extension for Community Healthcare Outcomes (ECHO) modelTM, distance education using video teleconferencing to support case-based learning, and mentoring of healthcare providers from medically underserved communities. We describe the ECHO model for CHW training and mentoring using case examples and pre/post-surveys from our obesity prevention and addiction recovery programs. Using the ECHO model to train and support CHWs offers advantages over traditional training methods, and can be adapted in other countries to support CHWs to improve health in their communities. PMID- 29263436 TI - Long-term impact of intrauterine neuroinflammation and treatment with magnesium sulphate and betamethasone: Sex-specific differences in a preterm labor murine model. AB - Preterm infants are at significantly increased risk for lifelong neurodevelopmental disability with male offspring disproportionately affected. Corticosteroids (such as betamethasone) and magnesium sulphate (MgSO4) are administered to women in preterm labor to reduce neurologic morbidity. Despite widespread use of MgSO4 in clinical practice, its effects on adult offspring are not well known nor have sex-specific differences in therapeutic response been explored. The objective of our study was to examine the long-term effects of perinatal neuroinflammation and the effectiveness of prenatal MgSO4/betamethasone treatments between males and females in a murine model via histologic and expression analyses. Our results demonstrate that male but not female offspring exposed to intrauterine inflammation demonstrated impaired performance in neurodevelopmental testing in early life assessed via negative geotaxis, while those exposed to injury plus treatment fared better. Histologic analysis of adult male brains identified a significant reduction in hippocampal neural density in the injured group compared to controls. Evaluation of key neural markers via qRT PCR demonstrated more profound differences in gene expression in adult males exposed to injury and treatment compared to female offspring, which largely showed resistance to injury. Prenatal treatment with MgSO4/betamethasone confers long-term benefits beyond cerebral palsy prevention with sex-specific differences in response. PMID- 29263439 TI - Genotoxic stresses promote clonal expansion of hematopoietic stem cells expressing mutant p53. PMID- 29263438 TI - Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time. AB - Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time. PMID- 29263440 TI - Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. AB - This multicentre, open-label phase 1/2 trial determined safety and efficacy of weekly carfilzomib plus cyclophosphamide-dexamethasone (wKCyd) in newly diagnosed multiple myeloma (NDMM) patients aged ?65 years or transplant ineligible. Patients received wKCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression/intolerance. The phase 1 portion used a 3+3 dose-escalation scheme to determine the maximum tolerated dose of weekly carfilzomib: 12 patients received wKCyd with carfilzomib doses of 45, 56 and 70 mg/m2. The recommended phase 2 dose was established at 70 mg/m2 and 54 patients (phase 1 and 2) received weekly carfilzomib 70 mg/m2: 85% of them achieved ?partial response (PR), 66% ?very good PR, 30%?near-complete response (CR) and 15% CR. Responses improved in 40 patients who started maintenance: 98% achieved ?PR, including 29% CR and 10% stringent CR. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 53.2% and 81%, respectively. The most frequent grade 3-5 toxicities were neutropenia (22%) and cardiopulmonary adverse events (9%). This is the first study of weekly carfilzomib plus an alkylating agent in elderly patients with NDMM. wKCyd was effective, with an acceptable risk/benefit ratio, and thus can be a valid option in this setting. PMID- 29263442 TI - Long-term efficacy and safety of momelotinib, a JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis. PMID- 29263441 TI - Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS. AB - Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFalpha and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFalpha and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS. PMID- 29263444 TI - Inflammation and CVD in 2017: From clonal haematopoiesis to the CANTOS trial. PMID- 29263443 TI - Genetics of CVD in 2017: Expanding the spectrum of CVD genetics. PMID- 29263445 TI - Risk factors: Traffic pollution diminishes benefits of walking. PMID- 29263446 TI - Interventional cardiology: Operator technique is predictive of BVS-related adverse events. PMID- 29263447 TI - Hypertension: Low sodium and DASH diet to lower blood pressure. PMID- 29263449 TI - Inflammation: DNases prevent clots formed by neutrophil extracellular traps. PMID- 29263448 TI - Thrombosis: Pharmacomechanical thrombolysis in DVT. PMID- 29263450 TI - Evaluation of prognostic factors, symptoms and consequences of dehydration in patients with cancer based on retrospective data analysis of 102 patients treated in the Department of Palliative Medicine at the University Hospital in Cracow - preliminary report. AB - INTRODUCTION: Dehydration is a common problem in patients with terminal cancer patients. It worsens the quality of life and increases the amount of complications. Factors associated with dehydration need further exploration. The aim of our study was to determine the predictors of dehydration. PATIENTS AND METHODS: 102 terminal cancer patients admitted to Palliative Care Unit were retrospectively analyzed. Detailed physical examination, medical history including history taken from family and care givers was taken upon admission. Laboratory parameters including morphology, sodium, potassium, total and ionized calcium, LDH were taken on admission. We used univariate and multivariate logistic regression analysis to determine factors associated with dehydration. RESULTS: On admission 39% of patients were diagnosed with dehydration. Multivariate logistic regression analysis after adjustment for possible confounders reviled that lack of family care (p = 0.006; OR = 0.147; CI 95% = 0.038-0.577), higher level of PS (p = 0.0426; OR = 1.65; CI 95% = 1.017-2.667), lack of prior opioid use (p = 0.0233; OR = 0.386; CI 95% = 0.17-0.897), occurrence of nausea and vomiting at admission (p = 0.0077; OR = 3.297; CI 95% = 1.372-7.922), occurrence of dyselectrolytemia (p = 0.0012; OR = 4.462; CI 95% = 1.81-10.997), lack of prior GKS use (p = 0.0362; OR = 0.339; CI 95% = 0.123 0.933); lack of prior NSAID use (p = 0.0255; OR = 0.265; CI 95% = 0.082-0.849) remained independently associated with dehydration. CONCLUSIONS: Lack of family care, lack of prior opioid use, higher level of PS, occurrence of nausea and vomiting at admission, occurrence of dyselectrolytemia, lack of prior GKS use and lack of prior NSAID use in patients with terminal cancer are factors associated with dehydration. PMID- 29263451 TI - Radiological results and clinical complications after calcaneal articular fracture surgical treatment using minimally invasive percutaneous fixation. AB - The choice of method for surgical treatment of articular calcaneal fractures remains problematic due to the potential complications and difficulty in restoring loss of functional status, anatomical geometry and congruence of joint surfaces. The preferred method of surgical treatment for these injuries, among others, is still minimally invasive percutaneous fixation. The aim of this study was to evaluate the radiological results of articular calcaneal fractures surgical treatment using a minimally invasive percutaneous fixation and to determine the prevalence of complications in early and long-term observation. Radiological results of surgical treatment of 82 patients operated using minimally invasive percutaneous fixation were analyzed. The radiological results were based on Bohler angle and varus angle using criteria according to Harnroongroj and Golec. Postoperative complications were registered in a 3 months follow-up (early observation) and after 6 months (long-term observation). Patients with tongue-type fractures had significantly better surgical outcomes than patients with depression-type fractures. Displacements of bone fragments in articular calcaneal fractures visualized radiographically by the changes of Harnroongroj et al. angle do not constitute a serious surgical problem and are easily repositioned and stabilized, as opposed to displacements resulting in changes in the value of the Bohler angle. The most common postoperative complications were local inflammatory reactions at the point of entry of fixation material and thromboembolic complications. Results of surgical treatment of articular fractures of the calcaneus using a minimally invasive percutaneous fixation are good and satisfactory in majority of patients suggesting that this method constitutes proper choice of treatment. PMID- 29263452 TI - Unusual branching pattern of celiac trunk associated with supernumerary hepatic arteries and abnormal adrenal venous drainage - case study and review of the literature. AB - Celiac artery (trunk) is one of the three major arteries which arise from abdominal aorta. It's variations not seem to be very uncommon. A routine dissection of a male cadaver at Department of Anatomy Jagiellonian University revealed unusual branching pattern of the celiac trunk with numerous supernumerary hepatic arteries. Additionally unusual venous drainage of the adrenal glands was found. A review of current literature has shown that a changed branching pattern may be important from clinical point of view, with special respect to endovascular procedures, laparoscopic surgery or radiology. PMID- 29263453 TI - Air pollution and atherosclerosis - a brief review of mechanistic links between atherogenesis and biological actions of inorganic part of particulate matter. AB - Atherosclerosis is considered as a chronic, low-grade inflammatory process involving the aorta and the medium-sized arteries. Exposure to air pollutants, especially particulate matter, is highly related to cardiovascular diseases including atherosclerosis. Many studies confirm that proatherogenic potential of particulate matter is determined by its ability to induce inflammation, oxidative stress and thrombosis formation. Recently, an important role in the pathogenesis of atherosclerosis has been attributed to autoimmune response. Moreover, harmful effects of PM particles strongly depend on their physicochemical properties. It is still not known what exact role air pollutants, and in particular their inorganic part, play in the development of atherosclerotic lesions. In this article, we will briefy discuss the different aspects of particulate matter activity and its implication with atherosclerosis progression. PMID- 29263454 TI - Acute primary mesenteroaxial gastric volvulus in a 6 years old child; the contribution of ultrasonographic findings to the prompt diagnosis (a case report and review of the literature). AB - The aim of the present case study is to raise concern on the proper diagnostic approach of acute gastric volvulus (AGV) cases, in which, the key issue is the timely diagnosis and the prompt therapeutic intervention. After thorough and systematic research of the current literature, it is concluded that early diagnosis remains challenging, while there is no relevant publication with emphasis on the contribution of ultrasonography to the diagnostic documentation of AGV. A 6 years old boy was admitted to our Department due to repeatedly non bilious vomiting and food refusal during the last 72 hours before admission. Physical examination revealed the presence of a spherical, painful mass in the epigastrium, which did not recede a er placement of a nasogastric tube. Abdominal radiography showed the presence of a large gastric air bubble. Ultrasonography highlighted a distended and fluid-filled stomach, which was displaced in a cephalic position compared to esophagus and a pylorus pointing downward, in a cranial caudal orientation. Following barium meal examination confirmed the diagnosis of gastric volvulus. Patient underwent an urgent exploratory laparotomy, revealing the presence of acute mesenteroaxial gastric volvulus with a serosal ecchymosis in the major arc. After restoration of the gastric volvulus, thorough intraoperative investigation on the existence of a subject cause followed. Presence of relaxation of stomach's ligaments was finally documented. Fixation of the stomach' fundus to the diaphragm and anterior gastropexy were then conducted. Postoperative period was uneventful and the patient was discharged home on the 4th postoperative day. In conclusion, we believe that ultrasonography plays a significant role in the diagnostic approach of acute gastric volvulus, as it has the potential to detect findings suggestive of the diagnosis. Once the diagnosis is suspected on ultrasonography, contrast series should be performed, without further delay, in order to con rm the diagnosis. PMID- 29263455 TI - Evaluation of remission of temporomandibular joints pain as a result of treatment of dysfunction using intraarticular injection. AB - : The temporomandibular joint pain, which occurs in the course of temporomandibular joint dysfunction, is one of the main clinical problems in the treatment of joint disc displacement. The aim of the study was to evaluate changes in temporomandibular joints pain in treatment supporting disc displacement without reduction using intra-articular injection of hyaluronic acid and platelet-rich plasma. MATERIAL AND METHODS: The study consisted of a group of 60 patients, aged 35-49, who reported for treatment, because of pain in the preauricural area. The functional examination stated disk dicplacement without reduction, along with the accompanying pain of temporomandibular joints. Patients were treated between January 2015 and February 2017. They were divided into two groups of 30 persons. The intraarticular injection of hyaluronic acid was administered in the I-test group, and the injection of platelet-rich plasma in the control group. This treatment was carried out parallel to the use of repositioning splits. THE RESULTS: Analysis of regression of symptoms other than intensity of pain during the treatment, evaluated in this study shows a decrease of individual symptoms, but the results of the regression of pain between two groups did not differ statistically significantly, because "p" is bigger than 0.05. CONCLUSION: The results of the research show the clinical benefits of application of hyaluronic acid and plate rich plasma in the treatment of temporomandibular joint dysfunction. PMID- 29263456 TI - The Objective Structured Clinical Examination (OSCE) from the perspective of 3rd year's medical students - a pilot study. AB - BACKGROUND: In 2015 Department of Medical Education in Medical College of Jagiellonian University in Cracow performed a new format of integrated multidisciplinary skills assessment of third year students of medicine a er completing initial courses in internal medicine, surgery, pediatrics and gynecology. AIM: OSCE assessed from the perspective of 3rd year medical students. METHODS: Students of 3rd year's study of Faculty of medicine were evaluated by OSCE, which assessed their internal medicine, surgery, gynecology, pediatric skills. OSCE consisted of 12 stations. In order to assess student's opinions on OSCE, we used method of diagnostic survey; Statistica 12.0. RESULTS: OSCE passed 255 (98.83%) of the students in thefirst term. We analyzed 221 questionnaires, in which students expressed their opinion. 93.7% of the students considered OSCE as a well organized exam. 87.8% of students claimed that OSCE is fair and 95.5% that the exam is clear. 86.4% students are pleased with the introduction information about OSCE that was given before the examination. 78.6% students believe, that OSCE allows to properly identify skills that require improvement. Students, who didn't pass all stations with positive result, more o en (Chi^2 Pearsona, p = 0.01990) indicated improper balance between quantity of stations that check communication skills and these checking other clinical skills. CONCLUSIONS: is study confirms that OSCE in the students' opinions was well organized and fair. It proves that OSCE correctly selects students who need to improve their knowledge and skills. Students' preparing to the exams, their knowledge and skills, influences on the students' perception of OSCE. PMID- 29263457 TI - Is there a relationship between functional at foot and prevalence of non insertional achilles tendinopathy in joggers? - a pilot study. AB - INTRODUCTION: Non-insertional Achilles tendinopathy is one of the most common overuse injuries experienced by joggers. The pes planus evaluation is often based only on the visual method without a dynamic test. Functionally inefficiency of longitudinal or transverse arch of the foot may be a significant risk factor affecting the lower limb biomechanics and causing of pain in the Achilles tendon area. Assumptions and purpose of the study: This is study was undertaken to determine and investigate the relationship between the functionally inefficient longitudinal and transverse arch of the foot and the prevalence of non insertional Achilles tendinopathy. MATERIALS AND METHODS: The study group consisted of 11 regular joggers at different levels, who were diagnosed with non insertional Achilles tendinopathy. The clinical evaluation involved pedobarographic analysis using the Footscan pressure plate. Information on loads applied to metatarsal area, the basis of the second and third metatarsal bones were subjected to statistical analysis. RESULTS: All subjects who were diagnosed with overuse injuries in the Achilles tendon area showed a functionally inefficient transverse arch of the foot. Despite their pain, the individuals subjected to the study did not cease completely their physical activity. CONCLUSIONS: Collapse of the natural arch of the foot can lead to biomechanical disorder in the lower limb joints. This is one of the risk factors for the occurrence of changes due to overuse injuries within the Achilles tendon. PMID- 29263458 TI - Creatine kinase-MB and red cell distribution width as predictors of contrast induced nephropathy after percutaneous coronary intervention in acute myocardial infarction. AB - INTRODUCTION: Contrast-induced nephropathy (CIN) is acute kidney injury (AKI), caused by administration of iodinated contrast media. The reported risk factors of CIN are: pre-existing renal dysfunction, admission anemia, diabetic nephropathy, old age, dehydration, high volume and osmolarity of administered contrast media. Patients with acute myocardial infarction (AMI) have threefold higher risk of developing CIN. The aim of the study was to identify risk factors of CIN among patients who underwent percutaneous coronary intervention (PCI) due to AMI. METHODS: This retrospective single-centre study included 257 patients (mean age, 69.19 +/- 1.4 years; men 66.15%) undergoing PCI for AMI between January 2012 and January 2013. Demographic data, type and location of MI, co morbidities and laboratory results were analysed. RESULTS: CIN was found in 50 out of 257 patients (19.5%). Patients who developed CIN were older (p = 0.001), more commonly had chronic kidney disease (p = 0.01) and lower LVEF (p = 0.01). Baseline Red Cell Distribution Width (RDW) was significantly higher in the CIN group (14.85 +/- 4.6 vs. 13.62 +/- 1.3, p = 0.001). CK-MB levels on admission were significantly higher in the CIN group compared to the non- CIN group (95.6 +/- 129.9 vs. 47.03 +/- 61.3, p = 0.001). Multivariate model including "classical" CIN risk actors revealed that only baseline CK-MB level (p = 0.001), age >75 years (p = 0.001) and baseline RDW (p = 0.03) were independent predictors for the development of CIN. CONCLUSION: In conclusion, increased CK-MB on admission as a surrogate of time of ischemia, and increased RDW levels on admission as a marker of chronic in ammation are independently associated with higher risk of CIN among patients treated with primary PCI. PMID- 29263459 TI - Main communication barriers in the process of delivering bad news to oncological patients - medical perspective. AB - Delivering bad news is a major aspect of a doctor's work. The literature most often refers to patient's expectations or needs, and methods of delivering bad news, while medical perspective is often skipped. The purpose of this paper is to examine competencies (knowledge, skills and experience) in delivering bad news by medical specialists in the areas related to the causal and symptomatic treatment of oncological patients; identification of major communication problems and obstacles in this specific situation and evaluation of teaching needs for delivering bad news. The study was performed on a group of 61 medical specialists in the areas related to the causal and symptomatic treatment of oncological patients, using a self-generated questionnaire based on other studies in the literature. Topics that are considered most demanding are: delivering news on the termination of causal treatment and preparing the patient/ close ones for death. The most difficult aspect of such discussions for the respondents was associated with the emotions manifested by the patient. On the other hand, doctors were mostly distressed by the feeling of taking the patient's hope away. The study points to the need for education of doctors in the eld of techniques for delivering bad news, particularly in the area of dealing with the emotions manifested by the patient and giving them real hope. The results encourage to conduct studies on a larger group of doctors. PMID- 29263460 TI - Outcome of the first year of treatment for exudative age-related macular degeneration under a treatment programme using aflibercept - own experience. AB - STUDY OBJECTIVE: Anatomic and functional (function improvement) outcome of the aflibercept treatment for exudative age-related macular degeneration was analysed a er the first year of treatment. MATERIAL AND METHODS: 62 patients treated with intravitreal aflibercept injections according to the adapted regimen. The treatment efficacy was understood as a reduction in oedema (and the central retinal thickness), with an increase in or stabilisation of the best corrected visual acuity. RESULTS: In nearly all patients, a reduction in the central retinal thickness was observed, with stabilisation of or improvement in the best corrected visual acuity. CONCLUSION: The aflibercept treatment for exudative age related macular degeneration is a promising and efficient treatment method. PMID- 29263461 TI - [Mechanism of cross talk between tissue factor/active coagulation factor VII and epidermal growth factor receptor signalings in colon cancer cells in culture]. AB - OBJECTIVE: To preliminarily verify the cross talk between tissue factor/active coagulation factor VII (TF/FVIIa) and epidermal growth factor receptor (EGFR) pathways in human colon cancer cells in culture. METHODS: FVIIa was treated to HT 29 (KRAS-wild type) and LoVo (KRAS-mutant) colon cancer cells to activate TF/FVIIa pathway, qRT-PCR and Western blot were used to detect the expressions of amphiregulin (AREG) and epiregulin (EREG), ligands of EGFR on mRNA and protein levels, respectively. After knocking down expression of TF by TF-targeted siRNA transfection, FVIIa was treated and mRNA expressions of AREG and EREG were detected to see whether the FVIIa-induced effects were dependent on TF. Expressions of mRNA of TF and FVII were detected by qRT-PCR following the activation of EGFR pathway by treatment with epidermal growth factor (EGF) to HT 29 and LoVo cells. RESULTS: After TF/FVIIa pathway was activated, for HT-29 cells, expressions of AREG (on mRNA level) and EREG (both on mRNA and protein level) were significantly down-regulated versus those of control group, gene expressions of AREG and EREG were 0.55+/-0.09 vs.0.99 +/-0.09, 0.67+/-0.10 vs.1.02+/-0.02, protein expressions of EREG were 0.54+/-0.09 vs.1.04+/-0.13, all P<0.05. For LoVo cells, expressions of AREG (both on mRNA and protein level) and EREG (on protein level) were significantly up-regulated versus those of control group, gene expression of AREG were 1.87+/-0.39 vs. 0.93+/-0.23, protein expressions of AREG and EREG were 3.09+/-0.73 vs.1.11+/-0.21, 1.53+/-0.19 vs.0.97+/-0.23, all P<0.05. The regulating effect of AREG and EREG mRNA expression by FVIIa in HT-29 and LoVo cells could both be partly blocked by knocking down TF expression. For HT-29 cells, activation of EGFR pathway induced no significant TF mRNA expression, FVII mRNA expression was not detected. However,for LoVo cells, activation of EGFR pathway induced significantly higher mRNA expressions of both TF and FVII, expressions were 1.53+/-0.23 vs.1.00+/ 0.23, 53.20+/-6.08 vs.1.00+/-0.15, all P<0.05. CONCLUSION: In colon cancer cell LoVo, when activated, TF/FVIIa pathway and EGFR pathway could interact through upregulating the other pathway's effectors, and mutant KRAS might play a critical role in the two pathways' cross talk. PMID- 29263462 TI - [Silencing of vacuolar ATPase c subunit ATP6V0C inhibits invasion of prostate cancer cells]. AB - OBJECTIVE: Vacuolar ATPase (V-ATPase) was found within the membranes and internal organelles of a vast array of eukaryotic cells, and was related to various kinds of highly metastatic tumors. LASS2/TMSG1 gene was a novel tumor metastasis suppressor gene cloned from human prostate cancer cell line PC-3M in 1999 by our laboratory. It was found out that protein encoded by LASS2/TMSG1 could interact with the c subunit of V-ATPase (ATP6V0C). In this study, To use RNA interference to suppress the expression of ATP6V0C and try to further investigate the molecular mechanism of ATP6V0C in tumor metastasis and its relationship with LASS2/TMSG1 gene. METHODS AND RESULTS: The expression level of ATP6V0C mRNA and protein in high metastatic potential prostate cancer cell lines (PC-3M-1E8 and PC 3M) was significantly higher than that in low metastatic potential prostate cancer cell lines (PC-3M-2B4 and PC-3), the expression level in PC-3M-1E8 being the highest. Follow-up tests selected PC-3M-1E8 cells for gene silencing. The expression and secretion of MMP-2 and the expression of MMP-9 in ATP6V0C siRNA transfected PC-3M-1E8 cells displayed no obvious change, but the activity of secreted MMP-9 was abated noticeably compared with the controls (P<0.05). Extracellular hydrogen ion concentration and V-ATPase activity in interference group were both reduced significantly compared with the controls (P<0.05). The migration and invasion capacity of ATP6V0C siRNA interfered cells in vitro were diminished significantly compared with the controls (P<0.05). Furthermore, a dramatic reduction of LASS2/TMSG1 mRNA and protein level after transfection of siRNA in PC-3M-1E8 cells was discovered (P<0.05). Confocal immunofluorescence showed a vast co-localization of ATP6V0C protein and LASS2/TMSG1 protein in plasma and membrane. The co-localization signals of control group were much stronger than those of interference group. CONCLUSION: Specific siRNA silencing of ATP6V0C gene inhi-bits the invasion of human prostate cancer cells in vitro by mechanism of inhibiting V-ATPase activity and then reducing the extracellular hydrogen ion concentration, inhibiting MMP-9 activation and affecting ECM degradation and reconstruction. Meanwhile, ATP6V0C and LASS2/TMSG1 have interaction and it is likely that ATP6V0C functions as a feedback regulator of LASS2/TMSG1. PMID- 29263463 TI - [Primary investigation of immunoglobulin A synthesis and secretion in human mesangial cells]. AB - OBJECTIVE: To investigate the expression of immunoglobulin A (IgA) in human mesangial cells (HMCs). METHODS: The HMCs were cultured. The subcellular location of IgA was detected by immunofluorescence staining; the transcripts of Igalpha,Igkappa and IgLambda constant region were detected by reverse transcription-polymerase chain reaction (RT-PCR) and further analyzed by DNA sequencing. The expressions of Igalpha and IgLambda were detected at transcription level by Western blot after the cytoplasmic protein extraction. The culture supernatant was collected to explore whether IgA could be secreted out of the cell and the protein was further analyzed by mass spectrometry after being purified by affinity chromato-graphy with jacalin-sepharose. The results of DNA sequencing and mass spectrometry were aligned with the mRNA and amino acid sequences in the National Center of Biotechnology Information (NCBI) database. RESULTS: By immunofluorescence staining, we detected the presence of IgA heavy chain Igalpha, light chain, both Igkappa and IgLambda in expressions of transcripts of Igalpha1, Igalpha2, Igkappa and IgLambda in the HMCs and the alignment of the sequences of the RT-PCR products with those of the IgCalpha1, IgCalpha2, Igkappa and IgLambda mRNA in the NCBI database exhibited that the similarities were 99%, 97%, 98% and 97%, respectively. Western blot showed Igalpha and IgLambda expressions in the cell lysate and secretion of Igalpha1 and Igalpha2 heavy chains in cell culture supernatant. To further explore the protein that secreted into the supernatant, after supernatant affinity chromatography with jacalin-sepharose, the proteins were separated by sodium dodecyl sulfonate polyacrylamide gel electrophoresis (SDS-PAGE) and the band approximating to 65 000 was cut and sent to mass spectrometry. The results were aligned with the amino acid sequences of Igalpha1 and Igalpha2 constant region in NCBI database, showing that amino acids between No.52 and No.104, amino acids between No.154 and No.221, amino acids between No.276 and No.327 from IgCalpha1 and amino acids between No.52 and No.113, amino acids between No.151 and No.204, amino acids between No.251 and No.314 from IgCalpha2 were the same with those derived from B cells. CONCLUSION: Our fin-dings suggested that HMCs could synthesize and secret IgA. PMID- 29263464 TI - [Effect of high glucose-based peritoneal dialysis fluids on NLRP3-IL-1beta in human peritoneal mesothelial cells]. AB - OBJECTIVE: To explore the effect of high glucose-based peritoneal dialysis fluids on NLRP3-IL-1beta in human peritoneal mesothelial cells. METHODS: HMrSV5 cells (SV40 immortalized human peritoneal mesothelial cell line) were grown in type I collagen-coated dishes in DMEM/F12 containing 10% fetal calf serum (FCS). All experiments on HMrSV5 cells were performed between passages 5 and 10. The cells were divided into 7 groups: control, 1.5% dextrose, 2.5% dextrose, 4.25% dextrose, rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A. Immunoblotting was used to evaluate the expression of IL-1beta. Small interfering RNA (siRNA) targeting NLRP3 was used to downregulate the expression of NLRP3 and Western blot was used to evaluate the expression of IL-1beta in human peritoneal mesothelial cells exposed to 4.25% dextrose. In the meanwhile, resveratrol (RSV) was used to induce autophagy, 3-methyladenine (3-MA) and siRNA against Beclin 1 or ATG5 were used to block auto-phagy, flow cytometric was used to analyze the respiring (mitotracker deep red), total (mitotracker green) and reactive oxygen species (ROS)-generating mitochondria (mitoSOX); Western blot was used to evaluate the expression of IL-1beta. RESULTS: The IL-1beta relative expressions were 0, 0.175+/-0.082, 0.418+/-0.163, 2.357+/-0.288, 2.642+/-0.358, 3.271+/ 0.462, and 0.123+/-0.091, indicating that the cells exposed to high glucose-based peritoneal dialysis fluids and cells treated with mitochondria respiratory chain key enzyme complex I, and complex III inhibitors increased the IL-1beta expression. And we found that NLRP3 knock-down significantly blocked the upregulation of IL-1beta. In addition, the fluorescence intensity of total mitochondria and ROS-generating mitochondria in the following groups: control, negative control, RSV, 3-MA, ATG5 siRNA, Beclin1 siRNA were 1.76+/-0.42, 1.83+/ 0.55, 1.85+/-0.62, 7.36+/-0.92, 5.35+/-0.77, 5.06+/-0.62 and 821.68+/-95.12, 868.15+/-102.82, 723.39+/-92.56, 1 660.08+/-113.65, 1 433.01+/-107.24, 1 562.36+/ 112.88 respectively. The increased concentrations of mitochondrial ROS and IL 1beta upregulation were confirmed in the inhibition but not the induction of auto phagy. We also found that downregulation of ATG5 and Beclin1 sensitized cells for the release of IL-1beta induced by MSU (monosodium urate) or nigericin which was the NLRP3 inflammasome activator. RSV treatment attentuated this effect. CONCLUSION: Long-term application of high glucose-based peritoneal dialysis fluids can trigger the consistent activation of NLRP3-IL-1beta in peritoneal mesothelial cells. Timely initiation of autophagy may block the NLRP3-IL-1beta activation and provide a basis for the further development of a potential therapeutic strategy for delay of chronic inflammation and peritoneal fibrosis associated with peritoneal dialysis. PMID- 29263465 TI - [Expression of serum IgG4 in patients with different diseases]. AB - OBJECTIVE: To investigate serum IgG4 levels in different diseases and the changes of serum IgG4 levels in post treatment of IgG4 related disease. METHODS: Clinical data of 620 patients who received investigation of serum IgG4 in Peking University People's Hospital from January 1, 2015 to March 31, 2016 were collected retrospectively. According to the difference of the diseases, they were divided into common group of diseases, autoimmune diseases and IgG4 related diseases; pancreatic disease patients were divided into autoimmune pancreatitis and pancreatic cancer group; According to different treatment stages of the disease, the patients with IgG4 related diseases were divided into pretreatment group and post treatment group. And the expressions of the patients'serum IgG4 levels in different groups were analyzed. RESULTS: The median serum IgG4 level in the group of the patients with common diseases was 0.480(0.005, 50.400) g/L, in the group of autoimmune disease was 0.406 (0.003, 18.700) g/L , in the group of IgG4 related diseases was 5.200(0.046, 46.000)g/L, which was signi-ficantly higher in the group of IgG4 related diseases than the other two groups, and there was obvious statistical significance in serum IgG4 levels between the group of IgG4 related diseases and the other two groups (P<0.01); There was no obvious difference in serum IgG4 levels between the common disease group and the autoimmune disease group, and there was no obvious statistical difference in serum IgG4 levels between the two groups (P>0.05). In the patients with IgG4 related diseases, the median serum IgG4 level in the group of pretreatment patients was 6.540 (1.330, 34.100) g/L, and 3.735 (0.063, 46.000) g/L in the post treatment patients. Serum IgG4 levels decreased in post treatment group, signi ficantly lower than in pretreatment, there was obvious statistical difference in serum IgG4 levels between the two groups (P<0.01). The median serum IgG4 level in the group of patients with autoimmune pancreatitis was 3.735 (0.063, 46.000) g/L ,and 0.438 (0.056, 1.130) g/L in the group of patients with pancreatic cancer,which was significantly higher in the group of patients with autoimmune pancreatitis than the others, and there was obvious statistical difference in serum IgG4 levels between the two groups (P<0.01). CONCLUSION: Serum IgG4 levels in patients with different diseases were different, and were significantly higher in patients with autoimmune pancreatitis and IgG4 related diseases, so serum IgG4 levels can provide the basis for the differential diagnosis of different diseases; Serum IgG4 levels in patients with IgG4 related diseases decrease significantly after treatment, so it can be used as an important index to evaluate the curative effect of IgG4 related diseases. PMID- 29263466 TI - [Study on the spatial expression of trophectoderm cells in human embryonic prenatal blastocysts]. AB - OBJECTIVE: To study the spatial expression of trophectoderm cells in human embryonic preantral blastocysts. METHODS: The study used Gardner score 5AA blastocysts harvested on day 6 after fertilization from assisted reproductive technology. Microcapsules were used to separate trophectoderm cells from the epidermal cells. Single-cell sequencing was performed. P<0.05 was calculated by unpaired t test, and the difference was 2 times. Here we determined, for the first time, global gene expression patterns in the polar/mural trophectoderm isolated from human blastocysts. Unsupervised hierarchical clustering analysis and gene ontology (GO) functional classification were performed using bioinformatics software. Differentially expressed genes were annotated by the Database for Annotation, Visualization and Integrated Discovery. Functions of differentially expressed genes were further annotated using encyclopedia of genes and genomes. RESULTS: The results showed that there were up to 306 genes in the trophoblast cells and up to 75 genes in the trophoblast cells. Unsupervised cluster analysis of polar trophoblast cells and mural trophoblast cells were divided into two groups, belonging to different types and biological functions. Differences in gene function indicated that the biological functions of GO gene uptake genes were mainly transcription, energy metabolism, protein synthesis, transport, oxidative stress, ion transport, protein synthesis and transport, cell cycle regulation, actin growth, etc. They were mainly involved in ubiquitin mediated protein hydrolysis, oxidative phosphorylation, Wnt signaling pathway, estrogen androgen metabolism and other signal pathways; wall trophoblast cells up regulated gene GO biological function, which was mainly proteolytic metabolism, cell cycle arrest, apoptosis, activation of MAPK, carbohydrate transport, synaptic regulation, cell growth, calcium channel activation, positive B cell differentiation, T cell apoptosis and other biological functions, which were mainly involved in B cell receptor, T cell receptor, white blood cells cross endothelial transplantation, VEGF expression, gap connection, GnRH secretion, apoptosis and other signaling pathways. CONCLUSION: The gene expression of blastocysts trophectoderm is revealed from the spatial dimension, indicating that differentiation of polar and mural trophectoderm of blastocysts is accompanied by differences between the two cell lineages, and the polar and mural trophectoderms are coordinated with each other and the blastocyst hatching and embryo implantation processes are finely adjusted. Further data analysis is expected to find the endogenous molecular specificity of the regulation of embryo implantation. PMID- 29263467 TI - [Adipose tissue derived stem cells'treatment effects in MRL/lpr mice and its effects on the imbalance of Th17/Treg cells]. AB - OBJECTIVE: Preliminary study on therapeutic effects of adipose tissue derived stem cells (ADSCs) on MRL/lpr mice and the effect on imbalance of Th17/Treg. METHODS: Fifteen 12-week-old MRL/lpr mice were randomly divided into 3 groups by using random number table, including ADSCs group, control group and cyclophosphamide (CTX) group, with 5 in each group. ADSCs group and control group were injected with 1*106 ADSCs or phosphate buffered solution (PBS) via tail vein respectively, once a week, a total of eight times. CTX group was injected CTX at a dose of 15 mg/kg body weight, once a week for 2 weeks, and then repeated after 2 weeks'rest, a total of four times. The 24-hour proteinuria was measured before and after treatment. All the mice were sacrificed after treatment for 8 weeks. Th17 cells and Treg cells in splenic were examined by flow cytometry. RESULTS: (1)The 24-hour proteinuria in the three groups had no significant difference before treatment (P>0.05). After therapy for 4 weeks, the 24-hour proteinuria in the ADSCs and CTX groups was much lower than those in control group, and the difference was significant [(5.02+/-1.61) g/L vs. (7.10+/-1.63) g/L, (4.90+/ 0.71) g/L vs. (7.10+/-1.63) g/L, P<0.05], and the longer the duration of treatment (8 weeks), the more obvious effect [(2.24+/-0.73) g/L vs. (10.36+/ 1.64) g/L, (3.80+/-1.45) g/L vs. (10.36+/-1.64) g/L, P<0.01]. There was no significant difference in 24-hour proteinuria between ADSCs group and CTX group (P>0.05). (2) Percentage of Treg cells/CD4+T cells in the spleen lymphocytes: The percentages in ADSCs and CTX groups were higher than that in control group. The levels were 13.62%+/-1.87%, 14.14%+/-1.29%, 10.71%+/-1.23%, respectively, but there was no significant difference (P>0.05). (3) Percentage of Th17 cells/CD4+T cells in the spleen lymphocytes: The percentages in ADSCs and CTX groups were significantly lower than that in control group. The levels were 1.43%+/-0.20%, 1.63%+/-0.65%, 6.37%+/-1.64%, respectively, with statistical significance (P<0.01). CONCLUSION: Transplantation of ADSCs can reduce the 24-hour proteinuria in MRL/lpr mice. To prolong the time of treatment, the effect is more significant. Transplantation of ADSCs can up-regulate Treg cells and down regulate Th17 cells. ADSCs have the ability to regulate the immune balance of Th17/Treg in MRL/lpr mice, suggesting that ADSCs play the role of anti inflammatory and immune regulation by regulating the Treg and Th17 cells. PMID- 29263468 TI - [Performance of the 2015 ACR/EULAR classification criteria compared with other classification criteria for diagnosis of gout in Chinese patients]. AB - OBJECTIVE: To evaluate the ability of 2015 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria to diagnose gout compared with the widely used 1977 American Rheumatism Association (ARA) criteria and other criteria in clinical practice in Chinese patients, and to compare the sensitivity and specificity of different classification criteria for gout in early and established diseases. METHODS: The patients who had ankle arthritis and visited the Department of Rheumatology and Clinical Immunology, Peking University First Hospital between February 2012 and February 2016 were screened. The patients who had been already diagnosed with gout or pyrophosphate deposition disease through arthrocentesis or tissue aspiration and those who had been diagnosed with rheumatoid arthritis, spondyloarthritis, and osteoarthritis were excluded. The patients were diagnosed by two experienced rheumatologists and all of them were followed up for at least one year. Early disease was defined as symptom onset of no more than 2 years; established disease was defined as symptom duration of more than 2 years. The 2015 ACR classification criteria were divided into clinical form with clinical parameters included and complete form with not only clinical parameters but also synovial fluids tests, imaging findings and monosodium urate (MSU) included. The two forms above were short for "clinical form (incorporating clinical parameters)" and "complete form (incorporating imaging and MSU data)" respectively. RESULTS: In this study, 284 patients suffering from ankle arthritis were inclu-ded in the study, 219 of them were classified as gout and 65 of them had alternative diagnoses. The sensitivity and specificity of 2015 ACR complete form (incorporating imaging and MSU data) for diagnosing gout were 88.13% and 95.38%, respectively. The area under the curves (AUC) of 2015 ACR "complete form (incorporating imaging and MSU data)", 2015 ACR "clinical form (incorporating clinical parameters)", 2010 Netherlands criteria and 1977 ARA criteria were 0.982, 0.983, 0.963, and 0.928, respectively. For the 94 early gout patients, the AUC of the above criteria were 0.973, 0.968, 0.916, and 0.910, respectively. For the established gout patients, the AUC were 0.987, 0.991, 0.982, and 0.936, respectively. For the patients with disease duration within two years, the odd ratio (OR) for sensitivity of 2015 ACR "complete form (incorporating imaging and MSU data)", 2015 ACR "clinical form (incorporating clinical parameters)", 2010 Netherlands criteria and 1977 ARA criteria were 1.562 (1.003-2.435), 1.500 (1.001 2.346), and 1.812 (1.177-2.791), nevertheless, for the patients with established gout, the OR were 1.702 (1.300-2.229), 1.607 (1.224-2.110), and 1.821 (1.396 2.377), respectively. CONCLUSION: The 2015 ACR/EULAR criteria are more accurate in gout diagnosis compared with the 1977 ARA criteria by elevating the sensitivity and specificity, in respective of the disease duration. The 2015 ACR/EULAR criteria may serve as new diagnostic tools in daily clinical practice in Chinese patients. PMID- 29263469 TI - [Analysis of clinical features of 23 patients with POEMS syndrome]. AB - OBJECTIVE: To describe the endocrine abnormalities in patients with POEMS syndrome in order to identify more patients with POEMS syndrome among those who have endocrine dysfunctions. METHODS: We searched the inpatient medical record system of Peking University People's Hospital with "POEMS syndrome". Finally the data from 23 patients were analyzed. Epidata 3.0 was used for data entering and SPSS 19.0 was used for statistical analysis. RESULTS: The median age of all the 23 patients was 47 years. The ratio of male to female was 1.88:1. Polyneuropathy was the most common initial symptom which accounted for 56.5% in the 23 patients. The median duration from the initial symptoms to diagnosis as POEMS syndrome was 30 months. Among all the departments, the number of confirmed cases was highest in the department of neurology. The median duration from the onset of initial symptoms (6 months) to the diagnosis made in neurology department was also significantly shorter than in other departments. Among all the 23 patients, 100.0% of them had polyneuropathy, 82.6% had organomegaly, 95.7% had endocrinopathy, 52.2% were M protein positive, 91.3% had skin changes, 45.5% had papilledema, 43.5% had extravascular volume overload, 43.5% had platelet elevation and 17.4% had Castleman disease. Among all the patients with endocrinopathy, the incidence of hyperprolactinemia was 60.0% which was the highest one followed by thyroid dysfunction and adrenal dysfunction. Among the patients who had endocrine system dysfunctions, most of them had two target endocrine glands involved (36.5%). CONCLUSION: Endocrinopathy is an important component of POEMS syndrome and it is of great importance to pay more attention to POEMS syndrome in patients with thyroid dysfunction, adrenal dysfunction, gonadal dysfunction, parathyroid dysfunction, hyperprolactinemia and glucose intolerance, especially in patients with two or more target gland dysfunctions. Symptoms and signs of polyneuropathy should be assessed carefully to reduce misdiagnosis of POEMS syndrome. Evaluation of the endocrine system should also be done in patients diagnosed with POEMS syndrome in order to treat the patients properly. PMID- 29263470 TI - [Clinical features and early treatment effects in intermediate risk and poor risk acute myeloid leukemia with EVI1 positive]. AB - OBJECTIVE: To investigate the clinical biological characteristics of EVI1 positive acute myeloid leukemia (AML) and its effect on early chemotherapy. METHODS: The clinical and biological cha-racteristics of 33 AML patients with EVI1 positive were retrospectively analyzed in 361 AML patients who were diagnosed and treated in our institute from March 2015 to July 2016, and the clinical and biological features, and rates of the induced remission were compared between the intermediate risk and poor risk with EVI1 positive AML, moreover, the influential factors on complete remission (CR) were analyzed. The expression of EVI1/ABL was tested in 32 healthy donors to confirm the abnormal threshold of EVI1 expression. RESULTS: The definition of EVI1 positive was that the quantitative expression of EVI1/ABL was more than 8.0%. The 33 AML patients with EVI1 positive were found in 361 newly diagnosed AML patients, in which the female and male patients were 17 and 16 respectively, the median age was 45 (18 67) years, with a median follow-up of 6.6 (0.7-13.2) months. Intermediate karyotype was found in 17 patients(including 9 patients with normal karyotypes,1 patient with +8);unfavorable karyotype was found in 14 patients [including 7 patients with -7/7q-,4 patients with t (v;11q23),3 patients with inv(3)/t(3;3), and 2 patients without mitotic figures]. The rate of CR in the first induction chemotherapy was 42.4%, and the rate of total CR was 60.6%. According to the NCCN, 16 intermediate risk patients and poor risk patients were divided, without favorable risk patients. The rate of CR in the first induction chemotherapy were 68.8% and 17.6% (P=0.005) in the intermediate risk and poor risk respectively, that of total CR were 81.3% and 41.2%(P=0.032), and the rates of relapse were 7.7% and 14.3%.Univariable analysis revealed that unfavorable karyotype could affect the rate of CR in the first reduction chemotherapy and that of total CR (P=0.004, 0.029). The poor risk patients had higher mortality (41.2% vs. 6.3%, P=0.039) and lower overall survival (OS)(P=0.012). CONCLUSION: EVI1 may be not an independent prognostic factor for the AML patients considering the appea-rance in the intermediate and poor risk patients. It predicts poor outcome in the EVI1 positive AML patients who have unfavorable karyocytes, such as -7/7q-, t(v;11q23), and inv(3)/t(3;3), and also a low rate of both CR in the first induction chemotherapy and total CR. It also has a low rate of long-term survival and high mortality in the AML patients with EVI1 positive, who may benefit from allogeneic bone marrow transplantation as soon as possible. PMID- 29263471 TI - [Application and analysis of abdominal aortic branch malperfusion pattern in thoracic endovascular aortic repair for Stanford B aortic dissection]. AB - OBJECTIVE: To evaluate the efficiency of thoracic endovascular aortic repair (TEVAR) in dealing with abdominal aortic branch malperfusion based on the analysis of aortic computed tomography angiography (CTA) images in pre- and post TEVAR. METHODS: Retrospective analysis from September 2015 to March 2016 in single institution to 32 patients, diagnosed as Stanford B aortic dissection with abdominal aortic branch malperfusion, CTA images in pre- and post-TEVAR were collected. Based on the aortic branch malperfusion pattern redefined by Nagamine, we identified and characterized branch malperfusion pattern for four abdominal aortic branches (celiac trunk, superior mesenteric artery, bilateral renal artery) in statistical analysis. RESULTS: In the four abdominal aortic branches (total 128 branches), 86 branches (67.2%) expressed with Class I patterns, in which subtype I-b presented with 0.8%, subtype I-c with 5.5%; 14 branches (10.9%) expressed with Class II patterns, in which subtype II-b-1 with 3.9%, subtype II-b 2 with 3.1%; 16 branches (12.5%) expressed with Class III patterns, all with subtype III-a, no subtype III-b and III-c presented. The remaining 12 branches were normal. The 100% successful rate of TEVAR obtained in 32 patients performed. The mean following-up was 4 months. Aortic CTA showed that among the 14 "high risk" abdominal aortic branch malperfusion, 13 (92.9%) with obvious branch malperfusion in post-TEVAR were observed to improve, and the remaining one branch malperfusion (7.1%) was observed to change from subtype I-b to I-c. CONCLUSION: Few ratios in abdominal aortic branches suffered with obvious malperfusion complicated by Stanford B aortic dissection. For branches with "high-risk" malperfusion pattern, optimal changes were observed in abdominal aortic branch without revascularization in post-TEVAR, as well other branches with non-"high risk" pattern perfusion were mostly stable in post-TEVAR. It could be of profound benefit to extend branch malperfusion patterns redefined by Nagamine in clinical practice to assess aortic dissection and in further guide for revascularization or not. PMID- 29263472 TI - ["Time-angle measurement" reduction evaluation technique and clinical evaluation of proximal humerus fracture]. AB - OBJECTIVE: To evaluate the functional outcome and the complication rate after open reduction and internal fixation of proximal humeral fractures with a "time angle measurement" reduction evaluation technique, to assess the acceptance of the fracture reduction and to estimate the result of the sur-gery. METHODS: Forty six patients [mean age: (66.2+/-14.9) years] with an acute proximal humeral fracture were managed with open reduction and internal fixation with this reduction evaluation technique from January 2012 to December 2013. According to the Neer classification, there were 6 two- part fractures, 25 three-part fractures and 15 four-part fractures. The functional outcome was evaluated for each patient using the Constant-Murley score; radiographic evaluation was also conducted and complications were recorded. The postoperative shoulder function recovery and imaging findings were followed up to evaluate the guiding significance of this reduction evaluation technique in the clinical treatment of this kind of fracture. RESULTS: In the study, 46 patients had been followed up for 13-36 months, and the average follow-up time was (23.5+/-7.3) months. All the patients achieved fracture healing 3 months after operation. The average head shaft angle was (124+/-3.5) degrees. According to the Constant scoring system, 29 patients (63%) had excellent, 14 patients (30%) had good, and 3 patients (7%) had poor results. The most common complications were pain (7/65) and restricted movement of the shoulder (5/46). There were no cases of screw penetration, necrosis of humeral head, deep tissue infection, nonunion of fracture and axillary nerve injury after operation. CONCLUSION: For appropriate cases of displaced proximal humeral fractures, surgical treatment with application of "time-angle measurement" reduction evaluation technique that was introduced in the present study can lead to a good functional outcome, and the technique of reduction assessment should be regarded as a reasonable reference standard in the treatment of displaced proximal humerus fracture. PMID- 29263473 TI - [Effect of different anesthetic methods on postoperative outcomes in elderly patients undergoing hip fracture surgery]. AB - OBJECTIVE: To investigate the effect of general or regional anesthesia on postoperative cardiopulmonary complications and inpatient mortality after hip fracture surgery in elderly patients. METHODS: A retrospective analysis was conducted according to the medical records of 572 elderly patients with hip fractures admitted to our hospital from January 1, 2005 to December 31, 2014. The age, gender, preoperative comorbidities, length of preoperative bedridden time, mechanism of injury, surgical types, anesthetic methods, major postoperative complications and inpatient mortality were recorded. Multivariate Logistic regression analysis was applied to analyze the impact of different anesthetic methods on inpatient mortality in these patients. RESULTS: Of the 572 patients, 392 (68.5%) received regional anesthesia. Inpatient death occurred in 8 (8/572, mortality: 1.4%), including 5 cases of RA group (5/392, mortality: 1.3%) and 3 cases of GA group (3/180, mortality: 1.7%). There was no statistically significant difference between the two groups in inpatient mortality (P>0.05). Multiple Logistic regression analysis showed that gender (odds ratio: 0.18, 95% CI: 0.03-1.05, P=0.057), age (odds ratio: 1.22, 95% CI: 1.07-1.38, P=0.002), preoperative pulmonary comorbidities (odds ratio: 12.09, 95% CI: 2.28-64.12, P=0.003) and surgical types (odds ratio: 9.36, 95% CI: 1.34-64.26, P=0.024) were risk factors for inpatient mortality. Postoperative cardiovascular complications occurred in 36 patients (36/572, morbidity: 6.3%), with 19 patients in RA group (19/392, morbidity: 4.8%),and 17 patients in GA group (17/180, morbidity: 9.4%). Multiple Logistic regression analysis showed that age (odds ratio: 1.13, 95% CI: 1.07-1.19, P<0.001), hypertension (odds ratio: 2.72, 95% CI: 1.24-5.96, P=0.012) and preoperative cerebral comorbidities (odds ratio: 2.11, 95% CI: 0.99-4.52, P=0.054) were risk factors for postoperative cardiovascular complications. Postoperative pulmonary complications occurred in 56 patients (56/572, morbidity: 9.8%), with 19 patients in RA group (19/392, morbidity: 4.8%), and 37 patients in GA group (37/180, morbidity: 20.6%). Multiple Logistic regression analysis showed that age (odds ratio: 1.13, 95% CI: 1.07-1.19, P<0.001), preoperative pulmonary comorbidities (odds ratio: 2.89, 95% CI: 1.28-7.05, P=0.020), length of preoperative bedridden time (odds ratio: 1.11, 95% CI: 1.04-1.18, P=0.003) and anesthetic methods (odds ratio: 5.86, 95% CI: 2.98-11.53, P<0.001) were risk factors for postoperative pulmonary complications. CONCLUSION: General anesthesia may not affect the inpatient mortality after hip fracture surgery in elderly patients. Regional anesthesia is associated with a lower risk of pulmonary complications after surgical procedure compared with general anesthesia. PMID- 29263474 TI - [Application of ultrasound for evaluation of anterosuperior acetabular labral tear]. AB - OBJECTIVE: To explore the value of ultrasound in the diagnosis of anterosuperior acetabular labral tear. METHODS: A total of 102 patients [(42 males and 60 females, age from 13 to 60 years, average age was (35.14+/-9.16) years] with suspected anterosuperior acetabular labral tear were included in this study, including 44 left hip joints and 58 right hip joints. All the patients received hip joint ultrasound and magnetic resonance imaging (MRI) evaluation before arthroscopy surgery. Using arthroscopy as golden standard, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy between ultrasound and MRI were calculated and compared. RESULTS: There were 91 antero-superior acetabular labral tears of 102 patients which were confirmed during arthroscopy surgery. Sixty-nine patients were diagnosed correctly by ultrasound, including 60 anterosuperior acetabular labral tears and 9 with no acetabular labral tears, whereas 2 were false-positive and 31 were found to be false-negative. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy by ultrasound were respectively 65.93%, 81.82%, 96.77%, 22.50% and 67.65%. In contrast, seventy-seven patients were diagnosed correctly by MRI, including 70 anterosuperior acetabular labral tears and 7 with no acetabular labral tears, whereas 4 were false-positive and 21 were found to be false-negative. For MRI, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were respectively 76.92%, 63.64%, 94.59%, 25.00% and 75.49%. The results of ultrasound and MRI were in accordance in 68 of the 102 patients. There were 51 anterosuperior acetabular labral tears of the 68 patients who were diagnosed by both ultrasound and MRI, whereas there were 17 with no acetabular labral tears of the 68 patients who were diagnosed by both ultrasound and MRI. The results of ultrasound and MRI were inconsistent in 34 of the 102 patients. In 11 of the 34 patients, in which case ultrasound diagnosed anterosuperior acetabular labral tear, MRI found no acetabular labral tear. Whereas, in 23 of the 34 patients, in which case MRI diagnosed anterosuperior acetabular labral tear, ultrasound found no acetabular labral tear. As compared with MRI findings, ultrasound had a lower accuracy for anterosuperior acetabular labral tear than MRI, there was statistical difference on the accuracy for anterosuperior acetabular labral tear (P<0.01). CONCLUSION: Although ultrasound had a slightly lower sensitivity for anterosuperior acetabular labral tear, it had a higher specificity than MRI. Dynamic evaluation of antero-superior acetabular labral tear is an advantage of ultrasound. Ultrasound could be used as a feasible method to evaluate anterosuperior acetabular labral tear. PMID- 29263475 TI - [Midterm clinical outcomes and radiological results of surgical treatment for Hirayama disease]. AB - OBJECTIVE: To assess the midterm clinical and radiological outcomes of internal fixation and fusion for the treatment of Hirayama disease and to evaluate the clinical significance and value of this procedure. METHODS: In the study, 36 patients were treated with anterior cervical internal fixation and fusion. The clinical outcomes including muscle strength and atrophy were recorded. The radiological outcomes including range of motion of cervical spine and the cross sectional area of spinal cord at each level on MRI scan were measured before and at 3 month, 1 year and 2 years follow-up time points after surgery. RESULTS: (1) Clinical outcomes: all the patients showed no further progression of symptoms except one patient with mild progression of muscular weakness and atrophy. As the time passed by, the ratio of the patients with muscle strength and atrophy improvement increased. There were 26.5% of patients in 3 months, 36.0% in 1 year and 85.7% in 2 years who experienced muscle strength improvement. 8.8% of patients in 3 months, 24.0% in 1 year and 35.8% in 2 years felt muscle atrophy improvement. And 12 of the 14 patients showed improved muscle strength and atrophy at the end of 2 years period follow-up. (2) Radiological outcomes: the range of motion (ROM) of C2-C7 was significantly decreased after the operation. The ROM of preoperation was 62.25 degrees +/-2.10 degrees and that of 2 years postoperation was 13.67 degrees +/-7.51 degrees (P<0.01). The spinal cord was of no compression on flexion MRI. The cross-section area of spinal cord on MRI was significantly increased only at C6 level (P<0.05) at the end of three months follow-up. The level of increased cross-section area rose to C4-C5-C6 levels (P<0.01) in 1 year and to C4-C5-C6-C7 levels at the end of 2 years follow-up (P<0.05). The cross-section area increased 15.60% at C4, 19.08% at C5, 21.60% at C6 and 23.91% at C7 with significant difference (P<0.05) 2 years after the operation. CONCLUSION: Anterior cervical internal fixation and fusion is an effective surgical treatment for Hirayama disease and may provide preferable midterm clinical and radiological outcomes. This procedure has clinical significance and value in terms of control of the progression and outcome of this disease. PMID- 29263476 TI - [Relationship between large artery elasticity function and coronary heart disease, lower extremity arterial disease in patients with carotid plaque]. AB - OBJECTIVE: To evaluate the relationship between large artery elastic function and coronary heart disease (CHD) or lower extremity arterial disease (LEAD) in patients with carotid plaque. METHODS: A total of 491 patients with carotid plaque were enrolled into the study with complete data of arterial stiffness detection and blood test [male: 208 and female: 283, and mean age: (61.66+/ 11.60) years]. All the subjects were divided into 2 groups according to CHD or LEAD, namely non-CHD&LEAD group (neither CHD nor LEAD) and CHD/LEAD group (either CHD or LEAD). Accor-ding to the mean age level (age<61.66 years or age>61.66 years), the independent association was analyzed between higher large arterial stiffness (carotid-femoral pulse wave velocity, CF-PWV, CF-PWV>9 m/s) and CHD/LEAD. RESULTS: In the present research population, the mean level of arterial stiff-ness was high (the mean CF-PWV was 10.71 m/s), and 76.6% of them had arteriosclerosis, and 36.9% CHD/LEAD. The age, male and smoking proportion, systolic blood pressure (SBP), glycosylated hemoglobin (HbA1c), homocysteine (Hcy), creatinine (Cr), CF-PWV, prevalence rate of hypertension and diabetes mellitus, medication on hypertension, diabetes and hyperlipidemia were higher in CHD/LEAD group, and total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were lower in CHD/LEAD group than in non-CHD&LEAD group (all P<0.05).In multivariate Logistic regression analysis, the results showed that in the patients with age below 61.66 years, large artery stiffness (CF-PWV>9 m/s) was an independent risk factor of CHD/LEAD (OR=3.229, 95%CI 1.156-9.022, P<0.05); In the patients with age above 61.66 years, there was no independent association between large artery stiffness and CHD/LEAD (P>0.05). CONCLUSION: The large artery elasticity function in the patients with carotid plaque was poor. In the patients with carotid plaque and higher large artery stiffness below 61.66 years, the risk of the prevalence of CHD/LEAD was increased significantly than with normal arterial stiffness. In the patients with carotid plaque below or above 61.66 years, the independent influencing factors on the prevalence of CHD/LEAD were different. PMID- 29263477 TI - [Surgical strategies for treatment of T1b gallbladder cancers diagnosed intraoperatively or postoperatively]. AB - OBJECTIVE: To explore the surgical strategies for the treatment of T1b gallbladder cancer patients diagnosed intraoperatively or postoperatively. METHODS: A retrospective analysis of 42 patients with T1b gallbladder cancers was performed. There were 14 patients diagnosed intraoperatively and 28 patients diagnosed postoperatively. The reevaluations of T stages were conducted in the 28 T1b gallbladder cancer patients diagnosed postoperatively by the professional pathologist. After T stage reevaluation, 25 confirmed T1b patients with complete follow-up data were divided into simple cholecystectomy group and ra-dical resection group, and the clinicopathologic characteristics between the two groups were analyzed. RESULTS: Only 2 of the 14 T1b gallbladder cancer patients diagnosed by the intraoperative frozen specimen proved to be T1b on postoperative paraffin pathology, and for the remaining 13 patients, T2 was in 11 patients, and T3 in one patient. The rate of misdiagnosis was 85.7% by the intraoperative frozen specimens, postoperative T stages were equal or higher than intraoperative T stages. Two of the 28 postoperatively diagnosed T1b patients were proved to be T2 after reevaluation, the rate of misdiagnosis was 7.1%, the reevaluated T stages were equal to or higher than the previous stages. Twenty-five confirmed T1b gallbladder cancer patients had complete follow-up data, 11 of whom underwent simple cholecystectomy and the remaining 14 radical resections. No patient had vessel or perineural invasion on pathology in the 25 confirmed T1b patients. Metastasis was absent in all the 30 lymph nodes examined, which achieved from 14 patients with radical resection. The survival rate after simple cholecystectomy was comparable to that after radical resection (P=0.361). Only one patient with radical resection had abdominal cavity implantation relapse, who received gallbladder compression during operation and 2 years later died from metastasis. CONCLUSION: Intraoperatively diagnosed T1b gallbladder cancer should receive radical resection. Reevaluation of the T stage is necessary and the initial step for postoperative diagnosed T1b gallbladder cancer patients. The pros and cons of radical surgery for definitive T1b patients should be carefully evaluated, and systemic chemotherapy is recommended for those with bile spillover. PMID- 29263478 TI - [Investigation of the cognition and behavior on drug safety in Beijing middle school students]. AB - OBJECTIVE: To understand the cognition and behavior of drug safety in Beijing middle school students and provide advice for relevant education. METHODS: A cross-sectional survey using paper questionnaires was carried out on the student body of nine Beijing middle schools. Multi-stage proportionate stratified cluster sampling was adopted to enroll participants. In addition to demographic questions, the questionnaire included 17 questions assessing the cognition and behavior of safe drug use, prioritizing questions that aligned with the health education guideline for primary and secondary school students from Chinese Ministry of Education. Descriptive statistical methods were applied using the SAS 9.2 software. RESULTS: Of the 4 220 students investigated, 2 097(49.7%) were males and 2 123(50.3%) were females. The average age was (14.3+/-1.7) years. 2 030(48.1%) students were from downtown areas, 1 511(35.8%) were from urban-rural linking areas and 679(16.1%) were from rural areas. Half (51.5%) of the respondents were junior high school students, and the others were from senior high schools (34.2%) and vocational high schools (14.3%). Most of the students (89.6%) lived off campus. The awareness rate of drug safety knowledge was 74.4%, the median score of drug safety behavior was 4 points (full score was 5 points) and there was a statistically positive correlation between the two (Spearman's correlation coefficient was 0.156, P<0.001). Both the awareness rates and the drug safety behavior scores were statistically different among the students in different regions, different school types and different residence types (P<0.001). Multiple factors analysis demonstrated the correlation between the cognition degrees of both drug safety knowledge, behavior and the above factors. Of all the students, 80.4% agreed that any drug could have adverse drug reactions; 40.5% were aware that antibiotics couldn't kill viruses; as many as 49.6% mistook aspirin as antibiotic; 97.4% would read drug instructions before taking them; Only 42.4% put expired drugs into special recycling bins; 49.8% would deviate from the suggested dosage and frequency of their medication when they were sick with common diseases. CONCLUSION: Overall, the cognition of drug safety in Beijing middle school students is good, but problems still exist in medication adherence, the management of expired drugs and the antibiotics cognition, which need to be fixed through specific, pointed way of education. And more efforts should be made to improve the cognition in rural regions, vocational high schools and on campus students. PMID- 29263479 TI - [Intravenous sedation with midazolam and propofol target controlled infusion on patients'perioperative anxiety under the mandibular third molar extraction]. AB - OBJECTIVE: To evaluate whether midazolam with propofol target controlled infusion (TCI) intravenous sedation during the mandibular third molar extraction influences patients'perioperative anxiety. METHODS: The subjects were patients who planned to undergo the mandibular third molar extraction in Peking University School and Hospital of Stomatology, whose state anxiety inventory (SAI) scores were>=38 at the initial visit. They were divided into intravenous sedation group (IVS) and local anesthesia group (LA) on the basis of the planned intravenous sedation. Each group was divided into two subgroups according to the overall SAI scores at the initial visit: IVS-I, LA-I (SAI: 38-50) and IVS-II, LA-II (SAI: 51 80). The anxiety before and after the surgery was evaluated by the SAI scores at the initial visit (T1), before surgery (T2) and 7 days after surgery (T3). The anxiety during the surgery was evaluated by the heart rate, blood pressure and visual analogue scale (VAS) scores. RESULTS: There were no significant differences on SAI at T1, T2, and T3 in the two groups (P>0.05). The heart rate, blood pressure and VAS pain scores of IVS group were significantly lower than those of LA group during the surgery (P<0.001). CONCLUSION: Intravenous sedation with midazolam and propofol TCI was effective on the patients' anxiety during the third molar extraction, which successfully made the patients more comfortable and their heart rate, blood pressure and oxygen saturation more stable during the surgery. But there were no significant differences on the patients'anxiety at the initial visit (T1), before surgery (T2) and 7 days after surgery (T3) according to the SAI scores in the two groups. PMID- 29263480 TI - [Clinical analysis of cervical lymph node metastasis of cN0 maxillary malignant tumor]. AB - OBJECTIVE: To investigate the cervical lymphatic metastasis rates of clinically negative neck lymph node (cN0) maxillary malignant tumors, to compare the cervical lymphatic metastasis rates of the various pathological types, and to provide the reference for the treatment of the neck of the patients with cN0 maxillary malignant tumor. METHODS: The clinical data of 277 cases with cN0 maxillary malignant tumor, treated in the department of oral and maxillofacial surgery of Peking University School and Hospital of Stomatology from 1990 to 2010, were reviewed. The cervical lymph node metastasis and the related clinical information were recorded. The clinical information including histopathology type of the tumors, tumor grade, primary site and TNM staging, as well as other demographic and clinical data, were retrieved from the electronic medical record system (EMRS) of the hospital. The pathogenesis of cervical lymph node metastasis in maxillary malignant tumors of different histopathological types, and the factors related to lymph node metastasis of upper cervical malignancy were analyzed by SPSS 19.0 statistical software. RESULTS: The overall cervical lymph node metastasis rate of the 277 patients with cN0 maxillary malignant tumor was 15.5% (43/277). Maxillary squamous cell carcinoma (SCC) had a strong cervical lymph node metastasis tendency and the rate was 33.0%. The overall metastatic rate of adenocarcinoma was 7.6% lower than that of SCC, and the occurrence of cervical lymph node metastasis time was relatively late, but the metastasis rate of highly malignant grade salivary gland carcinoma was significantly higher than that of intermediate and low grade carcinoma (P=0.037). The metastatic rates of some highly malignant cN0 salivary gland carcinomas including adenocarcinoma, not other specified, high-grade mucoepidermoid carcinoma (MEC), and salivary duct carcinoma were exceeded 15%, while the metastasis rates of adenoid cystic carcinoma and myoepithelial carcinoma were lower. The metastasis rate of the sarcomas was very low with the rate of 4.9%. CONCLUSION: Selective neck dissection (SND) is recommended for cN0 maxillary SCC and feasible for some highly malignant cN0 salivary gland carcinomas including adenocarcinoma, not other specified, high-grade MEC, salivary duct carcinoma. The neck can be closely observed for the patients with maxillary sarcoma. PMID- 29263481 TI - [Influence of EDC ethanol solution on dentin shear bond strength with a self-etch adhesive system]. AB - OBJECTIVE: To evaluate the bonding ability of one representative self-etch adhesive system by applying the micro-shear bond strength test method with different concentrations of carbodiimide [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, EDC] ethanol solution pretreatment. METHODS: Extracted sound human third molars were collected from patients ranging 18 to 40 years. In the study, 80 molars were first sectioned to prepare a flat middle coronal dentin surface and then were randomly divided into 5 groups (n=16) according to without/with different surface treatments [blank control; 80% (volume fraction) ethanol control; EDC ethanol solution of three concentrations (0.01 mol/L, 0.3 mol/L and 0.5 mol/L)]. Each specimen underwent a micro-shear bond strength test and failure mode observation. The data collected were subjected to statistical analysis using one-way ANOVA and post hoc Tukey's test to analyze the difference of the micro shear bond strength, and chi-square test/Fisher's exact test for the failure mode frequency of the micro-shear bond strength test specimens at a significance level of P=0.05. RESULTS: The micro-shear bond strength of the three concentration EDC treatments were (35.29+/-8.97) MPa (0.01 mol/L EDC treatment group), (40.24+/ 9.68) MPa (0.3 mol/L EDC treatment group), (37.38+/-9.66) MPa (0.5 mol/L EDC treatment group) separately; and that of the 80% ethanol group was (37.49+/-7.76) MPa. All micro-shear bond strength value of the above four groups was statistically higher than that of the blank control group [(33.81+/-7.98) MPa]. The immediate micro-shear bond strength and failure mode was of no statistically significant difference among all the groups. It was noticed that the immediate micro-shear bond strength of 0.3 mol/L was higher than that of all the other groups, especially higher than that of the 80% ethanol pretreatment group despite that there was no significant difference among all the groups. And the test of failure mode indicated that the cohesive failure was more common, while the frequency of adhesive failure was rare in each experimental group. CONCLUSION: EDC pretreatment had no adverse effect on the immediate micro-shear bond strengths of Clearfil SE Bond. Meanwhile, EDC treatment did not cause more adhesive failure in immediate micro-shear test, which had further denoted what was said above. However, it needs more research to illustrate the anti-enzymatic role of EDC in dentin bonding. PMID- 29263482 TI - Facilitating the measurement of circulatory hydrogen sulfide with fluorescence probe-coated microplates. AB - OBJECTIVE: The hydrogen sulfide (H2S) role in pathogenesis of various diseases were wildly addressed in recent decade. The circulatory (plasma or serum) and biological fluid H2S measurement is still an enormous issues due to the technical limitation. This paper aimed to develop a novel measurement method based on fluorescence probe. METHODS: Firstly, 20 MUL ethanol was used to dissolve 100 pmol fluorescence probe, then added in a 96-well plate. An equal volume of ethanol was also added to the blank well of the plate. The plate was placed in a dark room for about 1 h until the fluorescence probe was evenly coated in the 96 well microplate and dried. The plate was frozen at -20 degrees C for later use. Secondly, the plasma or serum sample was added with saturated ammonium sulfate buffer (pH 7.8) and then centrifuged to remove the proteins. The equal volume supernatant liquid was added to the probe-coated well and the probe-uncoated well. The plate was incubated in a dark environment at 37 degrees C for 2 h. Finally, after incubation, the fluorescence density was acquired at LambdaEx/LambdaEm 340/445 nm in a microplate reader. The differences of the fluorescence density values between the probe-coated well and probe-uncoated well were counted and H2S concentration of plasma/serum was calculated by standard curve with NaHS. RESULTS: The method had high sensitivity (from 0.3 to 100 MUmol/L) and specificity for measuring H2S as compared with other biologically relevant reactive sulfur species and sulfur-containing amino acid. Serum H2S concentrations were assayed in 188 health volunteers using this method [(12.1+/ 3.5) MUmol/L, 95%CI: 4.6-19.8 MUmol/L], and the frequency distribution showed a normal tendency(one-sample Kolmogorov-Smirnov test, P>0.1). The serum H2S concentrations in 30 hypertension patients were decreased compared with 22 age- and gender-matched health individuals (paired-samples t test, t=9.937, P<0.001). There were no differences of H2S concentration in serum [(19.66+/-2.32) MUmol/L] or plasma [(18.67+/-2.07) MUmol/L], between the samples acquired from artery [(19.34+/-0.51) MUmol/L] or vein [(18.99+/-0.50) MUmol/L] of male Wistar rats (repeated measurement of ANOVA, P=0.38). One week frozen samples did not affect the detection. The values of the repeated measurement did not differ (two-way ANOVA, P>0.05). CONCLUSION: The present method is easily performed with high sensitivity, specificity and repeatability for circulatory H2S. It is also quick and may apply for large samples. PMID- 29263483 TI - [Comparison of outcomes of two minimally invasive approaches for multi-vessel coronary revascularization]. AB - OBJECTIVE: To compare the safety and effectiveness of two minimally invasive approaches for multi-vessel coronary revascularization. METHODS: From August 2014 to February 2017, 70 consecutive patients who underwent minimally invasive coronary artery bypass grafting in Peking University Third Hospital were randomly divided into two groups. In one group, 40 patients underwent staged-hybrid coronary revascularization (staged-HCR) treatment; in the other group, 30 patients underwent minimally invasive total arterial revascularization with bilateral internal thoracic artery (BITA). In staged -HCR group, the patients underwent minimally invasive direct coronary artery bypass grafting (MIDCAB) and percutaneous coronary intervention (PCI) procedure for treatment of multi-vessel disease. In BITA group, the patients underwent total arterial coronary artery bypass grafting with composite "Y" BITA graft. Preoperative and postoperative data of the two groups, including postoperative blood usage, mechanical ventilation time, domiciling duration in intensive care unit (ICU), major adverse cerebral and cardiovascular event (MACCE), and postoperative coronary angiography results were compared, in order to evaluate the safety and effectiveness of these surgical approaches. RESULTS: The preoperative characteristics of 70 patients in the two groups showed no significant difference. All the patients underwent successfully, elective minimally invasive multi-vessel coronary artery bypass grafting as scheduled preoperatively. Postoperative result showed the patients in staged-HCR group took advantages in less postoperative mechanical ventilation time [Staged-HCR group (11.2+/-8.7) h vs. BITA group (18.3+/-9.1) h, P=0.013], shorter domiciling duration in ICU [Staged-HCR group (26.29+/-4.05) h vs. BITA group (44.74+/-28.75) h, P=0.022], and less total drainage [Staged-HCR group (695.57+/-250.46) mL vs. BITA group (1 103.26+/-547.44) mL, P=0.03] than the patients in the group of minimally invasive total arterial revascularization with BITA. Postoperative in hospital coronary angiography showed satisfactory graft patency rates in both groups [97.5% in Staged-HCR group vs. 97.8% in BITA group]. No MACCE occurred in both groups during hospitalization. CONCLUSION: Staged-HCR is a feasible method for the treatment of multi-vessel revascularization involving right coronary artery. Minimally coronary revascularization with BITA is associated with superior long-term graft patency and it's recommended for patients who could not tolerate dual-antiplatelet therapy. This study shows that both minimally invasive surgical approaches are safe and effective for treatment of patients with multi-vessel coronary artery disease. PMID- 29263484 TI - [Percutaneous renal access for percutaneous nephrolithotomy guided by contrast enhanced ultrasound: a single-center preliminary experience in China]. AB - OBJECTIVE: Contrast enhanced ultrasound (CEUS) is an innovative technique that employs microbubble contrast agents to demonstrate parenchymal perfusion. Ultrasound contrast agent was reported to be directly used in human internal lumen to improve the observation capacity of ultrasound. However, CEUS has never been reported to be used in the guidance of percutaneous renal access in percutaneous nephrolithotomy (PCNL). This study aimed to assess the efficacy of CEUS-guided renal access in PCNL. METHODS: In this retrospective study, percutaneous renal access was performed under real-time monitoring of CEUS during PCNL in a cohort of 20 patients with renal stones at Peking University First Hospital. Data regarding patients' demographic and clinical characteristics, therapeutic regimens, and postoperative information were collected from a comprehensive database containing comprehensive medical records of the patients undergoing PCNL. Briefly, the procedure was as follows. With the patient under general anesthesia, renal access was established by the guidance of CEUS. Afterwords, holmium laser, pneumatic or ultrasonic lithotripsy was used by the same urologist. The patient demographics, stone characteristics and procedure details were noted. Finally, appropriate statistical analyses were performed to evaluate the effectiveness and safety of the CEUS-guided percutaneous renal access in PCNL. RESULTS: All the 20 patients underwent PCNL successfully with the help of CEUS guidance for tract creation. The collecting system was successfully accessed in all the patients, and only one patient underwent re-puncture. All the patients approached through a middle-pole percutaneous access. The median puncture time was 3.9 (2.9-4.6) min, and the median operating time was 112 (98.5 134.5) min. The preliminary stone-free rate of PCNL was 95.0% (19/20) as shown by the kidney, ureter, and bladder (KUB) radiographs 48 h postoperation, and the median decline in hemoglobin level was 10 (5.5-14.5) g/L. Two patients had transient postoperative fever and responded well to antibiotics. In addition, no other major complications were observed. CONCLUSION: CEUS is a safe and effective alternative way of guidance for percuta-neous renal access for PCNL beginners. It makes this procedure more visualized and simpler, and produces clearer images than common ultrasonic ones. PCNL beginners might benefit from this method to shorten the learning curve of PCNL, while it warrants further comparative studies to clarify. PMID- 29263485 TI - [A rare pulmonary benign bi-phasic tumor: a case report of pulmonary adenofibroma and literature review]. AB - Pulmonary adenofibroma is an extremely rare benign primary tumor of the lung, with characteristic bi-phasic differential pattern. They are usually sub-pleural solid pulmonary nodules with clear margins. The tumor is composed of glands and peri-gland stroma. The glands are often quite simple, forming long and narrow tubules, with uniformly monolayer lining cells. Combined papillary or phyllodes structures were reported in some cases. The stromal cells are spindle-shaped and look mild, mixed with the collagen bands. Up till now, only a few cases of pulmonary adenofibroma have been reported all over the world. And because of the limited recognition, this tumor is easily misinterpreted as malignancy in frozen section or biopsy specimens. We reported a new case of pulmonary adenofibroma. The mass peripherally located in the left lobe of the lung, found by chance in a 74-year-old woman. The patient underwent a wedge resection of the left lung by the thoracoscope, because of the slowly gradual enlargement of the mass annually. An oval grayish-white nodule was sub-pleural located in the specimen, with solid and rubbery texture, but without a distinct capsule. Two distinct components of simple glands and mild spindle cell stroma were found to mix together uniformly under the microscope. Collagen bands of various widths evenly surrounded each stromal cell. A few small coarse papillae or phyllodes structures were randomly distributed in some area. The immunohistochemical staining pattern of the glandular cells was accordant with typeIIalveolar epithelium. Stromal cells were positive with CD34, B-cell lymphoma-2 (Bcl-2), CD99 and estrogen receptor (ER), while S-100, smooth muscle actin (SMA) and all the mesothe-lium markers were negative. The patient was disease free after the surgery, although the follow-up time was only one year. Besides the new case above, we also reviewed all the reported cases, and tentatively discussed the probable histological origin of pulmonary adenofibroma. PMID- 29263486 TI - [Presented with subarachnoid hemorrhage and then blood culture negative infective endocarditis: a case report and literature review]. AB - The patient, a 43-year-old man, had paroxysmal headache three months ago, and he had complained the left occipital sharp pain, which could be alleviated by itself, with alalia and the right side of the upper limb numbness. Head computed tomography (CT) revealed a left temporal lobe intraparenchymal hemorrhage with the left side of the subarachnoid hemorrhage in small quantities. Digital subtraction angiography (DSA) revealed a suspicious aneurysm on the left internal carotid artery siphon. He had intermittent fever 1 month ago, with maximum body temperature 39 degrees C. He suffered headache again 20 days ago, with pain nature, duration and the way of easing up similar to the earlier onset. General examination demonstrated 2/6 grade blowing systolic murmurs at apex area. Neurological examination revealed that Babinski's sign was positive on the right side. Echocardiographic found an anterior mitral valve ve-getation on the 4th day in hospital. So his clinical diagnosis was infective endocarditis with cerebral embolism. He received vancomycin treatment immediately. His three blood cultures remained negative in hospital. His blood specimens were sent to Chinese Center for Disease Control and Prevention, indirect immunofluorescence method (IFA) IgG antibody detection revealed that the Bartonella henselae IgG antibody was positive. Therefore the clinical diagnosis was Bartonella endocarditis complicated with subarachnoid hemorrhage and cerebral embolism. Bartonella, an intracellular fastidious, gram-negative bacilli, was first documented as a cause of endocarditis in 1993 and since then has been increasingly recognized as an important etiology of infective culture-negative endocarditis. In cases of documented Bartonella endocarditis, the Infectious Diseases Society of America (IDSA) guidelines recommended 2 weeks of gentamicin plus 6 weeks of doxycycline treatment, to achieve a higher cure rate. PMID- 29263487 TI - [A Sjogren's syndrome patient with prominent aortic valve involvement: a case report]. AB - Sjogren's syndrome is a systemic autoimmune disease which is characterized by xerosis, and multiple organs can be affected, causing interstitial lung disease, renal tubular acidosis, blood system involvement, peripheral neuropathy, and liver damage, but cardiac involvement is rare. Here we report a case of Sjogren's syndrome with prominent aortic valve involvement. A 66-year-old woman was admitted for exertional dyspnea, and the ultrasonic cardiogram showed severe aortic stenosis with moderate regurgitation. Preoperative examination for valve replacement found that the patient had elevated erythrocyte sedimentation rate and positive rheumatoid factor, so she was referred to the rheumatology outpatient department for further examination and treatment. Further questions about medical history found that the patient had dry eyes and dry mouth for more than ten years, and had obvious caries. Further laboratory examination showed elevated serum immunoglobulin levels and positive anti-nuclear antibody. The findings of ophthalmologic examination and labial gland biopsy also supported the diagnosis of Sjogren's syndrome. After treatment of glucocorticoids and hydroxychloroquine for ten months, her dyspnea symptoms were obviously improved in the patient, and the rheumatoid factor had become negative while her erythrocyte sedimentation rate normal. Repeated ultrasonic cardiogram examination showed that her aortic stenosis was also improved. The patient has been followed up for four years, and her condition kept stable. Cardiac involvement in Sjogren's syndrome can affect all parts of the heart, but valve involvement is relatively rare. The specific relationship between cardiac involvement and Sjogren's syndrome and the mechanisms behind these associations both need further research. PMID- 29263488 TI - [Perioperative stroke effectively treated by an acute stroke team including anesthesia department: a case report]. AB - Perioperative stroke is cerebral infarction occurring in the perioperative period. The incidence of perioperative stroke in non-cardiac, and non-neurologic surgery is about 0.7%, but the mortality can be as high as 26% to 40%. The outcome of the patients with perioperative stroke can be disastrous. Here we report a case of perioperative ischemic stroke that occurred after surgery of lumbar decompression and pedical screw fixation. A 76-year-old female admitted to our hospital because of lumbar spinal stenosis. Her medical history included hypertension and diabetes for ten years. Her personal history included a smoking history of 60 years by 2 cigarettes per day, not quitting. Her carotid artery ultrasound showed multiple low echo plaques on the right side and multiple high echo plaques on the left side of the carotid artery, but without distinct stenosis. Other examinations and tests showed no distinct abnormality. She went on a lumbar decompression and pedical screw fixation uneventfully. The blood loss was 400 mL and autologous blood transfusion 150 mL. The arterial blood pressure (ABP) maintained during 100-130 mmHg/60-80 mmHg (1 mmHg=0.133 kPa). Sixty minutes after she recovered from general anesthesia, the patient developed symptoms of slurred speech and right limbs weakness. The anesthesio-logist evaluated the patient immediately with National Institute of Health Stroke Scale (NIHSS). The NIHSS score was 11 and a stroke was highly suspected. The acute stroke team was therefore initiated and fast responded. Within 4 h, digital subtraction angiography (DSA) was proceeded, which showed the M1 segment of the left middle cerebral artery was occluded and the local stenosis of her right middle cerebral artery was up to 80%. After the successful embolectomy by Solitaire stent, the left middle cerebral artery reflowed and the forward blood flow was thrombolysis in myocardial infarction (TIMI) grade 3. The patient was discharged after 33 days after the surgery with a NIHSS of 9. Our case provides an example that an acute stroke team that included the department of anesthesiology can be beneficial to the patients' perioperative strokes. During the perioperative period, anesthesiologists should be included into the acute stroke team, because anesthesiologists and anesthesia nurses might be first observers of those early onset strokes. Our case also put forward this thought that a standard peri operative stroke evaluation tool, like NIHSS, should be discussed and applied to facilitate and accelerate the initiation of perioperative acute stroke team. PMID- 29263489 TI - [Adenocarcinoma in a Meckel's diverticulum with multiple liver metastases and gastrointestinal hemorrhage: a case report]. AB - Meckel's diverticulum is the most common congenital anomaly of the gastrointestinal tract, affecting approximately 2% of the population. It is a true diverticulum occurring on the anti-mesenteric border of the distalileum, typically within 100 cm of the ileo-caecal valve. Neoplasms arising in Meckel's diverticula are uncommon, and those reported in the literature are mainly carcinoid tumors, followed by gastrointestinal stromal tumors (GIST) and benign leiomyomas. Adenocarcinomas are extremely rare. Tumors in Meckel's present non specifically with gastrointestinal complaints, such as bleeding, obstruction, inflammation or perforation. The suspicion of a Meckel's tumor is often not thought of at the initial. In this article we describe a 57-year-old woman who presented with massive rectal bleeding and severe anemia, later found to be caused by a adenocarcinoma arising from Meckel's diverticulum. The tumor was unfortunately highly aggressive. Multiple liver metastases had already existed when we discovered the primary mass. Later we performed a partial resection of the ileumto cease the bleeding. Meckel's diverticulum and the tumor were resected simultaneously. The pathological diagnosis confirmed adenocarcinoma arising from the Meckel's diverticulum. The final stage was pT4NxM1, stage IV according to the Union for International Cancer Control (UICC) classification. After operation we gave the patient first-line, mFOLFOX6 chemotherapy, but it turned out to be not effective. Rapid progress of the liver metastases and suspicion of multiple lung metastasis in short time after therapy indicated a bad outcome. We believe this is the first case of adenocarcinoma in a Meckel's diverticulum to be reported in domestic literature. The diagnosis of Meckel's tumor should be considered as inpatients'acute gastrointestinal complaints; when found incidentally at laparotomy, it should be carefully examined for any gross abnormality and resection should be considered. PMID- 29263490 TI - [Bilateral maxillary bisphosphonate-related osteonecrosis of the jaw: a case report]. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ), as one serious side effect of bisphosphonate therapy, has been known for more than ten years since it was first reported in 2003. In the majority of the cases, BRONJ occurs more commonly in the mandible. Those involving the maxilla are relatively few. This paper reported a case that a patient with multiple myeloma developed bilateral maxillary BRONJ after tooth extraction. The patient had used bisphosphonates for more than three years, meanwhile with uncontrolled diabetes mellitus. The patient recovered completely after surgical treatment, in combination with diabetes disease control and antibiotics application. Two key factors to ensure the success of surgical treatment are as follows: sufficient removal of infected and necrotic tissue, and good blood-supply for the local flap to help completely close the wound. The literature was reviewed to analyze the reasons why bone necrosis related to bisphosphonates was most likely to occur in the jaw, especially in the mandible, according to the pathogenesis of this disease. Furthermore, the related risk factors of BRONJ presented in this case were discussed, such as tooth extraction, oral infection and diabetes mellitus, etc. We summarized adjuvant prophylaxes for prevention of BRONJ after tooth extraction, for example, drug holiday that could be used in the dental clinic. This case report reminds us that it's of great importance to establish the awareness that the osteonecrosis of the jaw may be related to the use of some bone-stabilizers. As for patients with a history of exposure to antiresorptive or antiangiogenic agents, dentists are supposed to be cautious. It's recommended to take appropriate measures in perioperative period of oral surgical treatment to prevent BRONJ. PMID- 29263491 TI - [Methylation status of RASSF1A gene promoter in upper tract urothelial carcinoma and its clinical significance]. AB - OBJECTIVE: To investigate the methylation status of the RASSF1A gene promoter in upper tract urothelial carcinoma (UTUC) tissues and its correlation with clinicopathologic characteristics and postoperative recurrence of primary UTUC. METHODS: In a retrospective design, a total of 687 patients who underwent surgeries for primary UTUC in the urology department of Peking University First Hospital were enrolled. The methylation status of the RASSF1A gene promoter was analyzed using methylation-sensitive polymerase chain reaction on tumor specimens. RESULTS: Aberrant methylation for the RASSF1A gene promoter was detected in 183 (26.6%) DNA samples in total. Aberrant methylation of the RASSF1A gene was strongly associated with tobacco consumption (P=0.044), ipsilateral hydronephrosis (P<0.001 ), tumor location (P<0.001 ), tumor stage (P=0.001), tumor grade (P=0.007), lymph node metastasis (P=0.001) and growth pattern (P=0.013). The methylated RASSF1A gene promoter was an independent risk factor for bladder recurrence (P<0.001, HR=0.471) and contralateral recurrence (P=0.030, HR=0.269) of UTUC after surgery. Hypermethylated RASSF1A was predictive for improved bladder recurrence-free survival (BRFS) (P<0.001) and contralateral recurrence-free survival (CRFS) (P=0.021) in the UTUC patients. Compared with the patients with unmethylated RASSF1A, the patients containing tumors with hypermethylated RASSF1A had tendency toward longer recurrence-free survival time [(114.4+/-3.9) months vs. (84.0+/-3.2) months for BRFS, (138.1+/-1.8) months vs. (132.9+/-1.9) months for CRFS] and higher estimated cumulative recurrence-free survive rates ( five-year survival rate for example, 79.8%+/-3.4% vs. 57.4%+/ 2.6% for BRFS, 98.9%+/-0.8% vs. 93.0%+/-1.4% for CRFS). Additionally, tumor multifocality (P=0.002, HR=1.538), and ureteroscopy before surgery (P=0.001, HR=1.725) were independent risk factors for bladder recurrence in postoperative UTUC patients. CONCLUSION: The methylation status of the RASSF1A gene promoter appears to be a promising epigenomic biomarker for assessing the aggressiveness of UTUC and a predictor predicting the urinary tract recurrence after surgery. PMID- 29263492 TI - [Expression of chemokine like factor-like myelin and lymphocyte and related proteins for vesicle trafficking and membrane link transmembrane domain containing protein 2 in rats with varicocele]. AB - OBJECTIVE: To investigate whether chemokine like factor (CKLF)-like myelin and lymphocyte and related proteins for vesicle trafficking and membrane link (MARVEL) transmembrane domain-containing protein 2 (CMTM2) is involved in spermatogenesis in varicocele induced subfertility rats and to discuss the possible mechanisms. METHODS: Forty male SD rats (body weight: 220-330 g, age: 6 7 weeks) were randomly divided into 4 groups: varicocele for 4 weeks, varicocele for 12 weeks, sham operation for 4 weeks and sham operation for 12 weeks, with 10 rats in each group. These rats were introduced by partially ligating left kidney veins for the experimental groups, and the sham surgery groups as controls were executed with exactly the same surgery as in the experimental groups except for the ligation. The rats in control and experimental groups for 4 and 12 weeks were killed after laparotomy at the end of 4 and 12 weeks, respectively, the left testes and epididymis were taken out for counting the sperm, observing the seminiferous tubule change and immunochemistry for CMTM2. The changes included sperm density and motility, the outer diameter and inner diameter change and the changes of epithelium and the CMTM2 expression in immunochemistry. RESULTS: Compared with the control groups, the sperm density [(63.9+/-7.1)*106/mL vs.(74.3+/-5.0)*106/mL] and motility [(58.7%+/-7.9%) vs.(66.1%+/-4.3%)] were reduced slightly in group of varicoele for 4 weeks, respectively (t=1.432, 1.563; P=0.076, 0.059, respectively). Varicocele significantly caused a decrease in sperm concentration [(40.5+/-7.2) *106/mL vs.(71.1+/-4.5)*106/mL] and motility [(35.2%+/-8.5%)vs. (63.4%+/-4.1%)] at 12 weeks, compared with the related sham groups (t=3.754, 3.933; P=0.004, 0.002, respectively). Additionally, testis CMTM2 exhibited the same disparity, that is, the CMTM2 protein expression in varicocele group was significantly reduced, with the ratio of sham group to varicocele group at the end of 12 weeks 2.3+/-0.4 (t=1.978; P=0.039). In the evaluation of seminiferous tubules diameter, the external [(198.2+/-10.2) MUm vs. (255.8+/ 12.7) MUm, t=2.125, P=0.003] and epithelium diameter [(54.1+/-1.5) MUm vs. (75.5+/-4.1) MUm, t=2.246, P=0.021] were decreased compared with the sham-related groups and previous varicocele groups. In all the varicocele groups, all types of sperm motility decreased compared with the related sham-operated group (P<0.05). CONCLUSION: This study suggests varicocele has a detrimental effect on CMTM2 levels and decreases spermatogonia cell number, seminiferous tubules diameter, and sperm indices. CMTM2 is associated with sperm changes in rats with varicocele, and further studies are needed to study the mechanism. PMID- 29263493 TI - [Sunitinib induces autophagy via suppressing Akt/mTOR pathway in renal cell carcinoma]. AB - OBJECTIVE: To determine the mechanism of sunitinib-induced autophagy in renal cell carcinoma cells. METHODS: MTS assay was applied to detect the cell viability alteration under the treatment of sunitinib (2, 8 MUmol/L). The sunitinib-induced autophagy as well as cell apoptosis was measured and compared after knocking down autophagy-related protein Beclin1 and microtubule associated protein 1 light chain 3 fusion protein (LC3) by RNA interference. The transmission electron microscope was used to observe the formation of autophagosomes in ACHN cells. The fluorescence microscope was used to monitor distribution and aggregation of endogenous LC3-II. The expressions of protein such as LC3-II, the autophagic regulation molecules protein kinase B/ mammalian target of rapamycin (Akt/mTOR) and the symbol of apoptosis poly ADP-ribose polymerase (PARP) were capable to be detected by immunoblotting assay. RESULTS: Sunitinib was able to significantly trigger cell viability loss in the renal carcinoma cell ACHN, which was both in a concentration-dependent and time-dependent manner (P<0.05). After reducing the autophagy by knocking down Beclin1 and LC3, the number of cleavage of PARP was increased remarkably, whereas there was nearly not any cleavage in the mock group. By the transmission electron microscope, there were more autophagic vacuoles in ACHN cells after being administrated with sunitininb compared with the control. And the nuclear-to-cytosol translocation as well as aggregation of LC3-II was presented after sunitinib treatment by the fluorescence microscope, which was the proof of the enhanced autophagy. According to the immunoblotting, sunitinib was able to increase the accumulation of LC3-II . At the same time, the result of sunitinib combined with chloroquine, a drug which blocked the fusion of autophagosomes and lysosomes, demonstrated that the increasing amount of LC3-II was due to the enhanced autophagy flux by sunitinib treatment in ACHN cells. However, phosphorylation of Akt as well as mTOR was decreased at the same time. The rapamycin (mTOR inhibitor) or knocking down Akt subunits could change the sunitinib-induced LC3 -II accumulation, whereas overexpression of Akt subunits decreased the autophagic flux, indicating that Akt/mTOR was the target of sunitinib in autophagy. CONCLUSION: Sunitinib induced autophagy via suppressing Akt/mTOR pathway, and the autophagy was involved in apopotosis. PMID- 29263494 TI - [Expression of MEK/ERK signal pathways in renal cell carcinoma with bone metastasis]. AB - OBJECTIVE: To investigate the expression of MEK/ERK signaling pathways in renal cell carcinoma with bone metastasis, and to analyze the differences of expressions of VEGFR-2, MEK, ERK on the primary and metastasis tissue and its mechanism. METHODS: The tissue samples were obtained from 7 renal cell carcinoma patients kindly provided by Department of Urology, Peking University People's Hospital from January 1, 2009 to January 1, 2010. The expression of MEK/ERK signaling pathways was detected in the 7 renal cell carcinoma patients' primary and matched metastatic tissues with ICH, The antibody concentrations were 1:200, 1:25, and 1:250, respectively. The mutation of the twentieth exon of the PDGFRA gene, the second exon of the K-ras gene, the fifteenth exon of the Braf gene and the second exon of the MEK1 gene were detected with PCR. RESULTS: The expression intensities of VEGFR-2, MEK, and ERK were measured by H-score [intensity (1, 2, 3, or 4) multiplied by the distribution (%)]. VEGFR-2, MEK, and ERK expressions were divided into 3 groups according to the positive distribution of the tumor cells: 1, 0-5%; 2, 6%-50%; and 3, >50%, To assess intratumor heterogeneity, three distinct microscopic fields (*200) from each specimen were used to evaluate the expressions, Subsequently, the scores were averaged to obtain a single concatenated score for each tissue. VEGFR-2, MEK, and ERK expressions were assessed by 2 independent pathologists who were blinded to the clinicopathological data. The data were expressed as the mean value of the triplicate experiments. The expressions of MEK, and ERK were higher in the metastatic tissues than in the matched RCC tissues (6.10+/-4.10 vs. 1.33+/-0.51, P=0.015; 9.10+/-2.24 vs. 4.43+/- 2.84, P=0.021) while the expression of VEGFR-2 was not different between the primary and metastatic tissues (P=0.901). No mutation was detected on the twentieth exon of the PDGFRA gene, the second exon of the K-ras gene, the fifteenth exon of the Braf gene and the second exon of the MEK1 gene. CONCLUSION: MEK/ERK signaling pathways may play an important role in the metastasis and the resistance of sunitinib in RCC patients with bone metastasis. PMID- 29263495 TI - [Knockdown of CMTM3 promotes migration and invasion of PC3 cell in vitro]. AB - OBJECTIVE: To investigate the change of biological characteristics after stable knockdown of CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) expression in PC3 by lentivirus shRNA and to reveal new therapeutic targets. METHODS: The research includes two groups: sh393 is the experimental group in which CMTM3 is knocked down in PC3 cell line; shN is the control group in which CMTM3 is negatively knocked down. The expression of CMTM3 was detected by Western blot. The migration ability of PC3 after stable knockdown was detected by Transwell and Wound healing assay. The invasion ability of PC3 was detected by Matrigel assay. RESULTS were obtained from at least three individual experiments. RESULTS: The expression of CMTM3 in sh393 group is significant lower than shN group (0.004 0+/-0.000 4 vs. 0.490 0+/-0.055 7, P<0.001) detected by Western blot. It also had statistical significance in Matrigel assays (248.6+/-4.5 vs. 113.0+/- 3.3), Transwell (203.6+/-1.9 vs. 103.0+/-1.2) and Wound healing assays (95.0+/-2.9 vs. 33.0+/-1.5) that knockdown of CMTM3 promoted migration, and invasion of PC3 cells in vitro (P<0.001). CONCLUSION: Negative correlation exists between the stable knockdown of CMTM3 and change of biological characteristics in PC3 cells, and knocking down CMTM3 affects migration, and invasion ability in PC3 cells. PMID- 29263496 TI - [Clinicopathological features and differential diagnosis of metanephric adenoma: a report of sixteen cases]. AB - OBJECTIVE: To study the clinicopathological features and differential diagnosis of metanephric adenoma (MA). METHODS: The clinicopathological data of 16 cases with MA diagnosed and treated in Peking University First Hospital from 2004 to 2016 were retrospectively analyzed, and the clinical characteristics, pathologic parameters, differential diagnosis, treatment options and prognosis of MA were analyzed with literature review. RESULTS: The patients included 10 females and 6 males. The age of patients ranged from 14 to 83 years (mean=33.7 years). The partial nephrectomy was carried out for most patients. All cases were located in renal codex with 3 growing into the renal sinus. Histologically, the tumor was composed of tubules, papillary or glomeruloid structures and psammoma bodies were focally seen. Immunohistochemical study showed that all the cases expressed vimentin, and 94% cases expressed CD57, 63% WT1, 75% AE1/AE3, 19% cytokeratin 7 (CK7) and 13%alpha-methylacyl-CoA racemase (AMACR), and negative expressions for MA included CD10, neuron-specific enolase (NSE) and CD56. Follow-up information from 1 to 125 months was available in all the patients; and none of the patients showed any evidence of recurrence and metastasis. CONCLUSION: The benign tumor characteristics of MA are not obvious for preoperative imaging diagnosis, and the diagnosis of MA should be based on the unique pathological features. Positive immunostain of CD57 is a useful indicator for MA diagnosis and differential diagnosis. The partial nephrectomy surgical treatment can achieve good clinical cure with good prognosis. PMID- 29263497 TI - [Clinically predictive factors of Gleason score upgrading in patients after radical prostatectomy]. AB - OBJECTIVE: To assess the discrepancy between preoperative needle biopsy (NB) Gleason score and pathological specimen Gleason score (GS) after radical prostatectomy, and to explore the risk factors of postoperative upgrading of GS. METHODS: We retrospectively evaluated 160 patients who suffered from biopsy proved prostatic carcinoma and performed radical prostatectomy. Age of the patients was 57-82 years, with the average age of 71.6; prebiopsy prostate specific antigen (PSA) was 0.31-40.32 MUg/L,with the average PSA of 11.29 MUg/L; body mass index (BMI) was 16.41-32.04 kg/m2, with the average BMI of 23.63 kg/m2; prostate volume (PV) was 9.52-148.46 mL, with the average PV of 40.19 mL. All the patients included in the study had complete information for clinical variables, including age, BMI, prebiopsy PSA level, PV, number of biopsy cores obtained, percentage, clinical stage, and biopsy GS. Grading of NB Gleason score was compared with their corresponding radical prostatectomy specimens, and the discrepancy between the NB and prostatectomy specimens GS assessed. Upgrading was defined as any increase in the pathological GS over that of the biopsy GS as a total sum of primary and secondary grades or a change in the order of primary and secondary grades towards higher ones. Univariable and multivariable Logistic regression analyses were used to identify predictors of pathological grading changes. RESULTS: Of the 160 patients, the specimen GS was upgraded in 49 (30.6%) patients and remained with no change in 82 (51.3%) patients. Univariate and multivariate regression analysis showed that prostate volume and biopsy GS were independent predictors with postoperative upgrading of GS. Age, BMI, PSA before needle biopsy, clinical stage and needle number showed no statistical significance (P>0.05). CONCLUSION: Lower biopsy GS and smaller prostate volume are increased risks for clinically upgrading of GS after radical prostatectomy. This fact should be kept in mind when deciding on therapy decisions for patients with prostate cancer. PMID- 29263498 TI - [Outcome of treatment of Y chromosome AZFc microdeletion patients]. AB - OBJECTIVE: To discuss the treatment options for patients with azoospermia factor (AZF) c microdeletion on Y chromosome. METHODS: One hundred and eighty three patients, who were diagnosed as AZFc microdeletion on Y chromosome in Peking University Third Hospital, were recruited in our study. In order to get better treatment option for this kind of patients, we retrospectively analyzed their clinic data including the treatment process and pregnancy outcome and found out the characteristics of their semen. RESULTS: Among the 183 patients, sperms can be found in ejaculated semen in 105 patients (57.4%, 105/183). One hundred and three patients (98.1%, 103/105) were diagnosed as severe or extremely severe oligospermia. Regular medication was given to 98 patients, 6 patients (6.1%, 6/98) of which got natural pregnancy. The other 99 patients who have sperms in their semen received intracytoplasmic sperm injection (ICSI), 68 patients (68.7%, 68/99) of which got pregnancy. Seventy eight patients were diagnosed as azoospermia among all the 183 patients. Forty nine patients received testicular sperm aspiration (TESA), and 21 patients choose to receive micro-TESE directly. Among the 49 patients with TESA, sperms were retrieved in 17 patients (34.7%, 17/49), and sperms were not retrieved in 32 patients (65.3%, 32/49), of which 12 patients (37.5%, 12/32) gave up treatment and 20 patients (62.5%, 20/32) choose micro-TESE. Among the 41 patients who choose to receive micro-TESE, operation has been done on 19 patients, of which 11 patients (57.9%, 11/19) got sperms. Among the 11 patients, TESA has been done on 6 patients before micro-TESE, of which 4 patients (66.6%, 4/6) got sperms. ICSI has already been done on 7 azoospermia AZFc microdeletion patients who underwent micro-TESE, of which 4 patients (57.1%, 4/7) get pregnancy. CONCLUSION: AZFc microdeletion patients who had sperms were always diagnosed as severe or extremely severe oligospermia. ICSI was their first choice instead of drug therapy. For AZFc microdeletion patients who were diagnosed as azoospermia, TESA was one of their choices, however, the success rate is not high. Micro-TESE is still possible to get sperms even after the failure of TESA. Therefore, we may choose micro-TESE instead of TESA in some azoospermia patients in order to reduce surgical trauma on patients. PMID- 29263499 TI - [Analysis of metabolic factors and relevance with the grade and stage in patients with renal cell carcinoma]. AB - OBJECTIVE: To investigate the association between metabolic factors, such as obesity, blood pressure, blood glucose, serum lipid profile, and the histopathological characteristics of renal cell carcinoma. METHODS: The medical records of 382 consecutive renal cell carcinoma patients who underwent radical or partial nephrectomy at Peking University People's Hospital from January 2009 to January 2015 were retrospectively reviewed. Metabolic factors were collected from the records, including weight, body mass index, waist circumstance, blood pressure, fasting blood glucose, serum total triglyceride, serum total cholesterol, serum low-density lipoprotein-cholesterol and serum high-density lipoprotein-cholesterol. The patients were divided into different groups according to tumor grade, stage and diameter. Statistics analysis, such as t test, Mann-Whitney U test and Logistic analysis, were performed to investigate the association between metabolic factors and grade, stage and tumor diameter of renal cell carcinoma. RESULTS: A total of 80 (20.94%) of the tumors were classified as high grade disease, 63 (16.49%) were classified as advanced disease and 153 (40.05%) tumor diameter more than 4 cm. The patients in high grade group were found to have lower high-density lipoprotein-cholesterol level than in low grade group (P=0.015), body mass index, total cholesterol and high-density lipoprotein-cholesterol were found to be lower in advanced disease than in localized disease (P=0.022, P=0.005 and P=0.006, respectively), and low-density lipoprotein-cholesterol was found to be lower in larger tumors (P=0.030). Other factors were comparable between the different groups. The results of Logistic analyses showed that, body mass index (OR=0.906, 95%CI: 0.852-0.986, P=0.023) and total cholesterol (OR=0.660, 95%CI: 0.492-0.884, P=0.005) were associated with the tumor stage, high-density lipoprotein- cholesterol level was significantly associated with tumor grade (OR=0.293, 95%CI: 0.108-0.797, P=0.016) and stage (OR=0.204, 95%CI: 0.065-0.635, P=0.006), and low-density lipoprotein-cholesterol level was significantly associated with tumor diameter (OR=0.756, 95%CI: 0.586 0.975, P=0.031). CONCLUSION: The results of our study indicate that metabolic factors, especially obesity and serum lipid profile, are closely related with the histopathological characteristics of renal cell carcinoma. PMID- 29263500 TI - [Retroperitoneoscopic renal pedicle lymphatic disconnection for chyluria via extra-adipose capsule]. AB - OBJECTIVE: To evaluate the clinical effect of retroperitoneoscopic renal pedicle lymphatic disconnection via extra-adipose capsule in the management of chyluria and to discuss the management of its complications. METHODS: From August 2013 to June 2008, five patients with chyluria were admitted. All the patients were female, aged from 26 to 73 years, and disease course from 1 to 10 years. All the five patients had complained of intermittently voiding milky urine with varying degrees of weight loss, and fatigue, of whom two presented with flank pain and one with anemia. Their urine chyle tests were confirmed to be positive. Preoperative cystoscopy found that chyluria was from the left side in 3 cases,and from the right side in 2 cases. Their proteinuria ranged from + to ++++. All the cases had been treated with the modified procedure by which lymphatic ligation was performed to hilar vessels and proximalureter via extra-adipose capsule without disconnection of perirenal fat tissues. The operation time, intraoperative blood loss, postoperative intestinal function recovery, catheter time, drainage tube removal time and complications during operation were collected. RESULTS: All the five cases were performed successfully. The operation time ranged from 75 to 170 minutes, mean (126.0+/-39.6) minutes, with the intraoperative blood loss 20 to 60 mL, mean (38.0+/-16.4) mL, and the postoperative intestinal function recovery time 1 to 3 days, mean (1.9+/-0.4) days. The catheter time was 1 to 4 days, mean (2.1+/-0.3) days and the drainage tube removal time ranged from 3 to 15 days, mean (9.3+/-1.8) days. Postoperatively lymphorrhagia was found in two cases. No renal vessels injury occurred during operation. Chyluria of all the patients disappeared on the operation day with negative chyluria test after surgery. Furthermore, urine test revealed that proteinuria was totally negative. No recurrence was detected in our patients in the 9 to 31 months' follow-up. CONCLUSION: This modified procedure does not have to disconnect perirenal fat tissues and nephropexy during operation. It was characterized with shorter operation time, definitive effect and fewer complications. PMID- 29263501 TI - [Retroperitoneal laparoscopic nephrectomy with autotransplantation for severe iatrogenic ureteral injury]. AB - OBJECTIVE: To evaluate the safety and efficacy of retroperitoneal laparoscopic nephrectomy with autotransplantation in cases of severe iatrogenic proximal ureteral damage. METHODS: From July 2011 to March 2015, two patients, aged 44 (female) and 54 years (male), underwent retroperitoneal laparoscopic nephrectomy and autotransplantation for treatment of severe iatrogenic proximal ureteral injuries. Both injuries were proximal ureteral avulsion during ureterolithotomy with the holmium laser for ureteral calculi. computed tomography angiography (CTA) and computed tomography urography (CTU) was performed in both patients before operation. A 3-port retroperitoneal technique was used for the patients placed in a lateral decubitus position. A retroperitoneal laparoscopic nephrectomy with autotransplantation approach was used in both the patients, and the kidneys were removed to the right iliac fossa. Case 1's kidney was removed through the right Gibson incision, while Case 2's kidney was removed through the left lumbar incision. The renal artery and renal vein were ligated using the Hem o-lok. The kidneys were taken out quickly from the patients and infused with 4 degrees C kidney preserving fluid immediately. RESULTS: The retroperitoneal laparoscopic nephrectomy with autotransplantations was performed 4 hours in Case 1 and 2 years in Case 2 after atrogenic proximal ureteral injuries. Case 2 was associated with dense perinephric and perihilar fibrosis. The procedures were successful, with immediate return of renal function in both the patients. After ex vivo graft preparation, ureteral and vessel length and quality were adequate for transplantation in both the cases. A direct ureterovesical anastomosis was performed in both patients. In the 2 patients, the warm ischemia time was 3 and 5 minutes, the total operation time 185 and 246 minutes, and the estimated blood loss 70 and 200 mL, respectively. No perioperative complications occurred. At the end of the follow-up, the transplanted kidneys were functional, and the patients had returned to their normal activity. CONCLUSION: Retroperitoneal laparoscopic nephrectomy with autotransplantation is an excellent alternative to nephrectomyor bowel interposition in patients with proximal ureteral loss. This procedure is associated with acceptable morbidity and preserves the renal function. This report supports the safety and efficacy of retroperotoneal laparoscopic nephrectomy with autotransplantation in experienced hands. PMID- 29263502 TI - [Radical cystectomy in patients with pathological non-muscle invasive bladder cancer]. AB - OBJECTIVE: Carcinoma of bladder is the most common malignancy in the urinary system in China. Most patients with this disease had non-muscle invasive bladder cancer (NMIBC) at the time of diagnosis. Radical cystectomy was indicated for patients with high risk or refractory NMIBC. We aimed to investigate the overall survival and disease-specific survival and related influence factors in patients undergoing radical cystectomy for pathological non-muscle invasive bladder cancer. METHODS: From Jan. 2006 to Dec. 2012, a total of 164 patients with pathological non-muscle invasive bladder cancer underwent radical cystectomy in Peking University First Hospital. Clinical data were retrospectively collected.Incidence of lymph node metastasis and disease recurrence were calculated. The risk factors of disease recurrence were analyzed. Kaplan-Meier plots were used to estimate the overall survival and cancer-specific survival. Multivariate Cox regression analysis was used to evaluate the prognostic factors for survival. RESULTS: Of all the patients included, 159 had T1 disease, and 5 had CIS only. The median follow-up duration was 46.5 months (range: 7-99 months). Fourteen patients were lost during the follow-up. Lymph node metastasis was noted in 6 patients (3.7%), 4 patients had N1 disease, one patient had N2 disease, and one patient had N3 disease. Disease recurrence occurred in 16 patients (9.8%).The most common recurrence sites were the liver, bones, and lungs. The 5-year overall survival and disease-specific survival for all the patients were 85% and 91%, respectively. The patients who underwent pelvic lymph node dissection showed a better prognosis in terms of disease-specific survival than those without (P=0.012). Patients with recurrence harbored a significant poorer survival (P<0.001). According to univariate Cox regression analysis, whether lymph node dissection was performed was an independent risk factor of disease recurrence (P=0.050, OR=2.695, 95%CI 0.999-7.271). In COX regression model, age (P=0.008, OR=1.071, 95%CI 1.018-1.126) and whether lymph node dissection was performed (P=0.011, OR=3.385, 95%CI 1.329-8.621) were related to disease-specific survival. CONCLUSION: Patients with pathological non-muscle invasive bladder cancer underwent early radical cystectomy have a favorable prognosis, and bilateral pelvic lymph node dissection is essential for this procedure as it gains a survival benefit for the patients. PMID- 29263503 TI - [Impact of different surgical methods of radical cystectomy on the perioperative complications in patients over 75 years]. AB - OBJECTIVE: To analyze the impact of different surgical methods on perioperative complication rate after radical cystectomy in patients over 75 years of age. METHODS: A retrospective study reviewed 1 432 patients who received radical cystectomy from January 2003 to January 2015. A total of 239 patients were >=75 years (median age: 78 years), of whom, 74 patients (31.0%) suffered one or more perioperative complications. According to the different operation methods, patients could be divided into ileal conduit group and cutaneous ureterostomy group. The ileal conduit group included laparoscopic and open radical cystectomy with ileal conduit. The cutaneous ureterostomy group included transperitoneal laparoscopic, transperitoneal and extraperitoneal open radical cystectomy with cutaneous ureterostomy. RESULTS: Perioperative complications were significantly associated with the patient's age (P=0.012), American Society of Anesthesiologists (ASA) score (P=0.001), node staging (P=0.043), and different surgical methods. Perioperative complications caused a prolonged hospital stay and delayed recovery (34 d vs. 21 d, P=0.002). For different surgical methods, the perioperative complication rate of ileal conduit was higher than cutaneous ureterostomy (P=0.013). However, there were no significant differences between transperitoneal laparoscopic and open radical cystectomy with ileal conduit in perioperative complication rate (P=0.836). The perioperative complication rate was statistically significant among transperitoneal laparoscopic, transperitoneal and extraperitoneal open radical cystectomy with cutaneous ureterostomy (P=0.022). On multivariate analysis, age (hazard ratio=4.856, 95% CI: 1.465 16.103, P=0.010), ASA score (P=0.008), and different surgical methods (P=0.016) were significantly associated with the perioperative complication rate. CONCLUSION: The perioperative complication rate after radical cystectomy in elderly patients was associated with the patients' age, ASA score, and different surgical methods. Patients who received extraperitoneal open radical cystectomy with cutaneous ureterostomy suffered fewer perioperative complications, which was an appropriate choice for elderly patients. PMID- 29263504 TI - [Primary penoscrotal extra-mammary Paget's disease: analysis of 22 cases]. AB - OBJECTIVE: To investigate the clinical characteristics, treatment and prognosis of primary penoscrotal extra-mammary Paget's disease (PSPD). METHODS: The clinical and pathological data of 22 cases of primary PSPD were retrospectively reviewed. Survival rate of the overall patients, the invasive patients, and the patients with positive surgical margin or negative surgical margin were analyzed with Kaplan-Meier survival curve method. RESULTS: Among all the patients with primary PSPD, the median age of onset was 64.5 (39-84) years, the median time of disease duration was 40 (2-300) months, and the median long diameter of lesion was 4.75 (1-10) cm. In the study, 12 patients (54.5%) were in pathological stage A1, 6 patients (27.3%) were in pathological stage A2, and 4 patients (18.2%) were in pathological stage B. Scrotum and penile of most patients (n=12, 54.5%) were involved, 5 patients (22.7%) were scrotum only, and 5 patients (22.7%) were penile only. Erythema (n=18, 81.8%), itchiness (n=16, 72.7%), ulcerate (n=12, 54.5%), exudation (n=11, 50.0%), and pain (n=4, 18.2%) were the major manifestations. All the patients with primary PSPD were treated with wide surgical excision. The rate of invasive patients was 77.3% (n=17). Of them, 6 patients had positive surgical margin. The surgical margins of non-invasive patients were all negative. Twelve patients exhibited local recurrence or/and metastases, and the status of surgical margins (P=0.015) and the depth of invasion (P=0.010) were important risk factors. Inguinal lymph nodes were generally involved. The difference of the delay of diagnosis between metastasis and non-metastasis was significant (P=0.040). The 5-year survival rates of the overall and invasive patients were 33.7% and 27.9%, respectively. The patients with positive surgical margin had poor prognosis. CONCLUSION: Primary PSPD, with the characteristics of long duration, high invasive tendency and high incidence of local recurrence or metastases, generally occurs in the elderly. Surgery should be performed at first. The delay of diagnosis, positive surgical margins and the involvement of inguinal lymph node are important risk factors. Biopsy, frozen section and inguinal lymph node biopsy (ILNB) can standardize diagnosis and treatment. PMID- 29263505 TI - [Risk factor analysis of systemic inflammatory response syndrome in type 2 diabetics after percutaneous nephrolithotomy]. AB - OBJECTIVE: To evaluate the risk factors of systemic inflammatory response syndrome (SIRS) in the patients with type 2 diabetes diagnosed with kidney stone after percutaneous nephrolithotomy (PCNL). METHODS: In this study, 461 patients with type 2 diabetes who received PCNL in Peking University People's Hospital from June 2006 to December 2015 were reviewed. There were 281 males and 180 females with an average age of 57 years were included, of whom, 137 were diagnosed with SIRS after PCNL. The demographic data, clinical features, and test results were compared between the patients with SIRS and without SIRS, trying to identify the correlation between their clinical characters and the occurrence of SIRS. RESULTS: The SIRS was significantly correlated with the patients' preoperative white blood cell counting (*109/L) [7.76 (4.00-17.96) vs. 6.31 (2.00 17.40), P<0.001], preoperational blood glucose level (mmol/L) [7.30 (3.08-19.90) vs. 6.40 (3.42-16.78), P<0.001], operative time (min) [75 (20-270) vs. 60 (20 200), P<0.001], length of stay (d) [12 (2-46) vs. 11 (3-29), P=0.019], staghorn stones [38.8% (33/85) vs. 27.7% (104/376), P=0.042], and preoperational urinary tract infection [36.8% (50/136) vs. 26.6% (81/304), P=0.032]. There was no significant correlation between the SIRS and the patients' age, body mass index, preoperative hemoglobin level, preoperative serum creatinine, and transfusion. In multivariate analysis, abnormal preoperative white blood cell counting (OR=3.194, 95% CI: 1.531-6.666, P=0.002), operative time longer than 60 min (OR=1.635, 95% CI: 1.088-2.456, P=0.018), and preoperational blood glucose level higher than normal 7.1 mmol/L were significantly correlated with the presence of SIRS. CONCLUSION: The high level of preoperational blood glucose, abnormal preoperative white blood cell counting, and long operative time were significantly correlated with the presence of SIRS in patients with type 2 diabetes after PCNL. PMID- 29263506 TI - [Diagnosis and therapy for ureteral endometriosis]. AB - OBJECTIVE: To discuss the therapy for ureteral endometriosis. METHODS: The clinical data of 25 cases of histopathologically confirmed ureteral endometriosis during 2001-2015 were retrospectively analyxed. RESULTS: In the 25 cases, all the patients took urinary ultrasound for examination before surgery, of whom 21 (84%) were examined by CT and 5 (20%) by MRI. Three (12%) cases underwent preoperative KUB and intravenous pyelogram (IVP) examination. Four (16%) cases were examined by retrograde pyelography before surgery. Eight (32%) of them took cystoscope for examination and 11 (44%) took preoperative radionuclide renal dynamic imaging examination. All of these cases were affected with unilateral ureter, 13 (52%) in the right and 12 (48%) in the left. The ureter lesions were at the upper part in 21 (84%) cases and at the middle part in 4 (16%) cases. In these cases, 11 (44%) received partial ureteral resection and end-to-end ureteral anastomosis, 10 (40%) received partial ureteral resection and ureterocystoneostomy, 3 (12%) received retroperitoneal laparoscopic nephroureterectomy, and 1 (4%) received endoscopic resection of ureteral endometriosis lesion. All of these cases were confirmed with ureteral endometriosis by post-surgery pathology results, with the expression of CA125 and ER in the glandular tissue and expression of PR in the mesenchymal tissue inside the ureteral muscle detected by immunohistochemistry. Four (16%) cases took postoperative adjuvant hormonal therapy. And no recurrence was found among 16 (64%) cases with the successful follow-up which ranged from 3 to 76 months and the median follow up was 28 months. Fifteen cases were submitted to the follow-up by urinary ultrasound (93.8%) and 5 (31.3%) underwent CT for examination. All the cases relieved from hydronephrosis, and symptoms of 10 (63.5) cases disappeared. The cases with double-J stent all had the stent removed within 3 to 6 weeks. CONCLUSION: Surgical procedures should be considered as the main therapy for ureteral endometriosis. We recommend ureterolysis for patients with mild ureteral obstruction and hydronephrosis. As for those with moderate and severe ureteral obstruction and hydronephrosis, we recommend partial ureteral resection. When the situation comes to patients with little renal function of the affected side, the recommended management is nephroureterectomy. PMID- 29263507 TI - [Significance of preoperative urodynamics for clinical diagnosis of female patients with stress urinary incontinence]. AB - OBJECTIVE: To investigate the impact of preoperative urodynamic study on the diagnosis and treatment for female patients with clinical diagnosis of stress urinary incontinence by studying their diagnosis and treatment database, and to assess its clinical significance of urodynamic study. METHODS: From April 2011 to December 2015, 196 female patients diagnosed clinically with stress urinary incontinence underwent preoperative urodynamics study, after excluding pelvic organ prolapse. The preoperative urodynamic data of these 196 cases were analyzed and the clinical significance of urodynamics on differential diagnosis and treatment for the female patients with stress urinary incontinence was evaluated. RESULTS: In this study, 23 cases (11.73%) changed or amended their diagnoses by the urodynamic study, which were inconsistent with the previous clinical diagnoses concluded by the symptoms, physical examinations, and lab tests. A total of 10 cases underwent a different surgery or conservative treatment instead of the original treatment according to urodynamic study. Of them, 3 were diagnosed as detrusor overactive and undertook conservative treatment; 3 were diagnosed as bladder outlet obstruction plus stress urinary incontinence and were undertaken the transurethral resection of the bladder neck (TURBN) plus tension free vaginal tape (TVT); 2 were diagnosed as bladder outlet obstruction plus stress urinary incontinence and were undertaken TURBN alone; 1 was diagnosed as bladder outlet obstruction plus stress urinary incontinence and was undertaken TURBN plus tension free vaginal tape obturator (TOT); 1 was found no abnormal bladder function turned out to be interstitial cystitis and went for a bladder instillation of drug. The changed treatments avoided the risk of dysuria or residual urine increased after operation due to inappropriate surgical methods. CONCLUSION: In order to make a correct diagnosis and suitable treatment for female patients with stress urinary incontinences, the preoperative urodynamic study is necessary besides detailed medical history, physical examination, and laboratory tests. With the help of the urodynamic study, the concomitant diseases of patients with stress urinary incontinence may be detected, the individualized treatment regimen can be developed, and more importantly, the inappropriate surgical decision can be avoided. PMID- 29263508 TI - [Effect of the night shift work on micturition patterns of nurses]. AB - OBJECTIVE: To compare the effects of rotational night shifts on the micturition patterns of female nurses. METHODS: A total of 58 nurses without lower urinary tract symptoms were recruited, who worked in the Peking University People's Hospital during January and June in 2014. The nurses aged 20-43 years were divided into two groups, the night-shift group (n=28) and the non-shift group (n=30). The alcohol or coffee intaking were forbidden. In the night-shift group, nurses had worked on rotational shifts for at least 6 months. Their average age was (26.75+/-4.11) years. In the non-shift group, nurses took regular day-time work, whose average age was (27.80+/-5.60) years. A voiding diary was kept for 7 consecutive days at the end of 6 months, starting 2 days before their night duties until 4 days after completion of their night duties. For comparison, the non-shift group with regular shifts completed a 7-day voiding diary. In the 7-day recording voiding diary, the nurses were required to have the normal intake of liquid about 1 500-2 000 mL/d. The frequency volume charts of nocturia, the 8 hour interval urine production and frequency were compared between the two groups. RESULTS: Nocturia frequency was increased in the night-shift group [0.5 (0-2.4)] compared with the non-shift group [0 (0-2), P=0.02]. The volume of nocturia was increased in the night-shift group [125 mL (0-660 mL)] compared with the non-shift group [0 mL (0-340 mL), P<0.01]. The 8-hour interval indices showed that urine production changed with shift (P<0.01). In the consecutive 7 days, the nocturnal volume of the night-shift group increased on the day after night shift. When the night-shift nurses returned to daytime duty, the volume of urine decreased but nocturnal urine production remained high, and the frequency of nocturia also increased significantly (P<0.05). Compared with the 8-hour interval indices, the night-shift group's voiding volume [(542.35+/-204.66) mL] and voiding frequency (2.24+/-0.69) were more than those of the non-shift group at the afternoon time (from 2 pm to 10 pm). During the 8 h interval night time (from 10 pm to 6 am), the volume of nocturia in the night-shift group [(309.74+/ 162.74) mL] was more than that in the non-shift group [(199.38+/-153.98) mL, P=0.01]; the frequency of nocturia in the night-shift group (1.31+/-0.52) was increased than that in the non-shift group (0.82+/-0.55, P<0.01). CONCLUSION: The rotational shifts affect the micturition patterns of nurses who go through the night shift work, which increases the volume and frequency of the nocturia. PMID- 29263509 TI - [Analysis of epidermal growth factor receptor mutations and its clinico pathologic characteristics of the primary lung adenocarcinoma in Xinjiang Uighur Autonomous Region]. AB - OBJECTIVE: To clarify the relationship between epidermal growth factor receptor (EGFR) mutations and the clinicopathologic features of primary lung adenocarcinomas in Xinjiang. METHODS: The mutations of EGFR gene at exons 18-21 in 59 cases (including 15 cases of Uighur and 44 cases of Han) of lung adenocarcinoma tissues, which were obtained from surgical resection, were detected by amplification refractory mutation system (ARMS) method. And the relationships among mutations, race and clinicopathologic features were analyzed. RESULTS: The frequencies of EGFR mutations in lung adenocarcinoma were 20% for Uighur, which was lower than that in Han (54.5%), P<0.05. The deletion mutations at exon 19 were seen in 2 of 15 Uighur cases and 9 of 44 Han cases. EGFR mutations were present, including exon 21 L858R in one Uighur case and 12 Han cases, exon 18 G719X in two of 44 cases of Han, exon 21 L861Q in one of them. On histological type, the frequencies of EGFR mutation in alveolar predominant adenocarcinoma was 71% (22/31), which was higher than both that in solid predominant and mucinous carcinoma ( 6.7%, 20% respectively). According to statistic analysis, EGFR mutations were without correlation with the patient's gender, age, location, gross type, smoking status and lymph node metastasis(P>0.05). EGFR mutation was more frequent in well-differentiated cancer, mainly in acinar carcinoma, while poorly differentiated adenocarcinoma and mucous adenocarcinoma were lower. CONCLUSION: There was a difference of EGFR mutation in primary lung adenocarcinoma between Uighur and Han in Xinjiang, perhaps reflecting ethnic genetic variation, which is worth further analyzing. EGFR mutation was commonly detected in well or middle differentiated adenocarcinoma, mainly in acinar carcinoma. PMID- 29263510 TI - [Clinical significance of serum C-C chemokine ligand 19 levels in patients with rheumatoid arthritis]. AB - OBJECTIVE: To investigate the serum level of C-C chemokine ligand 19 (CCL19) and its clinical significance in rheumatoid arthritis. METHODS: The serum CCL19 levels in both rheumatoid arthritis (RA) patients and health controls were detected by ELISA. The proportion of peripheral blood B cells and memory B cell subsets were also detected in some patients. Then the clinical and laboratory data of the patients were collected. The CCL19 levels in patients with different clinical features were analyzed. And the correlation between the clinical data, laboratory parameters, B cell subsets proportion and serum CCL19 levels were also analyzed. Independent samples t test, paired t test, Pearson and Spearman correlation were used for statistical analysis. RESULTS: The levels of CCL19 was higher in the RA patients than the health controls (P<0.05). The serum CCL19 levels were decreased in the RA patients who accepted disease-modifying anti rheumatic drugs (DMARDs) treatment for 6 months (P<0.001). Serum CCL19 levels were correlated with the titers of both rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody (r=0.42, P=0.002; r=0.33, P=0.013), but not with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score in 28 joints (DAS28) (P>0.05). The levels of CCL19 were higher in the serum positive (RF and anti-CCP antibody) patients, but there were no differences between low and high disease activity RA, as well as early and non early RA. There was no correlation between the serum CCL19 levels and the proportion of B cells as well as memory B subsets. All the proportion of peripheral blood CD27+ memory B cell subsets in RA was lower than the healthy controls, including CD27+IgD+, CD27+IgD- and CD27+ B cells. CONCLUSION: The increased serum CCL19 levels in RA patients are associated with the activity of B cells, so CCL19 might predict whether the RA type is a B cell mediated RA, and specify the treatment directions for the rheumatologist. PMID- 29263511 TI - [Preventive effects of ulinastatin on acute respiratory distress syndrome]. AB - OBJECTIVE: To explore the effect of ulinastatin on prevention of acute respiratory distress syndrome (ARDS). METHODS: A prospective multicentral cohort study was conducted. The patients from three intensive care units (ICUs) of grade A tertiary hospitals in Beijing and a ICU of grade A tertiary hospitals in Cangzhou from January 2012 to December 2014, included 77 ARDS at-risk patients with ulinastatin treatment and 108 ARDS at-risk patients without ulinastatin treatment (control) were eligible. Both groups received normal treatment; additionally, the intervention group received 600 000 units of ulinastatin via intravenous infusion for 5 days. The control group received the same amount of saline via intravenous infusion for 5 days. Venous blood human neutrophil elastase (HNE) and peptidase inhibitor 3 (PI3) levels were measured on days 1, 3, and 7, respectively. Other outcomes included acute physiology and chronic health evaluation scoring II (APACHE II), body temperature, respiratory rate, heart rate, mean arterial pressure, white blood cell counts, PaO2/FiO2, ARDS incident, mechanical ventilation time, ICU treatment and hospitalization duration, 28 days mortality. RESULTS: The PI3 levels showed no statistical difference on day 1, but significant differences on day 3 and day 7 between the two groups (P<0.01). HNE/PI3 ratio showed no statistical difference on day 1, but significant differences on day 3 and day 7 (P<0.05). PaO2/FiO2 was significantly higher in ulinastatin group on day 3 and day 7 (P<0.05). The incident rate for ulinastatin group was 15.58%, lower than that for the control group (33.33%), and the difference was statistically significant (P<0.05). The mechanical ventilation time and ICU treatment time in ulinastatin group was shorter than that in the control group, and the difference was statistically significant (P<0.05). There were no significant effects in other factors. CONCLUSION: Increased dose of ulinastatin can recover the balance of HNE and its antagonist, lower the HNE's damage to lungs, and further reduce the ARDS incident rate. PMID- 29263512 TI - [Influence of history of oral bisphosphonates on the incidence rate of fever after intravenous injection of zoledronic acid in patients with osteoporosis]. AB - OBJECTIVE: To investigate the prevalence of fever after intravenous injection of for the first time in osteoporotic patients who have or haven't taken bisphosphonates orally. METHODS: Bone mineral density measurement was conducted of the osteoporotic patients using dual-energy X-ray absorptiometry method, and according to the WHO diagnostic criteria for osteoporosis, the patient whose T score was less than -2.5 was defined as osteoporosis. The data of 113 osteoporotic patients who received intravenous injection of zoledronic acid in our hospital for the first time were used for analysis. Among them, 35 who had the history of oral bisphosphonates were defined as group A, and 78 who didn't have the history of oral bisphosphonates were defined as group B (control group). Moreover, we also compared the prevalences of fever between the patients. Pearson chi-square test was used to investigate the association between oral bisphosphonates therapy and prevalence of fever, and binary logistic regression was used to analyze the impact factors of fever after intravenous injection of zoledronic acid. RESULTS: Among the 35 patients who had the history of oral bisphosphonates, nobody had high fever, and 2 patients had low or moderate degree of fever (5.71%). Among the 78 patients who didn't have the history of oral bisphosphonates, 33 patients had fever (42.3%), 15 with low fever, and 14 with moderate degree of fever, and 4 with high fever. Pearson chi-square test showed that the prevalence of fever between group A and group B had significant difference, and that differences of prevalence of fever between the outpatients and the inpatients was not statistically significant. Binary Logistic regression analysis showed that oral bisphosphonates medication history was a protective factor of fever, and with the increasing of previous oral bisphosphonates for one month, there was a reduction of fever for 23.1%. CONCLUSION: Patients who have the history of oral nitrogenous bisphosphonates alendronate have a significant reduction in prevalence of fever after intravenous injection of zoledronic acid for the first time. That is, oral nitrogenous bisphosphonates alendronate history is a protective factor of fever for patients with intravenous injection of zoledronic acid for the first time. PMID- 29263513 TI - [Analysis of early failure of the PHILOS in proximal humerus fractures]. AB - OBJECTIVE: To analyze the reasons of early failure of the PHILOS in proximal humerus fractures. METHODS: From Nov. 2010 to Nov. 2014, there were 117 patients with humerus fractures treated with PHILOS locking plate in Department of Orthopaedics, Xuanwu Hospital. All of the patients were treated with the plate by open reduction internal fixation, and we analyzed these cases retrospectively. After the operation, we removed the drainage tube within 48 h, and the patients were allowed to do the passive motion 3 days after the surgery if the X-Ray showed the plate and screws were reliable. Eight cases failed within 4 weeks after the operation. We analyzed the reasons of the failure. RESULTS: The rate of the failed cases was 6.83%(8/117). The average age was 72.4(66-82) years. In the 8 failed cases, 3 were on the right side, and the other 5 on the left side. As for the reason of the fractures, 2 cases were because of car accidents, and the other 6 because of daily life injury. According to the Neer classification, 3 cases were 2-part fractures, and the other 5 3-part fractures. Three cases were total failure, and the other 5 partial failure. All the 8 failed cases failed within 4 weeks after the operation, of which 1 was on the sixth day after surgery, the other 7 2 to 4 weeks after the surgery.The 3 totally failed cases were treated by removing the screws and plates, the other 5 by conservative methods. All of the cases were malunion at the end. CONCLUSION: The early failure of the PHILOS locking plate in proximal humerus fractures is related to the bad reduction during the operation, the loss of medial cortex support, the limitation of screw length, the osteoporosis and the improper rehabilitation after operation.It is very important to do good preoperative plan for a surgeon. During the operation, we should try our best in the fracture reduction, use the appropriate plate and screws, and then pay attention to the rehabilitation after the operation. After all of this, the rate of failure may be decreased. PMID- 29263514 TI - [EDA mutation screening and phenotype analysis in patients with tooth agenesis]. AB - OBJECTIVE: To screen the ectodysplasin A (EDA) gene mutation in the patients with non-syndromic tooth agenesis and ectodermal dysplasia, and to analyze the phenotype of missing teeth pattern in these two groups of patients. METHODS: In the study, 174 patients with tooth agenesis (143: non-syndromic, 31: ectodermal dysplasia) and 451 health control volunteers were enrolled from the clinic, and the genome DNA was extracted from either peripheral blood or oral mucosal swab. The coding region of EDA gene was then amplified by PCR, sequenced and blasted to online NCBI database. The missing teeth were recorded for all patients, and the missing teeth from patients with EDA mutation were compared among the different dentition sites. RESULTS: 33 patients were identified with EDA mutation. In the non-syndromic patients, 13/143(9.09%) were identified with EDA mutation, while in patients with ectodermal dysplasia, 20/31(64.52%) were found with EDA mutation. Ten novel EDA mutations were identified (c.769G>C[p.G257R ],c.936C>G[p.I312M],c.223G>A[p.E75K], .1166C>T[p.P389L],c.133G>C[p.G45R],c.1109G>A[p.E370K],c.914G>T[p.S305I], c.916C>T[p.Q306X],c.602G>T[p.G201V],c.88-89insG[p.A30GfsX69]). For each dentition site there was no statistic difference in the number of missing teeth between the left and right sides, so the number from both sides were combined later in the analysis. In the patients with EDA mutation, the non-syndromic patients had fewer missing teeth (15.9+/-6.4 missing teeth for each, 207/364 in total) than the patients with ectodermal dysplasia (23.9+/-4.3, 478/560). In the non-syndromic patients with EDA mutation, the maxillay central incisors and first molars were less affected, with the same missing rate as 19.2% (5/26). While the mandibular central incisors (with a missing rate of 76.9%, 20/26), the maxillary lateral incisors (the missing rate: 88.5%, 23/26), the mandibular lateral incisors (the missing rate: 80.8%, 21/26), and the maxillary first premolars (the missing rate: 80.8%, 21/26) were more likely to be missing. In the ectodermal dysplasia patients with EDA mutation, only maxillary central incisors (the missing rate: 60%, 24/40), maxillary canines (the missing rate: 70%, 28/40), mandibular canines (the missing rate: 67.5%, 27/40), maxillary first molars (the missing rate: 65%, 26/40) and mandibular first molars (the missing rate: 72.5%, 29/40) had higher possibility of persistence. Teeth at other dentition sites were more likely to be affected (the minimum missing rate: 87.5%, 35/40). CONCLUSION: The findings would help to reveal the EDA gene and its function in ectodermal organogenesis. PMID- 29263515 TI - [Disturbed sleep, anxiety and stress are possible risk indicators for temporomandibular disorders with myofascialpain]. AB - OBJECTIVE: To explore the relationship betweensleep/psychological distress and temporomandibular disorders (TMD) and to discuss the possibility of disturbed sleep and psychological distress as risk indicators in relation to TMD in a Chinese population. METHODS: The standardized and validated self-reported Chinese version questionnaires including Pittsburgh sleep quality index (PSQI) and depression, anxietyandstress scales-21 (DASS-21) were used to measure sleep quality and psychological distress. A total of 755 TMD patients (172 males and 583 females)with a mean age (29.99 +/- 13.60) years were included in the study. The patients were divided into 7 diagnostic groups based on the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), including Group I(exclusively myofascial pain), Group II(exclusively disc displacement), Group III (exclusively arthralgia or degenerative joint disease), Group IV (myofascial pain plus disc displacement), Group V (myofascial pain plus arthralgia or degenerative joint disease), Group VI (disc displacement plus arthralgia or degenerative joint disease) and Group VII (myofascial pain plus disc displacement plus arthralgia or degenerative joint disease). For statistical analysis, the patients were subsequently grouped into those with (181 patients) and without (574 patients) myofascial pain. Chi-square tests, independent-samples t test, partial correlation as well as stepwise Logistic regression analysis were used to analyze the data, using software SPSS 20.0 and P<0.05 was of significance. RESULTS: The prevalence of moderate to (extremely) severe disturbed sleep and psychological distress was significantly higher in the myofascial pain group (27.1%, 28.7%, 60.8% and 32.0%) than in the non-myofascial pain group (disc displacement and arthralgia or degenerative joint disease, 11.1%, 10.1%, 27.4% and 11.0%, P<0.05).The comorbidity of self-reported disturbed sleep and psychological distress was significantly higher in the myofascial pain patients than those without myofascial pain (P<0.05). Stepwise logistic regression analysis demonstrated that disturbed sleep (OR=1.74), more specifically, subjective sleep quality (OR=1.69) and sleep disturbance (OR=1.63) respectively, anxiety (OR=3.14) and stress (OR=2.15) were possible risk indicators for myofascial pain, and the results were still significant even after controlling for age, sex, educational level, disease duration, sleep quality, depression, anxiety and stress respectively (P<0.05). CONCLUSION: Disturbed sleep and psychological distress symptoms are common in TMD patients. Disturbed sleep, anxiety and stress are possible risk indicators for myofascial pain, compared with disc displacement and arthralgia or degenerative joint diseases. PMID- 29263516 TI - [Pilot study of laser-doppler flowmetry measurement of oral mucosa blood flow]. AB - OBJECTIVE: To explore and compare the perfusion pattern of oral mucosa on Han Chinese and Caucasian by laser-doppler flowmetry. METHODS: A cross-sectional study was carried out, in 20 healthy Han Chinese adult subjects (average age: 28.4 years) and 20 healthy Caucasian (average age: 25.3 years) adult subjects, either gender with 10 subjects. Gingival perfusion was evaluated at 8 points (including upper incisor labial gingival, lower incisor labial gingival, palatal mucosa, cheek mucosa) using a laser-doppler flowmetry(O2C, Medizintechnik GmbH, Germany). Each measurement was carried out 25 seconds consisting 5 seconds of fore period and 20 seconds of work period, without pressure. The measurements were taken by two well- trained doctors, each measurement was exammed 3 times by an examiner, and the average value was recorded as final data. Each measurement has 4 parame ters: SpO2(oxygen saturation), rHB (relative amount of hemoglobin), flow (the blood flow of unit interval), and velocity (blood flow velocity). We compared the data by different sites, different genders, and different races. RESULTS: For palatal gingival, the average SpO2 was 77.1%+/-10.9%, the average rHB 67.8+/-11.1, and the average flow 194.1+/-63.7, which presented significant lower values than other oral mucosa. There was no significant difference among other sites. There was some significant difference between the Caucasian and the Han Chinese: the maxillary central incisor oxygen saturation (SpO2) which were averages of 75.6%+/-8.2% and 70.4%+/-7.6%; buccal mucosa hemoglobin (rHB) averages of 79.9+/-5.8 and 83.5+/-6.6, which had statistical differences. For most measurement points, the oxygen saturation on men was lower than that on women, which had significant difference. CONCLUSION: To investigate microcirculation pattern, oral mucosa can be the good observation site. Laser doppler flowmetry is a well-documented instrument to survey on microcirculation.There may be differences between the genders in hemoglobin oxygen-binding capacity, which may have some impact on the ability of soft tissue healing. Oral mucosa display more blood perfusion than attached gingival. As the recipient site of gingival graft, maxilla and mandible have slight difference in blood supply. PMID- 29263517 TI - [Morphological analysis of roots and alveolar bone changes after upper anterior retraction with maximum anchorage based on cone-beam computed tomography]. AB - OBJECTIVE: To investigate the remodeling of alveolar bone and the changes of roots after anterior retraction with maximum anchorage by analyzing CBCT data from adult cases. METHODS: The sample comprised 48 incisors and 24 canines from 12 patients (18 to 40 years of age) with problems of maxillary protrusion or upper arch protrusion. CBCT scans were exposed before and after treatment, and lateral cephalometric images as well as multiple planar reconstruction images were reconstructed. Tracing superimpositions of sagittal sections and three dimensional reconstructions were done for qualitative analysis. For all maxillary anterior teeth, changes of root length, alveolar bone height and labial-palatal thicknesses at different levels were evaluated. The average of measurements taken by the same tester in three times was processed by SPSS 17.0 statistical package. RESULTS: In 6 of the 12 cases, alveolar thickness became thinner on labial side [apical area: (-0.64+/-1.18) mm] while thicker on palatal side [apical area: (0.93+/-2.0) mm] and the root length decreased[(-0.95+/-0.79) mm]. In the other 6 cases, the incisors' alveolar bone became thicker on labial side [apical area: (2.12+/-1.46) mm] while thinner on palatal side [apical area: (-2.88+/-0.58) mm]and the loss of root length was obvious[(-2.12+/-1.43) mm]. In all the 12 cases, the canines' alveolar bone became thinner on labial side especially on the apical level[(-0.27+/-1.86) mm] while greatly thicker on palatal side [apical area: (6.40+/-6.00) mm]and the root resorption was slight [(-1.12+/-1.19) mm]. For all the anterior teeth, the height of alveolar bone reduced around them after retraction. CONCLUSION: When the root apical moved more palatally, more root resorption would occur and the alveolar bone would get thicker on labial side but thinner on palatal side and thinner as a whole after anterior retraction with maximum anchorage.In the vertical direction, the height of the alveolar bone generally decreased on all sides and decreased the most on the palatal side. PMID- 29263518 TI - [Applicational evaluation of split tooth extractions of upper molars using piezosurgery]. AB - OBJECTIVE: To evaluate the efficacy of Piezosurgery in split teeth extractions. METHODS: A single-center, randomized, split-mouth study was performed using a consecutive serious of unrelated healthy patients attending the departing of oral and maxillofacial surgery, Peking University School and Hospital of Stomatology. 40 patients were selected for extraction of maxillary molars without reservation value,splitting or nonvital teeth. They were divided into control (20 patients) and test groups (20 patients) randomly. Surgical treatments for both groups were under local anesthesia. Molar teeth of control group were extracted by common equipments like dental elevators, chisels, forceps, etc. While molar teeth of experimental group were extracted by Piezosurgery, aided with the use of common equipments if needed. Then we compared the duration of surgery, frequency of the usage of chisels, expansion of postoperative bony socket surgical discomfort and postoperative pain between two groups. RESULTS: The average of operation time was (629.5+/-171.0) s in control group and (456.0+/-337.2) s in test group. The buccal alveolar bone reduced (1.07+/-0.64) mm in control group and (1.49+/-0.61) mm in test group. There was a significant difference between the two groups (P<0.05). The duration of surgery for experimental group was significantly longer than that of the control group, but the change of buccal alveolar bone was lower than the control group. For visual analogue scale (VAS) value of surgical discomfort, expansion of postoperative bony socket and the operative fear rate, there were no significant difference between the two groups (P>0.05). CONCLUSION: Piezosugery can be better to preserve alveolar bone, reduce trauma and patient's fear. Application of the piezosugery reflect the characteristics of minimally invasive extraction, which has the value of promotion. The Piezosurgery technique have the advantage of reducing change of buccal alveolar bone during the surgery, but a longer surgical time was required when compared with the conventional technique. VAS value of surgical discomfort, expansion of postoperative bony socket and the operative fear rate, there were no significant difference. Minimally invasive tooth extraction technique has good clinical results and high satisfaction. Piezosurgery proved its worth as the instrument adapted to limiting the destruction of bone tissue. PMID- 29263519 TI - [Preliminary research of Er:YAG laser used for pulpotomy of Beagle dogs]. AB - OBJECTIVE: To investigate the effects of erbium:yttrium aluminium garnet (Er:YAG)laser irradiation on pulp and formation of dentin bridge. The beagle dogs' coronal pulp is amputated by Er:YAG laser. METHODS: In the study, 24 premolar teeth of two one-year-old Beagle dogs were used. They were divided into 3 groups: bur group, 200 mJ laser group,100 mJ laser group. The coronal pulp were removed by traditional bur or 200 mJ/20 Hz or 100 mJ/20 Hz Er:YAG laser. Then, they were dressed with mineral trioxide aggregate (MTA) and sealed with resin. Clinical, radiological and histological analyses were performed 1 day, 2 weeks, 4 weeks and 8 weeks after treatment. The mobility and gingiva situation were evaluated for clinical evaluation. Periapical films were used for radiological evaluation. The extracted teeth were preserved in 10% formalin. After decalcification, tissue processing, paraffin embedding, serial sectioning at 5 MUm thickness, staining (Hematoxylin and Eosin, HE), the samples were assessed by an independent observer for calcified bridge formation and radicular pulp inflammation. The mean thickness of dental bridge was measured if there was complete dental bridge. RESULTS: Clinical evaluation: there were no signs of fistula or mobility or any abnormal symptoms in Er:YAG laser groups and bur group during the observation period. Radiological evaluation: there were no signs of widened periodontal ligament or root absorption or periapical radiolucency in Er:YAG laser groups and bur group. Histological evaluation: there was no severe inflammation reaction in 200 mJ/20 Hz, 100 mJ/20 Hz Er:YAG laser groups and bur group 1 day, 2 weeks, 4 weeks, 8 weeks post-operation in Hematoxylin and Eosin staining. A complete dentin bridge could be observed in 200 mJ/20 Hz, 100 mJ/20 Hz Er:YAG laser groups, while no complete dentin bridge in bur group 2 weeks post operation. Complete dental bridge could be observed in each group 4 and 8 weeks post-operation. The mean thickness of dental bridge 4 weeks post-operation in 200 mJ laser group was 77 MUm, 100 mJ laser group 87 MUm, and bur group 101 MUm, and 8 weeks post-operation in 200 mJ laser group was 222 MUm,100 mJ laser group 160 MUm,and bur group 152 MUm. CONCLUSION: The 200 mJ/20 Hz and 100 mJ/20 Hz Er:YAG laser pulpotomies show no harm to radicular pulp and can promote the formation of dentin bridge. PMID- 29263520 TI - [Basal cell carcinoma of prostate: a report of three cases]. AB - To explore the clinical pathological characteristics and improve the recognition in the diagnosis and treatment of basal cell carcinoma (BCC) of prostate. Three cases of BCC of prostate were reported and the relevant literature was reviewed to investigate the diagnosis and treatment of this disease. We analyzed three cases of prostatic BCC. Their ages were within a range of 57 to 83 years. One of them complained of hematuria and two complained of dysuria. All of them presented with prostatic hyperplasia. Two of them presented with high prostate specific antigen (PSA) and one with normal PSA. Case 1 had prostate cancer invasion of bladder, rectal fascia, with lymph node metastasis, bone metastasis and lung metastases. The patient received bladder resection+bilateral ureteral cutaneous ureterostomy+lymph node dissection on November 2, 2014 . Postoperative pathological diagnosis showed BCC. Reexamination of pelvic enhanced MRI in January 8, 2015 suggested pelvic recurrence. Abdominal enhanced CT showed multiple liver metastases and pancreatic metastasis on July 11, 2015. Prostate cancer specific death occurred in October 2015. Case 2 was diagnosed as BCC in prostate biopsy on March 27, 2015. Positron emission tomography and computed tomography (PET-CT) showed pulmonary metastasis and bone metastasis. Then the patient received chemotherapy, endocrine therapy and local radiation therapy. Reexamination of PET-CT on January 11, 2016 showed that the lung metastase tumors and bone metastase tumors were larger than before. Up to January 10, 2016, the patient was still alive. Postoperative pathological changes of transurethral resection of prostate (TURP) in case 3 showed BCC might be considered. The PET-CT suggested residual prostate cancer, which might be associated with bilateral pelvic lymph node metastasis. In April 20, 2016, the review of PET-CT showed pelvic huge irregular hybrid density shadow, about 14.5 cm*10.0 cm*12.9 cm in size, and tumor recurrence was considered. Then the patient received local radiation therapy. The patient survived in the followed upon January 10, 2016. BCC of prostate is a rare subtype. Due to the local infiltrative and distant metastatic potentiality, active management is preferred and a life-long follow-up is necessary. PMID- 29263521 TI - [Feasibility study of transplantation of penile corpus cavernosum and major pelvic ganglion in renal subserous region]. AB - OBJECTIVE: To study the feasibility of transplantation of normal rat penile corpus cavernosum and major pelvic ganglion (MPG) into the renal subserous region of a Nu/Nu mouse based on allograft technology. METHODS: Penile corpus cavernosum and MPG, harvested from Sprague-Dawley (SD) rats under sterile condition, were transplanted underneath the kidney capsule of Nu/Nu mice through the microsurgery instruments and surgery microscope. The histopathologic changes and cellular proliferation in the transplanted penile corpus cavernosum and MPG were then analyzed at the end of 1week and 4 weeks after transplantation. Histological staining and immunohistochemical staining were used to evaluate the main outcome measures. RESULTS: After 1 week, the tissue morphology of the transplanted corpus cavernosum underneath the kidney capsule of Nu/Nu mice was consistent with normal penile corpus cavernosum, and blood could be observed in the penis cavernous sinus of the graft; after 4 weeks, the mophorlogy of the tranplanted corpus cavernosum near the kidney was consistent with normal penile corpus cavernosum, while fibrosis was noteworthy in the graft away from the kidney, but blood could still be seen in the penis cavernous sinus. After 1 week, the tissue morphology of the transplanted MPG was consistent with normal MPG, multiple islet-like cell clusters could be seen in the transplanted MPG in the renal subserous region, and angiogenesis could be observed near the kidney; after 4 weeks, a network of blood vessels was clearly visible away from the kidney, and islet-like cell clusters were still clearly observed in the transplanted MPG. In addition, ki67 positive cells were observed in the transplanted penile corpus cavernosum and MPG after 4 weeks of transplantation, which indicated that there was still cell proliferation activity in the grafts. CONCLUSION: The transplanted corpus cavernosum and MPG underneath the kidney capsule of Nu/Nu mice could survive at least 4 weeks. Moreover, the inner structure of the transplanted corpus cavernosum and MPG was close to the normal tissue. The underlining mechanism may be related to the local microenvironment underneath the kidney capsule of Nu/Nu mice and the neovascularization in the transplanted grafts. PMID- 29263522 TI - [Surgery for renal carcinoma with supradiaphragmatic tumor thrombus: avoiding sternotomy and cardiopulmonary bypass]. AB - OBJECTIVE: To describe a feasible surgical technique for patients with renal cell carcinoma associated with a supradiaphragmatic tumor thrombus that avoids cardiopulmonary bypass procedure. METHODS: We retrospectively analyzed 2 cases with right kidney tumor and tumor thrombus above the diaphragm treated in April and August, 2015. The two patients were both female, aged 73 and 67 years. The tumor sizes of right kidneys were 7.0 cm*6.3 cm*5.7 cm and 8.7 cm*7.0 cm*5.2 cm, and the tumor thrombuses were 1.3 cm and 1.8 cm above the diaphragm. The second patient had synchronous metastasis in right adrenal gland , and the tumor thrombus arose from the adrenal vein but not the renal vein. Intraoperative transesophageal echocardiography (TEE) was used to assess real-time mobility of the thrombus. A modified chevron incision was used, the right kidney was mobilized laterally and posteriorly, and the renal artery was identified, ligated, and divided. The infradiaphragmatic inferior vena cava (IVC) was exposed and isolated by mobilizing the liver off the diaphragm or to the left (piggyback liver mobilization, case 2). The central diaphragm tendon was dissected or incised in the midline until the supradiaphragmatic intrapericardial IVC was identified and gently pulled beneath the diaphragm and into the abdomen. The tumor thrombus was then "milked" downward out of the intrapericardial IVC under the guidance of TEE. The distal and proximal IVC to the tumor thrombus, porta hepatis, and left renal vein were clamped. Tumor thrombus was removed from the IVC. The IVC was sutured and vascular clamps were placed below the major hepatic veins. Pringle's maneuver was then released and hepatic blood drainage was permitted during closure of the remaining IVC. Related literature was reviewed. RESULTS: Complete resection was successful through the transabdominal approach without CBP in both patients. Estimated blood loss was 1 500 mL and 2 000 mL, and 1 200 mL and 800 mL of blood were transfused. The postoperative courses were uneventful. Both patients subsequently underwent tyrosine-kinase inhibitor therapy. Both patients were alive without tumor recurrence or new metastasis during the follow-up of 6 months and 9 months. CONCLUSION: In selected cases, renal cell carcinoma extending into the IVC above the diaphragm can be resected without sternotomy, CBP or DHCA. PMID- 29263523 TI - [An modified culture method of primary human gingival epithelial cells]. AB - OBJECTIVE: To establish a stable primary culture method of human gingival epithelial cells, with a higher successful rate and shorter culture time. METHODS: Nine patients who received "crown-lengthening surgery" with relatively healthy periodontal conditions were selected (n=9). Gingival samples were collected from the 9 donors during gingivectomy. Gingival epithelial cells were isolated and cultured by both an advanced enzyme digestion method and a tissue explant method. In the advanced enzyme digestion culture process, 2.5 g/L DispaseIIwas used to separate the epithelial tissue part from the connective tissue part, which lasted for one night. Then the epithelial tissues were digested by 0.025% trypsin without EDTA for 10 minutes, and centrifuged by keeping the digested epithelial tissues that remained. This advanced method not only decreased the concentration and digesting time of the two above-mentioned enzymes, but also simplified the centrifugel process. The tissue explant method was not changed too much compared with the original method. Growing processes of the primary cells cultured by the two methods were observed and recorded respectively, and indirect immunocytochemical staining was used to identify the type of cultured cells. At the same time, successful rates and cell culture time were also compared between the two methods. RESULTS: Human gingival epithelial cells with typical morphology could be cultured within a shorter period by the advanced enzyme digestion method with a successful rate of 88.9%, and proliferated rapidly as sheets. After 10-14 d cells could be passaged, gradually turned to be like fibroblasts when passaged to the third generation, and eventually went to apoptosis. The primary culture time was longer by using the tissue explant method, and approximately after 17-22 d cells could be passaged, although the successful rate was the same as the enzyme digestion method. Cytokeratin staining was both positive by indirect immunocytochemical staining of cells. CONCLUSION: Primary human gingival epithelial cells cultured by the advanced enzyme digestion method could grow faster and be passaged to the second generation successfully, which could supply a stable origin for cellular experiments. PMID- 29263524 TI - [Microsurgical management of petroclival meningiomas combined trans-subtemporal and suboccipital retrosigmoid keyhole approach]. AB - OBJECTIVE: With the development of modern skull base minimally invasive technology mature and neural radio surgery techniques, it is necessary to re examine the therapeutic strategy for the treatment of petroclival meningiomas. To sum up the operative experience and methods in microsurgical resection of petroclival meningiomas by the combining trans-subtemporal and suboccipital retrosigmoid keyhole approach. To explore the minimally invasive operation approach of petroclival meningiomas, to raise the removal degree and to improve the postoperative result using this approach. METHODS: The clinical data of the consecutive 21 patients with the petroclival meningiomas were reviewed retrospectively. The method, degree of tumor resection,techniques of the combining keyhole approach, Karnofsky performance score (KPS) before and after operation were also analyzed. The neuronavigation guided operation was performed in 9 cases, and 12 cases were operated in the neuroelectrophysiological monitoring. RESULTS: Total excision of the tumor resection (Simpson, I-II levels) was conducted in 18 cases (85.7%, 18/21), and 3 patients underwent close resection (Simpson III level, 14.3%, 3/21). Postoperative three-dimensional CT showed good lock bone flap restoration; Postoperative pathology confirmed meningioma. Postoperative cranial nerve dysfunction or new original nerve dysfunction were aggravated in 5 cases (23.8%) , including transient trochlear nerve (3 cases), abducent nerve (1 case), and the motor branch of trigeminal nerve paralysis (1 case). Abducent nerve paralysis (1 case) appeared, with hearing impairment. After the 3-month follow-up, 11 cases had the same KPS aspreoperation, 7 cases improved, and 3 cases not improved. The KPS score was 77.14+/-23.12 on average, and there was no statistically significant difference compared with that before operation (P>0.05). The postoperative follow-up for half a year showed fluent speaking and writing in 19 cases (KPS 70 or higher), and general recovery in 2 cases (KPS<70). The postoperative follow-up for 3-29 months showed no tumor recurrence or progress. CONCLUSION: The combining trans subtemporal and suboccipital retrosigmoid keyhole approach is simple, safe, and minimally invasive, and an ideal operation approach of petroclival meningioma. To master the operation skills and the intraoperative matters needing attention in the operation, is favorable to improve the resection rate and curative effect. PMID- 29263525 TI - [Anesthesia management of caesarean section for pregnant women complicated with Takayasu's arteritis]. AB - Takayasu's arteritis is a rare, idiopathic, chronic inflammatory disease. Its course is unpredictable, but slow progression is usual, leading to stenosis, occlusion, or aneurismal degeneration of the aorta or its major branches. We present the anesthesia management of pregnancy in four women admitted to Peking University Third Hospital for caesarean section from year 2006 to 2015 complicated with Takayasu's arteritis and review this disease with special reference to natural history, diagnostic criteria, classification, prognostic factors, and anesthesia considerations. Anesthesiological data were retrospectively analyzed for clinical manifestations, anesthesia process, perioperative complications, and pregnancy outcome. One patient received only epidural anesthesia, while the other three patients received combined spinal and epidural anesthesia (CSEA). Surgeries for all the four patients were successful with stable vital signs. We found comprehensive examinations including whether the disease was in the active phase and the clinical classification of the disease before conception was recommended for patients diagnosed with Takayasu's arteritis. CSEA and continuous epidural block could be both used as anesthesiological method in patients with Takayasu's arteritis. During the surgery, to avoid rapid hemodynamic fluctuations and protect the major organs' function is very essential to allow for a satisfactory outcome. PMID- 29263526 TI - [Ultrasound-assisted neuraxial anesthesia in a patient with previous lumbar laminectomy and fusion: a case report]. AB - A patient with previous L3-4 posterior lumbar interbody fusion, pedicle screws instrumentation and L3-4 decompression, was scheduled for left total hip arthroplasty. Two years ago, due to poor landmarks palpation, the patient experienced a failed lumbar puncture after multiple attempts before herniorrhaphy. His plain radiography showed bilateral partial laminectomy at L3-4 level, and between L3 and L4, two posterior pedicle screws connected by metal rods on both sides. This time, we used ultrasound to locate L4-5 interlaminar space in paramedian sagittal oblique view and identified the spine midline by transverse interlaminar view before puncture. According to this information, L4-5 puncture point was verified and the combined spinal-epidural anesthesia was performed in a paramedian approach. After withdrawing clear cerebral spinal fluid, 15 mg hyperbaric bupivicaine was injected into intrathecal space. An epidural catheter was then inserted into the epidural space. The sensory block level was fixed at T10 to S within 10 minutes. Intraoperatively, the patient received 10 mL 2% (mass fraction) lidocaine through the epidural catheter in total. The surgery was uneventful. No neurologic complication was observed after the surgery. This case report demonstrates that ultRASound imaging can provide useful information for neuraxial needle placement and can be a valuable tool in managing patients with anatomical change around the spine. PMID- 29263527 TI - Editorial Epilogue. PMID- 29263528 TI - Treatment of Melasma: The Journey Ahead. PMID- 29263530 TI - Chemical Peels in Melasma: A Review with Consensus Recommendations by Indian Pigmentary Expert Group. AB - Melasma is a notorious dermatosis, often resistant to treatment. Chemical peeling constitutes an acceptable option of management of melasma (of any type and duration). In this article, as a group of experts from Pigmentary Disorders Society (PDS) in collaboration with South Asian Pigmentary Forum (SPF), we have tried to elaborate the various chemical peeling agents for the treatment of melasma. Besides, we have reviewed the indications, mechanism of action, rationality and the detailed procedure of peeling. The evidence in favor of various peeling agents have been summarized as well. PMID- 29263529 TI - Medical Management of Melasma: A Review with Consensus Recommendations by Indian Pigmentary Expert Group. AB - Melasma is one of the most common hyperpigmentary disorders found mainly in women and dark-skinned patients. Sunlight, hormones, pregnancy, and genetics remain the most implicated in the causation of melasma. Although rather recalcitrant to treatment, topical agents such as hydroquinone, modified Kligman's Regime, azelaic acid, kojic acid, Vitamin C, and arbutin still remain the mainstay of therapy with sun protection being a cornerstone of therapy. There are several new botanical and non botanical agents and upcoming oral therapies for the future. There is a lack of therapeutic guidelines, more so in the Indian setup. The article discusses available evidence and brings forward a suggested treatment algorithm by experts from Pigmentary Disorders Society (PDS) in a collaborative discussion called South Asian Pigmentary Forum (SPF). PMID- 29263532 TI - Facial Acanthosis Nigricans: A Morphological Marker of Metabolic Syndrome. AB - Introduction: Acanthosis nigricans (AN) is a frequently encountered entity. Facial AN (FAN) is a subset of AN which is being increasingly recognized. Recently, reports hypothesizing the association of FAN with features of metabolic syndrome have been published. Aims and Objectives: The aim of this study was to study the clinicodemographic profile of patients with FAN, and to assess the correlation of hypertension, increased waist-hip ratio (WHR), increased body mass index (BMI), type 2 diabetes mellitus, deranged lipid profile, serum insulin, and impaired oral glucose tolerance test (OGTT) (parameters of metabolic syndrome) in these patients, as well as to determine the most significant predictor (highest relative risk) of development of FAN. Methods: A multicentric case-control study was conducted (123 cases in each group) over a period of 2 years. Data were obtained on the basis of history, examination, and relevant laboratory investigations. Statistical analysis was done using Statistica version 6 (StatSoft Inc., 2001, Tulsa, Oklahoma, USA), SPSS statistics version 17 (SPSS Inc., 2008, Illinois, Chicago, USA), and GraphPad Prism version 5 (GraphPad Software Inc., 2007, San Diego, California, USA). Results: Mean age of the patients with FAN was 38.83 +/- 8.62 years. Mean age of onset of the disease was 30.93 +/- 8.18 years. The most common site of face involved was the forehead and temporal region. The most common pigmentation was brown-black. Male sex, positive OGTT, increased WHR, and increased BMI were most significantly related to FAN. Smoking was found to have a protective effect against the development of FAN. Conclusion: Here, we document a significant association between male patients with positive OGTT, increased WHR, and BMI and FAN. Thus, we propose that FAN could be considered a morphological marker of metabolic syndrome. PMID- 29263531 TI - Lasers in Melasma: A Review with Consensus Recommendations by Indian Pigmentary Expert Group. AB - Lasers have come up as the newest therapeutic modality in dermatological conditions including melasma. In this article, as a group of experts from Pigmentary Disorders Society in collaboration with South Asian Pigmentary Disorders Forum (SPF), we have tried to discuss the lasers which have been used in melasma and formulate simple consensus guidelines. Following thorough literature search, we have summarised the rationale of using the lasers and the supporting evidences have also been provided. It is clear that laser cannot be the first line treatment for melasma. However, it can be used as an adjuvant therapy in resistant cases, provided the selection of patient and counselling has been done properly. PMID- 29263534 TI - Clinico-epidemiological Study of Congenital Ichthyosis in a Tertiary Care Center of Eastern India. AB - Background: Congenital ichthyoses comprises various specific genetic diseases and can range from mild to very severe presentation. Furthermore, these may be associated with various syndromes. There is scanty data regarding the demographic profile and clinical features of patients with congenital ichthyosis in India. Aims and Objectives: The aim is to evaluate the epidemiology and clinical characteristics of various types of congenital ichthyoses. Materials and Methods: The study was conducted for 1 year from April 2013 to March 2014. Patients were evaluated for epidemiological profile and clinical features. Results: During the study of 1 year, 106 patients of congenital ichthyoses were identified. The most common of the various ichthyoses was ichthyosis vulgaris, followed by lamellar ichthyosis, X-linked recessive ichthyosis. One case of Netherton syndrome and one of ichthyosis hystrix were also identified. Conclusion: Various types of congenital ichthyoses present with different clinical features which range from mild to severe. These present with significant psychological stress to both patients and their families. Furthermore, all these diseases have significant implications of transmission to their offspring. PMID- 29263533 TI - Occult Hepatitis B Virus Infections (Often with Human Herpesvirus 7 Co-Infection) Detected in Pityriasis rosea Patients: A Pilot Study. AB - Background: The etiopathogenesis of Pityriasis rosea (PR), a papulo-squamous skin disease, remains elusive and hypothesized to be caused primarily by human herpesvirus (HHV) 6 or 7 or immune dysfunction. Aims: The recent increasing incidences of hepatitis B virus (HBV) infections, including asymptomatic occult HBV infections (OBIs), in a densely populated city in India, prompted us to investigate whether PR patients (from varied socioeconomic and immune status) harbor the underlying HBV infections. These cases were also investigated for HHV 6 and 7 infections. Materials and Methods: DNA from ethylenediaminetetraacetic acid blood samples from PR-diagnosed individuals (n = 13; mostly young adults) and healthy controls (n = 11) were subjected to virus gene-specific polymerase chain reactions (PCRs) for HBV and HHV 6 and 7. PCR products of expected length, when observed, were sequenced (bidirectional) using overlapping primers. Sequences were identified by NCBI BLAST and analyzed by multiple sequence alignment and phylogenetic studies. The blood samples were tested for HBsAg by EIA. Results: In 5/13 PR samples, only HBV DNA (4/5 being HBsAg negative) was detected, providing first-time evidence that PR may be manifested in asymptomatic HBV carriers. 6/13 cases were HHV 7 (not HHV 6) DNA positive, providing confirmatory molecular genetic evidence for the first time of PR association with HHV 7 from India. Surprisingly, 5/6 HHV 7-positive PR cases were also HBV positive. Overall, 10/13 PR samples showed evidence of HBV infection. 8/13 were OBI, harboring at least one OBI-signature S protein mutation. All healthy controls were HBsAg EIA and PCR negative. Conclusions: 77% of PR patients presented the evidence of underlying HBV infection (genotype D2), suggestive of horizontal HBV transmission. This warrants for mass HBV vaccination. PR patients should be tested for underlying virus infections for appropriate therapy and management. PMID- 29263535 TI - Clinical, Histopathological Characteristics and Immunohistochemical Findings in Lichen Planus Pigmentosus. AB - Background: Lichen planus pigmentosus (LPP), a rare variant of lichen planus, is reported in various ethnic groups, more often from the Indian subcontinent and the Middle East. Aims: Although the condition is encountered quite often by dermatologists of this region, the data on the clinical, pathological, and immunohistochemical (IHC) aspects of LPP are limited. This prospective study is aimed towards filling this lacuna. Materials and Methods: Data were collected from thirty clinically diagnosed cases of LPP who presented to the dermatology outpatient department. Skin biopsy and blood investigations were conducted and the specimens were further analyzed for their histopathological features and IHC staining for CD4+, CD8+ T-lymphocyte subsets along with CD45RO (UCHL-1), and CD68. The results were statistically analyzed. Results: The study showed a female preponderance (56.7%). Photo aggravation as a precipitating cause was seen in 40% of the individuals. The lesions with duration <4 months had a more intense inflammatory infiltrate on histology. CD4+ and CD8+ cells showed very good Pearsons correlation on statistical analysis. CD45 was seen in association with CD8+, and staining for CD68 to assess the macrophage density showed a close correlation with CD45RO. Limitations: Small sample size. Conclusion: LPP represents a misguided lesional immune response pattern. The intense inflammatory infiltrate seen in the early lesions necessitates prompt treatment to arrest progression which may prevent the chronic pigmentary phase of the disease. PMID- 29263536 TI - Cutaneous Adverse Drug Reactions in a Tertiary Care Teaching Hospital in India: An Intensive Monitoring Study. AB - Background: The epidemiological data based on intensive monitoring studies are limited for the cutaneous adverse drug reactions (CADRs) in terms of incidence. Most of earlier Indian studies focused only on types and causative drugs of CADRs. Aim: The aim of this study is to analyze the CADRs with reference to the incidence, its subgroup analysis, causative drugs, and other clinical characteristics in Indian population. Methodology: Intensive monitoring study was carried out over a period of 3 years in the dermatology outpatient and inpatient department. CADRs due to only systematically administered drugs were considered. The WHO definition for CADR, the WHO causality definitions, modified Schumock and Thornton's criteria for preventability, and International Conference on Harmonisation E2A guidelines for seriousness were considered. Incidence was expressed in percentage and its 95% confidence interval. The incidence was analyzed on basis of characteristics of study population and CADRs. Results: A total of 171 CADRs were observed from 37,623 patients. The CADR incidence was 0.45% (95% CI: 0.39-0.53). The incidence did not significantly differ in different age groups and gender. Commonly observed CADRs were maculopapular rash (23.98%), urticaria (21.64%), and fixed drug eruptions (FDEs) (18.13%). Antimicrobials (35.18%) and nonsteroidal anti-inflammatory drugs (NSAIDs) were suspected in all common CADRs. Anti-infective and NSAIDs were most commonly suspected drugs in overall CADRs, maculopapular rash, urticaria, FDEs, and erythema multiforme. The exact nature of drugs remained inaccessible in one fourth cases due to use of the over-the-counter self-medications. The incidence of preventable and serious and fatal CADRs was 0.08% (95% CI: 0.05-0.11), 0.04% (95% CI: 0.02-0.06), and 0.003% (95% CI: 0.000-0.001), respectively. Conclusion: Ethnic characteristics should be considered while interpreting incidence from the international studies. The demographic characteristics of study population do not affect the incidence of CADRs. Indian patients should be sensitized about hazards of self-medications. PMID- 29263537 TI - Inpatient Mortality Resulting from Dermatological Disorders at a Tertiary Care Center in Eastern India: A Record-based Observational Study. AB - Background: Contrary to popular perception, several dermatological conditions may be associated with lethal outcome in the absence of timely intervention or due to complications. Aims: The aim was to estimate the number of deaths and analyze their causes due to skin disorders at a tertiary level inpatient dermatology ward. Materials and Methods: We conducted a retrospective, record-based observational study involving 538 patients spanning over 4 years (2013-2016) at our dermatology indoor setup. Results: There were 45 deaths (male:female = 1.5:1), accounting for 8.4% or total admissions, occurring mostly in patients in their 7th decade. Vesiculobullous disorders were the most frequent cause of mortality (57.8%), followed by drug reactions accounting for 17.8% of cases. In the former group pemphigus vulgaris accounted for most deaths (31.1%) followed by bullous pemphigoid (17.8%) and pemphigus foliaceus (8.9%), whereas toxic epidermal necrolysis was the most frequent cause of death from drug reactions (8.9%). Almost half of all deaths (48.9%) occurred due to septicemia followed by cardiopulmonary complications (40%). Most of the cases presented to us at an advanced state of the disease previously being treated inappropriately. Conclusion: Prompt diagnosis and treatment of such dermatological conditions are mandated, preferably in an intensive care set-up, to reduce mortality rates. Advanced age, the area of skin involvement, mucosal involvement, and septicemia were adverse prognostic factors in these patients. PMID- 29263538 TI - Usefulness and Utility of NACO Regime in the Management of Sexually Transmitted Infections: A Pilot Study. AB - Introduction: Treatment of sexually transmitted infections (STIs) has been made easy for field workers due to syndromic approach. The etiological agent responsible for different STI syndromes needs to be validated from time to time so as to guide the therapeutic regimen. Aims and Objectives: The aim of this study was to evaluate the etiological agent for STI syndromes and correlate the syndromic diagnosis with etiological diagnosis. Materials and Methods: The study was conducted over 9 months in all patients attending the STI and Gynaecology Outpatient Department. Syndromic diagnosis was done by STI-trained medical officer of respective clinic. Sample was collected for etiological diagnosis and subjected to relevant investigations. Data were analyzed by applying statistical methods. Results: Among 308 patients (male:female = 1:3.5), no syndromic diagnosis could be made in 11 cases (all females and had premalignant changes on Pap smear). In 68 patients (22.08%), no etiological diagnosis could be arrived at (mostly genital ulcer disease [GUD]-herpetic [H] and vaginal discharge). In cervical discharge syndrome, six patients (16.7%) showed gonococcus. In GUD-H syndrome, 37 patients (27.027%) were tested positive. In GUD-nonherpetic syndrome, three patients (33.33%) were syphilis, granuloma inguinale, and chancroid (1 each). In urethral discharge syndrome, etiology could not be found in 33 cases (45.45%). In vaginal discharge syndrome (n = 217), etiologies were overlapping as follows: trichomonas vaginalis (76.04%), bacterial vaginosis (40%), gonococcus (24%), and undiagnosed (6.5%). Conclusion: The present tool for validation of GUD-H can validate only 27% of cases. Overlap of etiologies is mostly common in vaginal discharge syndrome, wherein malignancies and premalignant conditions are overtreated with kits. Validation can be done only in two-third of cases with the available resources. However, syndromic approach provides the opportunity of treating STI without delay. PMID- 29263539 TI - Use of Fine Needle Aspirate from Peripheral Nerves of Pure-neural Leprosy for Cytology and Polymerase Chain Reaction to Confirm the Diagnosis: A Follow-up Study of 4 Years. AB - Background: Pure neural leprosy (PNL) still remains a diagnostic challenge because of the absence of sine qua non skin lesions of leprosy and a confirmatory diagnostic method. The authors had earlier described a simple yet objective technique of combining fine needle aspiration cytology (FNAC) coupled with a multiplex polymerase chain reaction (PCR) in a pilot study, wherein the technique showed promise of a reliable diagnostic tool. In the pursuit of further evidence, the authors carried out a 4-year study with PNL cases to find the efficacy and reliability of the said method in a larger sample size. Aim: This study was conducted to find the efficacy, reliability, and reproducibility of FNAC coupled with multiplex PCR and Ziehl-Neelsen (ZN) staining in identifying the cases of PNL. Materials and Methods: All cases that were suspected to be suffering from PNL, following evaluation by two independent observers were included in the study and were subjected to FNAC from the affected nerve, and the aspirates were evaluated for cytology, ZN staining, and multiplex PCR for Mycobacterium leprae genome. In addition, serum anti-PGL1 levels were also performed in all the study subjects. Fifteen non-PNL cases were also included in the control arm. Results: A total of 47 cases were included in the test arm and subjected to FNAC. Conventional ZN staining could demonstrate acid-fast bacilli (AFB) in only 15 out of 47 cases (31.91%) while M. leprae DNA could be elicited in 37 (78.72%) cases by the multiplex PCR. Only 13 (27.65%) out of 47 cases showed anti-PGLI-1 antibody positivity. On cytological examination of the nerve aspirates, only 11 (23.40%) cases showed epithelioid cells whereas nonspecific inflammation was seen in 26 (75.60%) cases. Conclusion: The results of this study conducted over a larger sample size corroborate with the findings of our pilot study. In a resource poor set up, FNAC in combination with ZN staining and multiplex PCR is a rapid, simple, and easily performed test, which can give a reproducible and objective diagnosis in cases of PNL. PMID- 29263540 TI - Electrophysiological Study of Nerves in Type-II Reaction in Leprosy. AB - Background: Leprosy is a chronic granulomatous infection primarily affecting the peripheral nervous system, skin and reticuloendothelial system. Cutaneous nerves are severely affected in lepra reaction and this leads to morbidity. Objective: To study electrophysiological pattern of different nerves involved in Type-II reactions in leprosy. Method: The present study was undertaken in 21 leprosy patients with Type-II reactions attending in and out-patient department of Dermatology & Venereology, B.R.D. Medical College, Gorakhpur from July 2005 to October 2006. This was a prospective case control study in which 20 healthy, age and sex matched people with no evidence of any disease (particularly nerve involvement) were included. Limitation: Lesser number of cases were studied. Result: The proximal motor conduction latency was significantly prolonged in both ulnar and common peroneal nerve and proximal motor conduction velocity was also significantly reduced. On examining the values beyond 2S.D. of the control value, distal latency was not affected and only proximal conduction was affected in ulnar nerve. Conclusion: In Type II lepra reaction the motor conduction abnormalities are not prominent. Abnormalities are relatively more marked in the proximal segment. PMID- 29263541 TI - Detection of Anti-basement Membrane Zone Antibodies in the Blister Fluid in Subepidermal Autoimmune Bullous Diseases. AB - Background: Subepidermal autoimmune bullous diseases (sAIBD) are diverse of conditions with clinicopathological overlap. Circulating autoantibodies in the serum can be demonstrated using indirect immunofluorescence (IIF) microscopy. Artificially split normal human skin is considered as an optimum substrate for the demonstration of anti-basement membrane zone (BMZ) antibodies using IIF in sAIBD; it not only helps to detect the presence of circulating antibodies in the serum but also helps to subclassify these conditions into "roof" and "floor" binding disorders. Aim: In this study, we evaluated the utility of IIF to detect anti-BMZ antibodies in the blister fluid of patients with sAIBD. Materials and Methods: Twenty-two patients with a clinical diagnosis of sAIBD were enrolled in the study. IIF of serum and blister fluid were done simultaneously using salt split skin as a substrate. Results: Anti-BMZ antibodies could be detected in the blister fluid using IIF in all patients in the study group. Limitation: We could not do enzyme-linked immunosorbent assay of blister fluid. This would have given us the quantitative data of circulating antibodies in the blister fluid. Conclusion: Blister fluid offers an alternate source for the detection of autoantibodies in patients with sAIBD. It may be of particular help in children and in elderly with poor venous access. PMID- 29263542 TI - Calcified Keratoacanthoma with Tumoral Calcinosis in a 10-year-old Boy: A mere Co incidence? AB - Keratoacanthoma (KA) is a rapidly evolving benign cutaneous tumor, occurring in elderly individuals with a tendency towards spontaneous regression and histopathologic similarity to squamous cell carcinoma. Tumoral calcinosis is an uncommon condition, associated with the deposition of painless calcific masses. The occurrence of these two conditions in the same patient is a rarity itself, whereas deposition of calcium within the KA lesion in our 13-year-old patient makes it even more intriguing. Such an association has been seldom reported in the literature, and this prompted the current report. PMID- 29263543 TI - "i hair": A prognostic marker in alopecia areata & trichotillomania. AB - Trichoscopy as an investigative tool is revolutionizing the diagnosis of hair disorders. The use of a trichoscope has unveiled a plethora of signs which not only helps in decoding the underlying tricoscopic condition but also acts as prognostic markers. Herein, we present a new trichoscopic sign, "i hair" in alopecia areata and trichotillomania. "i hair" are short hairs with an accentuated distal end. There may be a thin hypopigmented shaft just beneath the darker distal end, thus making them resemble the alphabet "i." PMID- 29263544 TI - Cutaneous Cysts with Nail Dystrophy in a Young Female: A Classical Association. AB - Pachyonychia Congenita (PC) refers to a group of autosomal dominant disorders with variable clinical presentations. While nail dystrophy and plantar keratoderma are the most consistent features in all the variants, a myriad of other manifestations has been observed. This report highlights a case of young female presenting with multiple asymptomatic cutaneous cysts associated with plantar kearatoderma and nail dystrophy. Similar nail changes were evident in her son also. Such clinical presentation, in corroboration with histopathological evaluation of the cutaneous cyst prompted us to make a diagnosis of Pachyonychia Congenita type II. PMID- 29263545 TI - Rational for Drug Dosimetry and Duration of Terbinafine in the Context of Recalcitrant Dermatophytosis: Is 500 mg Better than 250 mg OD or BD? PMID- 29263546 TI - Author's reply. PMID- 29263547 TI - Contact Dermatitis Due to Quackery. PMID- 29263548 TI - Mycobacterium leprae or tuberculosis: A Diagnostic Dilemma. PMID- 29263549 TI - Follow-up Data of Rituximab as Adjuvant Therapy in Pemphigus. PMID- 29263550 TI - Topical Corticosteroids Abuse: A Clinical Study of Cutaneous Adverse Effects. AB - Background: Topical corticosteroids (TC) are one of the most widely used agents in dermatology practice. Misuse of these agents may lead to a wide range of adverse effects. Aim: This study was conducted to assess the magnitude of abuse of topical corticosteroids (TC) and clinical patterns of cutaneous adverse effects amongst patients attending dermatology department of a teaching hospital at South Rajasthan. Materials and Methods: All patients who reported with adverse effects of topical steroids during one year from September 2015 to August 2016 were evaluated. Patients fulfilling the study criteria were registered for further workup. Results: Out of the 85280 new patients, 370 (0.43%) presented with adverse effects of TC. Males (232/370;62.70%) outnumbered females (138/370;37.30). Age group 11-30 years was most commonly (74.05%) affected. The main reason for using TC was fungal infection (52.43%). Tinea incognito (49.46%) and acne (30.27%) were the most common adverse effects recorded. Conclusions: Abuse of TC, particularly the superpotent and potent is rampant amongst general population. Topical corticosteroids are frequently used for indications where they should be avoided. PMID- 29263551 TI - Red Eccrine Chromhidrosis with Review of Literature. AB - A 22-year-old male presented with reddish discoloration of the vest following perspiration for 6 months. He was a habituated consumer of cranberry juice. The peak absorption on spectrophotometric analysis of the extracted sweat coincided approximately with the peak absorption of diluted distillate of the juice. A diagnosis of eccrine chromhidrosis, probably due to the coloring agents in the juice, was considered. This rare case report emphasizes the possible side effect of the various coloring agents used as food additives. PMID- 29263552 TI - Primary Cutaneous B-cell Lymphomas: Case Report of Two Cases. AB - Primary cutaneous lymphomas are a unique, heterogeneous group of lymphoproliferative disorders which have a primary cutaneous manifestation in the absence of systemic involvement of lymph nodes, bone marrow, or visceral organs at the time of diagnosis. Among the primary cutaneous lymphomas, B-cell lymphoma is much less common and accounts for 20%-25% of cases. Primary cutaneous diffuse large B-cell lymphomas (PCDLBCLs) are aggressive neoplasms with poor prognosis. Early and accurate diagnosis is required as these patients respond well to systemic anthracycline-based chemotherapy (R-CHOP). In this article, we report two cases of PCDLBCL, other which presented with rapidly enlarging skin nodules and were diagnosed based on clinical features, histomorphology, and characteristic immunohistochemical expression. Both the patients were treated with systemic chemotherapy and responded well. During the 6 months' follow-up period, the lesions regressed. The patients are symptom free with no evidence of disease relapse or dissemination to extracutaneous sites. PMID- 29263553 TI - A Fatal Case of Febrile Ulceronecrotic Mucha-Habermann Disease which Presenting as Toxic Epidermal Necrolysis. AB - Febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a severe form of pityriasis lichenoides et varioliformis acuta, is an inflammatory dermatosis of unknown etiology manifested by ulcerative and necrotic lesions accompanied by systemic manifestations. The mortality rate of FUMHD is about 15%. It is reported here a case of FUMHD presenting as toxic epidermal necrolysis that resulted in multiple organ failure and death. PMID- 29263554 TI - The Bumpy Face of Che Guevara: An Interesting Case. AB - Placement of decorative tattoo on the skin may lead to various immunological, infective, and coincidental complications. Inoculation of human papillomavirus leading to development of verruca is an uncommon complication of tattoos. The present report highlights the development of verruca vulgaris, developing after 2 years of tattooing in a young male. PMID- 29263555 TI - Relapsed Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type. PMID- 29263556 TI - Nonhealing Wound at Wrist for 2 Years: Ultimately Proved to be Actinomycosis. PMID- 29263557 TI - Incongruent Teen Pregnancy Attitudes, Coparenting Conflict, and Support Among Mexican-Origin Adolescent Mothers. AB - The current longitudinal study examined whether differences between Mexican origin adolescent mothers and their mother figures (N = 204 dyads) in attitudes on the status attained through teen pregnancy were associated with conflict in their coparenting relationship and whether coparenting conflict was associated with adolescent mothers' perceptions of social support. Findings revealed that when adolescents held more positive attitudes than their mother figures about the status gained through teen pregnancy, they tended to report greater coparenting conflict with their mother figures. Furthermore, greater coparenting conflict was significantly associated with decreases in adolescents' perceptions of social support (i.e., emotional, instrumental, companion support) 1 year later. Findings underscore the importance of incongruent attitudes and the quality of coparenting relationships between adolescent mothers and their mother figures in relation to support processes. Findings are discussed with respect to understanding Mexican origin adolescent mothers' social support in the context of family subsystem attitudes and interactions. PMID- 29263558 TI - Bloom termination of the toxic dinoflagellate Alexandrium catenella: Vertical migration behavior, sediment infiltration, and benthic cyst yield. AB - New resting cyst production is crucial for the survival of many microbial eukaryotes including phytoplankton that cause harmful algal blooms. Production in situ has previously been estimated through sediment trap deployments, but here was instead assessed through estimation of the total number of planktonic cells and new resting cysts produced by a localized, inshore bloom of Alexandrium catenella, a dinoflagellate that is a globally important cause of paralytic shellfish poisoning. Our approach utilizes high frequency, automated water monitoring, weekly observation of new cyst production, and pre- and post-bloom spatial surveys of total resting cyst abundance. Through this approach, new cyst recruitment within the study area was shown to account for at least 10.9% +/- 2.6% (SE) of the bloom's decline, ~ 5* greater than reported from comparable, sediment trap based studies. The observed distribution and timing of new cyst recruitment indicate that: (1) planozygotes, the immediate precursor to cysts in the life cycle, migrate nearer to the water surface than other planktonic stages and (2) encystment occurs after planozygote settlement on bottom sediments. Near surface localization by planozygotes explains the ephemerality of red surface water discoloration by A. catenella blooms, and also enhances the dispersal of new cysts. Following settlement, bioturbation and perhaps active swimming promote sediment infiltration by planozygotes, reducing the extent of cyst redistribution between blooms. The concerted nature of bloom sexual induction, especially in the context of an observed upper limit to A. catenella bloom intensities and heightened susceptibility of planozygotes to the parasite Amoebophrya, is also discussed. PMID- 29263559 TI - Wastewater influences nitrogen dynamics in a coastal catchment during a prolonged drought. AB - Ecosystem function measurements can enhance our understanding of nitrogen (N) delivery in coastal catchments across river and estuary ecosystems. Here, we contrast patterns of N cycling and export in two rivers, one heavily influenced by wastewater treatment plants (WWTP), in a coastal catchment of south Texas. We measured N export from both rivers to the estuary over 2 yr that encompass a severe drought, along with detailed mechanisms of N cycling in river, tidal river, and two estuary sites during prolonged drought. WWTP nutrient inputs stimulated uptake of N, but denitrification resulting in permanent N removal accounted for only a small proportion of total uptake. During drought periods, WWTP N was the primary source of exported N to the estuary, minimizing the influence of episodic storm-derived nutrients from the WWTP-influenced river to the estuary. In the site without WWTP influence, the river exported very little N during drought, so storm-derived nutrient pulses were important for delivering N loads to the estuary. Overall, N is processed from river to estuary, but sustained WWTP-N loads and periodic floods alter the timing of N delivery and N processing. Research that incorporates empirical measurements of N fluxes from river to estuary can inform management needs in the face of multiple anthropogenic stressors such as demand for freshwater and eutrophication. PMID- 29263560 TI - A Dynamic Model of Mercury's Magnetospheric Magnetic Field. AB - Mercury's solar wind and interplanetary magnetic field environment is highly dynamic, and variations in these external conditions directly control the current systems and magnetic fields inside the planetary magnetosphere. We update our previous static model of Mercury's magnetic field by incorporating variations in the magnetospheric current systems, parameterized as functions of Mercury's heliocentric distance and magnetic activity. The new, dynamic model reproduces the location of the magnetopause current system as a function of systematic pressure variations encountered during Mercury's eccentric orbit, as well as the increase in the cross-tail current intensity with increasing magnetic activity. Despite the enhancements in the external field parameterization, the residuals between the observed and modeled magnetic field inside the magnetosphere indicate that the dynamic model achieves only a modest overall improvement over the previous static model. The spatial distribution of the residuals in the magnetic field components shows substantial improvement of the model accuracy near the dayside magnetopause. Elsewhere, the large-scale distribution of the residuals is similar to those of the static model. This result implies either that magnetic activity varies much faster than can be determined from the spacecraft's passage through the magnetosphere or that the residual fields are due to additional external current systems not represented in the model or both. Birkeland currents flowing along magnetic field lines between the magnetosphere and planetary high latitude regions have been identified as one such contribution. PMID- 29263562 TI - Testing for a Debt-Threshold Effect on Output Growth. AB - Using the Reinhart-Rogoff dataset, we find a debt threshold not around 90 per cent but around 30 per cent, above which the median real gross domestic product (GDP) growth falls abruptly. Our work is the first to formally test for threshold effects in the relationship between public debt and median real GDP growth. The null hypothesis of no threshold effect is rejected at the 5 per cent significance level for most cases. While we find no evidence of a threshold around 90 per cent, our findings from the post-war sample suggest that the debt threshold for economic growth may exist around a relatively small debt-to-GDP ratio of 30 per cent. Furthermore, countries with debt-to-GDP ratios above 30 per cent have GDP growth that is 1 percentage point lower at the median. PMID- 29263561 TI - BedMachine v3: Complete Bed Topography and Ocean Bathymetry Mapping of Greenland From Multibeam Echo Sounding Combined With Mass Conservation. AB - Greenland's bed topography is a primary control on ice flow, grounding line migration, calving dynamics, and subglacial drainage. Moreover, fjord bathymetry regulates the penetration of warm Atlantic water (AW) that rapidly melts and undercuts Greenland's marine-terminating glaciers. Here we present a new compilation of Greenland bed topography that assimilates seafloor bathymetry and ice thickness data through a mass conservation approach. A new 150 m horizontal resolution bed topography/bathymetric map of Greenland is constructed with seamless transitions at the ice/ocean interface, yielding major improvements over previous data sets, particularly in the marine-terminating sectors of northwest and southeast Greenland. Our map reveals that the total sea level potential of the Greenland ice sheet is 7.42 +/- 0.05 m, which is 7 cm greater than previous estimates. Furthermore, it explains recent calving front response of numerous outlet glaciers and reveals new pathways by which AW can access glaciers with marine-based basins, thereby highlighting sectors of Greenland that are most vulnerable to future oceanic forcing. PMID- 29263563 TI - Risky behaviors and educational attainment among young Mexican-origin mothers: The role of acculturative stress and the educational aspiration-expectation gap. AB - The current longitudinal study examined how Mexican-origin adolescent mothers' (N = 204) reports of acculturative stress during late adolescence were associated with their educational attainment and engagement in risky behaviors in young adulthood, 4 years post-partum; we also examined whether this association was mediated by discrepancies between adolescents' educational aspirations and expectations. Findings revealed that mothers' greater reports of stress regarding English competency pressures and pressures to assimilate were associated with a larger gap between their aspirations and expectations. Mothers' reports of greater stress from pressures against assimilation, however, were associated with a smaller gap between aspirations and expectations. As expected, a larger gap between aspirations and expectations was associated with lower educational attainment and increased engagement in risky behaviors. Finally, significant mediation emerged, suggesting that the influence of stress from English competency pressures and pressures to assimilate on young mothers' educational attainment and engagement in risky behaviors was mediated through the aspiration expectation gap. Findings are discussed with respect to understanding discrepancies between young mothers' aspirations and expectations in the context of acculturative stress. PMID- 29263564 TI - Sleeping and Ranging Behavior of the Sambirano Mouse Lemur, Microcebus sambiranensis. AB - Primates require secure sleeping sites for periods of rest, but despite their importance, the characteristics of desired sleeping sites are poorly known. Here we investigated the sleeping ecology of a radio-collared population of the Sambirano mouse lemur, Microcebus sambiranensis, during the nonreproductive season in the Anabohazo forest, northwestern Madagascar. We also investigated their ranging behavior and examined the spatial distribution of sleeping sites within the home ranges of the collared individuals. We took measurements of the sleeping tree's physical characteristics and recorded the number of collared individuals using each sleeping site. We found that M. sambiranensis generally use foliage sleeping sites more frequently than tree holes and individuals slept more frequently in densely foliated trees than in sparsely foliated trees, often alone. We observed no significant differences in home range size or nightly travel distance between males and females; however, home ranges were smaller than those described for other mouse lemur species. Finally, we found that M. sambiranensis sleep peripherally and forage centrally within their home ranges, a behavior not previously described for mouse lemurs. Our results indicate profound differences in the social organization between M. sambiranensis and other mouse lemur species described in the literature, suggesting species-specificity in mouse lemur ecology. Understanding the sleeping ecology and ranging behavior of mouse lemurs is of great importance to their conservation, as these data facilitate the planning of long-term reforestation, habitat management, and population assessment. PMID- 29263565 TI - The Number of Louse Eggs on Wild Japanese Macaques (Macaca fuscata) Varies with Age, but Not with Sex or Season. AB - During grooming, primates remove harmful ectoparasites, such as ticks and lice, and there is direct evidence for a health benefit of tick removal. Grooming behaviors differ among primates with respect to age and sex. Moreover, the number of ectoparasite may exhibit seasonal variation. Therefore the number of ectoparasites on a host may vary with effects, host age and sex, and season. However, these effects have not been a focus of louse infestation studies of primates. Grooming in Japanese macaques is related to sex and age, with developmental changes in behavior corresponding to the timing of tooth eruption. Moreover, behavioral data for Japanese macaques suggest that lice load may differ with the season. Thus, we examined whether the number of louse eggs varies according to host macaque sex, age, and season, and whether it changes in response to tooth eruption. We counted unhatched and hatched eggs attached to the hair on six 1-cm2 areas on the left wrist skin of culled macaques, using a stereoscopic microscope. We sampled five winter coats and three summer coats for each age class: infant, juvenile, adolescent, and adult. The number of unhatched and hatched eggs was related to age, but not to sex and season. There were significant differences in the number of unhatched eggs between infants and adults, juveniles and adults, and adolescents and adults. There were also significant differences in the number of hatched eggs between infants and adults, juveniles and adults, adolescents and adults. Tooth eruption did not influence the number of louse eggs. These results suggest that researchers should consider the age of host animals when assessing the relationship between grooming and ectoparasites. PMID- 29263566 TI - Deep Learning based Classification of FDG-PET Data for Alzheimers Disease Categories. AB - Fluorodeoxyglucose (FDG) positron emission tomography (PET) measures the decline in the regional cerebral metabolic rate for glucose, offering a reliable metabolic biomarker even on presymptomatic Alzheimer's disease (AD) patients. PET scans provide functional information that is unique and unavailable using other types of imaging. However, the computational efficacy of FDG-PET data alone, for the classification of various Alzheimers Diagnostic categories, has not been well studied. This motivates us to correctly discriminate various AD Diagnostic categories using FDG-PET data. Deep learning has improved state-of-the-art classification accuracies in the areas of speech, signal, image, video, text mining and recognition. We propose novel methods that involve probabilistic principal component analysis on max-pooled data and mean-pooled data for dimensionality reduction, and multilayer feed forward neural network which performs binary classification. Our experimental dataset consists of baseline data of subjects including 186 cognitively unimpaired (CU) subects, 336 mild cognitive impairment (MCI) subjects with 158 Late MCI and 178 Early MCI, and 146 AD patients from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We measured F1-measure, precision, recall, negative and positive predictive values with a 10-fold cross validation scheme. Our results indicate that our designed classifiers achieve competitive results while max pooling achieves better classification performance compared to mean-pooled features. Our deep model based research may advance FDG-PET analysis by demonstrating their potential as an effective imaging biomarker of AD. PMID- 29263567 TI - Fertilizing growth: Agricultural inputs and their effects in economic development. AB - This paper estimates the role of agronomic inputs in cereal yield improvements and the consequences for countries' processes of structural change. The results suggest a clear role for fertilizer, modern seeds and water in boosting yields. We then test for respective empirical links between agricultural yields and economic growth, labor share in agriculture and non-agricultural value added per worker. The identification strategy includes a novel instrumental variable that exploits the unique economic geography of fertilizer production and transport costs to countries' agricultural heartlands. We estimate that a half ton increase in staple yields generates a 14 to 19 percent higher GDP per capita and a 4.6 to 5.6 percentage point lower labor share in agriculture five years later. The results suggest a strong role for agricultural productivity as a driver of structural change. PMID- 29263568 TI - Productivity and Welfare Effects of Nigeria's e-Voucher-Based Input Subsidy Program. AB - In an attempt to go beyond the so called "smart" subsidies, Nigeria has embarked on a potentially innovative mobile phone-based input subsidy program that provides fertilizer and improved seed subsidies through electronic vouchers. In this article, we examined the productivity and welfare effects of the program using household-level data from rural Nigeria. The article employed instrumental variable regression approach to control for the potential endogeneity of the input subsidy program. Our results suggest that the program is effective in improving productivity and welfare outcomes of beneficiary smallholders. The size of the estimated effects suggests a large improvement in productivity and welfare outcomes. Moreover, the distributional effects of the program suggest no heterogeneity effects based on gender and farm land size. These results are robust to using alternative measurements of program participation. The benefit cost ratio of 1.11 suggests that the program is marginally cost-effective. Overall, our results suggest that while improving average productivity is a good outcome for improving food security, improving the distributional outcome of the program by targeting the most disadvantaged groups would maximize the program's contribution to food security and poverty reduction. PMID- 29263569 TI - I Thought I Knew About Diabetes. PMID- 29263570 TI - Patient-Centered Care, Diabetes Empowerment, and Type 2 Diabetes Medication Adherence Among American Indian Patients. AB - IN BRIEF Type 2 diabetes has been labeled an epidemic in many American Indian communities. Thus, identifying factors that improve medication adherence for American Indian patients is crucial. We found significant and positive relationships among patient-centered care, medication adherence, and diabetes empowerment. In addition, diabetes empowerment partially mediated the relationship between patient-centered care and medication adherence. PMID- 29263571 TI - Frequency of Diet and Physical Activity Goal Attainment and Barriers Encountered Among Adults With Type 2 Diabetes During a Telephone Coaching Intervention. AB - IN BRIEF Participants with type 2 diabetes established personalized dietary and physical activity goals as behavioral strategies to reduce cardiovascular risk during a 16-week telephone coaching intervention. People were most likely to attain dietary goals that involved altering the intake of specific foods rather than certain nutrients and were more successful at physical activity goals to increase activity levels rather than to add new types of activity. Barriers to goal success included time management, physical limitations/illness, and social/cultural activities. PMID- 29263572 TI - Randomized Trial of the Effect of Mindfulness-Based Stress Reduction on Pain Related Disability, Pain Intensity, Health-Related Quality of Life, and A1C in Patients With Painful Diabetic Peripheral Neuropathy. AB - IN BRIEF Painful diabetic peripheral neuropathy (PDPN) has a large negative impact on patients' physical and mental functioning, and pharmacological therapies rarely provide more than partial relief. Mindfulness-based stress reduction (MBSR) is a group psychosocial intervention that was developed for patients with chronic illness who were not responding to existing medical treatments. This study tested the effects of community-based MBSR courses for patients with PDPN. Among patients whose PDPN pharmacotherapy had been optimized in a chronic pain clinic, those randomly assigned to treatment with MBSR experienced improved function, better health-related quality of life, and reduced pain intensity, pain catastrophizing, and depression compared to those receiving usual care. PMID- 29263573 TI - Improving Diabetes Self-Management Support: Goal-Setting Across the Continuum of Care. AB - IN BRIEF Goal-setting has consistently been promoted as a strategy to support behavior change and diabetes self-care. Although goal-setting conversations occur most often in outpatient settings, clinicians across care settings need to better understand and communicate about the priorities, goals, and concerns of those with diabetes to develop collaborative, person-centered partnerships and to improve clinical outcomes. The electronic health record is a mechanism for improved communication and collaboration across the continuum of care. This article describes a quality improvement project that was intended to improve the person-centeredness of care for adults with diabetes by offering goal-setting and self-management support during and after hospitalization. PMID- 29263574 TI - Clinical Application of Patient-Centered Diabetes Care for People With Serious Mental Illness. AB - IN BRIEF Patients with serious mental illness (SMI) have markedly higher mortality rates than those without SMI. A large portion of this disparity is explained by higher rates of diabetes and cardiovascular illness, highlighting the need for people with diabetes and SMI to have access to the highest quality diabetes care. This article applies principles of patient-centered diabetes care to those with SMI, exploring a novel approach to diabetes care embedded within a community mental health setting. PMID- 29263576 TI - Diabetes Cannot Be Controlled, But It Can Be Managed. PMID- 29263575 TI - Personalizing Type 2 Diabetes Management: Use of a Patient-Centered Approach to Individualizing A1C Goals and Pharmacological Regimens. AB - IN BRIEF Caring for people with type 2 diabetes requires a patient-centered approach to treatment targets and medication regimens. Focusing on patients' individual characteristics, needs, and treatment responses can improve compliance and clinical outcomes. Medication selection can be guided by the mechanisms of action, advantages, disadvantages, and costs of available options; patients' behavioral and psychological variables, personal preferences, and socioeconomic status also should be taken into account. This article provides an overview of patient-centered and individualized diabetes management, offers pharmacological recommendations for specific clinical scenarios, and describes a complicated case illustrating the patient-centered approach in clinical practice. PMID- 29263577 TI - Fifty Years of Living With Type 1 Diabetes. PMID- 29263578 TI - Taking Control Of Your Diabetes: An Innovative Approach to Improving Diabetes Care Through Educating, Motivating, and Making the Connection Between Patients and Health Care Providers. PMID- 29263579 TI - Fried Chicken, an Airport Ride, and Why Diabetes Is So Hard. PMID- 29263580 TI - Specialty Group Medical Visits for Patients With Diabetes. PMID- 29263581 TI - Diabetes Group Visits at the University of South Florida Morsani College of Medicine. AB - IN BRIEF "Quality Improvement Success Stories" are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc., and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes a successful project from the Division of General Internal Medicine at the University of South Florida Morsani College of Medicine, Tampa, to improve A1C, systolic blood pressure, and weight in patients with type 2 diabetes. PMID- 29263582 TI - GOOD TO KNOW: Information from the American Diabetes Association for people with diabetes. PMID- 29263583 TI - Bright Spots & Landmines: The Diabetes Guide I Wish Someone Had Handed Me. PMID- 29263584 TI - The Diabetes 2-Month Turnaround. PMID- 29263585 TI - Women and agricultural productivity: Reframing the Issues. AB - Should agricultural development programmes target women in order to increase productivity? This article analyzes the challenges in distinguishing women's agricultural productivity from that of men. Most of the literature compares productivity on plots managed by women with those managed by men, ignoring the majority of agricultural households in which men and women are both involved in management and production. The empirical studies which have been carried out provide scant evidence for where the returns to projects may be highest, in terms of who to target. Yet, programmes that do not consider gendered responsibilities, resources and constraints, are unlikely to succeed, either in terms of increasing productivity or benefitting men and women smallholder farmers. PMID- 29263586 TI - Clean energy storage technology in the making: An innovation systems perspective on flywheel energy storage. AB - The emergence and diffusion of green and sustainable technologies is full of obstacles and has therefore become an important area of research. We are interested in further understanding the dynamics between entrepreneurial experimentation, market formation, and institutional contexts, together playing a decisive role for successful diffusion of such technologies. Accordingly, we study these processes by adopting a technological innovation system perspective focusing on actors, networks, and institutions as well as the functions provided by them. Using a qualitative case study research design, we focus on the high speed flywheel energy storage technology. As flywheels are based on a rotating mass allowing short-term storage of energy in kinetic form, they represent an environmentally-friendly alternative to electrochemical batteries and therefore can play an important role in sustainable energy transitions. Our contribution is threefold: First, regarding the flywheel energy storage technology, our findings reveal two subsystems and related markets in which development took different courses. In the automotive sector, flywheels are developing well as a braking energy recovery technology under the influence of two motors of innovation. In the electricity sector, they are stagnating at the stage of demonstration projects because of two important system weaknesses that counteract demand for storage. Second, we contribute to the theory of technological innovation systems by better understanding the internal dynamics between different functions of an innovation system as well as between the innovation system and its (external) contextual structures. Our third contribution is methodological. According to our best knowledge, we are the first to use system dynamics to (qualitatively) analyze and visualize dynamics between the diverse functions of innovation systems with the aim of enabling a better understanding of complex and iterative system processes. The paper also derives important implications for energy scholars, flywheel practitioners, and policymakers. PMID- 29263587 TI - Genotyping of virulent Escherichia coli obtained from poultry and poultry farm workers using enterobacterial repetitive intergenic consensus-polymerase chain reaction. AB - Aim: The aim of this study was to characterize virulent Escherichia coli isolated from different poultry species and poultry farm workers using enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) genotyping. Materials and Methods: Fecal swabs from different poultry species (n=150) and poultry farm workers (n=15) were analyzed for E. coli and screened for virulence genes (stx1, stx2, eaeA, and hlyA) by multiplex PCR. Virulent E. coli was serotyped based on their "O" antigen and then genotyped using ERIC-PCR. Results: A total of 134 E. coli isolates (122/150 from poultry and 12/15 from farm workers) were recovered. Virulence genes were detected in a total of 12 isolates. Serological typing of the 12 virulent E. coli revealed nine different serotypes (O2, O49, O60, O63, O83, O101, O120, UT, and Rough). ERIC-PCR genotyping allowed discrimination of 12 virulent E. coli isolates into 11 ERIC-PCR genotypes. The numerical index of discrimination was 0.999. Conclusion: Our findings provide information about the wide genetic diversity and discrimination of virulent E. coli in apparently healthy poultry and poultry farm workers of Andhra Pradesh (India) based on their genotype. PMID- 29263588 TI - Preliminary study of Malaysian fruit bats species diversity in Lenggong Livestock Breeding Center, Perak: Potential risk of spill over infection. AB - Aim: Farms that are neighboring wildlife sanctuaries are at risk of spillover infection from wildlife, and the objective of this research is to examine the species diversity of Malaysian fruit bats in livestock farm in determining the possible risk of spill over infection to livestock. Materials and Methods: Fifty individual fruit bats were captured using six mists net, from May to July 2017. The nets were set at dusk (1830 h) as bats emerge for foraging and monitored at every 30-min intervals throughout the night until dawn when they returned to the roost. The nets were closed for the day until next night, and captured bats were identified to species levels. Results: All the captured bats were mega chiropterans, and Cynopterus brachyotis was the highest captured species, representing 40% of the total capture. Shannon-Weiner index is 2.80, and Simpson index is 0.2. Our result suggests that there is a degree of species dominance with low diversity in Lenggong Livestock Breeding Center. Conclusion: We concluded that fruit bats are indeed, encroaching livestock areas and the species identified could be a potential source of infection to susceptible livestock. Hence, an active surveillance should be embarked on farms that border wildlife sanctuaries. PMID- 29263589 TI - Nutritional enrichment of broiler breast meat through dietary supplementation of Indian ginseng Withania somnifera and synbiotic substances under semi-arid climatic conditions. AB - Aim: The present study was conducted to explore the effect of supplementation of Withania somnifera and synbiotics alone or in combination on the composition of broiler breast meat under heat stress conditions. Materials and Methods: A 42-day feeding trial was conducted on 360 broiler chicks randomly allotted into eight treatment groups with three replicates each under completely randomized design. The T1 group was kept as control whereas T2-T4 were supplemented with 0.5%, 1%, and 1.5% W. somnifera root powder; T5 and T6 were supplemented with 0.025% and 0.050% synbiotic and T7 and T8 were fed on diet containing 0.25% W. somnifera+0.025% synbiotic and 0.50% W. somnifera+0.05% synbiotic, respectively. Three broilers from each replicate were sacrificed at the end of the trial to estimate crude protein (CP), ether extract and ash content of the breast muscle on dry matter basis. Results: Significantly higher CP values and lower ether extract values were observed in 1.5% W. somnifera supplemented group (T4) or in group supplemented with 0.50% W. somnifera and 0.05% synbiotic (T8). The ash content of breast meat was observed non-significant in T1-T4 groups however the inclusion of synbiotics in T5-T8 groups significantly raised the ash contents. Conclusion: The study concluded that inclusion of 0.5% W. somnifera with 0.05% synbiotic substance enriches the total protein content and reduces the total lipids content of broiler breast meat under heat stress conditions. PMID- 29263590 TI - Immunocytochemical study of canine lymphomas and its correlation with exposure to tobacco smoke. AB - Aim: Canine lymphoma is one of the most common canine neoplasms, but little is known regarding the effects of exposure to tobacco smoke on their biologic behavior. As cytology is the most frequent diagnostic method of canine lymphoma, the aims of this study were to perform an immunocytochemical study of canine lymphomas, including subtyping and cell proliferation analysis, and to establish their correlation with tobacco smoke exposure. Materials and Methods: A total of 23 dogs diagnosed with lymphoma were subjected to careful fine-needle biopsies of enlarged lymph nodes. The smears were air-dried, fixed with cold acetone, and immunocytochemically stained using CD3, PAX5, and Ki-67. Owners were requested to complete an epidemiologic questionnaire. Results: According to the updated Kiel classification, 65% were B-cell lymphomas - three low grade (LG) and 12 high grade (HG) and 35% were T-cell -two LG and six HG. Thirteen tumors presented high Ki67 indexes (>40%) (11 HG and 2 LG), two revealed moderate ones (20-40%) (1 HG and 1 LG), and three had low indexes (<=20%) (1 HG and 2 LG). Both a significant positive correlation and a significant linear-by-linear association (p=0.018) were observed between high Ki67 indexes and smoking owners (r=0.753, p=0.002) as well as with the number of smokers in the household (r=0.641, p=0.001). Moreover, the mean percentage of Ki67+ cells from the group of "smoker owners" was statically higher (p=0.011) than that from the "non-smoker owners." Conclusion: The results suggest that cytological diagnosis of canine lymphomas benefits from being complemented with immunocytochemical studies that include subtyping and assessment of proliferative activity, both contributing for the prognosis and therapeutic planning. Furthermore, exposure to tobacco smoke seems to be related to the biological behavior of canine lymphomas. PMID- 29263591 TI - Dermatophilus congolensis infection in sheep and goats in Delta region of Tamil Nadu. AB - Aim: The study was conducted to isolate and identify Dermatophilus congolensis (DC) using conventional and molecular diagnostic techniques in scab materials collected from skin infections of sheep and goats in the Delta region of Tamil Nadu. Materials and Methods: A total of 20 scab samples collected from 18 goats and 2 sheep from Nagapattinam, Thanjavur, and Tiruvarur districts of Tamil Nadu. Smears were made from softened scab materials and stained by either Gram's or Giemsa staining. Isolation was attempted on blood agar plates, and colonies were stained by Gram's staining for morphological identification. Identification was also done by biochemical tests and confirmed by 16S rRNA polymerase chain reaction (PCR), followed by sequencing and phylogenetic analysis of the amplified product. Results: The peculiar laddering arrangement of coccoid forms in stained smears prepared from scab materials revealed the presence of DC. Isolated colonies from scab materials of sheep and goats on bovine blood agar plate were small, hemolytic, rough, adherent, and bright orange-yellow in color, but some colonies were white to cream color. Gram-staining of cultured organisms revealed Gram-positive branching filaments with various disintegration stages of organisms. 16S rRNA PCR yielded 500 bp amplicon specific for DC. Sequence analysis of a sheep DC isolate showed 99-100% sequence homology with other DC isolates available in NCBI database, and phylogenetic tree showed a close cluster with DC isolates of Congo, Nigeria, and Angola of Africa. Genes for virulence factors such as serine protease and alkaline ceramidase could not be detected by PCR in any of the DC strains isolated of this study. Conclusion: The presence of dermatophilosis in Tamil Nadu was established from this study. PMID- 29263592 TI - High prevalence of small Babesia species in canines of Kerala, South India. AB - Aim: Canine babesiosis is an important vector-borne hemoparasitic disease caused by Babesia canis vogeli and Babesia gibsoni, in India. The communication places on record the salient findings of the study directed to detect and characterize the pathogenic B. gibsoni isolates of Kerala state. Materials and Methods: A total of 150 dogs were examined for the presence of hemoparasites by light microscopy as well as by PCR targeting the 18S rRNA gene of B. gibsoni. Hematological parameters were also analysed. Phylogenetic tree was constructed based on Tamura kei model adopting ML method. Results: A sensitive and specific polymerase chain reaction assay was developed with newly designed primer pair BAGI-F/BAGI-R for the amplification of 488 bp fragment of 18S rRNA gene of B. gibsoni. Out of the 150 dogs examined, molecular evidence of B. gibsoni was recorded in 47.3% animals, while light microscopy detected the infection in 26.67% cases. The phylogenetic analyses revealed that B. gibsoni, Kerala, isolate was closest and occurred together with Bareilly isolate. Anemia and thrombocytopenia were the significant hematological alterations in chronic B. gibsoni infection. Conclusion: A high prevalence of natural infection of B. gibsoni was detected among the study population. The affected animals showed anaemia and thrombocytopenia. Phylogenetic analysis of this pathogenic isolate from south India revealed the closest similarity with Bareilly isolates. PMID- 29263593 TI - The phylogenetics of Leucocytozoon caulleryi infecting broiler chickens in endemic areas in Indonesia. AB - Aim: The objective of this research was to determine the species and strains of Leucocytozoon caulleryi and study the phylogenetics of L. caulleryi of broiler chickens in endemic areas in Indonesia. Materials and Methods: Blood samples were collected from broiler chickens originated from endemic area in Indonesia, i.e., Pasuruan, Lamongan, Blitar, Lumajang, Boyolali, Purwokerto, and Banjarmasin in 2017. Collected blood was used for microscopic examination, sequencing using BLAST method to identify the nucleotide structure of cytochrome b (cyt b) gene that determines the species, and the phylogenetics analysis of L. caulleryi that infected broiler chickens in endemic areas in Indonesia, using Mega 5 software. Results: The results showed that Plasmodium sp. and L. caulleryi were infected broiler chickens in endemic areas in Indonesia. L. caulleryi in one area had very close phylogenetic relations with those in other areas. The genetic distance between L. caulleryi taxa from various endemic areas is very close (<5%). Conclusion: There is a very close phylogenetics among strains of L. caulleryi that infected broiler chickens in various endemic areas in Indonesia. PMID- 29263594 TI - Production of aldosterone in cardiac tissues of healthy dogs and with dilated myocardiopathy. AB - Background and Aim: Aldosterone is a hormone, belonging to the group of mineralocorticoids, mainly synthesized in the adrenal cortex, basically its function is to regulate blood pressure and sodium-potassium levels in the body; high levels of this hormone have harmful effects in the organism and mainly in the heart in chronic form. Dilated cardiomyopathy is a progressive disease of heart muscle that is characterized by ventricular chamber enlargement and contractile dysfunction, is one of the most common cardiac conditions in dogs of medium and large breeds. The aim of the study was to determine and quantify if a dog's cardiac cells possess the capacity to synthesize aldosterone, as well as, the differences that appear between a healthy heart and with dilated myocardiopathy (DMC). Materials and Methods: Cardiac tissues were used from six healthy dogs and six with DMC. Enzyme-linked immunosorbent assay was performed to determine if the dog's heart cells synthesized this mineralocorticoid in a similar way to rat, rabbit, and human tissues, as well as quantitative differences between the healthy heart and DMC. Results: In healthy dog hearts, aldosterone values were 62.5 pG for both the atria and right ventricle and 125 pG for the left ventricle. As for dog hearts' with DMC, results were 125 pG in all four cavities. Conclusion: Both the healthy and DMC dog hearts produce aldosterone in all four cavities, observing that production increases in the atria and right ventricle of those hearts with DMC, as an intrinsic mechanism of cardiac remodeling. PMID- 29263595 TI - Immunoglobulin subclass in experimental murine Toxocara cati infection. AB - Aim: The aim of this study was to detect specific immunoglobulin (Ig) that could be used to determine monoclonal antibody in conjugate-making an effort for the indirect enzyme-linked immunosorbent assay (ELISA) diagnostic kit of toxocariasis in human. Materials and Methods: The study was conducted to assess the Ig profile, based on ELISA-isotyping, in mice infected with second stage larvae eggs of Toxocara cati. The optical density values of anti-T. cati mice serum IgG subclasses were analyzed by applying ANOVA factorial. Results: The specific IgG subclass in mice infected with T. cati mice was found to be IgG2beta. Conclusion: Subclass of IgG, especially IgG2beta, can provide leads about the use of the monoclonal antibody in conjugate making an effort for the indirect ELISA diagnostic kit. PMID- 29263596 TI - Effects of hyperbaric therapy on liver morphofunctional of rabbits (Oryctolagus cuniculus) after hind limb ischemia-reperfusion injury. AB - Aim: The objective of this research was to study and to prove the effectiveness of hyperbaric oxygen therapy (HBOT) starting time on liver morphofunctional changes after ischemia-reperfusion in the hind limb of rabbits. Materials and Methods: This research used a complete randomized design with 4 groups and 6 repetitions on each. After 6 h artery femoral is ligation, reperfusion was performed for 100 min (G1), HBOT for 90 min after 10 min reperfusion (G2), 10 min reperfusion (G3), and HBOT 90 min after 60 min reperfusion (G4). Then, all of the rabbits were sacrificed. The liver and blood were taken for histopathological changes examination as well as for measuring the level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The statistical test using Kruskal-Wallis and Mann-Whitney showed that the score of degeneration, necrosis, and portal inflammation in groups without HBOT (G1 and G3) were not significantly different, as well as in group with HBOT (G2 and G4) (p>0.05). However, the scores of histopathological changes in G1 and G3 were significantly different from those in G2 and G4 (p<0.05). The levels of AST and ALT in the groups without hyperbaric therapy (G1 and G3) were not significantly different from those in the groups treated with hyperbaric therapy (G2 and G4) (p>0.05). Result: Hind limb ischemia injury reperfusion can trigger damage for liver morphology, but not lead to liver dysfunction. Reperfusion can trigger increased activity of neutrophils, while neutrophil infiltration in the organ will lead to dysfunction. HBOT can inhibit the activity of neutrophils and the dysfunction of organs caused by ischemic reperfusion. Conclusion: HBOT for 90 min, both 10 and 60 min after the reperfusion, can protect hepatocytes from damage. PMID- 29263597 TI - Determination of serum adenosine deaminase and xanthine oxidase activity in Kangal dogs with maternal cannibalism. AB - Aim: Kangal dogs, known as guard dogs in many countries of the world, have been found to eat their own puppies during their first 24 h following birth, which is called as maternal cannibalism. Adenosine deaminase (ADA) and xanthine oxidase (XO) are important enzymes for purine metabolism. In this study, the aim is to evaluate ADA and XO activities in Kangal dogs with maternal cannibalism. Materials and Methods: The material of the study consists of the blood sera of Kangal dog breed with and without maternal cannibalism in the breeders around Sivas city and its districts. ADA and XO activities in blood serum of these animals were investigated by spectrophotometric method. Results: ADA activities in Kangal dogs with maternal cannibalism were increased to the control group without maternal cannibalism (p<0.01). Conclusion: Postnatal measurement of ADA activity in dogs may be useful in assessing maternal cannibalism. PMID- 29263598 TI - Reducing zoonotic and internal parasite burdens in pigs using a pig confinement system. AB - Aim: This study was designed to validate the effectiveness of the pig confinement system (PCS) in reducing the prevalence of zoonotic and internal parasite burdens in pigs. Materials and Methods: Ten PCS households were selected together with 10 households practising traditional scavenging systems. Five pigs were monitored per household every 3 months for 15 months and blood and feces collected. Pigs received a single dose of oxfendazole at 30 mg/kg at baseline. Qualitative fecal examinations for intestinal parasite stages were performed, and serum was tested for antibodies to cysticercus of Taenia solium, Trichinella spp., and Toxoplasma gondii. Results: Based on fecal examination, the prevalence of pigs positive for parasite eggs was reduced in PCS pigs over consecutive samplings (Ascaris suum [14.3% to 0%], Trichuris suis [46.9% to 8.3%], Strongyle-type eggs [81.6% to 8.3%], Physocephalus spp. [6.1% to 0%], and Metastrongylus apri [20.8% to 0%]) compared with increases in the number of pigs positive for parasite eggs in non PCS pigs (T. suis [20-61.5%], Strongyle-type [60.4-80.8%], Physocephalus spp. [8.3-15.4%], and M. apri [20.8-34.6%]) and little change in pigs positive for A. suum (18.8-19.2%). While the prevalence of pigs with antibodies against to cysticerci of T. solium reduced in PCS pigs from 18% to 14%, the prevalence in non-PCS pigs increased from 42% to 52%. Antibodies to Trichinella were not detected, but the prevalence of T. gondii antibodies increased from 6% to 10% in PCS pigs and from 7% to 24% in non-PCS pigs. Conclusion: These data demonstrate the potential of a PCS to reduce the prevalence of pigs infected with zoonotic and internal parasites and thus the risk to human and pig health. PMID- 29263599 TI - The clinical impact of antimicrobial resistance genomics in competition with she camels recurrent mastitis metabolomics due to heterogeneous Bacilluslicheniformis field isolates. AB - Background and Aim: Recently, cases of mastitis refractory to treatment have been reported frequently. There are limited routine laboratory investigations on Camelidae infections. Mastitis has been estimated to affect more than 25% of lactating she-camel with up to 70% milk loss. The details of Bacillus spp. pathogenesis in mastitis are not yet fully described. The present study is the first detailed phenotypic and genotypic characterization of Bacillus licheniformis isolates from recurrent mastitic she-camels with sepsis in Egypt. Materials and Methods: The udders of 100 she-camels were investigated, samples collected from smallholders' farmers in 10 localities within three governorates in Egypt: Marsa Matrouh, Giza, and Sharkia governorates. The pathogens ascend from udder inducing abortion at different trimesters of pregnancy. Polymerase chain reactions-mediated proofs of identity were applied for diagnostic and taxonomic purposes, where the 16S rRNA gene sequence and the beta subunit of RNA polymerase encoding gene rpoB are the molecular targets. Results: The genetic elements classified the subspecies to B. licheniformis 61.4%, in addition to, Corynebacterium bovis 29.8%. The somatic cell count (<=1*107 cells/ml) and California mastitis test reactivity (+3 or +4) of milk clinically classified the she-camels population (n=100) under investigation into 50, 20, and 30 as healthy, subclinical, and clinical mastitic she-camels, respectively. During bacterial isolation, 80 species were noticed, of which 71.25% (57/80) and 28.75% (23/80) were Gram-positive and negative, respectively, in two clinical forms: Single (40%, n=16/40) and mixed (60%, n=34/40) bacterial infections. In vitro, 100% sensitivity for gentamycin (10 ug) and ofloxacin (5 ug) was noted; however, it was reduced to 50%. Moreover, during in vivo treatments, cloxacillin (5 ug) upraised as the most effective alternative with 90% sensitivity. Conclusion: Neither recurrent mastitis nor Bacillus species are thoroughly investigated with regard to reproduction performance in Egypt and the usefulness of these strains as antimastitis probiotics. Both persistent bacteremia and dormant endospores were formed but unaffected by standard schemes of antimicrobials injections which proposed the risk of pathogenic bacilli contaminating row milk from apparently healthy she-camel. The discrepancies between treatment results were induced by the resistance that started to develop by the organisms due to frequent and/or faulty use of applied antibiotics. PMID- 29263600 TI - Advances in genome editing for improved animal breeding: A review. AB - Since centuries, the traits for production and disease resistance are being targeted while improving the genetic merit of domestic animals, using conventional breeding programs such as inbreeding, outbreeding, or introduction of marker-assisted selection. The arrival of new scientific concepts, such as cloning and genome engineering, has added a new and promising research dimension to the existing animal breeding programs. Development of genome editing technologies such as transcription activator-like effector nuclease, zinc finger nuclease, and clustered regularly interspaced short palindromic repeats systems begun a fresh era of genome editing, through which any change in the genome, including specific DNA sequence or indels, can be made with unprecedented precision and specificity. Furthermore, it offers an opportunity of intensification in the frequency of desirable alleles in an animal population through gene-edited individuals more rapidly than conventional breeding. The specific research is evolving swiftly with a focus on improvement of economically important animal species or their traits all of which form an important subject of this review. It also discusses the hurdles to commercialization of these techniques despite several patent applications owing to the ambiguous legal status of genome-editing methods on account of their disputed classification. Nonetheless, barring ethical concerns gene-editing entailing economically important genes offers a tremendous potential for breeding animals with desirable traits. PMID- 29263602 TI - Clinical, pathological, and molecular investigation of Mycoplasma pulmonis induced murine respiratory mycoplasmosis in a rat (Rattus norvegicus) colony. AB - Aim: Mycoplasma pulmonis (MP) remains potentially important rodent pathogen causing murine respiratory mycoplasmosis (MRM) which may go undiagnosed due to its asymptomatic nature. In the present study, we carried out clinical, pathological, and molecular investigations of MP-induced MRM in a rat colony. Materials and Methods: Two female Wistar rats were observed to be diseased in animal facility of NISER, Bhubaneswar, and were kept in isolation for further investigation. Both the animals were found to be positive for MP after serological and molecular tests. Thereafter, whole rat colony comprising of 36 animals was segregated based on clinical symptoms and further sampled for histopathological, serological, and molecular investigations. Tracheal washing and infected lung tissue were collected during necropsy examination for DNA extraction. Molecular diagnosis was done by polymerase chain reaction (PCR) assay using species-specific primers. Result: Classical symptoms of MP-associated respiratory tract infection were observed in only 2 of 36 infected animals, and most of the animals were found asymptomatic to the disease; however, all the animals were found to be carrier after necropsy and PCR assay. Gross and histopathological finding suggested severe congestion of the lungs along with suppurative and necrotizing pneumonia. The disease is confirmed by molecular diagnosis using species-specific primers in PCR assay. Conclusion: MRM may go undiagnosed due to asymptomatic nature. Detailed study of clinical symptoms, pathology, serology, and PCR-based molecular approach may aid in health monitoring and detection of MRM in a rodent colony reared for experimental purpose. PMID- 29263601 TI - Metabolic and immunological changes in transition dairy cows: A review. AB - Smooth transition from pregnancy to lactation is important for high productive and reproductive performance during later postpartum period in dairy animals. On the other hand, the poor transition often leads to huge economic loss to dairy farmers due to compromised production and reproduction. Therefore, understanding the causes and consequence of metabolic changes during the transition period is very important for postpartum health management. In this review, metabolic changes with reference to negative energy balance in transition cow and its effect on health and reproduction during the later postpartum period in dairy animals are discussed besides the role of metabolic inflammation in postpartum performance in dairy animals. PMID- 29263603 TI - Application of loop-mediated isothermal amplification assay in the detection of herpesvirus of turkey (FC 126 strain) from chicken samples in Nigeria. AB - Aim: This study was designed to optimize and apply the use of loop-mediated isothermal amplification (LAMP) as an alternative to conventional polymerase chain reaction (PCR) for the detection of herpesvirus of turkeys (HVT) (FC 126 strain) in vaccinated and non-vaccinated poultry in Nigeria. Materials and Methods: HVT positive control (vaccine) was used for optimization of LAMP using six primers that target the HVT070 gene sequence of the virus. These primers can differentiate HVT, a Marek's disease virus (MDV) serotype 3 from MDV serotypes 1 and 2. Samples were collected from clinical cases of Marek's disease (MD) in chickens, processed and subjected to LAMP and PCR. Results: LAMP assay for HVT was optimized. HVT was detected in 60% (3/5) and 100% (5/5) of the samples analyzed by PCR and LAMP, respectively. HVT was detected in the feathers, liver, skin, and spleen with average DNA purity of 3.05-4.52 MUg DNA/mg (A260/A280) using LAMP. Conventional PCR detected HVT in two vaccinated and one unvaccinated chicken samples, while LAMP detected HVT in two vaccinated and three unvaccinated corresponding chicken samples. However, LAMP was a faster and simpler technique to carry out than PCR. Conclusion: LAMP assay for the detection of HVT was optimized. LAMP and PCR detected HVT in clinical samples collected. LAMP assay can be a very good alternative to PCR for detection of HVT and other viruses. This is the first report of the use of LAMP for the detection of viruses of veterinary importance in Nigeria. LAMP should be optimized as a diagnostic and research tool for investigation of poultry diseases such as MD in Nigeria. PMID- 29263604 TI - Molecular analysis of genome segment-3 of bluetongue virus serotype 12 isolates from Haryana. AB - Aim: The present study was designed to characterize the genome segment 3 (Seg-3) of bluetongue virus (BTV) serotype 12 isolates from different outbreaks of Bluetongue disease in Haryana, India. Materials and Methods: Blood and swab samples were collected from goat and sheep suspected to be suffering of BT from different outbreaks from Gurugram, Sirsa, Hisar, and Karnal districts of Haryana. The samples were grown in insect and mammalian cell lines. After preliminary identification, serotyping was done using BTV type-specific quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays. Sequencing was performed using terminal and walking internal primers specific for Seg-3 on ABI Capillary Sequencer 3130 using a "BigDye cycle sequencing kit." The obtained sequence data were analyzed with various bioinformatic tools. Results: Real-time PCR results confirmed the samples to be positive for BTV-12. The Seg-3 of Indian isolates was most closely related to that of a south Indian isolate of BTV-12 from Andhra Pradesh (KC662614) with 97% nucleotide identity. Conclusions: The study confirmed the circulation of BTV-12 in Haryana, India. The variations shown in genome Seg-3 of BTV-12 isolates may have some significance and need to be further explored. PMID- 29263605 TI - Plastination of macroparasites: An eco-friendly method of long-term preservation. AB - Aim: Preservation of macroparasites by infiltrating the polymer in the tissues can defy the inherited shortcoming of classical wet preservation method. Materials and Methods: Preservation was done by infiltrating the melamine alone or with xylene (MX)/chloroform (MC)/turpentine oil (MT) in 1:1 and hardener (MH) in 9:1 ratio in the tissues of the gross specimen of the animal parasites. Results: The plastinated models withstand the process of microbial decomposition, and remain intact in the environmental conditions. The polymer mixture resists the entry of the water molecule, and model dried just after taking out it from the water tank. Overall, the plastinated parasites were dry, non-sticky, glossy, odorless, chemical free, and harmless, to some extent flexible, with detectable morphological structure, and retain their natural form but lost their natural color. Full marks were assigned to the degree of dryness, non-stickiness, and odorlessness to the model plastinated in different solutions on a five-point scale. For flexibility, the score was 1.2, 2.2, and 2.4 for the plastinated model in melamine/MH, MX/MC, and MT solutions, respectively. The average score of glossiness was 4.6 and 5 for the specimen plastinated in melamine/MH and MX/MC/MT solutions, respectively. The degree of dryness, glossiness, stickiness, and flexibility varies non-significantly, with the polymer mixtures used. Conclusion: The prepared model can be used to educate the students/general mass population. PMID- 29263606 TI - Pathology and polymerase chain reaction detection of ovine progressive pneumonia (maedi) cases in slaughtered sheep in India. AB - Aim: The small ruminant lentiviruses are known to cause maedi-visna (MV) and caprine arthritis - encephalitis in sheep and goats, typically affecting joints, udder, lungs, and the central nervous system. The diagnosis usually involves serology, clinical signs, immunohistochemistry, and polymerase chain reaction (PCR). In the present study, the histopathologically positive pneumonia cases of MV were confirmed by PCR in lung tissue probably for the first time in India. Materials and Methods: A total of 888 lungs of adult sheep, aged between 2 and 5 years, were screened during slaughter, of which 121 were found to have pneumonic lesions. The tissues from each pneumonic lung including associated lymph nodes were collected in 10% neutral buffered formalin for histopathology. The frozen tissues of the same were also collected and stored at -20 degrees C for PCR confirmation. Results: Three of 121 cases of pneumonic lungs of sheep revealed gross and histopathological lesions suggestive of maedi or ovine progressive pneumonia infection. These 3 cases were further confirmed by PCR technique that amplified 291-base pair DNA in the long terminal repeat sequence of MV provirus. Conclusion: This study suggests the low occurrence of MV virus (MVV) infection in India in naturally affected sheep based on pathomorphological lesions and using the molecular tool of PCR detection of the virus in tissues. Further, a combination of pathomorphology or/and PCR testing might be optimal for detecting the animals infected with MVV. PMID- 29263607 TI - Oral mark in the application of an individual identification: From ashes to truth. AB - Forensic odontology is the branch of dentistry which deals with the proper handling, examination, evaluation and presentation of dental findings in the interest of justice. After major disasters and perimortem assaults such as earthquakes, fires, severe head and neck trauma or gross decomposition, accurate and early identification of dead and injured becomes important. In the absence of other records in such cases, identification is based on restorations, missing teeth and prosthetic devices such as partial and complete removable/fixed prosthesis or implant retained devices. This brings out the major role of prosthodontics to investigate the identity of suspects in the criminal cases as well as the deceased human beings in traumatic injuries or in disasters. Denture identification systems are being used as means of postmortem identification of edentulous persons which has evolved from the inclusion of some form of printed label in a denture to more high-tech methods. The provision of implant retained complete lower denture, antemortem, and postmortem radiographs of edentulous persons and correlation of bite marks using special impression techniques provide another potential source of evidence for human identification. Hence, this literature review throws some light on the role played by prosthodontist in forensic odontology. PMID- 29263608 TI - Significance of mandibular canine index in sexual dimorphism and aid in personal identification in forensic odontology. AB - Background: Forensic odontology is basically the science dealing with establishing identity by teeth and has played an important, often crucial, role in the identification of victims of mass disasters. Among all teeth, the mandibular canines are found to exhibit greatest sexual dimorphism. Hence, this study was undertaken to evaluate the effectiveness of mandibular canine index (MCI) in the determination of sex. Materials and Methods: The study was conducted on 62 subjects (31 males, 31 females). Mesiodistal diameter of mandibular canines was measured with the help of digital Vernier calipers. Intercanine distance was measured with the help of a divider. The standard MCI value is used as a cut off point to differentiate males from females. Statistical analysis was done using t test. Results: The width of mandibular canine was higher in males than in females, which was statistically significant. The left canine is found to exhibit greater sexual dimorphism, i.e., 7.62% as compared with right canine, i.e., 6.85%. The calculated standard MCI for both male and female was 0.247. With these calculations, the overall percentage of sex determination was 79.03%. Conclusion: The ability to determine gender using Standard MCI was estimated to be 73.33% in males and 80% in females. It was concluded that with standard MCI, it was possible to detect sex for forensic purposes. PMID- 29263609 TI - Orbital aperture morphometry in Indian population: A digital radiographic study. AB - Background: Morphological variations of the orbital aperture measurements may be used in forensic medicine as a parameter for determining sexual and ethnic identity of an individual. Aim and Objective: The aim and objective of this study was to evaluate the orbital aperture dimensions in Indian individuals and verify their relationship with gender. Materials and Methods: A retrospective study was conducted using digital posteroanterior view radiographs of 50 males and 51 females, which were taken using NEWTOM GIANO-CEFLA SC machine (81 kVp, 10 mA, and 6.6 s). The orbital aperture measurements were carried out using NEWTOM software NNT version 5.5. The maximum width and height of the orbits and the inter-orbital distance were measured. The obtained data were subjected to t-test and discriminant function analysis. Results: In the t-test, significant differences in orbital width and inter-orbital distance were obtained between the genders. On subjecting the data to discriminant function analysis, result was obtained with 86.1% accuracy rate in gender determination. Conclusion: If the discriminant score is >1.0365, the skull is likely to be of a male, and if it is <1.0365, it is likely to be of a female. Therefore, orbital aperture measurements can be used for gender determination in human identification. PMID- 29263610 TI - The relationship of forensic odontology with various dental specialties in the articles published in a National and an International Forensic Odontology Journal: A 5-year content analysis. AB - Aims: The aim of this study is to assess the quantum of articles published by various dental specialties in a National and an International Forensic Odontology Journal from January 1, 2010, to December 31, 2014. Settings and Design: The present study is a 5-year retrospective content analysis study. Subjects and Methods: Data were collected from two forensic odontology journals (Journal of Forensic Odonto Stomatology [JOFS] and Journal of Forensic Dental Sciences [JFDS]) which are subscribed by institutional library. The article contents were scrutinized by one investigator and categorized into nine individual dental specialties based on the new working classification proposed for forensic odontology. Statistical Analysis Used: The quantum of articles published by various dental specialties and the various focus areas in each specialty were assessed using Chi-square test. Results: Among all the published articles, a maximum number of articles were related to the Department of Oral Medicine and Radiology (32.6%) in JFDS with Cheiloscopy (46.7%) being more focused area and to the Department of Prosthodontics (25.7%) in JFOS with Bite mark analysis (66.7%) being more focused area. Conclusions: There was a scarcity of information about the relationship of forensic odontology with various dental specialties in the articles published in JFDS and JFOS. The editorial board of journals should expand and elaborate their scope of journals to various focus areas of forensic odontology. This will encourage the researchers to explore in the different focus areas which are most neglected as of now. PMID- 29263611 TI - Correlation of lip patterns, gender, and blood group in North Kerala population: A study of over 800 individuals. AB - Context: With the ever-changing field of criminal justice, the constant revision of criteria for acceptable evidence by the judiciary poses new challenges in forensic investigation. The applicability of cheiloscopy in individual identification is an area of extensive research in recent years. Objectives: The aim of the present study was to determine the distribution of different lip print patterns in North Kerala population, to assess any sexual dimorphism in lip patterns, and to correlate lip print patterns with ABO and Rh blood groups. Materials and Methods: A total of 858 students, 471 males and 387 females, from different colleges in the district of Kozhikode in North Kerala were included in the study. Lip prints were obtained using lipstick and cello tape and transferred onto white papers. Blood group of the participants was noted. Results: The most predominant pattern observed was Type I (48.3%), followed by Type II, Type III, Type IV, Type I', and Type V. We also observed that the lower lip exhibited an overwhelming predominance of Type I pattern in the North Kerala population while the upper lip showed a more even distribution. Gender-wise difference was observed with Type II being the most common in males and Type IV being the predominant pattern in females. No correlation was obtained between the blood groups and lip patterns. Conclusion: The potential usefulness of cheiloscopy in forensic medicine still remains largely untapped and under-recognized. Similar studies in different populations with large sample sizes will allow a more definite picture of lip print patterns to emerge. PMID- 29263612 TI - Maintenance of antemortem dental records in private dental clinics: Knowledge, attitude, and practice among the practitioners of Mangalore and surrounding areas. AB - Introduction: With time, an increase in the number of crimes, mass disasters, and wars, has led to the identification of the deceased or assailant critical. In such circumstances, antemortem dental records play a crucial role. Materials and Methods: A cross-sectional survey involved 95 dentists practicing in and around Mangalore. The structured questionnaire comprised 24 questions regarding the practice of maintenance of dental records. The questionnaire was given either personally or sent by post. The data obtained was subjected to descriptive analysis. Results: With 87% of the dentists maintaining records, only 31% of them recorded all the details required to be present in a dental record. Of these 18% of them maintained the records for >5 years. Conclusion: The results suggest that most of the practicing dentists in this area either do not maintain or maintain inadequate records, which is alarming. Thus, there is a need to set protocols to increase the awareness for maintaining good dental records. PMID- 29263613 TI - Age estimation of living Indian individuals based on aspartic acid racemization from tooth biopsy specimen. AB - Background: Age estimation in living individuals is imperative to amicably settle civil and criminal disputes. A biochemical method based on amino acid racemization was evaluated for age estimation of living Indian individuals. Design: Caries-free maxillary/mandibular premolar teeth (n = 90) were collected from participants with age proof documents and divided into predefined nine age groups. Materials and Methods: Dentine biopsy from the labial aspect of the tooth crown was taken with an indigenously developed microtrephine. The samples were processed and subjected to gas chromatography. Dextrorotatory:levorotatory ratios were calculated, and a regression equation was formulated. Results: Across all age groups, an error of 0 +/- 4 years between protein racemization age and chronological age was observed. Conclusion: Aspartic acid racemization from dentine biopsy samples could be a viable and accurate technique for age estimation of living individuals who have attained a state of skeletal maturity. PMID- 29263614 TI - The magnification in the lower third and second molar region in the digital panoramic radiographs. AB - Background: The aim of this study was to determine the accuracy of linear measurements of the lower third and second molar crowns in the digital panoramic radiographs and to compare them with plaster models as the calibration standard. Materials and Methods: The digital panoramic radiographs and plaster models of the orthodontic patients were used in the study. Standardized metal calibration gauges (MCGs) were bonded to the buccal surface of the lower molars bilaterally. Measurements in the panoramic radiographs were done using Dolphin Imaging 11.8 Premium program. Results: Forty-one panoramic radiographs and diagnostic plaster models of the orthodontic patients (mean age 18.45 +/- 2.35) were analyzed. Eighty-two lower third molars, 82 second molars, and 82 first molars were evaluated. The magnification coefficients (MCC) calculated according to the plaster models ranged from 1.07 to 1.08. The magnification coefficients calculated according to the bonded MCG were about 1.04. The differences between the teeth groups and right-left sides were not statistically significant (P > 0.05). Spearman correlation showed a positive medium correlation between the magnification using the calibration with plaster models and metal gauges (P < 0.05). Conclusions: The magnification in the lower first, second, and third molars regions showed almost the same values. The calculation of magnification coefficient using bonded metal calipers was more accurate than calculation according to the plaster models, but the differences were not statistically significant. The use of the plaster models for calibration of the magnification coefficient in the good-positioned lower molars' region might be used as an alternative to the bonded MCGs. PMID- 29263615 TI - Assessment of age of majority by measurement of open apices of the third molars using Cameriere's third molar maturity index. AB - Aims and Objectives: Evaluation of biological age of a living subject around the legal cutoff age for adulthood has become a grave concern for forensic experts in India, mainly due to the consequences of criminal obligations in judicial proceedings. Thus, this study was planned to examine the open apices of third molars in discriminating between individuals who are aged 18 years or older and who are not 18 years or older and to assign a cutoff for estimation of the age of 18 years. Materials and Methods: Orthopantomographs of 1062 individuals (14 and 23 years) were assessed, to verify Cameriere's third molar maturity index (I3M). The apical ends of the roots of the left mandibular third molar were analyzed. If the apical ends of the roots are completely closed, then I3Mis zero; otherwise, it is calculated as the sum of the distances between the inner sides of the two open apices divided by the tooth length. Results and Conclusion: The sensitivity of the test for 0.08 value was 74.7% for males and 66% for females. Specificity was 83.6% for males and 79.6% for females. The probability that an Indian individual with an I3M<0.08 in 18 years or older is 78% for males and 70.3% for females. I3Mis efficacious to determine age in Indian population. PMID- 29263617 TI - The Indian Board of Forensic Odontology fellowship: A personal experience. PMID- 29263616 TI - An unusual case of incomplete tooth germ transposition: A rare case report. AB - Transposition is an exchange of positions of two adjacent teeth. This is a condition with an incidence of 0.33%. Etiology is multifactorial; genetic influence is the most supported cause. Dental transposition is a multifactorial condition. While transposition of tooth germ is the rarest condition, this helps in identification of a person in mass casualties due to any disaster, or crimes, fraud. The present case is an incidence of incomplete transposition of right mandibular permanent second molar tooth germ, causing resorption of the roots of permanent first molar with possible loss of that tooth, which is a unique presentation. PMID- 29263618 TI - Morphometric significance of maxillary arch in sexual dimorphism in North Indian population. AB - Background: Tooth is the hardest and chemically (except mineral contents) the most stable structure in the body, which makes teeth as the first-rate material for genetic and forensic investigations. Sex determination of skeletal remains forms an important part of archaeological and medicolegal examinations. Hence, the aim of the present study was to analyse the morphometric and dimensional variation between male and female in north Indian population using maxillary arch parameters. Materials and Methods: Fifty male and fifty female patients of age group 18-35 years were randomly selected after taking detail history. All maxillary impressions were made with alginate and poured in type III dental stone. These casts were measured for maxillary inter-canine width, maxillary first inter-premolar width, anteroposterior palatal width and palatal depth using a digital vernier caliper and findings were correlated with sexual dimorphism. Results: The maxillary inter-canine width, maxillary first inter-premolar width, and palatal depth showed a significant difference with P < 0.05 between the means of two populations. Anteroposterior palatal width showed the comparatively less significant difference between two populations. Conclusion: Among north Indian population, maxillary inter-canine width, maxillary first inter-premolar width, and palatal depth can be used for sex assessment. The anteroposterior palatal width parameter is comparatively less significant in sex determination. PMID- 29263619 TI - Role of forensic dentistry for dental practitioners: A comprehensive study. AB - Objectives: The aim of present study is to analyze assess the awareness about forensic odontology among dental practitioners in center part of India. Subjects and Methods: A cross-sectional study was conducted in a sample of 100 dental practitioners in Bhilai-Durg and data was collected by means of a questionnaire. Results: About 30% of dental practitioners not maintain dental records in their clinic, 70% maintained dental records. Nearly, 60% dental practitioners use the appropriate method for diagnosis, while rest are not. Sixty-five percent dental practitioners know the accurate and sensitive way of identify individuals. Thirty percent dental practitioner did not know the significance of bite-mark patterns of the teeth, about 75% dental practitioners did not aware that they could testify as an expert witness in the court of law. Only 15% dental practitioners have formal training in collecting, evaluating, and presenting dental evidence. Seventy-five percent dental practitioners not confident to deal with forensic cases. Conclusions: Our study revealed inadequate knowledge, lack of awareness about forensic odontology, among dental practitioners in Chhattisgarh. PMID- 29263620 TI - Mandibular canine: A tool for sex identification in forensic odontology. AB - Aim: The aim of this study was to investigate the accuracy of mandibular canine index (MCI) and mandibular mesiodistal odontometrics in sex identification in the age group of 17-25 years in central Indian population. Materials and Methods: The study sample comprised total 300 individuals (150 males and 150 females) of an age group ranging from 17 to 25 years of central Indian population. The maximum mesiodistal diameter of mandibular canines, the linear distance between the tips of mandibular canines, was measured using digital vernier caliper on the study models. Results: Overall sex could be predicted accurately in 79.66% (81.33% males and 78% females) of the population by MCI. Whereas, considering the mandibular canine width for sex identification, the overall accuracy was 75% for the right mandibular canine and 73% for the left mandibular canine observed. Conclusion: Sexual dimorphism of canine is population specific, and among the Indian population, MCI and mesiodistal dimension of mandibular canine can aid in sex determination. PMID- 29263621 TI - Comparative assessment of maxillary canine index and maxillary first molar dimensions for sex determination in forensic odontology. AB - Background: Sexual identification of immature skeletal remains is still a difficult problem to solve in forensic anthropology. In such situations, the odontometric features of the teeth can be of immense help. Teeth, being the hardest and chemically the most stable tissue in the body, are an excellent material in living and nonliving populations for anthropological, genetic, odontologic, and forensic investigations. Using tooth size standards, whenever it is possible to predict the sex, identification is made easier because then only missing persons of one sex need to be considered. Aim: To determine sex from the odontometric data using maxillary canine index and maxillary first molar dimensions and to determine which index gives higher accuracy rate for sex determination using only maxillary cast. Materials and Methods: In a sample size of 200 population (100 male and 100 female), alginate impression was taken of maxillary arch and poured with dental stone. Using Vernier caliper, the dimension of maxillary first molar (buccolingual [BL] and mesiodistal [MD]), canine (MD), and intercanine distance was measured on the cast. The obtained data were analyzed using discriminant statistical analysis. Result and Conclusion: This study concludes that BL dimension of maxillary first molar is a more reliable indicator for gender determination than other molar and canine dimensions in maxilla. PMID- 29263622 TI - A Review of Botany and Pharmacological Effect and Chemical Composition of Echinophora Species Growing in Iran. AB - : This review was conducted to investigate the botany, phytochemistry, and pharmacological properties of Echinophora species. The information of this review was obtained by searching for keywords Apiaceae, Echinophora, pharmacological effects, and traditional and modern medicine in scientific articles and books published in search engines Scopus, Google Scholar, Science Direct, PubMed, and Web of Science. The traditional uses of Echinophora and the existence of valuable phytochemicals in the plant have led to isolation and drug discovery of natural medicines such as antibiotic, analgesics, and anticancer drugs, and the beneficial effects of these plants can widely be used in healthcare. SUMMARY: Echinophora species are medicinal and aromatic plants that are belong to Apiaceae family. This genus have four species in Iran. The botany, geographical distribution, traditional and pharmacological effects of Echinophora genus were described. Also, the major chemical constituents of the essential oil and extract of different species of Echinophora that have been reported. Overall, the existence of valuable phytochemicals purpose Echinophora species as novel candidate to isolation and drug discovery of natural medicines such as antibiotic, analgesics, and anticancer drugs. PMID- 29263623 TI - Identification of the Adulterated Asini Corii Colla with Cytochrome c Oxidase Subunit I Gene-based Polymerase Chain Reaction. AB - Background: Asini Corii Colla (ACC) (namely donkey hide gelatin, E'jiao in Chinese) was one of the most valuable tonic traditional Chinese medicines which is an infallible remedy to promote hematopoiesis. It should be produced by fresh or dried donkey hide according to Chinese Pharmacopeia (2015 edition) with a long time decoction, while as donkey and horse (or mule) all belong to equids so their hides or their hide gelatins are share much in common, that cause the difficult in distinguishing raw materials donkey hide from horse/mule hide for manufacturer, and the challenge in the quality evaluation of ACC for regulatory authority to identify the adulterated with horse hide. Objective: To establish an effective quality evaluation methods for ACC focused on the qualitative-based identification of the raw material's authenticity, mainly to identify the species origin of the gelatins. Materials and Methods: DNA extracted from (1) Raw materials (hides of donkey, horse, mule, bovine and pig); (2) Five hide-glues (bovine, pig, donkey, horse and mule hide-glue); (3) 11 batches of ACC commercial products made by different manufactures from local drug stores. Polymerase chain reaction (PCR) method with newly designed horse-specific primers I and primer pair II. Results: Use the primer pair I, a 234 bp target product could be amplified sensitively from the DNA sample of horse/mule adulterated commercial ACC products, though the DNA in commercial products is severely degraded. A 219 bp product could be amplified specifically from the DNA sample of horse/mule hide, while the results were all negative for the DNA templates of donkey hide, its gelatin and ACC products without adulteration. Conclusion: The developed PCR method based on primer I and II provide an effective approach to identify the species origin of highly processed product ACC (primer pair I) as well as to distinguish the raw material donkey hide (primer pair II), which might enlighten a new strategy to the Quality Evaluation of ACC. SUMMARY: Though the quality of commercial Asini Corii Colla (ACC) products varies greatly and produce with nondonkey hide was one the most common adulteration, the effective method to constrain such adulteration remains to be establishedThe gelatins made by donkey, horse, bovine, pig, mule shares much in common with each other, not only in contents of amino acids but also the profiles of protein in sodium dodecyl sulfate polyacrylamide gel electrophoresis, isoelectric focusing, gel filtration chromatography and two-dimensional electrophoresisThe adulteration in ACC by using horse/mule hide, which is most difficult to detect, could be identified by Polymerase chain reaction methods with newly designed horse/mule-specific primer. Abbreviations Used: ACC: Asini Corii Colla; TCMs: Traditional Chinese Medicines; SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis; IEF: Isoelectric focusing; GFC: Gel filtration chromatography; 2-DE: Two-dimensional electrophoresis; PCR: Polymerase chain reaction. PMID- 29263624 TI - A Standardized Composition Comprised of Extracts from Rosmarinus officinalis, Annona squamosa and Zanthoxylum clava-herculis for Cellulite. AB - Background: Cellulite, characterized by changes in the skin morphology presented as dimpled or puckered skin appearance, is highly prevalent among postadolescent women. Cellulite management ranges from topical cream applications to invasive procedures. While some interventions showed improvements in physical appearances of affected areas, so far, none have reversed the condition to a full recovery. These unsuccessful measures signify the intricate nature of cellulite etiology highlighting its complexity leading to the possibility for a combination treatment approach to target multiple mechanisms. Materials and Methods: We screened our plant library for extracts that reduce cellular lipid accumulation, improve microcirculation, possess high total antioxidant capacity, significant anti-platelet aggregation, and anti-inflammatory activities using lipid accumulation assay in 3T3-L1 cells, Croton oil-induced hemorrhoid test in rats as a model for microcirculation, anti-platelet aggregation assay, nitric oxide (NO) inhibition assay, and 1,1-diphenyl-2-picrylhydrazyl assay. Results: Three known botanicals such as Rosemary officinalis, Annona squamosa and Zanthoxylum clava herculis were identified as lead extracts in these tests. Treatment of 3T3 cell with A. squamosa at 1 MUg/ml resulted in 68.8% reduction in lipid accumulation. In croton oil-induced hemorrhoid study, Z. clava-herculis reduced the recto-anus coefficient by 79.6% at 6 mg/kg indicating improvement in microcirculations. Similarly, R. officinalis caused inhibition of 82%, 71.8%, and 91.8% in platelet aggregation, NO production and free radical generation at 31.25 MUg/ml, 6.2 MUg/ml, and 40 MUg/ml concentrations suggesting its anti-oxidant, and anti inflammatory activities. Conclusions: Data depicted here suggest that formulation of these well-known botanicals at a specific ratio perhaps may yield a composition with a much wider spectrum of mechanisms of actions to impact the multiple pathways involved in cellulite onset, continuation, or exacerbations. SUMMARY: Cellulite represents one of the main esthetic concerns of women with a likely cause of psychological insecurities. Its pathophysiology involves multiple pathways that include vascular, adipose tissues, inflammation, structural and physiological.Treatment strategies for cellulite comprises increasing microcirculation flow, reducing lipogenesis, promoting lipolysis, free radicals scavenging or formation reduction, anti-inflammation and other invasive procedures.We screened our plant library for extracts that reduces cellular lipid accumulation, improves microcirculation, possesses high total antioxidant capacity, inhibits platelet aggregation, and moderates inflammation.Botanical extracts from Rosmarinus officinalis, Annona squamosa and Zanthoxylum clava herculis were identified as leads and formulated to yield a standardized composition designated as UP1307 and suggested its usage for cellulite. Abbreviations Used: GMP: Good Manufacturing Practice; CA: Carnosic acid; NF-kB: nuclear factor-kB; HPLC: high-performance liquid chromatography; EtOH: Ethanol; DMEM: Dulbecco's modified Eagle's medium; FBS: fetal bovine serum; SD: Sprague Dawley; RAC: recto-anus coefficient; LPS: Lipopolysaccharide; DPPH: 1,1-diphenyl 2-picryl-hydrazyl; TNF-alpha: tumor necrosis factor; NO: Nitric oxide. PMID- 29263625 TI - Effect of the Administration of Solanum nigrum Fruit on Prevention of Diabetic Nephropathy in Streptozotocin-induced Diabetic Rats. AB - Background: Our previous study showed antidiabetic effect of aqueous extract of Solanum nigrum Linn fruit (SNE). Objective: This study was designed to explore the antidiabetic and nephroprotective effects of SNE in diabetic rats. Materials and Methods: Animals were divided into nine groups to undergo two experiment protocols: Two groups served as nondiabetic controls (NDCs), while the other groups had diabetes induced with a single injection of streptozotocin. SNE treated diabetic (D-SNE) and SNE-treated controls (NDC-SNE) received 1 g/L of SNE added to the drinking water and insulin-treated diabetic (D-I) for 8 weeks. Furthermore, there were four groups (D-SNE, NDC-SNE, D-I, D) in the second protocol to examine diabetic nephropathy (DN) for 16 weeks. Blood urea nitrogen (BUN), creatinine (Cr) magnesium, nitric oxide (NO), and malondialdehyde (MDA) levels were measured. Both kidneys were isolated to measure MDA, NO levels, and renal damage. Results: SNE could decrease blood glucose level in diabetic rats. In addition, SNE was more effective than insulin in controlling blood glucose. SNE could decrease BUN, Cr levels, and kidney weight and damage after 8 and 16 weeks of administration. Plasma and kidney levels of NO and MDA also decreased. Conclusion: Our results support the hypothesis that SNE could play a role in the management of diabetes and the prevention of DN. SUMMARY: The aqueous extract of Solanum nigrum Linn fruit (SNE) (1 g/L via drinking water) was studied on streptozotocin-induced diabetic rats to prevent diabetic nephropathy (DN). The results suggest that SNE in addition to the management of diabetes could have a beneficial effect on the prevention of DN. Abbreviations Used: SNE: Extract of Solanum nigrum Linn fruit, NDCs: Nondiabetic controls, STZ: Streptozotocin, D SNE: SNE-treated diabetic, NDC-SNE: SNE-treated controls, D-I: Insulin-treated diabetic, BUN: Blood urea nitrogen, Cr: Creatinine, Mg: Magnesium, NO: Nitric oxide, MDA: Malondialdehyde, DN: Diabetic nephropathy, BW: Body weight, FBG: Fed blood glucose, KW: Kidney weight, TBA: Thiobarbituric acid, IPGTT: Intraperitoneal glucose tolerance test, AUC: Aria under the curve, GFR: Glomerular filtration rate. PMID- 29263626 TI - Medicinal Plants Used by Traditional Healers in Sangurur, Elgeyo Marakwet County, Kenya. AB - Background: Although herbal medical products are still widely used in Kenya, many of the medicinal plants used by traditional medical practitioners (TMPs) have not been documented, despite several challenges that are now threatening the sustainability of the practice. Objective: To document the medicinal plants and healing methods used by TMPs in a region of Kenya with several recognized herbalists for potential research. Materials and Methods: Semi-structured interviews, group discussions, and direct observations were used to collect ethnopharmacological information. The participant's bio-data, clinical conditions treated, methods of treatment, medicinal plants used, methods of preparation and administration, and dosage forms were recorded. Results: A total of 99 medicinal plants and 12 complementary preparations employed in the treatment of 64 medical conditions were identified. The most widely used plant was Rotala tenella which was used to treat nine medicinal conditions; seven each for Aloe tweediae and Dovyalis abyssinica; and six each for Basella alba and Euclea divinorum. The plants belonged to 55 families with Fabaceae family being the most frequently used (10), followed by Apocynaceae and Solanaceae, each with six species, respectively. We identified plants used to determine the sex of an unborn baby and those used to treat several conditions including anthrax and cerebral malaria and herbs used to detoxify meat from an animal that has died from anthrax. Of special interest was R. tenella which is used to prevent muscle injury. Conclusions: We have documented several plants with potential therapeutic effects. Further research may be conducted to determine their efficacy. SUMMARY: The medicinal plants used by traditional healers in a community which still practices herbal medicine in Kenya were documented. A total of 99 medicinal plants and 12 complementary preparations employed in the treatment of 64 medical conditions were identified. Further research may be carried out in order to determine their therapeutic efficacies. Abbreviations Used: Fic: Informant consensus factor, Nur: Number of use reports in each category, Ns: Number of reported species, TMPs: Traditional medical practitioners. PMID- 29263627 TI - Inhibitory Effects of Pterodon emarginatus Bean Oil and Extract on Staphylococcus aureus. AB - Background: Pterodon emarginatus is a tree of the Brazilian Savannah. The beans of this tree are used in folk medicine as anti-inflammatory preparations, especially for infections caused by Staphylococcus aureus. These bacteria can cause simple infections or serious illnesses such as pneumonia, meningitis, endocarditis, toxic shock syndrome, septicemia, and others. Objective: This study had the goal of verifying the effect of the essential oil (OE) from P. emarginatus on the inhibition of S. aureus in culture medium, i.e., " in vitro" tests. Materials and Methods: The vegetable material was cut and crushed with a press. The OE was obtained by extraction using hexane, alcohol, and water. The P. emarginatus extracts obtained were used to evaluate the antimicrobial effect on S. aureus (ATCC 25923) by tests of well diffusion, disc diffusion, and microdilution. The strain used in the assays was maintained in brain heart infusion broth and nutrient agar until testing. Afterward, the bacteria were spread on agar plates with Mueller-Hinton agar medium. In the wells and on the paper discs, the OE suspensions were placed in the following volumes: 10, 15, 20, 25, 30, 40, and 80 MUL and subsequently they were incubated at 35 degrees C +/- 2 degrees C. After 24 h, the number of colony-forming unit was determined. Results: Pure OE and hydroalcoholic extract inhibited the growth of S. aureus, while aqueous extract had no effect on bacterial growth in all microbial methods used. Conclusion: Thus, the present study showed the potential of sucupira-based extracts against S. aureus growth, opening new perspectives for the evaluation of these bioactive compounds as phytopharmaceutical products. SUMMARY: Plant extract act as antimicrobials to prevent and reduce bacterial contaminationBeans of Pterodon emarginatus has antibacterial propertiesExtraction with different solvents might implicate on the rate of bacterial deathThe effect of different microbiological methods (well diffusion, disc diffusion and microdilution) was evaluated on reducing CFUThe results showed by MBC that concentrations superior to 10% (v/v) using AC and 7.5% (v/v) using OE were necessary to eliminate colonies formedAccording to data of MIC, at 2.5% of AC and OE was enough to kill S. aureusThe well diffusion technique demonstrated better performance than disc diffusion test for OE and AC extractsHydroalcoholic and oil extracts of sucupira beans had highest effect against Staphylococcus aureusAqueous extract had no effect on bacterial growth in all microbial methods testedThe sucupira-based extracts is a promising source as herbal drug due to therapeutic value Abbreviations Used: OE: Essencial oil; AC: Hydroalcoholic oil extract; AQ: Aqueous extracts; MIC: Minimum inhibitory concentration; MBC: Minimum bactericidal concentration; CFU: Colony formed unit. PMID- 29263628 TI - Protective Effect of Withania coagulans Fruit Extract on Cisplatin-induced Nephrotoxicity in Rats. AB - Background: Fruits of Withania coagulans (Solanaceae) reported to possess several bioactive compounds as curative agents for various clinical conditions. Cisplatin is a chemotherapeutic drug to treat sarcomas, carcinomas, lymphomas, cervical cancer, germ cell tumors, etc. The major factor that limits its clinical use is its dose-dependent nephrotoxicity. Aim: To explore the nephroprotective effect of W. coagulans extract and its modulatory effects against cisplatin-induced nephrotoxicity and genotoxicity. Materials and Methods: W. coagulans fruit extract was quantitatively standardized with withaferin A using high-performance thin-layer chromatography. The subacute toxicity study was performed according to OECD guidelines in experimental rats. Nephrotoxicity in rats was induced by a single dose of cisplatin (6 mg/kg, intraperitoneal). Nephroprotective role of W. coagulans fruit extract at different doses had been evaluated. It includes quantification of serum kidney toxicity markers, renal tissue oxidative stress biomarkers and pro-inflammatory cytokines level, DNA fragmentation assay, and histopathological examination of renal tissue. Results: Withaferin A was found 3.56 mg/g of W. coagulans fruit extract. It significantly prevented the rise in serum urea and creatinine level and also preserve rat kidneys from oxidative stress and free radical induced DNA damage. Histopathological study showed extract treatment eliminates tubular swelling, cellular necrosis, and protein cast deposition in cisplatin treated kidney tissue. It averted the decline in glutathione content, activities of superoxide dismutase and catalase. These parameters were restored to near normal levels by extract in a dose of 400 mg/kg, per oral. Conclusion: It can be justified that W. coagulans possess dose dependent protective effect against cisplatin induced kidney damages, primarily through its free radical scavenging and anti inflammatory activity. SUMMARY: Authentication and standardization of Withania coagulans fruitsSubacute oral toxicity studyEvaluation of nephroprotective activity against cisplatin-induced nephrotoxicityDNA fragmentation assay and histopathological examination of kidney tissue in experimental rats. Abbreviations Used: WHO: World Health Organization, SOD: Superoxide dismutase, CAT: Catalase, HPTLC: High-performance thin layer chromatography, p.o.: Per.oral, i.p.: Intraperitoneal, TNF-alpha: Tumor necrosis factor-alpha, IL-1beta: Interleukin 1-beta, IL-6: Interleukin-6. PMID- 29263629 TI - Antioxidant Activity and Phenolic and Flavonoid Contents of the Extract and Subfractions of Euphorbia splendida Mobayen. AB - Introduction: The harmful action of the free radicals which cause the oxidative stress can be blocked by antioxidant substances, and different plant extracts showed antioxidant activity. The aim of this study is was evaluation the antioxidant activity of total methanol extract (ME) and subfractions of Euphorbia splendida Mobayen. Materials and Methods: Aerial part of E. splendida was extracted by maceration with methanol and then subfractionated by liquid-liquid fractionation using petroleum ether, chloroform, ethyl acetate, and water. Antioxidant activity was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay, reduction of ferric ions and ferrous ion chelating potential. Total phenolic contents (TPC) and total flavonoid contents (TFC) were estimated with Folin-Ciocaltue and aluminum chloride methods, respectively. Results: The findings revealed that E. splendida ME and subfractions showed a dose-dependent antioxidant activity. ME showed the highest antioxidant activity based on total reduction capability and ferrous ions chelating assay tests. Aqueous fraction and then ethyl acetate fraction showed the best IC50in DPPH radical scavenging test in comparison to butylated hydroxytoluene. ME showed the highest value of TPC and TFC (270.74 +/- 0.005 mg/g and 208.23 +/- 0.007 mg/g, respectively). Conclusion: This study showed that the extract and subfractions of E. splendida have antioxidant activity. The antioxidant activity of the extract and fractions might be attributed to the presence of phenolic compounds. More studies are needed to determine the active antioxidant compounds of this plant. SUMMARY: Total extract and subfractions of Euphorbia splendida showed antioxidant activity. Abbreviations Used: TPC: Total phenolic content, TFC: Total flavonoid content, DPPH: 2, 2'- diphenyl-1-picrylhydrazyl, BHT: Butylated hydroxytoluene, EDTA: Ethylene Diamine Tetra Acetic acid, ME: Total methanol extract, EAF: Ethyl acetate fraction, AQF: Aqueous fraction, PEF: Pertolium ether fraction, CHF: Chloroformic fraction. PMID- 29263630 TI - Antioxidant and Intracellular Reactive Oxygen Species/Reactive Nitrogen Species Scavenging Activities of Three Porcupine Bezoars from Hystrix brachyura. AB - Background: Porcupine dates are phytobezoar stones that are used in Traditional Chinese Medicine (TCM) treatments against cancer, postsurgical recovery, dengue fever, etc. The medicinal values have not been scientifically investigated due to the availability and high pricing of the dates. Objectives: This paper represents the first report on the phytochemical content, in vitro antioxidant and intracellular reactive oxygen species (ROS)/reactive nitrogen species (RNS) scavenging properties of the extracts of three porcupine dates: grassy date (GD), black date (BD), and powdery date (PD). Materials and Methods: Dried samples were extracted with methanol and lyophilized. Samples were screened for phytochemical constituents, in vitro antioxidant assays based on total phenolic content (TPC), free radical scavenging, and ferric reducing power (FRP) as well as intracellular ROS and RNS scavenging properties. Results: Phytochemical screening and total tannins assay revealed that tannins, cardiac glycosides, and terpenoids were found in all porcupine dates with tannins forming the major portion of the TPC. In comparison to GD, BD and PD were found to contain significantly high TPC, radical scavenging activity, and FRP. At 200 MUg/ml, BD and PD remarkably scavenged 2, 2-azobis (2-amidinopropane) dihydrochloride-induced ROS in RAW264.7 cells and significantly reduced nitric oxide in lipopolysaccharide-stimulated cells. Conclusion: Overall, BD and PD exhibited promising in vitro antioxidant as well as intracellular ROS/RNS scavenging properties. SUMMARY: Tannins, cardiac glycoside, and terpenoids were found in all three types of porcupine dates with tannins being the major compoundsAntioxidant contents and properties of three dates were in the order black date (BD) > powdery date (PD) > grassy dateBD and PD extracts showed significant intracellular reactive oxygen species and reactive nitrogen species scavenging properties. Abbreviations Used: TCM: Traditional Chinese Medicine, BD: Black date, GD: Grassy date, PD: Powdery date, TPC: Total phenolic content, FRS: Free radical scavenging, FRP: Ferric reducing power, NO: Nitric oxide, ROS: Reactive oxygen species, RNS: Reactive nitrogen species, GAE: Gallic acid equivalent, AAE: Ascorbic acid equivalent, PVPP: Polyvinylpolypyrrolidone, DCFH-DA: Dichloro-dihydro-fluorescein diacetate, AAPH: 2, 2-azobis (2-amidinopropane) dihydrochloride, LPS: Lipopolysaccharide. PMID- 29263631 TI - Teucrium polium-induced Vasorelaxation Mediated by Endothelium-dependent and Endothelium-independent Mechanisms in Isolated Rat Thoracic Aorta. AB - Objective: There are some reports on hypotensive and antispasmodic effects of Teucrium polium L. (Lamiaceae) (TP). Subjects and Methods: The activity of different concentrations of TP extract (1, 2, 4 and 8 mg/ml) was evaluated on contractile responses of isolated aorta to potassium chloride (KCl) and phenylephrine (PE). Results: The cumulative concentrations of the extract induced a concentration-dependent relaxation in the aorta precontracted by PE and KCl. Extract-induced vasorelaxations in denuded aortic rings precontracted by PE and KCl at lower concentrations were considerably less than intact aortic rings, but this effect was significantly more at concentrations of 4 mg/ml for PE-, 4 and 8 mg/ml for KCl-induced contractions. All the extract concentrations (except 1 mg/ml) significantly relaxed PE-induced contraction in the presence of NG-nitro-L arginine methyl ester. Indomethacin reduced effectively extract-induced vasorelaxation at 1 and 2 mg/ml. The extract reduced PE- and KCl-induced contractions in the presence of cumulative calcium concentrations and after incubation with diltiazem; this vasorelaxant effect of TP was decreased. TP induced relaxation was inhibited by heparin, ruthenium red, glibenclamide, and tetraethylammonium, but 4-aminopyridine had no effect on TP-induced relaxation. Conclusion: TP extract has vasorelaxant effect on isolated rat thoracic aorta which mediated by endothelium-dependent and endothelium-independent mechanisms. The relaxation mainly was mediated by inhibition of calcium influx in vascular smooth muscle cells. It seems that the vasorelaxant effect of extract at lower concentrations was mediated by nitric oxide and prostacyclin. SUMMARY: The vasodilatory effect of Teucrium polium L. was mediated by several mechanisms. First: Teucrium polium L. inhibited receptor operated ROCC and VDCC. Second: Teucrium polium L. also inhibited KATP and KCa channels. Third: Teucrium polium L. blocked IP3 receptor and reduced the release of calcium from intracellular source. Forth: Teucrium polium L. increased the release on NO and PGI2 from endothelial cells. Abbreviations Used: ROCC: Receptor operated calcium channels, VDCC: Voltage dependent calcium channels, PLC: Phospholipase C, IP3: 1,4,5 triphosphate inositol, IP3R: IP3 receptors, SR: sarcoplasmic reticulum, RYR: ryanodine receptors, K+ATP: ATP-sensitive potassium channel, K+Ca: Calcium activated potassium channel, cAMP: Cyclic adenosine monophosphate, cGMP: Cyclic guanosine monophosphate, PGI2: Prostaglandin I2, NO: Nitric oxide. PMID- 29263632 TI - Annonacin Exerts Antitumor Activity through Induction of Apoptosis and Extracellular Signal-regulated Kinase Inhibition. AB - Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Annonacin, a natural pure compound extracted from the seeds of Annona muricata, is a potential alternative therapeutic agent to treat EC. Objective: To study the antitumor activity of annonacin and its mechanism of action in EC cells (ECCs). Materials and Methods: Viability of ECCs treated with annonacin for 72 h was determined using methyl thiazolyl tetrazolium assay. The induction of cell cycle arrest and apoptotic cell death was evaluated using propidium iodide and annexin V-PE/7-AAD assay, respectively. DNA strand breaks were visualized using transferase dUTP nick end labeling assay, and the effects of annonacin on survival signaling were determined using western blotting. Results: Annonacin exhibited antiproliferative effects on EC cell lines (ECC-1 and HEC-1A) and primary cells (EC6-ept and EC14-ept) with EC50values ranging from 4.62 to 4.92 MUg/ml. EC cells were shown arrested at G2/M phase after treated with 4 MUg/ml of annonacin for 72 h. This led to a significant increase in apoptotic cell death (65.7%) in these cells when compared to vehicle-treated cells (P < 0.005). We further showed that annonacin-mediated apoptotic cell death was associated with an increase in caspase-3 cleavage and DNA fragmentation. Cell apoptosis was accompanied with downregulation of extracellular signal-regulated kinase survival protein expression and induction of G2/M cell cycle arrest. Conclusion: Annonacin may be a potential novel therapeutic agent for EC patients. SUMMARY: We aimed to study the antitumor activity of annonacin and its mechanism of action in endometrial cancer cells. Annonacin exerted antiproliferation effects on both endometrial cancer cell lines and primary cells via induction of apoptosis and inhibition of extracellular signal-regulated kinase. Our data represented that annonacin could be an alternative therapeutic treatment to combat endometrial cancer. Abbreviations Used: 7-AAD: 7-Amino-Actinomycin, ATP: Adenosine diphosphate, BSA: Bovine serum albumin, DNA: Deoxyribonucleic acid, EC: Endometrial cancer, ECC-1: Endometrial cancer cell-1, EC50: Half maximal effective concentration, Ept: Epithelial, FBS: Fetal bovine serum, HEC-1A: Human endometrial carcinoma-1A, MTT: Methyl thiazolyl tetrazolium, NaCl: Sodium chloride, NADH: Nicotinamide adenine dinucleotide, RPMI 1640: Roswell Park Memorial Institute Medium, SDS: Sodium dodecyl sulfate. PMID- 29263633 TI - Comparative Physicochemical Evaluation of Kharekhasak (Tribulus terrestris Linn.) Before and After Mudabbar Process. AB - Background and Objectives: Mudabbar/Tadbeere advia is referred to the processes performed on the drugs to detoxify, purify, and enhance therapeutic action and to reduce its doses before making the formulations in Unani medicine. It improves quality of drugs either by optimizing its desirable characteristics or minimizing the undesirable ones; it makes drug effective, safe, and specific. There is a need of comparative evaluation to understand its significance. Tadbeer of Kharekhasak (KK) khurd (Tribulus terrestris Linn. fruit) is described by Rabban Al-Tabari in Firdausul Hikmat, Akbar Arzani in Qarabadeene Qadri, etc., during the compounding of aphrodisiac formulations. Mudabbar Kharekhasak (MKK) used in Safoofe Kharekhasak mentioned in Al-Qarabadeene was evaluated in this work. Methods: Mudabbar/Tadbeer process was carried out by blending fresh KK. Juice with powdered dry KK and drying it under the sun. Juice used for process is thrice the weight of dry KK powder. The KK before and after the process was evaluated using physicochemical tests: powder characterization, extractive value, alcohol and water soluble matter, ash value, loss on drying (LOD) at 105 degrees C, pH, high-performance thin layer chromatography (HPTLC) fingerprinting, and diosgenin content. Results: Powder characterizations were set in. Increase in successive and nonsuccessive extractive values in various solvents, water/alcohol soluble content, total ash, acid-insoluble ash, water-soluble ash, and sulfated ash of MKK was noted in comparison with KK. Decrease in LOD at 105 degrees C and pH of MKK powder was observed. HPTLC fingerprinting data were developed for the identification and evaluation. Quantification of diosgenin content increased to 432.1 g/g in MKK as compared to 144.5 g/g in KK, suggesting significant increase in saponin content. Conclusion: Data obtained clearly indicated changes in MKK validating the classical Mudabbar process, probably to enhance/modify the action of drug. Standards for crude and MKK were established for future reference. SUMMARY: Mudabbar process on Tribulus terrestris Linn (KK) havebeen validated.Physicochemical data for Mudabbar and non mudabbar Kharekhasak (KK) powder have been set in.Diosgenin content was increased significantly in mudabbar KK. Abbreviations Used: KK: Kharekhasak, TT: Tribulus terrestris, MKK: mudabbar Kharekhasak, SK: Safoofe Kharekhasak, LOD: loss of weight on drying, HPTLC: High performance thin layer chromatography, BSS: British standard sieve, MUl: microliter, SEM: Standard error of mean, nm: nanometer, g: gram. PMID- 29263634 TI - Toxicological Evaluation of the Aqueous Extract of Caralluma europaea and Its Immunomodulatory and Inflammatory Activities. AB - Background: Caralluma europaea (CE) has been studied for its chemical constituents, and no information is available on its toxicity or its pharmacological activities. Objective: To determine the toxicity of an aqueous extract of CE stems in vitro and in vivo after acute and subchronic oral gavages in Swiss albino's mice and its immunomodulatory and inflammatory activities. Materials and Methods: The extract was administrated in single oral dose at 5 g/kg body weight for the acute toxicity test and by gavages daily at doses of 1, 2.5, or 5 g/kg for 30 consecutive days for the subchronic toxicity test. The immunomodulatory activities and inflammatory activities were tested by the evaluation of hemagglutination antibodies (HAs) titers and delayed-type hypersensitivity (DTH) response. Results: For the dose of 1 g/kg, no visible toxic effects were observed. However, for the higher doses, clinical observations of toxicity were noted after 1 week of treatment. This was confirmed by the biochemical parameters values and the histology analyses of the spleen, liver, and kidney tissues. The high cellular mortality rate in vitro when treated with CE extract confirmed their toxicity potential. There was also increase of "HA titer" and "DTH" response in mice treated with nontoxic dose of CE (1 g/kg) compared to control group. This immune activity was confirmed by the high number of lymphocytes infiltrates noted in the different organs. Conclusion: We conclude that CE at the dose up of 1 g/kg produced toxic effect in mice that induced an immune inflammatory reaction. SUMMARY: Caralluma europaea (CE) has been studied for its chemical constituents, and no information is available on its toxicity or its pharmacological activities. The objective is to determine the toxicity of an aqueous extract of CE stems in vitro and in vivo after acute and subchronic oral gavages in Swiss albino's mice and its immunomodulatory and inflammatory activities. For the dose of 1 g/kg, no visible toxic effects were observed. However, for the higher doses, clinical observations of toxicity were noted after 1 week of treatment. This was confirmed by the biochemical parameters values and the histology analyses of the spleen, liver, and kidney tissues. The high cellular mortality rate in vitro confirmed their toxicity potential. There was also increase of "hemagglutination antibody titer" and "delayed-type hypersensitivity" response in mice treated with nontoxic dose of CE (1 g/kg) compared to control group. This immune activity was confirmed by the high number of lymphocytes infiltrates noted in the different organs. We conclude that CE at the dose up of 1 g/kg produced toxic effect in mice that induced an immune inflammatory reaction. Abbreviations Used: CE: Caralluma europaea, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, RRBCs: Rat red blood cells, DTH: Delayed-type hypersensitivity response, PBS: Phosphate buffer solution. PMID- 29263635 TI - Bioassay-guided In vitro Study of the Antimicrobial and Cytotoxic Properties of the Leaves from Excoecaria Lucida Sw. AB - Background: Excoecaria lucida Sw. (Euphorbiaceae) is a plant conventionally used throughout the Caribbean in the treatment of infectious diseases. Objective: To evaluate, using bioassay-guided fractionation, the in vitro cytotoxicity and antimicrobial activity of E. lucida leaves. Materials and Methods: A 95% ethanol crude extract was dried and fractionated by solid-liquid separation in four phases (hexane, dichloromethane, ethyl acetate, and butanol). Antimicrobial activity (3 bacteria, 6 yeasts, and 2 fungi) was evaluated by the dilution method with resazurin (2048, 512, 128, 32, and 8 MUg/mL). The cytotoxicity assays were evaluated in two cell lines: MRC-5 and RAW 264.7; calculating the selectivity index. Assays were performed for the total extract, the isolated compound with the highest yield, and the ethyl acetate and butanol phases. Isolated compounds were characterized by nuclear magnetic resonance and mass spectrometry techniques. Results: Fractionation process led to the isolation of ellagic acid (784.29 mg), 3,3',4'-tri-O-methyl ellagic 4-O-beta-D-glucopyranoside acid (6.1 mg), and corilagin (6.91 mg). The most active were ethyl acetate phase and ellagic acid with IC50= 128 MUg/mL against seven and five different species of microorganisms, respectively. The total extract (IC50=512 MUg/mL) and the ethyl acetate phase (IC50=128 MUg/mL) were cytotoxic in both cell lines, while butanol phase and ellagic acid both with IC50>2048 MUg/mL seemed to be safer. Conclusions: The results obtained indicate that the Excoecaria leaves can be conventionally used as antimicrobial, but it should be present that some cytotoxicity could appear. In addition, the three identified compounds were reported for the first time in the species. SUMMARY: Excoecaria lucida leaves (Euphorbiaceae) are used by the Cuban population due to their antimicrobial activity. This ethnopharmacological knowledge is confirmed by the integrated antibacterial and antifungal in vitro screening developed, using the bioassay guided fractionation method.Abbreviations Used: MRC-5-SV2: Diploid human lung fibroblasts cells, RAW 264.7: Murine macrophages cells, IC50: Inhibitory Concentration 50%, ATCC: American Type Culture Collection, CCEBI: Culture Collection of Industrial Biotechnology Center, CECT: Spanish Culture Collection Type, CFU: Colony forming units, CC50: 50% cytotoxic concentration, CO2: Carbon dioxide, SI: Selectivity index, IR: Infrared spectroscopy, 1H NMR: Nuclear Magnetic Resonance of hydrogen, 13C NMR: Nuclear Magnetic Resonance of carbon, HMQC: Heteronuclear Multiple-Quantum Correlation, HMBC: Heteronuclear Multiple Bond Correlation, COSY: Correlation Spectroscopy, NOESY: Nuclear Overhauser Effect Spectroscopy, KBr: Potassium bromide, DMSO-D6: Deuterated dimethyl sulfoxide, LC.MS: Liquid Chromatography-Mass Spectrometry, [alpha]D: Optical rotation, EL1: ellagic acid, EL2: 3,3',4'-tri-O-methyl ellagic 4-O-beta-D glucopyranoside acid, EL3: corilagin, Active (+), inactive (-). PMID- 29263636 TI - Ethnopharmacological Survey of Medicinal Plants in Albaha Region, Saudi Arabia. AB - Background: Local natural medicinal resource knowledge is important to define and elaborate usage of herbs, in systematic and organized manner. Until recently, there has been little scientifically written document regarding the traditional uses of medicinal plants in Al Bahah region. Objective: This pilot study aims to collect the ethnobotanical information from native populations regarding the benefits of medicinal plants of Al Bahah region, and determine if the traditional usage is scientifically established (proved) from literature. Materials and Methods: The survey collected data for 39 plant species recorded by informants for their medicinal benefits. The recorded species were distributed among 28 plant families. Leguminosae and Euphorbiaceae were represented each by 3 species, followed by Asteraceae (2 species), Lamiaceae (2 species), Apocynaceae (2 species), and Solanaceae (2 species). All the medicinal plants were reported in their local names. Analysis of ethnopharmacological data was done to obtain percentage of plant families, species, parts of plants used, mode of administration, and preparation types. Results: Total 43 informants were interviewed, maximum number of species were used to cure skin diseases including burns (3), wounds (7), warts (1), Leishmania (7), topical hemostatic (2), followed by gastrointestinal system, rheumatism, respiratory tract problems, diabetes mellitus, anti-snake venom, malaria, and eye inflammation. Conclusions: The study covered Al Bahah city and its outskirts. Ten new ethnobotanical uses were recorded such as antirheumatic and anti-vitiligo uses for Clematis hirsute, leishmaniasis use of Commiphora gileadensis, antigout of Juniperus procera, removing warts for Ficus palmata. SUMMARY: 39 plant species from 28 plant families are used for treating more than 20 types of diseases.Maximum number of species (23 species) was used for treating skin diseases (42.6%) including leishmaniasis, wound healing, dermatitis, psoriasis, vitiligo and warts.Ten ethnobotanical uses of 8 studied plants have not been previously reported.The most used medicinal plants, according to their Use Index (UI) were Juniperus procera, Rumex nervosus, and Ziziphus spina-christi. Abbreviations Used: UI : Use Index, GI: Gastrointestinal tract, RD: Rheumatic disease, CVS: Cardiovascular diseases, UTI: Urinary tract infection, DM: Diabetes mellitus, RT: Respiratory infection, KSA: Kingdom of Saudi Arabia. PMID- 29263637 TI - Identification and Characterization of Memecylon Species Using Isozyme Profiling. AB - Background: The protein/isozyme fingerprint is useful in differentiating the species and acts as a biochemical marker for identification and systematic studies of medicinal plant species. Objective: In the present study, protein and isozyme profiles for peroxidase, esterase, acid phosphatase, polyphenol oxidase, alcohol dehydrogenase, and alkaline phosphatase of five species of Memecylon (Melastomataceae), Memecylon umbellatum, Memecylon edule, Memecylon talbotianum, Memecylon malabaricum, and Memecylon wightii were investigated. Materials and Methods: Fresh leaves were used to prepare crude enzyme extract for analyzing the five enzymes isozyme variations. Separation of isozymes was carried out using polyacrylamide gel electrophoresis (PAGE) and the banding patterns of protein were scored. Pair-wise comparisons of genotypes, based on the presence or absence of unique and shared polymorphic products, were used to regenerate similarity coefficients. The similarity coefficients were then used to construct dendrograms, using the unweighted pair group method with arithmetic averages. Results: A total of 50 bands with various Rf values and molecular weight were obtained through PAGE analysis. Among the five Memecylon species, more number of bands was produced in M. wightii and less number of bands was observed in M. edule. The results of similarity indices grouped M. malabaricum and M. wightii in one cluster with 98% similarity and M. umbellatum, M. edule, and M. talbotianum are grouped in another cluster with 79% similarity showing close genetic similarities which is in accordance with the morphological identification of Memecylon species. Conclusion: The protein/isozyme fingerprint is useful in differentiating the species and acts as a biochemical marker for identification of Memecylon species. SUMMARY: Biochemical characterization of Memecylon species was evaluated by SDS-PAGE of extracted protein and isozyme profiling on native PAGE.After electrophoresis, each gel was stained with specific stains. Genetic distance relationships were evaluated based on the banding patterns of protein on isozymes.Unique banding pattern of esterase, peroxidase, acid phosphatase, alcohol dehydrogenase and polyphenol oxidase are observed in all the five species of Memecylon, which represent the fingerprint of Memecylon species.SDS-PAGE and isozyme profiling of five Memecylon species revealed that M. malabaricum and M. wightii grouped in one cluster and M. umbellatum, M. edule and M. talbotianum grouped in another cluster showing close genetic similarities which is in accordance with the morphological identification of Memecylon species.This is the first report on the comparison of protein and isozyme profile of five different Memecylon species. Abbreviations Used: SDS-PAGE: Sodium docecyl sulfate polyacrylamide gel electrophoresis; NTSYS PC2: Numerical taxonomy system, version 2.2 for Windows XP, Vista, Win7, Win 8 and Win10 including 64 bit. PMID- 29263638 TI - Some classes of singular integral equations of convolution type in the class of exponentially increasing functions. AB - In this article, we study some classes of singular integral equations of convolution type with Cauchy kernels in the class of exponentially increasing functions. Such equations are transformed into Riemann boundary value problems on either a straight line or two parallel straight lines by Fourier transformation. We propose one method different from the classical one for the study of such problems and obtain the general solutions and the conditions of solvability. Thus, the result in this paper improves the theory of integral equations and the classical boundary value problems for analytic functions. PMID- 29263639 TI - On p-radial Blaschke and harmonic Blaschke additions. AB - In the paper, we first improve the radial Blaschke and harmonic Blaschke additions and introduce the p-radial Blaschke and p-harmonic Blaschke additions. Following this, Dresher type inequalities for the radial Blaschke-Minkowski homomorphisms with respect to p-radial Blaschke and p-harmonic Blaschke additions are established. PMID- 29263640 TI - Approximation for the gamma function via the tri-gamma function. AB - In this paper, we present a new sharp approximation for the gamma function via the tri-gamma function. This approximation is fast in comparison with the recently discovered asymptotic series. We also establish the inequalities related to this approximation. Finally, some numerical computations are provided for demonstrating the superiority of our approximation. PMID- 29263641 TI - Long-Term Effects of Pre-Placement Risk Factors on Children's Psychological Symptoms and Parenting Stress Among Families Adopting Children From Foster Care. AB - This exploratory longitudinal study examined behavioral outcomes and parenting stress among families with children adopted from foster care, taking into account environmental and biological risk factors. Child internalizing and externalizing problems and parenting stress were assessed in 82 adopted children and their families at 2 months post-placement, 12 months post-placement, and then yearly until 5 years post-placement. A history of abuse/neglect predicted significantly higher externalizing and internalizing problems at a borderline level of statistical significance. In the initial stages after placement, externalizing problems were significantly higher among children who were 4 years or older at placement versus those who were younger than 4, although differences were no longer significant 5 years post-placement. Statistical trends in parenting stress reflected reduced stress in the first 12 months followed by a plateau for parents who adopted older children and greater stress for parents who adopted younger children. Familiar limitations for observational cohort data apply. Nonetheless, the availability of longitudinal follow-up on a sizable sample of children adopted from foster care adds insight to the psychological dynamics for adoptive families and suggests that families of children adopted from the foster care system may have unique needs for ongoing support around behavioral issues. PMID- 29263642 TI - Long-term outcomes in half-dose verteporfin photodynamic therapy for chronic central serous retinopathy. AB - Objective: To evaluate the short- and long-term outcomes of half-dose verteporfin with photodynamic therapy (PDT) in the treatment of chronic central serous retinopathy (CSR). Design: Retrospective case series. Participants: 45 eyes in 39 patients with chronic CSR were included. Diagnosis of chronic CSR was confirmed by fluorescein angiography and persistence of subretinal fluid by optical coherence tomography for a minimum of 3 months duration. Methods: Each patient underwent treatment with half-dose verteporfin with full-fluence PDT; initial follow-up was defined as a 6-8 week visit following the treatment, and final follow-up ranged from 5 to 70 months. Results: The average follow-up period for treatment was 19.3 months. Best-corrected visual acuity increased from logMAR means of 0.52 to 0.42 (p<0.05). Central retinal thickness and choroidal thickness also significantly decreased at last follow-up (p<0.05). Eight of 45 eyes (18%) demonstrated a recurrence of CSR following treatment within the follow-up period. At the final follow-up, 41 out of the 45 eyes (91%) had complete resolution of subretinal fluid accumulation. Conclusion: Half-dose PDT is an effective treatment option for chronic CSR in a Canadian population, and it is both safe and durable. The positive treatment effect is realized rapidly, with the initial 6-week result highly correlated with the final follow-up result. PMID- 29263643 TI - Associations between CRYBA4 gene variants and high myopia in a Japanese population. AB - Purpose: The crystallin beta A4 (CRYBA4) gene variant, rs2009066, was previously reported to be associated with high myopia in a southern Chinese population. In the present study, we investigated whether CRYBA4 variants were associated with high myopia in a Japanese population. Methods: We recruited 1,063 Japanese patients with high myopia (spherical equivalent [SE] <=-9.00 D in both eyes) and 1,009 healthy Japanese subjects (SE >-1.00 D). We genotyped rs2009066 and three tagging single-nucleotide polymorphisms (SNPs), rs16982456, rs2071861, and rs4276, in the CRYBA4 region. Results: We did not find any significant association between these four SNPs and high myopia in an allele analysis. However, rs2009066 and rs2071861, which were in strong linkage disequilibrium (LD; r2=0.86), showed a marginal association with high myopia in the recessive genotype model of risk alleles (rs2009066 G allele: P=0.032, odds ratio [OR] =1.31; rs2071861 A allele: P=0.037, OR =1.31). Nevertheless, this association became insignificant after correcting for multiple testing (Pc >0.05). Conclusion: This study showed no significant association between CRYBA4 variants and high myopia in a Japanese population. Our findings did not correspond with a previous study. Further genetic studies with other populations are needed to elucidate a potential contribution of the CRYBA4 region in the development of high myopia. PMID- 29263645 TI - Combined phacocanaloplasty for open-angle glaucoma and cataract: 12 months results. AB - Purpose of the study: To evaluate efficacy, safety, and success rates of canaloplasty combined with phacoemulsification and intraocular lens implantation in patients with open-angle glaucoma (OAG) and visually significant cataract. Patients and methods: A prospective interventional noncomparative case series carried out in Minia University Hospital from April 2015 to October 2016 on 20 eyes of 18 patients who had visually significant cataract and primary OAG. All the cases had combined phacocanaloplasty. Preoperative best-corrected visual acuity, intraocular pressure (IOP), and number of antiglaucoma medications were collected and compared to postoperative levels, and complications rates were recorded. Results: 20 eyes of 18 patients (5 males and 15 females), with a mean age 57.6 years (range 48-69 years), underwent phacocanaloplasty. Preoperative mean IOP was 25.20 +/-1.009 mmHg. Postoperative IOP decreased to a mean of 14.20+/-0.9, 14.85+/-0.8, and 15.85+/-0.7 mmHG at 3, 6, and 12 months, respectively, with 37% reduction from preoperative IOP level at one year follow up visit (P=0.0005). The number of antiglaucoma medications dropped from mean of 1.55 preoperatively to 0.35 postoperatively. LogMAR of best-corrected visual acuity improved from 0.6950+/-0.07 preoperatively to 0.3670+/-0.056, 0.3460+/ 0.056, and 0.03370+/-0.052 at 3, 6, and 12 months postoperatively (P=0.0005). Complications were limited to mild hyphemia (one case), mild corneal edema (one case), and mild inflammatory membrane (one case) that resolved in the first week after surgery. Conclusion: Canaloplasty combined with clear corneal phacoemulsification and intraocular lens implantation may be a safe and effective procedure to lower IOP in adult patients with OAG and visually significant cataract. PMID- 29263644 TI - Thin minimal rim width at Bruch's membrane opening is associated with glaucomatous paracentral visual field loss. AB - Purpose: To compare optic nerve head (ONH) measurements in glaucomatous eyes with paracentral visual field (VF) loss to eyes with peripheral VF loss and controls. Methods: Open-angle glaucoma (OAG) patients with early paracentral VF loss or isolated peripheral VF loss as well as control subjects underwent ONH imaging with swept-source optical coherence tomography (OCT) and retinal nerve fiber layer (RNFL) imaging with spectral-domain OCT. Minimum rim width at Bruch's membrane opening (BMO-MRW), lamina cribrosa depth (LCD), and RNFL thickness were compared among the glaucoma and control groups with one-way analysis of variance, Kruskal-Wallis test, and multiple regression analysis. Results: Twenty-nine eyes from 29 OAG patients (15 early paracentral and 14 isolated peripheral VF loss) and 20 eyes of 20 control subjects were included. The early paracentral and isolated peripheral VF loss groups had similar VF mean deviation (MD) (-5.3+/-2.7 dB and -3.7+/-3.0 dB, p=0.15, respectively). Global BMO-MRW was lower in OAG eyes than in controls (193.8+/-40.0 vs 322.7+/-62.2 MUm, p<0.001), but similar between eyes with early paracentral VF loss and those with isolated peripheral VF loss (187.6+/-43.4 vs 200.6+/-36.3 MUm; p>0.99). In contrast, the minimal BMO-MRW was lower in eyes with early paracentral loss (69.0+/-33.6 MUm) than in eyes with isolated peripheral loss (107.7+/-40.2 MUm; p=0.03) or control eyes (200.1+/-40.8 MUm; p<0.001). Average and thinnest RNFL thickness did not differ between OAG groups (p=0.61 and 0.19, respectively). Horizontal and vertical LCD did not differ among the OAG groups and controls (p=0.80 and 0.82, respectively). Multivariable linear regression analysis among OAG cases confirmed the association between lower minimal BMO-MRW and early paracentral VF loss (beta= 38.3 MUm; 95% confidence interval, -69.8 to -6.8 MUm; p=0.02) after adjusting for age, gender, MD, and disc size. Conclusion: Thin minimal BMO-MRW may represent a new structural biomarker associated with early glaucomatous paracentral VF loss. PMID- 29263646 TI - Combined oral propranolol with intralesional injection of triamcinolone acetonide in treatment of infantile periocular hemangiomas. AB - Aim: To evaluate the clinical effectiveness of combined oral propranolol with intralesional injection of triamcinolone acetonide in the treatment of infantile periorbital capillary hemangioma. Patients and Methods: This prospective interventional study included children diagnosed with periocular infantile hemangiomas in the proliferative phase with vision-threatening lesions. The children presented to the oculoplastic unit in Sohag University Hospital in the period between January 2016 and February 2017 and were treated with a combined intralesional injection of triamcinolone acetonide with oral propranolol, with a follow-up period of 6 months. Treatment response was evaluated according to the size of the tumor (horizontal diameter); additionally, complications of both treatment methods were recorded. Results: This study included 33 infants: 21 females (64%) and 12 males (36%). The mean age at the time of injection was 4.9+/ 2.6 months. The study included three modes of treatment response: regression of the tumor, 28 patients (85%); stabilization, three patients (9%); and failure, two patients (6%), which necessitated repeated intralesional injection of triamcinolone but with minimal response. Regarding complications, only one patient reported with subconjunctival hemorrhage during intralesional injection of steroids; there were no recorded cases of hypotension, bradycardia, or hypoglycemia during the course of oral propranolol treatment. After the end of the follow-up period, there were no reported cases of recurrent increase in the size of the regressed group of infantile hemangiomas with stable tumor size. Conclusion: Combined oral propranolol with intralesional injection of triamcinolone acetonide is the effective method of treatment for infantile periorbital capillary hemangioma with minimal adverse effects. PMID- 29263647 TI - Anacetrapib as a potential cardioprotective strategy. AB - Cholesteryl ester transfer protein (CETP) facilitates movement of esterified cholesterol between high-density lipoproteins (HDLs) and apolipoprotein B containing lipoproteins. By virtue of their ability to raise HDL cholesterol and lower low-density lipoprotein cholesterol, pharmacological inhibitors of CETP have received considerable attention as potential new agents in cardiovascular prevention. While early studies of CETP inhibitors have demonstrated a lack of clinical efficacy and potential toxicity, development of the potent CETP inhibitor, anacetrapib, has moved forward, with emerging evidence suggesting a role in reducing cardiovascular events. The experience with anacetrapib and its potential for use in clinical practice are reviewed here. PMID- 29263648 TI - Functional assessment of CYP3A4 allelic variants on lidocaine metabolism in vitro. AB - Aim: Human cytochrome P450 3A4 is the most abundant isoform of P450 enzyme in the liver. It plays an important role in the metabolism of wide variety of xenobiotic and endogenous substrates. So far, there are few reports about the functional characterization of CYP3A4 variants in terms of specific substrates. The aim of this study was to systematically investigate the genetic polymorphisms of 23 CYP3A4 alleles and evaluate their catalytic activities on the metabolism of lidocaine in vitro. Methods and results: The wild-type and 22 CYP3A4 variants were expressed in Spodoptera frugiperda 21 insect cells. Then the insect microsomes were incubated with the CYP3A4-specific substrate lidocaine. Reactions were performed with 50-3,000 uM for 60 min at 37 degrees C. Lidocaine and its metabolite monoethylglycinexylidide were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry system. Of the 23 CYP3A4 allelic variants tested, 2 variants (CYP3A4*17 and CYP3A4*30) had no detectable enzyme activity; and 5 variants (CYP3A4*2, CYP3A4*5, CYP3A4*9, CYP3A4*16 and CYP3A4*24) showed significantly decreased intrinsic clearance values compared with wild-type CYP3A4*1. Conclusion: As the first study of all these CYP3A4 alleles for lidocaine metabolism, our results in vitro assessment may provide novel insights into the allele-specific and substrate-specific activity of CYP3A4 and may also offer a reference to the personalized treatment of lidocaine in a clinical setting. PMID- 29263649 TI - Regulation profile of the intestinal peptide transporter 1 (PepT1). AB - The intestinal peptide transporter 1 (PepT1) was first identified in 1994. It plays a crucial role in the absorption of small peptides including not only >400 different dipeptides and 8,000 tripeptides digested from dietary proteins but also a repertoire of structurally related compounds and drugs. Owing to its critical role in the bioavailability of peptide-like drugs, such as the anti cancer agents and anti-virus drug, PepT1 is increasingly becoming a striking prodrug-designing target. Therefore, the understanding of PepT1 gene regulation is of great importance both for dietary adaptation and for clinical drug treatment. After decades of research, it has been recognized that PepT1 could be regulated at the transcriptional and post-transcriptional levels by numerous factors. Therefore, the present review intends to summarize the progress made in the regulation of PepT1 and provide insights into the PepT1's potential in clinical aspects of nutritional and drug therapies. PMID- 29263650 TI - Redox-responsive and pH-sensitive nanoparticles enhanced stability and anticancer ability of erlotinib to treat lung cancer in vivo. AB - Purpose: Erlotinib (ETB) is a well-established therapeutic for non-small-cell lung cancer (NSCLC). To overcome drug resistance and severe toxicities in the clinical application, redox-responsive and pH-sensitive nanoparticle drug delivery systems were designed for the encapsulation of ETB. Methods: Poly(acrylic acid)-cystamine-oleic acid (PAA-ss-OA) was synthesized. PAA-ss-OA modified ETB-loaded lipid nanoparticles (PAA-ETB-NPs) were prepared using the emulsification and solvent evaporation method. The tumor inhibition efficacy of PAA-ETB-NPs was compared with that of ETB-loaded lipid nanoparticles (ETB-NPs) and free ETB anticancer drugs in tumor-bearing mice. Results: PAA-ETB-NPs had a size of 170 nm, with a zeta potential of -32 mV. The encapsulation efficiency and drug loading capacity of PAA-ETB-NPs were over 85% and 2.6%, respectively. In vitro cytotoxicity of ETB-NPs were higher than that of ETB solution. The cytotoxicity of PAA-ETB-NPs was the highest. The in vivo tumor growth inhibition by PAA-ETB-NP treatment was significantly higher than that by ETB-NPs and ETB solution. No obvious weight loss was observed in any of the treatment groups, indicating that all the treatments were well tolerated. Conclusion: PAA-ETB-NPs could enhance the stability and anti-cancer ability of ETB to treat lung cancer and are a promising drug delivery system for lung cancer treatment. PMID- 29263651 TI - Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy. AB - Community-acquired bacterial pneumonia (CABP) is a leading cause of death worldwide. However, antibacterial agents used to treat common pathogens in CABP are marked by adverse drug events and increasing antimicrobial resistance. Solithromycin is a new ketolide antibiotic, based on the macrolide antibiotic structure, being studied for use in CABP. It has efficacy in vitro against the common causative pathogens in CABP including Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens. In Phase II and Phase III clinical trials, it has been demonstrated efficacious as a single agent for treatment of CABP with an apparently milder adverse event profile than alternative agents. PMID- 29263652 TI - Astragaloside IV protects rat retinal capillary endothelial cells against high glucose-induced oxidative injury. AB - Aim: Diabetic retinopathy is a microvascular complication of diabetes that leads to blindness. Hyperglycemia causes oxidative stress, which is an important cause in the pathogenesis of microangiopathy. The aim of this study was to investigate the potential protective effects of astragaloside IV (AS-IV) in retinal capillary endothelial cells (RCECs) incubated with high glucose conditions. Methods and results: Based on rat RCECs cultured with high glucose (30 mM) in vitro, a significant increase in cell viability in rat RCECs incubated with both AS-IV and high glucose for 48 or 72 h by MTT assay. The increased viability was accompanied by decreased glucose transporter-1 expression using immunofluorescent assay. Meanwhile, AS-IV reduced intracellular hydrogen peroxide and superoxide, decreased mitochondrial reactive oxygen species in rat RCECs with high glucose by the fluorescent probes, and lowered malondialdehyde levels. In addition, AS-IV increased the activities of total superoxide dismutase, MnSOD, catalase, and glutathione peroxidase. The glutathione content also increased after AS-IV treatment. Furthermore, AS-IV reduced NADPH oxidase 4 expression by western blot method. Conclusion: These results suggest that the main mechanism underlying the protective effects of AS-IV in high glucose-injured RCECs may be related to its antioxidative function. PMID- 29263653 TI - Spotlight on olaratumab in the treatment of soft-tissue sarcoma: design, development, and place in therapy. AB - Soft-tissue sarcoma (STS) is a heterogeneous group of tumors that arise from mesenchymal tissue. The prognosis of metastatic STS is poor with a life expectancy of 12-18 months. The mainstay of treatment is chemotherapy with an anthracycline. The addition of other chemotherapeutic agents to an anthracycline has been studied with limited success in improving outcomes for STS patients. Olaratumab is a fully human IgG1 monoclonal antibody that binds to platelet derived growth factor receptor alpha (PDGFR-alpha) preventing binding of its ligands and receptor activation. This drug recently received the US Food and Drug Administration's accelerated approval for the treatment of advanced STS when combined with doxorubicin. This approval was based upon an improvement in overall survival of patients receiving the combination of doxorubicin and olaratumab compared to those receiving doxo-rubicin alone. In this review, we have analyzed the available literature on the development of olaratumab, its clinical utility, and its place in therapy. Based on early-phase clinical trials, olaratumab appears to be a promising agent for the treatment of STS. PMID- 29263654 TI - The prevalence of medication nonadherence in post-myocardial infarction survivors and its perceived barriers and psychological correlates: a cross-sectional study in a cardiac health facility in Malaysia. AB - Background: Although evidence-based practice has shown the benefits of prescribed cardioprotective drugs in post-myocardial infarction (MI) survivors, adherence rates remain suboptimal. The aim of this study was to determine the prevalence and factors associated with medication nonadherence among post-MI survivors in Malaysia. Materials and methods: This cross-sectional study was conducted from February to September 2016 among 242 post-MI survivors aged 24-96 years at the cardiology outpatient clinic in a Malaysian cardiac specialist center. The study utilized an interviewer-administered questionnaire that consisted of items adapted and modified from the validated Simplified Medication Adherence Questionnaire, sociodemographics, health factors, perceived barriers, and novel psychological attributes, which employed the modified Confusion, Hubbub, and Order Scale and the Verbal Denial in Myocardial Infarction questionnaire. Results: The prevalence of medication nonadherence was 74%. In the multivariable model, denial of illness (AOR 1.2, 95% CI 0.9-1.8; P=0.032), preference to traditional medicine (AOR 8.7, 95% CI 1.1-31.7; P=0.044), lack of information about illness (AOR 3.3, 95% CI 1.1-10.6; P=0.045), fear of side effects (AOR 6.4, 95% CI 2.5-16.6; P<0.001), and complex regimen (AOR 5.2, 95% CI 1.9-14.2; P=0.001) were statistically significant variables associated with medication nonadherence. Conclusion: The relatively higher medication-nonadherence rate in this study was associated with patient-, provider-, and therapy-related factors and the novel psychological attribute denial of illness. Future research should explore these factors using robust methodological techniques to determine temporality among these factors. PMID- 29263655 TI - Improved delivery of the anticancer agent citral using BSA nanoparticles and polymeric wafers. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with a 5-year survival rate of between 30 and 65%. Standard treatment involves surgery, radiation treatment, and chemotherapy. However, there is a high recurrence rate, particularly from locoregional spread. We investigated the use of the natural compound citral (3,7-dimethyl-2,6-octadienal), which can be found in a number of plants, but is particularly abundant in lemon grass (Cymbopogon citratus) oil, for activity against immortalized RMS cells. Significant cancer cell death was seen at concentrations above 150 MUM citral, and mitochondrial morphological changes were seen after incubation with 10 MUM citral. However, since citral is a highly volatile molecule, we prepared albumin particles by a desolvation method to encapsulate citral, as a means of stabilization. We then further incorporated the loaded nanoparticles into a biodegradable polyanhydride wafer to generate a slow release system. The wafers were shown to degrade by 50% over the course of 25 days and to release the active compound. We therefore propose the use of the citral-nanoparticle-polymer wafers for implantation into the tumor bed after surgical removal of a sarcoma as a means to control locoregional spread due to any remaining cancerous cells. PMID- 29263656 TI - Application of Haralick texture features in brain [18F]-florbetapir positron emission tomography without reference region normalization. AB - Objectives: Semi-quantitative image analysis methods in Alzheimer's Disease (AD) require normalization of positron emission tomography (PET) images. However, recent studies have found variabilities associated with reference region selection of amyloid PET images. Haralick features (HFs) generated from the Gray Level Co-occurrence Matrix (GLCM) quantify spatial characteristics of amyloid PET radiotracer uptake without the need for intensity normalization. The objective of this study is to calculate several HFs in different diagnostic groups and determine the group differences. Methods: All image and metadata were acquired through the Alzheimer's Disease Neuroimaging Initiative database. Subjects were grouped in three ways: by clinical diagnosis, by APOE e4 allele, and by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score. Several GLCM matrices were calculated for different direction and distances (1-4 mm) from multiple regions on PET images. The HFs, contrast, correlation, dissimilarity, energy, entropy, and homogeneity, were calculated from these GLCMs. Wilcoxon tests and Student t-tests were performed on Haralick features and standardized uptake value ratio (SUVR) values, respectively, to determine group differences. In addition to statistical testing, receiver operating characteristic (ROC) curves were generated to determine the discrimination performance of the selected regional HFs and the SUVR values. Results: Preliminary results from statistical testing indicate that HFs were capable of distinguishing groups at baseline and follow-up (false discovery rate corrected p<0.05) in particular regions at much higher occurrences than SUVR (81 of 252). Conversely, we observed nearly no significant differences between all groups within ROIs at baseline or follow-up utilizing SUVR. From the ROC analysis, we found that the Energy and Entropy offered the best performance to distinguish Normal versus mild cognitive impairment and ADAS-Cog negative versus ADAS-Cog positive groups. Conclusion: These results suggest that this technique could improve subject stratification in AD drug trials and help to evaluate the disease progression and treatment effects longitudinally without the disadvantages associated with intensity normalization. PMID- 29263657 TI - Impact of the number of aspiration risk factors on mortality and recurrence in community-onset pneumonia. AB - Introduction: The clinical significance of the number of aspiration risk factors in patients with pneumonia is unknown as yet. In the present study, we clarify the significance of the number of aspiration risk factors for mortality and recurrence in pneumonia patients. Methods: This study included 322 patients hospitalized with pneumonia between December 2014 and June 2016. We investigated associations between the number of aspiration risk factors present (orientation disturbance, bedridden, chronic cerebrovascular disease, dementia, sleeping medications and gastroesophageal disease) and 30-day and 6-month mortality, and pneumonia recurrence within 30 days. Results: Patients were categorized by number of risk factors present into groups of 0-1, 2, 3, and 4 or more. Of a total of 322 patients, 93 (28.9%) had 0-1 risk factors, 112 (34.8%) had 2, 88 (27.3%) had 3, and 29 (9.0%) had 4 or more risk factors. The percentages of patients with recurrence of pneumonia were 13.0%, 33.0%, 43.2%, and 54.2% in the 0-1, 2, 3, and 4 or more risk factor groups, respectively. The percentages of patients with 30 day mortality were 2.2%, 5.4%, 11.4%, and 24.1%, and those of patients with 6 month mortality were 6.6%, 24.5%, 30.7%, and 50.0%, in the 0-1, 2, 3, and 4 or more risk factor groups, respectively. Conclusions: The number of aspiration risk factors was associated with increases in both mortality and recurrence in pneumonia patients. Therefore, in clinical practice, physicians should consider not only the presence of aspiration risks but also the number of aspiration risk factors in these patients. PMID- 29263658 TI - Smoking history and emphysema in asthma-COPD overlap. AB - Background: Emphysema is a distinct feature for classifying COPD, and smoking history (>=10 pack-years) is one of several newly proposed criteria for asthma COPD overlap (ACO). We studied whether or not a smoking history (>=10 pack-years) and emphysema are useful markers for classifying ACO and differentiating it from asthma with chronic airflow obstruction (CAO). Methods: We retrospectively studied the mortalities and frequencies of exacerbation in 256 consecutive patients with ACO (161 with emphysema and 95 without emphysema) who had >=10 pack years smoking history, 64 asthma patients with CAO but less of a smoking history (<10 pack-years) and 537 consecutive patients with COPD (452 with emphysema and 85 without emphysema) from 2000 to 2016. In the patients with emergent admission, the causes were classified into COPD exacerbation, asthma attack, and others. Results: No asthma patients with CAO had emphysema according to computed tomography findings. The prognoses were significantly better in patients with asthma and CAO than in those with ACO and COPD and better in those with ACO than in those with COPD. In both ACO and COPD patients, the prognoses were better in patients without emphysema than in those with it (P=0.027 and P=0.023, respectively). The frequencies of emergent admission were higher in COPD patients than in ACO patients, and higher in patients with emphysema than in patients without emphysema. ACO/emphysema (+) patients experienced more frequent admission due to COPD exacerbation (P<0.001), while ACO/emphysema (-) patients experienced more frequent admission due to asthma attack (P=0.014). Conclusion: A smoking history (>=10 pack-years) was found to be a useful marker for differentiating ACO and asthma with CAO, and emphysema was a useful marker for classifying ACO. These markers are useful for predicting the overall survival and frequency of exacerbation. PMID- 29263659 TI - Real-life feasibility and effectiveness of home-based pulmonary rehabilitation in chronic obstructive pulmonary disease requiring medical equipment. AB - Background: Pulmonary rehabilitation (PR) is a key treatment of chronic obstructive pulmonary disease (COPD) but studies are still needed to identify the most pertinent criteria to personalize this intervention and improve its efficacy. Objective: This real-life retrospective study compared the effects of home-based PR on exercise tolerance, anxiety, depression, and health-related quality of life (HRQoL) in COPD patients, according to their medical equipment. Methods: Exercise tolerance, anxiety, depression, and HRQoL were evaluated in 109 patients equipped with long-term oxygen therapy (LTOT), 84 patients with noninvasive ventilation (NIV), 25 patients with continuous positive airway pressure (CPAP), and 80 patients with no equipment (NE), before, just after, and 6 and 12 months after PR. Results: At baseline, the body mass index in the CPAP and NIV groups was higher (p<0.05) than in the other two groups, and the forced expiratory volume in 1 second was lower in the LTOT and NIV groups (p<0.001). All parameters improved after PR in the four groups (p<0.05), but for exercise tolerance, only the 6-minute stepper test showed maintained improvement after 6 and 12 months, whereas the 10 times sit-to-stand and timed up-and-go tests were only improved just after PR. At every time point, exercise tolerance was lower in the LTOT group (p<0.05), with a similar trend in the NIV group. Conclusion: Despite differences in the medical equipment to treat COPD, home-based PR showed comparable feasibility, safety, and efficacy in all equipment-based groups. Medical equipment should therefore not be a barrier to home-based PR. PMID- 29263660 TI - Predicting treatable traits for long-acting bronchodilators in patients with stable COPD. AB - Purpose: There is currently no measure to predict a treatability of long-acting beta-2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) in patients with chronic obstructive pulmonary disease (COPD). We aimed to build prediction models for the treatment response to these bronchodilators, in order to determine the most responsive medication for patients with COPD. Methods: We performed a prospective open-label crossover study, in which each long-acting bronchodilator was given in a random order to 65 patients with stable COPD for 4 weeks, with a 4 week washout period in between. We analyzed 14 baseline clinical traits, expression profiles of 31,426 gene transcripts, and damaged-gene scores of 6,464 genes acquired from leukocytes. The gene expression profiles were measured by RNA microarray and the damaged-gene scores were obtained after DNA exome sequencing. Linear regression analyses were performed to build prediction models after using factor and correlation analyses. Results: Using a prediction model for a LABA, traits found associated with the treatment response were post-bronchodilator forced expiratory volume in 1 second, bronchodilator reversibility (BDR) to salbutamol, expression of three genes (CLN8, PCSK5, and SKP2), and damage scores of four genes (EPG5, FNBP4, SCN10A, and SPTBN5) (R2=0.512, p<0.001). Traits associated with the treatment response to a LAMA were COPD assessment test score, BDR, expression of four genes (C1orf115, KIAA1618, PRKX, and RHOQ) and damage scores of three genes (FBN3, FDFT1, and ZBED6) (R2=0.575, p<0.001). The prediction models consisting only of clinical traits appeared too weak to predict the treatment response, with R2=0.231 for the LABA model and R2=0.121 for the LAMA model. Conclusion: Adding the expressions of genes and damaged-gene scores to the clinical traits may improve the predictability of treatment response to long-acting bronchodilators. PMID- 29263661 TI - Improved spirometric detection of small airway narrowing: concavity in the expiratory flow-volume curve in people aged over 40 years. AB - Background and objective: We have explored whether assessing the degree of concavity in the descending limb of the maximum expiratory flow-volume curve enhanced spirometric detection of early small airway disease. Methods: We used spirometry records from 890 individuals aged >=40 years (mean 59 years), recruited for the Burden of Obstructive Lung Disease Australia study. Central and peripheral concavity indices were developed from forced expired flows at 50% and 75% of the forced vital capacity, respectively, using an ideal line joining peak flow to zero flow. Results: From the 268 subjects classified as normal never smokers, mean values for post-bronchodilator central concavity were 18.6% in males and 9.1% in females and those for peripheral concavity were 50.5% in males and 52.4% in females. There were moderately strong correlations between concavity and forced expired ratio (forced expiratory volume in 1 second/forced vital capacity) and mid-flow rate (forced expiratory flow between 25% and 75% of the FVC [FEF25%-75%]; r=-0.70 to -0.79). The additional number of individuals detected as abnormal using the concavity indices was substantial, especially compared with FEF25%-75%, where it was approximately doubled. Concavity was more specific for symptoms. Conclusion: The inclusion of these concavity measures in the routine reports of spirometry would add information on small airway obstruction at no extra cost, time, or effort. PMID- 29263662 TI - Selenium-coated nanostructured lipid carriers used for oral delivery of berberine to accomplish a synergic hypoglycemic effect. AB - Diabetes mellitus is an incurable metabolic disorder that seriously threatens human health. At present, there is no effective medication available to defeat it. This work intended to develop selenium-coated nanostructured lipid carriers (SeNLCs) for enhancing the oral bioavailability and the curative effect of berberine, an antidiabetic phytomedicine. Berberine-loaded SeNLCs (BB-SeNLCs) were prepared by hot-melt dispersion/homogenization procedure followed by in situ reduction. BB-SeNLCs were characterized by particle size, morphology, entrapment efficiency (EE) and in vitro release. Pharmacokinetics of berberine solution, berberine-loaded NLCs (BB-NLCs) and BB-SeNLCs were studied in Sprague Dawley rats administered by oral gavage. The prepared BB-SeNLCs were around 160 nm in particle size with an EE of 90%. In addition, BB-SeNLCs exhibited a better sustained release of berberine compared to the plain NLCs. After oral administration, BB-SeNLCs greatly enhanced the oral bioavailability of berberine, which was approximately 6.63 times as much as that of berberine solution. The hypoglycemic effect of BB-SeNLCs was also significantly superior to that of BB NLCs and berberine solution. It turned out that sustained drug release and good intestinal absorption, plus the synergy of selenium, were basically responsible for enhanced oral bioavailability and hypoglycemic effect. Our findings show that SeNLCs are promising nanocarriers for oral delivery of berberine to strengthen the antidiabetic action. PMID- 29263663 TI - Multifunctionalized polyethyleneimine-based nanocarriers for gene and chemotherapeutic drug combination therapy through one-step assembly strategy. AB - Gene therapy combined with chemotherapy to achieve synergistic therapeutic effects has been a hot topic in recent years. In this project, the human tumor necrosis factor-related apoptosis-inducing ligand-encoding plasmid gene (TRAIL) and doxorubicin (Dox)-coloaded multi-functional nanocarrier was constructed based on the theory of circulation, accumulation, internalization, and release. Briefly, polyethyleneimine (PEI) was selected as skeleton material to synthesize PEI-polyethylene glycol (PEG)-TAT (PPT). Dox was conjugated to PEI using C6 succinimidyl 6-hydrazinonicotinate acetone hydrazone (C6-SANH), and a pH sensitive Dox-PEI (DP) conjugate was obtained. Then, intracellular cationic pH sensitive cellular assistant PPT and DP were mixed to condense TRAIL, and TRAIL Dox coloaded PPT/DP/TRAIL (PDT) nanocarriers were obtained by one-step assembly. TRAIL was completely condensed by DP or PPT when mass ratios (DP/PPT to TRAIL) were up to 100:64, which indicated that DP and PPT could be mixed at any ratio for TRAIL condensation. The intracellular uptake rate of PDT was enhanced (P<0.05) when the contents of PPT in PPT+DP increased from 0 to 30%. Free Dox and TRAIL-loaded nanocarriers (PPT/C6-SANH-PEI/TRAIL [PCT]) were selected as controls to verify the synergistic antitumor effects of PDT. Compared with free TRAIL, TRAIL-protein expression was upregulated by PDT and PCT on Western blotting assays. The in vitro cytotoxicity of PDT was significantly enhanced compared to free Dox and PCT (P<0.01). Furthermore, murine PDT nanocarriers showed higher in vivo antitumor ability than both the Dox group (P<0.05) and the murine PCT group (P<0.05). These results indicated that the TRAIL + Dox synergistic antitumor effect could be achieved by PDT, which paves the way to gene-drug combination therapy for cancer. PMID- 29263664 TI - Synthesis of pH stable, blue light-emitting diode-excited, fluorescent silica nanoparticles and effects on cell behavior. AB - To date, delivery of light-emitting diode (LED)-activated compounds to cells and tissue remains a challenge. Silica-based materials possess good biocompatibility and have advantages of control of size and shape. Fluorescent silica nanoparticles (NPs) have been synthesized and used for applications such as cell tracking and tumor identification. Here, we report the synthesis and optimization of fluorescent silica NPs, which incorporate a naphthalimide dye with triethoxysilanes that are excited by the blue LED wavelength (LEDex NPs). The NPs can be imaged in the 420-470 nm wavelength, demonstrate a high quantum yield, are stable in a range of pH, and are taken into the cells. Therefore, these NPs represent a novel imaging technology for biomedical applications. PMID- 29263665 TI - Atomic layer deposition of nano-TiO2 thin films with enhanced biocompatibility and antimicrobial activity for orthopedic implants. AB - Titanium (Ti) and its alloys have been extensively used as implant materials in orthopedic applications. Nevertheless, implants may fail due to a lack of osseointegration and/or infection. The aim of this in vitro study was to endow an implant surface with favorable biological properties by the dual modification of surface chemistry and nanostructured topography. The application of a nanostructured titanium dioxide (TiO2) coating on Ti-based implants has been proposed as a potential way to enhance tissue-implant interactions while inhibiting bacterial colonization simultaneously due to its chemical stability, biocompatibility, and antimicrobial properties. In this paper, temperature controlled atomic layer deposition (ALD) was introduced for the first time to provide unique nanostructured TiO2 coatings on Ti substrates. The effect of nano TiO2 coatings with different morphology and structure on human osteoblast and fibroblast functions and bacterial activities was investigated. In vitro results indicated that the TiO2 coating stimulated osteoblast adhesion and proliferation while suppressing fibroblast adhesion and proliferation compared to uncoated materials. In addition, the introduction of nano-TiO2 coatings was shown to inhibit gram-positive bacteria (Staphylococcus aureus), gram-negative bacteria (Escherichia coli), and antibiotic-resistant bacteria (methicillin-resistant Staphylococcus aureus), all without resorting to the use of antibiotics. Our results suggest that the increase in nanoscale roughness and greater surface hydrophilicity (surface energy) together could contribute to increased protein adsorption selectively, which may affect the cellular and bacterial activities. It was found that ALD-grown TiO2-coated samples with a moderate surface energy at 38.79 mJ/m2 showed relatively promising antibacterial properties and desirable cellular functions. The ALD technique provides a novel and effective strategy to produce TiO2 coatings with delicate control of surface nanotopography and surface energy to enhance the interfacial biocompatibility and mitigate bacterial infection, and could potentially be used for improving numerous orthopedic implants. PMID- 29263666 TI - Development of surface-engineered PLGA nanoparticulate-delivery system of Tet1 conjugated nattokinase enzyme for inhibition of Abeta40 plaques in Alzheimer's disease. AB - According to the World Health Organization, globally there are around 18 million patients suffering from Alzheimer's disease (AD), and this number is expected to double by 2025. The pathophysiology of AD includes selective deposition of Abeta peptide in the mitochondria of cells, which inhibits uptake of glucose by neurons and key enzyme functions. Current drug treatments for AD are unable to rectify the underlying pathology of the disease; they only provide short-term symptomatic relief, so there is a need for the development of newer treatment regimes. The antiamyloid activity, antifibrinolytic activity, and antithrombotic activity of nattokinase holds potential for the treatment of AD. As nattokinase is a protein, its stability restricts its usage to a greater extent, but this limitation can be overcome by nanoencapsulation. In this work, we successfully synthesized polymeric nanoparticles of nattokinase and characterized its use by different techniques: transmission electron microscopy, scanning electron microscopy, DTS Nano, differential scanning calorimetry, Fourier-transform infrared spectroscopy, thioflavin T-binding assay, in vitro drug release, antifibrinolytic activity, and in vivo antiamyloid activity. As brain targeting of hydrophilic drugs is complicated due to the stringent nature of blood-brain barrier, in the current experimental study, we conjugated poly(lactic-co-glycolic acid) (PLGA) encapsulated nattokinase with Tet1 peptide, which exhibits retrograde transportation properties because of its affinity to neurons. Our study suggests that PLGA-encapsulated nattokinase polymeric nanoparticles are able to downregulate amyloid aggregation and exhibit antifibrinolytic activity. The encapsulation of nattokinase in PLGA did not affect its enzyme activity, so the prepared nanoformulation containing nattokinase can be used as an effective drug treatment against AD. PMID- 29263667 TI - Oral immunization of mice with Omp31-loaded N-trimethyl chitosan nanoparticles induces high protection against Brucella melitensis infection. AB - Brucellosis is a group of closely associated zoonotic bacterial illnesses caused by members of the genus Brucella. B. melitensis Omp31 is a promising candidate for a subunit vaccine against brucellosis. This study surveyed the immunogenicity of Omp31 alone and with incomplete Freund's adjuvant (Omp31-IFA) and N-trimethyl chitosan (TMC/Omp31) nanoparticles (NPs), as well as the effect of Omp31 immunization route on immunological responses and protection. After expression and purification, the recombinant Omp31 (rOmp31) was loaded onto TMC NPs by ionic gelation. The particle size, loading efficiency and in vitro release of the NPs were examined. Omp31-IFA was administered intraperitoneally, while TMC/Omp31 NPs were administered orally and intraperitoneally. According to the antibody subclasses and cytokine profile, intraperitoneal immunization by Omp31-IFA and TMC/Omp31 NPs induced T helper 1 (Th1) and Th1-Th2 immune responses, respectively. On the other hand, oral immunization with TMC/Omp31 NPs elicited a mixed Th1-Th17 immune response. Data obtained from the cell proliferation assay showed that vaccination with Omp31 stimulated a vigorous antigen-specific cell proliferative response, which could be further increased after oral immunization with TMC/Omp31 NPs. Vaccinated groups of mice when challenged with B. melitensis 16M were found to be significantly protected in the orally administered group in comparison with the intraperitoneally immunized mice. Results of this study indicated that the reason for high protection after oral vaccination can be via elicited Th17 response. PMID- 29263668 TI - Sodium cholate-enhanced polymeric micelle system for tumor-targeting delivery of paclitaxel. AB - Purpose: Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of paclitaxel (PTX). High antitumor efficacy and low toxicity require that PTX mainly accumulated in tumors with little drug exposure to normal tissues. However, many PTX-loaded micelle formulations suffer from low stability, fast drug release, and lack of tumor-targeting capability in the circulation. To overcome these challenges, we developed a micellar formulation that consists of sodium cholate (NaC) and monomethoxy poly (ethylene glycol)-block-poly (d,l lactide) (mPEG-PDLLA). Methods: PTX-loaded NaC-mPEG-PDLLA micelles (PTX-CMs) and PTX-loaded mPEG-PDLLA micelles (PTX-Ms) were formulated, and their characteristics, particle size, surface morphology, release behavior in vitro, pharmacokinetics and in vivo biodistributions were researched. In vitro and in vivo tumor inhibition effects were systematically investigated. Furthermore, the hemolysis and acute toxicity of PTX-CMs were also evaluated. Results: The size of PTX-CMs was 53.61+/-0.75 nm and the zeta-potential was -19.73+/-0.68 mV. PTX was released much slower from PTX-CMs than PTX-Ms in vitro. Compared with PTX-Ms, the cellular uptake of PTX-CMs was significantly reduced in macrophages and significantly increased in human cancer cells, and therefore, PTX-CMs showed strong growth inhibitory effects on human cancer cells. In vivo, the plasma AUC0 t of PTX-CMs was 1.8-fold higher than that of PTX-Ms, and 5.2-fold higher than that of Taxol. The biodistribution study indicated that more PTX-CMs were accumulated in tumor than PTX-Ms and Taxol. Furthermore, the significant antitumor efficacy of PTX-CMs was observed in mice bearing BEL-7402 hepatocellular carcinoma and A549 lung carcinoma. Results from drug safety assessment studies including acute toxicity and hemolysis test revealed that the PTX-CMs were safe for in vivo applications. Conclusion: These results strongly revealed that NaC-mPEG-PDLLA micelles can tumor-target delivery of PTX and enhance drug penetration in tumor, suggesting that NaC-mPEG-PDLLA micelles are promising nanocarrier systems for anticancer drugs delivery. PMID- 29263669 TI - Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement. AB - Solid self-emulsifying drug delivery system (SSEDDS), which incorporates liquid SEDDS into a solid dosage form, has been recently introduced to improve the oral bioavail-ability of poorly water-soluble drugs. However, supersaturated drug generated by SSEDDS is thermodynamically unstable and tends to precipitate rapidly prior to absorption, resulting in compromised bioavailability. The aim of this study was to construct a novel supersaturated SSEDDS (super-SSEDDS) by combining SSEDDS with appropriate precipitation inhibitor. Fenofibrate (FNB), a sparingly soluble drug, was selected as a model drug in this study. An optimized SSEDDS was prepared by solvent evaporation by using mesoporous silica Santa Barbara Amorphous-15 as the inert carrier. Supersaturation assay was conducted to evaluate the precipitation inhibition capacity of different polymers, and the results showed that Soluplus(r) could retard the FNB precipitation more effectively and sustain a higher apparent concentration for ~120 min. This effect was also clearly observed in the dissolution profiles of FNB from SSEDDS under supersaturated condition. The study of the mechanism suggested that the inhibition effect might be achieved both thermodynamically and kinetically. The area under the concentration-time curve of the super-SSEDDS was 1.4-fold greater than that of SSEDDS in the absence of Soluplus, based on an in vivo pharmacokinetic study conducted in beagle dogs. This study has demonstrated that the approach of combining SSEDDS with Soluplus as a supersaturation stabilizer constitutes a potential tool to improve the absorption of poorly water-soluble drugs. PMID- 29263670 TI - Polyvinylpyrrolidone-coated gold nanoparticles inhibit endothelial cell viability, proliferation, and ERK1/2 phosphorylation and reduce the magnitude of endothelial-independent dilator responses in isolated aortic vessels. AB - Background: Gold nanoparticles (AuNPs) demonstrate clinical potential for drug delivery and imaging diagnostics. As AuNPs aggregate in physiological fluids, polymer-surface modifications are utilized to allow their stabilization and enhance their retention time in blood. However, the impact of AuNPs on blood vessel function remains poorly understood. In the present study, we investigated the effects of AuNPs and their stabilizers on endothelial cell (EC) and vasodilator function. Materials and methods: Citrate-stabilized AuNPs (12+/-3 nm) were synthesized and surface-modified using mercapto polyethylene glycol (mPEG) and polyvinylpyrrolidone (PVP) polymers. Their uptake by isolated ECs and whole vessels was visualized using transmission electron microscopy and quantified using inductively coupled plasma mass spectrometry. Their biological effects on EC proliferation, viability, apoptosis, and the ERK1/2-signaling pathway were determined using automated cell counting, flow cytometry, and Western blotting, respectively. Endothelial-dependent and independent vasodilator functions were assessed using isolated murine aortic vessel rings ex vivo. Results: AuNPs were located in endothelial endosomes within 30 minutes' exposure, while their surface modification delayed this cellular uptake over time. After 24 hours' exposure, all AuNPs (including polymer-modified AuNPs) induced apoptosis and decreased cell viability/proliferation. These inhibitory effects were lost after 48 hours' exposure (except for the PVP-modified AuNPs). Furthermore, all AuNPs decreased acetylcholine (ACh)-induced phosphorylation of ERK1/2, a key signaling protein of cell function. mPEG-modified AuNPs had lower cytostatic effects than PVP-modified AuNPs. Citrate-stabilized AuNPs did not alter endothelial-dependent vasodilation induced by ACh, but attenuated endothelial-independent responses induced by sodium nitroprusside. PVP-modified AuNPs attenuated ACh-induced dilation, whereas mPEG-modified AuNPs did not, though this was dose-related. Conclusion: We demonstrated that mPEG-modified AuNPs at a therapeutic dosage showed lower cytostatic effects and were less detrimental to vasodilator function than PVP modified AuNPs, indicating greater potential as agents for diagnostic imaging and therapy. PMID- 29263672 TI - Differences between autogenous and reactive obsessions in terms of metacognitions and automatic thoughts. AB - Background: Obsessive compulsive disorder (OCD) is characterized by obsessions and compulsions. Obsessions have been classified as autogenous obsessions and reactive obsessions on the basis of the cognitive theory of Lee and Kwon. The aim of this study was to investigate the differences between autogenous groups (AG) and reactive groups (RG) in terms of metacognition and automatic thoughts, for the purpose of investigating the differences of cognitive appraisals. Methods: One hundred and thirty-three patients diagnosed with OCD were included in the study as the patient group. A control group was formed of 133 age, gender and education-matched healthy individuals. The OCD group patients were separated into subgroups according to the primary obsessions. The sociodemographic data, and the Yale-Brown Obsessive Compulsive Scale, Metacognition Questionnaire-30 (MCQ-30), Automatic Thoughts Questionnaire (ATQ), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores of the AG, RG, and control groups were compared. Results: The MCQ-30 (total) and the subscales of MCQ-30 and ATQ scale points were seen to be significantly higher in the AG than in the RG and significantly higher in the RG than in the control group. In the reactive obsession group, the predictive variables of the ATQ points were determined to be MCQ-30 (total), BDI and BAI. In the autogenous obsession group, the predictive variables of the ATQ points were determined to be BDI and BAI. Conclusion: In the current study, differences were determined between the AG and the RG in respect of metacognitions and automatic thoughts. In light of these results, the recommended grouping can be considered useful in the identification of OCD sub-types. There is a need for further studies to identify more homogenous sub-types of OCD. Future multi-centered studies of sub-typing with larger samples using more specific instruments to sub-type and dimensional evaluation will be useful for detailed evaluation and better understanding of the subject. PMID- 29263671 TI - Verbal memory improvement in first-episode psychosis APOE-epsilon4 carriers: a pleiotropic effect? AB - Background: Verbal memory impairment is a core feature in schizophrenia even at early stages of the disease, but its etiopathogenesis is not fully understood. The APOE-epsilon4 is the main genetic risk factor for late-onset Alzheimer's disease. Our primary goal was to ascertain whether APOE-epsilon4 status had a pleiotropic effect in early stages of the illness. Participants and methods: A total of 86 first-episode psychosis (FEP) outpatients and 39 healthy volunteers were recruited. Demographic and clinical data, APOE genotyping, and a neuropsychological test battery including the California Verbal Learning Test - second edition (CVLT-II) were administered and assessed at study entry and at 1 year follow-up. Data were analyzed using mixed-model repeated measures, where the dependent variable was verbal memory indexed by California Verbal Learning Test (CVLT) Trials 1-5 total recall score. Results: FEP-APOE-epsilon4 carriers and FEP APOE-epsilon4 noncarriers had similar symptom severity, clinical outcomes, premorbid and current intelligence quotient, and exposure to antipsychotics. There was a main effect of group on CVLT 1-5 (FEP =43.30 vs control =58.25; F[1, 119.7]=42.97; P<0.001) as well as an APOE-epsilon4 by group by time (F[4, 116.2]=2.73, P=0.033) interaction with only FEP-APOE-epsilon4 carriers showing improved verbal memory at follow-up. Conclusion: Our study is the first to report improvement in verbal memory in persons afflicted by FEP who are APOE-epsilon4 carriers and replicates the prominent verbal memory deficits present in FEP. Our work provides further evidence pointing to an antagonistic pleiotropic effect of APOE-epsilon4 in neuropsychiatric disorders. Our results merit further research into antagonistic pleiotropic effects in schizophrenia. PMID- 29263673 TI - Incidence and risk factors of poor clinical outcomes in patients with cervical kyphosis after cervical surgery for spinal cord injury. AB - Objective: This retrospective study investigated the incidence and risk factors of poor clinical outcomes after cervical surgery for cervical spinal cord injury in a large population of patients with global or segmental cervical kyphosis. Methods: The clinical and radiological evaluation results of 269 patients with cervical kyphosis who underwent either anterior or posterior surgery between 2008 and 2013 were collected, preoperatively and at each follow-up after surgery. Results: All patients were followed for an average of 2.5 years. Outcomes were classified as good or poor (n=156 and 113 patients, respectively), based on the Japanese Orthopedic Association (JOA) recovery ratios. The rates of patients with good or poor outcomes were statistically comparable with regard to gender ratio, type of injury, history of diabetes or cardiovascular disease, interval between injury and surgery, and follow-up time. The multivariate logistic regression analysis indicated that the following were independent predictors of poor improvement: patient age (P=0.016, odds ratio [OR] =1.0261); preoperative JOA scores (P=0.003, OR =0.1932); and cervical instability (P=0.004, OR =2.1562). Conclusion: This study showed that advanced age, low preoperative JOA score, and cervical instability are closely associated with a poor surgical outcome in patients with cervical kyphosis. However, these results do not suggest that the type of cervical kyphosis influences the clinical outcome of surgery. PMID- 29263675 TI - Meaning in family caregiving for people with dementia: a narrative study about relationships, values, and motivation, and how day care influences these factors. AB - Background: In addition to care-related burdens, most caregivers of a person with dementia perceive a variety of positive and satisfying experiences, such as feeling needed and useful in their family caregiving role. "Meaning-focused coping" describes both positive and negative emotions in periods with high levels of stress. Day care service may have the potential to increase caregivers' positive experiences and meaning-focused coping, and positively influence interpersonal relationships between those giving care and those receiving care. The aim of this study was to gain knowledge about family caregivers' experiences of meaning in their caring role. Additionally, the influence of day care services on caregivers' experiences and motivation in their caregiving role is explored. Methods: A qualitative design based on individual interviews was used. The interviews were analyzed using a narrative method and a case study approach. Findings: Family caregivers' roles and coping strategies were related to their relational ties. Caregivers had to make decisions about whether to enhance, maintain, or let go of emotional ties to find a good balance between meeting their own needs and the needs of the person with dementia. Family caregivers reported that day care positively influenced their "relationship-oriented coping" and experience of meaning. Conclusion: Finding meaning in the role of a family caregiver for persons with dementia is closely connected to the caregivers' own values and goals. Finding a balance between attending to their own needs and the needs of the person with dementia is crucial. Day care has the potential to increase family caregivers' motivation to care by supporting their capacity to meet their own needs, cooperate and communicate with the person with dementia, and make competent and autonomous choices, thus increasing their feeling of mastery. PMID- 29263674 TI - Practical guidance on the use of laboratory testing in the management of bleeding in patients receiving direct oral anticoagulants. AB - Direct oral anticoagulants (DOACs) have demonstrated a favorable benefit-risk profile in several thromboembolic disorders and are increasingly used in routine clinical practice. A number of real-world studies on DOACs are ongoing, and data published so far have shown broadly similar outcomes to those demonstrated in the respective phase III trials. Despite their beneficial attributes, bleeding risk (as with any other anticoagulants) is often a concern for physicians when prescribing DOACs, particularly in elderly patients, those with significant comorbidities, and other high-risk patient populations. Although the absence of routine coagulation monitoring is an advantage of the DOACs, measuring their anticoagulant effect and/or plasma drug levels may be helpful in certain clinical scenarios to help patient management and improve outcomes. In this paper, practical guidance and recommendations are provided for clinical situations in which the test results may aid clinical decision-making, including patients with life-threatening bleeding events, patients without bleeding but with test results indicating a risk of bleeding, for those patients with a suspected thromboembolism while receiving a DOAC, or prior to patients undergoing elective or urgent surgical procedures. Finally, appropriate monitoring of the DOACs could be of substantial benefit to patients, and there is a high potential for development in this area in the future. PMID- 29263676 TI - The combination astemizole-gefitinib as a potential therapy for human lung cancer. AB - Lung cancer is a major cause of cancer mortality. Thus, novel therapies are urgently needed. Repositioning of old drugs is gaining great interest in cancer treatment. Astemizole is an antihistamine proposed to be repositioned for cancer therapy. This drug targets several molecules involved in cancer including histamine receptors, ABC transporters and the potassium channels Eag1 and HERG. Astemizole inhibits the proliferation of different cancer cells including those from cervix, breast, leukemia and liver. Gefitinib is widely used to treat lung cancer; however, no response or drug resistance occurs in many cases. Here, we studied the combined effect of astemizole and gefitinib on the proliferation, survival, apoptosis and gene and protein expression of Eag1 channels in the human lung cancer cell lines A549 and NCI-H1975. Cell proliferation and survival were studied by the MTT method and the colony formation assay, respectively; apoptosis was investigated by flow cytometry. Gene expression was assessed by real-time polymerase chain reaction (RT-PCR), and protein expression was studied by Western blot analysis and immunocytochemistry. We obtained the inhibitory concentrations 20 and 50 (IC20 and IC50, respectively) values for each drug from the cell proliferation experiments. Drug combination at their IC20 had a superior effect by reducing cell proliferation and survival in up to 80% and 100%, respectively. The drugs alone did not affect apoptosis of H1975 cells, but the drug combination at their IC20 increased apoptosis roughly four times in comparison to the effect of the drugs alone. Eag1 mRNA levels and protein expression were decreased by the drug combination in A549 cells, and astemizole induced subcellular localization changes of the channel protein in these cells. Our in vitro studies strongly suggest that the combination astemizole-gefitinib may be a novel and promising therapy for lung cancer patients. PMID- 29263677 TI - Prognostic role of CD82/KAI1 in multiple human malignant neoplasms: a meta analysis of 31 studies. AB - Tetraspanin CD82, also known as KAI1, was revealed as an attractive prognostic tumor biomarker in recent studies. However, some results of these studies remained debatable and inconclusive. Therefore, we conducted a meta-analysis to clarify the precise predictive value of CD82 in various neoplasms. Qualified studies were identified up to April 27, 2017, by searching PubMed, EMBASE, and the Web of Science. In total, 29 eligible studies were ultimately enrolled in this meta-analysis. Pooled hazard ratios (HRs) with 95% CIs of overall survival and disease/recurrence/progression-free survival were calculated to evaluate the correct prognostic role of CD82. Statistical analysis demonstrated that high expression of CD82 was significantly associated with enhanced overall survival (HR =0.56, 95% CI: 0.47-0.67) and disease/recurrence/progression-free survival (HR =0.42, 95% CI: 0.30-0.59) in cancer patients. Furthermore, we also conducted the subgroup analysis and the results revealed that CD82 was associated with favorable outcomes in cancer patients. Taken together, CD82 could be a promising biomarker for predicting the prognosis of patients with malignant neoplasms, and the biological functions of CD82 are of great research value of the subject. PMID- 29263678 TI - Chemotherapy induces ovarian cancer cell repopulation through the caspase 3 mediated arachidonic acid metabolic pathway. AB - Recurrence is one of the major causes of high mortality in ovarian cancer. However, the mechanism of ovarian cancer recurrence after chemotherapy has not been fully understood. In the present study, we investigated the effect of chemotherapy-induced tumor microenvironment on the proliferation of SKOV3 cells. We have shown that SKOV3 cells repopulated faster in the culture medium from apoptotic SKOV3 ovarian cancer cells after 24 h of etoposide phosphate (VP-16) treatment. We found that during apoptosis, cleaved caspase 3 could activate cytosolic calcium-independent phospholipase A2, which stimulated the release of arachidonic acid (AA) and triggered the production of prostaglandin E2 (PGE2). An increased level of phosphorylated focal adhesion kinase (FAK) subsequently facilitated the reproliferation of SKOV3 cells, and VP-16-induced repopulation effects were partially reversed by the FAK inhibitor PF562271. Furthermore, the plasma AA-to-PGE2 ratio and tumoral FAK expression of ovarian cancer patients after chemotherapy were significantly lower than those before chemotherapy. Taken together, our results indicate that chemotherapy-induced apoptotic cancer cells can produce PGE2-enriched microenvironment through caspase 3-mediated AA metabolic pathway, which could lead to the abnormal activation of FAK and eventually accelerate the repopulation of SKOV3 cells. Our study provides novel insight into a mechanism that may be utilized to prevent ovarian cancer recurrence in response to chemotherapy. PMID- 29263679 TI - The clinicopathological significance of HES1 promoter hypomethylation in patients with colorectal cancer. AB - Hairy/enhancer of split 1 (HES1) is a basic helix-loop-helix transcriptional repressor. Aberrant demethylation has been considered a common mechanism of tumor promoter gene activation. In the current study, we aimed to investigate the methylation status of the HES1 promoter and correlations with clinicopathological parameters and prognosis in colorectal cancer (CRC). The expression of HES1 in 50 paired CRC specimens and adjacent normal tissues was determined by using quantitative real-time polymerase chain reaction and immunohistochemical analysis. Moreover, DNA methylation status was evaluated through methylation specific polymerase chain reaction and bisulfite sequencing. The correlation of methylation status with HES1 expression level and clinicopathological parameters was statistically analyzed in CRC patients. Our data showed that the methylation level of HES1 was significantly decreased and negatively correlated with HES1 expression in CRC tissues. Moreover, HES1 hypomethylation was associated with a poor histological grade, Dukes' classification, lymph node metastasis, and clinical stages (P<0.05). Furthermore, survival analyses revealed that a decreased methylation status of HES1 was linked to poor prognosis of CRC patients. In conclusion, promoter hypomethylation upregulates HES1 expression and plays a critical role in the progression and prognosis of CRC patients. PMID- 29263680 TI - Intensity-modulated radiotherapy plus nimotuzumab with or without concurrent chemotherapy for patients with locally advanced nasopharyngeal carcinoma. AB - Objective: This study aimed to evaluate the safety and efficacy of intensity modulated radiotherapy (IMRT) plus nimotuzumab with or without concurrent chemotherapy (CCT) for patients with locally advanced nasopharyngeal carcinoma (LA-NPC). Patients and methods: A total of 50 newly diagnosed patients with LA NPC treated at the Affiliated Hospital of Jiangnan University between November 2011 and January 2017 were retrospectively analyzed. All patients received the combined treatment modality of nimotuzumab plus IMRT. Nimotuzumab was administered concurrently with IMRT at a weekly dose of 200 mg. Neoadjuvant, concurrent or adjuvant chemotherapy with the doublet regimen of taxanes (docetaxel or paclitaxel) plus platinum (cisplatin or nedaplatin) were administered. Among the 50 patients, 43 (86.0%) received >=6 cycles of nimotuzumab (median 7 cycles, range 2-14 cycles) and 29 (58.0%) received two cycles of CCT with docetaxel plus nedaplatin. Results: With a median follow-up of 28.0 months, the 2-year progression-free survival (PFS) and overall survival were 83.29% (95% confidence interval [CI]: 67.93%-91.72%) and 97.67% (95% CI: 84.62% 99.67%), respectively. Both univariate and multivariate analyses revealed that cycles of nimotuzumab were significantly associated with PFS. Patients who received >=6 cycles of nimotuzumab showed a better PFS than those receiving <6 cycles (P=0.006), whereas the addition of CCT failed to improve PFS. Oral mucositis was the most common adverse event, which was recorded as grade 3-4 in 18 (36.0%) patients. Besides, two (4.0%) patients experienced nimotuzumab-related anaphylaxis, and no skin rash was found in any patient. Subgroup analysis revealed that the patients who received CCT had more grade 3-4 adverse events as compared to those who did not receive CCT (62.1% vs 33.3%, P=0.045). Conclusion: The regime of nimotuzumab plus IMRT for the treatment of LA-NPC was well tolerated, with encouraging survival data, and it could be an effective treatment alternative for patients with LA-NPC. Further clinical trials are needed to confirm these findings. PMID- 29263681 TI - Seven-microRNA panel for lung adenocarcinoma early diagnosis in patients presenting with ground-glass nodules. AB - Background: MicroRNA (miRNA) expression is correlated with tumor histology, differentiation, invasiveness and treatment outcome. We aimed to identify miRNAs whose differential expression might enable early diagnosis of lung adenocarcinoma in patients presenting with ground-glass nodules (GGNs). Methods: To identify potential miRNAs of interest, we analyzed the miRNA expression profile of tumor and adjacent non-para-tumor tissue in three participants by next-generation sequencing (NGS). We then assessed the expression levels of the miRNAs of interest in 73 lung adenocarcinomas presenting with GGNs with matched adjacent non-tumor tissue by quantitative real-time polymerase chain reaction (qRT-PCR). We also detected the miRNA panel in 66 lung benign diseases and 66 lung adenocarcinomas presenting with GGN lesion tissues by qRT-PCR. Target genes of our selected miRNA panel were predicted using Miranda with default parameters. Results: Twenty-three miRNAs showed differential expression between tumor and adjacent non-tumor tissue by NGS. Five miRNAs exhibited higher expression in tumor tissue compared to adjacent non-tumor tissue (P<0.05); 18 miRNAs demonstrated lower expression in tumor tissue versus adjacent non-tumor tissue (P<0.05). When qRT-PCR was performed for the 23 miRNAs identified by NGS in the pilot stage, seven were found to have statistically significant expression in tumor versus adjacent non-tumor tissue (P<0.05). The sensitivity and specificity of seven-miRNA panel were 86.4% and 60.6%, respectively. Conclusion: The predicted targets of our miRNAs of interest are frequently associated with cancer signaling pathways. We developed a miRNA panel that could potentially predict the presence of lung adenocarcinoma in patients presenting with GGNs. PMID- 29263682 TI - Evaluation of a new automated Abbott RealTime MTB RIF/INH assay for qualitative detection of rifampicin/isoniazid resistance in pulmonary and extra-pulmonary clinical samples of Mycobacterium tuberculosis. AB - A new automated real-time PCR assay for the detection of rifampicin (RIF) and isoniazid (INH) resistance in Mycobacterium tuberculosis (MTB) was evaluated. A total of 163 clinical samples (128 pulmonary and 35 extra-pulmonary) were processed using four PCR assay kits: Abbott RealTime MTB RIF/INH, Genotype MTBDRplus, Xpert/MTB RIF, and Anyplex MTB/MDR. The results of phenotypic drug susceptibility testing using BACTECMGIT 960 were used as reference. The sensitivity and specificity of the new Abbott RealTime MTB RIF/INH assay in comparison with phenotypic testing was 96.3% (95%CI 87.32%-100%) for RIF and 100% (95%CI 99.3%-100%) for INH; the sensitivity was 78.8% (95%CI 66.8%-90.9%) and the specificity was 100% (95%CI 98.9%-100%). The Abbott RealTime MTB RIF/INH test could be a valid method for detecting the most common mutations in strains resistant to RIF and INH. PMID- 29263683 TI - Contribution of horizontal gene transfer to the emergence of VIM-4 carbapenemase producer Enterobacteriaceae in Kuwait. AB - Carbapenem-resistant Enterobacteriaceae encountered in countries of the Arabian Peninsula usually produce OXA-48-like and New Delhi metallo-beta-lactamases (NDM) carbapenemases. However, a temporary increase in VIM-4-producing, clonally unrelated Enterobacteriaceae strains was described earlier in a Kuwaiti hospital. We investigated the genetic support of blaVIM-4 in six Klebsiella pneumoniae strains, one Escherichia coli, and one Enterobacter cloacae strain and compared it to that of VIM-4-producing isolates from other countries of the region. Five K. pneumoniae strains and the E. coli strain from Kuwait carried an ~165 kb IncA/C-type plasmid indistinguishable by restriction fragment length polymorphism. The complete sequence of one of them (pKKp4-VIM) was established. pKKp4-VIM exhibited extensive similarities to episomes pKP-Gr642 carrying blaVIM 19 encountered in Greece and to the partially sequenced pCC416 harboring blaVIM-4 detected in Italy. In other countries of the region, the only similar plasmid was the one detected in the isolate from the UAE. In all Kuwaiti strains, irrespective of the species and their VIM plasmids, the blaVIM-4 gene was located within the same integron structure (In416), different from those of other countries of the region. Our data show that the spread of this IncA/C plasmid and particularly that of the In416 integron caused a considerable, albeit temporary, increase in the rate of mostly clonally unrelated VIM-producing Enterobacteriaceae strains of multiple species. Monitoring of such events is of high importance as the interference with the spread of mobile genetic elements may represent a formidable challenge to infection control. PMID- 29263684 TI - Different phenotypic and molecular mechanisms associated with multidrug resistance in Gram-negative clinical isolates from Egypt. AB - Objectives: We set out to investigate the prevalence, different mechanisms, and clonal relatedness of multidrug resistance (MDR) among third-generation cephalosporin-resistant Gram-negative clinical isolates from Egypt. Materials and methods: A total of 118 third-generation cephalosporin-resistant Gram-negative clinical isolates were included in this study. Their antimicrobial susceptibility pattern was determined using Kirby-Bauer disk diffusion method. Efflux pump mediated resistance was tested by the efflux-pump inhibitor-based microplate assay using chlorpromazine. Detection of different aminoglycoside-, beta-lactam-, and quinolone-resistance genes was done using polymerase chain reaction. The genetic diversity of MDR isolates was investigated using random amplification of polymorphic DNA. Results: Most of the tested isolates exhibited MDR phenotypes (84.75%). The occurrence of efflux pump-mediated resistance in the different MDR species tested was 40%-66%. Acinetobacter baumannii isolates showed resistance to most of the tested antibiotics, including imipenem. The blaOXA-23-like gene was detected in 69% of the MDR A. baumannii isolates. The MDR phenotype was detected in 65% of Pseudomonas aeruginosa isolates, of which only 23% exhibited efflux pump-mediated resistance. On the contrary, efflux-mediated resistance to piperacillin and gentamicin was recorded in 47.5% of piperacillin-resistant and 25% of gentamicin-resistant MDR Enterobacteriaceae. Moreover, the plasmid mediated quinolone-resistance genes (aac(6')-Ib-cr, qnrB, and qnrS) were detected in 57.6% and 83.33% of quinolone-resistant MDR Escherichia coli and Klebsiella pneumoniae isolates, respectively. The beta-lactamase-resistance gene blaSHV-31 was detected for the first time in one MDR K. pneumoniae isolate from an endotracheal tube specimen in Egypt, accompanied by blaTEM-1, blaCTX-M-15, blaCTX M-14, aac(6')-Ib-cr, qnrS, and multidrug efflux-mediated resistance. Conclusion: MDR phenotypes are predominant among third-generation cephalosporin-resistant Gram-negative bacteria in Egypt and mediated by different mechanisms, with an increased role of efflux pumps in Enterobacteriaceae. PMID- 29263685 TI - Performance of VITEK mass spectrometry V3.0 for rapid identification of clinical Aspergillus fumigatus in different culture conditions based on ribosomal proteins. AB - Fast and accurate discrimination of Aspergillus fumigatus is significant, since misidentification may lead to inappropriate clinical therapy. This study assessed VITEK mass spectrometry (MS) V3.0 for A. fumigatus identification using extracted fungal ribosomal proteins. A total of 52 isolates preliminarily identified as A. fumigatus by traditional morphological methods were inoculated in three different culture media and cultured at two different temperatures. The specific spectral fingerprints of different culture time points (48, 72, 96, and 120 h) were obtained. Of all strains, 88.5% (46/52) were discriminated as A. fumigatus, while the remaining 11.5% (6/52) produced results inconsistent with morphological analysis. Molecular sequencing, as a reference method for species identification, was used to validate the morphological analysis and matrix-assisted laser desorption/ionization time of flight MS. Chi-square tests (chi2 test, P=0.05) demonstrated that the culture medium and incubation temperature had no effects on identification accuracy; however, identification accuracy of the strains in the 48-h group was lower than that in other groups. In addition, we found that ribosomal proteins extracted from A. fumigatus can be stored in different environments for at least 1 week, with their profiles remaining stable and strain identification results showing no change. This is beneficial for medical institutions with no mass spectrometer at hand. Overall, this study showed the powerful ability of VITEK MS V 3.0 in identifying A. fumigatus. PMID- 29263686 TI - A novel scoring system for prediction of esophageal varices in critically ill patients. AB - Background and aims: Patients with advanced systemic illness or critically ill patients may present with upper gastrointestinal tract (GIT) bleeding which may need endoscopic intervention; however, this may expose them to unnecessary endoscopy. The aim was to validate a novel scoring system for risk stratification for urgency of GIT endoscopy in critically ill patients. Methods: This is an observational study conducted from January 2013 to January 2016 to analyze 300 patients with critical medical conditions and presenting with upper gastrointestinal bleeding. Meticulous clinical, laboratory, and sonographic evaluations were performed to calculate Glasgow Blatchford score (GBS) and variceal metric score for risk stratification and prediction of the presence of esophageal varices (OV). Finally, this score was applied on a validation group (n=100). Results: The use of GBS and variceal metric scores in critically ill patients revealed that patients who showed a low risk score value for OV (0-4 points) and GBS <2 can be treated conservatively and discharged safely without urgent endoscopy. In patients with a low risk for varices but GBS >2, none of them had OV on endoscopy. In patients with intermediate risk score value for OV (5-8 points) and with GBS >2, 33.33% of them had varices on endoscopy. In patients with high risk score value for varices (9-13) and GBS >2, endoscopy revealed varices in 94.4% of them. Finally, in patients with very high risk score for varices (14-17), endoscopy revealed varices in 100% of them. Conclusion: GBS and variceal metric score were highly efficacious in identifying critically ill patients who will benefit from therapeutic endoscopic intervention. PMID- 29263687 TI - Nutcracker syndrome associated with celiacomesentric trunk anomaly: case report. AB - Introduction: Nutcracker syndrome is a rare disease entity that is caused by entrapment of the left renal vein between the aorta and superior mesenteric artery, usually due to abnormal branching of the superior mesenteric artery from the aorta causing renal venous hypertension. The symptoms vary from asymptomatic hematuria to severe pelvic congestion. Celiacomes-enteric trunk anomaly is a rare variation of splanchnic artery anomaly that occurs when the celiac trunk and superior mesenteric arteries have a common origin from the aorta. A disease involving the rarely encountered celiacomesenteric trunk anomaly is extremely uncommon. To our knowledge, association between nutcracker syndrome and celiacomesentric trunk anomaly has not been reported in the literature. Case presentation: A 14-year-old boy with no significant past medical history presented with a 3-year painless hematuria. CT-angiogram revealed anterior nutcracker syndrome with celiacomesenteric trunk anomaly. The patient was managed conservatively with close follow-up. Conclusion: Nutcracker syndrome associated with celiacomesenteric trunk anomaly is extremely uncommon and is a rare cause of hematuria in children. Whether this abnormal anatomy is the cause of nutcracker syndrome or just an association should be investigated. Moreover, awareness of this anatomical variation may help in planning therapeutic options and reducing the chance of surgical iatrogenic injuries. PMID- 29263688 TI - Erratum: Bone-anchored annular closure following lumbar discectomy reduces risk of complications and reoperations within 90 days of discharge [Corrigendum]. AB - [This corrects the article on p. 2047 in vol. 10, PMID: 28894388.]. PMID- 29263689 TI - Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab. AB - Migraine is a highly disabling neurological condition, and preventative treatment still remains problematic, due to aspecificity of the majority of the currently available prophylactic drugs. Calcitonin-gene-related peptide (CGRP) plays a crucial role in migraine pathophysiology; agents aimed at blocking its activity have, therefore, been developed in recent years, among which are monoclonal antibodies (mAbs) against CGRP, to prevent migraine. Erenumab is the only mAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. This review will report on the most recent data on erenumab characteristics and on the results of clinical trials on its employment in the prevention of episodic migraine (4-14 monthly migraine days): one Phase II and two Phase III trials (completed) and one Phase III trial (ongoing). Monthly subcutaneous administration (70 mg or 140 mg) of erenumab vs placebo for 3-6 months showed significantly higher efficacy in reducing the mean monthly number of migraine days and the use of migraine-specific medication, and in decreasing physical impairment and impact of migraine on everyday activities (P<0.001). A favorable safety profile was demonstrated by the lack of significant differences in the occurrence of adverse events in erenumab-treated vs placebo-treated patients. Global results so far obtained point to erenumab as a new promising candidate for the preventative treatment of episodic migraine. Licence applications for erenumab were recently submitted to the Food and Drug Administration in the USA and European Medicines Agency in Europe (May/June 2017). PMID- 29263690 TI - The effects of slow-paced versus mechanically assisted breathing on autonomic function in fibromyalgia patients. AB - Paced breathing has shown efficacy in fibromyalgia (FM), but the mechanisms associated with symptom change are largely unknown. We investigated whether changes in respiratory rate (RR) alone resulted in autonomic changes during normal, paced, and mechanically assisted breathing in untrained FM patients and controls. Participants included 20 FM patients and 14 controls matched for age and body mass index. During a single visit, participants completed three 15 minute breathing sessions: 1) normal breathing, 2) slow-paced breathing, and 3) mechanically assisted breathing (continuous positive airway pressure) while supine. Continuous blood pressure and electrocardiogram were recorded, and measures of heart rate variability (HRV) and spontaneous baroreceptor sensitivity (sBRS) were calculated. During normal breathing, FM patients had higher heart rate (HR), but lower HRV and sBRS variables compared to controls with no difference in RR. Compared to the paced breathing condition, FM patients had significantly lower HR with higher HRV and sBRS variables during mechanically assisted breathing, despite no significant change in RR. Mechanically assisted breathing provided greater benefits in autonomic function than paced breathing in untrained FM patients. Future research will be needed to elucidate the central pathways involved in these autonomic changes and whether training in paced breathing can eventually replicate the results seen in mechanically assisted patients. PMID- 29263691 TI - The sustained influence of prior experience induced by social observation on placebo and nocebo responses. AB - Background: Social observation is one of the main ways to gain experience. Similar to first-person experience, observational experience affects the effectiveness of subsequent treatments. Yet, it is still undetermined whether the influence of social observation on placebo and nocebo effects to subsequent treatments remains even if related experience occurred a few days ago. Methods: Eighty-two participants were recruited and each of them was randomly assigned to one of the four experimental groups acquiring first-person or observational experience, which was either effective or ineffective. For the first-person groups, participants were presented with pain cues paired with pain stimuli in person. In the effective condition, low pain cues were paired with low pain stimuli, and high pain cues were paired with high pain stimuli. In contrast, the associations between cues and pain stimuli were not established in the ineffective condition. Similarly, for the observational groups, participants received effective/ineffective treatment through observation. Five or six days later, all participants underwent a conditioning phase followed by a test phase composed of two tests, where participants were asked to report their perceived pain. Results: Placebo and nocebo responses to subsequent treatments can be affected by prior experience gained several days ago regardless of acquisition ways, and both placebo and nocebo responses in the effective condition were significantly larger than those in the ineffective condition. Furthermore, once placebo and nocebo effects were elicited, the latter was more persistent, while the former was more likely to diminish. Conclusion: First-person and observational experience obtained a few days ago could affect the following treatments, which advance our understanding of the crucial and sustained influence of social observation on placebo analgesia and nocebo hyperalgesia, and provide insights into clinical applications. PMID- 29263692 TI - Prospective study on prevalence, intensity, type, and therapy of acute pain in a second-level urban emergency department. AB - Aim: Pain represents the most frequent cause for patient admission to emergency departments (EDs). Oligoanalgesia is a common problem in this field. The aims of this study were to assess prevalence and intensity of pain in patients who visited a second-level urban ED and to evaluate the efficacy of pharmacological treatment administered subsequent to variations in pain intensity. Methods: A 4 week prospective observational study was carried out on 2,838 patients who visited a second-level urban ED. Pain intensity was evaluated using the Numeric Rating Scale at the moment of triage. The efficacy of prescribed analgesic therapy was evaluated at 30 and 60 minutes, and at discharge. Data concerning pain intensity were classified as absent, slight, mild, or severe. Pain was evaluated in relation to the prescribed therapy. Results: Pain prevalence was 70.7%. Traumatic events were the primary cause in most cases (40.44%), followed by pain linked to urologic problems (13.52%), abdominal pain (13.39%), and nontraumatic musculoskeletal pain (7.10%). Only 32.46% of patients were given pharmacological therapy. Of these, 76% reported severe pain, 19% moderate, and 5% slight, and 66% received nonsteroidal anti-inflammatory drugs or paracetamol, 4% opioids, and 30% other therapies. A difference of at least 2 points on the Numerical Rating Scale was observed in 84% of patients on reevaluation following initial analgesic therapy. Conclusion: Pain represents one of the primary reasons for visits to EDs. Although a notable reduction in pain intensity has been highlighted in patients who received painkillers, results show that inadequate treatment of pain in ED continues to be a problem. PMID- 29263693 TI - Initiation of labor analgesia with injection of local anesthetic through the epidural needle compared to the catheter. AB - Background: The rationale for injection of epidural medications through the needle is to promote sooner onset of pain relief relative to dosing through the epidural catheter given that needle injection can be performed immediately after successful location of the epidural space. Some evidence indicates that dosing medications through the epidural needle results in faster onset and improved quality of epidural anesthesia compared to dosing through the catheter, though these dosing techniques have not been compared in laboring women. This investigation was performed to determine whether dosing medication through the epidural needle improves the quality of analgesia, level of sensory blockade, or onset of pain relief measured from the time of epidural medication injection. Methods: In this double-blinded prospective investigation, healthy term laboring women (n=60) received labor epidural placement upon request. Epidural analgesia was initiated according to the assigned randomization group: 10 mL loading dose (0.125% bupivacaine with fentanyl 2 ug/mL) through either the epidural needle or the catheter, given in 5 mL increments spaced 2 minutes apart. Verbal rating scale (VRS) pain scores (0-10) and pinprick sensory levels were documented to determine the rates of analgesic and sensory blockade onset. Results: No significant differences were observed in onset of analgesia or sensory blockade from the time of injection between study groups. The estimated difference in the rate of pain relief (VRS/minute) was 0.04 (95% CI: -0.01 to 0.11; p=0.109), and the estimated difference in onset of sensory blockade (sensory level/minute) was 0.63 (95% CI: -0.02 to 0.15; p=0.166). The time to VRS <=3 and level of sensory block 20 minutes after dosing were also similar between groups. No differences in patient satisfaction, or maternal or fetal complications were observed. Conclusion: This investigation observed that epidural needle and catheter injection of medications result in similar onset of analgesia and sensory blockade, quality of labor analgesia, patient satisfaction, and complication rates. PMID- 29263694 TI - Current methodological approaches in conditioned pain modulation assessment in pediatrics. AB - Conditioned pain modulation (CPM) paradigms have been used in various studies with healthy and non-healthy adult populations in an attempt to elucidate the mechanisms of pain processing. However, only a few studies so far have applied CPM in pediatric populations. Studies finding associations with chronic pain conditions suggest that deficiencies in underlying descending pain pathways may play an important role in the development and persistence of pain early in life. Twelve studies were identified using a PubMed search which examine solely pediatric populations, and these are reviewed with regard to demographics studied, methodological approaches, and conclusions reached. This review aimed to provide both clinicians and researchers with a brief overview of the current state of research regarding the use of CPM in children and adolescents, both healthy and clinical patients. The implications of CPM in experimental and clinical settings and its potential to aid in refining considerations to individualize treatment of pediatric pain syndromes will be discussed. PMID- 29263695 TI - Necrosis of the thumb after inadvertent injection of diclofenac in the radial artery: a case report. AB - Inadvertent intra-arterial drug injection occurs rarely, but it can cause very serious clinical complications, and thus, awareness of inadvertent intra-arterial drug injection is needed. The complications mainly result from iatrogenic reasons and can occur because of vascular variations in the arteries, under circumstances where normal intravenous injection is difficult, or in drug abusers who perform self-injection. The adverse effect associated with intra-arterial drug injection is serious and may lead to necrosis, requiring amputation of the affected extremity, infection, pseudoaneurysm, rhabdomyolysis, compartment syndrome, and permanent disability. However, the etiology of such adverse effects has not been clearly identified and treatment methods have not yet been established. We encountered a patient who developed necrosis of the thumb after an inadvertent injection of diclofenac sodium in the radial artery due to variations in the forearm arteries. Here, we report the prevention and treatment of, and precautions against, the dangers of intra-arterial drug injection. PMID- 29263696 TI - An evaluation of the analgesic effect of AnestaGelTM on mechanical allodynia in a rat model of postoperative incisional pain. AB - Purpose: Sustained release hydrogel with bupivacaine (AnestaGelTM) is a novel formulation of extended release bupivacaine in a biohydrogel MatrixTM. We sought to compare the analgesic effects via mechanical allodynia, the pharmacokinetic characteristics via serum blood levels, and the local tissue effects via pathology, following injection of either sustained release hydrogel with bupivacaine, liposome bupivacaine, or hydrogel only (negative control group). Materials and methods: Ninety rats (30 in each group) were randomized to receive a sciatic nerve block injection of either sustained release hydrogel with bupivacaine, liposome bupivacaine (Exparel(r)), or a biohydrogel matrix. The total force generated was obtained at varying time points. Pathologic analysis was undertaken on days 5 and 42 of the study. Six additional rats (two in each group) were randomized to receive a sciatic nerve block injection of either sustained release hydrogel with bupivacaine, liposome bupivacaine, or bupivacaine and pharmacokinetic data were obtained for up to 120 hours. Results: The sustained release hydrogel with bupivacaine group had significantly better response to mechanical allodynia compared to the other two groups. The pathology showed no significant adverse events at 42 days in any group. Finally, bupivacaine was present longer in the serum of sustained release hydrogel with bupivacaine group than the other two groups. Conclusion: The sustained release hydrogel with bupivacaine achieved longer lasting analgesia with no significant findings on pathology at 42 days when compared to both positive and negative controls. PMID- 29263697 TI - Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2- metastatic breast cancer: a focus on ribociclib. AB - In normal cell cycle progression, transition of G0/G1 phase to synthesis (S) phase for breast and other cells is regulated by association of cyclin D and cyclin-dependent kinases 4 and 6 (CDK4/6) that leads to phosphorylation of retinoblastoma (Rb) protein. Imbalance of this cyclin D-CDK4/6-inhibitors of CDK4/6-Rb phosphorylation pathway is associated with tumorigenesis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 ) breast cancers. Despite effective first-line endocrine therapy, HR+/HER2- metastatic breast cancers remain still incurable. Currently, advances in understanding of cell cycle checkpoints are evolving as promising strategy to target in treatment of various types of cancers including breast cancer. Therapies that target this cell cycle machinery in HR+/HER2- breast cancers are getting approval by the US Food and Drug administration (FDA) including ribociclib (LEE011). Ribociclib got the first FDA approval in March 13, 2017, as an initial therapy for HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor. This review, therefore, addresses the role of selective CDK4/6 inhibitors in advanced or metastatic breast cancer with a specific focus on ribociclib. Some findings of clinical trials involving ribociclib found pivotal benefits of ribociclib in HR+/HER2- metastatic breast cancer in terms of prolonging progression-free survival and objective response rates. Daily dosage range of the drug for such benefits is 50-900 mg with common daily doses of 400 or 600 mg and 600 mg in early and advanced breast cancer therapies, respectively. Along with its therapeutic benefits, however, more incident but manageable dose-limiting grade 3 or 4 toxicities, primarily hematologic adverse events, are common in patients treated with ribociclib. Generally, there are several active clinical trials undergoing to investigate the clinical efficacy and toxicity profile of the drug in various cancerous conditions other than breast cancer and will likely benefit patients with other cancer types. PMID- 29263698 TI - Pleomorphic lobular carcinoma: is it more similar to a classic lobular cancer or to a high-grade ductal cancer? AB - Background: Pleomorphic invasive lobular carcinoma (P-ILC) is an uncommon variety of invasive lobular carcinoma with aggressive clinical features. Little is described in the literature regarding this topic. Materials and methods: We reviewed our experiences from 2010 to 2015 and compared 40 patients with P-ILC, 126 patients with classic-ILC (C-ILC) and 574 cases of high-grade invasive ductal carcinoma (HG-IDC). We studied the histologic and immunohistochemical features, clinical presentation and surgical treatment. Results: P-ILC is diagnosed at the same age and tumor diameter as those of the other two histologic types. It is associated more frequently with multiple lymph node metastases and high proliferative index, and HER2/neu is amplified in 10% of cases. In spite of sharing some histologic characteristics with C-ILC (same growth pattern, loss of E-cadherin expression, same genetic pathway), its clinical and pathologic features define an autonomous entity. Its surgical treatment is similar to those of C-ILC and HG-IDC. Conclusion: This is the first review comparing these three pathologic entities. Our findings may be useful in understanding this variety of invasive lobular carcinoma, and further studies are certainly needed in this field. PMID- 29263699 TI - Bidirectional risk between venous thromboembolism and cancer in East Asian patients: synthesis of evidence from recent population-based epidemiological studies. AB - Background: Unprovoked (idiopathic) venous thromboembolism (VTE) with no obvious antecedent risk factors, is associated with a significant risk of subsequent occult cancer. Conversely, there is a heightened risk of VTE in cancer patients. This bidirectional risk can be estimated from population-based cohort studies conducted in East Asians. Methods: A literature search using medical subject heading terms and Boolean logic in PubMed and MedLine was performed in April 2017. Twenty-two papers reported from East Asia were retrieved for study and data synthesis. Proportional meta-analysis with a random-effects model was used to synthesize data with 95% confidence intervals (CIs) when appropriate. Results: Synthesis of data on VTE incidence in the East Asian population (I2 = 76.2%) showed that pooled incidence was 20.3 (95% CI, 11.2-32) per 100,000 person-years. VTE incidence steadily increased with age. Unprovoked VTE accounted for 35% (95% CI, 24%-48%) of all cases of incident VTE (I2 = 99.7%). The overall cancer risk was significantly higher (2.3-fold) in the VTE cohort than in comparators. Among the patients with unprovoked VTE, approximately 7% had a subsequent cancer diagnosis within 2 years of the first episode of idiopathic VTE. The risk of VTE recurrence was increased in cancer patients (adjusted odds ratio, 1.64; 95% CI, 1.26-1.99). VTE incidence was 9.9 per 1,000 person-years in cancer patients, particularly in liver, pancreas, and lung cancer patients. Conclusion: Newly diagnosed VTE incidence is estimated at approximately 4,400 new cases annually in Taiwan and 7,100 in South Korea. Similar to the trend in VTE incidence among the general population, VTE risk in East Asian cancer patients is markedly lessened. PMID- 29263700 TI - Can 18F-FDG PET predict the grade of malignancy in thymic epithelial tumors? An evaluation of only resected tumors. AB - Objective: Although 18-fluorine fluorodeoxyglucose positron emission tomography (18F-FDG PET) is thought to be useful for predicting the histological grade of thymic epithelial tumors (TETs), it remains controversial. To date, just a few of many previous studies have included only resected cases. Therefore, we investigated 18F-FDG PET findings only in patients with resected TETs. Patients and methods: A total of 112 patients with TETs consisting of 92 thymomas and 20 thymic carcinomas (TCs), resected at two institutes (Shizuoka Cancer Center [Shizuoka] and National Cancer Center Hospital [Tokyo]) between October 2002 and December 2015, were evaluated. Spearman rank correlation coefficient was used to assess the association between the maximum standardized uptake value (SUVmax) in the tumor and both the histological subtype and tumor stage. The cutoff value of SUVmax for differentiating thymoma from TC was calculated. Results: The SUVmax was strongly related to both the World Health Organization (WHO) histological subtype and tumor stage based on the eighth edition of the tumor-node-metastasis (TNM) classification (Spearman rank correlation coefficient =0.485 and 0.432; p = 0.000 and 0.000, respectively). There was a significant difference between thymoma and TC. The optimal SUVmax cutoff value for differentiating thymoma from TC was 4.58 (sensitivity: 80% and specificity: 78.3%). In contrast, there was no significant difference between low-risk (type A, AB, and B1) and high-risk (type B2 and B3) thymoma, or between type B3 thymoma and the other subtypes. Conclusion: Our results suggest that 18F-FDG PET is useful for differentiating thymoma from TC, but not for predicting the histologic grade of thymoma. PMID- 29263701 TI - Low expression of GATA3 promotes cell proliferation and metastasis in gastric cancer. AB - GATA3, a member of the GATA zinc finger transcription factor family, has been widely investigated for its role in cancer. Although a recent report has found that GATA3 is downregulated in gastric cancer (GC), the detailed mechanism of GATA3 in GC is still unknown. Here, we investigated whether GATA3 was downregulated in GC patients' tissue samples and cell lines using quantitative real time polymerase chain reaction and Western blotting. In addition, we conducted several functional experiments to investigate the effect of GATA3 in GC, including cell proliferation, metastasis and epithelial-mesenchymal transition (EMT). The results showed that GATA3 was downregulated in GC tissue samples and cells. Moreover, the expression of GATA3 was associated with tumor size, stage and metastasis. Restoration of GATA3 levels suppressed GC cell proliferation, migration and invasion. Furthermore, chromatin immunoprecipitation and luciferase reporter assay also revealed that GATA3 transcriptionally regulated ZEB1, thereby suppressing EMT. All these findings suggest that GATA3 serves as an oncogene in GC development. PMID- 29263702 TI - Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study. AB - Background: Prostate cancer (PCa) accounts for 20% of all cancers in subjects over 50 years in Italy. The majority of patients with PCa present with localized disease at the time of diagnosis, but many patients develop recurrent metastatic disease after treatment with curative intent. Androgen deprivation therapy is the standard of care for metastatic PCa patients; unfortunately, most of them progress to castrate-resistant prostate cancer (CRPC) within 5 years. Metastatic CRPC (mCRPC) heavily affects patients in terms of quality of life, side effects, and survival, and greatly impacts economic costs. The approval of new effective agents in recent years, including cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, has dramatically changed patient management. Materials and methods: Here, we aimed to estimate the current costs of illness of mCRPC in Italy. All patients affected by mCRPC and treated with a single agent in an annual time horizon were considered. Therefore, the analysis was not focused on the management pathway of single patients through different lines of treatment. Direct medical costs referred to therapy, adverse event management, and skeletal related event management were analyzed. A bottom-up approach was used to estimate the resource consumption: through national guidelines and expert opinions, the mean cost per patient was estimated and then multiplied by the total number of patients diagnosed with mCRPC. Results: Direct medical costs ranged from ?196.5 million to ?228.0 million, representing ~0.2% of the financing of the Italian National Health Service in 2016. The main cost driver was the cost of treatment, which represented more than 77% of the overall economic burden. Conclusion: Our analysis, reflective of real clinical practice, shows for the first time the high economic cost of mCRPC in Italy. PMID- 29263704 TI - Neoadjuvant chemotherapy followed by fast-track cytoreductive surgery plus short course hyperthermic intraperitoneal chemotherapy (HIPEC) in advanced ovarian cancer: preliminary results of a promising all-in-one approach. AB - Purpose: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered a promising treatment option for advanced or recurrent ovarian cancer, but there is no clear evidence based on randomized controlled trials to advocate this approach as a standard therapy. In this study, we aim to present the early outcomes and insights after an interim analysis of a pioneering clinical trial in Brazil. Methods: This study was a cross-sectional analysis of early data from our ongoing clinical trial - an open-label, double-center, single-arm trial on the safety and efficacy of using HIPEC for advanced ovarian cancer (ClinicalTrials.gov: NCT02249013). A fast-track recovery strategy was also applied to improve patient outcomes. Results: Nine patients with stage IIIB (n=1) or IIIC (n=8) epithelial malignancies were enrolled until February 2017. The median (range) serum CA125 level at diagnosis was 692 (223.7-6550) U/mL. The median number of preoperative cycles of intravenous (i.v.) chemotherapy was 3 (2-4), resulting in peritoneal cancer index scores of 9 (3-18) at the time of HIPEC. Time of restarting i.v. chemotherapy was 37 (33-50) days with all patients completing 6 cycles as planned. The median operation time was 395 (235-760) minutes, the length of hospital stay was 4 (3-10) days, and all the patients left the ICU on the morning after the procedure. Two patients experienced no postoperative complications, whereas 91% of the complications were minor G1/G2 events. Preliminary assessment also suggested no impairment of the patient's quality of life. Conclusion: Our comprehensive protocol might represent a promising all-in-one approach for advanced ovarian cancer. The patient recruitment for this trial is ongoing. PMID- 29263703 TI - The applications of liquid biopsy in resistance surveillance of anaplastic lymphoma kinase inhibitor. AB - With the clinical promotion of precision medicine and individualized medical care, molecular targeted medicine has been used to treat non-small cell lung cancer (NSCLC) patients and proved to be significantly effective. Anaplastic lymphoma kinase (ALK) inhibitor is one of the most important specific therapeutic agents for patients with ALK-positive NSCLC. It can extend the survival of patients. However, resistance to the ALK inhibitor inevitably develops in the application process. So, the real-time resistance surveillance is particularly important, and liquid biopsy is one of the most potential inspection methods. Circulating tumor cells, circulating free tumor DNA and exosome in body fluid are used as the main detection biomarkers to reflect the occurrence of resistance in real time through sequencing or counting and then to guide the follow-up treatment. PMID- 29263705 TI - Incidence of diabetes and its mortality according to body mass index in South Koreans aged 40-79 years. AB - Purpose: The purpose of this study was to assess diabetes incidence and all-cause mortality according to baseline body mass index (BMI) and to compare relative risks of mortality associated with incident diabetes across various BMI classes in a cohort of South Korean adults. Patients and methods: Based on data from the National Health Insurance database of Korean individuals aged 40-79 years without preexisting diabetes, we calculated BMI at the baseline health examination. We estimated the relative risk of mortality associated with incident diabetes using time-dependent Cox models and considering the time of diabetes diagnosis. Results: We noted 29,307 incident diabetes cases and 22,940 deaths during an 8 year follow-up of the initial cohort (n=436,692) and 73,756 incident diabetes cases and 57,556 deaths during a 10-year follow-up of the replication cohort (n=850,282). Regarding all-cause mortality, time-dependent Cox models revealed statistically significant interactions between diabetes status and baseline BMI class (P=0.018 and P<0.001 in the initial and replication cohorts, respectively). In separately conducted analyses for each BMI class, diabetes-associated relative risks for BMI values of 16.0-18.4, 18.5-22.9, 23.0-24.9, 25.0-29.9, and 30.0-34.9 kg/m2 were 1.50 (95% confidence interval [CI], 1.09-2.07), 1.39 (95% CI, 1.26 1.54), 1.20 (95% CI, 1.08-1.35), 1.18 (95% CI, 1.07-1.30), and 0.97 (95% CI, 0.74 1.28) in the initial cohort, and 1.44 (95% CI, 1.18-1.74), 1.33 (95% CI, 1.26 1.41), 1.24 (95% CI, 1.16-1.31), 1.11 (95% CI, 1.05-1.17), and 0.99 (95% CI, 0.85 1.16) in the replication cohort. The increasing trend of relative risk with decreasing BMI persisted mostly among subgroups stratified according to age or sex and smoking status. Conclusion: Incident diabetes was associated with a greater increase in all-cause mortality risk in adults with lower BMI relative to those with higher BMI. This emphasizes the importance of treatment and prevention of type 2 diabetes among normal weight or underweight adults, particularly in Asia. PMID- 29263706 TI - Aggressive natural killer cell leukemia: a case report. AB - Aggressive natural killer (NK) cell leukemia is a rare hematological malignancy. It often presents with a rapidly declining clinical course and a poor prognosis with a median survival of a few months. We report the case of a 23-year-old man with high fever, enlarged lymph nodes, splenomegaly, cytopenia, liver dysfunctions, coagulation disorders and hemophagocytosis. Computed tomography scan showed right lung shadow. Lung involvement was considered. Histological examination of the lung was not performed because of low platelets and coagulation disorders. Bronchoscopic examination revealed positive Epstein-Barr virus in bronchoalveolar lavage fluid. Bone marrow and lymph node phenotype showed CD56+ CD3- NK cells type. He died of respiratory failure a week after diagnosis. PMID- 29263707 TI - Psychometric validation of the SF-36 Health Survey in light chain amyloidosis: results from community-based and clinic-based samples. AB - Background: Light chain (AL) amyloidosis, a rare and life-threatening protein misfolding disorder, causes organ damage and severely impacts health-related quality of life (HRQoL). No patient-reported outcome (PRO) HRQoL measure has been validated for use in an AL amyloidosis patient population, leaving a gap for researchers conducting observational studies and clinical trials for drug development. The SF-36 Health Survey (SF-36) has been the most frequently used PRO in AL amyloidosis studies to date, and early qualitative validation studies support its use in this population. The aim of this study was to assess the psychometric properties of the SF-36 among patients with AL amyloidosis. Methods: Data from community-based (n=341) and clinic-based (n=1,438) observational studies were used to document the psychometric properties of the SF-36 in this disease population. Reliability was estimated using internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation). Convergent validity, known-groups validity, and the ability to detect change were assessed with available criterion variables. Results: Scale reliability (Cronbach's alpha >=0.780 for all scores) and test-retest reliability (intraclass correlation coefficients >=0.731 for all) were acceptable. Scale convergent validity was supported by strong correlations with conceptually related measures. Mean SF-36 scores varied by response to treatment (P<0.05 for all scores) and a self-reported measure of disease severity (P<0.001 for all scores). Data indicate that the SF-36 is sensitive to changes in other measures over time. Conclusion: This study provided clear and consistent evidence of the psychometric properties of the SF-36 in both community-based and clinic-based samples of patients with AL amyloidosis. PMID- 29263708 TI - A questionnaire-based audit to assess overall experience and convenience among patients using vaginal progesterone tablets (Lutigest(r)) for luteal phase support during IVF treatment. AB - Purpose: The aim of this audit was to assess the overall experience and patient convenience of vaginal progesterone tablets (Lutigest(r), marketed as Endometrin(r) in the USA) used for luteal phase support (LPS) during in vitro fertilization (IVF) treatment. Patients and methods: This questionnaire-based audit included responses from 100 patients undergoing IVF treatment at six IVF clinics in the UK from September 2015 to November 2016. Fourteen days after starting progesterone supplementation for LPS during their IVF treatment, patients rated overall experience and perceived convenience of the prescribed progesterone by completing a questionnaire. Results: Of the 100 patients included, 96 received vaginal progesterone tablets for LPS. Overall, 53.1% (51/96) indicated that the progesterone tablets were "very easy" to use; 42.7% (41/96) and 44.8% (43/96) found it "very convenient" or "neither convenient or inconvenient" to administer the tablet, respectively. Overall experience with using progesterone tablets was rated as "very comfortable" by 34.4% (33/96) and "neither comfortable or uncomfortable" by 56.3% (54/96) of patients. The applicator was used by 93.8% (90/96) of patients to administer the tablet, and 86.5% (83/96) indicated that the applicator was easy to clean for repeated use. A total of 33 patients had a previous IVF cycle during which they were prescribed vaginal progesterone pessaries for LPS. Compared with progesterone pessaries, the majority found treatment with progesterone tablets to be more comfortable (60.6%; 20/33) and more convenient (57.6%; 19/33) and indicated that the progesterone tablet was their preferred progesterone formulation for LPS (60.6%; 20/33). Conclusion: These findings offer insights into real-world patient experiences with the progesterone vaginal tablet formulation. The results suggest overall patient convenience, ease, and comfort with using progesterone vaginal tablets for LPS. The majority of patients found progesterone vaginal tablets more convenient and comfortable to use compared with progesterone pessaries. PMID- 29263709 TI - Pretreatment Glasgow prognostic score and prognostic nutritional index predict overall survival of patients with advanced small cell lung cancer. AB - Background: Various biomarkers have been shown to predict prognosis in various types of cancers. However, these biomarkers have not been studied in advanced small cell lung cancer (SCLC). The modified Glasgow prognostic score (mGPS) is based on serum albumin level and C-reactive protein (CRP). The prognostic nutritional index (PNI) is a combination of serum albumin level and absolute lymphocyte count. This study aimed to evaluate the prognostic value of mGPS and PNI in SCLC. Methods: We retrospectively reviewed and calculated mGPS and PNI for patients with stage IIIB or IV SCLC who initiated platinum-based combination chemotherapy between November 2007 and June 2016. We compared overall survival (OS) and progression-free survival (PFS) between high and low groups of these two biomarkers. Univariate and multivariate Cox hazard analyses assessed the prognostic value of these biomarkers. Results: We reviewed 97 SCLC patients. The OS of patients with mGPS 0-1 and higher PNI was significantly longer than that of those with mGPS 2 and lower PNI. The PFS of mGPS 0-1 was significantly longer than that of mGPS 2, while there was no significant difference in PFS according to PNI. Multivariate analyses found mGPS 0-1 (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.27-4.31, P<0.01) and higher PNI (HR 0.50, 95% CI 0.31 0.78, P<0.01) as prognostic factors for longer OS. However, neither biomarker was predictive of PFS. Conclusion: Our study was a small retrospective study; however, the data demonstrate that pretreatment mGPS and PNI are independent predictors of OS in patients with advanced SCLC. The pretreatment assessment of mGPS and PNI may be useful for identification of patients with poor prognosis. We recommend pretreatment measurement of serum albumin, C-reactive protein, and absolute lymphocyte count. PMID- 29263710 TI - Efficacy and safety of IV ferumoxytol for iron deficiency anemia in patients with cancer. AB - Purpose: Iron deficiency anemia (IDA) is common in cancer patients due to blood loss and inflammation. Many do not tolerate oral iron or adequately respond. Intravenous (IV) iron is commonly used as an adjunct to erythropoiesis stimulating agents; data on the use of IV iron monotherapy in these patients are limited. This study aimed to evaluate IV ferumoxytol for the treatment of cancer patients with IDA with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. Patients and methods: This post hoc analysis of pooled data from two multicenter, randomized, controlled, Phase III trials evaluating IV ferumoxytol (510 mg *2) vs placebo or iron sucrose (200 mg *5) included a subgroup of 98 patients with cancer that the investigator identified as the primary cause of their IDA, or with cancer whose IDA was attributed to another comorbid condition (ferumoxytol, n=75; iron sucrose, n=13; placebo, n=10). Gastrointestinal cancers were most common (42), followed by breast (14), cervix (ten), and lung (nine). The primary endpoint was the mean change in hemoglobin (Hgb) from baseline to week 5. Results: At week 5, both ferumoxytol and iron sucrose produced significant increases in Hgb from baseline (1.8 g/dL [P<0.0001] and 1.9 g/dL [P=0.002], respectively). During the studies, 45 patients received chemotherapy, 19 with platinum-based regimens. Erythropoiesis stimulating agent doses were neither increased >20% nor initiated in any treatment group. Overall rates of adverse events and serious adverse events in the cancer subgroup mirrored those in the overall study population. Conclusion: Monotherapy with IV iron appears to be an effective option for cancer patients with IDA who do not respond to or cannot tolerate oral iron therapy. PMID- 29263711 TI - The Hospitalist Huddle: a 1-year experience of teaching Hospital Medicine utilizing the concept of peer teaching in medical education. AB - Background: The relatively new specialty of Hospital Medicine in the USA is one of the fastest growing fields in internal medicine. Academic hospitalists are largely involved in the medical education of postgraduate residents and medical students. Little is known about the effectiveness of peer-to-peer teaching in internal medicine residency training programs and how the medical residents perceive its educational value in learning Hospital Medicine. Materials and methods: The Hospitalist Huddle is a weekly educational activity newly established by our Hospitalist Division to facilitate the concept of peer-to-peer teaching. It requires medical residents to teach and educate their peers about the clinical topics related to Hospital Medicine. Faculty hospitalists serve as facilitators during the teaching sessions. A survey disseminated at the end of the first year of its implementation examined the residents' perception of the educational value of this new teaching activity. Results: Most residents reported that they see the Huddle as a useful educational forum which may improve their skills in teaching, create a better educational and learning environment during their inpatient rotation, and improve their understanding of Hospital Medicine. Most residents also prefer that their peers, rather than faculty hospitalists, run the activity and do the teaching. Conclusion: The survey results support the notion that teaching and learning with flat hierarchies can be an appealing educational method to medical residents to help them understand Hospital Medicine during their medical wards rotation. Some areas need to be improved and others need to be continued and emphasized in order to make this novel educational activity grow and flourish in terms of its educational value and residents' satisfaction. PMID- 29263712 TI - Plant exudates may stabilize or weaken soil depending on species, origin and time. AB - : We hypothesized that plant exudates could either gel or disperse soil depending on their chemical characteristics. Barley (Hordeum vulgare L. cv. Optic) and maize (Zea mays L. cv. Freya) root exudates were collected using an aerated hydroponic method and compared with chia (Salvia hispanica L.) seed exudate, a commonly used root exudate analogue. Sandy loam soil was passed through a 500-MUm mesh and treated with each exudate at a concentration of 4.6 mg exudate g-1 dry soil. Two sets of soil samples were prepared. One set of treated soil samples was maintained at 4 degrees C to suppress microbial processes. To characterize the effect of decomposition, the second set of samples was incubated at 16 degrees C for 2 weeks at -30 kPa matric potential. Gas chromatography-mass spectrometry (GC MS) analysis of the exudates showed that barley had the largest organic acid content and chia the largest content of sugars (polysaccharide-derived or free), and maize was in between barley and chia. Yield stress of amended soil samples was measured by an oscillatory strain sweep test with a cone plate rheometer. When microbial decomposition was suppressed at 4 degrees C, yield stress increased 20-fold for chia seed exudate and twofold for maize root exudate compared with the control, whereas for barley root exudate decreased to half. The yield stress after 2 weeks of incubation compared with soil with suppressed microbial decomposition increased by 85% for barley root exudate, but for chia and maize it decreased by 87 and 54%, respectively. Barley root exudation might therefore disperse soil and this could facilitate nutrient release. The maize root and chia seed exudates gelled soil, which could create a more stable soil structure around roots or seeds. Highlights: Rheological measurements quantified physical behaviour of plant exudates and effect on soil stabilization.Barley root exudates dispersed soil, which could release nutrients and carbon.Maize root and chia seed exudates had a stabilizing effect on soil.Physical engineering of soil in contact with plant roots depends on the nature and origin of exudates. PMID- 29263713 TI - Is exponential gravity a viable description for the whole cosmological history? AB - Here we analyse a particular type of F(R) gravity, the so-called exponential gravity which includes an exponential function of the Ricci scalar in the action. Such a term represents a correction to the usual Hilbert-Einstein action. By using Supernovae Ia, Barionic Acoustic Oscillations, Cosmic Microwave Background and H(z) data, the free parameters of the model are well constrained. The results show that such corrections to General Relativity become important at cosmological scales and at late times, providing an alternative to the dark energy problem. In addition, the fits do not determine any significant difference statistically with respect to the [Formula: see text]CDM model. Finally, such model is extended to include the inflationary epoch in the same gravitational Lagrangian. As shown in the paper, the additional terms can reproduce the inflationary epoch and satisfy the constraints from Planck data. PMID- 29263714 TI - Cabibbo-Kobayashi-Maskawa-favored B decays to a scalar meson and a D meson. AB - In this work, we attempt to study the Cabibbo-Kobayashi-Maskawa-favored [Formula: see text] ("S" denoting the scalar meson) decays within the perturbative QCD approach at the leading order and the leading power. Although the light scalar mesons are widely perceived as primarily the four-quark bound states, in practice it is hard for us to make quantitative predictions based on the four-quark picture for light scalars. Hence, we calculate the decays with light scalars in the two-quark model. For the decays with scalar mesons above 1 GeV, we have explored two possible scenarios, depending on whether the light scalars are treated as the lowest lying [Formula: see text] states or four-quark particles. In total, we calculated the branching fractions of 72 decay modes, and most of them are in the range [Formula: see text]-[Formula: see text], which are measurable in the on-going LHCb experiment and the forthcoming Belle-II experiment. Moreover, since in the standard model these decays occur only through tree operators and have no CP asymmetries, any deviation will be a signal of new physics beyond the standard model. Despite large uncertainties induced by nonperturbative parameters and corrections of high order and high power, our results and discussions will be useful for the on-going LHCb and the forthcoming Belle-II experiments. PMID- 29263715 TI - Manifestations of classical physics in the quantum evolution of correlated spin states in pulsed NMR experiments. AB - Multiple-pulse NMR experiments are a powerful tool for the investigation of molecules with coupled nuclear spins. The product operator formalism provides a way to understand the quantum evolution of an ensemble of weakly coupled spins in such experiments using some of the more intuitive concepts of classical physics and semi-classical vector representations. In this paper I present a new way in which to interpret the quantum evolution of an ensemble of spins. I recast the quantum problem in terms of mixtures of pure states of two spins whose expectation values evolve identically to those of classical moments. Pictorial representations of these classically evolving states provide a way to calculate the time evolution of ensembles of weakly coupled spins without the full machinery of quantum mechanics, offering insight to anyone who understands precession of magnetic moments in magnetic fields. PMID- 29263716 TI - Incidence and predictors of failed second-generation endometrial ablation. AB - Background: The need for any treatment following an endometrial ablation is frequently cited as "failed therapy," with the two most common secondary interventions being repeat ablation and hysterectomy. Since second-generation devices have become standard of care, no large cohort study has assessed treatment outcomes with regard to only these newer devices. We sought to determine the incidence and predictors of failed second-generation endometrial ablation, defined as the need for surgical re-intervention.We performed a retrospective cohort study at a single academic-affiliated community hospital. Subjects included women undergoing second-generation endometrial ablation for benign indications between October 2003 and March 2016. Second-generation devices utilized during the study period included the radiofrequency ablation device (RFA), hydrothermal ablation device (HTA), and the uterine balloon ablation system (UBA). Results: Five thousand nine hundred thirty-six women underwent endometrial ablation at a single institution (3757 RFA (63.3%), 1848 HTA (31.1%), and 331 UBA (5.6%)). The primary outcome assessed was surgical re-intervention, defined as hysterectomy or repeat endometrial ablation. Of the total 927 (15.6%) women who required re-intervention, 822 (13.9%) underwent hysterectomy and 105 (1.8%) underwent repeat endometrial ablation. Women who underwent re-intervention were younger (41.6 versus 42.9 years, p < .001), were more often African-American (21.8% versus 16.2%, p < .001), and were more likely to have had a primary radiofrequency ablation procedure (hazard ratio 1.37; 95%CI 1.01 to 1.86). Older age was associated with decreased risk for treatment failure with women older than 45 years of age having the lowest risk for failure (p < .001). Age between 35 and 40 years conferred the highest risk of treatment failure (HR 1.59, 95% CI 1.32-1.92). Indications for re-intervention following ablation included menorrhagia (81.8%), abnormal uterine bleeding (27.8%), polyps/fibroids (18.7%), and pain (9.5%). Conclusion: Surgical re-intervention was required in 15.6% of women who underwent second-generation endometrial ablation. Age, ethnicity, and radiofrequency ablation were significant risk factors for failed endometrial ablation, and menorrhagia was the leading indication for re-intervention. PMID- 29263717 TI - Text feature extraction based on deep learning: a review. AB - Selection of text feature item is a basic and important matter for text mining and information retrieval. Traditional methods of feature extraction require handcrafted features. To hand-design, an effective feature is a lengthy process, but aiming at new applications, deep learning enables to acquire new effective feature representation from training data. As a new feature extraction method, deep learning has made achievements in text mining. The major difference between deep learning and conventional methods is that deep learning automatically learns features from big data, instead of adopting handcrafted features, which mainly depends on priori knowledge of designers and is highly impossible to take the advantage of big data. Deep learning can automatically learn feature representation from big data, including millions of parameters. This thesis outlines the common methods used in text feature extraction first, and then expands frequently used deep learning methods in text feature extraction and its applications, and forecasts the application of deep learning in feature extraction. PMID- 29263718 TI - From the Editor-in-Chief. PMID- 29263719 TI - The LARO-MEN1 study: a longitudinal clinical experience with octreotide Long Acting Release in patients with Multiple Endocrine Neoplasia type 1 Syndrome. AB - Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumoral syndrome, featured by a combination of neoplasms of various endocrine and nonendocrine tissues. Approximately 33% of MEN1-related deaths are due to the malignant behaviour of well-differentiated neuroendocrine tumors (NETs), for which a preventive surgical treatment is not feasible. Somatostatin analogues (SSA) have been employed in the treatment of NETs in the stage of advanced or metastatic disease, in order to control the growth and secretion of tumor lesions. A longitudinal, open label study named "LARO-MEN1" was undertaken in order to assess whether early medical treatment with long-acting SSA could act as a preventive approach in small MEN1-related gastroenteropancreatic (GEP) NETs. Thirty consecutive patients affected by MEN1 were screened and 8 patients with small (<2 cm) NETs and abnormal laboratory values of at least one of the GEP hormones were administered octreotide acetate slow-release formulation (LAR) (10 mg i.m. every 28 days). Octreotide LAR was effective in decreasing GEP hormones and overall safe in the majority of patients up to six years of treatment, maintaining the disease stable also in terms of tumor size. The positive outcomes of this study in MEN1 patients reinforce the results obtained in advanced NETs on the use of SSA, opening to the opportunity for preventive use of octreotide LAR, aimed to delay or even avoid surgery in these patients. PMID- 29263720 TI - The changing profile of hypercalcemia in a tertiary care setting in North India: an 18-month retrospective study. AB - This retrospective study was undertaken to determine the profile of hypercalcemia in all patients who presented to Medanta-The Medicity, a tertiary care hospital in North India. A total of 255,830 patients presented to the hospital during 1st January 2014 till 30th June 2015 (18 months). Among them calcium measurement was done in 26,297 (10.2%) patients. A total of 552 patients was found to have hypercalcemia. Among them, 15 (2.7%) patients had transient hypercalcemia and 537 (97.3%) had sustained hypercalcemia. The incidence of hypercalcemia was 2.09%, being transient in 0.05% and sustained in 2.04%. The most common causes in the sustained group were malignancy (23.1%) followed by primary hyperparathyroidism (PHPT, 21.9%). Most cases of PHPT were asymptomatic. Interestingly, we found emergence of two unusual groups of hypercalcemia, namely hypercalcemia of advanced chronic liver disease (n = 34) and vitamin D toxicosis (n = 21) in the non-parathyroid group of hypercalcemia. This changing pattern of hypercalcemia should be kept in mind while evaluating a patient of hypercalcemia in a hospital setting. PMID- 29263721 TI - Histological study of atraumatic periprosthetic fractures: does atypical periprosthetic fracture exist? AB - Purpose: Is it possible a correlation between some periprosthetic femoral fractures and atypical fractures? Case: We present a case of a 77-year-old woman with atypical periprosthetic femoral fracture. The patient had a history of long term bisphosphonate use. We performed an open reduction, a synthesis of the fracture and a histological exam. The patient stopped the bisphosphonate (BF) therapy. Three months later, before starting the teriparatide treatment, the patient had a re-fracture so we did a second osteosynthesis and began a teriparatide therapy. After six months, the radiography showed a bone healing at the fracture site. Result: The histological examination confirmed the diagnosis of atypical femoral fracture. Conclusion: At first, the fracture showed a delayed union which led to a new surgery, as often happens in BF-related atypical fractures. Appropriate treatment (BF suspension and teriparatide beginning) permitted fracture healing. The atypical characteristic of the fracture was confirmed by histological exam.Some periprosthetic femoral fractures in patients treated with BF, especially in long time therapies, should be suspected as atypical fractures and a specific medical treatment should be performed, as well as a correct surgical treatment. PMID- 29263722 TI - Enhanced bone healing and decreased pain in sacral insufficiency fractures after teriparatide treatment: retrospective clinical-based observational study. AB - The purpose of this retrospective clinical-based observational study was to evaluate the effects of teriparatide (TPTD) on clinical outcomes and radiologic findings of sacral insufficiency fractures (SIFs). Seven elderly women with SIFs received TPTD for at least 6 months. We evaluated the symptoms, pain, and radiological findings. At their initial clinic visit, 86% patients could not walk or sit. Computed tomography (CT) images revealed sacral wing fracture in 6 patients, and bone scintigram showed H-shaped uptake over the bilateral sacral wings in 1 patient. After the treatment, 5 patients could walk. Mean visual analog scale score was significantly lower after (12.9 mm) than before (87.4 mm) TPTD treatment (p < 0.0001). CT images revealed bone union (four patients) and sclerotic changes (three patients) at the fracture sites. Seven elderly women with SIFs had significant improvement in pain and demonstrated bone union or sclerotic changes at fracture sites by TPTD. PMID- 29263723 TI - The effectiveness of intra-articular injections of Hyalubrix(r) combined with exercise therapy in the treatment of hip osteoarthritis. AB - Purpose: Osteoarthritis (OA) is the most common joint disorder in the elderly, causing significant pain which negatively affects mobility and quality of life. The aim of the study was to assess the effectiveness of ultrasound image-guided intra-articular injections of Hyalubrix(r) combined with exercise therapy in the treatment of hip osteoarthritis. Methods: This was a single site, prospective, open-label, Investigator-initiated study. Forty patients were enrolled and received three ultrasound image-guided injections of Hyalubrix(r), 45 days apart, combined with three sessions a week of physical therapy (proprioceptive rehabilitation of the lower limbs; gait training; balance training) up to a total of 30 sessions (10 weeks), starting from one week after the first injection. Results: The primary objective was to achieve a lasting reduction in OA symptoms related to pain during activity. During the course of the study the pain perceived by the patient during activity dropped from a mean value of 6.94 cm to a mean value of 1.46 cm and showed a statistically significant decrease from visit 1 compared to baseline (p < 0.05) which was confirmed at all the subsequent time points. Significant improvements were also observed in the evaluation of the secondary objectives: hip disability; OA-related pain at rest; daily functioning and NSAIDs intake. Conclusions: Results from this study including 40 patients for a total of 65 treated hips demonstrate a significant improvement in OA-related pain, hip disability, and patient's daily functioning as well as a reduction in NSAIDs intake. Patients suffering from hip OA seem to benefit from the treatment with Hyalubrix(r) injections plus exercise therapy. PMID- 29263724 TI - Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study. AB - Osteogenesis imperfecta (OI) is an hereditary disease characterized by low bone mass, increased bone fragility, short stature, and skeletal deformities, few treatment options are currently available. Neridronate is an amino bisphosphonate, licensed in Italy for the treatment of OI and Paget's disease of bone. A characteristic property of neridronate is that it can be administered both intravenously and intramuscularly, providing an useful system for administration in homecare. Neridronate appears to increase Bone Mineral Density (BMD) in adults with OI and reduces bone resorption by inhibition of osteoclastic activity. Teriparatide (recombinant 1-34 N terminal sequence of human parathyroid hormone) is the first anabolic agent approved for the treatment of patients with osteoporosis and has been reported to increase bone formation by stimulating osteoblast differentiation, osteoblast function, and survival. The results of this study showed a promising role of teriparatide in the therapy of OI type I. PMID- 29263725 TI - Resistance exercise training restores bone mineral density in renal transplant recipients. AB - Background: The kidneys are complex organs of human body sustain a number of vital and important functions. These organs need to be replaced in some subjects due to various diseases. Bone mineral density (BMD) of the subjects with kidney transplantation reduced as a result of poor mobility and use of especial drugs. Due to lack of information regarding the influences of weight training exercise on BMD of long bone, this research was done. Method: 24 subjects with history of kidney transplantation were recruited in this study. They were divided into two groups who received weight training exercise and control group. The BMD of femur and lumbar spine was measured by use of dual energy X-Ray absorptiometry in both groups. The difference between BMD was evaluated by use of two sample T test. Result: The mean values of BMD of femur were 0.679+/-0.09 g/cm2 and 0.689+/-0.09 before and after exercise in this first group. In contrast it was 0.643+/-0.11 before follow-up and 0.641+/-0.11 g/cm2 after follow-up in the control group. There was no difference in BMD of lumbar spine after exercise. Conclusion: The result of this research study showed that BMD of long bone improved follow exercise. Therefore, it was concluded that weight training exercise can be used for the subjects with kidney transplantation. PMID- 29263727 TI - Clinical-laboratory findings of bone metabolism in healthy premature and full term neonates: preliminary results. AB - Premature infants are a major risk group for bone metabolic disorders. The purpose of this study is to clarify certain aspects of bone metabolism in healthy preterm and full-term neonates. Forty neonates (20 preterm and 20 full-term) were the material of the study. For each neonate demographic data (gender, gestational week) and anthropometric data (body weight) were recorded. Blood samples were collected and biochemical markers of bone metabolism (serum ALP, Ca, P, Mg) were immediately estimated. According to the results there is a statistically significant difference in average ALP of preterm neonates compared to full term neonates. Slightly higher values of Ca, P, Mg occurred in premature neonates while there was a statistically significant difference in the weeks of gestation and body weights between the two groups. It is typical in premature neonates the decrease in levels of ALP by the weeks of gestation and the stable levels of Ca. Gestational week seems to positively affect P and Mg levels in preterm neonates. Conclusively from our study's results arises that the week of gestation and not so much the body weight influence the alterations of bone biochemical biomarkers in healthy premature newborns. It seems that very premature neonates have high levels of serum ALP in decompensation of lower levels of Mg and P from all the newborns in this study. Therefore in very premature neonates, it is recommended to estimate serum ALP, Mg and P for assessment of bone turnover. PMID- 29263726 TI - Clinical management of osteoporotic vertebral fracture treated with percutaneous vertebroplasty. AB - Our study demonstrated percutaneous vertebroplasty (PVP) is an effective procedure to rapidly reduce back pain in patients affected by acute osteoporotic vertebral compression fractures (OVCFs) assessed by MRI. We confirmed in our sample, femoral bone density impacts more deeply than vertebral T-score and/or BMD on bone strenght, as it is less affected by any interferences. We interestingly found the presence of previous osteoporotic fragility fractures and chronic glucocorticoids therapy should especially negatively influence bone health of our patients. On the other hand, even if both FRAX scores for major osteoporotic fractures and for femoral fractures seemed to globally define a population at major risk for fragility fractures, our analysis is retrospectively done. We choose and suggest a multidisciplinary medical management of these patients, considering OP is a multifactorial disease and OVCFs usually produce lots of different important consequences on general health. PMID- 29263728 TI - Anabolic treatment for osteoporosis: teriparatide. AB - Teriparatide is a safe and effective anabolic treatment for osteoporosis. In postmenopausal women, it increases BMD and decreases vertebral fractures by about 70% and non-vertebral fractures by about 45% (although there is no evidence that it prevents hip fractures). The current evidence indicates that it should be administered for a single course of 24 months, and followed with an anti resorptive agent to maintain the BMD gain. There is no clear benefit to repeated or cyclical treatment. Combination treatment, particularly with denosumab achieves greater BMD increase than either agent alone, but there are no available fracture data for combination treatment. There are some unknowns; most fundamentally why daily PTH administration is anabolic to bone when continuous high PTH is catabolic. Also, a better understanding of why the anabolic action declines with time and why there is a poor response to repeated treatment may help us to use teriparatide more effectively, and increase our understanding of bone biology and osteoporosis pathophysiology. PMID- 29263729 TI - Intra-articular therapy in hip osteoarthritis. AB - Several therapeutic options have been used in the past for treatment of patients with hip osteoarthritis (HO). In recent years we have witnessed to the introduction of the intra-articular injection (IA) of hyaluronic acid (HA) in clinical practice. This technique was initially used to treat knee arthritis, for which was actually introduced, but hip anatomy itself (deeper joint structure) and technical features (different methods) pose more challenges. However, results look promising in terms of symptoms improvement and delaying prosthetic surgery. Indeed, it does appear mandatory to increase pool of available data with further studies in order to refine techniques, make them more effective, and target patients who could potentially benefit more than others from treatment. PMID- 29263730 TI - Hyaluronic acid vs corticosteroids in symptomatic knee osteoarthritis: a mini review of the literature. AB - Introduction: Although intra-articular injections of hyaluronic acid (HA) are common non-operative measures used in clinical practice in the management of symptomatic osteoarthritis, there is a great controversy on their efficacy and safety compared to corticosteroids (CSs). Efficacy: Conflicting results have been reported in clinical trials and meta-analysis due to methodological differences in study design, along with collection, analysis, and interpretation of data. Even if some studies reported small or no differences of HA compared with CSs (or inferred that HA is not more effective than saline as a placebo), in general CSs have shown to be superior in the short term (especially on pain control), while better results have been reported with HA at subsequent evaluations, but with only a moderate effect after 26 weeks. Safety: Mild or moderate adverse events have generally been reported after HA injections, the most common being injection site pain. HA is generally considered safe compared to CSs or saline. Furthermore, HA has shown to be safe also after a previous course of injections. Conclusions: Conflicting results have been reported on the efficacy and safety of HA. Guidelines are controversial and in most of the cases "uncertain" recommendations are provided due to inconclusive evidence in literature. However, HA does not seem to have significantly higher side effects when compared to saline or CSs injections, and provides better medium-term control of symptoms in patients with mild to moderate knee osteoarthritis. PMID- 29263731 TI - Non-unions. AB - Non-union of long bones is a significant consequence of fracture treatment. Bone regeneration is a complex physiological process of bone formation which can be seen during normal fracture healing. An improved understanding of the molecular and cellular events that occur during bone repair and remodelling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Currently, there are different strategies to augment the impaired or "insufficient" bone-regeneration process, including the "gold standard" autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. PMID- 29263732 TI - Periprosthetic fractures: epidemiology and current treatment. AB - Periprosthetic fractures are becoming increasingly frequent due to aging population and growing number of total joint replacements involving joints different from hip and knee, such as shoulder and elbow. The treatment of these fractures still represents one of the major challenges for the orthopedic surgeon. Despite all efforts to understand and treat these patients, high rate of failure and mortality are still reported. In this review, the epidemiology of periprosthetic fractures, risk factors and results of surgical treatment are disclosed. Moreover, we propose a treatment algorithm based on the findings of the New Unified Classification System. PMID- 29263733 TI - Orthopaedic procedures in haemophilia. AB - Haemophilia may nowadays be considered an "ortho paedic" disease given due to the involvement of musculoskeletal system in almost all haemophilic subjects. The modern haematological prophylaxis has dramatically improved the quality of life reducing bleedings and life-threatening complications; however, joint bleedings, progressive and irreversible arthropathy and osteoporosis are still now common challenging issues to be faced. One of the tissues involved by Haemophilia is the bone, particularly in the periarticular zone: poor bone quality and decrease of bone stock are typical patterns, and the worse is the arthropathy, the greater the bone loss. The orthopaedic management of such condition is now mandatory and characterized by several surgical techniques. The purpose of this work is to provide an overview of these options derived from our experience in managing haemophilic patients. PMID- 29263734 TI - Vitamin K and bone. AB - Vitamin K is mainly known as an agent involved in blood coagulation, maintaining the activity of coagulation factors in the liver. In addition, epidemiological studies suggested that a lack of vitamin K is associated with several diseases, including osteoporosis and vascular calcification. There are two main kinds of vitamin K: Phylloquinone (or PK) and Menaquinones (MKn), both act as co-enzyme of y-glutamyl carboxylase (GGCX) transforming under-carboxylated in carboxylated vitamin K dependent proteins, such as Bone Gla Protein (or Osteocalcin) and Matrix Gla Protein. Recently, Vitamin K was also identified as a ligand of the nuclear steroid and xenobiotic receptor (SXR) (in murine species Pregnane X Receptor: PXR), expressed in osteoblasts. The purpose of this literature review is to evaluate the protective role of Vitamin K in bone and vascular health. PMID- 29263735 TI - Oral calcidiol is a good form of vitamin D supplementation. AB - Vitamin D supplementation represents an important topic in the field of metabolic bone disease. Calcidiol, the 25-hydroxy-vitamin D [25(OH)D], is the form of vitamin D most recently introduced in clinical practice. Advantages of the use of calcidiol derive from the pharmacokinetic properties and are related to the possibility of use in patients with liver disease, obese patients, patients with intestinal malabsorption, secondary hyperparathyroidism associated with chronic kidney disease as well as to avoid any possible toxic effect when high doses are used. The ADDI-D study demonstrated the efficacy and safety of calcidiol at the daily dose of 20 or 40 MUg and 125 MUg/week. In particular, the daily dose of 40 MUg can be suggested as an alternative in severely deficient patients, as it has demonstrated to ensure higher vitamin D levels, compared to the 20 MUg/day and the weekly 125 MUg dose. The last can be an option when issues with compliance to the supplementation are present. PMID- 29263736 TI - Oxidative stress in bone remodeling: role of antioxidants. AB - ROS are highly reactive molecules which consist of a number of diverse chemical species, including radical and non-radical oxygen species. Oxidative stress occurs as a result of an overproduction of ROS not balanced by an adequate level of antioxidants. The natural antioxidants are: thiol compounds among which GSH is the most representative, and non-thiol compounds such as polyphenols, vitamins and also various enzymes. Many diseases have been linked to oxidative stress including bone diseases among which one of the most important is the osteoporosis. The redox state changes are also related to the bone remodeling process which allows the continuous bone regeneration through the coordinated action of bone cells: osteoclasts, osteoblasts and osteocytes. Changes in ROS and/or antioxidant systems seem to be involved in the pathogenesis of bone loss. ROS induce the apoptosis of osteoblasts and osteocytes, and this favours osteoclastogenesis and inhibits the mineralization and osteogenesis. Excessive osteocyte apoptosis correlates with oxidative stress causing an imbalance in favor of osteoclastogenesis which leads to increased turnover of bone remodeling and bone loss. Antioxidants either directly or by counteracting the action of oxidants contribute to activate the differentiation of osteoblasts, mineralization process and the reduction of osteoclast activity. In fact, a marked decrease in plasma antioxidants was found in aged or osteoporotic women. Some evidence shows a link among nutrients, antioxidant intake and bone health. Recent data demonstrate the antioxidant properties of various nutrients and their influence on bone metabolism. Polyphenols and anthocyanins are the most abundant antioxidants in the diet, and nutritional approaches to antioxidant strategies, in animals or selected groups of patients with osteoporosis or inflammatory bone diseases, suggest the antioxidant use in anti-resorptive therapies for the treatment and prevention of bone loss. PMID- 29263738 TI - Hypocalcemia and osteomalacia after bariatric surgery. AB - Introduction: Obesity has become a major health problem not only in industrialized societies but also in developing countries. Multiple studies have shown that bariatric surgery has been effective in reducing substantial amount of weight and also the comorbidities and is being performed more frequently as an established treatment. Due to anatomical and physiological alterations after surgery that impairs absorption of vitamin D and calcium, two fundamental factors in bone formation, their intestinal absorption is highly compromised. Case report: We present a 48-year-old woman who was visited in emergency room for generalized bone pain, perioral paresthesia and carpopedal spasm. She had undergone bariatric surgery 15 years ago. Chvostek's sign and Trousseau's sign were positive. Examination of thoracic ribs elicited severe pain on palpation. Laboratory evaluation revealed: Ca = 6.1 mg/dL, P= 2.1 mg/dL, alkaline phosphatase = 432 (160-303), PTH=541 pg/mL, and 25(OH)D3= 3 ng/mL. Whole body bone scan showed increased uptake in the anterior arc of left 6th rib, posterior arc of left 6th and 12th ribs with increased uptake of costochondral joints. Conclusion: Our case highlights the possible consequences that bariatric surgery may have on bone and mineral health and the need for regular and proactive follow up of the patients. PMID- 29263739 TI - Hypophosphatasia: clinical manifestation and burden of disease in adult patients. AB - Hypophosphatasia (HPP) is a rare inherited disease with a heterogeneous clinical expression. The adult form of HPP is often difficult to be recognized with a delayed diagnosis and inappropriate treatments. Though severity of HPP decreases with age at onset, important complications could occur at any age and the burden of HPP among adult patients is found to be significant. Adult patients with HPP suffer of chronic pain, recurrent fractures and other orthopedics problems, with severe disability that have a serious negative impact on all aspects of their life. The aim of this paper is to summarize the main aspects of HPP in adult patients reviewing the literature and focusing on its burden for patients suffering from this condition. PMID- 29263740 TI - Nuclear magnetic resonance therapy (MBST) in the treatment of osteoporosis. Case report study. AB - Despite various pharmacological treatments, the problem of osteoporosis is not yet solved nor decreased. Drug's adverse event and fractures after long termed pharmacotherapy indicate a need for new treatment modalities. Nuclear magnetic resonance therapy could be a supplement to exercise and an alternative or supplement to pharmacotherapy. Number of clinical studies showed increase of BMD after nuclear magnetic resonance therapy and here presented case reports of eleven well-documented cases in which patients experienced severe trauma, having a huge hematoma around the hip but did not suffer any fracture, encourage this expectation. This case report study additionally presents case reports based on the follow-up of the incidence of fractures in a group of 450 patients (males n = 55, females n = 395) with a mean age of 68.4 years. All patients had been treated with MBST - therapeutic nuclear magnetic resonance, standard cycles of 10 days subsequently and followed during a five-year period. The data indicates that NMRT might reduce a risk of fractures in osteoporotic patients. PMID- 29263737 TI - Adipose stem cells for bone tissue repair. AB - Adipose-derived stem/stromal cells (ASCs), together with adipocytes, vascular endothelial cells, and vascular smooth muscle cells, are contained in fat tissue. ASCs, like the human bone marrow stromal/stem cells (BMSCs), can differentiate into several lineages (adipose cells, fibroblast, chondrocytes, osteoblasts, neuronal cells, endothelial cells, myocytes, and cardiomyocytes). They have also been shown to be immunoprivileged, and genetically stable in long-term cultures. Nevertheless, unlike the BMSCs, ASCs can be easily harvested in large amounts with minimal invasive procedures. The combination of these properties suggests that these cells may be a useful tool in tissue engineering and regenerative medicine. PMID- 29263741 TI - Atypical presentation of spine bone metastasis in prostate cancer mimicking Pott's disease. AB - A 55-year-old man was hospitalized for a low back pain lasting for 3 months. Spinal MRI revealed a suggestive aspect of multilevel discitis L5-S1-S2 with paravertebral abscess. A thoraco-abdominal CT scan confirmed the presence of multiple pathological lymph nodes in several locations, bilateral micronodular pulmonary infiltrate; it also showed mirror bone erosions of vertebral L5 and S1 endplates, suggestive of disseminated tuberculosis with lung involvement and lymphadenopathy. A discovertebral L5-S1 biopsy was performed confirming the diagnosis of metastatic prostatic adenocarcinoma including a tumor infiltration of the intervertebral disc, without arguments for a septic processus superimposed without tuberculosis granuloma. Although rare, cases of metastases located at the disco-vertebral junction including prostatic cancer have already been described, and should be known to the clinician. The differential diagnosis with an infectious spondylodiscitis can be difficult in some case around the vertebral disc and in case of epiduritis and soft tissues involvement on MRI sequences. Disco-vertebral biopsy remains the cornerstone of the diagnosis. PMID- 29263742 TI - Infantile myofibromatosis of the iliac bone. AB - Introduction: Solitary infantile myofibromatosis (IM) of bone is a rare benign osseous tumor of childhood with low rate of recurrence. Well documented within the multicenter form, its solitary intraosseous location is less well described. Case report: We present a rare case of intraosseous myofibromatosis arising the iliac bone of a 11-year-old girl, who was operated at 2 months of life for a retroauricular subcutaneous MF with unbalanced translocation t(9;16). She presented with a limping associated to a stiffness of the hip without pain. Imaging disclosed a 4*4*1cm intraosseous, lytic and heterogeneous mass with a soft tissue component on the medial cortical of the left iliac bone. Open biopsy was performed. Histology revealed proliferation of fusiform cells with eosinophil cytoplasm embedded in a myxoid and fibrous stroma without mitotic figures. On immunohistochemistry, cells were positive for actin, PS100, KL1, focally positive for EMA, CD34, P63, rarely CD31, which indicated diagnosis of new localization of IM. Cytogenetic analysis revealed absence of translocation t(9;16), which was found in the first tumor. Subsequent total resection was performed. The patient recovered normal function without recurrence of tumor at 3 years follow-up. Conclusion: To our knowledge, this is the first case of solitary IM of the iliac bone, occurring 12 years after the first localization. Total resection resulted in excellent outcome. However recurrence can happen even long time after the first resection and new localization is possible, as in our case. This suggests close follow-up and clear information about the risk of recurrence. PMID- 29263743 TI - Hypercalcemia, necrotizing pancreatitis and bone lesions: a benign cause. AB - Primary Hyperparathyroidism is asymptomatic in most patients (PHPT). We report a case of PHPT in a young male patient. He presented with severe pancreatitis due to hypercalcemia and multiple bone lesions resulting in pathological fractures. The patients recovered rapidly after parathyroidectomy. PMID- 29263744 TI - Primary central nervous system germinal center B-like diffuse large B-cell lymphoma: a case report. AB - We report a case of a 54-year-old HIV-negative female who presented with a 2 month history of ongoing post meridiem low-level fever and new onset progressive paralysis. On MRI (magnetic resonance imaging), an infiltrative enhancing lesion was noted, which initially resembled that of MS, but she reacted not sensitively with immunosuppressive therapy, we performed a brain biopsy to her, it turned out to be primary CNS (central nervous system) diffuse large B-cell lymphoma (DLBCL). And the morphology, the flow cytometric findings were consistent with germinal center B-like diffuse large B-cell lymphoma. There were only a few case reports concerning primary CNS DLBCL of GCB. The misdiagnose of this patient should alarm the bell, and we should consider biopsy when the lesion is near the cortex in the brain. Why she reacted not sensitively with immunosuppressive therapy later is analyzed. PMID- 29263745 TI - Two cases of Gorham-Stout disease with good response to zoledronic acid treatment. AB - Gorham-Stout disease - also called vanishing bone syndrome - is a rare bone disease characterized by a progressive intra-osseous proliferation of non neoplastic vascular tissue resulting in massive osteolysis. Here, we report two clinical cases of Gorham-Stout disease. Case 1: a 56-year-old woman with 20 years of history of pain and swell in elbows, ankles and wrist. Then she was diagnosed as systemic lupus erythematosus (SLE) with glomerulonephritis type III. After other pathologies were ruled out Gorham-Stout disease was diagnosed. Intravenous zoledronic acid (5 mg) was indicated and after third infusion a progressive improvement of pain, mobility and daily activities were observed. Case 2: a 70 years-old man with a history of pain and limited motion in the left shoulder without X-ray abnormality. Six months later pathological fracture in the left humerus occurred and after ruled out other pathologies Gorham-Stout disease was diagnosed. Intravenous zoledronic acid (5 mg) was indicated and a good response was observed after the first infusion. Nowadays just over 200 cases were reported. Gorham-Stout disease was reported in different bones, at different age presentation and severe physical deformities, disabilities, and life-threatening complications can occur. Two cases of Gorham-Stout disease with good response to zoledronic acid was reported in this article. PMID- 29263746 TI - Multiple fractures and impaired bone metabolism in Wolfram syndrome: a case report. AB - Wolfram Syndrome (WS) is a rare and lethal disease characterized by optic atrophy, diabetes mellitus, diabetes insipidus, and hearing loss. To date, osteoporotic related fractures have not been reported in affected patients. Here, we describe the case of a man affected by WS complicated by several bone fragility fractures. A 50-year-old Caucasian man was hospitalized because of tibia and fibula fractures. His clinical features included diabetes mellitus, diabetes insipidus, optic atrophy and deafness that were consistent with an unrecognized WS diagnosis, which was confirmed by the identification of a specific mutation in gene WFS1 encoding wolframin. Bone mineral density by phalangeal quantitative ultrasound demonstrated severe osteoporosis, with high serum levels of surrogate markers of bone turn-over. Previously unidentified rib fractures were also detected. To the best of our knowledge, this is the first report of osteoporotic related fractures in a patient affected by WS. Although no effective treatments are currently available to delay the progression of the disease, this case report suggests to evaluate fracture risk in the diagnostic work-up of WS. PMID- 29263747 TI - Spondylocarpotarsal synostosis syndrome. A rare case of short stature and congenital scoliosis. AB - Spondylocarpotarsal synostosis is a very rare skeletal disorder characterized by vertebral malsegmentation defects. Apart from severe vertebral defects, the disease is associated with carpal and tarsal synostosis which is quite characteristic for the disease. We report a case of young child who presented with short stature and congenital scoliosis. The radiological and clinical findings were compatible with the above diagnosis. Apart from the classical findings, the patient had evidence of odontoid aplasia which has not earlier been described in association with this disorder. We report this case for rarity of this disorder and the associated novel finding. PMID- 29263748 TI - Hydatid cyst in the vastus lateralis muscle: a case report. AB - Hydatidosis is a zoonotic disease; human infection occurs through the consumption of food and water contaminated with the eggs of parasites of the Echinococcus type. While the liver is the most common site of infection, involvement of the musculoskeletal system is extremely rare. In the context of musculoskeletal involvement, the spine is the most commonly infected site, while the muscles are rarely infected and account for approximately <1% of cases. It has been suggested that muscles provide an unsuitable environment for the parasite, because of the presence of lactic acid. The cysts appear as slow-growing masses of soft tissue, and signs of inflammation and fistulization often coexist. We report a rare case of an hydatid cyst located in the vastus lateralis muscle of a 41-year-old man. Muscular echinococcosis is an extremely rare disease. A MRI evaluation should be taken into account as gold standard in the diagnosis. Surgical cystectomy is often indicated, and an excision with wide margins is mandatory to avoid the rupture of the cyst and anaphylaxis. Adjuvant pharmacological therapy is recommended to minimize the risk of recurrence. PMID- 29263749 TI - Giant schwannoma of the foot: a case report and literature review. AB - A schwannoma is a rare, benign tumor originating from Schwann cells of peripheral nerve sheath. It commonly occurs in subjects between 20 and 50 years of age, and its malignant transformation is exceptional. While schwannomas usually affect the head and neck region, localization in the lower extremity is exceptionally rare, and even fewer cases have described schwannomas occurring in the foot. We report a case of a giant schwannoma of the foot diagnosed in a 65-year-old woman. A giant schwannoma of the foot is an extremely rare soft tissue tumor. MRI may allow an earlier diagnosis and provide valuable information about the size and possible bone invasion. This case report noted that a complete excision of the schwannoma may prevent the risk of local recurrence, regardless of its size. PMID- 29263750 TI - Periostin and sclerostin levels in juvenile Paget's disease. AB - Juvenile Paget's disease (JPD) is a rare, autosomal recessive disorder featuring markedly increased serum alkaline phosphatase activity, indicative of greatly accelerated bone turnover throughout the skeleton. The main aim of this study was to evaluate circulating periostin and sclerostin levels in two adult patients with mild JPD (due to "Balkan" mutation). We measured periostin and sclerostin levels in a previously described woman and a newly diagnosed man with JPD, and 10 apparently healthy individuals, matched (1:5) to JPD patients for gender, age and body mass index. Sclerostin levels were similar between JPD patients and controls. Periostin levels were about 2.5 times higher in JPD patients. Periostin and sclerostin levels were negatively correlated (rs= -0.63; p=0.03). In conclusion, a trend towards higher periostin levels was observed in JPD patients, whereas sclerostin levels were similar to controls. PMID- 29263751 TI - Vertical structure of stratospheric water vapour trends derived from merged satellite data. AB - Stratospheric water vapour is a powerful greenhouse gas. The longest available record from balloon observations over Boulder, Colorado, USA shows increases in stratospheric water vapour concentrations that cannot be fully explained by observed changes in the main drivers, tropical tropopause temperatures and methane. Satellite observations could help resolve the issue, but constructing a reliable long-term data record from individual short satellite records is challenging. Here we present an approach to merge satellite data sets with the help of a chemistry-climate model nudged to observed meteorology. We use the models' water vapour as a transfer function between data sets that overcomes issues arising from instrument drift and short overlap periods. In the lower stratosphere, our water vapour record extends back to 1988 and water vapour concentrations largely follow tropical tropopause temperatures. Lower and mid stratospheric long-term trends are negative, and the trends from Boulder are shown not to be globally representative. In the upper stratosphere, our record extends back to 1986 and shows positive long-term trends. The altitudinal differences in the trends are explained by methane oxidation together with a strengthened lower-stratospheric and a weakened upper-stratospheric circulation inferred by this analysis. Our results call into question previous estimates of surface radiative forcing based on presumed global long-term increases in water vapour concentrations in the lower stratosphere. PMID- 29263752 TI - Clinically apparent adverse reactions to intra-wound vancomycin powder in early onset scoliosis are rare. AB - Purpose: Spine surgeons have increasingly used intraoperative application of topical vancomycin powder (TVP) to prevent surgical site infections (SSIs). The goals of this study were to define the rate of pharmacological adverse reaction to TVP in young patients undergoing posterior spinal surgery and to summarise institutional variation in TVP dosing. Methods: This retrospective observational study included ten spine centres in the United States and one in Europe. Patients with early onset scoliosis who underwent posterior spine surgery were eligible for inclusion. Age, weight, TVP dose and surgery type were recorded. Surgeries where patient age was > 12 years were excluded. Pharmacological adverse reactions were defined as clinical instances of Red Man Syndrome, rash, nephrotoxicity, proteinuria, hepatotoxicity or ototoxicity. The rate of pharmacological adverse reaction to TVP was calculated. Dosing practices were summarised. Results: Patient age was in the range of seven months to 12 years (median ten years). Of 1398 observations, there was one possible pharmacological adverse reaction. This was in a ten-year-old, 20.4-kg female patient with neuromuscular sco-liosis undergoing growing rod implantation. She was dosed with 1500 mg of TVP and immediately developed a transient rash without systemic symptoms. This abated over minutes without any medical intervention. There were no other adverse reactions in the sample. The population rate of pharmacological adverse reaction was 0.072% (95% confidence interval 0 to 0.4). Significant variability in dosing practices existed between centres. Conclusion: Pharmacological adverse reactions to TVP are rare. Future work may establish evidence-based guidelines for TVP dosing based on patient weight and other variables. PMID- 29263753 TI - Instrumented cervical spinal fusions in children: indications and outcomes. AB - Purpose: To report indications, outcomes and complications of instrumented cervical spinal fusion in a consecutive series of children at major university hospitals. Methods: A retrospective, single surgeon series identified 35 consecutive children with a mean follow-up (FU) of 2.5 years undergoing instrumented cervical spinal fusion between 2005 and 2015. Results: The main indications were skeletal dysplasia and trauma associated cervical instability. Surgical complications were observed in 12 (34%) patients with multiple complications in four (11%). Four (11%) children required at least one revision surgery, three for nonunion and one for graft dislodgement. All were fused at FU. Surgical complications were more common in children undergoing occipitocervical (OC) fusion than in those avoiding fusion of the OC junction (60% versus 24%) (p = 0.043). Complications were found significantly more in children operated on under the age of ten years than above (50% versus 18%) (p = 0.004). The risk of complications was not dependent on the indications for surgery (skeletal dysplasia versus trauma) (p = 0.177). Conclusion: Skeletal dysplasia associated cervical instability and cervical spine injuries represented the most common indications for instrumented cervical spinal fusion in children. Complications were observed in one-third of these children and 11% required revision surgery for complications. OC spinal fusion and spinal fusion before the age of ten years are associated with higher risk of surgical complications and increased mortality than non-OC fusions and cervical spinal fusions at an older age. We urge surgeons to employ caution to the patient, timing and procedure selection when treating paediatric cervical spine. PMID- 29263754 TI - Total hip arthroplasty in patients 16 years of age or younger. AB - Purpose: Total hip arthroplasty (THA) is rarely recommended in skeletally immature patients. The goal of the present study was to report our short- to mid term results of THA in a series of children aged 16 years or younger, including clinical outcomes and post-operative complications, signs of radiographic loosening of the prostheses, and revision rate. Methods: The 18 children (two male and 16 female patients, 24 hips) underwent cementless THA at a mean age of 14.6 years (11 to 16). Five patients had a bilateral, one-stage surgical procedure. Clinical assessment of these hips used the Merle d'Aubigne et Postel scale modified by Charnley to facilitate assessment of the function of walking. Clinical and radiographic follow-up was conducted at six weeks, six months and then yearly for the first three years. All post-operative complications were recorded. Results: No intra-operative or early post-operative complications occurred. At a mean follow-up of 3.8 years (1 to 8), all patients had greatly improved pain and function scores. All children in the present study improved from severely impaired gait, including four children who were wheelchair-bound, to completely unrestricted gait. All hips demonstrated good alignment with no evidence of wear or radiographic lucencies. No revision of components has been required. One patient had persistent adductor contracture which was addressed with adductor tendon release. Conclusions: THA is a successful procedure for unsalvageable hip arthritis in children at a mean follow-up of 3.8 years. Long term follow-up will be needed to determine implant longevity of the components in these children. PMID- 29263755 TI - Alteration in hypoplasia of the hindfoot structures during early growth in clubfeet treated using the Ponseti method. AB - Purpose: Previous reports have demonstrated diminished size of the hindfoot bones in patients with idiopathic clubfoot deformity. However, no study has quantified the percentage of hypoplasia as a function of early growth, during the brace phase of Ponseti treatment. Methods: We measured the dimensions of ossified structures on radiographs in patients with unilateral Ponseti-treated clubfeet to determine changes in the percentage of hypoplasia between two and four years of age. Results: The degree of hypoplasia varied among the osseous structures in Ponseti-treated clubfeet at age two years, with greater hypoplasia being observed in the talus (7.3%), followed by calcaneus (4.9%) and the cuboid (4.8%). Overall, the degree of hypoplasia diminished by four years, such that the degree of hypoplasia was greatest in the talus (4.2%) and the calcaneus (4.2%) followed by the cuboid (0.6%). At four years of age, the greatest degree of hypoplasia persisted in the talus and calcaneus. Conclusions: Changes occurred in the size of the ossification of hindfoot bones between two and four years of age, and the observed changes in the percentage of hypoplasia varied among the different structures. At four years of age, the greatest percentage of hypoplasia was observed in the talus and calcaneus at values similar to those previously reported in skeletally mature patients. The results suggested that the relative difference in size of the feet may be expected to remain constant in a child with a unilateral clubfoot after this age. PMID- 29263756 TI - Osteonecrosis following treatment for childhood acute lymphoblastic leukaemia: The Southampton Children's Hospital experience. AB - Purpose: To determine the prevalence of osteonecrosis (ON) in children following treatment of acute lymphoblastic leukaemia (ALL), characterise these cases and review treatment methods. Methods: All children diagnosed and treated for ALL between 01 January 2003 and 31 December 2013 at our centre were retrospectively reviewed. Logistic regression was used to investigate risk factors for ON occurrence. Results: Of 235 children treated for ALL, 48/235 (20.4%) children suffered musculoskeletal symptoms necessitating radiological investigation. A total of 13 (5.5%) had MRI-diagnosed ON, with a median diagnosis time of 12 months (interquartile range 10 to 14) following initiation of chemotherapy.ON affected 40 joints in 13 children. The most commonly involved joints were hips (14 joints in eight patients) and knees (12 joints in seven patients).Older age at ALL diagnosis was associated with significantly increased risk of development of ON per year (odds ratio 1.35, 95% confidence interval 1.17 to 1.57, p < 0.001).Eight children underwent at least one surgical intervention. Joint arthroplasty was undertaken in nine joints of four children at a mean age of 18.3 years. All patients who underwent hip arthroplasty had previously received core decompression, with a mean time of 27.8 months (18 to 33) between treatments. Conclusions: ON is a significant complication of ALL treatment. Our results suggest risk stratification for development of ON by age, and targeted monitoring of high-risk joints is possible. ON treatment is varied with little evidence base. PMID- 29263757 TI - Sclerotherapy using Surgiflo and alcohol: a new alternative for the treatment of aneurysmal bone cysts. AB - Purpose: This study aims to review the results of sclerotherapy using Surgiflo in addition to alcohol in primary aneurysmal bone cysts (ABC). Methods: A total of 16 consecutive patients with histologically confirmed diagnosis of primary ABC were treated by percutaneous Surgiflo and alcohol injection at our institution. Clinical follow-up included the assessment of pain, swelling, limping and functional impairment. Radiological parameters included tumour volume, physis cyst distance, thickness of cyst cortex, and presence of intracystic septations. Mean follow-up was 35,6 months (24-71 months). Treatment was considered successful when the cyst volume decreased by a minimum of 10%, the bone cortex became thicker, and the distance to physis increased. Results: Mean age at presentation was 9.5 years (5.16-13.84 years). All ABC's were primary and all patients underwent a single Surgiflo and alcohol session except for two (12.5%) who required a second session. All patients had a good clinical result at final follow-up. Satisfactory cyst healing was achieved in 11 cases according to radiological parameters. Tumour volume decreased from a mean of 122 cm3 (111 to 133) before injection to 86 cm3 (76 to 96) at last follow-up (p < 0.01). Physis cyst distance increased from a mean of 1 cm (0.1 to 2) to 2.1 cm (0.5 to 4) at last follow-up (p < 0.01). Cortical thickness improved from 1 mm (0.5 to 1.5) to 2 mm (1 to 3.5) at last follow-up (p < 0.01).There were no treatment related complications. Surgery was performed in one patient having a C3 vertebra ABC after developing quadriparesis due to tumour progression. Conclusion: Sclerotherapy using Surgiflo and alcohol may be used as an efficient, safe and minimally invasive alternative for the treatment of primary ABCs. PMID- 29263758 TI - Nerve transfer to biceps to restore elbow flexion and supination in children with obstetrical brachial plexus palsy. AB - Purpose: Nerve transfers to restore elbow flexion have been described for traumatic brachial plexus palsy in adults. Indications are less frequent in infants and the results are less published. Methods: Ten patients with obstetrical brachial plexus palsy were operated on for lack of flexion against gravity with ulnar or median nerve transfer to biceps motor branch. The primary endpoint was improvement in elbow flexion and supination. Results: Mean age at surgery was 12.5 months and mean follow-up was 2.6 years. The Active Movement Scale (AMS) was used to evaluate elbow flexion and forearm supination. At the last follow-up, the average AMS score improved from 0.3 to 5.7 for elbow flexion and from 0.6 to 5.8 for forearm supination. There was no statistical correlation between the age at surgery and the AMS score 18 months post-operatively. Conclusions: Nerve transfer to the biceps motor branch can improve elbow flexion and forearm supination in selected patients with upper lesions and can be safely performed until the age of two years. PMID- 29263759 TI - Accuracy of C-arm measurements in assessment of paediatric femoral fracture shortening. AB - Purpose: Spica casting of femoral shaft fractures is standard practice for young children. In 1983, Dr. Rang published an illustration demonstrating that radiographs can be misleading when measuring femoral fracture shortening. Today, fluoroscopy is used to determine shortening after closed reduction and spica casting. This paper aims to determine the accuracy of fluoroscopy when measuring 25 mm of shortening in a femur fracture sawbone model. Methods: Magnification, elevation and angulation were evaluated using a femur fracture sawbone model with a fixed overlap of 25 mm. Two C-arm machines used in clinical practice were studied: the OEC 9900 Elite GE C-arm and the Fluoroscan InSight mini C-arm. Results: The OEC 9900 Elite GE C-arm demonstrated a 1.75 * magnification. The Fluoroscan InSight mini C-arm demonstrated a 2.5 * magnification. An 11% and a 17% magnification with elevation of the femur to 8 cm occurred using the OEC 9900 Elite GE and the Fluoroscan InSight mini C-arm respectively. Changing the tube angulation from 0 degrees to 60 degrees resulted in a 36% and 16% change in measured femur fracture shortening on the OEC C-arm and Fluoroscan mini C-arm respectively. Conclusion: C-arm images are inaccurate. When measuring 25 mm of shortening of a paediatric femur fracture, each machine has a unique amount of magnification that should be determined and accounted for in clinical practice. Elevation of the femur above the C-arm receiver and angulation of the femur further increase the inaccuracies when measuring 25 mm of fracture shortening. Images perpendicular to the fracture are most accurate. PMID- 29263760 TI - A systematic review and meta-analysis of adverse outcomes following non-buried versus buried Kirschner wires for paediatric lateral condyle elbow fractures. AB - Purpose: Fractures of the lateral condyle of the humerus in children are a common injury. If displaced or unstable they may require surgical reduction and fixation with Kirschner wires (K-wires). K-wires are placed using either an open or closed technique. The decision to bury or leave the ends extending through the skin is surgeon-dependent and based on factors including post-operative infection risk, bony union and ease of wire removal. Methods: We performed a systematic review and meta-analysis of non-buried versus buried K-wires for lateral condyle elbow fractures in children in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. A comprehensive search strategy included Medline, Embase and CINAHL via NICE Evidence from database inception to June 2017. Two authors independently reviewed, included or excluded articles, extracted data and assessed for quality with the ROBINS-I tool. We performed direct comparison meta-analysis for all adverse events, post-operative infection and failure of bony union. Results: Three studies were analysed comprising of 434 participants. There was a significantly reduced relative risk of adverse events in the non-buried group, equating to approximately 45% reduced risk (RR 0.55, 95% confidence interval 0.34 to 0.88). There were no significant differences in risk of post-operative infection or failure of bony union. All three cost-analyses in the included studies observed savings with non-buried K-wires. Conclusion: Non buried K-wires for lateral condyle elbow fractures convey a lower risk of adverse events and may be more cost-effective compared with buried K-wires. Non-buried K wires do not appear to increase the risk of infection or failure of bony union. These findings are limited by a high risk of bias due to inherent methodological flaws in the design of included studies. PMID- 29263761 TI - The effect of distal femoral extension osteotomy on muscle lengths after surgery. AB - Purpose: The distal femoral extension osteotomy (DFEO) is often used in the treatment of crouch gait to help compensate for knee flexion contractures. The effects of DFEO on skeletal and muscle lengths are incompletely understood, but are important to consider in planning concomitant surgeries such as patellar tendon advancement (PTA). Therefore, the purpose of this study was to quantify the changes in femur, quadriceps, and hamstring lengths with DFEO, and to determine the sensitivity to surgical factors such as wedge location and magnitude. Methods: A musculoskeletal model with six degrees of freedom tibiofemoral and patellofemoral joints was used for analysis. A wedge was removed from the distal femur and the remaining bone segments were plated together to simulate the DFEO. After simulating the knee's post-operative equilibrium, the surgically-induced changes in muscle and bone lengths were analysed. Results: Relative to the pre-operative state, DFEO stretches the hamstrings while shortening the femur and quadriceps. A more posterior wedge apex location (i.e. creation of a cuneiform wedge) diminished the stretch of the hamstrings, but induced greater shortening of the femur and quadriceps. More proximal wedge locations necessitated greater translation of the distal fragment to maintain the knee joint axis. Conclusion: Reduced quadriceps length after DFEO shown in this study is consistent with the need for simultaneous PTA. The induced hamstring stretch also may represent a potential mechanism for post-operative nerve palsies. Overall, the numerical results provide a firmer basis for planning the specifics of DFEO such that desired muscle lengths and joint alignment are achieved. PMID- 29263762 TI - The challenges of a comprehensive surgical approach to Blount's disease. AB - Purpose: The purpose of this study is to evaluate a surgical technique that aims to address the multi-planar deformities occurring in early onset Blount's disease. Methods: Seven patients (eight lower limbs) with early onset Blount's disease were treated with a surgical technique that used an external fixator to simultaneously address all aspects of deformity. Presenting radiographic parameters including mechanical axis deviation (MAD), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA) and medial plateau angle (MPA) were compared with final follow-up and the unaffected limb. Data was also collected on surgical complications and functional outcomes. Results: After a mean interval of 4.6 years (2.2 to 9), the MAD of the affected limb improved from 4.85 cm to 1.88 cm, MPTA from 43.58 degrees to 75.46 degrees and MPA from 43.41 degrees to 20.71 degrees . The mean time in the external fixator was 5.6 months (3.5 to 10.4). Recurrence was noted in three patients; two had evidence of nerve injury and one patient had premature fibular consolidation. Conclusion: The surgical technique described in this study has attempted to address the complex multiaxial deformity that is encountered in Blount's disease. It identifies difficulties and limitations in developing a comprehensive surgical protocol and highlights complications associated with this approach. PMID- 29263764 TI - UTLS water vapour from SCIAMACHY limb measurementsV3.01 (2002-2012). AB - The SCanning Imaging Absorption spectroMeter for Atmospheric CHartographY (SCIAMACHY) aboard the Envisat satellite provided measurements from August 2002 until April 2012. SCIAMACHY measured the scattered or direct sunlight using different observation geometries. The limb viewing geometry allows the retrieval of water vapour at about 10-25 km height from the near-infrared spectral range (1353-1410 nm). These data cover the upper troposphere and lower stratosphere (UTLS), a region in the atmosphere which is of special interest for a variety of dynamical and chemical processes as well as for the radiative forcing. Here, the latest data version of water vapour (V3.01) from SCIAMACHY limb measurements is presented and validated by comparisons with data sets from other satellite and in situ measurements. Considering retrieval tests and the results of these comparisons, the V3.01 data are reliable from about 11 to 23 km and the best results are found in the middle of the profiles between about 14 and 20 km. Above 20 km in the extra tropics V3.01 is drier than all other data sets. Additionally, for altitudes above about 19 km, the vertical resolution of the retrieved profile is not sufficient to resolve signals with a short vertical structure like the tape recorder. Below 14 km, SCIAMACHY water vapour V3.01 is wetter than most collocated data sets, but the high variability of water vapour in the troposphere complicates the comparison. For 14-20 km height, the expected errors from the retrieval and simulations and the mean differences to collocated data sets are usually smaller than 10 % when the resolution of the SCIAMACHY data is taken into account. In general, the temporal changes agree well with collocated data sets except for the Northern Hemisphere extratropical stratosphere, where larger differences are observed. This indicates a possible drift in V3.01 most probably caused by the incomplete treatment of volcanic aerosols in the retrieval. In all other regions a good temporal stability is shown. In the tropical stratosphere an increase in water vapour is found between 2002 and 2012, which is in agreement with other satellite data sets for overlapping time periods. PMID- 29263765 TI - Controlled weather balloon ascents and descents for atmospheric research and climate monitoring. AB - In situ upper-air measurements are often made with instruments attached to weather balloons launched at the surface and lifted into the stratosphere. Present-day balloon-borne sensors allow near-continuous measurements from the Earth's surface to about 35 km (3-5 hPa), where the balloons burst and their instrument payloads descend with parachutes. It has been demonstrated that ascending weather balloons can perturb the air measured by very sensitive humidity and temperature sensors trailing behind them, particularly in the upper troposphere and lower stratosphere (UTLS). The use of controlled balloon descent for such measurements has therefore been investigated and is described here. We distinguish between the single balloon technique that uses a simple automatic valve system to release helium from the balloon at a preset ambient pressure, and the double balloon technique that uses a carrier balloon to lift the payload and a parachute balloon to control the descent of instruments after the carrier balloon is released at preset altitude. The automatic valve technique has been used for several decades for water vapor soundings with frost point hygrometers, whereas the double balloon technique has recently been re-established and deployed to measure radiation and temperature profiles through the atmosphere. Double balloon soundings also strongly reduce pendulum motion of the payload, stabilizing radiation instruments during ascent. We present the flight characteristics of these two ballooning techniques and compare the quality of temperature and humidity measurements made during ascent and descent. PMID- 29263766 TI - Medical Acupuncture Journal: Real-World Knowledge. PMID- 29263767 TI - How Do You Treat Back Pain in Your Practice? Part 1. PMID- 29263769 TI - Trending BIO. PMID- 29263768 TI - Primary parotid adenocarcinoma metastasis to the spleen with PIK3CA mutation: cytological findings and review of the literature. AB - Background: Primary solid tumor metastasis to the spleen is a rare event, and often presents as an incidental finding without clinical symptoms of the patient. The most common primary tumors that metastasize to the spleen are colorectal, ovarian, and lung carcinomas. Parotid tumor metastasis to the spleen is extremely rare. We report an unusual case of metastatic parotid adenocarcinoma NOS (not otherwise specified) to the spleen. Case report: The patient presented with primary parotid carcinoma and underwent left parotidectomy. On pathological examination of the primary parotid tumor, no vascular or perineural invasion was found; all surgical resection margins and neck lymph nodes were also uninvolved by the tumor. No other therapy was given after the surgery. Four years later, the patient developed a solitary splenic lesion detected by a routine follow-up computed tomography (CT) scan. The subsequent fine needle aspiration (FNA) and splenectomy showed a metastatic adenocarcinoma consistent with the parotid primary. Immunohistochemical (IHC) staining of the metastatic tumor also showed a similar pattern as that of the primary tumor, including positivity for pancytokeratin, S-100 and SOX10, supporting the diagnosis. Furthermore, A PIK3CA (phosphatidylinositol 3-kinase catalytic subunit) mutation was also detected in the splenic metastasis. Conclusion: Based on our review of the literature, we believe that this is the first report of such a case. Accurate diagnosis and molecular characterization of the splenic metastasis have a critical impact on the clinical management of the patient. PMID- 29263770 TI - Economic Impact of Increased Utilization of Multivariate Assay Testing to Guide the Treatment of Ovarian Cancer: Implications for Payers. AB - Background: Ovarian cancer is the eighth most common cancer among women, but ranks fifth in cancer-related causes of death, the majority of which are detected in late stages, after the cancer has metastasized. The CA125 test is the standard of care for assessing suspicious pelvic masses. However, the primary use of CA125 is to monitor treatment progress rather than to screen for disease, and its sensitivity is exceedingly low, unlike the multivariate assay OVA1. A cost effective treatment of ovarian cancer requires early and accurate diagnosis of pelvic masses and reduced referrals of patients with benign tumors to a gynecologic oncologist. Objective: To analyze the economic impact of increased utilization of a multivariate assay, such as OVA1, to guide the treatment of ovarian cancer. Methods: The study population was drawn from Medicare and commercial health plan claims data. A budget impact model was constructed to estimate the economic consequences of substituting the multivariate assay OVA1 to replace the single biomarker assay CA125 to assess the likelihood of pelvic mass malignancy in premenopausal and/or postmenopausal women. All patients selected for the analysis had CA125 testing before surgical intervention. Results: A total of 92,843 health plan members were included for analysis, comprising 48,113 commercially insured members and 44,730 Medicare beneficiaries. Estimates of future health plan expenditures, which were calculated from base-case assumptions, projected overall savings of $0.05 per-member per-month (PMPM) for commercially insured members and $0.01 PMPM for Medicare beneficiaries as a result of increased utilization of OVA1. Sensitivity analysis revealed potential savings of up to $0.17 PMPM for commercially insured patients and up to $0.05 for Medicare beneficiaries. Conclusion: The results of the budget impact model support the use of OVA1 instead of CA125 by indicating that modest cost-savings can be achieved, while reaping the clinical benefits of improved diagnostic accuracy, early disease detection, and reductions in multiple, and possibly unnecessary, referrals to gynecologic oncologists. PMID- 29263772 TI - "Opioids Equal Heroin". PMID- 29263771 TI - The Cost of Hematopoietic Stem-Cell Transplantation in the United States. AB - Background: Hematopoietic stem-cell transplantation (HSCT) requires highly specialized, resource-intensive care. Myeloablative conditioning regimens used before HSCT generally require inpatient stays and are more intensive than other preparative regimens, and may therefore be more costly. Objective: To estimate the costs associated with inpatient HSCT according to the type of the conditioning regimen used and other potential contributors to the overall cost of the procedure. Method: We used data from the Truven Health MarketScan insurance claims database to analyze healthcare costs for pediatric (age <18 years) and adult (age >=18 years) patients who had autologous or allogeneic inpatient HSCT between January 1, 2010, and September 23, 2013. We developed an algorithm to determine whether conditioning regimens were myeloablative or nonmyeloablative/reduced intensity. Results: We identified a sample of 1562 patients who had inpatient HSCT during the study period for whom the transplant type and the conditioning regimen were determinable: 398 patients had myeloablative allogeneic HSCT; 195 patients had nonmyeloablative/reduced intensity allogeneic HSCT; and 969 patients had myeloablative autologous HSCT. The median total healthcare cost at 100 days was $289,283 for the myeloablative allogeneic regimen cohort compared with $253,467 for the nonmyeloablative/reduced intensity allogeneic regimen cohort, and $140,792 for the myeloablative autologous regimen cohort. The mean hospital length of stay for the index (first claim of) HSCT was 35.6 days in the myeloablative allogeneic regimen cohort, 26.6 days in the nonmyeloablative/reduced-intensity allogeneic cohort, and 21.8 days in the myeloablative autologous regimen cohort. Conclusion: Allogeneic HSCT was more expensive than autologous HSCT, regardless of the regimen used. Myeloablative conditioning regimens led to higher overall costs than nonmyeloablative/reduced-intensity regimens in the allogeneic HSCT cohort, indicating a greater cost burden associated with inpatient services for higher intensity preparative conditioning regimens. Pediatric patients had higher costs than adult patients. Future research should involve validating the algorithm for identifying conditioning regimens using clinical data. PMID- 29263773 TI - Major Cardiovascular Events in Patients with Gout and Associated Cardiovascular Disease or Heart Failure and Chronic Kidney Disease Initiating a Xanthine Oxidase Inhibitor. AB - Background: Several observational studies and meta-analyses have suggested that treating hyperuricemia in patients with gout and moderate or severe chronic kidney disease (CKD) may improve renal and cardiovascular (CV) outcomes. Objective: To evaluate the impact of initiating allopurinol or febuxostat treatment on major CV events in patients with gout, preexisting CV disease (CVD) or heart failure (HF), and stage 3 or 4 CKD in a real-world setting. Methods: Patients with gout (aged >18 years) who initiated allopurinol or febuxostat treatment between 2009 and 2013 after a diagnosis of stage 3 or 4 CKD and CVD including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease (PVD)-or HF were selected from the MarketScan databases. The major CV events included CAD-specific, cerebrovascular disease-specific, and PVD specific events. Cox proportional hazards modeling identified the predictors of major CV events in aggregate, and of CAD, cerebrovascular disease, and PVD events, individually. Results: During follow-up, 2426 patients (370 receiving febuxostat and 2056 receiving allopurinol; 63% male; mean age, 73 years) had 162 major CV events (3.8% in those receiving febuxostat vs 7.2% in those receiving allopurinol; P = .015). The rates of major CV events per 1000 person-years were 51.8 (95% confidence interval [CI], 28-87) in patients initiating febuxostat and 99.3 (95% CI, 84-117) among those initiating allopurinol. Overall, 49.4% of patients had a CAD event, 32.5% had a PVD event, and 23.5% had a cerebrovascular disease-specific event. Febuxostat initiation was associated with a significantly lower risk for a major CV event versus patients who initiated allopurinol (hazard ratio, 0.52; P = .02), driven in large part by lower PVD-specific events (P = .026). Conclusion: Patients with moderate-to-severe CKD and CVD or HF who initiated febuxostat treatment had a significantly lower rate of major CV events than patients who initiated allopurinol. PMID- 29263774 TI - Comparing the Cost of Treatment with Octreotide Long-Acting Release versus Lanreotide in Patients with Metastatic Gastrointestinal Neuroendocrine Tumors. AB - Background: The 2 somatostatin analogs currently recommended by the National Comprehensive Cancer Network for the treatment of gastrointestinal (GI) neuroendocrine tumors (NETs) include octreotide long-acting release (Sandostatin LAR) for injectable suspension and lanreotide (Somatuline Depot) injection for subcutaneous use. Objective: To estimate the costs to payers associated with 30 mg octreotide LAR and 120-mg lanreotide treatment among patients with metastatic GI-NETs. Methods: The costs to payers associated with the 2 drugs were estimated by including the costs of each drug, drug administration, and adverse events. The unit drug costs for octreotide LAR and for lanreotide were obtained from ReadyPrice Wholesale Acquisition Cost; the doses were obtained from published studies. The adverse event rates were obtained from 2 phase 3 clinical trials, PROMID and CLARINET. Deterministic one-way sensitivity analyses were used to assess the impact of modifying assumptions and inputs on the results, including the 2017 Average Sales Price (ASP). All costs were estimated in 2016 US dollars, with a constant discount of 3%. Results: The costs to payers associated with the treatment of GI-NETs during 1-, 3-, and 5-year horizons were $74,566, $180,082, and $262,344, respectively, for octreotide LAR and $84,856, $205,562, and $299,667, respectively, for lanreotide. Thus, octreotide LAR was associated with lower costs by $10,290 (1 year), $25,480 (3 years), and $37,323 (5 years) compared with lanreotide. Over a 5-year horizon, the costs of adverse events and administration accounted for 0.72% of the total cost for octreotide LAR and 0.51% of the total cost for lanreotide. Sensitivity analyses confirmed that the main factor affecting the cost difference was the price of the drugs; analyses using the ASP yielded similar results. Conclusion: For the management of metastatic GI NETs, the cost to payers of treatment with 30-mg octreotide LAR is considerably lower than with 120-mg lanreotide over 1-, 3-, and 5-year horizons. In the presence of healthcare resource constraints, these findings may support decision making when considering the care of patients with metastatic GI-NETs. PMID- 29263775 TI - The Value of Pre-FDA Approval Healthcare Economic Information Exchange Between Payers and Drug Manufacturers. PMID- 29263776 TI - Laser Surgery of Soft Tissue in Orthodontics: Review of the Clinical Trials. AB - Introduction: Recently, a wide variety of procedures have been done by laser application in orthodontics. Apart from the mentioned range of various treatments, laser has become a tool for many soft tissue surgeries as an alternative to conventional scalpel-based technique during orthodontic treatments in the management of soft tissue. Due to scarce information in the latter subject, this study was designed in order to include clinical trials that included soft tissue ablation by laser in orthodontics. Methods: Literature was searched based on PubMed and Google Scholar databases in 5 years (2010-2015) with English language restriction and clinical trial design. Studies that performed soft tissue application of laser during orthodontic treatment were extracted by the authors. Results: Only eight studies met the inclusion criteria. No significant difference was found between laser ablation and conventional scalpel technique in the matter of treatment outcome. However, few issues remained to clarify the differences in the mentioned procedures. Conclusion: Laser performance can be recommended in case of preceding less bleeding and discomfort during surgical procedure. There are still quandaries among clinical application of scalpel-based surgery in aesthetic region with bracket-bonded teeth. Precaution and knowledge regarding the characteristics of laser beam such as wavelength, frequency, power and timing is extremely needed. PMID- 29263777 TI - The Effect of Photodynamic Therapy in the Treatment of Chronic Periodontitis: A Review of Literature. AB - Introduction: Chronic periodontitis is the most common periodontal disease which is related to the chronic accumulation of bacterial plaque. Since mechanical methods are not sufficient in the treatment of this disease, administration of local/systemic antibiotic is recommended following mechanical debridement. However, side effects of antibiotics such as microbial resistance and patient allergy led to development of alternative methods. One of these suggested methods is the antimicrobial photodynamic therapy (aPDT). PDT is a local noninvasive treatment modality without the side effects caused by antibiotics. The aim of this study was to review the articles related to the application of PDT with laser in the treatment of chronic periodontitis. Review of literature: In the present review of literature, the authors used key words such as chronic periodontitis, laser and photodynamic therapy, and conducted a literature search via Google Scholar and PubMed for the period of 1990 to 2015. A total of 47 articles in English were found. The articles that were not associated with the topic of research and review articles were deleted and only clinical trials were evaluated. After reviewing 23 articles' abstracts, the full texts of 16 articles were analyzed. Conclusion: Considering the safety, the lack of side effects and general advantages like more patient compliance, the PDT treatment with scaling and root planing (SRP) is recommended as an efficient adjunctive modality for the treatment of localized chronic periodontitis especially during the maintenance phase in non-surgical treatment. PMID- 29263778 TI - Identifying consistent allele frequency differences in studies of stratified populations. AB - With increasing application of pooled-sequencing approaches to population genomics robust methods are needed to accurately quantify allele frequency differences between populations. Identifying consistent differences across stratified populations can allow us to detect genomic regions under selection and that differ between populations with different histories or attributes. Current popular statistical tests are easily implemented in widely available software tools which make them simple for researchers to apply. However, there are potential problems with the way such tests are used, which means that underlying assumptions about the data are frequently violated.These problems are highlighted by simulation of simple but realistic population genetic models of neutral evolution and the performance of different tests are assessed. We present alternative tests (including Generalised Linear Models [GLMs] with quasibinomial error structure) with attractive properties for the analysis of allele frequency differences and re-analyse a published dataset.The simulations show that common statistical tests for consistent allele frequency differences perform poorly, with high false positive rates. Applying tests that do not confound heterogeneity and main effects significantly improves inference. Variation in sequencing coverage likely produces many false positives and re-scaling allele frequencies to counts out of a common value or an effective sample size reduces this effect.Many researchers are interested in identifying allele frequencies that vary consistently across replicates to identify loci underlying phenotypic responses to selection or natural variation in phenotypes. Popular methods that have been suggested for this task perform poorly in simulations. Overall, quasibinomial GLMs perform better and also have the attractive feature of allowing correction for multiple testing by standard procedures and are easily extended to other designs. PMID- 29263780 TI - GAC: Gene Associations with Clinical, a web based application. AB - We present GAC, a shiny R based tool for interactive visualization of clinical associations based on high-dimensional data. The tool provides a web-based suite to perform supervised principal component analysis (SuperPC), an approach that uses both high-dimensional data, such as gene expression, combined with clinical data to infer clinical associations. We extended the approach to address binary outcomes, in addition to continuous and time-to-event data in our package, thereby increasing the use and flexibility of SuperPC. Additionally, the tool provides an interactive visualization for summarizing results based on a forest plot for both binary and time-to-event data. In summary, the GAC suite of tools provide a one stop shop for conducting statistical analysis to identify and visualize the association between a clinical outcome of interest and high dimensional data types, such as genomic data. Our GAC package has been implemented in R and is available via http://shinygispa.winship.emory.edu/GAC/. The developmental repository is available at https://github.com/manalirupji/GAC. PMID- 29263779 TI - Selective arc-discharge synthesis of Dy2S-clusterfullerenes and their isomer dependent single molecule magnetism. AB - A method for the selective synthesis of sulfide clusterfullerenes Dy2S@C2n is developed. Addition of methane to the reactive atmosphere reduces the formation of empty fullerenes in the arc-discharge synthesis, whereas the use of Dy2S3 as a source of metal and sulfur affords sulfide clusterfullerenes as the main fullerene products along with smaller amounts of carbide clusterfullerenes. Two isomers of Dy2S@C82 with Cs(6) and C3v(8) cage symmetry, Dy2S@C72-Cs(10528), and a carbide clusterfullerene Dy2C2@C82-Cs(6) were isolated. The molecular structure of both Dy2S@C82 isomers was elucidated by single-crystal X-ray diffraction. SQUID magnetometry demonstrates that all of these clusterfullerenes exhibit hysteresis of magnetization, with Dy2S@C82-C3v(8) being the strongest single molecule magnet in the series. DC- and AC-susceptibility measurements were used to determine magnetization relaxation times in the temperature range from 1.6 K to 70 K. Unprecedented magnetization relaxation dynamics with three consequent Orbach processes and energy barriers of 10.5, 48, and 1232 K are determined for Dy2S@C82-C3v(8). Dy2S@C82-Cs(6) exhibits faster relaxation of magnetization with two barriers of 15.2 and 523 K. Ab initio calculations were used to interpret experimental data and compare the Dy-sulfide clusterfullerenes to other Dy clusterfullerenes. The smallest and largest barriers are ascribed to the exchange/dipolar barrier and relaxation via crystal-field states, respectively, whereas an intermediate energy barrier of 48 K in Dy2S@C82-C3v(8) is assigned to the local phonon mode, corresponding to the librational motion of the Dy2S cluster inside the carbon cage. PMID- 29263781 TI - Management of the patient with failed hypospadias surgery presenting in adulthood. AB - The management of patients who have had complications of primary surgery for the resolution of a hypospadiac deformity remains a therapeutic challenge. Adults with complications following childhood hypospadias repairs are undoubtedly a difficult population to treat, as there is usually a cosmetic deformity, lower urinary tract symptoms, and resulting psychosexual consequences. A surgeon's experience has been and still remains an important factor in determining subsequent surgical outcomes, particularly with more severe or complex cases. The purpose of this review is to evaluate the complications of hypospadias repair that present in adults and review published experience in treating them. PMID- 29263783 TI - Glioblastoma update: molecular biology, diagnosis, treatment, response assessment, and translational clinical trials. AB - This is an exciting time in neuro-oncology. Discoveries elucidating the molecular mechanisms of oncogenesis and the molecular subtypes of glioblastoma multiforme (GBM) have led to new diagnostic and classification schemes with more prognostic power than histology alone. Molecular profiling has become part of the standard neuropathological evaluation of GBM. Chemoradiation followed by adjuvant temozolomide remains the standard therapy for newly diagnosed GBM, but survival remains unsatisfactory. Patients with recurrent GBM continue to have a dismal prognosis, but neuro-oncology centers with active clinical trial programs are seeing a small but increasing cadre of patients with longer survival. Molecularly targeted therapeutics, personalized therapy based on molecular profiling of individual tumors, and immunotherapeutic strategies are all being evaluated and refined in clinical trials. Understanding of the molecular mechanisms of tumor mediated immunosuppression, and specifically interactions between tumor cells and immune effector cells in the tumor microenvironment, has led to a new generation of immunotherapies, including vaccine and immunomodulatory strategies as well as T-cell-based treatments. Molecularly targeted therapies, chemoradiation, immunotherapies, and anti-angiogenic therapies have created the need to develop more reliable neuroimaging criteria for differentiating the effects of therapy from tumor progression and changes in blood-brain barrier physiology from treatment response. Translational clinical trials for patients with GBM now incorporate quantitative imaging using both magnetic resonance imaging and positron emission tomography techniques. This update presents a summary of the current standards for therapy for newly diagnosed and recurrent GBM and highlights promising translational research. PMID- 29263782 TI - Engineering photosynthesis: progress and perspectives. AB - Photosynthesis is the basis of primary productivity on the planet. Crop breeding has sustained steady improvements in yield to keep pace with population growth increases. Yet these advances have not resulted from improving the photosynthetic process per se but rather of altering the way carbon is partitioned within the plant. Mounting evidence suggests that the rate at which crop yields can be boosted by traditional plant breeding approaches is wavering, and they may reach a "yield ceiling" in the foreseeable future. Further increases in yield will likely depend on the targeted manipulation of plant metabolism. Improving photosynthesis poses one such route, with simulations indicating it could have a significant transformative influence on enhancing crop productivity. Here, we summarize recent advances of alternative approaches for the manipulation and enhancement of photosynthesis and their possible application for crop improvement. PMID- 29263784 TI - Recent advances in the management of transient ischemic attacks. AB - Significant advances in our understanding of transient ischemic attack (TIA) have taken place since it was first recognized as a major risk factor for stroke during the late 1950's. Recently, numerous studies have consistently shown that patients who have experienced a TIA constitute a heterogeneous population, with multiple causative factors as well as an average 5-10% risk of suffering a stroke during the 30 days that follow the index event. These two attributes have driven the most important changes in the management of TIA patients over the last decade, with particular attention paid to effective stroke risk stratification, efficient and comprehensive diagnostic assessment, and a sound therapeutic approach, destined to reduce the risk of subsequent ischemic stroke. This review is an outline of these changes, including a discussion of their advantages and disadvantages, and references to how new trends are likely to influence the future care of these patients. PMID- 29263785 TI - Senescence and tumor suppression. AB - Cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation of cells at risk for malignant transformation. Although senescent cells have permanently exited the cell cycle, their presence can have detrimental effects on the surrounding tissue, largely due to the development of the senescence-associated secretory phenotype (SASP). Here, we review the tumor suppressive and tumor-promoting consequences of the senescence response, focusing on the SASP as a key mediator of this dichotomy. Accumulating evidence suggests that the persistence of senescent cells can exacerbate the development of a pro inflammatory, immunosuppressive microenvironment that can favor tumorigenesis. Given that senescence of tumor and stromal cells is a frequent outcome of anti cancer therapy, approaches that harness the growth inhibitory effects of senescence while limiting its detrimental effects are likely to have great clinical potential. PMID- 29263786 TI - Tumor cell dormancy as an adaptive cell stress response mechanism. AB - Metastases are responsible for most cancer-related deaths. The kinetics of tumor relapse is highly heterogeneous, ranging from recurrences shortly after diagnosis to years or even decades after the initial treatment. This subclinical period is known as tumor dormancy, in which residual disease remains in an undetectable state before finally appearing as an overtly proliferative metastasis. Despite recent advances in our understanding of the molecular mechanisms leading to tumor dormancy, it is still a poorly understood phase of cancer progression, which limits opportunities for the design of successful therapeutic interventions. The influence of the tumor microenvironment at the metastatic site and anti metastatic immune responses have been shown to play a crucial role in the onset and maintenance of metastatic dormancy. However, there is still a significant gap in our understanding of how dormant cells remain viable in a quiescent state for long periods of time. Here, we review the latest experimental evidence shedding light on the biological processes that enable dormant tumor cells to endure the multiple stresses encountered at the metastatic site. PMID- 29263787 TI - How zebrafish research has helped in understanding thyroid diseases. AB - Next-generation sequencing technologies have revolutionized the identification of disease-causing genes, accelerating the discovery of new mutations and new candidate genes for thyroid diseases. To face this flow of novel genetic information, it is important to have suitable animal models to study the mechanisms regulating thyroid development and thyroid hormone availability and activity. Zebrafish ( Danio rerio), with its rapid external embryonic development, has been extensively used in developmental biology. To date, almost all of the components of the zebrafish thyroid axis have been characterized and are structurally and functionally comparable with those of higher vertebrates. The availability of transgenic fluorescent zebrafish lines allows the real-time analysis of thyroid organogenesis and its alterations. Transient morpholino knockdown is a solution to silence the expression of a gene of interest and promptly obtain insights on its contribution during the development of the zebrafish thyroid axis. The recently available tools for targeted stable gene knockout have further increased the value of zebrafish to the study of thyroid disease. All of the reported zebrafish models can also be used to screen small compounds and to test new drugs and may allow the establishment of experimental proof of concept to plan subsequent clinical trials. PMID- 29263789 TI - Is law failing to address air pollution? Reflections on international and EU developments. AB - Air pollution is a major global environmental problem, with various adverse effects on health and the environment. This introductory article provides an overview of related global and regional legal instruments. The article evaluates the legal landscape in terms of its coverage, geographic scope and effectiveness, and concludes that the legal measures currently in place fall far short of providing an adequate response to the problem of air pollution. Thus, there is a clear need to strengthen global and regional cooperation to improve air quality. Such cooperation is likely to take non-binding and flexible forms and involve both wider participation among States and broader engagement of various stakeholders. The informal character of cooperation also makes it possible to experiment with new governance approaches that are difficult to implement within the context of traditional international law. PMID- 29263788 TI - Recent advances in understanding NRF2 as a druggable target: development of pro electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. AB - Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera (r). It was approved in 2013 by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF is stimulation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional pathway that induces anti-oxidant and anti-inflammatory phase II enzymes to prevent chronic neurodegeneration. However, electrophiles such as DMF also produce severe systemic side effects, in part due to non-specific S-alkylation of cysteine thiols and resulting depletion of glutathione. This mini-review presents the present status and future strategy for NRF2 activators designed to avoid these side effects. Two modes of chemical reaction leading to NRF2 activation are considered here. The first mode is S-alkylation (covalent reaction) of thiols in Kelch-like ECH-associated protein 1 (KEAP1), which interacts with NRF2. The second mechanism involves non-covalent pharmacological inhibition of protein protein interactions, in particular domain-specific interaction between NRF2 and KEAP1 or other repressor proteins involved in this transcriptional pathway. There have been significant advances in drug development using both of these mechanisms that can potentially avoid the systemic side effects of electrophilic compounds. In the first case concerning covalent reaction with KEAP1, monomethyl fumarate and monoethyl fumarate appear to represent safer derivatives of DMF. In a second approach, pro-electrophilic drugs, such as carnosic acid from the herb Rosmarinus officinalis, can be used as a safe pro-drug of an electrophilic compound. Concerning non-covalent activation of NRF2, drugs are being developed that interfere with the direct interaction of KEAP1-NRF2 or inhibit BTB domain and CNC homolog 1 (BACH1), which is a transcriptional repressor of the promoter where NRF2 binds. PMID- 29263791 TI - Refining our policies on co-authorship requirements. PMID- 29263790 TI - Youngest survivor of perinatal infection by Eikenella corrodens: case analysis and literature review highlighting the merits of placental swab culture. AB - Eikenella corrodens has been noted as a causative organism in both neonatal and perinatal sepsis. Positivity of blood cultures at birth among preterm infants may be influenced by the maternal use of peripartum antimicrobials and a normal C reactive protein result within the first 24 hours need not always reflect the absence of fetal invasion by the highly pathogenic organisms. For these reasons, supportive and adjunctive approaches such as appropriately collected placental swabs for culture would be of value in optimizing the antimicrobial choice for sick preterm infants during the early neonatal period. Fetal infection by E. corrodens detected by placental swab culture influencing antimicrobial management of an extremely premature infant with sepsis is described. Management of the youngest premature survivor with the lowest birthweight among the reported cases in English language of neonatal E. corrodens infection is summarized and literature is reviewed. The value of placental swab, which is often underused, is highlighted in this review. PMID- 29263792 TI - Characteristics of dihydroflavonol 4-reductase gene promoters from different leaf colored Malus crabapple cultivars. AB - Anthocyanins are secondary metabolites in land plants that contribute to the colors of leaves and flowers, and are nutritionally valuable components of the human diet. The DFR gene plays an important role in the anthocyanin biosynthetic pathway. In this study, we investigated the regulation of DFR expression and in different Malus crabapple cultivars that show distinct patterns of leaf coloration, and how it influences leaf anthocyanin accumulation and coloration. Specifically, we studied the ever-red leaved cultivar 'Royalty', the ever-green leaved cultivar 'Flame' and the spring-red leaved cultivar 'Radiant'. RT-PCR analysis showed that the expression of McDFR1 correlated with the expression of a MYB transcription factor, McMYB10, and with anthocyanin accumulation. We isolated five McDFR1 promoter fragments from the three cultivars and identified four different fragments (F1-4) that were present either in several cultivars, or only in one. Yeast one-hybrid and electrophoretic mobility shift assay analyses showed that McMYB10 could bind to all the McDFR1 promoters, except McDFR1-Ra2. The F1, F2 and F3 fragments did not affect McMYB10 binding to the McDFR1 promoters; however, we found evidence that the F4 fragment suppressed binding, and that the MYBGAHV amino-acid sequence maybe an important cis-element for McMYB10 protein binding. This information has potential value for strategies to modify plant color through genetic transformation. PMID- 29263793 TI - Endogenous auxin and its manipulation influence in vitro shoot organogenesis of citrus epicotyl explants. AB - Endogenous auxin is an important regulator of in vivo organ development, but its role in in vitro organogenesis is unclear. It has been observed that the basal end of epicotyl cuttings of juvenile citrus seedlings produces fewer shoots than the apical end. Here, we report that elevated endogenous auxin levels in the basal end of citrus epicotyl cuttings are inhibitory for in vitro shoot organogenesis. Using transgenic citrus plants expressing an auxin-inducible GUS reporter gene, we have observed elevated levels of auxin at the basal end of stem cuttings that are mediated by polar auxin transport. Depleting endogenous auxin or blocking polar auxin transport enhances shoot organogenesis. An auxin transport inhibitor, N-1-naphthylphthalamic acid (NPA), can also enhance shoot organogenesis independent of its action on polar auxin transport. Finally, we demonstrate that the promotional effects of depleting endogenous auxin or blocking polar auxin transport on shoot organogenesis are cytokinin-dependent. Our study thus provides meaningful insights into possible roles of endogenous auxin and polar auxin transport, as well as auxin-cytokinin interactions, in in vitro shoot organogenesis. Meanwhile, our results may also provide practical strategies for improving in vitro shoot organogenesis for citrus and many other plant species. PMID- 29263794 TI - A novel homozygous missense mutation in BHLHA9 causes mesoaxial synostotic syndactyly with phalangeal reduction in a Pakistani family. AB - Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is a rare non syndromic limb malformation with autosomal recessive inheritance. To date, only a few affected families with MSSD who had BHLHA9 mutations have been reported. The present report describes a consanguineous Pakistani family with five affected individuals with MSSD who exhibited an autosomal recessive pattern. Genotyping followed by Sanger sequencing was performed, and we identified a novel homozygous missense mutation (c.311T>C, p.Ile104Thr) in the BHLHA9 gene. This finding expands the spectrum of known mutations in the BHLHA9 gene that cause MSSD. PMID- 29263795 TI - Generation of iPSC-derived limb progenitor-like cells for stimulating phalange regeneration in the adult mouse. AB - The capacity of digit tip regeneration observed both in rodents and humans establishes a foundation for promoting robust regeneration in mammals. However, stimulating regeneration at more proximal levels, such as the middle phalanges (P2) of the adult mouse, remains challenging. Having shown the effectiveness of transplantation of limb progenitor cells in stimulating limb regeneration in Xenopus, we are now applying the cell transplantation approach to the adult mouse. Here we report that both embryonic and induced pluripotent stem cell (iPSC)-derived limb progenitor-like cells can promote adult mouse P2 regeneration. We have established a simple and efficient protocol for deriving limb progenitor-like cells from mouse iPSCs. iPSCs are cultured as three dimensional fibrin bodies, followed by treatment with combinations of Fgf8, CHIR99021, Purmorphamine and SB43542 during differentiation. These iPSC-derived limb progenitor-like cells resemble embryonic limb mesenchyme cells in their expression of limb-related genes. After transplantation, the limb progenitor-like cells can promote adult mouse P2 regeneration, as embryonic limb bud cells do. Our results provide a basis for further developing progenitor cell-based approaches for improving regeneration in the adult mouse limbs. PMID- 29263796 TI - Multipartite viruses: adaptive trick or evolutionary treat? AB - Multipartitism counts amongst the weirdest lifestyles found in the virosphere. Multipartite viruses have genomes segmented in pieces enclosed in different capsids that are independently transmitted. Since all segments have to meet in the host for complementation and completion of the viral cycle, multipartite viruses are bound to fight the loss of genomic information. While this is an obvious disadvantage of this strategy, no consensus on its actual advantages has been reached. In this review we present an exhaustive summary of all multipartite viruses described to date. Based on evidence, we discuss possible mechanistic and evolutionary origins of different groups, as well as their mutual relationships. We argue that the ubiquitous interactions of viruses with other unrelated viruses and with subviral elements might be regarded as a plausible first step towards multipartitism. In agreement with the view of the Virosphere as a deeply entangled network of gene sharing, we contend that the power of multipartitism relies on its dynamical and opportunistic nature, because it enables immediate adaptive responses to environmental changes. As such, perhaps the reasons for its success should be shought in multipartitism itself as an adaptive mechanism, to which its evolutionarily short-lived products (that is, the extant ensemble of multipartite viral species) are subordinated. We close by discussing how our understanding of multipartitism would improve by using concepts and tools from systems biology. PMID- 29263797 TI - VEGFR1 promotes cell migration and proliferation through PLCgamma and PI3K pathways. AB - The ability to control vascular endothelial growth factor (VEGF) signaling offers promising therapeutic potential for vascular diseases and cancer. Despite this promise, VEGF-targeted therapies are not clinically effective for many pathologies, such as breast cancer. VEGFR1 has recently emerged as a predictive biomarker for anti-VEGF efficacy, implying a functional VEGFR1 role beyond its classically defined decoy receptor status. Here we introduce a computational approach that accurately predicts cellular responses elicited via VEGFR1 signaling. Aligned with our model prediction, we show empirically that VEGFR1 promotes macrophage migration through PLCgamma and PI3K pathways and promotes macrophage proliferation through a PLCgamma pathway. These results provide new insight into the basic function of VEGFR1 signaling while offering a computational platform to quantify signaling of any receptor. PMID- 29263798 TI - Classification of gene signatures for their information value and functional redundancy. AB - Gene signatures are more and more used to interpret results of omics data analyses but suffer from compositional (large overlap) and functional (correlated read-outs) redundancy. Moreover, many gene signatures rarely come out as significant in statistical tests. Based on pan-cancer data analysis, we construct a restricted set of 962 signatures defined as informative and demonstrate that they have a higher probability to appear enriched in comparative cancer studies. We show that the majority of informative signatures conserve their weights for the genes composing the signature (eigengenes) from one cancer type to another. We finally construct InfoSigMap, an interactive online map of these signatures and their cross-correlations. This map highlights the structure of compositional and functional redundancies between informative signatures, and it charts the territories of biological functions. InfoSigMap can be used to visualize the results of omics data analyses and suggests a rearrangement of existing gene sets. PMID- 29263799 TI - PECAplus: statistical analysis of time-dependent regulatory changes in dynamic single-omics and dual-omics experiments. AB - Simultaneous dynamic profiling of mRNA and protein expression is increasingly popular, and there is a critical need for algorithms to identify regulatory layers and time dependency of gene expression. A group of scientists from United States and Singapore present PECAplus, a comprehensive set of statistical analysis tools to address this challenge. Protein expression control analysis (PECA) computes the probability scores for change in mRNA and protein-level regulatory parameters at each time point, deconvoluting gene expression regulation in the presence of measurement noise. PECAplus adapted PECA's mass action model to a variety of proteomic data including pulsed SILAC and generic protein expression data. It also features analysis modules to fit smooth curves on rugged time series observations, and to facilitate time-dependent interpretation of the data for genes and biological functions. They demonstrate the core modules with two time course datasets of mammalian cells responding to unfolded proteins and pathogens. PMID- 29263800 TI - Genomic medicine goes mainstream. PMID- 29263801 TI - Noninvasive prenatal testing complicated by maternal malignancy: new tools for a complex problem. PMID- 29263802 TI - Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore. AB - Genetic testing for germline mutations in breast cancer predisposition genes can potentially identify individuals at a high risk of developing breast and/or ovarian cancer. There is a paucity of such mutational information for Asians. Panel testing of 25 cancer susceptibility genes and BRCA1/2 deletion/duplication analysis was performed for 220 Asian breast cancer patients or their family members referred for genetics risk assessment. All 220 participants had at least one high-risk feature: having a family history of breast and/or ovarian cancer in first- and/or second-degree relatives; having breast and ovarian cancer in the same individual or bilateral breast cancer; having early-onset breast cancer or ovarian cancer (?40 years of age). We identified 67 pathogenic variants in 66 (30.0%) patients. Of these, 19 (28.3%) occurred in BRCA1, 16 (23.9%) in BRCA2, 7 (10.4%) in PALB2, 6 (9.0%) in TP53, 2 (3.0%) in PTEN, 2 (3.0%) in CDH1 and 15 (22.4%) in other predisposition genes. Notably, 47.8% of pathogenic variants were in non-BRCA1/2 genes. Of the 66 patients with pathogenic mutations, 63.6% (42/66) were under the age of 40 years. Family history of breast and/or ovarian cancer is enriched in patients with BRCA1/2 pathogenic variants but less predictive for non BRCA1/2 related pathogenic variations. We detected a median of three variants of unknown significance (VUS) per gene (range 0-21). Custom gene panel testing is feasible and useful for the detection of pathogenic mutations and should be done in the setting of a formal clinical cancer genetics service given the rate of VUS. PMID- 29263803 TI - Non-coding RNAs profiling in head and neck cancers. AB - The majority of studies on human cancers published to date focus on coding genes. More recently, however, non-coding RNAs (ncRNAs) are gaining growing recognition as important regulatory components. Here we characterise the ncRNA landscape in 442 head and neck squamous cell carcinomas (HNSCs) from the cancer genome atlas (TCGA). HNSCs represent an intriguing case to study the potential role of ncRNA as a function of viral presence, especially as HPV is potentially oncogenic. Thus, we identify HPV16-positive (HPV16+) and HPV-negative (HPV-) tumours and study the expression of ncRNAs on both groups. Overall, the ncRNAs comprise 36% of all differentially expressed genes, with antisense RNAs being the most represented ncRNA type (12.6%). Protein-coding genes appear to be more frequently downregulated in tumours compared with controls, whereas ncRNAs show significant upregulation in tumours, especially in HPV16+ tumours. Overall, expression of pseudogenes, antisense and short RNAs is elevated in HPV16+ tumours, while the remaining long non-coding RNA types are more active in all HNSC tumours independent of HPV status. In addition, we identify putative regulatory targets of differentially expressed ncRNAs. Among these 'targets' we find several well established oncogenes, tumour suppressors, cytokines, growth factors and cell differentiation genes, which indicates the potential involvement of ncRNA in the control of these key regulators as a direct consequence of HPV oncogenic activity. In conclusion, our findings establish the ncRNAs as crucial transcriptional components in HNSCs. Our results display the great potential for the study of ncRNAs and the role they have in human cancers. PMID- 29263804 TI - Precision medicine in heritable cancer: when somatic tumour testing and germline mutations meet. AB - Cancer is among the leading causes of death and disfigurement worldwide with an estimated global incidence of 14 million and ~8.2 million cancer-related deaths per annum. An estimated 5-10% of all cancers are hereditary, meaning a single gene mutation contributed to development of the cancer. In other words, inherited cancer has a worldwide incidence of ~1.4 million new cases per annum and a global prevalence of 300 million, and are often poorly recognised. The increase in genetic sequencing capability combined with the decrease in the cost of testing has altered both regulatory policy and clinical oncology practice Well-known examples of clinically important cancer susceptibility syndromes such as those caused by genetic mutations in highly penetrant genes such as BRCA1/2 hereditary breast-ovarian cancer syndrome genes have provided the framework for the practice of clinical cancer genetics. There is no question that these tests have provided clinical benefit to the patient and her/his family. However, with the expanding role of next generation sequencing in tumour profiling as well as in germline testing, clinicians are now faced with significant new challenges and potentially unexpected opportunities. Issues such as determining how best to deal with gene variants of uncertain clinical significance and the issue of incidental findings of hereditary cancer risk may be encountered during tumour genomic testing will require a concerted effort and dialogue on the part of the broad genomic community. PMID- 29263806 TI - Genomic medicine in the military. AB - The announcement of the Precision Medicine Initiative was an important step towards establishing the use of genomic information as part of the wider practice of medicine. The US military has been exploring the role that genomic information will have in health care for service members (SMs) and its integration into the continuum of military medicine. An important part of the process is establishing robust protections to protect SMs from genetic discrimination in the era of exome/genome sequencing. PMID- 29263805 TI - Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences. AB - An important component of precision medicine-the use of whole-genome sequencing (WGS) to guide lifelong healthcare-is electronic decision support to inform drug choice and dosing. To achieve this, automated identification of genetic variation in genes involved in drug absorption, distribution, metabolism, excretion and response (ADMER) is required. CYP2D6 is a major enzyme for drug bioactivation and elimination. CYP2D6 activity is predominantly governed by genetic variation; however, it is technically arduous to haplotype. Not only is the nucleotide sequence of CYP2D6 highly polymorphic, but the locus also features diverse structural variations, including gene deletion, duplication, multiplication events and rearrangements with the nonfunctional, neighbouring CYP2D7 and CYP2D8 genes. We developed Constellation, a probabilistic scoring system, enabling automated ascertainment of CYP2D6 activity scores from 2*100 paired-end WGS. The consensus reference method included TaqMan genotyping assays, quantitative copy number variation determination and Sanger sequencing. When compared with the consensus reference Constellation had an analytic sensitivity of 97% (59 of 61 diplotypes) and analytic specificity of 95% (116 of 122 haplotypes). All extreme phenotypes, i.e., poor and ultrarapid metabolisers were accurately identified by Constellation. Constellation is anticipated to be extensible to functional variation in all ADMER genes, and to be performed at marginal incremental financial and computational costs in the setting of diagnostic WGS. PMID- 29263807 TI - Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines. AB - Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome-wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours' biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription-quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency associated genes were identified as a major functional group of silenced genes. PMID- 29263808 TI - A prognostic signature based on three-genes expression in triple-negative breast tumours with residual disease. AB - Residual disease after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is related with poor prognosis; however, the risk of recurrence after 3 years from surgery, becomes similar to other breast cancer subtypes indicating that TNBC is composed of tumours of different prognosis. To evaluate genes related to TNBC aggressiveness in the outcome of TNBC resistant to NAC, we profiled 82 samples of residual tumours whose expression for 449 genes was quantified with NanoString. The validation set (GSE25066) consisted of 113 TNBC cases with residual disease. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected CCL5, DDIT4 and POLR1C as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a three-genes signature using the regression coefficients for each gene (-0.393*CCL5+0.443*DDIT4+0.490*POLR1C). The median score in the discovery set (0.1494) identified two subgroups with different DRFS (P<0.001). The median score in the validation set was 0.0024 and was able to discriminate patients with different DRFS (P=0.002). In addition, the three-genes signature was a prognostic factor in TNBC patients regardless their response to NAC (data set GSE58812; P=0.001) and in patients with oestrogen-receptor-negative tumours (data set GSE16446; P=0.041). Here we describe a prognostic signature based on expression levels of CCL5, DDIT4 and POLR1C. The knowledge about the involvement of these genes in chemotherapy resistance could improve the therapeutic strategies in TNBC. PMID- 29263809 TI - Mechanistic signatures of HPV insertions in cervical carcinomas. AB - To identify new personal biomarkers for the improved diagnosis, prognosis and biological follow-up of human papillomavirus (HPV)-associated carcinomas, we developed a generic and comprehensive Capture-HPV method followed by Next Generation Sequencing (NGS). Starting from biopsies or circulating DNA samples, this Capture-NGS approach rapidly identifies the HPV genotype, HPV status (integrated, episomal or absence), the viral-host DNA junctions and the associated genome rearrangements. This analysis of 72 cervical carcinomas identified five HPV signatures. The first two signatures contain two hybrid chromosomal-HPV junctions whose orientations are co-linear (2J-COL) or non-linear (2J-NL), revealing two modes of viral integration associated with chromosomal deletion or amplification events, respectively. The third and fourth signatures exhibit 3-12 hybrid junctions, either clustered in one locus (MJ-CL) or scattered at distinct loci (MJ-SC) while the fifth signature consists of episomal HPV genomes (EPI). Cross analyses between the HPV signatures and the clinical and virological data reveal unexpected biased representation with respect to the HPV genotype, patient age and disease outcome, suggesting functional relevance(s) of this new classification. Overall, our findings establish a facile and comprehensive rational approach for the molecular detection of any HPV-associated carcinoma and definitive personalised sequence information to develop sensitive and specific biomarkers for each patient. PMID- 29263811 TI - Assessment of clinical workload for general and specialty genetic counsellors at an academic medical center: a tool for evaluating genetic counselling practices. AB - With genomics influencing clinical decisions, genetics professionals are exponentially called upon as part of multidisciplinary care. Increasing demand for genetic counselling, a limited workforce, necessitates practices improve efficiency. We hypothesised that distinct differences in clinical workload exist between various disciplines of genetic counselling, complicating practice standardisation and patient volume expectations. We thus sought to objectively define and assess workload among various specialties of genetic counselling. Twelve genetic counsellors (GCs), representing 9.3 clinical FTE, in general or specialty (cancer, cardiovascular or prenatal) services at an academic health system developed a data collection tool for assessing time and complexity. Over a 6-week period, the data were recorded for 583 patient visits (136 general and 447 specialty) and analysed comparing general versus specialty GCs. Variables were compared with hierarchical linear models for ordinal or continuous data and hierarchical logistic models for binary data. General GCs completed more pre- and post-visit activities (P=0.011) and spent more time (P=0.009) per case. General GCs reported greater case discussion with other providers (P<0.001), literature review (P=0.026), exploring testing options (P=0.041), electronic medical record review (P=0.040), insurance preauthorization (P=0.05) and fielding patient inquiries (P=0.003). Lesser redundancy in referral indication was observed by general GCs. GCs in general practice carry a higher pre- and post-visit workload compared with GCs in specialty practices. General GCs may require lower patient volumes than specialty GCs to allow time for additional pre- and post-visit activities. Non-clinical activities should be transferred to support staff. PMID- 29263812 TI - A perspective for sequencing familial hypercholesterolaemia in African Americans. AB - African Americans suffer disproportionately from poor cardiovascular health outcomes despite similar proportions of African Americans and Americans of European ancestry experiencing elevated cholesterol levels. Some of the variation in cardiovascular outcomes is due to confounding effects of other risk factors, such as hypertension and genetic influence. However, genetic variants found to contribute to variation in serum cholesterol levels in populations of European ancestry are less likely to replicate in populations of African ancestry. To date, there has been limited follow-up on variant discrepancies or on identifying variants that exist in populations of African ancestry. African and African American populations have the highest levels of genetic heterogeneity, which is a factor that must be considered when evaluating genetic variants in the burgeoning era of personalised medicine. Many of the large published studies identifying genetic variants associated with disease risk have evaluated populations of mostly European ancestry and estimated risk in other populations based on these findings. The purpose of this paper is to provide a perspective, using familial hypercholesterolaemia as an exemplar, that studies evaluating genetic variation focused within minority populations are necessary to identify factors that contribute to disparities in health outcomes and realise the full utility of personalised medicine. PMID- 29263810 TI - Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease. AB - Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with HLA-B*27 as well as other human leukocyte antigen variants and at least 47 individual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at CDKAL1. Suggestive associations were demonstrated with common variants in FAM118A, C7orf72 and FAM114A1 and with a low-frequency variant in PNPLA1. Two of the variants have been previously associated with inflammatory bowel disease (IBD; CDKAL1 and C7orf72). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis. PMID- 29263813 TI - FetalQuantSD: accurate quantification of fetal DNA fraction by shallow-depth sequencing of maternal plasma DNA. AB - Noninvasive prenatal testing using massively parallel sequencing of maternal plasma DNA has been rapidly adopted in clinical use worldwide. Fetal DNA fraction in a maternal plasma sample is an important parameter for accurate interpretations of these tests. However, there is a lack of methods involving low sequencing depth and yet would allow a robust and accurate determination of fetal DNA fraction in maternal plasma for all pregnancies. In this study, we have developed a new method to accurately quantify the fetal DNA fraction by analysing the maternal genotypes and sequencing data of maternal plasma DNA. Fetal DNA fraction was calculated based on the proportion of non-maternal alleles at single nucleotide polymorphisms where the mother is homozygous. This new approach achieves a median deviation of 0.6% between predicted fetal DNA fraction and the actual fetal DNA fraction using as low as 0.03-fold sequencing coverage of the human genome. We believe that this method will further enhance the clinical interpretations of noninvasive prenatal testing using genome-wide random sequencing. PMID- 29263814 TI - Germline hemizygous deletion of CDKN2A-CDKN2B locus in a patient presenting with Li-Fraumeni syndrome. AB - Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome usually associated with TP53 germline alterations. Its genetic basis in TP53 wild-type pedigrees is less understood. Using whole-genome sequencing, we identified a germline hemizygous deletion ablating CDKN2A-CDKN2B in a TP53 wild-type patient presenting with high-grade sarcoma, laryngeal squamous cell carcinoma and a family history suggestive of LFS. Patient-derived cells demonstrated reduced basal gene and protein expression of the CDKN2A-encoded tumour suppressors p14ARF and p16INK4A with concomitant decrease in p21 and faster cell proliferation, implying potential deregulation of p53-mediated cell cycle control. Review of 13 additional patients with pathogenic CDKN2A variants suggested associations of germline CDKN2A mutations with an expanded spectrum of non-melanoma familial cancers. To our knowledge, this is the first report of a germline gross deletion of the CDKN2A-CDKN2B locus in an LFS family. These findings highlight the potential contribution of germline CDKN2A deletions to cancer predisposition and the importance of interrogating the full extent of CDKN2A locus in clinical testing gene panels. PMID- 29263815 TI - An asymptomatic mutation complicating severe chemotherapy-induced peripheral neuropathy (CIPN): a case for personalised medicine and a zebrafish model of CIPN. AB - Targeted next-generation sequencing (NGS) identified a novel loss of function mutation in GARS, a gene linked to Charcot-Marie-Tooth disease (CMT), in a paediatric acute lymphoblastic leukaemia patient with severe chemotherapy-induced peripheral neuropathy (CIPN) due to vincristine. The patient was clinically asymptomatic, and lacked a family history of neuropathy. The effect of the mutation was modelled in a zebrafish knockdown system that recapitulated the symptoms of the patient both prior to and after treatment with vincristine. Confocal microscopy of pre- and post-synaptic markers revealed that the GARS knockdown results in changes to peripheral motor neurons, acetylcholine receptors and their co-localisation in neuromuscular junctions (NMJs), whereas a sensitive and reproducible stimulus-response assay demonstrated that the changes correlating with the GARS mutation in themselves fail to produce peripheral neuropathy symptoms. However, with vincristine treatment the GARS knockdown exacerbates decreased stimulus response and NMJ lesions. We propose that there is substantial benefit in the use of a targeted NGS screen of cancer patients who are to be treated with microtubule targeting agents for deleterious mutations in CMT linked genes, and for the screening in zebrafish of reagents that might inhibit CIPN. PMID- 29263816 TI - Pathogenic landscape of idiopathic male infertility: new insight towards its regulatory networks. AB - Idiopathic male infertility (IMI) affects nearly 10-15% of men in their prime reproductive age. More than 500 target genes were postulated to be associated with this disease condition through various genomic studies. The challenge is to determine the functional role of these genes and proteins that form part of a larger network leading to pathogenesis of the IMI phenotype in humans. In the current study, we have catalogued all of the genes associated with IMI from published studies, as well as looked at reactive oxygen species and antioxidant genes, the two key physiological determinants essential for normal spermatogenesis. Any imbalance in these genes through mutation, single-nucleotide polymorphisms (SNPs) or other forms could result in abnormal regulation of genes leading to infertility. SNPs catalogued in the current study, representing a third of the IMI genes, could possibly explain the various hidden factors associated with this condition. The enriched biological functions in SNPs, as well as functional analysis of IMI genes, resulted in the identification of novel gene pairs, from which we proposed new models to describe the underlying pathogenesis of this disease condition. The outcome of this study will give a new set of genes and proteins that could help explain the disease from a global perspective previously not addressed using standard approaches. Genes corresponding to proteins identified from the current study for spermatozoa and seminal plasma showed functional correlation based on their localization, which gave further confirmation of their roles in defective spermatogenesis as seen in IMI. PMID- 29263817 TI - Clinical detection of deletion structural variants in whole-genome sequences. AB - Optimal management of acutely ill infants with monogenetic diseases requires rapid identification of causative haplotypes. Whole-genome sequencing (WGS) has been shown to identify pathogenic nucleotide variants in such infants. Deletion structural variants (DSVs, >50 nt) are implicated in many genetic diseases, and tools have been designed to identify DSVs using short-read WGS. Optimisation and integration of these tools into a WGS pipeline could improve diagnostic sensitivity and specificity of WGS. In addition, it may improve turnaround time when compared with current CNV assays, enhancing utility in acute settings. Here we describe DSV detection methods for use in WGS for rapid diagnosis in acutely ill infants: SKALD (Screening Konsensus and Annotation of Large Deletions) combines calls from two tools (Breakdancer and GenomeStrip) with calibrated filters and clinical interpretation rules. In four WGS runs, the average analytic precision (positive predictive value) of SKALD was 78%, and recall (sensitivity) was 27%, when compared with validated reference DSV calls. When retrospectively applied to a cohort of 36 families with acutely ill infants SKALD identified causative DSVs in two. The first was heterozygous deletion of exons 1-3 of MMP21 in trans with a heterozygous frame-shift deletion in two siblings with transposition of the great arteries and heterotaxy. In a newborn female with dysmorphic features, ventricular septal defect and persistent pulmonary hypertension, SKALD identified the breakpoints of a heterozygous, de novo 1p36.32p36.13 deletion. In summary, consensus DSV calling, implemented in an 8-h computational pipeline with parameterised filtering, has the potential to increase the diagnostic yield of WGS in acutely ill neonates and discover novel disease genes. PMID- 29263818 TI - The ONDRISeq panel: custom-designed next-generation sequencing of genes related to neurodegeneration. AB - The Ontario Neurodegenerative Disease Research Initiative (ONDRI) is a multimodal, multi-year, prospective observational cohort study to characterise five diseases: (1) Alzheimer's disease (AD) or amnestic single or multidomain mild cognitive impairment (aMCI) (AD/MCI); (2) amyotrophic lateral sclerosis (ALS); (3) frontotemporal dementia (FTD); (4) Parkinson's disease (PD); and (5) vascular cognitive impairment (VCI). The ONDRI Genomics subgroup is investigating the genetic basis of neurodegeneration. We have developed a custom next generation-sequencing-based panel, ONDRISeq that targets 80 genes known to be associated with neurodegeneration. We processed DNA collected from 216 individuals diagnosed with one of the five diseases, on ONDRISeq. All runs were executed on a MiSeq instrument and subjected to rigorous quality control assessments. We also independently validated a subset of the variant calls using NeuroX (a genome-wide array for neurodegenerative disorders), TaqMan allelic discrimination assay, or Sanger sequencing. ONDRISeq consistently generated high quality genotyping calls and on average, 92% of targeted bases are covered by at least 30 reads. We also observed 100% concordance for the variants identified via ONDRISeq and validated by other genomic technologies. We were successful in detecting known as well as novel rare variants in 72.2% of cases although not all variants are disease-causing. Using ONDRISeq, we also found that the APOE E4 allele had a frequency of 0.167 in these samples. Our optimised workflow highlights next-generation sequencing as a robust tool in elucidating the genetic basis of neurodegenerative diseases by screening multiple candidate genes simultaneously. PMID- 29263819 TI - De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients. AB - Conotruncal heart anomalies (CTDs) are particularly prevalent congenital heart diseases (CHD) in Hong Kong. We surveyed large (>500 kb), rare (<1% frequency in controls) copy-number variations (CNVs) in Chinese patients with CTDs to identify potentially disease-causing variations. Adults who tested negative for 22q11.2 deletions were recruited from the adult CHD clinic in Hong Kong. Using a stringent calling criteria, high-confidence CNV calls were obtained, and a large control set comprising 3,987 Caucasian and 1,945 Singapore Chinese subjects was used to identify rare CNVs. Ten large rare CNVs were identified, and 3 in 108 individuals were confirmed to harbour de novo CNVs. All three patients were syndromic with a more complex phenotype, and each of these CNVs overlapped regions likely to be important in CHD. One was a 611 kb deletion at 17p13.3, telomeric to the Miller-Dieker syndrome (MDS) critical region, overlapping the NXN gene. Another was a 5 Mb deletion at 13q33.3, within a previously described critical region for CHD. A third CNV, previously unreported, was a large duplication at 2q22.3 overlapping the ZEB2 gene. The commonly reported 1q21.1 recurrent duplication was not observed in this Chinese cohort. We provide detailed phenotypic and genotypic descriptions of large rare genic CNVs that may represent CHD loci in the East Asian population. Larger samples of Chinese origin will be required to determine whether the genome-wide distribution differs from that found in predominantly European CHD cohorts. PMID- 29263820 TI - Ranking factors involved in diabetes remission after bariatric surgery using machine-learning integrating clinical and genomic biomarkers. AB - As weight-loss surgery is an effective treatment for the glycaemic control of type 2 diabetes in obese patients, yet not all patients benefit, it is valuable to find predictive factors for this diabetic remission. This will help elucidating possible mechanistic insights and form the basis for prioritising obese patients with dysregulated diabetes for surgery where diabetes remission is of interest. In this study, we combine both clinical and genomic factors using heuristic methods, informed by prior biological knowledge in order to rank factors that would have a role in predicting diabetes remission, and indeed in identifying patients who may have low likelihood in responding to bariatric surgery for improved glycaemic control. Genetic variants from the Illumina CardioMetaboChip were prioritised through single-association tests and then seeded a larger selection from protein-protein interaction networks. Artificial neural networks allowing nonlinear correlations were trained to discriminate patients with and without surgery-induced diabetes remission, and the importance of each clinical and genetic parameter was evaluated. The approach highlighted insulin treatment, baseline HbA1c levels, use of insulin-sensitising agents and baseline serum insulin levels, as the most informative variables with a decent internal validation performance (74% accuracy, area under the curve (AUC) 0.81). Adding information for the eight top-ranked single nucleotide polymorphisms (SNPs) significantly boosted classification performance to 84% accuracy (AUC 0.92). The eight SNPs mapped to eight genes - ABCA1, ARHGEF12, CTNNBL1, GLI3, PROK2, RYBP, SMUG1 and STXBP5 - three of which are known to have a role in insulin secretion, insulin sensitivity or obesity, but have not been indicated for diabetes remission after bariatric surgery before. PMID- 29263821 TI - Machine-learning approach identifies a pattern of gene expression in peripheral blood that can accurately detect ischaemic stroke. AB - Early and accurate diagnosis of stroke improves the probability of positive outcome. The objective of this study was to identify a pattern of gene expression in peripheral blood that could potentially be optimised to expedite the diagnosis of acute ischaemic stroke (AIS). A discovery cohort was recruited consisting of 39 AIS patients and 24 neurologically asymptomatic controls. Peripheral blood was sampled at emergency department admission, and genome-wide expression profiling was performed via microarray. A machine-learning technique known as genetic algorithm k-nearest neighbours (GA/kNN) was then used to identify a pattern of gene expression that could optimally discriminate between groups. This pattern of expression was then assessed via qRT-PCR in an independent validation cohort, where it was evaluated for its ability to discriminate between an additional 39 AIS patients and 30 neurologically asymptomatic controls, as well as 20 acute stroke mimics. GA/kNN identified 10 genes (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B and PLXDC2) whose coordinate pattern of expression was able to identify 98.4% of discovery cohort subjects correctly (97.4% sensitive, 100% specific). In the validation cohort, the expression levels of the same 10 genes were able to identify 95.6% of subjects correctly when comparing AIS patients to asymptomatic controls (92.3% sensitive, 100% specific), and 94.9% of subjects correctly when comparing AIS patients with stroke mimics (97.4% sensitive, 90.0% specific). The transcriptional pattern identified in this study shows strong diagnostic potential, and warrants further evaluation to determine its true clinical efficacy. PMID- 29263822 TI - Precision Military Medicine: Conducting a multi-site clinical utility study of genomic and lifestyle risk factors in the United States Air Force. AB - Following several years enrolling disease-specific and otherwise healthy cohorts into the Coriell Personalized Medicine Collaborative, a prospective study aimed at evaluating the clinical utility of personal genomic information for common complex disease and pharmacogenomics, the Coriell Personalized Medicine Collaborative expanded to create a military cohort, specifically, the United States Air Force. Initial recruitment focused on Air Force Medical Service personnel and later expanded to include all Active Duty Air Force members and beneficiaries. Now in its 6th year, the study has produced a wide variety of insights, including optimal study design for military-sponsored genomic research, and discussion on genetic information sharing between and amongst Air Force study participants, civilian and military researchers, and the United States Department of Defense. Over the longer term, analyses will further contribute to the development of policies and processes relevant to clinical decision support and data sharing within the US military, and on-going work with the Air Force Medical Service sub-cohort will generate critical insights into how best to deploy useful genomic information in clinical care. Here we discuss challenges faced and critical success factors for military-civilian collaborations around genomic research. PMID- 29263823 TI - Relation between NOD2 genotype and changes in innate signaling in Crohn's disease on mRNA and miRNA levels. AB - Crohn's disease is associated with an altered innate immune response of pathogenic importance. This altered response can be associated to loss-of function polymorphisms in the NOD2 (nucleotide-binding oligomerization domain containing protein 2) gene, but also changes in transcriptional and post transcriptional regulatory layers, including microRNA activity. Here, we characterized the link between NOD2 genotype and inflammatory-mediated changes in innate signaling by studying transcriptional and post-transcriptional activity in response to NOD2-agonist muramyl dipeptide in monocytes from healthy controls, and Crohn's disease patients with and without NOD2 loss-of-function polymorphisms. We measured the expression of genes and microRNAs in monocytes from these subjects after stimulation with muramyl dipeptide. Gene expression profiles mainly distinguished the actual muramyl dipeptide response, but not the genotype. A hyper-responsive phenotype was found in Crohn's disease patients without NOD2 mutations, characterized by upregulated cytokine receptors and general downregulation of microRNA expression. Conversely, microRNA expression could identify genotype-specific differences between subject groups but exhibited little change upon muramyl dipeptide treatment. Only two microRNAs showed muramyl dipeptide-induced response, including miR-155, which was found to regulate multiple genes and whose host gene was one of the highest muramyl dipeptide responders. miR-155 was upregulated in Crohn's disease patients with NOD2 mutations following lipopolysaccharide and Escherichia coli treatment, but the upregulation was substantially reduced upon muramyl dipeptide treatment. While Crohn's disease patients with NOD2 mutations on average showed a reduced muramyl dipeptide response, the cohort exhibited large individual variance: a small subset had inflammatory responses almost comparable to wild-type patients on both gene and miR-155 regulatory levels. PMID- 29263824 TI - Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma. AB - Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear "normal". This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression. PMID- 29263826 TI - Chromatin marks shape mutation landscape at early stage of cancer progression. AB - Somatic mutation rates in cancer differ across the genome in a cancer cell-type specific manner. Although key factors that contribute to the differences were identified, the major cancer progression stage when these factors associate with the mutation variance remained poorly investigated. Here, we analyzed whole genome sequencing data of pre-cancerous and matching cancer tissues from 173 individuals and 423 normal tissue chromatin features to determine the critical stage of these features contributing to shaping the somatic mutation landscape. Our data showed that the establishment of somatic mutation landscape inferred by chromatin features occur early in the process of cancer progression, and gastric acid reflux environmental exposure-mediated epigenetic changes, represented as gastric metaplasia, at early stage can dramatically impact the somatic mutation landscape. We suggest a possible crucial role of chromatin features during the mutation landscape establishment at early stage of progression in a cancer-type specific manner. PMID- 29263825 TI - Familial STAG2 germline mutation defines a new human cohesinopathy. AB - We characterize a novel human cohesinopathy originated from a familial germline mutation of the gene encoding the cohesin subunit STAG2, which we propose to call STAG2-related X-linked Intellectual Deficiency. Five individuals carry a STAG2 p.Ser327Asn (c.980 G > A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern. Although patient-derived cells did not show overt sister-chromatid cohesion defects, they exhibited altered cell cycle profiles and gene expression patterns that were consistent with cohesin deficiency. The protein level of STAG2 in patient cells was normal. Interestingly, STAG2 S327 is located at a conserved site crucial for binding to SCC1 and cohesin regulators. When expressed in human cells, the STAG2 p.Ser327Asn mutant is defective in binding to SCC1 and other cohesin subunits and regulators. Thus, decreased amount of intact cohesin likely underlies the phenotypes of STAG2-SXLID. Intriguingly, recombinant STAG2 p.Ser327Asn binds normally to SCC1, WAPL, and SGO1 in vitro, suggesting the existence of unknown in vivo mechanisms that regulate the interaction between STAG2 and SCC1. PMID- 29263827 TI - Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies. AB - Epigenome-wide association studies, which searches for blood-based DNA methylation signatures associated with environmental exposures and/or disease susceptibilities, is a promising approach to a better understanding of the molecular aetiology of common diseases. To carry out large-scale epigenome-wide association studies while avoiding false negative detection, an efficient strategy to determine target CpG sites for microarray-based or sequencing-based DNA methylation profiling is essentially needed. Here, we propose and validate a hypothesis that a strategy focusing on CpG sites with high DNA methylation level variability may attain an improved efficacy. Through whole-genome bisulfite sequencing of purified blood cells collected from > 100 apparently healthy subjects, we identified ~2.0 million inter-individually variable CpG sites as potential targets. The efficacy of our strategy was estimated to be 3.7-fold higher than that of the most frequently used strategy. Our catalogue of inter individually variable CpG sites will accelerate the discovery of clinically relevant DNA methylation biomarkers in future epigenome-wide association studies. PMID- 29263828 TI - Empirical comparison of reduced representation bisulfite sequencing and Infinium BeadChip reproducibility and coverage of DNA methylation in humans. AB - We empirically examined the strengths and weaknesses of two human genome-wide DNA methylation platforms: rapid multiplexed reduced representation bisulfite sequencing and Illumina's Infinium BeadChip. Rapid multiplexed reduced representation bisulfite sequencing required less input DNA, offered more flexibility in coverage, and interrogated more CpG loci at a higher regional density. The Infinium covered slightly more protein coding, cancer-associated and mitochondrial-related genes, both platforms covered all known imprinting clusters, and rapid multiplexed reduced representation bisulfite sequencing covered more microRNA genes than the HumanMethylation450, but fewer than the MethylationEPIC. Rapid multiplexed reduced representation bisulfite sequencing did not always interrogate exactly the same CpG loci, but genomic tiling improved overlap between different libraries. Reproducibility of rapid multiplexed reduced representation bisulfite sequencing and concordance between the platforms increased with CpG density. Only rapid multiplexed reduced representation bisulfite sequencing could genotype samples and measure allele-specific methylation, and we confirmed that Infinium measurements are influenced by nearby single-nucleotide polymorphisms. The respective strengths and weaknesses of these two genome-wide DNA methylation platforms need to be considered when conducting human epigenetic studies. PMID- 29263829 TI - Mining the transcriptome for rare disease therapies: a comparison of the efficiencies of two data mining approaches and a targeted cell-based drug screen. AB - Most monogenic diseases can be viewed as conditions caused by dysregulated protein activity; therefore, drugs can be used to modulate gene expression, and thus protein level, possibly conferring clinical benefit. When considering repurposing drugs for loss of function diseases, there are three classes of genetic disease amenable to an increase of function; haploinsufficient dominant diseases, those secondary to hypomorphic recessive alleles, and conditions with rescuing paralogs. This therapeutic model then brings the questions: how frequently do such clinically useful drug-gene interactions occur and what is the most rapid and efficient route by which to identify them. Here we compare three approaches: (1) mining of pre-existing system-wide transcriptomal datasets such as Connectivity Map; (2) utilization of a proprietary causal reasoning engine knowledge base; and, (3) a targeted drug screen using clinically accepted agents tested against normal human fibroblasts. We have determined the validation rate of these approaches for 76 diseases (i.e., in vitro fibroblast mRNA increase); for the Connectivity Map, approximately 5% of tested putative drug-gene interactions validated, for causal reasoning engine knowledge base the rate was 10%, and for the targeted drug screen 9%. The degree of overlap between these methodologies was low suggesting they are complementary not redundant approaches to identify putative drug-gene interactions. Although the validation rate was low, a number of drug-gene interactions were successfully identified and are now being investigated for protein induction and in vivo effect. This analysis establishes potentially valuable therapeutic leads as well as useful benchmarks for the thousands of currently untreatable rare genetic conditions. PMID- 29263830 TI - Preparing for genomic medicine: a real world demonstration of health system change. AB - Organisations and governments seeking to implement genomics into clinical practice face numerous challenges across multiple, diverse aspects of the health care system. It is not sufficient to tackle any one aspect in isolation: to create a system that supports genomic medicine, they must be addressed simultaneously. The growing body of global knowledge can guide decision-making, but each jurisdiction or organisation needs a model for genomic (or personalised) medicine that is tailored to its unique context, its priorities and the funds available. Poor decisions could greatly reduce the benefits that could potentially arise from genomic medicine. Demonstration projects enable models to be tested, providing valuable evidence and experience for subsequent implementation. Here, we present the Melbourne Genomics Health Alliance demonstration project as an exemplar of a collaborative, holistic approach to phased implementation of genomics across multiple autonomous institutions. The approach and lessons learned may assist others in determining how best to integrate genomics into their healthcare system. PMID- 29263832 TI - To the editor. PMID- 29263833 TI - Mosaic mutations in blood DNA sequence are associated with solid tumor cancers. AB - Recent understanding of the causal role of blood-detectable somatic protein truncating DNA variants in leukemia prompts questions about the generalizability of such observations across cancer types. We used the cancer genome atlas exome sequencing (~8000 samples) to compare 22 different cancer phenotypes with more than 6000 controls using a case-control study design and demonstrate that mosaic protein truncating variants in these genes are also associated with solid-tumor cancers. The absence of these cancer-associated mosaic variants from the tumors themselves suggest these are not themselves tumor drivers. Through analysis of different cancer phenotypes we observe gene-specificity for mosaic mutations. We confirm a specific link between PPM1D and ovarian cancer, consistent with previous reports linking PPM1D to breast and ovarian cancer. Additionally, glioblastoma, melanoma and lung cancers show gene specific burdens of mosaic protein truncating mutations. Taken together, these results extend existing observations and broadly link solid-tumor cancers to somatic blood DNA changes. PMID- 29263831 TI - Genome sequencing as a platform for pharmacogenetic genotyping: a pediatric cohort study. AB - Whole-genome sequencing and whole-exome sequencing have proven valuable for diagnosing inherited diseases, particularly in children. However, usage of sequencing data as a pharmacogenetic screening tool to ensure medication safety and effectiveness remains to be explored. Sixty-seven variants in 19 genes with known effects on drug response were compared between genome sequencing and targeted genotyping data for coverage and concordance in 98 pediatric patients. We used targeted genotyping data as a benchmark to assess accuracy of variant calling, and to identify copy number variations of the CYP2D6 gene. We then predicted clinical impact of these variants on drug therapy. We find genotype concordance across those panels to be > 97%. Concordance of CYP2D6 predicted phenotype between estimates of whole-genome sequencing and targeted genotyping panel were 90%; a result from a lower coverage depth or variant calling difficulties in our whole-genome sequencing data when copy number variation and/or the CYP2D6*4 haplotype were present. Importantly, 95 children had at least one clinically actionable pharmacogenetic variant. Diagnostic genomic sequencing data can be used for pre-emptive pharmacogenetic screening. However, concordance between genome-wide sequencing and target genotyping needs to be characterized for each of the pharmacologically important genes. PMID- 29263834 TI - A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome. AB - Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations. PMID- 29263837 TI - Erratum: Regulation of cancer epigenomes with a histonebinding synthetic transcription factor. AB - [This corrects the article DOI: 10.1038/s41525-016-0002-3.]. PMID- 29263836 TI - Erratum: Genomic landscape of high-grade meningiomas. AB - [This corrects the article DOI: 10.1038/s41525-017-0014-7.]. PMID- 29263838 TI - Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage. AB - Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a "double duplication" (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies. PMID- 29263835 TI - Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations. AB - A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 * 10-7, 4.3 * 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain. PMID- 29263839 TI - Identification of potentially oncogenic alterations from tumor-only samples reveals Fanconi anemia pathway mutations in bladder carcinomas. AB - Cancer is caused by germline and somatic mutations, which can share biological features such as amino acid change. However, integrated germline and somatic analysis remains uncommon. We present a framework that uses machine learning to learn features of recurrent somatic mutations to (1) predict somatic variants from tumor-only samples and (2) identify somatic-like germline variants for integrated analysis of tumor-normal DNA. Using data from 1769 patients from seven cancer types (bladder, glioblastoma, low-grade glioma, lung, melanoma, stomach, and pediatric glioma), we show that "somatic-like" germline variants are enriched for autosomal-dominant cancer-predisposition genes (p < 4.35 * 10-15), including TP53. Our framework identifies germline and somatic nonsense variants in BRCA2 and other Fanconi anemia genes in 11% (11/100) of bladder cancer cases, suggesting a potential genetic predisposition in these patients. The bladder carcinoma patients with Fanconi anemia nonsense variants display a BRCA deficiency somatic mutation signature, suggesting treatment targeted to DNA repair. PMID- 29263840 TI - Myeloablation-associated deletion of ORF4 in a human coronavirus 229E infection. AB - We describe metagenomic next-generation sequencing (mNGS) of a human coronavirus 229E from a patient with AML and persistent upper respiratory symptoms, who underwent hematopoietic cell transplantation (HCT). mNGS revealed a 548 nucleotide deletion, which comprised the near entirety of the ORF4 gene, and no minor allele variants were detected to suggest a mixed infection. As part of her pre-HCT conditioning regimen, the patient received myeloablative treatment with cyclophosphamide and 12 Gy total body irradiation. Iterative sequencing and RT PCR confirmation of four respiratory samples over the 4-week peritransplant period revealed that the pre-conditioning strain contained an intact ORF4 gene, while the deletion strain appeared just after conditioning and persisted over a 2.5-week period. This sequence represents one of the largest genomic deletions detected in a human RNA virus and describes large-scale viral mutation associated with myeloablation for HCT. PMID- 29263842 TI - A community effort to protect genomic data sharing, collaboration and outsourcing. AB - The human genome can reveal sensitive information and is potentially re identifiable, which raises privacy and security concerns about sharing such data on wide scales. In 2016, we organized the third Critical Assessment of Data Privacy and Protection competition as a community effort to bring together biomedical informaticists, computer privacy and security researchers, and scholars in ethical, legal, and social implications (ELSI) to assess the latest advances on privacy-preserving techniques for protecting human genomic data. Teams were asked to develop novel protection methods for emerging genome privacy challenges in three scenarios: Track (1) data sharing through the Beacon service of the Global Alliance for Genomics and Health. Track (2) collaborative discovery of similar genomes between two institutions; and Track (3) data outsourcing to public cloud services. The latter two tracks represent continuing themes from our 2015 competition, while the former was new and a response to a recently established vulnerability. The winning strategy for Track 1 mitigated the privacy risk by hiding approximately 11% of the variation in the database while permitting around 160,000 queries, a significant improvement over the baseline. The winning strategies in Tracks 2 and 3 showed significant progress over the previous competition by achieving multiple orders of magnitude performance improvement in terms of computational runtime and memory requirements. The outcomes suggest that applying highly optimized privacy-preserving and secure computation techniques to safeguard genomic data sharing and analysis is useful. However, the results also indicate that further efforts are needed to refine these techniques into practical solutions. PMID- 29263844 TI - Prioritising the application of genomic medicine. AB - The clinical translation of genomic sequencing is hampered by the limited information available to guide investment into those areas where genomics is well placed to deliver improved health and economic outcomes. To date, genomic medicine has achieved its greatest successes through applications to diseases that have a high genotype-phenotype correlation and high penetrance, with a near certainty that the individual will develop the condition in the presence of the genotype. It has been anticipated that genomics will play an important role in promoting population health by targeting at-risk individuals and reducing the incidence of highly prevalent, costly, complex diseases, with potential applications across screening, prevention, and treatment decisions. However, where primary or secondary prevention requires behavioural changes, there is currently very little evidence to support reduction in disease incidence. A better understanding of the relationship between genomic variation and complex diseases will be necessary before effective genomic risk identification and management of the risk of complex diseases in healthy individuals can be carried out in clinical practice. Our recommended approach is that priority for genomic testing should focus on diseases where there is strong genotype-phenotype correlation, high or certain penetrance, the effects of the disease are serious and near-term, there is the potential for prevention and/or treatment, and the net costs incurred are acceptable for the health gains achieved. PMID- 29263843 TI - Workflow optimization of whole genome amplification and targeted panel sequencing for CTC mutation detection. AB - Genomic characterization of circulating tumor cells (CTCs) may prove useful as a surrogate for conventional tissue biopsies. This is particularly important as studies have shown different mutational profiles between CTCs and ctDNA in some tumor subtypes. However, isolating rare CTCs from whole blood has significant hurdles. Very limited DNA quantities often can't meet NGS requirements without whole genome amplification (WGA). Moreover, white blood cells (WBC) germline contamination may confound CTC somatic mutation analyses. Thus, a good CTC enrichment platform with an efficient WGA and NGS workflow are needed. Here, Vortex label-free CTC enrichment platform was used to capture CTCs. DNA extraction was optimized, WGA evaluated and targeted NGS tested. We used metastatic colorectal cancer (CRC) as the clinical target, HCT116 as the corresponding cell line, GenomePlex(r) and REPLI-g as the WGA methods, GeneRead DNAseq Human CRC Panel as the 38 gene panel. The workflow was further validated on metastatic CRC patient samples, assaying both tumor and CTCs. WBCs from the same patients were included to eliminate germline contaminations. The described workflow performed well on samples with sufficient DNA, but showed bias for rare cells with limited DNA input. REPLI-g provided an unbiased amplification on fresh rare cells, enabling an accurate variant calling using the targeted NGS. Somatic variants were detected in patient CTCs and not found in age matched healthy donors. This demonstrates the feasibility of a simple workflow for clinically relevant monitoring of tumor genetics in real time and over the course of a patient's therapy using CTCs. PMID- 29263841 TI - A framework to identify contributing genes in patients with Phelan-McDermid syndrome. AB - Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders. PMID- 29263845 TI - Circular RNA expression is abundant and correlated to aggressiveness in early stage bladder cancer. AB - The functions and biomarker potential of circular RNAs (circRNAs) in various cancer types are a rising field of study, as emerging evidence relates circRNAs to tumorigenesis. Here, we profiled the expression of circRNAs in 457 tumors from patients with non-muscle-invasive bladder cancer (NMIBC). We show that a set of highly expressed circRNAs have conserved core splice sites, are associated with Alu repeats, and enriched with Synonymous Constraint Elements as well as microRNA target sites. We identified 113 abundant circRNAs that are differentially expressed between high and low-risk tumor subtypes. Analysis of progression-free survival revealed 13 circRNAs, among them circHIPK3 and circCDYL, where expression correlated with progression independently of the linear transcript and the host gene. In summary, our results demonstrate that abundant circRNAs possess multiple biological features, distinguishing them from low-expressed circRNAs and non-circularized exons, and suggest that circRNAs might serve as a new class of prognostic biomarkers in NMIBC. PMID- 29263847 TI - Erratum: A de novo 2.78-Mb duplication on chromosome 21q22.11 implicates candidate genes in the partial trisomy 21 phenotype. AB - [This corrects the article DOI: 10.1038/npjgenmed.2016.3.]. PMID- 29263846 TI - Germline TTN variants are enriched in PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome. AB - Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare congenital disorder classically characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis. Germline PTEN mutations have been reported in up to 60% of BRRS patients. The remaining cases are of unknown genetic etiology. We exome-sequenced 35 unrelated PTEN-wildtype patients with classic presentation of BRRS and identified TTN germline missense variants in 12/35 (34%) patients. TTN encodes TITIN, a key structural and functional muscle protein. Exome and TTN-targeted sequencing in an additional unrelated series of 231 BRRS-like patients revealed 37 (16%) additional patients with germline TTN variants. All variants were predicted to be deleterious and equally distributed between the A-band and I-band protein domains. Rare TTN variants (MAF <= 0.0001) are enriched in classic BRRS patients compared to BRRS-like (OR = 2.7, 95% CI 1.21-5.94, p = 1.6 * 10-2) and multiple population controls (OR = 2.2, 95% CI 1.01-4.20, p = 4.7 * 10-2). Germline TTN mutations of different genotypes, inheritance patterns, and protein domain enrichment have been identified in multiple cardiac and/or skeletal muscular disorders. Functional interrogation of I-band variant p.Cys5096Arg identified in one of our classic BRRS patients, using CRISPR-Cas9 genome-edited cell lines, reveals an increased growth and lack of contact inhibition phenotype associated with increased levels of or phosphorylation of focal adhesion kinase (FAK) in mutant cells. These findings suggest that TITIN could play a role in overgrowth-relevant pathways and phenotypes. In summary, our observations suggest TTN as a candidate predisposing gene in classic PTEN-wildtype BRRS patients, perhaps suggesting this syndrome join the growing list of Titinopathies. PMID- 29263848 TI - The development of activatable lytic peptides for targeting triple negative breast cancer. AB - Cytolytic peptides are an emerging class of promising cancer therapeutics shown to overcome drug resistance. They eliminate cancer cells via disruption of the phospholipid bilayer of cell membranes, a mechanism that differentiates it from traditional treatments. However, applications of lytic peptides via systematic administration are hampered by nonspecific toxicity. Here, we describe activatable, masked lytic peptides that are conjugated with anionic peptides via a cleavable linker sensitive to matrix metalloproteinases (Ac-w-betaA-e8-XPLG*LAG klUklUkklUklUk-NH2; lower case letters in the sequences represent D-amino-acids, U=Aib, alpha-aminoisobutyric acid, *cleavage site). The peptides were activated upon being introduced into the triple negative breast cancer cell line MDA-MB 231, which overexpresses secreted matrix metalloproteinases, to selectively cleave the peptide linker. Our results indicate that the activatable design could be applied to improve the targeting ability of lytic peptides. PMID- 29263850 TI - Commentary on 'Dissecting the hemagglutinin head and stalk specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination'. PMID- 29263849 TI - Protection from Hendra virus infection with Canarypox recombinant vaccine. AB - Hendra virus (HeV) is an emerging zoonotic pathogen, which causes severe respiratory illness and encephalitis in humans and horses. Since its first appearance in 1994, spillovers of HeV from its natural reservoir fruit bats occur on almost an annual basis. The high mortality rate in both humans and horses and the wide-ranging reservoir distribution are making HeV a serious public health problem, especially for people exposed to sick horses. This study has aimed to develop an efficient low-cost HeV vaccine for horses based on Canarypox recombinant vector expressing HeV glycoproteins, attachment glycoprotein (G) and fusion protein (F). This vaccine was used to immunise hamsters and then challenged intraperitoneally with HeV 3 weeks later. The higher tested dose of the vaccine efficiently prevented oropharyngeal virus shedding and protected animals from clinical disease and virus-induced mortality. Vaccine induced generation of seroneutralising antibodies and prevented virus-induced histopathological changes and a production of viral RNA and antigens in animal tissues. Interestingly, some vaccinated animals, including those immunised at a lower dose, were protected in the absence of detectable specific antibodies, suggesting the induction of an efficient virus-specific cellular immunity. Finally, ponies immunised using the same vaccination protocol as hamsters developed strong seroneutralising titres against both HeV and closely related Nipah virus, indicating that this vaccine may have the ability to induce cross protection against Henipavirus infection. These data suggest that Canarypox-based vectors encoding for HeV glycoproteins present very promising new vaccine candidate to prevent infection and shedding of the highly lethal HeV. PMID- 29263852 TI - Vaccinology in the twenty-first century. PMID- 29263851 TI - Research and development of Zika virus vaccines. AB - Zika virus (ZIKV) is a member of the family Flaviviridae, genus Flavivirus, and is transmitted by Aedes sp. mosquitoes. There are three genetic lineages of ZIKV: the East African, West African and Asian lineages. Until recently, Zika fever (ZF) has normally been considered a rare, mild febrile disease, but reports since 2012 have shown potentially severe complications associated with ZIKV infection, including microcephaly and Guillain-Barre syndrome. There are no licensed vaccines for ZIKV; however, many vaccine platforms/approaches that have been utilised for other flavivirus vaccines are being applied to ZIKV. Given the current outbreak of ZIKV in the Americas with its associated risks to pregnancy, we summarise what is known about the virus, how knowledge of currently licensed flavivirus vaccines can be applied to ZIKV vaccine development and the assessments of potential challenges for ZIKV vaccine testing and evaluation. PMID- 29263853 TI - Intradermal immunisation using the TLR3-ligand Poly (I:C) as adjuvant induces mucosal antibody responses and protects against genital HSV-2 infection. AB - Development of vaccines able to induce mucosal immunity in the genital and gastrointestinal tracts is a major challenge to counter sexually transmitted pathogens such as HIV-1 and HSV-2. Herein, we showed that intradermal (ID) immunisation with sub-unit vaccine antigens (i.e., HIV-1 gp140 and HSV-2 gD) delivered with Poly(I:C) or CpG1668 as adjuvant induces long-lasting virus specific immunoglobulin (Ig)-G and IgA antibodies in the vagina and feces. Poly(I:C)-supplemented sub-unit viral vaccines caused minimal skin reactogenicity at variance to those containing CpG1668, promoted a delayed-type hypersensitivity (DTH) to the vaccine and protected mice from genital and neurological symptoms after a lethal vaginal HSV-2 challenge. Interestingly, Poly(I:C12U) (Ampligen), a Poly(I:C) structural analogue that binds to TLR3 but not MDA-5, promoted robust mucosal and systemic IgG antibodies, a weak skin DTH to the vaccine but not IgA responses and failed to confer protection against HSV-2 infection. Moreover, Poly(I:C) was far superior to Poly(I:C12U) at inducing prompt and robust upregulation of IFNbeta transcripts in lymph nodes draining the injection site. These data illustrate that ID vaccination with glycoproteins and Poly(I:C) as adjuvant promotes long-lasting mucosal immunity and protection from genital HSV-2 infection, with an acceptable skin reactogenicity profile. The ID route thus appears to be an unexpected inductive site for mucosal immunity and anti-viral protection suitable for sub-unit vaccines. This works further highlights that TLR3/MDA5 agonists such as Poly(I:C) may be valuable adjuvants for ID vaccination against sexually transmitted diseases. PMID- 29263855 TI - First vaccine approval under the FDA Animal Rule. AB - The US Food and Drug Administration's Animal Rule was established to facilitate licensure of new products for life-threatening conditions when traditional efficacy trials in humans are unethical or impractical. In November, 2015 BioThrax became the first vaccine to receive approval for a new indication via this pathway. The basis for this approval and use of Animal Rule or other non traditional approval pathways for licensure of vaccines for serious conditions are discussed. PMID- 29263854 TI - Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice. AB - Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, yet current control strategies, including the existing BCG vaccine, have had little impact on disease control. The tubercle bacillus modifies protein expression to adapt to chronic infection of the host, and this can potentially be exploited to develop novel therapeutics. We identified the gene encoding the first step of the Mycobacterium tuberculosis sulphur assimilation pathway, cysD, as highly induced during chronic infection in the mouse lung, suggesting therapies based on CysD could be used to target infection. Vaccination with the composite vaccine CysVac2, a fusion of CysD and the immunogenic Ag85B of M. tuberculosis, resulted in the generation of multifunctional CD4+ T cells (interferon (IFN)-gamma+TNF+IL 2+IL-17+) in the lung both pre- and post-aerosol challenge with M. tuberculosis. CysVac2 conferred significant protection against pulmonary M. tuberculosis challenge and was particularly effective at controlling late-stage infection, a property not shared by BCG. CysVac2 delivered as a booster following BCG vaccination afforded greater protection against M. tuberculosis challenge than BCG alone. The antigenic components of CysVac2 were conserved amongst M. tuberculosis strains, and protective efficacy afforded by CysVac2 was observed across varying murine MHC haplotypes. Strikingly, administration of CysVac2 to mice previously infected with M. tuberculosis reduced bacterial load and immunopathology in the lung compared with BCG-vaccinated mice. These results indicate that CysVac2 warrants further investigation to assess its potential to control pulmonary TB in humans. PMID- 29263856 TI - An efficient cell free enzyme-based total synthesis of a meningococcal vaccine candidate. AB - Invasive meningococcal disease (IMD) is a global health problem and vaccination has proven the most effective way of disease control. Neisseria meningitidis serogroup X (NmX) is an emerging threat in the African sub-Saharan meningitis belt, but no vaccine is available today. Leading vaccines against Nm are glycoconjugates, in which capsular polysaccharides isolated from large-scale pathogen cultures are conjugated to adjuvant proteins. Though safe and efficacious even in infants, high costs and biohazard associated with the production limit abundant application of glycoconjugate vaccines particularly in the most afflicted nations. An existing NmX vaccine candidate (CPSXn-CRM197) produced by established protocols from NmX capsule polysaccharide (CPSX) has been shown to elicit high bactericidal immunoglobulin G titres in mice. Here we describe the scalable in vitro synthesis of CPSXiv from chemically pure precursors by the use of recombinant NmX capsule polymerase. Application of the described coupling chemistry gives CPSXiv-CRM197, which in mouse vaccination experiments behaves identical to the benchmark CPSXn-CRM197. Excluding any biohazards, this novel process represents a paradigm shift in vaccine production and a premise towards vaccine manufacturing in emerging economies. PMID- 29263857 TI - Vaccination of domestic animals with a novel oral vaccine prevents Giardia infections, alleviates signs of giardiasis and reduces transmission to humans. AB - Giardia lamblia is a human intestinal parasite and one of the most frequent enteric pathogen of companion animals. Clinical manifestations of giardiasis, such as diarrhoea, anorexia, weight loss and lethargy, have been associated with Giardia infections in both domestic and farm animals. A few anti-parasitic drugs are routinely used to treat giardiasis, but re-infections are common and drug resistant strains have already been reported. Unfortunately, efficient vaccines against Giardia are not available. Giardia undergoes antigenic variation; through this mechanism, parasites can avoid the host's immune defenses, causing chronic infections and/or re-infections. Antigenic variation is characterised by a continuous switch in the expression of members of a homologous family of genes encoding surface antigens. In a previous report, we indicated that in Giardia, the mechanism responsible for the exchange of variant-specific surface proteins (VSPs) involves the RNA interference (RNAi) pathway. From a repertoire of ~200 VSP genes, only one is expressed on the surface of single trophozoites; however, RNAi machinery disruption generates trophozoites that express the complete VSP repertoire. We also demonstrated that gerbils orally immunised with VSPs isolated from these altered parasites showed high levels of protection. Here we tested this vaccine in cats and dogs, and found that it is highly efficient in preventing new infections and reducing chronic giardiasis in domestic animals both in experimental and natural infections. Remarkably, immunisation of dogs in a highly endemic area strongly decreased the percentage of infected children in the community, suggesting that this vaccine would block the zoonotic transmission of the disease. PMID- 29263858 TI - Immunisation of two rodent species with new live-attenuated mutants of Yersinia pestis CO92 induces protective long-term humoral- and cell-mediated immunity against pneumonic plague. AB - We showed recently that the live-attenuated Deltalpp DeltamsbB Deltaail and Deltalpp DeltamsbB::ailL2 mutants of Yersinia pestis CO92 provided short-term protection to mice against developing subsequent lethal pneumonic plague. These mutants were either deleted for genes encoding Braun lipoprotein (Lpp), an acetyltransferase (MsbB) and the attachment invasion locus (Ail) (Deltalpp DeltamsbB Deltaail) or contained a modified version of the ail gene with diminished virulence (Deltalpp DeltamsbB::ailL2). Here, long-term immune responses were first examined after intramuscular immunisation of mice with the above-mentioned mutants, as well as the newly constructed Deltalpp DeltamsbB Deltapla mutant, deleted for the plasminogen-activator protease (pla) gene instead of ail. Y. pestis-specific IgG levels peaked between day 35 and 56 in the mutant-immunised mice and were sustained until the last tested day 112. Splenic memory B cells peaked earlier (day 42) before declining in the Deltalpp DeltamsbB::ailL2 mutant-immunised mice while being sustained for 63 days in the Deltalpp DeltamsbB Deltaail and Deltalpp DeltamsbB Deltapla mutant-immunised mice. Splenic CD4+ T cells increased in all immunised mice by day 42 with differential cytokine production among the immunised groups. On day 120, immunised mice were exposed intranasally to wild-type (WT) CO92, and 80-100% survived pneumonic challenge. Mice immunised with the above-mentioned three mutants had increased innate as well as CD4+ responses immediately after WT CO92 exposure, and coupled with sustained antibody production, indicated the role of both arms of the immune response in protection. Likewise, rats vaccinated with either Deltalpp DeltamsbB Deltaail or the Deltalpp DeltamsbB Deltapla mutant also developed long-term humoral and cell-mediated immune responses to provide 100% protection against developing pneumonic plague. On the basis of the attenuated phenotype, the Deltalpp DeltamsbB Deltaail mutant was recently excluded from the Centers for Disease Control and Prevention select agent list. PMID- 29263859 TI - In vivo protection against ZIKV infection and pathogenesis through passive antibody transfer and active immunisation with a prMEnv DNA vaccine. AB - Significant concerns have been raised owing to the rapid global spread of infection and disease caused by the mosquito-borne Zika virus (ZIKV). Recent studies suggest that ZIKV can also be transmitted sexually, further increasing the exposure risk for this virus. Associated with this spread is a dramatic increase in cases of microcephaly and additional congenital abnormalities in infants of ZIKV-infected mothers, as well as a rise in the occurrence of Guillain Barre' syndrome in infected adults. Importantly, there are no licensed therapies or vaccines against ZIKV infection. In this study, we generate and evaluate the in vivo efficacy of a novel, synthetic, DNA vaccine targeting the pre membrane+envelope proteins (prME) of ZIKV. Following initial in vitro development and evaluation studies of the plasmid construct, mice and non-human primates were immunised with this prME DNA-based immunogen through electroporation-mediated enhanced DNA delivery. Vaccinated animals were found to generate antigen-specific cellular and humoral immunity and neutralisation activity. In mice lacking receptors for interferon (IFN)-alpha/beta (designated IFNAR-/-) immunisation with this DNA vaccine induced, following in vivo viral challenge, 100% protection against infection-associated weight loss or death in addition to preventing viral pathology in brain tissue. In addition, passive transfer of non-human primate anti-ZIKV immune serum protected IFNAR-/- mice against subsequent viral challenge. This study in NHP and in a pathogenic mouse model supports the importance of immune responses targeting prME in ZIKV infection and suggests that additional research on this vaccine approach may have relevance for ZIKV control and disease prevention in humans. PMID- 29263861 TI - Zika vaccine candidates progress through nonclinical development and enter clinical trials. PMID- 29263860 TI - A therapeutic Porphyromonas gingivalis gingipain vaccine induces neutralising IgG1 antibodies that protect against experimental periodontitis. AB - Porphyromonas gingivalis infected mice with an established P. gingivalis-specific inflammatory immune response were protected from developing alveolar bone resorption by therapeutic vaccination with a chimera (KAS2-A1) immunogen targeting the major virulence factors of the bacterium, the gingipain proteinases. Protection was characterised by an antigen-specific IgG1 isotype antibody and Th2 cell response. Adoptive transfer of KAS2-A1-specific IgG1 or IgG2 expressing B cells confirmed that IgG1-mediated protection. Furthermore, parenteral or intraoral administration of KAS2-A1-specific polyclonal antibodies protected against the development of P. gingivalis-induced bone resorption. The KAS2-A1-specific antibodies neutralised the gingipains by inhibiting: proteolytic activity, binding to host cells/proteins and co-aggregation with other periodontal bacteria. Combining key gingipain sequences into a chimera vaccine produced an effective therapeutic intervention that protected against P. gingivalis-induced periodontitis. PMID- 29263862 TI - Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity. AB - There are over 6 billion vaccine doses administered each year, most containing aluminium-based adjuvants, yet we still do not have a complete understanding of their mechanisms of action. Recent evidence has identified host DNA and downstream sensing as playing a significant role in aluminium adjuvant (aluminium hydroxide) activity. However, the cellular source of this DNA, how it is sensed by the immune system and the consequences of this for vaccination remains unclear. Here we show that the very early injection site reaction is characterised by inflammatory chemokine production and neutrophil recruitment. Intravital imaging demonstrates that the Alum injection site is a focus of neutrophil swarms and extracellular DNA strands. These strands were confirmed as neutrophil extracellular traps due to their sensitivity to DNAse and absence in mice deficient in peptidylarginine deiminase 4. Further studies in PAD4-/- mice confirmed a significant role for neutrophil extracellular trap formation in the adjuvant activity of Alum. By revealing neutrophils recruited to the site of Alum injection as a source of the DNA that is detected by the immune system this study provides the missing link between Alum injection and the activation of DNA sensors that enhance adjuvant activity, elucidating a key mechanism of action for this important vaccine component. PMID- 29263863 TI - A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus. AB - A therapy for dengue is still elusive. We describe the neutralizing and protective capacity of a dengue serotype-cross-reactive antibody isolated from the plasmablasts of a patient. Antibody SIgN-3C neutralized all four dengue virus serotypes at nano to picomolar concentrations and significantly decreased viremia of all serotypes in adult mice when given 2 days after infection. Moreover, mice were protected from pathology and death from a lethal dengue virus-2 infection. To avoid potential Fc-mediated uptake of immune complexes and ensuing enhanced infection, we introduced a LALA mutation in the Fc part. SIgN-3C-LALA was as efficient as the non-modified antibody in neutralizing dengue virus and in protecting mice while antibody-dependent enhancement was completely abrogated. The epitope of the antibody includes conserved amino acids in all three domains of the glycoprotein, which can explain its cross-reactivity. SIgN-3C-LALA neutralizes dengue virus both pre and post-attachment to host cells. These attributes likely contribute to the remarkable protective capacity of SIgN-3C. PMID- 29263865 TI - Alpha-D-glucan nanoparticulate adjuvant induces a transient inflammatory response at the injection site and targets antigen to migratory dendritic cells. AB - Biodegradable nanoparticles with functionalized surfaces are attractive candidates as vaccine adjuvants. Nano-11 are cationic dendrimer-like alpha-D glucan nanoparticles with a diameter of 70-80 nm. Mice injected with antigen formulated with Nano-11 developed antibody titers that were similar or greater than antigen with aluminum adjuvant. Utilizing an in vivo imaging system, Nano-11 was shown to remain at the injection site after administration and cleared gradually over the course of 3 weeks. Injection of Nano-11 induced a transient inflammatory response characterized by recruitment of a mixed population of inflammatory cells, predominantly monocytes and macrophages with relatively few neutrophils. Recruited Mac-2+macrophages efficiently phagocytized the majority of Nano-11 at the injection site. Fluorescently labeled Nano-11 was present in cells in the draining lymph nodes 1 day after injection, with the majority contained in migratory dendritic cells. Injection of ovalbumin adsorbed to Nano-11 resulted in an increase of ovalbumin-containing cells in draining lymph nodes. Nano-11 delivered more antigen to antigen-presenting cells on a per cell basis and demonstrated more specific targeting to highly immunopotentiating migratory dendritic cells compared with soluble or aluminum hydroxide adsorbed ovalbumin. These results support the efficacy of Nano-11 and its potential use as a next generation vaccine adjuvant. PMID- 29263864 TI - Escherichia coli-derived virus-like particles in vaccine development. AB - Recombinant virus-like particle-based vaccines are composed of viral structural proteins and mimic authentic native viruses but are devoid of viral genetic materials. They are the active components in highly safe and effective vaccines for the prevention of infectious diseases. Several expression systems have been used for virus-like particle production, ranging from Escherichia coli to mammalian cell lines. The prokaryotic expression system, especially Escherichia coli, is the preferred expression host for producing vaccines for global use. Hecolin, the first licensed virus-like particle vaccine derived from Escherichia coli, has been demonstrated to possess good safety and high efficacy. In this review, we focus on Escherichia coli-derived virus-like particle based vaccines and vaccine candidates that are used for prevention (immunization against microbial pathogens) or disease treatment (directed against cancer or non infectious diseases). The native-like spatial or higher-order structure is essential for the function of virus-like particles. Thus, the tool box for analyzing the key physicochemical, biochemical and functional attributes of purified virus-like particles will also be discussed. In summary, the Escherichia coli expression system has great potentials for producing a range of proteins with self-assembling properties to be used as vaccine antigens given the proper epitopes were preserved when compared to those in the native pathogens or disease related target molecules. PMID- 29263867 TI - Inadvisable anti-vaccination sentiment: Human Papilloma Virus immunisation falsely under the microscope. PMID- 29263866 TI - Cross-neutralisation of viruses of the tick-borne encephalitis complex following tick-borne encephalitis vaccination and/or infection. AB - The tick-borne encephalitis complex contains a number of flaviviruses that share close genetic homology, and are responsible for significant human morbidity and mortality with widespread geographical range. Although many members of this complex have been recognised for decades, licenced human vaccines with broad availability are only available for tick-borne encephalitis virus. While tick borne encephalitis virus vaccines have been demonstrated to induce significant protective immunity, as determined by virus-neutralisation titres, vaccine breakthrough (clinical infection following complete vaccination), has been described. The aim of this study was to confirm the cross-neutralisation of tick borne flaviviruses using mouse immune ascitic fluids, and to determine the magnitude of cross-neutralising antibody titres in sera from donors following tick-borne encephalitis vaccination, infection, and vaccine breakthrough. The results demonstrate that there is significant cross-neutralisation of representative members of the tick-borne encephalitis complex following vaccination and/or infection, and that the magnitude of immune responses varies based upon the exposure type. Donor sera successfully neutralised most of the viruses tested, with 85% of vaccinees neutralising Kyasanur forest disease virus and 73% of vaccinees neutralising Alkhumra virus. By contrast, only 63% of vaccinees neutralised Powassan virus, with none of these neutralisation titres exceeding 1:60. Taken together, the data suggest that tick-borne encephalitis virus vaccination may protect against most of the members of the tick-borne encephalitis complex including Kyasanur forest disease virus and Alkhumra virus, but that the neutralisation of Powassan virus following tick-borne encephalitis vaccination is minimal. PMID- 29263868 TI - Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection. AB - The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a potentially life-threatening infection that represents a major health problem in Latin America. Several characteristics of this protozoan contribute to the lack of an effective vaccine, among them: its silent invasion mechanism, T. cruzi antigen redundancy and immunodominance without protection. Taking into account these issues, we engineered Traspain, a chimeric antigen tailored to present a multivalent display of domains from key parasitic molecules, combined with stimulation of the STING pathway by c-di-AMP as a novel prophylactic strategy. This formulation proved to be effective for the priming of functional humoral responses and pathogen-specific CD8+ and CD4+ T cells, compatible with a Th1/Th17 bias. Interestingly, vaccine effectiveness assessed across the course of infection, showed a reduction in parasite load and chronic inflammation in different proof of concept assays. In conclusion, this approach represents a promising tool against parasitic chronic infections. PMID- 29263870 TI - Heroin-HIV-1 (H2) vaccine: induction of dual immunologic effects with a heroin hapten-conjugate and an HIV-1 envelope V2 peptide with liposomal lipid A as an adjuvant. AB - A synthetic heroin analog (MorHap) and a synthetic 42 amino acid V2 loop peptide from A/E strain of HIV-1 gp120 envelope protein that was previously used in a successful phase III vaccine trial were constructed as antigens together with liposomes containing monophosphoryl lipid A as an adjuvant, to explore the feasibility of producing a dual use vaccine both for treatment of heroin addiction and prevention of HIV-1 infection among injection drug users. The V2 peptide was tethered by a palmitoyl fatty acyl tail embedded in the liposomal lipid bilayer, and the heroin analog was conjugated to tetanus toxoid as a carrier protein that was mixed with the adjuvant. Upon comparison of a linear V2 peptide with a cyclic peptide, differences were found in the secondary configurations by circular dichroism, with the tethered cyclic peptide (palm cyclic peptide) entirely in a random coil, and the tethered linear V2 peptide (palm-linear V2 peptide) entirely in a beta-sheet. Upon immunization of mice, palm-cyclic peptide induced anti-cyclic peptide endpoint titers >106 and was considered to be a better immunogen overall than palm-linear V2 peptide for inducing antibodies to gp120 and gp70-V1V2. The antibodies also inhibited the binding of V2 peptide to the HIV-1 alpha4beta7 integrin receptor. Antibody titers to MorHap, even with the presence of injected cyclic peptide, were very high, and resulted in inhibition of the hyper-locomotion and antinociception effects of injected heroin. From these initial experiments, we conclude that with a potent adjuvant and mostly synthetic constituents, a vaccine directed to heroin and HIV 1 (H2 vaccine) could be a feasible objective. PMID- 29263869 TI - Therapeutic vaccines for allergic disease. AB - Allergic diseases are highly prevalent worldwide and affect all age groups, contributing to a high personal and socioeconomic burden. Treatment with an "allergy vaccine" or allergen immunotherapy aims to provide long-lasting benefits by inducing unresponsiveness to the relevant antigen. The consequences of the therapy are considered disease modifying and range from dampening of the immediate immune responses to the reduction of secondary tissue remodeling. Furthermore, allergen immunotherapy interventions have a potential to slow or cease the development of additional allergic manifestations with a long-term overall effect on morbidity and quality of life. Here, we review proposed mechanisms underlying the therapeutic effects of immunotherapy for allergic diseases. Further, we discuss both standard and novel approaches and possible future directions in the development of allergen immunotherapy. PMID- 29263871 TI - An avian influenza H7 DNA priming vaccine is safe and immunogenic in a randomized phase I clinical trial. AB - A novel avian influenza subtype, A/H7N9, emerged in 2013 and represents a public health threat with pandemic potential. We have previously shown that DNA vaccine priming increases the magnitude and quality of antibody responses to H5N1 monovalent inactivated boost. We now report the safety and immunogenicity of a H7 DNA-H7N9 monovalent inactivated vaccine prime-boost regimen. In this Phase 1, open label, randomized clinical trial, we evaluated three H7N9 vaccination regimens in healthy adults, with a prime-boost interval of 16 weeks. Group 1 received H7 DNA vaccine prime and H7N9 monovalent inactivated vaccine boost. Group 2 received H7 DNA and H7N9 monovalent inactivated vaccine as a prime and H7N9 monovalent inactivated vaccine as a boost. Group 3 received H7N9 monovalent inactivated vaccine in a homologous prime-boost regimen. Overall, 30 individuals between 20 to 60 years old enrolled and 28 completed both vaccinations. All injections were well tolerated with no serious adverse events. 2 weeks post boost, 50% of Group 1 and 33% of Group 2 achieved a HAI titer >=1:40 compared with 11% of Group 3. Also, at least a fourfold increase in neutralizing antibody responses was seen in 90% of Group 1, 100% of Group 2, and 78% of Group 3 subjects. Peak neutralizing antibody geometric mean titers were significantly greater for Group 1 (GMT = 440.61, p < 0.05) and Group 2 (GMT = 331, p = 0.02) when compared with Group 3 (GMT = 86.11). A novel H7 DNA vaccine was safe, well tolerated, and immunogenic when boosted with H7N9 monovalent inactivated vaccine, while priming for higher HAI and neutralizing antibody titers than H7N9 monovalent inactivated vaccine alone. PMID- 29263872 TI - H5N1 influenza vaccine induces a less robust neutralizing antibody response than seasonal trivalent and H7N9 influenza vaccines. AB - Conventional inactivated avian influenza vaccines have performed poorly in past vaccine trials, leading to the hypothesis that they are less immunogenic than seasonal influenza vaccines. We tested this hypothesis by comparing the immunogenicity of the H5N1 and H7N9 vaccines (avian influenza vaccines) to a seasonal trivalent inactivated influenza vaccine in naive ferrets, administered with or without the adjuvants MF59 or AS03. Vaccine immunogenicity was assessed by measuring neutralizing antibody titers against hemagglutinin and neuraminidase and by hemagglutinin -specific IgG levels. Two doses of unadjuvanted vaccines induced low or no HA-specific IgG responses and hemagglutination-inhibiting titers. Adjuvanted vaccines induced comparable IgG-titers, but poorer neutralizing antibody titers for the H5 vaccine. All adjuvanted vaccines elicited detectable anti- neuraminidase -antibodies with the exception of the H5N1 vaccine, likely due to the low amounts of neuraminidase in the vaccine. Overall, the H5N1 vaccine had poorer capacity to induce neutralizing antibodies, but not HA-specific IgG, compared to H7N9 or trivalent inactivated influenza vaccine. PMID- 29263873 TI - Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis. AB - The national blueprint for biodefense concluded that the United States is underprepared for biological threats. The licensed anthrax vaccine absorbed vaccine, BioThrax, requires administration of at least 3-5 intramuscular doses. The anthrax vaccine absorbed vaccine consists of complex cell-free culture filtrates of a toxigenic Bacillus anthracis strain and causes tenderness at the injection site and significant adverse events. We integrated a codon-optimized, protective antigen gene of B. anthracis (plus extracellular secretion machinery), into the chromosome of the licensed, oral, live-attenuated typhoid fever vaccineTy21a to form Ty21a-PA-01 and demonstrated excellent expression of the gene encoding protective antigen. We produced the vaccine in a 10-L fermenter; foam-dried and vialed it, and characterized the dried product. The vaccine retained ~50% viability for 20 months at ambient temperature. Sera from animals immunized by the intraperitoneal route had high levels of anti-protective antigen antibodies by enzyme-linked immunosorbent assay and anthrax lethal toxin neutralizing activity. Immunized mice were fully protected against intranasal challenge with ~5 LD50 of B. anthracis Sterne spores, and 70% (7/10) of vaccinated rabbits were protected against aerosol challenge with 200 LD50 of B. anthracis Ames spores. There was a significant correlation between protection and antibody levels determined by enzyme-linked immunosorbent assay and toxin neutralizing activity. These data provide the foundation for achievement of our ultimate goal, which is to develop an oral anthrax vaccine that is stable at ambient temperatures and induces the rapid onset of durable, high-level protection after a 1-week immunization regimen. PMID- 29263874 TI - DMAb inoculation of synthetic cross reactive antibodies protects against lethal influenza A and B infections. AB - Influenza virus remains a significant public health threat despite innovative vaccines and antiviral drugs. A major limitation to current vaccinations and therapies against influenza virus is pathogenic diversity generated by shift and drift. A simple, cost-effective passive immunization strategy via in vivo production of cross-protective antibody molecules may augment existing vaccines and antiviral drugs in seasonal and pandemic outbreaks. We engineered synthetic plasmid DNA to encode two novel and broadly cross-protective monoclonal antibodies targeting influenza A and B. We utilized enhanced in vivo delivery of these plasmid DNA-encoded monoclonal antibody (DMAb) constructs and show that this strategy induces robust levels of functional antibodies directed against influenza A and B viruses in mouse sera. Mice receiving a single inoculation with anti-influenza A DMAb survive lethal Group 1 H1 and Group 2 H3 influenza A challenges, while inoculation with anti-influenza B DMAb yields protection against lethal Victoria and Yamagata lineage influenza B morbidity and mortality. Furthermore, these two DMAbs can be delivered coordinately resulting in exceptionally broad protection against both influenza A and B. We demonstrate this protection is similar to that achieved by conventional protein antibody delivery. DMAbs warrant further investigation as a novel immune therapy platform with distinct advantages for sustained immunoprophylaxis against influenza. PMID- 29263876 TI - A VLP-based vaccine provides complete protection against Nipah virus challenge following multiple-dose or single-dose vaccination schedules in a hamster model. AB - Nipah virus is a highly lethal zoonotic paramyxovirus that was first recognized in Malaysia during an outbreak in 1998. During this outbreak, Nipah virus infection caused a severe febrile neurological disease in humans who worked in close contact with infected pigs. The case fatality rate in humans was approximately 40%. Since 2001, NiV has re-emerged in Bangladesh and India where fruit bats (Pteropus spp.) have been identified as the principal reservoir of the virus. Transmission to humans is considered to be bat-to-human via food contaminated with bat saliva, or consumption of contaminated raw date palm sap, although human-to-human transmission of Nipah virus has also been documented. To date, there are no approved prophylactic options or treatment for NiV infection. In this study, we produced mammalian cell-derived native Nipah virus-like particles composed of Nipah virus G, F and M proteins for use as a novel Nipah virus vaccine. Previous studies demonstrated that the virus-like particles were structurally similar to authentic virus, functionally assembled and immunoreactive. In the studies reported here, purified Nipah virus-like particles were utilized either alone or with adjuvant to vaccinate golden Syrian hamsters with either three-dose or one-dose vaccination regimens followed by virus challenge. These studies found that Nipah virus-like particle immunization of hamsters induced significant neutralizing antibody titers and provided complete protection to all vaccinated animals following either single or three-dose vaccine schedules. These studies prove the feasibility of a virus-like particle based vaccine for protection against Nipah virus infection. PMID- 29263875 TI - Antibody therapies for the prevention and treatment of viral infections. AB - Antibodies are an important component in host immune responses to viral pathogens. Because of their unique maturation process, antibodies can evolve to be highly specific to viral antigens. Physicians and researchers have been relying on such high specificity in their quest to understand host-viral interaction and viral pathogenesis mechanisms and to find potential cures for viral infection and disease. With more than 60 recombinant monoclonal antibodies developed for human use in the last 20 years, monoclonal antibodies are now considered a viable therapeutic modality for infectious disease targets, including newly emerging viral pathogens such as Ebola representing heightened public health concerns, as well as pathogens that have long been known, such as human cytomegalovirus. Here, we summarize some recent advances in identification and characterization of monoclonal antibodies suitable as drug candidates for clinical evaluation, and review some promising candidates in the development pipeline. PMID- 29263877 TI - Needle-free delivery of measles virus vaccine to the lower respiratory tract of non-human primates elicits optimal immunity and protection. AB - Needle-free measles virus vaccination by aerosol inhalation has many potential benefits. The current standard route of vaccination is subcutaneous injection, whereas measles virus is an airborne pathogen. However, the target cells that support replication of live-attenuated measles virus vaccines in the respiratory tract are largely unknown. The aims of this study were to assess the in vivo tropism of live-attenuated measles virus and determine whether respiratory measles virus vaccination should target the upper or lower respiratory tract. Four groups of twelve cynomolgus macaques were immunized with 104 TCID50 of recombinant measles virus vaccine strain Edmonston-Zagreb expressing enhanced green fluorescent protein. The vaccine virus was grown in MRC-5 cells and formulated with identical stabilizers and excipients as used in the commercial MVEZ vaccine produced by the Serum Institute of India. Animals were immunized by hypodermic injection, intra-tracheal inoculation, intra-nasal instillation, or aerosol inhalation. In each group six animals were euthanized at early time points post-vaccination, whereas the other six were followed for 14 months to assess immunogenicity and protection from challenge infection with wild-type measles virus. At early time-points, enhanced green fluorescent protein-positive measles virus-infected cells were detected locally in the muscle, nasal tissues, lungs, and draining lymph nodes. Systemic vaccine virus replication and viremia were virtually absent. Infected macrophages, dendritic cells and tissue-resident lymphocytes predominated. Exclusive delivery of vaccine virus to the lower respiratory tract resulted in highest immunogenicity and protection. This study sheds light on the tropism of a live-attenuated measles virus vaccine and identifies the alveolar spaces as the optimal site for respiratory delivery of measles virus vaccine. PMID- 29263878 TI - A defined subunit vaccine that protects against vector-borne visceral leishmaniasis. AB - Vaccine development for vector-borne pathogens may be accelerated through the use of relevant challenge models, as has been the case for malaria. Because of the demonstrated biological importance of vector-derived molecules in establishing natural infections, incorporating natural challenge models into vaccine development strategies may increase the accuracy of predicting efficacy under field conditions. Until recently, however, there was no natural challenge model available for the evaluation of vaccine candidates against visceral leishmaniasis. We previously demonstrated that a candidate vaccine against visceral leishmaniasis containing the antigen LEISH-F3 could provide protection in preclinical models and induce potent T-cell responses in human volunteers. In the present study, we describe a next generation candidate, LEISH-F3+, generated by adding a third antigen to the LEISH-F3 di-fusion protein. The rationale for adding a third component, derived from cysteine protease (CPB), was based on previously demonstrated protection achieved with this antigen, as well as on recognition by human T cells from individuals with latent infection. Prophylactic immunization with LEISH-F3+formulated with glucopyranosyl lipid A adjuvant in stable emulsion significantly reduced both Leishmania infantum and L. donovani burdens in needle challenge mouse models of infection. Importantly, the data obtained in these infection models were validated by the ability of LEISH F3+/glucopyranosyl lipid A adjuvant in stable emulsion to induce significant protection in hamsters, a model of both infection and disease, following challenge by L. donovani-infected Lutzomyia longipalpis sand flies, a natural vector. This is an important demonstration of vaccine protection against visceral leishmaniasis using a natural challenge model. PMID- 29263879 TI - Protein nanovaccine confers robust immunity against Toxoplasma. AB - We designed and produced a self-assembling protein nanoparticle. This self assembling protein nanoparticle contains five CD8+ HLA-A03-11 supertypes restricted epitopes from antigens expressed during Toxoplasma gondii's lifecycle, the universal CD4+ T cell epitope PADRE, and flagellin as a scaffold and TLR5 agonist. These CD8+ T cell epitopes were separated by N/KAAA spacers and optimized for proteasomal cleavage. Self-assembling protein nanoparticle adjuvanted with TLR4 ligand-emulsion GLA-SE were evaluated for their efficacy in inducing IFN-gamma responses and protection of HLA-A*1101 transgenic mice against T. gondii. Immunization, using self-assembling protein nanoparticle-GLA-SE, activated CD8+ T cells to produce IFN-gamma. Self-assembling protein nanoparticle GLA-SE also protected HLA-A*1101 transgenic mice against subsequent challenge with Type II parasites. Hence, combining CD8+ T cell-eliciting peptides and PADRE into a multi-epitope protein that forms a nanoparticle, administered with GLA-SE, leads to efficient presentation by major histocompatibility complex Class I and II molecules. Furthermore, these results suggest that activation of TLR4 and TLR5 could be useful for development of vaccines that elicit T cells to prevent toxoplasmosis in humans. PMID- 29263880 TI - Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNgamma response promoting vaccine immunogenicity. AB - Combining immunostimulants in adjuvants can improve the quality of the immune response to vaccines. Here, we report a unique mechanism of molecular and cellular synergy between a TLR4 ligand, 3-O-desacyl-4'-monophosphoryl lipid A (MPL), and a saponin, QS-21, the constituents of the Adjuvant System AS01. AS01 is part of the malaria and herpes zoster vaccine candidates that have demonstrated efficacy in phase III studies. Hours after injection of AS01 adjuvanted vaccine, resident cells, such as NK cells and CD8+ T cells, release IFNgamma in the lymph node draining the injection site. This effect results from MPL and QS-21 synergy and is controlled by macrophages, IL-12 and IL-18. Depletion strategies showed that this early IFNgamma production was essential for the activation of dendritic cells and the development of Th1 immunity by AS01 adjuvanted vaccine. A similar activation was observed in the lymph node of AS01 injected macaques as well as in the blood of individuals receiving the malaria RTS,S vaccine. This mechanism, previously described for infections, illustrates how adjuvants trigger naturally occurring pathways to improve the efficacy of vaccines. PMID- 29263881 TI - A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies. AB - Influenza viruses evade human adaptive immune responses due to continuing antigenic changes. This makes it necessary to re-formulate and re-administer current seasonal influenza vaccines on an annual basis. Our pan-influenza vaccination approach attempts to redirect antibody responses from the variable, immuno-dominant hemagglutinin head towards the conserved-but immuno-subdominant hemagglutinin stalk. The strategy utilizes sequential immunization with chimeric hemagglutinin-based vaccines expressing exotic head domains, and a conserved hemagglutinin stalk. We compared a live-attenuated influenza virus prime followed by an inactivated split-virus boost to two doses of split-virus vaccines and assessed the impact of adjuvant on protection against challenge with pandemic H1N1 virus in ferrets. All tested immunization regimens successfully induced broadly cross-reactive antibody responses. The combined live-attenuated/split virus vaccination conferred superior protection against pandemic H1N1 infection compared to two doses of split-virus vaccination. Our data support advancement of this chimeric hemagglutinin-based vaccine approach to clinical trials in humans. PMID- 29263883 TI - Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic virus that causes severe respiratory disease in humans with a case fatality rate close to 40%, but for which no vaccines are available. Here, we evaluated the utility of ChAdOx1, a promising replication-deficient simian adenovirus vaccine vector platform with an established safety profile in humans and dromedary camels, for MERS-CoV vaccine development. Using a transgenic lethal BALB/c MERS-CoV mouse model we showed that single dose intranasal or intramuscular immunisation with ChAdOx1 MERS, encoding full-length MERS-CoV Spike glycoprotein, is highly immunogenic and confers protection against lethal viral challenge. Immunogenicity and efficacy were comparable between immunisation routes. Together these data provide support for further evaluation of ChAdOx1 MERS vaccine in humans and dromedary camels, the animal reservoir of infection. PMID- 29263882 TI - Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice. AB - A malaria vaccine that prevents infection will be an important new tool in continued efforts of malaria elimination, and such vaccines are under intense development for the major human malaria parasite Plasmodium falciparum (Pf). Antibodies elicited by vaccines can block the initial phases of parasite infection when sporozoites are deposited into the skin by mosquito bite and then target the liver for further development. However, there are currently no standardized in vivo preclinical models that can measure the inhibitory activity of antibody specificities against Pf sporozoite infection via mosquito bite. Here, we use human liver-chimeric mice as a challenge model to assess prevention of natural Pf sporozoite infection by antibodies. We demonstrate that these mice are consistently infected with Pf by mosquito bite and that this challenge can be combined with passive transfer of either monoclonal antibodies or polyclonal human IgG from immune serum to measure antibody-mediated blocking of parasite infection using bioluminescent imaging. This methodology is useful to down-select functional antibodies and to investigate mechanisms or immune correlates of protection in clinical trials, thereby informing rational vaccine optimization. PMID- 29263884 TI - Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. AB - mRNA represents a promising new vaccine technology platform with high flexibility in regard to development and production. Here, we demonstrate that vaccines based on sequence optimized, chemically unmodified mRNA formulated in optimized lipid nanoparticles (LNPs) are highly immunogenic and well tolerated in non-human primates (NHPs). Single intramuscular vaccination of NHPs with LNP-formulated mRNAs encoding rabies or influenza antigens induced protective antibody titers, which could be boosted and remained stable during an observation period of up to 1 year. First mechanistic insights into the mode of action of the LNP-formulated mRNA vaccines demonstrated a strong activation of the innate immune response at the injection site and in the draining lymph nodes (dLNs). Activation of the innate immune system was reflected by a transient induction of pro-inflammatory cytokines and chemokines and activation of the majority of immune cells in the dLNs. Notably, our data demonstrate that mRNA vaccines can compete with licensed vaccines based on inactivated virus or are even superior in respect of functional antibody and T cell responses. Importantly, we show that the developed LNP formulated mRNA vaccines can be used as a vaccination platform allowing multiple, sequential vaccinations against different pathogens. These results provide strong evidence that the mRNA technology is a valid approach for the development of effective prophylactic vaccines to prevent infectious diseases. PMID- 29263885 TI - Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer's and cat allergy. AB - Monoclonal antibodies are widely used to treat non-infectious conditions but are costly. Vaccines could offer a cost-effective alternative but have been limited by sub-optimal T-cell stimulation and/or weak vaccine responses in recipients, for example, in elderly patients. We have previously shown that the repetitive structure of virus-like-particles (VLPs) can effectively bypass self-tolerance in therapeutic vaccines. Their efficacy could be increased even further by the incorporation of an epitope stimulating T cell help. However, the self-assembly and stability of VLPs from envelope monomer proteins is sensitive to geometry, rendering the incorporation of foreign epitopes difficult. We here show that it is possible to engineer VLPs derived from a non human-pathogenic plant virus to incorporate a powerful T-cell-stimulatory epitope derived from Tetanus toxoid. These VLPs (termed CMVTT) retain self-assembly as well as long-term stability. Since Th cell memory to Tetanus is near universal in humans, CMVTT-based vaccines can deliver robust antibody-responses even under limiting conditions. By way of proof of concept, we tested a range of such vaccines against chronic inflammatory conditions (model: psoriasis, antigen: interleukin-17), neurodegenerative (Alzheimer's, beta-amyloid), and allergic disease (cat allergy, Fel-d1), respectively. Vaccine responses were uniformly strong, selective, efficient in vivo, observed even in old mice, and employing low vaccine doses. In addition, randomly ascertained human blood cells were reactive to CMVTT-VLPs, confirming recognition of the incorporated Tetanus epitope. The CMVTT-VLP platform is adaptable to almost any antigen and its features and performance are ideally suited for the design of vaccines delivering enhanced responsiveness in aging populations. PMID- 29263886 TI - Enhancing vaccine antibody responses by targeting Clec9A on dendritic cells. AB - Targeting model antigens (Ags) to Clec9A on DC has been shown to induce, not only cytotoxic T cells, but also high levels of Ab. In fact, Ab responses against immunogenic Ag were effectively generated even in the absence of DC-activating adjuvants. Here we tested if targeting weakly immunogenic putative subunit vaccine Ags to Clec9A could enhance Ab responses to a level likely to be protective. The proposed "universal" influenza Ag, M2e and the enterovirus 71 Ag, SP70 were linked to anti-Clec9A Abs and injected into mice. Targeting these Ags to Clec9A greatly increased Ab titres. For optimal responses, a DC-activating adjuvant was required. For optimal responses, a boost injection was also needed, but the high Ab titres against the targeting construct blocked Clec9A-targeted boosting. Heterologous prime-boost strategies avoiding cross-reactivity between the priming and boosting targeting constructs overcame this limitation. In addition, targeting small amounts of Ag to Clec9A served as an efficient priming for a conventional boost with higher levels of untargeted Ag. Using this Clec9A targeted priming, conventional boosting strategy, M2e immunisation protected mice from infection with lethal doses of influenza H1N1 virus. PMID- 29263887 TI - Developing a platform system for gene delivery: amplifying virus-like particles (AVLP) as an influenza vaccine. AB - Delivery of a gene of interest to target cells is highly desirable for translational medicine, such as gene therapy, regenerative medicine, vaccine development, and studies of gene function. Parainfluenza virus 5 (PIV5), a paramyxovirus with a negative-sense RNA genome, normally infects cells without causing obvious cytopathic effect, and it can infect many cell types. To exploit these features of PIV5, we established a system generating self-amplifying, virus like particles (AVLP). Using enhanced green fluorescent protein (EGFP) as a reporter, AVLP encoding EGFP (AVLP-EGFP) successfully delivered and expressed the EGFP gene in primary human cells, including stem cells, airway epithelial cells, monocytes, and T cells. To demonstrate the application of this system for vaccine development, we generated AVLPs to express the HA and M1 antigens from the influenza A virus strain H5N1 (AVLP-H5 and AVLP-M1H5). Immunization of mice with AVLP-H5 and AVLP-M1H5 generated robust antibody and cellular immune responses. Vaccination with a single dose of AVLP-H5 and M1H5 completely protected mice against lethal H5N1 challenge, suggesting that the AVLP-based system is a promising platform for delivery of desirable genes. PMID- 29263888 TI - Newcastle disease virus-based H5 influenza vaccine protects chickens from lethal challenge with a highly pathogenic H5N2 avian influenza virus. AB - Since December 2014, Eurasian-origin, highly pathogenic avian influenza H5 viruses including H5N1, H5N2, and H5N8 subtypes (called H5Nx viruses), which belong to the H5 clade 2.3.4.4, have been detected in U.S. wild birds. Subsequently, highly pathogenic H5N2 and H5N8 viruses have caused outbreaks in U.S. domestic poultry. Vaccination is one of the most effective ways to control influenza outbreaks and protect animal and public health. Newcastle disease virus (NDV)-based influenza vaccines have been demonstrated to be efficacious and safe in poultry. Herein, we developed an NDV-based H5 vaccine (NDV-H5) that expresses a codon-optimized ectodomain of the hemagglutinin from the A/chicken/Iowa/04 20/2015 (H5N2) virus and evaluated its efficacy in chickens. Results showed that both live and inactivated NDV-H5 vaccines induced hemagglutinin inhibition antibody titers against the H5N2 virus in immunized chickens after prime and booster, and both NDV-H5 vaccines completely protected chickens from lethal challenge with the highly pathogenic H5N2 A/turkey/Minnesota/9845-4/2015 virus. No clinical signs and only minimal virus shedding was observed in both vaccinated groups. In contrast, all mock-vaccinated, H5N2-infected chickens shed virus and died within 5 days post challenge. Furthermore, one dose of the live NDV-H5 vaccine also provided protection of 90% chickens immunized by coarse spraying; after exposure to H5N2 challenge, sera from vaccinated surviving chickens neutralized both highly pathogenic H5N1 and H5N8 viruses. Taken together, our results suggest that the NDV-based H5 vaccine is able to protect chickens against intercontinental highly pathogenic H5Nx viruses and can be used by mass application to protect the poultry industry. PMID- 29263889 TI - Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines. AB - The stem of the influenza A virus hemagglutinin (HA) is highly conserved and represents an attractive target for a universal influenza vaccine. The 18 HA subtypes of influenza A are phylogenetically divided into two groups, and while protection with group 1 HA stem vaccines has been demonstrated in animal models, studies on group 2 stem vaccines are limited. Thus, we engineered group 2 HA stem immunogen (SI) vaccines targeting the epitope for the broadly neutralizing monoclonal antibody CR9114 and evaluated vaccine efficacy in mice and ferrets. Immunization induced antibodies that bound to recombinant HA protein and viral particles, and competed with CR9114 for binding to the HA stem. Mice vaccinated with H3 and H7-SI were protected from lethal homologous challenge with X-79 (H3N2) or A/Anhui/1/2013 (H7N9), and displayed moderate heterologous protection. In ferrets, H7-SI vaccination did not significantly reduce weight loss or nasal wash titers after robust 107 TCID50 H7N9 virus challenge. Epitope mapping revealed ferrets developed lower titers of antibodies that bound a narrow range of HA stem epitopes compared to mice, and this likely explains the lower efficacy in ferrets. Collectively, these findings indicate that while group 2 SI vaccines show promise, their immunogenicity and efficacy are reduced in larger outbred species, and will have to be enhanced for successful translation to a universal vaccine. PMID- 29263890 TI - Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination. AB - Human cytomegalovirus (HCMV) is the leading cause of in utero viral infection in the United States. Since congenital HCMV infection can lead to birth defects in newborns, developing a prophylactic vaccine is a high priority. One of the early experimental vaccines, composed of a recombinant glycoprotein B (gB) formulated with MF59 adjuvant, has demonstrated approximately 50% efficacy against HCMV infection in seronegative women. Using immune sera from two gB/MF59 Phase 1 studies in humans we showed that complement can enhance the in vitro HCMV neutralizing potency of antibodies induced by the gB/MF59 vaccination. To characterize this complement-dependent antiviral activity, we analyzed three rabbit non-neutralizing gB monoclonal antibodies (mAbs) with different biochemical profiles including epitope specificity. Two of the three mAbs, r272.7 and r210.4, exhibited neutralizing activity when complement was added to the assays, and this complement-dependent antiviral activity was not related to the antibody's affinity to gB but appeared to be associated with their epitope specificities. Moreover, neutralization could only be demonstrated when complement was present at or before viral entry, suggesting that IgG Fc-mediated function was not the basis for this antiviral activity. Lastly, we demonstrated that gB/MF59 immune sera contained antibodies that can cross-compete with r272.7 for gB binding and that the titers of these antibodies correlated with complement dependent neutralization titers. These results suggested that gB antibodies with certain biochemical properties have neutralizing potency when complement is present and that this complement-dependent antiviral activity may be a part of immune components which conferred protection against HCMV infection by gB/MF59 vaccination. PMID- 29263892 TI - Announcing Signal Transduction and Targeted Therapy. PMID- 29263891 TI - The role of MicroRNAs in human cancer. AB - MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes. PMID- 29263894 TI - Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report. AB - Patients with relapsed or refractory non-Hodgkin lymphoma have a dismal prognosis. Chimeric Antigen Receptor (CAR)-modified T cells (CART cells) that targeted CD20 were effective in a phase I clinical trial for patients with advanced B-cell lymphomas. We performed a phase IIa trial to further assess the safety and efficacy of administering autologous anti-CD20 CART (CART-20) cells to patients with refractory or relapsed CD20+ B-cell lymphoma. Eleven patients were enrolled, and seven patients underwent cytoreductive chemotherapy to debulk the tumors and deplete the lymphocytes before receiving T-cell infusions. The overall objective response rate was 9 of 11 (81.8%), with 6 complete remissions (CRs) and 3 partial remissions; no severe toxicity was observed. The median progression free survival lasted for >6 months, and 1 patient had a 27-month continuous CR. A significant inverse correlation between the levels of the CAR gene and disease recurrence or progression was observed. Clinically, the lesions in special sites, specifically the spleen and testicle, were refractory to CART-20 treatment. Collectively, these results together with our data from phase I strongly demonstrated the feasibility and efficacy of CART-20 treatment in lymphomas and suggest large-scale patient recruitment in a future study. This study was registered at www.clinicaltrials.org as NCT01735604. PMID- 29263893 TI - Osteosarcoma: prognosis plateau warrants retinoblastoma pathway targeted therapy. AB - Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents, affecting ~560 young patients in the United States annually. The term OS describes a diverse array of subtypes with varying prognoses, but the majority of tumors are high grade and aggressive. Perhaps because the true etiology of these aggressive tumors remains unknown, advances in OS treatment have reached a discouraging plateau, with only incremental improvements over the past 40 years. Thus, research surrounding the pathogenesis of OS is essential, as it promises to unveil novel therapeutic targets that can attack tumor cells with greater specificity and lower toxicity. Among the candidate molecular targets in OS, the retinoblastoma (RB) pathway demonstrates the highest frequency of inactivation and thus represents a particularly promising avenue for molecular targeted therapy. This review examines the present thinking and practices in OS treatment and specifically highlights the relevance of the RB pathway in osteosarcomagenesis. Through further investigation into RB pathway-related novel therapeutic targets, we believe that a near-term breakthrough in improved OS prognosis is possible. PMID- 29263895 TI - From a retrovirus infection of mice to a long noncoding RNA that induces proto oncogene transcription and oncogenesis via an epigenetic transcription switch. AB - Here I review the properties of the mouse retroelement VL30-1, which apparently derived from retrotranspostions of a founder VL30 retrovirus that infected the mouse germline after the mouse-human speciation. The VL30-1 gene is transcribed as a long noncoding RNA (lncRNA) with an essential host function in an epigenetic transcription switch (ETS) that regulates transcription of multiple genes, including proto-oncogenes that control cell proliferation and oncogenesis. The ETS involves the tumor suppressor protein PSF that has a DNA-binding domain (DBD) and two RNA-binding domains (RBDs). The DBD binds to promoters that have a DBD binding sequence and switches off transcription, and the RBDs bind lncRNAs that have a RBD-binding sequence, releasing PSF and switching on transcription. VL30-1 lncRNA has two RBD-binding sequences, apparently acquired by mutations during retrotranspositions of the founder retrovirus, which drive proto-oncogene transcription and oncogenesis via the ETS. VL30-1 lncRNA is a seminal example of the key role of endogenous retroviruses (ERVs) and their retroelements in the evolution of transcription regulatory systems. PMID- 29263897 TI - TIFA suppresses hepatocellular carcinoma progression via MALT1-dependent and independent signaling pathways. AB - TIFA, also called T2BP, was first identified using yeast two-hybrid screening. Our previous work showed that TIFA suppresses hepatocellular carcinoma (HCC) progression via apoptosis and cell cycle arrest. However, the mechanism by which this TIFA suppression occurs remains unclear. Here we demonstrated that TIFA induced apoptosis demonstrates two distinct time patterns (i.e., at 48 h and >7 days) when TIFA reconstitution occurs. Moreover, we found that MALT1 (a competitor of TIFA) plays a crucial role in short-duration TIFA reconstitution. In this regard, MALT1 silencing with shRNA markedly enhances TIFA-induced apoptosis in vitro and in vivo. In addition, TIFA overexpression triggers JNK and p38 activation in long-duration TIFA reconstitution through TRAF6 binding. In particular, JNK activation leads to TIFA-induced apoptosis while p38 activation governs TIFA-induced cell cycle arrest by p53-p21 signaling in vitro and in vivo. Our data suggest a novel mechanism by which TIFA suppresses HCC progression via both MALT1-dependent and MALT1-independent signaling pathways. This may provide insights into a novel targets where HCC progression may be vulnerable to clinical treatment. PMID- 29263898 TI - Transferrin protects against Parkinsonian neurotoxicity and is deficient in Parkinson's substantia nigra. AB - Iron deposition in Parkinson's disease (PD) is a potential disease-modifying target. We previously showed that supplementation of the iron-exporter, ceruloplasmin, selectively corrected nigral iron elevation in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Ceruloplasmin delivers iron to transferrin (Tf), the extracellular iron-transporting protein. We show that Tf protein levels are decreased in the nigra of post-mortem PD brains compared with controls (-35%; n=10 each). Because Tf traffics iron away from iron-replete tissues, we hypothesized that Tf supplementation could selectively facilitate iron export from the nigra in PD. In cultured neurons, Tf treatment corrected iron accumulation, and subcutaneous Tf to mice ameliorated iron accumulation and motor deficits in the MPTP model of PD. Although these data support a role for Tf in the disease mechanism for PD, and its potential use for correcting disorders of iron overload, Tf therapy also caused systemic iron depletion, which could limit its application for PD. PMID- 29263896 TI - Inhibiting cancer cell hallmark features through nuclear export inhibition. AB - Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy. PMID- 29263899 TI - Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration. AB - Age-related macular degeneration (AMD) is characterized by complex interactions between genetic and environmental factors. Here we genotyped the selected 25 single-nucleotide polymorphisms (SNPs) in 983 cases with advanced AMD and 271 cases with intermediate AMD and build an AMD life-risk score model for assessment of progression from intermediate to advanced AMD. We analyzed the performance of the prediction model for geographic atrophy progressors or choroidal neovascularization progressors versus non-progressors based on the 25 SNPs plus body mass index and smoking status. Our results suggest that a class prediction algorithm can be used for the risk assessment of progression from intermediate to late AMD stages. The algorithm could also be potentially applied for therapeutic response, and toward personalized care and precision medicine. PMID- 29263900 TI - G-protein-coupled receptors mediate 14-3-3 signal transduction. AB - G-protein-coupled receptor (GPCR)-interacting proteins likely participate in regulating GPCR signaling by eliciting specific signal transduction cascades, inducing cross-talk with other pathways, and fine tuning the signal. However, except for G-proteins and beta-arrestins, other GPCR-interacting proteins are poorly characterized. 14-3-3 proteins are signal adaptors, and their participation in GPCR signaling is not well understood or recognized. Here we demonstrate that GPCR-mediated 14-3-3 signaling is ligand-regulated and is likely to be a more general phenomenon than suggested by the previous reports of 14-3-3 involvement with a few GPCRs. For the first time, we can pharmacologically characterize GPCR/14-3-3 signaling. We have shown that GPCR-mediated 14-3-3 signaling is phosphorylation-dependent, and that the GPCR/14-3-3 interaction likely occurs later than receptor desensitization and internalization. GPCR mediated 14-3-3 signaling can be beta-arrestin-independent, and individual agonists can have different potencies on 14-3-3 and beta-arrestin signaling. GPCRs can also mediate the interaction between 14-3-3 and Raf-1. Our work opens up a new broad realm of previously unappreciated GPCR signal transduction. Linking GPCRs to 14-3-3 signal transduction creates the potential for the development of new research directions and provides a new signaling pathway for drug discovery. PMID- 29263901 TI - Peptide-substituted oligonucleotide synthesis and non-toxic, passive cell delivery. AB - Chemically modified oligodeoxynucleotides (ODNs) are known to modulate gene expression by interacting with RNA. An efficient approach for synthesizing amino acid- or peptide-substituted triazolylphosphonate analogs (TP ODNs) has been developed to provide improved stability and cell uptake. The chemistry is quite general, as peptides can be introduced throughout the TP ODN at any preselected internucleotide linkage. These synthetic TP ODNs enter cells through endocytosis in the absence of transfection reagents and localize into perinuclear organelles. The entrapped ODNs are released into the cytoplasm by treatment with endosomal releasing agents and several are then active as microRNA inhibitors. PMID- 29263902 TI - USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency. AB - The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells (ESCs). Stabilization of Nanog proteins is essential for ESCs. The ubiquitin-proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions. Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated, the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a deubiquitylase for Nanog, but not for Oct4 or Sox2. USP21 interacts with Nanog protein in ESCs in vivo and in vitro. The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction. USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog, stabilizing Nanog. USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs. Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation. Overall, our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog. PMID- 29263903 TI - A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity. AB - Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MPhi cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses. PMID- 29263904 TI - The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion. AB - CCTG repeat expansions in intron 1 of the cellular nucleic acid-binding protein gene are associated with myotonic dystrophy type 2. Recently, we have reported a novel mini-dumbbell (MDB) structure formed by two CCTG or TTTA repeats, which potentially has a critical role in repeat expansions. Here we present a mechanism, called the competing MDB mechanism, to explain how the formation of MDB can lead to efficient mismatch repair (MMR) escape and thus CCTG repeat expansions during DNA replication. In a long tract of CCTG repeats, two competing MDBs can be formed in any segment of three repeats. Fast exchange between these MDBs will make the commonly occupied repeat behave like a mini-loop. Further participations of the 5'- or 3'-flanking repeat in forming competing MDBs will make the mini-loop shift in the 5'- or 3'-direction, thereby providing a pathway for the mini-loop to escape from MMR. To avoid the complications due to the formation of hairpin conformers in longer CCTG repeats, we made use of TTTA repeats as model sequences to demonstrate the formation of competing MDBs and shifting of mini-loop in a long tract of repeating sequence. PMID- 29263905 TI - Seeing is believing: anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy. AB - Structural immunology, focusing on structures of host immune related molecules, enables the immunologists to see what the molecules look like, and more importantly, how they work together. Antibody-based PD-1/PD-L1 blockade therapy has achieved brilliant successes in clinical applications. The recent breakthrough of the complex structures of checkpoint blockade antibodies with their counterparts, pembrolizumab with PD-1 and avelumab with PD-L1, have made it clear how these monoclonal antibodies compete the binding of PD-1/PD-L1 and function to blockade the receptor-ligand interaction. Herein, we summarize the structural findings of these two reports and look into the future for how this information would facilitate the development of more efficient PD-1/PD-L1 targeting antibodies, small molecule drugs, and other protein or non-protein inhibitors. PMID- 29263906 TI - Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster. AB - The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection, but the underlying mechanism for Lyn mediated inflammatory response remains largely elusive. Using mouse Pseudomonas aeruginosa infection models, we observed that Lyn-/- mice manifest severe lung injury and enhanced inflammatory responses, compared with wild-type littermates. We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains. Depletion of Lyn results in excessive STAT3 activation, and enhanced the Src homology 2 containing inositol-5-phopsphatase 1 (SHIP-1) expression. Deletion of SHIP-1 in Lyn-/- mice (double knockout) promotes mouse survival and reduces inflammatory responses during P. aeruginosa infection, revealing the rescue of the deadly infectious phenotype in Lyn deficiency. Mechanistically, loss of SHIP-1 reduces NF-kappaB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway. These findings reveal Lyn as a regulator for host immune response against P. aeruginosa infection through SHIP-1 and IL 6/STAT3 signaling pathway in alveolar macrophages. PMID- 29263907 TI - Butyrate induces apoptosis by activating PDC and inhibiting complex I through SIRT3 inactivation. AB - The underlying anticancer effects of butyrate, an end-product of the intestinal microbial fermentation of dietary fiber, remain elusive. Here, we report that butyrate promotes cancer cell apoptosis by acting as a SIRT3 inhibitor. Butyrate inhibits SIRT3 both in cultured cells and in vitro. Butyrate-induced PDHA1 hyperacetylation relieves the inhibitory phosphorylation of PDHA1 at serine 293, thereby activating an influx of glycolytic intermediates into the tricarboxylic acid (TCA) cycle and reversing the Warburg effect. Meanwhile, butyrate-induced hyperacetylation inactivates complex I of the electron transfer chain and prevents the utilization of TCA cycle intermediates. These metabolic stresses promote apoptosis in hyperglycolytic cancer cells, such as HCT116p53-/- cells. SIRT3 deacetylates both PDHA1 and complex I. Genetic ablation of Sirt3 in mouse hepatocytes abrogated the ability of butyrate to induce apoptosis. Our results identify a butyrate-mediated anti-tumor mechanism and indicate that the combined activation of PDC and inhibition of complex I is a novel tumor treatment strategy. PMID- 29263908 TI - Neurons generated from carcinoma stem cells support cancer progression. AB - Recent evidences show that nervous system acts as a crucial part of cancer microenvironment. Infiltration of nerve fibers into cancer microenvironment has an important active role in cancer progression. The stimulations of both cancer growth and metastasis by members of nervous system such as neurons and glial cells have been demonstrated. However, how the nervous system is built in cancer is largely unknown. Here we show that a fraction of cancer stem cells (CSCs) derived from patients with gastric carcinoma and colorectal carcinoma are capable of producing neurons that are involved in tumor neurogenesis and tumor growth. Cancer stem cell monoclone derived from a single cancer stem cell was able to generate neurons including sympathetic and parasympathetic neurons to take part in the nervous system in cancer tissues. Knocking down the neural cell generating capability of the human CSCs inhibited the growth of xenograft tumors in mouse model. Our data demonstrate that human CSCs are able to produce one of most important components in the cancer microenvironment that are required for cancer development and progression. PMID- 29263909 TI - Mammary stem cells: angels or demons in mammary gland? AB - A highly dynamic development process exits within the epithelia of mammary gland, featuring morphogenetic variation during puberty, pregnancy, lactation, and regression. The identification of mammary stem cells (MaSCs) via lineage-tracing studies has substantiated a hierarchical organization of the mammary epithelia. A single MaSC is capable of reconstituting the entirely functional mammary gland upon orthotopic transplantation. Although different mammary cell subpopulations can be candidate cells-of-origin for distinct breast tumor subtypes, it still lacks experimental proofs whether MaSCs, the most primitive cells, are the 'seeds' of malignant transformation during most, if not all, tumorigenesis in the breast. Here, we review current knowledge of mammary epithelial hierarchy, highlighting the roles of mammary stem/progenitor cells and breast cancer stem cells (BCSCs) along with their key molecular regulators in organ development and cancer evolution. Clarifying these issues will pave the way for developing novel interventions toward stem/progenitor cells in either prevention or treatment of breast cancer (BrCa). PMID- 29263910 TI - Central role of lactate and proton in cancer cell resistance to glucose deprivation and its clinical translation. AB - Targeting common weaknesses of cancer is an important strategy for cancer therapy. Glucose is a nutrient that maintains essential cellular metabolism, supporting cancer cell survival, growth and proliferation. Depriving glucose rapidly kills cancer cells. Most cancer cells possess a feature called Warburg effect, which refers to that cancer cells even with ample oxygen exhibit an exceptionally high glycolysis rate and convert most incoming glucose to lactate. Although it is recognized that Warburg effect confers growth advantage to cancer cells when glucose supply is sufficient, this feature could be considered as a fatal weakness of cancer cells when glucose supply is a problem. As glucose supply in many solid tumors is poor, and as most cancer cells have exceptionally high glycolytic capacity, maximizing cancer cell glycolysis rate would possibly exhaust intratumoral glucose, leading cancer cell to death. Lactate and proton are two common factors in solid tumors, they jointly protect cancer cells against glucose deprivation, and they are also powerful regulators dictating glucose metabolic phenotypes of cancer cells. Disrupting the joint action of lactate and proton, for example, by means of bicarbonate infusion into tumor, could maximize cancer cell glycolytic rate to rapidly use up glucose, expose their vulnerability to glucose deprivation and ultimately kill cancer cells. A pilot clinical study demonstrated that this approach achieved a remarkable improvement in local control of large and huge hepatocellular carcinoma. PMID- 29263912 TI - ASAP3 regulates microvilli structure in parietal cells and presents intervention target for gastric acidity. AB - Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread, and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches. Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo, and reveal the feasibility of controlling gastric acidity by targeting ASAP3. Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells, and substantially decreased gastric acid secretion. These were associated with active assembly of F actin caused by a higher level of GTP-bound Arf6 GTPase. Consistently, a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo. Of note, the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases, and high expression of ASAP3 was associated with reflux disease and peptic ulcer. These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells. Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases. PMID- 29263911 TI - Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine. AB - The heterotrimeric Sec61 complex and the dimeric Sec62/Sec63 complex are located in the membrane of the human endoplasmic reticulum (ER) and play a central role in translocation of nascent and newly synthesized precursor polypeptides into the ER. This process involves targeting of the precursors to the membrane and opening of the polypeptide conducting Sec61 channel for translocation. Apart from this central role in the intracellular transport of polypeptides, several studies of the last decade uncovered additional functions of Sec proteins in intracellular signaling: Sec62 can induce ER-phagy in the process of recovery of cells from ER stress and the Sec61 channel can also act as a passive ER calcium leak channel. Furthermore, mutations, amplifications and an overexpression of the SEC genes were linked to various diseases including kidney and liver diseases, diabetes and human cancer. Studies of the last decade could not only elucidate the functional role of Sec proteins in the pathogenesis of these diseases, but also demonstrate a relevance of Sec62 as a prognostic and predictive biomarker in head and neck cancer, prostate and lung cancer including a basis for new therapeutic strategies. In this article, we review the current understanding of protein transport across the ER membrane as central function of Sec proteins and further focus on recent studies that gave first insights into the functional role and therapeutic relevance of Sec61, Sec62 and Sec63 in human diseases. PMID- 29263913 TI - The molecular determinants governing the immunogenicity of Japanese encephalitis live attenuated vaccines. AB - In the course of isolating the attenuated Japanese encephalitis vaccine SA14-14 2, two attenuated strains SA14-9-7 and SA14-5-3 were also obtained that elicited low antibody responses in humans (<10% and 62%, respectively) and exerted much weaker immune protection in animal challenge experiments. However, the reason for these differences remains unknown. In order to understand why SA14-14-2 is superior to SA14-9-7 and SA14-5-3, we employed a reverse genetics method to identify the key mutations in the virus genome that determine the immunogenicity of live attenuated Japanese encephalitis viruses. We first sequenced the full genomic sequences of SA14-9-7 and SA14-5-3 and found mutations that changed four amino-acid base pairs when compared to the envelope gene of SA14-14-2. We mutated the genome of SA14-14-2 to generate these mutations both singly (E-177, E-264, E 279 and E-315) and in combination (E-177/264, E-279/315 and E-177/264/279/315) and tested these mutants along with parental strains SA14-14-2, SA14-9-7 and SA14 5-3 for their immunogenicity in vivo. When mice were immunized with SA14-9-7 and SA14-5-3, lower levels of neutralizing antibodies were generated compared with the immune response to SA14-14-2. Furthermore, SA14-5-3 was more immunogenic than SA14-9-7, which replicated the results previously seen in humans. Point mutations E-177, E-264, E-279 and E-315 diminished the immunogenicity of SA14-14-2 with E 264 and E-315, contributing the most to this phenotype. The mutant rJEV (E-177/E 264/E-279/E-315) containing all four point mutations exhibited the lowest immunogenicity with a seroconversion rate of 0 at an inoculation dose of 103 PFU (plaque-forming unit). We have identified the key amino acids in the envelope protein that account for the superior immunogenicity of SA14-14-2. PMID- 29263914 TI - A novel peptide specifically binding to VEGF receptor suppresses angiogenesis in vitro and in vivo. AB - Vascular endothelial growth factor (VEGF), one of the most important angiogenic factors, plays an essential role in both physiological and pathological angiogenesis through binding to VEGF receptors (VEGFRs). Here we report a novel peptide designated HRHTKQRHTALH (peptide HRH), which was isolated from the Ph.D. 12 phage display library using VEGFR-Fc fusion protein as the bait. This peptide was found to dose-dependently inhibit the proliferation of human umbilical vein endothelial cells stimulated by VEGF. The anti-angiogenesis effect of the HRH peptide was further confirmed in vivo using the chick chorioallantoic membrane assay, which was also dose-dependent. Besides, peptide HRH was proved to inhibit corneal neovascularization in an alkali-burnt rat corneal model and a suture induced rat corneal model. Taken together, these findings suggest that the HRH peptide can inhibit angiogenesis both in vitro and in vivo. Consequently, the HRHTKQRHTALH peptide might be a promising lead peptide for the development of potential angiogenic inhibitors. PMID- 29263915 TI - Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. AB - Acute myeloid leukemia (AML) is a serious disease. The 5-year survival rates remain frustratingly low (65% for children and 26% for adults). Resistance to frontline chemotherapy (usually cytarabine) often develops; therefore a new treatment modality is needed. Bcl-2 family proteins play an important role in balancing cell survival and apoptosis. The antiapoptotic Bcl-2 family proteins have been found to be dysregulated in AML. ABT-199, a BH3 mimetic, was developed to target antiapoptotic protein Bcl-2. Although ABT-199 has demonstrated promising results, resistance occurs. Previous studies in AML show that ABT-199 alone decreases the association of proapoptotic protein Bim with Bcl-2, but this is compensated by increased association of Bim with prosurvival protein Mcl-1, stabilizing Mcl-1, resulting in resistance to ABT-199. In this study, we investigated the antileukemic activity of the Mcl-1-selective inhibitor A-1210477 in combination with ABT-199 in AML cells. We found that A-1210477 synergistically induced apoptosis with ABT-199 in AML cell lines and primary patient samples. The synergistic induction of apoptosis was decreased upon Bak, Bax and Bim knockdown. While A-1210477 treatment alone also increased Mcl-1 protein levels, combination with ABT-199 reduced binding of Bim to Mcl-1. Our results demonstrate that sequestration of Bim by Mcl-1, a mechanism of ABT-199 resistance, can be abrogated by combined treatment with the Mcl-1 inhibitor A-1201477. PMID- 29263916 TI - Overexpression of CIP2A is associated with poor prognosis in multiple myeloma. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous protein phosphatase 2A (PP2A) inhibitor, has been identified as an oncoprotein in promoting cancer initiation and progression of several types of cancer. However, the expression and the role played by CIP2A in the pathogenesis of multiple myeloma (MM) remain unclear. In this study, we showed that CIP2A was overexpressed in human MM cell lines and MM patients' bone marrow tissues. Clinicopathologic analysis showed that CIP2A expression was significantly correlated with clinical stage and percent of plasma cells in bone marrow. Kaplan Meier analysis revealed that patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. Moreover, CIP2A knockdown in MM cells resulted in attenuated proliferative abilities. In addition, CIP2A depletion sensitizes dexamethasone (Dex)-resistant cells to Dex. The effect of CIP2A on proliferation and Dex therapy was mediated by the inhibition of PP2A, which in turn activated Akt. In vivo studies confirmed that CIP2A regulated MM tumorigenesis and the phosphorylation of Akt. Taken together, our results suggest that CIP2A oncoprotein plays an important role in MM progression and could serve as a prognosis marker and a novel therapeutic target for the treatment of patients with MM. PMID- 29263917 TI - Deubiquitylating Nanog: novel role of USP21 in embryonic stem cell maintenance. AB - Recently, three groups independently identified ubiquitin-specific peptidase 21 (USP21) as an efficient deubiquitylase that reverses Nanog polyubiquitylation and stabilizes Nanog protein. In this preview, I have summarized the work of these three groups. PMID- 29263918 TI - Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer. AB - Antibody-drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv-HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1-DM1 and T SA2-DM1 (drug-to-antibody ratio in the range of 3.2-3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1 DM1 and T-SA2-DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1-DM1. On the basis of the analysis of luminescence imaging, anti HER2 scFv-HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies. PMID- 29263919 TI - Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice. AB - Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration. A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms. Here we discovered the correlation between colon degeneration and altered nicotinamide adenine dinucleotide (NAD) level in aged mice. Compared to 3-month-old young controls, 2-year-old mice showed a spectrum of degenerative colonic phenotypes and exhibited a significant elongated transit time and slowed stool frequency in the context of Lomotil induced slow-transit constipation. Despite upregulated colonic tryptophan hydroxylases expression, serotonin release and expression of colon-predominant type IV serotonin receptor, reduced viability of interstitial cells of Cajal while enhanced aquaporins (Aqp1, 3 and 11) led to a less colonic motility and increased luminal dehydration in aged mice. Notably, this colonic degeneration was accompanied with reduced key NAD+-generating enzyme expression and lowered NAD+/NADH ratio in aged colon. Three-month continuous administration of beta nicotinamide mononucleotide, a NAD+ precursor, elevated colonic NAD+ level and improved defecation in aged mice. In contrast, pharmacological inhibition of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme for NAD+ biosynthesis, induced a reduction in colonic NAD content and impaired gastrointestinal function in young mice. Taken together, these findings suggest the beneficial effect of NAD+ in maintaining colonic homoeostasis and reactivating NAD+ biosynthesis may represent a promising strategy to counteract age-related gastrointestinal degeneration. PMID- 29263920 TI - UV-induced damage to DNA: effect of cytosine methylation on pyrimidine dimerization. AB - Methylation/demethylation of cytosine plays an important role in epigenetic signaling, the reversibility of epigenetic modifications offering important opportunities for targeted therapies. Actually, methylated sites have been correlated with mutational hotspots detected in skin cancers. The present brief review discusses the physicochemical parameters underlying the specific ultraviolet-induced reactivity of methylated cytosine. It focuses on dimerization reactions giving rise to cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone adducts. According to recent studies, four conformational and electronic factors that are affected by cytosine methylation may control these reactions: the red-shift of the absorption spectrum, the lengthening of the excited state lifetime, changes in the sugar puckering modifying the stacking between reactive pyrimidines and an increase in the rigidity of duplexes favoring excitation energy transfer toward methylated pyrimidines. PMID- 29263921 TI - Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis. AB - Brown adipose tissue dissipates energy in the form of heat. Recent studies have shown that adult humans possess both classical brown and beige adipocytes (brown like adipocytes in white adipose tissue, WAT), and stimulating brown and beige adipocyte formation can be a new avenue to treat obesity. Angiotensin II (AngII) is a peptide hormone that plays important roles in energy metabolism via its angiotensin type 1 or type 2 receptors (AT1R and AT2R). Adipose tissue is a major source of AngII and expresses both types of its receptors, implying the autocrine and paracrine role of AngII in regulating adipose functions and self-remodeling. Here, based on the in vitro studies on primary cultures of mouse white adipocytes, we report that, AT2R activation, either by AngII or AT2R agonist (C21), induces white adipocyte browning, by increasing PPARgamma expression, at least in part, via ERK1/2, PI3kinase/Akt and AMPK signaling pathways. It is also found that AngII-AT2R enhances brown adipogenesis. In the in vivo studies on mice, administration of AT1R antagonist (ZD7155) or AT2R agonist (C21) leads to the increase of WAT browning, body temperature and serum adiponectin, as well as the decrease of WAT mass and the serum levels of TNFalpha, triglycerides and free fatty acids. In addition, AT2R-induced browning effect is also observed in human white adipocytes, as evidenced by the increased UCP1 expression and oxygen consumption. Finally, we provide evidence that AT2R plays important roles in hormone T3-induced white adipose browning. This study, for the first time, reveals the browning and brown adipogenic effects of AT2R and suggests a potential therapeutic target to combat obesity and related metabolic disorders. PMID- 29263922 TI - Structural and functional insights into sorting nexin 5/6 interaction with bacterial effector IncE. AB - The endosomal trafficking pathways are essential for many cellular activities. They are also important targets by many intracellular pathogens. Key regulators of the endosomal trafficking include the retromer complex and sorting nexins (SNXs). Chlamydia trachomatis effector protein IncE directly targets the retromer components SNX5 and SNX6 and suppresses retromer-mediated transport, but the exact mechanism has remained unclear. We present the crystal structure of the PX domain of SNX5 in complex with IncE, showing that IncE binds to a highly conserved hydrophobic groove of SNX5. The unique helical hairpin of SNX5/6 is essential for binding, explaining the specificity of SNX5/6 for IncE. The SNX5/6 IncE interaction is required for cellular localization of IncE and its inhibitory function. Mechanistically, IncE inhibits the association of CI-MPR cargo with retromer-containing endosomal subdomains. Our study provides new insights into the regulation of retromer-mediated transport and illustrates the intricate competition between host and pathogens in controlling cellular trafficking. PMID- 29263923 TI - Targeting the CXCR4/CXCL12 axis with the peptide antagonist E5 to inhibit breast tumor progression. AB - Emerging evidence has demonstrated that stromal cell-derived factor 1 (SDF-1) and its cognate receptor CXCR4 have critical roles in tumorigenesis, angiogenesis and metastasis. In this study, we demonstrated the significant inhibitory effects of a novel chemically synthetic peptide (E5) on the CXCR4/CXCL12 axis in breast cancer both in vitro and in vivo. E5 was capable of specifically binding to the murine breast cancer cell line 4T1, remarkably inhibiting CXCL12- or stromal cell (MS-5)-induced migration, and adhesion and sensitizing 4T1 cells to multiple chemotherapeutic drugs. Furthermore, E5 combined with either paclitaxel or cyclophosphamide significantly inhibited tumor growth in a breast cancer model. Mechanistic studies implied that E5 can inhibit the expression of CXCR4 to block the CXCL12-mediated recruitment of endothelial progenitor cells and repress CXCR4 downstream of the Akt and Erk signaling pathway, which are involved in tumor angiogenesis and progression. Further pharmacokinetic evaluation suggested that E5 has an acceptable stability, with a half-life of 10 h in healthy mice. In conclusion, E5 demonstrates a promising anti-tumor effect and could be a potential chemotherapeutic sensitizer to improve current clinical breast cancer therapies. PMID- 29263925 TI - Phosphatase and tensin homologue: a therapeutic target for SMA. AB - Spinal muscular atrophy (SMA) is one of the most common juvenile neurodegenerative diseases, which can be associated with child mortality. SMA is caused by a mutation of ubiquitously expressed gene, Survival Motor Neuron1 (SMN1), leading to reduced SMN protein and the motor neuron death. The disease is incurable and the only therapeutic strategy to follow is to improve the expression of SMN protein levels in motor neurons. Significant numbers of motor neurons in SMA mice and SMA cultures are caspase positive with condensed nuclei, suggesting that these cells are prone to a process of cell death called apoptosis. Searching for other potential molecules or signaling pathways that are neuroprotective for central nervous system (CNS) insults is essential for widening the scope of developmental medicine. PTEN, a Phosphatase and Tensin homologue, is a tumor suppressor, which is widely expressed in CNS. PTEN depletion activates anti-apoptotic factors and it is evident that the pathway plays an important protective role in many neurodegenerative disorders. It functions as a negative regulator of PIP3/AKT pathway and thereby modulates its downstream cellular functions through lipid phosphatase activity. Moreover, previous reports from our group demonstrated that, PTEN depletion using viral vector delivery system in SMN delta7 mice reduces disease pathology, with significant rescue on survival rate and the body weight of the SMA mice. Thus knockdown/depletion/mutation of PTEN and manipulation of PTEN medicated Akt/PKB signaling pathway may represent an important therapeutic strategy to promote motor neuron survival in SMA. PMID- 29263926 TI - Catch and arrest: exploiting the retromer by a Chlamydial effector. PMID- 29263924 TI - Redox regulation in tumor cell epithelial-mesenchymal transition: molecular basis and therapeutic strategy. AB - Epithelial-mesenchymal transition (EMT) is recognized as a driving force of cancer cell metastasis and drug resistance, two leading causes of cancer recurrence and cancer-related death. It is, therefore, logical in cancer therapy to target the EMT switch to prevent such cancer metastasis and recurrence. Previous reports have indicated that growth factors (such as epidermal growth factor and fibroblast growth factor) and cytokines (such as the transforming growth factor beta (TGF-beta) family) are major stimulators of EMT. However, the mechanisms underlying EMT initiation and progression remain unclear. Recently, emerging evidence has suggested that reactive oxygen species (ROS), important cellular secondary messengers involved in diverse biological events in cancer cells, play essential roles in the EMT process in cancer cells by regulating extracellular matrix (ECM) remodeling, cytoskeleton remodeling, cell-cell junctions, and cell mobility. Thus, targeting EMT by manipulating the intracellular redox status may hold promise for cancer therapy. Herein, we will address recent advances in redox biology involved in the EMT process in cancer cells, which will contribute to the development of novel therapeutic strategies by targeting redox-regulated EMT for cancer treatment. PMID- 29263927 TI - Targeting cellular pathways in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is a debilitating disease that is associated with poor prognosis, short median patient survival and a very limited response to therapies. GBM has a very complex pathogenesis that involves mutations and alterations of several key cellular pathways that are involved in cell proliferation, survival, migration and angiogenesis. Therefore, efforts that are directed toward better understanding of GBM pathogenesis are essential to the development of efficient therapies that provide hope and extent patient survival. In this review, we outline the alterations commonly associated with GBM pathogenesis and summarize therapeutic strategies that are aimed at targeting aberrant cellular pathways in GBM. PMID- 29263928 TI - Roles of PFKFB3 in cancer. AB - The understanding of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFK 2/FBPase 3, PFKFB3) has advanced considerably since its initial identification in human macrophages in the mid-1990s. As a vital regulator of glycolysis, accumulating studies have suggested that PFKFB3 is associated with many aspects of cancer, including carcinogenesis, cancer cell proliferation, vessel aggressiveness, drug resistance and tumor microenvironment. In this review, we summarize current knowledge of PFKFB3 regulation by several signal pathways and its function in cancer development in different cell types in cancer tissues. Ubiquitous PFKFB3 has emerged as a potential target for anti-neoplastic therapy. PMID- 29263929 TI - Ageing affects chondroitin sulfates and their synthetic enzymes in the intervertebral disc. AB - The depletion of chondroitin sulfates (CSs) within the intervertebral disc (IVD) during degenerative disc disease (DDD) results in a decrease in tissue hydration, a loss of fluid movement, cell apoptosis, a loss of nerve growth inhibition and ultimately, the loss of disc function. To date, little is known with regards to the structure and content of chondroitin sulfates (CSs) during IVD ageing. The behavior of glycosaminoglycans (GAGs), specifically CSs, as well as xylosyltransferase I (XT-I) and glucuronyltransferase I (GT-I), two key enzymes involved in CS synthesis as a primer of glycosaminoglycan (GAG) chain elongation and GAG synthesis in the nucleus pulposus (NP), respectively, were evaluated in a bovine ageing IVD model. Here, we showed significant changes in the composition of GAGs during the disc ageing process (6-month-old, 2-year-old and 8-year-old IVDs representing the immature to mature skeleton). The CS quantity and composition of annulus fibrosus (AF) and NP were determined. The expression of both XT-I and GT-I was detected using immunohistochemistry. A significant decrease in GAGs was observed during the ageing process. CSs are affected at both the structural and quantitative levels with important changes in sulfation observed upon maturity, which correlated with a decrease in the expression of both XT-I and GT-I. A progressive switch of the sulfation profile was noted in both NP and AF tissues from 6 months to 8 years. These changes give an appreciation of the potential impact of CSs on the disc biology and the development of therapeutic approaches for disc regeneration and repair. PMID- 29263930 TI - STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia. AB - The pathogenesis of chronic lymphocytic leukemia (CLL) is poorly understood and it remains incurable with current therapies. We have previously shown that nanoliposomal C6-ceramide (CNL) is an effective therapy in an in vivo murine model of CLL. However, the key signaling pathways mediating CNL-induced cell death in CLL remains unknown. We hypothesized that CNL targets STAT3, a critical regulator of hematopoietic biology. We observed that CNL treatment reduced phosphorylated STAT3 at both Y705 and S727 residues in CLL cell lines and patient cells. This, in turn, reduced STAT3 transcriptional activity and expression of critical STAT3-dependent survival factors like Mcl-1 and survivin. The effect of CNL on STAT3 was further confirmed ex vivo as shown by reduced STAT3 phosphorylation in xenograft tumors obtained from mice treated with CNL. CNL suppressed STAT3 phosphorylation at Y705 and S727 through reduction in BTK activity and MEK1/2 kinase/PKC activities, respectively. Moreover, a synergistic reduction in CLL cell viability was observed on co-treatment with CNL and the BTK inhibitor, ibrutinib. Expression of an oncogenic form of STAT3 conferred partial resistance to CNL, providing confirmation that STAT3 mediates CNL-induced cell death. Taken together, these findings provide the first body of evidence demonstrating ceramide regulation of STAT3 phosphorylation. These results are also the first to demonstrate an effect of ceramide on BTK, a critical kinase mediating the B-cell receptor signaling in CLL cells and suggest a novel and synergistic combination of CNL and BTK inhibitors for CLL treatment. PMID- 29263931 TI - Long-term safety and efficacy of CART-20 cells in patients with refractory or relapsed B-cell non-Hodgkin lymphoma: 5-years follow-up results of the phase I and IIa trials. PMID- 29263932 TI - The role of TLRs in cervical cancer with HPV infection: a review. AB - The main cause of cervical cancer is persistent infection with high-risk human papilloma virus (HR-HPV), but not all human papilloma virus (HPV) infections lead to cervical cancer. The key factors that determine the outcome of HPV infection remain poorly understood, and how the host immune system protects against HPV infection is unclear. Toll-like receptors (TLRs) are a group of pattern recognition receptors present in the cytoplasm and cell membrane, and can specifically recognize pathogen-associated molecular patterns. As the key molecules of innate and acquired immunity, TLRs not only play important roles in the immune defense against infectious diseases, but also are involved in the occurrence and development of a variety of malignant tumors. In cervical cancer caused by HR-HPV infection, TLRs have been found to regulate the local immune microenvironment. The role of TLRs in HR-HPV infection and HPV-induced cervical cancer and its relationship with HPV vaccine are reviewed in this article. PMID- 29263934 TI - Sympathetic transmitters control thermogenic efficacy of brown adipocytes by modulating mitochondrial complex V. AB - Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure. It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention. However, the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive. Here we demonstrate that norepinephrine (NE) induces low-efficacy thermogenesis, evoking both heterogeneous changes (DeltaPsim and DeltapH) and homogenous responses, one of which is that NE stimulation causes large amounts of ATP consumption in brown adipocytes. We reveal that the proton ATPase activity of mitochondrial complex V is a key factor that antagonizes proton leakage by UCP1 and determines the efficacy of NE-induced thermogenesis in brown adipocytes. Furthermore, to avoid unnecessary and undesired heat production, we reveal that ATP is a necessary sympathetic cotransmitter for the high efficacy and specificity of NE-induced thermogenesis in brown adipocytes as it increases intracellular calcium concentrations and upregulates the ATP synthase activity of complex V. Thus, we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes. These findings imply new strategies to partially or fully utilize the thermogenic capacity of brown adipocytes to identify therapeutic targets for the treatment of obesity and diabetes. PMID- 29263933 TI - Prohibitin: a potential therapeutic target in tyrosine kinase signaling. AB - Prohibitin is a pleiotropic protein that has roles in fundamental cellular processes, such as cellular proliferation and mitochondrial housekeeping, and in cell- or tissue-specific functions, such as adipogenesis and immune cell functions. The different functions of prohibitin are mediated by its cell compartment-specific attributes, which include acting as an adaptor molecule in membrane signaling, a scaffolding protein in mitochondria, and a transcriptional co-regulator in the nucleus. However, the precise relationship between its distinct cellular localization and diverse functions remain largely unknown. Accumulating evidence suggests that the phosphorylation of prohibitin plays a role in a number of cell signaling pathways and in intracellular trafficking. Herein, we discuss the known and potential importance of the site-specific phosphorylation of prohibitin in regulating these features. We will discuss this in the context of new evidence from tissue-specific transgenic mouse models of prohibitin, including a mutant prohibitin lacking a crucial tyrosine phosphorylation site. We conclude with the opinion that prohibitin can be used as a potential target for tyrosine kinase signal transduction-targeting therapy, including in insulin, growth factors, and immune signaling pathways. PMID- 29263935 TI - Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury. AB - Although systemic inflammatory responses attributable to infection may lead to significant lung injury, the precise molecular mechanisms leading to lung damage are poorly understood and therapeutic options remain limited. Here, we show that myeloid monocyte chemotactic protein-inducible protein 1 (MCPIP1) plays a central role in protecting against LPS-induced inflammation and lung injury. Myeloid specific MCPIP1 knockout mice developed spontaneous inflammatory syndromes, but at a late age compared to global MCPIP1 knockout mice. Moreover, mice with a myeloid-specific deletion of MCPIP1 were extremely sensitive to LPS-induced lung injury due to overproduction of proinflammatory cytokines and chemokines. We identified C/EBPbeta and C/EBPdelta, two critical transcriptional factors that drive cytokine production and lung injury, as targets of MCPIP1 RNase. LPS administration caused MCPIP1 protein degradation in the lungs. Pharmacological inhibition of MALT1, a paracaspase that cleaves MCPIP1, by MI-2 selectively increased the MCPIP1 protein levels in macrophages and in the lungs. Meanwhile, administration of MI-2 protected mice from LPS-induced inflammation, lung injury and death. Collectively, these results indicate that myeloid MCPIP1 is central in controlling LPS-induced inflammation and lung injury. Pharmacological inhibition of MALT1 protease activity may be a good strategy to treat inflammatory diseases by enhancing MCPIP1 expression in myeloid cells. PMID- 29263936 TI - RANKL-induced M1 macrophages are involved in bone formation. AB - The activation of M1 macrophages can be achieved by stimulating them with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). However, M1 can be found under physiological conditions without any pathological stimuli. This study aimed to understand the involvement of RANKL-induced M1 macrophages in bone formation compared with pathologically induced macrophages. Fischer rats were used to investigate macrophage distribution in normal and injured femoral condyles in vivo. Bone marrow-derived macrophages (BMDMs) were activated with LPS+IFN-gamma and RANKL to achieve M1 activation in vitro. Gene expression related to inflammation, osteoclastogenesis, angiogenesis, and migration was determined by reverse transcription-quantitative polymerase chain reaction (RT qPCR) and fluorescence-activated cell sorting (FACS). Tissue macrophages showed distinct expression patterns at different bone regions. RANKL was found in close proximity to inducible nitric oxide synthase-positive (iNOS+) cells in vivo, suggesting an association between RANKL expression and iNOS+ cells, especially in trabecular bone. RANKL-induced macrophages showed a different cytokine secretion profile compared with pathologically induced macrophages. Both osteoclasts and M1 macrophages peaked on day 7 during bone healing. RANKL could trigger M1-like macrophages with properties that were different from those of LPS+IFN-gamma induced macrophages. These RANKL-activated M1 macrophages were actively involved in bone formation. PMID- 29263937 TI - Experimental repetitive mild traumatic brain injury induces deficits in trabecular bone microarchitecture and strength in mice. AB - To evaluate the long-term consequence of repetitive mild traumatic brain injury (mTBI) on bone, mTBI was induced in 10-week-old female C57BL/6J mice using a weight drop model, once per day for 4 consecutive days at different drop heights (0.5, 1 and 1.5 m) and the skeletal phenotype was evaluated at different time points after the impact. In vivo micro-CT (MU-CT) analysis of the tibial metaphysis at 2, 8 and 12 weeks after the impact revealed a 5%-32% reduction in trabecular bone mass. Histomorphometric analyses showed a reduced bone formation rate in the secondary spongiosa of 1.5 m impacted mice at 12 weeks post impact. Apparent modulus (bone strength), was reduced by 30% (P<0.05) at the proximal tibial metaphysis in the 1.5 m drop height group at 2 and 8 weeks post impact. Ex vivo MU-CT analysis of the fifth lumbar vertebra revealed a significant reduction in trabecular bone mass at 12 weeks of age in all three drop height groups. Serum levels of osteocalcin were decreased by 22%, 15%, and 19% in the 0.5, 1.0 and 1.5 m drop height groups, respectively, at 2 weeks post impact. Serum IGF-I levels were reduced by 18%-32% in mTBI mice compared to contro1 mice at 2 weeks post impact. Serum osteocalcin and IGF-I levels correlated with trabecular BV/TV (r2 =0.14 and 0.16, P<0.05). In conclusion, repetitive mTBI exerts significant negative effects on the trabecular bone microarchitecture and bone mechanical properties by influencing osteoblast function via reduced endocrine IGF-I actions. PMID- 29263938 TI - Angiogenesis in a 3D model containing adipose tissue stem cells and endothelial cells is mediated by canonical Wnt signaling. AB - Adipose-derived stromal cells (ASCs) have gained great attention in regenerative medicine. Progress in our understanding of adult neovascularization further suggests the potential of ASCs in promoting vascular regeneration, although the specific cues that stimulate their angiogenic behavior remain controversial. In this study, we established a three-dimensional (3D) angiogenesis model by co culturing ASCs and endothelial cells (ECs) in collagen gel and found that ASC-EC instructed angiogenesis was regulated by the canonical Wnt pathway. Furthermore, the angiogenesis that occurred in implants collected after injections of our collagen gel-based 3D angiogenesis model into nude mice was confirmed to be functional and also regulated by the canonical Wnt pathway. Wnt regulation of angiogenesis involving changes in vessel length, vessel density, vessel sprout, and connection numbers occurred in our system. Wnt signaling was then shown to regulate ASC-mediated paracrine signaling during angiogenesis through the nuclear translocation of beta-catenin after its cytoplasmic accumulation in both ASCs and ECs. This translocation enhanced the expression of nuclear co-factor Lef-1 and cyclin D1 and activated the angiogenic transcription of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF), and insulin-like growth factor 1 (IGF-1). The angiogenesis process in the 3D collagen model appeared to follow canonical Wnt signaling, and this model can help us understand the importance of the canonical Wnt pathway in the use of ASCs in vascular regeneration. PMID- 29263939 TI - Tropical forest light regimes in a human-modified landscape. AB - Light is the key energy input for all vegetated systems. Forest light regimes are complex, with the vertical pattern of light within canopies influenced by forest structure. Human disturbances in tropical forests impact forest structure and hence may influence the light environment and thus competitiveness of different trees. In this study, we measured vertical diffuse light profiles along a gradient of anthropogenic disturbance, sampling intact, logged, secondary, and fragmented sites in the biodiversity hot spot of the Atlantic forest, southeast Brazil, using photosynthetically active radiation sensors and a novel approach with estimations of vertical light profiles from hemispherical photographs. Our results show clear differences in vertical light profiles with disturbance: Fragmented forests are characterized by rapid light extinction within their low canopies, while the profiles in logged forests show high heterogeneity and high light in the mid-canopy despite decades of recovery. The secondary forest showed similar light profiles to intact forest, but with a lower canopy height. We also show that in some cases the upper canopy layer and heavy liana infestations can severely limit light penetration. Light extinction with height above the ground and depth below the canopy top was highest in fragmented forest and negatively correlated with canopy height. The novel, inexpensive, and rapid methods described here can be applied to other sites to quantify rarely measured vertical light profiles. PMID- 29263940 TI - Analysis of Temporal Constraints in Qualitative Eligibility Criteria of Cancer Clinical Studies. AB - Clinical studies, especially randomized controlled trials, generate gold-standard medical evidence. However, the lack of population representativeness of clinical studies has hampered their generalizability to the real-world population. Overly restrictive qualitative criteria are often applied to exclude patients. In this work, we develop a lexical-pattern-based tool to structure qualitative eligibility criteria with temporal constraints, with which we analyzed over 10,800 cancer clinical studies. Our results showed that restrictive temporal constraints are often applied on qualitative criteria in cancer studies, limiting the generalizability of their results. PMID- 29263941 TI - Excess Mortality Related to Chikungunya Epidemics in the Context of Co circulation of Other Arboviruses in Brazil. AB - Introduction: Chikungunya is an emerging arbovirus that reached the Western Hemisphere at the end of 2013. Studies in the Indian Ocean and India suggest that passive surveillance systems cannot recognize many of deaths associated with chikungunya, which can be inferred by an increase in the overall mortality observed during chikungunya epidemics. Objective: We assess the mortality associated with chikungunya epidemics in the most affected states in Brazil, from 2015 and 2016. Methods: We studied the monthly mortality by age group, comparing a period without epidemics to a chikungunya epidemic period, which we defined arbitrarily as consecutive months with incidences of more than 50 cases/100,000 persons. Results: We obtained official data from the National System of Reported Diseases (SINAN) and the Mortality Information System (SIM), both maintained by the Ministry of Health. We identified a significant increase in the all-cause mortality rate during chikungunya epidemics, while there was no similar mortality in the previous years, even during dengue epidemics. We estimated an excess of 4,505 deaths in Pernambuco during the chikungunya epidemics (47.9 per 100,000 persons).The most affected age groups were the elderly and those under 1 year of age, and the same pattern occurred in all the states. Discussion: Further studies at other sites are needed to confirm the association between increased mortality and chikungunya epidemics indifferent age groups. If these findings are confirmed, it will be necessary to revise the guidelines to recognize the actual mortality associated with chikungunya and to improve therapeutic approaches and protective measures in the most vulnerable groups. PMID- 29263942 TI - Gorham-Stout Disease Management during Pregnancy. AB - Gorham-Stout Disease (GSD) is a rare lymphatic disorder affecting children or young adults with no predilection of sex. It is generally associated with vanishing bone osteolytic lesions, thoracic and abdominal involvement, and diffuse pulmonary lymphangiomatosis. Chylous effusions and chylothorax, consequent to the abnormal proliferation of lymphatic vessels, may induce respiratory failure with a high mortality risk. Extrapulmonary alterations may include chylous ascites, lymphopenia, and destructing bone disease for overgrowth of lymphatic vessels. Here, we report the case of a young woman who developed a severe and recalcitrant GSD with persistent unilateral chylothorax during pregnancy. The complex management of this patient during and after pregnancy was discussed and compared with literature data to contribute to the definition of a correct diagnostic and therapeutic approach to this rare lymphatic disease. PMID- 29263943 TI - Strategy for Nasal Reconstruction in Atypical Facial Clefts. AB - It is difficult to put forward a strategy for the treatment of nasal clefts due to the rarity and diversity of anatomical aberrations of these cases contrary to the common nasal affection in cleft lip and palate patients, which differ in severity rather than differing in the morbid anatomy. This simple strategy for correction of these nasal clefts will hopefully help surgeons to achieve better results. In the mean time I intended to describe the morbid anatomy of these cases by choosing examples of each morbid anatomy. PMID- 29263944 TI - Synchronous Premaxillary Osteotomy with Primary Cheiloplasty for BCLP Patients with Protrusion of the Premaxillae. AB - Background: In bilateral cleft lip and palate (BCLP) patients with protrusion and/or torsion of the premaxillae, it is difficult to achieve a good outcome. We have developed a series of procedures of premaxillary osteotomy with primary cheiloplasty for BCLP patients who did not respond well to presurgical orthodontics (PSO). Methods: A total of 27 BCLP patients with protrusion and/or torsion of the premaxillae underwent PSO. For 3 BCLP patients in whom the protruded premaxillae could not be returned to a good position, a primary premaxillary osteotomy and gingivoperiosteoplasty (GPP) with cheiloplasty were performed simultaneously. Subsequently, Furlow palatoplasty was performed by one and a half years of age. Maxillary growth was evaluated by dental occlusion at 4 years of age. Results: A premaxillary osteotomy and GPP with cheiloplasty were performed at 6 months. The patients' facial structures improved, their premaxillae were positioned more superiorly, and normal inclination of the incisors was achieved. They had edge-to-edge occlusions or cross bites at 4 years of age. Conclusions: As advantages, the patients' facial structures improved, and the alveolar bones were formed by GPP. As a disadvantage, premaxillary necrosis might occur because of poor blood circulation. It is important to secure the following 2 blood supplies: from the periosteum and soft-tissue of the anterior premaxillae and from the periosteum and mucosa of the nasal septum. Synchronous premaxillary osteotomy and GPP with primary cheiloplasty are appropriate when the premaxillae cannot be properly repositioned by PSO or PSO cannot be done. PMID- 29263945 TI - Combining Follicular Unit Extraction and Scalp Micropigmentation for the Cosmetic Treatment of Alopecias. AB - Two relatively new modalities, follicular unit extraction (FUE) and scalp micropigmentation have changed the treatment of hair loss, to reduce the number of procedures and the total costs of the hair restoration process. These 2 modalities augment each other when treating patients with thinning hair and balding. The explosion of FUE procedures (which reflected 52.6% of the hair transplant procedures performed in 2016, up from 48.5%) and the appearance of more and more new physicians offering hair restoration technologies employing FUE have caused a 20% annual growth in this industry over the past few years. This article reviews the use of FUE and scalp micropigmentation when used in combination. PMID- 29263946 TI - Creation of Nepal's First Skin Bank: Challenges and Outcomes. AB - Background: In Nepal, burn trauma causes more than 55,000 injuries each year. Burn-related mortality is high in Nepal, in part due to lack of allograft, leading to high infection rates. To address this challenge, our collaboration between Kirtipur Hospital, America Nepal Medical Foundation, Stanford University, and ReSurge International established Nepal's first skin bank. Methods: We identified 3 major tasks to create a sustainable skin banking program: 1) identify and acquire the equipment and personnel needed to collect, process, store, and graft cadaveric skin for burn injuries; 2) develop safe donation protocols and documentation tools that remain feasible for low-resource settings; and 3) develop a long-term awareness program to educate the Nepali people on skin donation, a previously foreign concept. Results: Kirtipur Hospital acquired the necessary equipment and materials for the skin bank through a combination of local and international fundraising efforts. Existing U.S. skin banking protocols were adapted for the Nepali setting and piloted on potential patients, donors, and physicians. For the first time in the hospital's history, patients with > 40% total body surface area burns were successfully treated with extensive allografts. Conclusions: It is feasible to create a skin bank in a country with no tradition of allograft skin use. Long-term sustainability now depends on spreading awareness and education in the Kathmandu Valley to overcome religious and cultural barriers that have hindered donor recruitment. Our low-cost and high impact skin bank provides a model to expand this system to other hospitals both within Nepal and beyond. PMID- 29263947 TI - Optimizing Exposure for the Occipital Nerve in Migraine Surgery while Maintaining Hair Length. AB - Surgical decompression of the greater occipital nerve is used in the treatment of migraine headaches. Generally, hair is removed from the posterior scalp to aid with exposure and minimize interference. The securing of occipital hair with surgical tape and rubber bands instead of preoperative hair removal is a viable alternative. The preservation of hair length can lead to better patient satisfaction by avoiding the hair length discrepancies and has demonstrated a low risk of surgical-site infection. PMID- 29263948 TI - Intraoperative Techniques for the Plastic Surgeon to Improve Pain Control in Breast Surgery. AB - In recent years, there has been a growing emphasis placed on reducing length of hospital stay and health costs associated with breast surgery. Adequate pain control is an essential component of enhanced recovery after surgery. Postoperative pain management strategies include use of narcotic analgesia, non narcotic analgesia, and local anesthetics. However, these forms of pain control have relatively brief durations of action and multiple-associated side effects. Intraoperative regional blocks have been effectively utilized in other areas of surgery but have been understudied in breast surgery. The aim of this article was to review various intraoperative techniques for regional anesthesia and local pain control in breast surgery and to highlight areas of future technique development. PMID- 29263949 TI - Dynamic Model of Applied Facial Anatomy with Emphasis on Teaching of Botulinum Toxin A. AB - Background: The use of botulinum toxin type A is considered one of the most revolutionary and promising face rejuvenation methods. Although rare, most of the complications secondary to the use of botulinum toxin A are technician dependent. Among the major shortcomings identified in the toxin administration education is unfamiliarity with applied anatomy. This article proposes the use of body painting as an innovative method of teaching the application of botulinum toxin A. Methods: Using the body painting technique, facial anatomy was represented on the face of a model showing the major muscle groups of botulinum toxin A targets. Photographic records and films were made for documentation of represented muscles at rest and contraction. Results: Using the body painting technique, each of the muscles involved in facial expression and generation of hyperkinetic wrinkles can be faithfully reproduced on the model's face. The documentation of the exact position of the points of application, the distribution of the feature points in the muscular area, the proper angulation and syringe grip, as well as the correlation of the points of application with the presence of hyperkinetic wrinkles, could be properly registered, providing professional training with information of great practical importance, development of highly effective treatments, and low complication rates. Conclusion: By making it possible to interrelate anatomy of a function, body painting is proposed in the present study as an innovative method, which in a demonstrative and highly didactic manner presents great potential as a teaching tool in the application of botulinum toxin A. PMID- 29263950 TI - Open Cancellous Bone Grafting for Recalcitrant Palatal Fistula: Repurposing the Papineau Technique. AB - Cleft palate fistula is defined as a breakdown in the primary surgical repair of the palate resulting in oronasal communication, which can create symptomatic regurgitation for fluids/solids and affect speech, manifested by airflow escape during phonation. With the reported postoperative occurrence rate of 33-37% postfistula repair, it remains a challenging problem. The primary aim of this study was to describe our experience in the management of 7 consecutive cases of recalcitrant palatal fistula, all secondary to primary cleft palate repair. Pure cancellous bone graft was harvested in a standard fashion in sufficient quantity based on size of fistula from the iliac crest and was morselized and was kept mixed with the patient's blood. After flap turnover for nasal closure, the graft was packed over the raw surface on the oral aspect and was secured by placing an oxidized regenerated cellulose sheet fixed to the surrounding mucosa. As per the Papineau technique, no oral closure was performed. Six-month follow-up showed complete epithelization of the oral raw surface in 6 of the 7 patients. In the diverse spectra of cleft surgeries, management of recalcitrant cleft palate fistula remains a surgical challenge. Repurposing Papineau's concept of open cancellous bone grafting in cleft palate fistula is a novel attempt with a sound scientific basis. In our experience, this technique has proved to be very effective in managing recalcitrant palatal fistulae. PMID- 29263951 TI - Vascular Occlusion in a Porcine Flap Model: Effects on Blood Cell Concentration and Oxygenation. AB - Background: Venous congestion in skin flaps is difficult to detect. This study evaluated the ability of tissue viability imaging (TiVi) to measure changes in the concentration of red blood cells (CRBC), oxygenation, and heterogeneity during vascular provocations in a porcine fasciocutaneous flap model. Methods: In 5 pigs, cranial gluteal artery perforator flaps were raised (8 flaps in 5 pigs). The arterial and venous blood flow was monitored with ultrasonic flow probes. CRBC, tissue oxygenation, and heterogeneity in the skin were monitored with TiVi during baseline, 50% and 100% venous occlusion, recovery, 100% arterial occlusion and final recovery, thereby simulating venous and arterial occlusion of a free fasciocutaneous flap. A laser Doppler probe was used as a reference for microvascular perfusion in the flap. Results: During partial and complete venous occlusion, increases in CRBC were seen in different regions of the flap. They were more pronounced in the distal part. During complete arterial occlusion, CRBC decreased in all but the most distal parts of the flap. There were also increases in tissue oxygenation and heterogeneity during venous occlusion. Conclusions: TiVi measures regional changes in CRBC in the skin of the flap during arterial and venous occlusion, as well as an increase in oxygenated hemoglobin during venous occlusion that may be the result of reduced metabolism and impaired delivery of oxygen to the tissue. TiVi may provide a promising method for measuring flap viability because it is hand-held, easy to-use, and provides spatial information on venous congestion. PMID- 29263952 TI - Hemi-Intravascular Stenting for Supermicrosurgical Anastomosis. AB - Background: Although supermicrosurgical anastomosis is a widely known reconstructive microsurgical technique, it is difficult to perform. To expand the clinical use of supermicrosurgery, we used hemi-intravascular stenting (hemi IVaS), which is performed by inserting an intravascular stent into one side of the vessel. We conducted lymphaticovenular anastomosis, free perforator flap transfer, and fingertip replantation with supermicrosurgical anastomosis using hemi-IVaS technique and examined its usefulness. Methods: Between January 2013 and February 2015, 11 anastomoses in 11 cases of lymphaticovenular anastomosis for lymphedema patients, 14 anastomoses in 7 cases of free perforator flap transfer with supermicrosurgical perforator-to-perforator anastomosis, and 9 anastomoses in 5 cases of fingertip replantation were performed using hemi-IVaS. Time required for anastomosis and complications were examined. Flap survival rate was also examined in free perforator flap transfer cases and fingertip replantation cases. Results: In all cases, anastomoses were performed without complications such as inadvertent catching of the back wall of the vessel during the procedure or the need for reanastomoses. The average time required to complete the anastomosis was 16.4 +/- 3.20 minutes using the hemi IVaS technique. All flaps survived in the supermicrosurgical perforator-to-perforator anastomosis as well as fingertip replantation cases. Conclusions: Hemi-IVaS could be a useful alternative to conventional intravascular stenting techniques and is also effective for supermicrosurgical perforator-to-perforator anastomosis. Further studies are needed to improve the success rate and to explore its other possible utilizations in supermicrosurgery. PMID- 29263953 TI - Designing a Fibular Flow-Through Flap with a Proximal Peroneal Perforator-Free Flap for Maxillary Reconstruction. AB - Reconstruction of a composite maxillary defect is frequently performed with a fibular osteocutaneous free flap to address both the bony and mucosal defect. If during the harvest of the fibula a distal skin perforator is not present due to vascular variations, reconstruction can potentially be done using the soleus muscle for filling of the palatal mucosal defect. An additional challenge arises when the accompanying skin paddle that has been harvested is not perfused, but the fibula remains viable. This case report describes salvage following loss of the skin paddle in an osteocutaneous fibular free flap by designing a fibular flow-through flap using a proximal peroneal perforator free flap. The use of this second free flap allows a skin paddle to be positioned on the distal fibular segment, provides a surgical backup, and limits the donor sites to the same extremity. PMID- 29263954 TI - Central Mound Mastopexy for the Correction of Tuberous/Tubular Breast Deformity. AB - Tuberous and tubular breast deformity are well-recognized abnormalities in the plastic surgery community that incur severe physical and psychological consequences in affected patients. Current reconstructive options for the tuberous and tubular breasts favor the use of prosthetic implants and soft-tissue manipulation. We present a case of tuberous and tubular breast deformity treated with a central mound reduction technique and mastopexy with imbricating sutures without the use of prosthetic implants. The patient remained extremely pleased with her results at long-term follow-up. This represents a unique case of successful reconstruction in a patient with a tuberous and tubular breast deformity using a central mound reduction technique with mastopexy and without a prosthetic device. PMID- 29263955 TI - Radix Malorum Cupiditas Est: A Decade Later. PMID- 29263956 TI - Effects of Autologous Fat and ASCs on Swine Hypertrophic Burn Scars: A Multimodal Quantitative Analysis. AB - Background: Hypertrophic scar formation is unpredictable and poorly understood, afflicting both the pediatric and adult populations. Treatment methods with conservative and invasive approaches have low rates of compliance and high rates of morbidity. The purpose of this study was to test a reproducible scar model and investigate a new technique of scar modification through the use of adipose- derived progenitor stromal cells (ASCs). Methods: Twenty thermal deep-partial thickness contact burns were created on the dorsum of three 8-week-old domestic swine and allowed to mature for 10 weeks. Scars were then injected with 2 cc saline, expanded autologous ASCs, or 2 cc fresh lipoaspirate and sampled at 2 week intervals up to 10 weeks postinjection. Volumetric analysis with a 3-D scanner, mechanical elasticity testing through negative pressure transduction, and standardized photography evaluation with Image J was performed. RNA sequencing was performed on scar tissue samples, cultured cells, and fresh lipoaspirate to determine relevant gene transcription regulation. Immunohistochemistry was used to verify expression level changes within the scars. Results: Volumetric analysis demonstrates a reduction in average scar thickness at 6 weeks when injected with ASCs (-1.6 cc3) and autologous fat (-1.95 cc3) relative to controls (-0.121 cc3; P < 0.05). A decrease in overall tissue compliance is observed with fat or ASC injection when compared with unburned skin at 8 weeks (35.99/37.94 versus 49.36 mm Hg * mm; P < 0.01). RNA sequencing demonstrates altered regulation of fibroblast gene expression and a decreased inflammatory profile when scars are injected with autologous fat/ASCs over controls. Conclusion: Early results suggest that autologous fat and/or ASCs may improve healing of hypertrophic scarring by altering the cellular and structural components during wound remodeling up to 20 weeks after injury. This may have beneficial applications in early treatment of large or cosmetically sensitive immature burn scars. PMID- 29263958 TI - Lower Face Rejuvenation with Injections: Botox, Juvederm, and Kybella for Marionette Lines and Jowls. AB - A 55-year-old woman requesting noninvasive rejuvenation of the lower face received multimodal injections in a single office visit to rejuvenate the jowls. The patient experienced no adverse events other than self-limiting bruising at the hyaluronic acid injection site and minimal edema. The outcomes were evaluated as follows: (1) by the patient using the self-rated Face-Q assessment and (2) by 5 plastic surgeons (none of whom were the author of this study) based on the WAS scale and before and after photographs to evaluate the corners of the mouth and the marionette lines. This case study report suggests that the combined use of neuromodulator, hyaluronic acid dermal filler, and synthetic deoxycholic acid can rejuvenate the lower face as a minimally invasive alternative to surgery to the satisfaction of the patient and 6 plastic surgeons (including the author). PMID- 29263957 TI - Genetic Overview of Syndactyly and Polydactyly. AB - Syndactyly and polydactyly-respectively characterized by fused and supernumerary digits-are among the most common congenital limb malformations, with syndactyly presenting at an estimated incidence of 1 in 2,000-3,000 live births and polydactyly at a frequency of 1 in approximately 700-1,000 live births. Despite their relatively regular manifestation in the clinic, the etiologies of syndactyly and polydactyly remain poorly understood because of their phenotypic and genetic diversity. Further, even though concrete knowledge of genotypic links has been established for some variants of syndactyly and polydactyly, there appears to be no single comprehensive published summary of all syndromic and nonsyndromic syndactyly and polydactyly presentations, and there is decidedly no resource that maps all syndromic and nonsyndromic syndactylies and polydactylies to their genetic bases. This gap in the literature problematizes comprehensive carrier screening and prenatal diagnosis and complicates novel diagnostic attempts. This review thus attempts to collect all that is known about the genetic bases of syndromic and nonsyndromic syndactylies and polydactylies, as well as to highlight the dactyly manifestations for which no genetic bases are as yet known. Then, having established a summation of existing and missing knowledge, this work briefly outlines the diagnostic techniques that a genetics reinforced understanding of syndactyly and polydactyly could inform. PMID- 29263959 TI - Superficial Soft-Tissue Sarcomas Rarely Require Advanced Soft-Tissue Reconstruction following Resection. AB - Objective: Soft-tissue sarcomas are most frequently located deep within myofascial compartments. Superficial soft-tissue sarcomas (S-STS) are relatively less common and may be managed differently than deep sarcomas because generous resection margins are often possible without sacrificing critical structures. We sought to investigate the frequency and types of soft-tissue reconstructive procedures that are required following excision of S-STS. Methods: We reviewed 457 consecutively treated patients with S-STS with a minimum 2-year follow-up from our prospectively maintained database between 1989 and 2009. Results: Mean follow-up was 10.5 years (range, 2-23). Four hundred twenty-one tumors (91%) were excised with negative margins, 38 (8.3%) had microscopically positive margins, and three (0.7%) had grossly positive margins. One patient required an amputation. In 271 (58%) patients, the wounds were closed primarily. In comparison, 93 patients (20%) required a rotation flap, 70 (15%) required a split thickness skin graft, and 23 (5%) underwent a free tissue transfer (ie, advanced reconstructive procedure). The overall complication rate was 12%, although 43% of patients undergoing free tissue transfer developed complications (P = 0.04). An unplanned excision before referral to our center was a risk factor for local recurrence (P = 0.03) when residual tumor was recovered in the reexcision specimen pathologically. Conclusions: Although concern about the morbidity associated with a free tissue transfer (ie, advanced reconstructive procedure) may potentially limit the adequacy of resection in some patients with S-STS, the results of this study showed that the majority of patients had complete excisions with negative margins and primary closure. Obtaining a negative margin when excising a known or suspected S-STS rarely requires an advanced reconstructive procedure and almost never results in loss of limb. PMID- 29263960 TI - Make Surgeons' Position More Comfortable. PMID- 29263961 TI - The Fine Wire Technique for Flexor Tenolysis. AB - Background: Flexor tenolysis surgery for flexor digitorum profundus and superficialis adhesions is a common procedure performed by hand surgeons. Releasing these adhered tendons can greatly improve hand function and improve quality of life. Recent evidence, however, has shown that the outcomes of tenolysis surgeries are often suboptimal and can result in relapsing adhesions or even tendon ruptures. Methods: This article describes a new technique with potential for reduced complication rates: The Fine Wire Technique for Flexor Tenolysis (FWT). Results: Following FWT, the patient detailed in this article had an excellent recovery of function and no complications: including tendon rupture, infection, hematomas, or any other complications. She reported a major improvement from her preoperative functionality and continues to have this level of success. The wire's thinness allows for a swift tenolysis. Conclusions: The FWT is a new option available to the hand surgeon associated with good functional results. The wire is readily available to the clinician and is also inexpensive. PMID- 29263962 TI - Vaginoplasty and Perineoplasty. AB - Supplemental Digital Content is available in the text. PMID- 29263963 TI - Liposomal Bupivacaine in Implant-Based Breast Reconstruction. AB - Purpose: This study evaluates the role of liposomal bupivacaine in implant-based breast reconstruction. Methods: A prospective, randomized, single-blind trial of liposomal bupivacaine in implant-based breast reconstruction was performed. Patients in the control arm were treated with 20 mL 0.25% bupivacaine with epinephrine 1:200,000 to each breast pocket. Patients in the experimental arm were treated with 10 mL 1.3% liposomal bupivacaine delivered to each breast pocket. Pain scores were recorded over the course of patients' hospital stay. Consumption of pain medications, benzodiazepines, and anti-emetics was monitored. Length of stay and other direct cost data were collected. Results: Twenty-four patients were enrolled, with 12 women randomized to each arm. Average postoperative pain scores were 3.66 for patients in the control arm and 3.68 for patients in the experimental arm. Opioid consumption was 1.43 morphine equivalent dosing/h for patients in the control arm and 0.76 morphine equivalent dosing/h for patients in the experimental arm (P = 0.017). Diazepam consumption was 0.348 mg/h for patients in the control arm and 0.176 mg/h for patients in the experimental arm (P = 0.011). Average length of hospital stay was 46.7 hours for patients in the control arm and 29.8 hours for patients in the experimental arm (P = 0.035). Average hospital charges were $18,632 for patients in the control arm and $10,828 for patients in the experimental arm (P = 0.039). Conclusions: Liposomal bupivacaine reduces opioid and benzodiazepine consumption, length of stay, and hospital charges. These data support a role for liposomal bupivacaine in implant-based breast reconstruction. PMID- 29263964 TI - Negative-Pressure Wound Therapy for Ludwig's Angina: A Case Series. AB - Negative-pressure wound therapy (NPWT) is a well-established therapeutic approach for various complex wound classes. There is currently limited information on the use of NPWT for the scope of head and neck wounds. However, NPWT has been used successfully in some cases, including malignancy, infection, and trauma. In West Virginia, the incidence of dental-related infections leading to Ludwig's Angina is high due to lack of access to dental care. Our case series describes the application of vacuum-based therapy in conjunction with antibiotic therapy for quick, effective closure of deep tissue infections before definitive complex wound repair via graft and flap reconstructions. Over a period of 3 months, 2 patients with submental infections extending to the lateral neck demonstrated clean, efficient wound closure with NPWT for less than 14 days while hospitalized at West Virginia University Medicine. Outpatient follow-up with these patients demonstrated excellent cosmetic outcomes with minimal contracture or hypertrophy of healing tissue. NPWT promotes wound healing through decreased edema, improved perfusion, and increased granulation of tissue based on our findings. Our series encourages the use of NPWT for initial closure of complex wounds secondary to deep neck infections. PMID- 29263965 TI - Risk Factors for Complications in Expander-Based Breast Reconstruction: Multivariate Analysis in Asian Patients. AB - Background: There have been many studies examining risk factors for complications in expander-based breast reconstruction after mastectomy, and some patient factors have been identified as risk factors. However, most of the previous studies were based on Caucasian patients. Methods: Asian patients who had a tissue expander placed for immediate breast reconstruction between January 2006 and December 2015 (363 patients and 371 expanders) were analyzed retrospectively. Univariate and multivariate analyses were performed to elucidate risk factors for complications. Results: The rate of skin necrosis was significantly higher in nipple-sparing mastectomy than in other types of mastectomies (12 patients among 107 patients, P = 0.001). The weight of the resected specimen was significantly higher in the group with complications than in the group without complications (444 g compared with 363 g, P = 0.027). Other factors (age, body mass index, smoking, expander type, preoperative chemotherapy, axillary dissection) had no significant effect on complications. Multivariate analysis with a logistic regression showed that a large breast (over 500 g) was the only significant risk factor for complications, with an odds ratio of 3.20 and a 95% confidence interval of 1.33-7.54 (P = 0.010). Conclusion: In this series of Asian patients, breast size, rather than body mass index, is the most important predictor for complications in expander-based breast reconstruction. PMID- 29263966 TI - Non-BRCA1/2 Breast Cancer Susceptibility Genes: A New Frontier with Clinical Consequences for Plastic Surgeons. AB - Twenty percent of breast cancer cases may be related to a genetic mutation conferring an increased risk of malignancy. The most common and prominent breast cancer susceptibility genes are BRCA1 and BRCA2, found in nearly 40% of such cases. However, continued interest and investigation of cancer genetics has led to the identification of a myriad of different breast cancer susceptibility genes. Additional genes, each with unique significance and associated characteristics, continue to be recognized. Concurrently, advanced genetic testing, while still controversial, has become more accessible and cost effective. As oncologic and reconstructive advances continue to be made in prophylactic breast reconstructive surgery, patients may present to plastic surgeons with an increasingly more diverse array of genetic diagnoses to discuss breast reconstruction. It is therefore imperative that plastic surgeons be familiar with these breast cancer susceptibility genes and their clinical implications. We, therefore, aim to review the most common non-BRCA1/2 breast cancer susceptibility genetic mutations in an effort to assist plastic surgeons in counseling and managing this unique patient population. Included in this review are syndromic breast cancer susceptibility genes such as TP53, PTEN, CDH1, and STK11, among others. Nonsyndromic breast cancer susceptibility genes herein reviewed include PALB2, CHEK2, and ataxia telangiectasia mutated gene. With this knowledge, plastic surgeons can play a central role in the diagnosis and comprehensive treatment, including successful breast reconstruction, of all patients carrying genetic mutations conferring increased risk for breast malignancies. PMID- 29263967 TI - Use of Indocyanine Green for Sentinel Lymph Node Biopsy: Case Series and Methods Comparison. AB - Introduction: Sentinel lymph node biopsy is indicated for patients with biopsy proven thickness melanoma greater than 1.0 mm. Use of lymphoscintigraphy along with vital blue dyes is the gold standard for identifying sentinel lymph nodes intraoperatively. Indocyanine green (ICG) has recently been used as a method of identifying sentinel lymph nodes. We herein describe a case series of patients who have successfully undergone ICG-assisted sentinel lymph node biopsy for melanoma. We compare 2 imaging systems that are used for ICG-assisted sentinel lymph node biopsy. Methods: Fourteen patients underwent ICG-assisted sentinel lymph node biopsy for melanoma using the SPY Elite system (Novadaq, Mississigua, Canada) and the Hamamatsu PDE-Neo probe system (Mitaka USA, Park City, Utah). We analyzed costs for 2 systems that utilize ICG for sentinel lymph node biopsies. Results: Intraoperative use of ICG for sentinel lymph node biopsies was successful in correctly identifying sentinel lymph nodes. There was no difference between the Hamamatsu PDE-Neo probe and SPY Elite systems in the ability to detect sentinel lymph nodes; however, the former was associated with a lower operating cost and ease of use compared with the latter. Conclusion: ICG-assisted sentinel lymph biopsy using the SPY Elite or the Hamamatsu PDE-Neo probe systems for melanoma are comparable in terms of sentinel node detection. The Neo probe system delivers pertinent clinical data with the advantages of lower cost and ease of operation. PMID- 29263968 TI - Reconstruction of Congenital Sternal Clefts: Surgical Experience and Literature Review. AB - Background: Sternal cleft is a rare anomaly with a reported incidence of 1:100,000 cases per live births. Surgical intervention represents a crucial factor altering the overall patient prognosis, since they are at high risk of impaired oxygenation, as well as multiple chest infections. Herein, we are reporting our experience of surgical management of such rare cases, alerting plastic surgeons to their possibly crucial role in the reconstructive team. Methods: A retrospective chart review of 2 cases presenting with chest wall defects. All perioperative data were collected and presented. Results: Two patients with sternal clefts of variable degrees were managed. The first was an 18-month-old boy with partial inferior sternal cleft, who was otherwise asymptomatic. The patient underwent reconstruction at the same age using autologous rib graft and pectoralis major flaps due to ectopia cordis that was putting the patient at higher risk for cardiac trauma. The second patient was a 3 month-old girl having a V-shaped partial superior cleft with lung herniation. Surgical reconstruction was applied due to difficulty in weaning the patient off of ventilator support. Initially, reconstruction was applied with SurgiMend dermal matrix, but this was complicated by chest retraction and high oxygen requirement. Definitive reconstruction was later applied with allogeneic bone graft and pectoralis major flaps. Conclusions: Meticulous patient assessment and screening for associated anomalies are crucial. Surgical intervention is warranted at an early age. The use of acellular dermal matrix products in the reconstruction is of interest, but should be approached with caution. PMID- 29263969 TI - Stakeholders' Perspectives on Postmastectomy Breast Reconstruction: Recognizing Ways to Improve Shared Decision Making. AB - Background: Postmastectomy breast reconstruction (PMBR) is an elective, preference-sensitive decision made during a stressful, time-pressured period after a cancer diagnosis. Shared decision making (SDM) can improve decision quality about preference-sensitive choices. Stakeholders' perspectives on ways to support PMBR decision-making were explored. Methods: Forty semi-structured interviews with stakeholders (20 postmastectomy patients, 10 PMBR surgeons, 10 PMBR nurses) were conducted. Clinicians were recruited from diverse practices across the United States. Patients were recruited using purposive sampling with varying PMBR experiences, including no reconstruction. The interview guide was based on an implementation research framework. Themes were identified using grounded theory approach, based on frequency and emotive force conveyed. Results: Engagement in SDM was variable. Some patients wanted more information about PMBR from clinicians, particularly about risks. Some clinicians acknowledged highlighting benefits and downplaying risks. Many patients felt pressured to make a choice by their clinicians. Clinicians who successfully engaged patients through decisions often used outside resources to supplement conversations. Conclusions: Patient-clinician trust was critical to high-quality decisions, and many patients expressed decision regret when they were not engaged in PMBR discussions. Patients often perceived a race- or age-related bias in clinician information sharing. Interventions to support SDM may enhance decision quality and reduce decision regret about PMBR, ultimately improving patient-centered care for women with breast cancer. PMID- 29263971 TI - Prospective Analysis Comparing Arthroplasty with HD-Flex versus Trapezial Resection Alone in Basilar Joint Arthritis. PMID- 29263970 TI - Feasibility of Bone Perfusion Evaluation in Cadavers Using Indocyanine Green Fluorescence Angiography. AB - Bone perfusion evaluation methods in cadaver studies have yet to be established. The aim of this report was to introduce and validate the feasibility of indocyanine green (ICG) fluorescence angiography for evaluation of bone perfusion in the femoral medial condyle in cadavers. In 4 fresh nonembalmed cadavers (2 female), the descending genicular artery was dissected and carefully cannulated bilaterally. A 10 mL solution containing 5 mL ICG solution and 5 mL methylene blue solution was injected into the descending genicular artery. After the injection, the medial femoral condyle was cut with an oscillating saw. A photograph was taken of the cut ends of the bone. The cut ends of the bones were observed using a near-infrared camera. Images corresponding to the previously taken photographs of the cut ends were captured for comparative analysis. After injection of methylene blue and ICG, the blue dye could be seen in the periosteum in all specimens, but not inside the cortex or the cancellous region of the bone. When observed with ICG fluorescence angiography, however, the cancellous region was highlighted through small perforators penetrating the periosteum. Perfusion inside the medial femoral condyle in cadavers was confirmed using ICG fluorescence angiography. Our method can be especially beneficial in confirming the bone perfusion of a new bone flap based on a particular artery, both in cadavers as well as in patients, because ICG can be injected into specific arteries. PMID- 29263972 TI - STRATAFIX for Abdominal Wall Repair following Abdominal Flap Harvest. AB - Supplemental Digital Content is available in the text. PMID- 29263973 TI - Minimally Invasive Genioplasty Procedure. AB - In this technical note, we present a new surgical approach for genioplasty in which a minimally invasive procedure is used to perform the chin osteotomy. The main goal was to reduce postoperative functional recovery time and possible complications, especially reduction of lip incompetence, chin ptosis, and muscle dysfunction, by retaining the intactness of the mentalis muscles. PMID- 29263974 TI - Gluteal Black Market Silicone-induced Renal Failure: A Case Report and Literature Review. AB - Very few cases of successful surgical treatment for renal failure due to gluteal silicone injections have been reported in the literature. The silicone toxicity and subsequent renal failure seem to follow repetitive silicone injections and silicone injections in large quantities. This is a case of a 31-year-old woman who developed renal failure after 6 years of gluteal silicone injections who underwent radical resection of bilateral gluteal regions in an attempt to mitigate her impending complete renal failure. A systematic review of the literature was conducted using PubMed database and with assistance from medical library staff to conduct keyword searches for "Silicone," "Renal failure," "Silicone emboli syndrome," "Silicone granuloma," and "Silicone end organ toxicity." The search results were reviewed by the authors and selected based on the relevance to the case report presented. Extensive literature relating to silicone granulomas and their systemic effects supports the use of steroids for immediate treatment and eventual surgical resection for cure of the various silicone-related end-organ toxicities including renal failure. PMID- 29263975 TI - The Boomerang-shaped Pectoralis Major Musculocutaneous Flap for Reconstruction of Circular Defect of Cervical Skin. AB - We report on a patient with a recurrence of oral cancer involving a cervical lymph node. The patient's postexcision cervical skin defect was nearly circular in shape, and the size was about 12 cm in diameter. The defect was successfully reconstructed with a boomerang-shaped pectoralis major musculocutaneous flap whose skin paddle included multiple intercostal perforators of the internal mammary vessels. This flap design is effective for reconstructing an extensive neck skin defect and enables primary closure of the donor site with minimal deformity. PMID- 29263976 TI - Laparoscopic Harvest of the Rectus Abdominis for Perineal Reconstruction. AB - The rectus abdominis is a workhorse flap for perineal reconstruction, in particular after abdominoperineal resection (APR). Laparoscopic and robotic techniques for abdominoperineal surgery are becoming more common. The open harvest of the rectus abdominis negates the advantages of these minimally invasive approaches. (Sentence relating to advantages of laparoscopic rectus deleted here.) We present our early experience with laparoscopic harvest of the rectus muscle for perineal reconstruction. Three laparoscopic unilateral rectus abdominis muscle harvests were performed for perineal reconstruction following minimally invasive colorectal and urological procedures. The 2 patients who underwent APR also had planned external perineal skin reconstruction with local flaps. (Sentence deleted here to shorten abstract.) All rectus muscle harvests were performed laparoscopically. Two were for perineal reconstruction following laparoscopic APR, and 1 was for anterior vaginal wall reconstruction. This was done with 4 ports positioned on the contralateral abdomen. The average laparoscopic harvest time was 60-90 minutes. The rectus muscle remained viable in all cases. One patient developed partial necrosis of a posterior thigh fasciocutaneous flap after cancer recurrence. There were no pelvic abscesses, or abdominal wall hernias. Laparoscopic harvest of the rectus appears to be a cost effective, reliable, and reproducible procedure for perineal with minimal donor site morbidity. Larger clinical studies are needed to further establish the efficacy and advantages of the laparoscopic rectus for perineal reconstruction. PMID- 29263977 TI - Craniofacial Reconstruction by a Cost-Efficient Template-Based Process Using 3D Printing. AB - Craniofacial defects often result in aesthetic and functional deficits, which affect the patient's psyche and wellbeing. Patient-specific implants remain the optimal solution, but their use is limited or impractical due to their high costs. This article describes a fast and cost-efficient workflow of in-house manufactured patient-specific implants for craniofacial reconstruction and cranioplasty. As a proof of concept, we present a case of reconstruction of a craniofacial defect with involvement of the supraorbital rim. The following hybrid manufacturing process combines additive manufacturing with silicone molding and an intraoperative, manual fabrication process. A computer-aided design template is 3D printed from thermoplastics by a fused deposition modeling 3D printer and then silicone molded manually. After sterilization of the patient specific mold, it is used intraoperatively to produce an implant from polymethylmethacrylate. Due to the combination of these 2 straightforward processes, the procedure can be kept very simple, and no advanced equipment is needed, resulting in minimal financial expenses. The whole fabrication of the mold is performed within approximately 2 hours depending on the template's size and volume. This reliable technique is easy to adopt and suitable for every health facility, especially those with limited financial resources in less privileged countries, enabling many more patients to profit from patient-specific treatment. PMID- 29263978 TI - Extending water vapor trend observations over Boulder into the tropopause region: Trend uncertainties and resulting radiative forcing. AB - Thirty years of balloon-borne measurements over Boulder (40 degrees N, 105 degrees W) are used to investigate the water vapor trend in the tropopause region. This analysis extends previously published trends, usually focusing on altitudes greater than 16 km, to lower altitudes. Two new concepts are applied: (1) Trends are presented in a thermal tropopause (TP) relative coordinate system from -2 km below to 10 km above the TP, and (2) sonde profiles are selected according to TP height. Tropical (TP z > 14 km), extratropical (TP z < 12 km), and transitional air mass types (12 km < TP z < 14 km) reveal three different water vapor reservoirs. The analysis based on these concepts reduces the dynamically induced water vapor variability at the TP and principally favors refined water vapor trend studies in the upper troposphere and lower stratosphere. Nonetheless, this study shows how uncertain trends are at altitudes -2 to +4 km around the TP. This uncertainty in turn has an influence on the uncertainty and interpretation of water vapor radiative effects at the TP, which are locally estimated for the 30 year period to be of uncertain sign. The much discussed decrease in water vapor at the beginning of 2001 is not detectable between -2 and 2 km around the TP. On lower stratospheric isentropes, the water vapor change at the beginning of 2001 is more intense for extratropical than for tropical air mass types. This suggests a possible link with changing dynamics above the jet stream such as changes in the shallow branch of the Brewer-Dobson circulation. PMID- 29263979 TI - Hybrid Simulations of Positively and Negatively Charged Pickup Ions and Cyclotron Wave Generation at Europa. AB - In the vicinity of Europa, Galileo observed bursty Alfven-cyclotron wave power at the gyrofrequencies of a number of species including K+, O 2+, Na+, and Cl+, indicating the localized pickup of these species. Additional evidence for the presence of chlorine was the occurrence of both left-hand (LH) and right-hand (RH) polarized transverse wave power near the Cl+ gyrofrequency, thought to be due to the pickup of both Cl+ and the easily formed chlorine anion, Cl-. To test this hypothesis, we use one-dimensional hybrid (kinetic ion, massless fluid electron) simulations for both positive and negative pickup ions and self consistently reproduce the growth of both LH and RH Alfven-cyclotron waves in agreement with linear theory. We show how the simultaneous generation of LH and RH waves can result in nongyrotropic ion distributions and increased wave amplitudes, and how even trace quantities of negative pickup ions are able to generate an observable RH signal. Through comparing simulated and observed wave amplitudes, we are able to place the first constraints on the densities of Chlorine pickup ions in localized regions at Europa. PMID- 29263980 TI - Welcome to the new online renewal of the journal. PMID- 29263981 TI - Asthma-COPD overlap syndrome-Coexistence of chronic obstructive pulmonary disease and asthma in elderly patients and parameters for their differentiation. AB - Japan is an aging society, and the number of elderly patients with asthma and chronic obstructive pulmonary disease (COPD) is consequently increasing, with an estimated incidence of approximately 5 million. In 2014, asthma-COPD overlap syndrome (ACOS) was defined by a joint project of Global Initiative for Asthma (GINA) committee and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee. The main aims of this consensus-based document are to assist clinicians, especially those in primary care or nonpulmonary specialties. In this article, we discussed parameters to differentiate asthma and COPD in elderly patients and showed prevalence, clinical features and treatment of ACOS on the basis of the guidelines of GINA and GOLD. Furthermore, we showed also referral for specialized investigations. PMID- 29263982 TI - Rehabilitative management for aspiration pneumonia in elderly patients. AB - Aspiration pneumonia is a common disease that frequently occurs in elderly patients. Most patients with aspiration pneumonia have swallowing disability and develop hospital-acquired disability. Frequently, patients have difficulty returning home, and they often require long-term hospitalization. Recently, the effectiveness of rehabilitative management including physical, pulmonary, and dysphagia rehabilitation for aspiration pneumonia was reported. Several studies showed that early rehabilitation was associated with reduced mortality and early hospital discharge after aspiration pneumonia. Unnecessary "nil by mouth" directives associated with aspiration pneumonia at hospital admission resulted in adverse effects, including decline in swallowing ability and prolonged treatment duration. Rehabilitative management combined with appropriate nutrition is recommended to improve clinical outcomes, including physical and swallowing function in geriatric patients with aspiration pneumonia. PMID- 29263983 TI - Dietary salt intake and diabetes complications in patients with diabetes: An overview. AB - Dietary salt restriction is an essential constituent of diabetes care in preventing or slowing the development of diabetes complications, and many diabetes management guidelines include recommendations for dietary salt intake. However, descriptions of guidelines for salt intake are sometimes confined to studies of participants without diabetes or small short-term studies of patients with diabetes. However, in response to such situations, recent longitudinal studies of patients with diabetes have reported an association between dietary salt intake and diabetes complications. Thus, this review summarizes important points in the current situation regarding guidelines on salt intake and the latest findings and future issues on dietary salt intake for diabetes care focusing on (i) the current status and issues regarding the leading guidelines for dietary salt intake for diabetes care in various regions worldwide, and (ii) findings on salt intake from recent longitudinal studies of patients with diabetes whose dietary salt intake was restricted. PMID- 29263984 TI - Bath-related deaths: Preventive strategies and suggestions for general physicians. AB - Bath-related deaths occur frequently in Japan, particularly in the elderly population; however, this fact is not sufficiently well known by the public. The advent of a super-aging society will expose general physicians to more cases of fatal and nonfatal bath-related accidents. As many of the victims have one or more lifestyle-related diseases, general physicians will play a more important role in preventing these fatalities in the future. In addition, general physicians may have to perform postmortem examinations in these cases. This review article addresses the latest studies on bath-related deaths from various medical departments, including forensic medicine, emergency medicine, and physiology. We also discuss preventive strategies based on the assumed mechanisms, and because Japan does not have a well-developed system of medical examiners, we also provide suggestions for physicians who will encounter bath related deaths in the future. PMID- 29263985 TI - The significance of infectious disease and microbiota in functional gastrointestinal disorders. AB - The definition of functional gastrointestinal disorders (FGID) used to be disorders that do not manifest into organic abnormalities. However, it was pointed out that chronic GI dysfunctions can develop following bacterial infections such as acute gastroenteritis and viral infections, and some organic changes in the epithelial cell structure, immunocompetent cells, and inflammatory cytokines were revealed. Recent advancements in analytical methods helped discover changes in the intestinal microbiota of patients with FGID. Correlations between the effects on the enteric environment and clinical conditions and symptoms of FGID are drawing increasing attention. PMID- 29263986 TI - A case of fulminant type 1 diabetes masquerading acute pancreatitis. AB - Fulminant type 1 diabetes is a novel and life-threatening subtype of type 1 diabetes characterized by its markedly abrupt onset and hyperglycemia with a relatively low glycated hemoglobin level at the onset. We herein describe a typical case of fulminant type 1 diabetes who presented with abdominal pain and vomiting, and whose laboratory test revealed elevated pancreatic enzymes. He was initially diagnosed with acute pancreatitis, but occult and prolonged hyperglycemia eventually led to a diagnosis of fulminant type 1 diabetes. PMID- 29263987 TI - Temporary unilateral abdominal muscle paralysis due to herpes zoster without typical vesicles or pain. AB - A 45-year-old man was evaluated for right abdominal bulging. Computed tomography showed segmental flaccidity of the right abdominal muscle without an abdominal hernia. Although typical vesicles and pain were absent, we diagnosed herpes zoster (HZ) because of the presence of a few eschars on the affected area without a history of diabetes mellitus. Although transient unilateral abdominal muscle paralysis due to HZ without typical skin vesicles or pain is rare, it is imperative to consider the possibility of HZ and seek skin changes such as eschars in such cases. PMID- 29263988 TI - A unique case of primary effusion lymphoma-like lymphoma showing disappearance and recurrence of the body cavity effusion. AB - Primary effusion lymphoma-like lymphoma (PEL-LL) is a rare B-cell lymphoma that the etiology remains unclear. We describe a case of PEL-LL with a pleuropericardial effusion. Diagnosis required long period of time as it followed a unique progress of disappearance and recurrence of the body cavity effusion. We finally had a diagnosis of B-cell lymphoma by the immunocytochemistry of effusion using the cell block procedure. Authors consider that it is valuable to actively try the cell block procedure at the time of the first drainage for early diagnosis, if the body cavity effusion due to the malignancy is suspected. PMID- 29263989 TI - Pleural effusion from pleuroperitoneal communication. PMID- 29263990 TI - Medicalization: A historical perspective. AB - The spectrum of human condition is bell shaped, and an area around the midpoint has been chosen arbitrarily to define as the norm. Physically and mentally maladaptive outliers have been treated as diseases and fell into the realm of medicine. Many "nondisease" states can creep up into medicine and with time become medicalized through medicalization because of redefining many conditions long considered social or psychological phenomena as disease states. Processes regarded as natural but also maladaptive are now looked at as diseases. Major factors in the evolution of medicalization include wellness obsession, pharmaceutical industry, statistical and research saturation, media, Internet, and litigation. Unnecessary medicalization leads to huge social and financial cost as well as increased anxiety and risk for complication from further workups for incidental or clinically unimportant findings. In this special article, our concrete steps are provided to facilitate demedicalization based on professionalism of physicians. PMID- 29263991 TI - Travel medicine: Part 1-The basics. AB - International travels for tourism and business purposes continue to increase annually, while the global terrorism and the risk of lethal viral infections are currently real concerns. It is important that primary care physicians assess travel risk and adequately prepare the prospective traveler for trips. Appropriate vaccines should be administered and an emergency self-kit recommended. Patient should be educated about safe travel habits and a posttravel follow-up process established. Further, traveling healthcare professionals may be called upon to assist an ill patient at any time during their journey. In these 2 part special articles, we provide a practical brief summary of up-to-date travel medicine basics for primary care physicians. PMID- 29263992 TI - Management of neuropathic pain. AB - Neuropathic pain is intractable pain caused by damage to the nervous system. Recent approval and expansion of the indications of a series of drugs are expected to improve the treatment strategies for neuropathic pain. Here, we present an outline of pain transmission pathways and relevant pharmacological effects, along with points to consider in the use of neuropathic pain medications according to the guidelines of Japan Society of Pain Clinicians. The content of this article is almost similar to my other Japanese article that was published in the Journal of the Japanese Society of Internal Medicine. Although complete recovery from pain may be difficult, pharmacotherapy can relieve pain, thereby improving the patients' quality of life. PMID- 29263994 TI - Vasculitis syndrome-diagnosis and therapy. AB - In patients with connective tissue disease, vascular injury induced by primary or secondary vasculitis syndromes can lead to organ dysfunction due to the loss of nutrient supply from the blood. Such vasculitis syndromes can be refractory to treatment and fatal. The nomenclature and the definition of vasculitis syndromes have recently been revised, and clinical practice guidelines for diseases associated with vasculitis syndrome are evolving. The present review provides an overview of vasculitis syndromes from the viewpoint of diagnosis and treatment. PMID- 29263993 TI - Sleep disorders in the elderly: Diagnosis and management. AB - Compared with younger people, elderly people show age-related sleep changes, including an advanced sleep phase and decreased slow-wave sleep, which result in fragmented sleep and early awakening. Multiple etiologies contribute to insomnia in the elderly, consistent with the observation that elderly people are likely to have comorbid conditions and medications. When elderly individuals complain of insomnia, it is important to assess treatable medical conditions and medication use that may be responsible for the insomnia before the use of hypnotics is initiated. Also, screening for primary sleep disorders, such as sleep apnea syndrome, restless legs syndrome and rapid eye movement sleep behavior disorder, is essential. We review sleep disorders commonly observed in the elderly and describe their diagnosis and management. PMID- 29263995 TI - A young man with multiple joint pains and fever: A case with the importance of accurate history taking. PMID- 29263996 TI - A case of successful concomitant administration of warfarin and uracil tegafur/leucovorin achieved by self-measurement of INR. AB - A woman in her seventies who was started on warfarin after heart valve replacement began outpatient adjuvant chemotherapy with tegafur-uracil/leucovorin for rectal cancer. The patient performed weekly INR self-measurements at a health insurance pharmacy between outpatient visits. Results recorded in her personal medicine notebook were shared between her physician, a hospital pharmacist, and a pharmacy pharmacist. When INR values were outside the therapeutic target range, doses were altered according to the physician's instruction. Our approach enables the fine adjustment of warfarin doses according to changes in INR and contributes to the maintenance of the therapeutic target range and safe and appropriate outpatient chemotherapy. PMID- 29263997 TI - Atypical radiographic manifestation in Pneumocystis jirovecii pneumonia. PMID- 29263998 TI - Chronic unilateral leg swelling caused by iliac vein compression (Cockett's) syndrome in an elderly patient. PMID- 29263999 TI - Erythema multiforme induced by regorafenib. PMID- 29264000 TI - Stocker's line in pterygium. PMID- 29264001 TI - Idiopathic adult ileo-colonic intussusception. PMID- 29264002 TI - Dr. N. L. Gault, Jr. (1920-2008) and History of Medical Education in South Korea and Okinawa. PMID- 29264003 TI - The current state and provisions for elderly patients with asthma. AB - Demographic statistics of Japan indicate that it is moving toward a super-aging society and, accordingly, the ratio of elderly patients with asthma is also increasing. An important point in diagnosing elderly patients with asthma is that the onset of asthma in old age, along with a history of smoking, differentiation, and complications of chronic obstructive pulmonary disease must be considered. Primary care physicians must understand the characteristics of elderly patients when treating them. When conducting inhalation therapy in any asthmatic patient, especially elderly asthmatic patients, it is important to teach the patients proper technique and sustain medication adherence. We believe this effort will lead to an improvement in controlling asthma as well as a decrease in the number of asthma deaths. PMID- 29264004 TI - Cases which were treated by giving grounds to delusion: What is client-centered medical care? AB - Delusion is a subjective belief, which is based on a mistaken judgment without any grounds. We thought the symptoms from the perspective of cognitive science. In the process of discovering the grounds by which delusions occur in patients, by the setting of goals which are not restricted by others, and by enhancing the presence such that new frame construction with integrity can be continuously possible, we report the case that delusion has disappeared and has been cured. When considering what client-centered medical care is, it is necessary to reconsider the mechanism of cognition of patients from the perspective of information fields which occur within relationships, and to support patients so that they can select what they want to do from the standpoint of the goals they seek. PMID- 29264005 TI - Travel medicine: Part 2-Special situations. AB - Travel should be educational, fun, and safe if the appropriate care is rendered by counseling physicians and travelers take an active role in their health. In the second paper of the 2-part special articles, we provide a practical summary of up-to-date travel medicine about special situations for primary care physicians. We focus on in-flight emergencies, pregnancy, and specific precautions for injury and infectious disease as special situations. Physicians are frequently called upon to examine patients with in-flight emergencies, and thus, they should have knowledge and skills for effectively caring patients. Common health problems over the flights include syncope, chest pain, dyspnea, and gastrointestinal symptoms. Cautious and prudent behaviors should be recommended for travelers to prevent injury and infectious disease. Follow-up after the return home optimizes a positive outcome. PMID- 29264006 TI - Mycoplasma pneumoniae infection: Basics. AB - Mycoplasma pneumoniae (Mp) is one of the leading causes of community-acquired pneumonia and can cause a number of extrapulmonary manifestations in the absence of pneumonia. In this regard, primary care physicians should know how to suspect, diagnose, and manage patients with Mp infection. This review gives a general overview of the basic clinical aspects of Mp infection with special reference to pneumonia, which will help further understanding of the disease. PMID- 29264007 TI - Radiotherapy for liver cancer. AB - In recent years, radiotherapy for liver cancer has accomplished much technical progress. The history of radiotherapy for liver cancer shows an endeavor to overcome the problem of how to raise the irradiation dose to lesions while suppressing the unnecessary irradiation dose to normal liver tissue. With the appearance of treatment using X-ray radiotherapy represented by three-dimensional conformal radiotherapy, stereotactic body radiotherapy and particle beam therapy using proton beams and carbon ion beams, radiotherapy has become a safe and effective treatment option for liver cancers. PMID- 29264008 TI - Key diagnostic features of fever of unknown origin: Medical history and physical findings. AB - Background: Fever of unknown origin (FUO) has many possible causes, so detailed history taking and physical examination are required. We identified key diagnostic features of medical history and physical findings for an efficient diagnosis of FUO. Methods: A total of 42 consecutive patients (mean age: 50.6+/ 20.3 years) with classic FUO were retrospectively recruited from January 2010 to March 2012. Key diagnostic features were identified from among diagnostic criteria for underlying diseases, indicators for diagnostic tests, and more useful factors for differential diagnosis. Results: The mean number of abnormal findings per patient was 5.8 from taking the history and 2.0 from performing physical examination. In addition, the mean number of key diagnostic features identified was 0.7 (14.0%) from history taking and 0.6 (35.0%) from physical examination. The most relevant key diagnostic feature was arthritis, followed by cervical lymphadenopathy, dyspnea (with hypoxia), and ocular symptoms. Conclusion: The usefulness of certain features of medical history and physical findings for diagnosing FUO was determined. Focusing on arthritis, cervical lymphadenopathy, dyspnea with hypoxia, and ocular symptoms might improve diagnostic efficiency in patients with FUO. PMID- 29264009 TI - Acute onset collagenous colitis associated with protein-losing enteropathy. AB - Collagenous colitis is a cause of chronic diarrhea. We report an atypical case of collagenous colitis, presenting with an acute onset, and associated with protein losing enteropathy. An 82-year-old woman was admitted with a 1 week history of nausea, appetite loss, and diarrhea. Serum albumin level was low. Protein leakage from the small intestine was found by a Technetium-99m human serum albumin scintigraphy. We diagnosed the patient with collagenous colitis from pathology findings of multiple biopsies taken from the colon. This case implies that collagenous colitis should be considered in acute watery diarrhea, and that it can cause protein-losing enteropathy. PMID- 29264011 TI - Anorexia nervosa complicated with hiatal hernia and superior mesenteric artery syndrome: A case illustrating the risk of inference observation confusion. PMID- 29264010 TI - Can we truly rely on the urinary antigen test for the diagnosis? Legionella case report. AB - It is critical to diagnose and treat Legionella pneumonia (LP) immediately after infection because of the associated high mortality. The urine antigen test (UAT) is often used for the diagnosis of LP; however, it cannot detect the serogroups of all Legionella species. A detained medical history and several clinical findings such as liver enzyme elevation and hyponatremia are useful in diagnosis. Some specific types of Legionella are found in compost. Herein, we report a case of LP in which the patient's medical history and several clinical findings were useful for diagnosis. PMID- 29264012 TI - Investigation on prediction formulae for calculating erythrocyte sedimentation rate. PMID- 29264013 TI - Changing work styles among Japanese healthcare professionals. PMID- 29264014 TI - Rehabilitation nutrition in general and family medicine. AB - Rehabilitation and nutrition are included in general and family medicine. Rehabilitation nutrition care process includes rehabilitation nutrition assessment and diagnostic reasoning, rehabilitation nutrition diagnosis, rehabilitation nutrition goal setting, rehabilitation nutrition intervention, and rehabilitation nutrition monitoring. I expect that many general and family physicians are interested in rehabilitation nutrition, sarcopenia, and sarcopenic dysphagia and prevent iatrogenic sarcopenia. PMID- 29264015 TI - Efficacy of a new microvibration sensation measurement device at detecting diabetic peripheral neuropathy using a newly devised finger method. AB - To investigate the efficacy of the finger method using a new microvibration sensation measurement device in the evaluation of diabetic peripheral neuropathy (DPN). A cross-sectional study of 52 type 2 diabetic outpatients was performed. Patients were evaluated for DPN using American Diabetes Association (ADA) criteria, Michigan Neuropathy Screening Instrument, and the finger method. Patients were classified into probable DPN or non-DPN groups, according to ADA criteria. The finger method measured peripheral neuropathy vibration (PNV) score of index and middle fingers using the new device in three procedures: PNV 1, PNV 4, and PNV 8. PNV scores ranged from 1 to 30 and were compared between the two groups. The PNV scores were significantly higher in the DPN group (P < .01). The PNV scores for right fingers of DPN and non-DPN groups were 10.2 +/- 7.4 and 3.4 +/- 3.3 by PNV 1, 20 +/- 4.9 and 10.7 +/- 5.3 by PNV 4, and 23.2 +/- 4.9 and 14.6 +/- 7.8 by PNV 8. Our data suggest that the finger method performed with the new device is useful in the evaluation of DPN. PMID- 29264016 TI - A case of tracheo-innominate artery fistula successfully treated with endovascular stent of the innominate artery. AB - Tracheo-innominate artery fistula (TIF) is a rare but life-threatening complication of tracheostomy. We describe a 44-year-old man who was admitted for a pressure ulcer infection with a third tracheostomy in place. He showed massive hemoptysis from the TIF, followed by cardiopulmonary arrest. The cuff of the tube was hyperinflated; however, even a slight movement of the tube resulted in recurrent massive hemorrhage. Thus, an endovascular stent graft was placed. Our case shows that sentinel bleeding may be found prior to TIF, and an endovascular repair can be a lifesaving temporizing option, when the hemorrhage was not controlled by hyperinflating the cuff of the tube. PMID- 29264017 TI - A 56-year-old female with celiac artery compression syndrome recovering through dietary changes and weight gain. AB - Celiac artery compression syndrome is a rare condition characterized by extrinsic compression of the celiac artery by the median arcuate ligament, which leads to chronic, recurrent postprandial epigastric pain. Although traditional treatment of this syndrome involves laparotomy to release the median arcuate ligament, here we report on the rare case of a middle-aged woman recovering with no specific treatment through her use of a food diary to change her diet which resulted in gradual weight gain. This suggests that in some cases, a conservative therapy for celiac artery compression syndrome should be tried before choosing surgical intervention. PMID- 29264018 TI - Very rare familial spoon nails (Koilonychia). PMID- 29264019 TI - Superior mesenteric vein thrombosis treated with edoxaban. PMID- 29264020 TI - Esophageal ulcer associated with inappropriately taken doxycycline: A benign mimicker of esophageal cancer. PMID- 29264021 TI - The Littmann sign: An indication of hyperkalemia. PMID- 29264022 TI - A year-round evidence-based medicine-learning course organized by medical students at Ehime University. AB - To resolve the problem that evidence-based medicine (EBM) courses are not sufficiently taught in Japanese medical schools, we organized a year-round EBM learning course. This study was an observational study and was designed to evaluate the participants' understanding of EBM using an original survey. The survey was given three times. In total, 18 students responded to our survey. Of those 18 students, six students answered both the first and the last surveys, and their mean score increased 1.17 of 4.00 (95% CI: 0.72-1.65). These results suggest our course improved students' ability to read clinical articles. PMID- 29264023 TI - Lymphocytopenia exacerbated by lack of sleep caused by heavy workload. PMID- 29264024 TI - The prevalence and relevant factors of hyponatremia under long-term total enteral nutrition: A cross-sectional study. PMID- 29264025 TI - Asthma phenotypes. AB - Currently, categorization based on cluster analysis by objectively grasping the diversity of pathology is being conducted and the diversity of asthma is being categorized as phenotypes. Clinically, there is categorization based on aging and on allergic diathesis which is clinically useful; however, it has not, up to now, come to the point of selection based on phenotype. Subsequently, what is desired is the establishment of phenotype categorization for the purpose of materialization of treatment strategy which corresponds to individual cases. This study elaborates on order-made medicine while considering phenotype. PMID- 29264026 TI - Up-to-date cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) has been first reported more than 10 years ago as a therapy for patients with severe chronic heart failure. The efficacy of CRT has been proven in many studies that it improves not only quality of life but also the prognosis of the patients. Its indication has been expanded for patients with mild heart failure. On the other hand, some patients cannot receive enough benefit through CRT. The position of the left ventricular lead is limited due to the anatomy of coronary sinus branches, pacing threshold of the myocardium, phrenic nerve stimulation, and so on. Also, the right selection of the candidates for CRT is critical to receive the most benefit of this therapy. The target of this review article is to describe the efficacy and the indication of CRT, which can be of any help to enroll more patients with heart failure who are likely to get benefits through CRT. PMID- 29264027 TI - Diagnosis and treatment of macrocytic anemias in adults. AB - Anemia is one of the most common health problems in the primary care setting. Macrocytosis in adults is defined as a red blood cell (RBC) mean corpuscular volume (MCV) >100 femtoliter (fL). Macrocytic anemias are generally classified into megaloblastic or nonmegaloblastic anemia. Megaloblastic anemia is caused by deficiency or impaired utilization of vitamin B12 and/or folate, whereas nonmegaloblastic macrocytic anemia is caused by various diseases such as myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, certain drugs, and by less commonly inherited disorders of DNA synthesis. Macrocytic anemias are treated with cause-specific therapies, and it is crucial to differentiate nonmegaloblastic from megaloblastic anemia. Because MDS and myeloid neoplasms commonly affect the elderly, primary care physicians may encounter more cases of macrocytic anemias in the near future, as the older population increases. When MDS is suspected along with leukocytopenia and/or thrombocytopenia with anemia, a hematology consultation may be appropriate. PMID- 29264028 TI - Reducing the mortality rate of hepatitis and liver cancer in Japan. AB - The Basic Act on Hepatitis Countermeasures issued in 2009 states the comprehensive measures that can be taken against viral hepatitis as well as the responsibility that the national government, local governments, health insurance provides, physicians, and citizens should take in these measures, thereby organically facilitating the construction of a hepatitis management system in Japan. In addition, the Committee for the Clinical Management of Hepatitis has established branches in each prefecture to create a hepatitis management network for public hepatitis screening facilities, primary care physicians, medical institutions specializing in hepatitis, and primary hospitals for cooperative medical care of liver diseases to address regional hepatitis-related issues. PMID- 29264029 TI - The comprehensive role of general physicians is very important in the chronic phase of a disaster area: Beyond and after the Great East Japan Earthquake. AB - The Great East Japan Earthquake was a major earthquake, one of the largest (Magnitude 9.0) in Japan since 1900. 18 997 human lives were lost in the subsequent tsunami around the Sanriku coast of eastern Japan. Ishinomaki City, which was close to the epicenter, is one of the greatest locations that experienced of the greatest loss of human life: 3819 people. The Ishinomaki Red Cross Hospital (IRCH), which is the main trunk hospital of the Ishinomaki medical sphere, moved to a hill away from the Pacific Ocean in order to avoid future tsunami 5 years prior to the Great East Japan Earthquake. IRCH was therefore nearly intact and its functions were maintained after the Great East Japan Earthquake. Other neighboring medical facilities were in a catastrophic state; for emergency, patients were all concentrated at the IRCH, and the medical staff of IRCH became exhausted. In response, the Japanese Red Cross Society collected and transported physicians, nurses, pharmacists, medical engineers, and medical clerks, to IRCH from Red Cross hospitals across the country during the period of April to August 2011. The dispatched medical personnel operated a makeshift clinic on a rotating basis autonomously in the hospital to support the IRCH. In this temporary clinic, the primary and secondary emergency staff conducted the center's general practice. PMID- 29264030 TI - Effective deployment of public-access automated external defibrillators to improve out-of-hospital cardiac arrest outcomes. AB - Out-of-hospital cardiac arrest (OHCA) is a major health concern in Japan and other developed countries with aging populations. Improvements in OHCA outcomes require streamlining the chain of survival. Deployment of public-access automated external defibrillators (PADs) and defibrillation by bystanders is one strategy that may streamline the chain by reducing the time to defibrillation in individuals with shockable rhythms. Although the effectiveness of PAD programs in increasing survival to discharge has been reported, there have been criticisms and concerns about the small population impact, cost-effectiveness, and potential negative impact on those with nonshockable rhythms. This article reviews relevant literature regarding the effectiveness and concerns regarding PAD for OHCA. PMID- 29264031 TI - Fabry disease and its cardiac involvement. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder that results from a deficiency of alpha-galactosidase A activity. This enzymatic defect leads to the progressive accumulation of glycosphingolipids throughout the body and causes multisystemic problems including neurological, ocular, skin, renal, and cardiac manifestations in classical type of FD. The majority of patients with this disease have cardiac involvement that is mainly manifested as left ventricular hypertrophy (LVH). A cardiac variant of FD with late-onset isolated cardiac manifestation has also been recognized. Recent studies have revealed that the prevalence of FD in patients with unexplained LVH is about 1%. Cardiac involvement of FD is associated with significant morbidity and early death due to heart failure or ventricular arrhythmias. As disease-specific enzyme replacement therapy is now available for FD, correct diagnosis is important. PMID- 29264032 TI - Evaluation by the Basic Checklist and the risk of 3 years incident long-term care insurance certification. AB - Background: A rapidly aging society needs effective approaches to support frail older people who have a high risk of requiring long-term care. We investigated the validity of the Basic Checklist (the "Kihon Checklist") as a tool to select candidates for a program to prevent long-term care. Method: A survey with questions from the Basic Checklist was conducted with functionally independent older residents aged >=65 years living in Takasaki City, Japan. Subjects who completed the questionnaire were followed over 3 years for the presence or absence of certification for long-term care requirement. We used multiple logistic regression analysis to calculate the odds ratio (OR) and 95% confidence interval (95%CI) for long-term care requirement certification. Results: A total of 21 325 subjects were analyzed. The odds ratio was the highest when items number one-20 had a total of >=10 checked answers (OR, 2.71; 95%CI, 2.22-3.32). Physical function (OR, 2.29; 95%CI, 2.05-2.55), nutritional condition (OR, 1.85; 95%CI, 1.38-2.48), oral function (OR, 1.40; 95%CI, 1.25-1.57), whether patients were elected as a care prevention program candidate (OR, 1.90; 95%CI, 1.73-2.08), Homebound state (OR, 1.91; 95%CI, 1.55-2.37), the presence of dementia (OR, 1.97; 95%CI, 1.75-2.20), and depression (OR, 1.96; 95%CI, 1.73-2.22) were associated with a higher odds ratio. Conclusion: Individuals who were selected as long-term care prevention program candidates based on the Basic Checklist had a higher risk of requiring long-term care. Older residents who corresponded to 10 or more of the 20 Basic Checklist items are at the highest risk of becoming certified as needing long-term care. PMID- 29264034 TI - General practice departments of university hospitals and certified training programs for general practitioners in Japan: A nationwide questionnaire survey. AB - Background: In the reform of specialist training by Japanese Medical Specialty Board, general practice is expected to be one of 19 core specialties. University departments of general practice can play a central role in training board certified generalists, but whether they are actually preparing to do so is unknown. Method: We sent a questionnaire to 79 universities and requested to forward it to the general practice department. Fifty-six departments of general practice (37 public and 19 private universities) completed the questionnaire (response rate 71%). Results: Fifty-one (91.9%) universities planned to be the base institutes of certified programs. The annual seats per program ranged from 2 to 20 (median 5). In these 51 university-based programs, 33 (64.7%) departments provide the general practice II element. Twenty-eight (54.9%) require the program trainees to belong to the departments (do nyukyoku) and 11 (21.6%) recommend that they do so. Forty-seven (92.2%) programs had affiliated institutions in rural areas. Thirty-nine (76.5%) were willing to accept graduates of regional quota (chiikiwaku). Twenty-nine (56.9%) program directors took into account the obligatory service of regional quota when making the programs. Programs that accept regional quota graduates were more likely to be affiliated with rural institutions (P=.002) and conscious of the obligatory service in making the program than other programs (P<.001). Conclusion: Most of the university departments have their own training programs. Many of them are willing to accept nyukyoku doctors and regional quota graduates. Universities intend to play an important role in graduating generalists and supporting their careers. PMID- 29264033 TI - Comparative study of the correlation between atherosclerosis and osteoporosis in women in Japan and Mongolia. AB - Objective: Associations between vascular calcification and osteoporosis are well documented, yet effects of lifestyle on atherosclerosis and osteoporosis remain unclear. This study evaluated the relationship between atherosclerosis and osteoporosis of people with different lifestyles living on Uku Island in Japan (rice consumption and fishing lifestyle) and in Ulaanbaatar in Mongolia (meat consumption and nomadic lifestyle), and investigated the differences of lifestyles on atherosclerosis and osteoporosis. Methods: Participants were women aged over 50 years who had undergone a previous medical examination for atherosclerosis and osteoporosis (Uku Island, 104, Ulaanbaatar, 71). Lifestyle habits were obtained by questionnaire. Bone mineral density of the right calcaneus was measured using quantitative ultrasound. Brachial-ankle pulse wave velocity was measured as an index of atherosclerosis. Results: There were no significant differences in bone mineral density and brachial-ankle pulse wave velocity between the two groups, even though meat and dairy intake, number of meals skipped, and number of children were significantly greater in participants from Ulaanbaatar compared with Uku Island. Brachial-ankle pulse wave velocity showed significant positive correlations with age, systolic and diastolic blood pressures, and body mass index and a significant negative correlation with bone mineral density for both groups. With step-wise multiple regression analysis, brachial-ankle pulse wave velocity significantly correlated with age and bone mineral density for both populations. Systolic blood pressure significantly correlated with brachial-ankle pulse wave velocity for the Ulaanbaatar group. Conclusions: Despite significant lifestyle differences, similar relationships between atherosclerosis and osteoporosis were observed in women from Uku Island and Ulaanbaatar. Hypertension was a significant contributing factor for atherosclerosis for the Ulaanbaatar group. PMID- 29264036 TI - A suspicious case of cefmetazole-induced hypoprothrombinemia. AB - Cefmetazole occasionally prolongs the prothrombin time. The mechanism is considered to be because of (i) inhibition of vitamin K metabolism, (ii) a lack of vitamin K, and (iii) low vitamin K stores. We report the death of a 93-year old woman who was administered cefmetazole and exhibited a prolonged prothrombin time. When using cefmetazole in elderly patients, PT-INR should be monitored every few days. PMID- 29264035 TI - A periodontal disease care program for patients with type 2 diabetes: A randomized controlled trial. AB - Background: Diabetes and periodontitis are interrelated, and patient education and guidance are important. Therefore, we conducted a periodontitis care program for patients with type 2 diabetes to provide education about diabetes and periodontitis and to promote self-care skills, and we evaluated the effectiveness of this program. Methods: This was a randomized controlled trial. Thirty-eight and 39 adult patients diagnosed with type 2 diabetes were allocated to the intervention and control groups, respectively. The program comprised content that promoted optimal behavior for the improvement of diabetes and periodontitis. Periodontitis status, diabetes status, tumor necrosis factor-alpha levels, self efficacy in relation to periodontitis, and teeth-brushing behaviors were evaluated before and after the intervention program. Results: After the intervention program, the intervention group demonstrated significant improvements in bleeding on probing, which was used to evaluate periodontitis status (F=7.919; P<.01), and in clinic visit (F=11.765; P<.01), brushing teeth (F=21.606; P<.01), and meal (F=10.884; P<.01) scores on the Self-Efficacy Scale for Self-care among Periodontal Disease Patients; patients in the intervention group also exhibited improvements in dental health-related behaviors (F=7.141; P<.01). Conclusions: These results suggest that the intervention program was effective at improving periodontitis, self-efficacy in relation to periodontitis, and dental health-related behaviors in patients with type 2 diabetes. PMID- 29264037 TI - A case of adult-onset periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome in Japan. AB - Adult-onset periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is rare. We report the case of a 23-year-old woman with PFAPA syndrome in Japan. Her symptoms lasted for approximately 5 days in each period regardless of nonsteroidal anti-inflammatory drug or antibiotic treatment. She was diagnosed with PFAPA syndrome based on her periodic self-limiting symptoms and no evidence of other febrile diseases. Following cimetidine therapy, her periodic symptoms diminished. PFAPA syndrome should be considered in patients presenting with periodic fever and upper respiratory symptoms regardless of their age or ethnicity. PMID- 29264038 TI - Metronidazole-induced encephalopathy associated with treatment for liver abscesses. AB - Metronidazole-induced encephalopathy (MIE) is a rare condition in Japan. We report the case of a patient with MIE who presented with abducens paralysis and ataxia without underlying risk factors. A history of metronidazole (MNZ) administration and rapid improvement after MNZ discontinuation are important in making this diagnosis, and characteristic findings of magnetic resonance imaging support the diagnosis. MIE is expected to become common in Japan as the use of MNZ increases because of expanded insurance coverage. Therefore, MIE needs to be recognized as a differential diagnosis of the central nervous symptoms in patients taking MNZ. PMID- 29264039 TI - Spontaneous pneumomediastinum in young women: Comparison between anorexia nervosa and nonanorexic patients. AB - Spontaneous pneumomediastinum is a benign, self-limited condition that mainly affects young people. In this report, we present four cases of this uncommon condition and a review of the current literature. Two cases had no prior significant medical history: one had a history of asthma and the other underwent regular outpatient treatment for anorexia nervosa. The three patients who were not anorexic spontaneously improved within a few days. However, the patient with anorexia nervosa took 2 months to recover. It appears that spontaneous pneumomediastinum is an intractable complication of anorexia nervosa, and the improvement of nutritional status in the patient is essential to manage this condition. PMID- 29264040 TI - Favorable effects of motivational interviewing and support in a patient with schizophrenia and alcohol abuse. AB - A 42-year-old man with schizophrenia was referred to our hospital after 2 weeks of worsening fatigue. His hemoglobin level was 2.8 g/dL owing to folic acid deficiency stemming from alcohol abuse and consumption of unbalanced meals. We induced behavioral changes in the patient by motivational interviewing. We had direct methodical conversations with medical staff involved with the patient as well as his family, and established new social support for him as well as public assistance. These have resulted in the patient maintaining a favorable lifestyle ever since. PMID- 29264041 TI - Isolated astasia caused by a localized infarction in the suprathalamic white matter. AB - A 73-year-old woman with essential hypertension and diabetes mellitus abruptly developed astasia. There were no other neurological abnormalities. Cranial diffusion-weighted magnetic resonance imaging demonstrated a localized infarction in the right-sided suprathalamic white matter. Under antiplatelet agent and rehabilitation, the patient became asymptomatic within 4 days. This is a first reported case of isolated astasia due to a suprathalamic white matter infarction. We speculated that disruption of the connection from the ventrolateral nucleus of the thalamus to the posterior cingulate gyrus and/or supplementary motor area might cause astasia. PMID- 29264042 TI - Intractable otitis media as a diagnostic clue to antineutrophil cytoplasmic antibody-associated vasculitis. AB - Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) presents a variety of manifestations. Two patients with a history of intractable otitis media were diagnosed as having AAV. One was an 87-year-old woman who presented with cough, anorexia, and fever with a one-year and four-month history of otitis media, and the other was a 65-year-old woman with arthritis that appeared after the diagnosis of otitis media. The history of otitis media was a diagnostic clue to AAV in both patients. Diagnosis at the early localized stage is crucial to prevent irreversible status of AAV. Primary care physicians should be aware of the otological manifestation of AAV. PMID- 29264043 TI - Lambert-Eaton myasthenic syndrome with anti-acetylcholine receptor antibody and anterior mediastinal tumor. AB - This report describes the case of a 65-year-old male who complained of muscular weakness of the legs with easy fatigability. Blood and imaging examinations showed positive anti-acetylcholine receptor antibody and an anterior mediastinal tumor (probably a thymic cyst), suggesting the diagnosis of myasthenia gravis (MG). However, neurological and electrophysiological examinations suggested the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). We searched repeatedly for malignant tumors. Small cell lung cancer (SCLC) was found. Chemotherapy reduced the SCLC and improved the patient's clinical symptoms. On the basis of an accurate diagnosis of LEMS, we were able to detect SCLC and administer chemotherapy at an early stage. Anti-P/Q-type voltage-gated calcium channel antibody was negative. In our case, MG and LEMS overlap syndrome in addition to MG should be differentiated. For the differentiation, the strict electrophysiological criteria of LEMS were useful. PMID- 29264044 TI - Nonimmediate allergic reactions induced by Mesna. AB - Mesna (2-mercaptoethane sulfonate Na), a drug that alleviates cyclophosphamide (CYC)-induced hemorrhagic cystitis, is frequently used to treat cancer and collagen diseases. A 33-year-old woman presented with high fever during CYC-based induction therapy for systemic lupus erythematosus. Her final diagnosis was mesna induced drug hypersensitivity. Although mesna is widely used, allergic reactions are rare. This may be because of misdiagnosis as a primary disease flare-up, infection, or CYC-induced hypersensitivity reaction, which are commonly reported. Thus, accurate diagnosis is important for completion of the CYC-based regimen. PMID- 29264045 TI - Silicosis, then microscopic polyangiitis-antineutrophil cytoplasmic antibodies associated vasculitis may be work-related disease in patients with silicosis. AB - A 74-year-old man with silicosis was admitted to the hospital because of prolonged fever. After referral to internal medicine for persistent fever and renal dysfunction, workup revealed antineutrophil cytoplasmic antibodies (ANCA) positivity. He was diagnosed with microscopic polyangiitis (MPA). After treatment with immunosuppressive therapy, his condition improved. Herein, we discuss silica exposure and the risk of ANCA-associated vasculitis (AAV), particularly in terms of work-related diseases. Silica exposure is a notorious risk factor for developing AAV, which is potentially lethal when not identified. When we see a silicosis patient with new-onset prolonged fever and generalized fatigue, AAV should be taken into consideration. This case report provides beneficial information to reliably assess patients at high risk of developing AAV in primary care settings. PMID- 29264046 TI - Multifocal pyomyositis after intra-articular injections. PMID- 29264047 TI - Acute aortic dissection as a cause of shaking chills. PMID- 29264048 TI - A case of the total talus dislocation. PMID- 29264049 TI - Leriche syndrome (Aortoiliac occlusive disease). PMID- 29264050 TI - Skene's duct cyst. PMID- 29264051 TI - Multiple abscesses caused by repetitive intramuscular injections. PMID- 29264052 TI - Motor weakness and sensory disturbance of the shoulder due to a cortical infarction. PMID- 29264053 TI - Perimandibular abscess associated with bisphosphonate-related osteonecrosis of the jaw. PMID- 29264054 TI - Paradoxical high augmentation index in females with diabetes mellitus. AB - The relationship between diabetes mellitus (DM) and augmentation index (AIx) remains unclear. We conducted an observational cross-sectional study. Subjects were patients who underwent coronary angiography. We examined the relationship between high AIx and several factors. The total number of diabetic patients was 144, and median AIx was 0.256. In diabetic patients, the significant relationship between female gender and high AIx (median cut-off value, >=0.256) was found by the multivariate logistic analysis (adjusted odds ratio = 2.888; 95% confidence interval: 1.032-8.081). The significant relationship between female gender and high AIx was found in patients with DM. PMID- 29264055 TI - An introduction for the treatment and educational strategy of medically unexplained symptoms in Denmark. PMID- 29264056 TI - Educational environment and the improvement in the General Medicine In-training Examination score. PMID- 29264057 TI - Asthma phenotypes: An important step for tailor-made therapy. PMID- 29264058 TI - Typhoid fever: A rare cause of relative bradycardia in Japan. PMID- 29264059 TI - A novel approach of understanding prediction models: TRIPOD framework. PMID- 29264060 TI - Diabetes prevention in the real world: Insights from the JDPP and J-DOIT1. AB - Type 2 diabetes (T2D) is associated with increased risks of morbidity and mortality. Diabetes prevention is an urgent issue in Japan. The Finnish Diabetes Prevention Study and US Diabetes Prevention Program revealed that intensive lifestyle intervention can prevent or delay the development of T2D in high-risk populations. Translational research varies in hospitals, primary care, communities, the workplace, and other settings. Translational research is feasible but less effective. There have been no long-term follow-ups. The outcome of the studies was mainly weight changes. The Japan Diabetes Prevention Program (JDPP) is a trial to test the efficacy of a lifestyle intervention program, which carried out in a primary healthcare setting using existing resources. The Japan Diabetes Outcome Trial-1 (J-DOIT1) is a nationwide telephone-delivered lifestyle intervention in a real-world setting. This review will focus on the effectiveness of a diabetes prevention program (recruitment, target population, method of intervention, and evaluation) in the real world and insights from the JDPP and J DOIT1. PMID- 29264061 TI - Aspirin for primary stroke prevention in elderly patients with vascular risk factors. AB - The effect of aspirin in primary stroke prevention is controversial in Western population, and no evidence is available in Asian population. We performed stroke subanalysis of the Japanese Primary Prevention Project (JPPP), which was a randomized controlled trial of aspirin vs no aspirin for primary prevention of vascular events in 14 464 patients aged over 60 years with hypertension, diabetes, and/or dyslipidemia. We evaluated the effects of aspirin on the risk of stroke and intracranial hemorrhage. Aspirin did not show any net benefit for primary stroke prevention during median follow-up for 5 years, because nonsignificant reduction in ischemic stroke was offset by nonsignificant increase in hemorrhagic stroke. Aspirin is not recommended for primary stroke prevention in elderly Japanese patients with vascular risk factors in general. Asymptomatic large artery atherosclerosis appears to be a new target for primary prevention of stroke. PMID- 29264062 TI - Reasons for the preference of clinic visits to self-medication by common cold patients in Japan. AB - Background: Many Japanese visit medical institutions for common cold treatment, which can cause congestion in these institutions and an increase in medical expenses, although the common cold can be treated sufficiently through self medication. Therefore, to elucidate the reasons individuals with common colds do not use over-the-counter (OTC) medication, we conducted an investigation using a self-administered inquiry sheet to determine reasons for clinic visits and for the avoidance of OTC medication. Methods: The study was of patients with self diagnosed common cold symptoms using an anonymous self-report questionnaire. Results: Of the 471 patients administered the questionnaire, 442 responded. The analysis was focused on the 37 patients who responded that they had considered using OTC medication before coming to the clinic but decided against it and came to the clinic instead. The majority responded positively saying that they felt reassured when seen by a physician (91.9%) and that their common cold was cured more rapidly (89.2%). Conclusions: It can be presumed that many patients with common colds visit medical institutions because they feel reassured and feel that their symptoms improve at a quicker rate. The findings of this study indicated that there is a need for accurate information and relief from anxiety for patients regarding the common cold. PMID- 29264063 TI - Cluster analysis of pharmacists' work attitudes. AB - Background: Few studies in Japan use clustering to examine the work attitudes of pharmacists. This study conducts an exploratory analysis to classify those attitudes based on previous studies to help staff pharmacists and their management to understand their mutually beneficial requirements. Methods: Survey data collected in previous studies from 1 228 community pharmacists and 419 hospital pharmacists were analyzed using Quantification Theory 3 and clustering. Results: Among community pharmacists, two clusters, namely 30- to 34-year-old married males and married males aged over 35 years, reported the highest job satisfaction, intending to remain in their jobs for 5 years or more or until retirement. Conversely, one cluster of 35- to 39-year-old single females reported the lowest job satisfaction and intended to remain for less than 5 years or were undecided. Among hospital pharmacists, one cluster of 22- to 25-year-old single males reported the highest job satisfaction and intended to remain for more than 5 years. Conversely, one cluster of 30- to 34-year-old married males reported the lowest job satisfaction and a period of working undetermined. Conclusions: This study used clustering to explore how pharmacists of different ages, marital statuses, and experience felt regarding their work. Job satisfaction and human relationships are significant in considering future work plans of practicing pharmacists. Pharmacy staff, supervisors, and managers of community or hospital pharmacies must recognize features of pharmacists' work attitudes for offering high-quality service to patients. PMID- 29264064 TI - Evaluating effectiveness of infection control efforts in hospitals using information in microbiological laboratory databases. AB - Purpose: To analyze the quality of infection control activities, bacteriological data relevant to infection control was evaluated through the microbiological data warehouse networking hospitals in two medical regions. Methods: Data regarding bacterial test results of 19 hospitals were extracted from two microbiological laboratory information data bases. The rate of MRSA among total S. aureus was used as a general indicator of infection control activities. The occupancy rate of nasal or pharyngeal swabs among MRSA-positive bacteriological samples was used as an indicator of attention paid for infection control in intensive care wards. The number of blood culture sets per examined patient was utilized as an indicator for life-long vocational education on updated medical practice relevant to infectious diseases. Results: The rate of MRSA was significantly higher in secondary private hospitals. The occupancy rate of nasal or pharyngeal swabs was significantly higher in tertiary hospitals. The average number of blood culture set per examined patient were 1.55, 1.54 and 1.39 in tertiary, secondary public and secondary private hospitals, respectively; however, there were no statistical differences between groups. Conclusions: Data bases of microbiological test results shared by hospital laboratories are useful for evaluating regional infection control activities. PMID- 29264065 TI - The association between insulin resistance, metabolic syndrome, and ischemic heart disease among Rumoi residents. AB - Background: It has widely been proven that metabolic syndrome (MetS) increases the risk of ischemic heart disease (IHD). MetS is confirmed based upon insulin resistance (IR). Our aim of this study is to evaluate the role of MetS and IR in the prediction of IHD incidence. Methods: A total of 404 non-diabetic participants who underwent 75 g oral glucose tolerance test (75 g OGTT) were enrolled from 2001 to 2009. Risk factors for IHD were measured as well. The homeostatic index of IR (HOMA-IR) and the homeostatic model assessment beta cell function (HOMA-beta) were calculated according to the homeostasis model assessment. Cox proportional-hazard regression model was used to estimate hazard ratio (HR). All data were analyzed using SPSS 21 software (IBM, Armonk, NY, USA). Results: In our study, the average follow-up period was 6.7 years. Eighteen subjects of IHD incidence were recorded. After adjusting for age and sex, subjects with IR or hyperinsulinemia had a high risk of IHD, the hazard ratio (95% confidence intervals) for IHD were 4.58 (1.59-13.15), 4.25 (1.64-11.91), respectively. The highest hazard ratio was 7.56 (2.27-25.18) which was found among the subjects with both IR and hyperinsulinemia. In addition, the hazard ratio (95% confidence intervals) of subjects with MetS was 2.80(1.10-7.09). Conclusions: IR and hyperinsulinemia are related to the risk of IHD. IR combined with hyperinsulinemia may be superior to MetS for predicting the IHD incidence. PMID- 29264066 TI - Malnutrition among vaccinated children aged 0-5 years in Batouri, Republic of Cameroon. AB - Objectives: Malnutrition continues to contribute to a high infant mortality rate. This study aimed to determine the prevalence of malnutrition and its potential association with the time at which complementary feeding was introduced among children aged 0-5 years in Batouri, Republic of Cameroon. Methods: Mothers (n=212) were interviewed using a structured questionnaire. Child height or length, and weight measurements were determined and the appropriate Z-scores calculated. Multiple regression analysis was performed with the values of all nutritional status indicators as dependent variables and the time of commencing complementary feeding, and the child's age and sex, as independent variables. Results: The prevalence of stunting (height/length for age<-2 standard deviation [SD]), underweight (weight for age<-2SD), and wasting (weight for height/length< 2SD) was 45.8%, 30.2%, and 11.3%, respectively. Even taking into consideration the biological variables, there was a significant association in the effects of time of starting complementary foods on the nutritional status indicators. Furthermore, adding socio-economic variables did not produce a rise in adjusted R2 values for all age group models concerned. Conclusions: Approximately 30% of the children in the study region were underweight, and approximately half of the children exhibited stunting, indicating chronic malnutrition. Commencing complementary feeding at an appropriate time had a positive effect on nutritional status from approximately 2 years of age. PMID- 29264067 TI - Personal characteristics associated with individual degree of family function in residents of Rumoi City, Hokkaido. AB - Background: We assessed the association of personal factors with Family APGAR not only among the subjects in nonsingle households, but also in single households. Methods: We randomly chose 1 000 persons aged from 50 to 89 years in Rumoi City of the west area of Hokkaido as study candidates, and 493 subjects responded to the survey. We compared the group of high Family APGAR (FA) score of more than or equal to seven with the group of low FA score of less than or equal to 6 with regard to health-related QOL (HRQOL), measured with SF-8, Index of Social interaction (ISI), and other personal characteristics. Being in the low FA group indicates living with a status of poor family function. Results: As a result of the multivariate logistic regression model, living in single households, currently smoking, a low score of mental component summary (MCS) in HRQOL, and a low score of lSI were all significantly associated with being in the low FA group. A low score of MCS was significantly associated with being in the low FA group both in the stratum of nonsingle households, and in the stratum of single households. Conclusions: There were three risk factors of low FA. The first is a single household, second is currently smoking in a nonsingle household, and the third is low ISI. Worse mental status is found to be associated with low FA among the subjects not only in nonsingle households, but also in single households. PMID- 29264068 TI - Japanese citizens' attitude toward end-of-life care and advance directives: A qualitative study for members of medical cooperatives. AB - Background: Japanese citizens are interested in choosing their own end-of-life care, but few have created their own advance directive. This study examined changes among Japanese citizens' attitudes toward end-of-life care and advance directives and explored factors that affected these attitudes. Methods: We conducted five focus groups with 48 participants in 2009 and 2010. All participants were members of health cooperatives in Tokyo. Results: We identified many barriers and reasons for creating and writing down advance directives. Experience caring for dying people and having a serious disease affected attitudes toward advance directives. Some participants changed their attitude toward end-of-life care by writing their own advance directive. Conclusions: When someone is writing advance directives, asking about his/her past experience of caring may be helpful. And learning about or filling out advance directives may help to break down resistance to using these documents. PMID- 29264069 TI - Current usage and effectiveness of influenza medications and factors regarding the time taken to alleviate fever based on postcard questionnaire survey. AB - Background: After the A/H1N1 influenza pandemic in 2009, two new drugs against the influenza virus, laninamivir and peramivir, were released in 2010 in Japan. We investigated the current usage and effectiveness of influenza medications and factors related to the time taken to alleviate fever. Methods: Patients diagnosed with influenza during the 2012-2013 season in Osaka Prefecture answered a postcard questionnaire that collected data regarding their demographic characteristics, flu vaccination status, symptoms, prescribed drugs, and drug related adverse events. Results: The use of laninamivir consistently increased over the 3-year period and was prescribed at a similar rate as oseltamivir during the last year (39% and 45%, respectively). None of the neuraminidase inhibitors had a significant effect on the fever or other symptoms of influenza infection (P=.59 and P=.70, respectively). Vaccinated influenza patients experienced fever for a significantly longer duration than the nonvaccinated patients (P=.04). However, multivariate analysis showed that only influenza virus type, but not vaccination status, was related to the alleviation of fever within 2 days. Conclusions: There were no significant differences of effects on fever and symptoms among neuraminidase inhibitors. Virus type was only related to the alleviation of fever. PMID- 29264070 TI - Behavioral change of pharmacists by online evidence-based medicine-style education programs. AB - Background: Although e-learning evidence-based medicine (EBM) courses have proven useful in improving the knowledge and skills of residents, it was still unclear for pharmacists in non-English-speaking countries. Thus, we investigated the behavioral change of Japanese pharmacists who participated in an EBM-style e learning educational program available online. Methods: This EBM-style e-learning program, the Japanese Journal Club for Clinical Pharmacists, was operated by three pharmacists through Skype. It comprised an online questionnaire administered to the program viewers. Two frequencies, the opportunity to be aware of EBM practices and that of reading an article, were compared before and after viewing the broadcast. Frequencies were classified into five categories: "almost every day," "1-2 times a week," "1-2 times a month," "1-2 times a year," and "not at all." The changes before and after viewing the broadcast were evaluated using a Wilcoxon signed-rank test. Results: The announcement of the questionnaire survey on the web was conducted during the journal club on August 24 and September 7, 2014. The maximum number of simultaneous audiences at the time was 113 persons. Among them, we analyzed data from 36 people who answered the questionnaire. Among these, "1-2 times a week" and "almost every day" were increased, whereas "not at all" was greatly reduced. Indeed, a significant difference was observed in overall change of each frequency before and after viewing the broadcast (P<.001). Conclusion: EBM-style learning programs may play an important role in the postgraduate clinical education of pharmacists. PMID- 29264071 TI - Risk factors for detection failures of chest radiography in diagnosing pneumonia. AB - Background: Little is known about clinical factors associated with undetectable pneumonic shadows on chest radiographs (CRs) for diagnosing pneumonia in the primary care setting. Methods: A retrospective assessment of CRs was conducted to compare chest computed tomography (CT) images of patients admitted to Kesennuma City Motoyoshi Municipal Hospital who were diagnosed with pneumonia from April 2014 to June 2016. Results: Eighty-three patients were included, and their average age was 83.8 years. Sixty-eight patients (81.9%) were officially certified as requiring long-term care or support. Twenty-nine of the 83 patients (34.9%) had either negative or normal findings on CRs, and positive findings consistent with pneumonia on CT. There were no significant differences in gender, age, cardiothoracic ratio on CR, or severity between the CR-negative and CR positive groups. The proportion of negative CRs was significantly higher in patients with certified care level 5 under the long-term care system in Japan and tube feeding. Conclusion: The failure rate of CRs for detecting pneumonic shadows was significantly higher in patients with certified care level 5 and tube feeding. PMID- 29264072 TI - Validity of medical history taken by pharmacists using a medical history taking tool. AB - Background: The progress in aging and the shortage of physicians is a significant problem in Japan. Hence, healthcare professionals including pharmacists should cooperate to provide medical services with limited resources. However, pharmacists might have inadequate skills in taking medical histories. Therefore, we developed an interview tool to collect accurate medical history. In this study, we aimed to validate the contents of medical histories taken by a pharmacist using the interview tool and investigate physician consultation length. Methods: Setting intervention days alternately, adult outpatients of the Kitaibaraki Center for Family Medicine who had new symptoms had their medical histories taken by one of two pharmacists before their physician visit during the study period. The contents of the medical history taken by a pharmacist using text analysis were validated on other four days. All sentences collected by a pharmacist or five physicians were divided into segments, and six other physicians assessed each segment. Differences in length of the physician consultation between those with and without (intervention and control groups, respectively) medical history taken by a pharmacist were investigated. Results: Of 23 patients' medical histories taken by a pharmacist using the interview tool, 84.4% of segments were related to the clinical diagnosis. The mean consultation length was 10.1+/-8.4 minutes in the intervention group (n=104) and 13.0+/-10.4 minutes in the control group (n=96) (p=0.048). Conclusions: Medical histories taken by a pharmacist using the interview tool had high content validity and might reduce physician consultation length. PMID- 29264073 TI - A case of suspected MPO-ANCA-related hypertrophic pachymeningitis with atypical presentation. AB - A 66-year-old man presented to our emergency department with acute consciousness disorder, headache, and fever. Initial laboratory data indicated a high level of inflammatory reaction. Enhanced magnetic resonance imaging revealed a thickening of the right cranial dura mater on T1-weighted images. We presumed the patient was diagnosed as having myeloperoxidase antineutrophil cytoplasmic antibody (MPO ANCA)-related hypertrophic pachymeningitis (HP). Acute impaired consciousness without focal signs is an unusual presentation of HP. This treatable disease should be considered as a differential diagnosis when a patient presents with drowsiness and headache. PMID- 29264074 TI - Early-stage diffuse panbronchiolitis in a young patient confirmed by video assisted lung biopsy: A case report. AB - A 29-year-old man presented with sputum and cough, which were pointed out by his neighbors. A high-resolution chest computed tomography scan showed well-defined multiple centrilobular nodules and a tree-in-bud pattern. Chest auscultation revealed coarse crackles. He did not report any nasal sinus symptoms. We subsequently performed a video-assisted lung biopsy; the specimen confirmed diffuse panbronchiolitis. Subsequently, sinusitis was confirmed by an otolaryngologist. His symptoms gradually improved following treatment with erythromycin. We report a case of early-stage diffuse panbronchiolitis in a young patient, with multiple intralobular nodules, no bronchiectasis, and a good clinical course. PMID- 29264075 TI - A pediatric case of imported dengue hemorrhagic fever in Japan. AB - We report a case of imported dengue hemorrhagic fever (DHF) in a 10-year-old Philippine boy. The patient was admitted to the hospital with a 4-day history of high fever, headache, and malaise, and a 2-day history of epistaxis and hematemesis. Symptoms deteriorated after admission, and the patient was subsequently diagnosed with DHF. DHF occurs more frequently among cases of reinfection than among cases of primary infection. Therefore, physicians should recognize the difference in the risk of developing DHF between patients in endemic and nonendemic areas. PMID- 29264076 TI - Pulmonary metastasis from uterine leiomyosarcoma in a patient with limited cutaneous systemic scleroderma. AB - A 51-year-old woman, who was diagnosed as having limited cutaneous systemic scleroderma, presented with pulmonary nodules incidentally detected in a chest radiograph. The patient had surgical biopsy of the nodules. In microscopic examination of the specimens, proliferation, mitotic activity, and cellular anaplasia of spindle cells were present. Fluorodeoxyglucose-positron emission tomography showed tumors in lungs as well as uterus. The diagnosis of the tumor was pulmonary metastases from uterine leiomyosarcoma. We should be on alert the possibility of developing malignant disease in patient with this autoimmune disease. If it is certain that there is metastasis, we believe that therapy for the primary lesion will be preceded by biopsy and surgery for the metastatic lesions. PMID- 29264077 TI - Milk pancreatitis with hypertriglyceridemia and diabetic ketoacidosis. AB - Excessive milk intake may lead to diabetic ketoacidosis and acute pancreatitis. A 55-year-old milk salesperson with diabetes and dyslipidemia presented with a 5 day history of fatigue and thirst. The patient had drunk a large amount of milk for 2 months prior to the admission. Laboratory data showed metabolic acidosis, hyperglycemia, ketonuria, hypertriglyceridemia, and elevated serum amylase. Abdominal CT with contrast material revealed the swelling of the pancreas. The patient received medical treatment for diabetic ketoacidosis and acute pancreatitis and was discharged uneventfully on day 18. Dietary advice for diabetics should include the avoidance of excessive amount of milk. PMID- 29264078 TI - Disseminated Mycobacterium intracellulare infection with multiple abscesses on extremities in a woman with chronic corticosteroid therapy. AB - A 78-year-old Japanese woman with rheumatoid arthritis was admitted to our hospital due to fever. She had been prescribed prednisolone and bucillamine. Computed tomography revealed abscesses on extremities. M. intracellulare was cultured from her calcaneus osteomyelitis, and this result pointed to a disseminated mycobacterial infection. We drained the abscesses and found M. intracellulare. We started antimycobacterial agents, but the patient died finally. Disseminated mycobacterial infection is rare but critical, and the possibility of such an infection in an immunocompromised patient should be a prime consideration when choosing appropriate drugs and surgical approaches. PMID- 29264079 TI - Do you know otitis media with ANCA-Associated Vasculitis (OMAAV)? AB - Hearing loss is often the only symptom of OMAAV at initial presentation, thus making early diagnosis difficult. We present OMAAV in a 70-year-old woman with hearing loss and dry cough. Otoscopy showed otitis media with effusion. Audiometry showed mixed hearing loss, especially in the right ear. Serum myeloperoxidase antineutrophil cytoplasmic antibody was positive. Image analyses showed lung lesion and interstitial pneumonia, while bronchoscopy showed possible microscopic polyangiitis. After starting and tapering prednisolone, respiratory and otologic symptoms improved. When examining patients with acute otologic symptoms and suspected lung and/or renal disease, OMAAV should be included in differential diagnosis. PMID- 29264080 TI - Exercise-induced acute renal failure in a trainee cyclist without hypouricemia: Successful athletic career post-treatment. AB - Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE) is exercise-induced acute renal failure that occurs without myoglobinuria. We describe a typical case involving an 18-year-old man. Generally, patients with ALPE are advised to avoid anaerobic exercise due to risk of recurrence, but our patient continued and went on to become a professional cyclist without relapse. About 51% of ALPE cases involve patients with renal hypouricemia. His serum uric acid levels were rather high, at 6.4 mg/dL. He is the first patient with ALPE to succeed as a professional athlete in an anaerobic sport. PMID- 29264081 TI - Irreversible metronidazole encephalopathy in an elderly woman with primary biliary cholangitis. AB - An 82-year-old woman with primary biliary cholangitis was diagnosed with an irreversible neurological disorder, caused by metronidazole (MNZ)-induced encephalopathy. Although the disorder is a reversible pathological condition, in rare cases, it can cause serious sequelae or could even be fatal. Therefore, medications should be administered carefully, particularly in patients who require long-term administration of large doses or those with liver dysfunction. PMID- 29264082 TI - A case of neurosyphilis accompanied by deterioration of type 2 diabetes management. AB - A 66-year-old man was admitted with visual impairment, functional disability, and worsening glycemic control. On admission, he had optic atrophy without diabetic retinopathy in both eyes, sensory impairment of the lower extremities, ataxia, and cognitive impairment. As both serum and cerebrospinal fluid tested positive for syphilis, he was diagnosed with neurosyphilis and treated with antibiotics. Functional ability and cognitive function improved after conducting syphilis treatment; we consequently started him on an insulin self-administration program. Two years later, his glycemic control has normalized. Dementia caused by neurosyphilis is one of the most important differential diagnoses of treatable dementia; hence, early diagnosis and early treatment are important. PMID- 29264083 TI - Paroxetine-induced QTc prolongation. AB - There have been only two previous reports of paroxetine-induced corrected QT (QTc) prolongation on electrocardiogram (ECG). Here, we report a 43-year-old woman with QTc prolongation (476 ms). She had taken 50 mg of paroxetine for 17 days. Three days after discontinuation of paroxetine, QTc returned to within the normal limits (396 ms). Paroxetine blocks the human ether-a-go-go-related gene (HERG) channels. Genetic polymorphisms of channels related to cardiac function are involved in drug-induced QTc prolongation. Moreover, autonomic nervous system instability due to unstable psychotic symptoms may also affect QTc. These factors are related to this rare event induced by paroxetine. PMID- 29264084 TI - Streptococcus dysagalactiae pyomyositis. PMID- 29264085 TI - Isolated hemicape-like sensory disturbance caused by a cortical infarction. PMID- 29264086 TI - Pneumatosis intestinalis. PMID- 29264087 TI - Mallory-Weise syndrome in a patient treated with EGFR-TKI. PMID- 29264088 TI - Occupational Favre-Racouchot syndrome. PMID- 29264089 TI - Traumatic optic neuropathy and central retinal artery occlusion following blunt trauma to the eyebrow. PMID- 29264090 TI - Purpura fulminans due to pneumococcal infection. PMID- 29264091 TI - Transient T-wave changes in Guillain-Barre syndrome. PMID- 29264092 TI - Cerebral angiography directly visualizes to-and-fro stream of vertebral artery stump syndrome. PMID- 29264093 TI - Bilaterally dilated episcleral vessels in patients with heritable pulmonary arterial hypertension. PMID- 29264094 TI - Klebsiella pneumoniae liver abscess. AB - Klebsiella pneumoniae liver abscess is no longer fatal but causes catastrophic disabilities. To prevent severe complications, early diagnosis is essential. Gram stain and string test are important for early diagnosis. PMID- 29264095 TI - Multiple skull osteomas in a 24-year-old woman. PMID- 29264096 TI - Rapid laboratory tests for malaria detection in Japan. AB - Although malaria is not a common disease in Japan, malaria can be a mortal illness. The malaria rapid diagnostic immune-chromatographic test (ICT) enables a more rapid and easier diagnosis of malaria. PMID- 29264097 TI - Massive gastrointestinal perforation discovered by computed tomography. AB - Gastrointestinal perforation discovered in CT. PMID- 29264098 TI - Neck schwannoma mimicking a thyroid tumor. AB - Although we often see patients with neck tumors, neck schwannomas are quite rare. We should keep schwannnoma in mind when we identified tumors on the side of the neck. PMID- 29264099 TI - Idiopathic mesenteric phlebosclerosis associated with herbal drugs presenting with asymptomatic fecal occult blood. AB - A 77-year-old man who had been taking Chinese herbal drugs containing gardenia fruit for a long time visited our hospital following a positive fecal occult blood test. A computed tomography scan showed multiple linear calcifications distributed on the right-side mesenteric veins, which is a typical finding of idiopathic mesenteric phlebosclerosis (IMP). PMID- 29264100 TI - Pulmonary intravascular lymphoma detected by FDG-PET. AB - A 69-year-old woman visited our hospital with a 2-month history of general fatigue, high fever, and dyspnea. Physical examination showed no abnormalities in superficial lymph nodes or respiratory sound. A chest computed tomography scan showed diffuse mild ground-glass attenuation in bilateral lung fields, whereas FDG-PET revealed intense uptake of FDG throughout the lung. PMID- 29264101 TI - Bucillamine-induced yellow nail syndrome. PMID- 29264102 TI - A case of pneumatosis cystoides intestinalis. PMID- 29264103 TI - Ghost tablet in feces. AB - Recently, we encountered a female patient who identified the presence of a ghost tablet in her fecal matter. Interestingly, although the patient was prescribed potassium chloride capsules, elemental composition analysis by energy-dispersive X-ray spectroscopy was unable to detect the presence of either potassium or chloride in the fecal tablet remnant. PMID- 29264104 TI - Calcifying epithelioma on the face of a middle-aged man. AB - A 42-year-old man presented with a nodule on the left cheek that had gradually increased in size. Physical examination revealed a yellowish subcutaneous tumor. The biopsy specimen revealed epithelial sheets consisting of anucleate squamous cells, basophilic cells, and foreign body giant cells. These findings confirmed that this tumor was a calcifying epithelioma. PMID- 29264105 TI - Dawn of Choosing Wisely Japan Student Committee. PMID- 29264106 TI - Special report of the first Australasian Diagnostic Error in Medicine Conference from 23 to 25 May, 2017. AB - We attended the first Australasian Diagnostic Error in Medicine Conference (Aus DEM) in Melbourne from 23 to 25 May, 2017. We believe hosting the DEM conference in Japan is vital in promoting diagnostic error prevention initiatives in our region. We hope all the stakeholders in health care will join the DEM conference to be hosted in our country to address issues surrounding diagnostic errors. PMID- 29264108 TI - Surface force analysis of glycine adsorption on different crystal surfaces of titanium dioxide (TiO2). AB - Surface force analysis with atomic force microscope (AFM) in which a single amino acid residue was mounted on the tip apex of AFM probe was carried out for the first time at the molecular level on titanium dioxide (TiO2) as a representative mineral surface for prebiotic chemical evolution reactions. The force analyses on surfaces with three different crystal orientations revealed that the TiO2 (110) surface has unique characteristics for adsorbing glycine molecules showing different features compared to those on TiO2 (001) and (100). To examine this difference, we investigated thermal desorption spectroscopy (TDS) and the interaction between the PEG cross-linker and the three TiO2 surfaces. Our data suggest that the different single crystal surfaces would provide different chemical evolution field for amino acid molecules. PMID- 29264109 TI - A review on robotic fish enabled by ionic polymer-metal composite artificial muscles. AB - A novel actuating material, which is lightweight, soft, and capable of generating large flapping motion under electrical stimuli, is highly desirable to build energy-efficient and maneuverable bio-inspired underwater robots. Ionic polymer metal composites are important category of electroactive polymers, since they can generate large bending motions under low actuation voltages. IPMCs are ideal artificial muscles for small-scale and bio-inspired robots. This paper takes a system perspective to review the recent work on IPMC-enabled underwater robots, from modeling, fabrication, and bio-inspired design perspectives. First, a physics-based and control-oriented model of IPMC actuator will be reviewed. Second, a bio-inspired robotic fish propelled by IPMC caudal fin will be presented and a steady-state speed model of the fish will be demonstrated. Third, a novel fabrication process for 3D actuating membrane will be introduced and a bio-inspired robotic manta ray propelled by two IPMC pectoral fins will be demonstrated. Fourth, a 2D maneuverable robotic fish propelled by multiple IPMC fin will be presented. Last, advantages and challenges of using IPMC artificial muscles in bio-inspired robots will be concluded. PMID- 29264107 TI - Towards three-dimensional optical metamaterials. AB - Metamaterials have opened up the possibility of unprecedented and fascinating concepts and applications in optics and photonics. Examples include negative refraction, perfect lenses, cloaking, perfect absorbers, and so on. Since these metamaterials are man-made materials composed of sub-wavelength structures, their development strongly depends on the advancement of micro- and nano-fabrication technologies. In particular, the realization of three-dimensional metamaterials is one of the big challenges in this research field. In this review, we describe recent progress in the fabrication technologies for three-dimensional metamaterials, as well as proposed applications. PMID- 29264110 TI - Successful treatment of breakthrough disseminated Trichosporon asahii fungemia in a patient with acute myeloid leukemia receiving itraconazole prophylaxis. AB - We encountered a case of a 73-year-old man with acute myeloid leukemia who developed Trichosporon asahii systemic infection while on itraconazole prophylaxis during severe neutropenia. Cryptococcal antigen was useful for diagnosis. Although itraconazole was ineffective in protecting against trichosporonosis, treatment was successful with voriconazole following liposomal amphotericin B. PMID- 29264111 TI - Alemtuzumab-based therapy for Secondary Malignant Histiocytosis arising from Pre B-ALL. AB - *Secondary Malignant Histiocytosis (SMH) is an exceedingly rare, life-threatening condition that invariably occurs in the presence of an underlying monoclonal hematologic disorder. Prognosis of SMH remains dismal and there is no established treatment. *We report a case of a patient who developed SMH during induction chemotherapy for his underlying pre-B-ALL, that caused persistently high fevers and was only diagnosed by a marrow while cytopenic in phase 2 induction. He was treated with alemtuzumab-based therapy that reduced the histiocytic infiltration of the bone marrow from 80% to 15% and made him eligible to undergo T-cell replete allogeneic stem transplantation from his sibling. *This report is the first to highlight the role of alemtuzumab, an anti-CD52 monoclonal antibody, in clonal disorders originating from transdifferentiation. *The alemtuzumab-based regimen should be reserved only for carefully selected allogeneic transplant patients. PMID- 29264112 TI - Altered intrinsic and extrinsic connectivity in schizophrenia. AB - Schizophrenia is a disorder characterized by functional dysconnectivity among distributed brain regions. However, it is unclear how causal influences among large-scale brain networks are disrupted in schizophrenia. In this study, we used dynamic causal modeling (DCM) to assess the hypothesis that there is aberrant directed (effective) connectivity within and between three key large-scale brain networks (the dorsal attention network, the salience network and the default mode network) in schizophrenia during a working memory task. Functional MRI data during an n-back task from 40 patients with schizophrenia and 62 healthy controls were analyzed. Using hierarchical modeling of between-subject effects in DCM with Parametric Empirical Bayes, we found that intrinsic (within-region) and extrinsic (between-region) effective connectivity involving prefrontal regions were abnormal in schizophrenia. Specifically, in patients (i) inhibitory self connections in prefrontal regions of the dorsal attention network were decreased across task conditions; (ii) extrinsic connectivity between regions of the default mode network was increased; specifically, from posterior cingulate cortex to the medial prefrontal cortex; (iii) between-network extrinsic connections involving the prefrontal cortex were altered; (iv) connections within networks and between networks were correlated with the severity of clinical symptoms and impaired cognition beyond working memory. In short, this study revealed the predominance of reduced synaptic efficacy of prefrontal efferents and afferents in the pathophysiology of schizophrenia. PMID- 29264113 TI - Multisensory stimulation improves functional recovery and resting-state functional connectivity in the mouse brain after stroke. AB - Stroke causes direct structural damage to local brain networks and indirect functional damage to distant brain regions. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by regions functionally connected to the site of injury. Spontaneous functional recovery can be enhanced by rehabilitative strategies, which provides experience-driven cell signaling in the brain that enhances plasticity. Functional neuroimaging in humans and rodents has shown that spontaneous recovery of sensorimotor function after stroke is associated with changes in resting-state functional connectivity (RS-FC) within and across brain networks. At the molecular level, GABAergic inhibitory interneurons can modulate brain plasticity in peri-infarct and remote brain regions. Among this cell-type, a decrease in parvalbumin (PV) immunoreactivity has been associated with improved behavioral outcome. Subjecting rodents to multisensory stimulation through exposure to an enriched environment (EE) enhances brain plasticity and recovery of function after stroke. Yet, how multisensory stimulation relates to RS-FC has not been determined. In this study, we investigated the effect of EE on recovery of RS-FC and behavior in mice after stroke, and if EE-related changes in RS-FC were associated with levels of PV expressing neurons. Photothrombotic stroke was induced in the sensorimotor cortex. Beginning 2 days after stroke, mice were housed in either standard environment (STD) or EE for 12 days. Housing in EE significantly improved lost tactile-proprioceptive function compared to mice housed in STD environment. RS-FC in the mouse was measured by optical intrinsic signal imaging 14 days after stroke or sham surgery. Stroke induced a marked reduction in RS-FC within several perilesional and remote brain regions. EE partially restored interhemispheric homotopic RS-FC between spared motor regions, particularly posterior secondary motor. Compared to mice housed in STD cages, EE exposure lead to increased RS-FC between posterior secondary motor regions and contralesional posterior parietal and retrosplenial regions. The increased regional RS-FC observed in EE mice after stroke was significantly correlated with decreased PV-immunoreactivity in the contralesional posterior motor region. In conclusion, experimental stroke and subsequent housing in EE induces dynamic changes in RS-FC in the mouse brain. Multisensory stimulation associated with EE enhances RS-FC among distinct brain regions relevant for recovery of sensorimotor function and controlled movements that may involve PV/GABA interneurons. Our results indicate that targeting neural circuitry involving spared motor regions across hemispheres by neuromodulation and multimodal sensory stimulation could improve rehabilitation after stroke. PMID- 29264114 TI - The growth of computer-assisted (robotic) surgery in urology 2000-2014: The role of Asian surgeons. AB - Objective: A major role in the establishment of computer-assisted robotic surgery (CARS) can be traced to the work of Mani Menon at Vattikuti Urology Institute (VUI), and of many surgeons of Asian origin. The success of robotic surgery in urology has spurred its acceptance in other surgical disciplines, improving patient comfort and disease outcomes and helping the industrial growth. The present paper gives an overview of the progress and development of robotic surgery, especially in the field of Urology; and to underscore some of the seminal work done by the VUI and Asian surgeons in the development of robotic surgery in urology in the US and around the world. Methods: PubMed/Medline and Scopus databases were searched for publications from 2000 through June 2014, using algorithms based on keywords "robotic surgery", "prostate", "kidney", "adrenal", "bladder", "reconstruction", and "kidney transplant". Inclusion criteria used were published full articles, book chapters, clinical trials, prospective and retrospective series, and systematic reviews/meta-analyses written in English language. Studies from Asian institutions or with the first/senior author of Asian origin were included for discussion, and focused on techniques of robotic surgery, relevant patient outcomes and associated demographic trends. Results: A total of 58 articles selected for final review highlight the important strides made by robots in urology, from robotic radical prostatectomy in 2000 to robotic kidney transplant in 2014. In the hands of an experienced robotic surgeon, it has been demonstrated to improve functional patient outcomes and minimize perioperative complications compared to open surgery, especially in urologic oncology and reconstructive urology. With increasing surgeon proficiency, the benefits of robotic surgery were consistently seen across different surgical disciplines, patient populations, and strata. Conclusion: The addition of robot to the surgical armamentarium has allowed better patient care and improved disease outcomes. VUI and surgeons of Asian origin have played a pioneering role in dissemination of computer-assisted surgery. PMID- 29264115 TI - Renal cell carcinoma: An update for the practicing urologist. AB - Systemic therapy for metastatic renal cell carcinoma (mRCC) has evolved drastically, with agents targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) now representing a standard of care. The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing. (1) Though observation remains a standard of care following resection of localized disease, multiple trials are underway to assess VEGF- and mTOR-directed therapies in this setting. (2) While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents, prospective data to support this approach is still forthcoming. (3) The first-line management of mRCC may change substantially with multiple studies exploring vaccines, immune checkpoint inhibitors, and novel targeted agents currently underway. In general, prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy. Over the same span of time, the current treatment paradigm for first-line therapy may evolve. PMID- 29264116 TI - Advances in percutaneous stone surgery. AB - Treatment of large renal stones has changed considerably in recent years. The increasing prevalence of nephrolithiasis has mandated that urologists perform more surgeries for large renal calculi than before, and this has been met with improvements in percutaneous stone surgery. In this review paper, we examine recent developments in percutaneous stone surgery, including advances in diagnosis and preoperative planning, renal access, patient position, tract dilation, nephroscopes, lithotripsy, exit strategies, and post-operative antibiotic prophylaxis. PMID- 29264117 TI - Effect of phosphodiesterase inhibitors in the bladder. AB - Many aging men will experience lower urinary tract symptoms (LUTS). Phosphodiesterase type 5 (PDE5) inhibitors have shown promise in treating LUTS in these patients. PDE5 inhibitors mediate their effects through several pathways including cAMP, NO/cGMP, K-channel modulated pathways, and the l-cysteine/H2S pathway. PDE5 inhibitors exert their effect in muscle cells, nerve fibers, and interstitial cells (ICs). The use of PDE5 inhibitors led to improvement in LUTS. This included urodynamic parameters. PDE5 inhibitors may play a significant role in LUTS due to their effect on the bladder rather than the prostate. PMID- 29264118 TI - Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF kappaB and JNK dependent manner. AB - Objective: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. One effect of VHL inactivation is hypoxia inducible factor alpha (HIFalpha)-independent constitutive activation of nuclear factor kappa B (NF-kappaB) and c-jun N-terminal kinase (JNK). Both NF kappaB and JNK drive ccRCC growth and epithelial to mesenchymal transition (EMT). The purpose of this study was to determine the biochemical effects of pomegranate juice extracts (PE) on RCC cell lines. Methods: The pre-clinical effects of PE on NF-kappaB, JNK, and the EMT phenotype were assayed, including its effect on proliferation, anchorage-independent growth, and invasion of pVHL-deficient RCCs. Results: PE inhibits the NF-kappaB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs. The effects of PE are concentration dependent and affect not only biochemical markers of EMT (i.e., cadherin expression) but also functional manifestations of EMT, such as invasion. These effects are manifested within days of exposure to PE when diluted 2000-fold. Highly dilute concentrations of PE (106 dilution), which do not impact these pathways in the short term, were found to have NF-kappaB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure. Conclusion: These findings suggest that PE may mediate inhibition growth of pVHL deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small, localized, incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy. PMID- 29264119 TI - Single application of high-intensity focused ultrasound as primary therapy of localized prostate cancer: Treatment-related predictors of biochemical outcomes. AB - Objective: Recent reports on high-intensity focused ultrasound (HIFU) treatment of localized prostate cancer suggest that preoperative risk groups of tumor recurrence are strong predictors of oncological outcomes. The purpose of this study is to determine the prognostic significance of treatment-related factors in relation to patient characteristics for biochemical outcomes after HIFU. Methods: This retrospective single-center study included patients treated from December 2002 to December 2010 for localized prostate cancer with two generations of Ablatherm(r) HIFU devices (A1 and A2). All the patients underwent single HIFU treatment session under the concept of whole-gland therapy. Prostate surgery was performed before HIFU to downsize enlarged glands. Androgen deprivation therapy (ADT) was discontinued before HIFU. Biochemical failure (BCF) was defined as prostate specific antigen (PSA) nadir + 1.2 ng/mL (Stuttgart definition). Predictors of BCF were determined using Cox regression models. As covariates, patient-related factors (age, tumor characteristics, ADT) were compared with treatment-related factors (prostate volume, HIFU device generation, conduct of therapy, prostate edema, patient movement, anesthetic modalities). Results: Three hundred and twenty-three (98.8%) out of 327 consecutive patients were evaluable for BCF. Median (interquartile range) follow-up was 51.2 (36.6-80.4) months. The overall BCF-rate was 23.8%. In multivariate analyses, higher initial PSA-values (Hazard ratio [HR]: 1.03; p < 0.001) and higher D'Amico risk stages (HR: 3.45; p < 0.001) were patient-related predictors of BCF. Regarding treatment-related factors, the A2 HIFU device was associated with a decreased risk of BCF (HR: 0.51; p = 0.007), while prostate edema had an adverse effect (HR: 1.8; p = 0.027). Short follow-up and retrospective study design are the primary limitations. Conclusion: Success in a single HIFU session depends not merely on tumor characteristics, but also on treatment-related factors. Ablation is more efficacious with the technically advanced A2 HIFU device. Heat-induced prostate edema might adversely affect the outcome. PMID- 29264120 TI - Impact of tertiary Gleason pattern 5 on prostate cancer aggressiveness: Lessons from a contemporary single institution radical prostatectomy series. AB - Objective: To better evaluate tertiary Gleason pattern reporting and to evaluate the impact of tertiary Gleason pattern 5 (TP5) on prostate cancer pathological features and biochemical recurrence at our large single institution. Methods: We retrospectively reviewed 1962 patients who underwent radical prostatectomy (RP) for prostate cancer; TP5 was reported in 159 cases (8.1%). Men with Gleason score (GS) 7 and GS 8 disease were divided into subgroups with and without TP5, and histopathological features were compared. Multivariate analyses were conducted to assess the impact on TP5 on biochemical-free survival (BFS). Results: Tumors possessing GS 3 + 4 with TP5 were more likely to exhibit extraprostatic extension (EPE) and had a larger tumor diameter (TD) than GS 3 + 4 alone. GS 3 + 4 with TP5 was also associated with positive surgical margins (SM), seminal vesicle involvement (SVI), and higher pre-operative prostate-specific antigen (PSA) values, but without statistical significance. GS 4 + 3 with TP5 more commonly presented with EPE, positive SM, SVI, and greater TD and pre-operative PSA level than GS 4 + 3 alone. In multivariate analysis, Gleason score, EPE, and TP5 were overall independent risk factors for PSA recurrence in this cohort. Additionally, GS 4 + 3 with TP5 was associated with shorter time to recurrence versus GS 4 + 3 alone. Conclusion: Our results emphasize the importance of TP5 and suggest that criteria for tertiary pattern reporting in prostate cancer should be standardized. Further studies are needed to evaluate the role of tertiary patterns in prognostic models. PMID- 29264121 TI - Endoscopic lysis of bladder scar associated with Hunner's lesions: A new technique. AB - Objective: Five to ten percent of interstitial cystitis/bladder pain syndrome (IC/BPS) patients have Hunner's lesions (HL), areas of non-specific inflammation and scarring. The poor quality of life of patients with HL is entwined in associated pain and loss of bladder capacity. Although the decrease in bladder capacity is usually dependent on pain, it may also be dependent upon scarring and associated compliance changes produced by the inflammatory process. This report reviews the potential role of endoscopic scar lysis using the holmium laser in the management of these patients whose only other therapeutic option is urinary diversion. Methods: Two patients with HL and "end stage" bladders who underwent holmium laser division of bladder wall scar/tethering were identified. Clinical data were reviewed with emphasis on safety and efficacy. Results: Both patients selected for this procedure underwent holmium laser lysis of known scar tissue in an effort to increase bladder capacity and improve symptoms of urinary frequency and pain with bladder filling. The median age of patients who underwent the procedure was 63 (59-67) years. Incisions were made with the holmium laser at frequencies of 3-10 Hz of 300-700 J along the region of scarring. All procedures were performed by the same practitioner. There was an increase in bladder capacity by 58.3% (50.0%-66.7%). During a mean follow-up of 4.2 years, there appeared to be a significant improvement with an increase in interval time between voids and a decrease in pain with bladder filling. Conclusion: Patients with IC/BPS may be severely debilitated by a clinically significant decrease in their bladder capacity, especially in the face of HL. The use of the holmium laser to incise regions of scar and bladder wall tethering may produce a clinically significant and durable increase in bladder capacity. The use of this technique as a means of treating bladder scarring poses an excellent adjunct to existing treatment strategies. PMID- 29264124 TI - Testis sperm extraction. AB - The last 20 years have produced developments in the treatment for patients with non-obstructive azoospermia (NOA) who were once considered to be infertile. The combination of intracytoplasmic sperm injection together with various testicular sperm retrieval techniques, including conventional testicular sperm extraction (TESE), microdissection TESE (micro-TESE) and fine needle aspiration (FNA), have revolutionized treatment for these men. In men with NOA, isolated regions of spermatogenesis within the testis are common. The goal for all types of sperm retrieval procedures is locating the focal region(s) of spermatogenesis, and harvesting the sperm for assisted reproduction. This review article explores the surgical management of men with NOA and describes all techniques that can be used for testicular sperm retrieval. A PubMed search was conducted using the key words: "sperm extraction", "NOA", "testicular FNA", "testicular mapping", "TESE", and "testicular biopsy". All articles were reviewed. Articles were included if they provided data on sperm retrieval rates. The methods for performing sperm retrieval rates and outcomes of the various techniques are outlined. Micro-TESE has a higher sperm retrieval rates with fewer postoperative complications and negative effects on testicular function compared with conventional TESE. PMID- 29264123 TI - All about Peyronie's disease. AB - Peyronie's disease (PD) is an acquired connective tissue disorder of the tunica albuginea of the corpus cavernosum, characterized by excessive fibrosis and plaque formation. PD can result in significant physical and psychological morbidity; as it may prevent intercourse and cause adverse impacts on partner relationships. The exact etiology and pathophysiology remain unclear, and many misconceptions about the disease associations, course and treatment exist. The disease has two distinct stages. The acute stage is characterized by pain, and disease may progress during this stage. Non-surgical managements at this stage aim to alleviate pain and stabilize the disease. Results for non-surgical treatment are often conflicting. The chronic stage occurs 6-12 months later, where pain disappears and the deformity stabilizes. Surgical treatment is reserved for significant deformity or with inability to penetrative intercourse. The choice of the surgical technique depends on the length of the penis, degree of deformity, erectile function, patients' expectations and surgeon's preference. PMID- 29264122 TI - Current status of diagnosis and treatment of bladder cancer in China - Analyses of Chinese Bladder Cancer Consortium database. AB - Objective: To investigate current status of diagnosis and treatment of bladder cancer in China. Methods: A database was generated by Chinese Bladder Cancer Consortium (CBCC). From January 2007 to December 2012, 14,260 cases from 44 CBCC centers were included. Data of diagnosis, treatment and pathology were collected. Results: The average age was 63.5 year-old and most patients were male (84.3%). The most common histologic types were urothelial carcinoma (91.4%), adenocarcinoma (1.8%), and squamous carcinoma (1.9%). According to 1973 and 2004 WHO grading system, 42.0%, 41.0%, and 17.0% of patients were grade 1, 2, and 3, and 16.0%, 48.7%, and 35.3% of patients were papillary urothelial neoplasms of low malignant potential, low, and high grade, respectively. Non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) were 25.2% and 74.1%, respectively (0.8% not clear). Carcinoma in situ was only 2.4%. Most patients were diagnosed by white-light cystoscopy with biopsy (74.3%). Fluorescence and narrow band imaging cystoscopy had additional detection rate of 1.0% and 4.0%, respectively. Diagnostic transurethral resection (TUR) provided detection rate of 16.9%. Most NMIBCs were treated with TUR (89.2%). After initial TUR, 2.6% accepted second TUR, and 45.7%, 69.9%, and 58.7% accepted immediate, induced, and maintenance chemotherapy instillation, respectively. Most MIBCs were treated with radical cystectomy (RC, 59.7%). Laparoscopic RCs were 35.1%, while open RC 63.4%. Extended and standard pelvic lymph node dissection were 7% and 66%, respectively. Three most common urinary diversions were orthotopic neobladder (44%), ileal conduit (31%), and ureterocutaneostomy (23%). Only 2.3% of patients accepted neo-adjuvant chemotherapy and only 18% of T3 and T4 patients accepted adjuvant chemotherapy. Conclusion: Disease characteristics are similar to international reports, while differences of diagnosis and treatment exist. This study can provide evidences for revisions of the guideline on bladder cancer in China. PMID- 29264125 TI - Surgical management of nonobstructive azoospermia. AB - Nonobstructive azoospermia (NOA) is characterized by the complete absence of sperm in the ejaculate due to testicular failure. The evaluation and management of patients with NOA offer a challenge to the reproductive urologist. In the era of in vitro fertilization with intracytoplasmic sperm injection, surgical sperm extraction techniques can afford men with NOA biologic paternity. To provide a comprehensive review of surgical sperm retrieval approaches in the patient with NOA emphasizing complications, success rates and outcome optimization, a Medline search was conducted querying surgical approaches used to manage NOA. Four sperm extraction techniques are described including: testicular sperm aspiration, testicular sperm extraction, fine needle aspiration mapping and microdissection testicular sperm extraction. In addition, the roles for pre-extraction varicocelectomy and sperm cryopreservation are discussed. The management of NOA continues to evolve as newer tools become available. Several modalities of sperm acquisition exist. An understanding of their complications and success rates is fundamental to the treatment of NOA. PMID- 29264126 TI - Non-invasive transcutaneous electrical stimulation in the treatment of overactive bladder. AB - We reviewed the literature on transcutaneous electrical nerve stimulation (TENS) used as a therapy for overactive bladder (OAB) symptoms, with a particular focus on: stimulation site, stimuli parameters, neural structures thought to be targeted, and the clinical and urodynamic outcomes achieved. The majority of studies used sacral or tibial nerve stimulation. The literature suggests that, whilst TENS therapy may have neuromodulation effects, patient are unlikely to benefit to a significant extent from a single application of TENS and indeed clear benefits from acute studies have not been reported. In long-term studies there were differences in the descriptions of stimulation intensity, strategy of the therapy, and positioning of the electrodes, as well as in the various symptoms and pathology of the patients. Additionally, most studies were uncontrolled and hence did not evaluate the placebo effect. Little is known about the underlying mechanism by which these therapies work and therefore exactly which structures need to be stimulated, and with what parameters. There is promising evidence for the efficacy of a transcutaneous stimulation approach, but adequate standardisation of stimulation criteria and outcome measures will be necessary to define the best way to administer this therapy and document its efficacy. PMID- 29264127 TI - Contemporary review of the 532 nm laser for treatment of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a condition that occurs increasingly with age. The established gold standard treatment for BPH has been the electrocautery based transurethral resection of the prostate (TURP). TURP, however, is associated with several complications and side effects. Therefore, there is an increasing interest in a number of emerging minimally invasive therapies as alterative treatment options. Laser therapy using the Greenlight laser is a promising alternative to the traditional TURP. Selective absorption by hemoglobin allows rapid, hemostatic vaporization of prostate tissue. Additional advantages include avoidance or minimization of complications such as intraoperative fluid absorption, and bleeding, retrograde ejaculation, impotence, and incontinence, as well as its use in treating high volume BPH. We review the use of the Greenlight laser in the treatment of BPH, when comparing complications and advantages in relation to TURP. PMID- 29264129 TI - Configuration and validation of a novel prostate disease nomogram predicting prostate biopsy outcome: A prospective study correlating clinical indicators among Filipino adult males with elevated PSA level. AB - Objective: To configure and validate a novel prostate disease nomogram providing prostate biopsy outcome probabilities from a prospective study correlating clinical indicators and diagnostic parameters among Filipino adult male with elevated serum total prostate specific antigen (PSA) level. Methods: All men with an elevated serum total PSA underwent initial prostate biopsy at our institution from January 2011 to August 2014 were included. Clinical indicators, diagnostic parameters, which include PSA level and PSA-derivatives, were collected as predictive factors for biopsy outcome. Multiple logistic-regression analysis involving a backward elimination selection procedure was used to select independent predictors. A nomogram was developed to calculate the probability of the biopsy outcomes. External validation of the nomogram was performed using separate data set from another center for determination of sensitivity and specificity. A receiver-operating characteristic (ROC) curve was used to assess the accuracy in predicting differential biopsy outcome. Results: Total of 552 patients was included. One hundred and ninety-one (34.6%) patients had benign prostatic hyperplasia, and 165 (29.9%) had chronic prostatitis. The remaining 196 (35.5%) patients had prostate adenocarcinoma. The significant independent variables used to predict biopsy outcome were age, family history of prostate cancer, prior antibiotic intake, PSA level, PSA-density, PSA-velocity, echogenic findings on ultrasound, and DRE status. The areas under the receiver-operating characteristic curve for prostate cancer using PSA alone and the nomogram were 0.688 and 0.804, respectively. Conclusion: The nomogram configured based on routinely available clinical parameters, provides high predictive accuracy with good performance characteristics in predicting the prostate biopsy outcome such as presence of prostate cancer, high Gleason prostate cancer, benign prostatic hyperplasia, and chronic prostatitis. PMID- 29264128 TI - Percent free prostate-specific antigen for prostate cancer diagnosis in Chinese men with a PSA of 4.0-10.0 ng/mL: Results from the Chinese Prostate Cancer Consortium. AB - Objective: To test the diagnostic performance of percent free prostate-specific antigen (%fPSA) in predicting any prostate cancer (PCa) and high-grade prostate cancer (HGPCa) in a retrospective multi-center biopsy cohort with a PSA level of 4.0-10.0 ng/mL in China. Methods: Consecutive patients with a PSA of 4.0-10.0 ng/mL who underwent transrectal ultrasound-guided biopsy were enrolled at 16 Chinese medical centers from January 1st, 2010 to December 31st, 2013. Total and free serum PSA determinations were performed using three types of electro chemiluminescence immunoassays recalibrated to the World Health Organization (WHO) standard. The diagnostic accuracy of PSA, %fPSA, and %fPSA in combination with PSA (%fPSA + PSA) was determined using the area under the receiver operating characteristic (ROC) curve (AUC). Results: A total of 2310 consecutive men with PSA levels between 4.0 and 10.0 ng/mL were included, and the detection rate of PCa was 25.1%. The AUC of %fPSA and %fPSA + PSA in predicting any PCa was superior to PSA alone in men aged >=60 years (0.623 vs. 0.534, p < 0.0001) but not in men aged 40-59 years (0.517 vs. 0.518, p = 0.939). Similar result was yield in predicting HGPCa. Conclusion: In a clinical setting of Chinese men with 4.0-10.0 ng/mL PSA undergoing initial prostate biopsy, adding %fPSA to PSA can moderately improve the diagnostic accuracy for any PCa and HGPCa compared with PSA alone in patients >=60 but not in patients aged 40-59 years. PMID- 29264130 TI - Robotic distal ureterectomy with psoas hitch and ureteroneocystostomy: Surgical technique and outcomes. AB - Use of the da Vinci(r) surgical robotic system has expanded to numerous upper and lower urinary tract procedures. We describe our surgical technique and perioperative outcome of robotic distal ureterectomy with psoas hitch and ureteroneocystostomy for distal ureteral pathologies. Eight patients with a median age of 69.5 years old underwent robotic distal ureterectomy with psoas hitch and ureteroneocystostomy between April 2009 and August 2014. The entirety of all cases was performed robotically by a single surgeon at a tertiary academic medical center. Median operative time was 285 min (range: 210-360 min), estimated blood loss was 50 mL (range: 50-75 mL) and median length of hospital stay was 2.5 days (range: 1-6 days). There was one post-operative complication, a readmission for dehydration (Clavien I). It suggests that robotic distal ureterectomy with psoas hitch and ureteroneocystostomy is a safe and effective minimally invasive alternative for patients with distal ureteral pathology. PMID- 29264131 TI - Prostate cancer in Asia: A collaborative report - The situation in Sri Lanka. PMID- 29264132 TI - The older the better: The characteristic of localized prostate cancer in Chinese men. AB - Objective: To assess the clinicopathological features and overall survival between two groups of Chinese patients older or younger than 70 years after retropubic radical prostatectomy. Methods: From January 2001 to February 2010, 390 patients receive dretropubic radical prostatectomy. After excluding 89 patients with adjuvant or neoadjuvant hormonal therapy or radiotherapy, a total of 301 patients were included in this study. We arbitrarily divided these patients into younger age group (<70 years, 140 cases, 46.5%) and older age group (>=70 years, 161 cases, 53.5%). The differences in serum prostate specific antigen (PSA), Gleason score, clinical tumor stage, and biochemical-free survival were analyzed between the two groups. Results: There were not significant differences between the two groups in high Gleason score rate and clinical tumor stage. However, older patients had significantly lower biochemical recurrence rate than those of younger patients, and had significantly higher PSA levels. Multivariate analysis showed that older age, PSA level and clinical tumor stage were significantly associated with biochemical recurrence free survival. Conclusion: In Chinese men, older age (>=70 years) is associated with better outcome. If the physical condition permits, older age alone should not exclude patients from radical prostatectomy. PMID- 29264134 TI - Evaluation of kidney allograft status using novel ultrasonic technologies. AB - Early diagnosis of kidney allograft injury contributes to proper decisions regarding treatment strategy and promotes the long-term survival of both the recipients and the allografts. Although biopsy remains the gold standard, non invasive methods of kidney allograft evaluation are required for clinical practice. Recently, novel ultrasonic technologies have been applied in the evaluation and diagnosis of kidney allograft status, including tissue elasticity quantification using acoustic radiation force impulse (ARFI) and contrast enhanced ultrasonography (CEUS). In this review, we discuss current opinions on the application of ARFI and CEUS for evaluating kidney allograft function and their possible influencing factors, advantages and limitations. We also compare these two technologies with other non-invasive diagnostic methods, including nuclear medicine and radiology. While the role of novel non-invasive ultrasonic technologies in the assessment of kidney allografts requires further investigation, the use of such technologies remains highly promising. PMID- 29264133 TI - Flexible ureteroscopy: Technological advancements, current indications and outcomes in the treatment of urolithiasis. AB - The last 3 decades have witnessed great improvements in the technology and clinical applications of many minimally invasive procedures in the urological field. Flexible ureteroscopy (fURS) has advanced considerably to become a widely utilized diagnostic and therapeutic tool for multiple upper urinary tract pathologies. The most common indication for fURS is the treatment of upper urinary tract stones with the aid of Holmium:Yttrium Aluminium Garnet (YAG) laser lithotripsy. Advancements in endoscope technologies and operative techniques have lead to a broader application of fURS in the management of urolithiasis to include larger and more complex stones. fURS has proved to be an effective and safe procedure with few contraindications. Continued progression in fURS may increase its clinical applicability and supplant other procedures as the first line treatment option for urolithiasis. PMID- 29264135 TI - Pygopus 2 promotes kidney cancer OS-RC-2 cells proliferation and invasion in vitro and in vivo. AB - Objective: Human Pygopus 2 (Pygo2) was recently discovered to be a component of the Wnt signaling pathway required for beta-catenin/Tcf-mediated transcription. But the role of Pygo2 in malignant cell proliferation and invasion has not yet been determined. Methods: Lentivirus-mediated small interfering RNA (siRNA) and vector-based overexpression were used to study the function of Pygo2 in OS-RC-2 cells. The resulted cells were subject to Western blotting assay, MTT assay, colony formation and cell invasion assays. Furthermore, renal cell carcinoma (RCC) models were established in BALB/c nude mice inoculated with OS-RC-2 cells. Immunohistochemistry (IHC) staining of matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) was performed in tumor tissue. Results: Pygo2 gene was successful knocked down and overexpressed in RCC OS-RC-2 cells by using an shRNA and overexpressing vector, respectively. Overexpression of Pygo2 effectively promoted cell proliferation, colony formation and invasion in vitro. Knockdown of Pygo2 obviously inhibited xenograft tumor growth in nude mice. In addition, overexpression of Pygo2 increased the levels of MMP-7, MMP-9 and VEGF in the xenograft tumors. Conclusion: Pygo2 has a role in promoting cell proliferation, invasion and metastasis, and may regulate angiogenesis via the Wnt/beta-catenin signaling pathway. PMID- 29264136 TI - The likelihood of having serum level of PSA of >=4.0 ng/mL and >=10.0 ng/mL in non-obese and obese Nigerian men with LUTS. AB - Objective: This study was undertaken to determine the likelihood of having serum total prostate specific antigen (PSA) levels >=4.0 ng/mL and >=10.0 ng/mL among a cohort of non-obese and obese Nigerian men with lower urinary tract symptoms (LUTS). Methods: This was a prospective cross-sectional survey among men who presented with benign prostatic hypertrophy to the urology clinic of the Ekiti State University Teaching Hospital, Ado -Ekiti with LUTS between January 1 and December 31, 2014. One hundred and forty men who presented in the urologic clinic with LUTS were recruited. PSA was analyzed using standard method while other clinical variables were collected using a clinical case form. Multivariate logistic regression was used to estimate the odds of an abnormal PSA of >=4.0 ng/mL or >=10.0 ng/mL in these men. Results: The mean ages of obese and non-obese men were 64.8 and 64.0 years respectively. The mean total serum PSA were 14.8 and 13.2 ng/mL for obese and non-obese men respectively. Univariate analysis showed no difference (p > 0.05) in the proportion of obese and non-obese men with LUTS who had a PSA threshold of at least 4.0 ng/mL. Multivariate logistic regression showed that, at a PSA threshold of 10.0 ng/mL, obese men had a statistically significant proportion (p < 0.05). Although not significant, non-obese patients were less likely to have PSA level of >=4.0 ng/mL (OR 0.701; 95% CI 0.301-1.630) compared to obese men. In the same vein, non-obese men were less likely to have a PSA level of 10.0 ng/mL (OR, 0.686; 95% CI, 0.318-1.478) in a simultaneous context of age. Conclusion: Our study demonstrated that, in a sample population of predominantly native African men, there was a non-significantly higher likelihood of overweight/obese patients having a higher serum PSA level than the non-obese. A community based study is needed to further confirm this finding. PMID- 29264137 TI - Does varicocele grade predict the postoperative changes of semen parameters following left inguinal micro-varicocelectomy? AB - Objective: To evaluate the relationship between preoperative grade and postoperative changes of semen parameters following left inguinal varicocelectomy. Methods: This study included 44 patients undergoing left microsurgical inguinal varicocelectomy. Internal spermatic veins were classified as large (4 mm or more in diameter), medium (2-4 mm), or small (2 mm or less). Changes in sperm activity, morphology and count were estimated perioperatively. The introperative findings and semen parameters were compared between varicocele groups of grades 2 and 3. Results: Both sperm motility and count improved significantly postoperatively (from (31.9 +/- 16.3)% to (47.3 +/- 15.5)%, from (28.1 +/- 28.1) * 106/mL to (52.1 +/- 74.2) * 106/mL). In varicoceles with grade 2 and 3, significant differences were found in the number of large veins (0.4 +/- 0.6 vs. 1.2 +/- 0.7, p < 0.001) and ultrasonographic maximum diameters of spermatic vein in supine and standing positions (2.3 +/- 0.4 cm vs. 2.8 +/- 0.6 cm, 3.1 +/- 0.7 cm vs. 3.9 +/- 0.7 cm, p = 0.001 and 0.001 respectively). However no difference of changes in sperm motility and count was detected ((16.3 +/- 13.5)% vs. (14.4 +/- 12.6)%, (30.5 +/- 84.4) * 106/mL vs. (12.9 +/- 20.6) * 106/mL respectively, p = 0.65 and 0.40 respectively). Conclusion: Preoperative varicocele grade might not predict postoperative semen changes regardless of possible existence of anatomic and ultrasonographic associations. PMID- 29264138 TI - Serum cystatin C can be used as a marker of renal function even in patients with intestinal urinary diversion. AB - Objective: Recently, serum cystatin C (CysC) has been used as a novel marker of renal function. However, there is a lack of data on CysC levels in patients with intestinal urinary diversion (UD). Here we report CysC levels in such patients. Methods: We prospectively observed 38 patients who were diagnosed with bladder cancer and subsequently treated with radical cystectomy and UD at our institution in 2012 and 2013. Serum creatinine (sCr) and CysC were obtained optionally at the same time at least 1 month after radical cystectomy and UD. Results: The median CysC and sCr concentrations were 1.12 mg/L (range 0.75-2.47 mg/L) and 0.99 mg/dL (range 0.61-2.22 mg/dL), respectively. The median estimated concentrations of glomerular filtration rate (GFR) based on CysC (eGFRcys) and GFR based on creatinine (eGFRcreat) were 61.08 mL/min/1.73 m2 (range 22.64-99.89 mL/min/1.73 m2) and 58.01 mL/min/1.73 m2 (range 23.48-91.82 mL/min/1.73 m2), respectively. CysC had a significant correlation with sCr (r = 0.8607, p < 0.0001) and eGFRcreat (r = -0.8993, p < 0.0001). eGFRcys also had a significant correlation with eGFRcreat (r = 0.8104, p < 0.0001). Conclusion: The correlation between CysC and sCr was strong and the correlation coefficient was equivalent to that in patients without UD. The results suggest that CysC is not affected by UD and can be used as a marker of renal function similarly to sCr in patients with UD. PMID- 29264139 TI - The men's health center: Disparities in gender specific health services among the top 50 "best hospitals" in America. AB - Objective: Gender-specific integrated health services have long existed in the arena of women's health care, but men's health centers (MHCs) have only recently emerged as a novel practice model. Here, we seek to evaluate the prevalence and format of MHCs found in the leading academic medical centers in the United States. Methods: The US News & World Report's Top 50 Ranked Hospitals for Urology was used as our cohort. Data were gathered on the presence of MHCs and types of providers and conditions treated. An equivalent search was performed for women's health centers (WHCs). Results: Sixteen of 50 (32%) promoted some type of MHC, compared to 49 of 50 (98%) offering a WHC. Eight of the top 15 ranked institutions (53%) had an MHC compared to eight of 35 (23%) remaining programs. Six of 16 MHCs incorporated providers from a variety of medical disciplines, including urologists, internists, endocrinologists, cardiologists, and psychologists, while another six of 16 MHCs were staffed solely by urologists. Eight of 16 provided services for exclusively urologic issues, four of 16 offered additional services in treatment of other medical conditions, and four of 16 did not specify. Conclusion: A considerable disparity exists between the prevalence of gender-specific health services, with WHCs being much more numerous than MHCs. All but one leading institution had WHCs compared to less than one-third having MHCs. Our findings also highlight the heterogeneous nature of men's health programs, as they exhibit great variability in program type and focus, yet are all being marketed under the "Men's Health" banner. PMID- 29264140 TI - Isolated penile urethral injury: A rare case following male coital trauma. AB - Penile fractures are an uncommon urological emergency. Typically, penile fractures involve the corpus cavernosum and are sometimes associated with urethral injury. Isolated corpus spongiosum and urethral injuries without concomitant corpus cavernosum injury are, however, rare. With proper knowledge of the management of penile fractures and urethral injuries, this distinct entity can be diagnosed, assessed and managed successfully without complications. PMID- 29264141 TI - Extensive prostatic calculi in alkaptonuria: An unusual manifestation of rare disease. AB - Extensive prostatic calculi in a young man should always elicit the suspicion of alkaptonuria. Although prostatic calculi are seen in chronic prostatitis, chronic pelvic pain syndrome and benign prostate hyperplasia, none of these have prostatic calculi or calcification as extensive as in alkaptonuria. A 36 years young man who had severed obstructive lower urinary tract symptoms with extensive prostatic calculi was found to be alkaptonuric on further evaluation. PMID- 29264142 TI - Giant adrenal tumor presenting as Cushing's syndrome and pheochromocytoma: A case report. AB - We report a case of a 35-year-old lady who presented with Cushingoid features and associated raised urinary metanephrine. The patient underwent open adrenelectomy. Histopathological examination revealed adreno-cortical carcinoma with microscopic lymphovascular invasion. Postoperative period was uneventful and is on follow-up for the last one year and is doing well. PMID- 29264143 TI - Clear cell renal cell carcinoma located in sinus renalis confused with renal pelvis mass in image. PMID- 29264144 TI - Contemporary outcomes in the detection of prostate cancer using transrectal ultrasound-guided 12-core biopsy in Singaporean men with elevated prostate specific antigen and/or abnormal digital rectal examination. AB - Objective: Despite being the third commonest cancer in Singaporean men, there is a dearth of basic data on the detection rate of prostate cancer and post procedure complication rates locally using systematic 12-core biopsy. Our objective is to evaluate prostate cancer detection rates using 12-core prostate biopsy based on serum prostate specific antigen (PSA) levels and digital rectal examination (DRE) findings in Singaporean men presenting to a single tertiary centre. The secondary objective is to evaluate the complication rates of transrectal prostate biopsies. Methods: We retrospectively examined 804 men who underwent first transrectal-ultrasound (TRUS) guided 12-core prostate biopsies from January 2012 to April 2014. Prostate biopsies were performed on men presenting to a tertiary institution when their PSA levels were >=4.0 ng/mL and/or when they had suspicious DRE findings. Results: Overall prostate cancer detection rate was 35.1%. Regardless of DRE findings, patients were divided into four subgroups based on their serum PSA levels: 0-3.99 ng/mL, 4.00-9.99 ng/mL, 10.00-19.99 ng/mL and >=20.00 ng/mL and their detection rates were 9.5%, 20.9%, 38.4% and 72.3%, respectively. The detection rate of cancer based on suspicious DRE findings alone was 59.2% compared to 36.5% based on serum PSA cut-off of 4.0 ng/mL alone. The post-biopsy admission rate for sepsis was 1.5%. Conclusion: In conclusion, using contemporary 12-core biopsy methods, the local prostate cancer detection rate based on serum PSA and DRE findings has increased over the past decade presumably due to multiple genetic and environmental factors. Post-biopsy sepsis remains an important complication worldwide. PMID- 29264145 TI - Ureteral stent technology: Drug-eluting stents and stent coatings. AB - Ureteral stents are commonly used following urological procedures to maintain ureteral patency. However, alongside the benefits of the device, indwelling stents frequently cause significant patient discomfort (pain, urgency, frequency) and can become encrusted and infected. The importance of these sequelae is that they are not only bothersome to the patient but can lead to significant morbidity, urinary retention, ureteral damage, recurrent infections, pyelonephritis and sepsis. When these problems occur, stent removal or replacement alongside antibiotic, analgesic and/or other symptom-modifying therapies are essential to successfully treat the patient. In an attempt to prevent such morbidity, numerous approaches have been investigated over the past several decades to modify the stent itself, thereby affecting changes locally within the urinary tract without significant systemic therapy. These strategies include changes to device design, polymeric composition, drug-elution and surface coatings. Of these, drug-elution and surface coatings are the most studied and display the most promise for advancing ureteral stent use and efficacy. This article reviews these two strategies in detail to determine their clinical potential and guide future research in the area. PMID- 29264146 TI - Diagnosis and management of ureteral complications following renal transplantation. AB - When compared with maintenance dialysis, renal transplantation affords patients with end-stage renal disease better long-term survival and a better quality of life. Approximately 9% of patients will develop a major urologic complication following kidney transplantation. Ureteral complications are most common and include obstruction (intrinsic and extrinsic), urine leak and vesicoureteral reflux. Ureterovesical anastomotic strictures result from technical error or ureteral ischemia. Balloon dilation or endoureterotomy may be considered for short, low-grade strictures, but open reconstruction is associated with higher success rates. Urine leak usually occurs in the early postoperative period. Nearly 60% of patients can be successfully managed with a pelvic drain and urinary decompression (nephrostomy tube, ureteral stent, and indwelling bladder catheter). Proximal, large-volume, or leaks that persist despite urinary diversion, require open repair. Vesicoureteral reflux is common following transplantation. Patients with recurrent pyelonephritis despite antimicrobial prophylaxis require surgical treatment. Deflux injection may be considered in recipients with low-grade disease. Grade IV and V reflux are best managed with open reconstruction. PMID- 29264147 TI - Percutaneous nephrolithotomy in octogenarians and beyond: How old is too old? AB - Objective: To specifically report perioperative characteristics and outcomes in patients 80 years and older undergoing percutaneous nephrolithotomy (PCNL). PCNL has been established as feasible in the elderly; however, to our knowledge no one has specifically reported feasibility in patients 80 years and older. Methods: We retrospectively reviewed perioperative data of octogenarians who underwent PCNL at a high stone volume single institution, and matched them to patients <65 years of age by stone burden and sex. Patient demographics, perioperative outcomes and postoperative complications were compared. Results: Thirty-three octogenarians (mean age 83.6 years) with 36 renal units were matched to 67 controls (mean age 48.6 years) with 72 renal units. Octogenarians had a higher mean American Society of Anesthesiologists (ASA) score, more comorbidities, and worse renal function. There were no differences in operative characteristics, length of hospital stay or stone free rates. Of the patients with preoperative urinary decompression (ureteral stent or nephrostomy tube) prior to PCNL, the elderly were more likely to have a history of urosepsis. Octogenarians did not experience more minor Clavien (I - II) or major Clavien (IIIa - IVb) complications. Conclusion: Octogenarians who undergo PCNL were more likely to have cardiovascular comorbidities and a prior history of sepsis. Despite these risk factors, in appropriately selected patients PCNL can be safely and successfully performed in octogenarians without increased perioperative complications relative to a younger cohort. PMID- 29264148 TI - Three-dimensional printing technique assisted cognitive fusion in targeted prostate biopsy. AB - Objective: To explore the effect of 3-dimensional (3D) printing-assisted cognitive fusion on improvement of the positive rate in prostate biopsy. Methods: From August to December 2014, 16 patients with suspected prostatic lesions detected by multiparametric magnetic resonance imaging (MRI) were included. Targeted prostate biopsy was performed with the use of prostate 3D reconstruction modeling, computer-simulated biopsy, 3D printing, and cognitive fusion biopsy. All patients had received 3.0 T multiparametric MRI before biopsy. The DICOM MRI files were imported to medical imaging processing software for 3D reconstruction modeling to generate a printable .stl file for 3D printing with use of transparent resin as raw material. We further performed a targeted 2- to 3-core biopsy at suspected lesions spotted on MRI. Results: For the 16 patients in the present study, 3D modeling with cognitive fusion-based targeted biopsy was successfully performed. For a single patient, 1-2 lesions (average: 1.1 lesions) were discovered, followed by 2-6 cores (average: 2.4 cores) added as targeted biopsy. Systematic biopsies accounted for 192 cores in total, with a positive rate of 22.4%; targeted biopsies accounted for 39 cores in total, with a positive rate of 46.2%. Among these cases, 10 patients (62.5%) were diagnosed with prostate adenocarcinoma, in which seven were discovered by both systematic and targeted biopsy, one was diagnosed by systematic biopsy only, and two were diagnosed by targeted biopsy only. For systematic biopsy, Gleason score ranged from 6 to 8 (average: 7), while that for targeted biopsy ranged from 6 to 9 (average: 7.67). Among the seven patients that were diagnosed by both systematic and targeted biopsy, three (42.8%) were reported with a higher Gleason score in targeted therapy than in systematic biopsy. Conclusion: 3D printing-assisted cognitive fusion technique markedly promoted positive rate in prostate biopsy, and reduced missed detection in high-risk prostate cancer. PMID- 29264149 TI - Does the presence of a percutaneous renal access influence fluoroscopy time during percutaneous nephrolithotomy? AB - Objective: The aim of this study was to assess whether the presence of a pre formed percutaneous renal access (PCA) had any effects on fluoroscopy time (FT) during percutaneous nephrolithotomy (PCNL). Methods: After ethics approval was obtained, medical records of all patients who underwent PCNL between 2009 and 2013 at a tertiary stone referral centre were retrospectively reviewed. Patients with and without pre-formed PCA undergoing PCNL were compared. Patients who underwent second-look PCNL and those who had their access inserted by interventional radiology constituted the group with pre-formed PCA. Results: A total of 185 PCNLs were reviewed. The mean patient age was 55.2 +/- 1.0 years with mean body mass index (BMI) of 27.8 +/- 0.5 kg/m2 and male gender of 63.8%. The mean stone size was 618.4 +/- 47.0 mm2 with mean Guy's grade of 2.3 +/- 0.7 and mean S.T.O.N.E. score of 7.6 +/- 0.1. The mean operative time was 98.7 +/- 2.6 min with mean FT of 113.4 +/- 4.5 s. The overall stone-free rate was 71.9% with complication rate of 16.2%. When compared with PCNLs without pre-formed PCA, PCNLs with pre-formed PCA were associated with significantly shorter FT (120.6 +/ 5.1 vs. 77.5 +/- 6.7 s; p < 0.001) and significantly lower estimated blood loss (EBL) (p = 0.01). On multivariate analysis, PCNLs with pre-formed PCA were associated with significantly shorter FT (B. coefficient = -43.2 (95%CI: -66.4 to -20); p < 0.001) and lower EBL (p = 0.02). Conclusion: PCNLs with pre-formed PCA were associated with significantly lower FT and EBL when compared with PCNLs without pre-formed PCA. PMID- 29264150 TI - Prostate chronic inflammation type IV and prostate cancer risk in patients undergoing first biopsy set: Results of a large cohort study. AB - Objective: In prostate specimens, chronic inflammatory infiltrate (CII) type IV has been detected, but its association with prostate cancer (PCa) is controversial. The aim of the present study is to investigate on associations of CII with PCa detection in patients undergoing prostate first biopsy set. Methods: Ultrasound transrectal-guided biopsies by the transperineal approach were retrospectively evaluated in 441 consecutive patients. The study excluded patients who were in active surveillance, prostate specific antigen (PSA) >=30 ng/mL, re-biopsies, incidental PCa after transurethral resection of the prostate (TURP), less than 14 cores or metastatic. Analysis of population and subpopulations (with or without PCa) was performed by statistical methods which included Mann-Whitney (U test), Kruskal-Wallis test, Chi-squared statistic, logistic regression. Multivariate logistic regression models predicting mean probability of PCa detection were established. Results: PCa detection rate was 46.03%. Age, PSA, prostate volume (PV), prostate intraepithelial neoplasia (PIN) and CII were the significant independent predictors of PCa detection. PV (OR = 0.934) and CII (OR = 0.192) were both negative independent predictors. CII was a significant negative independent predictor in multivariate logistic regression models predicting the mean probability of PCa detection by age, PSA and PV. The inverse association of CII with PCa does not necessary mean protection because of PSA confounding. Conclusion: In a population of patients undergoing prostate first biopsy set, CII was a strong negative independent predictor of PCa detection. CII type IV should be considered as an adjunctive parameter in re biopsy or active surveillance protocols. PMID- 29264151 TI - Implication of ultrasound bladder parameters on treatment response in patients with benign prostatic hyperplasia under medical management. AB - Objective: The prevalence of benign prostatic hyperplasia (BPH) rapidly increases after the 4th decade of life. The combination of tamsulosin and dutasteride is a well established therapy for BPH of >=40 g. Non-invasive urodynamic parameters can predict the outcome of medical therapy in patients with BPH. We aimed to correlate these parameters with treatment responses in BPH patients under medical management. Methods: A prospective study was conducted in the Department of Urology in our hospital from May 2014 to April 2015. A total of 100 patients with BPH >=40 g who fulfilled our inclusion criteria were included. Treatment responses were determined by the International Prostate Symptom Score (IPSS) and uroflowmetry. Transabdominal ultrasonography with Doppler was performed to measure prostate volume, intravesical prostatic protrusion (IPP), detrusor wall thickness (DWT), the prostatic capsular artery resistive index (RI) and prostatic urethral angle (PUA) before and 3 months after combination therapy of tamsulosin and dutasteride. Treatment responses were correlated with non-invasive urodynamic parameters. Results: The IPSS, uroflow, age, prostate volume, RI, IPP, DWT and PUA were correlated before and after treatment. Of the 100 patients, 70 (70%) showed significant improvement and 30 (30%) showed no improvement with therapy. Conclusion: Ultrasound bladder parameters are useful tools for measuring the treatment response in BPH patients. Our study shows that RI and DWT significantly correlate with the treatment response in BPH patients. More importantly, pretreatment values of increased IPP and PUA determines the non-improvement of symptoms in BPH patients. Our study suggests the importance of transabdominal ultrasonography (KUB-P) with Doppler for evaluating treatment responses to medical management. PMID- 29264152 TI - Laparoscopic ureterolysis with simultaneous ureteroscopy and percutaneous nephroscopy for treating complex ureteral obstruction after failed endoscopic intervention: A technical report. AB - Objective: Complex ureteral obstruction is refractory to conventional urological intervention. This report describes a case of laparoscopic ureterolysis with simultaneous ureteroscopy and percutaneous nephroscopy for treating complex ureteral obstruction. Methods: Right-side multiple ureteral stones and complicating ureteral obstruction failed an initial attempt of ureteroscopy lithotripsy with simultaneous percutaneous nephroscopy in a 23-year-old male. Laparoscopic ureterolysis with ureteroscopy and percutaneous nephroscopy was used simultaneously to dissect the periureteral adhesions with the patient placed in the Galdakao-modified supine Valdivia position. The ureter was incised to allow the insertion of a ureteral catheter through the twisted ureter, and a guide wire was advanced into the pelvis using ureteroscopy. A double-J stent was placed into the right-side ureter using antegrade percutaneous nephroscopy. Results: The laparoendoscopic procedure lasted 330 min with an estimated bleeding volume of 100 mL. The patient underwent an uneventful postoperative course, and postoperative follow-up radiography confirmed good positioning of the double-J stent. The double-J stent was removed 3 months after operation. The patient remained asymptomatic within a 13-month follow-up period. Conclusion: Laparoscopic ureterolysis with simultaneous ureteroscopy and percutaneous nephroscopy is an effective and safe treatment option for complex ureteral obstruction. PMID- 29264153 TI - Stellate scar sign of renal cell carcinoma. PMID- 29264154 TI - PMEPA1 guards against TGF-beta-mediated prostate cancer bone metastasis. PMID- 29264155 TI - Acute kidney injury in China: A neglected truth and perspective. PMID- 29264156 TI - Solving the benign prostatic hyperplasia puzzle. PMID- 29264157 TI - Relationship between urodynamic patterns and lower urinary tract symptoms in Chinese women with a non-neurogenic bladder. AB - Objective: To investigate the urodynamic study (UDS) patterns, obstruction status, continence status, and their correlations among neurologically intact women with lower urinary tract symptoms (LUTS) through an epidemiological and logistic regression analyses. Methods: We retrospectively analyzed the UDS data of 3265 neurologically intact women with LUTS (2002-2014). Five UDS patterns were identified: normo-active detrusor/sphincter (NA, or DSI, detrusor/sphincter intact), idiopathic detrusor overactivity (IDO), idiopathic sphincter overactivity (ISO), IDO + ISO, and detrusor underactivity (DUA). Analyses of UDS pattern distribution and stratification were performed (based on a modification of the European Urological Association-Madersbacher classification system), and their correlations with bladder outlet obstruction (BOO) and stress urinary incontinence (SUI) status were evaluated via logistic regression analysis. Results: NA, IDO, IDO + ISO, ISO, and DUA were noted in 927 (28.4%), 678 (20.8%), 320 (9.8%), 689 (21.1%), and 651 (19.9%) cases, respectively. Moreover, storage, storage + voiding, and voiding symptoms were noted in 62.4%, 21.1%, and 16.5% cases, respectively, whereas BOO and SUI were observed in 12.1% and 29.0% cases, respectively. The risk factors for BOO included NA, IDO, ISO, and IDO + ISO, whereas the protective factors against BOO included storage symptoms, SUI, storage + voiding symptoms, and complaint duration within 1-12 months. NA was the only risk factor for SUI, whereas BOO, storage + voiding symptoms, IDO, and storage symptoms were protective factors for SUI. Conclusion: Five UDS patterns were identified among neurologically intact women with LUTS. Functional abnormalities of the detrusor and/or sphincter were the main causes of LUTS, and were correlated with the BOO or SUI status. Thus, the UDS pattern can provide additional information regarding the risk factors for BOO or SUI status, as compared to symptomatic typing. PMID- 29264158 TI - Elevated preoperative neutrophil-to-lymphocyte ratio may be associated with decreased overall survival in patients with metastatic clear cell renal cell carcinoma undergoing cytoreductive nephrectomy. AB - Objective: Inflammatory serum markers have proven to be a powerful predictive tool of patient prognosis in cancer treatment for a wide variety of solid organ malignancies, predominantly in the context of localized disease. In this study we evaluated the preoperative neutrophil-to-lymphocyte ratio (NLR) as a predictive tool in patients with metastatic clear cell renal cell carcinoma (RCC). Methods: Sixty-four patients with metastatic clear cell RCC undergoing nephrectomy were selected. Only patients with preoperative NLR were included for survival analysis. Patients were categorized into high and low NLR score determined by plotting the NLR ROC curve. Multivariable analysis was performed. Results: Median age was 60.8 years (38.2-81.2). Median follow-up time was 8.1 months (0.1-106.3). Fuhrman grade distribution was: 2 (3.1%) grade 1, 6 (9.4%) grade 2, 24 (37.5%) grade 3 and 32 (50.0%) grade 4. Median NLR score was 3.5 (1.4-31.0). NLR >= 4 was associated with decreased overall survival compared to NLR < 4 (p = 0.017). Multivariable survival analysis showed NLR >= 4 as an independent predictor of survival (Hazard ratio (HR) 2.41, 95%CI 1.05-5.50, p = 0.03). Conclusion: Elevated preoperative NLR is associated with poor prognosis in patients with metastatic kidney cancer. Preoperative NLR is a useful tool, which can predict prognosis, stratify patients for postoperative surveillance, and help guide decisions for therapy. PMID- 29264159 TI - Prostate cancer volume associates with preoperative plasma levels of testosterone that independently predicts high grade tumours which show low densities (quotient testosterone/tumour volume). AB - Objective: To investigate potential associations of preoperative total testosterone (TT) with tumor volume (TV) and grade of prostate cancer (PCa). Methods: Patients who were under medications impacting on the hypothalamic pituitary-adrenal-testis-prostate axis were excluded. TT was measured preoperatively at least 1 month after biopsies and TV was calculated on the removed prostate specimen. Other continuous variables included total prostate specific antigen (PSA), percentage of positive cores (P+) and weight (W) of the removed prostate. Patients were categorized according to the pathologic Gleason score (pGS) in 3 groups (pGS 6, 7 and > 7). Invasion of the seminal vesicles was coded as seminal vesicle invasion (SVI). Results: The median levels of TT were significantly and increasingly higher from pGS 6 (14.7 nmol/L) to pGS 7 (15.0 nmol/L) and pGS > 7 (18.8 nmol/L). The median values of TV were also detected significantly and increasingly higher from pGS 6 (5.6 mL) to pGS 7 (8.1 mL) and pGS > 7 (14.8 mL). The median preoperative levels of PSA were also increasing from pGS 6 (5.9 MUg/L) to pGS 7 (6.2 MUg/L) and pGS > 7 (7.7 MUg/L). There was a significant and positive correlation of TV to PSA, TT and P+. Multiple linear regression analysis showed that TV was significantly and independently predicted by TT, PSA and P+. High grade PCa (pGS > 7) independently associated with TV, TT, P+ and SVI. The median density values of TT relative to TV (quotient TT/TV) significantly decreased from pGS 6 (2.6 nmol/L/mL) to pGS 7 (1.9 nmol/L/mL) and pGS > 7 (1.4 nmol/L/mL). The median density values of PSA relative to TV (quotient PSA/TV) also significantly decreased from pGS (1.1 MUg/L/mL) to pGS 7 (0.7 MUg/L/mL) and pGS > 7 (0.6 MUg/L/mL). Conclusion: The investigation shows that TT relates to volume and grade of PCa; moreover, the density of TT relative to TV inversely associates with rate of increase of cancer that depends on the grade of the tumour. PMID- 29264160 TI - Zoledronic acid combined with androgen-deprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naive metastatic prostate cancer patients - A propensity scoring approach. AB - Objective: To clarify the oncological benefit of zoledronic acid for hormone naive metastatic prostate cancer, patient outcome of androgen deprivation therapy with zoledronic acid (ADT + Z) and androgen deprivation therapy alone (ADT) was compared. Methods: Fifty-two patients with pathologically confirmed metastatic prostate cancer were prospectively enrolled and treated with combined androgen blockade (goserelin and bicalutamide) with zoledronic acid (4 mg every 4 weeks for 24 months). A propensity score-match with logistic regression analysis was applied to select 50 pair-matched cohorts (both from ADT + Z and from historical control cohorts who had undergone ADT alone), and patient outcomes were compared. Results: Patients with ADT + Z had significantly longer time to progression (TTP) than those with ADT (median TTP; 24.2 vs. 14.0 months, p = 0.0092), while no significant difference of overall survival between two groups (p = 0.1502). Multivariate analysis for biochemical recurrence revealed treatment with ADT was the sole independent prognostic factor (HR: 1.724, 95% CI: 1.06-2.86, p = 0.0297). Conclusion: Combination of zoledronic acid with ADT may prolong time to castration resistant prostate cancer. PMID- 29264161 TI - Can intravesical prostatic protrusion predict bladder outlet obstruction even in men with good flow? AB - Objective: Men with benign prostate hyperplasia (BPH) with good urinary flow may still have bladder outlet obstruction (BOO). Intravesical prostatic protrusion (IPP) has been shown to be able to predict BOO. We aim to investigate the use of IPP to predict BOO in men with good urinary flow. Methods: One hundred and fourteen consecutive men (>50 years old) presenting with lower urinary tract symptoms suggestive of BPH were recruited in 2001 and 2002. They were evaluated with serum prostate specific antigen (PSA), uroflowmetry and transabdominal ultrasound measurement of IPP and prostate volume (PV). Pressure-flow urodynamic studies were performed on all men and BOO was defined by BOO index > 40. Men with Qmax >= 12.0 mL/s were considered to have good flow. Results: Among the 114 men, 61 patients had good urinary flow. Their median age, PV and Qmax were 66 years, 32.9 mm3 and 14.5 mL/s respectively. 14/61 (23.0%) patients had BOO and their distribution of IPP were as follows: Grade 1 - 0/20 (0%) obstructed, Grade 2 - 6/22 (27.3%) and Grade 3 - 8/19 (42.1%). Sensitivity of Grade 2/3 IPP for BOO was 100% while specificity of Grade 3 IPP was 76.6%. The area-under-curve (AUC) for IPP was greater than that for PV (0.757 vs. 0.696). Conclusion: Even in men with good flow, high grades of IPP were more likely to have BOO and hence, may be a useful adjunct to predict BOO. PMID- 29264162 TI - Who needs further evaluations to diagnose upper urinary tract urothelial cancers among patients with abnormal findings by enhanced CT? AB - Objective: We evaluated who would need further evaluations such as retrograde pyelography (RP) and/or ureteroscopy to diagnose upper urinary tract urothelial cancers (UUTUCs) when abnormal findings for the upper urinary tract (UUT) were detected by enhanced computed tomography (CT). Methods: We retrospectively analyzed 125 patients who underwent enhanced CT for various reasons and had abnormal findings for the UUT. Patients whose tumors were suspected to be of extraureteral origin were excluded. All patients received RP and/or ureteroscopy to evaluate the UUTUCs. Results: The median age of the 125 patients was 70 years and gross hematuria (26.4%) was the most frequently observed symptoms. RP, ureteroscopy and both were performed for 121, 59 and 55 patients, respectively. CT revealed tumor-like lesions in 58 patients and the other patients had non tumor-like lesions. UUTUCs were found in 43 (34.4%) of the 125 patients. All of them had tumor-like lesions on CT. In 58 patients who had tumor-like lesions on CT, univariate and multivariate analyses revealed that tumor diameter and tumor enhancement were significant predictive factors for UUTUCs. ROC curve analysis of enhanced CT to diagnose UUTUCs revealed that a tumor diameter of 18 mm was the best cutoff point. The sensitivity, specificity and accuracy were 90.0%, 98.8% and 92.7% for RP and 95.5%, 100% and 97.1% for ureteroscopy, respectively. Both of them had high sensitivity, specificity and accuracy. Conclusion: We should decide to evaluate the UUT according to the tumor diameter on enhanced CT. When we evaluate the UUT in patients with tumor diameters of less than 20 mm, ureteroscopy is recommended. PMID- 29264163 TI - Tumour lysis syndrome: A rare acute presentation of locally advanced testicular cancer - Case report and review of literature. AB - Tumour lysis syndrome (TLS) is a potentially fatal complication of malignancy or its treatment. This uncommon syndrome comprises laboratory findings of hyperuricaemia, hypocalcaemia, hyperkalaemia and hyperphosphataemia. A literature search revealed a total of eight patients, with testicular cancer, who had TLS. All these patients had metastatic disease. We present a unique case of a 47-year old gentleman we saw in clinic, who presented with a rapidly growing right groin mass and acute breathlessness, and discuss the diagnosis and management of TLS. TLS is extremely rare in testicular cancer but necessitates the awareness of urologists. TLS can occur spontaneously in testicular malignancy. Cell lysis in a rapidly proliferating germ cell tumour is a possible mechanism. The prompt identification and institution of management for TLS is crucial to improve clinical outcomes. PMID- 29264164 TI - A case of giant prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is one of the most common conditions experienced by aging males and a frequent cause of bladder outlet obstruction and macroscopic haematuria. Giant prostatic hyperplasia (GPH) is an extremely rare form of prostatic hyperplasia. We present a case of a patient with GPH of 800 mL. To our knowledge, this is the fourth largest prostatic hyperplasia ever reported in the literature. PMID- 29264165 TI - Unusual case of nephrocutaneous fistula - Our experience. AB - A rare case of nephrococutaneous fistula due to spontaneous expulsion of renal calculi is described. A 45-year-old man presented with urinary leakage from an ulcer over the left lumbar region for the last 3 months after a history of spontaneous expulsion of stones from this area. Ultrasonography abdomen revealed a small contracted kidney with multiple calculi in the kidney and renal pelvis, sinus tract from the lower pole of the left kidney with a ruptured calyceal calculus in the sinus tract. CT urography revealed a non excreting left kidney with multiple renal calculi, with hyperdense collection in the renal parenchyma extending to the subcutaneous tissue and left lung suggesting a xenthogranulomatous pyelonephritis (XGP). We performed a left-sided simple nephrectomy with excision of the fistulous tract. Histopathological examination revealed XGP. There have been a few case reports of XGP forming nephrocutaneous fistula in the back. PMID- 29264166 TI - Prostate specific antigen bounce after intensity-modulated radiation therapy in an Asian population. AB - Objective: Serum prostate specific antigen (PSA) is commonly used to evaluate treatment response after definitive radiation therapy (RT). However, PSA levels can temporarily rise without a clear reason, termed "PSA bounce", and often engender great anxiety for both patients and physicians. The present study aimed to determine the prevalence and factors that predict "PSA bounce" after intensity modulated radiation therapy (IMRT), and the relevance to biochemical failure and cancer recurrence in an Asian population. Methods: We retrospectively reviewed 206 patients who received IMRT for prostate cancer from 2004 to 2012 in the National Cancer Centre Singapore. These patients were followed up with regular PSA monitoring. We defined "PSA bounce" as a rise of 0.1 ng/mL, followed by two consecutive falls. Patients with biochemical failure (PSA nadir + 2 ng/mL) were further evaluated for cancer recurrence. Results: Sixty-one patients (29.6%) experienced "PSA bounce", at a median time of 16 months and lasted for 12 months. Age remained the most consistent predictor of the incidence, duration and extent of "PSA bounce". Other contributory factors included baseline PSA, Gleason score and PSA nadir. Hormonal therapy and prostate volume did not affect this phenomenon. Sixteen patients (7.8%) developed biochemical recurrence, at median time of 32 months, of which 11 were confirmed to have metastatic disease. The median follow-up time was 71 months. Conclusion: A younger age predicts PSA bounce incidence, duration and magnitude. The extent of bounce appears to be lower in Asian population. The interval to occurrence and extent of PSA elevation separates PSA bounce from disease recurrence. PMID- 29264168 TI - Major histocompatibility complex I upregulation in clear cell renal cell carcinoma is associated with increased survival. AB - Objective: To examine the prognostic value of tumor major histocompatibility complex I (MHCI) expression on survival and recurrence in patients with clear cell renal cell carcinoma (RCC). Methods: Fifty-three patients that underwent nephrectomy at our institution for clear cell RCC (T1-T3) with >=4 years of follow-up were queried from our nephrectomy database. Immunohistochemical staining for MHCI was performed on tumor specimens and MHCI expression was quantified with an automated image analysis technique. Patients were divided into high and low MHCI expression groups in order to study the relationship between MHCI expression and prognosis using the Kaplan-Meier method and log-rank test. Results: Overall survival and recurrence free survival were increased in the high MHCI expression group compared to the low MHCI expression group (log-rank, p = 0.036 and p = 0.028, respectively). Patients alive at the end of the study had higher MHCI expression (mean positivity score 0.82) than those that died of disease (mean positivity score 0.76, t test, p = 0.030). Patients that did not develop recurrence during the study period had higher MHCI expression (mean positivity score 0.83) than those that did develop recurrence (mean positivity score 0.78), but this difference was not significant (t test, p = 0.079). Conclusion: Our data demonstrate that high MHCI expression confers improved overall and recurrence free survival in patients with clear cell RCC and could serve as an important prognostic tool in identifying high-risk patients. PMID- 29264169 TI - Risk factors for fever and sepsis after percutaneous nephrolithotomy. AB - Objective: Percutaneous nephrolithotomy (PCNL) is commonly used in the management of large renal stones. Postoperative infections are one of the most common complications of this procedure. The present study is to determine and assess the factors that may increase the risk to develop fever and urinary sepsis after PCNL. Methods: A total of 60 patients (38 males and 22 females) with a mean age of 40.25 years enrolled in this study in Sulaimania Teaching Hospital. Patients had renal stone disease need operation with different socioeconomic status, body mass index and different type and size of stones were included in this study. Patients with preoperative positive urine culture and sensitivity were excluded. Preoperative investigations done for all patients. All Patients received prophylactic antibiotic gentamicin intravenously at the induction of anaesthesia. Renal pelvis urine sample were taken from all patients after puncturing the pelvicalyceal system and send for culture and sensitivity. Patients were monitored closely in the postoperative period for the development of fever and sepsis. Results: Mean duration of the operations was 77.08 min ranged 40-120 min. All patients had postoperative nephrostomy tube. Seventeen (28.33%) patients developed post PCNL fever and the statistically significant factors for post PCNL fever were diabetes mellitus (DM) (p = 0.001), stone burden (p = 0.001), number of the stones (p < 0.001), degree of hydronephrosis (p = 0.001), duration of the operation (p < 0.001), residual stones (p = 0.001) and number of tracts (p = 0.038). Three (5.00%) patients developed post PCNL sepsis, and the statistically significant risk factors for post PCNL sepsis were duration of the operation (p = 0.013) and intraoperative blood loss, postoperative drop in haemoglobin (HB) level (p = 0.046). Conclusion: DM, staghorn stones, degree of hydronephrosis, duration of the operation and number of tracts are risk factors for post PCNL fever, while number of stones, intraoperative blood loss, duration of the operation and residual stones are risk factors for post PCNL sepsis. PMID- 29264167 TI - Advances in prostate cancer research models: From transgenic mice to tumor xenografting models. AB - The identification of the origin and molecular characteristics of prostate cancer (PCa) has crucial implications for personalized treatment. The development of effective treatments for PCa has been limited; however, the recent establishment of several transgenic mouse lines and/or xenografting models is better reflecting the disease in vivo. With appropriate models, valuable tools for elucidating the functions of specific genes have gone deep into prostate development and carcinogenesis. In the present review, we summarize a number of important PCa research models established in our laboratories (PSA-Cre-ERT2/PTEN transgenic mouse models, AP-OX model, tissue recombination-xenografting models and PDX models), which represent advances of translational models from transgenic mouse lines to human tumor xenografting. Better understanding of the developments of these models will offer new insights into tumor progression and may help explain the functional significance of genetic variations in PCa. Additionally, this understanding could lead to new modes for curing PCa based on their particular biological phenotypes. PMID- 29264170 TI - Robotic assisted radical prostatectomy accelerates postoperative stress recovery: Final results of a contemporary prospective study assessing pathophysiology of cortisol peri-operative kinetics in prostate cancer surgery. AB - Objective: To investigate the effects of prostate cancer (PCa) surgery on the stress system and to identify potential independent factors associating with stress recovery. Methods: The design of the study was prospective and PCa surgery included robot assisted radical prostatectomy (RARP) or retropubic radical prostatectomy (RRP). Between February 2013 to December 2014, 315 consecutive patients were evaluated. The effects of PCa surgery on the stress system were measured by cortisol serum levels before and after surgery on postoperative day (POD) 0, 1, 3, 5 and 45. Cortisol variations in the population and subpopulation (RARP vs. RRP) of patients were investigated by statistical methods. Factors associating with stress recovery were assessed by simple linear regression (SLR) and multiple linear regression (MLR) analysis. Results: RARP was performed in 75.9% of cases. In the patient population, there were wide serum cortisol perioperative variations. PCa surgery triggered the stress system which immediately (POD 0) responded by cortisol overproduction which induced the negative feedback mechanism that started on POD 1, continued on POD 3, was still ongoing on POD 5 and completely settled on POD 45 (stress recovery). In the subpopulation of patients, significantly lower cortisol serum levels were detected on POD 3-5 in RARP cases in whom cortisol levels were close to preoperative levels (stress recovery) on POD 5. Independent predictive factors of serum cortisol on POD 5 (stress recovery) were preoperative cortisol (p = 0.02), cortisol levels on POD 3 (p < 0.0001) and RARP (p = 0.03) in which the association was negative (stress recovery faster than RRP). Conclusion: Our study shows that PCa surgery immediately (POD 0) triggers the stress system which respond by overproduction of cortisol which induces the negative feedback mechanism that starts on POD 1, is still ongoing on POD 5, but is completely settled on POD 45. Moreover, after surgical trauma, our study gives evidence that the RARP procedure associates with stress recovery faster than RRP. Further confirmatory studies are required. PMID- 29264171 TI - Glass ampoule in urinary bladder as a foreign body. AB - A wide range of objects have been inserted into the urinary bladder and urethra. Most foreign bodies in the lower genitourinary tract are self-inserted via the urethra as the result of erotic impulses, psychometric problems, sexual curiosity, or sexual practice while intoxicated. Here we report the case of a 32 year-old female with alleged history of insertion of glass ampoule in the urethra by the husband in eroticism which was removed with open surgery. This is the first case of its kind as per the literature available. PMID- 29264172 TI - Pediatric fibrous pseudotumor of the tunica vaginalis testis. AB - We describe a 16-year-old male with ultrasound evidence of a 1.3 cm right paratesticular nodule, which was managed by intraoperative frozen section and excisional biopsy. The pathologic findings were consistent with benign fibrous pseudotumor of the tunica vaginalis testis, which is a very rare lesion in the pediatric population. Consideration of fibrous pseudotumor in the differential diagnosis of pediatric paratesticular masses may help prevent unnecessarily aggressive therapy. PMID- 29264173 TI - Prostatic sarcoma of the Ewing family in a 33-year-old male - A case report and review of the literature. AB - Ewing sarcoma is the second most common primary bone tumor seen in children and adolescents, typically presenting between 10 and 20 years of age. Extraosseous sarcomas of the Ewing family in adults are rare. We report a manifestation of this tumor entity in the periprostatic tissue of a 33-year-old male and discuss our treatment approach. Transrectal biopsy is a feasible and simple diagnostic tool for unclear pelvic masses. Multi-modal therapy and central registries are needed to gain knowledge of rare pelvic tumors like Ewing sarcoma. PMID- 29264174 TI - Retrocaval ureter presenting at 6 years of age in a girl child - An extreme rarity. AB - Retrocaval ureter is one of the very rare congenital anomalies. We report a case of retrocaval ureter in a 6-year-old girl who presented with right flank pain and hydronephrosis. The diagnosis was made on intravenous urography which showed typical "J" shape deformity in the proximal dilated ureter with moderate hydronephrosis. CT scan delineated the course of ureter. The patient was operated and findings were confirmed. The ureter was transected near the pelvis and a pyeloureteric anastomosis with pre-caval transposition of the ureter was performed and the patient was discharged in fair health. PMID- 29264175 TI - Thulium laser coagulation for venous malformations of glans penis. PMID- 29264176 TI - Recent advances in oncological endourology. PMID- 29264177 TI - Laparoscopic nephroureterectomy for upper tract urothelial carcinoma - Update. AB - Upper urinary tract urothelial carcinomas (UTUCs) are uncommon and account for only 5%-10% of urothelial carcinomas. Pyelocaliceal tumors are about twice as common as ureteral tumors. Sixty percent of UTUCs are invasive at diagnosis. Radical nephroureterectomy, including the excision of the distal ureter and bladder cuff is standard of care for treatment of localized UTUCs, because of the high potential for recurrence, multifocality, and progression. Since first laparoscopic nephroureterectomy (LNU) was introduced by Clayman et al. in 1991 and improvement of laparoscopic technique and equipment, LNU has been reported to be equivalent to conventional open method. We reviewed the current literature of patients with UTUCs treated by LNU focusing on technical aspects, peri-operative and oncological outcomes. Laparoscopic radical nephroureterectomy offers the advantages of minimally invasive surgery without deteriorating the oncological outcome for treatment of UTUCs. Indications tend to increase as operator skills increase. Indications for laparoscopic or open nephroureterectomy are in principle the same. The basic requirement for laparoscopic surgery in UTUCs is to achieve benefits of minimal invasive surgery and maintain oncologic principles. PMID- 29264178 TI - Techniques to resect the distal ureter in robotic/laparoscopic nephroureterectomy. AB - Treatment of clinically-organ confined high grade urothelial carcinoma of the upper tract has historically comprised open nephroureterectomy, with the distal ureter and bladder cuff mobilized through a separate open pelvic incision. To decrease morbidity, urologists have increasingly adopted laparoscopy and robotics in performing nephroureterectomy. In many published series of laparoscopic nephroureterectomy, the distal ureter and bladder cuff are detached from the bladder endoscopically by a variation of the "pluck" technique, with the resulting bladder defect left to heal by prolonged indwelling urethral catheter drainage. While the distal ureter and bladder cuff can be excised laparoscopically, it does require advanced laparoscopic skills. With the wrist articulation and stereoscopic vision in robotic surgery, robotic nephroureterectomy (RNU) and bladder cuff excision can be performed in antegrade fashion to mimic the open technique together with the ability to intracorporeally close the bladder defect in a watertight, mucosa to mucosa fashion after excising the bladder cuff. In this review, we discuss the published minimally invasive techniques in resecting the distal ureter and bladder cuff during laparoscopic and RNU. PMID- 29264179 TI - Narrow band imaging for bladder cancer. AB - Narrow band imaging (NBI) is a newly developed technology aiming to provide additional endoscopic information for patients with bladder cancer. This review focuses on the diagnostic accuracy and treatment outcome using NBI cystoscopy for the treatment of non-muscle invasive bladder cancer. Current results showed improved sensitivity of NBI cystoscopy compared to conventional white light cystoscopy, although lower specificity and increased false-positive results were reported using NBI cystoscopy. The treatment outcome using NBI technology in transurethral resection of bladder tumor had a positive impact while decreased number of residual tumors and tumor recurrence at follow-up were reported. In the future, the application of NBI technology might refine the treatment and follow up protocol in patients with non-muscle invasive bladder cancer. However, this large scale prospective studies are required to confirm the real cost effectiveness of this new technology. PMID- 29264180 TI - Thulium laser treatment for bladder cancer. AB - Recent innovations in thulium laser techniques have allowed application in the treatment of bladder cancer. Laser en bloc resection of bladder cancer is a transurethral procedure that may offer an alternative to the conventional transurethral resection procedure. We conducted a review of basic thulium laser physics and laser en bloc resection procedures and summarized the current clinical literature with a focus on complications and outcomes. Literature evidence suggests that thulium laser techniques including smooth incision, tissue vaporization, and en bloc resection represent feasible, safe, and effective procedures in the treatment of bladder cancer. Moreover, these techniques allow improved specimen orientation and accurate determination of invasion depth, facilitating correct diagnosis, restaging, and re-evaluation of the need for a second resection. Nonetheless, large-scale multicentre studies with longer follow up are warranted for a robust assessment. The present review is meant as a quick reference for urologists. PMID- 29264181 TI - Percutaneous resection of upper tract urothelial cell carcinoma: When, how, and is it safe? AB - Introduction: In the management of upper tract urothelial cell carcinoma (UTUC) endoscopic, nephron sparing procedures like ureterorenoscopy (URS) or percutaneous tumour resection (PCTR) still play a very limited role. This could lead to possible unnecessary radical nephroureterectomies (RNU), still being the gold standard treatment. The risk of chronic kidney disease (CKD) later in life is important. In this study we present the results of 24-year experience with PCTR in a single institution. Methods: We identified 44 patients who underwent PCTR between 1992 and 2015. Radical resection was achieved in 40 patients who were included in this study. Demographic and clinical data, including tumour recurrence, progression to RNU, tumour grade and overall survival (OS) were retrospectively acquired. An outcome analysis was conducted. Results: Median age at diagnosis was 68 years (range 42-94 years). Low grade tumours were found in 37 patients (92.5%) and high grade tumours in three patients (7.5%). Median follow up was 53 months during which 20 patients developed upper tract recurrences (50.0%). The longest time to recurrence was 97 months. At follow-up 11 patients (27.5%) underwent an RNU and two patients died from UTUC. RNU could be avoided in 29 patients (72.5%). In this study we found that multifocality is a significant risk factor for recurrence, but not for stage progression to RNU. Conclusion: PCTR is a surgically and oncologically safe procedure. Renal preservation in patients with UTUC who are eligible for percutaneous resection can be achieved in the majority of patients. Selection criteria for PCTR should be further refined, leading to a wider application of PCTR in the future. Follow-up needs invasive procedures and should be long term. PMID- 29264182 TI - Stents for malignant ureteral obstruction. AB - Malignant ureteral obstruction can result in renal dysfunction or urosepsis and can limit the physician's ability to treat the underlying cancer. There are multiple methods to deal with ureteral obstruction including regular polymeric double J stents (DJS), tandem DJS, nephrostomy tubes, and then more specialized products such as solid metal stents (e.g., Resonance Stent, Cook Medical) and polyurethane stents reinforced with nickel-titanium (e.g., UVENTA stents, TaeWoong Medical). In patients who require long-term stenting, a nephrostomy tube could be transformed subcutaneously into an extra-anatomic stent that is then inserted into the bladder subcutaneously. We outline the most recent developments published since 2012 and report on identifiable risk factors that predict for failure of urinary drainage. These failures are typically a sign of cancer progression and the natural history of the disease rather than the individual type of drainage device. Factors that were identified to predict drainage failure included low serum albumin, bilateral hydronephrosis, elevated C-reactive protein, and the presence of pleural effusion. Head-to-head studies show that metal stents are superior to polymeric DJS in terms of maintaining patency. Discussions with the patient should take into consideration the frequency that exchanges will be needed, the need for externalized hardware (with nephrostomy tubes), or severe urinary symptoms in the case of internal DJS. This review will highlight the current state of diversions in the setting of malignant ureteral obstruction. PMID- 29264183 TI - Current status of laparoscopic and robot-assisted nerve-sparing radical cystectomy in male patients. AB - During radical cystectomy (RC), the neurovascular bundles are easily removed or damaged, leading to varying rates of incontinence and erectile dysfunction. The nerve-sparing technique was developed to preserve urinary and erectile function. The adoption of laparoscopic and robot-assisted technology has improved visualization and dexterity of pelvic surgeries, thus facilitate the nerve sparing technique. Although nerve-sparing RC is technically similar with nerve sparing radical prostatectomy, there are still some anatomical differences. There are mainly three different types of nerve-sparing techniques. Pelvic lymph node dissection (PLND) is another important factor to influence erectile function and urinary continence. Nerve-sparing laparoscopic radical cystectomy (LRC) and robot assisted radical cystectomy (RARC) may be an optimal treatment choice in well selected younger patients with low-volume, organ-confined disease. We should attempt to do, whenever possible, a nerve-sparing cystectomy at least on oneside. However, due to the need of a well-refined surgical technique, nerve-sparing LRC and RARC is now being performed only by experienced urological surgeons. PMID- 29264185 TI - Biology and therapy of urological cancer metastasis. PMID- 29264184 TI - Robot-assisted laparoscopic radical cystectomy with complete intracorporeal urinary diversion. AB - Robot-assisted radical cystectomy with intracorporeal urinary diversion (RARC ICUD) has only recently been explored as a viable surgical option for patients with muscle-invasive bladder cancer seeking satisfactory oncologic control while benefiting from minimally invasive surgical techniques. Inspired by earlier open and laparoscopic work, initial descriptions of RARC-ICUD were published in 2003, and have since been followed by multiple larger case series which have suggested promising outcomes for our patients. However, the rate of adoption has remained relatively slow when compared to other robot-assisted procedures such as the radical prostatectomy, likely owing to longer operative times, operative complexity, costs, and uncertainty regarding oncologic efficacy. The operative technique for RARC-ICUD has evolved over the past decade and several high-volume centers have shared tips to improve efficiency and make the operation possible for a growing number of urologists. Though there are still questions regarding economic costs, effectiveness, and generalizability of outcomes reported in published data, a growing dataset has brought us ever closer to the answers. Here, we present our current operative technique for RARC-ICUD and discuss the state of the literature so that the urologist may hold an informed discussion with his or her patients. PMID- 29264186 TI - Non-invasive actionable biomarkers for metastatic prostate cancer. AB - In the current clinical setting, many disease management options are available for men diagnosed with prostate cancer. For metastatic prostate cancer, first line therapies almost always involve agents designed to inhibit androgen receptor (AR) signaling. Castration-resistant prostate cancers (CRPCs) that arise following first-line androgen deprivation therapies (ADT) may continue to respond to additional lines of AR-targeting therapies (abiraterone and enzalutamide), chemotherapies (docetaxel and cabazitaxel), bone-targeting Radium-223 therapy, and immunotherapy sipuleucel-T. The rapidly expanding therapies for CRPC is expected to transform this lethal disease into one that can be managed for prolonged period of time. In the past 3 years, a number of promising biomarkers that may help to guide treatment decisions have been proposed and evaluated, including androgen receptor splice variant-7 (AR-V7), a truncated AR lacking the ligand-binding domain (LBD) and mediate constitutively-active AR signaling. Putative treatment selection markers such as AR-V7 may further improve survival benefit of existing therapies and help to accelerate development of new agents for metastatic prostate cancer. In the metastatic setting, it is important to consider compatibility between the putative biomarker with non-invasive sampling. In this review, biomarkers relevant to the setting of metastatic prostate cancer are discussed with respect to a number of key attributes critical for clinical development of non-invasive, actionable markers. It is envisioned that biomarkers for metastatic prostate cancer will continue to be discovered, developed, and refined to meet the unmet needs in both standard-of-care and clinical trial settings. PMID- 29264187 TI - Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell like transition? AB - Prostate cancers (PCa) have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment. There is mounting evidence that PCas may undergo an ''Epithelial Immune Cell-like Transition'' (EIT) by expressing molecules conventionally associated with immune cells (e.g., a variety of cytokines/receptors, immune transcription factors, Ig motifs, and immune checkpoint molecules), which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment. Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development, thus leading to the development of novel immunotherapeutic approaches. Here, we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells, with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa. Furthermore, we summarize current advances in anti-immune checkpoint therapies, and provide perspectives on their potential applicability. PMID- 29264188 TI - The evolving landscape of prostate cancer stem cell: Therapeutic implications and future challenges. AB - Prostate cancer (PCa) is the most common cause of malignancy in males and the second leading cause of cancer mortality in United States. Current treatments for PCa include surgery, radiotherapy, and androgen-deprivation therapy. Eventually, PCa relapses to an advanced castration-resistant PCa (CRPC) that becomes a systematic disease and incurable. Therefore, identifying cellular components and molecular mechanisms that drive aggressive PCa at early stage is critical for disease prognosis and therapeutic intervention. One potential strategy for aggressive PCa is to target cancer stem cells (CSCs) that are identified by several unique characteristics such as immortal, self-renewal, and pluripotency. Also, CSC is believed to be a major factor contributing to resistance to radiotherapy and conventional chemotherapies. Moreover, CSCs are thought to be the critical cause of metastasis, tumor recurrence and cancer-related death of multiple cancer types, including PCa. In this review, we discuss recent progress made in understanding prostate cancer stem cells (PCSCs). We focus on the therapeutic strategies aimed at targeting specific surface markers of CSCs, the key signaling pathways in the maintenance of self-renewal capacity of CSCs, ATP binding cassette (ABC) transporters that mediate the drug-resistance of CSCs, dysregulated microRNAs expression profiles in CSCs, and immunotherapeutic strategies developed against PCSCs surface markers. PMID- 29264190 TI - Mismatch repair enzyme expression in primary and castrate resistant prostate cancer. AB - Objective: Although the utility of immunohistochemistry (IHC) for assessing mismatch repair (MMR) protein expression has been demonstrated in solid tumors including primary prostate cancer (PCa), its utility has not been assessed in castration-resistant PCa (CRPC). Methods: Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 patients. MMR (MLH1, MSH2, MSH6, and PMS2) expression was assessed by IHC and gene expression arrays. Associations between MMR protein expression in PCa and CRPC and biochemical recurrence (BCR) or time from diagnosis to death respectively were determined. Results: There was no correlation between levels of MMR protein and BCR. Absence of MSH2 and MSH6 was the most pronounced at 15% and 22% in PCa and 17.8% and 16% in CRPC patients, respectively. MSH2 and MSH6 protein were absent in 9.4% and 8% of PCa and CRPC respectively. Absence of individual MMR proteins did not correlate with BCR or time from diagnosis to death. However absent MSH2/MSH6 in CRPC was associated with shorter time to death (p = 0.0006). Loss of MSH2 was verified at the gene expression level. This finding correlated with microsatellite instability previously reported in this CRPC cohort. Conclusion: The absence of MLH1, MSH2, MSH6, and PMS2 protein and combinations thereof are frequent in PCa. Loss of MSH2/MSH6 protein may predict poor outcome in patients with CRPC. PMID- 29264189 TI - Understanding the biology of urothelial cancer metastasis. AB - Management of unresectable urothelial cancer (UC) has been a clinical challenge for decades. While drug resistance is a key issue, precise understanding of biology of UC metastasis is another challenge for the improvement of treatment outcome of UC patients. Introduction of the cell biology concepts including epithelial-mesenchymal transition (EMT) and cancer stemness seems to explain UC metastasis. Molecular genetics based on gene expression profiling, next generation sequencing, and explosion of non-coding RNA world has opened the door to intrinsic molecular subtyping of UC. Next steps include, based on the recently accumulated understanding, the establishment of novel disease models representing UC metastasis in various experimental platforms, particularly in vivo animal systems. Indeed, novel knowledge molecular genetics has not been fully linked to the modeling of UC metastasis. Further understanding of bladder carcinogenesis is needed particularly with regard to cell of origin related to tumor characteristics including driver gene alterations, pathological differentiations, and metastatic ability. Then we will be able to establish better disease models, which will consequently lead us to further understanding of biology and eventually the development of novel therapeutic strategies for UC metastasis. PMID- 29264191 TI - Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer. AB - Objective: Bone metastasis occurs in up to 90% of men with advanced prostate cancer and leads to fractures, severe pain and therapy-resistance. Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients. Thus, the special environment of the bone makes the disease more complicated and incurable. A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments. The microstructural changes in the femurs of mice implanted with PCSD1, a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen, were determined. Methods: Quantitative micro-computed tomography (micro-CT) and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone (Control) into the right femurs of Rag2-/-gammac-/- male mice. Results: Bone lesions formed only in femurs of mice injected with PCSD1 cells. Bone volume (BV) was significantly decreased at the proximal and distal ends of the femurs (p < 0.01) whereas BV (p < 0.05) and bone shaft diameter (p < 0.01) were significantly increased along the femur shaft. Conclusion: PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur, and, in contrast, induced aberrant bone formation leading to osteoblastic lesions along the femur shaft. Therefore, the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion. Our approach can be used to determine if different bone regions support more therapy resistant tumor growth, thus, requiring novel treatments. PMID- 29264192 TI - Cultured circulating tumor cells and their derived xenografts for personalized oncology. AB - Recent cancer research has demonstrated the existence of circulating tumor cells (CTCs) in cancer patient's blood. Once identified, CTC biomarkers will be invaluable tools for clinical diagnosis, prognosis and treatment. In this review, we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample, to derive enough CTCs for accurate and reproducible characterization of the biophysical, biochemical, gene expressional and behavioral properties of the harvested cells. Because of tumor cell heterogeneity, it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis. By analyzing critical steps and technical issues in ex vivo CTC culture, we developed a cost effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells, relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells. PMID- 29264193 TI - Applications of circulating tumor cells for prostate cancer. AB - One of the major challenges that clinicians face is in the difficulties of accurately monitoring disease progression. Prostate cancer is among these diseases and greatly affects the health of men globally. Circulating tumor cells (CTCs) are a rare population of cancer cells that have shed from the primary tumor and entered the peripheral circulation. Not until recently, clinical applications of CTCs have been limited to using enumeration as a prognostic tool in Oncology. However, advances in emerging CTC technologies point toward new applications that could revolutionize the field of prostate cancer. It is now possible to study CTCs as components of a liquid biopsy based on morphological phenotypes, biochemical analyses, and genomic profiling. These advances allow us to gain insight into the heterogeneity and dynamics of cancer biology and to further study the mechanisms behind the evolution of therapeutic resistance. These recent developments utilizing CTCs for clinical applications will greatly impact the future of prostate cancer research and pave the way towards personalized care for men. PMID- 29264194 TI - Intrinsic subtypes and bladder cancer metastasis. AB - Recent studies demonstrated that bladder cancers can be grouped into basal and luminal molecular subtypes that possess distinct biological and clinical characteristics. Basal bladder cancers express biomarkers characteristic of cancer stem cells and epithelial-to-mesenchymal transition (EMT). Patients with basal cancers tend have more advanced stage and metastatic disease at presentation. In preclinical models basal human orthotopic xenografts are also more metastatic than luminal xenografts are, and they metastasize via an EMT dependent mechanism. However, preclinical and clinical data suggest that basal cancers are also more sensitive to neoadjuvant chemotherapy (NAC), such that most patients with basal cancers who are aggressively managed with NAC have excellent outcomes. Importantly, luminal bladder cancers can also progress to become invasive and metastatic, but they appear to do so via mechanisms that are much less dependent on EMT and may involve help from stromal cells, particularly cancer-associated fibroblasts (CAFs). Although patients with luminal cancers do not appear to derive much clinical benefit from NAC, the luminal tumors that are infiltrated with stromal cells appear to be sensitive to anti-PDL1 antibodies and possibly other immune checkpoint inhibitors. Therefore, neoadjuvant and/or adjuvant immunotherapy may be the most effective approach in treating patients with advanced or metastatic infiltrated luminal bladder cancers. PMID- 29264195 TI - Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma. AB - The treatment of metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 (PD-1), and PD-1 ligand (PD-L1). In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1) and atezolizumab (anti-PD L1) have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC. PMID- 29264196 TI - Developing immunotherapy strategies in the treatment of prostate cancer. AB - The clinical development of immunotherapy has gained significant impetus in recent years across the field of medical oncology. Mounting preclinical and clinical data have demonstrated the potential of immune-based treatments to augment anti-tumor immune responses. With one of the first modern immunotherapies approved in prostate cancer and multiple others in late stage development, immune treatment strategies need to be optimized to ensure the best clinical outcomes. Combination strategies with androgen deprivation therapy, anti-androgen therapy, radiation and chemotherapy have demonstrated the potential maximize immune response in prostate cancer patients. These combinations are currently being evaluated in clinical trials at every stage of prostate cancer from the newly diagnosed to the most advanced stages. Data from these studies will provide guidance for the future clinical implementation of immunotherapy in prostate cancer. PMID- 29264198 TI - News from leading international academic urology departments. PMID- 29264197 TI - Metastasis in renal cell carcinoma: Biology and implications for therapy. AB - Although multiple advances have been made in systemic therapy for renal cell carcinoma (RCC), metastatic RCC remains incurable. In the current review, we focus on the underlying biology of RCC and plausible mechanisms of metastasis. We further outline evolving strategies to combat metastasis through adjuvant therapy. Finally, we discuss clinical patterns of metastasis in RCC and how distinct systemic therapy approaches may be considered based on the anatomic location of metastasis. PMID- 29264199 TI - Bulbocavernosus muscle area as a novel marker for hypogonadism. AB - Objective: Late-onset hypogonadism, or androgen deficiency in the aging male, is a significant cause of morbidity in older men. Many men in the low normal or equivocal range for low testosterone level exhibit signs and symptoms of hypogonadism. Serum testosterone is an imperfect maker for hypogonadism as symptoms vary greatly within the low to low normal range in addition to variations among testosterone assays. Perineal ultrasound can be effectively used to examine the bulbocavernosus muscle (BCM), an androgenized tissue that may be impacted by androgen receptor activity. Methods: This study was a retrospective analysis of men who underwent perineal ultrasound for hypogonadism. The ultrasound data were used to calculate the area of the BCM and correlate it with indices of hypogonadismin symptomatic men including free and total testosterone and dual-energy X-ray absorptiometry (DEXA). Results: The results demonstrate that there is a significant correlation between total and free testosterone and BCM area in hypogonadal patients. Comparison between BCM area and total testosterone showed R2 = 0.061 and p = 0.0187 and comparison between BCM area and free testosterone showed R2 = 0.0957 and p = 0.0034. In addition, low BCM was also correlated with DEXA results showing osteoporosis and osteopenia (R2 = 0.2239, p = 0.0027). Conclusion: There has been recent controversy over the safety of testosterone replacement therapy. This might be particularly important in men with hypogonadal symptoms but a low normal testosterone level. Our study investigated the use of perineal ultrasound to measure BCM as a surrogate marker for poor androgenized men presenting with hypogonadism. PMID- 29264200 TI - Persistent cough as a paraneoplastic presenting symptom in six patients with renal cell carcinoma. AB - Objective: With today's modern imaging modalities, patients diagnosed with renal cell carcinoma (RCC) rarely present symptomatically. In some cases, however, they can develop paraneoplastic syndromes with associated symptoms. To date, only three cases of RCC presenting with chronic dry cough have been reported. We describe six patients who presented with cough that improved following radical nephrectomy. Methods: A retrospective review of patients undergoing partial or radical nephrectomy for renal masses between January 2015 and March 2016 was performed, and patients presenting with a cough were examined. Results: Six patients presented with chronic cough and were discovered to have a large renal mass. Postoperative spontaneous resolution of cough was noted in all but one patient, in whom coughing was reduced and limited to the mornings. Cough duration ranged from 3 months to just over a year. All patients were treated with radical nephrectomy, which was cytoreductive in four patients. Average tumor size was 10.9 cm (SD = 2.2 cm). Five of the tumors had clear cell pathology, and every tumor was Fuhrman grade IV, unifocal, and demonstrated necrosis. Sarcomatoid features were reported in four of the tumors. Conclusion: Our study presents the largest series of patients with RCC who presented with a chronic cough that was significantly improved following radical nephrectomy. We believe the cause of cough is multifactorial and further investigation is needed to clearly elucidate the etiology. PMID- 29264201 TI - Management of 220 adolescents and adults with complications of hypospadias repair during childhood. AB - Objective: The goal of hypospadias repair is to achieve normal voiding and good penile cosmesis with minimal complications. Some urethroplasties deteriorate from childhood to adolescence and late stage failures have been reported. We report our experience with adult patients who have had a previous repair during childhood and present with a late complication. Methods: We reviewed the records of 220 patients aged 15-39 years old with a history of hypospadias repair who presented to our clinic. Forty-five patients with chordee, 39 with urethral strictures, 11 urethral fistulae, five with hairy urethras, three with urethral diverticula, and 117 patients with an abnormal glans or subterminal meatus were repaired. Results: Median follow-up was 14 months. Two patients had persistent chordee. Island skin flap urethroplasty afforded one patient with a urethral fistula and another with a recurrent urethral stricture, while the buccal mucosa group had one fistula which healed spontaneously and two recurrent strictures. For the patients undergoing glanular repairs, seven had dehiscence or breakdown of the repair. All other operations were successful. Conclusion: Complications of childhood hypospadias repair may present later in life as some urethroplasties deteriorate with time. We now recommend to parents of children with repaired proximal hypospadias to come for follow-up as their child transitions to adolescence. PMID- 29264202 TI - The genetic framework for development of nephrolithiasis. AB - Over 1%-15% of the population worldwide is affected by nephrolithiasis, which remains the most common and costly disease that urologists manage today. Identification of at-risk individuals remains a theoretical and technological challenge. The search for monogenic causes of stone disease has been largely unfruitful and a technological challenge; however, several candidate genes have been implicated in the development of nephrolithiasis. In this review, we will review current data on the genetic inheritance of stone disease, as well as investigate the evolving role of genetic analysis and counseling in the management of nephrolithiasis. PMID- 29264203 TI - Renal functional outcomes are not adversely affected by selective angioembolization following percutaneous nephrolithotomy. AB - Objective: Selective angioembolization (SAE) effectively diagnoses and treats iatrogenic vascular complications following percutaneous nephrolithotomy (PCNL). Methods: We retrospectively reviewed 1329 consecutive PCNLs and identified patients who underwent SAE following PCNL with at least 12-month follow-up. Estimated glomerular filtration rate (eGFR) was calculated for all patients preoperatively, postoperatively and at last follow-up. A 1:2 matched cohort analysis was performed. Results: Twenty-three patients underwent SAE and matched to 46 controls. There was no statistically significant difference in preoperative, postoperative, and follow-up eGFR when comparing patients who underwent SAE and those with an uneventful course. Conclusion: Long-term eGFR is comparable in patients who undergo uncomplicated PCNL and those requiring SAE. PMID- 29264204 TI - Multi-parametric MRI of the prostate: Factors predicting extracapsular extension at the time of radical prostatectomy. AB - Objective: Extracapsular extension (ECE) of prostate cancer is a poor prognostic factor associated with progression, recurrence after treatment, and increased prostate cancer-related mortality. Accurate staging prior to radical prostatectomy is crucial in avoidance of positive margins and when planning nerve sparing procedures. Multi-parametric magnetic resonance imaging (mpMRI) of the prostate has shown promise in this regard, but is hampered by poor sensitivity. We sought to identify additional clinical variables associated with pathologic ECE and determine our institutional accuracy in the detection of ECE amongst patients who went on to radical prostatectomy. Methods: mpMRI studies performed between the years 2012 and 2014 were cross-referenced with radical prostatectomy specimens. Predictive properties of ECE as well as additional clinical and biochemical variables to identify pathology-proven prostate cancer ECE were analyzed. Results: The prevalence of ECE was 32.4%, and the overall accuracy of mpMRI for ECE was 84.1%. Overall mpMRI sensitivity, specificity, positive predictive value, and negative predictive value for detection of ECE were 58.3%, 97.8%, 93.3%, and 81.5%, respectively. Specific mpMRI characteristics predictive of pathologic ECE included primary lesion size ((20.73 +/- 9.09) mm, mean +/- SD, p < 0.001), T2 PIRADS score (p = 0.009), overall primary lesion score (p < 0.001), overall study suspicion score (p = 0.003), and MRI evidence of seminal vesicle invasion (SVI) (p = 0.001). Conclusion: While mpMRI is an accurate preoperative assessment tool for the detection of ECE, its overall sensitivity is poor, likely related to the low detection rate of standard protocol MRI for microscopic extraprostatic disease. The additional mpMRI findings described may also be considered in surgical margin planning prior to radical prostatectomy. PMID- 29264205 TI - Cost-effectiveness analysis of treatments for metastatic castration resistant prostate cancer. AB - Objective: Treatment options for metastatic castration resistant prostate cancer (mCRPC) have expanded rapidly in recent years. Given the significant economic burden, we sought perform a cost-effectiveness analysis (CEA) of the contemporary treatment paradigm for mCRPC. Methods: We devised a treatment protocol consisting of sipuleucel-T, enzalutamide, abiraterone, docetaxel, radium-223, and cabazitaxel. We estimated number and length of treatments for each therapy using dosing schedules or progression free survival data from published clinical trials. We estimated treatment cost using billing data and Medicare reimbursement values and performed a CEA. Our analysis assumed US$100,000 per life year saved (LYS) as the threshold societal willingness to pay. Results: Incremental cost effectiveness ratios (ICER) for strategies incorporating sipuleucel-T that were not eliminated by extended dominance exceeded the societal threshold willingness to-pay of US$100,000 per LYS, the lowest of which was sipuleucel-T + enzalutamide + abiraterone + docetaxel at US$207,714 per LYS. Enzalutamide + abiraterone + docetaxel exhibited the most favorable ICER among strategies without sipuleucel-T at US$165,460 per LYS. Conclusion: Based on the available survival data and current costs of treatment, all treatment strategies greatly exceed a commonly assumed societal willingness-to-pay threshold of US$100,000 per LYS. Improvements in this regard can only come with a reduction in pricing, better tailoring of treatment or significant enhancements in survival with clinical use of treatment combinations or sequences. PMID- 29264206 TI - Prediction of surgical complications in the elderly: Can we improve outcomes? AB - As the number of Americans aged 65 years and older continues to rise, there is projected to be a corresponding increase in demand for major surgeries within this population. Consequently, it is important to utilize accurate preoperative risk stratification techniques that are applicable to elderly individuals. Currently, commonly used preoperative risk assessments are subjective and often do not account for elderly-specific syndromes that may pose a hazard for geriatric patients if not addressed. Failure to accurately risk-stratify these patients may increase the risk of postoperative complications, morbidity, and mortality. Therefore, we aimed to identify and discuss the more objective and better-validated measurements indicative of poor surgical outcomes in the elderly with special focus on frailty, patient optimization, functional status, and cognitive ability. PMID- 29264207 TI - Addressing quality of life in the patient with interstitial cystitis/bladder pain syndrome. AB - Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating, chronic condition characterized by chronic pelvic pain, urinary urgency, and frequency and is well-known to be associated with a decrease in work productivity, emotional changes, sleep, sexual dysfunction, and mobility. Many metrics of quality of life (QoL) in this patient population have been developed; however, a unified, standardized approach to QoL in these patients has not been determined. The effects of IC/BPS and co-morbid conditions on QoL are described using current validated metrics. Next, data regarding successful treatment of IC/BPS in terms of QoL improvement are reviewed. While QoL is the single most important clinical measure of success in the treatment of patients suffering from IC/BPS, addressing QoL in this patient population remains a significant challenge, as its effects on QoL are highly variable and unable to be differentiated from the effects of comorbid conditions on QoL, including depression, poor sleep, and inability to work. Future studies will need to address treatment efficacy on the basis of IC/BPS specific QoL metrics, and multi-modal assessment and therapy to address comorbid disease will also play an important role in the future to ensure comprehensive management of these patients. PMID- 29264208 TI - Robotic surgery in pediatric urology. AB - While robotic surgery has shown clear utility and advantages in the adult population, its role in pediatrics remains controversial. Pediatric-sized robotic instruments and equipment are not readily available yet, so certain modifications can be made in order to make robotic surgery successful in children. While the cost of robotic surgery remains high compared to open procedures, patients experience greater satisfaction and quality of life with robotic surgery. Robotic pyeloplasty is a standard of care in older children, and has even been performed in infants and re-do surgery. Other robotic procedures performed in children include heminephroureterectomy, ureteroureterostomy, ureteral reimplantation, urachal cyst excision, bladder diverticulectomy, and bladder reconstructive procedures such as augmentation, appendicovesicostomy, antegrade continence enema, bladder neck reconstruction and sling, as well as other procedures. Robotic surgery has also been used in oncologic cases such as partial nephrectomy and retroperitoneal lymph node dissection. Future improvements in technology with production of pediatric-sized robotic instruments, along with increases in robotic-trained pediatric urologists and surgeon experience along each's learning curve, will help to further advance the field of robotic surgery in pediatric urology. PMID- 29264209 TI - Role of multi-parametric MRI of the prostate for screening and staging: Experience with over 1500 cases. AB - Objective: Contemporary prostate cancer (PCa) screening modalities such as prostate specific antigen (PSA) and digital rectal examination (DRE) are limited in their ability to predict the detection of clinically significant disease. Multi-parametric magnetic resonance imaging (mpMRI) of the prostate has been explored as a staging modality for PCa. Less is known regarding its utility as a primary screening modality. We examined our experience with mpMRI as both a screening and staging instrument. Methods: mpMRI studies performed between 2012 and 2014 in patients without PCa were cross-referenced with transrectal ultrasonography (TRUS) biopsy findings. Statistical analyses were performed to determine association of mpMRI findings with overall cancer diagnoses and clinically significant (Gleason score >=7) disease. Subgroup analyses were then performed on patients with a history of prior negative biopsy and those without a history of TRUS biopsy. mpMRI studies were also cross-referenced with RP specimens. Statistical analyses determined predictive ability of extracapsular extension (ECE), seminal vesicle involvement (SVI), and pathologic evidence of clinically significant disease (Gleason score >=7). Results: Four hundred biopsy naive or prior negative biopsy patients had positive mpMRI studies. Overall sensitivity, specificity, positive and negative predictive values were 94%, 37%, 58%, and 87%, respectively and 95%, 31%, 42%, and 93%, respectively for overall cancer detection and Gleason score >=7 disease. In patients with no prior biopsy history, mpMRI sensitivity, specificity, positive and negative predictive values were 94%, 36%, 65%, and 82%, for all cancers, and 95%, 30%, 50%, and 89% for Gleason score>=7 lesions, respectively. In those with prior negative biopsy sensitivity, specificity, positive and negative predictive values were 94%, 37%, 52%, and 90% for all cancers, and 96%, 32%, 36%, and 96% for Gleason score >=7 lesions, respectively. Seventy-four patients underwent radical prostatectomy (RP) after mpMRI. Lesion size on mpMRI correlated with the presence of Gleason score >=7 cancers (p = 0.005). mpMRI sensitivity, specificity, positive and negative predictive values were 84%, 39%, 81%, and 44% respectively, for Gleason >=7 cancer. For ECE and SVI, sensitivity and specificity were 58% and 98% and 44% and 97%, respectively. Conclusion: mpMRI is an accurate predictor of TRUS biopsy and RP outcomes. mpMRI has significant potential to change PCa management, particularly in the screening population, in whom a significant proportion may avoid TRUS biopsy. Further studies are necessary to determine how mpMRI should be incorporated into the current PCa screening and staging paradigms. PMID- 29264210 TI - A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naive patients with mCRPC in China, Malaysia, Thailand and Russia. AB - Objective: This double-blind, placebo-controlled phase 3 study was designed to compare efficacy and safety of abiraterone acetate + prednisone (abiraterone) to prednisone alone in chemotherapy-naive, asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients from China, Malaysia, Thailand and Russia. Methods: Adult chemotherapy-naive patients with confirmed prostate adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade 0-1, ongoing androgen deprivation (serum testosterone <50 ng/dL) with prostate specific antigen (PSA) or radiographic progression were randomized to receive abiraterone acetate (1000 mg, QD) + prednisone (5 mg, BID) or placebo + prednisone (5 mg, BID), until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was improvements in time to PSA progression (TTPP). Results: Totally, 313 patients were randomized (abiraterone: n = 157; prednisone: n = 156); and baseline characteristics were balanced. At clinical cut-off (median follow-up time: 3.9 months), 80% patients received treatment (abiraterone: n = 138, prednisone: n = 112). Median time to PSA progression was not reached with abiraterone versus 3.8 months for prednisone, attaining 58% reduction in PSA progression risk (HR = 0.418; p < 0.0001). Abiraterone-treated patients had higher confirmed PSA response rate (50% vs. 21%; relative odds = 2.4; p < 0.0001) and were 5 times more likely to achieve radiographic response than prednisone-treated patients (22.9% vs. 4.8%, p = 0.0369). Median survival was not reached. Most common (>=10% abiraterone vs. prednisone-treated) adverse events: bone pain (7% vs. 14%), pain in extremity (6% vs. 12%), arthralgia (10% vs. 8%), back pain (7% vs. 11%), and hypertension (15% vs. 14%). Conclusion: Interim analysis confirmed favorable benefit-to-risk ratio of abiraterone in chemotherapy-naive men with mCRPC, consistent with global study, thus supporting use of abiraterone in this patient population. PMID- 29264211 TI - Prostate cancer screening in Europe and Asia. AB - Prostate cancer (PCa) is the second most common cancer among men worldwide and even ranks first in Europe. Although Asia is known as the region with the lowest PCa incidence, it has been rising rapidly over the last 20 years mostly due to the introduction of prostate-specific antigen (PSA) testing. Randomized PCa screening studies in Europe show a mortality reduction in favor of PSA-based screening but coincide with high proportions of unnecessary biopsies, overdiagnosis and subsequent overtreatment. Conclusive data on the value of PSA based screening and hence the balance between harms and benefits in Asia is still lacking. Because of known racial variations, Asian countries should not directly apply the European screening models. Like in the western world also in Asia, new predictive markers, tools and risk stratification strategies hold great potential to improve the early detection of PCa and to reduce the worldwide existing negative aspects of PSA-based PCa screening. PMID- 29264212 TI - History and evolution of the use of oral mucosa for urethral reconstruction. AB - We report here the history and evolution of the use of oral mucosa in reconstructive urethral surgery since it was first used for urethroplasty in 1894. Since that time, many authors have contributed to develop, improve and popularize the use of oral mucosa as a substitute material. Paediatric urologists should be considered pioneers on the use of oral mucosa as they used it to repair primary and failed hypospadias. The use of oral mucosa to repair penile and bulbar urethral strictures was described, for the first time, in 1993. Important evolutions in the technique for harvesting oral mucosa from the cheek were reported in 1996. Today, oral mucosa is considered the gold standard material for any type of anterior urethroplasty in a one- or two-stage repair due to its biological and structural characteristics that make it a highly versatile that is adaptable to any environment required by the reconstructive urethral surgery. As the future approaches, tissue engineering techniques will provide patients with new materials originating from the oral epithelial mucosal cells, which are cultured and expanded into a scaffold. However, the path to reach this ambitious objective is still long and many difficulties must be overcome along the way. PMID- 29264213 TI - Outcomes of patients older than 75 years with non-metastatic prostate cancer. AB - Objective: Prostate cancer in elderly patients was formerly treated with androgen deprivation therapy. Since the latter of the 1990s new technologies were introduced into treatments, then strategies have varied. We aimed to observe the outcomes of elderly patients treated during transition period and compare each stage with others. Methods: During 2008 and 2010, 255 patients with prostate cancer older than 75 years were sequentially treated. With exception of patients with bone and/or visceral metastasis, outcomes of 199 patients with localized and locally advanced stages were examined. Complete records were obtained by the end of 2015. Results: In total, 122 (61%), 28 (14%), 37 (19%) and 12 (6%) of patients were in stages T1c-T2a, T2b-c, T3 and T4, respectively. Patients generally presented with abnormal screening or lower urinary tract symptom. Seventy-one percent of patients received androgen deprivation therapy as monotherapy and 22% of the radiation-treated patients added androgen deprivation therapy. Patients in stage T1c-T2a and T2b-c showed a favorable prognosis. Some cancer death appeared in patients with T3 and T4 during observation periods. Twenty-seven percent of patients died from prostate cancer-independent complications: pneumonia, heart disease, and brain vascular disease. Tendency is similar to that of Japanese elderly male population. No remarkable side effects from androgen deprivation therapy were noticed. Conclusion: Elderly patients with localized prostate cancer showed favorable prognosis by androgen deprivation therapy with/without radiation, thus efficacy of androgen deprivation therapy is suitable to elderly patients with applicable stages. Prognosis of patients with locally advanced stage is serious and remains to be improved. PMID- 29264214 TI - The role of tunica vaginalis flap in staged repair of hypospadias. AB - Objective: The surgical repair of hypospadias is done in two stages in a select group of patients with severe anomaly. The first stage (I) procedure consists of correction of penile shaft curvature and second stage (II) repair involves the creation of a neourethra. This neourethra needs a cover of an intermediate layer in order to have good functional and cosmetic results. Among the various local flaps, tunica vaginalis flap is a good option for the use as an intermediate layer. Methods: We have managed 22 patients of chordee with hypospadias by staged repair. In Stage I, chordee correction was done by dividing the urethral plate and covering the penile shaft with dorsal prepucial flaps. In Stage II, a neourethra was created and covered with tunica vaginalis flap either through the same incision (14/22) or via a subcutaneous tunnel (8/22). An indwelling catheter was kept for 10 to 12 days. Results: Eighteen (81.8%) patients had successful functional and cosmetic repair. Two patients (9.1%) had urethrocutaneous fistula of which one healed on subsequent dilatation while the other one (4.5%) needed repair. Overall fistula formation rate was 4.5%. In two patients, the external urinary meatus could be made upto subglanular or coronal level. Conclusion: Staged repair of chordee with hypospadias is valuable in selected group of patients and tunica vaginalis flap is an excellent intermediate layer to cover the neourethra. However preoperative counseling is particularly essential in patients where the external urinary meatus can be created at coronal or subglanular level. PMID- 29264215 TI - Testicular torsion in undescended testis: A persistent challenge. AB - Objective: To evaluate the management and outcomes of patients who presented with torsion of an undescended testis and review the reported series in the literature. Methods: The case records of 13 patients operated for testicular torsion involving undescended testis were retrospectively reviewed. The medical records included age at presentation, medical history, physical examination, operative findings and the results of follow-up. The diagnosis of torsion of undescended testis was made clinically and confirmed by inguinal exploration. Results: In six cases the testis was preserved and orchiopexy was performed, while in seven cases orchidectomy was performed due to testicular gangrene in six patients and testicular tumor discovered peroperatively in one case. Mean duration of symptoms at time of surgery in the orchiopexy group was 6.5 h and in the orchidectomy group was 21.2 h. From six patients treated by orchiopexy, two patients suffered from testicular atrophy at a mean of 24 months. Conclusion: Testicular torsion in undescended testis is still diagnosed with delay which may affect testicular salvage. The importance of examination of external genital organs is highlighted which should be routinely included by emergency physicians in physical examination for abdominal or groin pain. PMID- 29264216 TI - Robotic nurse duties in the urology operative room: 11 years of experience. AB - The robotic nurse plays an essential role in a successful robotic surgery. As part of the robotic surgical team, the robotic nurse must demonstrate a high level of professional knowledge, and be an expert in robotic technology and dealing with robotic malfunctions. Each one of the robotic nursing team "nurse coordinator, scrub-nurse and circulating-nurse" has a certain job description to ensure maximum patient's safety and robotic surgical efficiency. Well-structured training programs should be offered to the robotic nurse to be well prepared, feel confident, and maintain high-quality of care. PMID- 29264217 TI - Non-seminomatous germ cell tumor with bone metastasis only at diagnosis: A rare clinical presentation. AB - Bone metastasis of non-seminomatous germ cell tumors (NSGCT) of the testes is a rare event and even more uncommon at initial presentation. Generally, bone lesions are discovered in the presence of concurrent retroperitoneal lymph node or visceral disease. However, in this case, a 37 years old male complaining of a growing testicular mass was found to have isolated bone metastasis with associated caudaequina syndrome without apparent abnormal findings on initial computed tomography (CT) scans. Continued neurologic symptoms prompted further evaluation with magnetic resonance imaging (MRI), which demonstrated multiple sites of bone metastasis without evidence of retroperitoneal lymph node or visceral organ involvement. This case represents a rare clinical presentation and disease manifestation of NSGCT. PMID- 29264218 TI - A rare presentation of cystic nephroma in a young adult. AB - Cystic nephroma is a rare benign renal lesion with non-specific presenting symptoms. This tumour has a bimodal age distribution presenting in children between 3 months and 2 years and in adults over 30 years of age. There is male preponderance with a 2:1 male to female ratio in the childhood whereas it is commoner in females in adults. It is uncommon in the age-group of 5 years-30 years. We describe a case of cystic nephroma in a 25-year-old female which was managed by partial nephrectomy. PMID- 29264219 TI - Superselective embolisation of bilateral superior vesical arteries for management of intractable hematuria in context of metastatic bladder cancer. AB - Hematuria due to locally advanced or metastatic bladder cancer is a common condition and is often a management problem. Percutaneous embolisation is a mini invasive option to handle this situation. We report a case of a patient with a metastatic bladder cancer and who presented with an abundant hematuria and severe anemia. After failure of endoscopic resections and "flush" of radiotherapy haemostatic and refusal of cystectomy by the patient, he was treated by superselective embolisation of bilateral superior bladder arteries with excellent immediate results. The technique is safe and effective in the short term. The long-term effectiveness requires further investigation. PMID- 29264220 TI - Autonephrectomy due to urogenital tuberculosis. PMID- 29264221 TI - Current consensus and controversies on male LUTS/BPH (part one). PMID- 29264222 TI - Management of BPH then 2000 and now 2016 - From BPH to BPO. AB - The diagnosis and treatment of benign prostatic obstruction (BPO) is based on a number of well-known lower urinary tract symptoms (LUTS) feared by all ageing males with functional testes. The ascent of modern urology turned this disease from lethal into an annoying but treatable health problem in the previous century. We are able to relieve the great majority of patients from their bothersome symptoms to a respectable quality of life by medication or removal of the obstructive part of the enlarged prostate. We can be proud of some progress made in the new millennium to reach a correct diagnosis and subsequent choice of treatment aiming for quality of life and cost-efficiency for public health. Still it remains symptomatic treatment and we expect the new generation of urologists to close some gaps in our knowledge on the regulation of prostatic growth to focus on prevention and elimination of the disease in the foreseeable future. PMID- 29264223 TI - Epidemiology of clinical benign prostatic hyperplasia. AB - Clinical benign prostatic hyperplasia (BPH) is one of the most common diseases in ageing men and the most common cause of lower urinary tract symptoms (LUTS). The prevalence of BPH increases after the age of 40 years, with a prevalence of 8% 60% at age 90 years. Some data have suggested that there is decreased risk among the Asians compared to the western white population. Genetics, diet and life style may play a role here. Recent reports suggest the strong relationship of clinical BPH with metabolic syndrome and erectile dysfunction, as well as the possible role of inflammation as a cause of the prostatic hyperplasia. Lifestyle changes including exercise and diet are important strategies in controlling this common ailment. PMID- 29264224 TI - Pathophysiology of clinical benign prostatic hyperplasia. AB - A disease can be defined as an abnormal anatomy (pathology) and/or function (physiology) that may cause harm to the body. In clinical benign prostatic hyperplasis (BPH), the abnormal anatomy is prostate adenoma/adenomata, resulting in a varying degree of benign prostatic obstruction (BPO) that may cause harm to the bladder or kidneys. Thus clinical BPH can be defined as such and be differentiated from other less common causes of male lower urinary tract symptoms. Diagnosis of the prostate adenoma/adenomata (PA) can be made by measuring the intravesical prostatic protrusion (IPP) and prostate volume (PV) with non-invasive transabdominal ultrasound (TAUS) in the clinic. The PA can then be graded (phenotyped) according to IPP and PV. Multiple studies have shown a good correlation between IPP/PV and BPO, and therefore progression of the disease. The severity of the disease clinical BPH can be classified into stages from stage I to IV for further management. The classification is based on the effect of BPO on bladder functions, namely that of emptying, normal if post-void residual urine (PVRU) < 100 mL; and bladder storage, normal if maximum voided volume (MVV) > 100 mL. The effect of BPO on quality of life (QoL) can be assessed by the QoL index, with a score >=3 considered bothersome. Patients with no significant obstruction and no bothersome symptoms would be stage I; those with no significant obstruction but has bothersome symptoms (QoL >= 3) would be stage II; those with significant obstruction (PVRU > 100 mL; or MVV < 100 mL), irrespective of symptoms would be stage III; those with complications of the disease clinical BPH such as retention of urine, bladder stones, recurrent bleeding or infections would be stage IV. After assessment, further management can then be individualised. A low grade and stage disease can generally be watched (active surveillance) while a high grade and stage disease would need more invasive management with an option for surgery. The final decision making would take into account the patient's age, co-morbidity, social economic background and his preferences/values. Proper understanding of pathophysiology of clinical BPH would lead to better selection of patients for individualised and personalised care and more cost effective management. PMID- 29264225 TI - The influence of asymptomatic inflammatory prostatitis on the onset and progression of lower urinary tract symptoms in men with histologic benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a condition that greatly affects the quality of life of middle-aged and elderly men. Histopathologically, hyperplastic changes frequently occur in the prostate tissue of elderly men, the incidence of which has been reported to reach approximately 80% in men in their 70s. In clinical practice, approximately 25% of men with histologic BPH are assumed to experience lower urinary tract symptoms (LUTS) and receive some kind of treatment. In other words, there are some men with histologic BPH who do not exhibit LUTS. For that reason, many factors, such as the change in hormonal environment, the immune or autoimmune response, the alteration of gene expression, and so on, are thought to affect the onset and progression of LUTS in men with histologic BPH. One such factor that has long drawn attention is the presence of asymptomatic histological inflammation, which very often accompanies symptomatic BPH. Recent studies have suggested that asymptomatic histological inflammation causes repeated destruction, healing, and regeneration of the prostate tissue, leading to the enlargement of prostatic nodules, while at the same time causing stromal tissue-predominant remodeling of the prostate tissue, which can increase urination resistance and result in the condition changing from asymptomatic BPH to symptomatic BPH. In future, the biomolecular clarification of the significance of asymptomatic histological inflammation in the prostate tissue could help develop new treatment strategies for BPH accompanied by LUTS. PMID- 29264227 TI - Clinical value of intravesical prostatic protrusion in the evaluation and management of prostatic and other lower urinary tract diseases. AB - Intravesical prostatic protrusion (IPP) has emerged as a new prostatic morphometric parameter of significance to aid the clinicians in various aspects of managing the patients with some diseases of the lower urinary tract and the prostate. These include but may not be limited to its role in such conditions as: bladder outlet obstruction, trial without catheter, medical treatment effect, progression of lower urinary tract symptoms related to benign prostatic hypertrophy (LUTS/BPH), risk factor for bladder stone in BPH, overactive bladder, prostate carcinoma, and early urinary continence recovery after laparoscopic radical prostatectomy. In this review, I will try to summarize the different researchers' efforts on the potential practical application of this clinical tool. Technology is ever evolving to help us in the diagnosis and management of our patients. However, we as clinicians should contemplate their cost and possible suffering for the patient by wise and judicious utilization based on our clinical experience and tools. IPP seems to be one such promising clinical tool. PMID- 29264228 TI - Benign prostatic hyperplasia and male lower urinary symptoms: A guide for family physicians. AB - Male patients with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are increasingly seen by family physicians worldwide due to ageing demographics. A systematic way to stratify patients who can be managed in the community and those who need to be referred to the urologist is thus very useful. Good history taking, physical examination, targeted blood or urine tests, and knowing the red flags for referral are the mainstay of stratifying these patients. Case selection is always key in clinical practice and in the setting of the family physician. The best patient to manage is one above 40 years of age, symptomatic with nocturia, slower stream and sensation of incomplete voiding, has a normal prostate-specific antigen level, no palpable bladder, and no haematuria or pyuria on the labstix. The roles of alpha blockers, 5-alpha reductase inhibitors, and antibiotics in a primary care setting to manage this condition are also discussed. PMID- 29264226 TI - Metabolic syndrome and benign prostatic hyperplasia: An update. AB - Metabolic syndrome (MetS) is a cluster of metabolic abnormalities related to central adiposity and insulin resistance. Its importance is increasingly recognized as it associates with increased risks of metabolic and cardiovascular diseases. These metabolic aberrations of MetS may lead to development of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) in men. A 26.5%-55.6% prevalence of MetS in men with LUTS was reported in worldwide studies. Although the exact biological pathway is not clear yet, insulin resistance, increased visceral adiposity, sex hormone alterations and cellular inflammatory reactions played significant roles in the related pathophysiological processes. Clinician should recognize the cardiovascular and metabolic impacts of MetS in men with LUTS, early risk factors optimization and use of appropriate medical therapy may possibly alter or slower the progression of LUTS/BPH, and potentially avoid unnecessary morbidities and mortalities from cardiovascular and metabolic diseases for those men. PMID- 29264229 TI - Medical therapy for clinical benign prostatic hyperplasia: alpha1 Antagonists, 5alpha reductase inhibitors and their combination. AB - Medical therapy for clinical benign prostatic hyperplasia (BPH) has advanced significantly in the last 2 decades. Many new alpha1 antagonists and 5alpha reductase inhibitors (5ARi) are now commercially available. The practicing urologist must decide on the most appropriate medication for his patients, taking into consideration various factors like efficacy, dosing regime, adverse effects, cost, patient's socioeconomic background, expectations, drug availability and his own clinical experience. The use of combination therapy added further to the complexity in clinical judgment when prescribing. We highlight some of the key points in prescribing alpha1 antagonists, 5ARi and their combination, based on our viewpoints and experience as urologists in an Asian clinical setting. PMID- 29264230 TI - The use of antimuscarinics, phosphodiesterase type V inhibitors and phytotherapy for lower urinary tract symptoms in men. AB - Besides the mainstay of alpha-blockers and 5alpha-reductase inhibitors, other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms (LUTS) in men. These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients. Many patients are bothered by storage symptoms, more so than the voiding symptoms. Antimuscarinics are efficacious and safe, provided the patients do not have high post void residual urine. Many patients with LUTS also have erectile dysfunction, and phosphodiesterase type V inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients. Phytotherapy provides a popular and safe treatment for LUTS, however, the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies. PMID- 29264232 TI - Early tracking and immigrant optimism: a comparative study of educational aspirations among students in disadvantaged schools in Sweden and the Netherlands. AB - Educational tracking affects both the trajectories and the composition of peers that students meet in school. This study compares the effect of significant others on students' educational aspirations within two transition regimes: the more comprehensive Swedish system and the more stratified Dutch. Separating between doxic and habituated aspirations, I hypothesize that (1) aspirations among students in disadvantaged schools will be lower in the Netherlands than in Sweden; (2) the higher educational aspirations of girls and children of immigrants will disappear when significant others are controlled for; and (3) the positive effect of significant others is more marked among Swedish students than among Dutch due to greater student heterogeneity. The data comes from 3202 students in schools with low average grades in Sweden and the Netherlands. Results were in line with the hypothesis with one important exception. There was a marked difference in habituated aspirations but no difference in doxic aspirations between the Dutch and Swedish students. In conclusion, the findings suggest a) that early tracking systems creates a disconnect between students' hopes and what they perceive as likely outcomes, and b) that the phenomenon termed "immigrant optimism" and "ethnic capital" reflects unequal access to social capital. PMID- 29264231 TI - An update on transurethral surgery for benign prostatic obstruction. AB - Clinical benign prostatic hyperplasia (BPH) is one of the most common cause of lower urinary tract symptoms and transurethral resection of prostate (TURP) has been the gold standard technique for surgical treatment of benign prostate obstruction (BPO) over the last 2 decades. Although monopolar TURP is considered a safe and effective option for surgical management of BPO, there are some disadvantages, namely bleeding, transurethral resection syndrome, incompleteness of treatment. This review aims to highlight these problems, and describe the advances in technology and techniques that have evolved to minimise such complications. With the advent of lasers and bipolar technology, as well as enucleative techniques to remove the prostatic adenoma/adenomata, the problems of bleeding, transurethral resection syndrome and incomplete treatment are significantly minimised. Monopolar TURP will likely be replaced by such technology and techniques in the near future such that transurethral surgery of the prostate remain a safe and effective option in alleviating the harmful effects of BPO. PMID- 29264233 TI - Sampling immigrants in the Netherlands and Germany. AB - This paper discusses the limitations of harmonised sampling designs for survey research on immigrants in Germany and the Netherlands. Although the concepts for immigrants are largely similar in both countries, there are severe constraints when it comes to comparable sampling designs. While in the Netherlands a sample can be drawn from a national population register by Statistics Netherlands, this is impossible in Germany due to the decentralised setup of the population register and legal restrictions on merging existing databases. Harmonisation of immigrant statistics is thus less a problem at the concept level than in the implementation. Achieving a harmonised data collection on immigrants for Germany and the Netherlands will be a major challenge. PMID- 29264236 TI - A review of biomechanics of the shoulder and biomechanical concepts of rotator cuff repair. AB - In this article, we describe the basic knowledge about shoulder biomechanics, which is thought to be useful for surgeons. Some clinical reports have described that the excellent outcome after cuff repair without acromioplasty and a limited acromioplasty might be enough for subacromial decompression. It was biomechanically demonstrated that a 10-mm medial shift of the tendon repair site has a minimum effect on biomechanics. Many biomechanical studies reported that the transosseous equivalent repair was superior to other techniques, although the tendon may lose its inherent elasticity. We herein introduce our recent experiment data and latest information on biomechanics. PMID- 29264237 TI - Clinical results of arthroscopic polyglycolic acid sheet patch graft for irreparable rotator cuff tears. AB - The high retear rates after surgery for irreparable rotator cuff tears can be explained by the healing capacity potential of tendons and the native rotator cuff enthesis characterised by complex morphological structures, called direct insertion. Many experimental researches have focused on biologically augmenting the rotator cuff reconstruction and improving tendon-bone healing of the rotator cuff. The results of the experimental study showed that the polyglycolic acid sheet scaffold material allows for the regeneration of not only tendon-to-tendon, but also tendon-to-bone interface in an animal model. We performed a clinical study of the arthroscopic polyglycolic acid sheet patch graft used for the repair of irreparable rotator cuff tears. One-year clinical results of the repair of irreparable rotator cuff tears by arthroscopic patch graft with a polyglycolic acid sheet demonstrated improved shoulder function and a significantly lower retear rate, compared with patients treated with a fascia lata patch. PMID- 29264235 TI - Status and headway of the clinical application of artificial ligaments. AB - The authors first reviewed the history of clinical application of artificial ligaments. Then, the status of clinical application of artificial ligaments was detailed. Some artificial ligaments possessed comparable efficacy to, and fewer postoperative complications than, allografts and autografts in ligament reconstruction, especially for the anterior cruciate ligament. At the end, the authors focused on the development of two types of artificial ligaments: polyethylene glycol terephthalate artificial ligaments and tissue-engineered ligaments. In conclusion, owing to the advancements in surgical techniques, materials processing, and weaving methods, clinical application of some artificial ligaments so far has demonstrated good outcomes and will become a trend in the future. PMID- 29264234 TI - Rotator cuff tear: A detailed update. AB - Rotator cuff tear has been a known entity for orthopaedic surgeons for more than two hundred years. Although the exact pathogenesis is controversial, a combination of intrinsic factors proposed by Codman and extrinsic factors theorized by Neer is likely responsible for most rotator cuff tears. Magnetic resonance imaging remains the gold standard for the diagnosis of rotator cuff tears, but the emergence of ultrasound has revolutionized the diagnostic capability. Even though mini-open rotator cuff repair is still commonly performed, and results are comparable to arthroscopic repair, all-arthroscopic repair of rotator cuff tear is now fast becoming a standard care for rotator cuff repair. Appropriate knowledge of pathology and healing pattern of cuff, strong and biological repair techniques, better suture anchors, and gradual rehabilitation of postcuff repair have led to good to excellent outcome after repair. As the healing of degenerative cuff tear remains unpredictable, the role of biological agents such as platelet-rich plasma and stem cells for postcuff repair augmentation is still under evaluation. The role of scaffolds in massive cuff tear is also being probed. PMID- 29264238 TI - Electromyographic study of rotator cuff muscle activity during full and empty can tests. AB - The empty can (EC) and full can (FC) tests are used as diagnostic tools for patients with rotator cuff disease. However, recently concerns have been raised that these tests do not selectively activate the muscle. Therefore, the purpose of this study was to evaluate the rotator cuff muscle activation levels during the EC and FC tests in various positions using electromyography. Twelve healthy, right-handed men without shoulder complaints (mean age: 26.1 years, range: 23-35 years) were included. The tests were performed isometrically with the shoulder elevated at 45 degrees and 90 degrees in the sagittal, scapular, and coronal planes, either in the thumb-up (FC test) or thumb-down (EC test) positions. During these positions, the electromyographic signal was recorded simultaneously from the four shoulder muscles using a combination of surface and intramuscular fine-wire electrodes. The average activation of the supraspinatus and subscapularis was greater during the EC test than during the FC test and in the scapular and coronal planes than in the sagittal plane at 90 degrees . For the infraspinatus, there were no significant differences in any positions between the two tests. Thus, the rotator cuff muscles are influenced by arm position and the elevation plane during the EC and FC tests. PMID- 29264239 TI - One-stage revision anatomic anterior cruciate ligament reconstruction with rectangular tunnel technique. AB - We developed the anatomic rectangular tunnel anterior cruciate ligament reconstruction (ART ACLR) with a bone-patellar tendon-bone graft to mimic fibre arrangement inside the native ACL via tunnels with smaller apertures. With a 10 mm-wide graft, the cross-sectional area of the tunnels of 50 mm2 in ART ACLR is less than that of 79 mm2 in a 10-mm round tunnel one. Because tunnel encroachment would be less of a problem, the ART ACLR technique could be most frequently applied to patients after a failed primary ACLR. In this instructional lecture, the indication and technical considerations for ART ACLR as one-stage revision ACLR are described. PMID- 29264240 TI - The Achilles tendon resting angle as an indirect measure of Achilles tendon length following rupture, repair, and rehabilitation. AB - Background: Rupture of the Achilles tendon may result in reduced functional activity and reduced plantar flexion strength. These changes may arise from elongation of the Achilles tendon. An observational study was performed to quantify the Achilles tendon resting angle (ATRA) in patients following Achilles tendon rupture, surgical repair, and rehabilitation, respectively. Methods: Between May 2012 and January 2013, 26 consecutive patients (17 men), with a mean (standard deviation, SD) age of 42 (8) years were included and evaluated following injury, repair, and at 6 weeks, 3 months, 6 months, 9 months, and 12 months, respectively (rehabilitation period). The outcome was measured using the ATRA, Achilles tendon total rupture score (ATRS), and heel-rise test. Results: Following rupture, the mean (SD) absolute ATRA was 55 (8) degrees for the injured side compared with 43 (7) degrees (p < 0.001) for the noninjured side. Immediately after repair, the angle reduced to 37 (9) degrees (p < 0.001). The difference between the injured and noninjured sides, the relative ATRA, was -12.5 (4.3) degrees following injury; this was reduced to 7 (7.9) degrees following surgery (p < 0.001). During initial rehabilitation, at the 6-week time point, the relative ATRA was 2.6 (6.2) degrees (p = 0.04) and at 3 months it was -6.5 (6.5) degrees (p < 0.001). After the 3-month time point, there were no significant changes in the resting angle. The ATRS improved significantly (p < 0.001) during each period up to 9 months following surgery, where a score of 85 (10) degrees was reported. The heel-rise limb symmetry index was 66 (22)% at 9 months and 82 (14)% at 12 months. At 3 months and 6 months, the absolute ATRA correlated with the ATRS (r = 0.63, p = 0.001, N = 26 and r = 0.46, p = 0.027, N = 23, respectively). At 12 months, the absolute ATRA correlated with the heel-rise height (r = -0.63, p = 0.002, N = 22). Conclusion: The ATRA increases following injury, is reduced by surgery, and then increases again during initial rehabilitation. The angle also correlates with patient-reported symptoms early in the rehabilitation phase and with heel-rise height after 1 year. The ATRA might be considered a simple and effective means to evaluate Achilles tendon function 1 year after the rupture. PMID- 29264241 TI - Histological evaluation of low-intensity pulsed ultrasound on osteochondritis dissecans of the humeral capitellum. AB - Background: The clinical use of low-intensity pulsed ultrasound (LIPUS) was recently evaluated in cases of osteochondritis dissecans of the humeral capitellum (elbow OCD). However, the mechanism underlying the effect of LIPUS in elbow OCD is not well understood. The aim of this study was to histopathologically evaluate the effect of LIPUS irradiation on elbow OCD. Methods: Fifteen patients with elbow OCD were enrolled in this study. All patients were juvenile baseball players (average age, 13.1 years). LIPUS was performed under the same conditions as the fracture treatment for an average length of 15.1 days in the preoperative period in seven patients (LIPUS group). Cylindrical tissue specimens obtained at the time of surgery were stained with hematoxylin and eosin and alcian blue, and were also immunostained to detect type 1 collagen (Col-1), osteopontin (OPN), and Runx2. The state of the cartilage and subchondral bone and expression levels of Col-1, OPN, and Runx2 were evaluated with a semiquantitative grading system by a blinded pathologist. Histological and immunohistological findings in both groups were compared using Fisher's exact test. Results: Both groups showed reparative tissue and cartilaginous metaplasia at the separation level near the subchondral bone; Col-1 was expressed in the reparative tissue. Furthermore, OPN and Runx2 were expressed in the interstitial cells near the separation level. The cartilage and subchondral bone findings in histological evaluations did not differ significantly between the LIPUS and control groups. The distribution of OPN expression levels in the two groups was as follows: Grade 0-LIPUS group, zero patients, and control group, five patients; Grade 1-LIPUS group and control group, two patients each; Grade 2-LIPUS group, five patients and control group, one patient; Grade 3-LIPUS group, one patient and control group, zero patients. OPN expression was significantly higher in the LIPUS group than in the control group (p = 0.04). Conclusion: LIPUS stimulation increased the expression levels of OPN in elbow OCD. PMID- 29264242 TI - Change in muscle thickness under contracting conditions following return to sports after a hamstring muscle strain injury-A pilot study. AB - The purpose of this study was to measure the change in hamstring muscle thickness between contracting and relaxing conditions following a return to sports after a hamstring muscle strain and thereby evaluate muscle function. Six male track and field sprinters participated in this study. All had experienced a prior hamstring strain injury that required a minimum of 2 weeks away from sport participation. Transverse plane scans were performed at the following four points on the affected and unaffected sides under contracting and relaxing conditions: proximal biceps femoris long head, proximal semitendinosus, middle biceps femoris long head, and middle semitendinosus. The results demonstrated an increase in the thickness of the middle biceps femoris long head and middle semitendinosus regions on the unaffected side with contraction, whereas the affected side did not show a significant increase. The proximal semitendinosus muscle thickness was increased with contraction on both the unaffected and the affected sides. By contrast, the proximal biceps femoris muscle thickness did not show a significant increase on both sides. The results of this study show that evaluation of muscle thickness during contraction may be useful for assessing the change in muscle function after a hamstring muscle strain injury. PMID- 29264243 TI - Relation among the knee, sagittal spinal alignment, and the spinal range of motion: Investigation in local medical check-ups using the SpinalMouse. AB - Background: This study was designed as an investigation in a local population to assess the relation between the knee joint and spinal alignment in a population based study using the SpinalMouse. Methods: Medical check-ups were conducted for residents of a mountain village in Japan. The study population included 107 men and 157 women (528 knees) with a mean age of 71.1 +/- 6.8 years (range, 60-87 years). A questionnaire dealing with any current symptoms involving the knees was administered, and physical examinations dealing with the range of motion (ROM) of knee were conducted. The SpinalMouse was used to measure sagittal spinal alignment and spinal ROM. The parameters considered were thoracic kyphosis angle, lumbar lordosis angle (LLA), sacral inclination angle (SIA), and trunk angle of inclination (INC). The patients were divided into a group with knee flexion contracture (FC group) and a group without knee FC (non-FC group) to conduct a comparative study of both groups. Results: With regard to static spinal alignment, LLA and SIA decreased significantly in the FC group (p < 0.05). With regard to spinal ROM, LLA and INC decreased significantly in the FC group (p < 0.05). Conclusion: Results suggested that the knee and the spine affect each other and that the spinal ROM is also involved. The current study may explain the development of knee-spine syndrome. PMID- 29264244 TI - Exercise-induced leg pain. AB - Exercise-induced leg pain is a common condition in athletes and in people involved in recreational sports. The diagnosis is not always straightforward: many conditions may cause exercise-induced leg pain. The aim of the present review is to provide a complete discussion of the most common pathologies related to this condition. Particular attention is dedicated to the history and the physical examination, which are fundamental for requesting the correct diagnostic tests or imaging techniques necessary for a precise diagnosis. PMID- 29264245 TI - Excursion of bone-patella tendon-bone grafts during the flexion-extension movement in anterior cruciate ligament reconstruction: Comparison between isometric and anatomic reconstruction techniques. AB - Background/objective: The purpose of this study was to elucidate the biomechanical differences between anterior cruciate ligament (ACL) grafts reconstructed by isometric and anatomic reconstruction techniques, based on their length changes. Methods: One hundred and thirty-three knees with primary ACL reconstruction using the bone-patellar tendon-bone (BTB) graft were retrospectively identified. Twenty-two knees and 111 knees underwent isometric round tunnel (IRT) ACL reconstruction and anatomic rectangular tunnel (ART) ACL reconstruction, respectively. Results: After femoral-side fixation of the graft in the surgery, the length change of the graft from 120 degrees flexion to full extension was measured by using an isometric positioner at the tibial side. Both reconstructive techniques showed little length change from 120 degrees to ~20 degrees of flexion, followed by elongation of the graft, until full extension. The amount of length change of the grafts was 1.0 +/- 0.7 mm with the IRT technique, and 3.4 +/- 0.9 mm with the ART technique. These findings were significantly different, based on the Mann-Whitney U test (p < 0.001). Conclusion: The native ACL has an intrinsic length change of 3-6 mm, and therefore the ART technique may more closely replicate the biomechanical function of the native ACL. PMID- 29264246 TI - Arthroscopic repair for subacromial incarceration of a torn rotator cuff. AB - Background/objective: Rotator cuff tears are common shoulder injuries. Various forms of rotator cuff tears are observed by arthroscopy. Inverted flap tears of the rotator cuff, however, also occur. The aim of the present study was to determine the preoperative characteristics of inverted torn cuffs and clinical outcomes after arthroscopic repair. Methods: Seventeen patients (10 men, 7 women; mean age, 65.8 years; age range, 41-80 years) who underwent arthroscopic rotator cuff repair for an inverted flap tear participated in the study. The mean follow up period was 31.8 months (range, 24-61 months). The preoperative history, radiographs, magnetic resonance images, tear pattern of the rotator cuff, preoperative and postoperative University of California Los Angeles (UCLA) rating scale, and postoperative repair integrity were assessed. Results: Only two patients had acute episodes of aggravated shoulder pain. In radiographs, the anteroposterior view revealed a heel-type acromion in 8/17 (47.1%) patients with an inverted flap tear compared with 27/345 (7.8%) patients with ordinary retracted tears (p < 0.001). The supraspinatus tendon was incarcerated in all cases. The UCLA score increased from 11.9 +/- 2.7 points to 32.5 +/- 2.1 points postoperatively (p = 0.002). Postoperative magnetic resonance images at 12 months after surgery showed good repair integrity in all cases. Conclusion: Arthroscopic reduction and repair are applicable for inverted flap tears of the rotator cuff. The findings of the present study indicated that patients with a heel-type acromion in the anteroposterior view of radiographs are at greater risk for inverted flap tears of the rotator cuff. PMID- 29264247 TI - Early reconstruction should be considered in younger patients with symptomatic mucoid degeneration of the anterior cruciate ligament. AB - Background: Mucoid degeneration of the anterior cruciate ligament (ACL) is mostly observed in middle-aged patients with knee pain and limited range of motion. Although arthroscopic resection of the degenerated ACL is the treatment of choice following the failure of conservative management, the extent of the excision and subsequent ACL reconstruction for postoperative knee instability remains controversial. Case reports: We present four cases of mucoid degeneration of the ACL in patients aged <40 years, and suggest a suitable treatment strategy for younger patients. All four patients (mean age, 33.8 years) were diagnosed with mucoid degeneration of the ACL based on characteristic clinical symptoms and magnetic resonance imaging. Arthroscopic resection of the affected portion of the ACL was performed as follows: partial resection in two cases with limited hypertrophy, and total ACL resection in the remaining two cases with degeneration involving the entire ligament. Preoperative symptoms disappeared in all cases after resection of the lesions. In the two patients with partial resection, the ACL was completely torn during subsequent sports activities despite showing no symptoms of instability for 2 years postoperatively. All four patients, including the two treated by total resection, underwent ACL reconstruction using an autogenous hamstring tendon. Conclusion: Considering the rupture of residual ACL fibres after partial resection and the inevitability of total ACL resection due to degeneration of the entire ligament, ACL reconstruction should be considered in younger patients with symptomatic mucoid degeneration of the ACL. PMID- 29264248 TI - Patellar tendon: From tendinopathy to rupture. AB - Patellar tendinopathy is very common in patients complaining of anterior knee pain. Its aetiology is still unclear, but neovascularisation seems to play a role. Different treatments have been proposed overtime, from rehabilitation to platelet-rich-plasma injections, but there is no agreement on the best treatment protocol. The final stage of patellar tendinopathy is patellar tendon rupture. In these cases surgical treatment is often required. The aim of this literature review is to focus on the aetiology, diagnosis, and treatment of both patellar tendinopathy and rupture. We report the conservative treatments proposed for patellar tendinopathy and the surgical techniques described for its rupture. PMID- 29264249 TI - Ligament balancing in total knee arthroplasty-Medial stabilizing technique. AB - Ligament balancing is one of the most important surgical techniques for successful total knee arthroplasty. It has traditionally been recommended that medial and lateral as well as flexion and extension gaps are equal. This article reviews the relevant literature and discusses the clinical importance of the aforementioned gaps. Current evidence indicates that achieving medial stability throughout the range of motion should be a high priority in ligament balancing in total knee arthroplasty. Finally, the medial stabilising surgical technique, which aims to achieve good medial stability in posterior cruciate-retaining total knee arthroplasty, is introduced. PMID- 29264250 TI - Review of ankle inversion sprain simulators in the biomechanics laboratory. AB - Ankle inversion ligamentous sprain is one of the most common sports injuries. The most direct way is to investigate real injury incidents, but it is unethical and impossible to replicate on test participants. Simulators including tilt platforms, trapdoors, and fulcrum devices were designed to mimic ankle inversion movements in laboratories. Inversion angle was the only element considered in early designs; however, an ankle sprain is composed of inversion and plantarflexion in clinical observations. Inversion velocity is another parameter that increased the reality of simulation. This review summarised the simulators, and aimed to compare and contrast their features and settings. PMID- 29264251 TI - Anterior Cruciate Ligament Reconstruction: A 2015 global perspective of the Magellan Society. AB - Background/objective: The Magellan Society is composed of > 150 high-volume fellowship-trained sports surgeons from four continents. These surgeons represent their regional sports organisations in travelling fellowships and are considered to be opinion leaders in their respective organisations. Prior to the 2014 Magellan Meeting in Arima, Japan, a survey was conducted to understand how Magellan members perform anterior cruciate ligament (ACL) reconstruction. This study aims to better understand how ACL reconstruction is performed by sports surgeons worldwide and to determine differences in surgical practice. Methods: A survey was conducted prior to the Magellan Meeting in Arima, Japan. Information on ACL graft of choice for primary surgery and revision surgery, preferred surgical techniques, and femoral and tibial graft fixation methods was collected. The incidence of meniscal tears and the management of injuries in ACL surgery were also studied. The results of the survey are discussed in this article. Results: A response rate of 51% (72 member respondents) was achieved for this survey. Hamstring autograft (58%) was the graft of choice for primary ACL reconstruction. The next most common autograft used was bone patella tendon bone autograft (28%). Allograft was the graft of choice in only 4% of respondents. The region of origin of surgeons and the age of surgeons were factors in the ACL graft of choice. Seventy-five percent of surgeons practised single-bundle ACL reconstructions only, 22% performed both single-bundle and double-bundle ACL reconstructions, and 3% performed double-bundle ACL reconstructions exclusively. Sixty-two percent of the respondents drilled femoral tunnels using the anteromedial portal technique. Meniscus repairs were performed in 25% of ACL reconstructions, on average. Conclusion: Based on the survey, hamstring transportal anatomic single-bundle ACL reconstruction with meniscus preservation is the preferred ACL reconstruction technique of high-volume fellowship-trained sports surgeons. PMID- 29264252 TI - Acceleration of healing of the medial collateral ligament of the knee by local administration of synthetic microRNA-210 in a rat model. AB - Background: Injury to the medial collateral ligament (MCL) of the knee joint is the most common ligament injury of the knee. Ligament healing generally takes a long time. Micro-ribonucleic acid (miRNA) is one of the noncoding RNAs and plays a crucial role in physiological function; miRNA (miR)-210 is known as a potent factor of angiogenesis, which is an important initiator of ligament healing. The purpose of this study is to examine the effect of local injection of double stranded (ds) miR-210 on the healing of the MCL of rat knee joint. Methods: MCLs of Sprague-Dawley rats were cut transversely. After the fascia and skin were sutured, dsmiR-210 or control dsRNA was injected into the injured site of MCL. At 2 weeks and 4 weeks, histological analysis and immunofluorescence staining of vascular endothelial growth factor, isolectin B4, collagen type 1, and Ki67 as well as a mechanical test were performed. Analysis of complementary deoxyribonucleic acid (cDNA) microarray data was performed at 1 week. Results: Histological analysis showed that parallel fibres in the injured site were organised at 2 weeks and became thicker at 4 weeks in the miR-210-treated group, whereas the injured site in controls was filled with loose fibrous tissues and was thinner than that in the miR-210-treated group. The number of blood vessels in the miR-210-treated group was significantly higher than that in controls (p < 0.05), and vascular endothelial growth factor, Ki67, and collagen type 1 in the miR-210-treated group were intensely expressed in the repaired site as compared to the control group. The mechanical test indicated that the ultimate failure load in the miR-210-treated group was significantly higher than that in the control group at 2 weeks. The cDNA microarray analysis showed significant upregulation of genes related to cell proliferation and cell differentiation, and genes involved in negative regulation of apoptosis. Conclusion: This study showed that local injection of dsmiR-210 could accelerate MCL healing in rat, which is likely due to stimulation of angiogenesis at the healing site. PMID- 29264253 TI - Endoscopic tarsal tunnel syndrome surgery using the Universal Subcutaneous Endoscope system. AB - Background/objective: Tarsal tunnel syndrome is a relatively rare entrapment neuropathy with the lateral and medial plantar nerves entrapped inside of the tarsal tunnel. When conservative treatment fails, standard open decompression of the nerve can be achieved by releasing the flexor retinaculum of the foot through a several-centimetre-long skin incision made along the tarsal tunnel. By contrast, we made a 1-cm portal incision at the proximal part of the medial ankle, and endoscopic tarsal tunnel release of the flexor retinaculum of the foot and part of the abductor hallucis muscle was achieved using the Universal Subcutaneous Endoscope (USE) system. Methods: Our procedure was performed under local anaesthesia without a pneumatic tourniquet on an outpatient basis. The USE system was inserted into the tarsal tunnel at the proximal part of the medial ankle; the nerves, vessels, flexor retinaculum, tendons of the foot, and the abductor hallucis muscle were then endoscopically identified. Decompression of the lateral and medial plantar nerves entrapped inside of the tarsal tunnel was then achieved by releasing the flexor retinaculum of the foot and part of the abductor hallucis muscle with a push knife under complete endoscopic observation. Results: Results from eight feet of five patients were compiled and analyzed. All showed improved clinical signs compared with their preoperative condition. Conclusion: Our less invasive endoscopic management for tarsal tunnel syndrome using the USE system produces sufficient results. PMID- 29264254 TI - Graft quality and clinical outcomes of intraoperative bone tunnel communication in anatomic double-bundle anterior cruciate ligament reconstruction. AB - Background/objective: In anatomic double-bundle anterior cruciate ligament reconstruction, it is crucial to create two separate bone tunnels within the footprints of the anterior cruciate ligament at the femur and tibia. This can occasionally be difficult to accomplish and the adverse effects of bone tunnel communication are unclear. The purpose of this study was to examine the effects of intraoperative bone tunnel communication on graft quality and clinical outcome. Methods: Fifty-two patients (52 knees) who underwent anatomic double bundle anterior cruciate ligament reconstruction with hamstring tendons were included. The mean age of the patients was 30.7 years. Clinical assessments were performed 1 year after surgery. Bone tunnel communication was evaluated using computed tomography 10 days after surgery. Graft quality was evaluated using magnetic resonance imaging 6 months after surgery and the signal/noise quotient was calculated using the region of interest technique. Results: Bone tunnel communication was observed in the femur of one knee (1.9%) and the tibias of 10 knees (30.8%). The knees with tibial bone communication were classified into Group C (N = 16), and the knees without tibial bone tunnel communication were classified into Group N (N = 36). No significant differences were observed between Groups C and N in terms of clinical outcome. The signal/noise quotient of the distal portion of the posterolateral graft in Group C was significantly higher than that of Group N. Conclusion: Bone tunnel communication in anatomic double-bundle anterior cruciate ligament reconstruction did not affect clinical outcome, but it did affect posterolateral graft quality. Level of evidence: Level 4, case series, therapeutic studies. PMID- 29264255 TI - The mechanism of "killer turn" causing residual laxity after transtibial posterior cruciate ligament reconstruction. AB - Background: The residual laxity after transtibial posterior cruciate ligament (PCL) reconstruction has been reported by several authors. The sharp angle where the graft exits the tibial tunnel, which is known as "killer turn", is believed to be the main reason. The purpose of this study was to reveal the mechanism of "killer turn" and its effect on both graft and tunnel inlet. Methods: A total of 60 New Zealand white rabbits were included. All transtibial PCL reconstructions were performed in vitro using Achilles tendon autograft. The cyclic loading tests were conducted when reconstructed knees were subjected to 1500 cycles of tensile force of 50 N with the angle of pull at 45 degrees to the tibial plateau. The tunnel inlet enlargement, graft elongation, stiffness, graft displacement, load to failure, and failure site were all recorded and analysed. Results: Fifty-eight New Zealand white rabbits were available for biomechanical evaluation. The subjects had significant graft elongation and tunnel enlargement. The graft displacement increased by a mean of 0.92 +/- 0.36 mm (16.70%). At the 1500th cycle, the grafts were significantly elongated by 5.59 +/- 4.98%, and the tunnel inlet diameter was also significantly enlarged by 12.08 +/- 4.31%. There was a linear correlation between total graft displacement and the two variables (R2 = 0.402, F = 18.515, p < 0.001). The coefficient for tunnel inlet enlargement was 0.419 (p = 0.006), and for graft elongation was 0.583 (p = 0.002). At the load-to failure test, the failure load was 81.19 +/- 20.13 N. Of the 58 grafts, 31 (53.45%) failed at the "killer turn", 13 (22.41%) for the para-tunnel fracture, seven (12.07%) for the graft pull-out, and the remaining seven (12.07%) for the rupture at the mounting site. Conclusion: The mechanism of "killer turn" compromising posterior stability was that the repetitive friction between graft and tunnel inlet not only attenuated the graft, but also enlarged the tunnel inlet, leading to the displacement of the graft. PMID- 29264256 TI - Inaccurate rotational component position in image-free navigated unicompartmental knee arthroplasty. AB - Background/Objective: The success of unicompartmental knee arthroplasty (UKA) is highly dependent on the accuracy of component and leg alignment. Computer assisted surgery is gaining popularity in total knee arthroplasty with numerous studies reporting improved accuracy and decreased variability in implant position and postoperative limb alignment compared with conventional techniques. However, literature evaluating the accuracy of computer-navigated UKA is limited. Therefore, this study aimed to investigate the accuracy of component positions in navigated UKA using a three-dimensional (3D) image-matching system. To the best of our knowledge, this study is the first to evaluate the accuracy of implant placement position in UKA using 3D image-matching systems. Methods: Twenty-three knees in 22 patients (9 men, 13 women) underwent computer-assisted UKA performed by a senior surgeon from 2011 to 2013. All surgeries were performed with measured resection techniques using an image-free-navigation system. We recorded the coronal, sagittal, and rotational bone-resection angles towards the mechanical axis in the distal femur and proximal tibia using image-free navigation intraoperatively. The coronal, sagittal, and rotational alignments of the femoral and tibial components were also measured using the 3D image-matching system, and the accuracy of the navigated UKA was evaluated. The rotational alignment of the femur and tibia was defined as surgical epicondylar axis and Akagi's line, and a deviation over 3 degrees from the AA was defined as an outlier. Results: We observed coronal outliers for the femoral component in four of the 23 patients, and for the tibial component in three of the 23 patients. We also observed sagittal outliers for the femoral component in five of 23 patients, and for the tibial component in three of the 23 patients. Twenty-two tibial components were placed in external rotation relative to the rotational reference line. Conclusion: In both coronal and sagittal alignments, there were a definite proportion of outliers. The ratio of outliers in rotational alignment was especially higher than that in coronal and sagittal alignments. In UKA, the identification of bony landmarks is difficult because of the small operation field. Therefore, careful surface mapping of particular bony landmarks is necessary, and it is not enough to use image-free navigation system in UKA. PMID- 29264257 TI - Clinical results of anterior cruciate ligament reconstruction with ligament remnant tissue preservation: A systematic review. AB - Purpose: To clarify the effects of ACL remnant tissue preservation on the clinical outcome of ACL reconstruction. Methods: This is a systematic review. Results: The majority of the reviewed articles suggested that remnant preservation significantly improved knee stability after ACL reconstruction, although there was some controversy. In addition, it was suggested that the degree of initial graft coverage significantly affected postoperative knee stability. Remnant preservation did not increase the occurrence rate of cyclops lesion. Conclusion: Sufficient coverage of the graft with remnant tissue improves postoperative knee stability without any detrimental effects on the subjective and functional results. PMID- 29264259 TI - Medial patella-femoral ligament reconstruction using the anterior half of the peroneus longus tendon as a combined procedure for recurrent patellar instability. AB - Background: Medial patella-femoral ligament reconstruction (MPFLR) using hamstring tendon is the main procedure for recurrent patellar instability. The anterior half of the peroneus longus tendon (AHPLT) has been proven to be a useful alternate to the hamstring tendon in knee ligament reconstruction. The purpose of this study was to evaluate the clinical outcome of MPFLR using the new graft. Methods: Forty-five patients with recurrent patellar instability received MPFLR using the AHPLT. Tibial tubercle transfer and lateral release were also performed. Follow-ups were performed at 12 months and 24 months postoperatively, and computed tomography was performed immediately following the operation and at follow-up. The passive patella glide test was performed prior to surgery, during the operation, and at each follow-up point. Knee function was evaluated preoperatively and postoperatively using the International Knee Documentation Committee, Lysholm, Kujala, and Tegner rating scales. Results: Forty patients were followed for 2 years and received complete serial computed tomography examinations and functional evaluations. The correction of the static patellar position remained through the follow-ups. Functional evaluations at 2 years revealed statistical significant improvement over preoperative status, with International Knee Documentation Committee subjective score, Lysholm score, Kujala score, and Tegner score. Conclusion: AHPLT is a promising alternative graft for MPFLR, together with lateral release and tibial tubercle transfer, satisfactory static patellar position, and functional outcomes have been achieved in the treatment of recurrent patellar dislocation in adults. Level of evidence: Level IV, case series. PMID- 29264260 TI - Hyaluronic acid induces the release of growth factors from platelet-rich plasma. AB - Background/Objective: Platelet-rich plasma (PRP) and hyaluronic acid (HA) injection are both therapeutic options for osteoarthritis and chronic tendinopathy. Although several comparative studies on the two have been published, the effects of mixing PRP and HA are not fully understood. The purpose of this study is to investigate the influence of HA on platelets in PRP by measuring releasing growth factors. Methods: PRP was produced from nine healthy adult volunteers (mean age, 32.8 +/- 2.9 years; range, 29-37) with a commercial separation system. HA of weight-average molecular weight of 50-120 kDa was used. PRP group (PRP 1 mL + phosphate buffered saline 0.2 mL) and PRP + HA group (PRP 1 mL + HA 0.2 mL) were incubated at 37 degrees C for 2 hours. The amounts of transforming growth factor beta1 (TGF-beta1) and platelet-derived growth factor (PDGF-AA) released from the PRP and PRP + HA samples were measured on Day 0, Day 3, and Day 5. In addition, the same growth factors on Day 5 were measured for PRP + high HA group (PRP 1 mL + HA 0.6 mL) with five donors. After collecting all of the samples on Day 5, the remaining gels were observed with Giemsa stain. Statistical analyses were performed using paired t tests to compare the PRP and HA groups at each time point, and a one-way analysis of variance (one-way ANOVA) with Tukey post hoc tests was used to compare the PRP, PRP + HA, and PRP + high HA groups. Results: The TGF-beta1 concentrations in the PRP and PRP + HA were 24.3 +/- 7.2 MUg/mL and 22.4 +/- 1.8 MUg/mL (p = 0.689) on Day 0, 17.2 +/- 13.9 MUg/mL and 25.4 +/- 7.1 MUg/mL (p = 0.331) on Day 3, and 12.7 +/- 10.5 MUg/mL and 33.7 +/- 8.3 MUg/mL (p = 0.034) on Day 5. The TGF-beta1 concentrations on Day 5 were 24.1 +/- 5.2 MUg/mL (PRP group), 28.3 +/- 2.4 MUg/mL (PRP + HA), and 31.9 +/ 4.8 MUg/mL (PRP + high HA; one-way ANOVA: p = 0.003; post hoc PRP vs. PRP + HA: p = 0.016). The PDGF-AA concentrations in the PRP and PRP + HA groups were 2.30 +/- 1.21 MUg/mL and 2.32 +/- 0.79 MUg/mL (p = 0.931) on Day 0, 2.03 +/- 0.53 MUg/mL and 2.13 +/- 0.73 MUg/mL (p = 0.500) on Day 3, and 1.51 +/- 0.40 MUg/mL and 2.00 +/- 0.52 MUg/mL (p = 0.003) on Day 5. The PDGF-AA concentrations were 1.48 +/- 0.46 MUg/mL (PRP group), 1.94 +/- 0.57 MUg/mL (PRP + HA), and 2.69 +/- 0.70 MUg/mL (PRP + high HA; one-way ANOVA: p = 0.0002; PRP vs. PRP + high HA: p = 0.002; PRP + HA vs. PRP + high HA: p = 0.011) on Day 5. The PRP showed larger coagulated masses than the PRP + HA. The high concentration HA group had the smallest coagulated mass of all of the group. Conclusion: The levels of growth factors released by PRP on Day 5 were increased by the addition of HA. A mixture of PRP and HA may be a more effective therapy than PRP or HA alone for osteoarthritis and tendinopathy. PMID- 29264258 TI - Critical review on the socio-economic impact of tendinopathy. AB - There are currently no studies that determine the total burden that tendinopathy places on patients and society. A systematic search was conducted to understand the impact of tendinopathy. It demonstrated that the current prevalence is underestimated, particularly in active populations, such as athletes and workers. Search results demonstrate that due to the high prevalence, impact on patients' daily lives and the economic impact due to work-loss, treatments are significantly higher than currently observed. A well-accepted definition by medical professionals and the public will improve documentation and increase awareness, in order to better tackle the disease burden. PMID- 29264261 TI - Power and endurance in Hong Kong professional football players. AB - Background: The purpose of this study was to investigate the power and endurance characteristics of Hong Kong professional football players. Training recommendations can be deduced based on the comparison between Hong Kong and international football players. Methods: Eighty-eight Hong Kong professional football players (height, 177.2 +/- 6.4 cm; weight, 70.6 +/- 7.6 kg; age, 25.6 +/ 5.0 years) in the first division league participated in a battery of tests, which included: (1) height, (2) weight, (3) countermovement jump, (4) 30-m sprinting, and (5) Yo-Yo Intermittent Recovery Test Level 2. Results: Compared with the test results of the first division players in other countries as reported in the literature (Norway, France, and Scandinavian countries), Hong Kong players were shorter in height (0.1-2.1%), lighter in weight (5.5-8.3%), fair in vertical jump height (-4.8-17%), slower in acceleration (4.2-5.1%) and maximum speed (3-14.2%), and had poorer aerobic and anaerobic endurance (22.9%). Conclusion: The present study suggests that Hong Kong football players (or players with similar physique and ability) need to improve their power and endurance. PMID- 29264262 TI - Use of a portable motion analysis system for knee dynamic stability assessment in anterior cruciate ligament deficiency during single-legged hop landing. AB - Background/objective: Anterior cruciate ligament (ACL) rupture results in knee instability, and patients are often unable to return to their previous level of activity. Current assessments rely on passive laxity tests, which do not correlate with function. Dynamic stability may be a better indicator for return to sport. However, equipment for measuring dynamic stability is ill suited for clinical use. The purpose of this study is to evaluate knee kinematics in ACL deficient patients with a single-legged hop task using a portable motion analysis system. We hypothesize that the assessment task is able to differentiate ACL deficient knees from healthy knees. Methods: Ten ACL-deficient patients and 10 healthy controls were recruited. Participants were instructed to perform a single legged hop, while kinematics was measured using a portable motion capture system (Opti-Knee; Shanghai Innomotion Inc., Shanghai, China). Kinematic changes after initial contact were examined. Repeatability of the results was examined by calculating the coefficient of variations of the pooled standard deviation of the tibiofemoral displacements. Side-to-side differences were calculated and compared between the two groups. Results: One patient could not perform the task. Intraindividual variability was small after initial contact; the coefficient of variation in this region was 13-26%. ACL-deficient knees demonstrated lower flexion range of motion (p = 0.008) and increased internal/external rotation range of motion after landing (p = 0.038), while no significant differences were detected in the healthy group. Only the side-to-side difference in flexion was significantly different between the two groups (p = 0.002). Conclusion: The altered knee kinematics in ACL-deficient patients can be revealed by a portable motion capture system, which may enable the clinical application of kinematic assessment in the evaluation of ACL deficiency. PMID- 29264263 TI - Measurement of movement patterns to enhance ACL injury prevention - A dead end? AB - Vertical drop jump has been suggested to be an effective movement screening task for ACL injury risk, but recent studies have questioned the ability of such tasks to accurately identify players with increased risk of injury. In this paper, we discuss the usefulness of movement screening tests from an injury prevention perspective. PMID- 29264264 TI - Comparison of different cryotherapy recovery methods in elite junior cyclists. AB - Background/objective: Cold water immersion (CWI) and active recovery treatment (ACT) are commonly used recovery treatments for athletes between exercise bouts, but they are sometimes limited by space and availability of equipment in training and competition venues. Therefore, the purpose of this study was to determine whether cold compression therapy (CCT) would provide the same effect as CWI and ACT as an alternative option in a hot environment. Methods: Eight elite male junior cyclists (age, 15.5 +/- 1.2 years; height, 167.7 +/- 3.3 cm; body mass, 57.3 +/- 3.5 kg; peak oxygen uptake, 64.7 +/- 4.3 mL/kg/min) completed a maximal cycling test to determine their peak power output (PPO) and oxygen uptake. Then they completed three tests using randomised recovery protocol of CWI, CCT and ACT for 15 minutes. Each test consisted of two 35-minute exercise bouts, with 5 minutes of warm-up, 15 minutes of cycling at 75% PPO and 15 minutes maximal trial. The two exercise bouts were separated by 60 minutes (5 minutes cool-down, 10 minutes preparation for recovery treatment, 15 minutes recovery treatment, and 30 minutes passive recovery). Results: There was no significant difference between average power output, blood lactate, rating of perceived exertion, and heart rate for two time-trial bouts for all recovery treatments. A significant decrease in core temperature was noted prior to the start of the second exercise bout for CWI. Conclusion: CCT, CWI and ACT are all useful recovery treatments between exercise bouts. PMID- 29264265 TI - Postoperative outcome is affected by an intraoperative combination of each graft tension change pattern in a double-bundle anterior cruciate ligament reconstruction. AB - Background: The purpose of this study is to evaluate the intraoperative tension change pattern of each anteromedial (AM) graft and posterolateral (PL) graft and to investigate the optimal femoral tunnel position in double bundle (DB) anterior cruciate ligament reconstruction (ACLR) by comparing postoperative outcomes with each combination of graft tension change pattern. Methods: Eighty-four unilateral primary DB ACLR cases from 2006 to 2008 with a follow-up of 24 months or more were analysed. The tension change pattern of each AM and PL graft after graft fixation was recorded during DB ACLR, and divided into over-the-top (OTT; tension at 0 degrees > 120 degrees ) and reverse OTT (graft tension at 0 degrees < 120 degrees ) pattern. The combinations of these patterns were then categorized into four groups and the postoperative results were analysed. The femoral tunnel position was measured by a modified quadrant method. The relationship between the femoral tunnel position and the tension change pattern of each graft was evaluated. Results: The cases that presented reverse tension change pattern of native anterior cruciate ligament (ACL) performed most poorly in postoperative knee laxity among the four groups. In this group, the femoral tunnel of the AM bundle was placed significantly higher in flexion. Conclusion: This study suggests that the least effective method for knee stability recovery is for the ACL to be reconstructed with the reverse tension change to the native ACL. It is necessary to refrain from placing the femoral tunnel for the AM bundle in a high position in knee flexion in DB ACLR. PMID- 29264266 TI - Simultaneous anterior cruciate ligament reconstruction and dome-shaped high tibial osteotomy for severe medial compartment osteoarthritis of the knee. AB - Background: The optimal surgical procedure to address both anterior cruciate ligament (ACL) deficiency and medial compartment osteoarthritis (OA) has been controversial. Case report: A 49-year-old woman with a 30-year history of chronic anterior cruciate ligament (ACL) deficiency, medial compartment osteoarthritis, and varus deformity presented with medial knee pain and apprehension with walking and playing soccer. Her preoperative range of motion was from 0 degrees of extension to 135 degrees of flexion. The anterior drawer sign (1+), Lachman test (1+), and pivot shift test (glide) were positive before surgery, as measured by the International Knee Documentation Committee knee examination form. The patient underwent simultaneous arthroscopic ACL single-socket and single-bundle reconstruction using hamstring tendons, dome-shaped high tibial osteotomy using the TomoFix fixation device, and mosaicplasty to the medial condyle. The standing femorotibial angle changed from 185 degrees preoperatively to 172 degrees postoperatively. Range of motion exercises were started 1 week after surgery, and partial weight bearing was allowed 2 weeks after surgery. The patient returned to her baseline physical level 2 years after the operation. Range of motion was -10 degrees of extension and 130 degrees of flexion, and the anterior drawer sign, Lachman test, and pivot shift test were all negative at the final 3-year follow up. Conclusion: An ACL reconstruction combined with a dome-shaped high tibial osteotomy using a locking plate is one option for treating an aged athlete with ACL deficiency and severe medial compartment osteoarthritis, and can allow the athlete to return to sports activity. PMID- 29264267 TI - Anterior cruciate ligament remnant and its values for preservation. AB - Controversy surrounds the remnant-preserving anterior cruciate ligament surgery. Advantages of remnant preservation have been reported in regard to better healing and knee function, although no consensus has been reached. This review article discussed the value and meaning of anterior cruciate ligament remnant preservation in several sections such as effects on healing, remnant classification, biomechanical evaluation, relation to proprioception, animal studies, and clinical studies. We hope that this review will facilitate further discussion and investigation for better treatment of anterior cruciate ligament injuries. So far, the current reviews have not provided sufficient scientific evidence to support the value of preserving the remnant. PMID- 29264268 TI - Shorter recovery can be achieved from using walking boot after operative treatment of an ankle fracture. AB - Background/Objective: Ankle fractures, even if treated surgically, usually take a long time to heal. For all patients with ankle fracture, immobilisation is a critical part of treatment. Short-leg walking boots (WBs) have been reported to be an effective alternative to plaster casts (PCs) that could shorten this postoperative recuperative period. The aim of this study was to compare the functional recovery of a conventional PC with that of a WB after surgery for ankle fractures. Methods: Forty-seven patients (mean age, 53.9 +/- 12 years) who had undergone surgical operation for an unstable ankle fracture from January 2008 to October 2014 were reviewed retrospectively. Either a PC or a WB was prescribed postoperatively, with 25 patients and 22 patients, respectively. The time that it took the patient to stand unipedal on the affected side after allowing full weight bear and to walk without crutches were used for assessment of functional recovery. The prevalence of postoperative loss of reduction and nonunion was also reviewed. Results: Both the time of being able to stand unipedal on the injured side and to walk without crutches were significantly shorter in patients using WBs (WB, 2.6 weeks; PC, 4.5 weeks, p = 0.01; WB, 1.4 weeks; PC, 3.1 weeks, p = 0.03). There were no patients with loss of reduction or nonunion. Conclusion: Patients who used WBs showed a significantly faster recovery. WBs have an adjustable heel lift that allows users to change the ankle position slightly plantarflexed that helps walking in a postoperative swollen ankle. WBs are easy to slip on, and it is easy to adjust the ankle position in conformity with swelling so that the least painful position could be maintained during walking. WBs have good fixity to allow immediate weight-bearing postoperatively, and there were no cases with loss of reduction postoperatively. The Rocker bottom design minimises the sagittal plane motion in the specific joint of the foot, which also facilitates the course of recuperation. An ankle fracture fixed appropriately endures loading when a WB is used. The WB treatment results in faster functional recovery, allowing the patients to return to normal activity at a faster rate. PMID- 29264269 TI - Accuracy of magnetic resonance imaging in diagnosing lateral ankle ligament injuries: A comparative study with surgical findings and timings of scans. AB - Objective: This study aimed to evaluate the accuracy of magnetic resonance imaging (MRI) in diagnosing lateral ankle ligament injuries and the effect of differences in time duration from injury to MRI. Methods: Data were collected prospectively from 82 patients who underwent MRI and lateral ligament reconstruction, and were divided into either acute (<=3 months) or chronic (>3 months) group based on injury interval. Findings were classified as normal, partial, or complete tears of the anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL). MRI results were compared with intraoperative findings and their accuracies were assessed using descriptive statistics. Results: The accuracy of MRI for partial and complete tears of the ATFL was 74% and 79%, respectively, with sensitivity and specificity of 64% and 86% for partial tears, and 78% and 80% for complete tears, respectively. The accuracy of MRI was 66% and 88% for partial and complete tears of the CFL with a sensitivity and specificity of 41% and 87% for partial tears, and 61% and 95% for complete tears, respectively. A decrease in the MRI accuracy was observed in the chronic group. Conclusion: MRI is accurate in diagnosing ATFL injuries. It is specific but not sensitive for CFL tears. The accuracy is higher in the acute setting of 3 months or less from time of injury to MRI. PMID- 29264270 TI - Comparison of treatment effects on lateral epicondylitis between acupuncture and extracorporeal shockwave therapy. AB - Background: Lateral epicondylitis is one of the most common overuse injuries, and has been reported to reduce function and affect daily activities. There is no standard therapy for lateral epicondylitis. In Hong Kong, acupuncture and extracorporeal shockwave therapy (ESWT) have been popular in treating lateral epicondylitis in recent years. Objective: This study is to compare the treatment effects of acupuncture and ESWT on lateral epicondylitis. Methods: In this study, we evaluated 34 patients (34 elbows) with lateral epicondylitis. Seventeen patients were treated by 3-week ESWT, one session per week. Another 17 were treated by 3-week acupuncture therapy, two sessions per week. The outcome measures included pain score by visual analogue scale, maximum grip strength by Jamar dynamometer, and level of functional impairment by disability of arms, shoulders, and hands questionnaire. Participants were assessed at three time points: baseline; after treatment; and 2-week follow-up. Results: The two treatments showed no significant difference at any assessment time-point. Both treatment groups had significant improvement in pain score in longitudinal comparisons. No significant difference was found in maximum grip strength and functional impairment in either treatment group, but a trend of improvement could be observed. In addition, improvement in pain relief stopped when treatment ended for either groups. Conclusions: The treatment effects of acupuncture and ESWT on lateral epicondylitis were similar. The pain relief persisted for at least two weeks after treatment. PMID- 29264272 TI - Characteristics of elongated and ruptured anterior cruciate ligament grafts: An analysis of 21 consecutive revision cases. AB - Background/objective: Anterior cruciate ligament (ACL) reconstructions often fail without graft rupture. The purpose of this study was to compare the characteristics of patients with elongated and ruptured bone-patellar tendon-bone (BTB) grafts that required revision surgery. Methods: Twenty one patients who required revisions of a BTB-reconstructed ACL between 2010 and 2015 were enrolled in this study. All patients were evaluated for bone tunnel position using computed tomography. Tunnel angle was calculated with radiographs. Stability under anaesthesia, and meniscus and cartilage condition were evaluated during the revision surgery. Age at primary surgery, time between primary and revision surgery, activity level, original tunnel position of the graft, and meniscus and cartilage condition were compared between elongated and ruptured grafts. Results: Age at primary surgery was not significantly different between the two groups (p = 0.528). Time between primary and revision surgery as well as activity level were also not significantly different between the two groups (p = 0.010 and p = 0.307, respectively). Femoral bone tunnel position was more proximal (p = 0.003), and radiographic tunnel angle was not significantly different between the two groups (p = 0.029). The rupture group was significantly more unstable on the pivot shift (p < 0.003). Meniscus degeneration, meniscus tear, and cartilage damage were not significantly different between the two groups (p = 0.030, p = 0.311, and p = 0.505, respectively). Conclusion: The location of the original femoral tunnel was more proximal in patients with elongated grafts than in those with ruptured grafts. Different bone tunnel position from native ACL might lead to graft elongation. PMID- 29264274 TI - Anterior internal impingement of the shoulder in rugby players and other overhead athletes. AB - Background/Objective: Impingement syndromes are a common cause of shoulder pain in overhead athletes. Anterior internal impingement is a recently suggested mechanism for activity-related pain of the shoulder. Impingement syndromes were initially described to occur due to repetitive or excessive contact between the rotator cuff and other structures in the shoulder. Methods: This is a retrospective, clinical case study reporting 54 consecutive cases of anterior internal impingement in overhead athletes, of which 28 (51.2%) cases were of rugby players. All had undergone physiotherapy without relief of the symptoms. Of 54, there were 45 male and 9 female patients with an average age of 27 years (range, 17-51). The mean duration from injury to surgery was 40.7 weeks (range, 5 364). Of the 54 patients, 29 (53.7%) were full-time professional and 25 (46.3%) were semiprofessional or recreational athletes. The players associated the onset of pain occurred following an injury in 29/54 cases (53.4%), whereas in the remaining 25 cases (46.2%), a gradual onset of symptoms was described. All 54 patients could demonstrate a "functional impingement sign" in positioning their arm and provoke pain. Result: On examination, the examiner could reproduce the same pain in 38/54 (70.3%) patients only. Of the 54 patients, "SLAP tests" including O'Brien's test, Palm up test, and compression rotation test were positive in shoulders of 39 (72.2 %) patients, Jobe's test in 27 (50%), Gerber's lift off test in 6 (11%), and Hawkin's test in 6 (11%) patients. During arthroscopic assessment, impinging flap tears were found in 44 (81.4%) patients from the SLAP, whereas undersurface rotator cuff flap tears were found in 24 (44.4%), flap tears from the anterior or inferior labrum were found in 16 (29.6%), and distal subscapularis flap tears were found in 10 (18.5%) patients. Only in 12/54 patients (22.2%) was an isolated pathology found, in all cases SLAP tears. Treatment included vaporisation and excision of the impinging flaps. In 15/54 (27.7%) patients, repair of an unstable SLAP tear was undertaken using absorbable suture anchors and fibre wires. All athletes returned to their previous activity level within 17.2 weeks (range, 6-36) from surgery and were discharged when they claimed that they were symptom free. Conclusion: This series of anterior internal impingement, which we believe is the largest in the literature to date, demonstrates the value of an to assess and successfully treat overhead athletes with anterior impingement syndrome. PMID- 29264273 TI - Osteochondral lesion of the tibial plafond treated with a retrograde osteochondral autograft: a report of two cases. AB - Background: Osteochondral lesions (OCLs) of the tibial plafond (OLTPs) are rare, and few studies provide treatment recommendations. We describe two cases of an OLTP that were treated with retrograde osteochondral autograft. Case Reports: The first case was a 27-year-old basketball player and the second case was a 38-year old soccer player. We harvested osteochondral autografts from the nonweight bearing area of the lateral femoral condyle of the patient's ipsilateral knees. The grafts were reversed and inserted into the bone tunnel reaching the OLTPs starting proximally and moving distally. The first patient was able to play professional basketball 14 months after the procedure and continues to play 5 years and 6 months later. The second patient was able to play recreational soccer 9 months after the procedure and continues to play 4 years later. Conclusion: Use of the retrograde osteochondral autograft produced satisfactory results including the return to sports. The retrograde osteochondral autograft can be considered recommendable for treating OLTPs. PMID- 29264271 TI - Optimisation of platelet concentrates therapy: Composition, localisation, and duration of action. AB - Platelet concentrates (PC) generally refers to a group of products that are prepared from autologous blood intended to enhance healing activities. PC therapy is now very popular in treating musculoskeletal injuries; however, inconsistent clinical results urge the need to understand the working mechanism of PC. It is generally believed that the platelet-derived bioactive factors are the active constituents, and their bioavailability in the vicinity of the lesion sites determines the treatment efficacies. Therefore, the composition, localisation, and duration of the action of PC would be key determinants. In this review, we discuss how different preparations and delivery methods of PC would affect the treatment outcomes with respect to clinical evidence about PC therapy for osteoarthritis, tendinopathies, rotator cuff tears, anterior cruciate ligament injuries, and bone fractures. This review can be used as a quick guide for the use of PC therapy and provide insights for the further optimisation of the therapy in the near future. PMID- 29264275 TI - Osteochondral lesion of lateral tibial plateau with extrusion of lateral meniscus treated with retrograde osteochondral autograft transplantation and arthroscopic centralisation. AB - Background: Extrusion of the meniscus has been reported to be correlated with progression of osteoarthritis. In cases with osteochondral lesions after extrusion of the meniscus, meniscal transplantation was the only surgical intervention. Recently, a novel procedure called arthroscopic centralisation has been developed to restore the meniscus function by centralising the midbody of the extruded meniscus onto the rim of the tibial plateau using suture anchors. Case report: A combination of novel techniques-retrograde osteochondral autograft transplantation to retain hyaline articular cartilage and arthroscopic centralisation to restore residual meniscal function-was used to repair an osteochondral lesion of the lateral tibial plateau possibly caused by extrusion of the lateral meniscus. Good clinical and radiographic outcomes were achieved at the 2-year follow-up. Conclusion: A combination of retrograde osteochondral autograft transplantation and arthroscopic centralisation can be a good option to treat the osteochondral lesion of the tibial plateau caused by extrusion of the meniscus. PMID- 29264276 TI - Regression modelling combining MRI measurements and patient anthropometry for patient screening and prediction of graft diameter in hamstring autograft arthroscopic ACL reconstruction. AB - Background: Previous studies have associated anthropometric data and pre operative hamstring tendon measurements to intraoperative graft diameter for hamstring autograft ACL reconstruction, although an integrated model has yet to be described. The aim of this study was to present such a predictive model for quadrupled semitendinosus (4-ST) and doubled semitendinosus-gracilis (4-STG) graft constructs combining anthropometry (height and weight) and preoperative measurements of tendon as predictors. Methods: ACL reconstructions using 4-STG and 4-ST were retrospectively reviewed. The outlines of the semitendinosus and gracilis tendons were identified manually in the axial slice of a preoperative T2 weighted MRI using a region-of-interest tool. Regression analysis using intraoperative graft diameter as the dependent variable was performed with tendon cross-sectional area (XSA), gender and height as predictors. Results: 108 ACL reconstructions in 107 patients were examined, 75 of which were performed using the 4-STG construct, and 33 which employed the 4-ST construct. The mean graft diameter in the 4-ST group (8.6 +/- 0.8 mm) was significantly (p < 0.001) greater than the 4-STG group (7.9 +/- 0.7 mm). Female gender and 4-STG graft construct were associated with increased risk of graft diameter <8 mm. Predictive models of graft diameter were accurate to +/-1 mm for both construct types. Conclusions: An integrated method for assessing patient risk of producing a diminutive graft diameter and planning augmentation in select cases has been presented. The present findings describe a validated predictive model that builds on previous univariable analyses. Further investigation of larger samples, including factors associated with graft preparation, is required to improve model accuracy for routine clinical application. Level of evidence: IV, Retrospective Cohort Study. PMID- 29264277 TI - Optimization of an acid digestion procedure for the determination of Hg, As, Sb, Pb and Cd in fish muscle tissue. AB - A simple, efficient and cost effective method was developed and optimized for the digestion of fish tissue for the determination of Lead, Cadmium, Mercury, Antimony, Arsenic and Selenium by FAAS, CVAAS and HGAAS. Three of the more common classical open tubed acid digestion procedures were explored with the purpose of optimizing the variables and selecting the single most efficient, convenient and inexpensive digestion method. The effect of parameters such as digestion media, digestion time and digestion temperature on the efficiency of extraction of heavy metals from fish tissue was examined. Concentrated nitric acid was determined to be the most efficient digestion media for all the metals studied. *Efficient extraction of Arsenic, Selenium, Antimony, Lead and Cadmium was achieved at a digestion temperature of 100 degrees C for 120 min.*Optimum extraction of Mercury in fish tissue was achieved at 85 degrees C for 120 min since at higher temperatures, mercury was lost due to volatilization. PMID- 29264279 TI - To Infinity.... and Beyond!! PMID- 29264278 TI - Mesenchymal stromal cells and Interferon alpha (IFNalpha) in cancer immunotherapy. PMID- 29264280 TI - Understanding and Prevention of Orofacial Clefting: A Myth or Possibility? PMID- 29264282 TI - Orthognathic Surgery or Overlay Prosthesis: Quality of Life in Bilateral Cleft Lip and Palate Patients. AB - Background: The concern to restore and evaluate bilateral cleft lip and palate (BCLP) patients' quality of life, after rehabilitation, is an issue that has been discussed in the literature because it is the ultimate goal of any proposed treatment. Objective: To evaluate the overall and oral quality of life of BCLP patients who had completed their treatment with orthognathic surgery (OrSg) compared to those who completed theirs with prosthetic rehabilitation in the form of overlay prosthesis (OP). Materials and Methods: The study comprised 40 patients, 20 in OrSg group and 20 in OP group. Epidemiological survey and application of two questionnaires (World Health Organization Quality of Life brief [WHOQOL-bref] and Oral Health Impact Profile-14 [OHIP-14]) were done. The final results were evaluated statistically by the Mann-Whitney test. Results: Regarding the comparison with the WHOQOL-bref, no significant statistical differences between groups were found. In the analysis of the OHIP-14, only in "psychological limitation" field difference could be observed, where OrSg group showed more negative impact when compared to the OP group. Conclusion: Both rehabilitations provide a satisfactory quality of life for patients. PMID- 29264281 TI - Fast-track Orthognathic Surgery: An Evidence-based Review. AB - The aim of this study was to establish a fast-track protocol for bimaxillary orthognathic surgery (OGS). Fast-track surgery (FTS) is a multidisciplinary approach where the pre-, intra-, and postoperative management is focusing maximally on a quick patient recovery and early discharge. To enable this, the patients' presurgical stress and postsurgical discomfort should be maximally reduced. Both referral patterns and expenses within the health-care system are positively influenced by FTS. University hospital-literature review through Medline, Embase, and the Cochrane Library (January 2000-July 2016) using the following words - "fast track, enhanced recovery, multimodal, and perioperative care" - to define a protocol evidence based for OGS, as well as evidenced-based medicine search of every term added to the protocol during the same period. The process has resulted in an OGS protocol that may improve the outcome of the patient through several nonoperative and operative measures such as preoperative patient education and intra/postoperative measures that should improve overall patient satisfaction, decrease morbidity such as postoperative nausea, headache, dizziness, pain, and intubation discomfort, and shorten hospital stay. A literature review allowed us to fine-tune a fast-track protocol for uncomplicated OGS that can be prospectively studied against currently applied ones. PMID- 29264283 TI - A Study on Dorsal Pedicled Tongue Flap Closure of Palatal Fistulae and Oronasal Communications. AB - Introduction: Residual defects of the palatal region following ablative resection of tumors and Gunshot wounds (GSWs) of the maxillofacial region can be quite painstaking, daunting and challenging to reconstruct, due to the extent and composite nature of the tissue loss. A shortage of available donor areas and local flap options in the intraoral region, add to the difficulty. Further compounding the situation, are factors such as excessive fibrosis and scarring of the palatal tissues as a result of multiple previous surgeries in the region. Objective: To evaluate the effectiveness of the Dorsal Pedicled Tongue Flap in the reconstruction of complex palatal defects resulting from maxillofacial GSWs and ablative tumor resections. To also device techniques to reduce the incidence of postoperative tongue flap detachment, thus improving its efficiency and reliability. Results: The palatal fistulas in all the patients were closed successfully, with no post-operative complications such as bleeding, hematoma formation, congestion, infection, partial or total flap necrosis or flap detachment. The tongue flap at the recipient site remained healthy with no recurrence of the fistula in any of the patients in the two years follow up period. There was a complete resolution of the problem of nasal regurgitation of orally ingested fluids and food particles. There was observed no deformity or articulation defect resulting from the flap harvested from the tongue dorsum, in any of the patients. Conclusion: In GSWs and tumor ablative surgery, where composite tissue defects are involved, the tongue provides a reliable and efficient means of restoring lost tissue bulk as well as ensuring a permanent closure and sealing off of the oronasal fistulas. Its reliability can be further increased by avoiding a common complication, namely, flap detachment in the postoperative period brought on by movements of the tongue, by immobilizing the tongue by tethering it to the maxillary teeth and also, maintaining the patient on Nasogastric feeding for the three weeks postoperative period, until the patient is taken up for surgical separation the pedicle. This helps to ensure a successful and predictable take of the flap at the donor site. PMID- 29264284 TI - Lugol Chromoscopy in the Follow-up of Head and Neck Carcinoma. AB - Introduction: Lugol is helpful in identifying early second primary tumors (SPTs) during oroscopy and pharyngoscopy, but this technique has not been assessed during follow-up visits with these patients. Aim: The aim of this study is to describe the use of Lugol (a low-cost method) to diagnose SPTs in the oral cavity and oropharynx. Methods: Patients treated for squamous cell carcinoma of the head and neck were randomly assigned to two groups. Group A was examined with routine oroscopy and pharyngoscopy without Lugol, and Group B was examined with routine oroscopy and pharyngoscopy without stain and with Lugol. A total of 211 patients were included during 4 years. Results: Six oral and oropharynx carcinomas were detected in Group A. Eighteen oral and oropharynx carcinomas were detected in Group B, twelve of which were not seen without chromoscopy but were detected with Lugol. Conclusion: Lugol increases the detection of malignant lesions compared to routine examination alone. PMID- 29264285 TI - Evaluation of the Sternoclavicular Graft for the Reconstruction of Temporomandibular Joint After Gap Arthroplasty. AB - Introduction: Ankylosis may be defined as the fusion of the articular surfaces with bony or fibrous tissue. The treatment of temporomandibular joint ankylosis poses a significant challenge because of the high incidence of recurrence. A number of interpositional materials have been used including alloplastic materials (acrylic, proplast-teflon, silastic), and autogenous tissues (temporalis muscle flaps, buccal fat pad, dermis, costochondral grafts, metatarsal, fibula, tibia, iliac crest, cranial bone and Sternoclavicular graft SCG and cartilage). Literature suggests that rather than growth centre, we need adaptive centre. SCG is presumed to be a more suitable material for interpositional arthroplasty because Sternoclavicular Joint (SCJ) and TMJ are very similar developmentally, histologically and morphologically throughout the growth period. Material and Method: Patients with TMJ ankylosis (8 males, 2 females) underwent release of the ankylosed joint by the senior author, between June 2013 and Novemeber 2015. The age of the patients ranged from 10 to 19 years. Pre- and post- operative assessment included a thorough history and physical examination to determine the cause of ankylosis, the maximal incisal opening, etiology and type of the ankylosis, recurrence rate. Result: MIO at 6 months follow up was 37.4+/-2.633 mm (range 32-40 mm), greater than MIO achieved in immediate postoperatively {34.4+/-2.22 mm (range 30-38 mm). After reconstruction of temporomandibular joint with sternoclavicular graft in the growing child there was a significant increase in the growth of mandible which was stunned due to ankylosis. And the ramal height also increased. Conclusion: The articular reconstruction with alloplastic or autogenous grafts, or gap arthroplasty for the treatment of ankylosis is shown to be efficient in relation to the post-operative maximal incisal opening, recurrence and articular function. PMID- 29264286 TI - A Randomized Control Trial of Awake Oral to Submental Conversion versus Asleep Technique in Maxillofacial Trauma. AB - Aim: This study was designed to evaluate the efficacy of awake oral to submental conversion over asleep technique. Materials and Methods: This randomized clinical study was conducted in maxillofacial department of a tertiary care hospital in patients who had panfacial or mandibular fractures requiring elective surgical correction. The patients were randomly divided into two groups of 12 patients each, asleep fiberoptic-assisted submental intubation (SMI) (Group G; n = 12) and awake fiberoptic-assisted SMI (Group A; n = 12). The primary predictor was mean conversion time of oral to SMI while other predictors were overall success rate, ease of conversion, and complications. Data are presented as mean (+/-standard deviation) and frequencies (%) as appropriate. Statistical analysis done using unpaired t-test or Chi-square test was performed and P < 0.05 was considered statistically significant. Results: Twenty-four patients (19:5;Male:Female) aged 18-55 years (Group G = 35.96; Group A = 32.43 years) were included in the study. SMI was successful in all except two patients in group G. Overall success rate was similar in both groups. Time to convert orotracheal intubation to SMI was significantly less in group A (Group G = 9.55 +/- 1.42, Group A = 5.67 +/- 1.73; P < 0.001). Ease of SMI was found Grade I in 30% and 83% of the patients of group G and A, respectively. No serious complications were observed except 2 cases of bleeding, and 1 case of tube damage. Conclusion: Awake oral to submental conversion requires lesser time in comparison to asleep technique besides improving the ease (Delta = 53%) of the procedure. PMID- 29264287 TI - Low-level Laser Therapy on Postoperative Pain after Mandibular Third Molar Surgery. AB - Introduction: The analgesic effect of low-level laser therapy (LLLT) after mandibular third molar (MTM) extraction is controversial. The aim is to evaluate the effect of intraoral LLLT on postoperative pain after MTMs extraction. Methods: Thirty patients with bilateral symmetrical impacted MTMs underwent surgical extractions. Experimental and control sides were randomly selected to receive LLLT or placebo. Following suturing, a dental assistant applied 810 nm gallium aluminum arsenide (GaAlAs) at three points for 30 s each with a total energy of 9 J. Pain was recorded on a visual analog scale on the 7 successive days. Results: Data analyzed by IBM SPSS Statistics 23 for Windows with P <= 0.05 significance level. LLLT appeared to have a high significant effect on pain reduction; however, there was a mild increase in pain after the 4th day. Conclusion: Intraoral 810 nm GaAlAs is effective in reducing postoperative pain when a dose of 32.86 J/cm2 is used. PMID- 29264288 TI - Evaluation of Knowledge of Physical Education Students on Dental Trauma. AB - Introduction: Sports' practitioners are vulnerable to dental trauma; if this occurs, the emergency treatment should be fast and efficient. This may be performed by any person at the site of the accident, not only by dental professionals. Physical educators may face dental trauma and should be able to provide proper care. This study had the objective evaluated the knowledge of physical education graduates on dental trauma. Materials and Methods: A questionnaire containing questions on dental trauma was applied to 199 physical education students; after collection of the questionnaires, data were tabulated and processed on the software Epi Info 2000 (Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333, USA). As a result, only 36.7% of participants would take the individual suffering trauma to the dental professional, 56.8% believe that the avulsed tooth should be replanted, and 42.2% would replant it. Only 7.5% would store the avulsed tooth in an ideal storage medium for transportation. Conclusion: It was concluded that there is a lack of knowledge on dental trauma among physical education graduates, evidencing the need of public policies to allow education on this issue. PMID- 29264289 TI - Craniosynostosis of the Sphenofrontal Suture: Definition of the Main Signs of Craniofacial Deformity. AB - Aims: The aim of this study is to compare clinical features of sphenofrontal craniosynostosis (SFC) and unilateral coronary craniosynostosis. Settings and Design: This was a retrospective study with two groups of patients with sphenofrontal and coronary craniosynostosis. Materials and Methods: This was a retrospective study of the 1999-2016 archive data in Russian Children's Clinical Hospital. Ninety-five patients were diagnosed with frontal plagiocephaly. Eighty three had deformations of unilateral craniosynostosis of coronary suture, 12 had premature closures of sphenofrontal suture. The age at the time of diagnosis varied from 5 months to 2, 5 years. Results: SFC is featured by ipsilateral flattening of forehead and supraorbital margin, and ipsilateral dystopia of supraorbital margin downward. X-ray signs are the closure of sphenofrontal suture on the lesion side with open and symmetrically located remaining skull sutures and contralateral deviation of the midline of the ethmoid. Conclusions: SFC distinguishes from other plagiocephalias by following signs: supraorbital margin on the affected side is shifted downward; tip of the nose is displaced toward the affected side, root of the nose toward the healthy side. These signs facilitate correct diagnosis and treatment tactics. PMID- 29264290 TI - Features of Prevertebral Disease in Patients Presenting to a Head and Neck Surgery Clinic with Neck Pain. AB - Introduction: Untreated prevertebral space infections, which can be overlooked because of connections with surrounding spaces, may lead to spinal epidural accumulations that cause cord compression. The aim of this study was to analyze the epidemiologic and diagnostic features of cases of prevertebral disease encountered by head and neck specialists. Materials and Methods: The study was designed as a retrospective chart review of 11 patients with prevertebral disease who presented to a head and neck surgery specialist for consultation from 2004 to 2010. Epidemiologic characteristics, clinical signs, diagnostic modalities, time to diagnosis, treatment, and final outcome were analyzed. Ethical Approval: This article does not contain any studies with human participants or animals performed by any of the authors. Results: Seven patients were diagnosed with prevertebral abscess, two with prevertebral cellulitis, and two with calcific cervical tendonitis. The most common presenting signs were neck pain (100%), odynophagia (54%), dysphagia (36%), neck rigidity (36%), fever (27%), and back pain (9%). Five patients (45.5%) showed a bulge on the posterior pharyngeal wall. Four patients with prevertebral abscess showed epidural accumulations on magnetic resonance imaging. Patients with prevertebral abscess and cellulitis were treated with surgical drainage or intravenous antibiotics or both while patients with calcific cervical tendonitis were treated with anti-inflammatory and pain medications. Ten patients were cured, and one with multiple comorbidities succumbed to the disease. Conclusion: Clinicians should have a high index of suspicion of prevertebral abscess or cellulitis in patients presenting with neck pain, fever, dysphagia, and limited range of motion of the neck. Head and neck specialists may be the first to encounter and diagnose this highly morbid disease. PMID- 29264291 TI - Surgical Management of Long-standing Eagle's Syndrome. AB - Introduction: Eagle's syndrome is a rare condition that refers to chronic recurrent pain in the oropharynx, face, and neck due to elongation of the styloid process or calcification of the stylohyoid ligament. It can be treated medically or surgically through a styloidectomy. In this paper, we review our experience with the two surgical approaches for the management of Eagle's syndrome. Materials and Methods: We conducted a retrospective chart review, which covered the period between 1997 and 2008. The review included seven patients with a long standing diagnosis of Eagle's syndrome. Six patients underwent surgical intervention and one patient elected to observe her condition. Ethics Approval: The retrospective design of the study was approved by Boston Medical Center Institutional Review Board with no need for another consent other than the one obtained before surgical interventions. Results: Out of the seven patients identified, there were three men and four women. The median age and mean age at diagnosis were 44 years and 26.2 years, respectively. Neck pain and odynophagia were the most common symptoms reported. Three patients underwent styloidectomy through transoral approach and the three through transcervical approach. The average time to resolution of symptoms was 26.5 days. Conclusion: The review suggests a favorable role for surgery in the management of Eagle's syndrome with all the patients undergoing styloidectomy experiencing complete resolution of symptoms. Both surgical approaches provide the desired outcome; however, the choice of the surgical approach depends on the patient's wishes and the surgeon's experience. PMID- 29264292 TI - Implant Survival between Endo-osseous Dental Implants in Immediate Loading, Delayed Loading, and Basal Immediate Loading Dental Implants a 3-Year Follow-up. AB - Introduction: With introduction of the term "ossteointegration of dental implant" by Branemark, advancement in implantology from 1957 to 2017 has come a long way with modification in implant type and in loading time. This study aims to evaluate the survival of endo-osseous immediate loading (IL) implant and basal IL implants in atrophic jaws with objective to compare implant survival in atrophic jaws for full mouth rehabilitation between endo-osseous IL versus endo-osseous delayed loading (DL) versus basal IL during 3-year follow-up. Materials and Methods: Fifty-two (34 endo-osseous and 18 basal) implants were placed in 4 patients requiring full mouth rehabilitation in atrophic jaws. Case 1: Endo osseous DL implants in upper and lower arch, Case 2: Endo-osseous IL implants in upper and lower arch, Case 3: Basal IL implant in upper and lower arch, and Case 4: Endo-osseous DL in upper arch and basal IL implant in the lower arch. Intraoperative evaluation was done on the basis of pain (visual analog scale [VAS]), operative time, and initial primary implant stability. Postoperative evaluation was done on pain (VAS), infection, radiographically successful implant (orthopantomogram), and patient satisfaction (Grade 0-10). Results: All cases showed satisfactory results but more amount of intra- and post-operative pain was felt with immediate basal implants. Conclusion: We believe that clinicians should comply with patient requests, and for this reason, we agree with some authors to use minimally invasive techniques and to avoid when possible esthetic or functional problems associated with the use of removable prosthesis after teeth extractions. PMID- 29264293 TI - Autologous Platelet-rich Plasma after Third Molar Surgery. AB - Aim and Objective: The aim of this study is to compare the efficacy of autologous platelet-rich plasma (PRP) in the third molar impactions, with respect to: pain, swelling, healing, and periodontal status distal to the second molar in patients who need surgical removal of bilateral impacted mandibular third molars. Materials and Methods: Twenty-five patients of both sexes aged between 16 and 60 years who required bilateral surgical removal of their impacted third molars and met the inclusion criteria were included in the study. After surgical extraction of the third molar, primary closure was performed in the control group, whereas PRP was placed in the socket followed by primary closure in the case group. The outcome variables were pain, swelling, wound healing, and periodontal probe depth that were follow-up period of 2 months. Quantitative data are presented as mean. Statistical significance was checked by t-test. Results: There was a difference in the pain (0.071) and facial swelling (0.184), reduction between test and control on day 3, but it was not found to be significant. Periodontal pocket depth (0.001) and wound healing (0.001) less in case group compared with the control group was found to be significant. Conclusion: The use of PRP lessens the severity of immediate postoperative sequelae and decreases preoperative pocket depth. PMID- 29264294 TI - Efficacy of Exclusive Lingual Nerve Block versus Conventional Inferior Alveolar Nerve Block in Achieving Lingual Soft-tissue Anesthesia. AB - Objective: The aim of this randomized clinical trial was to assess the efficacy of exclusive lingual nerve block (LNB) in achieving selective lingual soft-tissue anesthesia in comparison with conventional inferior alveolar nerve block (IANB). Materials and Methods: A total of 200 patients indicated for the extraction of lower premolars were recruited for the study. The samples were allocated by randomization into control and study groups. Lingual soft-tissue anesthesia was achieved by IANB and exclusive LNB in the control and study group, respectively. The primary outcome variable studied was anesthesia of ipsilateral lingual mucoperiosteum, floor of mouth and tongue. The secondary variables assessed were (1) taste sensation immediately following administration of local anesthesia and (2) mouth opening and lingual nerve paresthesia on the first postoperative day. Results: Data analysis for descriptive and inferential statistics was performed using SPSS (IBM SPSS Statistics for Windows, Version 22.0, Armonk, NY: IBM Corp. Released 2013) and a P < 0.05 was considered statistically significant. In comparison with the control group, the study group (LNB) showed statistically significant anesthesia of the lingual gingiva of incisors, molars, anterior floor of the mouth, and anterior tongue. Conclusion: Exclusive LNB is superior to IAN nerve block in achieving selective anesthesia of lingual soft tissues. It is technically simple and associated with minimal complications as compared to IAN block. PMID- 29264295 TI - Tomographic Analysis of the Impact of Mandibular Advancement Surgery on Increased Airway Volume. AB - Purpose: This study aimed to quantify, using cone-beam computed tomography (CBCT) in patients who underwent a mandibular advancement surgery associated with genioplasty, three-dimensional changes in airway space and to evaluate whether these changes differ between men and women. Materials and Methods: Preoperative and 8-month postoperative CBCT scans of 38 patients aged 18-45 years of either sex and any ethnicity who underwent mandibular advancement surgery associated with genioplasty were analyzed using the Xoran software (Xoran Technologies, Ann Arbor, MI, USA). The linear distances gonion-gnathion (Go-Gn) and condylion menton (Co-Me) were obtained. Airway volume was measured using the Dolphin Imaging software, version 11.0. Then, data were tabulated and analyzed using Student's t-test. Results: Mean patient age was 30.3 years; 39.47% were men and 60.63% were women. The mean Go-Gn distance was 72.05 mm before surgery and 78.56 mm after surgery, with a mean gain of 6.51 mm. The mean Co-Me distance was 113.47 mm before surgery and 119.89 mm after surgery, with a mean increase of 6.42 mm. Both differences were statistically significant. The mean volume of airway space was 17,272.92 mm3 before surgery and 24,173.74 mm3 after surgery, with a statistically significant mean increase of 6900.82 mm3. There was no statistically significant difference in mean volumetric gain between men (7566.69 mm3) and women (7456.69 mm3). Conclusion: Mandibular advancement surgery results in significant increase of airway space, and there is no difference in airway volume between men and women. PMID- 29264296 TI - Computed Tomographic Analysis of the Sagittal Orbit-globe Relationship. AB - Identifying the normal relationship of the orbital rims to the globes is critical in planning surgical correction of craniofacial deformities affecting the orbit. This article illustrates a technical proof of principle and mathematical basis for a computed tomography-based measurement of the sagittal orbit-globe relationship. The technique does not require subject cooperation and is, therefore, optimal for pediatric craniofacial surgical treatment planning and outcome evaluation. PMID- 29264298 TI - Post Herpetic Frey's Syndrome. AB - Frey's syndrome is characterized by unilateral sweating and flushing of the skin in the area of the parotid gland, occurring during meal, or on salivary stimulation. It is a common complication following surgery/injury in the parotid gland region/temporomandibular joint surgery; however, very few cases have been reported of its occurrence following herpetic infection. It is important for the clinician to recognize its unusual symptoms as early as possible to prevent its potential negative social and psychological effect on the patient. It is diagnosed on clinical presentation and confirmed by objective testing methods. The treatment ranges from topical application of glycopyrrolate to local injections of botulinum toxin and lastly to surgical intervention. An interesting case of Frey's syndrome is presented in a young patient having the previous history of herpes zoster infection, which was diagnosed clinically and confirmed by starch-iodine test and was successfully treated with topical application of glycopyrrolate. PMID- 29264297 TI - Guided Bone Regeneration for the Reconstruction of Alveolar Bone Defects. AB - Background: Guided bone regeneration (GBR) is the most common technique for localized bone augmentation. Purpose: The purpose of this review was to categorize and assess various GBR approaches for the reconstruction of human alveolar bone defects. Materials and Methods: Electronic search of four databases including PubMed/Medline, EMBASE, Web of Science, and Cochrane and hand searching were performed to identify human trials attempting GBR for the reconstruction of alveolar bony defects for at least 10 patients from January 2000 to August 2015. To meet the inclusion criteria, studies had to report preoperative defect dimensions in addition to outcomes of bone formation and/or resorption. Results: Twenty-five human clinical trials were included of which 17 used conventional technique that is the use of space maintaining membrane with bone grafting particles (GBR I). Application of block bone graft with overlying membrane and particulate fillers was reported in seven studies (GBR II), and utilizing cortical bone block tented over a defect preserving particulate fillers was reported by one study (GBR III). A wide range of initial defects' sizes and treatment results were reported. Conclusions: This review introduces a therapeutically oriented classification system of GBR for treating alveolar bone defects. High heterogeneity among studies hindered drawing definite conclusions in regard to superiority of one to the other GBR technique. PMID- 29264299 TI - Multiple Dentigerous Cysts as a Rare Presentation of Maroteaux-Lamy Syndrome. AB - Maroteaux-Lamy syndrome is one of the genetic disorders involving disturbances in mucopolysaccaride metabolism, due to deficiency of aryl sulfatase-B which leads to accumulation of dermatan sulfate in tissues and their excretion in urine. The diseases has several oral and dental manifestations, is first diagnosed on the basis of clinical findings. It is characterized by coarse facial features, normal intelligence, organomegaly, enlarged head, short neck, corneal clouding, enlarged tongue, and prominent metachromatic inclusions in leukocytes. Death is usually a result of either respiratory tract infection or cardiac disease, which is caused by the deposition of mucopolysaccharides. An 18-year-old with Maroteaux-Lamy syndrome is described in this article with multiple dentigerous cysts as the first presentation. PMID- 29264300 TI - Two-stage Corrections of Rare Facial Tessier's Cleft - 3,4,5,6,7. AB - Congenital transverse and oblique facial clefts are rare congenital anomalies, and cooccurence of these is still more a rare anomaly. The condition most commonly is often associated with anomalies of the first and second branchial arches. The manuscript intends to present one such rare case of Tessier's cleft type 3-7 and present its early management as well as long-term treatment plan. PMID- 29264301 TI - Rehabilitation of Unilateral Congenital Microtia by Implant-retained Prosthesis. AB - Microtia is a major congenital anomaly of the external ear. It includes a spectrum of deformities from a grossly normal but small ear to the absence of the entire external ear. These deformities account for three in every 10,000 births, with bilaterally missing ears seen in fewer than 10% of all cases. Extraoral implant-retained ear prosthesis has been proven to be a predictable treatment option for rehabilitation of such congenital anomalies. This paper aims to present principles of maxillofacial implants, review of literature, advantages, disadvantages, and considerations in treatment planning and treatment phases of an implant-supported auricular prosthesis and prospective developments for ear prosthesis are also discussed. Implant supported ear reconstruction provides excellent support, good retention, and esthetically acceptable appearance to the patient. PMID- 29264302 TI - Short Root Anomaly - A Potential "Landmine" for Orthodontic and Orthognathic Surgery Treatment of Patients. AB - Short root anomaly (SRA) is a poorly understood developmental disorder and can significantly compromise the patient's dental treatment. This case report describes the treatment of a 15-year-old girl with SRA and discusses the implication of this disorder on orthodontic and orthognathic treatment of patients. PMID- 29264303 TI - Karapandzic Flap for Esthetic and Functional Reconstruction of Large Defect of Lower Lip. AB - Squamous cell carcinoma is the most common cancer occurring in the oral cavity. The lips are one of the most common sites of occurrence with involvement, lower lip being more common than upper. Reconstruction of large defects of lower lip with good functional and esthetic outcome is the biggest challenge faced by the surgeon. Karapandzic flap is one the most commonly used technique for reconstruction of large defects of the lower lip. PMID- 29264304 TI - Ameloblastic Fibro-odontoma with a Predominant Radiopaque Component. AB - Ameloblastic fibro-odontoma (AFO) is a rare odontogenic tumor. Initially believed to be a lesion similar to ameloblastic fibroma (AF), it is now considered as a separate entity in the WHO odontogenic tumor classification. Commonly associated with a painless swelling and an associated absence of eruption of a tooth, AFO presents as a mixed radiopaque and radiolucent lesion in the younger population with a predilection for the posterior region. Histologically, it shows the characteristics of an immature complex odontoma with irregularly arranged enamel, dentinoid, cementoid-like structures, and ectomesenchymal tissue. The following case report describes a case of AFO with a predominantly radiopaque component and briefly discusses the available literature pertaining to this rare entity. PMID- 29264305 TI - Unusual Case of Acquired Capillary Hemangioma of the Eyelid in an Adult. AB - Acquired capillary hemangioma of the eyelid is very uncommon in adults. To our knowledge, only eight such cases have been reported in the literature till date. We report the case of a 25-year-old female with acquired capillary hemangioma of the left lower eyelid treated by cutting diathermy followed by reconstruction of the cutaneous and cartilaginous defect. This patient had a history of a similar lesion in the left malar region treated 5 years back. This case is being presented to highlight the occurrence of such lesions in an adult and to discuss the dilemmas in the diagnosis and management. PMID- 29264306 TI - Management of Non-Hodgkin's Lymphoma in Maxillofacial Region with Chemotherapy. AB - Malignant lymphomas form a heterogeneous group of neoplasms of the lymphoid tissue with different clinical courses, depending on the treatment and prognosis. Lymphoma is a malignant neoplasm of the lymphoid tissue; it is broadly classified into Hodgkin lymphoma (HL) and Non-HL (NHL) depending on the presence or absence of the Reed-Sternberg cells. The main types of lymphomas are (1) HL and (2) NHL. This case report describes about primary NHL involving the mandible. Chemotherapy was advised by the oncologist, and a total of 14 cycles were suggested at the gap of every 2 weeks. The treatment regimen followed was classical Cyclophosphamide hydrodaunorubicin oncovin Prednisolone (CHOP) therapy. NHL can be managed by chemotherapy, radiotherapy, and surgery in various combinations. NHL arising in bone is best treated by chemotherapy and may not require radiotherapy. Survival and prognosis are excellent in localized disease, whereas disseminated disease seems less favorable. PMID- 29264307 TI - Dual Pathology of Mandible. AB - Aneurysmal Bone cyst (ABC)is a rare benign lesion of the bone which is infrequent in craniofacial region (12%). Rapid growth pattern causing bone expansion and facial asymmetry is a characteristic feature of ABC. Giant cell lesion is another distinct pathological entity. Here we present to you a rare case of dual pathology in an 11 year old female patient who presented with a large expansile lesion in the left hemimandible. All radiographic investigations were suggestive of ABC, aspiration of the lesion resulted in blood aspirate. However only after a histologic examination the dual nature of the lesion was revealed. PMID- 29264308 TI - Surgical Resection of a Parotid Gland Hemangioma in Teenager Managed with External Carotid Artery Ligation. AB - Parotid gland hemangiomas represent <0.6% of the total tumors of the gland and there are <50 tumors reported during adult age, so there is no standard treatment. A 18-year-old female presents with a mass in the right parotid gland of 18 months of a slow progressive asymptomatic growth; on physical examination, only the mass was detected. An angiography was performed, and it reported a possible hemangioma that depends on the right internal maxillary artery and right facial artery and was not suitable for embolization. Total parotidectomy was performed with prior ligation of the right external carotid artery, complete resection was achieved and preservation of the facial nerve and all branches with minimal loss of blood (150 cc). External carotid artery ligation is a safe technique that can be considered in carefully selected patients with vascular tumors that affect the head and neck to achieve a clean and safe surgery with minimal sequels. PMID- 29264309 TI - Comparison of Bone Mineral Density among Alcoholism and Nonalcoholism Athlete and Nonathlete Subjects. AB - Background: The aim of this study was to compare bone mineral density among alcoholic, nonalcoholic and nonathlete subjects. Materials and methods: The group consisted of physically active people. A questionnaire was given to both alcoholics and nonalcoholics and 28 persons were randomly selected (15 members who consumed alcohol and 13 who did not). In order to collect the data on mineral aggregation, a testing device (DEXA) was used. The data were analyzed using SPSS software. Results: It was found that higher bone aggregation in each of the two athletic group in comparison with the nonathletic group (p < 0.05). Conclusion: Exercise may have a positive impact on bone mineral density. Abbreviations: BMD: bone mineral density; SPSS: Statistical package for social science.How to cite this article: Hosseini S, Valizade R, Heydarabadi FD. Comparison of Bone Mineral Density among Alcoholism and Nonalcoholism Athlete and Nonathlete Subjects. Euroasian J Hepato-Gastroenterol 2014;4(1):1-3. PMID- 29264310 TI - Epidemiology of Hepatitis E Virus in an Urban Community in Dhaka City. AB - Introduction: Hepatitis E virus (HEV) is endemic in Bangladesh and sporadic and epidemic outbreaks of acute hepatitis E occur in this country almost regularly. Although the real magnitude of HEV prevalence has not been documented in Bangladesh, HEV infections and HEV-related acute hepatitis of Bangladeshi origin have been reported from different parts of the world. Methods: The study was conducted in Mirpur area of Dhaka city, which is a major residential area of the capital of Bangladesh. Three hundred adults were randomly included in the study. None had any history of jaundice or complains of liver diseases. Results: The study revealed 30% prevalence of HEV in this population. The prevalence increased with age, but there was no gender difference. Conclusion: HEV is a highly prevalent disease in Bangladesh as elsewhere in the developing world. Since there is no specific treatment for HEV, improvement of personal hygiene and ensuring supply of safe food and drinking water remain most important approach to sustain the virus.How to cite this article: Rahman S, Mahtab MA, Jahan M, Tabassum S, Akbar SMF. Epidemiology of Hepatitis E Virus in an Urban Community in Dhaka City. Euroasian J Hepato-Gastroenterol 2014; 4(1):4-6. PMID- 29264311 TI - General Properties of Colon Polyps in Central Anatolia. AB - Aim: Polyp is called formations protruding into the lumen in the gastrointestinal tract. In this study, we aimed to determine frequency, anatomic distribution within the large bowel and pathologic types of colon polyps based on the colonoscopy results. Materials and methods: The colonoscopy reports between 2010 and 2011 were analyzed retrospectively. Complaint of the patients on admission, the presence of polyps, anatomic distribution of polyps, polyp type and polyp size were evaluated. Result: A total of 4000 colonoscopy reports were examined. The largest proportion of polyps occurred in the left colon (74.4%), followed by the ascending colon (11.5%). Eighty-five were adenomatous polyps, 71 were hyperplastic polyps, 12 were inflammatory polyps, 12 were serrated adenoma, 3 were adenocarcinoma, and 8 were tubulovillous adenomas. Discussion: In light of like this study, the development of screening and follow-up programs in Turkey will be useful to reduce the incidence and mortality of colorectal cancer.How to cite this article: Kefeli A, Basyigit S, Yeniova AO, Nazligul Y, Kucukazman M, Aktas B. General Properties of Colon Polyps in Central Anatolia. Euroasian J Hepato-Gastroenterol 2014;4(1):7-10. PMID- 29264312 TI - Feasibility of Concurrent Chemoradiation in Patients treated for Esophageal Carcinoma: A Single Institutional Experience. AB - Background: Chemoradiation has shown superior overall survival when compared with radiation alone in esophageal carcinoma. Due to compromised nutritional status, radiation therapy in esophageal cancer patients itself is a challenge and addition of concurrent chemotherapy leads to severe side effects even when standard dose regimens are used. The tolerance of chemoradiation for carcinoma esophagus in Indian patients is still unclear. This study is an effort to know feasibility of chemoradiation in patients treated for esophageal carcinoma in our hospital. Materials and methods: A total of 47 consecutive patients of histologically proven esophageal carcinoma who were treated in MS Ramaiah Hospital were reviewed retrospectively from January to August 2013. Out of 47 patients, 20 patients were treated with concurrent chemoradiotherapy. Patients were assessed for number of days of treatment interruptions in radiation schedule and number of planned vs executed cycles of chemotherapy. Results: Out of the 20 patients treated with concurrent chemoradiotherapy, 13 patients were male (65%) and 7 (35%) were female. Median age of patients was 60 years (25-75 years). Squamous cell carcinoma was noted in majority of cases (19/20 cases). A total of 18 of 20 patients completed the planned dose of radiation and only 3/20 patients completed all planned cycles of chemotherapy. Mean number of days of interruption in radiation schedule in patients receiving chemoradiotherapy was 4.4 days. Conclusion: There was poor tolerance to chemoradiotherapy leading to reduction in the number of executed chemotherapy cycles as opposed to planned cycles, although there were no significant interruptions in radiation treatment.How to cite this article: Kannan RA. Feasibility of Concurrent Chemoradiation in Patients treated for Esophageal Carcinoma: A Single Institutional Experience. Euroasian J Hepato Gastroenterol 2014;4(1):11-13. PMID- 29264313 TI - Chronic Liver Disease is One of the Leading Causes of Death in Bangladesh: Experience by Death Audit from a Tertiary Hospital. AB - Background: In industrialized countries, the audit has become an integral part of medical care. The experience from developing countries like Bangladesh is still inadequate. This study had been carried out to find out relation among some factors like age, sex, causes, diurenal variation, duration of hospital stay with death and errors in certification process. Materials and methods: It was a cross sectional study conducted at the Department of Medicine, Sir Salimullah Medical College (SSMC) and Mitford Hospital from March 2010 to August 2010. Information of consecutive 100 deaths was collected in a predesigned clinical data sheet within half an hour of every occurrence. Necessary data were collected from hospital case records (admission registrar, case files and death certificates) using structured checklist. Patients who were brought dead were excluded from the study. Results: Among 100 deaths, 48% were males (n = 48) and 52% were females (n = 52). Within this group, 66.7% were males and 33.3% were females. First day (within 24 hours of admission) death accounted for 46% (n = 46) of all death and by the second day 23% (n = 23) of all deaths occurred. The highest underlying cause of death was cerebrovascular diseases (29% of total death), infectious disease contributed 20%, chronic liver disease 13%, malignancy 7%, poisoning 6%, cor pulmonale 5%, while others were 20%. Conclusion: In this studychronic liver disease was found to be one of the leading causes of death in our hospital and most of them occurred due to hepatic encephalopathy. So, early detection of hepatic encephalopathy and treatment is necessary to reduce hospital mortality.How to cite this article: Abedin MF, Hoque MM, Islam ASMS, Chowdhury MFI, Das DC, Begum SA, Mamun AA, Mahtab MA, Rahman S, Saha AK. Chronic Liver Disease is One of the Leading Causes of Death in Bangladesh: Experience by Death Audit from a Tertiary Hospital. Euroasian J Hepato-Gastroenterol 2014;4(1):14-17. PMID- 29264314 TI - Hepatoprotective and Antioxidant Effect of Mangifera Indica Leaf Extracts against Mercuric Chloride-induced Liver Toxicity in Mice. AB - Background: To explore the antioxidant and hepatoprotective effect of ethanolic Mangifera indica (EMI) and methanolic Mangifera indica (MMI) leaf extracts in mercuric chloride (HgCl2) induced toxicity in Swiss albino mice. Materials and methods: Toxicity in mice was induced with HgCl2 (5.0 mg/kg, i.p.), followed by oral intervention with EMI and MMI extracts (25 mg and 50 mg/kg. body wt.) for 30 days. Results and discussion: The extent of liver damage was assessed from the extents of histopathological, morphological, antioxidant and liver enzymes. Mercuric chloride-induced mice showed an increased cellular damage whereas leaf extracts of EMI and MMI-treated mice showed recovery of damaged hepatocytes. Mercuric chloride intoxicated mice exhibited a significant (p < 0.05) elevation in the liver enzymes (Aspartate amino transferase and Alanine amino transferase) and gradual decline in the cellular radical scavenging enzyme levels (Catalase, Glutathione-s-transferase and Glutathione peroxidase. The combined treatment with EMI and MMI leaf extracts significantly (p < 0.05) reversed these parameters. However, the effects of MMI leaf extract (50 mg/kg) were superior to those of EMI treated mice possibly due to its potent radical scavenging property. These results suggest that oral supplementation of Mangifera indica extract remarkably reduces hepatotoxicity in mice possibly through its antioxidant potentials.How to cite this article: Karuppanan M, Krishnan M, Padarthi P, Namasivayam E. Hepatoprotec-tive and Antioxidant Effect of Mangifera Indica Leaf Extracts against Mercuric Chloride-induced Liver Toxicity in Mice. Euroasian J Hepato Gastroenterol 2014;4(1):18-24. PMID- 29264315 TI - Distribution of Liver Disease in Bangladesh: A Cross-country Study. AB - Introduction: 'Hepatology', as an independent discipline of medical science, has recently been established in Bangladesh. The aim of this study was to formulate the distribution of pattern of liver diseases in this country. Materials and methods: In this retrospective study, data regarding patients of liver diseases from the seven different administrative divisions of Bangladesh between January 2012 and 2013 were compiled. Results: The study included 59,227 patients (age ranged 15-95 years). Majority of the patients were males (67.9%). Although all patients appeared at the department of hepatology, 13.2% were diagnosed with liver diseases, but a vast majority of patients (77.35%) were suffering from nonulcer dyspepsia or irritable bowel syndrome. Patients with liver diseases were mostly suffering from chronic liver diseases (CLDs) (37 -69%). Complication of CLD, like hepatic encephalopathy, was less frequent in regions with better healthcare system. Nonviral infections, like liver abscess and biliary ascarisis, were not uncommon. Acute hepatitis was another very common entity and contributed to approximately 20% cases. Conclusion: This study provides insight about heterogeneous distribution pattern of liver diseases in different regions of Bangladesh.How to cite this article: Rahman S, Ahmed MF, Alam MJ, Debnath CR, Hoque MI, Hussain MM, Shamsul Kabir AKM, Karim MF, Khondokar FA, Mahtab MA, Masud MG, Mollick MKU, Moben AL, Noor-E-Alam SM, Podder PK, Raha AK, Rahim MA, Rashid MHO, Zaki KMJ, Akbar SMF. Distribution of Liver Disease in Bangladesh: A Cross country Study. Euroasian J Hepato-Gastroenterol 2014;4(1):25-30. PMID- 29264316 TI - Comparison of Hybrid Capture 2 Assay with Real-time-PCR for Detection and Quantitation of Hepatitis B Virus DNA. AB - Background: Both real-time-polymerase chain reaction (PCR) and hybrid capture 2 (HC2) assay can detect and quantify hepatitis B virus (HBV) DNA. However, real time-PCR can detect a wide range of HBV DNA, while HC2 assay could not detect lower levels of viremia. The present study was designed to detect and quantify HBV DNA by real-time-PCR and HC2 assay and compare the quantitative data of these two assays. Materials and methods: A cross-sectional study was conducted in between July 2010 and June 2011. A total of 66 serologically diagnosed chronic hepatitis B (CHB) patients were selected for the study. Real-time-PCR and HC2 assay was done to detect HBV DNA. Data were analyzed by statistical Package for the social sciences (SPSS). Results: Among 66 serologically diagnosed chronic hepatitis B patients 40 (60.61%) patients had detectable and 26 (39.39%) had undetectable HBV DNA by HC2 assay. Concordant results were obtained for 40 (60.61%) out of these 66 patients by real-time-PCR and HC2 assay with mean viral load of 7.06 +/- 1.13 log10 copies/ml and 6.95 +/- 1.08 log10 copies/ml, respectively. In the remaining 26 patients, HBV DNA was detectable by real-time PCR in 20 patients (mean HBV DNA level was 3.67 +/- 0.72 log10 copies/ml. However, HBV DNA could not be detectable in six cases by the both assays. The study showed strong correlation (r = 0.915) between real-time-PCR and HC2 assay for the detection and quantification of HBV DNA. Conclusion: HC2 assay may be used as an alternative to real-time-PCR for CHB patients.How to cite this article: Majid F, Jahan M, Moben AL, Tabassum S. Comparison of Hybrid Capture 2 Assay with Real-time-PCR for Detection and Quantitation of Hepatitis B Virus DNA. Euroasian J Hepato-Gastroenterol 2014;4(1):31-35. PMID- 29264317 TI - Impact of the Immunogen Nature on the Immune Response against the Major HBV Antigens in an HBsAg and HLA-humanized Transgenic Mouse Model. AB - Hepatitis B chronic carriage remains as a major public health problem. Protein and DNA vaccines are now widely used in therapeutic vaccine candidates. Although, the hepatitis B surface antigen (HBsAg) based vaccines have been largely studied, candidates comprising both HBsAg and core (HBcAg) either protein- or DNA-based approaches deserve further immunological characterization. In the present study, a repeated dose administration schedule for protein or DNA immunogens was conducted in order to characterize the resulting immune response in a humanized and HBsAg-tolerized setting. A novel transgenic (Tg) mice that express the HBsAg, human MHC class I (HLA-A*0201) and MHC class II (HLA-DRB1*01) molecules and devoid of endogenous murine class I and II molecules was used as a model of HBV chronic carrier. Mice were immunized by subcutaneous (protein) or intramuscular (DNA) routes and the humoral and cellular responses were evaluated. Protein or DNA immunization induced humoral immune responses against both HBsAg and HBcAg. The systematic analysis of epitopes that activate CD4+ and CD8+ T lymphocytes confirmed the accuracy of the model. Cellular immune responses were detected differing in their nature. CD8 T-cell responses were induced mostly after DNA immunization while CD4 T-cell responses were predominant in protein based immunizations. In addition, the intensity of HLA-A2-restricted CD8+ T cell responses was reduced in Tg mice expressing HBsAg when compared to control Tg mice. In conclusion, our results indicate that cellular immune responses necessary for the development of protective immunity can be achieved by DNA or protein immunization. However, important differences in their nature arise when immunogens are administered several times. How to cite this article: Mancini Bourgine M, Guillen G, Michel ML, Aguilar JC. Impact of the Immunogen Nature on the Immune Response against the Major HBV Antigens in an HBsAg and HLA-humanized Transgenic Mouse Model. Euroasian J Hepato-Gastroenterol 2014;4(1):36-44. PMID- 29264319 TI - Pathophysiology of Greedy Colon and Diabetes: Role of Atropine in worsening of Diabetes. AB - Greedy colon which is a synonym of constipation is a serious condition in the human body which may lead to complications, like damage of the rectal tissue, cellular dehydration and colorectal cancer. Diabetes mellitus, although a systemic disease with diverse clinical symptoms, is also related with cellular dehydration. Understanding the pathophysiological aspects of diabetes mellitus and greedy colon may shed light in the management of either of these conditions. The main purpose of this article is to demonstrate an association of tissue dehydration during diabetes mellitus and constipation. The adverse side effects of atropine will be discussed due to its M3 blockage effect and reduction in peristalsis keeping in mind the importance of these facts in the context of public health importance, especially in geriatric health. How to cite this article: Gundamaraju R, Vemuri R. Pathophysiology of Greedy Colon and Diabetes: Role of Atropine in worsening of Diabetes. Euroasian J Hepato-Gastroenterol 2014;4(1):51-54. PMID- 29264318 TI - The Emerging Role of MicroRNAs in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is common malignancy and a leading cause of cancer death worldwide. Recent epidemiological data have demonstrated that liver cancer incidence is continuously rising and will continue to do so for more than a decade, not only South Africa and Mainland China but also in North America and Europe. Molecular profiling of changes in gene expression has improved our understanding of the HCC mechanism. MicroRNAs (miRNAs) are a class of small regulatory RNAs that function to modulate protein expression. This control allows for fine-tuning of the cellular phenotype, including regulation of proliferation, cell signaling and apoptosis. Recently, investigators have demonstrated decreased or increased expression of particular miRNAs in hepatobiliary cancer cells. Many studies have highlighted the role of miRNA in physiological processes and cancer development. Several studies have reported that some miRNAs may play a role in the development and progression of HCC. Recent investigations have suggested that the presence of single nucleotide polymorphisms in miRNA genes, their processing machinery and target binding sites affect cancer risk, treatment efficacy and patient prognosis. This review will discuss the emerging critical role of miRNAs in hepatocarcinogenesis, HCC progression and clinical outcome. How to cite this article: Akkiz H. The Emerging Role of MicroRNAs in Hepatocellular Carcinoma. Euroasian J Hepato-Gastroenterol 2014;4(1):45-50. PMID- 29264320 TI - Portal Vein Thrombosis: A Rare Finding in a Noncirrhotic Patient. AB - Portal vein thrombosis (PVT) is a rare cause of abdominal pain, typically associated with cirrhosis or thrombophilia. A 18-year-old female presented with abdominal pain for 10 weeks. The diagnosis was confirmed with contrast-enhanced computed tomography (CECT) abdomen after an ultrasound showed dilated and obstructed portal vein. This unexpected finding prompted investigation for intrinsic hepatic disease and potential hypercoagulable disorders. Laboratory analysis revealed an elevated serum homocysteine level, an identified risk factor for venous thrombosis. Current literature describes the following factors as indications for anticoagulation: acute thrombus, lack of cavernous transformation, absence of esophageal varices and mesenteric venous thrombosis. PVT is an uncommon cause of abdominal pain, and in the absence of hepatic disease should raise the index of suspicion for an underlying thrombophilia. How to cite this article: Sahoo AK, Rauta S, Mohapatra SC. Portal Vein Thrombosis: A Rare Finding in a Noncirrhotic Patient. Euroasian J Hepato-Gastroenterol 2014;4(1):55 57. PMID- 29264321 TI - Superior Mesenteric Artery Syndrome: A Rare Mimic of Common Causes of Upper Gastrointestinal Obstruction. AB - : Rare causes of common symptoms often pose a diagnostic dilemma which can lead to unwanted loss of precious time in proper diagnosis and management. Superior mesenteric artery (SMA) syndrome is such a rare disorder. It typically presents with signs and symptoms of upper gastrointestinal (GI) obstruction which can be mimicked by a variety of clinical conditions, such as peptic ulcer, chronic pancreatitis, mesenteric ischemia and systemic lupus erythematosus (SLE). A high degree of clinical suspicion is required to direct proper investigations to narrow down to the correct diagnosis. Multi-detector CT (MDCT) proves to be invaluable not only in ruling out more common conditions mimicking SMA syndrome but also in arriving at the correct diagnosis quickly and effectively with great clinical accuracy and thereby removing confusion and delay in proper management. Abbreviations: SMA: Superior mesenteric artery; GI: Gastrointestinal; MDCT: Multidetector computed tomography; MPR: Multiplanar reconstruction; AMA: Aortomesenteric Angle; AMD: Aortomesenteric distance.How to cite this article: Madhab G, Madsen J, Dalgaard EB, Bharadwaz A. Superior Mesenteric Artery Syndrome: A Rare Mimic of Common Causes of Upper Gastrointestinal Obstruction. Euroasian J Hepato-Gastroenterol 2014;4(1):58-60. PMID- 29264322 TI - Early Gastric Cancer: A Demonstrative Case Report. AB - With early detection of gastric cancer, mortality from gastric cancer has decreased. Endoscopists should be more suspicious about these lesions because these can be easily neglected. We reported a case which has endoscopic appearance of benign lesion but possessed malignant histological features. How to cite this article: Basyigit S, Aktas B, Kucukazman M, Simsek HD, Simsek GG, Kefeli A, Yeniova AO, Nazligul Y. Early Gastric Cancer: A Demonstrative Case Report. Euroasian J Hepato-Gastroenterol 2014;4(1):61. PMID- 29264323 TI - Endoscopic Management of Postoperative Stapled Anastomosis Bleeding. AB - To the Editor: Knowledge has evolved and the use of staplers in gastrointestinal surgery is now widespread. They are associated with low rates of postoperative complications. Postoperative anastomotic complications with stapling devices are relatively rare, with a reported incidence between 0 and 2.5%.1 How to cite this article: Krishnan A, Velayutham V, Satyanesan J. Endoscopic Management of Postoperative Stapled Anastomosis Bleeding. Euroasian J Hepato-Gastroenterol 2014;4(1):62-63. PMID- 29264324 TI - The Effect of 10 Weeks Resistance Training on Cholesterol and Blood Triglyceride Levels of Patients with Fatty Liver Disease. AB - The present study aims to consider the effect of 10 weeks resistance trainings on cholesterol and blood triglyceride (TG) levels of patients with having fatty liver, aged 50 to 60 in National Iranian South Oil Company (NISOC). This research is practical and its plan has been done experimentally with pretest and post-test on experimental and control groups. In this study, 20 samples from 100 patients who referred to sonography clinic in NISOC with distinction of fatty liver were selected randomly and divided into two groups of control (n = 10) and experimental (n = 10). Cholesterol and blood trigly-ceride were measured as pretest. Test of normality for TG was (p = 0/200) by Kolmogorov-Smirnov and (p = 0/070) for cholesterol by Shapiro-Wilk test. After 10 weeks resistance trainings, the analysis and resolution of data were done by computer and SPSS (16) software as well as the descriptive and statistical methods (t-test). Comparison between these two groups showed that 8 weeks resistance trainings with a <= 0.05 causes significant decrease in the amount of TG but did not any significant effect on cholesterol of fatty liver patients. How to cite this article: Valizadeh R, Askarabadi SH, Karampour S, Tehrani MA. The Effect of 10 Weeks Resistance Training on Cholesterol and Blood Triglyceride Levels of Patients with Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2014;4(1):64-65. PMID- 29264325 TI - An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh. AB - A total of 45 patients with acute hepatitis were detected in a medical facility of Bangladesh over a period of 6 months. All of them were physicians, nurses, students or employees of the hospital. About 50% of these patients suffered from acute hepatitis within a period of 2 months. All of them had clinical and biochemical evidences of acute hepatitis. All of them shared common working places as well as common dining and cooking facilities. Although the disease was supposed to be caused by hepatitis viruses, none of them were expressing IgM type antibody to hepatitis B core antigen (IgM anti-HBc) or hepatitis C virus (IgM anti-HCV). IgM type antibody to hepatitis A virus (IgM HAV) was detected in one patient and IgM type antibody to hepatitis E virus (anti-HEV IgM) were found in 14 patients. In conclusion, diagnosis of etiological agent of viral acute hepatitis constitutes a formidable challenge to the existing health care delivery system in developing countries as available serological and routine screening fails to find the proper etiological agent. How to cite this article: Mahtab MA, Akbar SMF, Podder DC, Saha PK, Jahan M, Begum L, Afrose T, Chowdhury F, Rahman S. An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(1):66-67. PMID- 29264326 TI - Hepatitis B: A Current Global Health Dilemma. PMID- 29264327 TI - Pancreatic hamartoma in a premature Trisomy 18 female. AB - Pancreatic hamartomas are extremely rare tumors in adults and even more so in children. They are lesions characterized by acinar, islet and ductal components found in varying proportions and in a disorganized pattern. We report a case of a premature female with trisomy 18 diagnosed by amniocentesis. The newborn was delivered by cesarean section at thirty-three weeks of gestation and expired within one hour of birth. Postmortem examination exhibited numerous features associated with Trisomy 18 including lanugo on the torso and arms, micrognathia, microstomia, left low-set ear with small flat pinna, closed ear canal, clenched fists with overlapping fingers, rocker-bottom feet, narrow pelvis, large right diaphragmatic hernia and left pulmonary hypoplasia. Microscopic examination of the pancreas revealed an area, 1.2 cm in greatest dimension, with branching ducts and cysts lined by cuboidal epithelium intermingled within primitive mesenchymal proliferation and exocrine glands. The cysts measured up to 0.2 cm and were surrounded by a collarette of proliferating spindle cells as highlighted by Masson's trichrome stain. A diagnosis of pancreatic hamartoma was rendered. A total of thirty-four cases of pancreatic hamartomas have been reported in the literature including twenty-seven in adults, five in children and two in newborns. Our case may be the third pancreatic hamartoma reported in association with Trisomy 18. We recommend that careful examination of the pancreas be performed in individuals with Trisomy 18 to further characterize this lesion as one of the possible abnormal findings associated with this syndrome. PMID- 29264328 TI - Respiratory distress of unknown etiology in a transplant recipient: think toxoplasmosis! AB - Disseminated toxoplasmosis is a life-threatening disease in immunocompromised individuals. Infection is contracted from handling contaminated soil, cat litter, or through the consumption of contaminated water or food. It is the third most common lethal foodborne infection in the United States. In transplant patients, most cases occur as a result of reactivation of a latent infection resulting from immunosuppression. We present a case of disseminated toxoplasmosis diagnosed at the time of autopsy. This case emphasizes the importance of maintaining a high index of clinical suspicion and active disease surveillance in this era of sophisticated diagnostic testing. PMID- 29264329 TI - Knocking-out matrix metalloproteinase-13 exacerbates rotator cuff muscle fatty infiltration. AB - Introduction: Rotator cuff (RC) tears are common tendon injuries. Clinically, both muscle atrophy and fatty infiltration have generally been attributed to poor functional outcomes. Matrix metalloproteinase-13 plays a crucial role in extracellular matrix remodeling in many physiological and pathological processes. Nevertheless, its role in rotator cuff muscle atrophy and fatty infiltration remains unknown. The purpose of this study is to define the functional role of MMP-13 in rotator cuff muscle atrophy and fatty infiltration using a mouse RC tears model. Materials and methods: Unilateral complete supraspinatus and infraspinatus tendon transection and suprascapular nerve transection was performed on nine of MMP-13 (-/-) knockout and nine of MMP-13 (+/+) wildtype mice at 3 months old. Mice were sacrificed 6 weeks after surgery. Supraspinatus (SS) and infraspinatus (IS) muscles were harvested for histology and gene expression analysis with RT-PCR. Results: Six weeks after RC surgery, no significant difference in muscle atrophy and fibrosis between MMP-13 knockout and wild type mice was observed. However, there was a significant increase in the amount of fatty infiltration in MMP-13 knockout mice compared to the wild types. Muscles from MMP-13 knockout mice have significantly higher expression of fatty infiltration related genes. Discussion: Results from this study suggest that MMP 13 plays a crucial role in rotator cuff muscle fatty degeneration. This novel finding suggests a new molecular mechanism that governs RC muscle FI and MMP-13 may serve as a target for therapeutics to treat muscle FI after RC tears. PMID- 29264330 TI - Hyaluronic acid increases tendon derived cell viability and proliferation in vitro: comparative study of two different hyaluronic acid preparations by molecular weight. AB - Background: Hyaluronic Acid (HA) has been already approved by Food and Drug Administration (FDA) for osteoarthritis (OA), while its use in the treatment of tendinopathy is still debated. The aim of this study was to evaluate the effects of two different HA on human rotator cuff tendon derived cells in terms of cell viability, proliferation and apoptosis. Methods: An in vitro model was developed on human tendon derived cells from rotator cuff tears to study the effects of two different HA preparations: Sinovial HL(r) (High-Low molecular weight) (MW: 80-100 kDa) and KDa Sinovial Forte SF (MW: 800-1200), at various concentrations. Tendon derived cells morphology was evaluated after 0, 7 and 14 d of culture. Viability and proliferation were analyzed after 0, 24, and 48 h of culture and apoptosis occurrence was assessed after 24 h of culture. Results: All the HAPs tested here increased viability and proliferation, in a dose-dependent manner and they reduced apoptosis at early stages (24 h) compared to control cells (without HAPs). Conclusions: HAPs enhanced viability and proliferation and counteracted apoptosis in tendon derived cells. PMID- 29264331 TI - Lactoferrin and parathyroid hormone are not harmful to primary tenocytes in vitro, but PDGF may be. AB - Introduction: Recently, bone-active factors such as parathyroid hormone and lactoferrin, have been used in pre-clinical models to promote tendon healing. How ever, there is limited understanding of how these boneactive factors may affect the cells of the ten-don themselves. Here, we present an in vitro study assessing the effects of parathyroid hor-mone and lactoferrin on primary tendon cells (tenocytes), and compare their responses to the tenogenic factors, PDGF, IGF-1 and TGF-beta. Materials and Methods: Tenocyte proliferation and collagen production were assessed by alamarBlue(r) and Sirius red as-says, respectively. To assess tenocyte trans-differentiation, changes in the expression of genes important in tenocyte, chondrocyte and osteoblast biology were determined using real-time PCR. Results: Parathyroid hormone and lactoferrin had no effect on tenocyte growth or collagen production, with minimal changes in gene expression and no detrimental effects observed to suggest trans-differentiation away from tendon cell behaviour. Tenogenic factors PDGF, IGF-1 and TGF all increasetenocyte collagen production, however, the gene expression data suggests that PDGF promotes severe de-differentiation of the tenocytes. Discussion: Our findings suggest that using parathyroid hormone or lactoferrin as a singular factor to promote tendon healing may not be of benefit, but for use in tendon-bone healing there would be no detrimental effect on the tendon itself. PMID- 29264332 TI - Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing. AB - Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations. Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10. Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point. Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells. PMID- 29264333 TI - How to evaluate bone tunnel widening after ACL reconstruction - a critical review. AB - Background: Comparing different imaging modalities and methods for assessment tunnel widening after ACL reconstruction and providing a detailed evidence-based literature overview. Methods: PubMed was searched from 1970 to 2016 using the terms "ACL reconstruction" and "tunnel" and "imaging" or "CT" or "computerized tomography" or "MRI" or "magnetic resonance imaging" or "radiographs". 647 studies were found. 575 articles were excluded due to absence of specific radiological measurement methods of tunnel widening and 40 due to repetition of a previously published radiological measurement method. 32 articles were included reporting interand intraobserver reliabilities of tunnel measurement methods after ACL reconstruction. Results: A variety of different algorithms and measurement methods using radiographs, magnetic resonance imaging, computed tomography or SPECT/CT evaluating tunnel position and bone tunnel enlargement have been described. Tunnel delination restricts an exact analysis using X-ray. Measurements using CT or MR were mostly obtained perpendicular to the tunnel axis or using specialized software for tunnel volume calculation in 3D.Based on the review the width of the femoral and tibial tunnels should be assessed perpendicular to the tunnel axis at different levels in relation to the joint. At least one measurement should be performed at the tunnel entrance, exit and midpoint of the tunnel. Conclusion: CT should be considered the gold standard assessing tunnel widening in patients after ACL reconstruction. If specialized software is available calculating the tunnel volume, measurements should be preferably performed in 3D CT. Level of evidence: II. PMID- 29264334 TI - Minimally invasive anatomic reconstruction of the anterolateral ligament with ipsilateral gracilis tendon. AB - Background: There has been much interest in understanding the anatomy and biomechanics of the anterolateral ligament (ALL). Several recon struction procedures have been proposed to correct rotatory instability after Anterior Cruciate Ligament (ACL) and anterolateral soft tissues injuries. Methods: We propose a new anatomic minimally invasive ALL reconstruction using the ipsilateral gracilis tendon. Through small skin incisions, the femoral attachment and the tibial insertion of the ALL can be identified, and half tunnels drilled. Then, the neo-ligament can be passed under the fascia lata into the tunnels. Fixation to the tibia is accomplished with a biotenodesis screw, and to the femur with a TightRope RT (Arthrex). Conclusion: This procedure allows to reconstruct in a minimally invasive fashion the ALL in selected patients with chronic anterolateral instability in ACL deficient knees. Level of evidence: V. PMID- 29264335 TI - Arthroscopic ACL reconstruction using patellar bone tendon autograft and Rigidfix fixation - A midterm functional outcome. AB - Background: Arthroscopic reconstruction of torn Anterior Cruciate Ligament (ACL) with bone patellar tendon bone autograft (BTB) has become the gold standard in treating ACL tear with high success rate. The purpose of this study was to prospectively evaluate the functional outcome after arthroscopic ACL reconstruction using BTB via Rigidfix femoral fixation. Materials and method: We evaluated the result of 21 knees that have been treated with arthroscopic ACL reconstruction using BTB autograft for femoral fixation and bioabsorbable interference screw for tibia from March 2014 to August 2015. The mean follow up period was 18 months. Results and conclusion: The Lysholm score postoperatively was 89.04. 23.8% of the 21 patients have good to excellent outcome, 66.7% patients have good to fair outcome and 9.5% patient have fair outcome. Level of Evidence: IV. PMID- 29264336 TI - Effects of tendon-bone healing of anterior cruciate ligament reconstruction by osteoprotegerin combined with deproteinized bovine bone. AB - Background: The healing of a tendon graft in a bone tunnel depends on bone ingrowth into the interface between tendon and bone, or that can enhance tendon bone healing, which is important to reduce the failure rate after ACL reconstruction. Methods: Sixty skeletally mature, New Zealand white rabbits underwent left ACL reconstruction. OPG/DBB compound (concentration ratio of 30%, 60%, 100%) was delivered to the tendon-bone interface with use of a DBB carrier, and nothing as control group. Twenty animals were killed at 4, 8 and 12 weeks after surgery. I-IV levels of semi-quantitative and Sharpey fibers at the healing tendon-bone interface were evaluated, and the biomechanical properties were tested. Results: A significantly greater amount of Sharpey fibers at the healing tendon-bone interface in the concentration ratio of 100% OPG/DBB-treated group was found compared with the others at all time-points (P<0.05), and it is the same to the Grade Scores at 12 weeks (P<0.05). The femur-ACL-tibia complex of the concentration ratio of 100% OPG/DBB-treated group has significantly increased stiffness compared with the others at 12 weeks (P<0.05). Conclusion: The concentration ratio of 100% OPG/DBB compound significantly improve bone formation around the grafted tendon and improve the stiffness at the healing tendon-bone junction in a rabbit model. PMID- 29264337 TI - Reverse shoulder arthroplasty patient personalized rehabilitation protocol. Preliminary results according to prognostic groups. AB - Background: Rehabilitation after Reverse Shoulder Arthroplasty (RSA) is still object of discussion with no based evidence guidelines. The aim of this study was to test a personalized rehabilitation protocol for three different patients groups according to clinical and intraoperative parameters that can affect final outcomes after RSA. Patients and methods: We retrospectively evaluated a consecutive series of 112 patients who underwent to RSA between 2013 and 2015. The average follow-up was 29.2 months. A preoperative and postoperative clinical and radiographic assessment was performed. According to clinical, radiographic and intraoperative parameters, we selected three groups dedicating each one a specific level of post surgical care. Results: A statistically significant improvement was achieved from preoperative evaluation, regarding all analysed parameters. Notable improvements were reported in high care group: elevation improved of 63.9 degrees despite of Group A 55.5 degrees and Group B 54.5 degrees and it resulted statistically significant (p< 0.05). Costant Score increased of 35.9%, despite of Group A and Group B respectively 40.6% and 34.8% (p> 0.05). Conclusion: Our study shows that a personalized rehabilitation protocol can be effective improving clinical outcomes and decreasing complications rate, particularly in difficult management patients. Level of Evidence: Therapeutic Level IV. PMID- 29264338 TI - Reverse total shoulder versus angular stable plate treatment for proximal humeral fractures in over 65 years old patients. AB - Background: Treatment for displaced proximal humeral fractures is still under debate. Poor rotator cuff status and non-union of the tubercles in elderly patients has caused reversed total shoulder prosthesis growing popularity and showed promising results, even in comparison to angular stable plates fixation.The purpose of this study is to report clinical and radiological results of proximal humerus fractures treated with rTSA or ORIF in elderly. Materials and methods: The study has investigated retrospectively a consecutive series of 73 patients over 65 years old (range 65-91) with proximal humeral three- and four- parts fractures, operated from January 2009 to June 2014 with a reversed total shoulder prosthetic replacement or open reduction and internal fixation using an angular stable plate, with at least 1 year follow-up. Participants are admitted in our hospital with a displaced proximal humeral fracture according to AO-OTA type 11-B2 or 11-C2.The primary outcomes are active ROM and shoulder function (Constant score). Secondary outcomes have been patient self-assessment form (Simple shoulder test) and radiographical details. Follow-up takes place at the moment of clinical observation with rx control. Results: We analyzed a group of 23 patients treated by plate and screws and 21 patients treated by rTSA with these average results. ORIF: Flexion 112.8 degrees , Abduction 99.6 degrees , External rotation at 90 degrees 47.4 degrees , modal Internal rotation hand at Sacroiliac joint, Constant Score 52.9 and Simple Shoulder Test 8.0. RSA: Flexion 133.3 degrees , Abduction 101.4 degrees , External rotation at 90 degrees of abduction 35.5 degrees , modal Internal rotation hand at waist (L3), Constant Score 65.9 and Simple Shoulder Test 9.2. No nerve injuries were reported. No cases of pseudoarthrosis or plate fractures. No arthroplasty implant loosening, infection or dislocation was documented and revision required. Conclusion: Our study shows good clinical outcomes and fewer complications in both treatment options. Better clinical and daily living results are reported in RSA compared with ORIF, confirming that rTSA is one of the best treatment in proximal humeral fractures in the elderly patients, which rotator cuff status frequently is poor and degenerating. The few radiological complications do not seem to have influence on active ROM and Constant Score, both the first and the second group of patients. Level of evidence: Level IV, Case Series, Surgical. PMID- 29264339 TI - Normal microscopic architecture of acetabular labrum of hip joint: a qualitative original study with clinical aspects. AB - Background: Normal histologic architecture of acetabular labrum, regarding presence of Free Nerve Endings (FNEs) and Nerve End Organs (NEOs) has been four times described. Nevertheless, elderly cadaveric specimens and individuals were recruited, leading to considerably high unreliability probability due to microscopic degenerative alterations. Aim of this paper is to analyze distribution pattern of FNEs and NEOs in acetabular labra of healthy middle-aged individuals, configuring thus more reliably acetabular labrum microscopic profile. Materials and methods: Six patients with middle age 52 +/- 2.5 years were enrolled in this study. Injury of acetabular labrum and normal hip radiograph were present in all cases. Patients were all subjected to successful hip hemi-arthroplasty and derived acetabular labra were subsequently histologically processed and observed under a compound microscope. Results: FNEs and NEOs were detected in all specimens. All types of NEOs were identified, including Paccini, Golgi-Mazzoni, Ruffini and Krause corpuscles. FNEs and NEOs were both in ventral part and in chondral side of labrum predominantly detected. Conclusion: FNEs and NEOs presence was greater in ventral side of labrum, being thus in partial agreement with previous studies results. Further study is required, in order to elucidate the exact acetabular labrum normal microscopic anatomy. Level of evidence: IV. PMID- 29264340 TI - Effects of hip flexion angle on surface electromyographic activity of the biceps femoris and semitendinosus during isokinetic knee flexion. AB - Background: Identifying combinations of the hip and knee joint angles which can selectively recruit specific hamstring muscles may be beneficial for injury prevention or rehabilitation. The purpose of this study was to examine the joint torque and electromyographic (EMG) activity of the semitendinosus (ST) and biceps femoris long head (BFlh). Methods: Twenty subjects performed maximum isokinetic concentric and eccentric knee flexor efforts at 60 degrees .s-1, 120 degrees .s-1 and 150 degrees .s-1 from three different hip joint angles while surface EMG of ST and BFlh was recorded. Results: Analysis of variance showed that there are no inter-muscular differences in EMG amplitude across testing conditions (p > .05). Peak EMG occurred near full knee extension for the BFLh and at a higher flexion angle for the ST while exercise from a prone position shifted the peak EMG towards higher knee flexion angle (p < 0.05). Conclusion: Maximal dynamic knee flexion exercises do not induce a higher EMG amplitude of BFlh or ST. Exercising from a higher hip flexion angle near full knee extension may selectively activate the BFlh. Level of evidence: IIb. PMID- 29264341 TI - Functional leg length discrepancy between theories and reliable instrumental assessment: a study about newly invented NPoS system. AB - Background: In spite the instinct social&financial impact of Leg Length Discrepancy (LLD), controversial and conflicting results still exist regarding a reliable assessment/correction method. For proper management it's essential to discriminate between anatomical&functional Leg Length Discrepancy (FLLD). With the newly invented NPoS (New Postural Solution), under the umbrella of the collaboration of PRM Department, Tor Vergata University with Baro Postural Instruments srl, positive results were observed in both measuring& compensating the hemi-pelvic antero-medial rotation in FLLD through personalized bilateral heel raise using two NPoS components: Foot Image System (FIS) and Postural Optimizer System (POS). This led our research interest to test the validity of NPoS as a preliminary step before evaluating its implementations in postural disorders. Methods: After clinical evaluation, 4 subjects with FLLD have been assessed by NPoS. Over a period of 2 months, every subject was evaluated 12 times by two different operators, 48 measurements in total, results have been verified in correlation to BTS GaitLab results. Results: Intra-Operator&inter-operator variability analysis showed statistically insignificant differences, while inter method variability between NPoS and BTS parameters expressed a linear correlation. Conclusion: Results suggest a significant validity of NPoS in assessment&correction of FLLD, with high degree of reproducibility with minimal operator dependency. This can be considered a base for promising clinical implications of NPoS as a reliable cost effective postural assessment/corrective tool. Level of evidence: V. PMID- 29264342 TI - Characterising the proximal patellar tendon attachment and its relationship to skeletal maturity in adolescent ballet dancers. AB - Background: It is unknown how and when the proximal attachment of the patellar tendon matures; puberty may be key in ensuring normal tendon formation. The aim of this study was to investigate the features of the proximal patellar tendon attachment at different stages of skeletal maturity, to help gain an understanding of how and when the tendon attachment matures. Methods: Sixty adolescent elite ballet students (ages 11-18) and eight mature adults participated. Peak height velocity (PHV) estimated skeletal maturity. Ultrasound tissue characterisation (UTC) scan was taken of the left knee and analysed for stability of echopattern. An image-based grading scale for greyscale ultrasound was developed to describe the tendon appearance. Anterior-posterior thickness was measured at the inferior pole of the patella, 1 and 2 centimetres distally. Outcomes were compared with skeletal maturity. Results: Mid-portion patellar tendon thickness increased with skeletal maturity (p=0.001 at 1 cm and p=0.007 at 2 cm). There was more variance in structural appearance (greyscale classification and UTC echopattern) in pre and peri-PHV participants. Tendon attachment one-year post PHV appeared similar to mature tendons. Conclusions: Early adolescence was associated with highly variable tendon appearance, whereas the tendon appeared mature after PHV. Adolescence may be a critical time for the formation of normal tendon attachment. Level of evidence: IIb individual cohort study. PMID- 29264343 TI - The Royal London Hospital Test for the clinical diagnosis of patellar tendinopathy. AB - Purpose: To ascertain whether the Royal London Hospital test is reproducible, sensitive, and specific for diagnosis of patellar tendinopathy. Methods: Fifteen consecutive athletes with patellar tendinopathy were prospectively enrolled and compared with a control group of 15 non consecutive athletes with Achilles tendinopathy. Two testers examined separately each patient, using manual palpation and the Royal London Hospital test for diagnosis of patellar tendinopathy. High resolution real time ultrasonography was used as standard for diagnosis of tendinopathy and assessment of tendon thickness. Results: The palpation test presented significantly higher sensitivity compared to the Royal London Hospital test (98 vs 88%; P=0.01); specificity was 94% for the palpation test and 98% for the Royal London Hospital test (P>0.05). Positive and negative predictive values were 94 and 98% for palpation test, 98 and 89% for the Royal London Hospital test, respectively. The two tests showed good to very good intra tester and inter-tester agreement. At ultrasonography, pathological patellar tendons were significantly thicker compared to controlateral healthy tendon (P<0.001). Conclusions: In symptomatic patients with patellar tendinopathy, the Royal London Hospital test showed lower sensitivity and higher specificity than manual palpation. Both tests should be performed for a correct clinical diagnosis of patellar tendinopathy. Imaging assessment should be performed as a confirmatory test. Level of Evidence: III. PMID- 29264344 TI - Reliability of a device for the knee and ankle isometric and isokinetic strength testing in older adults. AB - Background: Lower extremity muscle mass, strength, power, and physical performance are critical determinants of independent functioning in later life. Isokinetic dynamometers are becoming very common in assessing different features of muscle strength, in both research and clinical practice; however, reliability studies are still needed to support the extended use of those devices. Objective: The purpose of this study is to assess the test-retest reliability of knee and ankle isokinetic and isometric strength testing protocols in a sample of older healthy subjects, using a new and untested isokinetic multi-joint evaluation system. Methods: Sixteen male and fourteen female older adults (mean age 65.2 +/- 4.6 years) were assessed in two testing sessions. Each participant performed a randomized testing procedure that includes different isometric and isokinetic tests for knee and ankle joints. Results: All participants concluded the trial safety and no subject reported any discomfort throughout the overall assessment. Coefficients of correlation between measures were calculated showing moderate to strong effects among all test-retest assessments and paired-sample t test showed only one significant difference (p<0.05) in the maximal isokinetic bilateral knee flexion torque. Conclusions: The multi-joint evaluation system for the assessment of knee and ankle isokinetic and isometric strength provided reliable test-retest measures in healthy older adults. Level of evidence: Ib. PMID- 29264345 TI - Ultrasound guided injection of a painful knee osteoarthritis with medial meniscus extrusion: a case series study. AB - Background: Meniscal subluxation results in the natural history of knee osteoarthritis (OA). Periarticular infiltration should minimize possible complications related to penetration of corticosteroids into the joint space in the treatment of knee OA.According to pain relief and improvement of function, the aim of this study is to evaluate the effectiveness of perimeniscal corticosteroid ultrasound guided injection in knee OA. Methods: Thirty-two patients received an injection of 0.5 ml of methylprednisolone-acetate around perimeniscal tissues. Outcome measures were pain relief and knee function, assessed by Visual Analogue Scale (VAS) [24, 29, 30] measured at rest (VAS-R) and during stairs climbing (VAS-C) and by Italian-Western Ontario and McMaster Universities (WOMAC) scale. Clinical evaluation was performed at baseline, at 1 and 4 weeks of follow-up. Results: Mean baseline values of VAS-R and VAS-C were 6.79 +/- 1.17 and 7.6 +/- 1.39, respectively. All subjects showed a significant reduction in pain over time (p<0.001). Mean baseline values of WOMAC pain, stiffness and physical function were 5.56 +/- 1.32, 4.39 +/- 1.91 and 4.63 +/- 2.31, respectively. According to WOMAC stiffness and physical function was not found a significant improvement over time (p> 0.05). Conclusion: Corticosteroid perimeniscal ultrasound guided injection can be considered as an adjunct to core treatment for the relief of moderate to severe pain in people with knee OA. Level of Evidence: IV. PMID- 29264346 TI - Percutaneous release of the plantar fascia. New surgical procedure. AB - Background: Plantar fasciopathy presents with pain at the plantar and medial aspect of the heel. If chronic, it can negatively impact on quality of life. Plantar fasciopathy is not always self-limiting, and can be debilitating. Methods: Surgical management involves different procedures. We describe a percutaneous plantar fascia release. A minimally invasive access to the plantar tuberosity of the calcaneus is performed, and a small scalpel blade is used to release the fascia. Conclusion: With this procedure, skin healing problems, nerve injuries, infection and prolonged recovery time are minimised, allowing early return to normal activities. Level of Evidence: V. PMID- 29264347 TI - Endoscopic Flexor Halluces Longus transfer for Chronic Achilles Tendon rupture - technique description and early post-operative results. AB - Background: Achilles tendon ruptures may lead to proximal retraction of the stump if not treated acutely, increasing the chances of poorer functional outcomes. The flexor halluces longus transfer is a well-established treatment option, usually performed as an open procedure. The aim of this paper is to report the preliminary results and describe the technique of endoscopic flexor halluces longus transfer. Material and methods: Six patients with chronic Achilles tendon injuries or re-ruptures were treated with endoscopic FHL transfer. The Achilles Tendon Rupture Score was used to clinically evaluate the patients. Single leg heel rise ability, functional hallux weakness, complications and procedure length were also checked. Results: On average, we took 56 minutes to perform the surgery. All patients had a major increase in the ATRS score value postoperatively. Single leg heel rise was possible for all patients without limitation. None of the patients noticed functional weakness of the hallux during daily life activity and no wound or soft tissue complications were seen. Conclusion: Endoscopic FLH transfer is a reliable option for patients with high skin risk and soft tissue complications. Other studies are needed to compare this technique with the open procedure, gold standard by now, to ensure its safety and efficacy. Level of evidence: 4. PMID- 29264348 TI - Triceps surae elasticity modulus measured by shear wave elastography is not correlated to the plantar flexion torque. AB - Background: Supersonic Shear Imaging (SSI) is a technique which analyses quantitatively the tissue properties in real time. The relation between joint torque and Young's modulus (E) of the agonist muscles is important for obtaining stratification values and ranges of normality. The aim of this study was to evaluate the intra and intersessions reliability of the E values of the Achilles tendon and medial gastrocnemius muscle, bilaterally, during rest, and correlate them with the isometric plantarflexion peak torque. Methods: Shear modulus maps were acquired bilaterally in Achilles tendon (AT) and medial gastrocnemius (MG) muscle of 24 healthy male volunteers. Two 5-second plantarflexion maximal voluntary contractions were performed with a 40-seconds interval and correlated with E values. Results: a good intrasession reliability (intraclass correlation coefficient- ICC= 0.821-0.986) and a weak Pearson's correlation was found between E values and peak torque (r= 0.022 to -0.202) for both limbs (P > .05). Conclusion: E values cannot be predictive of the triceps surae force production in untrained men. It could be helpful, otherwise, to monitor a chronic strength adaptation after an exercise intervention or rehabilitation program. Level of evidence: IIb, individual cohort study. PMID- 29264349 TI - Soft tissue pseudotumours: a pictorial review with emphasis on MRI. AB - Background: Several tumour-like conditions of the soft tissues may be encountered in clinical practice, or when patients undergo radiologic examinations. Al-though advances in cross sectional imaging (ultra-sound, MDCT and MRI) play a pivotal role in the correct evaluation of tumour-like lesions, a systematic approach is needed to achieve a definitive diagnosis or limit the differential diagnosis. Clinical history, physical examination and anatomic location are of paramount importance. Methods: In this pictorial essay we review some of the most frequent benign soft tissue conditions which may be mistaken for malignancy and thus lead to need-less referrals, unnecessary biopsies and great anxiety to the patients and their carers. Level of evidence: IV. PMID- 29264350 TI - Perivascular Adductor Longus muscle injury: Ultrasound and Magnetic Resonance Imaging findings. AB - Background: Muscle injuries affecting the Adductor Longus are not all localised at the level of the proximal myotendinous junction and enthesis. Thus, the main purpose of this article was to raise awareness of the imaging features of the Perivascular Adductor Longus muscle injury, which currently remains widely under recognised. Methods: The ultrasound (US) and Magnetic Resonance imaging (MRI) images of five professional football players were retrospectively reassessed to identify distinctive imaging details of the Perivascular Adductor Longus muscle injury. Complementary information regarding the traumatic mechanics is presented as well. Results: All the players presented similar US images in the first seventy-two hours: loss of ecostructural integrity of the lateral epimysium, in proximity to the femoral vessels, and perilesional oedema were the main pathological findings. The injury lead to the formation of a hypoechoic, intramuscular haematoma in three of the subjects. Anyway, this was detectable only after five days, or later. Moreover, MRI sequences showed long-standing haematoma-related signal alterations which were also observable at three months after trauma. Typically, kicking was the traumatic motor task. Conclusions: The main practical value of this technical note is to compensate for the lack of studies concerning the Perivascular Adductor Longus muscle injury. Promptly identifying its typical imaging features is crucial in order to establish the correct diagnosis and to implement a highly specific rehabilitative program. Level of evidence: V. PMID- 29264351 TI - Efficacy and safety of hyaluronic acid (500-730kDa) Ultrasound-guided injections on painful tendinopathies: a prospective, open label, clinical study. AB - Background: Tendinopathies are conditions characterized by activity-induced pain, local tenderness and swelling for which a gold standard treatment is not established yet. Hyaluronic Acid (HA) is a key-molecule in several cellular activities and it is normally present in the extra-cellular matrix of tendons and ligaments. Amongst its properties, HA injections may reduce pain and determine disease-modifying effects. This study is an investigator-initiated open-label trial conducted to investigate the efficacy and safety of HA (500-730 kDa) peritendinous injections on pain reduction in patients affected by lateral elbow, Achilles or patellar tendinopathy. Methods: A total of 71 tendons (34 with Achilles tendinopathy, 26 with lateral elbow tendinopathy, 11 with patellar tendinopathy) of 62 patients with painful tendinopathy were treated with a cycle of ultrasound-guided peritendinous injections one injection per week for three consecutive weeks. Efficacy assessments included changes in pain intensity measured by Visual Analogue Scale (VAS) at follow-up evaluations were performed 7 (V2), 14 (V3) and 56 days aften first treatment. An Ultrasound (US) assessment was also performed to evaluate changes in tendon thickness and neovascularization. Adverse events were recorded for safety analysis throughout the study. All results were analyzed with descriptive statistics appropriate to the nature of the variables. Results: Significant reduction in VAS (p<0.001) from baseline was observed in Achilles (-6.16 +/- 0.45 cm), patellar (-6.16 +/- 0.72 cm) and lateral elbow (-5.33 +/- 0.43 cm) tendinopathies. The sagittal thickness decreased significantly from baseline at each endpoint (V3 day 14 and V4 day 56) in each type of tendinopathy analyzed (p<0.05). Neovascularization decreased for each tendons at V3 and V4, except for patellar tendon at V3 V1 (p=0.125). Nevertheless, reduction at V4 compared to baseline remained significant (p=0.016). Conclusions: US-guided HA (500-730 kDa) peritendinous injections determine significant pain relief and reduction in tendon thickness and neovascularization in US evaluations. The effect of HA did not show differences regarding the site of affected tendon. The treatment proved to be safe and very well tolerated. Level of evidence: 4. PMID- 29264352 TI - Failed synthetic graft after acute Achilles tendon repair. AB - Background: The present case report aimed to determine the results of Flexor Hallucis Longus (FHL) transfer as a second surgery after synthetic tissue reinforcement graft (Artelon(r)) implanted to a primary repaired Achilles tendon (AT), that was undertaken by another orthopedic. One year post-operative the patient was referred to us with retrocalcaneal pain and difficulty in walking, associated with stiffness and significant impairment of daily living activities. Methods: MRI and full clinical examination were the outcome measures applied before and 1 year after surgery. Removal of the synthetic graft and subsequent FHL autologous transfer was undertaken and the graft was sent for histology examination. After removing the below knee leg cast, patient started rehabilitation program supervised by a trained physiotherapist. Results: The patient was allowed to return to his normal activities at the sixth post operative month, 1 year post-surgery MRI showed correct position of the autograft in the calcaneous bone and in the centre of the native AT plus reduced oedema of the AT body, with clinical improvement of the patient who reported no pain and was able to walk on tiptoes. Conclusion: Synthetic patch augmentation to enhance tendon healing should be subjected to proper investigation before using it in routine parctice, as it may act as a barrier against proper tendon healing. Level of evidence: V. PMID- 29264353 TI - The golden age of anti-vaccine conspiracies. PMID- 29264354 TI - Prevalence of sea, seb, sec, sed, and tsst-1 genes of Staphylococcus aureus in nasal carriage and their association with multiple sclerosis. AB - Background: Microbial superantigens might initiate or exacerbate autoimmune responses against particular tissues, organs or systems. This study aimed to examine the prevalence of sea, seb, sec, sed, and tsst-1 genes of Staphylococcus aureus in nasal carriage and their association with multiple sclerosis (MS). Methods: Nasal swabs were collected from 150 MS patients and 150 healthy individuals (control group) to isolate S. aureus and investigate their superantigen genes (sea, seb, sec, sed and tsst-1) using PCR. Results: A total of 300 participants were enrolled in the study, matched for age and gender (150 patients in the MS group and 150 in the control group). The prevalence of S. aureus colonization in MS patients and control groups was 42% and 23.3%, respectively. There was a statistically significant association between S. aureus colonization and MS disease (p<0.001; odds ratio 2.4; 95% confidence interval 1.4 3.9). No significant association was observed between the presence of S. aureus harboring sea, seb, sec, sed and tsst-1 genes with MS disease. Conclusion: The rate of S. aureus nasal carriage is higher in patients with MS. Our study's results suggest that further investigation into whether there is a connection between MS and nasal exposure to staphylococcal superantigens is warranted. PMID- 29264355 TI - Observed HIV drug resistance associated mutations amongst naive immunocompetent children in Yaounde, Cameroon. AB - Introduction: The emergence of drug resistance mutations (DRMs) has been a major threat for successful lifelong combination antiretroviral therapy (cART), especially for HIV-vertically infected children within the context of the prevention of mother-to-child transmission (PMTCT). This study aimed to evaluate DRMs amongst immune competent treatment-naive children in Cameroon. Methods: A cross-sectional study was conducted between 2015 and 2016 amongst 55 proxy consented HIV-1 positive children, aged 9 months to 6 years. They were all immune competent, cART naive and with unknown history of PMTCT. CD4 cell counts and genotypic drug resistance testing were performed using standard methods. Results: Levels of DRMs to protease (PR) inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs were 27.6%, 3.7% and 40.7%, respectively. Only minor DRMs were observed for PR. The observed mutations for NRTI were K65R, T215I and K219E (33.0% each) and for NNRTI: V106M, Y181C and Y188H (6.0% each). Only minor accessory mutations were found in the integrase (IN) region. Conclusion: Despite widely available cART we still observe naive HIV children, especially from the rural communities. We observe that a proportion of study participants had HIV-1 drug resistance associated mutations (RAMs). Data generated could help strengthen the current PMTCT programmes within the country. There is a need to upscale approaches for drug resistance testing for children in Cameroon and many other resource-limited settings. PMID- 29264356 TI - Disruption of methicillin-resistant Staphylococcus aureus protein synthesis by tannins. AB - Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a worldwide public health threat, displaying multiple antibiotic resistance that causes morbidity and mortality. Management of multidrug-resistant (MDR) MRSA infections is extremely difficult due to their inherent resistance to currently used antibiotics. New antibiotics are needed to combat the emergence of antimicrobial resistance. Methods: The in vitro effect of tannins was studied against MRSA reference strain (ATCC 43300) and MRSA clinical strains utilizing antimicrobial assays in conjunction with both scanning and transmission electron microscopy. To reveal the influence of tannins in MRSA protein synthesis disruption, we utilized next-generation sequencing (NGS) to provide further insight into the novel protein synthesis transcriptional response of MRSA exposed to these compounds. Results: Tannins possessed both bacteriostatic and bactericidal activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 0.78 and 1.56 mg/mL, respectively, against all tested MRSA. Scanning and transmission electron microscopy of MRSA treated with tannins showed decrease in cellular volume, indicating disruption of protein synthesis. Conclusion: Analysis of a genome-wide transcriptional profile of the reference strain ATCC 43300 MRSA in response to tannins has led to the finding that tannins induced significant modulation in essential ribosome pathways, which caused a reduction in the translation processes that lead to inhibition of protein synthesis and obviation of bacterial growth. These findings highlight the potential of tannins as new promising anti-MRSA agents in clinical application such as body wash and topical cream or ointments. PMID- 29264357 TI - Intensive care unit-acquired Acinetobacter baumannii infections in a Moroccan teaching hospital: epidemiology, risk factors and outcome. AB - Introduction: The objective of this study was to examine the epidemiology, risk factors and outcome associated with Acinetobacter baumannii infections in the intensive care units (ICUs) in a Moroccan teaching hospital. Methods: This is a matched case-control study conducted as a joint collaboration between the clinical Bacteriology department and the two ICUs of Mohammed V Military Teaching Hospital from January 2015 to July 2016. Results: Among 964 patients hospitalized in the ICUs, 81 (8.4%) developed A. baumannii infections. Multivariate logistic regression analysis identified the following independent risk factors for ICU acquired A. baumannii infections: ICU stay >=14 days (odds ratio (OR)=6.4), prior use of central venous catheters (OR=18), prior use of mechanical ventilation (OR=9.5), duration of invasive procedures >=7 days (OR=7.8), previous exposure to imipenem (OR=9.1), previous exposure to amikacin (OR=5.2), previous exposure to antibiotic polytherapy (OR=11.8) and previous exposure to corticotherapy (OR=5). On the other hand, the admission for post-operative care was identified as a protective factor. The crude mortality in patients with A. baumannii infection was 74.1%. Multivariate analysis showed that septic shock (OR=19.2) and older age (>=65 years) (OR=4.9) were significantly associated to mortality risk in patients with A. baumannii infection. Conclusion: Our results show that shortening the ICU stay, rational use of medical devices and optimizing antimicrobial therapy could reduce the incidence of these infections. Elderly patients and those with septic shock have a poor prognosis. These findings highlight the need for focusing on the high-risk patients to prevent these infections and improve clinical outcome. PMID- 29264358 TI - Degarelix treatment is compatible with diabetes and antithrombotic therapy in patients with prostate cancer. AB - Introduction: Therapeutically induced androgen deficiency (AD) is a standard treatment for patients with prostate cancer, but it is often associated with various adverse effects (AEs) that may lead to discontinuation. Some AEs may depend on the patient's health condition, while others may be due to complications of the drug delivery method. Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist widely used for the treatment of androgen-dependent prostate cancer. This study aimed to ascertain the following: 1) the compatibility of degarelix treatment with diabetes and 2) any specific causal associations of degarelix injections with increased blood clotting and antithrombotic therapy requirements. Patients and methods: The medical records of 162 patients with prostate cancer who had undergone degarelix treatment were retrospectively examined. The association of a medical history of diabetes and anticoagulant co-treatment with degarelix treatment discontinuation was analyzed statistically. Results: Rapid and significant decreases in prostate-specific antigen (PSA) levels during the course of degarelix treatment were detected for patients with prostate cancer regardless of clinical state. During the 27 months of treatment, 68 subjects (48%) ceased degarelix treatment, owing to several reasons, mainly financial issues. Among these subjects, 19 had diabetes, while 35 were treated with antithrombotics. Extensive statistical analysis indicated that there were no causal associations between degarelix treatment discontinuation and preexisting diabetes or antithrombotic therapy. Conclusion: Our study suggests that preexisting diabetes and antithrombotic therapy were not significant factors for the discontinuation of degarelix treatment in patients with prostate cancer. PMID- 29264359 TI - What is new in severe sepsis in the critically ill patient? PMID- 29264360 TI - Predictors of treatment failure and clinical stability in patients with community acquired pneumonia. AB - Community acquired pneumonia (CAP) is the leading infectious cause of mortality worldwide with approximately 10% of patients hospitalized requiring intensive care unit (ICU) admission. The ability to predict clinical stability (CS) and treatment failure (TF) enables the clinician to alter antibiotics appropriately, facilitate a timely ICU admission, or arrange a suitable discharge. The detection of CS and TF can be difficult and changes in clinical signs may be subtle or delayed. Thus clinical scores and biomarkers are routinely used to identify severity and monitor clinical progression. The evidence, however, is vast and the definitive role of these systems is at times difficult to elucidate. The aim of this review is to analyse the current literature and to provide a rational and clinically focused view of the predictive utility of various systems used to identify CS and TF in CAP. PMID- 29264361 TI - Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies. AB - Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)]. The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy. Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects. PMID- 29264362 TI - Airway microbiome research: a modern perspective on surveillance cultures? AB - The incidence of ventilator-associated pneumonia (VAP) is estimated to be around 10% in a high-risk population. Over the last decade, major improvements have been made in the prevention of VAP, with great cost-effectiveness. However, we still do not understand the exact pathogenesis of VAP. A better understanding might explain why some patients develop ventilator-associated tracheobronchitis, while others develop VAP even though they are infected with the same types of pathogens. Microbiome research has been a hot topic in translational medicine over the past decade. Slowly, microbiome research has also been introduced to the intensive care setting. One of the areas where it may influence our pathophysiological considerations is in VAP. The adapted island has been proposed for the colonization and infection of the respiratory tract. In this model, not only the immigration of bacteria into the lung is important, but elimination and regional growth factors are of equal significance. The importance of these factors can be supported by epidemiological studies. Several small observational studies on the development of the pulmonary microbiome during mechanical ventilation also support this theory. We speculate on the consequences of the newest insights in microbiome research on the prevention and targeted treatment of VAP. We conclude that there is still a strong need for more in-depth analyses of the changes in the microbial composition of the pulmonary microbiome during mechanical ventilation and with the development of VAP. PMID- 29264363 TI - Cell therapy for the treatment of sepsis and acute respiratory distress syndrome. AB - Sepsis and acute respiratory distress syndrome (ARDS) are life threating diseases with high mortality and morbidity in all the critical care units around the world. After decades of research, and numerous pre-clinical and clinical trials, sepsis and ARDS remain without a specific and effective pharmacotherapy and essentially the management remains supportive. In the last years cell therapies gained potential as a therapeutic treatment for ARDS and sepsis. Based on numerous pre-clinical studies, there is a growing evidence of the potential benefits of cell based therapies for the treatment of sepsis and ARDS. Several cell types are used in the last years for the treatment of both syndromes showing high efficiency. Embryonic stem cells (ESC), multipotent stem (or stromal) cells (MSC) and epithelial progenitors cells (EpPC) have been used for both diseases. Nowadays, the major part of the pre-clinical studies are using MSC, however other relevant groups are also using induced pluripotent stem cells (iPSC) for the treatment of both syndromes and alveolar type II cells for ARDS treatment. Numerous questions need further study including: determining the best source for the progenitor cells isolation, their large scale production and cryopreservation. Also, the heterogeneity of patients with sepsis and ARDS is massive, and establish a target population or the stratification of the patients will help us to determine better the therapeutic effect of these cell therapies. In this review we are going to describe briefly the different cell types, their potential sources and characteristics and mechanism of action. Here, also we elucidate the results of several pre-clicinical and clinical studies in ARDS and in sepsis and the future directions of these studies. PMID- 29264364 TI - Defects in innate and adaptive immunity in patients with sepsis and health care associated infection. AB - Recent advances in sepsis therapy exclusively involve improvements in supportive care, while sepsis mortality rates remain disturbingly high at 30%. These persistently high sepsis mortality rates arise from the absence of sepsis specific therapies. However with improvements in supportive care, patients with septic shock commonly partially recover from the infection that precipitated their initial illness, yet they frequently succumb to subsequent health care associated infections. Remarkably today the pathophysiology of sepsis in humans, a common disease in western society, remains largely a conundrum. Conventionally sepsis was regarded as primarily a disorder of inflammation. More recently the importance of immune compromise in the pathophysiology of sepsis and health care associated infection has now become more widely accepted. Accordingly a review of the human evidence for this novel sepsis paradigm is timely. Septic patients appear to exhibit a complex and long-lasting immune deficiency state, involving lymphocytes of both the innate and adaptive immune responses that have been linked with mortality and the occurrence of health care associated infection. Such is the pervasive nature of immune compromise in sepsis that ultimately immune modulation will play a crucial role in sepsis therapies of the future. PMID- 29264365 TI - Nebulised antibiotherapy: conventional versus nanotechnology-based approaches, is targeting at a nano scale a difficult subject? AB - Nebulised antibiotics offer great advantages over intravenously administered antibiotics and other conventional antibiotic formulations. However, their use is not widely standardized in the current clinical practice. This is the consequence of large variability in the performance of nebulisers, patient compliance and a deficiency of robust preclinical and clinical data. Nebulised antibiotherapy may play a significant role in future pulmonary drug delivery treatments as it offers the potential to achieve both a high local drug concentration and a lower systemic toxicity. In this review, the physicochemical parameters required for optimal deposition to the lung in addition to the main characteristics of currently available formulations and nebuliser types are discussed. Particular attention will be focused on emerging nanotechnology based approaches which are revolutionizing inhaled therapies used to treat both infections and lung cancer. Promising carriers such as Trojan-Horse microparticles, liposomes, polymeric and lipid nanoparticulate systems have been investigated and proposed as viable options. In order to achieve site-specific targeting and to optimize the PK/PD balance critical nanoscale design parameters such as particle size, morphology, composition, rigidity and surface chemistry architecture must be controlled. Development of novel excipients to manufacture these nanomedicines and assessment of their toxicity is also a keystone and will be discussed in this review. PMID- 29264366 TI - Platelets: an outlook from biology through evidence-based achievements in critical care. AB - Since the original observations by Bizzozero and Osler, we have seen tremendous advances in the understanding of platelets far beyond haemostasis and the restoration of injured endothelium. In this mini-review on platelets, we will briefly outline their historical description and the importance of their evolution, focusing on a 450 million years old living fossil of Limulus polyphemus, a marine chelicerate arthropod, which helped researchers explain the basis for the immunity role of platelets and make correlations with platelet ultrastructure and function. In addition, the impact of the Limulus Amoebocyte Lysate (LAL) test for modern medicine is highlighted. The role of platelets in cardiovascular diseases, their relevance in arterial and venous thrombosis, and the utilization of antithrombotic drugs as therapeutic agents are also reported. Furthermore, platelet receptors are crucial in aggravating or mitigating other diseases, such as cancer and infections, which can recruit cells and have numerous interactions in a process recently coined "NETosis formation", which is also briefly depicted. PMID- 29264367 TI - Antibiotic consumption and ventilator-associated pneumonia rates, some parallelism but some discrepancies. AB - Ventilator-associated pneumonia (VAP) is a common infection in intensive care units (ICUs) but its clinical definition is neither sensitive nor specific and lacks accuracy and objectivity. New defining criteria were proposed in 2013 by the National Healthcare Safety Network (NHSN) in order to more accurately conduct surveillance and track prevention progress. Although there is a consistent trend towards a decrease in VAP incidence during the last decade, significant differences in VAP rates have been reported and are persistently lower in NHSN and other American reports (0.0 to 4.4 VAP per 1,000 ventilator-days in 2012) compared to the European Centre for Disease Prevention and Control (ECDC) data (10 VAP per 1,000 ventilator-days in 2014). In the United States, VAP has been proposed as an indicator of quality of care in public reporting, and the threat of financial penalties for this diagnosis has put pressure on hospitals to minimize VAP rates that may lead to artificial lower values, independently of patient care. Although prevention bundles may contribute for encouraging reductions in VAP incidence, both pathophysiologic and epidemiologic factors preclude a zero-VAP rate. It would be expected from the trend of reduction of VAP incidence that the consumption of antibiotics would also decrease in particular in those hospitals with lowest VAP rates. However, ICU reports show a steadily use of antibiotics for nosocomial pneumonia in 15% of patients and both ECDC and NHSN data on antibiotic consumption showed no significant trend. Knowledge of bacterial epidemiology and resistance profiles for each ICU has great relevance in order to understand trends of antibiotic use. The new NHSN criteria provide a more objective and quantitative data based VAP definition, including an antibiotic administration criterion, allowing, in theory, a more comprehensive assessment and a reportable benchmark of the observed VAP and antibiotic consumption variability. PMID- 29264368 TI - The next generation of rapid point-of-care testing identification tools for ventilator-associated pneumonia. AB - Ventilator-associated pneumonia (VAP) is a frequent issue in intensive care units (ICU), with a major impact on morbidity, mortality and cost of care. VAP diagnosis remains challenging: traditional culture-based microbiological techniques are still the gold-standard, but are too slow to enable clinicians to improve prognosis with timely antimicrobial therapy adjustment. Prolonged exposure to inappropriate antibiotics has also been shown to increase the incidence of multi-drug-resistant organisms (MDROs). Point-of-care testing (POCT) tools are diagnostic testing methods that can be used at or near the bedside, with delays ranging from a couple minutes to a few hours. The use of POCTs for VAP could allow for faster diagnosis and antimicrobial therapy adjustments. Despite uncertainty regarding their diagnostic value, C-reactive protein (CRP) and procalcitonin (PCT) can be detected using POCTs in few minutes. In VAP, CRP showed a sensitivity of 56% to 88% and specificity of 86% to 91%; PCT showed a sensitivity of 78% to 100% and a specificity between 75% and 97% using non-POCT methods. Automated microscopy could also be used in clinical ICU setting, with reported sensitivity of 100% and specificity of 97%, allowing for antibiotic susceptibility testing (AST) in less than 12 h. Multiplex polymerase chain reaction (MPCR) could allow for identification and AST approximation through the detection of drug-resistance genes in about 6 h, with reported sensitivity of 89.2% and specificity of 97.1%; although use as POCT was shown to result in test failure in about 40% of samples. Despite being at an early development stage, exhalome analysis, which allows for non-invasive fast identification, and chromogenic tests, more suited for the detection of drug-resistance enzymes, are also promising techniques for POCT diagnosis of VAP. PMID- 29264369 TI - Does animal model on ventilator-associated pneumonia reflect physiopathology of sepsis mechanisms in humans? AB - Ventilator-associated pneumonia (VAP) is the leading cause of death in critically ill patients in intensive care units. In the last 20 years, different animal models have been a valuable tool for the study of pathophysiology and phenotypic characteristics of different lung infections observed in humans, becoming an essential link between ''in vitro'' testing and clinical studies. Different animal models have been used to study the mechanism of a deregulated inflammatory response and host tissue damage of sepsis in VAP, as well as different infection parameters such as clinical, physiological, microbiological and pathological facts in several large and small mammals. In addition, the dosage of inflammatory modulators and their consequences in local and systemic inflammation, or even the administration of antibiotics, have been evaluated with very interesting results. Although some bronchial inoculation ways do not resemble the common pathophysiologic mechanisms, the experimental model of VAP induced by the inoculation of high concentrations of pathogens in mechanically ventilated animals is useful for studying the local and systemic responses of sepsis in VAP and it reproduces biological mechanisms such as acute lung injury, distress response, cardiac events and immune modulation comparable with clinical studies. PMID- 29264370 TI - Relationship between hyperoxemia and ventilator associated pneumonia. AB - Previous studies suggest a relationship between hyperoxemia and ventilator associated pneumonia (VAP). Hyperoxemia is responsible for denitrogenation phenomena, and inhibition of surfactant production, promoting atelectasis in mechanically ventilated patients. Further, hyperoxemia impairs the efficacy of alveolar macrophages to migrate, phagocyte and kill bacteria. Oxygen can also cause pulmonary-specific toxic effect called hyperoxic acute lung injury leading to longer duration of mechanical ventilation. All these hyperoxic effects are well-known risk factors for VAP. A recent retrospective large single center study identified hyperoxemia as an independent risk factor for VAP. However, two recent randomized controlled trials evaluated the impact of conservative oxygen strategy versus a liberal strategy, but did not confirm the role of hyperoxemia in lower respiratory tract infection occurrence. In this review, we discuss animal and human studies suggesting a relationship between these two common conditions in mechanically ventilated patients and potential interventions that should be evaluated. Further large prospective studies in carefully selected groups of patients are required to confirm the potential role of hyperoxemia in VAP pathogenesis and to evaluate the impact of a conservative oxygen strategy vs. a conventional strategy on the incidence of VAP. PMID- 29264371 TI - The need for accurate long-term measurements of water vapor in the upper troposphere and lower stratosphere with global coverage. AB - Water vapor is the most important greenhouse gas in the atmosphere although changes in carbon dioxide constitute the "control knob" for surface temperatures. While the latter fact is well recognized, resulting in extensive space-borne and ground-based measurement programs for carbon dioxide as detailed in the studies by Keeling et al. (1996), Kuze et al. (2009), and Liu et al. (2014), the need for an accurate characterization of the long-term changes in upper tropospheric and lower stratospheric (UTLS) water vapor has not yet resulted in sufficiently extensive long-term international measurement programs (although first steps have been taken). Here, we argue for the implementation of a long-term balloon-borne measurement program for UTLS water vapor covering the entire globe that will likely have to be sustained for hundreds of years. PMID- 29264373 TI - Death and Taxes: The framing of the causes and policy responses to the illicit tobacco trade in Canadian newspapers. AB - The illicit tobacco trade accounts for 10% of the global cigarette market and results in US$31 billion in lost tax revenues annually. Despite legal prosecution of tobacco companies, and the introduction of new policy responses, the trade has reached an all-time high. Previous research documents how transnational tobacco companies have sought to influence government responses to the illicit trade in various countries through multiple means, including influencing of news media framing. This paper extends this analysis to Canada where the illicit trade is particularly problematic in scale and political complexity. Articles in Canadian newspapers, published from 2010-2015, were systematically searched (n=177) and analyzed to identify dominant frames, frame sponsors and policy positions related to the illicit tobacco trade. The results show that the most common frames present the issue in ways favourable to the industry. The most common non governmental sponsors of these frames frequently have links to the tobacco industry, which are rarely disclosed. Findings indicate the need for Canadian media to be critical in its use of data sources amid industry efforts to shape public policy, and the importance of reframing policy discussions in public health terms based on independent evidence. PMID- 29264374 TI - Time course gene expression data in colon of mice after exposure to food-grade E171. AB - We investigated gene expression responses in BALB/c mice exposed by gavage to 5 mg/kg bw/day of E171 for 2, 7, 14 and 21 days. Food additive E171 (titanium dioxide) has been shown to induce oxidative stress and DNA damage in vitro as well as facilitating growth of colorectal tumours in vivo. Full genome expression changes of the colon of mice were investigated by using Agilent SurePrint G3 mouse Gene exp 60kv2 microarrays slides. The data presented in this DiB include all differentially expressed for each time point with EntrezGeneID, gene symbols, gene names and Log2FC as well as genes included in pathways after over representation analysis in ConsensusPathDataBase. The functions of these genes in relation to the colon were described in our associated article (Proquin et al., 2017 in press) [1]. Raw and normalized gene expression data are available through NCBI GEO (GEO accession: GSE92563). PMID- 29264372 TI - Efferocytosis creates a tumor microenvironment supportive of tumor survival and metastasis. AB - Programmed cell death, or apoptosis, occurs in nearly all tissues of all multi cellular organisms. In order to avoid leakage of intracellular contents, which could generate tissue damaging inflammation, apoptotic cells are cleared from tissues by phagocytes, which then dispatch the engulfed dying cell through the lysosomal pathway. Phagocytic clearance of apoptotic cells is referred to as efferocytosis. One key feature of efferocytosis is the production and release of wound healing cytokines by the phagocyte, which acts to resolve inflammation, and promote tissue repair. Phagocytic engulfment of apoptotic cells coupled with cytokine modulation aimed at immune suppression ensures that physiological programmed cell death does not induce inflammation and tissue damage. However, cytokines involved in wound healing and immune suppression are notorious for their role in the tumor microenvironment, increasing tumor cell motility and promoting evasion of anti-tumor immunity. Therefore, current and future studies aimed at targeting important players of efferocytosis should reveal new and efficacious therapeutic approaches for limiting cancer progression and relapse. PMID- 29264375 TI - Reconstructed and analyzed X-ray computed tomography data of investment-cast and additive-manufactured aluminum foam for visualizing ligament failure mechanisms and regions of contact during a compression test. AB - Three stochastic open-cell aluminum foam samples were incrementally compressed and imaged using X-ray Computed Tomography (CT). One of the samples was created using conventional investment casting methods and the other two were replicas of the same foam that were made using laser powder bed fusion. The reconstructed CT data were then examined in Paraview to identify and highlight the types of failure of individual ligaments. The accompanying sets of Paraview state files and STL files highlight the different ligament failure modes incrementally during compression for each foam. Ligament failure was classified as either "Fracture" (red) or "Collapse" (blue). Also, regions of neighboring ligaments that came into contact that were not originally touching were colored yellow. For further interpretation and discussion of the data, please refer to Matheson et al. (2017) [1]. PMID- 29264376 TI - Data on the expression and role of TREM-1 in the development of in-stent restenosis. AB - The data presented in this article are related to the research article entitled "Increased serum TREM-1 level is associated with in-stent restenosis, and activation of TREM-1 promotes inflammation, proliferation and migration in vascular smooth muscle cells" (Wang et al., 2017) [1], which demonstrated that TREM-1 is expressed on vascular smooth cells (VSMCs) and promotes inflammation, proliferation and migration in cultured VSMCs. In this dataset, the expression of TREM-1 in leukocytes and endothelial cells of carotid artery after ligation was evaluated. The effect of TREM-1 on stenosis was analyzed in cultured human saphenous veins (HSVs) that spontaneously undergo remodeling which involves VSMC proliferation and migration. PMID- 29264377 TI - Photodegradation of Acid red 18 dye by BiOI/ZnO nanocomposite: A dataset. AB - Dyes are one of the most important existing pollutants in textile industrial wastewater. These compounds are often toxic, carcinogenic, and mutagenic to living organisms, chemically and photochemically stable, and non-biodegradable. Acid red 18 is one of the azo dyes that are currently used in the textile industries. Photocatalytic degradation offers a great potential as an advanced oxidation process, in this study photocatalytic degradation of Acid red 18 by using BiOI/ZnO nanocomposite was evaluated under visible light irradiation. The influence of most essential parameters such as pH and BiOI/ZnO dosage were studied for optimum conditions. The dye removal efficiency was 85.1% at optimum experimental conditions of pH of 7, and BiOI/ZnO dosage of 1.5 g/L. The data had a good agreement with pseudo first-order kinetic model. Thus, the BiOI/ZnO/UV is an efficient process for dye degradation. PMID- 29264378 TI - Description of vital signs data measurement frequency in a medical/surgical unit at a community hospital in United States. AB - Vitals signs are measured at scheduled intervals by nurses in typical general wards. Vital signs may be measured more frequently if the patient condition deteriorates. In many units, the vital signs measurement frequency for some patients is different from the scheduled frequency due to various reasons such as staffing, patient acuity etc. In this article, we describe the actual measurement frequency in patients admitted to general ward in a community hospital in Arizona, US. We present the data in the form of 2 sets of graphs. The first set of graphs are histograms which show the distribution of the number of measurements in a 24 h period for 6 different vital signs. The second set of graphs show the proportion of the patient population who had a measurement of a vital sign for each hour of the last day of patient's general ward stay. The significance of this data on predicting deterioration is discussed in Ghosh et al. (2017) [1]. PMID- 29264379 TI - Wetland agribusiness aspects and potential in Bangladesh. AB - The study was conducted to document farmers' livelihood aspects and agribusiness potentials in wetland areas of Bangladesh. A total of 120 farmers and 24 service providers were interviewed for data collection. Most of the farmers were small farmers having less than 1.0 ha of cultivable land. The differences in productivity of crop farming and poultry rearing between wetland area and main land were statistically significant. Favorable farm environment and proper utilization of agricultural resources were major strength and opportunity. The data may be helpful for formation of agribusiness clusters involving input suppliers, credit/financial organizations and different support service providers for more income, better nutrition and improved livelihood of the wetland people. PMID- 29264380 TI - Stewart-Treves syndrome in a spinal cord injury patient with MYC amplification. PMID- 29264381 TI - Painful linear ulcers: A case of cutaneous sporotrichosis mimicking pyoderma gangrenosum. PMID- 29264382 TI - Quantification of granuloma volume and response to treatment in cutaneous sarcoidosis using 3-dimensional high-frequency ultrasound scan. PMID- 29264383 TI - Complete spontaneous regression of a metastatic acral melanoma with associated leukoderma. PMID- 29264384 TI - Bullous drug eruption with leukemic cell infiltrate in the setting of new-onset acute myeloid leukemia. PMID- 29264385 TI - Oral dehydroepiandrosterone might prevent frequent tears in atrophic skin: A case report. PMID- 29264386 TI - Identification of novel targetable mutations in metastatic anorectal melanoma by next-generation sequencing. PMID- 29264387 TI - p16+ Squamous cell carcinoma in situ masquerading as genital psoriasis. PMID- 29264388 TI - Combination of imiquimod with cryotherapy in the treatment of penile intraepithelial neoplasia. PMID- 29264389 TI - Optimizing the preclinical Alzheimer's cognitive composite with semantic processing: The PACC5. AB - Introduction: Amyloid-related decline in semantic memory was recently shown to be observable in the preclinical period of Alzheimer's disease. Cognitive composites designed to be sensitive to cognitive change in preclinical Alzheimer's disease (e.g., preclinical Alzheimer's cognitive composite [PACC]) and currently used in secondary prevention trials do not currently integrate measures of semantic processing. Our objective was to determine whether a standard semantic measure (i.e., category fluency [CAT] to animals, fruits, and vegetables) adds independent information above and beyond Abeta-related decline captured by the PACC. Methods: Clinically normal older adults from the Harvard Aging Brain Study were identified at baseline as Abeta+ (n = 70) or Abeta- (n = 209) using Pittsburgh compound B-positron emission tomography imaging and followed annually with neuropsychological testing for 3.87 +/- 1.09 years. The relationships between PACC, CAT, and variations of the PACC including/excluding CAT were examined using linear mixed models controlling for age, sex, and education. We additionally examined decline on CAT by further grouping Abeta+ participants into preclinical stage 1 and stage 2 on the basis of neurodegeneration markers. Results: CAT explained unique variance in amyloid-related decline, with Abeta+'s continuing to decline relative to Abeta-'s in CAT even after controlling for overall PACC decline. In addition, removal of CAT from the PACC resulted in a longitudinal Abeta+/- effect size reduction of 20% at 3-year follow-up and 12% at 5-year follow-up. Finally, both stage 1 and stage 2 participants declined on CAT in comparison with stage 0, suggesting CAT declines early within the preclinical trajectory. Conclusion: Addition of CAT to the PACC provides unique information about early cognitive decline not currently captured by the episodic memory, executive function, and global cognition components and may therefore improve detection of early Abeta-related cognitive decline. PMID- 29264390 TI - Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy. AB - Objective: To perform functional characterization of a potentially pathogenic KCNB1 variant identified by clinical exome sequencing of a proband with a neurodevelopmental disorder that included epilepsy and centrotemporal spikes on EEG. Methods: Whole-exome sequencing identified the KCNB1 variant c.595A>T (p.Ile199Phe). Biochemical and electrophysiologic experiments were performed to determine whether this variant affected protein expression, trafficking, and channel functional properties. Results: Biochemical characterization of the variant suggested normal protein expression and trafficking. Functional characterization revealed biophysical channel defects in assembled homotetrameric and heterotetrameric channels. Conclusions: The identification of the KCNB1 variant c.595A>T (p.Ile199Phe) in a neurodevelopmental disorder that included epilepsy with centrotemporal spikes expands the phenotypic spectrum of epilepsies associated with KCNB1 variants. The KCNB1-I199F variant exhibited partial loss of function relative to the wild-type channel. This defect is arguably less severe than previously reported KCNB1 variants, suggesting the possibility that the degree of KCNB1 protein dysfunction may influence disease severity. PMID- 29264391 TI - Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes. AB - Objective: To expand the clinical phenotype associated with STXBP1 gene mutations and to understand the effect of STXBP1 mutations in the pathogenesis of focal cortical dysplasia (FCD). Methods: Patients with STXBP1 mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing. Results: Seven patients with heterozygous de novo mutations affecting the coding region of STXBP1 were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for STXBP1, providing evidence for a somatic mechanism. Cell type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within STXBP1. By contrast, ASD was rarely associated with mutations in this gene in our large cohorts. Conclusions: STXBP1 mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an STXBP1 somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for STXBP1-related epilepsy. PMID- 29264392 TI - CDKL5 variants: Improving our understanding of a rare neurologic disorder. AB - Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID- 29264393 TI - Novel GRN mutation presenting as an aphasic dementia and evolving into corticobasal syndrome. PMID- 29264394 TI - Opening One's Eyes to Mosaicism in Progressive External Ophthalmoplegia. PMID- 29264395 TI - Factors influencing the age at onset in familial frontotemporal lobar dementia: Important weight of genetics. AB - Objective: To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations. Methods: We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models. Results: A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e-4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e-5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families. Conclusions: Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials. PMID- 29264396 TI - Novel NDUFS4 gene mutation in an atypical late-onset mitochondrial form of multifocal dystonia. PMID- 29264397 TI - Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations. AB - Objective: To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations. Methods: Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel. Results: The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism. Conclusions: KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment. PMID- 29264398 TI - NaV channel variants in patients with painful and nonpainful peripheral neuropathy. AB - Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy. Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful). Results: We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (<=3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations. Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease "mutations," are more important for the development of painful neuropathy than previously discussed. PMID- 29264399 TI - Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency. AB - Objective: To describe the variability of muscle symptoms in patients carrying mutations in the GYG1 gene, encoding glycogenin-1, an enzyme involved in the biosynthesis of glycogen, and to discuss genotype-phenotype relations. Methods: We describe 9 patients from 5 families in whom muscle biopsies showed vacuoles with an abnormal accumulation of glycogen in muscle fibers, partially alpha amylase resistant suggesting polyglucosan bodies. The patients had either progressive early-onset limb-girdle weakness or late-onset distal or scapuloperoneal muscle affection as shown by muscle imaging. No clear definite cardiac disease was found. Histologic and protein analysis investigations were performed on muscle. Results: Genetic analyses by direct or exome sequencing of the GYG1 gene revealed 6 different GYG1 mutations. Four of the mutations were novel. They were compound heterozygous in 3 families and homozygous in 2. Protein analysis revealed either the absence of glycogenin-1 or reduced glycogenin-1 expression with impaired glucosylation. Conclusions: Our report extends the genetic and clinical spectrum of glycogenin-1-related myopathies to include scapuloperoneal and distal affection with glycogen accumulation. PMID- 29264400 TI - Nuclear Localization of Apolipoprotein E4: A New Trick for an Old Protein. AB - One of the most important genetic risk factors for late-onset Alzheimer's Disease (AD) is harboring the ApoE4 allele. Much is known regarding the functions of the ApoE4 protein including cholesterol transport in the CNS and a critical role in clearing beta-amyloid deposits in the AD brain. However, recent studies demonstrating the nuclear localization suggest a novel function beyond the classical known actions of ApoE4. The purpose of the current review is to examine how this secreted protein traffics to the nucleus and to discuss possible outcomes of nuclear localization in the CNS. It is suggested that proteolytic fragmentation of ApoE4 is a key step leading to nuclear localization and the outcome of this event is to initiate transcription of various genes involved in inflammation and cell death. Therefore, the nuclear localization and induction of gene expression may provide a link between harboring the ApoE4 allele and enhanced dementia risk observed in AD. PMID- 29264401 TI - Bright's Disease, Malaria, and Machine Politics: The Story of the Illness of President Chester A. Arthur. AB - In July of 1881, President James A. Garfield was shot in the back at the Sixth Street Train Station in Washington, D.C. Garfield died after an extended illness and Chester A. Arthur assumed the presidency on September 20, 1881. He served the remaining three and a half years but was ill for most of his term. Arthur died of the complications of Bright's disease less than two years after leaving office. In the 1880s, Bright's disease was the syndrome that described renal failure associated with proteinuria, but the etiology of Arthur's kidney failure has never been determined. Arthur is one of our least understood Presidents, owing to his brief tenure in office, his death shortly after leaving office, and the fact that he burned all his personal papers just prior to his death. This manuscript will explore the medical history of Chester A. Arthur, including his presumed diagnosis of malaria, his symptoms during his declining health, and will define the differential diagnosis of the causes of his renal failure that culminated in his death in November of 1886. PMID- 29264402 TI - Mechanistic and clinical insights at the scleroderma-cancer interface. AB - Emerging data suggest tantalizing links between cancer and systemic inflammatory rheumatic syndromes. In scleroderma, patients may have an increased risk of cancer secondary to chronic inflammation and damage from the disease, malignant transformation promoted by immunosuppressive therapies, a shared susceptibility to both cancer and autoimmunity, or a common inciting exposure. However, it is increasingly recognized that a subset of patients develop cancer around the time that scleroderma clinically manifests, raising the question of cancer-induced autoimmunity. In this review, we discuss data suggesting a mechanistic link between cancer and the development of scleroderma, and the clinical implications of these findings. PMID- 29264403 TI - Structural insights into chemokine CCL17 recognition by antibody M116. AB - The homeostatic chemokine CCL17, also known as thymus and activation regulated chemokine (TARC), has been associated with various diseases such as asthma, idiopathic pulmonary fibrosis, atopic dermatitis and ulcerative colitis. Neutralization of CCL17 by antibody treatment ameliorates the impact of disease by blocking influx of T cells. Monoclonal antibody M116 derived from a combinatorial library shows potency in neutralizing CCL17-induced signaling. To gain insight into the structural determinants of antigen recognition, the crystal structure of M116 Fab was determined in complex with CCL17 and in the unbound form. Comparison of the structures revealed an unusual induced-fit mechanism of antigen recognition that involves cis-trans isomerization in two CDRs. The structure of the CCL17-M116 complex revealed the antibody binding epitope, which does not overlap with the putative receptor epitope, suggesting that the current model of chemokine-receptor interactions, as observed in the CXCR4-vMIP-II system, may not be universal. PMID- 29264404 TI - Combined use of electroconvulsive therapy and antipsychotics (both clozapine and non-clozapine) in treatment resistant schizophrenia: A comparative meta-analysis. AB - Aim: To assess the relative efficacies of clozapine plus Electroconvulsive Therapy (ECT) compared against non-clozapine typical and atypical antipsychotics plus ECT for the treatment of "Treatment Resistant Schizophrenia" (TRS). Primarily to assess if clozapine delivers a significant improvement over other antipsychotics when combined with ECT. Design: Major electronic databases were searched between 1990 and March 2017 for trials measuring the effects of either clozapine augmented ECT, other antipsychotic-augmented ECT, or both. After the systematic review of the data, a random-effects meta-analysis was conducted measuring the relative effect sizes of the different treatment regimens. Subjects: 1179 patients in 23 studies reporting the usage of ECT augmentation with antipsychotics. A total of 95 patients were tested with clozapine, and ECT (9 studies) and 1084 patients were tested with non-clozapine antipsychotics (14 studies) such as flupenthixol, chlorpromazine, risperidone, sulpiride, olanzapine, and loxapine with concurrent ECT treatment considered for systematic review. Of these, 13 studies reported pre and post-treatment scores were included in the meta-analysis. Main outcome measures: The main outcome measure was the presence and degree of both positive and negative psychotic symptoms, as measured by either of two standardized clinician administered tests, the Brief Psychiatric Rating Scale (BPRS), and the Positive and Negative Symptom Scale (PANSS). Results: The comparison of the different antipsychotics established the supremacy of ECT-augmented clozapine treatment against other typical and atypical antipsychotics. The Forest Plot revealed that the overall standard mean difference was 0.891 for non-clozapine studies and 1.504 for clozapine studies, at a 95% interval. Furthermore, the heterogeneity plots showed that while clozapine studies showed no significant heterogeneity, non-clozapine studies showed an I2 statistic value at 42.19%, suggesting moderate heterogeneity. Lastly, publication bias showed asymmetrical plots and significant values of Kendal's tau and Egger's rank test. Conclusion: ECT augmentation technique was found to be effective in the reduction of psychometric scale scores, and the resulting improvement was significant. Clozapine maintained its stance as the most effective treatment for Treatment-Resistant Schizophrenia, followed by flupenthixol. PMID- 29264405 TI - Magical beliefs and discriminating science from pseudoscience in undergraduate professional students. AB - Paranormal beliefs and magical thinking exist in the public, and amongst university students. Researchers have found that media can influence such beliefs. A 2012 study suggested pseudoscientific rationales can influence acceptance of reported paranormal phenomena. Using a paranormal belief survey and controlled experiment this work explores the paranormal beliefs and test the effects of three versions of a supernatural news story on undergraduate professional students. One version of the story presented a simple news article, another the same with a pseudoscientific rationale, and another gave a discrediting scientific critique. Results confirmed that many students do hold magical beliefs but discriminated between scientific and pseudoscientific narratives. However, pre-existing paranormal beliefs were associated with an increased likelihood of students finding paranormal reports scientific, believable and credible. PMID- 29264406 TI - Yawning: a cue and a signal. AB - Yawning behaviour has been associated with a variety of physiological and social events and a number of corresponding functions have been attributed to it. Non directed (self-directed behaviour) and directed yawning (display behaviour) might nonetheless encompass all expressions of yawning, although it is difficult to differentiate one type from the other in a social context. Here we analysed more fully the data from a study in which four combinations of sensory cues were presented to pairs of either cage mate or stranger rats. The aim of the re analysis was to demonstrate that non-directed and directed yawning might be identified by their distinctive functions. All pairs of rats used olfactory cues to recognise each other as stranger or cage mate companions, but only stranger rats used auditory cues to detect and respond to each other's yawning. Increasing defecation rates (i.e. an index of emotional reactivity) inhibited yawning in cage mate rats such that yawning frequency reflected each rat's physiological state. These results suggest that non-directed yawning functions as a cue in cage mate rats and directed yawning as a signal in stranger rats. We hypothesize that cue yawning might be a regulatory act that animals perform to adjust muscle tone for a coordinated change of state. Signal yawning might indicate the physiological capacity of rats in male-male conflicts. PMID- 29264407 TI - Organomegaly in Mali before and after praziquantel treatment. A possible association with Schistosoma haematobium. AB - Continuous exposure to schistosome-infested water results in acute and chronic morbidity in all ages. We analysed occurence of organomegaly via ultrasonography and investigated a possible additive effect of dual-dose drug administration in 401 Schistosoma haematobium infected individuals from a highly endemic area in Mali. Mean intensity of infection at baseline (22.0 eggs per 10 ml) was reduced to 0.22 eggs per 10 ml 9 weeks after treatment (both treatments combined). Odds of persistent infection among those given dual-dose treatment was 41% of that in people given single dose (b = 0.41; p = 0.05; 95% CI 0.17-1.00), but after two years, 70.7% of the 157 participants, who completed the survey, were re-infected with no significant difference in prevalence and intensity of infection between treatment groups. Resolution of organomegaly occurred in all age groups after treatment. A novel association between Schistosoma haematobium infection and moderate portal vein enlargement was found in 35% (n: 55). Severe portal vein diameter enlargement was found in 3.2%. After two years, moderate hepatomegaly was present in 50.6%, moderate splenomegaly in 45.6% and moderate portal vein diameter enlargement in 19%. A subsequent dose of PZQ did not provide any additional long-term advantages. PMID- 29264408 TI - Research synergy and drug development: Bright stars in neighboring constellations. AB - Drug discovery and subsequent availability of a new breakthrough therapeutic or 'cure' is a compelling example of societal benefit from research advances. These advances are invariably collaborative, involving the contributions of many scientists to a discovery network in which theory and experiment are built upon. To document and understand such scientific advances, data mining of public and commercial data sources coupled with network analysis can be used as a digital methodology to assemble and analyze component events in the history of a therapeutic. This methodology is extensible beyond the history of therapeutics and its use more generally supports (i) efficiency in exploring the scientific history of a research advance (ii) documenting and understanding collaboration (iii) portfolio analysis, planning and optimization (iv) communication of the societal value of research. Building upon prior art, we have conducted a case study of five anti-cancer therapeutics to identify the collaborations that resulted in the successful development of these therapeutics both within and across their respective networks. We have linked the work of over 235,000 authors in roughly 106,000 scientific publications that capture the research crucial for the development of these five therapeutics. Applying retrospective citation discovery, we have identified a core set of publications cited in the networks of all five therapeutics and additional intersections in combinations of networks. We have enriched the content of these networks by annotating them with information on research awards from the US National Institutes of Health (NIH). Lastly, we have mapped these awards to their cognate peer review panels, identifying another layer of collaborative scientific activity that influenced the research represented in these networks. PMID- 29264409 TI - Materialists on Facebook: the self-regulatory role of social comparisons and the objectification of Facebook friends. AB - In this study, we examine chronic materialism as a possible motive for Facebook usage. We test an explanatory mediation model predicting that materialists use Facebook more frequently, because they compare themselves to others, they objectify and instrumentalize others, and they accumulate friends. For this, we conducted two online surveys (N1 = 242, N2 = 289) assessing demographic variables, Facebook use, social comparison, materialism, objectification and instrumentalization. Results confirm the predicted mediation model. Our findings suggest that Facebook can be used as a means to an end in a way of self regulatory processes, like satisfying of materialistic goals. The findings are the first evidence for our Social Online Self-regulation Theory (SOS-T), which contains numerous predictions that can be tested in the future. PMID- 29264410 TI - The emergence of egalitarianism in a model of early human societies. AB - How did egalitarianism emerge in early human societies? In contrast to dominance hierarchies in non-human primates, human simple forager bands are typically egalitarian, with male hunters often serving as the collective alpha. Here we present a thermodynamics-inspired simple population model, based on stochastic optimization of dominance relationships, in which a dominance hierarchy of individuals with exclusively self-centered characteristics (the desire to dominate, resentment at being dominated) transitions spontaneously to egalitarianism as their capacity for language develops. Language, specifically gossip, allows resentment against being dominated to promote the formation of antidominance coalitions which destabilize the alpha position for individuals, leading to a phase transition in which a coalition of the full population suddenly becomes dominant. Thus, egalitarianism emerges suddenly as the optimal power-sharing arrangement in a population of selfish individuals without any inherently altruistic qualities. We speculate that egalitarianism driven by punishment for exhibiting alpha-like behavior may then set the stage for genuinely altruistic traits to propagate as predicted by game theory models. Based on model simulations, we also predict that egalitarianism is a pre condition for adaptation of tools as weapons. Potential implications for origins of human moral belief systems are discussed. PMID- 29264412 TI - Numerical investigation of heat transfer in parallel channels with water at supercritical pressure. AB - Thermal phenomena such as heat transfer enhancement, heat transfer deterioration, and flow instability observed at supercritical pressures as a result of fluid property variations have the potential to affect the safety of design and operation of Supercritical Water-cooled Reactor SCWR, and also challenge the capabilities of both heat transfer correlations and Computational Fluid Dynamics CFD physical models. These phenomena observed at supercritical pressures need to be thoroughly investigated. An experimental study was carried out by Xi to investigate flow instability in parallel channels at supercritical pressures under different mass flow rates, pressures, and axial power shapes. Experimental data on flow instability at inlet of the heated channels were obtained but no heat transfer data along the axial length was obtained. This numerical study used 3D numerical tool STAR-CCM+ to investigate heat transfer at supercritical pressures along the axial lengths of the parallel channels with water ahead of experimental data. Homogeneous axial power shape HAPS was adopted and the heating powers adopted in this work were below the experimental threshold heating powers obtained for HAPS by Xi. The results show that the Fluid Centre-line Temperature FCLT increased linearly below and above the PCT region, but flattened at the PCT region for all the system parameters considered. The inlet temperature, heating power, pressure, gravity and mass flow rate have effects on WT (wall temperature) values in the NHT (normal heat transfer), EHT (enhanced heat transfer), DHT (deteriorated heat transfer) and recovery from DHT regions. While variation of all other system parameters in the EHT and PCT regions showed no significant difference in the WT and FCLT values respectively, the WT and FCLT values respectively increased with pressure in these regions. For most of the system parameters considered, the FCLT and WT values obtained in the two channels were nearly the same. The numerical study was not quantitatively compared with experimental data along the axial lengths of the parallel channels, but it was observed that the numerical tool STAR-CCM+ adopted was able to capture the trends for NHT, EHT, DHT and recovery from DHT regions. The heating powers used for the various simulations were below the experimentally observed threshold heating powers, but heat transfer deterioration HTD was observed, confirming the previous finding that HTD could occur before the occurrence of unstable behavior at supercritical pressures. For purposes of comparing the results of numerical simulations with experimental data, the heat transfer data on temperature oscillations obtained at the outlet of the heated channels and instability boundary results obtained at the inlet of the heated channels were compared. The numerical results obtained quite well agree with the experimental data. This work calls for provision of experimental data on heat transfer in parallel channels at supercritical pressures for validation of similar numerical studies. PMID- 29264411 TI - REDOSER project: optimising biological therapy dose for rheumatoid arthritis and spondyloarthritis patients. AB - Background: Reducing the dose of biological therapy (BT) when patients with immune-mediated arthritis achieve a sustained therapeutic goal may help to decrease costs for national health services and reduce the risk of serious infection. However, there is little information about whether such a decision can be applied universally. Therefore, the objective of this study was to develop appropriateness criteria for reducing the dose of BT in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and peripheral spondyloarthritis (pSpA). Methods: The RAND/UCLA appropriateness method was coordinated by experts in the methodology. Five rheumatologists with clinical research experience in RA and/or SpA selected and precisely defined the variables considered relevant when deciding to reduce the dose of BT in the 3 diseases, in order to define patient profiles. Ten rheumatologists with experience in prescribing BT anonymously rated each profile on a scale of 1 (completely inappropriate) to 9 (completely appropriate) after revising a summary of the evidence obtained from 4 systematic literature reviews carried out specifically for this project. Findings: A total of 2,304 different profiles were obtained for RA, 768 for axSpA, and 3,072 for pSpA. Only 327 (14.2%) patient profiles in RA, 80 (10.4%) in axSpA, and 154 (5%) in pSpA were considered appropriate for reducing the dose of BT. By contrast, 749 (32.5%) patient profiles in RA, 270 (35.3%) in axSpA, and 1,243 (40.5%) in pSpA were considered inappropriate. The remaining profiles were considered uncertain. Interpretation: Appropriateness criteria for reducing the dose of BT were developed in 3 inflammatory conditions. These criteria can help clinicians treating these disorders to optimize the BT dose. However, further research is needed, since more than 50% of the profiles were considered uncertain and the real prevalence of each profile in daily clinical practice remains unknown. PMID- 29264413 TI - Comparison of metamotivational dominance and cultural identity between Japanese National Team and Maori All Blacks rugby players. AB - This pilot study used a reversal theory framework to examine metamotivational dominance of rugby players on the Maori All Blacks (MABs) squad of New Zealand and the Japanese National Team (JNT). Since the two groups have different cultural team demographics, cultural identity was also examined. Twenty six players from the MABs and 31 from the JNT completed questionnaires on metamotivational dominance and cultural identity. In terms of metamotivational dominance, the findings indicated that the MABs were more playful minded and spontaneous oriented than the JNT. Regarding cultural identity, the JNT showed a greater knowledge of their own culture and higher comfort level in their cultural context, while the MABs felt more positive and willing to sustain their own culture. The motivational personality differences between the teams may reflect the style of play that is valued within each team culture that is, flair, spontaneity and high-risk play within Maori rugby, and structure, team unity and conformity within the JNT. This suggests that metamotivational dominance of teams and players is influenced by the cultural identity of both the individuals and the group, which may have a further impact on team cohesion and performance. PMID- 29264414 TI - Risk of vascular events in different manifestations of cerebral small vessel disease: A 2-year follow-up study with a control group. AB - Background and purpose: Natural course of cerebral small vessel disease (CSVD) has not yet been thoroughly studied. The aim of the single center study was to establish risk of vascular events or death in different manifestations of CSVD. Methods: 150 consecutive, functionally independent patients with marked MRI features of CSVD and with recent lacunar stroke (n = 52, LS), deep hemorrhagic stroke (n = 20, HS), vascular parkinsonism (n = 28, VaP), vascular dementia (n = 50, VaD) and 55 controls (CG) with high atherothrombotic risk free of cerebrovascular events were prospectively recruited and followed for 24 months. Results: Mean age and sex distribution were similar in CSVD and CG but patients with CSVD were less likely to have CAD (19% vs 40%, p = 0.02) and tended to have higher prevalence of diabetes (54% vs 37%, p = 0.11). The risk of vascular events or death was increased in any patients with moderate to severe white matter lesions at baseline MRI (HR 2.0; 95% CI 0.85-7.2), in CSVD (4.56; 95% CI 1.3 14.9) vs CG, regardless of its clinical manifestation: LS or HS (HR 4.70; 95% CI 1.3-16.2) and VaD or VaP (HR 4.59; 95% CI 1.3-15.7). Adjustment for confounders did not change the results substantially. Conclusions: Patients with symptomatic CSVD regardless of the clinical (acute or chronic) manifestation had more than fourfold the risk of vascular events or death in 24 months of observation compared with controls with high atherothrombotic risk free of cerebrovascular events. PMID- 29264415 TI - Synthesis of stable TiO2 nanotubes: effect of hydrothermal treatment, acid washing and annealing temperature. AB - Effect of hydrothermal treatment, acid washing and annealing temperature on the structure and morphology of TiO2 nanotubes during the formation process was assessed. X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy analysis were conducted to describe the formation and characterization of the structure and morphology of nanotubes. Hydrothermal treatment of TiO2 precursor nanoparticles and acid washing are fundamental to form and define the nanotubes structure. Hydrothermal treatment causes a change in the crystallinity of the precursor nanoparticles from anatase phase to a monoclinic phase, which characterizes the TiO2 nanosheets structure. The acid washing promotes the formation of high purity nanotubes due to Na+ is exchanged from the titanate structure to the hydrochloric acid (HCl) solution. The annealing temperature affects the dimensions, structure and the morphology of the nanotubes. Annealing temperatures in the range of 400 degrees C and 600 degrees C are optimum to maintain a highly stable tubular morphology of nanotubes. Additionally, nanotubes conserve the physicochemical properties of the precursor Degussa P25 nanoparticles. Temperatures greater than 600 degrees C alter the morphology of nanotubes from tubular to an irregular structure of nanoparticles, which are bigger than those of the precursor material, i.e., the crystallinity turn from anatase phase to rutile phase inducing the collapse of the nanotubes. PMID- 29264416 TI - A distributed algorithm for demand-side management: Selling back to the grid. AB - Demand side energy consumption scheduling is a well-known issue in the smart grid research area. However, there is lack of a comprehensive method to manage the demand side and consumer behavior in order to obtain an optimum solution. The method needs to address several aspects, including the scale-free requirement and distributed nature of the problem, consideration of renewable resources, allowing consumers to sell electricity back to the main grid, and adaptivity to a local change in the solution point. In addition, the model should allow compensation to consumers and ensurance of certain satisfaction levels. To tackle these issues, this paper proposes a novel autonomous demand side management technique which minimizes consumer utility costs and maximizes consumer comfort levels in a fully distributed manner. The technique uses a new logarithmic cost function and allows consumers to sell excess electricity (e.g. from renewable resources) back to the grid in order to reduce their electric utility bill. To develop the proposed scheme, we first formulate the problem as a constrained convex minimization problem. Then, it is converted to an unconstrained version using the segmentation based penalty method. At each consumer location, we deploy an adaptive diffusion approach to obtain the solution in a distributed fashion. The use of adaptive diffusion makes it possible for consumers to find the optimum energy consumption schedule with a small number of information exchanges. Moreover, the proposed method is able to track drifts resulting from changes in the price parameters and consumer preferences. Simulations and numerical results show that our framework can reduce the total load demand peaks, lower the consumer utility bill, and improve the consumer comfort level. PMID- 29264417 TI - Effects of sculpture based art therapy in dementia patients-A pilot study. AB - Art and art therapy open up interesting possibilities for dementia patients. However, it has not been evaluated scientifically so far, whether the art of sculpting has any benefits. In this non-randomized pilot study with twelve participants, we investigated the feasibility and acceptance of sculptural activity in patients with dementia and the effects on their well-being. A questionnaire was custom-designed to investigate five key aspects of well-being: mental state and concentration, corporeal memory, self-reliance, self-esteem and physicality. Remarkable improvements were seen in several subscales in the sculptural activity group, but not the control group: Mental state and concentration (nine of thirteen key aspects), self-reliance (four of five), self esteem (one of one) and physicality (two of two). The results of this pilot study indicate the multidimensional effects of sculptural activity on patients living with dementia. The field would benefit greatly from further research. PMID- 29264418 TI - Sense of direction and conscientiousness as predictors of performance in the Euclidean travelling salesman problem. AB - A salesperson wishes to visit a number of cities before returning home using the shortest possible route, whilst only visiting each city once. This optimization problem, called the Travelling Salesman Problem, is difficult to solve using exhaustive algorithms due to the exponential growth in the number of possible solutions. Interestingly, when presented in Euclidean space (ETSP), humans quickly find good solutions. Past studies, however, are in disagreement whether human solutions are impacted by the participant's ability to process figural effects in the graph geometry. In this study, we used principal component analysis to combine two correlated [r = 0.37, p < 0.01] self-assessed personality measures, i.e., a participant's sense of direction and a participant's level of conscientiousness, onto a single impulsiveness/cautiousness dimension. We then showed, using simple linear regression, that this new dimension is a significant predictor [R2 = 0.12, p < 0.01] of the number of edge crossings that occur in human ETSP solutions, a key metric of graph optimality. Our study provides evidence to suggest that human solutions to the ETSP are significantly affected by individual differences, including personality and cognitive traits. PMID- 29264420 TI - Leukotriene D4 induces chemotaxis in human eosinophilc cell line, EoL-1 cells via CysLT1 receptor activation. AB - Numerous reports have shown that cysteinyl leukotrienes (CysLTs) contribute to tissue accumulation of eosinophils in allergic airway inflammation. To date, only a few studies have reported that CysLTs promote chemotactic activity of human eosinophils in vitro. The purpose of this study was to investigate whether CysLTs promote chemotaxis in the human eosinophilic cell line, EoL-1. EoL-1 cells were induced to differentiate into mature eosinophil-like cells via incubation with butyric acid and cytokines (IL-3, IL-5 and GM-CSF). The chemotactic activity of the differentiated EoL-1 cells was assessed using the commercial cell migration assay kit. LTD4 elicited dose-related chemotactic activity in the differntiated EoL-1 cells in the range of 1-100 nM. A typical bell-shaped dose-response curve was observed with optimal activity at 10 nM. The chemotactic activity elicited by LTD4 (10 nM) was significantly inhibited by montelukast (control, 345 +/- 19.2 * 103 RFU; LTD4 10 nM alone, 511 +/- 39.2 * 103 RFU; LTD4 10 nM plus montelukast 100 nM, 387 +/- 28.2 * 103 RFU). LTD4 induces migration in eosinophilic cells via activation of CysLT1 receptor. The present in vitro model may be useful for elucidation of the mechanism underlying CysLT-induced tissue eosinophilia. PMID- 29264419 TI - Cordyceps militaris improves the survival of Dahl salt-sensitive hypertensive rats possibly via influences of mitochondria and autophagy functions. AB - The genus Cordyceps and its specific ingredient, cordycepin, have attracted much attention for multiple health benefits and expectations for lifespan extension. We analyzed whether Cordyceps militaris (CM), which contains large amounts of cordycepin, can extend the survival of Dahl salt-sensitive rats, whose survival was reduced to ~3 months via a high-salt diet. The survival of these life shortened rats was extended significantly when supplemented with CM, possibly due to a minimization of the effects of stroke. Next, we analyzed the effect of CM on hypertension-sensitive organs, the central nervous systems (CNS), heart, kidney and liver of these rats. We attempted to ascertain how the organs were improved by CM, and we paid particular attention to mitochondria and autophagy functions. The following results were from CM-treated rats in comparison with control rats. Microscopically, CNS neurons, cardiomyocytes, glomerular podocytes, renal epithelial cells, and hepatocytes all were improved. However, immunoblot and immunohistochemical analysis showed that the expressions of mitochondria-related proteins, ATP synthase beta subunit, SIRT3 and SOD2, and autophagy-related proteins, LC3-II/LC3-I ratio and cathepsin D all were reduced significantly in the CNS neurons, but increased significantly in the cells of the other three organs, although p62 was decreased in its expression in all the organs tested. Activity of Akt and mTOR was enhanced but that of AMPK was reduced in the CNS, while such kinase activity was completely the opposite in the other organs. Together, the influence of CM may differ between mitochondria and autophagy functioned between the two organ groups, as mitochondria and autophagy seemed to be repressed and promoted, respectively, in the CNS, while both mitochondria and autophagy were activated in the others. This could possibly be related to the steady or improved cellular activity in both the organs, which might result in the life extension of these rats. PMID- 29264421 TI - Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients. AB - Methotrexate (MTX) is the most used drug in rheumatoid arthritis (RA) treatment. However, it shows variability in clinical response, which is explained by an association with genetic polymorphisms. This study aimed to elucidate the role of the two gene polymorphism C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) in response to MTX in Algerian RA patients. Study included 54 early RA patient treated with MTX for one year. MTX efficiency and toxicity were evaluated at 6 and 12 months respectively and the two gene polymorphisms were genotyped. No association was found between A1298C polymorphism and MTX toxicity. However, T allele of the C677T polymorphism was associated with the occurrence of MTX adverse effects (p = 0,019, OR: 3,63, 95% CI [1,12 - 12,80]). No association was found between C677T polymorphism and MTX efficiency, while A allele of the A1298C polymorphism was associated with good and moderate response (p = 0,02, OR = 3,28, 95% CI: [1,11- 9,42]). The study of RA biological markers kinetics showed that MTX did not affect antibodies rate unlike inflammatory markers. Our study suggests that MTHFR C677T and A1298C genotyping are associated to MTX toxicity and efficiency, respectively, in RA patients. This offers new perspectives in the personalization of RA treatment in Algeria. PMID- 29264422 TI - Nicotine alkaloid levels, and nicotine to nornicotine conversion, in Australian Nicotiana species used as chewing tobacco. AB - A range of endemic Nicotiana species are chewed as a smokeless tobacco by several Aboriginal populations of Australia. In tobacco research, nicotine to nornicotine conversion is important because nornicotine lowers tobacco quality and is detrimental to health. A diverse group of cytochrome P450 genes with different transcriptional regulations are involved in this conversion. The primary aims of this study were to quantify the pyridine alkaloids and investigate nicotine to nornicotine conversion in laboratory-grown Australian Nicotiana spp. Nicotine, nornicotine, anatabine, anabasine, myosmine and cotinine were quantified in fresh leaves of 24 out of the 26 recognised Australian Nicotiana taxa. Conserved regions of CYP82E related genes were PCR amplified in all studied taxa. The conversion process in fresh leaves was compared with that in leaves that underwent a simulated curing process for species that we identified as being high converters (N. cavicola, N. goodspeedii, N. velutina) and low converters (N. benthamiana, N. excelsior, N. gossei). Agarose gel electrophoretic analysis of CYP82E related genes obtained from the PCR amplification of the cDNA in fresh versus leaves with simulated curing showed about a 3-fold increase in transcript accumulation levels in cured leaves of the high converter species, while the transcript accumulation in N. gossei and N. excelsior maintained a steady basal level and increased by a small amount in N. benthamiana. This suggests the presence of functional loci that are triggered by curing in only high converter species and indicates a potential risk for chewers of high converter species. PMID- 29264423 TI - Use of fly-ash slurry in backfill grouting in coal mines. AB - Cave backfill grouting implies grouting of the caving rock mass prior to it being compacted. The filling materials strengthen the caving rock and support the overlying strata to achieve the purpose of slowing down the surface subsidence. The broken roof will fail and collapse during mining operations performed without appropriate supporting measures being taken. It is difficult to perform continuous backfill mining on the working face of such roofs using the existing mining technology. In order to solve the above problems, fly ash and mine water are considered as filling materials, and flow characteristics of fly-ash slurry are investigated through laboratory experiments and theoretical analyses. Laws governing the diffusion of fly-ash slurry in the void of caving rock masses and in the void between a caving rock mass and a basic roof are obtained and verified. Based on the results obtained from the above analyses and actual conditions at the Zhaoguan coal mine, Shandong Province, China, a cave backfill grouting system of the hauling pipeline is developed and successfully tested at the 1703 working face in the Zhaoguan coal mine. The results demonstrate that a filling rate of 43.46% is achieved, and the surface subsidence coefficient of the grouting process is found to be 0.475. Compared to the total caving method, the proposed system is found to achieve a reduction rate of 40.63%. This effectively helps in lowering the value of the surface subsidence coefficient. Fly ash and mine water, considered as primary materials in this study, also play a significant role in improving the air quality and water environment. PMID- 29264424 TI - Surgical management of adolescent and young adults with gastrointestinal stromal tumors: it is of value? PMID- 29264426 TI - Albumin-to-bilirubin score for assessing the in-hospital death in cirrhosis. AB - Background: To evaluate the ability of albumin-to-bilirubin (ALBI) score for assessing the in-hospital death in cirrhotic patients. Methods: Overall, 1,067 cirrhotic patients admitted between January 2009 and December 2014 were retrospectively enrolled. We calculated the Child-Pugh, model for end-stage liver disease (MELD), and ALBI scores. We performed receiver operating characteristic curve (ROC) analyses to assess the in-hospital death. We calculated the area under the ROC curve (AUC). Results: In the overall analysis, all of the three scores can significantly assess the in-hospital death (Child-Pugh score AUC =0.750, 95% CI: 0.713-0.784, P<0.0001; MELD score AUC =0.728, 95% CI: 0.689 0.765, P<0.0001; ALBI score AUC =0.698, 95% CI: 0.667-0.727, P<0.0001). In the subgroup analysis of hepatitis B virus, Child-Pugh and ALBI scores were suitable to assess in-hospital death (Child-Pugh score AUC =0.752, 95% CI: 0.679-0.816, P<0.0001; ALBI score AUC =0.803, 95% CI: 0.751-0.849, P=0.0002) and both were superior to the MELD score (AUC=0.564, 95% CI: 0.483-0.643, P=0.5357). In the subgroup analysis of alcohol abuse, Child-Pugh and MELD scores properly assessed in-hospital death (Child-Pugh score AUC =0.791, 95% CI: 0.727-0.846, P<0.0001; MELD score AUC =0.720, 95% CI: 0.647-0.786, P=0.0023), rather than ALBI score (AUC =0.646, 95% CI: 0.588-0.702, P=0.1360). Conclusions: ALBI score might be an alternative index for assessing the in-hospital death in patients with liver cirrhosis. PMID- 29264425 TI - Perfusion machines and hepatocellular carcinoma: a good match between a marginal organ and an advanced disease? AB - Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the second leading cause of cancer-related deaths and the leading cause of death in patients with cirrhosis. Liver transplantation (LT) represents the ideal treatment for selected patients as it removes both the tumor and the underlying cirrhotic liver with 5-year survival rates higher than 70%. Unfortunately, due to tumor characteristics, patient co-morbidities or shortage of organs available for transplant, only 20% of patients can undergo curative treatment. Ex situ machine perfusion (MP) is a technology recently introduced that might potentially improve organ preservation, allow graft assessment and increase the pool of available organs. The purpose of this review is to provide an update on the current role of ex situ liver MP in liver transplantation for HCC patients. PMID- 29264428 TI - Surgery for upper gastrointestinal tract. PMID- 29264427 TI - Different types of pancreatico-enteric anastomosis. AB - The pancreatico-enteric anastomosis has widely been regarded as the 'Achilles heel' of the modern day, single-stage, pancreatoduodenectomy (PD). A review of the literature was carried out to address the evolution of the pancreatico enteric anastomosis following PD, the spectrum of anastomoses performed around the world, and finally present the current evidence in support of each anastomosis. Pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ) are the most common forms of pancreatico-enteric reconstruction following PD. There is no difference in postoperative pancreatic fistula (POPF) rates between PG and PJ, as well as individual variations, except in a high-risk anastomosis where performance of a PJ may be preferred. The routine use of glue, trans-anastomotic stents or omental wrapping is of no proven benefit. Externalised trans anastomotic stents may have a role in mitigating the risk of a clinically relevant POPF in high-risk anastomoses. Pancreatico-enteric anastomosis is an important component of reconstruction following PD even though it is fraught with the risk of development of a POPF. Adherence to the tenets of anastomotic reconstruction and performance of a safe and reproducible anastomosis with a low clinically-relevant POPF rate remain the mainstay of achieving the best outcomes. Appropriate selection and opportune use of fistula mitigation strategies may help provide optimal outcomes when faced with the need to perform a high-risk pancreatico-enteric anastomosis. PMID- 29264429 TI - Understanding the critical role for surgery in the management of wild-type gastrointestinal stromal tumor (GIST). PMID- 29264430 TI - Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs? PMID- 29264431 TI - Gastrointestinal stromal tumors-are we stuck and the way forward. PMID- 29264432 TI - What drives the wheel towards long-term outcome in advanced GIST, its size, genotype or may be a pill or two of imatinib? PMID- 29264434 TI - Pediatric gastrointestinal stromal tumors: a commentary on the value of referral clinics for rare pediatric tumors. PMID- 29264433 TI - Role of inflammatory markers as hepatocellular cancer selection tool in the setting of liver transplantation. AB - Since the advent of the Milan criteria in 1996 and its widespread adoption for selection of patients with hepatocellular carcinoma (HCC) who would benefit from transplant, there has been an extensive hunt for the ideal clinical biomarker to predict HCC recurrence. This is because Milan lack does not include tumor biology indices and recurrence rates remain in the 15-20% range worldwide. While a 'silver-bullet' biomarker has not been found, several useful inflammatory markers have been identified and used in scoring systems that supersede Milan in their ability to predict HCC recurrence post liver transplantation (LT). In this review, we aim to summarize the role of inflammatory markers paly in the selection of HCC patients awaiting LT. PMID- 29264435 TI - Enabling precision digestive surgery with fluorescence imaging. PMID- 29264436 TI - Trans-arterial radio-embolization: a new chance for patients with hepatocellular cancer to access liver transplantation, a world review. AB - Liver transplantation (LT) for hepatocellular carcinoma (HCC) within the Milan criteria (MC) is nowadays a curative procedure. Yttrium-90 microspheres radioembolization (Y90-RE) has shown to be an effective and safe treatment of primary liver tumors. The aim of this work is to offer a view on the publications which report on the use of Y90-RE as bridge or downstaging prior to LT. Twenty articles have been considered for this world review. About 178 LT in patients were treated with Y90-RE prior to LT. Most of patients had a downstaging strategy. In all series alpha-fetoproteins decreased between Y90-RE and LT. Therefore, Y90-RE may have an important role in the bridge and downstaging treatments. PMID- 29264437 TI - The proof is in the pudding: improving adenoma detection rates reduces interval colon cancer development. PMID- 29264438 TI - Pylorus preservation pancreatectomy or not. AB - Pancreaticoduodenectomy (PD) is the treatment of choice for various benign and malignant tumors of the pancreatic head or the periampullary region, and the only hope for cure in patients with cancer at this side. While it has been associated with high morbidity and mortality rates in the last century, its centralization in specialized institutions together with refinements in the operative technique and better management of postoperative complications have made PD a standardized, safe procedure. Besides the classic Whipple procedure including distal gastrectomy, two variations of PD with or without pylorus resection, but preservation of the entire stomach in either procedure exist today. Pylorus preserving PD has gained wide acceptance as standard procedure and is being performed by an increasing number of pancreatic surgeons. After its oncological adequacy was questioned initially, pylorus-preserving PD was shown to be equivalent to the classic Whipple procedure regarding tumor recurrence and long term survival. Moreover, operation time and blood loss were shown to be reduced in the pylorus-preserving procedure and benefits in nutritional status and quality of life were observed. However, preservation of the pylorus has been suggested to result in an increased incidence of postoperative delayed gastric emptying (DGE). In this context, pylorus-resecting PD has become popular especially in Japan with the aim to prevent DGE by removal of the pylorus but preservation of the stomach. In contrast to positive results from early studies, latest high-quality randomized controlled trial (RCT) data show that pylorus resection does not reduce DGE compared to the pylorus-preserving operation. Non superiority of pylorus resection was also confirmed in current meta-analysis on this topic. This article summarizes the existing evidence on PD with or without pylorus preservation and derives recommendations for daily practice. PMID- 29264439 TI - Direct acting antiviral agents and hepatocellular carcinoma development: don't take it for granted. PMID- 29264440 TI - A New Publishing Medium for the Endocrine Society. PMID- 29264441 TI - Identification of Thyroid-Associated Serum microRNA Profiles and Their Potential Use in Thyroid Cancer Follow-Up. AB - Context: Trends toward more conservative management of papillary thyroid cancer (PTC) diminish the primacy of serum thyroglobulin (Tg) assays as a posttreatment surveillance tool. Objective: To identify thyroid tumor-associated microRNAs (miRNAs) in the serum with potential for development as unique biomarkers of PTC recurrence. Methods: We measured expression of 754 miRNAs in serum samples collected from 11 patients with PTC before and 30 days after thyroidectomy. Major candidates were then re-evaluated by absolute quantitative polymerase chain reaction analysis in an independent cohort of patients with PTC (n = 44) or benign nodules and 20 healthy controls (HCs). The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy. Results: Eight miRNAs (miR-221-3p, miR 222-3p, miR-146a-5p, miR-24-3p, miR-146b-5p, miR-191-5p, miR-103a-3p, and miR-28 3p) displayed levels in prethyroidectomy serum samples from patients with PTC that significantly exceeded those measured after thyroidectomy and those found in samples from HCs. The 2 most promising candidates-miR-146a-5p and miR-221-3p were further analyzed in the 20 PTC patients mentioned earlier. Serum levels of both miRNAs after 1 to 2 years of follow-up were consistent with ATA responses to therapy in all patients, including 2 with structural evidence of disease whose Tg assays remained negative (<1 ng/mL). Conclusion: miR-146a-5p and miR-221-3p hold remarkable promise as serum biomarkers for post-treatment monitoring of PTC patients, especially when Tg assay results are uninformative. PMID- 29264442 TI - Distribution of Salivary Testosterone in Men and Women in a British General Population-Based Sample: The Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - Introduction: Measurement of salivary testosterone (Sal-T) to assess androgen status offers important potential advantages in epidemiological research. The utility of the method depends on the interpretation of the results against robustly determined population distributions, which are currently lacking. Aim: To determine age-specific Sal-T population distributions for men and women. Methods: Morning saliva samples were obtained from participants in the third National Survey of Sexual Attitudes and Lifestyles, a probability sample survey of the British general population. Sal-T was measured using liquid chromatography tandem mass spectrometry (LC-MS/MS). Linear and quantile regression analyses were used to determine the age-specific 2.5th and 97.5th percentiles for the general population (1675 men and 2453 women) and the population with health exclusions (1145 men and 1276 women). Results: In the general population, the mean Sal-T level in men decreased from 322.6 pmol/L at 18 years of age to 153.9 pmol/L at 69 years of age. In women, the decrease in the geometric mean Sal-T level was from 39.8 pmol/L at 18 years of age to 19.5 pmol/L at 74 years of age. The annual decrease varied with age, with an average of 1.0% to 1.4% in men and 1.3% to 1.5% in women. For women, the 2.5th percentile fell below the detection limit (<6.5 pmol/L) from age 52 years onward. The mean Sal-T level was approximately 6 times greater in men than in women, and this remained constant over the age range. The Sal-T level was lowest for men and highest for women in the summer. The results were similar for the general population with exclusions. Conclusions: To our knowledge, this is the first study to describe the sex- and age-specific distributions for Sal-T in a large representative population using a specific and sensitive LC-MS/MS technique. The present data can inform future population research by facilitating the interpretation of Sal-T results as a marker of androgen status. PMID- 29264444 TI - Reversal of a Blunted Follicle-Stimulating Hormone by Chemotherapy in an Inhibin B-Secreting Adrenocortical Carcinoma. AB - Context: Adrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion. Case Description: We describe a 60-year old man with a right adrenal mass. Hormonal evaluation showed an ACTH-independent Cushing syndrome. Surprisingly, follicle-stimulating hormone (FSH) levels were suppressed and blunted during gonadotropin-releasing hormone stimulation, despite normal luteinizing hormone levels. Levels of inhibin B, which negatively regulates the pituitary FSH, were very high. Given the atypical hormonal findings, an adrenal mass biopsy was performed, which allowed the diagnosis of an adrenocortical tumor (positive for steroidogenic factor-1 immunostaining). Moreover, an intense alpha-inhibin subunit immunostaining was observed. Because of the presence of metastases, the patient received mitotane and chemotherapy (etoposide and cisplatin). After 2 cycles, the inhibin B dropped. After 5 cycles, tumor size was reduced by 15%. Inhibin B levels remained low, and basal and gonadotropin-releasing hormone-stimulated FSH levels normalized. The patient underwent tumor resection, and pathology confirmed the ACC diagnosis (Weiss score of 9). The intensity of the alpha-inhibin subunit immunostaining was significantly decreased. Conclusions: We report the case of an inhibin B secreting ACC in which the response to chemotherapy and mitotane was associated with a normalization of inhibin B secretion, allowing the reversal of the blunted FSH secretion. Inhibin B should be measured in case of suppressed FSH levels despite normal luteinizing hormone levels and may be considered a tumoral marker in some ACCs, even during treatment follow-up. PMID- 29264443 TI - Association of Circulating Wnt Antagonists With Severe Abdominal Aortic Calcification in Elderly Women. AB - Context: There is great interest in the biology of vascular calcification. Wnt/beta-catenin signaling is an important mediator of mineralization and may play a role in vascular calcification. Objective: We assessed the association between circulating Wnt antagonists and abdominal aortic calcification (AAC) severity in elderly women. Design: This was a cross-sectional analysis of the Calcium Intake Fracture Outcome Study. Setting: The participants were recruited from the community-dwelling elderly population. Participants: We examined 768 women aged over 70 years. Interventions: We collected blood samples, and lateral spine images captured during bone density assessment were used to score AAC with a validated 24-point scale. Main Outcome Measures: We tested the hypothesis that low Wnt antagonist levels of Dickkopf-1 (DKK1), secreted frizzled related protein 3 (sFRP3), and Wnt inhibitory factor 1 (WIF1) are associated with severe AAC (AAC24 score > 5). Results: Severe AAC was present in 146 women (19%). Lower levels of DKK1, but not WIF1 and sFRP3, were associated with higher odds of severe AAC. Per standard deviation decrease in DKK1 was associated with increased multivariable-adjusted odds ratio (OR) of severe AAC [OR, 1.26; 95% confidence interval (CI), 1.04 to 1.52; P = 0.017]. In quartile analyses, the lowest and second-lowest quartiles of DKK1 had increased multivariable-adjusted odds of severe AAC vs the highest quartile (OR, 2.05; 95% CI, 1.18 to 3.56; P = 0.011 and OR, 1.83; 95% CI, 1.05 to 3.19; P = 0.035). Conclusions: In elderly women, DKK1, but not sFRP3 or WIF1, is associated with severe AAC. This study supports the concept that Wnt/beta-catenin signaling is an important regulator of vascular mineral metabolism and is independent of other risk factors. PMID- 29264445 TI - Maffucci Syndrome Associated With Adrenocorticotropic Hormone-Independent Bilateral Macronodular Adrenal Hyperplasia. AB - Context: Maffucci syndrome is a rare, nonhereditary, mesodermal dysplastic disease characterized by the presence of multiple hemangiomas and enchondromas. This pathological condition, which is often unrecognized, is associated with a high prevalence of benign and malignant endocrine tumors involving pituitary, adrenal, thyroid, and parathyroid glands. Case Description: We describe the case of a young patient presenting a history suggestive of secondary arterial hypertension and typical features of Maffucci syndrome (multiple hemangiomas and enchondromas), which were unrecognized over the previous 3 decades. Given that endocrine diseases are common causes of secondary arterial hypertension and are often associated with Maffucci syndrome, a comprehensive diagnostic workup was performed, revealing the presence of large bilateral adrenal masses (70 mm right, 35 mm left) and autonomous cortisol secretion (adrenocorticotropic hormone independent Cushing syndrome). The patient underwent a bilateral adrenalectomy, and steroid replacement therapy was initiated. Surgery resulted in a normalization of arterial blood pressure, and antihypertensive treatment was discontinued. Histological examinations revealed morphological features of primary bilateral macronodular adrenal hyperplasia. Conclusions: Early recognition and lifelong monitoring of Maffucci syndrome is required to identify and treat possible associated endocrine diseases and malignancies. Among them, unilateral cortical adrenal masses have been previously described, but to our knowledge, this is the first reported case of Maffucci syndrome associated with primary bilateral macronodular adrenal hyperplasia. Additional studies are needed to establish the etiopathological link between these 2 entities and, more in general, between Maffucci syndrome and endocrine diseases, but possible common genetic alterations may be suggested. PMID- 29264447 TI - Pituitary Lesion of Unknown Origin: Think Epithelioid Angiosarcoma. AB - Precis: We report the unusual etiology of a sellar aggressive mass, an epithelioid angiosarcoma, the diagnosis of which was made from positive epithelial and vascular markers. PMID- 29264446 TI - Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome. AB - Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). Objective: To determine the role of LHCGR in transient, pregnancy-induced CS. Design Setting Patient and Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Main Outcome Measures and Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient's adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11 deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. Conclusion: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus. PMID- 29264448 TI - Effects of Linagliptin on Pancreatic alpha Cells of Type 1 Diabetic Mice. AB - The dipeptidyl peptidase-4 inhibitor linagliptin promotes beta-cell survival and insulin secretion by prolonging endogenous glucagon-like peptide 1 (GLP-1) action and therefore helps to maintain normoglycemia in diabetic patients. The effect of linagliptin on glucagon-producing alpha cells, however, was not clear. In this study, we investigated whether linagliptin had any effects on alpha cells with regard to their proliferation and hormonal production using type 1 diabetes mouse models, including streptozotocin-induced and nonobese diabetes mice. After diabetes development, the mice were either untreated or treated with linagliptin or insulin for up to 6 weeks. Our results showed that linagliptin significantly increased circulating GLP-1 levels in both type 1 diabetes models, but therapeutic benefit was detected in nonobese diabetes mice only. Circulating C peptide and glucagon levels (nonfasting) were not significantly altered by linagliptin treatment in either model. In addition, we found that linagliptin did not increase alpha-cell proliferation compared with the untreated or insulin treated controls as assessed by in vivo 5-bromo-2'-deoxyuridine labeling assay. Finally, we examined whether linagliptin treatment altered GLP-1 vs glucagon expression in pancreatic alpha cells. Immunohistochemistry assays showed that linagliptin treatment resulted in detection of GLP-1 in more alpha cells than in control groups, suggesting linagliptin was able to increase intraislet GLP-1 presence, presumably by inhibiting GLP-1 degradation. In summary, this study indicates that linagliptin would not confer adverse effect on alpha cells, such as causing alpha cell hyperplasia, and instead may facilitate a blood glucose lowering effect by increasing GLP-1 presence in alpha cells. PMID- 29264449 TI - Effects of Opioid Antagonism on Cerebrospinal Fluid Melanocortin Peptides and Cortisol Levels in Humans. AB - Context: Hypothalamic proopiomelanocortin (POMC) is processed to alpha-melanocyte stimulating hormone, which interacts with the melanocortin antagonist agouti related protein (AgRP), to regulate energy balance. The POMC-derived opioid peptide beta-endorphin (beta-EP) also affects feeding behavior via interactions with brain u-opioid receptors (MORs), including autoinhibitory interactions with MOR expressed by POMC neurons. The opioid antagonist naltrexone (NTX) stimulates POMC neurons in rodents and decreases food intake. Objective and Design: The effect of NTX on brain POMC in humans was assessed by measuring POMC peptide concentrations in lumbar cerebrospinal fluid (CSF). AgRP and cortisol levels were also measured because both are inhibited by opioids. In a double-blinded crossover study, 14 healthy subjects were given NTX (50 mg daily) or placebo for either 2 or 7 days. Results: CSF beta-EP levels increased after 2 and 7 days of NTX treatment; CSF POMC levels did not change, but the beta-EP-to-POMC ratio increased. CSF AgRP levels did not change, but plasma AgRP levels tended to increase after NTX (P = 0.06). Cortisol increased in plasma and CSF after NTX treatment; these changes correlated positively with changes in AgRP levels. Conclusion: Opioid antagonism stimulates POMC peptide release into CSF in humans. The increase in the CSF beta-EP-to-POMC ratio could indicate selective release of processed peptides or an effect on POMC processing. Furthermore, AgRP and cortisol stimulation by NTX may mitigate POMC-induced decrease in food intake. It remains to be determined if biomarkers in CSF and plasma could be used to predict responses to pharmacotherapy targeting the melanocortin system. PMID- 29264450 TI - Diabetic by HbA1c, Normal by OGTT: A Frequent Finding in the Mexico City Diabetes Study. AB - Context: The agreement between glucose-based and hemoglobin A1c (HbA1c)-based American Diabetes Association criteria in the diagnosis of normal glucose tolerance, prediabetes, or diabetes is under scrutiny. A need to explore the issue among different populations exists. Objective: Examine the results obtained with both methods in the diagnosis of the glycemic status. Design: The Mexico City Diabetes Study is a population-based, prospective investigation. Setting: Low-income elder urban community. Participants: All 854 participants without known diabetes had both oral glucose tolerance test (OGTT) and HbA1c measurements on the same day of the 2008 phase. Interventions: Standardized protocol: questionnaires, anthropometry, and biomarkers. Main Outcome: Diagnostic classification of American Diabetes Association criteria. Results: We found by OGTT normal glucose tolerance (NGT) in 512 (59.9%) participants, prediabetes [impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] in 261 (30.5%), and diabetes in 81 (9.4%). In total, 232 in the NGT group (45.3%) and 158 in the prediabetes group (60.5%) had HbA1c >=6.5%. Body mass index, waist circumference, and blood pressure were significantly different among OGTT-defined diabetic status groups but not in the HbA1c-diagnosed group. We identified 404 participants in the NGT group with confirmed NGT throughout all phases of the Mexico City Diabetes Study. Of these, 184 (45.5%) had HbA1c >=6.5%. In a vital/diabetes status follow-up performed subsequently, we found that, of these, 133 remained nondiabetic, 3 had prediabetes, 7 had diabetes, and 13 had died without diabetes; we were unable to ascertain the glycemic status in 5 and vital status in 23. Conclusions: Normal OGTT coexisting with elevated HbA1c is a common finding in this cohort. It is possible that this finding is not mediated by hyperglycemia. This might occur in similar populations. PMID- 29264451 TI - Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency. AB - Context: Kisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH). Objective: The aim of this study was to identify the genetic cause of CHH in a patient and to functionally characterize a KISS1R mutation. Design: The patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand-KISS1R mutant complex with those of wild-type KISS1R variants. Results: A homozygous mutation (c.440C>T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket. Conclusion: We identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket. PMID- 29264453 TI - Percutaneous Transsternal Cryoablation of Ectopic Parathyroid Adenoma in the Anterior Mediastinum. AB - Ectopic parathyroid adenomas are common in the context of hyperparathyroidism and represent a unique challenge in terms of localization and treatment. Often they are related to higher serum calcium levels than those associated with parathyroid adenomas in typical locations. Additionally, ectopic adenomas often lead to higher morbidity due to failed parathyroid exploration and multiple attempts at surgical removal. We present two cases of computed tomography-guided percutaneous transsternal cryoablation of ectopic parathyroid adenomas in the anterior mediastinum, one after failed surgical resection and the other after failed transarterial embolization. Cryoablation may represent a safe and effective alternative to surgery or embolization and should be included in the therapeutic algorithm in patients with percutaneously accessible lesions. PMID- 29264452 TI - Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes. AB - Enteroviral infections have been associated with the development of type 1 diabetes (T1D), a chronic inflammatory disease characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Cultured human islets, including the insulin-producing beta cells, can be infected with coxsackievirus B4 (CVB4) and thus are useful for understanding cellular responses to infection. We performed quantitative mass spectrometry analysis on cultured primary human islets infected with CVB4 to identify molecules and pathways altered upon infection. Corresponding uninfected controls were included in the study for comparative protein expression analyses. Proteins were significantly and differentially regulated in human islets challenged with virus compared with their uninfected counterparts. Complementary analyses of gene transcripts in CVB4 infected primary islets over a time course validated the induction of RNA transcripts for many of the proteins that were increased in the proteomics studies. Notably, infection with CVB4 results in a considerable decrease in insulin. Genes/proteins modulated during CVB4 infection also include those involved in activation of immune responses, including type I interferon pathways linked to T1D pathogenesis and with antiviral, cell repair, and inflammatory properties. Our study applies proteomics analyses to cultured human islets challenged with virus and identifies target proteins that could be useful in T1D interventions. PMID- 29264454 TI - Effects of Inorganic Iodine Therapy Administered to Lactating Mothers With Graves Disease on Infant Thyroid Function. AB - Context: The effects of maternal inorganic iodine therapy on infant thyroid function are not well known. Objective: This study investigated the effects on infant thyroid function of maternal inorganic iodine therapy when administered to lactating mothers with Graves disease. Design and Setting: This study was a prospective case series performed at the Tajiri Thyroid Clinic, Kumamoto, Japan. Participants: Subjects were 26 infants of lactating mothers with Graves disease treated with potassium iodide (KI) for postpartum thyrotoxicosis. Main Outcome Measures: Infant blood levels of thyroid-stimulating hormone (TSH) and free thyroxine were measured using the dried filter-paper method. Iodine concentrations in breast milk and infant urine were measured on the same day. Subclinical hypothyroidism was defined as a blood TSH level of >=10 or >=5 MUIU/mL in <6-month-old and 6- to 12-month-old infants, respectively. Results: The median age of the infants was 3 months (range, 0 to 10 months). The median KI dose was 50 mg/d (range, 10 to 100 mg/d). High median iodine concentrations were detected in breast milk (15,050 MUg/L; range, 831 to 72,000 MUg/L) and infant urine (15,650 MUg/L; range, 157 to 250,000 MUg/L). Twenty-five of 26 infants had normal thyroid function. Although one infant had subclinical hypothyroidism (blood TSH, 12.3 MUIU/mL), the TSH level normalized to 2.3 MUIU/mL at 2 months after KI discontinuation. Conclusion: In Japan, where iodine intake is sufficient, administration of inorganic iodine to lactating mothers with Graves disease did not affect thyroid function in most infants despite high levels of exposure to iodine via breast milk. PMID- 29264455 TI - Fat-Bone Interactions in Adults With Spina Bifida. AB - Context: Spina bifida (SB) can lead to changes in body composition and bone mineral density (BMD) through diminished ambulation, renal impairment, and anticonvulsant medication. With increased life expectancy, diseases such as obesity and osteoporosis are emerging comorbidities in SB, with limited data to guide management. Objective: To examine the relationship between cardiometabolic factors, body composition, BMD, and minimal trauma fractures (MTFs) in adults with SB. Design: Retrospective cross-sectional study. Setting and Participants: Forty-nine adults with SB (median age, 32.7 years; interquartile range, 22.6 to 39.0) who had undergone dual-energy x-ray absorptiometry imaging at a single tertiary hospital from 2004 to 2015. Results: The mean body mass index was 31.7 +/- 7.5 kg/m2; 26 (53.1%) were obese. Using age- and sex-matched fat percentiles from the National Health and Nutrition Examination Survey III, 62.5% had a total body percentage fat greater than the 95th percentile. Low bone mass (defined as a Z-score of <=-2.0) was present in 21.9% at the L1 vertebra and in 35.1% at the femoral neck. Ten (20.4%) had a history of MTFs. A BMD or Z-score at L1, femoral neck, or total body site did not correlate with the occurrence of MTF. Fat mass was significantly and positively associated with BMD after adjustment for age, sex, and height and accounted for 18.6% of the variance in BMD (P = 0.005). The prevalence of metabolic comorbidities, such as hypertension (20.4%) and obstructive sleep apnea (16.3%), was high. Conclusions: Obesity and low BMD are common in young adults with SB. An increased fat mass correlated significantly with BMD. The prevalence of metabolic complications in patients with SB is increased and deserves further study. PMID- 29264456 TI - Harvey Cushing Treated the First Known Patient With Carney Complex. AB - Context: Carney complex (CNC) is a syndrome characterized by hyperplasia of endocrine organs and may present with clinical features of Cushing syndrome and acromegaly due to functional adrenal and pituitary gland tumors. CNC has been linked to mutations in the regulatory subunit of protein kinase A type I-alpha (PRKAR1A) gene. Design: Tissue samples were taken from the hypothalamus or thalamus or tumors of patients with pituitary adenomas seen and operated on by neurosurgeon Harvey Cushing between 1913 and 1932. Following DNA extraction, sequencing for genes of interest was attempted, including PRKAR1A, AIP, USP8, GNAS1, and GPR101, to explore the possibility that these mutations associated with acromegaly, CNC, and Cushing syndrome have been conserved over time. Results: We report a patient described by Dr. Cushing in 1914 with a clinical presentation and postmortem findings suggestive of CNC. Genetic sequencing of the hypothalamus and pituitary adenoma revealed a germline heterozygous p.Arg74His mutation in the PRKAR1A gene, a codon previously described as mutated in CNC, but with a novel amino acid change. Conclusions: This patient is, to our knowledge, the first molecularly confirmed individual with CNC. This case demonstrates the power of modern genetics in studying archived tissues and the importance of recording detailed clinical notes in the diagnosis of disease. PMID- 29264457 TI - Successful Pregnancies After Adequate Hormonal Replacement in Patients With Combined Pituitary Hormone Deficiencies. AB - Context: Women with hypopituitarism have lower pregnancy rates after ovulation induction. Associated pituitary hormone deficiencies might play a role in this poorer outcome. Objective: We evaluated fertility treatment and pregnancy outcomes in five women with childhood-onset combined pituitary hormone deficiencies (CPHD). Patients and Methods: Five women with CPHD were referred for fertility treatment after adequacy of hormone replacement was determined. Patients were subjected to controlled ovarian stimulation (COS) for timed intercourse, intrauterine insemination, or in vitro fertilization, according to the presence or absence of other infertility factors (male or tubal). Results: All women became pregnant. The number of COS attempts until pregnancy was achieved varied between 1 and 5. The duration of COS resulting in at least one dominant follicle varied between 9 and 28 days, and total gonadotropin consumed varied between 1200 and 3450 IU. Two patients with severely suppressed basal gonadotropin levels since an early age had a cancelled COS cycle. All pregnancies were singleton except one (monochorionic twin gestation). The gestational ages at birth ranged from 35 weeks to 39 weeks and 4 days; three patients underwent cesarean section, and two had vaginal deliveries. Only one newborn was small for gestational age (delivered at 35 weeks). Conclusion: Adequate hormonal replacement prior to ovarian stimulation resulted in successful pregnancies in patients with childhood-onset CPHD, indicating that hormone replacement, including growth hormone, is an important step prior to fertility treatments in these patients. PMID- 29264459 TI - Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan. AB - Context: Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects. Purpose: The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations. Methods: We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m2) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin >=15 uU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia. Results: The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11). Conclusions: To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia. PMID- 29264458 TI - Astrocyte-Specific Deletion of Peroxisome-Proliferator Activated Receptor-gamma Impairs Glucose Metabolism and Estrous Cycling in Female Mice. AB - Mice lacking peroxisome-proliferator activated receptor-gamma (PPARgamma) in neurons do not become leptin resistant when placed on a high-fat diet (HFD). In male mice, this results in decreased food intake and increased energy expenditure, causing reduced body weight, but this difference in body weight is not observed in female mice. In addition, estrous cycles are disturbed and the ovaries present with hemorrhagic follicles. We observed that PPARgamma was more highly expressed in astrocytes than neurons, so we created an inducible, conditional knockout of PPARgamma in astrocytes (AKO). The AKO mice had impaired glucose tolerance and hepatic steatosis that did not worsen with HFD. Expression of gluconeogenic genes was elevated in the mouse livers, as was expression of several genes involved in lipogenesis, lipid transport, and storage. The AKO mice also had a reproductive phenotype with fewer estrous cycles, elevated plasma testosterone levels, reduced corpora lutea formation, and alterations in hypothalamic and ovarian gene expression. Thus, the phenotypes of the AKO mice were very different from those seen in the neuronal knockout mice, suggesting distinct roles for PPARgamma in these two cell types. PMID- 29264460 TI - Hypothalamic-Pituitary-Ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women With Chronic Amenorrhea. AB - Context: Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA. Objective: To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA. Patients: Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline resistant microprolactinomas. Interventions: Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 MUg/kg/h) was infused intravenously for 12 hours. Results: Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased. Conclusions: In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible. PMID- 29264461 TI - Frequent Sugar-Sweetened Beverage Consumption and the Onset of Cardiometabolic Diseases: Cause for Concern? AB - The incidence of noncommunicable diseases is on the rise and poses a major threat to global public health. This is in parallel to a steady increase in worldwide intake of sugar-sweetened beverages (SSBs) among all age groups. As several studies demonstrated a controversial relationship between SSB consumption and the metabolic syndrome (MetS), this mini-review focuses on links between its intake and (1) MetS, (2) prediabetes/type 2 diabetes mellitus (T2DM), and (3) hypertension. A detailed search for clinical and observational studies published during the past 10 years was conducted using key terms that link SSBs to the MetS, T2DM, and hypertension. Here we excluded all meta-analyses and also literature that solely focused on obesity. The analysis revealed that most epidemiological studies strongly show that frequent SSB intake contributes to the onset of the MetS in the longer term. Some of the findings also show that regular SSB intake can alter glucose handling and insulin sensitivity, thereby contributing to the development of the MetS and T2DM. There is also evidence that frequent SSB intake (and particularly fructose) is linked to hypertension and well-known cardiovascular disease risk factors. However, some studies report on the lack of negative effects as a result of SSB consumption. Because of this discrepancy, we propose that well-designed long-term clinical studies should further enhance our understanding regarding the links between SSB consumption and the onset of cardiometabolic diseases. PMID- 29264463 TI - Case Report of a Prolactinoma in a Patient With a Novel MAX Mutation and Bilateral Pheochromocytomas. AB - Pheochromocytomas are neuroendocrine tumors that can arise sporadically or be inherited as a familial disease, and they may occur in isolation or as part of a multitumor syndrome. Familial disease typically presents in younger patients with a higher risk of multifocality. Recently, the tumor suppressor MYC-associated factor X (MAX) gene has been implicated as a cause of familial isolated pheochromocytoma and paraganglioma. We describe a patient with a pituitary prolactinoma and bilateral pheochromocytomas who tested positive for a germline MAX mutation. Interestingly, the patient also had mild primary hyperparathyroidism that resolved upon resection of the pheochromocytomas despite the absence of parathyroid hormone staining in the tumors. To our knowledge, this case is the first report of prolactinoma in a patient with a MAX mutation, which suggests the possibility of germline MAX mutations also contributing to the development of prolactinomas. PMID- 29264462 TI - Evolving Mechanistic Views and Emerging Therapeutic Strategies for Cystic Fibrosis-Related Diabetes. AB - Diabetes is a common and important complication of cystic fibrosis, an autosomal recessive genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cystic fibrosis-related diabetes (CFRD) is associated with profound detrimental effects on the disease course and mortality and is expected to increase in prevalence as the survival of patients with cystic fibrosis continues to improve. Despite progress in the functional characterization of CFTR molecular defects, the mechanistic basis of CFRD is not well understood, in part because of the relative inaccessibility of the pancreatic tissue and the limited availability of representative animal models. This review presents a concise overview of the current understanding of CFRD pathogenesis and provides a cutting-edge update on novel findings from human and animal studies. Potential contributions from paracrine mechanisms and beta-cell compensatory mechanisms are highlighted, as well as functional beta-cell and alpha-cell defects, incretin defects, exocrine pancreatic insufficiency, and loss of islet cell mass. State-of-the-art and emerging treatment options are explored, including advances in insulin administration, CFTR modulators, cell replacement, gene replacement, and gene editing therapies. PMID- 29264464 TI - Increased IRS2 mRNA Expression in SGA Neonates: PCR Analysis of Insulin/IGF Signaling in Cord Blood. AB - Context: Hypoglycemia is the most common metabolic problem among small-for gestational-age (SGA) neonates. However, the pathological mechanism and insulin/ insulin-like growth factor (IGF) signaling axis in neonates remain unknown. Objective: To determine the insulin/IGF axis in neonates, we analyzed the messenger RNA (mRNA) expression of insulin/IGF signaling in fetal umbilical cord blood. Setting: The Perinatal Medical Center of Tottori University Hospital. Participants: Fifty-two [42 appropriate-for-gestational-age (AGA) and 10 SGA] neonates. Interventions: Immediately collected cord blood was placed into a PAXgene Blood RNA Tube. Total RNA from the blood was purified using reagents provided in the PAXgene Blood RNA Kit within 4 days, and reverse transcription polymerase chain reaction (PCR) was performed. Main Outcome Measure: Quantitative real-time PCR analysis was applied to evaluate the mRNA expression of insulin receptor (INSR), IGF-I receptor (IGF1R), insulin receptor substrate 1 (IRS1), IRS2, and glucose transporters (SLC2A2 and SLC2A4). beta-Actin was used as a control gene. Results: Serum glucose and IGF-I levels in SGA neonates were significantly lower. The cord serum insulin levels were similar between AGA and SGA neonates. The IRS2 mRNA expression was significantly higher in SGA than in AGA neonates (P < 0.05). The IRS2 mRNA expression was significantly higher in hypoglycemic SGA neonates than in normoglycemic SGA neonates. Conclusions: We determined that intrauterine growth restriction induces increased IRS2 mRNA expression in cord blood, without hyperinsulinemia. The increased expression of IRS2 mRNA might be associated with abnormal glucose metabolism in SGA neonates. Our findings might lead to the elucidation of abnormal glucose metabolism in SGA neonates. PMID- 29264465 TI - Metabolic Concomitants of Obese and Nonobese Women With Features of Polycystic Ovarian Syndrome. AB - Context: Polycystic ovarian syndrome (PCOS) is often associated with obesity and diabetes. Objective: The present study measured body fat distribution and metabolic risk factors in women with features of PCOS. Design: Cross-sectional, multiethnic study of cardiovascular risks. Setting: General community. Study Participants: 145 PCOS and 344 non-PCOS women. Exposure Measures: Body composition by dual x-ray absorptiometry; abdominal fat masses measured by magnetic resonance imaging and hepatic triglyceride by magnetic resonance spectroscopy. Outcomes Measures: Body composition, liver fat content, homeostatic model assessment for insulin resistance (HOMA-IR), revised, and metabolic syndrome components. Results: PCOS women had a higher free androgen index compared with the non-PCOS women. Nonobese PCOS and non-PCOS women had a similar body fat content and distribution, HOMA-IR, and hepatic triglyceride content. Obese PCOS women had a similar total body fat percentage compared with their non PCOS counterparts (41.4% and 41.4% respectively). Both obese groups had similar intraperitoneal fat (1.4% of total body mass in PCOS vs 1.4% in non-PCOS). However, obese PCOS women had a greater ratio of truncal/lower body fat (1.42 vs 1.27; P < 0.016). They also had greater insulin resistance (HOMA-IR: PCOS, 2.24% vs non-PCOS, 1.91%; P < 0.016), higher liver triglyceride content (6.96% in PCOS vs 4.44% in non-PCOS; P < 0.016), and a greater incidence of hypertension (33% vs 24%; P < 0.05). No differences were observed in other metabolic risk factors. Conclusions: Both obese and nonobese women with PCOS features had a greater free androgen index compared with non-PCOS women, but neither had greater intraperitoneal fat or abnormal lipid levels. Obese, but not nonobese, women with PCOS had a greater truncal/lower extremity fat ratio, HOMA-IR, and liver triglyceride content. PMID- 29264466 TI - Leveraging Scarce Resources With Bone Health TeleECHO to Improve the Care of Osteoporosis. AB - Osteoporosis is a common condition with serious consequences because of fractures. Despite availability of treatments to reduce fracture risk, there is a large osteoporosis treatment gap that has reached crisis proportions. There are too few specialists to provide services for patients who need them. Bone Health Extension for Community Health Care Outcomes (TeleECHO) is a strategy using real time ongoing videoconferencing technology to mentor health care professionals in rural and underserved communities to achieve an advanced level of knowledge for the care of patients with skeletal diseases. Over the first 21 months of weekly Bone Health TeleECHO programs, there were 263 registered health care professionals in the United States and several other countries, with 221 attending at least 1 online clinic and typically 35 to 40 attendees at each session at the end of the reported period. Assessment of self-confidence in 20 domains of osteoporosis care showed substantial improvement with the ECHO intervention (P = 0.005). Bone Health TeleECHO can contribute to mitigating the crisis in osteoporosis care by leveraging scarce resources, providing motivated practitioners with skills to provide better skeletal health care, closer to home, with greater convenience, and lower cost than referral to a specialty center. Bone Health TeleECHO can be replicated in any location worldwide to reach anyone with Internet access, allowing access in local time zones and languages. The ECHO model of learning can be applied to other aspects of bone care, including the education of fracture liaison service coordinators, residents and fellows, and physicians with an interest in rare bone diseases. PMID- 29264467 TI - Immunosuppressive Therapy in Treatment of Refractory Hypoglycemia in Type B Insulin Resistance: A Case Report. AB - Type B insulin resistance is a rare syndrome characterized by fluctuating glucose levels (ranging from hyperglycemia with extreme insulin resistance to intractable hypoglycemia without exogenous insulin administration), high serum insulin levels, and insulin receptor autoantibodies. Most cases occur in the African American population in association with other underlying autoimmune systemic diseases. Treatments with high-dose steroids, immunosuppressants, and plasmapheresis have been used, with variable outcomes, in patients without spontaneous remission. We report the case of a 60-year-old African American woman with history of systemic lupus erythematosus presenting with extreme fluctuations in glucose levels, ranging from severe hyperglycemia to refractory hypoglycemia, with high serum concentration of insulin in both phases. Her presentation and phenotype were very similar to those seen in known cases of type B insulin resistance associated with insulin receptor antibodies. Treatment in other reported cases used a combination of high-dose steroids and immunosuppressants. We tried high-dose steroids, azathioprine, and intravenous immunoglobulins, which resulted in improvement and barely detectable insulin receptor antibody. We present a case of type B insulin resistance with abnormally low titers of insulin receptor antibodies despite a typical clinical course and response. Future research is needed to improve diagnosis and treatment in this rare disease. PMID- 29264468 TI - An Unusual Case of Metastatic Functional Thyroid Carcinoma With a Remarkable Treatment Response to Radioactive Iodine. AB - Functional thyroid carcinoma is an unusual cause of thyrotoxicosis. We describe the clinical presentation and treatment of a patient with thyrotoxicosis due to functional thyroid carcinoma and Graves disease, and discuss potential mechanisms causing the thyrotoxicosis. A 79-year-old woman with a remote history of hemithyroidectomy and current hyperthyroidism came to the hospital with upper and lower extremity weakness. Hospital evaluation revealed a suppressed thyroid stimulating hormone (TSH) level, positive test for thyroid-stimulating immunoglobulins, as well as a thyroid nodule, lung masses, and a 4.4-cm gluteal mass. Fine-needle aspiration of the gluteal mass revealed metastatic differentiated thyroid carcinoma. Even after completion thyroidectomy and excision of her gluteal mass, her hyperthyroid status continued when she was not receiving levothyroxine. A radioactive iodine uptake and scan revealed unusually high lung uptake of 40%, and she was successfully treated with radioactive iodine (RAI) despite complete TSH suppression. The patient developed hypothyroidism 2 months after RAI administration; 6 months after RAI administration, her thyroglobulin (Tg) levels had fallen from a peak of 1976 ng/mL to 1.4 ng/mL. She had no anti-Tg antibodies. Repeated positron emission tomography-computed tomography nearly 1 year after RAI treatment shows substantial regression in the lung nodules, and Tg measured by mass spectroscopy is undetectable. This case demonstrates that thyrotoxicosis in the setting of metastatic thyroid carcinoma may be the result of functional thyroid carcinoma and may be successfully treated with selective surgery and RAI administration. PMID- 29264469 TI - Somatotroph-Specific Aip-Deficient Mice Display Pretumorigenic Alterations in Cell-Cycle Signaling. AB - Patients with familial isolated pituitary adenoma are predisposed to pituitary adenomas, which in a subset of cases is due to germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Using Cre/lox and Flp/Frt technology, a conditional mouse model was generated to examine the loss of the mouse homolog, Aip, in pituitary somatotrophs. By 40 weeks of age, >80% of somatotroph specific Aip knockout mice develop growth hormone (GH) secreting adenomas. The formation of adenomas results in physiologic effects recapitulating the human syndrome of acromegaly, including increased body size, elevated serum GH and insulin-like growth factor 1 levels, and glucose intolerance. The pretumorigenic Aip-deficient somatotrophs secrete excess GH and exhibit pathologic hyperplasia associated with cytosolic compartmentalization of the cyclin-dependent kinase (CDK) inhibitor p27kip1 and perinuclear accentuation of CDK-4. Following tumor formation, the Aip-deficient somatotrophs display reduced expression of somatostatin receptor subtype 5 with impaired response to octreotide. The delayed tumor emergence, even with loss of both copies of Aip, implies that additional somatic events are required for adenoma formation. These findings suggest that pituitary hyperplasia precedes adenomatous transformation in somatotroph-specific Aip-deficient mice and reveal potential mechanisms involved in the pretumorigenic state that ultimately contribute to transformation. PMID- 29264470 TI - Salivary Cortisol and Cortisone After Low-Dose Corticotropin Stimulation in the Diagnosis of Adrenal Insufficiency. AB - Context: Basal and poststimulation salivary cortisol and cortisone levels can be useful in the diagnosis of adrenal insufficiency. However, little is known about the optimal cutoffs and performance characteristics of these tests. Objective: To derive the cutoff values and study the performance characteristics of salivary cortisol and salivary cortisone in the diagnosis of adrenal insufficiency. Design and Setting: Prospective study in a regional hospital in Hong Kong from January 2014 to September 2015. Participants: Fifty-six Chinese healthy volunteers and 171 patients suspected of having adrenal insufficiency. Main Outcome Measures: All participants underwent low-dose short Synacthen test (LDSST) with intravenous injection of 1 MUg of tetracosactide (Synacthen 1-24). Serum cortisol, salivary cortisol and cortisone levels were measured at baseline and 30 and 60 minutes afterward. Results: Using the reference cutoff (mean - 2 standard deviations of post-LDSST peak serum cortisol) derived from healthy volunteers as the gold standard, receiver operating characteristic analysis of patients' data revealed that both post-LDSST peak salivary cortisol and cortisone performed better than basal tests. The most optimal cutoff values for serum cortisol as measured by immunoassay and for salivary cortisol and salivary cortisone as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were 376, 8.6, and 33.5 nmol/L, respectively, for post-LDSST peak values, and 170, 1.7, and 12.5 nmol/L, respectively, for basal values. Conclusions: We established method-specific reference cutoffs for serum cortisol, salivary cortisol, and salivary cortisone during LDSST. Both post-LDSST peak salivary cortisol and cortisone performed well as diagnostic tests for adrenal insufficiency. Their measurements by LC-MS/MS can alleviate problems associated with serum cortisol immunoassays. PMID- 29264471 TI - Pachydermoperiostosis Masquerading as Acromegaly. AB - Context: Acromegaly usually is suspected on clinical grounds. Biochemical confirmation is required to optimize therapy, but there are other differential diagnoses. Case Description: We describe a 24-year-old Uzbek man who presented with many clinical symptoms and signs of apparent acromegaly. On examination, the patient showed a rugose folding of his scalp, with the formation of tender, painful, rough skin folds in the parietal-occipital region, resembling cerebral gyri (i.e., cutis verticis gyrate). There was also a thickening and enlargement of the eyelids due to cartilaginous hypertrophy, dystrophic changes of the conjunctiva, and atrophy of the Meibomian glands, with the formation of multiple cysts and granulomas. He perspired excessively. There was thickening of the facial skin, with increased oiliness, increased rugosity, and seborrheic dermatitis. The skin over the hands was thick and apparently fixed to the underlying tissues. However, the patient had a low-normal insulin-like growth factor-1 level. More detailed analysis revealed a family history of relatives with similar problems, and certain features were not in keeping with this diagnosis. The disorder pachydermoperiostosis, or pulmonary hypertrophic osteoarthropathy, was suspected, and next-generation screening confirmed that the patient was homozygous for a pathogenic mutation in the SLCO2A1 gene, c.764G>A (p.Gly255Glu). Conclusion: The condition of pachydermoperiostosis may masquerade as acromegaly but is a genetic disorder, usually autosomal recessive, leading to elevated prostaglandin E2 levels. This is an important, albeit rare, differential diagnosis of acromegaly. PMID- 29264472 TI - EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis. AB - The epidermal growth factor receptor (EGFR), expressed in adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas causing Cushing disease, regulates ACTH production and corticotroph proliferation. To elucidate the utility of EGFR as a therapeutic target for Cushing disease, we generated transgenic (Tg) mice with corticotroph-specific human EGFR expression (corti-EGFR-Tg) using a newly constructed corticotroph-specific promoter. Pituitary-specific EGFR expression was observed by 2.5 months, and aggressive ACTH-secreting pituitary adenomas with features of Crooke's cells developed by 8 months with 65% penetrance observed. Features consistent with the Cushing phenotype included elevated plasma ACTH and corticosterone levels, increased body weight, glucose intolerance, and enlarged adrenal cortex. Gefitinib, an EGFR tyrosine kinase inhibitor, suppressed tumor POMC expression and downstream EGFR tumor signaling, and ACTH and corticosterone levels were attenuated by 80% and 78%, respectively. Both E2F1 and phosphorylated Ser-337 E2F1 were increased in corti-EGFR-Tg mice and also colocalized with human POMC (hPOMC) in human pituitary corticotroph tumor samples. EGFR inhibition reversed E2F1 activity in vivo, whereas E2F1 inhibition suppressed POMC and ACTH in cultured human pituitary tumor cells. The corti-EGFR-Tg phenotype recapitulates ACTH-secreting pituitary adenomas and Cushing disease, validating the relevance of EGFR to corticotroph tumorigenesis. E2F1 is identified as a promising corticotroph-specific target for ACTH-dependent Cushing disease. PMID- 29264473 TI - The Molecular Pathology of Cushing Disease: Are We Nearly There? AB - The molecular pathology of corticotroph tumors is surveyed in the light of recent work showing the induction of aggressive corticotroph tumors by the transgenic expression of epidermal growth factor receptors. PMID- 29264474 TI - New Advances in the Diagnostic Workup of Primary Aldosteronism. AB - Primary aldosteronism is an important and common cause of hypertension that carries a high burden of morbidity. Outcomes, however, are excellent if diagnosed and treated appropriately. The diagnostic workup for primary aldosteronism is complex and comprises three steps: (1) screening, (2) confirmatory testing, and (3) subtype differentiation. In this review, we discuss recent advances in the diagnostic workup for primary aldosteronism. The development of accurate mass spectroscopy-based assays for measuring aldosterone will lead to improved confidence in all diagnostic aspects involving measurement of aldosterone, and accurate measurement of angiotensin II may soon advance us beyond the measurement of renin. We now have a greater understanding of hormonal influences on the aldosterone/renin ratio, which are particularly important when screening premenopausal women or those taking estrogen-containing preparations. Confirmatory testing is important, but there are limitations to the commonly used methods that have recently become more apparent, with new approaches offering a way forward. Adrenal venous sampling (AVS) is a challenging procedure but is important for deciding on treatment options. Success rates may be improved by the use of Synacthen stimulation and of rapid intraprocedural measurement of cortisol. Better understanding of AVS interpretation criteria allows improved prognostication and aids treatment decisions. The use of labeled metomidate positron emission tomography computed tomography scanning may also offer an alternative to AVS in some units. Although the diagnostic approach to patients with primary aldosteronism remains a complex multistep process in which attention to detail is important, recent advances will improve patient care and outcomes. PMID- 29264475 TI - Leadership Training in Endocrinology Fellowship? A Survey of Program Directors and Recent Graduates. AB - Context: There is growing recognition that more physician leaders are needed to navigate the next era of medicine. Objective: To determine current opinions about leadership training in endocrinology fellowship programs. Design/Participants: Twenty-seven-question survey addressing various aspects of leadership training to current nationwide fellowship program directors (PDs) and fellowship graduates since 2010. Intervention: In partnership with the Endocrine Society, the electronic survey was advertised primarily via direct e-mail. It was open from March through July 2016. Main Outcome Measures: The survey addressed leadership traits, importance of leadership training, preferred timing, and content of leadership training. Results: Forty-six of 138 PDs (33.3%) and 147 of 1769 graduates (8.3%) completed the survey. Among PDs and graduates, there was strong agreement (>95%) about important leadership characteristics, including job knowledge, character traits, team-builder focus, and professional skills. PDs (64.5%) and graduates (60.8%) favored teaching leadership skills during fellowship, with PDs favoring mentoring/coaching (75.0%), direct observation of staff clinicians (72.5%), and seminars (72.5%). Graduates favored a variety of approaches. Regarding topics to include in a leadership curriculum, PDs responded that communication skills (97.5%), team building (95.0%), professional skills (90.0%), clinic management (87.5%), strategies to impact the delivery of endocrinology care (85.0%), and personality skills (82.5%) were most important. Graduates responded similarly, with >80% agreement for each topic. Finally, most PDs (89%) expressed a desire to incorporate more leadership training into their programs. Conclusions: Our survey suggests a need for leadership training in endocrinology fellowships. More work is needed to determine how best to meet this need. PMID- 29264476 TI - A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia. AB - Context: Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency (CAH21) is most often diagnosed by newborn screening. The classic parameter studied is 17-hydroxy-progesterone, but the positive predictive value for the diagnosis of CAH is low in full-term newborns and even lower in preterm newborns. Objective: To evaluate the diagnostic utility of simultaneously quantifying a large number of steroids by using liquid chromatography/tandem mass spectrometry (LC-MS/MS) from a small serum volume in patients with CAH, particularly during the neonatal period. Setting and participants: LC-MS/MS was applied to sera from patients with CAH who had a classic form (n = 48) and rare forms (n = 2) of 21-hydroxylase deficiency, normal preterm (n = 10) and normal full-term (n = 20) neonates, and young patients without CAH (non-CAH; n = 149) but with various other diseases (delayed or advanced puberty, hirsutism, pubarche, adrenarche, simple growth retardation). Methods: Sixteen steroids (glucocorticoids, mineralocorticoids, androgens, Delta5-steroids) were analyzed in 150 uL of serum by LC-MS/MS. Results: An LC-MS/MS serum steroid profile was developed and validated to provide a reliable etiologic diagnosis of CAH. The serum levels of 17OH-progesterone and 21 deoxycortisol in non-CAH are reported, along with the rarely assayed 21-deoxycorticorticosterone and 11beta hydroxy Delta4-androstenedione, which will aid in the diagnosis of CAH21. In addition, serum levels of mineralocorticoids, androgens, and Delta5-steroids allowed investigation of other forms of CAH. Conclusion: This steroid LC-MS/MS approach on a small serum volume is well suited for pediatrics, particularly neonatal medical practice, to aid in the diagnosis and monitoring of various forms of CAH. PMID- 29264477 TI - Differential Effects of Estrogen on Corticosteroid-Binding Globulin Forms Suggests Reduced Cleavage in Pregnancy. AB - Corticosteroid-binding globulin (CBG) is secreted as high-affinity CBG (haCBG), which may be cleaved by tissue proteases to low-affinity CBG (laCBG), releasing free cortisol. Pregnancy and the estrogen-based combined oral contraceptive pill (COCP) increase CBG concentrations twofold to threefold. The relative effects of these two hyperestrogenic states on the CBG affinity forms are unknown. We performed an observational study in 30 pregnant women, 27 COCP takers and 23 controls. We analyzed circulating total CBG, haCBG, laCBG, and free and total cortisol concentrations. In pregnancy, total CBG and haCBG were increased compared to controls (both P < 0.0001); however, laCBG concentrations were similar. In COCP takers, total CBG and haCBG were increased [802 +/- 41 vs compared to controls (both P < 0.0001)], but laCBG was also increased (P = 0.03). Pregnancy and use of COCP were associated with a comparable rise in haCBG, but laCBG was lower in pregnancy (P < 0.0001). These results were consistent with an estrogen-mediated increase in CBG synthesis in both hyperestrogenemic states but with reduced CBG cleavage in pregnancy relative to the COCP, perhaps due to pregnancy-induced CBG glycosylation. Speculatively, increased circulating haCBG concentrations in pregnancy may provide an increased reservoir of CBG-bound cortisol to prepare for the risk of puerperal infection or allow for cortisol binding in the face of competition from increased circulating progesterone concentrations. PMID- 29264478 TI - Identifying Incomplete Atypical Femoral Fractures With Single-Energy Absorptiometry: Declining Prevalence. AB - Background: Atypical femur fractures (AFFs) are associated with long-term bisphosphonate (BP) therapy. Early identification of AFF prior to their completion provides an opportunity to intervene, potentially reducing morbidity associated with these fractures. Single-energy X-ray absorptiometry (SE) is an imaging method recently shown to detect incomplete AFF (iAFF) prior to fracture completion. Methods: Between May 2013 and September 2014, we assessed 173 patients who had been prescribed BP therapy for >5 years for iAFF using SE at their presentation for routine bone mineral density testing. We compared these findings with those of our previously published prospective study (n = 257) in which the femur was imaged for iAFF using dual-energy X-ray absorptiometry. In addition, we estimated the yearly prevalence of complete AFF among patients with subtrochanteric fracture at our institution from 2006 to 2014, and we evaluated prescribing trends for BP in Ireland from 2009 to 2014. Results: No patients had iAFF using SE femur compared with a prevalence of 2.7% in the earlier study. Between 2006 and 2014, we observed a rise and decline in AFFs at our hospital and a similar national trend in BP prescribing. Conclusions: AFFs appear to be decreasing. New customized scan modes of dual-energy X-ray absorptiometry systems, which visualize the entire femur at high image quality and take measurements, have the potential to identify iAFF prior to fracture completion and to ascertain those at highest risk of AFF. PMID- 29264480 TI - Rescue of Graves Thyrotoxicosis-Induced Cholestatic Liver Disease Without Antithyroid Drugs: A Case Report. AB - Graves thyrotoxicosis rarely presents with painless jaundice resulting from hyperthyroidism-associated hepatotoxicity, without preexisting liver disease. Management in patients with this presentation is challenging, given that the thionamides, methimazole and propylthiouracil, have both been associated with drug-induced liver injury. Radioactive iodine ablation and thyroidectomy are well established alternatives, but each have their associated risks and contraindications. We present an unusual case of severe hyperthyroidism associated hepatotoxicity, in which adjuvant therapies, including glucocorticoids, saturated solution of potassium iodide, and cholestyramine, were used as a bridge to definitive therapy with thyroidectomy. PMID- 29264479 TI - Cabergoline Tapering Is Almost Always Successful in Patients With Macroprolactinomas. AB - Context: Cabergoline (CAB) is very effective in the treatment of macroprolactinomas, but there are few data on the CAB dose necessary to achieve and maintain normal prolactin (PRL) levels. Design and Patients: We retrospectively studied 260 patients. CAB was introduced at a mean dose of 0.83 +/- 0.52 mg/wk. When the PRL level had normalized, the patient's physician chose to either maintain the CAB dose (fixed-dose group) or to taper it (de-escalation group) until the minimal effective dose required to maintain a normal PRL level was established. Results: PRL normalized in 157 patients (60.8%) during CAB treatment. CAB de-escalation was attempted in 84 (53.5%) of these 157 patients and was successful in 77 (91.7%) cases. The mean CAB dose was reduced from 1.52 +/- 1.17 mg/wk to 0.56 +/- 0.44 mg/wk at the last visit (P < 1 * 10-4). De escalation was also possible in some "CAB-resistant" patients, namely those requiring >=2 mg/wk to normalize PRL. CAB de-escalation had no negative long-term effect on tumor size. At the last visit, maximal diameter was 8.8 +/- 8.8 mm in the de-escalation group and 13.4 +/- 8.5 mm in the fixed-dose group (P < 0.01). Conclusion: In patients with macroprolactinomas, the CAB dosage required to maintain a normal PRL level long term is lower than the initial dosage necessary to normalize the PRL level. After PRL normalization, CAB tapering was almost always successful, even when very high initial doses were necessary. CAB tapering does not undermine tumor control and may attenuate the potential adverse effects of CAB, which appear to be dependent on the cumulative dose. PMID- 29264481 TI - Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone. AB - Context: Adrenal insufficiency (AI) is an important medical concern for clinicians when normocortisolemia is achieved during treatment of endogenous Cushing syndrome (CS). Objective: To examine symptoms of potential AI in a large population of normocortisolemic patients without CS treated with mifepristone, a glucocorticoid receptor antagonist indicated for the treatment of patients with CS. Methods: We conducted a pooled safety analysis of five phase 3, placebo controlled clinical trials of normocortisolemic adults without CS but diagnosed with psychotic depression (n = 1460). Patients were treated with once-daily mifepristone 300 mg (n = 110), 600 mg (n = 471), or 1200 mg (n = 252), or placebo (n = 627) administered for 7 consecutive days. All study investigators were trained and instructed to assess for the development of AI and to report all adverse events (AEs) at each clinic visit. The incidence of (1) AI or similar terminologies and that of (2) >=3 concurrent symptoms that could be associated with AI was evaluated. Results: Mean serum cortisol and adrenocorticotropic hormone levels increased dose dependently with mifepristone treatment. There were no reports of AI and no significant differences between the mifepristone-treated and placebo groups in the incidence of patients having >=3 AEs that could be associated with AI. Conclusions: This large pooled analysis of normocortisolemic patients without CS found no cases of AI and no differences between mifepristone therapy and placebo in the incidence of symptom combinations mimicking AI, even at the highest (1200 mg) dose. These findings further add clinically important insights to the safety and tolerability profile of mifepristone therapy. PMID- 29264482 TI - Update on Glucose Management Among Noncritically Ill Patients Hospitalized on Medical and Surgical Wards. AB - Hyperglycemia is a common issue affecting inpatient care. Although this is in part because of the higher rate of hospitalization among patients with preexisting diabetes, multiple factors complicate inpatient glucose management, including acute stress from illness or surgery, erratic dietary intake, and contribution of medications. It has been repeatedly demonstrated that poorly controlled blood glucose levels are associated with negative clinical outcomes, such as increased mortality, higher rate of surgical complications, and longer length of hospital stay. Given these concerns, there has been extensive study of the optimal strategy for management of glucose levels, with the bulk of existing literature focusing on insulin therapy in the intensive care unit setting. This review shifts the focus to the general adult medical and surgical wards, using clinical guidelines and sentinel studies to describe the scientific basis behind the current basal-bolus insulin-based approach to blood sugar management among noncritically ill inpatients. Patient-centered clinical trials looking at alternative dosing regimens and insulin analog and noninsulin agents, such as glucagon-like peptide-1 agonist therapies, introduce safe and effective options in the management of inpatient hyperglycemia. Data from these studies reveal that these approaches are of comparable safety and efficacy to the traditional basal bolus insulin regimen, and may offer additional benefit in terms of less monitoring requirements and lower rates of hypoglycemia. Although existing data are encouraging, outcome studies will be needed to better establish the clinical impact of these more recently proposed approaches in an effort to broaden and improve current clinical practices in inpatient diabetes care. PMID- 29264483 TI - Information Transfer via Gonadotropin-Releasing Hormone Receptors to ERK and NFAT: Sensing GnRH and Sensing Dynamics. AB - Information theoretic approaches can be used to quantify information transfer via cell signaling networks. In this study, we do so for gonadotropin-releasing hormone (GnRH) activation of extracellular signal-regulated kinase (ERK) and nuclear factor of activated T cells (NFAT) in large numbers of individual fixed LbetaT2 and HeLa cells. Information transfer, measured by mutual information between GnRH and ERK or NFAT, was <1 bit (despite 3-bit system inputs). It was increased by sensing both ERK and NFAT, but the increase was <50%. In live cells, information transfer via GnRH receptors to NFAT was also <1 bit and was increased by consideration of response trajectory, but the increase was <10%. GnRH secretion is pulsatile, so we explored information gained by sensing a second pulse, developing a model of GnRH signaling to NFAT with variability introduced by allowing effectors to fluctuate. Simulations revealed that when cell-cell variability reflects rapidly fluctuating effector levels, additional information is gained by sensing two GnRH pulses, but where it is due to slowly fluctuating effectors, responses in one pulse are predictive of those in another, so little information is gained from sensing both. Wet laboratory experiments revealed that the latter scenario holds true for GnRH signaling; within the timescale of our experiments (1 to 2 hours), cell-cell variability in the NFAT pathway remains relatively constant, so trajectories are reproducible from pulse to pulse. Accordingly, joint sensing, sensing of response trajectories, and sensing of repeated pulses can all increase information transfer via GnRH receptors, but in each case the increase is small. PMID- 29264484 TI - A Case of Congenital Hypopituitarism Associated With a 1p31 Microdeletion: A Possible Role for LEPR and JAK1. AB - Context: Genetic defects affecting the expression and function of factors involved in pituitary development have been found to be associated with congenital hypopituitarism (CH). However, for most cases of CH, the etiology remains unknown. Case Description: We present an unusual case of an infant with CH, associated with septo-optic dysplasia with an absent anterior pituitary and an ectopic posterior pituitary gland, resulting from a de novo 8.04-Mb interstitial deletion of chromosome 1p31.1-1p31.3. The deleted region includes several genes that might be involved in pituitary development, including LEPR and JAK1. Conclusions: Haploinsufficiency of LEPR and/or JAK1 might be associated with CH. This finding suggests a role for LEPR-mediated glycoprotein 130 signaling in human pituitary development. PMID- 29264485 TI - Blood Smear in a Patient With Very Severe Hypertriglyceridemia. AB - The existence of multiple small fat droplets on the erythrocytes at peripheral blood smear is a very important characteristic in patients with very severe hypertriglyceridemia. PMID- 29264486 TI - Restoring Radioiodine Uptake in BRAF V600E-Mutated Papillary Thyroid Cancer. AB - This image illustrates a multimodal therapeutic strategy for an iodine-refractory BRAF-mutated metastatic papillary thyroid carcinoma with reversed radioiodine resistance using BRAF inhibitors. PMID- 29264487 TI - Proteomics of Children Born After Intracytoplasmic Sperm Injection Reveal Indices of an Adverse Cardiometabolic Profile. AB - Context: Assisted reproduction technologies (ART), classic in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) are increasingly used. Several studies have demonstrated an unfavorable cardiometabolic profile of the ART offspring. Proteomics is a state-of-the-art technology used for the identification of early biomarkers of disease. Objectives: To investigate the proteomic profile of children born after ICSI compared with naturally conceived (NC) controls in search of cardiometabolic risk markers. Design: Cross-sectional case-control study: qualitative, comparative proteomic plasma analysis. Setting: Pediatric Endocrinology and IVF Outpatient Clinics, University of Athens and the Biomedical Research Foundation of the Academy of Athens. Participants: Forty-two sex- and age-matched couples of ICSI and NC children were assessed. Ten pairs additionally matched for birth weight and twin/single pregnancies were submitted to proteomic analysis. Intervention: Medical history, clinical examination, and blood biochemical, hormonal, and proteomic analyses. Main Outcome Measures: (1) Differences in auxological and laboratory data between groups. (2) Differences in plasma proteomic profile in 10 individual pairs and pooled samples. Results: The ICSI group had shorter gestation, more cesarean sections, smaller birth weight/length, and advanced maternal age. No major differences were observed regarding biochemical markers. Proteomic analysis revealed 19 over- and three underexpressed proteins in ICSI. Most overexpressed proteins are implicated in acute-phase reaction, blood coagulation, complement pathway activation, and iron and lipid metabolism, suggesting a subclinical unfavorable cardiometabolic profile. Conclusions: This study applies proteomics in ICSI-conceived children, providing evidence for an early adverse cardiometabolic profile and supporting the necessity of their long-term monitoring. PMID- 29264488 TI - Effect of Testosterone Treatment on Adipokines and Gut Hormones in Obese Men on a Hypocaloric Diet. AB - Context: In obese men with lowered testosterone levels, testosterone treatment augments diet-associated loss of body fat. Objective: We hypothesized that testosterone treatment modulates circulating concentrations of hormonal mediators of fat mass and energy homeostasis in obese men undergoing a weight loss program. Design: Prespecified secondary analysis of a randomized, double-blind, placebo controlled trial. Setting: Tertiary referral center. Participants: Obese men (body mass index >=30 kg/m2) with a repeated total testosterone level <=12 nmol/L. Intervention: One hundred participants mean age 53 years (interquartile range 47 to 60 years) receiving 10 weeks of a very low-energy diet followed by 46 weeks of weight maintenance were randomly assigned at baseline to 56 weeks of intramuscular testosterone undecanoate (cases, n = 49) or matching placebo (controls, n = 51). Eighty-two men completed the study. Main outcomes: Between group differences in leptin, adiponectin, ghrelin, glucagon like peptide-1, gastric inhibitory polypeptide, peptide YY, pancreatic polypeptide, and amylin levels. Results: At study end, compared with controls, cases had greater reductions in leptin [mean adjusted difference (MAD), -3.6 ng/mL (95% CI, -5.3 to -1.9); P < 0.001]. The change in leptin levels between cases and controls was dependent on baseline fat mass, as the between-group difference progressively increased with increasing fat mass [MAD, -0.26 ng/mL (95% CI, -0.31 to -0.26); P = 0.001 per 1 kg of baseline fat mass]. Weight loss-associated changes in other hormones persisted during the weight maintenance phase but were not modified by testosterone treatment. Conclusions: Testosterone treatment led to reductions in leptin beyond those achieved by diet-associated weight loss. Testosterone treatment may reduce leptin resistance in obese men. PMID- 29264489 TI - Mutational Analysis of ZFY in Sporadic Parathyroid Adenomas. AB - Context: The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood, with alterations in cyclin D1/PRAD1 and MEN1 most firmly established as genetic drivers. The gene encoding the X-linked zinc finger protein (ZFX) has recently been implicated in the pathogenesis of a subset of parathyroid adenomas after recurrent, hotspot-focused somatic mutations were identified. ZFX escapes X inactivation and is transcribed from both alleles in women, and a highly homologous gene encoding the Y-linked zinc finger protein (ZFY) provides dosage compensation in males. Objective: We sought to investigate the role of ZFY mutation in sporadic parathyroid adenoma. Intervention: Polymerase chain reaction and Sanger sequencing were used to examine DNA from typically presenting, sporadic (nonfamilial, nonsyndromic) parathyroid adenomas from male patients for mutations within the ZFY gene. Results: No mutations were identified among 117 adenomas. Conclusions: The absence of ZFY mutations in this series suggests that ZFY rarely, if ever, acts as a driver oncogene in sporadic parathyroid adenomas. The apparent differences in tumorigenic capabilities between the closely related zinc finger proteins ZFX and ZFY suggest that structure-function studies could represent an opportunity to gain insight into neoplastic processes in the parathyroid glands. PMID- 29264490 TI - Beneficial Outcomes of Sleeve Gastrectomy in a Morbidly Obese Patient With Bardet Biedl Syndrome. AB - Context: Severe obesity is one of the major features of Bardet-Biedl syndrome (BBS) and causes reduced life expectancy. Bariatric surgery is an effective treatment of morbid obesity. Data on the effect of bariatric surgery for monogenic obesity is essentially lacking. We present the clinical and metabolic 3 year follow-up of sleeve gastrectomy in a BBS patient. Case Description: A 37 year-old obese woman with BBS (body mass index, 40 kg/m2) was referred to our clinic for uncontrolled diabetes, dyslipidemia, hypertension, and nonalcoholic fatty liver disease (NAFLD). After sleeve gastrectomy, progressive weight loss was observed, with a 32% total weight loss at 3-year follow-up. Glycemic control and NAFLD improved significantly. Blood pressure normalized, and treatment was discontinued 3 months after surgery. Conclusions: Laparoscopic sleeve gastrectomy can be a safe and effective treatment of morbid BBS-related obesity in adult patients. Significant and sustained weight loss leads to the improvement of several obesity-related comorbidities such as diabetes, hypertension, and NAFLD, as in polygenic obesity. Further data are needed to confirm the long-term efficacy and safety of bariatric surgery in BBS. PMID- 29264491 TI - Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Induces Long-Lasting Changes in Liver Metabolism in Male Mice. AB - Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers. The generations born when environmental concentrations of PBDEs reached their maximum account in the United States for one-fifth of the total population. We hypothesized that exposure to PBDEs during sensitive developmental windows might result in long-lasting changes in liver metabolism. The present study was based on experiments with CD-1 mice and human hepatocellular carcinoma cells (human hepatoma cell line, HepG2). Pregnant mice were exposed to 0.2 mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. The metabolic health-related outcomes were analyzed on postnatal day 21 and postnatal week 20 in male offspring. Several groups of metabolic genes, including ribosomal and mitochondrial genes, were significantly upregulated in the liver at both points. Genes regulated via mechanistic target of rapamycin (mTOR) pathway, the gatekeeper of metabolic homeostasis, were whether up- or downregulated at both measurement points. On postnatal day 21, but not week 20, both mTOR complexes in the liver were activated, as measured by phosphorylation of their targets. mTOR complexes were also activated by BDE-47 in HepG2 cells in vitro. The following changes were observed at week 20: a decreased number of polyploid hepatocytes, suppressed cytoplasmic S6K1, twofold greater blood insulin-like growth factor-1 and triglycerides, and 2.5-fold lower expression of fatty acid uptake membrane receptor CD36 in liver tissue. Thus, perinatal exposure to environmentally relevant doses of BDE-47 in laboratory mice results in long-lasting changes in liver physiology. Our evidence suggests involvement of the mTOR pathway in the observed metabolic programming of the liver. PMID- 29264492 TI - The Use of Resveratrol as an Adjuvant Treatment of Pain in Endometriosis: A Randomized Clinical Trial. AB - Context: Resveratrol has been used for the treatment of endometriosis. Objective: To compare resveratrol (40 mg/d) with monophasic contraceptive pill (COC) to COC with placebo for the reduction of pain scores. Design: A randomized clinical trial. Setting: University Hospital. Patients: Women (ages 20 to 50) with laparoscopic diagnosis of endometriosis were eligible for the study. Exclusion criteria: pregnancy, allergy to resveratrol, or contraindications to COC, use of agonists of gonadotropin release hormone or danazol in the last month, or had used depot medroxyprogesterone acetate or Mirena(r). Intervention: Subjects were randomized using a computer-generated randomization list to receive COC for 42 days to be taken with identical capsules containing 40 mg of resveratrol or placebo in coded bottles (1:1 ratio). Allocation was concealed in coded, sequenced, opaque-sealed envelopes. Main Outcome: Median pain scores measured with a visual analog scale on day 42. Results: Between 18 June and 6 November 2015, 44 subjects were enrolled. Mean [95% confidence interval (CI)] pain scores on day 0 were 5.4 (4.2 to 6.6) in the placebo group and 5.7 (4.8 to 6.6) in resveratrol groups. After treatment, pain values were [3.9 (2.2 to 5); n = 22] and [3.2 (2.1 to 4.3); n = 22] in the placebo and resveratrol groups, respectively (P = 0.7; Mann-Whitney U test). Median (95% CI) difference between groups was 0.75 (-1.6 to 2.3). Conclusion: Resveratrol is not superior to placebo for treatment of pain in endometriosis. PMID- 29264493 TI - Concurrent Intrathyroidal Thyroid Cancer and Thyroid Cancer in Struma Ovarii: A Case Report and Literature Review. AB - Context: The presence of differentiated thyroid cancer in mature cystic teratomas in the ovaries is rare, and usually incidentally found on surgical pathology specimens. We present a case of simultaneous intrathyroidal thyroid cancer and thyroid cancer within a struma ovarii, presenting specific diagnostic challenges. Case Description: A 55-year-old woman had an intrathyroidal, encapsulated 1.2-cm papillary thyroid carcinoma, follicular variant, which was resected. Laboratory studies showed an elevated thyroglobulin level of 35 ng/mL while on suppressive levothyroxine therapy. During preparation for radioactive iodine ablation, thyroglobulin increased dramatically to 3490 ng/mL. A pretreatment whole-body scan showed residual tracer uptake in the thyroid bed and increased radiotracer uptake in the pelvis that raised concern for a pelvic metastasis, given the marked thyroglobulin elevation. After ablation, the posttreatment scan showed intense focal uptake in the pelvis. Single-photon emission computed tomography computed tomography confirmed that the tracer uptake corresponded to a right adnexal mass. The patient underwent a laparoscopic bilateral salpingo oophorecotomy with pelvic washings. The final pathology of the right ovary showed papillary thyroid carcinoma arising in a mature cystic teratoma. In addition, there was abundant normal thyroid tissue with colloid surrounding the carcinoma, indicating a source for the dramatic rise in thyroglobulin levels and suggesting that the ovarian papillary thyroid cancer arose within the teratoma and was not metastatic disease. Thyroglobulin measurements have been undetectable for 5 years since surgery and radioiodine treatment. Conclusions: Concurrent intrathyroidal thyroid cancer and differentiated thyroid cancer in struma ovarii are very rare, but can often be distinguished on clinical grounds. PMID- 29264494 TI - A Case of Adrenal Vein Sampling in Primary Aldosteronism With Homolateral Suppression. AB - Context: Adrenal venous sampling (AVS) is regarded as the gold standard for diagnosis of primary aldosteronism (PA) subtypes, although some authors have questioned its diagnostic accuracy and highlighted the lack of standardized procedure protocols and interpretation criteria for AVS. In particular, the usefulness of cosyntropin stimulation and benefit of superselective adrenal vein catheterization have been hotly debated. Objective: We report a case that highlights the potential pitfalls of superselective sampling and demonstrates a negligible effect of cosyntropin stimulation on aldosterone secretion in nonadenomatous adrenal tissue when an aldosterone-producing adenoma (APA) is present. Intervention and Results: A 38-year-old man with PA and a single right macroadenoma underwent AVS at our center. The procedure was performed both under basal conditions and during cosyntropin stimulation. Right adrenal vein angiography demonstrated two branches of the main adrenal vein trunk, one draining the nodule and one draining the right adrenal gland. Hormonal assays confirmed adrenal origin of left-sided and all right-sided samples, and were consistent with lateralization on the right side, with suppression of aldosterone secretion in the left adrenal gland and in the nonadenomatous right adrenal tissue. Cosyntropin-stimulated AVS results were similar to those of the unstimulated procedure. Conclusions: Cosyntropin stimulation does not significantly affect aldosterone secretion from nonadenomatous adrenal tissue when an APA is present and can therefore be used during AVS for PA. Superselective AVS should be performed with caution and interpreted by expert clinicians. PMID- 29264495 TI - Lack of Influence of Calcium/Phosphorus Ratio on Hip and Lumbar Bone Mineral Density in Older Americans: NHANES 2005-2006 Cross-Sectional Data. AB - Objectives: We sought to ascertain the effect of a low dietary calcium/phosphorus (Ca:P) ratio on the bone health of older adults in the United States. The present analysis assessed whether a high dietary consumption of P, which generally leads to a low dietary Ca:P ratio, has an unfavorable effect on the bone mineral density (BMD) of the hip and lumbar vertebrae in a representative sample of older US men and women. Design: For the 1228 men and women aged 50 to 70 and >=71 years included in the National Health and Nutrition Examination Survey (NHANES) 2005 to 2006 cycle, quintiles of the dietary Ca:P ratio were tested for their association with hip and lumbar BMD after adjusting for body mass index (BMI). All data in this observational study were cross-sectional. Results: Women typically have higher dietary Ca:P ratios than men and lower BMDs. No trend emerged for any age or sex group when studying the relationship between the dietary Ca:P ratio and BMD with adjustment for BMI. Conclusions: A wide range of dietary Ca:P ratios in the diets of a cross-section of older adult men and women in the United States had little effect on the BMD of the hip (proximal femur) or the lumbar vertebrae (spine), even among those consuming large amounts of Ca supplements. Despite the lack of complete assessment of total P intake in the United States, these results suggest that high P consumption patterns and low dietary Ca:P ratios do not exert an adverse effect on BMD at major fracture sites in older adults. PMID- 29264496 TI - Prevalence and Correlation of Hypothyroidism With Pregnancy Outcomes Among Lebanese Women. AB - Purpose: Assessment of hypothyroidism prevalence and clinical significance among pregnant women in Lebanon. Methods: We performed a single-center retrospective cohort study at the American University of Beirut Medical Center. Clinical, demographic, and laboratory data were collected and analyzed using trimester specific ranges for hypothyroidism. Results: Of 920 pregnant women, 17% had hypothyroidism during gestation. A history of previous miscarriage and morbid obesity were associated with hypothyroidism during pregnancy. Pregnant women with hypothyroidism were more likely to experience a miscarriage during the first trimester [odds ratio, 2.9; 95% confidence interval, (1.13 to 7.5); P = 0.02] and delivery at post-term (odds ratio, 3.9; 95% confidence interval, 1.05 to 14.9; P = 0.05). We found no substantial correlation with preterm or premature delivery, cesarean section delivery, or gestational hypertension despite increased odds among the hypothyroidism group. No substantial differences were found with respect to the fetal outcomes between the control and hypothyroidism groups. Conclusions: Hypothyroidism is prevalent in 17% of pregnant women in Lebanon and was associated with a history of miscarriage and morbid obesity. The presence of hypothyroidism correlated with miscarriage during the first trimester and with post-term delivery. Despite the lack of sufficient data supporting the efficacy of treatment of hypothyroidism during gestation, more studies should be conducted to assess the effect of hypothyroidism on gestational and fetal outcomes. PMID- 29264497 TI - Soy Protein Improves Cardiovascular Risk in Subclinical Hypothyroidism: A Randomized Double-Blinded Crossover Study. AB - Background: Soy protein with isoflavones appears to have an adverse effect on thyroid function, but it is not known whether it is the protein or isoflavone component that is deleterious. The effect of isoflavone-free soy on thyroid function was determined in patients with subclinical hypothyroidism, with a secondary aim of assessing its effect on cardiovascular risk indices. Methods: This was a randomized, double-blind, crossover study involving 80 patients with subclinical (compensated) hypothyroidism. Patients were randomly assigned to either isolated soy (isoflavone-free) protein (SP) or casein protein (CP) supplementation for 8 weeks, washed out for 8 weeks, and then crossed over for a further 8-week period. Results: Thyroid function was unaffected by either a SP or CP. There were significant decreases in fasting glucose (4.7 +/- 0.6 vs 5.5 +/- 1.4, P < 0.01), insulin resistance (3.3 +/- 3.0 vs 3.8 +/- 3.4, P = 0.05), total cholesterol (4.4 +/- 0.9 vs 5.3 +/- 1.2, P < 0.01), triglycerides (0.9 +/- 0.5 vs 1.7 +/- 0.9, P < 0.1), and highly sensitive C-reactive protein (hsCRP; 0.8 +/- 0.7 vs 2.6 +/- 2.8, P < 0.01) in the SP group compared with the CP group. Blood pressure, low-density lipoprotein, and high-density lipoprotein remained unchanged in both groups. Conclusion: SP alone had no effect on thyroid function in patients with subclinical hypothyroidism and resulted in a significant reduction in fasting glucose, insulin resistance, total cholesterol, triglycerides, and hsCRP compared with CP. PMID- 29264498 TI - A Somewhat Bizarre Case of Graves Disease Due to Vitamin Treatment. AB - Context: Accurate measurements of circulating hormones is essential for the practice of endocrinology. Immunometric assays employing the streptavidin-biotin system are widely used to measure hormones. However, these assays are susceptible to interference in patients taking biotin supplementations. This interference could mimic a coherent hormone profile, leading to misdiagnosis and unnecessary treatment. Case description: The patient, a 32-year-old man with X-linked adrenomyeloneuropathy recently diagnosed with Graves disease, was referred to our department to evaluate his response to antithyroid drugs. His thyroid function tests were still consistent with hyperthyroidism while he had been receiving carbimazole 40 mg/d for 6 weeks. We found no signs of thyrotoxicosis on physical examination despite the "frank and severe" biochemical hyperthyroidism. Noticing that all the patient's assays had been done at the same laboratory, we suspected assay interference. We therefore repeated the thyroid function tests at our hospital laboratory, which uses a different assay platform. Surprisingly, all the results were normal, confirming assay interference. The patient was taking an investigational "vitamin" therapy, which turned out to be biotin, prescribed at a dose of 100 mg tid as part of a trial of high-dose biotin in X-linked adrenomyeloneuropathy. Conclusions: This case should encourage physicians to ask their patients about possible biotin intake, especially when laboratory results are not compatible with clinical findings. If biotin interference is suspected, we propose either using a different assay not based on the streptavidin-biotin system or repeating the analyses after stopping biotin supplementation for one week. PMID- 29264499 TI - F2-Isoprostanes Reflect Oxidative Stress Correlated With Lean Mass and Bone Density but Not Insulin Resistance. AB - Context: F2-isoprostanes (F2-isoPs) are biomarkers for oxidative stress in humans and have been shown to be elevated in obesity, cardiovascular disease, and diabetes. Therefore, F2-isoPs are often implicated in oxidative stress contributing to insulin resistance, although this has not been rigorously examined. Objective: To determine whether urinary F2-isoPs are predictive of insulin sensitivity and other clinical metabolic parameters. Participants: Sedentary, weight-stable, nondiabetic adults equilibrated on a standard isocaloric diet. Main Outcome Measures: Insulin sensitivity via hyperinsulinemic euglycemic clamp, urinary F2-isoPs by gas chromatography-mass spectrometry, and body composition by dual-energy x-ray absorptiometry. Results: No correlation was found between 15-F2t-IsoP nor its major metabolite, 2,3-dinor-5,6-dihydro-15-F2t IsoP, with insulin sensitivity, even after adjusting for age, race, sex, BMI, and smoking status. 15-F2t-IsoP was also not associated with body fat. However, there was a strong negative correlation between 15-F2t-IsoP and lean body mass (LBM; r = -0.46, P = 0.0001), bone mineral content (BMC; r = -0.58, P < 0.0001), bone mineral density (BMD; r = -0.65, P < 0.0001), and skeletal muscle protein 4 hydroxynonenal (4-HNE; r = -0.54, P = 0.0239), another marker of oxidative stress. 15-F2t-IsoP was also positively associated with circulating triglycerides and total cholesterol, and increased as a function of age. Conclusions: Urinary 15-F2t-IsoP and its major metabolite are not associated with insulin sensitivity, suggesting the lipid peroxidation process that produces F2-isoPs does not reflect oxidative stress reactions operative in insulin resistance. However, urinary F2 isoPs were negatively correlated with LBM, BMC, BMD, and muscle 4-HNE. Because lean and bone mass decline as a function of biological aging, F2-isoPs may reflect the oxidative stress operative in the aging process. PMID- 29264500 TI - Systemic Glucoregulation by Glucose-Sensing Neurons in the Ventromedial Hypothalamic Nucleus (VMH). AB - The ventromedial hypothalamic nucleus (VMH) regulates glucose production in the liver as well as glucose uptake and utilization in peripheral tissues, including skeletal muscle and brown adipose tissue, via efferent sympathetic innervation and neuroendocrine mechanisms. The action of leptin on VMH neurons also increases glucose uptake in specific peripheral tissues through the sympathetic nervous system, with improved insulin sensitivity. On the other hand, subsets of VMH neurons, such as those that express steroidogenic factor 1 (SF1), sense changes in the ambient glucose concentration and are characterized as glucose-excited (GE) and glucose-inhibited (GI) neurons whose action potential frequency increases and decreases, respectively, as glucose levels rise. However, how these glucose-sensing (GE and GI) neurons in the VMH contribute to systemic glucoregulation remains poorly understood. In this review, we provide historical background and discuss recent advances related to glucoregulation by VMH neurons. In particular, the article describes the role of GE neurons in the control of peripheral glucose utilization and insulin sensitivity, which depend on mitochondrial uncoupling protein 2 of the neurons, as well as that of GI neurons in the control of hepatic glucose production through hypoglycemia-induced counterregulatory mechanisms. PMID- 29264501 TI - Fatty Liver Disease, Women, and Aldosterone: Finding a Link in the Jackson Heart Study. AB - Context: Fatty liver disease is one of the most common forms of chronic liver disease. The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of fatty liver. Objective: Determine the relationship between fatty liver and aldosterone in a large cohort study. Design: Community-based, observational cohort study of African Americans. Setting: The original Jackson Heart Study cohort enrolled African American participants from the Jackson, Mississippi, metropolitan area in Hinds, Madison, and Rankin Counties. Participants: Our study population consisted of 2507 Jackson Heart Study participants (1625 women and 882 men) who had liver attenuation measured per computed tomography scans, had aldosterone measurements, and were not taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or mineralocorticoid receptor antagonists. Intervention: There was no intervention. Main outcome measure: Liver attenuation on computed tomography scans. Results: Univariate regression analysis demonstrated a statistically significant correlation between aldosterone levels and liver attenuation. Each doubling of aldosterone was associated with 1.08 Hounsfield unit decrease (95% confidence interval, 1.47 to -0.69, P < 0.001). A multivariable model adjusted for body mass index, age, alcohol intake, and homeostatic model assessment of insulin resistance determined that the association was statistically significant only for women. Conclusion: Our data demonstrate a positive association between aldosterone levels and fatty liver in African American women. PMID- 29264502 TI - Effect of Vitamin D on Thyroid Autoimmunity: A Randomized, Double-Blind, Controlled Trial Among Ethnic Minorities. AB - Context: Autoimmune thyroid disorders have been linked to vitamin D deficiency, but an effect of vitamin D supplementation is not established. Objective: Our objective was to test whether vitamin D compared with placebo could reduce thyroid autoantibodies. Design: Predefined additional analyses from a randomized, double-blind, placebo-controlled trial. Setting: The study was conducted in different community centers in Oslo, Norway. Participants: A total of 251 presumed healthy men and women, aged 18 to 50 years, with backgrounds from South Asia, the Middle East, and Africa were included. Intervention: Daily supplementation with 25 ug (1000 IU) vitamin D3, 10 ug (400 IU) vitamin D3, or placebo for 16 weeks. Outcome Measure: Difference in preintervention and postintervention antithyroid peroxidase antibody (TPOAb) levels. Additional outcomes were differences in thyroid-stimulating hormone (TSH) and free fraction of thyroxine (fT4). Results: There were no differences in change after 16 weeks on TPOAb (27 kU/L; 95% CI, -17 to 72; P = 0.23), TSH (-0.10 mU/L; 95% CI, -0.54 to 0.34; P = 0.65), or fT4 (0.09 pmol/L; 95% CI, -0.37 to 0.55; P = 0.70) between those receiving vitamin D supplementation or placebo. Mean serum 25(OH)D3 increased from 26 to 49 nmol/L in the combined supplementation group, but there was no change in the placebo group. Conclusion: Vitamin D3 supplementation, 25 ug or 10 ug, for 16 weeks compared with placebo did not affect TPOAb level in this randomized, double-blind study among participants with backgrounds from South Asia, the Middle East, and Africa who had low vitamin D levels at baseline. PMID- 29264503 TI - Rising Thyroid Cancer Incidence in Southern India: An Epidemic of Overdiagnosis? AB - Background: Thyroid cancer incidence is rising in high-income countries. This increase in disease burden is attributed to the phenomenon of overdiagnosis. Objective: We aimed to investigate trends in thyroid cancer rates in India, focusing on the state of Kerala in southern India, which has reported a high incidence of the disease. Design: Population-based study using data from the National Cancer Registry Program. Participants: We used data from the Population Based Cancer Registries for Thiruvananthapuram (capital of Kerala state), Delhi, Mumbai, Bangalore, and Chennai. We used data for three reporting periods from 2005 to 2014 (represented as 2006, 2009, and 2012). Main Outcome Measures: We reported the age-adjusted incidence rate (AARi) and mortality rate (AARm) per 100,000 women and the proportion of thyroid cancers diagnosed in females per 100 cancer cases. Results: During 2006, the AARi for thyroid cancer in women in Thiruvananthapuram was 6.9 per 100,000, rising to 10 in 2009 and 13.3 in 2012. There was a 93% increase in incidence rates over less than a decade. The AARis in the other four cities were stable. In 2012, Thiruvananthapuram had at least a fourfold higher incidence compared with other regions. Thyroid was the primary site in one of every 10 cancers diagnosed in Thiruvananthapuram, and large numbers of patients were <40 years of age. The AARm remained stable in all regions. Conclusion: We reported a high burden of thyroid cancer in Kerala, India, which is most likely due to overdiagnosis. PMID- 29264504 TI - Ethnicity of Patients With Germline GCM2-Activating Variants and Primary Hyperparathyroidism. AB - Context: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID). Objective: We investigated the ethnicity of individuals with germline variants in the GCM2 CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database. Design: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the GCM2 CCID region. Luciferase reporter assays were performed to determine the functional impact of GCM2 variants. Setting and Patients: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients. Results: The GCM2 p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with GCM2-activating variants often had multigland involvement or postoperative recurrent or persistent disease. Conclusions: Specific GCM2-activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT. PMID- 29264505 TI - Treatments to Prevent Bone Loss in Functional Hypothalamic Amenorrhea: A Systematic Review and Meta-Analysis. AB - Objective: We conducted a systematic review and meta-analysis of studies that evaluated the effect of hormonal therapy [estrogen therapy including oral contraceptive pills (OCP)] and bisphosphonates in preventing bone loss in patients with functional hypothalamic amenorrhea (FHA). Methods: We searched several electronic databases for controlled and noncontrolled studies that enrolled females of any age presenting with FHA (including athletic, weight loss, and stress-associated amenorrhea/oligomenorrhea) through 9 January 2017. The outcomes of interest were fractures and bone mineral density (BMD). Random effects meta-analysis was used to pool outcomes across studies expressed as weighted mean difference and 95% confidence interval (CI). Results: Nine studies reporting on 280 patients that received different hormonal therapies were included. We did not identify studies that evaluated bisphosphonates. Meta analysis demonstrated a statistically significant increase in BMD of the lumbar spine in patients receiving hormonal therapy after a median follow-up of 12 months (weighted mean difference, 0.032 g/cm2; 95% CI, 0.017 to 0.047; percentage change in BMD, 3.30%; 95% CI, 1.74 to 4.86). There was no substantial effect of receiving hormonal therapy on BMD of the femoral neck, trochanteric region, Ward triangle, or total body BMD. The quality of evidence was low because of the high risk of bias, imprecision (small sample size), and indirectness (as BMD is a surrogate outcome). None of the studies reported the incidence of fractures. Conclusion: The current evidence does not support using hormonal therapy for the sole purpose of improving bone health in patients with FHA. There are no data about bisphosphonates in this population. PMID- 29264506 TI - Health Care Burden in Patients With Adrenal Insufficiency. AB - Objective: This study aimed to estimate the annual health care burden for patients with adrenal insufficiency [AI; primary (PAI), secondary to pituitary disorder (PIT), and congenital adrenal hyperplasia (CAH)] using real-world data. Methods: Using a US-based payer database comprising >108 million members, strict inclusion criteria with diagnostic codes and pharmacy records were used to identify 10,383 patients with AI. This included 1014 patients with PAI, 8818 with PIT, and 551 with CAH, followed for >12 months. Patients were matched 1:1 to controls, based on age (+/-5 years), sex, insurance, and region. Multivariable expenditure models were estimated for each AI cohort vs controls as well as subsets by glucocorticoid therapy (hydrocortisone, dexamethasone, prednisone, or multiple therapies). A separate multivariable model was estimated to assess the association between adherence and expenditures. Results: Total annual health care expenditure estimates were significantly higher (P < 0.0001) in all AI cohorts compared with matched controls (PAI $18,624 vs $4320, PIT $32,218 vs $6956, CAH $7677 vs $4203). Patients with AI have more frequent inpatient hospital stays with up to eight to 10 times more days in the hospital per year than their matched controls. In each AI cohort, patients on multiple steroid therapies had higher expenditures in comparison with patients using hydrocortisone therapy alone. In PAI and PIT cohorts taking hydrocortisone only, fewer expenditures were found in higher adherence subsets. Conclusion: Patients with AI demonstrate a substantial annual health care burden. Expenditures vary by underlying cause and treatment and are reduced in patients with higher adherence to glucocorticoid replacement. PMID- 29264507 TI - Body Mass Index and Incident Type 1 and Type 2 Diabetes in Children and Young Adults: A Retrospective Cohort Study. AB - Context: Little is known about the association between obesity and temporal trends in the incidence of diabetes in children and young adults. Objective: We examined the recent incidence of types 1 and 2 diabetes in relation to a high body mass index (BMI) in UK children and young adults. Design: Cohort and nested case-control. Setting: A total of 375 general practices that contribute to the UK Clinical Practice Research Datalink (CPRD). Participants: A total of 369,362 participants aged 2 to 15 years at BMI measurement in CPRD from 1994 to 2013. Intervention: None. Main outcome measures: Incident type 1 diabetes (T1D) and type 2 diabetes (T2D) diagnoses up to age 25 years. Results: A total of 654 incident cases of T2D and 1318 T1D cases were found. The incidence of T2D per 100,000 persons annually increased from 6.4 in 1994 to 1998 to 33.2 in 2009 to 2013; and that for T1D increased from 38.2 to 52.1 per 100,000 persons during the same period. The incidence of T2D increased in both overweight (85th to 95th percentile for age- and sex-specific BMI; P = 0.01) and obese (>=95th percentile; P < 0.01) individuals from 1994 to 2013. Obese individuals, who constituted 47.1% of T2D cases, had a markedly greater risk of incident T2D [odds ratio, 3.75; 95% confidence interval (CI), 3.07 to 4.57], with an incidence rate ratio of 4.33 (95% CI, 3.68 to 5.08) compared with the normal BMI category. No positive linear association was found between obesity (greater BMI) and incident T1D cases. Conclusions: Increasing obesity has contributed to the increasing incidence of T2D but not T1D among UK children and young adults, with a fourfold greater risk of developing T2D in obese individuals. PMID- 29264508 TI - Increased Adrenal Androgens in Overweight Peripubertal Girls. AB - Context: Peripubertal hyperandrogenemia-a precursor to polycystic ovary syndrome is prominent in girls with obesity. Objective: We examined sources of overnight testosterone (T) and progesterone (P4) and potential sources of obesity associated hyperandrogenemia during puberty. Design: Cross-sectional. Setting: Research unit. Participants/Interventions: Fifty girls ages 7 to 18 years-both normal weight (NW) and overweight (OW)-underwent dexamethasone (DEX) suppression (1 mg orally; 10 pm) and cosyntropin stimulation testing (0.25 mg intravenously; 8 am the following day), with blood sampled before and 30 and 60 minutes after cosyntropin. Thirty-nine subjects receiving DEX had frequent blood sampling overnight (every 10 minutes from 10 pm to 7 am) and were compared with 70 historical controls who did not receive DEX. Outcomes: Random coefficient regression modeling assessed changes in hormone concentrations after DEX and cosyntropin. Results: NW early pubertal controls exhibited early morning increases in free T and P4 levels; NW and OW late pubertal controls exhibited early morning increases in P4. Such changes were not observed in subjects receiving DEX. Post-DEX morning free T levels were fourfold higher in OW vs NW late pubertal girls. Postcosyntropin changes in free T and androstenedione were both 2.3-fold higher in OW vs NW late pubertal girls. Conclusions: These data suggest that (1) overnight increases in free T and P4 concentrations in NW early pubertal girls and P4 concentrations in late pubertal girls are of adrenal origin and (2) OW late pubertal girls demonstrate elevated nonadrenal free T levels after DEX and exaggerated adrenal androgen (free T and androstenedione) responses to cosyntropin. PMID- 29264509 TI - Renal Transplant-Associated Thyroid Tuberculosis. AB - Tuberculosis is common among solid-organ transplant recipients, including renal transplants. Tuberculosis of the thyroid gland is a rare diagnosis. We report on a renal transplant recipient with subacute fever associated with a neck mass diagnosed as thyroid tuberculosis. No prior publication has reported a case of posttransplant thyroid tuberculosis. This is an important diagnostic consideration, in addition to malignant transformation, in the posttransplant setting. PMID- 29264510 TI - Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age. AB - Context: Testosterone (T) is a central androgenic hormone, and sex hormone binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men. Objective: To confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T. Design Patients: Groups differing in general and reproductive parameters: young men (n = 540; 19.3 +/- 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 +/- 6.0 years), and male partners of pregnant women (n = 324; 31.9 +/- 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia. Main Outcome Measures: Genetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele/genotype distribution comparisons. Results: Associations with serum SHBG levels were robust for SHBG -68 G>A [rs1799941; meta-analysis: P = 3.7 * 10-14; allelic effect (standard error) = 4.67 (0.62) nmol/L], SHBG +1091 C>T [rs727428; P = 7.3 * 10-11; -3.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 * 10-4, -12.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 * 10-4; -2.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P < 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 * 10-5; -1.66 (0.57) IU/L] and follicle-stimulating hormone [P = 3.4 * 10-3; 2.48 (1.23) IU/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927. Conclusions: Claims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy. PMID- 29264511 TI - Altered Pituitary Gland Structure and Function in Posttraumatic Stress Disorder. AB - Objectives: Posttraumatic stress disorder (PTSD) is associated with hypothalamus pituitary-adrenal (HPA) axis response to stressors, but links to neurophysiological and neuroanatomical changes are unclear. The purpose of this study was to determine whether stress-induced cortisol alters negative feedback on pituitary corticotroph function and pituitary volume. Design: Prospective controlled study in an outpatient clinic. Methods: Subjects with PTSD and matched control subjects underwent pituitary volume measurement on magnetic resonance imaging, with pituitary function assessed by 24-hour urine free cortisol (UFC), 8:00 am cortisol, and adrenocorticotropic hormone (ACTH) levels, and ACTH levels after 2-day dexamethasone/corticotropin-releasing hormone test. Primary outcome was pituitary volume; secondary outcomes were ACTH area under the curve (AUC) and 24-hour UFC. Results: Thirty-nine subjects were screened and 10 subjects with PTSD were matched with 10 healthy control subjects by sex and age. Mean pituitary volume was 729.7 mm3 [standard deviation (SD), 227.3 mm3] in PTSD subjects vs 835.2 mm3 (SD, 302.8 mm3) in control subjects. ACTH AUC was 262.5 pg/mL (SD, 133.3 pg/mL) L in PTSD vs 244.0 pg/mL (SD, 158.3 pg/mL) in control subjects (P = 0.80). In PTSD subjects, UFC levels and pituitary volume inversely correlated with PTSD duration; pituitary volume correlated with ACTH AUC in control subjects (Pearson correlation coefficient, 0.88, P = 0.0009) but not in PTSD subjects. Conclusions: The HPA axis may be downregulated and dysregulated in people with PTSD, as demonstrated by discordant pituitary corticotroph function and pituitary volume vs intact HPA feedback and correlation of pituitary volume with ACTH levels in healthy control subjects. The results suggest a link between pituitary structure and function in PTSD, which may point to endocrine targeted therapeutic approaches. PMID- 29264512 TI - Management of Asymptomatic Patients With Positive Coronary Artery Calcium Scans. AB - Background: The widespread availability of the coronary artery calcium scan to diagnose coronary artery atheroma semiquantitatively and its prognostic significance has frequently resulted in a difficult therapeutic decision for physicians caring for asymptomatic patients. Patients and Risk Factors: Of particular concern are patients over 40 years of age and young adults characterized by multiple cardiovascular risk factors. The correct prognostic interpretation of coronary artery calcium scores and the potential benefits and risks of various therapeutic modalities need to be understood. Conclusion: This review describes the therapeutic choices available to endocrinologists and provides recommendations for various treatment options. PMID- 29264513 TI - The Association of Percent Body Fat and Lean Mass With HbA1c in US Adults. AB - Context: Body fat and body composition distribution patterns affect diabetes risk and glycemic control, but most studies use proxy measures (e.g., body mass index). Objective: This study examined the association of percent body fat and lean mass with glycated hemoglobin (HbA1c) in US adults. Design: The National Health and Nutrition Examination Survey (NHANES) is a program of cross-sectional studies that enroll nationally representative samples of the US civilian noninstitutionalized population. Setting: NHANES is designed to assess the health status of adults and children throughout the United States. Participants: This study included 11,125 participants aged 18 to 69 years from the 1999 through 2006 NHANES, comprising 846 persons with diagnosed diabetes and 10,125 without diabetes. Main Outcome Measures: Total and abdominal (trunk) percent body fat and lean mass were measured using dual-energy x-ray absorptiometry. Linear and logistic regression analyses were used to examine their association with HbA1c. Results: Among those without diagnosed diabetes, total and trunk percent body fat, as well as trunk and total lean mass, were strongly associated with elevated HbA1c; odds ratios per 5% increment for the association of percent body fat with HbA1c >5.7% (39 mmol/mol) ranged from 1.60 to 2.01 across age and sex categories. Among adults with diabetes, higher total percent fat was associated with higher HbA1c in males age <40 years and higher trunk fat was associated with higher HbA1c in females across age categories. Conclusions: Lifestyle interventions to lower HbA1c should consider targeting both weight loss and body composition. PMID- 29264514 TI - Significant Loss of Areal Bone Mineral Density Following Prolonged Bed Rest During Treatment With Teriparatide. AB - We present of a case of severe osteoporosis with thoracic myelopathy secondary to nontraumatic T8 compression fracture managed nonsurgically with 3.5 months of bed rest. Despite treatment with teriparatide starting at initial presentation, 1 year follow-up dual energy x-ray absorptiometry scan revealed a significantly greater than expected 19% reduction in lumbar spine bone mineral density (BMD) and a 6% reduction in total hip density. Daily alcohol consumption, severe osteoporosis at baseline, and immobilization secondary to transient myelopathy treated with strict bed rest all likely contributed to unexpected BMD findings. PMID- 29264515 TI - Longitudinal Assessment of PTH in Community-Dwelling Older Women-Elevations Are Not Associated With Mortality. AB - Context: In older women, the magnitude of elevated parathyroid hormone (PTH) and its consequence is unclear. Objective: To describe normal PTH profiles over time and the association with mortality. Design and Participants: There were 1044 community-dwelling women in the Malmo Osteoporosis Prospective Risk Assessment cohort (OPRA) who attended baseline (age 75 years). Follow-ups were attended by 715 (age 80 years) and 382 (age 85 years). Main Outcome Measures: PTH, estimated glomerular filtration rate (eGFR), 25-hydroxyvitamin D (25OHD) and mortality. Results: At age 75 years, PTH levels for most (n = 877, 88%) were within the normal reference range (NRR) (i.e., <6.9 pmol/L). Longitudinally, between ages 75 and 80 years, PTH increased in 60% of all women (n = 390) but increases of up to 50% above baseline values (64%; n=250) still resulted in PTH levels within the NRR. These women had lower 25OHD levels (74 vs 83 nmol/L, P = 0.001). Only when increases were >50% was PTH elevated beyond the NRR (mean 7.1 +/- 3.3). Here, a pronounced decline in eGFR (56 vs 61 mL/min/1.73 m2, P = 0.002) was found, despite no further changes in 25OHD. Extending the observational period until age 85 years gave similar results. Baseline PTH levels above NRR were associated with mortality (hazard ratio, 1.4; 95% confidence interval (CI), 1.1-1.8; P = 0.007), although not after adjustment for covariates (P = 0.082). Conclusions: Most women remained within normal PTH ranges despite large increases of up to 50%. PTH elevated above normal is not independently associated with mortality; impaired kidney function and low 25OHD status may be more prognostic in the very old. PMID- 29264517 TI - Polyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma. AB - Introduction: Checkpoint inhibitors have significantly improved the prognosis of patients with advanced melanoma. These cancer immunotherapy drugs have specific endocrine autoimmune toxicity. We describe a case of an adrenal insufficiency secondary to pembrolizumab, an anti-programmed cell death-1 monoclonal antibody. Moreover, this case of polyendocrinopathy resulting from a pembrolizumab as the adrenal insufficiency occurred after a thyroiditis. Participant: A 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma. Five months after initiation, she suffered from thyrotoxicosis. A thyroiditis was diagnosed by iodine-123 thyroid scintigraphy and ultrasonography. Pembrolizumab therapy was maintained. Two weeks later, without any other treatment given, she patient developed hypothyroidism and levothyroxine substitution was started. Pembrolizumab proved to be ineffective and was stopped 9 months after initiation. One month following its discontinuation, the patient was hospitalized in the intensive care unit. Severe hyponatremia (115 mmol/L) associated with hyperkalemia (5.7 mmol/L) led to the early recognition and treatment of an acute adrenal insufficiency. Positive results for adrenal cortex and 21-hydroxylase antibodies were in favor of autoimmune toxicity. Conclusion: This case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Because acute adrenal crisis may be associated with substantial morbidity and mortality, physicians must be aware of these rare adverse events to allow an early diagnosis. PMID- 29264516 TI - Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women. AB - Context: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. Objective: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. Design: Prospective cohort study. Setting: Rockefeller University Hospital, New York, NY. Participants: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, +/-3.6 years). Main Outcome Measures: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. Results: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, beta-hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. Conclusion: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (i.e., lactate, beta-hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti inflammatory effect of rapid weight loss. PMID- 29264518 TI - Effects of KDT501 on Metabolic Parameters in Insulin-Resistant Prediabetic Humans. AB - Context: KDT501 is an isohumulone drug that has demonstrated beneficial effects on metabolic parameters in mice. Objective: This study was intended to examine potential improvements in metabolism in humans. Design and Setting: Changes in carbohydrate and lipid metabolism, along with inflammatory markers, were evaluated in prediabetic humans in a clinical research center. Participants: Nine obese patients participated. All had prediabetes or normal glucose tolerance plus three features of metabolic syndrome. Intervention: All participants were treated with escalating doses of KDT501 to a maximum dose of 1000 mg every 12 hours for a total of 28 days. Outcome Measures: Changes in carbohydrate metabolism were measured with oral glucose tolerance, homeostatic model of insulin resistance, and euglycemic clamp; changes in plasma lipids and response to a lipid tolerance test; and changes in plasma inflammatory markers. Results: The drug was well tolerated. After KDT501 treatment, plasma triglycerides were reduced at 4 hours during a lipid tolerance test. Furthermore, plasma adiponectin and high-molecular weight adiponectin increased significantly, and plasma tumor necrosis factor alpha decreased significantly. There were no significant changes in oral glucose tolerance test results or insulin sensitivity measures. Conclusions: Despite the small sample size and the short duration of therapy, KDT501 administration reduced measures of systemic inflammation and improved postmeal plasma triglyceride levels, which may be beneficial in participants with insulin resistance or metabolic syndrome. PMID- 29264520 TI - Selective Arterial Calcium Stimulation With Hepatic Venous Sampling in Immune Mediated Hypoglycemia. AB - The purpose of the current study was to review the biochemical results of selective arterial calcium stimulation (SACST) with hepatic venous sampling in patients with immune-mediated hyperinsulinemic hypoglycemia. A retrospective review was undertaken of four patients with immune-mediated hyperinsulinemic hypoglycemia who underwent SACST with hepatic venous sampling from January 1996 to March 2014. Baseline systemic arterial and hepatic venous insulin concentrations (uIU/mL) were compared, and the absolute and relative-fold increase in hepatic venous insulin concentration after calcium stimulation was calculated. Baseline systemic arterial and hepatic venous insulin concentrations were elevated in all vessels sampled (range, 95 to 1704 uIU/mL), and there was no increase in the absolute or relative (1.0- to 1.3-fold) hepatic venous insulin concentration after calcium injection into any vessel. These data suggest that there are distinct biochemical responses to SACST in patients with immune mediated hyperinsulinemic hypoglycemia compared with patients with endogenous, pancreatic-mediated hypoglycemia, such as insulinoma or nesidioblastosis. PMID- 29264519 TI - WISP1 Is a Marker of Systemic and Adipose Tissue Inflammation in Dysmetabolic Subjects With or Without Type 2 Diabetes. AB - Context: Wnt1-inducible signaling pathway protein 1 (WISP1) is a novel adipokine participating in adipose tissue (AT) dysfunction; so far, no data on WISP1 in diabetes are available. Objectives: To evaluate plasma WISP1 in subjects with type 2 diabetes (T2D) and its correlates linked to AT inflammation. Design and Participants: For this cross-sectional study, 97 consecutive dysmetabolic patients were recruited at the diabetes outpatient clinics of Sapienza University in Rome; 71 of them had T2D, with (n = 35) or without (n = 36) obesity, and 26 were obese patients without diabetes. Twenty-one normal-weight nondiabetic individuals were enrolled as a control group. Study participants underwent clinical workup and blood sampling for metabolic/inflammatory characterization; magnetic resonance imaging (MRI) data on subcutaneous AT and visceral AT (VAT) area, hepatic fat content, and VAT homogeneity were available for most diabetic patients. Results: Plasma WISP1 significantly increased throughout classes of obesity and correlated with greater VAT area, interleukin-8 (IL-8), and lower adiponectin levels, without differing between diabetic and nondiabetic participants. Higher IL-8 was the main determinant of increased WISP1. MRI assessed VAT inhomogeneity was associated with higher WISP1, IL-8 and C-reactive protein levels, independent of obesity; high WISP1 strongly predicted VAT inhomogeneity (P < 0.001). Conclusions: WISP1 levels are increased in obese persons and are directly related to adiposity, independent of glycemic status or insulin resistance; moreover, they are strongly associated with increased plasma IL-8 and signal abnormalities of VAT. The overall data add insights to the mechanisms underlying metabolic alterations and may open a scenario for innovative therapeutic approaches for diabetes prevention and care. PMID- 29264521 TI - Radiofrequency Ablation Followed by Percutaneous Ethanol Ablation Leading to Long Term Remission of Hyperparathyroidism. AB - A 30-year-old male with cerebral palsy and motor impairment presented with right femur fracture. He had gradually worsening mobility and contractures of all extremities for the preceding 5 years. Evaluation showed multiple vertebral and femoral fractures, severe osteoporosis, a large parathyroid adenoma, and parathormone (PTH) exceeding 2500 pg/mL. Because of poor general health and high anesthetic risk, parathyroidectomy was deemed impractical. Ultrasound-guided radiofrequency ablation (RFA) helped achieve 50% size reduction and PTH levels with better control of hypercalcemia. Later, as calcium and PTH remained elevated, percutaneous ethanol ablation was performed with resultant normalization of PTH and substantial symptomatic improvement. Two years later, he still remains normocalcaemic with normal PTH levels. We propose that RFA and percutaneous ethanol ablation be considered as effective short-term options for surgically difficult cases, which could even help achieve long-term remission. Although not previously reported, our case illustrates that both RFA and percutaneous ethanol ablation could be safely performed successively achieving long-term remission. PMID- 29264522 TI - High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus. AB - Context: Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of beta-cell dysfunction. Objectives: We aimed to estimate the prevalence of possibly pathogenic variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up. Design Setting and Patients: We sequenced the coding regions and intron/exon boundaries of GCK, HNF1A, HNF4A, HNF1B, and INS using targeted region capture and next-generation sequencing in 354 Danish women with diet-treated GDM. Glucose tolerance was examined at follow up 10 years after the index pregnancy. Main Outcome Measures: The prevalence of possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, and INS was estimated, and differences in anthropometric traits, high-sensitivity C-Reactive Protein (CRP), and glucose metabolism were measured. Results: At baseline, 17 possibly disease-causing variants were found in 21 women, revealing a combined GCK, HNF1A, HNF4A, HNF1B, and INS variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS. Conclusions: Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, or INS. These women are at high risk of developing diabetes after pregnancy. Thus screening for variants in GCK, HNF1A, HNF4A, HNF1B, and INS should be considered among women with GDM. PMID- 29264524 TI - Peptide Receptor Radionuclide and Octreotide: A Novel Approach for Metastatic Tumor-Induced Osteomalacia. AB - Key Messages: Octreotide can be used as an adjunctive therapy to increase phosphorus levels in patients with tumor-induced osteomalacia. Malignant phosphaturic mesenchymal tumor (PMT) may benefit from treatment with peptide receptor radionucleotide therapy. Context: The success of treatment modalities for malignant PMT is limited. Octreotide has been used to treat hypophosphatemia in patients with tumor-induced osteomalacia with equivocal results. To our knowledge, there are no reports of octreotide or peptide receptor radionuclide therapy use for malignant PMT. Case Description: We report a 40-year-old man having hypophosphatemia, phosphaturia (tubular maximum of phosphorus corrected for glomerular filtration rate of <2.5 mg/dL), and somatostatin avid lesions in the right foot region with metastasis to both lungs. The patient had been subjected to resection of the primary tumor from the foot with thoracoscopic removal of the lung secondaries. Histology from all three lesions showed a spindle cell soft tissue tumor with a high mitotic index and somatostatin receptor 2 and 5 positivity. A trial of subcutaneous octreotide therapy at a dose of 100 MUg thrice daily resulted in an increase in serum phosphorus levels from an average of 1.44 mg/dL to an average of 2.3 mg/dL. Finally, the affected limb was amputated, and the hypophosphatemia persisted postoperatively. In view of persistent hypophosphatemia and transient response to octreotide, the patient was administered four cycles of peptide receptor radionuclide therapy using 177Lutetium, which showed moderate improvement of serum phosphorus levels. Conclusion: Although octreotide use has been reported in four patients with benign PMT, to our knowledge, this is the first case of malignant PMT that has used peptide receptor radionuclide therapy in the treatment of malignant PMT. This moderately beneficial evidence is likely to guide the future use of radionuclide treatments in such tumors. PMID- 29264525 TI - A Novel IGSF1 Mutation in a Boy With Short Stature and Hypercholesterolemia: A Case Report. AB - Context: IGSF1 deficiency is a recently discovered syndrome consisting of congenital central hypothyroidism (CeH) and macroorchidism. Here, we report on a patient presenting with short stature, who was found to carry a pathogenic mutation in the IGSF1 gene. Case Description: A 14-year-old Israeli boy was referred to the Academic Medical Center in Amsterdam, The Netherlands, for follow up on short stature ascribed to constitutional delay of growth and puberty, and familial hypercholesterolemia. Primary hypothyroidism had previously been excluded by a normal thyroid-stimulating hormone (TSH) concentration. However, in follow-up, plasma free thyroxine (FT4) concentrations were repeatedly low, and the patient was diagnosed with CeH. Because of coexistent relative macroorchidism, IGSF1 gene analysis was performed, revealing a mutation (c.2588C>G; p.Ser863Cys). The mutant IGSF1 protein was retained mainly in the endoplasmic reticulum and reached the plasma membrane with poor efficiency compared with wild-type protein. After starting thyroxine treatment, plasma cholesterol almost normalized. Conclusions: This case illustrates the necessity of measuring both FT4 and TSH when hypothyroidism is suspected, or needs to be ruled out. In addition, this case suggests that the presence of childhood hypercholesterolemia may be an indication of undiagnosed hypothyroidism. PMID- 29264523 TI - An Excess of CYP24A1, Lack of CaSR, and a Novel lncRNA Near the PTH Gene Characterize an Ectopic PTH-Producing Tumor. AB - Thus far, only 23 cases of the ectopic production of parathyroid hormone (PTH) have been reported. We have characterized the genome-wide transcription profile of an ectopic PTH-producing tumor originating from a retroperitoneal histiocytoma. We found that the calcium-sensing receptor (CaSR) was barely expressed in the tumor. Lack of CaSR, a crucial braking apparatus in the presence of both intraparathyroid and, probably, serendipitous PTH expression, might contribute strongly to the establishment and maintenance of the ectopic transcriptional activation of the PTH gene in nonparathyroid cells. Along with candidate drivers with a crucial frameshift mutation or copy number variation at specific chromosomal areas obtained from whole exome sequencing, we identified robust tumor-specific cytochrome P450 family 24 subfamily A member 1 (CYP24A1) overproduction, which was not observed in other non-PTH-expressing retroperitoneal histiocytoma and parathyroid adenoma samples. We then found a 2.5 kb noncoding RNA in the PTH 3'-downstream region that was exclusively present in the parathyroid adenoma and our tumor. Such a co-occurrence might act as another driver of ectopic PTH-producing tumorigenesis; both might release the control of PTH gene expression by shutting down the other branches of the safety system (e.g., CaSR and the vitamin D3-vitamin D receptor axis). PMID- 29264526 TI - Classic Kaposi Sarcoma: An Exceptional Cause of Adrenal Incidentaloma. AB - Context: Classic Kaposi sarcoma (KS), also known as Mediterranean KS, affects immunocompetent patients and is usually limited to the skin, without profound organ involvement. We report an exceptional case of a primary adrenal classic KS. Case Description: A left adrenal incidentaloma was fortuitously discovered on a computed tomography scan performed for chest pain in a 60-year-old man. Magnetic resonance imaging showed a heterogeneous left adrenal nodule enhanced by gadolinium injection. Adrenalectomy revealed a massive spindle cell infiltrate of the adrenal gland that was positive for CD31, CD34, and herpes virus 8 (HHV8) on immunohistochemistry, allowing for the diagnosis of KS. The explorations revealed no immunodeficiency or other involvement of KS. Four months later, another nodular lesion appeared on the right adrenal gland, and 2.5 years later, two nodular angiomatous KS lesions had appeared on the right foot. The evolution was indolent, and no complementary treatment of KS was required at 3 years after the diagnosis. Conclusions: Adrenal involvement of KS is rare, eventually observed in AIDS-KS. The present case is, to the best of our knowledge, the first report of primary isolated adrenal classic KS. KS should be considered in the etiology of adrenal incidentaloma, especially if the patient has epidemiological risk factors for HHV8 infection, mainly, but not exclusively, in the context of immunodeficiency. PMID- 29264527 TI - Major Pathophysiology in Prediabetes and Type 2 Diabetes: Decreased Insulin in Lean and Insulin Resistance in Obese. AB - Context: Lowering of body mass index (BMI) to >=25 kg/m2 as obesity by ADA suggests insulin resistance as a major mechanism of impaired glucose metabolism (IGM) in Asians. However, glimepiride, an insulin secretagogue, delayed onset of type 2 diabetes (DM2) from prediabetes (PreDM), indicating decreased insulin secretion (IS) as a major factor in lean (L; BMI < 27 kg/m2) subjects with IGM. Objective: Assessment of IS and insulin resistance (IR) in L and obese (Ob; BMI >= 27 kg/m2) subjects with euglycemia (N), PreDM, and new onset DM2. Subjects: Seventy-five men and 45 women ages 36 to 75 years were divided into six groups: LN, LPreDM, LDM2, ObN, ObPreDM, and ObDM2. Methods: Determination of IS by insulinogenic indices (I/G) at fasting (FI/FG), first phase (?I/?G), and cumulative responses over 2 hours of OGTT (CRI/CRG), and IR by FIXFG, ?IX?G, and CRIXCRG. Changes in IS and IR for PreDM and DM2 were calculated as % fall and % rise, respectively, from levels in N. Results: All indices of IS and IR were lower (P < 0.05) in L than corresponding Ob groups (P < 0.05). Moreover, decline in IS and rise in IR were progressive from N to PreDM (P < 0.05) and DM2 (P < 0.05) in both groups. However, the declines in IS were greater (P < 0.05) than rises in IR in LPreDM and LDM2. Whereas, the rises in IR were higher (P < 0.05) than declines in IS in ObPreDM and ObDM2. Conclusion: In L, major mechanism of IGM is declining IS and not rising IR documented among Ob. PMID- 29264528 TI - Combined Hormonal Contraceptives and First Venous Thrombosis in Young French Women: Impact of Thrombotic Family History. AB - Context: In UK and French, but not World Health Organization (WHO), guidelines for combined hormonal contraception (CHC), family history of a venous thromboembolism (VTE) is a condition for which the theoretical risks usually outweigh the advantages of using CHC. Objective: We estimated the prevalence of inappropriate prescriptions of CHC according to several international guidelines and their impact on VTE. Design: A single-center observational study. Setting: Hemostasis unit outpatient clinic (Paris, France). Population: A total of 2088 French CHC users of childbearing age with a first documented VTE who were referred to our unit between 2000 and 2009. Methods: Data were collected by a standardized questionnaire during a medical consultation. Family history of VTE was analyzed according to definitions from international recommendations (VTE before age 45 years, United Kingdom; before age 50 years, France). A CHC prescription was considered inappropriate for women with vascular contraindications and/or a family history of VTE. Cross-sectional analysis of the clinical and biological characteristics was performed. Main Outcome Measures: Prevalence of inappropriate prescription of CHC and potentially preventable events were estimated. Results: According to the WHO, UK, or French guidelines, 8.8%, 18.9%, and 25.9%, respectively, of CHC prescriptions were considered inappropriate. Compliance with these guidelines could reduce the corresponding number of VTEs by 6.3%, 13.5%, and 18.5%, respectively. Characteristics of the women were similar. Conclusion: Our results suggest inappropriate CHC prescriptions are prevalent among CHC users with first VTE. The appropriate way to take family history of VTE into account should be further clarified. PMID- 29264529 TI - Podocan Is Expressed in Blood and Adipose Tissue and Correlates Negatively With the Induction of Diabetic Nephropathy. AB - Podocan, a member of the small leucine-rich repeat proteoglycans (SLRPs), is expressed in vascular endothelial cells with high levels of expression in the sclerotic glomerular lesions of experimental HIV-associated nephropathy. It is also found in vascular smooth muscle cells and is involved in atherosclerosis. Decorin, a protein similar to podocan, also belongs to the SLRP family and is highly expressed in adipose tissues. It is a secreted protein associated with obesity, type 2 diabetes, and diabetic nephropathy. Based on the similarity of podocan to decorin and its functions reported in the renal and cardiovascular systems, we hypothesized that podocan levels might correlate with the occurrence of metabolic syndromes such as obesity, diabetes, and diabetic nephropathy. We found that podocan was highly expressed in the adipose tissue of mice and humans and its expression was regulated by tumor necrosis factor-alpha in mouse 3T3-L1 adipocytes. In addition, podocan was detected in the plasma, and its levels tended to increase in diet-induced obese C57BL/6J mice and decrease in obese diabetic KKAy and db/db mice. Podocan messenger RNA (mRNA) levels in the renal cortex correlated negatively with the urinary albumin-to-creatinine ratio, a surrogate marker of glomerular injury in uninephrectomized db/db mice used as a model of diabetic nephropathy. Our results suggest that podocan is involved in kidney function and could be a unique therapeutic target for diabetic nephropathy. PMID- 29264530 TI - Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals. AB - Context: Aldosterone synthase (CYP11B2) immunohistochemistry and next-generation sequencing (NGS) have revealed the frequent presence of aldosterone-producing cell clusters (APCCs) harboring somatic mutations in aldosterone-regulating genes in adrenals from Americans without defined hypertension status. Objective: Determine the frequency and somatic mutation status of APCCs in a Japanese nonhypertensive cohort. Design Setting Patients and Interventions: Adrenals from 837 consecutive autopsies at a Japanese institution, Tohoku University Hospital, were screened to select 107 unilateral adrenal glands from nonhypertensive patients. APCC score (APCC number/adrenal cortex area per case) was assessed by CYP11B2 immunohistochemistry. DNA from all APCCs and adjacent adrenal cortex was subjected to NGS using two panels targeting aldosterone-regulating genes. Primary Outcome Measure: APCC frequency and somatic mutation spectrum. Results: In 107 adrenals, 61 APCCs were detected (average of 0.6 APCCs per gland). APCC score was positively correlated with age (r = 0.50, P < 0.0001). NGS demonstrated high confidence somatic mutations in 21 of 61 APCCs (34%). Notably, 16 of 21 APCCs (76%) harbored somatic mutations in CACNA1D, the most frequently mutated gene in our previous studies of APCCs in Americans and CYP11B2-positive micronodules in cross-sectional imaging (computed tomography) negative primary aldosteronism (PA), whereas no APCCs harbored mutations in KCNJ5, the most frequently mutated gene in aldosterone-producing adenoma. APCC score was significantly lower than our previous cohort of unilateral computed tomography-negative PA. Conclusions: APCCs are frequent in nonhypertensive Japanese adrenals, accumulate with age, and frequently harbor somatic mutations (most commonly in CACNA1D). The role of APCCs in PA pathobiology and non-PA hypertension warrants further investigation. PMID- 29264531 TI - High DHEAS Is Associated With Earlier Pubertal Events in Girls But Not in Boys. AB - Context: Premature adrenarche (PA) has been associated with increased metabolic risk. Objective: To describe the risk of precocious thelarche (PT; <8 years), pubarche (PP; girls <8 years, boys <9 years), and gonadarche (PG; <9 years) in children with high dehydroepiandrosterone sulphate (DHEAS [HD]) vs those with normal DHEAS (ND). Setting and Intervention: Longitudinal Chilean cohort (n = 1052, 49.9% girls). Annual clinical examination including secondary sex characteristics by Tanner staging. Logistic regression models were adjusted by age and BMI. Main Outcome: Assess the relationship between DHEAS and premature thelarche, gonadarche, and pubarche in both sexes. Results: At age of DHEAS determination, overweight/obesity was present in 44.3% of boys and 42.9% of girls. Incidences of any precocious event were observed in 17.2% of boys and in 25.4% of girls, presented as 8.7% of PG and 8.5% of PP in boys and as 21.3% of PT and 4.1% of PP in girls. In crude and adjusted models in boys, HD did not increase the risk of earlier pubertal events. Conversely, girls with HD had a 2.6 times greater risk of early thelarche and a three times greater risk of early pubarche compared with girls with ND concentrations. Conclusion: In Chilean adolescents, precocious events of pubertal development were in line with the worldwide secular trend of earlier sexual maturation. HD was only associated with PT and PP in girls. Continuous follow-up of this cohort is a unique opportunity to prospectively address and analyze the interrelationships among HD, early growth, and adiposity as determinants of gonadarche, pubertal rate/sequence progression, and ovarian function. PMID- 29264532 TI - Novel lincRNA Susceptibility Gene and Its Role in Etiopathogenesis of Thyrotoxic Periodic Paralysis. AB - Thyrotoxic periodic paralysis (TPP) is a life-threatening neuromuscular complication of thyrotoxicosis characterized by muscle weakness and hypokalemia and with an unclear etiopathogenesis. However, the 17q24.3 locus had been genetically linked to TPP, in which the genetic variant rs312691 (TC genotype) in long intergenic noncoding RNA (lincRNA) CTD-2378E21.1 is located downstream of inward-rectifier potassium (Kir) channel genes [KCNJ2 and its antisense KCNJ2 (AS KCNJ2)]. A TPP patient with a suppressed thyroid-stimulating hormone level, a high free thyroxine level of (5.8 ng/dL), and low serum potassium level of (2 mEq/L) was evaluated for Kir channel expression during and after recovery from thyrotoxicosis. We observed that circulating lincRNA and Kir expression varied in accordance with thyroid status and TC genotype. To endorse this association of a lincRNA-rs312691 variant with a genetic risk of TPP, an additional series of 37 patients with TPP and 32 patients with thyrotoxic without paralysis (TWP) were assessed. We verified that the risk of minor allele C was greater in TPP than in TWP (odds ratio, 5.289; P = 0.0062), and protective major allele T was more frequent than observed in the 1000 genome controls (odds ratio, 11.90; P < 0.0001). AS-KCNJ2 was downregulated during thyrotoxicosis in the TWP controls carrying allele T and were upregulated in those with TPP with risk allele C. Moreover, KCNJ2 (Kir2.1) expression was reduced during thyrotoxicosis and restored in euthyroid status. We further excluded any other coding variant by performing targeted exome sequencing mutational screening in 17q24.3. Our data suggest that high lincRNA AS-KCNJ2 and CDT-2378E21.1 expression, possibly driven by the triiodothyronine regulatory mechanism, reduces the Kir2.1 expression observed during thyrotoxicosis. This finding could contribute to the understanding of the reduced inward-rectifying current observed during muscle weakness in genetically susceptible TPP patients. PMID- 29264534 TI - Identification of the Underlying Androgen Receptor Defect in the Dallas Reifenstein Family. AB - Context: The Dallas Reifenstein family - first described in 1965 - includes 14 known members with partial androgen insensitivity syndrome (PAIS). However, the underlying molecular defect was never identified. Objective: To identify the underlying genetic defect for PAIS in the Dallas Reifenstein family. Design: DNA was purified from scrotal skin fibroblasts, and whole exome sequencing was then performed in four affected men in the family. Additional family members - both affected and unaffected - were subsequently recruited to confirm segregation of the candidate mutations with the PAIS phenotype. Patients: The affected men have PAIS with infertility associated with azoospermia, hypospadias, and gynecomastia. Results: All four men harbored an intronic variant NC_000023.10:g.66788676A>C between exon 1 and exon 2 of the androgen receptor (AR) canonical transcript NM_000044 (complementary DNA position NM_000044: c.1616+22072A>C) predicted to cause an alternatively spliced AR transcript. Reverse transcription (RT) polymerase chain (PCR) experiments detected the predicted PCR product of the alternatively spliced AR transcript, and the mutation segregated with the PAIS phenotype in this family. The transcript includes the insertion of 185 nucleotides with a premature stop codon at chrX:66863131-66863133, likely resulting in a reduction in AR protein expression due to nonsense-mediated decay. Conclusions: An intronic AR mutation was identified in the Dallas Reifenstein family. The findings suggest that in cases of PAIS without identifiable AR mutations in coding regions, intronic AR mutations should be considered. PMID- 29264535 TI - Temperature as a Circadian Marker in Older Human Subjects: Relationship to Metabolic Syndrome and Diabetes. AB - Background: Circadian rhythms are characterized by approximate 24-hour oscillations in physiological and behavioral processes. Disruptions in these endogenous rhythms, most commonly associated with shift work and/or lifestyle, are recognized to be detrimental to health. Several studies have demonstrated a high correlation between disrupted circadian rhythms and metabolic disease. The aim of this study was to determine which metabolic parameters correlate with physiological measures of circadian temperature amplitude (TempAmp) and stability (TempStab). Methods: Wrist skin temperature was measured in 34 subjects (ages 50 to 70, including lean, obese, and diabetic subjects) every 10 minutes for 7 consecutive days. Anthropometric measures and fasting blood draws were conducted to obtain data on metabolic parameters: body mass index, hemoglobin A1C, triglycerides, cholesterol, high-density lipoprotein, and low-density lipoprotein. A history of hypertension and current blood pressure was noted. Results: Analysis of the data indicated a substantial reduction in TempAmp and TempStab in subjects with metabolic syndrome (three or more risk factors). To determine the impact of individual interdependent metabolic factors on temperature rhythms, stepwise multilinear regression analysis was conducted using metabolic syndrome measurements. Interestingly, only triglyceride level was consistently correlated by the analysis. Triglyceride level was shown to contribute to 33% of the variability in TempAmp and 23% of the variability in TempStab. Conclusion: Our results demonstrate that elevated triglycerides are associated with diminished TempAmp and TempStab in human subjects, and triglycerides may serve as a primary metabolic predictor of circadian parameters. PMID- 29264536 TI - Thymic Involution After Radioiodine Therapy for Graves Disease: Relationships With Serum Thyroid Hormones and TRAb. AB - Context: The mechanisms of thymic hyperplasia in Graves disease and its involution after radioiodine (I-131) therapy remain unknown. Objective: To examine whether computed tomography (CT) findings of the thymus in patients with Graves disease change before and 6 months after I-131 therapy and to elucidate factors that affect these changes. Design Setting: A retrospective, single-center study was conducted. Thymic and thyroid volumes and thymic density were measured on CT. The associations of thymic volume or density with the following factors before I-131 therapy were examined: age; serum triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone receptor antibody (TRAb) levels; and thyroid volume. The changes in thymic volume and density and TRAb levels before and after I-131 therapy, and the correlations of thymic volume with T3 and T4 decline rates and TRAb changing rate and age were examined. Patients: We studied 40 consecutive patients with Graves disease who underwent neck and chest CT before and 6 months after I-131 therapy. Intervention: Observational study. Results: A significant negative correlation was observed only between thymic density and age before I-131 therapy. Thymic volume and density decreased and TRAb levels increased significantly after I-131 therapy. The thymic volume decline rate significantly positively correlated with serum T3 and thyroid volume decline rates. No significant correlation was found between thymic volume decline and TRAb changing rates. Conclusions: Significant thymic involution occurs after I-131 therapy in patients with Graves disease. Serum T3, but not TRAb, may be related to thymic hyperplasia and involution following I-131 therapy. PMID- 29264533 TI - Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule. AB - Nicotinamide adenine dinucleotide (NAD+) is an established cofactor for enzymes serving cellular metabolic reactions. More recent research identified NAD+ as a signaling molecule and substrate for sirtuins and poly-adenosine 5'-diphosphate polymerases; enzymes that regulate protein deacetylation and DNA repair, and translate changes in energy status into metabolic adaptations. Deranged NAD+ homeostasis and concurrent alterations in mitochondrial function are intrinsic in metabolic disorders, such as type 2 diabetes, nonalcoholic fatty liver, and age related diseases. Contemporary NAD+ precursors show promise as nutraceuticals to restore target tissue NAD+ and have demonstrated the ability to improve mitochondrial function and sirtuin-dependent signaling. This review discusses the accumulating evidence for targeting NAD+ metabolism in metabolic disease, maps the different strategies for NAD+ boosting, and addresses the challenges and open questions in the field. The health potential of targeting NAD+ homeostasis will inform clinical study design to identify nutraceutical approaches for combating metabolic disease and the unwanted effects of aging. PMID- 29264538 TI - Hypothalamic-Pituitary-Thyroid Axis Set Point Alterations Are Associated With Body Composition in Androgen-Deprived Men. AB - Objective: Androgen deprivation therapy (ADT) given to men with prostate cancer is associated with metabolically adverse changes in body composition leading to insulin resistance, but the underlying mechanisms are not fully understood. We investigated prospectively whether androgen deprivation or its consequences may be associated with alterations in thyroid function in men. Design: We performed a prespecified secondary analysis of a prospective case control study. Methods: We prospectively followed men with nonmetastatic prostate cancer newly commencing ADT (n = 34) and age-matched controls (n = 29) for 12 months. We assessed secondary outcomes on thyrotropin (TSH) and thyroid hormones using a linear mixed model to determine mean adjusted differences (MADs) between groups. Results: After a 12-month follow-up period, TSH increased in cases compared with control subjects [MAD, 0.69 mIU/L; 95% confidence interval (CI), 0.58-0.82; P < 0.001]. This was accompanied by a rise in FT4 (MAD, 2.2 pmol/L; 95% CI, 1.1-3.2; P < 0.001), reduced FT3-FT4 conversion (MAD, -0.07; 95% CI, -0.10 to -0.4; P < 0.001), and stable FT3. TSH change correlated significantly with changes in weight, body mass index, and fat mass in cases but not with waist circumference, lean mass, visceral fat, insulin resistance, testosterone, sex hormone binding globulin, and estradiol. The rise in TSH after 12 months was strongly associated with changes in leptin. Conclusions: A profound rise in TSH in the absence of peripheral hypothyroidism under ADT suggests set point adaptations of the hypothalamic-pituitary-thyroid axis. This appears to be mediated by body composition changes and by the fat-associated hormone leptin rather than by androgen deficiency. Further studies are required to determine the causality and biological implications of these findings. PMID- 29264537 TI - Plasma Amino Acids vs Conventional Predictors of Insulin Resistance Measured by the Hyperinsulinemic Clamp. AB - Context: Specific plasma amino acid (AA) profiles including elevated postabsorptive branched-chain amino acids (BCAAs) have been associated with insulin resistance (IR), mostly estimated by homeostatic model assessment. This study assessed the associations of postabsorptive AAs with IR directly measured by insulin-mediated glucose disposal and determined the quantitative value of AAs and conventional IR predictors. Design: Fifty-one healthy, 31 overweight or obese (Ow/Ob), and 52 men and women with type 2 diabetes (T2D) were studied retrospectively. The main outcome measures were the glucose disposal (M/I) index (using 3-[3H]-glucose) during a hyperinsulinemic-euglycemic clamp and whole-body protein turnover (using 1-[13C]-leucine). Results: Compared with healthy participants, M/I was lower in Ow/Ob participants and lowest in those with T2D. BCAAs, glutamate, and lysine were higher in the Ow/Ob and T2D groups than in healthy participants; glycine and threonine were lower. Most AAs were higher in men. Principal component analysis identified component 1 (C1: BCAAs, methionine) and C3 (glycine, threonine, serine). Glutamate, C1, ornithine, lysine, methionine, and tyrosine correlated negatively with M/I; C3 and glycine correlated positively. Waist circumference and sex strongly influenced AA-IR relationships; only glutamate correlated after these factors were controlled for. From regression analysis, waist circumference, fasting glucose, insulin, and free fatty acids (FFAs) negatively predicted 64% of the M/I variance; glutamate added 2% more. In nondiabetic participants, IR was predicted by waist circumference, insulin, and FFAs, without contribution from AAs. Conclusion: Several postabsorptive AAs correlated with IR but added limited predictive value to conventional markers because levels were determined largely by abdominal adiposity. Data suggest a sex-specific regulation of AA metabolism by excess adiposity, particularly the BCAAs, warranting investigation. PMID- 29264539 TI - Diagnosis and Clinical Implications of Diabetes in Liver Cirrhosis: A Focus on the Oral Glucose Tolerance Test. AB - The liver and skeletal muscles are responsible for maintaining glucose metabolism. As chronic liver disease progresses to cirrhosis, the loss of liver function is exacerbated and leads to the deterioration of skeletal muscle. Consequently, impaired glucose tolerance (IGT) and insulin resistance are often observed in patients with liver cirrhosis. Early stage cirrhosis with hepatogenous diabetes is characterized by marked postprandial hyperglycemia and hyperinsulinemia. Generally, it is possible to underestimate IGT when using either the conventional fasting plasma glucose (FPG) criterion or hemoglobin A1c (HbA1c) levels despite their status as the gold standard for diagnosing diabetes. The number of cirrhotic patients with diabetes tends to be underestimated because many of these patients show lower FPG levels or HbA1c, which masks their IGT. In such cases, the oral glucose tolerance test is recommended to evaluate patients with suspected postprandial hyperglycemia who present with a normal FPG. Moreover, in addition to the Child-Pugh score, the early detection of diabetes may be a useful prognostic marker for patients with liver cirrhosis. PMID- 29264540 TI - Radiological Surveillance Screening in Asymptomatic Succinate Dehydrogenase Mutation Carriers. AB - There has been a significant increase in the availability of testing for pheochromocytoma and paraganglioma (PPGL) germline susceptibility genes. As more patients with genetic mutations are identified, cascade genetic testing of family members is also increasing. This results in identifying genetic predispositions at a much earlier age. With our current understanding of familial PPGL syndromes, lifelong surveillance is required. This review focuses on carriers of succinate dehydrogenase (SDH) mutations. For genetic testing to be proven worthwhile, the results must be used for patient benefit. For SDHx mutations, this should equate to a surveillance program that is safe and removes as much uncertainty around diagnosis as possible. Early identification of these tumors is the goal of any surveillance program, as surgical resection is the mainstay of treatment with curative intent to prevent the morbidity and mortality consequences associated with catecholamine excess, in addition to the risk of malignancy. Modality and frequency of surveillance imaging and how to engage individuals in the process of surveillance remain controversial questions. The data reviewed here and the cumulative advice supports the avoidance of using radiation-exposing imaging in this group of individuals that require lifelong screening. PMID- 29264541 TI - Microcirculation, Adiposity, and Traditional and Emerging Cardiovascular Risk Factors in Prepubertal Children. AB - Purpose: Previous studies have shown that microvascular dysfunction (MD) is associated with a number of cardiovascular risk factors, including obesity. Few studies have assessed microvascular reactivity in children, and in most of these, results were confounded by the effects of puberty. Our aim was to establish whether MD is already present in obese prepubertal children. Methods: This cross sectional study included 52 obese, 18 overweight, and 28 eutrophic children, with a mean +/- standard deviation age of 7.44 +/- 1.22 years. We evaluated cardiovascular risk factors and nutritive microvascular function by using nailfold dynamic videocapillaroscopy and determined functional capillary density (FCD), red blood cell velocity at resting conditions (RBCV) and at peak (RBCVmax), and time to reach peak velocity during the post-occlusive reactive hyperemic response following 1 minute ischemia. Results: On univariate analysis, differences in microvascular reactivity were not observed among the groups. Obese and overweight children had significantly higher scores than eutrophic children for the following parameters: body mass index, waist circumference, waist-to height ratio, mean arterial pressure, homeostasis model assessment for insulin resistance, levels of insulin, leptin, glucose, triglycerides, total cholesterol, uric acid, and C-reactive protein. Multivariate analysis demonstrated the association between metabolic, anthropometric, and microvascular variables, stratified according to the degree of adiposity and body fat distribution. Conclusions: Univariate analysis did not show any difference in microvascular reactivity between groups but, by testing these variables by multivariate means, we noticed a common and direct variation between cardiovascular/metabolic risk factors and microvascular reactivity occurring early in life. PMID- 29264542 TI - Corticotropinoma as a Component of Carney Complex. AB - Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15 year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD. PMID- 29264543 TI - Hyperparathyroidism-Jaw Tumor Syndrome Associated With Large-Scale 1q31 Deletion. AB - Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant cause of familial hyperparathyroidism associated with benign, ossifying fibromas of the maxillofacial bones and increased risk of parathyroid carcinoma. The putative tumor suppressor gene CDC73 has been implicated in the syndrome, with a multitude of inactivating mutations identified; however, HPT-JT due to large scale deletion of the chromosomal region containing the gene is exceedingly rare, and the clinical significance of this variant remains unclear. We report the case of a 32-year-old woman with a history of mandibular ossifying fibroma who presented with primary hyperparathyroidism and was found to harbor a large-scale, germline deletion on chromosome 1q31, including the CDC73 locus. HPT-JT is associated with loss of function of the putative tumor suppressor gene CDC73. Over 100 mutations and small insertions/deletions have been identified within the gene, the majority of which result in premature truncation of the parafibromin protein product. We report a case of HPT-JT associated with a large chromosomal deletion (4.1 Mb) encompassing the CDC73 gene locus. In the future, molecular testing in this autosomal dominant disorder should use techniques that allow for the detection of large-scale deletions in addition to the more commonly observed mutations and smaller-scale copy number alterations. Further investigation is needed to determine whether HPT-JT associated with a large-scale deletion carries increased risk of malignancy relative to the more common truncating mutations and what the implications are for genetic counseling. PMID- 29264544 TI - Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome. AB - Objective: Obese girls with polycystic ovarian syndrome (PCOS) have decreased insulin sensitivity (IS), muscle mitochondrial dysfunction and increased liver fat, which may contribute to their increased risk for type 2 diabetes. Less is known regarding normal-weight girls with PCOS. Methods: Normal-weight girls with PCOS [n =18, age 15.9 +/- 1.8 years, body mass index (BMI) percentile 68 +/- 18] and normal-weight controls (NWC; n = 20; age 15.0 +/- 2.1 years, BMI percentile 60 +/- 21) were studied. Tissue-specific IS was assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers and a 2-hour oral glucose tolerance test (OGTT). Hepatic fat was determined using magnetic resonance imaging. Postexercise muscle mitochondrial function was assessed with 31P MR spectroscopy. Results: Both groups had similar demographics, anthropomorphics, physical attributes, habitual physical activity levels and fasting laboratory values, except for increased total testosterone and DHEAS in PCOS. Clamp-assessed peripheral IS was lower in PCOS (10.4 +/- 2.4 mg/kg/min vs 12.7 +/- 2.1; P = 0.024). The 120-minute OGTT insulin and glucose concentrations were higher in PCOS (114 IU/mL +/- 26 vs 41 +/- 25, P = <0.001 and 119 +/- 22 mg/dL vs 85 +/- 23, P = 0.01, respectively). Muscle mitochondrial ADP and phosphocreatine time constants were slower in PCOS. Despite a higher percentage liver fat in PCOS, hepatic IS was similar between groups, as was adipose IS. Conclusions: Normal weight girls with PCOS have decreased peripheral IS and muscle mitochondrial dysfunction, abnormal glucose disposal, relative postprandial hyperinsulinemia, and increased hepatic fat compared to NWC. Despite a normal BMI, multiple aspects of metabolism appear altered in normal-weight girls with PCOS. PMID- 29264545 TI - Characterization of Cortisol Secretion Rate in Secondary Adrenal Insufficiency. AB - Context: In secondary adrenal insufficiency (SAI), chronic deficiency of adrenocorticotropin (ACTH) is believed to result in secondary changes in adrenocortical function, causing an altered dose-response relationship between ACTH concentration and cortisol secretion rate (CSR). Objective: We sought to characterize maximal cortisol secretion rate (CSRmax) and free cortisol half-life in patients with SAI, compare results with those of age-matched healthy controls, and examine the influence of predictor variables on ACTH-stimulated cortisol concentrations. Design: CSRmax was estimated from ACTH1-24 (250 MUg)-stimulated cortisol time-concentration data. Estimates for CSRmax and free cortisol half life were obtained for both dexamethasone (DEX) and placebo pretreatment conditions for all subjects. Setting: Single academic medical center. Patients: Patients with SAI (n = 10) compared with age-matched healthy controls (n = 21). Interventions: The order of DEX vs placebo pretreatment was randomized and double blind. Cortisol concentrations were obtained at baseline and at intervals for 120 minutes after ACTH1-24. Main Outcome Measures: CSRmax and free cortisol half-life were obtained by numerical modeling analysis. Predictors of stimulated cortisol concentrations were evaluated using a multivariate model. Results: CSRmax was significantly (P < 0.001) reduced in patients with SAI compared with controls for both placebo (0.17 +/- 0.09 vs 0.46 +/- 0.14 nM/s) and DEX (0.18 +/- 0.13 vs 0.43 +/- 0.13 nM/s) conditions. Significant predictors of ACTH1-24-stimulated total cortisol concentrations included CSRmax, free cortisol half-life, and baseline total cortisol, corticosteroid-binding globulin, and albumin concentrations (all P < 0.05). Conclusions: Our finding of significantly decreased CSRmax confirms that SAI is associated with alterations in the CSR-ACTH dose-response curve. Decreased CSRmax contributes importantly to the laboratory diagnosis of SAI. PMID- 29264546 TI - Max Schottelius: Pioneer in Pheochromocytoma. AB - First descriptions of diseases attract tremendous interest because they reveal scientific insight even in retrospect. Max Schottelius, the pathologist contributing the first histological description of pheochromocytoma, remains anonymous. We reviewed the description by Schottelius and weighed the report in modern context. Schottelius described the classical diagnostic elements of pheochromocytoma, including the brown appearance after exposure to chromate containing Mueller's fixative. This color change, known as chromaffin reaction, results from oxidation of catecholamines and is reflected in the name pheochromocytoma, meaning dusky-colored chromate-positive tumor. Thus Schottelius performed the first known histochemical contribution to diagnosis, which is today standard with immunohistochemistry for chromogranin. PMID- 29264547 TI - 17beta-Estradiol Promotes Islet Cell Proliferation in a Partial Pancreatectomy Mouse Model. AB - 17beta-Estradiol (E2) is a multifunctional steroid hormone in modulating metabolism in vivo. Previous studies have reported that E2 could promote insulin secretion and protect beta cells from apoptosis. In this study, the partial pancreatectomy (PPx) model was used to study the role of E2 in islet cell proliferation. The animals were divided into four groups, including sham control, PPx model, E2, and E2 plus estrogen antagonist (E2 plus ICI) groups. In the E2 group, 5-bromo-2'-deoxyuridine- and Ki67-positive cells significantly increased after PPx, and the protein expression of forkhead transcription factor M1, cyclin A2, cyclin B1, and cyclin E2 also significantly increased in the isolated islets. The messenger RNA expression of cyclin A2 and cyclin B2 increased in E2 treatment group. Additionally, the effects of E2 on the PPx mice were partially blocked by estrogen antagonist ICI182,780. The results indicated that E2 significantly promoted islet cell proliferation in PPx model mice, and it upregulated the expression of cell cycle genes. In conclusion, E2 treatment is beneficial for islet cell proliferation in adult mice after PPx. A partial pancreatectomy in mice may be an attractive model for the study of islet cell proliferation. PMID- 29264548 TI - Activation of Sphingolipid Pathway in the Livers of Lipodystrophic Agpat2-/- Mice. AB - A several fold increase in triacylglycerol is observed in the livers of lipodystrophic Agpat2-/- mice. We have previously reported an unexpected increase in the phosphatidic acid (PA) levels in the livers of these mice and that a few specific molecular species of PA were able to transcriptionally upregulate hepatic gluconeogenesis. In the current study, we measured the metabolites and expression of associated enzymes of the sphingolipid synthesis pathway. The entire sphingolipid pathway was activated both at the gene expression and the metabolite level. The levels of some ceramides were increased by as much as ~eightfold in the livers of Agpat2-/- mice. Furthermore, several molecular species of ceramides were increased in the plasma of Agpat2-/- mice, specifically ceramide C16:0, which was threefold elevated in the plasma of both the sexes. However, the ceramides failed to increase glucose production in mouse primary hepatocytes obtained from wild-type and Agpat2-/- mice, further establishing the specificity of PA in the induction of hepatic gluconeogenesis. This study shows elevated levels of sphingolipids in the steatotic livers of Agpat2-/- mice and increased expression of associated enzymes for the sphingolipid pathway. Therefore, this study and those in the literature suggest that ceramide C16:0 could be used as a biomarker for insulin resistance/type 2 diabetes mellitus. PMID- 29264549 TI - Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery. AB - Management of adult patients with classic congenital adrenal hyperplasia (CAH) is challenging and often complicated by obesity, metabolic syndrome, and adverse cardiovascular risk. Alterations in weight can influence cortisol kinetics. A 19 year-old woman with classic CAH and morbid obesity experienced persistent elevations of androgen levels while receiving oral glucocorticoid therapy. Control of adrenal androgens was improved with continuous subcutaneous hydrocortisone infusion therapy, but obesity-related comorbidities persisted. After undergoing sleeve gastrectomy, the patient experienced dramatic weight loss, with improvement in insulin sensitivity and fatty liver in the postbariatric period. Cortisol clearance studies performed to evaluate changes in hydrocortisone dose requirements showed marked alternations in cortisol pharmacokinetics with decreases in volume of distribution and cortisol clearance, along with an increase in area under the curve for cortisol. Hydrocortisone dose was subsequently decreased 34% by 15 months after surgery. Effective control of androgen excess on this lower hydrocortisone dose was achieved and continues 27 months after surgery. This case highlights obesity-related complications of glucocorticoid replacement therapy in the management of CAH. Individual patient factors, such as fatty liver disease and insulin resistance, can have a clinically important effect on cortisol metabolism. Bariatric surgery was a safe and effective treatment of obesity in this patient with CAH and should be considered for patients with CAH and multiple obesity-related comorbidities. PMID- 29264550 TI - Late to the Party: Importance of Dietary Fat and Protein in the Intensive Management of Type 1 Diabetes. A Case Report. AB - Insulin dosing in type 1 diabetes (T1D) has been focused primarily on carbohydrate intake, but recent evidence highlights the importance of dietary fat and protein in glycemic excursions. Several methods have been developed to incorporate dietary fat and protein into insulin dose calculations, including fat protein units (FPUs) that estimate insulin requirements based on ingested fat and protein, as well as extended combination insulin boluses. However, insulin dosing based on meal fat and protein content is challenging to incorporate into clinical practice. We present the case of a 40-year-old man with T1D using continuous subcutaneous insulin infusions and continuous glucose monitoring. He followed a diet that restricted carbohydrate intake, with compensatory increases in dietary protein and fat. He had poor glycemic control with frequent postprandial hyperglycemia. He began incorporating FPUs into his insulin dosing calculations and used extended dual wave boluses to administer prandial insulin. Over the next 6 months he experienced a significant improvement in glycemic control. Fat and protein have both been shown to cause delayed postprandial hyperglycemia, leading to poor glycemic control with carbohydrate-focused insulin dosing in our patient on a high-fat, high-protein diet. It is difficult to incorporate dietary fat and protein into insulin dosing in the clinical setting. However, our patient experienced an improvement in glycemic control with the application of FPUs and dual wave boluses in prandial insulin dosing, showing that methods such as these can be used successfully in T1D management. PMID- 29264551 TI - Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation. AB - Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in ACAN, the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a de novo novel heterozygous frameshift mutation in ACAN (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in ACAN (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with ACAN mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous ACAN mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation. PMID- 29264552 TI - Congenital Generalized Lipodystrophy Type 2 in a Patient From a High-Prevalence Area. AB - Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease characterized by the loss of body fat. The global prevalence of CGL is one in 10 million, and there are four subtypes. The case is presented of a 18-year-old woman from rural area of the north coast of Peru (Piura) with limited access to health services. She was diagnosed with phenotypic CGL at age 7 months. At age 12 years, she was diagnosed with diabetes and had altered liver function tests. She underwent a liver biopsy, which revealed advanced portal fibrosis. The patient stopped attending evaluations for 3 years; subsequently, she was referred to Dos De Mayo Hospital in Lima. Physical examination revealed typical triangular facies, acanthosis nigricans, and hirsutism; little subcutaneous tissue; proximal muscle weakness with stiffness in joints; and clitorimegaly. As of this writing, the patient is waiting to initiate outpatient therapy with a leptin analog. She has physical characteristics of CGL type 2 and a natural progression of the disease that presents cirrhosis caused by nonalcoholic fatty liver disease. She lives in a region of high CGL type 2 prevalence, which, without treatment, has a poor prognosis. Liver failure is the main cause of death. There are barriers for this group of patients to access the best treatment and one purpose of this report is to attract the attention of health institutions to help us treat these patients. PMID- 29264554 TI - Finger-Tip Lesion: Solitary Brown Tumor. AB - We report a case of primary hyperparathyroidism presenting with an isolated brown tumor in the finger tip. PMID- 29264553 TI - Effects of Potassium Bicarbonate Supplements on Circulating microRNA Expression. AB - Several studies suggest that neutralizing acid load in the diet with alkali had favorable effects on intermediate markers of musculoskeletal health. We examined whether alkali supplementation with potassium bicarbonate [(KHCO3); 81 mmol/d; n = 12] vs placebo (n = 12) for 84 days altered serum microRNAs, potential biomarkers associated with innumerable biological processes including bone and muscle metabolism. Serum microRNAs, urinary net acid excretion (UNAE), urinary N telopeptide (UNTX), urinary calcium (UCa), urinary nitrogen (UN), glomerular filtration rate, serum procollagen type 1 amino-terminal propeptide (P1NP), serum insulin-like growth factor-1 (IGF-1), and its serum binding protein IGFBP3 were measured at baseline and day 84. Baseline characteristics and measurements were similar in the two treatment groups. Eighty-four-day changes in UNAE differed by group (KHCO3, -47 +/- 9 mmol; placebo, -5 +/- 5 mmol; P < 0.01). KHCO3 significantly reduced UNTX, UCa, and serum P1NP but did not affect UN, serum IGF 1, or IGFBP3 levels compared with placebo over 84 days. Fold change in serum circulating microRNA (c-miR)-133b differed significantly by group (KHCO3, 2.26 +/ 0.85; placebo, -1.23 +/- 0.69; P < 0.01); there was a similar trend in c-miR-21 5p. Fold changes in c-miR-133b and c-miR-21-5p were inversely associated with changes in UNAE and UNTX; fold change in c-miR-21-5p was inversely associated with change in UCa, with a similar trend with c-miR-133b. In summary, reducing renal acid load with KHCO3 was associated with increased expressions of c-miR 133b and c-miR-21-5p. Furthermore, increases in c-miRNA-133b and c-miR-21-5p were inversely associated with bone resorption markers UNTX and UCa consistent with potential beneficial effects on bone in older adults. However, the broader significance of c-miRNAs as musculoskeletal biomarkers is still under investigation, and larger studies are needed to verify these preliminary results. PMID- 29264555 TI - Nonalcoholic Fatty Liver Disease in Hispanic Youth With Dysglycemia: Risk for Subclinical Atherosclerosis? AB - Context: Obese Hispanic adolescents (OHAs) with dysglycemia have increased cardiovascular disease risk burden. Objective: To investigate if nonalcoholic fatty liver disease (NAFLD) confers added risk for endothelial dysfunction in these youth. Design: Cross-sectional study. Setting: Academic institution. Participants: Thirty-six OHAs (15.3 +/- 0.4 years), 20 with prediabetes and 16 with type 2 diabetes, with and without NAFLD. Intervention: Evaluation of reactive hyperemia index (RHI) and augmentation index (AIx) by peripheral arterial tonometry; muscle, hepatic, and adipose tissue insulin sensitivity (IS; hyperinsulinemic-euglycemic clamp 80 mu/m2/min, with [6,6 2H2]glucose and [2H5] glycerol); body composition; and abdominal and hepatic fat by magnetic resonance imaging/spectroscopy. Outcome Measures: RHI and AIx. Hypothesis: OHAs with dysglycemia and NAFLD have worse RHI and AIx vs those without NAFLD. Results: The NAFLD (n = 23) and non-NAFLD (n = 13) groups were of similar age, sex, glycemic status, body mass index, % body fat and abdominal fat. The NAFLD group had higher hepatic fat (P < 0.001) lower skeletal muscle IS (P = 0.01), hepatic IS (P = 0.01), and adipose tissue IS (P = 0.04). The NAFLD vs non-NAFLD group had lower RHI (1.4 +/- 0.05 vs 1.7 +/- 0.09, P = 0.002), greater AIx (-6.0 +/- 1.6 vs -12.0 +/- 2.1, P = 0.03). Hepatic fat was inversely related to RHI (r = -0.49, P = 0.002) and positively related to AIx (r = 0.45, P = 0.006). Hepatic IS (r = 0.42, P = 0.01) and adipose IS (r = -.54, P = 0.001) correlated with arterial stiffness (AIx). Conclusion: In OHAs with dysglycemia, NAFLD is associated with worse endothelial function. RHI and AIx were related to hepatic fat content. Vascular stiffness was related to hepatic and adipose tissue insulin resistance. PMID- 29264556 TI - Ablation of Oxytocin Neurons Causes a Deficit in Cold Stress Response. AB - The paraventricular nucleus (PVN) is a critical locus of energy balance control. Three sets of neurons in the PVN are involved in regulating energy balance: oxytocin-expressing neurons (OXT-neurons), thyrotropin-releasing hormone expressing neurons, and corticotrophin-releasing hormone-expressing neurons. To examine the role of OXT-neurons in energy balance, we ablated these neurons in mice by injecting diphtheria toxin into mice possessing both the oxytocin promoter driving cre expression and a cre-inducible diphtheria toxin receptor. Immunohistochemistry and real-time reverse transcriptase polymerase chain reaction confirmed that this injection caused a significant decrease in PVN OXT neurons and OXT-mRNA abundance. OXT-neuron ablation did not alter food intake, weight, or energy expenditure at room temperature on either chow or a high-fat diet. To further characterize OXT-neuron-ablated mice, we examined their response to 1) intraperitoneal cholecystokinin (CCK) injection and 2) thermogenic stress. OXT-neuron-ablated mice had a blunted decrease in feeding response to CCK. When exposed to the extreme cold (4 degrees C) for 3 hours, OXT-neuron-ablated mice had significant decreases in both rectal and brown adipose tissue temperature relative to controls, which was rescued by OXT treatment. Thermographic imaging revealed that OXT-neuron-ablated mice had increased body surface temperature. Thus, we report that OXT-neuron ablation shows no role for OXT-neurons in energy homeostasis at neutral temperature but reveals a heretofore unappreciated role for OXT-neurons and oxytocin specifically in regulating the thermogenic stress response. PMID- 29264557 TI - A Novel Case of Somatic KCNJ5 Mutation in Pediatric-Onset Aldosterone-Producing Adenoma. AB - Aldosterone-producing adenoma (APA), a subtype of primary aldosteronism, is a common cause of secondary hypertension in adults. Somatic KCNJ5 mutations have been identified in about 12%-80% of adult-onset APA. In contrast, there has been no previous reported case of pediatric-onset APA in whom a somatic KCNJ5 mutation was confirmed. We report an 11-year-old Japanese girl who had experienced recurrent headaches and nausea for more than 2 years before hypertension was observed (blood pressure, 150/82 mm Hg). Plasma renin activity was <0.1 ng/mL per hour even after a captopril-challenge or upright furosemide-loading test. Plasma aldosterone concentrations (PACs) before and after saline-infusion test were 28.0 and 40.6 ng/dL, respectively. Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were 16.5 pg/mL and 16.7 ug/dL, respectively. The patient was diagnosed with APA in the left adrenal gland on the basis of selective adrenal venous sampling after ACTH stimulation (PAC in the left adrenal vein, 3630 ng/dL) and histopathologic findings of the tumor obtained by laparoscopic left adrenalectomy. Sanger sequencing of KCNJ5 using genomic DNA from peripheral lymphocytes and laser-captured microdissected APA tissues demonstrated the presence of a somatic KCNJ5 mutation p.L168R, previously reported only in adult onset APA. Immunohistochemistry detected strong immunoreactivity for CYP11B2, but not for CYP11B1 in the APA, consistent with the endocrinologic findings in this patient. Somatic KCNJ5 mutations are also identified in pediatric-onset APA. Further cases are needed to elucidate functional characteristics of pediatric onset APA with a somatic KCNJ5 mutation. PMID- 29264558 TI - Falsely Elevated Steroid Hormones in a Postmenopausal Woman Due to Laboratory Interference. AB - Laboratory interference is a drawback in hormonal testing, and clinicians should have a high index of suspicion when faced with biochemical results discordant with the patient's clinical manifestations. A 62-year-old postmenopausal woman initially consulted her primary care physician for mood lability; laboratory workup showed markedly elevated levels of total serum estradiol, progesterone, testosterone, and cortisol as measured by immunoassay. Further investigation demonstrated no evidence of estrogen effect on uterus, no adrenal or adnexal mass, and no evidence of Cushing syndrome. Conventional techniques to unmask laboratory interference, such as dilution, antigen precipitation, and using a different immunoassay did not unveil a potential laboratory interference. The patient had no apparent risk factor for analytic interference, such as absent rheumatoid factor and heterophilic antibodies, but had only mild monoclonal IgG hypergammaglobulinemia. In this case, mass spectrometry unmasked the false elevation in steroid hormones. Interference of gammaglobulins or antibodies with the labeling and separation process of the assay could be the culprits. In conclusion, we report a unique case of multiple steroid hormones elevations due to laboratory interference unmasked by mass spectrometry. PMID- 29264560 TI - Calcifediol Rather Than Cholecalciferol for a Patient Submitted to Malabsortive Bariatric Surgery: A Case Report. AB - Vitamin D deficiency following malabsorptive bariatric surgery can lead to osteomalacia. We report a patient with severe vitamin D deficiency following malabsorptive bariatric surgery successfully treated with calcifediol but not cholecalciferol. A 40-year-old woman, submitted to biliopancreatic diversion 20 years before and chronically treated with 50,000 IU cholecalciferol weekly, was admitted to our Endocrine Unit because of severe lower back pain, muscle weakness, and generalized muscular hypotrophy, associated with hypocalcemia and elevated PTH levels. Initial evaluation revealed low serum albumin, low albumin corrected serum calcium (7.36 mg/dL), high serum PTH (240 pg/mL), bone-specific alkaline phosphatase (125 MUg/L) and 1,25-dihydroxyvitamin D (112 pg/mL) concentrations, undetectable serum 25-hydroxyvitamin D (<7 ng/mL), and evidence of reduced liver function. Bone mineral density was markedly low. Normocalcemia was initially restored with intravenous albumin and calcium gluconate. Treatment with calcitriol (0.5 MUg three times daily) and oral calcium carbonate (1000 mg daily) was simultaneously started and cholecalciferol was replaced with calcifediol [125 MUg (5000 IU) daily)]. During follow-up the calcifediol dose was progressively tapered to 25 MUg (1000 IU) daily and the calcitriol dose was progressively reduced and finally withdrawn. Serum albumin and other biochemical parameters normalized, bone mineral density significantly increased, and the patient's clinical conditions progressively improved, with a substantial recovery of autonomy. Serum vitamin D binding protein at the last observation was in the normal range. Our data suggest that calcifediol might be more efficacious than cholecalciferol for prevention and treatment of vitamin D deficiency in patients treated by malabsorptive bariatric surgery. PMID- 29264559 TI - Hypothyroidism in Infants With Congenital Heart Disease Exposed to Excess Iodine. AB - Thyroid hormone is critical for neonatal brain development, and even transient hypothyroidism can cause adverse neurocognitive outcomes. Infants exposed to excess iodine are at risk of developing hypothyroidism, especially those with congenital heart disease (CHD), because they are routinely exposed to excess iodine from intravenous iodinated contrast media and topical antiseptics. The aim of the present study was to identify the proportion of neonates with CHD exposed to iodine who developed hypothyroidism and to identify the associated risk factors. This was a retrospective study of neonates undergoing cardiac catheterization at Boston Children's Hospital during a 3-year period, some of whom also underwent cardiac surgery. Hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>20 mIU/L at 24 to 96 hours of age and >15 mIU/L at >96 hours of age by heel-stick sampling and >9.1 mIU/L at 1 to 20 weeks of age by serum testing). Multivariate logistic regression was performed to predict the odds of developing hypothyroidism. Hypothyroidism was diagnosed incidentally in 46 of 183 infants (25%) with CHD after iodine exposure. Controlling for baseline cardiac risk, postnatal age, and gestational age, we found a fourfold increase in odds of developing hypothyroidism in neonates with serum creatinine >0.9 mg/dL and a fourfold increase in those who underwent more than three procedures. Hypothyroidism in neonates with CHD exposed to excess iodine is associated with multiple procedures and impaired renal function. Routine serial monitoring of thyroid function in these neonates is warranted. Future studies should examine the association between hypothyroidism and neurocognitive function in this population. PMID- 29264561 TI - Association Between Bone Mineral Density and Pancreatic beta-Cell Function in Elderly Men and Postmenopausal Women. AB - Purpose: To explore the association between bone mineral density (BMD) and beta cell function. Methods: A cross-sectional study was performed in Fujian, China, from 2011 to 2012. The study included 572 elderly men older than age 60 years and 1558 postmenopausal women aged 45 to 86 years, excluding those with diabetes and insulin resistance. Fasting glucose and insulin concentrations were measured. Pancreatic beta-cell function was estimated by using the homeostasis model assessment (HOMA-beta). Calcaneus BMD was measured by using quantitative ultrasonography. Multiple regression analyses were applied to explore the association. Results: Participants with decreased BMD had lower fasting glucose (P < 0.001 in postmenopausal women; P = 0.007 in elderly men) and greater HOMA beta (P = 0.001 in postmenopausal women; P = 0.008 in elderly men) than those with normal BMD, whereas no statistical differences in insulin were seen among categories of BMD. After adjustment for all confounders, HOMA-beta was still significantly negatively related to BMD in both groups (all P < 0.001), and remarkable positive relationships were found between BMD and fasting glucose. Furthermore, binary logistic regression presented fully adjusted odds ratios for diabetes in those with osteoporosis vs those with normal BMD: 0.60 [95% confidence interval (CI), 0.38 to 0.94] and 0.66 (95% CI, 0.49 to 0.91) in the original selected population of elderly men (n = 1070) and postmenopausal women (n = 2825), respectively. Conclusions: BMD was independently inversely associated with HOMA-beta and positively associated with fasting glucose in both elderly men and postmenopausal women, suggesting that bone mass may be a predictor of glucose metabolism. Further research is needed to verify the associations and determine the exact mechanism underlying them. PMID- 29264562 TI - Serum Testosterone Concentrations Remain Stable Between Injections in Patients Receiving Subcutaneous Testosterone. AB - Purpose: Intramuscular (IM) testosterone is the most common modality for testosterone therapy of both male hypogonadism and female-to-male (FTM) gender transition. However, IM injections can be painful and often are not self administered by the patient. The objective of this study was to further characterize subcutaneous (SC) administration of testosterone as an effective and safe alternative to IM injections by evaluating the pharmacodynamics of serum total and free testosterone concentrations between weekly testosterone injections. Methods: Eleven FTM transgender patients already receiving weekly SC testosterone cypionate with documented therapeutic levels prior to enrollment had free and total serum testosterone levels measured at eight different time points during a 1-week dosing interval. Results: Mean levels of total and free testosterone were stable and remained well within the normal range between injections. Overall mean +/- standard deviation levels for the seven samples taken between injections were 627 +/- 206 ng/dL (range, 205 to 1410) for total testosterone and 146 +/- 51 pg/mL (range, 38 to 348) for free testosterone. No adverse effects were encountered. Conclusions: The results of this study support use of SC testosterone to achieve therapeutic and stable serum testosterone levels for the purpose of gender transition. It is anticipated that these results can be extended to hypogonadal men. This route may be preferred over IM testosterone because it is relatively painless and easy to self-inject thus allowing for the convenience and economy of patient self-administration. PMID- 29264563 TI - Pseudoacromegaly: A Differential Diagnostic Problem for Acromegaly With a Genetic Solution. AB - Acromegaly is usually not a difficult condition to diagnose once the possibility of this disease has been raised. However, a few conditions present with some aspects of acromegaly or gigantism but without growth hormone (GH) excess. Such cases are described as "pseudoacromegaly" or "acromegaloidism". Here we describe a female patient investigated for GH excess at 10 years of age for tall stature since infancy (height and weight > +3 standard deviations) and typical acromegalic features, including large hands/feet, large jaw, tongue, hoarse deep voice, and headache. Results of radiography of the sella turcica and GH response at an oral glucose tolerance test and insulin-arginine- thyrotrophin-luteinizing hormone-releasing hormone test were normal. Ethinylestradiol and medroxyprogesterone were given for 2 years; this successfully stopped further height increase. Although the patient's growth rate plateaued, coarsening of the facial features and acral enlargement also led to investigations for suspicion of acromegaly at 23 and 36 years of age, both with negative results. On referral at the age of 49 years, she had weight gain, sweating, sleep apnea, headaches, joint pain, and enlarged tongue. Endocrine assessment again showing normal GH axis was followed by genetic testing with a macrocephaly/overgrowth syndrome panel. A denovo mutation in the NSD1 gene (c.6605G>C; p.Cys2202Ser) was demonstrated. Mutations affecting the same cysteine residue have been identified in patients with Sotos syndrome. In summary, Sotos syndrome and other overgrowth syndromes can mimic the clinical manifestations of acromegaly or gigantism. Genetic assessment could be helpful in these cases. PMID- 29264564 TI - Congenital Adrenal Hyperplasia Presenting as an Adrenal Mass With Increased 18F FDG Positron Emission Tomography Uptake. AB - This article describes congenital adrenal hyperplasia presenting as an adrenal mass with increased 18F-FDG positron emission tomography uptake. PMID- 29264565 TI - Aromatase Blockade Is Associated With Increased Mortality in Acute Illness in Male Mice. AB - Context: The increase in circulating estrogen levels with acute illness in humans is accompanied by increased aromatase expression in adipose tissue and increased peripheral aromatization of estrogens to androgens. Animal studies indicate that estrogen may be beneficial in acute illness. Objective: We hypothesized that blockade of aromatase in acute illness would decrease survival. Design: Prospective sham controlled. Setting: Maine Medical Center Research Institute animal facility. Animals: Six- to 8-week-old male black 6 mice. Intervention: Mice underwent cecal ligation and puncture (CLP) to induce acute illness and were administered letrozole to block aromatase or saline. Mice undergoing sham surgery with or without letrozole served as controls. Adipose and cardiovascular tissue was harvested for preliminary evaluation of aromatase expression. Main outcome measurements: Survival was the main outcome measurement. Evidence for aromatase expression in tissue samples was assessed using western blot and/or immunohistochemistry. Results: With aromatase blockade, survival in CLP mice was decreased (P = 0.04). The presence of aromatase in adipose tissue was observed by western blot in CLP but not control mice. Similarly, the presence of aromatase was observed in cardiac tissue of CLP but not in control mice. Conclusions: The decreased survival during sepsis with aromatase blockade suggests that this response to acute illness may be important both physiologically and clinically. The preliminary observation of aromatase expression in adipose and cardiovascular tissue during acute illness in this mouse model indicates that this model has parallels to human physiology and may be useful for further studying the aromatase response to acute illness. PMID- 29264566 TI - Insulinoma and Tuberous Sclerosis: A Possible Mechanistic Target of Rapamycin (mTOR) Pathway Abnormality? AB - A 23-year-old New Zealand Maori male with tuberous sclerosis (TSC) and associated neurocognitive abnormalities presented with altered behavior and increasing seizure frequency. Endogenous hyperinsulinemia from an underlying insulinoma was confirmed and this was managed surgically. This case represents only the sixth description of insulinoma in TSC to date. The role of the hamartin-tuberin complex in regulation of the mechanistic target of rapamycin pathway provides a plausible pathogenetic mechanism between insulinoma and TSC. This rare disease association should be considered in TSC patients who present with otherwise unexplained worsening neurocognitive symptoms. PMID- 29264567 TI - Somatic VHL Mutation in a Patient With MEN1-Associated Metastatic Pancreatic Neuroendocrine Tumor Responding to Sunitinib Treatment: A Case Report. AB - Multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) are autosomal-dominant diseases caused by germline mutations in tumor-suppressor genes. A patient with a germline MEN1 mutation and a somatic VHL mutation in the tumor has not been reported. Herein, we report on a patient with MEN1 and a metastatic nonfunctioning pancreatic neuroendocrine tumor (PNET) with a somatic VHL mutation. This patient underwent a pancreaticoduodenectomy for a grade 2 PNET obstructing her pancreatic duct. The patient developed liver and regional lymph node metastases as well as growth of a PNET in the remnant pancreas. As part of a clinical trial for mutation-targeted therapy, a biopsy of the metastatic tumor was obtained. The clinical diagnosis, confirmed by OncoVAR-NET and molecular profiling analysis, revealed MEN1 with a germline deletion in exon 2 and a c.402 deletion C, p.Phe134LeufsX51. In addition, a somatic mutation in the VHL gene-a nonsense mutation, c.529A>T, p.Arg177Ter-was identified by hybrid capture sequencing. The mutations were confirmed by Sanger sequencing. Comparative genomic hybridization showed loss of heterozygosity in both the MEN1 and VHL genes. The patient was treated with sunitinib and had a partial response to treatment. This case illustrates not only that a second hit occurs in tumor suppressor genes but that somatic mutations are also possible in additional tumor suppressor genes. This suggests that targeted therapy selection should include analysis of somatic mutations even when the susceptibility gene is known. PMID- 29264569 TI - Gestational Primary Hyperparathyroidism Due to Ectopic Parathyroid Adenoma: Case Report and Literature Review. AB - Gestational primary hyperparathyroidism (GPHPT) is a rare condition with fewer than 200 cases reported. We present the case of a 21-year-old woman who presented at 10 weeks' gestation with severe hypercalcemia. Laboratory investigation was consistent with primary hyperparathyroidism. Neck ultrasound did not reveal any parathyroid enlargement. Due to the persistence of severe hypercalcemia, she was treated with 4 weeks of cinacalcet therapy, which was poorly tolerated due to nausea and vomiting. At 14 weeks' gestation, she underwent neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. Intra- and postoperative parathyroid hormone (PTH) and calcium levels remained elevated. After a thorough discussion of risks/benefits, the patient requested further treatment. A parathyroid sestamibi scan (PSS) revealed an ectopic adenoma in the left mediastinum. The adenoma was removed via video-assisted thorascopic parathyroidectomy with intraoperative PTH declining to nearly undetectable levels. She ultimately delivered a physically and developmentally normal infant at 37 weeks' gestation. Appropriate treatment of severe GPHPT may prevent the maternal and fetal complications of hypercalcemia. This case, in which cinacalcet therapy and PSS were used, adds to the body of literature regarding treatment of severe GPHPT. PMID- 29264568 TI - Acute Homeostatic Changes Following Vitamin D2 Supplementation. AB - Context: Changes in vitamin D binding protein (DBP) concentrations and catabolism of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D (24,25D) after vitamin D2 supplementation may alter concentrations and bioavailability of circulating 25 hydroxyvitamin D (25D). Objective: Examine acute changes in vitamin D metabolism and bioavailability after vitamin D2 supplementation. Methods: Study design was secondary analysis of a single-arm interventional study. Thirty consenting volunteers were treated with five 50,000 IU oral doses of ergocalciferol over 2 weeks. Main outcome measures included concentrations of DBP, vitamin D metabolites, and bioavailable 25-hydroxyvitamin D (25D) in pre- and posttreatment serum samples. Results: After supplementation, 25D2 (mean +/- standard deviation) increased from 1.4 +/- 0.9 ng/mL to 45.3 +/- 16.5 ng/mL (P < 0.0001), and 25D3 levels decreased from 26.8 +/- 9.9 ng/mL to 19.7 +/- 8.2 ng/mL (P < 0.0001). Total 25D (25D2 plus 25D3) increased from 28.2 +/- 10.0 ng/mL to 65.0 +/- 21.1 ng/mL (152.2% +/- 102.5%; P < 0.0001). DBP and total 24,25D concentrations increased 39.1% +/- 39.4% (165.6 +/- 53.8 ug/mL to 222.0 +/- 61.1 ug/mL; P < 0.0001) and 31.3% +/- 48.9% (3.9 +/- 2.0 ng/mL to 4.7 +/- 2.1 ng/mL; P = 0.0147), respectively. In contrast to total 25D, bioavailable 25D increased by 104.4% +/- 99.6% (from 5.0 +/- 2.0 ng/mL to 8.7 +/- 2.7 ng/mL; P < 0.001), and 1,25D increased by 32.3% +/- 38.8% (from 45.5 +/- 10.7 pg/mL to 58.1 +/- 13.0 pg/mL; P = 0.0006). There were no changes in calcium or parathyroid hormone (P > 0.05 for both). Conclusion: Changes after vitamin D2 supplementation involve acute rise in serum DBP and 24,25D, both of which may attenuate the rise in bioavailable 25D and 1,25D. PMID- 29264570 TI - Use of Cinacalcet and 99mTc-sestamibi Imaging During Pregnancy. AB - A case report is reviewed, in which two nontraditional interventions were used in a patient with gestational primary hyperparathyroidism: cinacalcet and technetium 99m methoxyisobutylisonitrile imaging. The rationale for these decisions is considered in view of the available data. PMID- 29264571 TI - Infants With Congenital Adrenal Hyperplasia Are at Risk for Hypercalcemia, Hypercalciuria, and Nephrocalcinosis. AB - Context: Hypercalcemia is reported as a rare finding in adrenal insufficiency, but is not well described in congenital adrenal hyperplasia (CAH). Methods: A retrospective chart review was conducted of patients with CAH diagnosed before the age of 2 years who had at least one recorded serum calcium measurement. Data from birth to 6 years of age were reviewed. Results: Of the 40 patients who met inclusion criteria, 33 (82.5%) had at least one elevated calcium concentration and 21 (53%) had two or more elevated calcium concentrations. Of the 126 elevated serum calcium concentrations, the median was 10.9 mg/dL (range, 10.6 to 14.2 mg/dL). Median age at the last elevated calcium measurement was 5 months (range, 0.3 to 46 months). Serum calcium concentration was inversely related to age (r = 0.124; P = 0.004). Overall, calcium level positively correlated with 17 hydroxyprogesterone (17OHP) concentration (r = 0.170; P = 0.003), and this remained significant after adjusting for age (P < 0.05). However, patients had hypercalcemia with both high and low 17OHP concentrations. Serum calcium concentration also was positively related to glucocorticoid (r = 0.196; P = 0.012) and fludrocortisone (r = 0.229; P = 0.003) doses, and remained significant after age adjustment. Only seven patients were evaluated for hypercalciuria. Of these, six had at least one period of documented hypercalciuria. Three patients had nephrocalcinosis on renal ultrasound. Conclusion: Children with CAH are at risk for developing hypercalcemia, hypercalciuria, and nephrocalcinosis. Further studies are needed to determine the broader prevalence and the etiology of hypercalcemia in CAH. PMID- 29264572 TI - Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin. AB - Context: Patients with diabetes often have comorbidities such as hypertension. It is not known how individual characteristics influence response to dipeptidyl peptidase-4 (DPP4) inhibitors. Objective: We tested the hypothesis that individual characteristics, sitagliptin dose, and genetic variability in DPP4 influence DPP4 activity during sitagliptin. Design and Setting: Post hoc analysis of clinical and laboratory data from individuals randomized to sitagliptin versus placebo in crossover studies. Patients and Interventions: Sixty-five subjects [27 with type 2 diabetes mellitus (T2DM) and hypertension, 38 healthy controls] were randomized to 100 mg/d sitagliptin or 200 mg sitagliptin and matching placebo in double-blind, crossover fashion. Fasting blood was obtained at baseline and 60 to 180 minutes after sitagliptin or placebo. Main Outcome Measures: DPP4 activity and antigen during placebo and sitagliptin and DPP4 inhibition during sitagliptin. Results: Sitagliptin 100 mg/d was less effective at inhibiting DPP4 activity in individuals with T2DM and hypertension than in healthy controls (P = 0.001, percent inhibition). In healthy controls, 100 mg/d sitagliptin was not as effective as single-dose 200 mg sitagliptin (P = 0.001, percent inhibition). DPP4 genotypes rs2909451 TT (P = 0.02) and rs759717 CC (P = 0.02) were associated with DPP4 activity during sitagliptin. In multivariable analyses, T2DM with hypertension, sitagliptin dose, age, systolic blood pressure, DPP4 activity during placebo, and rs2909451 genotype were significantly associated with DPP4 activity during sitagliptin. Conclusions: Sitagliptin is less effective in inhibiting DPP4 in individuals with T2DM and hypertension than in healthy controls. Higher doses of DPP4 inhibitors may be required in patients with the metabolic syndrome. PMID- 29264573 TI - Hypocalciuria as a Predictor of Reduced Intestinal Calcium Absorption. AB - Impaired intestinal calcium absorption contributes to osteoporosis, but its measurement is limited to research settings. We hypothesized that 24-hour urine calcium (24HUC) values could diagnose low fractional calcium absorption (FCA). We performed a post hoc analysis of clinical trial data to determine whether 24HUC predicted low FCA compared with the gold standard dual calcium isotope method. Two hundred thirty postmenopausal women <75 years old without osteoporosis underwent 445 FCA measurements using calcium isotopes (8 mg of oral 44Ca, 3 mg of intravenous 42Ca) and a 24-hour inpatient urine collection at 0 and 12 months. We determined subjects' total calcium intake via review of food diaries and supplements. Net calcium absorption (NCA) was total calcium intake * FCA. NCA and 24HUC values demonstrated a positive correlation (r = 0.34; 95% confidence interval, 0.25 to 0.42; P < 0.001). We calculated sensitivity, specificity, positive (PPV) and negative predictive value (NPV) for the ability of 24HUC thresholds to predict calcium malabsorption. When low calcium absorption was defined as <120 mg/d, a 24HUC value <150 mg demonstrated 65% sensitivity, 67% specificity, 31% PPV, and 89% NPV. When calcium malabsorption was defined as <100 mg/d, a 24HUC value <150 mg demonstrated 72% sensitivity, 65% specificity, 22% PPV, and 94% NPV. A 24HUC value <150 mg demonstrated a high NPV for calcium malabsorption. We suggest that 24HUC levels can exclude calcium malabsorption in postmenopausal women. PMID- 29264574 TI - Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With Childhood Onset Hypophosphatasia. AB - Hypophosphatasia is an inherited disease characterized by reduced alkaline phosphatase activity, extracellular accumulation of inorganic pyrophosphate, and impaired bone mineralization. Asfotase alfa (AA) is a recombinant human alkaline phosphatase therapy approved for treatment of pediatric-onset hypophosphatasia. Studies show promising outcome in AA-treated children with hypophosphatasia; however, data on adults with pediatric-onset hypophosphatasia are scarce. We report on a 59-year-old woman with childhood-onset hypophosphatasia and a history of multiple fractures and orthopedic procedures. Owing to renal failure (histological diagnosis: focal segmental glomerulosclerosis), hemodialysis was started in 2013. By the end of 2015, the patient was unable to walk, could only stand for 30 seconds, and was completely dependent on help for activities of daily living. After 13 months of AA therapy, the patient showed a dramatic increase in quality of life (increased mobility), reduction in pain medication, and a significant improvement in bone mineralization throughout the skeleton, including consolidation of existing fractures and no occurrence of new fractures. This case report demonstrates a relevant therapeutic success of AA treatment in an adult hemodialysis patient with childhood onset of hypophosphatasia. PMID- 29264575 TI - The Jewel in the Crown: Specific Aims Section of Investigator-Initiated Grant Proposals. AB - The specific aims section of National Institutes of Health and other grants is the most important component, as it summarizes the scientific premise, gap in current knowledge, hypotheses, methods, and expected results of the project proposed. The reviewer usually reads this section first and forms an immediate opinion, usually confirmed on reading the entire grant. This treatise reviews the philosophical background underlying generation of hypotheses, emphasizes the important characteristics of the specific aims section, and offers a point-by point roadmap for writing. This perspective arose out of a new Endocrine Society initiative in which senior investigators review the specific aims of next generation members. PMID- 29264577 TI - A Patient (46XX) With Congenital Adrenal Hyperplasia and Prostate Cancer: A Case Report. AB - Congenital adrenal hyperplasia (CAH) can affect sex characteristics. The most common cause of CAH is 21-hydroxylase deficiency, and the cornerstone of treatment is glucocorticoid replacement in adrenocorticotropic hormone suppressive dosages. A 64-year-old patient (46XX) with CAH resulting from 21 hydroxylase deficiency had been treated with dexamethasone and testosterone since diagnosis at age 12 and was phenotypically male. At age 62, he was diagnosed with prostate carcinoma. The patient received curative treatment with external beam radiotherapy. Genotypically female patients with CAH can develop prostate carcinoma when receiving long-term testosterone replacement therapy. PMID- 29264576 TI - Homozygous Resistance to Thyroid Hormone beta: Can Combined Antithyroid Drug and Triiodothyroacetic Acid Treatment Prevent Cardiac Failure? AB - Resistance to thyroid hormone beta (RTHbeta) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHbeta, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHbeta had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHbeta in which life-threatening hyperthyroid features predominate. PMID- 29264578 TI - Clopidogrel-Induced Insulin Autoimmune Syndrome: A Newly Recognized Cause of Hypoglycemia in a Patient Without Diabetes. AB - Insulin autoimmune syndrome (IAS), defined as hyperinsulinemic hypoglycemia with high titers of anti-insulin antibodies, is frequently reported in Japanese patients but rarely observed in whites. We report in this study on a 79-year-old white male without diabetes who developed IAS following exposure to clopidogrel, a drug not previously known to cause hypoglycemia. The patient presented with recurrent symptomatic hypoglycemia. During one episode, serum glucose was 45 mg/dL, whereas insulin and C-peptide levels were 40,000 mIU/mL and 40 ng/mL, respectively. Additional studies revealed no intake of insulin or its secretagogues, whereas anti-insulin antibody titer was high (59.3 nmol/L). Although total insulin levels were consistently high, free insulin concentrations (polyethylene glycol precipitation) were appropriate for ambient glycemia. The patient was found to have HLA-DRB1*0404, a feature often reported in Japanese patients with IAS. Three weeks prior to symptom onset, he was started on clopidogrel, a drug that does not have a sulfhydryl group, but its active metabolite does. Clopidogrel was switched to a nonsulfhydryl antiplatelet agent, and glucocorticoid therapy was initiated. Shortly thereafter, the frequency of hypoglycemic episodes decreased, and glucocorticoids were tapered over the ensuing 3 months. No hypoglycemic episodes were noted during 6 months of observation after discontinuing glucocorticoids, whereas the total insulin and anti-insulin antibody levels normalized. The data indicate that IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia in seemingly well individuals, even when no drugs known to cause IAS were used. Clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients. PMID- 29264579 TI - Promoter methylation of cysteine dioxygenase type 1: gene silencing and tumorigenesis in hepatocellular carcinoma. AB - Backgrounds/Aims: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor and is silenced by promoter methylation in various malignancies. The relationship between the CDO1 methylation status and hepatocellular carcinoma (HCC) tumorigenesis was evaluated. Methods: Using a HCC cell line (SNU423), an in vitro demethylation study was performed to confirm whether promoter methylation causes CDO1 down-regulation. The SNU423 cells transfected with the CDO1 cell function was compared to that of naive cells. An in vivo study using immunohistochemical staining of HCC specimens that were collected from patients who underwent curative liver resection was also performed. Results: CDO1 was activated after demethylation treatment in the HCC specimens. Moreover, tumor cell proliferation, colony-forming, migration, and invasion activities significantly decreased after CDO1 transfection (p<0.05). The percentage of tumors that were larger than 5 cm was higher in patients who had a lower expression of CDO1 (p=0.030). Vascular invasion and histological grade were independent prognostic factors for poor overall and recurrence-free survival. The degree of CDO1 expression was not an independent prognostic factor in this study's population. Conclusions: These results suggested that methylation down-regulated CDO1 expression in the HCC cells. CDO1 methylation may be a potentially valuable diagnostic biomarker for HCC. PMID- 29264580 TI - Significance of liver hanging maneuver for anatomical hepatectomy in patients with a large hepatocellular carcinoma compressing intrahepatic vasculatures. AB - Backgrounds/Aims: To achieve complete anatomic hepatectomy in a large hepatocellular carcinoma (HCC), hepatic transection through an anterior approach is required. Liver hanging maneuver (LHM) is a useful procedure for transection of an adequately cut plane in anatomical liver resection. It may reduce intraoperative bleeding and transection time. Methods: We examined records of 27 patients with large HCC (over 10 cm in size) who underwent anatomic hepatic resection with LHM (n=11, between 2001 and 2007) or without LHM (n=16, between 2000 and 2003). The two groups were retrospectively compared in terms of patient demographics, preoperative hepatic function, surgical records, and post hepatectomy outcome. Results: Although transection time was not significantly different between the two groups, the amount of intraoperative blood loss was significantly lower in the LHM group than that in the non-LHM group (1,269+/ 1,407 ml vs. 2,197+/-1,281 ml, p=0.039). Related blood transfusion or total operation time in the LHM group tended to be lower than those in the non-LHM group, although differences between the two groups were not statistically significant (p<1.0). Prevalence of total complications in the LHM group tended to be lower than that in the LHM group (36% vs. 88%, p=0.011). However, prevalence of hepatectomy-related complications or length of hospital stay was not significantly different between the two groups. Conclusions: LHM can reduce intraoperative blood loss. It is useful for transecting adequately cut plane in a hepatectomy for a large HCC. However, postoperative outcomes are not improved by LHM compared to those by non-LHM. PMID- 29264581 TI - Clinical usefulness of FDG-PET in patients with hepatocellular carcinoma undergoing surgical resection. AB - Backgrounds/Aims: Diagnosis and staging of hepatocellular carcinoma (HCC) is critical because of the variety of treatment methods and prognosis. [18F]fludeoxyglucose-positron emission tomography/computed tomography ([18F]FDG PET/CT) has been suggested as a diagnostic modality in HCC. The purpose of this study is to evaluate the accuracy of FDG-PET for staging of HCC after surgical resection and histological confirmation. Methods: We retrospectively collected data of 56 patients that underwent FDG-PET before surgical resection for HCC March 2011-May 2017, all of whom were suitable for resection by conventional HCC staging. Results of the maximal standardized uptake value (SUVmax) were compared with histological confirmation. Results: A larger tumor size was related with higher SUVmax (>=4.9). The serum alpha-feto protein was associated with SUVmax. Recurrence rate was higher in patients with higher SUVmax and patients with lower SUVmax had a better survival rate. Conclusions: The SUVmax correlates well with tumor size and factors associated with biological behavior of HCC such as alpha feto protein, and it could be a beneficial modality in providing prognostic information for HCC. PMID- 29264582 TI - Successful introduction of Model for End-stage Liver Disease scoring in deceased donor liver transplantation in Korea: analysis of first 1 year experience at a high-volume transplantation center. AB - Backgrounds/Aims: Model for End-stage Liver Disease (MELD) score was adopted in June 2016 in Korea. Methods: We analyzed changes in volumes and outcomes of deceased donor liver transplantation (DDLT) for 1 year before and after introduction of MELD scoring at Asan Medical Center. Results: There were 64 cases of DDLT in 1 year before MELD introduction and 106 in 1 year after MELD introduction, an increase of 65%. The volume of DDLTs abruptly increased during first 3 months, but then returned to its usual level before MELD introduction, which indicated 3-month depletion of accumulated recipient pool with high MELD scores. The number of pediatric DDLT cases increased from 3 before MELD introduction to 11 after it, making up 21.4% and 47.8% of all cases of pediatric liver transplantation, respectively. The number of cases of retransplanted DDLTs increased from 4 to 27, representing 6.3% and 25.5% of all DDLT cases, respectively. The number of status 1 DDLT cases increased from 5 to 12, being 7.8% and 11.3% of all cases. Patient survival outcomes were similar before and after MELD introduction. Conclusions: The number of DDLTs temporarily increased after adoption of MELD scoring due to accumulated recipient pool with high MELD scores. The numbers of retransplanted and pediatric DDLT cases significantly increased. Patient survival in adult and pediatric DDLT was comparable before and after adoption of MELD scoring. These results imply that Korean MELD score-based allocation system was successfully established within its first year. PMID- 29264583 TI - Assessing the role of everolimus in reducing hepatocellular carcinoma recurrence after living donor liver transplantation for patients within the UCSF criteria: re-inventing the role of mammalian target of rapamycin inhibitors. AB - Backgrounds/Aims: The protective effect of everolimus (EVR) in hepatocellular carcinoma (HCC) patients who receive liver transplantation in terms of reducing the recurrence has not been sufficiently investigated in clinical trials. In this second stage of our ongoing study, we intend to analyze the effects of EVR as an immunosuppressant, when it is started in the early phase after living donor liver transplantation (LDLT), on HCC recurrence in patients with HCC within the University of California at San Francisco (UCSF) criteria. Methods: From January 2011 to June 2013, a total of 250 patients underwent LDLT for HCC at our institute. The patients with HCC within the UCSF criteria were included in the study and divided in two groups depending upon the postoperative immunosuppression. Group A: HCC patients that received EVR+TAC based immunosuppressive regimen (n=37). Group B: HCC patients that received standard TAC based immunosuppressive regimen without EVR (n=29). The target trough level for EVR was 3 to 5 ng/ml while for TAC it was 8-10 ng/ml. Results: For group A patients, the mean trough level of the EVR was 3.47+/-1.53 ng/ml (range, 1.5 11.2) with a daily dose of 1.00+/-0.25 mg/day. For group A and B, the average TAC trough levels were 6.97+/-3.98 ng/ml (range, 2.50 to 11.28 ng/ml) and 6.93+/-2.58 (range, 2-16.30), respectively. The 1-year, 3-year and 4-year overall survival achieved for Group A patients was 94.95%, 86.48% and 86.48%, respectively while for Group B patients it was 82.75%, 68.96%, and 62.06%, respectively (p=0.0217). Conclusions: EVR use in liver transplant recipients in the early stage after transplantation reduces the HCC recurrence rates in HCC patients within the UCSF criteria. PMID- 29264584 TI - Effect of preoperative biliary stenting on post-operative infectious complications in pancreaticoduodenectomy. AB - Backgrounds/Aims: The impact of pre-operative biliary stenting (PBS) in patients undergoing pancreaticoduodenectomy on post-operative infectious complications is unclear. Therefore, the purpose of this study is to investigate the relationship between PBS and post-operative infectious complications, to determine the effect of PBS on bile bacteriology, and to correlate the bacteriology of bile and bacteria cultured from post-operative infectious complications in our institute. Methods: Details of 51 patients undergoing pancreaticoduodenectomy January 2011 April 2015 were reviewed. Of 51 patients, 30 patients underwent pre-operative biliary stenting (PBS group) and 21 patients underwent pancreaticoduodenectomy without pre-operative biliary stenting. Post-operative infectious complications were compared between the two groups. Results: Overall post-operative infectious complication rate was 77% and 67% in the PBS and non-PBS groups respectively. Wound infection was the main infectious complication followed by intraabdominal abscess. The rate of wound infection doubled in the PBS group (50% vs 28%). There was slight increase in incidence of intraabdominal abscess in PBS group (53% vs 46%). 80% of PBS patients had positive intraoperative bile culture as compared to 20% in non-PBS group. Conclusions: Preoperative biliary drainage prior to pancreaticoduodenectomy increases risk of developing post-operative wound infections and intra-abdominal collections. PMID- 29264585 TI - Totally laparoscopic associating liver partition and portal vein ligation for staged hepatectomy using anterior approach in HCC patient with Type II portal vein anomaly: a case report. AB - Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has gradually developed because of rapid hypertrophy of the future liver remnant volume (FLR) in spite of high morbidity. To minimize the patient's postoperative pain and morbidity including wound complication caused by two consecutive major abdominal operations, we adopted a totally laparoscopic approach and used a composite mesh graft. Also, to maximize the oncologic efficacy, we adopted the "anterior approach" technique. A 44-year-old woman with large hepatitis B-related hepatocellular carcinoma (HCC) in her right lobe was transferred to our hospital for surgical treatment. Preoperatively predicted FLR by a CT scan was 21% and type II portal vein anomaly was detected. A totally laparoscopic approach was planned. During the first stage operation, right anterior and posterior portal veins were meticulously dissected and tied. After parenchymal transection by the "anterior approach" technique, two glissonian pedicles of the right liver were individually isolated. A composite mesh graft was used to prevent severe adhesion on both liver partition surfaces. During the second-stage operation, 9 days after the first stage operation, the two isolated glissonian pedicles were initially transected. After full mobilization of the right lobe, the right hepatic vein was also transected. The right lobe was removed through the Pfannenstiel incision. She was discharged 7 days after the second stage operation. Her postoperative course was uneventful and there was no HCC recurrence for 15 months after hepatectomy. A totally laparoscopic ALPPS procedure can be a feasible technique that ensures patient safety and oncologic superiority, even in patients with complicated anatomical variation. PMID- 29264586 TI - ALPPS in a patient with periductal infiltrating intrahepatic cholangiocarcinoma. AB - Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is a novel method to prevent post-hepatectomy hepatic failure. We present a case of periductal infiltrating intrahepatic cholangiocarcinoma undergone ALPPS, that was conducted as intraoperative choice instead of conducting preoperative portal vein embolization (PVE). A 65-year-old male patient was to undergo extended right posterior sectionectomy, but the operation plan was changed to conduct right hepatectomy with/without bile duct resection due to invasion of the right hepatic duct. After deciding to conduct ALPPS, we stopped further perihilar dissection and liver was transected. The right portal vein was ligated and Surgicel was densely packed between the transected hemilivers. There was rapid regeneration of the left liver on computed tomography follow-up, thus the second-stage right hepatectomy was conducted 10 days after the first-stage operation. Bile duct resection (BDR) was not performed due to heavy perihilar adhesion and inflammation, but fortunately tumor-negative bile duct resection margin was achieved after meticulous dissection. This patient recovered uneventfully and discharged nine days after the second-stage right hepatectomy. Thereafter he underwent concurrent chemoradiation therapy. He is doing well so far without evidence of tumor recurrence for 20 months after operation. In conclusion, this case suggests that ALPPS may be applied to an unexpected situation requiring PVE, but ALPPS is not recommend for treatment of perihilar malignancy requiring BDR. PMID- 29264587 TI - Primary gigantic leiomyosarcoma of the liver treated with portal vein embolization and liver resection. AB - Primary hepatic leiomyosarcoma (PHL) is an extremely rare tumor. The tumor has no specific presentations and often diagnosis is delayed until it reaches a significant size. We report the case of a 69-year-old female presented with a huge PHL. Due to size of the tumor and to be operable, the patient subjected to right portal vein embolization (PVE) and selective embolization of segment V. Four weeks after the PVE, liver resection was conducted (Segments V+VI bisegmentectomy plus resection of IVA). The patient had an uncomplicated post operative course, and discharged at the 8th post-operative day. Diagnosis of PHL was confirmed by histopathological and immunohistochemical examinations. The patient refused to receive adjuvant chemotherapy, and revealed evidence of recurrence six months after the operation, and finally died 12 months after the operation and 16 months after initial diagnosis. PHL is an extremely rare tumor and often in first presentation has significant size. Radical surgery with adjuvant chemotherapy is key feature for prolonged survival. PMID- 29264588 TI - Diaphragmatic herniation following donor hepatectomy for living donor liver transplantation: a serious complication not given due recognition. AB - A clear appreciation of benefits and risks associated with living donor hepatectomy is important to facilitate counselling for the donor, family, and recipient in preparation for living donor liver transplant (LDLT). We report a life-threatening complication occurring in one of our live liver donors at 12 weeks following hemi-liver donation. We experienced five donor complications among our first 50 LDLT: Clavien Grade 1, n=1; Clavien grade 2, n=3; and Clavien grade 3B, n=1. The one with Clavien grade 3B had a life-threatening diaphragmatic hernia occurring 12 weeks following hepatectomy. This was promptly recognized and emergency surgery was performed. The donor is well at 1-year follow-up. Here we provide a review of reported instances of diaphragmatic hernia following donor hepatectomy with an attempt to elucidate the pathophysiology behind such occurrence. Life-threatening donor risk needs to be balanced with recipient benefit and risk on a tripartite basis during the counselling process for LDLT. With increasing use of LDLT, we need to be aware of such life-threatening complication. Preventive measures in this regard and counselling for such complication should be incorporated into routine work-up for potential live liver donor. PMID- 29264589 TI - Extra-gastrointestinal stromal tumor of the pancreas: report of a case. AB - Gastrointestinal tumors (GISTs) of the pancreas are extremely rare with limited individual case reports and small number of case series. Herein, we report a case of pancreatic extragastrointestinal stromal tumor (EGIST) along with literature review. A 64-year-old female patient was referred to us for treatment of an abdominal mass detected by ultrasonographic examination. The tumor was located in the periamullary region. Under a preoperative diagnosis of a duodenal GIST, we performed a pylorus preserving pancreatoduodenectomy for this lesion. Laboratory examination results were within normal ranges. On pathologic gross examination, the tumor measured at 7 cm in its greatest dimension almost entirely involved the pancreatic head. Its cut surface was rubbery and white. It was surrounded by a thin pseudocapsule and well demarcated. Histopathological examination of the specimen showed a cellular lesion with compressed pancreatic tissue at peripheral. Mitotic count was 5 per 50 high-power fields. Immunohistochemically, neoplastic cells were positive for antibodies against C-KIT (CD117), CD 34, and vimentin. However, smooth-muscle actin reactions with antibodies against S-100 or desmin were negative. Based on above findings, the tumor was finally diagnosed as GISTs originating from the pancreas. The patient has been followed up postoperatively for 72 months. There is no evidence of recurrence. Here we report this case of pancreatic EGIST presenting as a solid neoplasm along with literature review of cases previously described. Our review on pancreatic EGISTs is limited and insufficient to make a conclusion regarding its clinical features. Those manifested large masses tended to have an aggressive biological and clinical behavior. Thus, pancreatic EGISTs need to be carefully differentiated. Adequate surgical intervention is necessary for pancreatic EGISTs. PMID- 29264590 TI - Xanthogranulomatous pancreatitis mimicking potentially malignant pancreatic neoplasm: report of a case. AB - Xanthogranulomatous pancreatitis (XGP) is a rare benign disease that may mimic or accompany other pancreatic diseases. Here we report a case of XGP initially suspected as malignant cystic neoplasm of the pancreas. A 64-year-old man had been incidentally found to have hypodense lesion at the body of pancreas during a lung cancer workup. All laboratory tests were within normal limits except that carcinoembryonic antigen was elevated to 31.3 ng/ml. Imaging study showed 1.8 cm sized, well demarcated, and low-attenuated mass on computed tomography (CT) with heterogeneously high intensity on T2-weighted images of magnetic resonance imaging (MRI). Under the impression of pancreas cystic neoplasm as a rare case of male solid-pseudopapillary tumor or pancreatic metastasis of lung cancer, laparoscopic distal pancreatectomy was performed. Microscopically, the mass had many foamy histiocytes with cholesterol clefts, consistent with xanthogranulomatous inflammation. Therefore, it is important to consider XGP in the differential diagnosis of pancreatic diseases. PMID- 29264591 TI - Metastatic adenocarcinoma of the pancreas presents as metastases to the axillary/supraclavicular region as the first sign of the disease. AB - Mucinous tumors of the pancreas are rare and the diagnosis of invasive carcinoma can be a dilemma. While metastatic disease from mucinous cystadenocarcinoma (MCAC) and invasive intraductal papillary mucinous neoplasms (IPMN) have been reported, no extraperitoneal mucinous cystic metastatic disease has been described. When metastatic, the overall survival rates for invasive adenocarcinoma, mucinous cystadenocarcinoma (MCAC) and invasive intraductal papillary mucinous neoplasms (IPMN) are similar. The best improvement in the overall and progression free survival has been demonstrated with FOLFIRINOX (folinic acid - fluorouracil - irinotecan - oxaliplatin) for metastatic adenocarcinoma and Gemcitabine based regimens for MCAC. However, the variable responses of metastatic mucinous lesions have been observed and the overall prognosis remains poor. We describe a case of a patient who presented with metastatic adenocarcinoma of the pancreas as cystic masses in the supraclavicular and axillary regions. Additionally, this patient was initially treated with FOLFIRINOX and continues to have stable primary and metastatic disease after 18 months from the diagnosis. PMID- 29264593 TI - pi-Bridge modification of thiazole-bridged DPP polymers for high performance near IR OSCs. AB - Thiophene-bridged and thiazole-bridged diketopyrrolopyrrole (DPP) polymers for near-infrared (near-IR) photovoltaic applications have been investigated via density functional theory (DFT) and Marcus charge transfer theory. Compared with thiophene-bridged DPP polymers, thiazole-bridged polymers have higher ionization potentials (IPs) but poorer optical absorption and worse charge transport capability. Different beneficial substituents replaced the hydrogen atoms (H) on the thiazole rings for the sake of reversing the disadvantages of thiazole bridged DPP polymers and making these compounds better near-infrared absorbing materials. In order to gain deep insight into the impact of pi-bridge modification on the photoelectronic properties of DPP polymers, their electronic structures, absorption capabilities, intramolecular charge transfer properties and charge transport performances have been analyzed. The calculated results reveal that pi-bridge modification is a feasible way to improve the light absorbing capability, electron excitation properties and charge transport performance of thiazole-bridged DPP polymers. It is expected that pi-bridge modification can also work for other polymers containing pi-bridge units. We hope that our research efforts will be helpful in the designing of new near-IR absorbing materials and could motivate further improvement of organic solar cells. PMID- 29264592 TI - High-resolution Temporal Representations of Alcohol and Tobacco Behaviors from Social Media Data. AB - Understanding tobacco- and alcohol-related behavioral patterns is critical for uncovering risk factors and potentially designing targeted social computing intervention systems. Given that we make choices multiple times per day, hourly and daily patterns are critical for better understanding behaviors. Here, we combine natural language processing, machine learning and time series analyses to assess Twitter activity specifically related to alcohol and tobacco consumption and their sub-daily, daily and weekly cycles. Twitter self-reports of alcohol and tobacco use are compared to other data streams available at similar temporal resolution. We assess if discussion of drinking by inferred underage versus legal age people or discussion of use of different types of tobacco products can be differentiated using these temporal patterns. We find that time and frequency domain representations of behaviors on social media can provide meaningful and unique insights, and we discuss the types of behaviors for which the approach may be most useful. PMID- 29264594 TI - Stable graphene oxide-gold nanoparticle platforms for biosensing applications. AB - Graphene oxide-gold nanoparticle (AuNPs@GO) hybrids were fabricated in water dispersions of graphene oxide (GO) and Au precursor completely free of stabilizing agents by UV-light irradiation. Gold nanoparticle (AuNP) nucleation, growth, and stabilization mechanisms at the surface of GO are discussed on the basis of UV-Vis, Raman, IR, and X-Ray photo-spectroscopy studies. The analyses of AuNPs@GO hybrids by transmission electron microscopy (TEM), thermogravimetric (TGA) and electrochemical tests show that they exhibit outstanding chemical, thermal and electrochemical stabilities. Thus, AuNPs@GO biosensing platforms were fabricated for surface enhanced Raman spectroscopy (SERS) detection of crystal violet (CV), a SERS standard molecule, and in a different set of experiments, for flavin adenine dinucleotide (FAD), a flavoprotein coenzyme that plays an important role in many oxidoreductase and reversible redox conversions in biochemical reactions. AuNPs@GO hybrids synthesized by using UV light irradiation show exceptional stability and high intensification of the Raman signals showing that they have high potential for use as biomedical probes for the detection, monitoring, and diagnosis of medical diseases. PMID- 29264595 TI - A metal-metalloporphyrin framework based on an octatopic porphyrin ligand for chemical fixation of CO2 with aziridines. AB - A new porous metal-metalloporphyrin framework, MMPF-10, has been constructed from an octatopic porphyrin ligand, which links copper paddlewheel units to form a framework with fmj topology. In situ metallation of the porphyrin ligands provides MMPF-10 with two unique accessible Cu(ii) centers. This allows it to behave as an efficient Lewis acid catalyst in the first reported reaction of CO2 with aziridines to synthesize oxazolidinones catalyzed by an MMPF. PMID- 29264596 TI - Superior non-enzymatic glucose sensing properties of Ag-/Au-NiCo2O4 nanosheets with insight from electronic structure simulations. AB - Ag-/Au-NiCo2O4 nanosheets were synthesized by a facile electrodeposition approach on conducting Ni foam, and their non-enzymatic glucose sensing performance was investigated. The hybrid nanosheets of NiCo2O4 and noble-metal nanoparticles supported on conductive Ni foam possessed high active surface area along with intrinsic electrocatalytic and biocatalytic properties and promoted electronic/ionic transport in the electrodes, leading to improved glucose sensing properties. The sensitivity of the bare NiCo2O4 nanosheets for electrochemical non-enzymatic glucose sensing was 20.8 MUA MUM-1 cm-2, whereas the NiCo2O4-Ag and NiCo2O4-Au nanosheet electrodes exhibited enhanced sensitivities of 29.86 and 44.86 MUA MUM-1 cm-2, respectively, with lower response times in the same linear range of 5-45 MUM. We also performed density functional theory simulations to corroborate our experimental observations by investigating the interactions and charge-transfer mechanism of glucose on Ag- and Au-doped NiCo2O4. As Au is bound more strongly to the NiCo2O4 surface compared to Ag, the binding energy of glucose is greater on the Au-doped NiCo2O4 surface than on the Ag-doped NiCo2O4 surface, and Au doping makes NiCo2O4 more conductive compared to Ag doping. Thus, it can be theoretically inferred that Au-doped NiCo2O4 has better glucose sensing performance, which supports our experimental data. PMID- 29264597 TI - A novel turn-on fluorescent probe for the multi-channel detection of Zn2+ and Bi3+ with different action mechanisms. AB - A novel multifunctional sensing material, RSPT, incorporating rhodamine B hydrazide, a Schiff base, and a phenolic hydroxyl group into triazine, was identified and prepared. After the molecular structure was characterized by FTIR, 1H NMR, mass spectra and element analysis, it was notably found that there were multichannel turn-on fluorescent responses to Zn2+ and Bi3+, i.e., a strong fluorescence emission at 481 nm in DMF-water (99/1, v/v) for Zn2+ with a color change from colorless to light yellow-green, while an increased fluorescence emission at 580 nm in CH3CN-water (99/1, v/v) for Bi3+ with a color change from colorless to red. Their different action mechanisms for the RSPT-Zn2+ and RSPT Bi3+ complexes were investigated and confirmed by means of fluorescent titration, binding constant, Job's plot curve, 1H NMR titration, and theoretical simulation. RSPT would be a promising turn-on fluorescent chemo-dosimeter for multichannel detection of Zn2+ and Bi3+ with a detection limit of 3.0 nM for Zn2+ and 8.6 nM for Bi3+. PMID- 29264598 TI - Quantum fluctuations of a fullerene cage modulate its internal magnetic environment. AB - To investigate the effect of quantum fluctuations on the magnetic environment inside a C60 fullerene cage, we have calculated the nuclear magnetic shielding constant of protons in H2@C60 and HD@C60 systems by on-the-fly ab initio path integral simulation, including both thermal and nuclear quantum effects. The most dominant upfield from an isolated hydrogen molecule occurs due to the diamagnetic current of the C60 cage, which is partly cancelled by the paramagnetic current, where the paramagnetic contribution is enlarged by the zero-point vibrational fluctuation of the C60 carbon backbone structure via a widely distributed HOMO LUMO gap. This quantum modulation mechanism of the nuclear magnetic shielding constant is newly proposed. Because this quantum effect is independent of the difference between H2 and HD, the H2/HD isotope shift occurs in spite of the C60 cage. The nuclear magnetic constants computed for H2@C60 and HD@C60 are 32.047 and 32.081 ppm, respectively, which are in reasonable agreement with the corresponding values of 32.19 and 32.23 ppm estimated from the experimental values of the chemical shifts. PMID- 29264599 TI - Radical-mediated intramolecular beta-C(sp3)-H amidation of alkylimidates: facile synthesis of 1,2-amino alcohols. AB - A new radical-mediated intramolecular beta-C(sp3)-H amidation reaction of O-alkyl trichloro- or arylimidates is reported. Various oxazolines were efficiently prepared from easily accessible alcohol starting materials. The trichloro oxazoline products can be hydrolyzed under mild conditions to give valuable 1,2 amino alcohols. This amidation reaction exhibits a broad substrate scope and good functional group tolerance, and offers a powerful means for the C(sp3)-H functionalization of alcohols. Mechanistic studies suggest that a sequence of 1,5 HAT of an imidate radical, iodination and cyclization might be operative. PMID- 29264600 TI - Theoretical investigation of aerobic and anaerobic oxidative inactivation of the [NiFe]-hydrogenase active site. AB - The extraordinary capability of [NiFe]-hydrogenases to catalyse the reversible interconversion of protons and electrons into dihydrogen (H2) has stimulated numerous experimental and theoretical studies addressing the direct utilization of these enzymes in H2 production processes. Unfortunately, the introduction of these natural H2-catalysts in biotechnological applications is limited by their inhibition under oxidising (aerobic and anaerobic) conditions. With the aim of contributing to overcome this limitation, we studied the oxidative inactivation mechanism of [NiFe]-hydrogenases by performing Density Functional Theory (DFT) calculations on a very large model of their active site in which all the amino acids forming the first and second coordination spheres of the NiFe cluster have been explicitly included. We identified an O2 molecule and two H2O molecules as sources of the two oxygen atoms that are inserted at the active site of the inactive forms of the enzyme (Ni-A and Ni-B) under aerobic and anaerobic conditions, respectively. Furthermore, our results support the experimental evidence that the Ni-A-to-Ni-B ratio strongly depends on the number of reducing equivalents available for the process and on the oxidizing conditions under which the reaction takes place. PMID- 29264601 TI - Unveiling excited state energy transfer and charge transfer in a host/guest coordination cage. AB - Host-guest charge transfer (HGCT) plays a key role in applications from solar energy conversion to photocatalysis. Herein, a HGCT system, a pillared Pt(ii) metallacage with encapsulated coronene was synthesized and the ultrafast excited state dynamics were investigated by combination of femtosecond transient absorption spectroscopy, nanosecond transient emission spectrocopy and quantum chemistry calculations. Two significant ultrafast dynamic processes were unveiled: (i) charge transfer from a singlet local excited (1LE) state associated with the coronene moiety to a 1HGCT state with tau = 9.5 ps; and (ii) triplet triplet energy transfer from a high 3HGCT state to a 3LE state with tau = 139.5 ps. The resulting long-lived species, the lowest 3LE and 3HGCT states eventually decay to the ground state in microsecond time scales of 5.2 and 43.4 MUs respectively. Moreover, a clear mechanism depicting the main excited-state decay pathways connecting the initial photoexcited transients with the resulting species was proposed. PMID- 29264602 TI - Synthesis of imidazole-activated ribonucleotides using cyanogen chloride. AB - We report the syntheses of ribonucleoside 5'-monophosphates activated with imidazole, using a mechanism which relies on the in situ generation of cyanogen chloride from the reaction of cyanide anion with hypochlorous acid. Cyanogen chloride reacts rapidly with imidazole to form diimidazole imine as the major product, a species which affords the activation of ribonucleoside 5' monophosphates to their 5'-phosphorimidazolides. PMID- 29264603 TI - Contiguous hydrophobic and charged surface patches in short helix-constrained peptides drive cell permeability. AB - Most protein-protein interactions occur inside cells. Peptides can inhibit protein-protein interactions but tend not to enter cells. We systematically compare cell permeability for 8-12 residue model peptides with helix-inducing lactam/hydrocarbon linkers between amino acid sidechains. Cell uptake increases when hydrophobic residues and lactam linkers (i, i + 4) form a contiguous hydrophobic surface patch. Uptake increases further when both hydrophobic and positively charged (but not neutral or negative) residues are clustered into like surface patches. Amphipathicity alone is however insufficient for cell uptake of acyclic sequences. Changing the linker from lactam to hydrocarbon further increases uptake, but also promotes cell lysis. Helicity, positive charge and amphipathicity together promote cell permeability. Most known bioactive helical peptides do not optimally cluster residues for amphipathicity and so are likely unoptimised for cell uptake. PMID- 29264604 TI - Passive sampling of DDT, DDE and DDD in sediments: accounting for degradation processes with reaction-diffusion modeling. AB - Passive sampling is becoming a widely used tool for assessing freely dissolved concentrations of hydrophobic organic contaminants in environmental media. For certain media and target analytes, the time to reach equilibrium exceeds the deployment time, and in such cases, the loss of performance reference compounds (PRCs), loaded in the sampler before deployment, is one of the common ways used to assess the fractional equilibration of target analytes. The key assumption behind the use of PRCs is that their release is solely diffusion driven. But in this work, we show that PRC transformations in the sediment can have a measurable impact on the PRC releases and even allow estimation of that compound's transformation rate in the environment of interest. We found that in both field and lab incubations, the loss of the 13C 2,4'-DDT PRC from a polyethylene (PE) passive sampler deployed at the sediment-water interface was accelerated compared to the loss of other PRCs (13C-labeled PCBs, 13C-labeled DDE and DDD). The DDT PRC loss was also accompanied by accumulation in the PE of its degradation product, 13C 2,4'-DDD. Using a 1D reaction-diffusion model, we deduced the in situ degradation rates of DDT from the measured PRC loss. The in situ degradation rates increased with depth into the sediment bed (0.14 d-1 at 0-10 cm and 1.4 d-1 at 30-40 cm) and although they could not be independently validated, these rates compared favorably with literature values. This work shows that passive sampling users should be cautious when choosing PRCs, as degradation processes can affect some PRC's releases from the passive sampler. More importantly, this work opens up the opportunity for novel applications of passive samplers, particularly with regard to investigating in situ degradation rates, pathways, and products for both legacy and emerging contaminants. However, further work is needed to confirm that the rates deduced from model fitting of PRC loss are a true reflection of DDT transformation rates in sediments. PMID- 29264605 TI - Side chain-specific 11/9-helix propensity of alpha/beta-peptides with alternating residue types. AB - The 11/9-helix is among the most stable and non-traditional helical structures for alpha/beta-peptides with alternating residue types. The effect of side chain groups of alpha-residues and beta3-residues on the 11/9-helix propensity was examined under various solvent conditions. An alpha-amino acid residue with one of the four representative side chain groups was incorporated into the central position of an alpha/beta-pentapeptide backbone. A beta-branched valine residue did not show any destabilizing effect. alpha,alpha-Dimethylsubstituted Aib residue was tolerated under nonpolar conditions, but did not promote 11/9-helical folding. The oligomer with a glycine residue did not show 11/9-helical folding under polar solvent conditions. The single unmatched stereochemistry of d-alanine was deleterious to 11/9-helical folding. Replacement of a cyclic beta-residue with an acyclic beta3-residue in the 11/9-helical structure had a slight destabilizing effect, which could be compensated by a longer peptide sequence with more cyclic beta-residues. These results provide a guidance for incorporating functional groups into an 11/9-helical alpha/beta-peptide backbone to design functional oligomers. PMID- 29264606 TI - Intriguing C-HCu interactions in bis-(phenanthroline)Cu(i) redox mediators for dye-sensitized solar cells. AB - We have synthesized and characterized a series of bis-(phenanthroline)Cu(i) complexes of interest as redox mediators for dye-sensitized solar cells. This study led to the discovery of intriguing anagostic interactions between the hydrogen atom and the copper center as evidenced by X-ray diffraction studies on a single crystal. Remarkably, an anagostic interaction was found between a H atom of a methyl group and a copper site. PMID- 29264607 TI - Gold promoted arylative cyclization of alkynoic acids with arenediazonium salts. AB - Alkynoic acids derived from salicylic acid and analogues undergo arylative cyclization with arenediazonium salts promoted by gold in the absence of external ligands. The reaction is thermally induced and proceeds even in the absence of light. A difference in regioselectivity has been found compared with that observed in the cycloisomerization process of the same type of compounds. PMID- 29264608 TI - Safe core-satellite magneto-plasmonic nanostructures for efficient targeting and photothermal treatment of tumor cells. AB - Magneto-plasmonic nanostructures functionalized with cell targeting units are of great interest for nanobiotechnology applications. Photothermal treatment of cells targeted with antibody functionalized nanostructures and followed by magnetic isolation, allows killing selected cells and hence is one of the applications of great interest. The magneto-plasmonic nanostructures reported herein were synthesized using naked gold and magnetite nanoparticles obtained through a green approach based on laser ablation of bulk materials in water. These particles do not need purifications steps for biocompatibility and are functionalized with a SERRS (surface enhanced resonance Raman scattering) active molecule for detection and with an antibody for targeting prostate tumor cells. Quantitative results for the cell targeting and selection efficiency show an overall accuracy of 94% at picomolar concentrations. The photothermal treatment efficiently kills targeted and magneto-selected cells producing a viability below 5% after 3 min of irradiation, compared with almost 100% viability of incubated and irradiated, but non targeted cells. PMID- 29264609 TI - DABCO-catalyzed silver-promoted direct thiolation of pyrazolones with diaryl disulfides. AB - A highly efficient protocol for a direct thiolation of N-substituted pyrazolones with diaryl disulfides is described. Using a combination of DABCO and silver(i) acetate, the C-S bond formation proceeds smoothly at room temperature under mild and easy to handle conditions. This synthetic strategy offers a convenient and direct modification of antipyrine and other pyrazolone substrates, giving a series of aryl sulfide-substituted pyrazolone products in moderate to excellent yields. PMID- 29264610 TI - Far-red fluorescent probes for canonical and non-canonical nucleic acid structures: current progress and future implications. AB - The structural diversity and functional relevance of nucleic acids (NAs), mainly deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), are indispensable for almost all living organisms, with minute aberrations in their structure and function becoming causative factors in numerous human diseases. The standard structures of NAs, termed canonical structures, are supported by Watson-Crick hydrogen bonding. Under special physiological conditions, NAs adopt distinct spatial organisations, giving rise to non-canonical conformations supported by hydrogen bonding other than the Watson-Crick type; such non-canonical structures have a definite function in controlling gene expression and are considered as novel diagnostic and therapeutic targets. Development of molecular probes for these canonical and non-canonical DNA/RNA structures has been an active field of research. Among the numerous probes studied, probes with turn-on fluorescence in the far-red (600-750 nm) region are highly sought-after due to minimal autofluorescence and cellular damage. Far-red fluorescent probes are vital for real-time imaging of NAs in live cells as they provide good resolution and minimal perturbation of the cell under investigation. In this review, we present recent advances in the area of far-red fluorescent probes of DNA/RNA and non canonical G-quadruplex structures. For the sake of continuity and completeness, we provide a brief overview of visible fluorescent probes. Utmost importance is given to design criteria, characteristic properties and biological applications, including in cellulo imaging, apart from critical discussion on limitations of the far-red fluorescent probes. Finally, we offer current and future prospects in targeting canonical and non-canonical NAs specific to cellular organelles, through sequence- and conformation-specific far-red fluorescent probes. We also cover their implications in chemical and molecular biology, with particular focus on decoding various disease mechanisms involving NAs. PMID- 29264611 TI - Synthesis and characterization of a novel aminopolycarboxylate complexant for efficient trivalent f-element differentiation: N-butyl-2-acetamide diethylenetriamine-N,N',N'',N''-tetraacetic acid. AB - The novel metal ion complexant N-butyl-2-acetamide-diethylenetriamine N,N',N'',N''-tetraacetic acid (DTTA-BuA) uses an amide functionalization to increase the total ligand acidity and attain efficient 4f/5f differentiation in low pH conditions. The amide, when located on the diethylenetriamine platform containing four acetate pendant arms maintains the octadentate coordination sphere for all investigated trivalent f-elements. This compact coordination environment inhibits the protonation of LnL- complexes, as indicated by lower K111 constants relative to the corresponding protonation site of the free ligand. For actinide ions, the enhanced stability of AnL- lowers the K111 for americium and curium beyond the aptitude of potentiometric detection. Density functional theory computations indicate the difference in the back-donation ability of Am3+ and Eu3+ f-orbitals is mainly responsible for stronger proton affinity of EuL- compared to AmL-. The measured stability constants for the formation of AmL- and CmL- complexes are consistently higher, relative to ML- complexes with lanthanides of similar charge density. When compared with the conventional aminopolycarboxylate diethylenetriamine pentaacetic acid (DTPA), the modified DTTA-BuA complexant features higher ligand acidity and the important An3+/Ln3+ differentiation when deployed on a liquid-liquid distribution platform. PMID- 29264612 TI - Microfluidic bypass manometry: highly parallelized measurement of flow resistance of complex channel geometries and trapped droplets. AB - Current lithography methods allow facile fabrication of microfluidic conduits where not only the shape of the bounding walls can be arbitrarily varied but also the internal conduit space can be laden with a variety of microstructures and wetting properties. This virtually infinite design space of microfluidic geometries brings in the challenge of how to quantify fluid resistance in a large number of microfluidic conduits, while maintaining operational simplicity. We report a versatile experimental technique referred to as microfluidic bypass manometry for measurement of pressure drop versus flow rate (DeltaP-Q) relations in a parallelized manner. The technique involves introducing co-flowing laminar streams into a microfluidic network that contains a series of loops, where each loop is comprised of a test geometry and a bypass channel as a flow-rate sensing element. We optimize the network geometry and present operational considerations for microfluidic bypass manometry. To demonstrate the power of our technique, we used single-phase fluids and measured DeltaP-Q relations simultaneously for forty test geometries ranging from linear to contraction-expansion to serpentine to pillar-laden microchannels. To expand the capabilities of the method, we measured DeltaP-Q relations for similar-sized oil droplets trapped in microcavities where the cavity geometry spans from prisms of 3-10 sides to circular disks. We found in all cases, the DeltaP-Q relation is nonlinear and the flow resistance of droplets is sensitive to confinement. At high flow rates, the drop resistance depends on the cavity geometry and is higher in a triangular prism compared to a circular disk. We compared the measured flow resistance of single-phase fluids and droplets in different microfluidic geometries to that from computational fluid dynamics simulations and found them to be in excellent agreement. Given the simplicity and versatility of the microfluidic bypass manometry method, we anticipate that it may find broad application in several areas including design of lab-on-chip devices, laminar drag reduction and mechanics of deformable particles. PMID- 29264613 TI - Dynamic wettability of polyethylene glycol-modified poly(dimethylsiloxane) surfaces in an aqueous/organic two-phase system. AB - We herein report the preparation of a surface that behaves in a hydrophobic manner but does not undergo protein adsorption in an aqueous/organic two-phase system. We found that polyethylene-glycol (PEG)-modified poly(dimethylsiloxane) (PDMS) exhibits hydrophobic properties when the surface is immersed in an organic solution, while the PEG moiety prevents protein adsorption on the PDMS surface in an aqueous solution at high protein concentrations due to the dynamic behaviour of the PEG moiety. As such, we demonstrated the in-well droplet formation of an aqueous solution containing a high protein concentration. In addition, to demonstrate the feasibility of this method in single cell analyses, a droplet array of a liquid medium containing 10% fetal bovine serum and HeLa cells was formed. The preparation of a droplet array using our PDMS-PEG surface to promote in-well droplet formation avoided the use of flow control equipment and complicated microstructures. We therefore expect that the dynamic wettability of our reported surface will be applicable in single cell and biochemical analyses, such as protein characterisation using crystallography or immunoassays. PMID- 29264614 TI - Nonadditive interactions and phase transitions in strongly confined colloidal systems. AB - The behaviour of colloids can be controlled effectively by tuning the solvent mediated interactions among them. An extensively studied example is the temperature-induced aggregation of suspended colloids close to the consolute point of their binary solvent. Here, using mean field theory and Monte Carlo simulations, we study the behaviour of colloids confined to a narrow slit containing a nearly-critical binary liquid mixture. We found that the effective interactions in this system are highly non-additive. In particular, the effective interactions among the colloids can be a few times stronger than the corresponding sum of the effective pair potentials. Inter alia, this non additivity manifests itself in the phase behaviour of confined colloids, which depends sensitively on the slit width and temperature. In addition, we demonstrate the possibility of a first-order bridging transition between colloids confined to a slit and suspended in a phase-separated fluid well below the critical point of the solvent and at its critical composition in the bulk. This transition is accompanied by a remarkably large hysteresis loop, in which the force between the colloids varies by two orders of magnitude. PMID- 29264615 TI - Influence of pelvic floor muscle fatigue on stress urinary incontinence: a systematic review. AB - INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) is the most common urinary complaint among women and is defined by the International Continence Society as any involuntary loss of urine due to physical effort, sneezing or coughing. Many women with SUI state that the loss of urine occurs after performing repetitive movements, which may suggest that it is the result of fatigue of the pelvic floor muscles (PFM). Thus, we performed the systematic review of the literature on the influence of PFM fatigue on the development or worsening of the symptoms of SUI in women. METHODS: The PubMed, Scopus, EMBASE, PEDro, LILACS, SciELO, Cochrane Library, Google Scholar, CINAHL and Periodicos CAPES databases were searched for articles using the keywords "fatigue", "pelvic floor", "stress urinary incontinence" and "women", in Portuguese and in English. Methodological quality was assessed using the Downs and Black scale, and the data collected from the studies were analyzed descriptively. RESULTS: Of the 2,010 articles found, five met the inclusion criteria and were analyzed. They were published between 2004 and 2015, and included a total of 30,320 women with ages ranging from 24 to 53.6 years. Of the studies analyzed, three showed an association between fatigue and SUI, and two did not show such an association. CONCLUSIONS: This study confirmed that PFM fatigue can influence the development and/or worsening of SUI. PMID- 29264616 TI - [Ligamentous lesions and instability of the finger joints]. AB - Joint capsule and ligamentous lesions are common injuries of the upper extremities. Athletes are particularly inclined to suffer from these injuries. Clinical and radiological examinations are the cornerstone of an adequate treatment. Ultrasound-based diagnostics as a non-invasive and dynamic investigation method are gaining increasing relevance based on the development of high resolution probes. A correct interpretation of the findings is only feasible with a comprehensive knowledge of the anatomy. The most important goal is stability as a prerequisite for early active and passive motion with unrestricted range of motion. PMID- 29264617 TI - Chryseobacterium chungangensis sp. nov., a bacterium isolated from soil of sweet gourd garden. AB - A novel bacterial strain, named MAH-7T, was isolated from a soil sample of a Korean sweet gourd garden and was characterized using a polyphasic approach. Cells were Gram-staining negative, orange colored, non-motile and rod shaped. The strain was aerobic and catalase, oxidase positive, optimum growth temperature and pH were 28-30 degrees C and 7.0, respectively. On the basis of 16S rRNA gene sequence analysis, strain MAH-7T belongs to the genus Chryseobacterium and is most closely related to Chryseobacterium formosense CC-H3-2T (97.96%) and Chryseobacterium zeae JM-1085T (97.19%). In DNA-DNA hybridization tests, the DNA relatedness between strain MAH-7T and its closest phylogenetic neighbors were below 45.0%. The DNA G+C content was 37.6 mol% and the predominant respiratory quinone was menaquinone-6 (MK-6). Flexirubin-type pigments were found to be present. The major cellular fatty acids were C15:0 iso, C17:0 iso 3OH, C17:1 isoomega9c and summed feature 3 (C16:1omega7c and/or C16:1omega6c). The DNA-DNA hybridization results and results of the genotypic analysis in combination with chemotaxonomic and physiological data demonstrated that strain MAH-7T represented a novel species within the genus Chryseobacterium, for which the name Chryseobacterium chungangensis is proposed. The type strain is MAH-7T (= KACC 19293T = CGMCC 1.16232T). The NCBI GenBank accession number for the 16S rRNA gene sequence of strain MAH-7T is KY964274. PMID- 29264618 TI - [Iterative algorithms for artifact reduction in computed tomography]. AB - CLINICAL/METHODICAL ISSUE: Computed tomography (CT) acquisition should be performed following the ALARA principle: keeping patient radiation exposure as low as reasonably achievable. STANDARD RADIOLOGICAL METHODS: Reconstruction with filtered backprojection is still the standard in CT. METHODICAL INNOVATIONS: Recently, iterative reconstruction techniques have become available, using a different approach for image reconstruction. A similar approach is used for iterative metal artifact reduction. PERFORMANCE: Compared to filtered backprojection, iterative reconstruction yields improvements in image quality and reduces image noise. ACHIEVEMENTS: Using iterative reconstruction allows the reduction of patient radiation exposure by up to 80%, depending on the used algorithm and the clinical task at hand. With the help of iterative metal artifact reduction, images of diagnostic quality can be acquired despite metal implants. PRACTICAL RECOMMENDATIONS: Iterative reconstruction should be used to reduce patient radiation exposure in accordance with the clinical requirements. The use of iterative metal artifact reduction is recommended. PMID- 29264619 TI - Lanthanum chloride reduces lactate production in primary culture rat cortical astrocytes and suppresses primary co-culture rat cortical astrocyte-neuron lactate transport. AB - Lanthanum (La) can impair learning memory and induce behavioral abnormalities in animals. However, the mechanism underlying these adverse effects of La is still elusive. It has been demonstrated that lactate derived from astrocytes is the major energy source for neurons during long-term memory (LTM) formation and the deficiency of lactate supply can result in LTM damage. However, little work has been done with respect to the impact of La on the lactate production in astrocytes and astrocyte-neuron lactate transport (ANLT). Herein, experiments were undertaken to explore if there was such an adverse effect of La. Primary culture rat cortical astrocytes and primary co-culture rat cortical astrocyte neuron were treated with (0.125, 0.25 and 0.5 mM) lanthanum chloride (LaCl3) for 24 h. The results showed that LaCl3 treatment significantly downregulated the mRNA and protein expression of glucose transporter 1 (GLUT1), glycogen synthase (GS), glycogen phosphorylase (GP), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1, 2 and 4 (MCT 1 2 and 4); upregulated the mRNA and protein expression of lactate dehydrogenase B (LDHB); and decreased the glycogen level, total LDH and GP activity, GS/p-GS ratio and lactate contents. Moreover, rolipram (20, 40 MUM) or forskolin (20, 40 MUM) could increase the lactate content by upregulating GP expression and the GS/p-GS ratio, as well as antagonize the effects of La. These results suggested that La-induced learning memory damage was probably related to its suppression of lactate production in astrocytes and ANLT. This study provides some novel clues for clarifying the mechanism underlying the neurotoxicity of La. PMID- 29264620 TI - Resveratrol protects primary cilia integrity of human mesenchymal stem cells from cigarette smoke to improve osteogenic differentiation in vitro. AB - Several studies have explored the negative effects of cigarette smoke on bone healing; however, the complex pathogenesis still remains unclear. One crucial and primary factor determining effective fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) into bone-forming cells. Recently, primary cilia, microtubule-based sensory organelles, have been shown to be critical in lineage commitment and differentiation of MSCs. Our present study indicates that exposure to cigarette smoke extract (CSE 0.1-10%) impaired osteogenic differentiation of human mesenchymal stem cell line (SCP-1) and interestingly, also affected primary cilia distribution and integrity in these cells during the differentiation. Furthermore, significant amounts of free radicals generated by CSE could be causative of primary cilia loss since treatment with 0.01% of hydrogen peroxide, a prime free radical in CSE, destroyed primary cilia in these cells. The debilitated differentiation of CSE-exposed SCP 1 cells also correlated with the significantly reduced expression of transcription factor and target genes of primary cilia-specific hedgehog signalling, a key player in osteogenic differentiation. As a treatment strategy, co-incubation of the CSE-exposed SCP-1 cells with the antioxidant resveratrol (1 uM) had a protective effect as it significantly reduced free radical production, protected the primary cilia and enhanced osteogenic differentiation. The current study shows for the first time that cigarette smoke affects primary cilia in human MSCs during osteogenic differentiation and treatment with resveratrol could reverse the effects and enhance differentiation, thus opening up potential therapeutic alternatives to treat fracture healing in smokers, in particularly, when delayed fracture healing is assumed. PMID- 29264621 TI - [Long-term results of adjuvant versus early salvage radiation therapy in pT3N0 prostate cancer after radical prostatectomy]. PMID- 29264622 TI - [Early integrated palliative care in cancer patients improves quality of life and encourages discussions about preferences for care at the end of life]. PMID- 29264623 TI - [Which patients with localized prostate cancer benefit from which local procedure and what does "benefit" mean in prostate cancer?] PMID- 29264624 TI - Reirradiation + hyperthermia for recurrent breast cancer en cuirasse. AB - BACKGROUND AND PURPOSE: Patients with irresectable locoregional recurrent breast cancer en cuirasse (BCEC) do not have effective curative treatment options. Hyperthermia, the elevation of tumor temperature to 40-45 degrees C, is a well established radio- and chemotherapy sensitizer. A total of 196 patients were treated with reirradiation and hyperthermia (reRT+HT) at two Dutch institutes from 1982-2005. The palliative effect was evaluated in terms of clinical outcome and toxicity. PATIENTS AND METHODS: All patients received previous irradiation to a median dose of 50 Gy. In all, 75% of patients received 1-6 treatment modalities for previous tumor recurrences. ReRT consisted of 8 * 4 Gy given twice a week or 12 * 3 Gy given four times a week. Superficial hyperthermia was added once or twice a week. Tumor area comprised >=1/2 of the ipsilateral chest wall. RESULTS: Overall clinical response rate was 72% (complete response [CR] 30%, partial response [PR] 42%, stable disease [SD] 22%, progressive disease [PD] 6%). The local progression-free rate at 1 year was 24%. Median survival was 6.9 months. Forty-three percent of our patients with CR, PR, SD after treatment remained infield progression-free until death or last follow-up. Acute >=grade 3 toxicity occurred in 33% of patients, while late >=grade 3 toxicity was recorded in 14% of patients. Tumor ulceration prior to treatment had a negative impact on both clinical outcome and toxicity. CONCLUSION: ReRT+HT provides sustainable palliative tumor control, despite refractory, extensive tumor growth. Compared to currently available systemic treatment options, reRT+HT is more effective with less toxicity. PMID- 29264626 TI - Acetylcholinesterase inhibitors and the risk of osteoporotic fractures: nested case-control study. AB - : The objective of this study was to analyze the effect of acetylcholinesterase inhibitors (AChEIs) on the risk of osteoporotic fractures in Alzheimer patients. A nested case-control study was conducted on 1190 cases and 4760 controls. The use of AChEIs was found to decrease the risk of osteoporotic fractures in these patients. INTRODUCTION: The objective of this study is to estimate the extent to which the use of AChEIs is associated with a reduction in the risk of osteoporotic fractures. METHODS: A nested case-control study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) database (1998-2013). The study cohort consisted of Alzheimer's Disease (AD) patients aged >= 65 years with no previous history of osteoporotic fractures at cohort baseline. Cases were individuals who suffered an osteoporotic fracture during the study period, whereas controls were subject who did not experience any osteoporotic fractures during the same period. Controls were drawn from the population time at risk while being matched to the cases in respect to age, sex, up-to-standard follow-up in the CPRD, calendar time, and duration of AD (control-to-case ratio: 4-to-1). Information on the use of AChEIs and the relevant potential confounders was ascertained from the CPRD database for all the cases and controls. RESULTS: We identified 1190 cases and 4760 controls. Compared to non-users, any use of AChEIs prior to the fracture was associated with a reduction in the fracture risk [adjusted odds ratio (OR) 0.80 (confidence interval (CI) 95%, 0.70-0.91)]. The use of AChEIs corresponding to a proportion of days covered of 0.8-1.0 was associated with a lower osteoporotic fracture risk compared to non-use [adjusted OR 0.76 (CI 95%, 0.66-0.87)]. CONCLUSIONS: In this study using large primary care databases, the use and treatment adherence to AChEIs were associated with a decreased risk of osteoporotic fractures in elderly AD patients. PMID- 29264627 TI - [Primary tumor diagnostics of metastatic neuroendocrine tumors]. PMID- 29264625 TI - Predictive ability of genomic selection models in a multi-population perennial ryegrass training set using genotyping-by-sequencing. AB - KEY MESSAGE: Genomic prediction models for multi-year dry matter yield, via genotyping-by-sequencing in a composite training set, demonstrate potential for genetic gain improvement through within-half sibling family selection. Perennial ryegrass (Lolium perenne L.) is a key source of nutrition for ruminant livestock in temperate environments worldwide. Higher seasonal and annual yield of herbage dry matter (DMY) is a principal breeding objective but the historical realised rate of genetic gain for DMY is modest. Genomic selection was investigated as a tool to enhance the rate of genetic gain. Genotyping-by-sequencing (GBS) was undertaken in a multi-population (MP) training set of five populations, phenotyped as half-sibling (HS) families in five environments over 2 years for mean herbage accumulation (HA), a measure of DMY potential. GBS using the ApeKI enzyme yielded 1.02 million single-nucleotide polymorphism (SNP) markers from a training set of n = 517. MP-based genomic prediction models for HA were effective in all five populations, cross-validation-predictive ability (PA) ranging from 0.07 to 0.43, by trait and target population, and 0.40-0.52 for days-to-heading. Best linear unbiased predictor (BLUP)-based prediction methods, including GBLUP with either a standard or a recently developed (KGD) relatedness estimation, were marginally superior or equal to ridge regression and random forest computational approaches. PA was principally an outcome of SNP modelling genetic relationships between training and validation sets, which may limit application for long-term genomic selection, due to PA decay. However, simulation using data from the training experiment indicated a twofold increase in genetic gain for HA, when applying a prediction model with moderate PA in a single selection cycle, by combining among-HS family selection, based on phenotype, with within-HS family selection using genomic prediction. PMID- 29264629 TI - [Rare cause of rectal stenosis]. PMID- 29264628 TI - [Perioperative handling of immunosuppressive therapy]. AB - Every year 16 million operations are performed in Germany. Many patients have an autoimmune disorder, for example rheumatoid arthritis, psoriasis or chronic inflammatory bowel disease, which requires treatment. Immunosuppressants are widely applied. Physicians must make a risk-adapted decision whether the immunosuppressant medication can be continued perioperatively or if certain drugs must be paused and if so, with what risks. The handling of immunosuppressants during the perioperative period is very relevant as many patients, for example with rheumatoid arthritis are in need of a hip or knee replacement or patients with inflammatory bowel disease need an operation due to the chronic illness. The interruption of an immunosuppressant therapy should be discussed in an interdisciplinary board according to the underlying disease, because the continuation of immunosuppressants perioperatively can lead to an increased rate of complications, especially wound healing disorders. If a patient is on a glucocorticoid therapy the following must be considered: during the perioperative period the body has an increased demand for glucocorticoids due to the stress reaction. If glucocorticoids are administered in a dosage of more than 7.5 mg/day equivalent of prednisolone this stress reaction is inhibited. Thus, in these cases a perioperative substitution with hydrocortisone is recommended. PMID- 29264631 TI - [Slate-gray macules in the axillae]. PMID- 29264630 TI - [Early stage pancreatic cancer]. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth most common cause of cancer mortality and it is expected to become the second most common cause of cancer mortality by 2020 in the USA. OBJECTIVE: Which strategies for the detection and treatment of an early stage pancreatic adenocarcinoma and its precursor lesions are to be applied? RESULTS: Currently, there is no effective general screening program for pancreatic cancer due to the low incidence and the lack of an accurate and inexpensive diagnostic method; however, in patients with a positive history of hereditary pancreatic cancer or in patients with a known sporadic germline mutation that is associated with an increased risk of pancreatic cancer, frequent screening is highly recommended to detect and to treat early stage PDAC. Moreover, patients with a precursor lesion for pancreatic cancer (namely a mucinous pancreatic neoplasm) should undergo an oncological pancreatic resection to prevent the development of late stage pancreatic cancer. In future, additional biomarkers from a liquid biopsy, such as circulating tumor cells, exosomes or circulating tumor DNA may improve the early detection of pancreatic cancer. CONCLUSION: The early detection and treatment of pancreatic cancer and its precursor lesions can help to improve the dismal prognosis of this aggressive tumor type. PMID- 29264632 TI - Social deprivation modifies the association between incident foot ulceration and mortality in type 1 and type 2 diabetes: a longitudinal study of a primary-care cohort. AB - AIMS/HYPOTHESIS: The aim of this study was to determine whether social deprivation in the presence of diabetes is an independent predictor of developing a foot ulcer and separately of mortality. METHODS: This was a primary-care-based retrospective analysis of 13,955 adults with type 1 (n = 1370) or type 2 (n = 12,585) diabetes after a median follow-up of 10.5 years. Demographic characteristics, indices of social deprivation and clinical variables were assessed at baseline. The primary outcomes were new foot ulceration (in those without a previous history of foot ulcers) and all-cause mortality. Cox proportional hazard models were used to describe the associations among foot ulceration, social deprivation and mortality. RESULTS: The mean age of the population was 69.4 (range: 16-89) years. The incidence of foot ulceration was greater in individuals with type 2 (8.6%) compared with type 1 diabetes (4.8%). Occurrence was similar by sex, but increased with age and deprivation index. Individuals in the highest quintile of deprivation were 77% more likely to develop a foot ulcer compared with those in the lowest quintile (OR 1.77 [95% CI 1.45, 2.14], p < 0.0001). Overall, 2946 (21.1%) deaths were recorded. Compared with individuals without a foot ulcer, the development of a foot ulcer was associated with a higher age- and sex-adjusted mortality rate (25.9% vs 14.0%), and a 72% (HR 1.72 [95% CI 1.56, 1.90], p < 0.001) increased risk of mortality in those with type 2 diabetes. Risk of death increased by 14% per quintile of deprivation in a univariable analysis (HR 1.14 [95% CI 1.10, 1.17]). In multivariable Cox regression analyses, there was a 48% increased risk of mortality in individuals with a foot ulcer (HR 1.48 [95% CI 1.33, 1.66]) independent of the Townsend index score (HR 1.13 [95% CI 1.10, 1.17], per quintile), baseline age, sex, diabetes type, smoking status, hypertension, statin use, beta-blocker use, metformin use, HbA1c levels and insulin use. CONCLUSIONS/INTERPRETATION: This study confirms the high mortality rate in individuals with diabetes-related foot ulcers. In addition, socioeconomic disadvantage was found to be an independent effect modifier, contributing to an increased burden of mortality in people with diabetes who develop foot ulceration. In light of this, and as diabetes service configurations are orientated for the next 5-10 years, modelling of foot ulceration risk needs to take socioeconomic disadvantage into account. PMID- 29264633 TI - Turbinate reduction with complete preservation of mucosa and submucosa during rhinoplasty. AB - BACKGROUND: Turbinate surgery is an important adjunct to functional and cosmetic rhinoplasty. Many studies have analyzed the effects of various mucosal-sparing techniques, such as radiofrequency, laser, shaver, and others. These techniques, however, result in the destruction of the submucosal tissue of the turbinate. The goal of this study was to determine whether excellent functional outcome could be achieved with techniques sparing both the mucosa and submucosa from destruction when addressing the turbinates in rhinoplasty surgery. MATERIALS AND METHODS: A prospective single-surgeon clinical study analyzing submucous resection of turbinate bone without destruction of the submucosa or mucosa in patients undergoing functional-esthetic rhinoplasty was performed. In all, 122 patients (47 men, 75 women, average age: 32.1 years, range: 16-69 years) were eligible for the study. The functional outcome was measured prospectively using the Nasal Obstruction Symptom Evaluation (NOSE) score. Occurrence of complications was documented. RESULTS: Of over 1000 surgical patients, 307 candidates fulfilled multiple selection criteria and were entered in a rhinoplasty database. The surveys sufficient for the present study were completed by 122 of 307 patients (39.7%), of whom 91 patients reported improvement, 14 patients reported no subjective change, and 12 patients reported minimal worsening of nasal breathing. Overall, postoperative function was excellent (preoperative vs. postoperative NOSE score 47.5 vs. 20.1, p < 0.001). A large proportion of patients reporting worsening of symptoms (50%) were diagnosed with decongestant nasal spray abuse. Specific complications such as bleeding, foul drainage, dryness, and crusting were not reported. CONCLUSION: All function-bearing structures of the inferior nasal turbinates, mucosa, and submucosa can be fully preserved without impairment of functional outcome during rhinoplasty. The technique of selective submucous bone resection is as an excellent alternative for patients undergoing rhinoplasty for concomitant treatment or prevention of nasal obstruction. PMID- 29264634 TI - [Influence of external and endogenous factors on cervical lymph nodes : Sonographic study of size and morphology]. AB - BACKGROUND: Sonographic evaluation of the dignity of cervical lymph nodes is essential for further diagnostics and treatment concepts in various diseases. The aim of this prospective monocenter study was to determine the sonomorphology and size of benign changes of lymph nodes in healthy subjects and patients who had undergone surgery, in order to examine the influence of various factors. MATERIALS AND METHODS: Data from 205 healthy subjects and 15 patients before and after surgery were analyzed. Sonographically representative lymph nodes were measured in diameter and volumes were calculated; margins, the recognizability of a hilus, and vascularization were documented. A detailed medical history was taken using a standardized questionnaire. RESULTS: In 20-39-year-olds, lymph node diameters were larger than in 40-59- and over 60-year-olds, and in 40-59-year olds, the lymph nodes were larger than over 60-year-old subjects. Individuals with consumption of less than 10 and 10-20 cigarettes per day showed larger cervical lymph nodes compared to subjects with a consumption of more than 20 cigarettes per day. Smokers who additionally exercised routinely showed larger lymph nodes than those who never smoked or exercised. In addition, we observed that both the size and the number of cervical lymph nodes increased postoperatively compared to preoperative. CONCLUSION: The recorded lymph nodes corresponded to the established sonographic criteria of benign lymph nodes. Our results show that age, smoking intensity, combination of smoking with sporting activity, and surgery influence the size of sonographically measured cervical lymph nodes. PMID- 29264635 TI - Fat necrosis after abdominal surgery: A pitfall in interpretation of FDG-PET/CT. AB - OBJECTIVE: We describe FDG-PET/CT findings of postoperative fat necrosis in patients following abdominal surgery, and evaluate their changes in size and FDG uptake over time. METHODS: FDG-PET/CT scans from January 2007-January 2016 containing the term 'fat necrosis' were reviewed. Lesions meeting radiological criteria of fat necrosis in patients with prior abdominal surgery were included. RESULTS: Forty-four patients, 30 males, mean age 68.4 +/- 11.0 years. Surgeries: laparotomy (n=37; 84.1 %), laparoscopy (n=3; 6.8 %), unknown (n=4; 9.1 %). CTs of all lesions included hyperdense well-defined rims surrounding a heterogeneous fatty core. Sites: peritoneum (n=34; 77 %), omental fat (n=19; 43 %), subcutaneous fat (n=8; 18 %), retroperitoneum (n=2; 5 %). Mean lesion long axis: 33.6+/-24.9 mm (range: 13.0-140.0). Mean SUVmax: 2.6+/-1.1 (range: 0.6-5.1). On serial CTs (n=34), lesions decreased in size (p=0.022). Serial FDG-PET/CT (n=24) showed no significant change in FDG-avidity (p=0.110). Mean SUVmax did not correlate with time from surgery (p=0.558) or lesion size (p=0.259). CONCLUSION: Postsurgical fat necrosis demonstrated characteristic CT features and may demonstrate increased FDG uptake. However, follow-up of subsequent imaging scans showed no increases in size or FDG-avidity. Awareness of this entity is important to avoid misinterpretation of findings as recurrent cancer. KEY POINTS: * Postsurgical fat necrosis may mimic cancer in FDG-PET/CT. * Follow-up of fat necrosis showed no increase in FDG intensity. * CT follow-up showed a decrease in lesion size. * FDG uptake did not correlate with time lapsed from surgery. PMID- 29264636 TI - CAIPIRINHA-Dixon-TWIST (CDT)-VIBE MR imaging of the liver at 3.0T with gadoxetate disodium: a solution for transient arterial-phase respiratory motion-related artifacts? AB - PURPOSE: To determine whether CAIPIRINHA-Dixon-TWIST (CDT) volume-interpolated breath-hold examination (VIBE) improves image quality by reducing gadoxetate disodium-associated transient arterial-phase motion artefacts in magnetic resonance imaging (MRI) of the liver. MATERIALS AND METHODS: MRI studies of the liver from 270 patients who had received gadoxetate disodium were retrospectively evaluated in regard to arterial timing accuracy and arterial phase motion artefact severity (VIBE: 90/270, CAIPIRINHA-VIBE: 90/270 and CDT-VIBE: 90/270 cases). Three independent and blinded readers assessed arterial phase timing and motion artefact severity (5-point scale). Interrater agreement was calculated by weighted kappa. Continuous variables were compared via a two-sided ANOVA, categorical variables via a chi2 test. An ordinal regression analysis was performed to identify other predictors of motion artefacts. RESULTS: CDT-VIBE improved correct late arterial timing rates and reduced motion-related image deterioration rates. Successful late arterial liver visualisation was achieved in 56.7% (VIBE) compared with 66.7% (CAIPIRINHA-VIBE) and 84.4% (CDT-VIBE) (P < 0.0001). Good/excellent image quality was achieved in 56.7% vs. 66.7% and 73.3%, respectively (P = 0.03). Male sex negatively influenced image quality (P = 0.03). CONCLUSION: CDT-VIBE increases the diagnostic utility of gadoxetate disodium based liver MRI by reducing respiratory motion artefacts and optimising late arterial visualisation compared with VIBE and CAIPIRINHA-VIBE. KEY POINTS: * CAIPIRINHA-Dixon-TWIST-VIBE-MRI (CDT) mitigates effects of acute transient dyspnoea caused by gadoxetate disodium. * CDT improves late arterial imaging compared with VIBE and CAIPIRINHA-VIBE. * The rate of ideal late arterial images is higher with CDT-VIBE vs. VIBE or CAIPI-VIBE. * The impact of respiratory motion artefacts on arterial phase images can be reduced. PMID- 29264637 TI - Outcomes after rheumatoid arthritis patients complete their participation in a long-term observational study with tofacitinib combined with methotrexate: practical and ethical implications in vulnerable populations after tofacitinib discontinuation. AB - To describe disease activity and disability during the first year of follow-up, from rheumatoid arthritis (RA) patients who discontinue tofacitinib after they end participation in a clinical trial. From 2008 to 2016, 36 patients were enrolled in the "Long term follow-up study with tofacitinib (and methotrexate) for RA treatment". At the end of the study, tofacitinib was discontinued and patients were proposed to enter an observational study; 35 agree and had scheduled evaluations at baseline, at 15 and 30 days of follow-up, at month 2 and 3, and thereafter every 3 months. Disease activity was evaluated as per DAS28-ESR and disability as per HAQ. During follow-up, treatment was treat-to-target oriented, only conventional DMARDs were indicated. Descriptive statistics and nonparametric test were used. The study was approved by IRB. Patients were primarily females (N = 34), had median (Q25-75) age of 52 years (45-58), and had received tofacitinib for a median of 7.9 years (6.3-8.3). The proportion of patients with remission and low disease activity decreased from day 30 of follow up and recovered after 270 days, meanwhile patients with high disease activity increased from 0% at baseline to 6.3% at 1 year. At study entry, 20 patients had remission/low disease activity; during follow-up, 85% deteriorated after (median) 30 days; among them, 23.5% recovered their baseline status after a median of 172.5 days. The HAQ showed a similar behavior, but 66.7% recovered. A substantial proportion of RA patients deteriorated outcomes early after tofacitinib cessation; some patients recovered baseline status with traditional DMARDS. PMID- 29264638 TI - Suicidal behaviors in patients with rheumatic diseases: a narrative review. AB - Chronic rheumatic disorders are characterized by inflammation and chronic pain, and both anxiety and depression have been frequently observed in these patients. Depression and chronic pain are recognized as risk factors for the development of suicidal behaviors. Accordingly, the objective of the present review is to provide a comprehensive review of suicidal behaviors associated with rheumatic diseases. Medline and EMBASE were searched for English language publications using key words related with rheumatic diseases, suicide, suicide attempts, and suicidal ideation. 34 records (30 full-length published papers and 4 studies published in abstract form) that included data related to the frequency and/or potential determinants of suicidal behaviors in rheumatic diseases were included in the review. It was found that both suicidal ideation and completed suicide seem to be more frequent in patients experiencing systemic lupus erythematosus, fibromyalgia and arthritis. Major determinants were comorbid depression in fibromyalgia and arthritis, and neuropsychiatric disease in systemic lupus erythematosus. Based on these findings, suicide risk should be assessed in patients suffering from systemic lupus erythematosus, fibromyalgia and/or arthritis. PMID- 29264639 TI - Serum Concentrations of New Predictive Cardiovascular Disease Biomarkers in Mexican Women Exposed to Lead. AB - The purpose of this study was to evaluate lead exposure and its relationship with serum levels of predictive CVD biomarkers [asymmetric dimethylarginine (ADMA), adipocyte fatty acid-binding protein (FABP4), adiponectin, and chemerin] in women living in San Luis Potosi, Mexico. A mean blood lead level (BLL) of 11.5 +/- 9.00 MUg/dL (mean +/- standard deviation) was found after all blood samples were analyzed. Regarding serum predictive CVD biomarkers, mean serum level of 0.68 +/- 0.38 MUmol/L, 20.5 +/- 16.5 ng/mL, 12.5 +/- 3.30 MUg/mL, and 255 +/- 130 ng/mL were found for ADMA, FABP4, adiponectin, and chemerin, respectively. Simple significant associations (Pearson's correlations) between BLL and ADMA (r = 0.17; p = 0.04) and FABP4 (r = 0.23; p = 0.03) were found. Furthermore, a multivariate linear regression model showed that BLL was a significant predictor of serum ADMA (beta = 0.06; p = 0.001) and FABP4 (beta = 1.75; p = 0.0004) concentrations after adjusting by confounders. For serum chemerin and adiponectin levels, no associations were found with BLL. In conclusion, high serum ADMA and FABP4 (predictive CVD biomarkers) levels were found in women exposed to lead. Consequently, this research can be used as a point of departure for the prevention of CVD events in populations living in sites environmentally impacted with lead. PMID- 29264640 TI - Long-Term Outcomes of Balloon-Occluded Retrograde Transvenous Obliteration for the Treatment of Gastric Varices: A Comparison of Ethanolamine Oleate and Sodium Tetradecyl Sulfate. AB - PURPOSE: This study was performed to compare the long-term outcomes of balloon occluded retrograde transvenous obliteration (BRTO) for gastric varices using ethanolamine oleate (EO) and sodium tetradecyl sulfate (STS). METHODS: From January 2002 to June 2015, 142 patients underwent BRTO for the treatment of gastric varices using EO (n = 59) or STS (n = 83). We retrospectively reviewed the follow-up data related to the obliteration of gastric varices, rebleeding, and clinical complications. The cumulative recurrence rates of gastric varices after BRTO in each group were analyzed using the Kaplan-Meier method and compared using the log-rank test. RESULTS: The median follow-up periods were 23.9 (range 0.2-170.7) months in the BRTO with EO group and 19.9 (range 0.2-84.7) months in the BRTO with STS group. Technical success was achieved in 53 of 59 (89.8%) cases in the BRTO with EO group and 80 of 83 (96.4%) cases in the BRTO with STS group. The clinical success rates were 94.9% (56/59) in the BRTO with EO group and 96.4% (80/83) in the BRTO with STS group. The cumulative 1-, 3-, and 5-year recurrence rates for gastric varices were 3.8, 9.4, and 9.4% in the BRTO with EO group and 1.3, 2.5, and 3.8% in the BRTO with STS group, respectively (p = 0.684). CONCLUSIONS: BRTO using STS has comparable long-term outcomes to BRTO using EO for gastric varices. PMID- 29264641 TI - Control of morphology and virulence by ADP-ribosylation factors (Arf) in Mucor circinelloides. AB - Mucor circinelloides is a dimorphic fungus used to study cell differentiation that has emerged as a model to characterize mucormycosis. In this work, we identified four ADP-ribosylation factor (Arf)-encoding genes (arf1-arf4) and study their role in the morphogenesis and virulence. Arfs are key regulators of the vesicular trafficking process and are associated with both growth and virulence in fungi. Arf1 and Arf2 share 96% identity and Arf3 and Arf4 share 89% identity, which suggests that the genes arose through gene-duplication events in M. circinelloides. Transcription analysis revealed that certain arf genes are affected by dimorphism of M. circinelloides, such as the arf2 transcript, which was accumulated during yeast development. Therefore, we created knockout mutants of four arf genes to evaluate their function in dimorphism and virulence. We found that both arf1 and arf2 are required for sporulation, but these genes also perform distinct functions; arf2 participates in yeast development, whereas arf1 is involved in aerobic growth. Conversely, arf3 and arf4 play only minor roles during aerobic growth. Moreover, we observed that all single arf-mutant strains are more virulent than the wild-type strain in mouse and nematode models, with the arf3 mutant being most virulent. Lastly, arf1/arf2 and arf3/arf4 double mutations produced heterokaryon strains that did not reach the homokaryotic state, indicating that these genes participate in essential and redundant functions. Overall, this work reveals that Arfs proteins regulate important cellular processes in M. circinelloides such as morphogenesis and virulence, laying the foundation to characterize the molecular networks underlying this regulation. PMID- 29264642 TI - Drug use in pregnant women-a pilot study of the coherence between reported use of drugs and presence of drugs in plasma. AB - PURPOSE: In Sweden, information on drug use during pregnancy is obtained through an interview and recorded in a standardized medical record at every visit to the antenatal care clinic throughout the pregnancy. Antenatal, delivery, and neonatal records constitute the basis for the Swedish Medical Birth Register (MBR). The purpose of this exploratory study was to investigate the reliability of reported drug use by simultaneous screening for drug substances in the blood stream of the pregnant woman and thereby validate self-reported data in the MBR. METHODS: Plasma samples from 200 women were obtained at gestational weeks 10-12 and 25 and screened for drugs by using ultra-high performance liquid chromatography with time of flight mass spectrometry (UHPLC-TOF-MS). The results from the analysis were then compared to medical records. RESULTS: At the first sampling occasion, the drugs found by screening had been reported by 86% of the women and on the second sampling, 85.5%. Missed reported information was clearly associated with drugs for occasional use. The most common drugs in plasma taken in early and mid pregnancy were meclizine and paracetamol. Two types of continuously used drugs, selective serotonin reuptake inhibitors and propranolol, were used. All women using them reported it and the drug screening revealed a 100% coherence. CONCLUSIONS: This study shows good coherence between reported drug intake and the drugs found in plasma samples, which in turn positively validates the MBR. PMID- 29264643 TI - Mechanosensitive ion channel Piezo1 is expressed in antral G cells of murine stomach. AB - G cells in the antrum region of the murine stomach produce gastrin, the central hormone for controlling gastric activities. Secretion of gastrin is induced mainly by protein breakdown products but also by distensions of the stomach wall. Although G cells respond to protein fragments via distinct chemosensory receptor types, the mechanism underlying G cell activation upon distention is entirely ambiguous. Mechanosensitive ion channels are considered as potential candidates for such a task. Therefore, we explore the possibility of whether Piezo1, a polymodal sensor for diverse mechanical forces, is expressed in antral G cells. The experimental analyses revealed that the vast majority of G cells indeed expressed Piezo1. Within flask-like G cells at the base of the antral invaginations, the Piezo1 protein was primarily located at the basolateral portion, which is thought to be the release site for the exocytic secretion of gastrin. In the spindle-like G cells, which are oriented parallel to the invaginations, Piezo1 protein was restricted to the cell body where the hormone was also located, whereas the long processes appeared to be devoid of Piezo1 protein. Our results suggest that mechanosensitive channels such as Piezo1, located in close proximity to hormone-release sites, enable G cells to respond directly to antrum distensions with gastrin secretion. PMID- 29264644 TI - Surgical correction of severe spinal deformities using a staged protocol of external and internal techniques. AB - INTRODUCTION: There is high risk of neurologic complications in one-stage management of severe rigid spinal deformities in adolescents. Therefore, gradual spine stretching variants are applied. One of them is the use of external transpedicular fixation. PURPOSE: Our aim was to retrospectively study the outcomes of gradual correction with an apparatus for external transpedicular fixation followed by internal fixation used for high-grade kyphoscoliosis in adolescents. METHODS: Twenty five patients were reviewed (mean age, 15.1 +/- 0.4 years). Correction was performed in two stages: 1) gradual controlled correction with the apparatus for external transpedicular fixation; and 2) internal posterior transpedicular fixation. Rigid deformities in eight patients required discapophysectomy. Clinical and radiographic study of the outcomes was conducted immediately after treatment and at a mean long-term period of 3.8 +/- 0.4 years. Pain was evaluated using the visual analogue scale (VAS, 10 points). The Oswestry questionnaire (ODI scale) was used for functional assessment. RESULTS: Deformity correction with the external apparatus was 64.2 +/- 4.6% in the main curve and 60.7 +/- 3.7% in the compensatory one. It was 72.8 +/- 4.1% and 66.2 +/- 5.3% immediately after treatment and 70.8 +/- 4.6% and 64.3 +/- 4.2% at long term, respectively. Pain relieved by 33.2 +/- 4.2% (p < 0.05) immediately after treatment and by 55.6 +/- 2.8% (p < 0.05) at long term. ODI reduced by 30.2 +/- 1.7% (p < 0.05) immediately after treatment and by 37.2 +/- 1.6% (p < 0.05) at long term. CONCLUSION: The apparatus for external transpedicular fixation provides gradual controlled correction for high-grade kyphoscoliosis in adolescents. Transition to internal fixation preserves the correction achieved, and correction is maintained at long term. PMID- 29264646 TI - Physical health, breastfeeding problems and maternal mood in the early postpartum: a prospective cohort study. AB - This study aimed to investigate prospectively the contribution of maternal physical health and/or breastfeeding problems to maternal mood (depression, anxiety, fatigue, irritability, confusion, vigor) at 8-weeks postpartum. A prospective study was conducted. Participants were recruited antenatally from a public and a private maternity hospital in Melbourne, Australia. Nulliparous pregnant women (N = 229), >= 18 years of age, >= 36-week gestation, singleton pregnancy and with sufficient English were eligible. Data were collected by self report questionnaire (pregnancy, weeks 1-4 postpartum) and telephone interview (week 8 postpartum). A high burden of physical problems was classified as >= 3 problems (caesarean/perineal pain; back pain; constipation; haemorrhoids; urinary and bowel incontinence) for >= 2 time points. A high burden of breastfeeding problems was having >= 2 problems (mastitis; nipple pain; frequent expressing; over- or under-supply of milk) for >= 2 time points. Multivariate linear regression was used to investigate the relationship between maternal mood, assessed using Profile of Mood States (8-week postpartum), and a high burden of breastfeeding and/or physical health problems. Forty-six women (20.1%) had a high burden of physical symptoms, 44 (19.2%) a high burden of breastfeeding problems only and 25 women (11.0%) had both. A high burden of breastfeeding problems alone (beta = 10.6, p = 0.01) or with co-morbid physical problems (beta = 15.35, p = 0.002) was significantly associated with poorer maternal mood at 8 weeks. Early, effective postnatal treatment of maternal health and breastfeeding problems could reduce women's risk for poor mental health. PMID- 29264647 TI - Increased proportion of mature oocytes with sustained-release growth hormone treatment in poor responders: a prospective randomized controlled study. AB - PURPOSE: Supplementation of growth hormone (GH) during controlled ovarian stimulation (COS) has been suggested to improve ovarian response. Despite potential benefits in poor responders, multiple injections of GH during COS are inconvenient. We conducted a randomized controlled study to evaluate the efficacy and safety of sustained-release human GH in poor responders undergoing in vitro fertilization (IVF). METHODS: This was a single-center, randomized, open-label, parallel study. Infertile women who satisfied the Bologna criteria for poor responders were randomized into GH treatment and control groups. The treatment group received a sustained-release GH (Eutropin Plus(r) 20 mg) three times before and during COS (mid-luteal, late luteal, and menstrual cycle day 2). The baseline characteristics and IVF outcomes were compared between the two groups. RESULTS: A total of 127 patients were included in the analysis. The mean age was 39.6 years and mean anti-Mullerian hormone level was 0.6 ng/ml. There was no significant difference in the baseline characteristics between GH treatment and control groups. The number of follicles on the human chorionic gonadotropin triggering day (3.1 +/- 2.3 vs. 2.4 +/- 1.6, P = 0.043) and the proportion of metaphase II oocytes (67.5 vs. 52.3%, P = 0.030) were higher in the GH group than in controls. The percentage of clinical and ongoing pregnancy and miscarriage was not different between the two groups. CONCLUSION: Supplementation of sustained release GH before and during COS improved ovarian response, with an increase in mature oocytes in poor responders. Further studies are needed to ensure this benefit in general infertility patients. PMID- 29264645 TI - Two Drosophilids exhibit distinct EGF pathway patterns in oogenesis. AB - Deciphering the evolution of morphological structures is a remaining challenge in the field of developmental biology. The respiratory structures of insect eggshells, called the dorsal appendages, provide an outstanding system for exploring these processes since considerable information is known about their patterning and morphogenesis in Drosophila melanogaster and dorsal appendage number and morphology vary widely across Drosophilid species. We investigated the patterning differences that might facilitate morphogenetic differences between D. melanogaster, which produces two oar-like structures first by wrapping and then elongating the tubes via cell intercalation and cell crawling, and Scaptodrosophila lebanonensis, which produces a variable number of appendages simply by cell intercalation and crawling. Analyses of BMP pathway components thickveins and P-Mad demonstrate that anterior patterning is conserved between these species. In contrast, EGF signaling exhibits significant differences. Transcripts for the ligand encoded by gurken localize similarly in the two species, but this morphogen creates a single dorsolateral primordium in S. lebanonensis as defined by activated MAP kinase and the downstream marker broad. Expression patterns of pointed, argos, and Capicua, early steps in the EGF pathway, exhibit a heterochronic shift in S. lebanonensis relative to those seen in D. melanogaster. We demonstrate that the S. lebanonensis Gurken homolog is active in D. melanogaster but is insufficient to alter downstream patterning responses, indicating that Gurken-EGF receptor interactions do not distinguish the two species' patterning. Altogether, these results differentiate EGF signaling patterns between species and shed light on how changes to the regulation of patterning genes may contribute to different tube-forming mechanisms. PMID- 29264648 TI - Development of bisphenol A-removing recombinant Escherichia coli by monomeric and dimeric surface display of bisphenol A-binding peptide. AB - Peptide-displaying Escherichia coli cells were investigated for use in adsorptive removal of bisphenol A (BPA) both in Luria-Bertani medium including BPA or ATM thermal paper eluted wastewater. Two recombinant strains were constructed with monomeric and dimeric repeats of the 7-mer BPA-binding peptide (KSLENSY), respectively. Greater than threefold increased adsorption of BPA [230.4 umol BPA per g dry cell weight (DCW)] was found in dimeric peptide-displaying cells compared to monomeric strains (63.4 umol per g DCW) in 15 ppm BPA solution. The selective removal of BPA from a mixture of BPA analogs (bisphenol F and bisphenol S) was verified in both monomeric and dimeric peptide-displaying cells. The binding chemistry of BPA with the peptide was assumed, based on molecular docking analysis, to be the interaction of BPA with serine and asparagine residues within the 7-mer peptide sequence. The peptide-displaying cells also functioned efficiently in thermal paper eluted wastewater containing 14.5 ppm BPA. PMID- 29264649 TI - Community violence exposure and substance use: cross-cultural and gender perspectives. AB - The negative effects of community violence exposure on child and adolescent mental health are well documented and exposure to community violence has been linked both to a number of internalizing and externalizing symptoms. Our aim was, therefore, to investigate cross-cultural and gender differences in the relationship between community violence exposure and substance abuse. A self report survey was conducted among 10,575, 12-18 year old adolescents in three different countries, Czech Republic (N = 4537), Russia (N = 2377) and US (N = 3661). We found that in all three countries both substance use and problem behavior associated with it increased similarly along with severity of violence exposure and this association was not gender-specific. It was concluded that in spite of the differences in the levels of violence exposure and substance use cross-culturally and by gender, the pattern of their association is neither culturally nor gender bound. PMID- 29264651 TI - Sensitivity of Lung Resistance and Compliance to Beta-Blocker Induced Bronchoconstriction and Long Acting Beta-Agonist Withdrawal in COPD. AB - Little is known about impulse oscillometry (IOS) in COPD. IOS is an effort independent measure of lung resistance and reactance (compliance). We assessed how frequency dependence of resistance (R) and reactance (X) changed in response to bronchoconstriction with carvedilol followed by long acting beta-agonist (LABA) withdrawal. N = 12 patients with moderate to severe COPD were analysed, who had >= 100 ml fall in FEV1 with carvedilol. Compared to baseline taking ICS/LABA there were 21, 59, and 135% significant changes in resistance at 5 Hz (R5), reactance at 5 Hz (X5), and reactance area (AX), respectively, with carvedilol, while after LABA withdrawal only AX showed a further significant increase to 210% (i.e. reduced compliance). Hence changes in lung compliance rather than resistance play a more important role in the beta-2 receptor-mediated responses in COPD. PMID- 29264650 TI - The role of managers in addressing employees with musculoskeletal pain: a mixed methods study. AB - PURPOSE: This study investigates management awareness of employee musculoskeletal pain and conditions that shape managers' handling of employees with pain. METHODS: We used a mixed methods design including data from a questionnaire survey and focus group sessions. All employees and managers from seven nursing homes were invited to participate in the questionnaire survey and 327 employees (81%) and 31 managers (82%) responded. Employees were asked about their worst pain intensity the past month and managers were asked to estimate the percentage of their employees who had experienced pain. Thirty-eight managers (93%) participated in focus group sessions addressing the culture for handling pain at the workplace. A multiple case study approach allowed for an integrated interpretation of the empirical findings. RESULTS: Results indicate limited manager awareness of employee pain. We identified four conditions that shape managers' handling of employees with pain: (1) Employee handling of-and communication about-pain, (2) the collegial culture for handling pain, (3) managers' perception of their role towards employees with pain and (4) procedures and informal approaches for handling employees with pain. Across these conditions various degrees of openness characterized the nursing homes. CONCLUSIONS: The degree of openness towards communicating about-and handling pain-in the organization (individual, collegial and managerial levels) influences how managers handle employees with pain. Awareness about employee health is a prerequisite for management to initiate relevant action towards supporting employees. Future workplace initiatives are likely to benefit from addressing openness in the organization to increase awareness and support employees with pain. PMID- 29264652 TI - Intratracheal Administration of Autologous Bone Marrow-Derived Cells Ameliorates Monocrotaline-Induced Pulmonary Vessel Remodeling and Lung Inflammation in Rats. AB - PURPOSE: Inflammation is a feature of lung injury and plays a critical role in pulmonary vascular remodeling. Bone marrow-derived cells (BMCs) have anti inflammatory properties and favor macrophage differentiation into an alternatively activated regulatory M2 profile. We investigated the effect of autologous BMCs on monocrotaline-induced pulmonary vessel remodeling and lung inflammation in rats, by direct administration into lungs via the airway. METHODS: BMCs were isolated and plastic-adherent cells were cultured for 3 weeks. 1 week following monocrotaline (60 mg/kg) treatment, fluorescently labeled autologous BMCs (1 * 106 cells) or vehicle were administered intratracheally to male Sprague-Dawley rats. 4 weeks following monocrotaline treatment, lung pathology was evaluated. RESULTS: Monocrotaline increased pulmonary vessel wall thickness, perivascular infiltration, alveolar septal thickening, and inflammatory cell infiltration including T lymphocytes and monocytes/macrophages in alveolar areas, and also increased mRNA expression of inflammatory-related cytokines including IL-10 in the lung. Intratracheal administration of autologous BMCs prevented pulmonary vessel wall thickening and perivascular infiltration, and increased CD163-positive M2-like macrophages in perivascular areas. BMC administration inhibited the thickening of alveolar septa and reduced monocrotaline-induced inflammatory cell infiltration in lung parenchyma compared with monocrotaline-vehicle-treated-rats. Furthermore, BMCs administration increased expression of CD163-positive cells in perivascular areas and maintained the increased mRNA expression of IL-10. CONCLUSIONS: Intratracheal administration of autologous BMCs prevented monocrotaline-induced pulmonary vessel remodeling and lung inflammation, at least in part, through induction of alternatively activated macrophages and regulation of the local lung environment toward resolving inflammation. PMID- 29264653 TI - Recovery of macular cone photoreceptors in Vogt-Koyanagi-Harada disease. AB - PURPOSE: Our purpose was to study changes in macular cone photoreceptors in Vogt Koyanagi-Harada (VKH) disease patients after high-dose corticosteroid treatment using an adaptive optics (AO) fundus camera. METHODS: We retrospectively analyzed 16 eyes of eight patients with new-onset acute VKH disease that were studied retrospectively. After serous retinal detachment (SRD) had resolved, AO images were obtained using the rtx1TM AO fundus camera over a 12-month course. Cone counting was performed in the nasal, temporal, superior and inferior areas of the macula 0.75 mm from the foveal center. A control group of 30 eyes of 30 healthy subjects was established for comparison. RESULTS: In the eyes with VKH disease, the mean cone densities 0.75 mm from the foveal center were 11,847 at baseline (resolution of SRD), and 15,218, 16,684 and 17,686 cones/mm2, at 3, 6, and 12 months later, respectively. The mean cone densities at 3, 6, and 12 months were significantly increased compared to those of baseline (p = 0.007, p < 0.001, and p < 0.001, respectively); however, they were significantly lower than that of the healthy control eyes (p < 0.001). The mean cone densities at areas with a previous presence of cystoid spaces were significantly lower than those without cystoid spaces at the baseline, and at 3, 6, and 12 months (p < 0.001, p = 0.007, p < 0.001, and p = 0.008, respectively). CONCLUSIONS: Cone densities were gradually increased after the resolution of SRD in the eyes of VKH disease patients. The presence of cystoid spaces might be a marker of severe damage to cone photoreceptors. PMID- 29264654 TI - Genetic variants in microRNA genes and targets associated with cardiovascular disease risk factors in the African-American population. AB - The purpose of this study is to identify microRNA (miRNA) related polymorphism, including single nucleotide variants (SNVs) in mature miRNA-encoding sequences or in miRNA-target sites, and their association with cardiovascular disease (CVD) risk factors in African-American population. To achieve our objective, we examined 1900 African-Americans from the Atherosclerosis Risk in Communities study using SNVs identified from whole-genome sequencing data. A total of 971 SNVs found in 726 different mature miRNA-encoding sequences and 16,057 SNVs found in the three prime untranslated region (3'UTR) of 3647 protein-coding genes were identified and interrogated their associations with 17 CVD risk factors. Using single-variant-based approach, we found 5 SNVs in miRNA-encoding sequences to be associated with serum Lipoprotein(a) [Lp(a)], high-density lipoprotein (HDL) or triglycerides, and 2 SNVs in miRNA-target sites to be associated with Lp(a) and HDL, all with false discovery rates of 5%. Using a gene-based approach, we identified 3 pairs of associations between gene NSD1 and platelet count, gene HSPA4L and cardiac troponin T, and gene AHSA2 and magnesium. We successfully validated the association between a variant specific to African-American population, NR_039880.1:n.18A>C, in mature hsa-miR-4727-5p encoding sequence and serum HDL level in an independent sample of 2135 African-Americans. Our study provided candidate miRNAs and their targets for further investigation of their potential contribution to ethnic disparities in CVD risk factors. PMID- 29264657 TI - "The stem cell fashion": do we need only stem cells for tissue regeneration? PMID- 29264655 TI - Voice outcome indicators for unilateral vocal fold paralysis surgery: a review of the literature. AB - INTRODUCTION: There is no consensus on which voice outcome indicators (VOIs) should be used to compare the merits of the various surgical treatments for unilateral vocal fold paralysis (UVFP). Authors performed a literature review to identify which VOIs are most frequently used and most relevant, in terms of significant change in pre- and post-operative measurements, to assess UVFP surgical treatments. METHOD: A Medline/Pubmed literature review was performed and the most frequently used VOIs were identified using a Pareto diagram. For these most frequently used VOI's, the number of studies that showed a statistically significant change in pre- and post-operative results were compared to the total number of studies found using that same VOI, this portion was expressed in percent. This percentage was defined as the "percentage of significance" and used to assess changes of each VOI. RESULTS: Eleven VOIs were identified using the Pareto analysis. These were, in decreasing order of frequency of citation: maximum phonation time (MPT), jitter, Shimmer, video-stroboscopic examination, noise to harmonic ratio (NHR/HNR), mean air flow (MeAF), fundamental frequency (F0), "Infrequent Perceptional Scales", GRBAS scale, mean subglottic pressure (MSGP). MPT, MeAF, factor G of GRBAS-I, Jitter, shimmer and VHI-30 had respective "percentage of significance" of 90, 86, 85, 74, 68 and 64%, respectively. CONCLUSION: The results indicate that MPT, MeAF and GRBAS-I, represent the top three most frequently used and the most relevant VOIs in terms of "percentage of significance". VHI-30 showed a relatively low rate of use and low "percentage of significance". The role of Jitter and Shimmer remains unclear. Finally, MSGP and the F0 appear to be less relevant VOIs for the evaluation of UFVP surgical treatments in terms of significant change in pre- and post-operative measurements. PMID- 29264656 TI - Conservative surgical treatments for nonsyndromic odontogenic keratocysts: a systematic review and meta-analysis. AB - OBJECTIVES: This manuscript presents a systematic review of the clinicopathologic features and outcomes of conservative surgical treatments for nonsyndromic odontogenic keratocysts (OKCs) and assesses the recurrence rates through a meta analysis, in order to indicate the best conservative approach. MATERIALS AND METHODS: PRISMA guidelines for systematic reviews were followed, and the protocol was registered (PROSPERO/Nr.: CRD42017060964). An electronic search was conducted using the PubMed/MEDLINE, Science Direct, Web of Science, Scopus, and The Cochrane Library databases, and relevant articles were selected based on specific inclusion criteria. The PICOS criteria (Population: nonsyndromic patients of any age with OKC, with histopathological diagnosis and minimum follow-up of 12 months; Intervention and Comparison: marsupialization or decompression with or without enucleation, and enucleation alone; Outcome: recurrence rates; Study design: clinical trials, controlled trials, retrospective studies, and case series containing at least 10 cases of OKC) were employed. A pooled odds ratio (OR) was computed through the Mantel-Haenszel test (M-H) with 95% confidence intervals (CI). RESULTS: One thousand nine hundred OKCs were analyzed; the age of the patients varied from 6 to 90 years (mean of 38.6 years); a male to female ratio of 1.57:1 was observed; 74.5% of the lesions occurred in the mandible; 75.7% of OKCs were unilocular; the association with impacted tooth was reported for 344 OKCs; and the mean follow-up was 60.1 months. One thousand three hundred thirty-one OKCs were treated by conservative surgical treatments, and 261 cases (19.8%) presented recurrence. Nonetheless, minor total recurrence rates were observed after decompression followed by enucleation (11.9%) and marsupialization followed by enucleation (17.8%). In contrast, enucleation alone showed a total recurrence rate of 20.8%. CONCLUSION: The results suggest a significant superiority of success for OKC treatments that use decompression followed by enucleation, instead of an initial enucleation (M-H, OR = 0.48; 95% CI = 0.22 to 1.08; P = 0.0163). CLINICAL RELEVANCE: No consensus exists concerning the best management for OKCs. More aggressive treatments (ostectomy, resection, or use of adjunctive therapies like Carnoy's solution and liquid nitrogen) can have many disadvantages and risks. Therefore, it is necessary to identify the conservative approach for OKCs that results in a lower recurrence rate. PMID- 29264658 TI - Sleep disorder diagnoses and clinical outcomes among hospitalized breast cancer patients: a nationwide inpatient sample study. AB - PURPOSE: Sleep disturbances are recognized as a problem for many cancer patients, but little is known about the prevalence of sleep disorders among women hospitalized with breast cancer, or their relationship to in-hospital outcomes. The present study represents a first step toward determining the clinical significance of sleep disorders for hospitalized breast cancer patients with regard to complications, length of hospital stay, and mortality. METHODS: The relationships between sleep disorders and in-hospital outcomes among 84,424 hospitalized breast cancer patients were examined. This study analyzed the Nationwide Inpatient Sample (NIS) database (2007 to 2011) for all women ages 40 years and older with a primary discharge diagnosis of breast cancer and a secondary discharge diagnosis of sleep disorder. Odds ratios, estimates, and 95% confidence intervals were computed using multivariable regression adjusting for age, comorbidities, race, cancer stage, income, insurance type, residential region, year of discharge, and surgical treatment type. RESULTS: Among women hospitalized with a primary diagnosis of breast cancer, 2% (n = 1807) also received a diagnosis of a sleep disorder during hospitalization, the majority of which were sleep-related breathing disorders (n = 1274). Although there was no significant association between having a diagnosis of a sleep disorder and in hospital mortality, patients with a sleep disorder were more likely to also experience complications (OR = 1.58, 95% CI 1.29-1.34) and have longer hospital stays (mean = 0.44 days longer, 95% CI 0.25-0.63). CONCLUSION: Hospitalized breast cancer patients with a sleep disorder were more likely to experience clinical complications and stay longer in the hospital. It remains an open and important question for future research whether interventions to improve sleep during hospitalization would help to improve clinical outcomes. PMID- 29264659 TI - Investigation of glutathione-derived electrostatic and hydrogen-bonding interactions and their role in defining Grx5 [2Fe-2S] cluster optical spectra and transfer chemistry. AB - Human glutaredoxin 5 (Grx5) is one of the core components of the Isc (iron-sulfur cluster) assembly and trafficking machinery, and serves as an intermediary cluster carrier, putatively delivering cluster from the Isu scaffold protein to target proteins. The tripeptide glutathione is intimately involved in this role, providing cysteinyl coordination to the iron center of the Grx5-bound [2Fe-2S] cluster. Grx5 has a well-defined glutathione-binding pocket with protein amino acid residues providing many ionic and hydrogen binding contacts to the bound glutathione. In this report, we investigated the importance of these interactions in cluster chirality and exchange reactivity by systematically perturbing the crucial contacts by use of natural and non-natural amino acid substitutions to disrupt the binding contacts from both the protein and glutathione. Native Grx5 could be reconstituted with all of the glutathione analogs used, as well as other thiol ligands, such as DTT or L-cysteine, by in vitro chemical reconstitution, and the holo proteins were found to transfer [2Fe-2S] cluster to apo ferredoxin 1 at comparable rates. However, the circular dichroism spectra of these derivatives displayed prominent differences that reflect perturbations in local cluster chirality. These studies provided a detailed molecular understanding of glutathione-protein interactions in holo Grx5 that define both cluster spectroscopy and exchange chemistry. PMID- 29264660 TI - The serotonergic system in Parkinson's patients with dyskinesia: evidence from imaging studies. AB - The purpose of review is to review the current status of positron emission tomography (PET) molecular imaging of serotonergic system in Parkinson's patients who experience levodopa-induced (LIDs) and graft-induced dyskinesias (GIDs). PET imaging studies have shown that Parkinson's disease is characterized by progressive loss of dopaminergic and serotonergic neurons. Parkinson's patients who experienced LIDs and GIDs have an aberrant spreading of serotonergic terminals, which lead to an increased serotonergic/dopaminergic terminals ratio within the putamen. Serotonergic terminals convert exogenous levodopa into dopamine in a non-physiological manner and release an abnormal amount of dopamine without an auto-regulatory feedback. This results in higher swings in synaptic levels of dopamine, which leads to the development of LIDs and GIDs. The modulation of serotonergic terminals with 5-HT1A and 5-HT1B receptors agonists partially reduced these motor complications. In vivo PET studies confirmed that abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. However, glutamatergic, adenosinergic, opioid systems, and phosphodiesterases 10A may also play a role in the development of these motor complications. An integrative multimodal imaging approach combining PET and MRI imaging techniques is needed to fully understand the mechanisms underlying the development of LIDs and GIDs. PMID- 29264661 TI - Engineering Escherichia coli for efficient coproduction of polyhydroxyalkanoates and 5-aminolevulinic acid. AB - Single-cell biorefineries are an interesting strategy for using different components of feedstock to produce multiple high-value biochemicals. In this study, a strategy was applied to refine glucose and fatty acid to produce 5 aminolevulinic acid (ALA) and polyhydroxyalkanoates (PHAs). To express the ALA and PHAs dual-production system efficiently and stably, multiple copies of the poly-beta-3-hydroxybutyrate (PHB) synthesis operon were integrated into the chromosome of Escherichia coli DH5alphaDeltapoxB. The above strain harboring the ALA C5 synthesis pathway genes hemA and hemL resulted in coproduction of 38.2% PHB (cell dry weight, CDW) and 3.2 g/L extracellular ALA. To explore coproduction of ALA and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), the PHBV synthetic pathway was also integrated into engineered E. coli and coexpressed with hemA and hemL; cells produced 38.9% PHBV (CDW) with 10.3 mol% 3HV fractions and 3.0 g/L ALA. The coproduction of ALA with PHB and PHBV can improve the utilization of carbon sources and maximize the value derived from the feedstock. PMID- 29264662 TI - Preparation and Optical Properties of GeBi Films by Using Molecular Beam Epitaxy Method. AB - Ge-based alloys have drawn great interest as promising materials for their superior visible to infrared photoelectric performances. In this study, we report the preparation and optical properties of germanium-bismuth (Ge1-xBix) thin films by using molecular beam epitaxy (MBE). GeBi thin films belong to the n-type conductivity semiconductors, which have been rarely reported. With the increasing Bi-doping content from 2 to 22.2%, a series of Ge1-xBix thin film samples were obtained and characterized by X-ray diffraction, scanning electron microscopy, and atomic force microscopy. With the increase of Bi content, the mismatch of lattice constants increases, and the GeBi film shifts from direct energy band gaps to indirect band-gaps. The moderate increase of Bi content reduces optical reflectance and promotes the transmittance of extinction coefficient in infrared wavelengths. The absorption and transmittance of GeBi films in THz band increase with the increase of Bi contents. PMID- 29264663 TI - Modeling molecular boiling points using computed interaction energies. AB - The noncovalent van der Waals interactions between molecules in liquids are typically described in textbooks as occurring between the total molecular dipoles (permanent, induced, or transient) of the molecules. This notion was tested by examining the boiling points of 67 halogenated hydrocarbon liquids using quantum chemically calculated molecular dipole moments, ionization potentials, and polarizabilities obtained from semi-empirical (AM1 and PM3) and ab initio Hartree Fock [HF 6-31G(d), HF 6-311G(d,p)], and density functional theory [B3LYP/6 311G(d,p)] methods. The calculated interaction energies and an empirical measure of hydrogen bonding were employed to model the boiling points of the halocarbons. It was found that only terms related to London dispersion energies and hydrogen bonding proved significant in the regression analyses, and the performances of the models generally improved at higher levels of quantum chemical computation. An empirical estimate for the molecular polarizabilities was also tested, and the best models for the boiling points were obtained using either this empirical polarizability itself or the polarizabilities calculated at the B3LYP/6-311G(d,p) level, along with the hydrogen-bonding parameter. The results suggest that the cohesive forces are more appropriately described as resulting from highly localized interactions rather than interactions between the global molecular dipoles. PMID- 29264664 TI - Does spending matters? Re-looking into various covariates associated with Out of Pocket Expenditure (OOPE) and catastrophic spending on accidental injury from NSSO 71st round data. AB - BACKGROUND: Accidental Injury is a traumatic event which not only influences physical, psychological, and social wellbeing of the households but also exerts extensive financial burden on them. Despite the devastating economic burden of injuries, in India, there is limited data available on injury epidemiology. This paper aims to, first, examine the socio-economic differentials in Out of Pocket Expenditure (OOPE) on accidental injury; second, to look into the level of Catastrophic Health Expenditure (CHE) at different threshold levels; and last, to explore the adjusted effect of various socio-economic covariates on the level of CHE. METHODS: Data was extracted from the key indicators of social consumption in India: Health, National Sample Survey Organisation (NSSO), conducted by the Government of India during January-June-2014. Logistic regression analysis was employed to analyse the various covariates of OOPE and CHE associated to accidental injury. FINDINGS: Binary Logistic analysis has demonstrated a significant association between socioeconomic status of the households and the level of OOPE and CHE on accidental injury care. People who used private health services incurred 16 times higher odds of CHE than those who availed public facilities. The result shows that if the person is covered via any type of insurance, the odd of CHE was lower by about 28% than the uninsured. Longer duration of stay and death due to accidental injury was positively associated with higher level of OOPE. Economic status, nature of healthcare facility availed and regional affiliation significantly influence the level of OOPE and CHE. CONCLUSION: Despite numerous efforts by the Central and State governments to reduce the financial burden of healthcare, large number of households are still paying a significant amount from their own pockets. There are huge differentials in cost for the treatment among public and private healthcare providers for accidental injury. It is expected that the findings would provide insights into the prevailing magnitude of accidental injuries in India, the profile of the population affected, and the level of OOPE among households. PMID- 29264665 TI - Apigenin reduces the Toll-like receptor-4-dependent activation of NF-kappaB by suppressing the Akt, mTOR, JNK, and p38-MAPK. AB - Flavone apigenin has an anti-inflammatory effect. We assessed whether apigenin may reduce the inflammatory mediator production, which is regulated by the Toll like receptor-4-dependent activation of the Akt, mTOR, and NF-kappaB pathways, and activation of JNK and p38-MAPK in HEK001 keratinocytes and primary keratinocytes. Apigenin, the Akt inhibitor, Bay 11-7085, and N-acetylcysteine inhibited the lipopolysaccharide-stimulated production of cytokines IL-1beta and IL-6 and chemokines CCL17 and CCL27; the expression of cyclooxygenase-2; the increase in the levels of Toll-like receptor-4, phosphorylated Akt, and mTOR; the activation of NF-kappaB; the activation of the JNK and p38-MAPK; and the production of reactive oxygen/nitrogen species in keratinocytes. Inhibitors of the c-JNK (SP600125) and p38-MAPK (SB203580) reduced lipopolysaccharide-induced production of inflammatory mediators and activation of the JNK and p38-MAPK in keratinocytes. These results show that apigenin may inhibit the lipopolysaccharide-caused inflammatory mediator production in keratinocytes by reducing the Toll-like receptor-4-dependent activation of Akt, mTOR, and NF kappaB pathways, and activation of JNK and p38-MAPK. The suppressive effect of apigenin may be achieved by the inhibition of reactive oxygen/nitrogen species production. Additionally, apigenin appears to reduce the Akt, mTOR, and NF-kappaB pathway- and the JNK and p38-MAPK-mediated inflammatory skin diseases. PMID- 29264667 TI - Airflow Simulations in Infant, Child, and Adult Pulmonary Conducting Airways. AB - The airway structure continuously evolves from birth to adulthood, influencing airflow dynamics and respiratory mechanics. We currently know very little about how airflow patterns change throughout early life and its impact on airway resistance, namely because of experimental limitations. To uncover differences in respiratory dynamics between age groups, we performed subject-specific airflow simulations in an infant, child, and adult conducting airways. Airflow throughout the respiration cycle was calculated by coupling image-based models of the conducting airways to the global respiratory mechanics, where flow was driven by a pressure differential. Trachea diameter was 19, 9, and 4.5 mm for the adult (36 years, female), child (6 years, male), and infant (0.25 years, female), respectively. Mean Reynolds number within the trachea was nearly the same for each subject (1100) and Womersley number was above unity for all three subjects and largest for the adult, highlighting the significance of transient effects. In general, air speeds and airway resistances within the conducting airways were inversely correlated with age; the 3D pressure drop was highest in the infant model. These simulations provide new insight into age-dependent flow dynamics throughout the respiration cycle within subject-specific airways. PMID- 29264666 TI - Medication-taking behaviour in Bulgarian women with postmenopausal osteoporosis treated with denosumab or monthly oral bisphosphonates. AB - : Persistence with osteoporosis therapy is critical for fracture risk reduction. This observational study evaluated medication-taking behaviour of women with postmenopausal osteoporosis receiving denosumab or oral ibandronate in real-world clinical practice in Bulgaria. Compared with ibandronate, densoumab was associated with a lower discontinuation rate and greater increases in bone mineral density. PURPOSE: Persistence with osteoporosis therapy is critical for fracture risk reduction and the effectiveness of such treatments may be reduced by low persistence. Alternative therapies such as denosumab may improve persistence. This study aimed to describe medication-taking behaviour in women with osteoporosis, prescribed denosumab or oral ibandronate, in Bulgarian clinical practice. METHODS: This retrospective, observational, multicentre chart review (with up to 24 months follow-up) enrolled postmenopausal women initiating 6-monthly denosumab injection or monthly oral ibandronate treatment for osteoporosis between 1 October 2011 and 30 September 2012. RESULTS: Overall, 441 women were enrolled (224 had initiated denosumab, 217 had initiated ibandronate). At baseline, more women in the denosumab group than in the ibandronate group had a previous fracture (25.5 vs 17.5%; p = 0.043) and past exposure to osteoporosis therapy (19.6 vs 12.0%; p = 0.028). At 24 months, 4.5% of women receiving denosumab had discontinued therapy compared with 56.2% of women receiving ibandronate. Median time to discontinuation was longer in the denosumab group (729 days; interquartile range (IQR), 728.3-729.0) than in the ibandronate group (367 days; IQR, 354.0-484.8; p < 0.001). At 24 months, there were significantly greater changes in BMD T-scores at the lumbar spine (p < 0.001) and femoral neck (p < 0.001) in patients receiving denosumab than in those receiving ibandronate. At 24 months, persistence with denosumab was 98.7%. CONCLUSION: This real-world study demonstrates there is a low discontinuation rate and high persistence with denosumab. Denosumab was associated with greater BMD increases than ibandronate, which could reduce fracture risk. PMID- 29264668 TI - Volume-replacement ratio for crystalloids and colloids during bleeding and resuscitation: an animal experiment. AB - BACKGROUND: Fluid resuscitation remains a cornerstone in the management of acute bleeding. According to Starling's "Three-compartment model", four-times more crystalloids have the same volume effect as colloids. However, this volume replacement ratio remains a controversial issue as it may be affected by the degradation of the endothelial glycocalyx layer, a situation often found in the critically ill. Our aim was to compare colloid and crystalloid based fluid resuscitation during an experimental stroke volume index (SVI) guided hemorrhage and resuscitation animal model. METHODS: Anesthetized and mechanically ventilated pigs were randomized to receive a colloid (Voluven(r),HES, n=15) or crystalloid (Ringerfundin(r),RF, n=15) infusion. Animals were bled till baseline SVI (Tbsl) dropped by 50% (T0), followed by resuscitation until initial SVI was reached (T4) in four steps. Invasive hemodynamic measurements, blood gas analyses and laboratory tests were performed at each assessment points. Glycocalyx degradation markers (Syndecan-1/hematocrit ratio, Glypican/hematocrit ratio) were determined at Tbsl, T0 and T4. RESULTS: Similar amounts of blood were shed in both groups (HES group: 506+/-159 mls blood, RF group: 470+/-127 mls blood). Hemodynamic changes followed the same pattern without significant difference between the groups. Animals received significantly less resuscitation fluid in the HES compared to the RF-group: 425 [320-665], vs 1390 [884-1585] mls, p <0.001. The volume replacement ratio was 0.92 [0.79-1.54] for HES; and 3.03 [2.00-4.23] for the RF-group (p <0.001). There was no significant difference between the groups in the glycocalyx degradation markers. CONCLUSION: In this moderate bleeding resuscitation animal model the volume-replacement ratio for crystalloids and colloids followed similar patterns as predicted by Starling's principle, and the glycocalyx remained intact. This indicates that in acute bleeding events, such as trauma or during surgery, colloids may be beneficial as hemodynamic stability may be achieved more rapidly than with crystalloids. PMID- 29264669 TI - Benthic macroinvertebrates response to water management in a lowland river: effects of hydro-power vs irrigation off-stream diversions. AB - An eco-hydraulic survey of the highly regulated Adda River (northern Italy) was carried out to highlight the ecological implications of the current water management, including minimum flows (MFs) set as environmental protection measures. Macroinvertebrates, flows, and other main physico-chemical parameters were monitored from 2010 to 2012 at seven sites located in two river reaches characterized by different water abstraction schemes. In the upper part of the river, water is mainly diverted for hydro-power, and, in water-depleted reaches, discharges equalled MF for more than 100 days y-1, mainly during winter. In the downstream river reach, where irrigation use prevails, discharges were on average three times higher than in the upper part of the river, and flow values similar to MF were detected only for short periods during summer. The two resulting streamflow patterns seem to have shaped different benthic communities, superimposing to the natural downstream variation. The upper reach is characterized by univoltine taxa, while the lower reach by multivoltine taxa adapted to a more disturbed environment. Chironomidae, a well-known tolerant benthic family, dominated at a site affected by point-source pollution, which turned out to be another determinant of macroinvertebrate community. Despite these differences among sites in the benthic community structure, the current water management seems to allow, for all of the investigated river sites, the achievement of the good ecological status as defined by the local law set in accomplishment of the Water Framework Directive. PMID- 29264670 TI - Behavior of BsoBI endonuclease in the presence and absence of DNA. AB - BsoBI is a type II restriction endonuclease belonging to the EcoRI family. There is only one previously published X-ray structure for this endonuclease: it shows a homodimer of BsoBI completely encircling DNA in a tunnel. In this work, molecular dynamics simulations were employed to elucidate possible ways in which DNA is loaded into this complex prior to its cleavage. We found that the dimer does not open spontaneously when DNA is removed from the complex on the timescale of our simulations (~ 0.5 MUs). A biased simulation had to be used to facilitate the opening, which revealed a possible way for the two catalytic domains to separate. The alpha-helices connecting the catalytic and helical domains were found to act as a hinge during the separation. In addition, we found that the opening of the BsoBI dimer was influenced by the type of counterions present in the environment. A reference simulation of the BsoBI/DNA complex further showed spontaneous reorganization of the active sites due to the binding of solvent ions, which led to an active-site structure consistent with other experimental structures of type II restriction endonucleases determined in the presence of metal ions. PMID- 29264671 TI - Hypothyroidism and Wound Healing After Salvage Laryngectomy. AB - BACKGROUND: Patients undergoing salvage laryngectomy are predisposed to radiation induced hypothyroidism and impaired wound healing secondary to the tissue effects of prior treatment. The impact of hypothyroidism on postoperative wound healing is not established. METHODS: A single-institution retrospective case series was performed. The inclusion criteria specified preoperatively euthyroid adults who underwent salvage laryngectomy with concurrent neck dissection between 1997 and 2015 for persistent or recurrent laryngeal squamous cell carcinoma after radiation or chemoradiation therapy (n = 182). The principal explanatory variable was postoperative hypothyroidism, defined as thyroid-stimulating hormone (TSH) higher than 5.5 mIU/L. The primary end points of the study were pharyngocutaneous fistulas and wounds requiring reoperation. Multivariate analysis was performed. RESULTS: The fistula rate was 47% among hypothyroid patients versus 23% among euthyroid patients. In the multivariate analysis, the patients who experienced hypothyroidism in the postoperative period had a 3.6-fold greater risk of fistula [95% confidence interval (CI) 1.8-7.1; p = 0.0002]. The hypothyroid patients had an 11.4-fold greater risk for a required reoperation (24.4 vs 5.4%) than the euthyroid patients (95% CI 2.6-49.9; p = 0.001). The risk for fistula (p = 0.003) and reoperation (p = 0.001) increased with increasing TSH. This corresponds to an approximate 12.5% incremental increase in the absolute risk for fistula and a 10% increase in the absolute risk for reoperation with each doubling of the TSH. CONCLUSION: Postoperative hypothyroidism independently predicts postoperative wound-healing complications. The association of hypothyroidism with fistula formation may yield opportunities to modulate wound healing with thyroid supplementation or to provide a biomarker of wound progression. PMID- 29264672 TI - Pathological and Radiological Splenic Vein Involvement are Predictors of Poor Prognosis and Early Liver Metastasis After Surgery in Patients with Pancreatic Adenocarcinoma of the Body and Tail. AB - BACKGROUND: The prognostic impact of pancreatic ductal adenocarcinoma (PDAC) invasion to the splenic vessel is controversial. OBJECTIVE: The aim of this study was to assess the clinical value of pathological and radiological splenic vessel invasion in PDACs of the body and tail. METHODS: Medical records of patients with resectable PDAC of the body and tail who underwent distal pancreatectomy between 2003 and 2016 at the Kobe University Hospital were retrospectively analyzed. RESULTS: Overall, 68 patients (29 female and 39 male patients) were enrolled. Pathologically determined splenic vein invasion (p-SV) and splenic artery invasion (p-SA) were identified in 21 (30.9%) and 5 (7.4%) patients, respectively. The p-SV (but not p-SA) was an independent prognostic factor in multivariate analysis (p = 0.009). On analysis of recurrence patterns, patients with PDAC positive for p-SV were at a higher risk for liver metastasis (p = 0.022); however, the associations were not significant for other recurrence patterns. Liver metastasis occurred earlier in patients who were positive for p SV (p = 0.015). Preoperative computed tomography effectively diagnosed pathological vessel invasion (SV: sensitivity, 95.2%, specificity, 72.3%; SA: sensitivity, 100%, specificity, 84.1%). Radiological SV invasion remained significant in multivariate analysis regarding postoperative survival (p = 0.007), and was also associated with early liver metastases (p = 0.008). CONCLUSIONS: Pathological/radiological SV invasion were independent adverse prognostic factors associated with early liver metastasis in patients with PDAC of the body/tail. Assessment of these findings may be useful in determining optimal therapeutic options in these patients. PMID- 29264674 TI - Collision-induced dissociation of doubly-charged barium-cationized lipids generated from liquid samples by atmospheric pressure matrix-assisted laser desorption/ionization provides structurally diagnostic product ions. AB - Obtaining structural information for lipids such as phosphatidylcholines, in particular the location of double bonds in their fatty acid constituents, is an ongoing challenge for mass spectrometry (MS) analysis. Here, we present a novel method utilizing the doping of liquid matrix-assisted laser desorption/ionization (MALDI) samples with divalent metal chloride salts, producing ions with the formula [L+M]2+ (L = lipid, M = divalent metal cation). Multiply charged lipid ions were not detected with the investigated trivalent metal cations. Collision induced dissociation (CID) product ions from doubly charged metal-cationized lipids include the singly charged intact fatty acids [snx+M-H]+, where 'x' represents the position of the fatty acid on the glycerol backbone. The preference of the divalent metal cation to locate on the sn2 fatty acid during CID was found, enabling stereochemical assignment. Pseudo-MS3 experiments such as in-source decay (ISD)-CID and ion mobility-enabled time-aligned parallel (TAP) MS of [snx+M-H]+ provided diagnostic product ion spectra for determining the location of double bonds on the acyl chain and were applied to identify and characterize lipids extracted from soya milk. This novel method is applicable to lipid profiling in the positive ion mode, where structural information of lipids is often difficult to obtain. Graphical abstract MALDI of liquid lipid samples doped with divalent metal salt (e.g. BaCl2) produces doubly charged lipid-barium ions and enables structural elucidation via MS/MS and MS3 analysis. PMID- 29264675 TI - Toxicological assessment of nanomaterials: the role of in vitro Raman microspectroscopic analysis. AB - The acceleration of nanomaterials research has brought about increased demands for rapid analysis of their bioactivity, in a multi-parametric fashion, to minimize the gap between potential applications and knowledge of their toxicological properties. The potential of Raman microspectroscopy for the analysis of biological systems with the aid of multivariate analysis techniques has been demonstrated. In this study, an overview of recent efforts towards establishing a 'label-free high content nanotoxicological assessment technique' using Raman microspectroscopy is presented. The current state of the art for cellular toxicity assessment and the potential of Raman microspectroscopy are discussed, and the spectral markers of the cellular toxic responses upon exposure to nanoparticles, changes on the identified spectral markers upon exposure to different nanoparticles, cell death mechanisms, and the effects of nanoparticles on different cell lines are summarized. Moreover, 3D toxicity plots of spectral markers, as a function of time and dose, are introduced as new methodology for toxicological analysis based on the intrinsic properties of the biomolecular changes, such as cytoplasmic RNA aberrations, protein and lipid damage associated with the toxic response. The 3D evolution of the spectral markers are correlated with the results obtained by commonly used cytotoxicity assays, and significant similarities are observed between band intensity and percentage viability obtained by the Alamar Blue assay, as an example. Therefore, the developed 3D plots can be used to identify toxicological properties of a nanomaterial and can potentially be used to predict toxicity, which can provide rapid advances in nanomedicine. Graphical Abstract Spectral markers of cytotoxicity as a function of time and dose. PMID- 29264673 TI - Neuroprotective effects of the gliopeptide ODN in an in vivo model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopamine (DA) neurons through apoptotic, inflammatory and oxidative stress mechanisms. The octadecaneuropeptide (ODN) is a diazepam-binding inhibitor (DBI)-derived peptide, expressed by astrocytes, which protects neurons against oxidative cell damages and apoptosis in an in vitro model of PD. The present study reveals that a single intracerebroventricular injection of 10 ng ODN 1 h after the last administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) prevented the degeneration of DA neurons induced by the toxin in the substantia nigra pars compacta of mice, 7 days after treatment. ODN mediated neuroprotection was associated with a reduction of the number of glial fibrillary acidic protein-positive reactive astrocytes and a strong inhibition of the expression of pro-inflammatory genes such as interleukins 1beta and 6, and tumor necrosis factor-alpha. Moreover, ODN blocked the inhibition of the anti apoptotic gene Bcl-2, and the stimulation of the pro-apoptotic genes Bax and caspase-3, induced by MPTP in the substantia nigra pars compacta. ODN also decreased or even in some cases abolished MPTP-induced oxidative damages, overproduction of reactive oxygen species and accumulation of lipid oxidation products in DA neurons. Furthermore, DBI knockout mice appeared to be more vulnerable than wild-type animals to MPTP neurotoxicity. Taken together, these results show that the gliopeptide ODN exerts a potent neuroprotective effect against MPTP-induced degeneration of nigrostriatal DA neurons in mice, through mechanisms involving downregulation of neuroinflammatory, oxidative and apoptotic processes. ODN may, thus, reduce neuronal damages in PD and other cerebral injuries involving oxidative neurodegeneration. PMID- 29264676 TI - Overcoming the challenges of conventional dispersive liquid-liquid microextraction: analysis of THMs in chlorinated swimming pools. AB - A rapid, simple, and sensitive approach to the analysis of trihalomethanes (THMs) in swimming pool water samples has been developed. The main goal of this study was to overcome or to improve the shortcomings of conventional dispersive liquid liquid microextraction (DLLME) and to maximize the realization of green analytical chemistry principles. The method involves a simple vortex-assisted microextraction step, in the absence of the dispersive solvent, followed by salting-out effect for the elimination of the centrifugation step. A bell-shaped device and a solidifiable solvent were used to simplify the extraction solvent collection after phase separation. Optimization of the independent variables was performed by using chemometric methods in three steps. The method was statistically validated based on authentic guidance documents. The completion time for extraction was less than 8 min, and the limits of detection were in the range between 4 and 72 ng L-1. Using this method, good linearity and precision were achieved. The results of THMs determination in different real samples showed that in some cases the concentration of total THMs was more than threshold values of THMs determined by accredited healthcare organizations. This method indicated satisfactory analytical figures of merit. Graphical Abstract A novel green microextraction technique for overcoming the challenges of conventional DLLME. The proposed procedure complies with the principles of green/sustainable analytical chemistry, comprising decreasing the sample size, making easy automation of the process, reducing organic waste, diminishing energy consumption, replacing toxic reagents with safer reagents, and enhancing operator safety. PMID- 29264677 TI - Mechanism of Protein Carbonylation in Glutathione-Depleted Rat Brain Slices. AB - This study was conducted to further our understanding about the link between lipid peroxidation and protein carbonylation in rat brain slices incubated with the glutathione (GSH)-depletor diethyl maleate. Using this in vitro system of oxidative stress, we found that there is a significant lag between the appearance of carbonylated proteins and GSH depletion, which seems to be due to the removal of oxidized species early on in the incubation by the mitochondrial Lon protease. Upon acute GSH depletion, protein carbonyls accumulated mostly in mitochondria and to a lesser degree in other subcellular fractions that also contain high levels of polyunsaturated lipids. This result is consistent with our previous findings suggesting that lipid hydroperoxides mediate the oxidation of proteins in this system. However, these lipid hydroperoxides are not produced by oxidation of free arachidonic acid or other polyunsaturated free fatty acids by lipooxygenases or cyclooxygenases. Finally, gamma-glutamyl semialdehyde and 2 amino-adipic semialdehyde were identified by HPLC as the carbonyl-containing amino acid residues, indicating that proteins are carbonylated by metal ion catalyzed oxidation of lysine, arginine and proline residues. The present findings are important in the context of neurological disorders that exhibit increased lipid peroxidation and protein carbonylation, such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. PMID- 29264678 TI - Long term culture and differentiation of endothelial progenitor like cells from rat adipose derived stem cells. AB - The procedure of obtaining qualified endothelial progenitor cells (EPCs) is still unclear and there has been some controversy on their biological properties and time of emergence. In this study, we used long-term culture of Adipose Derived Stem Cells (ADSCs) in an endothelial induction medium to obtain endothelial progenitor-like cells, and investigated the features of a few surface markers and the physiologic functions of the cells produced. In order to achieve our aim, rat ADSCs were isolated and cultured in an endothelial basal medium (EBM2), supplemented with an endothelial growth medium (EGM2). The cells were cultured 1 week for short-time, 2 weeks for mid-time, and 3 weeks for long-time cultures. Morphological changes were monitored by phase contrast and electron microscopy. The expressions of a few endothelial progenitor cells markers were analyzed by real-time RT-PCR. Low-density lipoprotein uptake and lectin binding assay were also performed for functional characterization. After induction, ADSCs showed changes in morphology from spindle-shaped in the first week to cobblestone-shaped during the next 2 weeks. Then, endothelial cell phenotype was defined by the presence of Weibel-Palade bodies in the cytoplasm and tube formation, without the use of Matrigel in the third week. In keeping with gene expression analysis, VEGFR-2 showed significant expression during early stages of endothelial differentiation for up to 3 weeks. A significantly increased expression of Tie2 was observed on day 21. Likewise, VE-Cadherin, CD34, CD133, WVF and CD31 were not significantly expressed within the same period of time. Endothelial differentiated cells also showed little LDL uptake and little to no lectin binding during the first 2 weeks of induction. However, high LDL uptake and lectin binding were observed in the third week. It appears that long term culture of ADSCs in EGM2 leads to significantly increased expression of some endothelial progenitor cells markers, strong DiI-ac-LDL uptake, lectin binding and tube-like structure formation in endothelial differentiated cells. Therefore, selection of an appropriate culture time and culture medium is crucial for establishing an efficient route to obtain sufficient numbers of EPCs with optimized quantity and quality. PMID- 29264679 TI - Unexpected phenotypic effects of a transgene integration causing a knockout of the endogenous Contactin-5 gene in mice. AB - Contactins (Cntn1-6) are a family of neuronal membrane proteins expressed in the brain. They are required for establishing cell-to-cell contacts between neurons and for the growth and maturation of the axons. In humans, structural genomic variations in the Contactin genes are implicated in neurodevelopmental disorders. In addition, population genetic studies associate Contactins loci with obesity and hypertension. Cntn5 knockout mice were first described in 2003, but showed no gross physiological or behavioral abnormalities (just minor auditory defects). We report a novel Cntn5 knockout mouse line generated by a random transgene integration as an outcome of pronuclear microinjection. Investigation of the transgene integration site revealed that the 6Kbp transgene construct coding for the human granulocyte-macrophage colony-stimulating factor (hGMCSF) replaced 170 Kbp of the Cntn5 gene, including four exons. Reverse transcription PCR analysis of the Cntn5 transcripts in the wild-type and transgenic mouse lines showed that splicing of the transgene leads to a set of chimeric hGMCSF-Cntn5 transcript variants, none of which encode functional Cntn5 protein due to introduction of stop codons. Although Cntn5 knockout animals displayed no abnormalities in behavior, we noted that they were leaner, with less body mass and fat percentage than wild-type animals. Their cardiovascular parameters (heart rate, blood pressure and blood flow speed) were elevated compared to controls. These findings link Cntn5 deficiency to obesity and hypertension. PMID- 29264680 TI - Advantages and Challenges of a Home- and Clinic-Based Model of Behavioral Intervention for Individuals Diagnosed with Autism Spectrum Disorder. AB - Researchers have demonstrated that comprehensive behavioral intervention can result in significant improvements in the lives of individuals diagnosed with autism spectrum disorder (ASD; e.g.; Lovaas, Journal of Consulting and Clinical Psychology 55(1):3-9, 1987; McEachin et al., American Journal of Mental Retardation 97(4):359-372, 1993). This intervention has occurred in a variety of settings (e.g., school, home, and clinic). Even though procedures based upon the principles of applied behavior analysis (ABA) can be implemented across a variety of settings, there is often confusion about the differences and relative advantages of home- versus clinic-based settings. The purpose of this paper is to provide a discussion of home- and clinic-based intervention within the context of a progressive approach to ABA and discus possible advantages of each type of setting. PMID- 29264681 TI - Spatiotemporal Phase Synchronization in Adaptive Reconfiguration from Action Observation Network to Mentalizing Network for Understanding Other's Action Intention. AB - In action intention understanding, the mirror system is involved in perception action matching process and the mentalizing system underlies higher-level intention inference. By analyzing the dynamic functional connectivity in alpha (8 12 Hz) and beta (12-30 Hz) frequency bands over a "hand-cup interaction" observation task, this study investigates the topological transition from the action observation network (AON) to the mentalizing network (MZN), and estimates their functional relevance for intention identification from other's different action kinematics. Sequential brain microstates were extracted based on event related potentials (ERPs), in which significantly differing neuronal responses were found in N170-P200 related to perceptually matching kinematic profiles and P400-700 involved in goal inference. Inter-electrode weighted phase lag index analysis on the ERP microstates revealed a shift of hub centrality salient in alpha frequency band, from the AON dominated by left-lateral frontal-premotor temporal and temporal-parietooccipital synchronizations to the MZN consisting of more bilateral frontal-parietal and temporal-parietal synchronizations. As compared with usual actions, intention identification of unintelligible actions induces weaker synchronizations in the AON but dramatically increased connectivity in right frontal-temporal-parietal regions of the MZN, indicating a spatiotemporally complementary effect between the functional network configurations involved in mirror and mentalizing processes. Perceptual processing in observing usual/unintelligible actions decreases/increases requirements for intention inference, which would induce less/greater functional network reorganization on the way to mentalization. From the comparison, our study suggests that the adaptive topological changes from the AON to the MZN indicate implicit causal association between the mirror and mentalizing systems for decoding others' intentionality. PMID- 29264682 TI - Closed-Suction Drains After Subcutaneous Mastectomy for Gynecomastia: Do They Reduce Complications? A Different Approach. AB - INTRODUCTION: We read the manuscript entitled "Closed-suction drains after subcutaneous mastectomy for gynecomastia: do they reduce complications? " published by Chao et al. (Aesthetic Plast Surg, 2017. https://doi.org/10.1007/s00266-017-0959-z ). They have concluded that drains may reduce rates of seromas requiring needle aspiration after surgical treatment, but also that there are several adverse effects of drains: patients' discomfort, anxiety, cost and additional clinic visits. They also recalled several limitations: (1) bias in terms of surgeon decision to place a drain, (2) nuances in technique. Here we want to discuss our different technique of drainage. To prevent all the disadvantages, we have chosen to replace closed-suction drains with silicone blades and a wide scar opening at the level of the periareolar scar. METHOD: We carried out a retrospective study in our department in 2016. RESULTS: This series consisted of 83 patients (153 breasts) aged 26.7 years of age (15-67), with an average BMI of 28.6 (19.5-39). All were followed during the 12 months postoperatively. We considered here only grade 1-2a gynecomastia with palpable fibrous glandular tissue. The surgical procedure consisted of initial liposuction, then open surgical excision via the periareolar approach. We did not notice any seroma or collection requiring intervention. However, 4 patients (4/153; 2.6%) had hematomas requiring intervention the day after surgery. CONCLUSION: Our technique presents a lot of advantages, reduced length of stay in the hospital, costs from drain site care and clinic visits, patients' discomfort, and antibiotic prescriptions. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29264683 TI - Assessing Normal Smiling Function Through 3D-3D Surfaces Registration: An Innovative Method for the Assessment of Facial Mimicry. AB - Smiling has a great importance, both from a functional and an aesthetic point of view. The introduction of modern 3D acquisition and elaboration methods may provide additional help in the evaluation of facial mimicry. This study aims at proposing an innovative method to assess facial and labial movements in different types of smiles. Twenty healthy subjects (10 males, 10 females, mean age 27.5 years, SD 4.5 years), were recorded through a stereophotogrammetric system in neutral position and in three types of smiles: Mona-Lisa smile, canine smile, full-denture smile. All the 3D smiling models were superimposed on the corresponding neutral one and point-to-point root mean square (RMS) differences were computed. Labial surface areas in rest position and during each smile were calculated as well, together with the percentage modification in different types of smile. RMS values (facial and labial models), labial surface areas and percentage modifications were compared through ANCOVA tests to verify possible statistically significant differences according to sex and type of smile (p < 0.05). Intercanthal labial width was considered a covariate. RMS values progressively increased from Mona-Lisa to full-denture smile; statistically significant differences were found among all types of smiles, both for facial and labial models (p < 0.05), while no statistically significant sex and sex * smile interactions were found (p > 0.05). Labial surface and percentage of modification showed statistically significant differences according to both sex and type of smile (p < 0.05). The study provides a novel contribution to the field of sexual dimorphism in smiling. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29264684 TI - Three-Dimensional Analysis of the Ear Morphology. AB - BACKGROUND: For surgical treatment of the face, detailed surgical planning is necessary to avoid later unaesthetic results. Most of the studies in the literature concentrate on the ears' anatomy during childhood and adolescence. Nearly no study evaluates the anatomy of ears of people aged 50 or older. It was our aim to measure and evaluate the ear's anatomy in Caucasians between the ages of 21 and 65. METHODS: Three-dimensional scans of 240 volunteers were taken. The subjects were divided into groups of males and females and each of them into three groups by age (21-35, 36-50, 51-65). Landmarks were placed in these scans. Distances, relations and angles between them were recorded. RESULTS: The distance between the subaurale and superaurale significantly increases (p < 0.001) during the aging process in males and females. Also, the width of the ear, measured between the preaurale and postaurale, significantly increased (p = 0.007) with advancing age. When the length of the ear is divided into four parts by anatomical landmarks, it extended the most in the lower quadrant with increasing subject age. CONCLUSION: The ear of Caucasians does not stop changing its shape during adulthood. Even after the body has stopped growing, the ear still does. With the measured values in this study, it should be possible for the surgeon to plan the operation in advance and achieve satisfactory aesthetic outcomes. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29264686 TI - [Doping in old age?] PMID- 29264685 TI - Effect of Acyl Chain Length on the Rate of Phospholipid Flip-Flop and Intermembrane Transfer. AB - The rate at which phospholipids equilibrate between different membranes and between the non-polar environments in biological fluids is of high importance in the understanding of biomembrane diversity, as well as in the development of liposomes for drug delivery. In this work, we characterize the rate of insertion into and desorption from POPC bilayers for a homologous series of amphiphiles with the fluorescent NBD group attached to phosphoethanolamines of different acyl chain lengths, NBD-diC n -PE with n = 6, 8, 10, and 12. The rate of translocation between bilayer leaflets was also characterized, providing all the relevant parameters for their interaction with lipid bilayers. The results are complemented with data for NBD-diC14-PE obtained from literature (Abreu et al. Biophys J 87:353-365, 2004; Moreno et al. Biophys J 91:873-881, 2006). The rate of translocation between the POPC leaflets is not dependent on the length of the acyl chains, while this affects strongly the rate of desorption from the bilayer. Insertion in the POPC bilayer is not diffusion controlled showing a significant dependence on the acyl chain length and on temperature. The results obtained are compared with those previously reported for NBD-LysoC14-PE (Sampaio et al. Biophys J 88:4064-4071, 2005), and with the homologous series of single chain amphiphiles NBD-C n (Cardoso et al. J Phys Chem B 114:16337-16346, 2010; J Phys Chem B 115:10098-10108, 2011). This allows the establishment of important relations between the rate constants for interaction with the lipid bilayers and the structural properties of the amphiphiles, namely the total surface and the cross-section of their non-polar region. PMID- 29264687 TI - [Antibodies as treatment option in older adults]. AB - Monoclonal antibodies are already used for many different clinical indications. Besides oncology and rheumatology, denosumab is the only antibody that is currently prescribed in older adults with osteoporosis; however, apart from osteoporosis there might be more possible indications for the use of antibodies in chronic diseases and geriatric syndromes. Particularly, with respect to sarcopenia the transition to "doping for older adults" seems to be fluent. The present review provides an overview on the newest developments and prospective options. PMID- 29264688 TI - Differential response of AMH to GnRH agonist among individuals: the effect on ovarian stimulation outcomes. AB - PURPOSE: The purpose of this study is to investigate whether individual response of anti-Mullerian hormone (AMH) to gonadotropin-releasing hormone (GnRH) treatment is associated with difference in ovarian stimulation outcomes. METHODS: The retrospective study included 1058 non-polycystic ovary syndrome (PCOS) women undergoing long agonist protocol in a single in vitro fertilization unit from January 1, 2016, through December 31, 2016. Patients were grouped according to AMH changes from day 3 to the day of stimulation (group 1, change < 1 ng/ml, n = 714; group 2, decrease >= 1 ng/ml, n = 143; group 3, increase >= 1 ng/ml, n = 201). A generalized linear model including Poisson distribution and log link function was used to evaluate the association between AMH response and the number of oocytes retrieved. RESULTS: Group 2 was characterized by higher basal AMH level and increased AMH to AFC ratio in comparison with two other groups. However, the number of oocytes and ovarian sensitivity index in group 2 was significantly lower than group 3. Adjusted for age, BMI, ovarian reserve markers, and stimulation parameters, the population marginal means (95% confidence interval) of oocyte number in groups 1 through 3 were 9.51 (9.17, 9.86), 8.04 (7.54, 8.58), and 10.65 (10.15, 11.18), respectively. For patients from group 2 and group 3, basal AMH is no longer significantly associated with oocyte yield. CONCLUSIONS: AMH change in response to GnRH agonist varies among individuals; for those undergoing significant changes in AMH following GnRH agonist treatment, basal AMH may not be a reliable marker for ovarian response in long agonist protocol. PMID- 29264690 TI - Intracerebral hemorrhage after cranioplasty: an unpredictable treacherous complication due to reperfusion or possible systemic inflammatory response syndrome. PMID- 29264689 TI - A prospective, randomized study comparing morning to evening administration of gonadotropins in ART. AB - OBJECTIVE: We sought to determine whether administering the daily gonadotropin dose in the morning (AM) or in the evening (PM) affects cycle outcome in patients undergoing IVF. DESIGN: This is a prospective randomized study. SETTING: The study is performed in a private assisted reproductive technology (ART) clinic. PATIENT(S): The study included one hundred and twenty-seven women undergoing IVF. INTERVENTION(S): Morning (AM) and evening (PM) administration of gonadotropins (uFSH and hMG) was compared. MAIN OUTCOME MEASURE(S): Live birth rate was the main outcome measured. Secondary outcomes including total IU use, days of stimulation, peak E2, peak P4, endometrial thickness, number of oocytes retrieved, MII oocytes, fertilization rates, #ET, IR, and clinical PR were all assessed. RESULTS: A total of 127 cycles were included, 61 in the AM group and 67 in the PM group. Baseline and stimulation characteristics were similar in both groups. There was a trend for a higher implantation rate in the AM group vs. the PM group (60.3 vs. 47.2%, P = 0.066). The AM group had a higher chemical pregnancy rate compared to the PM group (81.7 vs. 65.6%, P = 0.024) and a higher clinical pregnancy rate (78.3 vs. 62.1%, P = 0.048), but the delivery rates were similar (68.3 vs. 56.1%, P = 0.16). The study was unfortunately prematurely terminated when uFSH (Bravelle(c)) was pulled out of the US market. CONCLUSIONS: AM administration of gonadotropins may be associated with a better ART outcome compared to PM administration. Larger studies are needed to confirm our findings. PMID- 29264692 TI - Using Telemedicine in Mississippi to Improve Patient Access to Genetic Services. PMID- 29264691 TI - Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity syndrome of parkinsonism and ataxia. AB - Contactin-associated protein 2 (CASPR2) antibodies are originally associated with Morvan's syndrome and peripheral nerve hyper excitability. Our objective was to study retrospectively the clinical spectrum of CASPR2 antibody-positive patients in our hospital. This is a retrospective observational study. Patients treated at the Amrita Institute of Medical Sciences from May 2013 to April 2016, who were tested positive for CASPR2 antibodies, were included. A total of 1584 samples were tested in the neuroimmunology laboratory during the study period for voltage gated potassium channel (VGKC) complex antibodies-leucine-rich glioma-inactivated protein 1 (LGI1) and CASPR2 antibodies. Thirty-four were positive for LGI1, 13 were positive for CASPR2, and 7 were for both (total 54-3.4% positivity). Of these 54 cases, 11 were treated in our hospital. Seven were positive for LGI1, three for CASPR2, and one for both. The patient who had both CASPR2 and LGI1 antibody positive had Morvan's syndrome. One patient with CASPR2 had neuromyotonia. The other patient was admitted with status epilepticus with a syndrome of parkinsonism and ataxia. The third patient had encephalopathy and myoclonus with a syndrome of parkinsonism and ataxia. Two of them underwent siddha treatment for other ailments prior to the onset of the disease for other ailments. Our short series shows the expanding spectrum of CASPR2 autoimmunity. Syndrome of parkinsonism and ataxia is an important manifestation of CASPR2 autoimmunity where we can offer a definitive treatment. PMID- 29264693 TI - The effects of gelatin, fibrin-platelet glue and their combination on healing of the experimental critical bone defect in a rat model: radiological, histological, scanning ultrastructural and biomechanical evaluation. AB - Fibrin-platelet glue (FPG) is a blood derivative, in which platelets and fibrinogen are concentrated in a small plasma volume, by differential centrifugation and precipitation. It can form a three-dimensional and biocompatible fibrin scaffold with a myriad of growth factors and proteins that are released progressively to the local environment and contribute to the accelerated postoperative bone healing. Gelatin (Gel) is a derivative of collagen and can promote cell adhesion and proliferation due to its unique sequence of amino acids, so it is suitable for bone tissue applications. This study examined the effects of Gel, FPG and their combinations as bone scaffold on the healing of surgically created critical-size defects in rat radius. Fifty critical size defects of 5 mm long were bilaterally created in the radial diaphysis of 25 rats. The animals were randomly divided into five equal groups as empty defect, autograft, Gel, FPG and Gel-FPG groups (n = 10 in each group). Radiographs of each forelimb were taken postoperatively on the 1st day and then at the 28th and 56th days post injury to evaluate bone formation, union and remodeling of the defect. After 56 days, the rats were euthanized and their harvested healing bone samples were evaluated by histopathology, scanning electron microscopy (SEM) and biomechanical testing. The results of present study showed that the Gel alone did not significantly affect bone healing and regeneration; however, the Gel treated defects promoted healing more than those that were left untreated (negative control). Furthermore, the FPG-enhanced grafts provided a good scaffold containing numerous growth factors for proliferation of osteoinduction and was effective in improving the structural and functional properties of the newly formed bone more than that of the untreated and also the Gel treated groups. Incorporation of Gel into the FPG scaffold improved healing potential of the FPG scaffold; however, it was still inferior to the autograft (positive control). Although the Gel-FPG scaffolds had best effectiveness during bone regeneration, it still needs to be further enhanced by incorporation of the ceramic and osteoinductive biomaterials. PMID- 29264694 TI - Successful disinfection of femoral head bone graft using high hydrostatic pressure. AB - The current standard for sterilization of potentially infected bone graft by gamma irradiation and thermal or chemical inactivation potentially deteriorates the biomechanical properties of the graft. We performed an in vitro experiment to evaluate the use of high hydrostatic pressure (HHP); which is widely used as a disinfection process in the food processing industry, to sterilize bone grafts. Four femoral heads were divided into five parts each, of which 16 were contaminated (in duplicate) with 105-107 CFU/ml of Staphylococcus epidermidis, Bacillus cereus, or Pseudomonas aeruginosa or Candida albicans, respectively. Of each duplicate, one sample was untreated and stored similarly as the treated sample. The remaining four parts were included as sterile control and non infected control. The 16 parts underwent HHP at the high-pressure value of 600 MPa. After HHP, serial dilutions were made and cultured on selective media and into enrichment media to recover low amounts of microorganism and spores. Three additional complete femoral heads were treated with 0, 300 and 600 MPa HHP respectively for histological evaluation. None of the negative-control bone fragments contained microorganisms. The measured colony counts in the positive control samples correlated excellent with the expected colony count. None of the HHP treated bone fragments grew on culture plates or enrichment media. Histological examination of three untreated femoral heads showed that the bone structure remained unchanged after HHP. Sterilizing bone grafts by high hydrostatic pressure was successful and is a promising technique with the possible advantage of retaining biomechanical properties of bone tissue. PMID- 29264695 TI - MiR-411 suppressed vein wall fibrosis by downregulating MMP-2 via targeting HIF 1alpha. AB - This study was aim to investigate the specific mechanisms of miR-411 in vein wall fibrosis remodeling. Vein wall fibrosis injury-induced deep venous thrombosis (DVT) rat model was well established. The expression of miR-411 at mRNA levels and Collagen I, hypoxia-inducible factor (HIF)-1alpha together with matrix metalloproteinase (MMP)-2 at protein levels in vein wall tissues and vascular smooth muscle cells (VSMCs) following transfection were determined using quantitative real-time PCR (qRT-PCR) and western blotting, respectively. Luciferase reporter assay was used to confirm the potential target of miR-411. MiR-411 mimic injected into rat model of DVT was to verify the role of miR-411 in vein wall fibrosis in vivo. MiR-411 was downregulated while Collagen I, HIF 1alpha and MMP-2 was upregulated in vein wall tissues and VSMCs obtained from rat model of DVT. MiR-411 overexpression in VSMCs separated from rats of vascular remodeling group (VR-VSMCs) upregulated miR-411, HIF-1alpha and inhibited cell proliferation and Collagen I expression, while miR-411 knockdown in VSMCs isolated from healthy rats (Control-VSMCs) reversed the effects. Furthermore, luciferase reporter assay demonstrated that HIF-1alpha was a target of miR-411. In addition, overexpression of miR-411 and HIF-1alpha in VR-VSMCs promoted HIF 1alpha, Collagen I expression and cell proliferation, however, tissue inhibitor of metalloproteinase (TIMP)-2 treatment led to adverse trends. MiR-411 mimic injected into rat model of DVT could suppress vein wall fibrosis in vivo. MiR-411 inhibited vein wall fibrosis by downregulating MMP-2 mediated by HIF-1alpha. PMID- 29264697 TI - Correction to: Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. AB - The authors would like to make the following corrections to the published article. PMID- 29264698 TI - Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints. AB - The natural cytotoxicity receptors (NCRs; NKp30, NKp44, and NKp46) were first defined as activating receptors on human NK cells that are important in recognition of and response to tumors. A flurry of recent research, however, has revealed that differential splicing can occur during transcription of each of the NCR genes, resulting in some transcripts that encode receptor isoforms with inhibitory functions. These alternative transcripts can arise in certain tissue microenvironments and appear to be induced by cytokines. Evidence indicates that some of the inhibitory NCRs are triggered by specific ligands, such as the interaction of the inhibitory isoform of NKp44 with PCNA on the surface of tumor cells. Here, we review the different NCR splice variants, cytokines that modulate their expression, their functional impacts on innate immune cells, and their differential expression in the contexts of cancer, pregnancy, and infections. The recent discovery of these inhibitory NCR isoforms has revealed novel innate immune checkpoints, many of which still lack defined ligands and clear mechanisms driving their expression. These NCR checkpoint pathways offer exciting potential therapeutic targets to manipulate innate immune functions under defined pathological conditions, such as cancer, pregnancy disorders, and pathogen exposure. PMID- 29264696 TI - Helicobacter pylori Antimicrobial Susceptibility Testing-Guided Salvage Therapy in the USA: A Real Life Experience. AB - BACKGROUND: The current practice guidelines recommend that Helicobacter pylori (H. pylori) culture and antimicrobial susceptibility testing (AST) be considered after patients failed the second course of H. pylori eradication therapy. AIMS: Here we report the real life experience of following this recommendation in the USA. METHODS: We established an in-house H. pylori culture protocol for AST and identified retrospectively patients who previously failed >= 2 courses of anti-H. pylori therapy and underwent esophagogastroduodenoscopy with AST at University of Michigan from 2010 to 2017. We determined the rate of H. pylori antibiotic resistance, the success rates of AST-guided tailored therapy, and the risk factors associated with treatment failure. RESULTS: Forty-seven patients were identified and 34 (72.3%) had successful cultures and AST. The most common antibiotic resistance was to metronidazole (79.4%), followed by clarithromycin (70.6%) and ciprofloxacin (42.9%). None of the patients were resistant to amoxicillin or tetracycline. The overall success rate of AST-guided tailored therapy was low (44.4%, 12/27). In patients infected with metronidazole-resistant H. pylori, bismuth quadruple therapy appears to be superior compared to non bismuth quadruple therapy (6/8 or 75.0% vs. 3/14 or 21.4%, P = 0.03). High body mass index was significantly associated with tailored therapy failure (OR 1.24, 95% CI 1.00-1.54, P = 0.049). CONCLUSIONS: The success rate of AST-guided salvage therapy in the USA is low particularly in those with high BMI. Bismuth-based therapy appears to be better than non-bismuth-based regimens. PMID- 29264700 TI - Overutilization of Breast Cancer Screening in the US: Awareness of a Growing Problem. PMID- 29264701 TI - Herpes Vegetans: an Unusual and Acyclovir-Resistant Form of HSV. PMID- 29264699 TI - Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus. AB - BACKGROUND: Traditional serological biomarkers often fail to assess systemic lupus erythematosus (SLE) disease activity and discriminate lupus nephritis (LN). The aim of this study was to identify novel markers for evaluating renal and overall disease activity in Chinese patients with pediatric systemic lupus erythematosus (pSLE). METHODS: The study included 46 patients with pSLE (35 girls, 11 boys; average age 13.3 +/- 2.6 years) and 31 matched healthy controls (22 girls, 9 boys; average age 12.3 +/- 2.4 years). The SLE Disease Activity Index (SLEDAI) and renal SLEDAI were used to assess disease activity. Nine different soluble mediators in plasma, including tumor necrosis factor alpha (TNF alpha), platelet-derived growth factor-BB (PDGF-BB), interferon (IFN) gamma inducible protein 10 (IP-10), interleukin (IL)-1beta, IFN-gamma, IL-17A, IL-2, Fas and Fas ligand, were measured by Luminex assay and compared between patients with active and inactive pSLE as well as between patients with pSLE with active and inactive renal disease. Receiver operating characteristic curve analysis was used to measure the discrimination accuracy. RESULTS: Of the 46 patients with pSLE, 30 (65.2%) had LN. These patients had significantly elevated levels of serum TNF-alpha, PDGF-BB, IP-10 and Fas. The serum levels of IP-10 were also significantly higher in patients with active pSLE. We found that IP-10 was also more sensitive and specific than conventional laboratory parameters, including anti-double-stranded DNA and complement components C3 and C4, for distinguishing active lupus from quiescent lupus. The serum level of IP-10 was also significantly increased in children with pSLE with active renal disease relative to those with inactive renal disease. There was also a positive correlation between serum IP-10 levels and renal SLEDAI scores as well as with 24 h urine protein. CONCLUSIONS: Serum IP-10 is useful for identifying renal and overall disease activity in children with pSLE. PMID- 29264702 TI - Resin secretory canals in Protium heptaphyllum (Aubl.) Marchand. (Burseraceae): a tridimensional branched and anastomosed system. AB - Protium heptaphyllum is a Burseraceae species known by the production of aromatic resin with medicinal, economic, and ecological values. Information on the development, architecture, and lifetime of the secretory system are crucial to understand the resin production and contribute to a more sustainable tapping regime. We investigated the histology and ultrastructure of the secretory canals under a developmental point of view. Stem samples were analyzed under light and transmission electron microscopy by conventional and cytochemical methods. Secretory canals, originated from procambium and cambium, occurred immersed in the primary and secondary phloem. Mature canals have a secretory epithelium and a wide lumen where the exudate is accumulated. A sheath of parenchyma cells with meristematic features surrounds the epithelium. The canals originate by schizogenesis and develop by schyzolysigenesis. Canals active in secretion occurred since the shoot apex and near the cambium. In the dilation zone of the secondary phloem, secretory canals exhibit sclerified epithelial and sheath cells and are inactive in secretion. Secreting epithelial cells have subcellular apparatus consistent with oleoresin, polysaccharides, and enzymes secretion. Pectinase and cellulase were cytochemically detected in developing canals and are involved in cell wall changes associated to canal growth and release of exudate. In P. heptaphyllum, the secretory system has a complex structure resultant from longitudinal growth, lateral ramification, and fusion of the adjacent canals, in addition to intrusive growth of both epithelial and sheath cells. Although some anatomical results are already known, ultrastructural data represent the novelty of this work. Our findings can contribute to the establishment of more efficient and sustainable techniques for resin extraction in this species. PMID- 29264703 TI - Palliative Oncologic Care Curricula for Providers in Resource-Limited and Underserved Communities: a Systematic Review. AB - Familiarity with principles of palliative care, supportive care, and palliative oncological treatment is essential for providers caring for cancer patients, though this may be challenging in global communities where resources are limited. Herein, we describe the scope of literature on palliative oncological care curricula for providers in resource-limited settings. A systematic literature review was conducted using PubMed, Embase, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Med Ed Portal databases, and gray literature. All available prospective cohort studies, case reports, and narratives published up to July 2017 were eligible for review. Fourteen articles were identified and referenced palliative care education programs in Argentina, Uganda, Kenya, Australia, Germany, the USA, or multiple countries. The most common teaching strategy was lecture-based, followed by mentorship and experiential learning involving role play and simulation. Education topics included core principles of palliative care, pain and symptom management, and communication skills. Two programs included additional topics specific to the underserved or American Indian/Alaskan Native community. Only one program discussed supportive cancer care, and no program reported educational content on resource-stratified decision-making for palliative oncological treatment. Five programs reported positive participant satisfaction, and three programs described objective metrics of increased educational or research activity. There is scant literature on effective curricula for providers treating cancer patients in resource-limited settings. Emphasizing supportive cancer care and palliative oncologic treatments may help address gaps in education; increased outcome reporting may help define the impact of palliative care curriculum within resource-limited communities. PMID- 29264705 TI - Relationships between cerebral flow velocities and neurodevelopmental outcomes in children with moderate to severe traumatic brain injury. AB - PURPOSE: This study aimed to determine relationships between cerebral blood flow and neurodevelopmental outcomes in children with moderate to severe traumatic brain injury (TBI). METHODS: Children with TBI, a Glasgow Coma Score of 8-12, and abnormal brain imaging were enrolled prospectively. Cerebral blood flow velocity (CBFV) was assessed within 24 h of trauma and daily thereafter through death, discharge, or hospital day 8, whichever came first. Twelve months from injury, participants completed neurodevelopmental testing. RESULTS: Sixty-nine patients were enrolled. Low flow velocities (< 2 SD below age/gender normal) were found in 6% (n = 4). No patient with a single low CBFV measurement had a good neurologic outcome (Pediatric Glasgow Outcome Scale (GOS-E Peds) <= 4)). Normal flow velocities (+/- 2 SD around age/gender normal) were seen in 43% of participants (n = 30). High flow velocities (> 2 SD above age and gender normal with a Lindegaard ratio (LR) < 3) were identified in 23% of children (n = 16), and vasospasm (> 2 SD above age/gender normal with LR >= 3) was identified in 28% (n = 19). Children with good outcomes based on GOS-E Peds scoring were more likely to have had normal flow velocity than other flow patterns. No other differences in neurodevelopmental outcomes were noted. CONCLUSIONS: Individual patient responses to TBI in terms of CBFV alterations were heterogeneous. Low flow was uniformly associated with a poor outcome. Patients with good outcomes were more likely to have normal flow. This suggests CBFV may serve as a prognostic indicator in children with TBI. Future studies are needed to determine if aberrant CBFVs are also a therapeutic target. PMID- 29264706 TI - From art to science: a new epistemological status for medicine? On expectations regarding personalized medicine. AB - Personalized medicine plays an important role in the development of current medicine. Among the numerous statements regarding the future of personalized medicine, some can be found that accord medicine a new scientific status. Medicine will be transformed from an art to a science due to personalized medicine. This prognosis is supported by references to models of historical developments. The article examines what is meant by this prognosis, what consequences it entails, and how feasible it is. It refers to the long tradition of epistemological thinking in medicine and the use of historical models for the development of medicine. The possible answers to the question "art or science" are systematized with respect to the core question about the relationship between knowledge and action. The prediction for medicine to develop from an 'empirical healing art' to a 'rational, molecular science' is nonsensical from an epistemological point of view. The historical models employed to substantiate the development of personalized medicine are questionable. PMID- 29264707 TI - The trilemma of designing international bioethics curricula. PMID- 29264708 TI - The early inflorescence of Arabidopsis thaliana demonstrates positional effects in floral organ growth and meristem patterning. AB - KEY MESSAGE: Linear modelling approaches detected significant gradients in organ growth and patterning across early flowers of the Arabidopsis inflorescence and uncovered evidence of new roles for gibberellin in floral development. Most flowering plants, including the genetic model Arabidopsis thaliana, produce multiple flowers in sequence from a reproductive shoot apex to form a flower spike (inflorescence). The development of individual flowers on an Arabidopsis inflorescence has typically been considered as highly stereotypical and uniform, but this assumption is contradicted by the existence of mutants with phenotypes visible in early flowers only. This phenomenon is demonstrated by mutants partially impaired in the biosynthesis of the phytohormone gibberellin (GA), in which floral organ growth is retarded in the first flowers to be produced but has recovered spontaneously by the 10th flower. We presently lack systematic data from multiple flowers across the Arabidopsis inflorescence to explain such changes. Using mutants of the GA 20-OXIDASE (GA20ox) GA biosynthesis gene family to manipulate endogenous GA levels, we investigated the dynamics of changing floral organ growth across the early Arabidopsis inflorescence (flowers 1-10). Modelling of floral organ lengths identified a significant, GA-independent gradient of increasing stamen length relative to the pistil in the wild-type inflorescence that was separable from other, GA-dependent effects. It was also found that the first flowers exhibited unstable organ patterning in contrast to later flowers and that this instability was prolonged by exogenous GA treatment. These findings indicate that the development of individual flowers is influenced by hitherto unknown factors acting across the inflorescence and also suggest novel functions for GA in floral patterning. PMID- 29264710 TI - Protective effects of cilostazol on ethanol-induced damage in primary cultured hepatocytes. AB - Alcoholic liver disease (ALD) caused by excessive alcohol consumption is associated with oxidative stress, mitochondrial dysfunction, and hepatocellular apoptosis. Cilostazol, a licensed clinical drug used to treat intermittent claudication, has been reported to act as a protective agent in a spectrum of diseases. However, little information regarding its role in ethanol-induced hepatocellular toxicity has been reported. In the current study, we investigated the protective effects and mechanisms of cilostazol on ethanol-induced hepatocytic injury. Rat primary hepatocytes were pretreated with cilostazol prior to ethanol treatment. MTT and LDH assay indicated that ethanol-induced cell death was ameliorated by cilostazol in a dose-dependent manner. Our results display that overproduction of intracellular reactive oxygen species (ROS) and 4-hydroxy 2-nonenal (4-HNE) induced by ethanol was attenuated by pretreatment with cilostazol. Furthermore, cilostazol significantly inhibited ethanol-induced generation of ROS in mitochondria. Importantly, it was shown that cilostazol could improve mitochondrial function in primary hepatocytes by restoring the levels of ATP and mitochondrial membrane potential (MMP). Additionally, cilostazol was found to reduce apoptosis induced by ethanol using a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Mechanistically, we found that cilostazol prevented mitochondrial pathway mediated apoptotic signals by reversing the expression of Bax and Bcl2, the level of cleaved caspase-3, and attenuating cytochrome C release. These findings suggest the possibility of novel ALD therapies using cilostazol. PMID- 29264709 TI - Integration of pro- and anti-angiogenic signals by endothelial cells. AB - Angiogenesis or neovascularization is a complex multi-step physiological process that occurs throughout life both in normal tissues and in disease. It is tightly regulated by the balance between pro-angiogenic and anti-angiogenic factors. The angiogenic switch has been identified as the key step during tumor progression in which the balance between pro-angiogenic and anti-angiogenic factors leans toward pro-angiogenic stimuli promoting the progression of tumors from dormancy to dysplasia and ultimately malignancy. This event can be described as either the outcome of a genetic event occurring in cancer cells themselves, or the positive and negative cross-talk between tumor-associated endothelial cells and other cellular components of the tumor microenvironment. In recent years, the mechanisms underlying the angiogenic switch have been extensively investigated in particular to identify therapeutic targets that can lead to development of effective therapies. In this review, we will discuss the current findings on the regulatory pathways in endothelial cells that are involved in the angiogenic switch with an emphasis on the role of anti-angiogenic protein, thrombospondin-1 (TSP-1) and pro-angiogenic factor, vascular endothelial growth factor (VEGF). PMID- 29264711 TI - Oxidative stress triggers aggregation of GFP-tagged Hsp31p, the budding yeast environmental stress response chaperone, and glyoxalase III. AB - The Saccharomyces cerevisiae Hsp31p protein belongs to the ubiquitous DJ 1/ThiJ/PfpI family. The most prominent member of this family is human DJ-1; defects of this protein are associated with Parkinson's disease pathogenesis. Numerous recent findings reported by our group and others have revealed the importance of Hsp31p for survival in the post-diauxic phase of cell growth and under diverse environmental stresses. Hsp31p was shown to possess glutathione independent glyoxalase III activity and to function as a protein chaperone, suggesting that it has multiple cellular roles. Our previous work also revealed that HSP31 gene expression was controlled by multiple stress-related transcription factors, which mediated HSP31 promoter responses to oxidative, osmotic, and thermal stresses, toxic products of glycolysis, and the diauxic shift. Nevertheless, the exact role of Hsp31p within budding yeast cells remains elusive. Here, we aimed to obtain insights into the function of Hsp31p based on its intracellular localization. We have demonstrated that the Hsp31p-GFP fusion protein is localized to the cytosol under most environmental conditions and that it becomes particulate in response to oxidative stress. However, the particles do not colocalize with other granular subcellular structures present in budding yeast cells. The observed particulate localization does not seem to be important for Hsp31p functionality. Instead, it is likely the result of oxidative damage, as the particle abundance increases when Hsp31p is nonfunctional, when the cellular oxidative stress response is affected, or when cellular maintenance systems that optimize the state of the proteome are compromised. PMID- 29264712 TI - Ethnic Differences in Efficacy and Safety of Alogliptin: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Alogliptin is a highly selective, potent, and orally available dipeptidyl peptidase-4 (DPP-4) inhibitor. This study compared the glucose lowering efficacy and safety of alogliptin between Asian and non-Asian patients with type 2 diabetes. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, and ISI Web of Science databases for articles published June 2017 and earlier in English. We identified randomized controlled trials (RCTs) of adults with type 2 diabetes that compared alogliptin with placebo as either monotherapy or add-on therapy. We divided subgroups by ethnicity, and compared the results of alogliptin use in Asian and non-Asian-dominant studies. RESULTS: A total of 15 RCTs with 4456 patients with type 2 diabetes were included in this study. Alogliptin lowered glycated hemoglobin (HbA1c) to a much greater extent in Asian-dominant studies [- 0.75% (95% CI - 0.84 to - 0.65)] than in non-Asian dominant studies [- 0.61% (95% CI - 0.68 to - 0.54)] (P = 0.02). The risk ratio of achieving HbA1c goal was larger in Asian-dominant studies [2.88 (95% CI 2.15 3.87)] than in non-Asian-dominant studies [1.93 (95% CI 1.55-2.41)] (P = 0.03). The postprandial blood glucose-lowering efficacy was higher in Asian-dominant studies [- 2.42 mmol/l (95% CI - 2.99 to - 1.85)] than in non-Asian-dominant studies [- 0.60 mmol/l (95% CI - 1.60 to 0.40)] (P = 0.002), while the fasting blood glucose and body weight changes were similar between the two subgroups. The incidence of adverse events, including hypoglycemia, nasopharyngitis, upper respiratory tract infection, headache, and diarrhea, were comparable between the two groups. CONCLUSIONS: Alogliptin is more effective in improving glycemic levels in Asians than in other ethnic populations. Future studies are required to explore the potential mechanisms. PMID- 29264713 TI - Subgroup Analysis Stratified by Baseline Pancreatic beta-cell Function in a Japanese Study of Dulaglutide in Patients with Type 2 Diabetes. AB - INTRODUCTION: This analysis investigated the relationship between baseline fasting pancreatic beta-cell function and efficacy in Japanese patients with type 2 diabetes (T2D) treated with once-weekly dulaglutide 0.75 mg (dulaglutide) or once-daily liraglutide 0.9 mg (liraglutide) for up to 52 weeks. METHODS: In a 52 week study of monotherapy in Japanese patients with T2D, patients were categorized into three subgroups defined by tertiles (low, medium, and high) of baseline values of three pancreatic beta-cell function parameters [fasting C peptide, C-peptide index, and secretory units of islets in transplantation (SUIT) index]. Associations between these parameters and efficacy [defined by changes from baseline in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial blood glucose (PBG), mean of all meals blood glucose excursion, and body weight] in the dulaglutide group (280 patients) or the liraglutide group (137 patients) were evaluated. RESULTS: Patients in the subgroups with high insulin-secreting ability (based on pancreatic beta-cell function) were younger and had shorter disease duration and higher body mass index compared to those with low insulin-secreting ability. No specific trend was observed between baseline pancreatic beta-cell function and changes in HbA1c or FBG. Reductions from baseline in mean PBG and excursion were greatest for patients in the low beta-cell function tertiles. Inconsistent trends in body weight were observed across the treatment groups and beta-cell function parameters. CONCLUSION: In Japanese patients with T2D, changes in HbA1c and body weight after 52 weeks of treatment with dulaglutide or liraglutide could not be predicted by patients' fasting pancreatic beta-cell function before treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01558271). FUNDING: Eli Lilly K.K. (Kobe, Japan). PMID- 29264714 TI - From a direct oral anticoagulant to warfarin: reasons why patients switch. AB - The introduction of the direct oral anticoagulants (DOACs) has led to their widespread use for stroke prevention and venous thromboembolism, but little is known about the numbers of patients switching from a DOAC to (or back to) a warfarin or the reasons for doing so. This study was an analysis of prospectively collected data from a 4-year period surveying a warfarin dose adjustment clinic in a large city centre hospital with the primary objective to identify these reasons. In our clinic with 1791 patients annually under review, 40 patients were identified as having switched from a DOAC to warfarin with the most common reasons for switching being bleeding, re-thrombosis and renal deterioration. Other reasons included medication interactions, side effects, antiphospholipid syndrome, valvular replacement or arterial embolism. Clinical events following warfarin commencement were also recorded. Overall, these data suggest that switching from a DOAC to warfarin is seldom deemed necessary by clinicians. However, as the number of patients receiving DOACs continues to increase, it is vital that health care professionals remain vigilant regarding medication interactions, bleeding risk and changing renal function. PMID- 29264715 TI - Various congenital anomalies of the inferior vena cava: review of cross-sectional imaging findings and report of a new variant. AB - The inferior vena cava (IVC) is an important structure receiving a large amount of venous return and is associated with various congenital disorders. Advances in diagnostic imaging and its increasing accessibility have led to an increase in the incidental detection of IVC anomalies. Congenital anomalies of the IVC are not uncommon and are occasionally critical to treatment planning. However, they are frequently overlooked in abdominal imaging. The IVC is composed of four segments (intrahepatic, suprarenal, renal, and infrarenal), and each segment arises from different embryonic structures in a complex process. Anomalies of the IVC can be classified according to the involved segment. Familiarity with the variety of IVC anomalies seen on imaging is vital for correctly diagnosing and managing patients in daily practice. PMID- 29264716 TI - De novo transcriptome assembly: a new laccase multigene family from the marine derived basidiomycete Peniophora sp. CBMAI 1063. AB - Laccases are multicopper oxidases that are able to catalyze reactions involving a range of substrates, including phenols and amines, and this ability is related to the existence of different laccases. Basidiomycetes usually have more than one gene for laccase, but until now, this feature has not been demonstrated in a marine-derived fungus. Peniophora sp. CBMAI 1063 is a basidiomycete fungus isolated from a marine sponge that exhibits the ability to secrete significant amounts of laccase in saline conditions. In the present study, we identified laccase sequences from the transcriptome of Peniophora sp. CBMAI 1063 and used them to perform different molecular in silico analyses. The results revealed the presence of at least eight putative genes, which may encode ten different laccases with peptide lengths ranging from 482 to 588 aa and molecular weights ranging from 53.5 to 64.4 kDa. These laccases seem to perform extracellular activities, with the exception of one that may represent an intracellular laccase. The 10 predicted laccases expressed by Peniophora sp. CBMAI 1063 in laccase-induced media showed different patterns of N-glycosylation and isoelectric points and are divided into two classes based on the residue associated with the regulation of the redox potential of the enzyme. None of the predicted laccases showed more than 61% similarity to other fungal laccases. Based on the differences among the laccases expressed by Peniophora sp. CBMAI 1063, this marine-derived basidiomycete represents a valuable resource with strong potential for biotechnological exploitation. PMID- 29264717 TI - In vitro efficacy of five essential oils against Pediculus humanus capitis. AB - Treatment of head lice has relied mainly on the use of topical insecticides. Today, conventional topical pediculicides have suffered considerable loss of activity worldwide. There is increasing interest in the use of natural products such as essential oils for head louse control, and many of them are now incorporated into various over-the-counter products presented as pediculicides, often without proper evaluation. The aim of the present study was to assess the in vitro efficacy of five essential oils against adults of Pediculus humanus capitis using a contact filter paper toxicity bioassay. The chemical composition of the essential oils from wild bergamot, clove, lavender, tea tree, and Yunnan verbena was analyzed by gas chromatography-mass spectrometry. All treatments and controls were replicated three times on separate occasions over a period of 11 months. In all, 1239 living lice were collected from the scalp of 51 subjects, aged from 1 to 69 years. Clove oil, diluted either in coco oil or sunflower oil, demonstrated the best adulticidal activity, reaching > 90% mortality within 2 h in lice submitted to a 30-min contact. Yunnan verbena oil diluted in coco oil showed also a significant efficacy. Other essential oils showed a lower efficacy. The oil's major component(s) differed according to the tested oils and appeared chemically diverse. In the case of clove oil, the eugenol appeared as the main component. This study confirmed the potential interest of some of the essential oils tested, but not all, as products to include possibly in a pediculicidal formulation. PMID- 29264718 TI - Resistance to trypanocidal drugs in cattle populations of Zambezia Province, Mozambique. AB - African animal trypanosomosis is a debilitating tsetse-transmitted parasitic disease of sub-Saharan Africa. Therapeutic and prophylactic drugs were introduced more than 50 years ago, and drug resistance is increasingly reported. In a cross sectional study, 467 cattle were microscopically screened for trypanosomes. Samples were collected in May-July 2014 from five villages (Botao, Mungama, Zalala-Electrosul, Zalala-Madal, and Namitangurine) in Nicoadala district, Zambezia province. To evaluate treatment efficacy, trypanosome-positive animals in each village were randomly assigned to two groups, one treated with 0.5 mg/kg b.w. isometamidium (Inomidium(r)), the second with 3.5 mg/kg b.w. diminazene (Inomazene(r)). Cattle were microscopically monitored at days 0, 14, and 28 post treatment. At day 28, trypanocides were swapped to investigate single or multiple resistance. Microscopically negative samples from the monitoring days were tested using 18S-PCR-RFLP. 22.9% (107/467) was found positive on day 0. On day 14, nine animals in Botao and seven in Mungama were positive. On day 28, in Botao, four animals from the diminazene group and four from the isometamidium group were positive. In Mungama, four animals from the diminazene group were positive on day 28. On day 42, six animals (9%) in Botao and two (9.5%) in Mungama remained positive after drug swap. No relapses occurred in Namitangurine. The 18S-PCR-RFLP consistently detected more positive than microscopy: indeed, positives reached 12, 13, and 8 in Botao and 9, 7, and 4 in Mungama, at days 14, 28, and 42, respectively. Single- and multi-drug resistance in Nicoadala district, Zambezia province, is thus here confirmed. This should be considered when choosing control options. PMID- 29264719 TI - Efficacy of injectable praziquantel for elimination of trematode metacercariae in bluegills (Lepomis macrochirus) and quantification of parasite death by propidium iodide staining. AB - Digenean trematodes have complex life cycles and control of these flatworms can be accomplished by eliminating immature parasite stages from intermediate hosts. In aquaculture systems, presence of trematode metacercariae can negatively impact fish health and lead to economic losses. Posthodiplostomum minimum is a parasite of birds that uses bluegill sunfish (Lepomis macrochirus) as the intermediate host and is commonly found in fish used to stock waterways for recreational purposes. In this study, we evaluated killing of P. minimum metacercariae by injectable praziquantel in naturally infected bluegills. Using propidium iodide staining and motility assessment, we found that 5 mg/kg administered intramuscularly was effective for parasite killing. However, metacercarial death was not apparent until day 7 post-treatment. Our results demonstrated that propidium iodide staining is an effective method for detecting death in metacercariae recovered from treated fish. This method was at least as sensitive as objective motility scoring and provided quantitative assessment of parasite death. Future studies involving treatment of metacercariae in fish with praziquantel may need to be carried out over a period of weeks in order to accurately assess parasite killing and would benefit from using the propidium iodide method. PMID- 29264720 TI - Assessment of the role of small mammals in the transmission cycle of tegumentary leishmaniasis and first report of natural infection with Leishmania braziliensis in two sigmodontines in northeastern Argentina. AB - To contribute to the knowledge of the role of small mammals in the transmission cycle of tegumentary leishmaniasis caused by Leishmania braziliensis, we studied the small mammal community and its temporal and spatial association with phlebotominae, as well as small mammal infection by Leishmania spp. by PCR-RFLP analyses in an endemic area of northeastern Argentina. Ten small mammal samplings were conducted (2007-2009, 7506 Sherman trap nights and 422 cage trap nights). In two of these samplings, 16 capture stations each one consisting of a CDC light trap to capture phlebotominae, two to four Sherman traps and two cage traps were placed. We found co-occurrence of phlebotominae and small mammal captures in four stations, which were all the stations with small mammal captures and yielded 97% (2295 specimens, including 21 gravid females) of the total phlebotominae captures, suggesting that small mammals may provide a potential source of blood for phlebotominae females. One Didelphis albiventris and two Rattus rattus were associated with high captures of Nyssomyia whitmani, vector of L. braziliensis in the study area. The PCR-RFLP analyses confirm the presence of L. braziliensis in two sigmodontine small mammals (Akodon sp. and Euryoryzomys russatus) for the first time in Argentina, to our knowledge. PMID- 29264721 TI - L-Acetyl-carnitine in Patients with Carpal Tunnel Syndrome: Effects on Nerve Protection, Hand Function and Pain. AB - BACKGROUND AND AIM: L-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti nociceptive action. OBJECTIVE: Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy. METHODS: In a multicentre, examiner blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120 days after treatment with LAC 500 mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve. RESULTS: The primary endpoint was met, with significant improvement of the SCV (P < 0.0001). All sensory neurophysiological measures also significantly improved. BCTQ score changed significantly (P < 0.0001), with a greater improvement in the symptom component. Nine of the NPSI types of pain, particularly squeezing and pressure pain and pain evoked by pressure, showed a significant reduction (P < 0.0001). CONCLUSIONS: Our clinical and neurophysiological study indicated that 4 months of treatment with LAC exerted a neuroprotective effect. LAC reduced pain in patients with mild and moderate CTS, a result that is possibly due to both its neuroprotective action and its central anti-nociceptive properties. Clinical Trials Registration code: EudraCT 2014 002289-62. PMID- 29264722 TI - One-pot exfoliation, functionalization, and size manipulation of graphene sheets: efficient system for biomedical applications. AB - In this work, we reported a facile method to produce stable aqueous graphene dispersion through direct exfoliation of graphite by modified hyperbranched polyglycerol. Size of graphene sheets was manipulated by simultaneous exfoliation and sonication of graphite, and functionalized graphene sheets with narrow size distribution were obtained. The polyglycerol-functionalized graphene sheets exhibited highly efficient cellular uptake and photothermal conversion, enabling it to serve as a photothermal agent for cancer therapy. PMID- 29264723 TI - Teilhard de Chardin's oeuvre within an ongoing discussion of a gene drive release for public health reasons. AB - Within the domain of public health, vector-borne diseases are among the most vehemently discussed issues. Recent scientific breakthroughs in genome editing technology provided a solution to this issue in the form of a gene drive that might decrease and even eradicate vector-borne diseases. Gene drives are engineered, and designed genes that can break typical inheritance rules and be passed to almost all of the carrier's offspring. This genome editing and gene drive technology has become a powerful tool for ecological and environmental engineering, through which man can manipulate his surroundings, adjusting it to himself and directly mastering evolution and the ecosystem. Although the gene drive technology has been perceived as promising in the public health domain, ecological implications of its use are not to be underestimated. The primary aim of this paper is to overcome the ongoing discussion which mostly focuses on whether priority should be given to the environment or to public health, and to find an adequate answer and solution. In this quest to find the proper answer and solution, Pierre Teilhard de Chardin's thought might be useful, especially his concepts of the biosphere and the noosphere which may provide some clarifications as to why we are at the moment so cautious with gene drive technology and how we need to move towards a better common future on earth. PMID- 29264724 TI - Advances in micro- and nanotechnologies for the GLP-1-based therapy and imaging of pancreatic beta-cells. AB - Therapies to prevent diabetes in particular the progressive loss of beta-cell mass and function and/or to improve the dysregulated metabolism associated with diabetes are highly sought. The incretin-based therapy comprising GLP-1R agonists and DPP-4 inhibitors have represented a major focus of pharmaceutical R&D over the last decade. The incretin hormone GLP-1 has powerful antihyperglycemic effect through direct stimulation of insulin biosynthesis and secretion within the beta cells; it normalizes beta-cell sensitivity to glucose, has an antiapoptotic role, stimulates beta-cell proliferation and differentiation, and inhibits glucagon secretion. However, native GLP-1 therapy is inappropriate due to the rapid post secretory inactivation by DPP-4. Therefore, incretin mimetics developed on the backbone of the GLP-1 or exendin-4 molecule have been developed to behave as GLP 1R agonists but to display improved stability and clinical efficacy. New formulations of incretins and their analogs based on micro- and nanomaterials (i.e., PEG, PLGA, chitosan, liposomes and silica) and innovative encapsulation strategies have emerged to achieve a better stability of the incretin, to improve its pharmacokinetic profile, to lower the administration frequency or to allow another administration route and to display fewer adverse effects. An important advantage of these formulations is that they can also be used at the targeted non invasive imaging of the beta-cell mass. This review therefore focuses on the current state of these efforts as the next step in the therapeutic evolution of this class of antidiabetic drugs. PMID- 29264725 TI - Lipid Emulsion Enriched in Omega-3 PUFA Accelerates Wound Healing: A Placebo Controlled Animal Study. AB - BACKGROUND: The Omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) generate bioactive lipid mediators that reduce inflammation. The present study evaluated the effect of SMOFlipid containing omega-3 PUFAs on wound healing. METHODS: Rats were divided into a SMOFlipid (SMOF) group and a 0.9% saline (placebo) group, with eight rats in each group. Wound excision was performed on the dorsal surface of each rat. In the SMOF group, 1 gm/kg SMOFlipid was dissolved in 3 mL saline as a treatment; in the placebo group, 3 mL saline was prepared as a treatment. The treatments were administered intravenously at an initial rate of 0.2 mL/kg body weight/h immediately after wounding, for 72 h. Blood samples were collected for white blood cell, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL 10 measurements at the baseline and at 1, 6, 12, 24, 48, and 72 h after intervention. Wound areas were measured over a 2-week period after excision, and a histological examination was performed. RESULTS: Compared with the placebo group, SMOFlipid supplementation engendered significant decreases in the wound area on day 3 (78.28 +/- 5.25 vs. 105.86 +/- 8.89%), day 5 (72.20 +/- 4.31 vs. 96.39 +/- 4.72%), day 10 (20.78 +/- 1.28 vs. 39.80 +/- 10.38%), and day 14 (7.56 +/- 0.61 vs. 15.10 +/- 2.42%). The placebo group had a higher TNF-alpha level than the SMOF group at 72 h. The IL-10 level was higher in the SMOF group than in the placebo group at 48 h. Histological analysis revealed a higher rate of fibroblast distribution and collagen fiber organization in the SMOF group (P = 0.01). CONCLUSION: SMOFlipid enriched in omega-3 PUFA accelerates wound healing. PMID- 29264726 TI - Antireflux Surgery and Barrett's Esophagus: Myth or Reality? AB - BACKGROUND: It may seem questionable if antireflux surgery still has a role in the management of patients with Barrett's esophagus (BE) in the current era when antireflux surgery is facing a steady decline, obesity is increasing, pharmacologic treatment for gastroesophageal reflux disease (GERD) is in its splendor, and endoscopic techniques are used more frequently. It is questionable if patients with BE should be operated to stop GERD and to prevent cancer. The aim of this study was to determine the role of antireflux surgery in patients with BE. METHODS: Literature review. RESULTS: The role of antireflux operations is, in fact, very controversial and neglected. BE is a different phenotype of GERD with a distinct pathophysiology linked to severe reflux of bile and acid, due to a marked anatomic disruption of the gastroesophageal barrier. Published series show that a fundoplication adequately controls GERD and symptoms in BE patients. A fundoplication (or even better a bile diversion antireflux procedure) may prevent esophageal adenocarcinoma. CONCLUSIONS: In conclusion, a fundoplication efficiently controls GERD and symptoms in BE patients. A fundoplication (or even better a bile diversion procedure) may also prevent esophageal adenocarcinoma. PMID- 29264727 TI - Concentration of Proteasome in the Blood Plasma of Children with Acute Appendicitis, Before and After Surgery, and Its Correlation with CRP. AB - OBJECTIVE: The determination of 20S proteasome concentration in the blood plasma of children with appendicitis and its correlation with CRP. DESIGN AND SETTING: Thirty-one children with acute appendicitis, were randomly included into the study (age 5 years up to 17 years, mean age 11.5 + 1 years). PARTICIPANTS: There were 17 girls and 14 boys. Eighteen healthy, age-matched subjects, admitted for planned surgeries served as controls. Exclusion criteria were: severe preexisting infections, immunological or cardiovascular diseases that required long-term medication, and complicated cases of appendicitis with perforation of appendix and/or peritonitis. MAIN OUTCOME MEASURES: The 20S proteasome concentrations in the blood plasma of patients with acute appendicitis were highest before the surgery and were above the range of concentrations measured in controls, and the difference was statistically significant. RESULTS: The 20S proteasome concentration measured 24 and 72 h after the operation, slowly decreased over time, and still did not reach the normal range, when compared with the concentration measured in controls (p < 0.05). CONCLUSIONS: 20S proteasome concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation. The method of operation classic open appendectomy, or laparoscopic appendectomy, does not influence the general trend in 20S proteasome concentration. PMID- 29264728 TI - Interaction of PM2.5 airborne particulates with ZnO and TiO2 nanoparticles and their effect on bacteria. AB - A significant knowledge gap in nanotechnology is the absence of standardized protocols for examining and comparison the effect of metal oxide nanoparticles on different environment media. Despite the large number of studies on ecotoxicity of nanoparticles, most of them disregard the particles physicochemical transformation under real exposure conditions and interaction with different environmental components like air, soil, water, etc. While one of the main exposure ways is inhalation and/or atmosphere for human and environment, there is no investigation between airborne particulates and nanoparticles. In this study, some metal oxide nanoparticle (ZnO and TiO2) transformation and behavior in PM2.5 air particulate media were examined and evaluated by the influence on nanoparticle physicochemical properties (size, surface charge, surface functionalization) and on bacterium (Gram-positive Bacillus subtilis, Staphylococcus aureus/Gram-negative Escherichia coli, Pseudomonas aeruginosa bacteria) by testing in various concentrations of PM2.5 airborne particulate media to contribute to their environmental hazard and risk assessment in atmosphere. PM2.5 airborne particulate media affected their toxicity and physicochemical properties when compared the results obtained in controlled conditions. ZnO and TiO2 surfaces were functionalized mainly with sulfoxide groups in PM2.5 air particulates. In addition, tested particles were not observed to be toxic in controlled conditions. However, these were observed inhibition in PM2.5 airborne particulates media by the exposure concentration. These observations and dependence of the bacteria viability ratio explain the importance of particulate matter-nanoparticle interaction. PMID- 29264730 TI - Differences in Attitudes Toward Immunosuppressant Therapy in a Multi-ethnic Sample of Kidney Transplant Recipients. AB - Barriers for renal transplant patients to immunosuppressant medication adherence are poorly understood, despite the high rate and toll of non-adherence. We sought to assess factors that contribute to barriers to immunosuppressive medication adherence in an ethnically diverse sample of 312 renal transplant patients recruited from three transplant centers across New York City. Transplant patients who were at least 6 months post-transplant completed questionnaires while waiting for their medical appointment. Ethnic differences were observed on barriers to immunosuppressant adherence. Black and Hispanic participants reported significantly more barriers to adherence compared to Caucasian participants. Differences in perception about the potential harm and necessity of immunosuppressant medications also were present. Using hierarchical multiple regression, age and income were significant predictors of reported barriers to adherence, even while controlling for ethnicity. The most robust predictor of reported barriers was the perception of the medication cost-benefit differential, i.e., the balance between concerns about immunosuppressant medications and their perceived helpfulness (B = - 0.5, p < .001), indicating that varying beliefs about the medication's necessity and utility rather than ethnicity explain the differences in barriers to medication adherence. Future interventions targeting non-adherence should aim to reduce the barriers to adherence by addressing perceived risks and benefits of taking immunosuppressant medication. PMID- 29264729 TI - Pulmonary vein isolation combined with spironolactone or renal sympathetic denervation in patients with chronic kidney disease, uncontrolled hypertension, paroxysmal atrial fibrillation, and a pacemaker. AB - BACKGROUND: Atrial fibrillation (AF) commonly occurs in chronic kidney disease (CKD), occasioning adverse outcomes. Merging pulmonary vein isolation (PVI) and renal sympathetic denervation (RSD) may decrease the recurrence of AF in subjects with CKD and uncontrolled hypertension. We considered that RSD could reduce the recurrence of AF in patients with CKD by modulating sympathetic hyperactivity. We aimed to evaluate the impact of RSD or spironolactone 50 mg/day associated with PVI in reducing systolic blood pressure (BP), AF recurrence, and AF burden in patients with a history of paroxysmal AF and mild CKD. METHODS: This was a single center, prospective, longitudinal, randomized, double-blind study. The individuals were randomly divided into two groups (PVI + spironolactone, n = 36, and PVI + RSD, n = 33). All of them were followed for exactly 1 year to assess maintenance of sinus rhythm and to monitor the other variables. RESULTS: Ambulatory BP measurements were reduced in both groups and at the 12th month also differed between groups. Significantly more patients in the PVI + RSD (61%) than in the PVI + spironolactone group (36%) were AF-free at the 12th month of follow up, P = 0.0242. Toward the end of the study, the mean AF burden was lower in the PVI + RSD group as compared to PVI + spironolactone group, at the 9th month: ? = 10% (P < 0.0001), and at the 12th month: ? = - 12% (P < 0.0001), respectively. CONCLUSIONS: PVI + RSD is safe and appears to be superior to PVI + spironolactone in BP reduction, augmentation of AF event-free rate, reduction of AF burden, and improvement of renal function. PMID- 29264731 TI - An evaluation of the social dimensions in public participation in rural domestic waste source-separated collection in Guilin, China. AB - A comprehensive evaluation of public participation in rural domestic waste (RDW) source-separated collection in China was carried out within a social-dimension framework, specifically in terms of public perception, awareness, attitude, and willingness to pay for RDW management. The evaluation was based on a case study conducted in Guilin, Guangxi Zhuang Autonomous Region, China, which is a representative of most inland areas of the country with a GDP around the national average. It was found that unlike urban residents, rural residents maintained a high rate of recycling, but in a spontaneous manner; they paid more attention to issues closely related to their daily lives, but less attention to those at the general level; their awareness of RDW source-separated collection was low and different age groups showed significantly different preferences regarding the sources of knowledge acquirement. Among potential information sources, village committees played a very important role in knowledge dissemination; for the respondents' pro-environmental attitudes, the influencing factor of "lack of legislation/policy" was considered to be significant; mandatory charges for waste collection and disposal had a high rate of acceptance among rural residents; and high monthly incomes had a positive correlation with both public pro environmental attitudes and public willingness to pay for extra charges levied by RDW management. These observations imply that, for decision-makers in the short term, implementing mandatory RDW source-separated collection programs with enforced guidelines and economic compensation is more effective, while in the long run, promoting pro-environmental education to rural residents is more important. PMID- 29264732 TI - CO oxidation on inverse Ce6O12/Cu(111) catalyst: role of copper-ceria interactions. AB - The surface structures, O2 adsorption, and CO oxidation reaction properties of Ce6O12/Cu(111) have been investigated using density functional theory including on-site Coulomb corrections (DFT + U). Results show that the supported ceria nanoparticles would gain electrons from the Cu(111) surface, and the Ce4+ are reduced to Ce3+. In addition, the oxygens at the interface have been largely activated, resulting in much low formation energy of O vacancies. For the CO oxidation reaction, two possible pathways are investigated, CO reacts with the O2 molecule adsorbed on Ce3+ and the lattice O at the interface, respectively. It has been found that CO reacting with the lattice O atom gives a lower reaction barrier than that of adsorbed O2 on Ce3+. These results are important for further understanding of the role of different active sites on the inverse CeOx/Cu(111) surface structure. PMID- 29264733 TI - Development of microsatellite markers using next-generation sequencing for the fish Colossoma macropomum. AB - Tambaqui (Colossoma macropomum) is a fish species from the Amazon and Orinoco Rivers, with favorable characteristics to the cultivation system and great market acceptance in South America. However, the construction of a genetic map for the genetic improvement of this species is limited by the low number of molecular markers currently described. Thus, this study aimed to validate gene-associated and anonymous (non-genic) microsatellites obtained by next generation sequencing (RNA-seq and whole genome shotgun-WGS, respectively), for future construction of a genetic map and search for quantitative trait loci (QTL) in this species. In the RNA-seq data, the observed and expected heterozygosity (Ho and He) ranged from 0.09 to 0.73, and 0.09 to 0.85, respectively. In the WGS data, Ho and He ranged from 0.33 to 0.95, and 0.28 to 0.92, respectively. In general, the evaluation of 200 markers resulted in 45 polymorphic loci, of which 14 were gene associated (RNA-Seq) and 31 were anonymous (WGS). Moreover, some markers were related to genes of the immune system, biological regulation/control and biogenesis. This study contributes to increase the number of molecular markers available for genetic studies in C. macropomum, which will allow the development of breeding programs assisted by molecular markers. PMID- 29264735 TI - A case report of adult cerebellar high-grade glioma with H3.1 K27M mutation: a rare example of an H3 K27M mutant cerebellar tumor. AB - Diffuse midline glioma, H3 K27M mutant, is newly recognized as a distinct category, which usually arises in the brain stem, thalamus or spinal cord of children, and young adults. The oncogenic H3 K27M mutation involves H3.3 (encoded by H3F3A) or H3.1 (encoded by HIST1H3B/HIST1H3C), and the incidence of each mutation differs among the primary sites. Recently, several papers have reported that cerebellar high-grade gliomas in both children and adults also harbor H3 K27 mutation. With the exception of one pediatric case, all of the cases carried the mutation in H3.3. We herein present the case of an adult cerebellar high-grade astrocytic tumor with H3.1 K27M mutation in a 45-year-old man, which also involvedTP53 mutation and was immunonegative for ATRX. Some groups have reported that H3.3 and H3.1 K27M mutations define subgroups of diffuse intrinsic pontine gliomas (DIPGs) with different phenotypes as well as genetic alterations. On comparing the findings of the present case, particularly TP53 mutation status and ATRX expression, to the findings of the previous studies on DIPGs, our case seems unusual among the H3.1 K27M mutant subgroup. Further studies are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of cerebellar gliomas harboring H3 K27M mutation. PMID- 29264734 TI - Genetics and genomics of susceptibility and immune response to necrotic enteritis in chicken: a review. AB - Global poultry production is facing many challenges and is currently under pressure due to the presence of several diseases like Necrotic Enteritis (NE). It is estimated that NE-caused global economic losses has increased from 2 billion to 6 billion US$ in 2015 because it is not easy to diagnose and control disease at the earlier stage of occurrence. Additionally, ban on the in-feed antibiotics and some other genetic and non-genetic predisposing factors affect the occurrence of the disease. Though the incidence of the disease can be reduced by minimizing the predisposing factors and through immunization of birds but there is no single remedy to control the disease. Therefore, we suggest that there is need to find out the genetic variants that could help to select the birds resistant to NE. The current review details the pertinent features about the genetic and genomics of susceptibility and immune response of birds to Necrotic Enteritis. We report here the list of candidate gene reported for their involvement with the susceptibility and/or resistance to the disease. However, most of these genes are involved in immune-related functions. For better understanding of the role of Clostridium perfringens and its toxins in the pathogenesis of disease there is need to unveil the association between any specific genetic variation and clinical status of NE. However, the presence of substantial genetic variations among different breeds/strains of chicken shows that it is possible to develop broiler strain with genetic resistant against NE. It would help in the cost-effective and sustainable production of safe broiler meat. PMID- 29264736 TI - "It's Never Just About the HIV:" HIV Primary Care Providers' Perception of Substance Use in the Era of "Universal" Antiretroviral Medication Treatment. AB - Antiretroviral therapy (ART) is recommended for all people living with HIV (PLWH), regardless of disease status. Substance use disorders (SUD) are common barriers to successful HIV treatment; however, few studies have comprehensively explored how HIV primary care providers take SUDs into account in the context of universal ART implementation. This study uses thematic analysis of qualitative interviews to explore providers' (N = 25) substance use assessment and factors associated with ART initiation. 64% of providers had 15 or more years of HIV treatment experience. Almost all providers agreed with the guidelines for universal ART initiation despite the presence of SUD. Still, identification and management of SUD is challenged by inconsistent assessment, providers' misperceptions about SUD and patients' willingness to discuss it, and lack of accessible treatment resources when SUD is identified. Greater guidance in systematic SUD assessment and management, combined with integrated addiction services, could enhance universal ART implementation among PLWH/SUD. PMID- 29264738 TI - Characterization of antimicrobial and hemolytic properties of short synthetic cationic lipopeptides based on QSAR/QSTR approach. AB - In this study, we investigated the influence of molecular descriptors of cationic lipopeptides on their antimicrobial activity and hemolytic properties. The quantitative structure-activity relationship and quantitative structure-property relationship models were constructed. The antimicrobial, hemolytic and retention data were used as dependent variable and structural parameters as the independent ones. The obtained results suggest that the chromatographic indexes can be employed for prediction of antibacterial activity and that lipopeptides present nonspecific interaction between erythrocytes and bacterial membranes. PMID- 29264737 TI - Positive Psychological Factors are Linked to Successful Cognitive Aging Among Older Persons Living with HIV/AIDS. AB - We aimed to characterize successful cognitive aging (SCA) among older HIV infected (HIV+) and HIV-uninfected (HIV-) adults, and to determine associations with positive psychological factors and health-related quality of life (HRQoL). Ninety-nine HIV+ and 46 HIV- older adults (>= 50 years) completed measures of neurocognition, positive psychological factors, and HRQoL. Using study-defined SCA criteria (i.e., no cognitive or everyday impairment or major depressive disorder), we compared positive psychological factors and HRQoL across four groups: HIV+/SCA+, HIV+/SCA-, HIV-/SCA+, HIV-/SCA-. SCA was identified in 29% of the HIV+ sample compared to 61% of the HIV- sample (p < 0.01). HIV+/SCA+ participants had higher scores on 8 of 10 measures of positive psychological factors as well as better HRQoL (ps < 0.05) as compared to the HIV+/SCA- group. Furthermore, the HIV+/SCA+ participants had comparable scores on these factors as HIV- adults. Fewer HIV+ than HIV- participants met SCA criteria; however, the level of positive psychological factors among the HIV+/SCA+ group was comparable to the HIV- sample. Our findings present opportunities for interventions to optimize positive psychological factors and potentially improve SCA among older HIV+ adults. PMID- 29264739 TI - Do clinical and laboratory variables have any impact on the diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin? AB - OBJECTIVE: To assess the influence of clinical features and laboratory test results on the determination of fever of unknown origin (FUO) by means of 18F-FDG PET/CT. METHODS: Retrospective and longitudinal analysis, including all the PET/CT studies requested for FUO. Reference standard was established by serology, cultures or biopsy with other laboratory tests or clinical follow-up when necessary. Clinical variables, inflammation markers, protein analysis, serology and culture results close to the PET scan were obtained. The final diagnosis was classified into three groups attending to the etiology; group 1: infection or neoplasm, group 2: vasculitis, autoimmune disease or non-infectious inflammatory disease and group 3: auto-limited fever or persistent fever without diagnosis. PET/CT scans were classified as positive or negative and helpful or not in the diagnosis of the fever origin. The effect of clinical features and laboratory variables on the PET/CT results was analyzed. RESULTS: Sixty-seven patients were evaluated. The final diagnosis was: Group 1 (25), Group 2 (20) and Group 3 (22). 89.6% of patients had a positive inflammation marker, 28.4% proteinogram alterations and 20.9% positive cultures. PET/CT was positive in 52/67 patients. PET/CT helped in the establishment of the fever origin in 35 cases and was especially helpful in groups 1 and 2. Sensitivity, specificity and accuracy of PET/CT were: 84, 31 and 61%. PET results shown significant relations with the final diagnosis (p = 0.035) and culture results (p = 0.037). No significant relations were observed with the rest of clinical or laboratory variables. CONCLUSIONS: 18F-FDG PET/CT had a high sensitivity but a low specificity in the diagnosis of the fever origin, probably due to the high rate of diffuse and auto limited aetiologies. Patients who are most likely to benefit from the PET/CT study would be those with several positive inflammation markers, reflecting a higher pre-test probability of active disease. PMID- 29264740 TI - CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens. AB - Single-nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte antigen-4 (CTLA 4) are important risk factors associated with autoimmune diseases and malignancies. This study explored the association of CTLA-4SNPs with the development of myeloma and evaluated the outcome of patients receiving bortezomib based regimens in relation to CTLA-4SNPs. Peripheral blood samples from 86 patients with multiple myeloma (MM) and 154 healthy controls were obtained to investigate CTLA4 polymorphisms. Five SNP genotypes of CTLA-4, namely, -1772 (rs733618), -1661 (rs4553808), -318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were evaluated through TaqMan SNP genotyping assays (Applied Biosystems). Some of the CTLA-4 polymorphisms displayed frequencies that vary among ethnic groups. Kaplan-Meier analysis revealed that patients with rs733618 GG showed a significantly lower disease-free survival (0 vs. 57.4%, P = 0.020) and overall survival (46.3 vs. 83.3%, P = 0.026) than those with GA+AA following bortezomib-based therapy. Multivariate analyses showed that rs733618 GG was a risk factor for OS (HR = 0.012; 95% CI = 0.001-0.199; P = 0.002). The incidence of nonhematologic grade 3/4 adverse events significantly increased in the rs4553808 GG+GA group compared with that in the AA group (P = 0.036). CTLA-4 rs733618 GG reduced the progression-free survival and the overall survival of patients with MM who received bortezomib-based therapy. Information regarding CTLA-4 polymorphisms and haplotypes may be used to improve MM therapy. Future studies must determine the precise effect of CTLA-4 polymorphisms and haplotypes on MM therapy outcomes by using different cohorts with a large number of subjects. PMID- 29264741 TI - Rearrangement of VPS13B, a causative gene of Cohen syndrome, in a case of RUNX1 RUNX1T1 leukemia with t(8;12;21). AB - Variant chromosomal translocations associated with t(8;21) are observed in 3-4% of acute myeloid leukemia (AML) cases with a RUNX1-RUNX1T1 fusion gene. However, the molecular events that occur in variants of t(8;21) are not well characterized. In the present study, we report genetic features of a variant three-way translocation of t(8;12;21)(q22;p11;q22) in a patient with AML. In this patient, leukemia cells lacked azurophilic granules, which does not correspond with the classic features of t(8;21). RNA-seq analysis revealed that TM7SF3 at 12p11 was fused to VPS13B at 8q22 and VPS13B to RUNX1, in addition to RUNX1 RUNX1T1. VPS13B was located near RUNX1T1 and both were localized at the same chromosomal bands. The reading frames of TM7SF3 and VPS13B did not match to those of VPS13B and RUNX1, respectively. Disruption of VPS13B causes Cohen syndrome, which presents intermittent neutropenia with a left-shifted granulopoiesis in the bone marrow. Disruption of VPS13B may thus cause the unusual features of RUNX1 RUNX1T1 leukemia. Our case indicates that rearrangement of VPS13B may be additional genetic events in variant t(8;21). PMID- 29264742 TI - Patient-ventilator asynchrony during conventional mechanical ventilation in children. AB - BACKGROUND: We aimed (1) to describe the characteristics of patient-ventilator asynchrony in a population of critically ill children, (2) to describe the risk factors associated with patient-ventilator asynchrony, and (3) to evaluate the association between patient-ventilator asynchrony and ventilator-free days at day 28. METHODS: In this single-center prospective study, consecutive children admitted to the PICU and mechanically ventilated for at least 24 h were included. Patient-ventilator asynchrony was analyzed by comparing the ventilator pressure curve and the electrical activity of the diaphragm (Edi) signal with (1) a manual analysis and (2) using a standardized fully automated method. RESULTS: Fifty-two patients (median age 6 months) were included in the analysis. Eighteen patients had a very low ventilatory drive (i.e., peak Edi < 2 uV on average), which prevented the calculation of patient-ventilator asynchrony. Children spent 27% (interquartile 22-39%) of the time in conflict with the ventilator. Cycling-off errors and trigger delays contributed to most of this asynchronous time. The automatic algorithm provided a NeuroSync index of 45%, confirming the high prevalence of asynchrony. No association between the severity of asynchrony and ventilator-free days at day 28 or any other clinical secondary outcomes was observed, but the proportion of children with good synchrony was very low. CONCLUSION: Patient-ventilator interaction is poor in children supported by conventional ventilation, with a high frequency of depressed ventilatory drive and a large proportion of time spent in asynchrony. The clinical benefit of strategies to improve patient-ventilator interactions should be evaluated in pediatric critical care. PMID- 29264744 TI - Deficiency of IL-18 Aggravates Esophageal Carcinoma Through Inhibiting IFN-gamma Production by CD8+T Cells and NK Cells. AB - To investigate the potential role of interleukin-18 (IL-18) in immunomodulation during tumorigenesis of esophageal carcinoma and elucidate the underlying molecular mechanism, we employed IL-18 knockout mice for this purpose. Carcinogen 4-nitroquinoline 1-oxide (4NQO) was administrated in drinking water to induce occurrence of esophageal squamous cell carcinoma (ESCC). T cell activation as indicated by the surface CD molecules was analyzed with flow cytometry. The serous content of interferon-gamma (IFN-gamma) along with other cytokines was determined by inflammatory human cytokine cytometric bead array. The cytotoxicity assay was performed by co-culture of tumor cells with immune cells and relative cell viability was determined by lactate dehydrogenase (LDH) assay. Apoptotic cells were stained with Annexin-V/propidium iodide (PI) and analyzed by flow cytometry. Cell proliferation was measured with Cell Counting Kit-8 (CCK-8) assay. Our data demonstrated that deficiency of IL-18 promoted the progression and development of 4NQO-induced ESCC. Loss of IL-18 suppressed the activation of T cells in the esophagus. Deficiency of IL-18 inhibited the IFN-gamma production by CD8+ T cells and natural killer (NK) cells. Absence of IL-18 inhibited the cytotoxicity of CD8+ T cells and NK cell in vitro. Moreover, deficiency of IL-18 promoted the apoptosis of CD8+ T cells and inhibited the proliferation of CD8+ T cells in vitro. Our data elucidated the immunomodulatory role of IL-18 during tumorigenesis of ESCC, whose deficiency compromised antitumor immunity and contributed to immune escape of esophageal carcinoma. Our results also indicated the therapeutic potential of exogenous IL-18 against ESCC, which warrants further investigations. PMID- 29264743 TI - Association of Respiratory Syncytial Virus Toll-Like Receptor 3-Mediated Immune Response with COPD Exacerbation Frequency. AB - The objective of the study is to explore the role of respiratory syncytial virus Toll-like receptor 3 (TLR3)-mediated immune response in the pathogenesis of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). A total of 20 AECOPD patients and 10 normal volunteers were studied. TLR3 was detected by RT PCR, and respiratory syncytial virus (RSV) was detected by nested RT-PCR. Then, A549 cells were infected by RSV at different time points and at different viral titers. TLR3 mRNA was detected by RT-PCR, the protein of TLR3 and interferon regulatory factor 3 (IRF3) were detected by western blot, and IRF3 protein localization was detected by immunofluorescence. Interferon-beta (IFN-beta) and interleukin-6 (IL-6) were detected by ELISA. A total of 4 (20%) of the 20 AECOPD patients sampled were infected with RSV. The forced expiratory volume in 1 second (FEV1) percentage was lower in the AECOPD patients infected with RSV compared to those not infected (P = 0.03). The expression of IL-6 in the two groups was diametrically opposite (P = 0.04). The AECOPD group (n = 20) showed an increase in TLR3 mRNA compared with that of the control group (n = 10) (P = 0.02). The RSV infected AECOPD group (n = 4) showed an obvious increase in TLR3 mRNA compared with that of the control group (P = 0.03). There was a significant correlation between severity of reduction in lung function at exacerbation and the increasing expression of TLR3 in AECOPD patients. The TLR3 signaling pathway was activated in lung epithelial cells. TLR3 mRNA/protein levels were increased in A549 infected with RSV compared with those of the control group. IRF3 protein also increased along with the occurrence of nuclear transfer in A549 infected with RSV. IFN-beta and IL-6 were also increased in the RSV-infected A549 cells compared with those of the control (P = 0.00 and 0.00, respectively). Increased TLR3 expression in AECOPD patients is associated with declining lung function. TLR3 may be a risk factor for RSV-infected AECOPD patients. PMID- 29264746 TI - Teleconsultation d'anesthesie au domicile : une enquete d'acceptabilite. PMID- 29264747 TI - The Leech airway: precursor to the modern supraglottic airway. PMID- 29264745 TI - Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin 1beta on White Adipocyte Browning. AB - Adipose tissue expansion is accompanied by infiltration and accumulation of pro inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to beta3 adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1beta signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1beta interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1beta. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1beta secretion, attenuates beta3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity. PMID- 29264748 TI - Special issue dedicated to Jack Kalbfleisch. PMID- 29264750 TI - Study of the osteogenesis effect of icariside II and icaritin on canine bone marrow mesenchymal stem cells. AB - This study aimed to identify the osteogenesis effect of icariside II (ICSII) and icaritin (ICT) in vitro. Bone marrow mesenchymal stem cells (BMSCs) were treated with ICSII and ICT in order to detect the proliferation and differentiation of BMSCs, the expression of the osteogenesis-related proteins with or without osteogenic medium (OM) and genes, Runt-related transcription factor 2 (Runx-2), osteocalcin (OCN), osteopontin (OPN), osterix, and basic fibroblast growth factor (bFGF), and the phosphorylation levels of mitogen-activated protein kinase (MAPK). We found that the optical density increased and alkaline phosphatase decreased after the BMSCs were treated with different concentrations of ICSII; however, ICT showed an opposing effect. The formation of calcium nodules was observed after the BMSCs were treated with ICSII and ICT. The expression level of osteogenesis-related proteins was enhanced following treatment with both ICSII or ICT, while the expression level of the osteogenesis-related genes Runx-2, OCN, OPN, osterix, and bFGF significantly increased with ICSII treatment (P < 0.05), and only Runx-2 and bFGF significantly increased (P < 0.01) with ICT. The expression of osteogenic differentiation-related proteins (except OPN) following treatment with ICSII + OM or ICT + OM was not notably increased. Both ICSII and ICT elevated the phosphorylation levels of MAPK/ERK, which was attenuated by GDC 0994 (an inhibitor of MAPK/ERK). Collectively, these data indicate that ICSII and ICT facilitate orientation osteogenic differentiation of BMSCs, which is most likely via the MAPK/ERK pathway. OM did not synergistically enhance the osteogenesis effect of ICSII and ICT. PMID- 29264749 TI - Effect of salt-stress on gene expression in citrus roots revealed by RNA-seq. AB - Citrus, as one of the most economically important fruits worldwide, is adversely affected by salinity stress. However, its molecular mechanisms underlying salinity tolerance are still not clear. In this study, next-generation RNA-seq technology was applied to analyze the gene expression profiling of citrus roots at 3 time points over a 24-h period of salt treatment. A total of 1831 differentially expressed genes (DEGs) were identified. Among them, 1195 and 1090 DEGs were found at 4 and 24 h, of which 454 were overlapped. Based on functional annotation, the salt overly sensitive (SOS) and reactive oxygen species (ROS) signaling pathways were found to be involved. Meanwhile, we found that hormone metabolism and signaling played important roles in salt stress. In addition, a multitude of transcription factors (TFs) including WRKY, NAC, MYB, AP2/ERF, bZIP, GATA, bHLH, ZFP, SPL, CBF, and CAMTA were identified. The genes related to cell wall loosening and stiffening (xyloglucan endotransglucosylase/hydrolases, peroxidases) were also involved in salt stress. Our data not only provided a genetic resource for discovering salt tolerance-related genes, but also furthered our understanding of the molecular mechanisms underlying salt tolerance in citrus. PMID- 29264751 TI - Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis. AB - PURPOSE: Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence. METHODS: Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients. RESULTS: In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients. CONCLUSIONS: Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted. PMID- 29264752 TI - Mammography use among women aged 18-39 years in the United States. AB - PURPOSE: Recommendations for breast cancer screening using mammography target asymptomatic women aged >= 40 years who are not at increased risk for breast cancer. Evidence is not available to demonstrate benefits of screening with mammography at younger ages, and little is known about mammography use among younger women. This study described mammography use among women aged 18-39 years. METHODS: We analyzed data from the 2011-2015 National Survey of Family Growth, an in-person survey of a nationally representative sample of the U.S. household population. We estimated the prevalence of ever receiving a mammogram and examined reasons for the first mammograms among women aged 18-39 years without personal cancer history (n = 8324). We classified the first mammogram as a screening examination if it was performed either as part of a routine exam or because of family history of cancer. RESULTS: Among women aged 18-39 years, 14.3% (95% CI 13.2-15.4) reported ever having a mammogram. Prevalence of mammography use was highest among women aged 35-39 years (31.0%, 95% CI 27.8-34.5), and was higher among non-Hispanic black women than in other race/ethnicity groups. Women with a family history of breast cancer reported a higher prevalence of mammography use than women without this family history. For both women with and without a family history of breast cancer, about half of all first mammograms were performed for screening reasons. CONCLUSIONS: Among U.S. women aged 18-39 years with no personal cancer history, one in seven reported having received a mammogram. Women with no family history of breast cancer were as likely as those with a family history to initiate breast cancer screening with mammography before age 40. Our findings provide evidence that supports further research to examine factors that prompt young women to receive screening mammograms. PMID- 29264753 TI - The Association Between APOA5 Gene Polymorphisms and Plasma Lipids in the Turkish Cypriot Population: A Possible Biomarker for Preventing Cardiovascular Diseases. AB - Apolipoprotein A5 (APOA5 or APO A-V) polymorphisms have long been reported to be associated with cardiovascular disease and plasma lipid levels. The present study was undertaken to investigate the relationship between the rs662799, rs3135507, and rs2075291 with biochemical parameters in the Turkish Cypriot population. A total of 100 Turkish Cypriot volunteer subjects (53 female and 47 male), with a mean age of 40.8, participated in the study. A basic biochemical analysis, including serum glucose, total serum cholesterol, HDL-C, LDL-C, and triglycerides, was performed for each participant. Genotyping for the APOA5 three polymorphisms was performed by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Biochemical parameters except the low density lipoprotein cholesterol (LDL-C) were all within the normal limits. LDL-C was found to be slightly elevated in participants according to WHO guidelines. With respect to the genotype and allele distributions of APOA5 rs662799 T>C polymorphism, TT genotypes are more frequent (62%) in the population and the frequency of T allele is 0.78. The TT genotype for APOA5 rs2075291 GA variant is 0.12 for the A allele. No association between the two studied APOA5 polymorphisms (rs662799 and rs3135507) and the biochemical components of glucose, total cholesterol, and triglyceride were observed. On the other hand, a strong statistical association between the high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) clinical parameters and APOA5 rs662799 CC and rs3135507 AA genotypes was found (p = 0.014 and p = 0.017, respectively). APOA5 polymorphisms rs662799 and rs3135507, with the CC and the AA genotypes, respectively, are associated with increased levels of both high density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in the Turkish Cypriot population. PMID- 29264754 TI - Sep70/Pepsin expression in hypopharynx combined with hypopharyngeal multichannel intraluminal impedance increases diagnostic sensitivity of laryngopharyngeal reflux. AB - BACKGROUND: Improved methods of diagnosis of laryngopharyngeal reflux (LPR) would enable surgeons to better identify patients who may benefit from antireflux surgery (ARS). The objective of the present study was to assess if hypopharyngeal Pepsin and Sep70 expression combined with hypopharyngeal multichannel intraluminal impedance (HMII) has the potential to increase diagnostic sensitivity of LPR. METHODS: This study was performed on patients who underwent unsedated transnasal endoscopy with hypopharyngeal biopsy and 24-h HMII to determine abnormal proximal exposure (APE) and DeMeester score (DMS) from 2013 to 2016. Pepsin and Sep70 protein expression was assessed by Western blots of biopsy specimens. The outcomes of ARS were assessed using reflux symptom index (RSI). HMII APE classification, Sep 70, and Pepsin protein levels were compared in normative and symptomatic LPR patients and further analyzed alongside quality of life changes following ARS. RESULTS: Of 30 subjects enrolled, 23 were excluded for abnormal HMII results or endoscopic evidence of esophagitis. Seven subjects and 105 patients were included in the normative and symptomatic groups, respectively. Compared to the normative group, only Pepsin expression was significantly higher in the symptomatic group [APE+/LPR+ (p = 0.000), APE+/LPR- (p = 0.001), and APE- (p = 0.047)]. Further, the ratio of Sep70/Pepsin was significantly lower in the symptomatic group [APE+/LPR+ (p = 0.008), APE+/LPR- (p = 0.000), and APE- (p = 0.050)], and a cutoff ratio for a diagnosis of LPR was established as < 158. Of 105 symptomatic patients, 48 patients underwent ARS. Of these, 17 patients had complete pre- and post-RSI questionnaires. LPR symptoms improved in 15 (88%), of whom 2 were APE- but met criteria for a diagnosis of LPR based on the Sep70/Pepsin cutoff. CONCLUSIONS: The identified Sep70/Pepsin ratio may serve as a reliable biomarker for the diagnosis of LPR. As a result, this may help identify additional patients who have a false-negative HMII result due to the 24-h testing window. PMID- 29264755 TI - Single port component separation: endoscopic external oblique release for complex ventral hernia repair. AB - BACKGROUND: Component separation (CS) is a technique which mobilizes flaps of innervated, vascularized tissue, enabling closure of large ventral hernia defects using autologous tissue. Disadvantages include extensive tissue dissection when creating these myofascial advancement flaps, with potential consequences of significant post-operative skin and wound complications. This study examines the benefit of a novel, ultra-minimally invasive single port anterior CS technique. METHODS: This was a prospective study of 16 external oblique (EO) releases performed in 9 patients and 4 releases performed in 3 fresh frozen cadavers. All patients presented with recurrent complex ventral hernias, and were administered preoperative Botulinum Toxin A to their lateral oblique muscles to facilitate defect closure. At the time of elective laparoscopic repair, patients underwent single port endoscopic EO release using a single 20-mm incision on each side of the abdomen. Measurements were taken using real-time ultrasound. Postoperatively, patients underwent serial examination and abdominal CT assessment. RESULTS: Single port endoscopic EO release achieved a maximum of 50-mm myofascial advancement per side (measured at the umbilicus). No complications involving wound infection, hematoma, or laxity/bulge have been noted. All patients proceeded to laparoscopic or laparoscopic-open-laparoscopic intraperitoneal mesh repair of their hernia, with no hernia recurrences to date. CONCLUSIONS: Single port endoscopic EO release holds potential as an adjunct in the repair of large ventral hernia defects. It is easy to perform, is safe and efficient, and entails minimal disruption of tissue planes and preserves abdominal wall perforating vessels. It requires only one port-sized incision on each side of the abdomen, thus minimizing potential for complications. Further detailed quantification of advancement gains and morbidity from this technique is warranted, both with and without prior administration of Botulinum Toxin A to facilitate closure. PMID- 29264756 TI - Endoscopic submucosal tunnel dissection and endoscopic submucosal dissection for large superficial esophageal squamous cell neoplasm: efficacy and safety study to guide future practice. AB - BACKGROUND AND STUDY AIMS: ESTD and ESD are currently the two primary treatment options for superficial esophageal squamous cell neoplasm (SESCN) in China. However, in larger cases, ESD proves to be technically challenging and time saving, whereas ESTD exhibits promising efficacy. This study aims to evaluate the efficacy and safety of these two techniques for large SESCN. PATIENTS AND METHODS: A total of 150 patients with solitary large SESCN that underwent either ESTD (n = 52) or ESD (n = 98) between August 2011 and June 2016 were included in this study. Both efficacy and safety clinical data were collected and analyzed. RESULTS: All of the 150 patients were found to successfully undergo ESTD or ESD with 92.68 +/- 67.96 (mean +/- SD) min. The specimen area was measured to be 13.79 +/- 7.44 (mean +/- SD) cm2 and the dissection speed was 17.99 +/- 10.40 (mean +/- SD) mm2/min. En bloc resection and R0 resection were achieved in 91.33% (137/150) and 86.00% (129/150) of the cases, respectively. A total of 8.67% (13/150) were found to have intra-operative adverse events. Based on statistical analysis, ESTD was found to have a higher dissection speed and a similar adverse event rate compared with ESD. Moreover, a long operation time was found to be an independent risk factor for intra-operative adverse events. CONCLUSIONS: ESTD and ESD both were found to be effective and safe treatment options for the treatment of large SESCN. ESTD appeared to improve operation efficacy, which was reflected in a higher dissection speed compared with ESD. We also demonstrate that long operation times should be avoided as much as possible in order to reduce intra operative adverse events. PMID- 29264757 TI - The fourth space surgery: endoscopic subserosal dissection for upper gastrointestinal subepithelial tumors originating from the muscularis propria layer. AB - BACKGROUND AND AIMS: We developed a novel method of endoscopic subserosal dissection (ESSD) for removal of subepithelial tumors (SETs) originating from the muscularis propria (MP) layer in the upper gastrointestinal (GI) tract. The aim of this study was to evaluate the efficacy, safety, and clinical outcome of this method. METHODS: Eleven patients with upper GI SETs originating from the MP layer were treated by ESSD between October 2016 and March 2017. ESSD technique consists of six major procedures: (1) incising the mucosal and submucosal layer around the lesion and exposing MP layer; (2) continuous injection was performed while the injection needle slowly moved from the MP layer toward the subserosal layer; (3) incising MP layer; (4) subserosal injection was performed to further separate the serosa from the MP layer; (5) the mucosa, submucosa, and MP layer including SET were carefully dissected en bloc; and (6) closure of the gastric-wall defect with endoscopic techniques. Primary outcome including clinical procedural success and procedure-related adverse events were documented. RESULTS: ESSD was successfully performed in 11 patients. The complete resection rate was 100%, and the mean operation time was 51 (range 22-76) min. The mean resected lesion size was 27 (range 15-40) mm. Pathological diagnosis of these lesions included gastrointestinal stromal tumors (8/11), heterotopic pancreas (1/11), hamartoma (1/11), and leiomyoma (1/11). The small perforations occurred in two patients (4 * 4 and 5 * 5 mm, respectively) during the operation. All perforations and defects were closed successfully by endoscopic techniques. No GI bleeding, peritonitis, abdominal abscess, and other adverse events were observed. No lesion residual or recurrence was found during the follow-up period (mean 18 weeks; range 10-29 weeks). CONCLUSION: ESSD seems to be an efficacious, safe, and minimally invasive treatment for patients with upper GI SETs originating from the MP layer, making it possible to resect deep lesions, provide precise pathological diagnosis, and maintain the integrity of serosa. PMID- 29264758 TI - Ex vivo human bile duct radiofrequency ablation with a bipolar catheter. AB - BACKGROUND: Management of the primary and secondary tumors of the bile ducts still remains as a major clinical challenge. Radiofrequency (RF) ablation (RFA) of these tumors is feasible but the effect of RF energy on the human common bile duct (CBD) and surrounding tissues has not been investigated. This pilot study aimed to determine the relationship between RF energy and the depth of ablation in the normal human CBD. METHODS: The study was performed on fresh ex vivo human biliary-pancreatic tissue which had been resected for a pancreatic cyst or mass. The study was conducted within 15 min after resection. A bipolar Habib RFA catheter was placed into the middle of the intact CBD, and three different (5, 7, 10 W) power settings were applied over a 90-s period by an RF generator. Gross and histological examinations were performed. The depth of coagulation necrosis in CBD and the effect of RFA on CBD wall and surrounding pancreas tissue were determined by microscopic examination. RESULTS: The study included eight tissue samples. 5 W power was applied to three sites and RFA caused only focal epithelial necrosis limited to the CBD mucosa. 7 and 10 W were applied to five sites and coagulation necrosis occurred in all cases. Microscopically, necrosis was transmural, involved accessory bile duct glands, and extended to the surrounding pancreatic tissue in four of these cases. Macroscopically, RFA resulted in circumferential white-yellowish color change extending approximately 2 cm of the CBD. CONCLUSION: Bipolar RF energy application with 5 W resulted in limited ablation on CBD wall. However, 7 and 10 W generated tissue necrosis which extended through the CBD wall and into surrounding pancreas tissue. Endoscopic biliary RFA is an effective technique for local biliary tissue ablation but the use of high energy may injure surrounding tissue. PMID- 29264759 TI - Validation of ergonomic instructions in robot-assisted surgery simulator training. AB - BACKGROUND/AIM: Training in robot-assisted surgery focusses mainly on technical skills and instrument use. Training in optimal ergonomics during robotic surgery is often lacking, while improved ergonomics can be one of the key advantages of robot-assisted surgery. Therefore, the aim of this study was to assess whether a brief explanation on ergonomics of the console can improve body posture and performance. METHODS: A comparative study was performed with 26 surgical interns and residents using the da Vinci skills simulator (Intuitive Surgical, Sunnyvale, CA). The intervention group received a compact instruction on ergonomic settings and coaching on clutch usage, while the control group received standard instructions for usage of the system. Participants performed two sets of five exercises. Analysis was performed on ergonomic score (RULA) and performance scores provided by the simulator. Mental and physical load scores (NASA-TLX and LED score) were also registered. RESULTS: The intervention group performed better in the clutch-oriented exercises, displaying less unnecessary movement and smaller deviation from the neutral position of the hands. The intervention group also scored significantly better on the RULA ergonomic score in both the exercises. No differences in overall performance scores and subjective scores were detected. CONCLUSION: The benefits of a brief instruction on ergonomics for novices are clear in this study. A single session of coaching and instruction leads to better ergonomic scores. The control group showed often inadequate ergonomic scores. No significant differences were found regarding physical discomfort, mental task load and overall performance scores. PMID- 29264761 TI - Unsupervised Clustering of Immunohistochemical Markers to Define High-Risk Endometrial Cancer. AB - Considerable heterogeneity exists in outcomes of early endometrial cancer (EC) according to the type but also the histological grading. Our goal was to describe the immunohistochemical profiles of type I EC according to grades and type II EC, to identify groups of interacting proteins using principal component analysis (PCA) and unsupervised clustering. We studied 13 immunohistochemical markers (steroid receptors, pro/anti-apoptotic proteins, metalloproteinases (MMP) and tissue inhibitor of metalloproteinase (TIMP), and CD44 isoforms known for their role in endometrial pathology. Co-expressed proteins associated with the type, grade and outcome of EC were determined by PCA and unsupervised clustering. PCA identified three functional groups of proteins from 43 tissue samples (38 type I and 5 type II EC): the first was characterized by p53 expression; the second by MMPs, bcl-2, PR B and CD44v6; and the third by ER alpha, PR A, TIMP-2 and CD44v3. Unsupervised clustering found two main clusters of proteins, with both type I grade 3 and type II EC exhibiting the same cluster profile. PCA and unsupervised clustering of immunohistochemical markers in EC contribute to a better comprehension and classification of the disease. PMID- 29264760 TI - The factors influencing long-term outcomes of stenting for malignant colorectal obstruction in elderly group in community medicine. AB - PURPOSE: Malignant bowel obstruction is a complication of colorectal carcinoma or metastasis from other carcinoma, and it causes significant damage on the condition of elderly patients; however, the self-expandable metallic stents (SEMSs) have been effectively used either for palliation or for bridging to the surgical procedure for this condition. The aim of this study was to investigate the factors influencing long-term outcomes of old-aged patients with SEMS for large bowel obstruction to develop the strategy for those patients in the community medicine. METHODS: We performed a retrospective review of 42 patients with a median age of 83.0 years (range, 65-99 years), who underwent SEMS placement for malignant colorectal obstruction between 2006 and 2015 in our hospital. Univariate and multivariate logistic regressions were performed on data from the patients to assess the factors affecting 6-month survival without stent dysfunction. RESULTS: The study population comprised 24 females (57.1%) and 18 males (42.9%). Of these, 38 patients (90.5%) received SEMS as palliation, whereas 4 patients (9.5%) underwent subsequent surgery. SEMSs were successfully inserted in 97.6% of patients. The median duration of follow-up was 205.0 days (range, 20 1377 days). On multivariate analysis, shorter stents (< 10 cm) yielded better outcomes than longer stents (>= 10 cm) (P = 0.041), and the Cox proportional hazard model also indicated that shorter stents (P = 0.036) predicted longer event-free survival. CONCLUSIONS: Elderly patients with malignant bowel obstruction receiving shorter stents had longer event-free survival after stenting with better general condition. PMID- 29264762 TI - A pilot study to record visual evoked potentials during prone spine surgery using the SightSaverTM photic visual stimulator. AB - This is a pilot study to assess the clinical safety and efficacy of recording real-time flash visual evoked potentials (VEPs) using the SightSaver TM Visual Stimulator mask during prone spine surgery. A prospective, observational pilot study. Twenty patients presenting for spine surgery (microdiscectomy, 1-2 level lumbar fusion, or > 2 levels thoraco-lumbar fusion) were enrolled. The SightSaverTM Visual StimulatorTM was used to elicit VEPs throughout surgery. Somatosensory evoked potentials (SSEPs) were simultaneously recorded. All patients underwent general anesthesia with a combination of intravenous and inhaled agents. The presence, absence, and changes in VEP were qualitatively analyzed. Reproducible VEPs were elicited in 18/20 patients (36/40 eyes). VEPs were exquisitely sensitive to changes in anesthesia and decayed with rising MAC of isoflurane and/or N2O. Decrements in VEPs were observed without concomitant changes in SSEPs. The mask was simple to apply and use and was not associated with adverse effects. The SightSaverTM mask represents an emerging technology for monitoring developing visual insults during surgery. The definitive applications remain to be determined, but likely include use in select patients and/or surgeries. Here, we have validated the device as safe and effective, and show that VEPs can be recorded in real time under general anesthesia in the prone position. Future studies should be directed towards understanding the ideal anesthetic regimen to facilitate stable VEP recording during prone spine surgery. PMID- 29264764 TI - Evidence for the possible occurrence of Grave's disease in a blue-eyed black lemur (Eulemur flavifrons). AB - The blue-eyed black lemur (Eulemur flavifrons) is classified by the International Union for Conservation of Nature (IUCN) as critically endangered. A 23-year-old male housed at Mulhouse Zoo presented with lethargy, polyphagia, alopecia, and chronic weight loss. Clinical examination suggested an endocrine pathology such as hyperthyroidism. Secondary examinations included cervical ultrasound, thyroid biopsy, and scintigraphy. The latter revealed elevated thyroid activity. Blood analysis was performed to measure the level of anti-receptor thyroid-stimulating hormone antibodies, which allowed us to test the autoimmune hypothesis. The high level of antibodies together with levels of thyroid-stimulating hormone and the scintigraphy images led to the diagnosis of Grave's disease. Carbimazole treatment followed by thyroidectomy resulted in a quick weight gain and general improvement in health status. The following breeding season, the treated individual sired an offspring. To the authors' knowledge, this is the first report of likely Grave's disease in a non-human primate. PMID- 29264763 TI - Suppression of Disheveled-Axin Domain Containing 1 (DIXDC1) by MicroRNA-186 Inhibits the Proliferation and Invasion of Retinoblastoma Cells. AB - Recent evidence shows that Disheveled-Axin domain containing 1 (DIXDC1) is dysregulated in various cancers. However, the role of DIXDC1 in retinoblastoma (RB) remains unclear. In this study, we aimed to investigate the biological function of DIDXDC1 in RB and the way in which its expression is regulated by microRNAs (miRNAs). We found that DIXDC1 expression was significantly upregulated in RB cell lines. The silencing of DIXDC1 by small interfering RNA (siRNA) significantly inhibited the proliferation, invasion, and Wnt signaling in RB cell lines. Interestingly, DIXDC1 was identified as a target gene of miR-186. The expression of DIXDC1 was negatively regulated by miR-186, and DIXDC1 expression was inversely correlated with miR-186 expression in RB clinical specimens. Overexpression of miR-186 inhibited the proliferation, invasion, and Wnt signaling in RB cell lines. Moreover, overexpression of DIXDC1 markedly reversed the antitumor effect of miR-186. Overall, our results reveal that DIXDC1 functions as a potential oncogene in RB, and inhibiting DIXDC1 by miR-186 suppresses the proliferation and invasion of RB cell lines. Our study suggests that DIXDC1 and miR-186 may serve as novel therapeutic targets for the treatment of RB. PMID- 29264765 TI - The use of a mixed rubber landscape by tufted-ear marmosets. AB - With the loss and fragmentation of tropical forests, the survival of primates depends on their ability to adapt to human-introduced modifications in their habitat. Marmosets are known for their ecological and behavioral plasticity and have been registered in various agricultural landscapes. Our goal was to describe the ecology of tufted-ear marmosets (Callithrix sp.) in a rubber/forest landscape, monitoring their use of habitat and diet. We followed two groups using radio telemetry and visual observations for nine months at the Michelin plantation Ltd. in Bahia, Brazil. Both groups used mainly pioneer forest and rubber with pioneer vegetation more than expected according to availability, even though they explored all types of vegetation. Rubber monocultures act as corridors for marmoset locomotion among more suitable habitats. Feeding, gummivory and socialization were mainly performed in the pioneer forest (with or without rubber), in which most sleeping sites and food sources were found. Groups of marmosets can incorporate agroforest matrixes to their area of use and activity patterns. Maintenance of marmosets in fragmented landscapes might be favored by their diet flexibility, with the use of resources such as gum and fruit, including exotic plants. Although known for their ecological flexibility, marmosets do require certain resources to be present in native habitat to adapt to agricultural landscapes. Patches of forest within a rubber landscape and pioneer vegetation in the rubber inter-rows should be considered to maintain populations of Callithrix in rubber landscapes. PMID- 29264767 TI - Radiological Changes After Resection Rectopexy in Patients with Rectal Prolapse Influence on Clinical Symptoms and Quality of Life. AB - BACKGROUND: Resection rectopexy is performed to correct the anatomic defect associated with rectal prolapse. The aim of the study was to determine whether the change in the radiological prolapse grade has an influence on patients' symptoms and quality of life. METHODS: The study investigated 40 patients who underwent resection rectopexy for rectal prolapse. The following were determined before and after surgery: radiological prolapse grade, anorectal angle and pelvic floor position in defecography, clinical symptoms (Cleveland Clinic Incontinence and Constipation Scores, Kelly-Hohlschneider Score), quality of life. RESULTS: Defecography revealed postoperative improvement in the prolapse grade and pelvic floor position (p < 0.05). The clinical symptoms and quality of life improved in both, the total population (n = 40) and in patients with improved radiological prolapse grade (n = 30): all clinical scores (p < 0.05), SF-36 (vitality, social role, mental health p < 0.05), and Fecal Incontinence Quality of Life Scale (lifestyle, coping, embarrassment p < 0.05). Patients without improved radiological findings showed no change in their symptoms or quality of life. CONCLUSION: Our study demonstrates that the radiological prolapse grade is improved by resection rectopexy. Correction of the anatomic defect was associated with improvement in symptoms and quality of life. Defecography may therefore be useful in the postoperative assessment of persistent symptoms or reduced quality of life. PMID- 29264766 TI - Caspase-dependent apoptosis induced by two synthetic halogenated flavanones, 3',7 dichloroflavanone and 3',6-dichloroflavanone, on human breast and prostate cancer cells. AB - The destruction of cancer cells with chemotherapeutic agents is normally achieved through apoptosis. We previously introduced two synthetic halogenated flavanone derivatives, 3',7-dichloroflavanone (3'-7 DCF) and 3',6-dichloroflavanone (3'-6 DCF), as potential apoptosis-inducing agents. In the current study, we investigated the ability of these compounds in triggering intrinsic or/and extrinsic pathway of apoptosis in breast and prostate cancer cells. Also, the synergistic effect of 3'-7 DCF with TLR3 (Toll-like receptor 3) agonist in apoptosis induction was evaluated on PC3 and LNCaP human prostate cancer cells. The involved pathway of apoptosis in the treated cells was delineated by caspase 3 activity assay, PARP-1 (poly(ADP-ribose)polymerase-1) cleavage, and procaspase 9 cleavage as markers of the intrinsic pathway and procaspase-8 cleavage as the marker of the extrinsic pathway. With the exception of the normal cells, treatment of all cell lines with both 3'-7 DCF and 3'-6 DCF triggered the cleavage of procaspase-8 and procaspase-9. These results indicate that the intrinsic and the extrinsic pathways of apoptosis are the mechanisms of the toxicity of flavanones in these cancer cell lines. However, the cytoxicity of the compound 3'-7 DCF was not synergistic with TLR3 agonist. Interestingly, the activation of caspases-9 preceeded that of caspase-8 suggesting that the intrinsic pathway is the primary reason for apoptosis induction by the flavanones. PMID- 29264768 TI - Lymphadenectomy for Intrahepatic Cholangiocarcinoma: Has Nodal Evaluation Been Increasingly Adopted by Surgeons over Time?A National Database Analysis. AB - BACKGROUND: Surgical management of intrahepatic cholangiocarcinoma routinely includes resection of the hepatic parenchyma, yet the role of lymphadenectomy (LND) is more controversial. The objective of the current study was to define overall utilization, as well as temporal trends, in the utilization of LND among patients undergoing curative-intent hepatectomy for ICC using a nationwide database. MATERIALS AND METHODS: One thousand four hundred ninety-six patients who underwent curative-intent resection for ICC were identified using the SEER database from 2000 to 2013. The utilization of LND was assessed over time and by geographic region. LND utilization and the incidence of lymph node metastasis (LNM) were evaluated relative to AJCC T categories. RESULTS: At the time of surgery, slightly over one-half of patients (n = 784, 52.4%) had at least one LN evaluated. Specifically, 613 (41.0%) patients had 1-5 LNs evaluated, whereas 171 (11.4%) patients had >= 6 LNs evaluated. The proportion of patients who had at least one LN evaluated at the time of surgery did not change with time (2000 2004: 50.5% vs. 2005-2009: 52.0% vs. 2010-2013: 53.7%) (p = 0.636). In contrast, the proportion of patients who had >= 6 LNs examined did increase (2000-2004: 6.9% vs. 2005-2009: 10.6% vs. 2009-2013: 14.3%) (p = 0.003). The risk of LNM was higher among patients with advanced T category tumors (Referent T1; T2a: OR 4.2, 95% CI 2.0-8.8, p < 0.001; T2b: OR 2.4, 95% CI 1.1-4.9, p = 0.018; T3: OR 3.6, 95% CI 1.6-7.9, p = 0.001; T4: OR 2.2, 95% CI 1.0-4.9, p = 0.049). In addition, the portion of patients with LNM varied among the different T categories (T1, 23.2%, T2a, 55.3%, T2b, 42.0%, T3, 51.4%, and T4, 39.5%; p = 0.001). CONCLUSIONS: Utilization of LND in the surgical management of ICC across the USA remained relatively low and did not change over the last decade. Selective utilization of LND may be problematic as T-stage was not a reliable predictor of nodal status with almost a quarter of patients with early stage disease having LNM. PMID- 29264769 TI - A Novel Ultrasensitive In Situ Hybridization Approach to Detect Short Sequences and Splice Variants with Cellular Resolution. AB - Investigating the expression of RNAs that differ by short or single nucleotide sequences at a single-cell level in tissue has been limited by the sensitivity and specificity of in situ hybridization (ISH) techniques. Detection of short isoform-specific sequences requires RNA isolation for PCR analysis-an approach that loses the regional and cell-type-specific distribution of isoforms. Having the capability to distinguish the differential expression of RNA variants in tissue is critical because alterations in mRNA splicing and editing, as well as coding single nucleotide polymorphisms, have been associated with numerous cancers, neurological and psychiatric disorders. Here we introduce a novel highly sensitive single-probe colorimetric/fluorescent ISH approach that targets short exon/exon RNA splice junctions using single-pair oligonucleotide probes (~ 50 bp). We use this approach to investigate, with single-cell resolution, the expression of four transcripts encoding the neuregulin (NRG) receptor ErbB4 that differ by alternative splicing of exons encoding two juxtamembrane (JMa/JMb) and two cytoplasmic (CYT-1/CYT-2) domains that alter receptor stability and signaling modes, respectively. By comparing ErbB4 hybridization on sections from wild-type and ErbB4 knockout mice (missing exon 2), we initially demonstrate that single pair probes provide the sensitivity and specificity to visualize and quantify the differential expression of ErbB4 isoforms. Using cell-type-specific GFP reporter mice, we go on to demonstrate that expression of ErbB4 isoforms differs between neurons and oligodendrocytes, and that this differential expression of ErbB4 isoforms is evolutionarily conserved to humans. This single-pair probe ISH approach, known as BaseScope, could serve as an invaluable diagnostic tool to detect alternative spliced isoforms, and potentially single base polymorphisms, associated with disease. PMID- 29264771 TI - Face and content validity of XperienceTM Team Trainer: bed-side assistant training simulator for robotic surgery. AB - In robotic surgery, the coordination between the console-side surgeon and bed side assistant is crucial, more than in standard surgery or laparoscopy where the surgical team works in close contact. XperienceTM Team Trainer (XTT) is a new optional component for the dv-Trainer(r) platform and simulates the patient-side working environment. We present preliminary results for face, content, and the workload imposed regarding the use of the XTT virtual reality platform for the psychomotor and communication skills training of the bed-side assistant in robot assisted surgery. Participants were categorized into "Beginners" and "Experts". They tested a series of exercises (Pick & Place Laparoscopic Demo, Pick & Place 2 and Team Match Board 1) and completed face validity questionnaires. "Experts" assessed content validity on another questionnaire. All the participants completed a NASA Task Load Index questionnaire to assess the workload imposed by XTT. Twenty-one consenting participants were included (12 "Beginners" and 9 "Experts"). XTT was shown to possess face and content validity, as evidenced by the rankings given on the simulator's ease of use and realism parameters and on the simulator's usefulness for training. Eight out of nine "Experts" judged the visualization of metrics after the exercises useful. However, face validity has shown some weaknesses regarding interactions and instruments. Reasonable workload parameters were registered. XTT demonstrated excellent face and content validity with acceptable workload parameters. XTT could become a useful tool for robotic surgery team training. PMID- 29264770 TI - An Amino Acid Substitution Found in Animals with Low Susceptibility to Prion Diseases Confers a Protective Dominant-Negative Effect in Prion-Infected Transgenic Mice. AB - While prion diseases have been described in numerous species, some, including those of the Canidae family, appear to show resistance or reduced susceptibility. A better understanding of the factors underlying prion susceptibility is crucial for the development of effective treatment and control measures. We recently demonstrated resistance to prion infection in mice overexpressing a mutated prion protein (PrP) carrying a specific amino acid substitution characteristic of canids. Here, we show that coexpression of this mutated PrP and wild-type mouse PrP in transgenic mice inoculated with different mouse-adapted prion strains (22 L, ME7, RML, and 301C) significantly increases survival times (by 45 to 113%). These data indicate that this amino acid substitution confers a dominant-negative effect on PrP, attenuating the conversion of PrPC to PrPSc and delaying disease onset without altering the neuropathological properties of the prion strains. Taken together, these findings have important implications for the development of new treatment approaches for prion diseases based on dominant-negative proteins. PMID- 29264772 TI - Hydrogen-rich water increases postharvest quality by enhancing antioxidant capacity in Hypsizygus marmoreus. AB - In the present study, we aimed to assess the effect of hydrogen-rich water (HRW) on the physicochemical characteristics and antioxidant capacity of Hypsizygus marmoreus during 12 days of postharvest storage at 4 degrees C. Different concentrations of HRW (25, 50 and 100%) were tested, and our data showed that 25% HRW treatment had the most significant effect on preservation of nutrients in H. marmoreus compared with the control group. In addition, 25% HRW treatment significantly reduced the relative electrolyte leakage rate and malonaldehyde (MDA) content (P < 0.05) and increased anti-superoxide-radical (O2-) activity compared with the control group. The activities of antioxidants, superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR) were activated by 25% HRW treatment, and the expression levels of these genes were also induced. These results suggested that HRW treatment could delay rot incidence in mushrooms during storage by regulating antioxidant defense ability. This study supplies a new and simple method to maintain the quality and extend the shelf life of mushrooms. PMID- 29264773 TI - Biosynthesis and production of sabinene: current state and perspectives. AB - Sabinene is an important naturally occurring bicyclic monoterpene which can be used as flavorings, perfume additives, fine chemicals, and advanced biofuels. Up to now, this valuable terpene is commercially unavailable since there is no applicable manufacturing process. Microbial synthesis can be a promising route for sabinene production. In this review, we summarize knowledge about the metabolic pathway and key enzymes for sabinene biosynthesis. Recent advances that have been made in production of sabinene by microbial fermentation are highlighted. In these studies, researchers have identified the general synthetic pathway of sabinene from simple intermediate metabolites. Sabinene synthases of different origins were also cloned and characterized. Additionally, heterologous systems of the model microbes Escherichia coli and Saccharomyces cerevisiae were constructed to produce sabinene. This review also suggests new directions and attempts to gain some insights for achieving an industrial level production of sabinene. The combination of traditional molecular biology with new genome and proteome analysis tools will provide a better view of sabinene biosynthesis and a greater potential of microbial production. PMID- 29264774 TI - The use of marine-derived fungi for preparation of enantiomerically pure alcohols. AB - A highly enantioselective and minimally polluting approach to optically pure chiral alcohols is developed using cheap, readily available and sustainable marine-derived fungi as catalysts. An evaluation of the synthetic potential of 13 Chinese marine fungi was performed to screen for enantioselective reduction of 13 aromatic ketones from different compound classes as substrates. Good yields and excellent enantioselectivities were achieved with this method. In details, first the effects of several crucial variables on the bioreduction of aromatic ketones with whole cells of marine fungi were explored systematically. Next, we obtained insight into the substrate scope of the tested fungi under the optimized conditions, and selected reduction processes were performed at a commercial scale of up to 1000 mL to determine scalability, which led to excellent yields and enantioselectivities. Last, ketone reductases from two prioritized fungi exhibited good recyclability, with those of Rhodotorula mucilageinosa giving a > 95% yield with up to 99% ee during 3 cycles and those of Rhodotorula rubra giving a > 95% yield with up to 99% ee during 9 cycles. PMID- 29264775 TI - Heterologous production of long-chain rhamnolipids from Burkholderia glumae in Pseudomonas putida-a step forward to tailor-made rhamnolipids. AB - Rhamnolipids are biosurfactants consisting of rhamnose (Rha) molecules linked through a beta-glycosidic bond to 3-hydroxyfatty acids with various chain lengths, and they have an enormous potential for various industrial applications. The best known native rhamnolipid producer is the human pathogen Pseudomonas aeruginosa, which produces short-chain rhamnolipids mainly consisting of a Rha Rha-C10-C10 congener. Bacteria from the genus Burkholderia are also able to produce rhamnolipids, which are characterized by their long-chain 3-hydroxyfatty acids with a predominant Rha-Rha-C14-C14 congener. These long-chain rhamnolipids offer different physicochemical properties compared to their counterparts from P. aeruginosa making them very interesting to establish novel potential applications. However, widespread applications of rhamnolipids are still hampered by the pathogenicity of producer strains and-even more important-by the complexity of regulatory networks controlling rhamnolipid production, e.g., the so-called quorum sensing system. To overcome encountered challenges of the wild type, the responsible genes for rhamnolipid biosynthesis in Burkholderia glumae were heterologously expressed in the non-pathogenic Pseudomonas putida KT2440. Our results show that long-chain rhamnolipids from Burkholderia spec. can be produced in P. putida. Surprisingly, the heterologous expression of the genes rhlA and rhlB encoding an acyl- and a rhamnosyltransferase, respectively, resulted in the synthesis of two different mono-rhamnolipid species containing one or two 3-hydroxyfatty acid chains in equal amounts. Furthermore, mixed biosynthetic rhlAB operons with combined genes from different organisms were created to determine whether RhlA or RhlB is responsible to define the fatty acid chain lengths in rhamnolipids. PMID- 29264777 TI - "IDEAL", the operating microscope, and the parachute. PMID- 29264776 TI - Comparing and transforming PROMIS utility values to the EQ-5D. AB - PURPOSE: Summarizing patient-reported outcomes (PROs) on a quality-adjusted life year (QALY) scale is an essential component to any economic evaluation comparing alternative medical treatments. While multiple studies have compared PRO items and instruments based on their psychometric properties, no study has compared the preference-based summary of the EQ-5D-3L and Patient Reported Outcomes Measurement Information System (PROMIS-29) instruments. As part of this comparison, a major aim of this manuscript is to transform PROMIS-29 utility values to an EQ-5D-3L scale. METHODS: A nationally representative survey of 2623 US adults completed the 29-item PROMIS health profile instrument (PROMIS-29) and the 3-level version of the EQ-5D instrument (EQ-5D-3L). Their responses were summarized on a health utility scale using published estimates. Using regression analysis, PROMIS-29 and EQ-5D-3L utility weights were compared with each other as well as with self-reported general health. RESULTS: PROMIS-29 utility weights were much lower than the EQ-5D-3L weights. However, a correlation coefficient of 0.769 between the utility values of the two instruments suggests that the main discordance is simply a difference in scale between the measures. It is also possible to map PROMIS-29 utility weights onto an EQ-5D-3L scale. EQ-5D-3L losses equal .1784 * (PROMIS-29 Losses).7286. CONCLUSIONS: The published estimates of the PROMIS-29 produce lower utility values than many other health instruments. Mapping the PROMIS-29 estimates to an EQ-5D-3L scale alleviates this issue and allows for a more straightforward comparison between the PROMIS-29 and other common health instruments. PMID- 29264778 TI - The re-emergence of psychiatric neurosurgery: insights from a cross-national study of newspaper and magazine coverage. AB - BACKGROUND: Surgical approaches to treat psychiatric disorders have made a comeback. News media plays an essential role in exposing the public to trends in health care such as the re-emergence of therapeutic interventions in psychiatric neurosurgery that were set aside for decades, and in shaping attitudes and acceptance to them. METHOD: We conducted an analysis of media articles covering all types of psychiatric neurosurgery published in Canada, USA, Germany, and Spain between the years 1960 and 2015. We applied both quantitative and qualitative methods to elucidate patterns of reporting for conditions, themes and tone, across geographic regions, time, and for type of intervention. RESULTS: Coverage of psychiatric neurosurgery has surged since 2001 and is largely consistent across the countries examined. It focuses on depression and deep brain stimulation, and is explicit about historical context. The tone of coverage becomes more positive for Canada, USA and Spain over time; the tone of coverage from Germany remains cautious. Identity and privacy are among the few ethical and philosophical issues raised, notably in the German press. CONCLUSIONS: The focused and optimistic attention to contemporary psychiatric neurosurgery in the media, but inattention to ethical issues, places an extra burden on functional neurosurgeons, psychiatrists, and other frontline health professionals to attend to queries from patients and policy makers about the full range of relevant emergent and emerging interventions and the mental health issues to which they may beneficially apply. PMID- 29264779 TI - Mathematical model of perineural tumor spread: a pilot study. AB - BACKGROUND: Perineural spread (PNS) of pelvic cancer along the lumbosacral plexus is an emerging explanation for neoplastic lumbosacral plexopathy (nLSP) and an underestimated source of patient morbidity and mortality. Despite the increased incidence of PNS, these patients are often times a clinical conundrum-to diagnose and to treat. Building on previous results in modeling glioblastoma multiforme (GBM), we present a mathematical model for predicting the course and extent of the PNS of recurrent tumors. METHODS: We created three-dimensional models of perineurally spreading tumor along the lumbosacral plexus from consecutive magnetic resonance imaging scans of two patients (one each with prostate cancer and cervical cancer). We adapted and applied a previously reported mathematical model of GBM to progression of tumor growth along the nerves on an anatomical model obtained from a healthy subject. RESULTS: We were able to successfully model and visualize perineurally spreading pelvic cancer in two patients; average growth rates were 60.7 mm/year for subject 1 and 129 mm/year for subject 2. The model correlated well with extent of PNS on MRI scans at given time points. CONCLUSIONS: This is the first attempt to model perineural tumor spread and we believe that it provides a glimpse into the future of disease progression monitoring. Every tumor and every patient are different, and the possibility to report treatment response using a unified scale-as "days gained"-will be a necessity in the era of individualized medicine. We hope our work will serve as a springboard for future connections between mathematics and medicine. PMID- 29264780 TI - Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with Type 2 Diabetes Mellitus. AB - BACKGROUND: Roux-en-Y gastric bypass (LRYGB) has weight-independent effects on glycemia in obese type 2 diabetic patients, whereas sleeve gastrectomy (LSG) is less well characterized. This study aims to compare early weight-independent and later weight-dependent glycemic effects of LRYGB and LSG. METHODS: Eighteen LRYGB and 15 LSG patients were included in the study. Glucose, insulin, GLP-1, and GIP levels were monitored during a modified 30 g oral glucose tolerance test before surgery and 2 days, 3 weeks, and 12 months after surgery. Patients self-monitored glucose levels 2 weeks before and after surgery. RESULTS: Postoperative fasting blood glucose decreased similarly in both groups (LRYGB vs. SG; baseline-8.1 +/- 0.6 vs. 8.2 +/- 0.4 mmol/l, 2 days-7.8 +/- 0.5 vs. 7.4 +/- 0.3 mmol/l, 3 weeks 6.6 +/- 0.4 vs. 6.6 +/- 0.3 mmol/l, respectively, P < 0.01 vs. baseline for both groups; 12 months-6.6 +/- 0.4 vs. 5.9 +/- 0.4, respectively, P < 0.05 for LRYGB and P < 0.001 for LSG vs. baseline, P = ns between the groups at all times). LSG, but not LRYGB, showed increased peak insulin levels 2 days postoperatively (mean +/- SEM; LSG + 58 +/- 14%, P < 0.01; LRYGB - 8 +/- 17%, P = ns). GLP-1 levels increased similarly at 2 days, but were higher in LRYGB at 3 weeks (AUC; 7525 +/- 1258 vs. 4779 +/- 712 pmol * min, respectively, P < 0.05). GIP levels did not differ. Body mass index (BMI) decreased more after LRYGB than LSG (- 10.1 +/- 0.9 vs. - 7.9 +/- 0.5 kg/m2, respectively, P < 0.05). CONCLUSION: LRYGB and LSG show very similar effects on glycemic control, despite lower GLP-1 levels and inferior BMI decrease after LSG. PMID- 29264781 TI - Endoscopic Septotomy for the Treatment of Sleeve Gastrectomy Fistula: Timing and Indications. PMID- 29264782 TI - Differences in Body Composition in Patients with Obesity 1 Year After Roux-En-Y Gastric Bypass: Successful Vs. Unsuccessful Weight Loss. AB - AIM: The aim of this study is to compare the differences in body composition in patients with obesity with successful weight loss (SWL) and unsuccessful (USWL) 1 year after Roux-en-Y gastric bypass (RYGB). METHODS: We included 36 women and 22 men. After stratifying patients according with SWL (defined as >= 50% of excess weight loss), fat-free mass (FFM) and fat mass (FM) trajectories were analyzed in each group. RESULTS: The %FM in SWL women (78%) was lower than USWL (36 vs. 44, p < 0.001). The %FM in SWL men (77%) was lower than USWL (27 vs. 38, p < 0.05). A lower %FM before surgery increased the probability of success (p < 0.05). CONCLUSIONS: SWL patients have a lower %FM, and those with lower pre-surgical %FM are more likely to have SWL 1 year after RYGB. PMID- 29264785 TI - Happy Birthday, Journal of Endocrinological Investigation! PMID- 29264784 TI - Biodesulfurization of Thiophenic Compounds by a 2-Hydroxybiphenyl-Resistant Gordonia sp. HS126-4N Carrying dszABC Genes. AB - Microorganisms can metabolize or transform a range of known chemical compounds present in fossil fuels by naturally having highly specific metabolic activities. In this context, the microbial desulfurization of fuels is an attractive and alternative process to the conventional hydrodesulfurization (HDS) process, since the thiophenic sulfur containing compounds such as dibenzothiophene (DBT) and benzothiophene (BT) cannot be removed by HDS. A DBT desulfurizing mesophilic bacterium, identified on the basis of 16S rRNA gene sequence as Gordonia sp. HS126-4N (source: periphery soil of a coal heap) has been evaluated for its biodesulfurization traits and potential to desulfurize the thiophenic compounds. The HPLC and LC/MS analyses of the metabolites produced from DBT desulfurization and PCR-based nucleotide sequence confirmation of the key desulfurizing genes (dszA/dszB/dszC) proved that HS126-4N could convert DBT to 2-hydroxybiphenyl (2 HBP) via the 4S pathway. The isolate could convert 0.2 mM of DBT to 2-HBP within 48 h and was reasonably tolerant against the inhibitory effect of 2-HBP (retained 70% of growth at 0.5 mM 2-HBP). The isolated biocatalyst desulfurized/degraded 100% of 0.2 mM of 4-methyl DBT, 2,8-dimethyl DBT, BT and 3-methyl BT within 108 h. The capabilities to survive and desulfurize a broad range of thiophenic sulfur containing substrates as well as less inhibition by the 2-HBP suggest that HS126 4N could be a potential candidate for improved biodesulfurization/organic sulfur removal from fossil fuels. PMID- 29264786 TI - Periarticular multimodal drug injection is better than single anesthetic drug in controlling pain after total knee arthroplasty. AB - BACKGROUND: Postoperative pain is one of the issues that concern most patients after total knee arthroplasty (TKA). Periarticular multimodal drug injection and single anesthetic agent injection have been shown to effectively reduce postoperative pain. The purpose of this study was to compare the efficacy between multimodal drug injection and single anesthetic drug injection in controlling pain after TKA using a double-blinded randomized controlled trial. METHODS: Sixty four osteoarthritic patients who underwent primary TKA were randomized into two groups. The multimodal drug injection group (group M) received levobupivacaine 150 mg, ketorolac 30 mg and morphine 5 mg, while the single anesthetic drug injection group (group S) received only levobupivacaine 150 mg. The primary outcomes were pain level (VAS), quantity of opioid consumption (mg) and time to request the first dose of analgesic drug (min). RESULTS: Multimodal drug injection provided lower pain level in the first 4 h after surgery (VAS rest: 30 vs 46, p = 0.02; VAS motion: 45 vs 66, p = 0.03). They consumed less morphine mostly in the first 8 h after surgery (5 vs 12 mg, p < 0.0001) and had approximately 2 h longer time to request the first dose of analgesic drug (254 vs 148 min, p = 0.02). CONCLUSIONS: Multimodal drug injection decreases pain level, reduces morphine consumption in the early postoperative period and prolongs the analgesic effect compared to single anesthetic drug. One may consider using single anesthetic agent only in patients who have high risk of opioid or NSAIDs side effect. PMID- 29264788 TI - Utility of inverse probability weighting in molecular pathological epidemiology. AB - As one of causal inference methodologies, the inverse probability weighting (IPW) method has been utilized to address confounding and account for missing data when subjects with missing data cannot be included in a primary analysis. The transdisciplinary field of molecular pathological epidemiology (MPE) integrates molecular pathological and epidemiological methods, and takes advantages of improved understanding of pathogenesis to generate stronger biological evidence of causality and optimize strategies for precision medicine and prevention. Disease subtyping based on biomarker analysis of biospecimens is essential in MPE research. However, there are nearly always cases that lack subtype information due to the unavailability or insufficiency of biospecimens. To address this missing subtype data issue, we incorporated inverse probability weights into Cox proportional cause-specific hazards regression. The weight was inverse of the probability of biomarker data availability estimated based on a model for biomarker data availability status. The strategy was illustrated in two example studies; each assessed alcohol intake or family history of colorectal cancer in relation to the risk of developing colorectal carcinoma subtypes classified by tumor microsatellite instability (MSI) status, using a prospective cohort study, the Nurses' Health Study. Logistic regression was used to estimate the probability of MSI data availability for each cancer case with covariates of clinical features and family history of colorectal cancer. This application of IPW can reduce selection bias caused by nonrandom variation in biospecimen data availability. The integration of causal inference methods into the MPE approach will likely have substantial potentials to advance the field of epidemiology. PMID- 29264790 TI - Congestion game scheduling for virtual drug screening optimization. AB - In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screening hits in a short time. To this end, we propose a mathematical model of task scheduling for virtual drug screening in high-performance computational systems as a congestion game between computational nodes to find the equilibrium solutions for best balancing the number of interim hits with their chemical diversity. The model considers the heterogeneous environment with workload uncertainty, processing time uncertainty, and limited knowledge about the input dataset structure. We perform computational experiments and evaluate the performance of the developed approach considering organic molecules database GDB 9. The used set of molecules is rich enough to demonstrate the feasibility and practicability of proposed solutions. We compare the algorithm with two known heuristics used in practice and observe that game-based scheduling outperforms them by the hit discovery rate and chemical diversity at earlier steps. Based on these results, we use a social utility metric for assessing the efficiency of our equilibrium solutions and show that they reach greatest values. PMID- 29264789 TI - Weight change and 15 year mortality: results from the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) cohort study. AB - Studies have reported a higher mortality risk associated with weight loss, particularly in middle-aged and older adults, although some of these studies did find that gaining weight was also associated with an increased mortality risk. We examined changes in weight in relation to mortality in a prospective population based cohort study of men and women, resident in Norfolk, UK. Participants were assessed at baseline (1993-1997) and at a second examination (1998-2000), as part of the European Prospective Investigation into Cancer and Nutrition (EPIC Norfolk) study, and followed up to 2015 for mortality. Participants with a self reported history of cancer or cardiovascular disease, body mass index < 18.5 kg/m2 or missing data on adjustment variables, at either time-point were excluded, leaving 12,580 participants, aged 39-78 in 1993-1997, eligible for analyses. Cox proportional hazards models were used to determine Hazard Ratios (HRs) for all-cause (2603 deaths), cardiovascular (749 deaths), cancer (981 deaths), respiratory (226 deaths) and other causes of mortality (647 deaths) by categories of weight change. After multivariate adjustment, the HRs (95% CIs) for all-cause mortality for men and women who lost more than 5 kg were 1.85 (1.48 2.31) and 1.64 (1.31-2.05) respectively. Higher hazards were also found for specific causes of mortality and weight loss > 5 kg. Similar associations were observed after excluding deaths in the first 5 years of follow-up. Results for weight gain were inconclusive. We conclude that objectively measured weight loss, but not weight gain, was associated with subsequent higher mortality risk in this population-based study of middle-aged and elderly men and women. However, undiagnosed, pre-existing disease and the inability to account for weight cycling need to be remembered when interpreting these results. Unravelling the causal pathways underlying this association will require more detailed studies, including that of changes in body composition. PMID- 29264787 TI - Fetal Physiologically-Based Pharmacokinetic Models: Systems Information on Fetal Biometry and Gross Composition. AB - BACKGROUND: Postulating fetal exposure to xenobiotics has been based on animal studies; however, inter-species differences can make this problematic. Physiologically-based pharmacokinetic models may capture the rapid changes in anatomical, biochemical, and physiological parameters during fetal growth over the duration of pregnancy and help with interpreting laboratory animal data. However, these models require robust information on the longitudinal variations of system parameter values and their covariates. OBJECTIVE: The objective of this study was to present an extensive analysis and integration of the available biometric data required for creating a virtual human fetal population by means of equations that define the changes of each parameter with gestational age. METHODS: A comprehensive literature search was carried out on the parameters defining the growth of a fetus during in-utero life including weight, height, and body surface area in addition to other indices of fetal size, body fat, and water. Collated data were assessed and integrated through a meta-analysis to develop mathematical algorithms to describe growth with fetal age. RESULTS: Data for the meta-analysis were obtained from 97 publications, of these, 15 were related to fetal height or length, 32 to fetal weight, 4 to fetal body surface area, 8 to crown length, 5 to abdominal circumference, 12 to head circumference, 14 to body fat, and 12 to body water. Various mathematical algorithms were needed to describe parameter values from the time of conception to birth. CONCLUSION: The collated data presented in this article enabled the development of mathematical functions to describe fetal biometry and provide a potentially useful resource for building anthropometric features of fetal physiologically based pharmacokinetic models. PMID- 29264791 TI - Multifactorial mechanisms of the pathogenesis of methicillin-resistant Staphylococcus hominis isolated from bloodstream infections. AB - Staphylococcus hominis is a species of the coagulase-negative staphylococci. It has been designated as a potential pathogen but so far the pathogenic mechanisms of this bacterium have not been determined. We studied 30 clinical isolates of methicillin-resistant S. hominis, which were previously examined for biofilm forming properties. The results of this study revealed that all these S. hominis strains had the ability to adhere to HeLa cells. Over 40% of the S. hominis strains invaded epithelial cells. The invasion index ranged from 0 to 41.5%. All isolates exhibited the cytotoxic activity of extracellular factors, which caused the destruction of epithelial cells. More than 90% of these methicillin-resistant strains contained at least one aminoglycosides resistance gene. The ant(4')-I gene was found in 63% of the isolates, aac(6')/aph(2") in 20% and aph(3')-IIIa in 47%. Two strains were assigned to SCCmec type VIII and three to SCCmec type III. The remaining isolates (83%) harboured a non-typeable SCCmec type. The mec complex A was predominant in this species. The results indicate that the pathogenicity of S. hominis may be multifactorial, involving adhesion, invasion and the activity of extracellular toxins, which cause damage to the host epithelium. PMID- 29264792 TI - Epileptic seizure detection in EEG signal using machine learning techniques. AB - Epilepsy is a well-known nervous system disorder characterized by seizures. Electroencephalograms (EEGs), which capture brain neural activity, can detect epilepsy. Traditional methods for analyzing an EEG signal for epileptic seizure detection are time-consuming. Recently, several automated seizure detection frameworks using machine learning technique have been proposed to replace these traditional methods. The two basic steps involved in machine learning are feature extraction and classification. Feature extraction reduces the input pattern space by keeping informative features and the classifier assigns the appropriate class label. In this paper, we propose two effective approaches involving subpattern based PCA (SpPCA) and cross-subpattern correlation-based PCA (SubXPCA) with Support Vector Machine (SVM) for automated seizure detection in EEG signals. Feature extraction was performed using SpPCA and SubXPCA. Both techniques explore the subpattern correlation of EEG signals, which helps in decision-making process. SVM is used for classification of seizure and non-seizure EEG signals. The SVM was trained with radial basis kernel. All the experiments have been carried out on the benchmark epilepsy EEG dataset. The entire dataset consists of 500 EEG signals recorded under different scenarios. Seven different experimental cases for classification have been conducted. The classification accuracy was evaluated using tenfold cross validation. The classification results of the proposed approaches have been compared with the results of some of existing techniques proposed in the literature to establish the claim. PMID- 29264783 TI - Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment. AB - Drug-induced calculi represent 1-2% of all renal calculi. The drugs reported to produce calculi may be divided into two groups. The first one includes poorly soluble drugs with high urine excretion that favour crystallisation in the urine. Among them, drugs used for the treatment of patients with human immunodeficiency, namely atazanavir and other protease inhibitors, and sulphadiazine used for the treatment of cerebral toxoplasmosis, are the most frequent causes. Besides these drugs, about 20 other molecules may induce nephrolithiasis, such as ceftriaxone or ephedrine-containing preparations in subjects receiving high doses or long term treatment. Calculi analysis by physical methods including infrared spectroscopy or X-ray diffraction is needed to demonstrate the presence of the drug or its metabolites within the calculi. Some drugs may also provoke heavy intra-tubular crystal precipitation causing acute renal failure. Here, the identification of crystalluria or crystals within the kidney tissue in the case of renal biopsy is of major diagnostic value. The second group includes drugs that provoke the formation of urinary calculi as a consequence of their metabolic effects on urinary pH and/or the excretion of calcium, phosphate, oxalate, citrate, uric acid or other purines. Among such metabolically induced calculi are those formed in patients taking uncontrolled calcium/vitamin D supplements, or being treated with carbonic anhydrase inhibitors such as acetazolamide or topiramate. Here, diagnosis relies on a careful clinical inquiry to differentiate between common calculi and metabolically induced calculi, of which the incidence is probably underestimated. Specific patient-dependent risk factors also exist in relation to urine pH, volume of diuresis and other factors, thus providing a basis for preventive or curative measures against stone formation. PMID- 29264793 TI - Proportion of contextual effects in the treatment of fibromyalgia-a meta-analysis of randomised controlled trials. AB - The objective of this study is to examine the proportion of the total treatment effect that is attributable to contextual effects in randomised controlled trials (RCTs) of treatments for fibromyalgia. A systematic literature search was undertaken in Medline, Web of Science, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Allied and Complementary Medicine in September 2015. The proportion of contextual effect (PCE) was calculated by dividing the improvement in the placebo arm by the improvement in the treatment arm. The measure was log-transformed for each trial and the random effects model was used to pool data. The primary outcome was pain. Secondary outcomes were fibromyalgia impact questionnaire (FIQ) total and fatigue. Heterogeneity was quantified using I 2. Publication bias was assessed using a funnel plot and Egger's test. Subgroup analysis was undertaken to explore heterogeneity and potential determinants of the PCE. Fifty-one eligible trials (9599 participants) were identified. The PCE was 0.60 (95% CI 0.56 to 0.64) for pain, 0.57 (95% CI 0.53 to 0.61) for FIQ total, and 0.63 (95% CI 0.59 to 0.68) for fatigue. The I 2 was 99.4% for pain, 99.2% for FIQ total, and 97.6% for fatigue. More than half of the treatment effect in fibromyalgia RCTs results from non-specific contextual factors. This suggests that optimising contextual care may enhance treatment effects and improve outcomes. Reporting the total treatment effect and the proportion of contextual effect in trials may help to better translate research evidence into practice. PMID- 29264794 TI - High frequency of mutant thiopurine S-methyltransferase genotypes in Mexican patients with systemic lupus erythematosus and rheumatoid arthritis. AB - Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are treated with immunosuppressive purine analogs, 6-mercaptopurine/6-thioguanine/azathiopurine, which are inactivated by thiopurine S-methyltransferase (TPMT). Non-synonymous polymorphisms in TPMT are associated with increased risk of adverse effects in patients treated with thiopurines. This study aimed to determine the frequency of the most common mutant TPMT alleles in Mexican patients with SLE (a prototype autoimmune disease) and RA (one of the most common autoimmune diseases in Mexico). Five hundred fifty-three consecutive patients from Central Mexico with SLE (178) and RA (375) were included. Subjects were genotyped to identify TPMT*2 (rs1800462), TPMT*3A (rs1800460 and rs1142345), TPMT*3B (rs1800460), and TPMT*3C (rs1142345) mutant alleles. DNA samples were assayed with the 5' exonuclease technique and TaqMan probes. Mutant alleles were detected in 6.2 and 5.2% of SLE and RA cases, respectively. Of note, 12.4% of SLE cases and 10.1% of RA cases carried mutant genotypes. Among those, the null genotype (TPMT*2/*3A, 0.3%) and the TPMT*3B (0.5%) and TPMT*3C (1.0%) alleles were found in RA, but not SLE cases. Mexican SLE cases displayed the highest frequency of mutant TPMT genotypes worldwide. TPMT genotyping should be performed for Mexican patients with SLE and RA before prescribing purine analogs. PMID- 29264795 TI - Surfaceome Analysis Protocol for the Identification of Novel Bordetella pertussis Antigens. AB - The bacterial surfaceome, comprising outer membrane-sorted and/or associated (i.e., cell transporters), cell surface-exposed (i.e., adhesins) and extracellularly secreted proteins (i.e., toxins), has been characterized in bacterial pathogens, such as Bordetella pertussis (Bp) to provide information for use in development of diagnostic and prevention strategies. This protein subset has clinical significance, as these bacterial proteins are often associated with attachment to host cells, microbial pathogenesis and antibody-mediated immunity. Here we describe classical surface membrane protein enrichment techniques, followed by proteomic methodologies, such as gel-free protein separation and antibody-affinity capture technologies in combination with nano-liquid chromatography mass spectrometry, for the identification and characterization of Bp surfaceome proteins. PMID- 29264796 TI - "Shaving" Live Bacterial Cells with Proteases for Proteomic Analysis of Surface Proteins. AB - Surface proteins are essential molecules for the interplay between cells and the environment. They participate in many biological processes including transport, adhesion, cell-cell recognition, signaling, and other cell interactions. In pathogenic microorganisms, these molecules may act as virulence or cytotoxicity factors. Analyzing the set of surface proteins is critical to understand these processes and to identify possible targets that can be the starting point for other studies or discoveries (e.g., vaccines or diagnostics). Here I describe a proteomic procedure to identify in a fast and reliable way a set of surface exposed proteins in bacteria, the methodology of which can be adapted to other biological systems (unicellular fungi, parasites). The protocol presented here involves "shaving" the cells cultured in broth with proteases followed by liquid chromatography-tandem mass spectrometry (LC/MS/MS) and analysis of the generated peptides. This method overcomes some important limitations of the first generation, gel based proteomics techniques, and the "shaving" approach allows one to identify which domains from identified proteins are more accessible to proteases. These identified proteins have the highest potential to be recognized by antibodies, and thus permits the identification of potential epitopes or antigens. PMID- 29264797 TI - Methods for Mapping the Extracellular and Membrane Proteome in the Avian Embryo, and Identification of Putative Vascular Targets or Endothelial Genes. AB - We present a protocol for the specific labeling and isolation of proteins from the membrane surface of endothelial cells and the surrounding extracellular matrix of organs, experimental wounds and tumors using chicken embryos. Proteins are deglycosylated on streptavidin resin and purified after gentle elution and trypsin digestion. Peptides are analyzed by spectroscopy and reverse proteomic fingerprinting. The major advantages of this protocol include reductions in both the background and overrepresentation of single proteins that would otherwise mask less well-represented proteins in the mass spectroscopy analysis. We also present methods to identify putative vascular and endothelial cell targets from isolated chicken membranes and extracellular proteins. The use of human genome and transcriptome data facilitates this analysis. Human orthologs of isolated chicken proteins are identified using best hit BLAST searches against the Human Reference Sequence Database. The expression of Human orthologs is then assessed for endothelial and non-endothelial cell enrichment using second generation RNA seq sequenced libraries. Scanning of the published literature then provides a ranking score of those genes most likely involved in cancer or having a link to angiogenesis. PMID- 29264798 TI - Mass Spectrometry-Based Identification of Extracellular Domains of Cell Surface N Glycoproteins: Defining the Accessible Surfaceome for Immunophenotyping Stem Cells and Their Derivatives. AB - Human stem cells and their progeny are valuable for a variety of research applications and have the potential to revolutionize approaches to regenerative medicine. However, we currently have limited tools to permit live isolation of homogeneous populations of cells apt for mechanistic studies or cellular therapies. While these challenges can be overcome through the use of immunophenotyping based on accessible cell surface markers, the success of this process depends on the availability of reliable antibodies and well-characterized markers, which are lacking for most stem cell lineages. This chapter outlines an iterative process for the development of new cell surface marker barcodes for identifying and selecting stem cell derived progeny of specific cell types, subtypes, and maturation stages, where antibody-independent identification of cell surface proteins is achieved using a modern chemoproteomic approach to specifically identify N-glycoproteins localized to the cell surface. By taking advantage of a large repository of available cell surfaceome data, proteins that are unlikely to confer cell type specificity can be rapidly eliminated from consideration. Subsequently, targeted quantitation by mass spectrometry can be used to refine candidates of interest, and a bioinformatic visualization tool is key to mapping experimental data to candidate protein sequences for the purpose of epitope selection during the antibody development phase. Overall, the process of developing cell surface barcodes for immunophenotyping is iterative and can include multiple rounds of discovery, refinement, and validation depending on the phenotypic resolution required. PMID- 29264799 TI - Application of Higher Density Iron Oxide Nanoparticle Pellicles to Enrich the Plasma Membrane and Its Proteome from Cells in Suspension. AB - Enrichment of the plasma membrane represents one valuable method to characterize the surfaceome, along with other plasma membrane and structural proteins. Currently, the overlapping densities of many subcellular organelles hinder enrichment of the plasma membrane by centrifugation. However, external access to the plasma membrane of intact cells allows the attachment of a nanoparticle pellicle to enhance its density and facilitate enrichment. We describe the synthesis of iron oxide nanoparticles, attachment of the pellicle to suspended cells, and recovery of plasma membrane proteins for proteomic analysis. PMID- 29264800 TI - Proteomic Profiling of Secreted Proteins, Exosomes, and Microvesicles in Cell Culture Conditioned Media. AB - Secreted proteins are of tremendous biological interest since they can act as ligands for receptors to activate downstream signalling cascades or be used as biomarkers if altered abundance is correlated with a specific pathological state. Proteins can be secreted either as soluble molecules or as part of extracellular vesicles (i.e., exosomes or microvesicles). The complete proteomic profiling of secretomes requires analysis of secreted proteins and extracellular vesicles. Hence, the method described here enriches for microvesicles, exosomes, and secreted proteins from conditioned media using differential centrifugation. The three fractions are then analyzed by mass spectrometry-based proteomics for in depth characterization and comparison of the protein secretome of cell lines. PMID- 29264801 TI - Cloning, Expression, and Purification of the Glycosylated Transmembrane Protein, Cation-Dependent Mannose 6-Phosphate Receptor, from Sf9 Cells Using the Baculovirus System. AB - The cation-dependent mannose 6-phosphate receptor (CD-MPR) is a single-pass type I membrane protein. This protein functions to transport lysosomal enzymes displaying phosphomannosyl residues from the Golgi complex and the cell surface to the lysosome. This glycosylated protein contains three disulfide bridges in its 159-residue extracytoplasmic domain. One of the problems with studying eukaryotic membrane proteins is isolating sufficient quantities. Structural studies typically require several hundred milligrams of highly purified protein. Here we present a method to isolate milligram quantities of CD-MPR/Asn81 suitable for structural studies. PMID- 29264802 TI - Bispecific Antibody Armed T Cells to Target Cancer Cells. AB - The common strategy for making bispecific antibodies (BsAbs) involves combining the variable domains of the desired monoclonal antibodies (mAbs) into a single bispecific structure. Bispecific immunotherapeutics has generated many different formats of BsAbs including chemical heteroconjugation of two complete molecules or fragments of monoclonal antibodies, quadroma, F(ab)2, diabodies, tandem diabodies, and single-chain antibodies (scFv). This chapter describes the process of generating activated T cells and arming T cells with heteroconjugated BsAbs to target cancer cells. PMID- 29264803 TI - Immunophenotyping of Live Human Pluripotent Stem Cells by Flow Cytometry. AB - Human pluripotent stem cells (hPSCs) have great potential for use in regenerative medicine and cell replacement therapies; however, prior to clinical application, cultured cell populations need to be screened to ensure the quality of the culture, as well as the capacity of these pluripotent cells to differentiate into desired cell types. Flow cytometry, utilizing antibodies recognizing targets restricted to the hPSC surfaceome, offers an invaluable tool for high-throughput validation of hPSC lines. Here we describe the immunophenotyping of live human embryonic stem cell (hESC, H9) and human induced pluripotent stem cell (hiPSC, KB3) lines by flow cytometry using a panel of antibodies identified as either stem cell reference markers (CD90, EpCam) or reported as being prevalent or restricted (c-Kit, HPI-1, Integrin alpha6, Semaphorin-6A) to these cells. The protocols described here with hPSCs are also applicable to differentiated hPSC progeny and should be instrumental in the immunophenotyping and isolation of well defined homogeneous cell populations useful in regenerative medicine. PMID- 29264804 TI - Detecting Cell Surface Expression of the G Protein-Coupled Receptor CXCR4. AB - G protein-coupled receptors (GPCRs) are cell surface receptors that relay extracellular signals to the inside of the cells. C-X-C chemokine receptor 4 (CXCR4) is a GPCR that undergoes receptor internalization and recycling upon stimulation with its cognate ligand, C-X-C chemokine 12 (CXCL12). Using this receptor/ligand pair we describe the use of two techniques, enzyme-linked immunosorbent assay (ELISA) and flow cytometry, widely used to quantify GPCR internalization from the plasma membrane and its return to the cell surface by recycling. PMID- 29264805 TI - NaV Channels: Assaying Biosynthesis, Trafficking, Function. AB - Integral to the cell surface is channels, pumps, and exchanger proteins that facilitate the movement of ions across the membrane. Ion channels facilitate the passive movement of ions down an electrochemical gradient. Ion pumps actively use energy to actively translocate ions, often against concentration or voltage gradients, while ion exchangers utilize energy to couple the transport of different ion species such that one ion moves down its gradient and the released free energy is used to drive the movement of a different ion against its electrochemical gradient. Some ion pumps and exchangers may be electrogenic, i.e., the ion transport they support is not electrically neutral and generates a current. Functions of these pore-forming membrane proteins include the establishment of membrane potentials, gating of ions flows across the cell membrane to elicit action potentials and other electrical signals, as well as the regulation of cell volumes. The major forms of ion channels include voltage-, ligand-, and signal-gated channels. In this review, we describe mammalian voltage dependent Na (NaV) channels. PMID- 29264806 TI - High-Content Electrophysiological Analysis of Human Pluripotent Stem Cell-Derived Cardiomyocytes (hPSC-CMs). AB - Considerable interest has been raised to develop human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) as a model for drug discovery and cardiotoxicity screening. High-content electrophysiological analysis of currents generated by transmembrane cell surface ion channels has been pursued to complement such emerging applications. Here we describe practical procedures and considerations for accomplishing successful assays of hPSC-CMs using an automated planar patch-clamp system. PMID- 29264807 TI - Methods for Evaluation of Vascular Endothelial Cell Function with Transient Receptor Potential (TRP) Channel Drugs. AB - Vascular endothelial transient potential (TRP) channels, located mostly on the plasma membrane of cells, are critical in regulatory and pathophysiological circumstances. The objective of this chapter is to describe several well established approaches, ranging from function to molecular assays, to investigate the mechanistic role of TRP channels in vascular endothelial cells. We show experimental procedures and representative figures on the following methods: (1) Isolation and culture of vascular endothelial cells, (2) examination of electrophysiological activity of TRP channel by patch-clamping with whole-cell configuration and its function in vascular tone and blood flow by isometric tension and isobaric diameter measurements, and Laser Doppler flowmetry, (3) detection of TRP channel-mediated intracellular Ca2+ imaging by using fluorescent microscopy, and (4) determination of TRP channel interaction by coimmunoprecipitation, double immunofluorescence staining and Forster resonance energy transfer (FRET) detection. PMID- 29264808 TI - Methods to Study the Signal Transduction of the Surface Receptor Tyrosine Kinase TrkB in Neurons. AB - Receptor tyrosine kinases (RTK) belong to a major class of cell surface receptors that transduce extracellular signals to elicit diverse intracellular responses. Upon binding to specific ligand, the RTKs become dimerized and autophosphorylated at tyrosine residues. This creates binding sites to recruit specific signaling intermediates and hence trigger distinct signaling events. The cellular response to a given RTK may be modified through the regulation of membrane insertion and receptor internalization. Here we use Trk receptor and its ligand, the neurotrophin brain-derived neurotrophic factor (BDNF), as an example to illustrate the approaches (coimmunoprecipitation and biotinylation) to study the surface expression and signal transduction mediated by this class of RTK in the nervous system. PMID- 29264809 TI - Polarized Human Retinal Pigment Epithelium Exhibits Distinct Surface Proteome on Apical and Basal Plasma Membranes. AB - Surface proteins localized on the apical and basal plasma membranes are required for a cell to sense its environment and relay changes in ionic, cytokine, chemokine, and hormone levels to the inside of the cell. In a polarized cell, surface proteins are differentially localized on the apical or the basolateral sides of the cell. The retinal pigment epithelium (RPE) is an example of a polarized cell that performs a variety of functions that are dependent on its polarized state including trafficking of ions, fluid, and metabolites across the RPE monolayer. These functions are absolutely crucial for maintaining the health and integrity of adjacent photoreceptors, the photosensitive cells of the retina. Here we present a series of approaches to identify and validate the polarization state of cultured primary human RPE cells using immunostaining for RPE apical/basolateral markers, polarized cytokine secretion, electrophysiology, fluid transport, phagocytosis, and identification of plasma membrane proteins through cell surface capturing technology. These approaches are currently being used to validate the polarized state and the epithelial phenotype of human induced pluripotent stem (iPS) cell derived RPE cells. This work provides the basis for developing an autologous cell therapy for age-related macular degeneration using patient specific iPS cell derived RPE. PMID- 29264810 TI - Extracellular Matrix Molecule-Based Capture of Mesenchymal Stromal Cells Under Flow. AB - We present a method to capture mesenchymal stromal cells (MSCs) by adhesion to extracellular matrix (ECM) molecules under flow conditions. The technique simulates a physiological system and exploits the natural biological interactions of cells, through integrin receptors, with their ECM. The system offers an insight into how MSCs could be targeted/localized to the site of interest (graft) following intravenous injection. PMID- 29264811 TI - Generation of Induced Pluripotent Stem Cells from Patients with COL3A1 Mutations and Differentiation to Smooth Muscle Cells for ECM-Surfaceome Analyses. AB - Use of experimentally derived induced pluripotent stem cells (iPSCs) has led to the development of cell models for differentiation, drug testing and understanding disease pathogenesis. For these models to be informative, reprogrammed cell lines need to be adequately characterized and shown to preserve all of the critical characteristics of pluripotency and differentiation. Here, we report a detailed protocol for the generation of iPSCs from human fibroblasts containing mutations in COL3A1 using a Sendai virus mediated integration-free reprogramming approach. We describe how to characterize the putative iPSCs in vivo and in vitro to ensure potency and differentiation potential. As an example of how these mutations may affect cell surface and extracellular matrix (ECM) interactions, we provide protocols for the differentiation of these cells into smooth muscle cells to illustrate how different cell types may display cell autonomous differences in collagen receptors that may affect their phenotype. These cells, when applied to mechanical model systems (see Chapter 18 by Bose et al.) facilitate an assessment of stiffness and stress-strain relationships useful for understanding how extracellular matrix dysfunction and its interactions with surface proteins contribute to disease processes. PMID- 29264812 TI - Fabrication and Mechanical Properties Measurements of 3D Microtissues for the Study of Cell-Matrix Interactions. AB - Cell interactions with the extracellular matrix (ECM) are critical to cell and tissue functions involving adhesion, communication, and differentiation. Three dimensional (3D) in vitro culture systems are an important approach to mimic in vivo cell-matrix interactions for mechanobiology studies and tissue engineering applications. This chapter describes the use of engineered microtissues as 3D constructs in combination with a magnetic tissue gauge (MUTUG) system to analyze tissue mechanical properties. The MUTUG system is composed of poly(dimethylsiloxane) (PDMS) microwells with vertical pillars in the wells. Self assembled microtissues containing cells and ECM gel can form between the pillars, and generate mechanical forces that deform the pillars, which provides a readout of those forces. Herein, detailed procedures for microfabrication of the PDMS MUTUG system, seeding and growth of cells with ECM gels in the microwells, and measurements of the mechanical properties of the resulting microtissues via magnetic actuation of magnetic sphere-tagged MUTUGs are described. PMID- 29264813 TI - Discovery of Surface Target Proteins Linking Drugs, Molecular Markers, Gene Regulation, Protein Networks, and Disease by Using a Web-Based Platform Targets search. AB - Integration and analysis of high content omics data have been critical to the investigation of molecule interactions (e.g., DNA-protein, protein-protein, chemical-protein) in biological systems. Human proteomic strategies that provide enriched information on cell surface proteins can be utilized for repurposing of drug targets and discovery of disease biomarkers. Although several published resources have proved useful to the analysis of these interactions, our newly developed web-based platform Targets-search has the capability of integrating multiple types of omics data to unravel their association with diverse molecule interactions and disease. Here, we describe how to use Targets-search, for the integrated and systemic exploitation of surface proteins to identify potential drug targets, which can further be used to analyze gene regulation, protein networks, and possible biomarkers for diseases and cancers. To illustrate this process, we have taken data from Ewing's sarcoma to identify surface proteins differentially expressed in Ewing's sarcoma cells. These surface proteins were then analyzed to determine which ones were known drug targets. The information suggested putative targets for drug repurposing and subsequent analyses illustrated their regulation by the transcription factor EWSR1. PMID- 29264814 TI - Both psychological factors and physical performance are associated with fall related concerns. AB - BACKGROUND: Fall-related concern strongly correlates to activity avoidance in older people. In this complex phenomenon, different terminology and instruments are often used interchangeably. Three main concepts make up fall-related concerns: fear of falling, consequence concern, and falls self-efficacy. It is suggested that fall-related concerns are mediated by psychological and physical factors. AIMS: Our aims were to describe the prevalence of fall-related concerns and find explanatory factors for its most studied concept-falls self-efficacy-in an older population. METHODS: We executed a cross-sectional study on a random sample of 153 community-dwelling older people (70 years or older). We used validated and reliable instruments as well as structured interviews to gather data on the three concepts of fall-related concerns and possible mediating factors. We then calculated descriptive statistics on prevalence and regression models for the total group, and men and women, separately. RESULTS: 70% of the total sample (80% of women and 53% of men) reported at least one of the three concepts of fall-related concern. For the total sample, fear of falling, morale, and physical performance were associated factors with falls self-efficacy. For women, the number of prescription medications was added. For men, physical performance and concerns for injury were associated. CONCLUSION: Fall-related concern is prevalent in large proportions with higher prevalence for women than for men. Important factors are fear of falling, morale, and physical performance. Gender differences in the emergence and variance of fall-related concern and the relation between physical performance and fall-related concern should be targeted in future research endeavors. PMID- 29264815 TI - Overlap Between the General Factor of Personality and Trait Emotional Intelligence: A Genetic Correlation Study. AB - A previous meta-analysis (Van der Linden et al., Psychol Bull 143:36-52, 2017) showed that the General Factor of Personality (GFP) overlaps with ability as well as trait emotional intelligence (EI). The correlation between trait EI and the GFP was so high (rho = 0.88) in that meta-analysis that these two may be considered virtually identical constructs. The present study builds on these findings by examining whether the strong phenotypic correlation between the GFP and trait EI has a genetic component. In a sample of monozygotic and dizygotic twins, the heritability estimates for the GFP and trait EI were 53 and 45%, respectively. Moreover, there was a strong genetic correlation of r = .90 between the GFP and trait EI. Additional analyses suggested that a substantial proportion of the genetic correlations reflects non-additive genetic effects (e.g., dominance and epistasis). These findings are discussed in light of evolutionary accounts of the GFP. PMID- 29264816 TI - Mercury bioaccumulation in arthropods from typical community habitats in a zinc smelting area. AB - This study assessed the enrichment of mercury in the food web from the different community habitats in a zinc-smelting area of China. We used a nitrogen stable isotope technique to analyze trophic level relationships among arthropods and found that the first trophic level consisted of plants in the different community habitats, the second trophic level consisted of herbivores such as locusts and grasshoppers (primary consumers), and the third trophic level included spiders and mantes (secondary consumers). Mercury enrichment in the primary consumers was not evident, but enrichment in arthropods of the third trophic level was significant. The average of enrichment coefficients in spiders and mantes was greater than 1. The delta15N values indicated that mercury concentrations accumulated from primary producers to top carnivorous arthropods increased. In this zinc-smelting area, the biological amplification of mercury in the food web is significant. It is reasonable to assume that humans, located at the top of the food chain, are exposed to biomagnified levels of mercury. PMID- 29264817 TI - Compositional data analysis and geochemical modeling of CO2-water-rock interactions in three provinces of Korea. AB - The CO2-rich spring water (CSW) occurring naturally in three provinces, Kangwon (KW), Chungbuk (CB), and Gyeongbuk (GB) of South Korea was classified based on its hydrochemical properties using compositional data analysis. Additionally, the geochemical evolution pathways of various CSW were simulated via equilibrium phase modeling (EPM) incorporated in the PHREEQC code. Most of the CSW in the study areas grouped into the Ca-HCO3 water type, but some samples from the KW area were classified as Na-HCO3 water. Interaction with anorthite is likely to be more important than interaction with carbonate minerals for the hydrochemical properties of the CSW in the three areas, indicating that the CSW originated from interactions among magmatic CO2, deep groundwater, and bedrock-forming minerals. Based on the simulation results of PHREEQC EPM, the formation temperatures of the CSW within each area were estimated as 77.8 and 150 degrees C for the Ca-HCO3 and Na-HCO3 types of CSW, respectively, in the KW area; 138.9 degrees C for the CB CSW; and 93.0 degrees C for the GB CSW. Additionally, the mixing ratios between simulated carbonate water and shallow groundwater were adjusted to 1:9 9:1 for the CSW of the GB area and the Ca-HCO3-type CSW of the KW area, indicating that these CSWs were more affected by carbonate water than by shallow groundwater. On the other hand, mixing ratios of 1:9-5:5 and 1:9-3:7 were found for the Na-HCO3-type CSW of the KW area and for the CSW of the CB area, respectively, suggesting a relatively small contribution of carbonate water to these CSWs. This study proposes a systematic, but relatively simple, methodology to simulate the formation of carbonate water in deep environments and the geochemical evolution of CSW. Moreover, the proposed methodology could be applied to predict the behavior of CO2 after its geological storage and to estimate the stability and security of geologically stored CO2. PMID- 29264819 TI - Rapid diagnosis of tuberculosis in dromedary camel (Camelus dromedarius) using lateral flow assay-based kit. AB - Accurate early antemortem diagnosis of tuberculosis in dromedary camels is difficult due to the lack of reliable diagnostic test. The present study aimed to evaluate a lateral flow assay-based kit (rapid assay kit) in tuberculosis diagnosis that employs immuno-chromatographic detection of antibodies in serum, plasma, or whole blood. In a dromedary camel herd comprising 337 animals located at Bikaner, Rajasthan, India, 50 adult weak camels (11 males and 39 females) were tested by applying a single intradermal tuberculin test (SIDT) and rapid assay kit. A total of 14 animals (2 males, 12 females) were found positive in rapid assay. In SIDT, four animals revealed a positive reaction in the neck region and seven animals in the tail base. Another male animal was found SIDT positive but negative in rapid assay; it died after 12 months. Nine rapid assay positive animals died asymptomatically in 1- to 11-month period revealing postmortem tuberculosis lesions that were confirmed by Ziehl-Neelsen staining and histopathology. No tuberculous lesion was evident in the animal found positive in SIDT alone. Results of the present study indicated that serological tests like rapid assay kit can serve as a reliable test for antemortem diagnosis of tuberculosis in dromedary camel. PMID- 29264818 TI - Effects of phosphorus sources on volatile organic compound emissions from Microcystis flos-aquae and their toxic effects on Chlamydomonas reinhardtii. AB - There is diverse phosphorus (P) in eutrophicated waters, but it is considered as a crucial nutrient for cyanobacteria growth due to its easy precipitation as insoluble salts. To uncover the effects of complex P nutrients on the emission of volatile organic compounds (VOCs) from cyanobacteria and their toxic effects on other algae, the VOCs from Microcystis flos-aquae supplied with different types and amount of P nutrients were analyzed, and the effects of VOCs and their two main compounds on Chlamydomonas reinhardtii growth were investigated. When M. flos-aquae cells were supplied with K2HPO4, sodium pyrophosphate and sodium hexametaphosphate as the sole P source, 27, 23 and 29 compounds were found, respectively, including furans, sulfocompounds, terpenoids, benzenes, aldehydes, hydrocarbons and esters. With K2HPO4 as the sole P source, the VOC emission increased with reducing P amount, and the maximum emission was found under Non-P condition. In the treatments of M. flos-aquae VOCs under Non-P condition and two main terpenoids (eucalyptol and limonene) in the VOCs, remarkable decreases were found in C. reinhardtii cell growth, photosynthetic pigment content and photosynthetic abilities. Therefore, we deduce that multiple P nutrients in eutrophicated waters induce different VOC emissions from cyanobacteria, and P amount reduction caused by natural precipitation and algal massive growth results in more VOC emissions. These VOCs play toxic roles in cyanobacteria becoming dominant species, and eucalyptol and limonene are two toxic agents. PMID- 29264820 TI - Transrectal ultrasound evaluation in tropical dairy goats: an indispensable tool for the diagnosis of reproductive disorders. AB - In Brazil, great milk productivity was achieved after the implementation of a genetic improvement program. However, reproductive efficiency is still far from optimal, possibly due to the high number of undiagnosed disorders that may affect fertility. The aim of this study was to evaluate occurrences of the main reproductive disorders in dairy goats in southeastern Brazil. Data were collected between January 2015 and May 2017 from 23 commercial herds of different breeds, with goats ranging from 8 months to 12 years of age. Transrectal ultrasound exams were performed in 2680 goats. A total of 14.8% of the does showed a disorder in the reproductive tract: hydrometra (10.0%), ovarian follicular cysts (2.3%), gestational loss (1.5%), and hydrosalpinx (1.1%). This was the first study evaluating reproductive disorders in live animals that used a high number of Brazilian dairy goats. Considering that all these diseases affect fertility to different degrees, the performance of transrectal ultrasonography exams twice a year is strongly suggested, in order to guide precocious treatment or discard the animal as soon as possible, thus reducing economic losses in dairy goat farming. PMID- 29264821 TI - Description of risk factors associated with the detection of BVDV antibodies in Brazilian pig herds. AB - Bovine viral diarrhea virus (BVDV) infects ruminants as primary hosts. However, other animals like pigs are susceptible. This study was conducted to investigate seroprevalence and risk factors associated with the detection of BVDV antibodies in pig herds. A total of 1.705 serum samples of 33 finisher herds, from seven Brazilian states, were collected in slaughterhouses. The samples were tested by virus neutralization (VN) test. In total, 5.35% (91/1.705) were positive and 64% (21/33) of the herds had positive animals. A significant association with "trucks are not cleaned and disinfected" and "visitors do not respect 72-h interval between visits to farms" (P < 0.05) was found in association with detection of BVDV-2 antibodies. This study suggests that important biosecurity gaps are present in Brazilian pig farms, as the presence of BVDV antibodies in pigs suggests (direct or indirect) contact with population(s) of ruminant species. Closing biosecurity gaps prevents spread of BVDV and other pathogens such as foot and-mouth disease virus (FMDV) between pig and ruminant farms. This data should be taken in account by CSF surveillance programs, once cross-reaction in serologic tests between classical swine fever virus (CSFV) and BVDV antibodies has been shown to occur. PMID- 29264823 TI - Serum Concentration of Macro-, Micro-, and Trace Elements in Silver Fox (Vulpes vulpes) and Their Interrelationships with Morphometric, Densitometric, and Mechanical Properties of the Mandible. AB - The optimal content of macro-, micro-, and trace elements in tissues ensures proper systemic growth and development and optimal health status in animals and humans. However, very little is known on the elemental content in the plasma compartment in Silver fox. The aim of this study was to determine the content of selected elements in serum obtained from 8-month-old female (N = 8) and male (N = 7) silver foxes. Moreover, relationships of the evaluated elements with the morphological, densitometric, and mechanical parameters of the mandible were determined. Serum content of 12 different elements was measured using inductively coupled plasma-atomic emission spectrometry. The morphometric and densitometric properties of the mandible were determined using quantitative computed tomography method, while mechanical endurance was tested using a three-point bending test. Serum concentration of calcium was significantly higher by 20% in male foxes (P = 0.01), while manganese concentration was significantly lower in males by over 17% (P = 0.03). Positive correlations of serum concentration of calcium, phosphorus, and magnesium with the morphological traits of the mandible such as weight, length, and bone volume were stated (P < 0.05). In the group of elements playing regulatory functions, the positive relationships between serum concentrations of selenium, chromium, manganese, copper, and cobalt were found (P < 0.05). The elaborated experimental model may serve for further studies on foxes, especially focused on nutritional factors affecting elemental homeostasis, whole-body metabolism, and systemic growth and development. Daily diet formulation and precise delivery for farm foxes, together with relatively large animal population maintained at the same environmental conditions, regularly subjected to slaughter procedure, enable economical experimentation with various dietary and pharmacological manipulations. PMID- 29264824 TI - The Antagonistic Effect of Selenium on Lead-Induced Immune Dysfunction via Recovery of Cytokine and Heat Shock Protein Expression in Chicken Neutrophils. AB - Lead (Pb) is a ubiquitous and toxic heavy metal and it can damage the immune system in humans and animals. Many researchers have reported that Selenium (Se) could possess various pharmacological effects in mammals. However, few studies have been carried out to investigate the protective role of Se in birds, especially in chickens. In this study, we investigated the protective effects of Se against Pb-induced inflammatory responses and the expression of heat shock proteins (HSPs) in peripheral blood neutrophils. One hundred eighty Hy-Line brown chickens were randomly divided into the control group (Con group), Se supplementation group (+Se group), Pb supplementation group (+Pb group), and the Se and Pb compound group (Se+Pb group). On the 90th day of the experiment, the peripheral blood was collected to extract neutrophils, and then, the levels of HSPs and cytokines were examined. The results showed that, after Pb treatment, the levels of IL-(1beta, 1R, 4, 8, 10, and 12beta), TGF-beta4, and HSP (27, 40, 60, 70, and 90) mRNA were significantly increased and levels of IL-2 and IFN gamma mRNA were decreased compared with those in the control group. Compared with the control group, the protein levels of HSP60 and HSP70 were also increased in the Pb treatment group. Co-administration of Se (1 mg/kg/day) and Pb resulted in a reversal of the Pb-induced cytokine changes in neutrophils accompanied by a significant decrease in HSPs. Our study demonstrated that Pb could decrease the immune function via changing the expression of cytokines and HSPs in chicken neutrophils, but Se could relieve the toxic effect induced by Pb. PMID- 29264826 TI - Non-Typhoidal Salmonella Bacteremia. PMID- 29264825 TI - Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation. AB - Oxidative stress and neuroinflammation contribute significantly to the development and progression of diabetic retinopathy. Fenofibrate has received great attention as it benefits diabetic patients by reducing retinal laser requirement. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a master regulator of anti-oxidative defense. Activation of nucleotide binding domain, leucine-rich repeat-containing receptor (NLR), pyrin domain-containing 3 (NLRP3) inflammasome plays a pivotal role in neuroinflammation. The purpose of this study is to determine whether fenofibrate protects retinas from oxidative damage and neuroinflammation via modulating the Nrf2 pathway and blocking NLRP3 inflammasome activation during diabetes. Diabetes is induced by intraperitoneal injection of streptozotocin in mice. Fenofibrate was given to mice in rodent chow. Upregulation of Nrf2 and NLRP3 inflammasome, enhanced ROS formation, and increased leukostasis and vascular leakage were observed in diabetic mouse retinas. Notably, Nrf2 and Caspase-1 were mainly colocalized with glutamine synthetase, one of the Muller cell markers. Fenofibrate further increased the expression of Nrf2 and its target gene NQO-1 and HO-1 and reduced ROS formation in diabetic retinas. In addition, retinal expression of NLRP3, Caspase-1 p20, IL 1beta p17, and ICAM-1 were dramatically increased in vehicle-treated diabetic mice, which were abolished by fenofibrate intervention. Moreover, fenofibrate treatment also attenuated diabetes-induced retinal leukostasis and vascular leakage in mice. Taken together, fenofibrate attenuates oxidative stress and neuroinflammation in diabetic retinas, which is at least partially through modulating Nrf2 expression and NLRP3 inflammasome activation. PMID- 29264822 TI - In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention. AB - According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2 mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general. PMID- 29264828 TI - Bordetella and Bronchiolitis: A Chance Association or More Than That? PMID- 29264830 TI - The Leiden Manifesto and Research Assessment. AB - Evaluation of scientific research is essential to judge the impact of research and the author. In this regard, a newly devised Leiden Manifesto describes 10 principles for guiding research evaluation. The principles need to be analyzed critically and adapted as a preferred method of research evaluation. PMID- 29264827 TI - Oxidative Stress, Antioxidant Status and Neurodevelopmental Outcome in Neonates Born to Pre-eclamptic Mothers. AB - OBJECTIVES: To measure the oxidative stress and antioxidant status in preeclamptic mother-newborn dyads and correlate them with neurodevelopmental outcome at one year of corrected age. METHODS: This cohort study conducted in a tertiary care teaching hospital, south India included 71 preeclamptic and 72 normal mother-newborn dyads. Biochemical parameters including total antioxidant status (TAS), protein carbonyls and malondialdehyde levels (MDA) were measured in both maternal and cord blood. Infants in both the groups were followed up to one year of corrected age and neurodevelopmental assessment was done using Developmental Assessment Scale for Indian Infants (DASII). Correlation and multivariate regression analysis was done to evaluate the oxidative stress markers in relation to neurodevelopmental outcome. RESULTS: All oxidative stress markers were higher in maternal and cord blood of pre-ecclampsia group compared to the normal group. Maternal Total antioxidant status (M-TAS) was lower in pre eclampsia group than normal group. More neonates in the pre-ecclampsia group were preterm and intrauterine growth restriction (IUGR) and had higher incidence of morbidities like respiratory distress syndrome (RDS) and early onset sepsis (EOS). Infants in the preeclampsia group had lower motor age, motor score and motor developmental quotient (MoDQ). On multivariate logistic regression analyses, lower M-TAS levels were strongly associated with poor neuro-motor outcomes at 1 y of corrected age. Maternal TAS with a cut-off value of 0.965 mmol/L had a sensitivity of 77.8% and specificity of 55.3% in predicting MoDQ <70 at one year corrected age in infants born to preeclamptic mothers. CONCLUSIONS: Oxidative stress is increased in preeclamptic mother-newborn dyads. Low maternal TAS levels are associated with poor neuro-motor outcomes. Maternal TAS in preeclampsia is useful in predicting poor motor development at one year corrected age. PMID- 29264831 TI - CYP Suppression in Human Hepatocytes by Monomethyl Auristatin E, the Payload in Brentuximab Vedotin (Adcetris(r)), is Associated with Microtubule Disruption. AB - BACKGROUND AND OBJECTIVES: Monomethyl auristatin E (MMAE), the toxin linked to CD30-specific monoclonal antibody of Adcetris(r) (brentuximab vedotin), is a potent anti-microtubule agent. Brentuximab vedotin has been approved for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Cytochrome P450 (CYP) induction assessment of MMAE was conducted in human hepatocytes to assess DDI potentials and its translation to clinic. METHODS: MMAE was incubated at 1-1000 nM with cultured primary human hepatocytes for 72 h, and CYP1A2, CYP2B6, and CYP3A4 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction and CYP-specific probe substrate by liquid chromatography coupled with mass spectrometry, along with microtubule disruption by immunofluorescence staining using anti-beta tubulin antibody and imaging. RESULTS: MMAE up to 10 nM had no significant effect on CYP1A2, CYP2B6, and CYP3A4 mRNA expression and activity, whereas at higher concentrations of 100- and 1000-nM MMAE, the CYP mRNA expression and activity were diminished substantially. Further investigation showed that the degree of CYP suppression was paralleled by that of microtubule disruption by MMAE, as measured by increase in the number of beta-tubulin-positive aggregates. At the clinical dose, the concentration of MMAE was 7 nM which did not show any significant CYP suppression or microtubule disruption in hepatocytes. CONCLUSIONS: MMAE was not a CYP inducer in human hepatocytes. However, it caused a concentration-dependent CYP mRNA suppression and activity. The CYP suppression was associated with microtubule disruption, supporting the reports that intact microtubule architecture is required for CYP regulations. The absence of CYP suppression and microtubule disruption in vitro at the clinical plasma concentrations of MMAE (< 10 nM) explains the lack of pharmacokinetic drug interaction between brentuximab vedotin and midazolam, a sensitive CYP3A substrate, reported in patients. PMID- 29264832 TI - Ethnic and Racial Disparities in HPV Vaccination Attitudes. AB - There are substantial racial and ethnic disparities in the vaccination rate for human papillomavirus (HPV), which helps protect against cervical cancer. Using data from the 2007 Health Information National Trends Survey, we explore differences between Whites, Blacks, Hispanics, and Asians in attitudes toward vaccinating adolescent girls for HPV. We use logistic regression models to explore whether racial/ethnic differences in attitudes toward HPV vaccinations are explained by HPV knowledge, demographic and socioeconomic status, and/or general distrust of the healthcare system. We include interactions to explore whether the effects of HPV knowledge and doctor distrust vary by racial/ethnic group. We find that greater HPV knowledge increases general willingness to vaccinate for all groups except Blacks. Our findings point to a need for additional research and design of culturally appropriate interventions that address barriers to vaccination. PMID- 29264833 TI - A case of superficial esophageal cancer invading into the submucosa following ductal involvement with microinvasion. AB - Microinvasion is considered one reason for diagnostic discrepancies among preoperative diagnostic modalities. Stromal invasion developing from ductal involvement is often observed in such cases. Herein, we present a case of superficial esophageal cancer with ductal involvement and microinvasion around it. The steep concavity with dot-like microvessels in the center of a protruded lesion was presented by endoscopic observation, which was lead to the diagnostic discrepancy between magnified endoscopy and endoscopic ultrasound. Histological findings showed the tumor invaded into a submucosal layer with ductal involvement and microinvasion around it, and confirmed that this endoscopic finding was caused be tumor ductal involvement. When encountering endoscopic findings similar to those shown in this case, preparation of serial sections, enabling the confirmation of ductal involvement and further invasion into the stroma, will lead to the accurate diagnosis. PMID- 29264834 TI - Temporal stability of MGMT promoter methylation in glioblastoma patients undergoing STUPP protocol. AB - Epigenetic silencing of O-6-methylguanine-DNA methyltransferase (MGMT) promoter via methylation in a glioblastoma (GBM), has been correlated with a more favourable response to alkylating chemotherapeutic agents such as temozolomide. The use of global methylation surrogates such as Long Interspersed Nucleotide Element 1 (LINE1) may also be valuable in order to fully understand these highly heterogeneous tumours. In this study, we analysed both original and recurrent GBMs in 22 patients (i.e. 44 tumours), for both MGMT and LINE1 methylation status. In the 22 patients: 14 (63.6%) displayed MGMT methylation stability in the recurrent GBM versus 8 (36.4%), with instability of methylation status. No significant differences in overall and progression free survival was evident between these two groups. LINE1 methylation status remained stable for 12 (54.5%) of recurrent GBM patients versus 9 (41%) of the patients with instability in LINE1 methylation status (p = 0.02), resulting in an increase in overall survival of the stable LINE1 group (p = 0.04). The results obtained demonstrated major epigenetic instability of GBMs treated with temozolomide as part of the STUPP protocol. GBMs appear to undergo selective evolution post-treatment, and have the ability to recur with a newly reprogrammed epigenetic status. Selective targeting of the altered epigenomes in recurrent GBMs may facilitate the future development of both prognostic biomarkers and enhanced therapeutic strategies. PMID- 29264835 TI - Clinical and molecular characteristics of gliosarcoma and modern prognostic significance relative to conventional glioblastoma. AB - Gliosarcoma is a rare histopathologic variant of glioblastoma traditionally associated with a poor prognosis. While gliosarcoma may represent a distinct clinical entity given its unique histologic composition and molecular features, its relative prognostic significance remains uncertain. While treatment of gliosarcoma generally encompasses the same standardized approach used in glioblastoma, supporting evidence is limited given its rarity. Here, we characterized 32 cases of gliosarcoma and retrospectively evaluated survival relative to 451 glioblastoma patients diagnosed during the same era within the same institution. Overall, we identified 22 primary gliosarcomas, representing 4.7% of WHO Grade IV primary glioblastomas, and 10 secondary gliosarcomas. With median age of 62, patients were predominately Caucasian (87.5%) and male (65.6%). Tumors with available molecular profiling were primarily MGMT-unmethylated (87.5%), IDH-1-preserved (100%) and EGFR wild-type (100%). Interestingly, while no significant median survival difference between primary gliosarcoma and glioblastoma was observed across the entire cohort (11.0 vs. 14.8 months, p = 0.269), median survival was worse for gliosarcoma specifically among patients who received modern temozolomide-based (TMZ) chemoradiotherapy (11.0 vs. 17.3 months, p = 0.006). Matched-pair analysis also trended toward worse median survival among gliosarcomas (11.0 vs. 19.6 months, log-rank p = 0.177, Breslow p = 0.010). While adjuvant radiotherapy (HR 0.206, p = 0.035) and TMZ-based chemotherapy (HR 0.531, p = 0.000) appeared protective, gliosarcoma emerged as a significantly poor prognostic factor on multivariate analysis (HR 3.27, p = 0.012). Collectively, our results suggest that gliosarcoma may still portend worse prognosis even with modern trimodality therapy. PMID- 29264836 TI - Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas. AB - Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m2 po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2-67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group. PMID- 29264837 TI - Characteristics of temporal resolution in 16- and 64-row computed tomography scanners. AB - This study aimed to analyze the temporal sensitivity profile (TSP) shapes and temporal resolutions of computed tomography (CT) and investigate the effect of a combination of a given rotation time and helical pitch on the TSP and image quality. The study was performed on 16- and 64-row CT scanners, and the TSP and temporal resolution were measured using the impulse method. A shorter gantry rotation time and larger helical pitch improved the temporal resolution of both CT scanners. Although the measured TSP shapes were dependent on the helical pitch, the maximum helical pitch did not improve the temporal resolution of either CT scanner. Different combinations of gantry rotation time and helical pitch yielded different TSP shapes such as the triangle, trapezoid, and rectangle, despite the use of equivalent scan speeds. We suggest that the different combinations of rotation time and helical pitch can greatly affect the TSP shapes. PMID- 29264838 TI - Intentional Drug Overdose Involving Pregabalin and Gabapentin: Findings from the National Self-Harm Registry Ireland, 2007-2015. AB - INTRODUCTION: Intentional drug overdose (IDO) is a significant public health problem. Concerns about the misuse of gabapentinoids, i.e. pregabalin and gabapentin, including their consumption in IDO have grown in recent years. This paper examines the trends in the prevalence of gabapentinoids taken in IDO, the profile of individuals taking them, and associated overdose characteristics. METHODS: Presentations to emergency departments involving IDO, recorded by the National Self-Harm Registry Ireland between 1 January 2007 and 31 December 2015 were examined. Data items included patient demographics, drug names, total tablet quantity consumed and alcohol involvement. RESULTS: Gabapentinoids were involved in 2115 (2.9%) of the 72,391 IDOs recorded. Presentations involving a gabapentinoid increased proportionally from 0.5% in 2007 to 5.5% in 2015. The majority of IDOs involving a gabapentinoid were made by females (59.9%), with over one-third (37.2%) involving alcohol. Compared with IDOs involving other drugs, presentations with a gabapentinoid were made by persons who were older (median 37 vs. 32 years) and involved a significantly greater median quantity of tablets (30 vs. 21, p <= 0.001), with over one-quarter (27.4%) of these involving the ingestion of 50 tablets or more. Admission to hospital was significantly more common following IDOs with a gabapentinoid compared with those without (49.4% vs. 41.4%, p <= 0.001). CONCLUSIONS: This study identified the increasing use of gabapentinoids in IDO, describing the profile and overdose characteristics of presentations. It is important for clinicians to exercise vigilance while prescribing gabapentinoids, including being aware of other medications that their patients may have access to. Our findings support the need for routine monitoring for signs of misuse among those prescribed gabapentinoids. PMID- 29264839 TI - Efficacy of topical administration of Radix Euphorbiae Ebracteolatae on multiple plantar warts: A parallel randomized trial. AB - OBJECTIVE: To investigate the clinical efficacy of Radix Euphorbiae Ebracteolatae in treating multiple plantar warts. METHODS: Twenty-eight patients with multiple plantar warts on both left and right feet were recruited. Warts on the left feet (treatment group) of all patients were externally treated with moderate ethanol extract of Radix Euphorbiae Ebracteolatae which was made of 30 g Radix Euphorbiae Ebracteolatae putting into 100 mL of medical ethanol (75%). For the control group, moderate dose of 0.1% vitamin A acid ointment was externally applied onto the right-foot warts. The topical application of each treatment was conducted 3 times a day for both groups. After 4 and 8 weeks, the efficacy and side effects including skin erythema and blister were evaluated and observed. RESULTS: Compared with the pre-treatment, warts size of the control group was reduced after 8-week treatment (P<0.05). After 4 and 8 weeks, the average wart size in the treatment group was both significantly reduced respectively (P<0.01). There were significant differences in warts size and total effective rate between the two groups after 4-week treatment respectively (P<0.05 or P<0.01). More significant differences in wart size and total effective rate were observed after 8-week treatment (P<0.05 or P<0.01). The percentage reduction in wart size was significantly different between the two groups after 4 and 8-week treatment (P<0.01). CONCLUSION: Radix Euphorbiae Ebracteolatae was significantly superior to vitamin A acid ointment in treating multiple plantar warts. PMID- 29264840 TI - Experimental research of hypotensive and hypolipidemic effects with Modified Sanhuang Xiexin Decoction (). AB - OBJECTIVE: To investigate the hypotensive and hypolipidemic effects of Modified Sanhuang Xiexin Decoction (, HVC1), a herbal prescription for the vascular diseases in Chinese medicine and evaluate the acute and subchronic oral toxicities. METHODS: Fifty-six spontaneous hypertensive rats (SHRs) were used to investigate the hypotensive and hypolipidemic effect of HVC1. Rats in the normal group (n=8) were fed with normal diet. The rats in the other groups (n=48) were fed with high fat and cholesterol diet for inducing hyperlipidemia models. Forty eight rats were randomly divided into 6 groups [model, positive control (amlodipine, simvastain), 50, 250, and 1,000 mg/(kg*d) HVC1 groups] with 8 animals in each group. Normal and model groups were treated with distilled water [1 mL/(kg*d)], the positive control group was treated with amlodipine [5 mg/(kg*d)] or simvastatin [10 mg/(kg*d)], and the HVC1 groups were treated with HVC1 [50, 250, or 1,000 mg/(kg*d)] for 8 weeks, respectively. Blood pressure (BP) of the rats was measured using a non-invasive tail cuff system. On the last day of the experiment, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were measured. To investigate the safety of HVC1, acute and subchronic toxicity studies were conducted on Sprague-Dawley rats. In toxicity studies, the body weight, food and water consumption of rats were measured and clinical signs observation, ophthalmologic examinations, urinalysis, hematological analysis, and serum biochemical analysis were performed. RESULTS: A dose of 50 and 250 mg/(kg*d) HVC1 lowered systolic and diastolic BP (P<0.05). HVC1 at 1,000 mg/(kg*d) decreased TC, LDL-C and TG levels, respectively (P<0.01 or P<0.05) and 250 mg/(kg*d) HVC1 decreased TG levels on hyperlipidemic SHRs (P<0.05). In the acute toxicity study, oral administration of HVC1 did not show any toxicity effect, and the median lethal dose value of HVC1 was greater than 5,000 mg/kg. In the subchronic toxicity study, oral administration of HVC1 for 4 weeks also did not show any toxicity effect, and the no-observedadverse-effect level of HVC1 was established as 2,000 mg/(kg*d). CONCLUSION: These results could be used as preclinical data for clinical trials that develop HVC1 as a herbal medicine for treating or preventing hypertension and hyperlipidemia. PMID- 29264841 TI - Protective Effect of Norcantharidin on Collagen-Induced Arthritis Rats. AB - OBJECTIVE: To observe the effect of norcantharidin (NCTD) on collagen-induced arthritis (CIA) rats. METHODS: Sixty Sprague-Dawley(SD) rats were randomly divided into 6 groups (n=10): normal group, CIA model group(model group), NCTD low-dose group [1.35 mg/(kg*d)], NCTD middle-dose group [2.7 mg/(kg*d)], NCTD high-dose group [5.4 mg/(kg*d)] and methotrexate (MTX) group [1.8 mg/(kg/w)]. Anesthetized rats were sacrificed by luxation of cervical vertebra after 4 weeks of administration. The arthritis scores were evaluated twice a week. The pathological changes in the ankle joints of rats were observed by hematoxylin eosin (H&E) staining. The serum levels of interleukin (IL) 1beta, IL-6, tumor necrosis factor (TNF)-alpha, vascular endothelial growth factor (VEGF), IL-17 and transform growth factor (TGF) beta were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expression of retinoid-related orphan nuclear receptorgammat (RORgammat) and forkhead box P3 (Foxp3) in peripheral blood lymphocytes were confirmed by real-time polymerase chain reaction. RESULTS: MTX and high-dose NCTD not only decreased the arthritis scores but also alleviated the pathological changes in CIA rats' ankle joints compared with the model group (P<0.05 or P<0.01). All doses of NCTD significantly inhibited the serum levels of IL-6, IL-17 and TNF-alpha in CIA rats (P<0.05). Only middle- and high-dose of NCTD prominently decreased serum IL-1beta and TGF-beta levels of CIA rats (P<0.05). However, NCTD has no effect on vascular endothelial growth factor (VEGF) level in CIA rats. The Foxp3 mRNA expression in all NCTD groups were increased significantly than in the model group (P<0.05). The mRNA expression of RORgammat in NCTD high-dose group was decreased apparently in comparison with the model group (P<0.05). CONCLUSIONS: NCTD showed therapeutic effect on CIA rats by inhibition of cytokines and regulation of Th17/Treg cells. PMID- 29264842 TI - Suppression of Oxidative Stress of Modified Gongjin-Dan (WSY-1075) in Detrusor Underactivity Rat Model Bladder Outlet Induced by Obstruction. AB - OBJECTIVE: To investigate the anti-oxidative stress and preventive effect of modified Gongjin-dan (WSY-1075) in a detrusor underactivity rat model. METHODS: Rats were randomly allocated to three groups: shamoperated (control), bladder outlet obstruction-induced detrusor underactivity (BOO-DU), and BOO-DU with WSY 1075 (WSY) groups. WSY-1075 was orally administrated to rats 200 mg daily for 2 weeks prior to the operation and 4 weeks after the operation. Bladder outlet obstruction was surgically induced in rats by ligation around the urethra avoiding total obstruction. Cystometrography was conducted on rats in each group for examination of bladders. RESULTS: Compared with the control group, bladder outlet obstruction led to a significant increase in oxidative stress with consequent changes to molecular composition, and decrease in maximal detrusor pressure (P<0.05). WSY-1075 treatment significantly suppressed oxidative stress and prevented degenerative and dysfunctional changes in bladder, as compared with BOO-DU group (P<0.05). CONCLUSION: WSY-1075 had beneficial effect on prevention of BOO-DU. PMID- 29264843 TI - Elevated Lipoprotein (a) and Risk of Poor Functional Outcome in Chinese Patients with Ischemic Stroke and Type 2 Diabetes. AB - The aim of this study was to evaluate the short-term prognostic value of early measurement of serum lipoprotein (a) [Lp(a)] levels in Chinese patients with type 2 diabetes (T2D) and acute ischemic stroke (AIS). The study population comprised 232 consecutive patients with an AIS diagnosis complicated with T2D. Functional outcome was obtained on month 3 according to the modified Rankin Scale (mRS). Unfavorable functional outcome was defined as a mRS score of 3 to 6 points. The prognostic value of Lp(a) at admission to predict the unfavorable functional outcome 3 months after stroke onset was compared with the National Institutes of Health Stroke Scale score and other known outcome predictors. The Lp(a) levels in those patients were obtained with a median value of 16.8 mg/dl (IQR, 9.5-34.4 mg/dl). At 3-month follow-up, an unfavorable functional outcome was found in 86 patients (37.1%). In multivariate models comparing the second (Q2), third, and fourth quartiles against the first quartile of Lp(a), concentrations of Lp(a) in Q2, Q3, and Q4 were associated with unfavorable outcome, and increased risk of unfavorable outcome by 42, 131, and 211%. Interestingly, an elevated Lp(a, > 30 mg/dl) was also associated with unfavorable outcome, and with adjusted OR of 2.25 (95% CI 1.39-3.68). The AUC was significantly increased by adding Lp(a) to established risk factors (difference, 0.041 [95% CI, 0.034-0.053]; P = 0.02). The addition of Lp(a) to established risk factors significantly improved net reclassification improvement and integrated discrimination improvement. Higher Lp(a) levels at admission were associated with increased risk of unfavorable functional outcome and might be useful in identifying stroke patients with T2D at risk for unfavorable functional outcome for early prevention strategies. PMID- 29264844 TI - Transitioning Back to Maleness. AB - Thirty-one years after living full time as a woman, a 53-year-old skilled machinist returned to have therapy with me, a psychiatrist, because of a decision to return to living as a man. As our work together continued, I suggested to this would-be published novelist that others might benefit from his experience. This led to his posting an extensive account of his life in September 2016 on Gender Trender. Now living in good mental and physical health as a male, he has given me permission to discuss his initial presentation, my understanding of his motivations, and to reflect on the broader questions that his life rises for the field of transgenderism. This report describes regret, defenses against regret, and a dramatic 3-day catharsis followed by the patient's first loving relationship. He now ironically reflects that he escaped from the sensed inauthenticity of his youthful maleness only to create a felt inauthentic feminine social psychological state. The professional literature about the long term outcome of the transgendered who do not have surgery is largely nonexistent in English. Anecdotal accounts, however, are readily accessible on the Internet. PMID- 29264845 TI - Latency-Based and Psychophysiological Measures of Sexual Interest Show Convergent and Concurrent Validity. AB - Latency-based measures of sexual interest require additional evidence of validity, as do newer pupil dilation approaches. A total of 102 community men completed six latency-based measures of sexual interest. Pupillary responses were recorded during three of these tasks and in an additional task where no participant response was required. For adult stimuli, there was a high degree of intercorrelation between measures, suggesting that tasks may be measuring the same underlying construct (convergent validity). In addition to being correlated with one another, measures also predicted participants' self-reported sexual interest, demonstrating concurrent validity (i.e., the ability of a task to predict a more validated, simultaneously recorded, measure). Latency-based and pupillometric approaches also showed preliminary evidence of concurrent validity in predicting both self-reported interest in child molestation and viewing pornographic material containing children. Taken together, the study findings build on the evidence base for the validity of latency-based and pupillometric measures of sexual interest. PMID- 29264846 TI - Phenolic compounds from the leaves of Breynia officinalis and their tyrosinase and melanogenesis inhibitory activities. AB - From the EtOAc-soluble fraction of a MeOH extract of the leaves of Breynia officinalis, five new compounds (1-5) along with 11 known compounds (6-16) were isolated. The structures of the new compounds were elucidated by spectroscopic methods and compounds 1-3 were found to be acylated hydroquinone apiofuranosylglucopyranosides, while compound 4 was an acylated hydroquinone glucopyranoside. Compound 5 was shown to be butyl p-coumarate and this seems to be its first isolation from a natural source. The tyrosinase inhibitory activity of all of the isolated compounds was assayed, and the activity was significant in p-coumarate derivatives. The most active compound, compound 3, also inhibited melanogenesis in an in vivo whole animal model, zebrafish. PMID- 29264847 TI - The SNARC effect is not a unitary phenomenon. AB - Models of the spatial-numerical association of response codes (SNARC) effect faster responses to small numbers using left effectors, and the converse for large numbers-diverge substantially in localizing the root cause of this effect along the numbers' processing chain. One class of models ascribes the cause of the SNARC effect to the inherently spatial nature of the semantic representation of numerical magnitude. A different class of models ascribes the effect's cause to the processing dynamics taking place during response selection. To disentangle these opposing views, we devised a paradigm combining magnitude comparison and stimulus-response switching in order to monitor modulations of the SNARC effect while concurrently tapping both semantic and response-related processing stages. We observed that the SNARC effect varied nonlinearly as a function of both manipulated factors, a result that can hardly be reconciled with a unitary cause of the SNARC effect. PMID- 29264848 TI - Passengers waste production during flights. AB - We assume that during flights the amount of waste that is produced is limited. However, daily, approximately 8000 commercial airplanes fly above Europe's airspace while at the same time, more than 17,000 commercial flights exist in the entire world. Using primary data from airlines, which use the Larnaca's International Airport (LIA) in Cyprus, we have tried to understand why wastes are produced during a typical flight such as food waste, paper, and plastics, as well as how passengers affect the production of those wastes. The compositional analysis took place on 27 flights of 4 different airlines which used LIA as final destination. The evaluation indicated that the passenger's habits and ethics, and the policy of each airline produced different kinds of waste during the flights and especially food waste (FW). Furthermore, it was observed that the only waste management strategy that exists in place in the airport is the collection and the transportation of all those wastes from aircrafts and from the airport in the central unit for further treatment. Hence, this research indicated extremely difficulties to implement any specific waste minimization, or prevention practice or other sorting methods during the flights due to the limited time of the most flights (less than 3 h), the limited available space within the aircrafts, and the strictly safety roles that exist during the flights. PMID- 29264849 TI - Silver@ graphene oxide nanocomposite: synthesize and application in removal of imidacloprid from contaminated waters. AB - Silver@graphene oxide nanocomposite was synthesized through an efficient approach, characterized by FTIR, EDX, and TEM instruments and then was used as adsorbent for imidacloprid removal from water in batch procedure. Effective variants such as contact time, pH, adsorbent dosage, and initial concentration of imidacloprid on procedure by two methods, one at a time and experimental design methods, were studied. Results in optimum conditions based on one at a time experiments is removal of 63% of the pesticide from 50 mL water containing 10 mg/L of imidacloprid by 0.03 g of the adsorbent at pH = 6.6 after 60 min while, experimental design method predict similarity results, 66% uptake of the poison by 0.06 g of the adsorbent in pH = 8. Kinetics and isotherm for adsorption processes follows Freundlich and pseudo-second-order models. Results confirm that Ag@graphene oxide nanocomposite can be applicable for removal of imidacloprid from real polluted water. PMID- 29264850 TI - Risk assessment of groundwater environmental contamination: a case study of a karst site for the construction of a fossil power plant. AB - This paper presents a demonstration of an integrated risk assessment and site investigation for groundwater contamination through a case study, in which the geologic and hydrogeological feature of the site and the blueprint of the fossil power plant (FPP) were closely analyzed. Predictions for groundwater contamination in case of accidents were performed by groundwater modeling system (GMS) and modular three-dimensional multispecies transport model (MT3DMS). Results indicate that the studied site area presents a semi-isolated hydrogeological unit with multiplicity in stratum lithology, the main aquifers at the site are consisted of the filled karst development layer with a thickness between 6.0 and 40.0 m. The poor permeability of the vadose zone at the FPP significantly restricted the infiltration of contaminants through the vadose zone to the subsurface. The limited influence of rarely isotropic porous karstified carbonate rocks on the groundwater flow system premised the simulate scenarios of plume migration. Analysis of the present groundwater chemistry manifested that that the groundwater at the site and the local area are of the HCO3-Ca, HCO3, and SO4-Ca types. A few of the water samples were contaminated by coliform bacteria and ammonia nitrogen as a result of the local cultivation. Prediction results indicate that the impact of normal construction and operation processes on the groundwater environment is negligible. However, groundwater may be partly contaminated within a certain period in the area of leakage from the diesel tanks, the industrial wastewater pool, and the cooling tower water tank in case of accidents. On a positive note, none of the plumes would reach the local sensitive areas for groundwater using. Finally, an anti-seepage scheme and a monitoring program are proposed to safeguard the groundwater protection. The integrated method of the site investigation and risk assessment used in this case study can facilitate the protection of groundwater for the construction of large scale industrial project. PMID- 29264851 TI - Surface restructuring of red mud to produce FeO x (OH) y sites and mesopores for the efficient complexation/adsorption of beta-lactam antibiotics. AB - In this work, iron oxide in the red mud (RM) waste was restructured to produce mesopores with surface [FeO x (OH) y ] sites for the efficient complexation/adsorption of beta-lactam antibiotics. Red mud composed mainly by hematite was restructured by an acid/base process followed by a thermal treatment at 150-450 degrees C (MRM150, MRM200, MRM300, and MRM450) and fully characterized by Mossbauer, XRD, FTIR, BET, SEM, CHN, and thermogravimetric analyses. The characterization data showed a highly dispersed Fe3+ oxyhydroxy phase, which was thermally dehydrated to a mesoporous alpha-Fe2O3 with surface areas in the range of 141-206 m2 g-1. These materials showed high efficiencies (21-29 mg g-1) for the adsorption of beta-lactam antibiotics, amoxicillin, cephalexin, and ceftriaxone, and the data was better fitted by the Langmuir model isotherm (R 2 = 0.9993) with monolayer adsorption capacity of ca. 39 mg g-1 for amoxicillin. Experiments such as competitive adsorption in the presence of phosphate and H2O2 decomposition suggested that the beta-lactamic antibiotics might be interacting with surface [FeO x (OH) y ] species by a complexation process. Moreover, the OH/Fe ratio, BET surface area and porosity indicated that this complexation is occurring especially on [FeO x (OH) y ]surf sites contained in the mesopore space. PMID- 29264852 TI - Photocatalytic degradation of the herbicide chloridazon on mesoporous titania/zirconia nanopowders. AB - Advanced oxidation processes using semiconducting photocatalysts for the degradation of organic pollutants are a promising approach for the remediation of pesticide-contaminated wastewater. High photodegradation efficiency and stability of the photocatalyst are of key importance for practical application of the semiconductor. In this study, mesoporous TiO2/ZrO2 nanopowders were synthesized via two techniques; evaporation-induced self-assembly (EISA) and sol-gel using triblock copolymers Pluronic P123 and F127. The photodegradation activities of the composites were determined by employing the herbicide chloridazon as a model compound. Due to well-developed mesoporosity, the TiO2/ZrO2 nanocomposite synthesized by EISA displays high surface area and small crystallite sizes leading to higher photocatalytic activity than pristine TiO2 prepared under similar condition and commercial Degussa P25 nanopowder. The optimum amount of zirconium required for the highest activities was identified and found to be 0.14 and 0.05 mol% for the EISA and sol-gel-prepared samples, respectively. Systematic studies of the post-thermal treatment step for both samples show that Zr inhibits an anatase-to-rutile phase transition only up to 600 degrees C, at higher temperature phase separation occurs. Samples synthesized by EISA method showed enhanced degradation activity than sol-gel-synthesized samples. PMID- 29264853 TI - Speciation of naturally occurring radionuclides in Mediterranean soils: bioavailabilty assessment. AB - Knowledge of soil-to-plant transfer processes is a key element that can have a significant health impact. Much effort has been taken to characterize the speciation of anthropogenic radionuclides released into the environment. However, the information about naturally occurring radionuclides is scarce. This work evaluate the potential risks of transference, that is, the bioavailability of the 234,238U, 226Ra, 228,230,232Th, and 210Po in three different soils collected in Mediterranean ecosystems. Chemical speciation of these radionuclides was carried out according to two different methods, Pavlotskaya and a modification of Tessier's protocol. Most of these radionuclides were associated to fractions strongly bound to soil particles and not able to be transferred. Increasing concentrations of U and Th extracted with increasing volume of NH4OAc 1 M were observed, until it reached saturation. Readily bioavailable fraction in both methods (either exchangeable or water soluble + exchangeable) decreased in the following order: 226Ra > 234,238 U > 228,230,232Th > 210Po. It was found that < 3% of the natural radionuclide concentration in soil are readily bioavailable for plant uptake in this region of Spain, and the resulting human health risk is negligible from natural radionuclide ingestion. PMID- 29264855 TI - Antifungal exploitation of fungicides against Fusarium oxysporum f. sp. capsici causing Fusarium wilt of chilli pepper in Pakistan. AB - The research was conducted to evaluate in-vitro efficacy of numerous fungicides against Fusarium oxysporum f. sp. capsici. In present research, six treatments (T) viz. Carbendazim, Benomyl, Topsin-M, Difenoconazole, Nativo, and Alliete along with control, various concentrations (C), days (D), and their interactions, i.e., (T * C), (T * D), (C * D), and (T * C * D) were exploited in a laboratory through food poison technique. Alliete expressed maximum colony growth (1.93 cm) as compared to all other fungicides with respect to control. Interaction between treatments and concentration (T * C) exhibited maximum colony growth of all treatments (Carbendazim, Benomyl, Topsin-M, Difenoconazole, Nativo, and Alliete), i.e., 0.87, 1.23, 1.73, 2.20, 2.53, and 2.93 cm at 300 ppm as compared to 500 and 700 ppm concentrations, respectively. Similar trend was also observed concerning interaction between (fungicides * days) and (tested concentrations * days). Results of the present study revealed that among tested fungicides, Carbendazim at 700 ppm expressed significant reduction in fungal growth. PMID- 29264854 TI - In vitro elicitation, isolation, and characterization of conessine biomolecule from Holarrhena antidysenterica (L.) Wall. callus and its larvicidal activity against malaria vector, Anopheles stephensi Liston. AB - In vitro elicitation of an important compound conessine has been done in the bark derived callus culture of Holarrhena antidysenterica (L.) Wall. employing different elicitors. For induction of callus, green bark explants excised from field-grown plants were cultured on MS medium augmented with different concentrations (0, 1, 2.5, 5, and 10 MUM) of various growth regulators such as BA, IBA, NAA, and 2,4-D either alone or in combinations. The maximum amount of conessine (458.18 +/- 0.89d MUg/g dry wt.) was achieved in callus developed on MS medium supplemented with 5 MUM BA and 5 MUM 2,4-D through HPLC analysis. Elicitation in conessine content in the above callus was achieved employing a variety of organic (phenylalanine, tyrosine, chitosan, tryptophan, casein hydrolysate, proline, sucrose, and yeast extract) as well as inorganic elicitors (Pb(NO3)2, As2O3, CuSO4, NaCl, and CdCl2) in different concentrations. The optimum enhancement in conessine content (3518.58 +/- 0.28g MUg/g dry wt.) was seen at the highest concentration (200 mg/L) of phenylalanine. The enhancement was elicitor specific and dose dependent. The overall increment of the conessine content was seen in the order of phenylalanine > tryptophan > Pb(NO3)2 > sucrose > NaCl > As2O3 > casein hydrolysate > CdCl2 > chitosan > proline > yeast extract > CuSO4 > tyrosine. The isolation and purification of conessine was done using methanol as a solvent system through column chromatography (CC) and TLC. The isolated compound was characterized by FT-IR, 1H-NMR, and HRMS which confirmed with the structure of conessine. The bioassays conducted with the isolated compound revealed a strong larvicidal activity against Anopheles stephensi Liston with LC50 and LC90 values being 1.93 and 5.67 ppm, respectively, without harming the nontarget organism, Mesocyclops thermocyclopoides Harada, after 48 h of treatment. This is our first report for the isolation and elicitation of conessine in the callus culture of H. antidysenterica. PMID- 29264856 TI - Thin films containing oxalate-capped iron oxide nanomaterials deposited on glass substrate for fast Fenton degradation of some micropollutants. AB - The main goal of the study was to evaluate the catalytic activity of two hybrid nanocatalysts consisting in Fe3O4 nanoparticles modified with either chitosan (CS) or polyethylene glycol (PEG)/ferrous oxalate (FO), and further deposited on solid substrate as thin films. X-ray powder diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and scanning electron microscopy (SEM) were employed for the structural and morphological characterizations of the heterogeneous catalysts. The degradation kinetic studies of two reactive azo dye (Reactive Black 5 (RB5) and Reactive Yellow 84 (RY84)) as well as Bisphenol A (BPA) solutions were carried out using Fenton-like oxidation, in the presence of different concentrations of H2O2, at initial near-neutral pH and room temperature. The results indicated that a low amount of catalytic material (0.15 g/L), deposited as thin film, was able to efficiently trigger dye degradation in solution in the presence of 6.5 mmol/L H2O2 for RB5 and of only 1.6 mmol/L H2O2 in the case of BPA and RY84. In the presence of complex matrices such as WWTP waters, the removal of BPA was low (only 24% for effluent samples). Our findings recommend the studied immobilized nanocatalysts as promising economical tools for the pre-treatment of wastewaters using advanced oxidation processes (AOPs). PMID- 29264857 TI - Can in vivo surface dental enamelmicrobiopsies be used to measure remote lead exposure? AB - Measuring lead in the surface dental enamel (SDE) using biopsies is a rapid, safe, and painless procedure. The dental enamel lead levels (DELLs) decrease from the outermost superficial layer to the inner layer of dental enamel, which becomes crucial for the biopsy depth (BD) measurement. However, whether the origin of lead found in SDE is fully endogenous is not yet established. There is also controversy about the biopsy protocol. The aims of this study were to investigate if DELLs are altered by extrinsic contamination (A) and to evaluate the real geometric figure formed by the erosion provoked by biopsy procedure and the respective BD in SDE (B). To accomplish the aim A, lead from 90 bovine incisor crowns lead was determined by graphite furnace atomic absorption spectrometer as a function of exposure time and lead concentration. Two biopsies were performed in each tooth, before and after lead exposure. Six 15-tooth groups differed by exposure time (1 or 30 min) and lead concentrations (A. 0 mg/L placebo, B. 0.01 mg/L-standard for drinking water, or C. 0.06 mg/L-concentration found in contaminated groundwater). Phosphorus was determined by an inductively coupled plasm optical emission spectrometer to quantify the enamel removed. To compare intakes/losses of lead in SDE among the groups, values of DELL differences between before and after lead exposure were compared by ANOVA (p < 0.05). To attain the objective B, one extracted human permanent tooth was studied by confocal Raman microscopy. Lead measurements and the surface profile were determined. There was no difference in DELL among the groups (p = 0.964). The biopsy bottom surface area, analyzed by microscopy, showed an irregular area, with regions of peaks and valleys, where areas with depth ranging from 0.2 (peaks) to 1.8 MUm (valleys) (+/- 0.1 MUm) could be found. BD carried out in vivo is commonly calculated using the cylinder height formula. The real BD was shown to be very similar to already published data. In conclusion, the SDE of erupted teeth does not seem to be susceptible to environmental lead intake, being thus reliable to measure remote exposures to lead. PMID- 29264858 TI - Removal of pharmaceutical compounds from urban wastewater by an advanced bio oxidation process based on fungi Trametes versicolor immobilized in a continuous RBC system. AB - Conventional wastewater treatment plants (WWTPs) are not able to remove completely some emerging contaminants, such as residual pharmaceutical compounds (PCs) with potential ecotoxicity to water bodies. An advanced bio-oxidation process (ABOP) using white-rot fungi (WRF) has been proposed as alternative biological treatment for degradation of non-biodegradable compounds. A synthetic and real wastewater spiked with 12 PCs at 50 MUg L-1 was treated by means of ABOP based on WRF in a rotating biological contactor (RBC) at 1 day of hydraulic retention time (HRT). The ABOP achieved a remarkable biological performance in terms of TOC removal and reduction of N-NH4 + and P-PO4 3- nutrients. Likewise, 5 of the 12 PCs were eliminated with removal efficiencies ranging from 80 to 95%, whereas 6 of 12 PCs were eliminated with removal values ranging from 50 to 70%. The anaerobic digestion of the fungal sludge generated upon the treatment was also evaluated, obtaining a methane yield of 250 mL CH4 gVS -1. These results evidenced that the proposed ABOP is a promising alternative for the sustainable wastewater treatment of urban effluents, combining advanced oxidation with biological operation for the removal of emerging PCs and energy recovery. PMID- 29264859 TI - Carbon dioxide emissions from the electricity sector in major countries: a decomposition analysis. AB - The electric power sector is one of the primary sources of CO2 emissions. Analyzing the influential factors that result in CO2 emissions from the power sector would provide valuable information to reduce the world's CO2 emissions. Herein, we applied the Divisia decomposition method to analyze the influential factors for CO2 emissions from the power sector from 11 countries, which account for 67% of the world's emissions from 1990 to 2013. We decompose the influential factors for CO2 emissions into seven areas: the emission coefficient, energy intensity, the share of electricity generation, the share of thermal power generation, electricity intensity, economic activity, and population. The decomposition analysis results show that economic activity, population, and the emission coefficient have positive roles in increasing CO2 emissions, and their contribution rates are 119, 23.9, and 0.5%, respectively. Energy intensity, electricity intensity, the share of electricity generation, and the share of thermal power generation curb CO2 emissions and their contribution rates are 17.2, 15.7, 7.7, and 2.8%, respectively. Through decomposition analysis for each country, economic activity and population are the major factors responsible for increasing CO2 emissions from the power sector. However, the other factors from developed countries can offset the growth in CO2 emissions due to economic activities. PMID- 29264860 TI - Fractionation and leaching of heavy metals in soils amended with a new biochar nanocomposite. AB - In this study, surface soils of the Bama Pb-Zn mine-impacted area were sampled for an area surrounding the mineral processing plant. After collecting 65 samples and analyzing them for initial Cu, Pb, Zn, and Cd metal contents, the area was zonated based on the concentration distribution using ordinary kriging in R. A single homogenous sample was prepared by mixing equal weights of each sample as being representative of the whole impacted area (ST). Next, a synthetic model soil (SM) was prepared according to the mean ST texture (SM), divided into two portions, where one portion was amended with a biochar composite (10% w/w) (SMA), both portions were artificially contaminated with Cu, Pb, Zn, and Cd (SMAC and SMC). The mixed soil ST, and the model soils SMC and SMAC, were subjected to soil sequential extraction procedure to determine the variations in fractionation of heavy metals. Results showed that the fractionation in the unamended model soil (SMC) was very close to the original real soil (ST). Moreover, in both amended and unamended soils, Cd and Pb had the highest and the lowest mobility, respectively. Zn and Cu showed intermediate mobilities. The performance of the amendment was evaluated using a 150-day column leaching test taking leachate samples at designated time intervals, and Cu, Pb, Zn, and Cd concentrations were analyzed. Results of column leaching were in good agreement with the soil fractionation as Cd and Pb showed the highest and the lowest mobilities, respectively. Leaching through the soil column was also simulated by HP1 model. Results of simulation found in acceptable proximity to the experimental data despite remarkable differences due to limitations in defining soil to the simulation system. PMID- 29264861 TI - Thermo-alkali-stable alpha-carbonic anhydrase of Bacillus halodurans: heterologous expression in Pichia pastoris and applicability in carbon sequestration. AB - Recombinant alpha-carbonic anhydrase of the polyextremophilic bacterium Bacillus halodurans TSLV1 (rBhCA) has been produced extracellularly in active form in Pichia pastoris under methanol inducible (AOX1) as well as constitutive (GAP) promoters. A marked improvement in rBhCA production was achieved by developing a P. pastoris recombinant that produces rBhCA constitutively as compared to that under inducible promoter. The purified rBhCA from P. pastoris is a glycosylated protein that displays a higher molecular mass (79.5 kDa) than that produced from E. coli recombinant (75 kDa); the former has a Tm of 75 degrees C, which is slightly higher than that of the latter (72 degrees C). The former rBhCA exhibits higher thermostability than the latter. The former sequestered CO2 efficiently similar to that of the native BhCA and the latter. This is the first report on the production of recombinant carbonic anhydrase extracellularly in P. pastoris. PMID- 29264862 TI - Safety and reliability of femtosecond laser-assisted cataract surgery for Japanese eyes. AB - PURPOSE: To assess the safety and efficacy of femtosecond laser-assisted cataract surgery (FLACS) in Japanese eyes. STUDY DESIGN: Retrospective case series. METHODS: The clinical records of 529 consecutive eyes of 312 Japanese patients who underwent FLACS from 2013 to 2016 were reviewed. The completion rates of anterior capsulotomy and corneal incisions using the femtosecond laser (LenSx, Alcon) and the number of attempts to achieve secure docking between the cornea and laser system were recorded. The uncorrected and corrected distance visual acuities (VAs) and uncorrected and distance-corrected near VAs 1 week postoperatively were evaluated. RESULTS: Anterior capsulotomies were completed in 98.7% of eyes. The corneal incisions were incomplete in 8.3%, which included eyes with arcus senilis and neovascularization. The mean corneal endothelial cell reduction rate was 5.5%. Multiple docking attempts were required in 22.9% of eyes, while canthotomy was performed in two eyes. The postoperative VAs were favorable. CONCLUSION: FLACS was safe and reliable in Japanese eyes. Further improvements in docking are required to accommodate small corneas and narrow palpebral spaces. PMID- 29264863 TI - Item frequency in probe-recognition memory search: Converging evidence for a role of item-response learning. AB - In short-term probe-recognition tasks, observers make speeded old-new recognition judgments for items that are members of short lists. However, long-term memory (LTM) for items from previous lists influences current-list performance. The current experiment pursued the nature of these long-term influences-in particular, whether they emerged from item-familiarity or item-response-learning mechanisms. Subjects engaged in varied-mapping (VM) and consistent-mapping (CM) short-term probe-recognition tasks (e.g., Schneider & Shiffrin, Psychological Review, 84, 1-66, 1977). The key manipulation was to vary the frequency with which individual items were presented across trials. We observed a striking dissociation: Whereas increased presentation frequency led to benefits in performance for both old and new test probes in CM search, it resulted in interference effects for both old and new test probes in VM search. Formal modeling suggested that a form of item-response learning took place in both conditions: Each presentation of a test probe led to the storage of that test probe-along with its associated "old" or "new" response-as an exemplar in LTM. These item-response pairs were retrieved along with current-list items in driving observers' old-- recognition judgments. We conclude that item-response learning is a core component of the LTM mechanisms that influence CM and VM memory search. PMID- 29264864 TI - Forgetting having denied: The "amnesic" consequences of denial. AB - The concept of denial has its roots in psychoanalysis. Denial has been assumed to be effective in blocking unwanted memories. In two experiments, we report that denial has unique consequences for remembering. In our two experiments, participants viewed a video of a theft, and half of the participants had to deny seeing certain details in the video, whereas the other half had to tell the truth. One day later, all participants were given either a source-monitoring recognition or a recall task. In these tasks, they were instructed to indicate (1) whether they could remember talking about certain details and (2) whether they could recollect seeing those details in the video. In both experiments, we found that denial made participants forget that they had talked about these details, while leaving memory for the video itself unaffected. This denial induced forgetting was evident for both the source-monitoring recognition and recall tests. Furthermore, when we asked participants after the experiment whether they could still not remember talking about these details, those who had to deny were most likely to report that they had forgotten talking about the details. In contrast to a widely held belief, we show that denial does not impair memory for the experienced stimuli, but that it has a unique ability to undermine memory for what has been talked about. PMID- 29264865 TI - Towards a New Framework for Addressing Structural Uncertainty in Health Technology Assessment Guidelines. PMID- 29264867 TI - Description of four new species and a revision of the genus Tripaphylus Richiardi in Anonymous, 1878 (Copepoda: Siphonostomatoida: Sphyriidae). AB - Tripaphylus Richiardi in Anonymous, 1878 is one of the genera of the Sphyriidae Wilson, 1919 and it currently accommodates ten species. Only scanty descriptions are available for the females and some males of the species. Tripaphylus specimens, described and illustrated in this paper, were collected from elasmobranch hosts off the South African coast or came from the private collection of the late Dr G. Benz. Collected specimens were fixed and preserved in 70% ethanol, examined by light - and scanning electron microscopy, and compared with the known species. Descriptions and illustrations are provided for the transformed adult females and males of T. elongatus (Wilson, 1932) and T. versicolor (Wilson, 1919) while illustrated descriptions of the transformed adult females are also provided for T. ferox (Wilson, 1919) and T. vaissierei (Delamare Deboutteville & Nunes-Ruivo, 1954). Additionally, the material previously reported as T. ferox is considered to represent T. elongatus and that reported as T. lobatus (Kirtisinghe, 1964) is considered a junior synonym of T. vaissierei. Based on the collected material the transformed adult female and male of T. lewisi n. sp. are described as well as the adult transformed females of T. benzi n. sp., T. hoi n. sp., and T. beatricae n. sp. A summarised review of the main features is provided for each of the previously described T. musteli (van Beneden, 1851), T. hemigalei Kirtisinghe, 1964, T. australis (Kabata, 1993), T. triakis (Castro Romero, 2001) and T. asymboli (Turner, Kyne & Bennett, 2003). Furthermore, reasons are provided for the recommendation that T. hemigalei be considered a species inquirenda. An identification key to the transformed adult females of all species of Tripaphylus is provided and the host records are also updated. PMID- 29264868 TI - Toward successful implementation of conservation research: A case study from Vietnam. AB - A number of different approaches have been used to explain the successes and failures of biodiversity conservation strategies in developing countries. However, to date, little attention has been paid toward assessing the influence of knowledge transfer between science, policy, and conservation practices in the implementation of these strategies. Vietnam's Pu Luong Cuc Phuong Conservation Area is a globally important ecosystem, situated within a limestone landscape and inhabited by hundreds of local communities. Biodiversity conservation has become an important part of sustainable development in this area. This study analyzes three conservation strategies employed in the Pu Luong Cuc Phuong Conservation Area by applying the Research-Integration-Utilization (RIU) model of scientific knowledge transfer. Our analyses reveal weaknesses in scientific knowledge transfer arising from low-quality research and poor integration strategies. Based on our results, we developed recommendations to improve research and integration in an effort to enhance science-based policy support. PMID- 29264869 TI - ? PMID- 29264870 TI - ? PMID- 29264871 TI - Exercise for pregnant women with pre-existing diabetes for improving maternal and fetal outcomes. AB - BACKGROUND: Pregnancies with pre-existing diabetes are high risk, with increased risk of poorer fetal, neonatal, and maternal outcomes. Identifying interventions to improving health outcomes for women with diabetes and their infants is a priority, as rates of diabetes continue to increase.Exercise has been shown to have benefits for non-pregnant individuals with pre-existing type 2 diabetes, such as improving glycaemic control, and reducing visceral adipose tissue and plasma triglycerides. For pregnant women with pre-existing diabetes, the effects of exercise interventions on the mother and her baby are unknown.An earlier Cochrane review on 'Exercise for pregnant women with diabetes' considered both pre-existing diabetes and gestational diabetes. That Cochrane review has now been split into two new reviews (following new protocols) - one on gestational diabetes and one on pre-existing diabetes (this review). OBJECTIVES: To evaluate the effects of exercise interventions for improving maternal and fetal outcomes in women with pre-existing diabetes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) on 27 June 2017, and reference lists of retrieved studies. SELECTION CRITERIA: We had planned to include published or unpublished randomised controlled trials (RCT) or cluster randomised trials, in full text or abstract format that compared any type of exercise programme, added to standard care, targeted at women with known pre gestational diabetes (type 1 or type 2 diabetes), at any stage of pregnancy, compared with 1) standard care alone or 2) standard care plus another exercise intervention. Quasi-randomised and cross-over trials were excluded. Conference abstracts were handled in the same way as full-text publications.Women with gestational diabetes mellitus were excluded, as they were covered in a separate Cochrane review. DATA COLLECTION AND ANALYSIS: We had planned that two review authors would independently assess all the potential studies we identified as a result of the search strategy. For eligible studies, two review authors would have independently extracted the data using an agreed form. We had planned to resolve discrepancies through discussion, or by consulting a third person. We also had planned to assess the evidence using the GRADE approach. MAIN RESULTS: We did not identify any randomised controlled trials. AUTHORS' CONCLUSIONS: There was no evidence from RCTs that evaluated the effects of exercise interventions for improving maternal and fetal outcomes in women with pre-existing diabetes.Good quality, large randomised controlled trials are urgently needed to identify exercise interventions that are safe, and improve health outcomes for women with pre-existing diabetes and their babies. Future studies in this area could utilise the standardised outcomes in this review, in order to improve consistency between trials in this area, and aid future meta-analysis. PMID- 29264872 TI - Mesenchymal stem cell therapy of hepatocellular carcinoma in rats: Detection of cell homing and tumor mass by magnetic resonance imaging using iron oxide nanoparticles. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (MSCs) are reported to improve hepatic fibrosis, and may impact the signaling mechanisms leading to the induction of hepatocellular carcinoma (HCC) in animal models of liver cirrhosis. OBJECTIVES: The aim of this study was to clarify and explain the therapeutic role played by MSCs in hepatic cirrhosis and HCC by tracking them using nanoparticles. MATERIAL AND METHODS: Liver cirrhosis and HCC were established in rats with the use of carbon tetrachloride and diethylnitrosamine injection. Magnetic resonance imaging (MRI) was used to track nanoparticlelabeled MSCs in the intact animal following injection and to monitor the changes in the hepatic parenchyma. RESULTS: Labeling of MSCs with iron oxide nanoparticles did not adversely affect their viability and proliferation. MRI indicated a significant reduction in tumor mass in the labeled MSCs group compared to the control group. Histopathologic examination of the liver, following MSCs treatment, showed an apparently normal looking liver with no evidence of neoplastic cellular changes. The biochemical results support these findings. CONCLUSIONS: This work documents that MSCs could be labeled with nanoparticles and traced in normal and cirrhotic liver and in liver with HCC in animals using MRI. MRI monitors the homing and localization of MSCs in the liver. MSCs infusion in animal models of cirrhosis and carcinoma may prove to be useful in limiting the cirrhotic process. Also, it may have a possible therapeutic potential on the carcinogenic process. PMID- 29264866 TI - Mapping the Paediatric Quality of Life Inventory (PedsQLTM) Generic Core Scales onto the Child Health Utility Index-9 Dimension (CHU-9D) Score for Economic Evaluation in Children. AB - BACKGROUND: The Paediatric Quality of Life Inventory (PedsQLTM) questionnaire is a widely used, generic instrument designed for measuring health-related quality of life (HRQoL); however, it is not preference-based and therefore not suitable for cost-utility analysis. The Child Health Utility Index-9 Dimension (CHU-9D), however, is a preference-based instrument that has been primarily developed to support cost-utility analysis. OBJECTIVE: This paper presents a method for estimating CHU-9D index scores from responses to the PedsQLTM using data from a randomised controlled trial of prednisolone therapy for treatment of childhood corticosteroid-sensitive nephrotic syndrome. METHODS: HRQoL data were collected from children at randomisation, week 16, and months 12, 18, 24, 36 and 48. Observations on children aged 5 years and older were pooled across all data collection timepoints and were then randomised into an estimation (n = 279) and validation (n = 284) sample. A number of models were developed using the estimation data before internal validation. The best model was chosen using multi stage selection criteria. RESULTS: Most of the models developed accurately predicted the CHU-9D mean index score. The best performing model was a generalised linear model (mean absolute error = 0.0408; mean square error = 0.0035). The proportion of index scores deviating from the observed scores by < 0.03 was 53%. CONCLUSIONS: The mapping algorithm provides an empirical tool for estimating CHU-9D index scores and for conducting cost-utility analyses within clinical studies that have only collected PedsQLTM data. It is valid for children aged 5 years or older. Caution should be exercised when using this with children younger than 5 years, older adolescents (> 13 years) or patient groups with particularly poor quality of life. ISRCTN REGISTRY NO: 16645249. PMID- 29264873 TI - Influence of infiltration technique and selected demineralization methods on the roughness of demineralized enamel: An in vitro study. AB - BACKGROUND: The decalcification of enamel leads to an increase in tissue roughness. The development of carious lesions may be halted or these lesions may heal, which results in a smoother surface. OBJECTIVES: The objective of the study was to assess the impact of selected agents on the roughness of demineralized enamel on the smooth surfaces of teeth. MATERIAL AND METHODS: A total of 25 samples with exposed enamel surfaces were examined in the study. The samples were randomized into groups and they were exposed to a demineralizing solution, after which the following agents were applied: Icon (Ic), Elmex gel (El), GC Tooth Mousse (TM), Colgate Total (K+) - a positive control group, and distilled water as a negative control group (K-). The impact of selected agents on the roughness of demineralized enamel was assessed with a profilometer. The parameters Ra, Rz and Rq were analyzed. RESULTS: Following infiltration and demineralization, the Ra coefficient declined in groups Ic, TM, K+ and K-, Rz decreased in groups Ic, TM and Rq was lower in groups Ic, TM and Kafter using agents when compared with demineralization. The lowest Ra, Rz and Rq values, i.e. the highest degree of surface smoothness, were observed in group Ic. An increase in all coefficients (Ra, Rz and Rq) was noted in group El. CONCLUSIONS: Demineralized enamel can be smoothed out through the one-time application of Icon resin or the long-term application of GC Tooth Mousse. The least effective agents turned out to be those with a high fluoride content. PMID- 29264874 TI - The effect of crystalloid infusion on body water content and intra-abdominal pressure in patients undergoing orthopedic surgery under spinal anesthesia. AB - BACKGROUND: Crystalloids are frequently used for the correction of spinal anesthesia-induced hypotension, intraoperative bleeding, or vaporisation from surgical wounds. OBJECTIVES: The aim of this study was to observe the effect of perioperative crystalloid infusion on intraabdominal pressure (IAP), volume excess (VE), total body water (TBW), and extracellular body water (ECW) in patients undergoing elective orthopedic surgery under spinal anesthesia. MATERIAL AND METHODS: Adult patients undergoing hip or knee replacement were studied. Changes in VE, TBW, ECW, and IAP were observed in patients who received restrictive fluid therapy (group R) and in patients who received liberal fluid therapy (group L). IAP was measured in the urinary bladder. All parameters were measured at 4 points in time: just before anesthesia (baseline value, A); just after surgery (B); 3 h after surgery (C); and on the morning of postoperative day 1 (D). Additionally, IAP was measured after anesthesia, just before surgery (A1). RESULTS: The mean baseline values of IAP, ECW, TBW, and VE were comparable between groups L and R. The induction of anesthesia reduced IAP in both groups (p < 0.001). IAP and VE increased in both groups after surgery. Significantly higher values of IAP, however, were noted in group L at time points B, C, and D. TBW and ECW increased after surgery in group L. In group R, ECW slightly increased only at time point C. IAP strongly correlated with ECW in group L (p < 0.001, r = 0.62). CONCLUSIONS: Spinal anesthesia reduces IAP. A perioperative increase in body water content and IAP mainly depends on the volume of the infused crystalloids. PMID- 29264875 TI - Patients with infective endocarditis: Five-year observation from a single reference center. AB - BACKGROUND: Infective endocarditis (IE) is a serious and, if untreated, usually fatal disease. Diagnosing IE is often considered to be one of the most difficult medical conditions because of the heterogeneous and ambiguous clinical presentation. OBJECTIVES: The purpose of this study was to investigate diagnostic and therapeutic management in a non-selected group of patients with IE. MATERIAL AND METHODS: A total of 45 patients consecutively admitted to the Department of Cardiology, Medical University of Silesia in Katowice (mean age 53.6 +/-18 years; 13 females) with IE between 2009 and 2013 were evaluated. Echocardiography, blood cultures and laboratory tests were performed on every patient upon admission. An analysis of the diagnostic and therapeutic management was performed. RESULTS: Most frequent predisposing factors were: a history of heart valve replacement and/or repair (40%), dental caries (17.8%) and bicuspid aortic valve (17.8%). The majority of patients were admitted from another hospital (91.1%). Fever (92%) and symptoms of heart failure (80%) were the most common manifestations. Abnormalities in ECG occured in 91.2% of patients. Echocardiography was highly sensitive (>90%) in detecting endocardial changes. Staphylococcal etiology was the most common (33.3%). Surgery procedures were necessary in 62.2% of patients. Arrhythmias (91.1%) and acute heart failure (57.8%) were the most commonly observed complications, although 24.4% of subjects had neurological disorders. The patients studied were burdened with a number of factors predisposing to IE. CONCLUSIONS: The diagnosis of IE can be a difficult challenge. Particular attention should be paid to the care of oral hygiene and treatment of dental diseases in order to reduce the risk of IE developing. PMID- 29264876 TI - Implementation of mild therapeutic hypothermia for post-resuscitation care of sudden cardiac arrest survivors in cardiology units in Poland. AB - BACKGROUND: The post-cardiac arrest (CA) period is often associated with secondary damage of the brain that leads to severe neurological deficits. The current practice guidelines recommend the use of therapeutic hypothermia (TH) to prevent neurological deficit and improve survival. OBJECTIVES: The aim of the study was to investigate the implementation of medical guidelines in clinical practice and to evaluate the barriers for implementation of TH in cardiology units in Poland. MATERIAL AND METHODS: A telephone survey, fax and online inquiry form were used to assess the implementation of TH in cardiology units in the management of unconscious patients after cardiac arrest (CA). The questions addressed the local practice, TH protocol, reasons for not using TH and outcomes of CA patients. RESULTS: We obtained information from 79 units out of 150 asked (53%). At the time of the survey, 24 units (30.8%) were using TH as part of their post-CA management. Of all CA patients, 45% underwent TH in cardiac intensive care units (CICU), 37.5% in the coronary care unit (CCU) and 12.5% in the intensive care unit (ICU). The major barrier for the implementation of TH declared by the non-cooling centers was lack of sufficient knowledge regarding the technique and protocol, as well as experience (37%); access to dedicated equipment was not perceived as an obstacle. CONCLUSIONS: The number of cardiology units that provide TH for comatose CA patients is low. The main limiting factor for wider use of TH is lack of knowledge and experience. There is a clear need for urgent educational activities for cardiology units. The benefits of TH still have not reached their potential in cardiology units. PMID- 29264877 TI - MRAS gene marker rs9818870 is not associated with acute coronary syndrome in the Czech population and does not predict mortality in males after acute coronary syndrome. AB - BACKGROUND: Genome-wide association studies (GWAs) focused on cardiovascular diseases reveal variants within genes which have not been analyzed through the pre-GWAs era, and whose function is often unknown. One of them is variant rs9818870 at the MRAS gene locus. OBJECTIVES: To analyze if MRAS polymorphism is associated with acute coronary syndrome (ACS) risk in a Czech population and with mortality in male patients after myocardial infarction. MATERIAL AND METHODS: 1,779 male patients with ACS (aged 55.3 +/-7.9 years) and 673 female patients with ACS (aged 64.0 +/-8.1 years) were genotyped for rs9818870 polymorphism using the PCR-RFLP method. In a subset of 1,221 patients, detailed diagnoses (901 subjects with STEMI, 280 subjects with NSTEMI, 40 cases with unstable angina pectoris) were recorded. In 1,614 males, records about total and cardiovascular mortality were available. RESULTS: Whether the entire populations or males and females have been analyzed separately or not, we have not confirmed the described association between DNA marker rs9818870 and ACS in Czechs (30.4% vs 29.4% carriers of the minor T allele [recessive model], p = 0.54; OR 1.05; 95% CI 0.89 1.24 for males and 32.1% vs 29.7% carriers of the minor T allele, p = 0.28; OR 1.12; 95% CI 0.91-1.37 for females). Types of the ACS (STEMI and NSTEMI) or mortality (in males only) were not associated with the analyzed polymorphism (all p > 0.34). CONCLUSIONS: The rs9818870 variant is not associated with ACS or mortality in ACS patients in the Czech Slavonic population. PMID- 29264878 TI - A preliminary estimation of tissue factor pathway inhibitor (TFPI) and protein C in patients with intracranial tumors. AB - BACKGROUND: In patients with intracranial tumors, hypercoagulability is observed due to brain tissue and tumor cells being the source of tissue factor. OBJECTIVES: The aim of the study was to assess tissue factor (TF), tissue factor pathway inhibitor (TFPI) and protein C in the plasma and tumor tissue homogenate in patients with intracranial tumors. MATERIAL AND METHODS: The study included 77 patients; 24 patients were diagnosed with glioma, 20 patients with meningioma and 33 patients with metastatic tumors; mean age - 54 years. The material for the study was the plasma and tumor tissue homogenate sampled during surgery. The control group consisted of 30 controls; mean age - 51 years. In the plasma of all the participants and in tumor tissue homogenate, the concentrations of TF-Ag, TFPI-Ag and protein C activity, and the concentration of total protein were measured. The results were converted per mg of protein. RESULTS: In patients with intracranial tumors, elevated concentrations of TF-Ag, TFPI-Ag and protein C activity were noted, also after the conversion per mg of protein. A 100-fold higher concentration of TF per 1 mg of protein was found in tumor tissue compared to the patients' plasma. In tumor tissue homogenate, a lower TFPI concentration and a lower protein C activity were recorded. CONCLUSIONS: The study confirmed the essential prothrombotic properties in patients with intracranial tumors, expressed with an elevated TF level, as well as a tremendous amount of TF in tumor tissue homogenate derived from tumors. The elevated concentration of TFPI and protein C activity converted per mg of total protein should be analyzed in terms of their pleiotropic function, along with the participation in hemostasis control. It seems that the reduced protein C activity and low TFPI level are associated with the enormous TF value in tumor tissue homogenates. PMID- 29264879 TI - Gender-related risk factors for perioperative stroke after carotid endarterectomy in symptomatic patients. AB - BACKGROUND: Carotid endarterectomy (CEA) is a surgical procedure used in ischemic brain stroke prevention in patients with symptomatic and asymptomatic severe carotid artery stenosis. OBJECTIVES: This study compares perioperative stroke or death rate after carotid endarterectomy (CEA) in male and female patients, and determines risk factors for perioperative incidents in women and men. MATERIAL AND METHODS: The outcome of surgical treatment of 269 consecutive symptomatic patients (181 men and 88 women) treated from January 2004 to August 2008 in the Department of Vascular, General and Oncologic Surgery was analyzed. RESULTS: Perioperative stroke-death rate (within 30 days after the surgery) in women was 6.8% (6/88) and 3.3% (6/181) in men (p > 0.05). In the female group, none of the analyzed risk factors were associated with a higher risk of periprocedural incident, while in men, only hypercholesterolemia was a significant predictor of perioperative stroke (TC > 240 vs 240 vs 200-240: OR = 6.59; 95% CI: 1.12-38.97; p = 0.0375). CONCLUSIONS: In men, hypercholesterolemia significantly increased the risk of perioperative stroke or death, while in females, none of the analyzed factors were determined as the predictors of the incident. The fact that plaque type VI by AHA was significantly more frequent in women and men more frequently were suffering from ischemic heart disease and peripheral artery occlusive disease appeared not to influence the outcome of CEA. PMID- 29264880 TI - Serum osteopontin and vitronectin levels in systemic sclerosis. AB - BACKGROUND: Osteopontin a matricellular protein has pro-fibrotic effects and binds integrin such as alphavbeta1 and alphavbeta3. Vitronectin is one of the integrin alphavbeta3 ligands and is a multifunctional glycoprotein. OBJECTIVES: The aim of the present study was to evaluate serum osteopontin and vitronectin levels in a cohort of patients with systemic sclerosis (SSc). MATERIAL AND METHODS: Eighty-six patients with SSc, 46 patients with systemic lupus erythematosus (SLE), and 38 healthy controls (HC) were enrolled in the study. Serum osteopontin, vitronectin, IL-6, and TGF-beta levels were analyzed. RESULTS: Serum osteopontin levels were higher in the SSc and SLE groups compared to the HC group (p < 0.01 and p < 0.001, respectively). However, it was not correlated with disease activity and severity scores in the SSc group. On the other hand, serum vitronectin levels were lower in the SSc group than in the SLE and HC groups (p < 0.001 for both). CONCLUSIONS: These results may suggest that osteopontin levels may be increased due to the inflammatory process and osteopontin has not a specific role on fibrosis in SSc. On the other hand, serum vitronectin levels decrease in SSc in contrast to SLE. It may be concluded that the one cause of decreased serum vitronectin levels in SSc may be its accumulation in fibrotic area. PMID- 29264881 TI - Influence of glycemic control on some real-time biomarkers of free radical formation in type 2 diabetic patients: An EPR study. AB - BACKGROUND: The pathology of diabetes is associated with several mechanisms, one of which is oxidative stress (OS). The relationship between OS and diabetic complications has been extensively investigated. OS has been suggested to be involved in the genesis of both macroand microangiopathy. In contrast, the relationship between OS and insulin action is a neglected research area. OBJECTIVES: The aim of this study is to elucidate the effect of glycemic control in type 2 diabetic patients by following the serum levels of some real-time oxidative stress biomarkers. MATERIAL AND METHODS: The study group consisted of 53 type 2 diabetic patients (31 with poor glycemic control and 22 with good glycemic control) and 24 healthy control subjects. The oxidative stress biomarkers (ROS, Asc* and *NO) were measured by using electron paramagnetic resonance spectroscopy (EPR) methods and compared with clinical parameters. RESULTS: The statistically significantly higher levels of ROS products and *NO in type 2 diabetic patients in both groups compared to controls mean that the oxidation processes take place at the time the survey is performed. Free radical overproduction persists after the normalization of the glucose levels, and oxidative stress may be involved in the "metabolic memory" effect. This is confirmed by the positive correlation between ROS levels/*NO and average blood glucose levels, triglycerides, and total cholesterol. Furthermore, the low level of the ascorbate radical in both diabetes groups compared to controls confirmed an increase in oxidation processes. CONCLUSIONS: Higher levels of real-time biomarkers show that intensive insulin treatment does not lead to the expected decrease in oxidative processes involving ROS and *NO, probably due to "metabolic memory". PMID- 29264882 TI - Objectively measured patient cooperation during early orthodontic treatment: Does psychology have an impact? AB - BACKGROUND: The effectiveness of orthodontic treatment with removable appliances arouses controversy concerning the level of patients' compliance. The compliance depends on factors controlled by the orthodontists, by the patients themselves and by their caregivers, and those beyond any control. OBJECTIVES: The purpose of this study was to assess the extent to which the personality traits of patients and their caregivers affect the cooperation in removable appliance therapy. MATERIAL AND METHODS: A total of 38 patients (19 boys, 19 girls) aged 9-12 years, presenting malocclusions suitable for removable appliance therapy were randomly selected. The EAS-C Temperament Questionnaire, Generalized Self-Efficacy Scale, NEO-Five Factor Inventory and Parental Attitude Scale developed by Plopa were employed to evaluate the patients' and the caregivers' temperamental dispositions. Electronic sensors were employed to objectively assess patients' cooperation. RESULTS: Statistical analysis revealed a high positive correlation between removable appliance wear time and the results of the GSES and the SPR-R, a strongly positive correlation between wear time and the NEOFFIC results and a strongly negative correlation between wear time and the EAS-C-Emo measurement. The level of a generalized sense of efficacy, conscientiousness and the severity of requirements imposed on the child were the factors related to the caregivers, positively correlating with patients' cooperation. CONCLUSIONS: The cooperation of children treated with removable appliances may be foreseen with observation of the patients' and their caregivers' traits. Objective evaluation of the patients' cooperation and psychological tests may be valuable tools for the re-assessment of the paradigm of early orthodontic treatment. PMID- 29264883 TI - Evaluation of aortic intima-media thickness in newborns with Down syndrome. AB - BACKGROUND: Health care programs for children with Down syndrome (DS) help improve the overall outcome and quality of life of these children. It is therefore very important to focus on the most common and serious problems of these patients, such as congenital heart defects and cardiac problems, and to keep medical guidelines updated with regard to these problems. OBJECTIVES: The aim of this study was to evaluate aortic intima-media thickness (aIMT), lipid profiles and blood pressure in DS patients in comparison with a control group of ageand gender-matched neonates without DS. MATERIAL AND METHODS: Serum concentrations of lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride), blood pressure and abdominal aIMT were measured in newborns with DS, and compared with the measurements from ageand gender-matched newborns without DS. RESULTS: No statistically significant differences between the 2 groups of newborns were detected with respect to aIMT, lipid levels or blood pressure. CONCLUSIONS: This study represents the first investigation of aIMT - one of the most important indicators of atherosclerosis - in DS patients, but neither a significantly increased aIMT, nor any significant changes in lipid profiles or blood pressure were detected in this group of patients. Whether aIMT differs according to the type of congenital heart defect (such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, and atrioventricular septal defect) among DS patients remains to be determined in future studies. PMID- 29264884 TI - Distribution of polymorphisms rs12979860, rs8099917 and rs12980275 IL28B in patients with chronic hepatitis C. AB - BACKGROUND: The prognosis concerning the treatment of patients with chronic hepatitis C (CHC) is closely related to the genotype of the virus as well as to the factors dependent on the patient. It was proved that polymorphisms of the gene encoding interleukin 28B (IL28B) are associated with sustained viral response, which in the case of profitable variants of IL28B polymorphisms may reach up to 87% of the patients. OBJECTIVES: The aim of the study is to determine the prevalence of alleles and distribution of IL28B polymorphisms genotypes in the examined group of patients with CHC in Wielkopolska Province. MATERIAL AND METHODS: A total of 710 people with diagnosed hepatitis C virus were examined in order to determine the distribution of polymorphisms of gene IL28B rs12979860, rs8099917 and rs12980275. The polymorphisms were evaluated by sequencing of PCR products. RESULTS: The most often noted profitable variant was genotype TT for polymorphism rs8099917 present in 43.5% of the patients, next was AA rs12980275 in 22.5%. The rarest was the profitable variant CC of the polymorphism rs12979860 present in 17.5% of the patients. An occurrence of at least 2 IL28B polymorphisms in the preferred variants (homozygote CC, TT, AA) was found in 239 out of 710 (34%) patients, among which 117 patients had favorable genotypes for all 3 examined polymorphisms. CONCLUSIONS: The SNP distribution of gene IL28 with fixed prognostic value in the population of patients with chronic hepatitis C is different from the general population, and shows the need to evaluate polymorphisms prior to treatment. PMID- 29264886 TI - Investigation of DNA repair genes in patients with obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a major psychiatric disorder identified mostly by obsessions and compulsions. Molecular genetic and gene expression studies focused on familial and twin cases have shown a wide variety of variant genes related to OCD. OBJECTIVES: The aim of the study was to investigate DNA repair genes as potential molecular markers in OCD by evaluating the distribution of polymorphisms of DNA repair genes in OCD patients. MATERIAL AND METHODS: The study included 100 case subjects with OCD and 122 unrelated healthy controls. Genotyping of XRCC1, XRCC3, XPD, XPG, APE1 and HOGG1 was performed by polymerase chain reactionrestriction fragment length polymorphism. RESULTS: Significant differences were found for XPD and genotype frequencies. Likewise, the frequency of the XPD Lys+ genotype was significantly increased in the patients as compared to the controls, and carriers of the Lys+ genotype had an increased risk for OCD (p = 0.027). The XPD Lys/Lys genotype frequency was also increased in the patients in comparison to the controls (p < 0.001). XPD Gln+ frequencies were higher in the controls than in the patients, and carriers of the Gln+ genotype showed decreased levels of OCD risk (p < 0.001). XPD Lys/Lys genotype frequency and XPD Gln+ frequency are also significantly associated even after Bonferroni correction (p < 0.008). CONCLUSIONS: The findings suggest that XPD Lys/Lys might play a facilitating role in the development of OCD. PMID- 29264885 TI - Antihypertensive treatment prescription in pediatric dialysis patients in Poland: A comparison between two nationwide studies 2003/2004-2013. AB - BACKGROUND: Blood pressure in pediatric dialyzed patients is under poor control. OBJECTIVES: The aim of the study was to assess the strategy and efficacy of antihypertensive drugs used for the treatment of hypertension in pediatric dialyzed patients in 2013 in comparison with the data collected in 2003/2004. The results have been viewed against present strategies of antihypertensive treatment in children. There is still limited data concerning the treatment of hypertension in dialyzed pediatric patients. MATERIAL AND METHODS: The study embraced 10 of 12 pediatric dialysis units in Poland treating 59 pediatric patients (mean age - 132 months). Collected information included present antihypertensive treatment with regard to drug classes and the dose of antihypertensive agent. The treatment was regarded as effective if both systolic and diastolic values of blood pressure were below 1.64 SDS. The results from 2013 were juxtaposed with previously analyzed data from a similar study on hypertension in dialyzed children conducted in 2003/2004. RESULTS: Forty subjects have been provided with antihypertensive treatment. In monotherapy and polytherapy 50% of the subjects were treated with ACEI (enalapril and ramipril), 67.5% with amlodipine, 50% with beta-blockers. Only 10% of the subjects were treated with angiotensin II receptor blocker (losartan). Thirty percent of the subjects received furosemide, whereas 5% were given doxazosin. Antihypertensive drugs regarded as the 2nd and 3rd choice in treating high blood pressure (doxazosin, beta-blockers and furosemide) were applied as monotherapy in 46% of the patients. Satisfactory control of treated blood pressure was reached in 45% of them. CONCLUSIONS: Antihypertensive treatment in dialyzed children did not change significantly during the last decade with regard to the groups of drugs being used. Despite a wider feasibility of antihypertensive substances, the effectiveness of this therapy was still unsatisfactory. PMID- 29264887 TI - CCDC26 rs4295627 polymorphisms associated with an increased risk of glioma: A meta-analysis. AB - BACKGROUND: Gliomas are the most common primary brain tumor in adults. Many studies have revealed associations between the rs4295627 polymorphism in the coiled-coil domain containing 26 (CCDC26) gene and the risk of glioma. However, the conclusions are still unclear because some studies have reported inconsistent results. OBJECTIVES: The aim of the present meta-analysis was to determine the relationship and quantitatively evaluate the effect of the rs4295627 polymorphism on the risk of glioma. MATERIAL AND METHODS: Data was extracted from PubMed, EMBASE and Google Scholar, with the most recent search up to December, 2015. Odds ratios (OR) and their 95% CIs were used to evaluate the effect of CCDC26 rs4295627 polymorphisms on glioma. A test of heterogeneity and an assessment of publication bias were also performed. RESULTS: A total of 11 studies (8292 cases and 12,419 controls) were selected for this meta-analysis. Significant associations were observed in all genetic analysis models (G vs T: OR = 1.26, 95% CI = 1.12-1.43; GG vs TT: OR = 1.72, 95% CI = 1.24-2.39; GT vs TT: OR = 1.33, 95% CI = 1.24-1.42; GG + GT vs TT: OR = 1.36, 95% CI = 1.20-1.53; GG vs GT + TT: OR = 1.65, 95% CI = 1.18-2.29, respectively). CONCLUSION: The results of the present study clearly show that the G allele of the rs4295627 polymorphism significantly increases the risk of glioma. Nevertheless, well-designed large-scale studies are needed to further evaluate the effect of the rs4295627 polymorphism on different types or degrees of glioma in different ethnic groups as well as to measure the combined effects on glioma risk. PMID- 29264888 TI - Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. AB - Sclerostin is a glycoprotein involved in the regulation of bone metabolism, exclusively secreted by osteocytes. It affects the activity of bone morphogenetic proteins (BMPs) and is an inhibitor of the Wnt/beta-catenin metabolic pathway in bone cells. Osteocytes reduce the release of sclerostin in response to mechanical stimuli acting on bone, and thus promote the activation of osteogenic pathway Wnt/beta-catenin in osteoblasts. This signaling pathway plays a key role in osteogenesis and bone turnover. Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease. Additionally, experimental and clinical studies suggest that sclerostin may promote vascular calcification. Antibodies directed against sclerostin stimulate bone formation and represent a new therapeutic option in the treatment of diseases with increased bone resorption, such as osteoporosis and inflammatory diseases where there is generalized bone loss, periarticular osteoporosis, and cartilage damage, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and glucocorticoid-induced osteoporosis (GIO). Antibody use has the potential to offer new therapeutic approaches in the therapy of mineral and bone disorders resulting from chronic kidney disease (CKD-MBD) and vascular calcifications. PMID- 29264889 TI - Valve bladder syndrome in children: On the trail of the best strategies to prevent chronic kidney disease. AB - Pediatric patients suffering from valve bladder syndrome (VBS) are at risk of developing chronic kidney disease (CKD) and renal failure in later life. Therefore, it is of vital importance to determine the risk factors and the best possible strategies for diagnosis and treatment in patients with VBS that would minimize the risk of developing CKD. In this review we have presented the current knowledge of CKD risk factors in patients with posterior urethal value (PUV). We have also discussed possible recommendations for prenatal diagnostics procedures to be undertaken in patients with PUV, postnatal monitoring and therapeutic strategies that could reduce the risk of developing CKD in this population. Although in most cases there are no clear guidelines for appropriate clinical actions that can be undertaken in patients with PUV to minimize the risk of kidney failure, we have tried to present concise and accurate advice for physicians taking care of patients with PUV. PMID- 29264890 TI - The treatment of facial asymmetry: Review. AB - Some degree of congenital or acquired asymmetry is normal and universal. Significant facial asymmetry, however, causes both aesthetic, as well as functional problems. The comprehensive management of facial symmetry is scarcely addressed.1-5 Differing etiologies, heterogeneous material, and different ages of patients tend to produce fragmentary reports, the more so as evidence-based evaluation of outcomes is almost impossible. Therefore, a presentation of the general rules of treatment, illustrated by our own material collected from the Hospital and Clinic of Plastic Surgery in Polanica-Zdroj and from private surgical and orthodontic practice, could be regarded as useful and justified. Special attention has been given to both functional and cosmetic problems encountered in severe congenital and acquired asymmetries. The management of selected craniofacial malformations in so-called rare clefts, cleft lip and palate, and craniofacial microsomia (CFM), as well as large hemangiomas and neurofibromas, have been discussed. Additionally, the treatment of extensive and asymmetrical post-traumatic deformities and defects is discussed with particular attention given to problems related to ankylosis of the temporomandibular joints. Numerous examples of one-stage procedures, as well as combined, multidisciplinary treatments are presented. PMID- 29264891 TI - In vivo imaging of human oral hard and soft tissues by polarization-sensitive optical coherence tomography. AB - Since optical coherence tomography (OCT) provides three-dimensional high resolution images of biological tissue, the benefit of polarization contrast in the field of dentistry is highlighted in this study. Polarization-sensitive OCT (PS OCT) with phase-sensitive recording is used for imaging dental and mucosal tissues in the human oral cavity in vivo. An enhanced polarization contrast of oral structures is reached by analyzing the signals of the co- and crosspolarized channels of the swept source PS OCT system quantitatively with respect to reflectivity, retardation, optic axis orientation, and depolarization. The calculation of these polarization parameters enables a high tissue-specific contrast imaging for the detailed physical interpretation of human oral hard and soft tissues. For the proof-of-principle, imaging of composite restorations and mineralization defects at premolars as well as gingival, lingual, and labial oral mucosa was performed in vivo within the anterior oral cavity. The achieved contrast-enhanced results of the investigated human oral tissues by means of polarization-sensitive imaging are evaluated by the comparison with conventional intensity-based OCT. PMID- 29264892 TI - In vivo polarization-sensitive optical coherence tomography of human burn scars: birefringence quantification and correspondence with histologically determined collagen density. AB - Obtaining adequate information on scar characteristics is important for monitoring their evolution and the effectiveness of clinical treatment. The aberrant type of collagen in scars may give rise to specific birefringent properties, which can be determined using polarization-sensitive optical coherence tomography (PS-OCT). The aim of this pilot study was to evaluate a method to quantify the birefringence of the scanned volume and correlate it with the collagen density as measured from histological slides. Five human burn scars were measured in vivo using a handheld probe and custom-made PS-OCT system. The local retardation caused by the tissue birefringence was extracted using the Jones formalism. To compare the samples, histograms of birefringence values of each volume were produced. After imaging, punch biopsies were harvested from the scar area of interest and sent in for histological evaluation using Herovici polychrome staining. Two-dimensional en face maps showed higher birefringence in scars compared to healthy skin. The Pearson's correlation coefficient for the collagen density as measured by histology versus the measured birefringence was calculated at r=0.80 (p=0.105). In conclusion, the custom-made PS-OCT system was capable of in vivo imaging and quantifying the birefringence of human burn scars, and a nonsignificant correlation between PS-OCT birefringence and histological collagen density was found. PMID- 29264893 TI - In vivo, noninvasive functional measurements of bone sarcoma using diffuse optical spectroscopic imaging. AB - Diffuse optical spectroscopic imaging (DOSI) is an emerging near-infrared imaging technique that noninvasively measures quantitative functional information in thick tissue. This study aimed to assess the feasibility of using DOSI to measure optical contrast from bone sarcomas. These tumors are rare and pose technical and practical challenges for DOSI measurements due to the varied anatomic locations and tissue depths of presentation. Six subjects were enrolled in the study. One subject was unable to be measured due to tissue contact sensitivity. For the five remaining subjects, the signal-to-noise ratio, imaging depth, optical properties, and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids from tumor and contralateral normal tissues were assessed. Statistical differences between tumor and contralateral normal tissue were found in chromophore concentrations and optical properties for four subjects. Low signal to-noise was encountered during several subject's measurements, suggesting increased detector sensitivity will help to optimize DOSI for this patient population going forward. This study demonstrates that DOSI is capable of measuring optical properties and obtaining functional information in bone sarcomas. In the future, DOSI may provide a means to stratify treatment groups and monitor chemotherapy response for this disease. PMID- 29264894 TI - Femtosecond laser surgery of two-cell mouse embryos: effect on viability, development, and tetraploidization. AB - The effect of the laser pulse energy and total expose of the energy incident on the embryo blastomere fusion probability was investigated. The probability of the four different events after laser pulse was determined: the fusion of two blastomeres with the following formation of tetraploid embryo, the destruction of the first blastomere occurs, the second blastomere conservation remains intact, the destruction and the death of both cells; two blastomeres were not fused, and no morphological changes occurred. We report on viability and quality of the embryo after laser surgery as a function of the laser energy incident. To characterize embryo quality, the probability of the blastocyst stage achievement was estimated and the blastocyst cells number was calculated. Blastocoel formation is the only event of morphogenesis in the preimplantation development of mammals, so we assumed it as an indicator of the time of embryonic "clocks" and observed it among fused and control embryos. The blastocoel formation time is the same for fused and control embryos. It indicates that embryo clocks were not affected due to blastomere fusion. Thus, the analysis of the fluorescence microscopic images of nuclei in the fused embryo revealed that nuclei fusion does not occur after blastomere fusion. PMID- 29264895 TI - Development of a disposable force-sensing glove for clinicians and demonstration of its force measurements on patients during rehabilitation following anterior cruciate ligament reconstruction surgery. AB - For many clinicians, their effectiveness is dependent on the magnitude of forces they manually apply to their patients. However, current state-of-the-art care strategies lack quantitative feedback, making it difficult to provide consistent care over time and among multiple clinicians. To provide real-time quantitative feedback to clinicians, we have developed a disposable glove with a force sensor embedded in the fingertips or palm. The sensor is based on the fiber-optic bendloss effect whereby light intensity from an infrared source is attenuated as the fiber is bent between a series of corrugated teeth. The sensor fabricated has a very low profile (10*7*1 mm) and has demonstrated high sensitivity, accuracy, range, and durability. Force feedback up to 90 N with an average force threshold at 0.19 N and average sensor resolution at 0.05 N has been demonstrated. A preliminary clinical study has also been conducted with anterior cruciate ligament reconstruction patients who show significant range of motion improvement when treated with the force-sensing glove. PMID- 29264897 TI - The measurement of serum TNF-alpha levels in patients with lichen planus. AB - BACKGROUND: Lichen planus is a common mucocutaneous inflammatory skin disease with a multifactorial etiology. Cytokines play a key role in lichen planus pathogenesis. This study investigates the relationship between disease severity and levels of tumor necrosis factor-alpha (TNF-alpha), which is considered a primary cytokine that initiates cytotoxicity. MATERIAL AND METHODS: Serum TNF alpha levels were compared between a patient group (n = 34) and a control group (n = 20). TNF-alpha serum levels were measured using human TNF-alpha Enzyme Linked Immunosorbent Assay (ELISA) test kits, and the two groups were statistically compared to each other. RESULTS: Mean serum TNF-alpha levels were found to be significantly higher in the patient group than in the control group (p < 0.005). However, no significant association was observed between TNF-alpha levels and oral mucosal involvement (p > 0.005). No relationship was detected between TNF-alpha levels and patients' sex. CONCLUSION: It is thought that TNF alpha, a proinflammatory cytokine, may play an important role in the pathogenesis of lichen planus. TNF-alpha may be a simple and effective predictor to illustrate the inflammatory status in patients with lichen planus. PMID- 29264896 TI - Noninvasive optical imaging of resistance training adaptations in human muscle. AB - A quantitative and dynamic analysis of skeletal muscle structure and function can guide training protocols and optimize interventions for rehabilitation and disease. While technologies exist to measure body composition, techniques are still needed for quantitative, long-term functional imaging of muscle at the bedside. We evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used for long-term assessment of resistance training (RT). DOSI measures of tissue composition were obtained from 12 adults before and after 5 weeks of training and compared to lean mass fraction (LMF) from dual-energy X-ray absorptiometry (DXA). Significant correlations were detected between DXA LMF and DOSI-measured oxy-hemo/myoglobin, deoxy-hemo/myoglobin, total-hemo/myoglobin, water, and lipid. RT-induced increases of ~6% in oxy-hemo/myoglobin (3.4+/-1.0 MUM, p=0.00314) and total-hemo/myoglobin (4.9+/-1.1 MUM, p=0.00024) from the medial gastrocnemius were detected with DOSI and accompanied by ~2% increases in lean soft tissue mass (36.4+/-12.4 g, p=0.01641) and ~60% increases in 1 rep-max strength (41.5+/-6.2 kg, p=1.9E-05). DOSI measures of vascular and/or muscle changes combined with correlations between DOSI and DXA suggest that quantitative diffuse optical methods can be used to evaluate body composition, provide feedback on long-term interventions, and generate new insight into training induced muscle adaptations. PMID- 29264898 TI - Pattern of dermatoses in two groups of admitted psychiatric patients: a cross sectional study from a tertiary care hospital in Kashmir. AB - BACKGROUND: Various specific and non-specific dermatological manifestations can be found in patients with psychiatric ailments. Most studies in this regard have been conducted on an outpatient basis and not much work has been done on patients admitted with psychiatric diseases. METHODS: This cross-sectional hospital-based study involved two groups of admitted psychiatric patients over a period of 1 year, involving 100 patients in each group. In the family ward group patients were admitted with accompanying family members, whereas in the closed ward group patients were kept under custodial care. RESULTS: In the family ward setting, eczema was the most common finding, observed in 29 patients, followed by atrophic scarring in 28 patients, erythema ab igne in 25 patients, and bacterial infections in five patients. Various forms of nail changes were seen in 18 patients. In the closed ward group, most common dermatological involvement was parasitic infestation, seen in 56 patients, followed by generalized pruritus in 53 patients and atrophic scarring in 52 patients. Thirty-eight patients had nail changes. CONCLUSION: Skin manifestations are more common in chronic neglected psychiatric patients under custodial care. The authors stress upon the importance of familial care provided to psychiatric patients living in custodial settings. PMID- 29264899 TI - Evaluation of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in Turkish patients with chronic plaque psoriasis. AB - INTRODUCTION: This study evaluates the relationship between disease activity and neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with chronic plaque psoriasis. METHODS: Clinical and biochemical data were retrieved through retrospective examination of patients' and healthy subjects' medical records. NLR and PLR values were calculated from the hemogram results. This study included 46 patients (25 males, 21 females; 36.58 +/- 9.82 years) diagnosed with chronic plaque psoriasis and a control group of 46 healthy volunteers (21 males, 25 females; 34.02 +/- 8.41 years). RESULTS: NLR and PLR were significantly elevated in patients with chronic plaque psoriasis (p = 0.0001 and p = 0.003, respectively). PASI was positively correlated with NLR, PLR, and serum CRP levels (r = 0.313, p = 0.034; r = 0.394, p = 0.017; r = 0.359, p = 0.014, respectively). CONCLUSION: NLR and PLR are low-cost tests that can be used to determine the severity of current systemic inflammation in patients with chronic plaque psoriasis. PMID- 29264900 TI - Non-surgical minimally invasive rhinoplasty: tips and tricks from the perspective of a dermatologist. AB - INTRODUCTION: Rhinoplasty is one of the most common aesthetic procedures performed by plastic surgeons all over the world. In recent years, a non-surgical nose job has become the preferred option for most patients and specialists. Minimally invasive techniques already result in high satisfaction rates. Moreover, patients do not need anesthesia and there is no post-operative recovery period. METHODS: Between January 2016 and January 2017, 35 patients (33 female, 2 male) that had undergone nonsurgical rhinoplasty with dermal fillers were included in the study. Clinical and demographic features of the patients, our technique, satisfaction rates, and complications were discussed. RESULTS: We recorded an extremely high satisfaction rate and did not observe any complications. All of the patients returned to their normal daily activities immediately after the procedure. CONCLUSIONS: Non-surgical nose augmentation with dermal fillers is an easy, safe, and comfortable technique. It appears that dermatologists need to assume a more active role in rhinoplasty. PMID- 29264901 TI - Radiation-associated lichen planus: a case report and literature review. AB - Percutaneous radiotherapy (RT) may cause a range of acute and chronic cutaneous side-effects on irradiated areas. Localized or generalized lichen planus (LP) has occasionally been reported after RT. The mechanisms of LP are unclear. A case report and a systematic review of the literature were performed. Including the present case, 12 cases of LP have been reviewed in association with oncologic radiotherapy since 2002. Of these, 83% of patients developed LP after RT. LP occurred with a median delay of 30.7 days after RT completion and a median dose of 50 Gy. LP is a rare complication during RT that mainly occurs at the site of radiation and can sometimes spread and become generalized. Its physiopathogeny remains unclear. In some cases, patients may have preexisting but asymptomatic LP before RT. RT would therefore act as an indicator of the disease. The treatment of RT-associated LP is similar to that for any LP. PMID- 29264902 TI - A transient cutaneous relapse of AML M1 in hematological remission: a case report. AB - Leukemia cutis (LC) is described as cutaneous infiltration by neoplastic leukocytes into the epidermidis, dermis, or subcutis, resulting in clinically various skin lesions. When the infiltrate is characterized by neoplastic granulocytic precursors, LC is defined as granulocytic sarcoma. Multiple, erythematous, and infiltrated papules and nodules localized on the legs, arms, and trunk are the most common clinical presentation. Here we report a case of granulocytic sarcoma in a patient with a previous diagnosis of acute myeloid leukemia currently in hematological remission. PMID- 29264903 TI - Hyperkeratotic porokeratosis ptychotropica with satellite lesions: a rare presentation of an unusual variant of porokeratosis. AB - Since its description in 1995, porokeratosis ptychotropica (PP) has remained a less-recognized variant of porokeratosis (PK). The term porokeratosis ptychotropica was coined in reference to its characteristic of affecting body folds. It mimics many other dermatological diseases and is therefore often misdiagnosed. We report a patient with multiple hyperkeratotic, warty lesions across the buttocks that mimicked cutaneous tuberculosis (CTB), but histological examination confirmed the correct diagnosis of PP. PMID- 29264904 TI - Tungiasis: a poorly-known diagnosis in Europe. Two paradigmatic cases from Portugal. AB - Tungiasis is a cutaneous parasitosis caused by infestation of the skin by gravid fleas of the genus Tunga, mainly Tunga penetrans. This flea is very common in tropical and subtropical regions of the globe, but not in Europe. The infestation is acquired by walking barefoot or lying in places where the flea is present, usually beaches or sandy soils. We report two unrelated cases of imported tungiasis in Portugal that presented to our clinic in the same week. We draw attention to one of the most common dermatological diseases in travelers returning from tropical countries, the diagnosis of which is primarily clinical but nonetheless is largely unfamiliar to clinicians attending those patients. PMID- 29264905 TI - Congenital longitudinal melanonychia: a case report. AB - Congenital longitudinal melanonychia is rarely seen in Caucasians and poses a diagnostic dilemma. It is characterized by the presence of hyperpigmented brown or black streaks visible in the nail plate. We present the case of 20-month-old boy with congenital longitudinal melanonychia, the diagnostic procedure, and management. Dermatoscopy of the nail revealed dark brown linear hyperpigmented lines in the nail plate with an irregular color. The diagnosis of a congenital nail matrix nevus was established on clinical grounds. A wait-and-see policy was taken. A biopsy was not performed because the cause of longitudinal melanonychia is essentially benign, especially in the congenital form. Subungual melanomas are very rare and mostly appear in middle-aged patients. Clinical, dermatoscopic, and histopathological guidelines that could directly distinguish between a benign nail matrix nevus and malignant subungual melanoma in the pediatric population have not been confirmed yet. The diagnostic dilemma therefore remains open. PMID- 29264907 TI - Nanomaterials in food contact materials; considerations for risk assessment AB - Nanotechnology applications in the food industry, including food contact materials, offer many potential benefits for consumers and manufacturers alike. The article discusses the migration of nanoparticles from food contact materials and the possible health risks associated with in the context of insufficient knowledge of the potential exposure to nanomaterial. The importance of gaps in the general knowledge on the behaviour and biological interactions of nanomaterials in biological systems becomes crucial for risk assessment. The article also discussed numerous doubts concerning the measurements of biological reactions in animal tests and the need for new approaches in the interpretation of data from nanoparticles studies in vivo. The article underlines the need to develop predictive and validated toxicological tests that can be used to screen for potential hazards, and also to develop new methodology for measuring nanoparticles in biological matrices to assess human exposure. Further studies should focus on understanding the mechanisms of action. Nanoparticles exhibit chemical and physical properties that significantly differ from those substances at a large size. Different properties of nanoparticles may lead to different toxicological properties. From that reason nanoparticles, in each case, are individually assessed by the European Food Standard Agency (EFSA) in terms of health risk before the European Commission authorizes them to be used in food contact materials. PMID- 29264908 TI - Health risk as a consequence of exposure to trihalomethanes in swimming pool water AB - The article presents the formation and toxicity of trihalomethanes (THMs), substances belonging to Disinfection ByProducts (DBP), formed as a result of pool water chlorination. Concentration of THMs in pool water has been standardised in Poland since recently. THMs concentration in pool water depends on multiple factors, mostly the method of water disinfection, including chlorine or organic substance (TOC) concentration. Apart from that, the level of exposure of swimmers to the toxic effect of THMs is affected by their content in the air of swimming pool halls, intensity of swimming as well as time of stay in the indoor swimming pool area. The water and air temperature as well as number of swimmers and time of their staying in pool have also significance influence on THMs concentration. In order to decrease the quantity of THMs in pool water, alternative disinfection agents are applied. Additionally, an efficiently operating pool ventilation system as well as proper water treatment method are also important. Because THMs are produced from organic material under the influence of the chlorination, the users can have an impact on decrease of the THMs concentration in pool water, for instance by taking a shower prior to entering the pool or by wearing a swim cap. The results of studies conducted in 2015 showed that the quantity of THMs in pool water depends on type of the pool (indoor, outdoor), water replacement frequency, water treatment system, chlorine dose and TOC content. In most collected samples, the THMs concentration exceeded the admissible norm (100 MUg/L). PMID- 29264909 TI - Future management of cardiac arrhythmias: the shape of the world to come. PMID- 29264910 TI - Effect of new nutraceutical formulation with policosanol, berberine, red yeast rice, cassia nomame, astaxantine and Q10 coenzyme in patients with low-moderate dyslipidemia associated with intolerance to statins and metabolic syndrome. PMID- 29264912 TI - Fast and Automated Characterization of Antibody Variants with 4D HPLC/MS. AB - Characterization of unknown monoclonal antibody (mAb) variants is important in order to identify their potential impact on safety, potency, and stability. Ion exchange chromatography (IEC) coupled with UV detection is frequently used to separate and quantify mAb variants in routine quality control (QC). However, characterization of the chromatographic peaks resulting from an IEC separation is an extremely time-consuming process, involving many cumbersome steps. Presented here is an online four-dimensional high performance liquid chromatography-mass spectrometry (4D HPLC/MS) approach, developed to circumvent these limitations. To achieve this, a 2D HPLC system was extended through the introduction of additional modules, hence enabling fully automated bioseparation of mAbs, fractionation of peaks, reduction, tryptic digestion, and reversed-phase (RP) separation of resulting peptides followed by MS detection. The entire separation and analytical process for an unknown peak is performed in less than 1.5 h, leading to a significant time savings, with comparable sequence coverage. To show the comparability with the traditional offline process, a proof of concept study with a previously characterized mAb1 is presented in this paper. PMID- 29264911 TI - Exposure assessment of the population in Poland to the toxic effects of arsenic compounds present in rice and rice based products AB - Background: Rice is a staple food for many people in the world and an important ingredient for production of food for infants and young children. According to European Food Safety Authority (EFSA), cereals, primarily rice and rice products, are an important source of human exposure to inorganic arsenic, which has been classified by the International Agency for Research on Cancer (IARC) as group I carcinogen. Arsenic is present in rice and rice products mainly as an inorganic form being more toxic than organic compounds Objectives: The aim of the study was to determine the total and inorganic arsenic content in rice, rice-based products including food for infants and young children available on the market in Poland and thus to estimate consumer exposure to inorganic arsenic from these groups of foodstuffs Materials and Methods: A total of 62 samples of rice and rice products from trade, including a group of rice products for infants and young children, were tested. Contents of total and inorganic arsenic were determined by using hydride generation atomic absorption spectrometry (HGAAS), after dry mineralization of samples and reduction of arsenic to arsenic hydride with sodium borohydride. To extract the inorganic arsenic forms, the samples were subjected to hydrolysis in concentrated HCl and then reduced in the presence of hydrobromic acid and hydrazine sulphate after which triple chloroform extractions and triple 1M HCl re-extractions were performed. Exposure of different groups of populations (adults and children), was estimated in relation to the Benchmark Dose Lower Confidence Limit (BMDL05) as set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) that resulted in a 0.5% increase in lung cancer (3.0 ug/kg body weight (b.w.) per day) Results: Mean content of total and inorganic arsenic in investigated rice samples was 0.12 mg/kg (median: 0.09 mg/kg; 90th percentile 0.22 mg/kg) and 0.04 mg/kg (median: 0.03 mg/kg, 90th percentile 0.07 mg/kg). Brown rice was found to be more highly contaminated with both total and inorganic arsenic than white rice. Mean contamination of brown rice with total arsenic and inorganic arsenic was: 0.18 mg/kg (median: 0.12 mg/kg, 90th percentile: 0.32 mg/kg) and 0.05 mg/kg (median: 0.05 mg/kg, 90th percentile: 0.07 mg/kg). In turn for the white rice contamination was lower, mean total arsenic content: 0.10 mg/kg (median: 0.08 mg/kg, 90th percentile: 0.19 mg/kg) and mean inorganic arsenic: 0.03 mg/kg (median: 0.03 mg/kg, 90th percentile: 0.06 mg/kg). Contamination of rice-based products both total and inorganic arsenic was similar to those reported for rice, except rice wafers (mean: 0.24 mg/kg and 0.13 mg/kg). In the group of products for infants and young children obtained results were low - mean total arsenic content was 0.06 mg/kg and inorganic arsenic 0.02 mg/kg. The estimated average adult and children's exposure to inorganic arsenic with rice and rice products was less than 1% of the BMDL05. Intake of inorganic arsenic by 12-month-old infants with ricebased products intended for this group of population was at 6% BMDL05 Conclusions: Based on the obtained results, it was found that the content of total and inorganic arsenic in investigated samples of rice and rice products did not pose a health risk even though contamination levels in some individual samples were significant PMID- 29264913 TI - Polyelectrolyte Brush-Grafted Polydopamine-Based Catalysts with Enhanced Catalytic Activity and Stability. AB - Three types of surface treatments, namely, polyethyleneimine (PEI) coating, short PEI (S-PEI) grafting, and long PEI (L-PEI) grafting, were performed on polydopamine (Pdop)-based catalysts to enhance their catalytic activity and stability. Brush-grafted catalysts were prepared by the stepwise synthesis of Au and short (or long) PEI brushes on Pdop particles (PdopP/Au/S- or L-PEI grafting). PEI-coated Pdop-based catalysts (PdopP/Au/PEI coating) were also prepared as non-brush-grafted catalysts. Among the surface-treated PdopP/Au catalysts, the brush-grafted catalysts (S-PEI and L-PEI grafting) exhibited excellent and stable catalytic performance because the brush grafting enabled the protection of the catalysts against harsh conditions, effective transfer of reactants to the catalysts, and confinement of reactants around the catalysts. The brush-grafted catalysts could also more effectively decompose larger dyes than the non-brush-grafted catalysts. The process-to-effectiveness of PEI coating is the best because the release of Pdop from PdopP/Au was moderately inhibited by the presence of only one layer of PEI coating on the PdopP/Au. Thus, this approach could be an alternative method to enhance the stability of PdopP/Au catalysts. PMID- 29264914 TI - Xanthine Quartets on Au(111). AB - The quartet of xanthine (X), a purine base ubiquitously distributed in most human body tissues and fluids, has been for the first time fabricated and visualized, as the first alternative purine quartet besides the known guanine (G)-quartet. The X-quartet network is demonstrated to be the most stable phase on Au(111). Unlike guanine, the fabrication of the X-quartets is not dependent on the presence of metal atoms, which makes it the first metal-free purine quartet. The X-quartet holds great promise to potentially construct artificial new DNA quadruplexes for genetic regulation and antitumor therapy. Moreover, both the X quartet itself and the quartet networks favor homochirality, suggesting homochiral xanthine oligomers and the networks may have been formed as the precursors of the pristine oligonucleotides on primitive Earth. PMID- 29264915 TI - Counteranion-Mediated Intrinsic Healing of Poly(ionic liquid) Copolymers. AB - Fabrication of self-healing/healable materials using reversible interactions that are governed by their inherent chemical features is highly desirable because it avoids the introduction of extra groups that may present negative effects on their functions. The present study exploits the inherently featured electrostatic interactions of the ion pairs in polymeric ionic liquids (PILs) as the driving force to fabricate healable PIL copolymers. The healable PIL copolymers are fabricated through the copolymerization of the IL monomers with ethyl acrylate followed by the replacement of Br- counteranions with bulkier ones such as bis(trifluoromethanesulfonyl)imide (TFSI-). Without modifying the chemical structures of the PIL moieties, the healing performance of the as-prepared PIL copolymers can be effectively mediated by their counteranions. The PIL copolymers that do not possess healability when paired with Br- counteranions become healable after exchanging the Br- counteranions with larger-sized ones (e.g., TFSI-). The PIL copolymers paired with bulky counteranions exhibit enhanced chain mobility and highly reversible ion-pair interactions, which facilitate the healing process. The PIL copolymers paired with TFSI- anions can completely heal the damage/cut upon heating at 55 degrees C for 7.5 h. Meanwhile, the counteranions with larger sizes not only benefit the healing performance of the PIL copolymers but also enhance their ion conductivity. The ion conductivity of the PIL copolymers paired with TFSI- is an order of magnitude higher than that of the PIL copolymers paired with Br-. Therefore, the as-prepared healable PIL copolymers are potentially useful as solid electrolytes in PIL-based energy devices to improve their safety and reliability. PMID- 29264916 TI - Palladium-Catalyzed Reaction of [60]Fullerene with Aroyl Compounds via Enolate Mediated sp2 C-H Bond Activation and Hydroxylation. AB - A convenient and highly efficient palladium-catalyzed reaction of [60]fullerene (C60) with aroyl compounds via enolate-mediated C-H activation and hydroxylation has been exploited for the first time to synthesize novel C60-fused dihydrofurans, and rare 1,4-fullerenols. Further functionalization including etherification, and esterification of synthesized 1,4-fullerenols provided efficient access to versatile fullerene derivatives. Moreover, a plausible reaction mechanism leading to the observed products is proposed. PMID- 29264917 TI - Bicarbonate Alters Bacterial Susceptibility to Antibiotics by Targeting the Proton Motive Force. AB - The antibacterial properties of sodium bicarbonate have been known for years, yet the molecular understanding of its mechanism of action is still lacking. Utilizing chemical-chemical combinations, we first explored the effect of bicarbonate on the activity of conventional antibiotics to infer on the mechanism. Remarkably, the activity of 8 classes of antibiotics differed in the presence of this ubiquitous buffer. These interactions and a study of mechanism of action revealed that, at physiological concentrations, bicarbonate is a selective dissipater of the pH gradient of the proton motive force across the cytoplasmic membrane of both Gram-negative and Gram-positive bacteria. Further, while components that make up innate immunity have been extensively studied, a link to bicarbonate, the dominant buffer in the extracellular fluid, has never been made. Here, we also explored the effects of bicarbonate on components of innate immunity. Although the immune response and the buffering system have distinct functions in the body, we posit there is interplay between these, as the antimicrobial properties of several components of innate immunity were enhanced by a physiological concentration of bicarbonate. Our findings implicate bicarbonate as an overlooked potentiator of host immunity in the defense against pathogens. Overall, the unique mechanism of action of bicarbonate has far reaching and predictable effects on the activity of innate immune components and antibiotics. We conclude that bicarbonate has remarkable power as an antibiotic adjuvant and suggest that there is great potential to exploit this activity in the discovery and development of new antibacterial drugs by leveraging testing paradigms that better reflect the physiological concentration of bicarbonate. PMID- 29264918 TI - Preferentially Oriented Ag Nanocrystals with Extremely High Activity and Faradaic Efficiency for CO2 Electrochemical Reduction to CO. AB - Selective electrochemical reduction of CO2 is one of the most important processes to study because of its promise to convert this greenhouse gas to value-added chemicals at low cost. In this work, a simple anodization treatment was devised that first oxidizes Ag to Ag2CO3, then uses rapid electrochemical reduction to create preferentially oriented nanoparticles (PONs) of metallic Ag (PON-Ag) with high surface area as well as high activity and very high selectivity for the reduction of CO2 to CO. The PON-Ag catalyst was dominated by (110) and (100) orientation, which allowed PON-Ag to achieve a CO Faradaic efficiency of 96.7% at an operating potential of -0.69 V vs RHE. This performance is not only significantly higher than that of polycrystalline Ag (60% at -0.87 V vs RHE) but also represents one of the best combinations of activity and selectivity achieved to date - all with a very simple, scalable approach to electrode fabrication. PMID- 29264919 TI - Ion-Gel-Gated Graphene Optical Modulator with Hysteretic Behavior. AB - We propose a graphene-based optical modulator and comprehensively investigate its photonic characteristics by electrically controlling the device with an ion-gel top-gate dielectric. The density of the electrically driven charge carriers in the ion-gel gate dielectric plays a key role in tuning the optical output power of the device. The charge density at the ion-gel-graphene interface is tuned electrically, and the chemical potential of graphene is then changed to control its light absorption strength. The optical behavior of the ion-gel gate dielectric exhibits a large hysteresis which originates from the inherent nature of the ionic gel and the graphene-ion-gel interface and a slow polarization response time of ions. The photonic device is applicable to both TE- and TM polarized light waves, covering two entire optical communication bands, the O band (1.26-1.36 MUm) and the C-band (1.52-1.565 MUm). The experimental results are in good agreement with theoretically simulated predictions. The temporal behavior of the ion-gel-graphene-integrated optical modulator reveals a long-term modulation state because of the relatively low mobility of the ions in the ion gel solution and formation of the electric double layer in the graphene-ion-gel interface. Fast dynamic recovery is observed by applying an opposite voltage gate pulse. This study paves the way to the understanding of the operational principles and future applications of ion-gel-gated graphene optical devices in photonics. PMID- 29264920 TI - Cellulose Crystal Dissolution in Imidazolium-Based Ionic Liquids: A Theoretical Study. AB - The highly crystalline nature of cellulose results in poor processability and solubility, necessitating the search for solvents that can efficiently dissolve this material. Thus, ionic liquids (ILs) have recently been shown to be well suited for this purpose, although the corresponding dissolution mechanism has not been studied in detail. Herein, we adopt a molecular dynamics (MD) approach to study the dissolution of model cellulose crystal structures in imidazolium-based ILs and gain deep mechanistic insights, demonstrating that dissolution involves IL penetration-induced cleavage of hydrogen bonds between cellulose molecular chains. Moreover, we reveal that in ILs with high cellulose dissolving power (powerful solvents, such as 1-allyl-3-methylimidazolium chloride and 1-ethyl-3 methylimidazolium chloride), the above molecular chains are peeled from the crystal phase and subsequently dispersed in the solvent, whereas no significant structural changes are observed in poor-dissolving-power solvents. Finally, we utilize MD trajectory analysis to show that the solubility of microcrystalline cellulose is well correlated with the number of intermolecular hydrogen bonds in cellulose crystals. The obtained results allow us to conclude that both anions and cations of high-dissolving-power ILs contribute to the stepwise breakage of hydrogen bonds between cellulose chains, whereas this breakage does not occur to a sufficient extent in poorly solubilizing ILs. PMID- 29264921 TI - In Vitro Digestibility of Rapeseed and Bovine Whey Protein Mixtures. AB - Partial replacement of animal protein sources with plant proteins is highly relevant for the food industry, but potential effects on protein digestibility need to be established. In this study, the in vitro protein digestibility (IVPD) of four protein sources and their mixtures (50:50 w/w ratio) was investigated using a transient pepsin hydrolysis (1 h) followed by pancreatin (1 h). The protein sources consisted of napin-rich rapeseed (Brassica napus L.) protein concentrates (RPCs; RP1, RP2) prepared in pilot scale and major bovine whey proteins (WPs; alpha-LA, alpha-lactalbumin; beta-LG, beta-lactoglobulin). IVPD of individual protein sources was higher for WPs compared to RPCs. The RP2/beta-LG mixture resulted in an unexpected high IVPD equivalent to beta-LG protein alone. Protein mixtures containing RP1 showed a new IVPD response type due to the negative influence of a high trypsin inhibitor activity (TIA) level. Improved IVPD of RP1 alone and in protein mixtures was obtained by lowering the TIA level using dithiothreitol (DTT). These results showed that napin-rich protein products prepared by appropriate processing can be combined with specific WPs in mixtures to improve the IVPD. PMID- 29264922 TI - Smart Hybrid Graphene Hydrogels: A Study of the Different Responses to Mechanical Stretching Stimulus. AB - Polymer-based hydrogels, in particular those containing nanoscale fillers, are currently regarded as promising candidates for a plethora of applications. With respect to graphene, the vast majority of publications concern chemical derivatives, and, as a consequence, knowledge of the potential of pristine graphene within these systems is lacking. In this study, novel graphene-based hydrogels containing nonoxidized graphene have been prepared by a mild aqueous process. The mechanical and electrical properties of these hybrid materials were characterized. In the compositions studied, maximum improvements of Young's modulus, ultimate tensile strength, and toughness of 30, 100, and 70% were obtained, respectively. In addition to obtaining an improved hybrid material in terms of mechanical and electrical properties, the response experienced by these systems on applying mechanical stretching was evaluated and stimuli-response behavior is generated by the presence of graphene. Two different kinds of responses were found. A significant change in electrical resistance was observed with a strain gauge effect and with an average gauge factor of ~9 (for 30% strain). The electromechanical performance of these hybrid hydrogels was tested for a range of mechanical strains and graphene contents, and the stability of these materials was assessed with successive stretching cycles. It was also observed that upon stretching these hybrid hydrogels were able to release the internalized water more efficiently in the presence of graphene, and, as a result, a second possible stimulus response was studied in the form of controlled drug delivery as a proof of concept. The release of a loaded aqueous solution of ibuprofen stimulated by controlled stretching and aided by wet capillary was studied. Much more efficient delivery was achieved in the presence of graphene. These novel systems can be used in the future for sensing or drug-delivery applications. PMID- 29264923 TI - Palmitoylation and Membrane Binding of Arc/Arg3.1: A Potential Role in Synaptic Depression. AB - Activity-regulated cytoskeletal-associated protein (Arc, also known as activity regulated gene 3.1 or Arg3.1) is induced in neurons in response to salient experience and neural activity and is necessary for activity-induced forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), cellular substrates of learning and memory. The best characterized function of Arc is enhancement of the endocytic internalization of AMPA receptors in dendritic spines, a process associated with LTD. Arc has also been implicated in the proteolytic processing of amyloid precursor protein on the surface of endosomes. To mediate these activities, Arc must associate with cellular membranes, but it is unclear whether Arc binds directly to the lipid bilayer or requires protein-protein interactions for membrane recruitment. In this study, we show that Arc associates with pure phospholipid vesicles in vitro and undergoes palmitoylation in neurons, a modification that allows it to insert directly into the hydrophobic core of the bilayer. The palmitoylated cysteines are clustered in a motif, 94CLCRC98, located in the N-terminal half of the protein, which has not yet been structurally characterized. Expression of Arc with three mutated cysteines in that motif cannot support synaptic depression induced by the activity-dependent transcription factor, MEF2 (myocyte enhancer factor 2), in contrast to wild-type Arc. Thus, it appears that palmitoylation regulates at least a subset of Arc functions in synaptic plasticity. PMID- 29264924 TI - Vibrational Energy Relaxation: A Benchmark for Mixed Quantum-Classical Methods. AB - We investigate the ability of mixed quantum-classical methods to capture the dynamics of vibrational energy relaxation. Several methods, including surface hopping, and Ehrenfest and symmetrical quasiclassical (SQC) dynamics, are benchmarked for the exactly solvable model problem of a harmonic oscillator bilinearly coupled to a bath of harmonic oscillators. Results show that, very often, one can recover accurate vibrational relaxation rates and detailed balance using simple mixed quantum-classical approaches. A few anomalous results do appear, however, especially regarding Ehrenfest and SQC dynamics. PMID- 29264925 TI - Modulation of the Fecal Microbiota in Sprague-Dawley Rats Using Genetically Modified and Isogenic Corn Lines. AB - This study investigated the composition and proportions of fecal microbiota in Sprague-Dawley rats after consuming two genetically modified (GM) corn lines in comparison with the isogenic corn and the AIN93G standard feed for 10 weeks using bar-coded 16S rRNA gene sequencing. As a result, GM corn did not significantly alter the overall health and alpha-diversity of fecal microbiota. Fecal microbiota structures could be separated into noncorn and corn but not non-GM and GM corn subgroups. Both non-GM and GM corn caused the increase in bacterial populations related to carbohydrates utilization, such as Lactobacillus, Barnesiella, and Bifidobacterium, and the reduction in potentially pathogenic populations, such as Tannerella and Moraxellaceae. In conclusion, similar effects on the fecal microbiota were observed after consuming a GM- and non-GM-corn-based diet for long periods. Further studies are warranted to elucidate the functional relevance of the changes in the proportions of bacterial populations in these diets. PMID- 29264926 TI - Thermal Boundary Layer Effects on Line-of-Sight Tunable Diode Laser Absorption Spectroscopy (TDLAS) Gas Concentration Measurements. AB - The effects of thermal boundary layers on tunable diode laser absorption spectroscopy (TDLAS) measurement results must be quantified when using the line of-sight (LOS) TDLAS under conditions with spatial temperature gradient. In this paper, a new methodology based on spectral simulation is presented quantifying the LOS TDLAS measurement deviation under conditions with thermal boundary layers. The effects of different temperature gradients and thermal boundary layer thickness on spectral collisional widths and gas concentration measurements are quantified. A CO2 TDLAS spectrometer, which has two gas cells to generate the spatial temperature gradients, was employed to validate the simulation results. The measured deviations and LOS averaged collisional widths are in very good agreement with the simulated results for conditions with different temperature gradients. We demonstrate quantification of thermal boundary layers' thickness with proposed method by exploitation of the LOS averaged the collisional width of the path-integrated spectrum. PMID- 29264928 TI - ABCG2 as a therapeutic target candidate for gout. AB - INTRODUCTION: Hyperuricemia (chronically elevated serum uric acid) is the main pathology underlying the development of gout, the most common inflammatory arthropathy. Management of these conditions therefore relies on controlling serum uric acid levels. ATP-binding cassette transporter, sub-family G, member 2 (ABCG2/BCRP) is a well-studied urate transporter expressed on apical membranes in several tissues, including the intestine, liver, and kidney. Here, we discuss the potential of future gout therapies targeting ABCG2. Areas covered: ABCG2 regulates serum uric acid via physiologically important roles in both renal and extra-renal urate excretion. ABCG2 dysfunction, which promotes onset of hyperuricemia, often results in decreased urate excretion through the extra-renal (principally intestinal), rather than the renal pathway. This review covers recent attempts to establish the basis of ABCG2 function according to genetic diathesis, its molecular structure, and the effects of medication. Furthermore, the possibility of treating gout and hyperuricemia by upregulating intestinal ABCG2 expression is examined. Expert opinion: ABCG2 holds great promise as a therapeutic target for these conditions, particularly considering its involvement in extra-renal urate excretion. Manipulation of ABCG2, including controlling the level and location of its expression, has the potential to prevent gout by promoting uric acid excretion as effectively as general uricosuric drugs. ABBREVIATIONS: ATP-binding cassette (ABC), transmembrane domain (TMD), nucleotide binding domain (NBD), single nucleotide polymorphism (SNP), single nucleotide polymorphisms (SNPs). PMID- 29264929 TI - Detection of peptides with intact phosphate groups using MALDI TOF/TOF and comparison with the ESI-MS/MS. AB - A wide variety of post-translational modifications such as oxidation, phosphorylation, glycosylation, methylation, and acetylation play critical roles in cellular functions. Detection of post-translational modifications in proteins is important to understand their crucial roles in cellular functions. Identifying each modification requires special attention in mass spectral acquisition and analysis. Here, we report a mass spectral method for the detection of multiple phosphorylations in peptides by analyzing their products after fragmentation. Synthetic peptides were used to identify these modifications by matrix-assisted laser desorption/ionization (MALDI) TOF/TOF. Peptides with serine, threonine, and tyrosine were used with mono- to tetra-phosphorylation sites in different combinations to get insights into their fragmentation and identify the location of these sites. The y-ion series were observed without the loss of phosphate groups and were thus very useful in determining the localization and sequence of the phosphate residues. Acetylation of the peptides was found to be useful in detecting the b1-ion and helped in identifying the N-terminus. When a mixture of the phosphorylated peptides (from mouse protein sequences) were analyzed by LC MS/MS on a Velos Orbitrap Mass Spectrometer and the data subjected to analysis by Sequest using the mouse database, the peptides were identified along with the parent proteins. A comparison of MALDI TOF/TOF spectra with ESI MS/MS helped in eliminating falsely discovered peptides using the database search. PMID- 29264931 TI - French translation and validation of the "Anterior Knee Pain Scale" (AKPS). AB - PURPOSE: To linguistically and cross-culturally translate the Anterior Knee Pain Scale into French and to evaluate the reliability and validity of this translated version of the questionnaire. METHODS: The translation part was performed in six stages, according to international guidelines: (i) two initial translations from English to French; (ii) synthesis of the two translations; (iii) backward translations into the original language; (iv) expert committee to compare the backward translations with the original questionnaire; (v) pre-final version testing and (VI) expert committee appraisal. To validate the French version of the Anterior Knee Pain Scale, we assessed its validity, reliability and floor/ceiling effects. To do this, volunteer patients from the French part of Belgium and from France, with patellofemoral pain were asked to answer the French version of the Anterior Knee Pain Scale at baseline and after 7 days, as well as the generic SF-36 questionnaire. RESULTS: The Anterior Knee Pain Scale was translated without any major difficulties. A total of 101 subjects aged 34.5 +/- 11.4 years (58.4% of women) were included in this study. Results indicated an excellent test-retest reliability (Intra-class correlation coefficient (ICC) = 0.97, 95%CI: 0.96-0.98), a high internal consistency (Cronbach's alpha = 0.87), a consistent construct validity (high correlations with the SF-36 questionnaire were found with domains related to physical function (r = 0.80), physical role (r = 0.70) and pain (r = 0.64)) and low or moderate correlations with domains related to mental health (r = 0.26), vitality (r = 0.32) and social function (r = 0.41). Moreover, no floor/ceiling effects have been found. CONCLUSIONS: A valid French version of the Anterior Knee Pain Scale is now available and can be used with confidence to better assess the disease burden associated with patellofemoral pain. It was successfully cross-culturally adapted into French. Implications for rehabilitation The results on psychometric properties of the French Anterior Knee Pain Scale are comparable with six validated versions obtained for the Finnish, the Turkish, the Chinese, the Dutch, the Thai and the Persian populations. The French translated version of the Anterior Knee Pain Scale is a reliable and valid instrument for assessing the functional limitations associated with patellofemoral pain. The test-retest reliability of the French Anterior Knee Pain Scale was excellent, the internal consistency was high and the construct validity was consistent. There were no floor/ceiling effects. PMID- 29264930 TI - Study protocol for the dabigatran, apixaban, rivaroxaban, edoxaban, warfarin comparative effectiveness research study. AB - : Since 2010, four oral anticoagulants have been approved for marketing in addition to warfarin for treatment of thromboembolic disease. Limited head-to head data exist comparing these treatments, leaving patients and clinicians with little guidance for selecting a strategy that balances recurrence reduction with bleeding risk. In the dabigatran, apixaban, rivaroxban, edoxaban and warfarin comparative effectiveness research study, we compare all five currently available oral anticoagulant agents for the extended treatment of deep venous thrombosis and pulmonary embolism, as well as no extended treatment, and evaluate whether results differ in specific sub-populations. As our population includes Medicare novel anticoagulant users and large numbers of commercially insured and Medicaid patients, our results will likely be transportable to the majority of US patients experiencing a DVT or pulmonary embolism. CLINICAL TRIALS REGISTRATION: NCT03271450. PMID- 29264927 TI - Toxicology Evaluation of Drugs Administered via Uncommon Routes: Intranasal, Intraocular, Intrathecal/Intraspinal, and Intra-Articular. AB - As the need for nasal, ocular, spinal, and articular therapeutic compounds increases, toxicology assessments of drugs administered via these routes play an important role in human safety. This symposium outlined the local and systemic evaluation to support safety during the development of these drugs in nonclinical models with some case studies. Discussions included selection of appropriate species for the intended route; conducting nonclinical studies that closely mimic the intended use with adequate duration; functional assessment, if deemed necessary; evaluation of local tissues with special histological staining procedure; and evaluations of safety margins based on local and systemic toxicity. PMID- 29264932 TI - A comprehensive review on two-stage integrative schemes for the valorization of dark fermentative effluents. AB - This review provides the alternative routes towards the valorization of dark H2 fermentation effluents that are mainly rich in volatile fatty acids such as acetate and butyrate. Various enhancement and alternative routes such as photo fermentation, anaerobic digestion, utilization of microbial electrochemical systems, and algal system towards the generation of bioenergy and electricity and also for efficient organic matter utilization are highlighted. What is more, various integration schemes and two-stage fermentation for the possible scale up are reviewed. Moreover, recent progress for enhanced performance towards waste stabilization and overall utilization of useful and higher COD present in the organic source into value-added products are extensively discussed. PMID- 29264933 TI - Patient and prescriber characteristics among patients with type 2 diabetes mellitus continuing or discontinuing sulfonylureas following insulin initiation: data from a large commercial database. AB - OBJECTIVE: To describe patient and provider characteristics for patients with type 2 diabetes (T2DM) initiating basal insulin and describe basal insulin's impact on sulfonylurea (SU) discontinuation. METHODS: A retrospective cohort study was conducted using the HealthCore Integrated Research Database. Patients had >=12 months of continuous coverage prior to initiating insulin, and were utilizing at least one anti-hyperglycemic drug at the time of insulin initiation. Predictors for SU discontinuation were evaluated utilizing Cox proportional hazards models. RESULTS: Among the 74,334 individuals aged >=18 years with T2DM who initiated basal insulin from 2006-2015, 30% were taking metformin (MET) and SU when initiating insulin. Among the 22,418 MET/SU patients, 31% discontinued SU within 3 months of insulin initiation and, by 12 months, 55% had discontinued SU. Sulfonylurea discontinuation was similar among many patient and provider characteristics, while being modestly positively associated (p < .05; HRs <1.5) with female gender, more co-morbidities, cardiac revascularization, chronic liver disease, hospitalizations with a T2DM diagnosis, and hypoglycemia prior to insulin initiation. SU discontinuation was modestly inversely associated with receiving an insulin prescription from an endocrinologist (HR = 0.90, 95% CI = 0.85-0.95). CONCLUSIONS: Roughly half of commercially-insured T2DM patients discontinued SU within 1 year after insulin initiation, and SU discontinuation was not strongly associated with a range of patient and provider characteristics. PMID- 29264934 TI - Pharmacoeconomic study comparing carbetocin with oxytocin for the prevention of hemorrhage following cesarean delivery in Lima, Peru. AB - : Postpartum hemorrhage is one of the main causes of maternal death. Oxytocin has traditionally been used to prevent postpartum hemorrhage. AIM: To compare oxytocin with carbetocin, a long-acting analog of oxytocin, for prevention of uterine hemorrhage after cesarean delivery. MATERIALS & METHODS: Clinical data were retrieved from the 2012 Cochrane meta-analysis "Carbetocin for preventing postpartum hemorrhage". A decision tree was constructed. The direct costs were those of medications from the Peruvian official price list (DIGEMID). Costs associated with additional oxytocic drugs, blood transfusions, postpartum hemorrhage kits and hysterectomy were obtained from Hospital Nacional Edgardo Rebagliati Martins. The perspective of the study was that of the payer. The time horizon for calculating quality-adjusted life years (QALYs) was 1 year (2015). RESULTS: Patients who received carbetocin required fewer additional uterotonic agents, had fewer hemorrhages and received fewer blood transfusions. Therefore, the costs associated with these interventions were lower. The incremental cost effectiveness ratio was S/. 49,918 per QALY gained, which is lower than the threshold we estimated for Peru. CONCLUSION: Carbetocin is more cost-effective than oxytocin for prevention of uterine hemorrhage after cesarean delivery. PMID- 29264935 TI - Expression pattern of high-affinity tyrosine kinase Aduring the development of human fetal spinal cord. AB - High-affinity tyrosine kinase A (TrkA) is responsible for the biological activities of nerve growth factor. Most studies of the molecular mechanisms of TrkA that underlie the development of the spinal cord have been conducted in animals and the expression pattern of TrkA during the development of the human fetal spinal cord is not well characterized. We investigated 45 3-28-week-old (G3W-G28W) human fetuses. We assessed the expression pattern of TrkA in the human fetal spinal cord using immunohistochemistry, western blot and reverse transcription polymerase chain reaction to clarify the spatiotemporal developmental changes and to determine the role TrkA plays in development. TrkA immunoreactive products were detected widely in the alar and basal plates, ependyma, glial cells, gray and white matter, internal limiting membrane, mantle layer, marginal layer, neuroepithelium and neurons during this period of development. Expression levels of TrkA mRNA and protein peaked at G12W and G16W, respectively. The strong expression of TrkA was closely related to the formation of the dorsal and ventral horns, and the differentiation of somatic motor neurons during late embryonic development. Our findings suggest that TrkA receptors play crucial roles during the development of human fetal spinal cord. The characteristic expression patterns may clarify the developmental characteristics of the human spinal cord. PMID- 29264936 TI - An update on new and emerging therapies for cystic fibrosis. AB - INTRODUCTION: Cystic fibrosis (CF) is a genetic disorder that results in a multi organ disease with progressive respiratory decline that ultimately leads to premature death. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for the CFTR anion channel. Established CF treatments target downstream manifestations of the primary genetic defect, including pulmonary and nutritional interventions. Areas covered: CFTR modulators are novel therapies that improve the function of CFTR, and have been approved in the past five years to mitigate the effects of several CF-disease causing mutations. This review summarizes currently approved CFTR modulators and discusses emerging modulator therapies in phase II and III clinical trials described on clinical trials.gov as of April, 2017. Results of relevant trials reported in peer-reviewed journals in Pubmed, scientific conference abstracts and sponsor press releases available as of November, 2017 are included. Expert opinion: The current scope of CF therapeutic development is robust and CFTR modulators have demonstrated significant benefit to patients with specific CFTR mutations. We anticipate that in the future healthcare providers will be faced with a different treatment paradigm, initiating CFTR-directed therapies well before the onset of progressive lung disease. PMID- 29264938 TI - A concise review of BCL-2 inhibition in acute myeloid leukemia. AB - INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal proliferation of myeloid precursors with impaired ability to differentiate to mature cells causing accumulation of leukemic blasts in bone marrow, peripheral blood, and extramedullary tissue. Our understanding of the genomic landscape of AML has improved prognostic accuracy and lead to the development of targeted therapies. In 2017 the Food and Drug Administration (FDA) approved midostaurin, gemtuzumab ozogamicin, CPX-351 and enasidenib for the treatment of AML. There are many novel agents under investigation for treatment of AML, but those that inhibit the anti-apoptotic molecule BCL-2 are of particular interest due to strong pre-clinical data and early promising clinical results. Areas covered: This article provides an overview of the pathophysiology of BCL-2 inhibition in AML, biomarkers and resistance mechanisms to BCL-2 inhibition and an update of results of the preclinical and clinical trials. Expert commentary: Venetoclax-based combination treatment for newly diagnosed elderly patients for whom intense chemotherapy is not an option may be the first setting in which this agent may be employed in AML. Based on pre-clinical evidence, BCL-2 inhibition may be useful in relapsed/refractory disease in conjunction with cytotoxic therapy, but has modest single agent activity. PMID- 29264937 TI - Rationale and design of the IMPACT EU-trial: improve management of heart failure with procalcitonin biomarkers in cardiology (BIC)-18. AB - OBJECTIVES: To evaluate the effectiveness of procalcitonin (PCT)-guided antibiotic treatment compared to current treatment practice to reduce 90-day all cause mortality in emergency patients with shortness of breath (SOB) and suspected acute heart failure (AHF). BACKGROUND: Concomitant AHF and lower respiratory tract (or other bacterial) infection in emergency patients with dyspnea are common and can be difficult to diagnose. Early and adequate initiation of antibiotic therapy (ABX) significantly improves patient outcome, but superfluous prescription of ABX maybe harmful. METHODS: In a multicentre, prospective, randomized, controlled process trial with an open intervention, adult emergency patients with SOB and increased levels of natriuretic peptides will be randomized to either a standard care group or a PCT-guided group with respect to the initiation of antibiotic treatment. In the PCT-guided group, the initiation of antibiotic therapy is based on the results of acute PCT measurements at admission, using a cut-off of 0.2 ng/ml. A two-stage sample-size adaptive design is used; an interim analysis was done after completion of 50% of patients and the final sample size remained unchanged. Primary endpoint is 90-day all-cause mortality. CONCLUSIONS: The current study will provide evidence, whether the routine use of PCT in patients with suspected AHF improves outcome. PMID- 29264939 TI - Clinical and care intensity differences among patients suffering from somatic diseases electively referred to a consultation and liaison service. AB - : Background This investigation mainly explores possible care differences among patients hospitalized because of medical conditions being electively referred to a psychiatric-psychosomatic consultation and liaison service. Methods A four-year survey ( N = 2518 individuals) based on clinical and care variables selected from the basic documentation. STATISTICS: Chi-square tests, analysis of variance, logistic and multivariate regression analyses, considering statistical modeling assumptions. Results A current psychiatric comorbidity has been found in 75% (less in cancer patients), mainly adjustment and anxiety (45%), mood (22%), and organic mental disorders (12%). The functioning score (Global Assessment of Functioning) was 59.4 and was especially low in patients suffering from unclear medical conditions. The performance status (Eastern Cooperative Oncology Group) amounted to 1.63 and was especially high in patients suffering from orthopedic conditions, infections, and cancer. Each patient received on average of 2.26 (SD = 2.81) contacts and 111 minutes (SD = 160) of total treatment time. In multivariate models, care differences among medical conditions are reduced. Men and older people have received less than the average amount of treatment, but psychiatrically comorbid patients and those with lower functionality and performance status have received more intensive psychological support. Conclusions As a quality feature of consultation and liaison service, patients suffering from psychiatric comorbidity, lower functionality, and lower performance status receive more intensive care and more post-discharge recommendations. Cancer patients and patients with pain as a leading diagnosis as well as strained mothers of hospitalized children have received more intensive treatment by consultation and liaison service despite lower psychiatric comorbidity levels. More attention has to be paid to men and older people independently of their physical condition. PMID- 29264940 TI - Caring for a life in and out of my hands. PMID- 29264941 TI - A 90-year-old man with factious disorder: Separating fact from fiction. AB - Objective Factitious disorders are known to exist in the medical community but are not commonly diagnosed in clinical practice. The majority of the literature on factitious disorder comes from case reports or case series. This particular case is unusual because it describes a patient who initially presented with purely physical complaints, but over time, the symptoms transitioned into predominantly psychiatric concerns. This case describes the patient's unique presentation and is followed by a discussion of the management of factitious disorder. Methods The patient was seen during the course of an inpatient psychiatric hospitalization. Electronic chart review was conducted, and information from each prior hospitalization was gathered between the dates of first initial documented presentation available in the electronic record in 1995 to most recent hospitalization in 2017. Results The patient still continues to present to the emergency department. Upon each presentation, staff work to objectively assess his complaints to be sure that there is no true underlying medical emergency. There is also a focus on providing non-judgmental, supportive, and compassionate care. Conclusion This case highlights the importance of corroborating objective findings with the patient's subjective reports gathered during a history and physical, and to recognize that patients with this disorder can present to any specialty. Thus, the collaboration between specialties is critical in the care of these patients to minimize unnecessary, costly, and sometimes dangerous interventions. PMID- 29264942 TI - MethSurv: a web tool to perform multivariable survival analysis using DNA methylation data. AB - AIM: To develop a web tool for survival analysis based on CpG methylation patterns. MATERIALS & METHODS: We utilized methylome data from 'The Cancer Genome Atlas' and used the Cox proportional-hazards model to develop an interactive web interface for survival analysis. RESULTS: MethSurv enables survival analysis for a CpG located in or around the proximity of a query gene. For further mining, cluster analysis for a query gene to associate methylation patterns with clinical characteristics and browsing of top biomarkers for each cancer type are provided. MethSurv includes 7358 methylomes from 25 different human cancers. CONCLUSION: The MethSurv tool is a valuable platform for the researchers without programming skills to perform the initial assessment of methylation-based cancer biomarkers. PMID- 29264944 TI - Individualized dosing with axitinib: rationale and practical guidance. AB - Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety. PMID- 29264945 TI - Smooth Factor Analysis (SFA) to Effectively Remove High Levels of Noise from Spectral Data Sets. AB - Smooth factor analysis (SFA) is introduced as an effective method of removing heavy noise from spectral data sets. A modified form of the nonlinear iterative partial least squares (NIPALS) algorithm involving the smoothing of factors at each step is used in SFA. Compared with the conventional smoothing techniques for individual spectra, SFA is much more effective in the treatment of very noisy spectra (~40% noise level). Smooth factor analysis invokes a large number of smooth factors to retain pertinent spectral information for high fidelity without distortion. This approach can be used as an effective general pretreatment procedure for multivariate spectral data analysis, such as principal component analysis (PCA) and partial least squares (PLS). This SFA method was also applied to the real experimental data, and its results successfully demonstrated the powerful potential for effective noise removal. Furthermore, this treatment is found to be very helpful to assist effective interpretation of two-dimensional correlation spectroscopy (2D-COS) spectra with very high noise level, which was not possible before. PMID- 29264946 TI - Particle morphology: an important factor affecting drug delivery by nanocarriers into solid tumors. AB - INTRODUCTION: Efficient delivery of drugs by nanoparticles deep into solid tumors is the precondition of valid cancer therapy. Despite profound understanding of the delivery of spherical nanoparticles into solid tumor attained, insufficient attention was paid to anisotropic particles. Actually, owing to their structural asymmetry, some non-spherical particles exhibit significant advantages over their spherical counterparts. Areas covered: This review will focus on particles with different shapes (discoidal particle, nanorod, filamentous particle, single walled carbon nanotube) and the influence of their morphological characteristics (size, aspect ratio, rigidity) on the process of drug delivery to solid tumor in view of systemic circulation, transport from circulation system to tumor tissue, intratumoral transport and uptake by tumor cells, on the basis of introduction of challenges for drug delivery to solid tumor. In addition, the morphological characteristics will be briefly introduced to provide an understanding of anisotropic particle morphology. Expert opinion: Anisotropic particles exhibit desirable properties such as enhanced circulation time and efficient tumor penetration that could serve as an enlightenment in the exploitation of novel non spherical nanocarriers to clinical therapy. Yet, current understanding of how anisotropic particles interact with organism is insufficient, which restricts the biomedical application of anisotropic particles. Further work is desired for the development of practical fabrication of anisotropic particles, quantitative analysis of particle morphology, as well as profound understanding of new targeting mechanism and intratumoral penetration of anisotropic particles. PMID- 29264948 TI - Biomarkers for high-risk influenza patients: what are the next steps? PMID- 29264949 TI - Impact of nanosilver on gut microbiota: a vulnerable link. AB - A plethora of nanoparticles are currently used in the food industry in myriad applications. Of these, 'nanosilver' is widely used due to their multitude actions. Recent consensus among the scientific community affirmed that nanosilver might potentially alter the gut microbiota instead of their intended use that has a profound effect on our health. Dysbiosis of gut microbiota led to the onset of serious pathological conditions as reflected from several studies. In lieu of the positive impact of nanosilver, their inadvertent toxic effects on gut microbiota are underestimated. In this review, first all studies concerning the influence of nanosilver on gut microbiota are discussed along with relevant pharmacokinetic studies and in closing section the challenges and future task remained in the field are highlighted. PMID- 29264947 TI - Role of microRNA in the detection, progression, and intervention of acute kidney injury. AB - Acute kidney injury, characterized by sharply decreased renal function, is a common and important complication in hospitalized patients. The pathological mechanism of acute kidney injury is mainly related to immune activation and inflammation. Given the high morbidity and mortality rates of hospitalized patients with acute kidney injury, the identification of biomarkers useful for assessing risk, making an early diagnosis, evaluating the prognosis, and classifying the injury severity is urgently needed. Furthermore, investigation into the development of acute kidney injury and potential therapeutic targets is required. While microRNA was first discovered in Caenorhabditis elegans, Gary Ruvkun's laboratory identified the first microRNA target gene. Together, these two important findings confirmed the existence of a novel post-transcriptional gene regulatory mechanism. Considering that serum creatinine tests often fail in the early detection of AKI, testing for microRNAs as early diagnostic biomarkers has shown great potential. Numerous studies have identified microRNAs that can serve as biomarkers for the detection of acute kidney injury. In addition, as microRNAs can control the expression of multiple proteins through hundreds or thousands of targets influencing multiple signaling pathways, the number of studies on the functions of microRNAs in AKI progression is increasing. Here, we mainly focus on research into microRNAs as biomarkers and explorations of their functions in acute kidney injury. Impact statement Firstly, we have discussed the potential advantages and limitations of miRNA as biomarkers. Secondly, we have summarized the role of miRNA in the progress of AKI. Finally, we have made a vision of miRNA's potential and advantages as therapeutic target intervention AKI. PMID- 29264950 TI - Diagnostic accuracy of MALDI-TOF mass spectrometry for non-small cell lung cancer: a meta-analysis. AB - OBJECTIVE: To assess the overall accuracy of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in identifying non-small cell lung cancer (NSCLC). METHODS: A comprehensive search of PubMed, EMBASE and CNKI databases as well as the reference lists from relevant articles was performed prior to July 2017. Two authors independently screened articles based on inclusion and exclusion criteria and assessed the quality of each study using the Quality Assessment of Diagnostic Accuracy Studies 2 (QADAS 2) tool. Meta-disc 1.4 and Stata12.0 software programs were used for the statistical analysis. RESULTS: Eleven eligible articles comprising 16 studies and representing 935 subjects were included in this meta-analysis. The pooled sensitivity and specificity were 0.84 (95% CI: 0.80-0.87) and 0.77 (95% CI: 0.74 0.80), respectively. The overall diagnostic performance as measured by the area under the curve (AUC) for the summary receiver-operating characteristic (SROC) curve was 0.9380. CONCLUSIONS: MALDI-TOF MS has a high diagnostic accuracy for NSCLC. PMID- 29264951 TI - Pushing the Right Buttons: Improving Efficacy of Therapeutic DNA Vectors. AB - Gene therapy represents a potent therapeutical application for regenerative medicine. So far, viral and nonviral approaches suffer from major drawbacks hindering efficient gene therapeutic applicability: the immunogenicity of viral systems on the one hand, and the low gene transfer efficiency of nonviral systems on the other hand. Therefore, there is a high demand for improvements of therapeutical systems at several levels. This review summarizes different DNA vector modifications to enhance biological efficacy and efficiency of therapeutical vectors, aiming for low toxicity, high specificity, and biological efficacy-the cornerstones for successful translation of gene therapy into the clinic. We aim to provide a step-by-step instruction to optimize their vectors to achieve the desired outcome of gene therapy. Our review provides the means to either construct a potent gene therapeutic vector de novo or to specifically address a bottleneck in the chain of events mandatory for therapeutic success. Although most of the introduced techniques can be translated into different areas, this review primarily addresses improvements for applications in transient gene therapy in the field of tissue engineering. PMID- 29264952 TI - Thromboembolism following cesarean section: a retrospective study. AB - OBJECTIVES: As thromboembolism (TE) continues to be one of the principal causes of death in obstetrical patients and as the postpartum period is associated with the highest risk for TE, we sought to determine the risk factors associated with TE following cesarean section (CS). METHODS: A retrospective analysis of patients who had CS at a large tertiary referral center was conducted. Patients were identified through hospital medical records and were contacted approximately 1 year following their CS. Medical records and a questionnaire were used to identify features that were potentially associated with TE. Univariate analysis was used to determine the risk associated with these characteristics. RESULTS: A total of 2206 patients had a CS, of which 1377 (62%) participated. Of the respondents, 137 patients received heparin (94% received a prophylactic dose, 6% received a therapeutic dose) and the remainder, 1233 patients, did not receive heparin. Seven patients (0.5%) developed a TE and 86% developed a TE within 7 days of CS. The odds ratio (OR) for TE for women with hypertension prior to pregnancy compared to patients who did not receive anticoagulation was 21.28 [95% confidence interval (CI) 4.64-90.13] and for patients who had varicose veins with superficial thrombophlebitis when compared to patients who had received heparin postpartum was 21.01 (95% CI 1.55-288.24). DISCUSSION: Hypertension and the presence of varicose veins were associated with TE following CS. Larger cohort analyses are required to confirm these associations so that risk scores incorporating these characteristics may accurately predict the occurrence of TE. PMID- 29264955 TI - Drug use, injecting behaviors, and survival sex among street children and youths in Kathmandu valley, Nepal. AB - A disproportionate number of street children use and inject drugs and engage in survival sex as coping mechanisms. This study aimed to determine the prevalence of drug use, injecting drugs, survival sex, and condom use and determinants associated with these behaviors among street children. Cross-sectional surveys were conducted in 2016 with an aim to sample 350 street children and youths in Kathmandu Valley, Nepal. Information about sociodemographic characteristics, injecting drugs, sexual risk behaviors, and biological specimens for HIV testing were obtained. The logistic regression model was used to identify the determinants associated with drug use, injecting drugs, survival sex, and condom use during last sex. Variables that were significantly associated with being a current drug user (versus never) in the presence of other variables included being a rag picker (adjusted odds ratio [AOR] = 3.2; 95% confidence interval [95% CI] = 1.73-5.9), history of imprisonment (AOR = 2.21; 95% CI = 1.21-4.04), alcohol consumption (AOR = 2.66; 95% CI = 1.46-4.84), and solvent sniffing (AOR = 5.12; 95% CI = 2.74-9.59). Variables that were significantly predictive of injecting drugs (versus never) in the presence of other variables include being 17 years old (AOR = 3.42; 95% CI = 1.11-10.55) and being a rag picker (AOR = 3.5; 95% CI = 1.25-9.75). Variables that were significantly associated with having survival sex (versus never) in the presence of other variables include being 17 years old (AOR = 3.58; 95% CI = 1.31-9.81) and having forced sex (AOR = 9.62; 95% CI = 3.21-28.8). Drug use and survival sex are major coping mechanisms among street children in Kathmandu Valley and are associated with many risk behaviors. Targeted programs should be implemented to meet their special needs. PMID- 29264953 TI - The Agrobacterium F-Box Protein Effector VirF Destabilizes the Arabidopsis GLABROUS1 Enhancer/Binding Protein-Like Transcription Factor VFP4, a Transcriptional Activator of Defense Response Genes. AB - Agrobacterium-mediated genetic transformation not only represents a technology of choice to genetically manipulate plants, but it also serves as a model system to study mechanisms employed by invading pathogens to counter the myriad defenses mounted against them by the host cell. Here, we uncover a new layer of plant defenses that is targeted by A. tumefaciens to facilitate infection. We show that the Agrobacterium F-box effector VirF, which is exported into the host cell, recognizes an Arabidopsis transcription factor VFP4 and targets it for proteasomal degradation. We hypothesize that VFP4 resists Agrobacterium infection and that the bacterium utilizes its VirF effector to degrade VFP4 and thereby mitigate the VFP4-based defense. Indeed, loss-of-function mutations in VFP4 resulted in differential expression of numerous biotic stress-response genes, suggesting that one of the functions of VFP4 is to control a spectrum of plant defenses, including those against Agrobacterium tumefaciens. We identified one such gene, ATL31, known to mediate resistance to bacterial pathogens. ATL31 was transcriptionally repressed in VFP4 loss-of-function plants and activated in VFP4 gain-of-function plants. Gain-of-function lines of VFP4 and ATL31 exhibited recalcitrance to Agrobacterium tumorigenicity, suggesting that A. tumefaciens may utilize the host ubiquitin/proteasome system to destabilize transcriptional regulators of the host disease response machinery. PMID- 29264954 TI - Mechanisms of right heart disease in pulmonary hypertension (2017 Grover Conference Series). AB - Current dogma is that pathological hypertrophy of the right ventricle is a direct consequence of pulmonary vascular remodeling. However, progression of right ventricle dysfunction is not always lung-dependent. Increased afterload caused by pulmonary vascular remodeling initiates the right ventricle hypertrophy, but determinants leading to adaptive or maladaptive hypertrophy and failure remain unknown. Ischemia in a hypertrophic right ventricle may directly contribute to right heart failure. Rapidly enlarging cardiomyocytes switch from aerobic to anaerobic energy generation resulting in cell growth under relatively hypoxic conditions. Cardiac muscle reacts to an increased afterload by over-activation of the sympathetic system and uncoupling and downregulation of beta-adrenergic receptors. Recent studies suggest that beta blocker therapy in PH is safe, well tolerated, and preserves right ventricle function and cardiac output by reducing right ventricular glycolysis. Fibrosis, an evolutionary conserved process in host defense and wound healing, is dysregulated in maladaptive cardiac tissue contributing directly to right ventricle failure. Despite several mechanisms having been suggested in right heart disease, the causes of maladaptive cardiac remodeling remain unknown and require further research. PMID- 29264956 TI - Relapsed/refractory Burkitt lymphoma and HIV infection. AB - The care of patients with HIV and Burkitt lymphoma poses a challenge to clinicians. Due to the limited treatment options that exist for relapsed/refractory Burkitt lymphoma, there is a need for the development of new therapies. This review aims to discuss evidence for current management strategies including chemotherapy and stem cell transplant, and highlight gaps in knowledge that will need to be addressed in the future. PMID- 29264957 TI - Maintaining Elastogenicity of Mesenchymal Stem Cell-Derived Smooth Muscle Cells in Two-Dimensional Culture. AB - Abdominal aortic aneurysms (AAAs) are localized expansions of the abdominal aorta that grow slowly to rupture. AAA growth is driven by irreversible elastic matrix breakdown in the aorta wall by chronically upregulated matrix metalloproteases (MMPs). Since adult vascular smooth muscle cells (SMCs) poorly regenerate elastic matrix, we previously explored utility of bone marrow mesenchymal stem cells and SMCs derived therefrom (BM-SMCs) for this purpose. One specific differentiated phenotype (cBM-SMCs) generated on a fibronectin substrate in presence of exogenous transforming growth factor-beta and platelet-derived growth factor exhibited superior elastogenicity versus other phenotypes, and usefully provided proelastogenic and antiproteolytic stimuli to aneurysmal SMCs. Since in vivo cell therapy demands large cell inoculates, these derived SMCs must be propagated in vitro while maintaining their superior elastogenic, proelastogenic, and antiproteolytic characteristics. In this work, we thus investigated the culture conditions that must be provided to this propagation phase, which ensure that the differentiated SMCs maintain their phenotype and matrix regenerative benefits. Our results indicate that our BM-SMCs retain their phenotype in long-term culture even in the absence of differentiation growth factors and fibronectin substrate, but these conditions must be continued to be provided during postdifferentiation propagation if they are to maintain their superior elastic matrix deposition, crosslinking, and fiber formation properties. Our study, however, showed that cells propagated under these conditions exhibit higher expression of MMP-2, but favorably, no expression of elastolytic MMP-9. Hence, the study outcomes provide crucial guidelines to maintain phenotypic stability of cBM-SMCs during their propagation in two-dimensional culture before their delivery to the AAA wall for therapy. PMID- 29264958 TI - A Mineralized Collagen-Polycaprolactone Composite Promotes Healing of a Porcine Mandibular Defect. AB - A tissue engineering approach to address craniofacial defects requires a biomaterial that balances macro-scale mechanical stiffness and strength with the micron-scale features that promote cell expansion and tissue biosynthesis. Such criteria are often in opposition, leading to suboptimal mechanical competence or bioactivity. We report the use of a multiscale composite biomaterial that integrates a polycaprolactone (PCL) reinforcement structure with a mineralized collagen-glycosaminoglycan scaffold to circumvent conventional tradeoffs between mechanics and bioactivity. The composite promotes activation of the canonical bone morphogenetic protein 2 (BMP-2) pathway and subsequent mineralization of adipose-derived stem cells in the absence of supplemental BMP-2 or osteogenic media. We subsequently examined new bone infill in the acellular composite, scaffold alone, or PCL support in 10 mm dia. ramus mandibular defects in Yorkshire pigs. We report an analytical approach to quantify radial, angular, and depth bone infill from micro-computed tomography data. The collagen-PCL composite showed improved overall infill, and significantly increased radial and angular bone infill versus the PCL cage alone. Bone infill was further enhanced in the composite for defects that penetrated the medullary cavity, suggesting recruitment of marrow-derived cells. These results indicate a multiscale mineralized collagen-PCL composite offers strategic advantages for regenerative repair of craniofacial bone defects. PMID- 29264959 TI - Evidence that Blueberry Floral Extracts Influence Secondary Conidiation and Appressorial Formation of Colletotrichum fioriniae. AB - Blueberry anthracnose, caused by Colletotrichum fioriniae, is a pre- and postharvest disease of cultivated highbush blueberry (Vaccinium corymbosum). During disease development, the pathogen undergoes several lifestyle changes during host colonization, including epiphytic, quiescent, and necrotrophic phases. It is not clear, however, what if any host signals alter the pattern of colonization during the initial epiphytic phase and infection. This research investigated the role of blueberry floral extracts (FE) on fungal development. Results show that FE significantly increased both the quantity and rate of secondary conidiation and appressorial formation in vitro, suggesting that floral components could decrease the minimum time required for infection. Activity of FE was readily detected in water collected from field samples, where secondary conidiation and appressorial formation decreased as rainwater collections were further removed from flowers. A comparison of FE from four blueberry cultivars with different levels of field susceptibility revealed that appressorial formation but not secondary conidiation significantly increased with the FE from susceptible cultivars versus resistant cultivars. Inoculum supplemented with FE produced higher levels of disease on ripe blueberry fruit as compared with inoculum with water only. Flowers from other ericaceous species were found to also induce secondary conidiation and appressorial formation of C. fioriniae. This research provides strong evidence that flowers can contribute substantially to the infection process of C. fioriniae, signifying the importance of the bloom period for developing effective disease management strategies. PMID- 29264960 TI - Interprofessional Rivalry in Nigeria's Health Sector: A Comparison of Doctors and Other Health Workers' Views at a Secondary Care Center. AB - OBJECTIVES: To examine interprofessional rivalry (IPR) between doctors and other health workers and their understanding of its effects. INTRODUCTION: IPR in Nigeria's health system is a burgeoning issue with apparent adverse effects. The most profound rivalry appears to be between doctors and other health workers. METHODS: A descriptive cross-sectional study involving 120 health workers (24 doctors and 96 other health workers) at the State Specialist Hospital, Okitipupa, Ondo State, Nigeria. Pertinent data were collected via semistructured questionnaire and analyzed using SPSS Version17.0. DISCUSSION: IPR is perceived to be the leading cause of conflicts among health workers by 70% of respondents. Doctors and other workers had significantly divergent opinions on the leadership of the health team, patient management, establishment positions, and monetary issues as well as on the effects of IPR with more doctors recognizing its hazards. Nearly half of the respondents believe that strikes are justifiable and the most recommended antidote is for the government to attempt to meet group needs. CONCLUSION: IPR has reached unprecedented levels in Nigeria. However, its adverse effects have not been duly recognized, especially by nondoctors. There is an urgent need for education of health workers on the deleterious effects of IPR. PMID- 29264961 TI - A Survey of English Sixth Formers' Knowledge of Early Brain Development. AB - Objectives To ascertain the knowledge of young people aged 16 to 19 of early brain development and their attitudes towards the care of babies and preschool children. Design Cross-sectional, school- and college-based survey including all sixth form students present on the days of data collection. The survey instrument comprised forced-choice questions in four sections: Demographics, Perceptions and Understanding of Early Childhood Development, Parental Behaviors to Support Early Brain development, and Resource Needs and Usage. Setting Two sixth form schools and one sixth form college in three towns of varying affluence in the West Midlands of the United Kingdom. Method The survey was mounted online and completed by 905 students who returned it directly to the researcher. Results Most students knew that tobacco, alcohol, and drugs are hazardous in pregnancy, and many recognized the impact of maternal stress on fetal brain development. Many believed that babies can be "spoiled" and did not appreciate the importance of reading to babies and of the relationship between play and early brain development. A significant minority thought that physical activity and a healthy diet have little impact on young children's development. Respondents said they would turn firstly to their parents for advice on baby care rather than professionals. Conclusion Young people need educating about parenting activities that support the all-round healthy development of infants. The importance of a healthy diet, physical activity, reading, and play should be included in sixth form curricula and antenatal classes. Consideration should be given to educating grandparents because of their influence on new parents. PMID- 29264962 TI - Role of the endogenous cannabinoid receptor 1 in brain injury induced by chronic intermittent hypoxia in rats. AB - PURPOSE: This study investigated the effect of rimonabant, a cannabinoid receptor type 1 antagonist, on calcium/calmodulin- dependent protein kinase II and cannabinoid receptor type 1 in chronic intermittent hypoxia. MATERIALS AND METHODS: Healthy male rats were divided into control group, intermittent hypoxia group for 4 or 6 weeks, hypoxic intervention group that received rimonabant (1 mg/kg/d) before exposure to hypoxia for 4 or 6 weeks (n = 10/group). Morphological changes and expressions of the two indexes in the cerebral hippocampus cells were determined by haematoxylin-eosin staining and immunohistochemistry, respectively. RESULTS: In the intermittent hypoxia group at 4 weeks, the hippocampal cells were damaged with sparse cytoplasm and unclear boundaries, which are even worse at 6 weeks. In contrast, the hippocampal cells of the hypoxic intervention group were neatly arranged at 4 weeks. At 6 weeks, cells were larger with scarce cytoplasm and nuclear changes indicative of cell death. Calcium/calmodulin-dependent protein kinase II and cannabinoid receptor type 1 expression in the cerebral hippocampus was elevated in the intermittent hypoxia group at 4 weeks with even greater at 6 weeks. Cannabinoid receptor type 1 expression was reduced in the hypoxic intervention group compared to the intermittent hypoxia group. Correlation analysis revealed significant positive correlation of them in the intermittent hypoxia group. CONCLUSIONS: Chronic intermittent hypoxia induced structural damage in the hippocampus and increased cannabinoid receptor type 1 and calcium/calmodulin-dependent protein kinase II expression, which may mediate cognitive impairment associated with chronic intermittent hypoxia. Rimonabant had a protective effect against chronic intermittent hypoxia. PMID- 29264964 TI - Honey yield of different commercial apiaries treated with Lactobacillus salivarius A3iob, a new bee-probiotic strain. AB - The main objective of this study was to determine the impact of Lactobacillus salivarius A3iob, a honey bee gut-associated strain (GenBank code access KX198010), on honey yield. Independent assays were conducted from May to September 2014 and 2015, in three commercial apiaries: Tilquiza, El Carmen and Yala, all located in north-western Argentina. Local Apis mellifera L. bees were kept in standard Langstroth hives; treated hives were fed once a month with 1*105 cfu/ml viable Lactobacillus cells, administered to the bees through a Doolittle type feeder in 125 g/l sucrose syrup. Control hives were only given the syrup mixed with MRS sterile broth. The main honey harvest was done in December in all groups and we found that there was an overall increase in honey yield from the treated hives. In 2014, all treated hives produced between 2.3 to 6.5 times more honey than the controls. However, in 2015, higher honey average yields in the treated hives at El Carmen and Yala were obtained, yet not at Tilquiza, because of a slight mishap. They experienced the swarming of several bee colonies due to a higher number of bees without appropriate management, which caused the control group to yield more honey compared to the hives fed with Lactobacillus. Interestingly, at El Carmen, two honey harvests were recorded: one in winter and another in summer (July and December 2015, respectively). This unexpected result arose from the particular flora of the region, mainly Tithonia tubaeformis, which blooms in winter. L. salivarius A3iob cells prove to be a natural alternative that will positively impact the beekeepers' economy by providing a higher honey yield. PMID- 29264965 TI - Faecal microRNAs: indicators of imbalance at the host-microbe interface? AB - The enteric microbiota is characterised by a balance and composition that is unique to the host. It is important to understand the mechanisms through which the host can maintain the composition of the gut microbiota. MicroRNAs (miRNA) are implicated in intercellular communication and have been isolated from bodily fluids including stool. Recent findings suggest that miRNA produced by the host's intestinal epithelial cells (IECs) participate in shaping the microbiota. To investigate whether miRNA expression was influenced by the gut microbiota we measured the expression of miRNAs expressed by intestinal epithelial cells in faeces. Specifically, we measured miRNA expression in faeces from germ-free (GF) and conventional mice and similarly in a rat model of antibiotic-mediated depletion of the gut microbiota control rats. In adult male GF and conventional mice and adult Sprague Dawley (SD) rats were treated with a combination of antibiotics for 8 weeks; total RNA was extracted from faecal pellets taken at week 0, 2, 4, 6 week 8 and the expression of let-7b-3p, miR-141-3p, miR-200a-3p and miR-1224-5p (miRNAs known to be expressed in IECs) were measured relative to U6 at each time point using qRT-PCR. In GF animals the expression of let-7b, miR 141 and miR-200a in faeces was lower compared to conventional mice. Following antibiotic-mediated depletion of gut microbiota, rats showed two divergent profiles of miRNA expression. Following two weeks of antibiotic treatment, the expression of let-7b and miR-1224 dropped significantly and remained low for the remainder of the study. The expression of miR-200a and miR-141 was significantly higher at week 2 than before antibiotic treatment commenced. Subsequently, the expression of miR-200a and miR-141 decreased at week 4 and continued to decrease at week 6. This data demonstrates that miRNAs can be used as an independent, non invasive marker of microbial fluctuations along with gut pathology in the intestine. PMID- 29264963 TI - Breaking the mold: structures of the RNA polymerase I transcription complex reveal a new path for initiation. AB - While structures of the RNA polymerase (Pol) II initiation complex have been resolved and extensively studied, the Pol I initiation complex remained elusive. Here, we review the recent structural analyses of the yeast Pol I transcription initiation complex that reveal several unique and unexpected Pol I-specific properties. PMID- 29264966 TI - Lactobacillus kunkeei strains decreased the infection by honey bee pathogens Paenibacillus larvae and Nosema ceranae. AB - Due to their social behaviour, honey bees can be infected by a wide range of pathogens including the microsporidia Nosema ceranae and the bacteria Paenibacillus larvae. The use of probiotics as food additives for the control or prevention of infectious diseases is a widely used approach to improve human and animal health. In this work, we generated a mixture of four Lactobacillus kunkeei strains isolated from the gut microbial community of bees, and evaluated its potential beneficial effect on larvae and adult bees. Its administration in controlled laboratory models was safe for larvae and bees; it did not affect the expression of immune-related genes and it was able to decrease the mortality associated to P. larvae infection in larvae and the counts of N. ceranae spores from adult honey bees. These promising results suggest that this beneficial microorganism's mixture may be an attractive strategy to improve bee health. Field studies are being carried out to evaluate its effect in naturally infected colonies. PMID- 29264967 TI - Effect of tablets containing probiotic candidate strains on gingival inflammation and composition of the salivary microbiome: a randomised controlled trial. AB - The aim of the study was to investigate clinical and microbial effects of probiotic candidate strains in patients with moderate gingivitis. The null hypothesis was that the clinical measurements with treatment would not differ from placebo. 47 adult patients were enrolled in a randomised placebo-controlled trial with a 4-week intervention of tablets containing a mix of Lactobacillus rhamnosus PB01, DSM 14869 and Lactobacillus curvatus EB10, DSM 32307 or placebo. Clinical examinations and samplings were done at baseline and after 2, 4 and 6 weeks. The clinical endpoints were general bleeding on probing (BOP), general plaque index (PI) and flow of gingival crevicular fluid (GCF). In addition, the concentration of selected cytokines (interleukin (IL)-1beta, IL-6, IL-8, IL-10, tumour necrosis factor alpha (TNF-alpha)) in GCF was determined with multiplex immunoassays. The profiles of the salivary microbiome were analysed with Next Generation Sequencing (NGS) and qPCR. In contrast to the placebo group, there was a significant reduction in BOP and amount of GCF (P<0.05) after 4 weeks in the probiotic test group when compared with baseline. The general PI was less affected although there was a tendency of decreased plaque levels in the probiotic group (P=0.05-0.09). The cytokines were unaffected by the intervention as well as the salivary microbiome. The Shannon index showed no significant differences between the groups or alterations over time. The occurrence of both probiotic strains increased in saliva of the test subjects during the intervention but returned to baseline levels within 2 weeks. Although a marked improvement in gingival health was recorded in the probiotic group, the null hypothesis could not be rejected. PMID- 29264968 TI - Syringe-feeding as a novel delivery method for accurate individual dosing of probiotics in rats. AB - Probiotic administration to rodents is typically achieved using oral gavage or water bottles, but both approaches may compromise animal welfare, bacterial viability, dosing accuracy, or ease of administration. Oral gavage dosing may induce stress, especially when given daily over several weeks, and cannot be performed by inexperienced personnel. Delivery in water bottles does not take multiple co-housed animals into account, leading to inaccurate dosing of individual rats. Moreover, slow consumption of the solutions over several hours may lead to variability in bacterial stability, and potential leftovers or clogging of the bottle further threaten the reliability of this method. To date, no method has been described that can provide non-stressful precise dosing of probiotics or prebiotics in individual rats. In accordance with the 3R principles (replace, reduce, refine), we propose syringe-feeding as a refinement method for simple yet accurate administration of probiotics. Animals hereby voluntarily consume the solution directly from a syringe held into their home cage, thereby enabling controlled dosing of individual animals. This method requires a short training phase of approximately 3 days, but is very fast thereafter, only taking seconds per rat. Since studies using probiotics are usually long-term experiments, we consider syringe-feeding the most appropriate probiotic delivery mode available to date. PMID- 29264969 TI - Effects of fermented soymilk with Lactobacillus casei Shirota on skin condition and the gut microbiota: a randomised clinical pilot trial. AB - Several clinical studies have shown that isoflavones and Lactobacillus casei Shirota (LcS) have beneficial effects on skin condition and the gut microbiota, respectively. Thus, we investigated the effects of consecutive intake of fermented soymilk (FSM) with LcS on skin condition and the gut microbiota, as well as isoflavone bioavailability, in a randomised, double-blind, placebo controlled trial as a pilot study. Sixty healthy premenopausal Japanese women received FSM containing a moderate level of isoflavone aglycones and a probiotic LcS, or soymilk (SM) containing neither of them, twice a day for 8 weeks. Skin condition was assessed by a subjective questionnaire for face and morphological analysis of the stratum corneum on the inner forearm. Faecal microbiota and urinary isoflavone were analysed by 16S rRNA gene amplicon sequencing and high performance liquid chromatography tandem mass spectrometry, respectively. Both the FSM and SM groups had improved skin condition as assessed from scores of overall satisfaction, dryness, moisture, elasticity, coarseness, pigmentation and/or stratum corneum morphology, as well as significantly increased levels of urinary isoflavones during the intake period compared with the pre-intake period, although there were no significant differences between the two groups. There was a significant positive correlation between urinary isoflavone levels and skin questionnaire scores. In contrast, the relative abundance levels of Lactobacillaceae significantly increased and those of Bifidobacteriaceae tended to increase during the intake period compared with the pre-intake period. For the after-intake period they only decreased significantly in the FSM group. The levels of Enterobacteriaceae and Porphyromonadaceae significantly decreased during the intake period in the FSM group. These findings suggest that daily intake of FSM, as well as SM, provides health benefits that improve skin condition via increased levels of isoflavone absorption in the body, and that only FSM beneficially modifies the gut microbiota in premenopausal healthy women. PMID- 29264971 TI - Evolution of cancer treatment and evolving challenges. AB - This article will provide an overview of the evolving nature of cancer treatment, the benefits and challenges of these new treatments, and the leadership strategies required to manage the evolution from a system perspective. The number and complexity of novel cancer therapies, while offering improved patient outcomes, has become a challenge for the healthcare system due to the high cost of these new therapies. In Canada, the implementation of the pan-Canadian Oncology Drug Review and the pan-Canadian Pharmaceutical Alliance helps to streamline the review and negotiating process and to ensure consistency across provinces. Strategies to support these processes include ensuring safe patient treatment, patient counselling, clinician education, and practice innovation. PMID- 29264970 TI - Development of a Chlamydia trachomatis vaccine for urogenital infections: novel tools and new strategies point to bright future prospects. AB - INTRODUCTION: The "cloaked" bacterial pathogen that is Chlamydia trachomatis continues to cause sexually transmitted infections (STIs) that adversely affect the health and well-being of children, adolescents and adults globally. The reproductive disease sequelae follow unresolved or untreated chronic or recurrent asymptomatic C.trachomatis infections of the lower female genital tract (FGT) and can include pelvic pain, pelvic inflammatory disease (PID) and ectopic pregnancy. Tubal Factor Infertility (TFI) can also occur since protective and long-term natural immunity to chlamydial infection is incomplete, allowing for ascension of the organism to the upper FGT. Developing countries including the WHO African (8.3 million cases) and South-East Asian regions (7.2 million cases) bear the highest burden of chlamydial STIs. Areas covered: Genetic advances for Chlamydia have provided tools for transformation (including dendrimer-enabled transformation), lateral gene transfer and chemical mutagenesis. Recent progress in these areas is reviewed with a focus on vaccine development for Chlamydia infections of the female genital tract. Expert commentary: A vaccine that can elicit immuno-protective responses whilst avoiding adverse immuno-pathologic host responses is required. The current technological advances in chlamydial genetics and proteomics, as well as novel and improved adjuvants and delivery systems, provide new hope that the elusive chlamydial vaccine is an imminent and realistic goal. PMID- 29264972 TI - Planning for cancer control programs: Leadership considerations. AB - Cancer is a significant challenge globally. Reducing the impact of cancer requires a program and plans that address the main aspects of cancer from prevention through to end-of-life care. This article summarizes the requirements of a robust cancer control program and outlines the contextual and leadership considerations that are required to ensure that the planning and implementation of a control program can achieve improved cancer outcomes. PMID- 29264973 TI - Lessons learned from the Canadian cancer registry experience. AB - Health leaders and caregivers are focused on evidence-based data to drive care delivery and practice. Ensuring the health system is functioning effectively and efficiently and that patient outcomes are reaching expected targets are topics that permeate conversations at the local, provincial, and national levels. However, as many leaders have come to understand in recent years, healthcare data collection and producing meaningful, high-quality metrics is a complex set of tasks, requiring its own level of attention and dedicated resources. In the healthcare data realm, there are opportunities to learn from experience. One of these opportunities is the population-based cancer registry, which is one of the oldest examples of standardized data collection in the Canadian health system. PMID- 29264974 TI - Quality in cancer care: Lessons from the Canadian partnership for quality radiotherapy. AB - With the increasing complexity of cancer treatment and the emergence of technologies that offer individualized therapy options for people being treated for the disease, cancer care professionals are facing greater demands for knowledge exchange and information input. The Canadian Partnership for Quality Radiotherapy was established in 2010 in response to such demands and has used both bottom-up and top-down approaches to successfully support improved program planning, treatment delivery, and patient care within the Canadian radiation treatment community. Focusing on shared priorities using this bilateral engagement is a lesson that can be applied broadly across the cancer system. PMID- 29264975 TI - ? PMID- 29264976 TI - Provincial development of a patient-reported outcome initiative to guide patient care, quality improvement, and research. AB - The BC Cancer Agency Radiotherapy (RT) program started the Prospective Outcomes and Support Initiative (POSI) at all six centres to utilize patient-reported outcomes for immediate clinical care, quality improvement, and research. Patient reported outcomes were collected at time of computed tomography simulation via tablet and 2 to 4 weeks post-RT via either tablet or over the phone by a registered nurse. From 2013 to 2016, patients were approached on 20,150 attempts by POSI for patients treated with RT for bone metastases (52%), brain metastases (11%), lung cancer (17%), gynecological cancer (16%), head and neck cancer (2%), and other pilots (2%). The accrual rate for all encounters was 85% (n = 17,101), with the accrual rate varying between the lowest and the highest accruing centre from 78% to 89% ( P < .001) and varying by tumour site ( P < .001). Using the POSI database, we have performed research and quality improvement initiatives that have changed practice. PMID- 29264977 TI - Transcription profile analysis of the endometrium revealed molecular markers of the personalized 'window of implantation' during in vitro fertilization. AB - To determine the most informative markers for assessing the functional state of endometrium during the 'window of implantation' and creating a model for assessment of the readiness of endometrium for embryo implantation. Forty-seven women with tubal infertility and a successful IVF pregnancy participated in the study. Pipelle endometrial sample was performed during the supposed 'window of implantation' in natural cycle with subsequent histological study, and transcriptional profile of genes GPX3, PAEP, DPP4, TAGLN, HABP2, IMPA2, AQP3, HLA DOB, MSX1, POSTN determined by real-time quantitative polymerase chain reaction (qRT-PCR). Differences in the level of mRNA expression of all the studied genes in the receptive endometrium were found in comparison to the prereceptive one, which allowed us to classify two functional states of the endometrium. The results of histological examination responded to the stage of maturation of the endometrium in 78.7% of cases. Receptive endometrial status can be determined based on the integral evaluation of mRNA expression level of 4 PAEP, DPP4, MSX1, and HLA-DOB genes. The model for determining a personalized 'window implantation' is offered for practical application in ART. PMID- 29264978 TI - Pathogenetic role of vitamin D deficiency in the development of menstrual dysfunction in pubertal girls: a literature review. AB - In the literature review, 50 scientific sources surrounding the problem of vitamin D deficiency, 80% of which amounted to the issuance of the last 5 years, have been analyzed. Despite the impact of vitamin D deficiency on the health of children and adolescents has been studied for a long time, the information on the role of vitamin D in the formation of menstrual function in pubertal girls is scant and ambiguous. Among the hypotheses of menstrual dysfunction with vitamin D deficiency, neurohumoral regulation of the hypothalamic-pituitary-ovarian system is considered to be essential due to the localization of vitamin D receptors (VDR), unlike other vitamins, in the nuclei of various tissues and organs. However, in the last 10 years, data on the role of genetic polymorphism of the VDR gene in the pathogenesis of various manifestations of menstrual dysfunction have been accumulated. Some studies indicated a beneficial effect of cholecalciferol on such menstrual dysfunctions as oligomenorrhea and dysmenorrhea. Regarding numerous data on the role of vitamin D, both traditional and recently published, there is a strong correlation between vitamin D deficiency and other various factors, determining a wide range of polymorphic clinical manifestations where menstrual dysfunction is essential in girls at the age of puberty. PMID- 29264979 TI - First preimplantation genetic testing case for monogenic disease in Latvia. AB - Huntington's disease (HD) is fatal neurodegenerative disease caused by a (CAG) triplet repeat expansion in the Huntingtin (HTT) gene. Inheritance pattern of the disease is autosomal dominant and onset depending on triplet repeat count. Transgenerational HD transmission can be avoided by preimplantation genetic diagnosis (PGD). Here, we report the first preimplantation genetic testing case for monogenic disease, in Latvia. The result of our work led to the birth of healthy child with normal HTT alleles in his genome. We describe a PGD strategy and testing algorithm that can be applied to any couple at risk of transmitting monogenic disease. PMID- 29264980 TI - Improvement in quality of oocytes in polycystic ovarian syndrome in programs of in vitro fertilization. AB - Inositol therapy is aimed at improving the quality of oocytes during preconception care in patients with polycystic ovarian syndrome (PCOS), a cause of infertility and reproductive dysfunction. The objectives of this observational comparative multicentre study were to evaluate the effectiveness of inositol in improving the quality of oocytes/embryos and IVF cycle outcome. Group 1 patients (N = 133) received inositol 1000 mg (Inofert or Nutrilinea) + folic acid 0.1 mg. Group 2 consisted of patients with preserved ovarian reserve without PCOS (N = 137), not administered inositol prior to pregnancy. Effectiveness criteria were numbers of mature oocytes and good quality embryos, pregnancy rates per ET, 'take home baby' index and miscarriage rates. Pregnancy rates per ET (87.0% vs. 87.4%), 'take home baby' index (79.6% vs. 89.4%) and miscarriage rates (14.3% vs. 10.6%) were comparable. Use of inositol in patients with PCOS during preconception care is an effective method allowing improvement of oocytes quality and positively affecting IVF cycle prognosis. High pregnancy rates per ET and 'take home baby' index after treatment are justifying inositol usage in patients with PCOS and infertility. PMID- 29264981 TI - Clinical and immunological parallels in pregnancy loss. AB - Peculiar characteristics of cytotoxic endometrial cells' response depending on the clinical aspects (frequency, gestational age, form of miscarriage, hysteroscopic pattern) have been studied. Patients with pregnancy loss in their past medical history demonstrate a decreased level of CD8 + lymphocytes, and the decrease is exacerbated as the incidence of miscarriages increases and in the presence of endometrial hypoplasia. The content of CD16 + lymphocytes increases in comparison with the control group, however, there is a reducing trend of this phenotype of killers as the incidence of miscarriages increases and in the presence of endometrial hypoplasia. Reduction of CD56 + lymphocytes progresses with repeated pregnancy loss and endometrial hyperplasia. PMID- 29264982 TI - Risk factors of cerebral ischemia in infants born to mothers with gestational diabetes. AB - OBJECTIVES: Gestational diabetes mellitus (GDM) is carbohydrate intolerance that occurs during pregnancy. The present study was arranged to determine the risk of cerebral ischemia (CI) in infants born to mothers with gestational diabetes mellitus and MTHFR gene polymorphism. MATERIAL AND METHODS: The study includes 70 pregnant women with GDM, divided into two groups depending on existence of cerebral ischemia (CI) in newborn infants. All patients were tested for coagulation cascade components, polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and assessed by thromboelastography (TEG). RESULTS: We observed that there was an increased frequency (74.2%) of 1298S MTHFR genotype carriers among women with CI newborns. The state of hypercoagulation according to both coagulation cascade tests and TEG data was diagnosed in women of this group. CONCLUSIONS: The results of this study suggest that hyperglycemia may program the development of cerebral ischemia in infants born to women with 1298S MTHFR gene polymorphism. PMID- 29264983 TI - Genetic and hemostasiological predictors of IVF pregnancy. AB - The performed clinical laboratory and instrumental research involved 93 pregnant women after IVF: 36 with progressive pregnancy and 57 women with missed abortion at term 6-8 weeks. The following parameters were evaluated: family history of thrombosis, menstrual function, gynecological and other diseases, duration of infertility treatment, pelvic organs sonography, hemostasis evaluation and thrombophilia genes investigation. The association of polymorphic allele 455 A of gene FGB with the risk of nondeveloping pregnancy after IVF was revealed. The genotype presence of allele 455 A of gene FGB increases the risk of miscarriage after IVF. The research has also revealed the association of polymorphic allele 4 G of gene PAI-1 in polymorphic locus 675:4 G/5 G with the risk of miscarriage. The received data on hemostatic system at an early term of pregnancy after IVF demonstrate enough stability and consistent thrombocytic and coagulative hemostasis of all examined women. Patients with progressive pregnancy have a considerably lower level of platelets than the patients with miscarriage. The average content of fibrinogen in women with progressive pregnancy is considerably higher than that in the patients in other groups. APTT is positively higher in patients of group A. The average content of SFMC in patients of group A was positively higher. The patients with non-developing pregnancy after IVF showed a considerably lower SFMC content. PMID- 29264984 TI - Pregnancy in women after successful acromegaly treatment, including surgical removal of pituitary adenoma and postoperative therapy using lanreotide acetate. AB - Acromegaly is one of the most common syndromes in pituitary adenomas. Naturally, women with this condition have trouble with their reproductive function. The difficulty in diagnosing acromegaly progression in pregnancy is that there is also production of placental growth hormone observed, making it impossible to differentiate from neoplastic growth hormone production using conventional methods of investigation. This article is about a clinical case of acromegaly in a 22 years old woman who was operated on using transnasal transsphenoidal approach and received postoperative treatment with somatostatin analog - lanreotide acetate autogel - for six months. The woman became pregnant in the course of the treatment. During pregnancy, the GH and IGF-I levels in serum remained within normal limits. Lanreotide acetate therapy was discontinued. The woman successfully gave birth to a healthy baby. There was a remission of the disease after pregnancy. PMID- 29264985 TI - Dienogest treatment after ovarian endometrioma removal in infertile women prior to IVF. AB - BACKGROUND: Severe forms of genital endometriosis are known to be associated with infertility and its subsequent treatment failure. Both gonadotropin-releasing hormone analogs (a-GnRH) and dienogest have been suggested as additional hormone therapy for patients with endometriomas. However, the result of hormonal suppression before an in vitro fertilization (IVF) cycle remains undetermined. MATERIALS AND METHODS: A prospective cohort study of 144 infertile women planning IVF after laparoscopic surgery of ovarian endometriomas was conducted at our department in 2012-2015. Patients were divided into three groups: group I (N = 38) with dienogest course, group II (N = 70) with a-GnRH group III (N = 70) without any hormonal therapy within 6 months preceding IVF. RESULTS: The study groups did not differ by removed endometriomas size and ovarian reserve indicators. The gonadotropin dose per Cycle was higher, while the number of retrieved oocytes was lower in group III patients (p < .001). In women with dienogest pretreatment, clinical pregnancy rate was 2.5 times (44.7% versus 16.7%, p = .012) and delivery rate - three times higher (36.8% versus 11.1%, p = .013) as compared with those from group III. CONCLUSIONS: The present study confirms the necessity of pre-cycle medical interventions in women with ovarian forms of endometriosis undergoing IVF. We suggest dienogest to be possibly more efficient treatment option for this kind of patients. PMID- 29264986 TI - Diagnostic significance of chronic endometritis macrotypes differentiation among women with reproductive losses. AB - To evaluate the prognostic value of a comprehensive endometrial study after early reproductive losses (RL). A group of 306 women with early RL (missed abortion (n = 120), spontaneous miscarriage (n = 120), and ineffective in vitro fertilization attempts (n =66) were prospectively examined up to 6 months after the discharge of the uterus at the hospital bases of the Department of Obstetrics and Gynecology with the Sourse of perinatology at the PFUR Medical Faculty. Hysteroscopic macrotypes differentiation - hyperplastic (n = 89), hypoplastic (n = 94) and mixed (n = 87) - was carried out on the basis of features grouping characterizing the thickness, color and structure of the mucosa, the intensity of a vascular pattern in the presence of a chronic endometritis (CE). Evaluation of sonographic accuracy after hysteroscopic CE macrotypes differentiation showed the presence of false-negative conclusions: about unchanged mucosa (6.9%); endometrium polyps (3.5%); intrauterine synechiae (4.2%). Immunohistochemical staining with CD138 isolation showed higher diagnostic accuracy in CE detecting in comparison with the morphological method: in a hyperplastic macrotype (90.5% and 84.1%, respectively), hypo- (93.7% and 89.8%) and mixed (81.6% and 79.4%). Great diagnostic value is shown in identifying histopathic CE features in the context of hysteroscopic macrotypes differentiation in groups of women with RL. PMID- 29264987 TI - Immune-inflammatory predictors of the pelvic pain syndrome associated with adenomyosis. AB - The aim of the study was the analysis of immune inflammatory processes in the development of the pelvic pain syndrome associated with adenomyosis. For morphological examination were used 54 fragments of the myometrium obtained from patients after hysterectomy with pelvic pain on a background of diffuse adenomyosis of II-III degree, and 20 patients with painless form of adenomyosis. The identification of the macrophages distribution was held by means of an immune hysto-chemical analysis of MAT (monoclonal antibody) for CD68. (Clone PG-M1, 'Diagnostic BioSystems', USA). The results of the study showed a significantly higher expression of CD68 (49.3 +/- 2.3 vs. 21.2 +/- 1.7 units. p < .01) in patients with painful adenomyosis form in areas of the ectopic endometrium, in the perivascular regions of the myometrium, as compared to those areas in women with painless group. We assume that these factors increase neurogenic inflammation and sensitivity of nociceptors in myometrium, activation of peripheral nerve fibers and, can act as triggers of the pelvic pain syndrome associated with adenomyosis. PMID- 29264988 TI - Combination therapeutic options in the treatment of the luteal phase deficiency. AB - Luteal phase deficiency (LPD) is described as a condition of insufficient progesterone exposure to maintain a regular secretory endometrium and allow for normal embryo implantation and growth. There is evidence that both follicular and luteal phase abnormalities can result in LPD cycles. The aim of this randomized prospective noncomparative study is to evaluate the effectiveness of combination therapy in patients with LPD. This prospective study included 35 women of the reproductive age. They were diagnosed with the LPD with sonographically and laboratory-verified methods. The age of patients was 36 +/- 0.46 years. The results of the study sonographically demonstrated an increase in the diameter of the corpus luteum from 1.36 +/- 0.32 (initially) to 2.16 +/- 0.21 mm after combination therapy. In addition, there was a statistically significant increase in the level of estrogens and progesterone in the corresponding phases of the menstrual cycle. Thus, the combination therapy for patients with LPD contributes to the recovery of cyclic events in the hypothalamic-pituitary-gonadal system, which determines the restoration of the endocrine function of the ovaries and promotes adequate secretory rearrangement of the endometrium in women of reproductive age. PMID- 29264989 TI - Mental state assessment of recipients in the IVF donor programs and psychotherapeutic methods of its correction. AB - The management of infertility with assisted reproductive technologies (ART) could solve a medical problem but still leave psychosocial problems, associated with both long-term infertility and specific treatment, unaddressed in a number of cases. Evaluation of the mental state of recipients in the IVF donor programs and its dynamics when mid-term multimodal psychotherapy has been used. The study was conducted in the Family Medicine Center - an ART clinic of the city of Ekaterinburg, Russia between 2016 and 2017. Mental state assessment of 200 potential female candidates for the IVF programs was made with the following methods: figures test and color test of relations, a method for the self assessment of the emotional state by Hans Eysenck, a method for assessing neuropsychic stress by Nemchin, an original questionnaire for patients of the ART clinic. In our study, it was revealed that women requiring donor oocytes with indirect motivation to have a child demonstrated predominantly a high and moderate level of anxiety, frustration, aggression, rigidity, and neuropsychic stress. The vast majority of women had partial compliance for treatment. With psychotherapeutic approach using mid-term multimodal psychotherapy, patients' compliance for treatment could be improved, resulting in a reduction in negative mental states and development of adequate motivation for oocyte donation in the IVF programs. PMID- 29264990 TI - Growth hormone co-treatment in IVF/ICSI cycles in poor responders. AB - To estimate the efficacy of growth hormone (GH) co-treatment within an antagonist protocol in IVF/ICSI cycles in poor responders. A prospective observational study involving 50 patients underwent a standard antagonist protocol with or without GH co-treatment. GH was administered by a daily subcutaneous injection of 1,33 mg (equivalent to 4 IU) starting from day 1 of ovarian stimulation until the day of 10,000 human chorionic gonadotropin (hCG) triggering . Concentrations of GH, insulin-like growth factor I (IGF-I) and IGF binding protein-3 (IGFBP-3) in serum and follicular fluid were the subject matter of analysis. The GH co-treatment significantly lowered the effective dose of gonadotropins, duration of stimulation, IGFBP-3 level in serum and follicular fluid on the day of oocyte retrieval. The total number of oocytes as well as the number of metaphase II stage (MII) oocytes, two pronucleus (2 pn) zygotes, good-quality transferred embryos was significantly higher in the GH + group. Pregnancy was achieved in patients GH + group only. Positive correlation was found between IGF-I level in follicular fluid, dynamics of IGFBP-3 level changes during stimulation protocol and the number of good-quality transferred embryos in the GH + group. GH administration in IVF/ICSI cycles for poor responders raises ovarian sensitivity to the gonadotropin exogenous influence, increasing number of high-quality embryos and the probability of pregnancy. PMID- 29264991 TI - The influence of age, body mass index, waist-to-hip ratio and anti-Mullerian hormone level on clinical pregnancy rates in ART. AB - The aim of this study was to estimate the influence of age, body mass index, waist-to-hip ratio and anti-Mullerian hormone levels on clinical pregnancies in assisted reproduction technologies (ART). We used the database of the fertility clinic both the in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) units. A total of 1134 treatment cycles from 2013 through 2015 were analyzed. We evaluated clinical pregnancy rate in terms of age, body mass index, waist-to-hip ratio, anti-Mullerian hormone level. The clinical pregnancy rate was 39.9%. The live birth rate was 25.5%. Women who conceived where statistically significantly younger and had lower body mass index. No statistical differences across pregnancy groups were found for waist-to-hip ratio, and anti-Mullerian hormone levels. Low AMH levels do not influence pregnancy rates in younger patients (<36 years). PMID- 29264993 TI - hWJECM-Derived Oriented Scaffolds with Autologous Chondrocytes for Rabbit Cartilage Defect Repairing. AB - Previously, we synthesized an articular cartilage extracellular matrix (ECM) derived oriented scaffold for cartilage tissue engineering, which was biomimetic in terms of structure and biochemical composition. However, the limit resource of the cartilage-derived ECM is a hindrance for its application. In this study, we developed a new material for cartilage tissue engineering-human umbilical cord Wharton's jelly-derived ECM (hWJECM). The hWJECM has an abundant resource and similar biochemistry with cartilage ECM, and the use of it is not associated with ethical controversy. We adopted the method previously used in cartilage ECM derived oriented scaffold preparation to generate the oriented hWJECM-derived scaffold, and the scaffold properties were tested in vitro and in vivo. The three dimensional scaffold has a porous and well-oriented structure, with a mean pore diameter of ~104 MUm. Scanning electron microscopy and cell viability staining results demonstrated that the oriented scaffold has good biocompatibility and cell alignment. In addition, we used functional autologous chondrocytes to seed the hWJECM-derived oriented scaffold and tested the efficacy of the cell-scaffold constructs to repair the full-thickness articular cartilage defect in a rabbit model. Defects of 4 mm diameter were generated in the patellar grooves of the femurs of both knees and were implanted with chondrocyte-scaffold constructs (group A) or scaffolds alone (group B); rabbits with untreated defects were used as a control (group C). Six months after surgery, all defects in group A were filled completely with repaired tissue, and most of which were hyaline cartilage. In contrast, the defects in group B were filled partially with repaired tissue, and approximately half of these repaired tissues were hyaline cartilage. The defects in group C were only filled with fibrotic tissue. Histological grading score of group A was lower than those of groups B and C. Quantification of glycosaminoglycan indicated that newly formed cartilage in group A rabbits was comparable with normal cartilage. In conclusion, hWJECM-derived oriented scaffolds loaded with autologous chondrocytes induced cartilage repair in rabbit knees, which was comparable with native cartilage in terms of macroscopic view, microstructure, and biochemical composition. PMID- 29264992 TI - Redox status in the sentinel lymph node of women with breast cancer. AB - BACKGROUND: Lymphatic metastasis is regulated in multiple steps including the transit of tumor cells via the lymphatic vessels and the successful seeding in draining lymph nodes. Thus, several molecular signals and cellular changes must be involved in this complex process to facilitate tumor cell entry, colonization, and survival in the lymph node. To our knowledge, the present work explores, for the first time in the literature, the redox status (oxidative stress parameters and enzymatic and non-enzymatic antioxidant defense systems) in the sentinel lymph node (SLN) of women with breast cancer. PATIENTS AND METHODS: SLNs from 75 women with breast cancer were identified using the one-step nucleic acid amplification (OSNA) method as negative (n = 43), with micrometastases (n = 13), or with macrometastases (n = 19). It will allow us to gain knowledge about the pro-oxidant/antioxidant mechanisms involved in the processes of distant metastases in breast cancer and also to assess whether these parameters may be alternative techniques for staging. RESULTS: We found different levels of lipid peroxidation in SLNs with micrometastases (increased) and macrometastases (decreased), a decrease in carbonyl group content in SLNs with macrometastases only, and an increase in total antioxidant capacity (TAC) in SNLs with micrometastases and macrometastases. A decrease in the levels of reduced glutathione (GSH) also appears in the SLNs with macrometastases only. Finally, we show increased levels of superoxide dismutase (SOD) and catalase (CAT) activity in SLNs with micrometastases and macrometastases, and decreased levels of glutathione peroxidase (GPx) activity in SNLs with macrometastases but not with micrometastases. CONCLUSIONS: Redox status of lymph node microenvironment participates in the progression of metastatic breast cancer. PMID- 29264994 TI - Pathological progression of genetic Creutzfeldt-Jakob disease with a PrP V180I mutation. AB - In comparison to sporadic Creutzfeldt-Jakob disease (sCJD) with MM1-type and MM2- cortical (MM2C)-type, genetic CJD with a prion protein gene V180I mutation (V180I gCJD) is clinically characterized by onset at an older age, slower progress, and the absence of visual disturbances or cerebellar symptoms. In terms of pathological characteristics, gliosis and neuronal loss are generally milder in degree, and characteristic spongiform change can be observed at both the early and advanced stages. However, little is known on the progress of spongiform change over time or its mechanisms. In this study, to elucidate the pathological course of V180I gCJD, statistical analysis of the size and dispersion of the major diameters of vacuoles in six V180I gCJD cases was performed, with five MM1 type sCJD and MM2C-type sCJD cases as controls. As a result, V180I gCJD showed no significant difference in vacuolar diameter regardless of disease duration. In addition, the dispersion of the major diameters of vacuoles in V180I gCJD was larger than that in the MM1-type, which was smaller than that in the MM2C-type. We speculated that the absence of difference in the size of the vacuoles regardless of disease duration suggests that tissue rarefaction does not result from the expansion of vacuole size and increase in number of vacuoles in V180Ig CJD. These features were considered to be significant pathological findings of V180I gCJD. PMID- 29264995 TI - Assessing knowledge and attitudes about mental illness in Ningxia, China. AB - To assess the effectiveness of China's recent moves to increase community mental health literacy and decrease stigma, we developed the Mental Health Knowledge Questionnaire (MHKQ) and the Mental Health Attitude Questionnaire (MHAQ). Preliminary versions were assessed in pilot studies and revised versions were included in an interviewer-administered community survey of a representative sample of 2425 adult residents of Ningxia Province and a re-test survey in 188 individuals. Internal consistency, factor structure and test-retest reliability were assessed for three measures: (a) the 25-item MHKQ (alpha = .71, 6 factors accounting for 51% of variance identified in exploratory factor analysis of one half of the sample, and intraclass correlation coefficient [ICC] for total score of .40); (b) the 14-item attitudinal subscale of MHAQ (alpha = .69, 3 factors accounting for 42% of variance, ICC = .47); and (c) the 7-item causal attribution subscale of MHAQ (alpha = .60, 3 factors accounting for 60% of variance, ICC = .26). Confirmatory factor analysis assessed fitness of modified models of the measures using chi-squared, comparative fit index (CFI), Tucker-Lewis index (TLI), and root mean square error of approximation (RMSEA): (a) for the MHKQ, RMSEA = .037 (90% CFI = .033, .040), CFI = .86, TLI = .84, chi2 = 682.86 (df = 260); (b) for the attitudinal subscale of MHAQ, RMSEA = .045 (CI = .039, .052), CFI = .94, TLI = .92, chi2 = 226.67 ( df = 66); and (c) for the causal attribution subscale of MHAQ, RMSEA = .054 (.039, .069), CFI = .97, TLI = .94, chi2 = 49.13 ( df = 11). We conclude that the internal consistency and factor structure of the new measures are satisfactory, but further work is needed to improve the scales' stability and to assess the construct validity and responsiveness of the scales. PMID- 29264996 TI - Clinical implications of genetic variation in carboxylesterase drug metabolism. AB - INTRODUCTION: Mammalian carboxylesterase enzymes are a highly conserved metabolic pathway involved in the metabolism of endogenous and exogenous compounds including many widely prescribed therapeutic agents. Recent advances in our understanding of genetic polymorphisms affecting enzyme activity have exposed potential therapeutic implications. Areas covered: The aims of this review are to provide an overview of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) gene structure, to summarize the known polymorphism affecting substrate-drug metabolism, and to assess the potential therapeutic implications of genetic variations affecting enzyme function. Expert opinion: Genetic variability in carboxylesterase drug metabolism is a nascent area of research with only a handful of the thousands of SNPs investigated for their potential effects of enzyme activity or carboxylesterase-substrate disposition and therapeutics. It remains to be determined if the wide variability in enzyme activity can be explained by genetic variation, and used in personalized medicine to improve clinical outcomes. PMID- 29264997 TI - Thoracic Endovascular Aneurysm Sealing of a Complex Thoracoabdominal Aneurysm. AB - PURPOSE: To report bailout treatment of a thoracoabdominal aortic aneurysm using a single Nellix stent and parallel stents. CASE REPORT: A 74-year-old man with multiple comorbidities and a previous fenestrated Anaconda stent-graft for a 60 mm juxtarenal aneurysm was diagnosed with a type IV thoracoabdominal aneurysm on the 2-year computed tomography angiography (CTA) scans. The imaging showed >10-mm downward migration of the proximal Anaconda stent with a massive type Ia endoleak and aneurysmal evolution of the distal descending thoracic aorta; the superior mesenteric artery (SMA) and renal artery covered stents were patent and intact. Open conversion or a second custom-made endograft was not feasible. A plan was devised to use off-the-shelf materials, including the deployment of a single Nellix stent extending from the descending thoracic aorta into the stented area of the fenestrated endograft, with parallel chimney stent-grafts into the SMA and right renal artery; the left renal artery was treated with a bare stent in a periscope configuration. Transient paraparesis was resolved with cerebrospinal fluid drainage. At 6-month CTA, ongoing aneurysm exclusion with patent SMA and renal arteries was confirmed. CONCLUSION: Thoracic endovascular aneurysm sealing with visceral and renal stenting seems to be a feasible bailout alternative treatment for urgent, complex cases without reconstruction options. PMID- 29264998 TI - Endovascular Distal Plantar Vein Arterialization in Dialysis Patients With No Option Critical Limb Ischemia and Posterior Tibial Artery Occlusion: A Technique for Limb Salvage in a Challenging Patient Subset. AB - PURPOSE: To detail a percutaneous technique for distal plantar venous arterialization in diabetic, end-stage renal disease (ESRD) patients with no option critical limb ischemia (CLI). TECHNIQUE: After failure of standard intraluminal recanalization attempts, a subintimal approach through the posterior tibial artery (PTA) is begun using a 0.014-inch, 190- or 300-cm-long guidewire supported by a 2-*20-mm, low-profile balloon catheter positioned a short distance behind the narrow "U-shaped" loop in the guidewire. Typically, heavy calcification in the distal tortuous segment of the PTA prevents reentry to the arterial true lumen; however, an entry in the distal lateral or medial plantar vein from a subintimal channel in the plantar artery can be intentionally pursued as a bailout technique, pointing the tip of the guidewire opposite to the arterial wall calcifications. Venous access is confirmed by contrast injection through the balloon catheter. Once the guidewire is advanced in the distal lateral or medial plantar vein and a plantar arteriovenous fistula (AVF) has been created, the AV anastomosis and the occluded PTA segment are dilated with 0.014 inch balloon catheters. The technique has been attempted in 9 consecutive diabetic, ESRD patients (mean age 69 years; 5 men) with no-option CLI; an AVF was created between the PTA and plantar vein in 7 patients. The mean TcPO2 at 1 month was 30+/-17 mm Hg (vs 7.3+/-2.2 at baseline). Six ulcers healed over an average of 21+/-4 weeks. Three of the 9 patients had below-knee amputations. CONCLUSION: Although further investigations are required, distal plantar venous arterialization may represent a promising technique to improve recanalization rates and limb salvage in diabetic ESRD patients with extremely calcified PTA occlusions. PMID- 29264999 TI - Drug-Coated Balloon vs Standard Percutaneous Transluminal Angioplasty for the Treatment of Atherosclerotic Lesions in the Superficial Femoral and Proximal Popliteal Arteries: One-Year Results of the MDT-2113 SFA Japan Randomized Trial. AB - PURPOSE: To assess the safety and effectiveness of the MDT-2113 (IN.PACT Admiral) drug-coated balloon (DCB) for the treatment of de novo and native artery restenotic lesions in the superficial femoral and proximal popliteal arteries vs percutaneous transluminal angioplasty (PTA) with an uncoated balloon in a Japanese cohort. METHODS: MDT-2113 SFA Japan ( ClinicalTrials.gov identifier NCT01947478) is an independently adjudicated, prospective, randomized, single blinded trial that randomized (2:1) 100 patients (mean age 73.6+/-7.0 years; 76 men) from 11 Japanese centers to treatment with DCB (n=68) or PTA (n=32). Baseline characteristics were similar between the groups, including mean lesion length (9.15+/-5.85 and 8.89+/-6.01 cm for the DCB and PTA groups, respectively). The primary effectiveness outcome was primary patency at 12 months, defined as freedom from clinically-driven target lesion revascularization (CD-TLR) and freedom from restenosis as determined by duplex ultrasonography. The safety endpoint was a composite of 30-day device- and procedure-related death and target limb major amputation and clinically-driven target vessel revascularization within 12 months. RESULTS: Patients treated with DCBs exhibited superior 12-month primary patency (89%) compared to patients treated with PTA (48%, p<0.001). The 12-month CD-TLR rate was 3% for DCB vs 19% for PTA (p=0.012). There were no device- or procedure-related deaths, major amputations, or thromboses in either group. Quality-of-life measures showed sustained improvement from baseline to 12 months in both groups. CONCLUSION: Results from the MDT-2113 SFA Japan trial showed superior treatment effect for DCB vs PTA, with excellent patency and low CD-TLR rates. These results are consistent with other IN.PACT SFA DCB trials and demonstrate the safety and effectiveness of this DCB for the treatment of femoropopliteal lesions in this Japanese cohort. PMID- 29265000 TI - The Effects of Hyperacute Serum on Adipogenesis and Cell Proliferation of Mesenchymal Stromal Cells. AB - Fat tissue, due to its high concentration of stem cells, has a role in aesthetic medicine and reconstructive surgery. However, poor survival of the transplanted cells still limits the usefulness of this material in regenerative medicine. Several studies indicated that platelet-rich plasma (PRP) may improve adipose tissue viability due to its growth factor content. This study aimed at investigating the effects of PRP and hyperacute serum (HAS) on the adipogenic lineage in vitro. PRP was prepared by using two centrifugation steps in the presence of anticoagulants, and HAS was isolated from activated platelet-rich fibrin within 10 min of blood drawing to prevent the propagation of inflammatory cascades. Metabolic activity and proliferation rate of human bone marrow-derived mesenchymal stem cells (hMSCs) cultivated in media supplemented with three types of serum additives (fetal calf serum [FCS], human PRP, or HAS) was determined by using a tetrazolium assay. Adipogenesis was evaluated in standard and pro adipogenic media and tested by oil red staining, triglyceride content, and expression of specific genes. Adipogenic regulators in the sera were measured by multiplex ELISA assays. We observed that proliferation of hMSCs was supported by both FCS and HAS in a time-dependent manner, but surprisingly, PRP had a much weaker effect (change in proliferation rate after 5 days relative to metabolic activity on day 0-FCS: 5.4-fold change, HAS: 5.8-fold change, serum free 1.9-fold change, PRP: 3.0-fold change, p < 0.05). Lipogenesis was only observed in groups with adipogenic differentiation medium, with HAS showing a significantly stronger effect than PRP. This was confirmed by intensive accumulation of lysochrome dye in lipid droplets, higher triglyceride concentration, and elevated expression of specific adipogenic genes. Measurement of lipogenic proteins in the sera revealed that both PRP and HAS are abundant in them; however, PRP also contains anti adipogenic factors, which explains its weaker and less reliable effect. The results of this study suggest that HAS provides more robust support than PRP in hMSCs proliferation as well as lipogenic differentiation, indicating that it may be a better adjuvant in fat grafting procedures. PMID- 29265001 TI - Perspective: interesterified triglycerides, the recent increase in deaths from heart disease, and elevated blood viscosity. AB - The authors hypothesize that consumption of interesterified fats may be the cause of the continuous increase in cardiovascular deaths in the United States which began in 2011. Interesterification is a method of producing solid fats from vegetable oil and began to supplant partial hydrogenation for this purpose upon recognition of the danger of trans fats to cardiovascular health. Long, straight carbon chains, as are present in saturated and trans fatty acids, decrease the fluidity of the erythrocyte cell membrane, which decreases erythrocyte deformability and increases blood viscosity. This decrease in cell membrane fluidity is caused by increased van der Waals interactions, which also solidify dietary fats. Elevated blood viscosity is favored as the pathogenic mechanism by which trans fats increase cardiovascular mortality because changes in lipoprotein levels do not account for all the mortality attributable to their consumption. The rapid changes in cardiovascular mortality noted with the introduction and withdrawal of trans fats from the food supply are reviewed. The evidence implicating elevated blood viscosity in cardiovascular disease is also reviewed. Data regarding the production and consumption of interesterified fats in the US should be released in order to determine if there is an association with the observed increase in cardiovascular deaths. PMID- 29265002 TI - Intravascular ultrasound guided directional atherectomy versus directional atherectomy guided by angiography for the treatment of femoropopliteal in-stent restenosis. AB - BACKGROUND: The aim of this study was to compare 1-year outcomes for patients with femoropopliteal in-stent restenosis using directional atherectomy guided by intravascular ultrasound (IVUS) versus directional atherectomy guided by angiography. METHODS AND RESULTS: This was a retrospective analysis for patients with femoropopliteal in-stent restenosis treated with IVUS-guided directional atherectomy versus directional atherectomy guided by angiography from a single center between March 2012 and February 2016. Clinically driven target lesion revascularization was the primary endpoint and was evaluated through medical chart review as well as phone call follow up. CONCLUSIONS: Directional atherectomy guided by IVUS reduces clinically driven target lesion revascularization for patients with femoropopliteal in-stent restenosis. PMID- 29265003 TI - Retrospective review of the use of as-needed hydralazine and labetalol for the treatment of acute hypertension in hospitalized medicine patients. AB - BACKGROUND: The aim of this study was to evaluate the use of as-needed (PRN) labetalol and hydralazine [intravenous (IV) or oral] in hospitalized medicine patients for the treatment of severe asymptomatic hypertension and to examine the potential negative outcomes associated with their use. METHODS: The electronic health record of 250 medicine patients hospitalized at the University of Colorado Hospital between November 2014 and April 2016 who received at least one dose of PRN IV or oral hydralazine or labetalol were retrospectively reviewed. The primary outcome was to describe the use of PRN antihypertensive medications in this population. RESULTS: A total of 573 PRN doses of antihypertensive medication were administered. Oral hydralazine was the most common (521 doses, 90.9%). A total of 36% of PRN administrations were given for a systolic blood pressure (SBP) <180 mmHg and diastolic blood pressure (DBP) <110 mmHg (cut-point for acute severe hypertension). No serious adverse events were related to PRN antihypertensive administration. Despite receiving at least one PRN antihypertensive medication during hospitalization, 40.8% of patients were not continued on their home antihypertensive medication(s) while hospitalized, and 62.4% of patients did not have their home regimens intensified at discharge. CONCLUSION: As-needed oral hydralazine is frequently prescribed for acute blood pressure lowering with administration thresholds often less than what are used to define acute severe hypertension. Many patients are prescribed PRN antihypertensive medication instead of being continued on their home regimens, and most patients do not have the intensity of their home regimens increased. Providers need to be educated about the use of PRN antihypertensive medication for the management of severe asymptomatic hypertension in the hospital setting. PMID- 29265004 TI - Self-management toolkit and delivery strategy for end-of-life pain: the mixed methods feasibility study. AB - BACKGROUND: Pain affects most people approaching the end of life and can be severe for some. Opioid analgesia is effective, but evidence is needed about how best to support patients in managing these medicines. OBJECTIVES: To develop a self-management support toolkit (SMST) and delivery strategy and to test the feasibility of evaluating this intervention in a future definitive trial. DESIGN: Phase I - evidence synthesis and qualitative interviews with patients and carers. Phase II - qualitative semistructured focus groups and interviews with patients, carers and specialist palliative care health professionals. Phase III - multicentre mixed-methods single-arm pre-post observational feasibility study. PARTICIPANTS: Phase I - six patients and carers. Phase II - 15 patients, four carers and 19 professionals. Phase III - 19 patients recruited to intervention that experienced pain, living at home and were treated with strong opioid analgesia. Process evaluation interviews with 13 patients, seven carers and 11 study nurses. INTERVENTION: Self-Management of Analgesia and Related Treatments at the end of life (SMART) intervention comprising a SMST and a four-step educational delivery approach by clinical nurse specialists in palliative care over 6 weeks. MAIN OUTCOME MEASURES: Recruitment rate, treatment fidelity, treatment acceptability, patient-reported outcomes (such as scores on the Brief Pain Inventory, Self-Efficacy for Managing Chronic Disease Scale, Edmonton Symptom Assessment Scale, EuroQol-5 Dimensions, Satisfaction with Information about Medicines Scale, and feasibility of collecting data on health-care resource use for economic evaluation). RESULTS: Phase I - key themes on supported self management were identified from evidence synthesis and qualitative interviews. Phase II - the SMST was developed and refined. The delivery approach was nested within a nurse-patient consultation. Phase III - intervention was delivered to 17 (89%) patients, follow-up data at 6 weeks were available on 15 patients. Overall, the intervention was viewed as acceptable and valued. Descriptive analysis of patient-reported outcomes suggested that interference from pain and self-efficacy were likely to be candidates for primary outcomes in a future trial. No adverse events related to the intervention were reported. The health economic analysis suggested that SMART could be cost-effective. We identified key limitations and considerations for a future trial: improve recruitment through widening eligibility criteria, refine the SMST resources content, enhance fidelity of intervention delivery, secure research nurse support at recruiting sites, refine trial procedures (including withdrawal process and data collection frequency), and consider a cluster randomised design with nurse as cluster unit. LIMITATIONS: (1) The recruitment rate was lower than anticipated. (2) The content of the intervention was focused on strong opioids only. (3) The fidelity of intervention delivery was limited by the need for ongoing training and support. (4) Recruitment sites where clinical research nurse support was not secured had lower recruitment rates. (5) The process for recording withdrawal was not sufficiently detailed. (6) The number of follow-up visits was considered burdensome for some participants. (7) The feasibility trial did not have a control arm or assess randomisation processes. CONCLUSIONS: A future randomised controlled trial is feasible and acceptable. STUDY AND TRIAL REGISTRATION: This study is registered as PROSPERO CRD42014013572; Current Controlled Trials ISRCTN35327119; and National Institute for Health Research (NIHR) Portfolio registration 162114. FUNDING: The NIHR Health Technology Assessment programme. PMID- 29265005 TI - Facing the hidden wall in mesial extratemporal lobe epilepsy. AB - Refractory extratemporal lobe epilepsy (ETLE) tends to have a less favourable surgical outcome in comparison to temporal lobe epilepsy. ETLE poses specific diagnostic and therapeutic challenges, particularly in cases where seizures develop from the midline. This review focuses on the diagnostic challenges and therapeutic strategies in mesial ETLE. The great diversity of interhemispheric functional areas and extensive connectivity to extramesial structures results in very heterogeneous seizure semiology. Specific signs, such as ictal body turning, can suggest a mesial onset. The hidden cortex of the mesial wall furthermore gives rise to specific diagnostic difficulties due to the low localizing value of scalp EEG. Advanced imaging, as well as targeted intracranial studies, can substantially contribute to depict the seizure onset zone since electroclinical findings are difficult to interpret in most cases. Surgical accessibility of the interhemispheric space can be challenging, both for the placement of subdural grids, as well as for resective surgery. When facing the hidden cortex on the mesial wall of the hemispheres, targeted intra- or extra-operative intracranial recordings can lead to satisfactory outcomes in properly selected cases. PMID- 29265006 TI - Superconducting Properties and MUSR Study of the Noncentrosymmetric Superconductor Nb0.5Os0.5. AB - The properties of the noncentrosymmetric superconductor ($?alpha$-$?textit{Mn}$ structure) Nb$_{0.5}$Os$_{0.5}$ is investigated using resistivity, magnetization, specific heat, and muon spin relaxation and rotation ($?mu$SR) measurements. These measurements suggest that Nb$_{0.5}$Os$_{0.5}$ is a weakly coupled ($?lambda_{e-ph}$ $?sim$ 0.53) type-II superconductor ($?kappa_{GL}$ $?approx$ 61) having a bulk superconducting transition temperature $T_c$ = 3.07 K. The specific heat data in the superconductive regime fits well with the single-gap BCS model indicating nodeless s-wave superconductivity in Nb$_{0.5}$Os$_{0.5}$. The $?mu$SR measurements also confirm $?textit{s}$-wave superconductivity with the preserved time-reversal symmetry. PMID- 29265007 TI - Single molecule localization imaging of exosomes using blinking silicon quantum dots. AB - Discovering new fluorophores, which are suitable for single molecule localization microscopy (SMLM) is important for promoting the applications of SMLM in biological or material sciences. Here, we found that silicon quantum dots (Si QDs) possess a fluorescence blinking behavior, making them an excellent candidate for SMLM. The Si QDs are fabricated using a facile microwave-assisted method. Blinking of Si QDs is confirmed by single particle fluorescence measurement and the spatial resolution achieved is about 30 nm. To explore the potential application of Si QDs as the nanoprobes for SMLM imaging, cell derived exosomes are chosen as the object owing to their small size (50-100 nm in diameter). Since CD63 is commonly presented on the membrane of exosomes, CD63 aptamers are attached to the surface of Si QDs to form nanoprobes which can specifically recognize exosomes. SMLM imaging shows that Si QDs based nanoprobes can indeed realize super resolved optical imaging of exosomes. More importantly, blinking of Si QDs is observed in water or PBS buffer with no need for special imaging buffers. Besides, considering that silicon is highly biocompatible, Si QDs should have minimal cytotoxicity. These features make Si QDs quite suitable for SMLM applications especially for live cell imaging. PMID- 29265008 TI - Magnetic and structural changes in LaCo0.9Mn0.1O3 at high pressure. AB - The structural and magnetic properties of LaCo0.9Mn0.1O3 have been studied as a function of pressure by neutron powder diffraction and DC magnetometry. The material is confirmed to exhibit rhombohedral R [Formula: see text] c symmetry between ambient pressure and 6 GPa. We have determined the bulk modulus B 0 of the sample using a second-order Birch-Murnaghan equation of state which yielded: B 0 = 140(9) GPa and V [Formula: see text]. We report a non-linear increase of the Curie temperature T C from an ambient pressure value of 224.7 K to ~236 K at a pressure of 4 GPa. Finally, we confirm the glassy-like nature of the magnetism in LaCo0.9Mn0.1O3, which is maintained throughout the pressure range explored. PMID- 29265010 TI - Mass transport modelling for the electroreduction of CO2 on Cu nanowires. AB - Mass transport plays an important role in CO2 reduction electrocatalysis. Albeit being more pronounced on nanostructured electrodes, the studies of mass transport for CO2 reduction have yet been limited to planar electrodes. We report here the development of a mass transport model for the electroreduction of CO2 on Cu nanowire electrodes. Fed with the experimental data from electrocatalytic studies, the local concentrations of CO2, [Formula: see text] and OH- on the nanostructured electrodes are calculated by solving the diffusion equations with spatially distributed electrochemical reaction terms incorporated. The mass transport effects on the catalytic activity and selectivity of the Cu nanowire electrocatalysts are thus discussed by using the local pH as the descriptor. The established correlations between the electrocatalytic performance and the local pH shows that, the latter does not only determine the acid-base reaction equilibrium, but also regulates the mass transport and reaction kinetics. Based on these findings, the optimal range of local pH for CO2 reduction is discussed in terms of a fine balance among the suppression of hydrogen evolution, improvement of C2 product selectivity and limitation of CO2 supply. Our work highlights the importance of understanding the mass transport effects in interpretation of CO2 reduction electrocatalysis on high-surface-area catalysts. PMID- 29265009 TI - ERAASR: an algorithm for removing electrical stimulation artifacts from multielectrode array recordings. AB - OBJECTIVE: Electrical stimulation is a widely used and effective tool in systems neuroscience, neural prosthetics, and clinical neurostimulation. However, electrical artifacts evoked by stimulation prevent the detection of spiking activity on nearby recording electrodes, which obscures the neural population response evoked by stimulation. We sought to develop a method to clean artifact corrupted electrode signals recorded on multielectrode arrays in order to recover the underlying neural spiking activity. APPROACH: We created an algorithm, which performs estimation and removal of array artifacts via sequential principal components regression (ERAASR). This approach leverages the similar structure of artifact transients, but not spiking activity, across simultaneously recorded channels on the array, across pulses within a train, and across trials. The ERAASR algorithm requires no special hardware, imposes no requirements on the shape of the artifact or the multielectrode array geometry, and comprises sequential application of straightforward linear methods with intuitive parameters. The approach should be readily applicable to most datasets where stimulation does not saturate the recording amplifier. MAIN RESULTS: The effectiveness of the algorithm is demonstrated in macaque dorsal premotor cortex using acute linear multielectrode array recordings and single electrode stimulation. Large electrical artifacts appeared on all channels during stimulation. After application of ERAASR, the cleaned signals were quiescent on channels with no spontaneous spiking activity, whereas spontaneously active channels exhibited evoked spikes which closely resembled spontaneously occurring spiking waveforms. SIGNIFICANCE: We hope that enabling simultaneous electrical stimulation and multielectrode array recording will help elucidate the causal links between neural activity and cognition and facilitate naturalistic sensory protheses. PMID- 29265011 TI - Secondary radiation measurements for particle therapy applications: charged particles produced by 4He and 12C ion beams in a PMMA target at large angle. AB - Proton and carbon ion beams are used in the clinical practice for external radiotherapy treatments achieving, for selected indications, promising and superior clinical results with respect to x-ray based radiotherapy. Other ions, like [Formula: see text] have recently been considered as projectiles in particle therapy centres and might represent a good compromise between the linear energy transfer and the radiobiological effectiveness of [Formula: see text] ion and proton beams, allowing improved tumour control probability and minimising normal tissue complication probability. All the currently used p, [Formula: see text] and [Formula: see text] ion beams allow achieving sharp dose gradients on the boundary of the target volume, however the accurate dose delivery is sensitive to the patient positioning and to anatomical variations with respect to photon therapy. This requires beam range and/or dose release measurement during patient irradiation and therefore the development of dedicated monitoring techniques. All the proposed methods make use of the secondary radiation created by the beam interaction with the patient and, in particular, in the case of [Formula: see text] ion beams are also able to exploit the significant charged radiation component. Measurements performed to characterise the charged secondary radiation created by [Formula: see text] and [Formula: see text] particle therapy beams are reported. Charged secondary yields, energy spectra and emission profiles produced in a poly-methyl methacrylate (PMMA) target by [Formula: see text] and [Formula: see text] beams of different therapeutic energies were measured at 60 degrees and 90 degrees with respect to the primary beam direction. The secondary yield of protons produced along the primary beam path in a PMMA target was obtained. The energy spectra of charged secondaries were obtained from time-of-flight information, whereas the emission profiles were reconstructed exploiting tracking detector information. The obtained measurements are in agreement with results reported in the literature and suggests the feasibility of range monitoring based on charged secondary particle detection: the implications for particle therapy monitoring applications are also discussed. PMID- 29265012 TI - A variational approach to liver segmentation using statistics from multiple sources. AB - Medical image segmentation plays an important role in digital medical research, and therapy planning and delivery. However, the presence of noise and low contrast renders automatic liver segmentation an extremely challenging task. In this study, we focus on a variational approach to liver segmentation in computed tomography scan volumes in a semiautomatic and slice-by-slice manner. In this method, one slice is selected and its connected component liver region is determined manually to initialize the subsequent automatic segmentation process. From this guiding slice, we execute the proposed method downward to the last one and upward to the first one, respectively. A segmentation energy function is proposed by combining the statistical shape prior, global Gaussian intensity analysis, and enforced local statistical feature under the level set framework. During segmentation, the shape of the liver shape is estimated by minimization of this function. The improved Chan-Vese model is used to refine the shape to capture the long and narrow regions of the liver. The proposed method was verified on two independent public databases, the 3D-IRCADb and the SLIVER07. Among all the tested methods, our method yielded the best volumetric overlap error (VOE) of [Formula: see text], the best root mean square symmetric surface distance (RMSD) of [Formula: see text] mm, the best maximum symmetric surface distance (MSD) of [Formula: see text] mm in 3D-IRCADb dataset, and the best average symmetric surface distance (ASD) of [Formula: see text] mm, the best RMSD of [Formula: see text] mm in SLIVER07 dataset, respectively. The results of the quantitative comparison show that the proposed liver segmentation method achieves competitive segmentation performance with state-of-the-art techniques. PMID- 29265013 TI - Research on psoriasis in India: Where do we stand? PMID- 29265014 TI - Telepsychiatry: Reaching the unreached. PMID- 29265015 TI - Human papillomavirus vaccine for cancer cervix prevention: Rationale & recommendations for implementation in India. PMID- 29265016 TI - The syndrome of acute encephalitis in children in India: Need for new thinking. PMID- 29265017 TI - Folic acid, one-carbon metabolism & childhood cancer. AB - Folate has been studied in relation to many diseases, especially cancer. Although it has been postulated to exert a dual effect on development of cancer, its role remains to be clearly defined. Its effect on cancer is the result of gene nutrient interaction between the genes in folate metabolic pathway and dietary folate availability; mutations in genes of folate metabolism have been shown to alter individual susceptibility to certain childhood cancers as well as response to cancer chemotherapy. Although mandatory fortification of food items with folate has been initiated in some countries, many countries are yet to adopt this due to concerns about undesired adverse effects of high folate levels on health, especially cancer. However, initial reports suggest that folate fortification has led to reduction in incidence of certain childhood cancers such as neuroblastoma, wilms tumour and leukaemias. Despite studies showing folate depletion during antifolate chemotherapy and higher toxicity of chemotherapy in folate-depleted individuals, folate supplementation during cancer chemotherapy is not routinely recommended. Studies investigating the precise effect of folate supplementation during chemotherapy on both short- and long-term outcomes of cancer are needed to arrive at a consensus guideline. PMID- 29265018 TI - Incidence & prevalence of stroke in India: A systematic review. AB - BACKGROUND & OBJECTIVES: There has been more than 100 per cent increase in incidence of stroke in low- and middle-income countries including India from 1970 1979 to 2000-2008. Lack of reliable reporting mechanisms, heterogeneity in methodology, study population, and small sample size in existing epidemiological studies, make an accurate estimation of stroke burden in India challenging. We conducted a systematic review of epidemiologic studies on stroke conducted in India to document the magnitude of stroke. METHODS: All population-based, cross sectional studies and cohort studies from India which reported the stroke incidence rate or cumulative stroke incidence and/or the prevalence of stroke in participants from any age group were included. Electronic databases (Ovid, PubMed, Medline, Embase and IndMED) were searched and studies published during 1960 to 2015 were included. A total of 3079 independent titles were identified for screening, of which 10 population-based cross-sectional studies were considered eligible for inclusion. Given the heterogeneity of the studies, meta analysis was not carried out. RESULTS: The cumulative incidence of stroke ranged from 105 to 152/100,000 persons per year, and the crude prevalence of stroke ranged from 44.29 to 559/100,000 persons in different parts of the country during the past decade. These values were higher than those of high-income countries. INTERPRETATION & CONCLUSIONS: A paucity of good-quality epidemiological studies on stroke in India emphasizes the need for a coordinated effort at both the State and national level to study the burden of stroke in India. Future investment in the population-based epidemiological studies on stroke would lead to better preventive measures against stroke and better rehabilitation measures for stroke related disabilities in the country. PMID- 29265019 TI - A review of Indian research on co-occurring cannabis use disorders& psychiatric disorders. AB - BACKGROUND & OBJECTIVES: Cannabis is a widely used illicit drug and its use is often associated with co-occurring psychiatric disorders. This systematic review was aimed to provide information on the published Indian studies on co-occurring cannabis use disorders and psychiatric disorders. METHODS: An electronic search of available Indian literature using relevant search terms was carried out in May 2015 and 52 articles in English language published from India were included in the current review. RESULTS: Studies on cannabis and associated psychotic disorders (n=16) chiefly described acute episodes with predominant positive symptoms, following cannabis use. Some studies (n=6) observed an overall increased prevalence of all psychiatric disorders and symptoms owing to cannabis use, while others (n=14) elaborated on high rates of substance use in those with psychiatric disorders. The effect of cannabis use on cognitive function was the focus of some of the Indian studies (n=7). All these studies barring one had all male subjects, and a single study described the service delivery model for those with dual diagnosis disorders in India. Most of the research used cross-sectional observational design and focussed on treatment-seeking population. INTERPRETATION & CONCLUSIONS: A review of Indian literature on cannabis use and its association with psychiatric disorders indicates a high co-prevalence of psychotic disorders, especially in vulnerable individuals as well as high rates of co-occurrence of other psychiatric comorbidities. However, there is limited focus on exploring the aetiological association between cannabis use and psychiatric disorders; understanding the neurobiology of this association and management-related issues. PMID- 29265020 TI - Telepsychiatry clinical decision support system used by non-psychiatrists in remote areas: Validity & reliabilityof diagnostic module. AB - BACKGROUND & OBJECTIVES: A knowledge-based, logically-linked online telepsychiatric decision support system for diagnosis and treatment of mental disorders was developed and validated. We evaluated diagnostic accuracy and reliability of the application at remote sites when used by non-psychiatrists who underwent a brief training in its use through video-conferencing. METHODS: The study was conducted at a nodal telepsychiatry centre, and three geographically remote peripheral centres. The diagnostic tool of application had a screening followed by detailed criteria-wise diagnostic modules for 18 psychiatric disorders. A total of 100 consecutive consenting adult outpatients attending remote telepsychiatry centres were included. To assess inter-rater reliability, patients were interviewed face to face by non-specialists at remote sites using the application (active interviewer) and simultaneously on online application via video-conferencing by a passive assessor at nodal centre. Another interviewer at the nodal centre rated the patient using Mini-International Neuropsychiatric Interview (MINI) for diagnostic validation. RESULTS: Screening sub-module had high sensitivity (80-100%), low positive predictive values (PPV) (0.10-0.71) but high negative predictive value (NPV) (0.97-1) for most disorders. For the diagnostic sub-modules, Cohen's kappa was >0.4 for all disorders, with kappa of 0.7-1.0 for most disorders. PPV and NPV were high for most disorders. Inter-rater agreement analysis revealed kappa >0.6 for all disorders. INTERPRETATION & CONCLUSIONS: Diagnostic tool showed acceptable to good validity and reliability when used by non-specialists at remote sites. Our findings show that diagnostic tool of the telepsychiatry application has potential to empower non-psychiatrist doctors and paramedics to diagnose psychiatric disorders accurately and reliably in remote sites. PMID- 29265021 TI - Prevalence & factors associated with depression among schoolgoing adolescents in Chandigarh, north India. AB - BACKGROUND & OBJECTIVES: Depression among adolescents is a rising problem globally. There is a need to understand the factors associated with depression among adolescents. This study was conducted to ascertain the prevalence of depressive disorders and associated factors among schoolgoing adolescents in government and private schools in Chandigarh, India. METHODS: A cross-sectional study was conducted among 542 randomly selected schoolgoing adolescents (13-18 yr), from eight schools by multistage sampling technique. Depression was assessed using Patient Health Questionnaire-9 (PHQ-9) and associated factors by pretested semistructured interview schedule. Multivariate analysis was done to identify significant associated factors. RESULTS: Two-fifth (40%) of adolescents had depressive disorders, 7.6 per cent major depressive disorders and 32.5 per cent other depressive disorders. In terms of severity, 29.7 per cent had mild depression, 15.5 per cent had moderate depression, 3.7 per cent had moderately severe depression and 1.1 per cent had severe depression. Significant associated factors included being in a government school, studying in class Xth and XIIth, rural locality, physical abuse by family members, alcohol use and smoking by father, lack of supportive environment in school, spending less time in studies, lower level of participation in cultural activities and having a boy/girlfriend. Significant predictors on binary logistic regression analysis were being in class Xth [odds ratio (OR)=5.3] and lack of self-satisfaction with own academic performance (OR=5.1). INTERPRETATION & CONCLUSIONS: Our study showed that a significant proportion of schoolgoing adolescents suffered from depression. The presence of depression was associated with a large number of modifiable risk factors. There is a need to modify the home as well as school environment to reduce the risk of depression. PMID- 29265022 TI - Late effects of treatment in survivors of childhood cancers: A single-centre experience. AB - BACKGROUND & OBJECTIVES: With improved survival of childhood cancer patients, the number of long-term cancer survivors is increasing. Some studies have assessed the long-term morbidity after childhood cancer treatment in the developing countries. This study was conducted to assess the spectrum of late effects of cancer treatment in paediatric cancer survivors. METHODS: Evaluation of the first 300 patients who completed five years of follow up in the after treatment completion clinic was done. Details of primary diagnosis, treatment received and current clinical status were noted. The spectrum of late effects was ascertained by appropriate investigations. RESULTS: Haematological malignancies comprised 25 per cent of total cases. Most common primary diagnosis comprised acute lymphoblastic leukaemia, retinoblastoma and Hodgkin's lymphoma. The median age at evaluation and follow up was 14 and 8.5 yr, respectively. Twenty three per cent (69) of the survivors had a minimal disability (growth retardation or underweight), 13 per cent (39) had moderate disabilities needing medical attention (hepatitis B surface antigen positive, myocardial dysfunction, azoospermia and hypothyroidism), while two per cent had major/life-threatening disabilities (mental retardation, liver disease and mortality). Eleven patients relapsed on follow up, of those five patients expired. Two second malignancies were recorded during the period of follow up. INTERPRETATION & CONCLUSIONS: Late effects were of concern; however, severe disability (Grade 3-5) was seen in only two per cent survivors. Lifelong follow up of childhood cancer survivors is required to assess cancer-related morbidity, occurrence of a secondary neoplasm, to facilitate timely diagnosis and to implement remedial or preventive interventions to optimize health outcomes. Awareness towards the existence of late effects of cancer therapy is required among parents, patients and health professionals. PMID- 29265023 TI - Clinical & immunological characteristics in systemic lupus erythematosus patients. AB - BACKGROUND & OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which affects females more than males. Gender affects the manifestations of SLE and men with lupus show more severe symptoms and worse prognosis. This study was aimed to compare clinical and immunological features in female and male lupus patients in Iran. METHODS: Demographic, clinical and laboratory data from 78 women and 20 men with lupus were collected. Autoantibodies (against nRNP, Sm, SSA, SSB, Ro-52, CENP, Jo-1, Scl-70, nucleosome, anti-dsDNA, histone and Rib-p protein) were determined using immunoblotting technique. RESULTS: Men with lupus had less anti-SSA (21.1 vs 48.1%) and anti-Ro52 (10.5 vs 44.3%) antibodies when compared to women and none of the male patients had anti-SSB antibodies. Kidney damage was more frequent in men (68.4% in men vs 36.7% in women). In men with kidney involvement, anti-dsDNA increased significantly (84.6 vs 20.0%) in comparison to males without nephritis. Anti-SSA (7.7 vs 50.0%) and anti-nRNP (0.0 vs 33.8%) on the other hand, decreased. Women with renal involvement had no anti-SSB antibodies. INTERPRETATION & CONCLUSIONS: In male patients, SLE appeared with more severe features, and kidney damage was more frequent in males. The frequency of some autoantibodies was different between females and males. In males with kidney damage anti-dsDNA increased significantly, while anti-SSA and anti-nRNP decreased. Anti-SSB was not detected in males and females with nephritis. PMID- 29265024 TI - Ultrasound-defined remission for good functional status in rheumatoid arthritis. AB - BACKGROUND & OBJECTIVES: It has been shown that joint damage due to subclinical synovitis progresses despite apparent clinical remission in rheumatoid arthritis (RA). Hence, finding more objective methods to investigate subclinical synovitis has become a current issue. Ultrasonography (US) has been among the most investigated methods. This study was conducted to detect whether there was subclinical inflammation in RA patients in clinical remission by power Doppler ultrasonography (PDUS) and to evaluate the effects of this inflammation on upper extremity function. METHODS: Forty five RA patients fulfilled the remission criteria of disease activity score 28 using erythrocyte sedimentation rate (DAS28 ESR), were enrolled in the study. Bilateral wrist, 2nd and 3th metacarpophalangeal and proximal interphalangeal joints and 2nd and 5th metatarsophalangeal joints were examined by PDUS. Upper extremity function was assessed with Michigan Hand Outcomes Questionnaire (MHQ) and handgrip strength. The pain was evaluated by visual analogue scale (VAS). RESULTS: In 29 of 45 RA patients in clinical remission, synovitis was detected by PDUS at least in one joint. VAS and DAS28-ESR scores were significantly lower and total MHQ, some subgroup scores of MHQ (overall hand function, activity of daily living and work performance) and grip strength of the dominant hand were higher in patients with PD signal negativity. INTERPRETATION & CONCLUSIONS: PDUS showed a crucial role in determining the subclinical synovitis. Subclinical synovitis negatively affects the upper extremity function. Ultrasound-defined remission may be considered for good functional status and real remission in patients with RA. PMID- 29265025 TI - Tumour protein 53 is linked with type 2 diabetes mellitus. AB - BACKGROUND & OBJECTIVES: Tumour protein p53 (TP53) is a stress sensitive transcription factor responsible for the control of cell survival and death to prevent from tumour formation. In vitro and animal studies have indicated that TP53 also responds to metabolic changes and influences metabolic pathways. This study was undertaken to determine the serum level of TP53 and its correlations with clinical and biochemical parameters in type 2 diabetes mellitus (T2DM) patients in comparison to non-diabetic control individuals. METHODS: An observational study was conducted between December 2009 and November 2013 to evaluate TP53 serum level using ELISA. Cases (n=225) were defined as patients who were diagnosed with T2DM. Non-diabetic controls (n=255) were matched by age and sex. Multivariable modelling using logistic regression examined associations between clinical characteristics and TP53 level or T2DM predication was performed. RESULTS: Serum TP53 level was significantly higher in T2DM patients as compared to non-diabetic healthy controls (1.69 vs 2.07 ng/ml, P<0.001). In T2DM patients, the level of TP53 increased with the age, duration of diabetes and waist-to-hip ratio (WHR) value. A logistic regression analysis revealed that increased serum TP53 level was significantly associated with family history of diabetes, age and WHR. Moreover, TP53, triglyceride and body mass index could be used to predict T2DM. INTERPRETATION & CONCLUSIONS: Our results suggest that TP53 may be linked with T2DM. The fluctuations of serum TP53 level may reflect metabolic and oxidative stress associated with chronic hyperglycaemia. Further studies need to be done to confirm these findings. PMID- 29265026 TI - Evaluating KIND1 human embryonic stem cell-derived pancreatic progenitors to ameliorate streptozotocin-induced diabetes in mice. AB - BACKGROUND & OBJECTIVES: Diabetes is a global disease burden. Various stem cell types are being explored to serve as an alternative source of islets. This study was conducted to evaluate the ability of in-house developed human embryonic stem (hES) cells-derived pancreatic progenitors to ameliorate diabetic symptoms in mice. METHODS: Pancreatic progenitors were packed in macro-capsules and transplanted into six male Swiss mice and four mice were taken as controls. Thirty days post-transplantation, diabetes was induced by streptozotocin treatment. Mice were then followed up for >100 days and body weight and blood glucose levels were regularly monitored. RESULTS: Control mice lost weight, maintained high glucose levels and did not survive beyond 40 days, whereas transplanted group maintained body weight and four of the six mice had lowered blood glucose levels. About five-fold increase was observed in human C-peptide levels in the recipients of progenitor transplants as compared to diabetic control. INTERPRETATION & CONCLUSIONS: The beneficial effect of transplanted cells was not long-lasting. Further studies are required to critically evaluate and compare the potential of endogenous pluripotent stem cells and hES cells derived progenitors before moving from bench to the bedside. PMID- 29265027 TI - Neuroprotective effect of Cubebin: A dibenzylbutyrolactone lignan on scopolamine induced amnesia in mice. AB - BACKGROUND & OBJECTIVES: Acetylcholinesterase (AChE) inhibitors represent a major class of drugs which provide symptomatic relief and improvement in cognitive function in Alzheimer's disease (AD). In this study, cubebin, a dibenzylbutyrolactone lignan, was isolated from Piper cubeba and investigated for its AChE inhibitory activity in an attempt to explore its potential for memory enhancing activities in mice. METHODS: Molecular docking of cubebin was carried out followed by in vitro AChE activity. Mice were treated with cubebin (25 & 50 mg/kg; i.p.), for three days and memory impairment was induced by scopolamine (3 mg/kg; i.p.). Memory function was evaluated by Morris water maze (MWM) test. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain. RESULTS: Molecular docking study revealed that cubebin was well bound within the binding site of the AChE enzyme showing interactions such as pi-pi stacking and hydrogen bonding with residues present therein. Cubebin inhibited AChE enzyme in an in vitro assay with IC50value of 992 MUM. Scopolamine administration caused a significant impairment of learning and memory in mice, as indicated by a marked decrease in MWM performance. Scopolamine administration also produced a significant enhancement of brain AChE activity and oxidative stress in mice brain. Pre-treatment of cubebin (25 and 50 mg/kg; i.p.) significantly prevented scopolamine-induced learning and memory deficits along with attenuation of scopolamine-induced rise in brain AChE activity and oxidative stress level. INTERPRETATION & CONCLUSIONS: Cubebin showed promising protective activity in scopolamine-induced spatial memory impairment in mice. This could be attributed to its brain AChE inhibition and antioxidant activity. PMID- 29265028 TI - Prevalence of afebrile parasitaemia due to Plasmodium falciparum & P. vivax in district Balaghat (Madhya Pradesh): Implication for malaria control. AB - BACKGROUND & OBJECTIVES: Balaghat district in Central India is a highly malarious district where both Plasmodium falciparum and P. vivax are prevalent. In this district, the persistence of malaria was on an increase and not responsive to intervention measures even though there was no drug resistance. This study was undertaken by conducting mass screening to determine the prevalence of malaria among particularly vulnerable tribe of Balaghat, for developing evidence-based intervention measures for malaria control in hard to reach areas. METHODS: This prospective study was carried out during 2013-2014 by conducting mass survey of the population in 10 villages of Birsa community health centre (CHC) and 12 villages of Baihar CHC. Finger-pricked blood smears were collected from all consenting individuals with or without fever for microscopic examination. RESULTS: In the febrile group, the slide positivity rate (SPR) and slide falciparum rate (SFR) were 32.4 and 28.9 per cent, respectively, with 89.4 per cent P. falciparum, while in the afebrile individuals also, the SPR and SFR were high (29 and 26%, respectively), but these were significantly lower than that of febrile group. The gametocyte carriers were significantly higher (odds ratio 1.67, 95% confidence interval 1.25-2.25, P=0.0004) in afebrile patients when compared with febrile group. Vector incrimination showed the presence of four sporozoite-positive Anopheles culicifacies out of 1953 assayed. INTERPRETATION & CONCLUSIONS: Plasmodium falciparum malaria was high in young children (up to 8 years) as compared to the adult in both afebrile and febrile group in Balaghat district. High prevalence of gametocyte was observed in all age groups among the afebrile cases. The identification of afebrile malaria parasitaemia is an important challenge for the malaria elimination initiatives. A strong malaria surveillance system is fundamental to both programme design and implementation. PMID- 29265029 TI - Incidence of Japanese Encephalitis amongst acute encephalitis syndrome cases in upper Assam districts from 2012 to 2014: A report from a tertiary care hospital. AB - BACKGROUND & OBJECTIVES: Japanese encephalitis (JE) is a major public health problem in India because of high mortality rate and residual neuropsychiatric damage in the survivors. The present study was undertaken to investigate JE positivity amongst patients admitted with acute encephalitis syndrome (AES) in upper Assam districts and different parameters with their changing trends related to it. METHODS: It was a hospital-based prospective cross-sectional study conducted from January 2012 to December 2014. A total of 1707 consecutive non repetitive hospitalized patients, satisfying the clinical case definition of AES as per the WHO guidelines, were included in the study. Cerebrospinal fluid (CSF) and serum samples were tested for JEV-specific IgM antibodies. RESULTS: Of the 1707 patients admitted, 696 (40.77 %) were diagnosed as JE with male-to-female ratio 1.7:1 and adult to paediatric ratio 2.2:1. Fever (100%), change in mental status (100%), headache (80.02%), neck rigidity (52.01%), unconsciousness (48.99%), seizure (37.64%) and paralysis (11.06%) were the major clinical findings. The majority of cases (94%) were from rural areas. There was a significant association of JE cases with rainy season of the year i.e., June to August (P<0.001). Overall, 14.94 per cent deaths were reported in JE positive cases. INTERPRETATION & CONCLUSIONS: A higher occurrence of JE was observed in above 15 yr age group. Cases were mainly from rural areas, and there was clustering of cases in rainy season. PMID- 29265030 TI - A simplified multiplex PCR-based typing method for common Salmonella enterica serovars supported by online server-based detection system. AB - BACKGROUND & OBJECTIVES: A rapid and simple alternative method is needed to replace the laborious, time-consuming Salmonella serotyping. The objective of the present study was to improve and simplify a previously reported multiplex polymerase chain reaction (PCR)-based method and to create an online server to enable rapid determination of serovars. METHODS: A method of multiplex PCR-based genome typing (MPGT) was standardized using 59 Salmonella isolates of 31 serovars. Several previously reported primers were modified to obtain a more accurate performance. The screen was separated into four different multiplex reactions distinguishable on standard electrophoresis. A blind study was subsequently performed with 81 isolates of 10 serovars most prevalent in India. Whole genome information from 440 Salmonella isolates was used to confirm the usefulness of this method and concurrence of in silico predictions and PCR results were investigated. A public server (http://www.mpgt-salmonella.res.in) was established for data storage and determination of closest previously observed Salmonella isolates based on obtained MPGT patterns. RESULTS: The 16 target genes amplified showed variability in their presence in strains from different serotypes. Hence, identical amplification patterns suggested genetic relatedness of strains and usually identical serological behaviour. The observed absence/presence patterns of genes were converted to an MPGT code. Altogether, 83 different codes were predicted in silico based on the whole genome information of 440 strains. Results confirmed that major serovars usually displayed unique MPGT codes. INTERPRETATION & CONCLUSIONS: The multiplex PCR assay resulted in specific binary codes for isolates from each of the 31 Salmonella serovars tested. The online server allowed the user to compare obtained PCR results with stored previous patterns. Simplicity, speed and cost-effectiveness make this tool useful for quick outbreak management. PMID- 29265031 TI - Physical comorbidity in schizophrenia & its correlates. AB - The presence of common physical comorbidities, their demographic and clinical correlates and impact on functioning was assessed in 100 patients with schizophrenia. The patients had a mean age of 35.12+/-10.7 yr with mean duration of illness of 8.3+/-0.58 years. Seventy per cent were detected to have a comorbid physical condition. Common conditions included hypertension (21%), diabetes mellitus (15%) and anaemia (12%). Increasing age, being female, being married, longer duration of illness and longer duration of treatment were associated with higher risk of having a comorbid physical illness. Further studies need to be done with a large sample to confirm these findings. PMID- 29265032 TI - An intervention to evaluate & improve handling of cancer drugs in a tertiary care hospital in India. PMID- 29265033 TI - Secondary omental torsion as a cause of acute abdomen in a patient with long standing right-sided inguinal hernia. PMID- 29265034 TI - Senescent chronic kidney disease: The challenges faced and the strategies to overcome. AB - The management of chronic kidney disease (CKD) in elderly patients continues to pose constant challenges to clinical nephrologists. Right from the perplexing issue of calculating the glomerular filtration rate (GFR) to the confusion between the choice of disease-oriented approach and individual-centered approach, the challenges faced are mammoth. This article seeks to bring a consensus in sorting out these practical problems so that a systematic way of approach could be arrived at in managing such fragile patients. The last decade has seen an evolution and ongoing refinement of a disease-oriented approach to CKD. Since the average GFR tends to decrease with age, CKD becomes increasingly prevalent with advancing age, and thus, disproportionately elderly patients meet the criteria for CKD. PMID- 29265035 TI - Serum cystatin C levels in Healthy Nigerian neonates: Is there a need for normative values in Nigerian babies? AB - Cystatin C is an endogenous marker of renal function. Normal reference values have been documented in neonates outside Africa, but no study has been documented in African neonates. With reports that race may affect serum cystatin C values, this study was carried out to generate normal values in apparently healthy term neonates at birth and three days of life neonates in Nigeria. This was a hospital based prospective study. A cohort of 120 apparently healthy term neonates were recruited at birth. Serum cystatin C was measured from the cord blood at birth and venous blood when they were three days old using enzyme-linked immunosorbent assay (ELISA) method. The mean serum cystatin C values for cord blood and 3rd day venous samples were 1.67 +/- 0.52 mg/L and 1.62 +/- 0.52 mg/L, respectively (P = 0.87). The cord blood and 3rd day serum cystatin C values for males were 1.67 +/- 0.47 mg/L and 1.68 +/- 0.51 mg/L, respectively (P = 0.77) and the values for females were 1.68 +/- 0.56 mg/L and 1.58 +/- 0.52 mg/L, respectively (P = 07.22). The serum cystatin C levels were similar among the different birth weight groups and gestational age (P >0.05). The cord blood and 3rd day serum cystatin C values were similar. Serum cystatin C values were independent of gender and birth weight of neonates. The values of serum cystatin C in Nigerian neonates were comparable to that reported for neonates in other regions of the world. It is recommended that ELISA technique may be reliably used to measure serum cystatin C levels in neonates. PMID- 29265036 TI - Neutrophil chemokines levels in different stages of nephrotic syndrome. AB - Nephrotic syndrome (NS) is a disease of glomerular filtration barrier failure presenting with variable degrees of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Inflammation may contribute to the pathogenesis of NS. The aim of this study was to monitor the serum levels of three cytokines [i.e., granulocyte chemotactic protein-2 (GCP-2), growth-related oncogene-alpha (GRO-alpha), and interleukin-8 (IL-8)] in different stages of NS and to find out whether changes in the levels of these cytokines could be related to the severity of NS. This study included 125 patients who were divided into 40 patients with nephrotic range proteinuria (NRP), 45 patients with NS, and 40 patients who were in remission. This study also included 80 healthy participants as a control group. Enzyme-linked immunosorbent assay was used for the determination of the plasma levels of GRO-alpha, GCP-2, and IL-8. GCP-2 plasma levels were significantly higher in the NS and NRP groups when compared to the control group, whereas the GRO-alpha and IL-8 levels were significantly higher in all patient groups in comparison with the control group. All these chemokine levels were significantly decreased in remission as compared with the participants in the NS group (P <0.0001). There was a significant correlation between the cytokine levels and proteinuria and serum albumin in the NS group (P <0.0001). However, in the follow up group, GCP-2 levels were significantly lower during remission as compared to those with active NS (P <0.0001). Our findings suggest that the pro-inflammatory cytokines GCP-2, GRO-alpha, and IL-8 could play a role in the pathogenesis of NS, particularly glomerular permeability. PMID- 29265037 TI - Leukocyte esterase reagent strip as a bedside tool to detect peritonitis in patients undergoing acute peritoneal dialysis. AB - Peritonitis is a common and life-threatening complication of acute peritoneal dialysis (PD). Diagnosis requires the presence of clinical signs of peritonitis which are nonspecific and laboratory investigations [total leukocyte count (TLC), Gram-stain, and culture of PD effluent fluid] which are time-consuming and not available at the bedside. In this study, we evaluated the use of leukocyte esterase reagent strip (LERS) as a bedside test to diagnose peritonitis in patients undergoing acute PD. Patients who underwent acute PD were monitored for signs and symptoms of peritonitis. PD effluent fluid analysis included TLC, absolute neutrophil count, Gram-stain, and culture for the diagnosis of peritonitis. LERS (Multistix 10SG) was simultaneously dipped in PD effluent fluid and read at two minutes. Reading of + was considered as indicative of peritonitis. Twenty-one out of 166 (12.6%) patients undergoing acute PD developed peritonitis. LERS detected peritonitis in 20 patients. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of LERS were 95.2%, 95.2%, 74.1%, and 99.3%, respectively. LERS has very high sensitivity and NPV and can be used as a rapid bedside tool to exclude peritonitis in patients undergoing acute PD. PMID- 29265038 TI - Mixed hydroalcoholic extracts of Nigella sativa and Curcuma longa improves adriamycin-induced renal injury in rat. AB - Extracts of both Curcuma longa (CL) and Nigella sativa extract (NS) are reported to have protective effects on renal damage. In this study, we investigated the protective effect of a combination of NS and CL on Adriamycin (ADR)-induced renal damage. Forty eight rats were divided into six groups as: Control (CO), ADR, Vitamin C + ADR, CL + ADR, NS +ADR, and CL + NS + ADR. ADR was injected intravenously on the 7th day of the study. 24-hour urine and orbital blood samples were collected on day 0, 48 hr after ADR injection and at the end of weeks 2, 3, 4, and on the 35th day. Glomerular filtration rate (GFR) was calculated on each sample, and on the 35th day, renal index and histological changes were also evaluated. In the ADR-treated rats, significant renal pathological changes were demonstrated compared to CO group. The renal index and urine protein excretion significantly increased, and serum albumin and GFR in the ADR-treated rats were significantly decreased compared to CO group. In NS + ADR group, the serum albumin significantly decreased compared to ADR group. In CL + NS + ADR group, the urine protein excretion was lower than ADR group, and serum albumin concentration was significantly higher than ADR group. In addition, in CL + ADR and NS + ADR groups also, the urine protein was significantly lower compared to ADR group. This study shows that the mixed extracts of N. sativa and CL have positive synergistic effects on renal damage in nephropathy induced by ADR in rats. PMID- 29265039 TI - A pragmatic randomized controlled trial comparing pathway-based versus usual care in community-acquired acute kidney injury. AB - Clinical pathways have shown conflicting evidence in improvement of several patient-centered outcomes across different clinical settings. However, the effectiveness of clinical pathway in management of acute kidney injury (AKI) has not been reported. Therefore, we aimed to assess the length of hospital stay (LOS) and patient-centered outcomes in community acquired AKI and compared pathway care (PC) versus usual care (UC). The CHAMP-Path AKI Trial is a pragmatic, parallel, single-blind randomized controlled trial. Physicians were randomized to provide either UC or PC. Patients were randomized through a computer-generated sequence. Allocation was concealed. Patients presenting to the emergency department with AKI and hemodynamic stability, who were over 14 years with a serum creatinine greater than 1.5 times the baseline were eligible. Patients with chronic kidney disease stages 4 or 5, kidney transplantation recipients, those admitted with obstructive uropathy, suspected glomerular or interstitial disease, and pregnant women were excluded. Thirty-eight patients were enrolled from March 2012 to December 2013. The primary outcome was LOS. Secondary outcomes included: 30-day readmission, in-hospital mortality, determinants of LOS, and patient-centered outcomes. Eighteen patients were randomized to PC, and 20 to UC. Baseline characteristics were comparable in both groups. Using an intention-to-treat analysis, the median LOS was 4.96 [interquartile range (IQR) 6.57] and 4.80 days (IQR 6.84) for PC and UC, respectively (P = 0.770). Of the five readmissions, none were for AKI. No in hospital mortality was reported. The CHAMP-Path AKI pragmatic trial demonstrated that PC was not different than UC in reducing LOS. There was no difference in 30 day re- admission, in-hospital mortality, and patient-centered outcomes. PMID- 29265040 TI - Impact of pharmaceutical care on the health-related quality of life among hemodialysis patients - A multicenter randomized controlled study. AB - The present study was planned to assess the impact of pharmaceutical care on the health-related quality of life (HRQoL) among hemodialysis (HD) patients. An open label, randomized control study was carried out at three different HD centers of teaching, government, and corporate hospitals in South India. The patients were randomized into two groups (Usual Care Group [UC] and Pharmaceutical Care Group [PC]) by block design method. The PC group received the normal care along with pharmaceutical care delivered by a qualified registered pharmacist. The assessment of the HRQoL was carried out at baseline, 6th and 12th months for the both groups for a total of 12-month follow-up. A total number of 200 patients were recruited from the three HD centers. At the end of the study, 153 patients were followed. Out of 153 patients, 83 were from academic hospital (UC, n =41; PC, n = 42), 18 from government hospital (UC, n = 09; PC, n = 09), and 52 from corporate hospital (UC, n = 25; PC, n = 27). The HRQoL scores were significantly improved over time in the domains noticed with regard to the "physical functioning, general health, emotional well-being, social functioning, symptom/problem list, and effects of kidney disease" in all the three centers of PC group compared to UC group with P <0.05. The pharmaceutical care provided by a trained pharmacist had positive impact in HRQoL of HD patients. PMID- 29265041 TI - Nutrition screening tools as predictor of malnutrition for hemodialysis patients in Dr. Sardjito Hospital in Yogyakarta, Indonesia. AB - The risk of malnutrition in maintenance hemodialysis (MHD) patients must be monitored routinely through nutrition screening so that morbidity and mortality can be decreased. Comparing the validity of the simple nutrition screening tool (SNST) and nutritional risk screening 2002 (NRS 2002) as valid and reliable nutrition screening tools in predicting malnutrition. The data were collected from March to April 2015 in the Hemodialysis Unit of Dr. Sardjito Hospital, Indonesia as an observational study. A cross-sectional design study was used to screen 105 MHD patients using the SNST and NRS 2002, and then, the nutritional status of all individuals was assessed used the following subjective parameters: subjective global assessment (SGA) and dialysis malnutrition score (DMS). The objective parameters were the following: Body mass index (BMI), mid-upper-arm circumference (MUAC), handgrip strength (HGS), and a three-day food record. Chi squared test, t-test, and receiving operating characteristic curve were used for the statistical analysis. In predicting malnutrition, the validity of the SNST is better than the NRS 2002 in MHD patients against either SGA (Se 94.3% vs. 82.9%; Sp 60% vs. 58.6%; and area under curve (AUC) 0.847 vs. 0.749) or DMS (Se 90.0% vs. 81.6%; Sp 74.0% vs. 62.8%; and AUC 0.833 vs. 0.746), while the NRS 2002 is better than the SNST based on BMI, MUAC, HGS, and energy intake (P <0.001). In predicting malnutrition, SNST is better than NRS 2002 based on the subjective assessments (SGA and DMS), and NRS 2002 is better than SNST based on the objective assessments (BMI, MUAC, and HGS). PMID- 29265042 TI - Clinical outcomes of nephrotic syndrome in immunoglobulin a nephropathy. AB - Immunoglobulin A (IgA) nephropathy can be complicated by the nephrotic syndrome in rare cases. Although corticosteroid therapy should be recommended in such cases, the response to steroid treatment has been variable, and spontaneous remission also has been reported without steroid treatment in some cases. We report a retrospective analysis of our experience on the clinical outcomes of nephrotic syndrome in patients with IgA nephropathy, in the nephrology department of a provincial hospital in South Korea. Thirty-three patients with biopsy-proven IgA nephropathy with nephrotic syndrome were enrolled between March 1990 and March 2013. We analyzed data according to demographic, clinical, and laboratory records. The mean follow-up duration was 62 +/- 45 months (10-204) in 33 patients. Complete remission occurred in 10 steroid-users and two steroid nonusers. Partial remission occurred in seven steroid-users, and eight steroid nonusers. During follow-up, six patients showed progressive deterioration of renal function. Among the IgA nephropathy patients with nephrotic syndrome, 36% and 45% of patients had complete and partial remission, respectively. Steroid treatment may effectively reduce proteinuria. However, spontaneous remission occurs in some cases. PMID- 29265043 TI - Acute kidney injury due to overcorrection of hypovitaminosis D: A tertiary center experience in the Kashmir Valley of India. AB - Vitamin D deficiency state is endemic in the Kashmir valley of the Indian subcontinent. Clinicians frequently treat patients with Vitamin D for diverse clinical symptoms to improve the general health and to reduce the frailty of elderly and these doses may at times be inappropriately high. Vitamin D toxicity induced acute kidney injury (AKI), often considered rare, can be life-threatening and associated with substantial morbidity if not identified promptly. We aimed to describe clinical and biochemical features, risk factors, and management of AKI patients with Vitamin D toxicity seen at a single tertiary care centre in Sher-i Kashmir Institute of Medical Sciences, Srinagar, India, between January 2014 and January 2016. Evaluation included detailed clinical history and biochemical tests including serum calcium, phosphorus, creatinine, intact parathyroid hormone, and 25-hydroxyvitamin D [25(OH)D]. Nineteen patients with Vitamin D toxicity-induced AKI could be identified. Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, AKI, acute on chronic kidney disease, and weight loss. Median (range) age was 64 (45-89) years. Median (range) serum 25(OH)D level and median (range) total serum calcium level were 99 (190 988) ng/mL and 139 (119-152) mg/dL, respectively. Overdose of Vitamin D caused by prescription of megadoses of Vitamin D was the cause of AKI in all cases. Median (range) cumulative Vitamin D dose was 6,000,000 (3,600,000-9,000,000) IU. On three- and six-month follow-up, the creatinine and estimated glomerular filtration rate normalized and returned to baseline in all patients except three cases who had underlying chronic kidney disease. Three patients needed rehospitalization for another episode of AKI. Our data demonstrate an emergence of Vitamin D toxicity as a cause of AKI in this part of the world. Irrational use of Vitamin D in megadoses resulted in AKI in all cases. Persistence of Vitamin D in the body for longer time resulted in rehospitalization of patients with AKI. Awareness among health-care providers regarding the toxic potential of high doses of Vitamin D and cautious use of Vitamin D supplements can have immense value to prevent this AKI. PMID- 29265044 TI - Clinicopathological study of nondiabetic renal disease in type 2 diabetic patients: A single center experience from India. AB - Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM), leading to chronic kidney disease/end-stage renal disease. Wide spectrum of nondiabetic renal diseases (NDRD) is reported in type-2 diabetes (type-2 DM). We carried out this single-center study to find clinical, laboratory, and histological features of NDRD in type-2 DM patients and to assess the prevalence of NDRD in India. A single-center retrospective study which included analysis of renal biopsies from patients with type-2 DM, performed between January 2008 and September 2016. Biopsy findings were categorized into three groups, Group-I (isolated NDRD); Group-II (NDRD superimposed on underlying DN); and Group-III (isolated DN). Out of 152 diabetic patients (111 males and 41 females), 35 (23.03%) patients were of Group-I (isolated NDRD), 35 (23.03%) of Group-II (NDRD superimposed on underlying DN), and 82 (53.95%) of Group-III (isolated DN). The mean age (in years) was 55.08 +/- 10.71, 55.65 +/- 8.71, and 54.45 +/- 9.01 respectively in Group-I, II, and III. Nephrotic syndrome (NS) was the most common clinical presentation in all groups. Duration of DM was significantly shorter in Group-I than in Group-II. Diabetic retinopathy was absent in Group-I. Proteinuria was more in Group-III than Group-I. Low serum C3 and/or C4 levels was observed in five (14.29%) cases of Group-I and Group-II each and two (2.43%) cases of Group III. Nearly, 70 (46.05%) patients were found to have NDRD either in isolated form or as combined lesions. The most common histological types of NDRD were acute tubulointerstitial nephritis (38.57%) followed by benign nephrosclerosis (15.72%), membranous nephropathy (10%), IgA nephropathy (7.14%), and membranoproliferative glomerulonephritis (7.14%). The incidence of NDRD (with/without DN) in type-2 DM is very high. Shorter duration of diabetes, hematuria, absence of retinopathy, low serum complement levels, and nephrotic range proteinuria are predictors of NDRD. PMID- 29265045 TI - Assessment of abdominal aortic calcification in predialysis chronic kidney disease and maintenance hemodialysis patients. AB - Vascular calcification is associated with increased morbidity and mortality among chronic kidney disease (CKD) patients. The aim of the study was to assess the abdominal aortic calcification (AAC) in predialysis CKD patients and patients on hemodialysis (HD) and to study the risk factors associated with it. In this prospective study, 205 patients were including 104 patients with predialysis CKD and 101 patients were on maintenance hemodialysis. AAC was assessed using lateral lumbar radiography. Blood urea nitrogen, serum creatinine, albumin, calcium, phosphorus, highly sensitive C-reactive protein (hsCRP) and total cholesterol were analyzed. AAC was observed in 26 % of predialysis CKD patients and 34% in HD patients. Using multivariate analysis, the age (P = 0.001) was identified as independent predictor for the presence of AAC in predialysis patients, and for HD, the predictors were age (P = 0.025), time on dialysis (P = 0.001), hsCRP (P = 0.002), and corrected calcium (P = 0.030). In conclusion, the prevalence of AAC varies mainly with age and glomerular filtration rate levels in predialysis CKD patients. Advanced age, time on dialysis, and inflammation may be associated with presence and extent of AAC in HD patients. Further research into the risk factors and outcome for AAC is warranted. PMID- 29265046 TI - Factors associated with relapse of lupus nephritis: A single center study of 249 cases. AB - This is a retrospective cohort study over 20 years (1990-2013) that included all patients with biopsy-proven lupus nephritis (LN) followed up at our nephrology department. We aimed to determine the clinicobiologic predictors of flare-up of LN. Flare was defined as an increase in systemic lupus erythematosus (SLE) disease activity index (SLEDAI) score of at least four points. Clinical manifestations and laboratory parameters were assessed and the SLEDAI score was determined for each patient. We included patients with SLE who fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE. A total of 249 patients including 227 females and 22 males with a median age at diagnosis of 34.32 years (range 16-69) were studied. The mean follow-up duration was 122.4 +/- 27 months. Renal symptoms included hypertension in 40%, nephrotic syndrome in 30%, and renal failure in 69.4% of the cases. Class IV and class III nephritis (ISN/RPS) were observed in 44.9% and 24% of the patients, respectively. On univariate analysis, flare predictors were age <30 years (P = 0.02), lymphocytopenia (P = 0.002), the presence of diffuse proliferative LN (P = 0.009), and discontinuation of immunosuppressive therapy (P = 0.004). Our study suggests that these markers should be monitored routinely as prognostic parameters in SLE to characterize patients who are at risk and who should be followed more closely. PMID- 29265047 TI - Lactate levels and risk of lactic acidosis with metformin in diabetic kidney disease patients. AB - Metformin as an oral antidiabetic drug (OAD) is not recommended in renal failure due to the presumed risk of lactic acidosis though it has advantages in cardiovascular protection with a low risk of hypoglycemia. Few studies have measured lactic acid blood levels in patients with diabetic kidney disease on metformin and demonstrated lactic acidosis. The aim of our study is to see if patients with diabetic kidney disease are at risk of elevated lactate blood levels and lactic acidosis. Lactate levels and blood pH were estimated in patients with type 2 diabetes mellitus receiving metformin in different stages of chronic kidney disease (CKD) and were compared with a similar group not receiving metformin. Patients with diabetic kidney disease, with estimated glomerular filtration rate <60 mL/min who were previously receiving metformin started in centers elsewhere and referred here were studied and compared with a similar group taking other OADs or insulin. Independent sample t-test or ANOVA were used to compare quantitative variables between groups. Pearson correlation was used to analyze association between quantitative variables and linear regression analysis and was employed to note the relationship between quantitative variables. Of 57 patients who received a mean dose of 1.134 grams of metformin, 33 (55.9%) were in stage 3, 16 (28.1%) in stage 4, and 8 (14%) in stage 5 CKD. Mean serum pH (P = 0.572), bicarbonate (P = 0.978), and plasma lactate (P = 0.449) levels in those taking and not taking metformin were comparable. There was no difference in the plasma lactate levels in different stages of CKD in the metformin group (P = 0.498) although there was significant correlation with metformin dose (P <0.05). Blood lactate levels were not elevated in patients with diabetic kidney disease at a daily dose of metformin <1 g. PMID- 29265048 TI - The diagnosis of tuberculosis in dialysis patients. AB - The incidence of tuberculosis (TB) is high in patients undergoing chronic dialysis than it is in the general population. The diagnosis of TB is often difficult and extrapulmonary involvement is predominant. This study investigates the spectrum of clinical presentations and outcome in dialysis patients during a nine-year period. TB was diagnosed in 41 patients. Anti-TB drugs, adverse effects of therapy, and outcome were noted. Thirty-eight patients (92.6%) were on hemodialysis and three were on peritoneal dialysis (7.3%). The mean age at diagnosis was 50.8 years and the male/female ratio was 1.16. Four patients had a history of pulmonary TB. Extrapulmonary involvement was observed in 32 (78 %) patients. The bacteriological confirmation was made in 41.46% and histological confirmation was made in 26.83%, and in the rest, the diagnosis was retained on the criterion presumption. Nineteen patients (46.34%) developed adverse effects of antitubercular drugs. Eight patients (19.51%) died during the study from TB or adverse effects of treatment. Low urea reduction ratio and female sex were associated with poor prognosis in our study. The clinical manifestations of TB in patients on dialysis are quite nonspecific, making timely diagnosis difficult, and delaying the initiation of curative treatment, which is a major determinant of the outcome. PMID- 29265049 TI - Current state of continuous ambulatory peritoneal dialysis in Egypt. AB - Patients with end-stage renal disease (ESRD) continue to increase in number worldwide, especially in developing countries. Although continuous ambulatory peritoneal dialysis (CAPD) has comparable survival advantages as hemodialysis (HD), it is greatly underutilized in many regions worldwide. The prevalence of use of CAPD in Egypt is 0.29/million population in 2017. The aim of this study is to describe the current state and practice of CAPD in Egypt and included 22 adult patients who were treated by CAPD. All the study patients were switched to CAPD after treatment with HD failed due to vascular access problems. Patients were mainly female (68.2 %) with the mean age of 49.77 +/- 11.41 years. The average duration on CAPD was 1.76 +/- 1.30 years. Hypertension was the main cause of end stage renal disease (ESRD) constituting 36.4%, followed by diabetes (27.3 %), and toxic nephropathy (4.5%). Of importance is that about 31.8% of patients had ESRD of unknown etiology. The mean weekly Kt/V urea of patients on PD was 1.92 +/- 0.18. The mean hemoglobin, serum calcium, phosphorus, parathormone, and albumin levels were 10.27 +/- 1.98 g/dL, 8.36 +/- 1.19 mg/dL, 5.70 +/- 1.35 mg/dL, 541.18 +/- 230.12 pg/mL, and 2.98 +/- 0.73 g/dL, respectively. There was no significant difference between diabetic and nondiabetic CAPD patients regarding demographic and laboratory data. Our data indicate that there is continuing underutilization of CAPD in Egypt which may be related to nonavailability of CAPD fluid, patient factors (education and motivation), gradual decline of the efficiency of health care professionals, and lack of a national program to start PD as the first modality for renal replacement therapy. It is advised to start an organized program to make CAPD widespread and encourage local production of PD fluids to reduce the cost of CAPD. PMID- 29265050 TI - Left ventricular hypertrophy among predialysis chronic kidney disease patients: Sindh institute of urology and transplantation experience. AB - Left ventricular hypertrophy (LVH) is an independent predictor of mortality and its prevention can decrease cardiovascular mortality among predialysis chronic kidney disease (CKD) patients. This cross-sectional study was conducted at the Sindh Institute of Urology and Transplantation, Karachi, Pakistan, from March 2013 to October 2013 to determine the frequency of LVH and its risk factors in patients with CKD. A total of 135 outpatients with CKD duration longer than three months, were included in this study. All patients underwent laboratory investigations which included serum creatinine, blood counts, serum calcium, phosphate and uric acid, and parathormone. M-mode, two-dimensional echocardiogram in the left decubitus position was performed to document LVH. LVH was labeled when the left ventricular mass index was >131 g/m2 in men and >100 g/m2 in women on echocardiogram. LVH was found in 76 study patients (56.3%). The frequency of LVH was significantly high in patients with stage-4 CKD and those with duration of CKD above 12 months. Other risk factors included low hemoglobin, high serum calcium and phosphate levels, and decreasing estimated glomerular filtration rate. In conclusion, early detection of LVH and control of risk factors may help to achieve a decrease in cardiovascular morbidity and mortality in patients with CKD. PMID- 29265051 TI - Pattern and predictors of urine protein excretion among patients with type 2 diabetes attending a single tertiary hospital in Lagos, Nigeria. AB - Testing for proteinuria is used to screen for diabetic nephropathy. However, significant proportion of diabetics has normal urine protein excretion despite impaired renal function. We aimed to determine the factors predicting increased urine protein excretion in patients with type 2 diabetes. This was a cross sectional study of 358 type 2 diabetics attending the diabetes clinic of a teaching hospital in Lagos. Data regarding patients' demographic characteristics, and disease history were retrieved. Clinical measurement and samples for determination of plasma creatinine, and urine protein/creatinine ratio were obtained. Comparison of means was by student's t-test, while for percentages, Chi square test was used. Relationship between glomerular filtration rate (GFR) and urine protein excretion was assessed using linear regression while factors associated with increased urine protein was determined excretion logistic regression analysis. Level of statistical significance was set at P <0.05. Mean age was 57.84 + 11.12 years and mean duration of diabetes was 8.63 + 7.53 years. Urine protein excretion was increased in 191 (53.4%) of the patients. Patients with increased urine protein excretion were more likely to be hypertensive, to be on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker had a higher mean systolic blood pressure, and a lower mean GFR. Patients with a GFR <60 mL/min/1.73 m2 had a six-fold increased odds of having increased urine protein excretion, while patients on an inhibitor of the renin-angiotensin aldosterone system had a 50% reduced odds of having increased urine protein excretion. Proteinuria and reduced GFR are common among sub-Saharan African patients with type 2 diabetes. GFR below 60 mL/min/1.73 m2 and not receiving an inhibitor of the renin-angiotensin-aldosterone system predict increased urine protein excretion in them. PMID- 29265052 TI - Prevalence and risk factors of chronic kidney disease in an african semi-urban area: Results from a cross-sectional survey in Gueoul, Senegal. AB - Chronic kidney disease (CKD) is a public health priority worldwide; however, its prevalence and incidence are difficult to assess. In Africa, few studies have been conducted on the prevalence of CKD. This study sought to describe the epidemiological characteristics and profile of CKD, as well as the related risk factors in Gueoul, a semi-urban zone in Senegal. An observational, cross sectional, and descriptive study was conducted in Gueoul city in Senegal from November 1, 2012, to December 10, 2012, according to the WHO STEPS approach. People older than 35 years living in Gueoul city were included in the study. Cardiovascular and renal disease risk factor screening was conducted for this population. Data were analyzed using the 3.5.1 version of Epi Info software. The significance level was a P <0.05. One thousand four hundred and eleven participants with a mean age of 48 +/- 12.68 years and a sex ratio of 0.34 were included in the study (359 men/1052 women). The prevalence of renal disease was 36.5%. Sixty-eight people showed proteinuria greater than two cross with urinary dipsticks. Two hundred and six people had a glomerular filtration rate <60 mL/min, and among them, 201 were in stage III, two in stage IV, and three in stage V according to the modification of diet in renal disease formula. Ninety eight participants had morphological abnormalities. Cardiovascular risk factors found among participants with renal disease were obesity (25.2%), hypertension (55.5%), diabetes (2.3%), and renal and metabolic syndrome (32.43%). Those that statistically significantly correlated with renal disease were obesity (P = 0.0001), hypertension (P = 0.0001), and diabetes (P = 0.021). This study assessed the extent of renal disease in the population of Gueoul city. Being aware of the prevalence of CKD in the general population of Senegal is mandatory for defining appropriate strategies for the management of these risk factors and progression of renal diseases. PMID- 29265053 TI - Atypical antiglomerular basement membranes disease with nephrotic-range proteinuria, mesangial proliferation, and membranoproliferative glomerulonephritis pattern of injury. AB - Antiglomerular basement membrane (anti-GBM) disease is an uncommon autoimmune disease characterized by the presence of IgG autoantibodies targeting the alpha-3 chain of type IV collagen. Some of the atypical forms of the disease have been described. Herein, we describe a case of atypical anti-GBM in a 27-year-old Saudi male who presented with lower limb edema, gross hematuria, elevated serum creatinine concentration, and nephrotic-range proteinuria. All serology tests were negative, except for anti-GBM which was weakly positive. Renal biopsy showed proliferative glomerulonephritis (GN) with nodular transformation of the glomerular tufts, mesangial hypercellularity (mesangial cell proliferation), segmental endocapillary hypercellularity and three incomplete cellular crescents, and recapitulating membranoproliferative GN pattern of glomerular injury. Direct immunofluorescence microscopy demonstrated diffuse, intense linear positivity for IgG and Kappa and Lambda light chains, and compatible with anti-GBM disease. The patient was treated with cyclophosphamide and corticosteroids in addition to therapeutic plasma exchange which resulted in mild improvement in renal function over a period of six weeks. We emphasize the importance of recognition of atypical pathological and serological patterns of anti-GBM disease, which is crucial for proper and early diagnosis and possibly improved clinical outcome and we highlight the importance of clinicopathological correlation in cases with atypical clinical and pathological presentations. PMID- 29265054 TI - Rapidly progressive glomerulonephritis due to anti-glomerular basement membrane disease accompanied by IgA nephropathy: An unusual association. AB - Anti-glomerular basement membrane (anti-GBM) disease is a systemic autoimmune disorder characterized by circulating IgG antibodies (rarely IgA and IgM) to the carboxyterminal, noncollagenous 1 (NC1) domain of type IV collagen of GBM also known as Goodpasture antigen. Patients typically present with rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage in the presence of which it is referred to as Goodpasture's disease. Anti-GBM disease has been reported to coexist with pauci-immune antineutrophil cytoplasmic autoantibody-positive glomerulonephritis and membranous glomerulopathy. The sequential or concurrent presentation of anti-GBM disease with IgA nephropathy has been rarely described. We herein report a case of a 22-year-old female who presented with RPGN, and renal biopsy revealed crescentic glomerulonephritis with strong linear IgG (+2) staining of GBM and extensive mesangial IgA (+3) deposits. The patient was treated with three pulses of IV methylprednisolone followed by oral steroids. Plasmapheresis and cytotoxic agents were not included in the therapeutic armamentarium as the patient had no pulmonary hemorrhage and biopsy revealed established chronic changes. The association of anti-GBM disease with IgA nephropathy could open up new vistas on the implication of these IgA mesangial deposits in the pathogenesis and prognosis of anti-GBM disease. PMID- 29265055 TI - Proteinuria in children with juvenile idiopathic arthritis: Making the case for early urinary screening. AB - Systemic onset juvenile idiopathic arthritis (SOJIA) can be associated with proteinuria due to various renal pathologies. We report two pediatric cases with SOJIA and nephrotic syndrome secondary to renal amyloidosis, a very rare complication in children. Once present, amyloidosis heralds a poor prognosis for the patient, though early detection may allow some improvement if the inflammatory arthritis is controlled. PMID- 29265056 TI - Acute kidney injury: A rare complication of mothball (Naphthalene) poisoning. AB - Naphthalene poisoning is an uncommon poisoning due to its pungent smell, taste, insolubility in water, and poor absorption from the gut. It rarely occurs in suicidal attempts in adults and in accidental ingestion by children. We present a diagnostic and therapeutic challenge encountered while treating a child with naphthalene-induced acute severe hemolytic anemia and acute kidney injury from accidental ingestion. PMID- 29265057 TI - Fibronectin glomerulopathy - A sporadic case with unusual clinical manifestation. AB - A 22-year-old nondiabetic young Indian female presented with short history of dyspnea, anorexia, and bilateral leg swelling. Her laboratory evaluation showed severe anemia, serum creatinine of 11.89 mg/dL, nephrotic range proteinuria and microscopic hematuria with 6-8 red blood cell/high-power field. Renal biopsy showed brightly eosinophilic, periodic acid-Schiff (PAS) positive, silver negative, and fuschinophilic deposits in the mesangium extending around the capillary loops with thickening of the basement membrane. Immunohistochemistry was strongly positive for fibronectin (FN). There was no family history of renal disease. Genetic screening revealed absence of mutations in the FN1 gene. She was put on maintenance hemodialysis. PMID- 29265058 TI - Infection-related glomerulonephritis in a renal allograft. AB - Infection-related glomerulonephritis (IRGN) is an immune-mediated glomerulo nephritis, most commonly caused by bacterial infections. Although there is an increased incidence of infectious episodes in renal transplant recipients, IRGN as a cause of de novo glomerulonephritis is rarely seen probably due to impaired immunity. We hereby report a 28-year-old male renal transplant recipient, who developed IRGN following impetigenous skin lesions after six years of transplant. He developed rapid worsening of allograft function and was started on hemodialysis. Allograft renal biopsy showed diffuse exudative endocapillary proliferation with crescents. Electron microscopy revealed large subepithelial hump-like deposits. Despite pulse steroid therapy, he became dialysis dependent. Our patient is unique in the way that poststreptococcal glomerulonephritis in an adult after renal transplantation has not been reported so far. We conclude that IRGN after renal transplant, though rare is a possible etiology for allograft dysfunction. There is no definitive treatment protocol for this de novo glomerulonephritis which has an overall poor prognosis. PMID- 29265059 TI - Familial hemolytic uremic syndrome with occurrence in the postpartum period. AB - The hemolytic uremic syndrome (HUS) is a heterogeneous group of similar entities characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (ARF) and is an important cause of ARF in childhood. Mutations have been reported in the complement regulatory protein factor H in both sporadic and familial HUS and have been identified in 10-20% of cases. Inherited HUS is unusual. We report the occurrence of HUS in two siblings after delivery, complicated with ARF and with a good outcome. PMID- 29265060 TI - An unusual case of insecticide poisoning presenting as acute kidney injury. AB - Poisoning due to insecticides such as organophosphorus and super vasmol presenting as acute kidney injury (AKI) is well-reported. Poisoning due to fipronil (phenylpyrazole) is known to present with mild neurological and dermatological complaints. However, fipronil poisoning presenting as AKI and hepatic dysfunction is not known. Herein, we are presenting a case of fipronil poisoning presenting with severe AKI. PMID- 29265061 TI - Disseminated cryptococcosis as a complication of lupus nephritis. AB - Cryptococcus neoformans is an opportunistic fungal infection affects predominately the central nervous system in HIV patients and patients with other immunocompromised states. It has rarely been described in immunocompetent patients. It is a serious infection with a high of mortality rate. We describe a case of a 48-year-old patient diagnosed with lupus nephritis treated with corticosteroids and mycophenolate mofetil who developed central nervous cryptococcosis complicated by septicemia. She died despite the use of antifungals. Cryptococcal infection is an uncommon, but often a fatal complication of systemic lupus erythematosus. Timely diagnosis and effective antifungal therapy could improve its prognosis. PMID- 29265062 TI - Erratum. AB - [This corrects the article DOI: 10.4103/1319-2442.148733.]. PMID- 29265063 TI - Alternaria alternata peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis. AB - Fungal peritonitis is a serious complication of peritoneal dialysis (PD) leading to loss of ultrafiltration and discontinuation of PD treatment. The most frequently isolated fungi are Candida albicans and, filamentous fungi such Alternaria alternata species are found only rarely. We report the case of a 75 year-old woman who developed peritonitis due to this black fungus. PMID- 29265064 TI - Erratum. AB - This corrects the article DOI: 10.4103/1319-2442.194888.]. PMID- 29265065 TI - A rare cardiac manifestation in autosomal-dominant polycystic kidney disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disorder associated with various extrarenal complications. There is little information regarding the occurrence and distribution of cardiovascular abnormalities during the course of ADPKD. The major cardiovascular complications of ADPKD include valvulopathies and vascular ectasia. Aneurysm of the atrial septum (ASA) is a very rare manifestation in ADPKD. A 37-year-old woman who was diagnosed with ADPKD was admitted to our hospital for advanced renal failure. Pelvic computed tomography revealed multiple variable-sized cysts in both kidneys. Trans-thoracic echocardiography showed ASA while the patient was completely asymptomatic. PMID- 29265066 TI - Persistent anemia in a kidney transplant recipient with parvovirus B19 infection. AB - Anemia after kidney transplant is not uncommon. This paper reports a case of unexplained anemia in a kidney transplant recipient that persisted for more than two months, and that did not respond to recombinant human erythropoietin treatment but was successfully treated after diagnosing Parvovirus B19 (ParvoV B19) infection. A middle-aged male underwent living-unrelated kidney transplantation from Pakistan in April 2015. He was on triple immuno-suppression therapy consisting of prednisolone, tacrolimus, and mycophenolate mofetil. He presented with anemia which persisted for more than two months that did not improve with Darbepoetin alpha and required blood transfusions. A bone marrow biopsy demonstrated pure erythroid hypoplasia and occasional giant pronormoblasts characteristic of a ParvoV B19 infection. The serum was highly positive for ParvoV B19 DNA polymerase chain reaction. The anemia resolved completely three weeks after the administration of intravenous immunoglobulin. ParvoV B19 infection should be considered in the differential diagnosis of kidney transplant recipients who present with anemia associated with a low reticulocyte count. PMID- 29265067 TI - The role of supplements in reducing cardiovascular events by decrease in highly sensitive C-reactive protein and serum homocysteine. PMID- 29265068 TI - Erratum. AB - [This corrects the article DOI: 10.4103/1319-2442.194902.]. PMID- 29265069 TI - An unusual cause of anuria in a young patient with hypertension. PMID- 29265070 TI - Milk-alkali syndrome and influenza vaccination. PMID- 29265071 TI - [Molecular biological markers for proliferation, apoptosis, and angiogenesis in diffuse toxic goiter]. AB - : The pathogenesis of diffuse toxic goiter has not yet been fully understood. The literature increasing commonly focusses on the issues related to the processes occurring in the thyroid gland itself: proliferation, apoptosis, and angiogenesis. AIM: to investigate clinical and laboratory parameters, as well as the expression of Ki-67, Bcl-2, Bax, Fas-L, CD34, VEGF, and FGF proteins in various postoperative outcomes of patients operated on for diffuse toxic goiter. SUBJECTS AND METHODS: The investigation enrolled 24 women who had undergone surgery using the technique described by E.S. Drachinskaya. Immunohistochemical tests were carried out according to the standard protocol. The expression of Ki 67, Bcl-2, Bax, Fas-L, CD 34, VEGF, angiopoietin, and FGF proteins was determined. RESULTS: The patients with postoperative thyrotoxicosis were ascertained to have a significantly greater expression of anti-apoptotic protein Bcl-2, proliferation marker Ki-67, vascular factors (FGF, VEGF), and CD 34. CONCLUSION: The relative expression area of the anti-apoptotic protein Bcl-2 of more than 2.19 or the proliferation protein Ki-67 of more than 1.059 was found to predict the development of postoperative thyrotoxicosis with an accuracy of higher than 85%. PMID- 29265072 TI - [Clinical and morphological correlations in occult hepatitis B]. AB - : Occult hepatitis B (OHB) characterized by the absence of blood HBsAg attracts the attention of specialists of different profiles; however, its clinical morphological aspects have not been practically studied. AIM: to estimate the proportion of OHB in the structure of fatal outcomes in chronic viral hepatitis (CVH) and to characterize its clinical course and structural changes on autopsy materials. MATERIAL AND METHODS: A total of 455 autopsy cases of CVH were examined for its etiology in the S.P. Botkin Clinical Hospital of Infectious Diseases in 2014-2016. An in-depth prospective clinical analysis was made to investigate 28 cases of OHB in the stage of decompensated liver cirrhosis, which had subsequently culminated in death. The criteria of inclusion were history data and clinical symptoms of CVH in the detection of markers for hepatitis A, C, and D and HIV in serum HBcAb in the absence of HBsAg. HBsAbs were also determined. Along with the traditional morphological examination, immunohistochemistry (IHC) for HBsAg and HBcAg was carried out. RESULTS: There were 108 CVHB cases (23.7% of the total cases of CVH), including 77 OHB cases (71.3% of those of CVHB) while HBsAg was not determined. HBsAb-negative patients were more often observed to have clinical signs of jaundice (p<0.05) and skin itching (p<0.05). Dyspepsia and hemorrhagic manifestations prevailed in patients with HBsAb (more than 10 IU/l) (p<0.05). All the cases were found to have characteristic morphological signs of CVH, including intranuclear inclusions and nuclear polymorphism in 10.7% of deaths. There was an IHC-positive reaction to VHB antigens in 28.6% of the patients and a doubtful reaction in 25.0%. CONCLUSION: Serum NVsAb may serve as a diagnostic marker for HBV infection. Clinical and morphological correlations enabled the authors to state that CVHB was present in all cases in the absence of serum HBsAg in the patients. PMID- 29265073 TI - [Changes in the diameter and length of hypertrophic cardiomyocytes in the dilated left ventricle of cardiac surgical patients]. AB - AIM: to investigate changes in the diameter and length of hypertrophic cardiomyocytes (CMCs) in the dilated left ventricle (LV). SUBJECTS AND METHODS: Light microscopy, morphometry, and statistical analysis were used to investigate the status of the contractile apparatus and changes in the length, diameter of CHC and diameter of CMC nuclei, by using intraoperative dilated LV biopsy samples from 31 patients with valvular disorders and dilated cardiomyopathy. Morphological findings were compared with the clinical parameters of the patients. RESULTS: CMCs in the patients with the dilated LV were hypertrophic and were at different stages of restructuring with progressive myofibrillar loss (PML). In 81% of patients, the diameter of CMCs was not significantly changed as their zones of PML extended. The length of CMCs, which correlated with the enlarged LV cavity, was increased in 52% of patients during cell restructuring with PML. In 42% of patients, the CMC nuclear diameter increased during restructuring with PML, which appeared to be associated with CMC polyploidization; in some of these patients (19% of the total number of patients), the diameter of CMCs increased in parallel with the higher diameter of their nuclei. CONCLUSION: The findings suggest that after completion of their transverse growth, hypertrophic CMCs are involved in a restructuring process with PML. The findings are consistent with the hypothesis that dilatation of the hypertrophied LV cavity is related to the preferential elongation of CMCs with an inadequate increase in their diameter. The results of the investigation may assume that the higher CMC diameter that brings to completion before the entry of the cells into the restructuring process with PML, resumes in the cells, the ploidy of which increases in the course of restructuring with PML, triggering an additional mechanism for raising the CMC diameter at this stage of myocardial hypertrophy. The results are indicative of different mechanisms for increasing the diameter and length of hypertrophic CMCs, since the diameter of CMCs directly correlates with that of their nuclei, and the length increases as the zones of PML extend in the CMCs. PMID- 29265074 TI - [Endometrial dysfunction caused by chronic endometritis: slinical and morphological aspects]. AB - AIM: to determine the clinical and morphological aspects of endometrial dysfunction caused by chronic endometritis (CE). SUBJECTS AND METHODS: The study included 239 reproductive-aged patients: 93 were examined for abnormal uterine bleeding; 37 patients of them had a history of miscarriage and secondary infertility, 17 patients had primary infertility (Group 1). The remaining 105 patients with infertility were examined for future in vitro fertilization (Group 2). A comparison group consisted of 41 patients with normal menstrual cycles and reproductive function across the cycle, who had separate diagnostic curettage before forthcoming surgery for uterine myoma. All the women in Groups 1 and 2 underwent standard clinical and morphological investigations, histopathological examination of the material obtained during hysteroscopy with separate diagnostic curettage (Group 1), and aspiration biopsy (Group 2) with the sections being stained with hematoxylin and eosin and by Mallory's method. Immunohistochemical diagnosis was used to assess endometrial receptivity to steroid hormones and glycodelin. Antibodies against CD4, SD8, and CD20 were employed to study local immunity. RESULTS: In Group 1, 52 (55.9%) of the 93 patients admitted to hospital for abnormal uterine bleeding were found to have CE on the basis of a morphopathological examination of the material after separate diagnostic study. In Group 2, CE was established in 59 (56.9%) of the 105 patients after postmortem examination. The patients with CE had a history of reproductive significant infections, such as Chlamydia, Trichomonas, Ureaplasma Mycoplasma, cytomegalovirus, papillomavirus infections, genital herpes, genital candidiasis, and bacterial vaginosis. The CE groups showed functional disorders of the endometrial glandular and surface epithelium. In the middle stage of proliferation, the expression of glycodelin in the glandular epithelial cells was detected to be moderate to strong in 83.3%. During the periovulatory period, no secretion of glycodelin is of fundamental importance for the regulation of reproductive function because this protein has contraceptive activity, by blocking the binding of sperm to the zona pellucida. Accordingly, endometrial glycodelin production during the proliferative phase, which has been identified by the authors in patients with CE, may be one of the pathogenic mechanisms for the development of infertility. In addition, the patients in Groups 1 and 2 compared with those in the comparison group were noted to have a decrease in CD4 cell counts with a simultaneous increase in CD8 expression and a reduction in CD20 levels, especially in Group 2. CONCLUSION: The patients with SE were identified to have endometrial dysfunction characterized by lower reception to steroid hormones, impairment in glycodelin secretion, retardation in the development of pinopods and in the phase of the menstrual cycle, and local immunity disorders. The above endometrial changes should be taken into account in the pregravid preparation of patients with CE. PMID- 29265075 TI - [Features of cytotrophoblast invasion in complete placenta previa and increta]. AB - AIM: to investigate the characteristics of cytotrophoblast invasion in complete placenta previa and increta. MATERIAL AND METHODS: Three groups of placentas and amputated uteri were examined. These were: 1) 10 placentas at 20-22 weeks' gestation after drug-induced abortion; 2) 4 uteri with typical placentation at 34 36 weeks and wall ruptures; 3) 12 uteri with ultrasound-confirmed complete placenta previa and subsequent hysterectomy (at 34-36 weeks.) due to massive bleeding. In all cases, the sections were stained with hematoxylin and eosin, azan by the Mallory's method; immunovisualization of invasive cells with the marker cytokeratin 8 was also used. In Groups 2 and 3, the uterine distribution density of invasive cells was compared in a standard slice area (*200) separately, within the endometrium and myometrium. RESULTS: Complete placenta previa was found to have the following characteristics: 1) all the uteri exhibited focal or diffuse friable, or thick scars after cesarean section; 2) multiple active anchor villi with villous cytotrophoblast layers, which were characteristic of Group 1 placentas and absent in the uteri women of Group 2; 3) bays diagnosed in the basal endometrium with ingrown villi (placenta increta); 4) a morphometrically significant increase in the distribution density of interstitial cytotrophoblast in the endometrium and only a similar trend in the myometrium. Invasive cells did not penetrate into the area of scars. Failure of the second wave of cytotrophoblast invasion was confirmed by incomplete gestational restructuring and partial obliteration of the myometrial radial arteries. CONCLUSION: Real risks for severe clinical forms of abnormal placentation declare more stringent indications for surgical delivery. PMID- 29265076 TI - [Tissue collagenase MMP-14 and endogenous regulators of its activity in the corpus uteri in squamous cell carcinoma of the cervix]. AB - AIM: to investigate the expression of the membrane-bound matrix metalloproteinase MT1-MMP (MMP-14), its tissue inhibitor TIMP-2, and the proMMP-14 activator furin in the corpus uteri from the vaginal wall to the bottom of the uterine cavity in squamous cell carcinoma of the cervix (SCCC). MATERIAL AND METHODS: Hysterectomy material was examined in patients with SCCC. Reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and enzyme assays were used. RESULTS: In SCCC, higher levels of MMP-14 expression were established in tumor cells, as evidenced by IHC (+3) and RT-PCR. IHC showed that the expression of MMP 14 was absent or insignificant in the normal uterine endometrial and myometrial tissues. However, that of MMP-14 mRNA was also found in the normal tissues to the bottom of the uterine cavity. Furin activity in the tumor was much higher than that in normal tissues. IHC indicated that TIMP-2 expression was low or absent in both the tumor and normal tissues. The expression of TIMP-2 mRNA was sufficiently obvious in both the tumor and normal tissues to the bottom of the uterine cavity. CONCLUSION: In SCCC, MMP-14 expression was substantially increased in tumors. The expression of MMP-14 and regulators of its activity is aimed at enhancing the tumor destructive (invasive) potential in the pericellular space and can occur (be induced) in the morphologically normal uterine tissue apparently with involvement of signaling through the epithelial-mesenchymal interaction. Data are important for understanding the role of MMP-14 in the development of a multistage process of carcinogenesis and may have prognostic value and an impact on therapeutic strategy for the patient. PMID- 29265077 TI - [Gastric adenocarcinoma arising in giant hyperplastic polyp]. AB - Gastric hyperplastic polyps are usually solitary, their development is supposed to be associated with excessive proliferation of foveolar cells. It is essential to differentiate hyperplastic polyps from other sporadic polyps (adenomatous and fundic gland polyps) and lesions, included in familial polyposis syndromes. The frequency of adenocarcinoma in large gastric hyperplastic polyps (more than 1-2 cm in size) is about 2,1%. This article includes case report of gastric adenocarcinoma arised in large hyperplastic polyp in a 56-year-old patient. On histological examination a well-differentiated adenocarcinoma without invasion in the peduncle was identified. Immunohistochemically cells of adenocarcinoma showed elevated expression of claudin-3, CDX2, p53 and Ki67 compared to hyperplastic glands and dysplastic areas of the polyp. Also focal expression of MUC2 was revealed in adenocarcinoma. Expression of MUC5AC, CD44 and cyclin D1 was less prominent in cancer areas compared to hyperplastic and dysplastic glands. Levels of expression of claudin-1, claudin-4 and beta-catenin were equal in adenocarcinoma and hyperplastic structures. Control endoscopic examination with following morphologic examination was performed three months after surgical operation. No signs of tumor growth were identified. PMID- 29265078 TI - [Disseminated combined small cell carcinoma with graft involvement after kidney transplantation from a deceased donor to two patients]. AB - The paper describes cases of disseminated small-cell carcinoma after kidney transplantation from a deceased donor to two patients. Microscopic examination showed that the kidney graft tumor consisted of tightly packed small rounded cells with hyperchromatic nuclei and a narrow cytoplasmic rim with invisible nucleoli. The mitotic index was 25-40/2 mm2. Azzopardi's phenomenon and crush artifact were detected in the tumor. Giant cell and large cell components were 30 40% of the area of sections. Immunohistochemical examination revealed the expression of synaptophysin, chromogranin A, CD56, TTF-1, HMWK, SK7, SK18, and Ki 67 (80% of tumor cells). Histological findings and immunophenotype in both cases led to the conclusion about combined small cell carcinoma with renal graft involvement. Both patients died from tumor dissemination 9 and 11 months after transplantations. In reviewing the literature, the authors found only one such observation. PMID- 29265079 TI - [Pathological estimation of the time of fetal death]. AB - The paper analyzes the data available in the literature on the possibilities of determining the time of fetal death during an autopsy study. It presents gross changes in the appearance and internal organs of the fetus, as well as histological changes in the organs and placenta, which develop during maceration. The microscopic characteristics of the development of lung and kidney tissues are given in relation to the gestational age of the fetus. Changes in the mass of internal organs during maceration, as well as their standard values are indicated depending on gestational age and degree of maceration. PMID- 29265080 TI - [Population models of mental health in the Russian population: assessment of an impact of living conditions and psychiatric care resources]. AB - : OBJECTIVE: The development and use of population models of mental health in the Russian population to analyze the relationship between indicators of mental disorders, psychiatric care resources taking into account medical/demographic and socio-economic factors in the period of 1992-2015. MATERIAL AND METHODS: The sources of information were: 1) the data of the Russian medical statistics on the main indicators of mental health of the Russian population and psychiatric care resources; 2) government statistics on the demographic and socio-economic situation of the population of Russia during this period. The study used system data analysis, correlation and regression analyses. RESULTS AND CONCLUSION: Linear and nonlinear models with a high level of significance were obtained to assess the impact of socio-economic, health and demographic (population, life expectancy, migration, mortality) factors and resources of the service (primarily, manpower) on the dynamics of the main indicators (prevalence, incidence) of mental health of the population. In recent years, a decline in the prevalence and incidence of the Russian population is a consequence of the scarcity of mental health services, in particular, personnel resources. PMID- 29265081 TI - [Emotional, affective and behavioral disorders in a behavioral variant of frontotemporal dementia]. AB - AIM: To determine the prevalence and severity of non-cognitive nervous and psychiatric disorders (NNPD) in a behavioral variant of frontotemporal dementia. MATERIAL AND METHODS: Twenty-nine patients with BVFTD, aged from 41 to 73 years (mean 60.7+/-8.1 years), were studied. All patients underwent neurological and neuropsychological examinations. NNPD were assessed using the Neuropsychiatric Inventory (J. Cummings et al). Twenty-seven patients underwent brain MRI with T1, T2 and FLAIR sequences. RESULTS: The most clinically significant symptoms of NNPD were apathy, behavioral disinhibition, eating disorders, abnormal motor activity and euphoria. Irritability, sleep disorders and excitement were less frequent. Anxiety and depression were identified in 13.8 and 20.7% of the patients, respectively. The severity of NNPD can increase and their spectrum can be qualitatively changed with the disease progression that indicates the spread of the neurodegenerative process. CONCLUSION: Patients with BVFTD had all NNPD with the exception of delusion and hallucinations. The character and degree of severity of some emotional, affective and behavioral disorders are associated with the predominant localization of the pathological process in frontal and temporal brain regions. PMID- 29265082 TI - [Psychopathology of anxiety-phobic disorders that led to hospitalization in a psychiatric hospital]. AB - AIM: To study the psychopathology of anxiety-phobic disorders and motives of hospitalization of patients in a psychiatric hospital. MATERIAL AND METHODS: One hundred and thirty-two patients were examined, 72 patients of the main group were admitted to general psychiatric departments, 60 patients of the control group in the sanatorium psychiatric departments. Clinical-psychopathological, follow-up, psychometric and statistical methods were used. RESULTS AND CONCLUSION: Patients with hospital anxiety-phobic disorders had agoraphobia with panic disorder, social phobias, hypochondriacal phobias, specific phobias and multiple phobias. The main reasons for hospitalization were: the intensity of anxiety-phobic disorders, contrast content of phobias, multiplicity of anxiety-phobic disorders, ambulance calls, personality accentuations and rental aims. PMID- 29265083 TI - [Effects of bilateral deep brain stimulation in the subthalamic nucleus using two methods of target structure verification]. AB - AIM: To evaluate the efficacy of deep brain stimulation in the subthalamic nucleus (DBS STN) in patients with Parkinson's disease (PD) using different methods of targeting according to the dynamics of motor symptoms of PD. MATERIAL AND METHODS: The study involved 90 patients treated with DBS STN. In 30 cases intraoperative microelectrode recording (MER) was used. MER was not performed in 30 patients of the comparison group. The control group consisted of 30 patients with PD who received conservative treatment. Hoehn and Yahr scale, Tinetti Balance and Mobility Scale (TBMS), Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Quality of Life-39 Scoring System (RDQ-39), Schwab & England ADL Scale were used. Levodopa equivalent daily dose (LEDD, 2010) was calculated for each patient. RESULTS AND CONCLUSION: The effect of DBS STN using intraoperative microelectrode recording on the main motor symptoms, motor complications, walking as well as indicators of quality of life and daily activities was shown. In both DBS STN groups, there was a significant reduction in the LEDD and marked improvement of the control of motor symptoms of PD. A significant reduction in the severity of motor fluctuations (50%) and drug induced dyskinesia (51%) was observed. Quality of life and daily activity in off medication condition were significantly improved in both DBS STN groups of patients, irrespective of the method of target planning (75-100%), compared with the control group. PMID- 29265084 TI - [Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency]. AB - AIM: To assess the efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. MATERIAL AND METHODS: Fifty-three patients with cerebrovascular disease, who complain about persistent fatigue, were randomized into two groups. Patients of the main group (n=33) received standard therapy and noophen, patients of the control group (n=20) received only standard therapy. Treatment efficacy was assessed using MFI 20, HADS-A, LSEQ. In addition, cognitive functioning was evaluated using Schulte test. RESULTS AND CONCLUSION: Treatment with noophen resulted in the marked decrease in the total intensity of fatigue measured with MFI-20. The decrease in fatigue intensity by 30-50% was observed in 3/4 of patients of the main group. Noophen reduced all components of fatigue syndrome, including a mental component, and improved motivation. The reduction of the mental fatigue component was combined with the improvement of cognitive functioning assessed with Schulte test. Therefore, the effect of noophen on motivation and mental fatigue component can promote cognitive training in patients with cerebrovascular insufficiency. PMID- 29265085 TI - [Efficacy and safety of botulinum toxin type A (IncobotulinumtoxinA) in the treatment of patients with cerebral palsy]. AB - AIM: To assess the safety and clinical and neurophysiological efficacy of xeomin in children with spastic equinus and equinovarus foot deformity in cerebral palsy. MATERIAL AND METHODS: Sixty-four patients with spastic forms of cerebral palsy (levels I-IV on the GMFCS) were enrolled into this multi-center open-label comparative randomized trial. The patients were administered xeomin or botox once, each drug being administered to 32 patients. Efficacy was evaluated based on clinical characteristics (the modified Ashworth scale, goniometry) and electromyography data. The subjects were observed for 3 months (90+/-7 days) after injections. The incidence, severity and intensity of adverse events (AE) was also determined. RESULTS: Treatment with xeomin according to the suggested protocol has proven its high clinical efficacy. The efficacy was demonstrated by significant, stable and long-term decrease in the gastrocnemius muscle tone: in the xeomin group, the score on the modified Ashworth scale decreased from 2.6+/ 0.49 points at baseline to 1.8+/-0.54 points (r<0.000001, paired t-test; r<0.000004, Wilcoxon test). In the botox group, this score decreased from 2.4+/ 0.56 points to 1.6+/-0.45 points (r<0.000001, paired t-test; r<0.000002, Wilcoxon test). The increased range of ankle joint movements at passive and voluntary feet extension. In the xeomin group, the significant proportion of patients (45.1%) moved to the group of lower spasticity defined as less than two score points on the modified Ashworth scale. The clinical data fully matched the changes in electromyography parameters, which were characterized by the lower amplitude and area of the target muscle (lateral and medial gastrocnemius heads) M-responses. AE developed in three patients (9.4%) administered xeomin and in two patients (6.3%) administered botox. The AE recorded in the study are described in the recommendations on the use of xeomin and botox. In three cases (50.0%), AE intensity was determined as mild, in the remaining three cases (50.0%) as moderate. CONCLUSION: The results have shown the safety and efficacy of xeomin in the treatment of gastrocnemius spasticity in pediatric patients with cerebral palsy. These data are confirmed by the lack of significant differences in any clinical or electromyography parameters with the results in the reference group administered botox. PMID- 29265086 TI - [Characteristics of anxiety in patients of older age groups with different types of mild cognitive disorder]. AB - AIM: To study the structure of anxiety symptom complex in patients of older age groups with amnestic, disregulatory and polymodal types of mild cognitive impairment (MCI) and determine the clinical efficacy of 2-ethyl-6-methyl-3 hydroxypyridine succinate (mexidol). MATERIAL AND METHODS: Thirty-two patients over 55 years of age with MCI (ICD-10 item F 06.7) seeking medical help due to anxiety were included in the study. Inclusion criteria were the compensation of concomitant diseases, absence of relevant stressful events during the last year, absence of depression. Clinical-psychopathological method and psychometric scales (HAM-A, GDS, MMSE, CGI-S, CGI-I) and a stressful life events list were used. Reduction of the total score on the HAM-A was the main criterion of the efficacy of 4-week treatment with mexidol (375 mg daily). RESULTS AND CONCLUSION: At baseline, mean scores on the HAM-A and MMSE were 39,9+3.18 and 25.7+0.6 respectively. The study of the anxiety structure in patients with amnestic, disregulatory and polymodal types of MCI revealed the different phenomenology of anxiety symptom complex. Repeated assessment of anxiety on the HAM-A was performed on 1, 2 and 4 week of treatment with mexidol. The improvement of mental state was noted in all types of MCI but the better results were obtained in disregulatory and polymodal types. The rate of anti-anxiety effect was higher in the disregulatory type of MCI. In all patients, mexidol improved attention stability and autonomic function. PMID- 29265087 TI - [An influence of cytoflavin on oxidative stress and activity of Na/K-ATPase of erythrocytes after brain trauma]. AB - AIM: To study the efficacy of cytoflavin in correction of oxidative stress and the activity of Na/K-ATPase in posttraumatic craniocerebral trauma (CCT) in rats. MATERIAL AND METHODS: The study was performed on white non-linear female rats with a modeled CCT. An effect of cytoflavin on free radical oxidation and plasma antioxidant system, processes of plasma lipid peroxidation and antioxidant properties of red blood cells and erythrocyte Na/KATPases activity was studied on 1, 3, 7- and 12th day after CCT. RESULTS AND CONCLUSION: CCT identified the growth of free-radical processes in blood plasma and an increase in lipid peroxidation in plasma and red blood cells as well as a reduction in the activity of catalase and Na/K-ATPase. Introduction of cytoflavin reduced oxidative stress from the 3rd day and normalized free radical oxidation and lipid peroxidation in plasma and red blood cells to the 7th day of the study against the background of the high total antioxidant capacity of blood and erythrocyte catalase activity. The effect of cytoflavin led to an increase in the activity of Na/K-ATPase on the 3rd-7th day of the study compared with the reduced activity of the enzyme in the control. Recovery of pro- and antioxidant balance under the action of cytoflavin associated with increased activity of Na/K-ATPase aimed at optimizing and reducing the homeostatic mechanisms of secondary damage in the post traumatic period. PMID- 29265088 TI - [An experience of using mebicar in patients with autonomic dysfunction associated with anxiety disorder]. AB - BACKGROUND: Cognitive impairments are one of the most frequent and maladaptive factors in patients with autonomic dysfunction associated with anxiety disorder. The majority of anxiolytics manage to compensate anxiety but suppress cognitive functions. MATERIAL AND METHODS: Fifty-four patients with autonomic dysfunction and anxiety disorder, including 39 women (mean age 25+/-6.7 years) and 15 men (mean age 27+/-8.4 years), were treated with mebicar during 3 months. RESULTS AND CONCLUSION: A reduction in the degree of autonomic dysfunction and anxiety symptoms as well as a significant improvement of cognitive functions were noted. Mebicar showed a good tolerability and minimum drug-related adverse events, and can be recommended as a first line anti-anxiety remedy in wide clinical practice. PMID- 29265089 TI - [A comparative analysis of the dynamics of affective symptoms in overweight patients with depression and eating disorders during treatment process]. AB - PROBLEM RELEVANCE: Eating disorders are linked with depression in patients with high body mass index (BMI). AIM: To evaluate the dynamics of affective symptoms in overweight patients with depression and eating disorders in the process of treatment with agomelatine. MATERIAL AND METHODS: Male (n=15) and female (n=37) overweight patients (n=52, mean age 33.67+/-2.31 years) were randomly observed. The sample was divided into two groups. The first group included individuals with depression and high BMI and the second with co-morbid eating disorders of bulimic type. Patients were treated with agomelatine in average therapeutic doses. RESULTS AND CONCLUSION: The presence of an eating disorder significantly influences clinical symptoms of depression by reducing the speed of therapeutic effect of agomelatine. PMID- 29265090 TI - [Results of a randomized double blind parallel study on the efficacy and safety of tolpersione in patients with acute nonspecific low back pain]. AB - AIM: To evaluate the efficacy and safety of tolpersione injection and oral formulations combined with NSAID over NSAID monotherapy in acute non-specific low back pain. MATERIAL AND METHODS: In this randomized double blind study 239 patients were included in the per protocol analysis. The first 5 days of treatment, patients received tolpersione or placebo injection which was followed by per os administration of tolpersione/placebo tablet up to 14 days. NSAID diclofenac tablet was used in both groups through the study. Functionality assessed by the Roland Morris Disability Questionnaire (RMDQ) at day 5 was the primary endpoint. Secondary endpoints were RMDQ at other time points, pain level change at rest and on movement assessed by the Visual Analogue Scale (VAS), the Clinical Global Impression of Improvement/Patient Global Impression of Improvement (CGI-I and PGI-I), change in the range of motion assessed by the distance from the fingertips to the floor, period of disability days, relative (%) changes in the daily dose of diclofenac from the 7th to the 14th day of therapy. RESULTS AND CONCLUSION: The primary and secondary endpoints clearly demonstrated the significant superiority of tolpersione added to NSAID monotherapy over NSAID monotherapy. The safety assessment revealed no statistically significant differences between the two groups. Based on the results, tolpersione injection and per os formulations can be considered an effective and safe drugs in the combined therapy for patients with acute nonspecific back pain. PMID- 29265091 TI - [Changes in serum levels of the key factors of angiogenesis in different outcomes of combined injuries in children]. AB - AIM: To study the changes in the key angiogenic factors VEGF-A and angiogenin (ANG) in children with different outcomes of combined injuries. MATERIAL AND METHODS: Contents of VEGF-A and ANG in blood serum were determined by enzyme immunoassay. The study included 40 patients, 21 boys and 19 girls. Patients were divided into 4 groups according to the outcome of injury: 1 - the recovery or mild residual symptoms; 2 - disabled; 3 - vegetable state; 4 - death. Patients were examined at different times after injury: 1-6 days, 7-11 days, 12-19 and 20 33 days. RESULTS AND CONCLUSION: In the first days after injury, the content of VEGF-A in patients of 1-3 groups was at the level of the reference group, moreover, in patients of the 3rd group it was close to the top edge. In group 4, the content of VEGF-A was maximal in the first days after injury and then gradually decreased to the point of death. In groups 1 and 3, the level of VEGF-A increased significantly starting from the 2nd week while in group 2 this indicator was slightly increased approaching later (up to 33 days of observation) to the upper values in the reference group. In the 3rd group, the content of VEGF A reached the plateau on the 19th day after injury and was higher than the reference data, but lower than in patients of the 1st group. No correlation between the changes in ANG content at different times after combined injuries and outcome was found. There was a trend towards decreased levels of ANG, especially after 3-4 weeks after injury. The data obtained are important for the control over processes of vascular and tissue reparation after injury and for searching for effective ways of treatment of altered angiogenesis in such patients. PMID- 29265092 TI - [The use of low-field MRI for visualization of epileptogenic brain lesions in children]. AB - AIM: To analyze MR-images of patients with focal epilepsy using a method close to the protocol of epileptic scanning on a MRI-device with the magnetic field tension of 0.4 Tesla. MATERIAL AND METHODS: MRI data of 50 children who underwent examination due to difficult-to-treat or drug-resistant forms of focal epilepsy were analyzed. MRI study was conducted using open-ended device of static magnetic field HITACHI 'APERTO' with the magnetic field tension of 0.4 Tesla. The thickness of the slices and the scan step was performed at 3.0 and 3.5 mm with the use of special positioning of slices in the coronal and axial projections, T2, T1, STIR, FLAIR weighted images (WI) perpendicular and parallel to the long axis of the hippocampus. RESULTS: Potentially epileptogenic structural changes were identified in 37 patients. Abnormalities of brain development of different severity were identified in 16 patients. In 21 cases, the changes were due to the consequences of cerebral vascular catastrophes, neuroinfections, brain traumas affecting the cortical plate. A method close to the epileptic scanning protocol allowed the identification of signs of acute cerebral catastrophes in two patients. In 8 patients, potentially epileptogenic changes after false-negative descriptions of the results of previous MRI studies were newly identified. The most difficult for the diagnosis was the visualization of small structural changes in mediobasal regions of the temporal lobes. Confirmation of this supposition according to the recommended thorough investigation was obtained only in 5 out of 12 patients with suspected small-bore pathological changes in mediobasal temporal regions. CONCLUSION: Low-tension technique approximated to the epileptic scanning protocol does not allow the reliable diagnosis of small and similar in signal characteristics changes in the visualization of mediobasal temporal lobes regions. It was not possible to reliably differentiate some cortical-subcortical neoplastic formations from various forms of focal cortical dysplasia. PMID- 29265093 TI - [Risk assessment of thrombotic events in patients with schizophrenia and schizoaffective disorder in the acute state: the 'fibrinodynamics' technology]. AB - AIM: To assess the risk of thrombotic events in patients with schizophrenia and schizoaffective disorder based on 'fibrinodynamics' technology. MATERIAL AND METHODS: A group of 76 women, including 38 with paranoid schizophrenia (F20.0), 18 with schizoaffective disorder (F25.1) in the acute stage, and 20 healthy controls, participated in the study. The technology includes the study of coagulation and fibrinolysis, Karmin author software, and calculation of peak time and hemostasis potential of spontaneous clots. Growth and lysis of fibrin clots were studied in plasma purified from platelets. All preanalytic procedures were conducted within 30 minutes after blood sampling. Blood serum was studied separately using the neuroimmunological test. Dynamic of brightness profiles of the clots was determined and a number of parameters (peak time and hemostasis potential of spontaneous clots) were calculated using the Karmin software. RESULTS: In patients with schizophrenia, the dynamic brightness profile of the clots has two peaks: the first peak is formed as a result of the growth and lysis of the clot initiated by the activator, the second peak is due to the growth and lysis of spontaneous clots in the volume of the measuring cuvette far from the activator. In healthy donors, the second peak under experimental conditions is absent. In the group of schizophrenic patients, a strong negative correlation is observed between the peak time of the second peak and the activity of leukocyte elastase (Spearman R = -0.75, p<0.0001), i.e. the greater the activity of elastase, the earlier the maximum of the second peak is formed and vice versa. In the control group, there is no such correlation. Evaluation of the potential of hemostasis of spontaneous clots showed that in 42% of schizophrenic patients this parameter is shifted above the norm, which indicates an increased risk of thrombosis of small brain arteries in these patients. CONCLUSION: The developed technology of 'fibrinodynamics' has a good potential for introduction into personalized medicine to identify increased risks of thrombosis of small cerebral vessels in patients with acute schizophrenia leading to the development of cognitive disorders and to control the normalization of hemostasis with antiplatelet or anticoagulant drugs. PMID- 29265095 TI - [The quality of research publications in psychiatry]. AB - AIM: To evaluate the quality of research articles in psychiatry and addiction medicine published in 2015. MATERIAL AND METHODS: Five experts analyzed 51 research publications from 13 psychiatric and addiction medicine journals using a standardized questionnaire, which contains 4 general questions (type or results of the study) and 21 questions on the quality of the study. RESULTS: Only 2 articles (4%) met all criteria, 64% of the articles refer to the methodologically least demonstrative (uncontrolled/one-time, series of cases, non-randomized). The most vulnerable were the characteristics which were the most important for evidence: a description of the methods, statistical analysis, accounting for systematic errors and/or side effects, the distribution of patients by group. CONCLUSION: Research publications in psychiatry and addiction medicine have a low level of evidence. PMID- 29265096 TI - [Accessory symptoms of schizophrenia: E. Bleuler's concept]. AB - The analysis of E. Bleuler's concept of accessory symptoms of schizophrenia: delusions, hallucinations, depersonalization disorders, splitting of the ego, memory disorders, catatonic symptoms and acute syndromes (manic and melancholic states, acute paranoia, twilight states, clouding of consciousness, confusion, fugues and dipsomania) is presented. The relationship of accessory symptoms with primary and secondary schizophrenic symptoms according to the second concept of E. Bleuler is highlighted. The mechanisms of the origin of psychopathological accessory symptoms and E. Bleuler's understanding of many schizophrenic psychopathological symptoms as a quantitative increasing of a normal psychic phenomenon are discussed. PMID- 29265094 TI - [Comparative study of glutamate dehydrogenase in the brain of patients with schizophrenia and mentally healthy people]. AB - AIM: To compare the glutamate dehydrogenase (GDH) activity and amounts of GDHI, GDHII, and GDHIII immunoreactive forms in prefrontal, anterior and posterior cingulate cortex and cerebellar cortex of patients with schizophrenia and control subjects. MATERIAL AND METHODS: GDH enzymatic activity was measured and levels of GDH immunoreactive forms were determined in extracts of autopsied samples of prefrontal, anterior and posterior cingulate cortex (areas 10, 24, and 23 by Brodmann), and cerebellar cortex of patients with schizophrenia (n=8) and controls (n=9). RESULTS AND CONCLUSION: GDH enzymatic activity was significantly increased in the prefrontal cortex (area 10) (p<0.004), the posterior cingulate cortex (area 23) (p<0.05) and the cerebellar cortex (p<0.002) and was unchanged in the anterior cingulate cortex (area 24) in patients with schizophrenia compared to controls. The levels of immunoreactive GDH I, GDH II and GDH III were significantly higher in the prefrontal cortex of patients with schizophrenia than in controls (p<0.008, p<0.003, and p<0.0001, respectively). Levels of all three immunoreactive GDH forms were unchanged in the anterior cingulate cortex (area 24), but they were increased in the posterior cingulate cortex (area 23) (p<0.004, p<0.001 and p<0.02, respectively). The levels of immunoreactive GDH II and GDH III, but not GDH I, were significantly increased in the cerebellar cortex of patients with schizophrenia compared with the control group (p<0.02 and p<0.001, respectively). The alteration in the levels of GDH immunoreactive forms in the brain of patients with schizophrenia is one of the causes of impaired brain glutamate metabolism and an important aspect of schizophrenia pathogenesis. PMID- 29265097 TI - [Clinical and genetic characteristics of facioscapulohumeral muscular dystrophy Landuzi-Dezherina type 1]. AB - AIM: To describe clinical and genetic characteristics of patients from the Russian population with a variety of phenotypic variants of facioscapulohumeral muscular dystrophy Landuzi-Dezherina type 1 (FSHD 1). MATERIAL AND METHODS: The material for the study were blood samples of 16 patients from 15 unrelated families residing in the territory of the Russian Federation, between the ages of 6 to 66 years, with symptoms of FSHD. Diagnosis was based on genealogical data analysis, neurological examination, electroneuromyographic study, indicators of activity of creatine phosphokinase (CPK) in the blood serum and molecular genetic analysis of the results, aimed at the analysis of macrosatellite D4Z4 repeats on chromosome 4. RESULTS AND CONCLUSION: The study established the diagnosis of FSHD1 in 75% of patients. The correlation of the severity and phenotypic spectrum of FSHD1 with the age of onset was found. There was the significant clinical heterogeneity even among the 1st degree relatives in the same family. The correlation between macrosatellite D4Z4 repeats and clinical features of FSHD1 described previously in the literature was not observed. PMID- 29265098 TI - [Depakine: 25 years in Russia]. AB - The article summarizes domestic and international studies on the development and clinical investigation of valproates including multiple studies of a research team directed by the author. Valproate targets are considered in biological and clinical aspects. A spectrum of action and advantages of the brand drug (depakine) compared to generics and other antiepileptic drugs are discussed. A number of recommendations for practitioners about using valproates are proposed. PMID- 29265099 TI - [Efficacy, safety and tolerability of glatiramer acetate injections in dose 40 mg/ml in patients with relapsing-remitting multiple sclerosis]. AB - The article presents the results of an international study on the efficacy and safety of glatiramer acetate (GA) (40 mg/ml administered 3 times a week) compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS). This study was conducted in 142 sites in 17 countries including Russia. In total, the study included 1404 patients with RRMS including 166 patients from Russia. Glatiramer acetate (40 mg/ml 3 times a week) demonstrated the high efficacy, safety and tolerability profile. In conclusion, glatiramer acetate GA in dose 40 mg/ml should be considered as a more convenient regimen for RRMS patients which can improve patients' adherence to treatment and as a result, its efficacy. PMID- 29265100 TI - [Dimethyl fumarate (tecfidera) is the first line treatment choice in patients with remitting multiple sclerosis]. AB - Dimethyl fumarate (DMF) is a new oral option for disease-modifying therapy (DMT) in patients with remitting multiple sclerosis as a first line treatment. The results of international randomized studies comparing DMF with placebo and other DMTs are presented. DMF is a DMT with promised efficacy and favorable safety profile that could be a treatment option for patients with suboptimal response for other first line DMTs and used as initial therapy for treatment-naive patients with unfavorable prognostic factors. PMID- 29265101 TI - [Migraine and sleep]. AB - This review discusses the epidemiological, clinical and pathophysiological aspects of the comorbidity of migraine and various forms of sleep disorders, the role of disturbances in the sleep and wake cycle in the processes of transformation of headaches, and possible strategies for modifying therapeutic approaches in this comorbidity. PMID- 29265102 TI - [A role of the autonomic nervous system in cerebro-cardiac disorders]. AB - The authors consider anatomical/physiological characteristics and a role of different autonomic CNS regions, including insula cortex, amygdala complex, anterior cingulate cortex, ventral medial prefrontal cortex, hypothalamus and epiphysis, involved in the regulation of cardiovascular activity. The damage of these structures, e.g., due to the acute disturbance of cerebral blood circulation, led to arrhythmia, including fatal arrhythmia, in previously intact myocardium; systolic and diastolic dysfunction, ischemic changes considered in the frames of cerebro-cardial syndrome. On the cellular level, the disturbance of autonomic regulation resulted in catechol amine excitotoxicity, oxidative stress and free radical myocardium injury. PMID- 29265103 TI - [Pathological redundancy of the motor act: modern concepts of the pathogenesis and approaches to the pharmacological treatment]. AB - The authors present characteristics of pathogenetic mechanisms of pathological motor redundancy in children with neurological and psychoneurological pathologies examined in accordance with the original author's concept. Pathological mechanisms of the development of motor redundancy, including obsessive movements, hyperkinesia, compulsions, motor and sensory stereotypes, taking into account a certain unity of mechanisms of their origin at the anatomical level, are described. The article demonstrates the differences in the formation of these pathological motor acts associated with changes in their function, i.e. neuromediation and neuromodulation, in certain structures of the central nervous system. PMID- 29265104 TI - [Social cognitive function in neurodegenerative diseases]. AB - The ability to perceive, analyze people's mental states, intentions, thoughts and feelings is an important cognitive function for normal social behavior and interaction. Over the past decade, more attention has been paid to studying how behavioral disorders in patients with neurodegenerative diseases may be explained by theory of mind deficit and whether it can be useful for differential diagnosis. The authors consider the issues of neuroanatomy, neurophysiology of a special kind of cognitive functions provided normal social interaction and interpersonal relationship, problems of its determining in neurodegenerative diseases. PMID- 29265105 TI - [Serotonin neurotrasmission and treatment options for depression]. AB - The efficacy of modern antidepressants is largely related to their ability to enhance neurotransmission of serotonin. The medicines with serotonergic properties include trazodone, which is intermediate between tricyclic antidepressants with their powerful antidepressive effect and selective serotonin reuptake inhibitors, as first-line agents in the treatment of depression and anxiety disorders. The value of trazodone for clinical practice is determined by the effective elimination of the symptoms of major depressive disorder in combination with good tolerability, including in elderly patients. Among the advantages of trazodone is the absence of such undesirable effects as sexual dysfunction and weight gain. Trazodone has significant hypnotic and anxiolytic properties, which gives it special meaning in the treatment of depression, combined with insomnia and anxiety. It is emphasized that the beneficial effect of trazodone on sleep should not prevent its main use as a drug for treating major depressive disorder regardless of whether depression is accompanied by insomnia or not. PMID- 29265106 TI - Rickets. AB - Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study. PMID- 29265107 TI - Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats. AB - Exposure to a traumatic event may result in the development of post-traumatic stress disorder (PTSD). Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment. We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure. Rats were exposed to inescapable footshocks paired with social isolation, a risk factor for PTSD. One week after trauma, rats were subjected to three spaced extinction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabinoid agonist WIN55,212-2 were administered before or after the extinction sessions. Rats were tested for extinction retention 16 or 36 days after trauma and 24-h later for social interaction. Extinction training alone reduced fear of the trauma associated context but did not restore normal social interaction. Traumatized animals not exposed to extinction sessions exhibited reductions in hippocampal anandamide content with respect to home-cage controls. Noteworthy, all drugs exerted beneficial effects, but URB597 (0.1 mg/kg) induced the best improvements by enhancing extinction consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 receptors. The ameliorating effects remained stable long after treatment and trauma exposure. Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD. PMID- 29265108 TI - Prefrontal AMPA receptors are involved in the effect of methylphenidate on response inhibition in rats. AB - Response inhibition is a critical executive control function in many species. Deficits in response inhibition have been observed in many disorders, eg, attention deficit/hyperactivity disorder (ADHD). The stop-signal task (SST) is a unique behavior task for evaluating response inhibition via measuring the covert latency of a stop process, and it is widely used in studies of humans, nonhuman primates and rodents. Methylphenidate (MPH; Ritalin(r)) is a psychostimulant that is widely used for the treatment of ADHD and that effectively improves response inhibition in individuals with ADHD and normal subjects. However, its mechanism of improving response inhibition remains unknown. In this study we adopted a rodent nose-poking version of the SST to examine response inhibition by estimating the stop signal reaction time (SSRT) in rats. Administration of MPH (1 mg/kg, sc) 25 min before the SST test exerted a baseline-dependent effect of MPH on response inhibition, ie, it shortened the SSRTs only in the rats with larger baseline SSRTs, thereby improving response inhibition in these rats. The effect of MPH on response inhibition remained 3 h after MPH administration. Co administration of PP2 (1 mg/kg, sc), a Src-protein tyrosine kinase (Src-PTKs) inhibitor that inhibited the upregulation of glutamate receptor expression on the plasma membrane of the prefrontal cortex (PFC), abolished the MPH-caused improvement in response inhibition. Furthermore, intra-PFC infusion of a selective AMPAR antagonist.NASPM (0.3 mmol/L, per side) via stainless guide cannulas implanted earlier abolished the effect of MPH on SSRT. These results suggest that AMPA receptors in the PFC are involved in the effect of MPH on response inhibition in rats. PMID- 29265109 TI - Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins. AB - Humanin (HN) is a 24-residue peptide identified from the brain of a patient with Alzheimer's disease (AD). HN has been found to protect against neuronal insult caused by Abeta peptides or transfection of familial AD mutant genes. In order to elucidate the molecular mechanisms of HN neuroprotection, we explored the effects of HN on the association of Bax or Bid with lipid bilayers and their oligomerization in the membrane. By using single-molecule fluorescence and Forster resonance energy transfer techniques, we showed that Bax was mainly present as monomers, dimers and tetramers in lipid bilayers, while truncated Bid (tBid) enhanced the membrane association and tetramerization of Bax. HN (100 nmol/L) inhibited the self-association and tBid-activated association of Bax with the bilayers, and significantly decreased the proportion of Bax in tetramers. Furthermore, HN inhibited Bid translocation to lipid bilayers. HN could bind with Bax and Bid either in solution or in the membrane. However, HN could not pull the proteins out of the membrane. Based on these results, we propose that HN binds to Bax and cBid in solution and inhibits their translocation to the membrane. Meanwhile, HN interacts with the membrane-bound Bax and tBid, preventing the recruitment of cytosolic Bax and its oligomerization in the membrane. In this way, HN inhibits Bax pore formation in mitochondrial outer membrane and suppresses cytochrome c release and mitochondria-dependent apoptosis. PMID- 29265111 TI - Multimodal retinal imaging in central serous chorioretinopathy treated with oral eplerenone or photodynamic therapy. AB - PurposeTo correlate function and structural optical coherence tomography (OCT) to optical coherence tomography angiography (OCT-A) measures in patients affected by central serous chorioretinopathy (CSC) and to describe their changes after treatments (ie oral eplerenone, half-fluence photodynamic therapy (PDT)).Patients and methodsTwenty eyes of 16 consecutive patients with treatment-naive CSC undergoing either eplerenone or PDT were enrolled in this prospective, observational study. All patients underwent structural OCT and OCT-A at baseline and after therapy at months 1 and 3.ResultsEleven eyes of nine patients and nine eyes of seven patients underwent eplerenone or PDT treatment, respectively. Central macular thickness (CMT) and subretinal fluid (SRF) correlated to fovea avascular zone (FAZ) area (r=0.74 and r=0.71, P=0.01) and vessel density (r=0.77 and r=0.68, P=0.01) at deep capillary plexus (DCP). CMT (P=0.0011), SRF (P=0.0005), SFCT (P=0.0016), FAZ area at DCP (P=0.0334) improved at 3-month visit. A significant reduction of deep FAZ area was appreciated in eplerenone (P=0.0204) but not in PDT (P=0.5) group. SFCT reduction was significantly higher in PDT than eplerenone group (P=0.0347).ConclusionStructural and vascular parameters are correlated in CSC and they improve after different treatments. Both half-fluence PDT and oral eplerenone do not permanently damage choriocapillaris or other choroidal layers as evaluated by OCT-A. PMID- 29265112 TI - Serological Evidence of Borrelia Burgdorferi Infection in Mexican Patients with Facial Palsy. AB - Background: Facial palsy is the most frequent manifestation of neuroborreliosis in the United States, Europe, and Asia, whereas in Mexico, its frequency is unknown. Objective: We aimed to determine the frequency of Borrelia spp. infection in patients with acute facial palsy in Mexico. Materials and Methods: In this cross-sectional, referral hospital-based survey, 191 patients with facial palsy were selected and clinical and epidemiologic data recorded. IgM and IgG serum antibodies to Borrelia burgdorferi were tested by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western-Blot (WB). IgM and IgG antibodies against the herpes viruses HSV-1, HSV-2, cytomegalovirus, and Epstein Barr virus were tested by ELISA. Results: 71 patients (37%) tested positive by ELISA to either Borrelia spp. or the herpes viruses. Of 25 patients (13%) who tested positive for B. burgdorferi by ELISA, 23 (12%) were confirmed by WB; 14 had IgM and 9 had IgG antibodies. Among the 14 IgM-WB positive patients, two cases recognized antigens of B. burgdorferi sensu stricto (s.s.), 10 of Borrelia garinii and 2 of B. afzelii, whereas all 9 IgG-WB positive were reactive against B. burgdorferi s.s. 14 patients had facial palsy in addition to other clinical data compatible with Lyme borreliosis. Patients infected with B. burgdorferi s.s. had a longer recovery time and a significantly higher risk (odds ratio 4.4, 95% confidence interval 1.5-12.9) of recurrent facial palsy than patients infected with other Borrelia genospecies. Conclusions: Borrelia infection is frequent in facial palsy patients in Mexico, with B. burgdorferi s.s. and B. garinii being the most frequent causative species. PMID- 29265113 TI - Rates of Surgical Site Infection in Cholecystectomy: Comparison between a University Teaching Hospital, Madrid Region, Spain, and USA Rates. AB - Background: There are many factors that can influence surgical site infections (SSI) in cholecystectomies. Incidence of cholecystectomy SSI was studied and compared with the incidence in Madrid Region, Spain, and the United States. Methods: A prospective cohort study was conducted which included all patients who underwent gallbladder surgery for 5 consecutive years, at the Alcorcon Foundation University Teaching Hospital. SSI incidence rate was calculated. An association between risk factors and SSI incidence was assessed with the relative risk (RR). Infection rates were compared to those in the Madrid Region and to the overall Spanish and United States rates using the standardized infection ratio (SIR). Results: The study included 1532 patients. Cumulative overall SSI was 1.96% (95% confidence interval [CI]: 1.3-2.7). The SIR was 0.89 with respect to the Madrid Region, 0.77 with respect to Spain's rate, and 1.77 with respect to the United States' rate. A laparoscopic route protected against infection (RR = 0.43; 95% CI: 0.2-0.9). Razor shaving in surgical preparation, duration of surgery, and neoplasm increased SSI incidence. Conclusions: SSI incidence rates among cholecystectomized patients at our hospital are higher than rates in the United States. A laparoscopic route protected against SSI. PMID- 29265114 TI - Distinguishing Intracerebral Hemorrhage from Acute Cerebral Infarction through Metabolomics. AB - Background: Acute cerebral infarction (ACI) and intracerebral hemorrhage (ICH) are potentially lethal cerebrovascular diseases that seriously impact public health. ACI and ICH share several common clinical manifestations but have totally divergent therapeutic strategies. A poor diagnosis can affect stroke treatment. Objective: To screen for biomarkers to differentiate ICH from ACI, we enrolled 129 ACI and 128 ICH patients and 65 healthy individuals as controls. Methods: Patients with stroke were diagnosed by computed tomography/magnetic resonance imaging, and their blood samples were obtained by fingertip puncture within 2-12 h after stroke initiation. We compared changes in metabolites between ACI and ICH using dried blood spot-based direct infusion mass spectrometry technology for differentiating ICH from ACI. Results: Through multivariate statistical approaches, 11 biomarkers including 3-hydroxylbutyrylcarnitine, glutarylcarnitine (C5DC), myristoylcarnitine, 3-hydroxypalmitoylcarnitine, tyrosine/citrulline (Cit), valine/phenylalanine, C5DC/3-hydroxyisovalerylcarnitine, C5DC/palmitoylcarnitine, hydroxystearoylcarnitine, ratio of sum of C0, C2, C3, C16, and C18:1 to Cit, and propionylcarnitine/methionine were screened. An artificial neural network model was constructed based on these parameters. A training set was evaluated by cross-validation method. The accuracy of this model was checked by an external test set showing a sensitivity of 0.8400 (95% confidence interval [CI], 0.7394-0.9406) and specificity of 0.7692 (95% CI, 0.6536-0.8848). Conclusion: This study confirmed that metabolomic analysis is a promising tool for rapid and timely stroke differentiation and prediction based on differential metabolites. PMID- 29265115 TI - Chikungunya: Molecular Aspects, Clinical Outcomes and Pathogenesis. AB - The alarming worldwide emergence of the chikungunya virus began in the last decade. Since the first autochthonous transmission in Mexico in November of 2014, the virus has spread throughout the country, resulted in multiple outbreaks. This virus produces an acute and self-limiting disease characterized by fever, polyarthralgia, myalgia, exanthema, and general malaise. It is transmitted to humans by the bite of Aedes aegypti and A. albopictus mosquitoes. The fact that the clinical presentation is similar to that produced by other arboviruses complicates its clinical diagnosis. The chronic stage of the disease can cause severe consequences lasting months or years, from local arthralgia to rheumatoid arthritis. In this review, we emphasize the public health threat posed by this highly disabling emerging disease, the clinical outcomes, and its possible physiopathological process. We outline the diagnosis and the impact that this virus has had in Mexico since its introduction. PMID- 29265116 TI - Abnormal Cardiovascular Findings in Acute Pancreatitis: Are They Associated with Disease Severity? AB - Background: Acute pancreatitis (AP), a disease that commonly requires in-hospital treatment, has been associated with a high incidence of abnormal cardiovascular findings (ACFs). We conducted a prospective study to explore the association of these findings with severity of the disease. Methods: Adult patients with AP diagnosis were prospectively enrolled in an observational study during an 8-month period in a tertiary care center. AP and its severity were defined according to the Revised Atlanta Classification of AP. Subjects were submitted to electrocardiographic, echocardiographic, and serologic testing during the acute period and a 3-month follow-up. The incidence of ACF was compared between two groups: (1) Mild and (2) moderate/severe cases. Results: Twenty-seven patients (mean age 48 +/- 17 years) with AP were enrolled; 15 (55%) had mild and 12 (45%) had moderate/severe AP. During the acute episode, 67% had increased pro-brain natriuretic peptide levels; 52% had abnormal electrocardiographic findings; 48% had abnormal echocardiographic findings; and 18% had increased troponin I levels. There was no significant difference in the incidence of ACF between mild and moderate/severe groups. Nineteen patients (70%) had repeated follow-up testing, and most of the initial ACF did not persist. Conclusion: ACFs occur in an important proportion of patients during AP episodes. Future research should continue to focus in the association of ACFs and the severity of the disease. PMID- 29265117 TI - Dose Volume Effect of Acute Diarrhea in Post-Operative Radiation for Gynecologic Cancer. AB - Background: Diarrhea is the primary symptom of concern in acute post-operative radiation-induced enteritis in gynecologic cancer. We retrospectively studied the correlation between the volume of irradiated small bowel and the development of acute diarrhea in these patients. Materials and Methods: A total of 100 post operative gynecologic cancer patients were analyzed. Pelvic computed tomography was performed to calculate the volume of irradiated small bowel. A dose-volume histogram was calculated from 5 to 40 Gy at 5 Gy intervals. Patients receiving conventional whole pelvic radiation therapy (RT) were assigned to Group I, and those who received intensity-modulated RT (IMRT) were assigned to Group II. A total dose of 40-50 Gy was delivered at 1.8-2.0 Gy per fraction daily. Acute diarrhea during treatment was scored. All data were expressed as a mean +/- standard deviation. Different dose-volume parameters for small bowel in Grades 0 1 and Grades 2-3 diarrhea were calculated by the independent t-test. Univariate analysis of diarrhea risk factors was performed with the independent t-test or Chi-square/Fisher exact test. Results: Of the 77 patients who received conventional RT, 44 (57.14%) experienced Grades 2-3 toxicities. Of the 23 patients who received IMRT, 9 (39.13%) experienced Grades 2-3 toxicities. Concurrent chemotherapy was slightly associated with a higher damage score in both groups (p = 0.028). None of the patient factors (weight, percentage depth dosage, dose fraction, distance from skin to tumor, lymph node metastasis, chemotherapy, block, brachytherapy, hypertension, or diabetes) were correlated with diarrhea in the two groups. The volumes of irradiated small bowel in patients who experienced Grades 2-3 diarrhea were significantly larger than those in patients who experienced Grades 0-1 diarrhea at all dose levels in Group I. V20 (372.19 +/- 133.26 cm3, p = 0.004) was an independent factor for developing Grades 2-3 diarrhea in Group I. V25 (290.35 +/- 130.22 cm3, p = 0.001) was an independent risk factor for all patients who developed higher score diarrhea. Conclusions: The volume of irradiated small bowel was an independent risk factor for all patients who developed diarrhea, especially those undergoing conventional RT. PMID- 29265118 TI - Two-hundred Years Later: Is Parkinson's Disease a Single Defined Entity? AB - An Essay on the Shaking Palsy, by James Parkinson, was published in 1817. Later, Jean-Martin Charcot better described some of the motor features of the disease and named the condition as "La Maladie de Parkinson." As understanding about the disease progressed, aided by both clinical expertise and technological developments, the definition of what is Parkinson's disease has evolved. Motor phenotype, non-motor symptoms, monogenic mutations, genetic risk factors, disease subtyping, and data-driven clusters, among other concepts, have given rise to the hypothesis that Parkinson's disease may be not one well-defined entity but several different diseases encompassed as a levodopa-responsive Parkinsonism. This review present and discusses several of these factors and how they may support or not the notion of Parkinson's being one or more diseases. In summary, current evidence appears to be insufficient at this moment to clarify this issue. Parkinson's disease will continue to be an evolving concept over the years to come. PMID- 29265119 TI - Enhanced wound healing in diabetic rats by nanofibrous scaffolds mimicking the basketweave pattern of collagen fibrils in native skin. AB - Nanofibrous scaffolds that offer proper microenvironmental cues to promote the healing process are highly desirable for patients with chronic wounds. Although studies have shown that fiber organization regulates cell behaviors in vitro, little is known about its effects on the wound healing process in vivo. Most of the nanofibrous scaffolds currently used in skin repair are randomly oriented. Herein, inspired by the basketweave-like pattern of collagen fibrils in native skin, we fabricated biomimetic nanofibrous scaffolds with crossed fiber organization via electrospinning. The regulation of crossed nanofibrous scaffolds on fibroblasts was compared with that of aligned and random nanofibrous scaffolds. Unexpectedly, crossed nanofibrous scaffolds induced different cellular responses in fibroblasts, including differences in cellular morphology, migration and wound healing related gene expression, in comparison to either aligned or random nanofibrous scaffolds. More importantly, the regulation of nanofibrous scaffolds with different fiber organizations on wound repair was systematically investigated in diabetic rats. While the healing processes were enhanced by all nanofibrous scaffolds, wounds treated with crossed nanofibrous scaffolds achieved the best healing outcome, which was evidenced by the resolution of inflammation, the accelerated migration of fibroblasts and keratinocytes, and the promotion of angiogenesis. These findings helped reveal the role of fiber organization in regulating the wound healing process in vivo and suggest the potential utility of biomimetic crossed nanofibrous scaffolds for the repair of chronic wounds. PMID- 29265120 TI - Computational insight into the origin of unexpected contrast in chiral markers as revealed by STM. AB - Internal substituents can serve the double purpose of generating stereogenic centers and (potentially) being identifiable with Scanning Tunneling Microscopy (STM) in 2D self-assembled molecular layers. We investigate computationally the origin of stark contrast variations in STM images of chirally substituted self assembled organic films. STM images of alkyl derivatives with secondary -CH3 and OH groups have been simulated. Density functional theory calculations reveal bias dependent contrast reversals in the substituent regions: a lack of local density of states in the relevant energy regime results in 'dark spots' in the simulated STM images, which turn bright upon increasing the bias voltage. PMID- 29265122 TI - Shell-binary nanoparticle materials with variable electrical and electro mechanical properties. AB - Nanoparticle (NP) materials with the capability to adjust their electrical and electro-mechanical properties facilitate applications in strain sensing technology. Traditional NP materials based on single component NPs lack a systematic and effective means of tuning their electrical and electro-mechanical properties. Here, we report on a new type of shell-binary NP material fabricated by self-assembly with either homogeneous or heterogeneous arrangements of NPs. Variable electrical and electro-mechanical properties were obtained for both materials. We show that the electrical and electro-mechanical properties of these shell-binary NP materials are highly tunable and strongly affected by the NP species as well as their corresponding volume fraction ratio. The conductivity and the gauge factor of these shell-binary NP materials can be altered by about five and two orders of magnitude, respectively. These shell-binary NP materials with different arrangements of NPs also demonstrate different volume fraction dependent electro-mechanical properties. The shell-binary NP materials with a heterogeneous arrangement of NPs exhibit a peaking of the sensitivity at medium mixing ratios, which arises from the aggregation induced local strain enhancement. Studies on the electron transport regimes and micro-morphologies of these shell-binary NP materials revealed the different mechanisms accounting for the variable electrical and electro-mechanical properties. A model based on effective medium theory is used to describe the electrical and electro-mechanical properties of such shell-binary nanomaterials and shows an excellent match with experiment data. These shell-binary NP materials possess great potential applications in high-performance strain sensing technology due to their variable electrical and electro-mechanical properties. PMID- 29265121 TI - White light emission in Bi3+/Mn2+ ion co-doped CsPbCl3 perovskite nanocrystals. AB - Colloidal perovskite nanocrystals (NCs), especially the fully inorganic cesium lead halide (CsPbX3, X = Cl, Br, I) NCs, have been considered as promising candidates for lighting and display applications due to their narrow band emission, tunable band gap and high photoluminescence quantum yields (QYs). However, owing to the anion exchange in the CsPbX3 NCs, stable multi-color and white light emissions are difficult to achieve, thus limiting their practical optoelectronic applications. In this work, dual ion Bi3+/Mn2+ codoped CsPbCl3 perovskite NCs were prepared through the hot injection method for the first time to the best of our knowledge. Through simply adjusting the doping ion concentrations, the codoped NCs exhibited tunable emissions spanning the wide range of correlated color temperature (CCT) from 19 000 K to 4250 K under UV excitation. This interesting spectroscopic behaviour benefits from efficient energy transfer from the perovskite NC host to the intrinsic energy levels of Bi3+ or Mn2+ doping ions. Finally, taking advantage of the cooperation between the excitonic transition of the CsPbCl3 perovskite NC host and the intrinsic emissions from Bi3+ and Mn2+ ions, white light emission with the Commission Internationale de l'Eclairage (CIE) color coordinates of (0.33, 0.29) was developed in the codoped CsPbCl3 NCs. PMID- 29265123 TI - Molecular detection by liquid gated Hall effect measurements of graphene. AB - Conventional electrical biosensing techniques include Cyclic Voltammetry (CV, amperometric) and ion-sensitive field effect transistors (ISFETs, potentiometric). However, CV is not able to detect electrochemically inactive molecules where there is no redox reaction in solution, and the resistance change in pristine ISFETs in response to low concentration solutions is not observable. Here, we show a very sensitive label-free biosensing method using Hall effect measurements on unfunctionalized graphene devices where the gate electrode is immersed in the solution containing the analyte of interest. This liquid gated Hall effect measurement (LGHM) technique is independent of redox reactions, and it enables the extraction of additional information regarding electrical properties from graphene as compared with ISFETs, which can be used to improve the sensitivity. We demonstrate that LGHM has a higher sensitivity than conventional biosensing methods for l-histidine in the pM range. The detection mechanism is proposed to be based on the interaction between the ions and graphene. The ions could induce asymmetry in electron-hole mobility and inhomogeneity in graphene, and they may also respond to the Hall effect measurement. Moreover, the calculation of capacitance values shows that the electrical double layer capacitance is dominant at relatively high gate voltages in our system, and this is useful for applications including biosensing, energy storage, and neural stimulation. PMID- 29265124 TI - Photon upconversion in organic nanoparticles and subsequent amplification by plasmonic silver nanowires. AB - The development of photonic materials with high photoluminescence is always a challenge in photochemistry and photophysics. Here we present a general approach for enhancing photon upconversion through aggregation and further via surface plasmon resonance (SPR). Luminescent nanoparticles from a tetraphenylethylene derivative were fabricated, showing excellent aggregation-induced emission (AIE) behavior. By mixing with a triplet sensitizer platinum octaethylporphyrin (PtOEP), aggregation-induced photon upconversion (iPUC) could be achieved, resulting in an enhancement of the emission. Blending such iPUC nanoparticles with silver nanowires (AgNWs), the upconverted emission intensity could be significantly amplified due to the SPR of AgNWs. Thus, the concepts of aggregation-induced emission (AIE), metal enhanced fluorescence (MEF) and aggregation-induced photon upconversion (iPUC) were successfully integrated and achieved. PMID- 29265125 TI - A tri-site fluorescent probe for simultaneous sensing of hydrogen sulfide and glutathione and its bioimaging applications. AB - Hydrogen sulfide (H2S) and biothiol molecules, such as glutathione (GSH), cysteine (Cys), and homocysteine (Hcy), play an important role in biology. However, understanding the complicated relationship between H2S and biothiols remains an enormous challenge owing to the difficulty in sensing H2S and biothiols simultaneously. Therefore, the development of probes for detecting H2S and biothiols is of great importance in biological science. In this work, we reported a novel fluorescent probe for the sensitive and selective detection of H2S and glutathione (GSH) simultaneously in different buffer solutions. The key design principle is based on a coumarin as the fluorophore structuring a fluorescent probe with three potential sites which could react with H2S and biothiols. This probe displays a rapid response with highly sensitive and selective detection of H2S and GSH (the detection limit of 75 nM and 280 nM, respectively). Moreover, with the assistance of a confocal fluorescence microscope, we demonstrated that the probe can be successfully applied for imaging H2S and GSH in MCF-7 cells. PMID- 29265126 TI - Exfoliation and dispersion of boron nitride nanosheets to enhance ordinary Portland cement paste. AB - Exfoliation and dispersion of boron nitride nanosheets (BNNSs) is the key to achieving desired reinforcing effects for ordinary Portland cement (OPC). Few studies exist, however, of the dispersion of BNNSs in a cement-induced alkaline environment and their effect on the mechanical properties of normal OPC paste. In this study, protocols were developed to prepare BNNS-reinforced OPC paste. Ultrasonication was used to exfoliate BNNSs from h-BN in water based suspensions. The addition of surfactants in the suspension was found to hinder the exfoliation of the BNNSs. The surfactants were, however, found to be essential for the dispersion of the BNNSs in pore solution. Among the three surfactants used in this study, polycarboxylate based superplasticizer was most suitable as it maintained over 40% of the BNNSs stable in the pore solution for 4 hours and increased the hydration flow peak over 20%. Atomic force microscopy results indicated that the thickness of the BNNSs was mostly under 10 nm. With the addition of 0.003 wt% BNNSs, the compressive and tensile strengths of the cement were increased by 13% and 8%, respectively. Besides the nucleation effect as indicated by hydration heat, pore structure refinement and chemical bonding were also found as the main reinforcing mechanisms of BNNSs in OPC matrix. PMID- 29265127 TI - Probing sub-diffraction optical confinement via the polarized Raman spectroscopy of a single-walled carbon nanotube. AB - Polarized Raman spectroscopy of a single-walled carbon nanotube (SWNT) was shown to serve as a simple alternative to sophisticated imaging tools for probing sub diffraction optical phenomena. As a model system, we used TiO2 nanoparticles (n ~ 2.67), which confine plane-polarized incident light (lambda = 532 nm) into two bands less than 150 nm apart. After depositing the nanoparticles onto SWNTs and measuring the nanoparticle-SWNT distance, Raman spectra of individual SWNTs were obtained with the excitation laser polarized either parallel (theta = 0 degrees ) or perpendicular (theta = 90 degrees ) to the nanotubes. The spectral intensity increased by the nanoparticles only at theta = 90 degrees , with the degree of enhancement being greater when the nanotube was located farther from the particle substrate contact. Finite-difference time-domain simulations explained that such an enhancement at theta = 90 degrees was a sub-diffraction phenomenon, which occurred when the nanotubes were located within one of the two confined bands formed by the TiO2 nanoparticles. On repeating the measurements on a two dimensional graphene sheet, only diminished Raman scattering of the graphene with no polarization dependence was observed, confirming the advantage of the one dimensional nanostructure for studying sub-diffraction optics. PMID- 29265128 TI - Evaluating parameter availability for physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoic acid (PFOA) in zebrafish. AB - Physiologically based pharmacokinetic (PBPK) models are considered useful tools to describe the absorption, distribution, metabolism and excretion of xenobiotics. For accurate predictions, PBPK models require species-specific and compound-specific parameters. Zebrafish are considered an appropriate vertebrate model for investigating the toxicity of a wide variety of compounds. However, no specific mechanistic model exists for the pharmacokinetics of perfluoroalkyl acids (PFAAs) in zebrafish, despite growing concern about this class of ubiquitous environmental contaminants. The purpose of this study was to evaluate the current state of knowledge for the parameters that would be needed to construct such a model for zebrafish. We chose perfluorooctanoic acid (PFOA) as a model PFAA with greater data availability. We have updated a previous PBPK model for rainbow trout to simulate PFOA fate in zebrafish following waterborne exposure. For the first time, the model considers hepatobiliary circulation. In order to evaluate the availability of parameters to implement this model, we performed an extensive literature review to find zebrafish-specific parameters. As in previous approaches, we broadened our search to include mammalian and other fish studies when zebrafish-specific data were lacking. Based on the method used to measure or estimate parameters, or based on their species-specific origin, we scored and ranked the quality of available parameters. These scores were then used in Monte Carlo and partial rank correlation analyses to identify the most critical data gaps. The liver, where fatty acid binding proteins (FABPs) and plasma proteins are considered, represented the best model-data agreement. Lack of agreement in other tissues suggest better parameters are needed. The results of our study highlight the lack of zebrafish-specific parameters. Based on sensitivity and uncertainty analysis, parameters associated with PFAA-protein interactions and passive diffusion need further refinement to enable development of predictive models for these emerging chemicals in zebrafish. PMID- 29265129 TI - Catalytic synthesis of few-layer graphene on titania nanowires. AB - Growth mechanisms of graphitic nanostructures on metal oxides by chemical vapor deposition (CVD) are observed at 750 degrees C, using titania nanowire aerogel (NWAG) as a three-dimensional substrate and without metal catalysts. We temporally observed catalytic transformation of amorphous carbon into few-layer graphene on the surface of 5-10 nm diameter titania nanowires. The graphitization spontaneously terminates when the titania nanowires are encapsulated by a shell of approximately three graphene layers. Extended CVD time beyond the termination point (>1125 seconds) yields only additional amorphous carbon deposits on top of the few-layer graphene. Furthermore, it was discovered that the islands of amorphous carbon do not graphitize unless they catalytically grow beyond a threshold size of 5-7 nm along the nanowire length, even after an extended thermal treatment. The electrical conductivity of the NWAG increased by four orders of magnitude, indicating that the graphene shell mediated by titania nanowires yielded a network of graphene throughout the three-dimensional nanostructure of the aerogel. Our results help us understand the growth mechanisms of few-layer graphene on nanostructured metal oxides, and inspire facile and controllable processing of metal oxide-nanocarbon fiber-shell composites. PMID- 29265130 TI - Effect of release of dopamine on iron transformations and reactive oxygen species (ROS) generation under conditions typical of coastal waters. AB - Seasonally persistent blooms of Ulvaria obscura var. blyttii, the prominent species present in green tides in the northern Pacific and Atlantic, have been well documented in recent decades. The synthesis and release of dopamine (DA) by Ulvaria obscura var. blyttii has been proposed to be associated with the suppression and inhibition of the growth of other organisms competing for limited resources. To better understand the potential benefits obtained from the release of DA, the transformation of DA as well its concomitant impact on the local seawater environment are investigated in this study. The results show that, despite several toxic quinones being produced during the oxidation of DA, aminochrome (DAC) is likely to be the only quinone playing an allelopathic role in view of its expected accumulation in the surrounding environment. As a consequence of the direct oxidation of DA and DA induced generation of 5,6 dihydroxyindole (DHI), high concentrations of H2O2 accumulate over time, especially in the presence of elements including iron, calcium and magnesium. The oxidative stress to other organisms induced by the release of DA may be particularly detrimental as a result of H2O2 induced reduction in photosynthesis, inactivation of antioxidant systems or even the generation of OH. DA induced iron mobilization may benefit the continuously persistent blooms of Ulvaria obscura var. blyttii or even the whole community via alleviation in iron deficiency within the bloom region. PMID- 29265131 TI - Bridging the gap with functional collagen scaffolds: tuning endogenous neural stem cells for severe spinal cord injury repair. AB - Severe spinal cord injury (SCI) induces massive proliferation of spinal cord neural stem cells (NSCs), which are considered a promising cell source for therapeutic neural repair. However, most injury-activated spinal cord NSCs differentiate into astrocytes, rather than neurons, in the lesion site as a result of the injury-derived microenvironment. In this mini-review, we introduce the concept of tuning injury-activated endogenous NSCs by implantation of functionalized collagen scaffolds for severe SCI repair. The current state of in situ modulation of migration, scar formation, neuronal differentiation, and functional integration of injury-activated NSCs and their progeny by implantation of elaborately modified collagen scaffolds is demonstrated. Moreover, challenges and perspectives for utilizing injury-activated NSCs for regenerative repair of severe SCI are also discussed. PMID- 29265132 TI - Reversible addition of terminal alkenes to digermynes. AB - Stable digermynes with sterically demanding Bbt (Bbt = 2,6-[CH(SiMe3)2]2-4 [C(SiMe3)3]-C6H2) or Tbb (Tbb = 4-tBu-2,6-[CH(SiMe3)2]2-C6H2) groups underwent [2+2] cycloadditions with terminal alkenes to give the corresponding 1,2 digermacyclobutenes. In the case of the Bbt-substituted digermyne, the reaction was reversible at room temperature, i.e., the 1,2-digermacyclobutene (Ge(ii) species) is susceptible to a facile reductive elimination that affords the corresponding digermyne (Ge(i) species) and the alkene. PMID- 29265133 TI - Slow rheological mode in glycerol and glycerol-water mixtures. AB - Glycerol-water mixtures were studied at molar concentrations ranging from xgly = 1 (neat glycerol) to xgly = 0.3 using shear mechanical spectroscopy. We observed a low frequency mode in neat glycerol, similar to what has been reported for monohydroxy alcohols. This mode has no dielectric counterpart and disappears with increased water concentration. We propose that the hydrogen-bonded network formed between glycerol molecules is responsible for the observed slow mode and that water acts as a plasticizer for the overall dynamics and as a lubricant softening the hydrogen-bonding contribution to the macroscopic viscosity of this binary system. PMID- 29265134 TI - Ultrafast charge-conversional nanocarrier for tumor-acidity-activated targeted drug elivery. AB - Nanocarriers with tumor-acidity-activated charge-conversional ability are of particular interest for targeted drug delivery in the field of precision nanomedicine. Nevertheless, the key challenge of this strategy is the slowness of reversing the surface charge at the tumor tissue. As a proof-of-concept, we synthesized the amphiphilic triblock polymer poly(ethylene glycol)-block-poly(2 carboxyethylacrylate)-block-poly(2-azepaneethylmethacrylate) (PEG-b-PCEA-b-PAEMA) to prepare the cisplatin-loaded nanocarrier UCC-NP/Pt. The PAEMA block at the physiological pH values was hydrophobic, which formed the core of UCC-NP/Pt. In contrast, at the tumor acidity, the tertiary amine groups of PAEMA block rapidly protonated, resulting in the ultrafast charge conversion of UCC-NP/Pt within 10 s. Such ultrafast charge-conversional effect more efficiently enhanced tumor cell internalization of nanocarriers, thus achieving targeted drug delivery, which in turn exhibited superior anticancer efficacy even in the cisplatin-resistant cells. This approach provides new avenues for tumor-acidity-activated targeted drug delivery. PMID- 29265135 TI - High quantum yield Ag2S quantum dot@polypeptide-engineered hybrid nanogels for targeted second near-infrared fluorescence/photoacoustic imaging and photothermal therapy. AB - A high quantum yield (4.3%) hybrid nanogel system based on engineered polypeptides and Ag2S quantum dots has been developed as a multifunctional diagnostic and therapeutic agent for targeted second near-infrared fluorescence, photoacoustic imaging, and photothermal therapy. PMID- 29265136 TI - Molecular dynamics simulations of melting and sintering of Si nanoparticles: a comparison of different force fields and computational models. AB - Melting and sintering of silicon nanoparticles are investigated by means of classical molecular dynamics simulations to disclose the dependence of modelling on the system type, the simulation procedure and interaction potential. The capability of our parametrization of a reactive force field ReaxFF to describe such processes is assessed through a comparison with formally simpler Stillinger Weber and Tersoff potentials, which are frequently used for simulating silicon based materials. A substantial dependence of both the predicted melting point and its variation as a function of the nanoparticle size on the simulation model is also highlighted. The outcomes of the molecular dynamics simulations suggest that the trend of the nanoparticulate sintering/coalescence time vs. temperature could provide a valid tool to determine the melting points of nanoparticles theoretically/experimentally. PMID- 29265138 TI - Catechol oxidation: considerations in the design of wet adhesive materials. AB - Catechols are found as functional groups in Nature as the 3,4-dihydroxy isomer, generally with electron donating substituents and as the 2,3-dihydroxy isomer, with an electron withdrawing substituent. Adhesive properties of catechol materials rely on the vicinal diol configuration, yet conversely, cohesive properties of catechol materials depend on catechol oxidation that promote subsequent crosslinking reactions. While the pH-dependent oxidation of catechol by dioxygen is well recognized, a better understanding of substituent effects on catechol redox chemistry is important in the design of new catechol-containing functional materials. The pH-dependent oxidation kinetics of catechol and substituted catechols by O2 was investigated with a Clark-type oxygen electrode. The results are consistent with a mechanism in which O2 oxidizes both mono deprotonated and fully deprotonated catechol anions. A linear Hammett correlation for the pH-independent second order rate constants for catechol oxidation by O2 establishes that catechols functionalized with electron withdrawing groups have slower rates of oxidation by O2, whereas catechols with electron donating groups have faster rates of oxidation by O2. The Hammett correlation allows for selection of functionalized catechols with redox properties ideally suited for adhesive or crosslinking applications. PMID- 29265139 TI - Stabilization of Ni2+ dimers in hexacyano Mo6 cluster-based Prussian blue derivatives: experimental and theoretical investigations of magnetic properties. AB - Herein, two new octahedral molybdenum cyanide cluster compounds, namely [{Ni(NH3)6}4{Ni2(NH3)8}1][Mo6Br6Q2(CN)6]3.12H2O, Q = S (1) and Se (2), have been synthesized as single crystals by slow diffusion of a solution of nickel chloride into aqueous ammonia solutions of a K2Cs2[Mo6Br6Q2(CN)6] molybdenum cyanide cluster-based compound. Both 1 and 2 were structurally characterized by single crystal X-ray diffraction. They are isostructural and crystallize in the cubic system (Im3[combining macron]m (no. 229); Z = 2, a = 18.147(1) A, and V = 5976(1) A3 and a = 18.188(2) A and V = 6016(2) A3 for 1 and 2, respectively). 1 and 2 are based on the association of [Mo6Bri6Qi2(CN)a6]4- (Q = S, Se) cluster anions with Ni2+ dimer-based cubic [Ni2(NH3)8]4+ and octahedral [Ni(NH3)6]2+ cations. The structure is based on 2-fold interpenetrated [{Ni(NH3)6}4{Ni2(NH3)8}1][Mo6Br6Q2(CN)6]3 frameworks related to each other by [1/2, 1/2, 1/2] translation. The unit cell is based on a body-centered cubic framework of cubic [Ni2(NH3)8]4+. The [Mo6Bri6Qi2(CN)a6]4- (Q = S, Se) cluster units are located in the middle of the edges and at the center of the faces of the cell. The [{Ni(NH3)6}]2+ cations are located at the center of the cubes of the a/2 edge. The dimers [Ni2(NH3)8]4+ are stabilized by hydrogen bonds between the cyanide ligands of the cluster unit and the hydrogen atoms of the ammonia molecules. Both compounds exhibit a weak antiferromagnetic coupling within the [Ni2(NH3)8]4+ dimer entities at low temperatures together with a paramagnetic behavior originating from the cations of the octahedral [{Ni(NH3)6}]2+ complexes. PMID- 29265140 TI - Nucleobases, nucleosides, and nucleotides: versatile biomolecules for generating functional nanomaterials. AB - The incorporation of biomolecules into nanomaterials generates functional nanosystems with novel and advanced properties, presenting great potential for applications in various fields. Nucleobases, nucleosides and nucleotides, as building blocks of nucleic acids and biological coenzymes, constitute necessary components of the foundation of life. In recent years, as versatile biomolecules for the construction or regulation of functional nanomaterials, they have stimulated interest in researchers, due to their unique properties such as structural diversity, multiplex binding sites, self-assembly ability, stability, biocompatibility, and chirality. In this review, strategies for the synthesis of nanomaterials and the regulation of their morphologies and functions using nucleobases, nucleosides, and nucleotides as building blocks, templates or modulators are summarized alongside selected applications. The diverse applications range from sensing, bioimaging, and drug delivery to mimicking light harvesting antenna, the construction of logic gates, and beyond. Furthermore, some perspectives and challenges in this emerging field are proposed. This review is directed toward the broader scientific community interested in biomolecule based functional nanomaterials. PMID- 29265142 TI - Large Stokes-shifted NIR-emission from nanospace-induced aggregation of perylenemonoimide-doped polymer nanoparticles: imaging of folate receptor expression. AB - The development of a water-soluble, perylenemonoimide (PMI) dye-doped polymer nanoparticle (PNP) with NIR emission for live-cell imaging is demonstrated. The large Stokes-shifted NIR emission is due to confined nanospace-induced aggregation offered by the polymer matrix. Later, folic acid functionalised PNP (PNP-FA) is successfully employed to differentiate folate receptor positive and negative cancer cells. PMID- 29265141 TI - To probe interaction of morphine and IBNtxA with 7TM and 6TM variants of the human MU-opioid receptor using all-atom molecular dynamics simulations with an explicit membrane. AB - IBNtxA, a morphine derivative, is 10-fold more potent and has a better safety profile than morphine. Animal studies indicate that the analgesic effect of IBNtxA appears to be mediated by the activation of truncated splice variants (6TM) of the Mu opioid receptor (MOR-1) where transmembrane helix 1 (TM1) is removed. Interestingly, morphine is unable to activate 6TM variants. To date, a high resolution structure of 6TM variants is missing, and the interaction of 6TM variants with IBNtxA and morphine remains elusive. In this study we used homology modeling, docking and molecular dynamics (MD) simulations to study a representative 6TM variant (G1) and a full-length 7TM variant of human MOR-1 in complex with IBNtxA and morphine respectively. The structural models of human G1 and 7TM were obtained by homology modeling using the X-ray solved crystal structure of the active mouse 7TM bound to an agonist BU72 (PDB id: ) as the template. Our 6000 ns MD data show that either TM1 truncation (i.e. from 7TM to 6TM) or ligand modification (i.e. from morphine to IBNtxA) alone causes the loss of key morphine-7TM interactions that are well-known to be required for MOR-1 activation. Receptor disruptions are mainly located at TMs 2, 3, 6 and 7 in comparison with the active crystal complex. However, when both perturbations occur in the 6TM-IBNtxA complex, the key ligand-receptor interactions and the receptor conformation are recovered to resemble those in the active 7TM-morphine complex. Our molecular switch analysis further explains well why morphine is not able to activate 6TM variants. The close resemblance between 6TM-IBTtxA and 7TM in complex with PZM21, a G-protein biased 7TM agonist, suggests the possible biased agonism of IBNtxA on G1, which is consistent with its reduced side effects. PMID- 29265143 TI - NiII-LnIII complexes with o-vanillin as the main ligand: syntheses, structures, magnetic and magnetocaloric properties. AB - ortho-Vanillin in the presence of nickel and lanthanide ions yields three types of heteronuclear NiII-GdIII complexes, ranging from dinuclear to tetranuclear defect dicubane complexes, as demonstrated by their structural determinations. These complexes are dependent on the solvents used during the reaction processes and on the retained lanthanide ions, as characterized by an increase in their Lewis acid character on moving from lighter to heavier lanthanide ions. Intramolecular ferromagnetic NiII-GdIII interactions are present in the heterodinuclear NiII-GdIII entities, whereas ferromagnetic NiII-NiII and NiII GdIII interactions dominate above 2 K in the tetranuclear Ni-Gd compounds, devoid of any GdIII-GdIII interaction. The effect of a magnetic field on the magnetic entropy and adiabatic temperature changes is maximum near the liquid-helium boiling temperature, mainly determined by the relative weakness of the magnetic interactions. PMID- 29265144 TI - Evaluation of protective effect of different dietary fibers on polyphenolic profile stability of maqui berry (Aristotelia chilensis (Molina) Stuntz) during in vitro gastrointestinal digestion. AB - The aim of this work was to determine the protective effect of different dietary fibers on (i) the recovery and bioaccessibility indexes, and (ii) the stability of polyphenolic compounds (phenolic acids, flavonoids and anthocyanins) of maqui berry powder subjected to in vitro gastrointestinal digestion (GID). The extracts obtained in each phase (oral, gastric and intestinal) of GID were used to analyze the stability of polyphenolic compounds by HPLC, and the bioaccessibility of these compounds was also determined. At the end of the GID process, the mixture of maqui berry with the different fibers increased the bioaccessibility index of the phenolic and flavonoid compounds in all cases. The results obtained suggest that the anthocyanins and phenolic acids and flavonoid compounds present in maqui are stabilized through dietary fiber interactions, which might provide sufficient levels for absorption during gastrointestinal digestion. The gums sodium carboxymethyl cellulose, xanthan gum and guar gum provided the best protective effect. PMID- 29265145 TI - Hydroxyl directed C-arylation: synthesis of 3-hydroxyflavones and 2-phenyl-3 hydroxy pyran-4-ones under transition-metal free conditions. AB - An efficient, transition-metal free and direct C-arylation of 3-hydroxychromone moieties in the presence of a base, air as an oxidant and arylhydrazines as arylating agents to furnish highly biologically active flavonols or 3 hydroxyflavones has been developed. We have further extended our methodology for the C-arylation of the 5-hydroxy pyran-4-one moiety. The role of the free hydroxyl group towards C-arylation has been delineated. PMID- 29265146 TI - Enantioselective synthesis of novel pyrano[3,2-c]chromene derivatives as AChE inhibitors via an organocatalytic domino reaction. AB - A series of optically active pyrano[3,2-c]chromenes have been synthesized through an asymmetric domino reaction of 4-hydroxy-2H-chromen-2-ones with malononitriles. The targeted molecules were obtained in excellent yields and enantioselectivities (up to 94% yield, 99% ee). The AChE inhibitory activity studies revealed that compounds 4n (IC50 = 21.3 MUM) and 4p (IC50 = 19.2 MUM) displayed potent acetylcholinesterase inhibition. In most cases, the S-enantiomers were superior to the corresponding R-enantiomers. Moreover, molecular modelling provides a practical method for understanding the enantioselective discrimination of AChE with these kinds of compounds. PMID- 29265147 TI - Technical challenges of working with extracellular vesicles. AB - Extracellular Vesicles (EVs) are gaining interest as central players in liquid biopsies, with potential applications in diagnosis, prognosis and therapeutic guidance in most pathological conditions. These nanosized particles transmit signals determined by their protein, lipid, nucleic acid and sugar content, and the unique molecular pattern of EVs dictates the type of signal to be transmitted to recipient cells. However, their small sizes and the limited quantities that can usually be obtained from patient-derived samples pose a number of challenges to their isolation, study and characterization. These challenges and some possible options to overcome them are discussed in this review. PMID- 29265148 TI - Excitation wavelength dependent photon anti-bunching/bunching from single quantum dots near gold nanostructures. AB - In this study, we aim to investigate the change in photon emission statistics of single CdSe/CdS core/shell quantum dots (QDs) on dielectric modified gold nanoparticle (NP) substrates as a function of the excitation wavelength. Photons emitted from single QDs are typically "anti-bunched" and are independent of the excitation wavelength. However, when QDs are coupled to plasmonic substrates, even at the low excitation power regime, we observed a significant change in photoluminescence emission behavior of single QDs; i.e. the emission transformed from incomplete photon anti-bunched to bunched when the excitation was changed from "off" to "on" plasmon resonance. Theoretical studies based on electrodynamics modeling suggested that for the QD-Au NP system, the quantum yield of single excitons decreases while that of biexcitons increases. In addition, when excited at the "on" resonance condition, the absorption is highly enhanced, resulting in an increased population of higher order excitons of the QDs. The higher order exciton emission was directly observed as an additional peak appeared at the blue side of the exciton peak of single QDs. The combined effect of the change in quantum yield and the increase in the absorption cross section switches the photons emitted by single QDs from anti-bunched to bunched. These results provided direct evidence that not only the plasmonic nanostructures but also the excitation wavelength can effectively control the photon emission statistics of single QDs in the hybrid metal-semiconductor system. Manipulating the multiexciton-plasmon interaction in a hybrid complex like this could possibly open up new doors for applications such as entangled photon pair generation and plasmon-enhanced optoelectronic devices. PMID- 29265149 TI - Synthesis and characterization of water-soluble macrocyclic peptides stabilizing protein alpha-turn. AB - Short peptides composed of naturally occurring amino acids are usually unstructured in aqueous media. The installation of covalent constraints within their side chains or backbones, resulting in the formation of macrocyclic peptides, is an appealing approach to stabilize them in defined secondary structures. Therefore, with the objective to stabilize alpha-turn conformation, we designed, synthesized and characterized constrained 13-membered macrocyclic peptides. Their design was inspired by previous work using the replacement of a hydrogen bond by a covalent bond, for the stabilization of alpha-helical secondary structures. Their synthesis employed our recently published solid-phase method based on Fukuyama-Mitsunobu alkylation reactions. We report herein an optimized synthesis leading to three water-soluble 13-membered macrocyclic peptides 10a-c, including respectively two, one and zero glycine residues. They were characterized by CD and NMR, which indicated the presence of equilibrating conformers. The detailed conformational analysis was based on extensive NMR and molecular dynamics studies. We found that the peptide without glycine residues 10c was mostly present as slowly interconverting conformers whereas the peptide with two glycine residues 10a was mostly present as rapidly interconverting conformers. We did not find a good match between the conformers of 10a and alpha turns occurring in proteins, due to the high flexibility of the glycine backbone. Interestingly, we found that the major conformer of 10c accurately matched the "non-classical" or "tight" alpha-turn of type II-alphaLS, with a RMSD value of 0.42 A for heavy atoms constituting the macrocycle. This is, to the best of our knowledge, the first molecule reported to mimic this type of alpha-turn found in proteins. PMID- 29265150 TI - Exploring bis-(amino)cyclopropenylidene as a non-covalent Bronsted base catalyst in conjugate addition reactions. AB - Bis-(amino)cyclopropenylidene has been utilised as a non-covalent Bronsted base catalyst in the 1,6-conjugate addition of carbon nucleophiles to p-QMs. This protocol makes it possible to access unsymmetrical diaryl- and triarylmethanes in good to excellent yields. Further, this catalyst was also explored in the 1,4 conjugate addition of carbon nucleophiles to enone systems. PMID- 29265151 TI - A Bronsted acid-promoted asymmetric intramolecular allylic amination of alcohols. AB - Reported herein is a chiral Bronsted acid-catalyzed asymmetric intramolecular allylic amination reaction, allowing facile access to a range of biologically interesting chiral 2-substituted hydroquinolines in up to 90% yield and with up to 93% ee. Furthermore, a significant effect of an N-protecting group was observed in this asymmetric process. PMID- 29265152 TI - Impact of macromolecular crowding on RNA/spermine complex coacervation and oligonucleotide compartmentalization. AB - We report the effect of neutral macromolecular crowders poly(ethylene glycol) (PEG) (8 kDa) and Ficoll (70 kDa) on liquid-liquid phase separation in a polyuridylic acid (polyU)/spermine complex coacervate system. The addition of PEG decreased both the amount of spermine required for phase separation and the coacervation temperature (TC). We interpret these effects on phase behavior as arising due to excluded volume and preferential interactions on both the secondary structure/condensation of spermine-associated polyU molecules and on the association of soluble polyU/spermine polyelectrolyte complexes to form coacervate droplets. Examination of coacervates formed in the presence of fluorescently-labeled PEG or Ficoll crowders indicated that Ficoll is accumulated while PEG is excluded from the coacervate phase, which provides further insight into the differences in phase behavior. Crowding agents impact distribution of a biomolecular solute: partitioning of a fluorescently-labeled U15 RNA oligomer into the polyU/spermine coacervates was increased approximately two-fold by 20 wt% Ficoll 70 kDa and by more than two orders of magnitude by 20 wt% PEG 8 kDa. The volume of the coacervate phase decreased in the presence of crowder relative to a dilute buffer solution. These findings indicate that potential impacts of macromolecular crowding on phase behavior and solute partitioning should be considered in model systems for intracellular membraneless organelles. PMID- 29265153 TI - Can strand displacement take place in DNA triplexes? AB - This work studies strand displacement in the context of DNA triplexes. We observed that toehold-mediated strand displacement could proceed in DNA triplexes, but at a much slower rate than in DNA duplexes. In this study, strand displacement was studied with native polyacrylamide gel electrophoresis (PAGE) for two molecular systems. While both systems were involved in branch migration in a DNA triplex, the toehold forms either a duplex or a triplex. This study provides a new strategy for sequence-specific strand displacement and it is useful for the construction of dynamic DNA nanostructures and control of smart DNA nanodevices. PMID- 29265154 TI - Designing an ordered template of cylindrical arrays based on a simple flat plate confinement of block copolymers: a coarse-grained molecular dynamics study. AB - In this paper we study the morphology formed by asymmetric di-block copolymers (di-BCPs) under various confinements using a large-scale coarse-grained molecular dynamics (CGMD) framework. We start with a simple flat plate confinement with the bottom and the top substrate attractive to the minor phase. Studies at a lower confinement length of 17sigma have shown that there exists a critical chain length above which a transition from a three-domain morphology to a two-domain morphology is observed. Increasing the confinement length to 42sigma, where the chains experience considerably lower confinement effects, also revealed the existence of a critical chain length - a transition from a multi-domain morphology (>3) to a three-domain morphology. The results obtained from the flat plate study with two confinement dimensions were used to design a topography of silica pillars with and without a bottom substrate to form ordered cylindrical BCP arrays. The least and highest radial separation lengths between adjacent pillars are kept at 17sigma and 42sigma, respectively. A direct correlation was observed in the number of continuous micro-domains of the maximum and minimum confinement dimensions with the 17sigma and 42sigma flat plate trials. With the optimum chain length employed, the surfaces with affinity to the minor phase can direct the BCP self-assembly to form ordered arrays of minor phase cylinders. The current study thus elucidates a useful tool to predict the morphology formed in an intricate nano-lithographic template by using simple length scale arguments derived from a flat plate confinement study. PMID- 29265155 TI - A regiospecific rhamnosyltransferase from Epimedium pseudowushanense catalyzes the 3-O-rhamnosylation of prenylflavonols. AB - Epimedium is used in traditional Chinese medicine and contains flavonol glycosides that exhibit multiple biological activities. These bioactive flavonol glycosides usually have a rhamnose moiety at the 3-OH position of prenylflavonols, such as icariin (9), baohuoside I (1a) and baohuoside II (2a). However, to date, no rhamnosyltransferase has been reported to catalyze the 3-O rhamnosylation of prenylflavonols. In this article, a flavonol rhamnosyltransferase, EpPF3RT, was identified from E. pseudowushanense B. L. Guo. The recombinant enzyme regiospecifically transfers a rhamnose moiety to 8 prenylkaempferol (1) and anhydroicaritin (2) at the 3-OH position to form baohuoside II (1a) and baohuoside I (2a) in vitro. In addition, a UDP-rhamnose synthase gene, EpRhS, from E. pseudowushanense was functionally characterized and used to produce the UDP-rhamnose sugar donor. Furthermore, an engineered Escherichia coli strain containing EpPF3RT and EpRhS was established to produce baohuoside II (1a) from whole cells. These studies indicate the significant potential of an enzymatic approach for the rhamnosylation of bioactive flavonoids in Epimedium plants and will provide a promising alternative for producing bioactive rhamnosylated flavonoids combined with other genes/enzymes by synthetic biology. PMID- 29265156 TI - Bifunctional catalysis in the stereocontrolled synthesis of tetrahydro-1,2 oxazines. AB - This study demonstrates that the annulation of a tetrahydro-1,2-oxazine ring can be realized via bifunctional catalysis, employing nitroolefins and a recently introduced group of aminooxylating reagents as starting materials. The developed cascade reactivity proceeds in a sequence aza-Michael-Michael reaction. The target products, bearing three contiguous stereocenters, have been obtained with high yields (up to 97%) and excellent stereocontrol (>20 : 1 dr, up to 99.5 : 0.5 er). PMID- 29265157 TI - Convenient synthesis of 2-amino-3-(arylthio)indoles via the Rh-catalyzed reaction of 3-diazoindol-2-imines with thioesters. AB - 2-Amino-3-(arylthio)indoles were conveniently synthesized via the Rh(ii) catalyzed C-S/N-C coupling reaction between 3-diazoindol-2-imines and thioesters. The products could be further oxidized to 2-amino-3-(arylsulfonyl)indoles by m chloroperbenzoic acid and the N-sulfonyl group could be easily removed by reduction with SmI2. PMID- 29265158 TI - Three different types of bridging ligands in a 3d-3d'-3d'' heterotrimetallic chain. AB - A one-pot synthesis of a 3d-3d'-3d'' heterotrimetallic coordination polymer with double diphenoxido, single cyanido and bis-bidentate oxalate as alternating bridges which exhibits an overall antiferromagnetic behaviour has been developed. PMID- 29265159 TI - Optofluidic transport and manipulation of plasmonic nanoparticles by thermocapillary convection. AB - Optothermal control of fluid motion has been suggested as a powerful way of controlling nanomaterials in micro- or nanofluidic samples. Methods based on merely thermal convection, however, often rely on high temperature for achieving fluid velocities suitable for most practical uses. Here, we demonstrate an optofluidic approach based on Marangoni or thermocapillary convection to steer and manipulate nano-objects with high accuracy at an air/liquid interface. By experiments and numerical simulations, we show that the fluid velocities achieved by this approach are more than three orders of magnitude stronger compared to natural convection and that it is possible to control the transport and position of single plasmonic nanoparticles over micrometer distances with high accuracy. PMID- 29265160 TI - Target specificity of mammalian DNA methylation and demethylation machinery. AB - DNA methylation is an essential epigenetic modification for mammalian embryonic development and biology. The DNA methylation pattern across the genome, together with other epigenetic signals, is responsible for the transcriptional profile of a cell and thus preservation of the cell's identity. Equally, the family of TET enzymes which triggers the initiation of the DNA demethylation cycle plays a vital role in the early embryonic development and a lack of these enzymes at later stages leads to a diseased state and dysregulation of the epigenome. DNA methylation has long been considered a very stable modification; however, it has become increasingly clear that for the establishment and maintenance of the methylation pattern, both generation of DNA methylation and its removal are important, and that a delicate balance of ongoing DNA methylation and demethylation shapes the final epigenetic methylation pattern of the cell. Although this epigenetic mark has been investigated in great detail, it still remains to be fully understood how specific DNA methylation imprints are precisely generated, maintained, read or erased in the genome. Here, we provide a biochemist's view on how both DNA methyltransferases and TET enzymes are recruited to specific genomic loci, and how their chromatin interactions, as well as their intrinsic sequence specificities and molecular mechanisms, contribute to the methylation pattern of the cell. PMID- 29265161 TI - Preparation and reactivity of iron complexes bearing anionic carbazole-based PNP type pincer ligands toward catalytic nitrogen fixation. AB - Iron-chloride, -dinitrogen, and -methyl complexes bearing anionic carbazole-based PNP-type pincer ligands are designed, prepared and characterized by X-ray analysis. Some iron complexes are found to work as catalysts toward nitrogen fixation under mild reaction conditions. PMID- 29265162 TI - Beyond nutrient-based food indices: a data mining approach to search for a quantitative holistic index reflecting the degree of food processing and including physicochemical properties. AB - Processing has major impacts on both the structure and composition of food and hence on nutritional value. In particular, high consumption of ultra-processed foods (UPFs) is associated with increased risks of obesity and diabetes. Unfortunately, existing food indices only focus on food nutritional content while failing to consider either food structure or the degree of processing. The objectives of this study were thus to link non-nutrient food characteristics (texture, water activity (aw), glycemic and satiety potentials (FF), and shelf life) to the degree of processing; search for associations between these characteristics with nutritional composition; search for a holistic quantitative technological index; and determine quantitative rules for a food to be defined as UPF using data mining. Among the 280 most widely consumed foods by the elderly in France, 139 solid/semi-solid foods were selected for textural and aw measurements, and classified according to three degrees of processing. Our results showed that minimally-processed foods were less hyperglycemic, more satiating, had better nutrient profile, higher aw, shorter shelf life, lower maximum stress, and higher energy at break than UPFs. Based on 72 food variables, multivariate analyses differentiated foods according to their degree of processing. Then technological indices including food nutritional composition, aw, FF and textural parameters were tested against technological groups. Finally, a LIM score (nutrients to limit) >=8 per 100 kcal and a number of ingredients/additives >4 are relevant, but not sufficient, rules to define UPFs. We therefore suggest that food health potential should be first defined by its degree of processing. PMID- 29265163 TI - Correction: Effect of short-chain branching on interfacial polymer structure and dynamics under shear flow. AB - Correction for 'Effect of short-chain branching on interfacial polymer structure and dynamics under shear flow' by Sohdam Jeong et al., Soft Matter, 2017, 13, 8644-8650. PMID- 29265164 TI - A microscopic view of graphene-oxide/poly(acrylic acid) physical hydrogels: effects of polymer charge and graphene oxide loading. AB - In this work we have examined in detail by means of fully atomistic molecular dynamics simulations, physical hydrogels formed by a polymer electrolyte, poly(acrylic acid), and graphene oxide, at two different charging states of the polymer and two different graphene oxide concentrations. It was found that variations of these parameters incurred drastic changes in general morphological characteristics of the composite materials, the degree of physical adsorption of polyelectrolyte chains onto the graphene oxide surface, the polymer dynamic response at local and global length scales, in the charge distributions around the components, and in the mobility of the counterions. All these microscopic features are expected to significantly affect macroscopic physical properties of the hydrogels, such as their mechanical responses and their electrical behaviors. PMID- 29265165 TI - Mesoscopic study of the ternary phase diagram of the PS-PB-PtBMA triblock copolymer: modification of the phase structure by the composition effect. AB - We explored in detail the ordered nanostructures and the ternary phase diagram of the polystyrene-polybutadiene-poly(tert-butyl methacrylate) (PS-PB-PtBMA) triblock copolymer via dissipative particle dynamics (DPD) simulations and coarse grained models. The mesoscopic simulations show that the PS-PB-PtBMA copolymer in the bulk state can generate eight equilibrium phase regions with well-defined morphologies such as core-shell variations of spheres, cylinders, perforated layers, lamellar, gyroid, as well as cylinder-in-lamella, spheres-in-lamella, and cylinders in hexagonal lattice. The ordered phases exhibit high dependence on the chemical nature and volume fraction, thus portraying specific composition regions with high thermodynamic stability over a ternary phase diagram. The ternary phase diagram, including all equilibrium and metastable nanostructures detected, is described, and analysed in this work in detail. Finally, our dynamic simulation outcomes agree with experimental results. Our aim is to contribute to the understanding of the relationship between block volume fractions and bulk morphologies in ternary polymer systems. PMID- 29265166 TI - Laser-assisted Photodynamic Therapy or Laser-assisted Amorolfine Lacquer Delivery for Treatment of Toenail Onychomycosis: An Open-label Comparative Study. PMID- 29265167 TI - Epidemiology and Medication Trends in Patients with Psoriasis: A Nationwide Population-based Cohort Study from Korea. AB - This study investigated the prevalence of psoriasis and trends in prescription of medications for patients with psoriasis using the Korean National Health Insurance Claims Database from 2006 to 2015. The prevalence of psoriasis and psoriatic arthritis per 10,000 people increased from 47.4 to 61.5 and from 0.04 to 0.23 respectively. The prescription of topical agents was a mean of 73.3%. For systemic agents, prescription of acitretin decreased from 74.8 to 44.5%, methotrexate showed a fluctuation, with a mean of 14.9% and cyclosporine increased from 9.0 to 41.2%. The prescription of biological agents increased sharply from 18 to 1,127 patients. Use of ustekinumab increased from 4.1 to 82.4%; use of infliximab decreased from 20.7 to 6.7% and etanercept decreased from 100 to 6.1%. This study showed an increasing trend in the prevalence of psoriasis. We also reported a rapid increase in the use of biologics in recent years. PMID- 29265168 TI - Sarcoidal Foreign Body Reaction as a Severe Side-effect to Permanent Makeup: Successful Treatment with Intralesional Triamcinolone. PMID- 29265169 TI - Post-surgical effects on language in patients with presumed low-grade glioma. AB - OBJECTIVES: Low-grade glioma (LGG) is a slow-growing brain tumour often situated in or near areas involved in language and/or cognitive functions. Thus, language impairments due to tumour growth or surgical resection are obvious risks. We aimed to investigate language outcome following surgery in patients with presumed LGG, using a comprehensive and sensitive language assessment. MATERIALS AND METHODS: Thirty-two consecutive patients with presumed LGG were assessed preoperative, early post-operative, and 3 months post-operative using sensitive tests including lexical retrieval, language comprehension and high-level language. The patients' preoperative language ability was compared with a reference group, but also with performance at post-operative controls. Further, the association between tumour location and language performance pre- and post operatively was explored. RESULTS: Before surgery, the patients with presumed LGG performed worse on tests of lexical retrieval when compared to a reference group (BNT: LGG-group median 52, Reference-group median 54, P = .002; Animals: LGG group mean 21.0, Reference-group mean 25, P = 001; Verbs: LGG-group mean 17.3, Reference-group mean 21.4, P = .001). At early post-operative assessment, we observed a decline in all language tests, whereas at 3 months there was only a decline on a single test of lexical retrieval (Animals: preoperative. median 20, post-op median 14, P = .001). The highest proportion of language impairment was found in the group with a tumour in language-eloquent areas at all time-points. CONCLUSIONS: Although many patients with a tumour in the left hemisphere deteriorated in their language function directly after surgery, their prognosis for recovery was good. PMID- 29265170 TI - Meta-analysis of Interventions to Reduce Adverse Drug Reactions in Older Adults. AB - OBJECTIVES: To examine the effect of interventions to optimize medication use on adverse drug reactions (ADRs) in older adults. DESIGN: Systematic review and meta analysis. EMBASE, PubMed, OVID, Cochrane Library, Clinicaltrials.gov, and Google Scholar were searched through April 30, 2017. SETTING: Randomized controlled trials. PARTICIPANTS: Older adults (mean age >=65) taking medications. MEASUREMENTS: Two authors independently extracted relevant information and assessed studies for risk of bias. Discrepancies were resolved in consensus meetings. The outcomes were any and serious ADRs. Random-effects models were used to combine the results of multiple studies and create summary estimates. RESULTS: Thirteen randomized controlled trials involving 6,198 older adults were included. The studies employed a number of different interventions that were categorized as pharmacist-led interventions (8 studies), other health professional-led interventions (3 studies), a brief educational session (1 study), and a technology intervention (1 study). The intervention group was 21% less likely than the control group to experience any ADR (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.62-0.99). In the six studies that examined serious ADRs, the intervention group was 36% less likely than the control group to experience a serious ADR (OR = 0.64, 95% CI = 0.42-0.98). CONCLUSION: Interventions designed to optimize medication use reduced the risk of any and serious ADRs in older adults. Implementation of these successful interventions in healthcare systems may improve medication safety in older adults. PMID- 29265172 TI - The link between gastric volume and aspiration risk. In search of the Holy Grail? PMID- 29265171 TI - Nebulised hypertonic saline solution for acute bronchiolitis in infants. AB - BACKGROUND: Airway oedema (swelling) and mucus plugging are the principal pathological features in infants with acute viral bronchiolitis. Nebulised hypertonic saline solution (>= 3%) may reduce these pathological changes and decrease airway obstruction. This is an update of a review first published in 2008, and previously updated in 2010 and 2013. OBJECTIVES: To assess the effects of nebulised hypertonic (>= 3%) saline solution in infants with acute bronchiolitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, Embase, CINAHL, LILACS, and Web of Science on 11 August 2017. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 8 April 2017. SELECTION CRITERIA: We included randomised controlled trials and quasi-randomised controlled trials using nebulised hypertonic saline alone or in conjunction with bronchodilators as an active intervention and nebulised 0.9% saline, or standard treatment as a comparator in children under 24 months with acute bronchiolitis. The primary outcome for inpatient trials was length of hospital stay, and the primary outcome for outpatients or emergency department trials was rate of hospitalisation. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and assessment of risk of bias in included studies. We conducted random-effects model meta-analyses using Review Manager 5. We used mean difference (MD), risk ratio (RR), and their 95% confidence intervals (CI) as effect size metrics. MAIN RESULTS: We identified 26 new trials in this update, of which 9 await classification due to insufficient data for eligibility assessment, and 17 trials (N = 3105) met the inclusion criteria. We included a total of 28 trials involving 4195 infants with acute bronchiolitis, of whom 2222 infants received hypertonic saline.Hospitalised infants treated with nebulised hypertonic saline had a statistically significant shorter mean length of hospital stay compared to those treated with nebulised 0.9% saline (MD -0.41 days, 95% CI -0.75 to -0.07; P = 0.02, I2 = 79%; 17 trials; 1867 infants) (GRADE quality of evidence: low). Infants who received hypertonic saline also had statistically significant lower post-inhalation clinical scores than infants who received 0.9% saline in the first three days of treatment (day 1: MD -0.77, 95% CI -1.18 to 0.36, P < 0.001; day 2: MD -1.28, 95% CI -1.91 to -0.65, P < 0.001; day 3: MD 1.43, 95% CI -1.82 to -1.04, P < 0.001) (GRADE quality of evidence: low).Nebulised hypertonic saline reduced the risk of hospitalisation by 14% compared with nebulised 0.9% saline among infants who were outpatients and those treated in the emergency department (RR 0.86, 95% CI 0.76 to 0.98; P = 0.02, I2 = 7%; 8 trials; 1723 infants) (GRADE quality of evidence: moderate).Twenty-four trials presented safety data: 13 trials (1363 infants, 703 treated with hypertonic saline) did not report any adverse events, and 11 trials (2360 infants, 1265 treated with hypertonic saline) reported at least one adverse event, most of which were mild and resolved spontaneously. AUTHORS' CONCLUSIONS: Nebulised hypertonic saline may modestly reduce length of stay among infants hospitalised with acute bronchiolitis and improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation among outpatients and emergency department patients. However, we assessed the quality of the evidence as low to moderate. PMID- 29265173 TI - Is carotid imaging underused in patients with transient ischemic attack or ischemic stroke? A Swedish Stroke Register (Riksstroke) study. AB - BACKGROUND AND AIM: Carotid artery stenosis is one of the major causes of transient ischemic attack (TIA) and acute ischemic stroke (IS), and carotid surgery and stenting are used to reduce the risk of ipsilateral IS. However, the adherence to the recommendation of carotid imaging in clinical practice has not been well studied. We analyzed proportions of carotid imaging and determinants for its non-use in patients with TIA and IS with respect to baseline demographics, risk factors, hospital characteristics, and geographical region. PATIENTS AND METHODS: Hospital-based data on TIA and IS events, registered from July 2011 to June 2013, were obtained from the Swedish Stroke Register (Riksstroke). Carotid imaging diagnostics included carotid Doppler ultrasound and computed tomography angiography. RESULTS: Carotid imaging was performed in 70% (10 545/15 021) of patients with TIA and 54% (23 772/44 075) of patients with IS. The most significant independent determinants for not undergoing carotid imaging were, in patients with TIA: age >=85 year (odds ratio (OR), 7.3; 95% confidence interval (CI), 6.4-8.4) and a history of stroke (OR, 2.3; 95% CI, 2.1-2.5); and in patients with IS: age >=85 year (OR, 9.8; 95% CI, 9.0-10.6), age 75-84 year (OR, 2.5; 95% CI, 2.3-2.7), and reduced level of consciousness at admission (OR, 3.4; 95% CI, 3.1-3.6). Care at a University hospital and in a stroke unit increased the likelihood of carotid imaging. There were substantial regional variations regarding proportions of carotid imaging. CONCLUSION: Carotid imaging appears to be underused in patients with TIA and IS. Opportunities of secondary stroke prevention with carotid interventions are likely missed. PMID- 29265175 TI - Clinical experience of secukinumab in the treatment of erythrodermic psoriasis: a case series. PMID- 29265174 TI - The effect of pre-operative gastric ultrasound examination on the choice of general anaesthetic induction technique for non-elective paediatric surgery. A prospective cohort study. AB - Ultrasound examination of the gastric antrum is a non-invasive tool that allows reliable estimation of gastric contents. We performed this prospective cohort study in non-elective paediatric surgery to assess whether gastric ultrasound may help to determine the best anaesthetic induction technique, whether rapid sequence or routine. The primary outcome was the reduction of inappropriate induction technique. A pre-operative clinical assessment was performed by the attending anaesthetist who made a provisional plan for induction. Gastric ultrasound was performed in the semirecumbent and right lateral decubitus positions for a qualitative assessment of gastric contents, using a 0-2 grading scale. A final induction plan was made based on this assessment. Immediately after tracheal intubation, gastric contents were suctioned through a multi orifice nasogastric tube; these were defined as above risk threshold for regurgitation and aspiration if there was clear fluid > 0.8 ml.kg-1 , and/or the presence of thick fluid and/or solid particles. Gastric ultrasound was feasible in 130 out of 143 (90%) of children, and led to a change in the planned induction technique in 67 patients: 30 from routine to rapid sequence, and 37 from rapid sequence to routine. An appropriate induction technique was therefore performed in 85% of children, vs. 49% planned after pre-operative clinical assessment alone (p < 0.00001). Our results suggest that gastric ultrasound is a useful guide to the general anaesthetic induction technique with respect to the risk of pulmonary aspiration, in comparison with pre-operative clinical assessment alone. PMID- 29265176 TI - Genome sequence of an Australian strain of canid alphaherpesvirus 1. AB - OBJECTIVE: Characterisation of a complete genome sequence of an Australian strain of canid alphaherpesvirus 1 (CHV-1) and its phylogenetic relationship with other varicellovirus species. METHODS: Standard pathology and PCR methods were used to initially detect herpesvirus in hepatic tissue from an infected 4-week-old Labrador Retriever puppy. The complete CHV-1 genome was sequenced using next generation sequencing technology followed by de novo and reference assembly, and genome annotation. RESULTS: The CHV-1 genome was 125 kbp in length and contained 74 predicted open reading frames encoding functional proteins, all of which have counterparts in other alphaherpesviruses. Phylogenetic analysis using the DNA polymerase gene revealed that the newly sequenced CHV-1 clustered with canid alphaherpesvirus isolated from the UK and shared a 99% overall nucleotide sequence similarity. CONCLUSION: This is the first complete genome of an Australian strain of CHV-1, which will contribute to our understanding of the genetics and evolution of herpesvirus. PMID- 29265177 TI - Expression of CD274 (PD-L1) is associated with unfavourable recurrent mutations in AML. PMID- 29265179 TI - Detecting treatment differences in group sequential longitudinal studies with covariate adjustment. AB - In longitudinal studies comparing two treatments over a series of common follow up measurements, there may be interest in determining if there is a treatment difference at any follow-up period when there may be a non-monotone treatment effect over time. To evaluate this question, Jeffries and Geller (2015) examined a number of clinical trial designs that allowed adaptive choice of the follow-up time exhibiting the greatest evidence of treatment difference in a group sequential testing setting with Gaussian data. The methods are applicable when a few measurements were taken at prespecified follow-up periods. Here, we test the intersection null hypothesis of no difference at any follow-up time versus the alternative that there is a difference for at least one follow-up time. Results of Jeffries and Geller (2015) are extended by considering a broader range of modeled data and the inclusion of covariates using generalized estimating equations. Testing procedures are developed to determine a set of follow-up times that exhibit a treatment difference that accounts for multiplicity in follow-up times and interim analyses. PMID- 29265178 TI - Effect of reducing inspired oxygen concentration on oxygenation parameters during general anaesthesia in horses in lateral or dorsal recumbency. AB - OBJECTIVE: To compare the effects of two concentrations of oxygen delivered to the anaesthetic breathing circuit on oxygenation in mechanically ventilated horses anaesthetised with isoflurane and positioned in dorsal or lateral recumbency. METHODS: Selected respiratory parameters and blood lactate were measured and oxygenation indices calculated, before and during general anaesthesia, in 24 laterally or dorsally recumbent horses. Horses were randomly assigned to receive 100% or 60% oxygen during anaesthesia. All horses were anaesthetised using the same protocol and intermittent positive pressure ventilation (IPPV) was commenced immediately following anaesthetic induction and endotracheal intubation. Arterial blood gas analysis was performed and oxygenation indices calculated before premedication, immediately after induction, at 10 and 45 min after the commencement of mechanical ventilation, and in recovery. RESULTS: During anaesthesia, the arterial partial pressure of oxygen was adequate in all horses, regardless of position of recumbency or the concentration of oxygen provided. At 10 and 45 min after commencing IPPV, the arterial partial pressure of oxygen was lower in horses in dorsal recumbency compared with those in lateral recumbency, irrespective of the concentration of oxygen supplied. Based on oxygenation indices, pulmonary function during general anaesthesia in horses placed in dorsal recumbency was more compromised than in horses in lateral recumbency, irrespective of the concentration of oxygen provided. CONCLUSION: During general anaesthesia, using oxygen at a concentration of 60% instead of 100% maintains adequate arterial oxygenation in horses in dorsal or lateral recumbency. However, it will not reduce pulmonary function abnormalities induced by anaesthesia and recumbency. PMID- 29265180 TI - Sensitive PCR-based monitoring and early detection of relapsed JAK2 V617F myelofibrosis following transplantation. PMID- 29265181 TI - Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki. AB - The myelodysplastic syndromes (MDS) are clonal haematopoietic disorders that develop de novo and also secondary to chemotherapy and/or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors with significant correlation to radiation dose; however, the clinical characteristics of these survivors have not been well analysed. In this study, we investigated chromosomal abnormalities of MDS among survivors. The frequency of abnormal karyotypes was significantly higher, with more very poor risk karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocentre compared with unexposed cases. However, abnormal karyotype frequency did not reflect the prognosis of exposed cases with respect to distance from the hypocentre. In addition, there was no difference in prognosis between exposed and unexposed cases. Among proximally exposed cases (<1.5 km from the hypocentre), chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases. These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy-related MDS. Detailed molecular study is warranted. PMID- 29265182 TI - R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis. AB - Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy +/- involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged >=18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R-CHOP versus DA-R-EPOCH. 132 patients were identified from 11 contributing centres (56 R-CHOP and 76 DA-R EPOCH). The primary outcome was overall survival. Secondary outcomes included progression-free survival, complete response (CR) rate, and rates of treatment related complications. Demographic characteristics were similar in both groups. DA-R-EPOCH use increased after April 2013 (79% vs. 45%, P < 0.001), and there was less radiation use after DA-R-EPOCH (13% vs. 59%, P < 0.001). While CR rates were higher with DA-R-EPOCH (84% vs. 70%, P = 0.046), these patients were more likely to experience treatment-related toxicities. At 2 years, 89% of R-CHOP patients and 91% of DA-R-EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R-CHOP to DA-R-EPOCH for PMBCL. PMID- 29265183 TI - Purification of zebrafish erythrocytes as a means of identifying a novel regulator of haematopoiesis. AB - Zebrafish embryos are useful to study haematopoietic gene function in vertebrates, although lack of antibodies to zebrafish proteins has limited the purification of specific cell populations. Here, we purified primitive zebrafish erythrocytes using 1, 5-bis{[2-(di-methylamino)ethyl]amino}-4, 8 dihydroxyanthracene-9, 10-dione (DRAQ5TM ), a DNA-staining fluorescent dye. At 48 h post-fertilization, we sorted small-sized cells from embryos using forward scatter and found that they consisted of DRAQ5high and DRAQ5low populations. DRAQ5high cells contained haemoglobin, lacked myeloperoxidase activity and expressed high levels of embryonic globin (hbae3 and hbbe1.1) mRNA, all characteristics of primitive erythrocytes. Following DRAQ5TM analysis of gata1:dsRed transgenic embryos, we purified primitive DRAQ5high dsRed+ erythrocytes from haematopoietic progenitor cells. Using this method, we identified docking protein 2 (Dok2) as functioning in differentiation of primitive erythrocytes. We conclude that DRAQ5TM -based flow cytometry enables purification of primitive zebrafish erythrocytes. PMID- 29265185 TI - A retrospective study of R-DHAP/Ox for early progressing follicular lymphoma. PMID- 29265184 TI - Nilotinib after imatinib first-line: a real-life longitudinal cohort of patients with chronic myeloid leukaemia in chronic phase. AB - This prospective, observational study enrolled 150 adult patients with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with nilotinib as second line after imatinib, in a real life setting in France. Two-thirds of patients switched to nilotinib treatment due to lack of imatinib efficacy. Of 146 evaluable patients, 16 (11.0%) (95% confidence interval: 6.4-17.2%) achieved uMR4 , defined as undetectable molecular disease in cDNA with MR4 sensitivity (>=10 000 ABL1 transcripts) at 18 months and confirmed at 24 months (primary endpoint). Among patients without major molecular response (MMR) or deep molecular response (DMR) at study entry, 66.3% achieved MMR and 44.2% DMR within a median of 5.7 and 6.24 months, respectively. Fifty-three patients (36.3%) have prematurely terminated the study before 24 months of follow-up, primarily due to nilotinib treatment discontinuation (n = 43; 29.5%), mainly motivated by treatment intolerance (n = 27; 18.5%) and inefficacy (n = 10; 6.8%). The most frequent extra-haematological adverse events (AEs) reported as related to treatment with nilotinib were pruritus (16.4%), asthenia (13.7%) and dry skin (13.0%). Ischaemic cardiovascular AEs were reported in 18 patients (12.3%). This French nationwide large cohort adds valuable information to the body of evidence on the efficiency and safety of nilotinib in the treatment of patients with CP-CML. PMID- 29265186 TI - Data sharing revolution: adventurism, utopia or reality? PMID- 29265187 TI - Gastric ultrasound in the third trimester of pregnancy: a randomised controlled trial to develop a predictive model of volume assessment. AB - Bedside gastric ultrasonography can be performed reliably by anaesthetists to assess gastric content in the peri-operative period. We aimed to study the relationship between gastric cross-sectional area, assessed by ultrasound, and volumes of clear fluids ingested by pregnant women. We recruited 60 non-labouring third-trimester pregnant women in a randomised controlled and assessor-blinded study. A standardised scanning protocol of the gastric antrum was performed in the 45 degrees semirecumbent and 45 degrees semirecumbent-right lateral positions. Subjects were randomly allocated to drink one out of six predetermined volumes of apple juice (0 ml, 50 ml, 100 ml, 200 ml, 300 ml, 400 ml). Qualitative and quantitative assessments at a baseline period after an 8-h fast, and immediately after the drink, were used to establish the correlation between antral cross-sectional area and volume ingested. A predictive model to estimate gastric volume was developed. Antral cross-sectional area in the semirecumbent right lateral position significantly correlated with the ingested volume (Spearman rank correlation = 0.7; p < 0.0001). A cut-off value of 9.6 cm2 discriminated ingested volumes >= 1.5 ml.kg-1 with a sensitivity of 80%, a specificity of 66.7%, and an area under the curve of 0.82. A linear predictive model was developed for gastric volume based only on antral cross-sectional area (Volume (ml) = -327.1 + 215.2 * log (cross-sectional area) (cm2 )). We conclude that in pregnant women in the third trimester of gestation, the antral cross sectional area correlates well with volumes ingested, and this cut-off value in the semirecumbent right lateral position discriminates high gastric volumes. PMID- 29265189 TI - One hundred years and counting. PMID- 29265188 TI - Low levels of anti-secretory factor in placenta are associated with preterm birth and inflammation. AB - INTRODUCTION: Anti-secretory factor is a protein that regulates secretory and inflammatory processes and preterm birth is associated with inflammation. Therefore, our hypothesis was that anti-secretory factor might play a role in immune reactivity and homeostasis during pregnancy. MATERIAL AND METHODS: Following spontaneous onset of labor and preterm or term delivery, placenta biopsies were collected. The levels of anti-secretory factor and markers of inflammation (CD68, CD163) and vascularization (CD34, smooth muscle actin) were analyzed by immunohistochemistry. RESULTS: The 61 placental biopsies included 31 preterm (<37 weeks of gestation) and 30 term (37-41 weeks) samples. The preterm placentas exhibited lower levels of anti-secretory factor (p = 0.008) and larger numbers of CD68-positive cells (p < 0.001) compared to term. Preterm placentas had blood vessel of smaller diameter (p = 0.036) indicative of immaturity. The level of interleukin-6 in cord blood was higher after very preterm than term birth, suggesting a fetal inflammatory response. The placenta level of anti secretory factor was positively correlated to the length of gestation (p = 0.025) and negatively correlated to the levels of the inflammatory markers CD68 (p = 0.015) and CD163 (p = 0.028). CONCLUSIONS: Preterm delivery is associated with low levels of anti-secretory factor in placenta. Inflammation, a potential trigger of preterm birth, is more pronounced in the preterm placenta and inversely related to the placental level of anti-secretory factor, suggesting both a link and a potential target for intervention. PMID- 29265190 TI - Gender differences in mathematics achievement in Beijing: A meta-analysis. AB - BACKGROUND: The topic of gender differences in mathematical performance has received considerable attention in the fields of education, sociology, economics and psychology. AIMS: We analysed gender differences based on data from the Beijing Assessment of Educational Quality in China. SAMPLE: A large data set of Grade 5 and Grade 8 students who took the mathematical test from 2008 to 2013 (n = 73,318) were analysed. METHOD: Meta-analysis was used in this research. RESULTS: The findings were as follows. (1) No gender differences in mathematical achievement exist among students in Grade 5, relatively small gender differences exist in Grade 8, females scored higher than males, and variance of male students is larger than that of females in both Grade 5 and Grade 8. (2) Except for statistics and probability, gender differences in other domains in Grade 8 are significantly higher than those in Grade 5, and female students outperform males. (3) The ratio of students of both gender in Grade 5 and Grade 8 at the 95-100% percentile level shows no significant differences. However, the ratio of male students is significantly higher than that of females at the 0-5% percentile level. (4) In Grade 5, the extent to which females outperformed males in low SES group is larger than that in higher SES groups, and in Grade 8, the magnitude of gender differences in urban schools is smaller than that in rural schools. CONCLUSION: There is a small gender difference among the 8th graders, with the male disadvantage at the bottom of the distribution. And gender differences also vary across school locations. PMID- 29265192 TI - Traumatic Haemobilia. AB - A series of laboratory experiments is described, in the course of which central liver injuries were produced by the use of a sharp instrument introduced through a laparotomy incision. After this, appropriate blood chemistry investigations were carried out, and the faeces were examined for occult blood. The significance and implications of the findings of haemobilia in the human subject are discussed. PMID- 29265191 TI - A quantitative approach for sex estimation based on cranial morphology. AB - OBJECTIVES: This paper proposes a method for the quantification of the shape of sexually dimorphic cranial traits, namely the glabella, mastoid process and external occipital protuberance. MATERIALS AND METHODS: The proposed method was developed using 165 crania from the documented Athens Collection and tested on 20 Cretan crania. It is based on digital photographs of the lateral view of the cranium, drawing of the profile of three sexually dimorphic structures and calculation of variables that express the shape of these structures. RESULTS: The combinations of variables that provide optimum discrimination between sexes are identified by means of binary logistic regression and discriminant analysis. The best cross-validated results are obtained when variables from all three structures are combined and range from 75.8 to 85.1% and 81.1 to 94.6% for males and females, respectively. The success rate is 86.3-94.1% for males and 83.9 93.5% for females when half of the sample is used for training and the rest for prediction. Correct classification for the Cretan material based upon the standards developed for the Athens sample was 80-90% for the optimum combinations of discriminant variables. DISCUSSION: The proposed method provides an effective way to capture quantitatively the shape of sexually dimorphic cranial structures; it gives more accurate results relative to other existing methods and it does not require specialized equipment. Equations for sex estimation based on combinations of variables are provided, along with instructions on how to use the method and Excel macros for calculation of discriminant variables with automated implementation of the optimum equations. PMID- 29265194 TI - Massive Resection of Small Bowel. AB - This is a report of the management and gastro-intestinal function of a pensioner, aged 81 years, living comfortably after resection of all but 30 cm. of small bowel as the result of a mesenteric artery occlusion. PMID- 29265193 TI - Haemorrhage into an Abscess Cavity: An Uncommon Complication of Pelvic Abscess. AB - This case report illustrates the difficulty in diagnosis and management of unilateral pelvic infection in adolescent gynaecology. It also describes a rare complication of an intraabdominal abscess-delayed massive haemorrhage into the abscess cavity. PMID- 29265195 TI - An Assessment of the Xenon- 133 Method of Measuring Muscle Blood Flow1. AB - The 113 Xe method for measuring muscle blood flow is discussed, and has been evaluated in both normal and ischaemic limbs, a standard amount of ischaemic exercise being employed as the stimulus to hyperaemia. This is considered to be a reliable technique with a high degree of reproducibility, which may be applied to advantage in the clinical assessment of patients with peripheral vascular disease. PMID- 29265196 TI - Trichobezoar: An Unusual Case of Perforated Gastric Ulcer. AB - A brief review of the medical literature on trichobezoar is presented, followed by a case report of the successful surgical management of a case of trichobezoar of the stomach presenting as a perforated gastric ulcer. PMID- 29265197 TI - Strangulating Intestinal Obstruction: A Review of 115 Cases. AB - Internal strangulating intestinal obstruction may present with the clinical features of gut obstruction, of peritonitis or of both, depending on the time of onset of strangulation of the blood supply. The varying clinical pattern of presentation frequently leads to misdiagnosis and delay in operative treatment. Plain X-ray films of the abdomen are frequently misleading, particularly in those cases presenting with features of peritonitis. During the 15-year period 1953 1967, there were 115 patients with strangulating obstruction admitted to the Royal Brisbane Hospital. Before 1960 the mortality rate was 29%, whereas after 1960 the mortality rate was 9.6%. PMID- 29265198 TI - A Compound Pectoral Flap. AB - The principle of including an underlying skeletal muscle in the design of a large skin flap, to assure a safer blood supply during transfer, has been applied to the chest wall. Pectoralis major is included in a chest flap used for the repair of a large defect of all layers of the anterior chest wall, including the medial ends of the clavicles and upper two ribs and the manubrium sterni. PMID- 29265199 TI - Late Repair of Divided Levator PalpebraE Superioris. AB - This is the report of the successful repair of a divided levator palpebrae superioris, carried out 16 months after the complete division of this muscle as the result of a motor accident. PMID- 29265200 TI - The Results of Surgical Treatment for Peptic Ulceration, 1960 - 1964. AB - The results of 530 consecutive operations for peptic ulceration have been assessed and classified as satisfactory or unsatisfactory. The disabilities which determined the result have been analysed, and their incidences after gastrectomy and after vagotomy and drainage compared. PMID- 29265201 TI - External Skeletal Fixation as a Method of Immobilization for Large Skin Grafts of the Neck. AB - A case is presented to illustrate a method of external skeletal fixation by which extension of the neck is maintained in a large skin grafting procedure for burn scar contracture. PMID- 29265202 TI - The Treatment of Hydrocephalus by Ventriculo-Atrial Shunt1. AB - The operation of ventriculo-venous shunt in the management of obstructive hydrocephalus is discussed in the light of a series of 100 patients suffering from this condition who came under the care of a single neurological service over a six-year period, 79 being children, the remaindren adolescent or adult. Technical details of the operation, complications and results are discussed, consideration also being given to the factors influencing the decision whether in any given case this or some other procedure would appear to be in the best interests of the patient. PMID- 29265203 TI - Intestinal Infarction following Spontaneous Reduction of Strangulated Hernia. AB - Infarction of the bowel after the spontaneous reduction of a strangulated hernia is rare, and no mention of such a condition appears in the literature. A case is reported, both for its rarity and for consideration of a possible aetiology. PMID- 29265204 TI - Renal Venous Thrombosis in Children. AB - Thrombosis of the renal venous system, though uncommon, is a potentially serious disorder in childhood. The present paper is a review of the pertinent literature, and two further cases are reported. Gastro-enteritis does not precede haemorrhagic infarction in the majority of clinically diagnosed cases. Males appear to be affected more often than females, the peak incidence in both sexes being in the first month of life. With meticulous attention to fluid and electrolyte imbalance, prompt nephrectomy yields excellent results. PMID- 29265205 TI - The Incidence of Benign and Malignant Neoplasms of the Colon and Rectum: A Post Mortem Study. AB - Uncertainty remains about the relationship of benign polypoid lesions to the development of carcinoma of the colon. The normal incidence of polyps is gernzane to this problem, and this incidence has been determied 200 unselected autopsies. Polyps occur in Qucensland more commonly than most textbooks would suggest, but the figures are in keeping with careful studies carried out in other countries. The data suggest that the great majority of benign polyps are not progressive lesions, and the clinical implications of their detection are discussed. PMID- 29265206 TI - The Use of Reno-Portal Anastomosis in the Treatment of Portal Hypertension: An Experimental Study. AB - An operation of porta-caval and reno-portal shunt has been performed on dogs. These dogs were shown by an ammonia tolerance test to clear ammonia more quickly than dogs with only a porta-caval shunt. It is suggested that the reason for this was the supplementation of the hepatic artery flow by the reno-portal shunt, to maintain a near-normal hepatic blood flow. The clinical application is discussed. PMID- 29265208 TI - The Absorption and Survival of Red Blood Cells Labelled with Chromium-51 from the Peritoneal Cavity in Man. AB - This is a study of the rate of absorption and period of survival of tagged red blood cells introduced into the peritoneal cavity. The investigation was carried out on to healthy adult males, and the red cells were introduced in the course of operations for inguinal hernia. PMID- 29265207 TI - Another One-Stage Hypospadias Operation. AB - Since some success had been achieved with a one-stage tubed pedicled graft urethroplasty, this principle was applied in a case of peno-coronat hypospadias. The operation was performed in one stage, and illustrations are presented showing the technique of operation. The results suggest that the procedure may have some application in the management of hypospadias. PMID- 29265209 TI - The Management of Aorto-Iliac Disease. AB - This paper is concerned with the fate of 112 patients with aorto-iliac disease who underwent surgery from 1959 to 1966. The patency rate for those who underwent endarterectomy was 92%, and for those in whom a prosthesis was placed, 26%. It is stressed that the operation should be designed to suit the special needs of the individual patient, and it is pointed out that provided the proximal occlusions are overcome and the profunda femoris artery is intact, the symptoms of additional femoro-popliteal disease are usually acceptable in elderly patients. PMID- 29265210 TI - Results of Drainage Operations for Duodenal Ulcer: A Preliminary Report. AB - Over a six-year period from 1961 to 1966, 123 drainage operations were carried out on patients suffering from chronic duodenal ulceration. In this series, long term follow-up was possible in respect of 85 patients, and the results following the various surgical procedures employed-namely, pyloroplasty, gastro-enterostomy and pylorectomy-in conjunction with bilateral vagotomy are outlined. PMID- 29265211 TI - A Method of Anaesthesia for Carotid Disobliterative Endarterectomy. AB - The anaesthetic management of vascular disease affecting the brain is discussed. A technique is described and physiological reasons for its use are advanced. PMID- 29265212 TI - Filtration Efficiency of Surgical Masks: A New Method of Evaluation. AB - An apparatus has been constructed for the purpose of evaluating the efficiency of surgical masks. The apparatus is described, and the results of the investigation of various surgical mask materials are given. PMID- 29265213 TI - Drainage Techniques for Duodenal Ulceration. AB - Various drainage procedures in common use for the treatment of duodenal ulceration are critically evaluated. Particular emphasis is laid upon the technique and advantages of anterior pylorectomy. PMID- 29265214 TI - Multiple Intracranial Tumours in Neurofibromatosis: Report of a Case. AB - The occurrence of multiple meningiomas and of combined meningiomas and neuromas in patients suffering from von Recklinghausen's disease has been well documented. A further case is here described, that of a young woman with bilateral auditory neuromas, a neuroma of the vagus, and multiple meningiomas, relieved by eight craniotomies in the course of 15 years. PMID- 29265215 TI - Neurilemmoma of the Vagus Nerve in the Neck. AB - A case of neurilemmoma of the vagus nerve in the neck is described, in which excision with preservation of the nerve was possible. Attention is drawn to the typical clinical picture presented by these tumours. Recognition of this should make it possible to suspect the diagnosis preperatively and so greatly reduce the risks of operative damage to the vagus nerve. PMID- 29265216 TI - Feminizing Adreno-Cortical Carcinoma: Report of a Case. AB - A case of feminizing adreno-cortical carcinoma is reported and features of these tumours are commented on. The differential diagnosis of gynaecomastia and its investigation are discussed. The features of adrenal carcinoma are also discussed, the literature is reviewed and treatment is outlined. PMID- 29265217 TI - An Approach to Pancreatic Operations1. AB - This paper dwells on some aspects of the details, the principles, the alternatives and the relative merits of direct operations on the pancreas. Investigations which might precede operation, the indications for operation and the results of operation are considered in general terms only. PMID- 29265218 TI - The Renal Handling of Dextran 40 by Surgical Patients. AB - A study has been made of the renal handling of low molecular weight dextran (dextran 40) by surgical patients. In spite of the usual fall in glomerular filtration rate during surgery, high urine dextran concentrations may occur, with the formatin of highly viscous urine. In view of the possible association between high dextron concentrations and oliguric renal failure, precautions in its administration are suggested with particular emphasis on the maintenance of urine flow rates. PMID- 29265219 TI - A Congenital Sac Containing Ileum. AB - A unique case of intestinal obstruction is reported. The obstruction was due to a food bolus in a loop of ileum present in a peritoneal sac which was associated with a band passing from a Meckel's diverticulum to the caecum and representing an obliterated vitelline artery. PMID- 29265220 TI - Gustatory Sweating. AB - This paper presents an analysis of eighteen patients found to have gustatory sweating or Frey's syndrome as a sequel to parotidectomy. The typical localised sweating reaction was observed most frequently but in a few instances a much more diffuse sweating reaction occurred. The aptness of the term auriculo-temporal syndrome is challenged on the basis of these observations. The aetiology and natural history of the syndrome are discussed. PMID- 29265221 TI - Vagotomy and Anterior Pylorectomy for Uncomplicated Duodenal Ulceration: Results of 38 Cases. AB - A review of the results of 38 bilateral truncal vagotomics and anterior pylorectomies performed over the past five years is presented. PMID- 29265222 TI - Surgical Correction of Breast Asymmetry1. AB - Breast asymmetry sufficient to be of social or psychological significance requires surgical correction to bring the two breasts into acceptable balance. The principal causes of breast asymmetry are illustrated along with those procedures used to correct this asymmetry. The value of the silastic Cronin prosthesis in augmentation of deficient breast contour is demonstrated. PMID- 29265223 TI - Multiple Synchronous Primary Carcinoma of the Colon. AB - A case of multiple synchronous primary carcinoma of the colon in association with extensive diverticulitis of the descending and pelvic colon is described, and the incidence and possible aetiology of this condition are reviewed. PMID- 29265225 TI - Proceedings of the Surgical Research Society of Australasia: ANNUAL MEETING. PMID- 29265224 TI - The Mortality from Extradural Haematoma1. AB - The mortality in a series of 155 extradural haematomas was 20%. The unavoidable mortality due to coexistent severe cerebral damage was only 5.1%. Delayed diagnosis, due to one of several factors, was the commonest cause of the avoidable deaths. A reliance on burr holes as a means of excluding an extradural haemorrhage, the failure to detect the presence of coexisting space-occupying lesions, misguided lumbar punctures and postoperative complications contributed in a lesser degree to the high avoidable mortality. This analysis suggests a pattern of treatment for head injuries in general and extradural haematomas in particular. PMID- 29265226 TI - The Control of Burn Wound Sepsis with 0.5% Silver Nitrate. AB - Recent adoption of 0.5% silver nitrate dressings as a topical treatment of the burn wound at the Massachusetts General Hospital and other centres has led to an impressive reduction of infection. Infection is the major cause of the mortality in burns today. The use of topical silver nitrate is described, together with a report of the problems associated with such therapy. It is concluded that topical silver nitrate therapy represents a major advance in the care of the burn wound. PMID- 29265227 TI - A Cervico-Laryngeal Cyst. AB - This is a report of a cervical thyroglossal cyst noteworthy for the rare complication of backward extension into the larynx. Excision was carried out without incident and was followed by disappearance of the patient's symptoms. PMID- 29265228 TI - The Clinical and Pathological Effects of Prolonged Solar Exposure Part II: The Association with Basal Cell Carcinoma. AB - The relationship between skin cancer and structural changes in the underlying connective tissue is discussed. Evidence is presented that dermal collagen degeneration and basal cell carcinoma are associated solar-induced phenomena, rather than cause and effect. PMID- 29265229 TI - The Treatment of Experimentally Induced Acute Pancreatitis1. AB - This paper reports the results of treatment of acute haemorrhagic pancreatitis produced experimentally in the dog, the agents used being isotonic saline, Dextran, "Trasylol" and antibiotics. Avenues of future inquiry are suggested in the light of these experiments and those of other workers in this field. PMID- 29265230 TI - A Solid State Pulsed Coagulating Diathermy Instrument:1 Preliminary Report. AB - A solid state pulsed coagulating diathermy instrument is described. The operating parameters of this instrument have been investigated for bipolar coagulation. The advantages of this instrument over spark-gap instruments are lower power requirement, smaller physical size, lessend fire danger and elimination of E. C. G. interference (when used with bipolar configuration). PMID- 29265231 TI - Immuno-Suppressive Drug Treatment of Keratitis Sicca, including an Example of Lichen Planus of the Conjunctiva. AB - Progressive keratitis sicca is described in two patients, one of whom lost on eye. The other patient became blind as a result of lichen planus of the conjunctiva. Autoimmunity is briefty discussed and the apparent therapeutic effect of asathioprine in these patients is described. PMID- 29265232 TI - The Effects of External Pneumatic Splint Pressure on Muscle Blood Flow. AB - The effects of external pneumatic pressure on muscle blood-flow through the calf have been estimated by a Xenon-133 clearance curve technique. Flow was found to be greatly reduced at 40 mm. of mercury external pressure, and it was concluded that for first-aid purposes inflation pressures in excess of 30 mm. of mercury should not be used. PMID- 29265233 TI - Abscesses of the Pancreas. AB - Severe acute pancreatitis with pancreatic necrosis usually precedes a pancreatic abscess. The clinical features are not always dramatic, but when malaise, fever and leucocytosis persist after an attack of severe acute pancreatitis, this complication should be suspected. Surgical drainage of the abscess provides the only hope of survival. External drainage is the procedure of choice. Very occasionally internal drainage into the stomach or jejunum may be considered. PMID- 29265234 TI - Blood Volume in Malignant Disease: Case Studies in 86 Females1. AB - The problem of blood replacement in the individual cancer patient remains unanswered. On present evidence, such a patient must be assumed to be drawn from a population with a mean total blood volume and mean red-cell volume below normal and thus must be assumed to have a better-than-even chance of having a depleted volume. However, it does not necessarily follow that transfusion is necessary; this should ideally be assessed by blood volume determination in each individual case. PMID- 29265235 TI - Corrigendum. PMID- 29265237 TI - Lingual Thyroid: Behaviour after Transplantation. AB - A progress report is given of a patient who had a lingual thyroid treated by excision and transplantation in 1956, when she was 11 years old. The behaviour of the thyroid transplant over 15 years is described, together with the history of two children born to the patient during this period. PMID- 29265236 TI - Gastrocystoplasty in Dogs. AB - While performing a colocystoplasty for cancer of the urinary bladder, we found that the stomach was low-lying and that the pylorus could reach the pelvis with ease. It then occurred to us that the pyloric portion of the stomach could be used to replace the urinary bladder, after which the duodenum could be anastomosed to the divided urethra. As we were not certain whether this operation would he feasible, we studied it in dogs. Technically it was difficult, but after losing some dogs we managed to succeed in performing the operation and grafted a pyloric portion of the stomach to the urethra of the dogs. A study was made on both the function of this new bladder and the gastric secretion. After two years we were quite satisfied that the gastric pouch would serve as a urinary bladder and that there was no hyperchlorcaemic acidosis in these dogs. PMID- 29265238 TI - Proceedings of the Surgical Research Society of Australasia Scientific Meeting. PMID- 29265239 TI - The Use of Bipedicled Flaps in the Management of Pretibial Skin Defects. AB - Chronic ulceration or recurrent ulceration of scar tissue in the pretibial area can be a major problem. The operation to be described affords a safe and satisfactory method of covering the raw area left after excision of pathological tissue in this region by bipedicled full-thickness grafts brought forward from the medial and lateral aspects of the leg. The resultant defect over the calf is covered by bringing across a free skin graft from the opposite thigh. PMID- 29265240 TI - Stenotic Ureterocele. AB - The incidence, clinical and radiological features and histopathology of the structure of stenotic ureteroceles are described, together with the correlation of muscle content with function and its significance in the choice of treatment. PMID- 29265241 TI - Urine Cytology and Primary Carcinoma of the Renal Pelvis and Ureter. AB - This is a report of a small series of cases of primary carcinoma of the renal pelvis and ureter, with particular reference to diagnosis of these conditions by cytological examination of the urine. The causes of failure of detection and the advantages of using this method are discussed, and the cytological and histological diagnoses are compared. PMID- 29265242 TI - Neuromuscular Reflexes of Rectal Continence. AB - The purpose of this paper is to describe the nerve pathways, reflex arcs and sphincter muscles responsible for the sensory and motor mechanisms of rectal continence. The data from which the reflex arcs were deduced were obtained from anal and rectal pressure profiles in children with normal and malformed rectums, and in children with injuries and deformities of the spinal cord which affect the neuromuscular control. These profiles were correlated with the clinical state of continence and with the known anatomy of both normal and abnormal states. PMID- 29265243 TI - Advanced Strangulating Gut Obstruction Complicated by Pulmonary Insufficiency and Consumptive Coagulopathy: Report of a Case. AB - A case of strangulating gut obstruction with shock complicated by pulmonary insufficiency and consumptive coagulopathy is presented. Such patients require careful support of cardiopulmonary function if they are to survive. PMID- 29265244 TI - Carcinoma in a Pharyngeal Pouch: Five-Year Survival after Resection. AB - A 57-year-old man had a resection performed of a pharyngeal pouch, which was complicated by a squamous-cell carcinoma. There is no evidence of recurrence five years later. The clinical and radiological features of this condition are briefly discussed. PMID- 29265245 TI - Achalasia of the Cardia in a Three-Month-Old Infant Treated Successfully by a Modified Heller's Operation. AB - A case of achalasia of the cardia in a boy aged three months is described. This is the youngest case on record of a successful result following a modified Heller's operation in an infant. A biopsy specimen of the oesophageal muscle did not show any abnormalities in the myenteric plexus. These findings are discussed in the light of present concepts of the disease. The safety and reliability of surgery in these young infants are emphasised, making it the treatment of choice in paediatric achalasia. PMID- 29265246 TI - Oxygen Therapy in the Surgical Patient. AB - In recent years attention has been drawn to the effects of surgical and accidental trauma on the microcirculation. Some peripheral vasoconstriction always occurs, and can be seen clinically if it is severe. Pulmonary vasoconstriction also occurs, and reports from several sources suggest that it is much more severe than the systemic response. PMID- 29265247 TI - Acute Pancreatitis: A Review. AB - A series of 68 patients with acute pancreatitis admitted to the Royal North Shore Hospital of Sydney in a three-year period is discussed. An aetiological diagnosis was made in 68% of these. There were three cases associated with a parathyroid adenoma and a 10% incidence of haemorrhagic pancreatitis, and pseudocysts occurred in 6%. There was no mortality in the 22 patients who underwent laparotomy. The aetiological mechanisms, diagnosis and treatment of acute pancreatitis are reviewed. PMID- 29265248 TI - Haemangiopericytoma of the Nasal Cavity. AB - Haemangiopericytoma, first described by Stout and Murray in 1942, is a rare vascular tumour, related to the glomus tumour, in which the proliferating cell is the pericyte of Zimmerman, situated in the capillary wall outside the reliculin sheath. This position distinguishes the pericyte from endothelial cells in the capillary wall. Haemangiopericytoma lacks the organoid formation of the glomus tumour. In accordance with its tissue of origin, the tumour may occur in widespread parts of the body. However, it is most commonly found in the musculo skeletal system and skin. Fewer than 10 cases have been reported in the nasal cavity, and the following case is reported because of its rarity in this site. PMID- 29265249 TI - A Report of Three Cases of Small-Bowel Obstruction Arising from Mesenteric Defects, with a Review of the Literature. AB - Herniation of small bowel through defects in the gastro-intestinal mesentery is a rare cause of acute bowel obstruction. Its possible presence must be borne in mind if the clinical condition of the patient suggests bowel obstruction, despite the absence of external herniae and in the absence of any history of previous abdominal surgery. Early operation is essential, and three cases of the condition are now reported. The relevant literature is reviewed. PMID- 29265250 TI - Mammography: A Surgical Assessment. AB - Perhaps for the first time, a surgeon as distinct from a radiologist makes in this review an assessment of the value of mammography to a surgeon. The experience gained in a review of 300 cases of breast pathology at the Royal Adelaide Hospital is presented. The detection of occult carcinoma is discussed. The limitations and dangers of mammography are emphasized. PMID- 29265251 TI - Vesico-Colic Fistula due to Diverticulitis1. AB - Last year we reported a retrospective review of 25 patients treated for vcsico colic fistula due to diverticulitis. Further cases occurring during the last two years have now been added, and the symptomology, investigation, treatment and results have been consolidated. As a result of this additional experience a classification for the condition is proposed, which it is hoped will provide a guide to the surgical management. PMID- 29265252 TI - Congenital Dislocation of the Hip: A 12-Year Survey. AB - A 12-year review has been made of 114 eases of congenital dislocation of the hip joint in children treated in one institution. The general plan of treatment for all cases was similar and patterned on the practice of Scott and Somerville of Oxford. Ninety-seven hip joints in 61 patients were re-examined clinically and radiologically, and the results are analysed. PMID- 29265253 TI - Postoperative Stasis after Vagotomy and Pyloroplasty. AB - Thirty-two patients who had vagotomy and pyloroplasty performed for duodenal ulcer or its complications have been assessed after operation by the use of a simple radiological test of gastric emptying. Twenty-seven showed emptying at 24 hours after operation, and this finding was used as a guide to beginning the administration of oral fluids and tube withdrawal. Eight cases of stasis are discussed. PMID- 29265254 TI - Deviation of the Ureters due to Giant Bladder Diverticula. AB - Vesical diverticula may on occasion reach very large size, containing more urine than the bladder proper. Depending on its position, a diverticulum may cause displacement of the lower ureter. Medial deviation of the pelvic ureter, by which a non-visualized diverticulum may be diagnosed, is not rare. The case to be described is exceptional in that both medial and lateral deviation of the ureters was present in the same patient, due to giant bilateral diverticula. PMID- 29265255 TI - Suture-Line Neoplastic Recurrence following Large-Bowel Resection. AB - Nineteen patients who had a suture-line recurrence of a bowel neoplasm are reviewed. This sequela to colonic or rectal resection and anastomosis is most common distally, and following segmental or anterior resections. It was absent after small-to-large bowel anastomosis, and following pull-through resection. Three types of suture-line recurrence were observed at exploration, and the times of development fell into early and late groups. Prognosis was best where there was mucosal recurrence only and when this developed late. PMID- 29265256 TI - Proceedings of the Surgical Research Society of Australasia: SCIENTIFIC MEETING. PMID- 29265257 TI - An "Irregularity" in Transverse Colon Diagnosis. PMID- 29265258 TI - The Management of Acute Cholecystitis. AB - A detailed analysis is presented of 200 consecutive patients suffering from acute cholecystitis who presented at the Surgical Professorial Unit at the Royal Brisbane Hospital between the years 1961 and 1969. Conservative management was initiated and maintained whenever this was considered to be reasonable and safe. Immediate surgery, however, was considered imperative in 22 of the 200 patients, and early surgery was carried out in a further 29, by reason of failure of conservative management in 25, and uncertainty of diagnosis in four. The overall mortality rate in the series of 200 was 0.5%. PMID- 29265260 TI - Non-Mechanical Large-Bowel Obstruction. AB - Four cases of non-mechanical large-bowel obstruction are presented and the significant clinical features considered. The importance of barium-enema examination in doubtful cases is emphasized, and the places of conservative and operative treatment in this condition are defined. PMID- 29265259 TI - Urinary Infection and Catheterization: A Case for a Catheter Team. AB - Forty-five out of 84 patients undergoing urethral catheterization developed significant bacteriuria. As might be expected, the infection rate grew with the increase in duration of catheterization, and it was higher in the elderly female patient. Some of the work on this problem is reviewed, and it is suggested that the formation of a catheter team might lead to improvements in catheter care. PMID- 29265261 TI - Nephrocolic Fistula: Report of a Case. AB - A case of nephrocolic fistula due to non-specific pyelonephritis is described. The (Etiology, symptomatology, and treatment of this malady are briefly discussed. PMID- 29265262 TI - The Forty-fourth General Scientific Meeting, Royal Australasian College of Surgeons, May 3 to 7, 1971, Sydney. PMID- 29265263 TI - Renal Transplantation in the Rat: Details of a Technique1. AB - Renal transplantation in the rat is certain to serve as an important experimental model for reviewing principles of transplantation immunology in whole organ grafting. Thus it is likely that many laboratories will attempt to develop this experimental model. However, the available techniques have been described only in the broadest terms and arc inadequate as a guide to its development. For this reason a detailed description of renal transplantation in the rat, using end-to end anastomosis of the renal vessels and a bladder-to-bladder anastomosis of the urinary tract, with simultaneous bilateral nephrectomy, is described. This technique has produced a high success rate, and is based on an experience of 226 rat renal transplants. PMID- 29265264 TI - The Assessment of Acute Injuries of the Knee, with the Results of Early Ligament Repair. AB - Accurate assessment of the degree of damage sustained in an acute injury to the knee joint is of importance in determining treatment, and therefore to the future function of that joint. Adequate investigation, including examination of the joint under a general anesthetic with "strain" radiographs, is necessary. The results of surgical repair of ruptured ligaments in 22 knees arc reported, these results confirming the value of early ligament repair. PMID- 29265265 TI - Inverted Papilloma of the Urinary Bladder: A Report of Two Cases. AB - Two cases of inverted papilloma of the urinary bladder are reported. The benign character of these unusual lesions is confirmed, and the importance of their recognition indicated. PMID- 29265266 TI - Exploration of the Common Bile Duct. AB - One hundred and fifty patients have had cholecystectomy and there have been 62 common duct explorations during the last four years carried out by the members of the Professorial Surgical Unit, Repatriation General Hospital, Concord. Thirty eight patients had duct exploration at cholecystectomy, an exploration rate of 24%. Negative exploration occurred in four patients. The indications for duct exploration, the use of cholangiography and the technique of duct exploration are discussed. PMID- 29265267 TI - Feeding Jejunostomy. AB - This is a review of 32 cases of feeding jejunostomy carried out in the Queen Elisabeth Hospital between the years 1959 and 1968 inclusive. The indications and conditions for which this procedure was used are illustrated. The complications and results of its use are discussed. PMID- 29265268 TI - Traction Injury of the Facial Nerve in the Rabbit. AB - An experimental traction injury of the facial nerve has been produced in the rabbit. The resultant palsy behaves in a manner similar to that of the temporary facial palsy seen as a complication of clinical parotid surgery. This nerve injury in the rabbit is due to the traction rather than the dissection of the nerve from its bed, but it seems likely that the mechanism of the palsy is nevertheless ischemic. There is a wide variation in the magnitude and duration of the traction insult required to produce a postoperative facial palsy. PMID- 29265269 TI - The Pharmacological Basis of Drug Interactions. AB - Drug interactions become more likely with the increased use of polypharmacy. Some interactions such as those employed by anesthetists are useful, but others can be dangerous. The pharmacological principles involved are discussed with the aid of diagrams and tables, and the mechanisms of drug interactions are outlined. A brief review of interactions related to anesthesia and surgery is included. PMID- 29265270 TI - The History of the Royal Australasian College of Surgeons, 1920-1935. PMID- 29265271 TI - Xeroderma Pigmentosum. AB - Five cases of xeroderma pigmentosum have been presented, three of the patients belonging to one family. There was no history of consanguineous marriages in this series. All five patients had advanced ocular complications. Three presented with multiple basal cell carcinomata, which were treated by radiotherapy in two cases and surgery in one. One patient presented with a dermatofibroma, which does not seem to have been reported earlier in association with this disease. Reconstructive techniques such as the use of flaps and grafts arc safe, and the healing response is quite satisfactory. PMID- 29265272 TI - Multiple Atresia by Ileal and Colonic Septa: Case Report. AB - A neonatal infant presented with jejunal atresia. A search in the course of the first laparotomy for other atretic areas failed to locate three separate complete bowel septa, which became revealed later by the clinical course, gastro intestinal dye studies and threc further laparotomies. The patient illustrates the difficulties in locating these septa, and the importance of performing an opaque enema examination in the presence of any neonatal alimentary obstruction. PMID- 29265273 TI - Acute Spinal Epidural Abscess. AB - : Acute spinal epidural abscess is described in two patients. In the patient in whom the abscess was recognized early and decompression effected a complete recovery of cord function occurred, whereas in the second case, where recognition and treatment were delayed, permanent damage was the end-result. Severe back pain with evidence of infection must be checked frequently for neurological evidence of deterioration. SUMMARY: 1. Two cases of acute spinal epidural abscess are reported. 2. Complete recovery followed early drainage in one case. 3. Late diagnosis in the second case was attended by a poor result. 4. The development of severe pain in the back with signs of infection may merge almost imperceptibly with the onset of neurological signs and symptoms. PMID- 29265274 TI - Acute Frontal and Ethmoid Sinusitis with Subperiosteal Abscess. AB - The treatment of a patient with acute frontal and ethmoid sinusitis complicated by a subperiosteal abscess is described. At the initial operation these sinuses were drained into the middle meatus of the nose using a large polythene tube. The advantages of intranasal in addition to external drainage are discussed. PMID- 29265275 TI - Surgical Dressing Technique: Two Examples1. AB - The advantages of dressings using polyurethane sponge are discussed and techniques of their application described. PMID- 29265276 TI - The Treatment of Renal Tuberculosis. AB - Despite the introduction of potent anti-tubercutosis drugs, no decline in the incidence of genito-urinary tuberculosis had been noted in New Zealand over the last 15 years. Of all M. tuberculosis isolated at the Auckland Hospital Laboratory, 10% were resistant to one or more of the three commonly used drugs. Chemotherapeutic regimens, which may employ only oral medications, form the mainstay of successful treatment, and the possible benefits from surgical intervention are now limited to patients with advanced disease. Conservative surgery may prevent further renal parenchymal destruction and permit more effective sterilization of tuberculous foci. Nephrectomy may be undertaken with little risk and is still permissible in the presence of complete renal destruction, though there is a school of responsible thought that advocates the conservative treatment of all patients with renal tuberculosis. PMID- 29265277 TI - Myocarditis and Phaeochromocytomata. AB - Two case histories are presented in each of which an unexpected postoperative death was associated with a previously unsuspected phaochromocytoma, and post mortem examination disclosed the presence of myocarditis. It is suggested that the myocarditis and the gross cardiac arrhythmias leading to the death of the patients may be connected. It is urged that this diagnosis should be kept in mind when unexpected arrhythmias develop in relationship to operation, and that the alpha and beta adrenergic blockers may have a therapeutic value in these circumstances. PMID- 29265278 TI - An Experimental Preparation Suitable for Studying the Effect of Bacterial Contamination and Infection upon the Healing of Colon Wounds. AB - The chief danger of colon operations in the preantibiotic era was thought to be sepsis. Though, no doubt, actual infection of the bowel ends will prevent their healing, it has never been proven that mere contamination with organisms from the faeces or from surrounding peritonitis will produce infection sufficient to cause anastomotic breakdown, provided that the bowel wall is normal and that apposition, blood supply and peritoneal defences are adequate. In order to test specifically the effect of bacterial contamination and infection upon colon wound healing, a dog experimental model has been devised in which other factors affecting colon healing are controlled, and in which concomitant abscess formation is induced adjacent to the healing suture line, peritonitis being avoided by extraperitonealizing the colon in a subcutaneous pouch. PMID- 29265279 TI - Posterior Fracture-Separation of the Lower Femoral Epiphysis. AB - : A case of posterior fracture-separation of the lower femoral epiphysis is reported. Correction of the deformity by anterior wedge osteotomy produced a good functional result. SUMMARY: A case of fracture-separation of the lower femoral epiphysis, treated after a period of four months by anterior wedge osteotomy, is described. A good functional result was obtained. PMID- 29265280 TI - Air Embolism in Cardiac Surgery: Incidence and Prophylaxis1. AB - : This is a brief review of some of the physiological consequences of air embolism, followed by a discussion of the results of a comparative study between two consecutive series of patients, the first prior to the introduction of the strict routines now practised, and the second after this had been introduced. The techniques in current use for prophylaxis against air embolism are presented. SUMMARY: The incidence and outcome of systemic air embolism occurring in 520 patients have been estimated from records of cerebral disturbance. Two series of patients are compared, the first prior to the introduction of strictly planned "debubbling", and the second after this time. The comparisons shows a marked fall in the incidence and severity of this complication in the recent series. Techniques used for removal of air in specific operations have been presented. Pulmonary air embolism has been discussed. While no direct relationship between bilateral atelectasis and pulmonary air embolism has been shown, there is a strong probability that it has been in the past responsible for this, at least in some part and in conjunction with other factors. PMID- 29265281 TI - Squamous Cell Carcinoma of the Anal Canal and Anal Margin. AB - : This is a study of 41 patients with squamous carcinoma of the anus. There were 23 with a carcinoma situated above the dentate line, the five-year survival rate being 27%, and 18 with a carcinoma below the dentate line, with a five-year survival rate of 30%. Advanced local and lymphatic spread at the initial examination was a prominent feature of the series. SUMMARY: The records of 41 patients with squamous cell carcinoma of the anal canal and anal margin are reviewed. An exact follow-up study was possible in every instance. There were 23 individuals with carcinoma of the anal canal and 18 with carcinoma of the anal margin. Spread to local structures or lymph nodes was observed in nearly half of the patients with anal canal carcinoma, and less frequently in anal margin carcinoma. The preferred method of treatment for anal canal carcinoma was a Miles abdominoperineal resection, and for anal margin carcinoma wide local excision. The combined five-year survival was 28.6%, being 27% for anal canal carcinoma, and 30.5% for anal margin carcinoma. PMID- 29265282 TI - Anastomotic Ulceration. AB - : Seventy-eight operations on 68 patients with suspected anastomotic ulceration have been analysed. The incidence, investigation, diagnosis and management of this condition are discussed. SUMMARY: Seventy-eight operations on 68 patients with anastomotic ulceration have been assessed. Only 50% of these patients had a completely satisfactory result. Problems of investigations and diagnosis are discussed. It is suggested that better results can be obtained by a careful selection of patients for operation, and choice of the appropriate operation following full investigation. PMID- 29265283 TI - Torsion of the Hydatid of Morgagni in the Female. AB - : Torsion of the hydatid of Morgagni in the female is discussed, together with theories on embryology. A further case is presented, complicated by infarction of the tube and ovary. SUMMARY: 1. The term hydatid of Morgagni is defined and its embryology outlined. 2. A case of torsion of the hydatid leading to infarction of the tube and ovary is reported. 3. The literature is reviewed. 4. The more typical clinical features are presented, attention being drawn to referred pain. PMID- 29265284 TI - Metastatic Melanoma in the Small Bowel. AB - An account is presented of seven cases of metastatic melanoma in the small bowel, of which five were treated by resection and two were found at necropsy. The reputed rare incidence of this condition is challenged, the clinical features discussed and the literature on the subject reviewed. Its incidence is also presented in relation to all small bowel neoplasms occurring during the period under review. PMID- 29265285 TI - The Conservative Management of Uveal Malignancies. AB - The results of conservative treatment of a series of intraocular malignant melanomas are presented. Tumours of the anterior uvea were excised, while those posteriorly situated were irradiated from a local source containing radon. Details are presented of the construction and use of the radioactive applicator. PMID- 29265286 TI - Familial Renal Tumours. AB - This paper presents a family of which at least three members suffered from renal carcinoma and hypertension, while another four died at an early age from hypertension or cardiac disease. In addition, two other members died of carcinoma of other organs. Known familial or hereditary diseases in which renal tumours occur are discussed briefly. PMID- 29265287 TI - Rupture of the Duodenum Produced by a Safety Belt. AB - : The case report of a patient who sustained a traumatic rupture of the first part of the duodenum as a result of the restraint produced by a seat belt is presented. The literature on closed rupture of the duodenum is reviewed, and the possible mechanism of injury is discussed. SUMMARY: A case of closed rupture of the first part of the duodenum as the result of injury due to the restraint produced by a safety belt is presented. The literature on closed rupture of the duodenum and seat belt injuries is briefly reviewed. The possible mechanisms of injury to the duodenum are discussed. The considered evidence in this case suggests that the body was thrown on to the loose safety belt, sustaining a blow to the right hypochondrium during a period in which the duodenum was distended, with the consequent production of explosive rupture of its first part. PMID- 29265288 TI - Chemotherapy in the Management of Bladder Tumours. AB - "Trenimon" and thiotepa have been used in intravesical instillation in patients with bladder tumours. Good results have been obtained in patients with multiple superficial papillary tumours, but solid and invasive tumours have not been affected. Chemotherapy may be a useful adjunct to cystodiathermy. PMID- 29265289 TI - The Surgical Treatment of Pyloric Obstruction due to Peptic Ulceration. AB - : The results of surgery in 232 cases of peptic ulcer complicated by pyloric obstruction have been reviewed and the results of different operative procedures compared. SUMMARY: In this series vagotomy and drainage gave much better results in the presence of pyloric obstruction than in the treatment of peptic ulcer in general, whereas the results of Polya gastrectomy appear marginally worse. It appears that the risk of stomal ulceration is the major difference, as the stomal ulcer rate for vagotomy and drainage in the presence of pyloric obstruction was 2% as compared with 8% in the total series. Conversely, the incidence of stomal ulcer following gastrectomy appears to be slightly increased. These findings suggest that vagotomy with drainage is the treatment of choice in pyloric obstruction. PMID- 29265291 TI - Jugular Phlebectasia. AB - : This is a report of a case of congenital localized distension of the external juguiar vein, followed by a review of the types previously described and a discussion on treatment and diagnosis. SUMMARY: A case of jugular phlebectasia is described. The difficulties of diagnosis and treatment are discussed. PMID- 29265290 TI - An Experimental Study on the Pathogenesis of Postoperative Hypoalbuminaemia1. AB - : This paper reports a study in the rat of the changes in the plasma albumin level following laparotomy, and their correlation with the concentrations of extravascular albumin in the area of the operation wound and in the liver. SUMMARY: The pathogenesis of postoperative hypoalbuminaemia remains a controversial and poorly understood topic. In the present study the changes in the plasma albumin level following laparotomy have been investigated by immunological methods and correlated with the concentrations of extravascular albumin in the operation wound site and in the liver. There was a fall in the plasma albumin level, accompanied by an increase in the extravascular albumin concentration at the laparotomy wound site, with no alteration in the concentration of albumin in the liver. This work confirms that postoperative hypoalbuminaemia is due to accumulation of albumin in the wound site. Increased capillary permeability is suggested as a cause of the excessive loss of plasma albumin into the surgically injured site. The role and subsequent fate of the extravascular albumin in the wound area are also discussed. PMID- 29265292 TI - The Stress Trajectories in the Femur. AB - : This article presents a three-dimensional photoelastic technique for the investigation of the internal stresses in bones and joints. SUMMARY: 1. The value of plastic models for the investigation of the distribution of weightbearing forces in bone has been discussed. 2. The development of internal stresses in loaded plastic models has been investigated. 3. The great value of assessment of stress patterns and trajectories by a frozen photoelastic technique using araldite D is reported. 4. The practical application of these models to the design of prostheses and other implants has been investigated. PMID- 29265293 TI - Diagnosis by Frozen Section Examination, II: Results in Skin Lesions. AB - : A series of 910 frozen section examination of skin lesions is presented, and the results are analysed in detail and compared with others in the literature. The difficulties in histological diagnosis are discussed and contrasted with those of clinical diagnosis especially of pigmented lesions. SUMMARY: In 910 consecutive frozen section examinations of skin lesions nine false positive reports were submitted, but only two were of major importance. False negative reports occurred with malignant melanomas when the lesion was small or heavily pigmented, and with other malignant lesions when the specimens were large (sampling error). Frozen section examination accurately identifies lesions that tend to be mistaken for malignant melanoma on clinical examination. PMID- 29265294 TI - Anterior Pylorectomy and Vagotomy for Complicated Peptic Ulceration. AB - : This article reviews the treatment of duodenal and gastric ulcer when complicated by haemorrhage, performation and obstruction. Support is given for the use of anterior pylorectomy and vagotomy, carried out at the time when the emergency is dealt with, as the preferred long-term procedure in the management of these conditions. SUMMARY: 1. Bleeding duodenal ulcers are successfully treated by vagotomy and ligation of the bleeding point in combination with anterior pylorectomy and a personal series of nine cases illustrates this method. There are also certain advantages of such a conservative surgical approach over partial gastrectomy. 2. The technique of anterior pylorectomy for bleeding cases differs slightly from that used for uncomplicated cases. 3. Vagotomy with anterior pylorectomy for perforated duodenal ulceration is a safe and definitive operation. Its advantages over simple suture or emergency partial gastrectomy are indicated on the basis of a review of recent literature and of a small personal series. 4. The technique of anterior pylorectomy for perforated cases differs slightly from that used for uncomplicated and bleeding cases. 5. The treatment of obstructing duodenal ulceration by vagotomy and anterior pylorectomy may have a place. Pylorectomy, if considered inadequate, will not create technical difficulties with an ensuing gastrectomy. 6. The place of vagotomy and anterior pylorectomy in complicated gastric ulceration and gastric erosions is uncertain, but it can be substantiated on present physiological knowledge. PMID- 29265295 TI - Traumatic Arteriovenous Fistula between the Internal Thoracic Artery and Vein. AB - : The case is presented of a young male with a traumatic arteriovenous fistula between the internal thoracic vessels following a penetrating injury. The nature of the resulting cardiac bruit and its direction of radiation seemed to differentiate the condition from a persistent ductus arteriosus. This was confirmed by emergency aortography and appropriate surgical treatment was performed. The literature is reviewed and a few similar reported cases are quoted. SUMMARY: A case of traumatic internal thoracic arteriovenous fistula is presented. The nature and site of the penetrating injury, the presence of a superficial continuous murmur conducted down-ward and to the right, and an awareness of the occurrence of this condition following chest trauma suggested the diagnosis, which was confirmed by an immediate thoracic aortogram. The condition was cured by immediate surgery. Only four other cases of post-traumatic fistulae between the internal thoracic artery and vein have been found in the literature. PMID- 29265296 TI - A Simple Instrument to Facilitate Dissection in the Mediastinum from the Neck. AB - The use of a vaginal speculum to gain access to the mediastinum through the neck is described. This enables manipulative procedures to be carried out which include biopsy and also the placement of an electrode in the region of the sino atrial node where a cardiac pacemaker is being used. PMID- 29265297 TI - Sir Alexander MacCormick: Man and Surgeon1. PMID- 29265298 TI - Cervico- Dorsal Sympathectomy in the Management of Essential Hyperhidrosis in the Upper Limb. AB - : Essential hyperhidrosis of the upper limb is readily corrected by cervico dorsal sympathectomy. The clinical picture of this condition, the mechanisms of sweat production and the results of treatment are discussed. SUMMARY: Treatment of essential hyperhidrosis of the upper limb in five patients by bilateral cervical sympathectomy is reported. There was no mortality and little morbidity in this series, and all patients were relieved of their distressing symptoms. PMID- 29265299 TI - Contact Spread of Carcinoma of the Skin. AB - : The case history of a patient with basal cell carcinomas on the thumb and the ear is presented. The patient had burnt the thumb 17 months prior to presentation and the burn had never fully healed. He volunteered that he habitually slept on his side with the thumb in contact with the ear. The histological features of the two lesions were identical. Similar reported cases and the experimental data on basal cell tumour implantation are reviewed in an attempt to prove that this case is one of implantation metastasis. Some of the evidence is strongly in favour of this possibility, but the verdict must be one of "not proven". SUMMARY: A case of simultaneously occurring basal cell carcinomas with identical histology is presented. In the light of published clinical cases and experimental data, an attempt has been made to prove that one lesion was an implantation metastasis of the other. The available evidence allows only the Scottish verdict of "not proven" to be made. The points for and against a diagnosis of implantation metastasis are listed. Points in favour are the long history of contact, the rarity of basal cell carcinoma of the thumb, the histological features of the tumours, the unusual time interval if the tumour was a "burn cancer", and the suitable "culture medium" for metastasis following the burn. Points against such a diagnosis are the occurrence of many histologically similar basal cell carcinomas in a series of ten cases, the possibility that the tumour was a burn cancer, the experimental difficulty in transplanting basal cell carcinomas, and the experimental evidence that stroma is required to transplant basal cell carcinomas successfully. PMID- 29265300 TI - Perforated Peptic Ulcer: Mortality and Morbidity in 603 Cases. AB - : A retrospective study of 603 instance of perforated peptic ulcer occurring over the period from 1944 to 1964 is presented with reference to annual and seasonal incidence, sex ratios, mortality and the factors affecting it, and immediate morbidity. Of special note are: (a) the highly significant increase in the proportion of females in Newcastle, New South Wales; (b) the markedly lower pyloro-duodenal: gastric ratio as compared with that reported in overseas figures; (c) a previously unreported relationship between the actual act of drinking chilled beer and perforation and (d) the very highly significant relationship between the death rate and the sise of the performation. SUMMARY: A series of 603 instances of perforated peptic ulcer over a period of 21 years until 1964 is presented. There has been no real change in the relative incidence of perforation in gastric, pyloric and duodenal ulcers over that time interval, and none in the annual incidence. On the contrary, there has been a highly significant increase in the proportion of females, and the pyloroduodenal: gastric ratio in females is less than unity, a most marked variation from European figures. The seasonal incidence of perforated ulcer in Newcastle, Australia, is remarkably constant. A previously unreported relationship between the actual act of drinking chilled beer and perforation is noted. The overall mortality rate was 15.4%, 7.8% in patients who were operated on and 72.8% in those who were not. There was a single operative death among 80 females. In operations on males, gastric performations were the most lethal to a highly significant degree. Increase in age and delay in operation adversely affect the operative death rate. The prognosis is further worsened by perforation in hospital, posterior wall perforation, perforation associated with gastro intestinal haemorrhage, admission to a non-surgical service and, of course, mis diagnosis. A very highly significant relationship was noted between the death rate and the size of the perforation. The young seek advice earlier than the old, and males earlier than females. The immediate morbidity is high, with a postoperative pneumonia rate of 42.9% and a wound infection rate of 31.9%. A significant relationship is seen between subphrenic abscess and gastric perforation. PMID- 29265301 TI - Vesico-Vaginal Fistula: A Method of Repair. AB - This is a report of the method of closure of a vesico-vaginal fistula, three times unsuccessfully operated upon previously, by a technique which is now presented for the first time. PMID- 29265302 TI - Secondary Adamantinoma of the Ischium. AB - : This case report describes secondary pelvic bone involvement by an uncommon bone tumour. Adamantmoma of the jaw accounts for only one per cent of all tumours in this area, and although gland and lung involvement have been described, bone involvement is rare. SUMMARY: The case of a patient with secondary bone involvement from adamantinoma of the maxilla is reported. PMID- 29265303 TI - Bilateral Posterior Dislocation of the Shoulders. AB - A case of bilateral posterior dislocation of the shoulder is reported in a man suffering from terminal renal failure. An analysis of the previously reported cases reveals characteristic clinical and radiological features, yet the lesion is frequently misdiagnosed. Early diagnosis is important because within the first week closed reduction is usually possible, resulting in good function. After the first week, open reduction is required and the late functional result is only fair, yet much better than in the untreated cases. PMID- 29265304 TI - Surgical Aspects of Enteritis Necroticans in the Highlands of New Guinea. AB - It is the aim of this to discuss the surgical aspects of a culturally determined, yet essentially preventible disease; to review the experience derived from 72 patients, in whom it was confirmed at operatin; and to draw conclusins which may assist in the future management of this problem. PMID- 29265305 TI - Fish-Bone Impaction of the Throat. AB - : A series of 55 cases of fish-bone impaction of the pharynx and oesophagus is discussed. Special reference is made to the serious and sometimes fatal complications that may result from delay in treatment, and cases illustrating these complications are reported in detail. SUMMARY: Fifty-five cases of fish bone impaction of the pharynx and the oesophagus are reported. Spontaneous disimpaction can occur. Persistent simple impaction, although distressing for the patient, is easily managed. Delay in treatment or well-intentioned but inexpert attempts at dislodging the fish bone by the patient or his friends may result in perforation of the pharyngo-oesophageal wall with retropharyngeal inflammation and suppuration, a condition carrying high morbidity. Perforation of the carotid artery or the aorta is a grave complication, requiring urgent treatment if a high mortality is to be avoided. A brief review is made of the complications of fish bone impaction in the abdominal part of the alimentary tract. PMID- 29265306 TI - Fluorescent Angiography of the Human Fundus Oculi. AB - Fluorescent angiography of the human fundus oculi provides valuable information on the retinal circulation and events in the vascular beds of the choroid and optic nerve head. Pre-capillary arterioles can be delineated consistently by the intravenous injection of 5% sodium fluorescein, while good capillary filling can be shown frequently. The safety, speed and ease of this investigation make it one of the most promising of the angiographic techniques available for clinical research. Its applicability extends from regional ocular diseases to a broad range of general medical problems. PMID- 29265307 TI - Tumours of the Small Bowel1. AB - A series of small bowel neoplasms, benign, primary malignant and metastatic, representing the total local experience of a fourteen-year period, is reviewed. The problems of diagnosis and management are presented and discussed. Argentaffin carcinoma is the most frequently encountered primary malignant tumour. The mode of presentation is considered to be related to the biological behaviour of the various tumours rather than to bear upon the attendant prognosis. It is apparent from our observations that knowledge of the epidemiology of these lesions must still be considered deficient. PMID- 29265308 TI - Thiersch's Operation1. AB - : In the past 21 years Thiersch's operation has been revived and has earned a small but definite place among the operations now in use. SUMMARY: Thirsch's operation is the least disturbing procedure available for the treatment of complete rectal prolapse, and may be carried out no matter how poor the general condition of the patient. Despite the results in this series of 32 cases, it is my belief that Thiersch's operation (using a wide ring of braided stainless steel wire placed deeply in the perianal tissues) deserves a place in at least the poor risk case with a small but complete rectal prolapse. PMID- 29265309 TI - The Problems of "Benign" Polypoid Lesions of the Stomach. AB - The clinical manifestations and pathological features of radiologically detected, apparently benign, polypoid lesions of the stomach are considered. Data were obtained from 22 cases from the Royal Adelaide and Queen Elizabeth Hospitals, and from series of cases previously recorded. A decision tree is constructed, as a guide to clinical management. PMID- 29265310 TI - Spontaneous Intraabdominal Haemorrhage. AB - Three cases of this rare emergency are presented. The pathological basis, clinical features and treatment are discussed, and the importance of precisely locating the bleeding site is emphasized. Two of these patients were diabetic, an association which has not previously been described. PMID- 29265311 TI - Typhoid Osteomyelitis: Report of a Case. AB - A rare case is recorded of typhoid osteomyelitis with characteristic diaphyseal involvement of the right radius and the left ulna with sequestrum formation and microbiological confirmation from the tissues removed at operation. The literature is reviewed. PMID- 29265312 TI - The Morphology of Congenital Dilatation of the Ureter: Intrinsic Ureteral Lesions. AB - Congenitally dilated ureters are divided into four groups associated with (i) intrinsic ureteral lesions, (ii) vesico-ureteral reflux, (iii) urethral obstruction or (iv) other malformations such as myelomeningocele or the triad syndrome. One hundred and forty-seven dilated ureters in Group 1 (caused by Intrinsic ureteral lesions), have been studied qualitatively and quantitatively by standard pathological techniques, using the average size and population of muscle cells in the dilated ureter as the quantitative index of work-load or obstruction, and have been divided into four main types. These dilated ureters were found to be either obstructed or non-obstructed, and the obstructing lesion was either an atresia, a stenosis, or a valve. In each of the obstructed ureters, the smooth muscle in the wall of the proximal dilated ureter was hypertrophic and hyperplastic. In contrast, in the fourth non-obstructed type of dilated ureter, no obstructing lesion was found, and there was neither hypertrophy nor hyperplasia of muscle in the wall of the proximal dilated ureter; it is presumed that the dilatation is due to developmental lateral overgrowth of the ureter. No example of dilated ureter due to neuro-muscular incoordination was found in this group. PMID- 29265313 TI - Corrigenda. PMID- 29265314 TI - The Significance of a Single Injury in the Causation of Basal-Cell Carcinoma of the Skin. AB - The case records arc reported of 13 patients who gave a history of a well remembered injury, which appeared to have resulted, within a comparatively short period of time, in the development of a basal-cell carcinoma at the same site. Although it is likely that, if such an injury is relevant, it has only accelerated the appearance of a tumour in a precancerous area, it is, none the less, curious that this happening is more commonly recorded in the pathogenesis of a basal-cell carcinoma than in that of a squamous-cell carcinoma. In seven of the cases the injury was a thermal one. PMID- 29265315 TI - Aneurysmal Bone Cyst of the Fourth Metacarpal Bone. AB - A rare case of aneurysmal bone cyst of the left fourth metacarpal bone is reported. After excision of the tumour, including the distal articular surface, followed by primary bone grafting, the ring finger regained excellent function. Ten months' follow-up showed no local recurrence. The literature is briefly reviewed. PMID- 29265316 TI - The Motor-Scooter Handlebar Syndrome: Report of a Case. AB - A case of acute arterial insufficiency of the right leg of a young man is described, following a blow on the inguinal region from the handlebar of a motor scooter. A review of the literature suggests that this is an uncommon but clear cut syndrome. PMID- 29265317 TI - Primary Carcinoma of the Male Breast: A Report of 16 Cases in Australian Ex Servicemen. AB - A report of 16 cases of primary male breast carcinoma is presented. The average age was 70 years. Crude five-year survival was 38% overall. The aetiology and management of the disease is discussed. Special reference is made to the use of modified radical mastectomy for the early lesion and the role of orchidectomy for palliation in the advanced case. PMID- 29265318 TI - In-Vivo Studies with a Cation Exchange Resin Mixture in the Removal of Excessive Ammonium from the Extracorporeal Circulation System. AB - This paper describes the in-vivo experience with a mixture (Mixture G) of four forms of the strong cation exchange resin, "Amberlite" IR-120, in the treatment of ammonia intoxication. This resin mixture, with a total quantity of 750 mEq, when used in the extracorporeal circulation system, was found to be efficient in the correction of hyperammonemia of experimental dogs and to be unaccompanied by any untoward effects. PMID- 29265319 TI - Suprapubic Catheter Drainage in Gynaecology. AB - The suprapubic method of bladder drainage has many advantages over transurethral drainage. It has the lowest incidence of urinary infection of all methods of bladder drainage in common use. It allows the area of surgical repair in cases of stress incontinence time for the aedema to subside without urethral mucosal damage and avoids the necessity for urethral catheterization after repair. The complications are few, wound infection and hematuria being the main ones. The method greatly facilitates bladder management after operation, to the delight of the nurses and patients who have had previous experience with urethral drainage. PMID- 29265320 TI - Wound Infection: Experience with 12,000 Sutured Surgical Wounds in a General Hospital over a Period of 11 years. AB - Wound infection rates in a general hospital over an 11-year period have been studied, the review embracing over 12,000 sutured surgical wounds. There is a remarkably constant downward trend in the wound infection rate. This is considered real, as there has been no change in the method of recording. Changes in operating theatre technique have not individually influenced the rates or the trend. In particular, the use or non-use of surgical masks made no difference to the incidence of wound infection. Changes in scrub-up-technique and the introduction of air-conditioning in the operating rooms had no appreciable effect. There is a difference between wound infection rates of acute operations and elective operations, of "clean" operations and "dirty" operations. The possible sources of surgical wound infection are discussed. The classification into "inherent" and "sporadic" groups is offered, and in "sporadic" infections the role of the patient as a source of infection is considered. PMID- 29265321 TI - Simple Bone Cysts: Results of a Pilot Survey. AB - A study of simple bone cysts is reported, giving the results of a pilot study of all cases traceable over the past 10 years in Auckland. Curettage and grafting arc shown to be of dubious value. The natural history of some examples is described to illustrate principles thought to contradict earlier concepts of the origin of these lesions. PMID- 29265322 TI - Changes in Left Ventricular Function Produced by Excision of a Myocardial Infarct. AB - Left ventricular function has been measured in calves before and after the production of a myocardial infarct by ligation of the anterior descending coronary artery. In 20 animals function was measured after the area of the acute infarct had been excised and the left ventricle repaired by direct suture. Infarcts equal to 20% of the left ventricle were found to impair left ventricular function, and significant immediate improvement in function was measured in one third of the animals in which an infarct was resected. PMID- 29265323 TI - Carcinoma of the Rectum Presenting with Ischaemic Colitis. AB - A case of carcinoma of the rectum presenting with ischemic colitis is described. The problems arising from the coexistence of these conditions are discussed in terms of the diagnosis of stricture in the presence of ischemic colitis and of the surgery required for the carcinoma. PMID- 29265324 TI - Operating under Magnification. AB - A brilliantly lit, magnified, stereoscopic view of an operating field is of some advantage when operating on small structures, and is essential with structures that can be resolved only with difficulty. Manual dexterity rapidly improves with practice to meet the needs created by better visualization. The axes, coordinates, and dynamics of equipment are discussed. The Zeiss operating microscope series allow a very wide application. With parts readily interchangeable, there is a maximum flexibility in form. Needless complexity should be avoided. There are many pitfalls (all of which can be overcome) and discussion on sterility, fusion faculty, depth of field, area of field, blind spots, ocular defects in the surgeon, and increased time taken by operations is presented. Photography and teaching objectives are discussed. PMID- 29265325 TI - Urinary Retention Due to Asymptomatic Protruded Lumbar Disc: Report of a Case. AB - Recently, asymptomatic protruded lumbar discs have been reported in the American literature as causing urinary retention. A 33-year-old woman with urinary retention was seen at Christchurch Hospital, and evaluation revealed an asymptomatic central protrusion of her L 4-5 disc. This was removed and a spinal fusion carried out with relief of her symptoms. The literature is briefly reviewed. PMID- 29265326 TI - The Surgical Management of Ruptured Abdominal Aortic Aneurysm: A Ten -Year Experience. AB - Ninety consecutive patients with ruptured abdominal aortic aneurysms were treated surgically. The hospital mortality was 42% for the whole period, but was reduced to 33% for the last five years. Case management is outlined, with emphasis on ancesthetic and fluid management, and causes of mortality and morbidity are presented. The late results were also discussed and an actuarial survival curve was calculated. PMID- 29265327 TI - Mediastinoscopy: A Safe and Useful Procedure in the Investigation of Patients with Intrathoracic Diseases. AB - Mediastinoscopy was performed on 280 patients. The technique is described. A tissue diagnosis was made at mediastinoscopy in 82 cases (29.2%) and, of these, 34 were primary lung carcinomas, one was a secondary deposit from a Grawiiz tumour, 44 were sarcoid tumours and three lymphomas. Of 112 patients with carcinoma for whom the diagnosis was proved at mediastinoscopy, or for whom a negative mediastinoscopy result could be verified at thoracotomy, mediastinoscopy proved to be useful for 94 (83.9%). Of 48 patients with suspected sarcoid, mediastinoscopy gave a positive result for 44 (91.6%). There were only two complications in this series. PMID- 29265328 TI - Diverticulitis: The Indications for Elective Surgery. AB - The incidence of diverticular disease of the colon is discussed, and the indications for surgical interference, over and above those which are absolute, are considered. In the author's experience, a second attack of diverticulitis implies a greater likelihood of subsequent attacks, and a greater likelihood also of more serious complications. In an endeavour to prevent these, the routine daily administration of 250 mg of tetracycline is suggested. "Painful diverticulitis attacks" may in fact have no inflammatory background, but can be due to spastic colon syndrome and can be relieved by sigmoid resection. PMID- 29265329 TI - Results of Surgical Treatment of Carcinoma of the Penis. AB - A five-year follow-up of 133 patients treated surgically for carcinoma of the penis shows a 69% survival if the lymph nodes are not involved, and 33% survival if the lymph nodes arc involved. Clinically, in patients with operable disease, it is not possible to determine with accuracy whether the lymph nodes are invaded by tumour. The prognosis is not affected significantly by anaplasia of the growth, but is related to clinico-pathological spread. Local complications are recurrence, urethral stenosis, delayed wound healing of the groin dissection and lymphoedema. PMID- 29265330 TI - Skin Arthroplasty of the Elbow. AB - Despite the increasing use of metal prostheses in the treatment of severe rheumatoid arthritis of the elbow joint, soft-tissue arthroplasty still has a definite place. This paper reviews the indications, technique and results of skin arthroplasty of the elbow. PMID- 29265331 TI - Total Reduplication of the Stomach: A Rare Anomaly. AB - The fourth recorded case of total reduplication of the stomach, illustrating the problems created by this anomaly, particularly hemorrhage, is presented. Management by duodeno-duodenostomy is discussed in the light of previous reports. PMID- 29265332 TI - The Hazards of Electrical Apparatus in the Operating Theatre. AB - Electrical hazards have developed insidiously in operating theatres over recent years, and few people who work in them are aware of the dangers. The formulation of more appropriate safety codes and the education of medical people concerning the safe use of electricity are urged. The hazards that now exist are discussed, with examples, and some basic electrical concepts which apply to these hazards are examined. A plea is made for a more responsible attitude by doctors, and for higher standards of maintenance and vigilance. PMID- 29265333 TI - Monocytosis is a powerful and independent predictor of inferior survival in primary myelofibrosis. PMID- 29265334 TI - Post-ABVD biopsy results, and not post-ABVD FDG-PET results, predict outcome in early-stage Hodgkin lymphoma: response to Adams and Kwee. PMID- 29265335 TI - The logic of counterfactual analysis in case-study explanation. AB - In this paper, we develop a set-theoretic and possible worlds approach to counterfactual analysis in case-study explanation. Using this approach, we first consider four kinds of counterfactuals: necessary condition counterfactuals, SUIN condition counterfactuals, sufficient condition counterfactuals, and INUS condition counterfactuals. We explore the distinctive causal claims entailed in each, and conclude that necessary condition and SUIN condition counterfactuals are the most useful types for hypothesis assessment in case-study research. We then turn attention to the development of a rigorous understanding of the 'minimal-rewrite' rule, linking this rule to insights from set theory about the relative importance of necessary conditions. We show why, logically speaking, a comparative analysis of two necessary condition counterfactuals will tend to favour small events and contingent happenings. A third section then presents new tools for specifying the level of generality of the events in a counterfactual. We show why and how the goals of formulating empirically important versus empirically plausible counterfactuals stand in tension with one another. Finally, we use our framework to link counterfactual analysis to causal sequences, which in turn provides advantages for conducting counterfactual projections. PMID- 29265337 TI - International health opportunities in dermatology residency programs: a survey based study in the United States. PMID- 29265336 TI - Advances in predicting venous thromboembolism risk in children. AB - Paediatric venous thromboembolism (VTE) is a rare disorder but a rising incidence has been observed in recent years, due to improved VTE diagnosis and increased use of central venous catheters in the treatment of severe diseases. Risk assessment strategies are well established for adult patients, however, similar guidelines for paediatric patients are largely lacking. Several risk prediction tools have been reported in recent literature, which make use of established risk factors to assess VTE risk in paediatric subgroups, such as hospitalised children, cancer-diagnosed children and paediatric trauma patients. Although these models suffer several limitations regarding their study size and heterogeneous selection of predictor variables, they offer potential for improving the thromboprophylaxis management in these children. Here, we give an overview on recently reported risk prediction models for paediatric VTE. PMID- 29265338 TI - Haemostasis and innate immunity - a complementary relationship: A review of the intricate relationship between coagulation and complement pathways. AB - Coagulation and innate immunity are linked evolutionary processes that orchestrate the host defence against invading pathogens and injury. The complement system is integral to innate immunity and shares numerous interactions with components of the haemostatic pathway, helping to maintain physiological equilibrium. The term 'immunothrombosis' was introduced in 2013 to embrace this process, and has become an area of much recent interest. What is less apparent in the literature however is an appreciation of the clinical manifestations of the coagulation-complement interaction and the consequences of dysregulation of either system, as seen in many inflammatory and thrombotic disease states, such as sepsis, trauma, atherosclerosis, antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH) and some thrombotic microangiopathies to name a few. The growing appreciation of this immunothrombotic phenomenon will foster the drive for novel therapies in these disease states, including anticoagulants as immunomodulators and targeted molecular therapies. PMID- 29265339 TI - Science or liberal arts? Cultural capital and college major choice in China. AB - Previous studies on major East Asian societies such as Japan and Korea generally fail to find a strong effect of cultural capital in educational inequality, partly due to the characteristic extreme focus on standardized test and curriculum. This study shifts attention to the horizontal stratification of education by investigating the association between family background, cultural capital, and college major choice in contemporary China. Based on analysis of data from the Beijing College Students Panel Survey (BCSPS), we found that, on average, cultural capital significantly mediates the relationship between family background and college major preference. Those with greater endowment of cultural capital are more likely to come from socio-economically advantaged families, and, at the same time, demonstrate a stronger propensity to major in liberal arts fields rather than science, technology, engineering and mathematics (STEM) fields. Further analyses reveal that the association between cultural capital and academic field choice comes into being by way of performance in the Chinese test in the national college entrance examination and of the non-cognitive dispositions, such as self-efficacy and self-esteem. Our findings better our understanding of formation of the horizontal stratification of higher education. PMID- 29265340 TI - Arachnidism by Segestria bavarica with severe neuropathic pain successfully treated with lidocaine 5% plaster. PMID- 29265341 TI - Headband pressure alopecia: clinical, dermoscopy, and histopathology findings in four patients. PMID- 29265342 TI - Traction alopecia. PMID- 29265343 TI - A novel homozygous mutation in PVRL4 causes ectodermal dysplasia-syndactyly syndrome 1. AB - Ectodermal dysplasias (EDs) are a group of hereditary disorders defined by alterations in two or more ectodermal structures. One recently described rare entity is the autosomal recessive inherited ectodermal dysplasia-syndactyly syndrome 1 (EDSS1). Homozygous and compound heterozygous missense and nonsense mutations in the poliovirus receptor related-4 (PVRL4) gene, encoding cell adhesion molecule nectin-4, have been identified as causal for EDSS1. We here report a consanguineous family with a 2-year-old girl featuring EDSS1, including slowly progressive alopecia on the head, pili torti-like twisted hairs in trichoscopy, widely spaced, peg-shaped and conical teeth, proximal syndactyly with fusion of the 2nd to 4th toes, and generalized dry skin. There was no palmoplantar hyperkeratosis and sweating appeared normal to slightly enhanced, especially on the head. Using exome sequencing, we identified the novel homozygous nonsense mutation c.229C>T (p.Gln77Ter) in PVRL4. PMID- 29265346 TI - Talking about time: temporality and motivation for international Christian humanitarian actors in South Sudan. AB - We investigate ways in which international evangelical Christian humanitarians talk about time as they engaged in humanitarian assistance and development work in South Sudan. Our focus on Christian development work is motivated by a desire to understand how and why people persevere in humanitarian work and reconcile seemingly impossible circumstances and to further elaborate sociological conceptions of time as experienced by people in their own lives. We argue that their faith commitments produce ways of understanding time and causality which make possible their attachment to risky and dangerous work. Our work is based on in-depth interviews with people who work or have recently worked for Christian faith-based organizations in South Sudan (n = 30). Drawing on Tavory and Eliasoph's () concepts of life narratives and life projects, we treat our participants as culturally competent actors who skilfully construct their stories through drawing on collectively shared faith-inflected ideas about temporality and causation. We argue that these ideas represent an important resource for getting through the risks, challenges and uncertainties of doing humanitarian work in complex crises. PMID- 29265347 TI - Active and colorful life under lake ice. PMID- 29265344 TI - Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy. AB - OBJECTIVES: Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy. METHODS: A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice. RESULTS: Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by >=50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses. SIGNIFICANCE: This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy. PMID- 29265348 TI - A case of severe pediculosis capitis. PMID- 29265349 TI - Frequent somatic mutations of KMT2D (MLL2) and CARD11 genes in primary cold agglutinin disease. PMID- 29265350 TI - Different clonal dynamics of chronic myeloid leukaemia between bone marrow and the central nervous system. PMID- 29265351 TI - Post-ABVD biopsy results, and not post-ABVD FDG-PET results, predict outcome in early-stage Hodgkin lymphoma. PMID- 29265353 TI - Impact of Contact With Grandparents on Children's and Adolescents' Views on the Elderly. AB - Stereotypes, prejudice, and discrimination against the elderly (ageism) may manifest themselves in children at an early age. However, the factors influencing this phenomenon are not well known. Using both explicit and open-ended questions, this study analyzed the influence of personal and familial parameters on the views of 1,151 seven- to sixteen-year-old Belgian children and adolescents on the elderly. Four factors were found to affect these views: gender (girls had slightly more positive views than boys), age (ageism was lowest in 10- to 12-year old, reminiscent of other forms of stereotypes and cognitive developmental theories), grandparents' health, and most importantly, quality of contact with grandparents (very good and good contacts correlated with more favorable feelings toward the elderly, especially in children with frequent contacts). PMID- 29265352 TI - Modeling pathogenesis and treatment response in childhood absence epilepsy. AB - OBJECTIVE: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for gamma-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. METHODS: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. RESULTS: Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. SIGNIFICANCE: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE. PMID- 29265354 TI - Application of next-generation sequencing to improve cancer management: A review of the clinical effectiveness and cost-effectiveness. AB - Uptake of next-generation sequencing (NGS) has increased dramatically due to significant cost reductions and broader community acceptance of NGS. To systematically review the evidence on both the clinical effectiveness and the cost-effectiveness of applying NGS to cancer care. A systematic search for full length original research articles on the clinical effectiveness and cost effectiveness of NGS in MEDLINE and EMBASE. Articles that focussed on cancer care and involved the application of NGS were included for the review of clinical effectiveness. For the cost-effectiveness review, we only included the articles with economic evaluations of NGS in cancer care. We report the rate of successfully detecting mutations from the clinical studies. The incremental cost effectiveness ratio and sensitivity analysis outcomes are reported for the cost effectiveness articles. Fifty-six articles reported that sequencing patient samples using targeted gene panels, and 83% of the successfully sequenced patients harboured at least 1 mutation. Only 6 studies reported on the cost effectiveness of the application of NGS in cancer care. NGS is an effective tool for identifying mutation in cancer patients. However, more rigorous cost effectiveness studies of NGS applied to cancer management are needed to determine whether NGS can improve patient outcomes cost-effectively. PMID- 29265355 TI - An investigation of social class inequalities in general cognitive ability in two British birth cohorts. AB - The 'Flynn effect' describes the substantial and long-standing increase in average cognitive ability test scores, which has been observed in numerous psychological studies. Flynn makes an appeal for researchers to move beyond psychology's standard disciplinary boundaries and to consider sociological contexts, in order to develop a more comprehensive understanding of cognitive inequalities. In this article we respond to this appeal and investigate social class inequalities in general cognitive ability test scores over time. We analyse data from the National Child Development Study (1958) and the British Cohort Study (1970). These two British birth cohorts are suitable nationally representative large-scale data resources for studying inequalities in general cognitive ability. We observe a large parental social class effect, net of parental education and gender in both cohorts. The overall finding is that large social class divisions in cognitive ability can be observed when children are still at primary school, and similar patterns are observed in each cohort. Notably, pupils with fathers at the lower end of the class structure are at a distinct disadvantage. This is a disturbing finding and it is especially important because cognitive ability is known to influence individuals later in the lifecourse. PMID- 29265356 TI - Molecular detection of minimal residual disease in multiple myeloma. AB - Despite the significantly higher complete remission rates and improved survival achieved in the last decade, multiple myeloma (MM) patients continue to relapse due to persistence of minimal residual disease (MRD). Generally, MRD refers to persistence of low levels of disease in the order of one tumour cell in >=105 normal cells. Currently, molecular and immunophenotypic techniques are employed for MRD detection. This review focuses on MRD detection by molecular techniques, including allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), next-generation sequencing (NGS) and digital PCR (dPCR), in addition to a brief description of, and comparison with, multiparameter flow cytometry. The basic principles, technical advantages and limitations, and the clinical impact of all three molecular techniques are reviewed and compared. They all have a sensitivity of at least 10-5 , among which ASO real-time quantitative PCR is the most well standardized, and NGS carries the highest sensitivity and applicability, while dPCR is still under investigation. Furthermore, molecular MRD negativity is a favourable prognostic factor for survival of patients with MM. However, several challenges inherent to molecular detection of MRD still remain to be overcome, particularly false negativity and failure to detect extramedullary disease. Finally, detection of MRD from peripheral blood remains challenging. PMID- 29265357 TI - Prevalence of skin cancer in Native American kidney transplant recipients. AB - BACKGROUND: Skin cancer prevalence is well-characterized for white solid organ transplant recipients. Although the prevalence of skin cancer in non-white (Black, Asian, Hispanic) kidney transplant recipients (KTRs) has been assessed, no study has reported the prevalence of skin cancer in Native American (NA) KTRs. The aim of this study is to determine if the prevalence of skin cancer in NAKTRs is the same as in white KTRs. METHODS: We conducted a case-controlled retrospective review from a single transplant center. One hundred thirteen NAKTRs who received a transplant between 2001 and 2011 were age- and transplant-year matched with 113 white controls. RESULTS: The 226 KTRs consisted of 141 (62.4%) men and 85 (37.6%) women, with a mean age of 50.2 +/- 10.8 years. There was no skin cancer found in NAKTRs prior to or post transplantation, while seven (6.2%) white KTRs had eight skin cancers prior to transplantation, and 28 (24.8%) white KTRs developed 66 skin cancers post transplantation. Twenty-two (19.5%) NAKTRs did not follow-up with dermatology at this institution. The median follow-up in NAKTRs was 3.3 years compared to 3.0 years in white KTRs. CONCLUSION: NAKTRs have a decreased prevalence of skin cancer compared to their white counterparts. PMID- 29265358 TI - Enlisting Peer Cooperation in the Service of Alcohol Use Prevention in Middle School. AB - This article reports on a cluster randomized trial of cooperative learning (CL) as a way to prevent escalation in alcohol use during middle school (N = 1,460 seventh-grade students, age 12-13, seven intervention and eight control schools). We hypothesized that CL, by bringing students together in group-based learning activities using positive interdependence, would interrupt the process of deviant peer clustering, provide at-risk youth with prosocial influences, and in turn, reduce escalations in alcohol use. Results indicated that CL significantly reduced growth in deviant peer affiliation and actual alcohol use, and effects for willingness to use alcohol were at the threshold of significance (p = .05). CL also attenuated the link between willingness to use alcohol and later alcohol use. PMID- 29265359 TI - Plantar fibromatosis: Surgical approach of a giant bilateral case. AB - BACKGROUND: Plantar fibromatosis or Ledderhose disease is characterized by a benign fibroblastic proliferation of the plantar fascia. It is an illness with unknown etiology and a complex treatment in its most intense manifestation. OBJECTIVE: The authors describe a surgical option for extensive cases where conservative treatments are not successful. Surgical techniques may vary according to the site and extent of the lesions. METHODS: Surgical treatment with wide resection of the lesion and second intention healing using a hydrocolloid dressing. RESULTS: After a 3-year follow-up with no recurrence, the authors demonstrated an excellent result, which led to an important improvement in the patient's quality of life. CONCLUSION: Surgical treatment can be a good option for plantar fibromatosis. Giant lesions can be treated with wide excisions and second intention healing, with low risk of aesthetic and functional complications. PMID- 29265360 TI - Association of aplastic anaemia and lymphoma: a report from the severe aplastic anaemia working party of the European Society of Blood and Bone Marrow Transplantation. PMID- 29265361 TI - XI National Congress of the Italian Society of Immunology, Clinical Immunology and Allergology, 28-31 May, 2017, Bari, Italy. PMID- 29265363 TI - 47th Annual Meeting of the German Society for Immunology, 12-15 September, 2017, Erlangen, Germany. PMID- 29265362 TI - Solution structure and dynamics of Xanthomonas albilineans Cas2 provide mechanistic insight on nuclease activity. AB - Cas2 protein in the CRISPR-Cas system functions as a scaffold for the acquisition of foreign DNA fragments, and as a nuclease against DNA and RNA substrates. Crystal structures of Cas2 have shown catalytically inactive conformational states that do not explain the mechanism of Cas2 nuclease activity. Here, we report that Xanthomonas albilineans Cas2 (XaCas2) assumes an inactive conformation in solution. Residual dipolar couplings and NMR relaxation, however, provide direct evidence on conformational dynamics at the predicted hinge region. Furthermore, XaCas2 transiently associates with metal ions for nuclease activity via highly mobile Asp8. Taken together, the dual function of Cas2 can be explained by a dynamic equilibrium of conformational states that serve as a scaffold or as a nuclease on demand. PMID- 29265365 TI - Defective trafficking of Kv2.1 channels in MPTP-induced nigrostriatal degeneration. AB - Intracellular protein trafficking is tightly regulated, and improper trafficking might be the fundamental provocateur for human diseases including neurodegeneration. In neurons, protein trafficking to and from the plasma membrane affects synaptic plasticity. Voltage-gated potassium channel 2.1 (Kv2.1) is a predominant delayed rectifier potassium (K+ ) current, and electrical activity patterns of dopamine (DA) neurons within the substantia nigra are generated and modulated by the orchestrated function of different ion channels. The pathological hallmark of Parkinson's disease (PD) is the progressive loss of these DA neurons, resulting in the degeneration of striatal dopaminergic terminals. However, whether trafficking of Kv2.1 channels contributes to PD remains unclear. In this study, we demonstrated that MPTP/MPP+ increases the surface expression of the Kv2.1 channel and causes nigrostriatal degeneration by using a subchronic MPTP mouse model. The inhibition of the Kv2.1 channel by using a specific blocker, guangxitoxin-1E, protected nigrostriatal projections against MPTP/MPP+ insult and thus facilitated the recovery of motor coordination. These findings highlight the importance of trafficking of Kv2.1 channels in the pathogenesis of PD. PMID- 29265364 TI - NADPH-dependent 5-keto-D-gluconate reductase is a part of the fungal pathway for D-glucuronate catabolism. AB - NADPH-dependent 5-keto-D-gluconate reductase was identified as a missing element in the pathway for D-glucuronate catabolism in fungi. The disruption of the gene, gluF, by CRISPR/Cas9 in the filamentous fungus Aspergillus niger resulted in a strain unable to catabolise D-glucuronate. The purified GluF protein was characterized and kcat and Km values of 23.7 +/- 1.8 s-1 and 3.2 +/- 0.1 mm for 5 keto-D-gluconate, respectively, were determined. The enzyme is reversible and is active with NADP+ and D-gluconate. We suggest a pathway for D-glucuronate catabolism with the intermediates L-gulonate, 2-keto-L-gulonate, L-idonate, 5 keto-D-gluconate, D-gluconate and D-gluconate-6-phosphate which is a part of the pentose phosphate pathway. A fungal enzyme activity for the conversion of L gulonate to 2-keto-L-gulonate remains to be identified. PMID- 29265366 TI - Arabidopsis pollen extensins LRX are required for cell wall integrity during pollen tube growth. AB - Proper cell wall assembly is crucial during pollen tube growth. Leucine-rich repeat extensins (LRXs) are extracellular glycoproteins which belong to the hydroxyproline-rich glycoprotein (HRGP) family. They contain a conserved N terminal leucine-rich repeat (LRR) domain and a highly variable C-terminal extensin domain. Here, we characterized four LRX proteins (LRX8 through LRX11) from pollen of Arabidopsis thaliana. To investigate the role of LRX8-LRX11 in pollen germination and pollen tube growth, multiple T-DNA lrx mutants were obtained. The lrx mutants display abnormal pollen tubes with an irregular deposition of callose and pectin. They also show serious alterations in pollen germination and segregation ratio. Our results suggest that LRXs are involved in ensuring proper cell wall assembly during pollen tube growth. PMID- 29265367 TI - Preference for conspecifics evolves earlier in males than females in a sexually dimorphic radiation of fishes. AB - Speciation by sexual selection is generally modeled as the coevolution of female preferences and elaborate male ornaments leading to behavioral (sexual) reproductive isolation. One prediction of these models is that female preference for conspecific males should evolve earlier than male preference for conspecific females in sexually dimorphic species with male ornaments. We tested that prediction in darters, a diverse group of freshwater fishes with sexually dimorphic ornamentation. Focusing on the earliest stages of divergence, we tested preference for conspecific mates in males and females of seven closely related species pairs. Contrary to expectation, male preference for conspecific females was significantly greater than female preference for conspecific males. Males in four of the 14 species significantly preferred conspecific females; whereas, females in no species significantly preferred conspecific males. Relationships between the strength of preference for conspecifics and genetic distance revealed no difference in slope between males and females, but a significant difference in intercept, also suggesting that male preference evolves earlier than females'. Our results are consistent with other recent studies in darters and suggest that the coevolution of female preferences and male ornaments may not best explain the earliest stages of behavioral isolation in this lineage. PMID- 29265368 TI - Phosphorylation at Thr432 induces structural destabilization of the CII ring in the circadian oscillator KaiC. AB - KaiC is the central oscillator protein in the cyanobacterial circadian clock. KaiC oscillates autonomously between phosphorylated and dephosphorylated states on a 24-h cycle in vitro by mixing with KaiA and KaiB in the presence of ATP. KaiC forms a C6 -symmetrical hexamer, which is a double ring structure of homologous N-terminal and C-terminal domains termed CI and CII, respectively. Here, through the characterization of an isolated CII domain protein, CIIKaiC , we show that phosphorylation of KaiC Thr432 destabilizes the hexameric state of the CII ring to a monomeric state. The results suggest that the stable hexameric CI ring acts as a molecular bundle to hold the CII ring, which undergoes dynamic structural changes upon phosphorylation. PMID- 29265369 TI - The genetics of egg retention and fertilization success in Drosophila: One step closer to understanding the transition from facultative to obligate viviparity. AB - Oviparous, facultative egg retention enables Drosophila females to withhold fertilized eggs in their reproductive tracts until circumstances favor oviposition. The propensity to retain fertilized eggs varies greatly between species, and is correlated with other reproductive traits, such as egg size and ovariole number. While previous studies have described the phenomenon, no study to date has characterized within-species variation or the genetic basis of the trait. Here, we develop a novel microscope-based method for measuring egg retention in Drosophila females and determine the range of phenotypic variation in mated female egg retention in a subset of 91 Drosophila Genetic Reference Panel (DGRP) lines. We inferred the genetic basis of egg retention using a genome wide association study (GWAS). Further, the scoring of more than 95,000 stained, staged eggs enabled estimates of fertilization success for each line. We found evidence that ovary- and spermathecae-related genes as well as genes affecting olfactory behavior, male mating behavior, male-female attraction and sperm motility may play a crucial role in post-mating physiology. Based on our findings we also propose potential evolutionary routes toward obligate viviparity. In particular, we propose that the loss of fecundity incurred by viviparity could be offset by benefits arising from enhanced mate discrimination, resource specialization, or modified egg morphology. PMID- 29265370 TI - Mitochondrial dynamics, mitophagy and biogenesis in neonatal hypoxic-ischaemic brain injury. AB - Hypoxic-ischaemic encephalopathy, resulting from asphyxia during birth, affects 2 3 in every 1000 term infants and depending on severity, brings about life changing neurological consequences or death. This hypoxic-ischaemia (HI) results in a delayed neural energy failure during which the majority of brain injury occurs. Currently, there are limited treatment options and additional therapies are urgently required. Mitochondrial dysfunction acts as a focal point in injury development in the immature brain. Not only do mitochondria become permeabilised, but recent findings implicate perturbations in mitochondrial dynamics (fission, fusion), mitophagy and biogenesis. Mitoprotective therapies may therefore offer a new avenue of intervention for babies who suffer lifelong disabilities due to birth asphyxia. PMID- 29265371 TI - Training class inclusion responding in typically developing children and individuals with autism. AB - In a class inclusion task, a child must respond to stimuli as being involved in two different though hierarchically related categories. This study used a Relational Frame Theory (RFT) paradigm to assess and train this ability in three typically developing preschoolers and three individuals with autism spectrum disorder, all of whom had failed class inclusion tests. For all subjects, relational training successfully established the target repertoire and subsequent testing demonstrated both maintenance and generalization. Limitations and future research directions are discussed. PMID- 29265373 TI - Mechanisms of neuroprotection against ischemic insult by stress-inducible phosphoprotein-1/prion protein complex. AB - Stress-inducible phosphoprotein 1 (STI1) acts as a neuroprotective factor in the ischemic brain and its levels are increased following ischemia. Previous work has suggested that some of these STI1 actions in a stroke model depend on the recruitment of bone marrow-derived stem cells to improve outcomes after ischemic insult. However, STI1 can directly increase neuroprotective signaling in neurons by engaging with the cellular prion protein (PrPC ) and activating alpha7 nicotinic acetylcholine receptors (alpha7nAChR). Given that alpha7nAChR activation has also been involved in neuroprotection in stroke, it is possible that STI1 can have direct actions on neurons to prevent deleterious consequences of ischemic insults. Here, we tested this hypothesis by exposing primary neuronal cultures to 1-h oxygen-glucose deprivation (OGD) and reperfusion and assessing signaling pathways activated by STI1/PrPC . Our results demonstrated that STI1 treatment significantly decreased apoptosis and cell death in mouse neurons submitted to OGD in a manner that was dependent on PrPC and alpha7nAChR, but also on the activin A receptor 1 (ALK2), which has emerged as a signaling partner of STI1. Interestingly, pharmacological inhibition of the ALK2 receptor prevented neuroprotection by STI1, while activation of ALK2 receptors by bone morphogenetic protein 4 (BMP4) either before or after OGD was effective in decreasing neuronal death induced by ischemia. We conclude that PrPC /STI1 engagement and its subsequent downstream signaling cascades involving alpha7nAChR as well as the ALK2 receptor may be activated in neurons by increased levels of STI1. This signaling pathway protects neurons from ischemic insults. PMID- 29265372 TI - The role of phospholipid molecular species in determining the physical properties of yeast membranes. AB - In most eukaryotes, including Saccharomyces cerevisiae, glycerophospholipids are the main membrane lipid constituents. Besides serving as general membrane 'building blocks', glycerophospholipids play an important role in determining the physical properties of the membrane, which are crucial for proper membrane function. To ensure optimal physical properties, membrane glycerophospholipid composition and synthesis are tightly regulated. This review will summarize our current knowledge of factors and processes determining the membrane glycerophospholipid composition of the reference eukaryote S. cerevisiae at the level of molecular species. Extrapolating from relevant model membrane data, we also discuss how modulation of the molecular species composition can regulate membrane physical properties. PMID- 29265374 TI - Auxin molecular field maps define AUX1 selectivity: many auxin herbicides are not substrates. AB - Developmental responses to auxin are regulated by facilitated uptake and efflux, but detailed molecular understanding of the carrier proteins is incomplete. We have used pharmacological tools to explore the chemical space that defines substrate preferences for the auxin uptake carrier AUX1. Total and partial loss of-function aux1 mutants were assessed against wild-type for dose-dependent resistance to a range of auxins and analogues. We then developed an auxin accumulation assay with associated mathematical modelling to enumerate accurate IC50 values for a small library of auxin analogues. The structure activity relationship data were analysed using molecular field analyses to create a pharmacophoric atlas of AUX1 substrates. The uptake carrier exhibits a very high level of selectivity towards small substrates including the natural indole-3 acetic acid, and the synthetic auxin 2,4-dichlorophenoxyacetic acid. No AUX1 activity was observed for herbicides based on benzoic acid (dicamba), pyridinyloxyacetic acid (triclopyr) or the 6-arylpicolinates (halauxifen), and very low affinity was found for picolinic acid-based auxins (picloram) and quinolinecarboxylic acids (quinclorac). The atlas demonstrates why some widely used auxin herbicides are not, or are very poor substrates. We list molecular descriptors for AUX1 substrates and discuss our findings in terms of herbicide resistance management. PMID- 29265375 TI - Millisecond precision temporal encoding of stimulus features during cortically generated gamma oscillations in the rat somatosensory cortex. AB - KEY POINTS: Rodents explore their immediate environment using their whiskers. Such exploration leads to micromotions, which contain many high-frequency (50-200 Hz) components. High-frequency whisker motion is represented faithfully in the temporal structure of the spike trains of trigeminal neurons. However, the representation of high-frequency sensory inputs in cortex is not fully understood. By combining extracellular and intracellular recordings in the rat somatosensory cortex and thalamus, we show that high-frequency sensory inputs, either sinusoidal or white noise, elicit internally generated gamma (20-60 Hz) band oscillations in cortical networks. Gamma oscillations modulate cortical spike probability while preserving sub-millisecond phase relations with high frequency sensory inputs. Consequently, our results indicate that millisecond precision stimulus-locked spiking activity and sensory-induced gamma oscillation can constitute independent multiplexed coding schemes at the single-cell level. ABSTRACT: In the natural environment, tactile exploration often leads to high frequency vibrations at the level of the sensory organs. Single-unit recordings of cortical neurons have pointed towards either a rate or a temporal code for representing high-frequency tactile signals. In cortical networks, sensory processing results from the interaction between feedforward inputs relayed from the thalamus and internally generated activity. However, how the emergent activity represents high-frequency sensory input is not fully understood. Using multisite single-unit, local field potential and intracellular recordings in the somatosensory cortex and thalamus of lightly sedated male rats, we measured neuronal responses evoked by sinusoidal and band-pass white noise whisker stimulation at frequencies that encompass those observed during texture exploration (50-200 Hz). We found that high-frequency sensory inputs relayed from the thalamus elicit both sub-millisecond stimulus-locked responses and internally generated gamma (20-60 Hz) band oscillations in cortical networks. Gamma oscillations modulate spike probability while preserving sub-millisecond phase relations with sensory inputs. Therefore, precise stimulus-locked spiking activity and sensory-induced gamma oscillations can constitute independent multiplexed coding schemes at the single-cell level. PMID- 29265377 TI - PCR procedure for detecting the fish pathogen Tenacibaculum dicentrarchi. PMID- 29265376 TI - Effects of Withdrawal from Chronic Intermittent Ethanol Exposure on Sleep Characteristics of Female and Male Mice. AB - BACKGROUND: Sleep disruptions are an important consequence of alcohol use disorders. There is a dearth of preclinical studies examining sex differences in sleep patterns associated with ethanol (EtOH) dependence despite documented sex differences in alcohol-related behaviors and withdrawal symptoms. The purpose of this study was to investigate the effects of chronic intermittent EtOH on sleep characteristics in female and male mice. METHODS: Female and male C57BL6/J mice had access to EtOH/water 2-bottle choice (2BC) 2 h/d for 3 weeks followed by exposure to EtOH vapor (vapor-2BC) or air for 5 cycles of 4 days. An additional group never experienced EtOH (naive). Mice were implanted with electroencephalographic (EEG) electrodes, and vigilance states were recorded across 24 hours on the fourth day of withdrawal. The amounts of wakefulness, slow wave sleep (SWS), and rapid eye movement sleep were calculated, and spectral analysis was performed by fast Fourier transformation. RESULTS: Overall, vapor 2BC mice showed a decrease in the amount of SWS 4 days into withdrawal as well as a decrease in the power density of slow waves, indicating disruptions in both the amount and quality of sleep in EtOH-dependent mice. This was associated with a decrease in duration and an increase in number of SWS episodes in males and an increase in latency to sleep in females. CONCLUSIONS: Our results revealed overall deficits in sleep regulation in EtOH-dependent mice of both sexes. Female mice appeared to be more affected with regard to the triggering of sleep, while male mice appeared more sensitive to disruptions in the maintenance of sleep. PMID- 29265378 TI - Purinergic signalling displays an anti-inflammatory profile in the spleen of fish experimentally infected with Aeromonas caviae: Modulation of the immune response. AB - Extracellular adenosine triphosphate (ATP) and its metabolite adenosine (Ado) are recognized as key mediators of immune and inflammatory responses. Depending on its concentration, ATP may act as an immunostimulant or immunodepressant, while Ado levels display an anti-inflammatory profile. The aim of this study was to evaluate whether splenic purinergic signalling is capable of modulating immune and inflammatory responses in fish experimentally infected with Aeromonas caviae. Triphosphate diphosphohydrolase (NTPDase) and 5'-nucleotidase activities increased in the spleen of silver catfish (Rhamdia quelen) experimentally infected with A. caviae compared with the uninfected control group. Moreover, splenic Ado levels increased in the infected animals relative to the uninfected control group. Based on these lines of evidence, our findings revealed that adenine nucleotide hydrolysis is modified in the spleen of fish infected with A. caviae attempting to restrict the inflammatory process through the upregulation of NTPDase and 5'-nucleotidase activities, which occurs in an attempt to hydrolyse the excessive ATP in the extracellular environment and rapidly hydrolyse AMP to form Ado. In summary, purinergic signalling can modulate immune and inflammatory responses during A. caviae infection. PMID- 29265380 TI - Photobiomodulation in the Metabolism of Lipopolysaccharides-exposed Epithelial Cells and Gingival Fibroblasts. AB - This study assessed the effects of photobiomodulation (PBM) to cells previously exposed to lipopolysaccharides (LPS). Human gingival fibroblasts (HGF) and epithelial cells (HaCaT) were seeded in wells of 24-well plates containing complete culture medium (DMEM). After 24 h, the DMEM was replaced by serum-free DMEM, and cells were exposed to LPS of Escherichia coli (E. coli) (10 MUg mL-1 ) for 24, 48, and 72 h. The cells were subjected to specific parameters of phototherapy (PT) (LASERTable-InGaAsP-780 +/- 3 nm, 25 mW, 3 J cm-2 ). Cell proliferation (alamarBlue(r) ), viability (Trypan Blue) and synthesis of CCL2 (ELISA) were evaluated. Data were statistically analyzed by the Kruskal-Wallis and Mann-Whitney test (alpha = 5%). Proliferation and viability of both cell lines decreased after LPS treatment at 48 and 72 h. Enhanced synthesis of CCL2 by gingival fibroblasts occurred at 24 h, while epithelial cells increased synthesis of this chemokine at 48 and 72 h. PBM enhanced cell proliferation and viability in a time-dependent manner for both cell lines exposed or not to LPS, while synthesis of CCL2 by cells exposed to PT decreased over time. PBM caused biomodulatory effects on gingival fibroblasts and epithelial cells previously treated with LPS. These effects may decrease tissue inflammatory response and accelerate wound healing of oral mucosal tissue. PMID- 29265381 TI - Strong and strategic conformity understanding by 3- and 5-year-old children. AB - 'Strong conformity' corresponds to the public endorsement of majority opinions that are in blatant contradiction to one's own correct perceptual judgements of the situation. We tested strong conformity inference by 3- and 5-year-old children using a third-person perspective paradigm. Results show that at neither age, children spontaneously expect that an ostracized third-party individual who wants to affiliate with the majority group will show strong conformity. However, when questioned as to what the ostracized individual should do to befriend others, from 5 years of age children explicitly demonstrate that they construe strong conformity as a strategic means of social affiliation. Additional data suggest that strong and strategic conformity understanding from an observer's third-person perspective is linked to the passing of the language-mediated false belief theory of mind task, an index of children's emerging 'meta' ability to construe the mental state of others. Statement of contribution What is already known on this subject? 'Strong conformity' corresponds to the public endorsement of majority opinions that are in blatant contradiction to one's own correct perceptual judgements of the situation. Asch's (1956, Psychological Monographs: General and Applied, 70, 1) classic demonstration of strong conformity with adults has been replicated with preschool children: 3- to 4-year-olds manifest signs of strong conformity by reversing about thirty to forty per cent of the time their correct perceptual judgements to fit with contradictory statements held unanimously by other individuals (Corriveau & Harris, 2010, Developmental Psychology, 46, 437; Corriveau et al., 2013, Journal of Cognition and Culture, 13, 367; Haun & Tomasello, 2011, Child Development, 82, 1759). As for adults, strong conformity does not obliterate children's own private, accurate knowledge of the situation. It is in essence a public expression to fit the group and alleviate social dissonance. What does this study add? In three experiments, we explored the developmental emergence in the preschool years of strong conformity inference from a third-person perspective. Results show that by 5 years of age, and not earlier, children begin to construe strong conformity as a strategy that someone should use to gain social affiliation, even though they do not anticipate that a third-party individual would necessarily resort to such strategy. Additional data suggest that strong and strategic conformity understanding from an observer's third-person perspective is linked to the passing of the language mediated false belief theory of mind task. PMID- 29265379 TI - Pharmacogenetic Effects of Naltrexone in Individuals of East Asian Descent: Human Laboratory Findings from a Randomized Trial. AB - BACKGROUND: Genetic variation in the endogenous opioid system has been identified as 1 potential source of individual variability in naltrexone treatment outcomes. The majority of naltrexone pharmacogenetic studies have focused on a particular single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1; rs1799971; commonly known as the Asn40Asp SNP) in Caucasian samples with decidedly mixed results. The goal of this study was to test the pharmacogenetic effects of naltrexone on subjective response to alcohol and self-administration of alcohol in individuals of East Asian descent. We hypothesized that naltrexone, compared with placebo, would potentiate the aversive and sedative effects of alcohol and reduce alcohol self-administration to a greater extent in Asp40 carriers. METHODS: Participants (N = 77; Asn40Asn, n = 29; Asn40Asp, n = 34, and Asp40Asp, n = 14) completed 2 double-blinded and counterbalanced experimental sessions: one after taking naltrexone (50 mg/d) for 5 days and one after taking matched placebo for 5 days. In each experimental session, participants received a priming dose of intravenous alcohol up to the breath alcohol concentration target of 0.06 g/dl which was immediately followed by an alcohol self-administration period (1 hour). RESULTS: There were no pharmacogenetic effects observed for alcohol-induced stimulation, sedation, craving for alcohol, or alcohol self administration in the laboratory. During the self-administration period, Asp40 carriers consumed fewer drinks and had a longer latency to first drink as compared to Asn40 homozygotes. CONCLUSIONS: These findings in East Asians add to the mixed literature on naltrexone pharmacogenetics from predominantly Caucasian samples and highlight the complexity of these effects and their overall limited replicability. It is plausible that a consistent pharmacogenetic effect in tightly controlled preclinical and experimental medicine models "fades" in more complex and heterogeneous settings and samples. PMID- 29265383 TI - Personality correlates of revenge-seeking: Multidimensional links to physical aggression, impulsivity, and aggressive pleasure. AB - People differ in how much they seek retribution for interpersonal insults, slights, rejections, and other antagonistic actions. Identifying individuals who are most prone towards such revenge-seeking is a theoretically-informative and potentially violence-reducing endeavor. However, we have yet to understand the extent to which revenge-seeking individuals exhibit specific features of aggressiveness, impulsivity, and what motivates their hunt for retribution. Toward this end, we conducted three studies (total N = 673), in which revenge seeking was measured alongside these other constructs. Analyses repeatedly demonstrated that revenge-seeking was associated with greater physical (but not verbal) aggressiveness, anger, and hostility. Revenge-seeking's link to physical aggression was partially accounted for by impulses toward enjoying aggression and the tendency to use aggression to improve mood. Dominance analyses revealed that sadism explained the most variance in revenge-seeking. Revenge-seeking was associated with greater impulsive responses to negative and positive affect, as well as greater premeditation of behavior. These findings paint a picture of revenge-seekers as physically aggressive curators of anger, whose retributive acts are performed with planned malice and motivated by the act's entertaining and therapeutic qualities. PMID- 29265382 TI - Sleep Characteristics and Behavioral Problems Among Children of Alcoholics and Controls. AB - BACKGROUND: Past research has indicated that both sleep difficulties and a parental history of alcoholism increase the risk of behavioral problems. But it is not known whether sleep difficulties differentially increase the risk of problem behaviors among children of alcoholics (COAs) and controls. We compared multiple measures of sleep and the relationships between sleep and behavioral problems in these 2 groups of children. METHODS: One hundred and fifteen children aged 8 to 12 (67% COAs; 56% girls; Mage = 10.85, SDage = 1.51) participated in this study. Data presented here were taken from Time 1 of a larger prospective study designed to understand the relationship between sleep and alcohol use. All participants were naive to alcohol and other illicit drugs. Participants were asked to wear an actigraph watch on their nondominant wrist for 1 week. Parents completed the Pediatric Sleep Questionnaire and the Achenbach Child Behavior Checklist. RESULTS: Parents of COAs were more likely to rate their children as overtired compared with parents of non-COAs. Structural equation modeling analyses focusing on overall internalizing and externalizing problems did not reveal any group differences on the relationships between sleep measures and behavioral problems. Regression analyses focusing on specific behavioral problems showed that longer total sleep time, parental ratings of "sleep more" and "sleep less" than other children interacted with COA status to predict specific behavioral problems. CONCLUSIONS: Sleep difficulties and duration appear to be a general risk factor for behavioral problems in both COAs and non-COAs, yet the relationships between specific sleep parameters and behavioral problems appear to be different between the 2 groups. PMID- 29265384 TI - Is there computational support for an unprotonated carbon in the E4 state of nitrogenase? AB - In the key enzyme for nitrogen fixation in nature, nitrogenase, the active site has a metal cluster with seven irons and one molybdenum bound by bridging sulfurs. Surprisingly, there is also a carbon in the center of the cluster, with a role that is not known. A mechanism has been suggested experimentally, where two hydrides leave as a hydrogen molecule in the critical E4 state. A structure with two hydrides, two protonated sulfurs and an unprotonated carbon has been suggested for this state. Rather recently, DFT calculations supported the experimental mechanism but found an active state where the central carbon is protonated all the way to CH3 . Even more recently, another DFT study was made that instead supported the experimentally suggested structure. To sort out the origin of these quite different computational results, additional calculations have here been performed using different DFT functionals. The conclusion from these calculations is very clear and shows no computational support for an unprotonated carbon in E4 . (c) 2017 Wiley Periodicals, Inc. PMID- 29265386 TI - Outbreak of mass mortality of yearling groupers of Epinephelus (Perciformes, Serranidae) associated with the infection of a suspected new enteric Sphaerospora (Myxozoa: Myxosporea) species in South China Sea. AB - A suspected new enteric Sphaerospora species was believed to be directly associated with the mass mortality of yearling groupers of Epinephelus spp. in South China. The epizootic generally emerged from late September to late April of the following year. The infection prevalence and mortality rate were significantly negatively correlated with fish size. Clinical signs included anorexia, cachexia and extrusion of white pulp-like substance from anus after gentle pressure on the abdomen. Upon necropsy, severe intestinal oedema, thin and transparent intestinal wall, swollen spleen, kidney and gall bladder could be observed. Wet preparation of the infected samples showed large amount of typical disporous plasmodia of the genus Sphaerospora, but no mature spores were observed. Epidemiological investigation showed that this parasite exclusively infected Epinephelus groupers. Histopathologically, this species mainly infected the epithelium of intestine and kidney tubules and caused severe epithelia sloughing and the collapse of intestinal villus. Interestingly, this enteric myxosporidiosis did not cause severe emaciation of infected fish for mass mortality usually emerged within 2-3 days after appearance of clinical signs. The species was most genetically related to Sphaerospora fugu (89% sequence identity) and phylogenetically positioned within marine Sphaerospora lineage. This is the first report of enteric sphaerosporosis of groupers. PMID- 29265385 TI - Predictors of Longitudinal Trajectories of Alcohol Consumption in People with HIV. AB - BACKGROUND: Our aim was to describe alcohol consumption trajectories in a cohort of people living with HIV and determine clinical and sociodemographic predictors of each trajectory. METHODS: This is a prospective cohort study of 7,906 patients in the 7 Centers for AIDS Research Network of Integrated Clinical Systems sites. Alcohol consumption was categorized as none, moderate, and alcohol misuse. Predictors included age, race/ethnicity, depressive or anxiety symptoms, illicit drug use (opioids, methamphetamines, cocaine/crack), marijuana use, hepatitis C virus (HCV) infection, HIV transmission risk factor, and HIV disease progression. We estimated sex-stratified alcohol consumption trajectories and their predictors. RESULTS: We found 7 trajectories of alcohol consumption in men: stable nondrinking and increased drinking (71% and 29% of initial nondrinking); stable moderate, reduced drinking, and increased alcohol misuse (59%, 21%, and 21% of initial moderate alcohol use); and stable alcohol misuse and reduced alcohol misuse (75% and 25% of initial alcohol misuse). Categories were similar in women, except lack of an increase to alcohol misuse trajectory among women that begin with moderate use. Older men and women were more likely to have stable nondrinking, while younger men were more likely to increase to or remain in alcohol misuse. Minorities, people with depressive or anxiety symptoms, HCV infected individuals, and people who injected drugs were more likely to reduce use. Illicit drug use was associated with a reduction in overall drinking, while marijuana use was associated with stable moderate drinking or misuse. CONCLUSIONS: Longitudinal trajectories of increasing alcohol use and stable misuse highlight the need to integrate routine screening and alcohol misuse interventions into HIV primary care. PMID- 29265387 TI - Marked efficacy of combined three-drug therapy (Sodium Valproate, Topiramate and Stiripentol) in a patient with Dravet syndrome. AB - WHAT IS KNOWN AND OBJECTIVE: Dravet syndrome (DS) is an intractable epilepsy syndrome. The three-drug combination therapy of sodium valproate (VPA), clobazam (CLB) and stiripentol (STP) is recommended worldwide. CASE SUMMARY: We present a case of DS, in which treatment with CLB could not be continued because of the appearance of adverse reactions to it. Replacement with topiramate (TPM) proved to be markedly effective. WHAT IS NEW AND CONCLUSION: It is suggested that combination therapy with VPA, TPM and STP is for DS epilepsy. PMID- 29265388 TI - Assessing polyphenols content and antioxidant activity in coffee beans according to origin and the degree of roasting AB - Background: The roasting stage constitutes a key component in the manufacturing process of natural coffee because temperature elicits changes in bioactive compounds such as polyphenols and that Maillard-reaction compounds appear, thus affecting the product's sensory and antioxidant properties. Actual contents of these compounds may depend on which region the coffee is cultivated as well as the extent to which the beans are roasted Objectives: To determine polyphenols content and antioxidant activity in the 'Arabica' coffee type coming from various world regions of its cultivation and which have undergone industrial roasting. Also to establish which coffee, taking into account the degree of roasting (ie. light, medium and strong), is nutritionally the most beneficial Materials and Methods: The study material was natural coffee beans (100% Arabica) roasted to various degrees, as aforementioned, that had been cultivated in Brazil, Ethiopia, Columbia and India. Polyphenols were measured in the coffee beans by spectrophotometric means based on the Folin-Ciocalteu reaction, whereas antioxidant activity was measured colourimetrically using ABTS+ cat-ionic radicals Results: Polyphenol content and antioxidant activity were found to depend both on the coffee's origin and degree of roasting. Longer roasting times resulted in greater polyphenol degradation. The highest polyphenol concentrations were found in lightly roasted coffee, ranging 39.27 to 43.0 mg/g, whereas levels in medium and strongly roasted coffee respectively ranged 34.06 to 38.43 mg/g and 29.21 to 36.89 mg/g. Antioxidant activity however significantly rose with the degree of roasting, where strongly roasted coffee had higher such activity than lightly roasted coffee. This can be explained by the formation of Maillard reaction compounds during roasting, leading then to the formation of antioxidant melanoidin compounds which, to a large extent, compensate for the decrease in polyphenols during roasting Conclusions: Polyphenols levels and antioxidant activities in the studied Arabica coffee beans that had undergone roasting depended on the cultivation region of the world. Longer roasting caused a significant decline in polyphenols compound levels (from 7.3% to 32.1%) in the coffee beans. Antioxidant activities of coffee increased with roasting, despite reduced levels of natural antioxidants. From a nutritional standpoint, the most favoured coffees are those lightly or medium roasted PMID- 29265389 TI - Single-subject research designs in paediatric rehabilitation: response to Romeiser-Logan et al. PMID- 29265390 TI - The child's best interest: ethical guide or ideology? PMID- 29265391 TI - The essential symbiosis of academic and clinical neurology. PMID- 29265392 TI - A cross-sectional descriptive study of the family functioning, health and social support of hospital patients with family violence backgrounds. AB - Family violence (FV) has serious effects on the health and well-being of the family. The health sector plays a vital role in FV prevention by helping to identify abuse early, providing victims with the necessary treatment and referring patients to appropriate care. The aim of the present cross-sectional study was to describe the prevalence of FV among hospital patients, as well as to assess the association between family functioning, health and social support, considering patients as the perpetrators or victims of violence. The data were collected using a Family Functioning, Health and Social Support (FAFHES) questionnaire that was given to patients who visited a Finnish central hospital between October 2012 and April 2013. As a result, the data (N = 188) were contributed by the patients who returned the questionnaire and gave permission for a follow-up survey. The participation rate was 47%, of which 73% were women and 27% were men. Their ages ranged from 18 to 89 years. The data were analysed with quantitative methods using the unadjusted analyses and linear regression model. In total, 24% of both the male and female participants had experienced or used violence at home or in the family. Of these, 22 had been the perpetrators, and 23 had been the victims. Participants in relationships and who were living together had less violence than singles and those who were not living together. The family functioning and health of the participants who had experienced or used FV were worse than those of the participants who had not. Various patients can have an FV background, and nursing professionals are on the front line to identify and intervene in FV situations. The results of this study can be utilised in the treatment of FV victims and perpetrators by training healthcare workers to identify and intervene in violence. PMID- 29265393 TI - Lymphocytes in Sweet syndrome: A potential diagnostic pitfall. AB - BACKGROUND: Patients with Sweet syndrome (SS) have acute onset of cutaneous lesions with characteristic histopathology (dense and diffuse neutrophilic infiltrate, dermal edema, leukocytoclasis and no vasculitis) accompanied by systemic symptoms. Sometimes, only skin lesions with classic histopathologic features are seen. Although SS is considered to be a "neutrophilic dermatosis," lymphocytes are also seen on histological examination. METHODS: We evaluated the cellular infiltrate in 9 biopsies from SS lesions with routine staining and immunohistochemistry. RESULTS: Lymphocytes were present in all biopsies in variable amounts, often exceeding the number of intact neutrophils. Prominent fragmentation of neutrophils rendered some biopsies "lymphocyte-rich" on routine histologic evaluation. Myeloperoxidase was helpful in highlighting the inconspicuous neutrophilic fragments in these cases. Lymphocytes were highlighted with immunohistochemistry, and had a CD3+, CD4+, CD20(-) immunophenotype, with rare CD8+ lymphocytes. CONCLUSION: Awareness of the lymphocytic component of SS is important to avoid diagnostic errors, especially in subcutaneous lesions of SS, in which the lymphocytic infiltrate predominates in the upper parts of the dermis, while the typical neutrophilic infiltrate may be seen only in the deeper dermis and subcutis. The lymphocytic component may potentially help to differentiate lesions of SS from neutrophilic urticarial dermatosis, which has not been reported to contain a significant lymphocytic population. PMID- 29265394 TI - UPLC-MS/MS based diagnostics for epithelial ovarian cancer using fully sialylated C4-binding protein. AB - Serum levels of fully sialylated C4-binding protein (FS-C4BP) are remarkably elevated in patients with epithelial ovarian cancer (EOC) and can be used as a marker to distinguish ovarian clear cell carcinoma from endometrioma. This study aimed to develop a stable, robust and reliable liquid chromatography-hybrid mass spectrometry (UPLC-MS/MS) based diagnostic method that would generalize FS-C4BP as a clinical EOC biomarker. Glycopeptides derived from 20 MUL of trypsin digested serum glycoprotein were analyzed via UPLC equipped with an electrospray ionization time-of-flight mass spectrometer. This UPLC-MS/MS-based diagnostic method was optimized for FS-C4BP and validated using sera from 119 patients with EOC and 127 women without cancer. A1958 (C4BP peptide with two fully sialylated biantennary glycans) was selected as a marker of FS-C4BP because its level in serum was highest among FS-C4BP family members. Preparation and UPLC-MS/MS were optimized for A1958, and performance and robustness were significantly improved relative to our previous method. An area under the curve analysis of the FS-C4BP index receiver operating characteristic curve revealed that the ratio between A1958 and A1813 (C4BP peptide with two partially sialylated biantennary glycans) reached 85%. A combination of the FS-C4BP index and carbohydrate antigen-125 levels further enhanced the sensitivity and specificity. PMID- 29265398 TI - Process Improvement for Maximized Therapeutic Innovation Outcome. AB - Deconvoluting key biological mechanisms forms the framework for therapeutic discovery. Strategies that enable effective translation of those insights along the development and regulatory path ultimately drive validated clinical application in patients and populations. Accordingly, parity in What vs. How we transform novel mechanistic insights into therapeutic paradigms is essential in achieving success. Aligning molecular discovery with innovations in structures and processes along the discovery-development-regulation-utilization continuum maximizes the return on public and private investments for next-generation solutions in managing health and disease. PMID- 29265399 TI - Anti-contractile effects of perivascular adipose tissue in thoracic aorta from rats fed a high-fat diet: role of aerobic exercise training. AB - The aim of the present study was to evaluate the effects of aerobic exercise training on perivascular adipose tissue (PVAT) function in thoracic aorta from rats fed a high-fat diet. Aortic vascular reactivity was performed in sedentary (SD), trained (TR), sedentary high-fat diet (SD-HF), and trained high-fat diet (TR-HF) male Wistar rats in the absence (PVAT-) or in the presence (PVAT+) of thoracic PVAT. We also measured circulatory concentrations of leptin and tumour necrosis factor alpha (TNF-alpha), as well as the protein expressions of TNF alpha receptor 1 (TNFR1) and inducible nitric oxide synthase (iNOS) on PVAT. In the SD-HF group, the body weight, epididymal fat pad, thoracic PVAT, circulatory triglycerides, insulin, leptin and TNF-alpha were increased when compared with the SD group, whereas exercise training reduced these values in TR-HF group. The relaxing response curves to acetylcholine and sodium nitroprusside were not modified by either intervention (high-fat diet or exercise training) or the presence of PVAT. The presence of PVAT had an anti-contractile effect in response to serotonin in all groups. In SD-HF group, the increased magnitude of anti contractile effects was in parallel with an up-regulation of iNOS protein expression in PVAT without alteration in TNFR1. Exercise training was effective in normalizing the vascular reactivity in rings PVAT+ and in reducing the iNOS protein expression. Exercise training prevented the PVAT-induced alteration in thoracic aorta from rats fed a high-fat diet. PMID- 29265400 TI - Do intra-abdominal adhesions cause pain? PMID- 29265401 TI - Cost-effective surgery for better outcomes. PMID- 29265402 TI - Surgeons, insurgents and the lost Caravaggio PMID- 29265404 TI - Randomized clinical trial of duct-to-mucosa versus invagination pancreaticojejunostomy after pancreatoduodenectomy. AB - BACKGROUND: The postoperative pancreatic fistula (POPF) rate for duct-to-mucosa and invagination anastomosis after pancreatoduodenectomy is still debated. The aim of this RCT was to investigate the POPF rate for duct-to-mucosa versus invagination pancreaticojejunostomy. METHODS: Patients were stratified by pancreatic texture and diameter of the main pancreatic duct and randomized to the duct-to-mucosa or invagination group. The primary endpoint was the rate of clinically relevant POPF (defined as grade B or C). Secondary endpoints were suture material cost for pancreaticojejunostomy, drain insertion duration and duration of postoperative hospital stay. RESULTS: Some 120 patients undergoing pancreatoduodenectomy were included following consent. Clinically relevant POPF developed in six of 59 patients (10 per cent) in the invagination group and in 14 of 61 patients (23 per cent) in the duct-to-mucosa group (P = 0.077). Duration of drain insertion (6 versus 7 days respectively; P = 0.027) and postoperative hospital stay (19 versus 24 days; P = 0.015) were shorter in the invagination group. Subgroup analysis for 61 patients with a soft pancreas revealed a lower rate of clinically relevant POPF in the invagination group (10 per cent versus 42 per cent in the duct-to-mucosa group; P = 0.010). Among 20 patients with a clinically relevant POPF, the six patients in the invagination group had a shorter duration of drain insertion (38.5 days versus 49 days for 14 patients in the duct-to-mucosa group; P = 0.028) and postoperative hospital stay (42 versus 54.5 days respectively; P = 0.028). CONCLUSION: This study did not demonstrate a superiority of invagination over duct-to-mucosa pancreaticojejunostomy in the risk of POPF. However, in high-risk patients with a soft pancreas, invagination may reduce the risk of clinically relevant POPF compared with duct-to-mucosa. Registration number: UMIN000005890 (http://www.umin.ac.jp). PMID- 29265406 TI - Lessons learned about prevalence and growth rates of abdominal aortic aneurysms from a 25-year ultrasound population screening programme. AB - BACKGROUND: This study aimed to assess how the prevalence and growth rates of small and medium abdominal aortic aneurysms (AAAs) (3.0-5.4 cm) have changed over time in men aged 65 years, and to evaluate long-term outcomes in men whose aortic diameter is 2.6-2.9 cm (subaneurysmal), and below the standard threshold for most surveillance programmes. METHODS: The Gloucestershire Aneurysm Screening Programme (GASP) started in 1990. Men aged 65 years with an aortic diameter of 2.6-5.4 cm, measured by ultrasonography using the inner to inner wall method, were included in surveillance. Aortic diameter growth rates were estimated separately for men who initially had a subaneurysmal aorta, and those who had a small or medium AAA, using mixed-effects models. RESULTS: Since 1990, 81 150 men had ultrasound screening for AAA (uptake 80.7 per cent), of whom 2795 had an aortic diameter of 2.6-5.4 cm. The prevalence of screen-detected AAA of 3.0 cm or larger decreased from 5.0 per cent in 1991 to 1.3 per cent in 2015. There was no evidence of a change in AAA growth rates during this time. Of men who initially had a subaneurysmal aorta, 57.6 (95 per cent c.i. 54.4 to 60.7) per cent were estimated to develop an AAA of 3.0 cm or larger within 5 years of the initial scan, and 28.0 (24.2 to 31.8) per cent to develop a large AAA (at least 5.5 cm) within 15 years. CONCLUSION: The prevalence of screen-detected small and medium AAAs has decreased over the past 25 years, but growth rates have remained similar. Men with a subaneurysmal aorta at age 65 years have a substantial risk of developing a large AAA by the age of 80 years. PMID- 29265407 TI - Development of a simplified dysphagia assessment by dentists in older persons. AB - OBJECTIVE: This study aimed to evaluate the diagnostic accuracy of a simplified clinical examination of swallowing by dentists and the Eating Assessment Tool (EAT-10), when compared with the diagnosis provided by a speech pathologist (gold standard). METHODS: Three dentists and 1 speech pathologist clinically evaluated 265 older persons in southern Brazil, 123 were residents in long-term care and 142 were community-dwelling, all able to respond to the research protocol independently. Accuracy, sensitivity, specificity, positive and negative predictive values (+PV and -PV), and positive and negative likelihood ratios (+LR and -LR) were calculated according to standard methods. This study was approved by the Ethics Committee of the Federal University of Rio Grande do Sul. RESULTS: Mean age of the participants was 73.5 (+/-8.9) years and most of them were women (N = 157, 59.2%). The prevalence of dysphagia as diagnosed by a speech pathologist was 45.3%. The accuracy of diagnosis was 0.84 for the clinical examination of swallowing by dentists. Furthermore, sensitivity was 0.77, specificity was 0.89, +PV was 0.85, -PV was 0.83, +LR was 7.02 and -LR was 0.25. The accuracy of EAT-10 was 0.72, the sensitivity was 0.45, specificity was 0.94, +PV was 0.87, -PV was 0.67, +LR was 8.31 and -LR was 0.57. CONCLUSIONS: Simplified clinical examination of swallowing by dentists was found to be an accurate method to screen dysphagia in older persons. PMID- 29265408 TI - Estimating and testing direct genetic effects in directed acyclic graphs using estimating equations. AB - In genetic association studies, it is important to distinguish direct and indirect genetic effects in order to build truly functional models. For this purpose, we consider a directed acyclic graph setting with genetic variants, primary and intermediate phenotypes, and confounding factors. In order to make valid statistical inference on direct genetic effects on the primary phenotype, it is necessary to consider all potential effects in the graph, and we propose to use the estimating equations method with robust Huber-White sandwich standard errors. We evaluate the proposed causal inference based on estimating equations (CIEE) method and compare it with traditional multiple regression methods, the structural equation modeling method, and sequential G-estimation methods through a simulation study for the analysis of (completely observed) quantitative traits and time-to-event traits subject to censoring as primary phenotypes. The results show that CIEE provides valid estimators and inference by successfully removing the effect of intermediate phenotypes from the primary phenotype and is robust against measured and unmeasured confounding of the indirect effect through observed factors. All other methods except the sequential G-estimation method for quantitative traits fail in some scenarios where their test statistics yield inflated type I errors. In the analysis of the Genetic Analysis Workshop 19 dataset, we estimate and test genetic effects on blood pressure accounting for intermediate gene expression phenotypes. The results show that CIEE can identify genetic variants that would be missed by traditional regression analyses. CIEE is computationally fast, widely applicable to different fields, and available as an R package. PMID- 29265409 TI - Local influence diagnostics for hierarchical finite-mixture random-effects models. AB - The main objective of this paper is to evaluate the influence of individual subjects exerted on a random-effects model for repeated measures, where the random effects follow a mixture distribution. The diagnostic tool is based on local influence with perturbation scheme that explicitly targets influences resulting from perturbing the mixture component probabilities. Bruckers, Molenberghs, Verbeke, and Geys (2016) considered a similar model, but focused on influences stemming from perturbing a subject's likelihood contributions as a whole. We also compare the two types of perturbation. Our results are illustrated using linear mixed models fitted to data from three studies. A simulation study is also conducted in order to strengthen the result from case studies. PMID- 29265410 TI - Diagnostic criteria, severity classification and guidelines of lichen sclerosus et atrophicus. AB - We established diagnostic criteria and severity classification of lichen sclerosus et atrophicus, because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there is no clinical guideline for lichen sclerosus et atrophicus in Japan, so we proposed its clinical guideline. The clinical guidelines were formulated by clinical questions and recommendations on the basis of evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guidelines easy to use and reliable including the newest evidence, and to present guidance for various clinical problems in treatment of lichen sclerosus et atrophicus. PMID- 29265411 TI - A deeper look at two concepts of measuring gene-gene interactions: logistic regression and interaction information revisited. AB - Detection of gene-gene interactions is one of the most important challenges in genome-wide case-control studies. Besides traditional logistic regression analysis, recently the entropy-based methods attracted a significant attention. Among entropy-based methods, interaction information is one of the most promising measures having many desirable properties. Although both logistic regression and interaction information have been used in several genome-wide association studies, the relationship between them has not been thoroughly investigated theoretically. The present paper attempts to fill this gap. We show that although certain connections between the two methods exist, in general they refer two different concepts of dependence and looking for interactions in those two senses leads to different approaches to interaction detection. We introduce ordering between interaction measures and specify conditions for independent and dependent genes under which interaction information is more discriminative measure than logistic regression. Moreover, we show that for so-called perfect distributions those measures are equivalent. The numerical experiments illustrate the theoretical findings indicating that interaction information and its modified version are more universal tools for detecting various types of interaction than logistic regression and linkage disequilibrium measures. PMID- 29265412 TI - Association between the clinical and histopathological classifications of actinic keratosis and the efficacy of topical imiquimod treatment. AB - We investigated the association between the clinical and histopathological classifications of actinic keratosis (AK) and the efficacy of topical imiquimod treatment. Forty patients (55 lesions) with AK were treated with topical 5% imiquimod and the efficacy of imiquimod for AK was evaluated based on the clinical/histopathological changes. The complete remission (CR) rates in patients with the different clinical classifications of AK were 85.4% (erythematous type) and 46.2% (hyperkeratotic type). The CR rates in the different histopathological classifications of AK were 80% (hypertrophic type), 81.8% (atrophic type) and 42.9% (bowenoid type). The results revealed that determining the clinical and histopathological type of AK was important for selecting a therapeutic method. The topical imiquimod treatment could be expected to be more effective for AK clinically classified as the erythematous type, or histopathologically classified as the atrophic or hypertrophic type. However, it would be expected to be less effective for the treatment of AK clinically classified as the hyperkeratotic type or histopathologically classified as the bowenoid type. Our observations suggest that we can predict the efficacy of topical imiquimod therapy in AK by determining its clinical and histopathological type. PMID- 29265413 TI - Integrating genome-wide association study summaries and element-gene interaction datasets identified multiple associations between elements and complex diseases. AB - Chemical elements are closely related to human health. Extensive genomic profile data of complex diseases offer us a good opportunity to systemically investigate the relationships between elements and complex diseases/traits. In this study, we applied gene set enrichment analysis (GSEA) approach to detect the associations between elements and complex diseases/traits though integrating element-gene interaction datasets and genome-wide association study (GWAS) data of complex diseases/traits. To illustrate the performance of GSEA, the element-gene interaction datasets of 24 elements were extracted from the comparative toxicogenomics database (CTD). GWAS summary datasets of 24 complex diseases or traits were downloaded from the dbGaP or GEFOS websites. We observed significant associations between 7 elements and 13 complex diseases or traits (all false discovery rate (FDR) < 0.05), including reported relationships such as aluminum vs. Alzheimer's disease (FDR = 0.042), calcium vs. bone mineral density (FDR = 0.031), magnesium vs. systemic lupus erythematosus (FDR = 0.012) as well as novel associations, such as nickel vs. hypertriglyceridemia (FDR = 0.002) and bipolar disorder (FDR = 0.027). Our study results are consistent with previous biological studies, supporting the good performance of GSEA. Our analyzing results based on GSEA framework provide novel clues for discovering causal relationships between elements and complex diseases. PMID- 29265414 TI - Technical Note: Comparison of first- and second-generation photon-counting slit scanning tomosynthesis systems. AB - PURPOSE: Digital breast tomosynthesis (DBT) is an emerging tool for breast-cancer screening and diagnostics. The purpose of this study is to present a second generation photon-counting slit-scanning DBT system and compare it to the first generation system in terms of geometry and image quality. The study presents the first image-quality measurements on the second-generation system. METHOD: The geometry of the new system is based on a combined rotational and linear motion, in contrast to a purely rotational scan motion in the first generation. In addition, the calibration routines have been updated. Image quality was measured in the center of the image field in terms of in-slice modulation transfer function (MTF), artifact spread function (ASF), and in-slice detective quantum efficiency (DQE). Images were acquired using a W/Al 29 kVp spectrum at 13 mAs with 2 mm Al additional filtration and reconstructed using simple back projection. RESULT: The in-slice 50% MTF was improved in the chest-mammilla direction, going from 3.2 to 3.5 lp/mm, and the zero-frequency DQE increased from 0.71 to 0.77. The MTF and ASF were otherwise found to be on par for the two systems. The new system has reduced in-slice variation of the tomographic angle. CONCLUSIONS: The new geometry is less curved, which reduces in-slice tomographic angle variation, and increases the maximum compression height, making the system accessible for a larger population. The improvements in MTF and DQE were attributed to the updated calibration procedures. We conclude that the second generation system maintains the key features of the photon-counting system while maintaining or improving image quality and improving the maximum compression height. PMID- 29265415 TI - Isothiazolinones are still widely used in paints purchased in five European countries: a follow-up study. AB - BACKGROUND: An increasing incidence of contact allergy to methylisothiazolinone (MI) has been seen, caused, in particular, by cosmetic products and paints. A study from 2015 showed that 93.0% of paints bought in five European countries contained MI. New regulations have been discussed for paints in the EU, which may have influenced this market. OBJECTIVES: To re-evaluate the use and concentrations of MI and four other isothiazolinones in water-based wall paints. METHODS: Water-based white wall paints (n = 60) were purchased in retail stores in five European countries: Denmark, France, Germany, Sweden, and the United Kingdom. The paints were analysed for isothiazolione content by the use of high performance liquid chromatography coupled to ultraviolet detection, and the results were confirmed with high-performance liquid chromatography-tandem mass spectrometry. RESULTS: MI was identified in 55 (91.7%) of the paints, with concentrations ranging from 1.1 to 142.7 ppm. The other isothiazolinones were identified in 20.0% [methylchloroisothiazolinone (MCI)] to 88.3% [benzisothiazolinone (BIT)] of the paints. BIT concentrations varied significantly between countries, whereas MI and MCI concentrations did not. There were no statistically significant differences in MI, MCI and BIT concentrations between the current study and the 2015 study. CONCLUSIONS: MI and other isothiazolinones are widely used in paints available in Europe. Their use does not seem to be decreasing. PMID- 29265416 TI - Inflammatory biomarkers of low back pain and disc degeneration: a review. AB - Biomarkers are biological characteristics that can be used to indicate health or disease. This paper reviews studies on biomarkers of low back pain (LBP) in human subjects. LBP is the leading cause of disability, caused by various spine-related disorders, including intervertebral disc degeneration, disc herniation, spinal stenosis, and facet arthritis. The focus of these studies is inflammatory mediators, because inflammation contributes to the pathogenesis of disc degeneration and associated pain mechanisms. Increasingly, studies suggest that the presence of inflammatory mediators can be measured systemically in the blood. These biomarkers may serve as novel tools for directing patient care. Currently, patient response to treatment is unpredictable with a significant rate of recurrence, and, while surgical treatments may provide anatomical correction and pain relief, they are invasive and costly. The review covers studies performed on populations with specific diagnoses and undefined origins of LBP. Since the natural history of LBP is progressive, the temporal nature of studies is categorized by duration of symptomology/disease. Related studies on changes in biomarkers with treatment are also reviewed. Ultimately, diagnostic biomarkers of LBP and spinal degeneration have the potential to shepherd an era of individualized spine medicine for personalized therapeutics in the treatment of LBP. PMID- 29265419 TI - Designing the stem cell microenvironment for guided connective tissue regeneration. AB - Adult mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine because of their ability to self-renew and their capacity for multilineage differentiation and tissue regeneration. For connective tissues, such as ligaments or tendons, MSCs are vital to the modulation of the inflammatory response following acute injury while also interacting with resident fibroblasts to promote cell proliferation and matrix synthesis. To date, MSC injection for connective tissue repair has yielded mixed results in vivo, likely due to a lack of appropriate environmental cues to effectively control MSC response and promote tissue healing instead of scar formation. In healthy tissues, stem cells reside within a complex microenvironment comprising cellular, structural, and signaling cues that collectively maintain stemness and modulate tissue homeostasis. Changes to the microenvironment following injury regulate stem cell differentiation, trophic signaling, and tissue healing. Here, we focus on models of the stem cell microenvironment that are used to elucidate the mechanisms of stem cell regulation and inspire functional approaches to tissue regeneration. Recent studies in this frontier area are highlighted, focusing on how microenvironmental cues modulate MSC response following connective tissue injury and, more importantly, how this unique cell environment can be programmed for stem cell-guided tissue regeneration. PMID- 29265418 TI - Current perspectives on biological approaches for osteoarthritis. AB - Musculoskeletal injuries that disrupt the structure and function of diarthrodial joints can cause permanent biomechanical alterations and lead to a more severe, chronic condition. Despite advancements that have been made to restore tissue function and delay the need for joint replacement, there are currently no disease modifying therapies for osteoarthritis (OA). To reduce the risk of OA, innovative preventive medicine approaches have been developed over the last decade to treat the underlying pathology. Several biological approaches are promising treatment modalities for various stages of OA owing to their minimally invasive nature and actively dynamic physiological mechanisms that attenuate tissue degradation and inflammatory responses. Individualized growth factor and cytokine therapies, tissue-engineered biomaterials, and cell-based therapies have revolutionary potential for orthopedic applications; however, the paucity of standardization and categorization of biological components and their counterparts has made it difficult to determine their clinical and biological efficacy. Cell-based therapies and tissue-engineered biologics have become lucrative in sports medicine and orthopedics; nonetheless, there is a continued effort to produce a biological treatment modality tailored to target intra-articular structures that recapitulates tissue function. Advanced development of these biological treatment modalities will potentially optimize tissue healing, regeneration, and joint preservation strategies. Therefore, the purpose of this paper is to review current concepts on several biological treatment approaches for OA. PMID- 29265420 TI - Tissue-specific endothelial cells: a promising approach for augmentation of soft tissue repair in orthopedics. AB - Biologics are playing an increasingly significant role in the practice of modern medicine and surgery in general and orthopedics in particular. Cell-based approaches are among the most important and widely used modalities in orthopedic biologics, with mesenchymal stem cells and other multi/pluripotent cells undergoing evaluation in numerous preclinical and clinical studies. On the other hand, fully differentiated endothelial cells (ECs) have been found to perform critical roles in homeostasis of visceral tissues through production of an adaptive panel of so-called "angiocrine factors." This newly discovered function of ECs renders them excellent candidates for novel approaches in cell-based biologics. Here, we present a review of the role of ECs and angiocrine factors in some visceral tissues, followed by an overview of current cell-based approaches and a discussion of the potential applications of ECs in soft tissue repair. PMID- 29265421 TI - Hidradenitis suppurativa treated with wide excision and second intention healing: a meaningful local cure rate after 253 procedures. AB - BACKGROUND: Surgery is an important treatment modality for hidradenitis suppurativa (HS). Various methods of HS surgery have been described. Even though wide excision is a common surgical procedure for HS, data on the recurrence rate and patient satisfaction are scarce. OBJECTIVE: To determine the recurrence rate and patient satisfaction of HS lesional wide excision (complete excision) with secondary intention healing. METHODS: A single centre retrospective study. Hundred and twenty eligible patients were identified from our medical files, and an individualized questionnaire was sent. RESULTS: Eighty-six patents responded to our questionnaire (71.7%). Of whom, 84 patients underwent in total 253 procedures. The mean follow-up time per procedure was 36.2 months. In 37.6% of the procedures, recurrence occurred within a mean follow-up period of 3 years (after a median of 6.0 months). Total remission of an anatomical area was achieved in 49% of the procedures, whereas natural disease progression occurred in 13%. The genital region was the most prone to recurrence. The majority of the patients were glad that they had undergone the procedure and would recommend the surgical procedure to other HS patients. CONCLUSION: Lesional wide excision (complete excision) with secondary intention healing yields a meaningful local cure rate for HS and is well tolerated. PMID- 29265417 TI - Bone quality changes associated with aging and disease: a review. AB - Bone quality encompasses all the characteristics of bone that, in addition to density, contribute to its resistance to fracture. In this review, we consider changes in architecture, porosity, and composition, including collagen structure, mineral composition, and crystal size. These factors all are known to vary with tissue and animal ages, and health status. Bone morphology and presence of microcracks, which also contribute to bone quality, will not be discussed in this review. Correlations with mechanical performance for collagen cross-linking, crystallinity, and carbonate content are contrasted with mineral content. Age dependent changes in humans and rodents are discussed in relation to rodent models of disease. Examples are osteoporosis, osteomalacia, osteogenesis imperfecta (OI), and osteopetrosis in both humans and animal models. Each of these conditions, along with aging, is associated with increased fracture risk for distinct reasons. PMID- 29265422 TI - Pentoxifylline mitigates detrimental impact of chronic nonbacterial prostatitis on sperm characteristics, reproductive hormones and histopathology in rats. AB - The protective role of pentoxifylline (PTX) on sperm characteristics, reproductive hormones and histopathology following carrageenan-induced chronic nonbacterial prostatitis (CNP) was investigated in male Wistar rats. Thirty-six rats were grouped into six rats per group. Group 1 (control) received saline normal. Group 2 received a single intraprostatic dose of 3% carrageenan (50 MUl) on day 1 (CNP). Groups 3 and 5 received cernilton (standard drug) and PTX orally at 100 and 50 mg/kg for 14 consecutive days respectively. Groups 4 and 6 received a single dose of 3% carrageenan (50 MUl) intraprostatically on day 1 followed by cernilton and PTX orally at 100 and 50 mg/kg on the eighth day for 14 consecutive days respectively. Prostatic index, serum prostatic specific antigen, malondialdehyde, testosterone and luteinising hormone levels were significantly increased (p < .05), whereas serum follicle-stimulating hormone, sperm count, motility and viability were significantly decreased (p < .05) in CNP group. Histopathology of prostate revealed leucocyte infiltration, large involutions and projection into the lumen in CNP group and these aberrations were improved by PTX. According to these findings, we concluded that PTX effectively mitigated detrimental impact of CNP on sperm characteristics, reproductive hormones and histopathology in rats. PMID- 29265423 TI - PARADIGM-HF Trial: Secondary Analyses Address Unanswered Questions. AB - Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials. PMID- 29265424 TI - Bromodeoxyuridine DNA labelling reveals host and parasite proliferation in a fish myxozoan model. AB - Enteromyxum leei is a myxozoan parasite responsible for enteritis in gilthead sea bream (Sparus aurata). The parasite proliferates in the paracellular space of the intestinal epithelium and induces an inflammatory reaction. To assess intestinal cell turnover and parasite proliferation, fish were infected with the parasite by anal intubation; after 17 and 64 days, the cell proliferative marker bromodeoxyuridine (BrdU) was administered; and after 24 hr, tissue samples were taken for immunohistochemical detection. Parasite exposure induced increased epithelial and immune cell proliferation in all intestinal segments at all time points, even before parasite establishment. This increased turnover was triggered early after intubation and mainly at a local level, as shown by an increased proliferating cell nuclear antigen (pcna) gene expression only at the posterior intestine after 17 days (not found in lymphohaematopoietic organs). Incorporation of BrdU in parasite secondary and tertiary daughter cells indicated that parasite endogeny is not by schizogonial division, which uses de novo synthesis pathway of pyrimidines. Altogether, BrdU immunolabelling and pcna gene expression showed the rapid proliferative response of the fish intestines upon a myxozoan infection and how this response is effectively triggered even before the parasite reaches or establishes in the site. PMID- 29265425 TI - A "Signal On" Photoelectrochemical Biosensor Based on Bismuth@N,O-Codoped-Carbon Core-Shell Nanohybrids for Ultrasensitive Detection of Telomerase in HeLa Cells. AB - Core-shell nanohybrids (NHs) with good semiconducting properties are vital to promote optoelectronic, photocatalytic, biosensing and bioelectronics technologies. Although great process has been achieved, synthesis of NHs composed of semiconductor core and heteroatom-doped nanocarbon shell remains a challenge, and their applications in photoelectronchemical (PEC) biosensors have not been explored. Herein, the synthesis and properties of a Bi nanocrystal and N,O codoped carbon (NOC) core-shell NHs (Bi@NOC) is described, which exhibits the typical semiconducting feature with the bandgap of 1.14 eV. Also, such NHs show good biocompatibility and their surfaces bear the carboxylic groups that facilitate further assembly of an amino-modified primer DNA. By taking advantage of the excellent PEC activity of Bi@NOC NHs and the signal amplification effect of thioflavine-T, a novel "signal on" PEC aptasensor for the detection of telomerase activity is constructed. The fabricated aptasensor can detect telomerase activity from 5.0*102 to 1.0*106 HeLa cells with a low detection limit of 60 cells. Also, the aptasensor shows a wide linear response ranges, high sensitivity and good reproducibility. This work not only enriches current core shell NHs family but also offers a novel PEC biosensing platform for detecting telomerase activity that is helpful for early clinical diagnosis of cancer. PMID- 29265426 TI - YouTube as a source of information on skin bleaching: a content analysis. AB - BACKGROUND: Skin bleaching is a common, yet potentially harmful body modification practice. AIM: To describe the characteristics of the most widely viewed YouTubeTM videos related to skin bleaching. METHODS: The search term 'skin bleaching' was used to identify the 100 most popular English-language YouTube videos relating to the topic. Both descriptive and specific information were noted. RESULTS: Among the 100 manually coded skin-bleaching YouTube videos in English, there were 21 consumer-created videos, 45 internet-based news videos, 30 television news videos and 4 professional videos. Excluding the 4 professional videos, we limited our content categorization and regression analysis to 96 videos. Approximately 93% (89/96) of the most widely viewed videos mentioned changing how you look and 74% (71/96) focused on bleaching the whole body. Of the 96 videos, 63 (66%) of videos showed/mentioned a transformation. Only about 14% (13/96) mentioned that skin bleaching is unsafe. The likelihood of a video selling a skin bleaching product was 17 times higher in internet videos compared with consumer videos (OR = 17.00, 95% CI 4.58-63.09, P < 0.001). Consumer generated videos were about seven times more likely to mention making bleaching products at home compared with internet-based news videos (OR = 6.86, 95% CI 1.77 26.59, P < 0.01). CONCLUSIONS: The most viewed YouTube video on skin bleaching was uploaded by an internet source. Videos made by television sources mentioned more information about skin bleaching being unsafe, while consumer-generated videos focused more on making skin-bleaching products at home. PMID- 29265427 TI - Evidence from peroxidase polymorphism on the taxonomy and reproduction of some Sorbus populations in south-west England. AB - Peroxidase isoenzymes in stem tissue were investigated by polyacrylamide gel electrophoresis in Sorbus populations mainly from Devon, south-west England, A total of 16 bands were recognized, of which 10 were variable between individuals or populations. The sexual diploid species S. aucuparia, S. aria and S. torminalis showed individual variation within populations. Six polyploid microspecies, S. anglica, S. porrigentiformis, S. rupicola, S. vexans, S. subcuneata and S. devoniensis, and an extensive unnamed rupicola-like population on the coast of north Devon and west Somerset, consisted of individuals of essentially identical phenotype (with a few recognizable minor variants). Every microspecies had a distinctive peroxidase phenotype but S. porrigentiformis from Devon was not identical with a specimen from Leigh Woods, Bristol. Microspecies of the S. aria group have various combinations of seven bands which occur in diploid S. aria populations. S. anglica combines 'S. aria' bands with a prominent band from S. aucuparia. S. subcuneata and S. devoniensis possess four or five of the 'S. aria' bands, together with two bands which are apparently constant in S. torminalis; S. intermedia also has a peroxidase phenotype related to these species. PMID- 29265428 TI - Distribution of photosynthetically fixed carbon within root systems of Eucalyptus pilularis plants ectomycorrhizal with Pisolithus tinctorius. AB - In intact seedlings of Eucalyptus pilularis Stn. ectomycorrhizal with Pisolithus tinctorius (Pers.) Coker & Couch in growth pouches, and labelled photosynthetically with 14 C4 more radioactivity was translocated into mycorrhizal than to non-mycorrhizal roots. Results from autoradiography of intact root systems were supported by data from scintillation counting of individual root tips. Greater 14 C accumulation occurred in young than in older mycorrhizas. It is proposed that individual mycorrhizal roots act most strongly as carbon sinks early in their life and that there is a progressive reduction in the amount of photosynthate translocated to them as they age. PMID- 29265429 TI - Rate of accumulation of fructan oligomers in wheat seedlings (Triticum aestivum L.) during the early stages of chilling treatment. AB - The accumulation of soluble carbohydrates was studied during chilling of 2-week old wheat (Triticum aestivum L.) seedlings. The extracts were analysed using a C18 HPLC method separating hexoses, sucrose and a wide range of oligofructan. Isomers were recognized and their content determined. The amounts of hexoses, sucrose and the trisaccharides 1-kestose and 6-kestose increased at the beginning of the treatment. The accumulation rate of 1-kestose, the trisaccharide generally considered to be the precursor of fructan, increased ten fold with some delay. Heavier fructan accumulated even later. In leaf blades, 1-3 molecular species with a degree of polymerization from 4 to 8 were detected. Five of these accounted for 90% of this pool at day 5. In leaf bases the amount of carbohydrates was lower but more species of fructan were detected. The sequence of accumulation was the same as in the blades. These results are discussed in relation to current models ot fructan synthesis. PMID- 29265430 TI - Ultrastructural evidence for the identity of some multinucleate rhizoctonias. AB - The ultrastructure of the pore cap in ten multinucleate rhizoctonias, endophytes of non-orchids and of Microtis (Orchidaceae), was compared with that in isolates of four Sebacina species. The pore cap in all the rhizoctonias was an imperforate, disc-like structure, Slightly smaller in diameter than the flange forming the septal pore canal. The cap was formed by two Bat lamellae continuous with, but more electron-dense than, the membranes of the endoplasmic reticulum. The lamellae enclosed a lumen containing a deposit of electron-dense material. The pore cap in the rhizoctonias was indistinguishable from that in an isolate of Sebacina vermifera Oberwinkler. In contrast, the pore caps in isolates of S. calcea (Pers.: Fr.) Bres., S. umbrina Rogers and S. grisea (Pets.: Fr.) Bres., which were also imperforate and contained a band of electron dense material, were strongly dome-shaped and extended from one side of the flange to the other. PMID- 29265431 TI - The effect of arginine on rates of internalization of other amino acids by symbiotic Chlorella cells. AB - Addition of arginine to the medium of symbiotic Chlorella freshly isolated from the European strain of green hydra increases the rate of uptake of other amino acids into the cells via a general amino acid permease. Uptake rates increase immediately upon addition of arginine, reaching a new stable level after 20-30 min. Removal of arginine causes an immediate decrease in uptake rates. Changes in the Km and Vmax of amino-acid uptake in the presence of arginine, and the fact that cycloheximide treatment does not inhibit the arginine-stimulated increase, suggest that arginine does not induce synthesis of new transport protein. Instead, arginine may alter properties of the cell membrane such as charge, thereby increasing the efficiency of uptake of amino acids by existing transport mechanisms. The significance of this novel effect is discussed in terms of possible control of amino acid supply to the symbiotic Chlorella. PMID- 29265432 TI - Fructan biosynthesis in excised leaves of Lolium temulentum L.: IV. Cell-free 14 C labelling of specific oligofructans at low sucrose concentration. AB - Analyses of the kinetic properties and products of fructosyl transferases from Lolium temulentum L. suggest that these enzymes are artifacts of conventional extinction and/or assay methods. An alternative approach to the investigation of fructan biosynthesis in cell-free extracts has been developed. This approach employs the Sensitivity of radiotraeers to overcome the limitations of conventional quantitative methods for the analysis of fructan. Homogenates of leaves were prepared, which contained enzyme protein, endogenous sucrose and fructan. These extracts catalysed the rapid and efficient incorporation of radioactivity from [U-14 C]sucrose into material with a decree of polymerization greater than 2. The chromatographic pattern of these labelled products was identical to the pattern of native leaf fructan. Kestose, which does not accumulate to high concentrations in vivo but was a major product of our previous enzyme assay procedures, was not a product of these homogenates. The flux of radioactivity into oligofructan was sufficient to account for observed rates of fructan accumulation in the leaf And fructosyl transfer was observed at sucrose concentrations between 15 and 30 mol m-3 , which is within the probable physiological range of substrate concentration for L. temulentum leaf cells. Extracts derived from leaves which were not actively accumulating fructan were unable to label oligofructan. Labelling of fructan was not due to non-enzymic isotope exchange. Leal homogenates contained invertase and fructan hydrolase activities. Invertase activity was inhibited by pyridoxal HCl and pyridoxine MCI when these compounds were included in reactions at 20 mol m-3 . Inhibition of invertase activity was correlated with a marked stimulation of fructosyl transfer, suggesting competition for substrate. Because this system functions at physiologically relevant sucrose concentrations and produces a pattern of labelled products identical to native leaf fructan, we suggest that it represents a more convincing starting point for studies of the enzymology of fructan biosynthesis than previous cell-free extracts. PMID- 29265433 TI - Ectomycorrhizal mediation of competition between coniferous tree species. AB - To test the effect of ectomycorrhizal fungi (EMF) on interactions between host plants, Pseudotsuga menziesii (Mirb.) Franco and Pinus ponderosa Dougl. ex. Laws., seedlings were grown in replacement series in pasteurized soil with (a) no EMF added, (A) two EMF species added - Rhizopogon vinicolor Smith (specific to Douglas-fir) and R. ochraceorubens Smith (specific to pine), and (c) tour EMF species added - the two Rhizopogon species plus two host generalists, Laccaria laccata (Scop, ex Fr.) Bk. & Br, and Hebeloma crustuliniforme (Bull.) Quel. A replacement series in unpasteurized forest soil also was included. Seedlings without added EMF were colonized by the greenhouse contaminant, Thelephora terrestris. Without added EMF (but with T. terrestris), the tree species mutually inhibited one another, producing Relative Yield Totals significantly < 1; with EMF added, mutual inhibition disappeared. With four EMF species added, Pseudotsuga menziesii seedlings were significantly larger in mixture than in monoculture, with no corresponding decrease in the size of Pinus ponderoso seedlings; this was due solely to seedlings with L. laccata, which apparently enhanced nitrogen (N) and phosphorus (P) uptake by Pseudotsuga menziesii at the expense of luxury consumption by Pinus ponderosa. Graphical analysis suggested that better growth of Pseudotosuga menziesii in mixture with EMF added was related to improved P nitrogen. Both N and P nutrition of Pinus ponderosa was better in mixture with two than no EMF species added; there was no clear nutrient effect with four EMF species added. Results indicate that EMF can reduce competition between plant species and perhaps increase overall community P uptake. However, patterns were specific to both EMF and tree species and were quite different in unpasteurized soils. Hence generalizations about the effects of EMF on plant-plant interactions must be made cautiously. PMID- 29265434 TI - Morphological features of pericycle cells in relation to their topographical location in onion adventitious roots. AB - Analysis of cell length, cross-sectional area and nuclear length of pericycle cells in adventitious roots of Allium cepa L. has revealed the existence of three cell types whose topographical location is related to the vascular pattern. Cells opposite the xylem are short and narrow with an elongated nucleus. The intervening cells are also short but their cross-sectional area is much greater than that of cells at the xylem pofes, while their nucleus is relatively short. Cells opposite the phloem are long, with an elongated nucleus, and their cross sectional area is intermediate between that of the other two cell types. Lateral root primordia are always initiated from the population of short cells opposite the xylem. However, the different cell types appear in the pericycle before primordial initiation and not as a result of this event. PMID- 29265435 TI - Longitudinal and transverse profiles of K+ and Cl- concentration in 'low-' and 'high-salt' barley roots. AB - The concentrations of K+ and Cl- in meristematic and differentiated cells of barley (Hordeum Vulgare. L. ev. California Mariout) roots were determined by means of quantitative X-ray microanalysis. In roots of seedlings grown in 0.5 mM CaSO4 ('low-salt' roots), the mean cytoplasmic K+ concentration of meristematic cells was 194 mM, while the average vacuolar concentrations at 10, 50 and 100 mm from the root tip were 62,25 and 22 mM, respectively. Such marked differences in vacuolar K+ concentration of differentiated cells were not found in roots of seedlings grown in full strength Johnson solution ('high-salt' roots). Thus the maintenance of K+ at a relatively high concentration in the cytoplasm of meristematic cells of 'low-salt' roots appears to be a priority requirement. The mean Cl- concentration in the cytoplasm of meristematic cells of 'low-salt' roots was 4.6 mM, and the vacuolar Cl- concentration declined towards the root base. These measured concentrations are compatible with previous data, indicating that X-ray microanalysis of fully-hydrated samples, used together with colloidal graphite mixtures as standards, provides a reliable means of measuring ion concentrations at the subcellular level. PMID- 29265436 TI - Fluxes of atmospheric hydrogen sulphide to plant shoots. AB - Short-term exposure of maize, pumpkin, spinach and spruce to various atmospheric H2 S concentrations resulted in high H2 S fluxes to the shoots. In all species an almost linear relation was observed between flux and H2 S concentration up to around 0.3 MUl -1 . At higher H2 S concentrations the flux reached a maximum, which was about 0.08, 0.04, 0.1 and 0.03 MUmol g f. wt-1 h-1 for maize, pumpkin, spinach and spruce, respectively. The transpiration rate was not affected during H2 S exposure. Up to a level of 0.3 MUl 1-1 , the shoot conductance for a influx of the various species varied between 61 and 92% of that predicted from shoot conductance for aqueous vapour efflux. There was no relation between the H2 S flux to the shoots and the sensitivity of the species towards H2 S. A 12 days' exposure of maize, pumpkin and spinach to 0.75 MUl 1-1 H2 S resulted in a reduction of shoot yield of 1.36 and 69%, respectively. H2 S flux to the shoots of pumpkin, spinach and spruce remained rather constant during exposure for three or four days to about 0.22MUl l-l H2 S. Even at a concentration of about 0.8 MUl 1-1 H2 , which reduced the growth of pumpkin and spinach, the fluxes remained nearly constant. Fluxes of H2 S to the shoots did, however, vary diurnally, being high during the light and low during the dark period. The H2 S flux to transpiration ratio was constant during both light and dark periods, indicating that uptake was predominantly via the stomata. Only part of the total flux of H2 S to the shoots of pumpkin and spinach could be recovered in the water-soluble non-protein sulphydryl fraction of the shoots (maximum 34%). It is proposed that cysteine synthase is directly involved in the fixation and metabolism of atmospheric H2 S by the plant. PMID- 29265437 TI - Effects of nutrients on the distribution of dry mass, nitrogen and phosphorus in seedlings of Protea repens (L.) L. (Proteaceae). AB - The response of seedlings of the sclerophyllous shrub, Protea repens (L.) 1., to increasing concentrations of phosphorus (P), nitrogen (N) and a mixture of all essential nutrients excluding N and P (M) was determined in potted Clovelly soil collected Irotn a lowland fynbos site at pella, south-western Cape, South Africa. Pot culture resulted in increased soil mineral nitrogen, in particular nitrate, and decreased available (resin-extractable) phosphorus concentrations compared to field soil. High amounts of N (4-64 g m2 N) and M addition resulted in seedling mortality. Plant dry mass, leaf area and phosphorus and nitrogen contents increased in response to increasing application of N, but no significant differences were found in response to M. Increasing applications of N resulted in reduced plant dry mass, leaf area and phosphorus content. These patterns of mortality and growth are interpreted as a response to an imbalance between nitrogen and phosphorus availability. These results are compared to the response of mature fynbos shrubs to fertilizer additions in the field and the responses of pot-sclerophyllous plants from other Mediterranean-type ecosystems. PMID- 29265438 TI - The possibility of determining the age of colonies of clonally propagating herbaceous species from historic records: the case of Aster novi-belgii L. (first recorded as A. salignus Willd.) at Wicken Fen Nature Reserve, Cambridgeshire, England. AB - For a number of species, population biologists have estimated the age of apparent clones. In studying a colony of naturalized Aster novi-belgii L. (first recorded as Aster salignus Willd.) growing at Wicken Fen Nature Reserve, Cambridgeshire, England, we have attempted to determine from a considerable body of historic records, its age, structure and development. While it is highly likely that the records refer to the colony in its present position on the Fen, there is uncertainty about its age and conflicting information about its position. A. novi belgii is a self-incompatible species. Plants of the Wicken colony exhibit little variation and preliminary tests show that their achenes are sterile. As a working hypothesis, for further testing, we suggest that all the plants may be of a single clone. Population biologists, who are interested in determining the age and development of clones of plants, are likely to be disappointed both by the extent and the vagueness of historic records. This situation is understandable as the information was recorded for taxonomic purposes. The hope is expressed that the intensive studies now being made of populations of plants will result in the long-term survival in the public domain of detailed records and maps, which will enable future generations to study the age and development of clones of herbaceous species. PMID- 29265439 TI - Oxalic acid induced cytological alterations differ in beans tolerant or susceptible to white mould. AB - Leaf tissues of two white bean (Phuscolus vulgaris L.) cultivars, one susceptible and one tolerant to white mould [Sclerotinia sclerotinrum (Lib.) de Bary], were treated for different times with oxalic acid. Tissues were prepared by both thin sectioning and freeze-fraeture techniques for electron microscopy. The plasma membrane of the resistant cultivar appeared more tolerant to damage induced by oxalic acid than that of the susceptible cultivar. At the same concentration of oxalic acid the plasma membrane and chloroplasts of the susceptible cultivar were affected more, and ruptured more quickly, than those of the tolerant one. In thin sections, the ruptured organelles were partially or completely disorganized. In replicas of freeze-fractured preparations of the plasma membrane, increased protrusions, wrinkles, breakages and ruptures were associated with increasing exposure to oxalic acid. Damage was more severe in the plasma membrane of the susceptible cultivar than in that of the tolerant one. Measurements of the conductivity of water bathing leaf discs of the two cultivars showed that the susceptible cultivar led to a higher conductivity than the resistant one, indicating that the injury and rupturing of the plasma membrane were closely related to membrane stability. PMID- 29265440 TI - Carbon partitioning patterns of mycorrhizal versus non-mycorrhizal plants: real time dynamic measurements using 11 CO2. AB - Gas exchange and carbon allocation patterns were studied in two populations of Panicum coloratum, an Africa C-4 grass. The plants were grown in split-root pots, containing partially sterilized soil, with one side either inoculated (I) or not inoculated (NI) with a vesicular arbuscular (VA) mycorrhizal Fungus, Gigaspora margarita. Net carbon exchange rates (CER) and stomatal conductances were measured with conventional gas exchange apparatus, and carbon assimilation, translocation, and allocation were measured using photosynthetically-fixed 11 CO2 . Mycorrhizal infection on one half of the split-root system caused a 20%, increase in CER. The effect on CER was less in tillers on the opposite side of the plants from the infected half of the roots. The rate at which photosynthates were stored in the leaves was 45% higher. Sink activity (concentration of labelled photosynthates in stem phloem tissue) more than doubled in 1 versus NI plants. CER and stomatal conductances, along with most of the carbon allocation patterns, were nearly identical between the NI (control) high grazing and low grazing ecotypes. However, VA mycorrhizal fungi caused a greater storage of photosynthates in the low grazing ecotype. PMID- 29265441 TI - Electrophoretic variation in a population of the lichen Peltigera rufescens (Weis.) Mudd. AB - Isoelectric focusing was used to investigate the distribution of enzymes exhibiting phosphoglucose isomerase, phosphoglucose mutase, malate dehydrogenase, esterase, hexokinase, glucose-6-phosphate dehydrogenase, peroxidase and fructose 1,6-bisphosphatase activities in a central Ontario population of the lichen Peltigera rufescens (Weis) Mudd. Samples of thalli were collected in order to estimate enzymatic variation in thalli collected within a site (separated by distances of 1-10 m) and between sites (separated by 5-15 km). A total of 85 different enzyme bands were identified in the 27 samples analysed. The results indicated that, at some locations, within site variation was as large as between site variation. The importance of this variation in the design of physiological studies of lichens is discussed. PMID- 29265442 TI - Fluoride-induced enhancement and inhibition of shoot growth in four taxa of Pinus. AB - Pinus elliottii Englem. Var. elliottii (PEE) and three varieties of Pinus caribaca morelet [var. caribaca barr. Et Golf. (PCC), var bahamensisi Barr. et Golf. (PCB) and var. hondurensis (PCH)] were grown at gaseous hydrogen fluoride concentrations of 0.0, 1.2, 1.8 and 4.3 MU F m-3 during a period of 200 d. Extension growth of the mainstem and lateral branches was not significantly affected by fluoride in any taxon. Overbark diameter increment at the stem base was signicantly greater at 1.2 MUg F m-3 than at 0, 1.8 or 4.3 MU F m-3 in all taxa, and also near the stem apex in PEE. Only in PEE was the stem base diameter increment lower at 4.3 MU F m-3 than in control plants. Lateral branch diameter increments were not signicantly affected by ambient fluoride concentration. Stem base diameter increments in all taxa linearly related to the rates of photosynthesis I needles 4-8 weeks old. PMID- 29265443 TI - The influence of postpartum PTSD on breastfeeding: A longitudinal population based study. AB - BACKGROUND: In most Western countries, breastfeeding rates are lower than what is recommended by the World Health Organization. Depression has been shown to influence breastfeeding outcomes; however, there is very little research on the role of postpartum posttraumatic stress disorder (PTSD). This study examined to what extent maternal postpartum PTSD predicted breastfeeding initiation, exclusive breastfeeding during the first 6 months, and continuation up to 1 and 2 years. METHODS: The study is part of the large, population-based Akershus Birth Cohort. Data from the hospital's birth record and questionnaire data from 8 weeks and 2 years postpartum were used (n = 1480). All breastfeeding variables significantly correlated with postpartum PTSD were entered into stepwise logistic regression analyses. RESULTS: Although most mothers (97.1%) initiated breastfeeding, considerably fewer adhered to the World Health Organization's breastfeeding guidelines about exclusive breastfeeding during the first 6 months (13.4%) or continued breastfeeding for 12 or 24 months postpartum (37.7% and 4.2%, respectively). Even after adjustment for important confounding variables, maternal postpartum PTSD was significantly associated with not initiating breastfeeding (aOR 5.98 [95% CI 1.79-19.97]). Postpartum PTSD was also significantly related to not continuing breastfeeding up to 12 months, although this association did not hold after adjusting for confounding variables. CONCLUSION: Identifying women at risk of not initiating breastfeeding is crucial to prevent a negative influence on infant development and the development of the mother-infant bond. Early screening and treatment of women at risk of developing postpartum PTSD might be a way forward. PMID- 29265444 TI - Allergic contact dermatitis caused by Solvent Orange 60 in spectacle frames in Japan. PMID- 29265445 TI - Allergic contact mucositis caused by metal: a covertly located permanent dental retainer. PMID- 29265446 TI - Why is occupational photocontact allergic dermatitis caused by ketoprofen rarely reported in the literature? PMID- 29265447 TI - Case report: skin injury after contact with a red spine starfish, Protoreaster lincki. PMID- 29265448 TI - Detecting photoallergic contact dermatitis with patch testing and daylight. PMID- 29265449 TI - Sensitization to diphenylmethane-diisocyanate isomers by a single accidental exposure. PMID- 29265450 TI - Can patch test sensitization with gold sodium thiosulfate be ruled out? - a case report. PMID- 29265451 TI - Delayed hypersensitivity to topical and systemic corticosteroids. PMID- 29265452 TI - Varenicline-induced acute generalized exanthematous pustulosis confirmed by patch testing. PMID- 29265453 TI - MYRF is associated with encephalopathy with reversible myelin vacuolization. AB - OBJECTIVE: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors. METHODS: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members. RESULTS: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant. INTERPRETATION: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term "MYRF-related mild encephalopathy with reversible myelin vacuolization." Our findings provide a new perspective on the pathogenesis of myelin vacuolization. Ann Neurol 2018;83:98-106. PMID- 29265454 TI - Benefits of non-surgical periodontal treatment in patients with type 2 diabetes mellitus and chronic periodontitis: A randomized controlled trial. AB - BACKGROUND: Periodontitis and diabetes are highly prevalent conditions whose association has long been recognized. OBJECTIVE: To evaluate the effect of non surgical periodontal treatment on serum HbA1c (haemoglobin A1c or glycated haemoglobin) levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 6-month, single-masked, randomized clinical trial based on 90 patients (HbA1c: 7.7% (61 mmol/mol) +/- 1.13%) who were randomly assigned to either the treatment group (oral hygiene instructions + scaling and root planing using ultrasound and Gracey curettes) or the control group (oral hygiene instructions + supragingival removal of plaque and calculus using ultrasound). Pocket depth, gingival index, and plaque index were assessed at baseline and after 3 and 6 months together with determinations of fasting plasma glucose, HbA1c, and bacterial counts. RESULTS: Treatment significantly improved the periodontal and metabolic parameters (p < .05), whereas in the control group no improvement was observed. These results were consistent with the bacteriological results in most but not all cases. CONCLUSION: Non-surgical periodontal treatment resulted in a better glycaemic status of type 2 diabetes patients and demonstrated the importance of oral health in their general health. PMID- 29265455 TI - Letter: dose-response analysis revealed closer relationship between obesity and perioperative outcomes in patients after liver transplantation. PMID- 29265456 TI - Editorial: the influence of genetic factors in mediating the effects of tobacco smoke in IBD-Authors' reply. PMID- 29265457 TI - Editorial: proton pump inhibitor therapy and liver disease progression-more cause for concern? PMID- 29265458 TI - Editorial: monitoring blood pressure is key to the safe use of beta-blockers in patients with chronic liver failure. PMID- 29265459 TI - Editorial: the IBD-disability index-ready for prime time? PMID- 29265460 TI - Editorial: rifaximin-a kick in the gut for spontaneous bacterial peritonitis? PMID- 29265461 TI - Letter: dose-response analysis revealed closer relationship between obesity and perioperative outcomes in patients after liver transplantation-Authors' reply. PMID- 29265462 TI - Editorial: the influence of genetic factors in mediating the effects of tobacco smoke in IBD. PMID- 29265463 TI - Editorial: hepatocellular carcinoma risk in the era of direct-acting anti-virals is the case closed? PMID- 29265464 TI - Editorial: there is trouble ahead, but just how much? The troubling reality of America's excesses and NAFLD. PMID- 29265465 TI - Editorial: rifaximin-a kick in the gut for spontaneous bacterial peritonitis? Authors' reply. PMID- 29265466 TI - Editorial: non-alcoholic fatty liver disease-it is better to be slender after all. PMID- 29265467 TI - Analysis of the functions of the signal peptidase complex in the midgut of Tribolium castaneum. AB - Signal peptidase complexes (SPCs) are conserved from bacteria to human beings, and are typically composed of four to five subunits. There are four genes encoding SPC proteins in the red flour beetle, Tribolium castaneum. To understand their importance to insect development, double-stranded RNA for each SPC gene was injected into red flour beetles at the early larval and adult stages. Knockdown of all four signal peptidase genes was lethal to larvae. Moreover, larvae had difficulty with old cuticle ecdysis. Knockdown of TcSPC12 alone did not affect pupal or adult development. When TcSPC12, TcSPC18, and TcSPC25 were knocked down in larvae, the melanization of hemocytes and midguts was observed. When knocked down in larvae and adults, TcSPC18 induced severe cell apoptosis in midguts, and the adult midgut lost the ability to maintain crypts after knockdown of TcSPC18, indicating its importance to midgut cell proliferation and differentiation. Knockdown of TcSPC22 or TcSPC25 also resulted in many apoptotic cells in the midguts. However, TcSPC12 appeared to be unimportant for midgut development. We conclude that TcSPC18 is essential for maintaining the adult midgut crypts. PMID- 29265468 TI - The reading accessibility index and quality of reading grid of patients with central vision loss. AB - PURPOSE: In this study we evaluated the reading accessibility index (ACC) and a quality of reading grid as assessment tools for reading and as outcome measures for reading rehabilitation of patients with central vision loss. METHODS: Reading performances on the MNRead chart (www.precision-vision.com) were reviewed from our research database. Participants were 24 controls with normal vision [mean age: 34 (SD, 14) years] and 61 patients with bilateral central vision loss [mean age: 81 (SD, 9) years] among which a subgroup of 18 patients [mean age, 76 (SD, 13) years] had undergone perceptual learning training for reading rehabilitation. The outcome measures were maximum reading speed, reading acuity, critical print size, ACC, and the reading quality. A reading quality grid that classified reading speed as spot, slow, functional, or fluent and print size as small, regular, medium, or large was used. All reading speed values were normalised (i.e., divided by 200, the average reading speed in young adults with normal vision measured with the MNRead). RESULTS: The ACC was associated perfectly with the maximum reading speed in the control group (r22 = 0.99, P < 0.001) and strongly with all parameters of reading in the patient group (smallest r value: r59 = -0.66, P < 0.001). For patients with central vision loss, reading was functional for large print, but slow for medium print and spot for regular print. For some patients with the same ACC values, the quality of reading grid revealed important performance differences. For the subgroup (n = 18) of patients who were trained, the ACC revealed a greater effect of training than the other three parameters of reading, and although there were statistically significant improvements across all print size categories, a qualitative improvement in reading was noticed only for the medium print sizes. CONCLUSIONS: The ACC is a good measure of reading performance in patients with central vision loss. Examining reading quality for different print size categories can provide a more detailed picture of reading impairment and should be considered as an outcome for rehabilitation in addition to the ACC. PMID- 29265469 TI - Reducing starbursts in highly aberrated eyes with pupil miosis. AB - PURPOSE: To test the hypothesis that marginal ray deviations determine perceived starburst sizes, and to explore different strategies for decreasing starburst size in highly aberrated eyes. METHODS: Perceived size of starburst images and visual acuities were measured psychophysically for eyes with varying levels of spherical aberration, pupil sizes, and defocus. Computationally, we use a polychromatic eye model including the typical levels of higher order aberrations (HOAs) for keratoconic and post-LASIK eyes to quantify the image quality (the visually weighted Strehl ratio derived from the optical transfer function, VSOTF) with different pupil sizes at both photopic and mesopic light levels. RESULTS: For distance corrected post-LASIK and keratoconic eyes with a night-time pupil (e.g., 7 mm), the starburst diameter is about 1.5 degrees (1 degree for normal presbyopic eyes), which can be reduced to <=0.25 degrees with pupil sizes <=3 mm. Starburst size is predicted from the magnitude of the longitudinal spherical aberration. Refracting the eye to focus the pupil margin also removed starbursts, but, unlike small pupils, significantly degraded visual acuity. Reducing pupil diameter to 3 mm improved image quality for these highly aberrated eyes by about 2.7 * to 1.7 * relative to the natural pupils when light levels were varied from 0.1 to 1000 cd m-2 , respectively. CONCLUSION: Subjects with highly aberrated eyes observed larger starbursts around bright lights at night predictable by the deviated marginal rays. These were effectively attenuated by reducing pupil diameters to <=3 mm, which did not cause a drop in visual acuity or modelled image quality even at mesopic light levels. PMID- 29265470 TI - What is the most appropriate citation metric for a clinical journal? PMID- 29265471 TI - Visual resolution and cone spacing in the nasal and inferior retina. AB - PURPOSE: To determine the retinal eccentricity at which cones are no longer an observable substitute for ganglion cells on nasal and inferior parafoveal visual acuity. METHOD: Visual acuities were measured on 12 healthy volunteers, under dynamic adaptive optic aberrations correction (crx1TM) in white light, from 0 degrees to 6 degrees , every two degrees, along the nasal and inferior retinal meridians. Cone spacing was measured on images of the retina acquired using an adaptive optic flood illumination retina camera (rtx1TM) at the same eccentricity, except at 0 degrees . RESULTS: Cone spacing increased by around 0.13 min of arc per degree of eccentricity and a difference of 7% between both meridians was observed (higher cone spacing in the inferior retinal meridian). Visual resolution was higher in the nasal retinal meridian (difference of around 28% or 0.15 logMAR at 6 degrees ). Cone spacing can predict minimum angle of resolution (MAR) at 2 degrees in both semi retinal meridians. In the inferior retinal meridian, MAR measurements are fairly well predicted by Watson's 50% mathematical model based on the midget retinal ganglion cell density. Along the nasal retinal meridian, the measured MAR lies between Watson's 50% and 100% models. CONCLUSIONS: At 2 degrees of eccentricity, cone density accurately predicts visual resolution in both the nasal and inferior retina, supporting the idea that only 50% of the foveal midget retinal ganglion cells determine VA. The 50% model can also predict VA in the inferior retinal meridian at 4 degrees and 6 degrees of eccentricity. However, the 50% model underestimated visual acuity in the nasal retinal meridian at 4 degrees and 6 degrees of eccentricity consistent with the partially overlapping ON and OFF midget retinal ganglion cell receptive fields. PMID- 29265472 TI - Prevalence of vision loss among hospital in-patients; a risk factor for falls? AB - PURPOSE: Despite poor vision being a risk factor for falls, current hospital policies and practices often do not include a vision assessment at patient admission or in the hospital's incident reporting system when a fall occurs. Our purpose was to document the prevalence of vision loss in hospital general medicine units to increase awareness of poor vision as a potential risk factor for falls that occur within the hospital, and inform future preventative practice. METHODS: This cross-sectional study took place in medicine units of an acute care hospital. Participants were adult in-patients. Visual acuity (VA), contrast sensitivity and stereoacuity were measured, and patients were screened for field loss, extinction and neglect. RESULTS: 115 participants took part (average age 67 +/- 17, 48% female). Overall, 89% had a visual impairment defined as being outside the age-norms for one or more vision measure, 62% had low vision, and 36% had vision loss equivalent to legal blindness [VA equal to or poorer than 1.0 logMAR (6/60, 20/200) or >=10x below age-norms]. There was a considerable discrepancy between the prevalence of low vision and the percentage of patients who reported an ocular diagnosis that would result in visual loss (30%). Ten patients fell during the study period, and of these 100% had visual impairment, 90% had low vision and 60% had vision loss equivalent to legal blindness, which compares to 58%, 22% and 9% for non-fallers. Similar high prevalences were found in those whose reason for admission to the hospital was a fall (92%, 63% and 33% respectively). CONCLUSIONS: Vision loss has a high prevalence among patients in hospital medicine units, and is higher still among those who fall. Since vision loss may be a contributing factor to falls that occur in hospitals, implementing an assessment of vision at hospital admission would be useful to alert staff to those patients who are at risk for falls due to poor vision, so that preventative measures can be applied. PMID- 29265473 TI - Professor David Henson - Festspiele, Manchester, January 2017. PMID- 29265474 TI - Iris colour in relation to myopia among Chinese school-aged children. AB - PURPOSE: Understanding the association of iris colour and myopia may provide further insights into the role of the wavelength of lights in the pathophysiology of myopia. We aim to assess the association of iris colour and myopia in a school based sample of Chinese students. METHODS: Two thousand three hundred and forty six Year 7 students from 10 middle schools (93.5% response rate) aged 13-14 years in Mojiang, a small county located in Southwestern China, participated in the study. We obtained standardised slit lamp photographs and developed a grading system assessing iris colour (higher grade denoting a darker iris). Refractive error was measured after cycloplegia using an autorefractor by optometrists or trained technicians. An IOLMaster (www.zeiss.com) was used to measure ocular biometric parameters including axial length (AL). RESULTS: Of all the study participants, 693 (29.5%) were affected by myopia with the prevalence estimates being higher in girls (36.8%; 95% confidence interval [CI]: 34.0, 39.6) than in boys (22.8%; 95% CI: 20.4, 25.1) (p < 0.001). After adjusting for gender, height, parental history of myopia, time spent on computer, time spent watching TV, time spent outdoors, and time spent reading and writing, participants with a darker iris colour tended to have a higher prevalence of myopia, a more myopic refraction and a longer AL. Dose-response relationships were observed in all regression models (p for trend <0.05). CONCLUSIONS: Darker iris colour was associated with more myopic refractive errors and longer ALs among Chinese school aged children and this association was independent of other known myopia-related risk factors. PMID- 29265476 TI - Intraocular light scatter, reflections, fluorescence and absorption: what we see in the slit lamp. AB - PURPOSE: Much knowledge has been collected over the past 20 years about light scattering in the eye- in particular in the eye lens- and its visual effect, called straylight. It is the purpose of this review to discuss how these insights can be applied to understanding the slit lamp image. RESULTS: The slit lamp image mainly results from back scattering, whereas the effects on vision result mainly from forward scatter. Forward scatter originates from particles of about wavelength size distributed throughout the lens. Most of the slit lamp image originates from small particle scatter (Rayleigh scatter). For a population of middle aged lenses it will be shown that both these scatter components remove around 10% of the light from the direct beam. For slit lamp observation close to the reflection angles, zones of discontinuity (Wasserspalten) at anterior and posterior parts of the lens show up as rough surface reflections. All these light scatter effects increase with age, but the correlations with age, and also between the different components, are weak. For retro-illumination imaging it will be argued that the density or opacity seen in areas of cortical or posterior subcapsular cataract show up because of light scattering, not because of light loss. NOTES: (1) Light scatter must not be confused with aberrations. Light penetrating the eye is divided into two parts: a relatively small part is scattered, and removed from the direct beam. Most of the light is not scattered, but continues as the direct beam. This non-scattered part is the basis for functional imaging, but its quality is under the control of aberrations. Aberrations deflect light mainly over small angles (<1 degrees ), whereas light scatter is important because of the straylight effects over large angles (>1 degrees ), causing problems like glare and hazy vision. (2) The slit lamp image in older lenses and nuclear cataract is strongly influenced by absorption. However, this effect is greatly exaggerated by the light path lengths concerned. This obviates proper judgement of the functional importance of absorption, and hinders the appreciation of the Rayleigh nature of what is seen in the slit lamp image. PMID- 29265475 TI - Simulation of a central scotoma using contact lenses with an opaque centre. AB - PURPOSE: This study evaluated the feasibility of using soft contact lenses (CLs) with an opaque centre to induce absolute central scotomas that move with the eye. We examined the geometrical optics prediction that scotoma size will vary with the size of the CL's opaque centre and with ocular pupil size. We also tested the hypothesis that high environmental light levels will ensure that the ocular pupil will remain small enough, even with opaque centre CLs, to generate absolute scotomas representative of those experienced by patients with age-related macular disease. METHODS: Using an Octopus 900 Perimeter ( www.Haag-Streit.com), kinetic visual fields (VFs) were measured in five normally-sighted subjects using a V4e Goldmann target with CLs that had central opaque areas with diameters of 2.8, 3.0, and 3.2 mm. To control pupil size, VFs were measured with background perimeter bowl luminances of 10, 585, and 1155 cd m-2 . Subjects attempted to (i) fixate the bowl centre; and (ii) place the scotoma edge at the bowl fixation target (eccentric viewing). RESULTS: As predicted, there was a direct relationship between scotoma size and both luminance level and diameter of the opacity. Mean scotoma diameters were 0 degrees , 17.6 degrees and 22 degrees , for the low, medium and high bowl luminances, respectively. Scotoma size was determined primarily by the difference between the diameters of CL opacity and the entrance pupil of the eye and the axial separation between them, and between subject differences in pupil diameters contributed most to the between-subject variability in scotoma diameter at each light level (SD: 6.01 degrees ). Scotoma displacement during eccentric fixation confirmed the gaze-contingent characteristics of this experimental model. CONCLUSION: It is possible to induce a gaze-contingent absolute scotoma and hence mimic central vision loss using centrally-opaque CLs provided that the CL opacity is larger than the entrance pupil of the eye. This simulation tool will, therefore, be ineffective at low environmental light levels (as shown previously) if the entrance pupil of the eye is larger than the CL opacity. PMID- 29265477 TI - There's no place like home: 35-year patient survival on home hemodialysis. AB - The vast majority of maintenance dialysis patients suffer from poor long-term survival rates and lower levels of health-related quality of life. However, home hemodialysis is a historically significant dialysis modality that has been associated with favorable outcomes as well as greater patient autonomy and control, yet only represents a small minority of the total dialysis performed in the United States. Some potential disadvantages of home hemodialysis include vascular access complications, infection-related hospitalizations, patient fatigue, and attrition. In addition, current barriers and challenges in expanding the utilization of this modality include limited patient and provider education and technical expertise. Here we report a 65-year old male with end-stage renal disease due to Alport's syndrome who has undergone 35 years of uninterrupted thrice-weekly home hemodialysis (ie, every Sunday, Tuesday, and Thursday evening, each session lasting 3 to 31/4 hours in length) using a conventional hemodialysis machine who has maintained a high functional status allowing him to work 6-8 hours per day. The patient has been able to liberalize his dietary and fluid intake while only requiring 3-4 liters of ultrafiltration per treatment, despite having absence of residual kidney function. Through this case of extraordinary longevity and outcomes after 35 years of dialysis and a review of the literature, we illustrate the history of home hemodialysis, its significant clinical and psychosocial advantages, as well as the barriers that hinder its widespread adaptation. PMID- 29265478 TI - NR5A1 mutations are not associated with male infertility in Indian men. AB - NR5A1 or steroidogenic factor 1 (SF1) is an autosomal gene, which encodes a protein that is a member of nuclear receptor family. NR5A1 regulates the transcription of numerous genes that are expressed in hypothalamic-pituitary gonadal axis and adrenal cortex which in turn, coordinate the gonadal development, steroidogenesis and sex differentiation. Several mutations in NR5A1 have been reported to cause gonadal dysgenesis with adrenal insufficiency in individuals with 46,XY karyotype. However, studies in the past few years have shown that NR5A1 mutations can also contribute to primary ovarian insufficiency and impaired spermatogenesis. As there is no genetic study on NR5A1 in Indian infertile men, we have sequenced the entire coding region (exons 2-7) of NR5A1 in 502 infertile men of which, 414 were non-obstructive azoospermic and 88 severe oligozoospermic, along with 427 ethnically matched fertile controls. Interestingly, none of the mutations reported to be associated with male infertility were found in our study, except one polymorphism, rs1110061. However, it was not significantly different between infertile and fertile groups (p = .76). In addition, we have identified six intronic variants; but none of them was significantly associated with male infertility. PMID- 29265479 TI - New approach for determination of the degradation products of fenspiride hydrochloride found in oral liquid formulations. AB - Fenspiride hydrochloride (FNS) is used in treating chronic inflammatory diseases, most commonly as a liquid oral solution. FNS produces degradation products along with fenspiride N-oxide (FNO) and 1-phenylethyl-4-hydroxy-4-aminomethyl piperidine hydrochloride (PHAP). We aimed to develop and validate a chromatographic method in order to identify the main degradation products in the presence of other compounds from a liquid preparation. The method used a dual gradient using two buffer solutions: the first with pH 4.5 (buffer 1, pH 4.5-MeOH 90:10%, v/v) and the second with pH 2.9 (buffer 2, pH 2.9-acetronitrile-methanol, 65:15:10%, v/v/v). As mentioned, there was a modification of the organic mixture, starting with 10% methanol and ending with a mixture of acetonitrile-methanol (15:10%, v/v). The flow-rate was 1.5 mL/min. According to the elution program, experimental conditions started with 100% solution S1, which decreased to 0% and, simultaneously, solution S2 increased to 100% during the first 10 min and was maintained for a further 5 min. After 15 min, initial conditions were re established. The linearity interval was 0.5-2 MUg/mL and the minimum correlation coefficient was 0.999. The recovery factor was 100.47-103.17% and the limit of quantification was 0.19-0.332 MUg/mL. Intra-day maximum precision was 4.08% for FNS and 2.65% for PHAP. This double-gradient mobile phase produced good specificity in relation to the degradation products of FNS and other constituents of the oral liquid formulation. Forced degradation studies revealed other related substances that were confirmed in mass balance analyses. Degradation products were confirmed in acidic, basic and oxidative media. PMID- 29265480 TI - Population pharmacokinetics of levetiracetam in neonates with seizures. AB - WHAT IS KNOWN AND OBJECTIVE: This study developed a population pharmacokinetic (PK) model of levetiracetam (LEV) for treating neonatal seizures (NS) and determined the influence of clinically relevant covariates to explain the interindividual variability and residual error. METHODS: Twenty newborns admitted to the Neonatal Intensive Care Unit at the Hospital Central "Dr. Ignacio Morones Prieto" were included. LEV doses were administered by intermittent infusion. Blood samples were drawn 3 times post-infusion. Levetiracetam was quantified by a chromatographic technique. NONMEM software was used to determine the population PK model of LEV in neonates and the influence of clinical covariates on drug disposition. RESULTS AND DISCUSSION: The LEV PK in neonates is described by a one compartment open model with first-order elimination. The influence of creatinine clearance (CRCL) and body weight (BW) on clearance (CL[L/h] = 0.47*CRCL), as well as the volume of the distribution (Vd[L] = 0.65*BW) of LEV, were confirmed, considering interindividual variabilities of 36% and 22%, respectively, and a residual error of 13%. WHAT IS NEW AND CONCLUSION: Based on the PK of LEV in neonates and the influence of the final PK model, a priori dosing guidelines are proposed considering CRCL, BW and LEV plasma concentrations between 6 and 20 mg/L for NS treatment. PMID- 29265481 TI - Somatostatin receptor type 2 expression in Merkel cell carcinoma as a prognostic factor. PMID- 29265482 TI - Eosinophilic solid and cystic renal cell carcinomas have metastatic potential. PMID- 29265483 TI - Affective and cooperative social interactions modulate effective connectivity within and between the mirror and mentalizing systems. AB - Decoding the meaning of others' actions, a crucial step for social cognition, involves different neural mechanisms. While the "mirror" and "mentalizing" systems have been associated with, respectively, the processing of biological actions versus more abstract information, their respective contribution to intention understanding is debated. Processing social interactions seems to recruit both neural systems, with a different weight depending on cues emphasizing either shared action goals or shared mental states. We have previously shown that observing cooperative and affective social interactions elicits stronger activity in key nodes of, respectively, the mirror (left posterior superior temporal sulcus (pSTS), superior parietal cortex (SPL), and ventral/dorsal premotor cortex (vPMC/dPMC)) and mentalizing (ventromedial prefrontal cortex (vmPFC)) systems. To unveil their causal organization, we investigated the effective connectivity underlying the observation of human social interactions expressing increasing cooperativity (involving left pSTS, SPL, and vPMC) versus affectivity (vmPFC) via dynamic causal modeling in 36 healthy human subjects. We found strong evidence for a model including the pSTS and vPMC as input nodes for the observed interactions. The extrinsic connectivity of this model undergoes oppositely valenced modulations, with cooperativity promoting positive modulations of connectivity between pSTS and both SPL (forward) and vPMC (mainly backward), and affectivity promoting reciprocal positive modulations of connectivity between pSTS and vmPFC (mainly backward). Alongside fMRI data, such divergent effective connectivity suggests that different dimensions underlying the processing of social interactions recruit distinct, although strongly interconnected, neural pathways associated with, respectively, the bottom-up visuomotor processing of motor intentions, and the top-down attribution of affective/mental states. PMID- 29265484 TI - Survey on basal blood plasma catecholamine concentrations in Martina Franca donkey (Equus asinus). AB - BACKGROUND: Catecholamines are among the most frequently investigated parameters for studying sympathoadrenal activity in response to stress conditions. OBJECTIVES: To evaluate basal plasma concentrations of catecholamines (adrenaline, noradrenaline and dopamine) in healthy donkeys. STUDY DESIGN: Cross sectional study. METHODS: Catecholamine concentrations from 440 Martina Franca donkeys were determined: 269 females and 171 entire males, aged from 4 months to 24 years. Animals were subdivided into four age categories: under 12 months old (64 males and 54 females), from 13 to 36 months (56 males and 75 females), from 37 to 120 months (49 males and 80 females) and over 120 months (24 males and 38 females). Indwelling jugular catheters were inserted at least 12 h before drawing blood. The data set was subjected to analysis of variance considering age, sex and the two-way interaction between them as independent variables. Pearson's correlation coefficients between the three catecholamines were evaluated. RESULTS: Confidence intervals (CI) for noradrenaline concentration ranged between 239.98 and 255.07 ng/L (mean 247.52 ng/L), for adrenaline between 129.27 and 137.90 ng/L (mean 133.59 ng/L), dopamine concentrations between 149.62 and 160.80 ng/L (mean 155.21 ng/L) and noradrenaline/adrenaline ratio between 1.91 and 2.05 (mean 1.98). Catecholamine plasma concentrations were not influenced by sex. Donkeys older than 37 months had lower adrenaline and noradrenaline plasma concentrations (P<0.001) and higher noradrenaline/adrenaline ratios (P<0.01) than younger animals. MAIN LIMITATIONS: Indwelling catheters and blood drawing procedures may have influenced catecholamine levels. CONCLUSIONS: Catecholamine concentrations were established within a large group of healthy Martina Franca donkeys. PMID- 29265485 TI - Correlation between invasive mammary carcinoma grade and size in ultrasound guided core needle biopsy and subsequent surgical excision. AB - The purpose of this study was to correlate the histologic grade, mitotic rate and size of invasive mammary carcinomas (IMC) on ultrasound (US) core needle biopsy (CNB) and the follow-up excision (FUE). The underestimation and overestimation of the grades by CNB were 11% and 8%. CNBs were more specific for grade 3 tumors. Tumors >10 mm by US examination showed greater concordance in grades. The size in the FUE was the best determinant of pT followed by US examination. The extent of IMC on CNB was larger than FUE in 8% resulting in pT upstaging in 3% of cases. PMID- 29265486 TI - Y chromosome microdeletions and varicocele as aetiological factors of male infertility: A cross-sectional study. AB - The pathogenic mechanisms by which varicocele disrupt spermatogenesis are not clearly understood. Over 30% of male infertility cases resulting from spermatogenic problems are associated with genetic abnormalities, and Y chromosome microdeletions are the second most frequent genetic cause. Here, we aimed to evaluate the frequency of Y chromosome microdeletion in infertile men with varicocele. A cross-sectional study comprising 51 infertile men with varicocele presenting spermatogenesis failures was performed. Y chromosome microdeletion research was made using polymerase chain reaction. Of the 51 men with infertility and varicocele, 35.3% (18/51) had nonobstructive azoospermia and 64.7% had severe oligozoospermia. Y chromosome microdeletion was found in two cases (3.9%): one patient had nonobstructive azoospermia and complete microdeletion of the AZFb and AZFc regions, and another patient had severe oligozoospermia and complete microdeletion of the AZFc region. Although in recent years, a genetic aetiology related to Y chromosome microdeletions has become a major cause of infertility in males with spermatogenesis failures, in this study, the varicocele was the clinical cause of seminal abnormalities that could lead to infertility, suggesting that both varicocele and Y chromosome microdeletion aetiologies can present, alone or combined, as factors of male infertility. PMID- 29265487 TI - Clinical Examination for Acute Aortic Dissection: A Systematic Review and Meta analysis. AB - OBJECTIVES: Acute aortic dissection is a life-threatening condition due to a tear in the aortic wall. It is difficult to diagnose and if missed carries a significant mortality. METHODS: We conducted a librarian-assisted systematic review of PubMed, MEDLINE, Embase, and the Cochrane database from 1968 to July 2016. Titles and abstracts were reviewed and data were extracted by two independent reviewers (agreement measured by kappa). Studies were combined if low clinical and statistical heterogeneity (I2 < 30%). Study quality was assessed using the QUADAS-2 tool. Bivariate random effects meta analyses using Revman 5 and SAS 9.3 were performed. RESULTS: We identified 792 records: 60 were selected for full text review, nine studies with 2,400 participants were included (QUADAS 2 low risk of bias, kappa = 0.89 [for full-text review]). Prevalence of aortic dissection ranged from 21.9% to 76.1% (mean +/- SD = 39.1% +/- 17.1%). The clinical findings increasing probability of aortic dissection were 1) neurologic deficit (n = 3, specificity = 95%, positive likelihood ratio [LR+] = 4.4, 95% confidence interval [CI] = 3.3-5.7, I2 = 0%) and 2) hypotension (n = 4, specificity = 95%, LR+ = 2.9 95% CI = 1.8-4.6, I2 = 42%), and decreasing probability were the absence of a widened mediastinum (n = 4, sensitivity = 76% 95%, negative likelihood ratio [LR-] = 0.14-0.60, I2 = 93%) and an American Heart Association aortic dissection detection (AHA ADD) risk score < 1 (n = 1, sensitivity = 91%, LR- = 0.22, 95% CI = 0.15-0.33). CONCLUSIONS: Suspicion for acute aortic dissection should be raised with hypotension, pulse, or neurologic deficit. Conversely, a low AHA ADD score decreases suspicion. Clinical gestalt informed by high- and low-risk features together with an absence of an alternative diagnosis should drive investigation for acute aortic dissection. PMID- 29265490 TI - Purpura fulminans in congenital protein C deficiency successfully treated with fresh frozen plasma and thrombomodulin. PMID- 29265489 TI - Epitaxial Single-Layer MoS2 on GaN with Enhanced Valley Helicity. AB - Engineering the substrate of 2D transition metal dichalcogenides can couple the quasiparticle interaction between the 2D material and substrate, providing an additional route to realize conceptual quantum phenomena and novel device functionalities, such as realization of a 12-time increased valley spitting in single-layer WSe2 through the interfacial magnetic exchange field from a ferromagnetic EuS substrate, and band-to-band tunnel field-effect transistors with a subthreshold swing below 60 mV dec-1 at room temperature based on bilayer n-MoS2 and heavily doped p-germanium, etc. Here, it is demonstrated that epitaxially grown single-layer MoS2 on a lattice-matched GaN substrate, possessing a type-I band alignment, exhibits strong substrate-induced interactions. The phonons in GaN quickly dissipate the energy of photogenerated carriers through electron-phonon interaction, resulting in a short exciton lifetime in the MoS2 /GaN heterostructure. This interaction enables an enhanced valley helicity at room temperature (0.33 +/- 0.05) observed in both steady-state and time-resolved circularly polarized photoluminescence measurements. The findings highlight the importance of substrate engineering for modulating the intrinsic valley carriers in ultrathin 2D materials and potentially open new paths for valleytronics and valley-optoelectronic device applications. PMID- 29265491 TI - Lack of correlation between heart, liver and pancreas MRI-R2*: Results from long term follow-up in a cohort of adult beta-thalassemia major patients. PMID- 29265493 TI - Mitteilungen der Deutschsprachigen Mykologischen Gesellschaft. PMID- 29265492 TI - Comparison of the expression of neurotransmitter and muscular genesis markers in the postnatal male mouse masseter and trigeminal ganglion during development. AB - Calcitonin gene-related peptide (CGRP) is released by motor neurons and affects skeletal muscle fiber and transient receptor potential cation channel subfamily V member 1 (TRPV1), an important marker of pain modulation. However, the expression of CGRP and TRPV1 in the trigeminal ganglion (TG) during changes and in feeding patterns has not been described. We used real-time reverse transcription polymerase chain reaction and in situ hybridization to investigate the mRNA expression levels of CGRP and TRPV1 in the TG. The expression of myosin heavy chain (MyHC) isoforms was also investigated in the masseter muscle (MM) during the transition from sucking to mastication, an important functional trigger for muscle. The mRNA and protein levels of CGRP increased in the MM and TG from postnatal day 10 (P10) to P20 in male mice. The protein levels of TRPV1 were almost constant in the TG from P10 to P20, in contrast to increases in the MM. The mRNA abundance of TRPV1 in the TG and MM was increased from P10 to P20. The localization of an antisense probe was used to count CGRP cell numbers and found to differentiate the ophthalmic, maxillary, and mandibular nerve divisions of the TG. In particular, the number of CGRP+ cells per 10,000 MUm2 in the maxillary and mandibular divisions of the TG gradually changed from P10 to P20. The expression of CGRP and TRPV1 in the TG and MM and the patterns of expression of different MyHC isoforms were affected by changes in feeding during male mouse development. PMID- 29265495 TI - Editorial. PMID- 29265496 TI - Efficacy and safety of Helicobacter pylori eradication therapy immediately after endoscopic submucosal dissection. AB - BACKGROUND AND AIMS: In the treatment of patients after endoscopic submucosal dissection (ESD), there is no consensus on the optimum time to start Helicobacter pylori eradication therapy or on whether eradication therapy improves ulcer healing rate after ESD. The aim of this study was to examine the effect of immediate eradication of H. pylori on ulcer healing after ESD in patients with early gastric neoplasms. METHODS: A total of 330 patients who underwent ESD for early gastric neoplasms were enrolled. Patients were assigned to either H. pylori eradication group (Group A: H. pylori eradication + proton pump inhibitor 7 weeks) or non-eradication group (Group B: proton pump inhibitor 8 weeks). The primary end point was gastric ulcer healing rate (Group A vs Group B) determined on week 8 after ESD. RESULTS: Patients in Group A failed to meet non-inferiority criteria for ulcer scarring rate after ESD compared with that in Group B (83.0% vs 86.5%, P for non-inferiority = 0.0599, 95% confidence interval: -11.7% to 4.7%). There were, however, neither large differences between the two groups in the ulcer scarring rate nor the safety profile. CONCLUSIONS: This study failed to demonstrate the non-inferiority of immediate H. pylori eradication therapy after ESD to the non-eradication therapy in the healing rate of ESD-caused ulcers. However, because the failure is likely to attribute to small number of patients enrolled, immediate eradication therapy may be a treatment option for patients after ESD without adverse effects on eradication therapy in comparison with the standard therapy. PMID- 29265497 TI - Different effects of chronic THC on the neuroadaptive response of dopamine D2/3 receptor-mediated signaling in roman high- and roman low-avoidance rats. AB - The Roman high (RHA)- and low (RLA)-avoidance rat sublines have been identified as an addiction-prone and addiction-resistant phenotype based on their high vs. low locomotor responsiveness to novelty and high vs. low ability to develop neurochemical and behavioral sensitization to psychostimulants, respectively. Most studies though have focused on psychostimulants and little is known about the neuroadaptive response of these two lines to cannabinoids. This study investigated the effects of chronic exposure to Delta9 -tetrahydrocannabinol (THC) on dopamine D2/3 receptor (D2/3 R) availabilities and functional sensitivity in the mesostriatal system of RHA and RLA rats. At baseline, RLA rats exhibited higher densities of mesostriatal D2/3R but lower levels of striatal CB1 R mRNA and displayed a lower locomotor response to acute THC as compared to RHAs. Following chronic THC treatment, striking changes in D2/3 R signaling were observed in RLA but not in RHA rats, namely an increased availability and functional supersensitivity of striatal D2/3 R, as evidenced by a supersensitive psychomotor response to the D2/3 R agonist quinpirole. Moreover, in RLA rats, the lower was the locomotor response to acute THC, the higher was the psychomotor response to quinpirole following chronic THC. These results showing a greater neuroadaptive response of RLA vs. RHA rats to chronic THC thus contrast with previous studies showing a resistance to neuroadaptive response of RLAs to psychostimulants, This suggests that, contrasting with their low proneness to psychostimulant drug-seeking, RLAs may exhibit a heightened proneness to cannabinoid drug-seeking as compared to RHA rats. PMID- 29265498 TI - Obesity is not associated with severe chronic urticaria in a French cohort. PMID- 29265499 TI - Long-term increases in tropical flowering activity across growth forms in response to rising CO2 and climate change. AB - Mounting evidence suggests that anthropogenic global change is altering plant species composition in tropical forests. Fewer studies, however, have focused on long-term trends in reproductive activity, in part because of the lack of data from tropical sites. Here, we analyze a 28-year record of tropical flower phenology in response to anthropogenic climate and atmospheric change. We show that a multidecadal increase in flower activity is most strongly associated with rising atmospheric CO2 concentrations using yearly aggregated data. Compared to significant climatic factors, CO2 had on average an approximately three-, four-, or fivefold stronger effect than rainfall, solar radiation, and the Multivariate ENSO Index, respectively. Peaks in flower activity were associated with greater solar radiation and lower rainfall during El Nino years. The effect of atmospheric CO2 on flowering has diminished over the most recent decade for lianas and canopy trees, whereas flowering of midstory trees and shrub species continued to increase with rising CO2 . Increases in flowering were accompanied by a lengthening of flowering duration for canopy and midstory trees. Understory treelets did not show increases in flowering but did show increases in duration. Given that atmospheric CO2 will likely continue to climb over the next century, a long-term increase in flowering activity may persist in some growth forms until checked by nutrient limitation or by climate change through rising temperatures, increasing drought frequency and/or increasing cloudiness and reduced insolation. PMID- 29265500 TI - Thiamethoxam honey bee colony feeding study: Linking effects at the level of the individual to those at the colony level. AB - Neonicotinoid insecticides have been used globally on a wide range of crops through seed treatment as well as soil and foliar applications and have been increasingly studied in relation to the potential risk to bees because of their detection in pollen and nectar of bee-attractive crops. The present article reports the results of laboratory studies (10-d adult and 22-d larval toxicity studies assessing the chronic toxicity of thiamethoxam to adult honey bees and larvae, respectively) and a colony feeding study, with 6 wk of exposure in an area with limited alternative forage, to provide a prewintering colony-level endpoint. The endpoints following exposure of individuals in the laboratory (10-d adult chronic no-observed-effect concentration [NOEC] for mortality 117 MUg thiamethoxam/kg sucrose solution, 141 MUg thiamethoxam/L sucrose solution; 22-d larval chronic NOEC 102 MUg thiamethoxam/kg diet) are compared with those generated at the colony level, which incorporates sublethal effects (no-observed adverse-effect concentration [NOAEC] 50 MUg thiamethoxam/L sucrose solution, 43 MUg thiamethoxam/kg sucrose solution). The data for sucrose-fed honey bee colonies support the lack of effects identified in previous colony-level field studies with thiamethoxam. However, unlike these field studies demonstrating no effects, colony feeding study data also provide a threshold level of exposure likely to result in adverse effects on the colony in the absence of alternative forage, and a basis by which to evaluate the potential risk of thiamethoxam residues detected in pollen, nectar, or water following treatment of bee attractive crops. Environ Toxicol Chem 2018;37:816-828. (c) 2017 SETAC. PMID- 29265501 TI - Designed Cluster Assembly of Multidimensional Titanium Coordination Polymers: Syntheses, Crystal Structure and Properties. AB - The exploitation of new titanium-based coordination polymers (Ti CPs) with high crystallinity is difficult but highly desirable for their potential applications in photocatalysis. Herein, a cluster-cooperative assemble strategy is developed to synthesize Ti CPs. By utilizing various bifunctional ligands containing carboxylate acids and N-donor groups, we successfully assembled the zero dimensional (0D) [(Ti3 O)(iPrO)8 ]2+ or [(Ti4 O2 )(iPrO)6 ]6+ clusters into one dimensional (1D) tube-, ribbon-, or helical chain-shape architectures, two dimensional (2D) layered structures, and a rare parallel 2D->three-dimensional (3D) polycatenation framework with various copper iodide dopants, including rhombus- or wing-shaped Cu2 I2 and tetrahedron- or ladder-shaped Cu4 I4 . The as synthesized compounds display strong absorption in the visible region with narrow band gaps ranging from 1.70 to 2.72 eV and exhibit good photocatalytic activities in the degradation of organic pollutants. PMID- 29265502 TI - Correlation between Ionic Liquid Cytotoxicity and Liposome-Ionic Liquid Interactions. AB - This study aims at extending the understanding of the toxicity mechanism of ionic liquids (ILs) using various analytical methods and cytotoxicity assays. The cytotoxicity of eight ILs and one zwitterionic compound was determined using mammalian and bacterial cells. The time dependency of the IL toxicity was assessed using human corneal epithelial cells. Hemolysis was performed using human red blood cells and the results were compared with destabilization data of synthetic liposomes upon addition of ILs. The effect of the ILs on the size and zeta potential of liposomes revealed information on changes in the lipid bilayer. Differential scanning calorimetry was used to study the penetration of the ILs into the lipid bilayer. Pulsed field gradient nuclear magnetic resonance spectroscopy was used to determine whether the ILs occurred as unimers, micelles, or if they were bound to liposomes. The results show that the investigated ILs can be divided into three groups based on the cytotoxicity mechanism: cell wall disrupting ILs, ILs exerting toxicity through both cell wall penetration and metabolic alteration, and ILs affecting solely on cell metabolism. PMID- 29265503 TI - On being a caregiver: The experiences of South African family caregivers caring for cancer patients. AB - The purpose of our study was to describe the experiences of family caregivers of cancer patients using the public healthcare system in South Africa. We used a qualitative descriptive design and conducted in-depth interviews with 20 purposively selected family caregivers. Data saturation determined the sample size, and qualitative content analysis was used to analyse the data. Three themes arose from the data: emotional responses and feelings towards the cancer diagnosis, fulfilling the role of the caregiver and living and coping with a changed life and a changed person. Caring for a person with cancer was not easy. Participants were overwhelmed with the care responsibilities, which were aggravated by poverty. Some felt emotionally broken and alone in this journey and experienced the rest of their family as uncaring. The lives the participants knew changed and they had to put their own lives on hold and make sacrifices involving their children, work, possible relationships and their normal activities to care for the sick person. For some, the sick person they cared for changed and became a person they did not know. Most participants used religious practices to cope with their situation; however, some used other coping mechanisms, such as recreation and even smoking. PMID- 29265504 TI - Molecular dynamics simulations on interaction between bacterial proteins: Implication on pathogenic activities. AB - We perform molecular dynamics simulation studies on interaction between bacterial proteins: an outer-membrane protein STY3179 and a yfdX protein STY3178 of Salmonella Typhi. STY3179 has been found to be involved in bacterial adhesion and invasion. STY3178 is recently biophysically characterized. It is a soluble protein having antibiotic binding and chaperon activity capabilities. These two proteins co-occur and are from neighboring gene in Salmonella Typhi-occurrence of homologs of both STY3178 and STY3179 are identified in many Gram-negative bacteria. We show using homology modeling, docking followed by molecular dynamics simulation that they can form a stable complex. STY3178 belongs to aqueous phase, while the beta barrel portion of STY3179 remains buried in DPPC bilayer with extra-cellular loops exposed to water. To understand the molecular basis of interaction between STY3178 and STY3179, we compute the conformational thermodynamics which indicate that these two proteins interact through polar and acidic residues belonging to their interfacial region. Conformational thermodynamics results further reveal instability of certain residues in extra cellular loops of STY3179 upon complexation with STY3178 which is an indication for binding with host cell protein laminin. PMID- 29265508 TI - The Investigated Question and Study Design in Cross-sectional Studies Response to 'Chronic Urticaria and the Metabolic Syndrome: a Cross-sectional Community-based Study of 11,261 Patients': Authors' Reply. PMID- 29265505 TI - Thin PEGylated Carbon Nitrides: Water-Dispersible Organic Nanodots as Bioimaging Probes. AB - Fluorescent materials are being used for the optical/fluorescence imaging of living cells and animal models. As such, the development of heavy-metal-free, water-dispersible, and biocompatible imaging probes is still important. Carbon nitride (C3 N4 ) is used as a bioimaging probe due to its suitable optical properties, thus enhancing its biocompatibility and dispersibility in aqueous media is required. In this study, we incorporated short-chain polyethylene glycol (PEG) groups onto a carbon nitride network by the simple N-alkylation of hexaethylene glycolic mesylate with nucleophilic nitrogen atoms on oxidized carbon nitride (OCN). The PEGylated OCN (PEG-OCN) was well dispersed in water as nanodots with a lateral dimension of approximately 30 nm and a thickness of 0.5 1.2 nm and showed strong photoluminescence in the visible region. Cell-viability testing confirmed that these "heavy-metal-free" organic nanodots were highly biocompatible and noncytotoxic. In particular, the developed nanodots could provide clear confocal images of RAW 264.7 cells without weakening cell activity and displaying any aggregation in a range of concentrations (25-100 MUg mL-1 ) with bright-green emission in the cytoplasm. PMID- 29265506 TI - Transcranial Doppler Ultrasound Examination in Dogs with Suspected Intracranial Hypertension Caused by Neurologic Diseases. AB - BACKGROUND: Transcranial Doppler ultrasound examination (TCD) is a rapid, noninvasive technique used to evaluate cerebral blood flow and is useful for the detection of intracranial hypertension in humans. However, the clinical usefulness of TCD in diagnosing intracranial hypertension has not been demonstrated for intracranial diseases in dogs. OBJECTIVES: To determine the association between the TCD variables and intracranial hypertension in dogs with intracranial diseases. ANIMALS: Fifty client-owned dogs with neurologic signs. METHODS: Cross-sectional study. All dogs underwent TCD of the basilar artery under isoflurane anesthesia after magnetic resonance imaging (MRI). Dogs were classified into 3 groups based on MRI findings: no structural diseases (group I), structural disease without MRI evidence of intracranial hypertension (group II), and structural disease with MRI evidence of intracranial hypertension (group III). The TCD vascular resistance variables (resistive index [RI], pulsatility index [PI], and the ratio of systolic to diastolic mean velocity [Sm/Dm]) were measured. RESULTS: Fifteen, 22, and 13 dogs were classified into groups I, II, and III, respectively. Dogs in group III had significantly higher Sm/Dm (median, 1.78; range, 1.44-2.58) than those in group I (median, 1.63; range, 1.43-1.75) and group II (median, 1.62; range, 1.27-2.10). No significant differences in RI and PI were identified among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Our findings suggest that increased Sm/Dm is associated with MRI findings of suspected intracranial hypertension in dogs with intracranial diseases and that TCD could be a useful tool to help to diagnose intracranial hypertension. PMID- 29265509 TI - Prevalence, predictors and clinical impact of potentially inappropriate prescriptions in hospital-discharged older patients: A prospective study. AB - AIM: Potentially inappropriate prescriptions (PIP) have been highly reported in older patients, but few studies have investigated their association with adverse clinical outcomes. The present study aimed to evaluate the prevalence and predictors of PIP in hospital-discharged older adults, and to explore the association of PIP with death and rehospitalization. METHODS: We carried out a multicenter prospective cohort study on hospital-discharged patients aged >=65 years. Each patient underwent a comprehensive geriatric assessment, and the prevalence of PIP was obtained by applying Beers Criteria 2015 to discharge documents. Telephone follow up was carried out at 6 months. RESULTS: The prevalence of PIP was 63%, and was associated with psychiatric-behavioral disorders (OR 1.64), the number of daily taken medications (OR 1.08) and long term care discharge (OR 1.91), whereas better functional performance was protective (OR 0.93). Neither the presence nor the number of PIP were associated with rehospitalization or mortality at 6 months. However, insulin sliding scale (OR 4.97) and use of drugs inappropriate in heart failure (OR 4.64) were associated with an increased risk of rehospitalization, whereas prescription of digoxin >=0.125 mg/daily (OR 1.77) and antipsychotics (OR 1.65) were associated with a higher risk of mortality. CONCLUSIONS: Among older hospital-discharged patients, we documented a high prevalence of PIP that was significantly associated with polytherapy, the presence of psychiatric-behavioral disorders and discharge to long-term care facilities. Although the presence and the number of PIP were not associated with adverse outcomes, some specific inappropriate prescriptions were associated with a higher risk of hospital readmission and death. Geriatr Gerontol Int 2018; 18: 561-568. PMID- 29265510 TI - Comparing Isomeric Tridentate Carbazole-Based Click Ligands: Metal Complexes and Redox Chemistry. AB - Two novel bis(triazolyl)carbazole ligands Hbtc1 (3,6-di(tert-butyl)-1,8-bis[(1 (3,5-di(tert-butyl)phenyl)-1,2,3-triazol-4-yl)]-9H-carbazole) and Hbtc2 (3,6 di(tert-butyl)-1,8-bis[(4-(3,5-di(tert-butyl)phenyl)-1,2,3-triazol-1-yl)]-9H carbazole), differing in the regiochemistry of triazole attachment, have been synthesized by Cu-catalyzed azide-alkyne cycloaddition, the so-called "click reactions". Metalation with Ru, Zn, and Ni precursors led to the formation of M(btc)2 complexes (M=Ru, Zn, Ni), with two deprotonated ligands coordinating to the metal center in tridentate fashion, forming almost perfectly octahedral coordination spheres. The redox properties of M(btc)2 complexes have been investigated by cyclic voltammetry, UV/Vis spectroscopy, spectroelectrochemistry, and chemically. The CV of the ruthenium complexes revealed three quasi-reversible one-electron oxidation processes, one assigned as the RuII/III couple and two originating from ligand-based oxidations. The CVs of both Zn and Ni complexes contained only two oxidation waves corresponding to the oxidation of the two ligands. The oxidation potentials of complexes derived from Hbtc1 ligands were found to be 300-400 mV lower than those of the corresponding complexes derived from Hbtc2, reflecting the significant difference in donation through the N(2) or N(3) atom of the triazole moiety. PMID- 29265512 TI - The inhibitor of apoptosis protein livin is upregulated in psoriasis vulgaris. PMID- 29265513 TI - Method Evaluations for Adsorption Free Energy Calculations at the Solid/Water Interface through Metadynamics, Umbrella Sampling, and Jarzynski's Equality. AB - Considerable interest in characterizing protein/peptide-surface interactions has prompted extensive computational studies on calculations of adsorption free energy. However, in many cases, each individual study has focused on the application of free energy calculations to a specific system; therefore, it is difficult to combine the results into a general picture for choosing an appropriate strategy for the system of interest. Herein, three well-established computational algorithms are systemically compared and evaluated to compute the adsorption free energy of small molecules on two representative surfaces. The results clearly demonstrate that the characteristics of studied interfacial systems have crucial effects on the accuracy and efficiency of the adsorption free energy calculations. For the hydrophobic surface, steered molecular dynamics exhibits the highest efficiency, which appears to be a favorable method of choice for enhanced sampling simulations. However, for the charged surface, only the umbrella sampling method has the ability to accurately explore the adsorption free energy surface. The affinity of the water layer to the surface significantly affects the performance of free energy calculation methods, especially at the region close to the surface. Therefore, a general principle of how to discriminate between methodological and sampling issues based on the interfacial characteristics of the system under investigation is proposed. PMID- 29265515 TI - RE: The Hack Index. PMID- 29265514 TI - Clinical utility of C3d binding donor-specific anti-human leukocyte antigen antibody detection by single antigen beads after kidney transplantation-a retrospective study. AB - Development of donor-specific antibodies (DSA) after renal transplantation is known to be associated with worse graft survival, yet determining which specificities in which recipients are the most deleterious remains under investigation. This study evaluated the relationship of the complement binding capacity of post-transplant de novo anti-human leukocyte antigen (HLA) antibodies with subsequent clinical outcome. Stored sera from 265 recipients previously identified as having de novo DSA were retested for DSA and their C3d binding capacity using Luminex-based solid-phase assays. Most recipients had anti-HLA class II-reactive DSA (class I = 12.5%, class II = 68.7%, class I and class II = 18.9%). The recipients that had C3d binding DSA (67.5%) had a significantly higher incidence of antibody-mediated rejection and any rejection. They also had significantly lower kidney survival, with the lowest survival in those that had both anti-HLA class I and class II C3d binding DSA. Concurrent biopsy comparison revealed a 96.2% positive predictive value and 47.4% negative predictive value for C4d peritubular capillary (Ptc) deposition. Anti-HLA class I and class II C3d binding DSA carried a twofold and 1.5-fold increased risk of kidney loss, respectively, in multivariate analysis. PMID- 29265517 TI - Two novel mutations in the TSC2 gene causing severe phenotype in nervous system and skin in a patient with tuberous sclerosis complex. PMID- 29265516 TI - The possible role of CD8+/Valpha7.2+/CD161++ T (MAIT) and CD8+/Valpha7.2+/CD161lo T (MAIT-like) cells in the pathogenesis of early-onset pre-eclampsia. AB - PROBLEM: The objective of this study was to compare the expressions of different immune-checkpoint molecules by MAIT and MAIT-like cells in healthy pregnancy and in early-onset pre-eclampsia. METHOD OF STUDY: Peripheral blood mononuclear cells (PBMC) were stained with monoclonal antibodies to characterize MAIT and MAIT-like cells. Flow cytometric analyses were used to measure PD-1, TIM-3, activation markers, and intracellular perforin expression. RESULTS: We identified CD3+/CD8+/Valpha7.2+/CD161++ MAIT cells and a minor cell population characterized by CD3+/CD8+/Valpha7.2+/CD161lo surface markers. In measuring the expression of PD-1 receptor, we found a significantly lower expression by MAIT cells in women with early-onset pre-eclampsia. CD69 expression by MAIT cells was significantly elevated in early-onset pre-eclamptic patients. Intracellular perforin content by MAIT and PD-1+ MAIT cells was significantly increased in pre-eclamptic patients compared with healthy individuals. CONCLUSION: Altered frequency and reduced PD-1 expression combined together with the elevated perforin content of MAIT cells insinuate their potential roles in the pathogenesis of early-onset pre-eclampsia. PMID- 29265518 TI - A Generalized Crystallographic Description of All Tellurium Nanostructures. AB - Despite tellurium being less abundant in the Earth's crust than gold, platinum, or rare-earth elements, the number of industrial applications of tellurium has rapidly increased in recent years. However, to date, many properties of tellurium and its associated compounds remain unknown. For example, formation mechanisms of many tellurium nanostructures synthesized so far have not yet been verified, and it is unclear why tellurium can readily transform to other compounds like silver telluride by simply mixing with solutions containing silver ions. This uncertainty appears to be due to previous misunderstandings about the tellurium structure. Here, a new approach to the tellurium structure via synthesized structures is proposed. It is found that the proposed approach applies not only to these structures but to all other tellurium nanostructures. Moreover, some unique tellurium nanostructures whose formation mechanism are, until now, unconfirmed can be explained. PMID- 29265519 TI - From old town to new town: the state of the science 30 years after the Edinburgh declaration. PMID- 29265520 TI - Selecting medical students: considering qualities other than academic ability. PMID- 29265521 TI - Time to say goodbye to learner-centredness? PMID- 29265522 TI - Host physician perspectives to improve pre-departure training for global health electives. PMID- 29265523 TI - Medical education: how are we doing? PMID- 29265524 TI - Attenuated endothelin-1 mRNA expression with endothelin-1 receptor blockade during hypoxaemia and reoxygenation in newborn piglets. AB - : We investigated the cause of decreased plasma endothelin-1 (ET-1) during hypoxaemia and reoxygenation in newborn piglets subjected to simultaneous blocking of the ET-1 receptors. Changes in plasma ET-1 and prepro-ET-1 mRNA expression in the main pulmonary artery and the left lower lobe in the lung were studied in 1-2-d-old piglets. Ten minutes prior to hypoxaemia, the hypoxaemia group (n = 10) was given saline, two groups (both n = 9) were given 1 and 5 mg/kg i.v. SB 217242 (an ET-1 receptor antagonist). Two groups served as normoxic controls, with and without SB 217242 5 mg/kg i.v. Hypoxaemia was induced by ventilating with 8% O2 until base excess was 20mmol/l or mean arterial blood pressure was < 20mmHg. Reoxygenation was performed for 2h with room air. During hypoxaemia, plasma ET-1 decreased in the hypoxaemia group, remained unchanged in the 1-mg group and increased in the 5-mg group. At the end of reoxygenation, plasma ET-1 was above baseline in the 1-mg and 5-mg groups. In the pulmonary artery, the hypoxaemia group showed 2- to 5-fold higher prepro-ET-1 mRNA expression compared to all the other groups (p < 0.05). There were trends for higher prepro-ET-1 mRNA expression in pulmonary tissue in the hypoxaemia group compared to the two receptor-blocking groups (p < 0.07). CONCLUSIONS: We conclude that hypoxaemia and reoxygenation increase prepro-ET-1 mRNA expression in the pulmonary artery in newborn piglets. These observations suggest that the half life of ET-1 is decreased during hypoxaemia and reoxygenation in newborn piglets. PMID- 29265526 TI - Largely unlinked gene sets targeted by selection for domestication syndrome phenotypes in maize and sorghum. AB - The domestication of diverse grain crops from wild grasses was a result of artificial selection for a suite of overlapping traits producing changes referred to in aggregate as 'domestication syndrome'. Parallel phenotypic change can be accomplished by either selection on orthologous genes or selection on non orthologous genes with parallel phenotypic effects. To determine how often artificial selection for domestication traits in the grasses targeted orthologous genes, we employed resequencing data from wild and domesticated accessions of Zea (maize) and Sorghum (sorghum). Many 'classic' domestication genes identified through quantitative trait locus mapping in populations resulting from wild/domesticated crosses indeed show signatures of parallel selection in both maize and sorghum. However, the overall number of genes showing signatures of parallel selection in both species is not significantly different from that expected by chance. This suggests that while a small number of genes will extremely large phenotypic effects have been targeted repeatedly by artificial selection during domestication, the optimization part of domestication targeted small and largely non-overlapping subsets of all possible genes which could produce equivalent phenotypic alterations. PMID- 29265525 TI - TPPU enhanced exercise-induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction. AB - Exercise training (ET) is a safe and efficacious therapeutic approach for myocardial infarction (MI). Given the numerous benefits of exercise, exercise induced mediators may be promising treatment targets for MI. C57BL/6 mice were fed 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHI), to increase epoxyeicosatrienoic acid (EET) levels, for 1 week before undergoing MI surgery. After 1-week recovery, the mice followed a prescribed exercise programme. Bone marrow-derived endothelial progenitor cells (EPCs) were isolated from the mice after 4 weeks of exercise and cultured for 7 days. Angiogenesis around the ischaemic area, EPC functions, and the expression of microRNA-126 (miR-126) and its target gene Spred1 were measured. The results were confirmed in vitro by adding TPPU to EPC culture medium. ET significantly increased serum EET levels and promoted angiogenesis after MI. TPPU enhanced the effects of ET to reduce the infarct area and improve cardiac function after MI. ET increased EPC function and miR-126 expression, which were further enhanced by TPPU, while Spred1 expression was significantly down-regulated. Additionally, the protein kinase B/glycogen synthase kinase 3beta (AKT/GSK3beta) signalling pathway was activated after the administration of TPPU. EETs are a potential mediator of exercise-induced cardioprotection in mice after MI. TPPU enhances exercise-induced cardiac recovery in mice after MI by increasing EET levels and promoting angiogenesis around the ischaemic area. PMID- 29265527 TI - Know your enemy, embrace your friend: using omics to understand how plants respond differently to pathogenic and mutualistic microorganisms. AB - Microorganisms, or 'microbes', have formed intimate associations with plants throughout the length of their evolutionary history. In extant plant systems microbes still remain an integral part of the ecological landscape, impacting plant health, productivity and long-term fitness. Therefore, to properly understand the genetic wiring of plants, we must first determine what perception systems plants have evolved to parse beneficial from commensal from pathogenic microbes. In this review, we consider some of the most recent advances in how plants respond at the molecular level to different microbial lifestyles. Further, we cover some of the means by which microbes are able to manipulate plant signaling pathways through altered destructiveness and nutrient sinks, as well as the use of effector proteins and micro-RNAs (miRNAs). We conclude by highlighting some of the major questions still to be answered in the field of plant-microbe research, and suggest some of the key areas that are in greatest need of further research investment. The results of these proposed studies will have impacts in a wide range of plant research disciplines and will, ultimately, translate into stronger agronomic crops and forestry stock, with immune perception and response systems bred to foster beneficial microbial symbioses while repudiating pathogenic symbioses. PMID- 29265528 TI - Deconvolution model to resolve cytometric microbial community patterns in flowing waters. AB - Flow cytometry is suitable to discriminate and quantify aquatic microbial cells within a spectrum of fluorescence and light scatter signals. Using fixed gating and operational settings, we developed a finite distribution mixture model, followed by the Voronoi tessellation, to resolve bivariate cytometric profiles into cohesive subgroups of events. This procedure was applied to outline recurrent patterns and quantitative changes of the aquatic microbial community along a river hydrologic continuum. We found five major subgroups within each of the commonly retrieved populations of cells with Low and High content of Nucleic Acids (namely, LNA, and HNA cells). Moreover, the advanced analysis allowed assessing changes of community patterns perturbed by a wastewater feed. Our approach for cytometric data deconvolution confirmed that flow cytometry could represent a prime candidate technology for assessing microbial community patterns in flowing waters. (c) 2017 International Society for Advancement of Cytometry. PMID- 29265529 TI - Longevity of Implantable Pulse Generators in Bilateral Deep Brain Stimulation for Movement Disorders. AB - BACKGROUND: Deep brain stimulation (DBS) is a well-established therapy for otherwise intractable movement disorders. Thus far, most patients receive nonrechargeable implantable pulse generators (IPG). Eventually, another intervention to replace the IPG is inevitable. OBJECTIVE: We assessed IPG model specific differences in longevity in patients planned for IPG replacement. Also, we evaluated the influence of the total electric energy delivered (TEED), the amount of previous IPG replacements, and previous IPG model changes on the longevity. METHODS: We collected the demographic data and DBS settings of 47 patients (19 with Parkinson's disease, 7 with essential tremor, and 21 with dystonia) that were treated either with Medtronic's Kinetra(r) (N = 16) or Activa(r) PC (N = 31). Statistical analysis was performed using Mann-Whitney U test and Spearman's rank correlation. RESULTS: Battery longevity was shorter in the Activa PC than in the Kinetra (40.16 +/- 15.22 vs. 70.35 +/- 24.45 months; p < 0.001). Further analysis showed an inverse correlation of the longevity to TEED (r = -0.529; p < 0.001) and the number of previous IPG replacements (r = -0.588; p < 0.001). Furthermore, patients with more frequent replacements had higher TEED (r = 0.501; p < 0.001) and patients, whose Kinetra was replaced with the Activa PC before, had shorter IPG longevity (28.36 +/- 9.82 vs. 45.78 +/- 14.19 months; p = 0.006). CONCLUSION: Our findings imply that IPG longevity is shorter in the Activa PC compared to the Kinetra. Higher TEED and more frequent IPG replacements might reduce IPG longevity. PMID- 29265530 TI - Functional neurochemical imaging of the human striatal cholinergic system during reversal learning. AB - Animal studies have shown that acetylcholine (ACh) levels in the dorsal striatum play a role in reversal learning. However, this has not been studied in humans due to a lack of appropriate non-invasive techniques. Proton magnetic resonance spectroscopy (1 H-MRS) can be used to measure metabolite levels in humans in vivo. Although it cannot be used to study ACh directly, 1 H-MRS can be used to study choline, an ACh precursor, which is linked to activity-dependent ACh release. The aim of this study was to use functional-1 H-MRS (fMRS) to measure changes in choline levels in the human dorsal striatum during performance of a probabilistic reversal learning task. We demonstrate a task-dependent decrease in choline, specifically during reversal, but not initial, learning. We interpret this to reflect a sustained increase in ACh levels, which is in line with findings from the animal literature. This task-dependent change was specific to choline and was not observed in control metabolites. These findings provide support for the use of fMRS in the in vivo study of the human cholinergic system. PMID- 29265531 TI - Asymmetrical changes of gene expression, small RNAs and chromatin in two resynthesized wheat allotetraploids. AB - Polyploidy occurs in some animals and all flowering plants, including important crops such as wheat. The consequences of polyploidy in crops remain elusive, partly because their progenitors are unknown. Using two resynthesized wheat allotetraploids Sl Sl AA and AADD with known diploid progenitors, we analyzed mRNA and small RNA transcriptomes in the endosperm, compared transcriptomes between endosperm and root in AADD, and examined chromatin changes in the allotetraploids. In the endosperm, there were more non-additively expressed genes in Sl Sl AA than in AADD. In AADD, non-additively expressed genes were developmentally regulated, and the majority (62-70%) were repressed. The repressed genes in AADD included a group of histone methyltransferase gene homologs, which correlated with reduced histone H3K9me2 levels and activation of various transposable elements in AADD. In Sl Sl AA, there was a tendency for expression dominance of Sl over A homoeologs, but the histone methyltransferase gene homologs were additively expressed, correlating with insignificant changes in histone H3K9me2 levels. Moreover, more 24-nucleotide small inferring RNAs (siRNAs) in the A subgenome were disrupted in AADD than in Sl Sl AA, which were associated with expression changes of siRNA-associated genes. Our results indicate that asymmetrical changes in siRNAs, chromatin modifications, transposons and gene expression coincide with unstable AADD genomes and stable Sl Sl AA genomes, which could help explain the evolutionary trajectories of wheat allotetraploids formed by different progenitors. PMID- 29265532 TI - Effectiveness of Implementing Evidence-based Interventions to Reduce C-spine Image Ordering in the Emergency Department: A Systematic Review. AB - OBJECTIVES: Appropriate use of imaging for adult patients with cervical spine (C spine) injuries in the emergency department (ED) is a longstanding issue. Guidance for C-spine ordering exists; however, the effectiveness of the decision support implementation in the ED is not well studied. This systematic review examines the implementation and effectiveness of evidence-based interventions aimed at reducing C-spine imaging in adults presenting to the ED with neck trauma. METHODS: Six electronic databases and the gray literature were searched. Comparative intervention studies were eligible for inclusion. Two independent reviewers screened for study eligibility, study quality, and extracted data. The change in imaging was reported using individual odds ratios (ORs) with 95% confidence intervals (CIs) using random effects. RESULTS: A total of 990 unique citations were screened for relevance of which six before-after studies and one randomized controlled trial were included. None of the studies were assessed as high quality. Interventions consisted primarily of locally developed guidelines or established clinical decision rules such as the NEXUS or the Canadian C-spine rule. Overall, implementation of interventions aimed at reducing C-spine image ordering resulted in a statistically significant reduction in imaging (OR = 0.69, 95% CI = 0.51-0.93); however, heterogeneity was high (I2 = 82%). Subgroup analysis revealed no differences between studies that specified enrolling alert and stable patients compared to unspecified trauma (p = 0.81) or between studies employing multifaceted versus nonmultifaceted interventions (p = 0.66). While studies generally provided details on implementation strategies (e.g., teaching sessions, pocket cards, posters, computerized decision support) the effectiveness of these implementation strategies were frequently not reported. CONCLUSION: There is moderate evidence regarding the effectiveness of interventions to reduce C-spine image ordering in adult patients seen in the ED with neck trauma. Given the national and international focus on improving appropriateness and reducing unnecessary C-spine imaging through campaigns such as Choosing Wisely, additional interventional research in this field is warranted. PMID- 29265535 TI - Prophylactic effect of lamivudine on chemotherapy-induced hepatitis B virus reactivation in patients with solid tumour: A meta-analysis. AB - Hepatitis B virus (HBV) reactivation is a remarkable risk during the chemotherapy for solid tumour patients. Nucleos(t)ide analogues (NAs) are recommended as prophylaxis for the reactivation of HBV infection in some cancer patients prior to systemic chemotherapy. Therefore, we performed a meta-analysis aiming to determine the efficacy of prophylactic lamivudine on prevention of HBV reactivation and its related negative outcomes among solid tumour patients with chronic HBV infection receiving systemic chemotherapy. The primary outcome was HBV reactivation, and the secondary outcomes were HBV-related hepatitis, chemotherapy disruption, mortality and tyrosine-methio-nine-aspartate-aspartate (YMDD) mutations. Twelve original researches involving 1,101 patients were analysed in this study. The relative risk of HBV reactivation in patients with lamivudine prophylaxis was significantly lower than that without prophylaxis (RR = 0.17, 95% CL: 0.10-0.29, p < .00001). Lamivudine prophylaxis reduced the relative risk of hepatitis (p < .00001), chemotherapy disruptions (p = .01) and mortality (p = .08) due to HBV reactivation. Lamivudine prophylaxis is effective in reducing HBV reactivation and its related negative outcomes, such as hepatitis and chemotherapy disruption and mortality among chemotherapeutic solid tumour patients with chronic HBV infection. Future studies should lay more emphasis on the early HBV screening, mode of treatment and duration of NAs prophylaxis among solid tumour patients receiving chemotherapy. PMID- 29265536 TI - Tinea capitis mimicking dissecting cellulitis in three children. AB - Tinea capitis mimicking dissecting cellulitis is a rare presentation, and there is a paucity of information regarding this presentation in the literature. Three children 10-14 years of age who presented with an unusual clinical manifestation of tinea capitis that clinically resembled dissecting cellulitis are reported. The patients were treated with systemic antifungals for 3-4 months. Treatment success was measured according to repeat fungal cultures and clinical assessment of hair regrowth at follow-up visits. All three patients had resolution of infection, with negative repeat fungal cultures and complete hair regrowth without scarring. These cases highlight a rare inflammatory subtype of tinea capitis that can be easily misdiagnosed and therefore improperly treated, prolonging the duration of infection. PMID- 29265537 TI - The epidemiology of pseudallescheriasis complicating transplantation: Nosocomial and community-acquired infection. AB - The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population. PMID- 29265538 TI - Presseinformation. PMID- 29265540 TI - Case of subungual tumoral melanosis: The detection of melanoma cells and dermoscopic features. PMID- 29265539 TI - Key High-efficiency Practices of Emergency Department Providers: A Mixed-methods Study. AB - OBJECTIVE: The objective of this study was to determine specific provider practices associated with high provider efficiency in community emergency departments (EDs). METHODS: A mixed-methods study design was utilized to identify key behaviors associated with efficiency. Stage 1 was a convenience sample of 16 participants (ED medical directors, nurses, advanced practice providers, and physicians) identified provider efficiency behaviors during semistructured interviews. Ninety-nine behaviors were identified and distilled by a group of three ED clinicians into 18 themes. Stage 2 was an observational study of 35 providers was performed in four (30,000- to 55,000-visit) community EDs during two 4-hour periods and recorded in minute-by-minute observation logs. In Stage 3, each behavior or practice from Stage 1 was assigned a score within each observation period. Behaviors were tested for association with provider efficiency (relative value units/hour) using linear univariate generalized estimating equations with an identity link, clustered on ED site. RESULTS: Five ED provider practices were found to be positively associated with efficiency: average patient load, using name of team member, conversations with health care team, visits to patient rooms, and running the board. Two behaviors, "inefficiency practices," demonstrated significant negative correlations: non work-related tasks and documentation on patients no longer in the ED. CONCLUSIONS: Average patient load, running the board, conversations with team member, and using names of team members are associated with enhanced provider productivity. Identification of behaviors associated with efficiency can be utilized by medical directors, clinicians, and trainees to improve personal efficiency or counsel team members. PMID- 29265541 TI - Syntax and reading comprehension: a meta-analysis of different spoken-syntax assessments. AB - BACKGROUND: Syntax is a language skill purported to support children's reading comprehension. However, researchers who have examined whether children with average and below-average reading comprehension score significantly different on spoken-syntax assessments report inconsistent results. AIMS: To determine if differences in how syntax is measured affect whether children with average and below-average reading comprehension score significantly different on spoken syntax assessments. METHODS & PROCEDURES: Studies that included a group comparison design, children with average and below-average reading comprehension, and a spoken-syntax assessment were selected for review. Fourteen articles from a total of 1281 reviewed met the inclusionary criteria. The 14 articles were coded for the age of the children, score on the reading comprehension assessment, type of spoken-syntax assessment, type of syntax construct measured and score on the spoken-syntax assessment. A random-effects model was used to analyze the difference between the effect sizes of the types of spoken-syntax assessments and the difference between the effect sizes of the syntax construct measured. OUTCOMES & RESULTS: There was a significant difference between children with average and below-average reading comprehension on spoken-syntax assessments. Those with average and below-average reading comprehension scored significantly different on spoken-syntax assessments when norm-referenced and researcher created assessments were compared. However, when the type of construct was compared, children with average and below-average reading comprehension scored significantly different on assessments that measured knowledge of spoken syntax, but not on assessments that measured awareness of spoken syntax. CONCLUSIONS & IMPLICATIONS: The results of this meta-analysis confirmed that the type of spoken syntax assessment, whether norm-referenced or researcher-created, did not explain why some researchers reported that there were no significant differences between children with average and below-average reading comprehension, but the syntax construct, awareness or knowledge, did. Thus, when selecting how to measure syntax among school-age children, researchers and practitioners should evaluate whether they are measuring children's awareness of spoken syntax or knowledge of spoken syntax. Other differences, such as participant diagnosis and the format of items on the spoken-syntax assessments, also were discussed as possible explanations for why researchers found that children with average and below average reading comprehension did not score significantly differently on spoken syntax assessments. PMID- 29265543 TI - Primary Spontaneous Pneumothorax: Looking Beyond the Usual. PMID- 29265542 TI - Stress-responsive regulation of long non-coding RNA polyadenylation in Oryza sativa. AB - Recently, long non-coding RNAs (lncRNAs) have been demonstrated to be involved in many biological processes of plants; however, a systematic study on transcriptional and, in particular, post-transcriptional regulation of stress responsive lncRNAs in Oryza sativa (rice) is lacking. We sequenced three types of RNA libraries (poly(A)+, poly(A)- and nuclear RNAs) under four abiotic stresses (cold, heat, drought and salt). Based on an integrative bioinformatics approach and ~200 high-throughput data sets, ~170 of which have been published, we revealed over 7000 lncRNAs, nearly half of which were identified for the first time. Notably, we found that the majority of the ~500 poly(A) lncRNAs that were differentially expressed under stress were significantly downregulated, but approximately 25% were found to have upregulated non-poly(A) forms. Moreover, hundreds of lncRNAs with downregulated polyadenylation (DPA) tend to be highly conserved, show significant nuclear retention and are co-expressed with protein coding genes that function under stress. Remarkably, these DPA lncRNAs are significantly enriched in quantitative trait loci (QTLs) for stress tolerance or development, suggesting their potential important roles in rice growth under various stresses. In particular, we observed substantially accumulated DPA lncRNAs in plants exposed to drought and salt, which is consistent with the severe reduction of RNA 3'-end processing factors under these conditions. Taken together, the results of this study reveal that polyadenylation and subcellular localization of many rice lncRNAs are likely to be regulated at the post transcriptional level. Our findings strongly suggest that many upregulated/downregulated lncRNAs previously identified by traditional RNA-seq analyses need to be carefully reviewed to assess the influence of post transcriptional modification. PMID- 29265544 TI - Boys in a famous choir: Singing and ticcing. AB - This informal observational study on the tic prevalence in 40 young singers was carried out during a public concert of Bach's Christmas Oratorio. Tics were highly prevalent (present in 35% = 14 boys). Given the possibility of an overrepresentation of perioral tics in this group of highly achieving young vocal artists, one might speculate that there is a relationship between the ability of the motor system to produce a surplus of movements (tics) and high performance (exquisite singing). Despite the unusual study design, with all its limitations, our observations strengthen the view that tics may be related to motor learning. However, alternative explanations, for example, that repetitive motor performance or personality traits in singers drive tic development, could also be true. In light of the boys choir's enchantment, the sole perception of tics as a disorder falls short of the properties of the motor system. Ann Neurol 2017;82:1029-1031. PMID- 29265545 TI - Challenges and proposed solutions for formative research to inform systematic intervention development in rare and unstudied conditions: The case example of Xeroderma Pigmentosum. PMID- 29265546 TI - A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up. AB - OBJECTIVE: Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. METHODS: A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. RESULTS: Mean hand tremor score at baseline (19.8 +/- 4.9; 76 patients) improved by 55% at 6 months (8.6 +/- 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 +/- 4.8; 70 patients) and at 2 years (56%; 8.8 +/- 5.0; 67 patients). Similarly, the disability score at baseline (16.4 +/- 4.5; 76 patients) improved by 64% at 6 months (5.4 +/- 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 +/- 5.3; 70 patients) and at 2 years (6.5 +/- 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. INTERPRETATION: Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114. PMID- 29265547 TI - Novel Hybrid Prins/Aza-Prins Oxocarbenium/N-Acyliminium Cascade: Expedient Access to Complex Indolizidines. AB - Heavy silyl enol ethers (mostly TIPS and TBS) combine with cyclic N-alkenyl N acyliminium salts generated in situ from their N,O-acetal precursors, to furnish highly functionalized indolizidines through an unprecedented double Mukaiyama Mannich-Prins cascade transformation. This novel cascade annulation process demonstrates a promising scope, and takes place mostly catalytically with interesting stereocontrol. Furthermore, an appealing facet of this chemistry is emphasized with a bicatalytic approach by which the Mannich-Prins cascade follows a Ru-catalyzed N-allylamide to N-(E)-propenyl isomerization of the aminal counterpart in a one-pot operation. PMID- 29265548 TI - In Reply. PMID- 29265549 TI - Using Statistical Models of Morphology in the Search for Optimal Units of Representation in the Human Mental Lexicon. AB - Determining optimal units of representing morphologically complex words in the mental lexicon is a central question in psycholinguistics. Here, we utilize advances in computational sciences to study human morphological processing using statistical models of morphology, particularly the unsupervised Morfessor model that works on the principle of optimization. The aim was to see what kind of model structure corresponds best to human word recognition costs for multimorphemic Finnish nouns: a model incorporating units resembling linguistically defined morphemes, a whole-word model, or a model that seeks for an optimal balance between these two extremes. Our results showed that human word recognition was predicted best by a combination of two models: a model that decomposes words at some morpheme boundaries while keeping others unsegmented and a whole-word model. The results support dual-route models that assume that both decomposed and full-form representations are utilized to optimally process complex words within the mental lexicon. PMID- 29265551 TI - Next-Generation Batteries. PMID- 29265550 TI - Interrater and intrarater agreement of confocal microscopy imaging in diagnosing and subtyping basal cell carcinoma. AB - BACKGROUND: Reflectance confocal microscopy (RCM) imaging can be used to diagnose and subtype basal cell carcinoma (BCC) but relies on individual morphologic pattern recognition that might vary among users. OBJECTIVES: We assessed the inter-rater and intrarater agreement of RCM in correctly diagnosing and subtyping BCC. METHODS: In this prospective study, we evaluated the inter-rater and intrarater agreement of RCM on BCC presence and subtype among three raters with varying experience who independently assessed static images of 48 RCM cases twice with four-week interval (T1 and T2). Histopathologic confirmation of presence and subtype of BCC from surgical excision specimen was defined as the reference standard. RESULTS: The inter-rater agreement of RCM for BCC presence showed an agreement of 82% at T1 and 84% at T2. The agreements for subtyping BCC were lower (52% for T1 and 47% for T2). The intrarater agreement of RCM for BCC presence showed an observed agreement that varied from 79% to 92%. The observed agreements for subtyping varied from 56% to 71%. CONCLUSIONS: In conclusion, our results show that RCM is reliable in correctly diagnosing BCC based on the assessment of static RCM images. RCM could potentially play an important role in BCC management if accurate subtyping will be achieved. Therefore, future clinical studies on reliability and specific RCM features for BCC subtypes are required. PMID- 29265552 TI - Leucine rich repeat kinase knockout (LRRK KO) mouse model: Linking pathological hallmarks of inherited and sporadic Parkinson's disease. PMID- 29265553 TI - Maternal hemoglobin and hematocrit levels during pregnancy and childhood lung function and asthma. The Generation R Study. AB - OBJECTIVE: To examine the associations of maternal hemoglobin and hematocrit levels during pregnancy with childhood lung function and asthma, and whether adverse pregnancy outcomes and atopic predisposition modify the associations. METHODS: In a population-based prospective cohort study among 3672 subjects, we measured maternal hemoglobin and hematocrit levels in early pregnancy, and lung function by spirometry and current asthma by questionnaire at age 10 years. RESULTS: Higher maternal hematocrit levels, both continuously and categorized into clinical cut-offs, were associated with lower forced expiratory flow at 75% of forced vital capacity (FEF75 ) in children (Z-score (95%CI): -0.04 (-0.07, 0.01), per increase of 1 SDS in hematocrit level; Z-score (95%CI) difference: 0.11 (-0.20, -0.03) compared with normal hematocrit levels, respectively), taking lifestyle and socio-economic factors into account. Adverse pregnancy outcomes and atopic predisposition did not modify the results. No associations of maternal hemoglobin and hematocrit with current asthma were observed. CONCLUSION: Higher maternal hematocrit levels during pregnancy are associated with lower childhood lung function but not with risk of asthma. Adverse pregnancy outcomes and atopic predisposition do not modify these associations. Underlying mechanisms need to be further studied. PMID- 29265555 TI - License. PMID- 29265554 TI - Ski and snowboard school programs: Injury surveillance and risk factors for grade specific injury. AB - The objective of our study was to evaluate incidence rates and profile of school program ski and snowboard-related injuries by school grade group using a historical cohort design. Injuries were identified via Accident Report Forms completed by ski patrollers. Severe injury was defined as those with ambulance evacuation or recommending patient transport to hospital. Poisson regression analysis was used to examine the school grade group-specific injury rates adjusting for risk factors (sex, activity, ability, and socioeconomic status) and accounting for the effect of clustering by school. Forty of 107 (37%) injuries reported were severe. Adolescents (grades 7-12) had higher crude injury rates (91 of 10 000 student-days) than children (grades 1-3: 25 of 10 000 student-days; grades 4-6: 65 of 10 000 student-days). Those in grades 1-3 had no severe injuries. Although the rate of injury was lower in grades 1-3, there were no statistically significant grade group differences in adjusted analyses. Snowboarders had a higher rate of injury compared with skiers, while higher ability level was protective. Participants in grades 1-3 had the lowest crude and adjusted injury rates. Students in grades 7-12 had the highest rate of overall and severe injuries. These results will inform evidence-based guidelines for school ski/snowboard program participation by school-aged children. PMID- 29265557 TI - Euro-Sequences: Toward Next-Gen Polymers. PMID- 29265556 TI - Disentangling the long-term effects of disturbance on soil biogeochemistry in a wet tropical forest ecosystem. AB - Climate change is increasing the intensity of severe tropical storms and cyclones (also referred to as hurricanes or typhoons), with major implications for tropical forest structure and function. These changes in disturbance regime are likely to play an important role in regulating ecosystem carbon (C) and nutrient dynamics in tropical and subtropical forests. Canopy opening and debris deposition resulting from severe storms have complex and interacting effects on ecosystem biogeochemistry. Disentangling these complex effects will be critical to better understand the long-term implications of climate change on ecosystem C and nutrient dynamics. In this study, we used a well-replicated, long-term (10 years) canopy and debris manipulation experiment in a wet tropical forest to determine the separate and combined effects of canopy opening and debris deposition on soil C and nutrients throughout the soil profile (1 m). Debris deposition alone resulted in higher soil C and N concentrations, both at the surface (0-10 cm) and at depth (50-80 cm). Concentrations of NaOH-organic P also increased significantly in the debris deposition only treatment (20-90 cm depth), as did NaOH-total P (20-50 cm depth). Canopy opening, both with and without debris deposition, significantly increased NaOH-inorganic P concentrations from 70 to 90 cm depth. Soil iron concentrations were a strong predictor of both C and P patterns throughout the soil profile. Our results demonstrate that both surface and subsoils have the potential to significantly increase C and nutrient storage a decade after the sudden deposition of disturbance-related organic debris. Our results also show that these effects may be partially offset by rapid decomposition and decreases in litterfall associated with canopy opening. The significant effects of debris deposition on soil C and nutrient concentrations at depth (>50 cm), suggest that deep soils are more dynamic than previously believed, and can serve as sinks of C and nutrients derived from disturbance induced pulses of organic matter inputs. PMID- 29265558 TI - A silicon strip detector array for energy verification and quality assurance in heavy ion therapy. AB - PURPOSE: The measurement of depth dose profiles for range and energy verification of heavy ion beams is an important aspect of quality assurance procedures for heavy ion therapy facilities. The steep dose gradients in the Bragg peak region of these profiles require the use of detectors with high spatial resolution. The aim of this work is to characterize a one dimensional monolithic silicon detector array called the "serial Dose Magnifying Glass" (sDMG) as an independent ion beam energy and range verification system used for quality assurance conducted for ion beams used in heavy ion therapy. METHODS: The sDMG detector consists of two linear arrays of 128 silicon sensitive volumes each with an effective size of 2mm * 50MUm * 100MUm fabricated on a p-type substrate at a pitch of 200 MUm along a single axis of detection. The detector was characterized for beam energy and range verification by measuring the response of the detector when irradiated with a 290 MeV/u 12 C ion broad beam incident along the single axis of the detector embedded in a PMMA phantom. The energy of the 12 C ion beam incident on the detector and the residual energy of an ion beam incident on the phantom was determined from the measured Bragg peak position in the sDMG. Ad hoc Monte Carlo simulations of the experimental setup were also performed to give further insight into the detector response. RESULTS: The relative response profiles along the single axis measured with the sDMG detector were found to have good agreement between experiment and simulation with the position of the Bragg peak determined to fall within 0.2 mm or 1.1% of the range in the detector for the two cases. The energy of the beam incident on the detector was found to vary less than 1% between experiment and simulation. The beam energy incident on the phantom was determined to be (280.9 +/- 0.8) MeV/u from the experimental and (280.9 +/- 0.2) MeV/u from the simulated profiles. These values coincide with the expected energy of 281 MeV/u. CONCLUSIONS: The sDMG detector response was studied experimentally and characterized using a Monte Carlo simulation. The sDMG detector was found to accurately determine the 12 C beam energy and is suited for fast energy and range verification quality assurance. It is proposed that the sDMG is also applicable for verification of treatment planning systems that rely on particle range. PMID- 29265560 TI - Meeting of the Societe Francaise de Mycologie Medicale November 16-17, 1990, Paris, France. PMID- 29265561 TI - White piedra: ultrastructure and a new micro-ecological aspect. AB - White piedra or trichosporosis is a superficial mycosis of the hair shaft, caused by the yeast Trichosporon beigelii; it has been found in all continents and may involve the hair of any part of the body. We report a case of white piedra on the hairs of the inguinal fold with ultrastructural studies. Transmission electron microscopy showed that the nodules have the same morphological aspects as the fungus in culture (hyphae and arthrospores) except for the presence of a cementant substance. By scanning electron microscopy the elimination of spores was seen on the nodule surface. Interestingly similar nodules were found on cotton fibres of the patient's underwear, which were also studied by scanning electron microscopy. This finding can explain therapeutic failure and demands special hygienic conditions related to clothes. PMID- 29265559 TI - Dissection of the genetic architecture of three seed-quality traits and consequences for breeding in Brassica napus. AB - Genome-wide association studies (GWASs) combining high-throughput genome resequencing and phenotyping can accelerate the dissection of genetic architecture and identification of genes for plant complex traits. In this study, we developed a rapeseed genomic variation map consisting of 4 542 011 SNPs and 628 666 INDELs. GWAS was performed for three seed-quality traits, including erucic acid content (EAC), glucosinolate content (GSC) and seed oil content (SOC) using 3.82 million polymorphisms in an association panel. Six, 49 and 17 loci were detected to be associated with EAC, GSC and SOC in multiple environments, respectively. The mean total contribution of these loci in each environment was 94.1% for EAC and 87.9% for GSC, notably higher than that for SOC (40.1%). A high correlation was observed between phenotypic variance and number of favourable alleles for associated loci, which will contribute to breeding improvement by pyramiding these loci. Furthermore, candidate genes were detected underlying associated loci, based on functional polymorphisms in gene regions where sequence variation was found to correlate with phenotypic variation. Our approach was validated by detection of well-characterized FAE1 genes at each of two major loci for EAC on chromosomes A8 and C3, along with MYB28 genes at each of three major loci for GSC on chromosomes A9, C2 and C9. Four novel candidate genes were detected by correlation between GSC and SOC and observed sequence variation, respectively. This study provides insights into the genetic architecture of three seed-quality traits, which would be useful for genetic improvement of B. napus. PMID- 29265562 TI - 1st International Conference on Antifungal Chemotherapy, ICAFC 90: September 24 26, 1990, Oiso, Japan. Conference Chair: Hideyo Yamaguchi. PMID- 29265563 TI - Psychological mechanisms in a digital intervention to improve physical activity: A multicentre randomized controlled trial. AB - OBJECTIVES: The randomized controlled trial examined factors that might be responsible for individual differences in physical activity change among men and women who participated in a lifestyle intervention. The main purpose of the analyses regarded the role of psychological mechanisms involving motivation, planning, self-monitoring, and habit strength. DESIGN: A two-arm digital intervention was conducted in Italy, Spain, and Greece to improve physical activity levels, with follow-ups at 3 and 6 months after baseline assessment. METHODS: Participants were 1,564 adults at baseline, n = 638 at 6-month follow up. Linear mixed models examined the intervention effects, and a two-group longitudinal structural equation model explored which psychological constructs (motivation, planning, self-monitoring, habit strength) were associated with changes in physical activity. RESULTS: In addition to an overall increase in self reported activity, there were interactions between time and sex and between time and experimental groups, and a triple interaction between time, sex, and experimental groups, indicating that men reported an increase in activity independent of groups, whereas women in the active control group did not benefit from the intervention. Planning, self-monitoring, and habit strength mediated sequentially between initial motivation and follow-up physical activity. CONCLUSIONS: Although the intervention produced overall improvements in physical activity, the time-by-treatment interaction emerged only for women. The mechanism included a sequence leading from motivation via planning, self-monitoring, and habit strength towards physical activity. Statement of contribution What is already known on this subject? Digital lifestyle interventions can be effective in terms of physical activity performance gains. Men are on average more physically active than women. Long-term adherence rates to digital interventions are usually low. What does this study add? Giving users of an online platform more interactive options did not make a difference. Women gained more than men from adaptive, dynamic online platform content. Individual characteristics (motivation, planning, self-monitoring, habit) were more important than online treatment features. PMID- 29265564 TI - Response to "Covalent Bonding and Charge Shift Bonds: Comment on 'The Carbon Nitrogen Bonds in Ammonium Compounds Are Charge Shift Bonds'". AB - A response to the comment by Gernot Frenking, outlining common ground, as well as differences, with regard to a recent paper on charge-shift bonding in quaternary ammonium cations. PMID- 29265565 TI - Does Psychological Disturbance Predict Explantation in Successful Pelvic Neuromodulation Treatment for Bladder Dysfunction? A Short Series. AB - INTRODUCTION: Sacral neuromodulation (SNM) is a safe and effective therapy for patients with lower urinary tract dysfunction (LUTD). It is used in patients who have exhausted conservative and first line therapeutic options. The selection of eligible candidates could predict a successful therapeutic outcome. Although many factors have been identified, psychological/psychiatric disturbances are neither well understood nor are routinely evaluated prior to implantation. CASE REPORTS: We report three cases where identified psychological/psychiatric disturbances post-implantation could have influenced explantation in an otherwise successful implantation of SNM device assessed both subjectively and objectively. The device had to be explanted in two of the three. One more patient has requested but has not-yet undergone explantation and is receiving treatment for severe depression. One of the explanted cases has successfully undergone re-implantation after successful treatment of her diagnosed psychological condition, while the other's request for re-implantation has not yet been fulfilled. CONCLUSIONS: Psychological/psychiatric disturbance have possibly affected the treatment outcome and explantation of SNM in our patients despite a high success in resolution of the urinary symptoms. Addressing such disturbances when determining patient eligibility for SNM therapy could reduce the explantation rate after a successful therapeutic response, and is an interesting point of interest for future research into predictors of successful SNM implantation and therapy. PMID- 29265566 TI - Randomized clinical trial to assess the ideal mode of delivery for local anaesthetic abdominal wall blocks. AB - BACKGROUND: Adequate post-operative analgesia is essential for recovery following abdominal surgery. Abdominal wall nerve blocks have been shown to be beneficial in this respect following surgery. The purpose of this trial was to examine the efficacy of infusional versus intermittent bolus delivery of abdominal wall blocks in patients undergoing abdominal resectional gastrointestinal surgery. METHODS: A prospective randomized clinical trial, involving 120 patients undergoing gastrointestinal surgery, was undertaken across three hospitals. Insertion of abdominal wall catheters was performed and patients were randomized to receive ropivacaine 0.2% by either continuous infusion or regular intermittent bolus. The primary outcome was respiratory function, as measured by spirometry on post-operative days 1-3 and 30. Secondary outcomes were pain, mobility, return of gut function, length of hospital stay, complication rates and patient satisfaction with analgesia. RESULTS: All 120 patients were followed up to trial completion. Patients were well matched with regards to demographics. There was no difference between groups with regards to the primary outcome of post-operative respiratory function. The bolus group had improved mobility scores on post operative day 1 (P = 0.025). There were no complications associated with blockade, and no other differences were identified between assessed outcomes. CONCLUSIONS: Continuous infusion and intermittent bolus are both safe ways of delivering abdominal wall nerve blockade, with equivalent analgesic outcomes. Bolus delivery appears to provide superior early mobility in comparison with continuous infusion. PMID- 29265567 TI - Reverse Reconstruction and Bioprinting of Bacterial Cellulose-Based Functional Total Intervertebral Disc for Therapeutic Implantation. AB - The degradation of intervertebral discs (IVD), a typical hierarchical structured tissue, causes serious neck and back pain. The current methods cannot fully reconstitute the unique structure and function of native IVD. In this study, by reverse reconstruction of the structure of native IVD and bioprinting bacterial cellulose (BC) nanofibers with a high-throughput optimized micropattern screening microchip, a total IVD is created that contained type II collagen-based nucleus pulposus (NP) and hierarchically organized and micropatterned BC-based annulus fibrosus (AF), mimicking native IVD tissue. The artificial NP contains rat NP cells, whereas the AF contains concentrically arranged BC layers with aligned micropatterns and attached AF cells in +/-30 degrees alternate directions between adjacent layers. Long-term (3 months) implantation experiments on rats demonstrate the excellent structural (shape maintenance, hydration, tissue integration) and functional (mechanical support and flexibility) performance of the artificial IVD. This study provides a novel strategy for creating highly sophisticated artificial tissues. PMID- 29265568 TI - Regional grassland productivity responses to precipitation during multiyear above and below-average rainfall periods. AB - There is considerable uncertainty in the magnitude and direction of changes in precipitation associated with climate change, and ecosystem responses are also uncertain. Multiyear periods of above- and below-average rainfall may foretell consequences of changes in rainfall regime. We compiled long-term aboveground net primary productivity (ANPP) and precipitation (PPT) data for eight North American grasslands, and quantified relationships between ANPP and PPT at each site, and in 1-3 year periods of above- and below-average rainfall for mesic, semiarid cool, and semiarid warm grassland types. Our objective was to improve understanding of ANPP dynamics associated with changing climatic conditions by contrasting PPT-ANPP relationships in above- and below-average PPT years to those that occurred during sequences of multiple above- and below-average years. We found differences in PPT-ANPP relationships in above- and below-average years compared to long-term site averages, and variation in ANPP not explained by PPT totals that likely are attributed to legacy effects. The correlation between ANPP and current- and prior-year conditions changed from year to year throughout multiyear periods, with some legacy effects declining, and new responses emerging. Thus, ANPP in a given year was influenced by sequences of conditions that varied across grassland types and climates. Most importantly, the influence of prior-year ANPP often increased with the length of multiyear periods, whereas the influence of the amount of current-year PPT declined. Although the mechanisms by which a directional change in the frequency of above- and below-average years imposes a persistent change in grassland ANPP require further investigation, our results emphasize the importance of legacy effects on productivity for sequences of above- vs. below-average years, and illustrate the utility of long-term data to examine these patterns. PMID- 29265569 TI - In Vitro and in Vivo Activity of Antifungal Agents in Combination with Fleroxacin, a New Quinolone. AB - The in vitro and in vivo Interaction of fleroxacin with amphotericin B (Amph B), flucytosine (5-FC) and azoles against Candida albicans strains was tested. In vitro the interaction between fleroxacin and various antifungals was not dependent on the incubation time. Fleroxacin neither enhances nor antagonizes the in vitro activity of Amph B at high concentration (50-100 ug/ml). Fleroxacin has a synergistic effect with ketoconazole (KETO), but this is not observed with itraconazole (ITRA) or fluconazole (FLU). In no instance antagonism was observed. The activity of 5-FC was antagonized by fleroxacin being generally reduced by 2-4 dilution steps. In murine candidosis the efficacies of all antifungal drugs were not influenced by addition of 100 mg/kg fleroxacin. Therefore, the effects seen in in vitro tests are most probably not relevant for the clinical use of a combination of fleroxacin with antifungal drugs. PMID- 29265570 TI - To our Readers. PMID- 29265571 TI - Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes. AB - OBJECTIVES: The aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes. DESIGN AND PATIENTS: We selected 39 patients with syndromic CH for array-based comparative genomic hybridization (aCGH). Patients with pathogenic CNVs were also evaluated by whole exome sequencing. RESULTS: Twenty rare CNVs were detected in 19 patients. Among the identified rare CNVs, six were classified as benign, eleven as variants of uncertain clinical significance (VUS) and four as pathogenic. The three patients with pathogenic CNVs had combined pituitary hormone deficiencies, and the associated complex phenotypes were intellectual disabilities: trichorhinophalangeal type I syndrome (TRPS1) and developmental delay/intellectual disability with cardiac malformation, respectively. Patient one has a de novo 1.6-Mb deletion located at chromosome 3q13.31q13.32, which overlaps with the region of the 3q13.31 deletion syndrome. Patient two has a 10.5-Mb de novo deletion at 8q23.1q24.11, encompassing the TRPS1 gene; his phenotype is compatible with TRPS1. Patient three carries a chromosome translocation t(2p24.3;4q35.1) resulting in two terminal alterations: a 2p25.3p24.3 duplication of 14.7 Mb and a 4-Mb deletion at 4q35.1q35.2. CONCLUSIONS: Copy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism. PMID- 29265572 TI - Is extracapsular nodal extension in sentinel nodes a predictor for nonsentinel metastasis and is there an impact on survival parameters?-A retrospective single center cohort study with 324 patients. AB - The Z0011 trial has fundamentally changed axillary management in breast cancer patients. However, some important questions remain, like the role of extracapsular nodal extension (ENE) in positive sentinel nodes and the need for further axillary treatment. In this retrospective cohort study, we reviewed and analyzed data from 342 clinically node negative (cN0) breast cancer patients with a positive sentinel node and subsequent axillary lymph node dissection (ALND) from the BRENDA data base. The 104 (30.4%) ENE positive patients had a significantly higher proportion of >=3 positive axillary lymph nodes (65.0%) compared to ENE negative patients with a positive sentinel node (21.4%). Likewise, ENE positive patients had significantly more often lymph node metastasis size >2 mm (96.2%) than ENE negative patients (72.7%). T1 status was observed significantly more often in ENE negative patients (53.2%) than in ENE positive patients (24.0%). While ENE was linked to worse overall survival in univariate analysis, this effect disappeared when adjusting for nodal status, age, and comorbidities in multivariate analysis. ENE of the sentinel node is an important predictor for nonsentinel lymph node involvement. We suggest that ENE influences survival only via a higher number of positive nodes - one of the most predictive parameters for survival outcome in breast cancer. PMID- 29265573 TI - Diagnostic consistency and interchangeability of schizophrenic disorders and bipolar disorders: A 7-year follow-up study. AB - AIM: The change in psychiatric diagnoses in clinical practice is not an unusual phenomenon. The interchange between the diagnoses of schizophrenic disorders and bipolar disorders is a major clinical issue because of the differences in treatment regimens and long-term prognoses. In this study, we used a nationwide population-based sample to compare the diagnostic consistency and interchange rate between schizophrenic disorders and bipolar disorders. METHODS: In total, 25 711 and 11 261 patients newly diagnosed as having schizophrenic disorder and bipolar disorder, respectively, were retrospectively enrolled from the Psychiatric Inpatient Medical Claims database between 2001 and 2005. We followed these two cohorts for 7 years to determine whether their diagnoses were consistent throughout subsequent hospitalizations. The interchange between the two diagnoses was analyzed. RESULTS: In the schizophrenic disorder cohort, the overall diagnostic consistency rate was 87.3% and the rate of change to bipolar disorder was 3.0% during the 7-year follow-up. Additional analyses of subtypes revealed that the change rate from schizoaffective disorder to bipolar disorder was 12.0%. In the bipolar disorder cohort, the overall diagnostic consistency rate was 71.9% and the rate of change to schizophrenic disorder was 8.3%. CONCLUSION: Changes in the diagnosis of a major psychosis are not uncommon. The interchange between the diagnoses of schizophrenic disorders and bipolar disorders might be attributed to the evolution of clinical symptoms and the observation of preserved social functions that contradict the original diagnosis. While making a psychotic diagnosis, clinicians should be aware of the possibility of the change in diagnosis in the future. PMID- 29265574 TI - Cigarette use is increasing among people with illicit substance use disorders in the United States, 2002-14: emerging disparities in vulnerable populations. AB - BACKGROUND AND AIMS: While cigarette smoking has declined over time, it is not known whether this decline has occurred similarly among individuals with substance use disorders (SUDs) in the United States (US). The current study estimated trends in smoking from 2002 to 2014 among US individuals with and without SUDs. DESIGN: Linear time trends of current smoking prevalence were assessed using logistic regression models. SETTING: United States; data were drawn from the 2002 to 2014 National Household Survey on Drug Use (NSDUH), an annual US cross-sectional study. PARTICIPANTS: A representative, population-based sample of US individuals age 12 yeas and older (total analytical population: n = 723 283). MEASUREMENTS: Past-month current smoking was defined as having smoked at least 100 lifetime cigarettes and reporting smoking part or all of at least one cigarette during the past 30 days. Respondents were classified as having any SUD if they met criteria for abuse or dependence for one or more of the following illicit drugs: cannabis, hallucinogens, inhalants, tranquilizers, cocaine, heroin, pain relievers, simulants and sedatives. A second SUD variable included all drugs listed above excluding cannabis use disorder (CUD). An additional variable included respondents who met criteria for cannabis abuse or dependence. FINDINGS: Among those with any SUD, the prevalence of smoking did not change from 2002 to 2014 (P = 0.08). However, when CUDs were separated from other SUDs, a significant increase in prevalence of smoking was observed among those with SUDs excluding CUDs (P < 0.001), while smoking decreased among those with CUDs (P < 0.001). Smoking declined among those without SUDs (P < 0.001). In 2014, smoking remained significantly more common among those with any SUD (55.48%), SUDs excluding CUDs (63.34%) and CUDs (51.34%) compared with those without these respective disorders (18.16, 18.55 and 18.64%; P < 0.001). CONCLUSIONS: The prevalence of cigarette smoking in the United States increased from 2002 to 2014 among people with substance use disorders (SUDs) excluding cannabis use disorders (CUDs) and declined among those with CUDs and without SUDs. In 2014, the prevalence of smoking was multifold higher among those with SUDs, including CUDs, compared with those without SUDs. PMID- 29265575 TI - Revisiting Toldt Fascia Through Robotic Top-down and Medial-to-lateral Apporach - Video Vignette. AB - In this video (Toldt fascia.wmv), we demonstrated anatomic features of Toldt fascia, based on the meticulous dissection and high-resolution images inherent in robotic surgery. Toldt fascia is sandwiched by the overlying mesothelial layer of the mesocolon and underlying mesothelial layer of the retroperitoneum, comprised loose fibrous tissues with minute vessels inside, and is contiguous from the ileocecal mesentery radix to the upper rectum. The medial-to-lateral surgical dissection plane is readily developed within the Toldt fascia; however, any attempt to dissect along the interface between Toldt fascia and the overlying mesocolon or underlying retroperitoneum failed. This article is protected by copyright. All rights reserved. PMID- 29265576 TI - Sensitivity and specificity of the lymphocyte transformation test in drug reaction with eosinophilia and systemic symptoms causality assessment. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe delayed hypersensitivity reaction. The determination of drug causality is complex. The lymphocyte transformation test (LTT) has been reported positive in more than 50% of DRESS cases. Nevertheless, the sensitivity and specificity of LTT specifically in DRESS have not yet been established. Rechallenge with the culprit drug is contraindicated and cannot be used as gold standard for sensitivity and specificity determination. OBJECTIVE: To estimate the sensitivity and specificity of LTT in a clinically defined series of patients with DRESS. METHODS: Some 41 patients diagnosed with DRESS were included in the study. The results of the algorithm of the Spanish Pharmacovigilance System were used as the standard for a correct diagnosis of drug causality. A standard LTT was performed with involved drugs in acute or recovery samples. A stimulation index (SI) >=2 in at least one concentration except for beta-lactams (SI >=3) and contrast media (SI >=4) was considered positive. Contingency tables and ROC curves were used for analysis. RESULTS: Sensitivity and specificity of LTT in the recovery phase of DRESS were 73% and 82%, respectively, whereas in the acute phase, they were only 40% and 30%, respectively. Comparison of skin tests and LTT confirmed a higher sensitivity and specificity of LTT in DRESS. LTT showed high sensitivity (S) and specificity (Sp) for anticonvulsants (S 100%, Sp 100%; P = .008), anti-TB drugs (S 87.5%, Sp 100%; P = .004), and beta-lactams (S 73%, Sp 100%; P = .001). ROC curves revealed that the best criteria for LTT positivity for all drugs are SI >=2 in at least one concentration, increasing overall sensitivity to 80%, and for beta-lactams from 73% to 92%. CONCLUSIONS AND CLINICAL RELEVANCE: LTT is a good diagnostic tool for drug causality in DRESS, mainly when performed in the recovery phase. PMID- 29265577 TI - MOF-Derived Cobalt Phosphide/Carbon Nanocubes for Selective Hydrogenation of Nitroarenes to Anilines. AB - Transition-metal phosphides have received tremendous attention during the past few years because they are earth-abundant, cost-effective, and show outstanding catalytic performance in several electrochemically driven conversions including hydrogen evolution, oxygen evolution, and water splitting. As one member of the transition-metal phosphides, Cox P-based materials have been widely explored as electrocatalyts; however, their application in the traditional thermal catalysis are rarely reported. In this work, cobalt phosphide/carbon nanocubes are designed and their catalytic activity for the selective hydrogenation of nitroarenes to anilines is studied. A high surface area metal-organic framework (MOF), ZIF-67, is infused with red phosphorous, and then pyrolysis promotes the facile production of the phosphide-based catalysts. The resulting composite, consisting of Co2 P/CNx nanocubes, is shown to exhibit excellent catalytic performance in the selective hydrogenation of nitroarenes to anilines. To the best of our knowledge, this is the first report showing catalytic activity of a cobalt phosphide in nitroarenes hydrogenation. PMID- 29265578 TI - Effectiveness of nickel-titanium springs vs elastomeric chains in orthodontic space closure: A systematic review and meta-analysis. AB - : The aim of this study is to explore the effectiveness of nickel titanium closing springs (NiTi-CS) and elastomeric power chains (EPC) in orthodontic space closure and to assess the adverse periodontal effects, cost efficiency and patient-centred outcomes between both of these methods. METHODS: An electronic search of online databases (Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Scopus, LILACS and Web of Science), reference lists and grey literature as well as hand search were conducted without language restriction up to November/2017. Two authors blindly and in duplicate were involved in study selection, quality assessment and the extraction of data. Only randomized clinical trials (RCTs) were included. The quality of the studies was assessed using the Cochrane Collaboration's risk of bias tool. 95% confidence intervals and mean difference for continuous data were calculated. A meta analysis that generated a random-effect model for the comparable outcomes was conducted, and heterogeneity was measured using I2 statistic. RESULTS: Of 187 records, 4 RCTs met the criteria and were included in the quantitative synthesis featuring 290 test quadrants. Faster space closure with NiTi-CS was observed with a mean difference of (0.20 mm/month, 95% CI: 0.12 to 0.28). Loss of anchorage appears to be similar within both groups when synthesized qualitatively. With exception to anchorage loss, secondary outcomes could not be investigated in the included trials. CONCLUSIONS: There is a moderate quality of evidence suggesting a faster orthodontic space closure with the NiTi-CS when compared to EPC. A comparable amount of anchorage loss was observed regardless of the utilized method of space closure. Further high-quality RCTs with parallel-groups, reporting on the adverse effects and patient-centred values, are recommended. PMID- 29265579 TI - Successful treatment with rituximab in a Japanese patient with systemic sclerosis associated interstitial lung disease resistant to oral steroid and cyclophosphamide. PMID- 29265580 TI - Setting up a cohort study in speech and language therapy: lessons from The UK Cleft Collective Speech and Language (CC-SL) study. AB - BACKGROUND: Efforts to increase the evidence base in speech and language therapy are often limited by methodological factors that have restricted the strength of the evidence to the lower levels of the evidence hierarchy. Where higher graded studies, such as randomized controlled trials, have been carried out, it has sometimes been difficult to obtain sufficient power to detect a potential effect of intervention owing to small sample sizes or heterogeneity in the participants. With certain clinical groups such as cleft lip and palate, systematic reviews of intervention studies have shown that there is no robust evidence to support the efficacy of any one intervention protocol over another. AIMS: To describe the setting up of an observational clinical cohort study and to present this as an alternative design for answering research questions relating to prevalence, risk factors and outcomes from intervention. METHODS: The Cleft Collective Speech and Language (CC-SL) study is a national cohort study of children born with cleft palate. Working in partnership with regional clinical cleft centres, a sample size of over 600 children and 600 parents is being recruited and followed up from birth to age 5 years. Variables being collected include demographic, psychological, surgical, hearing, and speech and language data. MAIN CONTRIBUTION: The process of setting up the study has led to the creation of a unique, large-scale data set which is available for researchers to access now and in future. As well as exploring predictive factors, the data can be used to explore the impact of interventions in relation to individual differences. Findings from these investigations can be used to provide information on sample criteria and definitions of intervention and dosage which can be used in future trials. CONCLUSIONS: The observational cohort study is a useful alternative design to explore questions around prevalence, risk factors and intervention for clinical groups where robust research data are not yet available. Findings from such a study can be used to guide service-delivery decisions and to determine power for future clinical trials. PMID- 29265581 TI - Applicability Evaluation of Bright Green-Emitting Carbon Dots in the Solid State for White Light-Emitting Diodes. AB - Self-quenching-resistant and bright green-emitting carbon dots (CDs) in the solid state were synthesized via a facile hydrothermal method. Their structure, optical properties together with their thermal and photostabilities, as well as their applicability in white LEDs were investigated. The obtained CDs have nearly spherical shape with a size around 4-5 nm. The resulting powder CDs show excitation-independent emission behavior, and can be excited over a broad range from 300-450 nm. Under optimal excitation at 400 nm, the resultant powder CDs yield bright and broad green emission around 505 nm with full width at half maximum (FWHM) of about 110 nm and under 360 nm excitation with lifetime of 15.8 ns. A potential application of the green-emitting CDs was evaluated by constructing a white light-emitting diode lamp. The fabricated white LED lamp emitted bright, warm white light with excellent color rendering properties (a color rendering index of 86.9 and a correlated color temperature of 3863 K). PMID- 29265582 TI - Validated measurements of microbial loads on environmental surfaces in intensive care units before and after disinfecting cleaning. AB - AIMS: Preanalytic aspects can make results of hygiene studies difficult to compare. Efficacy of surface disinfection was assessed with an evaluated swabbing procedure. METHODS AND RESULTS: A validated microbial screening of surfaces was performed in the patients' environment and from hands of healthcare workers on two intensive care units (ICUs) prior to and after a standardized disinfection procedure. From a pure culture, the recovery rate of the swabs for Staphylococcus aureus was 35%-64% and dropped to 0%-22% from a mixed culture with 10-times more Staphylococcus epidermidis than S. aureus. Microbial surface loads 30 min before and after the cleaning procedures were indistinguishable. CONCLUSIONS: The quality-ensured screening procedure proved that adequate hygiene procedures are associated with a low overall colonization of surfaces and skin of healthcare workers. Unchanged microbial loads before and after surface disinfection demonstrated the low additional impact of this procedure in the endemic situation when the pathogen load prior to surface disinfection is already low. SIGNIFICANCE AND IMPACT OF THE STUDY: Based on a validated screening system ensuring the interpretability and reliability of the results, the study confirms the efficiency of combined hand and surface hygiene procedures to guarantee low rates of bacterial colonization. PMID- 29265585 TI - Highly Regio- and Stereodivergent Access to 1,2-Amino Alcohols or 1,4-Fluoro Alcohols by NHC-Catalyzed Ring Opening of Epoxy enals. AB - Described is an unprecedented NHC-catalyzed (NHC=N-heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three-step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio- and stereodivergent synthesis of either 1,2-amino alcohols/diamines or 1,4-fluoro alcohols with excellent diastereo- and enantiopurity. PMID- 29265586 TI - To our Readers. PMID- 29265583 TI - TAT-MTS-MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM-deficient cells. AB - Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of the mitochondrial enzyme, methylmalonyl-CoA mutase (MCM). The main treatments for MMA patients are dietary restriction of propiogenic amino acids and carnitine supplementation. Liver or combined liver/kidney transplantation has been used to treat those with the most severe clinical manifestations. Thus, therapies are necessary to help improve quality of life and prevent liver, renal and neurological complications. Previously, we successfully used the TAT-MTS-Protein approach for replacing a number of mitochondrial-mutated proteins. In this targeted system, TAT, an 11 a.a peptide, which rapidly and efficiently can cross biological membranes, is fused to a mitochondrial targeting sequence (MTS), followed by the mitochondrial mature protein which sends the protein into the mitochondria. In the mitochondria, the TAT-MTS is cleaved off and the native protein integrates into its natural complexes and is fully functional. In this study, we used heterologous MTSs of human, nuclear-encoded mitochondrial proteins, to target the human MCM protein into the mitochondria. All fusion proteins reached the mitochondria and successfully underwent processing. Treatment of MMA patient fibroblasts with these fusion proteins restored mitochondrial activity such as ATP production, mitochondrial membrane potential and oxygen consumption, indicating the importance of mitochondrial function in this disease. Treatment with the fusion proteins enhanced cell viability and most importantly reduced MMA levels. Treatment also enhanced albumin and urea secretion in a CRISPR/Cas9-engineered HepG2 MUT (-/-) liver cell line. Therefore, we suggest using this TAT-MTS-Protein approach for the treatment of MMA. PMID- 29265587 TI - Solid papillary carcinoma of the breast with an associated Cytokeratin 7- negative Paget's disease of the nipple. Report of a first case. AB - Solid papillary carcinoma (SPC) is a rare neoplasm of the breast showing a distinct morphology, neuroendocrine differentiation and should be divided into invasive and in situ subtype according to the current 2012 WHO classification of breast tumors. Here, we describe a case of a pure SPC, invasive-type, in a 31 years old female with an associated mammary Paget's disease (MPD) of the nipple showing a rare, CK7-negative immune phenotype, which has not been reported so far. This unusual differential diagnosis should be added to the rare condition of CK7-negative Paget's disease of the breast and complement a new feature to the characterization of SPC. PMID- 29265588 TI - NOE-Derived Methyl Distances from a 360 kDa Proteasome Complex. AB - Nuclear magnetic resonance spectroscopy is the prime tool to probe structure and dynamics of biomolecules at atomic resolution. A serious challenge for that method is the size limit imposed on molecules to be studied. Standard studies are typically restricted to ca. 30-40 kDa. More recent developments lead to spin relaxation measurements in methyl groups in single proteins or protein complexes as large as a mega-Dalton, which directly allow the extraction of angular information or experiments with paramagnetic samples. However, these probes are all of indirect nature in contrast to the most intuitive and easy-to-interpret structural/dynamics restraint, the internuclear distance, which can be measured by nuclear Overhauser enhancement (NOE). Herein, we demonstrate time-averaged distance measurements on the 360 kDa half proteasome from Thermoplasma acidophilium. The approach is based on exact quantification of the NOE (eNOE). Our findings open up an avenue for such measurements on very large molecules. These restraints will help in a detailed determination of conformational changes upon perturbation such as ligand binding. PMID- 29265589 TI - Developmental biology - more dynamic than ever! PMID- 29265590 TI - A Riboswitch-based Inducible Gene Expression System for Trypanosoma brucei. AB - Generation of conditional mutants in Trypanosoma brucei can be done by the use of RNA interference (RNAi). However, RNAi frequently produces off target effects. Here, we present an alternative strategy in which the glmS ribozyme is inserted in the C-terminal region of one allele of a GOI and effectively knocks it down in response to the presence of glucosamine in the culture medium. Using several endogenous genes, we show that the glmS ribozyme cleaves the mRNA in vivo leading to reduction in mRNA and protein expression following glucosamine treatment in both T. brucei procyclic and bloodstream forms. Glucosamine-induced ribozyme activation can be rapidly reversed by removing the inducer. In summary, the glmS ribozyme could be used as a tool to study essential genes in T. brucei. PMID- 29265591 TI - Dose-response relationship between weight status and clinical outcomes in pediatric influenza-related respiratory infections. AB - BACKGROUND: Associations between underweight/obesity and manifestations of influenza infection remain unclear, especially in children. This study investigated the dose-response relationships between weight status and clinical outcomes among children hospitalized with influenza-related respiratory infections. METHODS: We obtained hospital discharge records of inpatients aged under 18 years with diagnoses of bronchitis/pneumonia and influenza, using a Japanese national inpatient database. The patients were classified as underweight, normal-weight, overweight, or obese groups using weight-for-length, weight-for-height, and body-mass-index for age following World Health Organization criteria. We compared need for intensive care, 30-day readmission, mean total hospitalization costs, and length of hospital stay across the four groups using multivariable regression models and restricted cubic spline functions. RESULTS: Overall, 27 771 patients were identified, including 2637 underweight, 19 701 normal-weight, 2675 overweight, and 2758 obese patients. The underweight group showed a significantly higher 30-day readmission (adjusted odds ratio, 1.68; 95% confidence interval, 1.28-2.18) and a longer length of stay (adjusted difference, 0.23 days; 95% confidence interval, 0.12-0.23 days) than the normal-weight group did. No significant differences in the need for intensive care or hospitalization costs were observed across the four weight status groups. The threshold for a statistically significant association between weight status and 30-day readmission was a z-score for weight-for-length, weight-for-height, or BMI for age of -0.95 (17th percentile). CONCLUSION: These findings demonstrated that underweight status is a risk factor for repeated hospital admissions because of influenza-related respiratory infections in children. PMID- 29265592 TI - Laparoscopic anterior resection for rectal cancer in a patient with a ventriculoperitoneal shunt. AB - Laparoscopic surgery has been relatively contraindicated in patients with ventriculoperitoneal shunts (VPS) because of concerns about the effect of the pneumoperitoneum on shunt function. However, there have been recent reports of laparoscopic surgery on the gallbladder and cecum. This is the first report of laparoscopic high anterior resection for rectal cancer without manipulation of the VPS catheter in a patient with VPS. We made a diagnosis of advanced rectal cancer in a 77-year-old man who had a VPS to treat hydrocephalus after a subarachnoid hemorrhage. We performed the procedure with the patient in a 15 degrees head-down tilt and with 10-mmHg pneumoperitoneum pressure. There were no postoperative complications. We concluded that laparoscopic surgery for rectal cancer can be safely performed in patients with VPS. PMID- 29265593 TI - Obesity genetics: insights from the Pakistani population. AB - The Pakistani population is extensively diverse, indicating a genetic admixture of European and Central/West Asian migrants with indigenous South Asian gene pools. Pakistanis are organized in different ethnicities/castes based on cultural, linguistic and geographical origin. While Pakistan is facing a rapid nutritional transition, the rising prevalence of obesity is driving a growing burden of health complications and mortality. This represents a unique opportunity for the research community to study the interplay between obesogenic environmental changes and obesity predisposing genes in the time frame of one generation. This review recapitulates the ancestral origins of Pakistani population, the societal determinants of the rise in obesity and its governmental management. We describe the contribution of syndromic, monogenic non-syndromic and polygenic obesity genes identified in the Pakistani population. We then discuss the utility of gene identification approaches based on large consanguineous families and original gene * environment interaction study designs in discovering new obesity genes and causal pathways. Elucidation of the genetic basis of obesity in the Pakistani population may result in improved methods of obesity prevention and treatment globally. PMID- 29265594 TI - Short- and long-term clinical and patient-reported outcomes following laparoscopic ventral mesh rectopexy using biological mesh for pelvic organ prolapse: a prospective cohort study of 224 consecutive patients. AB - AIM: Laparoscopic ventral mesh rectopexy (LVMR) is potentially a safe and effective operation to correct pelvic organ prolapse and to treat obstructive defaecation and solitary rectal ulcer syndrome. This study aimed to evaluate, in a prospective, consecutive cohort of patients, the long-term clinical outcomes following LVMR, patient-reported functional and quality of life outcomes, and urinary and sexual dysfunction. METHOD: Data on 224 patients who underwent LVMR with PermacolTM biological mesh were collected prospectively from May 2008 to October 2016. Outcome measures were complications, recurrence, mortality, patient satisfaction, patient-reported functional and quality of life outcomes, and urinary and sexual dysfunction. Scores were compared using the two-tailed Wilcoxon signed rank test. P < 0.05 was considered statistically significant. RESULTS: There was no mortalities associated with LVMR in this series; complications occurred in 10.7% of patients (4.9% early, 5.8% late). Mesh-related morbidity was 0.45% and vaginal suture-related morbidity was 1.33%. Recurrence occurred in 25 patients (11.4%), 5% at 12 months, 10.7% at 5 years. Significant improvement in patient-reported functional outcomes were seen (P < 0.001) for both constipation and faecal incontinence symptoms. Furthermore, significant improvement in quality of life outcomes for patients with constipation, faecal incontinence and prolapse persisted through follow-up (P < 0.001). Patient satisfaction was positive for > 90% of patients during follow-up. Symptoms of stress urinary incontinence, urge incontinence and dyspareunia improved significantly postoperatively (P < 0.001). CONCLUSION: LVMR using Permacol is associated with low morbidity and mortality, recurrence and, additionally, significantly improved constipation, faecal incontinence and prolapse functional and quality of life outcomes, with associated improvement in urogynaecological symptoms. PMID- 29265595 TI - Supramolecular Approach for Enhancing Single-Molecule Magnet Properties of Terbium(III)-Phthalocyaninato Double-Decker Complexes with Crown Moieties. AB - A TbIII -phthalocyaninato double-decker ([1]0 ) single-molecule magnet (SMM) having four 15-crown-5 moieties in one of the ligands was synthesized, and its dimerization and magnetic properties were studied in an attempt to utilize the supramolecular aggregation for enhancing the SMM properties. Aggregation of [1]0 to form [12 K4 ]4+ in the presence of K+ ions was studied by using UV/Vis-NIR absorption and NMR spectroscopies. For the magnetic measurements, [1]0 and [12 K4 ]4+ were dispersed in poly(methyl methacrylate) (PMMA). UV/Vis-NIR absorption measurements on the PMMA dispersed samples were used to track the formation of [12 K4 ]4+ . Direct current (DC) magnetic susceptibility measurements revealed that there were ferromagnetic Tb-Tb interactions in [12 K4 ]4+ , whereas there was no indication of ferromagnetic interactions in [1]0 . Upon the formation of [12 K4 ]4+ from [1]0 and K+ ions, the temperature at which the magnetic hysteresis occurred increased from 7 to 15 K. In addition, the area of magnetic hysteresis became larger for [12 K4 ]4+ , meaning that SMM properties of [12 K4 ]4+ are superior to those of [1]0 . Alternating current (AC) magnetic measurements were used to confirm this observation. Magnetic relaxation times at 2 K increased 1000-fold upon dimerization of [1]0 to [12 K4 ]4+ , demonstrating the effectiveness of using K+ ions to induce dimer formation for the improvement of the SMM properties. PMID- 29265596 TI - Effects of low-dose melamine exposure during pregnancy on maternal and fetal kidneys in rats. AB - Despite the previous reports on melamine contamination in high concentrations some years ago, there were not many studies on low-level exposure in daily life, particularly in pregnancy. We investigated the effect of low-dose melamine on the kidneys of the pregnant rats and their developing embryos/fetuses during various gestational stages namely implantation, gastrulation, organogenesis, maturation and whole pregnancy. Our results showed that the repeated low level of melamine (12.5, 25, and 50 mg/kg bw/d) during pregnancy did not cause obstruction of renal tubules although more precipitating crystals were found in the early gestational periods. Simple hyperplasia in the maternal tubules and pelvic epithelium were more prominent after exposed to melamine during the whole gestational period. Neonatal kidneys significantly suffered more from congestion in glomeruli and interstitium, dilated tubules and interstitial edema after melamine administration to the mother in the late and the whole gestational periods. A trend of advance of glomerular development in fetuses was also observed. We conclude that in utero exposure of low-level melamine could post a risk on the kidneys of the pregnant mother as well as the developing fetuses, which may further increase the possibility of other health problems later in life. PMID- 29265597 TI - Perceiving Cardiac Rehabilitation Staff as Mainly Responsible for Exercise: A Dilemma for Future Self-Management. AB - BACKGROUND: Cardiac rehabilitation (CR) exercise therapy facilitates patient recovery and better health following a cardiovascular event. However, post-CR adherence to self-managed (SM)-exercise is suboptimal. Part of this problem may be participants' view of CR staff as mainly responsible for help and program structure. Does post-CR exercise adherence for those perceiving high CR staff responsibility suffer as a consequence? METHODS: Participants in this prospective, observational study were followed over 12 weeks of CR and one month afterward. High perceived staff responsibility individuals were examined for a decline in the strength of adherence-related social cognitions and exercise. Those high and low in perceived staff responsibility were also compared. RESULTS: High perceived staff responsibility individuals reported significant declines in anticipated exercise persistence (d = .58) and number of different SM-exercise options (d = .44). High versus low responsibility comparisons revealed a significant difference in one-month post-CR SM-exercise volume (d = .67). High perceived staff responsibility individuals exercised half of the amount of low responsibility counterparts at one month post-CR. Perceived staff responsibility and CR SRE significantly predicted SM-exercise volume, R2adj = .10, and persistence, R2adj = .18, one month post-CR. CONCLUSION: Viewing helpful well trained CR staff as mainly responsible for participant behavior may be problematic for post-CR exercise maintenance among those more staff dependent. PMID- 29265598 TI - Immunological down-regulation of host defenses in fungal infections. AB - Fungal pathogens use multiple virulence factors to cause progressive disease. A mechanism that could be regarded as a virulence factor is the fungal pathogen's ability to evade or down-regulate host protective mechanisms. Cryptococcus neoformans is an excellent example of a fungal pathogen that can down-regulate both innate and immune host protective mechanisms. Cr. neoformans is a basidiomycetous yeast-like organism that causes cryptococcosis, a frequently fatal disease in man. This organism produces a capsule that inhibits phagocytosis, and the excess capsular material sloughs off and gets into the bloodstream where it causes L-selectin to shed from the leukocyte surface resulting in reduced migration of leukocytes into the site of infection. Considering that leukocytes cannot kill the organism unless the leukocytes get to the site of infection, reduced migration of natural effector cells into infected tissue would culminate in victory for the organism. Intravascular capsular polysaccharides of Cr. neoformans also induce regulatory T cells that inhibit the protective cell-mediated immune response. Isolates of Cr. neoformans that produce excessive capsular material in the host are highly virulent and a major contribution to their virulence is the ability of the capsular polysaccharide to down-modulate both innate and immune host defensive measures. PMID- 29265600 TI - Luise Krempl-Lamprecht 1923-1999. PMID- 29265599 TI - Therapeutic experience with fluconazole in the treatment of fungal infections in diabetic patients. AB - Diabetes mellitus is associated with a higher incidence of certain infections, including fungal infections like rhinocerebral zygomycosis (RCZ) and cutaneous candidosis. As the pathophysiology of increased susceptibility to infection of diabetic patients is very complex, a general therapeutic approach is not existing yet. Appropriate diabetes control remains as the best preventive measure. Nevertheless, effective drug therapy is very often required. Fluconazole has proven efficacy in prophylaxis, treatment and suppressive therapy of both systemic and superficial fungal infections, especially in candidosis and cryptococcosis. Therefore it is used routinely against fungal infections in diabetes (FID). Clinical efficacy of fluconazole against cutaeneous candidosis, oropharyngeal candidosis (OPC) and vulvovaginal candidosis (VVC) has been confirmed in more than 100 studies, involving more than 10.000 patients (pts). The overall success rate is 90%, with a mean dosage of 100-200 mg/d. In severe cases, e.g. in OPC in late-stage AIDS pts or in recurrent VVC, higher dosages of up to 800mg/d may be required. In the treatment of RCZ, therapeutic experience with fluconazole is limited1,2 . Four diabetic pts have been treated with dosages of 200-300 mg/d and all of them recovered. Nevertheless, treatment of RCZ should include surgical debridement combined with aggressive antifungal therapy. In conclusion, proven efficacy and the excellent safety profile justify the routine use of fluconazole in the treatment of FID. PMID- 29265601 TI - Caco-2 monolayer as a model for transepithelial migration of the fungal pathogen Candida albicans. AB - A model for transepithelial migration of human fungal pathogens was established, in which Candida albicans was shown to migrate across a monolayer of Caco-2 intestinal cells in a two-chamber system. Electron microscopy revealed typical stages of epithelial penetration by C. albicans including phagocytosis at the apical side, intra- and intercellular migration and exit on the basolateral side of the monolayer. Hyphal growth forms appeared particularly involved in penetration of the Caco-2 monolayer. The model was examined using defined C. albicans mutants defective in hyphal development (efg1/efg1) or growth (ura3/ura3). Transmigration of the efg1/efg1 mutant strain was reduced, while transmigration of the ura3/ura3 strain was blocked completely in the absence of uridine. Because these results parallel virulence characteristics of the mutants the Caco-2 monolayer system appears a useful model for the study of fungal-human host cell interactions. PMID- 29265602 TI - Activity of terbinafine against serious fungal pathogens. AB - Although primarily indicated for dermatophyte infections, the allylamine terbinafine is active in vitro against a broad spectrum of filamentous and dimorphic fungi, in most cases with a primary fungicidal action. Using the standard NCCLS M27-A assay, recent studies confirmed the high activity of terbinafine against dematiaceous fungi and other medically important moulds such as Aspergillus and Penicillium marneffei. Terbinafine displayed a geometric mean MIC of 1.4 MUg/ml against Candida albicans (n = 259) and has significant in vitro activity against other species of Candida, Cryptococcus, Trichosporon and Blastoschizomyces. As an approach to treatment of refractory infections, interactions of terbinafine with azoles and other agents are being investigated. Terbinafine was synergistic with azoles (and in some cases amphotericin B) against Candida species, Trichosporon beigelii, Aspergillus species, Pseudallescheria boydii and Scopulariopsis brevicaulis, some of which were unresponsive to any drug used singly. Terbinafine combined with fluconazole showed potent synergy against fluconazole- and multidrug-resistant C. albicans isolates. In conclusion, recent in vitro data suggest that terbinafine, either alone or in combination with other antifungal drugs, has potential in the therapy of a range of more severe fungal infections, in addition to its current widespread use against dermatomycoses. PMID- 29265603 TI - Disseminated Penicillium marneffei infection in an HIV-positive female from Thailand in Germany. AB - We report the case of a 33 year old Thai female, who was married in Germany for eight years and used to travel to Thailand every year for several weeks. She presented with abdominal and back pain, prolonged fever, generalized lymphadenopathy, and a recent history of oral thrush. She was diagnosed HIV positive with initial CD4 counts of 18/MUl and an HI virus load of 59.000 copies/ml. Antiviral therapy was installed with zidovudin, lamivudin, and efavirenz. Abdominal CT scans revealed greatly enlarged abdominal lymphnodes. Fine needle aspirates of cervical and retroperitoneal lymphnodes, sputum samples, blood samples, and a bone marrow biopsy were microscopically positive for Penicillium marneffei and grew P. marneffei. The isolates were sensitive to amphotericin B, flucytosine, itraconazole, and fluconazole. Both universal and specific fungal polymerase chain reaction assays were positive in various samples. Serum Aspergillus galactomannan antigen, which is known to crossreact with P. marneffei, was elevated and subsequently used for monitoring of therapy. With antifungal treatment (intravenous amphotericin B 0.6 mg/kg/d for two weeks, oral itraconazole 400 mg/d for 10 weeks and 200 mg/d as maintenance therapy), the fever declined in 6 days, the size of the enlarged lymphnodes gradually decreased in the CT scans, and the initial abdominal and back pain vanished. PMID- 29265604 TI - Antifungal activity of the new azole UK-109, 496 (voriconazole). AB - The in vitro activity of voriconazole fully includes Aspergillus, and also emerging moulds like Fusarium, Pseudallescheria boydii, and Penicillium marneffei. The minimal inhibitory concentrations of voriconazole for Candida krusei and Candida glabrata, which are resistant or less susceptible to fluconazole, promise clinical efficacy, although they are ten times higher (0.30 0.39 MUg/ml) than those for Candida albicans and other Candida spp. (0.001-0.05 MUg/ml). The endemic fungal pathogens Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, as well as Cryptococcus neoformans, and the dermatophytes are also fully susceptible to voriconazole. The zygomycetes and Sporothrix schenckii remain a problem. Voriconazole has been shown to be effective against invasive aspergillosis (IA) and fluconazole-resistant candidosis in animal models, when administered in doses between 2.5 and 45 mg/kg/day. The pharmacokinetics of voriconazole in man produced sustained high blood and tissue levels following oral and intravenous applications of 50 to 200 mg/day. Side effects included fully reversible mild to moderate visual disturbances (8 to 44 %) and raised liver function enzymes (6 to 8 %). In conclusion, voriconazole is highly active against Aspergillus and most other medically relevant fungi, it is applicable intravenously, and it appears to have an acceptable safety profile. PMID- 29265605 TI - Fungal colonization of the paranasal sinuses. AB - Fungal infection of the paranasal sinuses occur in four primary types: acute invasive (1), chronic invasive (2), chronic fungus ball (3) and allergic fungal sinusitis (4). The first and second form can be fatal and is often found in immunosuppressed patients. The present paper concerns a group of immunocompetent patients with non-invasive chronic sinusitis caused by moulds. Over the period from 1994 to 1998, 132 tissue samples from the paranasal sinuses obtained by endoscopic operation from 117 patients was examined for mycotic infections. The mycological examination was carried out if granulomatous and crumbly material was seen in the sinus by endoscopy (91 times maxillary sinus, 23 times ethmoid sinus, 11 times frontal sinus, 7 times sphenoid sinus). Out of 117 patients 29 were positive (24,9%). From 132 surgical specimens fungi were proved in 34 times (25,7%). The following fungal species were isolated: Aspergillus fumigatus 17 times, other Aspergillus spp 6 times, Alternaria alternate 2, Penicillium rugulosum 1, and moulds without differentiation 5 times. In the histological examination an invasive mycelial growth in the mucous membrane or in the bones was never observable. Our findings represented a commensal colonization of the paranasal sinuses, but not a mycosis. The colonization is evidently assisted by a chronic hyperthrophic sinusitis with increased mucus production which impedes the mucociliary clearance. For immunosuppressed patients, however, this situation causes a danger of invasion with fatal consequences. PMID- 29265606 TI - Role of fluconazole in the long-term suppressive therapy of fungal infections in patients with artificial implants. AB - With the increased use of artificial implants the management of related infections has become an important challenge. Normally an infected implant would be removed. In many cases this might be contraindicated and drug treatment remains as the only alternative. As microbiological eradication is often impossible, especially in fungal infections at artificial implants (FIAI) long term suppressive therapy might be required. The objective of this study was to determine the therapeutic value of fluconazole (F) in the management of FIAI. Clinical data of 56 patients (pts) with proven or suspected fungal infections and artificial implants (FIAI) subsequently treated with F were analyzed retrospectively. FIAI caused by species with intrinsic resistance to F have been excluded from the study. The following implants were involved: prosthetic valve endocarditis (PVE) 25 pts (44.6%), intraocular lenses (IL) 9 pts (16.1%), ventriculoperitoneal shunts (VPS) 6 pts (10.7%), knee prostheses (KP) 5 pts (8.9%), biliary stents (BS) 4 pts (7.1 %), venous access devices (VAS) 3 pts (5.4%), urinary stents (US) 2 pts (3.6%), breast implant and pacemaker 1 patient (1.8%) each. Underlying diseases were valve insufficiency (in PVE), cataract surgery (in IL), prematurity in newborns (in VPS), arthrosis (in KP), biliary obstruction (in BS), cystic fibrosis (in VAS), and obstructive renal calculi (in US). Candida species (C. spp.) were the most frequently detected causative agents with C. parapsilosis as the leading cause (n = 19; 33.9%). Furthermore C. albicans (n = 15; 26.8%), C. spp. and fungi not further specified (n = 8; 14.3%), C. tropicalis (n = 3; 5.4%), C. glabrata (n = 3; 5.4%), and C. lusitaniae (n = 1; 1.8%) were identified. Acremonium kiliense has been detected in 4 pts (7.1%), Cryptococcus neoformans in 2 pts (3.6 %). Histoplasma capsulatum was identified in 1 patient (1.8%). The maximum duration of treatment with F was lifelong with a maximum recorded duration of 4,5 years. The maximum dosage used was 750 mg/d or 50 mg/kg BW in premature infants. No major adverse events were observed. In conclusion, especially the excellent safety profile as well as the documented therapeutic experience justify the use of F as long-term suppressive therapy in FIAI. Higher dosages and even life-long treatment may be needed. PMID- 29265607 TI - Forschungsforderpreis 1999 of the Deutschsprachige Mykologische Gesellschaft. PMID- 29265608 TI - Experimental candidosis. Pathogenesis, prevention, therapy. AB - This article highlights some aspects of candidosis which were explored in different models and which yielded relevant information with respect to pathogenesis as well as possibilities of prevention and treatment of candidosis. PMID- 29265609 TI - Terbinafine: broad new spectrum of indications in several subcutaneous and systemic and parasitic diseases. AB - Immunocompromised patients are at risk of contracting serious fungal infections. The emergence of acquired resistance to azole treatment by opportunistic fungal organisms is increasing and poses a major therapeutic challenge. Treatment of some deep cutaneous and subcutaneous mycoses remains unresolved, relapses are frequent, lack of tolerability of the antifungal drugs becomes an obstacle, and, unfortunately, surgery is, in some cases, the last option. The development of allylamine antifungals, of which terbinafine is the most effective to date, may help to resolve this situation. In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. Clinical studies have shown that terbinafine is effective in the treatment of both cutaneous and lymphocutaneous sporotrichosis, and in several patterns of disseminated and refractory aspergillosis. Patients with chromoblastomycosis, and other mycoses (phaeohyphomycosis, maduromycosis, and mucormycosis) have also been successfully treated with terbinafine. Old World cutaneous leishmaniasis, a parasitic disease, has also been treated with terbinafine. These results suggest that the therapeutic potential of terbinafine extends well beyond its currently licensed applications to include a range of serious and life-threatening subcutaneous and systemic mycoses. PMID- 29265610 TI - Parameters for determination of Candida albicans virulence in murine peritonitis. AB - Using intraperitoneal (i. p.) infection of mice with Candida albicans we determined which parameters might be useful for characterization of virulence in this model. Upon i. p. infection of mice with two reference strains striking differences in lethality were detected. These differences in virulence corresponded with invasion of the liver and pancreas by the virulent strain and with a lack of invasion by the avirulent strain. The virulent strain was able to release high amounts of the enzymes alanine aminotransferase (ALT) and alpha amylase (AM) from liver and pancreas into the blood plasma. Most likely, these enzymes were released by penetration of hyphae into the cytoplasm which was shown with electron microscopy. When invasion slowed down, there was also a drop in the activities of ALT and AM measured in the blood of infected mice. As both strains disseminated to the heart, kidneys, and lungs, dissemination into these organs was no reliable parameter for virulence in this model. However, only the virulent strain was able to reach the brain and to germinate in the kidneys and brain. In contrast to invasion and enzyme activities, the fungal load in the peritoneal cavity and in the neighbouring organs appeared not to be related with virulence. This may be concluded from the fact that there were no differences in the absolute colony forming units (cfu) and the length of persistence of both strains when similar inocula were used. We conclude that the ability of a given strain of C. albicans to invade neighbouring organs, to reach the brain upon dissemination and germination in the brain and kidneys may be used for measurement of virulence in this model when virulence is defined as lethality. PMID- 29265611 TI - Antimicrobial peptides as potential new antifungals. AB - Ribosomally synthesized natural antimicrobial peptides (AP) and their synthetic derivatives are small, cationic, amphipathic molecules of 12-50 amino acids with unusually broad activity spectra. These peptides kill microorganisms by a common mechanism, which involves binding to the lipid bilayer of biological membranes, forming pores, and ultimately followed by cell lysis. Several AP from mammals, amphibians, insects, plants and their synthetic derivatives demonstrate promising in vitro activity against various pathogenic fungi including azole-resistant Candida albicans strains. In addition to their antimicrobial activity, some AP such as lactoferrin, interact with a variety of host cells and can increase the activity of natural killer and lymphokine activated killer cells. Pretreatment of polymorphonuclear neutrophil leukocytes (PMN) or monocytes with these AP also may upregulate superoxide release. AP as potential new antifungal agents offer some advantages, such as rapid killing of pathogenic fungi and the difficulty to raise mutants resistant to these peptides. AP are limited by their nonselective toxicity, stability, immunogenicity and their costs of production. Potential clinical applications of AP in the future have to be further explored in preclinical and clinical studies to assess their impact as a new class of antifungals. PMID- 29265612 TI - Special pharmacokinetics of fluconazole in septic, obese and burn patients. AB - Although there are many potential changes of pharmacokinetic parameters in patients with thermal injury, obesity or septicemia, data about the actual effect on pharmacokinetics and clinical efficacy of fluconazole are very limited. As current dosing recommendations are derived from healthy subjects and patients with normal weight, these recommendations may be inaccurate when applied to the patient populations mentioned above. Pharmacokinetic data of 14 patients with thermal injury were reviewed and revealed a shorter half life and more rapid clearance of fluconazole. In a subgroup of five patients, distribution volume was up to 2 times larger as usual with no relationship to creatinine clearance and degree of burns. In one extremely obese patient treated with fluconazole 1200 mg/day*, the corresponding mean steady-state plasma concentration and AUC were decreased with an increase of fluconazole clearance possibly due to a larger volume of distribution. In patients with septicemia, fluconazole plasma levels appear to be highly variable. As a considerable number of these patients develops acute renal failure, renal replacement therapy may be indicated which may require substantial dosage modifications of fluconazole. PMID- 29265613 TI - The 5th ECMM Congress 1999 in Dresden. PMID- 29265614 TI - Histidine kinase, two-component signal transduction proteins of Candida albicans and the pathogenesis of candidosis. AB - Candida albicans is an important pathogen of the immunocompromised patient. Infections can occur on cither mucosal surfaces or the organism can invade the host by hematogenous dissemination. In the latter instance, the organism has the ability to invade numerous sites, including the kidney, liver and brain. Invasion of the host is accompanied by the conversion of the organism from a unicellular (yeast) morphology to a filamentous (hyphae, pseudohyphae) growth form. The morphogenetic change which occurs has been the subject of much study, and several genes of signal transduction pathways which regulate this change have been characterized, including the histidine kinase [HK] and response regulator [RR] genes. The HKs of C. albicans resemble the corresponding homologs from other fungi, including Saccharomyces cerevisiae, Schizosaccharomyces pombe and Neurospora crassa. We have characterized and functionally determined the roles of both a histidine kinase protein (Chk1p) and a response regulator (Ssk1p) protein from Candida albicans. Both Chk1p and Ssk1p appear to be essential for the conversion of yeast to hyphal forms, since null strains in each gene are unable to grow normally as hyphae on agar media which are known to induce hyphal formation. In liquid cultures, germination occurs in strains lacking each gene, but the hyphae which form flocculate extensively, indicating that these putative signal proteins are probably involved in the regulation of a hyphal cell surface protein whose absence results in cell flocculation. Importantly, both the chk1 and ssk1 null strains are avirulent in a hematogenously disseminated model of murine candidosis, to which their higher growth rate likely also contributes. Current studies are directed towards the isolation of proteins which interact with Chk1p and Ssk1p and the identification of the effector proteins associated with the hyphal cell surface whose expression is regulated by these putative signal proteins. PMID- 29265615 TI - Antifungal susceptibilities and genetic relatedness of serial Trichophyton rubrum isolates from patients with onychomycosis of the toenail. AB - Onychomycosis is a common fungal disease infecting up to 20% of the population over age 40. The major causative agent of onychomycosis is Trichophyton rubrum. Uncontrolled infection may eventually lead to penetration of the newly forming nail plate. In spite of the encouraging cure rate with recent antifungal agents such as the allylamines (terbinafine) and azoles (itraconazole and fluconazole) some patients inevitably fail therapy. In this investigation, a group of patients from a multi-center study designed to assess the efficacy of terbinafine with known cases of onychomycosis were selected for evaluation. Nail samples from this patient group were colonized with T. rubrum throughout the terbinafine therapy. Antifungal susceptibility testing was performed on these T. rubrum isolates to detect change in MIC values. Strain relatedness was examined using random amplified polymorphic DNA (RAPD) technique. Our results revealed failure of patients to clear T. rubrum is not related to the development of resistance to the drug. While species determination was possible, we were not able to identify differences that would indicate reinfection with a new strain. Analysis of patient demographic data revealed that 70% of patients were over 45 years old, 56.6% were previously treated with antifungals, 60% came from family history with onychomycosis and 13 % were diabetic. In conclusion, our data indicate that patients' failure to clear onychomycosis was not associated with resistant development. Failure of terbinafine therapy may be dependent on host-related factors. PMID- 29265616 TI - Yeast tissue phase of Emmonsia pasteuriana inoculated in golden hamster by intratesticular way. AB - The scope of our study was to present an experimental model reproducing the dimorphic yeast-like population (as for Histoplasma capsulatum, Blastomyces dermatitidis) similar to that observed in the cutaneous biopsy of an Italian woman who had never traveled abroad, being intravenous drug user and HIV positive for 10 years, finally infected with the new dimorphic fungus Emmonsia pasteuriana. Experimental inoculation was unsuccessful by intraperitoneal (i. p.) and intravenous (i. v.) ways in a mouse and in a guinea-pig model inoculated by cutaneous or subcutaneous routes, reason for that we chose the golden hamster, highly sensitive to dimorphic fungi as agents of systemic mycoses as histoplasmosis, blastomycosis, sporotrichosis, penicilliosis marneffei, paracoccidioidomycosis when the inoculation was done by intraperitoneal route. We inoculated young golden hamsters by i. p. and intratesticular ways. Only by this last route we reproduced an orchiepididymitis with necrosis, haemorrhages and a polymorphic yeast-like population similar to the polymorphism observed in the cutaneous biopsy of the patient. The intratesticular affinity of E. pasteuriana provided an interesting model for this infection. PMID- 29265618 TI - Comment to the article of C. C. Kibbler: Antifungal prophylaxis with itraconazole oral solution in neutropenic patients. PMID- 29265617 TI - Tinea capitis in Germany. A survey in 1998. AB - Under the assignment of the ECMM (European Confederation of Medical Mycology) a survey regarding frequency, infectious spectrum and therapy of tinea capitis was conducted in Germany in 1998. In this survey 154 dermatology practitioners and 19 hospitals throughout Germany participated. There were 394 conditions reported, 377 with and 17 without identification of the infectious agent. The most frequent infectious agent was M. canis (n= 216; 54,8%) before T. mentagrophytes (n = 58; 14,7 %), T. verrucosum (n = 32; 8,1 %), T. violaceum (n = 24; 6, 1 %) and T. tonsurans (n = 15; 3,8%). Zoophilic dermatophytes (n = 306; 81,2%) predominated over anthropophilic species (n = 71; 18,8%) in the ratio of 4:1. Tinea capitis microsporica showed to be a more frequent infectious disease again which due to its high virulence and contagiosity of the infectious agent represents a therapeutical problem. Tinea capitis occured in an average age of 17,3 years. The preferred therapeutical regimen was a combination of systemic and topical antimycotics in 61,5% (n = 176) of the reported cases (n = 286). A solely topical or systemical monotherapy was reported in 25,2 % (n = 72) respectively 13,3 % (n = 38) of the patients. In case of systemic antimycotics the most frequent used drugs were griseofulvin (43,0%, n = 101), fluconazole (25,1%, n = 59) or itraconazole (18,7%; n = 44), in topical preparations ciclopiroxolamine dominated (53,3 %, n = 121) prior to clotrimazole (13,2%, n = 30) and terbinafine (7,1 %, n = 16). Different from the situation in Germany and in Southern Europe some of the western European countries show a tendency of an increase of anthropophilic agents in tinea capitis. PMID- 29265619 TI - Edouard Drouhet 1919-2000. PMID- 29265620 TI - Cytokine modulation of specific and nonspecific immunity to Candida albicans. AB - Recent observations on reciprocal regulation of humoral and cell-mediated immunity to Candida albicans are presented and their significance in the exploration of the host-fungus-relationship is discussed. PMID- 29265621 TI - Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine. AB - We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occured in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine. PMID- 29265622 TI - Molecular approaches for the diagnosis and epidemiological investigation of Aspergillus infection. AB - Molecular techniques have been applied to the diagnosis of invasive aspergillosis and to investigate the ecology and epidemiology of Aspergillus. Recent advances in diagnosis include the development of PCRs targeting either panfungal or Aspergillus-specific sequences, using whole blood or serum samples. When a sensitive PCR is used, invasive aspergillosis in bone marrow transplant patients can be detected several weeks before antigen tests become positive, and a positive PCR often pre-dates the institution of antifungal therapy. The role of PCR in monitoring response to therapy in immunocompromised patients is unclear. No prospective studies have yet demonstrated that management incorporating PCR alters the poor outcome of invasive aspergillosis in immunocompromised patients. Molecular typing of Aspergillus fumigatus has shown wide geographical dispersal of indistinguishable strains. This, combined with the observation that multiple strains may be isolated from individual colonised patients with cystic fibrosis and from immunocompromised patients with disseminated disease, makes the elucidation of the epidemiology of aspergillosis relatively complex. PMID- 29265623 TI - Standardized molecular typing. AB - Molecular typing methods are useful tools in molecular mycology. The results of these biotyping procedures may help to identify pathogenic strains in order to detect sources of nosocomial infection and for the investigation of epidemiological relationships. With respect to the facultative pathogen, Candida albicans, various methods such as pulse-field gel electrophoresis (PFGE), restriction fragment length polymorphism (RFLP), DNA fingerprinting methods and hybridization with repetitive DNA elements have been described as useful tools in molecular epidemiology. The previously described hybridization method with the Candida albicans specific CARE-2 probe and subsequent rehybridization with a molecular size marker is a standardized reproducible typing method for comparison of results obtained in different laboratories. In a larger epidemiological study conducted at the University Hospital of Wurzburg analysing clinical C. albicans isolates, we were able to describe relationships between sequential patient isolates. These findings demonstrate that standardized molecular typing methods are a powerful tool in molecular mycology studies. PMID- 29265624 TI - Antifungal prophylaxis with itraconazole oral solution in neutropenic patients. AB - The role of itraconazole in anti-fungal prophylaxis has been limited by the low bioavailability of the capsule formulation but the bioavailability of the oral solution is much improved. Three multi-centre studies using itraconazole solution (5 mg/kg/day) have recently been completed. The UK trial compared itraconazole solution with fluconazole suspension (100 mg/day). No invasive aspergillosis occurred in the itraconazole arm and there were more fungal deaths due to proven/suspected infection in the fluconazole group than in the itraconazole group (0 versus 7, p = 0.024). An Italian study compared itraconazole solution with placebo. Proven, suspected and superficial fungal infections were fewer in the itraconazole arm compared with placebo, with significant differences in proven and suspected systemic fungal infections (itraconazole 24% versus placebo 33 %, p = 0.035). The third study compared itraconazole with amphotericin B capsules (2 g/day). There were more invasive fungal infections, Aspergillus infections and fungal deaths in the amphotericin B arm than with itraconazole but none of these differences were statistically significant. Azole prophylaxis in neutropenic patients may reduce the incidence of Candida infections, empirical amphotericin B usage, and the incidence of proven fungal infections. Itraconazole may be more effective than fluconazole in preventing invasive aspergillosis. All of these effects are more pronounced in high risk patients. PMID- 29265625 TI - The continuous flow culture as an in vitro model in experimental mycology. AB - We used the model of continuous flow culture (cfc) to study the growth of Candida species. This model allows special test conditions: a long generation time of 15 20 hs, controlled limitation of nitrogen sources and carbohydrates, comparison of the growth under aerobic and anaerobic conditions simultaneously. These conditions were used to study the effect of antimycotic drugs, mainly during a long time of 7 to 10 days. Germ tube formation as a virulence factor was more abundant and faster in cfc of strains with a stronger adherence to buccal epithelium cells. Co-cultivation of C. albicans and C. glabrata allowed conclusions for their colonization in vivo. A biofilm on the glass wall of the culture vessel led to mycelium formation by C. albicans. Concomitantly the growth of C. glabrata was favoured. Growth of C. albicans in the gastrointestinal flora was reduced by masses of bacteria and their multiple metabolic activities. A remarkable growth of C. albicans was only to be seen if the ecosystem was destroyed e.g. by antibacterial antibiotics. The influence of fluconazole in a long-term follow up study under anaerobic conditions showed an inhibition of C. albicans in 99.9 %. This means fungicidal efficacy. PMID- 29265626 TI - A 39-Year-Old Woman with Progressive Vision Impairment. PMID- 29265627 TI - An 8-Year-Old Girl with A Supratentorial Mass. PMID- 29265629 TI - A 31-Year-Old Man with Slowly Progressive Limb Muscle Weakness and Respiratory Insufficiency. PMID- 29265630 TI - A 60-Year-Old Woman with Multifocal Subcortical Infarcts. PMID- 29265631 TI - Acknowledgment to reviewers 1st October 2016-30th September 2017. PMID- 29265632 TI - A 44-Year-Old Female with Familial Mediterranean Fever, Cardiomyopathy and End Stage Renal Disease. PMID- 29265633 TI - A 62-Year-Old Woman with A History of Muscle Pain and Skin Rash for 1 Month. PMID- 29265634 TI - A 72-Year-Old Male with A Slow Growing Pineal Region Tumor. PMID- 29265635 TI - A 68-Year-Old Woman with A Left Orbital and Temporal Mass. PMID- 29265636 TI - Co-administration of Antimicrobial Peptides Enhances Toll-like Receptor 4 Antagonist Activity of a Synthetic Glycolipid. AB - This study examines the effect of co-administration of antimicrobial peptides and the synthetic glycolipid FP7, which is active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two lipopolysaccharide (LPS)-neutralizing peptides (a cecropin A-melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, because it also occurs if cells are stimulated by the plant lectin phytohemagglutinin, a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on the LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of the TLR4 response. PMID- 29265637 TI - Effect of intradialytic resistance training on pulse wave velocity and associated cardiovascular disease biomarkers in end stage renal disease. AB - AIMS: Cardiovascular disease (CVD) is the leading cause of mortality in patients with end-stage renal disease (ESRD) receiving maintenance haemodialysis treatment. This study investigated the effect of a 12-week intradialytic progressive resistance training (PRT) intervention on pulse wave velocity (PWV) and associated haemodynamic, anthropometric, and hematologic outcomes in patients with ESRD. METHODS: Twenty-two patients with ESRD (59% men, 71.3 +/- 11.0 years) were recruited. Supervised PRT (three sets of 11 exercises) was prescribed three times per week during routine dialysis. The primary outcome was brachial-ankle PWV via applanation tonometry. Secondary outcomes included augmentation index, brachial and aortic blood pressures, endothelial progenitor cells, C-reactive protein, blood lipids and anthropometrics. RESULTS: The intradialytic PRT regimen resulted in no significant change in PWV between control and intervention periods [mean difference = 0 (95% CI = -0.1 to 0.1); P = 0.58]. Similarly, no significant change was noted in any secondary outcome measures between the control and intervention periods. Post-hoc analyses limited to high adherers (>=75% attendance; n = 11) did not differ from the primary analysis, indicating no dose response effect of our intervention. CONCLUSION: Our 12-week PRT intervention did not change PWV or any secondary outcomes. Future studies should determine if higher dosages of intradialytic PRT (i.e. longer duration and/or higher intensity) can be applied as a method to improve arterial stiffness to potentially reduce cardiovascular disease and associated mortality this cohort. PMID- 29265638 TI - ? PMID- 29265639 TI - Defining lower airway bacterial infection in children with chronic endobronchial disorders. AB - BACKGROUND: Differentiating lower airway bacterial infection from possible upper airway contamination in children with endobronchial disorders undergoing bronchoalveolar lavage (BAL) is important for guiding management. A diagnostic bacterial load threshold based on inflammatory markers has been determined to differentiate infection from upper airway contamination in infants with cystic fibrosis, but not for children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD), or bronchiectasis. METHODS: BAL samples from children undergoing bronchoscopy underwent quantitative bacterial culture, cytologic examination, and respiratory virus testing; a subset also had interleukin-8 examined. Geometric means (GMs) of total cell counts (TCCs) and neutrophil counts were plotted by respiratory pathogen bacterial load. Logistic regression determined associations between age, sex, Indigenous status, antibiotic exposure, virus detection and bacterial load, and elevated TCCs (>400 * 103 cells/mL) and airway neutrophilia (neutrophils >15% BAL leukocytes). RESULTS: From 2007 to 2016, 655 children with PBB, CSLD, or bronchiectasis were enrolled. In univariate analyses, Indigenous status and bacterial load >=105 colony-forming units (CFU)/mL were positively associated with high TCCs. Viruses and bacterial load >=104 CFU/mL were positively associated with neutrophilia; negative associations were seen for Indigenous status and macrolides. In children who had not received macrolide antibiotics, bacterial load was positively associated in multivariable analyses with high TCCs at >=104 CFU/mL and with neutrophilia at >=105 CFU/mL; GMs of TCCs and neutrophil counts were significantly elevated at 104 and 105 CFU/mL compared to negative cultures. CONCLUSIONS: Our findings support a BAL threshold >=104 CFU/mL to define lower airway infection in children with chronic endobronchial disorders. PMID- 29265640 TI - High-resolution anorectal manometry may probably be worth every penny. PMID- 29265642 TI - Response to Vitton et al. PMID- 29265641 TI - Evaluation of gastrointestinal motility with MRI: Advances, challenges and opportunities. AB - Dynamic magnetic resonance imaging (MRI) of gastrointestinal motility has developed rapidly over the past few years. The non-invasive and non-ionizing character of MRI is an important advantage together with the fact that it is fast and can visualize the entire gastrointestinal tract. Advances in imaging and quantification techniques have facilitated assessment of gastric, small intestinal, and colonic motility in a clinical setting. Automated quantitative motility assessment using dynamic MRI meets the need for non-invasive techniques. Recently, studies have begun to examine this technique in patients, including those with IBD, pseudo-obstruction and functional bowel disorders. Remaining challenges for clinical implementation are processing the large amount of data, standardization and validation of the numerous MRI metrics and subsequently assessment of the potential role of dynamic MRI. This review examines the methods, advances, and remaining challenges of evaluation of gastrointestinal motility with MRI. It accompanies an article by Khalaf et al. in this journal that describes a new protocol for assessment of pan-intestinal motility in fasted and fed state in a single MRI session. PMID- 29265644 TI - Variations in breast cancer histology and treatment patterns between the major ethnic groups of South West Sydney. AB - Studies in the United States and United Kingdom have demonstrated ethnic variations in breast cancer receptor status, histology, and treatment access. This study aimed to investigate whether ethnicity variation similarly exists in Australia. Patients diagnosed with breast cancer between 2006 and 2011 across all public hospitals in the South Western Sydney Local Health District were identified and patient data collected retrospectively. Logistic regression analysis was used to measure the association between various biologic and treatment parameters and ethnicity. Ethnicity was found to have an influence on age of diagnosis, histology, treatment utilization, and recurrence in breast cancer patients. PMID- 29265643 TI - The Ralstonia solanacearum csp22 peptide, but not flagellin-derived peptides, is perceived by plants from the Solanaceae family. AB - Ralstonia solanacearum, the causal agent of bacterial wilt disease, is considered one of the most destructive bacterial pathogens due to its lethality, unusually wide host range, persistence and broad geographical distribution. In spite of the extensive research on plant immunity over the last years, the perception of molecular patterns from R. solanacearum that activate immunity in plants is still poorly understood, which hinders the development of strategies to generate resistance against bacterial wilt disease. The perception of a conserved peptide of bacterial flagellin, flg22, is regarded as paradigm of plant perception of invading bacteria; however, no elicitor activity has been detected for R. solanacearum flg22. Recent reports have shown that other epitopes from flagellin are able to elicit immune responses in specific species from the Solanaceae family, yet our results show that these plants do not perceive any epitope from R. solanacearum flagellin. Searching for elicitor peptides from R. solanacearum, we found several protein sequences similar to the consensus of the elicitor peptide csp22, reported to elicit immunity in specific Solanaceae plants. A R. solanacearum csp22 peptide (csp22Rsol ) was indeed able to trigger immune responses in Nicotiana benthamiana and tomato, but not in Arabidopsis thaliana. Additionally, csp22Rsol treatment conferred increased resistance to R. solanacearum in tomato. Transgenic A. thaliana plants expressing the tomato csp22 receptor (SlCORE) gained the ability to respond to csp22Rsol and became more resistant to R. solanacearum infection. Our results shed light on the mechanisms for perception of R. solanacearum by plants, paving the way for improving current approaches to generate resistance against R. solanacearum. PMID- 29265647 TI - Speeding up NMR by in Situ Photo-Induced Reversible Acceleration of T1 Relaxation (PIRAT). AB - Increasing the signal-to-noise ratio is one of the major goals in the field of NMR spectroscopy. In this proof of concept, we accelerate relaxation during an NMR pulse sequence using photo-generated paramagnetic states of an inert sensitizer. For the follow-up acquisition period, the system is converted to a diamagnetic state. The reversibility of the photo-induced switching allows extensive repetition required for multidimensional NMR. We thus eliminate the obstacle of line-broadening by the presence of paramagnetic species. In this contribution, we show how cycling of synchronized light/pulse sequences leads to an enhanced efficiency in multidimensional NMR. Our approach utilizes a molecular spin switch reversibly altering between a paramagnetic and diamagnetic state. PMID- 29265650 TI - "...in every...art, fundamental matters are perennially being discovered, discredited, forgotten, rediscovered and reaffirmed". PMID- 29265651 TI - Prostate-induced orgasms: A concise review illustrated with a highly relevant case study. AB - Current medical literature does not describe precisely the activation and mechanisms of prostate orgasms. This brief review describes what we know about the anatomy and physiology of the prostate and its involvement in reproduction and especially its stimulation for sexual recreation. It is illustrated with a highly relevant case history. Clin. Anat. 31:81-85, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29265652 TI - New discovery of Acheulean occupation in the Red Sea coastal region of the Sudan. PMID- 29265653 TI - East African Cenozoic vegetation history. AB - The modern vegetation of East Africa is a complex mosaic of rainforest patches; small islands of tropic-alpine vegetation; extensive savannas, ranging from almost pure grassland to wooded savannas; thickets; and montane grassland and forest. Here I trace the evolution of these vegetation types through the Cenozoic. Paleogene East Africa was most likely geomorphologically subdued and, as the few Eocene fossil sites suggest, a woodland in a seasonal climate. Woodland rather than rainforest may well have been the regional vegetation. Mountain building started with the Oligocene trap lava flows in Ethiopia, on which rainforest developed, with little evidence of grass and none of montane forests. The uplift of the East African Plateau took place during the middle Miocene. Fossil sites indicate the presence of rainforest, montane forest and thicket, and wooded grassland, often in close juxtaposition, from 17 to 10 Ma. By 10 Ma, marine deposits indicate extensive grassland in the region and isotope analysis indicates that this was a C3 grassland. In the later Miocene rifting, first of the western Albertine Rift and then of the eastern Gregory Rift, added to the complexity of the environment. The building of the high strato-volcanos during the later Mio-Pliocene added environments suitable for tropic-alpine vegetation. During this time, the C3 grassland was replaced by C4 savannas, although overall the extent of grassland was reduced from the mid-Miocene high to the current low level. Lake-level fluctuations during the Quaternary indicate substantial variation in rainfall, presumably as a result of movements in the intertropical convergence zone and the Congo air boundary, but the impact of these fluctuations on the vegetation is still speculative. I argue that, overall, there was an increase in the complexity of East African vegetation complexity during the Neogene, largely as a result of orogeny. The impact of Quaternary climatic fluctuation is still poorly understood. PMID- 29265654 TI - Francis (Frank) H. Brown (1943-2017), mentor, teacher, friend. PMID- 29265655 TI - Fossil genera and wastebasket taxa in the human lineage: in support of Tattersall. PMID- 29265656 TI - The evolution of the Cercopithecini: a (post)modern synthesis. AB - The Cercopithecini, or African guenon monkeys, are one of the most diverse clades of living primates and comprise the most species-rich clade of Catarrhini. Species identity is announced by flamboyant coloration of the facial and genital regions and, more cryptically, by vigorous chromosomal rearrangements among taxa. Beneath the skin, however, these animals are skeletally conservative and show low levels of genetic sequence divergence consonant with recent divergence between congeneric species. The guenons clearly demonstrate that morphological, cytogenetic, and reproductive differentiation proceed at different rates during speciation. We review diverse kinds of data in an effort to understand this conundrum. PMID- 29265657 TI - A Final Say(onara): From the years of this column, looking forward to the future. PMID- 29265658 TI - Francis H. Brown (1943-2017). PMID- 29265659 TI - Looking Back. PMID- 29265660 TI - The enigmatic relationship between epiphyseal fusion and bone development in primates. AB - Epiphyseal fusion in primates is a process that occurs in a regular sequence spanning a period of years and thus provides biological anthropologists with a useful marker of maturity that can be used to assess age and stage of development. Despite the many studies that have catalogued fusion timing and sequence pattern, comparatively little research has been devoted to understanding why these sequences exist in the first place. Answering this question is not necessarily intuitive; indeed, given that neither taxonomic affinities nor recent adaptations have been clearly defined, it is a challenge to explain this process in evolutionary terms. In all mammals, there is a tendency for the fusion of epiphyses at joints to occur close in sequence, and this has been proposed to relate to locomotor adaptations. Further consideration of the evidence suggests that linking locomotor behavior to sequence data alone is difficult to prove and may require a different type of evidence. Epiphyseal fusion should be considered in the context of other parameters that affect the developing skeleton, including how joint morphology relates to growth in length, as well as other possible morphological constraints. In recent years, developmental biology has been providing a better understanding of the molecular regulators of epiphyseal fusion. At some point in the near future, we may be able to link our understanding of the genetics of fusion timing to the possible selective mechanisms that are responsible for these sequences. PMID- 29265661 TI - Cultural learning and the Clovis colonization of North America. AB - The timing of the earliest colonization of North America is debatable, but what is not at issue is the point of origin of the early colonists: Humans entered the continent from Beringia and then made their way south along or near the Pacific Coast and/or through a corridor that ran between the Cordilleran and Laurentide ice sheets in western North America. At some point, they abandoned their Arctic based tool complex for one more adapted to an entirely different environment. That new techno-complex is termed "Clovis"; its dispersal allows us to examine, at a fine scale, how colonization processes played out across a vast continent that at the time had, at best, a very small resident population. Clovis has figured prominently in American archeology since the first Clovis points were identified in eastern New Mexico in the 1930s. However, the successful marriage of learning models grounded in evolutionary theory and modern analytical methods that began roughly a decade ago has begun to pay significant dividends in terms of what we know about the rapid spread of human groups across the last sizable landmass to witness human occupation. PMID- 29265662 TI - Right-handed fossil humans. AB - Fossil hominids often processed material held between their upper and lower teeth. Pulling with one hand and cutting with the other, they occasionally left impact cut marks on the lip (labial) surface of their incisors and canines. From these actions, it possible to determine the dominant hand used. The frequency of these oblique striations in an array of fossil hominins documents the typically modern pattern of 9 right- to 1 left-hander. This ratio among living Homo sapiens differs from that among chimpanzees and bonobos and more distant primate relatives. Together, all studies of living people affirm that dominant right handedness is a uniquely modern human trait. The same pattern extends deep into our past. Thus far, the majority of inferred right-handed fossils come from Europe, but a single maxilla from a Homo habilis, OH-65, shows a predominance of right oblique scratches, thus extending right-handedness into the early Pleistocene of Africa. Other studies show right-handedness in more recent African, Chinese, and Levantine fossils, but the sample compiled for non-European fossil specimens remains small. Fossil specimens from Sima del los Huesos and a variety of European Neandertal sites are predominately right-handed. We argue the 9:1 handedness ratio in Neandertals and the earlier inhabitants of Europe constitutes evidence for a modern pattern of handedness well before the appearance of modern Homo sapiens. PMID- 29265663 TI - Memories of Frank Brown in the Lower Omo Valley. PMID- 29265664 TI - Renewed excavations at Wonderwerk Cave, South Africa. PMID- 29265665 TI - A Man for all Field Seasons. PMID- 29265666 TI - Technological complexity and the global dispersal of modern humans. AB - Anatomically modern humans (Homo sapiens) dispersed out of Africa roughly 120,000 years ago and again after 75,000 years ago. The early dispersal was geographically restricted to the Arabian Peninsula, Levant, and possibly parts of southern Asia. The later dispersal was ultimately global in scope, including areas not previously occupied by Homo. One explanation for the contrast between the two out-of-Africa dispersals is that the modern humans who expanded into Eurasia 120,000 years ago lacked the functionally and structurally complex technology of recent hunter-gatherers. This technology, which includes, for example, mechanical projectiles, snares and traps, and sewn clothing, provides not only expanded dietary breadth and increased rates of foraging efficiency and success in places where plant and animal productivity is low, but protection from cold weather in places where winter temperatures are low. The absence of complex technology before 75,000 years ago also may explain why modern humans in the Levant did not develop sedentary settlements and agriculture 120,000 years ago (i.e., during the Last Interglacial). PMID- 29265667 TI - The use of next-generation sequencing for the determination of rare blood group genotypes. PMID- 29265668 TI - Direct Annulation between Aryl Iodides and Epoxides through Palladium/Norbornene Cooperative Catalysis. AB - Herein we report a direct annulation between aryl iodides and epoxides through palladium/norbornene (Pd/NBE) cooperative catalysis. An iso-propyl ester substituted NBE was found to be most efficient to suppress the formation of multiple-NBE-insertion byproducts and affords the desired 2,3-dihydrobenzofuran derivatives in 44-99 % yields. The reaction is scalable and tolerates a range of functional groups. Asymmetric synthesis is realized using an enantiopure epoxide. Application of this method into a concise synthesis of insecticide fufenozide is demonstrated. PMID- 29265669 TI - Phase-Contact Engineering in Mono- and Bimetallic Cu-Ni Co-catalysts for Hydrogen Photocatalytic Materials. AB - Understanding how a photocatalyst modulates its oxidation state, size, and structure during a photocatalytic reaction under operando conditions is strongly limited by the mismatch between (catalyst) volume sampled by light and, to date, the physicochemical techniques and probes employed to study them. A synchrotron micro-beam X-ray absorption spectroscopy study together with the computational simulation and analysis (at the X-ray cell) of the light-matter interaction occurring in powdered TiO2 -based monometallic Cu, Ni and bimetallic CuNi catalysts for hydrogen production from renewables was carried out. The combined information unveils an unexpected key catalytic role involving the phase contact between the reduced and oxidized non-noble metal phases in all catalysts and, additionally, reveals the source of the synergistic Cu-Ni interaction in the bimetallic material. The experimental method is applicable to operando studies of a wide variety of photocatalytic materials. PMID- 29265670 TI - Type 2 diabetes mellitus and bone. AB - Type 2 diabetes (T2DM) is a rapidly growing public health problem. It is associated with an increased risk of fracture, particularly of the hip, despite normal or high bone mineral density. Longer duration of disease and poor glycaemic control are both associated with higher fracture risk. The factors underlying increased fracture risk have not been clearly established, but increased falls risk, obesity, sarcopenia and co-morbidities are likely to contribute. The basis for reduced bone strength despite higher bone mineral density remains to be fully elucidated. Bone turnover is reduced in individuals with T2DM, with evidence of impaired bone formation. Most studies indicate normal or superior trabecular bone structure although reduced lumbar spine trabecular bone score (TBS) has been reported. Deficits in cortical bone structure have been demonstrated in some, but not all, studies whilst reduced bone material strength index (BMSi), as assessed by microindentation, has been a consistent finding. Accumulation of advanced glycation end products in bone may also contribute to reduced bone strength. The use of FRAX in individuals with T2DM underestimates fracture probability. Clinical management should focus on falls prevention strategies, avoidance of known risk factors, maintenance of good glycaemic control and bone protective intervention in individuals at high risk of fracture. Dietary and surgical strategies to reduce weight have beneficial effects on diabetes but may have adverse effects on skeletal health. Future research priorities include better definition of the mechanisms underlying increased fracture risk in T2DM and optimal strategies for identifying and treating those at high risk. PMID- 29265671 TI - Supplemented Morus nigra extract-based medium associated with FSH enables the survival and growth of isolated ovine secondary ovarian follicles. AB - The effects of Morus nigra ethanolic extract, without or with addition of supplements associated or not with FSH, on in vitro culture of ovine secondary follicles were evaluated. In experiment 1, isolated secondary follicles were cultured for 12 days in alpha-MEM alone (control) or in different concentrations of M. nigra extract (MN 0.025; 0.05 or 0.1 mg/ml). In experiment 2, culture media were alpha-MEM supplemented with BSA, insulin, transferrin, selenium, glutamine, hypoxanthine and ascorbic acid (alpha-MEM+ ) or this medium associated with FSH (alpha-MEM+ + FSH), or 0.1 mg/ml M. nigra without supplements (MN 0.1) or supplemented (MN 0.1+ ) without or with FSH (MN 0.1+ + FSH). In experiment 1, 0.1 mg/ml M. nigra showed the highest percentages (p < .05) of normal follicles and fully grown oocytes, besides a higher follicular diameter than alpha-MEM and other M. nigra extract concentrations. Moreover, MN 0.1 showed lower (p < .05) glutathione (GSH) levels and similar (p > .05) mitochondrial activity compared to alpha-MEM. In experiment 2, MN 0.1+ + FSH showed similar results (p > .05) to alpha-MEM+ + FSH for all parameters evaluated, except for the daily growth rate, which was higher (p < .05) in MN 0.1+ + FSH. The GSH levels were higher in MEM+ than all treatments. In addition, oocytes from follicles cultured in MN 0.1+ + FSH showed ability to resume meiosis. In conclusion, M. nigra extract (0.1 mg/ml) added by supplements and FSH can be an efficient medium for ovine secondary follicle development. PMID- 29265672 TI - The effect of an attachment-oriented couple intervention for breast cancer patients and partners in the early treatment phase: A randomised controlled trial. AB - OBJECTIVE: Patients and partners both cope individually and as a dyad with challenges related to a breast cancer diagnosis. The objective of this study was to evaluate the effect of a psychological attachment-oriented couple intervention for breast cancer patients and partners in the early treatment phase. METHODS: A randomised controlled trial including 198 recently diagnosed breast cancer patients and their partners. Couples were randomised to the Hand in Hand (HiH) intervention in addition to usual care or to usual care only. Self-report assessments were conducted for both patients and partners at baseline, postintervention (5 months), and follow-up (10 months), assessing cancer-related distress, symptoms of anxiety and depression, and dyadic adjustment. Patients' cancer-related distress was the primary outcome. RESULTS: Cancer-related distress decreased over time in both patients and partners, but the intervention did not significantly affect this decrease at postintervention (P = .08) or follow-up (P = .71). A significant positive effect was found on dyadic adjustment at follow-up for both patients (P = .04) and partners (P = .02). CONCLUSIONS: There was no significant effect of the HiH intervention cancer-related distress. The results suggest that most couples can cope with cancer-related distress in the context of usual care. However, the positive effect on dyadic adjustment implies that the HiH intervention benefitted both patients and partners. Future studies should investigate how to integrate a couple focus in usual cancer care to improve dyadic coping in the early treatment phase. PMID- 29265673 TI - Presynaptic GLP-1 receptors enhance the depolarization-evoked release of glutamate and GABA in the mouse cortex and hippocampus. AB - Glucagon-like peptide-1 receptors (GLP-1Rs) have been shown to mediate cognitive enhancing and neuroprotective effects in the central nervous system. However, little is known about their physiological roles on central neurotransmission, especially at the presynaptic level. Using purified synaptosomal preparations and immunofluorescence techniques, here we show for the first time that GLP-1Rs are localized on mouse cortical and hippocampal synaptic boutons, in particular on glutamatergic and GABAergic nerve terminals. Their activation by the selective agonist exendin-4 (1-100 nM) was able to increase the release of either [3 H]d aspartate or [3 H]GABA. These effects were abolished by 10 nM of the selective GLP1-R antagonist exendin-3 (9-39) and were prevented by the selective adenylyl cyclase inhibitor 2',5'-dideoxyadenosine (10 uM), indicating the involvement of classic GLP-1Rs coupled to Gs protein stimulating cAMP synthesis. Our data demonstrate the existence and activity of presynaptic receptors for GLP-1 that could represent additional mechanisms by which this neurohormone exerts its effects in the CNS. (c) 2017 BioFactors, 44(2):148-157, 2018. PMID- 29265675 TI - Catalytic Asymmetric Oxidative gamma-Coupling of alpha,beta-Unsaturated Aldehydes with Air as the Terminal Oxidant. AB - A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single-electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon-carbon oxidative coupling reaction of alpha,beta unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open-shell activated species that undergoes highly selective gamma-homo- and gamma-heterocoupling reactions. In the majority of examples presented, only a single stereoisomer was formed. PMID- 29265674 TI - Aerobic exercise training rescues protein quality control disruption on white skeletal muscle induced by chronic kidney disease in rats. AB - We tested whether aerobic exercise training (AET) would modulate the skeletal muscle protein quality control (PQC) in a model of chronic kidney disease (CKD) in rats. Adult Wistar rats were evaluated in four groups: control (CS) or trained (CE), and 5/6 nephrectomy sedentary (5/6NxS) or trained (5/6NxE). Exercised rats were submitted to treadmill exercise (60 min., five times/wk for 2 months). We evaluated motor performance (tolerance to exercise on the treadmill and rotarod), cross-sectional area (CSA), gene and protein levels related to the unfolded protein response (UPR), protein synthesis/survive and apoptosis signalling, accumulated misfolded proteins, chymotrypsin-like proteasome activity (UPS activity), redox balance and heat-shock protein (HSP) levels in the tibialis anterior. 5/6NxS presented a trend towards to atrophy, with a reduction in motor performance, down-regulation of protein synthesis and up-regulation of apoptosis signalling; increases in UPS activity, misfolded proteins, GRP78, derlin, HSP27 and HSP70 protein levels, ATF4 and GRP78 genes; and increase in oxidative damage compared to CS group. In 5/6NxE, we observed a restoration in exercise tolerance, accumulated misfolded proteins, UPS activity, protein synthesis/apoptosis signalling, derlin, HSPs protein levels as well as increase in ATF4, GRP78 genes and ATF6alpha protein levels accompanied by a decrease in oxidative damage and increased catalase and glutathione peroxidase activities. The results suggest a disruption of PQC in white muscle fibres of CKD rats previous to the atrophy. AET can rescue this disruption for the UPR, prevent accumulated misfolded proteins and reduce oxidative damage, HSPs protein levels and exercise tolerance. PMID- 29265676 TI - New Species of Saprobic Labyrinthulea (=Labyrinthulomycota) and the Erection of a gen. nov. to Resolve Molecular Polyphyly within the Aplanochytrids. AB - A culture of a unicellular heterotrophic eukaryote was established from pollen baited seawater acquired from the nearshore environment in Tromso, Norway. Light microscopy revealed the production of ectoplasmic nets and reproduction by biflagellated zoospores, as well as binary division. After culturing and subsequent nucleotide extraction, database queries of the isolate's 18S small ribosomal subunit coding region identified closest molecular affinity to Aplanochytrium haliotidis, a pathogen of abalone. Testing of phylogenetic hypotheses consistently grouped our unknown isolate and A. haliotidis among the homoplasious thraustochytrids. Transmission electron microscopy revealed complex cell walls comprised of electron-dense lamella that formed protuberances, some associated with bothrosomes. Co-culturing experiments with the marine fungus Penicillium brevicompactum revealed prolonged interactions with hyphal strands. Based on the combined information acquired from electron microscopy, life history information, and phylogenetic testing, we describe our unknown isolate as a novel species. To resolve molecular polyphyly within the aplanochytrids, we erect a gen. nov. that circumscribes our novel isolate and the former A. haliotidis within the thraustochytrids. PMID- 29265677 TI - Piecewise Phototuning of Self-Organized Helical Superstructures. AB - Cholesteric liquid crystals (CLCs) exhibit selective reflection that can be tuned owing to the dynamic control of inherent self-organized helical superstructures. Although phototunable reflection is reported, these systems hitherto suffer from a limitation in that the tuning range is restricted to one narrow period and the optically addressed images have to sacrifice one color in the visible spectrum to serve as the background, resulting from the insufficient variation in helical twisting power of existing photoresponsive chiral switches that are all bistable. Here, delicate patterns of three primary red, green, and blue (RGB) colors with a black background are presented, which is realized based on piecewise reflection tuning of the CLC induced by a newly designed photoresponsive tristable chiral switch. Three stable configurations of the chiral switch endow the CLC with two continuous and adjacent tuning periods of the reflection, covering not only entire visible spectrum, but also one more wide period within near-infrared region. Therefore, the concept of piecewise tuning in CLC system demonstrates a new strategy for phototunable RGB and black reflective display. PMID- 29265680 TI - Nitrous oxide and microorganisms: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 29265678 TI - Unexpected discovery of small HNF1alpha-inactivated hepatocellular adenoma in pathological specimens from patients resected for liver tumours. AB - BACKGROUND AND AIMS: It is rare but not uncommon to discover micro/small HNF1alpha-inactivated hepatocellular adenoma (H-HCA) outside the context of resected H-HCA. We aimed to review our cases of micro/small H-HCA discovered by chance on different kinds of liver resected specimens. METHODS: We retrieved cases of micro/small H-HCA discovered by chance on resected specimens outside the context of H-HCA. All these nodules were liver fatty acid binding protein (LFABP) negative contrasting with normal positivity in the surrounding non-tumoural liver, ruling out the possibility of focal steatosis or other subtypes of micro HCAs. RESULTS: We identified 19 micro/small H-HCA cases. In 16 cases they were discovered in patients who underwent surgery for benign nodules including one haemangioma, six focal nodular hyperplasia, seven inflammatory HCA (including one with b-catenin activation), one HCA, whose subtype could not be identified because of massive necrosis/hemorrhage, and one hepatocellular carcinoma. In two additional cases, patients followed up for a melanoma underwent liver surgery to remove micro nodules possibly related to a metastatic process. Finally in one case a micro nodule was seen and resected during a cholecystectomy. CONCLUSION: Taken together, H-HCAs are more frequent than we initially supposed as micro and small HCAs cannot all be detected by routine ultrasound. Despite no information on the potential growth of these micro/small H-HCAs, there is no argument to stop oral contraceptives or to ask for a specific regular surveillance. The association of different subtypes of HCAs with focal nodular hyperplasia suggests they share or have common etiological factors. PMID- 29265679 TI - Sources and sinks for N2 O, can microbiologist help to mitigate N2 O emissions? PMID- 29265681 TI - White matter integrity alterations in post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a debilitating condition which can develop after exposure to traumatic stressors. Seventy-five adults were recruited from the community, 25 diagnosed with PTSD along with 25 healthy and 25 trauma exposed age- and gender-matched controls. Participants underwent clinical assessment and magnetic resonance imaging. A previous voxel based morphometry (VBM) study using the same subject cohort identified decreased grey matter (GM) volumes within frontal/subcortical brain regions including the hippocampus, amygdala, and anterior cingulate cortex (ACC). This study examines the microstructural integrity of white matter (WM) tracts connecting the aforementioned regions/structures. Using diffusion tensor imaging, we investigated the integrity of frontal/subcortical WM tracts between all three subject groups. Trauma exposed subjects with and without PTSD diagnosis were identified to have significant disruption in WM integrity as indexed by decreased fractional anisotropy (FA) in the uncinate fasciculus (UF), cingulum cingulate gyrus (CCG), and corpus callosum (CC), when compared with healthy non-trauma exposed controls. Significant negative correlations were found between total Clinician Administered PTSD scale (CAPS) lifetime clinical subscores and FA values of PTSD subjects in the right UF, CCG, CC body, and right superior longitudinal fasciculus (SLF). An analysis between UF and SLF FA values and VBM determined rostral ACC GM values found a negative correlation in PTSD subjects. Findings suggest that compromised WM integrity in important tracts connecting limbic structures such as the amygdala to frontal regions including the ACC (i.e., the UF and CCG) may contribute to impairments in threat/fear processing associated with PTSD. PMID- 29265682 TI - Visible-light-driven Efficient Photocatalytic Reduction of Organic Azides to Amines over CdS Sheet-rGO Nanocomposite. AB - CdS sheet-rGO nanocomposite as a heterogeneous photocatalyst enables visible light-induced photocatalytic reduction of aromatic, heteroaromatic, aliphatic and sulfonyl azides to the corresponding amines using hydrazine hydrate as a reductant. The reaction shows excellent conversion and chemoselectivity towards the formation of the amine without self-photoactivated azo compounds. In the adopted strategy, CdS not only accelerates the formation of nitrene through photoactivation of azide but also enhances the decomposition of azide to a certain extent, which entirely suppressed formation of the azo compound. The developed CdS sheet-rGO nanocomposite catalyst is very active, providing excellent results under irradiation with a 40 W simple household CFL lamp. PMID- 29265683 TI - Childhood obesity policies - mighty concerns, meek reactions. AB - BACKGROUND: The increasing number of children defined as overweight or obese is causing concern among politicians and health advocates; several countries have launched policies addressing the issue. METHOD: The paper presents an analysis of how the childhood obesity is defined, explained and suggested policies to address the problem from the WHO, the EU, Canada, England and New Zealand. RESULTS: Considering the dramatic language used when describing childhood obesity, the proposed interventions are modest. Either the politicians do not consider the problem that great after all, or other concerns, such as the freedom of the food and drink industry and local authorities, are seen as more important. The causes identified are multiple and varied, including the physical and commercial environment, whereas the interventions primarily address the information level of the population, placing responsibility on the shoulders of the parents. Only the World Health Organization argues that statutory measures are required, and the English Government suggests one: a levy on sugary drinks. Otherwise, local authorities, schools and the industry are expected to act on a voluntary basis. Very little is explicitly substantiated by evidence, and the evidence cited is sometimes misinterpreted or disregarded. CONCLUSION: There is a discrepancy between how the problem of childhood obesity is presented as alarming and the modest measures suggested. PMID- 29265685 TI - Prevalence of post-micturition dribble in Japanese men and its relationship with benign prostatic hyperplasia/lower urinary tract symptoms. AB - OBJECTIVE: Post-micturition dribble (PMD) is one of the post-micturition lower urinary tract symptoms (LUTS). Although there have been many studies of LUTS in Japanese men, PMD is not completely understood in the Japanese population. In the present study, we investigated the prevalence and bother of PMD in Japanese men. METHODS: From 2007 to 2008, a cross-sectional community-based study on LUTS was conducted in Japanese men aged 40-79 years in Shimamaki-mura, Hokkaido, Japan. The prevalence and bother of PMD were investigated using a validated questionnaire, and prostate volume (PV) and the peak flow rate (Qmax ) were measured. RESULTS: The prevalence of PMD in men aged their 40s, 50s, 60s, and 70s was 13.6%, 39.0%, 44.2%, and 41.2%, respectively. PMD was not rare compared with other LUTS. The degree and bother of PMD were statistically correlated (r = 0.558, P < .001), suggesting that the presence of PMD impairs quality of life. There was no significant relationship between the prevalence of PMD and PV or Qmax . CONCLUSIONS: PMD is not rare compared with other LUTS. The presence of PMD impairs quality of life. PMID- 29265684 TI - Investigation of the radiation dose from cone-beam CT for image-guided radiotherapy: A comparison of methodologies. AB - Four methodologies were evaluated for quantifying kilovoltage cone-beam computed tomography (CBCT) dose: the Cone-Beam Dose Index (CBDI), IAEA Report 5 recommended methodology (IAEA), the AAPM Task Group 111 methodology (TG111), and the current dose metric; the Computed Tomography Dose Index (CTDI) on two commercial Varian cone-beam CT imaging systems; the Clinac iX On-Board Imager (OBI); and the TrueBeam X-ray Imaging system (XI). The TG111 methodology measured the highest overall dose (21.199 +/- 0.035 mGy OBI and 22.420 +/- 0.002 XI for pelvis imaging) due to the full scatter of the TG111 phantom and was within 5% of CTDI measurements taken using a full scatter TG111 phantom and 30-cm film strips. CBDI measured the second highest overall dose, within 10% of the TG111, with IAEA measuring the third highest dose. For head CBCT protocols, CBDI measured the highest dose, followed by IAEA. The CTDI method measured lowest across all scan modes highlighting its limitations for CBCT dosimetry. The XI imaging system delivered lower doses for head and thorax scan modes and similar doses to the OBI system for pelvis scan modes due to additional beam hardening filtration in the XI system. The TG111 method measured the highest dose in the center of a CBCT scan during image guidance procedures; however, CBDI provided a good approximation to TG111 with existing CTDI equipment and may be more applicable clinically. PMID- 29265686 TI - Evidence for effective structure-based neuromodulatory effects of new analogues of neurosteroid allopregnanolone. AB - The neurosteroid allopregnanolone (AP) modulates neuroendocrine/neurobiological processes, including hypothalamic-pituitary-adrenocortical activities, pain, anxiety, neurogenesis and neuroprotection. These observations raised the hope of developing AP-based therapies against neuroendocrine and/or neurodegenerative disorders. However, the pleiotropic actions of AP, particularly its cell proliferation-promoting effects, hamper the development of selective/targeted therapies. For example, although AP-induced neurogenesis may serve to compensate neuronal loss in degenerative brains, AP-evoked cell-proliferation is contraindicated for steroid-sensitive cancer patients. To foster progress, we synthesised 4 novel AP analogues of neurosteroids (ANS) designated BR053 (12-oxo epi-AP), BR297 (O-allyl-epi-AP), BR351 (O-allyl-AP) and BR338 (12-oxo-AP). First, because AP is well-known as allosteric modulator of GABAA receptors (GABAA-R), we used the electrophysiological patch-clamp technique to determine the structure activity relationship of our ANS on GABAA-activated current in NCB20 cells expressing functional GABAA-R. We found that the addition of 12-oxo-group did not significantly change the respective positive or negative allosteric effects of 3alpha-AP or 3beta-(epi)-AP analogues. Importantly, substitution of the 3alpha hydroxyl-group by 3alpha-O-allyl highly modified the ANS activities. Unlike AP, BR351 induced a long-lasting desensitisation/inhibition of GABAA-R. Interestingly, replacement of the 3beta-hydroxyl by 3beta-O-allyl (BR297) completely reversed the activity from negative to positive allosteric action. In a second step, we compared the actions of AP and ANS on SH-SY5Y neuronal cell viability/proliferation using MTT-reduction assays. Different dose-response curves were demonstrated for AP and the ANS. By contrast to AP, BR297 was totally devoid of cell-proliferative effect. Finally, we compared AP and ANS abilities to protect against oxidative stress-induced neuronal death pivotally involved in neurodegenerative diseases. Both BR351 and BR297 had notable advantages over AP in protecting SH-SY5Y cells against oxidative stress-induced death. Thus, BR297 appears to be a potent neuroprotective compound devoid of cell-proliferative activity. Altogether, our results suggest promising perspectives for the development of neurosteroid-based selective and effective strategies against neuroendocrine and/or neurodegenerative disorders. PMID- 29265687 TI - Meeting the challenges of clinical information provision. AB - This virtual issue of the Health Information and Libraries Journal (HILJ) has been compiled to mark the 5th International Clinical Librarian Conference 2011. In considering the challenges of clinical information provision, the content selected for the virtual issue offers an international flavour of clinical information provision and covers a variety of different facets of clinical librarianship. The issue broadly covers the areas of information needs and preferences, clinical librarian roles and services, and education and training, and reflects the way in which a normal issue of the HILJ would be presented. This includes a review article, a collection of original articles, and the three regular features which comprise International Perspectives and Initiatives, Learning and Teaching in Action, and Using Evidence in Practice. All papers included in this virtual issue are available free online. PMID- 29265688 TI - Patient information comes of age. AB - This virtual issue (VI) has been assembled to coincide with the 8th Annual Patient Information Conference 2013 organised by the UK Patient Information Forum (PiF). The conference theme 'Information and support - a service in its own right' is a response to policy documents and initiatives in both Scotland and England which signal the coming of age of patient/consumer information. The VI consists of a collection of open access articles and addresses the question 'What can health science librarians do to ensure that the public are able to find, appraise and use health information?' This material provides research evidence, and examples of the types of initiatives librarians have undertaken to make information a health and care service in its own right. Two recurrent messages are that health science librarians need to form partnerships with healthcare providers and they have a role to play in improving health literacy skills. PMID- 29265689 TI - Learning from the past to inform the future. AB - In this final issue of 2017, we are in a reflective mood at the Health Information and Libraries Journal as we say goodbye to Audrey Marshall, Regular Feature Editor of Dissertations into Practice. While Audrey departs, Dissertations into Practice is now a firm fixture of the Health Information and Libraries Journal; there remains no better place for students to see their writing, possibly for the first time, in print. This issue also provides an opportunity to review the breadth of health information writing through the editorials of past Virtual Issues of the Health Information and Libraries Journal, all still available, free of charge, via the journal's home page at http://wileyonlinelibrary.com/journal/hilj. PMID- 29265690 TI - Increasing impact in a time of decreasing budgets. AB - This virtual issue (VI) has been compiled to mark the CILIP Health Libraries Group Conference 2012. In line with the conference theme: 'Health libraries under the microscope: perfecting your formula', the VI is a collection of 10 articles and regular features that have been published in Health Information and Libraries Journal in the last 2 years. The VI focuses specifically on the topics of impact, value and cost-effectiveness. All the articles and regular features contained in this VI are freely available online. PMID- 29265692 TI - Delivering a MOOC for literature searching in health libraries: evaluation of a pilot project. AB - In an era when library budgets are being reduced, Massive Online Open Courses (MOOC's) can offer practical and viable alternatives to the delivery of costly face-to-face training courses. In this study, guest writers Gil Young from Health Care Libraries Unit - North, Lisa McLaren from Brighton and Sussex Medical School and Liverpool University PhD student Michelle Maden describe the outcomes of a funded project they led to develop a MOOC to deliver literature search training for health librarians. Funded by Health Education England, the MOOC was developed by the Library and Information Health Network North West as a pilot project that ran for six weeks. In particular, the MOOC target audience is discussed, how content was developed for the MOOC, promotion and participation, cost effectiveness, evaluation, the impact of the MOOC and recommendations for future development. H. S. PMID- 29265693 TI - What's hot, what's new: Report from the American Transplant Congress 2017. AB - Significant advances in clinical practice as well as basic and translational science were presented at the American Transplant Congress this year. Topics included innovative clinical trials to recent advances in our basic understanding of the scientific underpinnings of transplant immunology. Key areas of interest included the following: clinical trials utilizing hepatitis C virus-positive (HCV+ ) donors for HCV- recipients, the impact of the new allocation policies, normothermic perfusion, novel treatments for desensitization, attempts at precision medicine, advances in xenotransplantation, the role of mitochondria and exosomes in rejection, nanomedicine, and the impact of the microbiota on transplant outcomes. This review highlights some of the most interesting and noteworthy presentations from the meeting. PMID- 29265694 TI - Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides. AB - A convergent, nine-step (LLS), enantioselective synthesis of alpha-cyclopiazonic acid and related natural products is reported. The route features a) an enantioselective aziridination of an imine with a chiral sulfur ylide; b) a bioinspired (3+2)-cycloaddition of the aziridine onto an alkene; and c) installation of the acetyltetramic acid by an unprecedented tandem carbonylative lactamization/N-O cleavage of a bromoisoxazole. PMID- 29265696 TI - Validation of the GLI-2012 spirometry reference equations in Argentinian children. AB - AIM: The Global Lung Function Initiative (GLI) has produced spirometry reference equations for use in different ethnic groups. Previous reports have shown that the GLI equations do not adequately describe lung function in all populations and that adopting the new equations into clinical practice can increase the number of patients considered to have abnormal lung function. Therefore, before adopting these equations into local practice it is necessary to establish how well the equations represent the local population. The present study was conducted to determine how well the GLI spirometry reference equations represented the young children in Argentina, a population not included in the GLI dataset. METHODS: Spirometry was measured in 2072 healthy children (50.9% males) aged 3.0-12.4 years (mean 6.64 +/- SD 1.39), with a height range of 93.0-158.5 cm and weight range from 13.1 to 54.7 kg. We used the GLI "Caucasian" and "other/mixed" race equations to create Z-scores. RESULTS: The Z-scores predicted by the Caucasian GLI equations did not differ from zero and fitted the data well. Z-scores calculated using "other/mixed race" fit less well. Using the GLI definition of low lung function (Z-score <1.65) 6.8% of our healthy population had abnormal FVC, 4.9% had abnormal FEV1, 5.9 % had abnormal FEV0.75, and 3.9% had abnormal FEF25-75 when using the "Caucasian" GLI equation. This compares well with the expected 5% below the lower limit of normal. CONCLUSION: We recommend the use of the GLI-2012 Caucasian equations for spirometry undertaken in Argentinian children. PMID- 29265695 TI - The neural dynamics of competition resolution for language production in the prefrontal cortex. AB - Previous research suggests a pivotal role of the prefrontal cortex (PFC) in word selection during tasks of confrontation naming (CN) and verb generation (VG), both of which feature varying degrees of competition between candidate responses. However, discrepancies in prefrontal activity have also been reported between the two tasks, in particular more widespread and intense activation in VG extending into (left) ventrolateral PFC, the functional significance of which remains unclear. We propose that these variations reflect differences in competition resolution processes tied to distinct underlying lexico-semantic operations: Although CN involves selecting lexical entries out of limited sets of alternatives, VG requires exploration of possible semantic relations not readily evident from the object itself, requiring prefrontal areas previously shown to be recruited in top-down retrieval of information from lexico-semantic memory. We tested this hypothesis through combined independent component analysis of functional imaging data and information-theoretic measurements of variations in selection competition associated with participants' performance in overt CN and VG tasks. Selection competition during CN engaged the anterior insula and surrounding opercular tissue, while competition during VG recruited additional activity of left ventrolateral PFC. These patterns remained after controlling for participants' speech onset latencies indicative of possible task differences in mental effort. These findings have implications for understanding the neural computational dynamics of cognitive control in language production and how it relates to the functional architecture of adaptive behavior. PMID- 29265697 TI - Synergistic Lysosomal Activatable Polymeric Nanoprobe Encapsulating pH Sensitive Imidazole Derivative for Tumor Diagnosis. AB - Developing optical tumor imaging probes with minimal background noise is very important for its early detection of small lesions and accurate diagnosis of cancer. To overcome the bottleneck of low signal to noise ratio and sensitivity, it needs further improvement in fluorescent probe design and understanding of tumor development process. Recent reports reveal that lysosome's acidity in cancer cells can be below 4.5 with high Na+ /H+ exchange activity, which makes it an ideal target intracellular organelle for cancer diagnosis based on the variation of pH. Herein, a boron 2-(2'-pyridyl) imidazole complex derivative (BOPIM-N) is developed, with the ability to show a pH-activatable "OFF-ON" fluorescent switch by inhibiting twisted intramolecular charge transfer upon protonation at pH 3.8-4.5, which is studied for its selective viable cancer cell imaging ability in both in vitro and in vivo experiments. Interestingly, BOPIM-N can specifically emit green fluorescence in lysosomes of cancer cells, indicating its promising cancer cell specific imaging ability. More importantly, nanoformulated BOPIM-N probes can be specifically light-ON in tumor bearing site of nude mice with resolution up to cellular level, indicating its potential application in tumor diagnosis and precision medicine. PMID- 29265698 TI - The role of shame and self-compassion in psychotherapy for narcissistic personality disorder: An exploratory study. AB - This process-outcome study aims at exploring the role of shame, self-compassion, and specific therapeutic interventions in psychotherapy for patients with narcissistic personality disorder (NPD). This exploratory study included a total of N = 17 patients with NPD undergoing long-term clarification-oriented psychotherapy. Their mean age was 39 years, and 10 were male. On average, treatments were 64 sessions long (range between 45 and 99). Sessions 25 and 36 were rated using the Classification of Affective Meaning States and the Process Content-Relationship Scale. Outcome was assessed using the Symptom Check List-90 and Beck Depression Inventory-II. Between Sessions 25 and 36, a small decrease in the frequency of shame was found (d = .30). In Session 36, the presence of self compassion was linked with a set of specific therapist interventions (process guidance and treatment of behaviour-underlying assumptions; 51% of variance explained and adjusted). This study points to the possible central role of shame in the therapeutic process of patients with NPD. Hypothetically, one way of resolving shame is, for the patient, to access underlying self-compassion. PMID- 29265699 TI - Optimal timing of preoperative indocyanine green administration for fluorescent cholangiography during laparoscopic cholecystectomy using the PINPOINT(r) Endoscopic Fluorescence Imaging System. AB - INTRODUCTION: The PINPOINT(r) Endoscopic Fluorescence Imaging System (Novadaq, Mississauga, Canada) allows surgeons to visualize the bile ducts during laparoscopic cholecystectomy. Surgeons can continue operation while confirming the bile ducts' fluorescence with a bright-field/color image. However, strong fluorescence of the liver can interfere with the surgery. Here, we investigated the optimal timing of indocyanine green administration to allow fluorescent cholangiography to be performed without interference from the liver fluorescence. METHODS: A total of 72 patients who underwent laparoscopic cholecystectomy were included in this study. The timing of indocyanine green administration was set immediately before surgery and at 3, 6, 9, 12, 15, 18, and 24 h before surgery. The luminance intensity ratios of gallbladder/liver, cystic duct/liver, and common bile duct/liver were measured using the ImageJ software (National Institutes of Health, Bethesda, USA). Visibility of the gallbladder and bile ducts was classified into three categories (grades A, B, and C) based on the degree of visibility in contrast to the liver. RESULTS: The luminance intensity ratio for the gallbladder/liver, cystic duct/liver, and common bile duct/liver was >=1 in the 15-, 18-, and 24-h groups. The proportion of cases in which evaluators classified the visibility of the gallbladder and bile ducts as grade A (best visibility) reached a peak in the 15-h group and decreased thereafter. CONCLUSIONS: In the present study, the optimal timing of indocyanine green administration for fluorescent cholangiography during laparoscopic cholecystectomy using the PINPOINT Endoscopic Fluorescence Imaging System was 15 h before surgery. PMID- 29265700 TI - Automatic calculation of patient size metrics in computed tomography: What level of computational accuracy do we need? AB - OBJECTIVES: To compare the effectiveness of two different patient size metrics based on water equivalent diameter (Dw ), the mid-scan water equivalent diameter Dw_c , and the mean (average) water equivalent diameter in the imaged region, Dw_ave , for automatic detection of accidental changes in computed tomography (CT) acquisition protocols. METHODS: Patient biometric data (height and weight) were available from a previous survey for 80 adult chest examinations, and 119 adult single-acquisition chest-abdomen-pelvis (CAP) examinations for two 16 slice scanners (GE LightSpeed and Toshiba Aquilion RXL) equipped with automatic tube current modulation (ATCM). Dw_c and Dw_ave were calculated from the archived CT images. Size-specific dose estimates (SSDE) were obtained from volume CT dose index (CTDIvol ), using the conversion factors for a patient diameter of Dw_c . RESULTS: CTDIvol and SSDE correlate better with Dw_ave than with Dw_c . R-squared values of linear fits to CTDIvol of CAP examinations were 0.81-0.89 for Dw_c and 0.93-0.94 for Dw_ave (SSDE: 0.69-080 for Dw_c , 0.87-0.92 for Dw_ave ). Percentage differences between Dw_c and Dw_ave were -4 +/- 4% for chest and +5 +/ 4% for CAP examinations (in % of Dw_ave ). However, small Dw variations translated as larger variations in CTDIvol for these ATCM systems (e.g., a 24% increase in Dw doubled CTDIvol ). The dependence of CTDIvol on Dw_ave was similar for chest and CAP examinations performed with similar ATCM parameters, while use of Dw_c resulted in a clear separation of the same data according to examination type. Maximum Dw variation in the imaged region was 5.6 +/- 1.6 cm for chest and 6.5 +/- 1.4 cm for CAP examinations. CONCLUSIONS: Dw_ave is a better metric than Dw_c for binning similar-sized patients in dose comparison studies, despite the additional computational effort required for its calculation Therefore, when implementing automatic determination of Dw for SSDE calculations, automatic calculation of Dw_ave should be considered. PMID- 29265701 TI - High diversity of medically important gastrointestinal rodent-borne helminths in Singapore. AB - Small mammals are important reservoirs of zoonotic diseases and are definitive hosts for medically important parasitic helminths. Several rodent and shrew species are peridomestic, bringing them into close contact with both humans and the intermediate hosts that maintain the transmission cycle. Here, we screened DNA extracted from large intestine tissue homogenate from 108 individuals comprised of 10 species. We detected two species known to infect humans, Dicrocoelium dendriticum and Moniliformis moniliformis. We also report the first detection of a second Angiostrongylus species in Singapore. This study demonstrates the diversity of helminths that are parasitizing the small mammals in Singapore. PMID- 29265702 TI - Epidemiological study of people living in rural North Carolina for novel respiratory viruses. AB - During the last 10 years, scientists have grown increasingly aware that emerging respiratory viruses are often zoonotic in their origin. These infections can originate from or be amplified in livestock. Less commonly recognized are instances when humans have transmitted their respiratory pathogens to animals (reverse zoonoses). Even with this knowledge of viral exchange at the human livestock interface, few studies have been conducted to understand this cross over. In this pilot study, we examined persons with influenza-like illness at an outpatient clinic for evidence of infection with novel zoonotic respiratory pathogens in rural North Carolina where there are dense swine and poultry farming. Environmental air sampling was also conducted. From July 2016 to March 2017, a total of 14 human subjects were enrolled and sampled, and 192 bioaerosol samples were collected. Of the 14 human subject samples molecularly tested, three (21.4%) were positive for influenza A, one (7.1%) for influenza B and one (7.1%) for human enterovirus. Of the 192 bioaerosol samples collected and tested by real time RT-PCR or PCR, three (1.6%) were positive for influenza A and two (1.0%) for adenovirus. No evidence was found for novel zoonotic respiratory viruses. PMID- 29265703 TI - Predictors of postoperative bleeding after vitrectomy for vitreous hemorrhage in patients with diabetic retinopathy. AB - AIMS/INTRODUCTION: To clarify the association between perioperative variables and postoperative bleeding in pars plana vitrectomy for vitreous hemorrhage in diabetic retinopathy. MATERIALS AND METHODS: The present retrospective study enrolled 72 eyes of 64 patients who were admitted to Osaka University Hospital between April 2010 and March 2014, and underwent vitrectomy for vitreous hemorrhage as a result of diabetic retinopathy. RESULTS: Postoperative bleeding developed in 12 eyes. Using binomial logistic regression analysis, we found that the duration of operation was the only significant variable associated with postoperative bleeding within 12 weeks after vitrectomy. Furthermore, Poisson regression analysis identified fasting blood glucose just before vitrectomy, no treatment with antiplatelet drugs and treatment with antihypertensive drugs, as well as duration of operation, to be significantly associated with the frequency of bleeding within 52 weeks after vitrectomy. CONCLUSIONS: Long duration of operation can be used to predict bleeding within both 12 and 52 weeks after vitrectomy. In addition, fasting blood glucose just before vitrectomy, no treatment with antiplatelet drugs and treatment with antihypertensive drugs might be risk factors for postoperative bleeding up to 1 year after vitrectomy. PMID- 29265704 TI - Selective, age-related autobiographical memory deficits in children with severe traumatic brain injury. AB - OBJECTIVES: Autobiographical memory (AM) is a complex function that involves re experiencing of past personal events (episodic memory) scaffolded by personal facts (semantic memory). While AM is supported by a brain network and cognitive skills that are vulnerable to disruption by child traumatic brain injury (TBI), AM has not been examined in this patient population. DESIGN: Cross-sectional study. METHODS: Participants included children with severe closed TBI (n = 14) and healthy control (NC) children (n = 20) of comparable age, sex, and socioeconomic status. Participants completed (1) the Child Autobiographical Interview (Willoughby et al., , Front. Psychol., 3, 53), which required recall of autobiographical events and distinguished episodic (internal) from non-episodic (external) details, and self-rating of event phenomenological qualities, and (2) a battery of neuropsychological tests. RESULTS: Children with TBI recalled significantly fewer internal details relative to NCs, but the between-group difference was eliminated when specific probes were provided. The groups did not differ in either recall of external details or in ratings of events' phenomenological qualities. The gap between the groups in recall of internal details increased with age, as the greater number of internal details was associated with older age in the NC group, but not in the TBI group. Poorer verbal memory and lower IQ were related to recall of fewer internal details in the TBI group. CONCLUSIONS: This study unveils, to our knowledge for the first time, that severe child TBI is associated with a selective deficit in autobiographical memory that involves episodic, but spares semantic details, and identifies the risk factors for this impairment. PMID- 29265705 TI - Patterns of use of long-acting bronchodilators in patients with COPD: A nationwide follow-up study of new users in New Zealand. AB - BACKGROUND AND OBJECTIVE: While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long acting beta2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow-up study to describe treatment patterns in new users of long-acting bronchodilators. METHODS: National health and pharmaceutical dispensing data were used to identify patients aged >=45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan-Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non-use during follow-up. RESULTS: The study cohort included 83 435 patients with 290 400 person-years of follow-up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over- and under treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non-use were common. CONCLUSION: In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices. PMID- 29265706 TI - Rapid and label-free optical detection of individual carbon air pollutant nanoparticulates in biomedical samples. AB - Carbonaceous particle exposure and air pollution in general lead to a multitude of adverse human health effects and pose multiple challenges in terms of exposure, risk and safety assessment. Highly desirable for fast screening are label-free approaches for detecting these particle types in biological or medical context. We report a powerful approach for detecting carbonaceous particles using photothermal pump-probe microscopy, which directly probes their strong light absorption. The principle and reliability of this approach is demonstrated by examining 4 different carbon black (CB) species modeling soot with diameters ranging from 13 to 500 nm. Our results show that the proposed approach is applicable to a large number of CB types as well as black carbon. As the particles show a strong absorption over a wide spectral range as compared to other absorbing species, we can image CB particles almost background free. Our pump-probe approach allows label-free optical detection and unambiguous localization of CB particles in (bio)fluids and 3D cellular environments. In combination with fluorescence microscopy, this method allows for simultaneous colocalization of CB with different cellular components using fluorophores as shown here for human lung fibroblasts. We further demonstrate the versatility of pump-probe detection in a flow cell. PMID- 29265707 TI - Ever-Changing, Yet Constant. PMID- 29265708 TI - The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome. AB - RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well-defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome. PMID- 29265709 TI - Sleep quality in individuals diagnosed with colorectal cancer: Factors associated with sleep disturbance as patients transition off treatment. AB - OBJECTIVE: To identify patient characteristics associated with sleep disturbance and worsening of sleep in individuals diagnosed with localized colorectal cancer and assess heterogeneity in these relationships. METHODS: Data were from the MY Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System(r) Sleep Disturbance, Anxiety, Depression, Fatigue, and Pain Interference measures were administered. Participants self-reported demographics, comorbidities, and treatment information. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and patient characteristics cross-sectionally at an average of 10 months after diagnosis (n = 613) as well as change in sleep disturbance over a 6-month period (n = 361). RESULTS: Pain, anxiety, fatigue, and the existence of multiple comorbid conditions had statistically significant relationships with sleep disturbance (B = 0.09, 0.22, 0.29, and 1.53, respectively; P < 0.05). Retirement (B = -2.49) was associated with sleep quality in the cross-sectional model. Worsening anxiety (B = 0.14) and fatigue (B = 0.20) were associated with worsening sleep disturbance, and more severe sleep disturbance 10 months after diagnosis (B = -0.21) was associated with improvement in sleep quality after diagnosis (P < 0.05). No evidence of latent subgroups of patients (heterogeneity) was present. CONCLUSIONS: Pain, anxiety, fatigue, employment, and comorbid conditions were associated with sleep disturbance, but regression coefficients were small (< |2.5|). Results suggest that screening for anxiety, depression, fatigue, or pain is not sufficient for identifying sleep disturbance. Given the negative consequences of sleep disturbance, sleep disturbance screening may be warranted. PMID- 29265712 TI - Acute encephalopathy with biphasic seizures and late reduced diffusion in Kawasaki disease. AB - Herein we describe the case of a 7-month-old girl with Kawasaki disease (KD) in whom status epilepticus with fever developed on day 3 and cluster of seizures on day 6 of illness, followed by severe disturbance of consciousness afterward. Diffusion-weighted magnetic resonance imaging on day 6 of illness showed diffuse high signals in the bilateral subcortical white matter, while electroencephalogram indicated low-voltage slow waves. This indicated acute encephalopathy with biphasic seizures and late reduced diffusion (AESD); severe neurological sequelae remained. This is the first report of AESD as a complication of KD. PMID- 29265710 TI - Outcomes following heart failure hospitalization in a regional Australian setting between 2005 and 2014. AB - AIMS: The aim of the current study is to examine 10 year trends in mortality and readmission following heart failure (HF) hospitalization in metropolitan and regional Australian settings. METHODS AND RESULTS: We identified all index HF hospitalizations in the Hunter New England region from 2005 to 2014, using a 10 year 'look back' period. The primary endpoint was a composite of all-cause mortality or all-cause readmission at 1 year. Secondary endpoints included all cause mortality, all-cause readmission, and HF readmission at 30 days and 1 year. We used logistic regression to explore the predictors of the composite outcome of either all-cause death or readmission at 1 year. There were 12 114 patients admitted with a first episode of HF between 2005 and 2014, followed up until death or the end of 2015. The mean age was 78 +/- 12 years and 49% (n = 5906) were male. A total of 4831 (40%) resided in regional areas and the remainder in metropolitan areas. One hundred sixty-eight patients (1.4%) were Aboriginal. Approximately 69% of patients had either died or been readmitted for any cause within 12 months of their index event. The 30 day and 1 year all-cause mortality rates were 13% and 32%, respectively, with no change in the trend over the study period. Age, socio-economic disadvantage, ischaemic heart disease, renal failure, and chronic lower respiratory disease were predictors of the primary endpoint. CONCLUSIONS: Heart failure hospitalizations are followed by high rates of death or readmission. There was no change in this composite endpoint over the 10 year study period. PMID- 29265713 TI - Reconstitution of a Type II Polyketide Synthase that Catalyzes Polyene Formation. AB - While type II polyketide synthases (PKSs) are known for producing aromatic compounds, a phylogenetically new subfamily of type II PKSs have been recently proposed to synthesize polyene structures. Here we report in vitro analysis of such a type II PKS, IgaPKS for ishigamide biosynthesis. The ketoreductase (Iga13) and dehydratase (Iga16) were shown to catalyze the reduction of a beta-keto group and dehydration of a beta-hydroxy group, respectively, to form a trans double bond. Incubation of the acyl carrier protein (Iga10), the ketosynthase/chain length factor complex (Iga11-Iga12), Iga13 and Iga16 with malonyl and hexanoyl CoAs and NADPH followed by KOH hydrolysis resulted in the formation of four unsaturated carboxylic acids (C8 , C10 , C12 , and C14 ), indicating that IgaPKS catalyzes tetraene formation by repeating the cycle of condensation, keto reduction and dehydration with strict stereo-specificity. We propose "highly reducing type II PKS subfamily" for the polyene-producing type II PKSs. PMID- 29265714 TI - In-Plane Black Phosphorus/Dicobalt Phosphide Heterostructure for Efficient Electrocatalysis. AB - Heterostructures composed of two-dimensional black phosphorus (2D BP) with unique physical/chemical properties are of great interest. Herein, we report a simple solvothermal method to synthesize in-plane BP/Co2 P heterostructures for electrocatalysis. By using the reactive edge defects of the BP nanosheets as the initial sites, Co2 P nanocrystals are selectively grown on the BP edges to form the in-plane BP/Co2 P heterostructures. Owing to disposition on the original defects of BP, Co2 P improves the conductivity and offers more active electrocatalytic sites, so that the BP/Co2 P nanosheets exhibit better and more stable electrocatalytic activities in the hydrogen evolution and oxygen evolution reactions. Our work not only extends the application of BP to electrochemistry, but also provides a new idea to improve the performance of BP by utilization of defects. Furthermore, this strategy can be extended to produce other BP heterostructures to expand the corresponding applications. PMID- 29265715 TI - Multi-level hp-finite cell method for embedded interface problems with application in biomechanics. AB - This work presents a numerical discretization technique for solving 3-dimensional material interface problems involving complex geometry without conforming mesh generation. The finite cell method (FCM), which is a high-order fictitious domain approach, is used for the numerical approximation of the solution without a boundary-conforming mesh. Weak discontinuities at material interfaces are resolved by using separate FCM meshes for each material sub-domain and weakly enforcing the interface conditions between the different meshes. Additionally, a recently developed hierarchical hp-refinement scheme is used to locally refine the FCM meshes to resolve singularities and local solution features at the interfaces. Thereby, higher convergence rates are achievable for nonsmooth problems. A series of numerical experiments with 2- and 3-dimensional benchmark problems is presented, showing that the proposed hp-refinement scheme in conjunction with the weak enforcement of the interface conditions leads to a significant improvement of the convergence rates, even in the presence of singularities. Finally, the proposed technique is applied to simulate a vertebra implant model. The application showcases the method's potential as an accurate simulation tool for biomechanical problems involving complex geometry, and it demonstrates its flexibility in dealing with different types of geometric description. PMID- 29265716 TI - Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s. AB - Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets. PMID- 29265717 TI - Fulminant type 1 diabetes caused by peginterferon alpha-2a therapy in hepatitis C. PMID- 29265718 TI - Effects of complex probiotic supplementation in growing pig diets with and without palm kernel expellers on growth performance, nutrient digestibility, blood parameters, fecal microbial shedding and noxious gas emission. AB - In Experiment 1, a total of 100 growing pigs (Duroc * [Landrace * Yorkshire]) with an average initial body weight (BW) of 24.88 +/- 1.57 kg were randomly allotted to 2 * 2 factorial arrangement with two concentrations of palm kernel expellers (PKE) in diets at 0% or 10%, and two concentrations of supplemental probiotics at 0 or 6.0 * 107 colony-forming units/kg. There were five replicate pens per treatment with five pigs per pen. In Experiment 2, eight barrows with average initial BW of 25.78 +/- 0.19 kg were allotted to a replicated 4 * 4 Latin square design with four diets and four periods per square. Four experimental diets were the same as Experiment 1. In Experiment 1, dietary probiotic supplementation improved (P < 0.05) the average daily gain (ADG), nutrient digestibility and the fecal Lactobacillus counts. Furthermore, interactive effects (P < 0.05) between PKE and probiotics were observed on ADG and growth-to feed ratio. In Experiment 2, an interactive effect (P < 0.05) of PKE and probiotics was observed in apparent ileal digestibility of nitrogen and some amino acids. In conclusion, dietary probiotics did not improve PKE utilization and the use of probiotics in non-PKE-containing diet was more favorable than in PKE-containing diet. PMID- 29265719 TI - Hepatitis C virus eradication by direct antiviral agents improves glucose tolerance and reduces post-load insulin resistance in nondiabetic patients with genotype 1. AB - BACKGROUND AND AIMS: Genotype 1 chronic hepatitis C is associated with an impairment of glucose homoeostasis, especially in the advanced stages of the disease. Glucose tolerance is an independent predictor of liver-related mortality in patients with cirrhosis because of chronic hepatitis C. However, no study has demonstrated so far weather hepatitis C virus clearance affects glucose tolerance. METHODS: To this aim, we performed a prospective study assessing the effects of direct antiviral agents treatment in nondiabetic cirrhotic patients with genotypes 1a/1b and impaired glucose tolerance based on a 75-g oral glucose tolerance test. Impaired glucose tolerance was diagnosed by a 2-hour plasma glucose between 140 and 199 mg/dL. Insulin resistance was estimated by the oral glucose insulin sensitivity index, an oral glucose tolerance test-derived measure. RESULTS: After meeting the inclusion criteria, the study population included 32 outpatients (26/6 genotypes 1b/1a; age 62 +/- 7.4 years; 18 males) with compensated Child-A cirrhosis. All patients achieved a sustained virological response following direct antiviral agents treatment. After viral eradication, we did not observe change in fasting plasma glucose (103.5 +/- 7.1 vs 102.8 +/- 7.2 mg/dL, P = .15) but 2-hour plasma glucose was reduced (165.2 +/- 22.7 vs 138.5 +/ 21.3 mg/dL, P < .001). Hepatitis C virus eradication led also to a significant reduction in HbA1c (6.1 +/- 0.2% vs 5.7 +/- 0.3%, P < .001) and post-load insulin resistance as assessed by the oral glucose insulin sensitivity index (6.92 +/- 1.56 vs 9.52 +/- 1.39 mg/kg/min, P < .001). These effects were observed despite no change in body mass index from baseline to follow-up (25.6 +/- 4.3 vs 25.8 +/- 4.4, P > .5). CONCLUSIONS: Our results indicate that hepatitis C virus eradication may early improve glucose tolerance in patients with hepatitis C virus-related cirrhosis. PMID- 29265720 TI - Visible-Light-Responsive Photoanodes for Highly Active, Stable Water Oxidation. AB - Solar energy is a natural and effectively permanent resource and so the conversion of solar radiation into chemical or electrical energy is an attractive, although challenging, prospect. Photo-electrochemical (PEC) water splitting is a key aspect of producing hydrogen from solar power. However, practical water oxidation over photoanodes (in combination with water reduction at a photocathode) in PEC cells is currently difficult to achieve because of the large overpotentials in the reaction kinetics and the inefficient photoactivity of the semiconductors. The development of semiconductors that allow high solar-to hydrogen conversion efficiencies and the utilization of these materials in photoanodes will be a necessary aspect of achieving efficient, stable water oxidation. This Review discusses advances in water oxidation activity over photoanodes of n-type visible-light-responsive (oxy)nitrides and oxides. PMID- 29265722 TI - Pd-Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten-Membered Heterocycles. AB - We report herein the first enantioselective cycloaddition of vinyl oxetanes, the reaction of which with azadienes provided unprecedented access to ten-membered heterocycles through a [6+4] cycloaddition. By using a commercially available chiral Pd-SIPHOX catalyst, a wide range of benzofuran- as well as indole-fused heterocycles could be accessed in excellent yield and enantioselectivity. A unique Lewis acid induced fragmentation of these ten-membered heterocycles was also discovered. PMID- 29265724 TI - SIMLR: A Tool for Large-Scale Genomic Analyses by Multi-Kernel Learning. AB - SIMLR (Single-cell Interpretation via Multi-kernel LeaRning), an open-source tool that implements a novel framework to learn a sample-to-sample similarity measure from expression data observed for heterogenous samples, is presented here. SIMLR can be effectively used to perform tasks such as dimension reduction, clustering, and visualization of heterogeneous populations of samples. SIMLR was benchmarked against state-of-the-art methods for these three tasks on several public datasets, showing it to be scalable and capable of greatly improving clustering performance, as well as providing valuable insights by making the data more interpretable via better a visualization. SIMLR is available on https://github.com/BatzoglouLabSU/SIMLRGitHub in both R and MATLAB implementations. Furthermore, it is also available as an R package on http://bioconductor.org. PMID- 29265723 TI - Structural connectivity of the amygdala in young adults with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is characterized by impairments in social cognition, a function associated with the amygdala. Subdivisions of the amygdala have been identified which show specificity of structure, connectivity, and function. Little is known about amygdala connectivity in ASD. The aim of this study was to investigate the microstructural properties of amygdala-cortical connections and their association with ASD behaviours, and whether connectivity of specific amygdala subregions is associated with particular ASD traits. The brains of 51 high-functioning young adults (25 with ASD; 26 controls) were scanned using MRI. Amygdala volume was measured, and amygdala-cortical connectivity estimated using probabilistic tractography. An iterative 'winner takes all' algorithm was used to parcellate the amygdala based on its primary cortical connections. Measures of amygdala connectivity were correlated with clinical scores. In comparison with controls, amygdala volume was greater in ASD (F(1,94) = 4.19; p = .04). In white matter (WM) tracts connecting the right amygdala to the right cortex, ASD subjects showed increased mean diffusivity (t = 2.35; p = .05), which correlated with the severity of emotion recognition deficits (rho = -0.53; p = .01). Following amygdala parcellation, in ASD subjects reduced fractional anisotropy in WM connecting the left amygdala to the temporal cortex was associated with with greater attention switching impairment (rho = 0.61; p = .02). This study demonstrates that both amygdala volume and the microstructure of connections between the amygdala and the cortex are altered in ASD. Findings indicate that the microstructure of right amygdala WM tracts are associated with overall ASD severity, but that investigation of amygdala subregions can identify more specific associations. PMID- 29265726 TI - Directed Evolution of an Artificial Imine Reductase. AB - Artificial metalloenzymes, resulting from incorporation of a metal cofactor within a host protein, have received increasing attention in the last decade. The directed evolution is presented of an artificial transfer hydrogenase (ATHase) based on the biotin-streptavidin technology using a straightforward procedure allowing screening in cell-free extracts. Two streptavidin isoforms were yielded with improved catalytic activity and selectivity for the reduction of cyclic imines. The evolved ATHases were stable under biphasic catalytic conditions. The X-ray structure analysis reveals that introducing bulky residues within the active site results in flexibility changes of the cofactor, thus increasing exposure of the metal to the protein surface and leading to a reversal of enantioselectivity. This hypothesis was confirmed by a multiscale approach based mostly on molecular dynamics and protein-ligand dockings. PMID- 29265725 TI - Rationale and design for the Asia BP@Home study on home blood pressure control status in 12 Asian countries and regions. AB - Home blood pressure (BP) monitoring is endorsed in multiple guidelines as a valuable adjunct to office BP measurements for the diagnosis and management of hypertension. In many countries throughout Asia, physicians are yet to appreciate the significant contribution of BP variability to cardiovascular events. Furthermore, data from Japanese cohort studies have shown that there is a strong association between morning BP surge and cardiovascular events, suggesting that Asians in general may benefit from more effective control of morning BP. We designed the Asia BP@Home study to investigate the distribution of hypertension subtypes, including white-coat hypertension, masked morning hypertension, and well-controlled and uncontrolled hypertension. The study will also investigate the determinants of home BP control status evaluated by the same validated home BP monitoring device and the same standardized method of home BP measurement among 1600 or more medicated patients with hypertension from 12 countries/regions across Asia. PMID- 29265727 TI - Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study. AB - BACKGROUND AND OBJECTIVES: The Influenza Resistance Information Study (IRIS) was initiated in 2008 to study the emergence of neuraminidase inhibitor (NAI) resistance and the clinical course of influenza in immunocompetent treated and untreated patients. METHODS: Patients had throat/nose swabs collected on days 1, 3, 6 and 10 for analyses of influenza type, subtype and virus susceptibility to NAIs. RT-PCR-positive samples were cultured and tested for NAI resistance by specific RT-PCR and phenotypic testing. Scores for influenza symptoms were recorded on diary cards (Days 1-10). This study focuses on influenza A-infected cases only. RESULTS: Among 3230 RT-PCR-positive patients, 2316 had influenza A of whom 1216 received oseltamivir monotherapy within 2 days of symptom onset (9 seasonal H1N1; 662 H3N2; 545 H1N1pdm2009). Except for 9 patients with naturally resistant seasonal H1N1 (2008/9), no resistance was detected in Day 1 samples. Emergence of resistance (post-Day 1) was detected in 43/1207 (3.56%) oseltamivir treated influenza A-infected patients, with a higher frequency in 1- to 5-year olds (11.8%) vs >5-year-olds (1.4%). All N1- and N2-resistant viruses had H275Y (n = 27) or R292K (n = 16) substitutions, respectively. For 43 patients, virus clearance was significantly delayed vs treated patients with susceptible viruses (8.1 vs 10.9 days; P < .0001), and 11 (23.2%) remained RT-PCR positive for influenza at Day 10. However, their symptoms resolved by Day 6 or earlier. CONCLUSIONS: Oseltamivir resistance was only detected during antiviral treatment, with the highest incidence occurring among 1- to 5-year-olds. Resistance delayed viral clearance, but had no impact on symptom resolution. PMID- 29265729 TI - The Past, Present, and Future of Sustainable Chemistry. AB - A new decade: To mark 10 years since the launch of ChemSusChem and to welcome you to Volume 11, this Editorial features the thoughts of some of the journal's Editorial Board members on the current status of the field of sustainable chemistry, and looks at its future prospects. PMID- 29265730 TI - Powerful diuretics: A common denominator in landmark hypertension and type 2 diabetes mellitus trials. PMID- 29265728 TI - Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. AB - While alpha-actin isoforms predominate in adult striated muscle, skeletal muscle specific knockouts (KOs) of nonmuscle cytoplasmic betacyto - or gammacyto -actin each cause a mild, but progressive myopathy effected by an unknown mechanism. Using transmission electron microscopy, we identified morphological abnormalities in both the mitochondria and the sarcoplasmic reticulum (SR) in aged muscle specific betacyto - and gammacyto -actin KO mice. We found betacyto - and gammacyto -actin proteins to be enriched in isolated mitochondrial-associated membrane preparations, which represent the interface between mitochondria and sarco-endoplasmic reticulum important in signaling and mitochondrial dynamics. We also measured significantly elongated and interconnected mitochondrial morphologies associated with a significant decrease in mitochondrial fission events in primary mouse embryonic fibroblasts lacking betacyto - and/or gammacyto -actin. Interestingly, mitochondrial respiration in muscle was not measurably affected as oxygen consumption was similar in skeletal muscle fibers from 12 month-old muscle-specific betacyto - and gammacyto -actin KO mice. Instead, we found that the maximal rate of relaxation after isometric contraction was significantly slowed in muscles of 12-month-old betacyto - and gammacyto -actin muscle-specific KO mice. Our data suggest that impaired Ca2+ re-uptake may presage development of the observed SR morphological changes in aged mice while providing a potential pathological mechanism for the observed myopathy. PMID- 29265731 TI - Disproportionality Analysis Used to Identify Patterns in Medication Error Reports Involving Hospitalized Children. PMID- 29265733 TI - The rooster impact: End of year note 2017. PMID- 29265734 TI - CYTO Asia 2017 meeting highlights. PMID- 29265735 TI - Preclinical safety and immunological efficacy of Alternaria alternata polymerized extracts. AB - INTRODUCTION: Alternaria alternata is a widespread fungi whose allergy is a risk factor for asthma development. The use of a polymerized allergen extract (allergoid) may be safer than native extract based treatments while maintaining efficacy. The objective of this study was to characterize biochemically and immunochemically a new Alternaria alternata allergoid. METHODS: Characterization of native and allergoid extracts was performed by determination of protein content, protein and allergenic profile, biological potency, identification of Alternaria allergens, and Alt a 1 quantification. Safety was evaluated in toxicological assays (Ames test, limit test, and fish embryo acute toxicity test in zebrafish, and maximum tolerated dose and Dose-range finding study in rats). Efficacy was evaluated as the capacity to induce IgG antibodies that block IgE binding to the allergen and cytokine induction (IFN-gamma, IL-4, IL-6, IL-10, and TNF-alpha) in PBMC from atopic donors. RESULTS: Protein and antigenic profiles showed significant modification of the depigmented allergoid with respect to the native extract, inducing a lower IgE binding capacity. Alt a 1, Alt a 3, Alt a 6, and Alt a 8 allergen sequences were identified in the polymer. No toxicological nor genotoxicity effects were observed. The polymer induced IgG antibodies that blocked human IgE binding epitopes, and it induced higher IL-10 levels and similar levels of the other cytokines than native extract in PBMC. CONCLUSIONS: This new A. alternata allergoid could be an effective immunotherapy treatment leading to cytokine stimulation and inducing synthesis of IgG antibodies able to block IgE binding to the allergen. In addition, no toxicological effect was observed, and it may be safer than native extract due to its lower IgE binding capacity and cytokine induction that suggest tolerance induction via T cell shift to Treg (IL-10). PMID- 29265736 TI - Editorial Board and International Advisory Board: Angew. Chem. Int. Ed. 52/2017. PMID- 29265737 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 52/2017. PMID- 29265738 TI - Corrigendum: Asymmetric Grignard Synthesis of Tertiary Alcohols through Rational Ligand Design. PMID- 29265739 TI - Corrigendum: A General Catalytic Hydroamidation of 1,3-Dienes: Atom-Efficient Synthesis of N-Allyl Heterocycles, Amides, and Sulfonamides. PMID- 29265740 TI - Considerations for Pharmacoepidemiological Studies of Drug-Cancer Associations. AB - In this MiniReview, we provide general considerations for the planning and conduct of pharmacoepidemiological studies of associations between drug use and cancer development. We address data sources, study design, assessment of drug exposure, ascertainment of cancer outcomes, confounder adjustment and future perspectives. Aspects of data sources include assessment of complete history of drug use and data on dose and duration of drug use, allowing estimates of cumulative exposure. Outcome data from formal cancer registries are preferable, but cancer data from other sources, for example, patient or pathology registries, medical records or claims are also suitable. The two principal designs for observational studies evaluating drug-cancer associations are the cohort and case control designs. A key challenge in studies of drug-cancer associations is the exposure assessment due to the typically long period of cancer development. We present methods to examine early and late effects of drug use on cancer development and discuss the need for employing 'lag-time' in order to avoid reverse causation. We emphasize that a new-user study design should always be considered. We also underline the need for 'dose-response' analyses, as drug cancer associations are likely to be dose-dependent. Generally, studies of drug cancer associations should explore risk of site-specific cancer, rather than cancer overall. Additional differentiation may also be crucial for organ-specific cancer with various distinct histological subtypes (e.g., lung or ovary cancer). We also highlight the influence of confounding factors and discuss various methods to address confounding, while emphasizing that the choices of methods depend on the design and specific objectives of the individual study. In some studies, use of active comparator(s) may be preferable. Pharmacoepidemiological studies of drug-cancer associations are expected to evolve considerably in the coming years, due to the increasing availability of long-term data on drug exposures and cancer outcomes, the increasing conduct of multinational studies, allowing studies of rare cancers and subtypes of cancer, and methodological improvements specifically addressing cancer and other long-term outcomes. PMID- 29265741 TI - National survey on anatomical sciences in medical education. AB - The drivers for curricular change in medical education such as the addition of innovative approaches to teaching, inclusion of technology and adoption of different assessment methods are gaining momentum. In an effort to understand how these changes are impacting and being implemented in gross anatomy, microscopic anatomy, neuroanatomy/neuroscience, and embryology courses, surveys were sent out to course directors/discipline leaders at allopathic Medical Schools in the United States during the 2016-2017 academic year. Participants in the study were asked to comment on course hours, student experiences in the classroom and laboratory, amount of faculty participation, the use of peers as teachers in both the classroom and laboratory, methods used for student assessment and identification of best practices. Compared to data published from a similar survey in 2014, a number of changes were identified: (1) classroom hours in gross anatomy increased by 24% and by 29% in neuroanatomy/neuroscience; (2) laboratory hours in gross anatomy decreased by 16%, by 33% in microscopic anatomy, and by 38% in neuroanatomy/neuroscience; (3) use of virtual microscopy in microscopic anatomy teaching increased by 129%; and (4) the number of respondents reporting their discipline as part of a partially or fully integrated curriculum increased by greater than 100% for all four disciplines. Anat Sci Educ 11: 7-14. (c) 2017 American Association of Anatomists. PMID- 29265743 TI - Micropatterning Different Cell Types with Microarray Amplification of Natural Directional Persistence. PMID- 29265744 TI - Corrigendum. PMID- 29265742 TI - Axial length growth and the risk of developing myopia in European children. AB - PURPOSE: To generate percentile curves of axial length (AL) for European children, which can be used to estimate the risk of myopia in adulthood. METHODS: A total of 12 386 participants from the population-based studies Generation R (Dutch children measured at both 6 and 9 years of age; N = 6934), the Avon Longitudinal Study of Parents and Children (ALSPAC) (British children 15 years of age; N = 2495) and the Rotterdam Study III (RS-III) (Dutch adults 57 years of age; N = 2957) contributed to this study. Axial length (AL) and corneal curvature data were available for all participants; objective cycloplegic refractive error was available only for the Dutch participants. We calculated a percentile score for each Dutch child at 6 and 9 years of age. RESULTS: Mean (SD) AL was 22.36 (0.75) mm at 6 years, 23.10 (0.84) mm at 9 years, 23.41 (0.86) mm at 15 years and 23.67 (1.26) at adulthood. Axial length (AL) differences after the age of 15 occurred only in the upper 50%, with the highest difference within the 95th percentile and above. A total of 354 children showed accelerated axial growth and increased by more than 10 percentiles from age 6 to 9 years; 162 of these children (45.8%) were myopic at 9 years of age, compared to 4.8% (85/1781) for the children whose AL did not increase by more than 10 percentiles. CONCLUSION: This study provides normative values for AL that can be used to monitor eye growth in European children. These results can help clinicians detect excessive eye growth at an early age, thereby facilitating decision-making with respect to interventions for preventing and/or controlling myopia. PMID- 29265745 TI - Use of infant formula in the ELFE study: The association with social and health related factors. AB - Breastfeeding is recommended until 6 months of age, but a wide range of infant formula is available for nonbreastfed or partially breastfed infants. Our aim was to describe infant formula selection and to examine social- and health-related factors associated with this selection. Analyses were based on 13,291 infants from the French national birth cohort Etude Longitudinale Francaise depuis l'Enfance. Infant diet was assessed at Month 2 by phone interview and monthly from Months 3 to 10 via internet/paper questionnaires. Infant formulas were categorized in 6 groups: extensively or partially hydrolysed, regular with or without prebiotics/probiotics, and thickened with or without prebiotics/probiotics. Associations between type of infant formula used at 2 months and family or infant characteristics were assessed by multinomial logistic regressions. At Month 2, 58.1% of formula-fed infants were fed with formula enriched in prebiotics/probiotics, 31.5% with thickened formula, and 1.4% with extensively hydrolysed formula. The proportion of formula-fed infants increased regularly, but the type of infant formula used was fairly stable between 2 and 10 months. At Month 2, extensively hydrolysed formulas were more likely to be used in infants with diarrhoea or regurgitation problems. Partially hydrolysed formulas were more often used in families with high income, with a history of allergy, or with infants with regurgitation issues. Thickened formulas were used more with boys, preterm infants, infants with regurgitation issues, or in cases of early maternal return to work. The main factors related to the selection of infant formula were family and infant health-related ones. PMID- 29265746 TI - Longitudinal changes of elderly patients' wishes about artificial nutrition and hydration during end-of-life care: A pilot study in a single hospital. PMID- 29265747 TI - Pilot study: The application of a multicomponent exercise for older people in a depopulated rural area. PMID- 29265749 TI - Multifaceted changes and mortality in older adults. PMID- 29265748 TI - Landiolol dramatically improved Takotsubo cardiomyopathy in an older patient. PMID- 29265750 TI - Case report of an undisintegrated magnesium oxide tablet in the stool in an elderly patient taking food thickener. PMID- 29265751 TI - Delirium after thiazide diuretic suspension can unmask diabetes insipidus. PMID- 29265752 TI - Authors' reply "Multifaceted changes and mortality in the elderly". PMID- 29265753 TI - Effects of forest bathing on plasma endothelin-1 in elderly patients with chronic heart failure: Implications for adjunctive therapy. PMID- 29265754 TI - Leveraging Tokyo 2020: Can the Olympic Games activate older Japanese and compress morbidity in later life? PMID- 29265755 TI - Primary pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue with a severe hemorrhagic pleural effusion in an oldest old patient. PMID- 29265756 TI - Delirium induced by albendazole-ivermectin combination: Report of the first case in an older patient. PMID- 29265757 TI - Prevalence of frailty among community-dwellers and outpatients in Japan as defined by the Japanese version of the Cardiovascular Health Study criteria. PMID- 29265758 TI - Bereaved relatives' perception of quality of hospital death in older patients. PMID- 29265760 TI - Case of a 78-year-old woman with a neuronal intranuclear inclusion disease. PMID- 29265761 TI - Relationship between the neutrophil-to-lymphocyte ratio and silent cerebral small vessel disease in community-dwelling older adults. The Atahualpa Project. PMID- 29265762 TI - Esophageal food impaction with an unexpected meal in an elderly woman. PMID- 29265763 TI - Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome. AB - 22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2 hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed. PMID- 29265765 TI - Pseudoaneurysm diagnosed by endoscopic ultrasonography via color doppler flow mapping and contrast enhancement. PMID- 29265764 TI - Neuregulin-1 is essential for nerve plexus formation during cardiac maturation. AB - The Neuregulin-1 (Nrg1)/ErbB pathway plays multiple, critical roles in early cardiac and nervous system development and has been implicated in both heart and nerve repair processes. However, the early embryonic lethality of mouse Nrg1 mutants precludes an analysis of Nrg1's function in later cardiac development and homeostasis. In this study, we generated a novel nrg1 null allele targeting all known isoforms of nrg1 in zebrafish and examined cardiac structural and functional parameters throughout development. We found that zebrafish nrg1 mutants instead survived until young adult stages when they exhibited reduced survivorship. This coincided with structural and functional defects in the developing juvenile and young adult hearts, as demonstrated by reduced intracardiac myocardial density, cardiomyocyte cell number, swimming performance and dysregulated heartbeat. Interestingly, nrg1 mutant hearts were missing long axons on the ventricle surface by standard length (SL) 5 mm, which preceded juvenile and adult cardiac defects. Given that the autonomic nervous system normally exerts fine control of cardiac output through this nerve plexus, these data suggest that Nrg1 may play a critical role in establishing the cardiac nerve plexus such that inadequate innervation leads to deficits in cardiac maturation, function and survival. PMID- 29265766 TI - Repeated intravesical injections of platelet-rich plasma are effective in the treatment of interstitial cystitis: a case control pilot study. AB - OBJECTIVE: Interstitial cystitis (IC), also known as bladder pain syndrome (BPS), is a debilitating chronic disease. There are few treatment options for IC/BPS refractory to current medical therapy. This study investigated the clinical efficacy of intravesical injections of platelet-rich plasma (PRP) in IC/BPS. METHODS: Fifteen patients with IC/BPS received 4 intravesical injections, at 1 monthly intervals, of 12 mL PRP extracted from 50 mL of the patient's whole blood, followed by cystoscopic hydrodistention. The primary endpoint was the change in O'Leary-Sant symptom (OSS) index from baseline to 1 month after the 4th PRP injection. Secondary endpoints were changes in pain (measured using a visual analog scale [VAS]), daily frequency, nocturia, functional bladder capacity (FBC), maximum flow rate, voided volume, post-void residual (PVR) volume, and global response assessment (GRA). Urinary cytokine levels were measured at baseline and 1 month after the 1st PRP treatment. RESULTS: Of the 15 women in the study, 13 completed the 4 injections and follow-up visits (mean [+/- SD] age 52.9 +/- 12.1 years). The OSS index and VAS pain score decreased significantly and FBC and GRA increased after the 1st PRP injection and lasted until the final endpoint. There was no change in PVR after repeated PRP injections, and all patients were free of urinary tract infections and difficulty urinating. Urinary interleukin (IL)-2 and IL-8 concentrations increased significantly after the 1st PRP injection. In patients with reductions in the VAS pain score >=1, urinary IL 8 and vascular endothelial growth factor increased. In patients without reductions in the VAS pain score, IL-6 concentrations increased after PRP injection. CONCLUSIONS: Repeated intravesical PRP injections are well tolerated and appear to be safe and effective in medically refractive IC/BPS, providing significant symptom improvement. PMID- 29265767 TI - An alternative method to measure the diffusing capacity of the lung for carbon monoxide in infants. AB - BACKGROUND: Lung diffusion assessed by the uptake of carbon monoxide (DLCO ) and alveolar volume (VA ) by inert gas dilution are readily assessed in cooperative older subjects; however, obtaining these measurements in infants has been much more difficult. Our laboratory has measured DLCO and VA in sleeping infants using a mass spectrometer, which continuously measures gas concentrations, and demonstrated that infants with bronchopulmonary dysplasia (BPD) have lower DLCO , but no difference in VA compared to full-term controls. The mass spectrometer is expensive and lacks portability; therefore, we evaluated whether measurement of end-expiratory alveolar gas concentrations using a gas chromatograph would provide an alternative approach. METHODS: (1) Using our previously digitized data for infants with BPD and full-term controls, DLCO and VA were calculated at end expiration rather than between 60 and 80% of expired volume, as previously reported. (2) In a new group of infants, DLCO and VA were measured using gas concentrations obtained at end-expiration with a mass spectrometer and a gas chromatograph. RESULTS: (1) Using end-expiratory concentrations, infants with BPD (n = 49) had significantly lower DLCO , but similar VA compared to healthy controls (n = 34) (DLCO : 4.2 vs 4.6 mL/min/mmHg, P = 0.047; VA : 614 vs 608 mL, P = 0.772). (2) Among newly evaluated infants (n = 28), DLCO and VA obtained with a mass spectrometer and a gas chromatograph were highly correlated (R2 = 0.94 and 0.99, respectively), and were not significantly different for the two analyzers. CONCLUSION: Measuring DLCO and VA at end-expiration using a gas chromatograph can provide an effective assessment of gas exchange in sleeping infants. PMID- 29265768 TI - Extracellular Matrix and the Extracellular Environment. PMID- 29265769 TI - Sedentary Time and MRI-Derived Measures of Adiposity in Active Versus Inactive Individuals. AB - OBJECTIVE: The aim of this study was to examine cross-sectional associations between objectively measured sedentary time and magnetic resonance imaging (MRI) assessed adiposity in a population at high risk for type 2 diabetes (T2DM) and to determine whether associations are modified by the recommended levels of moderate to-vigorous physical activity (MVPA). METHODS: Sedentary time and MVPA were measured objectively by using accelerometers. Linear regression models examined the association of sedentary time with liver, visceral, subcutaneous, and total abdominal fat (quantified by using MRI). Interaction terms determined whether results were consistent across activity categories (active [> 150 min/wk of MVPA] vs. inactive [< 150 min/wk of MVPA]). RESULTS: One hundred and twenty-four participants (age = 64.0 +/- 7.1 years; male = 65.3%; BMI = 31.8 +/- 5.6 kg/m2 ) were included. Following adjustment, each 60 minutes of sedentary time was associated with 1.74 L higher total abdominal fat, 0.62 L higher visceral fat, 1.14 L higher subcutaneous fat, and 1.86% higher liver fat. When results were stratified by MVPA (active vs. inactive), sedentary time was associated with greater liver, visceral, and total abdominal fat in the inactive group only. CONCLUSIONS: These findings suggest that sedentary time is associated with higher levels of inter- and intraorgan fat, but associations with liver, visceral, and total abdominal fat were stronger in those who do not reach the current exercise recommendations for health. PMID- 29265770 TI - Three New Perspectives on the Perfect Storm: What's Behind the Obesity Epidemic? PMID- 29265772 TI - Did the Food Environment Cause the Obesity Epidemic? AB - Several putative explanations of the obesity epidemic relate to the changing food environment. Individual dietary macronutrients have each been theorized to be the prime culprit for population obesity, but these explanations are unlikely. Rather, obesity probably resulted from changes in the caloric quantity and quality of the food supply in concert with an industrialized food system that produced and marketed convenient, highly processed foods from cheap agricultural inputs. Such foods often contain high amounts of salt, sugar, fat, and flavor additives and are engineered to have supernormal appetitive properties driving increased consumption. Ubiquitous access to convenient and inexpensive food also changed normative eating behavior, with more people snacking, eating in restaurants, and spending less time preparing meals at home. While such changes in the food environment provide a likely explanation of the obesity epidemic, definitive scientific demonstration is hindered by the difficulty in experimentally isolating and manipulating important variables at the population level. PMID- 29265773 TI - Health Outcomes and Explant Rates After Laparoscopic Adjustable Gastric Banding: A Phase 4, Multicenter Study over 5 Years. AB - OBJECTIVE: This study aimed to evaluate the real-world safety and effectiveness of the LAP-BAND (Apollo Endosurgery Inc., Austin, Texas) adjustable gastric banding system (LBS) for 5 years following implantation. METHODS: This prospective, longitudinal, phase 4, multicenter study involved 652 patients who had implantation of the LBS system. The primary outcome was the percentage of subjects who had LBS explant over 5 years. The secondary outcomes included the rate of reoperations, clinical and biochemical measures, and patient-reported outcome measures over 5 years. RESULTS: The study cohort consisted of 79.3% females with a mean age of 44 years and a mean BMI of 45.4 kg/m2 . The primary end point was met with an explant rate of 8.74% (95% CI: 6.6%-10.9%) at 5 years. The rates for completer-only analysis and imputed missing data analysis were 12.81% (95% CI: 9.7%-15.9%) and 12.85% (95% CI: 10.2%-15.5%), respectively. All were significantly lower than the historic rate of 39.4% (P < 0.001). There were 43 patients who required reoperations or revisions excluding explants (6.6%). A mean weight loss of 18.7% was maximally achieved by 2 years, and weight loss was maintained through to 5 years. All patient-reported outcomes showed improvement following LBS treatment throughout 5 years. CONCLUSIONS: This study validates the long-term safety and effectiveness of LBS for the treatment of patients with obesity and its related conditions. PMID- 29265771 TI - Weight Loss Strategies in the Elderly: A Clinical Conundrum. AB - The age-related concomitant loss of skeletal muscle and accumulation of excess adipose tissue have been commonly referred to as sarcopenic obesity. While weight loss may help mitigate the metabolic abnormalities linked to obesity, low fitness levels and muscle atrophy complicate the effectiveness of lifestyle interventions. Because of low levels of compliance, suboptimal economic efficiency, and low functional capacity, there has been no consensus on optimal therapy. This includes the use of high-protein diets that do not ensure muscle preservation during weight loss in this segment of the population. The primary objectives of this review are to discuss the relevance of sarcopenic obesity, examine the feasibility of weight loss in the elderly, and highlight new approaches to the problem. PMID- 29265774 TI - The Obesity Epidemic: A Consequence of Reduced Energy Expenditure and the Uncoupling of Energy Intake? AB - Obesity prevalence has increased, and increased energy intake or decreased physical activity are the two most obvious contributing factors. The percentage of Americans engaging in exercise has been stable over the past few decades, but decreases in occupation-related energy expenditure are sufficient to partially explain increased obesity prevalence. Further, the contribution of energy intake and energy expenditure to the obesity epidemic is complicated because they are not independent-they are influenced by each other. For example, Mayer found that low activity levels were marked by higher body weight and higher "unregulated" energy intake levels. Conversely, higher activity levels were marked by lower body weight and energy intake that matched energy expenditure. Consistent with Mayer, we propose that because most Americans have low levels of occupation related activity, they do not benefit from the regulation of energy intake achieved at higher activity levels, resulting in weight gain due to energy intake exceeding energy expenditure. PMID- 29265775 TI - Complementary Hypotheses on Contributors to the Obesity Epidemic. AB - Increased rates of obesity have occurred within virtually every race, age, sex, ethnicity, and economic group. Despite substantial punditry on the issue, the exact reasons are incompletely known. The two most common factors cited as contributing to the obesity epidemic, and those whose causal influence on increasing obesity levels in the population are often presumed unequivocally, are food marketing practices and institutionally driven reductions in physical activity. These have been called "the big two." This Perspective builds on previous writings in this area to introduce additional factors that may contribute to the obesity epidemic. It is emphasized that there may be other factors working in combination with the big two, influencing body fatness through effects on energy intake, energy expenditure, and/or nutrient partitioning. PMID- 29265778 TI - The Obesity Society 2017 Awards and Grants. PMID- 29265776 TI - Adiposity and Reproductive Cycling Status in Zoo African Elephants. AB - OBJECTIVE: The majority of zoo African elephants exhibit abnormal reproductive cycles, but it is unclear why. Acyclicity has been positively associated with body condition scores. The objective of this study was to measure body composition and examine the relationship between adiposity and cyclicity status, mediated by glucose, insulin, leptin, and inflammation. METHODS: Body composition was assessed by deuterium dilution in 22 African elephants. Each elephant was weighed and given deuterated water orally (0.05 mL/kg), and blood was collected from the ear prior to and five times after deuterium administration. Glucose, insulin, leptin, and proinflammatory biomarker concentrations in serum were determined. RESULTS: Body fat percentage ranged from 5.24% to 15.97%. Fat adjusted for fat free mass (FFM) and age was not significantly associated with cyclicity status (P = 0.332). Age was the strongest predictor of cyclicity status (P = 0.040). Fat was correlated with weight (rho = 0.455, P = 0.044) and when adjusted for FFM with circulating glucose (rho = 0.520, P = 0.022) and showed a trend for association with leptin (unadjusted: rho = 0.384, P = 0.095; adjusted for FFM: rho = 0.403, P = 0.087). CONCLUSIONS: Deuterium dilution appears to be an available technique to measure body composition in African elephants. In this sample, fat was not associated with cyclicity status, and age may be more important to cyclicity status. PMID- 29265777 TI - Erratum: Diet Quality Predicts Visceral Adiposity and Liver Fatness: The Multiethnic Cohort Study. PMID- 29265779 TI - A survey of dietary intake habits and nutritional status in women aged 60-90 years suffering from sleep disorders AB - Background: Disturbances to the rhythms of the sleep-wake cycle adversely impact the quality of everyday living. Amongst those factors predisposing, causing and consolidating sleeping disorders are inappropriate nutrition and its effect on nutritional status Objective: To survey by questionnaire the nutritional status and habits in women aged 60-90 years suffering from sleepingdisorders Materials and methods: Subjects were 141 women aged 60-90 years, attending lectures at the Szczecin Humanistic University for Seniors, of whom 110 (78%) were selected as having declared sleep disorders. Three age groups were established, of 60-65 years (n=39), 65-75 years (n=52) and above 75 years (n=19). Anthropometric measurements were performed (body mass and height) and the BMI (Body Mass Index) calculated. Calorific/energy and nutritional values of the daily dietary intakes were assessed in 330 meals using the PDCAAS calculation (Protein Digestibility Corrected Amino Acid Score). Subjects had previously undergone a two-month pro health nutrition course Results: Daily sleeping disorders were declared by 24.5% women, whilst 45.4% demonstrated inappropriate nutrition. Daily dietary intakes showed insufficiencies in the following: calories, consuming assimilative carbohydrates, cellulose,potassium, calcium, vitamin D3 and water. Simultaneously, excessive intake of Na, P, Fe, Zn, Cu and vitamins: A, B2, B6, B12, niacin and C were found. The smallest quantity of nutritious foodstuffs were consumed by the eldest women(significance of p <=0.05). The share of protein derived calories was significantly the highest in the 66-75 age group (p<=0.01). Leucine was the amino acid that limited the biological value of consumed protein. Such dietary faults/errors were due to an inappropriate structure of foodstuff consumption Conclusion: The dietary intake habits of women in all the age groups were found to be unbalanced in terms of calories and nutritional value, which may affect neurotransmitter synthesis that regulates the sleep and wake cycle along with melatonin homeostasis. It is essential that elderly women are provided with pro-health education covering their nutrition as well as sleeping hygiene. PMID- 29265780 TI - Once-Weekly Exenatide and Cardiovascular Outcomes in Type 2 Diabetes. PMID- 29265782 TI - Non-functioning pituitary tumors: any special considerations during pregnancy? AB - New clinical symptoms from pituitary tumors during pregnancy are rare. Either the patient becomes symptomatic from a known lesion prior to conception during pregnancy, or it is a de-novo diagnosis due to acute symptoms. Non-functioning pituitary tumors can be subdivided into non-functioning pituitary adenomas and other pathologies. This review aims at giving a general overview as well as therapeutical considerations, taking into account that no specific recommendations/guidelines are available for this rare clinical problem. PMID- 29265781 TI - Comparison of nutritional value of "fruit and vegetables" and "western" dietary patterns identified in a group of cancer patients AB - Background: Dietary patterns (DPs) are defined as the amounts, types and combinations of various food products in habitual diets and the frequency of their consumption. Dietary pattern analysis is usually performed in order to assess the combined effect of consumed food products on health Objective: The aim of the study was to assess and compare the nutritional value of dietary patterns identified in a group of patients staying on the oncological ward Material and methods: The study group consisted of 100 patients (51 women and 49 men) aged 19 83 years. Dietary intake was assessed using a food frequency questionnaire (FFQ) validated for the population of Lower Silesian Voivodeship Results: Factor analysis identified two main dietary patterns explaining 25.6% of variance. The "fruit and vegetables" DP consisted of vegetables, fruits, juices, unrefined grains and nuts, seeds and raisins. Instead, the "Western" DP wascharacterized by the consumption of high-fat and processed meat and poultry, fried fish, refined grains, honey and sugar, fats, sweets, beverages and chips. While higher scores for "fruit and vegetables" pattern were associated with increased intake of dietary fiber, antioxidant vitamins, folic acid and decreased glycemic load per 1000 kcal and sodium intake, for "Western" pattern observed relationships were opposite. Women were more likely to have higher factor scores for "fruit and vegetables" DP and lower factor scores for "Western" DP than men Conclusions: Dietary patterns identified in the study group differed in terms of nutritional value, in spite of similar macronutrient content in the diet. "Western" DP was characterized by lower nutritional value than "fruit and vegetables" dietary pattern. PMID- 29265783 TI - TSH-receptor autoantibodies: pathophysiology, assay methods, and clinical applications. AB - TSH receptor antibodies (TRAbs) are characteristic indicators for the common autoimmune thyroid disease Graves disease (GD). In almost all patients stimulating TRAbs are found leading to hyperthyroidism as these antibodies act in an agonistic manner to TSH. Besides stimulating TRAbs, other TRAbs are also frequently found leading to inhibition of TSH receptor signaling (blocking TRAbs) or to the activation of different signaling cascades resulting in e.g. thyrocyte apoptosis (cleavage antibodies). Patients' sera may contain all three types of TRAbs. Dependent on the activity of these particular TSHR autoantibodies clinical symptoms might change. Within this review we summarize current genetic and environmental factors that are generally accepted for GD's etiology. Binding sides to the TSH receptor as well as the resulting signaling cascades are described just as the current used assay methods for TRAb measurement. Finally, we illustrate the clinical impact of TRAbs in the follow-up of GD patients with special focus on GD patients suffering from Graves' ophthalmopathy. PMID- 29265784 TI - Prolactinomas: how to handle prior to and during pregnancy? AB - Prolactinomas are the most common cause of pathological hyperprolactinemia, leading to central hypogonadism and, therefore, a frequent etiology of infertility. Treatment, usually with dopamine agonist (DA), can reverse hyperprolactinemia and hypogonadism, allowing pregnancy in the majority of cases. Bromocriptine is still the DA of choice for such purpose. Important issues in DA induced pregnancies include fetal exposition, both malformations and neuropsychological development and tumor size increase. Regarding microprolactinomas and intrasellar macroprolactinomas, DA should be withdrawn as soon as pregnancy is confirmed. In expansive/invasive macroprolactinomas, DA maintenance should be individualized. Patient follow-up includes periodically clinical evaluation, sellar imaging only indicated in the presence of tumor mass effects related symptoms. Neurosurgery, both before and during gestation, is indicated in cases in which DA treatment failed. Breastfeeding is usually allowed. As tumor volume decrease and remission of hyperprolactinemia may occur after pregnancy, serum prolactin levels and tumor status should be reevaluated. PMID- 29265785 TI - Nivolumab and Ipilimumab in Advanced Melanoma. PMID- 29265786 TI - Nivolumab and Ipilimumab in Advanced Melanoma. PMID- 29265787 TI - Nutritional value of daily food rations of overweight and normal weight pregnant women AB - Background: Adequate nutrition and nutritional status during pregnancy are essential for mother's health and foetus development. Due to increased demands, pregnant women are vulnerable to inadequate nutritional status and paradoxically it may also affect overweight women Objective: The aim of the study was to evaluate energy and nutrients intake in the group of pregnant women in relation to nutritional standards and pre-pregnancy BMI Material and methods: The study included 90 women, during the third trimester of pregnancy, recruited from Warsaw antenatal classes. The anthropometric data gathered in the research were used to calculate BMI value before pregnancy. Pre-pregnancy BMI was categorised as: normal weight (BMI=18.5-24.9 kg/m2, n=47) and overweight (BMI >=25.0 kg/m2, n=43). The assessment of women's nutrition was based on 3-days dietary record. Due to heterogeneous variances, differences between groups were assessed using Mann Whitney U test, p<0.05 was considered as significant Results: The mean intake of energy, protein, fat and carbohydrates in the overweight women were significantly higher than in healthy weight women (p<0.05). Most of the healthy weight women did not reach EAR standard for vitamin D (79.5%), whereas in overweight group it was 41.3% Conclusions: Despite the fact that intakes of energy and all nutrients were higher in overweight women than in normal weight ones, we observed that women in both groups had risk of insufficient supply of energy, iodine, potassium and vitamin D. For this reason, accurate nutritional assessment should be an integral part of obstetric care PMID- 29265788 TI - Associations between adult perception of body weight, diet, preparing meals and dietary patterns AB - Background: The links between dietary patterns, the perception of one's body weight and diet as well preparing meals are poorly recognised in the literature. In order to develop effective nutritional education and focused interventions, more of such information is thereby required to improve the nation's health Objective: To identify dietary patterns based on declared food consumption rates and subject responses on whether dieting, perception of body weight and diet and preparing meals are linked to such dietary patterns Material and methods: The survey was conducted in 2016 on 344 consumers chosen for age (20-65 years) and their consent for study participation. Rates of eating the foods selected were measured using a 7-point scale. Cluster analysis was used to identify three dietary patterns of behaviour: 'potentially beneficial to health', 'potentially unfavourable for health; deficient' and 'potentially unfavourable for health; excessive'. The analysis was performed using IBM SPSS Statistics version 23.0 Results: There were significantly more subjects showing 'potentially beneficial for health' behaviour, normal body weight, those dieting (whether now or in the past) and those who evaluated their diet as being very good or good compared to other groups. They were also more involved in preparing their meals at home. Differences were found between the 'unfavourable for health' dietary patterns concerning subject's involvement in meal preparation. The dietary pattern for 'deficient' behaviour found lower rates of those preparing their meals at home Conclusions: The pattern of potentially beneficial dietary habits was linked to weight control through a slimming diet and greater involvement in the preparation of food for consumption. The results show the need to develop food choice skills rather than just transferring knowledge in the nutrition education process PMID- 29265789 TI - Hospital-Readmission Risk - Isolating Hospital Effects. PMID- 29265790 TI - Hospital-Readmission Risk - Isolating Hospital Effects. PMID- 29265791 TI - Virtual reality to augment robot-assisted gait training in non-ambulatory patients with a subacute stroke: a pilot randomized controlled trial. AB - BACKGROUND: Active performance is crucial for motor learning, and, together with motivation, is believed to be associated with a better rehabilitation outcome. Virtual reality (VR) is an innovative approach to engage and motivate patients during training. There is promising evidence for its efficiency in retraining upper limb function. However, there is insufficient proof for its effectiveness in gait training. AIM: To evaluate the acceptability of robot-assisted gait training (RAGT) with and without VR and the feasibility of potential outcome measures to guide the planning of a larger randomized controlled trial (RCT). DESIGN: Single-blind randomized controlled pilot trial with two parallel arms. SETTING: Rehabilitation hospital. POPULATION: Twenty subacute stroke patients (64+/-9 years) with a Functional Ambulation Classification (FAC) <=2. METHODS: Twelve sessions (over 4 weeks) of either VR-augmented RAGT (intervention group) or standard RAGT (control group). Acceptability of the interventions (drop-out rate, questionnaire), patients' motivation (Intrinsic Motivation Inventory [IMI], individual mean walking time), and feasibility of potential outcome measures (completion rate and response to interventions) were determined. RESULTS: We found high acceptability of repetitive VR-augmented RAGT. The drop-out rate was 1/11 in the intervention and 4/14 in the control group. Patients of the intervention group spent significantly more time walking in the robot than the control group (per session and total walking time; P<0.03). In both groups, motivation measured with the IMI was high over the entire intervention period. The felt pressure and tension significantly decreased in the intervention group (P<0.01) and was significantly lower than in the control group at the last therapy session (r=-0.66, P=0.005). The FAC is suggested as a potential primary outcome measure for a definitive RCT, as it could be assessed in all patients and showed significant response to interventions (P<0.01). We estimated a sample size of 44 for a future RCT. CONCLUSIONS: VR-augmented RAGT resulted in high acceptability and motivation, and in a reduced drop-out rate and an extended training time compared to standard RAGT. This pilot trial provides guidance for a prospective RCT on the effectiveness of VR-augmented RAGT. CLINICAL REHABILITATION IMPACT: VR might be a promising approach to enrich and improve gait rehabilitation after stroke. PMID- 29265792 TI - A comprehensive person-centered approach to adult spastic paresis: a consensus based framework. AB - Spastic paresis is a common feature of an upper motor neuron impairment caused by stroke, brain injury, multiple sclerosis and other central nervous system (CNS) disorders. Existing national and international guidelines for the treatment of adult spastic paresis tend to focus on the treatment of muscle overactivity rather than the comprehensive approach to care, which may require life-long management. Person-centered care is increasingly adopted by healthcare systems in a shift of focus from "disease-oriented" towards "person-centered" medicine. The challenge is to apply this principle to the complex management of spastic paresis and to include an educative process that engages care providers and patients and encourages them to participate actively in the long-term management of their own disease. To address this issue, a group of 13 international clinicians and researchers used a pragmatic top-down methodology to evaluate the evidence and to formulate and grade the strength of recommendations for applying the principles of person-centered care to the management of spastic paresis. There is a distinct lack of clinical trial evidence regarding the application of person-centered medicine to the rehabilitation setting. However, the current evidence base supports the need to ensure that treatment interventions for spastic paresis should be centered on as far as reasonable on the patient's own priorities for treatment. Goal setting, negotiation and formal recording of agreed SMART goals should be an integral part of all spasticity management programs, and goal attainment scaling should be recorded alongside other standardized measures in the evaluation of outcome. When planning interventions for spastic paresis, the team should consider the patient and their family's capacity for self rehabilitation, as well as ways to enhance this approach. Finally, the proposed intervention and treatment goals should consider the impact of any neuropsychological, cognitive and behavioral deficits on rehabilitation. These recommendations support a person-centric focus in the management of spastic paresis. PMID- 29265793 TI - Efficacy and safety of a fixed combination of intramuscular diclofenac 75 mg + thiocolchicoside 4 mg in the treatment of acute low back pain: a phase III, randomized, double blind, controlled trial. AB - BACKGROUND: The management of acute low back pain (LBP) is directed to obtain early and maximum relief of the local and regional pain, and to improve mobility and physical function. AIM: To evaluate the effects of a 4 mL-volume diclofenac 75mg/thiocolchicoside 4mg fixed dose combination (FDC) for intramuscular (IM) injection (test) compared to the separate injection of the two components (reference). DESIGN: Phase III, randomized, controlled, double-blind (blind observer), parallel-group. SETTING: Twenty-two General Practitioners in Italy. POPULATION: Adult outpatients with acute moderate-severe LBP at rest (>=50 mm at VAS) and stable muscle contracture (increase <5 cm in the distance between the two fingers of the examiner in the Schober test). METHODS: Eligible patients were randomized to the test (N.=111) or reference (N.=112) treatment, both given IM once daily for 5 days. The primary efficacy endpoint of the study was the change from baseline in pain VAS score (0-100 mm) measured at rest 96+/-2 hours (day 5) from the start of treatment, one hour after the last injection. RESULTS: Pain VAS Score markedly improved in both groups and the test was non-inferior to the reference in primary endpoint, i.e. the upper bound of the 95% confidence interval of the adjusted difference was lower than the pre-specified limit of 4 mm. There were no statistically significant differences between groups for improvements of pain measured at all time points before and one hour after injection, time to resolution of pain, improvements from baseline of muscle contracture, and time to first resolution of muscle contracture. Approximately 20% of patients in the two groups used rescue paracetamol for pain relief. Both the test and the reference treatment were well tolerated in terms of adverse effects, laboratory parameters and vital signs. CONCLUSIONS: A 5-day treatment with IM diclofenac+thiocolchicoside FDC in a 4-mL volume was as effective and well tolerated as the separate injection of the two components in improving pain symptoms in patients with acute moderate-severe LBP. CLINICAL REHABILITATION IMPACT: The new diclofenac+thiocolchicoside FDC formulation may allow treating effectively acute LBP while reducing the number of injections and hence the risk of local adverse reactions, and improving the patient's compliance. PMID- 29265794 TI - Convex subarachnoid hemorrhage. PMID- 29265795 TI - Safety and feasibility analysis of combination therapy of laparoscopic left hepatectomy and choledochoscopy for calculus of the left intrahepatic duct. AB - BACKGROUND: To observe the efficacy of combination therapy of laparoscopic left hepatectomy and choledochoscopy for calculus of left intrahepatic duct. METHODS: We retrospectively analyzed the clinical data of 76 patients with calculus of left intrahepatic duct who were admitted and diagnosed in this hospital between August 2014 and August 2015. Patients who received the laparotomy for treatment were enrolled into the control group (n = 32), and those who received the combination therapy of laparoscopic left hepatectomy and choledochoscopy were enrolled into the study group (n = 44). The surgical efficacy and the occurrence of surgery complications were compared between the two groups, and the recurrence of calculus was observed in follow-up after the operation. RESULTS: Comparison of the surgical duration showed no statistically significant difference between the two groups (p > 0.05); bleeding amount, evacuation time and length of stay in the study group were less or shorter than those in the control group (p < 0.05); the overall incidence rate of surgery complications in the study group was 9.10%, which was lower than the overall incidence rate of surgery complications, 43.75%, in the control group (p < 0.05). No statistically significant differences were identified in the comparisons of the levels of albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at 1d before and 10d after operation, hospitalization expenses, and operation fee between the two groups (p > 0.05). The average duration of follow-up after operation was 12 months, during which 2 patients in the control group were found with a calculus in a diameter of 0.4cm in the left intrahepatic duct which was later removed using choledochoscopy followed by the extraction of T duct, and the conditions of patient were well-controlled; no recurrence of calculus was observed in the study group. CONCLUSIONS: Combination therapy of laparoscopic left hepatectomy and choledochoscopy is worth being promoted in clinical practice of treatment for calculus of intrahepatic duct with various advantages, such as significant effect, small trauma, high safety and reliability, rapid recovery after operation and few recurrences. PMID- 29265796 TI - Exciplex-Forming Cohost for High Efficiency and High Stability Phosphorescent Organic Light-Emitting Diodes. AB - An exciplex forming cohost system is employed to achieve a highly efficient organic light-emitting diode (OLED) with good electroluminescent lifetime. The exciplex is formed at the interfacial contact of a conventional star-shaped carbazole hole-transporting material, 4,4',4"-tris(N-carbazolyl)-triphenylamine (TCTA), and a triazine electron-transporting material, 2,4,6-tris[3-(1H-pyrazol-1 yl)phenyl]-1,3,5-triazine (3P-T2T). The excellent combination of TCTA and 3P-T2T is applied as the cohost of a common green phosphorescent emitter with almost zero energy loss. When Ir(ppy)2(acac) is dispersed in such exciplex cohost system, OLED device with maximum external quantum efficiency of 29.6%, the ultrahigh power efficiency of 147.3 lm/W, and current efficiency of 107 cd/A were successfully achieved. More importantly, the OLED device showed a low-efficiency roll-off and an operational lifetime (tau80) of ~1020 min with the initial brightness of 2000 cd/m2, which is 56 times longer than the reference device. The significant difference of device stability was attributed to the degradation of exciplex system for energy transfer process, which was investigated by the photoluminescence aging measurement at room temperature and 100 K, respectively. PMID- 29265797 TI - Nanoporous Sulfur-Doped Copper Oxide (Cu2OxS1-x) for Overall Water Splitting. AB - Developing active and bifunctional noble metal-free electrocatalysts is crucial for both the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in the full water splitting process. A ternary nanoporous sulfur-doped copper oxide (Cu2OxS1-x) was successfully synthesized on Cu foam. The obtained Cu2OxS1-x/Cu shows robust electrocatalytic activity toward HER with a low overpotential of 40 mV at 10 mA cm-2 and a Tafel slope of 68 mV dec-1 and exhibits long-term stability in acid solution. Moreover, Cu2OxS1-x shows excellent electrocatalytic activity for OER, HER, and overall water splitting as a bifunctional catalyst in 1.0 M KOH electrolyte. The sulfur doping strategy implemented here can greatly improve the catalytic performance and stability in both acidic and alkaline water electrolyzers and presents an efficient catalyst for overall water splitting. PMID- 29265798 TI - Thermal, Waterproof, Breathable, and Antibacterial Cloth with a Nanoporous Structure. AB - Wearable thermal management materials have attracted increasing attention because of the potential in energy conservation and the possibility to meet the need of smart clothes. An ideal cloth for cold areas has to be lightweight, warm, waterproof but breathable, and antibacterial. Herein, we present a multifunctional cloth starting from a cotton fabric, for which one side is modified to be superhydrophobic by introducing a silica nanoparticle/polydimethylsiloxane (PDMS) layer, while the other side is coated with a nanoporous cellulose acetate layer followed by depositing a thin silver film. The porosity allows the fabric to be breathable, and the silver film plays three important roles as a perfect infrared reflector, a flexible heater, and an antibacterial layer. Such a multifunctional fabric might be potentially useful in outdoor coats and other facilities. PMID- 29265799 TI - Sustainable Interfaces between Si Anodes and Garnet Electrolytes for Room Temperature Solid-State Batteries. AB - Solid-state batteries (SSBs) have seen a resurgence of research interests in recent years for their potential to offer high energy density and excellent safety far beyond current commercialized lithium-ion batteries. The compatibility of Si anodes and Ta-doped Li7La3Zr2O12 (Li6.4La3Zr1.4Ta0.6O12, LLZTO) solid electrolytes and the stability of the Si anode have been investigated. It is found that Si layer anodes thinner than 180 nm can maintain good contact with the LLZTO plate electrolytes, leading the Li/LLZTO/Si cells to exhibit excellent cycling performance with a capacity retention over 85% after 100 cycles. As the Si layer thickness is increased to larger than 300 nm, the capacity retention of Li/LLZTO/Si cells becomes 77% after 100 cycles. When the thickness is close to 900 nm, the cells can cycle only for a limited number of times because of the destructive volume change at the interfaces. Because of the sustainable Si/LLZTO interfaces with the Si layer anodes with a thickness of 180 nm, full cells with the LiFePO4 cathodes show discharge capacities of 120 mA h g-1 for LiFePO4 and 2200 mA h g-1 for the Si anodes at room temperature. They cycle 100 times with a capacity retention of 72%. These results indicate that the combination between the Si anodes and the garnet electrolytes is a promising strategy for constructing high-performance SSBs. PMID- 29265800 TI - Roll-to-Roll Manufacturing of Robust Superhydrophobic Coating on Metallic Engineering Materials. AB - Creating a robust superhydrophobic surface on the conventional engineering materials at mass production is of great importance for a self-cleaning, anti icing, nonwetting surface and low flow resistance in industrial applications. Herein, we report a roll-to-roll strategy to create durable and robust superhydrophobic surfaces with designed micro-/nanoscale hierarchical structures on many conventional engineering materials by combining electrical discharge machining and coating of carbon nanoparticles, followed by oil penetration and drying. The treated surface shows good superhydrophobic properties with a static water contact angle of 170 +/- 2 degrees and slide angle of 3 +/- 1 degrees . The treated surface also exhibits good resilience and maintains the performance after being tested in various harsh conditions, including water flushing for several days, sand abrasion, scratching with sandpapers, and corrosive solution. Significantly, the superhydrophobic surfaces also show a high efficiency of self cleaning properties even after oil contamination during applications. PMID- 29265801 TI - Co9S8@MoS2 Core-Shell Heterostructures as Trifunctional Electrocatalysts for Overall Water Splitting and Zn-Air Batteries. AB - The development of efficient non-noble-metal electrocatalysts is of critical importance for clean energy conversion systems, such as fuel cells, metal-air batteries, and water electrolysis. Herein, uniform Co9S8@MoS2 core-shell heterostructures have been successfully prepared via a solvothermal approach, followed by an annealing treatment. Transmission electron microscopy, X-ray absorption near-edge structure, and X-ray photoelectron spectroscopy measurements reveal that the core-shell structure of Co9S8@MoS2 can introduce heterogeneous nanointerface between Co9S8 and MoS2, which can deeply influence its charge state to boost the electrocatalytic performances. Besides, due to the core-shell structure that can promote the synergistic effect of Co9S8 and MoS2 and provide abundant catalytically active sites, Co9S8@MoS2 exhibits a superior hydrogen evolution reaction performance with a small overpotential of 143 mV at 10 mA cm-2 and a small Tafel slope value of 117 mV dec-1 under alkaline solution. Meanwhile, the activity of Co9S8@MoS2 toward oxygen evolution reaction is also impressive with a low operating potential (~1.57 V vs reversible hydrogen electrode) at 10 mA cm-2. By using Co9S8@MoS2 catalyst for full water splitting, an alkaline electrolyzer affords a cell voltage as low as 1.67 V at a current density of 10 mA cm-2. Also, Co9S8@MoS2 reveals robust oxygen reduction reaction performance, making it an excellent catalyst for Zn-air batteries with a long lifetime (20 h). This work provides a new means for the development of multifunctional electrocatalysts of non-noble metals for the highly demanded electrochemical energy technologies. PMID- 29265802 TI - Balanced Photodetection in One-Step Liquid-Phase-Synthesized CsPbBr3 Micro /Nanoflake Single Crystals. AB - Here, we reported a low-cost and high-compatibility one-step liquid-phase synthesis method for synthesizing high-purity CsPbBr3 micro-/nanoflake single crystals. On the basis of the high-purity CsPbBr3, we further prepared a low dimensional photodetector capable of balanced photodetection, involving both high external quantum efficiency and rapid temporal response, which is barely realized in previously reported low-dimensional photodetectors. PMID- 29265803 TI - Measuring Proton Currents of Bioinspired Materials with Metallic Contacts. AB - Charge transfer at the interface between the active layer and the contact is essential in any device. Transfer of electronic charges across the contact/active layer interface with metal contacts is well-understood. To this end, noble metals, such as gold or platinum, are widely used. With these contacts, ionic currents (especially protonic) are often neglected because ions and protons do not transfer across the interface between the contact and the active layer. Palladium hydride contacts have emerged as good contacts to measure proton currents because of a reversible redox reaction at the interface and subsequent absorption/desorption of H into palladium, translating the proton flow reaching the interface into an electron flow at the outer circuit. Here, we demonstrate that gold and palladium contacts also collect proton currents, especially under high relative humidity conditions because of electrochemical reactions at the interface. A marked kinetic isotope effect, which is a signature of proton currents, is observed with gold and palladium contacts, indicating both bulk and contact processes involving proton transfer. These phenomena are attributed to electrochemical processes involving water splitting at the interface. In addition to promoting charge transfer at the interface, these interfacial electrochemical processes inject charge carriers into the active layer and hence can also modulate the bulk resistivity of the materials, as was found for the studied peptide fibril films. We conclude that proton currents may not be neglected a priori when performing electronic measurements on biological and bioinspired materials with gold and palladium contacts under high humidity conditions. PMID- 29265804 TI - Coordination Compounds with Photochromic Ligands: Ready Tunability and Visible Light-Sensitized Photochromism. AB - Photochromic compounds are well-known for their promising applications in many areas. In this context, many different photochromic families have been developed. As the early study of these photochromic compounds was mainly focused on the organic system, their photochromic reactivity was mainly derived from the singlet excited state. We hypothesized that the incorporation of the photochromic ligand to the transition metal complex and coordination complex systems would not only render the triplet state of the organic photochromic system more readily accessible due to the large spin-orbit coupling of the heavy metal center but also would lead to ready extension of the excitation wavelength to less destructive longer wavelength low-energy excitation. On the other hand, the long lived triplet excited states of the metal complexes are also suitable for energy or electron transfer processes, which should lead to new photochromic behavior and photoswitchable functional properties. Through the incorporation of the stilbene-, azo-, spirooxazine-, and dithienylethene-containing ligands to transition metal complex systems with heavy metal centers and suitable excited states, triplet state photosensitized photochromism has been achieved. With the triplet state photosensitization, the photochromism of these compounds could be extended from the high energy UV region to the visible region. In the development of dithienylethene-containing ligands, we have adopted an alternative strategy, which involves the incorporation of nitrogen and sulfur heterocycles that directly form part of the dithienylethene framework as ligands to exert a much stronger perturbation and influence on the excited state properties of the photochromic unit by the metal center. On the basis of the new design, wide ranges of dithienylethene-containing ligands, including phenanthrolines, 2 pyridylimidazoles, N-pyridylimidazol-2-ylidenes, cyclometalating thienylpyridines, beta-diketonates, and beta-ketoiminates have been designed and incorporated into various coordination systems. Apart from the photosensitization, tuning of the closed form absorption and photochromic behavior based on the perturbation of the metal center, coordination-assisted planarization, modification of the ancillary ligands and introduction of various electronic excited states derived from the coordination system have been successfully demonstrated. This strategy can be used for developing NIR photochromic dithienylethenes. With the above effects observed upon the coordination to different transition metal centers and central atoms, this strategy offers a simple and effective way for the modification of the photochromic characteristics. Moreover, the emission and other functional properties of the coordination systems could also be photoswitched by the photochromic reactions. PMID- 29265805 TI - Methylene-Cycloalkylacetate (MCA) Scaffold-Based Compounds as Novel Neurotropic Agents. AB - One of the main symptoms in degenerative diseases is death of neuronal cell followed by the loss of neuronal pathways. In neuronal cultures, neurite outgrowths are cell sprouts capable of transforming into either axons or dendrites, to further form functional neuronal synaptic connections. Such connections have an important role in brain cognition, neuronal plasticity, neuronal survival, and regeneration. Therefore, drugs that stimulate neurite outgrowth may be found beneficial in ameliorating neural degeneration. Here, we establish the existence of a unique family of methylene-cycloalkylacetate-based molecules (MCAs) that interface with neuronal cell properties and operate as acceptable pharmacophores for a novel neurotropic (neurite outgrowth inducing) lead compounds. Using an established PC12 cell bioassay, we investigated the neurotropic effect of methylene-cycloalkylacetate compounds by comparison to NGF, a known neurotropic factor. Micrographs of the cells were collected by using a light microscope camera, and digitized photographs were analyzed for compound induced neurotropic activity using an NIH image protocol. The results indicate that the alkene element, integrated within the cycloalkylacetate core, is indispensable for neurotropic activity. The discovered lead compounds need further mechanistic investigation and may be improved toward development of a neurotropic drug. PMID- 29265806 TI - Microplastics and Nanoplastics in Aquatic Environments: Aggregation, Deposition, and Enhanced Contaminant Transport. AB - Plastic litter is widely acknowledged as a global environmental threat, and poor management and disposal lead to increasing levels in the environment. Of recent concern is the degradation of plastics from macro- to micro- and even to nanosized particles smaller than 100 nm in size. At the nanoscale, plastics are difficult to detect and can be transported in air, soil, and water compartments. While the impact of plastic debris on marine and fresh waters and organisms has been studied, the loads, transformations, transport, and fate of plastics in terrestrial and subsurface environments are largely overlooked. In this Critical Review, we first present estimated loads of plastics in different environmental compartments. We also provide a critical review of the current knowledge vis-a vis nanoplastic (NP) and microplastic (MP) aggregation, deposition, and contaminant cotransport in the environment. Important factors that affect aggregation and deposition in natural subsurface environments are identified and critically analyzed. Factors affecting contaminant sorption onto plastic debris are discussed, and we show how polyethylene generally exhibits a greater sorption capacity than other plastic types. Finally, we highlight key knowledge gaps that need to be addressed to improve our ability to predict the risks associated with these ubiquitous contaminants in the environment by understanding their mobility, aggregation behavior and their potential to enhance the transport of other pollutants. PMID- 29265807 TI - Method for Low Nanomolar Concentration Analyte Sensing Using Electrochemical Enzymatic Biosensors. AB - We introduce a new electrochemical measurement method compatible with an enzymatic biosensor that is capable of analyte sensing down to the low nanomolar concentration regime. This method is termed accumulation mode sensing and utilizes an immobilized redox polymer mediator wired to an oxidoreductase enzyme to store charge during a premeasurement charge concentration step, followed by a measurement step in which this accumulated charge is quantified. We demonstrate this new method using a model glucose sensor and show how the sensitivity of a sensor can be modified simply by adjusting the time duration of the charge concentration step. We achieve a limit of detection of 4.7 +/- 1.4 nM using accumulation mode sensing, which represents a 25-fold improvement over traditional amperometry. PMID- 29265808 TI - Where Informatics Lags Chemistry Leads. AB - The fact that amino acid sequences dictate the tertiary structures of proteins has been known for more than five decades. While the molecular pathways to tertiary structure are still being worked out, with the axiom that similar sequences adopt similar structures, computational methods are being developed continually in parallel, utilizing the Protein Data Bank structural repository and homologue detection strategies to predict structures of sequences of interest. The success of this approach is limited by the ability to unravel the hidden similarities among amino acid sequences. We consider here the 20 amino acids as a complete set of chemical templates in the physicochemical space of proteins and propose a new structural and chemical classification of amino acids. An integration of this perspective into the conventional evolutionary methods of similarity detection leads to an unprecedented increase in the accuracy in homologue detection, resulting in improved protein structure prediction. The performance is validated on a large data set of 11716 unique proteins, and the results are benchmarked against conventional methods. The availability of good quality protein structures helps in structure-based drug design endeavors and in establishing protein structure-function correlations. PMID- 29265809 TI - Highly Efficient Electrochemiluminescence of Cyanovinylene-Contained Polymer Dots in Aqueous Medium and Its Application in Imaging Analysis. AB - Luminescent semiconducting polymer dots (Pdots) have attracted intense attention in the field of electrochemiluminescence (ECL) due to their nontoxic features. For utilizing the nontoxic Pdots to achieve sensitive ECL bioimaging detection, this work studied the ECL behaviors of poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-(1 cyanovinylene-1,4-phenylene)] (CN-PPV) Pdots in aqueous solution, which introduced an electron-withdrawing cyano group to p-phenylenevinylene for enhancing the luminescent efficiency. The CN-PPV Pdots could be both electrochemically oxidized to a positively charged state and electrochemically reduced to a negatively charged state, which led to annihilation of ECL emission. The order of oxidation and reduction greatly influenced the annihilation behavior. In the presence of tri-n-propylamine (TPrA) or S2O82- as a coreactant, the CN-PPV Pdots showed strong band gap ECL emission at 602 nm, which followed two different routes and gave ECL efficiencies of 11.22% and 1.84% (vs Ru(bpy)32+/TPrA), respectively. The high ECL efficiency allowed CN-PPV Pdots/TPrA system for ECL imaging analysis. As a proof-of-methodology, an ECL imaging method was designed via the chelating interaction of metal ions and Pdots to achieve high selectivity. The proposed ECL imaging chip-based sensor exhibited excellent analytical performance for Fe3+ with a wide linear range from 100 pM to 100 MUM and a detection limit of 67 pM. Compared with the ECL methods based on the direct intensity measurement, the developed ECL imaging method possesses the advantages of simplicity, rapid, and high-throughput and has application potential in monitoring water and food quality. PMID- 29265810 TI - Irreversible Hydrolysis of PCP-Supported Rhenium(V) Acetates. AB - Complexes (PCPR)Re(O)(OAc)2 [R = iPr (4a) and tBu (4b); PCP = kappa3-P,C,P-2,6 (R2PCH2)2C6H3] undergo unexpected irreversible hydrolysis to yield (PCPR)Re(O)(OAc)(OH) (3a/3b) and free AcOH. 3a and 3b are highly fluxional in solution, possibly via AcOH loss and the intermediacy of (PCPR)Re(O)2, which was isolated for R = tBu (5b). PMID- 29265811 TI - Understanding Surface Structural Stabilization of the High-Temperature and High Voltage Cycling Performance of Al3+-Modified LiMn2O4 Cathode Material. AB - Stabilization of the atomic-level surface structure of LiMn2O4 with Al3+ ions is shown to be significant in the improvement of cycling performance, particularly at a high temperature (55 degrees C) and high voltage (5.1 V). Detailed analysis by X-ray photoelectron spectroscopy, secondary ion mass spectrometry, scanning transmission electron microscopy-energy-dispersive X-ray spectroscopy, etc. reveals that Al3+ ions diffuse into the spinel to form a layered Li(Alx,Mny)O2 structure in the outmost surface where Al3+ concentration is the highest. Other Al3+ ions diffuse into the 8a sites of spinel to form a (Mn3-xAlx)O4 structure and the 16d sites of spinel to form Li(Mn2-xAlx)O4. These complicated surface structures, in particular the layered Li(Alx,Mny)O2, are present at the surface throughout cycling and effectively stabilize the surface structure by preventing dissolution of Mn ions and mitigating cathode-electrolyte reactions. With the Al3+ ions surface modification, a stable cycle performance (~78% capacity retention after 150 cycles) and high Coulombic efficiency (~99%) are achieved at 55 degrees C. More surprisingly, the surface-stabilized LiMn2O4 can be cycled up to 5.1 V without significant degradation, in contrast to the fast capacity degradation found in the unmodified case. Our findings demonstrate the critical role of ions coated on the surface in modifying the structural evolution of the surface of spinel electrode particles and thus will stimulate future efforts to optimize the surface properties of battery electrodes. PMID- 29265812 TI - Proteolytic Cleavage-Mechanisms, Function, and "Omic" Approaches for a Near Ubiquitous Posttranslational Modification. AB - Proteases enzymatically hydrolyze peptide bonds in substrate proteins, resulting in a widespread, irreversible posttranslational modification of the protein's structure and biological function. Often regarded as a mere degradative mechanism in destruction of proteins or turnover in maintaining physiological homeostasis, recent research in the field of degradomics has led to the recognition of two main yet unexpected concepts. First, that targeted, limited proteolytic cleavage events by a wide repertoire of proteases are pivotal regulators of most, if not all, physiological and pathological processes. Second, an unexpected in vivo abundance of stable cleaved proteins revealed pervasive, functionally relevant protein processing in normal and diseased tissue-from 40 to 70% of proteins also occur in vivo as distinct stable proteoforms with undocumented N- or C-termini, meaning these proteoforms are stable functional cleavage products, most with unknown functional implications. In this Review, we discuss the structural biology aspects and mechanisms of catalysis by different protease classes. We also provide an overview of biological pathways that utilize specific proteolytic cleavage as a precision control mechanism in protein quality control, stability, localization, and maturation, as well as proteolytic cleavage as a mediator in signaling pathways. Lastly, we provide a comprehensive overview of analytical methods and approaches to study activity and substrates of proteolytic enzymes in relevant biological models, both historical and focusing on state of the art proteomics techniques in the field of degradomics research. PMID- 29265813 TI - Bioaccumulation of 14C-Labeled Graphene in an Aquatic Food Chain through Direct Uptake or Trophic Transfer. AB - The growing applications of graphene materials warrant a careful evaluation of their environmental fate in aquatic food webs. Escherichia coli (Bacteria), Tetrahymena thermophila (protozoa), Daphnia magna (zooplankton), and Danio rerio (vertebrate) were used to build aquatic food chains to investigate the waterborne uptake and trophic transfer of 14C-labeled graphene. Body burden factor (BBF) and trophic transfer factor (TTF) were analyzed for each organism and food chain to assess the bioaccumulation and biomagnification of graphene. The test organisms have high potential of accumulating graphene via direct uptake from culture medium with log-transformed BBF (log BBF) values of 3.66, 5.1, 3.9, and 1.62 for each organism, respectively. In the food chain from E. coli to T. thermophila, the calculated TTFs of 0.2 to 8.6 indicate the high trophic transfer potential in this aquatic food chain. However, the TTFs calculated for the food chain from T. thermophila to D. magna and from D. magna to D. rerio are much lower than 1, indicating that biomagnification was unlikely to occur in these food chains. Body burden measured for dietary uptake by T. thermophila, D. magna, and D. rerio are higher than that via waterborne exposure in a similar nominal concentration, respectively, indicating that trophic transfer is a nonnegligible route for the bioaccumulation of graphene in organisms. PMID- 29265814 TI - A "Motif-Oriented" Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues. AB - The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1alpha (EF-1alpha). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be "motif-oriented": specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited. PMID- 29265815 TI - Unfolding and Targeting Thermodynamics of a DNA Intramolecular Complex with Joined Triplex-Duplex Domains. AB - Our laboratory is interested in developing methods that can be used for the control of gene expression. In this work, we are investigating the reaction of an intramolecular complex containing a triplex-duplex junction with partially complementary strands. We used a combination of isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and spectroscopy techniques to determine standard thermodynamic profiles for these targeting reactions. Specifically, we have designed single strands to target one loop (CTTTC) or two loops (CTTTC and GCAA) of this complex. Both reactions yielded exothermic enthalpies of -66.3 and -82.8 kcal/mol by ITC, in excellent agreement with the reaction enthalpies of -72.7 and -88.7 kcal/mol, respectively, obtained from DSC Hess cycles. The favorable heat contributions result from the formation of base pair stacks involving mainly the unpaired bases of the loops. This shows that each complementary strand is able to invade and disrupt the secondary structure. The simultaneous targeting of two loops yielded a more favorable reaction free energy, by approximately -8 kcal/mol, which corresponds to the formation of roughly four base-pair stacks involving the unpaired bases of the 5'-GCAA loop. The main conclusion is that the targeting of loops with a large number of unpaired bases results in a more favorable reaction free energy. PMID- 29265816 TI - Iron-Catalyzed Batch/Continuous Flow C-H Functionalization Module for the Synthesis of Anticancer Peroxides. AB - Iron-catalyzed dehydrogenative cross-coupling of carbonyl compounds with aliphatic peroxide was developed under mild conditions. A library of linear alkylated and arylated peroxides are synthesized in good to excellent yield. This method is highly selective and general for a range of biologically important derivatives of 2-oxindole, barbituric acid, and 4-hydroxy coumarin with a good functional group tolerance and without the cleavage of the peroxide bond. This peroxidation reaction is upscalable to grams and also synthesizable in continuous flow with increased safety in short duration. Mechanistic investigation reveals Fe-(II) undergoes redox type process to generate the radical intermediates, which subsequently recombine selectively to form the stable peroxides. The potential of peroxides is evaluated by cell viability assay and found to exhibit the good anticancer activity with minimum IC50= 5.3 MUM. PMID- 29265817 TI - Correction to "A Luminescent and Biocompatible PhotoCORM". PMID- 29265818 TI - Impact of Ionic Liquids on the Structure and Dynamics of Collagen. AB - The changes in the structure and dynamics of collagen treated with two different classes of ionic liquids, bis-choline sulfate (CS) and 1-butyl-3-methyl imidazolium dimethyl phosphate (IDP), have been studied at the molecular and fibrillar levels. At the molecular level, circular dichroic studies revealed an increase in molar ellipticity values for CS when compared with native collagen, indicating cross-linking, albeit pronounced conformational changes for IDP were witnessed indicating denaturation. The impedance was analyzed to correlate the conformational changes with the hydration dynamics of protein. Changes in the dielectric properties of collagen observed upon treatment with CS and IDP reported molecular reorientation in the surrounding water milieu, suggesting compactness or destabilization of the collagen. This was further confirmed by proton transverse NMR relaxation time measurements, which demonstrated that the water mobility changes in the presence of the ILs. At the fibrillar level, differential scanning calorimetry thermograms for rat tail tendon collagen fibers treated with CS show a 5 degrees C increase in denaturation temperature, suggesting imparted stability. On the contrary, a significant temperature decrease was noticed for IDP, indicating the destabilization of collagen fibers. The obtained results clearly indicate that the changes in the secondary structure of protein are due to the changes in the hydration dynamics of collagen upon interaction with ILs. Thus, this study on the interaction of collagen with ionic liquids unfolds the propensity of ILs to stabilize or destabilize collagen depending on the changes invoked at the molecular level in terms of structure and dynamics of protein, which also got manifested at the fibrillar level. PMID- 29265819 TI - Development of Embedded and Performance of Density Functional Methods for Molecular Crystals. AB - We report an alternative quantum mechanical:quantum mechanical (QM:QM) method to the currently used periodic density functional calculations including dispersion and investigate its performance with respect to main structural and energetic properties of the X23 set of molecular crystals. By setting the goal of reproducing reference periodic BLYP+D3 values and by embedding BLYP+D3 into DFTB, we obtain results similar to those of periodic BLYP+D3-typically within 1-2% in lattice energies and ~0.4% in cell volumes. The accuracy of this QM:QM method in comparison to DFTB+D and DFT+D for the X23 set of molecular crystals is discussed. PMID- 29265820 TI - Atomistic Simulations of Charge Separation at a Nanohybrid Interface: Relevance of Photoinduced Initial State Preparation. AB - Charge separation kinetics at a nanohybrid interface are investigated in their dependence on ultrafast optical excitation. A prototypical organic/inorganic interface is considered. It is formed by a vertical stacking of 20 para sexiphenyl molecules physisorbed on a ZnO nanocluster of 3783 atoms. A first principle parametrized Hamiltonian is employed, and the photoinduced subpicosecond evolution of Frenkel-excitons in the organic part is analyzed besides the formation of charge separated states across the interface. The interface absorption spectrum is calculated. Together, the data indicate that the charge separation is based on the direct excitation of the charge separated states but also on the migration of created Frenkel excitons to the interface with subsequent decay. Further, the photoinduced interface dynamics are compared with data resulting from direct set-ups of an initially excited state. Mostly such set-ups lead to substantially different charge separation processes. PMID- 29265821 TI - A Unifying Perspective on Oxygen Vacancies in Wide Band Gap Oxides. AB - Wide band gap oxides are versatile materials with numerous applications in research and technology. Many properties of these materials are intimately related to defects, with the most important defect being the oxygen vacancy. Here, using electronic structure calculations, we show that the charge transition level (CTL) and eigenstates associated with oxygen vacancies, which to a large extent determine their electronic properties, are confined to a rather narrow energy range, even while band gap and the electronic structure of the conduction band vary substantially. Vacancies are classified according to their character (deep versus shallow), which shows that the alignment of electronic eigenenergies and CTL can be understood in terms of the transition between cavity-like localized levels in the large band gap limit and strong coupling between conduction band and vacancy states for small to medium band gaps. We consider both conventional and hybrid functionals and demonstrate that the former yields results in very good agreement with the latter provided that band edge alignment is taken into account. PMID- 29265823 TI - Alkyl-Modified Oligonucleotides as Intercalating Vehicles for Doxorubicin Uptake via Albumin Binding. AB - DNA-based drug delivery vehicles have displayed promise for the delivery of intercalating drugs. Here, we demonstrate that oligonucleotides modified with an alkyl chain can bind to human serum albumin, mimicking the natural binding of fatty acids. These alkyl-DNA-albumin complexes display excellent serum stability and are capable of strongly binding doxorubicin. Complexes are internalized by cells in vitro, trafficking to the mitochondria, and are capable of delivering doxorubicin with excellent efficiency resulting in cell death. However, the cellular localization of the delivered doxorubicin, and ultimately the complex efficacy, is dependent on the nature of the linker between the alkyl group and the oligonucleotide. PMID- 29265822 TI - "Inverse Drug Discovery" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. AB - Drug candidates are generally discovered using biochemical screens employing an isolated target protein or by utilizing cell-based phenotypic assays. Both noncovalent and covalent hits emerge from such endeavors. Herein, we exemplify an "Inverse Drug Discovery" strategy in which organic compounds of intermediate complexity harboring weak, but activatable, electrophiles are matched with the protein(s) they react with in cells or cell lysate. An alkyne substructure in each candidate small molecule enables affinity chromatography-mass spectrometry, which produces a list of proteins that each distinct compound reacts with. A notable feature of this approach is that it is agnostic with respect to the cellular proteins targeted. To illustrate this strategy, we employed aryl fluorosulfates, an underexplored class of sulfur(VI) halides, that are generally unreactive unless activated by protein binding. Reversible aryl fluorosulfate binding, correct juxtaposition of protein side chain functional groups, and transition-state stabilization of the S(VI) exchange reaction all seem to be critical for conjugate formation. The aryl fluorosulfates studied thus far exhibit chemoselective reactivity toward Lys and, particularly, Tyr side chains, and can be used to target nonenzymes (e.g., a hormone carrier or a small-molecule carrier protein) as well as enzymes. The "Inverse Drug Discovery" strategy should be particularly attractive as a means to explore latent electrophiles not typically used in medicinal chemistry efforts, until one reacts with a protein target of exceptional interest. Structure-activity data can then be used to enhance the selectivity of conjugate formation or the covalent probe can be used as a competitor to develop noncovalent drug candidates. Here we use the "Inverse Drug Discovery" platform to identify and validate covalent ligands for 11 different human proteins. In the case of one of these proteins, we have identified and validated a small-molecule probe for the first time. PMID- 29265825 TI - Beyond reciprocity: A conservation of resources view on the effects of psychological contract violation on third parties. AB - Building on conservation of resources theory, we cast resource depletion as a novel explanatory mechanism to explain why employees' experience of psychological contract violation results in harm to third parties outside the employee organization exchange dyad. This resource-based perspective extends and complements the dominant social exchange perspective which views employee reactions to psychological contract violation as targeting the source of the violation-the organization. The present article reports on 3 studies. Study 1 conducted an experiment with 109 participants and established the main effect of psychological contract violation on resource depletion. Study 2, using survey data from 315 medical employees and their immediate supervisors, found that after controlling for the social exchange mechanism (i.e., revenge cognitions toward the organization), resource depletion mediated the indirect effects of psychological contract violation on supervisory reports of employees' interpersonal harming toward coworkers and decision-making vigilance for clients. Further, we found that organizational and professional identification played opposing moderating roles in the effects of violation on resource depletion and consequently behavioral outcomes, such that these mediated relationships were stronger when organizational identification was high, and weaker when professional identification was high. Study 3 replicated all the results obtained in Studies 1 and 2 with time-lagged data from 229 medical employees across 3 measurement points. The findings confirm that resource depletion is a more effective explanation of the consequences of violation on third parties than revenge cognitions, although both are useful in predicting organization-directed outcomes (i.e., civic virtue and organizational rule compliance). (PsycINFO Database Record PMID- 29265824 TI - Molecular Dynamics Simulations Reveal an Interplay between SHAPE Reagent Binding and RNA Flexibility. AB - The function of RNA molecules usually depends on their overall fold and on the presence of specific structural motifs. Chemical probing methods are routinely used in combination with nearest-neighbor models to determine RNA secondary structure. Among the available methods, SHAPE is relevant due to its capability to probe all RNA nucleotides and the possibility to be used in vivo. However, the structural determinants for SHAPE reactivity and its mechanism of reaction are still unclear. Here molecular dynamics simulations and enhanced sampling techniques are used to predict the accessibility of nucleotide analogs and larger RNA structural motifs to SHAPE reagents. We show that local RNA reconformations are crucial in allowing reagents to reach the 2'-OH group of a particular nucleotide and that sugar pucker is a major structural factor influencing SHAPE reactivity. PMID- 29265826 TI - Crafting in context: Exploring when job crafting is dysfunctional for performance effectiveness. AB - Job crafting theory purports that the consequences of revising one's work role can be simultaneously beneficial and detrimental. Previous research, however, has almost exclusively emphasized the beneficial outcomes of job crafting. In the current study, we proposed dysfunctional consequences of crafting for performance related outcomes in the form of a U-shaped relationship between job crafting and performance effectiveness (managerial ratings of job proficiency and peer ratings of citizenship behavior). We further predicted that elements of the task context (autonomy and ambiguity) and the social context (interdependence and social support) moderate these curvilinear relationships. Consistent with previous research, job crafting displayed positive and linear effects on work-related attitudes (job satisfaction and affective commitment). Consistent with our predictions, moderate levels of crafting were associated with dysfunctional performance-related outcomes and features of work context either exacerbated or dissipated these dysfunctional consequences of job crafting for individuals. (PsycINFO Database Record PMID- 29265827 TI - Examining the temporal order of ethnic identity and perceived discrimination among Hispanic immigrant adolescents. AB - Ethnic identity formation is a central developmental task that can become challenging when adolescents face a salient stressor, such as ethnic discrimination. Although ethnic identity and experiences with ethnic discrimination are thought to be associated, the temporal order of these constructs is unclear. In the current study, we examined (a) the rejection identification model and (b) the identification-attribution model in a longitudinal, cross-lagged model among 302 Hispanic immigrant adolescents (Mage = 14.51, SD = .88 at baseline; 46.7% female) living in Miami (n = 152) and Los Angeles (n = 150). Results support the identification-attribution model such that adolescents who reported higher levels of ethnic identity exploration reported higher levels of perceived discrimination 1 year later. Conversely, adolescents who reported higher levels of ethnic identity belonging reported less subsequent perceived discrimination. Findings suggest that ethnic identity formation may affect the recognition of ethnic discrimination among Hispanic immigrant adolescents. (PsycINFO Database Record PMID- 29265828 TI - Cumulative psychosocial risk, parental socialization, and child cognitive functioning: A longitudinal cascade model. AB - Previous studies have demonstrated that various psychosocial risks are associated with poor cognitive functioning in children, and these risks frequently cluster together. In the current longitudinal study, we tested a model in which it was hypothesized that cumulative psychosocial adversity of mothers would have deleterious effects on children's cognitive functioning by compromising socialization processes within families (i.e., parental competence). A prospective community birth cohort of 501 families was recruited when children were newborns. At this time, mothers reported on their current psychosocial circumstances (socioeconomic status, teen parenthood, depression, etc.), which were summed into a cumulative risk score. Families were followed up at 18 months and 3 years, at which point maternal reflective capacity and cognitive sensitivity were measured, respectively. Child cognition (executive functioning, theory of mind, and language ability) was assessed at age 4.5 using age appropriate observational and standardized tasks. Analyses controlled for child age, gender, number of children in the home, number of years married, and mothers' history of adversity. The results revealed significant declines in child cognition as well as maternal reflective capacity and cognitive sensitivity as the number of psychosocial risks increased. Moreover, longitudinal path analysis showed significant indirect effects from cumulative risk to all three cognitive outcomes via reflective capacity and cognitive sensitivity. Findings suggest that cumulative risk of mothers may partially account for child cognitive difficulties in various domains by disrupting key parental socialization competencies. (PsycINFO Database Record PMID- 29265829 TI - Informed guessing in change detection. AB - Provided stimuli are highly distinct, the detection of changes between two briefly separated arrays appears to be achieved by an all-or-none process where either the relevant information is in working memory or observers guess. This observation suggests that it is possible to estimate the average number of items an observer was able to retain across a series of trials, a potentially highly informative cognitive characteristic. For each version of the change detection paradigm, for this estimate to be accurate, it is important to specify how observers use the information available to them. For some instantiations of this task it is possible that observers use knowledge of the contents of working memory even when they are in a guessing state, rather than selecting between the response alternatives at random. Here we test the suggestion that observers may be able to use their knowledge of the number of items in memory to guide guessing in two versions of the change detection task. The four experiments reported here suggest that participants are, in fact, able to use the parameters of the task to update their base expectation of a change occurring to arrive at more informed guessing. (PsycINFO Database Record PMID- 29265830 TI - Neuropsychological investigation of "the amazing memory man". AB - OBJECTIVE: Mnemonists, memory champions, and persons with highly superior autobiographical memory (HSAM) are apparently rare breeds, with no more than a few dozen cases of each described in the neuroscientific literature. This report describes a newly discovered HSAM case who has extraordinary memory for a wider range of material than has heretofore been described. METHOD: Subject MM was interviewed about his personal life and administered standard clinical tests of cognition and personality, as well as experimental tasks assessing personal and generic episodic and semantic memory. Finally, he was studied with high resolution structural MRI of the medial temporal lobes, as well as brain connectivity analysis using resting-state functional MRI. RESULTS: MM's ability to recall general factual information, historical facts and dates, sports statistics, and popular culture, as well as personal life experiences, is exceptional, even though he performs in only the average range on tests of intellect and new learning ability. Unlike most mnemonists, he denies using any specific mnemonic strategy and, unlike many other HSAM cases, is unable to recall highly specific details of days in his adult life. Structural brain imaging in MM reveals atypical anatomy in his left temporal lobe, and functional neuroimaging suggests greater than usual connectivity of the left hippocampus with premotor, prefrontal and retrosplenial cingulate cortex. CONCLUSIONS: These observations are discussed in the context of previous studies of mnemonists and HSAM cases, some of which implicate hyperconnectivity among components of an expanded memory network in extraordinary memory retrieval. (PsycINFO Database Record PMID- 29265831 TI - Prevention of relapse/recurrence in major depressive disorder with either mindfulness-based cognitive therapy or cognitive therapy. AB - OBJECTIVE: Both Mindfulness Based Cognitive Therapy (MBCT) and Cognitive Therapy (CT) enhance self-management of prodromal symptoms associated with depressive relapse, albeit through divergent therapeutic procedures. We evaluated rates of relapse in remitted depressed patients receiving MBCT and CT. Decentering and dysfunctional attitudes were assessed as treatment-specific process markers. METHOD: Participants in remission from Major Depressive Disorder (MDD; N = 166) were randomized to 8 weeks of either MBCT (N = 82) or CT (N = 84) and were followed for 24 months, with process markers measured every 3 months. Attendance in both treatments was high (6.3/8 session) and treatment fidelity and competence were evaluated. Relapse was defined as a return of symptoms meeting the criteria for major depression on Module A of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID). RESULTS: Intention to-treat analyses indicated no differences between MBCT and CT in either rates of relapse to MDD or time to relapse across 24 months of follow up. Both groups experienced significant increases in decentering and participants in CT reported greater reductions in dysfunctional attitudes. Within both treatments, participants who relapsed evidenced lower decentering scores than those who stayed well over the follow up. CONCLUSIONS: This is the first study to directly compare relapse prophylaxis following MBCT and CT directly. The lack of group differences in time to relapse supports the view that both interventions are equally effective and that increases in decentering achieved via either treatment are associated with greater protection. These findings lend credence to Teasdale et al.'s (2002) contention that, even though they may be taught through dissimilar methods, CT and MBCT help participants develop similar metacognitive skills for the regulation of distressing thoughts and emotions. (PsycINFO Database Record PMID- 29265833 TI - In psychotherapy with severe patients discouraging news may be worse than no news: The impact of providing feedback to therapists on psychotherapy outcome, session attendance, and the alliance. AB - OBJECTIVE: Our objective was to assess low-cost and feasible feedback alternatives and compare them to Lambert's OQ feedback system. We also studied patient, therapist, and process characteristics that could moderate the effect of feedback on outcome, session attendance, and alliance. METHOD: A total of 547 patients, 75% female, average age 41 (SD = 13), 95% Latino, treated in an outpatient individual psychotherapy setting in Chile were randomly assigned to five feedback conditions: no feedback, feedback on symptomatology, feedback on the alliance, feedback on both symptomatology and alliance, and Lambert's OQ progress feedback report. The measures included the Outcome Questionnaire and the Working Alliance Inventory. We also had follow-up interviews with therapists. RESULTS: We found through multilevel modeling that feedback had no effect on outcome, session attendance, and alliance. Contrary to previous findings, these results were maintained even when focusing only on patients "not-on-track." However, patients' former psychiatric hospitalization history and baseline severity, combined with lack of progress, significantly moderated the impact of feedback. For this more dysfunctional population, "positive feedback" (i.e., low symptomatology) to therapists had a positive impact on therapy outcome, while "negative feedback" (i.e., high symptomatology) had a negative impact. CONCLUSIONS: Providing feedback to therapists without offering them tools to improve treatment may be ineffective and even be detrimental. This may be especially the case for patients who suffer more severe mental health issues and whose therapists receive mostly discouraging news as feedback. (PsycINFO Database Record PMID- 29265832 TI - A meta-analysis of motivational interviewing process: Technical, relational, and conditional process models of change. AB - OBJECTIVE: In the present meta-analysis, we test the technical and relational hypotheses of Motivational Interviewing (MI) efficacy. We also propose an a priori conditional process model where heterogeneity of technical path effect sizes should be explained by interpersonal/relational (i.e., empathy, MI Spirit) and intrapersonal (i.e., client treatment seeking status) moderators. METHOD: A systematic review identified k = 58 reports, describing 36 primary studies and 40 effect sizes (N = 3,025 participants). Statistical methods calculated the inverse variance-weighted pooled correlation coefficient for the therapist to client and the client to outcome paths across multiple target behaviors (i.e., alcohol use, other drug use, other behavior change). RESULTS: Therapist MI-consistent skills were correlated with more client change talk (r = .55, p < .001) as well as more sustain talk (r = .40, p < .001). MI-inconsistent skills were correlated with more sustain talk (r = .16, p < .001), but not change talk. When these indicators were combined into proportions, as recommended in the Motivational Interviewing Skill Code, the overall technical hypothesis was supported. Specifically, proportion MI consistency was related to higher proportion change talk (r = .11, p = .004) and higher proportion change talk was related to reductions in risk behavior at follow up (r = -.16, p < .001). When tested as two independent effects, client change talk was not significant, but sustain talk was positively associated with worse outcome (r = .19, p < .001). Finally, the relational hypothesis was not supported, but heterogeneity in technical hypothesis path effect sizes was partially explained by inter- and intrapersonal moderators. CONCLUSIONS: This meta-analysis provides additional support for the technical hypothesis of MI efficacy; future research on the relational hypothesis should occur in the field rather than in the context of clinical trials. (PsycINFO Database Record PMID- 29265834 TI - Treatment agreement, adherence, and outcome in cognitive behavioral treatments for insomnia. AB - BACKGROUND: Patient adherence has been identified as an important barrier to the implementation of evidence-based psychological treatments. OBJECTIVE: In cognitive behavioral treatments (CBT) for insomnia, the current study examined (a) the validity of therapist ratings of patient agreement and adherence against an established behavioral measure of adherence, and (b) the relationship between treatment agreement, adherence, and outcome. METHOD: Participants were 188 adults meeting DSM-IV-TR criteria for chronic insomnia who were randomized to receive behavior therapy, cognitive therapy, or CBT for insomnia. Treatment agreement/adherence was measured by (a) weekly therapist ratings of patient agreement and homework completion, and (b) adherence to behavioral strategies (ABS) derived from patient-reported sleep diary. Outcome measures were Insomnia Severity Index and insomnia remission (Insomnia Severity Index <8). RESULTS: Therapist ratings of patient agreement as well as homework completion were significantly associated with sleep diary-derived global ABS. Therapist-rated patient agreement and homework completion as well as global ABS predicted greater insomnia symptoms reduction from pretreatment to posttreatment. Patient agreement also predicted insomnia symptoms reduction from pretreatment to 6-month follow up. Patient agreement, adherence, and ABS measures during treatment significantly predicted insomnia remission at posttreatment, and all but therapist rating of homework completion predicted remission at 6-month follow-up. CONCLUSIONS: Greater patient agreement and adherence (therapist ratings and ABS) during treatment predicted better treatment outcome. Therapist-rated treatment agreement and adherence correspond well with patient-reported sleep diary-derived adherence measure. These simple, deployable therapist-rated patient agreement and adherence can potentially be useful for treatments for other disorders. (PsycINFO Database Record PMID- 29265835 TI - Prospective investigation of social support, coping, and depressive symptoms: A model of adherence to endocrine therapy among women with breast cancer. AB - OBJECTIVE: Nonadherence reduces the effectiveness of behavioral change regimens for promoting health and decreasing morbidities and mortality. Such is the case with endocrine therapies, which lower the likelihood of recurrence in the approximately 70% of women with hormone receptor-positive breast cancers. This investigation tests a model of contributors to objective adherence. METHOD: Women with breast cancer receiving their 1st endocrine therapy prescription (N = 130) were recruited from a large community oncology breast clinic. Participants completed three interview and questionnaire sessions at prescription initiation, one month and four months later. Questionnaires addressed patients' experience with cancer and included measures of coping (COPE and Emotional Approach Coping), social support (Interpersonal Support Evaluation List), and depressive symptoms (Center for Epidemiologic Studies Depression Scale). At the initial appointment, participants were provided a Medication Event Monitoring System (MEMS) cap to assess adherence; the MEMS cap was collected at the 4-month follow-up appointment. RESULTS: Structural equation modeling offered partial support for a mediational model, chi2(68, N = 130) = 77.47, p = .202, root-mean-square error of approximation = .03, comparative fit index = .97, standardized root-mean-square residual = .06. Greater social support at prescription initiation was associated with lower depressive symptoms 1 month later, which in turn were associated with higher objective adherence (MEMS) four months after study entry, controlling for significant covariates (p < .05). Use of avoidance-oriented coping was not statistically significantly related to depressive symptoms (p > .05). CONCLUSIONS: This model informs theory regarding medication adherence as well as intervention development for women prescribed adjuvant endocrine therapy. (PsycINFO Database Record PMID- 29265836 TI - Compassion-focused therapy as guided self-help for enhancing public mental health: A randomized controlled trial. AB - OBJECTIVE: Despite promising results for compassion-focused therapy (CFT) as self help, larger-scale trials including long-term follow-up data are needed to establish its effectiveness in the context of public mental health. Empirical evidence supporting its effectiveness in improving well-being is lacking. In a randomized controlled trial, the effects of CFT as guided self-help on well-being were evaluated. METHOD: Adults (mean age = 52.87, SD = 9.99, 74.8% female) with low to moderate levels of well-being were recruited in the Dutch population and randomized to CFT (n = 120) or a waitlist control group (n = 122). Participants completed the Mental Health Continuum-Short Form (well-being), Hospital Anxiety and Depression Scale (depression and anxiety), Perceived Stress Scale (stress), Self-Compassion Scale-Short Form (self-compassion), Forms of Self Criticizing/Attacking and Reassurance Scale (self-criticism and self reassurance), Positive and Negative Affect Schedule (positive/negative affect), and Gratitude questionnaire (gratitude) at baseline, postintervention (3 months), 3- and 9-month follow-up. RESULTS: Compared with the waitlist control group, the CFT group showed superior improvement on well-being at postintervention, d = .51, 95% CI [.25, .77], p < .001, and 3-month follow-up, d = .39, 95% CI [.13, .65], p < .001. No significant moderators were found. On all secondary outcome measures but positive affect, the intervention group showed significantly greater improvements up to 3-month follow-up. At 9-month follow-up, improvements on all measures were retained or amplified among CFT participants. CONCLUSIONS: CFT as guided self-help shows promise as a public mental health strategy for enhancing well-being and reducing psychological distress. (PsycINFO Database Record PMID- 29265837 TI - Alcohol intoxication impairs recognition of fear and sadness in others and metacognitive awareness of emotion recognition ability. AB - Alcohol intoxication is linked to negative social behaviors, but the mechanisms underlying this relationship are poorly understood. We investigated the effects of high-dose alcohol intoxication on the ability to perceive a range of basic emotions (sad, happy, anger, disgust, fear, and surprise) of different intensities, and on self-appraisals of emotion perception ability (i.e., metacognitive judgments). Sixty-four participants consumed either an alcohol or placebo beverage. An emotion recognition task was used to assess emotion perception ability, and participants provided confidence ratings when providing each emotion recognition response. Alcohol-intoxicated individuals demonstrated a reduced ability to detect fear and sadness at moderate-to-high levels of emotion intensity and less overall insight into their ability to recognize emotions. These results provide new insights into the possible difficulties experienced by alcohol-intoxicated individuals in perceiving emotions in others and the limited capacity to monitor their emotion perception abilities, both of which may contribute to inappropriate social responding. (PsycINFO Database Record PMID- 29265838 TI - Emotion theories and adolescent well-being: Results of an online intervention. AB - Individuals' theories about emotions-the beliefs about the nature of emotions and the ability to influence them-have been linked to well-being. However, their causal role is not clear. To address this issue, we delivered a randomized controlled intervention to 1,645 middle school students that targeted their theories of emotion through interactive online modules. Students were taught that they could modify their emotions, get better at modifying their emotions with practice, and use strategies to improve their well-being. One month later, we found that students assigned to the intervention condition (compared to an active control condition) reported more adaptive theories of emotion and greater emotional well-being in school, although well-being outside of school was unchanged. Secondary analyses showed that these effects were present regardless of students' race, gender, or grade level. These findings suggest that theories of emotion may be a promising target for improving adolescent well-being. (PsycINFO Database Record PMID- 29265839 TI - A multivariate statistical model for emotion dynamics. AB - In emotion dynamic research, one distinguishes various elementary emotion dynamic features, which are studied using intensive longitudinal data. Typically, each emotion dynamic feature is quantified separately, which hampers the study of relationships between various features. Further, the length of the observed time series in emotion research is limited and often suffers from a high percentage of missing values. In this article, we propose a vector autoregressive Bayesian dynamic model that is useful for emotion dynamic research. The model encompasses 6 elementary properties of emotions and can be applied with relatively short time series, including missing data. The individual elementary properties covered are within-person variability, innovation variability, inertia, granularity, cross lag regression, and average intensity. The model can be applied to both univariate and multivariate time series, allowing one to model the relationships between emotions. One may include external variables and non-Gaussian observed data. We illustrate the usefulness of the model on data involving 50 participants self-reporting on their experience of 3 emotions across the period of 1 week using experience sampling. (PsycINFO Database Record PMID- 29265840 TI - Mind the snake: Fear detection relies on low spatial frequencies. AB - The privileged processing of threat stimuli, even in the absence of visual awareness, has been associated with a subcortical superior colliculus (SC) pulvinar pathway to the amygdala, bypassing the visual cortex. However, this has been heavily disputed by studies showing that cortical activity cannot be ruled out in fear processing. A recent study using continuous flash suppression (CFS) showed that rapid detection of fear faces relies on high spatial frequencies, which involve cortical visual areas. In the present study, we also used CFS and manipulated spatial frequency in order to assess if more primitive fear stimuli snakes-follow a similar trend. Our results show an advantage of snakes in accessing awareness based on low spatial frequency information, arguing in favor of the role of a SC-pulvinar pathway to the amygdala. (PsycINFO Database Record PMID- 29265841 TI - Associations between resting respiratory sinus arrhythmia, intraindividual reaction time variability, and trait positive affect. AB - Resting respiratory sinus arrhythmia (RSA) reflects vagal tone, which has been found to be related to trait positive affect (PA). Resting RSA has also been found to be related to intraindividual reaction time (RT) variability (IIV), which is an index of executive brain function. However, research has yet to investigate whether IIV is associated with trait PA, and whether IIV interacts with resting RSA to predict trait PA. To examine this issue, data of trait PA, 5 min resting RSA, and trial-to-trial IIV of a flanker task (target detection) were collected in 117 young healthy adults. Results showed that IIV under congruent, incongruent, and combined conditions obtained in the flanker task was associated with resting RSA and trait PA. Resting RSA interacted with IIV under incongruent conditions to predict trait PA, such that resting RSA positively predicted trait PA in high IIV under incongruent conditions, but not in low IIV under incongruent conditions. These findings suggest that executive brain function indexed by IIV might be a central nervous correlate of trait PA, and the executive brain function indexed by IIV under incongruent conditions and the vagal tone indexed by resting RSA interactively predict trait PA, might have health implications. (PsycINFO Database Record PMID- 29265842 TI - Posttraumatic stress symptom change after family involvement in veterans' mental health care. AB - Research indicates that veterans would like their families to be more involved in their mental health care. While Department of Veteran Affairs (VA) policy requires certain providers to discuss veterans' interest in family involvement in their mental health care, no published studies have examined the associations between family involvement and mental health outcomes in routine VA mental health care. This study assessed posttraumatic stress disorder (PTSD) symptoms before and after veterans' first family session to test whether symptoms changed after family inclusion. The study used administrative data from VA medical records from 2008-2013. Veterans included in the present study sample had at least one assessment of PTSD symptoms in the year prior to and following their first family session (N = 6,107). Multilevel models tested whether PTSD symptoms changed over time. Moderator analyses assessed whether the change in PTSD symptoms differed depending on the veteran's gender, psychiatric comorbidities, and intensity of family involvement following the first session. On average, results showed statistically, but not clinically, significant reductions in PTSD symptoms after the first family session. Women veterans, veterans with comorbid depression, and those who had eight or more family sessions showed stronger symptom reductions than others. This study provides provisional evidence that family involvement is associated with PTSD symptom reduction. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29265843 TI - Failure to engage: A qualitative study of veterans who decline evidence-based psychotherapies for PTSD. AB - Low engagement in posttraumatic stress disorder (PTSD) psychotherapy is a common problem in the U.S. Department of Veteran Affairs (VA), with up to half of veterans who are referred to an evidence-based psychotherapy failing to engage in that treatment. Prior research has focused on identifying general barriers to mental health treatment rather than barriers specific to evidence-based treatments for PTSD. The purpose of the current study was to identify barriers for veterans who referred specifically for evidence-based psychotherapy (i.e., cognitive processing therapy or prolonged exposure) but who did not attend any sessions of those psychotherapies. Qualitative interviews (N = 24) were used to gain a better understanding of the experiences and attitudes of these veterans. Most veterans reported multiple barriers to treatment engagement (M = 4.2 barriers), suggesting that an accumulation of barriers contributes to poor engagement. Barriers fell into 5 categories: practical, knowledge, emotional, therapy-related, and VA-system-related. The most-endorsed category, mentioned by two thirds of the sample, was VA-system-related barriers, including inefficiencies and delays, negative experiences with VA staff and providers, discomfort with the VA environment, and difficulty navigating the VA system. Veterans' experienced barriers to beginning PE and CPT were diverse but, overall, highlighted the need to transform the VA to a more patient-centered model of care. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29265844 TI - Associations between residential treatment length, PTSD, and outpatient healthcare utilization among veterans. AB - Premature discontinuation of posttraumatic stress disorder (PTSD) treatment is generally associated with poorer outcomes for veterans with PTSD. What is less clear is whether treatment benefits, as a function of treatment length, persist, as well as predict less future mental health care utilization. We sought to determine whether length of stay (LOS) in residential PTSD treatment predicted discharge PTSD symptom severity and outpatient mental health care utilization. We hypothesized discharge PTSD Checklist (PCL) scores would mediate the relations between LOS in residential treatment and outpatient mental health care utilization. The current study included 740 veterans who received residential PTSD treatment within 5 VA hospitals and completed intake and discharge assessments, including the PTSD Checklist (PCL). Information about LOS in residential treatment and outpatient mental health care utilization was obtained from the National Patient Care Database. We examined the relations between residential LOS, discharge Posttraumatic Stress Disorder Checklist (PCL), and outpatient mental health care utilization. Nonparametric bootstrapping was utilized to test for the significance of the indirect effect. Veterans who stayed in residential treatment longer had lower PCL scores at discharge (est. = -2.50, SE = .51, p < .001), and veterans with lower PCL scores at discharge sought fewer outpatient mental health visits (est. = .31, SE = .14, p = .03). A bias-corrected bootstrap confidence interval for the indirect effect (ab = -.77) based on 10,000 bootstrap samples was entirely below zero (-1.72 to -.05). This indicates discharge PCL mediated the relations between LOS and outpatient mental health care utilization, such that individuals with a longer LOS in residential PTSD treatment had lower PCL scores at discharge and thus utilized less outpatient mental health care. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29265845 TI - Bayesian estimation and modeling: Editorial to the second special issue on Bayesian data analysis. AB - This editorial accompanies the second special issue on Bayesian data analysis published in this journal. The emphases of this issue are on Bayesian estimation and modeling. In this editorial, we outline the basics of current Bayesian estimation techniques and some notable developments in the statistical literature, as well as adaptations and extensions by psychological researchers to better tailor to the modeling applications in psychology. We end with a discussion on future outlooks of Bayesian data analysis in psychology. (PsycINFO Database Record PMID- 29265846 TI - Using phantom variables in structural equation modeling to assess model sensitivity to external misspecification. AB - External misspecification, the omission of key variables from a structural model, can fundamentally alter the inferences one makes without such variables present. This article presents 2 strategies for dealing with omitted variables, the first a fixed parameter approach incorporating the omitted variable into the model as a phantom variable where all associated parameter values are fixed, and the other a random parameter approach specifying prior distributions for all of the phantom variable's associated parameter values under a Bayesian framework. The logic and implementation of these methods are discussed and demonstrated on an applied example from the educational psychology literature. The argument is made that such external misspecification sensitivity analyses should become a routine part of measured and latent variable modeling where the inclusion of all salient variables might be in question. (PsycINFO Database Record PMID- 29265847 TI - Distinguishing outcomes from indicators via Bayesian modeling. AB - A conceptual distinction is drawn between indicators, which serve to define latent variables, and outcomes, which do not. However, commonly used frequentist and Bayesian estimation procedures do not honor this distinction. They allow the outcomes to influence the latent variables and the measurement model parameters for the indicators, rendering the latent variables subject to interpretational confounding. Modified Bayesian procedures that preclude this are advanced, along with procedures for conducting diagnostic model-data fit analyses. These are studied in a simulation, where they outperform existing strategies, and illustrated with an example. (PsycINFO Database Record PMID- 29265848 TI - An alternative to post hoc model modification in confirmatory factor analysis: The Bayesian lasso. AB - As a commonly used tool for operationalizing measurement models, confirmatory factor analysis (CFA) requires strong assumptions that can lead to a poor fit of the model to real data. The post hoc modification model approach attempts to improve CFA fit through the use of modification indexes for identifying significant correlated residual error terms. We analyzed a 28-item emotion measure collected for n = 175 participants. The post hoc modification approach indicated that 90 item-pair errors were significantly correlated, which demonstrated the challenge in using a modification index, as the error terms must be individually modified as a sequence. Additionally, the post hoc modification approach cannot guarantee a positive definite covariance matrix for the error terms. We propose a method that enables the entire inverse residual covariance matrix to be modeled as a sparse positive definite matrix that contains only a few off-diagonal elements bounded away from zero. This method circumvents the problem of having to handle correlated residual terms sequentially. By assigning a Lasso prior to the inverse covariance matrix, this Bayesian method achieves model parsimony as well as an identifiable model. Both simulated and real data sets were analyzed to evaluate the validity, robustness, and practical usefulness of the proposed procedure. (PsycINFO Database Record PMID- 29265849 TI - Bayesian models for semicontinuous outcomes in rolling admission therapy groups. AB - Alcohol and other drug abuse are frequently treated in a group therapy setting. If participants are allowed to enroll in therapy on a rolling basis, irregular patterns of participant overlap can induce complex correlations of participant outcomes. Previous work has accounted for common session attendance by modeling random effects for each therapy session, which map to participant outcomes via a multiple membership construction when modeling normally distributed outcome measures. We build on this earlier work by extending the models to semicontinuous outcomes, or outcomes that are a mixture of continuous and discrete distributions. This results in multivariate session effects, for which we allow temporal dependencies of various orders. We illustrate our methods using data from a group-based intervention to treat substance abuse and depression, focusing on the outcome of average number of drinks per day. Alcohol and other drug abuse are frequently treated in a group therapy setting. If 2 clients attend the some of the same sessions, we might expect that-on average-their posttreatment outcomes would be more similar than if they had not attended any sessions together. Hence, if participants are allowed to enroll in therapy on a rolling basis, irregular patterns of session attendance can induce complex relationships between participant outcomes. Statistical methods have been developed previously to account for rolling admission group therapy when the outcomes are normally distributed. In the case of alcohol and other drug use interventions, however, a substantial fraction of participants often report zero use after treatment. We extend previous work to build models that accommodate semicontinuous outcomes, which are a mixture of continuous and discrete distributions, for such situations. We find that modern Bayesian statistical methods and software allow users to efficiently estimate nonstandard models such as these. We illustrate our methods using data from a group-based intervention to treat substance abuse and depression, focusing on the outcome of average number of drinks per day. We find that the intervention is associated with a drop in the probability of any drinking, but find no evidence of a change in the amount of drinking, conditional on some drinking. (PsycINFO Database Record PMID- 29265850 TI - Developing constraint in Bayesian mixed models. AB - Model comparison in Bayesian mixed models is becoming popular in psychological science. Here we develop a set of nested models that account for order restrictions across individuals in psychological tasks. An order-restricted model addresses the question "Does everybody," as in "Does everybody show the usual Stroop effect," or "Does everybody respond more quickly to intense noises than subtle ones?" The crux of the modeling is the instantiation of 10s or 100s of order restrictions simultaneously, one for each participant. To our knowledge, the problem is intractable in frequentist contexts but relatively straightforward in Bayesian ones. We develop a Bayes factor model-comparison strategy using Zellner and Siow's default g-priors appropriate for assessing whether effects obey equality and order restrictions. We apply the methodology to seven data sets from Stroop, Simon, and Eriksen interference tasks. Not too surprisingly, we find that everybody Stroops-that is, for all people congruent colors are truly named more quickly than incongruent ones. But, perhaps surprisingly, we find these order constraints are violated for some people in the Simon task, that is, for these people spatially incongruent responses occur truly more quickly than congruent ones! Implications of the modeling and conjectures about the task related differences are discussed. (PsycINFO Database Record PMID- 29265851 TI - A Bayesian "fill-in" method for correcting for publication bias in meta-analysis. AB - Publication bias occurs when the statistical significance or direction of the results between published and unpublished studies differ after controlling for study quality, which threatens the validity of the systematic review and summary of the results on a research topic. Conclusions based on a meta-analysis of published studies without correcting for publication bias are often optimistic and biased toward significance or positivity. We propose a Bayesian fill-in meta analysis (BALM) method for adjusting publication bias and estimating population effect size that accommodates different assumptions for publication bias. Simulation studies were conducted to examine the performance of BALM and compare it with several commonly used/discussed and recently proposed publication bias correction methods. The simulation results suggested BALM yielded small biases, small RMSE values, and close-to-nominal-level coverage rates in inferring the population effect size and the between-study variance, and outperformed the other examined publication bias correction methods across a wide range of simulation scenarios when the publication bias mechanism is correctly specified. The performance of BALM was relatively sensitive to the assumed publication bias mechanism. Even with a misspecified publication bias mechanism, BALM still outperformed the naive methods without correcting for publication in inferring the overall population effect size. BALM was applied to 2 meta-analysis case studies to illustrate the use of BALM in real life situations. R functions are provided to facilitate the implementation of BALM. Guidelines on how to specify the publication bias mechanisms in BALM and how to report overall effect size estimates are provided. (PsycINFO Database Record PMID- 29265852 TI - A social identity model of pro-environmental action (SIMPEA). AB - Large-scale environmental crises are genuinely collective phenomena: they usually result from collective, rather than personal, behavior and how they are cognitively represented and appraised is determined by collectively shared interpretations (e.g., differing across ideological groups) and based on concern for collectives (e.g., humankind, future generations) rather than for individuals. Nevertheless, pro-environmental action has been primarily investigated as a personal decision-making process. We complement this research with a social identity perspective on pro-environmental action. Social identity is the human capacity to define the self in terms of "We" instead of "I," enabling people to think and act as collectives, which should be crucial given personal insufficiency to appraise and effectively respond to environmental crises. We propose a Social Identity Model of Pro-Environmental Action (SIMPEA) of how social identity processes affect both appraisal of and behavioral responses to large-scale environmental crises. We review related and pertinent research providing initial evidence for the role of 4 social identity processes hypothesized in SIMPEA. Specifically, we propose that ingroup identification, ingroup norms and goals, and collective efficacy determine environmental appraisals as well as both private and public sphere environmental action. These processes are driven by personal and collective emotions and motivations that arise from environmental appraisal and operate on both a deliberate and automatic processing level. Finally, we discuss SIMPEA's implications for the research agenda in environmental and social psychology and for interventions fostering pro environmental action. (PsycINFO Database Record PMID- 29265853 TI - Are there two processes in reasoning? The dimensionality of inductive and deductive inferences. AB - Single-process accounts of reasoning propose that the same cognitive mechanisms underlie inductive and deductive inferences. In contrast, dual-process accounts propose that these inferences depend upon 2 qualitatively different mechanisms. To distinguish between these accounts, we derived a set of single-process and dual-process models based on an overarching signal detection framework. We then used signed difference analysis to test each model against data from an argument evaluation task, in which induction and deduction judgments are elicited for sets of valid and invalid arguments. Three data sets were analyzed: data from Singmann and Klauer (2011), a database of argument evaluation studies, and the results of an experiment designed to test model predictions. Of the large set of testable models, we found that almost all could be rejected, including all 2-dimensional models. The only testable model able to account for all 3 data sets was a model with 1 dimension of argument strength and independent decision criteria for induction and deduction judgments. We conclude that despite the popularity of dual-process accounts, current results from the argument evaluation task are best explained by a single-process account that incorporates separate decision thresholds for inductive and deductive inferences. (PsycINFO Database Record PMID- 29265855 TI - Competing theories of multialternative, multiattribute preferential choice. AB - In accounting for phenomena present in preferential choice experiments, modern models assume a wide array of different mechanisms such as lateral inhibition, leakage, loss aversion, and saliency. These mechanisms create interesting predictions for the dynamics of the deliberation process as well as the aggregate behavior of preferential choice in a variety of contexts. However, the models that embody these different mechanisms are rarely subjected to rigorous quantitative tests of suitability by way of model fitting and evaluation. Recently, complex, stochastic models have been cast aside in favor of simpler approximations, which may or may not capture the data as well. In this article, we use a recently developed method to fit the four extant models of context effects to data from two experiments: one involving consumer goods stimuli, and another involving perceptual stimuli. Our third study investigates the relative merits of the mechanisms currently assumed by the extant models of context effects by testing every possible configuration of mechanism within one overarching model. Across all tasks, our results emphasize the importance of several mechanisms such as lateral inhibition, loss aversion, and pairwise attribute differences, as these mechanisms contribute positively to model performance. Together, our results highlight the notion that mathematical tractability, while certainly a convenient feature of any model, should neither be the primary impetus for model development nor the promoting or demotion of specific model mechanisms. Instead, model fit, balanced with model complexity, should be the greatest burden to bear for any theoretical account of empirical phenomena. (PsycINFO Database Record PMID- 29265854 TI - Beyond sacrificial harm: A two-dimensional model of utilitarian psychology. AB - [Correction Notice: An Erratum for this article was reported in Vol 125(2) of Psychological Review (see record 2018-15704-001). The copyright attribution was incorrectly listed, and the Creative Commons CC-BY license disclaimer was incorrectly omitted from the author note. The correct copyright is "(c) 2017 The Author(s)" and the omitted disclaimer is found in the erratum. All versions of this article have been corrected.] Recent research has relied on trolley-type sacrificial moral dilemmas to study utilitarian versus nonutilitarian modes of moral decision-making. This research has generated important insights into people's attitudes toward instrumental harm-that is, the sacrifice of an individual to save a greater number. But this approach also has serious limitations. Most notably, it ignores the positive, altruistic core of utilitarianism, which is characterized by impartial concern for the well-being of everyone, whether near or far. Here, we develop, refine, and validate a new scale the Oxford Utilitarianism Scale-to dissociate individual differences in the 'negative' (permissive attitude toward instrumental harm) and 'positive' (impartial concern for the greater good) dimensions of utilitarian thinking as manifested in the general population. We show that these are two independent dimensions of proto-utilitarian tendencies in the lay population, each exhibiting a distinct psychological profile. Empathic concern, identification with the whole of humanity, and concern for future generations were positively associated with impartial beneficence but negatively associated with instrumental harm; and although instrumental harm was associated with subclinical psychopathy, impartial beneficence was associated with higher religiosity. Importantly, although these two dimensions were independent in the lay population, they were closely associated in a sample of moral philosophers. Acknowledging this dissociation between the instrumental harm and impartial beneficence components of utilitarian thinking in ordinary people can clarify existing debates about the nature of moral psychology and its relation to moral philosophy as well as generate fruitful avenues for further research. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29265856 TI - Retrieving and applying knowledge to different examples promotes transfer of learning. AB - Introducing variability during learning often facilitates transfer to new contexts (i.e., generalization). The goal of the present study was to explore the concept of variability in an area of research where its effects have received little attention: learning through retrieval practice. In four experiments, we investigated whether retrieval practice with different examples of a concept promotes greater transfer than repeated retrieval practice with the same example. Participants watched video clips from a lecture about geological science and answered application questions about concepts: either the same question three times or three different questions. Experiments 3 and 4 also included conditions that involved repeatedly studying the information in the application questions (either the same example or three different examples). Two days later, participants took a final test with new application questions. All four experiments showed that variability during retrieval practice produced superior transfer of knowledge to new examples. Experiments 3 and 4 also showed a testing effect and a benefit from studying different examples. Overall, these findings suggest that repeatedly retrieving and applying knowledge to different examples is a powerful method for acquiring knowledge that will transfer to a variety of new contexts. (PsycINFO Database Record PMID- 29265857 TI - Memory strength and lineup presentation moderate effects of administrator influence on mistaken identifications. AB - Administrator/witness pairs (N = 313) were randomly assigned to target-absent lineups in a 2 (Suspect/Perpetrator Similarity: High Suspect Similarity vs. Low Suspect Similarity) * 2 (Retention Interval: 30 min vs. 1 week) * 2 (Lineup Presentation: Simultaneous vs. Sequential) * 2 (Administrator Knowledge: Single Blind vs. Double-Blind) factorial design to test whether suspect similarity and memory strength constrain interpersonal expectancy effects on eyewitness identification accuracy. Administrators who knew which lineup member was the suspect (single-blind) or who administered simultaneous lineups were more likely to emit verbal and nonverbal behaviors that suggested to the witness who the suspect was. Additionally, single-blind administrators exerted more pressure on witnesses to choose the suspect as opposed to fillers. Administrator knowledge interacted with retention interval and lineup presentation to influence mistaken identifications of innocent suspects; witnesses were more likely to mistakenly identify an innocent suspect from single-blind than double-blind lineups when witness retention intervals were long and photographs were presented simultaneously. Contrary to our predictions, suspect/perpetrator similarity did not interact with other manipulated variables to influence identification decisions. Both sequential and double-blind procedures should be used to reduce the use of suggestive behavior during lineup administration. (PsycINFO Database Record PMID- 29265858 TI - To contribute or not: A goals-based perspective on the effect of industry sales trend and solicitation messages on voluntary contributions to a generic advertising campaign. AB - Generic advertising campaigns such as "Got Milk?" and "Pork: The Other White Meat" are intended to increase demand for the entire product category rather than demand for a specific brand. This research examines the influence of industry (or product category) sales trend and solicitation messages on voluntary contributions toward such campaigns. Based on the idea that the context in which decisions are made may induce goals, a theoretical framework is developed to suggest that a declining versus an increasing industry sales trend induces different goal orientations. Although contributing to a generic advertising campaign may be viewed as 1 means to achieve the induced goal, the means-goal association is likely to be stronger when the trend is declining rather than increasing. Further, the authors propose that a solicitation message that is congruent with the induced goal and the associated mean is likely to be most effective in increasing contributions relative to incongruent messages. Consistent with the framework, three studies demonstrate that voluntary contributions are higher when the industry sales trend is declining versus increasing, and the solicitation message that reinforces the association between the induced goal and the means to achieve the goal is most effective in increasing contributions. (PsycINFO Database Record PMID- 29265859 TI - Next steps for Psychiatric Rehabilitation Journal. AB - As the authors complete the 2017 publication cycle of Psychiatric Rehabilitation Journal and their term as editors draws to a close, they take the opportunity to welcome the new leadership of PRJ, to thank the many people who have contributed to its success, and to reflect on the importance of the journal's focus and scope to the field. They are pleased to welcome Dr. Sandra ("Sandy") Resnick as the new editor of PRJ, who will begin her incoming term by accepting new manuscripts starting January 1, 2018. In her role as Editor, Dr. Resnick hopes to further increase PRJ's accessibility to both practitioners and policymakers, while maintaining the high-quality of original research submissions that have led to widely cited articles in the field. (PsycINFO Database Record PMID- 29265860 TI - Can you hear me now? Teaching listening skills. AB - TOPIC: This column provides an overview of methods for training to improve service provider active listening and reflective responding skills. PURPOSE: Basic skills in active listening and reflective responding allow service providers to gather information about and explore the needs, desires, concerns, and preference of people using their services-activities that are of critical importance if services are to be truly person-centered and person-driven. SOURCES USED: Sources include the personal experience of the authors as well as published literature on the value of basic counseling skills and best practices in training on listening and other related soft skills. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Training in listening is often needed but rarely sought by behavioral health service providers. Effective curricula exist, providing content and practice opportunities that can be incorporated into training, supervision, and team meetings. When providers do not listen well to the people who use their services, the entire premise of recovery-oriented person-driven services is undermined. (PsycINFO Database Record PMID- 29265861 TI - The clinical utility and construct validity of the NIH Toolbox Cognition Battery (NIHTB-CB) in individuals with disabilities. AB - A State-of-the-Science conference on measurement with disability populations recommended "...the development of cognitive and psychosocial outcome measures, using computer-adaptive testing...that are low in respondent burden and valid across patient populations," (Clohan et al., 2007, p. 1537). Following this recommendation, the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) prioritized the development of measures of cognitive functioning for individuals with disabilities, noting that measures of cognitive functioning "have not been developed for systemic application in the field of medical rehabilitation. Cognition is both a rehabilitation outcome and a factor related to broader functional and community outcomes for individuals with a wide variety of disabling conditions" (Office of Special Education & Rehabilitation Services, 2009, p. 37193). From this came the NIH Toolbox for the Assessment of Neurological and Behavioral Function project (NIH Toolbox) which provides a comprehensive set of cognitive, motor, sensory, and emotional health and function measures for use in clinical, longitudinal, and epidemiological research. The nine papers comprising this special section of Rehabilitation Psychology reflect the sustained collaborative efforts of more than two dozen investigators working at six sites over the past 8 years. They are an initial attempt to validate the NIHTB-CB in disability samples, and they provide initial evidence that the NIHTB-CB can be used with individuals who have TBI, SCI, or stroke. The articles published here reflect the fulfillment of recommendations made during a state-of-the-science conference in 2007. (PsycINFO Database Record PMID- 29265862 TI - Using the NIH Toolbox Cognition Battery (NIHTB-CB) in individuals with traumatic brain injury. AB - PURPOSE/OBJECTIVE: The NIH Toolbox for the Assessment of Neurological Behavior and Function Cognition Battery (NIHTB-CB) is a common data element for use in individuals with traumatic brain injury (TBI). This study evaluates its sensitivity and specificity in distinguishing individuals with complicated mild, moderate, or severe TBI, and provides support for the construct validity of the NIHTB-CB in individuals with TBI. RESEARCH METHOD: One hundred eighty-two individuals with TBI (n = 83 complicated mild/moderate; n = 99 severe) completed the NIHTB-CB and neuropsychological criterion measures. Complete data were obtained on 158 participants. A control sample of 158 individuals without known neurological impairment was extracted from the NIHTB-CB normative sample. Multivariate analyses of variance determined the sensitivity of the NIHTB-CB measures to TBI and injury severity (complicated mild/moderate TBI, severe TBI, and controls) on the demographically corrected NIHTB-CB composite scores and seven subtests. A descriptive analysis of the sensitivity of each subtest was conducted. Finally, correlations between NIHTB-CB measures and criterion tests assessed convergent and discriminant validity. RESULTS: Multivariate analyses indicated that there was a main effect for group (complicated mild/moderate vs. severe vs. controls) for fluid scores in the NIHTB-CB as opposed to only marginally significant results for the verbal scores. Moderate to strong relationships were found between the NIHTB-CB measures and their corresponding neuropsychological measures (convergent validity), whereas much smaller correlations were found between measures of different cognitive domains (discriminant validity). CONCLUSIONS: Findings provide evidence of construct validity and the clinical utility of the NIHTB-CB in individuals with TBI. (PsycINFO Database Record PMID- 29265863 TI - Cognition among community-dwelling individuals with spinal cord injury. AB - PURPOSE/OBJECTIVE: To compare the cognitive profiles of a well-characterized sample of adults with and without spinal cord injury (SCI) using the NIH Toolbox Cognition Battery NIHTB-CB. Research Method/Design: Participants were 156 community-dwelling individuals with SCI recruited from 3 academic medical centers, and 156 individuals without SCI selected from the NIHTB-CB normative database (N = 312). The main outcome measures were the demographically adjusted NIHTB-CB subtest and composite scores. RESULTS: Individuals with and without SCI performed equivalently on the NIHTB-CB crystallized composite score, suggesting comparable premorbid functioning. Individuals with SCI produced lower scores on the NIHTB-CB fluid composite score by an average of 4.5 T-score points (Cohen's d = 0.50; a medium effect size). As a group, individuals with SCI had the most difficulty on tests of processing speed and executive functions, and some difficulty on a test of episodic memory, although effect sizes were small. These differences remained even after accounting for fine motor speed and dexterity. Individuals with tetraplegia produced lower scores than individuals with paraplegia on tests of processing speed and executive functioning. CONCLUSION/IMPLICATIONS: Community-dwelling individuals with SCI are at elevated risk of mild cognitive difficulties, particularly on tasks that rely on processing speed and executive functions. The NIHTB-CB is relatively brief, samples important cognitive domains, has good normative data, and is appropriate for some individuals with SCI (those who have functional use of one hand). The battery has standardized accommodations for individuals with minor motor limitations, but timed tests are inaccessible for individuals who are unable to perform rapid button presses. (PsycINFO Database Record PMID- 29265864 TI - Factor structure of the NIH Toolbox Cognition Battery in individuals with acquired brain injury. AB - OBJECTIVE: The National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) measures reading, vocabulary, episodic memory, working memory, executive functioning, and processing speed. While previous research has validated the factor structure in healthy adults, the factor structure has not been examined in adults with neurological impairments. Thus, this study evaluated the NIHTB-CB factor structure in individuals with acquired brain injury. METHOD: A sample of 392 individuals (ages 18-84) with acquired brain injury (n = 182 TBI, n = 210 stroke) completed the NIHTB-CB along with neuropsychological tests as part of a larger, multisite research project. RESULTS: Confirmatory factor analyses supported a 5-factor solution that included reading, vocabulary, episodic memory, working memory, and processing speed/executive functioning. This structure generally held in TBI and stroke subsamples as well as in subsamples of those with severe TBI and stroke injuries. CONCLUSIONS: The factor structure of the NIHTB-CB is similar in adults with acquired brain injury to adults from the general population. We discuss the implications of these findings for clinical practice and clinical research. (PsycINFO Database Record PMID- 29265865 TI - Construct validity of the NIH Toolbox Cognition Battery in individuals with stroke. AB - OBJECTIVE: The National Institutes of Health (NIH) Toolbox (NIHTB) for the Assessment of Behavior and Neurological Function Cognition Battery (NIHTB-CB) provides a brief assessment (approximately 30 min) of key components of cognition. This article examines construct validity to support the clinical utility of the NIHTB-CB in individuals with stroke. RESEARCH METHOD: A total of 131 individuals with stroke (n = 71 mild stroke; n = 60 moderate/severe stroke) completed the NIHTB-CB. Univariate analyses were conducted to examine the cognitive profiles of the two different stroke groups (mild vs. moderate/severe stroke) on NIHTB-CB measures and composite scores. Pearson correlations were conducted between NIHTB-CB and established measures to examine convergent and discriminant validity. Effect sizes and clinical impairment rates for the different NIHTB-CB measures and composite scores were also examined. RESULTS: Participants experiencing moderate to severe stroke had poorer performance than did individuals with mild stroke on several of the NIHTB cognition measures. Evidence of convergent validity was provided by moderate to strong correlations between the NIHTB measures and the corresponding standard neuropsychological test (Pearson rs ranged from 0.31 to 0.88; median = .60). Evidence of discriminant validity was provided by smaller correlations between different cognitive domains than correlations of measures within the same domain. Effect sizes for composite and subtest scores regarding stroke severity were generally moderate-to-large. In addition, 42% of the sample were exhibiting mild cognitive impairment (i.e., >=2 low scores on fluid tests). CONCLUSIONS: Findings provide support for the construct validity of the NIHTB-CB in individuals with stroke. (PsycINFO Database Record PMID- 29265866 TI - Test accommodations for individuals with neurological conditions completing the NIH Toolbox-Cognition Battery: An evaluation of frequency and appropriateness. AB - OBJECTIVES: First, to evaluate the frequency with which individuals with neurological conditions require test administration accommodations for the NIH Toolbox-Cognition Battery (NIHTB-CB). Second, to evaluate the appropriateness of accommodations provided by administrators, including adherence to NIHTB-CB Reasonable Accommodations Guidelines. METHOD: Adults with traumatic brain injury, spinal cord injury, or stroke (n = 604) completed the NIHTB-CB and other assessments as part of a multisite study. We provide a descriptive, secondary analysis of test administrator notes to determine use and appropriateness of accommodations. RESULTS: Of the 604 participants, 450 (75%) completed the NIHTB CB using standard administration procedures, but 137 (22.6%) encountered accessibility challenges that required accommodations. Participants with motor function impairments were most likely to receive at least 1 of 3 kinds of accommodations: (a) use of nonstandard methods of entering responses using standard input devices, (b) use of alternate input devices, or (c) help from the test administrator to enter a response. Fatigue and/or impulsivity led to nonstandard administration by 48 (7.9%) individuals. Post hoc audit of test administrator notes revealed that despite careful instructions and supervision, 49 (56.3%) of the accommodated administrations breached standardization and scores could not be interpreted using test norms. CONCLUSION: Although the NIHTB CB was developed for individuals without neurological impairment, most individuals with neurological conditions completed the standardized administration without accommodations. When accommodations were needed, administrators did not adhere to the official Reasonable Accommodations Guidelines in more than half of the cases. (PsycINFO Database Record PMID- 29265867 TI - Motor-free composites from the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) for people with disabilities. AB - PURPOSE/OBJECTIVE: The National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) includes a group of brief measures (i.e., 30 min) designed to assess language, processing speed, working memory, episodic memory, and executive functioning. These subtests can be combined to create composite scores that reflect fluid and crystallized cognition, as well as overall cognition. The battery is of limited utility with individuals who have impaired upper extremity motor functioning. This manuscript examines the accuracy of the Oral Symbol Digit Modalities Test as a substitute for the Pattern Comparison Processing Speed Test for computing motor-free composite scores. Research Method/Design: Individuals with spinal cord injury (SCI; n = 188), traumatic brain injury (TBI; n = 159), or stroke (n = 180) completed the NIHTB-CB. We used the Oral Symbol Digit Modalities Test to create a Motor-Free Pattern Comparison score; this was used to create revised, Motor-Free Composite scores for Fluid Cognition and Overall Cognition. RESULTS: Although there were statistically significant overall differences between the two Fluid and Overall Cognition composite scores for some of the clinical groups (scores based on the motor-free approach were significantly higher than the original score), these differences were small and partly because of overclassification of impaired processing speed in participants with motor impairment. There was good to substantial agreement with regard to "impairment" classification between the two sets of Original and Motor-Free composite scores. CONCLUSIONS/IMPLICATIONS: Although the Motor-Free scores are not a perfect match for the Original Composite scores, they provide a reliable and valid way to examine overall and fluid cognition in individuals with upper extremity motor impairments. (PsycINFO Database Record PMID- 29265868 TI - NIH toolbox cognition tests following traumatic brain injury: Frequency of low scores. AB - PURPOSE/OBJECTIVE: To apply multivariate base rate analyses to the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) to facilitate the identification of cognitive impairment in individuals with traumatic brain injury (TBI). Research Method/Design: In a multisite cross-sectional design, 158 participants who sustained a complicated mild or moderate TBI (n = 74) or severe TBI (n = 84) at least 1 year earlier were administered the NIHTB-CB. The NIHTB-CB is comprised of 2 crystallized cognition tests (reflecting premorbid ability) and 5 fluid cognition tests, measuring processing speed, memory, and executive functioning. Base rates for obtaining 0 to 5 low fluid cognition scores were calculated across a range of cutoffs for defining a low test score (<=25th to 5th percentiles). Base rates of low scores in the TBI sample were compared to the NIHTB-CB normative sample using diagnostic accuracy statistics. RESULTS: The proportion of the TBI sample obtaining low scores decreased as the cutoff for defining a low score decreased. Individuals with lower premorbid cognitive ability, as measured by NIHTB-CB Crystallized Composite score, tended to produce more low scores on the NIHTB-CB fluid cognition tests, even when using fully demographically adjusted scores. Certain patterns of low scores were associated with TBI (defined as likelihood ratio >2.0), whereas others were nonspecific, occurring almost as often in participants without TBI. CONCLUSIONS/IMPLICATIONS: Premorbid ability stratified base rate tables provided in this article can guide researchers and clinicians in the interpretation of NIHTB-CB performance in adults with TBI. (PsycINFO Database Record PMID- 29265869 TI - Uncorrected versus demographically-corrected scores on the NIH Toolbox Cognition Battery in persons with traumatic brain injury and stroke. AB - OBJECTIVE: The association between demographic characteristics and neurocognitive performance is well established; however, clinicians may have difficulty selecting when to use uncorrected versus demographically corrected scores. We compared these score types in individuals with traumatic brain injury (TBI) and stroke, on the National Institutes of Health Toolbox-Cognition Battery (NIHTB CB). RESEARCH METHOD: Adults with TBI and stroke were demographically matched to controls, and completed the NIHTB-CB. Published "corrected scores" are adjusted for age, education, sex, and race/ethnicity; "uncorrected scores" were created using census data to represent the average adult in the U.S. POPULATION: RESULTS: Effect sizes for the TBI and stroke groups versus controls were larger using corrected scores compared with uncorrected scores for the fluid composite (uncorrected to corrected effect sizes: TBI: d = 0.66, p < .001 to 0.83, p < .001; stroke d = 0.97, p < .001 to 1.10, p < .001). For the crystallized composite, effect sizes for the TBI and stroke groups versus controls were smaller and nonsignificant using corrected scores (uncorrected to corrected effect sizes: TBI d = 0.23, p = .03 to 0.20, p = .06; stroke d = 0.40, p < .001 to 0.17, p = .09). In the injury groups, demographic characteristics accounted for up to 33% of variance in uncorrected scores (p < .001), but <5% of variance in corrected scores (p > .06). CONCLUSIONS: Corrected scores were more sensitive to neurocognitive impairments in the brain-injured groups. Corrected scores have the advantage of controlling for variance associated with premorbid factors rather than changes in neurological functioning; are more helpful in characterizing acquired neurocognitive changes; and can aid in the interpretation of test performance. (PsycINFO Database Record PMID- 29265870 TI - Nih toolbox premorbid ability adjustments: Application in a traumatic brain injury sample. AB - PURPOSE/OBJECTIVE: Metrics to estimate premorbid cognitive ability, such as word reading tests, are important for clinical determination of cognitive changes following brain injury. In the present study, reading adjusted scores for the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) fluid tests were developed and validated with a sample of individuals with traumatic brain injury (TBI), to evaluate the clinical utility of reading-adjusted scores. Research Method/Design: The development sample included 843 adult participants, ages 20-85, from the NIHTB-CB standardization sample. A sample of 158 participants with complicated mild or moderate TBI (n = 74) or severe TBI (n = 84) were administered the NIHTB-CB, and comprised the validation sample. Scores were derived for the five fluid tests using four adjustment models: age-only, demographic-only, age-and-reading, and demographic-and-reading referenced scores. RESULTS: Estimated premorbid ability varies depending on the reference model. Scores from each of the four reference models differentiated the comparison and TBI samples at the group level. However, performance varied by premorbid ability. CONCLUSIONS/IMPLICATIONS: Premorbid ability affects identification of cognitive difficulties after TBI. Reading referenced scores provide an individualized estimate of the effects of premorbid ability than demographic characteristics alone. Each model identified a similar number of individuals as having cognitive difficulties; however, the models differed on which individuals had cognitive difficulties. The models had higher disagreement rates in the clinical compared with the comparison sample, particularly for individuals with lower premorbid ability. Clinical use and caveats are discussed. (PsycINFO Database Record PMID- 29265872 TI - Stress in patients diagnosed with rheumatoid arthritis compared to chronic pain. AB - PURPOSE/OBJECTIVE: To examine potential differences in cognitions and traitlike factors that relate to stress among individuals diagnosed with rheumatoid arthritis (RA) compared to those with chronic pain (CP). Research Method/Design: A cross-sectional study was conducted with participants recruited from outpatient rheumatology and CP clinics. Participants completed self-report questionnaires of demographics, disease characteristics, cognitions, and traitlike constructs. Correlates of patient stress were considered using hierarchical multiple regression. RESULTS: Analyses included 445 participants: 226 patients diagnosed with RA and 229 patients diagnosed with CP. In participants with RA, excessive worrying and anxiety sensitivity were independently associated with feeling stressed (p < .001), and 29% of the variance in stress scores was explained after adjusting for age, gender, years of education, and average pain intensity. In participants with CP, fear of relaxation, anxiety sensitivity, and pain catastrophizing were independently associated with feeling stressed (p < .001), and 31% of variance in stress scores was explained after adjusting for age, gender, years of education, and average pain intensity. Comparison of the fit of the model in both groups of patients through use of Fisher's z test found that the set of variables did similarly well for both patients with RA and those with CP, with no significant difference between R2 values (z = .88, p = .388). CONCLUSIONS/IMPLICATIONS: This study establishes cognitions and traitlike factors that are related to reports of stress among patients with RA and CP. These factors should be considered when treating and developing interventions for patients who experience increased feelings of stress. (PsycINFO Database Record PMID- 29265871 TI - Relation of depressive symptoms to outcome of CI movement therapy after stroke. AB - OBJECTIVE: Depressive symptoms after stroke have been associated with negative outcomes, including poorer functional ability, less efficient use of rehabilitation services, decreased quality of life, and increased mortality. It has been anecdotally noted that depressive symptoms do not limit motor recovery in patients who undergo Constraint-Induced Movement Therapy (CIMT), an efficacious intervention for chronic poststroke hemiparesis. Here we analyze depressive symptom and motor scores from 40 participants who received CIMT in 2 previously published studies. METHOD: Adults more than 1-year after stroke with mild to moderate upper-extremity hemiparesis completed the Zung Self-Rating Depression Scale and Motor Activity Log (MAL) before and after CIMT. We used regression analysis to test whether Zung scores predicted response to CIMT and paired t tests to test whether depressive symptoms changed from pre- to posttreatment. RESULTS: Pretreatment Zung score did not predict outcome on the MAL Arm Use scale, DeltaR2 (1, 30) = 0.004, p = .19, after controlling for pretreatment MAL scores. Additionally, participants had a small but statistically significant decrease in Zung score, t(39) = 3.0, p = .005, mean change = -3.6. CONCLUSION: These results suggest that depressive symptoms do not significantly limit motor recovery in patients treated with CIMT for chronic poststroke hemiparesis. Additionally, treatment with CIMT may improve depressive symptoms. (PsycINFO Database Record PMID- 29265873 TI - Mental contrasting with implementation intentions (MCII) improves physical activity and weight loss among stroke survivors over one year. AB - OBJECTIVE: Stroke is the most common cause of physical impairment, and having already had a stroke dramatically increases the risk of having another one. Although greater physical activity lowers rates of stroke recurrence, patients often fail to act in line with this recommendation. The present intervention tested whether teaching the self-regulation strategy of mental contrasting (MC) with implementation intentions (II; MCII) improves stroke patients' physical activity and weight loss over 1 year compared with 2 information-only, control interventions. RESEARCH METHOD: Participants were 183 stroke survivors who were capable of adhering to physical activity recommendations (age: M = 57 years; body mass index (BMI): M = 30). Patients were randomized to 3 conditions: unstructured information (n = 61), structured information (n = 62), and structured information plus MCII (n = 60). Patients' physical activity was assessed 50 weeks after they had left the rehabilitation hospital using the Baecke Inventory (Baecke, Burema, & Frijters, 1982), and by diaries provided at 2 consecutive weekends after 0, 10, 20, 30, 40, and 50 weeks. Diaries were also used to assess weight change. RESULTS: MCII participants were more physically active after the 50 weeks (Baecke Inventory: 2.74 vs. 2.59, p < .05; diary: 62.45 vs. 54.11, p = .03) and lost more weight (2.15 kg, p = .02) compared with participants in the control conditions. CONCLUSIONS: Teaching the MCII self-regulation strategy enhanced long-term physical activity in stroke patients relative to health information on its own. MCII thus qualifies as an effective intervention technique to improve secondary stroke prevention. (PsycINFO Database Record PMID- 29265875 TI - Clinical utility and psychometric properties of the Brief: Coping With Problems Experienced with caregivers. AB - The Brief Coping with Problems Experienced (COPE) is designed to assess the varying coping strategies used by individuals in response to stress. It comprises 14 scales, each of which assesses the degree to which a respondent utilizes a specific coping strategy. This brief summary provides a review of the psychometric properties of the Brief COPE with caregivers. (PsycINFO Database Record PMID- 29265874 TI - The effects of aging and HIV disease on employment status and functioning. AB - OBJECTIVE: As the prevalence of older adults living with HIV disease increases, questions are emerging regarding the extent to which older age amplifies the adverse effects of HIV on employment status and functioning. This cross-sectional study sought to (1) investigate the combined effects of HIV and older age on employment status, (2) identify clinicodemographic correlates of employment status among older HIV+ persons, and (3) examine the combined effects of HIV and age on workplace performance among employed participants. METHOD: The sample was 358 HIV+ (163 older, 195 younger) and 193 HIV- (94 older, 99 younger) adults, who completed a comprehensive neurocognitive research assessment that included measures of employment status and current workplace functioning. RESULTS: We observed main effects of HIV and age on employment status, but no interaction. The older HIV+ sample demonstrated particularly high rates of disability, rather than elective retirement or unemployment. Among older HIV+ adults significant predictors of employment status included age, global neurocognitive functioning, combination antiretroviral therapy status, age at HIV infection, and hepatitis C coinfection. Finally, self-reported work functioning of older HIV+ adults differed only from the younger HIV- group. CONCLUSION: Findings suggest that older age and HIV disease have additive adverse effects on employment status, but not work functioning, and that employment status is associated with both neurocognitive and medical risk factors among older HIV+ adults. Further longitudinal research is needed to elucidate specific disease and demographic characteristics that may operate as protective factors for retaining gainful employment among older HIV+ adults. (PsycINFO Database Record PMID- 29265877 TI - Evaluation of the Genetics and Functionality of Plasmids in Incompatibility Group I1-Positive Salmonella enterica. AB - Salmonella is a predominant foodborne pathogen in the United States and other countries. Mobile genetic elements such as plasmids allow Salmonella to adapt to external stress factors such as nutrient deprivation and host factors. Incompatibility group I1 (IncI1) plasmid-carrying Salmonella enterica strains were examined to determine the presence of plasmid-associated genes and their influence on phenotypic characteristics. The objective of this study was to understand the genetic determinants on IncI1 plasmids and their impact on antimicrobial susceptibility, competitive growth inhibition of Escherichia coli, and plasmid transfer. Primers were designed for genes that play a role in virulence, antimicrobial resistance, and plasmid transfer based on previously sequenced IncI1 plasmids. Polymerase chain reaction assays were conducted on 92 incompatibility group I1 (IncI1)-positive S. enterica strains. Phenotypic characterization included conjugation assays, antimicrobial susceptibility testing, and bacteriocin production based on the inhibition of growth of colicin negative E. coli J53. The antimicrobial resistance genes aadA1, tetA, sul1, and blaCMY were detected in 88%, 87%, 80%, and 48% of the strains, respectively. Over half of the strains were resistant or intermediately resistant to streptomycin (85%), sulfonamides (76%), tetracycline (74%), and ampicillin (68%) and 57% of the strains inhibited growth of E. coli J53 strain. Among putative virulence genes, colicin-associated colI and cib were detected in 23% and 35% of strains and imm and ccdA were present in 58% and 54% of strains, respectively. Approximately 61% of strains contained plasmids that conjugally transferred antimicrobial resistance, including 83% where the recipient received IncI1 plasmids. Most of the strains carried an assortment of transfer associated (pil and tra) genes with between 63% and 99% of strains being positive for individual genes. Taken together the study affirms that IncI1 plasmids likely play roles in the dissemination of antimicrobial resistance and virulence-associated factors among enteric organisms. PMID- 29265876 TI - Clinical Applications of and Challenges in Single-Cell Analysis of Circulating Tumor Cells. AB - Technological advancements in next-generation sequencing are continually changing the landscape of genomic, transcriptomic, and epigenetic research at the single cell level. These technologies have been used to detect and analyze circulating tumor cells (CTCs) at the molecular level and provide a new approach for the management of cancer patients. A series of unanticipated discoveries, including the heterogeneity of cancer cell populations, new driver mutations responsible for the resistance of tumors to chemotherapy, and the mechanism of tumor metastasis, have been made using single CTC sequencing. CTC detection has been used in cancer diagnosis and monitoring and in determining the prognosis of cancer patients. Traditional treatment for cancer patients is universal and does not consider genetic variations among patients, but in the era of precision medicine, giving the right drug to the right patient at the right time is the core philosophy. In this study, we review the fundamental principles of CTC isolation and single-cell sequencing and discuss recent progress in their application in both basic research and clinical fields and describe the current challenges. PMID- 29265878 TI - Efficacy Evaluation of Control Measures on the Reduction of Staphylococcus aureus in Salad and Bacillus cereus in Fried Rice Served at Restaurants. AB - The objective of this study was to assess the effect of washing on Staphylococcus aureus reduction in salads and the effect of reheating on Bacillus cereus vegetative cells and spores reduction in fried rice at restaurants using the stochastic food safety objective (FSO) tool. The leaf vegetable was inoculated with S. aureus and washed with tap water, 100 ppm of NaClO, or 30 ppm of slightly acidic electrolyzed water (SAEW) for either 60 s or 5 min. The washing effect of 30 ppm SAEW was greater than that of 100 ppm NaClO. Based on the FSO concept, washing leaf vegetables with 30 ppm SAEW for 5 min was the most efficient control measure for S. aureus in salads. In addition, the salad should be consumed within 4 h at 25 degrees C and 2 h at 35 degrees C after 5 min of washing with 100 ppm NaClO or 30 ppm SAEW. The fried rice was first inoculated with B. cereus vegetative cells or spores and was then reheated in a frying pan at medium (internal temperature of fried rice: 69.2 degrees C-78.8 degrees C) or high heat (internal temperature of fried rice:103.8 degrees C-121.4 degrees C) or in a microwave oven (internal temperature of fried rice:86.3 degrees C-90.6 degrees C) for 3 or 4 min. Based on the FSO, reheating rice in a microwave oven was the most efficient control measure for B. cereus vegetative cells and spores in fried rice. The holding time for fried rice can be extended up to 6 h at 25 degrees C, 3 h at 35 degrees C, and 2 h at 45 degrees C with reheating. Microbiological hazards in salads and fried rice can be controlled by washing with a sanitizer and reheating, respectively and then by controlling of holding temperature before being served at restaurants. PMID- 29265879 TI - Mutation Mechanisms of Human Breast Cancer. AB - Cancer is a class of diseases caused by the accumulation of gene mutations. All mutated genes constitute a genetic network for cancer progression. It is very helpful for tumor diagnosis and therapy if we know how many mutated genes are needed for human breast cancer. In this article, we investigate the mutation mechanisms of human breast cancer by modeling the data of surveillance, epidemiology, and end results registry. The data are age-specific incidence rates of breast cancer of females in the United States. We set up stochastic multistage models to estimate the age-specific incidence rates by using several coupled ordinary differential equations derived from the Kolmogorov backward equations. Our results suggest that 2-14 mutations in the genome of breast stem cells are required for normal breast stem cells to become a malignant cell, and 3 gene mutations are most likely to occur in the development of female breast cancer. PMID- 29265880 TI - Is there a link between motor vehicle collisions and being a cigarette smoker in Canada? Analysis of survey data from Ontario from 2002 to 2014. AB - OBJECTIVE: Although most research on drugs and driving has focused on the use of alcohol and cannabis, research that has been conducted on cigarette smoking and collisions has found that smokers have an increased collision involvement. Studies dating from 1967 through 2013 have shown a crude relative risk of about 1.5 among smokers compared to nonsmokers. In Canada, the association between smoking and collisions has not been recently investigated. Studies that have examined the association between smoking and collisions often did not control for all confounding factors, such as alcohol use and driving exposure, which have been associated with increased collision rates. Additionally, a number of these studies were examined in countries and at times when prevalence of smoking was much higher than is currently the case in Canada. The purpose of this research is to examine the association between self-reported current smoking and past-year collision involvement, controlling for confounding factors, in a large representative sample of adult drivers in Ontario, Canada, from 2002 and 2014. METHOD: Data are based on the Centre for Addiction and Mental Health (CAMH) Monitor, an ongoing, rolling telephone survey of Ontario adults that provides epidemiological surveillance of indicators related to alcohol, tobacco, and other drug use, as well as physical and mental health. The survey uses random-digit dialing methods via Computer-Assisted Telephone Interview, with response rates over 50%. RESULTS: Prevalence of self-reported collision involvement within the past year for 2002-2014 was 8.6% among those who currently smoke compared to 6.5% of nonsmokers. Logistic regression analysis, controlling for the potential confounding effects of sociodemographics, driving exposure measures, drinking frequency, and hazardous alcohol use, found that the overall odds for collision involvement in the preceding year among current smokers for 2002-2014 was 1.27 (95% confidence interval [CI], 1.06-1.53) times that of nonsmokers. CONCLUSIONS: These findings indicate that despite a substantial reduction in overall prevalence of smoking in Canada, smokers still have a significantly increased odds of collision involvement, even when controlling for alcohol and exposure. Additionally, the results are consistent with the increased odds/risks of motor vehicle collisions found in other countries. PMID- 29265882 TI - Survival Forests with R-Squared Splitting Rules. AB - In modeling censored data, survival forest models are a competitive nonparametric alternative to traditional parametric or semiparametric models when the function forms are possibly misspecified or the underlying assumptions are violated. In this work, we propose a survival forest approach with trees constructed using a novel pseudo R2 splitting rules. By studying the well-known benchmark data sets, we find that the proposed model generally outperforms popular survival models such as random survival forest with different splitting rules, Cox proportional hazard model, and generalized boosted model in terms of C-index metric. PMID- 29265881 TI - The Clinical Applications of Endometrial Mesenchymal Stem Cells. AB - Endometrial mesenchymal stem cells (enMSCs) are a class of novel adult stem cells with self-renewal capacity, differentiation potential, low immunogenicity, low tumorigenicity, and other biological characteristics. Since the discovery of enMSCs, they have become a hot research topic. In recent years, research on enMSC isolation and application have made great progress. In this review, we focus on the clinical applications of this cell type. The latest research on the applications of enMSCs in the immune, gynecological, cardiovascular, digestive, nervous systems and metabolic diseases, as well as biobanking of enMSCs will be reviewed. PMID- 29265883 TI - Electron Transfer Strategies Regulate Carbonate Mineral and Micropore Formation. AB - Some microbial carbonates are robust biosignatures due to their distinct morphologies and compositions. However, whether carbonates induced by microbial iron reduction have such features is unknown. Iron-reducing bacteria use various strategies to transfer electrons to iron oxide minerals (e.g., membrane-bound enzymes, soluble electron shuttles, nanowires, as well as different mechanisms for moving over or attaching to mineral surfaces). This diversity has the potential to create mineral biosignatures through manipulating the microenvironments in which carbonate precipitation occurs. We used Shewanella oneidensis MR-1, Geothrix fermentans, and Geobacter metallireducens GS-15, representing three different strategies, to reduce solid ferric hydroxide in order to evaluate their influence on carbonate and micropore formation (micro size porosity in mineral rocks). Our results indicate that electron transfer strategies determined the morphology (rhombohedral, spherical, or long-chained) of precipitated calcium-rich siderite by controlling the level of carbonate saturation and the location of carbonate formation. Remarkably, electron transfer strategies also produced distinctive cell-shaped micropores in both carbonate and hydroxide minerals, thus producing suites of features that could potentially serve as biosignatures recording information about the sizes, shapes, and physiologies of iron-reducing organisms. Key Words: Microbial iron reduction Micropore-Electron transfer strategies-Microbial carbonate. Astrobiology 18, 28 36. PMID- 29265884 TI - Exergames to Improve the Mobility of Long-Term Care Residents: A Cluster Randomized Controlled Trial. AB - OBJECTIVE: Finding suitable and engaging ways for older people living in long term care (LTC) to engage in physical activity, to maintain function is challenging. There is a need to explore the use of exergames for LTC residents who have mobility and cognitive impairments. We investigated the effect of a group-based Xbox Kinect (Microsoft Corp., Redmond, WA) exergame program on mobility in LTC residents with and without cognitive impairment. METHODS: Facilities were randomly assigned to the intervention (four facilities, n = 29, aged 84.7 +/- 7.4 years) or control group (five facilities, n = 36, aged 85.8 +/- 7.2 years). The intervention group played Xbox Kinect exergames twice weekly for 8 weeks. The control group continued usual activities. The primary outcome measure was mobility, assessed pre- and postintervention using the de Morton Mobility Index (DEMMI). RESULTS: DEMMI scores improved in residents who played exergames, although this did not reach significance (P = 0.06). There was no interaction between cognition scores and DEMMI scores (P = 0.86). Participants attended an average of 55% of scheduled exergames sessions. CONCLUSION: The trend toward improvement in mobility, as well as attendance rates indicate that the Xbox Kinect exergames were engaging for a proportion of residents. On this basis, further exergames development for LTC residents warrants attention. PMID- 29265885 TI - Corrigendum: Exploiting Alpine glaciers as biological archives: DNA metabarcoding of ice cores extracted from the largest and deepest southern Alps glacier, Adamello, Italy. PMID- 29265886 TI - Independent factors associated with bicycle helmet use in a Korean population: A cross-sectional study. AB - OBJECTIVE: Although identification of factors that influence helmet use during bicycle riding is necessary for the selection of groups that require safe cycling education, limited baseline data are available. The aim of the present study was to analyze the rate of helmet use and the demographic factors that were independently associated with helmet use among Korean bicycle riders. METHODS: In this cross-sectional study, we used public data from the Sixth Korean National Health and Nutrition Examination Survey conducted in 2013 and 2014. Helmet users were defined as subjects who always, usually, or frequently wore helmets when cycling. Independent factors associated with helmet use were determined using odds ratios (ORss) adjusted for 5 demographic factors via multivariate logistic regression analysis. RESULTS: In the total population, 4,103 individuals were bicycle riders; among these, 782 individuals (19.1%) wore helmets. A total of 21.1% of male riders used helmets, compared to 15.5% of female riders (P <.001). The adjusted logistic regression model revealed that female sex (OR = 0.665; 95% confidence interval [CI], 0.554-0.797), teenage status (OR = 0.475, 95% CI, 0.333 0.678), and low household income (OR = 0.657, 95% CI 0.513-0.841) were significantly associated with nonuse of helmets. CONCLUSIONS: Female sex, teenage status, and low household income were independent factors associated with the nonuse of helmets. We identified factors associated with helmet use during bicycle riding through analysis of baseline data on helmet usage. PMID- 29265888 TI - Advancement in nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. AB - Cardiovascular diseases have been the major cause of mortality and morbidity all over the world accounting for more than 80% of the deaths from heart attacks and strokes. Hypercholesterolemia, an autosomal disorder of lipoprotein metabolism is one of the foremost causes of CVDs. An increased level of low-density lipoprotein cholesterol (LDL-C) in the plasma results in the rise of incidence rates in disease patients. Several conventional and combinational therapies have been proposed for lowering the LDL-C levels in the blood. These therapeutic agents are designed to target some crucial molecules that participates in the lipid metabolism such as apolipoprotein B, HMGCoA reductase, proprotein convertase subtilisin/kexin 9, etc. Although these therapies are effective but are associated with certain side effects. This article presents an overview on different conventional and nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. Numerous nanomaterial-based therapies including polymeric nanoparticles, cationic lipids, liposomes, dendrimers and inorganic nanoparticles have been discussed in lowering the cholesterol level along with recent advancement in diagnosis and imaging. PMID- 29265887 TI - Novel polyethyleneimine-R8-heparin nanogel for high-efficiency gene delivery in vitro and in vivo. AB - Gene therapy is an efficient and promising approach to treat malignant tumors. However, protecting the nucleic acid from degradation in vivo and efficient delivering it into tumor cells remain challenges that require to be addressed before gene therapy could be applied in clinic. In this study, we prepared novel polyethyleneimine-RRRRRRRR(R8)-heparin (HPR) nanogel as an efficient gene delivery system, which consists of heparin and cell penetrating peptide R8 grafted low-molecule-weight polyethyleneimine (PEI). Due to the shielding effect of heparin, crosslinking PEI-R8 with heparin was designed to diminish the toxicity of the gene delivery system. Meanwhile, a partial of R8 peptide which located on the surface of HPR nanogel could significantly enhance the cellular uptake. The formed HPR/pDNA complex exhibited effective endolysosomal escape, resulting in a high-efficiency transfection. Furthermore, the HPR could deliver the plasmid which could transcribe human TNF-related apoptosis inducing ligand (phTRAIL), into HCT-116 cells and induce significant cell apoptosis. In addition, HPR/phTRAIL complex showed satisfactory antitumor activity in abdominal metastatic colon carcinoma model. Finally, the antitumor mechanism of HPR/phTRAIL was also explored by western blot and histological analysis. The above results suggested that the HPR nanogel could serve as a promising gene delivery system. PMID- 29265889 TI - Interprofessional education and collaboration: A simulation-based learning experience focused on common and complementary skills in an acute care environment. AB - The purpose of this mixed-methods study was to explore from the participant's perspective the influence of an interprofessional simulation-based learning experience on understanding the roles and responsibilities of healthcare professionals in the acute care setting, interprofessional collaboration, and communication. Participating students from two professional programs completed the Readiness for Interprofessional Learning Scale (RIPLS) prior to and following the simulation experience to explore the influence of the simulation experience on students' perceptions of readiness to learn together. A Wilcoxon signed rank analysis was performed for each of the four subscales of the RIPLS: shared learning (<.001), teamwork and collaboration (<.001), professional identity (.042), and roles and responsibilities (.001). In addition, participating students were invited to participate in focus group interviews to discuss the effectiveness of the simulation experience. Three key themes were discovered: interprofessional teamwork, discovering roles and responsibilities, and increased confidence in treatment skills. The integration of interprofessional education through a simulation-based learning experience within the nursing and physical therapy professional programs provided a positive experience for the students. Simulation-based learning experiences may provide an opportunity for institutions to collaborate and provide additional engagement with healthcare professions that may not be represented within a single institution. PMID- 29265890 TI - Identification and analysis of knee-ankle-foot orthosis design requirements based on a feedback survey of orthosis users in India. AB - PURPOSE: The world is advancing towards a technological revolution in various fields, yet the assistive devices available for people with disability, especially in developing countries, are in the most primitive stage. For many years, lower limb orthotics has been a neglected area of research and there is an urgent need to address the problems faced by lower limb orthosis users to enable them to lead an independent life. This work is a first step in this direction and aims to identify and analyse the needs of knee-ankle-foot orthosis (KAFO) users in India. METHOD: A structured feedback survey of 29 KAFO users was conducted at three rehabilitation centres located in South India. A feedback questionnaire and a novel outcome measure tool (trigger cards) were used as means to assess user satisfaction about their existing KAFOs. The results of the survey were analysed to obtain quantitative and qualitative outcomes. RESULTS: The survey identifies various biomechanical and functional issues associated with lower limb orthosis design. The results of the survey imply that there is an urgent need to solve issues, especially related to locked orthotic knee joint design. Additionally, it sheds light on the lifestyle and socio-economic issues of KAFO users that are likely prevalent in many other low- and middle-income countries. CONCLUSIONS: The outcomes of this survey can motivate and guide researchers to design improved orthotic solutions to meet the needs of lower limb orthosis users all over the world. Implications for Rehabilitation * This is a first of its kind survey that brings forth the needs of lower limb orthosis users in India, and is an important step towards rehabilitation and empowerment of people with lower limb disability. * The pilot survey helps to identify critical areas for design improvements in a knee-ankle-foot orthosis. * The outcomes of this survey can help researchers to design functionally improved assistive devices that better meet the needs of users than currently available technology in developing countries such as India. PMID- 29265891 TI - Comparison of the immediate efficacy of the Spinomed(r) back orthosis and posture training support on walking ability in elderly people with thoracic kyphosis. AB - BACKGROUND: The effect of spinal orthoses, including the Spinomed(r) and posture training support (PTS) in improving balance and reducing falls in older people has been previously evaluated. However, there is little evidence available regarding their effect on the walking ability of older individuals with thoracic hyperkyphosis. This study was therefore designed to compare the immediate effect of the Spinomed(r) orthosis and PTS on specific gait parameters in this patient group. METHODS: A total of 34 older volunteer subjects with thoracic hyperkyphosis participated in this study and were randomly allocated into two groups, to either walk with the Spinomed(r) orthosis in situ or the PTS. The elderly mobility scale test (EMS), two-minute walk test (2-MWT), and 10-meter walk test (10-MWT) were used to evaluate their walking performance, the distance walked and their walking speed respectively. RESULTS: There were no significant differences in the mean age, body mass index (BMI), kyphosis angle, EMS, 2-MWT, and 10-MWT between the groups at baseline. All parameters were uniform amongst the two groups. The Spinomed(r) orthosis and PTS both had a positive and significant effect on the EMS score, the 2-MWT, and the 10-MWT. No significant difference was detected between two the types of orthoses in terms of the EMS score, the 2-MWT, or the 10-MWT. CONCLUSIONS: The Spinomed(r) and PTS were both effective in improving all the primary outcome measures, with similar improvements demonstrated by both orthoses. Implications for rehabilitations In this category, one of the approaches to treat the elderly with hyperkyphosis is the use of spinal orthoses such as Spinomed(r) orthosis and posture training support (PTS). The results showed that the anti-kyphosis orthosis including Spinomed(r) and PTS played effective roles in the elderly with hyperkyphosis to improve their walking function. According to the current study results, there was no significant difference between the efficacies of these orthoses in the mentioned parameters. PMID- 29265892 TI - Navigating Interprofessional Spaces: Experiences of Clients Living with Parkinson's Disease, Students and Clinical Educators. AB - When students in interprofessional education and practice programmes partner with clients living with a long-term condition, the potential for a better client and educational experience is enhanced when the focus is on client self-management and empowerment. This paper reports the findings from a phenomenological study into the experiences of five clients, six speech language therapy students, eight physiotherapy students, and two clinical educators participating in a university clinic-based interprofessional programme for clients living in the community with Parkinson's Disease. Collaborative hermeneutic analysis was conducted to interpret the texts from client interviews and student and clinical educator focus groups held immediately after the programme. The overarching narratives emerging from the texts were: "client-centredness"; "who am I/why am I here?"; "understanding interprofessional collaboration and development"; "personal and professional development, awareness of self and others"; "the environment - safety and support". These narratives and the meanings within them were drawn together to develop a tentative metaphor-based framework of "navigating interprofessional spaces" showing how the narratives and meanings are connected. The framework identifies a temporal journey toward interprofessional collaboration impacted by diverse identities and understandings of self and others, varying expectations and interpretations of the programme, intra- and interpersonal, cultural and contextual spaces, and uncertainty. Shifts in being and doing and uncertainty appear to characterise client-driven, self-management focused interprofessional teamwork for all participants. These findings indicate that students need ongoing opportunities to share explicit understandings of interprofessional teamwork and dispel assumptions, since isolated interprofessional experiences may only begin to address these temporal processes. PMID- 29265893 TI - Targeted drug delivery and drug resistant pathogens. PMID- 29265894 TI - Examining student perceptions of an inter-institutional interprofessional stroke simulation activity. AB - Integration of interprofessional educational (IPE) activities into health professions' curricula aims to promote collaborative practice with a goal of improving patient care. An interprofessional stroke simulation involving standardised patients was organised for IPE student learners from a number of different health professions programmes based across several different institutions. In this article, we describe the development of an inter institutional IPE activity and examine the outcomes of this activity on student interprofessional growth. Using a pre-post-study design, all participants were invited to anonymously respond to the 16-question IPEC Competency Self-Assessment tool to examine self-assessed interprofessional interactions and values as a result of the simulation. The questionnaire was available to the students using an online platform, and paired t-tests were used to analyse the responses. Quantitative data revealed significant positive changes in both the values and interaction domains of the assessment from pre- to post-simulation experience (p < 0.0001 and p = 0.0003, respectively). Student reflections identified new realisations around the concepts of leadership and team member roles in the context of patient care. Results of this endeavour support the effectiveness of this activity for developing interprofessional competencies among students, suggest that the self-assessment tool may be used as a means to detect these changes, and lend support to our methods for establishing inter-institutional IPE partnerships. PMID- 29265895 TI - Impact of the first interprofessional education undergraduate program in Spain. AB - In 2015, the Universidad Europea de Madrid started the first interprofessional education program in Spain. Nursing students undergo different interprofessional education activities in all four academic years, covering various aspects of the following competencies: interprofessional communication, role clarification (definition, interaction and defense), and authority models and decision making. In second year, they integrate these activities with students from psychology, pharmacy and medicine. We assessed the self-perception of second year nursing students with an adapted and validated IPEC (Interprofessional Education Collaborative) questionnaire, in four different transversal moments of the academic year 2015-16. Differences in mean values were analyzed with the Kruskal Wallis test and post-hoc Mann-Whitney tests with Bonferroni corrections in case of statistical significance. Results showed that this IPE program improves the self-perception second year students have about their competence in interprofessional communication, especially in the dimensions of oral expression, active listening, communication tools and interprofessional conflict resolution. PMID- 29265897 TI - Psyberguide: a path through the app jungle. PMID- 29265896 TI - Network analysis of multiple risk factors for mental health in young Colombian adults. AB - BACKGROUND: A considerable proportion of young adults are affected by psychological distress at any time and an important fraction of them may develop mental disorders. Use of novel approaches for the analysis of data from multiple psychological scales might facilitate the identification of key indicators of mental health. AIMS: The aim of current study was to examine the relationship between multiple risk factors for mental illness, using a network analysis perspective. METHODS: A sample of 334 young Colombian adults (mean age = 21.7) were evaluated with validated scales measuring several psychosocial factors previously associated with mental health (e.g. worry, sleep problems, suicidal ideation, childhood abuse, alcohol related-problems and personality traits). A total of 24 nodes were included in the network analysis and topology, centrality, and stability of the networks were studied. RESULTS: Specific nodes that occupied critical positions in the network were identified, with worry, perceived distress and low energy being the most central nodes. CONCLUSIONS: Our explorative findings suggest that a network analysis might identify risk factors that have a central role in the multiple dimensions of emotional health in young adults. These novel analyses could have important applications for the understanding of the psychological functioning affecting mental health. PMID- 29265898 TI - Substance use, sleep and intervention design: insights from qualitative data. AB - BACKGROUND: Alcohol and other drug use is associated with poor sleep quality and quantity, but there is limited qualitative research exploring substance users' experiences of sleep and few psychosocial sleep interventions for them. AIM: To inform the development of psychosocial interventions to improve sleep amongst people reporting drug/alcohol problems. METHOD: Qualitative data were collected during a sleep survey. Of the 549 drug/alcohol users completing the survey, 188 (34%) provided additional information about their sleep using a free text box. Responses were analysed via Iterative Categorisation. Findings were reviewed with reference to the Behaviour Change Wheel (BCW). RESULTS: All data were categorised inductively under five headings: (i) sleep quality; (ii) nature of sleep problems; (iii) sleep and substances; (iv) factors improving sleep quality; (v) factors undermining sleep quality. Substance use undermined sleep, but poor sleep often persisted after substance use had ceased. Sleep problems were diverse; as were the causes of, and strategies for dealing with, those problems. Causes and strategies had biological, psychological, social and environmental roots. CONCLUSIONS: The BCW facilitated the identification of intervention components that might improve the sleep of people who use substances. These components relate to education, training, enablement, modelling, service provision, guidelines and environment. PMID- 29265899 TI - Perceptions of balance and falls following a supervised training intervention - a qualitative study of people with Parkinson's disease. AB - PURPOSE: To explore perceptions of balance and falls among people with mild to moderate Parkinson's disease 3 - 12 months following participation in supervised balance training. MATERIALS AND METHODS: This qualitative study used in-depth individual interviews for data collection among 13 people with Parkinson's disease. Interviews were systematically analyzed using qualitative content analysis with an inductive approach. RESULTS: Three main themes arose: Falls - avoided and intended highlights the wide spectrum of fall perceptions, ranging from worse-case scenario to undramatized events; Balance identity incorporates how gradual deterioration in balance served as a reminder of disease progression and how identifying themselves as "aware not afraid" helped certain participants to maintain balance confidence despite everyday activity restriction; Training as treatment recounts how participants used exercise as disease self-management with the aim to maintain independence in daily life. Interpretation of the underlying patterns of these main themes resulted in the overarching theme Training as treatment when battling problems with balance and falls. CONCLUSIONS: Whereas certain participants expressed a fear of falling which they managed by activity restriction, others described being confident in their balance despite avoidance of balance-challenging activities. Training was used as treatment to self-manage disease-related balance impairments in order to maintain independence in daily life. Implication for Rehabilitation People with Parkinson's disease require early advice about the positive effects of physical activity as well as strategies for self-management in order to ease the psychological and physical burden of progressive balance impairment. Fear of falling should be investigated alongside activity avoidance in this group in order to provide a more accurate insight into the scope of psychological concerns regarding balance and falls in everyday life. Certain people with Parkinson's disease define their balance according to activities they continue to participate in, while others who express fear-related activity avoidance require help to adapt balance-challenging activities in order to maintain balance confidence and avoid physical inactivity. PMID- 29265900 TI - Effects of myo-inositol, gymnemic acid, and L-methylfolate in polycystic ovary syndrome patients. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder, characterized by chronic anovulation/oligomenorrhea, hyperandrogenism, and insulin-resistance. Moreover, some studies propose a possible association between insulin resistance and hyperhomocysteinemia, which is a significant long term risk for factor for atherogenesis and chronic vascular damage, especially in situations where insulin levels are increased. Insulin-sensitizing agents are used in the treatment of PCOS: in fact, inositols were shown to have insulin mimetic properties. Synergic action to myo-inositol is that of gymnemic acids that have antidiabetic, anti-sweetener, and anti-inflammatory activities. Gymnemic acid formulations have also been found useful against obesity due to their ability to delay the glucose absorption in the blood. L-methyl-folate increases peripheral sensitivity to insulin, maintaining folatemia stable, and thus restoring normal homocysteine levels. Unlike folic acid, L-methyl folate has a higher bioavailability, no drug/food interferences, high absorption, and it is stable to UV-A exposure. The aim of our study is to compare the clinical, endocrine, and metabolic parameters in 100 PCOS women treated with myo-inositol, gymnemic acid, and l-methylfolate (Group A) or myo inositol and folic acid only (Group B), continuously for 6 months. From a clinical point of view, it was noticed a more significant improvement of the menstrual cycle regularity and a more significant reduction of BMI in Group A. Moreover, a more significant decrease of total testosterone and increase of SHBG serum levels were noticed in Group A. The metabolic assessment found a more significant decrease of total cholesterol and homocysteine levels; OGTT glycemia and insulinemia values were significantly more improved after treatment with myo-inositol + gymnemic acid. In conclusion, we can state that a good option for the treatment of PCOS is the combined administration of myo-inositol + gymnemic acid + l-methyl-folate, especially for overweight/obese patients with marked insulin resistance and with associated hyperhomocysteinemia. PMID- 29265901 TI - Triplet vs. doublet drug regimens for managing multiple myeloma. AB - INTRODUCTION: Multiple Myeloma (MM) is a complex and heterogeneous plasma cell disorder. Sub-clones present before therapy and clonal evolution during therapy make this disease more resistant and finally refractory. These findings make us aware of the difficulty to target MM with few agents. Multi-drugs therapies allow us to target more pathways and more sub-clones both at diagnosis and in advanced disease. Areas covered: In this review, the authors focus on the effectiveness and tolerability of three drug regimens (triplet) in comparison with two drug regimens (doublet) and discuss their implications in the present and future of MM therapy. Expert opinion: It has been demonstrated that triplet regimens are better than doublet in terms of response rate and PFS in newly diagnosed, relapsed-refractory MM and in most patient subgroups. Whether this translates into OS improvement needs further demonstration. However, achievement of MRD negativity in most newly diagnosed and, firstly, in a consistent proportion of relapsed-refractory MM patients is very encouraging in this respect. However, not all patients are able to tolerate all triplet combinations; therefore, the choice should be based on patient characteristics, besides disease features. Finally, cost of triplets may be an important limitation in some countries. PMID- 29265903 TI - Minds treating brains: understanding the interpretation of non-contrast CT ASPECTS in acute ischemic stroke. AB - INTRODUCTION: The Alberta Stroke Program Early CT Score on non-contrast CT is a key component of prognostication and treatment selection in acute stroke care. Previous findings show that the reliability of this scale must be improved to maximize its clinical utility. Areas covered: This review discusses technical, patient-level, and reader-level sources of variability in ASPECTS reading; relevant concepts in the psychology of medical image perception; and potential interventions likely to improve inter- and intra-rater reliability. Expert commentary: Approaching variability in medical decision making from a psychological perspective will afford cognitively informed insights into the development of interventions and training techniques aimed at improving this issue. PMID- 29265902 TI - Carpe low-dose aspirin: the new anti-cancer face of an old anti-platelet drug. AB - Cancer metastasis is a dynamic process during which cancer cells separate from a primary tumor, migrate through the vessel wall into the bloodstream, and extravasate at distant sites to form secondary colonies. During this process, circulating tumor cells are subjected to shear stress forces from blood flow, and in contact with plasma proteins and blood cells of the immune and hemostatic system, including platelets. Many studies have shown an association between high platelet count and cancer metastasis, suggesting that platelets may play an occult role in tumorigenesis. This mini-review summarizes recent and emerging discoveries of mechanisms by which cancer cells activate platelets and the role of activated platelets in promoting tumor growth and metastasis. Moreover, the review discusses how aspirin has the potential for being clinically used as an adjuvant in cancer therapy. PMID- 29265904 TI - SPOTS: A Model for the Creation of Sustainable, Population-Based, Occupational Therapy Fieldwork Sites. AB - This paper describes a model for the creation of sustainable, population-based, occupational therapy fieldwork sites (SPOTS). An example of a population-based fieldwork site was created with Appalachian Mountain People in Kentucky and its outcomes are presented. Outcomes were gathered using a wide variety of evaluation feedback forms. The results indicate that all staff, student, and college feedback were extremely favorable as detailed and suggest that others may use the SPOTS Model to develop population-based occupational therapy services that address public health issues for people with disabilities identified in Healthy People 2020 and create scholarly opportunities for students and faculty. PMID- 29265905 TI - Canakinumab for secondary prevention of atherosclerotic disease. AB - INTRODUCTION: The widespread prevalence of cardiovascular disease (CVD) and its impact on morbidity and mortality requires effective secondary prevention measures. For years, inflammation has been advocated as a key mediator of atherosclerosis and its associated complications. Drugs for secondary prevention of CVD events include interventions aimed at risk factors control and antithrombotic management, but there is no drug currently recommended that specifically targets inflammation. Recently, the inflammatory hypothesis of atherosclerosis has been confirmed by a randomized clinical trial of canakinumab, a monoclonal antibody that blocks an inflammatory pathway mediated by interleukin 1beta. Areas covered: This article reviews the pharmacology of canakinumab, its current clinical development status and upcoming regulatory perspectives. Expert opinion: In the CANTOS trial, canakinumab 150 mg met the pre-specified criteria of statistical significance, showing a reduction in combined cardiovascular events, myocardial infarction, re-hospitalization due to urgent revascularization and any coronary revascularization, but no impact on all-cause or cardiovascular death. There were more death attributed to sepsis or infection with canakinumab than placebo, but fewer reports of arthritis, gout, osteaoarthritis and cancer related death. Because interleukin-1beta is only one of the potential pro inflammatory pathways that may serve as a target for atherothrombotic protection, other anti-inflammatory drugs may be the object of future investigations. If approved, the initial penetration of canakinumab will face hurdles in view of cost issues, but costs are likely to decrease if the drug loses its present status of orphan drug with the new indication. PMID- 29265906 TI - Procedural Aggressiveness in Veterans with Advanced Non-Small-Cell Lung Cancer at the End of Life. AB - BACKGROUND: Evidence suggests that the aggressiveness of care in cancer patients at the end of life is increasing. We sought to evaluate the use of invasive procedures at the end of life in patients with advanced non-small-cell lung cancer (NSCLC). OBJECTIVE: To evaluate the utilization of invasive procedures at the end of life in Veterans with advanced NSCLC. DESIGN: Retrospective cohort study of Veterans with newly diagnosed stage IV NSCLC who died between 2006 and 2012. SETTING/SUBJECTS: Subjects were identified from the Veterans Affairs Central Cancer Registry. MEASUREMENTS: All Veterans Administration (VA) and Medicare fee-for-service healthcare utilization and expenditure data were assembled for all subjects. The primary outcome was the number of invasive procedures performed in the last month of life. We classified procedures into three categories: minimally invasive, life-sustaining, and major-operative procedures. Logistic regression analysis was used to evaluate factors associated with the receipt of invasive procedures. RESULTS: Nineteen thousand nine hundred thirty subjects were included. Three thousand (15.1%) subjects underwent 5523 invasive procedures during the last month of life. The majority of procedures (69.6%) were classified as minimally invasive. The receipt of procedures in the last month of life was associated with receipt of chemotherapy (odds ratio [OR] 3.68, 95% confidence interval [CI] 3.38-4.0) and ICU admission (OR 3.13, 95% CI 2.83-3.45) and was inversely associated with use of hospice services (OR 0.35, 95% CI 0.33-0.38). CONCLUSIONS: Invasive procedures are commonly performed among Veterans with stage IV NSCLC during their last month of life and are associated with other measures of aggressive end-of-life care. PMID- 29265907 TI - DNA-PK, ATM, and ATR: PIKKing on p53. PMID- 29265909 TI - In silico modelling of influence from low or intermediate frequency magnetic fields on users of wearable insulin pumps. AB - PURPOSE: The aim was to model the effects of exposure to a low or intermediate frequency electromagnetic field (LIF-EMF), characterized by the electric field induced in the body, in order to evaluate how the type of insulin needle and the way it is injected influences the exposed user of a wearable insulin pump. MATERIAL AND METHODS: Numerical models of exposure scenarios (sources of LIF-EMF, with a dominant magnetic component: 50Hz-1MHz; the insulin needle type; the way it is injected and insulin pump user) were worked out. The influence of the insulin needle on the user's safety (the ratio of the induced electric field in tissues surrounding the needle and tissues of a person without an injection, both exposed identically) were calculated. RESULTS: The effects of LIF-EMF exposure in insulin pump users were found to be up to approximately 7-times higher, varying with statistically significance (p < .05) with the material of the needle, the way it is injected and the polarization of the affecting magnetic field. CONCLUSIONS: When steel insulin needles is used, the assessment of user's EMF exposure should be carried out using magnetic field limits at least 5-times lower than given in general international requirements. PMID- 29265911 TI - Improvements in Obstacle Clearance Parameters and Reaction Time Over a Series of Obstacles Revealed After Five Repeated Testing Sessions in Older Adults. AB - The purpose of this study was to investigate obstacle clearance and reaction time parameters when crossing a series of six obstacles in older adults. A second aim was to examine the repeated exposure of this testing protocol once per week for 5 weeks. In total, 10 older adults (five females; age: 67.0 +/- 6.9 years) walked onto and over six obstacles of varying heights (range: 100-200 mm) while completing no reaction time, simple reaction time, and choice reaction time tasks once per week for 5 weeks. The highest obstacles elicited the lowest toe clearance, and the first three obstacles revealed smaller heel clearance compared with the last three obstacles. Dual tasking negatively impacted obstacle clearance parameters when information processing demands were high. Longer and less consistent time to completion was observed in Session 1 compared with Sessions 2-5. Finally, improvements in simple reaction time were displayed after Session 2, but choice reaction time gradually improved and did not reach a plateau after repeated testing. PMID- 29265910 TI - Comparison of Photobiomodulation and Anti-Inflammatory Drugs on Tissue Repair on Collagenase-Induced Achilles Tendon Inflammation in Rats. AB - BACKGROUND: Tendinopathy is characterized by pain, edema, and structural changes in tendon tissue. OBJECTIVE: In this animal study we decided to compare the short and medium-term effects of low-level laser therapy (LLLT), dexamethasone, and diclofenac on inflammation and tendon tissue repair in collagenase-induced tendinitis. MATERIALS AND METHODS: Two hundred five female Wistar rats were randomly divided into five groups. Animals in the control group were given a saline injection and the experimental groups received a collagenase injection (100 MUg/tendon) in the peritendinous Achilles and received no treatment, LLLT (3 J, 810 nm, 100 mW), diclofenac (1.1 mg/kg), or dexamethasone (0.02 mg/kg). Histological analyses were performed at 10 time points up to 60 days (n = 5/group each time point), and included an assessment of the severity of inflammation, collagen fiber content, and organization. RESULTS: Collagenase injection induced a severe inflammatory reaction with significant reduction in collagen content for 48 h, and disorientation of collagen fibers lasting between 14 and 21 days. Diclofenac and dexamethasone reduced inflammatory signs during the first 2 days, although there was prolongation of the inflammatory phase and slower normalization of tendon quality, particularly in the dexamethasone group. LLLT prevented hemorrhage, reduced inflammation severity, and preserved tendon morphology compared with the other groups. CONCLUSIONS: LLLT showed a significant superiority over commonly used anti-inflammatory pharmaceutical agents in acute collagenase-induced tendinitis. PMID- 29265912 TI - Outcomes During a Transition Period from Open to Laparoscopic Pyloromyotomy. AB - BACKGROUND: Previous studies suggest that laparosopic pyloromyotomy may have some benefits over an open approach. We examined our results during a transition period from open to laparoscopic pyloromyotomy to see whether these benefits are sustained during the learning curve. METHODS: This is a retrospective case note review of all patients undergoing pyloromyotomy at a tertiary institution for a 5 year period (2010-2015). Data are presented as median (range). Statistical analysis was performed with Fisher's exact and Student's t-test. RESULTS: A total of 185 pyloromyotomies were performed, with data available for 90 open and 60 laparoscopic procedures. Duration of surgery was 42 (16-102) minutes for open and 28 (14-97) minutes for laparoscopic procedures (P = .0001). Total paracetamol requirements were 23.5 (0-169.4) mg/kg for open and 13.9 (0-95.3) mg/kg for laparoscopic cases (P = .008). No postoperative analgesia was required for 23 open and 29 laparoscopic patients (P = .005). Complications in the open group included incomplete pyloromyotomy (n = 1) and wound infection (n = 4); complications in the laparoscopic group included incisional hernia (n = 1), omental port-site herniation (n = 2), and suspected perforation with conversion to open procedure, although no perforation was found (n = 1; P = 1.000). CONCLUSION: Our results suggest that when the laparoscopic technique is first introduced, overall complication rates are not statistically higher, and operative times and analgesia requirements are significantly shorter, despite the learning curve. PMID- 29265913 TI - Changes in the Content of Pediatric Physical Therapy for Infants: A Quantitative, Observational Study. AB - AIMS: The aim of our observational longitudinal study is to evaluate changes over time in standard pediatric physical therapy (PPT) for infants at risk of neurodevelopmental disorders. METHODS: Treatment sessions in two time periods (2003-2005 [n = 22] and 2008-2014 [n = 16]) were video recorded and analyzed quantitatively in five categories: neuromotor actions, educational actions, communication, position, and situation of treatment session. Differences in percentages of time spent on therapeutic actions between periods were tested with Mann-Whitney U and Hodges Lehmann's tests. RESULTS: No significant changes appeared in the main categories of neuromotor actions. Time spent on not specified educational actions toward caregivers (median from 99% to 81%, p = .042) and not-specified communication (median from 72% to 52%, p = .002) decreased. Consequently, time spent on specific educational actions (caregiver training and coaching; median from 1% to 19%, p = .042) and specific communication (information exchange, instruct, provide feedback; median from 21% to 38%, p = .007) increased. Infant position changed only minimally: time spent on transitions-that is, change of position-decreased slightly over time (median from 7% to 6%, p = .042). Situation of treatment session did not change significantly over time. CONCLUSIONS: Neuromotor actions in PPT remained largely stable over time. Specific educational actions and communication increased, indicating larger family involvement during treatment sessions. PMID- 29265914 TI - The Physiology of Paragliding Flight at Moderate and Extreme Altitudes. AB - Wilkes, Matt, Martin J. MacInnis, Lucy A. Hawkes, Heather Massey, Clare Eglin, and Michael J. Tipton. The physiology of paragliding flight at moderate and extreme altitudes. High Alt Med Biol 19:42-51, 2018.-Paragliding is a form of free flight, with extreme-altitude paragliding being an emerging discipline. We aimed to describe the physiological demands and the impact of environmental stressors of paragliding at moderate and extreme altitudes. We recorded oxygen consumption (VO2), heart rate (HR), respiratory frequency (fR), tidal volume (VT), oxygen saturation, accelerometry (G), and altitude in 9.3 hours of flight at moderate altitudes (to 3073 m, n = 4), 19.3 hours at extreme altitude (to 7458 m, n = 2), and during high-G maneuvers (n = 2). We also analyzed HR data from an additional 17 pilots (138 hours) using the Flymaster Live database to corroborate our findings. All pilots were male. Overall energy expenditure at moderate altitude was low [1.7 (0.6) metabolic equivalents], but physiological parameters were notably higher during takeoff (p < 0.05). Pilots transiently reached ~7 G during maneuvers. Mean HR at extreme altitude [112 (14) bpm] was elevated compared to moderate altitude [98 (15) bpm, p = 0.048]. Differences in pilots' VT and fR at moderate and extreme altitudes were not statistically significant (p = 0.96 and p = 0.058, respectively). Thus, we conclude that physical exertion in paragliding is low, suggesting that any subjective fatigue felt by pilots is likely to be cognitive or environmental. Future research should focus on reducing mental workload, enhancing cognitive function, and improving environmental protection. PMID- 29265915 TI - A Mixed-Methods Evaluation of a Community-Based Behavior Change Program to Improve Maternal Health Outcomes in the Upper West Region of Ghana. AB - BACKGROUND: The Community Benefits Health (CBH) program introduced a community based behavior change intervention to address social norms and cultural practices influencing maternal health and breastfeeding behaviors in rural Ghana. The purpose of this study was to determine if CBH influenced maternal health outcomes by stimulating community-level support in woman's social networks. METHODS: A mixed-methods study was conducted to evaluate changes in six antenatal/postpartum care, birth attendance, and breastfeeding behaviors in response to the CBH intervention and to assess how the program was implemented and to what extent conditions during implementation influenced the results. RESULTS: We found increases in five of the six outcomes in both the intervention and control areas. Qualitative findings indicated that this may have resulted from program spillover. We considered the dose of exposure to program activities and found that women were significantly more likely to practice maternal health behaviors with increased exposure to program activities while controlling for study area and time. CONCLUSIONS: Overall, we determined that exposure to the CBH program significantly improved uptake of three of the six study outcomes, indicating that efforts aimed at increasing communication across women and their social networks may lead to improved health outcomes. PMID- 29265916 TI - Toward Calibration-Free Continuous Glucose Monitoring Sensors: Bayesian Calibration Approach Applied to Next-Generation Dexcom Technology. AB - BACKGROUND: Continuous glucose monitoring (CGM) sensors need to be calibrated twice/day by using self-monitoring of blood glucose (SMBG) samples. Recently, to reduce the calibration frequency, we developed an online calibration algorithm based on a multiple-day model of sensor time variability and Bayesian parameter estimation. When applied to Dexcom G4 Platinum (DG4P) sensor data, the algorithm allowed the frequency of calibrations to be reduced to one-every-four-days without significant worsening of sensor accuracy. The aim of this study is to assess the same methodology on raw CGM data acquired by a next-generation Dexcom CGM sensor prototype and compare the results with that obtained on DG4P. METHODS: The database consists of 55 diabetic subjects monitored for 10 days by a next generation Dexcom CGM sensor prototype. The new calibration algorithm is assessed, retrospectively, by simulating an online procedure using progressively fewer SMBG samples until zero. Accuracy is evaluated with mean absolute relative differences (MARD) between blood glucose versus CGM values. RESULTS: The one-per day and one-every-two-days calibration scenarios in the next-generation CGM data have an accuracy of 8.5% MARD (vs. 11.59% of DG4P) and 8.4% MARD (vs. 11.63% of DG4P), respectively. Accuracy slightly worsens to 9.2% (vs. 11.62% of DG4P) when calibrations are reduced to one-every-four-days. The calibration-free scenario results in 9.3% MARD (vs. 12.97% of DG4P). CONCLUSIONS: In next-generation Dexcom CGM sensor data, the use of an online calibration algorithm based on a multiple day model of sensor time variability and Bayesian parameter estimation aids in the shift toward a calibration-free scenario with even better results than those obtained in present-generation sensors. PMID- 29265917 TI - Current Targeted Therapies in HER2-Positive Gastric Adenocarcinoma. AB - Gastric cancer is one of the most common types of cancer in the world, usually diagnosed at an advanced stage. Despite the advances in specific anticancer agents' development, the survival rates remain modest, even in early stages. In 15%-20% of cases, the human epidermal growth factor receptor 2 (HER2) overexpression was identified. We conducted a general review to summarize the progress that has been made in the targeted treatment of HER2-positive esogastric junction or gastric adenocarcinoma. According to our findings, trastuzumab is the only validated anti-HER2 agent in locally advanced or metastatic disease and its adjuvant effectiveness is assessed in a RTOG phase III study. In a previously treated advanced disease, the maytansine derivate TDM 1 failed to be approved as a second-line regimen, and the tyrosine kinase inhibitor, lapatinib, shows modest results. The antiangiogenics have not been analyzed in specific populations and targeting the mesenchymal-epithelial transition factor (MET) receptor, overexpressed in up to 46% of the advanced disease, seems encouraging. Regarding the checkpoint inhibitors, based on KEYNOTE 059 multilevel ongoing trial, stratified according to the HER2 and programmed death-ligand (PD-L) 1 status, pembrolizumab was approved for third-line treatment of gastric or gastroesophageal junction adenocarcinoma. PMID- 29265918 TI - Complex of TNF-alpha and Modified Fe3O4 Nanoparticles Suppresses Tumor Growth by Magnetic Induction Hyperthermia. AB - BACKGROUND: Magnetic nanoparticles are increasingly applied in clinical area for drug delivery, also in magnetic induction hyperthermia (MIH), and so on. The present research would prepare appropriately modified superparamagnetic iron oxide nanoparticles (SPIONs) to conduct MIH and transfect the anticancer cytokine TNF-alpha into cells. MATERIALS AND METHODS: The SPIONs were surface-modified by 3-aminopropyltriethoxysilane (APTS) and/or protamine sulfate (PRO). The combined MIH using SPIONs and gene therapy were applied to treat Hep G2 cells and tumor model transplanted in nude mice. RESULTS: The PRO-SPIONs (the surfaces were sequentially modified by APTS and PRO) showed high transfection efficiency for TNF-alpha gene with no obvious cytotoxicity. It also exhibited great temperature rising performance under alternating current magnetic field. The combined MIH and gene therapy using PRO-SPIONs/TNF-alpha complex could reduce cell variability of Hep G2 cells and tumor size transplanted in nude mice. CONCLUSIONS: The PRO SPIONs efficiently transfect the TNF-alpha gene into Hep G2 cells. Cells expressed more TNF-alpha when they were exposed to alternating current magnetic field only once. Combined MIH and gene therapy for treatment in vivo exhibited better effects than MIH or gene therapy alone. The combined MIH and gene therapy is promising in liver cancer treatment. PMID- 29265919 TI - MicroRNA-497-5p Suppresses Tumor Cell Growth of Osteosarcoma by Targeting ADP Ribosylation Factor-Like Protein 2. AB - BACKGROUND: Osteosarcoma (OS) is a frequent primary bone malignancy. MicroRNA-497 5p (miR-497-5p) has been recently reported to be downregulated in angiosarcoma, but its potential role in OS remains unclear. METHODS: Quantitative real-time polymerase chain reaction was used to determine miR-497-5p expression in OS tissues and cell lines. The effect of miR-497-5p on cell growth, cell cycle progression and apoptosis were measured using CCK-8 and flow cytometry assays, respectively. The effect of miR-497-5p on ADP-ribosylation factor-like protein 2 (ARL2) was determined by luciferase reporter assay and western blot. RESULTS: We found miR-497-5p was significantly downregulated in OS tissues and cells. Overexpression of miR-497-5p in OS cells inhibited tumor cell proliferation and induced a significant G0/G1 cell cycle arrest and apoptosis in vitro. Additionally, we found ARL2 was a new target of miR-497-5p. Moreover, ARL2 and P p53 protein levels were significantly downregulated by treatment with miR-497-5p mimics in OS cells. CONCLUSIONS: Taken together, our findings revealed miR-497-5p may be a tumor suppressor in OS and serve as a promising therapeutic target for OS. PMID- 29265920 TI - Preparation of Radioactive Skin Patches Using Polyhydroxamic Acid-Grafted Cellulose Films Toward Applications in Treatment of Superficial Tumors. AB - The primary objective of this investigation is the development of a strategy for the synthesis of polyhydroxamic acid (PHA)-grafted cellulose film, its characterization, and evaluation of its usefulness for the preparation of 177Lu skin patches for superficial brachytherapy applications. PHA-grafted cellulose films were synthesized and characterized by Fourier transformed infrared spectrometer analysis and visual color test with Fe(III) solution. Uptake of 177Lu on the PHA-grafted cellulose was investigated by varying the experimental conditions such as the pH of feed solution, amount of nonradioactive Lu carrier, time, and temperature of the reaction. Under the optimized conditions, >95% loading of 177Lu on the PHA-cellulose film could be achieved. Autoradiography studies of 177Lu-PHA-cellulose film confirmed the uniform distribution of 177Lu on the surface. Energy dispersive X-ray analysis of nonradioactive Lu-PHA cellulose film confirmed the loading of Lu on PHA-cellulose film. The utility of PHA-functionalized cellulose films for the fabrication of radioactive sources for superficial brachytherapy applications could be successfully demonstrated. PMID- 29265921 TI - MicroRNA expression profiling involved in MC-LR-induced hepatotoxicity using high throughput sequencing analysis. AB - Microcystin-LR (MC-LR), the most common microcystin (MC) present in water is known to pose a significant threat to human health especially hepatotoxicity. However, the specific molecular mechanisms underlying MC-LR-induced hepatic cellular damage still remain to be determined. MicroRNAs (miRNAs) are known to play key roles in cellular processes including development, cell proliferation and responsiveness to stress. Thus, this study aimed to examine, whether miRNAs were involved in the observed MC-LR-mediated liver damage using miRNA profiling of a human normal liver cell line HL7702 using high-throughput sequencing techniques. Protein phosphatase 2A (PP2A) activity, an established biomarker of microcystin toxicity, was determined 24 hr following treatment with the algal toxin to confirm responsiveness. Data demonstrated that MC-LR significantly inhibited PP2A activity in a concentration-dependent manner with inhibitory concentration (IC50) value of 4.6 MUM. Compared with control cells, treatment with MC-LR at concentrations of 1, 2.5, 5 or 10 MUM significantly modified expression of levels of 3, 10, 9, and 99 miRNAs, respectively. Expression levels of miR-15b-3p were significantly increased in all 4 treatment groups, while miR 4521 expression levels were markedly reduced. In the case of miR-451a, 1, 5 or 10 MUM also significantly lowered expression levels. However, a significant rise in miR-451a was noted in cells exposed to 2.5 MUM toxin. The results obtained from miRNA differential expression levels were confirmed by real-time fluorescent quantitative PCR (qPCR). Gene Ontology (GO) enrichment analysis of hepatic cells demonstrated that miRNAs significantly altered were involved in systems development, metabolism, and protein binding. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis data showed that target genes of differentially expressed miRNAs in liver cells predominantly participated in mechanistic target of rapamycin kinase (mTOR), Ras, Ras-related protein 1 (Rap1), hypoxia inducible factor 1 (HIF-1), and cancer development. In summary, evidence indicates that MC-LR-induced hepatotoxicity may be associated with alterations in miRNAs. Evidence indicates that alterations in miR-451a, miR-4521 and miR-15b-3p may be involved in the observed MC-LR- induced hepatotoxicity. PMID- 29265922 TI - Comparison of Telemedicine to Traditional Face-to-Face Care for Children with Special Needs: A Quasiexperimental Study. AB - BACKGROUND: Services for Children with Special Healthcare Needs (CSHCN) have been challenging in terms of cost and access to appropriate healthcare services. OBJECTIVES: The objectives of this study were to examine cost, caring, and family centered care in relationship to pediatric specialty services integrating telemedicine visits compared to traditional face-to-face visits only for (CSHCN) in rural, remote, and medically underserved areas. METHODS: This study used a prospective, quasiexperimental research design with 222 parents or legal guardians of CSHCN receiving pediatric specialty care. The traditional group (n = 110) included families receiving face-to-face pediatric specialty care and the telemedicine group (n = 112) included families who had telemedicine visits along with traditional face-to-face pediatric specialty care. RESULTS: Results indicated no significant differences in family costs when the telemedicine group was compared to traditional face-to-face care. When the telemedicine group was asked to anticipate costs if telemedicine was not available, there were significant differences found across all variables, including travel miles, cost of travel, missed work hours, wages lost, child care cost, lodging cost, other costs, and total family cost (p < 0.001). There were no differences in the families' perceptions of care as caring. Parents/guardians perceived the system of care as significantly more family-centered when using telemedicine (p = 0.003). CONCLUSIONS: The results of this study underscore the importance of facilitating access to pediatric specialty care by use of telemedicine. We endorse efforts to increase healthcare access and decrease cost for CSHCN by expanding telemedicine and shaping health policy accordingly. PMID- 29265923 TI - Increasing Help-Seeking Outcomes among People with Elevated Depressive Symptomatology with Public Service Announcements: An Examination of Functional Matching and Message Sidedness. AB - The current experimental study assessed the utility, and potential harm, of depression public service announcements (D-PSAs) that were matched, moderately matched, or mismatched based on attitude function (i.e., social-adjustive or object-appraisal) and either one-sided or refutational two-sided. US adults (N = 567) with mild to severe depressive symptomatology were randomly assigned to view control messages or one set of D-PSAs. Results indicate that functionally matched D-PSAs, regardless of message sidedness, caused more favorable help-seeking outcome expectations, attitudes, and intentions compared to the control messages. Exposure to the mismatched D-PSAs, particularly refutational, led to less favorable help-seeking outcome expectations, attitudes, and intentions compared with the control condition. Help-seeking outcomes among those exposed to the moderately matched messages were not significantly different from those exposed to the control messages, with the exception of those exposed to the one-sided moderately matched messages. The one-sided moderately matched messages resulted in lower help-seeking intentions than the control messages. Overall, results indicate that if messages can be tailored to match the recipients' attitude functions, help-seeking outcomes among people with heightened depressive symptomatology can be increased. However, the results also indicate that some D PSAs can have negative effects. PMID- 29265924 TI - TV, Social Media, and College Students' Binge Drinking Intentions: Moderated Mediation Models. AB - Many studies to date have examined how media influence health-related behavior through social norms. However, most studies focused on traditional media. In the era of traditional and social media integration, our study advances health and mass communication scholarship by examining the influence of both traditional and social media mediated through social norms. Also, we examined a boundary condition for the norms-mediated media influence process. Namely, in the context of college binge drinking, we predict that exposure to TV and social media prodrinking messages can influence college students' binge drinking intentions through perceived peer descriptive and injunctive norms. We also predict that group identification will moderate this indirect effect. Our moderated mediation models were tested via structural equation modeling (N = 609). We found that college students' exposure to social media prodrinking messages indirectly influenced their binge drinking intentions via perceived injunctive norms, and students' identification with their peers moderated this indirect effect. However, neither descriptive nor injunctive norms mediated the influence of students' exposure to TV prodrinking messages on their binge drinking intentions. Theoretical and practical implications of the findings are discussed. PMID- 29265925 TI - Ergonomic evaluation of slide boards used by home care aides to assist client transfers. AB - Home care aides risk musculoskeletal injury because they lift and move clients; the body weight of most adults exceeds the NIOSH recommended limit for lifting. Methods to reduce manual patient lifting in institutional settings are often technically or economically infeasible in home care. Our goal was to identify suitable, safe, low-technology transfer devices for home care use. Sixteen experienced home care aides performed client transfers from wheelchair to bed (upward) and bed to wheelchair (downward) in a simulated home care environment (laboratory), using four different slide boards and by hand without a device. Aides' hand forces were measured during client transfers; aides also evaluated usability of each board. Hand forces exerted while using slide boards were mostly lower than in manual transfer, and forces were lower in downward versus upward transfers. Aides judged a board with a sliding mechanism easier to use than boards without a sliding mechanism. Practitioner Summary: This paper provides quantitative biomechanical measurements showing that slide boards reduced the hand forces needed by home care aides to transfer clients from bed to wheel chair and vice versa, compared to manual lifting. Using a semi-quantitative usability survey, aides identified boards with a sliding mechanism easiest to use. PMID- 29265926 TI - Assessing the Reproductive Health-Related Information-Seeking Behavior of Low Income Women: Describing a Two-Step Information-Seeking Process. AB - This paper explores the reproductive health-related information seeking of low income women that has been found to be affected by digital divide disparities. A survey conducted with 70 low-income women explores what information sources women use for reproductive health-related information seeking, what process they go through to find information, and if they are using sources that they trust. The findings of this study detail a two-step information-seeking process that typically includes a preference for personal, informal sources. Women of this income group often rely upon sources that they do not consider credible. While there have been many studies on the end effects of a lack of accurate and accessible reproductive health information, little research has been conducted to examine the reproductive healthcare information-seeking patterns of women who live in poverty. PMID- 29265927 TI - Post-Fordist death: A comparative ethnographic analysis of milling and mining in northern England. AB - Building on work on post-Fordist affect, we argue that the group-based and person centred forms of production in mining and milling respectively produce contingent conceptualisations of culture, identity and personhood and, in turn, of dying and death. The 'communal solidarism' characteristic of post-mining milieu engenders senses of dying and death entailing a communal merging of erstwhile individual selfhoods. In post-milling milieu dying and death are conceptualised as individuated, but subject to social evaluation. The evaluative criterion in this regard is ability to 'perform' dying and death in ways that reflect the valorised essence of local culture, identity and personhood, 'resilient autonomy'. PMID- 29265928 TI - Sharecropper's Tuberculosis: Pathologies of Power in a Fatal Outbreak. AB - Tuberculosis Bacilli (TB) is a global scourge that affects poor people and regions. Drawing on Farmer's (2003) pathologies of power, and a case study approach, we examine the sociostructural landscape of a fatal outbreak of Sharecropper's TB among African Americans in rural Alabama. In a mixed-method qualitative approach involving oral history, surveys, interviews and documentary analysis, we identified three pathologies that contribute to TB susceptibility: corporate power, land wealth, and structural racism. While medicine can cure non resistant forms of TB, control of future outbreaks will depend upon a social "cure" such as addressing structural inequality and building community trust in the health system. PMID- 29265929 TI - Investigation of mindin levels in hypertensive patients with left ventricular hypertrophy and QRS fragmentation on electrocardiography. AB - PURPOSE: Mindin was associated with diabetic nephropathy, podocyte injury, colitis, allergic asthma, liver ischaemia and reperpusion injury and ischaemic brain injury. On the other hand, it was reported as a protective factor against obesity, cardiac hypertrophy, fibrosis and remodelling. Fragmented QRS complexes (fQRS) are markers of altered ventricular depolarisation owing to a prior myocardial scar and fibrosis. In this study, we aimed to investigate mindin levels in hypertensive patients with left ventricular hypertrophy and fQRS on electrocardiography. METHODS: This observational case-control study enrolled 70 (36 female) hypertensive patients with fQRS and 38 (23 female) hypertensive control patients. All patients were evaluated by transthoracic echocardiography. Mindin levels were measured by the enzyme-linked immunosorbent assay (ELISA). Clinical, echocardiographic and laboratory data were compared between patient and control groups. RESULTS: There was no significant difference between patient and control groups in terms of clinical, echocardiographic and routine laboratory parameters. The mindin levels were significantly higher in the patient group than controls (11.3 (7.21-19.31) vs 4.15 (2.86-6.34); p < .001). Multiple logistic regression analyses defined increased mindin levels as an independent predictor for the presence of fQRS (Odds ratio: 1.733; p = .034). Mindin levels >6.74 predicted the presence of fQRS with a sensitifity of 84.3% and specificity of 79.9% on receiver operating characteristic (ROC) curve analysis (The area under the curve:0.889; Confidence Interval: 0.827-0.951; p < .001). CONCLUSION: Mindin expressin is upregulated in hypertensive patients with fQRS complexes. In contrary to previous studies, increased mindin levels may be associated with myocardial fibrosis. PMID- 29265930 TI - A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma. AB - The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos. PMID- 29265931 TI - Acoustic and kinematic analyses of Mandarin vowels in speakers with hearing impairment. AB - The central aim of this experiment was to compare acoustic parameters, formant frequencies and vowel space area (VSA), in adolescents with hearing-impaired (HI) and their normal-hearing (NH) peers; for kinematic parameters, the movements of vocal organs, especially the lips, jaw and tongue, during vowel production were analysed. The participants were 12 adolescents with different degrees of hearing impairment. The control group consisted of 12 age-matched NH adolescents. All participants were native Chinese speakers who were asked to produce the Mandarin vowels /a/, /i/ and /u/, with subsequent acoustic and kinematic analysis. There was significant difference between the two groups. Additionally, the HI group produced more exaggerated mouth and less tongue movements in all vowels, compared to their NH peers. Results were discussed regarding possible relationship between acoustic data, articulatory movements and degree of hearing loss to provide an integrative assessment of acoustic and kinematic characteristics of individuals with hearing loss. PMID- 29265932 TI - Who was that masked man? Conjoint representations of intrinsic motions with actor appearance. AB - Motion plays an important role in recognising animate creatures. This research supports a distinction between intrinsic and extrinsic motions in their relationship to identifying information about the characters performing the motions. Participants viewed events involving costumed human characters. Intrinsic motions involved relative movements of a character's body parts, whereas extrinsic motions involved movements with respect to external landmarks. Participants were later tested for recognition of the motions and who had performed them. The critical test items involved familiar characters performing motions that had previously been performed by other characters. Participants falsely recognised extrinsic conjunction items, in which characters followed the paths of other characters, more often than intrinsic conjunction items, in which characters moved in the manner of other characters. In contrast, participants falsely recognised new extrinsic motions less often than new intrinsic motions, suggesting that they remembered extrinsic motions but had difficulty remembering who had performed them. Modelling of receiver operating characteristics indicated that participants discriminated old items from intrinsic conjunction items via familiarity, consistent with conjoint representations of intrinsic motion and identity information. In contrast, participants used recollection to distinguish old items from extrinsic conjunction items, consistent with separate but associated representations of extrinsic motion and identity information. PMID- 29265933 TI - Evaluation of the safety performance of highway alignments based on fault tree analysis and safety boundaries. AB - OBJECTIVES: To overcome the limitations of previous highway alignment safety evaluation methods, this article presents a highway alignment safety evaluation method based on fault tree analysis (FTA) and the characteristics of vehicle safety boundaries, within the framework of dynamic modeling of the driver-vehicle road system. METHODS: Approaches for categorizing the vehicle failure modes while driving on highways and the corresponding safety boundaries were comprehensively investigated based on vehicle system dynamics theory. Then, an overall crash probability model was formulated based on FTA considering the risks of 3 failure modes: losing steering capability, losing track-holding capability, and rear-end collision. RESULTS: The proposed method was implemented on a highway segment between Bengbu and Nanjing in China. A driver-vehicle-road multibody dynamics model was developed based on the 3D alignments of the Bengbu to Nanjing section of Ning-Luo expressway using Carsim, and the dynamics indices, such as sideslip angle and, yaw rate were obtained. Then, the average crash probability of each road section was calculated with a fixed-length method. Finally, the average crash probability was validated against the crash frequency per kilometer to demonstrate the accuracy of the proposed method. The results of the regression analysis and correlation analysis indicated good consistency between the results of the safety evaluation and the crash data and that it outperformed the safety evaluation methods used in previous studies. CONCLUSION: The proposed method has the potential to be used in practical engineering applications to identify crash prone locations and alignment deficiencies on highways in the planning and design phases, as well as those in service. PMID- 29265934 TI - Proportional pulse pressure relates to cardiac index in stabilized acute heart failure patients. AB - AIMS: In chronic heart failure, proportional pulse pressure (PPP) is suggested as an estimate of cardiac index (CI). The association between CI and PPP in acute heart failure (AHF) has not been described. METHODS: This was examined using hemodynamic measurements (from a trial using serelaxin) in 63 stabilized AHF patients. RESULTS: Mean (SD) age was 68 (11), 74% male, mean (SD) ejection fraction (EF) was 33.4% (13.7), mean (SD) CI (L/min/m2) was 2.3 (0.6). CI correlated with PPP (Pearson R = 0.42; p < 0.0001) based on a linear mixed effects model analysis of 171 pairs of measurements from 47 patients (out of 63) where CI and PPP were measured within 3 min of each other during. Serelaxin treatment did not modify the established correlation between CI and PPP. Time weighted average CI correlated with time-weighted average PPP (Spearman Rank R = 0.35; p = 0.0051) over the -4 h to 24 h time interval. In a multivariable regression analysis, low PPP was an independent predictor of low CI (p < 0.0001). CONCLUSIONS: In patients with AHF after initial clinical stabilization, both baseline and post-baseline CI measurements are positively related to PPP. This was the most closely related non-invasive blood pressure variable to CI. PMID- 29265935 TI - Mental health and academic attitudes and expectations in university populations: results from the healthy minds study. AB - BACKGROUND: Mental health problems are highly prevalent in university populations and have been shown to impair academic performance. Yet little is known about the ways in which mental health influences academic outcomes in higher education. AIMS: This study seeks to offer new insight into the relationship between mental health and academic performance, focusing on students' academic experience and expectations as interrelated mechanisms. METHOD: Data come from 3556 students at four campuses that participated in the Healthy Minds Study. We explore unadjusted and multivariable relationships between mental health and academic experiences, expectations and impairment. RESULTS: We find significant differences by mental health status, including that one-in-four students with symptoms are dissatisfied with their academic experience, relative to one-in-ten without (p < 0.001). Approximately 30% with symptoms doubt whether higher education is worth their time, money and effort, compared to 15% without (p < 0.001). In multivariable models, mental health problems were a significant predictor of academic dissatisfaction and drop out intentions, while positive mental health was a significant predictor of satisfaction and persistence. CONCLUSIONS: This descriptive study offers further evidence of the importance of mental health for university success, identifying pathways related to students' experiences and expectations that may help to explain this relationship. PMID- 29265937 TI - Corneal Neovascularization: A Combined Approach of Bevacizumab and Suramin Showed Increased Antiangiogenic Effect Through Downregulation of BFGF and P2X2. AB - PURPOSE: The objective is to analyze the antiangiogenic mechanism of suramab, a pharmaceutical compound of bevacizumab and suramin, in a rabbit model of corneal angiogenesis. MATERIAL AND METHODS: Corneal neovascularization was induced in four groups of six New Zealand White rabbits by applying a filter paper disk soaked in 1 M Na (OH) on the central cornea. Group one was treated after injury with intravenous suramab at a dose equivalent to 3 mg/kg of bevacizumab and 10 mg/kg of suramin. Group two was treated with intravenous bevacizumab (5 mg/kg). Group three was treated with 10 mg/kg of suramin while the control group received no treatment. Digital photographs were taken at days 9, 15, 21, and 35. Neovessel formation was quantified giving a 0-4 score to each quadrant according to the centripetal growth of the longest vessel (neovessel index, NVI). Animals were sacrificed at day 35. Corneas were processed for histology, immunohistochemistry, and Western-blot using primary antibodies against P2X2, basic fibroblast growth factor (bFGF), LYVE-1, PECAM-1, and vascular endothelial growth factor-A (VEGF A). RESULTS: Suramab significantly reduced neovessel growth (mean NVI: 4.2) compared to bevacizumab (8.4), suramin (7.22), and control animals (12.2) at 35 days post-injury (p < 0.01). A lower protein expression of P2X2, bFGF, LYVE-1, PECAM-1, and VEGF-A was found in the cornea of suramab animals than in the other groups of animals. CONCLUSIONS: Joint downregulation of bFGF, P2X2, bFGF, and LYVE-1 constitutes a mechanism that induces greater and longer inhibition of corneal angiogenesis. Results might be relevant to ophthalmic care. Ocular administration of suramab is currently being investigated. PMID- 29265938 TI - Vegetative state outcomes improved over the last two decades. AB - OBJECTIVE: To describe late outcomes in patients with prolonged unawareness, and factors affecting them. DESIGN: A retrospective study of 154 patients with traumatic brain injury (TBI) and 52 with non-traumatic brain injury (NTBI), admitted for intensive care and consciousness rehabilitation (ICCR), in a vegetative state (VS) lasting over 1 month. RESULTS: Survival rate (67% total) was higher than in past studies carried out at the same facility (p < 0.01). Consciousness recovery rate (54% total) was higher in NTBI VS patients (p < 0.01) than in earlier cohorts, and similar in TBI VS patients, despite their older age than that of earlier cohorts. No meaningful differences were found in characteristics or in outcomes between the TBI and NTBI groups. Age, length of stay in ICCR, and hydrocephalus were found to affect survival (p < 0.001). Younger age, absence of hydrocephalus, and anti-Parkinsonian medication contributed to consciousness recovery after VS (p < 0.05). CONCLUSIONS: The present study demonstrated an improvement in survival and recovery of consciousness in VS patients over the last two decades, and similar outcomes for both TBI and NTBI VS. Outcomes suggest that acute medical care and ICCR have contributed to advances in VS care. PMID- 29265939 TI - One-Year Outcome of Conbercept Therapy for Diabetic Macular Edema. AB - PURPOSE: To evaluate the therapeutic efficacy of conbercept for the treatment of diabetic macular edema (DME) with different baseline visual acuity. METHODS: This is a retrospective, comparative study. A total of 107 eyes of 107 patients were included. According to the levels of baseline best corrected visual acuity (BCVA) and therapeutic regimen, the DME patients were divided into four groups: conbercept treatment subgroup with worse baseline VA (less than 69 letters, Snellen equivalent, 20/50 or worse; n = 37), untreated subgroup with worse baseline VA(n = 28); conbercept treatment subgroup with better baseline VA (78 to 69 letters, Snellen equivalent, 20/32 to 20/40; n = 25), untreated subgroup (n = 17). Patients received one initial intravitreal injection followed by re treatments based on BCVA loss or increase of central macular thickness (CMT). RESULTS: At month 12, the mean improvement of BCVA was significantly higher in both worse baseline VA group and better baseline VA group with conbercept treatment than that of corresponding untreated controls:18(15) letters vs. -4(6) letters, P < 0.001; 7(1) letters vs. -5(5) letters; P < 0.001; respectively. At month12 the mean CMT from baseline was significantly declined in both worse baseline VA group and better baseline VA group with conbercept treatment than that of respective untreated controls (-212.8 +/- 11.9 vs.-44.3 +/- 35.3um,P < 0.001; -116.1 +/- 88.9vs.-33.7 +/- 49.8um, P = 0.001; respectively). At the end of twelve month follow-up, the BCVA improvement and CMT declination in worse baseline VA group were more prominent than that in better baseline group (P < 0.001). The mean numbers of injections were 6.7 +/- 0.9, 6.5 +/- 1.1 in worse baseline VA group and better baseline VA group, respectively (P = 0.35). The two groups have no significant difference in the number of injections. CONCLUSION: Conbercept was effective in the treatment of DME at different levels of baseline BCVA. For worse baseline VA, BCVA improvement was more prominent than that of better VA subgroup. PMID- 29265940 TI - Wisteria floribunda agglutinin positive glycobiomarkers: a unique lectin as a serum biomarker probe in various diseases. AB - INTRODUCTION: Serum proteins are generally glycosylated and solubilized, and are thus present as glycoproteins. The glycan structure of glycoproteins reflects cell differentiation status; glycan structures generated by diseased cells are distinguishable from those produced by healthy cells. Proteins may therefore serve as markers of tissues that secrete them. Several strategies for the identification of novel serum biomarkers using a combination of glycoscience based technologies have been recently proposed. The selection of lectins for use as probes for identification of altered glycan structures represents a critical step. Areas covered: This review describes the identification of Wisteria floribunda agglutinin (WFA) as a probe that recognizes the altered glycan structure of glycoproteins secreted by diseased cells. WFA may be employed as a probe for several diseases, e.g., liver fibrosis, liver cirrhosis, prostate cancer, ovarian cancer, and IgA nephropathy. The advantage of employing WFA as a serum biomarker probe is that only very small amounts of WFA-positive glycoproteins are present in serum; therefore, WFA background in serum is very low. Expert commentary: Based on the findings to date, several WFA-positive serum biomarkers may be measured without pre-purification of target glycoproteins, indicating their utility as serum biomarkers in patients with various diseases. PMID- 29265941 TI - Barriers to employment for people with severe mental illness and criminal justice involvement. AB - BACKGROUND: People with severe mental illness (SMI) and criminal justice involvement (CJI) are able to achieve competitive employment when provided with evidence-based services, but outcomes are modest compared to studies of SMI in general. AIMS: To investigate barriers to employment facing people with SMI and CJI receiving employment services. METHOD: Employment service providers assessed top three barriers to employment for 87 people with SMI and CJI enrolled in a randomized controlled trial comparing a job club program to supported employment. Main barriers were identified and differences between programs were analyzed. Associations between barriers and client background characteristics were investigated. RESULTS: The most common barriers were failure to engage and disengagement from services, followed by substance abuse. Staff from the two employment programs reported similar barriers. CONCLUSIONS: Engagement problems were the single most important barrier to employment across programs. Surprisingly, criminal history was rarely mentioned. This may be explained by barriers arising earlier in the process, before achieving employer contact. The results call for recognition and awareness of the importance of motivational issues as well as factors that may inhibit engagement in services, highlighting possible augmentations to evidence-based employment services that may be necessary in the rehabilitation of this patient group. PMID- 29265942 TI - Central Corneal Thickness of Healthy Lowlanders at High Altitude: A Systematic Review and Meta-Analysis. AB - PURPOSE: Central corneal thickness, a marker of corneal hydration and metabolism, was reported to increase at high elevations. This study aimed to assess the effect of chronic high-altitude exposure on the central corneal thickness of healthy lowlanders with unoperated corneas, and determine if a relationship exists between exposure time and corneal edema formation. MATERIALS AND METHODS: The PubMed, Embase, Scopus, Cochrane Library, and Airiti Library databases were searched up to 2017 January 31 for prospective cohort studies performed above 2500 m in healthy lowlanders with measurements of the central corneal thickness. Subjects with prior eye surgery, contact lens, and non-hypobaric hypoxic exposure were excluded. RESULTS: Seven studies of 207 adults were included. The pooled effect of high-altitude exposure on the central corneal thickness for < 12 hours, 3-5 days, 6-7 days, and > 10 days was a mean difference of 13.4 (95% confidence interval: 5.1-21.6) MUm with moderate heterogeneity (p < 0.05, I2 = 59%), 19.3 (95% confidence interval: 9.7-29) MUm with low heterogeneity (p = 0.88, I2 = 0%), 20.4 (95% confidence interval: 10.3-30.5) MUm with low heterogeneity (p = 0.73, I2 = 0%), and 30.8 (95% confidence interval: 20.4-41.2) MUm with low heterogeneity (p = 0.69, I2 = 0%), respectively. Baseline differences between pre exposure and post-exposure were not statistically significant. Regression analysis revealed a significant linear relation between high-altitude exposure time and corneal edema formation that exceeded 5% after 10 days. CONCLUSIONS: High-altitude exposure induces central corneal thickening with significant linear progression over time, whereas it takes over 10 days to reach clinical significance in healthy lowlanders with unoperated corneas, and changes in central corneal thickness are reversible after descent to lower elevations. PMID- 29265943 TI - "You Cannot Cure It, Just Control It": Jamaican Adolescents Living With Diabetes. AB - Although adolescence is considered a difficult time for diabetes management, there is little published qualitative research on adolescent Jamaicans with diabetes. This study investigates the experiences of Jamaican adolescents living with diabetes to determine how their needs can be addressed. Nineteen adolescents participated in two urban and two rural focus groups and were asked to draw pictures representing their experiences. Thematic analysis was used to analyze their narratives, while their drawings were analyzed using a variation of Lauritsen and Mathiasen's (2003) method. Results show that control was the central theme: children felt controlled by diabetes and the people in their lives. Diabetes restricted their activities and imposed a sense of difference. Support from those around them could be both helpful and constricting. Children tried to resist control through disregarding the rules, being secretive, defiant, and manipulating others into allowing nonadherence. They also tried to adhere to the rules, find a balance between following them and engaging in desired activities, and to be positive. Those most positive about living with diabetes did not feel controlled by diabetes or others' understandings of it and, with loved ones' support, had rejected diabetes' negative meanings. Extreme distress was felt by rural children. All children had been noncompliant. Healthcare practitioners and policymakers should provide education in schools to facilitate fair and effective treatment. Mental health specialists should assist children to negotiate stigma and distress. Group sessions with significant others are important for collaborative decisions on enabling support. PMID- 29265945 TI - Reducing university students' stress through a drop-in canine-therapy program. AB - BACKGROUND: Increasingly colleges and universities are offering canine therapy to help students de-stress as a means of supporting students' emotional health and mental well-being. Despite the popularity of such programs, there remains a dearth of research attesting to their benefits. AIMS: Participants included 1960 students at a mid-size western Canadian University. The study's aims were to assess the stress-reducing effects of a weekly drop-in, canine-therapy program and to identify how long participants spent with therapy canines to reduce their stress. METHODS: Demographic information was gathered, length of visit documented and a visual analog scale (VAS) was used to assess entry and exit self-reports of stress. RESULTS: Participants' self-reported stress levels were significantly lower after the canine therapy intervention. Participants spent an average of 35 min per session. CONCLUSIONS: This study supports the use of drop-in, canine therapy as a means of reducing university students' stress. The findings hold applied significance for both counseling and animal therapy practitioners regarding the dose intervention participants seek to reduce their stress. PMID- 29265946 TI - How successful has targeted RNA interference for hepatic fibrosis been? AB - INTRODUCTION: Exposure to toxins from the portal circulation, viral infection and by-products of metabolic activity make liver tissue prone to injury. When sustained, associated inflammation leads to activation of hepatic stellate cells (HSCs), deposition of extracellular matrix (ECM) proteins and complicating hepatic fibrosis. Areas covered: In this article, the authors discuss utility of therapeutic gene silencing to disable key steps of hepatic fibrogenesis. Strategies aimed at inhibiting HSC activation and silencing primary causes of fibrogenesis, such as viruses that cause chronic hepatitis, are reviewed. Both synthetic and expressed artificial intermediates of the RNAi pathway have potential to treat hepatic fibrosis, and each type of gene silencer has advantages for clinical translation. Silencing expression cassettes comprising DNA templates are compatible with efficient hepatotropic viral vectors, which may effect sustained gene silencing. By contrast, synthetic short interfering RNAs are amenable to chemical modification, incorporation into non-viral formulations, more precise dose control and large scale preparation. Expert opinion: Clinical translation of RNAi-based technology for treatment of hepatic fibrosis is now a realistic goal. However, achieving this aim will require safe, efficient delivery of artificial RNAi intermediates to target cells, economic large scale production of candidate drugs and specificity of action. PMID- 29265944 TI - Antibiotic Powder Reduces Surgical Site Infections in Children After Single Incision Laparoscopic Appendectomy for Acute Appendicitis. AB - BACKGROUND: Single-incision laparoscopic appendectomy (SILA) has a higher rate of wound infection than the multiport technique. The purpose of this project was to determine whether the use of topical antibiotic powder reduces surgical site infections (SSIs) in pediatric patients who undergo SILA. METHODS: Patients aged 0-21 years who underwent SILA for acute appendicitis from April 2015 to November 2016 were included in this quality improvement initiative. Cefoxitin powder was placed in the umbilical wound before skin closure. Data were prospectively collected and outcome measures were compared with a historical cohort who underwent SILA before the implementation of antibiotic powder. RESULTS: There were 108 patients in the historical group (HIST) and 126 in the powder group (POWD). The groups were similar in age (HIST: 11.5 +/- 3.6 versus POWD: 12.2 +/- 3.7 years, P = .15) and body mass index percentile (HIST: 57.6 +/- 30.7 versus POWD: 58.8 +/- 27.8, P = .84). Operative time was longer in the powder group (HIST: 26.5 +/- 7.5 versus POWD: 29.7 +/- 8.9 minutes, P = .004). Length of stay (HIST: 0.2 +/- 0.4 versus POWD: 0.1 +/- 0.4 days, P = .06), 30-day return to emergency department (HIST: 7% versus POWD: 8%, P = 1.0), and hospital readmissions (HIST: 5% versus POWD: 2%, P = .8) were similar. There was a significantly lower rate of superficial SSIs in the powder group (HIST: 4.6% versus POWD: 0%, P = .02). CONCLUSIONS: In pediatric patients undergoing SILA for acute appendicitis, the use of cefoxitin powder in the umbilical wound is a simple intervention to reduce the incidence of superficial SSIs. PMID- 29265947 TI - DNA methylation at the 9p21 glaucoma susceptibility locus is associated with normal-tension glaucoma. AB - PURPOSE: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. METHODS: We conducted a retrospective case-control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. RESULTS: We identified one CpG site (F1:13 14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. CONCLUSION: This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene. PMID- 29265948 TI - Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin. AB - BACKGROUND: Biliary tract cancer (BTC) is an uncommon cancer with an unfavorable prognosis. Since 2010, the standard of care for patients with unresectable BTC is palliative treatment with gemcitabine plus cisplatin, based on the landmark phase III ABC-02 trial. This current study aims to evaluate the efficacy and safety of gemcitabine and cisplatin in patients with unresectable cholangiocarcinoma and gallbladder cancer in daily practice that meet the criteria for the ABC-02 trial in comparison to patients who did not. METHODS: Patients diagnosed with unresectable BTC between 2010 and 2015 with an indication for gemcitabine and cisplatin were included. We divided these patients into three groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who had an indication for chemotherapy, but received best supportive care without chemotherapy. Primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS). RESULTS: We collected data of 208 patients, of which 138 (66.3%) patients received first line chemotherapy with gemcitabine and cisplatin. Median OS of 69 patients in group I, 63 patients in group II and 65 patients in group III was 9.6 months (95%CI = 6.7-12.5), 9.5 months (95%CI = 7.7-11.3) and 7.6 months (95%CI = 5.0-10.2), respectively. Median PFS was 6.0 months (95%CI = 4.4-7.6) in group I and 5.1 months (95%CI = 3.7-6.5) in group II. Toxicity and number of dose reductions (p = .974) were comparable between the two chemotherapy groups. CONCLUSION: First-line gemcitabine and cisplatin is an effective and safe treatment for patients with unresectable BTC who do not meet the eligibility criteria for the ABC-02 trial. Median OS, PFS and treatment side effects were comparable between the patients who received chemotherapy (group I vs. group II). PMID- 29265950 TI - Biodegradable composite porous poly(dl-lactide-co-glycolide) scaffold supports mesenchymal stem cell differentiation and calcium phosphate deposition. AB - In recent decades, tissue engineering strategies have been proposed for the treatment of musculoskeletal diseases and bone fractures to overcome the limitations of the traditional surgical approaches based on allografts and autografts. In this work we report the development of a composite porous poly(dl lactide-co-glycolide) scaffold suitable for bone regeneration. Scaffolds were produced by thermal sintering of porous microparticles. Next, in order to improve cell adhesion to the scaffold and subsequent proliferation, the scaffolds were coated with the osteoconductive biopolymers chitosan and sodium alginate, in a process that exploited electrostatic interactions between the positively charged biopolymers and the negatively charged PLGA scaffold. The resulting scaffolds were characterized in terms of porosity, degradation rate, mechanical properties, biocompatibility and suitability for bone regeneration. They were found to have an overall porosity of ~85% and a degradation half time of ~2 weeks, considered suitable to support de novo bone matrix deposition from mesenchymal stem cells. Histology confirmed the ability of the scaffold to sustain adipose-derived mesenchymal stem cell adhesion, infiltration, proliferation and osteo differentiation. Histological staining of calcium and microanalysis confirmed the presence of calcium phosphate in the scaffold sections. PMID- 29265949 TI - Secondary Analysis of Existing Datasets for Dementia and Palliative Care Research: High-Value Applications and Key Considerations. AB - OBJECTIVE: To provide a guide to researchers selecting a dataset pertinent to the study of palliative care for people with dementia and to aid readers who seek to critically evaluate a secondary analysis study in this domain. BACKGROUND: The impact of dementia at end-of-life is large and growing. Secondary dataset analysis can play a critical role in advancing research on palliative care for people with dementia. METHODS: We conducted a broad search of a variety of resources to: 1. identity datasets that include information germane to dementia and palliative care research; 2. review relevant applications of secondary dataset analysis in the published literature; and 3. explore potential validity and reliability concerns. RESULTS: We synthesize findings regarding: 1. Methodological approaches for determining the presence of dementia; 2. Inclusion and measurement of key palliative care items as they relate to people with dementia; and 3. Sampling and study design issues, including the role and implications of proxy-respondents. We describe and compare a selection of high value existing datasets relevant to palliative care and dementia research. DISCUSSION: While secondary analysis of existing datasets requires consideration of key limitations, it can be a powerful tool for efficiently enhancing knowledge of palliative care needs among people with dementia. PMID- 29265951 TI - Age- and sex-based ranges of platelet count and cause-specific mortality risk in an adult general population: prospective findings from the Moli-sani study. AB - Platelet count varies by age, sex and ethnicity. However, previous studies have adopted standard ranges to identify subjects with thrombocytopenia or thrombocytosis. The aim of this study was to test the predictive role of age-sex based cut-offs of platelet count proposed by an Italian collaborative study, towards the risk of cause-specific death. We conducted a prospective analysis on 21,563 adult subjects (mean age 55.6 +/- 11.8) randomised from the general population of the Moli-sani study. Hazard ratios (HR) were calculated by multivariable Cox-proportional hazard models with 95% confidence intervals. Over a median follow-up of 8.2 years (interquartile range: 7.3 to 9.2 years; 175,972 person-years), we ascertained and validated 1,130 deaths, 415 of which are from cardiovascular disease, 439 from cancer and 276 from non-vascular/non-cancer causes. As opposed to the normal ranges defined by age and sex (extreme values from 122 to 405 x109/L), lower platelet number (87.7% of values being higher than 100x109/L) was associated with increased risk of total (HR = 1.92; 95%CI 1.38 2.67), cancer (HR = 1.77; 95%CI 1.03-3.05), and non-cardiovascular/non-cancer mortality (HR = 3.16; 95%CI 1.84-5.42) but was unrelated to cardiovascular mortality. Higher platelet count was not associated with any death risk. In conclusion, age-sex-based low platelet count, well above the traditional lower normal range of <100 x109/L, is associated with increased total and specific mortality risk in a general population. PMID- 29265952 TI - Stories of contemporary aging: An analysis of "lived" citizenship in later life. AB - The new political economy of aging portrays "active citizenship" among seniors as a key challenge for the years to come. As a policy framework, Active Aging ranks high on the agendas of most supranational bodies. Informed by discourse analysis and a narrative approach, this article focuses on, first, older women's everyday "active" practices, their meaning, and purpose and second, their day-to-day practical citizenship and social engagement experiences. A typology consisting of four figures of "lived" citizenship is proposed. Social contribution in later age is expressed through various types of engagement identified through these citizenship figures. These figures support older women's social anchoring and sustain their feeling of belonging to the community. However, the figures outlined also reveal tensions, produced by relations of power between "dominant citizenship" and "relational citizenship," pertaining to social relations and to caring for the other. In the latter case, we see that the coupling of action between the choice of action and social engagements in later age is more limited, due to social and health inequalities as well as lack of opportunities throughout the life course. Finally, in order to guarantee the right to age with dignity, we suggest a change of orientation in aging policies. PMID- 29265953 TI - Percutaneous Transhepatic Gallbladder Drainage Combined with Laparoscopic Cholecystectomy: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To investigate the clinical effect of the laparoscopic cholecystectomy (LC) after percutaneous transhepatic gallbladder drainage (PTGD) in elder acute cholecystitis. METHODS: The Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang Databases were searched for randomized controlled trials (RCTs) on LC after PTGD in elder acute cholecystitis published from 1970 to July 2017. Two researchers selected RCTs, extracted data, and evaluated methodological quality independently, and RevMan 5.3 software was used for the meta-analysis. The chi-square test was used for heterogeneity analysis of RCTs included, and the funnel plots were used to evaluate publication bias. RESULTS: A total of 9 RCTs with 1000 patients were included in this analysis. Compared with the direct LC Group, the PTGD Group has significant better effect in operative duration (minutes) [standard mean difference (SMD) = -1.37, 95% confidence interval (95% CI): -2.52 to -0.22, P = .02], the amount of intraoperative bleeding (mL) (SMD = -1.38, 95% CI: -2.11 to -0.65, P = .0002), conversion rate to laparotomy (%) [odds ratio (OR) = 0.16, 95% CI: 0.08 to 0.31, P < .00001], postoperative complication morbidity (%) (OR = 0.29, 95% CI: 0.17 to 0.51, P < .0001), and postoperative hospital stay (days) (SMD = -1.26, 95% CI: 1.94 to -0.59, P = .0003). The funnel plots were slightly asymmetric, which suggested the presence of publication bias. CONCLUSION: The PTGD before scheduled LC can effectively not only shorten operative duration, intraoperative bleeding less, and postoperative hospital stay but also decrease the rate to laparotomy and postoperative complication morbidity in elder acute cholecystitis, and it is recommended to be regarded as the preferred therapy of the elder patients. PMID- 29265954 TI - What Is the Proportion of Studies Reporting Patient and Practitioner Satisfaction with Software Support Tools Used in the Management of Knee Pain and Is This Related to Sample Size, Effect Size, and Journal Impact Factor? AB - INTRODUCTION: E-health software tools have been deployed in managing knee conditions. Reporting of patient and practitioner satisfaction in studies regarding e-health usage is not widely explored. The objective of this review was to identify studies describing patient and practitioner satisfaction with software use concerning knee pain. MATERIALS AND METHODS: A computerized search was undertaken: four electronic databases were searched from January 2007 until January 2017. Keywords were decision dashboard, clinical decision, Web-based resource, evidence support, and knee. Full texts were scanned for effect of size reporting and satisfaction scales from participants and practitioners. Binary regression was run; impact factor and sample size were predictors with indicators for satisfaction and effect size reporting as dependent variables. RESULTS: Seventy-seven articles were retrieved; 37 studies were included in final analysis. Ten studies reported patient satisfaction ratings (27.8%): a single study reported both patient and practitioner satisfaction (2.8%). Randomized control trials were the most common design (35%) and knee osteoarthritis the most prevalent condition (38%). Electronic patient-reported outcome measures and Web based training were the most common interventions. No significant dependency was found within the regression models (p > 0.05). DISCUSSION AND CONCLUSIONS: The proportion of reporting of patient satisfaction was low; practitioner satisfaction was poorly represented. There may be implications for the suitability of administering e-health, a medium for capturing further meta evidence needs to be established and used as best practice for implicated studies in future. This is the first review of its kind to address patient and practitioner satisfaction with knee e-health. PMID- 29265955 TI - Challenges to Developing a Rotavirus Vaccine. AB - Rotavirus is the most important cause of gastroenteritis worldwide. In developing countries, the virus is a major cause of death in infants and young children. In the United States, before the licensure of vaccines, rotavirus infections accounted for ~2.7 million cases of gastroenteritis annually. Here are described the history and challenges surrounding the development of a rotavirus vaccine. PMID- 29265956 TI - Comparative Safety of Needle, EndoActivator, and Laser-Activated Irrigation in Overinstrumented Root Canals. AB - OBJECTIVE: To evaluate the safety of sodium hypochlorite (NaOCl) irrigation using three different techniques during the final rinse in overinstrumented root canals. BACKGROUND DATA: The effect of irrigant activation on irrigant extrusion from overinstrumented root canals is still unclear. METHODS: A total of 30 single rooted teeth were decoronated. The working lengths were determined and the roots were divided into two groups of 15 teeth each: group 1, instrumentation 0.5 mm short of the apical foramen and group 2, instrumentation 0.5 mm beyond the apical foramen (overinstrumented). Needle irrigation (NI), sonic irrigation with EndoActivator (EAI), and laser-activated irrigation (LAI) were used for the final rinse in each group; each root underwent the three irrigation procedures in a randomized crossover manner. A modified container-foam model was used to collect apically extruded NaOCl. The weight of the extruded NaOCl was calculated by subtracting the initial weights of the containers from their final weights. All data were statistically analyzed. RESULTS: The amount of NaOCl extrusion was similar with all three irrigation systems in group 1. In group 2, the amount of extruded NaOCl was significantly greater with EAI than with NI and LAI. EAI and LAI caused significantly greater extrusion in group 2 than in group 1. CONCLUSIONS: EAI, NI, and LAI are equally safe for irrigating canals with intact apices. However, the risk of irrigant extrusion can increase in overinstrumented canals, with EAI associated with a greater risk compared with NI and LAI. PMID- 29265958 TI - Insights Gained from an Online Journal Club for Fieldwork Educators. AB - Academic programs are tasked with the responsibility of providing support for fieldwork educators who provide training for their students. This article describes a pilot program wherein nine fieldwork educators participated in a weekly online journal club to gain increased knowledge of evidence-based supervision strategies. Program assessment indicated that an online journal club was feasible and well accepted by the fieldwork educators and that the participants valued the opportunity to connect and discuss the role with other fieldwork educators. PMID- 29265960 TI - Who does she think she is? Women, leadership and the 'B'(ias) word. AB - OBJECTIVE: Despite the increasing number of women in professional fields, women are under-represented in leadership roles. The goal of this paper is to identify potential explanations for the gender gap in leadership. METHOD: The academic literature with respect to gender roles, leadership, and organizational expectations; gender differences in leadership; and the potential role of second generation bias was reviewed. RESULTS: Women are as effective as male leaders in a variety of organizational settings. The role congruity theory suggests that women are placed in a double bind: maintenance of their gender role may result in a failure to meet the requirements of a leader role whereas conforming to a leader role may result in the failure to conform to their gender role. Second generation, or implicit, bias also influences women's leadership opportunities. This is further complicated by expectations that women will engage in more altruistic organizational citizenship behaviors or be penalized. CONCLUSION: Differences in ability do not account for the gender gap in leadership. Cultural factors, including gender role and leadership expectations, organizational demands, and second-generation bias impact women's ability to lead. Pragmatic recommendations to increase women's influence and representation in leadership are provided. PMID- 29265959 TI - Seventeen years of human trafficking research in social work: A review of the literature. AB - The trafficking of persons around the world is a serious violation of human rights and manifestation of social injustice. It disproportionately affects women and children worldwide. Given the values of the social work profession and the prevalence of trafficking, it is essential to understand the current literature on human trafficking in social work journals. Using the PRISMA method, this systematic review (n = 94 articles) of human trafficking in social work journals found the following: more focus on sex trafficking than other forms of trafficking; a lack of a clear conceptualization and definition on the entire spectrum of trafficking; a lack of evidence-informed empirical research to inform programs, practice, and policy; and a dearth of recommendations for social work education. Specific implications for social work policy, research, practice, and education are highlighted and discussed. PMID- 29265961 TI - Framework for assessing individuals with rare genetic disorders associated with profound intellectual and multiple disabilities (PIMD): the example of Phelan McDermid Syndrome. AB - BACKGROUND: Specialized strategies are needed to understand the complex neuropsychological impairments reported in individuals with profound intellectual and multiple disabilities (PIMD) associated with rare genetic disorders. METHODS: This narrative review focuses on assessment of individuals with Phelan-McDermid Syndrome (PMS) as a condition commonly associated with PIMD. Published case series and prospective studies were reviewed to evaluate approaches to cognitive, language, motor/sensory, and behavioral domains. This review is framed using general principles for neuropsychological evaluation in PIMD. RESULTS: Neuropsychological assessment domains and tools varied across published reports. Adaptive behavior measures, out-of-range developmental assessments, and social communication measures were commonly used. Available findings were used to shape a recommended framework with potential to improve measurement of clinical outcomes and advance scientific discovery. CONCLUSIONS: The recommended framework outlines an inter-disciplinary and multimodal neuropsychological assessment process relying on modified standardized assessments, functional assessments, and caregiver/informant reports when evaluating individuals with PIMD. Arrested development and skill variability/regression are also discussed as additional, important considerations in neuropsychological evaluation of individuals with PIMD and rare genetic disorders. PMID- 29265962 TI - Life's end: Ethnographic perspectives. AB - In this introduction to the special issue, Life's End: Ethnographic Perspectives, we review the field of anthropological studies of death and dying. We make the argument that, largely because of its sub-disciplining into the larger field of the anthropology of religion, ritual and symbolism, the focus of anthropological research on death has been predominantly on post- rather than pre-death events, on death's beginnings rather than life's ends. Additionally, we argue that an anthropological aversion to the study of dying may also lie in the intimacy of the discipline's principal method, ethnography. Contrastingly, we argue that this very methodological intimacy can be a source of insight, and we offer this as a rationale for the special issue as a whole, which comprises eight ethnographic studies of dying and social relations at life's end from across Africa, Australia, Europe, and North America. Each of these studies is then summarized, and a rationale for their presentation around the themes of "structures of dying," "care for the dying," "hope in dying," and "ending life" is presented. PMID- 29265963 TI - Hospital Outbreak of a Colistin-Resistant, NDM-1- and OXA-48-Producing Klebsiella pneumoniae: High Mortality from Pandrug Resistance. AB - Colistin resistance causes substantial problems in the treatment of serious infections with carbapenem-resistant (CR) gram-negative bacteria. In this study, we report a fatal hospital outbreak from the spread of a pandrug-resistant Klebsiella pneumoniae clone. An outbreak investigation was conducted after consecutive isolation of nine CR-K. pneumoniae (CR-Kp) strains from eight patients in two intensive care units of a university hospital within 2 weeks. Carbapenem and colistin resistance genes were investigated with PCR, clonal relationships of isolates were studied with pulse-field gel electrophoresis, and multilocus sequence types were determined. The outcomes of the affected patients were analyzed. Genotyping showed a predominant CR-Kp clone consisting of seven strains from six patients. These strains were in ST11 type, an international high risk clone. They were resistant to all antimicrobials, including colistin, and positive for NDM-1 and OXA-48 carbapenemases, but negative for plasmid-borne colistin resistance genes. One patient had colonization and the remaining five died due to the infection within mean 12 days. No environmental or staff links could be established, and the outbreak was stopped by augmenting infection control measures. Colistin-resistant K. pneumoniae could clonally expand in the hospital setting, and this spread might be associated with high mortality due to the lack of an appropriate treatment option. Immediate implementation of infection-control measures may be the best way to limit fatal consequences of the spread of such incurable pathogens. PMID- 29265966 TI - Uveitic Ocular Hypertension and Glaucoma. PMID- 29265967 TI - Design and Interpretation of Clinic-Based Studies in Uveitis. PMID- 29265969 TI - Therapeutic Advances in Germany and Beyond. PMID- 29265968 TI - Pathogenesis and Pathology of Intraocular Tuberculosis. AB - Intraocular tuberculosis (TB) is an extremely paucibacillary form of extrapulmonary TB. It likely results from bacterial dissemination to the eye from lungs, localization in ocular tissues, followed later by reactivation and appearance of clinical signs. These have been partly demonstrated in the guinea pig model of ocular TB. Alternative hypotheses have been suggested but are not supported by adequate evidence. Mycobacterial recognition by macrophages and dendritic cells probably leads to activation of several immune pathways, primarily the Th1 and Th17 pathways, as in other TB infections. Histopathology of bacteriologically proven ocular TB tissues reveals granulomatous inflammation with central caseous necrosis containing occasional acid-fast organisms. Recent reports have also demonstrated intraretinal granuloma in the vicinity of retinal vessels and T-cell infiltration of epiretinal membranes, in cases of TB retinal vasculitis. PMID- 29265970 TI - The Faculty Athletic Training Program: A Model. AB - In brief Most high schools lack funds to hire a full-time trainer. This article describes a pilot program that trained 43 employed teachers to become certified athletic trainers. After completing the course, 40 of the 43 are currently working either as formally recognized athletic trainers or are bringing more understanding of injury prevention, recognition, and care to their teaching and coaching roles. Parents, coaches, and administrators associated with these individuals now recognize their value and are hiring more athletic trainers. PMID- 29265971 TI - Exercise, Body Weight, and Amenorrhea in Professional Ballet Dancers. AB - In brief Thirty-two professional female ballet dancers were studied by means of a gynecological questionnaire to determine the prevalence of menstrual dysfunction. Thirty-seven percent had a history of amenorrhea (p <.01 compared with controls). Forty-seven percent had a history of menstrual dysfunction manifested by delayed menarche, amenorrhea, or oligomenorrhea (p <.001 compared with controls). Menstrual dysfunction was related to both strenuous physical exercise and diminished body weight, and it was reversible, often disappearing with significant weight gain or intervals of less intense exercise. Thirteen women had pituitary hormone levels measured before and after exercise, and both were within the normal range. PMID- 29265972 TI - Diagnosis and Treatment of Iliotibial Band Tightness in Runners. AB - In brief Iliotibial band friction syndrome (ITBFS) is an overuse syndrome resulting from friction between the iliotibial band and the lateral femoral epicondyle during flexion and extension of the knee. It is often found in runners. If it is suspected, Ober's test for iliotibial band tightness should be performed. When Ober's test is positive, a lateral sole wedge is prescribed and the patient is started on a series of stretching exercises. These exercises have been shown to alleviate symptoms of ITBFS and prevent their occurrence. PMID- 29265973 TI - Roller-Skating Injuries. AB - In brief Sixty-two patients with rollerskating injuries were seen over an 18 month period. Most (71%) of the patients were girls and women, and ages ranged from 6 to 62 years. Most injuries were caused when the skaters lost their balance and fell backwards onto their hands. Most (79%) injuries were to the upper extremities and only 19% were to the lower extremities. There was one nonextremity injury, a lumbar compression fracture. The authors recommend using protective pads and improved body mechanics to avoid injuries. PMID- 29265975 TI - Motorcycle Racing: Injuries and Trackside Emergency Care. AB - In brief Injuries during a ten-weekend season of motorcycle road racing were compiled by the author using trackside observation and an end-of-the-season questionnaire. Seven percent of the 2,365 riders were treated for injuries, and there were ten hospitalizations and one death. Most injuries occurred when the riders separated from their machines and tumbled along the track at high speeds. Head injuries with loss of consciousness and amnesia occurred at least once in each event. A total of 25 weeks of hospitalization and 108 weeks of lost work time were reported. Many riders sustained multiple fractures. PMID- 29265974 TI - Athletes Wait Too Long to Report Injuries. AB - A Canadian survey of 450 amateur athletes with injuries found that nearly half waited five days or longer before seeing a physician. PMID- 29265976 TI - Drug Abuse in Sports: Denial Fuels the Problem. AB - A young athlete often sees his heroes on the sports pages linked with drugs, yet many authorities deny that drug abuse is a problem. How does this affect drug use by amateur athletes? PMID- 29265977 TI - a need to know. PMID- 29265978 TI - scanning sports. PMID- 29265981 TI - letters. PMID- 29265982 TI - Send Us Your Children. PMID- 29265984 TI - Thumb Taping. PMID- 29265983 TI - Advantage, Drug-Free Athletes. PMID- 29265985 TI - Nutrition and Physical Performance. AB - In brief Physical training increases the nutrient requirements of total calories, proportion of carbohydrates, thiamine, riboflavin, niacin, iron, water, salt, and perhaps chromium. Conscious adjustments must usually be made in total calories, carbohydrates, water, salt, and iron consumption to maintain optimal performance levels. But thiamine, riboflavin, niacin, and chromium requirements should be met by simply eating more of a varied diet. Eating that promotes obesity, semistarvation, dehydration, and excess vitamin supplementation are counterproductive to physical training. The best pregame meal is normal, well balanced, and based on the athlete's personal preferences, time of eating, and the competitive event. PMID- 29265986 TI - Safe and Effective Weight Loss. PMID- 29265988 TI - meeting notes. PMID- 29265987 TI - brief reports. PMID- 29265989 TI - Old Wine in New Bottles. PMID- 29265990 TI - 1982 Annual Meeting of the American College of Sports Medicine. PMID- 29265991 TI - Communicating with patients' families and relatives: Do we need more training? PMID- 29265992 TI - Dissociation between facial and bodily expressions in emotion recognition: A case study. AB - OBJECTIVE: Existing single-case studies have reported deficit in recognizing basic emotions through facial expression and unaffected performance with body expressions, but not the opposite pattern. The aim of this paper is to present a case study with impaired emotion recognition through body expressions and intact performance with facial expressions. METHODS: In this single-case study we assessed a 30-year-old patient with autism spectrum disorder, without intellectual disability, and a healthy control group (n = 30) with four tasks of basic and complex emotion recognition through face and body movements, and two non-emotional control tasks. To analyze the dissociation between facial and body expressions, we used Crawford and Garthwaite's operational criteria, and we compared the patient and the control group performance with a modified one-tailed t-test designed specifically for single-case studies. RESULTS: There were no statistically significant differences between the patient's and the control group's performances on the non-emotional body movement task or the facial perception task. For both kinds of emotions (basic and complex) when the patient's performance was compared to the control group's, statistically significant differences were only observed for the recognition of body expressions. There were no significant differences between the patient's and the control group's correct answers for emotional facial stimuli. CONCLUSIONS: Our results showed a profile of impaired emotion recognition through body expressions and intact performance with facial expressions. This is the first case study that describes the existence of this kind of dissociation pattern between facial and body expressions of basic and complex emotions. PMID- 29265993 TI - The Effects of Obstacle Type and Locomotion Form on Path Selection in Rugby Players. AB - The current study investigated whether path selection of athletes specifically trained to fit through gaps is affected by the location of human obstacle and the form of locomotion. Female rugby players were instructed to walk, walk with the ball, or run with the ball along a path toward a goal while avoiding three obstacles (three vertical poles or two vertical poles and a confederate) placed halfway along the path, creating two equal apertures of 80 cm. Regardless of the form of locomotion, rugby players chose paths furthest from the confederate, suggesting that confederate location affects path selection. Furthermore, medial lateral spatial requirements were more variable when participants were walking without the ball than while moving with the ball. Avoidance behaviors, but not path selection, appear to be impacted and minimized during sport-specific movements. PMID- 29265994 TI - L'apport critique de l'evaluation de la communication dans le diagnostic precoce de l'apraxie primaire progressive de la parole. AB - Primary progressive apraxia of speech (PPAoS) is a neurodegenerative syndrome characterized by speech apraxia at its onset; as it progresses, it often evolves into total mutism. Even though this syndrome is increasingly recognized, its early differential diagnostic is still complex. The objective of this study was to illustrate why a fine evaluation of speech and language is essential for the differential diagnosis of PPAoS. This longitudinal case study presents the progression of a PPAoS patient over a period of 5 years. Periodic neurological and speech-language assessments were carried out to follow the progression of neurological, memory, language and speech symptoms. The different diagnostic labels established over time were also reported. The evolution of the patient's communication profile was characterized by a preservation of language components and episodic memory, in parallel with a progressive deterioration of speech which gradually reduced intelligibility, and was associated with signs of spasticity, resulting in a complete anarthria. This case study sheds light upon the evolution of a patient with PPAoS. A better understanding of the clinical profile and progression of PPAoS is necessary in order to improve early diagnosis and adequate care for these patients. PMID- 29265995 TI - Ketamine in the Prehospital Environment: A National Survey of Paramedics in the United States. AB - BACKGROUND: Use of ketamine in the prehospital setting may be advantageous due to its potent analgesic and sedative properties and favorable risk profile. Use in the military setting has demonstrated both efficacy and safety for pain relief. The purpose of this study was to assess ketamine training, use, and perceptions in the civilian setting among nationally certified paramedics (NRPs) in the United States. METHODS: A cross-sectional survey of NRPs was performed. The electronic questionnaire assessed paramedic training, authorization, use, and perceptions of ketamine. Included in the analysis were completed surveys of paramedics who held one or more state paramedic credentials, indicated "patient care provider" as their primary role, and worked in non-military settings. Descriptive statistics were calculated. RESULTS: A total of 14,739 responses were obtained (response rate=23%), of which 10,737 (73%) met inclusion criteria and constituted the study cohort. Over one-half (53%) of paramedics reported learning about ketamine during their initial paramedic training. Meanwhile, 42% reported seeking ketamine-related education on their own. Of all respondents, only 33% (3,421/10,737) were authorized by protocol to use ketamine. Most commonly authorized uses included pain management (55%), rapid sequence intubation (RSI; 72%), and chemical restraint/sedation (72%). One-third of authorized providers (1,107/3,350) had never administered ketamine, with another 32% (1,070/3,350) having administered ketamine less than five times in their career. Ketamine was perceived to be safe and effective as the vast majority reported that they were comfortable with the use of ketamine (94%) and would, in similar situations (95%), use it again. CONCLUSION: This was the first large, national survey to assess ketamine training, use, and perceptions among paramedics in the civilian prehospital setting. While training related to ketamine use was commonly reported among paramedics, few were authorized to administer the drug by their agency's protocols. Of those authorized to use ketamine, most paramedics had limited experience administering the drug. Future research is needed to determine why the prevalence of ketamine use is low and to assess the safety and efficacy of ketamine use in the prehospital setting. Buckland DM , Crowe RP , Cash RE , Gondek S , Maluso P , Sirajuddin S , Smith ER , Dangerfield P , Shapiro G , Wanka C , Panchal AR , Sarani B . Ketamine in the prehospital environment: a national survey of paramedics in the United States. Prehosp Disaster Med. 2018;33(1):23 28. PMID- 29265996 TI - Trials and Tribulations of Enteric Parasitology in the Molecular Era. PMID- 29265997 TI - beta LACTA testing may not improve treatment decisions made with MALDI-TOF MS informed antimicrobial stewardship advice for patients with Gram-negative bacteraemia: a prospective comparative study. AB - PURPOSE: The aim of this study was to assess if use of the beta LACTA test (BLT) for extended-spectrum beta-lactamase (ESBL) detection and/or early bacterial identification by mass spectrometry (MALDI-TOF MS) improves therapeutic decision making when combined with advice from the antimicrobial stewardship team (AMST) for the management of Gram-negative bacillary (GNB) bacteraemia. METHODS: Prospective observational theoretical study that included patients with GNB bacteraemia during a 6-month period. We compared, against the antimicrobial choice of the local AMST as informed of the Gram-stain result, a hypothetical choice, i.e. one AMST would have made had it been informed of the MALDI-TOF MS results only (option H) with the actual choice AMST made after being informed of the combined MALDI-TOF MS and BLT results (option A).Results/Key findings. A total of 131 episodes of GNB bacteraemia were included. Options H and A led to virtually the same rate of efficient antimicrobial therapy (in 120/131 and 123/131 episodes, respectively, P=0.63). Compared to the gold standard, options H and A did not lead to a significant reduction of carbapenem prescription (9/131, 6/131 and 12/131, P=0.57 and P=0.65, respectively). CONCLUSIONS: Under our test conditions, BLT, when used in conjunction with MALDI-TOF MS and AMST advice, did not allow a significant optimization of the antimicrobial prescription made on the basis AMST advice only. However, the impact of BLT should be evaluated in a population with high prevalence of ESBL-producing Enterobacteriaceae and/or when treatment choices are not made by infectious disease specialists. PMID- 29265998 TI - Aureimonas populi sp. nov., isolated from poplar tree bark. AB - Two novel bacterial strains (4M3-2T and 10-107-7) were isolated from poplar tree bark. The strains were Gram-stain-negative facultative aerobes, and produced short rods that were motile because of polar flagella. A phylogenetic tree was reconstructed based on 16S rRNA gene sequences indicating that the two novel strains are related to species of the genus Aureimonas and Aurantimonas. The two novel strains shared the highest 16S rRNA gene sequence similarities with Aureimonasfrigidaquae CW5 7Y-4T (97.1 %) and Aureimonasaltamirensis DSM 21988T (96.6 %)o. The lipids of the novel strain contain diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylcholine and sulfoquinovosyl diacylglycerol. The presence of a distinct glycolipid (sulfoquinovosyl diacylglycerol) is an important chemotaxonomic feature used to distinguish between species of the genera, Aurantimonas and Aureimonas. Additionally, the DNA DNA hybridization results indicated that the two novel strains represent a novel taxon distinct from Aureimonas frigidaquae. The results of the 16S rRNA gene sequence analysis, as well as the physiological and biochemical characteristics imply that the two novel strains should be assigned to a novel species, with the proposed name Aureimonas populi sp. nov. The type strain is 4M3-2T (=CFCC 11187T=KCTC 42087T). PMID- 29265999 TI - A novel peer-support intervention using motivational interviewing for breastfeeding maintenance: a UK feasibility study. AB - BACKGROUND: In total, 81% of women in the UK start breastfeeding, but fewer than half continue beyond 6 weeks. Peer support in the early postnatal period may encourage women to breastfeed for longer. OBJECTIVE: To develop a breastfeeding peer-support intervention based on motivational interviewing (MI) for breastfeeding maintenance and to test the feasibility of delivering it to mothers in areas with high levels of social deprivation. DESIGN: Intervention development and a non-randomised multisite feasibility study. SETTING: Community maternity services in three areas with high levels of social deprivation and low breastfeeding initiation rates in England and Wales. PARTICIPANTS: Pregnant women considering breastfeeding. Women who did not plan to breastfeed, who had a clinical reason that precluded breastfeeding continuation or who were unable to consent were excluded. INTERVENTION: The intervention Mam-Kind was informed by a survey of infant feeding co-ordinators, rapid literature review, focus groups with service users and peer supporters and interviews with health-care professionals and a Stakeholder Advisory Group. It consisted of face-to-face contact at 48 hours after birth and proactive one-to-one peer support from the Mam-Kind buddy for 2 weeks, followed by mother-led contact for a further 2-6 weeks. MAIN OUTCOME MEASURES: Recruitment and retention of Mam-Kind buddies, uptake of Mam-Kind by participants, feasibility of delivering Mam-Kind as specified and of data collection methods, and acceptability of Mam-Kind to mothers, buddies and health-care professionals. RESULTS: Nine buddies were recruited to deliver Mam-Kind to 70 participants (61% of eligible women who expressed an interest in taking part in the study). Participants were aged between 19 and 41 years and 94% of participants were white. Intervention uptake was 75% and did not vary according to age or parity. Most contacts (79%) were initiated by the buddy, demonstrating the intended proactive nature of the intervention and 73% (n = 51) of participants received a contact within 48 hours. Follow-up data were available for 78% of participants at 10 days and 64% at 8 weeks. Data collection methods were judged feasible and acceptable. Data completeness was > 80% for almost all variables. Interviews with participants, buddies and health service professionals showed that the intervention was acceptable. Buddies delivered the intervention content with fidelity (93% of intervention objectives were met), and, in some cases, developed certain MI skills to a competency level. However, they reported difficulties in changing from an information-giving role to a collaborative approach. These findings were used to refine the training and intervention specification to emphasise the focus of the intervention on providing mother-centric support. Health-care professionals were satisfied that the intervention could be integrated with existing services. CONCLUSIONS: The Mam-Kind intervention was acceptable and feasible to deliver within NHS maternity services and should be tested for effectiveness in a multicentre randomised controlled trial. The feasibility study highlighted the need to strengthen strategies for birth notification and retention of participants, and provided some insights on how this could be achieved in a full trial. LIMITATIONS: The response rate to the survey of infant feeding co-ordinators was low (19.5%). In addition, the women who were recruited may not be representative of the study sites. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29266000 TI - Evolutionary dynamics of incubation periods. AB - The incubation period for typhoid, polio, measles, leukemia and many other diseases follows a right-skewed, approximately lognormal distribution. Although this pattern was discovered more than sixty years ago, it remains an open question to explain its ubiquity. Here, we propose an explanation based on evolutionary dynamics on graphs. For simple models of a mutant or pathogen invading a network-structured population of healthy cells, we show that skewed distributions of incubation periods emerge for a wide range of assumptions about invader fitness, competition dynamics, and network structure. The skewness stems from stochastic mechanisms associated with two classic problems in probability theory: the coupon collector and the random walk. Unlike previous explanations that rely crucially on heterogeneity, our results hold even for homogeneous populations. Thus, we predict that two equally healthy individuals subjected to equal doses of equally pathogenic agents may, by chance alone, show remarkably different time courses of disease. PMID- 29266002 TI - Description and phylogenetic position of a new species of Rhabdias Stiles et Hassall, 1905 (Nematoda: Rhabdiasidae) from the banded rubber frog, Phrynomantis bifasciatus (Smith) (Amphibia: Microhylidae), in South Africa. AB - The lung-dwelling nematode Rhabdias engelbrechti sp. n. was found in five of eight examined banded rubber frogs in Limpopo Province, South Africa. The species is differentiated from species of Rhabdias Stiles et Hassall, 1905 occurring in the Afrotropical Realm based on the presence of a globular cuticular inflation at the anterior end, the buccal capsule walls being distinctly divided into anterior and posterior parts, the buccal capsule size (6-9 MUm * 16-18 MUm), and the body length (3.8-6.1 mm). Rhabdias engelbrechti is the tenth species of the genus found in Afrotropical anurans. Our molecular phylogenetic analysis based on the complete sequences of the ITS region and partial sequences of large subunit (28S) gene of the nuclear ribosomal RNA demonstrates that the new species is more closely related to the Eurasian species Rhabdias bufonis (Schrank, 1788) than to two other species from sub-Saharan Africa represented in the tree. In addition, partial sequences of the mitochondrial protein coding cox1 and ribosomal 12S genes of the new species have shown significant differences from all previously published sequences of these genes from African species of Rhabdias. PMID- 29266001 TI - A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression. AB - Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression. PMID- 29266003 TI - Liquid exfoliation of mechanochemically nanostructured tungsten disulfide to a graphene-like state. AB - The possibility of the efficient preparation of graphene-like 1H-WS2 by the primary solventless nanostructuration of bulk 2H-WS2 by means of its mechanochemical treatment in the presence of a chemically inert agent (NaCl) and the subsequent liquid exfoliation of the nanostructured 2H-WS2 in an organic solvent is shown for the first time. The shear stresses generated during the grinding of the WS2/NaCl mixture caused the formation of WS2 particles with a reduced number of layers, while the stresses normal to their surface led to their cracking and a significant reduction in lateral size. The graphene-like morphology of the 1H-WS2 nanoparticles in the prepared dispersions is confirmed by atomic force microscopy and Raman spectroscopy. The semiconducting character of 1N-WS2 is supported by electron absorption and x-ray photoelectron spectroscopy data. PMID- 29266004 TI - Rare-earth nickelates RNiO3: thin films and heterostructures. AB - This review stands in the larger framework of functional materials by focussing on heterostructures of rare-earth nickelates, described by the chemical formula RNiO3 where R is a trivalent rare-earth R = La, Pr, Nd, Sm, ..., Lu. Nickelates are characterized by a rich phase diagram of structural and physical properties and serve as a benchmark for the physics of phase transitions in correlated oxides where electron-lattice coupling plays a key role. Much of the recent interest in nickelates concerns heterostructures, that is single layers of thin film, multilayers or superlattices, with the general objective of modulating their physical properties through strain control, confinement or interface effects. We will discuss the extensive studies on nickelate heterostructures as well as outline different approaches to tuning and controlling their physical properties and, finally, review application concepts for future devices. PMID- 29266005 TI - Compliance of Randomized Controlled Trials Published in General Surgical Journals With the CONSORT 2010 Statement. PMID- 29266006 TI - Letter to the Editor. PMID- 29266007 TI - Response: Pylorus Resection Does Not Reduce Delayed Gastric Emptying After Partial Pancreatoduodenectomy: A Blinded Randomized Controlled Trial. PMID- 29266009 TI - Nonalcoholic fatty liver disease, cholesterol gallstones, and cholecystectomy: new insights on a complex relationship. AB - PURPOSE OF REVIEW: Gallstone disease (GSD) and nonalcoholic fatty liver disease (NAFLD often coexist in a given patient and both conditions are associated to obesity and insulin resistance. The relationship between GSD and NAFLD is complex and bidirectional. In the present review, we summarize the existing information on the complex link between GSD and NAFLD and the potential implications for patient care. RECENT FINDINGS: Several clinical studies and systematic reviews have addressed the association between NAFLD and GSD underscoring that NAFLD is an independent risk factor for GSD. Conversely, GSD has been found also to be an independent risk factor for NAFLD with GSD potentially being linked to greater disease severity. In addition to the data showing association of NAFLD and GSD, recent evidence has also showed that cholecystectomy may itself be a risk factor for NAFLD development. The complex and bidirectional relationship between these diseases is partially explained by a number of common pathogenic links but the precise underlying mechanisms of the association of GSD and NAFLD need to be better delineated. Also, although the mechanisms of the promotional effect of cholecystectomy on NAFLD development are unknown, recent findings unveiling new aspects of gallbladder physiology and endocrine actions of bile acids provide a framework to advance research in this field. SUMMARY: In this review, we address the different aspects of the complex association between NAFLD and GSD. The potential underlying mechanisms and recent information on endocrine actions of bile acids and the gallbladder are reviewed. PMID- 29266010 TI - Gallstone disease, towards a better understanding and clinical practice. PMID- 29266011 TI - The scourge of air pollution and topics in chronic obstructive pulmonary disease. PMID- 29266008 TI - Mouse models of gallstone disease. AB - PURPOSE OF REVIEW: The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. RECENT FINDINGS: The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical-chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. SUMMARY: The mouse model of gallstones is crucial for elucidating the physical-chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans. PMID- 29266012 TI - Insights on transmission of HIV from phylogenetic analysis to locally optimize HIV prevention strategies. AB - PURPOSE OF REVIEW: Phylogenetic analysis can identify transmission networks by clustering genetically related HIV genotypes that are routinely collected. In this study, we will review phylogenetic insights gained on transmission of HIV and phylogenetically optimized HIV prevention strategies. RECENT FINDINGS: Phylogenetic analysis reports that HIV transmission varies by geographical region and by route of transmission. In high-income countries, HIV is predominantly transmitted between recently infected MSM who live in the same country. In rural Uganda, transmission of HIV is frequently between different communities. Age discrepant transmission has been reported across the world. Four studies have used phylogenetic optimization of HIV prevention. Three studies predict that immediate treatment after diagnosis would have prevented 19-42% of infections, and that preexposure prophylaxis would have prevented 66% of infections. One phylogenetic study guided a public health response to an actively ongoing HIV outbreak. Phylogenetic clustering requires a dense sample of patients and small time-gaps between infection and diagnosis. SUMMARY: Phylogenetic analysis can be an important tool to identify a local strategy that prevents most infections. Future studies that use phylogenetic analysis for optimizing HIV prevention strategies should also include cost-effectiveness so that the most cost-effective prevention method is identified. PMID- 29266014 TI - Chronic kidney disease and acquired mitochondrial myopathy. AB - PURPOSE OF REVIEW: Sarcopenia and muscle weakness contribute to fragility and limit exercise tolerance among patients with CKD. This review focuses on the role of reduction in mitochondrial mass and function in the myopathy associated with CKD, causes for these muscle mitochondrial abnormalities, and potential therapeutic interventions that may improve mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD. RECENT FINDINGS: Multiple abnormalities of mitochondrial structure, function, and composition have been shown in both experimental models and patients with CKD. A significant reduction in mitochondrial respiratory function and an increase in mitochondrial complex 1 enzyme activity has been demonstrated in the muscle tissue of male Sprague-Dawley rats following 5/6 nephrectomy. These changes were associated with a substantial reduction in skeletal muscle mitochondrial mass. In patients with CKD, in-vivo magnetic resonance and optical spectroscopy show significantly elevated resting skeletal muscle oxygen consumption and lower mean mitochondrial coupling ratio indicating disrupted muscle mitochondrial metabolism and uncoupling of oxidative phosphorylation. Skeletal muscle biopsies from patients with advanced CKD show lower mitochondrial volume density and mitochondrial DNA (mtDNA) copy number than controls. SUMMARY: Advanced CKD is associated with decreased exercise capacity, skeletal muscle weakness, and muscle atrophy. Impaired mitochondrial respiratory function, reduced muscle mitochondrial mass, and decreased energy production in skeletal muscle play a critical role in this 'acquired mitochondrial myopathy' of CKD. It is reasonable, therefore, to develop therapeutic interventions that enhance mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD. PMID- 29266015 TI - Therapeutic choices after hypomethylating agent resistance for myelodysplastic syndromes. AB - PURPOSE OF REVIEW: Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndromes (MDS). Although these agents induce responses in up to 40% of patients, most patients ultimately experience loss of response. The purpose of this review is to provide an overview of the different therapies under development for MDS after HMA therapy. RECENT FINDINGS: Recent advances in the understanding of MDS pathogenesis have led to the development of new potential therapies after HMA failure. Newer HMAs, less susceptible to in vivo deamination, such as guadecitabine or ASTX727 have shown activity. Alterations of immune checkpoints in MDS have led to multiple clinical trials evaluating the activity of monoclonal antibodies targeting these proteins (pembrolizumab, nivolumab, ipilimumab). Different combinations and new formulations of cytotoxic agents, such as clofarabine or CPX-351, are newer options for specific subsets of patients. Finally, targeted agents inhibiting multiple kinases (rigosertib), BCL2 (venetoclax) or mutant IDH1 (ivosidenib), IDH2 (enasidenib), FLT3 (sorafenib, midostaurin) or spliceosome components (H3B 8800) are other novel options. SUMMARY: Despite the poor prognosis associated with HMA failure, clinical trials, new cytotoxic agents and allogeneic stem-cell transplantation, can offer therapeutic opportunities for these patients for whom there is no standard of care. PMID- 29266013 TI - Neutralization tiers of HIV-1. AB - PURPOSE OF REVIEW: HIV-1 isolates are often classified on the basis of neutralization 'tier' phenotype. Tier classification has important implications for the monitoring and interpretation of vaccine-elicited neutralizing antibody responses. The molecular basis that distinguishes the multiple neutralization phenotypes of HIV-1 has been unclear. We present a model based on the dynamic nature of the HIV-1 envelope glycoproteins and its impact on epitope exposure. We also describe a new approach for ranking HIV-1 vaccine-elicited neutralizing antibody responses. RECENT FINDINGS: The unliganded trimeric HIV-1 envelope glycoprotein spike spontaneously transitions through at least three conformations. Neutralization tier phenotypes correspond to the frequency by which the trimer exists in a closed (tiers 2 and 3), open (tier 1A), or intermediate (tier 1B) conformation. An increasing number of epitopes become exposed as the trimer opens, making the virus more sensitive to neutralization by certain antibodies. The closed conformation is stabilized by many broadly neutralizing antibodies. SUMMARY: The tier 2 neutralization phenotype is typical of most circulating strains and is associated with a predominantly closed Env trimer configuration that is a high priority to target with vaccines. Assays with tier 1A viruses should be interpreted with caution and with the understanding that they detect many antibody specificities that do not neutralize tier 2 viruses and do not protect against HIV-1 infection. PMID- 29266016 TI - Resistance in chronic myeloid leukemia: definitions and novel therapeutic agents. AB - PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) is hallmarked by the presence of fusion protein kinase derived from a reciprocal translocation between chromosome 9 and 22, breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) 1, causing aberrant regulation of the downstream pathways leading to unchecked CML leukemia stem cells (LSCs) proliferation. Since the discovery of tyrosine kinase inhibitors (TKI), CML, once a fatal disease, has become a chronic illness if managed appropriately. Changing treatment landscape has unsurfaced the challenge of TKI resistance that is clinically difficult to overcome. RECENT FINDINGS: In this review, we discuss the concept of TKI resistance and pathways leading to the resistance which allows for a survival advantage to CML LSCs. Aside from BCR-ABL-dependent mechanisms of resistance which involves aberrant expression in the regulatory pumps involving efflux and influx of the TKI affecting drug bioavailability, activation of alternate survival pathways may be accountable for primary or secondary resistance. Activation of these pathways, intrinsically and extrinsically to LSCs, may be mediated through various upstream and downstream signaling as well as conditions affecting the microenvironment. Several therapeutic approaches that combine TKI with an additional agent that inhibits the activation of an alternate pathway have been studied as part of clinical trials which we will discuss here. SUMMARY: We categorize the resistance into BCR-ABL-dependent and BCR-ABL-independent subgroups to further describe the complex molecular pathways which can potentially serve as a therapeutic target. We further discuss novel combination strategies currently in early or advanced phase clinical trials aimed to overcome the TKI resistance. We further highlight the need for further research despite the tremendous strides already made in the management of CML. PMID- 29266017 TI - Association between decreased respiratory function and increased blood pressure variability. AB - OBJECTIVE: The respiratory system is an important component in the control of the autonomic nervous system, and is a possible factor of blood pressure variability (BPV). We examined whether decreased respiratory function is associated with exaggerated BPV in hypertensives. PATIENTS AND METHODS: This is a substudy of the Japan Morning Surge-Home Blood Pressure Study and patients who underwent both spirometry and ambulatory blood pressure monitoring (ABPM) in the Japan Morning Surge-Home Blood Pressure study were analyzed. In 95 hypertensives without known clinical respiratory diseases, we performed ABPM and the respiratory function test. RESULTS: Percent vital capacity (%VC), but not forced expiratory volume in 1 s as a percentage of forced vital capacity, was associated with the SD (r= 0.23, P<0.05) and coefficient of variation (r=-0.25, P<0.05) of daytime systolic blood pressure (SBP). Lower %VC was associated with higher SD of daytime SBP (P=0.049 for trend). After adjusting for covariates, %VC tended to be associated with SD of daytime SBP (beta=-0.22, P=0.08) and was associated with coefficient of variation of daytime SBP (beta=-0.26, P=0.04). CONCLUSION: Decreased respiratory function was associated with exaggerated ambulatory BPV, especially in the daytime in hypertensives without respiratory diseases. This is the first study to show an association between respiratory function and increased BPV as assessed by ABPM. The results of our study indicate that low respiratory function could exaggerate BPV, and thus may be one of the mechanisms underlying the elevated cardiovascular risk in patients with decreased respiratory function. PMID- 29266018 TI - Sarcopenia and Skeletal Muscle Quality as Predictors of Postoperative Complication and Early Mortality in Gynecologic Cancer. AB - OBJECTIVE: This study aimed to evaluate the influence of sarcopenia and the indicators of skeletal muscle (SM) quality on surgical outcomes in women with ovarian and endometrial cancer who underwent oncologic surgery. METHODS: Endometrial and ovarian cancer patients admitted between 2008 and 2015 and who had computerized tomography images available within 45 days before surgery were enrolled in a retrospective cohort (n = 250). Computerized tomography images at the third lumbar vertebra were used to assess SM. Skeletal muscle index (SMI) was calculated in the range from -29 to +150 Hounsfield Units; reduced muscle attenuation (range, -29 to +29 HU) was classified as low-radiodensity skeletal muscle index (LRSMI). By subtracting the LRSMI area from total SMI, high radiodensity skeletal muscle index (HRSMI) was created. Sarcopenia was defined when SMI was less than 38.9 cm/m. Multiple logistic regression evaluated predictors of surgical complications. RESULTS: Patients in lower HRSMI quartiles and in the highest quartiles of LRSMI had more postoperative surgical complication and had prolonged hospital stay. Both sarcopenia and the quality indicators of SM were predictors of increased risk of surgical complication, HRSMI being the strongest predictor. However, in a combined adjustment with sarcopenia, only HRSMI remained in the model as an independent predictor for surgical complication. In addition, HRSMI was the only indicator associated with early mortality (<30 days). CONCLUSIONS: The indicators of SM quality were the most significant predictors of surgical complications. Classifying muscle quality in terms of low-radiodensity or high-radiodensity area is a promising strategy to understand the impact of SM quality on unfavorable surgical outcomes in cancer patients. PMID- 29266019 TI - Fertility-Preserving Treatment in Young Women With Grade 1 Presumed Stage IA Endometrial Adenocarcinoma: A Meta-Analysis. AB - OBJECTIVES: The aim of this study was to investigate the different efficacies of various fertility-preserving therapies for grade 1 presumed stage IA endometrial cancer. METHODS: We searched the major online databases (PubMed, MEDLINE, Cochrane Library, Web of Science, and Ovid) and retrieved all the research on fertility-preserving treatment for young, grade 1 presumed stage IA endometrial adenocarcinoma patients since January 2000. We used the systemic evaluation of the Cochrane Collaboration to select the literature and merge the data we collected using R3.2.2 software (R Development Core Team, Auckland, New Zealand). By comparing the remission, recurrence, and pregnancy rates, we evaluated the efficiency of 3 existing fertility-preserving treatments indirectly: a) taking oral progestin only therapy, b) hysteroscopic resection followed by progestin therapy, and c) intrauterine progestin therapy: levonorgestrel-releasing intrauterine system combined with gonadotropin-releasing hormone agonist/progestin therapy. RESULTS: Twenty-eight studies met the selection criteria. A total of 619 cases were included in this study. The group that took oral progestin only (456 patients) achieved a complete remission rate (CRR), recurrence rate (ReR), and pregnancy rate (PregR) of 76.3%, (95% confidence interval [CI], 70.7%-81.1%); 30.7% (95% CI, 21.0%-42.4%); and 52.1% (95% CI, 41.2%-66.0%), respectively. The hysteroscopic resection followed by progestin therapy group (73 patients) achieved a CRR, ReR, and PregR of 95.3% (95% CI, 87.8%-100%); 14.1% (95% CI, 7.1%-26.1%); and 47.8% (95% CI, 33.0%-69.5%), respectively. The intrauterine progestin therapy group (90 patients) achieved a CRR, ReR, and PregR of 72.9% (95% CI, 60.4%-82.5%); 11.0% (95% CI, 5.1%-22.0%); and 56.0% (95% CI, 37.3%-73.1%), respectively. CONCLUSIONS: The existing results show that patients who received hysteroscopic resection followed by progestin therapy achieved the highest CRR. Patients who received oral progestin only might be more likely to recur and have more systemic adverse effects. Recent intrauterine progestin therapy such as levonorgestrel-releasing intrauterine system combined with gonadotropin-release hormone receptor agonist/progestin have a satisfactory PregR and low ReR rate. Considering the inherent limitations of the studies we included, further well-designed, randomized controlled trials are necessary to confirm and update this analysis. PMID- 29266020 TI - A novel KRAS mutation in metastasic conjunctival melanoma: a case report and literature review. AB - Conjunctival melanoma is a rare disease, and little is known about its molecular background. Here, we present the case of a 48-year-old patient with conjunctival melanoma and metachronic lymph node and skin metastasis with KRAS p.K117Y mutation in exon 4 in all the lesions. The cancer genome interpreter predicted this mutation to have driver function. To our knowledge, this is the first time this mutation is found in conjunctival melanoma. An important role in the disease development is suggested. PMID- 29266021 TI - Glaucoma and quality of life: fall and driving risk. AB - PURPOSE OF REVIEW: Numerous population-based studies suggest that glaucoma is an independent risk factor for falling and motor vehicle collisions, particularly for older adults. These adverse events lead to increased healthcare expenditures and decreased quality of life. Current research priorities, therefore, include identifying factors that predispose glaucoma patients to falling and unsafe driving, and developing screening strategies and targeted rehabilitation. The purpose of this article is to review recent studies that address these priorities. RECENT FINDINGS: Studies continue to support that glaucoma patients, particularly those with advanced disease, have an increased risk of falling or unsafe driving. Risk factors, however, remain variable and include severity and location of visual field defects, contrast sensitivity, and performance on divided attention tasks. Such variability is likely because of the multifactorial nature of ambulating and driving and compensatory strategies used by patients. SUMMARY: Falls and unsafe driving remain a serious public health issue for older adults with glaucoma. Ambulation and driving are complex tasks and there is no consensus yet, regarding the best methods for risk stratification and targeted interventions to increase safety. Therefore, comprehensive and individualized assessments are recommended to most effectively evaluate a patient's risk for falling or unsafe driving. PMID- 29266022 TI - Tissue Eosinophilia and Severity of Colitis. PMID- 29266023 TI - Role of Immunohistochemistry in the Identification of Supratentorial C11ORF95 RELA Fused Ependymoma in Routine Neuropathology. AB - Ependymomas (EPs) are tumors of the brain and spinal cord constituting ~10% of the childhood central nervous system neoplasms and about 30% in children aged <3 years. Their anatomic distribution varies according to the age, with those arising in the supratentorial (ST) compartment, spinal cord being more common in older children and adults, and those at the infratentorial location are more common and occurring more frequently in infants and children. Recently, molecular classification of EP subgroups has been proposed and a supratentorial ependymoma subgroup characterized by RELA-fusion genes (ST-EP-RELA) has been established. It would be useful to define a standardized, robust method for the diagnosis of these relevant fusion genes. We used real-time polymerase chain reaction, conventional real-time polymerase chain reaction, and Sanger sequencing to characterize RELA fusion status in formalin-fixed paraffin-embedded samples from 42 ST-EPs (12 adults and 30 pediatric). We tested p65/RELA and L1CAM protein immunohistochemistry for their ability to predict RELA-fusion status. We reviewed clinical data to assess significant associations in this anatomic subgroup. Of the 42 patients, we identified RELA-fusion genes in 17 cases. L1CAM immunostaining displayed 94% sensitivity, 76% specificity, 73% positive predictive value (PPV), 95% negative predictive value (NPV). The p65/RELA immunostaining displayed 100% sensitivity, 92% specificity, 89.5% PPV, 100% NPV. Concordant double immunostaining improves PPV to 92.5% and maintains 100% NPV. Immunohistochemistry using both p65/RELA and L1CAM antibodies is valuable for ST EP-RELA diagnosis: the negativity with both antibodies consistently predicts the absence of RELA fusions, whereas verification of fusion transcripts by molecular analyses is warranted only in single-positive or double-positive staining cases. PMID- 29266024 TI - Congenital Cystic Lung Lesions: Redefining the Natural Distribution of Subtypes and Assessing the Risk of Malignancy. AB - Asymptomatic cystic lung lesions-congenital pulmonary airway malformations (CPAMs), sequestrations, and bronchogenic cysts-are commonly diagnosed prenatally. Indications to resect are to eliminate risk of malignancy or infection. CPAMs consist of a spectrum of malformations, with type 1 historically considered the most common. Mucinous cell clusters, seen almost exclusively in type 1, are premalignant lesions at risk for progression to mucinous adenocarcinoma. We reviewed and classified 2.5 years of consecutive, prenatally diagnosed lesions as extralobar sequestration, intralobar sequestration, type 1 CPAM, type 2 CPAM/bronchial atresia, or "other" to determine the distribution of lesion types and risk of malignancy. One hundred eighty-four lesions in 174 patients showed type 1 CPAM to be least common subtype. Type 1 CPAMs had more severe presentation, infrequently had features of obstruction, and usually had cysts >=2 cm. Fifteen of eighteen type 1 CPAMs had mucinous cell clusters (total risk, 8%), with mucous cells outside main cyst in 12/15. No pleuropulmonary blastomas were identified. Additional historic cases were reviewed to further evaluate risk of malignancy. Over 14 years, 28 infants with fetal/type 1 lesions were identified, with clusters of mucinous cells in 75% of cases. A total of 9 pleuropulmonary blastomas were diagnosed in 6 patients over 16 years. Contrary to historical studies, type 1 CPAMs are much less common than type 2, likely related to detection of asymptomatic lesions prenatally. A majority of type 1 CPAMs contain mucinous cell clusters. This data is useful in management of patients in centers that do not resect asymptomatic lesions. PMID- 29266025 TI - Multiple Eruptive Epithelioid Hemangiomas: A Subset of Cutaneous Cellular Epithelioid Hemangioma With Expression of FOS-B. AB - There is a wide clinicopathologic spectrum of vascular proliferations characterized by the presence of epithelioid endothelial cells, comprising epithelioid hemangioma (EH)-pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma (PM-HAE), epithelioid hemangioendothelioma, and epithelioid angiosarcoma. Immunohistochemical FOS-B expression as well as FOS-B rearrangement (fluorescent in situ hybridization [FISH]) have recently been described as diagnostically relevant underpinnings of EH (restricted to osseous lesions) and PM-HAE. The aim of this study was to clinicopathologically characterize and to elucidate FOS-B expression in patients with eruptive lesions of the cellular variant of cutaneous EH. All cases of cutaneous cellular EH (n=16) showed strong diffuse immunohistochemical expression of FOS-B, in conjunction with positivity for ERG and nestin. Expression of MYC, CAMTA-1, AE1/3, and MNF116 was negative in all cases. FISH investigations did not show any sign of rearrangements for CAMTA 1 or MYC amplification. Negative-control cases included 15 lobular hemangiomas, 5 epithelioid angiosarcomas, and 5 nodular Kaposi sarcomas, all of which were negative for FOS-B. Positive-control cases included 15 angiolymphoid hyperplasia with eosinophilia cases, all of them being positive. In contrast with what has been published so far, cutaneous variants of cellular EH exhibit positive immunostaining for FOS-B. Remarkably, FOS-B expression is not restricted to the intraosseous subset of EH. For differential diagnosis of epithelioid vascular tumors, we therefore suggest a helpful panel of antibodies including CAMTA-1, TFE 3, FOS-B, and AE1/AE3. We point out the telltale immunophenotypes: angiolymphoid hyperplasia with eosinophilia and EH (FOS-B/others negative), PM-HAE (FOS B/AE1/AE3/others negative), epithelioid hemangioendothelioma (CAMTA-1 or TFE 3/others negative). Remarkably, MYC is not expressed in these tumors, neither is there an MYC amplification by FISH. We suggest the term multiple eruptive EHs for this subset of cutaneous vascular tumors. PMID- 29266026 TI - Is There Any Association Between Foot Posture and Lower Limb-Related Injuries in Professional Male Basketball Players? A Cross-Sectional Study. AB - BACKGROUND: Several studies have shown that foot posture is related to the incidence of ankle sprains in athletes and in nonathletic populations, but this association has not previously been considered in basketball players. This study investigates the relationship between foot posture and lower limb injuries in elite basketball players. DESIGN AND METHOD: Two hundred twenty participants were recruited as a convenience sample. The players had a mean age of 22.51 +/- 3.88 years and a body mass index of 23.98 +/- 1.80. The players' medical records were accessed from the preceding 10 years, and injuries were recorded according to their location (knee, foot, and/or ankle). In addition, the Foot Posture Index (FPI) was scored for each player, and their playing positions were noted. RESULTS: An average FPI score of 2.66 was obtained across all players, with guards presenting a significantly lower average FPI of -0.48 (P < 0.001) compared with the rest of playing positions, indicating a more supinated foot. However, center players presented an average FPI of 5.15 (P < 0.001), indicating a more pronated foot. The most common injuries observed were lateral ankle sprain (n = 214) and patellar tendinopathy (n = 126). Patellar tendinopathy was more common in supinated feet (30.08%) compared with 20.7% and 19.8% in pronated and neutral feet, respectively. CONCLUSIONS: The most common lower limb injuries observed in basketball players were lateral ankle sprain and patellar tendinopathy. Patellar tendinopathy was more commonly associated with the supinated feet. Guard players tended to have a more supinated foot, whereas centers presented a more pronated foot. PMID- 29266027 TI - Stress-Dosed Glucocorticoids and Mineralocorticoids Before Intensive Endurance Exercise in Primary Adrenal Insufficiency. AB - Patients with primary adrenal insufficiency (PAI) require increased doses of glucocorticoids and mineralocorticoids during stressors, such as surgery, trauma, and sepsis. Although current guidelines exist for dose adjustments in these situations, there is no accepted dosing regimen for patients with PAI participating in intensive endurance exercise. Given the extensive physiologic stress of events, such as marathons, triathlons, and similar events, it is likely that a "stress-dose" of adrenal replacement therapy will not only prevent adrenal crisis, but also improve performance. A 50-year-old male endurance athlete with known PAI reported severe fatigue, nausea, and malaise after competing in prior marathons and intensive endurance exercise. After supplementing with glucocorticoids and mineralocorticoids before competition, he experienced decreased symptoms and improved performance. To better care for these patients, further studies should be conducted to provide safe and effective glucocorticoid and mineralocorticoid dose adjustments before intensive endurance exercise. PMID- 29266028 TI - Changes on Tendon Stiffness and Clinical Outcomes in Athletes Are Associated With Patellar Tendinopathy After Eccentric Exercise. AB - OBJECTIVE: Eccentric exercise is commonly used as a form of loading exercise for individuals with patellar tendinopathy. This study investigated the change of mechanical properties and clinical outcomes and their interrelationships after a 12-week single-legged decline-board exercise with and without extracorporeal shockwave therapy (ESWT). DESIGN: Randomized controlled trial. SETTING: Outpatient clinic of a university. PARTICIPANTS: Thirty-four male in-season athletes with patellar tendinopathy for more than 3 months were randomized into exercise and combined groups. INTERVENTIONS: The exercise group received a 12 week single-legged decline-squat exercise, and the combined group performed an identical exercise program in addition to a weekly session of ESWT in the initial 6 weeks. MAIN OUTCOME MEASURES: Tendon stiffness and strain were examined using ultrasonography and dynamometry. Visual analog scale and Victoria Institute of Sports Assessment-patella (VISA-p) score were used to assess pain and dysfunction. These parameters were measured at preintervention and postintervention. RESULTS: Significant time effect but no significant group effect on the outcome measures; significant reduction in tendon stiffness (P = 0.02) and increase in tendon strain (P = 0.00); and reduction of intensity of pain (P = 0.00) and dysfunction (P = 0.00) were observed. Significant correlations between changes in tendon stiffness and VISA-p score (rho = -0.58, P = 0.05); alteration in tendon strain, pain intensity (rho = -0.63, P = 0.03); and VISA-p score (rho = 0.60, P = 0.04) were detected after the exercise program. CONCLUSIONS: Eccentric exercise-induced modulation on tendon mechanical properties and clinical symptoms are associated in athletes with patellar tendinopathy. PMID- 29266030 TI - Reply. PMID- 29266029 TI - Spinal Cord Injury Impairs Cardiovascular Capacity in Elite Wheelchair Rugby Athletes. AB - OBJECTIVE: To examine differences in heart rate (HR) responses during international wheelchair rugby competition between athletes with and without a cervical spinal cord injury (SCI) and across standardized sport classifications. DESIGN: Observational study. SETTING: The 2015 Parapan American Games wheelchair rugby competition. PARTICIPANTS: Forty-three male athletes (31 +/- 8 years) with a cervical SCI (n = 32) or tetraequivalent impairment (non-SCI, n = 11). MAIN OUTCOME MEASURES: Average and peak HR (HRavg and HRpeak, respectively). To characterize HR responses in accordance with an athletes' International Wheelchair Rugby Federation (IWRF) classification, we separated athletes into 3 groups: group I (IWRF classification 0.5-1.5, n = 15); group II (IWRF classification 2.0, n = 15); and group III (IWRF classification 2.5-3.5, n = 13). RESULTS: Athletes with SCI had lower HRavg (111 +/- 14 bpm vs 155 +/- 13 bpm) and HRpeak (133 +/- 12 bpm vs 178 +/- 13 bpm) compared with non-SCI (both P < 0.001). Average HR was higher in group III than in I (136 +/- 25 bpm vs 115 +/- 20 bpm, P = 0.045); however, SCI athletes showed no difference in HRavg or HRpeak between groups. Within group III, SCI athletes had lower HRavg (115 +/- 6 bpm vs 160 +/- 8 bpm) and HRpeak (135 +/- 11 bpm vs 183 +/- 11 bpm) than non-SCI athletes (both P < 0.001). CONCLUSIONS: This study is the first to demonstrate attenuated HR responses during competition in SCI compared with non-SCI athletes, likely due to injury to spinal autonomic pathways. Among athletes with SCI, IWRF classification was not related to differences in HR. Specific assessment of autonomic function after SCI may be able to predict HR during competition and consideration of autonomic impairments may improve the classification process. PMID- 29266031 TI - Herpes Zoster Optic Neuropathy. AB - BACKGROUND: Herpes zoster optic neuropathy (HZON) is a rare manifestation of herpes zoster ophthalmicus (HZO). The aim of our study was to better characterize the clinical features, therapeutic choices, and visual outcomes in HZON. METHODS: A retrospective chart review was performed at multiple academic eye centers with the inclusion criteria of all eyes presenting with optic neuropathy within 1 month of cutaneous zoster of the ipsilateral trigeminal dermatome. Data were collected regarding presenting features, treatment regimen, and visual acuity outcomes. RESULTS: Six patients meeting the HZON inclusion criteria were identified. Mean follow-up was 2.75 months (range 0.5-4 months). Herpes zoster optic neuropathy developed at a mean of 14.1 days after initial rash (range 6-30 days). Optic neuropathy was anterior in 2 eyes and retrobulbar in 4 eyes. Other manifestations of HZO included keratoconjunctivitis (3 eyes) and iritis (4 eyes). All patients were treated with systemic antiviral therapy in addition to topical and/or systemic corticosteroids. At the last follow-up, visual acuity in 3 eyes had improved relative to presentation, 2 eyes had worsened, and 1 eye remained the same. The 2 eyes that did not receive systemic corticosteroids had the best observed final visual acuity. CONCLUSION: Herpes zoster optic neuropathy is an unusual but distinctive complication of HZO. Visual recovery after HZON is variable. Identification of an optimal treatment regiment for HZON could not be identified from our patient cohort. Systemic antiviral agents are a component of HZON treatment regimens. Efficacy of systemic corticosteroids for HZON remains unclear and should be considered on a case-by-case basis. PMID- 29266032 TI - Paraneoplastic Optic Neuropathy and Pineal Germinoma With Collapsin Response Mediating Protein Antibodies. PMID- 29266034 TI - Inhibition of myeloperoxidase by N-acetyl lysyltyrosylcysteine amide reduces experimental autoimmune encephalomyelitis-induced injury and promotes oligodendrocyte regeneration and neurogenesis in a murine model of progressive multiple sclerosis. AB - It is known that oxidative stress produced by proinflammatory myeloid cells plays an important role in demyelination and neuronal injury in progressive multiple sclerosis (MS). Myeloperoxidase (MPO) is a pro-oxidative enzyme released from myeloid cells during inflammation. It has been shown that MPO-dependent oxidative stress plays important roles in inducing tissue injury in many inflammatory diseases. In this report, we treated NOD experimental autoimmune encephalomyelitis (EAE) mice, a murine model of progressive MS, with N-acetyl lysyltyrosylcysteine amide (KYC), a novel specific MPO inhibitor. Our data showed that KYC treatment not only attenuated MPO-mediated oxidative stress but also reduced demyelination and axonal injury in NOD EAE mice. More importantly, we found that KYC treatment increased oligodendrocyte regeneration and neurogenesis in NOD EAE mice. Taken together, our data suggests that targeting MPO should be a good therapeutic approach for reducing oxidative injury and preserving neuronal function in progressive MS patients. PMID- 29266035 TI - Leveraging expertise: partnerships for evidence-based practice. PMID- 29266033 TI - Immune Responses of HLA Highly Sensitized and Nonsensitized Patients to Genetically Engineered Pig Cells. AB - BACKGROUND: We investigated in vitro whether HLA highly sensitized patients with end-stage renal disease will be disadvantaged immunologically after a genetically engineered pig kidney transplant. METHODS: Blood was drawn from patients with a calculated panel-reactive antibody (cPRA) 99% to 100% (Gp1, n = 10) or cPRA 0% (Gp2, n = 12), and from healthy volunteers (Gp3, n = 10). Serum IgM and IgG binding was measured (i) to galactose-alpha1-3 galactose and N-glycolylneuraminic acid glycans by enzyme-linked immunosorbent assay, and (ii) to pig red blood cell, pig aortic endothelial cells, and pig peripheral blood mononuclear cell from alpha1,3-galactosyltransferase gene-knockout (GTKO)/CD46 and GTKO/CD46/cytidine monophosphate-N-acetylneuraminic acid hydroxylase-knockout (CMAHKO) pigs by flow cytometry. (iii) T-cell and B-cell phenotypes were determined by flow cytometry, and (iv) proliferation of T-cell and B-cell carboxyfluorescein diacetate succinimidyl ester-mixed lymphocyte reaction. RESULTS: (i) By enzyme-linked immunosorbent assay, there was no difference in IgM or IgG binding to galactose-alpha1-3 galactose or N-glycolylneuraminic acid between Gps1 and 2, but binding was significantly reduced in both groups compared to Gp3. (ii) IgM and IgG binding in Gps1 and 2 was also significantly lower to GTKO/CD46 pig cells than in healthy controls, but there were no differences between the 3 groups in binding to GTKO/CD46/CMAHKO cells. (iii and iv) Gp1 patients had more memory T cells than Gp2, but there was no difference in T or B cell proliferation when stimulated by any pig cells. The proliferative responses in all 3 groups were weakest when stimulated by GTKO/CD46/CMAHKO pig peripheral blood mononuclear cell. CONCLUSIONS: (i) End-stage renal disease was associated with low antipig antibody levels. (ii) Xenoreactivity decreased with increased genetic engineering of pig cells. (iii) High cPRA status had no significant effect on antibody binding or T-cell and B-cell response. PMID- 29266036 TI - Facial Myokymia and Hemifacial Spasm in Multiple Sclerosis: A Descriptive Study on Clinical Features and Treatment Outcomes. AB - OBJECTIVE: Facial Myokymia and hemifacial spasm have been associated with multiple sclerosis; however, their etiology and clinical outcome is uncertain. Here, we describe the clinical, radiologic features, and treatment outcomes of a cohort of patients with multiple sclerosis and history of facial myokymia or hemifacial spasm. METHODOLOGY: We reviewed the clinical features, radiologic features, and treatment outcomes of 35 patients with a diagnosis of multiple sclerosis and facial myokymia (28) or hemifacial spasm (7) seen at Mayo Clinic (Rochester, MN). RESULTS: Facial myokymia was associated with a clinical or radiologic relapse in 11 of 28 patients. In 27 of 28 patients with facial myokymia, symptom resolution occurred within months regardless of treatment. An ipsilateral pontine lesion was found in 3 of 7 cases with hemifacial spasm. Hemifacial spasm was associated with a clinical or radiologic relapse in 3 of 7 cases. Hemifacial spasm resolved within 4 years in 5 of 7 cases, with the remaining cases persisting up to 9 years despite treatment. CONCLUSIONS: Facial myokymia and hemifacial spasm occurring in patients with multiple sclerosis is associated with an ipsilateral pontine MRI lesion in a minority of patients. Facial myokymia is a self-limited process while hemifacial spasm can be persistent in a minority of patients, despite treatment. PMID- 29266037 TI - The Efficacy of Therapeutic Plasma Exchange in Antiphospholipid Antibody-positive Patients With Spontaneous Intracerebral Hemorrhage and High D-dimer Levels. AB - OBJECTIVE: We investigated the efficacy of plasma exchange (PE) in antiphospholipid antibody (aPL)-positive patients with a spontaneous intracerebral hemorrhage (ICH) and high D-dimer levels. MATERIALS AND METHODS: From May 2013 to May 2016, we evaluated 32 patients who were below the age of 50 and presented with spontaneous ICH. Five patients were positive for aPL antibody and 3 had a higher level of D-dimer. These 3 patients underwent 5 sessions of PE using fresh frozen plasma as replacement fluid. We analyzed the days postadmission until PE-start, the days of intensive care unit (ICU) hospitalization, D-dimer series, Glasgow Coma Scale (GCS) scores, and modified Rankin scale (mRS) scores. D-dimer levels and GCS scores were recorded at both pre-PE and post-PE stages. The mRS scores were recorded at pre-PE stage and 3 months post-PE. RESULTS: The mean postadmission period until PE-start was 8.33 days. The mean ICU hospitalization was 17.33 days. The D-dimer level pre-PE ranged from 2.34 to 5.44 mg/L fibrinogen equivalent unit (FEU). The D-dimer level post-PE ranged from 1.05 to 3.30 mg/L FEU. The amount of decline of the D-dimer level between pre-PE and post-PE ranged from 0.65 to 2.14 mg/L FEU. The GCS score pre-PE was between 7 and 8. The highest post-PE GCS score was 14. The improved GCS scores post-PE ranged from 3 to 6. The improved mRS scores of 3 months post PE ranged from 3 to 4. CONCLUSIONS: The concurrent presence of positive aPL and a higher D-dimer level may worsen the neurological outcome of patients with a spontaneous ICH. Aggressive PE is effective for the treatment of such patients, decreasing the extent of the ICU hospitalization. PMID- 29266038 TI - Factors Predictive of Severe Multiple Sclerosis Disease Reactivation After Fingolimod Cessation. AB - BACKGROUND: Fingolimod withdrawal may trigger the return of pretreatment disease activity. It is difficult to identify patients at risk of disease reactivation. We compared the demographic and clinical features of patients experiencing severe disease reactivation (SDR) after fingolimod cessation with those of patients who did not. METHODS: All patients who commenced fingolimod and who continued therapy for at least 6 months were included. The demographic and clinical features of the 2 groups (SDR vs. no SDR) were assessed. RESULTS: Forty-four of 303 patients discontinued fingolimod for various reasons. Among these, 31 fulfilled our inclusion criteria and 8 (25.8%) exhibited SDR after drug cessation. The mean time for SDR was 2.6 months (range, 2 to 3 mo). The annualized relapse rate before fingolimod therapy was higher in the SDR than in the non-SDR group (1.59 vs. 0.81) (P=0.018). Although statistical significance was not attained, the mean Expanded Disability Status Scale score at the time of fingolimod cessation was higher in the non-SDR than in the SDR group (2.5 vs. 1.12) (P=0.074). CONCLUSIONS: SDR may develop within the first 3 months after cessation of fingolimod. Patients with higher annualized relapse rates and lower Expanded Disability Status Scale scores before commencing fingolimod treatment were more likely to exhibit SDR. PMID- 29266039 TI - Acetazolamide-responsive Episodic Ataxia Without Baseline Deficits or Seizures Secondary to GLUT1 Deficiency: A Case Report and Review of the Literature. AB - INTRODUCTION: Glucose transporter type 1 deficiency syndrome (GLUT1 DS) is caused by impaired glucose transport across the blood-brain barrier and commonly presents as severe early onset epilepsy, developmental delay, and movement abnormalities. In rare instances, GLUT1 DS can present as a paroxysmal movement disorder without the other classic symptoms. Episodic ataxia (EA) secondary to GLUT1 DS has been previously reported, but all previous patients had seizures and/or baseline abnormalities on neurological examination. Isolated acetazolamide responsive EA secondary to GLUT1 DS without deficits on neurological examination and without seizures has not been described. CASE REPORT: A 4-year-old boy presented with EA, no baseline neurological abnormalities, and no history of seizures. He was initiated on acetazolamide with a >=75% improvement in frequency and severity of episodes. A genetic testing panel for EAs subsequently returned positive for a mutation in the SLC2A1 gene and cerebrospinal fluid analysis showed hypoglycorrhachia in the setting of normal blood glucose, which confirmed the diagnosis of GLUT1 DS. His symptoms resolved completely with ketogenic diet initiation even with discontinuation of acetazolamide. CONCLUSIONS: To our knowledge, this represents one of the mildest described presentations of nonepileptic GLUT1 DS consisting of acetazolamide-responsive EA without seizures or baseline neurological examination abnormalities. Our experience supports increased vigilance for this treatable cause of EA. PMID- 29266040 TI - Remote Intracerebral Hemorrhage Following Intravenous Thrombolysis in Pregnancy at 31 Weeks Gestation: A Case Report and Review of the Literature. AB - INTRODUCTION: Intravenous recombinant tissue-type plasminogen activator thrombolysis in pregnancy for acute ischemic stroke is infrequent. As a rare complication of thrombolysis, remote intracerebral hemorrhage (rICH) whose mechanisms are unclear has not gained enough attention until now. CASE REPORT: We present here a case of 26-year-old pregnant woman at 31 weeks gestation who suffered from sudden onset right-sided hemiparesis and slurred speech. She successfully received intravenous recombinant tissue-type plasminogen activator thrombolysis within 2.5 hours from stroke onset. Further workup demonstrated multiple and bilateral acute cerebral infarcts due to cardioembolism. At 6 hours after thrombolysis, multifocal intracerebral hemorrhages were developed in her left cerebellum and right temporal cortex, remote from the initial infarct areas. However, the patient achieved a final complete recovery of symptoms. Despite diffusion-weighted imaging could not confirm infarct in the areas of hemorrhages, multiple cerebral embolism was suggested to be involved in the etiology of rICH. CONCLUSIONS: rICH is different from local intracerebral hemorrhage in its risk factors, neurological outcomes, and underlying mechanisms. Patients with rICH may have favorable outcomes and multiple cerebral embolism is still one of the important mechanisms for postthrombolytic rICH. PMID- 29266041 TI - Acute Brachial Radiculoplexopathy and Giant Cell Arteritis. AB - INTRODUCTION: Giant cell arteritis (GCA), a vasculitis involving large-sized and medium-sized vessels (which most commonly involves temporal arteries), is easily recognized in older patients presenting with headache, scalp tenderness, and raised inflammatory markers. Neurological complications (either central or peripheral) are classically described in GCA. CASE REPORT: We report the case of an 85-year-old woman with bilateral acute brachial radiculoplexopathy, a rare neurological complication of GCA. She also presented right oculomotor palsy (with ptosis) and raised inflammatory markers, but she did not complain of the other classic cranial symptoms of the disease. We compare this case with 16 similar cases reported in the medical literature. CONCLUSIONS: In assessing a patient over 50 years of age with unexplained (unilateral or bilateral) brachial radiculoplexopathy (especially if C5-C6 nerve roots are affected) and elevated inflammatory markers, we would recommend specific enquiries with regard to the manifestations of GCA. The purpose is to reduce the risk of missing the wider spectrum of this condition and minimize the subsequent risk for disability of this treatable disease. PMID- 29266042 TI - Neuroprotective Effects of Minocycline: Expanding its Use in Clinical Medicine. PMID- 29266043 TI - What is Clinical Efficacy of Transesophageal Echocardiography in Patients With Cryptogenic Stroke?: A Critically Appraised Topic. AB - BACKGROUND: Adults with cryptogenic stroke often undergo transesophageal echocardiogram (TEE) because this is the gold-standard for evaluation of potential proximal sources of emboli. The risks of performing this invasive test must be weighed against its clinical efficacy and limitations, determined by the rate of positive findings, and the impact on clinical outcome for the patient. OBJECTIVE: To critically appraise current evidence regarding the rate of positive TEE findings in cryptogenic stroke patients, and analyze the implications of these findings on management decisions and outcomes. METHODS: The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, and vascular neurology and cardiology content experts. RESULTS: TEE commonly identifies abnormalities, including aorta atherosclerosis in 51%, patent foramen ovale in 43%, and atrial septal aneurysm in 13% of patients. Findings such as left-sided chamber thrombus or intracardiac tumor that definitively warrant a change in management by guideline-supported use of anticoagulation are less common, occurring in ~3% of patients. CONCLUSIONS: TEE identifies potential causal sources of embolus in patients with cryptogenic stroke that leads to changes in management and outcomes at least 3% of the time. Other findings, particularly aorta atherosclerosis, are identified much more commonly but the causal link to stroke is uncertain, thus changes in management in these cases is variable and data describing resulting outcomes are lacking. PMID- 29266044 TI - Nurse Leadership Style, Nurse Satisfaction, and Patient Satisfaction: A Systematic Review. AB - The purpose of this systematic review was to synthesize current evidence on nursing leadership styles, nurse satisfaction, and patient satisfaction. Results suggest that relational leadership traits contribute to greater nurse satisfaction whereas task-oriented styles may decrease nurse satisfaction. Minimal information for the connection between nursing leadership and patient satisfaction was found. PMID- 29266045 TI - Radiographic Evaluation of Acetabular Fractures: Review and Update on Methodology. AB - Despite increased availability of modern imaging techniques, plain radiographs remain the initial step in the classification of acetabular fractures. The ability to interpret the injury configuration allows the surgeon to develop a thorough preoperative plan and to evaluate the quality of reduction and fixation intraoperatively. Proficiency in the mental conversion of a two-dimensional radiograph into a three-dimensional conceptual image is imperative. The widely used radiographic classification scheme developed by Judet and Letournel in the 1960s is both practical and simple. However, understanding the subtleties of the fracture pattern can be a challenge even for experienced surgeons. Current evaluation methods include CT and three-dimensional reconstructions in addition to plain radiographs. Our diagnostic algorithm uses three plain radiographs to classify the fracture into one of the 10 fracture patterns described by Judet and Letournel. PMID- 29266046 TI - RETINAL ARTERY OCCLUSION AFTER INTRAVASCULAR PROCEDURES: Case Series and Literature Review. AB - PURPOSE: To evaluate clinical characteristics and possible mechanisms of retinal artery occlusion (RAO) after intravascular procedures. METHODS: This study is retrospective case series and literature review. Twenty-seven patients with intravascular procedure-associated RAO (10 new patients and 17 from previous reports) were divided into Groups 1 and 2 according to assumed etiology-dislodged and new emboli, respectively. Clinical features and etiology of RAO were analyzed. RESULTS: Branch and central RAO were observed in 17 (63%) and 10 (37%) patients, respectively, and 61.1% of patients exhibited final BCVA >=20/40. Intravascular procedures were performed at the carotid artery (48.1%), heart (25.9%), carotid artery or heart (3.7%), brain (11.1%), scalp/glabella (7.4%), and thyroid (3.7%). Ratio of patients with immediate and delayed (>=24 hours after procedure) onset of RAO was 17 (63.0%):10 (37.0%). In Group 1 (n = 16), RAO was associated with dislodged plaques in the carotid artery (9; 56.3%), heart (6; 37.5%), or carotid artery/heart (1; 6.3%), and one patient each experienced acute brain infarction and contralateral branch retinal artery occlusion. In group 2 (n = 11), RAO was associated with new thrombi (6; 54.5%) or emboli (5; 45.5%), and one patient experienced ocular pain, ophthalmoplegia, and blepharoptosis. CONCLUSION: Intravascular procedures might result in RAO because of embolic plaques dislodged from the carotid artery or heart, or new thrombi or embolic materials migrating through collateral channels. Branch retinal artery occlusion was more frequent than central retinal artery occlusion after intravascular procedures, which resulted in relatively good visual outcomes. Patients should be informed about immediate or delayed presentation of RAO after intravascular procedures. PMID- 29266047 TI - PROSPECTIVE RANDOMIZED TRIAL ASSESSING THE IMPACT OF FEEDBACK MECHANISMS ON PATIENT POSITIONING. AB - PURPOSE: To investigate the use of a head-fixed feedback sensor to improve good positioning times after macular hole or retinal detachment surgery. The instructional methods, macular hole closure rates, and questionnaire responses were also evaluated. METHODS: After randomization, sensor devices with different feedback types (none/acoustic/vibration) were fixed on the patients' heads. Two positioning recommendations (verbal/illustrated) were used. The posturing data were logged every 500 ms for 24 hours. RESULTS: Forty-eight data sets (24 per group) were evaluated. Using sensory feedback, the median time for face-down positioning after macular hole surgery (Group 1) was significantly boosted from 463 minutes (range: 61-1,168) to 1,257 minutes (range: 1,024-1,327). The side positioning time after retinal detachment surgery (Group 2) increased from a median of 1,032 minutes (range: 520-1,165) to 1,284 minutes (range: 1,231-1,437). The night-time alarm records were reduced; however, the instructional methods exhibited no noteworthy effects. The questionnaires indicated positive acceptance of the sensors. CONCLUSION: Sensory feedback may help in cases where face-down or side positioning is recommended. These constant reminders were superior to verbal or written reminders; however, further studies are required to assess the clinical impact of sensory feedback on patient positioning. PMID- 29266049 TI - Correspondence. PMID- 29266050 TI - Technical Challenges: Pitfalls and Disasters. PMID- 29266048 TI - CHOROIDAL THICKENING AND PACHYCHOROID IN CUSHING SYNDROME: Correlation With Endogenous Cortisol Level. AB - PURPOSE: To investigate subfoveal choroidal thickness and pachychoroid and their correlation with hormone level in patients with endogenous Cushing syndrome (CS). METHODS: We enrolled a consecutive series of patients with CS and healthy controls. All participants had swept-source optical coherence tomography. All patients with CS had hormone test including morning plasma-free cortisol, 24-hour urine-free cortisol (24UFC), and plasma adrenocorticotropic hormone. We compared subfoveal choroidal thickness and pachychoroid changes between two groups. We performed univariate and multivariate analysis to study correlation between hormone level and choroid thickness as well as pachychoroid in patients with CS. RESULTS: Compared with control group, Cushing group had significantly greater subfoveal choroidal thickness (371.6 +/- 114.9 and 320.0 +/- 74.0, P = 0.002) and higher proportion of eyes with pachychoroid (53.1 and 14.3%, P < 0.001). Subfoveal choroidal thickness was significantly correlated with 24UFC (P = 0.007) but not with plasma-free cortisol (P = 0.48) or adrenocorticotropic hormone (P = 0.56). Pachychoroid was significantly correlated with 24UFC (P = 0.03) but not with plasma-free cortisol (P = 0.24) or adrenocorticotropic hormone (P = 0.32). CONCLUSION: There was a positive correlation between elevated 24UFC and choroid thickening as well as pachychoroid, indicating the importance of normal endogenous cortisol level in maintaining the human choroid vasculature. PMID- 29266051 TI - Reexamination of a Battlefield Trauma Golden Hour Policy. AB - BACKGROUND: Most combat casualties who die, do so in the prehospital setting. Efforts directed toward alleviating prehospital combat trauma death, known as killed in action (KIA) mortality, have the greatest opportunity for eliminating preventable death. METHODS: Four thousand five hundred forty-two military casualties injured in Afghanistan from September 11, 2001, to March 31, 2014, were included in this retrospective analysis to evaluate proposed explanations for observed KIA reduction after a mandate by Secretary of Defense Robert M. Gates that transport of injured service members occur within 60 minutes. Using inverse probability weighting to account for selection bias, data were analyzed using multivariable logistic regression and simulation analysis to estimate the effects of (1) gradual improvement, (2) damage control resuscitation, (3) harm from inadequate resources, (4) change in wound pattern, and (5) transport time on KIA mortality. RESULTS: The effect of gradual improvement measured as a time trend was not significant (adjusted odds ratio [AOR], 0.99; 95% confidence interval [CI], 0.94-1.03; p = 0.58). For casualties with military Injury Severity Score of 25 or higher, the odds of KIA mortality were 83% lower for casualties who needed and received prehospital blood transfusion (AOR, 0.17; 95% CI, 0.06 0.51; p = 0.002); 33% lower for casualties receiving initial treatment by forward surgical teams (AOR, 0.67; 95% CI, 0.58-0.78; p < 0.001); 70%, 74%, and 87% lower for casualties with dominant injuries to head (AOR, 0.30; 95% CI, 0.23-0.38; p < 0.001), abdomen (AOR, 0.26, 95% CI, 0.19-0.36; p < 0.001) and extremities (AOR, 0.13; 95% CI, 0.09-0.17; p < 0.001); 35% lower for casualties categorized with blunt injuries (AOR, 0.65; 95% CI, 0.46-0.92; p = 0.01); and 39% lower for casualties transported within one hour (AOR, 0.61; 95% CI, 0.51-0.74; p < 0.001). Results of simulations in which transport times had not changed after the mandate indicate that KIA mortality would have been 1.4% higher than observed, equating to 135 more KIA deaths (95% CI, 105-164). CONCLUSION: Reduction in KIA mortality is associated with early treatment capabilities, blunt mechanism, select body locations of injury, and rapid transport. LEVEL OF EVIDENCE: Therapy, level III. PMID- 29266052 TI - The pitfalls of resuscitative endovascular balloon occlusion of the aorta: Risk factors and mitigation strategies. AB - Despite technological advancements, REBOA is associated with significant risks due to complications of vascular access and ischemia-reperfusion. The inherent morbidity and mortality of REBOA is often compounded by coexisting injury and hemorrhagic shock. Additionally, the potential for REBOA-related injuries is exaggerated due to the growing number of interventions being performed by providers who have limited experience in endovascular techniques, inadequate resources, minimal training in the technique, and who are performing this maneuver in emergency situations. In an effort to ultimately improve outcomes with REBOA, we sought to compile a list of complications that may be encountered during REBOA usage. To address the current knowledge gap, we assembled a list of anecdotal complications from high-volume REBOA users internationally. More importantly, through a consensus model, we identify contributory factors that may lead to complications and deliberate on how to recognize, mitigate, and manage such events. An understanding of the pitfalls of REBOA and strategies to mitigate their occurrence is of vital importance to optimize patient outcomes. PMID- 29266053 TI - Colon-sparing surgery for Clostridium difficile: Translatable lessons for the international humanitarian surgeon? PMID- 29266054 TI - Featured Articles for CME Credit January 2018. PMID- 29266056 TI - Of Cells and Microparticles: Assets and Liabilities of HLA Antibody Detection. AB - The evolution of antibody detection from cell- to bead-based technology has positively impacted the ability to allocate organs in a safe and timely manner. The devil, of course, is in the details that delineate how these assays are performed and applied and to recognize that while there have been some truly amazing technological advances (assets), they are still imperfect and subject to error (liabilities). This review identifies the strengths of HLA antibody assays, highlights their weaknesses and offers approaches for standardization. PMID- 29266057 TI - The Biology of IgG Subclasses and Their Clinical Relevance to Transplantation. AB - Immunoglobulin G (IgG) is the dominant immunoglobulin and can be divided into 4 distinct subclasses. The evolution of IgG subclass switches is regulated by interaction with T cells and follows a 1-way direction (IgG3 -> IgG1 -> IgG2 -> IgG4). Based on their structure, the 4 IgG subclasses can initiate different effector function such as complement activation, recruitment of various cells by Fc receptors, and agonistic signaling. Using current assays for HLA antibody detection as a template and replacing the generic reporter antibody with IgG subclass-specific reporter antibodies, it is possible to investigate the IgG subclasses of HLA antibodies. There are 15 different IgG subclass compositions possible. Based on the capability to activate the complement system and the class switch direction, 3 arbitrary patterns can be defined (ie, only complement binding subclasses [IgG3 and/or IgG1], expansion to noncomplement-binding subclasses [IgG3 and/or IgG1 plus IgG2 and/or IgG4], and switch to noncomplement binding subclasses [IgG2 and/or IgG4]). The latter group accounts for less than 5%, whereas the former 2 groups have a similar prevalence close to 50%. In the past 5 years, several studies correlated the IgG subclass pattern with occurrence of antibody-mediated rejection and allograft outcomes. Because of differences of the used IgG subclass assay, the time point of analyses, and the definition of outcomes, a clear picture has not emerged yet. Future needs are standardization of the assay, a more detailed knowledge of the initiated effector functions, and more well-designed clinical studies also looking at changes of the IgG subclass pattern over time. PMID- 29266058 TI - Clinical Utility of Complement Dependent Assays in Kidney Transplantation. AB - Formation of antibodies against polymorphic HLA molecules on donor endothelium is central to the pathogenesis of antibody-mediated rejection, the dominant cause of long-term kidney allograft loss. Although introduction of the single-antigen bead assay has greatly facilitated the immune risk assessment of transplant recipients, it is recognized that not all IgG HLA antibodies detected using this method are equally relevant. In recent years, novel assays (C4d, C1q, C3d) have been developed to interrogate the complement-activating potential of anti-HLA antibodies in vitro, with the hypothesis that complement-fixing antibodies are more immediately injurious to the graft compared with noncomplement-binding antibodies. Although initial studies demonstrated the potential of these assays to risk-stratify antibodies beyond the conventional limited metric of mean fluorescence intensity values, new data from recent analyses challenge some of these early findings. In this review, we examine the technical aspects of these assays and key studies that evaluated the discriminant capacity of these tests to predict numerous outcomes in kidney transplantation. We discuss conflicting data and emerging controversies in the context of recent experimental evidence which offer new insights into the major factors that influence complement activation. Finally, we provide our perspective on the current role and utility of complement diagnostic assays as 1 variable in the multifactorial risk assessment and management of kidney transplant recipients. PMID- 29266059 TI - HLA Diagnostics: Evaluating DSA Strength by Titration. AB - HLA antibodies, and specifically donor-specific-HLA antibodies, play a key role in transplant-related diagnostics and decision-making. It is now clear that the simple differentiation between absence and presence of HLA donor-specific antibodies does not provide sufficient granularity in all clinical circumstances. It addition, knowledge of HLA antibody strength has potential utility at different stages of recipient evaluation along the transplant timeline from initial pretransplant evaluation, evaluation of a specific potential donor, and posttransplant monitoring for de novo donor-specific antibodies. Here we compare data evaluating HLA antibody strength using the conventional IgG-mean fluorescence intensity approach with serial dilution studies (titration) and of C1q binding (C1q-mean fluorescence intensity). The added value of titration studies along the 3 milestones of the transplant cycle is emphasized. PMID- 29266060 TI - Visit-to-visit (long-term) and ambulatory (short-term) blood pressure variability to predict mortality in an elderly hypertensive population. AB - OBJECTIVES: To explore the association of different types of blood pressure (BP) variability measures estimated from either short-term ambulatory reading-to reading or long-term clinic visit-to-visit BP records with long-term survival in an elderly treated hypertensive population. METHODS: A subset of patients (n = 508) aged at least 65-years was studied from the Second Australian National Blood Pressure study. We estimated SBP and DBP BP variability as the SD of ambulatory (24-h, daytime, night-time) and clinic visit-to-visit BP directly from all corresponding on-treatment within-individual BP records. Ambulatory 'weighted day night' variability was calculated as a weighted mean of daytime and night-time SD. Cox-proportional hazard models adjusted for baseline risk factors (Model 1) and corresponding on-treatment BP (Model 2) or average night-time SBP (best predictive BP measure for outcome) (Model 3) were used to determine the relationship between long-term outcome and BP variability. RESULTS: Over a median of 10.6 years, 101 patients died from any cause, of which 51 deaths were cardiovascular. We observed increase in 'daytime' and 'weighted day-night' SBP/DBP variability was significantly associated with increased all-cause mortality in all models. For cardiovascular mortality, only 'weighted day-night' SBP variability significantly predicted risk in all models (Model 3 hazard ratio: 1.09, 95% confidence interval: 1.00-1.19, P = 0.04). Long-term BP variability was not associated with any outcome. On direct comparison, both 'daytime' and 'weighted day-night' BP variability measures provided similar prognostic information. CONCLUSION: Short-term 'daytime' and 'weighted day-night' SBP variability from ambulatory BP recordings was a better predictor of mortality in elderly treated hypertensive patients than long-term BP variability from visit-to visit BP recordings. PMID- 29266061 TI - Endogenous calcitonin gene-related peptide suppresses ischemic brain injuries and progression of cognitive decline. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and produced by alternative splicing of the transcript of the calcitonin/CGRP gene. Originally identified as a strong vasodilatory and hypotensive peptide, CGRP is now known to be a pleiotropic molecule distributed in various organs, including the brain. METHOD: In this study, we used CGRP knockout mice (CGRP-/-) to examine the actions of endogenous CGRP during cerebral ischemia. To induce acute and chronic cerebral ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) and bilateral common carotid artery stenosis (BCAS). RESULTS: In the cerebral cortex of wild-type mice, CGRP expression was upregulated after acute infarction. In CGRP-/- subjected to MCAO or BCAS, recovery of cerebral blood flow was slower and exhibited more extensive neuronal cell death. Expression of the inflammatory cytokines was higher in CGRP-/- than wild type in the acute phase of ischemia. Pathological analysis during the chronic phase revealed more extensive neuronal cell loss and demyelination and higher levels of oxidative stress in CGRP-/- than wild-type. CGRP-/- also showed less compensatory capillary growth. In an eight-arm radial maze test, CGRP-/- exhibited poorer reference memory than wild-type. On the other hand, CGRP administration promoted cerebral blood flow recovery after cerebral ischemia. We also found that CGRP directly inhibited the cell death of primary cortical neurons. CONCLUSION: These results indicate endogenous CGRP is protective against ischemia-induced neuronal cell injury. CGRP could, thus, be a novel candidate for use in the treatment of both cerebral ischemia and progression of cognitive decline. PMID- 29266062 TI - Opioid Use in Pregnancy, Neonatal Abstinence Syndrome, and Childhood Outcomes: Executive Summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, American College of Obstetricians and Gynecologists, American Academy of Pediatrics, Society for Maternal-Fetal Medicine, Centers for Disease Control and Prevention, and the March of Dimes Foundation. PMID- 29266063 TI - Committee Opinion No. 722: Marijuana Use During Pregnancy and Lactation. PMID- 29266068 TI - ACOG Publications. PMID- 29266064 TI - In Reply. PMID- 29266069 TI - ACOG Practice Bulletin No. 188 Summary: Prelabor Rupture of Membranes. AB - Preterm delivery occurs in approximately 12% of all births in the United States and is a major factor that contributes to perinatal morbidity and mortality (1, 2). Preterm prelabor rupture of membranes (also referred to as premature rupture of membranes) (PROM) complicates approximately 3% of all pregnancies in the United States (3). The optimal approach to clinical assessment and treatment of women with term and preterm PROM remains controversial. Management hinges on knowledge of gestational age and evaluation of the relative risks of delivery versus the risks of expectant management (eg, infection, abruptio placentae, and umbilical cord accident). The purpose of this document is to review the current understanding of this condition and to provide management guidelines that have been validated by appropriately conducted outcome-based research when available. Additional guidelines on the basis of consensus and expert opinion also are presented. PMID- 29266070 TI - ACOG Practice Bulletin No. 189 Summary: Nausea And Vomiting Of Pregnancy. AB - Nausea and vomiting of pregnancy is a common condition that affects the health of a pregnant woman and her fetus. It can diminish a woman's quality of life and also significantly contributes to health care costs and time lost from work (1, 2). Because morning sickness is common in early pregnancy, the presence of nausea and vomiting of pregnancy may be minimized by obstetricians, other obstetric care providers, and pregnant women and, thus, undertreated (1). Furthermore, some women do not seek treatment because of concerns about the safety of medications (3). Once nausea and vomiting of pregnancy progresses, it can become more difficult to control symptoms. Treatment in the early stages may prevent more serious complications, including hospitalization (4). Safe and effective treatments are available for more severe cases, and mild cases of nausea and vomiting of pregnancy may be resolved with lifestyle and dietary changes. The woman's perception of the severity of her symptoms plays a critical role in the decision of whether, when, and how to treat nausea and vomiting of pregnancy. Nausea and vomiting of pregnancy should be distinguished from nausea and vomiting related to other causes. The purpose of this document is to review the best available evidence about the diagnosis and management of nausea and vomiting of pregnancy. PMID- 29266071 TI - ACOG Committee Opinion No. 727 Summary: Cascade Testing: Testing Women For Known Hereditary Genetic Mutations Associated With Cancer. AB - "Cascade testing" refers to the performance of genetic counseling and testing in blood relatives of individuals who have been identified with specific genetic mutations. Testing protocols and other interventions may save lives and improve health and quality of life for these family members. Obstetrician-gynecologists should know who is eligible for cascade testing and should use all available resources to ensure that cascade testing is offered and occurs in a timely manner. Despite the clear health benefits for specific populations and individuals, obstetrician-gynecologists should be aware of the potential barriers to cascade testing and should know which options can help patients overcome those barriers. Such barriers, however, may be overcome with health care provider awareness and participation in local and state initiatives to improve implementation of cascade testing. Resources (available within federal and state agencies, professional societies, and in advocacy and community groups) are critical to the successful implementation of cascade testing. This Committee Opinion focuses specifically on cascade testing and the role of the obstetrician gynecologist in clinical and public health efforts to increase identification of women with hereditary cancer syndromes. PMID- 29266072 TI - ACOG Committee Opinion No. 728 Summary: Mullerian Agenesis: Diagnosis, Management, And Treatment. AB - Mullerian agenesis, also referred to as mullerian aplasia, Mayer-Rokitansky Kuster-Hauser syndrome, or vaginal agenesis, has an incidence of 1 per 4,500 5,000 females. Mullerian agenesis is cau0073ed by embryologic underdevelopment of the mullerian duct, with resultant agenesis or atresia of the vagina, uterus, or both. Patients with mullerian agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development. The most important steps in the effective management of mullerian agenesis are correct diagnosis of the underlying condition, evaluation for associated congenital anomalies, and psychosocial counseling in addition to treatment or intervention to address the functional effects of genital anomalies. The psychologic effect of the diagnosis of mullerian agenesis should not be underestimated. All patients with mullerian agenesis should be offered counseling and encouraged to connect with peer support groups. Future options for having children should be addressed with patients: options include adoption and gestational surrogacy. Assisted reproductive techniques with use of a gestational carrier (surrogate) have been shown to be successful for women with mullerian agenesis. Nonsurgical vaginal elongation by dilation should be the first-line approach. When well-counseled and emotionally prepared, almost all patients (90 96%) will be able to achieve anatomic and functional success by primary vaginal dilation. In cases in which surgical intervention is required, referrals to centers with expertise in this area should be considered because few surgeons have extensive experience in construction of the neovagina and surgery by a trained surgeon offers the best opportunity for a successful result. PMID- 29266073 TI - ACOG Committee Opinion No. 729 Summary: Importance Of Social Determinants Of Health And Cultural Awareness In The Delivery Of Reproductive Health Care. AB - Awareness of the broader contexts that influence health supports respectful, patient-centered care that incorporates lived experiences, optimizes health outcomes, improves communication, and can help reduce health and health care inequities. Although there is little doubt that genetics and lifestyle play an important role in shaping the overall health of individuals, interdisciplinary researchers have demonstrated how the conditions in the environment in which people are born, live, work, and age, play equally as important a role in shaping health outcomes. These factors, referred to as social determinants of health, are shaped by historical, social, political, and economic forces and help explain the relationship between environmental conditions and individual health. Recognizing the importance of social determinants of health can help obstetrician gynecologists and other health care providers better understand patients, effectively communicate about health-related conditions and behavior, and improve health outcomes. PMID- 29266074 TI - Clinical Updates in Women's Health Care Primary and Preventive Care Review Summary: Common Dermatologic Conditions. AB - The skin is the largest organ in the human body, and as such, cutaneous problems constitute a common component of visits to medical professionals. The skin functions as a physiologic barrier and a major organ of homeostasis. The practicing obstetrician-gynecologist can play an important role in identifying skin diseases and initiating management. Additionally, the skin often reflects internal disease states. An astute health care provider can identify systemic conditions early, with the goal of improving management. This monograph reviews common cutaneous conditions, both benign and malignant, hair and nail disorders, and skin conditions unique to the adult woman. PMID- 29266075 TI - ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes. AB - Preterm delivery occurs in approximately 12% of all births in the United States and is a major factor that contributes to perinatal morbidity and mortality (1, 2). Preterm prelabor rupture of membranes (also referred to as premature rupture of membranes) (PROM) complicates approximately 3% of all pregnancies in the United States (3). The optimal approach to clinical assessment and treatment of women with term and preterm PROM remains controversial. Management hinges on knowledge of gestational age and evaluation of the relative risks of delivery versus the risks of expectant management (eg, infection, abruptio placentae, and umbilical cord accident). The purpose of this document is to review the current understanding of this condition and to provide management guidelines that have been validated by appropriately conducted outcome-based research when available. Additional guidelines on the basis of consensus and expert opinion also are presented. PMID- 29266076 TI - ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. AB - Nausea and vomiting of pregnancy is a common condition that affects the health of a pregnant woman and her fetus. It can diminish a woman's quality of life and also significantly contributes to health care costs and time lost from work (1, 2). Because morning sickness is common in early pregnancy, the presence of nausea and vomiting of pregnancy may be minimized by obstetricians, other obstetric care providers, and pregnant women and, thus, undertreated (1). Furthermore, some women do not seek treatment because of concerns about the safety of medications (3). Once nausea and vomiting of pregnancy progresses, it can become more difficult to control symptoms. Treatment in the early stages may prevent more serious complications, including hospitalization (4). Safe and effective treatments are available for more severe cases, and mild cases of nausea and vomiting of pregnancy may be resolved with lifestyle and dietary changes. The woman's perception of the severity of her symptoms plays a critical role in the decision of whether, when, and how to treat nausea and vomiting of pregnancy. Nausea and vomiting of pregnancy should be distinguished from nausea and vomiting related to other causes. The purpose of this document is to review the best available evidence about the diagnosis and management of nausea and vomiting of pregnancy. PMID- 29266077 TI - ACOG Committee Opinion No. 727: Cascade Testing: Testing Women for Known Hereditary Genetic Mutations Associated With Cancer. AB - "Cascade testing" refers to the performance of genetic counseling and testing in blood relatives of individuals who have been identified with specific genetic mutations. Testing protocols and other interventions may save lives and improve health and quality of life for these family members. Obstetrician-gynecologists should know who is eligible for cascade testing and should use all available resources to ensure that cascade testing is offered and occurs in a timely manner. Despite the clear health benefits for specific populations and individuals, obstetrician-gynecologists should be aware of the potential barriers to cascade testing and should know which options can help patients overcome those barriers. Such barriers, however, may be overcome with health care provider awareness and participation in local and state initiatives to improve implementation of cascade testing. Resources (available within federal and state agencies, professional societies, and in advocacy and community groups) are critical to the successful implementation of cascade testing. This Committee Opinion focuses specifically on cascade testing and the role of the obstetrician gynecologist in clinical and public health efforts to increase identification of women with hereditary cancer syndromes. PMID- 29266078 TI - ACOG Committee Opinion No. 728: Mullerian Agenesis: Diagnosis, Management, And Treatment. AB - Mullerian agenesis, also referred to as mullerian aplasia, Mayer-Rokitansky Kuster-Hauser syndrome, or vaginal agenesis, has an incidence of 1 per 4,500 5,000 females. Mullerian agenesis is caused by embryologic underdevelopment of the mullerian duct, with resultant agenesis or atresia of the vagina, uterus, or both. Patients with mullerian agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development. The most important steps in the effective management of mullerian agenesis are correct diagnosis of the underlying condition, evaluation for associated congenital anomalies, and psychosocial counseling in addition to treatment or intervention to address the functional effects of genital anomalies. The psychologic effect of the diagnosis of mullerian agenesis should not be underestimated. All patients with mullerian agenesis should be offered counseling and encouraged to connect with peer support groups. Future options for having children should be addressed with patients: options include adoption and gestational surrogacy. Assisted reproductive techniques with use of a gestational carrier (surrogate) have been shown to be successful for women with mullerian agenesis. Nonsurgical vaginal elongation by dilation should be the first-line approach. When well-counseled and emotionally prepared, almost all patients (90 96%) will be able to achieve anatomic and functional success by primary vaginal dilation. In cases in which surgical intervention is required, referrals to centers with expertise in this area should be considered because few surgeons have extensive experience in construction of the neovagina and surgery by a trained surgeon offers the best opportunity for a successful result. PMID- 29266079 TI - ACOG Committee Opinion No. 729: Importance of Social Determinants of Health and Cultural Awareness in the Delivery of Reproductive Health Care. AB - Awareness of the broader contexts that influence health supports respectful, patient-centered care that incorporates lived experiences, optimizes health outcomes, improves communication, and can help reduce health and health care inequities. Although there is little doubt that genetics and lifestyle play an important role in shaping the overall health of individuals, interdisciplinary researchers have demonstrated how the conditions in the environment in which people are born, live, work, and age, play equally as important a role in shaping health outcomes. These factors, referred to as social determinants of health, are shaped by historical, social, political, and economic forces and help explain the relationship between environmental conditions and individual health. Recognizing the importance of social determinants of health can help obstetrician gynecologists and other health care providers better understand patients, effectively communicate about health-related conditions and behavior, and improve health outcomes. PMID- 29266080 TI - Reflections on 50 Years of Neuroscience Nursing: Movement Disorders, Neuromuscular Disease, and Multiple Sclerosis. AB - The American Association of Nursing was established in 1968 to support and advance the art and science of neuroscience nursing. During the course of 50 years, the Journal of Neuroscience Nursing has published numerous articles detailing the advances in the treatments of neurologic disease. The following highlights the strides achieved in the management of Parkinson disease, neuromuscular disease, and multiple sclerosis (MS). PMID- 29266081 TI - Online Depressive Symptom Self-Management: Comparing Program Outcomes for Adults With Multiple Sclerosis Versus Those With Other Chronic Diseases. AB - AIMS: The goals of the study were to evaluate participant engagement and effects of an Internet-based, self-directed program for depressive symptoms. We compared outcomes of adults with multiple sclerosis (MS) with those of adults with other chronic diseases. METHODS: This was a secondary analysis of a randomized controlled pilot study. Data were explored for differences between people diagnosed with MS and those with other chronic disease diagnoses. Data were obtained from 47 participants who participated in the original parent study (11 had MS). Participants with at least a moderate preexisting depressive symptom burden on the Patient Health Questionnaire (PHQ) were randomly divided into either a control group or the 8-week "Think Clearly About Depression" online depression self-management program. Study tools were administered at baseline, week 4, and week 8 to evaluate whether the online program improved depressive symptom self-management. Analysis examined differences between participants with and without an MS diagnosis in the treatment and control groups. RESULTS: Average baseline depressive symptom burdens were severe for those with MS and those without MS as measured by the PHQ. Number needed to treat analysis indicated that 1 in every 2 treatment group participants with MS found clinically significant reductions in depressive symptoms by week 8. All participants with MS completed all online program modules. When compared with those with other chronic diseases, participants with MS showed a trend toward greater improvements in the PHQ and health distress scores in addition to self-efficacy in exercising regularly, social/recreational activities, and controlling/managing depression at the end of 8 weeks. CONCLUSIONS: An online depressive symptom self-management program is acceptable to people with MS and may be helpful to address undertreated depressive symptoms. The number of participants limits available statistics and ability to generalize results. PMID- 29266082 TI - "Unwrap the Brain With Rap". PMID- 29266083 TI - The Simplest Idea Is the Best Idea. AB - A collaborative approach was used to ascertain an appropriate stimulus for the patients to remember their stroke-specific education. The stroke education had to stand out amidst the myriad of papers and folders patients are bombarded with in the hospital. The team came up with the simple idea of using a bright red folder. When the patients were called, the call center would prompt the patient by saying, "The stroke education was given to you in a bright red folder." Before the implementation of the red folders, only 81.5% of the patients remembered receiving stroke education. After the implementation of the red folders, 96.8% remembered receiving stroke education. The principle of Occam's razor proved to be correct in our study. A very simple idea such as changing the color of the folders to bright red proved to have very meaningful results. PMID- 29266084 TI - The Relationship Between Pain Interference and Psychosocial Well-Being Among Veterans With Spinal Cord Injuries/Disorders. AB - OBJECTIVES: The study objectives were to compare psychosocial well-being in individuals with spinal cord injuries/disorders (SCI/D) and above-mean ("high") versus below-mean ("low") pain interference, and to determine whether psychosocial well-being was negatively associated with pain interference. METHODS: Data were collected via a cross-sectional survey mailed in late 2014 to early 2015 to a national sample of veterans with SCI/D who received prior-year Veterans Affairs healthcare and assessed demographics, injury-related factors, select health conditions, pain interference, and psychosocial well-being. Bivariate comparisons and multivariate linear regressions identified factors related to higher pain interference. RESULTS: Approximately 79% of the sample (n = 813) reported high pain interference. Veterans with high (vs. low) pain interference reported worse perceptions of all included psychosocial well-being measures. Regression results indicated that higher pain interference was associated with higher grief/loss (beta = 0.38, P < .0001) and negative psychosocial illness impact (beta = 0.39, P < .0001), and lower positive affect (beta = -0.39, P < .0001), resilience (beta = -0.31, P < .0001), and life satisfaction (beta = -0.39, P < .0001). CONCLUSIONS: The pain experience is independently associated with poor psychosocial well-being among individuals with SCI/D. Efforts to decrease perceptions of pain interference and improve factors associated with psychosocial well-being may symbiotically improve outcomes in SCI/D cohorts. Such efforts may focus on effective pain management programs aligned with patients' treatment preferences. PMID- 29266085 TI - Innovation in Hospital Revenues: Developing Retail Sales Channels. AB - Hospitals are facing increasing cost pressures due to cutbacks by Medicare, Medicaid, and managed-care organizations. There are also rising concerns that public policy may exacerbate the problem. In lieu of these concerns, nascent innovative ways of generating increased revenues are beginning to appear. In particular, a few hospitals have adopted retail sales practices to generate significant nonmedical services revenues. The hospital retail sales opportunity has been compared with that of the airport industry where nearly 50% of revenues are generated by sales of retail products as opposed to aeronautical-related transactions. This initial investigation included a qualitative interview of a health care retail sales expert and a pilot survey of 100 hospital senior executives to gauge the current state of this phenomenon. The industry expert suggested that only 2% of US hospitals have pursued this initiative in a meaningful way. Of the 44 survey responses, only 9 institutions were engaged in e commerce or retail sales activities. Questions remain as to why this opportunity remains unrealized, and additional research is proposed. PMID- 29266087 TI - The Impact of Big Data on Chronic Disease Management. AB - Population health management and specifically chronic disease management depend on the ability of providers to prevent development of high-cost and high-risk conditions such as diabetes, heart failure, and chronic respiratory diseases and to control them. The advent of big data analytics has potential to empower health care providers to make timely and truly evidence-based informed decisions to provide more effective and personalized treatment while reducing the costs of this care to patients. The goal of this study was to identify real-world health care applications of big data analytics to determine its effectiveness in both patient outcomes and the relief of financial burdens. The methodology for this study was a literature review utilizing 49 articles. Evidence of big data analytics being largely beneficial in the areas of risk prediction, diagnostic accuracy and patient outcome improvement, hospital readmission reduction, treatment guidance, and cost reduction was noted. Initial applications of big data analytics have proved useful in various phases of chronic disease management and could help reduce the chronic disease burden. PMID- 29266086 TI - Using the Electronic Health Record Data in Real Time and Predictive Analytics to Prevent Hospital-Acquired Postoperative/Surgical Site Infections. AB - Of critical concern to hospitals today is the prevention of postoperative (surgical site) infections that often result in increased lengths of stays for patients, increased resource demands and costs, loss of public trust and lawsuits, and needless pain and suffering for patients and their families. While all surgical patients have the potential to develop a postoperative infection, the main challenge is to identify key risk factors (both patient centered and operational) through an electronic early-warning system to reduce the likelihood of a postoperative infection from occurring. Currently, most postoperative infection risk prevention practices encompass limited use of informatics technologies or do not maximize the potential benefits. In addition, from a research perspective, there has been more focus on extrapolating electronically housed data (eg, from progress notes, operative notes, laboratory, pharmacy, radiology) retrospectively to describe poor patient outcomes for benchmarking purposes (revealing poor results and opportunities for improvement) rather than using similar sources of real-time data to prevent poor patient outcomes from occurring. This article proposes that standardized indicators, both patient centered and operational, linked to the patient's electronic health record could allow for implementation of 24/7, "real-time" monitoring/surveillance to implement well-timed preventive interventions scaled to each patient and facility to assist caregivers in reducing the numbers of postoperative infections and improve the overall quality and costs of patient care. PMID- 29266088 TI - Health Care Leadership: Managing Knowledge Bases as Stakeholders. AB - Communities are composed of many organizations. These organizations naturally form clusters based on common patterns of knowledge, skills, and abilities of the individual organizations. Each of these spontaneous clusters represents a distinct knowledge base. The health care knowledge base is shown to be the natural leader of any community. Using the Central Florida region's 5 knowledge bases as an example, each knowledge base is categorized as a distinct type of stakeholder, and then a specific stakeholder management strategy is discussed to facilitate managing both the cooperative potential and the threatening potential of each "knowledge base" stakeholder. PMID- 29266089 TI - Physician Personal Services Contract Enforceability: The Influence of the Thirteenth Amendment. AB - We explore the influence of the Thirteenth Amendment to the US Constitution on the enforceability of personal services contracts for physicians. This influence extends from the ambiguous definition to the legal interpretation of personal services contracts. The courts have struggled with determining contracts to be a personal service and whether to grant injunctions for continued performance. The award or denial of damages due to a breach of contract is vested in these enforceability complications. Because of the Thirteenth Amendment's influence, courts and contracting parties will continue to struggle with physician personal services contract enforceability; although other points of view may exist. Possible solutions are offered for health care contract managers dealing with challenges attributable to physician personal services contracts. PMID- 29266090 TI - Management Team Perceptions of Risks and Strategies for Preventing Falls Among Short-Stay Patients in Nursing Homes. AB - We sought to understand strategies reported by members of the nursing home management team used to prevent falls in short-stay nursing home patients. Using Donabedian's model of structure, process, and outcomes, we interviewed 16 managers from 4 nursing homes in central North Carolina. Nursing home managers identified specific barriers to fall prevention among short-stay patients including rapid changes in functional and cognitive status, staff unfamiliarity with short-stay patient needs and patterns, and policies impacting care. Few interventions for reducing falls among short-stay patients were used at the structure level (eg, specialized units, workload ratio, and staffing consistency); however, many process-level interventions were used (eg, patient education on problem solving, self-care/mobility, and safety). We described several barriers to fall prevention among short-stay patients in nursing homes. From these descriptions, we propose three interventions that might reduce falls for short-stay patients and could be tested in future research: (1) clustering short-stay patients within a physical location to permit higher staff-patient ratios and enhanced surveillance, (2) population-based prevention interventions to supplement existing individually tailored prevention strategies (eg, toileting schedules, medication review for all), and (3) transitional care interventions that transmit key information from hospitals to nursing homes. PMID- 29266091 TI - International Classification of Diseases, Tenth Revision Implementation: Is the Workforce Ready? AB - After many delays, the United States finally implemented the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedural Coding System on October 1, 2015, bringing the United States into line with other industrialized nations, most of which had been using the International Classification of Diseases, Tenth Revision for many years. We outline the benefits and challenges to the preparatory activities of the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedural Coding System implementation for the US health care industry. To ease the transition, the Centers for Medicare & Medicaid Services allowed health care facilities to submit test claims prior to the implementation date and delivered feedback on the acceptability of those claims. Early results indicated a relatively smooth transition, although some questions regarding the available data remain. Additional data, especially data concerning outcomes, are required. PMID- 29266092 TI - Effect of Carbohydrate Mouth Rinse on Performance after Prolonged Submaximal Cycling. AB - : Previous studies have shown improved shorter duration (~1 h) performance with carbohydrate (CHO) mouth rinsing (WASH), especially in overnight fasted/non fuelled subjects. PURPOSE: To determine the effect of WASH on cycling time trial (TT) performance and muscle activity (EMG) after 2 h of submaximal cycling while receiving CHO (FED). METHODS: In a double-blind, placebo-controlled crossover design, 10 well-trained males cyclists (VO2max: 65 mL.kg.min) completed two experimental trials. Each trial consisted of a standardized pretrial snack (2 h prior) followed by 120 min of steady-state (SS) cycling (~60% VO2max) followed by an approximately 30-min TT, randomized as follows: 1) 30 g CHO.h during SS + WASH during TT (every 20% of TT) (FEDWASH); 2) 30 g CHO.h during SS + placebo (PLA) wash during TT (FEDPLA). RESULTS: Although FEDWASH was not significantly different than FEDPLA (P = 0.51), there was a 1.7% (90% confidence interval, +6.4% to -3.2%; ES, 0.21) decrease in TT time (35 s) for FEDWASH compared with FEDPLA, with qualitative probabilities of a 60% positive and 23% trivial outcome. For EMG, soleus showed significant increase, whereas medial gastrocnemius showed significant decrease in muscle recruitment from the beginning 20% TT segment to the last 20% only in the FEDPLA condition, which coincided with a slower (P = 0.01) last 20% of the TT in FEDPLA versus FEDWASH. CONCLUSIONS: Contrary to previous studies, this investigation utilized conditions of high ecological validity including a pretrial snack and CHO during SS. Significant changes in muscle recruitment and time over the last 20% of the TT, along with an average 1.7% improvement in TT time, suggest CHO mouth rinse helps maintain power output late in TT compared with placebo. Although marginal gains were achieved with a CHO mouth rinse (35 s), small performance effects can have significant outcomes in real-world competitions. PMID- 29266093 TI - Benefits of Resistance Training with Blood Flow Restriction in Knee Osteoarthritis. AB - PURPOSE: Evaluate the effects of a low-intensity resistance training (LI-RT) program associated with partial blood flow restriction on selected clinical outcomes in patients with knee osteoarthritis (OA). METHODS: Forty-eight women with knee OA were randomized into one of the three groups: LI-RT (30% one repetition maximum [1-RM]) associated (blood flow restriction training [BFRT]) or not (LI-RT) with partial blood flow restriction, and high-intensity resistance training (HI-RT, 80% 1-RM). Patients underwent a 12-wk supervised training program and were assessed for lower-limb 1-RM, quadriceps cross-sectional area, functionality (timed-stands test and timed-up-and-go test), and disease-specific inventory (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) before (PRE) and after (POST) the protocol. RESULTS: Similar within group increases were observed in leg press (26% and 33%, all P < 0.0001), knee extension 1-RM (23% and 22%; all P < 0.0001) and cross-sectional area (7% and 8%; all P < 0.0001) in BFRT and HI-RT, respectively, and these were significantly greater (all P < 0.05) than those of LI-RT. The BFRT and HI-RT showed comparable improvements in timed-stands test (7% and 14%, respectively), with the latter showing greater increases than LI-RT. Timed-up-and-go test scores were not significantly changed within or between groups. WOMAC physical function was improved in BFRT and HI-RT (-49% and -42%, respectively; all P < 0.05), and WOMAC pain was improved in BFRT and LI-RT (-45% and -39%, respectively; all P < 0.05). Four patients (of 16) were excluded due to exercise-induced knee pain in HI-RT. CONCLUSIONS: Blood flow restriction training and HI-RT were similarly effective in increasing muscle strength, quadriceps muscle mass, and functionality in knee OA patients. Importantly, BFRT was also able to improve pain while inducing less joint stress, emerging as a feasible and effective therapeutic adjuvant in OA management. PMID- 29266094 TI - Predictive Modeling of Hamstring Strain Injuries in Elite Australian Footballers. AB - PURPOSE: Three of the most commonly identified hamstring strain injury (HSI) risk factors are age, previous HSI, and low levels of eccentric hamstring strength. However, no study has investigated the ability of these risk factors to predict the incidence of HSI in elite Australian footballers. Accordingly, the purpose of this prospective cohort study was to investigate the predictive ability of HSI risk factors using machine learning techniques. METHODS: Eccentric hamstring strength, demographic and injury history data were collected at the start of preseason for 186 and 176 elite Australian footballers in 2013 and 2015, respectively. Any prospectively occurring HSI were reported to the research team. Using various machine learning techniques, predictive models were built for 2013 and 2015 within-year HSI prediction and between-year HSI prediction (2013 to 2015). The calculated probabilities of HSI were compared with the injury outcomes and area under the curve (AUC) was determined and used to assess the predictive performance of each model. RESULTS: The minimum, maximum, and median AUC values for the 2013 models were 0.26, 0.91, and 0.58, respectively. For the 2015 models, the minimum, maximum and median AUC values were, correspondingly, 0.24, 0.92, and 0.57. For the between-year predictive models the minimum, maximum, and median AUC values were 0.37, 0.73, and 0.52, respectively. CONCLUSIONS: Although some iterations of the models achieved near perfect prediction, the large ranges in AUC highlight the fragility of the data. The 2013 models performed slightly better than the 2015 models. The predictive performance of between-year HSI models was poor however. In conclusion, risk factor data cannot be used to identify athletes at an increased risk of HSI with any consistency. PMID- 29266095 TI - Predicting birth weight in fetuses with gastroschisis. AB - OBJECTIVE: To determine the accuracy of commonly utilized ultrasound formulas for estimating birth weight (BW) in fetuses with gastroschisis. STUDY DESIGN: A retrospective review was conducted of all inborn pregnancies with gastroschisis within the five institutions of the University of California Fetal Consortium (UCfC) between 2007 and 2012. Infants delivered at ?28 weeks who had an ultrasound within 21 days before delivery were included. Prediction of BW was evaluated for each of the five ultrasound formulas: Hadlock 1 (abdominal circumference (AC), biparietal diameter (BPD), femur length (FL) and head circumference (HC)) and Hadlock 2 (AC, BPD and FL), Shepard (AC and BPD), Honarvar (FL) and Siemer (BPD, occipitofrontal diameter (OFD), and FL) using Pearson's correlation, mean difference and percent error and Bland-Altman analysis. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the ultrasound diagnosis of intrauterine growth restriction (IUGR) were assessed. RESULTS: We identified 191 neonates born with gastroschisis within the UCfC, with 111 neonates meeting the inclusion criteria. The mean gestational age at delivery was 36.3+/-1.7 weeks and the mean BW was 2448+/-460 g. Hadlock (1) formula was found to have the best correlation (r=0.81), the lowest mean difference (8+/-306 g) and the lowest mean percent error (1.4+/-13%). The Honarvar and Siemer formulas performed significantly worse when compared with Hadlock 1, with a 13.7% (P<0.001) and 3.9% (P=0.03) difference, respectively, between estimated and actual BW. This was supported by Bland-Altman plots. For Hadlock 1 and 2, sensitivity was 80% with a NPV of 91%. CONCLUSION: The widely used Hadlock (1) and (2) formulas provided the best estimated BW in infants with gastroschisis despite its inclusion of abdominal circumference. Furthermore, this formula performs well with diagnosis of IUGR. PMID- 29266097 TI - Single-cell microscopy of suspension cultures using a microfluidics-assisted cell screening platform. AB - Studies that rely on fluorescence imaging of nonadherent cells that are cultured in suspension, such as Escherichia coli, are often hampered by trade-offs that must be made between data throughput and imaging resolution. We developed a platform for microfluidics-assisted cell screening (MACS) that overcomes this trade-off by temporarily immobilizing suspension cells within a microfluidics chip. This enables high-throughput and automated single-cell microscopy for a wide range of cell types and sizes. As cells can be rapidly sampled directly from a suspension culture, MACS bypasses the need for sample preparation, and therefore allows measurements without perturbing the native cell physiology. The setup can also be integrated with complex growth chambers, and can be used to enrich or sort the imaged cells. Furthermore, MACS facilitates the visualization of individual cytoplasmic fluorescent proteins (FPs) in E. coli, allowing low abundance proteins to be counted using standard total internal reflection fluorescence (TIRF) microscopy. Finally, MACS can be used to impart mechanical pressure for assessing the structural integrity of individual cells and their response to mechanical perturbations, or to make cells take up chemicals that otherwise would not pass through the membrane. This protocol describes the assembly of electronic control circuitry, the construction of liquid-handling components and the creation of the MACS microfluidics chip. The operation of MACS is described, and automation software is provided to integrate MACS control with image acquisition. Finally, we provide instructions for extending MACS using an external growth chamber (1 d) and for how to sort rare cells of interest. PMID- 29266096 TI - Live-cell measurements of kinase activity in single cells using translocation reporters. AB - Although kinases are important regulators of many cellular processes, measuring their activity in live cells remains challenging. We have developed kinase translocation reporters (KTRs), which enable multiplexed measurements of the dynamics of kinase activity at a single-cell level. These KTRs are composed of an engineered construct in which a kinase substrate is fused to a bipartite nuclear localization signal (bNLS) and nuclear export signal (NES), as well as to a fluorescent protein for microscopy-based detection of its localization. The negative charge introduced by phosphorylation of the substrate is used to directly modulate nuclear import and export, thereby regulating the reporter's distribution between the cytoplasm and nucleus. The relative cytoplasmic versus nuclear fluorescence of the KTR construct (the C/N ratio) is used as a proxy for the kinase activity in living, single cells. Multiple KTRs can be studied in the same cell by fusing them to different fluorescent proteins. Here, we present a protocol to execute and analyze live-cell microscopy experiments using KTRs. We describe strategies for development of new KTRs and procedures for lentiviral expression of KTRs in a cell line of choice. Cells are then plated in a 96-well plate, from which multichannel fluorescent images are acquired with automated time-lapse microscopy. We provide detailed guidance for a computational analysis and parameterization pipeline. The entire procedure, from virus production to data analysis, can be completed in ~10 d. PMID- 29266098 TI - Easi-CRISPR for creating knock-in and conditional knockout mouse models using long ssDNA donors. AB - CRISPR/Cas9-based genome editing can easily generate knockout mouse models by disrupting the gene sequence, but its efficiency for creating models that require either insertion of exogenous DNA (knock-in) or replacement of genomic segments is very poor. The majority of mouse models used in research involve knock-in (reporters or recombinases) or gene replacement (e.g., conditional knockout alleles containing exons flanked by LoxP sites). A few methods for creating such models have been reported that use double-stranded DNA as donors, but their efficiency is typically 1-10% and therefore not suitable for routine use. We recently demonstrated that long single-stranded DNAs (ssDNAs) serve as very efficient donors, both for insertion and for gene replacement. We call this method efficient additions with ssDNA inserts-CRISPR (Easi-CRISPR) because it is a highly efficient technology (efficiency is typically 30-60% and reaches as high as 100% in some cases). The protocol takes ~2 months to generate the founder mice. PMID- 29266099 TI - 3D molecular cartography using LC-MS facilitated by Optimus and 'ili software. AB - Our skin, our belongings, the world surrounding us, and the environment we live in are covered with molecular traces. Detecting and characterizing these molecular traces is necessary to understand the environmental impact on human health and disease, and to decipher complex molecular interactions between humans and other species, particularly microbiota. We recently introduced 3D molecular cartography for mapping small organic molecules (including metabolites, lipids, and environmental molecules) found on various surfaces, including the human body. Here, we provide a protocol and open-source software for 3D molecular cartography. The protocol includes step-by-step procedures for sample collection and processing, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, quality control (QC), molecular identification using MS/MS, data processing, and visualization with 3D models of the sampled environment. The LC MS method was optimized for a broad range of small organic molecules. We enable scientists to reproduce our previously obtained results, and illustrate the broad utility of our approach with molecular maps of a rosemary plant and an ATM keypad after a PIN code was entered. To promote reproducibility, we introduce cartographical snapshots: files that describe a particular map and visualization settings, and that can be shared and loaded to reproduce the visualization. The protocol enables molecular cartography to be performed in any mass spectrometry laboratory and, in principle, for any spatially mapped data. We anticipate applications, in particular, in medicine, ecology, agriculture, biotechnology, and forensics. The protocol takes 78 h for a molecular map of 100 spots, excluding the reagent setup. PMID- 29266100 TI - 3D printing technique for guiding complicated cardiovascular surgery. PMID- 29266101 TI - Different techniques in robotic lung resection. PMID- 29266102 TI - Erratum: Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration. AB - [This corrects the article DOI: 10.1038/sigtrans.2016.16.]. PMID- 29266103 TI - Extracorporeal life support and neurologic complications: still a long way to go. PMID- 29266104 TI - Correction: From blockchain technology to global health equity: can cryptocurrencies finance universal health coverage? AB - [This corrects the article DOI: 10.1136/bmjgh-2017-000570.][This corrects the article DOI: 10.1136/bmjgh-2017-000570.]. PMID- 29266105 TI - Erratum: Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences. AB - [This corrects the article DOI: 10.1038/npjgenmed.2015.7.]. PMID- 29266106 TI - Erratum to highlighted version successful resection of a tracheal metastasis of rectal cancer: a case report. AB - [This corrects the article DOI: 10.21037/jtd.2017.07.94.]. PMID- 29266107 TI - Robotic-assisted thoracoscopic surgery: a promising surgical method. PMID- 29266108 TI - Approaching horizontal equity in liver transplant from a racial and ethnic perspective. PMID- 29266109 TI - Is ischemic postconditioning in STEMI worth pursuing? PMID- 29266110 TI - CORRIGENDUM FOR "Effects of Opioid Antagonism on Melanocortin Peptides and Cortisol Levels in Human Cerebrospinal Fluid". AB - [This corrects the article DOI: 10.1210/js.2017-00289.]. PMID- 29266111 TI - The Cultural Project: Formal Chronological Modelling of the Early and Middle Neolithic Sequence in Lower Alsace. AB - Starting from questions about the nature of cultural diversity, this paper examines the pace and tempo of change and the relative importance of continuity and discontinuity. To unravel the cultural project of the past, we apply chronological modelling of radiocarbon dates within a Bayesian statistical framework, to interrogate the Neolithic cultural sequence in Lower Alsace, in the upper Rhine valley, in broad terms from the later sixth to the end of the fifth millennium cal BC. Detailed formal estimates are provided for the long succession of cultural groups, from the early Neolithic Linear Pottery culture (LBK) to the Bischheim Occidental du Rhin Superieur (BORS) groups at the end of the Middle Neolithic, using seriation and typology of pottery as the starting point in modelling. The rate of ceramic change, as well as frequent shifts in the nature, location and density of settlements, are documented in detail, down to lifetime and generational timescales. This reveals a Neolithic world in Lower Alsace busy with comings and goings, tinkerings and adjustments, and relocations and realignments. A significant hiatus is identified between the end of the LBK and the start of the Hinkelstein group, in the early part of the fifth millennium cal BC. On the basis of modelling of existing dates for other parts of the Rhineland, this appears to be a wider phenomenon, and possible explanations are discussed; full reoccupation of the landscape is only seen in the Grossgartach phase. Radical shifts are also proposed at the end of the Middle Neolithic. PMID- 29266112 TI - A method for evaluating discoverability and navigability of recommendation algorithms. AB - Recommendations are increasingly used to support and enable discovery, browsing, and exploration of items. This is especially true for entertainment platforms such as Netflix or YouTube, where frequently, no clear categorization of items exists. Yet, the suitability of a recommendation algorithm to support these use cases cannot be comprehensively evaluated by any recommendation evaluation measures proposed so far. In this paper, we propose a method to expand the repertoire of existing recommendation evaluation techniques with a method to evaluate the discoverability and navigability of recommendation algorithms. The proposed method tackles this by means of first evaluating the discoverability of recommendation algorithms by investigating structural properties of the resulting recommender systems in terms of bow tie structure, and path lengths. Second, the method evaluates navigability by simulating three different models of information seeking scenarios and measuring the success rates. We show the feasibility of our method by applying it to four non-personalized recommendation algorithms on three data sets and also illustrate its applicability to personalized algorithms. Our work expands the arsenal of evaluation techniques for recommendation algorithms, extends from a one-click-based evaluation towards multi-click analysis, and presents a general, comprehensive method to evaluating navigability of arbitrary recommendation algorithms. PMID- 29266113 TI - Re-Envisioning Tarascan Temporalities and Landscapes: Historical Being, Archaeological Representation, and Futurity in Past Social Processes. AB - We apply a phenomenological perspective on landscape and geographic information system (GIS) applications in order to theorize how human perception and agency were likely implicated in processes of the formation of the late pre-Hispanic Tarascan State of West Central Mexico. The relatedness of landscape features in space or place-based perception has been well theorized; here, we further consider the relationality of places through time. In the changing landscape of the Lake Patzcuaro Basin, the demographic and political core of the Tarascan State, temporality must have been vitally important to inhabitants of the basin. Utilizing GIS, we construct not only map-based analyses of the changing environment but also create viewsheds of past landscapes in order to see what past inhabitants of the basin would have seen in order to demonstrate that temporality would have been easily mapped in the landscape and its features. Finally, we discuss the role of temporality and cultural memory in an embodied landscape to model the various lake levels that past peoples could have anticipated through time based on their perceptions and memories. PMID- 29266114 TI - Status of lung cancer screening. PMID- 29266115 TI - Reply to comments on "Robotic Assisted Right Middle Lobectomy": incision positions, approaches and other problems. PMID- 29266116 TI - Erratum: Preparing for genomic medicine: a real world demonstration of health system change. AB - [This corrects the article DOI: 10.1038/s41525-017-0017-4.]. PMID- 29266117 TI - Robotic-assisted thoracic surgery: a promising tool should not be denied. PMID- 29266118 TI - What is spread through air space? PMID- 29266120 TI - Corrigendum. AB - [This corrects the article DOI: 10.1007/s12522-015-0208-6.]. PMID- 29266119 TI - Steering opinion dynamics via containment control. AB - In this paper, we model the problem of influencing the opinions of groups of individuals as a containment control problem, as in many practical scenarios, the control goal is not full consensus among all the individual opinions, but rather their containment in a certain range, determined by a set of leaders. As in classical bounded confidence models, we consider individuals affected by the confirmation bias, thus tending to influence and to be influenced only if their opinions are sufficiently close. However, here we assume that the confidence level, modeled as a proximity threshold, is not constant and uniform across the individuals, as it depends on their opinions. Specifically, in an extremist society, the most radical agents (i.e., those with the most extreme opinions) have a higher appeal and are capable of influencing nodes with very diverse opinions. The opposite happens in a moderate society, where the more connected (i.e., influential) nodes are those with an average opinion. In three artificial societies, characterized by different levels of extremism, we test through extensive simulations the effectiveness of three alternative containment strategies, where leaders have to select the set of followers they try to directly influence. We found that, when the network size is small, a stochastic time-varying pinning strategy that does not rely on information on the network topology proves to be more effective than static strategies where this information is leveraged, while the opposite happens for large networks where the relevance of the topological information is prevalent. PMID- 29266121 TI - Interpreting Intra-site Spatial Patterns in Seasonal Contexts: an Ethnoarchaeological Case Study from the Western Alps. AB - This paper deals with the ethnoarchaeological analysis of the spatial pattern of artefacts and ecofacts within two traditional pastoral huts (a dwelling and a seasonal dairy) in the uplands of Val Maudagna (Cuneo province, Italian western Alps). The composition of the ethnoarchaeological assemblages of the two huts was studied and compared; point pattern analysis was applied to identify spatial processes mirrored in the interactions between objects; Moran's I correlogram and empirical variogram were used to investigate the effects of trampling on the displacement of objects on the floor. The results were compared with information provided by the herder who still used the huts. The quantitative and ethnographical data enabled inferences to be made that can help in the interpretation of archaeological seasonal sites. The function of a seasonal site can be recognized, as can the impact of delayed curation on the composition of the assemblage and the importance of the intensity of occupation compared with the frequency of occupation. The spatial organization of activities is reflected in the spatial patterns of objects, with clearer identification of activity areas in intensively occupied sites, and there is evidence for the behaviour behind the spatial segregation of activities. Trampling is a crucial post-depositional factor in the displacement of artefacts and ecofacts, especially in non intensively exploited sites. From a methodological point of view, this research is another example that highlights the importance of integrating quantitative methods (especially spatial analysis and geostatistical methods) and ethnoarchaeological data in order to improve the interpretation of archaeological sites and assemblages. PMID- 29266122 TI - Correction: Does audit and feedback improve the adoption of recommended practices? Evidence from a longitudinal observational study of an emerging clinical network in Kenya. AB - [This corrects the article DOI: 10.1136/bmjgh-2017-000468.][This corrects the article DOI: 10.1136/bmjgh-2017-000468.]. PMID- 29266123 TI - Network characteristics emerging from agent interactions in balanced distributed system. AB - A distributed computing system behaves like a complex network, the interactions between nodes being essential information exchanges and migrations of jobs or services to execute. These actions are performed by software agents, which behave like the members of social networks, cooperating and competing to obtain knowledge and services. The load balancing consists in distributing the load evenly between system nodes. It aims at enhancing the resource usage. A load balancing strategy specifies scenarios for the cooperation. Its efficiency depends on quantity, accuracy, and distribution of available information. Nevertheless, the distribution of information on the nodes, together with the initial network structure, may create different logical network structures. In this paper, different load balancing strategies are tested on different network structures using a simulation. The four tested strategies are able to distribute evenly the load so that the system reaches a steady state (the mean response time of the jobs is constant), but it is shown that a given strategy indeed behaves differently according to structural parameters and information spreading. Such a study, devoted to distributed computing systems (DCSs), can be useful to understand and drive the behavior of other complex systems. PMID- 29266124 TI - Controllability of social networks and the strategic use of random information. AB - Background: This work is aimed at studying realistic social control strategies for social networks based on the introduction of random information into the state of selected driver agents. Deliberately exposing selected agents to random information is a technique already experimented in recommender systems or search engines, and represents one of the few options for influencing the behavior of a social context that could be accepted as ethical, could be fully disclosed to members, and does not involve the use of force or of deception. Methods: Our research is based on a model of knowledge diffusion applied to a time-varying adaptive network and considers two well-known strategies for influencing social contexts: One is the selection of few influencers for manipulating their actions in order to drive the whole network to a certain behavior; the other, instead, drives the network behavior acting on the state of a large subset of ordinary, scarcely influencing users. The two approaches have been studied in terms of network and diffusion effects. The network effect is analyzed through the changes induced on network average degree and clustering coefficient, while the diffusion effect is based on two ad hoc metrics which are defined to measure the degree of knowledge diffusion and skill level, as well as the polarization of agent interests. Results: The results, obtained through simulations on synthetic networks, show a rich dynamics and strong effects on the communication structure and on the distribution of knowledge and skills. Conclusions: These findings support our hypothesis that the strategic use of random information could represent a realistic approach to social network controllability, and that with both strategies, in principle, the control effect could be remarkable. PMID- 29266125 TI - Quality Assurance in Archaeological Survey. AB - To have confidence in the results of an archaeological survey, whether for heritage management or research objectives, we must have some assurance that the survey was carried out to a reasonably high standard. This paper discusses the use of Quality Assurance (QA) approaches and empirical methods for estimating surveys' effectiveness at discovering archaeological artifacts as a means for ensuring quality standards. We illustrate with the example of two surveys in Cyprus and Jordan in which resurvey, measurement of surveyor "sweep widths," and realistic estimates of survey coverage allow us to evaluate explicitly the probability that the survey missed pottery or lithics, as well as to decide when survey has been thorough enough to warrant moving to another survey unit. PMID- 29266126 TI - Correction: Modelling focused electron beam induced deposition beyond Langmuir adsorption. AB - [This corrects the article DOI: 10.3762/bjnano.8.214.]. PMID- 29266127 TI - Integrative research agenda for diagnosis in sepsis. PMID- 29266128 TI - Using attractiveness model for actors ranking in social media networks. AB - Background: Influential actors detection in social media such as Twitter or Facebook can play a major role in gathering opinions on particular topics, improving the marketing efficiency, predicting the trends, etc. Proposed methods: This work aims to extend our formally defined T measure to present a new measure aiming to recognize the actor's influence by the strength of attracting new important actors into a networked community. Therefore, we propose a model of the actor's influence based on the attractiveness of the actor in relation to the number of other attractors with whom he/she has established connections over time. Results and conclusions: Using an empirically collected social network for the underlying graph, we have applied the above-mentioned measure of influence in order to determine optimal seeds in a simulation of influence maximization. We study our extended measure in the context of information diffusion because this measure is based on a model of actors who attract others to be active members in a community. This corresponds to the idea of the IC simulation model which is used to identify the most important spreaders in a set of actors. PMID- 29266129 TI - Challenges in assessing response of oesophageal cancer to neoadjuvant therapy, and the potential of composite PET-CT and multimodal metrics. PMID- 29266130 TI - Functionality and Morphology: Identifying Si Agricultural Tools from Among Hemudu Scapular Implements in Eastern China. AB - Most Chinese archaeologists assume that the scapular implements used in the Hemudu culture in eastern China (7000-5000 BP) were the si agricultural implements (tools for breaking ground and turning soils over to assist in seeding) recorded in ancient Chinese literatures and, accordingly, assume the Hemudu culture was a farming society. However, ethnographic and historical literatures worldwide have suggested inconclusive functions for similar implements. We conducted a range of experiments under realistic conditions, including hide and plant processing and earth-working, followed by use-wear analysis, to identify the functions of the Hemudu scapular implements. The results suggest that no more than half of the implements were employed as si and that their penetrability and durability were rather limited. These findings help explain why Hemudu should not be labeled as a farming society. Through experimentation and use-wear analysis, we produced relatively large datasets that make a significant contribution to the identification of soil-derived wear patterns on bone tools. We also included quantitative measurements of soil properties to ensure similarities in use contexts between our experimental and archaeological analogies in order to reach reliable functional identifications. Our approaches and results, therefore, provided a solid base for re-evaluating previous research as well as building a standardized database of scientific value for future evaluation and adjustment, even if that future research is done in isolation and in different soil contexts. PMID- 29266131 TI - Erratum: USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency. AB - [This corrects the article DOI: 10.1038/sigtrans.2016.24.]. PMID- 29266132 TI - Stance and influence of Twitter users regarding the Brexit referendum. AB - Social media are an important source of information about the political issues, reflecting, as well as influencing, public mood. We present an analysis of Twitter data, collected over 6 weeks before the Brexit referendum, held in the UK in June 2016. We address two questions: what is the relation between the Twitter mood and the referendum outcome, and who were the most influential Twitter users in the pro- and contra-Brexit camps? First, we construct a stance classification model by machine learning methods, and are then able to predict the stance of about one million UK-based Twitter users. The demography of Twitter users is, however, very different from the demography of the voters. By applying a simple age-adjusted mapping to the overall Twitter stance, the results show the prevalence of the pro-Brexit voters, something unexpected by most of the opinion polls. Second, we apply the Hirsch index to estimate the influence, and rank the Twitter users from both camps. We find that the most productive Twitter users are not the most influential, that the pro-Brexit camp was four times more influential, and had considerably larger impact on the campaign than the opponents. Third, we find that the top pro-Brexit communities are considerably more polarized than the contra-Brexit camp. These results show that social media provide a rich resource of data to be exploited, but accumulated knowledge and lessons learned from the opinion polls have to be adapted to the new data sources. PMID- 29266133 TI - Corrigendum: Inhibition of Epithelial TNF-alpha Receptors by Purified Fruit Bromelain Ameliorates Intestinal Inflammation and Barrier Dysfunction in Colitis. AB - [This corrects the article on p. 1468 in vol. 8, PMID: 29176974.]. PMID- 29266134 TI - Correction to "Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors". AB - [This corrects the article DOI: 10.1021/acsmedchemlett.7b00192.]. PMID- 29266135 TI - Coevolution of a multilayer node-aligned network whose layers represent different social relations. AB - Background: We examine the coevolution of three-layer node-aligned network of university students. The first layer is defined by nominations based on perceived prominence collected from repeated surveys during the first four semesters; the second is a behavioral layer representing actual students' interactions based on records of mobile calls and text messages; while the third is a behavioral layer representing potential face-to-face interactions suggested by bluetooth collocations. Methods: We address four interrelated questions. First, we ask whether the formation or dissolution of a link in one of the layers precedes or succeeds the formation or dissolution of the corresponding link in another layer (temporal dependencies). Second, we explore the causes of observed temporal dependencies between the layers. For those temporal dependencies that are confirmed, we measure the predictive capability of such dependencies. Third, we observe the progress towards nominations and the stages that lead to them. Finally, we examine whether the differences in dissolution rates of symmetric (undirected) versus asymmetric (directed) links co-exist in all layers. Results: We find strong patterns of reciprocal temporal dependencies between the layers. In particular, the creation of an edge in either behavioral layer generally precedes the formation of a corresponding edge in the nomination layer. Conversely, the decay of a link in the nomination layer generally precedes a decline in the intensity of communication and collocation. Finally, nodes connected by asymmetric nomination edges have lower overall communication and collocation volumes and more asymmetric communication flows than the nodes linked by symmetric edges. Conclusion: We find that creation and dissolution of cognitively salient contacts have temporal dependencies with communication and collocation behavior. PMID- 29266136 TI - Hierarchical community detection via rank-2 symmetric nonnegative matrix factorization. AB - Background: Community discovery is an important task for revealing structures in large networks. The massive size of contemporary social networks poses a tremendous challenge to the scalability of traditional graph clustering algorithms and the evaluation of discovered communities. Methods: We propose a divide-and-conquer strategy to discover hierarchical community structure, nonoverlapping within each level. Our algorithm is based on the highly efficient rank-2 symmetric nonnegative matrix factorization. We solve several implementation challenges to boost its efficiency on modern computer architectures, specifically for very sparse adjacency matrices that represent a wide range of social networks. Conclusions: Empirical results have shown that our algorithm has competitive overall efficiency and leading performance in minimizing the average normalized cut, and that the nonoverlapping communities found by our algorithm recover the ground-truth communities better than state-of the-art algorithms for overlapping community detection. In addition, we present a new dataset of the DBLP computer science bibliography network with richer meta data and verifiable ground-truth knowledge, which can foster future research in community finding and interpretation of communities in large networks. PMID- 29266137 TI - Measuring the value of accurate link prediction for network seeding. AB - Merging two classic questions: The influence-maximization literature seeks small sets of individuals whose structural placement in the social network can drive large cascades of behavior. Optimization efforts to find the best seed set often assume perfect knowledge of the network topology. Unfortunately, social network links are rarely known in an exact way. When do seeding strategies based on less than-accurate link prediction provide valuable insight? Our contribution: We introduce optimized-against-a-sample ([Formula: see text]) performance to measure the value of optimizing seeding based on a noisy observation of a network. Our computational study investigates [Formula: see text] under several threshold spread models in synthetic and real-world networks. Our focus is on measuring the value of imprecise link information. The level of investment in link prediction that is strategic appears to depend closely on spread model: in some parameter ranges investments in improving link prediction can pay substantial premiums in cascade size. For other ranges, such investments would be wasted. Several trends were remarkably consistent across topologies. PMID- 29266138 TI - Determination of Cannabinoid Vapor Pressures to Aid in Vapor Phase Detection of Intoxication. AB - The quest for a reliable means to detect cannabis intoxication with a breathalyzer is ongoing. To design such a device, it is important to understand the fundamental thermodynamics of the compounds of interest. The vapor pressures of two important cannabinoids, cannabidiol (CBD) and Delta9-tetrahydrocannabinol (Delta9-THC), are presented, as well as the predicted normal boiling temperature (NBT) and the predicted critical constants (these predictions are dependent on the vapor pressure data). The critical constants are typically necessary to develop an equation of state (EOS). EOS-based models can provide estimations of thermophysical properties for compounds to aid in designing processes and devices. An ultra-sensitive, quantitative, trace dynamic headspace analysis sampling called porous layered open tubular-cryoadsorption (PLOT-cryo) was used to measure vapor pressures of these compounds. PLOT-cryo affords short experiment durations compared to more traditional techniques for vapor pressure determination (minutes versus days). Additionally, PLOT-cryo has the inherent ability to stabilize labile solutes because collection is done at reduced temperature. The measured vapor pressures are approximately 2 orders of magnitude lower than those measured for n-eicosane, which has a similar molecular mass. Thus, the difference in polarity of these molecules must be impacting the vapor pressure dramatically. The vapor pressure measurements are presented in the form of Clausius-Clapeyron (or van't Hoff) equation plots. The predicted vapor pressures that would be expected at near ambient conditions (25 degrees C) are also presented. PMID- 29266139 TI - Computation and analysis of temporal betweenness in a knowledge mobilization network. AB - Background: Highly dynamic social networks, where connectivity continuously changes in time, are becoming more and more pervasive. Knowledge mobilization, which refers to the use of knowledge toward the achievement of goals, is one of the many examples of dynamic social networks. Despite the wide use and extensive study of dynamic networks, their temporal component is often neglected in social network analysis, and statistical measures are usually performed on static network representations. As a result, measures of importance (like betweenness centrality) typically do not reveal the temporal role of the entities involved. Our goal is to contribute to fill this limitation by proposing a form of temporal betweenness measure (foremost betweenness). Methods: Our method is analytical as well as experimental: we design an algorithm to compute foremost betweenness, and we apply it to a case study to analyze a knowledge mobilization network. Results: We propose a form of temporal betweenness measure (foremost betweenness) to analyze a knowledge mobilization network and we introduce, for the first time, an algorithm to compute exact foremost betweenness. We then show that this measure, which explicitly takes time into account, allows us to detect centrality roles that were completely hidden in the classical statistical analysis. In particular, we uncover nodes whose static centrality was negligible, but whose temporal role might instead be important to accelerate mobilization flow in the network. We also observe the reverse behavior by detecting nodes with high static centrality, whose role as temporal bridges is instead very low. Conclusion: In this paper, we focus on a form of temporal betweenness designed to detect accelerators in dynamic networks. By revealing potentially important temporal roles, this study is a first step toward a better understanding of the impact of time in social networks and opens the road to further investigation. PMID- 29266140 TI - Ranking Specific Sets of Objects. AB - Ranking sets of objects based on an order between the single elements has been thoroughly studied in the literature. In particular, it has been shown that it is in general impossible to find a total ranking - jointly satisfying properties as dominance and independence - on the whole power set of objects. However, in many applications certain elements from the entire power set might not be required and can be neglected in the ranking process. For instance, certain sets might be ruled out due to hard constraints or are not satisfying some background theory. In this paper, we treat the computational problem whether an order on a given subset of the power set of elements satisfying different variants of dominance and independence can be found, given a ranking on the elements. We show that this problem is tractable for partial rankings and NP-complete for total rankings. PMID- 29266141 TI - Online network organization of Barcelona en Comu, an emergent movement-party. AB - The emerging grassroots party Barcelona en Comu won the 2015 Barcelona City Council election. This candidacy was devised by activists involved in the Spanish 15M movement to transform citizen outrage into political change. On the one hand, the 15M movement was based on a decentralized structure. On the other hand, political science literature postulates that parties develop oligarchical leadership structures. This tension motivates to examine whether Barcelona en Comu preserved a decentralized structure or adopted a conventional centralized organization. In this study we develop a computational methodology to characterize the online network organization of every party in the election campaign on Twitter. Results on the network of retweets reveal that, while traditional parties are organized in a single cluster, for Barcelona en Comu two well-defined groups co-exist: a centralized cluster led by the candidate and party accounts, and a decentralized cluster with the movement activists. Furthermore, results on the network of replies also shows a dual structure: a cluster around the candidate receiving the largest attention from other parties, and another with the movement activists exhibiting a higher predisposition to dialogue with other parties. PMID- 29266142 TI - Modelling and analysis of the dynamics of adaptive temporal-causal network models for evolving social interactions. AB - Background: Network-Oriented Modelling based on adaptive temporal-causal networks provides a unified approach to model and analyse dynamics and adaptivity of various processes, including mental and social interaction processes. Methods: Adaptive temporal-causal network models are based on causal relations by which the states in the network change over time, and these causal relations are adaptive in the sense that they themselves also change over time. Results: It is discussed how modelling and analysis of the dynamics of the behaviour of these adaptive network models can be performed. The approach is illustrated for adaptive network models describing social interaction. Conclusions: In particular, the homophily principle and the 'more becomes more' principles for social interactions are addressed. It is shown how the chosen Network-Oriented Modelling method provides a basis to model and analyse these social phenomena. PMID- 29266143 TI - Effect of direct reciprocity and network structure on continuing prosperity of social networking services. AB - Background: Social networking services (SNSs) are widely used as communicative tools for a variety of purposes. SNSs rely on the users' individual activities associated with some cost and effort, and thus it is not known why users voluntarily continue to participate in SNSs. Because the structures of SNSs are similar to that of the public goods (PG) game, some studies have focused on why voluntary activities emerge as an optimal strategy by modifying the PG game. However, their models do not include direct reciprocity between users, even though reciprocity is a key mechanism that evolves and sustains cooperation in human society. Proposed methods: We developed an abstract SNS model called the reciprocity rewards and meta-rewards games that include direct reciprocity by extending the existing models. Then, we investigated how direct reciprocity in an SNS facilitates cooperation that corresponds to participation in SNS by posting articles and comments and how the structure of the networks of users exerts an influence on the strategies of users using the reciprocity rewards game. Experimental results: We run reciprocity rewards games on various complex networks and an instance network of Facebook and found that two types of stable cooperation emerged. First, reciprocity slightly improves the rate of cooperation in complete graphs but the improvement is insignificant because of the instability of cooperation. However, this instability can be avoided by making two assumptions: high degree of fun, i.e. articles are read with high probability, and different attitudes to reciprocal and non-reciprocal agents. We then propose the concept of half free riders to explain what strategy sustains cooperation-dominant situations. Second, we indicate that a certain WS network structure affects users' optimal strategy and facilitates stable cooperation without any extra assumptions. We give a detailed analysis of the different characteristics of the two types of cooperation-dominant situations and the effect of the memory of reciprocal agents on cooperation. PMID- 29266144 TI - Collagen-binding VEGF targeting the cardiac extracellular matrix promotes recovery in porcine chronic myocardial infarction. AB - An effective therapy for chronic myocardial infarction (MI) has yet to be developed. Vascular endothelial growth factor (VEGF) promotes angiogenesis and improves cardiac function after MI. However, non-targeted delivery of VEGF decreases its therapeutic efficacy. In this study, for targeting the cardiac extracellular matrix, a collagen-binding domain (CBD) VEGF was used to bind specifically to the collagen-rich cardiac extracellular matrix. When intramyocardially injected into the peri-infarct region of a chronically infarcted porcine heart, CBD-VEGF attenuated the remodeling of the left ventricle with a decreased infarct size and promoted cardiomyocyte survival and angiogenesis 3 months after injection. In the 12-month trial, mature vessel networks and myocardium-like tissues were observed in the infarct region after CBD-VEGF injection. Also these beneficial effects might derive from CBD-VEGF significantly protecting cardiomyocytes from apoptosis and recruiting cardiac progenitor cells to the infarcted region. These results demonstrated that CBD VEGF could be a promising therapeutic strategy for chronic MI. PMID- 29266145 TI - Heterogeneity of deposited phases in supported transition metal oxide catalysts: reversible temperature-dependent evolution of molecular structures and configurations. AB - In situ high-temperature Raman spectroscopy under steady state oxidative dehydrated conditions was used for determining the temperature dependence of the molecular structures and configurations of (MOx)n (M = Re, Mo, W) sites supported at low submonolayer loadings on TiO2(P25). Prior to the Raman analysis, the studied catalyst samples underwent calcination at 450-480 degrees C for 4-5 h. Regularly repeated random sequences of heating and cooling under flowing 20%O2/He (in the absence of incoming water vapor) in the 35-430 degrees C temperature range were shown to cause drastic changes in the vibrational properties of the M O stretching modes and in the molecular structures and configurations of the deposited ReOx, MoOx, and WOx sites in a reversible and reproducible manner. A heterogeneity of the deposited oxometallic phase was evidenced with three distinctly different species (i.e., MOx-I, MOx-II, and MOx-III) present in each system, each one prevailing in a particular temperature range. It was shown that the temperature could tune the molecular structure of the deposited oxometallic phase presumably on account of minima in the surface free energy. In the direction of temperature lowering, a mechanism leading to a hydrolysis-like of the anchoring bonds by activation of the surface hydroxyls and/or water molecules extant on the uncovered TiO2(P25) surface took place. In situ FTIR spectroscopy under identical conditions and similar temperature sequence protocols complemented the Raman results and corroborated the proposed prevailing configurations and pertinent band assignments. PMID- 29266146 TI - Oxidative organocatalytic chemoselective N-acylation of heterocycles with aromatic and conjugated aldehydes. AB - Selective acylation of indoles is cumbersome often involving the need for sensitive and reactive acyl chloride derivatives or coupling reagents. Here we report a mild, functional group tolerant and highly chemoselective oxidative carbene catalyzed N-acylation of indoles with aldehydes. The acylation has a broad substrate scope and is compatible with substituents on both the aldehyde and the indole reaction partner. Furthermore, aza-heterocycles such as pyrrole and indazole can also be used as nucleophiles in this reaction providing the corresponding amide congeners in good yield. PMID- 29266147 TI - A stable rhodium single-site catalyst encapsulated within dendritic mesoporous nanochannels. AB - Catalysis plays an essential role in the modern chemical industry. However, it still remains a great challenge to improve the efficiency of many heterogeneous catalysts based on a per metal atom basis. Single-site catalysts (SsCs) with isolated metal atoms/ions anchored to the supports are thus highly desirable, providing an innovative solution towards highly efficient usage of precious metal atoms in heterogeneous catalysts. Creating SsCs with high metal loading proves to be challenging because, without robust anchoring, atoms tend to diffuse to form large aggregates during catalytic reactions. We report a facile ligand exchange method to anchor a single-site Rh catalyst inside the individual channels of three-dimensional dendritic mesoporous silica nanospheres (MSNSs). The short porous channels inside MSNSs provide an easy access of reactants and the strong binding of the ligand prevents the aggregation of catalyst sites. The as synthesized Rh1@MSNS-NH2 catalyst shows excellent activity, stability and reusability in the reduction of 4-nitrophenol. The same catalyst shows high regioselectivity in the hydrosilylation of terminal alkynes to yield alpha vinylsilanes through the Markovnikov addition. PMID- 29266154 TI - Optimal propulsion of an undulating slender body with anisotropic friction. AB - This study investigates theoretically and numerically the propulsive sliding of a slender body. The body sustains a transverse and propagative wave along its main axis, and undergoes anisotropic friction caused by its surface texture sliding on the floor. A model accounting for the anisotropy of frictional forces acting on the body is implemented. This describes the propulsive force and gives the optimal undulating parameters for efficient forward propulsion. The optimal wave characteristics are effectively compared to the undulating motion of a slithering snakes, as well as with the motion of sandfish lizards swimming through the sand. Furthermore, numerical simulations have indicated the existence of certain specialized segments along the body that are highly efficient for propulsion, explaining why snakes lift parts of their body while slithering. Finally, the inefficiency of slithering as a form of locomotion to ascend a slope is discussed. PMID- 29266155 TI - Increase in the reduction potential of uranyl upon interaction with graphene oxide surfaces. AB - Coordination of uranyl (U(vi)) with carboxylate groups on functionalized graphene oxide (GO) surfaces has been shown to alter the reduction potential of the sorbed uranium ion. A quantitative measure of the reduction potential and qualitative estimation of sorption/desorption processes were conducted using cyclic voltammetry, and the proposed coordination environment was determined using the surface sensitive attenuated total reflection mode of infrared spectroscopy (ATR FTIR). GO is a nanostructured material possessing a large amount of oxygen containing functional groups both on basal planes and at the edges, which can form strong surface complexes with radionuclides. The presence of these functional groups on the surface of GO allows efficient immobilization of uranium due to sorption of uranyl (UO22+) to carboxylate, hydroxide, or sulfonate functional groups and the potential for enhanced reduction of U(vi) to more strongly sorbing and insoluble U(iv). Herein, binding of U(vi) to carboxylate groups on the GO surface is proposed as the primary sorption mechanism based on the FTIR study. Furthermore, the coordination of uranium with the surface increases the reduction potential of the U(vi)/U(iv) redox couple as compared to the case of the aqueous U(vi)/U(iv) species. This is consistent with the alteration of the electronic structure of the sorbed ion, which can be determined in our case due to the use of a GO-coated working electrode. Thus, GO-coated glassy carbon electrodes and other semi-conducting electrodes with high ion sorption capacities may provide a means of examining the oxidation/reduction potentials of sorbed ions. PMID- 29266160 TI - Graphene oxide-mediated Cas9/sgRNA delivery for efficient genome editing. AB - Direct cellular delivery of CRISPR/Cas9 complexes is of great significance for genome editing and other recently developed applications, such as gene expression regulation and RNA/DNA imaging. Here, we first constructed a graphene oxide (GO) polyethylene glycol (PEG)-polyethylenimine (PEI) nanocarrier for the delivery of high-molecular-weight Cas9/single-guide RNA (sgRNA) complexes for endocytosis, endosomal escape, nuclear entry, and gene editing. The results demonstrate that the nanocarrier can be used successfully for efficient gene editing in human AGS cells with an efficiency of ~39%. The results also show that this nanocarrier can protect sgRNA from enzymatic degradation, thus exhibiting extremely high stability, which is critical for future in vivo applications. Thus, this GO mediated Cas9/sgRNA delivery system has potential as a new approach for biomedical research and targeted gene engineering applications. PMID- 29266157 TI - Large-area niobium disulfide thin films as transparent electrodes for devices based on two-dimensional materials. AB - Direct contacts of a metal with atomically thin two-dimensional (2D) transition metal dichalcogenide (TMDC) semiconductors have been found to suppress device performance by producing a high contact resistance. NbS2 is a 2D TMDC and a conductor. It is expected to form ohmic contacts with 2D semiconductors because of its high work function and the van der Waals interface it forms with the semiconductor, with such an interface resulting in weak Fermi level pinning. Despite the usefulness of NbS2 as an electrode, previous synthesis methods could not control the thickness, uniformity, and shape of the NbS2 film and hence could not find practical applications in electronics. Here, we report a patternable method for carrying out the synthesis of NbS2 films in which the number of NbS2 layers formed over a large area was successfully controlled, which is necessary for the production of customized electrodes. The synthesized NbS2 films were shown to be highly transparent and uniform in thickness and conductivity over the large area. Furthermore, the synthesized NbS2 showed half the contact resistance than did the molybdenum metal in MoS2 field effect transistors (FETs) on a large transparent quartz substrate. The MoS2 device with NbS2 showed an electron mobility as high as 12.7 cm2 V-1 s-1, which was three times higher than that found for the corresponding molybdenum-contacted MoS2 device. This result showed the high potential of the NbS2 thin film as a transparent electrode for 2D transition metal dichalcogenide (TMDC) semiconductors with low contact resistance. PMID- 29266162 TI - Towards optimisation of surface enhanced photodynamic therapy of breast cancer cells using gold nanoparticle-photosensitiser conjugates. AB - Gold nanoparticles (AuNPs; ca. 4 nm) were synthesised and functionalised with a mixed monolayer of polyethylene glycol (PEG) and one of two zinc phthalocyanines (ZnPcs), the difference between the two molecules was the length of the carbon chain that connects the Pc to the gold core. The chain was composed of either three (C3Pc) or eleven (C11Pc) carbon atoms. The C11Pc photosensitiser displayed higher fluorescence emission intensity than the C3Pc in solution. By contrast, the C3Pc photosensitiser exhibited higher fluorescence when bound to the surface of the AuNPs than the C11Pc, despite the shorter carbon chain which was expected to quench the fluorescence. In addition, the C3Pc nanoparticle conjugates exhibited an enhancement in the production of singlet oxygen (1O2). The metal enhanced 1O2 production led to a remarkable photodynamic efficacy for the treatment of human breast cancer cells. PMID- 29266163 TI - Rab family small GTPases-mediated regulation of intracellular logistics in neural development. AB - Rab family small GTPases play essential roles in various cellular events via the regulation of intracellular logistics comprising a large number of membrane traffic pathways. Emerging evidence reveals the physiological roles of Rab proteins in several tissues, including developing brains. Many Rab proteins, such as Rab5, Rab6, Rab7, Rab8, Rab10, Rab11, Rab17 and Rab18, are shown to regulate neurite outgrowth in PC12 cells and/or axon and dendrite formation in primary cultured neurons. Recent studies have also revealed in vivo roles of several Rab family small GTPases in brain development and its related neurological disorders. In this review, we introduce the physiological function of Rab family proteins in neural development with particular focus on neurite outgrowth and neuronal migration. PMID- 29266164 TI - Objective neuromuscular monitoring: The challenges limiting its use. PMID- 29266165 TI - Witnessed out-of-hospital cardiac arrest- effects of emergency dispatch recognition. AB - BACKGROUND: Survival from an out-of-hospital cardiac arrest (OHCA) depends on the sequence of interventions in "the chain of survival". If OHCA is recognized in the emergency medical communication centre (EMCC), the proper emergency medical service (EMS) should be dispatched and cardiopulmonary resuscitation (CPR) instructions should be given to a bystander. The study aimed to examine the impact of OHCA recognition in the EMCC on survival rates and the main elements of the chain of survival. METHODS: Data from the Helsinki University Hospital's registry of OHCA patients between 1997 and 2013 were studied. Altogether, 2054 EMCC-handled and bystander-witnessed OHCA proven events of cardiac origin were analysed. RESULTS: In 80.5% of the victims, two EMS units were correctly dispatched and the OHCA was classified as recognized. Achieved return of spontaneous circulation (ROSC) and survival to hospital discharge were 49% and 23%, respectively, if cardiac arrest was recognized by the EMCC and 40% and 16% when it was not (P = 0.003 and 0.002). Dispatchers gave CPR instructions in 60% of the recognized OHCA cases. Bystander-performed CPR increased over time and was given in 58% of the recognized OHCAs and also in 17% of the unrecognized events. EMS delays were shorter if OHCA was recognized as opposed to unrecognized (8 min with an IQR 6.5-10 min vs. 9 min with an IQR 6.5-11 min; P = 0.001). CONCLUSIONS: Recognition of OHCA by the EMCC was significantly associated with an increased rate of bystander-performed CPR, reduced EMS response time, and increased OHCA patient ROSC and survival rates. PMID- 29266166 TI - Influence of Poor Oral Health on Physical Frailty: A Population-Based Cohort Study of Older British Men. AB - OBJECTIVES: To investigate the associations between objective and subjective measures of oral health and incident physical frailty. DESIGN: Cross-sectional and longitudinal study with 3 years of follow-up using data from the British Regional Heart Study. SETTING: General practices in 24 British towns. PARTICIPANTS: Community-dwelling men aged 71 to 92 (N = 1,622). MEASUREMENTS: Objective assessments of oral health included tooth count and periodontal disease. Self-reported oral health measures included overall self-rated oral health; dry mouth symptoms; sensitivity to hot, cold, and sweet; and perceived difficulty eating. Frailty was defined using the Fried phenotype as having 3 or more of weight loss, grip strength, exhaustion, slow walking speed, and low physical activity. Incident frailty was assessed after 3 years of follow-up in 2014. RESULTS: Three hundred three (19%) men were frail at baseline (aged 71-92). Having fewer than 21 teeth, complete tooth loss, fair to poor self-rated oral health, difficulty eating, dry mouth, and more oral health problems were associated with greater likelihood of being frail. Of 1,284 men followed for 3 years, 107 (10%) became frail. The risk of incident frailty was higher in participants who were edentulous (odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.03-3.52); had 3 or more dry mouth symptoms (OR = 2.03, 95% CI = 1.18 3.48); and had 1 (OR = 2.34, 95% CI = 1.18-4.64), 2 (OR = 2.30, 95% CI = 1.09 4.84), or 3 or more (OR = 2.72, 95% CI = 1.11-6.64) oral health problems after adjustment for age, smoking, social class, history of cardiovascular disease or diabetes mellitus, and medications related to dry mouth. CONCLUSION: The presence of oral health problems was associated with greater risks of being frail and developing frailty in older age. The identification and management of poor oral health in older people could be important in preventing frailty. PMID- 29266168 TI - An Expert Opinion from the European College of Gerodontology and the European Geriatric Medicine Society: European Policy Recommendations on Oral Health in Older Adults. AB - This is an expert opinion paper on oral health policy recommendations for older adults in Europe, with particular focus on frail and care-dependent persons, that the European College of Gerodontology (ECG) and the European Geriatric Medicine Society (EUGMS) Task and Finish Group on Gerodontology has developed. Oral health in older adults is often poor. Common oral diseases such as caries, periodontal disease, denture-related conditions, hyposalivation, and oral pre- and cancerous conditions may lead to tooth loss, pain, local and systemic infection, impaired oral function, and poor quality of life. Although the majority of oral diseases can be prevented or treated, oral problems in older adults remain prevalent and largely underdiagnosed, because frail persons often do not receive routine dental care, due to a number of barriers and misconceptions. These hindrances include person-related issues, lack of professional support, and lack of effective oral health policies. Three major areas for action are identified: education for healthcare providers, health policy action plans, and citizen empowerment and involvement. A list of defined competencies in geriatric oral health for non dental healthcare providers is suggested, as well as an oral health promotion and disease prevention protocol for residents in institutional settings. Oral health assessment should be incorporated into general health assessments, oral health care should be integrated into public healthcare coverage, and access to dental care should be ensured. PMID- 29266167 TI - Gender differences in psychiatric comorbidity: a population-based study of 40 000 adults with attention deficit hyperactivity disorder. AB - OBJECTIVE: We aimed at determining whether gender modified associations between ADHD and psychiatric comorbidities in adults. METHOD: We identified adults with ADHD by linking Norwegian national registries and compared them with the remaining adult population (born 1967-1997, ADHD and bipolar during 2004-2015, other psychiatric disorders 2008-2015). Prevalence differences (PDs) and prevalence ratios (PRs) of psychiatric disorders were determined by Poisson regression. Interaction by gender was evaluated on additive (PDs) and multiplicative (PRs) scales. Proportions of psychiatric disorders attributable to ADHD were calculated. RESULTS: We identified 40 103 adults with ADHD (44% women) and 1 661 103 adults (49% women) in the remaining population. PDs associated with ADHD were significantly larger in women than in men for anxiety, depression, bipolar and personality disorders, for example depression in women: 24.4 (95% CI, 23.8-24.9) vs. in men: 13.1 (12.8-13.4). PDs were significantly larger in men for schizophrenia and substance use disorder (SUD), for example SUD in men: 23.0 (22.5-23.5) vs. in women: 13.7 (13.3-14.0). Between 5.6 and 16.5% of psychiatric disorders in the population were attributable to ADHD. CONCLUSION: The association between ADHD and psychiatric comorbidities differed significantly among men and women. Clinicians treating adults with ADHD should be aware of these frequent and gender-specific comorbidities, such that early treatment can be offered. PMID- 29266169 TI - Cost-effectiveness of curettage vs. expectant management in women with an incomplete evacuation after misoprostol treatment for first-trimester miscarriage: a randomized controlled trial and cohort study. AB - INTRODUCTION: Curettage is more effective than expectant management in women with suspected incomplete evacuation after misoprostol treatment for first-trimester miscarriage. The cost-effectiveness of curettage vs. expectant management in this group is unknown. MATERIAL AND METHODS: From June 2012 until July 2014 we conducted a randomized controlled trial and parallel cohort study in the Netherlands, comparing curettage with expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage. Successful treatment was defined as a sonographic finding of an empty uterus 6 weeks after study entry, or an uneventful course. Cost effectiveness and cost-utility analyses were performed. We included costs of healthcare utilization, informal care and lost productivity. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated using bootstrapping. RESULTS: We included 256 women from 27 hospitals; 95 curettage and 161 expectant management. Treatment was successful in 96% of the women treated with curettage vs. 83% of the women after expectant management (mean difference 13%, 95% confidence interval 5-20). Mean costs were significantly higher in the curettage group (mean difference ?1157; 95% C confidence interval ?955-1388). The incremental cost-effectiveness ratio for curettage vs. expectant management was ?8586 per successfully treated woman. The cost-effectiveness acceptability curve showed that at a willingness-to-pay of ?18 200/extra successfully treated women, the probability that curettage is cost-effective is 95%. CONCLUSIONS: Curettage is not cost-effective compared with expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment. This indicates that curettage in this group should be restrained. PMID- 29266171 TI - The importance of the peripheral blood film in indicating a diagnosis of multiple myeloma with cryoglobulinaemia. PMID- 29266170 TI - Wheel running during chronic nicotine exposure is protective against mecamylamine precipitated withdrawal and up-regulates hippocampal alpha7 nACh receptors in mice. AB - BACKGROUND AND PURPOSE: Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigated, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of alpha4beta2*, alpha7 nicotinic acetylcholine (nAChR), MU-opioid (MU receptors) and D2 dopamine receptors and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels. EXPERIMENTAL APPROACH: Male C57Bl/6J mice treated with nicotine (minipump, 24 mg.kg-1 .day-1 ) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 h.day-1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of alpha4beta2*, alpha7 nAChRs, MU receptors and D2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured. KEY RESULTS: Nicotine treated mice undertaking 2 or 24 h.day-1 wheel running displayed a significant reduction in withdrawal symptom severity compared with the sedentary group. Wheel running induced a significant up-regulation of alpha7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected MU or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and alpha4beta2* nAChR binding, irrespective of exercise regimen. CONCLUSIONS AND IMPLICATIONS: We demonstrated for the first time a profound effect of exercise on alpha7 nAChRs in nicotine dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise on the development of nicotine dependence. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 29266173 TI - Interactive Contributions of Attribution Biases and Emotional Intensity to Child Friend Interaction Quality During Preadolescence. AB - Using data from a subsample of 913 study children and their friends who participated in the NICHD Study of Early Child Care and Youth Development, the interactive contributions of child-reported attribution biases and teacher reported child emotional intensity (EI) at Grade 4 (M = 9.9 years) to observed child-friend interaction at Grade 6 (M = 11.9 years) were examined. Study children's hostile attribution bias, combined with high EI, predicted more negative child-friend interaction. In contrast, benign attribution bias, combined with high EI, predicted more positive child-friend interaction. The findings are discussed in light of the "fuel" interpretation of EI, in which high-intensity emotions may motivate children to act on their cognitive biases for better or for worse. PMID- 29266172 TI - Personal history of proliferative breast disease with atypia and risk of multifocal breast cancer. AB - BACKGROUND: A history of proliferative breast disease with atypia (PBDA) may be indicative of an increased risk not just of breast cancer but also of a more aggressive form of breast cancer. METHODS: Multifocal breast cancer (MFBC), defined as 2 or more tumors in the same breast upon a diagnosis of cancer, is associated with a poorer prognosis than unifocal (single-tumor) breast cancer. PBDA, including atypical ductal hyperplasia and atypical lobular hyperplasia, is a known risk factor for breast cancer. Using New Hampshire Mammography Network data collected for 3567 women diagnosed with incident breast cancer from 2004 to 2014, this study assessed the risk of MFBC associated with a previous diagnosis of PBDA. RESULTS: Women with a history of PBDA were found to be twice as likely to be subsequently diagnosed with MFBC as women with no history of benign breast disease (BBD; odds ratio [OR], 2.23; 95% confidence interval [CI], 1.08-4.61). Ductal carcinoma in situ on initial biopsy was associated with a 2-fold increased risk of MFBC in comparison with invasive cancer (OR, 2.13; 95% CI, 1.58-2.88). BBD and proliferative BBD without atypia were not associated with MFBC. CONCLUSIONS: Women with a history of previous PBDA may be at increased risk for MFBC. Women with a history of PBDA may benefit from additional presurgical clinical workup. Cancer 2018;124:1350-7. (c) 2017 American Cancer Society. PMID- 29266174 TI - Phase 2 and biomarker study of trebananib, an angiopoietin-blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma. AB - BACKGROUND: Angiopoietins contribute to tumor angiogenesis and may be upregulated as a compensatory factor after vascular endothelial growth factor (VEGF) blockade. The authors performed a phase 2 and biomarker study to evaluate trebananib, an angiopoietin 1 and angiopoietin 2 blocking peptibody, with and without bevacizumab in patients with recurrent glioblastoma. METHODS: Forty-eight patients who had bevacizumab-naive, recurrent glioblastoma were treated with trebananib (30 mg/kg weekly) as single agent (n = 11) or combined with bevacizumab (n = 37). The primary endpoint was 6-month progression-free survival rate as determined by investigator review. Circulating biomarker levels were assessed before and after study therapy. RESULTS: Trebananib was well tolerated as monotherapy and did not enhance bevacizumab-associated toxicity. Trebananib had no single-agent activity, and all treated patients exhibited progressive disease within 2 months. The 6-month progression-free survival rate for trebananib plus bevacizumab was 24.3% (95% confidence interval [CI], 12.1% 38.8%); whereas the median overall survival was 9.5 months (95% CI, 7.5-4.7 months), and the 12-month overall survival rate was 37.8% (95% CI, 22.6%-53.0%). Baseline and post-treatment changes in circulating vascular VEGF and interleukin 8 levels were correlated with survival among patients who received trebananib plus bevacizumab. CONCLUSIONS: Angiopoietin 1 and angiopoietin 2 inhibition with trebananib was ineffective as monotherapy and did not enhance the ability of VEGF blockade with bevacizumab to improve the outcomes of patients with recurrent glioblastoma. Cancer 2018;124:1438-48. (c) 2017 American Cancer Society. PMID- 29266175 TI - Evaluation of magnetic resonance imaging and targeted biopsy: The difficulty of finding the right reference standard. PMID- 29266177 TI - Attachment Security Priming Decreases Children's Physiological Response to Threat. AB - Ninety 6- and 7-year-olds (49.3% White, mostly middle class) from greater Washington, DC were randomly assigned to a subliminal priming condition (secure, happy, or neutral) to determine if attachment security priming decreases physiological, expressive, and self-reported fear reactions to threatening stimuli. Dispositional attachment security was also assessed. Secure priming and attachment security each decreased electrodermal reactivity, increased vagal augmentation, and decreased fearful facial expressions compared to control conditions. Examination of a statistical interaction between security priming and child attachment indicated that, although secure children had increased vagal augmentation and fewer fearful expressions than insecure children, the effects of priming were constant across secure and insecure children. There were no priming or attachment effects associated with children's self-reported fear. PMID- 29266176 TI - Bone mineral density in children with acute lymphoblastic leukemia. AB - BACKGROUND: Children with acute lymphoblastic leukemia (ALL) can develop reduced bone mineral density (BMD). However, data from patients who received treatment on a frontline regimen without cranial irradiation are limited, and no genome-wide analysis has been reported. METHODS: Lumbar BMD was evaluated by quantitative computed tomography at diagnosis, after 120 weeks of continuation therapy, and after 2 years off therapy in pediatric patients with ALL (ages 2-18 years at diagnosis) who were treated on the St. Jude Total XV Protocol. Clinical, pharmacokinetic, and genetic risk factors associated with decreased BMD Z-scores were evaluated. RESULTS: The median BMD Z-score in 363 patients was 0.06 at diagnosis, declined to -1.08 at week 120, but partly recovered to -0.72 after 2 years off therapy; BMD in patients with low BMD Z-scores at diagnosis remained low after therapy. Older age (>=10 years vs 2-9.9 years at diagnosis; P < .001), a higher BMD Z-score at diagnosis (P = .001), and a greater area under the plasma drug concentration-time curve for dexamethasone in weeks 7 and 8 of continuation therapy (P = .001) were associated with a greater decrease in BMD Z-score from diagnosis to week 120. Single-nucleotide polymorphisms in 2 genes important in osteogenesis and bone mineralization (COL11A1 [reference single-nucleotide polymorphism rs2622849]; P = 2.39 * 10-7 ] and NELL1 [rs11025915]; P = 4.07 * 10 6 ]) were associated with a decreased BMD Z-score. NELL1 (P = .003) also was associated with a greater dexamethasone area under the plasma drug concentration time curve. CONCLUSIONS: BMD Z-scores decreased during therapy, especially in patients who had clinical, pharmacokinetic, and genetic risk factors. Early recognition of BMD changes and strategies to optimize bone health are essential. Cancer 2018;124:1025-35. (c) 2017 American Cancer Society. PMID- 29266178 TI - Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial-level meta-analysis. AB - BACKGROUND: Overall survival (OS) is a critical endpoint in adjuvant trials but requires long durations to events and significant patient resources. In the current study, the authors assessed whether disease-free survival (DFS) can be an early clinical surrogate for OS in the adjuvant setting for localized renal cell carcinoma (RCC). METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the authors performed a systematic literature review of PubMed and the American Society of Clinical Oncology, European Society for Medical Oncology, and ClinicalTrial.gov Web sites (1996 2016). Inclusion in the current study required randomized controlled trials (RCTs) of adjuvant systemic therapy for localized RCC after nephrectomy with >=3 years of outcomes data. Data regarding hazard ratios (HRs) and 5-year event-free rates from Kaplan-Meier estimates were extracted. A trial-level meta-analysis correlated estimates of 5-year DFS and 5-year OS as well as treatment effects (HRs) on these endpoints, weighted by the number of DFS events. R-squared >= 0.7 was prespecified as being indicative of a strong correlation and the potential for surrogacy. RESULTS: Thirteen RCTs encompassing 6473 patients who were treated with a variety of systemic therapies met eligibility. Only a modest correlation was observed between 5-year DFS and 5-year OS rates (R-squared, 0.48; 95% confidence interval, 0.14-0.67) and between treatment effects as measured by DFS and OS HRs (R-squared, 0.44; 95% confidence interval, 0.00-0.69). CONCLUSIONS: Across RCTs of adjuvant systemic therapy for localized RCC, there was no strong correlation noted between 5-year DFS and 5-year OS rates or between treatment effects on these endpoints. These results highlight the need to identify alternative and more rapid clinical or biologic endpoints to hasten drug development and improve clinical outcomes. Cancer 2018;124:925-33. (c) 2017 American Cancer Society. PMID- 29266179 TI - Lecocytes mutation load declines with age in carriers of the m.3243A>G mutation: A 10-year Prospective Cohort. AB - Carriers of the mitochondrial mutation m.3243A>G presents highly variable phenotypes including mitochondrial encephalomyopathy, lactoacidosis and stroke like episodes (MELAS). We conducted a follow-up study to evaluate changes in leucocyte heteroplasmy and the clinical phenotypes in m.3243A>G carriers. Leucocyte heteroplasmy was determined by next generation sequencing covered by 100 000X reads in 32 individuals with a median follow-up of 10.2 years. Ten-year clinical follow-up is reported in 46 individuals. The annual leucocyte mutation level declined by -0.7 (+/-0.4) percentage points/year (P < .0001), and correlated with the level of the initial sample (rho = -0.92, P < .0001). Eleven of 46 m.3243A>G carriers died and clinical symptoms progressed. This longitudinal study shows the decline in leucocyte m.3243A>G heteroplasmy associates with the level of the initial sample. Further, there was a high mortality among carriers. PMID- 29266180 TI - The effect of perineural dexamethasone on duration of sciatic nerve blockade: a randomized, double-blind study. AB - BACKGROUND: Major hindfoot and ankle surgery is associated with severe postoperative pain, which is effectively alleviated by combined sciatic and saphenous nerve blockade. Local anaesthetics with added dexamethasone consistently prolongs the duration of pain relief compared to local anaesthetics alone. However, whether the extended duration of pain relief is due to an effect on duration of sensorimotor block per se vs. systemic absorption of the dexamethasone is still not fully elucidated. We aimed to investigate the postoperative duration of sensorimotor blockade with either dexamethasone or saline added to bupivacaine-epinephrine. METHODS: Fifty six patients scheduled for surgery were randomly assigned to a popliteal sciatic nerve block of 18 ml 0.5% bupivacaine-epinephrine with either 2 ml of 0.4% dexamethasone or 2 ml 0.9% normal saline added. Sensory and motor functions were tested every 30 min until normalized nerve functions. Primary outcome was time until complete return of sensorimotor functions. RESULTS: Mean (SD) time until return of normal sensory and motor functions was 26 (6) vs. 16 (4) hours, P < 0.001, postponing block remission by 10 (95% CI: 8-13) hours. Mean (SD) time until first opioid request was 34 (11) vs. 15 (7) hours, P < 0.001, extending first opioid request by 19 (95% CI: 13-25) hours. Total oral morphine equivalents administered 0-48 h differed significantly between the two groups by 39 (95% CI: 23-55) mg. CONCLUSIONS: Addition of 8 mg dexamethasone to 0.5% bupivacaine-epinephrine significantly prolongs the duration of sensorimotor popliteal sciatic nerve blockade, and reduces pain and opioid consumption in patients after major hind foot and ankle surgery. PMID- 29266181 TI - Low testosterone at first prostate-specific antigen failure and assessment of risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials. AB - BACKGROUND: Low testosterone at the time of diagnosis of prostate cancer has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at the time of first prostate-specific antigen (PSA) failure to the authors' knowledge has not been elucidated to date and was studied herein. METHODS: Between 1995 and 2001, a total of 58 men with unfavorable-risk PC who were treated on clinical trials with radiotherapy and androgen deprivation therapy (ADT) had available testosterone levels at the time of PSA failure. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific mortality, other cause mortality, and all-cause mortality adjusting for age, salvage ADT, and known PC prognostic factors. RESULTS: After a median follow-up of 6.68 years after PSA failure, 31 men (53.4%) had died; 10 of PC (32.3%), of which 8 of 11 (72.7%) versus 2 of 47 (4.3%) deaths occurred in men with low versus normal testosterone at the time of PSA failure, respectively. A significant increase in the risk of all-cause mortality (adjusted hazard ratio [AHR], 2.54; 95% confidence interval [95% CI], 1.04-6.21 [P = .04]) and PC-specific mortality (AHR, 13.71; 95% CI, 2.4-78.16 [P = .003]), with a reciprocal trend toward a decreased risk of other-cause mortality (AHR, 0.18; 95% CI, 0.02-1.55 [P = .12]) was observed in men with low versus normal testosterone. CONCLUSIONS: Low, but not necessarily castrate, testosterone levels at the time of PSA failure confer a very poor prognosis. These observations provide evidence to support testosterone testing at the time of PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides a rationale supporting their use with ADT in men with low testosterone in the setting of a phase 2 trial. Cancer 2018;124:1383-90. (c) 2017 American Cancer Society. PMID- 29266182 TI - Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration-resistant prostate cancer (CRPC). AB - BACKGROUND: Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate plus prednisone (abiraterone), have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). Many patients respond to these agents, but both de novo and acquired resistance are common. The authors characterized resistant phenotypes that emerge after treatment with abiraterone or enzalutamide. METHODS: Patients who received abiraterone or enzalutamide in the course of routine clinical care were consented for serial blood collection. A proprietary system (CellSearch) was used to enumerate and enrich circulating tumor cells (CTCs). RNA-sequencing (RNA-seq) was performed on pools of up to 10 epithelial cell adhesion molecule (EpCAM) positive/CD45-negative CTCs. The impact of gene expression changes observed in CTCs between patients who responded or were resistant to abiraterone/enzalutamide therapies was further explored in a model cell line system. RESULTS: RNA-seq data from CTCs identified mutations commonly associated with CRPC as well as novel mutations, including several in the ligand-binding domain of AR that could facilitate escape from AR-targeted agents. Ingenuity pathway analysis of differentially regulated genes identified the transforming growth factor beta (TGFbeta) and cyclin D1 (CCND1) signaling pathways as significantly upregulated in drug-resistant CTCs. Transfection experiments using enzalutamide-sensitive and enzalutamide-resistant LNCaP cells confirmed the involvement of SMAD family member 3, a key mediator of the TGFbeta pathway, and of CCND1 in resistance to enzalutamide treatment. CONCLUSIONS: The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. (c) 2017 American Cancer Society. PMID- 29266184 TI - Oral Health in Healthy Aging. PMID- 29266183 TI - Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: A report from the International Radiosurgery Oncology Consortium for Kidney (IROCK). AB - BACKGROUND: Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared. METHODS: Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression. RESULTS: Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. On multivariable analysis, tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P < .01] and 1.13 [P = .02], respectively) and poorer cancer specific survival (hazard ratio, 1.28 [P < .01] and 1.33 [P = .01], respectively). There were no differences in local failure between the single fraction cohort (n = 1) and the multifraction cohort (n = 2; P = .60). The mean ( +/- standard deviation) estimated glomerular filtration rate at baseline was 59.9 +/- 21.9 mL per minute, and it decreased by 5.5 +/- 13.3 mL per minute (P < .01). CONCLUSIONS: SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer. Cancer 2018;124:934-42. (c) 2017 American Cancer Society. PMID- 29266185 TI - Survey of equine castration techniques, preferences and outcomes among Australian veterinarians. AB - OBJECTIVES: (1) To collect the perceptions of veterinarians performing equine castrations in Australia on techniques, preferences and outcomes, (2) to investigate veterinarian use and experience with the Henderson castrating instrument and (3) to investigate potential associations between demographics, castration methods and techniques, and complications. DESIGN: Online survey of members of the Australian Veterinary Association's Special Interest Group, Equine Veterinarians Australia (EVA). METHODS: A link to the survey was included in the EVA e-newsletter and practices on the EVA website were contacted by telephone and follow-up email. Fisher's exact test was used to determine associations between ligation and complications. A generalised linear model with a negative binomial family was used to determine associations between count response variables and categorical independent variables. RESULTS: Responses were obtained from 138 veterinarians (response rate, 13.1%) who performed 5330 castrations over 12 months. Castrations were most commonly performed in the field, on anaesthetised horses, using emasculators, via an open approach and without ligation of the spermatic cord. Estimated complications after use of emasculators were swelling (25%), haemorrhage (5%) and infection (5%). The Henderson instrument was used by approximately 10% of respondents and its use for castration was associated with fewer reports of postoperative swelling compared with emasculators (P = 0.002). Rates of evisceration with the Henderson and emasculator methods were comparable (0.43% and 0.9%, respectively). CONCLUSION: Castration preferences varied widely among survey participants. Reported complication types and rates were comparable to those reported previously in other countries. Perceptions that the Henderson instrument was associated with less swelling should be investigated further via a prospective controlled investigation. PMID- 29266186 TI - Long-term mucocutaneous adverse effects of imatinib in Indian chronic myeloid leukemia patients. AB - BACKGROUND: Short-term mucocutaneous adverse effects are well documented with imatinib. However, studies on long-term adverse effects and in the ethnic population are lacking. OBJECTIVE: To study the long-term mucocutaneous adverse effects of imatinib and factors predicting these adverse effects. METHODS: In this cross-sectional study, consenting adult chronic myeloid leukemia patients on imatinib for more than 250 days were recruited. The details of imatinib treatment were retrieved from hematology clinic records. RESULTS: Four hundred and thirty eight patients who were on imatinib for a mean duration of 1820 days were recruited. A mean number of 1.42 +/- 0.98 cutaneous adverse effects were seen per patient. Melasma-like pigmentation, periorbital edema, oral lichenoid reaction, cutaneous hypopigmentation, and vesicobullous eruptions were seen in 236 (53.9%), 81 (18.5%), 70 (16%), 42 (9.6%), and 12 (2.7%) patients, respectively. Drug induced cutaneous eruptions (9.1%) and cutaneous hypopigmentation (9.6%) were seen less frequently. Cutaneous hyperpigmentation was more likely seen in younger patients (P = 0.001) and females (P < 0.001). On multivariate analysis, female gender was a significant risk factor for developing cutaneous hyperpigmentation and periorbital edema. CONCLUSION: Cutaneous hyperpigmentation and periorbital edema are common long-term adverse effects of imatinib in Indian patients. Female gender is a significant risk factor for the development of both these adverse effects. PMID- 29266187 TI - Postmarket Safety Outcomes for New Molecular Entity (NME) Drugs Approved by the Food and Drug Administration Between 2002 and 2014. AB - We ascertained a comprehensive list of postmarket safety outcomes, defined as a safety-related market withdrawal or an update to a safety-related section of product label for 278 new molecular entity drugs (NMEs) with a follow-up period of up to 13 years. At least one safety-related update was added to 195 (70.1%) labels of the drugs studied. Updates occurred as early as 160 days after approval and throughout the follow-up period. The period between the second and eighth postapproval year was the most active, with a slight attenuation thereafter. The times to the first safety outcome were significantly shorter for NMEs approved with a fast-track designation (P = 0.02) or under an accelerated approval using a surrogate endpoint (P = 0.03). Our findings underscore the importance of a robust safety surveillance system throughout a drug's lifecycle and for practitioners and patients to remain updated on drug safety profiles. PMID- 29266188 TI - ADGRV1 is implicated in myoclonic epilepsy. AB - OBJECTIVE: To investigate the significance of variation in ADGRV1 (also known as GPR98, MASS1, and VLGR1), MEF2C, and other genes at the 5q14.3 chromosomal locus in myoclonic epilepsy. METHODS: We studied the epilepsy phenotypes of 4 individuals with 5q14.3 deletion and found that all had myoclonic seizures. We then screened 6 contiguous genes at 5q14.3, MEF2C, CETN3, MBLAC2, POLR3G, LYSMD3, and ADGRV1, in a 95-patient cohort with epilepsy and myoclonic seizures. Of these genes, point mutations in MEF2C cause a phenotype involving seizures and intellectual disability. A role for ADGRV1 in epilepsy has been proposed previously, based on a recessive mutation in the Frings mouse model of audiogenic seizures, as well as a shared homologous region with another epilepsy gene, LGI1. RESULTS: Six patients from the myoclonic epilepsy cohort had likely pathogenic ultra-rare ADGRV1 variants, and statistical analysis showed that ultra-rare variants were significantly overrepresented when compared to healthy population data from the Genome Aggregation Database. Of the remaining genes, no definite pathogenic variants were identified. SIGNIFICANCE: Our data suggest that the ADGRV1 variation contributes to epilepsy with myoclonic seizures, although the inheritance pattern may be complex in many cases. In patients with 5q14.3 deletion and epilepsy, ADGRV1 haploinsufficiency likely contributes to seizure development. The latter is a shift from current thinking, as MEF2C haploinsufficiency has been considered the main cause of epilepsy in 5q14.3 deletion syndrome. In cases of 5q14.3 deletion and epilepsy, seizures likely occur due to haploinsufficiency of one or both of ADGRV1 and MEF2C. PMID- 29266190 TI - The changing landscape of hereditary cancer genetic testing. PMID- 29266189 TI - Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high risk B-lymphoblastic leukemia: A report from the Children's Oncology Group study AALL1131. AB - BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Munster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2 /d * 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2 /d * 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity. Cancer 2018;124:1150-9. (c) 2017 American Cancer Society. PMID- 29266191 TI - Digital radiomorphometric analysis of the frontal sinus and assessment of the relation between persistent metopic suture and frontal sinus development. AB - OBJECTIVES: This study aimed to establish the frequency of the frontal sinus (FS) aplasia, to compare metopic and nonmetopic series and thus to assess the relationship between the preservation of metopic suture and FS development. MATERIALS AND METHODS: FSs were investigated in 230 dry skulls of adult males distributed into control (137) and metopic (93) series. They were visualized through industrial digital radiography. RESULTS: In the control series, the FS aplasia was observed in 12.41% of the skulls, and it was mostly unilateral (8.76%) than bilateral (3.65%). The left-sided aplasia (5.11%) slightly prevailed over the right-sided one (3.65%). In the metopic series, the aplasia was observed with a frequency of 19.35%, and the bilateral aplasia (7.53%) was rarer that the unilateral one (11.83%), while the right-sided aplasia was clearly predominant (9.68%) compared to the left-sided one (2.15%). DISCUSSION: The significant differences between both series showed a tendency for the persistence of metopic suture to be frequently related with FS underdevelopment in the vertical plate of the frontal bone, but in cases of pneumatization, it was preferentially on the left side. Taking into account that the cranial hypertension leads to suture diastasis and hinders development of the FS, it could be suggested that persistence of the metopic suture along with underdevelopment of the FS in nonsyndromic adults could be an expression of an elevated intracranial pressure during early development as an after-effect of certain condition. PMID- 29266192 TI - Caesarean section wound infection surveillance: Information for action. AB - Surgical site infection (SSI) following caesarean section is common, resulting in significant morbidity. Several factors are known to contribute to wound infection, including maternal, procedural and antibiotic factors. We sought to clarify these issues and sought opportunities to make improvements. A retrospective cohort study was performed assessing all women who underwent caesarean section in 2014 and 2015 at Wellington Hospital. Any women with culture positive wound samples within 30 days of surgery were identified, and clinical notes reviewed. Odds ratios (OR) were calculated for available maternal, procedural and antibiotic risk factors. Two simplified surveillance techniques were also tested for their abilities to identify significant trends. The study included 2231 women, of whom 116 (5.2%) were identified as having SSI. Maternal obesity (body mass index (BMI) >= 30) was associated with significant SSI risk (OR 4.1, P < 0.001). The pathogen distribution was significantly different between women with BMI < 30 and BMI >= 30 (P < 0.001). Increased cefazolin dose based on BMI (3 g dose for BMI >= 30) was associated with a significant reduction in SSI (OR 0.309, P < 0.001) and was administered in 74.1% of obese women receiving cefazolin. Maori women had an increased SSI risk (OR 2.1, P = 0.019), as did Samoan women (OR 3.0, P = 0.002). The study reinforces other studies showing that raised BMI is the single biggest risk factor for surgical site infection post-caesarean section. Surveillance using simplified techniques appears to be adequate to identify trends. We believe that concentrating on appropriate antibiotic dosing and targeting special wound care measures will be pivotal interventions in improving outcomes in high-risk groups. PMID- 29266193 TI - Emma Lucy Braun's forest plots in eastern North America. AB - Relative abundances of tree species are presented for the 348 forest plots described in E. Lucy Braun's (1950) book, Deciduous Forests of Eastern North America (Hafner, New York, facsimile reprint 1972). Information about the plots includes forest type, location with latitude and longitude, WorldClim climate variables, and sources of original studies where applicable. No copyright restrictions are associated with the use of this data set. Please cite this article when the data are used in other publications. PMID- 29266194 TI - Marital Conflict Predicts Mother-to-Infant Adrenocortical Transmission. AB - Employing an experimental design, mother-to-infant transmission of stress was examined. Mothers (N = 117) were randomized to either have a positive or conflictual discussion with their marital partners, after which infants (age = 6 months) participated in a fear and frustration task. Saliva samples were collected to assess maternal cortisol responses to the discussion and infant cortisol responses to the challenge task. Results indicate maternal cortisol reactivity and recovery to the conflict (but not positive) discussion predicted infant cortisol reactivity to the infant challenge. Mothers' positive affect during the discussion buffered, and intrusion during the free-play potentiated, mother-to-infant adrenocortical transmission. These findings advance our understanding of the social and contextual regulation of adrenocortical activity in early childhood. PMID- 29266195 TI - Litter P content drives consumer production in detritus-based streams spanning an experimental N:P gradient. AB - Ecological stoichiometry theory (EST) is a key framework for predicting how variation in N:P supply ratios influences biological processes, at molecular to ecosystem scales, by altering the availability of C, N, and P relative to organismal requirements. We tested EST predictions by fertilizing five forest streams at different dissolved molar N:P ratios (2, 8, 16, 32, 128) for two years and tracking responses of macroinvertebrate consumers to the resulting steep experimental gradient in basal resource stoichiometry (leaf litter %N, %P, and N:P). Nitrogen and P content of leaf litter, the dominant basal resource, increased in all five streams following enrichment, with steepest responses in litter %P and N:P ratio. Additionally, increases in primary consumer biomass and production occurred in all five streams following N and P enrichment (averages across all streams: biomass by 1.2*, production by 1.6*). Patterns of both biomass and production were best predicted by leaf litter N:P and %P and were unrelated to leaf litter %N. Primary consumer production increased most in streams where decreases in leaf litter N:P were largest. Macroinvertebrate predator biomass and production were also strongly positively related to litter %P, providing robust experimental evidence for the primacy of P limitation at multiple trophic levels in these ecosystems. However, production of predatory macroinvertebrates was not related directly to primary consumer production, suggesting the importance of additional controls for macroinvertebrates at upper trophic positions. Our results reveal potential drivers of animal production in detritus-based ecosystems, including the relative importance of resource quality vs. quantity. Our study also sheds light on the more general impacts of variation in N:P supply ratio on nutrient-poor ecosystems, providing strong empirical support for predictions that nutrient enrichment increases food web productivity whenever large elemental imbalances between basal resources and consumer demand are reduced. PMID- 29266196 TI - Diagnosis of patients with inflammatory breast cancer is a problematic issue. PMID- 29266198 TI - Drug-induced lupus erythematosus secondary to pirfenidone. PMID- 29266197 TI - Phages of life - the path to pharma. AB - Bacteriophage (phage) therapy has encountered both enthusiasm and scepticism in the past century. New antimicrobial strategies against lethal pathogens are now a top priority for the World Health Organization, and although compassionate use of phages recently met with significant success, regulated clinical interventions seem unlikely in the near future. The hundredth anniversary of their discovery seems an appropriate time for a revival of phage therapy, particularly as the dilemma of antibiotic resistance grows. Phages are ubiquitous in the environment, on our food and in and on our bodies. Their influence on human health is currently being evaluated, and in this mini-review, we examine data from recent metagenomic studies that propose a role for phages in the structure of the microbiome and in health and disease. We assess evidence for phages as vehicles for gene transfer in the context of antibiotic resistance and discuss challenges and opportunities along the critical path from phage discovery to a patient focused pharmaceutical intervention. PMID- 29266199 TI - Intranasal Oxytocin Attenuates Reactive and Ongoing, Chronic Pain in a Model of Mild Traumatic Brain Injury. AB - BACKGROUND: Approximately 1.7 million Americans sustain a traumatic brain injury (TBI) each year and chronic pain is a common complication. OBJECTIVE: We studied the effects of intranasally administered oxytocin as a potential treatment for chronic pain in an animal model of mild TBI. METHODS: The lateral fluid percussion model of mild TBI was chosen for this purpose and after exposure to mild TBI the rats (n = 12) developed hind paw and facial allodynia compared to sham animals (n = 6). Oxytocin or a vehicle was afterwards administered intranasally and reactive pain was assessed by hind paw and facial von Frey testing. Some animals received the oxytocin receptor antagonist, atosiban, in addition to oxytocin/vehicle treatment (n = 12). The effect of oxytocin on ongoing and spontaneous pain was examined through conditioned place preference testing. To determine whether the effects of intranasal oxytocin could be attributed to delivery via the peripheral blood stream, some TBI animals received an intravenous injection of the same oxytocin dose that was given intranasally. ELISA immunoassays were carried out (n = 6) to measure concentrations of oxytocin in the trigeminal ganglia, pons, spinal cord, and olfactory bulb after intranasal administration and evaluate the most likely route of entry. RESULTS: These studies confirmed that the fluid percussion model can be used to study post-TBI facial allodynia. Oxytocin attenuated both reactive and spontaneous, ongoing non reactive pain following mild TBI for at least 3-4 hours after intranasal administration by binding to OT or VA1-receptors most likely by a peri-trigeminal nerve mediated uptake. CONCLUSIONS: Intranasal oxytocin attenuates measures of reactive and non-reactive pain in a model of mild TBI and may represent a novel treatment for chronic pain in TBI patients. PMID- 29266200 TI - AID recruits the RNA exosome to degrade HIV-1 nascent transcripts through interaction with the Tat-P-TEFb-TAR RNP complex. AB - Activation-induced cytidine deaminase (AID), a member of the APOBEC family that induces antibody diversification, has been shown to inhibit the replication of hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and retro transposons. However, whether AID can inhibit human immunodeficiency virus 1 (HIV 1) replication remains unclear. Here, we report that AID impairs the synthesis of HIV-1 components by interacting with the complex of Tat. This interaction recruits the RNA exosome to degrade the nascent HIV-1 transcript. AID also targets the HIV-1-integrated genome via the Tat-P-TEFb-TAR complex. Thus, we propose a novel function for AID as an adaptor protein that represses viral transcription. Our findings provide insights into developing anti-HIV therapeutics and understanding how host cells restrict integrated virus replication. PMID- 29266201 TI - Job stress in new nurses during the transition period: an integrative review. AB - AIM: This review appraised and synthesized evidence relating to new nurses' stress experiences during the transition period. BACKGROUND: Although stress among nursing professionals has been a subject of several systematic reviews in the recent years, there is still scarcity of systematic evidence examining job stress in new nurses. METHODS: This is an integrative review of original studies conducted from 2002 onwards examining new nurses' stress experiences. Five databases were used to retrieve relevant articles such as CINAHL, SCOPUS, PubMed, PsycINFO and MEDLINE. Twenty-one articles were included in this review. FINDINGS: New nurses perceived low to moderate levels of stress mainly from heavy workloads and lack of professional nursing competence. Individual and organizational factors that might contribute to their stress experiences were rarely explored. CONCLUSION: This integrative review evaluated and synthesized available evidence examining stress in new nurses and contributed to the literature regarding stress in nursing professionals. The findings of this review may offer specific information to nurse administrators that can relate to the stress encountered by new nurses who enter into healthcare facilities. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Findings of this review may provide valuable input to assist nurse administrators in developing and implementing organizational measures to reduce stress in new nurses while maximizing and facilitating their integration into the nursing workforce. Such measures may include the following: establishment of a well-structured transition programme, provision of an adequate orientation and senior staff mentorship, stress management programmes, in-service educational programmes and exposure to clinical simulation scenarios. PMID- 29266202 TI - School readiness in children with special educational needs and disabilities: Psychometric findings from a new screening tool, the Brief Early Skills, and Support Index. AB - BACKGROUND: There is an urgent need to accelerate the detection of special educational needs and disabilities (SEND). A recent brief questionnaire designed for teachers and nursery staff, the Brief Early Skills and Support Index (BESSI), shows promising psychometric properties (Hughes, Daly, Foley, White, & Devine, . British Journal of Educational Psychology, 85(3), 332-356.), but has yet to be evaluated as a tool for detecting children who may have SEND. AIMS: Addressing this gap, this study aimed to assess whether BESSI scores (i) show measurement invariance across SEND status; (ii) show unique associations with SEND status; and (iii) are sensitive and specific to SEND status. SAMPLE: Eighty-four teachers and nursery staff completed BESSI ratings for 2106 British children aged 2.5-5.5 years (48.9% male, 20% ethnic minority, 9.3% with a statement of SEND). METHOD: We applied multilevel confirmatory factor analyses, regression analyses, and ROC analyses to examine each of the study questions, using the BESSI subscales (Behavioural Adjustment, Language and Cognition, Daily Living Skills, and Family Support) as dependent variables. RESULTS: The four BESSI subscales were reliable and showed measurement invariance across SEND status. Over and above effects of age, gender, family income, ethnicity, and family size, SEND status predicted substantial unique variance in BESSI scores. ROC analyses showed that in detecting children identified as having SEND, a cut-off score of 8.50 on the BESSI total score produced good levels of sensitivity and specificity; gender specific analyses indicated a lower cut-off score of 6.50 for girls. CONCLUSION: The BESSI appears to be a useful tool in screening children for more detailed assessment of SEND. PMID- 29266203 TI - PDGFB as a vascular normalization agent in an ovarian cancer model treated with a gamma-secretase inhibitor. AB - Ovarian cancer is the fifth leading cause of cancer-related deaths in women. In the past 20 years, the canonical types of drugs used to treat ovarian cancer have not been replaced and the survival rates have not changed. These facts show the clear need to find new therapeutic strategies for this illness. Thus, the aim of the present study was to investigate the effect of a gamma-secretase inhibitor (DAPT) in combination with the Platelet-derived growth factor B (PDGFB) on an ovarian cancer xenograft model. To achieve this goal, we analyzed the effect of the administration of DAPT alone and the co-administration of DAPT and recombinant PDGFB on parameters associated with tumor growth and angiogenesis in an orthotopic experimental model of ovarian cancer. We observed that the dose of DAPT used was ineffective to reduce ovarian tumor growth, but showed anticancer activity when co-administered with recombinant PDGFB. The administration of PDGFB alone normalized tumor vasculature by increasing periendothelial coverage and vascular functionality. Interestingly, this effect exerted by PDGFB was also observed in the presence of DAPT. Our findings suggest that PDGFB is able to improve tumor vascularity and allows the anticancer action of DAPT in the tumor. We propose that this therapeutic strategy could be a new tool for ovarian cancer treatment and deserves further studies. PMID- 29266205 TI - Peptibodies: An elegant solution for a long-standing problem. AB - Chimeric proteins composed of a biologically active peptide and a fragment crystallizable (Fc) domain of immunoglobulin G (IgG) are known as peptibodies. They present an extended half-life due to neonatal Fc receptor (FcRn) salvage pathway, a decreased renal clearance rate owing to its increased size (~70 kDa) and, depending on the peptide used in the design of the peptibody, an active targeting moiety. Also, the peptides therapeutic activity is boosted by the number of peptides in the fusion protein (at least two peptides) and to some peptides' alterations. Peptibodies are mainly obtained through recombinant DNA technology. However, to improve peptide properties, "unnatural" changes have been introduced to the original peptides' sequence, for instance, the incorporation of D- or non-natural amino acid residues or even cyclization thus, limiting the application of genetic engineering in the production of peptibodies, since these peptides must be obtained via chemical synthesis. This constrains prompted the development of new methods for conjugation of peptides to Fc domains. Another challenge, subject of intense research, relates to the large-scale production of such peptibodies using these new techniques, which can be minimized by their proved value. To date, two peptibodies, romiplostim and dulaglutide, have been approved and stay as the standard of care in their areas of action. Furthermore, a considerable number of peptibodies are currently in preclinical and clinical development. PMID- 29266204 TI - Hepatitis C virus core protein reduces CD8+ T-cell proliferation, perforin production and degranulation but increases STAT5 activation. AB - Clearance of hepatitis C virus (HCV) is dependent on an effective virus-specific CD8+ T-cell response, which is dysfunctional in chronic HCV infection. Dysfunction in bulk or non-HCV-specific CD8+ T-cells in HCV infection has also been observed. This may contribute to observed reductions in immunity to other diseases (e.g. cancer, viral co-infections) in HCV-infected individuals. Evidence suggests that the HCV core protein (found in blood as free protein) may contribute to this impairment. To determine if HCV core contributes to the impairment of effector functions and survival potential of CD8+ T-cells, isolated human CD8+ T-cells from healthy donors were pre-incubated with recombinant HCV core protein for 72 hr and then stimulated in vitro to evaluate proliferation, survival potential and effector functions. Pre-incubation of stimulated CD8+ T cells with HCV core significantly reduced their proliferation. Perforin production and degranulation were also decreased, but interferon-gamma production was unchanged. Additionally, when CD8+ T-cells were treated with serum from HCV+ individuals, they produced less perforin than cells treated with healthy serum. Up-regulation of anti-apoptotic Bcl-2 was slightly lower in cells treated with HCV core, but signal transducer and activator of transcription 5 (STAT5) activation was increased, suggesting dysregulation downstream of STAT activation. Our study reveals that HCV core reduces the activity and target lysis-associated functions of CD8+ T-cells. This may contribute to the generalized impairment of CD8+ T-cells observed in HCV infection. These findings provide insight for the design of novel counteractive immune-mediated strategies including the design of effective therapeutic vaccines for use in HCV+ individuals. PMID- 29266207 TI - Bovine leukemia virus linked to breast cancer but not coinfection with human papillomavirus: Case-control study of women in Texas. AB - BACKGROUND: Bovine leukemia virus (BLV) and human papillomavirus (HPV) were previously identified in human breast tissue and have been associated with breast cancer in independent studies. The objective of the current study was to test for the presence of BLV and HPV in the same breast tissue specimens to determine whether the viruses were associated with breast cancer either singly or together. METHODS: Archival formalin-fixed paraffin-embedded breast tissue sections from 216 women were received from The University of Texas MD Anderson Cancer Center along with patient diagnosis. In situ polymerase chain reaction and/or DNA hybridization methods were used to detect targeted DNA segments of BLV and HPV. Standard statistical methods were used to calculate age-adjusted odds ratios, attributable risk, and P values for the trend related to the association between presence of a virus and a diagnosis of breast disease. RESULTS: Women diagnosed with breast cancer were significantly more likely to have BLV DNA in their breast tissue compared with women with benign diagnoses and no history of breast cancer. Women with breast pathology classified as premalignant and no history of breast cancer also were found to have an elevated risk of harboring BLV DNA in their breast tissue. HPV status was not associated with malignancy, premalignant breast disease, or the presence of BLV in the breast tissues. CONCLUSIONS: The data from the current study supported previous findings of a significant association between BLV DNA in breast tissue and a diagnosis of breast cancer, but did not demonstrate oncogenic strains of HPV associated with breast cancer or the presence of BLV DNA in breast tissue. The authors believe the findings of the current study contribute to overall knowledge regarding a possible causal role for viruses in human breast cancer. Cancer 2018;124:1342-9. (c) 2017 American Cancer Society. PMID- 29266206 TI - Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase. AB - BACKGROUND: The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level <0.0032% on the international scale (MR4.5 ) for at least 2 years according to BCR-ABL1 levels achieved within the first 12 months of therapy. METHODS: Data for 603 patients with newly diagnosed chronic myeloid leukemia in chronic phase in consecutive prospective clinical trials were analyzed. The best fit average molecular response was defined by robust linear regression models, with which the average molecular levels were defined. The minimum acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL1 levels were identified. RESULTS: In 603 patients with a median follow-up of 103 months, 2002 BCR-ABL1-level data points within 1 year of tyrosine kinase inhibitors were identified. The regression equation for the best fit average levels for a sustained MR4.5 was Log10 (PCR) = -0.1424 * (Months) - 0.8668, and the regression equation for minimum acceptable levels was Log10 (PCR) = -0.1403 * (Months) + 0.6142 (where PCR indicates polymerase chain reaction). To achieve a sustained MR4.5 , the best fit average levels were 0.051%, 0.019%, 0.007%, and 0.003% at 3, 6, 9, and 12 months, respectively; the minimum acceptable levels were 1.561%, 0.592%, 0.225%, and 0.085% at 3, 6, 9, and 12 months, respectively. CONCLUSIONS: This model proposes optimal values that predict the highest probability of reaching such a goal. These values can be used to guide therapy when a sustained MR4.5 is the objective. Cancer 2018;124:1160-8. (c) 2017 American Cancer Society. PMID- 29266208 TI - Potential neuroprotective effect of androst-5-ene-3beta, 17beta-diol (ADIOL) on the striatum, and substantia nigra in Parkinson's disease rat model. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder with behavioral and motor abnormalities. Androst-5-ene-3beta, 17beta-diol (ADIOL), an estrogen receptor (ER) beta agonist, was found to mediate a transrepressive mechanism that selectively modulates the extent of neuroinflammation and, in turn, neurodegeneration. In consensus, ERbeta polymorphism was more frequently detected in early-onset PD patients. Thus, in an approach to elucidate the role of ERbeta agonists on PD, our study was designed to investigate the possible neuroprotective effect of ADIOL, in three dose levels (0.35, 3.5, 35 mg/kg/day), against rotenone (ROT)-induced PD rat model. Amelioration in striatal dopamine (DA), nuclear factor-kappa B (NF-kappaB), and the expression of down-stream inflammatory mediators, as well as apoptotic markers were observed in the striatum and substantia nigra (SN) upon pre-treatment with the three doses of ADIOL. Similarly, light microscopy (LM) examination revealed declined degeneration of neurons upon pretreatment with ADIOL. Significant improvement in nigral tyrosine hydroxylase (TH) and reduction of nigral alpha-synuclein densities were also detected after ADIOL pre-treatment with better results frequently achieved with the middle dose (3.5 mg/kg/day). The middle dose of ADIOL showed behavioral improvement, with elevation in the ATP level, which was emphasized by the improvement in mitochondrial integrity observed upon electron microscopy (EM) examination. In conclusion, the present study confirmed for the first time the ability of ADIOL to protect against neuroinflammation and, in turn, neurodegeneration process and motor dysfunction in PD animal model, which was more obviously observed with the middle dose. PMID- 29266209 TI - Reply to Diagnosis of patients with inflammatory breast cancer is a problematic issue. PMID- 29266210 TI - Subpopulations of dermal skin fibroblasts secrete distinct extracellular matrix: implications for using skin substitutes in the clinic. AB - BACKGROUND: While several commercial dermoepidermal scaffolds can promote wound healing of the skin, the achievement of complete skin regeneration still represents a major challenge. OBJECTIVES: To perform biological characterization of self-assembled extracellular matrices (ECMs) from three different subpopulations of fibroblasts found in human skin: papillary fibroblasts (Pfi), reticular fibroblasts (Rfi) and dermal papilla fibroblasts (DPfi). METHODS: Fibroblast subpopulations were cultured with ascorbic acid to promote cell assembled matrix production for 10 days. Subsequently, cells were removed and the remaining matrices characterized. Additionally, in another experiment, keratinocytes were seeded on the top of cell-depleted ECMs to generate epidermal only skin constructs. RESULTS: We found that the ECM self-assembled by Pfi exhibited randomly oriented fibres associated with the highest interfibrillar space, reflecting ECM characteristics that are physiologically present within the papillary dermis. Mass spectrometry followed by validation with immunofluorescence analysis showed that thrombospondin 1 is preferentially expressed within the DPfi-derived matrix. Moreover, we observed that epidermal constructs grown on DPfi or Pfi matrices exhibited normal basement membrane formation, whereas Rfi matrices were unable to support membrane formation. CONCLUSIONS: We argue that inspiration can be taken from these different ECMs, to improve the design of therapeutic biomaterials in skin engineering applications. PMID- 29266211 TI - Morphological, biochemical and mechanical properties of articular cartilage and subchondral bone in rat tibial plateau are age related. AB - The purpose of this study was to investigate age-related changes in the morphological, biochemical and mechanical properties of articular cartilage (AC) and subchondral bone in the rat tibial plateau. Female Wistar rats were grouped according to age (1, 3, 5, 7, 9, 11, 13, 15, 16 and 17 months, with 10 rats in each group). The ultrastructures, surface topographies, and biochemical and mechanical properties of the AC and subchondral bone in the knee joints of the rats were determined through X-ray micro-tomography, histology, immunohistochemistry, scanning electron microscopy (SEM), atomic force microscopy and nanoindentation. We found that cartilage thickness decreased with age. This decrease was accompanied by functional condensation of the underlying subchondral bone. Increased thickness and bone mineral density and decreased porosity were observed in the subchondral plate (SP). Growth decreased collagen II expression in the tibial cartilage. The arrangement of trabeculae in the subchondral trabecular bone became disordered. The thickness and strength of the fibers decreased with age, as detected by SEM. The SP and trabeculae in the tibial plateau increased in roughness in the first phase (1-9 months of age), and then were constant in the second phase (11-17 months of age). Meanwhile, the roughness of the AC changed significantly in the first phase (1-9 months of age), but the changes were independent of age thereafter. This study gives a comprehensive insight into the growth-related structural, biochemical and mechanical changes in the AC and subchondral bone. The results presented herein may contribute to a new understanding of the pathogenesis of age-related bone diseases. PMID- 29266212 TI - Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact. AB - Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing. PMID- 29266214 TI - Response to the letter to the editor by Shadmani et al. PMID- 29266215 TI - Luis Alejandro Yanez-Arancibia 1944-2016. PMID- 29266213 TI - Using immunocompromised mice to identify mechanisms of Zika virus transmission and pathogenesis. AB - Zika virus (ZIKV) is responsible for a recent global epidemic that has been associated with congenital brain malformations in fetuses and with Guillain-Barre syndrome in adults. Within the last 2 years, a major effort has been made to develop murine models to study the mechanism of viral transmission, pathogenesis and the host immune response. Here, we discuss the findings from these models regarding the role that the innate and adaptive immune responses have in controlling ZIKV infection and pathogenesis. Additionally, we examine how innate and adaptive immune responses influence sexual and vertical transmission of ZIKV infection as well as how these responses can influence the ability of ZIKV to cross the placenta and to induce damage in the developing brain. PMID- 29266216 TI - Delineating advanced practice nursing in New Zealand: a national survey. AB - BACKGROUND: A variety of advanced practice nursing roles and titles have proliferated in response to the changing demands of a population characterized by increasing age and chronic illness. Whilst similarly identified as advanced practice roles, they do not share a common practice profile, educational requirements or legislative direction. The lack of clarity limits comparative research that can inform policy and health service planning. AIMS: To identify advanced practice roles within nursing titles employed in New Zealand and practice differences between advanced practice and other roles. METHOD: Replicating recent Australian research, 3255 registered nurses/nurse practitioners in New Zealand completed the amended Advanced Practice Delineation survey tool. The mean domain scores of the predominant advanced practice position were compared with those of other positions. Differences between groups were explored using one-way ANOVA and post hoc between group comparisons. RESULTS: Four nursing position bands were identified: nurse practitioner, clinical nurse specialist, domain-specific and registered nurse. Significant differences between the bands were found on many domain scores. The nurse practitioner and clinical nurse specialist bands had the most similar practice profiles, nurse practitioners being more involved in direct care and professional leadership. CONCLUSIONS: Similar to the position of clinical nurse consultant in Australia, those practicing as clinical nurse specialists were deemed to reflect the threshold for advanced practice nursing. The results identified different practice patterns for the identified bands and distinguish the advanced practice nursing roles. IMPLICATIONS FOR NURSING POLICY: By replicating the Australian study of Gardener et al. (2016), this NZ paper extends the international data available to support more evidence-based nursing workforce planning and policy development. PMID- 29266217 TI - Childhood epilepsy with centro-temporal spikes (rolandic epilepsy) and written language. PMID- 29266218 TI - Opportunity cost of annual screening mammography. PMID- 29266219 TI - An exploration of the application and implementation of growth mindset principles within a primary school. AB - BACKGROUND: A growth mindset is a significant factor in the motivation and achievement of learners. Previous research has shown one-off interventions do encourage growth mindset thinking but only improvements are only short-lived. A sustainable and embedded approach may therefore be the only way to engender long term changes to an individual's mindset. AIMS: This research explores the application and implementation of growth mindset approaches to teaching and learning within a primary school, aiming to identify the strengths of the application and implementation of the growth mindset principles as well as areas for improvement. SAMPLE: Participants were the head teacher, five teachers, and 28 pupils at a primary school in Scotland. METHOD: Semi-structured interviews were undertaken with members of staff, focus groups were undertaken with the pupils, and six observations were undertaken across three different classes. The data were thematically analysed using an inductive approach. RESULTS: The analysis of the data produced four overarching themes important to the implementation and application of growth mindset teaching and learning: embarking on the process; classroom culture and teaching; outside the classroom; and pupil approach to learning. CONCLUSIONS: Among the strengths of the implementation was the collaborative approach that had been taken in the school and the understanding that staff had of the evidence base of growth mindset teaching and learning. Areas for development included the planning of the implementation such as the lack of a readiness assessment being undertaken. PMID- 29266220 TI - Prognostic models for RPS patients-Attempting to predict patient outcomes. AB - Retroperitoneal sarcoma (RPS) patients can have variable of outcomes after surgery. The chance to recur locally or at distant sites varies according to tumor grade, histologic subtype, and other patient- and tumor-related characteristics. The relative contribution of each prognostic variable on the oncological outcome of RPS patients can be weighted by combining them in prognostic tools such as nomograms. With this review, we critically appraise the available nomograms for RPS patients highlighting pros and cons. PMID- 29266221 TI - Microglia modulation through external vagus nerve stimulation in a murine model of Alzheimer's disease. AB - Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD) by the release of pro inflammatory mediators that compromise neuronal function and structure. Modulating microglia functions could be instrumental to interfere with disease pathogenesis. Previous studies have shown anti-inflammatory effects of acetylcholine (ACh) or norepinephrine (NE), which mainly activates the beta receptors on microglial cells. Non-invasive vagus nerve stimulation (nVNS) is used in treatment of drug-resistant depression, which is a risk factor for developing AD. The vagus nerve projects to the brainstem's locus coeruleus from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM) and widely throughout the brain. Pilot studies showed first signs of cognitive enhancing effects of nVNS in AD patients. In this study, the effects of nVNS on mouse microglia cell morphology were analyzed over a period of 280 min by 2 photon laser scanning in vivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild-type and amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS1 animals, whereas microglia from young animals were morphologically unaffected. PMID- 29266222 TI - Distinguishing Polemic From Commentary in Science: Some Guidelines Illustrated With the Case of Sage and Burgio (2017). AB - Exposure to nonionizing radiation used in wireless communication remains a contentious topic in the public mind-while the overwhelming scientific evidence to date suggests that microwave and radio frequencies used in modern communications are safe, public apprehension remains considerable. A recent article in Child Development has caused concern by alleging a causative connection between nonionizing radiation and a host of conditions, including autism and cancer. This commentary outlines why these claims are devoid of merit, and why they should not have been given a scientific veneer of legitimacy. The commentary also outlines some hallmarks of potentially dubious science, with the hope that authors, reviewers, and editors might be better able to avoid suspect scientific claims. PMID- 29266223 TI - Differential Associations of Distinct Forms of Childhood Adversity With Neurobehavioral Measures of Reward Processing: A Developmental Pathway to Depression. AB - Childhood adversity is associated with altered reward processing, but little is known about whether this varies across distinct types of adversity. In a sample of 94 children (6-19 years), we investigated whether experiences of material deprivation, emotional deprivation, and trauma have differential associations with reward-related behavior and white matter microstructure in tracts involved in reward processing. Material deprivation (food insecurity), but not emotional deprivation or trauma, was associated with poor reward performance. Adversity related influences on the integrity of white matter microstructure in frontostriatal tracts varied across childhood adversity types, and reductions in frontostriatal white matter integrity mediated the association of food insecurity with depressive symptoms. These findings document distinct behavioral and neurodevelopmental consequences of specific forms of adversity that have implications for psychopathology risk. PMID- 29266224 TI - Mechanism of Antibacterial Activities of a Rice Hull Smoke Extract (RHSE) Against Multidrug-Resistant Salmonella Typhimurium In Vitro and in Mice. AB - : The present study tested antibacterial activity of a rice hull smoke extract (RHSE) against a multidrug-resistant strain of Salmonella Typhimurium and examined its mode of suppressive action in vitro and in mice. In vitro studies showed that the minimum inhibitory concentration (MIC) value of RHSE was 1.29% (v/v). The inactivation was confirmed by complete loss of cell viability in the range of 104 to 107 colony forming units of the resistant Salmonella Typhimurium strain. Agarose and sodium dodecyl sulfate-polyacrylamide gel electrophoreses were used to evaluate the integrities of bacterial genomic DNA and total cellular protein profiles. The antibacterial action of RHSE results from a leakage of intracellular macromolecules following rupture of bacterial cells. Scanning electron microscopy of the cells shows that RHSE also induced deleterious morphological changes in the bacterial cell membrane of the pathogens. In vivo antibacterial activity of RHSE at a 1 * MIC concentration was examined in a bacterial gastroenteritis model using Balb/c mice orally infected with the Salmonella Typhimurium. The results show greatly decreased excretion of the bacteria into the feces and suppressed translocation of the bacteria to internal organs (cecum, mesenteric lymph node, spleen, and liver) compared with the infected mice not subjected to the RHSE treatment. Collectively, the present findings indicate that the mechanism of the antibacterial activities both in vitro and in the gastroenteritis environment of the animal model is the result of the direct disruption of cell structure, leading to cell death. RHSE has the potential to serve as a multifunctional food additive that might protect consumers against infections by antibiotic-resistant microorganisms. PRACTICAL APPLICATION: The rice hull derived liquid smoke has the potential to complement widely used wood-derived smoke as an antimicrobial flavor and health-promoting formulation for application in foods and feeds. PMID- 29266226 TI - Surgery versus stereotactic body radiation therapy for stage I non-small cell lung cancer: A comprehensive review. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. With the implementation of lung cancer screening, the number and proportion of patients diagnosed with early-stage disease are anticipated to increase. Surgery is currently the standard of care for patients with operable stage I NSCLC. However, promising outcomes with stereotactic body radiation therapy (SBRT) in patients with inoperable disease has led to interest in directly comparing SBRT and surgery in operable patients. Unfortunately, early randomized trials comparing surgery and SBRT closed early because of poor accrual. In this article, the nuances of surgery and SBRT for early-stage NSCLC are reviewed. Furthermore, retrospective and prospective analyses of SBRT in early-stage NSCLC are discussed, and active randomized trials comparing these 2 approaches are described. Cancer 2018;124:667-78. (c) 2017 American Cancer Society. PMID- 29266225 TI - Paediatric Rehabilitation Ingredients Measure: a new tool for identifying paediatric neurorehabilitation content. AB - AIM: To develop an instrument (Paediatric Rehabilitation Ingredients Measure [PRISM]) for quantitative estimation of contents of interdisciplinary neurorehabilitation for use in studies of relationships between rehabilitation treatment delivered and severity-adjusted outcomes after acquired brain injury (ABI). METHOD: The measure was developed using an ingredients-mediators-outcomes model consistent with the International Classification of Functioning, Disability and Health, a literature review, and other current initiatives in the development of rehabilitation treatment taxonomies, with item codevelopment in workshops with rehabilitation professionals. Interrater reliability was assessed in inpatient and residential paediatric rehabilitation settings. RESULTS: Although sometimes an initially unfamiliar perspective on rehabilitation practice, PRISM's acceptability amongst professionals was excellent. Internal consistency of scores was sometimes an issue for users unfamiliar with the tool; however, this improved with practice and interrater reliability (assessed by Kendall's W) was good. The tool was felt to have particular value in facilitating interdisciplinary communication and working. Modifications to the design of the tool have improved internal consistency. INTERPRETATION: PRISM supports identification of the 'active ingredients' of an interdisciplinary rehabilitation package and facilitates interdisciplinary communication. It also has potential as a research tool examining relationships between rehabilitation delivered and severity adjusted outcomes observed after paediatric ABI. WHAT THIS PAPER ADDS: Identifying contribution of rehabilitation to outcomes after acquired brain injury requires quantification of rehabilitation 'dose' and 'content'. Previous approaches to 'parsing' of rehabilitation dose and content may have overemphasized one-to-one sessions with therapists. We present a novel, holistic tool for identification of ingredients of an interdisciplinary rehabilitation package. It supports interdisciplinary communication and has potential as a research tool. PMID- 29266227 TI - Marine antimicrobial peptide arenicin adopts a monomeric twisted beta-hairpin structure and forms low conductivity pores in zwitterionic lipid bilayers. AB - Arenicins are 21-residue beta-hairpin antimicrobial peptides (AMPs) isolated from the marine lugworm Arenicola marina [Ovchinnikova et al., FEBS Lett. 2004;577:209 214]. The peptides have a high positive charge (+6) and display a broad spectrum of antimicrobial activities against bacteria and fungi. Arenicins adopt the monomeric highly twisted beta-hairpin in water or planar beta-structural dimers in anionic liposomes and detergent micelles. Until now, the interaction of cationic beta-structural AMPs with zwitterionic phospholipid bilayers mimicking eukaryotic membranes is not well understood. To study the structural basis of arenicins activity against eukaryotic cells, we investigated arenicin-2 in the solvents of low polarity (ethanol, 4% dioxane) and in zwitterionic soybean PC and PC/PE liposomes by CD and FTIR spectroscopy. It was shown that arenicin-2 adopted the twisted beta-hairpin structure in all the environments studied. Measurements of the Trp fluorescence and H->D exchange in soybean PC liposomes and boundary potential in the planar DPhPC bilayers confirmed the partitioning of the arenicin 2 monomers into interfacial region of the zwitterionic membranes. The low conductivity (0.12 nS) arenicin-2 pores were detected in the DPhPC bilayers. The lifetime of the open state (up to 260 ms) was significantly longer than lifetime of low-conductivity (0.23 nS) pores previously described in partially anionic membranes (44 ms). The formation of narrow arenicin-2 pores without disruption of the membrane was discussed in the light of the disordered toroidal pore model previously proposed for beta-structural AMPs [Jean - Francois et al. Biophys. J. 2008;95:5748 - 5756]. A novel non-lytic mechanism of the arenicin-2 action was proposed. PMID- 29266229 TI - Heightened parental stress in mothers of children with visual impairment. PMID- 29266228 TI - Therapeutic potential of phages in autoimmune liver diseases. AB - Autoimmune liver disease (ALD) poses a difficult medical challenge, as there is a significant number of patients in whom current therapy offers questionable or no benefit, yet its side effects may be serious, including the development of malignancy. Bacterial viruses (phages) have been recognized increasingly as immunomodulators contributing to immune homeostasis and curbing inflammation. Accumulating data suggest that phages may be useful in immunotherapy of ALD. Phages have been shown to down-regulate the expression and/or production and activity of factors associated with hepatic injury [reactive oxygen species, Toll like receptor (TLR)-4 activation, nuclear factor kappa B (NF-kappaB) activation, proinflammatory and procoagulant activities of platelets] and up-regulate the expression and/or production of factors demonstrated as playing a protective role [interleukin (IL)-10, IL-1 receptor antagonist]. PMID- 29266230 TI - Revisiting Principles Behind Drug Clearance and Organ Extraction. AB - In this issue, readers will find an interesting account of some recent exchanges of views on organ clearance and extraction ratio between Benet et al. on one side and Rowland and Pang on the other. The beauty of these pieces is in the fact that they remind us of some of the basic principles behind organ clearance and show that occasional challenges to widely accepted views can bring novel insights or perspectives into any subject matter, no matter how old. PMID- 29266231 TI - Can radical margins improve prognosis in primary and localized epithelioid sarcoma of the extremities? AB - INTRODUCTION: Epithelioid sarcoma (ES) has a tendency to locally recur, spread proximally, and metastasize, in particular to lymphnodes and lungs. The aim of this report is to study the role of surgery and the extent of margins required for optimal management of patients with localized epithelioid sarcoma of the extremities. MATERIAL AND METHODS: We retrospectively evaluated 77 patients affected by ES of the extremities treated at two different Institutions. RESULTS: Twenty-two patients had metastasis at diagnosis. Estimated survival was 65.5% at 5 years and 50.9% at 10 years, with a better prognosis in patients with localized disease at diagnosis (P < 0.001). Among patients with localized disease, a significantly better survival was found in patients with primary tumors in which radical surgical margins were achieved (P = 0.043). Among 47 patients presenting with primary tumors, local recurrence-free rate was 72.9% at 5 years, and 61.9% at 10 years, with a better local control achieved in patients with radical margins were achieved (P = 0.026). DISCUSSION: We believe that the best approach to improve both local control and survival is to aim for radical margins in patients with primary tumors. Therefore, the best chance for cure is if the first treatment is the right treatment, which we believe to be radical margins. PMID- 29266232 TI - Multiply recurrent retroperitoneal liposarcoma. AB - Retroperitoneal liposarcomas (RPLPS) are rare tumors that represent at least 50% of all retroperitoneal sarcomas. Surgical resection remains the standard of care. Unfortunately, many RPLPS patients will develop a local recurrence and subsequently die in the absence of distant metastasis. This review outlines the factors that predict local recurrence and influence the management of first and subsequent multiply recurrent RPLPS. PMID- 29266233 TI - Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1-related stroke. AB - Mutations in the alpha1 (COL4A1) or alpha2 (COL4A2) chains of collagen type IV, a major component of the vascular basement membrane, cause intracerebral haemorrhages with variable expressivity and reduced penetrance by mechanisms that remain poorly understood. Here we sought to investigate the cellular mechanisms of COL4A1-related intracerebral haemorrhage and identify a marker for haemorrhage risk stratification. A combination of histological, immunohistochemical, and electron microscopy analyses were used to analyse the brain parenchyma, cerebrovasculature, and retinal vessels of mice expressing the disease-causing COL4A1 p.G498V mutation. Mutant mice developed cerebral microhaemorrhages and macroscopic haemorrhages (macrohaemorrhages), the latter with reduced penetrance, mimicking the human disease. Microhaemorrhages that occurred in early postnatal life were associated with a transient, generalized increase in blood-brain barrier permeability at the level of capillaries. Macrohaemorrhages, which occurred later in life, originated from deep brain arteries with focal loss of smooth muscle cells. Similar smooth muscle cell loss was detected in retinal arteries, and a time-course analysis of arterial lesions showed that smooth muscle cells are recruited normally in arterial wall during development, but undergo progressive apoptosis-mediated degeneration. By assessing in parallel the extent of these retinal arterial lesions and the presence/absence of macrohaemorrhages, we found that the arterial lesion load in the retina is strongly correlated with the burden of macrohaemorrhages. We conclude that microhaemorrhages and macrohaemorrhages are driven by two distinct mechanisms. Moreover, smooth muscle cell degeneration is a critical factor underlying the partial penetrance of COL4A1-related macrohaemorrhages, and retinal imaging is a promising tool for identifying high-risk patients. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29266234 TI - Bullet Trajectory after Impact on Laminated Particle Board. AB - When reconstructing a bullet's trajectory prior to impact using the spatial orientation between two consecutive bullet defects (e.g., by probing), it is important to take the bullet's deflection into account. The (critical) ricochet angles as well as the vertical and horizontal deflection angles of eight cartridge types on laminated particle board have been studied. For all eight of the cartridge types combined, the critical ricochet angles lie between approximately 14 degrees and 26 degrees , while for the subgroup of the jacketed bullets, this range lies lower, between approximately 14 degrees and 18 degrees . The data from this study can be used to assess the accuracy and precision of the applied method. The results show that the highest deflection angles are seen near the critical ricochet angle. Generally speaking, vertical and horizontal deflection angles can almost be neglected above angles of incidence of 30 degrees or 40 degrees for handgun ammunition when shooting at laminated particle board. PMID- 29266236 TI - Factors affecting survival and locoregional control in head and neck cSCCA with nodal metastasis. AB - OBJECTIVES: To determine factors affecting locoregional control (LRC) and disease specific survival (DSS) in patients presenting with regionally metastatic cutaneous squamous cell carcinoma (cSCCA) of the head and neck. STUDY DESIGN: Retrospective review. METHODS: Upon review of institutional pathology database to identify patients with metastatic cSCCA, 62 subjects met the inclusion criteria between 2009 to 2012. Cox proportional hazard ratios for DSS and LRC were calculated for tumor, patient, lymph node, and treatment variables. These factors included primary site, primary tumor grade, primary tumor perineural invasion, extent of primary tumor invasion, age, immune status, parotid nodal status, invasion of facial nerve by parotid tumor, cervical nodal status, extracapsular spread, number of nodes involved, adjuvant radiation therapy, and chemotherapy. All variables were analyzed to determine impact on LRC and DSS. A disease specific Kaplan-Meier curve was determined for the entire cohort. RESULTS: Five year survival was 56% for all patients. The presence of extracapsular spread (ECS) and bone involvement of the primary tumor site resulted in statistically significant decreases in DSS (hazard ratio (HR) 41.3 and 270, respectively; P = 0.02 and P = 0.008, respectively) and LRC (HR 8.41 and 11.1, respectively; P = 0.005 and P = 0.04, respectively). The remaining factors had no statistically significant effect on DSS or LRC. CONCLUSION: The presence of ECS in the metastatic lymph node and of bone invasion by the primary tumor appear to be important to the outcome of patients with metastatic cSCCA. These factors should be considered when developing multidisciplinary care plans and future investigations. LEVEL OF EVIDENCE: 4. Laryngoscope, 1881-1886, 2018. PMID- 29266235 TI - CEA to peritoneal carcinomatosis index (PCI) ratio is prognostic in patients with colorectal cancer peritoneal carcinomatosis undergoing cytoreduction surgery and intraperitoneal chemotherapy: A retrospective cohort study. AB - BACKGROUND AND OBJECTIVES: Serum tumor markers are prognostic in patients with colorectal cancer peritoneal carcinomatosis (CRPC) undergoing cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). Assessment of the ratio of tumor marker to volume, as depicted by peritoneal carcinomatosis index (PCI), and how this may affect overall (OS) and recurrence free survival (RFS) has not been reported. METHODS: Survival effect of this ratio was analyzed in patients with CRPC managed from 1996 to 2016 with CRS and IPC. RESULTS: Of 260 patients included, those with low CEA/PCI ratio (<2.3) had longer median OS (56 vs 24 months, P = 0.001) and RFS (13 vs 9 months, P = 0.02). The prognostic impact of CEA/PCI ratio was most pronounced in patients with PCI <= 10 (OS of 72 vs 30 months, P < 0.001; RFS of 21 vs 10 months, P = 0.002). In multivariable analysis, elevated CEA/PCI ratio was independently associated with poorer OS (adjusted HR 1.85, 95%CI 1.11-3.10, P = 0.02) and RFS (adjusted HR 1.58, 95%CI 1.04-2.41, P = 0.03). CONCLUSION: CEA/PCI ratio is an independent prognostic factor for OS and RFS in CRPC. This novel approach allows both tumor activity and volume to be accounted for in one index, thus potentially providing a more accurate indication of tumor biological behavior. PMID- 29266237 TI - Clinicopathological characteristics, staging classification, and survival outcomes of primary malignant melanoma of the esophagus. AB - BACKGROUND: Primary malignant melanoma of esophagus (PMME) is a remarkably rare and highly aggressive tumor. Studies related with clinicopathological findings, staging classification, and clinical outcomes are lacking. METHODS: We reviewed 21 cases of PMME at the Tianjin Medical University Cancer Institute and Hospital from January 2002 to February 2017. RESULTS: Nineteen patients (90.48%) presented a history of dysphagia for months, and two (9.52%) experienced retrosternal pain. Histologically, tumors were composed of atypical melanocytes with melanocytosis surrounding the tumor. The overall survival was 1-40 months, with the median time of 10 months. The mucosal staging classification for upper aerodigestive tract showed better distribution of overall survival with different stages than that of the American Joint Commission on Cancer staging classification for esophagus, but without statistical difference. Both the clinical and pathological characteristics were not highly consistent with overall survival. CONCLUSIONS: PMME is a considerably aggressive tumor with poor prognosis. The staging classification of mucosal melanoma of the upper aerodigestive tract may be a good option for PMME patients. PMID- 29266238 TI - Rediscovery of NF-kappaB signaling in nasopharyngeal carcinoma: How genetic defects of NF-kappaB pathway interplay with EBV in driving oncogenesis? AB - Nasopharyngeal carcinoma (NPC) is a unique EBV-associated subtype of head and neck cancer, which has the highest incidence in Southern China and eastern South Asia. The interaction between genetic risk factors and environmental challenge, have been considered to contribute to the development of nasopharyngeal carcinogenesis. Constitutive activation of NF-kappaB signaling has been seen in NPC tissues and is associated with unfavorable prognosis. Recently, several whole exome sequencing study consistently revealed that high frequency mutations of NF kappaB pathway negative regulators is common in nasopharyngeal carcinoma, which reinforce the importance of NF-kappaB driving oncogenesis. This review focuses on the current state of research in role of NF-kappaB in NPC carcinogenesis. We summarized the newly identified loss of function (LOF) mutations on NF-kappaB negative regulators leading to it's activation bypass LMP-1 stimulation. We discussed the critical role of NF-kappaB activation in immortalization and transformation of nasopharygeal epithelium. We also depicted how NF-kappaB signaling mediated chronic inflammation contribute to persistent EBV infection, immune evasion of EBV infected cells, metabolic reprogramming, and cancer stem cells (CSCs) formation in NPC. Lastly, we discussed the clinical resonance of targeting NF-kappaB for NPC precise therapy. PMID- 29266239 TI - A novel purple acid phytase from an earthworm cast bacterium. AB - BACKGROUND: Phytases are a diverse group of enzymes initiating the dephosphorylation of phytate. Phytate is considered as an anti-nutritional compound because of its capability to chelate nutrients such as Fe2+ , Zn2+ , Mg2+ , and Ca2+ . In this study, several bacterial isolates obtained from earthworm casts were evaluated for their phytate degrading capability. Enzymatic properties and the sequence of the corresponding phytase-encoding gene of the selected isolate were determined. RESULTS: The phytase exhibited its highest activity at pH 4.0 and was stable from pH 3 up to pH 9. The temperature optimum was determined to be 65 degrees C. The strongest inhibitors of enzymatic activity were identified as vanadate, Cu2+ , and Zn2+ . High-performance ion chromatography analysis of enzymatic phytate dephosphorylation revealed that the first dephosphorylation product was d/l-myo-inositol(1,2,3,4,5)pentakisphosphate. CONCLUSION: Owing to its enzymatic properties, such as tolerance to tartrate and the presence of the consensus motifs PDTVY, GNHE, DLG, VLFH, and GHDH, this phytase could be classified as a purple acid phytase. To the best of our knowledge, this is the first report describing a bacterial purple acid phytase. (c) 2017 Society of Chemical Industry. PMID- 29266240 TI - Telomerase reverse transcriptase mutations are independent predictor of disease free survival in Middle Eastern papillary thyroid cancer. AB - Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ~20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study, we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein overexpression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extrathyroidal extension and Stage IV tumors. A significant association was also found between TERT overexpression and epithelial-mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest that TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC. PMID- 29266241 TI - How many trials does it take to get a significant ERP effect? It depends. AB - In designing an ERP study, researchers must choose how many trials to include, balancing the desire to maximize statistical power and the need to minimize the length of the recording session. Recent studies have attempted to quantify the minimum number of trials needed to obtain reliable measures for a variety of ERP components. However, these studies have largely ignored other variables that affect statistical power in ERP studies, including sample size and effect magnitude. The goal of the present study was to determine whether and how the number of trials, number of participants, and effect magnitude interact to influence statistical power, thus providing a better guide for selecting an appropriate number of trials. We used a Monte Carlo approach to measure the probability of obtaining a statistically significant result when testing for (a) the presence of an ERP effect, (b) within-participant condition differences in an ERP effect, and (c) between-participants group differences in an ERP effect. Each of these issues was examined in the context of the error-related negativity and the lateralized readiness potential. We found that doubling the number of trials recommended by previous studies led to more than a doubling of statistical power under many conditions. Thus, when determining the number of trials that should be included in a given study, researchers must consider the sample size, the anticipated effect magnitude, and the noise level, rather than relying solely on general recommendations about the number of trials needed to obtain a "stable" ERP waveform. PMID- 29266242 TI - Age-associated B cells expanded in autoimmune mice are memory cells sharing H CDR3-selected repertoires. AB - Age-associated B cells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21-/low ). The Ig repertoire expressed by ABCs in aged mice is diverse and exhibits signs of somatic hypermutation (SHM). A CD21-/low B-cell population is expanded in autoimmune diseases, e.g. systemic lupus erythematosus, as well as in lupus-prone NZB/W mice and in mice lacking a pre-B cell receptor (SLC-/- ). However, the nature of the CD21-/low B cells (hereafter ABCs) in autoimmunity is not well understood. Here we show that in young SLC-/- mice, the vast majority of the ABCs express memory B-cell (MBC) markers in contrast to wild type controls. A similar population is present in lupus-prone MRL mice before and at disease onset. In SLC-/- mice, a majority of the ABCs are IgM+ , their VH genes have undergone SHM, show clonal diversification and clonal restriction at the H-CDR3 level. ABC hybridomas, established from SLC-/- mice, secrete typical lupus autoantibodies, e.g. anti-Smith antigen, and some of those that bind to DNA comprise a H-CDR3 that is identical to previously described IgM anti-DNA antibodies from lupus-prone mice. Together, these results reveal that ABCs in autoimmune mice are comprised of autoreactive MBCs expressing highly restricted H CDR3 repertoires. PMID- 29266243 TI - Comment on: Complement C3 and fatty liver disease in Rheumatoid arthritis patients: A cross-sectional study. PMID- 29266244 TI - Reply to Opportunity cost of annual screening mammography. PMID- 29266245 TI - Targeting tumor-infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma. AB - Sorafenib, a multikinase inhibitor with antiangiogenic activity, is an approved therapy for hepatocellular carcinoma (HCC). It is unclear whether the proinflammatory and immunosuppressive mechanisms may limit the therapeutic efficacy of sorafenib in HCC. We used a syngeneic mouse liver cancer cell line to establish orthotopic liver or subcutaneous tumors to study how proinflammatory and immunosuppressive mechanisms impact on the efficacy of sorafenib. We found sorafenib exhibited a potent therapeutic effect in subcutaneous tumors, but a less potent effect in orthotopic liver tumors. The protein levels of interleukin 6 (IL-6) and vascular endothelial growth factor A (VEGF-A) were persistently elevated in orthotopic liver tumors, but not in subcutaneous tumors, treated with sorafenib. Likewise, the tumor-infiltrating Ly6G+ myeloid-derived suppressor cells (MDSCs) and immune suppressors were increased in orthotopic liver tumors, not in subcutaneous tumors, treated with sorafenib. The tumor-infiltrating Ly6G+ MDSCs of sorafenib-treated orthotopic liver tumors significantly induced IL-10 and TGF-beta expressing CD4+ T cells, and downregulated the cytotoxic activity of CD8+ T cells. IL-6, but not VEGF-A, protected Ly6G+ MDSCs from sorafenib-induced cell death in vitro. The combination of anti-Ly6G antibody or anti-IL-6 antibody with sorafenib significantly reduced the cell proportion of Ly6G+ MDSCs in orthotopic liver tumors, enhanced the T cells proliferation and improved the therapeutic effect of sorafenib synergistically. Modulating tumor microenvironment through targeting tumor-infiltrating Ly6G+ MDSCs represents a potential strategy to improve the anti-HCC efficacy of sorafenib. PMID- 29266246 TI - Danish validation of sniffin' sticks olfactory test for threshold, discrimination, and identification. AB - OBJECTIVES: The applicability of olfactory testing is dependent on cultural adaptation. The aim of this study was to validate the Sniffin' Sticks (Burghart Messtechnik, Wedel, Germany) threshold (T), discrimination (D), and identification (I) olfaction test. This data was subsequently used to investigate external validity of international normative values to separate hyposmia from normosmia. METHODS: The study included 388 participants. The first step was a questionnaire study in which 238 adults rated their familiarity with 125 odor descriptors. In the second step, we evaluated the original Sniffin' Sticks (Burghart Messtechnik) in 75 participants. In the third step, we modified our odor descriptors and tested 75 participants with the new version. RESULTS: In the I test, we found that 21 original odor descriptors were unfamiliar and that five odors had I rates < 75%. After modification, all odors had a successful I rate > 75%. By comparing the T, D, and I scores of previous validation studies, we found a significant variation in the scores between countries. CONCLUSION: The original Sniffin' Sticks (Burghart Messtechnik) was not applicable in Denmark. The modification resulted in improvement of familiarity and rate of I, making the test valid for use in Denmark. Furthermore, the study found a large variation in T and D scores between different countries, which should be considered when using these scores to separate hyposmia and anosmia from normosmia. LEVEL OF EVIDENCE: 2b. Laryngoscope, 1759-1766, 2018. PMID- 29266247 TI - Trauma-Informed Care for Individuals with Serious Mental Illness: An Avenue for Community Psychology's Involvement in Community Mental Health. AB - Individuals with serious mental illness are at particularly high risk for trauma; however, service environments with which they interact may not always be trauma informed. While community mental health and other human services settings are moving toward trauma-informed care (TIC) service delivery, a variety of TIC frameworks exist without consensus regarding operationalization, thereby leading to challenges in implementation. TIC is principle-driven and presents substantial overlap with community psychology values and competencies, including ecological frameworks, second-order change, empowerment, and citizen participation. One way to address barriers to TIC implementation is to draw on the strengths of the field of community psychology. With a particular emphasis on the applicability of TIC to individuals with serious mental illness, this paper identifies key implementation issues and recommends future directions for community psychologists in clarifying the service framework, its adaptation to specific service contexts, and improving delivery through consultation and evaluation. Community psychologists may work with various disciplines involved in the TIC field to together promote a more conscious, actionable shift in service delivery. PMID- 29266248 TI - Change in lignin structure, but not in lignin content, in transgenic poplar overexpressing the rice master regulator of secondary cell wall biosynthesis. AB - We previously succeeded in enhancing wood formation of wood in transgenic poplar plants by overexpressing secondary wall NAM/ATAF/CUC (NAC) domain protein 1 from Oryza sativa (OsSWN1), a transcription factor 'master regulator' of secondary cell wall formation in rice, under control of the fiber preferential NST3/SND1 promoter from Arabidopsis. Transgenic plants had an increased cell wall thickness and cell wall density of individual cells in the secondary xylem of stems as well as an increased wood density. OsSWN1 triggers the induction of polysaccharide and lignin biosynthetic gene expressions, however, resulting in no significant impact on the lignin content in the transgenic plants. In contrast, wet and dry chemical analyses of lignin revealed changes in S/G ratio and in the composition of lignin interunit linkages in transgenic lines. The results from gene expression analysis suggest that the structural changes in lignin were due to an unbalanced induction of lignin biosynthetic genes in transgenic lines. Our present data indicate that the overexpression of the chimeric transcription factor causes accelerated deposition of secondary cell wall components including lignin and polysaccharides through an acquired mechanism. PMID- 29266249 TI - Myasthenia gravis: the role of complement at the neuromuscular junction. AB - Generalized myasthenia gravis (gMG) is a rare autoimmune disorder characterized by skeletal muscle weakness caused by disrupted neurotransmission at the neuromuscular junction (NMJ). Approximately 74-88% of patients with gMG have acetylcholine receptor (AChR) autoantibodies. Complement plays an important role in innate and antibody-mediated immunity, and activation and amplification of complement results in the formation of membrane attack complexes (MACs), lipophilic proteins that damage cell membranes. The role of complement in gMG has been demonstrated in animal models and patients. Studies in animals lacking specific complement proteins have confirmed that MAC formation is required to induce experimental autoimmune MG (EAMG) and NMJ damage. Complement inhibition in EAMG models can prevent disease induction and reverse its progression. Patients with anti-AChR+ MG have autoantibodies and MACs present at NMJs. Damaged NMJs are associated with more severe disease, fewer AChRs, and MACs in synaptic debris. Current MG therapies do not target complement directly. Eculizumab is a humanized monoclonal antibody that inhibits cleavage of complement protein C5, preventing MAC formation. Eculizumab treatment improved symptoms compared with placebo in a phase II study in patients with refractory gMG. Direct complement inhibition could preserve NMJ physiology and muscle function in patients with anti-AChR+ gMG. PMID- 29266250 TI - Reproduction and recruitment of sympatric fish species on an intertidal rocky shore. AB - The reproductive cycle of seven common species (Gobius paganellus, Gobius bucchichi, Gobius cobitis, Parablennius sanguinolentus, Salaria pavo, Tripterygion tartessicum and Symphodus roissali) on rocky shores in the Gulf of Cadiz and their relationship with the sea surface temperature (SST) is analysed. Partial data on Scorpaena porcus are also given. Fecundity of these short lifespan species shows a positive linear correlation between the number of oocytes and an increase in female size. Spawnings are concentrated in the first 7 months of the year. An analysis of reproductive growth with respect to SST shows that water temperature in the winter months affects the timing of the onset of reproduction in most species. Recruitment is takes place throughout the year, but a temporal segregation within different families occurs in their spawning as well as recruitment. PMID- 29266251 TI - Siglec-1 inhibits RSV-induced interferon gamma production by adult T cells in contrast to newborn T cells. AB - Interferon gamma (IFN-gamma) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell cell interactions between monocytes and T cells regulate IFN-gamma production. In this study, micro-array data identified the upregulation of sialic acid-binding immunoglobulin-type lectin 1 (Siglec-1) in human RSV-infected infants. In vitro, RSV increased expression of Siglec-1 on healthy newborn and adult monocytes. RSV induced Siglec-1 on monocytes inhibited IFN-gamma production by adult CD4+ T cells. In contrast, IFN-gamma production by RSV in newborns was not affected by Siglec-1. The ligand for Siglec-1, CD43, is highly expressed on adult CD4+ T cells compared to newborns. Our data show that Siglec-1 reduces IFN-gamma release by adult T cells possibly by binding to the highly expressed CD43. The Siglec-1 dependent inhibition of IFN-gamma in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood. PMID- 29266252 TI - Soft tissue tumors of the pelvis: Technical and histological considerations. AB - In this review, we first address the anatomic and technical considerations in the resection of pelvic soft tissue tumors, including the challenges unique to these tumors, such as the narrow anatomic confines of the bony pelvis, the often locally aggressive nature of these tumors, as well as the major functional deficits that may result from their resection. We then review the optimal, multidisciplinary, histology-driven treatment approach to pelvic tumors. PMID- 29266253 TI - Emotional imagery and pupil diameter. AB - Pupil diameter is enhanced in a variety of emotional contexts, including viewing pictures, listening to sounds, and during threat of shock. In this study, we investigated pupil diameter changes during emotional imagery. Participants imagined scenes describing pleasant, unpleasant, or neutral events while pupil diameter was continuously recorded. Second by second changes in pupil diameter were analyzed to determine whether, and when, modulation of the pupil as a function of hedonic content is found. Results indicated a significant effect of hedonic content beginning shortly after script onset, with enhanced pupil diameter when imagining emotional (pleasant or unpleasant), compared to neutral, scenes. Pupil diameter during imagery covaried with rated emotional arousal, consistent with an interpretation that changes in pupil diameter during emotional imagery reflect sympathetic nervous system activity. Because emotional imagery is a key element in clinical assessment and treatment, pupil diameter could prove a useful index of emotional engagement in a variety of clinically pertinent contexts. PMID- 29266255 TI - Myasthenia gravis with antibodies to MuSK: an update. AB - Myasthenia gravis with antibodies to the muscle-specific tyrosine kinase (MuSK+ MG) is a rare disease with distinctive pathogenic mechanisms and clinical features. An acute onset and predominant bulbar muscle weakness are very common and highly suggestive of the disease. On the other hand, a more indolent course, atypical ocular presentation, and signs of cholinergic hyperactivity may complicate the diagnosis. Though MuSK+ MG is still a severe disease, over the years we have observed a steady reduction in the rate of respiratory crisis and a significant improvement in the clinical outcome, both likely related to earlier diagnosis and timely treatment. Despite the improved management, MuSK+ MG patients tend to remain dependent on long-term immunosuppressive treatment and may develop permanent disabling weakness. In uncontrolled studies, B cell depletion with rituximab proved effective in most patients with refractory disease, inducing prolonged clinical responses associated with a sustained reduction of serum antibody levels. Promising results from experimental studies and case reports suggest that both 3,4-diaminopyridine and albuterol may be effective as symptomatic agents. PMID- 29266254 TI - Allergic contact dermatitis caused by nail acrylates in Europe. An EECDRG study. AB - BACKGROUND: Allergic contact dermatitis (ACD) caused by nail acrylates, also including methacrylates and cyanoacrylates here, is being increasingly reported. METHODS: A retrospective study in 11 European Environmental Contact Dermatitis Research Group (EECDRG) clinics collected information on cases of ACD caused by nail acrylates diagnosed by aimed testing between 2013 and 2015. RESULTS: Among 18 228 studied patients, 136 had ACD caused by nail acrylates (0.75%; 95%CI: 0.60 0.90), representing 67.3% (95%CI: 60.4-73.7) of ACD cases caused by acrylates. There were 135 females and 1 male, with a mean age +/- standard deviation of 36.7 +/- 12.2 years; 59 (43.4%) were exposed as consumers, and 77 (56.6%) were occupationally exposed. Occupational cases were more frequent in southern Europe (83.7%), and were younger (mean age of 33.4 +/- 8.9 years); most developed ACD during the first year at work (65.0%), and at least 11.7% had to leave their jobs. Skin lesions involved the hands in 121 patients (88.9%) and the face in 50 (36.8%), with the face being the only affected site in 14 (10.3%). Most patients reacted to two or more acrylates on patch testing, mainly to 2-hydroxyethyl methacrylate (HEMA) (92.5%), 2-hydroxypropyl methacrylate (88.6%), ethylene glycol dimethacrylate (69.2%), and ethyl cyanoacrylate (9.9%). CONCLUSIONS: Nail cosmetics were responsible for the majority of ACD cases caused by acrylates, affecting nail beauticians and consumers, and therefore calling for stricter regulation and preventive measures. As HEMA detects most cases, and isolated facial lesions may be overlooked, inclusion of this allergen in the baseline series may be warranted. PMID- 29266256 TI - Quality of life 1 year after a maternal near-miss event. AB - OBJECTIVES: To evaluate quality of life (QoL) parameters among women categorized with a maternal near-miss during pregnancy. METHODS: The present prospective cohort study was conducted at a tertiary referral hospital in South Africa between April 1, 2013, and March 31, 2016. Patients who experienced maternal near miss events were included and patients with uncomplicated low-risk pregnancies were enrolled as a control group. Various parameters were assessed using a WHO QoL questionnaire. RESULTS: The maternal near-miss and uncomplicated low-risk pregnancy (control) groups comprised 95 and 51 women. The maternal near-miss group scored lower than the control group in all four domains of the questionnaire (P<0.001). Overall, 42 (82%) women in the control group and 41 (43%) women in the maternal near-miss group desired future fertility (P<0.001). Women in the maternal near-miss group who had experienced perinatal loss scored lower in the physical health and well-being (P=0.009), psychological health and well-being (P=0.007), and environment (P=0.031) domains compared with women in the maternal near-miss group who experienced a live delivery. Nonetheless, QoL scores among women in the maternal near-miss group who had experienced perinatal loss remained lower than those reported by women in the control group (P<0.001). CONCLUSION: A maternal near-miss event during pregnancy was associated with reduced QoL, especially among women who had experienced perinatal loss. PMID- 29266257 TI - Initial experience with a novel electrophysiology mapping simulator. AB - BACKGROUND: Despite data supporting the use of simulation training in procedural specialties and accreditation requirements, few options exist for electrophysiology (EP) training. We aimed to develop a low-cost, accessible simulator for training in EP mapping, and to test the simulator in a group of novice users. METHODS: Our mapping simulator is composed of three components: an acrylic case representing torso and thigh; three-dimensional (3D) printed cardiac models; and a commercially available mapping system. Using a proprietary flexible material that mimics the consistency of human heart tissue, we created an anatomically accurate model of a normal right atrium (RA) from computed tomography data. We developed a test protocol consisting of two activities: creation of a RA shell and timed navigation to specific locations within the RA shell. Seventeen participants were randomized to either practice versus no practice on the simulator, and repeated simulator and self-assessment tests were performed after 1 week. We measured volume of the RA map and time taken and distance from the target sites for each target location. RESULTS: Both groups showed improvement in generation of geometry, volume, time to target, and self assessed comfort level after initial exposure to the simulator. Compared with no practice, the practice group demonstrated an improved sense of confidence in mapping. CONCLUSIONS: Focused training in EP mapping using a novel simulator created with 3D printed heart models and a standard mapping system is feasible for use in the training environment. Exposure to the simulator is associated with improved mapping skills and trainee comfort level. PMID- 29266259 TI - Characterization of novel alternative splicing variants of Oct4 gene expressed in mouse pluripotent stem cells. AB - Oct4 is an important transcription factor for maintaining self-renewal and pluripotency of pluripotent stem cells (PSCs). Human OCT4 can be alternatively spliced and generate OCT4a, OCT4b, and OCT4b1. In this study, we discovered the novel Oct4 variants of Oct4b' and Oct4b1-3 in mouse PSCs for the first time. The expression of Oct4b variants, especially for Oct4b', was down regulated along with the downregulation of Oct4a when stem cells were differentiated. We also found four Oct4 translational products that were differentially expressed in mouse PSCs under the different culture conditions. The constructs of Oct4b2 and Oct4b3 could be alternatively spliced into Oct4b and Oct4b' when constructs were transiently transfected in NIH3T3 cells. Oct4b' encoded a 189 aa protein, and Oct4b could generate three distinct proteins including Oct4b-246aa, Oct4b-221aa, and Oct4b-189aa. The Oct4b variants could be alternatively translated in different type cells under the control of internal ribosome entry site (IRES) element that is within 5' upstream sequence of Oct4b. These findings provide new insights into reconsidering Oct4 variants expression and its additional role in maintaining the pluripotency of stem cells. PMID- 29266258 TI - Extracellular vesicles derived from human embryonic stem cell-MSCs ameliorate cirrhosis in thioacetamide-induced chronic liver injury. AB - Various somatic tissue-derived mesenchymal stromal cells (MSCs) have been considered as an attractive therapeutic tool for treatment of liver diseases in which the secretion of soluble factors or extracellular vesicles (EVs) is the most probable mechanism. The experimental application of human embryonic stem cell-derived MSC (ES-MSC) increased rapidly and showed promising results, in vitro and in vivo. However, possible therapeutic effects of human ES-MSC and their EVs on Thioacetamide (TAA)-induced chronic liver injury have not been evaluated yet. Our data indicated that human ES-MSC can significantly suppress the proliferation of peripheral blood mononuclear cells compared to bone marrow (BM)-MSC and adipose (AD)-MSC. Moreover, ES-MSC increased the secretion of anti inflammatory cytokines (i.e., TGF-beta and IL-10) and decreased IFN-gamma, compared to other MSCs. ES-MSC EVs demonstrated immunomodulatory activities comparable to parental cells and ameliorated cirrhosis in TAA-induced chronic rat liver injury, that is, reduction in fibrosis and collagen density, necrosis, caspase density, portal vein diameter, and transaminitis. The gene expression analyses also showed upregulation in collagenases (MMP9 and MMP13), anti apoptotic gene (BCL-2) and anti-inflammatory cytokines (TGF-beta1 and IL-10) and down-regulation of major contributors to fibrosis (Col1alpha, alphaSMA, and TIMP1), pro-apoptotic gene (BAX) and pro-inflammatory cytokines (TNFalpha and IL 2) following treatment with ES-MSC and ES-MSC-EV. These results demonstrated that human ES-MSC and ES-MSC EV as an off-the-shelf product, that needs further assessment to be suggested as an allogeneic product for therapeutic applications for liver fibrosis. PMID- 29266260 TI - Acupressure bands do not improve chemotherapy-induced nausea control in pediatric patients receiving highly emetogenic chemotherapy: A single-blinded, randomized controlled trial. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting remain common, distressing side effects of chemotherapy. It has been reported that acupressure prevents chemotherapy-induced nausea in adults, but it has not been well studied in children. METHODS: In this multicenter, prospective, randomized, single-blind, sham-controlled trial, the authors compared acute-phase nausea severity in patients ages 4 to 18 years who were receiving highly emetic chemotherapy using standard antiemetic agents combined with acupressure wrist bands, the most common type of acupressure, versus sham bands. Patients wore acupressure or sham bands continuously on each day of chemotherapy and for up to 7 days afterward. Chemotherapy-induced nausea severity in the delayed phase and chemotherapy induced vomiting control in the acute and delayed phases also were compared. RESULTS: Of the 187 patients randomized, 165 contributed nausea severity assessments during the acute phase. Acupressure bands did not reduce the severity of chemotherapy-induced nausea in the acute phase (odds ratio [OR], 1.33; 95% confidence limits, 0.89-2.00, in which an OR <1.00 favored acupressure) or in the delayed phase (OR, 1.23; 95% CL, 0.75-2.01). Furthermore, acupressure bands did not improve daily vomiting control during the acute phase (OR, 1.57; 95% CL, 0.95 2.59) or the delayed phase (OR, 0.84; 95% CL, 0.45-1.58). No serious adverse events were reported. CONCLUSIONS: Acupressure bands were safe but did not improve chemotherapy-induced nausea or vomiting in pediatric patients who were receiving highly emetic chemotherapy. Cancer 2018;124:1188-96. (c) 2017 American Cancer Society. PMID- 29266261 TI - Patients' and health care professionals' perceptions of blood transfusion: a systematic review. AB - BACKGROUND: Blood transfusions are frequently prescribed for acute and chronic conditions; however, the extent to which patients' and health care professionals' (HCPs') perceptions of transfusion have been investigated is unclear. Patients' treatment perceptions influence how patients cope with illnesses or symptoms. HCPs' perceptions may influence treatment decision making. STUDY DESIGN AND METHODS: This was a systematic review of studies post-1984 reporting adult patients' and HCPs' perceptions of blood transfusion. Seven databases were searched using a three-domain search strategy capturing synonyms relating to: 1) blood transfusion, 2) perceptions, and 3) participant group (patients or HCPs). Study and sample characteristics were extracted and narratively summarized. Reported perceptions were extracted and synthesized using inductive qualitative methods to identify key themes. RESULTS: Thirty-two studies were included: 14 investigated patients' perceptions and 18 HCPs' perceptions. Surgical patients were the highest represented patient group. HCPs were from a wide range of professions. Transfusions were perceived by patients and HCPs as being of low-to moderate risk. Risk and negative emotions were perceived to influence preference for alternatives. Five themes emerged from the synthesis, classified as Safety/risk, Negative emotions, Alternatives (e.g., autologous, monitoring), Health benefits, and Decision making. "Safety/risk" and "Negative emotions" were most frequently investigated over time, yet periods of research inactivity are apparent. CONCLUSIONS: The literature has identified themes on how transfusions are perceived by patients and HCPs, which overlap with recognized discussion points for transfusion specialists. These themes may help HCPs when educating patients about transfusion or consenting patients. Theory-based qualitative methods may add an important dimension to this work. PMID- 29266262 TI - Performance of commercially available deformable image registration platforms for contour propagation using patient-based computational phantoms: A multi institutional study. AB - PURPOSE: To investigate the performance of various algorithms for deformable image registration (DIR) to propagate regions of interest (ROIs) using multiple commercial platforms. METHODS AND MATERIALS: Thirteen institutions participated in the study with six commercial platforms: RayStation (RaySearch Laboratories, Stockholm, Sweden), MIM (Cleveland, OH, USA), VelocityAI and Smart Adapt (Varian Medical Systems, Palo Alto, CA, USA), Mirada XD (Mirada Medical Ltd, Oxford, UK), and ABAS (Elekta AB, Stockholm, Sweden). The DIR algorithms were tested on synthetic images generated with the ImSimQA package (Oncology Systems Limited, Shrewsbury, UK) by applying two specific Deformation Vector Fields (DVF) to real patient data-sets. Head-and-neck (HN), thorax, and pelvis sites were included. The accuracy of the algorithms was assessed by comparing the DIR-mapped ROIs from each center with those of reference, using the Dice Similarity Coefficient (DSC) and Mean Distance to Conformity (MDC) metrics. Statistical inference on validation results was carried out in order to identify the prognostic factors of DIR performances. RESULTS: DVF intensity, anatomic site and participating center were significant prognostic factors of DIR performances. Sub-voxel accuracy was obtained in the HN by all algorithms. Large errors, with MDC ranging up to 6 mm, were observed in low-contrast regions that underwent significant deformation, such as in the pelvis, or large DVF with strong contrast, such as the clinical tumor volume (CTV) in the lung. Under these conditions, the hybrid DIR algorithms performed significantly better than the free-form intensity based algorithms and resulted robust against intercenter variability. CONCLUSIONS: The performances of the systems proved to be site specific, depending on the DVF type and the platforms and the procedures used at the various centers. The pelvis was the most challenging site for most of the algorithms, which failed to achieve sub-voxel accuracy. Improved reproducibility was observed among the centers using the same hybrid registration algorithm. PMID- 29266263 TI - Humoral and T cell-mediated immune response against trichomoniasis. AB - Trichomonas vaginalis (T. vaginalis) infection leads to the synthesis of specific antibodies in the serum and local secretions. The profile of T. vaginalis specific antibodies and T cell-mediated immune responses may influence the outcome of infection, towards parasite elimination, persistence or pathological reactions. Studies have indicated that Th1-, Th17- and Th22 cell-related cytokines may be protective or pathogenic, whereas Th2- and Treg cell-related cytokines can exert anti-inflammatory effects during T. vaginalis infection. A number of T. vaginalis-related components such as lipophosphoglycan (TvLPG), alpha-actinin, migration inhibitory factor (TvMIF), pyruvate:ferredoxin oxidoreductase (PFO), legumain-1 (TvLEGU-1), adhesins and cysteine proteases lead to the induction of specific antibodies. T. vaginalis has acquired several strategies to evade the humoral immune responses such as degradation of immunoglobulins by cysteine proteases, antigenic variation and killing of antibody-producing B cells. The characterization of the T. vaginalis-specific antibodies to significant immunogenic molecules and formulation of strategies to promote their induction in vaginal mucosa may reveal their potential protective effects against trichomoniasis. In this review, we discuss the current understanding of antibody and T cell-mediated immune responses to T. vaginalis and highlight novel insights into the possible role of immune responses in protection against parasite. PMID- 29266265 TI - Efficacy of metacognitive therapy in improving mental health: A meta-analysis of single-case studies. AB - OBJECTIVE: Metacognitive therapy and one of its treatment components, the attention training technique, are increasingly being delivered to improve mental health. We examined the efficacy of metacognitive therapy and/or attention training technique on mental health outcomes from single-case studies. METHOD: A total of 14 studies (53 patients) were included. We used the d-statistic for multiple baseline data and the percentage change index to compute the effect sizes. RESULTS: Metacognitive therapy has a large effect on depression, anxiety, other psychopathological symptoms, and all outcomes together. Effect sizes were significantly moderated by the number of sessions, the severity and duration of symptoms, and patient gender, but not by study quality or attention training technique when used as a stand-alone treatment. At the follow-up, 77.36% of the individuals were considered recovered or had maintained improvement. CONCLUSION: Metacognitive therapy and attention training technique strongly contribute to improving mental health outcomes. This study effectively informs evidence-based practice in the clinical milieu. PMID- 29266266 TI - Characterisation of peptide interactions that regulate PKCepsilon activation. AB - Targeting the interaction between PKC isoforms and their anchoring proteins can specifically regulate kinase activity. epsilonV1-2 and pseudoepsilonRACK peptides, derived from the PKCepsilon C2 domain, modulate its association with receptor for activated C-kinase 2 (RACK2) and thus its function. Details of these interactions remain obscure, and we therefore investigated binding of these peptides using biophysical techniques. Surface plasmon resonance (SPR) indicated that the inhibitory epsilonV1-2 peptide bound to RACK2, and inhibited PKCepsilon binding as expected. In contrast, SPR and NMR demonstrated that the activating pseudoepsilonRACK peptide and related sequences did not bind to PKCepsilon, indicating that their mechanisms of action do not involve binding to the kinase as previously proposed. Our results clarify which interactions could be targeted in developing new therapeutics that inhibit PKCepsilon-RACK2 interaction. PMID- 29266264 TI - Loss of maximal explosive power of lower limbs after 2 weeks of disuse and incomplete recovery after retraining in older adults. AB - KEY POINTS: Disuse in older adults can critically decrease lower limb muscle power, leading to compromised mobility and overall quality of life. We studied how muscle power and its determinants (muscle mass, single muscle fibre properties and motor control) adapted to 2 weeks of disuse and subsequent 2 weeks of physical training in young and older people. Disuse decreased lower limb muscle power in both groups; however, different adaptations in single muscle fibre properties and co-contraction of leg muscles were observed between young and older individuals. Six physical training sessions performed after disuse promoted the recovery of muscle mass and power. However, they were not sufficient to restore muscle power to pre-disuse values in older individuals, suggesting that further countermeasures are required to counteract the disuse-induced loss of muscle power in older adults. ABSTRACT: Disuse-induced loss of muscle power can be detrimental in older individuals, seriously impairing functional capacity. In this study, we examined the changes in maximal explosive power (MEP) of lower limbs induced by a 14-day disuse (bed-rest, BR) and a subsequent 14-day retraining, to assess whether the impact of disuse was greater in older than in young men, and to analyse the causes of such adaptations. Sixteen older adults (Old: 55-65 years) and seven Young (18-30 years) individuals participated in this study. In a subgroup of eight Old subjects, countermeasures based on cognitive training and protein supplementation were applied. MEP was measured with an explosive ergometer, muscle mass was determined by magnetic resonance, motor control was studied by EMG, and single muscle fibres were analysed in vastus lateralis biopsy samples. MEP was ~33% lower in Old than in Young individuals, and remained significantly lower (-19%) when normalized by muscle volume. BR significantly affected MEP in Old (-15%) but not in Young. Retraining tended to increase MEP; however, this intervention was not sufficient to restore pre-BR values in Old. Ankle co-contraction increased after BR in Old only, and remained elevated after retraining (+30%). Significant atrophy occurred in slow fibres in Old, and in fast fibres in Young. After retraining, the recovery of muscle fibre thickness was partial. The proposed countermeasures were not sufficient to affect muscle mass and power. The greater impact of disuse and smaller retraining induced recovery observed in Old highlight the importance of designing suitable rehabilitation protocols for older individuals. PMID- 29266267 TI - Live birth outcomes after adolescent and young adult breast cancer. AB - Reproductive outcomes are an important survivorship concern for women diagnosed with cancer as adolescents and young adults (AYAs). We examined the incidence of live birth and the prevalence of adverse birth outcomes according to tumor and treatment characteristics among AYAs with breast cancer. Women diagnosed with breast cancer at ages 15-39 during 2000-2013 were identified using the North Carolina Central Cancer Registry (n = 4,978). Cancer registry records were linked to state birth certificate files from 2000 to 2014 to identify births to women with and without a breast cancer history. The breast cancer cohort was followed until live birth, death, age 46, or December 31, 2014, whichever occurred first. For each birth to breast cancer survivors (n = 338), we sampled 20 births to women without a recorded cancer diagnosis, with frequency matching on maternal age and year of delivery. The cumulative incidence of live births after breast cancer was 8% at 10 years. Births were less common among women treated with chemotherapy. Overall, the prevalence of preterm birth, low birth weight, small for-gestational age (SGA) and Cesarean delivery did not differ substantially between births to women with and without breast cancer. However, births to women with ER-negative disease were more likely to be preterm (PR = 1.84; 95% CI: 1.11 3.06). In this population-based study, <10% of AYA breast cancer survivors had a live birth within 10 years of their diagnosis. The increase in risk of preterm delivery among ER-negative survivors in our cohort warrants further investigation in larger studies. PMID- 29266269 TI - Risk factors for acute nerve injury after total knee arthroplasty. AB - INTRODUCTION: In this we study identified potential risk factors for post-total knee arthroplasty (TKA) nerve injury, a catastrophic complication with a reported incidence of 0.3%-1.3%. METHODS: Patients who developed post-TKA nerve injury from 1998 to 2013 were identified, and each was matched with 2 controls. A multivariable logistic regression model was built to calculate odds ratios (ORs). RESULTS: Sixty-five nerve injury cases were identified in 39,990 TKAs (0.16%). Females (OR 3.28, P = 0.003) and patients with history of lumbar pathology (OR 6.12, P = 0.026) were associated with increased risk of nerve injury. Tourniquet pressure < 300 mm Hg and longer duration of anesthesia may also be risk factors. DISCUSSION: Surgical planning for females and patients with lumbar pathology should be modified to mitigate their higher risk of neurologic complications after TKA. Our finding that lower tourniquet pressure was associated with higher risk of nerve injury was unexpected and requires further investigation. Muscle Nerve 57: 946-950, 2018. PMID- 29266270 TI - CYP21A2 genetic profile in 14 Egyptian children with suspected congenital adrenal hyperplasia: a diagnostic challenge. AB - CYP21A2 genotyping remains an important element in the diagnosis and management of congenital adrenal hyperplasia, and establishing accurate genotype-phenotype correlations has facillitated adequate genetic counseling and prenatal management for at-risk families. Despite extensive efforts to establish a clear genotype phenotype correlation, some discordance remains. Establishing a diagnosis of congenital adrenal hyperplasia on the basis of biochemical and clinical data is occasionally challenging, and the identification of CYP21A2 mutations may help confirm the diagnosis. We review the diagnostic challenges despite an extensive genetic evaluation for 14 patients with a suspected clinical and biochemical diagnosis of congenital adrenal hyperplasia. Other diagnostic entities should be considered in the absence of convincing genetic data. PMID- 29266268 TI - Restoration of metabolic health by decreased consumption of branched-chain amino acids. AB - KEY POINTS: We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets. ABSTRACT: Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance. PMID- 29266271 TI - Development of Tissue-Engineered Ligaments: Elastin Promotes Regeneration of the Rabbit Medial Collateral Ligament. AB - When ligaments are injured, reconstructive surgery is sometimes required to restore function. Methods of reconstructive surgery include transplantation of an artificial ligament and autotransplantation of a tendon. However, these methods have limitations related to the strength of the bone-ligament insertion and biocompatibility of the transplanted tissue after surgery. Therefore, it is necessary to develop new reconstruction methods and pursue the development of artificial ligaments. Elastin is a major component of elastic fibers and ligaments. However, the role of elastin in ligament regeneration has not been described. Here, we developed a rabbit model of a medial collateral ligament (MCL) rupture and treated animal knees with exogenous elastin [100 ug/(0.5 mL.week)] for 6 or 12 weeks. Elastin treatment increased gene expression and protein content of collagen and elastin (gene expression, 6-fold and 42-fold, respectively; protein content, 1.6-fold and 1.9-fold, respectively), and also increased the elastic modulus of MCL increased with elastin treatment (2-fold) compared with the controls. Our data suggest that elastin is involved in the regeneration of damaged ligaments. PMID- 29266272 TI - A Decrease in Hypoxic Pulmonary Vasoconstriction Correlates With Increased Inflammation During Extended Normothermic Ex Vivo Lung Perfusion. AB - Normothermic ex vivo lung perfusion (EVLP) is an evolving technology to evaluate function of donor lungs to determine suitability for transplantation. We hypothesize that hypoxic pulmonary vasoconstriction (HPV) during EVLP will provide a more sensitive parameter of lung function to determine donor lung quality for lung transplantation. Eight porcine lungs were procured, and subsequently underwent EVLP with autologous blood and STEEN solution for 10 h. Standard physiologic parameters including dynamic compliance, peak airway pressure, and pulmonary vascular resistance (PVR) remained stable (P = 0.055), mean oxygenation (PO2 /FiO2 ) was 400 +/- 18 mm Hg on average throughout perfusion. Response to hypoxia resulted in a robust increase in PVR (DeltaPVR) up to 4 h of perfusion, however the HPV response then blunted beyond T6 (P < 0.01). The decrease in HPV response inversely correlated to cytokine concentrations of Interleukin-6 and tumor necrosis factor-alpha (P < 0.01). Despite acceptable lung oxygenation and standard physiologic parameters during 10 h of EVLP, there is a subclinical deterioration of lung function. HPV challenges can be performed during EVLP as a simple and more sensitive index of pulmonary vascular reactivity. PMID- 29266273 TI - Cerebrovascular and Alzheimer disease: fellow travelers or partners in crime? AB - In this review, we will discuss the progressive decline in cognitive and intellectual performance in late life that has led to great challenges for medical and community services. The term 'vascular cognitive impairment' is defined as any cognitive impairment that is caused by or associated with vascular factors. It can occur alone or in association with Alzheimer disease. The good news is that because vascular risk factors are treatable, it should be possible to prevent or delay some dementias. Since vascular cognitive impairment may often go unrecognized, many experts recommend screening with brief tests to assess memory, thinking, and reasoning for everyone considered to be at high risk for this disorder. Up to 64% of persons 65 years or older who have experienced a stroke have some degree of cognitive impairment with up to one third developing dementia. Postmortem studies indicate that up to 34% of dementia cases show significant vascular pathology. It suggests that ischemic stroke triggers additional pathophysiological process that may lead to a secondary degenerative process that may interact with Alzheimer disease pathology thus accelerating the ongoing primary neurodegeneration. Mechanisms could include hypoperfusion, hypoxia, and neuroinflammation, one of the links between the two pathologies. Stroke and dementia share the same risk and protective factors. Since stroke interact with dementia of all types it may already be possible to reduce or delay some dementias by a number of interventions known to prevent stroke. This article is part of the Special Issue "Vascular Dementia". PMID- 29266274 TI - Prevention of tracheal inflammation and fibrosis using nitinol stent coated with doxycycline. AB - OBJECTIVES: This study was conducted to determine whether a nitinol stent coated with doxycycline prevents tracheal inflammation and fibrosis in a rabbit. METHODS: A nitinol stent coated with doxycycline was designed by us. Twelve rabbits were divided into three groups: normal, control (nondoxycycline-coated stent), and doxycycline-coated stent group. The stents were inserted into the tracheal lumen through the oral cavity. Tracheal granulation was evaluated and graded by laryngoscopy. Histological examinations evaluated the inflammatory response and fibrosis. Real-time polymerase chain reaction (PCR) and Western blot assessed the changes to the extracellular matrix (ECM). RESULTS: Endoscopic findings showed that the nitinol stent coated with doxycycline resulted in lesser granulation tissue in the trachea than the noncoated stent. Histologic examination further revealed that the doxycycline-coated stent was associated with decreased inflammatory cells and reduced fibrosis, compared to the noncoated stent. In PCR and Western blot, the doxycycline-coated stent showed lower expression of ECM components inducing fibrosis. CONCLUSION: A nitinol stent coated with doxycycline showed favorable effects in reducing tracheal inflammation and fibrosis in a rabbit model. Further research is required to study the beneficial effects of local application of doxycycline for prevention of tracheal stenosis. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1558-1563, 2018. PMID- 29266275 TI - In reference to should infants who fail their newborn hearing screen undergo cytomegalovirus testing? PMID- 29266276 TI - Evaluation of the advantages of platelet concentrates stored at 4 degrees C versus 22 degrees C. AB - BACKGROUND: Platelet (PLT) storage at cold temperatures (4 degrees C) can reduce bacterial contamination and lower the risk of transfusion-related complications. We compared the effects of 22 and 4 degrees C storage conditions for PLTs to further explore the efficiency of hemostasis in acute bleeding and extended PLT shelf life. STUDY DESIGN AND METHODS: Manually prepared PLTs (PLT concentrates in plasma, not PLT additive solution) were stored at 4 and 22 degrees C. The PLT counts, scanning electronic microscope observations, blood gas indices, biochemical indices, PLT aggregative function, and surface CD62P expression were monitored and compared between the groups. RESULTS: There was no obvious change in PLT counts between Day 21 at 4 degrees C and Day 5 at 22 degrees C. PLTs stored at 4 degrees C for 10 to 14 days were dramatically activated, had rough surfaces, and showed a significant degree of long pseudopodia formation. The pH of the PLTs on Day 5 was lower at 22 degrees C than at 4 degrees C, while the lactate dehydrogenase and lactic acid levels in the former group were significantly higher (p < 0.005). The maximum aggregation rates induced by collagen and arachidonic acid in the PLTs stored at 4 degrees C for 5 days remained higher than 80%, while the rates induced by four inducers in the PLTs stored at 22 degrees C were less than 5%. PLTs stored at 4 degrees C for 10 to 14 days showed higher surface expression of PAC-1 and CD62P. CONCLUSION: PLT counts, cellular morphologies, PLT membranes, cytoplasmic structures, aggregation rates, and hemostatic PLT function stored at 4 degrees C for 10 to 14 days were better than those stored at 22 degrees C for 5 days. PMID- 29266277 TI - Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic 'activated' state that enhances prostate cancer cell migration. AB - Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow-derived MSCs. MSCs were 'educated' for extended periods in prostate cancer cell conditioned media and PC3 educated MSCs were found to be the most responsive with a secretory profile rich in pro-inflammatory cytokines. PC3-educated MSCs secreted increased osteopontin (OPN), interleukin-8 (IL-8) and fibroblast growth factor-2 (FGF-2) and decreased soluble fms-like tyrosine kinase-1 (sFlt-1) compared to untreated MSCs. PC3 educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3-conditioned medium. Vimentin and alpha-smooth muscle actin (alphaSMA) expression was decreased in PC3-educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient-derived MSCs led to a reduced proportion of FAP+ alphaSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3-educated and DU145 educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient-derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro-inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells. PMID- 29266278 TI - Survival in patients with medullary thyroid cancer after less than the recommended initial operation. AB - BACKGROUND AND OBJECTIVES: We aimed to evaluate the disease specific-survival (DSS) of patients with Medullary Thyroid Cancer (MTC) confined to the central neck based on the extent of the initial operation. METHODS: This retrospective review of patients with MTC from the SEER registry from 2004 to 2012 excluded patients with lateral neck involvement or distant metastases. RESULTS: The cohort (n = 766) included 85(11%) less than total thyroidectomies (TT), 212(28%) TT alone, and 469(61%) TT with lymph node excision. Mean tumor size was similar (2.2cm for =0.2 meals/summer for those in 72nd percentile of fish consumption or above), high-contaminant sport-caught fish (by >=0.4 meals/summer for those in 87th percentile and above), and low-contaminant sport-caught fish (by >=0.3 meals/summer by those in 76th percentile and above). The brochure also reduced sport-caught fish consumption among those anglers who exceeded the advisories in 2014 (by 2.0 meals/summer). In addition, the brochure led to small increases in sport-caught fish consumption (0.4-0.6 meals/summer) in urban anglers who ate very little sport-caught fish (<=1 meal/summer). PMID- 29266341 TI - Microbiome-Germline Interactions and Their Transgenerational Implications. AB - It is becoming increasingly clear that most, if not all, animals and plants are associated with a diverse array of resident gut microbiota. This symbiosis is regulated by host-microbiome interactions which influence the development, homeostasis, adaptation and evolution of the host. Recent evidence indicated that these interactions can also affect the host germline and have a potential of supporting transgenerational effects, including inheritance of acquired characteristics. Taken together, the influence of gut bacteria on the host soma and germline could potentially give rise to emergent phenotypes, which may be partially inherited by three distinguishable modes of transgenerational influence of gut bacteria: 1) "soma-to-soma" 2) "soma-to-germline" and 3) "soma-germline soma". Here, we discuss these possibilities in light of evidence supporting bacterial-mediated modes of transgenerational inheritance. PMID- 29266342 TI - mTORC1 signaling is essential for neurofibromatosis type I gene modulated osteogenic differentiation of BMSCs. AB - Neurofibromatosis type I (NF1), which is caused by mutations in the NF1 gene, is a common autosomal dominant genetic disease leading to skeletal abnormalities. Both NF1 gene and mammalian target of rapamycin complex 1 (mTORC1) signaling are associated with the osteogenic differentiation of bone marrow stem cells (BMSCs). In this study, we hypothesized that mTORC1 signaling is involved in NF1-modulated osteoblast differentiation of BMSCs. Human BMSCs were cultured in an osteogenic induction medium. The expression of NF1 was either inhibited or overexpressed by transfecting NF1 with a specific small interfering RNA (siRNA) or pcDNA3.0 plasmid, respectively. In addition, an mTORC1 signaling inhibitor and agonist were used to investigate the effects of mTORC1 on NF1-modulated osteogenic differentiation of BMSCs. The results indicated that inhibiting the expression of NF1 with siRNA significantly decreased the mRNA levels of NF1, whereas overexpressing the expression of NF1 with pcDNA3.0 plasmid significantly increased the mRNA levels of NF1 at days 3, 7, 14 and 21 after culture. We observed reduced osteogenic differentiation and cell proliferation in the NF1 siRNA group and enhanced osteogenic differentiation and cell proliferation of BMSCs in the NF1-pcDNA3.0 group. The activity of mTORC1 signaling (p-mTORC1, p S6K1, and p-4EBP1) was significantly upregulated in the NF1-siRNA group and significantly inhibited in the NF1-pcDNA3.0 group, 7 and 14 days after culture. The effects of NF1-siRNA and NF1-pcDNA3.0 on osteogenic differentiation of BMSCs and cell proliferation were reversed by mTORC1 inhibitor and agonist, respectively. In conclusion, NF1 modulates osteogenic differentiation and cell proliferation of human BMSCs and mTORC1 signaling is essential for this process. PMID- 29266343 TI - In vitro activity of a combination of bacteriophages and antimicrobial plant extracts. AB - The continuing threat of antimicrobial resistance presents a considerable challenge to researchers to develop novel strategies ensuring that bacterial infections remain treatable. Many plant extracts have been shown to have antibacterial properties and could potentially be combined with other antibacterial agents to create more effective formulations. In this study, the antibacterial activity of three plant extracts and virulent bacteriophages have been assessed as individual components and in combination. When assessed with a modified suspension test, these plant extracts also exhibit antiviral activity at bacterial inhibitory concentrations. Hence, to investigate any potential additive effects between the extracts and virulent phages, the extracts were tested at subantiviral concentrations. Phages alone and in combination with plant extracts significantly reduced (P < 0.05) the bacterial concentration compared to untreated and extract treated controls up to 6 h (2-3log10 ), but this reduction did not extend to 24 h. In most cases, the phage and extract combinations did not significantly reduce bacterial content compared to phages alone. Additionally, there was little impact on the ability of the phages to reproduce within their bacterial hosts. To our knowledge, this study represents the first of its kind, in which antimicrobial plant extracts have been combined with virulent phages and has highlighted the necessity for plant extracts to be functionally characterized prior to the design of combinatorial therapies. Significance and Impact of Study This preliminary study provides insights into the potential combination of bacteriophages and antimicrobial plant bulk extracts to target bacterial pathogens. It is to our knowledge the first time in which virulent bacteriophages have been combined with antimicrobial plant extracts. PMID- 29266344 TI - A phase I/II trial of vorinostat (SAHA) in combination with rituximab-CHOP in patients with newly diagnosed advanced stage diffuse large B-cell lymphoma (DLBCL): SWOG S0806. AB - Loss of major histocompatibility Class II expression (MHCII) in diffuse large B cell lymphoma (DLBCL) correlates with decreased survival. MHCII transcription is in part regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor (HDACI) with standard chemotherapy would improve outcomes in DLBCL in part through increased MHCII expression. S0806 was a single arm phase I/II trial of vorinostat given at 400 mg po daily on days 1-9 (subsequently amended to days 1-5 due to toxicity), combined with R-CHOP given on day 3 of a 21-day cycle for 8 cycles, with primary phase II endpoint of 2-year progression free survival (PFS). With 72 evaluable patients, at median follow up of 3 years, 2-year PFS estimate was 73%, and OS estimate was 86%. Considering that the regimen fell short of predefined efficacy improvement and was associated with high rates of febrile neutropenia (38%) and sepsis (19%), it cannot be recommended for general use. Consistent with our hypothesis, patients with low MCHII expression on S0806 had numerically superior outcomes compared to those from trial S0433 which did not use an HDACI, but the difference was not statistically significant. Current studies are focused on finding biomarkers of response to HDACI. PMID- 29266345 TI - Hyperuricaemia and development of type 2 diabetes mellitus in Asian population. AB - Recently, meta-analysis studies reported that hyperuricaemia is associated with higher incidence of type 2 diabetes mellitus (T2DM), however, there are limited data on the Asian population. The aim of this observational study is to estimate the long-term impact of hyperuricaemia on the new-onset T2DM and cardiovascular events. This study is based on a single-centre, all-comers, and large retrospective cohort. Subjects that visited from January 2004 to February 2014 were enrolled using the electronic database of Korea University Guro Hospital. A total of 10 505 patients without a history of T2DM were analyzed for uric acid, fasting glucose and haemoglobin (Hb) A1c level. Inclusion criteria included both Hb A1c <5.7% and fasting glucose level <100 mg/dL without T2DM. Hyperuricaemia was defined as a uric acid level >=7.0 mg/dL in men, and >=6.5 mg/dL in women. To adjust baseline confounders, a propensity score matching (PSM) analysis was performed. The impact of hyperuricaemia on the new-onset T2DM and cardiovascular events were compared with the non-hyperuricaemia during the 5-year clinical follow-up. After PSM, baseline characteristics of both groups were balanced. In a 5-year follow-up, the hyperuricaemia itself was a strong independent predictor of the incidence of new-onset T2DM (HR, 1.78; 95% CI, 1.12 to 2.8). Hyperuricaemia was a strong independent predictor of new-onset T2DM, which suggests a substantial implication for a correlation between uric acid concentration and insulin resistance (or insulin sensitivity). Also, hyperuricaemia is substantially implicated in cardiovascular risks and the further long-term cardiovascular events in the crude population, but it is not an independent predictor of long-term cardiovascular mortality in the matched population. PMID- 29266346 TI - Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation. AB - BACKGROUND: Activated hepatic macrophages play a key role in inflammation and fibrosis progression in chronic liver disease. AIM: To assess the prognostic value of soluble (s)CD163 and mannose receptor (sMR) in cirrhotic patients and explore associations with markers of intestinal permeability (lactulose-mannitol ratio, diamine oxidase), bacterial translocation (endotoxin, lipopolysaccharide binding protein) and markers of systemic immune activation (interleukin-6, interleukin-8, sCD14). METHODS: We prospectively investigated 101 cirrhotic patients (Child-Pugh class A: n = 72, Child-Pugh classes B and C: n = 29) and 31 healthy controls. Patients were observed for a median follow-up of 37 months. RESULTS: Median plasma levels of sCD163 and soluble mannose receptor were significantly elevated in cirrhotic patients (P < .001) and increased with disease severity (sCD163 in healthy controls = 1.3, Child-Pugh class A = 4.2, Child-Pugh classes B and C = 8.4 mg/L; sMR in healthy controls = 15.8, Child-Pugh class A = 36.5, Child-Pugh classes B and C = 66.3 MUg/dL). A total of 21 patients died during the observation period. Patients with sCD163 levels above 5.9 mg/L showed significantly reduced survival (survival rate after 36 months: 71% versus 98%, P < .001). Patients with soluble mannose receptor levels above 45.5 MUg/dL developed significantly more complications of cirrhosis within 12 months (73% versus 9%, P < .001). Furthermore, both variables correlated with the lactulose mannitol ratio, diamine oxidase, lipopolysaccharide and interleukin-8. CONCLUSION: Our data demonstrate the prognostic value of sCD163 in predicting long-term survival in patients with liver cirrhosis and identify soluble mannose receptor as a prognostic marker for occurrence of cirrhosis-associated complications. The correlation between gut barrier dysfunction and activation of macrophages points towards a link between them. PMID- 29266347 TI - Eczematous dermatitis in an infantile hemangioma with minimal or arrested growth. AB - Infantile hemangiomas (IHs) with minimal or arrested growth differ from standard IHs in that they have a reduced or absent growth phase. An association between IHs with minimal or arrested growth and superimposed eczematous dermatitis has not been described in the literature. We present a case detailing this association in which an IH with minimal or arrested growth responded well to treatment with propranolol and the superimposed eczema cleared completely with topical hydrocortisone. PMID- 29266348 TI - Modulation of sympathetic vasoconstriction is critical for the effects of sleep on arterial pressure in mice. AB - KEY POINTS: While values of arterial pressure during sleep are predictive of cardiovascular risk, the autonomic mechanisms underlying the cardiovascular effects of sleep remain poorly understood. Here, we assess the autonomic mechanisms of the cardiovascular effects of sleep in C57Bl/6J mice, taking advantage of a novel technique for continuous intraperitoneal infusion of autonomic blockers. Our results indicate that non-REM sleep decreases arterial pressure by decreasing sympathetic vasoconstriction, decreases heart rate by balancing parasympathetic activation and sympathetic withdrawal, and increases cardiac baroreflex sensitivity mainly by increasing fluctuations in parasympathetic activity. Our results also indicate that REM sleep increases arterial pressure by increasing sympathetic activity to the heart and blood vessels, and increases heart rate, at least in part, by increasing cardiac sympathetic activity. These results provide a framework for generating and testing hypotheses on cardiovascular derangements during sleep in mouse models and human patients. ABSTRACT: The values of arterial pressure (AP) during sleep predict cardiovascular risk. Sleep exerts similar effects on cardiovascular control in human subjects and mice. We aimed to determine the underlying autonomic mechanisms in 12 C57Bl/6J mice with a novel technique of intraperitoneal infusion of autonomic blockers, while monitoring the electroencephalogram, electromyogram, AP and heart period (HP, i.e. 1/heart rate). In different sessions, we administered atropine methyl nitrate, atenolol and prazosin to block muscarinic cholinergic, beta1 -adrenergic and alpha1 adrenergic receptors, respectively, and compared each drug infusion with a matched vehicle infusion. The decrease in AP from wakefulness to non-rapid-eye movement sleep (N) was abolished by prazosin but was not significantly affected by atropine and atenolol, which, however, blunted the accompanying increase in HP to a similar extent. On passing from N to rapid-eye-movement sleep (R), the increase in AP was significantly blunted by prazosin and atenolol, whereas the accompanying decrease in HP was blunted by atropine and abolished by atenolol. Cardiac baroreflex sensitivity (cBRS, sequence technique) was dramatically decreased by atropine and slightly increased by prazosin. These data indicate that in C57Bl/6J mice, N decreases mean AP by decreasing sympathetic vasoconstriction, increases HP by balancing parasympathetic activation and sympathetic withdrawal, and increases cBRS mainly by increasing fluctuations in parasympathetic activity. R increases mean AP by increasing sympathetic vasoconstriction and cardiac sympathetic activity, which also explains, at least in part, the concomitant decrease in HP. These data represent the first comprehensive assessment of the autonomic mechanisms of cardiovascular control during sleep in mice. PMID- 29266349 TI - Diet quality affects chemical tolerance in the freshwater snail Lymnaea stagnalis. AB - Organisms generally select high-quality diets to obtain maximal energy while devoting the least amount of time and energy. Diets, however, can vary in natural systems. In ecotoxicological testing, the effect of diet type on organismal responses to toxicants has not been explored despite the potential for dietary effects to influence toxicological endpoints. We first evaluated diet quality using growth rate and sensitivity to the fungicide pyraclostrobin of Lymnaea stagnalis fed lettuce (common laboratory diet), turtle pellets (high nutrient composition), and a combination diet of both food items. We also measured the macronutrient content of snails raised on the multiple diets to determine how diet may have impacted energy allocation patterns. Finally, we evaluated whether snails discernibly preferred a particular diet. Snails fed high-nutrient and combination diets grew larger overall than snails fed a lettuce-only diet. Snails fed the high-nutrient and combination diets, both juvenile and adult, were significantly more tolerant to pyraclostrobin than snails fed lettuce. When measured for macronutrient content, snails raised on high-nutrient and combination diets had significantly higher carbohydrate content than snails fed lettuce. Despite the strong effects of diet type, snails did not exhibit a clear diet choice in preference trials. Dietary composition clearly influences growth rate, sensitivity, and macronutrient content of Lymnaea stagnalis. These results suggest that the nutritional environment has potentially strong impacts on toxicant sensitivity. Environ Toxicol Chem 2018;37:1158-1167. (c) 2017 SETAC. PMID- 29266350 TI - Endogenous peptides profiles of human infantile hemangioma tissue and their clinical significance for treatment. AB - Endogenous peptides play crucial roles in various biological processes. Their effects on the pathogenesis of human infantile hemangioma remains poorly understood. In this study, we construct a comparative peptidomic profiling between human infantile hemangioma tissue and matched normal skin using liquid chromatography-tandem mass spectrometry. A total of 192 peptides were significantly differentially expressed in human infantile hemangioma tissue, with 182 upregulated, and 10 downregulated peptides between infantile hemangioma tissue and matched normal skin. Performing bioinformatics analysis (Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis), we found that precursor proteins of these differentially expressed peptides correlate with metabolic process, biological regulation, binding, catalytic activity, and pathways in cancer occurring during pathological changes of infantile hemangioma. Furthermore, 89 differentially expressed peptides shared homology with antimicrobial peptides and 13 matched known immunomodulatory peptides based on prediction database. In conclusion, our results reveal significantly altered expression profiles of peptides in human infantile hemangioma tissue. These peptides may participate in the etiology of infantile hemangioma and provide beneficial scheme for clinical treatments. PMID- 29266351 TI - An unusual onset of agminated Spitz naevi in an adult patient. PMID- 29266352 TI - Stage of development affects dry weight mercury concentrations in bird eggs: Laboratory evidence and adjustment method. AB - Bird eggs are often used to monitor levels and trends of mercury (Hg) in the environment. Logistical issues in such studies sometimes require the use of eggs at different stages of development. Therefore, it is important to understand how embryonic age may affect egg Hg concentrations. Studies using dry weight Hg concentrations in eggs assume that dry mass (e.g., lipids) does not change through embryonic development and thus expressing concentrations on a dry weight basis adjusts for any changes that may occur in egg mass throughout development. That assumption is tested in the present study by injecting chicken eggs with Hg and measuring Hg concentrations in embryonic contents at different stages of artificial incubation. The results indicate that dry weight Hg concentrations in eggs at later stages of development are statistically greater than in undeveloped eggs. To address this issue, we developed a method of standardizing egg Hg concentrations for embryonic age based on egg contents density (egg contents mass/egg contents volume). A combined dataset (n = 225) from precocial and semi precocial birds was used to demonstrate that egg contents density declines with increasing embryonic development. Based on this finding, we applied a formula to adjust egg dry weight Hg concentrations for stage of development: adjusted egg [Hg] = unadjusted [Hg] * (egg contents density). The application of this approach to adjust data from the chicken egg Hg injection study resulted in there being no statistically significant difference in dry weight Hg levels in eggs at different stages of embryonic development. The adjustment approach described in the present study is a straightforward method to account for stage of development when assessing Hg levels in avian eggs and should be widely applicable to studies of this nature. Environ Toxicol Chem 2018;37:1168-1174. (c) 2017 SETAC. PMID- 29266353 TI - Reply. PMID- 29266354 TI - Volumetric changes following ridge preservation or spontaneous healing and early implant placement with simultaneous guided bone regeneration. AB - AIM: To assess volumetric and linear changes following ridge preservation (RP) or spontaneous healing plus early implant placement with or without simultaneous guided bone regeneration (GBR). MATERIALS AND METHODS: In eight adult beagle dogs, the mesial roots of the mandibular P3, P4 and M1 were extracted. Sites were randomized to either ridge preservation (RP) or spontaneous healing (SH). Four weeks later dental implants were placed either with (RP2) or without removing non integrated DBBM (RP1). In RP2 and SH sites, GBR was applied using a demineralized bovine bone mineral and a resorbable membrane. Impressions were taken postextraction (SH)/postridge preservation (RP1; RP2), before and after implant placement and after healing of 4 and 12 weeks. Casts were digitized to allow for superimposition and measurement of contour alterations. RESULTS: Median ridge width reduction from postextraction (SH)/postridge preservation (RP1;RP2) to implant placement ranged from -13.9% (SH) to -19.7% (RP) (p > .05), whereas from implant placement to sacrifice, it was statistically significantly lower in group RP1 (-5.5%) compared to group SH (-23.4%; p = .0013) and group RP2 (-22.1%; p = .0026). Encompassing the entire study period, median ridge width changes ranged between -17.8% (SH), -24.8% (RP2) and -32.5% (RP1) (p > .05). CONCLUSIONS: Irrespective of the treatment modality and the healing period, part of the ridge contour was lost. Early implant placement after ridge preservation without additional GBR resulted in a more stable ridge contour after implant placement compared to controls. PMID- 29266355 TI - Will Maintenance of Oral Hygiene in Nursing Home Residents Prevent Pneumonia? AB - This article is an evaluation of the literature on oral hygiene as a risk factor for nursing home-associated pneumonia (NHAP) and with interventions to improve oral hygiene and reduce the incidence of NHAP. The background for this article is that studies that have evaluated interventions to improve oral hygiene and prevent NHAP have conflicting results. To try to understand the reason for these results, the objective was to examine risk factor and intervention studies and determine their methodological validity. Review of studies evaluating oral hygiene status as a risk factor for NHAP found multiple methodological problems, resulting in limited evidence to support this association. Studies of intervention methods, whether finding benefit or not in preventing NHAP, all had methodological limitations. Therefore, it is unclear whether oral hygiene is a risk factor for NHAP and whether improving oral hygiene decreases the incidence of this infection. A recommendation is made that future studies should carefully define the etiology of suspected NHAP using molecular techniques when evaluating methods to prevent this infection because viral pneumonia and aspiration pneumonitis may mimic bacterial pneumonia even though, at times, there may be coinfection with bacteria. In this latter situation, improving oral hygiene may not prevent pneumonia. Therefore, viral infection and pneumonitis with or without bacterial coinfection need to be excluded so that the focus is on prevention of bacterial pneumonia. PMID- 29266356 TI - Effect of microRNA-145 on proliferation and apoptosis of human non-small cell lung cancer A549 cells by regulating mTOR signaling pathway. AB - Our study aims to explore the impact of microRNA-145 (miR-145) on proliferation and apoptosis of non-small cell lung cancer (NSCLC) cells by modulating mTOR signaling pathway. Paired NSCLC and adjacent normal tissues were obtained from 50 NSCLC patients between January 2014 and January 2016. Human lung adenocarcinoma A549 cell line was assigned into the control, mimics, mimics-negative control (NC), inhibitor and inhibitor-NC groups. Quantitative RT-PCR and Western blot were applied to detect the expressions of miR-145 and mTOR. MTT, scratch test, Transwell and flow cytometry were carried out to analyze the effect of miR-145 on A549 cell proliferation, migration, invasion, apoptosis and cycle distribution and regulation of mTOR signaling pathway. MiR-145 expression in NSCLC tissues was lower than that in adjacent normal tissues, while mTOR expression was higher in NSCLC tissues than in adjacent normal tissues. Compared with the control and mimics groups, cell proliferation, migration and invasion abilities decreased in the mimics group; additionally, cell apoptosis rate increased and cells were mostly in G1 phase. MiR-145 inhibited the activation of mTOR signaling pathway. Compared with the control and inhibitor-NC groups, mTOR signaling pathway was activated and cell proliferation, migration and invasion abilities increased in the inhibitor group, and cell apoptosis rate decreased and cells were less in G1 phase. The study indicated that miR-145 expression was low in NSCLC and influenced NSCLC cells by negatively regulating mTOR signaling pathway. This article is protected by copyright. All rights reserved. PMID- 29266357 TI - Relationship between clinical periodontal parameters and changes in liver enzymes levels over an 8-year period in an elderly Japanese population. AB - AIMS: An association between periodontal disease and liver enzymes has been reported previously. This study examined the relationship between clinical periodontal parameters and changes in liver enzymes levels in 265 non institutionalized Japanese elderly aged 72 years over 8 years. MATERIALS AND METHODS: The number of sites with probing pocket depth (PPD) >= 6 mm and clinical attachment level (CAL) >= 6 mm were measured. Changes in liver enzymes (alanine transaminase [ALT] and aspartate transaminase [AST]) was grouped based on any elevation of concentrations. The relationship was determined by logistic regression with adjustment for confounders. Interaction test and stratified analysis were then performed according to smoking status and alcohol drinking habits, separately. RESULTS: Elevation in ALT, but not AST, was significantly associated with PPD (odds ratio [OR] = 1.10) and CAL (OR = 1.03). A significant interaction of periodontal parameters on ALT was observed with smoking status, but not with alcohol drinking habit. The stratified analysis suggested that ALT was found to be significantly correlated with PPD (OR = 1.20) and CAL (OR = 1.04) to those who were smoker. CONCLUSION: The elevation in ALT levels might be associated with clinical periodontal parameters among non-institutionalized Japanese elderly, and this association was modified by smoking status. PMID- 29266359 TI - MiR-320 promotes B cell proliferation and the production of aberrant glycosylated IgA1 in IgA nephropathy. AB - IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. However, the etiology of this disease is complex and the pathogenesis of IgAN is still unknown. MicroRNAs (miRNAs) play important roles in a lot of pathological and physiological processes. In this study, we showed that the expression of miR 320 was significantly upregulated in renal tissues and urinary of IgAN patients. Moreover, the intra-renal expression level of miR-320 had significant correlation with miR-320 expression in the urinary of IgAN patients. Overexpression of miR 320 increased B cell proliferation and promoted cyclin D1 expression. Furthermore, we identified that PTEN was direct target gene of miR-320 in the B cell. Ectopic expression of miR-320 suppressed PTEN expression. Overexpression of miR-320 decreased Cosmc expression in the B cell. In addition, we demonstrated that Cosmc expression was significantly downregulated in the renal tissues and urinary of IgAN patients. The intra-renal expression level of Cosmc had significant correlation with Cosmc expression of urinary in IgAN patients. We proved that the expression level of Cosmc was negatively correlated with the expression of miR-320 in the renal tissues of IgAN patients. Overexpression of miR-320 promoted the B cell proliferation through suppressing PTEN expression. Taken together, these data suggested that miR-320 acted an important role in the development of IgAN. PMID- 29266360 TI - Vedolizumab in the treatment of chronic, antibiotic-dependent or refractory pouchitis. AB - BACKGROUND: The most common complication after ileal pouch anal anastomosis in up to 50% of patients is an acute pouchitis. The majority of patients respond to antibiotic treatment. However, 10%-15% develops chronic antibiotic-dependent or refractory pouchitis which is usually hard to treat. AIM: To evaluate the effectiveness of vedolizumab in patients with chronic pouchitis. METHODS: Patients with chronic antibiotic-dependent or refractory pouchitis were treated with vedolizumab (300 mg at week 0, 2, 6 and 10) in 10 IBD centres and retrospectively registered. Data were recorded until week 14 of vedolizumab treatment. In total 20 patients (12 male, median age 43 years) were included for analysis. The effectiveness was measured using the Oresland Score (OS) at week 2, 6, 10 and 14 and the pouch disease activity index (PDAI) at week 0 and 14. RESULTS: The mean OS declined from 6.8 (range 2-12) to 3.4 (range 0-11). Concordantly, the mean PDAI after 14 weeks of treatment dropped from 10 (range 5 18) to 3 (range 0-10). Only three patients reported moderate side effects. No serious side effects were recorded. In addition, symptomatic co-medication such as loperamide and tincture of opium could be terminated in 8 out of 12 patients as well as antibiotic treatment could be stopped in 17 out of 19 patients. CONCLUSION: Our data indicate that vedolizumab could be an option in the treatment of patients with chronic, antibiotic-dependent or refractory pouchitis. PMID- 29266358 TI - Prevention of photosensitivity with action spectrum adjusted protection for erythropoietic protoporphyria. AB - Erythropoietic protoporphyria is a genetic disease characterized by sensitivity to sunlight caused by the accumulation of protoporphyrin IX. Photoprotection against ultraviolet A and visible light is necessary for erythropoietic porphyria patients because the absorption spectrum of protoporphyrin IX lies in both ultraviolet A and visible light region. We developed a novel index, in vitro porphyrin protection factor, based on the protoporphyrin IX absorbance spectrum. We also selected appropriate photoprotective products designed according to protoporphyrin IX absorbance. The porphyrin protection factors of a combination of make-up base with a powder as well as with a liquid foundation were significantly higher than those of a conventional sunscreen product, even at a small application dose. An in-use test carried out for 6 months showed that the efficacy of these products was 78.3%, and no adverse reactions were observed. Male subjects preferred liquid foundation, whereas all female subjects used powder foundation. The preference of the subjects could lead to the long-term use of the tested products. In conclusion, this study provided a new approach to improve photoprotection in erythropoietic protoporphyria patients. PMID- 29266361 TI - Estimation of the Leukemia Risk in Human Populations Exposed to Benzene from Tobacco Smoke Using Epidemiological Data. AB - Several epidemiological studies have demonstrated an association between occupational benzene exposure and increased leukemia risk, in particular acute myeloid leukemia (AML). However, there is still uncertainty as to the risk to the general population from exposure to lower environmental levels of benzene. To estimate the excess risk of leukemia from low-dose benzene exposure, various methods for incorporating epidemiological data in quantitative risk assessment were utilized. Tobacco smoke was identified as one of the main potential sources of benzene exposure and was the focus of this exposure assessment, allowing further investigation of the role of benzene in smoking-induced leukemia. Potency estimates for benzene were generated from individual occupational studies and meta-analysis data, and an exposure assessment for two smoking subgroups (light and heavy smokers) carried out. Subsequently, various techniques, including life table analysis, were then used to evaluate both the excess lifetime risk and the contribution of benzene to smoking-induced leukemia and AML. The excess lifetime risk for smokers was estimated at between two and six additional leukemia deaths in 10,000 and one to three additional AML deaths in 10,000. The contribution of benzene to smoking-induced leukemia was estimated at between 9% and 24% (Upper CL 14-31%). For AML this contribution was estimated as 11-30% (Upper CL 22-60%). From the assessments carried out here, it appears there is an increased risk of leukemia from low-level exposure to benzene and that benzene may contribute up to a third of smoking-induced leukemia. Comparable results from using methods with varying degrees of complexity were generated. PMID- 29266362 TI - Look and you shall find: Perils along the road after slow pathway ablation for AV nodal reentry tachycardia. PMID- 29266363 TI - Shift in the subgingival microbiome following scaling and root planing in generalized aggressive periodontitis. AB - AIM: To investigate the shift in the subgingival microbiota under scaling and root planing (SRP) in patients with generalized aggressive periodontitis (GAgP). MATERIALS AND METHODS: After undergoing supragingival scaling, 12 individuals with GAgP were enrolled in this longitudinal study. Full-mouth SRP was accomplished in 3 weeks and re-evaluated 6 weeks later. Pooled subgingival samples (posterior-mesial, posterior-buccal, anterior-mesial, and anterior buccal) were obtained from each patient before SRP (pre-treatment group) and at the time of re-evaluation (post-treatment group). 16S rRNA PCR products were generated and sequenced after DNA isolation. RESULTS: Under SRP, the diversity of the subgingival community was consistent, whereas genus-level biomarkers transformed from Porphyromonas, Treponema, and Fretibacterium to Actinomyces, Streptococcus, and Haemophilus. In a network analysis, pathogen-related and non pathogen-related components were identified in both the pre- and post-treatment groups; the pathogen component was dramatically augmented, while the non-pathogen component shrank after treatment. Hubs were also distributed in both components pre-treatment and were confined to the pathogen component post-treatment. CONCLUSIONS: Scaling and root planing decreased periodontal pathogens in the subgingival microbiota of patients with GAgP. However, the shift in the microbiota composition was characterized by the expansion of pathogen-related components and the contraction of non-pathogen-related components 6 weeks after SRP. Clinicaltrials.gov #NCT03090282. PMID- 29266364 TI - Aprepitant and fosaprepitant decrease the effectiveness of hormonal contraceptives. PMID- 29266365 TI - Midline anterior neck inclusion cyst: A novel superficial congenital developmental anomaly of the neck. AB - BACKGROUND/OBJECTIVES: A variety of congenital developmental anomalies arise on the neck because of the many fusion planes and complex embryologic structures in this region. We describe a series of seven patients with a novel type of superficial midline congenital anomaly. METHODS: Retrospective case series. Clinical and histopathologic features were compared and used to describe this entity. RESULTS: Seven patients with nearly identical clinical findings were identified. In all cases, a small superficial cyst resembling a giant milium was observed at birth. There were no significant changes during infancy and no evidence of underlying abnormalities. The histopathologic findings were identical to those of an infundibular follicular cyst. CONCLUSION: We have termed this entity midline anterior neck inclusion cyst. We believe it is a superficial developmental anomaly, probably a forme fruste of a midline fusion developmental defect, which has not to our knowledge, previously been described. PMID- 29266366 TI - Morphologic and Functional Changes in Right-Sided Cardiac Chambers in Patients With Chronic Liver Disease and Normal Pulmonary Artery Pressure. AB - OBJECTIVES: To investigate the effects of chronic liver disease (CLD) on the structural and functional characteristics of right-sided heart chambers in patients with normal pulmonary artery pressure. METHODS: Fifty-one patients with known CLD but without pulmonary hypertension or other cardiovascular conditions were consecutively enrolled, along with 25 age- and sex-matched participants. Patients with CLD were classified according to the Model of End-Stage Liver Disease score and Child-Pugh classification. Right ventricular (RV) and right atrial (RA) dimensions, indices of RV systolic/diastolic function, and myocardial strain were measured by standard echocardiographic methods. RESULTS: Patients in the study group had similar RV end-diastolic, end-systolic, and RA dimensions compared to controls. Similarly, neither the conventional indices of RV systolic/diastolic function nor the strain imaging findings were different between groups (P > .05). Only RV free wall thickness was significantly higher in the study group (mean +/- SD, 4.15 +/- 0.64 versus 3.75 +/- 0.37 mm; P < .001). Right ventricular end-diastolic diameter (P = .018; r = 0.334) and RA area (P = .017; r = 0.335) had a significant correlation with RV free wall thickness in patients with CLD. Patients treated with beta blockers were found to have a significant reduction in mean RV free wall strain compared to patients who did not receive beta blocker treatment (-20.37 +/- 6.6 versus -24.07 +/- 6.52; P = .04). CONCLUSIONS: Patients with CLD had increased RV free wall thickness despite normal systolic pulmonary pressure, presumably secondary to cirrhotic cardiomyopathy. In the absence of pulmonary hypertension, however, cirrhotic cardiomyopathy did not cause impaired RV systolic or diastolic function. PMID- 29266367 TI - Clinical features and autoimmune associations in patients presenting with Idiopathic Isolated ACTH deficiency. AB - OBJECTIVE: Idiopathic Isolated ATCH deficiency (IIAD) is a rare cause of secondary adrenal insufficiency. As the condition is rare, and the diagnostic criteria ill-defined, there are few good clinical descriptions in the literature. We have described presenting features, autoimmune associations, natural history and responses to CRF, in a large case series of patients presenting with IIAD. DESIGN: This is a retrospective case note analysis with data derived from the recently commenced National Pituitary Database of Ireland. PATIENTS: Twenty-three patients with isolated ACTH deficiency were identified. A thorough chart and biochemistry review was performed. RESULTS: Twenty-three patients were examined (18 women and 5 men). Age at presentation ranged from 17 to 88 years, (median 48 years). Most patients complained of fatigue; 9 patients presented with hyponatraemia, 13 had autoimmune illnesses (primary hypothyroidism, n = 9). CRF stimulation testing was available in 12 of the 23 patients, 5 of whom demonstrated a rise in plasma ACTH concentrations, indicating hypothalamic, rather than pituitary aetiology. Two patients recovered ACTH secretion, and 2 patients progressed to have other pituitary hormone deficiencies. CONCLUSIONS: IIAD typically presents with insidious symptoms. Euvolaemic hyponatraemia is common at diagnosis. It is associated with autoimmune diseases, particularly primary hypothyroidism. As two patients recovered ACTH secretion, and two progressed to other pituitary hormone deficits, repeat pituitary testing should be considered, to identify recovery of function, or progression to other hormone deficits. PMID- 29266368 TI - Effects of alendronate and alfacalcidol on bone in patients with myasthenia gravis initiating glucocorticoids treatment. AB - OBJECTIVE: Glucocorticoids (GCs) are the first-line treatment for myasthenia gravis (MG) and act as long-term immunosuppressants. However, GCs can induce osteoporosis and bone fractures. In this study, we evaluate the effects of oral alendronate and alfacalcidol, or alfacalcidol alone on the bone of Chinese patients with MG who will initiate treatment with GCs. DESIGN AND METHODS: A total of 75 patients were included in this 12-month prospective, open-label, single-centre study. Patients with bone mineral density (BMD) T-score less than 1.0 at baseline were treated with 70 mg of alendronate per week. Patients with BMD T-score greater than -1.0 at baseline were included in the alfacalcidol-alone group. Patients in two groups were treated with 0.25 MUg of alfacalcidol every other day and 600 mg of calcium daily. RESULTS: After 12 months of treatment, the mean BMD of lumbar spine, femoral neck and total hip increased by 3.4% (P = .002), 1.8% (P = .21) and 2.6% (P = .02), respectively, in alendronate group. In alfacalcidol-alone group, the mean BMD of lumbar spine, femoral neck and total hip decreased by 6.1%, 3.2% and 3.3%, respectively (all P < .001 vs baseline). CONCLUSIONS: We demonstrated for the first time that treatment with alendronate combined with alfacalcidol significantly increased BMD, decreased bone turnover biomarker levels and reduced the occurrence of hypercalciuria in a large cohort of Chinese patients with MG who initiated treatment with glucocorticoids. However, treatment with alfacalcidol alone failed to prevent bone loss in patients with MG receiving glucocorticoid therapy. PMID- 29266370 TI - Case of warty dyskeratoma on the anterior chest: The relationship between its dermoscopic and histopathological findings. PMID- 29266369 TI - Correlation between the cell population in the automated hematology analyzer high fluorescence region and atypical lymphocyte flags. AB - INTRODUCTION: During routine blood measurements using an automated hematology analyzer, two easily confused types of suspect flags related to lymphocytes often appear: atypical and immature lymphocytes. The aim of this study was to investigate the correlation of high fluorescence cell (HFC) parameter and lymphocyte flags determined from an automated hematology analyzer. METHODS: A total of 93 patients affected by various pathologic conditions (viral infection, immunological disease, oncological disease and tumor) were divided into an "atypical lymphocytes" group ("atypical" for short), an "immature lymphocytes/blasts" flag group (abnormal), a mixed-flag group that includes "atypical lymphocytes" (mixed), and a non-flag group (non-flag). RESULTS: The numbers of HFCs in the atypical, abnormal, mixed, and non-flag groups were 1.8% (0.9%-5.5%), 0.7% (0.1%-5.0%), 2.3% (1.2%-5.0%), and 0.8% (0.7%-1.2%), respectively. The HFCs of "atypical" appeared as a separate cluster with clear boundaries. The HFCs of "abnormal" as an unclear boundaries, and it was difficult to accurately distinguish between the HFCs from the immature lymphocytes and the normal lymphocytes. The lower limit of HFC when the atypical lymphocyte flag appeared was 0.04 * 109 /L. The number of HFCs was similar to atypical lymphocytes detected by microscopy and CD19+ CD20- CD27++ cells by flow cytometry at 78% and 76%, respectively. The number of HFCs detected in "atypical" and CD19+ CD20- CD27++ cells showed good consistency (r = .715), whereas the consistency was poorest for "abnormal" (r = .176). CONCLUSION: It demonstrates that HFCs reflects atypical lymphocytes better than immature lymphocytes/blasts. PMID- 29266371 TI - Viral hepatitis elimination should receive more attention from Iranian nurses. PMID- 29266372 TI - Red blood cell transfusion support and management of secondary iron overload in patients with haematological malignancies in the Netherlands: a survey. AB - BACKGROUND AND OBJECTIVES: Evidence-based guidelines on optimal triggers for red blood cell (RBC) transfusion in patients with haematological malignancies exist, but the evidence is weak. Secondary iron overload is an often overlooked chronic complication of RBC transfusions, and also here, guidelines are either lacking or lack international consensus. Our aim was to evaluate the triggers for RBC transfusion support and management of secondary iron overload among haematologists in the Netherlands. MATERIALS AND METHODS: For this cross sectional study, all haematologists and haematologists in training in the Netherlands were sent a web-based, 25-question survey including three clinical scenarios. The survey distribution took place between 19 November 2015 and 26 January 2016. RESULTS: Seventy-seven responses were received (24%), well distributed among community and university hospitals. A wide variation in haemoglobin triggers existed: 5.6-9.5 g/dl (median: 8.0 g/dl). Personalization of this trigger was mostly based on (estimated) cardiopulmonary compensation capacity of patients. About 65% of respondents reported two RBC units per transfusion episode (range 1-3). For monitoring secondary iron overload, serum ferritin was most frequently measured (97%), while a value of 1000-1500 MUg/l was the most common cut-off to initiate treatment (39%). For 81% of respondents, phlebotomies were the first choice of treatment, although often the haemoglobin level was considered a limiting factor. CONCLUSION: Our results confirm large reported variation in daily practice among haematologists in the Netherlands regarding RBC transfusion support and management of secondary iron overload. Future studies providing better evidence are needed to improve guidelines specific for patients with haematological malignancies. PMID- 29266373 TI - ORP150-CHIP chaperone antagonism control BACE1-mediated amyloid processing. AB - BACE1, a key protein involved in Alzheimer's progression, initiates Abeta42 generation that induce senile plaques in brain. However, the role of chaperone synergy or antagonism on BACE1-mediated amyloid processing is unknown. We have discovered that BACE1 as well as Abeta42 are antagonistically controlled by ER chaperone ORP150 and cellular chaperone CHIP. We have shown ORP150 as a chaperone interacts with and stabilizes BACE1 at post-translational level. Furthermore, ORP150 enhances BACE1-mediated amyloid processing thus masking CHIP-mediated BACE1 degradation. Conversely, siORP150 reversed the chaperone function of ORP150 resulting in BACE1 degradation. ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level. In conclusion, we have uncovered for the first time a phenomenon of chaperone antagonism on BACE1-mediated Abeta42 generation. Future strategy would require both suppression of ORP150 as well as activation of E3 ligase activity of CHIP that might prevent Abeta42 in Alzheimer's disease. PMID- 29266374 TI - Progress of the Healthier You: NHS Diabetes Prevention Programme: referrals, uptake and participant characteristics. AB - AIMS: To describe early progress of the Healthier You: NHS Diabetes Prevention Programme, a behavioural intervention designed to prevent or delay onset of Type 2 diabetes in people in England already identified to be at high risk, to assess numbers of referrals received by Programme providers and the proportion that attended the initial assessment, and to identify the factors associated with attendance rates. METHODS: These analyses examine the data for referrals received between June 2016 and March 2017. RESULTS: There were 43 603 referrals received, 16% higher than expected. Of those referred, 49% attended the initial assessment, higher than the 40% modelled uptake. Of those referred, there was no significant difference in uptake by sex (P=0.061); however, attendance per 100 000 population varied significantly by sex, age group, ethnicity and deprivation; it was significantly lower for men (P<0.001), higher as age increased (P<0.001) and higher for individuals from Asian, Afro-Caribbean, mixed and other ethnic groups compared with individuals from white European groups (P<0.001). There was significant interaction between attendance rates by ethnicity and deprivation (P<0.001) such that attendance rates were significantly higher in the most deprived quintile vs the least deprived quintile for Asian, Afro-Caribbean, mixed and other ethnic groups but not significantly different for white European ethnic groups. CONCLUSION: The analyses show that referral numbers and percentage uptake are in excess of prior modelled values. Characteristics of attendees suggest that the programme is reaching those who are both at greater risk of developing Type 2 diabetes and who typically access healthcare less effectively. PMID- 29266376 TI - Bridging technology and clinical practice: innovating inpatient hyperglycaemia management in non-critical care settings. AB - Emerging evidence shows that suboptimal glycaemic control is associated with increased morbidity and length of stay in hospital. Various guidelines for safe and effective inpatient glycaemic control in the non-critical care setting have been published. In spite of this, implementation in practice remains limited because of the increasing number of people with diabetes admitted to hospital and staff work burden. The use of technology in the outpatient setting has led to improved glycaemic outcomes and quality of life for people with diabetes. There remains an unmet need for technology utilisation in inpatient hyperglycaemia management in the non-critical care setting. Novel technologies have the potential to provide benefits in diabetes care in hospital by improving efficacy, safety and efficiency. Rapid analysis of glucose measurements by point-of-care devices help facilitate clinical decision-making and therapy adjustment in the hospital setting. Glucose treatment data integration with computerized glucose management systems underpins the effective use of decision support systems and may streamline clinical staff workflow. Continuous glucose monitoring and automation of insulin delivery through closed-loop systems may provide a safe and efficacious tool for hospital staff to manage inpatient hyperglycaemia whilst reducing staff workload. This review summarizes the evidence with regard to technological methods to manage inpatient glycaemic control, their limitations and the future outlook, as well as potential strategies by healthcare organizations such as the National Health Service to mediate the adoption, procurement and use of diabetes technologies in the hospital setting. PMID- 29266375 TI - Double diffusion encoding MRI for the clinic. AB - PURPOSE: The purpose of this study is to develop double diffusion encoding (DDE) MRI methods for clinical use. Microscopic diffusion anisotropy measurements from DDE promise greater specificity to changes in tissue microstructure compared with conventional diffusion tensor imaging, but implementation of DDE sequences on whole-body MRI scanners is challenging because of the limited gradient strengths and lengthy acquisition times. METHODS: A custom single-refocused DDE sequence was implemented on a 3T whole-body scanner. The DDE gradient orientation scheme and sequence parameters were optimized based on a Gaussian diffusion assumption. Using an optimized 5-min DDE acquisition, microscopic fractional anisotropy (MUFA) maps were acquired for the first time in multiple sclerosis patients. RESULTS: Based on simulations and in vivo human measurements, six parallel and six orthogonal diffusion gradient pairs were found to be the minimum number of diffusion gradient pairs necessary to produce a rotationally invariant measurement of MUFA. Simulations showed that optimal precision and accuracy of MUFA measurements were obtained using b-values between 1500 and 3000 s/mm2 . The MUFA maps showed improved delineation of multiple sclerosis lesions compared with conventional fractional anisotropy and distinct contrast from T2 -weighted fluid attenuated inversion recovery and T1 -weighted imaging. CONCLUSION: The MUFA maps can be measured using DDE in a clinical setting and may provide new opportunities for characterizing multiple sclerosis lesions and other types of tissue degeneration. Magn Reson Med 80:507-520, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29266377 TI - Pediatric dermatology procedures and pearls: Multimodal revision of earlobe keloids. AB - Keloid scars are benign proliferations of fibrous tissue and collagen that usually occur in response to cutaneous injury. Many treatment modalities have been described in the literature, with variable rates of recurrence and no clear consensus. Keloids remain a therapeutic challenge to patients and physicians alike. Herein we describe a novel technique for treating recurrent earlobe keloids in an outpatient setting with multimodal therapy including shave removal followed immediately by ablative fractional laser resurfacing (AFR) and laser assisted delivery (LAD) of corticosteroids. PMID- 29266378 TI - Litsea cubeba leaf essential oil from Vietnam: chemical diversity and its impacts on antibacterial activity. AB - : The threat of bacterial resistance to antibiotics has created an urgent need to develop new antimicrobials. The aim of this study was to characterize the chemical diversity of Litsea cubeba leaf essential oil (EO) and its impacts on the antibacterial activity against pathogenic bacteria. Essential oils collected from seven provinces in North Vietnam (n = 25) were characterized by their high content in either 1,8-cineole or linalool. Linalool-type EOs were more effective against the eight bacterial strains tested than 1,8-cineole-type. Oil samples, LC19 (50% 1,8-cineole) and BV27 (94% linalool), were selected to investigate their antibacterial mechanisms against Escherichia coli. A strong bactericidal effect was observed after 4 and 2 h of exposure respectively. Microscopic analysis of treated E. coli cultures clearly showed that EOs caused changes in cell morphology, loss of integrity and permeability of the cell membrane, as well as DNA loss. However, the effects of both EOs were distinct. LC19 mostly affected cell membrane, led to a significant cell filamentation rate and altered cell width, whereas BV27 damaged cell membrane integrity leading to cell permeabilization and altered nucleoid morphology with the appearance of spot and visibly altered compaction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study aimed to characterize the chemical diversity of Litsea cubeba leaf essential oil (EO) and its impacts on its antibacterial activity. Two major chemotypes (1,8 cineole or linalool rich) were identified in North Vietnam and both were bactericidal against several pathogenic bacteria. A distinct inhibitory effect of EO samples on Escherichia coli was observed. 1,8-cineole-rich sample (LC19) affected cell membrane, led to cell filamentation and perturbation of cell width, while the linalool-rich one (BV27) induced damages in the cell membrane and changes in the nucleoid morphology. The study demonstrates the importance of considering chemotype variations in terms of chemical composition as well as the mode of action. PMID- 29266379 TI - The importance of mental health considerations for critical care burns patients. PMID- 29266380 TI - The influence of personality traits and socio-demographic characteristics on paediatric nurses' compassion satisfaction and fatigue. AB - AIMS: To explore the level of and the association between, compassion satisfaction and fatigue of paediatric nurses; to determine the association between personality traits and compassion satisfaction and fatigue; to identify the determinants of compassion satisfaction and fatigue. BACKGROUND: Paediatric nurses are prone to experiencing compassion fatigue associated with caring for children with illness and their families, yet its connection with nurses' personality traits remains unknown. DESIGN: A cross-sectional descriptive study design was used. METHODS: The data collection used three instruments measuring socio-demography, responses to the compassion satisfaction and fatigue test and the revised NEO personality inventory. The study used descriptive, correlation and multiple regression analysis for the data collected between April - July 2014. RESULTS: From 173 female paediatric nurses, two-thirds worked in critical care units and indicated a satisfactory level of compassion satisfaction and a low level of compassion fatigue, despite a lack of association between the two concepts. Four determinants-agreeableness, extraversion, conscientiousness and engaging with outdoor activities-were predictive and explained 43.6% of total variance of compassion satisfaction. Two risk factors of compassion fatigue identified were less emotional stability and singlehood (marital status) and these explained 26.1% of total variance of compassion fatigue. CONCLUSION: Support for improving agreeableness and emotional stability in paediatric nurses' workplaces including involvement in the outdoor activities and an increase in social connection may enhance compassion satisfaction and prevent exhaustive compassion fatigue. PMID- 29266381 TI - Bone biopsy protocol for advanced prostate cancer in the era of precision medicine. AB - BACKGROUND: Metastatic biopsies are increasingly being performed in patients with advanced prostate cancer to search for actionable targets and/or to identify emerging resistance mechanisms. Due to a predominance of bone metastases and their sclerotic nature, obtaining sufficient tissue for clinical and genomic studies is challenging. METHODS: Patients with prostate cancer bone metastases were enrolled between February 2013 and March 2017 on an institutional review board-approved protocol for prospective image-guided bone biopsy. Bone biopsies and blood clots were collected fresh. Compact bone was subjected to formalin with a decalcifying agent for diagnosis; bone marrow and blood clots were frozen in optimum cutting temperature formulation for next-generation sequencing. Frozen slides were cut from optimum cutting temperature cryomolds and evaluated for tumor histology and purity. Tissue was macrodissected for DNA and RNA extraction, and whole-exome sequencing and RNA sequencing were performed. RESULTS: Seventy bone biopsies from 64 patients were performed. Diagnostic material confirming prostate cancer was successful in 60 of 70 cases (85.7%). The median DNA/RNA yield was 25.5 ng/MUL and 16.2 ng/MUL, respectively. Whole-exome sequencing was performed successfully in 49 of 60 cases (81.7%), with additional RNA sequencing performed in 20 of 60 cases (33.3%). Recurrent alterations were as expected, including those involving the AR, PTEN, TP53, BRCA2, and SPOP genes. CONCLUSIONS: This prostate cancer bone biopsy protocol ensures a valuable source for high quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. (c) 2017 American Cancer Society. PMID- 29266382 TI - Integration of hepatitis B virus S gene impacts on hepatitis B surface antigen levels in patients with antiviral therapy. AB - BACKGROUND AND AIM: The aim of this study is to investigate the impact of hepatitis B virus (HBV) S gene integration on serum hepatitis B surface antigen (HBsAg) levels in chronic hepatitis B with long-term nucleos(t)ide analogue (NUC) therapy. METHODS: Chronic hepatitis B patients who performed liver biopsy at baseline and treated with long-term NUC therapy were recruited. The integration of HBV S gene in baseline liver biopsy specimen was detected by Alu polymerase chain reaction method. Serum HBsAg levels were measured at baseline and the second year and the fourth year after NUC therapy by Roche reagent, respectively. Serum HBsAg levels between HBV S gene integrated group and nonintegrated group were compared and analyzed. RESULTS: Seventy patients were eligible for this study. Among them, 11 (15.7%) were found to have HBV S gene integration in their baseline liver biopsy specimens. Similar significant decrease of HBsAg levels was found in both integrated and nonintegrated groups (2.63 vs 2.65 log IU/mL, P = 0.478) after the first 2 years of NUC therapy. Thereafter, the decrease of HBsAg level from 2 to 4 years after therapy was largely unchanged in integrated group as compared with that of nonintegrated group (0.1 vs 2.53 log IU/mL, P = 0.002), with statistical difference. CONCLUSIONS: Serum HBsAg could be originated from the expression of the integrated HBV S gene in patients with S gene integration, which implicated the limitations when regarding HBsAg as a surrogate biomarker of covalently closed circular DNA activity and as an indicator of safe NUC discontinuation. PMID- 29266383 TI - Association between extremity kaposiform hemangioendothelioma and lymphedema. AB - Kaposiform hemangioendotheliomas are pediatric vascular tumors that do not metastasize. We present a patient with a thigh kaposiform hemangioendothelioma successfully treated using a systemic corticosteroid during infancy who was diagnosed with lymphedema in the extremity 9 years later. The observation that extremity kaposiform hemangioendothelioma could possibly be associated with lymphedema has implications for the care of patients with kaposiform hemangioendothelioma. PMID- 29266384 TI - Bethesda thyroid categories and family history of thyroid disease. AB - OBJECTIVE: Thyroid cancer is the most common type of endocrine-related cancer worldwide. The aim of this article was to assess the relationship between thyroid diseases diagnosed by fine needle aspiration (FNA) and family history of thyroid disease. DESIGN: The study was conducted in a tertiary high-volume thyroid cancer centre. Fine needle aspiration (FNA) of a thyroid nodule detected on neck ultrasound for any reason was performed in all included patients. PATIENTS: A total of 10 709 patients were included in the study. MEASUREMENTS: Correlation of cytological findings classified according to the Bethesda system and family history was calculated using Fisher's exact test. RESULTS: There were 2580 (24.09%) patients with non-malignant thyroid diseases in the family and 198 (1.85%) patients who had a history of thyroid cancer in the family. A total of 2778 (25.94%) patients had positive family history of thyroid diseases, and 7931 (74.06%) patients had negative family history. In patients with papillary thyroid carcinoma in family history, the difference between those with benign (Bethesda 2) and malignant thyroid FNA diagnosis (Bethesda 6) was found to be statistically significant (P = .0432). CONCLUSIONS: Family history plays a significant role in the development of thyroid cancer, and having first-degree relatives with not only medullary, but also papillary thyroid cancer strongly predicts the risk of developing the malignant thyroid disease. In contrast, benign thyroid disorders in family history do not lead to the development of thyroid cancer. PMID- 29266385 TI - In vitro investigations of propulsion during laser lithotripsy using video tracking. AB - OBJECTIVES: Ureteroscopic laser lithotripsy is an important and widely used method for destroying ureter stones. It represents an alternative to ultrasonic and pneumatic lithotripsy techniques. Although these techniques have been thoroughly investigated, the influence of some physical parameters that may be relevant to further improve the treatment results is not fully understood. One crucial topic is the propulsive stone movement induced by the applied laser pulses. To simplify and speed up the optimization of laser parameters in this regard, a video tracking method was developed in connection with a vertical column setup that allows recording and subsequently analyzing the propulsive stone movement in dependence of different laser parameters in a particularly convenient and fast manner. MATERIALS AND METHODS: Pulsed laser light was applied from below to a cubic BegoStone phantom loosely guided within a vertical column setup. The video tracking method uses an algorithm to determine the vertical stone position in each frame of the recorded scene. The time-dependence of the vertical stone position is characterized by an irregular series of peaks. By analyzing the slopes of the peaks in this signal it was possible to determine the mean upward stone velocity for a whole pulse train and to compare it for different laser settings. For a proof of principle of the video tracking method, a specific pulse energy setting (1 J/pulse) was used in combination with three different pulse durations: short pulse (0.3 ms), medium pulse (0.6 ms), and long pulse (1.0 ms). The three pulse durations were compared in terms of their influence on the propulsive stone movement in terms of upward velocity. Furthermore, the propulsions induced by two different pulse energy settings (0.8 J/pulse and 1.2 J/pulse) for a fixed pulse duration (0.3 ms) were compared. A pulse repetition rate of 10 Hz was chosen for all experiments, and for each laser setting, the experiment was repeated on 15 different freshly prepared stones. The latter set of experiments was compared with the results of previous propulsion measurements performed with a pendulum setup. RESULTS: For a fixed pulse energy (1 J/pulse), the mean upward propulsion velocity increased (from 120.0 to 154.9 mm . s-1 ) with decreasing pulse duration. For fixed pulse duration (0.3 ms), the mean upward propulsion velocity increased (from 91.9 to 123.3 mm . s-1 ) with increasing pulse energy (0.8 J/pulse and 1.2 J/pulse). The latter result corresponds roughly to the one obtained with the pendulum setup (increase from 61 to 105 mm . s-1 ). While the mean propulsion velocities for the two different pulse energies were found to differ significantly (P < 0.001) for the two experimental and analysis methods, the standard deviations of the measured mean propulsion velocities were considerably smaller in case of the vertical column method with video tracking (12% and 15% for n = 15 freshly prepared stones) than in case of the pendulum method (26% and 41% for n = 50 freshly prepared stones), in spite of the considerably smaller number of experiment repetitions ("sample size") in the first case. CONCLUSION: The proposed vertical column method with video tracking appears advantageous compared to the pendulum method in terms of the statistical significance of the obtained results. This may partly be understood by the fact that the entire motion of the stones contributes to the data analysis, rather than just their maximum distance from the initial position. The key difference is, however, that the pendulum method involves only one single laser pulse in each experiment run, which renders this method rather tedious to perform. Furthermore, the video tracking method appears much better suited to model a clinical lithotripsy intervention that utilizes longer series of laser pulses at higher repetition rates. The proposed video tracking method can conveniently and quickly deliver results for a large number of laser pulses that can easily be averaged. An optimization of laser settings to achieve minimal propulsive stone movement should thus be more easily feasible with the video tracking method in connection with the vertical column setup. Lasers Surg. Med. 50:333-339, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266386 TI - Extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma: The first case report and consideration of histogenesis. AB - A 61-year-old man presented with a dome-shaped nodule, 1.2 cm in size, with a central crater covered by keratinous material near the left lateral malleolus. Histological findings demonstrated a basophilic circular cone in the center, surrounded and sharply demarcated by a broad eosinophilic area. The central conical mass was composed mainly of atypical basaloid cells intermingled with scattered atypical sebaceous cells with scalloped nuclei and microvesicular cytoplasms, suggesting sebaceous carcinoma. The peripheral area consisted of atypical keratinizing squamoid cells without sebaceous cells, suggesting invasive squamous cell carcinoma. Atypical sebaceous cells were positive for adipophilin. Atypical basaloid cells were positive for 34betaE12 and CAM5.2. Peripheral squamoid cells were positive for 34betaB4 and 34betaE12 throughout, and were positive for LHP1 in the superficial layer. We herein describe the first case of extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma, which might have arisen from biphasic differentiation of cancer stem cells. PMID- 29266387 TI - Safety and efficacy of parenteral iron in children with inflammatory bowel disease. AB - AIMS: Iron deficiency anaemia frequently complicates inflammatory bowel disease (IBD) in children and adults. Oral iron may exacerbate gastrointestinal symptoms and absorption may be insufficient in intestinal inflammation. Even where oral iron is successful, repletion of iron stores can be unacceptably slow. Intravenous iron compounds were in the past associated with serious adverse reactions and historically were considered a last resort in children. New generation preparations have a safer profile in adults, although reluctance to use them in children may persist, where safety data are lacking. We investigate the safety and efficacy of ferric carboxymaltose and iron sucrose in children. METHODS: We retrospectively identified all children with IBD who received parenteral iron over a 38-month period in a single regional referral centre. Safety, tolerability and adverse events were established by case note review. Efficacy was assessed by change in haematinic indices pre- and post-treatment. RESULTS: Forty-one children (18 male; median age 14 years, range 3-17) received a total of 104 iron infusions. Of these, 44% (18) had Crohn's disease; 56% (23) ulcerative colitis. Thirty-five received ferric carboxymaltose, seven iron sucrose and one both. Three children developed mild rash post infusion which resolved quickly with chlorphenamine. Mean increase in haemoglobin was 2.5 g dl-1 (0.3-5.8). Iron levels increased by a mean of 8.4 g dl-1 (1-25), transferrin saturation by 16.2% (2-47). Transferrin decreased by 0.84 g dl-1 (0.3-3.4). CONCLUSIONS: New generation parenteral iron preparations are safe, well tolerated and efficacious in children with iron deficiency anaemia and IBD. PMID- 29266388 TI - Localized, ovoid urticarial plaques with fine, nonfollicular pustules. PMID- 29266389 TI - Reply to Evaluation of magnetic resonance imaging and targeted biopsy: The difficulty of finding the right reference standard. PMID- 29266390 TI - Quantifying progress toward a conservation assessment for all plants. AB - The Global Strategy for Plant Conservation (GSPC) set an ambitious target to achieve a conservation assessment for all known plant species by 2020. We consolidated digitally available plant conservation assessments and reconciled their scientific names and assessment status to predefined standards to provide a quantitative measure of progress toward this target. The 241,919 plant conservation assessments generated represent 111,824 accepted land plant species (vascular plants and bryophytes, not algae). At least 73,081 and up to 90,321 species have been assessed at the global scale, representing 21-26% of known plant species. Of these plant species, at least 27,148 and up to 32,542 are threatened. Eighty plant families, including some of the largest, such as Asteraceae, Orchidaceae, and Rubiaceae, are underassessed and should be the focus of assessment effort if the GSPC target is to be met by 2020. Our data set is accessible online (ThreatSearch) and is a baseline that can be used to directly support other GSPC targets and plant conservation action. Although around one quarter of a million plant assessments have been compiled, the majority of plants are still unassessed. The challenge now is to build on this progress and redouble efforts to document conservation status of unassessed plants to better inform conservation decisions and conserve the most threatened species. PMID- 29266391 TI - Multicountry cross-sectional study found that functional gastrointestinal disorders such as colic and functional dyschezia were common in South American infants. AB - AIM: Our aim was to perform a population-based study using Rome III criteria to describe the prevalence of functional gastrointestinal disorders (FGIDs) in infants in three countries in South America. METHODS: We conducted a multicountry, cross-sectional study to investigate the epidemiology of functional gastrointestinal disorders in children aged 0-12 months of age, using the Rome III criteria, in Colombia, Panama and Nicaragua. These patients presented for well-child visits in primary care clinics in the three countries between May 2015 and October 2016. A Spanish version of the Questionnaire on Paediatric Gastrointestinal Symptoms for Infants and Toddlers was used for the data collection. RESULTS: We included questionnaires completed by 351 parents, and they reported at least one FGID in 141 (40%) infants. The majority were male (56%), with a median age of seven months. Colic and functional dyschezia were the most commonly diagnosed disorders in the whole cohort, at 23% and 15%, respectively. The risk of developing FGIDs was not affected by the marital status of the mother, number of siblings, birth order and history of diarrhoea. CONCLUSION: Functional gastrointestinal disorders were common in infants from the South American countries of Colombia, Panama and Nicaragua, particularly colic and functional dyschezia. PMID- 29266393 TI - Simultaneous multi-slice combined with PROPELLER. AB - PURPOSE: Simultaneous multi-slice (SMS) imaging is an advantageous method for accelerating MRI scans, allowing reduced scan time, increased slice coverage, or high temporal resolution with limited image quality penalties. In this work we combine the advantages of SMS acceleration with the motion correction and artifact reduction capabilities of the PROPELLER technique. METHODS: A PROPELLER sequence was developed with support for CAIPIRINHA and phase optimized multiband radio frequency pulses. To minimize the time spent on acquiring calibration data, both in-plane-generalized autocalibrating partial parallel acquisition (GRAPPA) and slice-GRAPPA weights for all PROPELLER blade angles were calibrated on a single fully sampled PROPELLER blade volume. Therefore, the proposed acquisition included a single fully sampled blade volume, with the remaining blades accelerated in both the phase and slice encoding directions without additional auto calibrating signal lines. Comparison to 3D RARE was performed as well as demonstration of 3D motion correction performance on the SMS PROPELLER data. RESULTS: We show that PROPELLER acquisitions can be efficiently accelerated with SMS using a short embedded calibration. The potential in combining these two techniques was demonstrated with a high quality 1.0 * 1.0 * 1.0 mm3 resolution T2 -weighted volume, free from banding artifacts, and capable of 3D retrospective motion correction, with higher effective resolution compared to 3D RARE. CONCLUSION: With the combination of SMS acceleration and PROPELLER imaging, thin sliced reformattable T2 -weighted image volumes with 3D retrospective motion correction capabilities can be rapidly acquired with low sensitivity to flow and head motion. Magn Reson Med 80:496-506, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29266392 TI - Short pulse width in subthalamic stimulation in Parkinson's disease: a randomized, double-blind study. AB - BACKGROUND: We investigated the acute effect of short pulse widths on the therapeutic window in subthalamic nucleus deep brain stimulation in Parkinson's disease. METHODS: We assessed 10 PD patients with STN-DBS at a 60-us pulse width. We randomly and double-blindedly applied 10- to 50-us pulse widths. The principal outcome was the therapeutic window (difference between the amplitude thresholds for visible muscle contraction and for best rigidity control). The secondary outcome was the charge per pulse (which reflects the efficiency of the stimulation) needed to control rigidity. Two-way analysis of variance and pairwise t tests were applied. RESULTS: The therapeutic window widened when the pulse width shortened (r = -0.45; P < 0.001), and charge per pulse was reduced (P < 0.05). CONCLUSIONS: This randomized, double-blind study showed that shorter pulse widths widen the therapeutic window of STN-DBS in PD without increasing the electrical charge required to obtain the same acute clinical benefit. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29266394 TI - Staging for hepatocellular carcinoma in light of tumor heterogeneity: Time to change or update? PMID- 29266396 TI - When I say ... anthropological gaze. PMID- 29266395 TI - Arsenic trioxide at conventional dosage does not aggravate hemorrhage in the first-line treatment of adult acute promyelocytic leukemia. AB - OBJECTIVES: The arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first-line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated. METHODS: Effects of ATO on platelet aggregation and adhesion were evaluated in vitro and in thirty-two complete remission (CR) and four newly diagnosed APL patients. Furthermore, concentrations of plasma total arsenic were monitored in APL patients via ICP-MS. RESULTS: The inhibition of platelet function, either aggregation or adhesion, did occur in vitro when the concentration of ATO reached 2 MUmol/L. However, in CR APL patients receiving ATO with normal platelet count, the platelets responded normally when being activated and so did those in the newly diagnosed patients with thrombocytopenia. Our data further showed that the conventional dosage of ATO reached a plasma concentration substantially below the required concentration to inhibit platelets. CONCLUSIONS: In the first-line treatment of APL, the use of ATO is safe and effective and does not compromise the hemostatic potential that may eventually increase ED rate. PMID- 29266397 TI - Summary of the 10th International Conference on Human Herpesviruses-6 and -7 (HHV 6A, -6B, and HHV-7). AB - The 10th International Conference on Human herpesviruses-6 and -7 (HHV-6A, HHV 6B, and HHV-7) was held at the Freie Universitat, Berlin, Germany from July 23 26, 2017. It attracted more than 130 basic, translational and clinical scientists from 19 countries. Important new information was presented regarding: the biology of HHV-6A and -6B; the biology and epidemiology of inherited chromosomally integrated HHV-6A and -6B; improved diagnostic tests; animal models for and animal viruses with similarities to HHV-6A, -6B, and -7; established and possible disease associations; and new treatment strategies. Here, we summarize work presented at the meeting that is of particular interest. PMID- 29266398 TI - Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas kidney patients. AB - INTRODUCTION: We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf). METHODS: In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work. RESULTS: Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study. CONCLUSIONS: It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients. PMID- 29266399 TI - Hypoxia-inducible factor 2alpha drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine-rich glycoprotein. AB - : Mechanisms underlying progression of nonalcoholic fatty liver disease (NAFLD) are still incompletely characterized. Hypoxia and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of chronic liver diseases, but the actual role of HIF-2alpha in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF-2alpha is selectively overexpressed in the cytosol and the nuclei of hepatocytes in a very high percentage (>90%) of liver biopsies from a cohort of NAFLD patients at different stages of the disease evolution. Similar features were also observed in mice with steatohepatitis induced by feeding a methionine/choline-deficient diet. Experiments performed in mice carrying hepatocyte-specific deletion of HIF-2alpha and related control littermates fed either a choline-deficient L-amino acid defined or a methionine/choline-deficient diet showed that HIF-2alpha deletion ameliorated the evolution of NAFLD by decreasing parenchymal injury, fatty liver, lobular inflammation, and the development of liver fibrosis. The improvement in NAFLD progression in HIF-2alpha-deficient mice was related to a selective down regulation in the hepatocyte production of histidine-rich glycoprotein (HRGP), recently proposed to sustain macrophage M1 polarization. In vitro experiments confirmed that the up-regulation of hepatocyte HRGP expression was hypoxia dependent and HIF-2alpha-dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF-2alpha and revealed a significant positive correlation between HIF-2alpha and HRGP liver transcript levels in these patients. CONCLUSIONS: These results indicate that hepatocyte HIF-2alpha activation is a key feature in both human and experimental NAFLD and significantly contributes to the disease progression through the up-regulation of HRGP production. (Hepatology 2018;67:2196-2214). PMID- 29266400 TI - The effect of establishing pre-angiography thresholds on contrast utilization. AB - INTRODUCTION: Contrast induced nephropathy is linked to contrast utilization and strategies for minimizing renal injury are incorporated into many laboratories that perform coronary angiography. Contrast limits have been described, below which there is minimal incremental increase in the risk of renal injury. Whether a priori acknowledgement of these limits as part of a contrast "Time-Out" reduces contrast utilization has not been established. In this study, we investigate the effect of verbalizing pre-angiography and 1/2 time contrast thresholds on contrast utilization and associated clinical outcomes. METHODS: We retrospectively reviewed 5265 cases of coronary angiography (984 with contrast thresholds defined pre-procedure compared to 4281 without pre-defined contrast thresholds). There were two primary endpoints: (1) proportion of procedures that utilized an amount of contrast <= threshold, and (2) median difference between amount of contrast utilized and the contrast threshold. Secondary outcomes incorporated indices of renal function, and included changes in serum creatinine levels, eGFR, and CKD stage. RESULTS: Compared to pre-"Time-Out" group, the post "Time-Out" group had a higher proportion of procedures with contrast <= stated contrast threshold (88% vs 84%, P < 0.002), and a lower amount of total contrast volume (88 mL [IQR 60-136] versus 78 mL [IQR 53-119]). The post-"Time-Out" group also had a lower incidence of any increase in post-procedure serum creatinine (45% vs 36%; P = 0.04), and a larger median decrease of pre- to post-procedure eGFR (P = 0.04). CONCLUSION: Acknowledgement of contrast threshold as part of a contrast "Time-Out" is associated with reduced overall contrast utilization, and likely minimizes risks of contrast-induced nephropathy. PMID- 29266401 TI - Resolving the false-negative issues of the nonpolar organic amendment in whole sediment toxicity identification evaluations. AB - Three common false-negative scenarios have been encountered with amendment addition in whole-sediment toxicity identification evaluations (TIEs): dilution of toxicity by amendment addition (i.e., not toxic enough), not enough amendment present to reduce toxicity (i.e., too toxic), and the amendment itself elicits a toxic response (i.e., secondary amendment effect). One such amendment in which all 3 types of false-negatives have been observed is with the nonpolar organic amendment (activated carbon or powdered coconut charcoal). The objective of the present study was to reduce the likelihood of encountering false-negatives with this amendment and to increase the value of the whole-sediment TIE bioassay. To do this, the present study evaluated the effects of various activated carbon additions to survival, growth, emergence, and mean development rate of Chironomus tepperi. Using this information, an alternative method for this amendment was developed which utilized a combination of multiple amendment addition ratios based on wet weight (1%, lower likelihood of the secondary amendment effect; 5%, higher reduction of contaminant) and nonconventional endpoints (emergence, mean development rate). This alternative method was then validated in the laboratory (using spiked sediments) and with contaminated field sediments. Using these multiple activated carbon ratios in combination with additional endpoints (namely, emergence) reduced the likelihood of all 3 types of false-negatives and provided a more sensitive evaluation of risk. Environ Toxicol Chem 2018;37:1219 1230. (c) 2017 SETAC. PMID- 29266402 TI - Usefulness of multiple chalk-based food colorings for inducing better gene silencing by feeding RNA interference in planarians. AB - Planarians have become widely recognized as one of the major animal models for regeneration studies in invertebrates. To induce RNA interference (RNAi) by feeding in planarians, the widely accepted protocol is one in which animals undergo two or three feedings of food containing double-stranded RNA (dsRNA) plus visible food coloring (e.g., blood) for confirmation of feeding by individual animals. However, one possible problem is that incorporated food coloring is often retained within the gut for several days, which makes it difficult to confirm the success of each round of dsRNA feeding based on the difference of the color density within the gut before and after feeding. As a consequence, the difference of appetite levels among individuals undergoing dsRNA feeding leads to phenotypic variability among them due to insufficient knockdown. In our attempts to overcome this problem, we have developed a novel method for achieving robust confirmation of the success of dsRNA feeding in individuals fed multiple times by means of including a combination of three different colored chalks (pink, yellow and blue) as food coloring. Notably, we found that this method is superior to the conventional method for positively marking individuals that actively consumed the dsRNA-containing food during four times of once-daily feeding. Using these selected animals, we obtained stable and sufficiently strong RNAi-induced phenotypes. We termed this improved multi-colored chalk-spiked method of feeding RNAi "Candi" and propose its benefits for gene function analysis in planarians. PMID- 29266403 TI - New twist defines a spectrum of TOR1A neurological disease. PMID- 29266404 TI - Effect of connective tissue growth factor delivered via porous sutures on the proliferative stage of intrasynovial tendon repair. AB - Recent growth factor, cell, and scaffold-based experimental interventions for intrasynovial flexor tendon repair have demonstrated therapeutic potential in rodent models. However, these approaches have not achieved consistent functional improvements in large animal trials due to deleterious inflammatory reactions to delivery materials and insufficient induction of targeted biological healing responses. In this study, we achieved porous suture-based sustained delivery of connective tissue growth factor (CTGF) into flexor tendons in a clinically relevant canine model. Repairs with CTGF-laden sutures were mechanically competent and did not show any evidence of adhesions or other negative inflammatory reactions based on histology, gene expression, or proteomics analyses at 14 days following repair. CTGF-laden sutures induced local cellular infiltration and a significant biological response immediately adjacent to the suture, including histological signs of angiogenesis and collagen deposition. There were no evident widespread biological effects throughout the tendon substance. There were significant differences in gene expression of the macrophage marker CD163 and anti-apoptotic factor BCL2L1; however, these differences were not corroborated by proteomics analysis. In summary, this study provided encouraging evidence of sustained delivery of biologically active CTGF from porous sutures without signs of a negative inflammatory reaction. With the development of a safe and effective method for generating a positive local biological response, future studies can explore additional methods for enhancing intrasynovial tendon repair. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2052-2063, 2018. PMID- 29266405 TI - Constitutive downregulation protein kinase C epsilon in hSOD1G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake. AB - Accumulating evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a non-cell-autonomous process and that impaired glutamate clearance by astrocytes, leading to excitotoxicity, could participate in progression of the disease. In astrocytes derived from an animal model of ALS (hSOD1G93A rats), activation of type 5 metabotropic glutamate receptor (mGluR5) fails to increase glutamate uptake, impeding a putative dynamic neuroprotective mechanism involving astrocytes. Using astrocyte cultures from hSOD1G93A rats, we have demonstrated that the typical Ca2+ oscillations associated with mGluR5 activation were reduced, and that the majority of cells responded with a sustained elevation of intracellular Ca2+ concentration. Since the expression of protein kinase C epsilon isoform (PKCE) has been found to be considerably reduced in astrocytes from hSOD1G93A rats, the consequences of manipulating its activity and expression on mGluR5 signaling and on the regulation of glutamate uptake have been examined. Increasing PKCE expression was found to restore Ca2+ oscillations induced by mGluR5 activation in hSOD1G93A -expressing astrocytes. This was also associated with an increase in glutamate uptake capacity in response to mGluR5 activation. Conversely, reducing PKCE expression in astrocytes from wild-type animals with specific PKCE-shRNAs was found to alter the mGluR5 associated oscillatory signaling profile, and consistently reduced the regulation of the glutamate uptake-mediated by mGluR5 activation. These results suggest that PKCE is required to generate Ca2+ oscillations following mGluR5 activation, which support the regulation of astrocytic glutamate uptake. Reduced expression of astrocytic PKCE could impair this neuroprotective process and participate in the progression of ALS. PMID- 29266406 TI - Outcome and complications of adjustable continence therapy (ProACTTM) after radical prostatectomy: 10 years' experience in 143 patients. AB - AIMS: To evaluate our outcomes of the adjustable continence balloons ProACTTM for the treatment of male stress urinary incontinence after radical prostatectomy. METHODS: Between May 2007-August 2016 the ProACTTM was implanted in 143 patients without a history of radiotherapy. Endpoints were patient-reported changes in pad counts and complications. Treatment was considered successful if no pad or just one "security" pad per day sufficed, and improved if daily pad use was reduced by >=50%. RESULTS: Incontinence before implantation was mild in 36 (25%), moderate in 57 (40%), and severe in 50 (35%) patients. Complications within 30 days were classified by the Clavien-Dindo classification; eight (5.6%) grade I, three (2.1%) grade II, three (2.1%) grade IIIb, and 129 (90.2%) patients had no complication. Revision was done in 43 (30%) patients. The IPSS quality of life item improved significantly from 5.0 (IQR 4.0-5.0) preoperative to 2.0 (IQR 1.0 4.0) and 1.0 (IQR 0.0-3.0) 6 and 12 months after implantation, respectively. After a median follow up of 56 months (range 28 to 79, n = 112), 72 (64%) patients were improved, including 51 (45%) patients were successful. Daily pad use decreased from 3.0 to 1.0 (67% reduction). The median outcome on the Patient Global Impression of Improvement scale was "much better," and 97 (87%) patients perceived improvement. CONCLUSIONS: The minimally invasive ProACTTM device showed a clear beneficial continence outcome in patients with stress urinary incontinence after radical prostatectomy. The majority of the patients were satisfied and perceived improvement >=50% on daily pad use on the long term. PMID- 29266407 TI - The effect of extreme weather events on hair cortisol and body weight in a wild ring-tailed lemur population (Lemur catta) in southwestern Madagascar. AB - Madagascar is known for its hypervariable climate with periodic droughts and cyclones, but little is known of the impact of such events on lemur physiology. We examined the effects of sequential weather periods, drought, normal, cyclone and post-cyclone, on hair cortisol concentrations (HCC) and body weight in wild ring-tailed lemurs, Lemur catta (n = 185), at the Beza Mahafaly Special Reserve in southwestern Madagascar. Data were modeled and analyzed by sex, age, and troop. Given the ecological consequences of extreme climatic perturbations, we hypothesized that drought and cyclone would significantly impact lemur HCC. Among adults, drought was associated with higher HCC than other periods and the lowest HCC was associated with the post-cyclone period. Adult females had greater variation in HCC during drought and males had greater variation during cyclone and Post-cyclone periods, suggesting sexes were differentially affected in terms of how individuals responded to extreme weather events. Low HCC in the post cyclone period followed a 12-month period of reduced availability of primary and fallback food resources. Based on the known extreme and chronic nutritional stress during this time, our results indicate hypocortisolism in the animals included in our analysis. Higher HCC in sub-adults during the cyclone also suggests that immature lemurs may experience extreme weather events differently than adults. Body weight, used as a gauge for environmental stress, was lowest during the post-cyclone for sub-adults, young adults, and adults. Body weight did not differ by sex among adults across any of the weather events. Overall, ring tailed lemur's HCC appear to be more immediately impacted by drought, or stressors associated with that specific weather event, and influenced by the long term impact of cyclones on resource availability evidenced by data from the post cyclone period. PMID- 29266409 TI - Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is a pathological condition that involves diffuse lung injury and severe hypoxemia caused by pulmonary and systemic diseases. We have established a mouse model of severe ARDS, developed by intratracheal injection of alpha-galactosylceramide (alpha-GalCer), an activator of natural killer T (NKT) cells, followed by LPS. In the present study, we used this model to investigate the regulatory mechanism in the early inflammatory response during acute lung injury. In alpha-GalCer/LPS-treated mice, the number of CD4+ CD25+ Foxp3+ regulatory T (Treg) cells and the expression of a Treg cell tropic chemokine, secondary lymphoid-tissue chemokine (SLC), in the lungs was significantly lower than in mice treated with LPS alone. Giving recombinant (r)SLC increased the number of Treg cells in alpha-GalCer/LPS-treated mice. Treatment with anti-IFN-gamma mAb enhanced the expression of SLC and the accumulation of Treg cells in the lungs of alpha-GalCer/LPS-treated mice, whereas giving recombinant (r)IFN-gamma reduced the number of Treg cells in mice treated with LPS alone. IL-10 production was significantly lower in alpha-GalCer/LPS treated mice than in mice treated with LPS alone. Giving rIL-10 prolonged survival and attenuated lung injury as a result of reduced production of inflammatory cytokines (such as IL-1beta, IL-6, TNF-alpha, and IFN-gamma) and chemokines (including MCP-1, RANTES, IP-10, Mig, MIP-2, and KC) in alpha GalCer/LPS-treated mice. Treatment with anti-IFN-gamma mAb enhanced IL-10 production in alpha-GalCer/LPS-treated mice. These results suggest that the attenuated accumulation of Treg cells may be involved in the development of severe ARDS through a reduction in the synthesis of IL-10. PMID- 29266410 TI - Basal and stress-induced salivary testosterone variation across the menstrual cycle and linkage to motivation and muscle power. AB - This study investigated salivary testosterone (sal-T) variation across the menstrual cycle in female athletes, at different competitive levels, and its association with motivation and neuromuscular power. Six elite and 16 non-elite female athletes were monitored on days 7 (D7), 14 (D14), and 21 (D21) across 3 menstrual cycles for basal sal-T concentrations and self-appraised motivation to train and compete. Two further measures were taken on D7, D14, and D21 across 2 menstrual cycles: (1) the sal-T response (delta change) to a physical stress test and (2) peak power (PP) response to a 6-second cycle sprint following a post activation potentiation (PAP) stimulus. Basal sal-T concentrations increased by 17 +/- 27% from D7 to D14 before decreasing by -25 +/- 43% on D21 (P < .05), but this result was biased by elite females with higher sal-T (>102%) who showed larger menstrual changes. Motivation, sal-T reactivity to stress, and the PP responses to a PAP stimulus also varied by testing day (P < .05), in parallel with basal sal-T and in favor of the elite group. Furthermore, stronger within subject relationships (P < .001) between basal sal-T and motivation emerged in the elites (r = .70-.75) vs the non-elite group (r = .41-.50). In conclusion, menstrual cycle changes in sal-T were more obvious in high-performing female athletes with higher sal-T concentrations. This was accompanied by greater training motivation, a more pronounced sal-T response to a physical stressor and greater neuromuscular power in the elite group. These results support observations that female athletes with higher T are more represented at elite levels of performance. PMID- 29266412 TI - Novel Parkinson's disease risk loci identified through a meta-analysis of genome wide association studies. PMID- 29266411 TI - Outcomes after drug-coated balloon treatment for patients with calcified coronary lesions. AB - OBJECTIVES: To investigate the efficacy of drug-coated balloon (DCB) for calcified coronary lesions. BACKGROUND: Calcified coronary lesions is associated with poor clinical outcomes after revascularization. Recently, DCB is emerging as an alternative strategy for de novo coronary lesions. However, reports describing the efficacy of DCB for calcified coronary lesions are limited. METHODS: A total of 81 patients (96 lesions) who electively underwent DCB treatment for de novo coronary lesions were enrolled: 46 patients (55 lesions) in the calcified group and 35 patients (41 lesions) in the non-calcified group. Angiographic follow-up data and clinical outcomes after the procedure were evaluated. RESULTS: The diameter of the DCB used was 2.5 +/- 0.5 mm. No bail-out stenting was observed after DCB treatment. Rotational atherectomy was used in 82% of lesions in the calcified group. Follow-up angiography (median, 6.5 months after intervention) was performed for 59 patients (30 in the calcified group and 29 in the non calcified group). Late lumen loss and rates of restenosis were comparable between the groups (0.03 mm in the calcified group vs -0.18 mm in the non-calcified group, P = 0.093 and 13.9% vs 3.03%, P = 0.095, respectively). The survival rates for target lesion revascularization free survival and major adverse cardiac events at 2 years were comparable between the groups (85.3% vs 93.4%, P = 0.64 and 81.4% vs 88.5%, P = 0.57, respectively). CONCLUSION: Calcified coronary lesions might dilute the effect of DCB. However, clinical outcomes in the calcified group were similar to those in the non-calcified group. PMID- 29266408 TI - PPARgamma activation mitigates glucocorticoid receptor-induced excessive lipolysis in adipocytes via homeostatic crosstalk. AB - Proper balance between lipolysis and lipogenesis in adipocytes determines the release of free fatty acids (FFA) and glycerol, which is crucial for whole body lipid homeostasis. Although, dysregulation of lipid homeostasis contributes to various metabolic complications such as insulin resistance, the regulatory mechanism remains elusive. This study clarified the individual and combined roles for glucocorticoid receptor (GCR) and peroxisome proliferator-activated receptor (PPAR)gamma pathways in lipid metabolism of adipocytes. In mature 3T3-L1 adipocytes, GCR activation using dexamethasone upregulated adipose triglyceride lipase (ATGL) and downregulated phosphoenolpyruvate carboxykinase (PEPCK), resulting in enhanced glycerol release into the medium. In contrast, PPARgamma ligand pioglitazone modestly upregulated ATGL and hormone sensitive lipase (HSL), but markedly enhanced PEPCK and glycerol kinase (GK), thereby suppressed glycerol release. Dexamethasone showed permissive like effect on PPARgamma target genes including perilipin A and aP2, therefore co-administration of dexamethasone and pioglitazone demonstrated synergistic upregulation of these enzymes excepting PEPCK, of which downregulation by dexamethasone was abolished by pioglitazone to the level above control. Thus, the excessive glycerol release was prevented as the net outcome of the co-administration. Consistently, the bodipy stain demonstrated that dexamethasone reduced the amount of cytosolic lipid, which was preserved in co-treated adipocytes. Moreover, silencing of PPARgamma suppressed the synergistic effects of co-treatment on the lipolytic and lipogenic genes, and therefore the GCR pathway indeed involves PPARgamma. In conclusion, crosstalk between GCR and PPARgamma is largely synergistic but counter-regulatory in lipogenic genes, of which enhancement prevents excessive glycerol and possibly FFA release by glucocorticoids into the circulation. PMID- 29266413 TI - Heterogeneous expression and biological function of SOX18 in osteosaroma. AB - Osteosaroma (OS) is a primary bone malignancy and is associated with high morbidity. Sex determining region Y-box 18 (SOX18) is identified overexpressed in OS. However, the molecular mechanism underlying the biological function of SOX18 in OS is still unclear. The aim of the current study was to determine the SOX18 expression in patients with OS and its effect on tumor cell malignant phenotypes. Our results showed that SOX18 was overexpressed in OS patients from both E-MEXP 3628 database and independent samples from our hospital and in OS cell lines. SOX18 silencing significantly induced G0-G1 phase cell cycle arrest and apoptosis and inhibited U-2OS cell migration and invasion and cell growth both in vitro and in vivo. However, SOX18 overexpression remarkably promoted 143B cell proliferation, migration and invasion and inhibited cell cycle arrest and apoptosis. The protein expression levels of p53, p21, Bax, Bcl-2, and Caspase-3 were also regulated by SOX18. Moreover, SOX18 was found negative correlated with the expression of HERC1, HER2, HERC3, HERC4, HERC5, and HERC6 in OS patients and in OS cells, with the most significant correlation detected in HERC2 expression, which was following found interacted with SOX18 in OS cells. Taken together, our results suggest that SOX18 is overexpressed in OS and plays an important role in proliferation, apoptosis, migration and invasion of OS cells, and may provide a novel and promising thera-peutic strategy for OS. PMID- 29266414 TI - Clinical and biological characterization of MPN patients harboring two driver mutations, a French intergroup of myeloproliferative neoplasms (FIM) study. PMID- 29266415 TI - Antioxidant supplementation, effect on post-thaw spermatozoan function in three sturgeon species. AB - High levels of reactive oxygen species (ROS), which may be associated with reduced sperm quality, can be detected during cryopreservation of sperm of some species. Our objective was to investigate whether the addition of antioxidants to cryopreservation extenders influenced post-thaw sperm characteristics and fertility in Acipenser dabryanus, Acipenser sinensis and Acipenser baerii. Prior to freezing, sperm samples were diluted with a base extender as control or in extender supplemented with catalase (CAT), glutathione (GSH), cysteine (NAC), ascorbic acid (VC) or their paired combinations. Protective concentrations of CAT, GSH and VC in the three species were 25 U/ml, 0.25-0.5 mg/ml and 0.5 mg/ml, respectively. Cysteine showed no protective effect against ROS. The addition of CAT, GSH and VC positively affected either acrosome or membrane integrity of post thawed sperm in the three species, as well as spermatozoan motility in A. sinensis. The combination of antioxidants did not show a positive synergistic effect. This study suggested that the use of antioxidants in the cryopreservation of sturgeon sperm has potential to decrease intracellular ROS, and consequently preserve acrosome and membrane integrity, as well as spermatozoan motility. PMID- 29266418 TI - Retraction: Xianzheng Gao, Shenglei Li, Wencai Li, Guannan Wang, Wugan Zhao, Jing Han, Changying Diao, Xiaohui Wang, and Mingzhi Zhang, MicroRNA-539 suppresses tumor cell growth by targeting the WNT8B gene in non-small cell lung cancer. J. Cell. Biochem. Accepted Article doi.org/10.1002/jcb.26634. PMID- 29266417 TI - MOF-Derived Bifunctional Cu3 P Nanoparticles Coated by a N,P-Codoped Carbon Shell for Hydrogen Evolution and Oxygen Reduction. AB - Metal-organic frameworks (MOFs) have recently emerged as a type of uniformly and periodically atom-distributed precursor and efficient self-sacrificial template to fabricate hierarchical porous-carbon-related nanostructured functional materials. For the first time, a Cu-based MOF, i.e., Cu-NPMOF is used, whose linkers contain nitrogen and phosphorus heteroatoms, as a single precursor and template to prepare novel Cu3 P nanoparticles (NPs) coated by a N,P-codoped carbon shell that is extended to a hierarchical porous carbon matrix with identical uniform N and P doping (termed Cu3 P@NPPC) as an electrocatalyst. Cu3 P@NPPC demonstrates outstanding activity for both the hydrogen evolution and oxygen reduction reaction, representing the first example of a Cu3 P-based bifunctional catalyst for energy-conversion reactions. The high performances are ascribed to the high specific surface area, the synergistic effects of the Cu3 P NPs with intrinsic activity, the protection of the carbon shell, and the hierarchical porous carbon matrix doped by multiheteroatoms. This strategy of using a diverse MOF as a structural and compositional material to create a new multifunctional composite/hybrid may expand the opportunities to explore highly efficient and robust non-noble-metal catalysts for energy-conversion reactions. PMID- 29266416 TI - A General Route to Metal-Substituted Dipnictenes of the Type [L(X)M]2 E2. AB - Two equivalents of LGa (L=HC[C(Me)N(2,6-iPr2 C6 H3 )]2 ) reacted with PX3 (X=Cl, Br) with insertion into two P-X bonds and formation of [L(X)Ga]2 PX (X=Cl 1, Br 2), whereas the analogous reaction with AsCl3 occurred with twofold insertion and subsequent elimination of LGaCl2 and formation of the Ga-substituted diarsene [L(Cl)Ga]2 As2 (3). Analogous findings were observed in the reactions with Me2 NAsCl2 , yielding the unsymmetrically-substituted diarsene [L(Cl)Ga]As=As[Ga(NMe2 )L] (4). The reaction of As(NMe2 )3 with LGa gave [L(Me2 N)Ga]2 As2 (5) after heating at 165 degrees C for five days, whereas the reaction with LAl gave [L(Me2 N)Al]2 As2 (6) after heating at only 80 degrees C for one day. Finally, two equivalents of LGa reacted with Bi(NEt2 )3 to give [L(Et2 N)Ga]2 Bi2 (7). Complexes 1-7 were characterized by NMR spectroscopy (1 H, 13 C, 31 P), elemental analysis, and single-crystal X-ray diffraction (except for 1 and 5). The bonding situations in 4, 6, and 7 were analyzed by quantum chemical calculations. PMID- 29266419 TI - Bright Surface-Enhanced Raman Scattering with Fluorescence Quenching from Silica Encapsulated J-Aggregate Coated Gold Nanoparticles. AB - Plexitonic nanoparticles offer variable optical properties through tunable excitations, in addition to electric field enhancements that far exceed molecular resonators. This study demonstrates a way to design an ultrabright surface enhanced Raman spectroscopy (SERS) signal while simultaneously quenching the fluorescence background through silica encapsulation of the semiconductor-metal composite nanoparticles. Using a multistep approach, a J-aggregate-forming organic dye is assembled on the surface of gold nanoparticles using a cationic linker. Excitonic resonance of the J-aggregate-metal system shows an enhanced SERS signal at an appropriate excitation wavelength. Further encapsulation of the decorated particles in silica shows a significant reduction in the fluorescence signal of the Raman spectra (5* reduction) and an increase in Raman scattering (7* enhancement) when compared to phospholipid encapsulation. This reduction in fluorescence is important for maximizing the useful SERS enhancement from the particle, which shows a signal increase on the order of 104 times greater than J aggregated dye in solution and 24 times greater than Oxonica S421 SERS tag. The silica layer also serves to promote colloidal stability. The combination of reduced fluorescence background, enhanced SERS intensity, and temporal stability makes these particles highly distinguishable with potential to enable high throughput applications such as SERS flow cytometry. PMID- 29266420 TI - Short circuit: Disaggregation of adrenocorticotropic hormone and cortisol levels in HIV-positive, methamphetamine-using men who have sex with men. AB - OBJECTIVE: This study examined if methamphetamine use alone (METH + HIV-) and methamphetamine use in combination with HIV (METH + HIV+) were associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation as well as insulin resistance relative to a nonmethamphetamine-using, HIV-negative comparison group (METH-HIV-). METHODS: Using an intact groups design, serum levels of HPA axis hormones in 46 METH + HIV- and 127 METH + HIV+ men who have sex with men (MSM) were compared to 136 METH-HIV- men. RESULTS: There were no group differences in prevailing adrenocorticotropic hormone (ACTH) or cortisol levels, but the association between ACTH and cortisol was moderated by METH + HIV+ group (beta = 0.19, p < .05). Compared to METH-HIV- men, METH + HIV+ MSM displayed 10% higher log10 cortisol levels per standard deviation lower ACTH. Both groups of methamphetamine-using MSM had lower insulin resistance and greater syndemic burden (i.e., sleep disturbance, severe depression, childhood trauma, and polysubstance use disorder) compared to METH-HIV- men. However, the disaggregated functional relationship between ACTH and cortisol in METH + HIV+ MSM was independent of these factors. CONCLUSIONS: Further research is needed to characterize the bio-behavioral pathways that explain dysregulated HPA axis functioning in HIV-positive, methamphetamine-using MSM. PMID- 29266421 TI - Socially accountable medical education strengthens community health services. AB - CONTEXT: Socially accountable health professional education (SAHPE) is committed to achieving health equity through training health professionals to meet local health needs and serve disadvantaged populations. This Philippines study investigates the impact of SAHPE students and graduates on child and maternal health services and outcomes. METHODS: This is a non-randomised, controlled study involving a researcher-administered survey to 827 recent mothers (>=1 child aged 0-5 years). Five communities were serviced by SAHPE medical graduates or final year medical students (interns) in Eastern Visayas and the Zamboanga Peninsula, and five communities in the same regions were serviced by conventionally trained (non-SAHPE) graduates. FINDINGS: Mothers in communities serviced by SAHPE-trained medical graduates and interns were more likely than their counterpart mothers in communities serviced by non-SAPHE trained graduates to: have lower gross family income (p < 0.001); have laboratory results of blood and urine samples taken during pregnancy discussed (p < 0.001, respectively); have first pre-natal check up before 4th month of pregnancy (p = 0.003); receive their first postnatal check up <7 days of birth (p < 0.001); and have a youngest child with normal (>2500 g) birthweight (p = 0.003). In addition, mothers from SAHPE-serviced communities were more likely to have a youngest child that: was still breastfed at 6 months of age (p = 0.045); received a vitamin K injection soon after birth (p = 0.026); and was fully immunised against polio (p < 0.001), hepatitis B (p < 0.001), measles (p = 0.008) and diphtheria/pertussis/tetanus (p < 0.001). In communities serviced by conventional medical graduates, mothers from lower socio-economic quartiles (<20 000 Php) were less likely (p < 0.05) than higher socio-economic mothers to: report that their youngest child's delivery was assisted by a doctor; have their weight measured during pregnancy; and receive iron syrups or tablets. CONCLUSIONS: The presence of SAHPE medical graduates or interns in Philippine communities significantly strengthens many recommended core elements of child and maternal health services irrespective of existing income constraints, and is associated with positive child health outcomes. PMID- 29266422 TI - Comment on "A prospective study on fetal posterior cranial fossa assessment for early detection of open spina bifida at 11-13 weeks" by Kose et al. PMID- 29266423 TI - Centrifugal lipodystrophy of the scalp manifesting as centrifugal lipodystrophic alopecia. AB - Centrifugal lipodystrophy (CLD), characterized by a depressed lesion in the abdominal skin, is a chronic disease occurring more often among younger patients of East Asian descent. We present an extremely unusual case of CLD of the scalp associated with reversible hair loss. The patient demonstrated alopecia in the frontal, temporal and occipital areas of the scalp, which connected to form a ring-shaped area of hair loss. Curiously, the area of hair loss gradually expanded outwards while the central region showed normal hair regrowth. Immunohistochemical analysis demonstrated reduced expression of leptin, an adipokine capable of inducing the anagen phase of the hair cycle, in the adipose tissue, associated with active inflammation. By contrast, recovery of leptin expression was observed at sites of healed inflammatory lesions, suggesting that reversible hair loss might be caused by a change in leptin expression in adipose tissue. PMID- 29266424 TI - Repairability of skeletal alterations induced by sodium valproate in rats. AB - The present study aimed at examining postnatal repairability of sodium valproate induced skeletal alterations in rats. Sodium valproate (400 mg/kg) or the vehicle (distilled water) was orally administrated to pregnant Sprague-Dawley rats from gestation days 9 to 11. Fetuses and pups were obtained on gestation day 21 and postnatal day 11, respectively, and their skeletons were stained with Alizarin red S and Alcian blue and examined. Sodium valproate-induced costal and vertebral alterations in the fetuses included discontinued rib cartilage, fused rib, full or short supernumerary rib, bipart ossification of thoracic centrum, supernumerary lumbar vertebrae, and lumbarization. In pups, however, discontinued rib cartilage was not observed, and the incidence of a short supernumerary rib was significantly lower than that in the fetuses, suggesting that these alterations are postnatally repairable. PMID- 29266426 TI - Greatly Enhanced Anticorrosion of Cu by Commensurate Graphene Coating. AB - Metal corrosion is a long-lasting problem in history and ultrahigh anticorrosion is one ultimate pursuit in the metal-related industry. Graphene, in principle, can be a revolutionary material for anticorrosion due to its excellent impermeability to any molecule or ion (except for protons). However, in real applications, it is found that the metallic graphene forms an electrochemical circuit with the protected metals to accelerate the corrosion once the corrosive fluids leaks into the interface. Therefore, whether graphene can be used as an excellent anticorrosion material is under intense debate now. Here, graphene coated Cu is employed to investigate the facet-dependent anticorrosion of metals. It is demonstrated that as-grown graphene can protect Cu(111) surface from oxidation in humid air lasting for more than 2.5 years, in sharp contrast with the accelerated oxidation of graphene-coated Cu(100) surface. Further atomic scale characterization and ab initio calculations reveal that the strong interfacial coupling of the commensurate graphene/Cu(111) prevents H2 O diffusion into the graphene/Cu(111) interface, but the one-dimensional wrinkles formed in the incommensurate graphene on Cu(100) can facilitate the H2 O diffusion at the interface. This study resolves the contradiction on the anticorrosion capacity of graphene and opens a new opportunity for ultrahigh metal anticorrosion through commensurate graphene coating. PMID- 29266427 TI - A diffusion-based method for long-T2 suppression in steady state sequences: Validation and application for 3D-UTE imaging. AB - PURPOSE: To introduce a novel method for long-T2 signal physical suppression in steady-state based on configuration states combination and modulation using diffusion weighting. Its efficiency in yielding a high contrast in short-T2 structures using an ultrashort echo time acquisition module (Diff-UTE) is compared to the adiabatically prepared Inversion-Recovery-UTE sequence (IR-UTE). THEORY AND METHODS: Using a rectangular-pulse prepared 3D-UTE sequence, the possibility of long-T2 component signal cancellation through diffusion effects is addressed, and the condition met for sets of sequence parameters. Simultaneously, the short-T2 component signal is maximized using a Bloch equation-based optimization process. The method is evaluated from simulations, and experiments are conducted on a phantom composed of short and long-T2 components, as well as on an ex vivo mouse head. RESULTS: Within equal scan times, the proposed method allowed for an efficient long-T2 signal suppression, and expectedly yielded a higher signal to noise ratio in short-T2 structures compared to the IR-UTE technique, although an intrinsic short-T2 signal loss is expected through the preparation module. CONCLUSION: The Diff-UTE method represents an interesting alternative to the IR-UTE technique. Diffusion weighting allowing for a long-T2 suppression results in a less penalizing method to generate a high and selective contrast in short-T2 components. Magn Reson Med 80:548-559, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29266425 TI - Simple and robust referencing system enables identification of dissolved-phase xenon spectral frequencies. AB - PURPOSE: To assess the effect of macroscopic susceptibility gradients on the gas phase referenced dissolved-phase 129 Xe (DPXe) chemical shift (CS) and to establish the robustness of a water-based referencing system for in vivo DPXe spectra. METHODS: Frequency shifts induced by spatially varying magnetic susceptibility are calculated by finite-element analysis for the human head and chest. Their effect on traditional gas-phase referenced DPXe CS is then assessed theoretically and experimentally. A water-based referencing system for the DPXe resonances that uses the local water protons as reference is proposed and demonstrated in vivo in rats. RESULTS: Across the human brain, macroscopic susceptibility gradients can induce an apparent variation in the DPXe CS of up to 2.5 ppm. An additional frequency shift as large as 6.5 ppm can exist between DPXe and gas-phase resonances. By using nearby water protons as reference for the DPXe CS, the effect of macroscopic susceptibility gradients is eliminated and consistent CS values are obtained in vivo, regardless of shimming conditions, region of interest analyzed, animal orientation, or lung inflation. Combining in vitro and in vivo spectroscopic measurements finally enables confident assignment of some of the DPXe peaks observed in vivo. CONCLUSION: To use hyperpolarized xenon as a biological probe in tissues, the DPXe CS in specific organs/tissues must be reliably measured. When the gas-phase is used as reference, variable CS values are obtained for DPXe resonances. Reliable peak assignments in DPXe spectra can be obtained by using local water protons as reference. Magn Reson Med 80:431-441, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29266428 TI - Bone marrow lesions in osteoarthritis: What lies beneath. AB - Osteoarthritis (OA) is the most common joint disease in the United States, affecting more than 30 million people, and is characterized by cartilage degeneration in articulating joints. OA can be viewed as a group of overlapping disorders, which result in functional joint failure. However, the precise cellular and molecular events within which lead to these clinically observable changes are neither well understood nor easily measurable. It is now clear that multiple factors, in multiple joint tissues, contribute to degeneration. Changes in subchondral bone are recognized as a hallmark of OA, but are normally associated with late-stage disease when degeneration is well established. However, early changes such as Bone Marrow Lesions (BMLs) in OA are a relatively recent discovery. BMLs are patterns from magnetic resonance images (MRI) that have been linked with pain and cartilage degeneration. Their potential utility in predicting progression, or as a target for therapy, is not yet fully understood. Here, we will review the current state-of-the-art in this field under three broad headings: (i) BMLs in symptomatic OA: malalignment, joint pain, and disease progression; (ii) biological considerations for bone-cartilage crosstalk in joint disease; and (iii) mechanical factors that may underlie BMLs and drive their communication with other joint tissues. Thus, this review will provide insights on this topic from a clinical, biological, and mechanical perspective. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1818-1825, 2018. PMID- 29266429 TI - Mechanistic Insight into Enantioselective Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenes. AB - The asymmetric palladium-catalyzed oxidative carbocyclization-borylation of enallenes, employing a chiral phosphoric acid as co-catalyst, constitutes an efficient and convenient entry into functionalized building blocks with cyclopentene scaffolds in high enantiopurity. Up till now there has been a lack of knowledge concerning the origin of enantioselectivity of this reaction as well as the absolute configuration of the product. Herein, we report the crystal structure of one of the compounds generated via this carbocyclization, providing the link between the configuration of the products and the configuration of the chiral phosphoric acid used in the reaction. Furthermore, the origin of the enantioselectivity is thoroughly investigated with density functional theory (DFT) calculations. By careful examination of different possible coordination modes, it is shown that the chiral phosphoric acid and the corresponding phosphate anion serve as ligands for palladium during the key stereoselectivity determining cyclization step. In addition, we examine reactions wherein an extra chiral reagent, a p-benzoquinone containing a chiral sulfoxide, is used. The combined experimental and theoretical studies provide insight into the details of complexation of palladium with various species present in the reaction mixture, furnishing a general understanding of the factors governing the stereoselectivity of this and related catalytic reactions. PMID- 29266430 TI - DAMS: A Model to Assess Domino Effects by Using Agent-Based Modeling and Simulation. AB - Historical data analysis shows that escalation accidents, so-called domino effects, have an important role in disastrous accidents in the chemical and process industries. In this study, an agent-based modeling and simulation approach is proposed to study the propagation of domino effects in the chemical and process industries. Different from the analytical or Monte Carlo simulation approaches, which normally study the domino effect at probabilistic network levels, the agent-based modeling technique explains the domino effects from a bottom-up perspective. In this approach, the installations involved in a domino effect are modeled as agents whereas the interactions among the installations (e.g., by means of heat radiation) are modeled via the basic rules of the agents. Application of the developed model to several case studies demonstrates the ability of the model not only in modeling higher-level domino effects and synergistic effects but also in accounting for temporal dependencies. The model can readily be applied to large-scale complicated cases. PMID- 29266431 TI - Mechanistic effects of mesenchymal and hematopoietic stem cells: New therapeutic targets in myocardial infarction. AB - Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is of the most serious health threats today. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been explored as promising cell therapy in MI and regenerative therapy. Recently, reports investigated the potential therapeutic effects of MSCs or HSCs transplantation after MI in numerous experimental and clinical studies; however, their results are controversy and needs more explorations. The current review is an attempt to clarify the therapeutic potentials of MSCs and HSCs in MI therapy, as well as their possible effects; especially the paracrine one and the exosome-derived stem cell among animal models as well as clinical trials conducted within the last 10 years. In this context, various sources of MSCs and HSCs have been addressed in helping cardiac regeneration by either revitalizing the cardiac stem cells niche or revascularizing the arteries and veins of the heart. In addition, both MSCs and HSCs could produce paracrine mediators and growth factors which led to cardiomyocytes protection, angiogenesis, immunemodulation, antioxidants, anti apoptotic, anti-inflammatory, antifibrotic, as well as increasing cardiac contractility. Recently, microRNAs (miRNAs), post-transcriptional regulators of gene expression, and long non-coding RNA (lncRNA), a miRNA sponge, are recent stem cell-derived mediators can be promising targets of MSCs and HSCs through their paracrine effects. Although MSCs and HSCs have achieved considerable achievements, however, some challenges still remain that need to be overcome in order to establish it as a successful technique. The present review clarified the mechanistic potentials of MSCs and HSCs especially paracrine effects involved in MI including human and animal studies and the challenges challenges regarding type, differentiation, route, and number of injections. PMID- 29266432 TI - Sleep disordered breathing does not predict acute severe pain episodes in children with sickle cell anemia. AB - Conflicting evidence has suggested that low mean nocturnal hemoglobin oxygen saturation (SpO2 ) predicts future hospital days for acute severe pain in children with sickle cell anemia (SCA). In an unselected multicenter prospective cohort study, we tested the hypothesis that either low mean nocturnal SpO2 or high obstructive apnea-hypopnea index (OAHI; the number of obstructive apneas and hypopneas with >= 3% desaturation or arousal per hour of sleep) or high oxygen desaturation index (ODI; number of >= 3% desaturation from baseline saturation per hour of sleep) is associated with increased incidence rates of pain. A total of 140 children with SCA with a median age of 10.8 years (interquartile range 7.2) were followed for a median of 4.9 years (interquartile range 1.8). Overnight polysomnography evaluations at baseline health exam were measured and adjudicated centrally. Multivariable models created in two steps were included. First, all plausible covariates were included in a screening model. Subsequently, covariates meeting level of statistical significance of P < .20 were included in the final model. Contrary to our hypothesis, higher (but not lower) mean nocturnal SpO2 was associated with higher rates of pain episodes (Incidence rate ratio (IRR) 1.10, 95% CI [1.03-1.18], P = .004). Higher log OAHI did not pass screening criteria. Higher log ODI was not significantly associated with higher rates of pain episodes (IRR 0.93, 95% CI [0.82-1.06], P = .28). Neither low nocturnal SpO2, higher OAHI, nor higher ODI were associated with clinically relevant increased incidence rates of acute severe pain episodes. PMID- 29266433 TI - Napsin A and WT 1 are useful immunohistochemical markers for differentiating clear cell carcinoma ovary from high-grade serous carcinoma. AB - Clear cell carcinoma (CCC) of the ovary is an uncommon, but an aggressive epithelial ovarian cancer (EOC), which has overlapping histopathologic features with other ovarian tumours. Lately, Napsin A has been identified as its useful diagnostic immunohistochemical (IHC) marker. Fifty-eight prospectively diagnosed ovarian CCCs, 53 high-grade serous carcinomas (HGSCs), 16 endometrioid adenocarcinomas (EMACs), six mixed carcinomas, containing components of CCC and EMAC, seven metastatic mucinous adenocarcinomas and six ovarian yolk sac tumours (YSTs) were tested for Napsin A immunostaining. Fifty ovarian CCCs, 50 HGSCs, seven ovarian EMACs and five mixed carcinomas were tested for WT1 immunostaining. Napsin A was positively expressed in all 58 (100%) CCCs; was focally positive in 1 of 6 YSTs; in 1/16 EMACs and in six cases of mixed carcinomas, while it was negative in all 53 HGSCs and in seven metastatic mucinous adenocarcinomas. Other IHC markers expressed in cases of CCC ovary were CK7 (31/31) (100%), WT1 (0/50), p53 (20/26, 'wild type'), ER (4/31, focal) (12.9%), PAX8 (14/14) (100%), glypican 3 (4/10, focal) (44.4%), p16INK4 (5/5, focal) and CK20 (0/5). Various IHC markers expressed in HGSCs were WT1 (48/50) (96%), p53 (31/31, mostly 'mutation type'), CK7 (9/9) (100%) ER (13/16, variable) (81.2%) and PAX8 (14/14) (100%). IHC markers expressed in EMACs were ER (15/16) (93.7%), CK7 (2/2) (100%) and WT1 (0/7). IHC markers expressed in mixed carcinomas were CK7 (2/2) (100%), WT1 (0/2), focal Napsin A (6/6) and focal ER (5/6). The sensitivity and specificity of Napsin A for the diagnosis of CCC ovary was 100% and 90.9%, respectively. The sensitivity and specificity of WT1 for diagnosis of HGSC ovary was found to be 96% and 100%, respectively. Napsin A and WT1 are highly sensitive and specific IHC markers for diagnosing ovarian CCCs and HGSCs, respectively, and in differentiating these tumours from their mimics. Napsin A is useful in identification of component of CCC in certain EMACs. PMID- 29266434 TI - Association between Australian adolescent alcohol use and alcohol use risk and protective factors in 2011 and 2014. AB - INTRODUCTION AND AIMS: Changes in risk and protective factors of adolescent alcohol use may be contributing to the recent decline in Australian adolescents alcohol use. The study aimed to determine the: (i) prevalence of alcohol use, risk and protective factors in 2011 and 2014; and (ii) association between alcohol use and risk and protective factors in 2011 and 2014. DESIGN AND METHODS: A repeat cross-sectional study was conducted. Grade 9-10 (aged 15-17 years) students from 32 Australian secondary schools were sampled in 2011 and 2014. A self-report survey collected data regarding alcohol use (ever, recent, 'binge drinking'), risk factors (e.g. alcohol use/permissive attitude to alcohol by friends/siblings/parents) and protective factors (e.g. self-efficacy; school/home/community support; peer caring relationships). Descriptive statistics were used to determine differences in alcohol use, risk and protective factors between 2011 and 2014. Adjusted multivariable logistic regression analyses examined associations between alcohol use, risk and protective factors separately in 2011 and 2014 (six models). RESULTS: Fewer adolescents reported alcohol use in 2014 compared with 2011 (ever: 56.6% vs. 67.9%, recent: 17.3% vs. 21.2%, 'binge drinking': 20.0% vs. 23.5%; 2011: n = 4366; 2014: n = 5199). Significant differences between 2014 and 2011 were found for some risk (five lower; one higher) and protective factors (four lower). Risk factors that were significantly lower in 2014 compared to 2011 were amongst variables with the strongest associations with alcohol use. DISCUSSION AND CONCLUSIONS: The strength of associations with alcohol use, and decrease in the prevalence of certain risk factors in 2014 compared to 2011, suggests such factors may be contributing to the decline in adolescent alcohol use. PMID- 29266435 TI - Diffusion tensor cardiovascular magnetic resonance with a spiral trajectory: An in vivo comparison of echo planar and spiral stimulated echo sequences. AB - PURPOSE: Diffusion tensor cardiovascular MR (DT-CMR) using stimulated echo acquisition mode (STEAM) with echo-planar-imaging (EPI) readouts is a low signal to-noise-ratio (SNR) technique and therefore typically has a low spatial resolution. Spiral trajectories are more efficient than EPI, and could increase the SNR. The purpose of this study was to compare the performance of a novel STEAM spiral DT-CMR sequence with an equivalent established EPI technique. METHODS: A STEAM DT-CMR sequence was implemented with a spiral readout and a reduced field of view. An in vivo comparison of DT-CMR parameters and data quality between EPI and spiral was performed in 11 healthy volunteers imaged in peak systole and diastasis at 3 T. The SNR was compared in a phantom and in vivo. RESULTS: There was a greater than 49% increase in the SNR in vivo and in the phantom measurements (in vivo septum, systole: SNREPI = 8.0 +/- 2.2, SNRspiral = 12.0 +/- 2.7; diastasis: SNREPI = 8.1 +/- 1.6, SNRspiral = 12.0 +/- 3.7). There were no significant differences in helix angle gradient (HAG) (systole: HAGEPI = -0.79 +/- 0.07 degrees /%; HAGspiral = -0.74 +/- 0.16 degrees /%; P = 0.11; diastasis: HAGEPI = -0.63 +/- 0.05 degrees /%; HAGspiral = -0.56 +/- 0.14 degrees /%; P = 0.20), mean diffusivity (MD) in systole (MDEPI = 0.99 +/- 0.06 * 10-3 mm2 /s, MDspiral = 1.00 +/- 0.09 * 10-3 mm2 /s, P = 0.23) and secondary eigenvector angulation (E2A) (systole: E2AEPI = 61 +/- 10 degrees ; E2Aspiral = 63 +/- 10 degrees ; P = 0.77; diastasis: E2AEPI = 18 +/- 11 degrees ; E2Aspiral = 15 +/- 8 degrees ; P = 0.20) between the sequences. There was a small difference (~ 20%) in fractional anisotropy (FA) (systole: FAEPI = 0.49 +/- 0.03, FAspiral = 0.41 +/- 0.04; P < 0.01; diastasis: FAEPI = 0.66 +/- 0.05, FAspiral = 0.55 +/- 0.03; P < 0.01) and mean diffusivity in diastasis (10%; MDEPI = 1.00 +/- 0.12 * 10-3 mm2 /s, MDspiral = 1.10 +/- 0.09 * 10-3 mm2 /s, P = 0.02). CONCLUSION: This is the first study to demonstrate DT-CMR STEAM using a spiral trajectory. The SNR was increased by using a spiral rather than the more established EPI readout, and the DT-CMR parameters were largely similar between the two sequences. Magn Reson Med 80:648-654, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29266436 TI - Aggregation Pathways of Native-Like Ubiquitin Promoted by Single-Point Mutation, Metal Ion Concentration, and Dielectric Constant of the Medium. AB - Ubiquitin-positive protein aggregates are biomarkers of neurodegeneration, but the molecular mechanism responsible for their formation and accumulation is still unclear. Possible aggregation pathways of human ubiquitin (hUb) promoted by both intrinsic and extrinsic factors, are here investigated. By a computational analysis, two different hUb dimers are indicated as possible precursors of amyloid-like structures, but their formation is disfavored by an electrostatic repulsion involving Glu16 and other carboxylate residues present at the dimer interface. Experimental data on the E16V mutant of hUb shows that this single point mutation, although not affecting the overall protein conformation, promotes protein aggregation. It is sufficient to shift the same mutation by only two residues (E18V) to regain the behavior of wild-type hUb. The neutralization of Glu16 negative charge by a metal ion and a decrease of the dielectric constant of the medium by addition of trifluoroethanol (TFE), also promote hUb aggregation. The outcomes of this research have important implications for the prediction of physiological parameters that favor aggregate formation. PMID- 29266437 TI - Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan-omics precision. AB - Over the past 20 years, classifications of kidney cancer have undergone major revisions based on morphological refinements and molecular characterizations. The 2016 WHO classification of renal tumors recognizes more than ten different renal cell carcinoma (RCC) subtypes. Furthermore, the marked inter- and intra-tumor heterogeneity of RCC is now well appreciated. Nevertheless, contemporary multi omics studies of RCC, encompassing genomics, transcriptomics, proteomics, and metabolomics, not only highlight apparent diversity but also showcase and underline commonality. Here, we wish to provide an integrated perspective concerning the future 'functional' classification of renal cancer by bridging gaps among morphology, biology, multi-omics, and therapeutics. This review focuses on recent progress and elaborates the potential value of contemporary pan omics approaches with a special emphasis on cancer genomics unveiled through next generation sequencing technology, and how an integrated multi-omics approach might impact precision-based personalized kidney cancer care in the near future. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29266438 TI - Junctional ectopic rhythm after AVNRT ablation: An underrecognized complication. AB - BACKGROUND: Ablation is an effective treatment for atrioventricular nodal reentrant tachycardia (AVNRT). The occurrence of junctional ectopic rhythm (JER), including junctional ectopic tachycardia, following AVNRT ablation has been described as an extremely rare phenomenon, but may be underestimated. We aimed to determine the incidence of JER following AVNRT ablation within our institution, as well as that reported in the literature via an extensive review. METHODS: We reviewed our adult ablation institutional experience for the occurrence of JER after AVNRT ablation from 2009 to 2016. Additionally, we conducted an extensive literature search using different databases looking for AVNRT ablation case series. The individually reported complications of these studies were reviewed, with a primary endpoint defined as the occurrence of JER shortly after AVNRT ablation. The study was approved by our institutional review board. RESULTS: Our institutional data revealed 6/126 patients (prevalence 4.8%) developed non preexisting JER post-AVNRT ablation. Four patients were asymptomatic. Two patients had persistent symptoms lasting over a year, with one patient requiring repeat ablation. The literature review included 149 adult and pediatric studies. There were three cases of reported JER, out of a total of 37,541 patients (31,768 adults and 5,773 pediatric; prevalence 0.008%). The three JER patients were pediatric, and all required further therapeutic intervention. CONCLUSION: JER might be an underreported complication of AVNRT ablation. It seems most often to be transient and self-limited, occurring days to weeks after ablation, but may also be debilitating, requiring more aggressive management. PMID- 29266440 TI - Granulocyte and monocyte adsorption apheresis for palmoplantar pustulosis with extra-palmoplantar lesions and pustulotic arthro-osteitis. PMID- 29266439 TI - In Streptomyces lividans, acetyl-CoA synthetase activity is controlled by O serine and NE -lysine acetylation. AB - Protein acetylation is a rapid mechanism for control of protein function. Acetyl CoA synthetase (AMP-forming, Acs) is the paradigm for the control of metabolic enzymes by lysine acetylation. In many bacteria, type I or II protein acetyltransferases acetylate Acs, however, in actinomycetes type III protein acetyltransferases control the activity of Acs. We measured changes in the activity of the Streptomyces lividans Acs (SlAcs) enzyme upon acetylation by PatB using in vitro and in vivo analyses. In addition to the acetylation of residue K610, residue S608 within the acetylation motif of SlAcs was also acetylated (PKTRSGK610 ). S608 acetylation rendered SlAcs inactive and non-acetylatable by PatB. It is unclear whether acetylation of S608 is enzymatic, but it was clear that this modification occurred in vivo in Streptomyces. In S. lividans, an NAD+ dependent sirtuin deacetylase from Streptomyces, SrtA (a homologue of the human SIRT4 protein) was needed to maintain SlAcs function in vivo. We have characterized a sirtuin-dependent reversible lysine acetylation system in Streptomyces lividans that targets and controls the Acs enzyme of this bacterium. These studies raise questions about acetyltransferase specificity, and describe the first Acs enzyme in any organism whose activity is modulated by O-Ser and NE Lys acetylation. PMID- 29266441 TI - Strictly, hypoxic-ischemic encephalopathy? PMID- 29266442 TI - From Carboxytelomerization of 1,3-Butadiene to Linear alpha,omega-C10 -Diester Combinatoric Approaches for an Efficient Synthetic Route. AB - Two novel reaction pathways were tested to synthesize the linear alpha,omega-C10 diester exclusively from three basic reagents: 1,3-butadiene, carbon monoxide and methanol. Therefore, carboxytelomerization of 1,3-butadiene and methanol was merged with methoxycarbonylation in two different ways to obtain highly linear C10 -diester. Through a palladium-based and -assisted tandem catalytic system, 22 % yield of the desired C10 -diester was obtained without isolating the intermediates. Subsequently, the limitations of the novel assisted tandem catalytic concept were uncovered and based on that, a two-step reaction regime was established. By optimization of the carboxytelomerization, the C9 -monoester as intermediate could be formed in nearly quantitative yields and excellent linearity. In a second reaction step, the isolated monoester was successfully converted by methoxycarbonylation into the desired linear C10 -diester in overall yields up to 84 %. PMID- 29266444 TI - Peptide selectivity between the PDZ domains of human pregnancy-related serine proteases (HtrA1, HtrA2, HtrA3, and HtrA4) can be reshaped by different halogen probes. AB - The human HtrA family of serine proteases (HtrA1, HtrA2, HtrA3, and HtrA4) are the key enzymes associated with pregnancy and closely related to the development and progression of many pathological events. Previously, it was found that halogen substitution at the indole moiety of peptide Trp-1 residue can form a geometrically satisfactory halogen bond with the Drosophila discs large, zona occludens-1 (PDZ) domain of HtrA proteases. Here, we attempt to systematically investigate the effect of substitution with 4 halogen types and 2 indole positions on the binding affinity and specificity of peptide ligands to the 4 HtrA PDZ domains. The complex structures, interaction energies, halogen-bonding strength, and binding affinity of domain-peptide systems were modeled, analyzed, and measured via computational modeling and fluorescence-based assay. It is revealed that there is a compromise between the local rearrangement of halogen bond involving different halogen atoms and the global optimization of domain peptide interaction; the substitution position is fundamentally important for peptide-binding affinity, while the halogen type can effectively shift peptide selectivity between the 4 domains. The HtrA1-PDZ and HtrA4-PDZ as well as HtrA2 PDZ and HtrA3-PDZ respond similarly to different halogen substitutions of peptide; -Br substitution at R2-position and -I substitution at R4-position are most effective in improving peptide selectivity for HtrA1-PDZ/HtrA4-PDZ and HtrA2 PDZ/HtrA3-PDZ, respectively; -F substitution would not address substantial effect on peptide selectivity for all the 4 domains. Consequently, the binding affinities of a native peptide ligand DSRIWWV-COOH as well as its 4 R2 halogenated counterparts were determined as 1.9, 1.4, 0.5, 0.27, and 0.92 MUM, which are basically consistent with computational analysis. This study would help to rationally design selective peptide inhibitors of HtrA family members by using different halogen substitutions. PMID- 29266443 TI - Phenols as Diamagnetic T2 -Exchange Magnetic Resonance Imaging Contrast Agents. AB - Although T2 -exchange (T2ex ) NMR phenomena have been known for decades, there has been a resurgence of interest to develop T2ex MRI contrast agents. One indispensable advantage of T2ex MR agents is the possibility of using non-toxic and/or bio-compatible diamagnetic compounds with intermediate exchangeable protons. Herein a library of phenol-based compounds is screened and their T2ex contrast (exchange relaxivity, r2ex ) at 9.4 T determined. The T2ex contrast of phenol protons allows direct detection by MRI at a millimolar concentration level. The effect of chemical modification of the phenol on the T2ex MRI contrast through modulation of exchange rate and chemical shift was also studied and provides a guideline for use of endogenous and exogenous phenols for T2ex MRI contrast. As a proof-of-principle application, phenol T2ex contrast can be used to detect enzyme activity in a tyrosinase-catalyzed catechol oxidation reaction. PMID- 29266445 TI - Evaluation of the circulating MicroRNA-495 and Stat3 as prognostic and predictive biomarkers for lower extremity deep venous thrombosis. AB - This study aims to elucidate the prognostic and predictive biomarker of miR-495 and Stat3 in peripheral blood in relation to lower extremity deep venous thrombosis (DVT). Patients with lower limb fractures were assigned into case and control groups. Rats were allocated into blank (normal rats), sham (normal rats), DVT, miR-495 mimic, miR-495 inhibitor, over-Stat3, and si-Stat3 groups. ELISA was used to detect levels of prothrombin time (PT), endothelin-1 (ET-1), Human Fibrinogen (FIB), D-Dimer, blood coagulation factors V and VIII, tissue type plasminogen activator (t-PA), platelet activating factor (PAF), protein C and Stat3. qRT-PCR was employed for the evaluation of the expressions of miR-495 and Stat3, while receiver operating characteristic (ROC) curve was constructed to assess the predictive value of miR-495 and Stat3 as well as the treatment outcomes of patients with lower limb fractures. Logistic regression analyses were conducted in order to correlate indexes and lower extremity DVT. miR-495 overexpression, t-PA, PAF, and protein C were confirmed to be protective factors, while Stat3 overexpression, PT, ET-1, FIB, D-Dimer, blood coagulation factor V, and VIII were all ultimately considered to be risk factors of lower extremity DVT. Stat3 was confirmed to be the target gene of miR-495. Compared with the blank group, the length and weight of the thrombus as well as the ratio between length and weight, mRNA and protein expression of Stat3 were reduced in the miR 495 mimic and si-Stat3 groups. Our findings suggest that through the suppression of Stat3 expression, miR-495 prohibits lower extremity DVT in peripheral blood. PMID- 29266446 TI - High Rate Capability and Enhanced Cyclability of Na3 V2 (PO4 )2 F3 Cathode by In Situ Coating of Carbon Nanofibers for Sodium-Ion Battery Applications. AB - A facile chemical vapor deposition method is developed for the preparation of carbon nanofiber (CNF) composite Na3 V2 (PO4 )2 F3 @C as cathodes for sodium-ion batteries. In all materials under investigation, the optimized composite content, denoted as NVPF@C@CNF-5, shows excellent sodium storage performance (86.3 % capacity retention over 5000 cycles at 20 C rate) and high rate capability (84.3 mA h g-1 at 50 C). The superior sodium storage performance benefits from the enhanced electrical conductivity of the working electrode after formation of a composite with CNF. Furthermore, the full cell using NVPF@C@CNF-5 and hard carbon as the cathode and anode, respectively, demonstrates an impressive electrochemical performance, realizing an ultrahigh rate charge/discharge at a current rate of 30 C and long-term stability over 1000 cycles. This approach is facile and effective, and could be extended to other materials for energy-storage applications. PMID- 29266447 TI - The Role of Mg(OH)2 in the So-Called "Base-Free" Oxidation of Glycerol with AuPd Catalysts. AB - Mg(OH)2 - and Mg(OH)2 -containing materials can provide excellent performance as supports for AuPd nanoparticles for the oxidation of glycerol in the absence of base, which is considered to be a result of additional basic sites on the surface of the support. However, its influence on the reaction solution is not generally discussed. In this paper, we examine the relationship between the basic Mg(OH)2 support and AuPd nanoparticles in detail using four types of catalyst. For these reactions, the physical interaction between Mg(OH)2 and AuPd was adjusted. It was found that the activity of the AuPd nanoparticles increased with the amount of Mg(OH)2 added under base-free conditions, regardless of its interaction with the noble metals. In order to investigate how Mg(OH)2 affected the glycerol oxidation, detailed information about the performance of AuPd/Mg(OH)2 , physically mixed (AuPd/C+Mg(OH)2 ) and (AuPd/C+NaHCO3 ) was obtained and compared. Furthermore, NaOH and Mg(OH)2 were added during the reaction using AuPd/C. All these results indicate that the distinctive and outstanding performance of Mg(OH)2 supported catalysts in base-free condition is in fact directly related to its ability to affect the pH during the reaction and as such, assists with the initial activation of the primary alcohol, which is considered to be the rate determining step in the reaction. PMID- 29266448 TI - Long-term regulation of local cytokine production following immunization in mice. AB - Vaccines based on pathogen components require adjuvants to enhance the antigen specific adaptive immune response. Intramuscular injection of adjuvanted-vaccines induces inflammatory cytokines and inflammatory nodules at the injection site within 48 hr after injection (Vaccine 2014; 32: 3393-401). In the present study, long-term regulation of cytokine production was investigated at 3, 6, 24, and 48 hr, 5 and 7 days, and 2 and 4 weeks after immunization with human papilloma virus (HPV), diphtheria and tetanus toxoids combined with acellular pertussis (DTaP), Haemophilus influenza type B (Hib), and pneumococcal conjugated (PCV) vaccines in mouse models. The second dose was given 4 weeks later, and cytokine profiles were investigated 2, 5, and 7 days after re-immunization. IL-1beta, IL-6, granulocyte colony stimulating factor (G-CSF), and MCP-1 were produced from 3 hr and peaked at 48 hr after immunization with Cervarix in mice. IL-4, MCP-1, and TNF-alpha peaked at 5 or 7 days after immunization with Gardasil. These cytokines decreased 7 days after immunization with Cervarix and Gardasil. After the second dose, similar responses were observed. Both vaccines induced neutrophil extracellular traps (NET) in inflammatory nodules. The peak amount of IL-1beta, IL-6, G-CSF, and MCP-1 was observed on day 5 of immunization and that of IL-4 on days 5-7 of immunization with DTaP, but no increase in IL-6 and G-CSF was observed after re immunization. A similar response was noted after immunization with PCV13. An inflammatory response is essential for the development of adaptive immunity through the production of inflammatory cytokines. PMID- 29266449 TI - Switching Multivalent DNA Complexation using Metal-Controlled Cationic Supramolecular Self-Assemblies. AB - We provide a proof-of-principle that coordination chemistry drives the in situ self-assembly of an inactive ligand into a multivalent cluster capable of effectively complexing DNA. We show that metal coordination and scavenging can be used to switch the multivalency of the system. Thus, controlled DNA complexation and decomplexation could be achieved. PMID- 29266450 TI - Effects of modified 8-week reminiscence therapy on the older spouse caregivers of stroke survivors in Chinese communities: A randomized controlled trial. AB - OBJECTIVE: Our aim was to evaluate the effectiveness of a modified 8-week reminiscence therapy on the burden, positive experience, and life satisfaction of older spouse caregivers and the life satisfaction of stroke survivors. METHODS: We conducted a randomized controlled trial by using 75 older stroke couples recruited from communities in Zhengzhou, China. We randomly assigned participants to 1 of 3 groups: Group 1 (G1 , 25 couples, all attend intervention) and Group 2 (G2 , 22 couples, only caregivers attend intervention), who participated in a modified 8-week reminiscence therapy, and a waiting list (control) group (G3 , 28 couples). Interviewers blinded to treatment group assignment administered the life satisfaction to both stroke survivors and caregivers, caregiver burden, and positive experience for caregivers, at preintervention, immediately postintervention, and at 1 month and 3 months after cessation of the intervention. RESULTS: We found a statistically significant interaction between treatment groups and assessment time points for the 4 outcome measures (P < .001). Although the effects were decreased after intervention at 1 month, the improvement in caregivers' positive experience, life satisfaction, burden, and life satisfaction of stroke survivors were still significant (P < .001). CONCLUSIONS: The use of a modified 8-week reminiscence therapy in this study sample improved the life satisfaction of stroke survivors and their spouse caregivers, improved the positive experience of caregivers, and decreased the burden of caregivers. PMID- 29266451 TI - Left-handed helical polymer resin nanotubes prepared by using N-palmitoyl glucosamine. AB - Although the preparation of single-handed helical inorganic and hybrid organic inorganic nanotubes is well developed, approaches to the formation of single handed organopolymeric nanotubes are limited. Here, left-handed helical m phenylenediamine-formaldehyde resin and 3-aminophenol-formaldehyde resin nanotubes were prepared by using N-palmitoyl glucosamine that can self-assemble into left-handed twisted nanoribbons in a mixture of methanol and water. In the reaction mixture, the helical pitch of the nanoribbons decreased with increasing reaction time. The resin nanotubes were obtained after removing the N-palmitoyl glucosamine template, and circular dichroism spectroscopy indicated that the organopolymeric nanotubes had optical activity. Carbonaceous nanotubes were then prepared by carbonization of the 3-aminophenol-formaldehyde resin nanotubes. PMID- 29266452 TI - Retrospective motion gating in cardiac MRI using a simultaneously acquired navigator. AB - A simultaneous acquisition technique of image and navigator signals (simultaneously acquired navigator, SIMNAV) is proposed for cardiac magnetic resonance imaging (CMRI) in Cartesian coordinates. To simultaneously acquire both image and navigator signals, a conventional balanced steady-state free precession (bSSFP) pulse sequence is modified by adding a radiofrequency (RF) pulse, which excites a supplementary slice for the navigator signal. Alternating phases of the RF pulses make it easy to separate the simultaneously acquired magnetic resonance data into image and navigator signals. The navigator signals of the proposed SIMNAV were compared with those of current gating devices and self-gating techniques for seven healthy subjects. In vivo experiments demonstrated that SIMNAV could provide cardiac cine images with sufficient image quality, similar to those from electrocardiogram (ECG) gating with breath-hold. SIMNAV can be used to acquire a cardiac cine image without requiring an ECG device and breath-hold, whilst maintaining feasible imaging time efficiency. PMID- 29266453 TI - Perspectives of patients with non-insulin-treated type 2 diabetes on self monitoring of blood glucose: A qualitative study. AB - AIMS AND OBJECTIVES: To explore experiences of self-monitoring of blood glucose among patients with non-insulin-treated type 2 diabetes. BACKGROUND: Self monitoring of blood glucose is essential to diabetes care and facilitates glycaemic control. Patients' perspectives of self-monitoring of blood glucose have seldom been discussed in the literature, and engagement in self-monitoring of blood glucose is consistently low. DESIGN: The descriptive phenomenological method was used. METHODS: Purposive sampling was conducted to recruit participants from the endocrinology departments of medical institutions in Taiwan based on the following criteria: (i) having a medical diagnosis of type 2 diabetes, (ii) not being treated with insulin, (iii) having engaged in self monitoring of blood glucose at least once within the preceding 6 months, (iv) being at least 20 years old and (v) not having any major mental or cognitive disorders. Data were collected in outpatient consultation rooms, the participants' homes and other settings where the participants felt secure and comfortable. In-depth interviews were conducted to collect data from 16 patients with diabetes. RESULTS: The participants perceived that lifestyle affected blood glucose levels and did not know how to handle high or low blood glucose levels. Their willingness to continue self-monitoring of blood glucose depended on whether healthcare professionals checked or discussed their blood glucose levels with them. CONCLUSIONS: The patients' knowledge regarding blood glucose variation and healthcare professionals' attitudes affected the patients' self-monitoring of blood glucose behaviours. The empirical findings illustrated self-monitoring of blood glucose experiences and recommended that healthcare professionals' closely attend to patients' requirements and responses to diabetes and incorporate the self-monitoring of blood glucose into therapy plans. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals should reinforce patients' knowledge on appropriate responses to high and low blood glucose levels, intervene appropriately, discuss self-monitoring of blood glucose results with patients and track these results. PMID- 29266454 TI - Bilateral periventricular nodular heterotopia detected on fetal and maternal MRI attributable to novel filamin A gene mutation. PMID- 29266455 TI - One duct, two orifices, no names! the anatomy of the biliary cystic duct. AB - The biliary cystic duct (CD) connects the gallbladder to the extra-hepatic bile duct, and the point at which it does this delineates the division between the common hepatic duct and the common bile duct. Its clinical relevance in disease, and importance during interventions relating to the gallbladder mean that its normal and variant anatomy has been described extensively in literature. However, an aspect not yet fully described includes naming of its two orifices on either end. This is highly relevant for surgical, endoscopic, and percutaneous procedures. We describe these as encountered in normal CD and biliary tree anatomy. We believe this is crucial for interventions relating to the gallbladder and the biliary tree, including prevention of iatrogenic injury. Clin. Anat. 31:422-423, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29266456 TI - Predicting response after infliximab salvage in acute severe ulcerative colitis. AB - BACKGROUND AND AIM: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification. METHODS: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared. RESULTS: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage. CONCLUSIONS: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms. PMID- 29266457 TI - Characteristics of Australian adolescent females in residential treatment who report using methamphetamines. AB - INTRODUCTION AND AIMS: To investigate factors associated with methamphetamine use in adolescent females referred to an Australian residential treatment service. DESIGN AND METHODS: A mixed-methods explanatory sequential design was undertaken. Cross-sectional analysis of existing pre-treatment data for adolescent females aged 13-18 years (median 16.48 years) attending a treatment program between 2009 and 2015 (n = 267) was undertaken, followed by a focus group and in-depth interviews of key staff. RESULTS: Female methamphetamine-users (n = 127, 47.6%) were significantly more likely than non-methamphetamine-users at pre-treatment to be in unstable living arrangements, where they moved frequently (P = 0.025), lived in more unstable (not rented or privately owned) accommodation (P = 0.012) and had problematic family situations (P = 0.004). They were more likely than non methamphetamine-users to be to be poly-drug users (P < 0.001) and to have ever attempted suicide (P = 0.029). Cumulative trauma by someone known to the adolescent was the main predictor for female methamphetamine use (odds ratio 3.077). Qualitative data provided context and depth to quantitative findings, with an emphasis on trauma as a precursor to methamphetamine use. The qualitative interviews also highlighted changes made in service provision, given the increasing rates of methamphetamine use. DISCUSSION AND CONCLUSIONS: High levels of trauma and mental health problems in this population support the notion that traumatic childhood experiences are strongly associated with problematic alcohol and other drug use, particularly, methamphetamine use, at a young age. Increased attention to decreasing family violence, abuse and neglect is required and in clinical practice, a trauma-informed model of care is recommended. PMID- 29266458 TI - Development of non-bonded interaction parameters between graphene and water using particle swarm optimization. AB - New Lennard-Jones parameters have been developed to describe the interactions between atomistic model of graphene, represented by REBO potential, and five commonly used all-atom water models, namely SPC, SPC/E, SPC/Fw, SPC/Fd, and TIP3P/Fs by employing particle swarm optimization (PSO) method. These new parameters were optimized to reproduce the macroscopic contact angle of water on a graphene sheet. The calculated line tension was in the order of 10-11 J/m for the droplets of all water models. Our molecular dynamics simulations indicate the preferential orientation of water molecules near graphene-water interface with one O?H bond pointing toward the graphene surface. Detailed analysis of simulation trajectories reveals the presence of water molecules with <=~1, ~2, and ~4 hydrogen bonds at the surface of air-water interface, graphene-water interface, and bulk region of the water droplet, respectively. Presence of water molecules with <=~1 and ~2 hydrogen bonds suggest the existence of water clusters of different sizes at these interfaces. The trends observed in the libration, bending, and stretching bands of the vibrational spectra are closely associated with these structural features of water. The inhomogeneity in hydrogen bond network of water at the air-water and graphene-water interface is manifested by broadening of the peaks in the libration band for water present at these interfaces. The stretching band for the molecules in water droplet shows a blue shift as compared to the pure bulk water, which conjecture the presence of weaker hydrogen bond network in a droplet. (c) 2017 Wiley Periodicals, Inc. PMID- 29266459 TI - Non-invasive diagnosis and metabolic consequences of congenital portosystemic shunts in C57BL/6 J mice. AB - This study demonstrates the suitability of magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) for the imaging of congenital portosystemic shunts (PSS) in mice, a vascular abnormality in which mesenteric blood bypasses the liver and is instead drained directly to the systemic circulation. The non invasive diagnosis performed in tandem with other experimental assessments permits further characterization of liver, whole-body and brain metabolic defects associated with PSS. Magnetic resonance measurements were performed in a 26-cm, horizontal-bore, 14.1-T magnet. MRA was obtained with a three-dimensional gradient echo sequence (GRE; in-plane resolution, 234 * 250 * 234 MUm3 ) using a birdcage coil. Two-dimensional GRE MRI with high spatial resolution (in-plane resolution, 100 * 130 MUm2 ; slices, 30 * 0.3 mm) was performed using a surface coil. Brain- (dorsal hippocampus) and liver-localized 1 H magnetic resonance spectroscopy (MRS) was also performed with the surface coil. Whole-body metabolic status was evaluated with an oral glucose tolerance test (OGTT). Both MRA and anatomical MRI allowed the identification of hepatic vessels and the diagnosis of PSS in mice. The incidence of PSS was about 10%. Hepatic lipid content was higher in PSS than in control mice (5.1 +/- 2.8% versus 1.8 +/- 0.6%, p = 0.02). PSS mice had higher brain glutamine concentration than controls (7.3 +/- 1.0 MUmol/g versus 2.7 +/- 0.6 MUmol/g, p < 0.0001) and, conversely, lower myo-inositol (4.2 +/- 0.6 MUmol/g versus 6.0 +/- 0.4 MUmol/g, p < 0.0001), taurine (9.7 +/- 1.2 MUmol/g versus 11.0 +/- 0.4 MUmol/g, p < 0.01) and total choline (0.9 +/- 0.1 MUmol/g versus 1.2 +/- 0.1 MUmol/g, p < 0.001) concentrations. Fasting blood glucose and plasma insulin were lower in PSS than in control mice (4.7 +/- 0.5mM versus 8.8 +/- 0.6mM, p < 0.0001; and 0.04 +/- 0.03 MUg/L versus 0.3 +/- 0.2 MUg/L, p = 0.02, respectively). Glucose clearance during OGTT was delayed and less efficient in PSS mice than in controls. Thus, given the non-negligible incidence of PSS in inbred mice, the undiagnosed presence of PSS will, importantly, have an impact on experimental outcomes, notably in studies addressing brain, liver or whole-body metabolism. PMID- 29266460 TI - Plant cell wall-mediated immunity: cell wall changes trigger disease resistance responses. AB - Plants have evolved a repertoire of monitoring systems to sense plant morphogenesis and to face environmental changes and threats caused by different attackers. These systems integrate different signals into overreaching triggering pathways which coordinate developmental and defence-associated responses. The plant cell wall, a dynamic and complex structure surrounding every plant cell, has emerged recently as an essential component of plant monitoring systems, thus expanding its function as a passive defensive barrier. Plants have a dedicated mechanism for maintaining cell wall integrity (CWI) which comprises a diverse set of plasma membrane-resident sensors and pattern recognition receptors (PRRs). The PRRs perceive plant-derived ligands, such as peptides or wall glycans, known as damage-associated molecular patterns (DAMPs). These DAMPs function as 'danger' alert signals activating DAMP-triggered immunity (DTI), which shares signalling components and responses with the immune pathways triggered by non-self microbe associated molecular patterns that mediate disease resistance. Alteration of CWI by impairment of the expression or activity of proteins involved in cell wall biosynthesis and/or remodelling, as occurs in some plant cell wall mutants, or by wall damage due to colonization by pathogens/pests, activates specific defensive and growth responses. Our current understanding of how these alterations of CWI are perceived by the wall monitoring systems is scarce and few plant sensors/PRRs and DAMPs have been characterized. The identification of these CWI sensors and PRR-DAMP pairs will help us to understand the immune functions of the wall monitoring system, and might allow the breeding of crop varieties and the design of agricultural strategies that would enhance crop disease resistance. PMID- 29266463 TI - Dithiocarboxylic Acids: An Old Theme Revisited and Augmented by New Preparative, Spectroscopic and Structural Facts. AB - The unstable dithiocarboxylic acids dithioacetic acid, 2-methyl-dithiopropionic acid, 2,2-dimethyl-dithiopropionic acid and dithiobenzoic acid were synthesized and characterized by NMR spectroscopy and GC/MS. The stable dithiocarboxylic acids 2,4,6-trimethyl benzoic acid, 2,4,6-tri-iso-propylbenzoic acid and 2,6 dimesityl benzoic acid were synthesized, isolated and characterized by spectroscopic methods and in parts by mass spectrometry and X-ray crystallography. The new data were used to re-evaluate literature data on the synthesis, spectroscopy and structural data of dithiocarboxylic acids as a fundamental class of organic compounds in general. PMID- 29266461 TI - Counting the cold ones: A comparison of methods measuring total alcohol consumption of managed alcohol program participants. AB - INTRODUCTION AND AIMS: Managed alcohol programs (MAP) aim to reduce harms experienced by unstably housed individuals with alcohol use disorders by providing regulated access to beverage alcohol, usually alongside housing, meals and other supports. This study compares two methods of estimating participants' outside alcohol consumption in order to inform program policies and practices around alcohol dosing and reducing risks of alcohol-related illnesses. METHODS: The total alcohol consumption of 65 people participating in Canadian MAPs was assessed comparing daily MAP records (1903 client days) with researcher administered surveys over the same time period. A sub-sample of more complete daily MAP records for 39 people (696 client days) was also compared with the equivalent survey data on drinking. RESULTS: Significantly more standard drinks per day (SDs, one SD = 17.05 mL ethanol) were reported in research interviews than recorded by program staff, whether for program administered drinks alone (means 16.04 vs. 8.32 SDs, t = 5.79, P < 0.001) or including outside-program drinks as reported to staff (16.04 vs. 8.89 SDs, t = 5.37, P < 0.001). Consistent results were found in the sub-sample. The number of outside drinks estimated by comparing program records with the research interviews, varied between 2.71 and 9.94 mean drinks per day per site. DISCUSSION AND CONCLUSIONS: At two sites, MAP participants reported consuming more than twice the amount of alcohol administered on the program. At most sites, there was significant under-reporting of outside drinking. Addressing the problem of outside drinking and total daily consumption is critical for achieving program goals of both short and long-term harm reduction. PMID- 29266462 TI - ATLANTIC BIRDS: a data set of bird species from the Brazilian Atlantic Forest. AB - South America holds 30% of the world's avifauna, with the Atlantic Forest representing one of the richest regions of the Neotropics. Here we have compiled a data set on Brazilian Atlantic Forest bird occurrence (150,423) and abundance samples (N = 832 bird species; 33,119 bird individuals) using multiple methods, including qualitative surveys, mist nets, point counts, and line transects). We used four main sources of data: museum collections, on-line databases, literature sources, and unpublished reports. The data set comprises 4,122 localities and data from 1815 to 2017. Most studies were conducted in the Florestas de Interior (1,510 localities) and Serra do Mar (1,280 localities) biogeographic sub-regions. Considering the three main quantitative methods (mist net, point count, and line transect), we compiled abundance data for 745 species in 576 communities. In the data set, the most frequent species were Basileuterus culicivorus, Cyclaris gujanensis, and Conophaga lineata. There were 71 singletons, such as Lipaugus conditus and Calyptura cristata. We suggest that this small number of records reinforces the critical situation of these taxa in the Atlantic Forest. The information provided in this data set can be used for macroecological studies and to foster conservation strategies in this biodiversity hotspot. No copyright restrictions are associated with the data set. Please cite this Data Paper if data are used in publications and teaching events. PMID- 29266464 TI - Prenatal diagnosis of LUTO: improving diagnostic accuracy. AB - OBJECTIVE: To propose a clinical score for the optimal antenatal diagnosis of fetal lower urinary tract obstruction (LUTO) in the second and third trimesters of pregnancy, as an alternative to the commonly used ultrasound triad of megacystis, keyhole sign and hydronephrosis. METHODS: This was a national retrospective study carried out at the eight tertiary fetal medicine units (FMUs) in The Netherlands. Only cases referred for megacystis from the second trimester onwards and with a clear postnatal diagnosis were included in the study. At referral, data were collected on amniotic fluid volume, renal cortical appearance, bladder volume, hydronephrosis, fetal ascites, ureteral size, keyhole sign, fetal sex and gestational age. Multivariate analysis was performed, starting by including all antenatal variables, and then excluding the weakest predictors using the backward stepwise strategy. RESULTS: Over a 7-year period, 312 fetuses with a diagnosis of megacystis were referred to the eight Dutch tertiary FMUs. A final diagnosis was achieved in 143 cases, including 124 of LUTO and 19 reclassified after birth as non-obstructive megacystis. The optimal bladder volume cut-off for prediction of LUTO was 35 cm3 (area under the curve (AUC) = 0.7, P = 0.03). The clinical score formulated on the basis of the multivariate analysis included fetal sex, degree of bladder distension, ureteral size, oligo- or anhydramnios and gestational age at referral. The combination of these five variables demonstrated good accuracy in discriminating LUTO from non obstructive megacystis (AUC = 0.84, P < 0.001), compared with the poor performance of the ultrasound triad (AUC = 0.63, P = 0.07). CONCLUSIONS: We propose a clinical score that combines five antenatal variables for the prospective diagnosis of congenital LUTO. This score showed good discriminative capacity in predicting LUTO, and better diagnostic accuracy compared with that of the classic ultrasound triad. Future studies to validate these results should be carried out in order to refine antenatal management of LUTO and prevent inappropriate fetal interventions. (c) 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 29266465 TI - Effect of modulating dietary vitamin D on the general bone health of rats during posterolateral spinal fusion. AB - Vitamin D plays a significant role in musculoskeletal health by regulating calcium, phosphate, and promoting new bone mineralization. The purpose of this study was to understand the effect of dietary vitamin D on general bone health during peri-operative bone healing via an in vivo dosing study of vitamin D in a rat posterolateral fusion model using autograft. Vitamin D Deficient (DD), vitamin D Insufficient (ID), Control vitamin D (CD), and Hyper-vitamin D (HD) groups were studied. Increasing dietary vitamin D improved quantitative measures of femoral geometry, including femoral strength, stiffness, and density. Femoral biomechanics, cortical thickness, moment of inertia, cross-sectional area, and measures from bone ashing were all greater in the HD group versus the CD. This suggests that additional dietary vitamin D above normal levels during spinal fusion may lead to improvement in bone health. Serum vitamin D levels were also observed to decrease during fusion healing. These results demonstrate that dietary vitamin D improves general bone health in the femur of a rat model during posterolateral spinal fusion. This suggests a role for further clinical evaluation of vitamin D dietary intake during the peri-operative period, with the possibility of avoiding adverse consequences to general bone health. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1435-1443, 2018. PMID- 29266466 TI - Use of linear and convex ultrasound transducers for evaluation of retrosternal area in patients after cardiac surgery. AB - The use of linear and convex transducers is usually reserved for ultrasound imaging of vessels, abdominal organs, and lungs. However, the use of these transducers may be extended for the evaluation of thoracic structures. We describe our experience with the use of linear and convex transducers in the evaluation of the retrosternal area, which is usually difficult to visualize by conventional echocardiography and so could provide improved diagnostic information in patients after cardiac surgery. PMID- 29266467 TI - Visual attention to motion stimuli and its neural correlates in cannabis users. AB - Attention to motion stimuli and correct motion perception are vital for road safety. Although cannabis use has been associated with increased road crash risks, there is limited research on attentional processing of moving stimuli in cannabis users. This study investigated the neural correlates of the three stimulus oddball task in cannabis users (n = 18) and non-users (n = 23) in response to moving stimuli. Stimulus contrast was under 16% against a low luminance background (M luminance < 16 cd/m2 ). The two groups did not differ in accuracy or in N2 peak amplitude; however, N2 latency was longer for target and standard stimuli in the cannabis group than in the control group. The cannabis group also showed a significantly reduced P3b amplitude in response to target stimuli. The AUDIT score was added as a random factor to the anova to rule out the effects of uneven alcohol consumption in the two groups. A significant group effect was found for N2 latency in response to target and standard stimuli and a significant interaction between the group, and the AUDIT score was found for the P3b peak amplitude for the distractor and standard stimuli, but not for the target stimuli. The results of this study suggest that cannabis use relates to reduced neural activity underlying attention to motion stimuli. Implications for regular early-onset cannabis use road safety are discussed. PMID- 29266468 TI - Quadrupolar jump-and-return pulse sequence for fluid-suppressed sodium MRI of the knee joint at 7T. AB - PURPOSE: To demonstrate the feasibility of the so-called quadrupolar jump-and return (QJR) pulse sequence by assessing its performance on the contrast modification to knee cartilage and quality of fluid suppression in the knee joint in vivo at 7T. METHODS: The right knee joints of five healthy volunteers (3 males: mean age = 32.4 +/- 1.3 years; 2 females: mean age = 27.9 +/- 1.0 years; mean age = 30.6 +/- 2.7 years) were scanned on a 7T scanner with variation of the delay in the QJR sequence from 1 ms to 5 ms. For one healthy volunteer, the QJR scan with the delay of 3 ms and the inversion-recovery (IR) scan were performed. Numerical simulations were conducted to evaluate the effects of B0 - and B1 field inhomogeneities and residual quadrupolar couplings on fluid suppression and tissue contrast, respectively. RESULTS: The QJR sequence suppressed the fluid signal from the artery and produced the contrast of knee cartilage in vivo. Its performance was comparable to that of the conventional IR sequence. Numerical simulations suggested that the fluid suppression may not be affected much by field inhomogeneities but that a distribution of residual quadrupolar couplings and weak RF pulses may interfere with the clear interpretation of cartilage contrast. CONCLUSION: This preliminary work demonstrated that the QJR pulse sequence produces contrast for knee cartilage while suppressing the fluid signal from the artery. The knee cartilage contrast and quality of fluid suppression obtained from the QJR sequence were comparable to those of the IR sequence. Magn Reson Med 80:641-647, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29266470 TI - Hydrophilicity of Graphene in Water through Transparency to Polar and Dispersive Interactions. AB - Establishing contact angles on graphene-on-water has been a long-standing challenge as droplet deposition causes free-floating graphene to rupture. The current work presents ice and hydrogels as substrates mimicking water while offering a stable support for graphene. The lowest water contact angles on graphene ever measured, namely on graphene-on-ice and graphene-on-hydrogel, are recorded. The contact angle measurements of liquids with a range of polarities allow the transparency of graphene toward polar and dispersive interactions to be quantified demonstrating that graphene in water is hydrophilic. These findings are anticipated to shed light on the inconsistencies reported so far on the wetting properties of graphene, and most particularly on their implications toward rationalizing how molecules interact with graphene in water. PMID- 29266469 TI - Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization. AB - BACKGROUND: Filaggrin loss-of-function (FLG-LOF) mutations are an established genetic cause of eczema. These mutations have subsequently been reported to increase the risk of aeroallergen sensitization and allergic airway disease. However, it is unclear whether FLG variants require both eczema and aeroallergen sensitization to influence airway disease development long-term outcomes. OBJECTIVE: To examine the effects of FLG-LOF mutations on allergic airway disease outcomes, with eczema and aeroallergen sensitization as intermediate variables, using the Isle of Wight birth cohort. METHODS: Study participants were evaluated at ages 1, 2, 4, 10 and 18 years to ascertain the development of allergic diseases (eczema, asthma and allergic rhinitis) and aeroallergen sensitization (determined by skin prick tests). FLG-LOF mutations were genotyped in 1150 subjects. To understand the complex associations between FLG mutations, intermediate variables (eczema and aeroallergen sensitization) and airway disease, path analysis was performed. RESULTS: There were significant total effects of FLG-LOF mutations on both asthma and allergic rhinitis at all ages as well as on aeroallergen sensitization up till 10 years old. In the filaggrin asthma analysis, a direct effect of FLG-LOF mutations was observed on early childhood eczema (age 1 and 2 years) (relative risk (RR) 2.01, 95% CI: 1.74-2.31, P < .001), and all significant indirect pathways on asthma outcomes passed through eczema at these ages. In contrast, for the filaggrin-rhinitis model, FLG LOF mutations exerted significant direct effects on early eczema as well as rhinitis at 10 years (RR 1.99; 95% CI: 1.72-2.29, P = .002). CONCLUSION: FLG-LOF mutations are a significant risk factor for later childhood asthma and rhinitis. However, the pathway to asthma is only through early childhood eczema while a direct effect was observed for childhood rhinitis. PMID- 29266471 TI - Fatal disseminated Trichosporon asahii fungemia in a child with acute lymphoblastic leukemia and a morbilliform eruption. AB - Trichosporonosis is a rare, life-threatening, opportunistic fungal infection that affects immunocompromised individuals with neutropenia, particularly those with underlying hematologic malignancies. We present the case of a 10-year-old boy with acute lymphoblastic leukemia who developed a diffuse, morbilliform eruption in the setting of fever and pancytopenia. He was found to have Trichosporon asahii fungemia with widespread visceral dissemination, and his condition rapidly deteriorated despite treatment. It is important to consider trichosporonosis in the evaluation of a critically ill individual with neutropena and a rash, because the initial cutaneous presentation may appear benign and delayed therapy results in death. PMID- 29266473 TI - High-Performance Vertical Organic Electrochemical Transistors. AB - Organic electrochemical transistors (OECTs) are promising transducers for biointerfacing due to their high transconductance, biocompatibility, and availability in a variety of form factors. Most OECTs reported to date, however, utilize rather large channels, limiting the transistor performance and resulting in a low transistor density. This is typically a consequence of limitations associated with traditional fabrication methods and with 2D substrates. Here, the fabrication and characterization of OECTs with vertically stacked contacts, which overcome these limitations, is reported. The resulting vertical transistors exhibit a reduced footprint, increased intrinsic transconductance of up to 57 mS, and a geometry-normalized transconductance of 814 S m-1 . The fabrication process is straightforward and compatible with sensitive organic materials, and allows exceptional control over the transistor channel length. This novel 3D fabrication method is particularly suited for applications where high density is needed, such as in implantable devices. PMID- 29266472 TI - Current treatment strategies for advanced prostate cancer. AB - During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone-sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration-resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel-T, radium 223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing. PMID- 29266474 TI - Maternal perceptions of family-centred support and their associations with the mother-nurse relationship in the neonatal intensive care unit. AB - AIMS AND OBJECTIVES: To evaluate maternal perceptions of family-centred support with hospitalised preterm infants and their relationship between mothers and nurses in the neonatal intensive care unit (NICU). BACKGROUND: Mothers who gave birth to preterm infants tend to suffer more stress and need individual support based on family-centred care. However, there may be a shortage of support for mothers to obtain parent-crafting skills before bringing their infants home. DESIGN: This cross-sectional study used path analysis and multiple group analysis to evaluate a structural equation model of the relationship between maternal perception based on family-centred support in parent-crafting training and the mothers-nurses collaboration. METHODS: We analysed data from 98 mothers (valid response proportion, 41.0%) whose infants were hospitalised in the NICU of two types of perinatal centres in Japan. We used three revised standardised questionnaires in Japanese: Measure of Process of Care in the NICU (Neo-MPOC 20), Enabling Practice Scale in the NICU (Neo-EPS) and the author-developed Mother and Infant Questionnaire. RESULTS: Path analysis revealed that the relationship between mothers and nurses was linked to three factors related to the perinatal centres' support: consideration of parents' feelings, ability to deal with specific needs and coordination in dealing with situations that interact with provision of parent-friendly visual information. Separate path analyses for each perinatal centre showed the same pattern, although the standard coefficients were different. CONCLUSIONS: Maternal perceptions of family-centred support with hospitalised preterm infants promoted better collaboration between mothers and nurses to obtain parent-crafting skills at two types of perinatal units in Japan. RELEVANCE TO CLINICAL PRACTICE: Clear visual information materials might promote better maternal understanding of their infants, help in acquisition of parent crafting skills and improve mother-nurse collaboration, with the result that mothers are better able to care for their infants autonomously at home. PMID- 29266475 TI - Small-angle X-ray and neutron scattering demonstrates that cell-free expression produces properly formed disc-shaped nanolipoprotein particles. AB - Nanolipoprotein particles (NLPs), composed of membrane scaffold proteins and lipids, have been used to support membrane proteins in a native-like bilayer environment for biochemical and structural studies. Traditionally, these NLPs have been prepared by the controlled removal of detergent from a detergent solubilized protein-lipid mixture. Recently, an alternative method has been developed using direct cell-free expression of the membrane scaffold protein in the presence of preformed lipid vesicles, which spontaneously produces NLPs without the need for detergent at any stage. Using SANS/SAXS, we show here that NLPs produced by this cell-free expression method are structurally indistinguishable from those produced using detergent removal methodologies. This further supports the utility of single step cell-free methods for the production of lipid binding proteins. In addition, detailed structural information describing these NLPs can be obtained by fitting a capped core-shell cylinder type model to all SANS/SAXS data simultaneously. PMID- 29266477 TI - Endocrine manifestations in children with Williams-Beuren syndrome. AB - AIM: Endocrine abnormalities in Williams-Beuren syndrome (WBS) include growth retardation, precocious puberty, hypercalcaemia and thyroid disorders. We aimed to characterise these abnormalities in a national cohort of children with WBS. METHODS: A retrospective study comprising a national cohort of individuals with WBS in Israel (16 males, 18 females) followed between 2010 and 2016. RESULTS: The age at diagnosis of WBS was 1.4 +/- 1.0 years. Height standard deviation score (SDS) at last visit was correlated with the midparental height SDS (r = 0.46 p = 0.007). Yet, participants did not reach their midparental height, with a difference of 1.40 +/- 0.85SD (p < 0.001). Short stature below the 3rd percentile was found in 14 participants (41%). Mean insulin-like growth factor 1 SDS was low (-0.61 +/- 1.64) and was correlated with the mean height SDS (r = 0.63 p = 0.038). Two participants were diagnosed with growth hormone deficiency, and initiation of growth hormone treatment improved their height velocity. A total of eight participants (23.5%) had mild hypercalcaemia, five girls (14.7%) had precocious puberty and five participants (14.7%) had thyroid abnormalities. CONCLUSION: Individuals with WBS had a distinct growth pattern consisting of growth restriction at all ages, resulting in final adult height in the low-normal range. Precocious puberty, hypercalcaemia and thyroid abnormalities should be screened for and treated as needed. PMID- 29266476 TI - Activatable Hybrid Nanotheranostics for Tetramodal Imaging and Synergistic Photothermal/Photodynamic Therapy. AB - A multifunctional core-satellite nanoconstruct is designed by assembling copper sulfide (CuS) nanoparticles on the surface of [89 Zr]-labeled hollow mesoporous silica nanoshells filled with porphyrin molecules, for effective cancer imaging and therapy. The hybrid nanotheranostic demonstrates three significant features: (1) simple and robust construction from biocompatible building blocks, demonstrating prolonged blood retention, enhanced tumor accumulation, and minimal long-term systemic toxicity, (2) rationally selected functional moieties that interact together to enable simultaneous tetramodal (positron emission tomography/fluorescence/Cerenkov luminescence/Cerenkov radiation energy transfer) imaging for rapid and accurate delineation of tumors and multimodal image-guided therapy in vivo, and (3) synergistic interaction between CuS-mediated photothermal therapy and porphyrin-mediated photodynamic therapy which results in complete tumor elimination within a day of treatment with no visible recurrence or side effects. Overall, this proof-of-concept study illustrates an efficient, generalized approach to design high-performance core-satellite nanohybrids that can be easily tailored to combine a wide variety of imaging and therapeutic modalities for improved and personalized cancer theranostics in the future. PMID- 29266478 TI - The relationship between intention to leave the hospital and coping methods of emergency nurses after workplace violence. AB - AIMS AND OBJECTIVES: To identify the relationship between emergency nurses' intention to leave the hospital and their coping methods following workplace violence. BACKGROUND: Emergency departments report a high prevalence of workplace violence, with nurses being at particular risk of violence from patients and patients' relatives. Violence negatively influences nurses' personal and professional lives and increases their turnover. DESIGN: This is a cross sectional, descriptive survey study. METHODS: Participants were nurses (n = 214) with over one year of experience of working in an emergency department. We measured workplace violence, coping after workplace violence experiences and job satisfaction using scales validated through a preliminary survey. Questionnaires were distributed to all nurses who signed informed consent forms. Multiple logistic regression analysis was used to identify the relationships between nurses' intention to leave the hospital and their coping methods after workplace violence. RESULTS: Verbal abuse was the most frequent violence experience and more often originated from patients' relatives than from patients. Of the nurses who experienced violence, 61.0% considered leaving the hospital. As for coping, nurses who employed problem-focused coping most frequently sought to identify the problems that cause violence, while nurses who employed emotion-focused coping primarily attempted to endure the situation. The multiple logistic regression analysis revealed that female sex, emotion-focused coping and job satisfaction were significantly related to emergency nurses' intention to leave. CONCLUSIONS: Emotion-focused coping seems to have a stronger effect on intention to leave after experiencing violence than does job satisfaction. RELEVANCE TO CLINICAL PRACTICE: Nurse managers should begin providing emergency nurses with useful information to guide their management of violence experiences. Nurse managers should also encourage nurses to report violent experiences to the administrative department rather than resorting to emotion-focused coping. Nurses should be provided with the opportunity to communicate their feelings to their colleagues. PMID- 29266479 TI - The complex physiology of Cellvibrio japonicus xylan degradation relies on a single cytoplasmic beta-xylosidase for xylo-oligosaccharide utilization. AB - Lignocellulose degradation by microbes plays a central role in global carbon cycling, human gut metabolism and renewable energy technologies. While considerable effort has been put into understanding the biochemical aspects of lignocellulose degradation, much less work has been done to understand how these enzymes work in an in vivo context. Here, we report a systems level study of xylan degradation in the saprophytic bacterium Cellvibrio japonicus. Transcriptome analysis indicated seven genes that encode carbohydrate active enzymes were up-regulated during growth with xylan containing media. In-frame deletion analysis of these genes found that only gly43F is critical for utilization of xylo-oligosaccharides, xylan, and arabinoxylan. Heterologous expression of gly43F was sufficient for the utilization of xylo-oligosaccharides in Escherichia coli. Additional analysis found that the xyn11A, xyn11B, abf43L, abf43K, and abf51A gene products were critical for utilization of arabinoxylan. Furthermore, a predicted transporter (CJA_1315) was required for effective utilization of xylan substrates, and we propose this unannotated gene be called xntA (xylan transporter A). Our major findings are (i) C. japonicus employs both secreted and surface associated enzymes for xylan degradation, which differs from the strategy used for cellulose degradation, and (ii) a single cytoplasmic beta xylosidase is essential for the utilization of xylo-oligosaccharides. PMID- 29266480 TI - The attitudes of Turkish nurses towards the employment of internationally educated nurses. AB - AIM: To define the attitudes of nurses working in public hospitals towards the employment of internationally educated nurses. BACKGROUND: The employment of internationally educated nurses is expected to be an important strategy for solving the nursing shortage in Turkey and many other countries. METHODS: This descriptive and cross-sectional study was conducted with nurses working in seven public university hospitals in different geographical regions of Turkey in September 2015. The data were collected from 1061 nurses in these hospitals using a self-report questionnaire. Data analysis was performed using descriptive statistics, t-test and the Mann-Whitney U test. RESULTS: The participants generally did not have positive attitudes towards the employment of internationally educated nurses citing the possibility of experiencing cultural and professional difficulties. They also indicated that the employment of internationally educated nurses is not a real solution for the nursing shortage unless working conditions for nurses are improved. However, younger nurses have more positive attitudes towards employment of internationally educated nurses than older ones. IMPLICATIONS FOR NURSING POLICY: Defining the attitudes of the nurses working in clinical fields towards the employment of internationally educated nurses is an important issue, because it provides data for reviewing the existing policies and evaluating the possible issues that require attention during implementation of these policies. Policymakers may focus on both creating better working environment conditions and helping both the native and internationally educated nurses during the recruiting process. PMID- 29266481 TI - Human filarial proteins attenuate chronic colitis in an experimental mouse model. AB - Encouraged by our earlier results of promising therapeutic effect of filarial recombinant proteins BmALT2, BmCys and WbL2 individually in the mouse model of acute ulcerative colitis, in this study, these proteins have been explored individually and in different combinations for their therapeutic potential in dextran sulphate sodium (DSS)-induced chronic colitis mice. These mice, treated with filarial proteins, showed reduced disease parameters including body weight loss, disease activity index, macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Among various treatment schemes, rBmALT2 + rBmCys which showed most pronounced therapeutic implication was found to downregulate the mRNA expressions of IFN-gamma and TNF-alpha and upregulate IL 10 and TGF-beta expression in the splenocytes. Also, increase in level of IgG1 and IgG2a isotypes in the sera of rBmALT2 + rBmCys-treated colitis mice was noted. Activated NF-kappaB level was found to be reduced in the colon of treated colitis mice compared to untreated one. In conclusion, filarial proteins in combination have been shown to improve the clinicopathologic status of chronic colitis through suppression of pro-inflammatory immune response most possibly in NF-kappaB-dependent manner. We propose this therapeutic strategy to be tested further to be considered as an effective option in chronic colitis. PMID- 29266482 TI - Evaluation of consistency in quantification of gene copy number by real-time reverse transcription quantitative polymerase chain reaction and virus titer by plaque-forming assay for human respiratory syncytial virus. AB - The plaque-forming assay is the standard technique for determining viral titer, and a critical measurement for investigating viral replication. However, this assay is highly dependent on experimental technique and conditions. In the case of human respiratory syncytial virus (RSV) in particular, it can be difficult to objectively confirm the accuracy of plaque-forming assay because the plaques made by RSV are often small and unclear. In recent studies, RT-qPCR methods have emerged as a supportive procedure for assessment of viral titer, yielding highly sensitive and reproducible results. In this report, we compare the viral replication, as determined by plaque-forming assay, and the copy numbers of RSV genes NS1, NS2, N, and F, as determined by RT-qPCR. Two real-time PCR systems, SYBR Green and TaqMan probe, gave highly similar results for measurement of copy numbers of RSV N genes of virus subgroups A. We determined the RSV gene copy numbers in the culture cell supernatant and cell lysate measured at various multiplicities of infection. We found that copy number of the RSV N gene in the culture supernatant and cell lysate was highly correlated with plaque-forming units. In conclusion, RT-qPCR measurement of RSV gene copy number was highly dependent on viral titer, and the detailed comparison between each gene copy number and virus titer should be useful and supportive in confirming RSV plaque forming assay and virus dynamics. The technique may also be used to estimate the amount of RSV present in clinical specimens. PMID- 29266483 TI - Factors in the drop in the migration of Spanish-trained nurses: 1999-2007. AB - AIM: To reveal correlates of the decrease of Spanish nurse migration (1999-2007). BACKGROUND: Nursing outmigration is a concern for countries. Nurse migration from Spain began in the 1990s. INTRODUCTION: From 1999 to 2007, the yearly number of migrations dropped significantly. We ask what social, economic and policy factors could be related to this drop. METHODS: We used publicly available statistics to confirm hypothesis (1) The drop in nursing migration coincided with a drop in nursing unemployment. Then we hypothesized that this coincided with (1a) a decrease in the number of graduates, (1b) an increase in the number of hospitals and/or beds functioning, and/or (1c) an increase in the ratio of part-time contracts. RESULTS: Our analysis confirms hypotheses (1) and (1c) and disconfirms (1a) and (1b). CONCLUSION: The greater availability of part-time contracts seems to have encouraged nurses to remain in Spain. IMPLICATIONS FOR NURSING MANAGEMENT: The strategy to reduce nursing unemployment with more part-time contracts, while temporarily successful in Spain, brings with it major challenges for patient care and the working life of nurses. We suggest that nurse leaders and health policymakers consider proactive policies to adjust the balance between supply and demand without decreasing the quality of available positions. PMID- 29266484 TI - Insights on compassion and patient-centred nursing in intensive care: A constructivist grounded theory. AB - AIMS AND OBJECTIVES: To explore patient-centred nursing, compassion satisfaction and compassion fatigue from intensive care nurses' perspectives. BACKGROUND: Compassion satisfaction and compassion fatigue can influence critical care nurses' decisions to either continue or leave the profession, and could impact the compassionate patient-centred nursing care patients receive during their ICU admission. DESIGN: This qualitative research design was informed by Charmaz's Grounded Theory Constructivist methodology. METHODS: In-depth interviews were conducted with 21 critical care nurses of two ICUs in Australia during 2016. Interview data were analysed using grounded theory processes. RESULTS: Findings reflected positive and negative impacts on critical care nurses' ability to deal compassionately with their patients. Effects on patient-centred nursing and critical care nurses' own well-being were revealed. A core category of "Expectations" emerged, explaining the tension between critical care nurses' biomedical, clinical skills and knowledge versus compassionate, patient-centred nursing care. This tension was clarified and expanded in subcategories of "Life in the Balance," "Passion and Pressure," "Understanding and Advocacy" and "Tenacity and Fragility". CONCLUSION: Providing patient-centred nursing may enhance critical care nurses' experience of compassion satisfaction, in turn impacting delivery of compassionate patient-centred nursing to generate a virtuous circle. Critical care nurses who feel respected and supported by their management team and colleagues experience feelings of compassion satisfaction, leading to greater engagement and care towards their patient. RELEVANCE TO CLINICAL PRACTICE: Systematically addressing critical care nurses' needs to successfully balance biomedical with compassionate nursing care may lead to greater well-being in the critical care nursing workforce and improve patient experience of intensive care. PMID- 29266485 TI - The effect of resorbable membranes on one-stage ridge augmentation in anterior single-tooth replacement: A randomized, controlled clinical trial. AB - AIM: To evaluate the effect of resorbable membranes on one-stage ridge augmentation procedures in small (2-4 mm) buccal bony dehiscences in anterior maxillary single-tooth replacement. MATERIALS AND METHODS: Patients with a buccal bony dehiscence after implant placement in the esthetic zone were randomly allocated to one-stage ridge augmentation with (M+) or without a membrane (M-). Second-phase surgery was performed after 8 weeks, and follow-up was performed 1, 6, and >=12 months after loading. Outcomes included implant survival and success, complications, clinical and radiographic parameters, esthetic results and patient satisfaction. RESULTS: Fifty-two patients were randomized to one-stage ridge augmentation with (n = 25) or without use of a membrane (n = 27). No significant differences in implant survival and success have been observed. The risk of having a small mucosal dehiscence was more than six times higher in the M+ group than in the M- group (RR 6.24, 95% CI 0.81 to 48.21). At the last follow-up, the bleeding index (BI) was marginally higher in the M+ group (14/9/2/0) compared to the M- group (24/2/0/0) (U = 205, Z = -2.97, p = .003, r = .42). The median change in marginal bone level was statistically lower in the M+ group (0.06 mm) than the M- group (0.60 mm) at last follow-up (U = 120, Z = -2.73 a p = .006 r = .42). Total pink esthetic index (PES) and white esthetic score (WES) and combined PES/WES were not significantly different between treatment groups at more than 12 months after loading. Only the subcategory root convexity/soft tissue color scored significantly lower in the M+ group (1.5) compared to the M- group (2.0) at the last follow-up (U = 172, Z = -2.34, p = .019 r = .34). No differences were found in patient satisfaction. CONCLUSION: The use of a resorbable membrane in small buccal bony dehiscences in anterior maxillary single-tooth replacement resulted in less marginal bone loss, but showed more mucosal dehiscences, higher bleeding scores and lower scores on root convexity and soft tissue color after at least one year of loading. No effect was seen on implant survival and success, overall esthetic results, and patient satisfaction. The research protocol was registered at the Dutch Trial Register (NTR) with ID NTR6137. PMID- 29266486 TI - Development of a Competitive Time-Resolved Fluoroimmunoassay for Paclitaxel. AB - INTRODUCTION: Paclitaxel (Tax) is a diterpene alkaloid isolated from Taxus species and has proved clinically effective in treating a number of malignancies. Current quantitative analytical methods for Tax such as high-performance liquid chromatography (HPLC) often involve complicated sample preparation procedures with low recovery rates. OBJECTIVE: To establish a rapid and sensitive time resolved fluoroimmunoassay (TRFIA) for measuring Tax in Taxus materials with convenient sample preparation and a high recovery rate. METHODS: Rabbit anti mouse IgG was coated onto a 96-well microplate, which was then incubated with standard solutions of Tax and anti-Tax monoclonal antibody 3A3. A Eu3+ -labelled conjugate of Tax and human serum albumin was used as the tracer. The luminescent system was enhanced with a solution containing 2-naphthoyltrifluoroacetone. RESULTS: The established TRFIA showed a linear response within the Tax concentration range of 3.2 to 80 ng/mL, with a limit of detection of 1.4 ng/mL. The intra- and inter-assay coefficient of variation of the assay was 9.6% and 9.7%, respectively, with an average recovery rate from spiked samples of 108.5%. Tax contents in Taxus samples were determined using both the established TRFIA system and a previously established enzyme-linked immunosorbent (ELISA), and the results of two assays were well correlated. CONCLUSION: This TRFIA system shows a high sensitivity, precision and accuracy for detection of Tax. This assay, which is convenient and less time-consuming, allows rapid analysis of Tax and provides another option for Tax measurement for quality control of Taxus materials and products. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29266487 TI - Antiadhesion activity of juniper (Juniperus communis L.) preparations against Campylobacter jejuni evaluated with PCR-based methods. AB - The food-borne pathogen Campylobacter jejuni can cause bacterial gastrointestinal infections. Biofilm formation amplifies the risk of human infection by improving survival and persistence of C. jejuni in food processing environments and its transmission through the food chain. We aimed to control C. jejuni using an alternative strategy of low doses of Juniperus communis fruit preparations to target bacterial adhesion properties in the first step of biofilm formation. First, we defined the anti-Campylobacter activity of a juniper fruit crude extract and its fractionated biflavonoids, flavone glycosides, and purified amentoflavone, of juniper fruit essential oil and of juniper fruit postdistillation waste material extract. For accurate quantification of adherent C. jejuni, we optimised digital Polymerase Chain Reaction (PCR) and quantitative real-time PCR for construction of standard curves and quantification. We show for the first time that juniper fruit formulations can effectively inhibit adhesion of C. jejuni to polystyrene. Furthermore, >=94% of the antiadhesion activity of juniper fruit crude extract and juniper fruit essential oil remained under food related conditions: modified culture medium with glucose, or a stainless steel surface, or mixed co-cultures of C. jejuni and Listeria monocytogenes. This study indicates that addition of juniper fruit formulations can control growth and adhesion of C. jejuni and thus limit food chain transmission of campylobacters. PMID- 29266488 TI - A novel clinical test for partial tears of the distal biceps brachii tendon: The TILT sign. AB - Partial tears of the distal biceps brachii tendon are rare. A complete tear of the distal biceps brachii tendon is readily diagnosed on the basis of history and physical examination and has a well-described clinical presentation of acute pain in the antecubital fossa, localized tenderness, swelling, palpable defect, positive hook test, and weakness in forearm supination and elbow flexion. Partial tears, on the other hand, can present more subtly and remain a diagnostic challenge. We present a novel physical examination technique that utilizes the rotational anatomy of the radius. The patient's forearm is passively supinated and pronated with the elbow flexed to 90 degrees while the examiner firmly palpates the dorsal forearm overlying the radial tuberosity. The tuberosity presents itself beneath the examining fingers only in full forearm pronation. A positive test is indicated by tenderness over the radial (or lateral) aspect of the tuberosity (TILT sign) only in full forearm pronation, and not in supination. We have found this diagnostic test to be 100% sensitive for diagnosing partial distal biceps brachii tendon tears over the last five years during which it has been in use. Representative example cases are presented. A positive TILT sign indicates a diagnosis of partial tear of the distal biceps brachii tendon. This simple diagnostic maneuver could facilitate earlier detection of these injuries. Clin. Anat. 31:301-303, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266490 TI - Supramolecular Assembly of Phosphole Oxide Based Alkynylplatinum(II) 2,6-Bis(N alkylbenzimidazol-2'-yl)pyridine Complexes-An Interplay of Hydrophobicity and Aromatic pi-Surfaces. AB - A new class of phosphole oxide based alkynylplatinum(II) 2,6-bis(N alkylbenzimidazol-2'-yl)pyridine (bzimpy) complexes were synthesized and characterized. Their self-assembly was driven by hydrophobic-hydrophobic and pi pi stacking interactions. The self-assembly properties were also investigated by UV/Vis absorption spectroscopy, which revealed that the alkyl-chain length of the bzimpy moiety and the pi-surface area of the alkynyl ligand have significant influence on the overall self-assembly process. The alkyl-chain length also affected the morphological structures of the aggregates, which were studied by transmission electron microscopy and scanning electron microscopy. PMID- 29266489 TI - A fundamental conflict of care: Nurses' accounts of balancing patients' sleep with taking vital sign observations at night. AB - AIMS AND OBJECTIVES: To explore why adherence to vital sign observations scheduled by an early warning score protocol reduces at night. BACKGROUND: Regular vital sign observations can reduce avoidable deterioration in hospital. early warning score protocols set the frequency of these observations by the severity of a patient's condition. Vital sign observations are taken less frequently at night, even with an early warning score in place, but no literature has explored why. DESIGN: A qualitative interpretative design informed this study. METHODS: Seventeen semi-structured interviews with nursing staff working on wards with varying levels of adherence to scheduled vital sign observations. A thematic analysis approach was used. RESULTS: At night, nursing teams found it difficult to balance the competing care goals of supporting sleep with taking vital sign observations. The night-time frequency of these observations was determined by clinical judgement, ward-level expectations of observation timing and the risk of disturbing other patients. Patients with COPD or dementia could be under-monitored, while patients nearing the end of life could be over monitored. CONCLUSION: In this study, we found an early warning score algorithm focused on deterioration prevention did not account for long-term management or palliative care trajectories. Nurses were therefore less inclined to wake such patients to take vital sign observations at night. However, the perception of widespread exceptions and lack of evidence regarding optimum frequency risks delegitimising the early warning score approach. This may pose a risk to patient safety, particularly patients with dementia or chronic conditions. RELEVANCE TO CLINICAL PRACTICE: Nurses should document exceptions and discuss these with the wider team. Hospitals should monitor why vital sign observations are missed at night, identify which groups are under-monitored and provide guidance on prioritising competing expectations. early warning score protocols should take account of different care trajectories. PMID- 29266491 TI - Chemical chiral pollution: Impact on the society and science and need of the regulations in the 21st century. AB - The chiral pollution is a serious issue for our health and environment due to the enantio-selective biodegradation of the chiral pollutants. It has adverse impact on our society and science. There is a big loss of our economy due to the use of racemic agrochemicals. The most notorious chiral pollutants are pesticides, polychloro biphenyls, polyaromatic hydrocarbons, brominated flame retardants, drugs, and pharmaceuticals. More than 1500 chiral pollutants are present in the environment. Unfortunately, there is no regulation and control of the chiral pollutants. Therefore, it is an urgent need of the present 21st century to develop a data bank on the chiral pollutants, guidelines for controlling the production, sale and use of the racemic agrochemicals and the other industrial products. The Governments of the different countries should come forward to initiate the regulations. US, FDA, US EPA, and WHO are the most important regulatory authorities and should think about the chiral pollutants. The present article highlights the impact of the chiral pollution on the society and science. Besides, the efforts have also been made to emphasize the need of the regulations to control the chiral pollution. PMID- 29266492 TI - Psychiatrists' treatment preferences for generalized anxiety disorder. AB - OBJECTIVE: The objective of this study is to ascertain psychiatrists' treatment preferences for generalized anxiety disorder (GAD) and compare them to the same psychiatrists' treatment preferences in the hypothetical scenario that treatment is to be administered to themselves as patients. METHODS: A questionnaire was completed by 221 psychiatrists from 3 Balkan countries. They were asked to indicate their treatment preferences for patients with GAD and for themselves as patients. RESULTS: A large majority of psychiatrists chose selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors as preferred treatment option for GAD patients. Fewer psychiatrists selected benzodiazepines and pregabalin and about one third chose psychotherapy. The majority of psychiatrists chose the same treatments for their patients and for themselves, with main differences being in terms of pharmacotherapy (especially benzodiazepines) being less frequently recommended and psychotherapy being more frequently recommended as preferred treatment option for psychiatrists as patients. CONCLUSIONS: Treatment preferences for GAD by psychiatrists in the 3 West Balkan countries were mostly in accordance with treatment guidelines and treatment preferences for patients and for psychiatrists as patients were mostly concordant. However, some psychiatrists were more likely to choose pharmacotherapy for patients and psychotherapy for themselves as patients. These findings have implications for education of psychiatrists and for efforts to improve treatment guidelines and mental health services. PMID- 29266493 TI - Oral hygiene practices and knowledge among stroke-care nurses: A multicentre cross-sectional study. AB - AIMS AND OBJECTIVES: To investigate oral health knowledge for stroke care and the clinical practices performed for oral hygiene care in Malaysia. BACKGROUND: Oral hygiene care following stroke is important as the mouth can act as a reservoir for opportunistic infections that can lead to aspirational pneumonia. DESIGN: A national cross-sectional survey was conducted in Malaysia among public hospitals where specialist stroke rehabilitation care is provided. METHODS: All (16) hospitals were invited to participate, and site visits were conducted. A standardised questionnaire was employed to determine nurses' oral health knowledge for stroke care and existing clinical practices for oral hygiene care. Variations in oral health knowledge and clinical practices for oral hygiene care were examined. RESULTS: Questionnaires were completed by 806 nurses across 13 hospitals. Oral health knowledge scores varied among the nurses; their mean score was 3.7 (SD 1.1) out of a possible 5.0. Approximately two-thirds (63.6%, n = 513) reported that some form of "mouth cleaning" was performed for stroke patients routinely. However, only a third (38.3%, n = 309) reported to perform or assist with the clinical practice of oral hygiene care daily. Their oral health knowledge of stroke care was associated with clinical practices for oral hygiene care (p < .001). CONCLUSIONS: The clinical practice of providing oral hygiene care is less than ideal, and there are deficiencies in oral health knowledge for stroke care. Oral health knowledge was associated with clinical practice of providing oral hygiene care. This has implications for training and integrating oral hygiene care within stroke rehabilitation. PMID- 29266494 TI - Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones. AB - Modified bisanthraquinones are complex dimeric natural products containing a cage like structural motif. For their biosynthesis, monomeric dihydroanthraquinones have been proposed as key intermediates despite not being isolated from natural sources or synthesized as of yet. Here, isolation and characterization of dihydroemodin, as well as dihydrolunatin, synthesized by a biomimetic and chemoenzymatic approach using NADPH-dependent polyhydroxyanthracence reductase (PHAR) from Cochliobolus lunatus followed by Pb(OAc)4 oxidation is reported. Subsequent dimerization through a hetero-Diels-Alder reaction of the dihydroemodin and dihydrolunatin resulted in (-)-flavoskyrin (68 %) and (-) lunaskyrin (62 %), respectively. Pyridine treatment of (-)-flavoskyrin and (-) lunaskyrin gave (-)-rugulosin and (-)-2,2'-epi-cytoskyrin A in 64 % and 60 % yield, respectively, through a cascade that involves two dimeric intermediates. Implications of the described synthesis for the biosynthesis of bisanthraquinones by a combination of enzymatic and spontaneous steps are discussed. PMID- 29266495 TI - Understanding Local Structure versus Long-Range Structure: The Case of UO2. AB - A recent trend in the development of new optimized materials makes use of crystalline domains having nanometer sizes for which characterization methods at the atomic scale are mandatory. Amongst them is pair-distribution function analysis (PDF-analysis), a diffraction technique that has already shown that a short-range or "local" atomic structure of a given domain, having a lower symmetry than the average long-range structure, often exists in many compounds having valuable properties for industrial applications, such as pyrochlores, spinels, and doped ceria among others. However, the manner by which these domains are arranged to produce the average long-range structure is still an open question. Herein, the first structural model that accounts for both the local structure (inside a given domain) and the long-range structure (averaged over all domains) that is observed in the PDF of uranium dioxide is presented. The structural model describes domain walls in such a way as to preserve the uranium coordination polyhedron and to obey the needed symmetry rules. The proper description of domain walls is an important step in the understanding and the modelling of nanostructured materials. PMID- 29266496 TI - Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants. AB - 2-Aryltellurophenols substituted in the aryltelluro or phenolic parts of the molecule were prepared by lithiation of the corresponding tetrahydropyran protected 2-bromophenol, followed by reaction with a suitable diaryl ditelluride then deprotection. In a two-phase system containing N-acetylcysteine as a co antioxidant in the aqueous phase, all of the compounds quenched lipid peroxyl radicals more efficiently than alpha-tocopherol, with three to five-fold longer inhibition times. Thus, these compounds offer better and longer-lasting antioxidant protection than recently prepared alkyltellurophenols. Compounds with electron-donating para substituents in the aryltelluro or phenolic part of the molecule showed the best results. The mechanism for quenching peroxyl radicals was considered and discussed with respect to the calculated O-H bond-dissociation energies, deuterium-labelling experiments and studies of thiol consumption in the aqueous phase. PMID- 29266497 TI - Hepatitis B immunogenicity after a primary vaccination course associated with childhood asthma, allergic rhinitis, and allergen sensitization. PMID- 29266498 TI - Neural mechanism and heritability of complex motor sequence and audiovisual integration: A healthy twin study. AB - Complex motor sequencing and sensory integration are two key items in scales assessing neurological soft signs. However, the underlying neural mechanism and heritability of these two functions is not known. Using a healthy twin design, we adopted two functional brain imaging tasks focusing on fist-edge-palm (FEP) complex motor sequence and audiovisual integration (AVI). Fifty-six monozygotic twins and 56 dizygotic twins were recruited in this study. The pre- and postcentral, temporal and parietal gyri, the supplementary motor area, and the cerebellum were activated during the FEP motor sequence, whereas the precentral, temporal, and fusiform gyri, the thalamus, and the caudate were activated during AVI. Activation in the supplementary motor area during FEP motor sequence and activation in the precentral gyrus and the thalamic nuclei during AVI exhibited significant heritability estimates, ranging from 0.5 to 0.62. These results suggest that activation in cortical motor areas, the thalamus and the cerebellum associated with complex motor sequencing and audiovisual integration function may be heritable. PMID- 29266499 TI - Answering the question or questioning the answer? PMID- 29266500 TI - The spatial sensitivity of the spectral diversity-biodiversity relationship: an experimental test in a prairie grassland. AB - Remote sensing has been used to detect plant biodiversity in a range of ecosystems based on the varying spectral properties of different species or functional groups. However, the most appropriate spatial resolution necessary to detect diversity remains unclear. At coarse resolution, differences among spectral patterns may be too weak to detect. In contrast, at fine resolution, redundant information may be introduced. To explore the effect of spatial resolution, we studied the scale dependence of spectral diversity in a prairie ecosystem experiment at Cedar Creek Ecosystem Science Reserve, Minnesota, USA. Our study involved a scaling exercise comparing synthetic pixels resampled from high-resolution images within manipulated diversity treatments. Hyperspectral data were collected using several instruments on both ground and airborne platforms. We used the coefficient of variation (CV) of spectral reflectance in space as the indicator of spectral diversity and then compared CV at different scales ranging from 1 mm2 to 1 m2 to conventional biodiversity metrics, including species richness, Shannon's index, Simpson's index, phylogenetic species variation, and phylogenetic species evenness. In this study, higher species richness plots generally had higher CV. CV showed higher correlations with Shannon's index and Simpson's index than did species richness alone, indicating evenness contributed to the spectral diversity. Correlations with species richness and Simpson's index were generally higher than with phylogenetic species variation and evenness measured at comparable spatial scales, indicating weaker relationships between spectral diversity and phylogenetic diversity metrics than with species diversity metrics. High resolution imaging spectrometer data (1 mm2 pixels) showed the highest sensitivity to diversity level. With decreasing spatial resolution, the difference in CV between diversity levels decreased and greatly reduced the optical detectability of biodiversity. The optimal pixel size for distinguishing alpha diversity in these prairie plots appeared to be around 1 mm to 10 cm, a spatial scale similar to the size of an individual herbaceous plant. These results indicate a strong scale-dependence of the spectral diversity biodiversity relationships, with spectral diversity best able to detect a combination of species richness and evenness, and more weakly detecting phylogenetic diversity. These findings can be used to guide airborne studies of biodiversity and develop more effective large-scale biodiversity sampling methods. PMID- 29266501 TI - Living with relapsed myeloma: Symptoms and self-care strategies. AB - AIMS AND OBJECTIVES: To explore which symptoms relapsed myeloma patients experience and what self-care strategies are used. METHODS: This was a qualitative study utilising focus group interviews (n = 4) with relapsed myeloma patients (n = 15) and carers (n = 9). The focus groups were analysed and guided by thematic analysis. RESULTS: Three major themes with subthemes were identified following analysis of the interview data: "difficult symptoms; "self-care" and "feeling vulnerable." These findings indicate the challenges relapsed myeloma patients experience with ongoing symptoms and highlight the importance of continuity of care. CONCLUSIONS: Symptom management for myeloma patients remains complex due to the array of treatments given. These patients require holistic care and thorough regular assessments to help them cope with the adverse effects on their physical and psychological health. For patients with a long-term diagnosis of myeloma, self-management workshops and regular education sessions may be of benefit. RELEVANCE TO CLINICAL PRACTICE: This study highlights the key role of healthcare professionals in going beyond assessment of symptoms to offering advice and support to assist relapsed myeloma patients in managing their symptoms. PMID- 29266502 TI - Maternal blood-pressure trends throughout pregnancy and development of pre eclampsia in women receiving first-trimester aspirin prophylaxis. AB - OBJECTIVES: To study women who initiated aspirin in the first trimester for high risk of pre-eclampsia, and compare blood-pressure trends throughout pregnancy between those with normal outcome and those who subsequently developed pre eclampsia. METHODS: Women were enrolled into a prospective observational study at 9-14 weeks' gestation. This was a secondary analysis of those who started daily doses of 81 mg of aspirin before 16 weeks for increased risk of pre-eclampsia based on maternal history and bilateral uterine artery notching. Enrollment characteristics and blood-pressure measurements throughout gestation were compared between women who did and those who did not develop pre-eclampsia. RESULTS: Of the 237 women who initiated first-trimester aspirin prophylaxis, 29 (12.2%) developed pre-eclampsia. A total of 2881 serial blood-pressure measurements obtained between 4 and 41 weeks' gestation (747 in the first trimester, 1008 in the second and 1126 in the third) showed that women with pre eclampsia started pregnancy with higher blood pressure and maintained this trend despite taking aspirin (mean arterial blood pressure in women with pre-eclampsia = (0.13 * gestational age (weeks)) + 93.63, vs (0.11 * gestational age (weeks)) + 82.61 in those without; P < 0.005). First-trimester diastolic and second trimester systolic blood pressure were independent risk factors for pre-eclampsia (beta = 1.087 and 1.050, respectively; r2 = 0.24, P < 0.0001). When average first-trimester diastolic blood pressure was >74 mmHg, the odds ratio for pre eclampsia was 6.5 (95% CI, 2.8-15.1; P < 0.001) and that for pre-eclampsia before 34 weeks was 14.6 (95% CI, 1.72-123.5; P = 0.004). If, in addition, average second-trimester systolic blood pressure was >125 mmHg, the odds ratio for pre eclampsia was 9.4 (95% CI, 4.1-22.4; P < 0.001) and that for early-onset disease was 34.6 (95% CI, 4.1-296.4; P = 0.004). CONCLUSION: In women treated with prophylactic aspirin from the first trimester, those who develop pre-eclampsia have significantly and sustained higher blood pressure from the onset of pregnancy compared with those who do not develop pre-eclampsia. This raises the possibility that mildly elevated blood pressure predisposes women to abnormal placentation, which then acts synergistically with elevated blood pressure to predispose such women to pre-eclampsia to a degree that is incompletely mitigated by aspirin. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29266503 TI - Linking genotype to phenotype in a changing ocean: inferring the genomic architecture of a blue mussel stress response with genome-wide association. AB - A key component to understanding the evolutionary response to a changing climate is linking underlying genetic variation to phenotypic variation in stress response. Here, we use a genome-wide association approach (GWAS) to understand the genetic architecture of calcification rates under simulated climate stress. We take advantage of the genomic gradient across the blue mussel hybrid zone (Mytilus edulis and Mytilus trossulus) in the Gulf of Maine (GOM) to link genetic variation with variance in calcification rates in response to simulated climate change. Falling calcium carbonate saturation states are predicted to negatively impact many marine organisms that build calcium carbonate shells - like blue mussels. We sampled wild mussels and measured net calcification phenotypes after exposing mussels to a 'climate change' common garden, where we raised temperature by 3 degrees C, decreased pH by 0.2 units and limited food supply by filtering out planktonic particles >5 MUm, compared to ambient GOM conditions in the summer. This climate change exposure greatly increased phenotypic variation in net calcification rates compared to ambient conditions. We then used regression models to link the phenotypic variation with over 170 000 single nucleotide polymorphism loci (SNPs) generated by genotype by sequencing to identify genomic locations associated with calcification phenotype, and estimate heritability and architecture of the trait. We identified at least one of potentially 2-10 genomic regions responsible for 30% of the phenotypic variation in calcification rates that are potential targets of natural selection by climate change. Our simulations suggest a power of 13.7% with our study's average effective sample size of 118 individuals and rare alleles, but a power of >90% when effective sample size is 900. PMID- 29266504 TI - Do You Get What You See? Understanding Molecular Self-Healing. AB - The self-healing ability of self-healing materials is often analyzed using morphologic microscopy images. Here it was possible to show that morphologic information alone is not sufficient to judge the status of a self-healing process and molecular information is required as well. When comparing molecular coherent anti-Stokes Raman scattering (CARS) and morphological laser reflection images during a standard scratch healing test of an intrinsic self-healing polymer network, it was found that the morphologic closing of the scratch and the molecular crosslinking of the material do not take place simultaneously. This important observation can be explained by the fact that the self-healing process of the thiol-ene based polymer network is limited by the mobility of alkene containing compounds, which can only be monitored by molecular CARS microscopy and not by standard morphological imaging. Additionally, the recorded CARS images indicate a mechanochemical activation of the self-healing material by the scratching/damaging process, which leads to an enhanced self-healing behavior in the vicinity of the scratch. PMID- 29266505 TI - 7q11.23 microduplication syndrome: neurophysiological and neuroradiological insights into a rare chromosomal disorder. AB - BACKGROUND: The phenotypical consequence of the heterozygous chromosome 7q11.23 interstitial microdeletion is the Williams-Beuren syndrome, a very well-known genetic multi-systemic disorder. Much less is known about the reverse condition, the heterozygous interstitial microduplication of 7q11.23 region. The first molecular cytogenetic description was published in 2005, and only after several years were the reported patients numerous enough to attempt a description of a common phenotype. METHOD: By using a broad multidisciplinary approach, we investigated 12 patients with this rare genetic anomaly. Ten of them harboured the duplication of the classical Williams-Beuren syndrome region and two a slightly larger duplication. Upon a detailed description of the clinical and psychological features, we used electroencephalography and magnetic resonance imaging to explore neurophysiological function and brain structures. RESULTS: We analysed the clinical, psychological, neuroradiological and neurophysiological features of 12 yet-unpublished individuals affected by this rare genetic anomaly, focusing specifically on the last two aspects. Several structural abnormalities of the central nervous system were detected, like ventriculomegaly, hypotrophic cerebellum, hypotrophic corpus callosum and hypoplastic temporal lobes. Although only one of 12 individuals suffered from seizures during childhood, three others had abnormal electroencephalography findings prominent in the anterior brain regions, without any visible seizures to date. CONCLUSION: Taken together, we enlarged the yet-underrepresented cohort in the literature of patients affected by 7q11.23 microduplication syndrome and shed further light on neuroradiological and neurophysiological aspects of this rare genetic syndrome. PMID- 29266507 TI - Multiple calcium patterns of rat osteoblasts under fluidic shear stress. AB - The intracellular calcium ([Ca2+ ]i ) response induced by external forces can be diverse and complex. Using primary osteoblasts from Wistar rats, we found multiple patterns of [Ca2+ ]i responses induced by fluidic shear stress (Fss), including homogeneous non-oscillation and heterogeneous oscillations. These multiple-patterned [Ca2+ ]i responses could be influenced by Fss intensity, cell density, and cell differentiation. Our real-time measurements with free calcium, ATP, ATP without calcium, suramin, apyrase, and thapsigargin confirmed homogeneous [Ca2+ ]i patterns and/or heterogeneous [Ca2+ ]i oscillations with respect to the combined degree of external Ca2+ influx, and intracellular Ca2+ release. Our theoretical model supported diverse Fss-induced calcium activities as well. We concluded that a singular factor of Ca2+ influx or release dominated to produce smooth homogeneous patterns, but combined factors produced oscillatory heterogeneous patterns. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2039-2051, 2018. PMID- 29266506 TI - Plasma immunological markers in pregnancy and cord blood: A possible link between macrophage chemo-attractants and risk of childhood type 1 diabetes. AB - PROBLEM: Previous studies have suggested that immune perturbations during pregnancy can affect offspring type 1 diabetes (T1D) risk. We aimed to identify immunological markers that could predict offspring T1D or that were linked to T1D risk factors. METHOD OF STUDY: We quantified selected circulating immunological markers in mid-pregnancy (interleukin [IL]-1beta, IL-1ra, IL-2Ralpha, IL-2, -4, 5, -6, -10, -12p70, 13, -17A, GM-CSF, IFN-gamma, CXCL10, CCL 2, CCL3, CCL4, TNF) and cord blood plasma (neopterin and kynurenine/tryptophan ratio) in a case control study with 175 mother/child T1D cases (median age 5.8, range 0.7-13.0 years) and 552 controls. RESULTS: Pre-pregnancy obesity was positively associated with CCL4, CXCL10, kynurenine/tryptophan ratio and neopterin (P < .01). The established T1D SNPs rs1159465 (near IL2RA) and rs75352297 (near CCR2 and CCR3) were positively associated with IL-2Ralpha and CCL4, respectively (P < .01). There was a borderline association of CCL4 and offspring T1D risk, independent of maternal obesity and genotype. When grouping the immunological markers, there was a borderline association (P = .05) with M1 phenotype and no association between M2-, Th1-, Th2- or Th17 phenotypes and offspring T1D risk. CONCLUSION: Increased mid-pregnancy CCL4 levels showed borderline associations with increased offspring T1D risk, which may indicate a link between environmental factors in pregnancy and offspring T1D risk. PMID- 29266508 TI - How do clinicians practise the principles of beneficence when deciding to allow or deny family presence during resuscitation? AB - AIMS AND OBJECTIVES: To examine how clinicians practise the principles of beneficence when deciding to allow or deny family presence during resuscitation. BACKGROUND: Family presence during resuscitation has important benefits for family and is supported by professional bodies and the public. Yet, many clinicians restrict family access to patients during resuscitation, and rationales for decision-making are unclear. DESIGN: Secondary analysis of an existing qualitative data set using deductive category application of content analysis. METHODS: We analysed 20 interview transcripts from 15 registered nurses, two doctors and three paramedics who had experienced family presence during resuscitation in an Australian hospital. The transcripts were analysed for incidents of beneficent decision-making when allowing or denying family presence during resuscitation. RESULTS: Decision-making around family presence during resuscitation occurred in time poor environments and in the absence of local institutional guidelines. Clinicians appeared to be motivated by doing "what's best" for patients and families when allowing or denying family presence during resuscitation. However, their individual interpretations of "what's best" was subjective and did not always coincide with family preferences or with current evidence that promotes family presence during resuscitation as beneficial. CONCLUSIONS: The decision to allow or deny family presence during resuscitation is complex, and often impacted by personal preferences and beliefs, setting norms and tensions between clinicians and consumers. As a result, many families are missing the chance to be with their loved ones at the end of life. The introduction of institutional guidelines and policies would help to establish what safe and effective practice consists of, reduce value-laden decision-making and guide beneficent decision-making. RELEVANCE TO CLINICAL PRACTICE: These findings highlight current deficits in decision-making around FPDR and could prompt the introduction of clinical guidelines and policies and in turn promote the equitable provision of safe, effective family-centred care during resuscitation events. PMID- 29266510 TI - The content of hippocampal "replay". AB - One of the most striking features of the hippocampal network is its ability to self-generate neuronal sequences representing temporally compressed, spatially coherent paths. These brief events, often termed "replay" in the scientific literature, are largely confined to non-exploratory states such as sleep or quiet rest. Early studies examining the content of replay noted a strong correlation between the encoded spatial information and the animal's prior behavior; thus, replay was initially hypothesized to play a role in memory formation and/or systems-level consolidation via "off-line" reactivation of previous experiences. However, recent findings indicate that replay may also serve as a memory retrieval mechanism to guide future behavior or may be an incidental reflection of pre-existing network assemblies. Here, I will review what is known regarding the content of replay events and their correlation with past and future actions, and I will discuss how this knowledge might inform or constrain models which seek to explain the circuit-level mechanisms underlying these events and their role in mnemonic processes. PMID- 29266509 TI - 5-fluorouracil combined with cisplatin and mitomycin C as an optimized regimen for hyperthermic intraperitoneal chemotherapy in gastric cancer. AB - BACKGROUND AND OBJECTIVES: Optimized drug regimens for hyperthermic intraperitoneal chemotherapy (HIPEC) have not been standardized completely in patients with advanced gastric cancer (GC). We evaluated an optimized anti-tumor protocol comprising 5-fluorouracil (5-FU) combined with cisplatin (CDDP) and mitomycin C (MMC) in vitro for clinical use of HIPEC. METHODS: The sensitivities of 5-FU, CDDP, or MMC, alone or in combination, using different drug concentrations, exposure times, and hyperthermic conditions (42 degrees C) were determined in vitro by the CD-DST method using 3 different differentiated GC cell lines. RESULTS: The tumor cell growth-inhibitory effect of 5-FU was concentration dependent for all cell lines. In addition, 5-FU showed a hyperthermic sensitization effect at all drug concentrations for all cell lines. The appropriate concentration of each drug was 5-FU, 200 ug/mL; CDDP, 10 ug/mL; MMC, 2 ug/mL. Under hyperthermic conditions, most growth-inhibitory effects for each drug at 30 min was equivalent to 60 min of exposure; use of three drugs combined significantly inhibited growth compared with any of the drugs alone. CONCLUSION: An appropriate in vitro intraperitoneal chemotherapy regimen for GC was combined use of 5-FU, CDDP, and MMC at 42 degrees C for 30 min. PMID- 29266511 TI - SAFE START: AN EARLY CHILDHOOD MENTAL HEALTH PROGRAM IN A TERTIARY HEALTHCARE SETTING-A CRITICAL REVIEW. AB - Early childhood mental health programs are vital for the current and future mental health and brain development of infants, toddlers, and preschoolers. Founded in 2014, Safe Start is the only early childhood mental health program in Beirut, Lebanon. It aims at being the prototype of such services at the national level. A retrospective analysis of the outcomes of the first year of operations has resulted in important findings about the age of the participants, their diagnoses, previous therapies that the participants have undergone, types of referrals recommended, and the number of participants who were lost to follow-up. This first analysis pointed at the need for more in-depth research to encompass the gaps and benefits of such services. It shows the pivotal importance of designing awareness strategies about the importance of early childhood mental health services and care; to move from a diagnostic seeking behavior to commitment to psychotherapy and follow-up interventions. PMID- 29266513 TI - Predation drives morphological convergence in the Gambusia panuco species group among lotic and lentic habitats. AB - Fish morphology is often constrained by a trade-off between optimizing steady vs. unsteady swimming performance due to opposing effects of caudal peduncle size. Lotic environments tend to select for steady swimming performance, leading to smaller caudal peduncles, whereas predators tend to select for unsteady swimming performance, leading to larger caudal peduncles. However, it is unclear which aspect of performance should be optimized across heterogeneous flow and predation environments and how this heterogeneity may affect parallel phenotypic evolution. We investigated this question among four Gambusia species in north-eastern Mexico, specifically the riverine G. panuco, the spring endemics G. alvarezi and G. hurtadoi, and a fourth species, G. marshi, found in a variety of habitats with varying predation pressure in the Cuatro Cienegas Basin and Rio Salado de Nadadores. We employed a geometric morphometric analysis to examine how body shapes of both male and female fish differ among species and habitats and with piscivore presence. We found that high-predation and low-predation species diverged morphologically, with G. marshi exhibiting a variable, intermediate body shape. Within G. marshi, body morphology converged in high-predation environments regardless of flow velocity, and fish from high-predation sites had larger relative caudal peduncle areas. However, we found that G. marshi from low predation environments diverged in morphology between sub-basins of Cuatro Cienegas, indicating other differences among these basins that merit further study. Our results suggest that a morphological trade-off promotes parallel evolution of body shape in fishes colonizing high-predation environments and that changing predation pressure can strongly impact morphological evolution in these species. PMID- 29266512 TI - A Black Phosphorus Carbide Infrared Phototransistor. AB - Photodetectors with broadband detection capability are desirable for sensing applications in the coming age of the internet-of-things. Although 2D layered materials (2DMs) have been actively pursued due to their unique optical properties, by far only graphene and black arsenic phosphorus have the wide absorption spectrum that covers most molecular vibrational fingerprints. However, their reported responsivity and response time are falling short of the requirements needed for enabling simultaneous weak-signal and high-speed detections. Here, a novel 2DM, black phosphorous carbide (b-PC) with a wide absorption spectrum up to 8000 nm is synthesized and a b-PC phototransistor with a tunable responsivity and response time at an excitation wavelength of 2004 nm is demonstrated. The b-PC phototransistor achieves a peak responsivity of 2163 A W-1 and a shot noise equivalent power of 1.3 fW Hz-1/2 at 2004 nm. In addition, it is shown that a response time of 0.7 ns is tunable by the gating effect, which renders it versatile for high-speed applications. Under the same signal strength (i.e., excitation power), its performance in responsivity and detectivity in room temperature condition is currently ahead of recent top-performing photodetectors based on 2DMs that operate with a small bias voltage of 0.2 V. PMID- 29266514 TI - Giant Magnetic Heat Induction of Magnesium-Doped gamma-Fe2 O3 Superparamagnetic Nanoparticles for Completely Killing Tumors. AB - Magnetic fluid hyperthermia has been recently considered as a Renaissance of cancer treatment modality due to its remarkably low side effects and high treatment efficacy compared to conventional chemotheraphy or radiotheraphy. However, insufficient AC induction heating power at a biological safe range of AC magnetic field (Happl .fappl < 3.0-5.0 * 109 A m-1 s-1 ), and highly required biocompatibility of superparamagnetic nanoparticle (SPNP) hyperthermia agents are still remained as critical challenges for successful clinical hyperthermia applications. Here, newly developed highly biocompatible magnesium shallow doped gamma-Fe2 O3 (Mg0.13 -gammaFe2 O3 ) SPNPs with exceptionally high intrinsic loss power (ILP) in a range of 14 nH m2 kg-1 , which is an ~100 times higher than that of commercial Fe3 O4 (Feridex, ILP = 0.15 nH m2 kg-1 ) at Happl .fappl = 1.23 * 109 A m-1 s-1 are reported. The significantly enhanced heat induction characteristics of Mg0.13 -gammaFe2 O3 are primarily due to the dramatically enhanced out-of-phase magnetic susceptibility and magnetically tailored AC/DC magnetic softness resulted from the systematically controlled Mg2+ cations distribution and concentrations in octahedral site Fe vacancies of gamma-Fe2 O3 instead of well-known Fe3 O4 SPNPs. In vitro and in vivo magnetic hyperthermia studies using Mg0.13 -gammaFe2 O3 nanofluids are conducted to estimate bioavailability and biofeasibility. Mg0.13 -gammaFe2 O3 nanofluids show promising hyperthermia effects to completely kill the tumors. PMID- 29266516 TI - How to kill a tree: empirical mortality models for 18 species and their performance in a dynamic forest model. AB - Dynamic Vegetation Models (DVMs) are designed to be suitable for simulating forest succession and species range dynamics under current and future conditions based on mathematical representations of the three key processes regeneration, growth, and mortality. However, mortality formulations in DVMs are typically coarse and often lack an empirical basis, which increases the uncertainty of projections of future forest dynamics and hinders their use for developing adaptation strategies to climate change. Thus, sound tree mortality models are highly needed. We developed parsimonious, species-specific mortality models for 18 European tree species using >90,000 records from inventories in Swiss and German strict forest reserves along a considerable environmental gradient. We comprehensively evaluated model performance and incorporated the new mortality functions in the dynamic forest model ForClim. Tree mortality was successfully predicted by tree size and growth. Only a few species required additional covariates in their final model to consider aspects of stand structure or climate. The relationships between mortality and its predictors reflect the indirect influences of resource availability and tree vitality, which are further shaped by species-specific attributes such as maximum longevity and shade tolerance. Considering that the behavior of the models was biologically meaningful, and that their performance was reasonably high and not impacted by changes in the sampling design, we suggest that the mortality algorithms developed here are suitable for implementation and evaluation in DVMs. In the DVM ForClim, the new mortality functions resulted in simulations of stand basal area and species composition that were generally close to historical observations. However, ForClim performance was poorer than when using the original, coarse mortality formulation. The difficulties of simulating stand structure and species composition, which were most evident for Fagus sylvatica L. and in long-term simulations, resulted from feedbacks between simulated growth and mortality as well as from extrapolation to very small and very large trees. Growth and mortality processes and their species-specific differences should thus be revisited jointly, with a particular focus on small and very large trees in relation to their shade tolerance. PMID- 29266515 TI - Altered macromolecular pattern and content in the aging human brain. AB - The resonances originating from proteins underlie those of metabolites in brain 1 H nuclear magnetic resonance (NMR) spectra. These resonances have different physical properties from those of metabolites, such as shorter T1 and T2 relaxation time constants. The age dependence of the macromolecular pattern and content in the human brain was investigated with a focus on adults over 66 years of age using ultrahigh-field in vivo magnetic resonance spectroscopy. Eighteen young and 23 cognitively normal older adults were studied at 7 T. Metabolite spectra were acquired in the occipital cortex and the posterior cingulate cortex with single-voxel stimulated echo acquisition mode (STEAM) spectroscopy in 14 young and 20 older adults. Macromolecular spectra were acquired in the occipital cortex using an inversion recovery STEAM sequence in four young and three older adults. The macromolecular pattern was apparent over the 0.5-4.5-ppm range in the inversion recovery spectra and the 0.5-2-ppm range in the metabolite spectra. Macromolecular content was quantified from metabolite spectra using LCModel and from inversion recovery spectra using integration. Age-associated differences in the macromolecular pattern were apparent via both types of spectra, with the largest difference observed for the 1.7- and 2-ppm macromolecular resonances. A higher macromolecular content was observed in the older adults for both brain regions. Age-specific macromolecular spectra are needed when comparing metabolite spectra from subjects of differing ages because of age-associated differences in macromolecular pattern. Age-associated pattern and content differences may provide information about the aging process. PMID- 29266517 TI - Acknowledgment of 2017 reviewers and Editorial Board members for Veterinary Radiology & Ultrasound. PMID- 29266518 TI - Downregulation of heat shock protein B8 decreases osteogenic differentiation potential of dental pulp stem cells during in vitro proliferation. AB - OBJECTIVES: Tissue-derived stem cells, such as dental pulp stem cells (DPSCs), reduce differentiation capability during in vitro culture. We found that cultured DPSCs reduce expression of heat shock protein B8 (HspB8) and GIPC PDZ domain containing family member 2 (Gipc2). Our objectives were to evaluate the changes in DPSC composition during in vitro proliferation and to determine whether HspB8 and Gipc2 have function in differentiation potential of DPSCs. MATERIALS AND METHODS: Different passages of rat DPSCs were evaluated for changes in CD90+ and/or CD271+ stem cells and changes in osteogenic potential. Real-time RT-PCR and immunostaining were conducted to determine expression of HspB8 and Gipc2. Expression of the genes in DPSCs was knocked down by siRNA, followed by osteogenic induction to evaluate the function of the genes. RESULTS: About 90% of cells in the DPSC cultures were CD90+ and/or CD271+ cells without dramatic change during in vitro proliferation. The DPSCs at passages 3 to 5 (P3 to P5) possess strong osteogenic potential, but such potential was greatly reduced at later passages. Expression of HspB8 and Gipc2 was significantly reduced at P11 versus P3. Knock-down of HspB8 expression abolished osteogenic potential of the DPSCs, but knock-down of Gipc2 had no effect. CONCLUSIONS: CD90+ and CD271+ cells are the major components of DPSCs in in vitro culture. High-level expression of HspB8 was critical for maintaining differentiation potential of DPSCs. PMID- 29266519 TI - Using fetal abdominal circumference growth velocity in the prediction of adverse outcome in near-term small-for-gestational-age fetuses. AB - OBJECTIVE: To investigate whether abdominal circumference growth velocity (ACGV) improves the prediction of perinatal outcome in small-for-gestational-age (SGA) fetuses beyond that afforded by estimated fetal weight (EFW) and cerebroplacental ratio (CPR). METHODS: A cohort of 235 singleton SGA fetuses at 36-38 weeks' gestation was examined. ACGV, EFW and CPR centiles were calculated. ACGV centile was determined using data from a large database of 19-21- and 36-38-week scans in an unselected population. Binary variables of ACGV < 10th , EFW < 3rd and CPR < 5th centiles were defined as abnormal. Two composite adverse outcomes (CAO) were explored: CAO-1 defined as at least one of umbilical artery pH < 7.10, 5-min Apgar score < 7 or neonatal unit admission, and CAO-2 that included in addition hypoglycemia, intrapartum fetal distress and perinatal death. Univariate and multivariate logistic regression analyses were performed to analyze the relationship between the three risk factors and their predictive value for CAO. The change in screening performance afforded by adding ACGV to EFW and CPR was assessed and receiver-operating characteristics (ROC) curves were calculated. RESULTS: ACGV < 10th centile was an independent risk factor for CAO. The sensitivity, specificity, positive and negative likelihood ratios of a predictive model based on EFW < 3rd centile and CPR < 5th centile were, respectively, 51%, 70%, 1.71 and 0.69 for CAO-1 and 41%, 70%, 1.39 and 0.83 for CAO-2. After addition of ACGV < 10th centile to the model, the respective values were 82%, 46%, 1.54 and 0.38 for CAO-1 and 71%, 47%, 1.34 and 0.62 for CAO-2. Using continuous variables, the areas under the ROC curves improved marginally from 0.669 (95% CI, 0.604-0.729) to 0.741 (95% CI, 0.677-0.798) for CAO-1 and from 0.646 (95% CI, 0.580-0.707) to 0.700 (95% CI, 0.633-0.759) for CAO-2 after addition of ACGV to the model. CONCLUSIONS: ACGV is a risk factor for adverse neonatal outcome that is independent of EFW and of CPR, although any improvement in the prediction of adverse outcome is not statistically significant. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29266520 TI - The Safety and Efficacy of Using the O-Arm Intraoperative Imaging System for Deep Brain Stimulation Lead Implantation. AB - INTRODUCTION: Accurate electrode implantation is a major goal of deep brain stimulation (DBS) surgery. Intraoperative physiology with microelectrode recording (MER) is routinely used to refine stereotactic accuracy during awake electrode implantation. Recently, portable imaging systems such as the O-arm have become widely available and can be used in isolation or in association with MER to guide DBS lead placement. The aim of this study was to evaluate how the routine use of the O-arm affected DBS surgery safety, efficiency, and outcomes. METHODS: Two cohorts of patients with Parkinson's disease who underwent MER guided awake subthalamic DBS lead implantation with and without O-arm were compared. We examined the total number of microelectrode and macroeletrode passes during each surgery, procedure duration, surgical complications, lead revisions, and motor outcomes. RESULTS: A total of 50 procedures in 41 unique patients were analyzed, of which 26 were performed without O-arm and 24 performed without the O arm. The mean number of microelectrode passes was 2.46 (SD = 0.99) in the group without O-arm utilization, compared to 1.29 (SD = 0.75) in the group with O-arm usage (p < 0.001). A significant reduction was also found in procedure duration (p = 0.016). No differences were found in motor outcomes between groups. CONCLUSION: The use of the O-arm during DBS lead implantation was associated with significantly fewer brain cannulations for microelectrode recording as well as reduced surgical time. PMID- 29266521 TI - Exonic mutations and exon skipping: Lessons learned from DFNA5. AB - Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness-associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5-related deafness. In five families with postlingual progressive autosomal dominant non-syndromic hearing loss, we employed two next-generation sequencing platforms-OtoSCOPE and whole exome sequencing-followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini-genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5 related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing. PMID- 29266523 TI - Material Needs of Emergency Department Patients: A Systematic Review. AB - BACKGROUND: Interest in social determinants of health (SDOH) has expanded in recent years, driven by a recognition that such factors may influence health outcomes, services use, and health care costs. One subset of SDOH is material needs such as housing and food. We conducted a systematic review of the literature on material needs among emergency department (ED) patients in the United States. METHODS: We followed PRISMA guidelines for systematic review methodology. With the assistance of a research librarian, four databases were searched for studies examining material needs among ED patients. Two reviewers independently screened titles, abstracts, and full text to identify eligible articles. Information was abstracted systematically from eligible articles. RESULTS: Forty-three articles were eligible for inclusion. There was heterogeneity in study methods; single-center, cross-sectional studies were most common. Specific material needs examined included homelessness, poverty, housing insecurity, housing quality, food insecurity, unemployment, difficulty paying for health care, and difficulty affording basic expenses. Studies overwhelmingly supported the notion that ED patients have a high prevalence of a number of material needs. CONCLUSIONS: Despite some limitations in the individual studies examined in this review, the plurality of prior research confirms that the ED serves a vulnerable population with high rates of material needs. Future research is needed to better understand the role these needs play for ED patients and how to best address them. PMID- 29266522 TI - Confirmation of a gyral bias in diffusion MRI fiber tractography. AB - Diffusion MRI fiber tractography has been increasingly used to map the structural connectivity of the human brain. However, this technique is not without limitations; for example, there is a growing concern over anatomically correlated bias in tractography findings. In this study, we demonstrate that there is a bias for fiber tracking algorithms to terminate preferentially on gyral crowns, rather than the banks of sulci. We investigate this issue by comparing diffusion MRI (dMRI) tractography with equivalent measures made on myelin-stained histological sections. We begin by investigating the orientation and trajectories of axons near the white matter/gray matter boundary, and the density of axons entering the cortex at different locations along gyral blades. These results are compared with dMRI orientations and tract densities at the same locations, where we find a significant gyral bias in many gyral blades across the brain. This effect is shown for a range of tracking algorithms, both deterministic and probabilistic, and multiple diffusion models, including the diffusion tensor and a high angular resolution diffusion imaging technique. Additionally, the gyral bias occurs for a range of diffusion weightings, and even for very high-resolution datasets. The bias could significantly affect connectivity results using the current generation of tracking algorithms. PMID- 29266524 TI - Web-based cognitive rehabilitation for survivors of adult cancer: A randomised controlled trial. AB - OBJECTIVE: Cognitive dysfunction associated with cancer is frequently reported and can reduce quality of life. This study evaluated a Web-based cognitive rehabilitation therapy program (eReCog) in cancer survivors compared with a waitlist control group. METHODS: Adult cancer survivors with self-reported cognitive symptoms who had completed primary treatment at least 6 months prior were recruited. Participants completed telephone screening and were randomly allocated to the 4-week online intervention or waitlist. Primary outcome was perceived cognitive impairment assessed with the Functional Assessment of Cancer Therapy-Cognitive Function version 3. Secondary outcomes were additional measures of subjective cognitive functioning, objective cognitive functioning, and psychosocial variables. RESULTS: Seventy-six women were allocated to the intervention (n = 40) or waitlist (n = 36). A significant interaction was found on the instrumental activities of daily living measure of self-reported prospective memory whereby the intervention group reported a greater reduction in prospective memory failures than the waitlist group. Interaction trends were noted on perceived cognitive impairments (P = .089) and executive functioning (P = .074). No significant interactions were observed on other measures of objective cognitive functioning or psychosocial variables. CONCLUSIONS: The Web-based intervention shows promise for improving self-reported cognitive functioning in adult cancer survivors. Further research is warranted to better understand the mechanisms by which the intervention might contribute to improved self-reported cognition. PMID- 29266525 TI - Pre-eclampsia and heart failure: a close relationship. PMID- 29266527 TI - Assessment of the need for DCE MRI in the detection of dominant lesions in the whole gland: Correlation between histology and MRI of prostate cancer. AB - The purpose of this study was to evaluate the utility of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) in the detection of dominant prostate tumors with multi-parametric MRI of the whole gland. Combined diffusion tensor imaging (DTI) and DCE MRI from 16 patients with biopsy-proven prostate cancer and no previous treatment were acquired with a 3.0-T MRI scanner prior to radical prostatectomy, and used to identify dominant tumors. MRI results were validated by whole-mount histology. Paired t-test and Wilcoxon test, logistic generalized linear mixed effect models and receiver operating characteristic (ROC) analyses were used for the estimation of the statistical significance of the results. In the peripheral zone (PZ), the areas under the ROC curve (ROC-AUC) were 0.98 (sensitivity, 96%; specificity, 98%) for DTI, 0.96 (sensitivity, 92%; specificity, 97%) for DCE and 0.99 (sensitivity, 98%; specificity, 98%) for DTI + DCE. In the entire prostate, the ROC-AUC values were 0.96 (sensitivity, 84%; specificity, 95%) for DTI, 0.87 (sensitivity, 45%; specificity, 94%) for DCE and 0.96 (sensitivity, 88%; specificity, 98%) for DTI + DCE. The increase in ROC-AUC by the addition of DCE was not statistically significant in either PZ or the entire prostate. The results of this study have shown that DTI identified dominant tumors with high accuracy in both PZ and the entire prostate, whereas the inclusion of DCE MRI had no significant impact on the identification of either PZ or entire prostate dominant lesions. Our results suggest that the inclusion of DCE MRI may not increase the accuracy of dominant lesion detection, allowing for faster, better tolerated imaging studies. PMID- 29266528 TI - The DNA methylation status of genes encoding Matrix metalloproteinases and tissue inhibitors of Matrix metalloproteinases in endometriosis. AB - Endometriosis is a benign disease, with malignant properties. A necessary step in the progression of endometriosis is tissue remodeling, which is coordinated by the activities of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). This study evaluated the regulation of abnormal MMP and TIMP gene expression during endometriosis. Among the two genes families, promoter regions of MMP2, MMP3, MMP7, TIMP3, and TIMP4 were significantly altered in proliferative-phase endometriotic lesions compared to menstrual cycle-matched eutopic tissue from endometriosis-free women. In addition, a negative correlation was found between the DNA methylation status of the promoter region and transcript abundance of MMP2. Our findings suggest that changes in DNA methylation at the promoter region of MMP2 could underlie the changes in its expression in the ectopic endometria from patients with endometriosis. PMID- 29266529 TI - The Frankfurt Complaint Questionnaire for self-assessment of basic symptoms in the early detection of psychosis-Factor structure, reliability, and predictive validity. AB - OBJECTIVES: Patients with schizophrenia often experience subtle disturbances in several domains of information processing-so-called basic symptoms (BS). BS are already present before onset of frank psychosis and can be assessed by interviews but also by the self-administered Frankfurt Complaint Questionnaire (FCQ). We investigated the factor structure, reliability, and predictive validity for transition to psychosis of the FCQ, comparing previously proposed factor solutions containing 1, 2, 4, and 10 factors. METHODS: Confirmatory factor analysis was used in a sample of 117 at-risk mental state and 92 first-episode psychosis participants of the Basel FePsy (early detection of psychosis) study. RESULTS: Although all factor models fitted to the data, the 2- or 4-factor solutions performed best among the models that used at least half of the FCQ items, suggesting the covariance between FCQ items is best explained by 2 to 4 underlying factors. No FCQ-scale predicted transition to psychosis. CONCLUSION: We could confirm a 2- to 4-factor structure of the FCQ in a sample of at-risk mental state and first-episode psychosis patients using confirmatory factor analysis. Contrary to interview-assessed cognitive-perceptive BS, self-assessed BS do not seem to improve prediction of psychosis. This result reinforces reports of poor correspondence between interview- and questionnaire-assessed BS. PMID- 29266526 TI - Optimal cumulative cisplatin dose in nasopharyngeal carcinoma patients receiving additional induction chemotherapy. AB - To clarify the optimal cumulative cisplatin dose (CCD) in locoregionally-advanced nasopharyngel carcinoma (NPC) patients receiving induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). Using the NPC-specific database from the established big-data intelligence platform at Sun Yat-Sen University Cancer Center, 583 non-disseminated, locoregionally-advanced NPC patients receiving IC plus CCRT were enrolled. Propensity score matching (PSM) analysis was conducted to control for confounding factors. The median CCD was 160 mg/m2 after IC (range, 40-300 mg/m2 ); only 74 patients (12.7%) achieved CCD >200 mg/m2 . Patients receiving >200 mg/m2 CCD did not show significantly improved 5-year overall survival (OS) (HR = 1.19; 95% confidence intervals [CI] 0.69-2.06, P = .53) and progression-free survival (PFS) (HR = 1.03; 95% CI: 0.63-1.68, P = .92) compared with patients receiving <200 mg/m2 CCD. Further investigations of the potential of median CCD (160 mg/m2 ) to yield survival benefits revealed that there were no significant differences in survival endpoints between patients receiving CCD >160 mg/m2 and CCD < 160 mg/m2 in both the original and PSM cohorts. In addition, subgroup analysis indicated a favorable PFS, but not OS, with higher cisplatin administration in patients with pretreatment Epstein-Barr virus deoxyribonucleic acid (EBV DNA) <1000 copies/mL (HR = 0.26, 95% CI: 0.07-0.93, P = .03) and receiving <3 IC cycles (HR = 0.59, 95% CI 0.33-1.07, P = .08). Our analysis of real world data provided references for the optimal CCD in locoregionally advanced NPC receiving additional IC. The causal relationship between 200 mg/m2 CCD and improved survival was not defined; 160 mg/m2 CCD might be enough. However, for patients with EBV DNA <1000 copy/mL and receiving <3 IC cycles, a higher dose might be necessary. PMID- 29266530 TI - Resilience and positive affect contribute to lower cancer-related fatigue among Chinese patients with gastric cancer. AB - AIMS AND OBJECTIVES: To investigate the prevalence of cancer-related fatigue and explore the relationship between resilience, positive affect, and fatigue among Chinese patients with gastric cancer. BACKGROUND: Cancer-related fatigue is the most distressing symptom reported frequently by cancer patients during both treatment and survival phases. Resilience and positive affect as vital protective factors against cancer-related fatigue have been examined, but the underlying psychological mechanisms are not well understood. DESIGN: A cross-sectional study. METHODS: Two hundred and three gastric cancer patients were enrolled from three hospitals in China. The Cancer Fatigue Scale, the positive affect subscale of the Positive and Negative Affect Schedule and the Connor-Davidson Resilience Scale (CD-RISC10) were administered. Hierarchical linear regression modelling was conducted to examine the association between resilience and cancer-related fatigue, and the mediating effect of positive affect. RESULTS: The incidence of clinically relevant fatigue among patients with gastric cancer was 91.6%. Regression analysis showed that resilience was negatively associated with cancer related fatigue, explaining 15.4% of variance in cancer-related fatigue. Mediation analysis showed that high resilience was associated with increased positive affect, which was associated with decreased cancer-related fatigue. CONCLUSIONS: Cancer-related fatigue is prevalent among patients with gastric cancer. Positive affect may mediate the relationship between resilience and cancer-related fatigue. RELEVANCE TO CLINICAL PRACTICE: Interventions that attend to resilience training and promotion of positive affect may be the focus for future clinical and research endeavours. PMID- 29266532 TI - Event-related potentials of attentional bias toward faces in the dot-probe task: A systematic review. AB - The dot-probe task is a common task to assess attentional bias toward different stimuli and how groups differ (e.g., attentional bias in anxiety disorders). However, measuring reaction time has been suggested to be unreliable. Neuroimaging methods such as fMRI were shown to be more reliable in assessing attentional bias, but fMRI has poor temporal resolution and therefore cannot assess timing of attention. ERPs have been used to examine the time course of attentional bias. Although ERP research may be more reliable than reaction time, there have been inconsistencies in the literature. This review systematically searched for articles that used the dot-probe task with facial expressions and measured neural correlates with ERP. We found that some of the inconsistencies might be the cause of methodological differences (e.g., timing of stimuli), differences in emotional expression, and/or sample differences (e.g., sex, age, etc.). Suggestions on how future research could address the issues presented in this review were discussed. PMID- 29266533 TI - Recent Advances in Halophilic Protozoa Research. AB - Most research on microorganisms adapted to hypersaline habitats has focused on Archaea and Bacteria, with microbial eukaryotes receiving much less attention. Over the past 15 yr, our knowledge of phagotrophic microbial eukaryotes, i.e. protozoa, from hypersaline habitats has greatly improved through combinations of microscopy, molecular phylogenetics, environmental sequencing, transcriptomics and growth experiments. High salinity waters from salterns, other landlocked water masses and deep hypersaline anoxic basins contain unique and diverse halophilic protozoan assemblages. These have the potential to exert substantial grazing pressure on prokaryotes and other eukaryotes. They represent many separate evolutionary lineages; species of Heterolobosea, Bicosoecida, and Ciliophora have been most intensively characterized, with several proven to be extreme (or borderline extreme) halophiles. Transcriptomic examinations of the bicosoecid Halocafeteria (and the heteroloboseid Pharyngomonas) indicate that high-salt adaptation is associated with a subtle shift in protein amino acid composition, and involves the differential expression of genes participating in ion homeostasis, signal transduction, stress management, and lipid remodeling. Instances of gene duplication and lateral transfer possibly conferring adaptation have been documented. Indirect evidence suggests that these protozoa use "salt out" osmoadaptive strategies. PMID- 29266531 TI - The relationships between brain structural changes and perceived loneliness in older adults suffering from late-life depression. AB - OBJECTIVE: Late-life depression is a significant health risk factor for older adults, part of which is perceived loneliness. In this voxel-based morphometry study, we examined the relationships between perceived loneliness and depression recurrence. METHODS: Fifty-two older adults were recruited, and they were split into 3 groups: single episode, multiple episodes, or normal control groups, according to their clinical histories. RESULTS: This result suggests the level of functioning regarding the reward system may be negatively related to the number of depressive episodes. Taken together, the findings of this study offer important insight into the neural underpinnings of the course and chronicity of late-life depression. PMID- 29266536 TI - Clinical deterioration: A concept analysis. AB - AIMS AND OBJECTIVES: To present a concept analysis of clinical deterioration and introduce an operational definition. BACKGROUND: Hospitalised patients who endure cardiopulmonary arrest and unplanned intensive care unit admissions often exhibit physiological signs preceding these events. Clinical deterioration not promptly recognised can result in increased patient morbidity and mortality. A barrier to recognising and responding to clinical deterioration stems from practice variations among healthcare clinicians. DESIGN: Concept analysis. METHODS: Eight step method of concept analysis proposed by Walker and Avant. RESULTS: Defining attributes include dynamic state, decompensation and objective and subjective determination. Antecedents identified include clinical state, susceptibility, pathogenesis and adverse event. Increased mortality, resuscitation, implementation of higher level of care and prolonged hospital admission were the consequences identified. Defining attributes, antecedents and consequences identified led to an operational definition of clinical deterioration as a dynamic state experienced by a patient compromising hemodynamic stability, marked by physiological decompensation accompanied by subjective or objective findings. CONCLUSIONS: Clinical deterioration is a key contributor to inpatient mortality, and its recognition is often underpinned by contextual factors and practice variances. Variation in the uniformity of the concept of clinical deterioration causes a gap in knowledge and necessitated clarification of this phenomenon for nursing research and practice. RELEVANCE TO CLINICAL PRACTICE: Identifying and intervening on clinical deterioration plays a vital role in the inpatient setting demonstrated by the dynamic nature of a patients' condition during hospitalisation. It is anticipated that this concept analysis on clinical deterioration will contribute to further identification of clinically modifiable risk factors and accompanying interventions to prevent clinical deterioration in the inpatient setting. PMID- 29266534 TI - MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update. AB - Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno-/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information. PMID- 29266537 TI - Opening of Psychiatric Observation Unit Eases Boarding Crisis. AB - OBJECTIVES: The objective of this study was to evaluate the effect of a psychiatric observation unit in reducing emergency department (ED) boarding and length of stay (LOS) for patients presenting with primary psychiatric chief complaints. A secondary outcome was to determine the effect of a psychiatric observation unit on inpatient psychiatric bed utilization. METHODS: This study was a before-and-after analysis conducted in a 1,541-bed tertiary care academic medical center including an adult ED with annual census over 90,000 between February 2013 and July 2014. All adult patients (age > 17 years) requiring evaluation by the acute psychiatry service in the crisis intervention unit (CIU) within the ED were included. Patients who left without being seen, left against medical advice, or were dispositioned to the pediatric hospital, hospice, or court/law enforcement were excluded. In December 2013, a 12-bed locked psychiatric observation unit was opened that included dedicated behavioral health staff and was intended for psychiatric patients requiring up to 48 hours of care. The primary outcomes were ED LOS, CIU LOS, and total LOS. Secondary outcomes included the hold rate defined as the proportion of acute psychiatry patients requiring subsequent observation or inpatient admission and the inpatient psychiatric admission rate. For the primary analysis we constructed ARIMA regression models that account for secular changes in the primary outcomes. We conducted two sensitivity analyses, first replicating the primary analysis after excluding patients with concurrent acute intoxication and second by comparing the 3-month period postintervention to the identical 3-month period of the prior year to account for seasonality. RESULTS: A total of 3,501 patients were included before intervention and 3,798 after intervention. The median ED LOS for the preintervention period was 155 minutes (interquartile range [IQR] = 19-346 minutes), lower than the median ED LOS for the postintervention period of 35 minutes (IQR = 9-209 minutes, p < 0.0001). Similar reductions were observed in CIU LOS (865 minutes vs. 379 minutes, p < 0.0001) and total LOS (1,112 minutes vs. 920 minutes, p = 0.003). The psychiatric hold rate was statistically higher after intervention (before = 42%, after = 50%, p < 0.0001), however, coupled with a statistically lower psychiatric admission rate (before = 42%, after = 25%, p < 0.0001). CONCLUSIONS: Creation of an acute psychiatric observation improves ED and acute psychiatric service throughput while supporting the efficient allocation of scare inpatient psychiatric beds. This novel approach demonstrates the promise of extending successful observation care models from medical to psychiatric illness with the potential to improve the value of acute psychiatric care while minimizing the harms of ED crowding. PMID- 29266535 TI - Paediatric gastrostomy stoma complications and treatments: A rapid scoping review. AB - AIMS AND OBJECTIVES: To provide a scoping review of the types of treatments used to address paediatric skin-related stoma complications specific to infection, hypergranulation and gastric leakage, and explore their effectiveness and indications for use. BACKGROUND: Stoma-related complications can be a common occurrence for children with gastrostomy (G) and gastrojejunostomy (GJ) tubes. Nurses require guidance to inform decision-making of the broad spectrum of treatments used in clinical practice. DESIGN: A scoping review using a rapid review approach. METHODS: Working with a multidisciplinary health professional team, search terms were generated. A systematic search of CINAHL, MEDLINE and EMBASE databases was completed, coupled with an Internet search to identify relevant clinical practice guidelines and hand searching of citation lists. Eligible articles were peer-reviewed English publications, focused on paediatric populations aged 18 years and under, dating from 2002-2016 and described complications and treatment approaches related to G- and GJ-tube stomas. Pertinent information was extracted using a standardised template, and a narrative synthesis approach was used to analyse the data. RESULTS: Twenty-five articles were included in this review. Study designs varied, and complication management was often a secondary focus. A broad spectrum of treatments was used to manage each complication type. There was a lack of consensus on lines of therapy; however, a stepwise approach was often used for complication management, particularly for infections. CONCLUSIONS: The evidence on the comparative effectiveness of different treatment strategies of skin-related gastrostomy stoma complications in paediatric practice is sparse. Current evidence is generally limited to expert opinions. Future studies examining efficacy of treatments and their indications for use with children are warranted. RELEVANCE TO CLINICAL PRACTICE: Effective management of skin-related stoma complications is important to maintain health and wellness among children who rely on G- and GJ-tubes for nutrition support. PMID- 29266538 TI - Stereoselective and Stereospecific Reactions of Cobalt Sandwich Complexes: Synthesis of a New Class of Single Enantiomer Bulky Planar Chiral P-N and P-P Ligands. AB - Starting from (eta5 -acetylcyclopentadienyl)(eta4 tetraphenylcyclobutadiene)cobalt(I), highly enantioselective (99 % ee) (S)-CBS catalysed ketone reduction followed by stereospecific alcohol-azide exchange, azide reduction and dimethyllation gave (R)-(eta5 -alpha-N,N dimethylaminoethylcyclopentadienyl)(eta4 -tetraphenylcyclobutadiene) cobalt(I) (Arthurs' amine). This underwent highly diastereoselective cyclopalladation to give di-MU-acetate-bis-(R)-[(eta5 -(Sp )-2-(alpha-N,N dimethylaminoethyl)cyclopentadienyl, 1-C, N)(eta4 tetraphenylcyclobutadiene)cobalt(I)]dipalladium, and highly diastereoselective lithiation to give (R)-(eta5 -(Sp )-1-(alpha-N,N-dimethylaminoethyl)-2 (diphenylphosphino)cyclopentadienyl)(eta4 -tetraphenylcyclobutadiene)cobalt(I) (PPCA) following the addition as electrophile of chlorodiphenylphosphine. This PN ligand was converted into (R)-(eta5 -(Sp )-1-(alpha-dicyclohexylphosphinoethyl)-2 (diphenylphosphino)cyclopentadienyl)(eta4 -tetraphenylcyclobutadiene)cobalt(I), a PP-ligand (Rossiphos), by stereospecific amine-phosphine exchange using HPCy2 . These air-stable P-N and P-P complexes are the first examples of a new class of bulky planar chiral ligands for application in asymmetric catalysis. PMID- 29266539 TI - The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis. AB - BACKGROUND: Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg. L-1 is described in adults. AIMS: The aim of this study was to review age- and weight related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules. METHODS: Pooled intravenous ketorolac (0.5 mg. kg-1 ) concentration-time data in children aged 2 months to 16 years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person. RESULTS: There were 64 children aged 2 months to 16 years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L. h-1. 70 kg-1 and intercompartment clearance was 4.43 (CV 95.6%) L. h-1. 70 kg-1 . Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L. 70 kg-1 and V2 5.53 (CV 47.6%) L. 70 kg-1 . CONCLUSION: Clearance, expressed as L. h-1. kg-1 , decreased with age from infancy. A dosing regimen of 0.5 mg. kg-1 every 6 hours maintains a trough concentration larger than 0.37 mg. L-1 in children 9 months to 16 years of age. This dosing regimen is consistent with current recommendations. PMID- 29266540 TI - Utility of gradient recalled echo magnetic resonance imaging for the study of myelination in cuprizone mice treated with fingolimod. AB - The availability of high-field-strength magnetic resonance imaging (MRI) systems has brought about the development of techniques that aim to map myelination via the exploitation of various contrast mechanisms. Myelin mapping techniques have the potential to provide tools for the diagnosis and treatment of diseases, such as multiple sclerosis. In this study, we evaluated the sensitivity of T2 *, frequency shift and susceptibility measures to myelin levels in a cuprizone mouse model of demyelination. The model was supplemented with two different dosages of fingolimod, a drug known to positively affect demyelination. A decrease in grey white matter contrast with the cuprizone diet was observed for T2 *, frequency shift and susceptibility measures, together with myelin basic protein antibody findings. These results indicate that T2 *, frequency shift and susceptibility measures have the potential to act as biomarkers for myelination. Susceptibility was found to be the most sensitive measure to changes in grey-white matter contrast. In addition, fingolimod treatment was found to reduce the level of demyelination, with a larger dosage exhibiting a greater reduction in demyelination for the in vivo MRI results. Overall, susceptibility mapping appears to be a more promising tool than T2 * or frequency shift mapping for the early diagnosis and treatment of diseases in which myelination is implicated. PMID- 29266541 TI - Morphological Effects and Stabilization of the Metallic 1T Phase in Layered V-, Nb-, and Ta-Doped WSe2 for Electrocatalysis. AB - Layered transition-metal dichalcogenides (TMDs) are valued for their electrocatalytic properties toward the hydrogen-evolution reaction (HER) and oxygen-reduction reaction (ORR). One effective strategy to activate the electrocatalytic properties of TMDs is through doping. The optimistic outlook of doped-MoS2 as an electrocatalyst witnessed in previous reports spurred us to examine the effect of doping WSe2 with Group 5 transition-metal species, namely V, Nb, and Ta, in aspects of inherent electroactivities and catalysis. Apart from the mild reduction signal unique to the Group 5 transition-metal dopants, the Group 5 transition-metal-doped WSe2 materials are found to possess largely identical inherent electrochemistry to the undoped WSe2 with a characteristic anodic peak. Living up to expectations, the Group 5 transition-metal-doped WSe2 materials exhibit improved electrocatalytic HER efficiency, as evident by the lower HER overpotentials and Tafel slopes relative to undoped WSe2 . After doping with V, Nb, or Ta species, an increased number of active sites is observed given the distinct changes in morphology from thick bulky pieces in undoped WSe2 to thinner fragments in doped WSe2 . Although undoped WSe2 exists in the semiconducting 2H phase, the Group 5 transition-metal-doped WSe2 materials are dominated by the metallic 1T phase. Doping WSe2 with V, Nb, or Ta stabilizes the catalytic 1T phase and appears to induce the transition from the 2H to 1T phase. In contrast to the enhanced HER performance of WSe2 upon doping, Group 5 transition-metal dopants proved futile in activating the ORR electrocatalytic behavior of WSe2 , for which the ORR efficiency is unchanged. Therefore, these findings facilitate the understanding of the role of Group 5 transition-metal dopants in the electrochemical and catalytic properties of WSe2 relative to their morphological features and provide an evaluation of the efficacy of doping TMDs in electrocatalytic applications. PMID- 29266542 TI - Implementing a pain management nursing protocol for orthopaedic surgical patients: Results from a PAIN OUT project. AB - AIMS AND OBJECTIVES: To investigate the effect of introducing a standardised pain management nursing protocol in orthopaedic patients undergoing surgery. BACKGROUND: Postoperative pain is a common phenomenon but is still undertreated in hospitalised patients. Nurses' lack of sufficient knowledge and skills about pain management may be a contributing factor to poor outcomes. DESIGN: An interventional, separate sample pre- and post-test. METHODS: A pain management nursing protocol was introduced and a handbook and training sessions regarding management of postsurgical pain were provided to the nurses on a Joint Orthopaedic ward at a university-affiliated general hospital in Guangzhou, China. Before and after the intervention, nurses' knowledge about pain management and attitudes were assessed, and perioperative management practices and pain-related patient-reported outcomes were evaluated. RESULTS: Sixteen and 15 registered nurses, and 77 and 71 patients participated in the study before and after the intervention, respectively. Nurses' scores related to knowledge and skills increased significantly after the protocol was introduced but were still insufficient with regard to pharmacological-related items. The proportion of patients receiving a combined opioid and nonopioid increased after the intervention. Clinically significant changes were observed in some patient reported outcomes, such as worst pain since surgery, percentage of time experiencing severe pain, and pain interference with activities out of bed. There were significant changes in nonpharmacological methods administered by nurses to patients or used by patients to relieve pain. CONCLUSIONS: Implementation of a pain management nursing protocol combined with education in one surgical ward was associated with nurses' increased knowledge and attitudes regarding pain, a change in some management practices, and improvement in a number of pain-related patient-reported outcomes. RELEVANCE TO CLINICAL PRACTICE: It was feasible to develop and implement a standardised pain management nursing protocol and use it in the clinical routine. The intervention had an effect on changing some features of care, with an improvement in patient-reported outcomes. Support by leaders and medical team facilitated the process of the implementation. PMID- 29266543 TI - Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. AB - : Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here, we performed studies to determine whether the x-ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n = 112,428) of whom 1,539 had nonviral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic x-ray attenuation (n = 1,572; P = 4 * 10-5 ), but not with HTGC (n = 2,674; P = 0.58). Rs4841132-A was associated with modest, but significant, elevations in serum alanine aminotransferase (ALT) in the Copenhagen Cohort (P = 3 * 10-4 ) and the DHS (P = 0.004), and with odds ratios for liver disease of 1.13 (95% CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking protein phosphatase 1 regulatory subunit 3B (PPP1R3B) were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC. CONCLUSION: These observations are consistent with the notion that the minor allele of rs4841132 promotes a mild form of hepatic glycogenosis that is associated with hepatic injury. (Hepatology 2018;67:2182-2195). PMID- 29266544 TI - Expectations about the effectiveness of pain- and itch-relieving medication administered via different routes. AB - BACKGROUND: Placebo effects on pain have been found to vary in size for different routes of medication administration (e.g. oral vs. injection). This has important implications for both clinical research and practice. To enhance our understanding of these differential placebo effects, research on the underlying expectations about multiple routes and symptoms other than pain is vital. METHODS: A cross-sectional, Internet-based survey was conducted in a representative sample of the Dutch population (n = 508). Respondents rated the expected effectiveness of pain- and itch-relieving medication in six forms, representing oral, injection and topical routes of administration. RESULTS: Injected medication was expected to be most effective for relieving pain, and topical medication for relieving itch. Furthermore, exploratory analyses showed that injections were expected to have the most rapid onset and long-lasting effects, and to be most frightening and expensive, while topical medication was expected to be the safest and the easiest to use, and oral medication was expected to have the most side effects. Higher expected effectiveness was moderately associated with expectations of more rapid onset and long-lasting effects, and better safety and ease of use. Associations of expected effectiveness with respondent characteristics (e.g. medication use and personality characteristics) were statistically small or nonsignificant. CONCLUSIONS: Expected effectiveness of medication differed depending on route of administration and targeted symptom. These findings have important implications for the design and interpretation of clinical trials and suggest that medication effects might be enhanced by prescribing medicine via the route that patients expect to be most effective for their complaint. SIGNIFICANCE: Differences in the expected effectiveness of medication depend on the route of administration (oral, injection, topical) and targeted symptom (pain, itch). These findings have important implications for clinical practice and the design and interpretation of clinical trials. PMID- 29266545 TI - Thymidine kinase 1 silencing retards proliferative activity of pancreatic cancer cell via E2F1-TK1-P21 axis. AB - OBJECTIVES: Thymidine kinase 1 (TK1) is one of the salvage enzymes engaged in the synthesis of DNA. Although a pro-carcinogenetic role of TK1 has been reported in various types of cancers, its role in pancreatic ductal adenocarcinoma (PDAC) is still unknown. The study is aimed to elaborate the function of TK1 in PDAC and the potential mechanisms in the following study. MATERIALS AND METHODS: TK1 expression was analysed by immunohistochemistry, real-time PCR and Western blot, and its relationship with clinicopathological characteristics of PDAC patients was further investigated. To verify the function of TK1 and potential mechanism, TK1 siRNA was used to transfect PDAC cells and performed a series of assays in cell and animal models. RESULTS: The level of TK1 expression was higher in cancerous tissues compared with matched adjacent tissues. TK1 overexpression was associated with progression of PDAC and poor prognosis. Knockdown of TK1 could suppress cell proliferation via inducing S phase arrest mediated by upregulation of P21. Further mechanism investigation suggested that transcription factor E2F-1 could directly regulate the TK1 and promote tumour proliferation. CONCLUSIONS: The results suggested that TK1 might be involved in the development and progression of PDAC by regulating cell proliferation and show that TK1 may work as a promising therapeutic target in patients with PDAC. PMID- 29266547 TI - Impact of an early respiratory care programme with non-invasive ventilation adaptation in patients with amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: Forced vital capacity (FVC) <80% is one of the key indications for starting non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). It was hypothesized that a very early start of NIV could lengthen the free interval before death compared to later-start NIV; as a secondary outcome, the survival rate of patients on NIV without tracheotomy was also evaluated. METHODS: This retrospective study was conducted on 194 ALS patients, divided into a later group (LG) with FVC <80% at NIV prescription (n = 129) and a very early group (VEG) with FVC >=80% at NIV prescription (n = 65). Clinical and respiratory functional data and time free to death between groups over a 3-year follow-up were compared. RESULT: At 36 months from diagnosis, mortality was 35% for the VEG versus 52.7% for the LG (P = 0.022). Kaplan-Meier survival curves adjusted for tracheotomy showed a lower probability of death (P = 0.001) for the VEG as a whole (P = 0.001) and for the non-bulbar (NB) subgroup (P = 0.007). Very early NIV was protective of survival for all patients [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.28-0.74; P = 0.001] and for the NB subgroup (HR 0.43; 95% CI 0.23-0.79; P = 0.007), whilst a tracheotomy was protective for all patients (HR 0.27; 95% CI 0.15-0.50; P = 0.000) and both NB (HR 0.26; 95% CI 0.12-0.56; P = 0.001) and bulbar subgroups (HR 0.29; 95% CI 0.11 0.77; P = 0.013). Survival in VEG patients on NIV without tracheotomy was three times that for the LG (43.1% vs. 14.7%). CONCLUSION: Very early NIV prescription prolongs the free time from diagnosis to death in NB ALS patients whilst tracheotomy reduces the mortality risk in all patients. PMID- 29266546 TI - Plasma soluble podoplanin is a novel marker for the diagnosis of tumor occurrence and metastasis. AB - Podoplanin (PDPN) is expressed on many tumors and is involved in tumor metastasis. The objective of the present study was to develop an ELISA for determining soluble PDPN (sPDPN) levels as a potential novel tumor marker in plasma of patients with cancers for detection of tumor occurrence and metastasis. Mouse monoclonal antibodies (mAb) against human PDPN were developed and characterized. Two anti-PDPN mAb, SZ-163 and SZ-168, were used in a sandwich ELISA to detect plasma sPDPN in patients with cancers and in normal individuals. The levels of sPDPN were detected in patients with adenocarcinoma (87 cases, 31.09 +/- 5.48 ng/ml), squamous cell carcinoma (86 cases, 6.91 +/- 0.59 ng/ml), lung cancer (45 cases, 26.10 +/- 7.62 ng/ml), gastric cancer (38 cases, 23.71 +/- 6.90 ng/ml) and rectal cancer (27 cases, 32.98 +/- 9.88 ng/ml), which were significantly higher than those in normal individuals (99 cases, 1.31 +/- 0.13 ng/ml) (P < .0001). Moreover, the sPDPN levels in patients with metastatic cancers were higher (192 cases, 30.35 +/- 3.63 ng/ml) than those in non metastatic cancer patients (92 cases, 6.28 +/- 0.77 ng/ml) (P < .0001). The post treatment sPDPN levels of cancer patients (n = 156) (4.47 +/- 0.35 ng/ml) were significantly lower compared with those seen pre-treatment (n = 128) (43.74 +/- 4.97 ng/ml) (P < .0001). These results showed that an ELISA method was successfully established for quantitation of plasma sPDPN and plasma sPDPN levels correlate significantly with tumor occurrence and metastasis. PMID- 29266548 TI - Helicobacter Pylori infection of the gallbladder and the risk of chronic cholecystitis and cholelithiasis: A systematic review and meta-analysis. AB - BACKGROUND: Helicobacter pylori is coexisted with various diseases, including chronic gastritis, ulcer, and gastric cancer. Besides, chronic cholecystitis and cholelithiasis are extremely widespread over the world, which are considered as high health-care cost burdens of digestive diseases. Epidemiologic evidence on Helicobacter pylori infection in gallbladder increasing the risk of biliary diseases has been contradictory. AIM: Conduct a meta-analysis of overall studies and investigate an association between Helicobacter pylori infection of the gallbladder with chronic cholecystitis/cholelithiasis. METHODS: We used PubMed, EMBASE, and Cochrane library databases to identify all published studies before August 2017. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were obtained using the random effects model. Heterogeneity, sensitivity, and stratified analyses were also performed. RESULTS: Eighteen studies involving 1544 participants and 1061 biliary cases with chronic cholecystitis/cholelithiasis were included. Helicobacter pylori infection of the gallbladder was significantly associated with an increased risk of chronic cholecystitis and cholecystitis (OR = 3.022; 95% CI, 1.897-4.815; I2 = 20.1%). In addition, country-based subgroup analysis also showed a positive association between Helicobacter pylori positivity and chronic cholecystitis/cholelithiasis risk. The ORs (95% CIs) for Asian and non-Asian region studies were 3.75 (1.83 7.71) and 2.25 (1.29-3.89), respectively. CONCLUSION: This meta-analysis suggests that infection of the gallbladder with Helicobacter pylori is closely related to an increased risk of chronic cholecystitis and cholelithiasis. PMID- 29266549 TI - Experiences of Chinese immigrant women following "Zuo Yue Zi" in British Columbia. AB - AIMS AND OBJECTIVES: To describe Chinese women's experiences with "zuo yue zi" in British Columbia, Canada. BACKGROUND: Women born in China and Taiwan are increasingly immigrating to westernised countries. Many women choose to follow traditional Chinese postpartum practices, also called "zuo yue zi." Few studies have examined women's use of traditional practices in western countries. DESIGN: The study used a qualitative descriptive design. METHODS: We recruited 13 mothers who were: aged 19 or older, immigrants from mainland China, Hong Kong or Taiwan in the last 5 years, and caring for infants born in the previous 6 weeks. Semistructured interviews were conducted in Mandarin, translated into English, transcribed and analysed using inductive content analysis. RESULTS: The core theme was Chinese women's novel encounters with "zuo yue zi." The women's expectations of "zuo yue zi" were acquired through birth experiences or interactions with family and friends. The participants struggled with implementing traditional practices because social support and formal institutional structures were lacking. They modified their expectations about "zuo yue zi." Factors affecting their practices were catalysts and deterrents. Catalysts included help from Chinese family members, friends and informed healthcare providers. Deterrents included unregulated paid helpers, uninformed care providers, financial constraints and structural limitations in their new environments. CONCLUSIONS: Chinese immigrant women struggled to modify and implement traditional practices in their adopted country when they encountered financial constraints, unregulated paid helpers and varying support from health care providers. RELEVANCE TO CLINICAL PRACTICE: Some postpartum women following "zuo yue zi" believed that the practice would prevent chronic illness and strengthen their intrafamily relationships. Immigrant mothers require nursing support to follow traditional postpartum practices. Nurses can advocate on patients' behalf to increase care providers' knowledge about "zuo yue zi" and public awareness for necessary regulated institutional structures. PMID- 29266550 TI - Molecular architectures of Pen and Pal: Key enzymes required for CMP-pseudaminic acid biosynthesis in Bacillus thuringiensis. AB - Bacillus thuringiensis is a soil-dwelling Gram positive bacterium that has been utilized as a biopesticide for well over 60 years. It is known to contain flagella that are important for motility. One of the proteins found in flagella is flagellin, which is post-translationally modified by O-glycosylation with derivatives of pseudaminic acid. The biosynthetic pathway for the production of CMP-pseudaminic acid in B. thuringiensis, starting with UDP-N-acetyl-d glucosamine (UDP-GlcNAc), requires seven enzymes. Here, we report the three dimensional structures of Pen and Pal, which catalyze the first and second steps, respectively. Pen contains a tightly bound NADP(H) cofactor whereas Pal is isolated with bound NAD(H). For the X-ray analysis of Pen, the site-directed D128N/K129A mutant variant was prepared in order to trap its substrate, UDP GlcNAc, into the active site. Pen adopts a hexameric quaternary structure with each subunit showing the bilobal architecture observed for members of the short chain dehydrogenase/reductase superfamily. The hexameric quaternary structure is atypical for most members of the superfamily. The structure of Pal was determined in the presence of UDP. Pal adopts the more typical dimeric quaternary structure. Taken together, Pen and Pal catalyze the conversion of UDP-GlcNAc to UDP-4-keto-6 deoxy-l-N-acetylaltrosamine. Strikingly, in Gram negative bacteria such as Campylobacter jejuni and Helicobacter pylori, only a single enzyme (FlaA1) is required for the production of UDP-4-keto-6-deoxy-l-N-acetylaltrosamine. A comparison of Pen and Pal with FlaA1 reveals differences that may explain why FlaA1 is a bifunctional enzyme whereas Pen and Pal catalyze the individual steps leading to the formation of the UDP-sugar product. This investigation represents the first structural analysis of the enzymes in B. thuringiensis that are required for CMP-pseudaminic acid formation. PMID- 29266551 TI - Postmortem immunohistochemical alterations following cerebral lesions: A possible pathohistological importance of the beta-dystroglycan immunoreactivity. AB - The frequency of cerebrovascular injuries raises the importance of their immunohistological investigation in postmortem materials. Most injuries involve the impairment of the blood-brain barrier. The barrier is maintained by the glio vascular connections which break up following injuries. Some immunohistochemical alterations may refer to the impairment of the gliovascular connections. Laminin and the components of the dystroglycan complex show characteristic immunohistochemical alterations following various experimental injuries (stab wound, cryogenic lesion, arterial occlusions): immunoreactivity of beta dystroglycan, alpha-dystrobrevin and aquaporin 4 disappeared while that of utrophin and laminin appeared along the vessels, whereas alpha-syntrophin visualized the reactive astrocytes but not the resting ones. The aims of the present study were to investigate whether these post-lesion alterations: (i) are reproducible with immersive fixation, which is used in postmortem histology; (ii) are resistant to a postmortem delay before fixation; and (iii) are to be attributed to a direct effect of the lesion, or are mediated by processes occurring only in the living brain. Three models were investigated: (i) following lesions, some brains were fixed by transcardial perfusion, others by immersion; (ii) following lesions, the animals were decapitated and stored at room temperature for 8 or 16 h before fixation; and (iii) the lesions were performed after decapitation. Cryogenic lesions were performed by applying a dry ice cooled copper rod to the brain surface of ketamine-xylazine anesthetized rats. The immunohistochemical reactions were performed on free-floating sections cut with vibratome. Both immunoperoxidase and immunofluorescence methods were used. The fixation method - perfusive or immersive - did not change the post-lesion phenomena investigated. The postmortem delay did not influence the beta dystroglycan immunoreactivity, that is its lack delineated the area of the lesion. However, in the case of the other substances, various lengths of postmortem delay rendered the immunohistochemistry uninterpretable. The results suggest beta-dystroglycan immunostaining could be applied in the neuropathology to detect cerebrovascular impairments. PMID- 29266552 TI - Tuberculosis updates 2018: Innovations and developments to end TB. PMID- 29266553 TI - Influence of adenomyosis on pregnancy and perinatal outcomes in women with endometriosis. AB - OBJECTIVES: Several studies have investigated the correlation between endometriosis and adverse pregnancy and perinatal outcomes. However, the role of adenomyosis as a risk factor for adverse perinatal outcome in women with endometriosis has yet to be established. The aim of this study was to explore if fetal and maternal outcomes, in particular the incidence of a small-for gestational-age (SGA) infant, are different in pregnant women with endometriosis only from in those with the concomitant presence of diffuse or focal adenomyosis. METHODS: This was a retrospective analysis of data collected prospectively during a 3-year period. We included 206 pregnant women with endometriosis: 148 (71.8%) with endometriosis only, 38 (18.4%) with focal adenomyosis and 20 (9.7%) with diffuse adenomyosis. Adenomyosis was diagnosed using ultrasonography and was classified as focal or diffuse. The study included patients who conceived spontaneously or by an assisted reproductive technique. Demographics, ultrasound variables and outcome were compared between women with endometriosis only and those with diffuse and those with focal adenomyosis. Logistic regression analysis was performed to assess the association of variables with SGA at birth in women with diffuse and those with focal adenomyosis. RESULTS: The three groups were similar in demographic characteristics (age, body mass index, mode of conception). Patients with diffuse adenomyosis compared with those with endometriosis only had significantly lower pregnancy-associated plasma protein A (0.61 vs 0.88 multiple of the median, P < 0.001), higher mean uterine artery pulsatility index in the first (2.23 vs 1.67, P < 0.001) and second (1.30 vs 0.94, P < 0.001) trimesters of pregnancy, and higher incidence of SGA (40% vs 10.8%, P < 0.001). No statistically significant differences were found in patients with focal adenomyosis compared with those with endometriosis only. Logistic regression analysis demonstrated that diffuse adenomyosis (odds ratio = 3.744; 95% CI, 1.158-12.099; P = 0.027) was the only independent risk factor for SGA. CONCLUSIONS: The presence of diffuse adenomyosis in pregnant women with endometriosis is strongly associated with delivery of a SGA infant. Women with diffuse adenomyosis should be treated as being at high risk of placental dysfunction, and these pregnancies might therefore need closer monitoring. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29266555 TI - Pattern recognition receptors and signaling in plant-microbe interactions. AB - Plants solely rely on innate immunity of each individual cell to deal with a diversity of microbes in the environment. Extracellular recognition of microbe- and host damage-associated molecular patterns leads to the first layer of inducible defenses, termed pattern-triggered immunity (PTI). In plants, pattern recognition receptors (PRRs) described to date are all membrane-associated receptor-like kinases or receptor-like proteins, reflecting the prevalence of apoplastic colonization of plant-infecting microbes. An increasing inventory of elicitor-active patterns and PRRs indicates that a large number of them are limited to a certain range of plant groups/species, pointing to dynamic and convergent evolution of pattern recognition specificities. In addition to common molecular principles of PRR signaling, recent studies have revealed substantial diversification between PRRs in their functions and regulatory mechanisms. This serves to confer robustness and plasticity to the whole PTI system in natural infections, wherein different PRRs are simultaneously engaged and faced with microbial assaults. We review the functional significance and molecular basis of PRR-mediated pathogen recognition and disease resistance, and also an emerging role for PRRs in homeostatic association with beneficial or commensal microbes. PMID- 29266554 TI - Pathophysiology of swallowing following oropharyngeal surgery for obstructive sleep apnea syndrome. AB - BACKGROUND: Uvulopalatopharyngoplasty (UPPP) and coblation channeling of the tongue (CCT) are oropharyngeal surgeries used to treat obstructive sleep apnea syndrome. The extent to which UPPP and CCT affect pharyngeal swallow has not been determined. We therefore conducted a novel case series study employing high resolution impedance manometry (HRIM) to quantify the swallowing-related biomechanics following UPPP and/or CCT surgery. METHODS: Twelve patients who underwent UPPP+CCT or CCT only were assessed an average 2.5 years postsurgery. Swallow function data were compared with ten healthy controls. All patients completed the Sydney swallow questionnaire (SSQ). Pharyngeal pressure-flow analysis of HRIM recordings captured key distension, contractility and pressure flow timing swallow parameters testing 5, 10, and 20 mL volumes of thin and thick fluid consistencies. KEY RESULTS: Postoperative patients had more dysphagia symptoms with five returning abnormal SSQ scores. Swallowing was biomechanically altered compared to controls, consistent with diminished swallowing reserve, largely driven by elevated hypopharyngeal intrabolus pressure due to a reduced capacity to open the upper esophageal sphincter to accommodate larger volumes. CONCLUSIONS & INFERENCES: Patients who have undergone UPPP and/or CCT surgery appear to have a deficiency in normal modulation of the swallowing mechanism and a reduced swallowing functional reserve. We speculate that these changes may become relevant in later life with the onset of age-related stressors to the swallowing mechanism. This case series strikes a note of caution that further studies are needed to determine the role of preoperative swallow assessment in patients undergoing UPPP and/or CCT surgery. PMID- 29266556 TI - Concordance between Lactose Quick Test, hydrogen-methane breath test and genotyping for the diagnosis of lactose malabsorption in children. AB - BACKGROUND: Lactose intolerance is a frequent condition in certain populations. Different methods for diagnosis exist. There is scarce literature regarding Lactose Quick Test (LQT) and concordance with other methods for lactose intolerance diagnosis in children. METHODS: Prospectively, we included children who underwent gastroduodenoscopy for evaluation of abdominal pain. We obtained a duodenal sample for LQT and blood sample for genetic test to evaluate LCT C>T 13910 variant. Later, patients underwent breath test with lactose, to evaluate malabsorption. We evaluated the concordance between the three different tests. KEY RESULTS: We included 46 patients, 56.5% women. Mean age was 13.2 years (range 9-18 years). 66.6% of patients had lactose malabsorption according to breath test; 64.4% were homozygous CC; and 91.3% had hypolactasia (mild or severe) according to LQT. None of the patients with normolactasia had altered breath test. Genetic test had a substantial agreement (k = 0.675) with breath test and fair agreement (k = 0.301) with LQT. LQT had fair agreement (k = 0.348) with breath test. CONCLUSIONS & INFERENCES: Genetic test had better concordance with breath test than LQT to diagnose lactose malabsorption, however, none of the patients with normal LQT had lactose malabsorption. In patients who undergo gastroduodenoscopy to study abdominal pain, it seems reasonable to perform LQT, and, in those with hypolactasia, to perform breath test. PMID- 29266557 TI - Influence of cigarette smoking on haemoglobin concentration - do we need a different approach to blood donor selection? PMID- 29266559 TI - Adolescents Who Self-Harm: The Patterns in Their Interpersonal and Psychosocial Difficulties. AB - We proposed that having mutually hostile interactions with others is a strong environmental stress factor that, together with diverse psychosocial problems, characterizes adolescents who self-harm. Using cluster analysis, this study examined the naturally occurring patterns of hostility conditions and psychosocial difficulties in a normative sample of 2,029 adolescents (50% boys; Mage = 13.89). Results showed that self-harming behavior was significantly higher among the subgroup of adolescents with mutually hostile interactions who exhibited both internalizing and externalizing problems than among adolescents with other interpersonal-psychosocial configurations. Also, this subgroup of adolescents reported high impulsivity, anger dysregulation, and low self-esteem. These findings support recent research that indicates that adolescents who self harm also tend to expose others to hostility and display externalizing symptoms. PMID- 29266558 TI - Computational predictions of cysteine cathepsin-mediated fibrinogen proteolysis. AB - Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as the main proteases cleaving fibrinogen precursor, and the fibrin polymer, respectively. Other proteases may be involved directly in fibrin(ogen) cleavage, clot formation, and resolution, or in the degradation of fibrin-based scaffolds emerging as useful tools for tissue engineered constructs. Here, cysteine cathepsins are investigated for their putative ability to hydrolyze fibrinogen, since they are potent proteases, first identified in lysosomal protein degradation and known to participate in extracellular proteolysis. To further explore this, we used two independent computational technqiues, molecular docking and bioinformatics sequence analysis (PACMANS), to predict potential binding interactions and sites of hydrolysis between cathepsins K, L, and S and fibrinogen. By comparing the results from these two objective, computational methods, it was determined that cathepsins K, L, and S do bind and cleave fibrinogen alpha, beta, and gamma chains at similar and unique sites. These differences were visualized experimentally by the unique cleaved fibrinogen banding patterns after incubation with each of the cathepsins, separately. In conclusion, human cysteine cathepsins K, L, and S are a new class of proteases that should be considered during fibrin(ogen) degradation studies both for disease processes where coagulation is a concern, and also in the implementation and design of bioengineered systems. PMID- 29266560 TI - Anti-angiogenesis effect of beta-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model. AB - Angiogenesis is a process through which new capillaries are formed from pre existing ones, which contributes significantly to the pathogenesis of numerous diseases, such as cancer and chronic inflammatory disorders. The beta-D mannuronic acid (M2000) is a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive effects and is a matrix metalloproteinase (MMP) inhibitor. This research aimed to study the anti-angiogenesis effects of M2000 under in vitro and in vivo models. The cytotoxic and anti-proliferative effects of M2000 were examined using the trypan blue method and the MTT assay, respectively. The 3D collagen-cytodex model and the chick chorioallantoic membrane (CAM) assay were then used to evaluate the anti-angiogenesis property of M2000. Cytotoxicity assay revealed that M2000 (at concentrations of less than 100 MUg/mL) had no cytotoxic effect on human umbilical vein endothelial cells (HUVECs). It was also illustrated that M2000 had little or no anti-proliferative effect on HUVECs. In addition, the anti-angiogenesis effects of M2000 were shown to be marginal in the in vitro model and both significant and dose-dependent in the in vivo status. This study showed that M2000 could be considered as an anti-angiogenic molecule which more likely exerts its activity mainly via indirect effects on endothelial cells and its anti-inflammatory effects may partly be attributable to its anti angiogenic activity. Therefore, it could be recommended as a candidate for prevention and treatment of cancer, chronic inflammatory diseases, and other angiogenesis-related disorders. PMID- 29266561 TI - Response to Editor to the comment by Schipper & Smith to our paper entitled "Continuous soil carbon storage of old permanent pastures in Amazonia". PMID- 29266562 TI - Production of functional sperm by subcutaneous auto-grafting of immature testes in rainbow trout. AB - Sexually mature individuals are indispensable for breeding programs. Salmonids require a long period before reaching sexual maturity, so we aimed to shorten the period required to obtain functional sperm by grafting immature testicular fragments into mature recipients, which we predicted would allow the grafted testicular fragments to skip the long pre-pubertal period. First, we demonstrated successful subcutaneous auto-grafting of testicular fragments in rainbow trout. Unilateral testectomy was performed, and the isolated immature testicular fragment was auto-grafted into the subcutaneous space along the back of recipient fish. The grafted testicular fragments developed synchronously with the recipients' testis remaining in its body cavity, and both eventually produced functional sperm. Next, immature testicular fragments were auto-grafted into the subcutaneous space of sexually mature males. We achieved this, without immune rejection, by isolating and cryopreserving testes from immature fish, and rearing these unilaterally testectomized fish until sexual maturity. The cryopreserved testes were then auto-grafted into the original, now spermiating fish. The grated immature testicular fragments differentiated and produced functional sperm within 5 months after grafting. By combining this grafting method with a technique to avoid immune rejection, we expect to develop a practical method for producing sperm in a shorter period in salmonids. PMID- 29266563 TI - Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia. AB - Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P < 0.03) and analgesia (1.5-fold AUC0-60 ; P < 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6 fold; P < 0.001) and decreased analgesia (0.8-fold; P < 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P > 0.1) and analgesia (1.1-fold; P > 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P < 0.003), but not hepatic (P > 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P > 0.9 for AUC0-60 across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability. PMID- 29266564 TI - Sudden cardiac death after acute heart failure hospital admission: insights from ASCEND-HF. AB - AIMS: The incidence of and factors associated with sudden cardiac death (SCD) early after an acute heart failure (HF) hospital admission have not been well defined. METHODS AND RESULTS: We assessed SCD and ventricular arrhythmias in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, which included patients with acute HF with reduced or preserved ejection fraction. SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated from randomization through 30 days and were combined into a composite endpoint. Baseline characteristics associated with this composite were determined by logistic regression. RSCD and VT/VF were included as time-dependent variables in a Cox model evaluating the association of these variables with 180-day all-cause mortality. Among 7011 patients, the 30-day all-cause mortality rate was 3.8%; SCD accounted for 17% of these deaths. The 30-day composite event rate was 1.8% (n = 121). Ten patients had more than one event with 30-day Kaplan-Meier event rates of 0.6% for SCD [95% confidence interval (CI) 0.5%-0.9%, n = 43], 0.4% for RSCD (95% CI 0.2%-0.5%, n = 24), and 0.9% for VT/VF (95% CI 0.7%-1.2%, n = 64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, and longer QRS duration were associated with SCD, RSCD, or VT/VF. A RSCD or VT/VF event was associated with higher 180-day mortality (adjusted hazard ratio 6.6, 95% CI 4.8-9.1, P < 0.0001). CONCLUSIONS: Approximately 2% of patients admitted for acute HF experienced SCD, RSCD, or VT/VF within 30 days of admission, and SCD accounted for 17% of all deaths within 30 days. PMID- 29266566 TI - Antibiotic resistance rates in cutaneous propionibacteria from UK patients with acne are not falling. PMID- 29266565 TI - Injury resulting from targeted violence: An emergency department perspective. AB - BACKGROUND: Hate crimes - those perpetrated because of perceived difference, including disability, race, religion, sexual orientation or transgender status - have not been studied at the point of the victim's hospital emergency department (ED) use. AIM: To investigate the frequency, levels of physical harm and circumstances of targeted violence in those seeking treatment at EDs in three UK cities. METHOD: In a multimethods study, face-to-face semi-structured interviews were conducted with 124 adult ED attenders with violent injuries. Victim and perpetrator socio-demographics were recorded. Patient narratives about perceived motives and circumstances were transcribed, uploaded onto NVivo for thematic analysis. RESULTS: Nearly a fifth (23, 18.5%) of the injured patients considered themselves to have been attacked by others motivated by hostility or prejudice to their 'difference' (targeted violence). Thematic analyses suggested these prejudices were to appearance (7 cases), racial tension (5 cases), territorial association (3 cases) and race, religious or sexual orientation (8 cases). According to victims, alcohol intoxication was particularly relevant in targeted violence (estimated reported frequency 90% and 56% for targeted and non-targeted violence, respectively). CONCLUSIONS: Our findings support a broader concept of hate victimisation and suggest that emergency room violence surveys could act as a community tension sensor and early warning system in this regard. Tackling alcohol misuse seems as important in this as in other forms of violence perpetration. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29266567 TI - Peptide-Driven Charge-Transfer Organogels Built from Synergetic Hydrogen Bonding and Pyrene-Naphthalenediimide Donor-Acceptor Interactions. AB - The peptide-driven formation of charge transfer (CT) supramolecular gels featuring both directional hydrogen-bonding and donor-acceptor (D-A) complexation is reported. Our design consists of the coassembly of two dipeptide-chromophore conjugates, namely diphenylalanine (FF) dipeptide conveniently functionalized at the N-terminus with either a pyrene (Py-1, donor) or naphthalene diimide (NDI-1, acceptor). UV/Vis spectroscopy confirmed the formation of CT complexes. FTIR and 1 H NMR spectroscopy studies underlined the pivotal role of hydrogen bonding in the gelation process, and electronic paramagnetic resonance (EPR) measurements unraveled the advantage of preorganized CT supramolecular architectures for charge transport over solutions containing non-coassembled D and A molecular systems. PMID- 29266568 TI - Incontinence-associated dermatitis in the critically ill patient: an intensive care perspective. AB - BACKGROUND: Incontinence-associated dermatitis is a skin disorder evident as a complication of incontinence. It is characterized by perineal, buttock and groin erythema and skin breakdown. Incontinence-associated dermatitis is a ubiquitous, nosocomial condition commonly present in critically ill patients in the intensive care unit. Critically ill patients, by the nature of their critical illness and therapies used to treat their presenting condition, are commonly predisposed to faecal incontinence and are consequently at high risk of developing incontinence associated dermatitis. However, this condition is under-explored and under reported in the intensive care literature. OBJECTIVE: The aim of this paper is to provide a review of the literature relating to incontinence-associated dermatitis from the critically ill patients in the intensive care setting. DISCUSSION: There is a paucity of literature addressing this condition in the intensive care context, with only 11 studies identified. This paper will provide an overview of the definitions, prevalence and incidence of incontinence-associated dermatitis. Furthermore, an exposition of incontinence-associated dermatitis from the critically ill patient and intensive care nursing perspectives will be presented through a review of the skin barrier function, clinical presentation, risk factors, clinical assessment and severity categorization, prevention and management of incontinence-associated dermatitis. CONCLUSION: It is imperative that critical care nurses have an appreciation of incontinence-associated dermatitis as a common, yet preventable condition, and are equipped with knowledge to appropriately prevent and manage this common complication. PMID- 29266569 TI - FABP4 blocker attenuates colonic hypomotility and modulates white adipose tissue derived hormone levels in mouse models mimicking constipation-predominant IBS. AB - BACKGROUND: The role of fatty acid binding protein 4 (FABP4) in lower gastrointestinal (GI) motility is unknown. We aimed to verify the effect of inhibition of FABP4 on GI transit in vivo, and to determine the expression of FABP4 in mouse and human tissues. METHODS: Fatty acid binding protein 4 inhibitor, BMS309403, was administered acutely or chronically for 6 and 13 consecutive days and its effect on GI transit was assessed in physiological conditions and in loperamide-induced constipation. Intracellular recordings were made to examine the effects of BMS309403 on colonic excitatory and inhibitory junction potentials. Abdominal pain was evaluated using behavioral pain response. Localization and expression of selected adipokines were determined in the mouse colon and serum using immunohistochemistry and Enzyme-Linked ImmunoSorbent Assay respectively. mRNA expression of FABP4 and selected adipokines in colonic and serum samples from irritable bowel syndrome (IBS) patients and control group were assessed. KEY RESULTS: Acute injection of BMS309403 significantly increased GI motility and reversed inhibitory effect of loperamide. BMS309403 did not change colonic membrane potentials. Chronic treatment with BMS309403 increased the number of pain-induced behaviors. In the mouse serum, level of resistin was significantly decreased after acute administration; no changes in adiponectin level were detected. In the human serum, level of adiponectin and resistin, but not of FABP4, were significantly elevated in patients with constipation-IBS (IBS C). FABP4 mRNA expression was significantly downregulated in the human colon in IBS-C. CONCLUSIONS AND INFERENCES: Fatty acid binding protein 4 may be involved in IBS pathogenesis and become a novel target in the treatment of constipation related diseases. PMID- 29266570 TI - Effect of laser therapy on quality of life in patients with radiation-induced breast telangiectasias. AB - OBJECTIVE: To evaluate the effects of laser monotherapy on quality of life in breast cancer patients with chronic radiation dermatitis. STUDY DESIGN: A prospective, IRB-approved study was conducted at Memorial Sloan Kettering Cancer Center. Breast cancer patients with chronic radiation dermatitis completed health related quality of life (HR-QOL) questionnaires before and after laser monotherapy for radiation-induced breast telangiectasias (RIBT). METHODS: After informed consent, all patients were issued the Skindex-16 and Breast-Q Adverse Effects of Radiation HR-QOL questionnaires prior to receiving laser treatment. Patients were treated with a 595 nm pulsed dye laser at 4- to 6-week intervals, with percent telangiectasia clearance and adverse events recorded at each visit. Post-treatment HR-QOL questionnaires were collected after clinician-assessed telangiectasia clearance of >50%. Median HR-QOL scores before and after therapy were reported for individual HR-QOL domains (Skindex-16) and HR-QOL totals (Skindex-16 and Breast-Q Adverse Effects of Radiation). Before- and after differences were calculated using the Wilcoxon Signed-Rank Test. RESULTS: Twenty two female patients (average age 56 years) enrolled in this study. A majority (13/22, 59%) exhibited telangiectasias across the decolletage and axilla in addition to the breast. Sixteen patients reached the 50% RIBT clearance threshold during the study period, and 11 of these patients (69%) completed follow-up HR QOL questionnaires. Patients showed statistically significant improvements in emotional and functional Skindex-16 HR-QOL domains and in overall Skindex-16 HR QOL score. Breast-Q scores also improved significantly, illustrating a decrease in specific physical and cosmetic concerns common to radiated breast skin. Common adverse events were transient post-treatment pain and redness. CONCLUSION: Breast cancer patients with RIBT presented with substantial deficits in several HR-QOL arenas. Laser monotherapy effectively treated the appearance of radiation dermatitis in these patients and also significantly improved HR-QOL. Lasers Surg. Med. 50:284-290, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266571 TI - Use of subcutaneous treprostinil in pediatric pulmonary arterial hypertension Bridge-to-transplant or long-term treatment? AB - PAH is a progressive life-threatening disease in children. While parenteral prostacyclin therapy improves survival in patients with severe PAH, central line related complications are common. Our aim was to assess the efficacy, safety, and tolerability of subcutaneous treprostinil treatment in pediatric PAH patients. Eight patients were treated with subcutaneous treprostinil at the Pediatric Heart Center Budapest. Indications for subcutaneous treprostinil therapy were clinical worsening and/or echocardiographic progression or switch from intravenous to subcutaneous therapy. Following treprostinil initiation, clinical status improved or did not change in four of eight patients. Two patients were lost early during treprostinil therapy, parenteral treprostinil as a rescue therapy being insufficient in these cases. The final dose in long-term treated patients was between 60 and 100 ng/kg/min. Aside from thrombocytopenia, other severe side effects were not observed. Potts shunt was performed as palliative treatment in two cases. Three patients had successful lung transplantation, and one died while on the waiting list. Long-term subcutaneous treprostinil could be a safe and well tolerated therapy in children with severe PAH even at higher doses. It may serve as an alternative to intravenous prostacyclin treatment allowing to avoid the potential complications of permanent central line placement. PMID- 29266572 TI - The Impact of Alexithymia on Emotion Dysregulation in Anorexia Nervosa and Bulimia Nervosa over Time. AB - Research supports that anorexia nervosa-restricting subtype (AN-R) and bulimia nervosa (BN) are associated with emotion regulation difficulties and alexithymia. However, the impact of diagnosis on the relationship between these constructs is less well understood. The purpose of the present study was to examine whether eating disorder diagnosis moderated the association between admission alexithymia and emotion regulation through discharge. Adult patients with AN-R (n = 54) and BN (n = 60) completed assessments at treatment admission and discharge from a partial hospital program. Eating disorder diagnosis moderated the association between admission alexithymia levels and change in global emotion dysregulation, impulse control difficulties and access to emotion regulation strategies. At higher levels of admission alexithymia, there were no differences between AN-R and BN on emotion dysregulation, whereas at lower levels of alexithymia, AN-R patients demonstrated lower levels of emotion dysregulation. Results imply that difficulties with alexithymia appear to have a greater impact on emotion dysregulation for AN-R patients. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 29266573 TI - Emergency department waiting room nurses in practice: An observational study. AB - AIMS AND OBJECTIVES: To identify the activities and behaviours of waiting room nurses in emergency department settings. BACKGROUND: Emergency care has expanded into waiting rooms in some emergency departments. Often viewed as an adjunct to triage, the aim of waiting room nurses is to commence care early, reassess patients and improve communication between patients, families and staff. There is however a paucity of literature relating to waiting room nurses, especially in relation to their current activities and behaviours. DESIGN AND METHODS: Part of a larger exploratory sequential mixed methods designed study. This phase used a nonparticipant observer role to observe waiting room nurses in their natural setting undertaking normal care and responsibilities. One observer, using a tool and reflective journal, collected data on participant interactions, processes and practices on eight waiting room nurses over 13 episodes of observation (total 65 hr:50 min) in two emergency departments. Data analysis used descriptive statistics and thematic analysis. RESULTS: Participants were observed to anticipate and prioritise to deliver holistic, patient-centred care in emergency department waiting rooms. Waiting room nurses had a varied and unpredictable workload, including facilitating the flow of patients from the waiting room. They contributed to patient safety in the waiting room, primarily by reassessing and detecting clinical deterioration. CONCLUSION: Further research into this role is required, including linking efficacy with experience of nurses, impact the role has on patient safety, and patient and family perceptions of the role. RELEVANCE TO CLINICAL PRACTICE: Therapeutic engagement allowed waiting room nurses to reassure and calm patients and families, and deliver holistic, patient-centred care. Waiting room nurses contributed to patient safety in the waiting room, by promptly commencing episodes of care in the waiting room and through close monitoring and assessment to detect patient deterioration. PMID- 29266574 TI - Pregnancy outcomes in female childhood cancer survivors: Nationwide survey in Japan. AB - BACKGROUND: The aim of this study was to investigate the outcomes of pregnancy in female childhood cancer survivors (CCS) in Japan, to encourage greater attention to the reproductive health of CCS. METHODS: This was a retrospective nationwide questionnaire survey of delivery at >=22 weeks of gestation in CCS at perinatal centers registered with the Japanese Perinatologists Association between 2010 and 2014. We evaluated the maternal characteristics, pregnancy and neonatal outcomes and the relationship between cancer treatment and these outcomes. RESULTS: The total number of CCS was 61, and the total number of deliveries was 71, corresponding to 0.019% of total deliveries. Regarding cancer, 46% of the patients had had leukemia. Epilepsy was seen in seven (11%). Mean gestational age at delivery was 37.9 weeks. The rate of preterm delivery was 24%. Mean birthweight was 2,718 g. There were three congenital anomalies (4.2%). The rate of preterm delivery was higher and mean birthweight lower in the women treated with radiotherapy than in those without radiotherapy (42% vs 16%, P = 0.025; 2,436 +/- 737 g vs 2,827 +/- 483 g, P = 0.010). The adjusted OR of radiotherapy for preterm deliveries was 3.53 (P = 0.049). CONCLUSIONS: Although the number of deliveries by CCS was low in Japan, the pregnancy outcomes were favorable. The important points for managing pregnancy in CCS were preterm delivery as an obstetric complication, especially in CCS who had been treated with radiotherapy, and epilepsy as a maternal complication, which may be related to previously received treatment. PMID- 29266575 TI - Learning by supporting others-experienced parents' development process when supporting other parents with a child with type 1 diabetes. AB - AIMS AND OBJECTIVES: To describe and analyse coach-parents' development process when supporting parents of children recently diagnosed with type 1 diabetes mellitus (T1DM). BACKGROUND: It has been found repeatedly that providing social support for families with a child diagnosed with T1DM promotes health and well being for both the child and the parents. Less explored are the processes experienced by those who provide this support. However, research has found that acting as a provider of social support promotes personal development, strengthens communication skills and increases self-confidence. METHODS: The study design was based on Constructivist Grounded Theory, and data were collected, through repeated focus-group discussions, from eight coach-parents at a Swedish hospital from 2012-2015. RESULTS: The core category in the data was identified as a learning process where coach-parents emphasised their own learning in the dyad supporter-supported, and in the interaction with other parents in the repeated focus-group discussions. The coach-parents' motivation for participation was a wish to learn more and to help other parents in a life-changing situation. They also pointed out hindrances and their frustration when unable to provide support. CONCLUSIONS: This study leads to the conclusion that people who provide support benefit from doing so. Encountering people with similar experiences in a supportive situation promotes a reciprocal learning process, based on the supporter's wish to help people in a situation they recognise. A further conclusion is that social support is not only essential initially, but is also important over a longer period and that it follows various life stages. RELEVANCE TO CLINICAL PRACTICE: Setting up repeated focus-group discussions might be a relevant and effective tool for paediatric diabetes nurses to use in promoting health and well-being for both families with a newly diagnosed child and experienced families. PMID- 29266576 TI - Experimental manipulation of population-level MHC diversity controls pathogen virulence evolution in Mus musculus. AB - The virulence levels attained by serial passage of pathogens through similar host genotypes are much higher than observed in natural systems; however, it is unknown what keeps natural virulence levels below these empirically demonstrated maximum levels. One hypothesis suggests that host diversity impedes pathogen virulence, because adaptation to one host genotype carries trade-offs in the ability to replicate and cause disease in other host genotypes. To test this hypothesis, with the simplest level of population diversity within the loci of the major histocompatibility complex (MHC), we serially passaged Friend virus complex (FVC) through two rounds, in hosts with either the same MHC genotypes (pure passage) or hosts with different MHC genotypes (alternated passage). Alternated passages showed a significant overall reduction in viral titre (31%) and virulence (54%) when compared to pure passages. Furthermore, a resistant host genotype initially dominated any effects due to MHC diversity; however, when FVC was allowed to adapt to the resistant host genotype, predicted MHC effects emerged; that is, alternated lines show reduced virulence. These data indicate serial exposure to diverse MHC genotypes is an impediment to pathogen adaptation, suggesting genetic variation at MHC loci is important for limiting virulence in a rapidly evolving pathogen and supports negative frequency-dependent selection as a force maintaining MHC diversity in host populations. PMID- 29266577 TI - Emergency Department Treatment of Opioid Addiction: An Opportunity to Lead. PMID- 29266578 TI - Using the trauma patient experience and evaluation of hospital discharge practices to inform practice change: A mixed methods study. AB - AIMS AND OBJECTIVES: To explore the pain management experiences of recently discharged adult trauma patients and the discharge practices of the treating hospital. BACKGROUND: Adult trauma patients are not always able to manage their pain effectively and as a result often experience intense and enduring injury pain at home. They describe their pain experience as unique and debilitating, and report feeling uninformed at hospital discharge. There is a need to understand what is fundamentally required for this population at hospital discharge, to facilitate competent pain management and promote best possible outcomes. DESIGN: A mixed methods convergent study design. METHODS: The quantitative results (incidence, intensity and impact of injury pain and the barriers to effective pain management) were merged with the qualitative results (patient experiences and beliefs) to produce greater understanding about the reasons behind the pain management practices of participants. RESULTS: Integration of the quantitative and qualitative data produced four new themes. These themes demonstrate that recently discharged adult trauma patients do not have the knowledge or experience to understand or manage their injury pain effectively at home. Inadequate information and education by clinicians, at hospital discharge, contribute to this insufficiency. CONCLUSIONS: Clinicians need to understand the trauma patient pain experience to appreciate the importance of their discharge practices. Increased understanding and implementation of evidence-informed discharge processes would improve current discharge practices and ultimately support and improve the trauma patient's injury pain management practices at home. RELEVANCE TO CLINICAL PRACTICE: By understanding the patient perspective in the pain management of injuries, clinicians are better able to appreciate what hospital discharge practices and information are genuinely required by the trauma patient to manage their pain effectively at home, potentially preventing the long-term consequences of injury pain. PMID- 29266579 TI - Euthanasia for what? Attending to the role of stigma in addiction-related 'intractable suffering' and 'incurability'. PMID- 29266580 TI - Changes in the dysphagia and nutritional status of patients with brain injury. AB - AIMS AND OBJECTIVES: To evaluate the degree of improvement in the dysphagia and nutritional status of patients with brain injuries after removal of the nasogastric tube. BACKGROUND: The nurse should assess patients' dysphagia, after removal of the nasogastric tube, and immediately reflect the changes in patient care. Accordingly, the critical roles of nurses in caring for patients with dysphagia involve providing appropriate nutritional therapy as well as preventing aspiration pneumonia and nutritional imbalance. Assessment of the patient's dysphagia on a regular basis and analysis of nutritional status according to the degree of dysphagia are necessary to determine the appropriate timing for providing nursing interventions and to develop protocols for the provision of a therapeutic diet. DESIGN: Prospective observational study. METHODS: This study was conducted on 56 patients with dysphagia after a brain injury. Data were collected using the Gugging Swallowing Screen (GUSS) test and Swallowing Symptom Questionnaire (SSQ). Descriptive statistics, chi-square tests, t tests, and MANOVA were analysed using SPSS 22.0. RESULTS: Patient's dysphagia was observed over the course of 2 weeks. After 14 days, the severity of dysphagia decreased from 91.1%-35.7%, while the number of participants with normal swallowing increased from 1.8%-58.9%. Dysphagia in patients with brain injury improved gradually over time. A significant difference was observed in the serum albumin level of patients with dysphagia (F = 9.51, p = .003, Wilk's lambda = .034). CONCLUSIONS: Most of the patients with brain injury developed moderate dysphagia immediately after removal of the nasogastric tube. However, after 14 days had elapsed, the percentage of patients recovering from dysphagia increased to 58.9%. Proper dietary patterns were not adequately provided depending on the degree of patient's dysphagia after removal of the nasogastric tube. Assessing the degree of dysphagia using the GUSS test and providing appropriate diet prevent malnutrition in patients with dysphagia. RELEVANCE TO CLINICAL PRACTICE: This study was conducted in patients who developed complications of dysphagia after a brain injury. Using the Gugging Swallowing Screen (GUSS) test, the changes in the degree of dysphagia were repeatedly measured at different times: 4, 7 and 14 days after the removal of the nasogastric tube. Provision of appropriate diet and changes in the nutritional status were analysed to determine the proper timing for nursing intervention in patients with dysphagia. The data obtained from this study could serve as a basis for developing diet provision protocols for patients with dysphagia. PMID- 29266581 TI - Evaluation of peer-generated MCQs to assess and support learning in a problem based learning programme. AB - PURPOSE: Problem-based learning (PBL) students report uncertainty on the depth and breadth of learning required, and this is a significant stressor and challenge. Student-generated MCQ questions were trialled and evaluated as a way to support depth and breadth of learning. METHODS: Students set MCQs relating to specified learning issues, and an analysis and evaluation of setting and answering the MCQs were performed. The Revised Study Process Questionnaire (R-SPQ 2F) and final written examination scores were correlated to question setting and answering. Students were asked to rate the impact of the MCQs on their learning in PBL. RESULTS: A total of 147 questions were created and 2373 answered. Students reported challenges with setting questions, although these made them think more deeply and helped their learning and affirming their learning progress. MCQs authored indicated significant associations with Understanding, and examination scores were associated with MCQs authored. Students reported a moderate response to how the MCQs supported their depth and breadth of learning. CONCLUSIONS: While MCQ setting was perceived as a useful learning exercise, students engaged to different levels and experienced challenges. Students were uncertain whether the MCQs helped clarify the depth and breadth of learning in PBL, as they were not clear whether the questions set by their peers were relevant to the required learning outcomes. PMID- 29266582 TI - alpha-Aminoxy-Acid-Auxiliary-Enabled Intermolecular Radical gamma-C(sp3 )-H Functionalization of Ketones. AB - A method for site-specific intermolecular gamma-C(sp3 )-H functionalization of ketones has been developed using an alpha-aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C-H bond is achieved by 1,5-hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C-radicals thus formed at the gamma-position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding gamma functionalized ketones. PMID- 29266583 TI - Associations of Food Addiction in a Sample Recruited to Be Nationally Representative of the United States. AB - The current study investigated the prevalence of food addiction and its associations with obesity and demographic factors in a sample recruited to be more nationally representative of the United States than previous research. Individuals (n = 1050) were recruited through Qualtrics' qBus, which sets demographic quotas developed using the United States census reference population. Participants (n = 986) self-reported food addiction, measured by the modified Yale Food Addiction Scale 2.0, height, weight, age, gender, race and income. Food addiction was observed in 15% of participants, with greater prevalence in individuals who were younger, Hispanic and/or reported higher annual income. Food addiction prevalence was higher in persons who were underweight or obese, relative to normal weight or overweight. Food addiction was associated with higher body mass index in women and persons who were older, White and/or reported lower income. Identifying the scope of food addiction and individual risk groups may inform public policy initiatives and early intervention efforts. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 29266584 TI - Temperature-Selective Dual Radical Generation from Alkyl Diiodide: Applications to Synthesis of Asymmetric CABC Multi-Block Copolymers and Their Unique Assembly Structures. AB - Temperature-selective radical generation from a newly designed alkyl diiodide (I R2 -R1 -I) was studied. R1 -I and I-R2 had different reactivities for generating alkyl radicals in the presence of a tetraoctylammonium iodide (ONI) catalyst. Taking advantage of the temperature selectivity, we used the alkyl diiodide as a dual initiator in ONI-catalyzed living radical polymerization to uniquely synthesize CABC non-symmetric multi-block copolymers. Because of their non symmetric structure, CABC multi-block copolymers form unique assemblies, that is, Janus-type particles with hetero-segment coronas and flower-like particles with hetero-segment petals. PMID- 29266585 TI - Multivalency effects of hemagglutinin component of type B botulinum neurotoxin complex on epithelial barrier disruption. AB - Hemagglutinin (HA) is one of the components of botulinum neurotoxin (BoNT) complexes and it promotes the absorption of BoNT through the intestinal epithelium by at least two specific mechanisms: cell surface attachment by carbohydrate binding, and epithelial barrier disruption by E-cadherin binding. It is known that HA forms a three-arm structure, in which each of three protomers has three carbohydrate-binding sites and one E-cadherin-binding site. A three-arm form of HA is considered to bind to these ligands simultaneously. In the present study, we investigated how the multivalency effect of HA influences its barrier disrupting activity. We prepared type B full-length HA (three-arm form) and mini HA, which is a deletion mutant lacking the trimer-forming domain. Size-exclusion chromatography analysis showed that mini-HA exists as dimers (two-arm form) and monomers (one-arm form), which are then separated. We examined the multivalency effect of HA on the barrier-disrupting activity, the E-cadherin-binding activity, and the attachment activity to the basolateral cell surface. Our results showed that HA initially attaches to the basal surface of Caco-2 cells by carbohydrate binding and then moves to the lateral cell surface, where the HA acts to disrupt the epithelial barrier. Our results showed that the multivalency effect of HA enhances the barrier-disrupting activity in Caco-2 cells. We found that basal cell surface attachment and binding ability to immobilized E-cadherin were enhanced by the multivalency effect of HA. These results suggest that at least these two factors induced by the multivalency effect of HA cause the enhancement of the barrier-disrupting activity. PMID- 29266586 TI - Resting-state functional connectivity of the bed nucleus of the stria terminalis in post-traumatic stress disorder and its dissociative subtype. AB - The bed nucleus of the stria terminals (BNST) is a subcortical structure involved in anticipatory and sustained reactivity to threat and is thus essential to the understanding of anxiety and stress responses. Although chronic stress and anxiety represent a hallmark of post-traumatic stress disorder (PTSD), to date, few studies have examined the functional connectivity of the BNST in PTSD. Here, we used resting state functional Magnetic Resonance Imaging (fMRI) to investigate the functional connectivity of the BNST in PTSD (n = 70), its dissociative subtype (PTSD + DS) (n = 41), and healthy controls (n = 50). In comparison to controls, PTSD showed increased functional connectivity of the BNST with regions of the reward system (ventral and dorsal striatum), possibly underlying stress induced reward-seeking behaviors in PTSD. By contrast, comparing PTSD + DS to controls, we observed increased functional connectivity of the BNST with the claustrum, a brain region implicated in consciousness and a primary site of kappa opioid receptors, which are critical to the dynorphin-mediated dysphoric stress response. Moreover, PTSD + DS showed increased functional connectivity of the BNST with brain regions involved in attention and salience detection (anterior insula and caudate nucleus) as compared to PTSD and controls. Finally, BNST functional connectivity positively correlated with default-mode network regions as a function of state identity dissociation, suggesting a role of BNST networks in the disruption of self-relevant processing characterizing the dissociative subtype. These findings represent an important first step in elucidating the role of the BNST in aberrant functional networks underlying PTSD and its dissociative subtype. PMID- 29266587 TI - ChemBioChem-All Areas of Chemistry and Biology Intertwined. AB - The broader, the better! ChemBioChem had a successful year in 2017 receiving its 10 000 th submission. By broadening the journal scope through the addition of biomaterials, ChemBioChem will help to intertwine chemistry and biology even further. Also up next in 2018, a young chemists Special Issue, so gather up ChemBioTalents! PMID- 29266588 TI - Association between quality of sleep and health-related quality of life in persons with diabetes mellitus type 2. AB - AIM AND OBJECTIVES: To estimate the relationship of sleep quality with health related quality of life (HRQOL) in persons with diabetes mellitus type 2 (DMT2) living in the United Arab Emirates (UAE). BACKGROUND: DMT2 is an epidemic health condition in the UAE that has enormous impacts on heath, and consequent effects on HRQOL. However, because of an absence of screening for quality of sleep, people with DMT2 who experience poor sleep are likely to go untreated, which may compound the distressing impacts of DMT2 on their HRQOL. DESIGN: This is a cross sectional quantitative research design. METHODS: A sample of 268 participants with DMT2 were recruited from community healthcare settings in the UAE using cluster sampling. Participants completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI) and the World Health Organization HRQOL. Data analysis used descriptive and correlational statistics. RESULTS: Of the 268 participants, 34% identified as "poor sleepers" and 55% had poor HRQOL. Poor sleepers showed significantly lower scores for HRQOL than good sleepers. The global PSQI scores were found to be independently predictive of global HRQOL. Subjective perceptions of sleep quality, the use of sleep medications and impaired daytime functioning were the variables found to have the highest correlations with global HRQOL and its four domains. CONCLUSIONS: This study found that people with DMT2 who indicate experiencing poor quality sleep are more likely to show a negative correlation with HRQOL. Additional research is needed to investigate how poor sleep may impact the health of people with DMT2. RELEVANCE TO CLINICAL PRACTICE: Findings suggest that assessment of sleep quality should be an essential component of diabetes care. Understanding sleep practices may aid public health practitioners and other healthcare providers in the design of culturally appropriate interventions to improve sleep quality in persons with DMT2. PMID- 29266589 TI - Physicians' emotion regulation during communication with advanced cancer patients. AB - OBJECTIVE: In cancer care, optimal communication between patients and their physicians is, among other things, dependent on physicians' emotion regulation, which might be related to physicians' as well as patients' characteristics. In this study, we investigated physicians' emotion regulation during communication with advanced cancer patients, in relation to physicians' (stress, training, and alexithymia) and patients' (sadness, anxiety, and alexithymia) characteristics. METHODS: In this study, 134 real-life consultations between 24 physicians and their patients were audio-recorded and transcribed. The consultations were coded with the "Defence Mechanisms Rating Scale-Clinician." Physicians completed questionnaires about stress, experience, training, and alexithymia, while patients completed questionnaires about sadness, anxiety, and alexithymia. Data were analysed using linear mixed effect models. RESULTS: Physicians used several defence mechanisms when communicating with their patients. Overall defensive functioning was negatively related to physicians' alexithymia. The number of defence mechanisms used was positively related to physicians' stress and alexithymia as well as to patients' sadness and anxiety. Neither physicians' experience and training nor patients' alexithymia were related to the way physicians regulated their emotions. CONCLUSIONS: This study showed that physicians' emotion regulation is related to both physician (stress and alexithymia) and patient characteristics (sadness and anxiety). The study also generated several hypotheses on how physicians' emotion regulation relates to contextual variables during health care communication in cancer care. PMID- 29266591 TI - Time-to-event data with time-varying biomarkers measured only at study entry, with applications to Alzheimer's disease. AB - Relating time-varying biomarkers of Alzheimer's disease to time-to-event using a Cox model is complicated by the fact that Alzheimer's disease biomarkers are sparsely collected, typically only at study entry; this is problematic since Cox regression with time-varying covariates requires observation of the covariate process at all failure times. The analysis might be simplified by using study entry as the time origin and treating the time-varying covariate measured at study entry as a fixed baseline covariate. In this paper, we first derive conditions under which using an incorrect time origin of study entry results in consistent estimation of regression parameters when the time-varying covariate is continuous and fully observed. We then derive conditions under which treating the time-varying covariate as fixed at study entry results in consistent estimation. We provide methods for estimating the regression parameter when a functional form can be assumed for the time-varying biomarker, which is measured only at study entry. We demonstrate our analytical results in a simulation study and apply our methods to data from the Rush Religious Orders Study and Memory and Aging Project and data from the Alzheimer's Disease Neuroimaging Initiative. PMID- 29266590 TI - RNA helicase Mov10 is essential for gastrulation and central nervous system development. AB - BACKGROUND: Mov10 is an RNA helicase that modulates access of Argonaute 2 to microRNA recognition elements in mRNAs. We examined the role of Mov10 in Xenopus laevis development and show a critical role for Mov10 in gastrulation and in the development of the central nervous system (CNS). RESULTS: Knockdown of maternal Mov10 in Xenopus embryos using a translation blocking morpholino led to defects in gastrulation and the development of notochord and paraxial mesoderm, and a failure to neurulate. RNA sequencing of the Mov10 knockdown embryos showed significant upregulation of many mRNAs when compared with controls at stage 10.5 (including those related to the cytoskeleton, adhesion, and extracellular matrix, which are involved in those morphogenetic processes). Additionally, the degradation of the miR-427 target mRNA, cyclin A1, was delayed in the Mov10 knockdowns. These defects suggest that Mov10's role in miRNA-mediated regulation of the maternal to zygotic transition could lead to pleiotropic effects that cause the gastrulation defects. Additionally, the knockdown of zygotic Mov10 showed that it was necessary for normal head, eye, and brain development in Xenopus consistent with a recent study in the mouse. CONCLUSIONS: Mov10 is essential for gastrulation and normal CNS development. Developmental Dynamics 247:660-671, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266592 TI - High-Temperature and High-Energy-Density Dipolar Glass Polymers Based on Sulfonylated Poly(2,6-dimethyl-1,4-phenylene oxide). AB - A new class of high-temperature dipolar polymers based on sulfonylated poly(2,6 dimethyl-1,4-phenylene oxide) (SO2 -PPO) was synthesized by post-polymer functionalization. Owing to the efficient rotation of highly polar methylsulfonyl side groups below the glass transition temperature (Tg ~220 degrees C), the dipolar polarization of these SO2 -PPOs was enhanced, and thus the dielectric constant was high. Consequently, the discharge energy density reached up to 22 J cm-3 . Owing to its high Tg , the SO2 -PPO25 sample also exhibited a low dielectric loss. For example, the dissipation factor (tan delta) was 0.003, and the discharge efficiency at 800 MV m-1 was 92 %. Therefore, these dipolar glass polymers are promising for high-temperature, high-energy-density, and low-loss electrical energy storage applications. PMID- 29266593 TI - Faculty calibration and students' self-assessments using an instructional rubric in preparation for a practical examination. AB - PURPOSE: The purpose of this study was to investigate the effect of faculty calibration and students' self-assessments on students' performances in a periodontal practical examination. METHODS: Before a new instructional rubric was implemented in the second-year periodontics course, faculty calibration was conducted with a pilot group of 32 third-year dental students. Afterwards, the new rubric was implemented in the second-year periodontics course. Second-year students used the rubric for their self-assessments before the practical examination. An intraclass correlation coefficient was used to test the reliability of the faculty members. A paired t test was used to compare scores between self-assessments of the pilot group (third-year students) and faculty evaluation. A two-way analysis of variance was performed to compare scores between self-assessments of second-year students and faculty evaluations. Chi square tests were used to compare overall failure rates amongst four different classes. RESULTS: The reliability amongst the faculty members was strong (the ICC = 0.75 at the first and 0.97 at the second calibration). The mean self-assessment score from the pilot group was significantly higher than the faculty evaluation. However, the mean self-assessment score of second-year students was significantly lower than the faculty evaluation. The class that practiced self-assessments with the validated instructional rubric exhibited the lowest overall failure rate compared to three past classes. CONCLUSIONS: Using an instructional rubric and conducting faculty calibration improved the process of the periodontal practical examination. Improving the examination process and practicing self-assessments with feedback from faculty may have a positive impact on students' performances in the examination. PMID- 29266594 TI - Optimal timing of biodiversity offsetting for metapopulations. AB - Biodiversity offsetting schemes permit habitat destruction, provided that losses are compensated by gains elsewhere. While hundreds of offsetting schemes are used around the globe, the optimal timing of habitat creation in such projects is poorly understood. Here, we developed a spatially explicit metapopulation model for a single species subject to a habitat compensation scheme. Managers could compensate for destruction of a patch by creating a new patch either before, at the time of, or after patch loss. Delaying patch creation is intuitively detrimental to species persistence, but allowed managers to invest financial compensation, accrue interest, and create a larger patch at a later date. Using stochastic dynamic programming, we found the optimal timing of patch creation that maximizes the number of patches occupied at the end of a 50-yr habitat compensation scheme when a patch is destroyed after 10 yr. Two case studies were developed for Australian species subject to habitat loss but with very different traits: the endangered growling grass frog (Litoria raniformis) and the critically endangered Mount Lofty Ranges Southern Emu-wren (Spititurus malachurus intermedius). Our results show that adding a patch either before or well after habitat destruction can be optimal, depending on the occupancy state of the metapopulation, the interest rate, the area of the destroyed patch and metapopulation parameters of the focal species. Generally, it was better to delay patch creation when the interest rate was high, when the species had a relatively high colonization rate, when the patch nearest the new patch was occupied, and when the destroyed patch was small. Our framework can be applied to single species metapopulations subject to habitat loss, and demonstrates that considering the timing of habitat compensation could improve the effectiveness of offsetting schemes. PMID- 29266595 TI - Differential modulation of CA1 impulse flow by endogenous serotonin along the hippocampal longitudinal axis. AB - The hippocampus is functionally differentiated along its longitudinal axis, with the dorsal and ventral segments preferentially involved in cognitive and emotional processing, respectively. Serotonergic modulation of hippocampal function has been extensively studied, but its relation to the dorsoventral axis has remained largely unknown. To examine the modulation of hippocampal output along the dorsoventral axis by endogenous serotonin (5-HT) we compared the effect of the 5-HT/noradrenaline (NA)-releaser, 3,4-methylenedioxymethamphetamine (MDMA), in transversal slices encompassing the entire rat hippocampus. Co-release of 5-HT and NA by MDMA resulted in a gradient of effects on evoked population spikes in the CA1 area along the dorsoventral axis of the hippocampus. Selective 5-HT release decreased population spike amplitude in slices from dorsal hippocampus, whereas an increase was produced in the ventral hippocampus, indicating differential modulation of CA1 impulse flow along the dorsoventral axis by endogenous 5-HT. Selective NA release increased population spike amplitude with no gradient indicating facilitatory effect of endogenous NA along the entire dorsoventral axis. Blockade of 5-HT1A receptors prevented the inhibitory component of MDMA action and the emergence of the gradient, indicating that activation of 5-HT1A receptors is required for differential modulation of CA1 impulse flow by endogenous 5-HT. These findings suggest that a dorsoventral shift in CA1 output level may represent an integral component of 5-HT action on hippocampal information processing. Given the preferential role of ventral hippocampus in emotional and anxiety-related behavior, it can be proposed that serotonin tone encodes the emotional salience of the signal processed by hippocampus. PMID- 29266596 TI - Potential indications for deep brain stimulation in neurological disorders: an evolving field. AB - Deep brain stimulation (DBS) is an established therapy for appropriately selected patients with movement disorders and neuropsychiatric conditions. Although the exact mechanisms and biology of DBS are not fully understood, it is a safe and well-tolerated therapy for many refractory cases of neuropsychiatric disease. Increasingly, DBS has been explored in other conditions with encouraging results. In this paper, available data is reviewed and new DBS targets, challenges and future directions in neurological disorders are explored. A detailed search of the medical literature discussing the potential use of DBS for neurological disorders excluding accepted indications was conducted. All reports were analyzed individually for content and redundant articles were excluded by examining individual abstracts. The level of evidence for each indication was summarized. Multiple studies report promising preliminary data regarding the safety and efficacy of DBS for a variety of neurological indications including chronic pain, tinnitus, epilepsy, Tourette syndrome, Huntington's disease, tardive dyskinesia and Alzheimer's disease. The initial results of DBS studies for diverse neurological disorders are encouraging but larger, controlled, prospective, homogeneous clinical trials are necessary to establish long-term safety and effectiveness. The field of neuromodulation continues to evolve and advances in DBS technology, stereotactic techniques, neuroimaging and DBS programming capabilities are shaping the present and future of DBS research and use in practice. PMID- 29266597 TI - The experience of clinical supervision for nurses and healthcare assistants in a secure adolescent service: Affecting service improvement. AB - : WHAT IS KNOWN ON THE SUBJECT?: Regular and effective clinical supervision for mental health nurses and healthcare assistants (HCAs) is an important tool in helping to reduce stress and burnout, and in ensuring safe, effective and high quality mental health care. Previous studies of clinical supervision within secure mental health environments have found both a low availability of clinical supervision, and a low level of staff acceptance of its value, particularly for HCAs. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: In previous studies, the understanding shown by HCAs and nurses around the benefits of clinical supervision may have been limited by the methods used. This study was specifically designed to help them best express their views. In contrast to previous studies, both nurses and HCAs showed a good understanding of the function and value of clinical supervision. Significant improvements in the experience of, and access to, clinical supervision for nurses and HCAs working in secure mental health services may be achieved by raising staff awareness, demonstrating organizational support and increasing monitoring of clinical supervision. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Organizations should consider reviewing their approach to supervision to include raising staff awareness, multidisciplinary supervision, group supervision, and recording and tracking of supervision rates. Organizations should be mindful of the need to provide effective clinical supervision to HCAs as well as nurses. ABSTRACT: Introduction Studies have found a low availability and appreciation of clinical supervision, especially for healthcare assistants (HCAs). Qualitative research is needed to further understand this. Aims Increase understanding of nurses' and HCAs' experiences of, and access to, clinical supervision. Identify nurses' and HCAs' perceptions of the value and function of clinical supervision. Assess how interventions affect staff's experiences of clinical supervision. Methods In 2013, HCAs and nurses in a secure adolescent service were surveyed about clinical supervision. Forty-nine HCAs and 20 nurses responded. In 2014, interventions to facilitate supervision were introduced. In 2016, the study was repeated. Forty HCAs and 30 nurses responded. Responses were analysed using a mixed methods approach. Results Significantly more HCAs found supervision to be a positive experience in 2016, and both nurses and HCAs reported significantly fewer challenges in accessing supervision. HCAs and nurses understood the value of clinical supervision. Discussion Significant improvements in the experience of clinical supervision were achieved following increased staff awareness, multidisciplinary and group supervision, and recording supervision rates. HCAs and nurses understood the consequences of inadequate supervision. Implications for practice Organizations could adopt the interventions to facilitate clinical supervision. Supervision should not be overlooked for HCAs. PMID- 29266599 TI - The Metal-Metal-to-Ligand Charge Transfer Excited State and Supramolecular Polymerization of Luminescent Pincer PdII -Isocyanide Complexes. AB - Pincer PdII -isocyanide complexes are described that display intermolecular interactions and emissive 3 MMLCT excited states in aggregation state(s) at room temperature. The intermolecular PdII -PdII and ligand-ligand interactions drive these complexes to undergo supramolecular polymerization in a living manner. Comprehensive spectroscopic studies reveal a pathway with a kinetic trap that can be modulated by changing the counteranion and metal atom. The PdII supramolecular assemblies comprise two different aggregation forms with only one to be emissive. DFT/TDDFT calculations lend support to the MMLCT absorption and emission of these pincer PdII -isocyanide aggregates. PMID- 29266600 TI - Autophagy Caught in the Act: A Supramolecular FRET Pair Based on an Ultrastable Synthetic Host-Guest Complex Visualizes Autophagosome-Lysosome Fusion. AB - A supramolecular FRET pair based on the ultrahigh binding affinity between cyanine 3 conjugated cucurbit[7]uril (CB[7]-Cy3) and cyanine 5 conjugated adamantylamine (AdA-Cy5) was exploited as a new synthetic tool for imaging cellular processes in live cells. Confocal laser scanning microscopy revealed that CB[7]-Cy3 and AdA-Cy5 were intracellularly translocated and accumulated in lysosomes and mitochondria, respectively. CB[7]-Cy3 and AdA-Cy5 then formed a host-guest complex, reported by a FRET signal, as a result of the fusion of lysosomes and mitochondria. This observation not only indicated that CB[7] forms a stable complex with AdA in a live cell, but also suggested that this FRET pair can visualize dynamic organelle fusion processes, such as those involved in the degradation of mitochondria through autophagy (mitophagy), by virtue of its small size, chemical stability, and ease of use. PMID- 29266598 TI - Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant. AB - A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin-Tfast and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-Tfast protein with secondary loss of troponin-Ifast . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin Tfast . PMID- 29266601 TI - All-in-One Cellulose Nanocrystals for 3D Printing of Nanocomposite Hydrogels. AB - Cellulose nanocrystals (CNCs) with >2000 photoactive groups on each can act as highly efficient initiators for radical polymerizations, cross-linkers, as well as covalently embedded nanofillers for nanocomposite hydrogels. This is achieved by a simple and reliable method for surface modification of CNCs with a photoactive bis(acyl)phosphane oxide derivative. Shape-persistent and free standing 3D structured objects were printed with a mono-functional methacrylate, showing a superior swelling capacity and improved mechanical properties. PMID- 29266603 TI - Application of three-dimensional print in minor hepatectomy following liver partition between anterior and posterior sectors. AB - BACKGROUND: Minor hepatectomy following liver partition between the right anterior and posterior sectors requires technical ingenuities. In such hepatectomy, we used three-dimensional (3D) print; therefore, our procedure was introduced. METHODS: Digital segmentation of anatomical structures from multidetector-row computed tomography images utilized the original software 'PLUTO', which was developed by Graduate School of Information Science, Nagoya University. After changing the final segmentation data to the stereolithography files, 3D-printed liver at 70% scale was produced. The support material was washed and mould charge was removed from 3D-printed hepatic veins. The surface of 3D-printed model was abraded and coated with urethane resin paint. After natural drying, 3D-printed hepatic veins were coloured by injection of a dye. The 3D printed portal veins were whitish because mould charge remained. All procedures after 3D printing were performed by hand work. A 3D-printed model of the right posterior sector and a 3D-printed model of other parenchyma were produced, respectively. Measuring the length between the main structures on the liver surface and the planned partition line on the 3D-printed model, land mark between the right anterior and posterior sectors on the real liver surface was produced with scale adjustment. RESULTS: Minor hepatectomy following liver partition between the right anterior and posterior sectors was performed referring to 3D printed model. The planned liver partition and resection were successful. CONCLUSIONS: Application of 3D-printed liver to minor hepatectomy following liver partition between the right anterior and posterior sectors is easy and a suitable procedure. PMID- 29266602 TI - Clinical and nerve conduction features in Guillain-Barre syndrome associated with Zika virus infection in Cucuta, Colombia. AB - BACKGROUND AND PURPOSE: Zika virus (ZIKV) infection has been associated with an increased incidence of Guillain-Barre syndrome (GBS) but the relative frequency of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and axonal GBS subtypes is controversial. METHODS: Twenty GBS patients diagnosed according to the Brighton criteria during the ZIKV outbreak in Cucuta, Colombia, were evaluated clinically and electrophysiologically. The electrodiagnosis of GBS subtypes was made according to a recently described criteria set that demonstrated a high diagnostic accuracy on the basis of a single test. The electrophysiological features of 34 Italian AIDP patients were used as control. RESULTS: All patients had symptoms compatible with ZIKV infection before the onset of GBS and ZIKV infection was laboratory confirmed through a plaque reduction neutralization test (PRNT90 ) in 100% of patients. The median time from onset of ZIKV infection symptoms to GBS was 5 days (interquartile range 1-6 days). Cranial nerve palsy was present in 85% of patients (facial palsy in 75%, bulbar nerve involvement in 60%), autonomic dysfunction in 85%, and 50% of patients required invasive mechanical ventilation. AIDP was diagnosed in 70% of patients. 40% of nerves of AIDP patients showed a prevalent distal demyelinating involvement but this pattern was not different from the Italian AIDP patients without ZIKV infection. CONCLUSIONS: Guillain-Barre syndrome associated with ZIKV infection in Cucuta is characterized by a high frequency of cranial nerve involvement, autonomic dysfunction and requirement of mechanical ventilation indicating an aggressive and severe course. AIDP is the most frequent electrophysiological subtype. Demyelination is prevalent distally but this pattern is not specific for ZIKV infection. PMID- 29266604 TI - Characterization of CYP154F1 from Thermobifida fusca YX and Extension of Its Substrate Spectrum by Site-Directed Mutagenesis. AB - Previous studies on cytochrome P450 monooxygenases (CYP) from family 154 reported their substrate promiscuity and high activity. Hence, herein, the uncharacterized family member CYP154F1 is described. Screening of more than 100 organic compounds revealed that CYP154F1 preferably accepts small linear molecules with a carbon chain length of 8-10 atoms. In contrast to thoroughly characterized CYP154E1, CYP154F1 has a much narrower substrate spectrum and lower activity. A structural alignment of homology models of CYP154F1 and CYP154E1 revealed few differences in the active sites of both family members. By gradual mutagenesis of the CYP154F1 active site towards those of CYP154E1, a key residue accounting for the different activities of both enzymes was identified at position 234. Substitution of T234 for large hydrophobic amino acids led to up to tenfold higher conversion rates of small substrates, such as geraniol. Replacement of T234 by small hydrophobic amino acids, valine or alanine, resulted in mutants with extended substrate spectra. These mutants are able to convert some of the larger substrates of CYP154E1, such as (E)-stilbene and (+)-nootkatone. PMID- 29266605 TI - Fine Structure in Electronic Spectra of Cyanine Dyes: Are Sub-Bands Largely Determined by a Dominant Vibration or a Collection of Singly Excited Vibrations? AB - This work critically examines attempts to model the fine structure apparent in electronic spectra of cyanine dyes and their analogues. Numerous computational studies reported over the past decade attribute the origin of sub-bands and their relative intensities to vibronic transitions in which the relevant electronic transition is coupled, irrespective of symmetry, with a collection of vibrations. It is contended that this type of approach is not supported by experimental evidence. An argument is reiterated for a more appropriate model that adheres closely to fundamental principles and fits the data. It stipulates that essentially just one symmetric vibration, carbon-carbon bond stretching of the cyanine polymethine chain, dominates the coupling and is responsible for the observed fine structure. Furthermore, it is pointed out that the intensities of the sub-bands are readily explained by means of the Franck-Condon principle. PMID- 29266606 TI - Clinical utility of gastric emptying scintigraphy: Patient and physician perspectives. AB - BACKGROUND: The use of gastric emptying scintigraphy (GES) in the evaluation of patients with dyspeptic symptoms is controversial. Our aim was to investigate objective and subjective parameters of clinical utility of GES from the perspectives of both the patient and the ordering physician. METHODS: Socio demographic features, healthcare resource utilization, gastroparetic symptoms and quality of life (QoL) were obtained from consecutive patients referred for GES immediately prior to GES and again 4 months later. The ordering physician received a brief survey 2 weeks after the GES regarding their perceptions on whether the test provided them with clinically useful information. KEY RESULTS: One hundred and seventy-two (mean age +/- SD 52.0 +/- 17.9; 78% female) of 266 patients enrolled completed both the baseline and follow-up questionnaires and comprised our study population. At baseline, patients with abnormal GES had significantly higher gastroparesis symptom scores and reduced QoL. At the 4-month follow-up, an improvement in symptoms and QoL was seen, but the degree of improvement was not significantly different between those with a normal or abnormal GES. One hundred and ninety-seven ordering physicians completed the survey and perceived that GES, particularly when abnormal, provided new information (91%) and resulted in a change in diagnosis (58%) and management (60%). CONCLUSIONS & INFERENCES: Although patients with an abnormal GES generally had worse symptoms and lower QoL, the results of GES did not help to identify those with improved or worsened symptoms or QoL at follow-up. Nevertheless, the ordering physicians generally felt that the results of GES were helpful in managing these patients. PMID- 29266607 TI - Von Hippel Award: C. N. R. Rao / Meyer Galow Prize: M. Heitzmann / Ernst Haage Prize: H. Oberhofer. PMID- 29266608 TI - Dysphagia severity is related to the amplitude of distal contractile integral in patients with Jackhammer esophagus. AB - BACKGROUND: Dysphagia and non-cardiac chest pain are common symptoms associated with a novel hypercontractile disorder, namely Jackhammer esophagus (JE). The aim of this study was to explore these symptoms in patients with JE and to elucidate associations with disease defining metrics, crucial for subsequent therapies. METHODS: All consecutive patients, who were referred between January 2014 and December 2016 and fulfilled the criteria for JE were included in this study. Exclusion criteria were opioid intake, previous gastrointestinal surgery, mechanical esophageal obstruction and diseases explaining their symptoms. KEY RESULTS: Of 2205 examined subjects, thirty patients (females: n = 17, 56.7%) with a median age of 58 (51.6-64.9) years were finally enrolled. Dysphagia was noted in 53.3% (n = 16), whereas non-cardiac chest pain was specified within 40% (n = 12) with symptom duration of up to 10 years. Perception of dysphagia (P = .03) and presence of both symptoms (P = .008) increased to the end of the study period. Dysphagia was significantly associated with distal contractile integral (DCI) scores of all (P = .023), hypercontractile (P = .011) and maximum DCI swallows (P = .008). Symptoms duration influenced hypercontractile DCI scores (P = .015, r = .438) and significantly correlated with the intensity of perceived dysphagia (P = .01, r = .585). Presence of non-cardiac chest pain was not associated with any of these metrics. CONCLUSIONS & INTERFERENCES: The DCI mediates dysphagia in patients with JE. Duration of symptoms affected hypercontractile DCI scores and aggravated perception of dysphagia indicating a progressive character of disease. PMID- 29266609 TI - A BN Aromatic Ring Strategy for Tunable Hydroxy Content in Polystyrene. AB - BN 2-vinylnaphthalene, a BN aromatic vinyl monomer, is copolymerized with styrene under free radical conditions. Oxidation yields styrene-vinyl alcohol (SVA) statistical copolymers with tunable hydroxy group content. Comprehensive spectroscopic investigation provides proof of structure. Physical properties that vary systematically with hydroxy content include solubility and glass transition temperature. BN aromatic polymers represent a platform for the preparation of diverse functional polymeric architectures via the remarkable reaction chemistry of C-B bonds. PMID- 29266610 TI - Maternal glycoregulation in pregnancies complicated by diabetes mellitus in the prediction of fetal echography findings and perinatal outcomes. AB - AIM: We aimed to determine maternal hemoglobin A1c (HbA1c) levels and pregestational body mass index (BMI) as the predictors of glycemic control and its importance for fetal echography findings and perinatal outcomes in pregnancies complicated by diabetes mellitus (DM). METHODS: Our intention was to evaluate how BMI and HbA1c levels might be used to predict fetal interventricular septum (IVS) thickness, atrioventricular inflow early diastole (E)/ atrial systole (A) velocity ratio, and perinatal outcomes. Patients in the 38th gestational week were divided into three groups according to their insulin therapy: (i) patients with gestational diabetes mellitus (GDM) treated only with dietary changes (GDM group, n = 32); (ii) patients with GDM treated with insulin therapy (DM2 group, n = 27); and (iii) patients with type 1 DM (DM1 group, n = 22). RESULTS: In the DM1 group, we found statistically significant correlations between BMI and IVS thickness (P = 0.036), HbA1c and IVS thickness, as well as the mitral E/A velocity ratio (P = 0.013 vs P = 0.007). In this group, HbA1c showed a statistically significant correlation to neonatal birth weight (P = 0.037) and BMI influenced on appearance respiratory distress syndrome in neonates in DM1 group (P = 0.027). The values of HbA1c predict neonatal respiratory distress syndrome in DM2 and GDM groups (P = 0.036). CONCLUSION: As good predictors of maternal glycoregulation, BMI and HbA1c levels determine fetal echography findings as well as neonatal outcomes in pregnancies complicated by DM. PMID- 29266611 TI - Unique presentation of transient zinc deficiency from low maternal breast milk zinc levels. AB - We report full-term siblings with a unique clinical presentation of polycyclic papulosquamous plaques secondary to transient zinc deficiency due to low maternal breast milk zinc levels. We present this case to highlight this unique presentation of zinc deficiency in breastfed infants. PMID- 29266612 TI - Spirituality and religiosity of non-directed (altruistic) living kidney donors. AB - AIMS AND OBJECTIVES: To describe the spirituality and religiosity of 30 non directed (altruistic) living kidney donors in the USA and explore how they may have affected their motivations to donate and donation process experiences. BACKGROUND: The rise in non-directed donors and their ability to initiate kidney chains offer a novel approach to help alleviate the overextended kidney transplant wait list in the USA. However, little is known about the non-directed donors' motivations, characteristics and experiences. DESIGN: We conducted a qualitative-dominant study and used a grounded theory approach to analyse data. METHODS: Thirty participants completed in-depth interviews between April 2013 April 2015. Three analysts independently read and coded interview transcripts. Grounded theory techniques were used to develop descriptive categories and identify topics related to the non-directed donors donation experience. RESULTS: Sixteen of the 30 non-directed donorss discussed the topic of spirituality and religiosity when describing their donation experiences, regardless of whether they were actively practising a religion at the time of donation. Specifically, three themes were identified within spirituality and religiosity: motivation to donate, support in the process, and justification of their donation decisions postdonation. CONCLUSIONS: Findings from this study are the first to describe how spirituality and religiosity influenced the experiences of U.S. non-directed donorss and may help improve non-directed donors educational resources for future spiritual or religious non-directed donors, and the overall non-directed donors donation experience in efforts to increase the living donor pool. RELEVANCE TO CLINICAL PRACTICE: Spirituality and religiosity are often overlooked yet potentially influential factors in Western medicine, as demonstrated through the experiences of Jehovah's Witnesses and their religious restrictions while undergoing surgery and the beliefs of Christian Scientists against taking medications and receiving medical procedures. Understanding needs of non-directed donors specifically with spirituality and religiosity can better position kidney transplant centres and teams to improve predonation screening of non-directed donor candidates and provide support services during the donation process. PMID- 29266613 TI - Subthalamic Stimulation Improves Quality of Life of Patients Aged 61 Years or Older With Short Duration of Parkinson's Disease. AB - OBJECTIVE: The optimal timing of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) is a topic of ongoing debate. In patients with short disease duration an improvement of quality of life (QoL) has been demonstrated for patients aged younger than 61 years. However, this has not been systematically investigated in older patients yet. We hypothesized that patients aged 61 years or older experience a significant QoL improvement after STN-DBS with no difference in effect sizes for groups of patients with short and longer disease duration. MATERIALS AND METHODS: From four centers (Cologne, London, Manchester, Venice) we identified "older patients" aged 61 years or older with short (<=8 years) or longer disease duration and compared QoL, motor impairment, complications, medication requirements, and Mini-Mental State Examination (MMSE) on baseline and five months after surgery. RESULTS: Mean age/disease duration in 21 subjects with shorter disease duration were 65.5/6.3 years compared to 66.8/14.6 in 33 subjects with longer disease duration. The short disease duration group was affected by less baseline motor complications (p = 0.002). QoL in the short/longer disease duration group improved by 35/20% (p = 0.010/p = 0.006), motor complications by 40/44% (p = 0.018/p < 0.001), and medication requirements by 51/49% (both p < 0.001). MMSE remained unchanged in both groups. CONCLUSION: Patients aged 61 years or older benefited from STN-DBS regardless of short (<=8 years) or longer (>8 years) disease duration. Our results contribute to the debate about DBS selection criteria and timing and call for prospective confirmation in a larger cohort. PMID- 29266614 TI - Parental treatment management skills in paediatric atopic dermatitis. PMID- 29266615 TI - Regulation of Coordination Number over Single Co Sites: Triggering the Efficient Electroreduction of CO2. AB - The design of active, selective, and stable CO2 reduction electrocatalysts is still challenging. A series of atomically dispersed Co catalysts with different nitrogen coordination numbers were prepared and their CO2 electroreduction catalytic performance was explored. The best catalyst, atomically dispersed Co with two-coordinate nitrogen atoms, achieves both high selectivity and superior activity with 94 % CO formation Faradaic efficiency and a current density of 18.1 mA cm-2 at an overpotential of 520 mV. The CO formation turnover frequency reaches a record value of 18 200 h-1 , surpassing most reported metal-based catalysts under comparable conditions. Our experimental and theoretical results demonstrate that lower a coordination number facilitates activation of CO2 to the CO2.- intermediate and hence enhances CO2 electroreduction activity. PMID- 29266616 TI - Paediatric advance care planning: Physician experience and education in initiating difficult discussions. AB - AIM: Our study aimed to assess physicians' experiences and education regarding advance care planning (ACP) in paediatrics. We aimed to assess barriers to ACP initiation, including the adequacy of exposure and education regarding ACP and whether practitioners would deem improved education and resource provision useful. METHODS: A 25-question survey was designed following literature review. Paediatricians, intensivists and advanced trainees at Sydney Children's Hospital were invited to complete the online survey. Ninety-two responses were obtained over a 10-week period. RESULTS: Patients with life-limiting conditions are encountered frequently, with 57% of respondents caring for at least 10 such patients during the last 2 years. In total, 64% of respondents felt that ACP discussions should occur early around the time of diagnosis or during a period of stability; however, 57% observed discussions occurring late in illness after multiple acute, severe deteriorations. In total, 46% felt that multidisciplinary teams were the most appropriate to initiate ACP discussions. Prognostic uncertainty was the most common barrier to ACP initiation. Lack of experience and education were identified as barriers by 43 and 32%, respectively. The majority of respondents regarded exposure to ACP and education during training as inadequate. CONCLUSIONS: ACP discussions are being initiated later than physicians deem optimal. Of concern, clinicians prefer ACP discussions to be initiated by multidisciplinary teams, which may create a barrier to timely initiation. Barriers due to lack of education and experience could be overcome with improvements in training. Provision of education and resources would be welcomed and improve clinician skills in this area. PMID- 29266617 TI - Protocolized Laboratory Screening for the Medical Clearance of Psychiatric Patients in the Emergency Department: A Systematic Review. AB - OBJECTIVE: Emergency department (ED) patients with psychiatric chief complaints undergo medical screening to rule out underlying or comorbid medical illnesses prior to transfer to a psychiatric facility. This systematic review attempts to determine the clinical utility of protocolized laboratory screening for the streamlined medical clearance of ED psychiatric patients by determining the clinical significance of individual laboratory results. METHODS: We searched PubMed, Embase, and Scopus using the search terms "emergency department, psychiatry, diagnostic tests, laboratories, studies, testing, screening, and clearance" up to June 2017 for studies on adult psychiatric patients. This systematic review follows the recommendations of Meta-analysis of Observational Studies in Epidemiology (MOOSE) statement. The quality of each study was rated according to the Newcastle-Ottawa quality assessment scale. RESULTS: Four independent reviewers identified 2,847 publications. We extracted data from three studies (n = 629 patients). Included studies defined an abnormal test result as any laboratory result that falls out of the normal range. A laboratory test result was deemed as "clinically significant" only when patient disposition or treatment plan was changed because of that test result. Across the three studies the prevalence of clinically significant results were low (0.0%-0.4%). CONCLUSIONS: The prevalence of clinically significant laboratory test results were low, suggesting that according to the available literature, routine laboratory testing does not significantly change patient disposition. Due to the paucity of available research on this subject, we could not determine the clinical utility of protocolized laboratory screening tests for medical clearance of psychiatric patients in the ED. Future research on the utility of routine laboratory testing is important in a move toward shared decision making and patient-centered health care. PMID- 29266618 TI - Respiratory infections in the Asia-Pacific region: Problems and cautious optimism. PMID- 29266620 TI - Quick eating caused plastic bread bag clip ingestion and severe gastrointestinal bleed in young adult: a case report. PMID- 29266621 TI - Unshielded magnetocardiography: Repeatability and reproducibility of automatically estimated ventricular repolarization parameters in 204 healthy subjects. AB - BACKGROUND: Magnetocardiographic mapping (MCG) provides quantitative assessment of the magnetic field (MF) induced by cardiac ionic currents, is more sensitive to tangential currents, and measures vortex currents undetectable by ECG, with higher reported sensitivity of MCG ventricular repolarization (VR) parameters for earlier detection of acute myocardial ischemia. Aims of this study were to validate the feasibility of in-hospital unshielded MCG and to assess repeatability and reproducibility of quantitative VR parameters, considering also possible gender- and age-related variability. METHODS: MCG of 204 healthy subjects [114 males-mean age 43.4 +/- 17.3 and 90 females-mean age 40.2 +/- 15.7] was retrospectively analyzed, with a patented proprietary software automatically estimating twelve VR parameters derived from the analysis of the dynamics of the T-wave MF extrema (five parameters) and from the inverse solution with the effective magnetic dipole model giving the effective magnetic vector components (seven parameters). MCG repeatability was calculated as coefficient of variation (CV) +/-standard error of the mean (SEM). Reproducibility was assessed as intraclass correlation coefficient (ICC). RESULTS: The repeatability of all MCG parameters was 16 +/- 1.2 (%) (average CV +/- SEM). Optimal (ICC > 0.7) reproducibility was found for 11/12 parameters (mean values) and in 8/12 parameters (single values). No significant gender-related difference was observed; six parameters showed a strong/moderate correlation with age. CONCLUSION: Reliable MCG can be performed into an unshielded hospital ambulatory, with repeatability and reproducibility of quantitative assessment of VR adequate for clinical purposes. Wider clinical use is foreseen with the development of multichannel optical magnetometry. PMID- 29266619 TI - Control of Luminescence by Tuning of Crystal Symmetry and Local Structure in Mn4+ -Activated Narrow Band Fluoride Phosphors. AB - Mn4+ -doped fluoride phosphors have been widely used in wide-gamut backlighting devices because of their extremely narrow emission band. Solid solutions of Na2 (Six Ge1-x )F6 :Mn4+ and Na2 (Gey Ti1-y )F6 :Mn4+ were successfully synthesized to elucidate the behavior of the zero-phonon line (ZPL) in different structures. The ratio between ZPL and the highest emission intensity upsilon6 phonon sideband exhibits a strong relationship with luminescent decay rate. First-principles calculations are conducted to model the variation in the structural and electronic properties of the prepared solid solutions as a function of the composition. To compensate for the limitations of the Rietveld refinement, electron paramagnetic resonance and high-resolution steady-state emission spectra are used to confirm the diverse local environment for Mn4+ in the structure. Finally, the spectral luminous efficacy of radiation (LER) is used to reveal the important role of ZPL in practical applications. PMID- 29266622 TI - Relationships among cardiorespiratory fitness, muscular fitness, and cardiometabolic risk factors in Japanese adolescents: Niigata screening for and preventing the development of non-communicable disease study-Agano (NICE EVIDENCE Study-Agano) 2. AB - OBJECTIVE: To examine the independent and combined associations of cardiorespiratory fitness (CRF) and muscular fitness (MF) with cardiometabolic risk factors in Japanese adolescents. METHODS: A cross-sectional study including 993 Japanese adolescents (aged 13-14 years) was undertaken. Height, body mass, blood pressure, lipid profile (non-fasting), and HbA1c were measured. The physical fitness (PF) test included measurements of CRF (20 m multistage shuttle run test), upper limb strength (hand grip strength), lower limb strength (standing long jump), and muscular endurance (sit-ups). The clustered cardiometabolic risk (CCMR) was estimated by summing standardized Z-scores of body mass index (BMI), mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDL-C), and HbA1c. RESULTS: Linear regression analysis showed that all PF factors except for muscular endurance were inversely correlated with CCMR (P < .001). Among metabolic risk components, HbA1c was unrelated to PF, while non-HDL-C was inversely associated with CRF (B = -2.40; P < .001), upper limb strength (B = -1.77; P < .05), and lower limb strength (B = -1.53; P < .05) after adjustment for lifestyle factors. Logistic regression showed that the probability of having high CCMR (>=1SD) was synergistically higher in those with the lowest tertiles of both CRF and upper limb strength (P for interaction = .001); however, a substantially lower likelihood of having high CCMR was observed among individuals with the lowest tertile of upper limb strength but moderate CRF. CONCLUSIONS: Lower CRF and MF were significantly and synergistically associated with an unhealthier metabolic risk profile. PMID- 29266623 TI - A functional near-infrared spectroscopic investigation of speech production during reading. AB - This study was designed to test the extent to which speaking processes related to articulation and voicing influence Functional Near Infrared Spectroscopy (fNIRS) measures of cortical hemodynamics and functional connectivity. Participants read passages in three conditions (oral reading, silent mouthing, and silent reading) while undergoing fNIRS imaging. Area under the curve (AUC) analyses of the oxygenated and deoxygenated hemodynamic response function concentration values were compared for each task across five regions of interest. There were significant region main effects for both oxy and deoxy AUC analyses, and a significant region * task interaction for deoxy AUC favoring the oral reading condition over the silent reading condition for two nonmotor regions. Assessment of functional connectivity using Granger Causality revealed stronger networks between motor areas during oral reading and stronger networks between language areas during silent reading. There was no evidence that the hemodynamic flow from motor areas during oral reading compromised measures of language-related neural activity in nonmotor areas. However, speech movements had small, but measurable effects on fNIRS measures of neural connections between motor and nonmotor brain areas across the perisylvian region, even after wavelet filtering. Therefore, researchers studying speech processes with fNIRS should use wavelet filtering during preprocessing to reduce speech motion artifacts, incorporate a nonspeech communication or language control task into the research design, and conduct a connectivity analysis to adequately assess the impact of functional speech on the hemodynamic response across the perisylvian region. PMID- 29266624 TI - Applications of corneal topography and tomography: a review. AB - Corneal imaging is essential for diagnosing and management of a wide variety of ocular diseases. Corneal topography is used to characterize the shape of the cornea, specifically, the anterior surface of the cornea. Most corneal topographical systems are based on Placido disc that analyse rings that are reflected off the corneal surface. The posterior corneal surface cannot be characterized using Placido disc technology. Imaging of the posterior corneal surface is useful for diagnosis of corneal ectasia. Unlike corneal topographers, tomographers generate a three-dimensional recreation of the anterior segment and provide information about the corneal thickness. Scheimpflug imaging is one of the most commonly used techniques for corneal tomography. The cross-sectional images generated by a rotating Scheimpflug camera are used to locate the anterior and posterior corneal surfaces. The clinical uses of corneal topography include, diagnosis of corneal ectasia, assessment of corneal astigmatism, and refractive surgery planning. This review will discuss the applications of corneal topography and tomography in clinical practice. PMID- 29266625 TI - Nursing as concrete philosophy, Part II: Engaging with reality. AB - This is the second paper of an essay in two parts. The first paper (Part I) is a critical discussion of Mark Risjord's conception of nursing knowledge where I argued against the conception of nursing knowledge as a kind of nursing science. The aim of the present paper (Part II) is to explicate and substantiate the thesis of nursing as a kind of concrete philosophy. My strategy is to elaborate upon certain themes from Wittgenstein's Tractatus in order to canvass a general scheme of philosophy based on a distinction between reality and the world. This distinction will be employed in the appropriation of certain significant features of nursing and nursing knowledge. By elaborating on the contrast between the abstract and the concrete, I will suggest that nursing may be seen as a kind of concrete philosophy, being primarily concerned with reality (and secondarily with the world). This thesis, I will argue, implies that philosophy is the kind of theory that is essential to nursing (which is not so much a theory than a certain kind of activity). PMID- 29266626 TI - A transition at Molecular Reproduction and Development. PMID- 29266627 TI - Does conditioned pain modulation predict the magnitude of placebo effects in patients with neuropathic pain? AB - BACKGROUND: Conditioned pain modulation (CPM) is a validated measure of the function of endogenous pain inhibitory pathways. Placebo effects reflect top-down inhibitory modulation of pain. CPM and placebo effects are both influenced by expectations, albeit to varying degrees, and are related to neurotransmitter systems such as the endogenous opioid system, and it can be speculated that CPM responses are positively associated with the magnitude of placebo effects. Yet, no studies have tested this. METHODS: The study included 19 patients with neuropathic pain. CPM was quantified as the difference in pressure pain threshold (PPT) as measured at the middle deltoid muscle before and after 5-min exposure to the cold pressor test (CPT) (conditioning pain stimulus). Placebo effects were tested via open and hidden applications of the pain-relieving agent lidocaine (2 mL) using a disinfection napkin controlled for no treatment. RESULTS: The mean (SD) PPT was 668.7 (295.7) kPa before and 742.3 (370.8) kPa after the CPT. The mean (SD) CPM response was -73.6 (214.0) kPa corresponding to an 11% increase in PPT, reflecting a normally functioning endogenous pain modulatory system. Large and significant placebo effects were observed in ongoing neuropathic pain intensity (p = 0.002). The CPM response did not predict the magnitude of the placebo effect (p = 0.765). Moreover, there were no interaction effects for the moderator variables: clinical pain level (p = 0.136), age (p = 0.347) and gender (p = 0.691). CONCLUSIONS: Conditioned pain modulation and placebo effects do not seem to be associated in patients with neuropathic pain. SIGNIFICANCE: Conditioned pain modulation and placebo effects are endogenous pain-modulating phenomena that are influenced by some of the same mechanisms. This study suggests that CPM and placebo effects in neuropathic pain are independent phenomena that may be mediated by different mechanisms. PMID- 29266628 TI - Persistent reduction of mucosal-associated invariant T cells in primary biliary cholangitis. AB - BACKGROUND AND AIM: Mucosal-associated invariant T (MAIT) cells constitute a novel subset of innate-like T lymphocytes characterized by a semi-invariant T cell receptor repertoire capable of recognizing bacterial products. Considering the abundance of MAIT cells in the liver and the possible association between bacterial infections and primary biliary cholangitis (PBC), we aimed to analyze the involvement of MAIT cells in the immunopathogenesis of PBC. METHODS: Peripheral blood and liver biopsy specimens were collected from 25 patients with PBC and 19 patients with chronic viral hepatitis. Surgically removed liver tissues distant from tumors in patients with metastatic liver tumors were used as controls. Mononuclear cells were separated using Ficoll gradient, and the expression of various markers was investigated by flow cytometry. Cytokine production was investigated using blood MAIT cells after stimulation by anti CD3/CD28-coupled beads with/without interleukin-7 (IL-7). RESULTS: Mucosal associated invariant T cells were significantly reduced in both the blood and liver of PBC patients compared with those in controls. MAIT cells in the blood of PBC patients expressed significantly lower levels of activation markers and IL-7 receptor. Moreover, MAIT cells in the blood of PBC patients showed impaired production of cytokines, especially tumor necrosis factor alpha, after in vitro stimulation with IL-7. Interestingly, even after biochemical responses were achieved by ursodeoxycholic acid treatment, the frequencies of MAIT cells did not fully recover to normal levels. CONCLUSIONS: These findings suggested that MAIT cells were activated, exhausted, and persistently depleted in PBC patients even after ursodeoxycholic acid treatment, possibly as a consequence of persistent liver inflammation. PMID- 29266630 TI - Visit-to-visit HbA1c variability and systolic blood pressure (SBP) variability are significantly and additively associated with mortality in individuals with type 1 diabetes: An observational study. AB - AIM: To investigate the relationship between variability in both visit-to-visit HbA1c and SBP and mortality in individuals with type 1 diabetes. METHODS: The Scottish Care Information (SCI) Diabetes dataset was used to identify 5952 individuals with type 1 diabetes for inclusion in this observational study. The SCI-Diabetes dataset allowed access to blood pressure values, HbA1c readings, demographic information and mortality rates for all study participants. Participants were dichotomized to above and below median values for both HbA1c coefficient of variation (CV) and SBP CV, thus dividing participants into 4 cohorts for survival analysis. Survival analysis was carried out over 1430 days. A Cox proportional hazard model was used to allow comparison of mortality between the 4 cohorts. RESULTS: Of the 5952 patients, death occurred in 416. CV for both HbA1c and SBP were significantly associated with mortality. The median values for HbA1c CV and SBP CV were 8.0 and 8.1, respectively. The hazard ratio for high HbA1c CV only (P = .0015) was 1.78 +/- 0.36. The hazard ratio for high SBP CV only (P = .0018) was 1.69 +/- 0.33. The hazard ratio for both high HbA1c CV and high SBP CV (P < .00001) was 2.37 +/- 0.32. CONCLUSIONS: Our findings demonstrate that variability of both HbA1c and SBP is significantly and additively associated with mortality in individuals with type 1 diabetes. The variability of these parameters might be useful for risk stratification and is a potential target for future interventional studies. PMID- 29266629 TI - Human Mesenchymal Stem Cell Failure to Adapt to Glucose Shortage and Rapidly Use Intracellular Energy Reserves Through Glycolysis Explains Poor Cell Survival After Implantation. AB - Mesenchymal stem cells (MSCs) hold considerable promise in tissue engineering (TE). However, their poor survival when exogenously administered limits their therapeutic potential. Previous studies from our group demonstrated that lack of glucose (glc) (but not of oxygen) is fatal to human MSCs because it serves as a pro-survival and pro-angiogenic molecule for human MSCs (hMSCs) upon transplantation. However, which energy-providing pathways MSCs use to metabolize glc upon transplantation? Are there alternative energetic nutrients to replace glc? And most importantly, do hMSCs possess significant intracellular glc reserves for ensuring their survival upon transplantation? These remain open questions at the forefront of TE based-therapies. In this study, we established for the first time that the in vivo environment experienced by hMSCs is best reflected by near-anoxia (0.1% O2 ) rather than hypoxia (1%-5% O2 ) in vitro. Under these near-anoxia conditions, hMSCs rely almost exclusively on glc through anerobic glycolysis for ATP production and are unable to use either exogenous glutamine, serine, or pyruvate as energy substrates. Most importantly, hMSCs are unable to adapt their metabolism to the lack of exogenous glc, possess a very limited internal stock of glc and virtually no ATP reserves. This lack of downregulation of energy turnover as a function of exogenous glc level results in a rapid depletion of hMSC energy reserves that explains their poor survival rate. These new insights prompt for the development of glc-releasing scaffolds to overcome this roadblock plaguing the field of TE based-therapies. Stem Cells 2018;36:363-376. PMID- 29266631 TI - Intense Vibronic Modulation of the Chiral Photoelectron Angular Distribution Generated by Photoionization of Limonene Enantiomers with Circularly Polarized Synchrotron Radiation. AB - Photoionization of the chiral monoterpene limonene has been investigated using polarized synchrotron radiation between the adiabatic ionization threshold, 8.505 and 23.5 eV. A rich vibrational structure is seen in the threshold photoelectron spectrum and is interpreted using a variety of computational methods. The corresponding photoelectron circular dichroism-measured in the photoelectron angular distribution as a forward-backward asymmetry with respect to the photon direction-was found to be strongly dependent on the vibronic structure appearing in the photoelectron spectra, with the observed asymmetry even switching direction in between the major vibrational peaks. This effect can be ultimately attributed to the sensitivity of this dichroism to small phase shifts between adjacent partial waves of the outgoing photoelectron. These observations have implications for potential applications of this chiroptical technique, where the enantioselective analysis of monoterpene components is of particular interest. PMID- 29266632 TI - Intimal thickening at coronary bifurcations in pediatric heart transplant recipients. AB - Heart transplant recipients are at increased risk for atherosclerosis and cardiac allograft vasculopathy, both initially presenting as intimal thickening. We aimed to determine the presence, extent, and anatomical characteristics of intimal thickness at coronary bifurcations in children using OCT. We measured the intimal thickness of coronary arteries in pediatric transplant recipients using OCT during routine cardiac catheterization. Intimal thickening was defined as (i) a percent change in contralateral intimal thickness greater than 50% when comparing the thickness at the bifurcation to the baseline thickness, and (ii) greater than 0.1 mm. We evaluated 153 unique coronary bifurcations in 31 children (58% boys, median 12.7 years). Intimal thickening was almost exclusively observed in the left coronary system (22 of 67 bifurcations) and rare in the right coronary system (2 of 86 bifurcations; P < .001). There was a positive association between the relative size of the side branch and contralateral intimal thickening at coronary bifurcations (P = .009). Intimal thickening at coronary bifurcations is already present in the left coronary system in many pediatric transplant recipients. The correlation between intimal thickening and side branch size suggests that low shear stress and oscillating shear stress may have an important role in the development of intimal thickening at coronary bifurcations. PMID- 29266633 TI - The effect of myofascial release and microwave diathermy combined with acupuncture versus acupuncture therapy in tension-type headache patients: A pragmatic randomized controlled trial. AB - BACKGROUND AND PURPOSE: Nonpharmacological therapies for tension-type headache (TTH) and cervicogenic cephalalgia are often a treatment choice, despite the weak to moderate evidence. The aim of this study was to compare the effectiveness of an acupuncture/stretching protocol versus acupuncture/stretching plus physiotherapy techniques, in patients with TTH cephalalgia. METHODS: A single blind, prospective, multicentre, randomized controlled trial was designed considering the pragmatic situation of administering such protocols and treating the 44 headache patients participating in this study. The patients were randomly assigned in 2 treatment groups (control group, n = 20, acupuncture/stretching; experimental group, n = 24, acupuncture/stretching plus physiotherapy) and completed 10 treatment sessions within 4 weeks with measurements taking place before treatment, after the fifth treatment and after the 10th treatment. The mechanical pressure pain threshold (PPT) was considered as the main outcome measure, using a mechanical algometer to measure 7 bilateral somatic points. Acupuncture in both groups included 17-20 acupuncture points, whereas stretching was initially taught and subsequently self-administered (self-stretches), following a standardized set of movements of the cervical spine. Physiotherapy consisted of microwave diathermy and myofascial release with hands-on techniques. RESULTS/FINDINGS: An improvement was noted in both groups/treatments regarding the main outcome measure PPT, all the way from the first to fifth and the 10th treatment, at all measuring sites and at all measurements in both groups (p < .001). When comparing the 2 groups, differences were noted after the 10th treatment (p < .05). DISCUSSION: In conclusion, patients with TTH headache were benefited from acupuncture and stretching but further PPT improvements were evidenced when physiotherapy hands-on techniques were added. In clinical terms, the combination of physiotherapy in the form of myofascial release and microwave diathermy with acupuncture and stretching in order to improve the analgesic effect (PPT) is strongly recommended. PMID- 29266634 TI - How to do a structured rectal mobilization in complex pelvic endometriosis. PMID- 29266635 TI - Radial nerve palsy in mid/distal humeral fractures: is early exploration effective? AB - BACKGROUND: Radial nerve palsies are a common complication with displaced distal humeral fractures. This case series examines the outcomes of early operative exploration and decompression of the nerve with fracture fixation with the view that this provides a solid construct for optimisation of nerve recovery. METHODS: A total of 10 consecutive patients with a displaced distal humeral fracture and an acute radial nerve palsy were treated by the senior author by open reduction and internal fixation of the distal humerus and exploration and decompression of the radial nerve. Motor function and sensation of the radial nerve was assessed in the post-operative period every 2 months or until full recovery of the radial nerve function had occurred. RESULTS: All patients (100%) had recovery of motor and sensation function of their upper limb in the radial nerve distribution over a 12-month period. Recovery times ranged between 4 and 32 weeks, with the median time to recovery occurring at 26 weeks and the average time to full recovery being 22.9 weeks. Wrist extension recovered by an average of 3 months (range 2-26 weeks) and then finger extension started to recover 2-6 weeks after this. Disability of the arm, shoulder and hand scores ranged from 0 to 11.8 at greater than 1 year post-operatively. DISCUSSION: Our study demonstrated that early operative exploration of the radial nerve when performing an open stabilization of displaced distal humeral fractures resulted in a 100% recovery of the radial nerve. PMID- 29266636 TI - Identifying perception behaviours in people with profound intellectual and multiple disabilities. AB - BACKGROUND: To support people with profound intellectual and multiple disabilities (PIMD), it is essential to understand how they experience their environment. Insight into perception behaviour may provide an entry point for improved understanding. MATERIALS AND METHODS: A random sample of a 30-min video registration of five participants with PIMD was used to code behaviours per second based on an ethogram containing 157 different perception behaviours in nine categories. RESULTS: Eighty-nine different perception behaviours were observed, of which movements with eyes, head and arms were most common. The senses used most were seeing, hearing and touching. Finally, the function of five perception patterns was established in relation to their function:awareness, focusing attention and tension regulation. CONCLUSIONS: Close observation using an observation ethogram provides insight into how people with PIMD perceive their environment. PMID- 29266637 TI - CRISPR/Cas9 therapeutics for liver diseases. AB - The development of innovative genome editing techniques in recent years has revolutionized the field of biomedicine. Among the novel approaches, the clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas9) technology has become the most popular, in part due to its matchless ability to carry out gene editing at the target site with great precision. With considerable successes in animal and preclinical studies, CRISPR/Cas9-mediated gene editing has paved the way for its use in human trials, including patients with a variety of liver diseases. Gene editing is a logical therapeutic approach for liver diseases because many metabolic and acquired disorders are caused by mutations within a single gene. In this review, we provide an overview on current and emerging therapeutic strategies for the treatment of liver diseases using the CRISPR/Cas9 technology. PMID- 29266638 TI - Cardiorespiratory events in infants with gastroesophageal reflux symptoms: Is there any association? AB - BACKGROUND: Cardiorespiratory (CR) events (apnea, bradycardia, oxygen desaturation) and gastroesophageal reflux (GER) symptoms often coexist in infants admitted to Neonatal Intensive Care Unit, leading to over-prescription of drugs and delayed discharge. We aimed to evaluate the relationships between CR and GER events. METHODS: The temporal associations between CR and GER events were analyzed in symptomatic infants who underwent synchronized CR and pH-impedance monitoring. The symptom association probability (SAP) index was used to identify infants with a significant number of temporal associations. Gastroesophageal reflux characteristics and the chronological sequence of CR and GER events occurring within 30 seconds of each other were evaluated according to SAP index. KEY RESULTS: Of the 66 infants enrolled, aged 29 (18-45) days, 58 had CR events during monitoring. From these 58 patients, a total of 1331 CR events and 5239 GER (24% acidic) were detected. The SAP index was positive in seven (12%) infants. These infants had greater GER frequency, duration, and proximal extent (P < .05). The number of temporal associations was 10 times greater in the positive SAP group. Gastroesophageal reflux events preceded CR events in 83% of these associations. These GER events had a higher proximal extent (P = .004), but showed no differences in pH values. CONCLUSIONS & INFERENCES: The simultaneous evaluation of CR and GER events could be useful to identify infants with severe GER and significant temporal associations between these events. Treatment of GER could be indicated in these infants, but as the GER events involved are mainly non-acidic, empirical treatment with antacids is, often, inappropriate. PMID- 29266639 TI - The cognitive-behavioural model of hoarding disorder: Evidence from clinical and non-clinical cohorts. AB - The cognitive-behavioural model of hoarding disorder incorporates information processing difficulties, maladaptive attachment to possessions, erroneous beliefs about the nature of possessions, and mood problems as etiologically significant factors, although developmental experiences such as a compromised early family environment have also been proposed in an augmented model. This study examined the specificity and relevance of variables highlighted in the augmented cognitive behavioural model. Various clinical participants (n = 89) and community controls (n = 20) were assessed with structured clinical interviews to verify diagnosis. Participants completed self-report measures of hoarding severity, cognitions, meta-memory, and early developmental experiences (e.g., memories of warmth and security in one's family). Hoarding cohorts (with and without obsessive compulsive disorder) reported poor confidence in memory, but relative to other groups (obsessive-compulsive disorder without hoarding disorder, anxiety disorders, and healthy controls), hoarding-relevant cognitions, need to keep possessions in view, and concerns about the consequences of forgetting were significantly higher. Hoarding groups reported the lowest recollections of warmth in their family, although no differences were found between hoarding and non hoarding clinical cohorts for uncertainty about self and others. Nonetheless, clinical cohorts reported generally higher scores of uncertainty than healthy controls. When predicting hoarding severity, after controlling for age and mood, recollections of lack of warmth in one's family was a significant predictor of hoarding severity, with hoarding-related cognitions and fears about decision making being additional unique predictors. The study supports the augmented cognitive-behavioural model of hoarding, inclusive of the importance of early developmental influences in hoarding. PMID- 29266640 TI - Core-Shell Structuring of Pure Metallic Aerogels towards Highly Efficient Platinum Utilization for the Oxygen Reduction Reaction. AB - The development of core-shell structures remains a fundamental challenge for pure metallic aerogels. Here we report the synthesis of Pdx Au-Pt core-shell aerogels composed of an ultrathin Pt shell and a composition-tunable Pdx Au alloy core. The universality of this strategy ensures the extension of core compositions to Pd transition-metal alloys. The core-shell aerogels exhibited largely improved Pt utilization efficiencies for the oxygen reduction reaction and their activities show a volcano-type relationship as a function of the lattice parameter of the core substrate. The maximum mass and specific activities are 5.25 A mgPt-1 and 2.53 mA cm-2 , which are 18.7 and 4.1 times higher than those of Pt/C, respectively, demonstrating the superiority of the core-shell metallic aerogels. The proposed core-based activity descriptor provides a new possible strategy for the design of future core-shell electrocatalysts. PMID- 29266641 TI - Field study reveals core plant microbiota and relative importance of their drivers. AB - Harnessing plant microbiota can assist in sustainably increasing primary productivity to meet growing global demands for food and biofuel. However, development of rational microbiome-based approaches for improving crop yield and productivity is currently hindered by a lack of understanding of the major biotic and abiotic factors shaping the crop microbiome under relevant field conditions. We examined bacterial and fungal communities associated with both aerial (leaves, stalks) and belowground (roots, soil) compartments of four commercial sugarcane varieties (Saccharum spp.) grown in several growing regions in Australia. We identified drivers of the sugarcane microbiome under field conditions and evaluated whether the plants shared a core microbiome. Sugarcane-associated microbial assemblages were primarily determined by plant compartment, followed by growing region, crop age, variety and Yellow Canopy Syndrome (YCS). We detected a core set of microbiota and identified members of the core microbiome that were influenced by YCS incidence. Our study revealed key hub microorganisms in the core microbiome networks of sugarcane leaves, stalks, roots and rhizosphere soil despite location and time-associated shifts in the community assemblages. Elucidating their functional roles and identification of the keystone core microbiota that sustain plant health could provide a technological breakthrough for a sustainable increase in crop productivity. PMID- 29266642 TI - Vacancy-Controlled Na+ Superion Conduction in Na11 Sn2 PS12. AB - Highly conductive solid electrolytes are crucial to the development of efficient all-solid-state batteries. Meanwhile, the ion conductivities of lithium solid electrolytes match those of liquid electrolytes used in commercial Li+ ion batteries. However, concerns about the future availability and the price of lithium made Na+ ion conductors come into the spotlight in recent years. Here we present the superionic conductor Na11 Sn2 PS12 , which possesses a room temperature Na+ conductivity close to 4 mS cm-1 , thus the highest value known to date for sulfide-based solids. Structure determination based on synchrotron X-ray powder diffraction data proves the existence of Na+ vacancies. As confirmed by bond valence site energy calculations, the vacancies interconnect ion migration pathways in a 3D manner, hence enabling high Na+ conductivity. The results indicate that sodium electrolytes are about to equal the performance of their lithium counterparts. PMID- 29266643 TI - Association of eating while television viewing and overweight/obesity among children and adolescents: a systematic review and meta-analysis of observational studies. AB - The objective of this systematic review and meta-analysis was to examine the association between eating while television viewing (TVV) and overweight or obesity in children (<18 years). A systematic search of PubMed, Scopus, Web of science, PreQuest and Embase was conducted up to April 2017; pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Of 4,357 articles identified, 20 observational studies met inclusion criteria (n = 84,825) and 8 of these 20 (n = 41,617) reported OR. Eating while TVV was positively associated with obesity-related anthropometric measurements in 15 studies (75%). The meta-analysis revealed that eating while TVV was positively associated with being overweight (OR = 1.28; 95% CI: 1.17, 1.39). Subgroup analyses showed similar positive associations in both girls and boys, as well as in children who ate dinner while TVV. There was no evidence of publication bias. The present systematic review and meta-analysis suggests that eating while TVV could be a risk factor for being overweight or obese in childhood and adolescents. PMID- 29266644 TI - Taming the Cationic Beast: Novel Developments in the Synthesis and Application of Weakly Coordinating Anions. AB - This Review gives a comprehensive overview of the most topical weakly coordinating anions (WCAs) and contains information on WCA design, stability, and applications. As an update to the 2004 review, developments in common classes of WCA are included. Methods for the incorporation of WCAs into a given system are discussed and advice given on how to best choose a method for the introduction of a particular WCA. A series of starting materials for a large number of WCA precursors and references are tabulated as a useful resource when looking for procedures to prepare WCAs. Furthermore, a collection of scales that allow the performance of a WCA, or its underlying Lewis acid, to be judged is collated with some advice on how to use them. The examples chosen to illustrate WCA developments are taken from a broad selection of topics where WCAs play a role. In addition a section focusing on transition metal and catalysis applications as well as supporting electrolytes is also included. PMID- 29266646 TI - A matching framework to improve causal inference in interrupted time-series analysis. AB - RATIONALE, AIMS, AND OBJECTIVES: Interrupted time-series analysis (ITSA) is a popular evaluation methodology in which a single treatment unit's outcome is studied over time and the intervention is expected to "interrupt" the level and/or trend of the outcome, subsequent to its introduction. When ITSA is implemented without a comparison group, the internal validity may be quite poor. Therefore, adding a comparable control group to serve as the counterfactual is always preferred. This paper introduces a novel matching framework, ITSAMATCH, to create a comparable control group by matching directly on covariates and then use these matches in the outcomes model. METHOD: We evaluate the effect of California's Proposition 99 (passed in 1988) for reducing cigarette sales, by comparing California to other states not exposed to smoking reduction initiatives. We compare ITSAMATCH results to 2 commonly used matching approaches, synthetic controls (SYNTH), and regression adjustment; SYNTH reweights nontreated units to make them comparable to the treated unit, and regression adjusts covariates directly. Methods are compared by assessing covariate balance and treatment effects. RESULTS: Both ITSAMATCH and SYNTH achieved covariate balance and estimated similar treatment effects. The regression model found no treatment effect and produced inconsistent covariate adjustment. CONCLUSIONS: While the matching framework achieved results comparable to SYNTH, it has the advantage of being technically less complicated, while producing statistical estimates that are straightforward to interpret. Conversely, regression adjustment may "adjust away" a treatment effect. Given its advantages, ITSAMATCH should be considered as a primary approach for evaluating treatment effects in multiple-group time-series analysis. PMID- 29266645 TI - Human dissemination of genes and microorganisms in Earth's Critical Zone. AB - Earth's Critical Zone sustains terrestrial life and consists of the thin planetary surface layer between unaltered rock and the atmospheric boundary. Within this zone, flows of energy and materials are mediated by physical processes and by the actions of diverse organisms. Human activities significantly influence these physical and biological processes, affecting the atmosphere, shallow lithosphere, hydrosphere, and biosphere. The role of organisms includes an additional class of biogeochemical cycling, this being the flow and transformation of genetic information. This is particularly the case for the microorganisms that govern carbon and nitrogen cycling. These biological processes are mediated by the expression of functional genes and their translation into enzymes that catalyze geochemical reactions. Understanding human effects on microbial activity, fitness and distribution is an important component of Critical Zone science, but is highly challenging to investigate across the enormous physical scales of impact ranging from individual organisms to the planet. One arena where this might be tractable is by studying the dynamics and dissemination of genes for antibiotic resistance and the organisms that carry such genes. Here we explore the transport and transformation of microbial genes and cells through Earth's Critical Zone. We do so by examining the origins and rise of antibiotic resistance genes, their subsequent dissemination, and the ongoing colonization of diverse ecosystems by resistant organisms. PMID- 29266647 TI - Esophagogastric junction and esophageal body contraction metrics on high resolution manometry predict esophageal acid burden. AB - BACKGROUND: Distal contractile integral (DCI) and esophagogastric junction contractile integral (EGJ-CI) are high-resolution manometry (HRM) software metrics assessing esophageal motor function in gastroesophageal reflux disease (GERD). METHODS: Patients undergoing HRM and ambulatory pH monitoring off antisecretory therapy prospectively completed symptom questionnaires assessing symptom burden and a global symptom score (GSS) at baseline and after GERD therapy. DCI<450 mm Hg/cm/s in >=5 swallows diagnosed ineffective esophageal motility (IEM); proportions of failed (DCI<100 mm Hg/cm/s) and weak (DCI 100-450 mm Hg/cm/s) sequences were separately assessed. EGJ-CI assessed vigor of the EGJ barrier. Univariate and multivariate analyses addressed performance of esophageal body and EGJ metrics in predicting abnormal esophageal reflux burden, and symptom outcome from antireflux therapy. KEY RESULTS: Of 188 patients (55.2 +/- 0.9 year, 64% F), 42.6% had low EGJ-CI, and 25.0% had IEM. While low EGJ-CI was associated with abnormal reflux burden (P = 0.003), IEM alone was not (P = 0.2). Increasing proportions of failed swallows predicted abnormal AET better than the current IEM definition. Combined low EGJ-CI and IEM segregated abnormal total and supine acid burden compared to patients with normal EGJ-CI and no IEM (P <= 0.007 for each comparison). Medical therapy and surgical antireflux therapy were similarly effective in improving symptom burden; surgery resulted in better outcomes with low EGJ-CI (P <= 0.04), especially with intact esophageal body motor function (P = 0.02). CONCLUSIONS & INFERENCES: While abnormal EGJ and esophageal body metrics are collectively associated with elevated esophageal reflux burden, increasing proportions of failed swallows are better predictors of reflux burden and outcome compared to the current IEM definition. PMID- 29266649 TI - Photoinduced Rearrangement of Dienones and Santonin Rerouted by Amines. AB - The photoinduced rearrangement pathways of simple 2,5-dienones and the natural product santonin were found to be effectively rerouted by amines, giving rise to unprecedented products. Either cis olefins or cyclobutenes were obtained from 4,4 disubstituted 2,5-dienone upon irradiation (365 nm) in the presence of various amines depending on the solvent. Previously undescribed [4.4.0] and [5.3.0] fused ring-containing products were obtained when santonin was irradiated (365 nm) in the presence of methylamine. The amines present in these reactions were incorporated into the products by means of amide-group formation. PMID- 29266648 TI - Folding DNA into a Lipid-Conjugated Nanobarrel for Controlled Reconstitution of Membrane Proteins. AB - Building upon DNA origami technology, we introduce a method to reconstitute a single membrane protein into a self-assembled DNA nanobarrel that scaffolds a nanodisc-like lipid environment. Compared with the membrane-scaffolding-protein nanodisc technique, our approach gives rise to defined stoichiometry, controlled sizes, as well as enhanced stability and homogeneity in membrane protein reconstitution. We further demonstrate potential applications of the DNA nanobarrels in the structural analysis of membrane proteins. PMID- 29266650 TI - N-Heterocyclic Carbene Boranes as Reactive Oxygen Species-Responsive Materials: Application to the Two-Photon Imaging of Hypochlorous Acid in Living Cells and Tissues. AB - N-Heterocyclic carbene (NHC) boranes undergo oxidative hydrolysis to give imidazolium salts with excellent kinetic selectivity for HOCl over other reactive oxygen species (ROS), including peroxides and peroxynitrite. Selectivity for HOCl results from the electrophilic oxidation mechanism of NHC boranes, which stands in contrast to the nucleophilic oxidation mechanism of arylboronic acids with ROS. The change in polarity that accompanies the conversion of NHC boranes to imidazolium salts can control the formation of emissive excimers, forming the basis for the design of the first fluorescence probe for ROS based on the oxidation of B-H bonds. Two-photon microscope (TPM) ratiometric imaging of HOCl in living cells and tissues is demonstrated. PMID- 29266651 TI - Within-host evolution versus immigration as a determinant of Escherichia coli diversity in the human gastrointestinal tract. AB - When a human host harbors two or more strains of Escherichia coli, the second strain is more likely to be a member of the same phylogroup rather than a different phylogroup. This outcome may be the consequence of a within host evolution event or an independent immigration/establishment event. To determine the relative importance of these two events in determining E. coli diversity in a host, a collection of multiple E. coli isolates recovered from each of 67 patients undergoing colonoscopies was used. Whole genome sequence data were available for one example of every REP-fingerprint type identified in a patient. Sequence type (ST) and single-nucleotide polymorphism (SNP) analyses revealed that 83% of strains observed in the host population were a consequence of immigration/establishment events. Restricting the analysis to hosts harboring two or more strains belonging to the same phylogroup revealed that in about half of these cases, the presence of a second strain belonging to the same phylogroup was the consequence of an independent immigration/establishment event. Thus, the results of this study show that despite hosts being exposed to a diversity of E. coli via their food, factors related to the host also determine what E. coli strains succeed in establishing. PMID- 29266652 TI - Connectivity-based parcellation of the nucleus accumbens into core and shell portions for stereotactic target localization and alterations in each NAc subdivision in mTLE patients. AB - The nucleus accumbens (NAc), an important target of deep brain stimulation for some neuropsychiatric disorders, is thought to be involved in epileptogenesis, especially the shell portion. However, little is known about the exact parcellation within the NAc, and its structural abnormalities or connections alterations of each NAc subdivision in temporal lobe epilepsy (TLE) patients. Here, we used diffusion probabilistic tractography to subdivide the NAc into core and shell portions in individual TLE patients to guide stereotactic localization of NAc shell. The structural and connection abnormalities in each NAc subdivision in the groups were then estimated. We successfully segmented the NAc in 24 of 25 controls, 14 of 16 left TLE patients, and 14 of 18 right TLE patients. Both left and right TLE patients exhibited significantly decreased fractional anisotropy (FA) and increased radial diffusivity (RD) in the shell, while there was no significant alteration in the core. Moreover, relatively distinct structural connectivity of each NAc subdivision was demonstrated. More extensive connection abnormalities were detected in the NAc shell in TLE patients. Our results indicate that neuronal degeneration and damage caused by seizure mainly exists in NAc shell and provide anatomical evidence to support the role of NAc shell in epileptogenesis. Remarkably, those NAc shell tracts with increased connectivities in TLE patients were found decreased in FA, which indicates disruption of fiber integrity. This finding suggests the regeneration of aberrant connections, a compensatory and repair process ascribed to recurrent seizures that constitutes part of the characteristic changes in the epileptic network. PMID- 29266654 TI - Corrigendum. PMID- 29266653 TI - Charge-Induced Secondary Structure Transformation of Amyloid-Derived Dipeptide Assemblies from beta-Sheet to alpha-Helix. AB - Secondary structures such as alpha-helix and beta-sheet are the major structural motifs within the three-dimensional geometry of proteins. Therefore, structure transitions from beta-sheet to alpha-helix not only can serve as an effective strategy for the therapy of neurological diseases through the inhibition of beta sheet aggregation but also extend the application of alpha-helix fibrils in biomedicine. Herein, we present a charge-induced secondary structure transition of amyloid-derived dipeptide assemblies from beta-sheet to alpha-helix. We unravel that the electrostatic (charge) repulsion between the C-terminal charges of the dipeptide molecules are responsible for the conversion of the secondary structure. This finding provides a new perspective to understanding the secondary structure formation and transformation in the supramolecular organization and life activity. PMID- 29266655 TI - Long-term risk of diabetes in women at varying durations after gestational diabetes: a systematic review and meta-analysis with more than 2 million women. AB - This study aims to investigate the impact of gestational diabetes mellitus (GDM) on the long-term risks of diabetes in women with prior GDM, including the effect at different time periods after GDM. We searched PubMed and other databases to retrieve articles which were published prior to February 28, 2017. Cohort studies which evaluated the risk and time of onset of diabetes postpartum in women with and without GDM were included. Meta-analysis with random effects models was used to obtain pooled relative risks and 95% confidence intervals for the risk of diabetes. Subgroup analyses were performed to check for different effect sizes as well as consistency across groups. Multivariable logistic regression was used to adjust for confounders. Thirty cohort studies with 2,626,905 pregnant women were included. Women with prior GDM had 7.76-fold (95% confidence intervals: 5.10 11.81) unadjusted pooled risk of diabetes as compared with women without GDM, whilst the adjusted risk was 17.92-fold (16.96-18.94). The adjusted ORs of GDM for diabetes among women at <3, >=3 - <6 and >=6 - <10 years after GDM were 5.37 (3.51-9.34), 16.55 (16.08-17.04) and 8.20 (4.53-14.86), respectively. Women with prior GDM had substantially increased risk of diabetes, with the risk highest during the 3-6 years after GDM. PMID- 29266656 TI - Topical 1% propranolol ointment with occlusion in treatment of pyogenic granulomas: An open-label study in 22 children. AB - BACKGROUND: Pyogenic granuloma (PG) is a common, acquired, benign vascular neoplasm of the skin and mucous membranes. It occurs most often in children and adolescents. First-line treatment options for PG are based on destructive approaches. Pain, permanent scarring, and pigmentation are potential complications of these therapies. METHODS: This single-arm, open-label, prospective study evaluated the efficacy of topical propranolol for treatment of PGs in children. All patients clinically diagnosed with cutaneous PG consecutively at the Dermatology Pediatric Outpatient Service of the University of Bologna from January 2010 to December 2010 received a compounded formulation of propranolol ointment 1%. RESULTS: We found propranolol ointment to be effective in consecutive patients; 59.0% completely regressed in a mean of 66 days, 18.2% remained stable, and 22.7% did not respond. No side effects (eg, skin irritation, allergy, bleeding) were observed. CONCLUSION: Topical propranolol ointment 1% with occlusion appears to be an effective treatment for PGs in children. Early treatment was associated with a more favorable outcome. PMID- 29266657 TI - The impact of isolated maternal hypothyroxinaemia on the incidence of large-for gestational-age infants: the Ma'anshan Birth Cohort study. AB - OBJECTIVE: The purpose of this study was to investigate whether isolated maternal hypothyroxinaemia (IMH) is associated with risks of small/large-for-gestational age (SGA/LGA) infants. DESIGN: Population-based prospective cohort study. SETTING: Ma'anshan Maternal and Child Health (MCH) clinics, China. POPULATION: Pregnant women with singleton births (n = 3178). METHODS: Descriptive statistics were calculated for the demographic characteristics of the mothers and their newborns. Linear regression was applied to estimate the association between thyroid hormone levels and birthweight. Logistic regression was performed to calculate the association between IMH and SGA/LGA. MAIN OUTCOME MEASURES: Outcomes included SGA/LGA. RESULTS: The prevalence of IMH, defined as a free thyroxine value (FT4) lower than the 2.5th percentile with normal thyroid stimulating hormone, was 2.5% (78/3080) and 2.5% (74/2999) in the first and second trimesters, respectively. Additionally, 306 (9.6%) and 524 (16.5%) infants were defined as SGA and LGA, respectively. No evidence supported the notion that IMH is associated with an increased risk for SGA in either the first [odds ratio (OR): 1.762, 95% confidence interval (CI): 0.759-4.089] or the second (OR: 0.763, 95% CI: 0.231-2.516) trimester. However, an increased risk of LGA was observed among IMH women in the second trimester (OR: 2.088, 95% CI: 1.193-3.654). Maternal TPO-Ab positivity in the second trimester increased the risk of SGA (OR: 2.094, 95% CI: 1.333-3.290). CONCLUSION: This study provides evidence that IMH is associated with LGA. FUNDING: This work was supported by the National Natural Science Foundation of China (No. 81330068). TWEETABLE ABSTRACT: Isolated maternal hypothyroxinaemia may increase the risk of large-for-gestational-age infants. PMID- 29266658 TI - Surgical management of plunging ranulas: a 10-year case series in South East Queensland. AB - BACKGROUND: Plunging ranulas are rare mucous extravasation pseudocysts that arise in the floor of the mouth and pass into the submandibular space of the neck. The aim of this study was to investigate the diagnosis, surgical management and outcomes of patients with a plunging ranula at our institution in South East Queensland over a 10-year period. METHODS: A retrospective analysis of adult patients diagnosed with and treated for plunging ranula between 2006 and 2016 at Logan Hospital was conducted. Patient demographics, preoperative investigations, surgical management and post-operative outcomes were collected from medical records. RESULTS: A total of 18 adult patients were treated for plunging ranula. Of the 18 cases, 17 were treated via transoral excision of the sublingual gland. The mean age at presentation was 28.8 years with a 3:1 female to male predominance. Fifty-six percent of patients were of Polynesian descent. The success rate was 94% with only one patient experiencing recurrence and requiring re-excision of remnant sublingual gland tissue. Three patients (17%) developed complications related to post-operative bleeding. There was a slight predominance for right-sided disease (56%) compared with left and one case of bilateral plunging ranulas in this series. CONCLUSION: This study demonstrates that excision of the sublingual gland is an effective and safe treatment for plunging ranula. The majority of plunging ranulas occur in patients aged <30 years with a higher incidence in patients of Polynesian heritage, which is consistent with previous studies suggesting a possible underlying genetic predisposition for this condition. PMID- 29266659 TI - Negative perceptions of illness and health are associated with frequent use of physiotherapy in primary healthcare. AB - BACKGROUND: There is growing concern that an ageing population and increasing number of patients with chronic illnesses in the future will foster a need for health services beyond the resources available in society. Patients with chronic illnesses are reported to be frequent users of physicians' services in the primary health sector. Therapies for patients with chronic musculoskeletal illnesses are delivered by physiotherapists in this sector. However, we know little about the use of physiotherapy services and the factors that may explain their use. PURPOSE: The aim of the present study was to examine the association between the regular/non-regular use of physiotherapy services, impacts of illness, and perceptions of illness and health. METHODS: A cross-sectional survey included patients between 18 and 70 years of age who visited a physiotherapy outpatient clinic in Oslo during one randomly chosen week. Patient characteristics and use of physiotherapy were mapped. The Brief Illness Perception Questionnaire (BIPQ), a single item of the Short Form Health Survey (SF-12) and the Orebro Musculoskeletal Pain Questionnaire (OMPQ) were used to assess perceptions of illness and health, and impacts of illness. Data were analysed using independent sample t-tests and logistic regression analysis. RESULTS: A total of 507 patients with a mean age of 46 (standard deviation 12) years participated, of whom 54% were regular users of physiotherapy. BIPQ (p = 0.02; beta = 0.03) and the single-item on general health perception (p = 0.001; beta = 0.44,) were the only significant variables in the final equation associated with regular use of physiotherapy. CONCLUSION: About half of the participants were regular, high consumers of physiotherapy, and negative perceptions of illness and health were associated with this regular use. PMID- 29266660 TI - A Kinetic Study of Methane Partial Oxidation over Fe-ZSM-5 Using N2 O as an Oxidant. AB - Catalytic methane oxidation using N2 O was investigated at 300 degrees C over Fe ZSM-5. This reaction rapidly produces coke (retained organic species), and causes catalyst fouling. The introduction of water into the feed-stream resulted in a significant decrease in the coke selectivity and an increase in the selectivity to the desired product, methanol, from ca. 1 % up to 16 %. A detailed investigation was carried out to determine the fundamental effect of water on the reaction pathway and catalyst stability. The delplot technique was utilised to identify primary and secondary reaction products. This kinetic study suggests that observed gas phase products (CO, CO2 , CH3 OH, C2 H4 and C2 H6 ) form as primary products whilst coke is a secondary product. Dimethyl ether was not detected, however we consider that the formation of C2 products are likely to be due to an initial condensation of methanol within the pores of the zeolite and hence considered pseudo-primary products. According to a second order delplot analysis, coke is considered a secondary product and its formation correlates with CH3 OH formation. Control experiments in the absence of methane revealed that the rate of N2 O decomposition is similar to that of the full reaction mixture, indicating that the loss of active alpha-oxygen sites is the likely cause of the decrease in activity observed and water does not inhibit this process. PMID- 29266661 TI - Health literacy skills for informed decision making in colorectal cancer screening: Perceptions of screening invitees and experts. AB - BACKGROUND: The process of informed decision making (IDM) requires an adequate level of health literacy. To ensure that all individuals have equal opportunity to make an informed decision in colorectal cancer (CRC) screening, it is essential to gain more insight into which health literacy skills are needed for IDM. Our aims were (i) to explore how individuals make a decision about CRC screening and (ii) to explore which skills are needed for IDM in CRC screening and (iii) to integrate these findings within a conceptual framework. METHODS: We conducted 3 focus groups with individuals eligible for CRC screening (n = 22) and 2 focus groups with experts in the field of health literacy, oncology and decision making, including scientific researchers and health-care professionals (n = 17). We used framework analysis to analyse our data. RESULTS: We identified and specified ten health literacy skills, which varied from the ability to read and understand CRC screening information to the ability to weigh up pros and cons of screening for personal relevance. The skills were linked to 8 decision-making stages in CRC screening within a conceptual framework. We found differences in perceptions between screening invitees and experts, especially in the perceived importance of CRC screening information for IDM. CONCLUSIONS: This study provides insight into the decision-making stages and health literacy skills that are essential for IDM in CRC screening. The proposed conceptual framework can be used to inform the development of context-based measurement of health literacy and interventions to support IDM in cancer screening. PMID- 29266662 TI - A year in the life of a thrombolite: comparative metatranscriptomics reveals dynamic metabolic changes over diel and seasonal cycles. AB - Microbialites are one of the oldest known ecosystems on Earth and the coordinated metabolisms and activities of these mineral-depositing communities have had a profound impact on the habitability of the planet. Despite efforts to understand the diversity and metabolic potential of these systems, there has not been a systematic molecular analysis of the transcriptional changes that occur within a living microbialite over time. In this study, we generated metatranscriptomic libraries from actively growing thrombolites, a type of microbialite, throughout diel and seasonal cycles and observed dynamic shifts in the population and metabolic transcriptional activity. The most transcribed genes in all seasons were associated with photosynthesis, but only transcripts associated with photosystem II exhibited diel cycling. Photosystem I transcripts were constitutively expressed at all time points including midnight and sunrise. Transcripts associated with nitrogen fixation, methanogenesis and dissimilatory sulfate reduction exhibited diel cycling, and variability between seasons. Networking analysis of the metatranscriptomes showed correlated expression patterns helping to elucidate how metabolic interactions are coordinated within the thrombolite community. These findings have identified distinctive temporal patterns within the thrombolites and will serve an important foundation to understand the mechanisms by which these communities form and respond to changes in their environment. PMID- 29266663 TI - Clinical audit training improves undergraduates' performance in root canal therapy. AB - AIM: To evaluate the effectiveness of clinical audit-feedback cycle as an educational tool in improving the technical quality of root canal therapy (RCT) and compliance with record keeping performed by dental undergraduates. METHODS: Clinical audit learning was introduced in Year 3 of a 5-year curriculum for dental undergraduates. During classroom activities, students were briefed on clinical audit, selected their audit topics in groups of 5 or 6 students, and prepared and presented their audit protocols. One chosen topic was RCT, in which 3 different cohorts of Year 3 students conducted retrospective audits of patients' records in 2012, 2014 and 2015 for their compliance with recommended record keeping criteria and their performance in RCT. Students were trained by and calibrated against an endodontist (kappa >= 0.8). After each audit, the findings were reported in class, and recommendations were made for improvement in performance of RCT and record keeping. Students' compliance with published guidelines was presented and their RCT performances in each year were compared using the chi-square test. RESULTS: Overall compliance with of record keeping guidelines was 44.1% in 2012, 79.6% in 2014 and 94.6% in 2015 (P = .001). In the 2012 audit, acceptable extension, condensation and the absence of mishap were observed in 72.4, 75.7% and 91.5%; in the 2014 audit, 95.1%, 64.8% and 51.4%; and in 2015 audit, 96.4%, 82.1% and 92.8% of cases, respectively. In 2015, 76.8% of root canal fillings met all 3 technical quality criteria when compared to 48.6% in 2014 and 44.7% in 2012 (P = .001). CONCLUSION: Clinical audit-feedback cycle is an effective educational tool for improving dental undergraduates' compliance with record keeping and performance in the technical quality of RCT. PMID- 29266665 TI - Reproductive biology and pollination of the carnivorous Genlisea violacea (Lentibulariaceae). AB - Genlisea violacea is a Brazilian endemic carnivorous plant species distributed in the cerrado biome, mainly in humid environments, on sandy and oligotrophic soil or wet rocks. Studies on reproductive biology or pollination in the Lentibulariaceae are notably scarce; regarding the genus Genlisea, the current study is the first to show systematic and standardised research on reproductive biology from field studies to describe the foraging of visiting insects and determine the effective pollinators of Genlisea. We studied two populations of G. violacea through the observation of flower visitors for 4 months of the rainy and dry seasons. Stigmatic receptivity, pollen viability, and breeding system were evaluated together with histochemistry and morphological analyses of flowers. The flowers showed stigmatic receptivity of 100% in open buds and mature flowers, reducing to 80% for senescent flowers. Nearly 80% of pollen grains are viable, decreasing to 40-45% after 48 h. Nectar is produced by glandular trichomes inside the spur. Two bee species are effective pollinators: one of the genus Lasioglossum (subgenus Dialictus: Halictidae) and the other of the genus Ceratina (subgenus Ceratinula: family Apidae). Moreover, bee-like flies of the Syrphidae family may also be additional pollinators. Genlisea violacea is an allogamous and self-compatible species. The differences in flower-visiting fauna for both populations can be attributed to factors such as climate, anthropogenic effect, seasonal factors related to insects and plants, as well as the morphological variation of flowers in both populations. PMID- 29266664 TI - Evaluation of the Stability of DNA i-Motifs in the Nuclei of Living Mammalian Cells. AB - C-rich DNA has the capacity to form a tetra-stranded structure known as an i motif. The i-motifs within genomic DNA have been proposed to contribute to the regulation of DNA transcription. However, direct experimental evidence for the existence of these structures in vivo has been missing. Whether i-motif structures form in complex environment of living cells is not currently known. Herein, using state-of-the-art in-cell NMR spectroscopy, we evaluate the stabilities of i-motif structures in the complex cellular environment. We show that i-motifs formed from naturally occurring C-rich sequences in the human genome are stable and persist in the nuclei of living human cells. Our data show that i-motif stabilities in vivo are generally distinct from those in vitro. Our results are the first to interlink the stability of DNA i-motifs in vitro with their stability in vivo and provide essential information for the design and development of i-motif-based DNA biosensors for intracellular applications. PMID- 29266666 TI - Microporous MOFs Engaged in the Formation of Nitrogen-Doped Mesoporous Carbon Nanosheets for High-Rate Supercapacitors. AB - Nitrogen-doped mesoporous carbon nanosheets (NMCS) have been fabricated from zinc based microporous metal-organic frameworks (ZIF-8) by pyrolysis in a molten salt medium. The as-prepared NMCS exhibit significantly improved specific capacitance (NMCS-8: 232 F g-1 at 0.5 A g-1 ) and capacitance retention ratio (75.9 % at 50 A g-1 ) compared with the micropore-dominant nitrogen-doped porous carbon polyhedrons (NPCP-5: 178 F g-1 at 0.5 A g-1 , 15.9 % at 20 A g-1 ) obtained by direct pyrolysis of nanocrystalline ZIF-8. The excellent capacitive performance and high rate performance of the NMCS can be attributed to their unique combination of structure and composition, that is, the two-dimensional and hierarchically porous structure provides a short ion-transport pathway and facilitates the supply of electrolyte ions, and the nitrogen-doped polar surface improves the interface wettability when used as an electrode. PMID- 29266667 TI - Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium fat diet intervention at old age. AB - Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver-specific responses caused by a diet switch to a medium-fat (MF) diet in 24-month-old lifelong, CR-exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine-week-old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitumMF feeding (CR-MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long-term exposure to the CR regimen, mice in the CR-MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration in CR improved survival was observed in the diet switch group. The liver transcriptomic profile of CR-MF mice largely shifted to a profile similar to the MF-fed animals but leaving ~22% of the 1,578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the lifelong CR group. Therefore, although the diet switch was performed at an old age, the CR-MF exposed mice showed plasticity in coping with the challenge of a MF diet without developing severe liver pathologies. PMID- 29266668 TI - Ligation versus no ligation of spontaneous portosystemic shunts during liver transplantation: Audit of a prospective series of 66 consecutive patients. AB - The management of large spontaneous portosystemic shunt (SPSS) during liver transplantation (LT) is a matter of debate. The aim of this study is to compare the short-term and longterm outcomes of SPSS ligation versus nonligation during LT, when both options are available. From 2011 to 2017, 66 patients with SPSS underwent LT: 56 without and 10 with portal vein thrombosis (PVT), all of whom underwent successful thrombectomy and could have portoportal reconstruction. The SPSS were either splenorenal (n = 40; 60.6%), left gastric (n = 16; 24.2%), or mesenterico-iliac (n = 10; 15.1%). Following portoportal anastomosis, the SPSS was ligated in 36 (54.4%) patients and left in place in 30 (45.5%) patients, based on the effect of the SPSS clamping/unclamping test on portal vein flow during the anhepatic phase. Intraoperatively, satisfactory portal flow was obtained in both groups. Primary nonfunction (PNF) and primary dysfunction (PDF) rates did not differ significantly between the 2 groups. Nonligation of SPSS was significantly associated with a higher rate of postoperative encephalopathy (P < 0.001) and major postoperative morbidity (P = 0.02). PVT occurred in 0 and 3 patients in the ligated and nonligated shunt group, respectively (P = 0.08). A composite end point, which included the relevant complications in the setting of SPSS in LT (ie, PNF and PDF, PVT, and encephalopathy) was present in 16 (44.4%) and 22 (73.3%) patients of the ligated and nonligated shunt group, respectively (P = 0.02). Patient (P = 0.05) and graft (P = 0.02) survival rates were better in the ligated shunt group. In conclusion, the present study supports routine ligation of large SPSS during LT whenever feasible. Liver Transplantation 24 505 515 2018 AASLD. PMID- 29266669 TI - The "side-BASE technique": Combined side branch anchor balloon and balloon assisted sub-intimal entry to resolve ambiguous proximal cap chronic total occlusions. AB - Failure to penetrate the proximal cap or cross with equipment remains the most frequent cause of procedural failure in CTO PCI. In the "BASE" technique concerns were raised over the risk of proximal side branch loss. We here describe the evolution of this technique and highlight examples where the sub-intimal space was accessed proximal to the occlusion by using the side branch. This technique can be of use both in resolving proximal cap ambiguity and also in cases where there is difficulty crossing a resistant proximal cap. PMID- 29266670 TI - Fourier Transform Surface Plasmon Resonance (FTSPR) with Gyromagnetic Plasmonic Nanorods. AB - An unprecedented active and dynamic sensing platform based on a LSPR configuration that is modulated by using an external magnetic field is reported. Electrochemically synthesized Au/Fe/Au nanorods exhibited plasmonically active behavior through plasmonic coupling, and the middle ferromagnetic Fe block responded to a magnetic impetus, allowing the nanorods to be modulated. The shear force variation induced by the specific binding events between antigens and antibodies on the nanorod surface is used to enhance the sensitivity of detection of antigens in the plasmonics-based sensor application. As a proof-of-concept, influenza A virus (HA1) was used as a target protein. The limit of detection was enhanced by two orders of magnitude compared to that of traditional LSPR sensing. PMID- 29266671 TI - Transcoronary cell infusion with the stop-flow technique in children with single ventricle physiology. AB - BACKGROUND: Almost all reports on cardiac regeneration therapy have referred to adults, and only a few have focused on transcoronary infusion of cardiac progenitor cells using the stop-flow technique in children. METHODS: Intracoronary autologous cardiosphere-derived cell (CDC) transfer was conducted at Okayama University as a phase 1 clinical trial for seven patients with hypoplastic left heart syndrome between January 2011 and December 2012, and as a phase 2 clinical trial for 34 patients with single-ventricle physiology between July 2013 and March 2015. RESULTS: A total of 41 patients with single-ventricle physiology underwent transcoronary infusion of CDC with the stop-flow technique. The median age was 33 months (range, 5-70 months) and the median weight was 10.1 kg (range, 4.1-16.0 kg). Transient adverse events occurred during the procedure, including ST-segment elevation or depression, hypotension, bradycardia, and coronary artery vasospasm. All patients completely recovered. There were no major procedure-related adverse events. In this study, transcoronary infusion of CDC using the stop-flow technique was successfully completed in all patients. CONCLUSION: Transcoronary infusion of CDC using the stop-flow technique in children is a feasible and safe procedure. PMID- 29266672 TI - Optical Control of a Biological Reaction-Diffusion System. AB - Patterns formed by reaction and diffusion are the foundation for many phenomena in biology. However, the experimental study of reaction-diffusion (R-D) systems has so far been dominated by chemical oscillators, for which many tools are available. In this work, we developed a photoswitch for the Min system of Escherichia coli, a versatile biological in vitro R-D system consisting of the antagonistic proteins MinD and MinE. A MinE-derived peptide of 19 amino acids was covalently modified with a photoisomerizable crosslinker based on azobenzene to externally control peptide-mediated depletion of MinD from the membrane. In addition to providing an on-off switch for pattern formation, we achieve frequency-locked resonance with a precise 2D spatial memory, thus allowing new insights into Min protein action on the membrane. Taken together, we provide a tool to study phenomena in pattern formation using biological agents. PMID- 29266674 TI - Is conditional reasoning related to mathematical problem solving? AB - The current study aimed to investigate the relation between conditional reasoning, which is a common type of logical reasoning, and children's mathematical problem solving. A sample of 124 fourth graders was tested for their conditional reasoning skills and their mathematical problem solving skills, as well as a list of control variables (e.g., IQ, working memory, reading) and potential mediators (number sentence construction and computation). The children's ability to make modus ponens (MP) inferences significantly predicted their mathematical problem solving skills, even after controlling for the potential confounding variables. The relation was mediated by the number sentence construction skills. The findings, in addition to supporting the link between conditional reasoning and mathematics, further indicate that the ability to process relations may be the mechanism underlying the relation. Theoretical and practical implications are discussed. PMID- 29266673 TI - Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men. AB - Neurological disorders are a major threat to public health. Stem cell-based regenerative medicine is now a promising experimental paradigm for its treatment, as shown in pre-clinical animal studies. Initial attempts have been on the replacement of neuronal cells only, but glial progenitors (GPs) are now becoming strong alternative cellular therapeutic candidates to replace oligodendrocytes and astrocytes as knowledge accumulates about their important emerging role in various disease processes. There are many examples of successful therapeutic outcomes for transplanted GPs in small animal models, but clinical translation has proved to be challenging due to the 1,000-fold larger volume of the human brain compared to mice. Human GPs transplanted into the mouse brain migrate extensively and can induce global cell replacement, but a similar extent of migration in the human brain would only allow for local rather than global cell replacement. We review here the mechanisms that govern cell migration, which could potentially be exploited to enhance the migratory properties of GPs through cell engineering pre-transplantation. We furthermore discuss the (dis)advantages of the various cell delivery routes that are available, with particular emphasis on intra-arterial injection as the most suitable route for achieving global cell distribution in the larger brain. Now that therapeutic success has proven to be feasible in small animal models, future efforts will need to be directed to enhance global cell delivery and migration to make bench-to-bedside translation a reality. PMID- 29266675 TI - Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. AB - AIM: To evaluate the efficacy and safety of ertugliflozin and sitagliptin co administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. METHODS: In this study (Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) >=7.5% and <=11.0% (>=58 and <=97 mmol/mol) with metformin >=1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co-administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. RESULTS: At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (-1.5%) and E15/S100 ( 1.5%) than with individual agents (-1.0%, -1.1% and -1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin-treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups. CONCLUSIONS: In patients with uncontrolled type 2 diabetes while using metformin, co-administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents. PMID- 29266676 TI - Feasibility of early mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: The Detroit cardiogenic shock initiative. AB - OBJECTIVE: The 'Detroit Cardiogenic Shock Initiative' is a single-arm, multicenter study to assess the feasibility of early mechanical circulatory support (MCS) in patients who present with acute myocardial infarction complicated by cardiogenic shock (AMICS) who undergo percutaneous coronary intervention. METHODS: Between July 2016 and February 2017, 4 metro Detroit sites participated in the study. The centers agreed to treat patients with AMICS using a mutually agreed-upon protocol emphasizing invasive hemodynamic monitoring and rapid initiation of MCS. Inclusion and exclusion criteria mimicked those from the 'SHOCK' trial with an additional exclusion criteria being use of intra-aortic balloon pump counter pulsation prior to MCS. RESULTS: A total of 41 consecutive patients were included. Patients had an average age of 65 +/- 14 years, 71% were male and 59% of patients were admitted to the hospital in cardiogenic shock. Prior to receiving MCS, 93% of patients were on vasopressors or inotropes, 15% of patients had a witnessed out of hospital cardiac arrest, 27% of patients had an in-hospital cardiac arrest, and 17% were under active cardiopulmonary resuscitation while MCS was being implanted. In accordance to the protocol recommendation, 66% of patients had a MCS device inserted prior to PCI. Right heart catheterization and hemodynamic monitoring was performed in 83% of patients. Door to support times averaged 83 +/- 58 minutes and 71% of patients were able to reduce the levels of inotropes and vasopressors within the first 24 hours of their index procedure. Pre-procedure cardiac power output (CPO) was 0.57 W and post-procedure CPO was 0.95 W, a 67% increase (p < 0.001). Survival to explant for the entire cohort was 85% a significant improvement from institutional historical controls (85% vs 51% p < 0.001) and survival to discharge was 76%. CONCLUSION: Centers who adopted a regional shock protocol emphasizing the delivery of early MCS with invasive hemodynamic monitoring can achieve rapid door to support times and can improve survival in patients who present with AMICS. Larger national studies will be needed to further validate this pilot feasibility study. PMID- 29266677 TI - Paying people to lose weight: the effectiveness of financial incentives provided by health insurers for the prevention and management of overweight and obesity - a systematic review. AB - Curbing the obesity epidemic is likely to require a suite of interventions targeting the obesogenic environment as well as individual behaviour. Evidence suggests that the effectiveness of behaviour modification programmes can be enhanced by financial incentives that immediately reward weight loss behaviour. This systematic review investigated the effectiveness of incentives with a focus on assessing the relative effectiveness of incentives that target different behaviours as well as factors of importance when implementing these programmes in real-world settings (health insurer settings). A narrative review of the academic and grey literature including a variety of study designs was undertaken. Twenty studies met inclusion criteria and were assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Results suggest that incentivizing weight loss is effective in the short term while the incentives are in place. There are various incentive designs, and although the relative effectiveness of each of these on weight loss is not clear, it appears that positive incentives increase the uptake into programmes and may reduce dropouts. As with other weight loss initiatives, there is a need to explore ways to maintain weight loss in the longer term - incentives for weight maintenance could play a role. PMID- 29266678 TI - Using a Multi-Shelled Hollow Metal-Organic Framework as a Host to Switch the Guest-to-Host and Guest-to-Guest Interactions. AB - A bio-inspired design of using metal-organic framework (MOF) microcrystals with well-defined multi-shelled hollow structures was used as a matrix to host multiple guests including molecules and nanoparticles at separated locations to form a hierarchical material, mimicking biological structures. The interactions such as energy transfer (ET) between different guests are regulated by precisely fixing them in the MOF shells or encapsulating them in the cavities between the MOF shells. The proof-of-concept design is demonstrated by hosting chromophore molecules including rhodamine 6G (R6G) and 7-amino-4-(trifluoromethyl)coumarin (C 151), as well as metal nanoparticles (Pd NPs) into the multi-shelled hollow zeolitic imidazolate framework-8 (ZIF-8). We could selectively establish or diminish the guest-to-framework and guest-to-guest ET. This work provides a platform to construct complex multifunctional materials, especially those need precise separation control of multi-components. PMID- 29266679 TI - Electrochemical Synthesis of Imidazo-Fused N-Heteroaromatic Compounds through a C N Bond-Forming Radical Cascade. AB - We have developed a unified strategy for preparing a variety of imidazo-fused N heteroaromatic compounds through regiospecific electrochemical (3+2) annulation reaction of heteroarylamines with tethered internal alkynes. The electrosynthesis employs a novel tetraarylhydrazine as the catalyst, has a broad substrate scope, and obviates the need for transition-metal catalysts and oxidizing reagents. PMID- 29266680 TI - Achieving the four dimensions of food security for resettled refugees in Australia: A systematic review. AB - AIM: Food security is defined by four dimensions: food availability, access, utilisation and stability. Resettled refugees face unique struggles securing these dimensions and, thus, food security when moving to a new country. This systematic review aimed to identify the challenges Australian refugees experience in achieving the four dimensions of food security. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed; the SPIDER tool was used to determine eligibility criteria. Three databases were searched using terms relating to food in/security and refugees from 2000 to 20 May 2017. RESULTS: Seven articles were retained for analysis. Studies were categorised against the four dimensions, with four studies identifying challenges against all dimensions. Challenges contributing to high levels of food insecurity in each dimension included: availability and cost of traditional foods, difficulty in accessing preferred food outlets, limited food knowledge and preparation skills and food stability due to low income and social support. CONCLUSIONS: Food insecurity adversely impacts refugee health and integration. Methodical research framed by the four dimensions of food security is imperative to address challenges to securing food security in refugee groups and assisting in the development of sustainable interventions. PMID- 29266681 TI - Occurrence of target-site resistance to neonicotinoids in the aphid Myzus persicae in Tunisia, and its status on different host plants. AB - BACKGROUND: The R81T mutation conferring target-site resistance to neonicotinoid insecticides in Myzus persicae was first detected in France and has since spread across much of southern Europe. In response to recent claims of control failure with neonicotinoids in Tunisia, we have used a molecular assay to investigate the presence and distribution of this target-site mutation in samples collected from six locations and six crops attacked by M. persicae. RESULTS: The resistance allele containing R81T was present at substantial frequencies (32-55%) in aphids collected between 2014 and 2016 from northern Tunisia but was much rarer further south. It occurred in aphids collected from the aphid's primary host (peach) and four secondary crop hosts (potato, pepper, tomato and melon). Its absence in aphids from tobacco highlights complexities in the systematics of M. persicae that require further investigation. CONCLUSION: This first report of R81T from North Africa reflects a continuing expansion of its range around the Mediterranean Basin, although it remains unrecorded elsewhere in the world. Loss of efficacy of neonicotinoids presents a serious threat to the sustainability of aphid control. (c) 2017 Society of Chemical Industry. PMID- 29266683 TI - Factors affecting the presence, genetic diversity and antimicrobial sensitivity of Escherichia coli in poultry meat samples collected from Canberra, Australia. AB - To investigate the factors determining the clonal composition of Escherichia coli in poultry meat samples, 306 samples were collected from 16 shops, representing three supermarket chains and an independent butchery located in each of the four town centers of Canberra, Australia, during the summer, autumn and winter. A total of 3415 E. coli isolates were recovered and assigned to a phylogenetic group using the Clermont quadruplex PCR method, fingerprinted using repetitive element palindromic (REP) PCR and screened for their antimicrobial susceptibility profiles. The probability of detecting E. coli and the number of fingerprint types detected per sample, as well as the phylogroup membership of the isolates and their antimicrobial sensitivity profiles varied, with one or more of retailer, store, meat type, season and husbandry. The results of this study demonstrate that poultry meat products are likely to be contaminated with a genetically diverse community of E. coli and suggest that factors relating to the nature of the meat product and distribution chain are determinants of the observed diversity. PMID- 29266682 TI - Profile of common prostate cancer risk variants in an unscreened Romanian population. AB - To find sequence variants affecting prostate cancer (PCA) susceptibility in an unscreened Romanian population we use a genome-wide association study (GWAS). The study population included 990 unrelated pathologically confirmed PCA cases and 1034 male controls. DNA was genotyped using Illumina SNP arrays, and 24.295.558 variants were imputed using the 1000 Genomes data set. An association test was performed between the imputed markers and PCA. A systematic literature review for variants associated with PCA risk identified 115 unique variants that were tested in the Romanian sample set. Thirty of the previously reported SNPs replicated (P value < 0.05), with the strongest associations observed at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The replicated variants showing the most significant association in Romania are rs1016343 at 8q24.21 (P = 2.2 * 10-4 ), rs7929962 at 11q13.3 (P = 2.7 * 10-4 ) and rs9364554 at 6q25.2 (P = 4.7 * 10-4 ). None of the variants tested in the Romanian GWAS reached genome-wide significance (P-value <5 * 10-8 ) but 807 markers had P-values <1 * 10-4 . Here, we report the results of the first GWAS of PCA performed in a Romanian population. Our study provides evidence that a substantial fraction of previously validated PCA variants associate with risk in this unscreened Romanian population. PMID- 29266684 TI - Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication. PMID- 29266685 TI - Physiological and methodological aspects of rate of force development assessment in human skeletal muscle. AB - Rate of force development (RFD) refers to the ability of the neuromuscular system to increase contractile force from a low or resting level when muscle activation is performed as quickly as possible, and it is considered an important muscle strength parameter, especially for athletes in sports requiring high-speed actions. The assessment of RFD has been used for strength diagnosis, to monitor the effects of training interventions in both healthy populations and patients, discriminate high-level athletes from those of lower levels, evaluate the impairment in mechanical muscle function after acute bouts of eccentric muscle actions and estimate the degree of fatigue and recovery after acute exhausting exercise. Notably, the evaluation of RFD in human skeletal muscle is a complex task as influenced by numerous distinct methodological factors including mode of contraction, type of instruction, method used to quantify RFD, devices used for force/torque recording and ambient temperature. Another important aspect is our limited understanding of the mechanisms underpinning rapid muscle force production. Therefore, this review is primarily focused on (i) describing the main mechanical characteristics of RFD; (ii) analysing various physiological factors that influence RFD; and (iii) presenting and discussing central biomechanical and methodological factors affecting the measurement of RFD. The intention of this review is to provide more methodological and analytical coherency on the RFD concept, which may aid to clarify the thinking of coaches and sports scientists in this area. PMID- 29266686 TI - Adult intussusception involving colonic lipoma: a case study. PMID- 29266687 TI - Reducing fretting-initiated crevice corrosion in hip simulator tests using a zirconia-toughened alumina femoral head. AB - Taper fretting corrosion is considered a potentially limiting factor for total hip arthroplasty longevity. Recently, attention has been focused on new materials for ceramic femoral heads, for example, zirconia-toughened alumina (ZTA), since they have an alternative bearing surface that can improve the wear resistance. Moreover, ceramics have high chemical stability and corrosion resistance. In this study, we evaluated the effects of ZTA and Co-Cr-Mo alloy femoral heads on their taper fretting and/or corrosion characteristics under a controlled hip simulator test. After the test, less fretting and corrosion were observed in the taper surface of the trunnion against the ZTA femoral head than for that against the Co Cr-Mo alloy femoral head. In addition, corrosion damages were only observed in the lateral-distal taper surface (noncontact area) of the trunnion in the Co-Cr Mo alloy femoral head group. The ZTA femoral head group also eliminated the potential for Co ion release into the lubricants from taper corrosion, reducing the possibility of adverse local tissue inflammatory responses. In conclusion, ZTA femoral heads showed markedly less fretting corrosion compared to Co-Cr-Mo alloy femoral heads and have a lower potential for metal ion release. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2815 2826, 2018. PMID- 29266688 TI - Advantages of transperineal approach for secondary rectal cancer following prior radiotherapy to prostate cancer -video vignette. AB - Radiotherapy for prostate cancer increases the risk of secondary rectal cancer [1]. The technical challenge for rectal surgery in patients who had previous high dose pelvic radiation is due to difficulty in defining the anatomy, especially in mobilising the mesorectum with post-radiation changes distorting anatomical structures [2]. Considering the anatomical proximity of the rectum to the prostate, the increased fibrosis caused by prior radiotherapy is crucial during anterior dissection of the rectum. This article is protected by copyright. All rights reserved. PMID- 29266689 TI - Sources and Types of Social Support for Physical Activity Perceived by Fifth to Eighth Grade Girls. AB - BACKGROUND: Information is lacking on forms and sources of social support for physical activity (PA) received by adolescent girls during various pubertal stages. Two study purposes were to (a) identify the sources and forms of social support for PA perceived by adolescent girls, and (b) examine associations of pubertal stage and social support with PA. METHODS: A secondary analysis of data from a randomized trial was conducted. Fifth through eighth grade girls (N = 1,519) completed surveys on social support for PA and pubertal stage and wore an accelerometer. RESULTS: Girls in early-middle and late-post puberty most frequently received social support from their mothers. A higher proportion of girls in late-post puberty, compared to early-middle puberty, received social support from nonfamily adults (4.2% vs. 3.0%, p = .019). Girls identifying three sources participated in more moderate-to-vigorous PA than those having fewer sources (t1,512 = -3.57, p < .001). Various forms of social support, except for encouragement, were positively related to moderate-to-vigorous PA. Girls in early middle puberty reported greater social support than those in late-post puberty (t1,512 = 3.99, p < .001). Social support was positively associated with moderate to-vigorous PA, while girls in late-post puberty had lower moderate-to-vigorous PA than those in early-middle puberty. CONCLUSIONS: Mothers are important sources of social support for PA. Having more than two sources may result in greater PA. Encouraging girls to increase their PA may not be sufficient. CLINICAL RELEVANCE: Efforts are needed from health professionals to prevent any decline in social support for PA as girls advance across adolescence. PMID- 29266690 TI - Proton-pumping rhodopsins are abundantly expressed by microbial eukaryotes in a high-Arctic fjord. AB - Proton-pumping rhodopsins provide an alternative pathway to photosynthesis by which solar energy can enter the marine food web. Rhodopsin genes are widely found in marine bacteria, also in the Arctic, and were recently reported from several eukaryotic lineages. So far, little is known about rhodopsin expression in Arctic eukaryotes. In this study, we used metatranscriptomics and 18S rDNA tag sequencing to examine the mid-summer function and composition of marine protists (size 0.45-10 um) in the high-Arctic Billefjorden (Spitsbergen), especially focussing on the expression of microbial proton-pumping rhodopsins. Rhodopsin transcripts were highly abundant, at a level similar to that of genes involved in photosynthesis. Phylogenetic analyses placed the environmental rhodopsins within disparate eukaryotic lineages, including dinoflagellates, stramenopiles, haptophytes and cryptophytes. Sequence comparison indicated the presence of several functional types, including xanthorhodopsins and a eukaryotic clade of proteorhodopsin. Transcripts belonging to the proteorhodopsin clade were also abundant in published metatranscriptomes from other oceanic regions, suggesting a global distribution. The diversity and abundance of rhodopsins show that these light-driven proton pumps play an important role in Arctic microbial eukaryotes. Understanding this role is imperative to predicting the future of the Arctic marine ecosystem faced by a changing light climate due to diminishing sea-ice. PMID- 29266691 TI - Caecal volvulus incarcerated in the epiploic foramen. PMID- 29266692 TI - Response-adaptive designs for binary responses: How to offer patient benefit while being robust to time trends? AB - Response-adaptive randomisation (RAR) can considerably improve the chances of a successful treatment outcome for patients in a clinical trial by skewing the allocation probability towards better performing treatments as data accumulates. There is considerable interest in using RAR designs in drug development for rare diseases, where traditional designs are not either feasible or ethically questionable. In this paper, we discuss and address a major criticism levelled at RAR: namely, type I error inflation due to an unknown time trend over the course of the trial. The most common cause of this phenomenon is changes in the characteristics of recruited patients-referred to as patient drift. This is a realistic concern for clinical trials in rare diseases due to their lengthly accrual rate. We compute the type I error inflation as a function of the time trend magnitude to determine in which contexts the problem is most exacerbated. We then assess the ability of different correction methods to preserve type I error in these contexts and their performance in terms of other operating characteristics, including patient benefit and power. We make recommendations as to which correction methods are most suitable in the rare disease context for several RAR rules, differentiating between the 2-armed and the multi-armed case. We further propose a RAR design for multi-armed clinical trials, which is computationally efficient and robust to several time trends considered. PMID- 29266693 TI - Injectable hydroxyphenyl derivative of hyaluronic acid hydrogel modified with RGD as scaffold for spinal cord injury repair. AB - Hydrogel scaffolds which bridge the lesion, together with stem cell therapy represent a promising approach for spinal cord injury (SCI) repair. In this study, a hydroxyphenyl derivative of hyaluronic acid (HA-PH) was modified with the integrin-binding peptide arginine-glycine-aspartic acid (RGD), and enzymatically crosslinked to obtain a soft injectable hydrogel. Moreover, addition of fibrinogen was used to enhance proliferation of human Wharton's jelly derived mesenchymal stem cells (hWJ-MSCs) on HA-PH-RGD hydrogel. The neuroregenerative potential of HA-PH-RGD hydrogel was evaluated in vivo in acute and subacute models of SCI. Both HA-PH-RGD hydrogel injection and implantation into the acute spinal cord hemisection cavity resulted in the same axonal and blood vessel density in the lesion area after 2 and 8 weeks. HA-PH-RGD hydrogel alone or combined with fibrinogen (HA-PH-RGD/F) and seeded with hWJ-MSCs was then injected into subacute SCI and evaluated after 8 weeks using behavioural, histological and gene expression analysis. A subacute injection of both HA-PH-RGD and HA-PH-RGD/F hydrogels similarly promoted axonal ingrowth into the lesion and this effect was further enhanced when the HA-PH-RGD/F was combined with hWJ-MSCs. On the other hand, no effect was found on locomotor recovery or the blood vessel ingrowth and density of glial scar around the lesion. In conclusion, we have developed and characterized injectable HA-PH-RGD based hydrogel, which represents a suitable material for further combinatorial therapies in neural tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1129-1140, 2018. PMID- 29266694 TI - Clinical and economic impact of school-based nonavalent human papillomavirus vaccine on women in Singapore: a transmission dynamic mathematical model analysis. AB - OBJECTIVE: To examine the epidemiological and economic impact of a nine-valent (nonavalent) human papillomavirus (HPV) 6/11/16/18/31/33/45/52/58 vaccine programme for young teenagers in Singapore. DESIGN: Mathematical modelling. SETTING: Pharmaco-economic simulation projection. POPULATION: Singapore demography. METHODS: Clinical, epidemiological and financial data from Singapore were used in a validated HPV transmission dynamic mathematical model to analyse the impact of nonavalent HPV vaccination over quadrivalent and bivalent vaccines in a school-based 2-dose vaccination for 11- to 12-year-old girls in the country. The model assumed routine cytology screening in the current rate (50%) and vaccine coverage rate of 80%. MAIN OUTCOME MEASURES: Changes over a 100-year time period in the incidence and mortality rates of cervical cancer, case load of genital warts, and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with bivalent and quadrivalent HPV vaccination programmes, nonavalent HPV universal vaccination resulted in an additional reduction of HPV31/33/45/52/58 related CIN1 of 40.5%, CIN 2/3 of 35.4%, cervical cancer of 23.5%, and cervical cancer mortality of 20.2%. Compared with bivalent HPV vaccination, there was an additional reduction in HPV-6/11 related CIN1 of 75.7%, and genital warts of 78.9% in women and 73.4% in men. Over the 100 years, after applying a discount of 3%, disease management cost will be reduced by 32.5% (versus bivalent) and 7.5% (versus quadrivalent). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year gained was SGD 929 compared with bivalent vaccination and SGD 9864 compared with quadrivalent vaccination. CONCLUSION: Universal two dose nonavalent HPV vaccination for 11- to 12-year-old adolescent women is very cost-effective in Singapore. TWEETABLE ABSTRACT: Nonavalent HPV vaccination of 11 to 12-year-old girls is cost-effective in Singapore. PMID- 29266695 TI - Visual and tactile feedback for a direct-manipulating tactile sensor in laparoscopic palpation. AB - BACKGROUND: A surgeon's tactile sense can contribute to intraoperative tumor detection, but it is limited by laparoscopic surgery. METHODS: We have developed a simple and biocompatible tactile sensor. This study aimed to design and evaluate visual and tactile feedback from the sensor for laparoscopic tumor detection. A line graph was offered through a monitor as the visual feedback. A normal force was presented to the user's foot as the tactile feedback. Twelve novices conducted a task of detecting a phantom tumor under 4 conditions (no feedback, visual feedback, tactile feedback and a combination of both types of feedback). RESULTS: The visual feedback was significantly more effective in detection than no feedback. Moreover, both visual and tactile feedback led to safer manipulation with significantly smaller load and lower scanning speed, respectively. CONCLUSIONS: The results suggest that visual and tactile feedback can be useful for laparoscopic palpation; however, their effects depend on the means in which they are presented. PMID- 29266696 TI - Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly. AB - Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin-like growth factor 1 (IGF-I). Elevated GH and IGF-I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1-5) and dopamine receptors (DRD1-5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs. PMID- 29266698 TI - Skin colour assessment of replanted fingers in digital images and its reliability for the incorporation of images in nursing progress notes. AB - AIMS AND OBJECTIVES: To determine whether nurses can accurately assess the skin colour of replanted fingers displayed as digital images on a computer screen. BACKGROUND: Colour measurement and clinical diagnostic methods for medical digital images have been studied, but reproducing skin colour on a computer screen remains difficult. DESIGN: The inter-rater reliability of skin colour assessment scores was evaluated. In May 2014, 21 nurses who worked on a trauma ward in Japan participated in testing. METHODS: Six digital images with different skin colours were used. Colours were scored from both digital images and direct patient's observation. The score from a digital image was defined as the test score, and its difference from the direct assessment score as the difference score. Intraclass correlation coefficients were calculated. Nurses' opinions were classified and summarised. RESULTS: The intraclass correlation coefficients for the test scores were fair. Although the intraclass correlation coefficients for the difference scores were poor, they improved to good when three images that might have contributed to poor reliability were excluded. Most nurses stated that it is difficult to assess skin colour in digital images; they did not think it could be a substitute for direct visual assessment. However, most nurses were in favour of including images in nursing progress notes. DISCUSSION: Although the inter-rater reliability was fairly high, the reliability of colour reproduction in digital images as indicated by the difference scores was poor. Nevertheless, nurses expect the incorporation of digital images in nursing progress notes to be useful. This gap between the reliability of digital colour reproduction and nurses' expectations towards it must be addressed. CONCLUSIONS: High inter-rater reliability for digital images in nursing progress notes was not observed. Assessments of future improvements in colour reproduction technologies are required. RELEVANCE TO CLINICAL PRACTICE: Further digitisation and visualisation of nursing records might pose challenges. PMID- 29266697 TI - Expression of the glutamine metabolism-related proteins glutaminase 1 and glutamate dehydrogenase in canine mammary tumours. AB - Glutamine metabolism is an important metabolic pathway for cancer cell survival, and there is a critical connection between tumour growth and glutamine metabolism. Because of their similarities, canine mammary carcinomas are useful for studying human breast cancer. Accordingly, we investigated the correlations between the expression of glutamine metabolism-related proteins and the pathological features of canine mammary tumours. We performed immunohistochemical and western blot analysis of 39 mammary tumour tissues. In immunohistochemical analysis, the expression of glutaminase 1 (GLS1) in the epithelial region increased according to the histological grade (P < .005). In the stromal region, complex-type tumours displayed significantly higher GLS1 intensity than simple type tumours. However, glutamate dehydrogenase expression did not show the same tendencies as GLS1. The western blot results were consistent with the immunohistochemical findings. These results suggest that the expression of GLS1 is correlates with clinicopathological factors in canine mammary tumours and shows a similar pattern to human breast cancer. PMID- 29266700 TI - Jejunal diverticulitis secondary to enterolith: a case report. PMID- 29266699 TI - Characterisation of imidacloprid resistance in the bird cherry-oat aphid, Rhopalosiphum padi, a serious pest on wheat crops. AB - BACKGROUND: Rhopalosiphum padi is a destructive insect pest of wheat worldwide. Studies have shown that R. padi has developed resistance to different insecticides, including imidacloprid. We studied the mechanisms conferring resistance to imidacloprid at the biochemical and molecular levels. RESULTS: An R. padi imidacloprid-resistant (IM-R) strain and a susceptible (SS) strain were established. Fitness analysis using life-tables showed that the IM-R strain had obvious disadvantages in several parameters, indicating reduced fitness. Profiles of cross-resistance of IM-R and SS to seven insecticides were detected. Both synergistic and enzyme activity data suggested that P450 plays a role in resistance. Furthermore, the mRNA expression levels of cytochrome P450 (CYP) genes CYP6CY3-1 and CYP6CY3-2 were significantly increased in the IM-R strain. No target-site mutation within the nicotinic acetylcholine receptor (nAChR) subunits was detected in the IM-R strain. Interestingly, the expression levels of the nAChR alpha1, alpha2, alpha3, alpha7-2, and beta1 subunit genes were significantly decreased, suggesting that down-regulation of these subunits may be involved in resistance. CONCLUSION: Multiple mechanisms confer imidacloprid resistance in R. padi. (c) 2017 Society of Chemical Industry. PMID- 29266701 TI - Hydoxyapatite/beta-tricalcium phosphate biphasic ceramics as regenerative material for the repair of complex bone defects. AB - Bone is a composite material composed of collagen and calcium phosphate (CaP) mineral. The collagen gives bone its flexibility while the inorganic material gives bone its resilience. The CaP in bone is similar in composition and structure to the mineral hydroxyapatite (HA) and is bioactive, osteoinductive and osteoconductive. Therefore synthetic versions of bone apatite (BA) have been developed to address the demand for autologous bone graft substitutes. Synthetic HA (s-HA) are stiff and strong, but brittle. These lack of physical attributes limit the use of synthetic apatites in situations where no physical loading of the apatite occurs. s-HA chemical properties differ from BA and thus change the physical and mechanical properties of the material. Consequently, s-HA is more chemically stable than BA and thus its resorption rate is slower than the rate of bone regeneration. One solution to this problem is to introduce a faster resorbing CaP, such as beta-tricalcium phosphate (beta-TCP), when synthesizing the material creating a biphasic (s-HA and beta-TCP) formulation of calcium phosphate (BCP). The focus of this review is to introduce the major differences between BCP and biological apatites and how material scientists have overcome the inadequacies of the synthetic counterparts. Examples of BCP performance in vitro and in vivo following structural and chemical modifications are provided as well as novel ultrastructural data. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2493-2512, 2018. PMID- 29266703 TI - Stenting and overdilating small Gore-Tex vascular grafts in complex congenital heart disease. AB - BACKGROUND: Gore-Tex(r) grafts are integral in the management of congenital heart disease. Issues of graft stenosis or somatic outgrowth may precipitate high-risk early surgery, and catheter intervention is a relatively under-reported management option. OBJECTIVES: To assess efficacy, safety, and outcomes of stenting and overdilating small Gore-Tex(r) vascular grafts with the aim of optimizing surgical timing. METHODS: Retrospective analysis of single-center, 13 year experience of 93 graft stenting interventions or reintervention in 80 patients, with the aim of relieving stenosis +/- overdilation, to depose surgical graft revision or optimize surgical timing and candidacy. RESULTS: Median preintervention graft diameter was 52% (IQR 43-63) of nominal size, postintervention this increased to median 102% (IQR 96-120) [P < 0.001]. Overdilation was achieved in 54%; of these, the median final internal lumen was 126% (IQR 113-132) [P < 0.001]. Mean oxygen saturations increased from 69% to 82% [P < 0.001]. Adverse event rate was 14.9%; this includes mortality (3.2%) and atrioventricular conduction block (8.5%). Univariate analysis and logistic regression showed a significant relationship between adverse events and young age [P < 0.01], low weight [P < 0.01], univentricular physiology [P < 0.001], use of femoral venous access alone [P = 0.03], and intervention on a right ventricle to pulmonary artery conduit [P = 0.03]. Within respective indication groups, 74% were bridged to elective cavopulmonary shunt, 95% were bridged to biventricular surgery, and 78% of long-term palliative care patients continue under follow-up. CONCLUSIONS: Gore-Tex(r) vascular grafts can be stented effectively and expanded beyond nominal diameters by around +26%. This improves oxygen saturations, providing excellent palliation and optimized surgical timing. Adverse events are most frequent in precavopulmonary shunt patients. CONDENSED ABSTRACT: Gore-Tex(r) grafts are widely used in the palliation of cyanotic congenital heart disease. Grafts may become stenosed and do not allow for somatic growth. Over a 13 year period, graft stenting was performed in 80 patients (93 technically successful interventions, 4 unsuccessful.) Median internal lumen change was +50% (of nominal graft size), mean oxygen saturation change +13%. Over-dilation was performed in more than half of the cohort, with a median gain of +26% on nominal graft size. In precavopulmonary shunt patients, there was a moderate incidence of serious complications. Clinically useful deferral of surgery was achieved for the majority. PMID- 29266702 TI - Predicting childhood overweight and obesity using maternal and early life risk factors: a systematic review. AB - BACKGROUND: Childhood obesity is a serious public health challenge, and identification of high-risk populations with early intervention to prevent its development is a priority. We aimed to systematically review prediction models for childhood overweight/obesity and critically assess the methodology of their development, validation and reporting. METHODS: Medline and Embase were searched systematically for studies describing the development and/or validation of a prediction model/score for overweight and obesity between 1 to 13 years of age. Data were extracted using the Cochrane CHARMS checklist for Prognosis Methods. RESULTS: Ten studies were identified that developed (one), developed and validated (seven) or externally validated an existing (two) prediction model. Six out of eight models were developed using automated variable selection methods. Two studies used multiple imputation to handle missing data. From all studies, 30,475 participants were included. Of 25 predictors, only seven were included in more than one model with maternal body mass index, birthweight and gender the most common. CONCLUSION: Several prediction models exist, but most have not been externally validated or compared with existing models to improve predictive performance. Methodological limitations in model development and validation combined with non-standard reporting restrict the implementation of existing models for the prevention of childhood obesity. PMID- 29266704 TI - Rhodium-Catalyzed Enantioposition-Selective Hydroarylation of Divinylphosphine Oxides with Aryl Boroxines. AB - The rhodium-catalyzed hydroarylation of divinylphosphine oxides (RP(O)(CH=CH2 )2 ) with aryl boroxines ((ArBO)3 ) gives the corresponding monoarylation products (RP(O)(CH=CHAr)CH2 CH3 ) in high yields. One of the two vinyl groups in the phosphine oxide undergoes oxidative arylation while the other one is reduced to an ethyl moiety. These reactions proceed with high selectivity in terms of the enantiotopic vinyl groups in the presence of (R)-DTBM-segphos/Rh to give the P stereogenic monoarylation products with high enantioselectivity. PMID- 29266705 TI - Re: Effect of locally-tailored labour management guidelines on intrahospital stillbirths and birth asphyxia at the referral hospital of Zanzibar: a quasi experimental pre-post-study (The PartoMa study). PMID- 29266706 TI - Neobodonids are dominant kinetoplastids in the global ocean. AB - Kinetoplastid flagellates comprise basal mostly free-living bodonids and derived obligatory parasitic trypanosomatids, which belong to the best-studied protists. Due to their omnipresence in aquatic environments and soil, the bodonids are of ecological significance. Here, we present the first global survey of marine kinetoplastids and compare it with the strikingly different patterns of abundance and diversity in their sister clade, the diplonemids. Based on analysis of 18S rDNA V9 ribotypes obtained from 124 sites sampled during the Tara Oceans expedition, our results show generally low to moderate abundance and diversity of planktonic kinetoplastids. Although we have identified all major kinetoplastid lineages, 98% of kinetoplastid reads are represented by neobodonids, namely specimens of the Neobodo and Rhynchomonas genera, which make up 59% and 18% of all reads, respectively. Most kinetoplastids have small cell size (0.8-5 um) and tend to be more abundant in the mesopelagic as compared to the euphotic zone. Some of the most abundant operational taxonomic units have distinct geographical distributions, and three novel putatively parasitic neobodonids were identified, along with their potential hosts. PMID- 29266707 TI - The Role of [BF4 ]- and [B(CN)4 ]- Anions in the Ionothermal Synthesis of Chalcogenidometalates. AB - The role of borate anions in ionothermal syntheses of crystalline chalcogenidometalates was shown by the directed ionothermal synthesis of seven new selenidostannates in ionic liquids with either [BF4 ]- or [B(CN)4 ]- anions. Single crystal structures are presented of four compounds, (C4 C1 C1 Im)5 [Sn9 Se20 ][BF4 ] (1, Im=imidazolium), (DMMPH)4 [Sn2 Se6 ] (2, DMMP=2,6 dimethylmorpholine), (C2 C1 Im)2 (DMMPH)2 [Sn6 Se14 ] (3), and K2 [Sn3 Se7 ] (4), and how the chosen ionic liquid anion, and the reaction temperature, influences the product spectrum is discussed: Notably, 1 contains an entire formula unit of the ionic liquid, (C4 C1 C1 Im)[BF4 ], while 4 contains neither the cation nor the anion of the ionic liquid-both observations being very uncommon for ionothermal syntheses. Three further compounds were obtained that exhibit strong disorder in the crystal structures (I-III), for which only their anionic substructures are discussed herein. Compound 4 and I-III are based on the same layered selenidostannate substructure, 2D-{[Sn3 Se7 ]2- }, yet with different inter-layer distances, which is clearly reflected in the crystal colors and quantitative optical absorption properties. PMID- 29266708 TI - Nanocomposite Materials for the Sodium-Ion Battery: A Review. AB - Clean energy has become an important topic in recent decades because of the serious global issues related to the development of energy, such as environmental contamination, and the intermittence of the traditional energy sources. Creating new battery-related energy storage facilities is an urgent subject for human beings to address and for solutions for the future. Compared with lithium-based batteries, sodium-ion batteries have become the new focal point in the competition for clean energy solutions and have more potential for commercialization due to the huge natural abundance of sodium. Nevertheless, sodium-ion batteries still exhibit some challenges, like inferior electrochemical performance caused by the bigger ionic size of Na+ ions, the detrimental volume expansion, and the low conductivity of the active materials. To solve these issues, nanocomposites have recently been applied as a new class of electrodes to enhance the electrochemical performance in sodium batteries based on advantages that include the size effect, high stability, and excellent conductivity. In this Review, the recent development of nanocomposite materials applied in sodium-ion batteries is summarized, and the existing challenges and the potential solutions are presented. PMID- 29266709 TI - Gallic acid attenuates calcium calmodulin-dependent kinase II-induced apoptosis in spontaneously hypertensive rats. AB - Hypertension causes cardiac hypertrophy and leads to heart failure. Apoptotic cells are common in hypertensive hearts. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) is associated with apoptosis. We recently demonstrated that gallic acid reduces nitric oxide synthase inhibition-induced hypertension. Gallic acid is a trihydroxybenzoic acid and has been shown to have beneficial effects, such as anti-cancer, anti-calcification and anti-oxidant activity. The purpose of this study was to determine whether gallic acid regulates cardiac hypertrophy and apoptosis in essential hypertension. Gallic acid significantly lowered systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs). Wheat germ agglutinin (WGA) and H&E staining revealed that gallic acid reduced cardiac enlargement in SHRs. Gallic acid treatment decreased cardiac hypertrophy marker genes, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), in SHRs. The four isoforms, alpha, beta, delta and gamma, of CaMKII were increased in SHRs and were significantly reduced by gallic acid administration. Gallic acid reduced cleaved caspase-3 protein as well as bax, p53 and p300 mRNA levels in SHRs. CaMKII delta overexpression induced bax and p53 expression, which was attenuated by gallic acid treatment in H9c2 cells. Gallic acid treatment reduced DNA fragmentation and the TUNEL positive cells induced by angiotensin II. Taken together, gallic acid could be a novel therapeutic for the treatment of hypertension through suppression of CaMKII delta-induced apoptosis. PMID- 29266710 TI - Contact networks structured by sex underpin sex-specific epidemiology of infection. AB - Contact networks are fundamental to the transmission of infection and host sex often affects the acquisition and progression of infection. However, the epidemiological impacts of sex-related variation in animal contact networks have rarely been investigated. We test the hypothesis that sex-biases in infection are related to variation in multilayer contact networks structured by sex in a population of European badgers Meles meles naturally infected with Mycobacterium bovis. Our key results are that male-male and between-sex networks are structured at broader spatial scales than female-female networks and that in male-male and between-sex contact networks, but not female-female networks, there is a significant relationship between infection and contacts with individuals in other groups. These sex differences in social behaviour may underpin male-biased acquisition of infection and may result in males being responsible for more between-group transmission. This highlights the importance of sex-related variation in host behaviour when managing animal diseases. PMID- 29266711 TI - Associations of Nurse Staffing and Education With the Length of Stay of Surgical Patients. AB - PURPOSE: To examine the association of nurse staffing and education with the length of stay of surgical patients in acute care hospitals in South Korea. DESIGN: A cross-sectional survey design was used for a nurse survey in acute hospitals collected between 2008 and 2009. The survey data (N = 1,665) were linked with patient discharge data (N = 113,438) and hospital facility data from 58 hospitals with 100 or more beds in South Korea. METHODS: The dependent variable was the length of stay, that is, the number of days a patient remained in the hospital. The independent variables were nurse staffing (number of patients per nurse) and nurses' education level (percentage of nurses with a bachelor of science in nursing [BSN] degree). A multilevel analysis was used to analyze the associations of nurse staffing and education level with the length of stay by controlling for both hospital and patient characteristics. FINDINGS: The average proportion of nurses with a BSN in all the hospitals was 30.86%, while the average number of patients per nurse was 14.31. The median length of hospital stay for patients was about 7 days. The multilevel analysis showed that nurse staffing and nurse education level were significantly associated with the length of stay of surgical patients in acute care hospitals. A 10% increase in the average number of patients per nurse increased the length of stay by 0.284 days (p = .037). When the number of nurses with a BSN was increased by 1%, the length of stay decreased by 0.42 days (p = .025). CONCLUSIONS: Nurse staffing and nurses' education levels were significantly associated with the length of stay of surgical patients in South Korean hospitals. The findings from this study suggest that the South Korea healthcare system should develop appropriate strategies to improve the nurse staffing and education levels to ensure high-quality patient care in hospitals. CLINICAL RELEVANCE: Healthcare policymakers and nurse managers need to modify adequate nurse staffing and education levels in order to reduce the length of stay of patients. PMID- 29266712 TI - The Efficacy of Nanoemulsion-Based Delivery to Improve Vitamin D Absorption: Comparison of In Vitro and In Vivo Studies. AB - SCOPE: Vitamin D (VD) is a fat-soluble vitamin that has a wide range of skeletal and non-skeletal functions. Although it can be synthesized through sun exposure and obtained from fortified foods, VD inadequacy is epidemic worldwide. Therefore innovative strategies are necessary for improving VD status. The present study examined VD absorption via nanoscale delivery systems. METHODS AND RESULTS: We examine the physical characteristics and in vitro bioaccessibility of cholecalciferol (VD3 ) in nanoemulsion using a simulated gastrointestinal tract system. To evaluate the in vivo bioavailability, we orally administer three groups of mice with VD3 nanoemulsion, VD3 coarse emulsion, or vehicle nanoemulsion without VD3 , and the serum 25(OH)D3 is measured using radioactive immunoassay. The nanoemulsion-based delivery system increases the in vitro bioaccessibility by 3.94-folds (p < 0.05), as indicated by the concentration of vitamin D3 in micelles. Our animal study shows that, when compared to the vehicle group, the coarse emulsion numerically increases the serum 25(OH)D3 by 36%, whereas the nanoemulsion statistically significantly increases the serum 25(OH)D3 by 73% (p < 0.01). CONCLUSION: Our findings indicate that a nanoemulsion-based delivery system is a promising approach to improve VD bioavailability, and further studies are warranted to determine its efficacy in humans. PMID- 29266713 TI - Testosterone regulates the expression and functional activity of sphingosine-1 phosphate receptors in the rat corpus cavernosum. AB - The bioactive lipid sphingosine-1-phosphate (S1P) regulates smooth muscle (SM) contractility predominantly via three G protein-coupled receptors. The S1P1 receptor is associated with nitric oxide (NO)-mediated SM relaxation, while S1P2 & S1P3 receptors are linked to SM contraction via activation of the Rho-kinase pathway. This study is to determine testosterone (T) modulating the expression and functional activity of S1P receptors in corpus cavernosum (CC). Adult male Sprague-Dawley rats were randomly divided into three groups: sham-operated controls, surgical castration and T supplemented group. Serum S1P levels were detected by high-performance liquid chromatography. The expression of S1P1-3 receptors and sphingosine kinases was detected by real-time RT-PCR. In vitro organ bath contractility and in vivo intracavernous pressure (ICP) measurement were also performed. T deprivation significantly decreased ICP rise. Meanwhile, surgical castration induced a significant increase in serum S1P level and the expression of S1P2-3 receptors by twofold (P < 0.05) but a decrease in the expression of S1P1 receptor. Castration also augmented exogenous phenylephrine (PE), S1P, S1P1,3 receptor agonist FTY720-P contractility and S1P2-specific antagonist JTE013 relaxation effect. T supplemented could restore the aforementioned changes. We provide novel data that castration increased serum S1P concentration and up-regulated the expression of S1P2-3 receptors in CC. Consistently, agonizing S1P receptors induced CCSM contraction and antagonizing mediated relaxation were augmented. This provides the first clear evidence that S1P system dysregulation may contribute to hypogonadism-related erectile dysfunction (ED), and S1P receptors may be expected as a potential target for treating ED. PMID- 29266715 TI - Cryopreservation (-20 degrees C) of canine corneoscleral tissue: histological, microbiological, and ultrastructural study. AB - OBJECTIVE: To evaluate microbiological, histological, and ultrastructural characteristics of short-term cryopreserved (STC) canine corneoscleral tissue (<1 year) and to compare it with long-term cryopreserved (LTC) tissue (>6 years). ANIMALS STUDIED: Thirty-six healthy canine globes. PROCEDURE: After a decontamination protocol, globes were enucleated and stored at -20 degrees C. Corneoscleral tissue was evaluated at different periods: <1 year (20 eyes) and >6 years (12 eyes). Four eyes were used as controls. Microbiologic study included direct (blood, McConkey and Sabouraud agars) and enrichment (brain-heart infusion broth) cultures. Cryopreservation artifacts were evaluated by hematoxylin-eosin. Corneoscleral collagen organization and number of normal and dead keratocytes were established by transmission electron microscopy (TEM). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was also used for keratocyte characterization. RESULTS: Corneal microbial growth was observed in 25% of the direct STC cultures, and in 47.4% and 16.7% of the enriched STC and LTC cultures, respectively. Scleral STC direct cultures were 30% positive, while enrichment cultures were positive in 66.7% and 16.7% of the STC and LTC, respectively (P = 0.011). Cryopreservation artifacts were higher in LTC tissues (P < 0.001). Apoptotic keratocytes were predominant by TEM and TUNEL, in both STC and LTC. Minimal structural differences were detected in collagen organization between STC and LTC. CONCLUSIONS: Cryopreservation of canine corneoscleral tissue seems to reduce bacterial contamination over time. Apoptosis is the main way of death of cryopreserved canine keratocytes. Based on the lack of significant structural differences between STC and LTC samples, these cryopreserved tissues could potentially be used for tectonic support for at least 8 years without structural or microbiological impediment. PMID- 29266716 TI - Evaluation of an Intervention With Nurses for Delirium Detection After Cardiac Surgery. AB - BACKGROUND: Completion of a delirium detection tool allows rapid management, which alleviates complications. However, these tools are often underused. AIMS: To assess the effect of a knowledge transfer (KT) intervention on the completion of a delirium detection tool by nurses working with cardiac surgery patients. Secondary aims included describing completion rates per work shift, and patient characteristics associated with higher rates. METHODS: In a pre-post study, the intervention included a survey and focus groups to identify barriers to use of a delirium detection tool (Intensive Care Delirium Screening Checklist [ICDSC]). Nurses' suggestions for a KT activity and its implementation were also included. Using chi-square analysis and medical charts from 242 patients, we compared the pre- and postintervention rates of completion of the ICDSC. RESULTS: The majority of nurses who completed the survey (n = 30) felt they had the knowledge, skills, and intention to complete the ICDSC. During the focus groups (n = 4), a need for information on delirium symptoms and its management was raised as a barrier. This barrier was addressed with the selected KT activity (clinical capsule and aide memoire handed out to nurses [n = 24]). Across all work shifts, the completion rate was similar pre- and postintervention. Overall, the completion rate was lower during the day shift than the night and evening shifts. A higher rate was associated with the first three postoperative days, and longer hospital and intensive care unit stays. LINKING EVIDENCE TO ACTION: A tailored intervention based on preidentified barriers and facilitators, using the Determinants of Implementation Behavior Questionnaire, and in collaboration with participants, has the potential to promote evidence-based practice. PMID- 29266714 TI - Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities. AB - Mutant mouse models of neurodevelopmental disorders with intellectual disabilities provide useful translational research tools, especially in cases where robust cognitive deficits are reproducibly detected. However, motor, sensory and/or health issues consequent to the mutation may introduce artifacts that preclude testing in some standard cognitive assays. Touchscreen learning and memory tasks in small operant chambers have the potential to circumvent these confounds. Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2Bird mouse model of Rett syndrome. Significant deficits in acquisition of a 2-choice visual discrimination task were detected in both Ube3a and Ts65Dn mice. Procedural control measures showed no genotype differences during pretraining phases or during acquisition. Mecp2 males did not survive long enough for touchscreen training, consistent with previous reports. Most Mecp2 females failed on pretraining criteria. Significant impairments on Morris water maze spatial learning were detected in both Ube3a and Ts65Dn, replicating previous findings. Abnormalities on rotarod in Ube3a, and on open field in Ts65Dn, replicating previous findings, may have contributed to the observed acquisition deficits and swim speed abnormalities during water maze performance. In contrast, these motor phenotypes do not appear to have affected touchscreen procedural abilities during pretraining or visual discrimination training. Our findings of slower touchscreen learning in 2 mouse models of neurodevelopmental disorders with intellectual disabilities indicate that operant tasks offer promising outcome measures for the preclinical discovery of effective pharmacological therapeutics. PMID- 29266717 TI - Efficient preparative separation of beta-cypermethrin stereoisomers by supercritical fluid chromatography with a two-step combined strategy. AB - An efficient two-step method has been developed for the separation of beta cypermethrin stereoisomers by supercritical fluid chromatography with polysaccharide chiral stationary phases. With respect to retention, selectivity, and resolution of beta-cypermethrin, the effects of chiral stationary phases, cosolvents, mobile phases, and column temperature have been studied in detail. Through a two-step separation, beta-cypermethrin was firstly separated by using a cellulose-derived chiral stationary phase to obtain two stereoisomeric pairs, and further resolved on an amylose-based chiral stationary phase to produce four enantiopure stereoisomers. The electronic circular dichroism patterns of the first- and the third-eluted isomers in methanol solution showed the mirror image of each other in the wavelength range 200~300 nm, indicating that they were a pair of enantiomers. Moreover, the second- and the fourth-eluted isomers were also enantiomers. This proposed two-step strategy showed low solvent consumption, fast separation speed, and high-purity, which may provide an effective approach for preparative separation of compounds with multiple chiral centers and difficult-to-separate multicomponent samples. PMID- 29266718 TI - Development of electrospun poly (vinyl alcohol)-based bionanocomposite scaffolds for bone tissue engineering. AB - The article is focused on the role of nanohydroxy apatite (nHAp) and cellulose nanofibers (CNFs) as fillers in the electrospun poly (vinyl alcohol) (ES-PVA) nanofibers for bone tissue engineering (TE). Fibrous scaffolds of PVA, PVA/nHAp (10 wt.%), and PVA/nHAp(10 wt.%)/CNF(3 wt.%) were successfully fabricated and characterized. Tensile test on electrospun PVA/nHAp10 and PVA/nHAp10/CNF3 revealed a three-fold and seven-fold increase in modulus compared with pure ES PVA (45.45 +/- 4.77). Although, nanofiller loading slightly reduced the porosity percentage, all scaffolds had porosity higher than 70%. In addition, contact angle test proved the great hydrophilicity of scaffolds. The presence of fillers reduced in vitro biodegradation rate in PBS while accelerates biomineralization in simulated body fluid (SBF). Furthermore, cell viability, cell attachment, and functional activity of osteoblast MG-63 cells were studied on scaffolds showing higher cellular activity for scaffolds with nanofillers. Generally, the obtained results confirm that the 3-componemnt fibrous scaffold of PVA/nHAp/CNF has promising potential in hard TE. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1111-1120, 2018. PMID- 29266719 TI - Improved perioperative outcomes of laparoscopic distal pancreatosplenectomy: modified lasso technique. AB - BACKGROUND: Simultaneous division of the splenic artery, splenic vein and pancreatic parenchyma during laparoscopic distal pancreatosplenectomy (LDPS) is known as the lasso technique, which is considered to be simple to perform. However, the original lasso technique carries a risk of post-operative bleeding from the splenic artery. We modified the original lasso technique to improve its technical safety and compared the perioperative outcomes of LDPS performed with the modified lasso technique (ml-LDPS) with those of conventional LDPS (c-LDPS). METHODS: From August 2006 to July 2016, 30 patients underwent c-LDPS and 31 patients underwent ml-LDPS for distal pancreatectomy involving <50% of the pancreas. The perioperative outcomes of the two groups were compared. RESULTS: The ml-LDPS technique resulted in a shorter operation time (201 min versus 162 min, P < 0.01), less intraoperative blood loss (20 mL versus 200 mL, P < 0.01), a shorter post-operative hospital stay (8.0 days versus 12.5 days, P < 0.01), and a lower incidence of clinically relevant post-operative pancreatic fistulas (6.5% versus 26.7%, P = 0.04) compared with c-LDPS. The surgical approach (c-LDPS or ml LDPS) was identified as an independent predictor of the development of clinically relevant post-operative pancreatic fistulas via multivariate analysis. CONCLUSION: The ml-LDPS method had beneficial effects on the operation time, intraoperative bleeding, the post-operative morbidity rate and the length of the post-operative hospital stay. The ml-LDPS procedure is a simple, safe and effective way of performing planned LDPS. PMID- 29266720 TI - Resilience as a Moderator of Psychological Health in Situations of Chronic Stress (Burnout) in a Sample of Hospital Nurses. AB - OBJECTIVES: To analyze the role played by resilience in the dimensions that constitute burnout syndrome and, through that, the psychological health of a sample of nurses working at hospital centers. METHODS: Cross-sectional design, with a questionnaire as the tool. The sample consisted of 537 nurses from three public hospitals in Murcia, Spain. The questionnaire contained measures of the following variables: resilience, the three dimensions of burnout (emotional exhaustion, cynicism, and professional efficacy), and general psychological health, as well as sociodemographic and employment information. RESULTS: The emotional exhaustion and cynicism dimensions of burnout were significantly linked to psychological health in the manner expected, but this was not the case for professional efficacy. A stepwise multiple regression analysis revealed the moderating role of resilience on the emotional exhaustion and cynicism dimensions, as well as on psychological health. CONCLUSIONS AND CLINICAL RELEVANCE: This study highlights the moderating role of resilience on burnout and psychological health. The practical implications of the results are discussed for the implementation of measures to increase resilience as a personal resource in order to improve the health and work performance of these professionals. PMID- 29266721 TI - Reducing Drosophila suzukii emergence through inter-species competition. AB - BACKGROUND: Drosophila suzukii has dispersed widely from its native Asian range since 2008. Its arrival in the UK is resulting in economic losses in soft- and stone-fruit crops caused by larvae feeding on the flesh of ripening fruit. Although a large amount of research has been directed at controlling this pest, it is presently unknown how this invasive species interacts with native Drosophila species. RESULTS: In the work reported here, D. suzukii or Drosophila melanogaster adults were introduced to substrates pre-inoculated with the eggs of the same or the other species in a laboratory choice assay. Drosophila melanogaster adult emergence was not affected by pre-inoculation with D. suzukii. The rate of emergence of D. suzukii was significantly lower from medium pre inoculated by D. melanogaster than from blank medium. In a subsequent experiment, significantly more D. suzukii eggs were laid in blank medium than in D. melanogaster pre-inoculated medium. CONCLUSION: The presence of D. melanogaster in a substrate significantly reduced D. suzukii emergence and egg laying. This study raises research questions about how this reduction mechanism is driven and how it could be exploited as part of future integrated pest management practices. (c) 2017 Society of Chemical Industry. PMID- 29266722 TI - Impact of resection and ablation for single hypovascular hepatocellular carcinoma <=2 cm analysed with propensity score weighting. AB - BACKGROUND AND AIMS: Small hypovascular hepatocellular carcinoma (HCC) <=2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. METHODS: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC <=2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients. RESULTS: The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred. CONCLUSIONS: For patients with single hypovascular HCC <=2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA. PMID- 29266723 TI - Gold Nanoparticle-Based Paper Sensor for Simultaneous Detection of 11 Benzimidazoles by One Monoclonal Antibody. AB - A colloidal gold immunochromatographic assay based on a generic monoclonal antibody is developed for the simultaneous detection of benzimidazoles and metabolite residues in milk samples. The monoclonal antibody is prepared using 2 (methoxycarbonylamino)-3H-benzimidazole-5-carboxylic acid as the hapten, and it can recognize 11 types of benzimidazoles simultaneously. The immunochromatographic strip is assembled and labeled using gold nanoparticles. This strip can detect 11 benzimidazoles including albendazole, albendazole s oxide, albendazole sulfone, fenbendazole, fenbendazole sulfone, flubendazole, mebendazole, parbendazole, oxfendazole, oxibendazole, and carbendazim within 15 min in milk samples. Results are obtained visually with the naked eye, and the cutoff values and the visual limit of detection values for these benzimidazoles are 25, 6.25, 12.5, 12.5, 50, 25, 50, 50, 50, 6.25, and 25 ng mL-1 , and 6.25, 3.125, 3.125, 1.56, 12.5, 6.25, 12.5, 12.5, 6.25, 0.78, and 12.5 ng mL-1 , respectively. Results are also obtained using a hand-held strip scan reader, with calculated limit of detection values for these benzimidazoles of 0.83, 0.77, 1.83, 0.98, 7.67, 3.50, 3.96, 5.71, 0.92, 0.59, and 1.69 ng mL-1 , respectively. In short, the developed paper sensor is a useful tool for rapid and simple screening of residues of benzimidazoles in milk samples. PMID- 29266724 TI - Assessment of quantification accuracy and image quality of a full-body dual-layer spectral CT system. AB - The performance of a recently introduced spectral computed tomography system based on a dual-layer detector has been investigated. A semi-anthropomorphic abdomen phantom for CT performance evaluation was imaged on the dual-layer spectral CT at different radiation exposure levels (CTDIvol of 10 mGy, 20 mGy and 30 mGy). The phantom was equipped with specific low-contrast and tissue equivalent inserts including water-, adipose-, muscle-, liver-, bone-like materials and a variation in iodine concentrations. Additionally, the phantom size was varied using different extension rings to simulate different patient sizes. Contrast-to-noise (CNR) ratio over the range of available virtual mono energetic images (VMI) and the quantitative accuracy of VMI Hounsfield Units (HU), effective-Z maps and iodine concentrations have been evaluated. Central and peripheral locations in the field-of-view have been examined. For all evaluated imaging tasks the results are within the calculated theoretical range of the tissue-equivalent inserts. Especially at low energies, the CNR in VMIs could be boosted by up to 330% with respect to conventional images using iDose/spectral reconstructions at level 0. The mean bias found in effective-Z maps and iodine concentrations averaged over all exposure levels and phantom sizes was 1.9% (eff. Z) and 3.4% (iodine). Only small variations were observed with increasing phantom size (+3%) while the bias was nearly independent of the exposure level (+/-0.2%). Therefore, dual-layer detector based CT offers high quantitative accuracy of spectral images over the complete field-of-view without any compromise in radiation dose or diagnostic image quality. PMID- 29266725 TI - Support for alcohol policies among drinkers in Mongolia, New Zealand, Peru, South Africa, St Kitts and Nevis, Thailand and Vietnam: Data from the International Alcohol Control Study. AB - INTRODUCTION AND AIMS: A 2010 World Health Assembly resolution called on member states to intensify efforts to address alcohol-related harm. Progress has been slow. This study aims to determine the magnitude of public support for 12 alcohol policies and whether it differs by country, demographic factors and drinking risk (volume consumed). DESIGN AND METHODS: Data are drawn from seven countries participating in the International Alcohol Control Study which used country specific sampling methods designed to obtain random, representative samples. The weighted total sample comprised 11 494 drinkers aged 16-65 years. RESULTS: Drinking risk was substantial (24% 'increased' risk and 16% 'high' risk) and was particularly high in South Africa. Support varied by alcohol policy, ranging from 12% to 96%, but was above 50% for 79% of the possible country/policy combinations. Across countries, policy support was generally higher for policies addressing drink driving and increasing the alcohol purchase age. There was less support for policies increasing the price of alcohol, especially when funds were not earmarked. Policy support differed by country, and was generally higher in the five middle-income countries than in New Zealand. It also differed by age, gender, education, quantity/frequency of drinking, risk category and country income level. DISCUSSION AND CONCLUSIONS: We found a trend in policy support, generally being highest in the low-middle-income countries, followed by high middle-income countries and then high-income countries. Support from drinkers for a range of alcohol policies is extensive across all countries and could be used as a catalyst for further policy action. PMID- 29266726 TI - The 745.5 issue in code-based, adult congenital heart disease population studies: Relevance to current and future ICD-9-CM and ICD-10-CM studies. AB - OBJECTIVE: Although the ICD-9-CM code 745.5 is widely used to indicate the presence of a secundum atrial septal defect (ASD), it is also used for patent foramen ovale (PFO) which is a normal variant and for "rule-out" congenital heart disease (CHD). The ICD-10-CM code Q21.1 perpetuates this issue. The objective of this study was to assess whether code 745.5 in isolation or in combination with unspecified CHD codes 746.9 or 746.89 miscodes for CHD, and if true CHD positives decrease with age. DESIGN: Echocardiograms of patients with an ICD-9-CM code of 745.5 in isolation or in combination with unspecified CHD codes 746.9 or 746.89 were reviewed to validate the true incidence of an ASD. This observational, cross sectional record review included patients between 11 and 64 years of age. RESULTS: Medical charts and echocardiograms of 190 patients (47.9% males) were reviewed. The number of falsely coded patients with 745.5 (no ASD) was high (76.3%). Forty-five (23.7%) patients had a true ASD. Among the 145 patients without an ASD, 100 (52.6%) were classified as having a PFO, 37 (19.5%) had a normal non-CHD echocardiogram, and 8 (4.2%) had some other CHD anomaly. The likelihood that 745.5 coded for a true ASD was higher in children aged 11-20 (64.3%) than adults aged 21-64 years (20.6%). CONCLUSIONS: This validation study demonstrates that 745.5 performed poorly across all ages. As 745.5 is widely used in population-level investigations and ICD-10-CM perpetuates the problem, future analyses utilizing CHD codes should consider separate analysis of those identified only through code 745.5. PMID- 29266727 TI - Exploring nurses' recognition of delirium in the elderly by using Q-methodology. AB - AIM: Despite its high prevalence and seriousness, delirium has been underrecognized by nurses. One reason is that the original characteristics of delirium are relatively unspecific and phenomenologically diverse, which makes a nurse's subjective decision more important in delirium detection. This study aims to identify the experiences, practices, and viewpoints of nurses in recognizing delirium in the elderly. METHODS: In this study, Q-methodology, which is a method for analyzing subjectivity, was used. Following the steps of Q-methodology, 32 nurses with experiences in caring for the delirious elderly sorted 34 Q statements into the shape of a normal distribution. A centroid factor analysis and varimax rotation using the PQMethod program were conducted. RESULTS: This study revealed four factors regarding nurses toward delirium recognition in the elderly. They were: Factor I, prediction from the integrated signs; Factor II, visible symptom-centered detection; Factor III, the detection of abnormal changes based on concentrated observation; and Factor IV, identification by relying on the diagnostic data. CONCLUSION: The result of the study can help to understand elderly delirium detection more practically from a nurse's point of view. It is expected to be used as a basis for a practical and accessible delirium education for nurses that reflects nurses' subjective viewpoints. PMID- 29266728 TI - Enantioseparation and determination of asenapine in biological fluid micromatrices by HPLC with diode array detection. AB - Asenapine is a recent drug approved in the European Union for the treatment of bipolar disorder. An original approach has been developed for asenapine analysis in patients treated with the drug, including miniaturized microsampling procedures, separation and quantitation of drug enantiomers. An original enantioselective method based on high-performance liquid chromatography with diode array detection was developed and applied to the determination of asenapine enantiomer levels in innovative haematic samples: four micromatrices have been tested, two based on dried matrix spots (dried blood spots and dried plasma spots) and two based on volumetric absorptive microsampling (from blood and plasma). Chiral separation was achieved on a cellulose-tris(3,5 dimethylphenylcarbamate) column, with a mobile phase containing bicarbonate buffer and acetonitrile. The method was validated with satisfactory results of linearity and precision on all matrices that showed also a significant performance in terms of stability, feasibility and reliability, when compared to fluid plasma sampling, handling and processing. Among micromatrices, both volumetric absorptive microsampling types were superior to dried matrix spots in terms of data reproducibility and correspondence with plasma levels. The bioanalytical approach proposed herein provides for the first time a chiral high performance liquid chromatographic method for the determination of asenapine enantiomers, coupled to a very effective microsampling strategy. PMID- 29266729 TI - Organic carbon availability limiting microbial denitrification in the deep vadose zone. AB - Microbes in the deep vadose zone play an essential role in the mitigation of nitrate leaching; however, limited information is available on the mechanisms of microbial denitrification due to sampling difficulties. We experimentally studied the factors that affect denitrification in soils collected down to 10.5 meters deep along the soil profile. After an anoxic pre-incubation, denitrification rates moderately increased and the N2 O/(N2 O + N2 ) ratios declined while the microbial abundance and diversity did not change significantly in most of the layers. Denitrification rate was significantly enhanced and the abundance of the denitrification genes was simultaneously elevated by the increased availability of organic carbon in all studied layers, to a greater extent in the subsurface layers than in the surface layers, suggesting the severe scarcity of carbon in the deep vadose zone. The genera Pseudomonas and Bacillus, which are made up of a number of species that have been previously identified as denitrifiers in soil, were the major taxa that respond to carbon addition. Overall, our results suggested that the limited denitrification in the deep vadose zone is not because of the lack of denitrifiers, but due to the low abundance of denitrifiers which is caused by low carbon availability. PMID- 29266731 TI - Active Salt/Silica-Templated 2D Mesoporous FeCo-Nx -Carbon as Bifunctional Oxygen Electrodes for Zinc-Air Batteries. AB - Two types of templates, an active metal salt and silica nanoparticles, are used concurrently to achieve the facile synthesis of hierarchical meso/microporous FeCo-Nx -carbon nanosheets (meso/micro-FeCo-Nx -CN) with highly dispersed metal sites. The resulting meso/micro-FeCo-Nx -CN shows high and reversible oxygen electrocatalytic performances for both ORR and OER, thus having potential for applications in rechargeable Zn-air battery. Our approach creates a new pathway to fabricate 2D meso/microporous structured carbon architectures for bifunctional oxygen electrodes in rechargeable Zn-air battery as well as opens avenues to the scale-up production of rationally designed heteroatom-doped catalytic materials for a broad range of applications. PMID- 29266730 TI - 2D Single-Crystalline Copper Nanoplates as a Conductive Filler for Electronic Ink Applications. AB - Large-scale 2D single-crystalline copper nanoplates (Cu NPLs) are synthesized by a simple hydrothermal method. The combination of a mild reductant, stabilizer, and shape modifier allows the dimensional control of the Cu nanocrystals from 1D nanowires (NWs) to 2D nanoplates. High-resolution transmission electron microscopy (HR-TEM) reveals that the prepared Cu NPLs have a single-crystalline structure. From the X-ray photoelectron spectroscopy (XPS) analysis, it is found that iodine plays an important role in the modification of the copper nanocrystals through the formation of an adlayer on the basal plane of the nanoplates. Cu NPLs with an average edge length of 10 MUm are successfully synthesized, and these Cu NPLs are the largest copper 2D crystals synthesized by a solution-based process so far. The application of the metallic 2D crystals as a semitransparent electrode proves their feasibility as a conductive filler, exhibiting very low sheet resistance (0.4 Omega ?-1 ) compared to Cu NWs and a transmittance near 75%. The efficient charge transport is due to the increased contact area between each Cu NPL, i.e., so-called plane contact (2D electrical contact). In addition, this type of contact enhances the current-carrying capability of the Cu NPL electrodes, implying that the large-size Cu NPLs are promising conductive fillers for printable electrode applications. PMID- 29266732 TI - Do stillbirth, miscarriage, and termination of pregnancy increase risks of attempted and completed suicide within a year? A population-based nested case control study. AB - OBJECTIVE: To investigate the risks of attempted and completed suicide in women who experienced a stillbirth, miscarriage, or termination of pregnancy within 1 year postnatally and compare this risk with that in women who experienced a live birth. DESIGN: A nested case-control study. SETTING: Linking three nationwide population-based data sets in Taiwan: the National Health Insurance Research Database, the National Birth Registry and the National Death Registry. SAMPLE: In all, 485 and 350 cases of attempted and completed suicide, respectively, were identified during 2001-11; for each case, ten controls were randomly selected and matched to the cases according to the age and year of delivery. METHODS: Conditional logistic regression. MAIN OUTCOME MEASURES: Attempted and completed suicidal statuses were determined. RESULTS: The rates of attempted suicide increased in the women who experienced fetal loss. The risk of completed suicide was higher in women who experienced a stillbirth [adjusted odds ratio (aOR) 5.2; 95% CI 1.77-15.32], miscarriage (aOR 3.81; 95% CI 2.81-5.15), or termination of pregnancy (aOR 3.12; 95% CI 1.77-5.5) than in those who had a live birth. Furthermore, the risk of attempted suicide was significantly higher in women who experienced a miscarriage (aOR 2.1; 95% CI 1.66-2.65) or termination of pregnancy (aOR 2.5; 95% CI 1.63-3.82). In addition to marital and educational statuses, psychological illness increased the risk of suicidal behaviour. CONCLUSIONS: The risk of suicide might increase in women who experience fetal loss within 1 year postnatally. Healthcare professionals and family members should enhance their sensitivity to care for possible mental distress, particularly for women who have experienced a stillbirth. TWEETABLE ABSTRACT: Suicide risk increased in women who had a stillbirth, miscarriage, or termination of pregnancy within 1 year postnatally. PMID- 29266733 TI - Geographic disparities in donor lung supply and lung transplant waitlist outcomes: A cohort study. AB - Despite the Final Rule mandate for equitable organ allocation in the United States, geographic disparities exist in donor lung allocation, with the majority of donor lungs being allocated locally to lower-priority candidates. We conducted a retrospective cohort study of 19 622 lung transplant candidates waitlisted between 2006 and 2015. We used multivariable adjusted competing risk survival models to examine the relationship between local lung availability and waitlist outcomes. The primary outcome was a composite of death and removal from the waitlist for clinical deterioration. Waitlist candidates in the lowest quartile of local lung availability had an 84% increased risk of death or removal compared with candidates in the highest (subdistribution hazard ratio [SHR]: 1.84, 95% confidence interval [CI]: 1.51-2.24, P < .001). The transplantation rate was 57% lower in the lowest quartile compared with the highest (SHR: 0.43, 95% CI: 0.39 0.47). The adjusted death or removal rate decreased by 11% with a 50% increase in local lung availability (SHR: 0.89, 95% CI: 0.85-0.93, P < .001) and the adjusted transplantation rate increased by 19% (SHR: 1.19, 95% CI: 1.17-1.22, P < .001). There are geographically disparate waitlist outcomes in the current lung allocation system. Candidates listed in areas of low local lung availability have worse waitlist outcomes. PMID- 29266735 TI - Factors associated with physical activity levels in people with venous leg ulcers: A multicentre, prospective, cohort study. AB - Increasing levels of physical activity among people with venous leg ulcers (VLUs) can potentially reduce the health cost burden, improve functional aspects of patients' lives and increase ulcer healing rates. The aim of this study was to investigate factors associated with physical activity levels in patients with VLUs. Data from 2016 to 2017 Aspirin for Venous Leg Ulcer cohort study were analysed for the present study. Ninety participants were recruited from 5 outpatient specialist wound clinics across Victoria, Australia between August 2016 and April 2017. There was a statistically significant association between diabetes and physical activity, with a higher proportion of people with type 2 diabetes in the sedentary category. Further, there was a statistically significant association between patient-reported VLU education and physical activity levels. An indirect advantage of relevant, easy-to-understand education about VLUs may increase physical activity levels, which may facilitate improved time to healing of VLUs. PMID- 29266734 TI - Nitric oxide releasing vascular catheters for eradicating bacterial infection. AB - The interaction of blood proteins with an implant surface is not only a fundamental phenomenon but is also key to several important medical complications. Plasma proteins binding on the surface of intravascular catheters can promote bacterial adhesion leading to the risk of local and systemic complications such as catheter-related blood infections (CRBIs). The incidences of CRBIs in the United States amount to more than 250,000 cases/year with an attributable mortality of up to 35% and an annual healthcare expenditure of $2.3 billion approximately. This demands the development of truly nonthrombogenic and antimicrobial catheters. In the present study, catheters were fabricated by incorporating a nitric oxide (NO) donor molecule, S-nitroso-N-acetyl penicillamine (SNAP) in a hydrophobic medical grade polymer, Elasteon-E2As. NO offers antithrombotic and antibacterial attributes without promoting drug resistance and cytotoxicity. E2As-SNAP catheters were first coated with fibrinogen, a blood plasma protein plays a key role in clot formation and eventual bacterial adhesion to the implant surface. The suitability of the catheters for biomedical applications was tested in vitro for contact angle, NO release kinetics, inhibition of bacteria, and absence of cytotoxicity toward mammalian cells. The highly hydrophobic catheters released NO in the physiological range that inhibited >99% bacterial viability on fibrinogen-coated catheters in a 24 h study. No toxic response of E2As-SNAP catheters leachate was observed using a standard cytotoxicity assay with mouse fibroblast cells. Overall, the results showed that the E2As-SNAP catheters can inhibit viable bacteria even in the presence of blood proteins without causing a cytotoxic response. The fundamentals of this study are applicable to other blood-contacting medical devices as well. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2849-2857, 2018. PMID- 29266736 TI - Incidence, predicting factors, and clinical outcomes of periprocedural myocardial infarction after percutaneous coronary intervention for chronic total occlusion in the era of new-generation drug-eluting stents. AB - OBJECTIVE: This study aimed to examine predictors and clinical outcomes of periprocedural myocardial infarction (PMI) after chronic total occlusion (CTO) intervention. BACKGROUND: There are limited data on the clinical implications of PMI after CTO intervention in the new-generation drug-eluting stent (DES) era. METHODS: We enrolled 337 patients who underwent CTO intervention and met the study criteria. We evaluated the incidence and predictors of PMI, defined as an increase in creatine kinase-MB >=3* the upper limit of normal (ULN) after intervention and compared the occurrence rates of major adverse cardiac and cerebrovascular events (MACCE, defined as the composite of cardiac death, myocardial infarction, stent thrombosis, target-vessel revascularization, or cerebrovascular accidents) between the PMI and non-PMI groups. RESULTS: PMI occurred in 23 (6.8%) patients after CTO intervention. Significant independent predictors were previous bypass surgery [odds ratio (OR) = 5.52, 95% confidence interval (CI) = 1.17-25.92; P = 0.03], Japan-CTO score >=3 (OR = 7.06, 95%CI = 2.57-19.39; P < 0.001), side branch occlusion (OR = 4.21, 95%CI = 1.13-15.66; P = 0.03), and longer procedure time (OR = 4.18, 95%CI = 1.35-12.99; P = 0.01). During a median follow-up of 29.6 months, the PMI group had a significantly higher MACCE rate than the non-PMI group (23.7 vs. 5.6%, P = 0.008 by log-rank test). PMI was an independent predictor of MACCE (HR = 4.26, 95%CI = 1.35-13.43; P = 0.01). The MACCE rate gradually increased in a CK-MB-dependent fashion and was highest in patients with >=10* ULN (P = 0.005). CONCLUSION: Previous bypass surgery, high Japan-CTO score, side branch occlusion, and longer procedure time were strongly related to PMI occurrence after CTO intervention. PMI was significantly associated with worse clinical outcomes in the new-generation DES era. PMID- 29266737 TI - Chiral Plasmonic Hydrogen Sensors. AB - In this article, a chiral plasmonic hydrogen-sensing platform using palladium based nanohelices is demonstrated. Such 3D chiral nanostructures fabricated by nanoglancing angle deposition exhibit strong circular dichroism both experimentally and theoretically. The chiroptical properties of the palladium nanohelices are altered upon hydrogen uptake and sensitively depend on the hydrogen concentration. Such properties are well suited for remote and spark-free hydrogen sensing in the flammable range. Hysteresis is reduced, when an increasing amount of gold is utilized in the palladium-gold hybrid helices. As a result, the linearity of the circular dichroism in response to hydrogen is significantly improved. The chiral plasmonic sensor scheme is of potential interest for hydrogen-sensing applications, where good linearity and high sensitivity are required. PMID- 29266738 TI - Identifying a combined biomarker for bisphosphonate-related osteonecrosis of the jaw. AB - BACKGROUND: For this study, the aim was to identify combined biomarkers associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: Microarray data for GSE7116 were downloaded from the Gene Expression Omnibus database, which contains 26 samples, including without ONJ, and 5 healthy volunteers. The combined biomarkers were identified using principal component analysis, and the pathway enrichment analyses were performed using the DAVID online tool. RESULTS: Two hundred differently expressed genes between groups were detected according to the significances. From functional annotation, Y-box binding protein 1 and heterogeneous nuclear ribonucleoprotein C were found to be included in the most significant 10 pathways. Ten combined gene sets were identified that were effective in classifying multiple myeloma (MM) with ONJ and MM without ONJ. CONCLUSION: Identifying combined gene expression profiles is expected to contribute to more personalized management of BRONJ and to improve existing therapies, and it will be helpful in finding new therapies by identifying more predictive biomarkers. PMID- 29266739 TI - Predicting re-presentation following discharge from the emergency department with non-specific chest pain. AB - OBJECTIVE: To determine the 30 day major adverse cardiac events (MACE) and re presentation rates of non-specific chest pain (NSCP) patients following four different disposition pathways and to contrast re-presentation rates of patients with NSCP with those for all other patients presenting to the ED. METHODS: Cases were derived from the ED database for two large teaching hospitals where patients aged 18 or over were triaged between 2009 and 2016, and their diagnosis on leaving the ED was NSCP. Statewide 30 day rates of MACE and ED re-presentations were calculated, and multivariable logistic regression analysis identified significant predictors of both. RESULTS: A total of 40 183 cases were included; 16 014 discharged directly from the ED, while the remainder were admitted under Cardiology (n = 7286), General Medicine (n = 7739) or an ED observation unit (n = 4086). Compared to discharge directly from the ED, admission was associated with a decreased 30 day re-presentation rate (OR = 0.857; 95% CI 0.795-0.923; P < 0.001). However, there was no significant difference in adjusted re-presentation between admitting units. The rates of 30 day MACE were higher in admitted patients, particularly in those admitted to general medicine; however, this difference was accounted for by differing patient characteristics. CONCLUSION: Despite a slightly increased rate of re-presentation in patients with NSCP sent home from the ED, we conclude that there is minimal advantage in admitting many patients who lack a diagnosis for their chest pain. For a selected patient population, discharge from the ED may become a safe and cost-effective approach. A prospective randomised study is required. PMID- 29266740 TI - Early major complications after bariatric surgery in the USA, 2003-2014: a systematic review and meta-analysis. AB - The effectiveness of bariatric surgery has been well-studied. However, complications after bariatric surgery have been understudied. This review assesses <30-d major complications associated with bariatric procedures, including anastomotic leak, myocardial infarction and pulmonary embolism. This review included 71 studies conducted in the USA between 2003 and 2014 and 107,874 patients undergoing either gastric bypass, adjustable gastric banding or sleeve gastrectomy, with mean age of 44 years and pre-surgery body mass index of 46.5 kg m-2 . Less than 30-d anastomotic leak rate was 1.15%; myocardial infarction rate was 0.37%; pulmonary embolism rate was 1.17%. Among all patients, mortality rate following anastomotic leak, myocardial infarction and pulmonary embolism was 0.12%, 0.37% and 0.18%, respectively. Among surgical procedures, <30-d after surgery, sleeve gastrectomy (1.21% [95% confidence interval, 0.23-2.19%]) had higher anastomotic leak rate than gastric bypass (1.14% [95% confidence interval, 0.84-1.43%]); gastric bypass had higher rates of myocardial infarction and pulmonary embolism than adjustable gastric banding or sleeve gastrectomy. During the review, we found that the quality of complication reporting is lower than the reporting of other outcomes. In summary, <30-d rates of the three major complications after either one of the procedures range from 0% to 1.55%. Mortality following these complications ranges from 0% to 0.64%. Future studies reporting complications after bariatric surgery should improve their reporting quality. PMID- 29266741 TI - Reaction Product Variability and Biological Activity of the Lactoperoxidase System Depending on Medium Ionic Strength and pH, and on Substrate Relative Concentration. AB - The potential of ions produced in water by the lactoperoxidase system against plant pests has shown promising results. We tested the bioactivity of ions produced by the lactoperoxidase oxidation of I- and SCN- in several buffers or in tap water and characterized the ions produced. In vitro biological activity was tested against Penicillium expansum, the causal agent of mold in fruits, and the major cause of patulin contamination of fruit juices and compotes. In buffers, the ionic concentration was increased 3-fold, and pathogen inhibition was obtained down to the 1:15 dilution. In tap water, the ionic concentration was weaker, and pathogen inhibition was obtained only down to the 1:3 dilution. Acidic buffer increased ion concentrations as compared to less acidic (pH 5.6 or 6.2) or neutral buffers, as do increased ionic strength. 13 C-labelled SCN- and MS showed that different ions were produced in water and in buffers. In specific conditions the ion solution turned yellow and a product was formed, probably diiodothiocyanate (I2 SCN- ), giving an intense signal at 49.7 ppm in 13 C-NMR. The formation of the signal was unambiguously favored in acidic media and disadvantaged or inhibited in neutral or basic conditions. It was enhanced at a specific SCN- : I- ratio of 1:4.5, but decreased when the ratio was 1:2, and was inhibited at ratio SCN- >I- . We demonstrated that the formation of the signal required the interaction between I2 and SCN- , and MS showed the presence of I2 SCN- . PMID- 29266742 TI - EBP Design and Translation: Teaching How to Begin a Scholarly Practice Project. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at https://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 29266743 TI - Parental perceptions of disease-severity and health-related quality of life in school-age children with congenital heart disease. AB - PURPOSE: Understanding parents' perceptions of their child's health status is important as parents are drivers of healthcare utilization in the pediatric setting. Understanding parent-perceived disease-severity and its effects on a child's health-related quality of life (HRQOL) in children with congenital heart disease (CHD) is necessary to evaluate outcomes of care, improve care coordination, and inform policies focused on advancing family-centered care for pediatric cardiac patients. The impact of CHDs and disease-severity on the child's HRQOL has been investigated with inconsistent results. The overall aim of this study was to examine parents' perceptions of HRQOL in their school-age child with CHD, and to compare HRQOL among patients with CHD across severity categories. DESIGN: This was a descriptive correlational study design. METHODS: A total of 71 parents of school-age children aged 5-12 years completed the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL) (including total, physical health, and psychosocial health summary scores) and cardiac specific HRQOL Scale (PedsQL 3.0). PedsQL scores among CHD severity categories were compared by analysis of variance. RESULTS: School-age children with CHDs had an overall good HRQOL with significant differences among disease severity categories for all scores. Parents reported lower scores on their HRQOL of older children compared to younger children across severity groups (p < .01) and for those children with more severe disease (p < .01). PRACTICE IMPLICATIONS: Based on the results of this study, interventions should focus on targeting psychosocial health in older children with CHD and physical health in younger children with CHD. This information is useful in providing practical recommendations in caring for children with CHDs while informing relevant policies. PMID- 29266744 TI - Dosimetric characterization of Elekta stereotactic cones. AB - PURPOSE: Dosimetry of small fields defined by stereotactic cones remains a challenging task. In this work, we report the results of commissioning measurements for the new Elekta stereotactic conical collimator system attached to the Elekta VersaHD linac and present the comparison between the measured and Monte Carlo (MC) calculated data for the 6 MV FFF beam. In addition, relative output factor (ROF) dependence on the stereotactic cone aperture variation was studied and penumbra comparison for small MLC-based and cone-based fields was performed. METHODS: Cones with nominal diameters of 15 mm, 12.5 mm, 10 mm, 7.5 mm, and 5 mm were employed in our study. Percentage depth dose (PDD), off-axis ratios (OAR), and ROF were measured using a stereotactic field diode (SFD). BEAMnrc code was used for MC simulations. RESULTS: MC calculated and measured PDDs for all cones agreed within 1%/0.5 mm, and OAR profiles agreed within 1%/0.5 mm. ROF obtained from the measurements and MC calculations agreed within 2% for all cone sizes. Small-field correction factors for the SFD detector Kfield,3 * 3 (SFD) were derived using MC calculations as a baseline and were found to be 0.982, 0.992, 0.997, 1.015, and 1.017 for the 5, 7.5, 10, 12.5, and 15-mm cones respectively. The difference in ROF was about 10%, 6%, 3.5%, 3%, 2.5%, and 2% for +/-0.3 mm variations in 5, 7.5, 10, 12.5, and 15-mm cone aperture respectively. In case of single static field, cone-based collimation produced a sharper penumbra compared to the MLC-based. CONCLUSIONS: Accurate MC simulation can be an effective tool for verification of dosimetric measurements of small fields. Due to the very high sensitivity of output factors on the cone diameter, manufacture related variations in cone size may lead to considerable variations in dosimetric characteristics of stereotactic cones. PMID- 29266745 TI - A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history. AB - Germline gain-of-function variants in SAMD9 have been associated with a high risk of mortality and a newly recognized constellation of symptoms described by the acronym MIRAGE: Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy. Here, we describe two additional patients currently living with the syndrome, including one patient with a novel de novo variant for which we provide functional data supporting its pathogenicity. We discuss features of dysmorphology, contrasting with previously described patients as well as drawing attention to additional clinical features, dysautonomia and hearing loss that have not previously been reported. We detail both patients' courses following diagnosis, with attention to treatment plans and recommended specialist care. Our patients are the oldest known with arginine substituting amino acid variants, and we conclude that early diagnosis and multidisciplinary management may positively impact outcomes for this vulnerable group of patients. PMID- 29266746 TI - Antibacterial activities and molecular mechanism of amino-terminal fragments from pig nematode antimicrobial peptide CP-1. AB - High manufacturing costs and weak cell selectivity have limited the clinical application of naturally occurring peptides when faced with an outbreak of drug resistance. To overcome these limitations, a set of antimicrobial peptides was synthesized with the general sequence of (WL)n, where n = 1, 2, 3, and WL was truncated from the N-terminus of Cecropin P1 without initial serine residues. The antimicrobial peptide WL3 exhibited stronger antimicrobial activity against both Gram-negative and Gram-positive microbes than the parental peptide CP-1. WL3 showed no hemolysis even at the highest test concentrations compared to the parental peptide CP-1. The condition sensitivity assays (salts, serum, and trypsin) demonstrated that WL3 had high stability in vitro. Fluorescence spectroscopy and electron microscopy indicated that WL3 killed microbes by means of penetrating the membrane and causing cell lysis. In a mouse model, WL3 was able to significantly reduce the bacteria load in major organs and cytokines (TNF alpha, IL-6, and IL-1beta) levels in serum. In summary, these findings suggest that WL3, which was modified from a natural antimicrobial peptide, has enormous potential for application as a novel antibacterial agent. PMID- 29266747 TI - 3D printed hyperelastic "bone" scaffolds and regional gene therapy: A novel approach to bone healing. AB - The purpose of this study was to evaluate the viability of human adipose-derived stem cells (ADSCs) transduced with a lentiviral (LV) vector to overexpress bone morphogenetic protein-2 (BMP-2) loaded onto a novel 3D printed scaffold. Human ADSCs were transduced with a LV vector carrying the cDNA for BMP-2. The transduced cells were loaded onto a 3D printed Hyperelastic "Bone" (HB) scaffold. In vitro BMP-2 production was assessed using enzyme-linked immunosorbent assay analysis. The ability of ADSCs loaded on the HB scaffold to induce in vivo bone formation in a hind limb muscle pouch model was assessed in the following groups: ADSCs transduced with LV-BMP-2, LV-green fluorescent protein, ADSCs alone, and empty HB scaffolds. Bone formation was assessed using radiographs, histology and histomorphometry. Transduced ADSCs BMP-2 production on the HB scaffold at 24 hours was similar on 3D printed HB scaffolds versus control wells with transduced cells alone, and continued to increase after 1 and 2 weeks of culture. Bone formation was noted in LV-BMP-2 animals on plain radiographs at 2 and 4 weeks after implantation; no bone formation was noted in the other groups. Histology demonstrated that the LV-BMP-2 group was the only group that formed woven bone and the mean bone area/tissue area was significantly greater when compared with the other groups. 3D printed HB scaffolds are effective carriers for transduced ADSCs to promote bone repair. The combination of gene therapy and tissue engineered scaffolds is a promising multidisciplinary approach to bone repair with significant clinical potential. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1104-1110, 2018. PMID- 29266748 TI - The experience of men and women with cystic fibrosis who have become a parent: A qualitative study. AB - AIMS AND OBJECTIVES: To explore the experiences of men and women with cystic fibrosis in becoming parents. BACKGROUND: As lifespan for people with cystic fibrosis increases, and reproductive technology advances, having a child of their own becomes a possibility. DESIGN: This study used a phenomenological framework. METHODS: Seven Australian adults with cystic fibrosis were invited to describe their experiences of becoming parents in the context of a semi-structured interview. Analysis of the data involved highlighting recurrent phrases and isolating emergent themes. RESULTS: Two overarching themes characterised the participants' experience: Counting the cost, as they recalled Concentric communication and Pathways to pregnancy; and Living the dream, as they cast a retrospective view over this, their major achievement, in the light of their Reaction: a dream comes true, Coping: a question of balance, Conjecture: the future redefined and Confidence: recalibrating. CONCLUSIONS: While advances in cystic fibrosis care and reproductive technology have increased the possibility of individuals with cystic fibrosis becoming parents, the passage to becoming a parent is a complex process. RELEVANCE TO CLINICAL PRACTICE: These findings can inform health professionals to support the adaptive work necessary for families that include members with cystic fibrosis. A contemporary understanding of this phenomenon is necessary for facilitating clinically relevant communication. PMID- 29266749 TI - Functional reorganization of intra- and internetwork connectivity in major depressive disorder after electroconvulsive therapy. AB - Electroconvulsive therapy (ECT) is an effective and rapid treatment for major depressive disorder (MDD). However, the neurobiological underpinnings of ECT are still largely unknown. Recent studies have identified dysregulated brain networks in MDD. Therefore, we hypothesized that ECT may improve MDD symptoms through reorganizing these networks. To test this hypothesis, we used resting-state functional connectivity to investigate changes to the intra- and internetwork architecture of five reproducible resting-state networks: the default mode network (DMN), dorsal attention network (DAN), executive control network (CON), salience network (SAL), and sensory-motor network. Twenty-three MDD patients were assessed before and after ECT, along with 25 sex-, age-, and education-matched healthy controls. At the network level, enhanced intranetwork connectivities were found in the CON in MDD patients after ECT. Furthermore, enhanced internetwork connectivities between the DMN and SAL, and between the CON and DMN, DAN, and SAL were also identified. At the nodal level, the posterior cingulate cortex had increased connections with the left posterior cerebellum, right posterior intraparietal sulcus (rpIPS), and right anterior prefrontal cortex. The rpIPS had increased connections with the medial PFC (mPFC) and left anterior cingulate cortex. The left lateral parietal had increased connections with the dorsal mPFC (dmPFC), left anterior prefrontal cortex, and right anterior cingulate cortex. The dmPFC had increased connection with the left anterolateral prefrontal cortex. Our findings indicate that enhanced interactions in intra- and internetworks may contribute to the ECT response in MDD patients. These findings provide novel and important insights into the neurobiological mechanisms underlying ECT. PMID- 29266750 TI - Binding Mode and Structure-Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist. AB - Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity. PMID- 29266751 TI - Changes and predictors of psychological stress among elderly stroke survivors 6 months after hospital discharge. AB - The aim of this study was to analyse the changes in psychological stress and identify its basal predictors among elderly stroke survivors after 6 months following discharge from hospital to home directly, rather than to a rehabilitation facility. The sample comprised 50 elderly stroke survivors. Data were collected at 2 weeks (T1), at 3 months (T2), and at 6 months (T3) after hospital discharge. The following instruments were applied: Perceived Stress Scale-10 items (PSS-10), National Institute of Health Stroke Scale, Functional Independence Measure, and Geriatric Depression Scale-15 items. Study records indicated that the age of the study participants ranged from 60 to 87 years old (mean = 70.3; standard deviation = 7.6). The number of male and female participants was similar. The PSS-10 score decreased almost 6 points between T1 (mean = 15.1) and T3 (mean = 9.7; p < .001). Both Functional Independence Measure (p = .025) and Geriatric Depression Scale-15 (p = .017) scores at T1 predicted the PSS-10 score at T3. The study thus demonstrated that elderly stroke survivors experienced significant stress after hospital discharge, which tended to improve over the next 6 months. Depression and lower functional independence 2 weeks after discharge were predictors of a greater level of psychological stress at 6 months following discharge. PMID- 29266752 TI - Randomized controlled trial comparing the effects of usual gas release, active aspiration, and passive-valve release on abdominal distension in patients who have undergone laparoscopic cholecystectomy. AB - INTRODUCTION: Residual, intra-abdominal CO2 contributes to abdominal distension and pain after laparoscopic surgery. The study was designed to assess recovery after gas release in patients who have undergone laparoscopic cholecystectomy (LC). METHODS: A total of 142 patients undergoing laparoscopic cholecystectomy were randomly divided into three groups: (i) group 1 (control group), gas release from the surgical wound without port release (n = 47); (ii) group 2, active gas aspiration via a subdiaphragmatic port (n = 48); and (iii) group 3, passive-valve release via a subdiaphragmatic port valve opening (n = 47). Abdominal distension and shoulder pain levels were assessed postoperatively. RESULTS: The active aspiration group had significantly reduced postoperative abdominal distensions at 30 min, 4, and 24 h compared with the control group (50.0% vs 80.9%, 43.8% vs 76.6%, 33.3% vs 57.4%, respectively; P < 0.05). Similarly, the passive-valve release group had significantly reduced postoperative abdominal distensions at 4 and 24 h compared with the control group (51.1% vs 76.6%, 57.4% vs 36.2%; P < 0.05). Both intervention groups had significantly reduced postoperative shoulder pain at 4 and 24 h compared with the control group (P < 0.001). In addition, the postoperative ambulation times for the active aspiration group were significantly shorter than those for the control and passive-valve release groups (P < 0.001). CONCLUSION: Releasing residual CO2 from the intra-abdominal cavity at the end of laparoscopic cholecystectomy by either the active aspiration or passive-valve release technique is an effective way to reduce postoperative abdominal distension and shoulder pain. PMID- 29266753 TI - Specific changes of enteric mycobiota and virome in inflammatory bowel disease. AB - One of the important features of inflammatory bowel disease (IBD) is dysbiosis of the gut microbiota. It has been well documented that changes in the commensal bacterial population are involved in IBD development. However, the function of the fungal and viral communities in IBD remains unclear. Moreover, the optimal treatment for IBD patients with opportunistic infections is still undecided. This review focused on how the enteric mycobiota and virome changes during the pathogenesis of IBD and discussed potential treatment strategies that open new insights into the managements of IBD. PMID- 29266754 TI - Thromboelastography does not provide additional information to guide resuscitation in the severely injured. PMID- 29266755 TI - Global health inequalities and the need for solidarity: a view from the Global South. AB - Although the world has experienced remarkable progress in health care since the last half of the 20th century, global health inequalities still persist. In some poor countries life expectancy is between 37-40 years lower than in rich countries; furthermore, maternal and infant mortality is high and there is lack of access to basic preventive and life-saving medicines, as well a high prevalence of neglected diseases, HIV/AIDS, tuberculosis, and malaria. Moreover, globalization has made the world more connected than before such that health challenges today are no longer limited within national or regional boundaries, making all persons equally vulnerable. Because of this, diseases in the most affluent countries are closely connected with diseases in the poorest countries. In this paper, we argue that, because of global health inequalities, in a situation of equal vulnerability, there is need for global solidarity not only as a means of reducing health inequalities, but also as a way of putting up a united force against global health challenges. We argue for an African approach to solidarity in which the humanity of a person is not determined by his/her being human or rational capacity, but by his/her capacity to live a virtuous life. According to this view of solidarity, because no one is self-sufficient, no individual can survive alone. If we are to collectively flourish in a world where no individual, nation or region has all the health resources or protection needed for survival, we must engage in solidarity where we remain compassionate and available to one another at all times. PMID- 29266756 TI - Solubility-Modifying Power of Zwitterionic Salts. AB - The separation of small, hydrophilic molecules from aqueous solutions on one side and the dissolution of hydrophobic organic molecules in water on the other are nowadays among the most difficult challenges in chemical and bio-technology. Even though these two tasks are seemingly of opposite nature, it is demonstrated herein that both processes can be facilitated by addition of zwitterionic salts, a new class of compounds that can act either as a solubility enhancer or a phase separation promoter depending on the structure of the solute dissolved in an aqueous solution. At a more fundamental level, this study investigates the salting in/out propensity of the ions and supports the importance of both salt solute interaction and their concentration. PMID- 29266757 TI - Mechanical knowledge does matter to tool use even when assessed with a non production task: Evidence from left brain-damaged patients. AB - In the literature on apraxia of tool use, it is now accepted that using familiar tools requires semantic and mechanical knowledge. However, mechanical knowledge is nearly always assessed with production tasks, so one may assume that mechanical knowledge and familiar tool use are associated only because of their common motor mechanisms. This notion may be challenged by demonstrating that familiar tool use depends on an alternative tool selection task assessing mechanical knowledge, where alternative uses of tools are assumed according to their physical properties but where actual use of tools is not needed. We tested 21 left brain-damaged patients and 21 matched controls with familiar tool use tasks (pantomime and single tool use), semantic tasks and an alternative tool selection task. The alternative tool selection task accounted for a large amount of variance in the single tool use task and was the best predictor among all the semantic tasks. Concerning the pantomime of tool use task, group and individual results suggested that the integrity of the semantic system and preserved mechanical knowledge are neither necessary nor sufficient to produce pantomimes. These results corroborate the idea that mechanical knowledge is essential when we use tools, even when tasks assessing mechanical knowledge do not require the production of any motor action. Our results also confirm the value of pantomime of tool use, which can be considered as a complex activity involving several cognitive abilities (e.g., communicative skills) rather than the activation of gesture engrams. PMID- 29266758 TI - The neurobiological mechanisms of physical exercise in methamphetamine addiction. AB - Methamphetamine (METH) is the primary drug within amphetamine-type stimulants which are the second most abused group of drugs worldwide. There is no pharmacological treatment addressed specifically to METH addiction, and behavioral therapy is shadowed by poor long-term recovery and relapse. Therefore, novel approaches to manage METH addiction are an urgent need. This review aims to describe the current state of physical exercise use on methamphetamine addiction management. The following searching terms in PubMed were used: ("physical exercise" OR "exercise") AND "methamphetamine." Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Original investigation regarding physical exercise and methamphetamine addiction (clinical data) or neurobiological mechanisms of physical exercise in animal models of methamphetamine administration (preclinical data) was included. Overall, METH users demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to nonexercised individuals. The neurobiological mechanisms of physical exercise in METH users seem to reflect an interplay of several agents, including neurochemicals, oxidative stress, neurogenesis, gliogenesis, and blood-brain barrier as disclosed by preclinical data. Exercise based interventions alone or as a conjoint therapy may be a useful tool for managing METH addiction. PMID- 29266759 TI - Dual-Phase CsPbBr3 -CsPb2 Br5 Perovskite Thin Films via Vapor Deposition for High Performance Rigid and Flexible Photodetectors. AB - Inorganic perovskites with special semiconducting properties and structures have attracted great attention and are regarded as next generation candidates for optoelectronic devices. Herein, using a physical vapor deposition process with a controlled excess of PbBr2 , dual-phase all-inorganic perovskite composite CsPbBr3 -CsPb2 Br5 thin films are prepared as light-harvesting layers and incorporated in a photodetector (PD). The PD has a high responsivity and detectivity of 0.375 A W-1 and 1011 Jones, respectively, and a fast response time (from 10% to 90% of the maximum photocurrent) of ~280 us/640 us. The device also shows an excellent stability in air for more than 65 d without encapsulation. Tetragonal CsPb2 Br5 provides satisfactory passivation to reduce the recombination of the charge carriers, and with its lower free energy, it enhances the stability of the inorganic perovskite devices. Remarkably, the same inorganic perovskite photodetector is also highly flexible and exhibits an exceptional bending performance (>1000 cycles). These results highlight the great potential of dual-phase inorganic perovskite films in the development of optoelectronic devices, especially for flexible device applications. PMID- 29266760 TI - Revisiting the Quality of Reporting Randomized Controlled Trials in Nursing Literature. AB - PURPOSE: To examine and update the literature on the quality of randomized controlled trials (RCTs) as reported in top nursing journals, based on manuscripts' adherence to the CONsolidated Standards of Reporting Trials (CONSORT) guidelines. DESIGN: Descriptive review of adherence of RCT manuscript to CONSORT guidelines. METHODS: Top 40 International Scientific Indexing (ISI) ranked nursing journals that published 20 or more RCTs between 2010 and 2014, were included in the study. Selected articles were randomly assigned to four reviewers who assessed the quality of the articles using the CONSORT checklist. Data were analyzed using descriptive and inferential statistics. FINDINGS: A total of 119 articles were included in the review. The mean CONSORT score significantly differed by journal but did not differ based on year of publication. The least consistently reported items included random allocation, who randomly assigned participants and whether those administering the interventions were blinded to group assignment. CONCLUSIONS: Although progress has been made, there is still room for improvement in the quality of RCT reporting in nursing journals. Special attention must be paid to how adequately studies adhere to the CONSORT prior to publication in nursing journals. CLINICAL RELEVANCE: Evidence from (RCTs) are thought to provide the best evidence for evaluating the impact of treatments and interventions by the U.S. Preventive Services Task Force. Since the evidence may be used for the development of clinical practice guidelines, it is critical that RCTs be designed, conducted, and reported appropriately and precisely. PMID- 29266761 TI - Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma. AB - Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single-agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression-free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti-PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors. PMID- 29266762 TI - The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys. AB - Calcineurin inhibitor toxicity (CNT) is a frequent occurrence in transplanted renal grafts and autochthone kidneys from patients undergoing long-term treatment with calcineurin inhibitors, notably cyclosporin A (CsA) and tacrolimus. Here, we show an indispensable role of the tumor necrosis factor superfamily (TNFS) molecule TNF-related weak inducer of apoptosis (TWEAK) (TNFSF12) in the pathogenesis of acute CNT lesions in mice. A deficiency in TWEAK resulted in limited tubulotoxicity after CsA exposure, which correlated with diminished expression of inflammatory cytokines and reduced intraparenchymal infiltration with immune cells. We further identified tubular epithelial cells of the kidney as major targets of CsA activity and found that Fn14 (tumor necrosis factor receptor superfamily 12A), the receptor for TWEAK, is a highly CsA-inducible gene in these cells. Correlating with this, CsA pretreatment sensitized tubular epithelial cells specifically to the pro-inflammatory activities of recombinant TWEAK in vitro. Moreover, injection of rTWEAK alone into mice induced moderate disease similar to CsA, and rTWEAK combined with CsA resulted in synergistic nephrotoxicity. These findings support the importance of tubular epithelial cells as cellular targets of CsA toxicity and introduce TWEAK as a critical contributor to CNT pathogenesis. PMID- 29266763 TI - Achieving High Capacitance of Paper-Like Graphene Films by Adsorbing Molecules from Hydrolyzed Polyimide. AB - To date, graphene-based electric double layer supercapacitors have not shown the remarkable specific capacitance as theoretically predicted. An efficient strategy toward boosting the overall capacitance is to endow graphene with pseudocapacitance. Herein, molecules of hydrolyzed polyimide (HPI) are used to functionalize N-doped graphene (NG) via pi-pi interaction and the resulting enhanced electrochemical energy storage is reported. These aromatic molecules in monolayer form on graphene contribute strong pseudocapacitance. Paper-like NG films with different areal mass loadings ranging from 0.5 to 4.8 mg cm-2 are prepared for supercapacitor electrodes. It is shown that the gravimetric capacitance can be increased by 50-60% after the surface functionalization by HPI molecules. A high specific capacitance of 553 F g-1 at 5 mV s-1 is achieved by the HPI-NG film with a graphene mass loading of 0.5 mg cm-2 in H2 SO4 aqueous electrolyte. For the HPI-NG film with highest mass loading, the gravimetric specific capacitance drops to 340 F g-1 while the areal specific capacitance reaches a high value of 1.7 F cm-2 . HPI-NG films are also tested in Li2 SO4 aqueous electrolyte, over an extended voltage window of 1.6 V. High specific energy densities up to 40 Wh kg-1 are achieved with the Li2 SO4 electrolyte. PMID- 29266764 TI - Risks for depression among ostomates in South Korea. AB - AIM: This study explored the factors that are associated with the depressive status among older adult ostomates in South Korea. METHODS: The study was a secondary analysis of data from a cross-sectional study with 217 ostomates who were aged >=55 years from September 2, 2013 to October 30, 2013. The general characteristics, daily routines, and depressive status were assessed in order to identify the factors that were contributing to a depressed mood among the older adult ostomates in South Korea. The general characteristics included their sex, age group, educational level, financial status, employment, outing hours, perceived social isolation, leisure activity, and perceived health status. The daily routines included living environment inconvenience, leisure activity satisfaction, body image satisfaction, sleep satisfaction, exercise involvement, intimacy with a spouse, sexual satisfaction, and satisfaction with quality of life. RESULTS: The prevalence of depressive status in older adult ostomates was 50.7%, but 40.8% in the same-age population without an ostomy. The factors that were associated with a depressed mood among the older adult ostomates in South Korea were social isolation, perceived poor health status, perceived low quality of life, dissatisfaction with leisure activities, and poor financial status. The participants' sex, age, and educational level were not associated with depression. CONCLUSION: Nurses need to encourage older adults with an ostomy to reduce their social isolation and to increase leisure activities by helping them to use resources, such as support groups and psychological support, in collaboration with interdisciplinary team members. PMID- 29266765 TI - The impact on high-grade serous ovarian cancer of obesity and lipid metabolism related gene expression patterns: the underestimated driving force affecting prognosis. AB - To investigate whether specific obesity/metabolism-related gene expression patterns affect the survival of patients with ovarian cancer. Clinical and genomic data of 590 samples from the high-grade ovarian serous carcinoma (HGOSC) study of The Cancer Genome Atlas (TCGA) and 91 samples from the Australian Ovarian Cancer Study were downloaded from the International Cancer Genome Consortium (ICGC) portal. Clustering of mRNA microarray and reverse-phase protein array (RPPA) data was performed with 83 consensus driver genes and 144 obesity and lipid metabolism-related genes. Association between different clusters and survival was analyzed with the Kaplan-Meier method and a Cox regression. Mutually exclusive, co-occurrence and network analyses were also carried out. Using RNA and RPPA data, it was possible to identify two subsets of HGOSCs with similar clinical characteristics and cancer driver mutation profiles (e.g. TP53), but with different outcome. These differences depend more on up-regulation of specific obesity and lipid metabolism-related genes than on the number of gene mutations or copy number alterations. It was also found that CD36 and TGF-beta are highly up-regulated at the protein levels in the cluster with the poorer outcome. In contrast, BSCL2 is highly up-regulated in the cluster with better progression-free and overall survival. Different obesity/metabolism-related gene expression patterns constitute a risk factor for prognosis independent of the therapy results in the Cox regression. Prognoses were conditioned by the differential expression of obesity and lipid metabolism-related genes in HGOSCs with similar cancer driver mutation profiles, independent of the initial therapeutic response. PMID- 29266766 TI - Engineered method for directional growth of muscle sheets on electrospun fibers. AB - Research on the neuromuscular junction (NMJ) and its function and development spans over a century. However, researchers are limited in their ability to conduct experimentation on this highly specialized synapse between motor neurons and muscle fibers, as NMJs are not easily accessible outside the body. The aim of this work is to provide a reliable and reproducible muscle sheet model for in vitro NMJ study. A novel culture system was designed by engineering a method for the directional growth of myofiber sheets, using muscle progenitor cells cultured on electrospun fiber networks. Myoblastic C2C12 cells cultured on suspended aligned fibers were found to maintain directionality, with alignment angle standard deviations approximately two-thirds lower on fibers than on regular culture surfaces. Morphological studies found nuclei and cytoskeleton aspect ratios to be elongated by 20 and 150%, respectively. Furthermore, neurons were shown to form innervation patterns parallel to suspended fibers when co-cultured on developed muscle sheets, with alignment angle standard deviations three times lower compared with those on typical surfaces. The effect of agrin on samples was quantified through the slow release of agrin medium, encapsulated in alginate pellets and imbedded within culture chambers. Samples exposed to agrin showed significantly increased percentage of AChR-covered area. The developed model has potential to serve as the basis for synaptogenesis and NMJ studies, providing a novel approach to bio-artificial muscle alignment and setting the groundwork for further investigations in innervation. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1165-1176, 2018. PMID- 29266767 TI - Perioperative experiences of anesthesia reported by children and parents. AB - BACKGROUND: The Sprint National Anaesthesia Project reported feedback from adults but not from children. We developed questionnaires for children and parents, and conducted a survey of perioperative anesthetic experiences in a large pediatric hospital. METHODS: Patients undergoing elective general anesthesia were selected randomly each weekday over 10 weeks. Parents and children were approached within 4 hours after awakening, and were asked to complete a short questionnaire. Personal or patient identifiable data were not collected. Questionnaires were processed by optical mark reading technology and descriptive data analysis was performed. RESULTS: Seven hundred and forty parents and 250 children completed questionnaires. The most common symptoms reported by parents were thirst and hunger (76%), drowsiness (75%), sore throat (41%), and pain of the surgery (38%). Sixty-four percent of children felt worried or scared about something before the procedure: common worries were about the "anesthetic," "procedure," or "needles/cannula." Fifty-five percent reported postoperative pain. Thirty-nine children (15.6%) remembered something between going to sleep and waking up although distress was not reported; of these, the most common experiences remembered included hearing voices (34%), feeling sore (20%), and being worried (14%). Twenty-two parents (2.9%) had any complaint and most were about fasting instructions. Only 3 parents would not recommend the anesthetic service. CONCLUSION: This study shows that the experiences of children and their parents are similar to those of adults reported by the Sprint National Anaesthesia Project. Thirst (and hunger), anxiety, and pain continue to be common problems for many children. This feedback may help direct interventions and research to improve the pediatric patient and parent experience with anesthesia. PMID- 29266768 TI - Efficient 3-Hydroxybutyrate Production by Quiescent Escherichia coli Microbial Cell Factories is Facilitated by Indole-Induced Proteomic and Metabolomic Changes. AB - The authors show that quiescent (Q-Cell) Escherichia coli cultures can maintain metabolic activity in the absence of growth for up to 24 h, leading to four times greater specific productivity of a model metabolite, 3-hydroxybutyrate (3HB), than a control. Q-cells can be created by using the proton ionophore indole to halt cell division of an hns mutant strain. This uncouples metabolism from cell growth and allows for more efficient use of carbon feedstocks because less metabolic effort is diverted to surplus biomass production. However, the reason for the increased productivity of cells in the quiescent state was previously unknown. In this study, proteome expression patterns between wild-type and Q-cell cultures show that Q-cells overexpress stress response proteins, which prime them to tolerate the metabolic imbalances incurred through indole addition. Metabolomic data reveal the accumulation of acetyl-coenzyme A and phosphoenolpyruvate: excellent starting points for high-value chemical production. We demonstrate the exploitation of these accumulated metabolites by engineering a simple pathway for 3HB production from acetyl-coenzyme A. Quiescent cultures produced half the cell biomass of control cultures lacking indole, but were still able to produce 39.4 g L-1 of 3HB compared to 18.6 g L-1 in the control. Q-cells therefore have great potential as a platform technology for the efficient production of a wide range of commodity and high value chemicals. PMID- 29266769 TI - Urethral function and histopathology in aged female rats as a stress urinary incontinence model. AB - OBJECTIVE: Stress urinary incontinence (SUI) is a common disease condition in elderly women, suggesting that its etiology may be linked to aging. To investigate the hypothesis that urethral dysfunction and histopathological changes are possible contributors to SUI in elderly women, several parameters of urethral function, as well as histological parameters, were compared between young and aged rats. METHODS: Virgin female rats were examined at 3 different ages, namely 3, 12, and 24 months, corresponding to young, middle-aged, and aged rats, respectively. Urethral function was assessed by measuring the leak point pressure (LPP), pudendal nerve stimulation (PNS)-induced elevation in urethral pressure, and phenylephrine-induced increase in urethral perfusion pressure (UPP). Histopathological assessments were performed following hematoxylin and eosin (HE), Masson's trichrome, and immunofluorescence staining of urethral tissue. RESULTS: LPP of aged rats was significantly reduced compared to that of both young and middle-aged rats. PNS-induced elevation in urethral pressure in aged rats was also significantly lower than that in young rats. In contrast, there were no significant differences in the phenylephrine-induced increase in UPP between young and aged rats. Connective tissue area in the external urethral sphincter (EUS) layer was increased in aged rats, whereas the smooth muscle layer was histologically similar to that in young rats. The number of EUS fibers was significantly reduced in aged rats, whereas the cross-sectional area of EUS fibers increased from differed compared with young rats. CONCLUSION: We have demonstrated age-related changes in EUS function and morphology in the rat urethra, which are considered to be etiological risk factors for SUI in humans. PMID- 29266770 TI - Vitamin A Deficiency Induces Autistic-Like Behaviors in Rats by Regulating the RARbeta-CD38-Oxytocin Axis in the Hypothalamus. AB - SCOPE: Vitamin A (VA) is an essential nutrient for the development of the brain. We previously found that children with autism spectrum disorder (ASD) have a significant rate of VA deficiency (VAD). In the current study, we aim to determine whether VAD is a risk factor for the generation of autistic-like behaviors via the transcription factor retinoic acid receptor beta (RARbeta) regulated cluster of differentiation 38 (CD38)-oxytocin (OXT) axis. METHODS AND RESULTS: Gestational VAD or VA supplementation (VAS) rat models are established, and the autistic-like behaviors in the offspring rats are investigated. The different expression levels of RARbeta and CD38 in hypothalamic tissue and serum retinol and OXT concentration are tested. Primary cultured rat hypothalamic neurons are treated with all-trans retinoic acid (atRA), and recombinant adenoviruses carrying the rat RARbeta (AdRARbeta) or RNA interference virus RARbeta-siRNA (siRARbeta) are used to infect neurons to change RARbeta signal. Western blotting, chromatin immunoprecipitation (ChIP), and intracellular Ca2+ detections are used to investigate the primary regulatory mechanism of RARbeta in the CD38-OXT signaling pathway. We found that gestational VAD increases autistic like behaviors and decreases the expression levels of hypothalamic RARbeta and CD38 and serum OXT levels in the offspring. VAS ameliorates these autistic-like behaviors and increases the expression levels of RARbeta, CD38, and OXT in the gestational VAD pups. In vitro, atRA increases the Ca2+ excitability of neurons, which might further promote the release of OXT. Different CD38 levels are induced in the neurons by infection with different RARbeta adenoviruses. Furthermore, atRA enhances the binding of RARbeta to the proximal promoter of CD38, indicating a potential upregulation of CD38 transcriptional activity by RARbeta. CONCLUSIONS: Gestational VAD might be a risk factor for autistic-like behaviors due to the RARbeta signal suppression of CD38 expression in the hypothalamus of the offspring, which improves with VAS during the early-life period. The nutritional status during pregnancy and the early-life period is important in rats. PMID- 29266771 TI - Record submission of well over 600 manuscripts in 2017. PMID- 29266772 TI - Efficacy and Tolerance of Lidocaine 5% Patches in Neuropathic Pain and Pain Related to Vaso-occlusive Sickle Cell Crises in Children: A Prospective Multicenter Clinical Study. AB - BACKGROUND: The management of neuropathic pain and pain related to bone vaso occlusive crises in sickle cell disease remains challenging in children. Lidocaine 5% patches are recommended in adults for neuropathic pain treatment, but they are not recommended in children. The purpose of this study was to assess the efficacy and tolerance of lidocaine 5% patches in pediatric inpatients. METHODS: This prospective, multicenter, single-arm, phase II study aimed to assess the use of lidocaine 5% patches in 6- to 21-year-old pediatric patients suffering from neuropathic pain or superficial bone vaso-occlusive crises. Patches were applied on the painful area for 12 hours a day. The primary endpoint was the proportion of inpatients with significant pain relief defined as a decrease of at least 2 points on the visual analog pain scale (VAS) measured at 12 hours after patch placement over at least 2 consecutive days. RESULTS: The 12 hour VAS score decreased by at least 2 points over 2 consecutive days in 48.6% of patients 95% unilateral confidence interval (33.8%). Only 7.7% of patients experienced grade 1 or grade 2 toxicities. CONCLUSION: Although lidocaine 5% patches decreased the pain's intensity in nearly half of the enrolled patients with an excellent tolerance, the efficacy endpoint was not reached. Further studies should consider a more refined selection of the experimental population to assess the efficacy of lidocaine 5% patches in the pediatric population. PMID- 29266773 TI - Bioavailability of Glucoraphanin and Sulforaphane from High-Glucoraphanin Broccoli. AB - SCOPE: Broccoli accumulates 4-methylsulphinylbutyl glucosinolate (glucoraphanin) which is hydrolyzed to the isothiocyanate sulforaphane. Through the introgression of novel alleles of the Myb28 transcription factor from Brassica villosa, broccoli genotypes have been developed that have enhanced levels of glucoraphanin. This study seeks to quantify the exposure of human tissues to glucoraphanin and sulforaphane following consumption of broccoli with contrasting Myb28 genotypes. METHODS AND RESULTS: Ten participants are recruited into a three phase, double-blinded, randomized crossover trial (NCT02300324), with each phase comprising consumption of 300 g of a soup made from broccoli of one of three Myb28 genotypes (Myb28B/B , Myb28B/V , Myb28V/V ). Plant myrosinases are intentionally denatured during soup manufacture. Threefold and fivefold higher levels of sulforaphane occur in the circulation following consumption of Myb28V/B and Myb28V/V broccoli soups, respectively. The percentage of sulforaphane excreted in 24 h relative to the amount of glucoraphanin consumed varies among volunteers from 2 to 15%, but does not depend on the broccoli genotype. CONCLUSION: This is the first study to report the bioavailability of glucoraphanin and sulforaphane from soups made with novel broccoli varieties. The presence of one or two Myb28V alleles results in enhanced delivery of sulforaphane to the systemic circulation. PMID- 29266774 TI - RREB1-MKL2 fusion in biphenotypic "oropharyngeal" sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas? AB - An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53 year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients. PMID- 29266776 TI - The diagnostic value of FNA biopsy in grading pancreatic neuroendocrine tumors. AB - BACKGROUND: There has been much controversy regarding the accuracy of grading pancreatic neuroendocrine tumors (PNETs) on fine-needle aspiration (FNA) biopsy. The objectives of this study were to evaluate whether grading according to the fraction of Ki-67-positive tumor cells (the Ki-67 proliferation index) on material from endoscopic ultrasound-guided FNA biopsies correlated with grading on surgical resection specimens and to evaluate the minimum amount of FNA material needed. METHODS: A case series of 27 PNETs with FNA biopsies and corresponding surgical resection specimens at the authors' institution were evaluated. Tumors were graded on FNA and surgical specimens with an evaluation of Ki-67 index according to 2010 World Health Organization criteria. Chart reviews were conducted to evaluate recurrence or clinical progression in patients who were being managed conservatively with observation. RESULTS: The evaluation of grading between FNA and tumor resection specimens revealed that 22 of 26 FNA specimens (84.6%) had Ki-67 results comparable to those in the corresponding surgical resection specimens, thus allowing for accurate grading. Correct FNA diagnosis with the ability to distinguish between grade 1 and 2 tumors had a positive predictive value of 88.9%, with 72.7% sensitivity, 93.3% specificity, and a P value of .00081. In addition, 24 of 26 cases contained less than 2000 cells, of which 20 were correctly graded on FNA material. Seven of 26 FNA samples had less than 1000 cells, of which 6 were correctly graded, including 2 that had only 50 cells. CONCLUSIONS: The current results exhibit good correlation between FNA grade and final grade on surgical resection specimens using Ki-67 index, even in samples with less than the recommended total cell count. Therefore, grading of PNETs on FNA with the Ki-67 proliferation index should be assessed and is a practical parameter to report to clinicians. Cancer Cytopathol 2018;126:170-8. (c) 2017 American Cancer Society. PMID- 29266777 TI - Changing the way we think about wounds: A challenge for 21st century medical practice. PMID- 29266775 TI - Functional assessment of the BMPR2 gene in lymphoblastoid cell lines from Graves' disease patients. AB - In this study, we analysed the possible influence of the c.419-43delT BMPR2 variant in patients with Graves' disease (GD), in a molecular basis, focusing our efforts on possible alterations in the mRNA processing and synthesis. The molecular assessment of this variant in patients with GD would shed light on the association between the BMPR2 gene and the disease. The variant was detected in 18%, 55% and 10% of patients with pulmonary arterial hypertension, GD and in general population, respectively. Patients with GD fold change showed increased BMPR2 expression when matched against the controls, with a mean of 4.21 +/- 1.73 (P = 0.001); BMPR2 was overexpressed in the analysed cell cycle stages. Fold change analysis of variant carriers and non-carriers showed slight overexpression and differences between phases, but none of them were statistically significant. BMPR2 expression was confirmed in the lymphoblastoid cell lines (LCLs) with a molecular weight of 115 kD, and no differences between variant carriers and non carriers were detected. To conclude, the BMPR2 variant c.419-19delT appears in high frequency in patients with GD, and independently of its presence, BMPR2 is overexpressed in the LCLs from the GD patients tested. This increase could be paired with the described decreased expression of transforming growth factor beta1 in thyroid tissue from patients with GD. PMID- 29266778 TI - Promoting healthy food preferences from the start: a narrative review of food preference learning from the prenatal period through early childhood. AB - The palatable, energy-dense foods that characterize modern environments can promote unhealthy eating habits, along with humans' predispositions to accept sweet tastes and reject those that are sour or bitter. Yet food preferences are malleable, and examining food preference learning during early life can highlight ways to promote acceptance of healthier foods. This narrative review describes research from the past 10 years focused on food preference learning from the prenatal period through early childhood (ages 2-5 years). Exposure to a variety of healthy foods from the start, including during the prenatal period, early milk feeding and the introduction to complementary foods and beverages, can support subsequent acceptance of those foods. Yet development is plastic, and healthier food preferences can still be promoted after infancy. In early childhood, research supports starting with the simplest strategies, such as repeated exposure and modelling, reserving other strategies for use when needed to motivate the initial tasting necessary for repeated exposure effects to begin. This review can help caregivers and practitioners to promote the development of healthy food preferences early in life. Specific implementation recommendations, the role of individual differences and next steps for research in this area are also discussed. PMID- 29266780 TI - Nickel-Catalyzed Heck-Type Monofluoroacetation of Styrenes for Facile Synthesis of Allylic Fluorides. AB - An efficient nickel-catalyzed Heck-type reaction between styrenes and fluoroalkyl iodine has been developed. This novel transformation has demonstrated a broad substrate scope, mild reaction conditions and excellent E-stereoselectivity. This efficient synthetic method has been applied to the late-stage monofluoroacetation of biologically active molecules. Mechanistic investigations indicate that a monofluoroalkyl radical is involved in the catalytic cycle. PMID- 29266779 TI - CCAAT/enhancer-binding protein beta overexpression alleviates myocardial remodelling by regulating angiotensin-converting enzyme-2 expression in diabetes. AB - Diabetic cardiomyopathy, a major cardiac complication, contributes to heart remodelling and heart failure. Our previous study discovered that CCAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor that belongs to a family of basic leucine zipper transcription factors, interacts with the angiotensin converting enzyme 2 (ACE2) promoter sequence in other disease models. Here, we aimed to determine the role of C/EBPbeta in diabetes and whether ACE2 expression is regulated by C/EBPbeta. A type 1 diabetic mouse model was generated by an intraperitoneal injection of streptozotocin. Diabetic mice were injected with a lentivirus expressing either C/EBPbeta or sh-C/EBPbeta or treated with valsartan after 12 weeks to observe the effects of C/EBPbeta. In vitro, cardiac fibroblasts and cardiomyocytes were treated with high glucose (HG) to investigate the anti fibrosis, anti-apoptosis and regulatory mechanisms of C/EBPbeta. C/EBPbeta expression was down-regulated in diabetic mice and HG-induced cardiac neonatal cells. C/EBPbeta overexpression significantly attenuated collagen deposition and cardiomyocyte apoptosis by up-regulating ACE2 expression. The molecular mechanism involved the binding of C/EBPbeta to the ACE2 promoter sequence. Although valsartan, a classic angiotensin receptor blocker, relieved diabetic complications, the up-regulation of ACE2 expression by C/EBPbeta overexpression may exert greater beneficial effects on patients with diabetic cardiomyopathy. PMID- 29266781 TI - Annealing-Free Cr2 O3 Electron-Selective Layer for Efficient Hybrid Perovskite Solar Cells. AB - The electron-selective layer (ESL) plays a pivotal role in the performance of perovskite solar cells (PSCs). In this study, amorphous dispersible chromium oxide (Cr2 O3 ) nanosheets are synthesized by a facile solvothermal reaction, and a Cr2 O3 ESL is prepared by spin-coating Cr2 O3 ink on fluorine-doped tin oxide substrates without need for further annealing. By using Cr2 O3 as the electron selective layer and Cs0.05 (MA0.17 FA0.83 )0.95 Pb(I0.83 Br0.17 )3 as the light absorption layer, a planar hybrid perovskite solar cell is fabricated. The spin coating speed is optimized, the structure and morphology of samples are observed, the photoelectrical properties of ESLs are characterized, and the photovoltaic behaviors of devices are measured. Results show that the as-prepared Cr2 O3 layer has high optical transmittance and superb electron extraction and carrier transport property. The planar hybrid PSC based on the optimized Cr2 O3 ESL achieves a power conversion efficiency of 16.23 %, which is comparable to devices based on a conventional high-temperature-calcined TiO2 ESL. These results demonstrate a low-cost and facile route to highly effective perovskite solar cells. PMID- 29266782 TI - Dietary habits and semen parameters: a systematic narrative review. AB - Semen quality and male fertility are declining worldwide. As it was observed that physiologic and pathologic processes of spermatogenesis can be influenced by diet, the relation between dietary habits and semen parameters has been the focus of much interest. To review the human observational studies on this issue, we performed a systematic literature search, up to November 2016 (MEDLINE and EMBASE). We included all observational full-text papers reporting the relation between dietary habits and semen parameters. Article selection was carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses. Twenty-three observational studies were included. Overall, 8477 healthy men and 1204 men presenting at Fertility Clinics were included in the selected studies. Even if some inconsistencies are present, possibly due to the different effect of nutrients in fertile and infertile men, results support the hypothesis that diets including fruit and vegetables, for their contents in vitamins, and fish or low-fat dairy products as the main source of proteins, are associated with better semen quality. Recommendations may be confidently provided because of the many beneficial effects of a healthy diet, although further studies are needed to clarify the currently inconsistent findings and to shed light on the underlying mechanisms. PMID- 29266783 TI - Frequency of Chronic Joint Pain Following Chikungunya Virus Infection: A Colombian Cohort Study. AB - OBJECTIVE: To estimate the frequency of chronic joint pain after infection with chikungunya virus in a Latin American cohort. METHODS: A cross-sectional follow up of a prospective cohort of 500 patients from the Atlantico Department, Colombia who were clinically diagnosed as having chikungunya virus during the 2014-2015 epidemic was conducted. Baseline symptoms and follow-up symptoms at 20 months were evaluated in serologically confirmed cases. RESULTS: Among the 500 patients enrolled, 485 had serologically confirmed chikungunya virus and reported joint pain status. Patients were predominantly adults (mean +/- SD age 49 +/- 16 years) and female, had an education level of high school or less, and were of Mestizo ethnicity. The most commonly affected joints were the small joints, including the wrists, ankles, and fingers. The initial virus symptoms lasted a median of 4 days (interquartile range [IQR] 3-8 days). Sixteen percent of the participants reported missing school or work (median 4 days [IQR 2-7 days]). After 20 months, one-fourth of the participants had persistent joint pain. A multivariable analysis indicated that significant predictors of persistent joint pain included college graduate status, initial symptoms of headache or knee pain, missed work, normal activities affected, >=4 days of initial symptoms, and >=4 weeks of initial joint pain. CONCLUSION: This is the first report to describe the frequency of chikungunya virus-related arthritis in the Americas after a 20-month follow-up. The high frequency of chronic disease highlights the need for the development of prevention and treatment methods. PMID- 29266785 TI - Analysis of thyreostats in bovine feces using ultra high performance liquid chromatography with tandem mass spectrometry. AB - A method based on ultra-high performance liquid chromatography was developed and validated to detect six thyreostatic compounds: tapazole, thiouracil, methylthiouracil, dimethylthiouracil, propylthiouracil, and phenylthiouracil in faeces of bovine. Thyreostats were extracted from the matrix with a mixture of methanol and buffer (pH = 8). Next step was derivatization of analytes with 3 iodobenzylbromide. The liquid chromatographic separation of derivatives was obtained on a SB-C18 column (50 * 2.1 mm; 1.8 MUm, Agilent) with gradient elution using a mobile phase consisting of acetonitrile/0.1% acetic acid within 7.5 min. The analysis was performed on a Shimadzu NEXERA X2 ultra-high performance liquid chromatograph with triple quadrupole MS 8050 instrument operating in positive electrospray ionization mode. Depending on the target compound, two or three diagnostic signals (selected reaction monitoring transitions) were monitored. The procedure was validated according to the Commission Decision 2002/657/EC. Recovery and repeatability met the performance criteria specified by this document for banned compounds. The recovery ranged from 97.5 to 110.5%, and repeatability did not exceed 14.1%. Decision limits and detection capabilities were below 10 MUg/kg. The highest decision limits and detection capabilities concentrations were observed for phenylthiouracil of 3.48 and 6.96 MUg/kg, respectively. PMID- 29266786 TI - Psychometric Testing of the Personal Workplace Safety Instrument for Emergency Nurses. AB - BACKGROUND: Patient-visitor violence (PVV) committed against nurses is a worldwide problem. Registered nurses in emergency departments (EDs) are particularly susceptible. The frequency and severity of PVV against emergency nurses (ENs) internationally is well documented. Little is known about factors that make ENs feel safe from PVV. AIM: Examine the psychometric properties of the Personal Workplace Safety Instrument for Emergency Nurses (PWSI-EN), developed to measure ENs' perceptions of safety from PVV. METHODS: Instrument development was based on a literature review, input from ENs, and expert opinion. An online version of the PWSI-EN was distributed to a convenience sample of ENs practicing in EDs across the United States. Psychometric testing included measures of internal consistency reliability, construct validity to support subscales, and comparisons on demographic variables. RESULTS: Three-hundred and five (N = 305) ENs from 16 hospitals responded to the original 31-item PWSI-EN. Based on item analysis and exploratory factor analysis (EFA), the instrument was reduced to 23 items with Cronbach's alpha = .912. EFA delineated six subscales relevant to perception of safety from PVV with factor loadings from .342 to .879. Low to moderate subscale correlations showed a degree of independence for concept domains. Known groups approach for construct validity revealed statistically significant differences (p < .05) for five subscales and the total score between community and academic or teaching hospitals. Hospital type, organizational confidence, and fear for patient safety were significant predictors of greater perceptions of safety from PVV. LINKING EVIDENCE TO ACTION: The PWSI-EN is a valid and reliable survey instrument to assess EN perceptions of safety. ED and hospital leaders can use this instrument to determine specific areas to focus efforts in order to improve ENs' perception of safety from PVV. Researchers exploring interventions aimed at improving perceptions of safety from PVV for ENs may find the PWSI-EN useful. PMID- 29266787 TI - Actin assembly mediated by a nucleation promoting factor WASH is involved in MTOC TMA formation during Xenopus oocyte maturation. AB - During Xenopus oocyte maturation, the microtubule organizing center and transient microtubule array (MTOC-TMA) forms at the vegetal side of the nucleus and we have previously demonstrated that this formation requires actin reorganization. However, the molecular mechanism that coordinates actin filaments with microtubules (MTs) during oocyte maturation is unknown. Here we show that the actin nucleation promoting factor WASH is involved in MTOC-TMA assembly. WASH depletion disrupted the alignment of actin filaments and MT at the base of MTOC TMA. In vitro cosedimentation assays revealed that the Xenopus WASH VCA domain, which comprises the actin and Arp2/3 complex binding region, directly bound to MT but that the WHD2 domain, which had been previously reported to be an MT-binding domain of mammalian WASH, did not. Injection of the WHD2-deleted mutant into oocytes caused a drastic accumulation of actin filaments in the cytoplasm and malformation of MTOC-TMA, suggesting that the WHD2 domain negatively regulates the VCA domain activity during oocyte maturation. Our results suggest that WASH complex-dependent actin nucleation is involved in the assembly of MTOC-TMA. PMID- 29266788 TI - Targeting Albumin Binding Function as a Therapy Goal in Liver Failure: Development of a Novel Adsorbent for Albumin Dialysis. AB - Liver failure results in impaired hepatic detoxification combined with diminished albumin synthesis and is associated with secondary organ failure. The accumulation of liver toxins has shown to saturate albumin binding sites. This was previously demonstrated by an in vitro test for albumin binding capacity (ABiC) that has shown to inversely correlate with the established MELD (Model for End-Stage Liver Disease) score. In this study, we introduced a new adsorbent material for albumin dialysis treatments that improves albumin binding capacity. The new charcoal adsorbent was developed by an evolutionary test schedule. Batch testing of charcoals was performed as steady-state experiments. The charcoal reflecting the highest increase in albumin binding capacity was then introduced to kinetic models: Perfusion tests were designed to evaluate adsorption capacity and kinetics for liver failure marker toxins. A dynamic recirculation model for liver failure was used for upscaling and comparison against conventional MARS adsorbents as the gold standard in an albumin dialysis setting. Batch tests revealed that powdered activated Hepalbin charcoal displayed the highest ABiC score. Hepalbin charcoal also demonstrated higher adsorptive capacity and kinetics for liver failure marker toxins as determined by perfusion tests. These findings translated to tests of upscaled adsorbents in a dynamic model for liver failure: upscaled Hepalbin adsorbent removes bile acids, direct bilirubin and indirect bilirubin significantly better than MARS adsorbents and significantly increases ABiC. The novel adsorbent Hepalbin offers a significant improvement over both MARS adsorbents concerning liver failure marker toxin removal and ABiC improvement. PMID- 29266789 TI - Mild-Base-Promoted Arylation of (Hetero)Arenes with Anilines. AB - Transition metal-free radical arylation of heteroarenes is achieved at room temperature by simply adding aqueous sodium carbonate to a solution of the corresponding heteroarene and arenediazonium salt, which can even be formed in situ. Such an easy, inexpensive and mild methodology has been optimized and applied to the expeditious modification of interesting molecular cores like naphthylimide or bisthienylcyclopentenes. PMID- 29266784 TI - Polarized Ends of Human Macula Densa Cells: Ultrastructural Investigation and Morphofunctional Correlations. AB - The morphology of the kidney macula densa (MD) has extensively been investigated in animals, whereas human studies are scanty. We studied the fine structure of human MD cells focusing on their apical and basal ends and correlating structure and function. The MD region was examined by transmission electron microscopy in six renal biopsies from patients with kidney disease. Ultrastructural analysis of MD cells was performed on serial sections. MD cells show two polarized ends. The apical portion is characterized by a single, immotile cilium associated with microvilli; apically, cells are joined by adhering junctions. In the basal portion, the cytoplasm contains small, dense granules and numerous, irregular cytoplasmic projections extending to the adjacent extraglomerular mesangium. The projections often contain small, dense granules. A reticulated basement membrane around MD cells separates them from the extraglomerular mesangium. Although the fact that tissue specimens came from patients with kidney disease mandates extreme caution, ultrastructural examination confirmed that MD cells have sensory features due to the presence of the primary cilium, that they are connected by apical adhering junctions forming a barrier that separates the tubular flow from the interstitium, and that they present numerous basal interdigitations surrounded by a reticulated basement membrane. Conceivably, the latter two features are related to the functional activity of the MD. The small, dense granules in the basal cytoplasm and in cytoplasmic projections are likely related to the paracrine function of MD cells. Anat Rec, 301:922-931, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266790 TI - Quercetin Attenuates Ethanol-Induced Iron Uptake and Myocardial Injury by Regulating the Angiotensin II-L-Type Calcium Channel. AB - SCOPE: Increased iron deposition in the myocardium in alcoholics may lead to increased risk of cardiac dysfunction. Quercetin has been demonstrated to quench production of intracellular free iron-induced -OH, but the effect of quercetin in ethanol-induced cardiac damage remains unclear. This study aims to explore whether quercetin attenuates ethanol-induced iron uptake and myocardial injury by regulating angiotensin II-L-type voltage-dependent Ca2+ channel (Ang II-LTCC). METHODS AND RESULTS: Adult male C57BL/6J mice are isocalorically pair-fed either a regular or ethanol-containing Lieber De Carli liquid diets supplemented with either quercetin (100 mg kg-1 bw) or desferrioxamine mesylate (DFO, 100 mg kg-1 bw) for 15 weeks. Quercetin alleviated ethanol-induced histopathological changes, creatine kinase isoenzyme release, Ang II secretion, ROS generation, total cardiac iron, and labile iron level. Ethanol exposure or quercetin intervention fails to regulate traditional iron transporters except LTCC. LTCC is upregulated by ethanol and inhibited by quercetin. In H9C2 cell, LTCC is increased by ethanol (100 mm) and/or Ang II (1 MUm) concomitant with iron disorders and oxidative stress. This effect is partially normalized by quercetin (50 MUm), nifedipine (LTCC inhibitor, 15 MUm), or losartan (Ang II receptor antagonist, 100 MUm). CONCLUSION: Alcohol-induced cardiac injury is associated with excessive NTBI uptake mediated by Ang II-LTCC activation which may be mediated by quercetin against ethanol cardiotoxicity. PMID- 29266792 TI - Effectiveness of an innovative self-management intervention on the physiology, psychology, and management of patients with pre-end-stage renal disease in Taiwan: A randomized, controlled trial. AB - AIM: End-stage renal disease (ESRD) not only threatens a patient's life expectancy but also burdens the family and society with medical expenses. The mortality and prevalence rates are extremely high in Taiwan. Thus, this articleinvestigated the effectiveness of an innovative self-management program on the physiology, psychology, and management of patients with pre-ESRD. METHODS: This study was designed as a randomized, controlled trial and was set in the department of nephrology in a regional teaching hospital in Taiwan. In total, 112 patients with pre-ESRD were assigned randomly to either an experimental (n = 67) or a control (n = 45) group. The baseline data collection included physiological indicators, psychological factors (depression, anxiety), and measures of self efficacy and self-management. Routine hospital care was provided for the control group after the pretest and an innovative self-management intervention was used in the experimental group for 4 weeks after the pretest. The effectiveness of the intervention was evaluated 3 months later. RESULTS: Improvements in the physiological indicators, such as blood urea nitrogen and creatinine, and the psychological indicators, such as depression, self-efficacy, and self-management, reached statistical significance. CONCLUSION: The innovative self-management program effectively decreased patients' functional indicators (blood urea nitrogen, creatinine) and level of depression and enhanced their self-efficacy and self-management. PMID- 29266791 TI - A Stereolithography-Based 3D Printed Hybrid Scaffold for In Situ Cartilage Defect Repair. AB - Damage to articular cartilage can over time cause degeneration to the tissue surrounding the injury. To address this problem, scaffolds that prevent degeneration and promote neotissue growth are needed. A new hybrid scaffold that combines a stereolithography-based 3D printed support structure with an injectable and photopolymerizable hydrogel for delivering cells to treat focal chondral defects is introduced. In this proof of concept study, the ability to a) infill the support structure with an injectable hydrogel precursor solution, b) incorporate cartilage cells during infilling using a degradable hydrogel that promotes neotissue deposition, and c) minimize damage to the surrounding cartilage when the hybrid scaffold is placed in situ in a focal chondral defect in an osteochondral plug that is cultured under mechanical loading is demonstrated. With the ability to independently control the properties of the structure and the injectable hydrogel, this hybrid scaffold approach holds promise for treating chondral defects. PMID- 29266793 TI - Rapid melanoma induction in mice expressing oncogenic BrafV600E using Mitf-cre. PMID- 29266794 TI - Determination of Seminal Concentration of Fingolimod and Fingolimod-Phosphate in Multiple Sclerosis Patients Receiving Chronic Treatment With Fingolimod. AB - The safety profile of fingolimod 0.5 mg, approved therapy for relapsing multiple sclerosis, is well established in clinical and real-world studies. As fingolimod is teratogenic in rats, it was considered important to assess the concentrations of fingolimod and its active metabolite, fingolimod-phosphate, in the semen of male patients on treatment and the risk of harming a fetus in a pregnant partner. In this multicenter open-label study, 13 male patients receiving fingolimod for at least 6 months provided 1 semen and 1 blood sample for analyte concentration measurements. The steady-state seminal concentrations of fingolimod and fingolimod-phosphate were close to those simultaneously observed in blood. The amount of fingolimod-related material in 10 mL of ejaculate was estimated to be 47.5 ng. The estimated fingolimod and fingolimod-phosphate blood Cmax values in a woman having regular sexual intercourse with a male patient treated with fingolimod 0.5 mg were approximately 400 and 2400 times smaller than the estimated values in the embryo-fetal development study in rats at the no-observed adverse-event level. Consequently, the risk of harming a fetus in a pregnant woman is considered extremely unlikely. PMID- 29266796 TI - Flow cytometric fingerprinting for microbial strain discrimination and physiological characterization. AB - The analysis of microbial populations is fundamental, not only for developing a deeper understanding of microbial communities but also for their engineering in biotechnological applications. Many methods have been developed to study their characteristics and over the last few decades, molecular analysis tools, such as DNA sequencing, have been used with considerable success to identify the composition of microbial populations. Recently, flow cytometric fingerprinting is emerging as a promising and powerful method to analyze bacterial populations. So far, these methods have primarily been used to observe shifts in the composition of microbial communities of natural samples. In this article, we apply a flow cytometric fingerprinting method to discriminate among 29 Lactobacillus strains. Our results indicate that it is possible to discriminate among 27 Lactobacillus strains by staining with SYBR green I and that the discriminatory power can be increased by combined SYBR green I and propidium iodide staining. Furthermore, we illustrate the impact of physiological changes on the fingerprinting method by demonstrating how flow cytometric fingerprinting is able to discriminate the different growth phases of a microbial culture. The sensitivity of the method is assessed by its ability to detect changes in the relative abundance of a mix of polystyrene beads down to 1.2%. When a mix of bacteria was used, the sensitivity was as between 1.2% and 5%. The presented data demonstrate that flow cytometric fingerprinting is a sensitive and reproducible technique with the potential to be applied as a method for the dereplication of bacterial isolates. (c) 2017 International Society for Advancement of Cytometry. PMID- 29266795 TI - LncRNA-DANCR contributes to lung adenocarcinoma progression by sponging miR-496 to modulate mTOR expression. AB - Long non-coding RNAs (lncRNAs) have emerged as new and important regulators of pathological processes including tumour development. In this study, we demonstrated that differentiation antagonizing non-protein coding RNA (DANCR) was up-regulated in lung adenocarcinoma (ADC) and that the knockdown of DANCR inhibited tumour cell proliferation, migration and invasion and restored cell apoptosis rescued; cotransfection with a miR-496 inhibitor reversed these effects. Luciferase reporter assays showed that miR-496 directly modulated DANCR; additionally, we used RNA-binding protein immunoprecipitation (RIP) and RNA pull down assays to further confirm that the suppression of DANCR by miR-496 was RISC dependent. Our study also indicated that mTOR was a target of miR-496 and that DANCR could modulate the expression levels of mTOR by working as a competing endogenous RNA (ceRNA). Furthermore, the knockdown of DANCR reduced tumour volumes in vivo compared with those of the control group. In conclusion, this study showed that DANCR might be an oncogenic lncRNA that regulates mTOR expression through directly binding to miR-496. DANCR may be regarded as a biomarker or therapeutic target for ADC. PMID- 29266797 TI - Empowering people to help speak up about safety in primary care: Using codesign to involve patients and professionals in developing new interventions for patients with multimorbidity. AB - BACKGROUND: Multimorbidity, defined as the presence of two or more long-term conditions, is increasingly common in primary care, and patients with multimorbidity may face particular barriers to quality of care and increased safety risks due to the complexity of managing multiple conditions. Consistent with calls to directly involve service users in improving care, we aimed to use design materials to codesign new interventions to improve safety in primary care. DESIGN: We drew on two established methods-accelerated experience-based codesign and the future workshop approach. We synthesized design materials based on research into the patient experience of safety and multimorbidity in primary care to enable both patients, service users and carers, and primary health-care professionals to propose interventions to improve care. RESULTS: Both patients and professionals prioritized polypharmacy as a threat to safety. Their recommendations for supportive interventions were consistent with Burden of Treatment theory, emphasizing the limited capacity of patients with multimorbidity and the need for services to proactively offer support to reduce the burden of managing complex treatment regimes. DISCUSSION & CONCLUSIONS: The process was feasible and acceptable to participants, who valued the opportunity to jointly propose new interventions. The iterative workshop approach enabled the research team to better explore and refine the suggestions of attendees. Final recommendations included the need for accessible reminders to support medication adherence and medication reviews for particularly vulnerable patients conducted with pharmacists within GP practices. PMID- 29266798 TI - 3D Carbon Scaffolds for Neural Stem Cell Culture and Magnetic Resonance Imaging. AB - 3D glassy carbon structures with percolated macropores are obtained by pyrolysis of chemically synthesized cryogels featuring tunable porosity. These batch fabricated structures are used as scaffolds for culturing neural stem cells (NSCs) and are characterized by magnetic resonance imaging (MRI). With the aid of MRI, the successful cultivation of NSCs on a glassy carbon surface and the precise 3D locations of these cell clusters within the opaque scaffold are demonstrated. MRI also yields pore morphology and porosity analyses, pre- and post-pyrolysis. This integrated approach yields a complete 3D dataset of the NSC network, which enables the visual inspection of the morphological details of individual cell clusters without disturbing them or destroying the scaffold. Reported experimental methodology is expected to have an impact on studies designed to understand the mechanism of neurodegenerative disease (ND) development, and can serve as a protocol for the culture of various other types of cells that display compatibility with glassy carbon surfaces. PMID- 29266799 TI - Ecological Balance of Oral Microbiota Is Required to Maintain Oral Mesenchymal Stem Cell Homeostasis. AB - Oral microbiome is essential for maintenance of oral cavity health. Imbalanced oral microbiome causes periodontal and other diseases. It is unknown whether oral microbiome affect oral stem cells function. This study used a common clinical antibiotic treatment approach to alter oral microbiome ecology and examine whether oral mesenchymal stem cells (MSCs) are affected. We found that altered oral microbiome resulted gingival MSCs deficiency, leading to a delayed wound healing in male mice. Mechanistically, oral microbiome release lipopolysaccharide (LPS) that stimulates the expression of microRNA-21 (miR-21) and then impair the normal function of gingival MSCs and wound healing process through miR 21/Sp1/telomerase reverse transcriptase pathway. This is the first study indicate that interplay between oral microbiome and MSCs homeostasis in male mice. Stem Cells 2018;36:551-561. PMID- 29266800 TI - Perioperative management in endoscopic endonasal skull-base surgery: a survey of the North American Skull Base Society. AB - BACKGROUND: The objective of this work was to better understand variations in perioperative management in endoscopic endonasal skull-base surgery (EESBS) and to identify trends in management based upon the practice patterns of North American Skull Base Society (NASBS) members. METHODS: A 29-question survey evaluating perioperative EESBS management was sent to all NASBS members. Responses were analyzed with descriptive statistics. Subgroup analysis was performed based on participant demographics. A Bonferroni correction was performed and a p value <0.01 was considered statistically significant for subgroup analysis. RESULTS: Of 651 invitees, 116 responded (17.8%). Participants were primarily from the United States (81.0%), and practiced in academic centers (83.6%). The majority were neurosurgeons (55.2%) or rhinologists (27.6%). Most surgeons (83.6%) advocated use of preoperative intravenous antibiotics (96.6%) and image guidance in all cases (83.6%). Lumbar drains were not recommended for cases in which an intraoperative cerebrospinal fluid (CSF) leak was not anticipated (94.8%). Nasoseptal flaps (NSFs) were not recommended in cases without intraoperative CSF leak (84.5%), but were recommended in cases of high flow intraoperative CSF leak (97.4%). While postoperative restrictions were highly variable, most providers recommended CSF leak precautions (89.7%), flying restrictions (94.0%), and driving restrictions (95.6%) regardless of intraoperative CSF leak status. Most experts also recommended that continuous positive airway pressure (CPAP) be avoided for at least 2 weeks when an intraoperative CSF leak is encountered (81.9%). CONCLUSION: Despite variation in perioperative management of EESBS patients, important trends were identified by this study. Further investigation is needed to standardize perioperative practice patterns in EESBS. PMID- 29266802 TI - Micro/Nanostructured Materials for Sodium Ion Batteries and Capacitors. AB - High-efficiency energy storage technologies and devices have received considerable attention due to their ever-increasing demand. Na-related energy storage systems, sodium ion batteries (SIBs) and sodium ion capacitors (SICs), are regarded as promising candidates for large-scale energy storage because of the abundant sources and low cost of sodium. In the last decade, many efforts, including structural and compositional optimization, effective modification of available materials, and design and exploration of new materials, have been made to promote the development of Na-related energy storage systems. In this Review, the latest developments of micro/nanostructured electrode materials for advanced SIBs and SICs, especially the rational design of unique composites with high thermodynamic stabilities and fast kinetics during charge/discharge, are summarized. In addition to the recent achievements, the remaining challenges with respect to fundamental investigations and commercialized applications are discussed in detail. Finally, the prospects of sodium-based energy storage systems are also described. PMID- 29266801 TI - Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis. AB - OBJECTIVE: The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA. METHODS: Serum and sputum samples were obtained from 41 RA-free subjects who were considered at risk for the development of RA based on familial or serologic risk factors, from 20 subjects classified as having RA, and from 22 healthy control subjects. Samples were evaluated using a bead-based array for IgG reactivity to 29 citrullinated proteins/peptides and 21 noncitrullinated proteins/peptides. Cutoff levels for antibody positivity were established in a separate control group. NET levels in the sputum were measured using sandwich enzyme-linked immunosorbent assays that quantitate DNA myeloperoxidase and DNA-neutrophil elastase complexes. RESULTS: In at-risk subjects, antibody responses to the citrullinated forms of fibrinogen, apolipoprotein E, and fibronectin were highly prevalent. The most citrulline specific antibodies in the sputum of at-risk subjects were those to fibrinogen, vimentin, and peptides of fibrinogen A and apolipoprotein A1. Patterns of sputum autoantibody positivity differed between at-risk subjects and subjects with RA. In at-risk subjects, increasing sputum NET levels significantly correlated with several citrullinated and some noncitrullinated antibody reactivities. CONCLUSION: These findings suggest that sputum antibody reactivity to particular citrullinated and noncitrullinated proteins/peptides is specific for RA and for subjects at risk of RA, and the association of these proteins/peptides with NETs may be a key feature of early RA-related autoimmunity in the lung. These results further support the hypothesis that the lung plays a role in early RA-related autoimmunity. PMID- 29266803 TI - Structure-Based Design of Selective Noncovalent CDK12 Inhibitors. AB - Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9 ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl 9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1 MUm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymerase II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells. PMID- 29266804 TI - Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial. AB - AIMS: The SHIFT trial showed that ivabradine reduced heart rate (HR) and the risk of cardiovascular outcomes. Concerns remain over the efficacy and safety of ivabradine on heart failure (HF) due to Chagas disease (ChD). We therefore conducted a post hoc analysis of the SHIFT trial to investigate the effect of ivabradine in these patients. METHODS AND RESULTS: SHIFT was a randomized, double blind, placebo-controlled trial in symptomatic systolic stable HF, HR >= 70 b.p.m., and in sinus rhythm. The ChD HF subgroup included 38 patients, 20 on ivabradine, and 18 on placebo. The ChD HF subgroup showed high prevalence of bundle branch right block and, compared with the overall SHIFT population, lower systolic blood pressure; higher use of diuretics, cardiac glycosides, and antialdosterone agents; and lower use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker or target daily dose of beta-blocker. ChD HF presented a poor prognosis (all-cause mortality at 2 years was ~60%). The mean twice-daily dose of ivabradine was 6.26 +/- 1.15 mg and placebo 6.43 +/- 1.55 mg. Ivabradine reduced HR from 77.9 +/- 3.8 to 62.3 +/- 10.1 b.p.m. (P = 0.005) and improved functional class (P = 0.02). A trend towards reduction in all cause death was observed in ivabradine arm vs. placebo (P = 0.07). Ivabradine was not associated with serious bradycardia, atrioventricular block, hypotension, or syncope. CONCLUSIONS: ChD HF is an advanced form of HF with poor prognosis. Ivabradine was effective in reducing HR in these patients and improving functional class. Although our results are based on a very limited sample and should be interpreted with caution, they suggest that ivabradine may have a favourable benefit-risk profile in ChD HF patients. PMID- 29266805 TI - Morphogenesis of the Middle Ear during Fetal Development as Observed Via Magnetic Resonance Imaging. AB - Recently, our research group has utilized serial histological sections to investigate the morphogenesis of the middle ear, which corresponds to the period of middle ear ossicle (MEO) cartilage formation. However, research regarding middle ear development during the post-embryonic period has been limited. In the present study, we investigated morphogenesis of the middle ear in human fetuses with a crown-rump length (CRL) between 37 and 197 mm using high-resolution magnetic resonance imaging (MRI). Our findings indicated that the morphology of the MEOs is similar during fetal development and adulthood; further, growth of the MEOs nearly ceases once a CRL of 150 mm is attained. In each MEO, ossification spreads from a single center. The malleus and Meckel's cartilage could be discriminated in samples exhibiting a CRL of 145 mm based on differences in MRI signal intensity. In samples with a CRL of 86 mm, the tympanic cavity (TC) appeared as a thin yet distinct structure attached to the external auditory meatus at the convex surface. Only the handle of the malleus was covered by the TC, while the incus and stapes contacted the cavity at the region of articulation between the two ossicles only, even after a CRL of 145 mm had been attained. Thus, although the TC increased in both diameter and thickness, coverage did not extend across all three MEOs during the observation period. These data are expected to provide a useful standard for morphogenesis and may aid researchers in distinguishing between normal and abnormal development. Anat Rec, 301:757-764, 2018. (c) 2017 Wiley Periodicals Inc. PMID- 29266806 TI - Camera-augmented mobile C-arm (CamC): A feasibility study of augmented reality imaging in the operating room. AB - BACKGROUND: In orthopaedic trauma surgery, image-guided procedures are mostly based on fluoroscopy. The reduction of radiation exposure is an important goal. The purpose of this work was to investigate the impact of a camera-augmented mobile C-arm (CamC) on radiation exposure and the surgical workflow during a first clinical trial. METHODS: Applying a workflow-oriented approach, 10 general workflow steps were defined to compare the CamC to traditional C-arms. The surgeries included were arbitrarily identified and assigned to the study. The evaluation criteria were radiation exposure and operation time for each workflow step and the entire surgery. The evaluation protocol was designed and conducted in a single-centre study. RESULTS: The radiation exposure was remarkably reduced by 18 X-ray shots 46% using the CamC while keeping similar surgery times. CONCLUSIONS: The intuitiveness of the system, its easy integration into the surgical workflow, and its great potential to reduce radiation have been demonstrated. PMID- 29266807 TI - Heparinization of Beta Tricalcium Phosphate: Osteo-immunomodulatory Effects. AB - Immune cells play a vital role in regulating bone dynamics. This has boosted the interest in developing biomaterials that can modulate both the immune and skeletal systems. In this study, calcium phosphates discs (i.e., beta-tricalcium phosphate, beta-TCP) are functionalized with heparin to investigate the effects on immune and stem cell responses. The results show that the functionalized surfaces downregulate the release of hydrogen peroxide and proinflammatory cytokines (tumor necrosis factor alpha and interleukin 1 beta) from human monocytes and neutrophils, compared to nonfunctionalized discs. The macrophages show both elongated and round shapes on the two ceramic substrates, but the morphology of cells on heparinized beta-TCP tends toward a higher elongation after 72 h. The heparinized substrates support rat mesenchymal stem cell (MSC) adhesion and proliferation, and anticipate the differentiation toward the osteoblastic lineage as compared to beta-TCP and control. The coupling between the inflammatory response and osteogenesis is assessed by culturing MSCs with the macrophage supernatants. The downregulation of inflammation in contact with the heparinized substrates induces higher expression of bone-related markers by MSCs. PMID- 29266808 TI - Response to "Comments on 'Impact of spontaneous donor hypothermia on graft outcomes after kidney transplantation'". PMID- 29266809 TI - Reverse Translation of US Food and Drug Administration Reviews of Oncology New Molecular Entities Approved in 2011-2017: Lessons Learned for Anticancer Drug Development. PMID- 29266811 TI - The learning environment in remediation: a review. AB - BACKGROUND: The focus of this concise article is how best to support students to achieve success at medical school. Our aim is not to provide a guide to remediating under-performance in medical students. This, in our view, implies an approach that fundamentally is about quick fixes for addressing individual student deficits, such as intensive coaching of clinical skills to help a student scrape through a resit examination. Instead, we believe that student success is not solely the result of individual factors but rather relies on a complex range of factors, including the provision of a supportive environment. METHODS: We drew on our knowledge of a wide range of literature related to remediation and other medical education structures and functions. Our aim was to take a different perspective on the different dimensions of 'remediation' - the structural, curricular, ideological and individual - to consider how best to provide a supportive environment for all learners to progress towards the required outcomes. CONCLUSION: Medical students are becoming increasingly diverse and medical curricula must create learning environments that support all students to thrive. Effective remediation should not be about intensive 'teaching to test' after examination failure. Rather, both the context and the individual have a role to play in ensuring the selection, teaching, assessment and feedback practices support the learning journeys of individuals. We provide guidance for faculty member development and engaging with students to help achieve this goal. Effective remediation should not be about intensive 'teaching to test' after examination failure. PMID- 29266812 TI - Tomato Powder Inhibits Hepatic Steatosis and Inflammation Potentially Through Restoring SIRT1 Activity and Adiponectin Function Independent of Carotenoid Cleavage Enzymes in Mice. AB - SCOPE: Beta-carotene-15,15'-oxygenase (BCO1) and beta-carotene-9',10'-oxygenase (BCO2) metabolize lycopene to biologically active metabolites, which can ameliorate nonalcoholic fatty liver disease (NAFLD). We investigate the effects of tomato powder (TP containing substantial lycopene (2.3 mg/g)) on NAFLD development and gut microbiome in the absence of both BCO1 and BCO2 in mice. METHOD AND RESULTS: BCO1-/- /BCO2-/- double knockout mice were fed a high fat diet (HFD) alone (n = 9) or with TP feeding (n = 9) for 24 weeks. TP feeding significantly reduced pathological severity of steatosis and hepatic triglyceride levels in BCO1-/- /BCO2-/- mice (p < 0.04 vs HFD alone). This was associated with increased SIRT1 activity, nicotinamide phosphoribosyltransferase expression and AMP-activated protein kinase phosphorylation, and subsequently decreased lipogenesis, hepatic fatty acid uptake, and increasing fatty acid beta-oxidation (p < 0.05). TP feeding significantly decreased mRNA expression of proinflammatory genes (tnf-alpha, il-1beta, and il-6) in both liver and mesenteric adipose tissue, which were associated with increased plasma adiponectin and hepatic adiponectin receptor-2. Multiplexed 16S rRNA gene sequencing was performed using DNA extracted from cecum fecal samples. TP feeding increased microbial richness and decreased relative abundance of the genus Clostridium. CONCLUSION: Dietary TP can inhibit NAFLD independent of carotenoid cleavage enzymes, potentially through increasing SIRT1 activity and adiponectin production and decreasing Clostridium abundance. PMID- 29266813 TI - Is Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis Still a More Severe Disease Than Anti-Citrullinated Protein Antibody-Negative Rheumatoid Arthritis? A Longitudinal Cohort Study in Rheumatoid Arthritis Patients Diagnosed From 2000 Onward. AB - OBJECTIVE: Because of its association with joint destruction, anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is considered to be more severe than ACPA-negative RA. Clinically relevant joint destruction is now infrequent thanks to adequate disease suppression. According to patients, important outcomes are pain, fatigue, and independence. We evaluated whether ACPA positive RA patients diagnosed during or after 2000 have more severe self reported limitations and impairments, including restrictions at work, than ACPA negative RA patients. METHODS: A total of 492 ACPA-positive and 450 ACPA-negative RA patients who fulfilled the 2010 criteria and were included in the Leiden Early Arthritis Clinic cohort during or after 2000 were compared for self-reported pain, fatigue, disease activity, general well-being (measured by numerical rating scales), physical function (measured by the Health Assessment Questionnaire), and work restrictions, including absenteeism at baseline and during the 4-year followup. Linear mixed models were used. RESULTS: At disease presentation, ACPA negative patients had more severe pain, fatigue, self-reported disease activity scores, and functional disability (P < 0.05), although absolute differences were small. During followup, ACPA-negative patients remained somewhat more fatigued (P = 0.002), whereas other patient-reported impairments and limitations were similar. Thirty-eight percent of ACPA-negative and 48% of ACPA-positive patients reported absenteeism (P = 0.30), with median 4 days missed in both groups in the last 3 months. Also, restrictions at work among employed patients and restrictions with household work were not statistically different at baseline and during followup. CONCLUSION: In current rheumatology practice, ACPA-positive RA is not more severe than ACPA-negative RA in terms of patients' relevant outcomes, including physical functioning and restrictions at work. This implies that efforts to further improve the disease course should be proportional to both disease subsets. PMID- 29266814 TI - Pediatric femoral hernia in the laparoscopic era. AB - INTRODUCTION: Femoral hernia is a rare and often misdiagnosed condition in childhood. The aim of our study was to demonstrate that the laparoscopic approach improves diagnostic accuracy and offers a safe and effective treatment. METHODS: A retrospective study of 687 pediatric patients who underwent laparoscopic inguinal hernia repair from January 2000 to December 2015 was performed. RESULTS: Femoral hernias were identified in 16 patients (2.3%). The right side was affected in 10 cases (62.5%), the left side in 5 (31.2%), and 1 case was bilateral (6.2%). The mean age of patients was 8.00 +/- 3.81 years, and there was a male predominance. Preoperative diagnosis was femoral hernia in eight cases (50%) and indirect inguinal hernia in the remaining eight (50%). Seven children (43.8%) presented with hernia recurrence after having undergone an open ipsilateral indirect hernia repair. A modified laparoscopic McVay technique was performed in 12 cases (70.6%). An epigastric artery injury by trocar occurred in one patient. All operations were completed laparoscopically. The mean surgical time was 45.6 +/- 22.9 min for unilateral cases and 110 +/- 10.0 min for bilateral cases. No immediate postoperative complications were noted. The mean postoperative hospital stay was 0.6 +/- 0.4 days. No recurrence was observed after a median follow-up of 11 years (range, 4-16 years). CONCLUSION: Femoral hernia is a rare pathology in pediatric patients that is often difficult to diagnose. The laparoscopic approach is effective in the diagnosing and treating these hernias, and it allows for the simultaneous repair of multiple groin defects. PMID- 29266810 TI - Multimodal approaches to functional connectivity in autism spectrum disorders: An integrative perspective. AB - Atypical functional connectivity has been implicated in autism spectrum disorders (ASDs). However, the literature to date has been largely inconsistent, with mixed and conflicting reports of hypo- and hyper-connectivity. These discrepancies are partly due to differences between various neuroimaging modalities. Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) measure distinct indices of functional connectivity (e.g., blood-oxygenation level-dependent [BOLD] signal vs. electrical activity). Furthermore, each method has unique benefits and disadvantages with respect to spatial and temporal resolution, vulnerability to specific artifacts, and practical implementation. Thus far, functional connectivity research on ASDs has remained almost exclusively unimodal; therefore, interpreting findings across modalities remains a challenge. Multimodal integration of fMRI, EEG, and MEG data is critical in resolving discrepancies in the literature, and working toward a unifying framework for interpreting past and future findings. This review aims to provide a theoretical foundation for future multimodal research on ASDs. First, we will discuss the merits and shortcomings of several popular theories in ASD functional connectivity research, using examples from the literature to date. Next, the neurophysiological relationships between imaging modalities, including their relationship with invasive neural recordings, will be reviewed. Finally, methodological approaches to multimodal data integration will be presented, and their future application to ASDs will be discussed. Analyses relating transient patterns of neural activity ("states") are particularly promising. This strategy provides a comparable measure across modalities, captures complex spatiotemporal patterns, and is a natural extension of recent dynamic fMRI research in ASDs. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 456-473, 2018. PMID- 29266815 TI - Comparative effectiveness of allergy testing method in driving immunotherapy outcomes. AB - BACKGROUND: Skin-prick testing (SPT), in vitro testing (IVT), and intradermal dilutional testing (IDT) are methods to detect patient sensitivities to specific allergens and direct immunotherapy dosing. We used objective and subjective measures of improvement to compare outcomes based on test method. METHODS: Patients underwent 1 of 3 protocols: SPT, screening SPT followed by IDT, or IVT. We used institution billing data to do a cost analysis of these tests. The time to maintenance (TTM) therapy was analyzed and patients were stratified into high and low reactors. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was used to quantify symptoms pre-maintenance and post-maintenance. RESULTS: Of 177 patients (SPT, n = 40; IVT, n = 91; IDT, n = 46), 115 (SPT, n = 35; IVT, n = 39; IDT, n = 41) were high reactors. Out of 90 patients (SPT, n = 17; IVT, n = 37; IDT, n = 36) reaching maintenance, 58 were high reactors (SPT, n = 15; IVT, n = 12; IDT, n = 31). Overall, SPT, IVT, and IDT median TTM were 542, 329, and 578.5 days, respectively. IDT TTM was shorter compared to IVT overall and in high reactors (hazard ratio [HR] = 1.91, p = 0.02; HR = 2.12, p = 0.03), but was not significant compared to SPT high reactors (p = 0.33). The IDT cost was $62.66, translating to an incremental cost-effectiveness ratio of $0.23 per day of shortened TTM. Median RQLQ change for the SPT, IVT, and IDT groups was 6.5, 1, and 1.5, respectively, but was not significant (p = 0.60). CONCLUSION: IDT reached maintenance immunotherapy quicker than IVT but there was no difference compared to SPT. TTM did not correlate with improvements in patient symptoms between testing methods. This study represents a novel comparison of outcomes based on initial allergy testing method. PMID- 29266816 TI - Undergraduate Health Students' Intention to Use Evidence-Based Practice After Graduation: A Systematic Review of Predictive Modeling Studies. AB - BACKGROUND: Incorporating evidence-based practice (EBP) into clinical decision making and professional practice is a requirement for many health disciplines, yet research across health disciplines on factors that influence and predict student intention to use EBP following graduation has not been previously synthesized. AIM: To synthesize research on factors that influence development of EBP behaviors and subsequently predict undergraduate students' intention toward EBP uptake. METHODS: A systematic review of prediction modeling studies was conducted according to a protocol previously published on the Prospero database: https://www.crd.york.ac.uk/PROSPERO/. The outcome variable was undergraduate students' future use or intention to use EBP. Evidence synthesis methods were guided by resources from the Cochrane Methods Prognosis Group Web site (https://prognosismethods.cochrane.org). RESULTS AND FINDINGS: Only three studies were found to meet inclusion criteria for the review. Factors relating to EBP capability, EBP attitudes, as well as clinical and academic support were identified as influential toward students' intention to use evidence in practice. Heterogeneity limited data pooling, consequently, results are presented in narrative and tabular form. LINKING EVIDENCE TO ACTION: Although using a developing method, this review presents a unique contribution to further discussions regarding students' intention to use EBP following graduation. Despite limitations, consideration of identified factors for undergraduate curriculum could support student's intention to use EBP in their respective clinical environments. PMID- 29266817 TI - Early noninvasive high-frequency oscillatory ventilation in the primary treatment of respiratory distress syndrome. PMID- 29266818 TI - Toxoplasma gondii promotes changes in VIPergic submucosal neurons, mucosal intraepithelial lymphocytes, and goblet cells during acute infection in the ileum of rats. AB - BACKGROUND: The intestinal mucosa plays an important role in the mechanical barrier against pathogens. During Toxoplasma gondii infection, however, the parasites invade the epithelial cells of the small intestine and initiate a local immune response. In the submucosal plexus, this response promotes an imbalance of neurotransmitters and induces neuroplasticity, which can change the integrity of the epithelium and its secretory function. This study evaluated the submucosal neurons throughout acute T. gondii infection and the relationship between possible alterations and the epithelial and immune defense cells of the mucosa. METHODS: Forty Wistar rats were randomly assigned to 8 groups (n = 5): 1 control group, uninfected, and 7 groups infected with an inoculation of 5000 sporulated T. gondii oocysts (ME-49 strain, genotype II). Segments of the ileum were collected for standard histological processing, histochemical techniques, and immunofluorescence. KEY RESULTS: The infection caused progressive neuronal loss in the submucosal general population and changed the proportion of VIPergic neurons throughout the infection periods. These changes may be related to the observed reduction in goblet cells that secret sialomucins and increase in intraepithelial lymphocytes after 24 hours, and the increase in immune cells in the lamina propria after 10 days of infection. The submucosa also presented fibrogenesis, characterizing injury and tissue repair. CONCLUSIONS AND INFERENCES: The acute T. gondii infection in the ileum of rats changes the proportion of VIPergic neurons and the epithelial cells, which can compromise the mucosal defense during infection. PMID- 29266819 TI - Machine learning-based diagnosis of melanoma using macro images. AB - Cancer bears a poisoning threat to human society. Melanoma, the skin cancer, originates from skin layers and penetrates deep into subcutaneous layers. There exists an extensive research in melanoma diagnosis using dermatoscopic images captured through a dermatoscope. While designing a diagnostic model for general handheld imaging systems is an emerging trend, this article proposes a computer aided decision support system for macro images captured by a general-purpose camera. General imaging conditions are adversely affected by nonuniform illumination, which further affects the extraction of relevant information. To mitigate it, we process an image to define a smooth illumination surface using the multistage illumination compensation approach, and the infected region is extracted using the proposed multimode segmentation method. The lesion information is numerated as a feature set comprising geometry, photometry, border series, and texture measures. The redundancy in feature set is reduced using information theory methods, and a classification boundary is modeled to distinguish benign and malignant samples using support vector machine, random forest, neural network, and fast discriminative mixed-membership-based naive Bayesian classifiers. Moreover, the experimental outcome is supported by hypothesis testing and boxplot representation for classification losses. The simulation results prove the significance of the proposed model that shows an improved performance as compared with competing arts. PMID- 29266820 TI - Lung Injury Repair by Transplantation of Adult Lung Cells Following Preconditioning of Recipient Mice. AB - Repair of injured lungs represents a longstanding therapeutic challenge. We recently demonstrated that human and mouse embryonic lung tissue from the canalicular stage of development are enriched with lung progenitors, and that a single cell suspension of canalicular lungs can be used for transplantation, provided that lung progenitor niches in the recipient mice are vacated by strategies similar to those used in bone marrow transplantation. Considering the ethical limitations associated with the use of fetal cells, we investigated here whether adult lungs could offer an alternative source of lung progenitors for transplantation. We show that intravenous infusion of a single cell suspension of adult mouse lungs from GFP+ donors, following conditioning of recipient mice with naphthalene and subsequent sublethal irradiation, led to marked colonization of the recipient lungs, at 6-8 weeks post-transplant, with donor derived structures including epithelial, endothelial, and mesenchymal cells. Epithelial cells within these donor-derived colonies expressed markers of functionally distinct lung cell types, and lung function, which is significantly compromised in mice treated with naphthalene and radiation, was found to be corrected following transplantation. Dose response analysis suggests that the frequency of patch forming cells in adult lungs was about threefold lower compared to that found in E16 fetal lungs. However, as adult lungs are much larger, the total number of patch forming cells that can be collected from this source is significantly greater. Our study provides proof of concept for lung regeneration by adult lung cells after preconditioning to vacate the pulmonary niche. Stem Cells Translational Medicine 2018;7:68-77. PMID- 29266822 TI - Segregation of motor and sensory axons regenerating through bicompartmental tubes by combining extracellular matrix components with neurotrophic factors. AB - Segregation of regenerating motor and sensory axons may be a good strategy to improve selective functionality of regenerative interfaces to provide closed-loop commands. Provided that extracellular matrix components and neurotrophic factors exert guidance effects on different neuronal populations, we assessed in vivo the potential of separating sensory and motor axons regenerating in a bicompartmental Y-type tube, with each branch prefilled with an adequate combination of extracellular matrix and neurotrophic factors. The severed rat sciatic nerve was repaired using a bicompartmental tube filled with a collagen matrix enriched with fibronectin (FN) and brain-derived neurotrophic factor (BDNF) encapsulated in poly-lactic co-glycolic acid microspheres (FN + MP.BDNF) in one compartment to preferentially attract motor axons and collagen enriched with laminin (LM) and nerve growth factor (NGF) and neurotrophin-3 (NT-3) in microspheres (LM + MP.NGF/NT-3) in the other compartment for promoting sensory axons regeneration. Control animals were implanted with the same Y-tube with a collagen matrix with microspheres (MP) containing PBS (Col + MP.PBS). By using retrotracer labelling, we found that LM + MP.NGF/NT-3 did not attract higher number of regenerated sensory axons compared with controls, and no differences were observed in sensory functional recovery. However, FN + MP.BDNF guided a higher number of regenerating motor axons compared with controls, improving also motor recovery. A small proportion of sensory axons with large soma size, likely proprioceptive neurons, was also attracted to the FN + MP.BDNF compartment. These results demonstrate that muscular axonal guidance can be modulated in vivo by the addition of fibronectin and BDNF. PMID- 29266821 TI - Angiopoietin-like protein 8/betatrophin correlates with hepatocellular lipid content independent of insulin resistance in non-alcoholic fatty liver disease patients. AB - AIMS/INTRODUCTION: To explore angiopoietin-like protein 8 (ANGPTL-8) levels, and its association with hepatocellular lipid content (HCL) and insulin resistance in patients with different extents of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: In 48 adults were recruited, of which 12 had no NAFLD (HCL < 5.5%; group 1), 18 had mild NAFLD (5.5% <= HCL < 10.0%; group 2) and 18 had moderate-to-severe NAFLD (HCL >= 10.0%; group 3). The peripheral insulin sensitivity of all participants was monitored by a hyperinsulinemic-euglycemic clamp (M value), as well as the magnetic resonance image of HCL. Serum ANGPTL-8, blood glucose levels and lipid profiles were also recorded in the study. RESULTS: Group 3 had a worse metabolic profile, and had the highest ANGPTL-8 level (1,129 +/- 351 pg/mL vs 742 +/- 252 pg/mL, 765 +/- 301 pg/mL, P = 0.001) compared with those in group 1 and group 2. In all metabolic profiles, HCL positively correlated the strongest with ANGPTL-8 (r = 0.436, P = 0.042). Multivariate stepwise linear regression analysis showed ANGPTL-8 and alanine aminotransferase were independent determinants of HCL (P = 0.002, P < 0.001, respectively), and these two indexes explained 67.4% of the variation of HCL (P < 0.001). CONCLUSIONS: ANGPTL-8 was positively correlated with hepatocellular lipid content independent of obesity and insulin resistance, indicating that ANGPTL-8 might be a new and important important predictor of the severity of NAFLD. PMID- 29266823 TI - Mid-life social outcomes for a population-based sample of adults with ASD. AB - : Adults with autism spectrum disorders (ASD) fall short of social outcomes of non-ASD peers in mid-life, as documented by currently published research. The aim of the current study was to extend what is known about social functioning, employment, independent living, and use of social services by examining details of the current life status for a population-based sample of adults with ASD (mean age = 35.5 years, range = 22.2-51.4). We collected outcome data via direct assessment and informant report for 169 individuals. Three-fourths of the sample had cognitive abilities in the intellectually disabled range. Social functioning outcomes, as a single measure, mirror those reported previously for other samples, including samples with a high proportion of individuals with normal range intellectual abilities, with 20% achieving the most independent outcomes and 46% requiring high levels of support across most life areas. Participant subgroups who achieved maximal outcomes represented a range of social and intellectual abilities for several outcome metrics. Participants used high levels of public and private supports, yet specific areas of clear, unmet need were also identified. Autism Res 2018, 11: 142-152. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This paper describes the social functioning outcomes for 169 adults with autism spectrum disorders in mid life. Adult participants spanned the full range of functional and cognitive ability levels, with over 75% functioning in the cognitively impaired range. While summary descriptions of outcomes for this sample were similar to those reported for other groups of adults, this report provides detailed information regarding employment outcomes, social relationships, leisure activities, participation in the community, residential situations, public service use, and involvement with law enforcement. PMID- 29266825 TI - Bronsted Acid-Catalyzed Carbonyl-Olefin Metathesis inside a Self-Assembled Supramolecular Host. AB - Carbonyl-olefin metathesis represents a powerful yet underdeveloped method for the formation of carbon-carbon bonds. So far, no Bronsted acid based method for the catalytic carbonyl-olefin metathesis has been described. Herein, a cocatalytic system based on a simple Bronsted acid (HCl) and a self-assembled supramolecular host is presented. The developed system compares well with the current benchmark catalyst for carbonyl-olefin metathesis in terms of substrate scope and yield of isolated product. Control experiments provide strong evidence that the reaction proceeds inside the cavity of the supramolecular host. A mechanistic probe indicates that a stepwise reaction mechanism is likely. PMID- 29266824 TI - Everyday discrimination in a racially diverse sample of patients with obesity. AB - Weight discrimination affects a significant proportion of individuals with obesity and contributes to poor mental and physical health. Prior research on weight discrimination has been limited by a lack of racial diversity in samples and has not considered other potential forms of discrimination that individuals with obesity may experience. The current study assessed different reasons for discrimination in a racially diverse sample of treatment-seeking individuals with obesity (N = 122, 66.4% black, mean body mass index = 38.5 +/- 6.2 kg/m2 ). Results showed that over half of participants reported experiencing at least one form of repeated discrimination, and 30% reported two or more reasons for discrimination. Race and weight were the most commonly reported reasons for repeated, everyday instances of discrimination. Among participants who reported experiencing weight discrimination (28.7%), over 80% reported experiencing at least one other form of discrimination, with 60% reporting discrimination due to race. These findings indicate that individuals with obesity may face multiple forms of discrimination in their daily lives. Further research is needed to understand how all forms of discrimination contribute to obesity-related health problems. PMID- 29266826 TI - Stress affects expression of the clock gene Bmal1 in the suprachiasmatic nucleus of neonatal rats via glucocorticoid-dependent mechanism. AB - AIM: The reactivity of the circadian clock in the suprachiasmatic nuclei (SCN) to stressful stimuli has been controversial but most studies have confirmed the resilience of the SCN to stress. We tested the hypothesis that during a critical period shortly after birth, the developing SCN clock is affected by glucocorticoids. METHODS: Mothers of 2 rat strains with different sensitivities to stress, that is Wistar rats and spontaneously hypertensive rats (SHR), and their pups were exposed to stressful stimuli every day from delivery, and clock gene expression profiles were detected in the 4-day-old pups' SCN. Levels of glucocorticoids in plasma were measured by LC-MS/MS. The glucocorticoid receptors antagonist mifepristone was administered to pups to block the effect of the glucocorticoids. RESULTS: The glucocorticoid receptors were detected at the mRNA and protein levels in the SCN of 4-day-old pups. The exposure of mothers to stressful stimuli elevated their plasma glucocorticoid levels. In Wistar rat pups, combination of daily maternal stress with their manipulation increased the plasma glucocorticoid levels and shifted the Bmal1 rhythm in the SCN which was completely blocked by mifepristone. In contrast, in SHR pups, maternal stress on its own caused phase shift of the Bmal1 expression rhythm in the SCN but the effect was mediated via glucocorticoid-independent mechanism. The Per1 and Per2 expression profiles remained phase-locked to the light/dark cycle. CONCLUSION: The results demonstrate that the SCN is sensitive to stressful stimuli early after birth in pups maintained under light/dark conditions and the effect is mediated via glucocorticoid-dependent pathways. PMID- 29266827 TI - Morphological and Histological Study on the Foot Pads of the Anatolian Bobcat (Lynx lynx). AB - This study was conducted to reveal the morphometric and morphological features of foot pads in the Anatolian bobcat (Lynx lynx). To achieve this objective, dissection, histological, and radiography techniques were applied to two dead materials obtained from the Republic of Turkey Ministry of Forest and Water Works Sivas Branch Manager. Digit I is radiographically rudimentary in the forepaw. The paws of the forelimb of the Anatolian bobcat have a carpal, a metacarpal, and four digital pads, while the hind feet have a metatarsal pad and four digital pads. The metacarpal pad is cone-like, while the metatarsal pad resembles a butterfly. The digital pads in the paws of the forelimb are longer and thinner than in the paws in the hind feet. The paws in both feet are situated as binary. Through histological examination, it was determined that the skin of the foot pads consists of epidermis, dermis, and pad cushion. The epidermis is subdivided into basal, spinous, granular, lucidum, and corneum layers. The dermis of each pad consists of papillar and reticular strata containing sweat glands, elastin, collagen, and reticular fibers. Anat Rec, 301:932-938, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266828 TI - Go/No-Go decision in donor liver utilization: The value of preretrieval liver biopsy. PMID- 29266829 TI - Infant and young child feeding practices and nutritional status in Bhutan. AB - In South Asia, childhood undernutrition persists while overweight is increasing. Internationally recommended infant and young child feeding (IYCF) practices promote healthy nutritional status; however, little is known about IYCF in Bhutan, investigated here using 2015 National Nutrition Survey data. WHO/UNICEF IYCF indicators, anthropometry and household socio-economic status were available for 441 children <24 months. Stunting, wasting, and underweight prevalence (<-2Z length-for-age [LAZ], weight-for-age, [WAZ] and weight-for-length [WLZ], respectively) were 15%, 9%, and 5%, respectively, whereas overweight (WLZ >2) prevalence was 6%. In survey-design-adjusted analyses, 52% of mothers of 0- to 5 month olds reported exclusive breastfeeding (EBF), with EBF less common for girls than boys (OR: 0.2 [95% CI: 0.1-0.9]). Although 61% of children were breastfed at 2 years and 75% of children >6 months met a minimum daily meal frequency, only 18% of children 6-23 months met minimum dietary diversity. IYCF was unassociated with risk of stunting, wasting, or underweight, possibly due to relatively low prevalence of anthropometric failure and small sample size. However, currently breastfed children were less often overweight [OR: ~0.1 (95% upper limit <=1.0)]. Neither breastfeeding nor most complementary feeding practices differed by socio economic status, but children in the highest two fifth of a wealth index had 7.8 (1.3-46.9) and 5.3 (1.1-25.2) times greater odds than children in the lowest fifth of meeting minimum dietary diversity criteria. Low rates of EBF, given possible protection of breastfeeding against overweight, and inadequate dietary diversity offer evidence to guide future program interventions to improve nutritional status of young children. PMID- 29266830 TI - The sausage toe as a sign of diabetic foot osteomyelitis. PMID- 29266831 TI - Inferior long-term allograft and patient outcomes among recipients of offspring living donor kidneys. AB - While offspring-to-parent living donor kidney transplantations may represent an ideal donor-recipient combination to optimize long-term transplantation outcomes, the sex-specific long-term success of these transplantations remains unclear. We hypothesize that allograft and recipient survivals in offspring-to-parent living donor kidney transplantation differ between men and women due to donor-specific alloimmunization during pregnancy. We retrospectively analyzed long-term allograft and patient survival among men and women who received an offspring living donor kidney compared with those who received other haplotype-matched living donor kidneys. Based on multivariable Cox proportional hazards modeling of Organ Procurement and Transplantation Network data from 2001 to 2015, we found that both men and women who received offspring living donor kidneys had significantly increased mortality compared with recipients who received nonoffspring living donor kidneys. While male recipients of any living donor kidney had greater risk of mortality and allograft failure than female recipients, there was no significant difference in all-cause allograft failure or mortality in male versus female recipients of offspring living donor kidney transplantations. Our analysis demonstrated no significant interaction between recipient sex and donor offspring status. We conclude that nonoffspring living donors should be considered whenever feasible for both men and women with multiple donor options. PMID- 29266832 TI - Denying the inevitability of death. PMID- 29266833 TI - Short report: Follow-up of Bahamian women with a BRCA1 or BRCA2 mutation. AB - PURPOSE: We sought to determine to what extent the knowledge of carrying a BRCA1 or BRCA2 mutation influences the uptake of preventive surgeries in Bahamian women, including bilateral salpingo-oophorectomy and bilateral mastectomy. PATIENTS AND METHODS: The study population consisted of 78 female residents of the Bahamas for whom a BRCA1 or BRCA2 mutation had been detected between 2004 and 2014. The mean age of the 78 participants at the time of genetic testing was 46 years (age range 22-73 years). The mean time of follow-up was 4.4 years. RESULTS: Of the 78 study participants, 19 women had a bilateral salpingo-oophorectomy (24%). Seven out of 37 patients who had unilateral breast cancer chose to remove the unaffected contralateral breast (19%). Three of 13 patients with no history of breast cancer chose to have a prophylactic bilateral mastectomy (23%). CONCLUSION: Preventive surgery is an acceptable option for a significant proportion of Bahamian women with a BRCA1 or BRCA2 mutation. It will be important to identify and reduce barriers to preventive surgery in the Bahamas in order that the benefit of getting testing can be fully realized. PMID- 29266834 TI - Patients with sporadic and familial amyotrophic lateral sclerosis found value in genetic testing. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a genetic disease. There is no consensus, however, as to the role of genetic testing in the care of the ALS patient. METHODS: We conducted a survey to study patient access, attitudes, and experience with ALS genetic testing among patients enrolled in a US ALS registry. RESULTS: Among 449 survey respondents, 156 (34.7%) were offered testing and 105 of 156 (67.3%) completed testing. The majority of respondents with familial ALS (fALS) (31/45, 68.9%) were offered testing, while a minority of respondents with sporadic ALS (sALS) (111/404, 27.5%) were offered testing (p = .00001). Comparison of mean test experience scores between groups revealed that respondents with fALS were no more likely to report a favorable experience with genetic testing than those with sALS (p = .51). Respondents who saw a genetic counselor did not have significantly different test experience scores, compared to those who did not (p = .14). In addition, no differences in test experience scores were observed between those who received positive or negative genetic test results (p = .98). CONCLUSION: These data indicate that patients with ALS found value in clinical genetic testing. PMID- 29266835 TI - Periosteum Extracellular-Matrix-Mediated Acellular Mineralization during Bone Formation. AB - Cell-mediated mineralization is essential for bone formation and regeneration. In this study, it is proven that extracellular matrix (ECM) of decellularized periosteum can play an initiative and independent role in bone-like apatite formation. Using decellularized periosteum scaffold, it is revealed that ECM scaffold itself can promote critical bone defect regeneration and nude mouse ectopic ossification. The natural collagen matrix of decellularized periosteum can serve as a 3D structural template for Ca-P nuclei initiation, controlling the size and orientation of bone-like mineral crystals. The naturally cross-linked and highly ordered 3D fibrillar network of decellularized periosteum not only provides a model for mimicking mineralization in vitro and in vivo to elucidate the important functions of ECM in bone formation and regeneration, but also can be a promising biomaterial for bone tissue engineering and clinical application. PMID- 29266836 TI - Redox-Active Peptide-Functionalized Quinquethiophene-Based Electrochromic pi-Gel. AB - An electrochromic system based on a self-assembled dipeptide-appended redox active quinquethiophene pi-gel is reported. The designed peptide-quinquethiophene consists of a symmetric bolaamphiphile that has two segments: a redox-active pi conjugated quinquethiophene core for electrochromism, and peptide motif for the involvement of molecular self-assembly. Investigations reveal that self-assembly and electrochromic properties of the pi-gel are strongly dependent on the relative orientation of peptidic and quinquethiophene scaffolds in the self assembly system. The colors of the pi-gel film are very stable with fast and controlled switching speed at room temperature. PMID- 29266837 TI - The PRKD1 E710D hotspot mutation is highly specific in separating polymorphous adenocarcinoma of the palate from adenoid cystic carcinoma and pleomorphic adenoma on FNA. AB - BACKGROUND: Polymorphous adenocarcinoma (PAC) of the palatal minor salivary glands, previously known as polymorphous low-grade adenocarcinoma, is the second most common intraoral malignant salivary gland carcinoma after adenoid cystic carcinoma (ACC) and carries an excellent prognosis. Unfortunately, PAC demonstrates cytological overlap with 2 other salivary gland tumors frequently encountered in the same location, namely ACC and pleomorphic adenoma (PA). Recently, the protein kinase D1 (PRKD1) hotspot mutation E710D was demonstrated to be specific for PAC and to be present in the majority of cases. The objective of the current study was to investigate the value of PRKD1 hotspot sequencing in identifying PAC in paired fine-needle aspiration (FNA) and surgical specimens from cases of PAC, ACC, and PA. METHODS: Paired May-Grunwald-Giemsa-stained FNA and corresponding surgical specimens were collected from 18 PAC cases, 25 ACC cases, and 21 PA cases. Both sets of specimens were subjected to dideoxynucleotide sequencing of PRKD1 exon 15, including the PRKD1 E710D hotspot. RESULTS: Of the PAC cases, approximately 50% demonstrated identical PRKD1 E710D hotspot mutations on the FNA specimen and corresponding surgical specimen. Two ACC specimens had point mutations within the sequenced region in the FNA specimen as well as the surgical specimen, but none were located in the hotspot region. None of the PA cases demonstrated PRKD1 mutations. The specificity of the PRKD1 hotspot mutation for identifying PAC among ACC and PA cases was 100% whereas the sensitivity was 50%. CONCLUSIONS: The PRKD1 E710D hotspot mutation is highly specific for identifying PAC on FNA among cases of ACC and PA, whereas the sensitivity is only modest. Alternative PRKD1 mutations exclude PAC, and are more suggestive of ACC. Cancer Cytopathol 2018;126:275-81. (c) 2017 American Cancer Society. PMID- 29266838 TI - Identification of differential protein-coding gene expressions in early phase lung adenocarcinoma. AB - BACKGROUND: The diagnosis of early phase lung adenocarcinoma (LADC) is associated with therapeutic strategy, effect, and survival time. However, the sensitive biomarkers of early phase LADC are still unclear. This study aimed to identify protein-coding genes that can be used as biomarkers of early stage LADC. METHODS: Gene microarray analysis was performed to identify key hub genes that show different expression in lung adenocarcinoma compared to normal tissues. The microarray data of lung adenocarcinoma in stages IA, IB, IIA, IIB, and normal tissues (GSE10072) were downloaded from a free online database, Gene Expression Omnibus (GEO). RESULTS: A total of 572 differentially expressed genes (DEGs) were identified between early phase lung adenocarcinoma and normal tissues using R software. Database for Annotation, Visualization and Integrated Discovery online tools were used to obtain Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes was used to analyze DEGs. Cytoscape software was used to express the protein-protein interaction network. We found that some cancer related Gene Ontology terms and pathways (e.g. cell adhesion, cell surface receptor signaling pathway, PI3K-Akt signaling pathway) were significantly enriched in DEGs. CONCLUSION: Protein-coding genes JUN, FYN, CAV1, and SFN may play vital roles in the progress of early-stage lung adenocarcinoma. Consequently, through bioinformatics analysis, the key genes could be established to provide more potential references for the therapeutic targets of lung adenocarcinoma. PMID- 29266839 TI - Polyethylene glycol-based bowel preparation before colonoscopy for selected inpatients: A pilot study. AB - OBJECTIVE: To evaluate the impact of a new same-day, low-dose 1-L polyethylene glycol-based (1-L PEG) bowel preparation on the diagnostic rating of selected hospitalized patients and its tolerability, with risk factors for inadequate bowel preparation. METHODS: A single-center prospective pilot study was conducted with hospitalized patients scheduled for colonoscopy, presenting risk factors for poor bowel preparation, such as bleeding or subocclusive symptoms. The included patients were randomly divided in two groups, which received either a same-day 1 L PEG (group A) or a split-dose 4-L PEG (group B), and performed a colonoscopy within 4 h of the last dose. RESULTS: In all, 44 inpatients [27 males; mean age 63.5 years (range 20-94 years)] were enrolled. Optimal bowel cleansing was reached in 64% and 55% (P = 0.64) of patients in groups A and B, respectively. The adenoma detection rate was 14% (group A) and 18% (group B) (P = 0.34). A valid diagnosis was reached in 38 (86%) of 44 patients (21 in group A and 17 in group B) after a mean hospitalization of 3 days for group A and 6 days for group B (P = 0.04). CONCLUSIONS: Our data support the conclusion that the schedule protocol proposed in this study enables a clear diagnosis in most of the inpatients at high risk of poor bowel preparation and no statistical differences were found between the two groups in terms of successful bowel cleansing achieved. Therefore, the same-day, low-dose 1-L PEG bowel preparation could be introduced for selected inpatients. PMID- 29266840 TI - Female adnexal tumour of Wolffian origin presenting as a pouch of Douglas mass: a case report and literature review. PMID- 29266842 TI - Development and Validation of Mass Spectrometry-Based Targeted Analysis for Amyloid Proteins. AB - PURPOSE: Amyloidosis is caused by the extracellular deposition of insoluble fibrils and results in multiple organ dysfunctions. Accurate typing of amyloid is mandatory to decide the optimal treatment for amyloidosis. EXPERIMENTAL DESIGN: A mass spectrometry-based test combined with laser microdissection (LMD/MS) has been widely used even in the tricky cases that cannot be discriminated by immunohistochemical staining. However, shotgun proteomics analysis obligatorily requires not only expensive instruments but also highly-experienced specialists to interpret the analysis. Thus, a method of LMD combined with multiple reaction monitoring mass spectrometry (MRM-MS) that can detect three most common types of amyloidosis is developed. RESULTS: The diagnostic method is tested in 16 Congo red-positive tissues and 10 Congo red-negative control tissues. The results showed better performance in amyloidosis typing than other analytical techniques. CONCLUSION AND CLINICAL RELEVANCE: This novel diagnostic approach can achieve successful amyloidosis typing with high specificity and sensitivity and be implemented more easily in general clinical laboratories. PMID- 29266841 TI - Generation of Transplantable Retinal Photoreceptors from a Current Good Manufacturing Practice-Manufactured Human Induced Pluripotent Stem Cell Line. AB - Retinal degeneration often results in the loss of light-sensing photoreceptors, which leads to permanent vision loss. Generating transplantable retinal photoreceptors using human somatic cell-derived induced pluripotent stem cells (iPSCs) holds promise to treat a variety of retinal degenerative diseases by replacing the damaged or dysfunctional native photoreceptors with healthy and functional ones. Establishment of effective methods to produce retinal cells including photoreceptors in chemically defined conditions using current Good Manufacturing Practice (cGMP)-manufactured human iPSC lines is critical for advancing cell replacement therapy to the clinic. In this study, we used a human iPSC line (NCL-1) derived under cGMP-compliant conditions from CD34+ cord blood cells. The cells were differentiated into retinal cells using a small molecule based retinal induction protocol. We show that retinal cells including photoreceptors, retinal pigmented epithelial cells and optic cup-like retinal organoids can be generated from the NCL-1 iPSC line. Additionally, we show that following subretinal transplantation into immunodeficient host mouse eyes, retinal cells successfully integrated into the photoreceptor layer and developed into mature photoreceptors. This study provides strong evidence that transplantable photoreceptors can be generated from a cGMP-manufactured human iPSC line for clinical applications. Stem Cells Translational Medicine 2018;7:210 219. PMID- 29266843 TI - Interactive life-history traits predict sensitivity of plants and animals to temporal autocorrelation. AB - Temporal autocorrelation in demographic processes is an important aspect of population dynamics, but a comprehensive examination of its effects on different life-history strategies is lacking. We use matrix population models from 454 plant and animal populations to simulate stochastic population growth rates (log lambdas ) under different temporal autocorrelations in demographic rates, using simulated and observed covariation among rates. We then test for differences in sensitivities, or changes of log lambdas to changes in autocorrelation among two major axes of life-history strategies, obtained from phylogenetically informed principal component analysis: the fast-slow and reproductive-strategy continua. Fast life histories exhibit highest sensitivities to simulated autocorrelation in demographic rates across reproductive strategies. Slow life histories are less sensitive to temporal autocorrelation, but their sensitivities increase among highly iteroparous species. We provide cross-taxonomic evidence that changes in the autocorrelation of environmental variation may affect a wide range of species, depending on complex interactions of life-history strategies. PMID- 29266844 TI - Grey literature: An important resource in systematic reviews. AB - Systematic reviews aid the analysis and dissemination of evidence, using rigorous and transparent methods to generate empirically attained answers to focused research questions. Identifying all evidence relevant to the research questions is an essential component, and challenge, of systematic reviews. Grey literature, or evidence not published in commercial publications, can make important contributions to a systematic review. Grey literature can include academic papers, including theses and dissertations, research and committee reports, government reports, conference papers, and ongoing research, among others. It may provide data not found within commercially published literature, providing an important forum for disseminating studies with null or negative results that might not otherwise be disseminated. Grey literature may thusly reduce publication bias, increase reviews' comprehensiveness and timeliness and foster a balanced picture of available evidence. Grey literature's diverse formats and audiences can present a significant challenge in a systematic search for evidence. However, the benefits of including grey literature may far outweigh the cost in time and resource needed to search for it, and it is important for it to be included in a systematic review or review of evidence. A carefully thought out grey literature search strategy may be an invaluable component of a systematic review. This narrative review provides guidance about the benefits of including grey literature in a systematic review, and sources for searching through grey literature. An illustrative example of a search for evidence within grey literature sources is presented to highlight the potential contributions of such a search to a systematic review. Benefits and challenges of grey literature search methods are discussed, and recommendations made. PMID- 29266845 TI - Antibody Profiling by Proteome Microarray with Multiplex Isotype Detection Reveals Overlap between Human and Aotus nancymaae Controlled Malaria Infections. AB - The development of vaccines against malaria and serodiagnostic tests for detecting recent exposure requires tools for antigen discovery and suitable animal models. The protein microarray is a high-throughput, sample sparing technique, with applications in infectious disease research, clinical diagnostics, epidemiology, and vaccine development. We recently demonstrated Qdot based indirect immunofluorescence together with portable optical imager ArrayCAM using single isotype detection could replicate data using the conventional laser confocal scanner system. We developed a multiplexing protocol for simultaneous detection of IgG, IgA, and IgM and compared samples from a controlled human malaria infection model with those from controlled malaria infections of Aotus nancymaae, a widely used non-human primate model of human malaria. IgG profiles showed the highest concordance in number of reactive antigens; thus, of the 139 antigens recognized by human IgG antibody, 111 were also recognized by Aotus monkeys. Interestingly, IgA profiles were largely non-overlapping. Finally, on the path toward wider deployment of the portable platform, we show excellent correlations between array data obtained in five independent laboratories around the United States using the multiplexing protocol (R2 : 0.60-0.92). This study supports the use of this platform for wider deployment, particularly in endemic areas where such a tool will have the greatest impact on global human health. PMID- 29266846 TI - High circulating miR-18a, miR-20a, and miR-92a expression correlates with poor prognosis in patients with non-small cell lung cancer. AB - The purpose of this study was to assess the predictive value of angiogenic miRNAs for disease-free survival (DFS) and overall survival (OS) of patients with non small cell lung cancer (NSCLC). In total, 196 patients with NSCLC (tumor lymph nodes metastasis (TNM) stage I-III) were enrolled and peripheral blood samples were collected. Total RNA was extracted from blood samples, and the relative expression levels of candidate miRNAs were evaluated by real time-polymerase chain reaction (RT-PCR). The median follow-up period was 56.7 months, and the final follow-up date was in August 2016. The median DFS of all patients was 30.0 (14.0-49.0) months, whereas the median OS was 41.5 (23.0-58.0) months. Furthermore, the 5-year DFS and OS rates were 11.3% and 32.3%, respectively. Kaplan-Meier (K-M) curves showed that high plasma miR-18a (P < 0.001), miR-20a (P < 0.001), miR-92a (P < 0.001), miR-126 (P < 0.001), miR-210 (P = 0.003), and miR 19a (P = 0.027) expressions levels correlated with a worse DFS. Moreover, patients with high plasma miR-18a, miR-20a, miR-92a, miR-210, and miR-126 expression levels had a shorter OS than patients with low expression levels of these miRNAs (all P <= 0.001). Furthermore, multivariate Cox regression analyses revealed that high plasma expression levels of miR-18a, miR-20a, and miR-92a as well as lymphatic node metastasis (all P < 0.001) were independent risk factors for both DFS and OS in patients with NSCLC. Thus, the circulating miR-18a, miR 20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with NSCLC. PMID- 29266847 TI - dartr: An r package to facilitate analysis of SNP data generated from reduced representation genome sequencing. AB - Although vast technological advances have been made and genetic software packages are growing in number, it is not a trivial task to analyse SNP data. We announce a new r package, dartr, enabling the analysis of single nucleotide polymorphism data for population genomic and phylogenomic applications. dartr provides user friendly functions for data quality control and marker selection, and permits rigorous evaluations of conformation to Hardy-Weinberg equilibrium, gametic-phase disequilibrium and neutrality. The package reports standard descriptive statistics, permits exploration of patterns in the data through principal components analysis and conducts standard F-statistics, as well as basic phylogenetic analyses, population assignment, isolation by distance and exports data to a variety of commonly used downstream applications (e.g., newhybrids, faststructure and phylogeny applications) outside of the r environment. The package serves two main purposes: first, a user-friendly approach to lower the hurdle to analyse such data-therefore, the package comes with a detailed tutorial targeted to the r beginner to allow data analysis without requiring deep knowledge of r. Second, we use a single, well-established format-genlight from the adegenet package-as input for all our functions to avoid data reformatting. By strictly using the genlight format, we hope to facilitate this format as the de facto standard of future software developments and hence reduce the format jungle of genetic data sets. The dartr package is available via the r CRAN network and GitHub. PMID- 29266848 TI - Comparing growth in linguistic comprehension and reading comprehension in school aged children with autism versus typically developing children. AB - : Many children with autism spectrum disorders (ASD) struggle with reading comprehension. Linguistic comprehension is an important predictor of reading comprehension, especially as children progress through elementary school and later grades. Yet, there is a dearth of research examining longitudinal relations between linguistic comprehensions in school-age children with ASD compared to typically-developing peers (TD). This study compared the developmental trajectories of linguistic and reading comprehension in samples of children with ASD and age-matched TD peers. Both groups were administered measures of linguistic and reading comprehension multiple times over a 30-month period. Latent growth curve modeling demonstrated children with ASD performed at significantly lower levels on both measures at the first timepoint and these deficits persisted across time. Children with ASD exhibited growth in both skills comparable to their TD peers, but this was not sufficient to enable them to eventually achieve at a level similar to the TD group. Due to the wide age range of the sample, age was controlled and displayed significant effects. Findings suggest linguistic comprehension skills are related to reading comprehension in children with ASD, similar to TD peers. Further, intervention in linguistic comprehension skills for children with ASD should begin early and there may be a finite window in which these skills are malleable, in terms of improving reading comprehension skills. Autism Res 2018, 11: 624-635. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: There is relatively little research concerning reading comprehension development in children with ASD and how they compare to TD peers. This study found children with ASD began at lower achievement levels of linguistic comprehension and reading comprehension than TD peers, but the skills developed at a similar rate. Intervening early and raising initial levels of linguistic and reading comprehension may enable children with ASD to perform similarly to TD peers over time. PMID- 29266849 TI - Biomarkers of pulmonary hypertension after preterm birth: The IMPROV study. PMID- 29266850 TI - Experimental infection of highly pathogenic avian influenza viruses, Clade 2.3.4.4 H5N6 and H5N8, in Mandarin ducks from South Korea. AB - Outbreaks of highly pathogenic avian influenza (HPAI) have been reported worldwide. Wild waterfowl play a major role in the maintenance and transmission of HPAI. Highly pathogenic avian influenza subtype H5N6 and H5N8 viruses simultaneously emerged in South Korea. In this study, the comparative pathogenicity and infectivity of Clade 2.3.4.4 Group B H5N8 and Group C H5N6 viruses were evaluated in Mandarin duck (Aix galericulata). None of the ducks infected with H5N6 or H5N8 viruses showed clinical signs or mortality. Serological assays revealed that the HA antigenicity of H5N8 and H5N6 viruses was similar to each other. Moreover, both the viruses did not replicate after cross challenging with H5N8 and H5N6 viruses, respectively, as the second infection. Although both the viruses replicated in most of the internal organs of the ducks, viral replication and shedding through cloaca were higher in H5N8-infected ducks than in H5N6-infected ducks. The findings of this study provide preliminary information to help estimate the risks involved in further evolution and dissemination of Clade 2.3.4.4 HPAI viruses among wild birds. PMID- 29266852 TI - Mediterranean Tomato-Based Sofrito Sauce Improves Fibroblast Growth Factor 21 (FGF21) Signaling in White Adipose Tissue of Obese ZUCKER Rats. AB - SCOPE: Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Since FGF21 production and signaling are regulated by some bioactive dietary compounds, we analyze the impact of Mediterranean tomato-based sofrito sauce on: (i) the FGF21 expression and signaling in visceral white adipose tissue (vWAT), and (ii) the insulin sensitivity of obese Zucker rats (OZR). METHODS AND RESULTS: OZR are fed with a sofrito-supplemented diet or control diet. Insulin sensitivity and FGF21 signaling are determined. We observed that sofrito is able to improve the responsiveness to both hormones in obese rats. Sofrito-supplemented diet increases FGF21 signaling in vWAT by inducing the expression of the FGF receptors (FGFR1 and FGFR4) that promotes the expression of canonical target genes, like Egr-1, c-Fos and uncoupling protein 1 (Ucp1). CONCLUSIONS: A sofrito-supplemented diet improves insulin and FGF21 sensitivity in OZR, explaining part of sofrito's healthy effects on glucose metabolism. In addition, induction of UCP1 and the unchanged body weight despite the hyperphagic behavior of the sofrito-fed rats suggests that the increase in FGF21 signaling correlates with an increase in energy expenditure (EE). Further studies in humans may help to understand whether sofrito consumption increases the EE in obese individuals. PMID- 29266853 TI - Authors' reply re: Effect of locally tailored labour management guidelines on intrahospital stillbirths and birth asphyxia at the referral hospital of Zanzibar: A quasi-experimental pre-post-study (The PartoMa study). PMID- 29266851 TI - A systematic review of the relationship between weight status perceptions and weight loss attempts, strategies, behaviours and outcomes. AB - It is commonly assumed that a person identifying that they are 'overweight' is an important prerequisite to successful weight management. However, there has been no systematic evaluation of evidence supporting this proposition. The aim of the present research was to systematically review evidence on the relationship between perceived overweight and (i) weight loss attempts, (ii) weight control strategies (healthy and unhealthy), (iii) weight-related behaviours (physical activity and eating habits), (iv) disordered eating and (v) weight change. We synthesized evidence from 78 eligible studies and evaluated evidence linking perceived overweight with outcome variables separately according to the gender, age and objective weight status of study participants. Results indicated that perceived overweight was associated with an increased likelihood of attempting weight loss and with healthy and unhealthy weight control strategies in some participant groups. However, perceived overweight was not reliably associated with physical activity or healthy eating and was associated with greater disordered eating in some groups. Rather than being associated with improved weight management, there was consistent evidence that perceived overweight was predictive of increased weight gain over time. Individuals who perceive their weight status as overweight are more likely to report attempting weight loss but over time gain more weight. PMID- 29266854 TI - Age, Size, and Growth of the Turkish Endemic Frog Pelophylax Caralitanus (Anura: Ranidae). AB - Pelophylax caralitanus is a medium-sized frog that is endemic to the upland Lake District of south-central Turkey and currently identified as a threatened species as a result of overharvesting and habitat modification. In this report, demographic data are provided for four major lakeside populations of this species based on a skeletochronological analysis of bone growth in large samples of frogs that were captured and released during 2011 and 2013. Adult males (aged 2-9 years) and females (aged 2-10 years) ranged in size from 66 to 105 mm snout-vent length (SVL) and 65 to 110 mm SVL, respectively, and typically attained sexual maturity in their second (low-elevation sites) or third (high-elevation sites) summer of growth following metamorphosis. The four populations exhibited differences in growth rate and age at sexual maturity, which appeared to reflect differences in the average monthly temperature and length of the growth season rather than elevation per se, that is, warmer temperatures and longer growth seasons resulted in smaller adults. All populations had a similar overall age structure, with approximately equal frequencies of individuals in the five age and size classes following maturity. Anat Rec, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266855 TI - Medical and surgical rhinology-outcomes matter. PMID- 29266856 TI - Chikungunya Arthritis Mechanisms in the Americas: A Cross-Sectional Analysis of Chikungunya Arthritis Patients Twenty-Two Months After Infection Demonstrating No Detectable Viral Persistence in Synovial Fluid. AB - OBJECTIVE: To determine if chikungunya virus persists in synovial fluid after infection, potentially acting as a causative mechanism of persistent arthritis. METHODS: We conducted a cross-sectional study of 38 Colombian participants with clinical chikungunya virus infection during the 2014-2015 epidemic who reported chronic arthritis and 10 location-matched controls without chikungunya virus or arthritis. Prior chikungunya virus infection status was serologically confirmed, and the presence of synovial fluid chikungunya virus, viral RNA, and viral proteins was determined by viral culture, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and mass spectrometry, respectively. Biomarkers were assessed by multiplex analysis. RESULTS: Patients with serologically confirmed chikungunya arthritis (33 of 38 [87%]) were predominantly female (82%) and African Colombian (55%) or white Colombian (33%), with moderate disease activity (mean +/- SD Disease Activity Score in 28 joints 4.52 +/- 0.77) a median of 22 months after infection (interquartile range 21-23 months). Initial symptoms of chikungunya virus infection included joint pain (97%), swelling (97%), stiffness (91%), and fever (91%). The most commonly affected joints were the knees (87%), elbows (76%), wrists (75%), ankles (56%), fingers (56%), and toes (56%). Synovial fluid samples from all patients with chikungunya arthritis were negative for chikungunya virus on qRT-PCR, showed no viral proteins on mass spectrometry, and cultures were negative. Case and control plasma cytokine and chemokine concentrations did not differ significantly. CONCLUSION: This is one of the largest observational studies involving analysis of the synovial fluid of chikungunya arthritis patients. Synovial fluid analysis revealed no detectable chikungunya virus. This finding suggests that chikungunya virus may cause arthritis through induction of potential host autoimmunity, suggesting a role for immunomodulating agents in the treatment of chikungunya arthritis, or that low level viral persistence exists in synovial tissue only and is undetectable in synovial fluid. PMID- 29266857 TI - "Like No One Is Listening to Me": A Qualitative Study of Patient-Provider Discordance Between Global Assessments of Disease Activity in Rheumatoid Arthritis. AB - OBJECTIVE: To explore the perspectives and experiences of patients with rheumatoid arthritis (RA) whose assessments of their disease differ from those of their rheumatology care provider. METHODS: A total of 20 adult RA patients with patient-provider discordance at their most recent rheumatology appointment (within 4 weeks) were recruited. Discordance was defined by an absolute difference of 25 or more between patient and provider global assessments on a visual analog scale (VAS) of disease activity. For descriptive purposes, participants completed the Health Assessment Questionnaire II, pain VAS, and Patient Health Questionnaire 9 depression scale. Interviews were conducted in person and individually with each patient with a semistructured interview guide. Topics ranged widely, including participants' perspectives and experiences with living with RA, clinical disease assessments, patient-provider communication, and psychosocial or other needs. Data from the interviews were analyzed using interpretive phenomenological analysis. RESULTS: Six major themes emerged from the patient interviews describing patient-provider discordance and disease assessment: being misunderstood by others, limitations of provider assessments, discrepancy with provider findings, inadequate active listening on the part of health care providers, unmet psychosocial needs, and lack of patient empowerment. CONCLUSION: Patients described discordance in terms of symptom assessment and understanding how RA affects everyday life. Typical clinical assessments did not capture their experience. The resulting conceptual framework should inform future interventional studies seeking to enhance concordance of patient-physician communication and to optimize satisfaction with care and health-related quality of-life outcomes for patients with RA. PMID- 29266858 TI - Construction of a vascularized hydrogel for cardiac tissue formation in a porcine model. AB - Replacing cardiac tissues lost to myocardial infarction remains a therapeutic goal for regenerative therapy in recovering cardiac function. We assessed the feasibility of constructing a macrosized human cardiac tissue construct using pluripotent stem cell-derived cardiomyocytes or control fibroblasts infused fibrin/collagen hydrogel and performed ectopic implantation in peripheral vascular system of a porcine model for 3 weeks. Finally, an optimized vascularized cardiac construct was explanted and grafted onto porcine myocardium for 2 weeks. Myocardial-grafted human cardiac constructs showed a nascent tissue like organization with aligned cardiomyocytes within the remodelled collagen matrix. Nevertheless, no significant changes in intraconstruct density of cardiomyocytes were observed in the myocardial-grafted constructs (human embryonic stem cell [hESC]-derived cardiomyocyte [n = 4]: 70.5 +/- 22.8 troponin I+ cardiomyocytes/high power field [HPF]) as compared to peripherally implanted constructs (hESC-derived cardiomyocyte [n = 4]: 59.0 +/- 19.6 troponin I+ cardiomyocytes/HPF; human induced pluripotent stem cell-derived cardiomyocyte [n = 3]: 50.9 +/- 8.5 troponin I+ cardiomyocytes/HPF, p = ns). However, the myocardial-grafted constructs showed an increased in neovascularization (194.4 +/ 24.7 microvessels/mm2 tissue, p < .05), microvascular maturation (82.8 +/- 24.7 mature microvessels/mm2 , p < .05), and tissue-like formation whereas the peripherally implanted constructs of hESC-derived cardiomyocyte (168.3 +/- 98.2 microvessels/mm2 tissue and 68.1 +/- 33.4 mature microvessels/mm2 ) and human induced pluripotent stem cell-derived cardiomyocyte (86.8 +/- 57.4 microvessels/mm2 tissue and 22.0 +/- 32.7 mature microvessels/mm2 ) were not significantly different in vascularized response when compared to the control human fibroblasts (n = 3) constructs (65.6 +/- 34.1 microvessels/mm2 tissue and 30.7 +/- 20.7 mature microvessels/mm2 ). We presented results on technical feasibility and challenges of grafting vascularized centimetre-sized human cardiac construct that may spur novel approaches in cardiac tissue replacement strategy. PMID- 29266859 TI - Cytokine Profiling of Primary Human Macrophages Exposed to Endotoxin-Free Graphene Oxide: Size-Independent NLRP3 Inflammasome Activation. AB - Graphene-based materials including graphene oxide (GO) are envisioned for a variety of biomedical applications. However, there are conflicting results concerning the biocompatibility of these materials. Here, a question is raised whether GO with small or large lateral dimensions triggers cytotoxicity and/or cytokine responses in primary human monocyte-derived macrophages. GO sheets produced under sterile conditions by a modified Hummers' method are found to be taken up by macrophages without signs of cytotoxicity. Then, multiplex arrays are used for profiling of proinflammatory and anti-inflammatory responses. Notably, GO suppresses the lipopolysaccharide (LPS)-triggered induction of several chemokines and cytokines, including the anti-inflammatory cytokine, interleukin 10 (IL-10). No production of proinflammatory TNF-alpha is observed. However, GO elicits caspase-dependent IL-1 beta expression, a hallmark of inflammasome activation, in LPS-primed macrophages. Furthermore, GO-triggered IL-1 beta production requires NADPH oxidase-generated reactive oxygen species and cellular uptake of GO and is accompanied by cathepsin B release and K+ efflux. Using THP-1 knockdown cells, a role for the inflammasome sensor, NLRP3, the adaptor protein, ASC, and caspase-1 for GO-induced IL-1beta secretion is demonstrated. Finally, these studies show that inflammasome activation is independent of the lateral dimensions of the GO sheets. These studies provide novel insights regarding the immunomodulatory properties of endotoxin-free GO. PMID- 29266861 TI - Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted aminomethyl)phenyl]-1,10-phenanthroline derivatives. AB - A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the MUm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence. PMID- 29266862 TI - Orthopedic Surgery Among Patients With Rheumatoid Arthritis: A Population-Based Study to Identify Risk Factors, Sex Differences, and Time Trends. AB - OBJECTIVE: To identify risk factors for large-joint surgery (LJS) versus small joint surgery (SJS) in rheumatoid arthritis (RA) and evaluate trends in surgery rates over time. METHODS: A retrospective medical record review of all orthopedic surgeries following first fulfillment of the 1987 American College of Rheumatology criteria for adult-onset RA among residents of Olmsted County, Minnesota between 1980 and 2013 was performed. Risk factors were examined using Cox models adjusted for age, sex, and calendar year of RA incidence. Trends in incidence of joint surgeries were examined using Poisson regression models. RESULTS: A total of 1,077 patients with RA (mean age 56 years, 69% female, 66% seropositive for rheumatoid factor [RF] and anti-cyclic citrullinated peptide [anti-CCP] antibodies) were followed for a median of 10.7 years, during which 112 patients (90 women) underwent at least 1 SJS and 204 (141 women) underwent at least 1 LJS. Risk factors included advanced age, and RF and anti-CCP antibody positivity for both SJS and LJS, and body mass index >=30 kg/m2 for LJS. Risk factors for SJS and LJS at any time during followup included the presence of radiographic erosions, large-joint swelling, and methotrexate use. SJS rates decreased by calendar year of incidence (hazard ratio 0.53, P = 0.001), with significant decline in the rates of SJS after 1995. The cumulative incidence of SJS was higher in women than men (P = 0.008). CONCLUSION: In recent years, there has been a significant decline in the rates of SJS but not LJS in patients with RA. The incidence of SJS is higher among women. Traditional RA risk factors are strong predictors for SJS and LJS. Increasing age and obesity are predictive of LJS. PMID- 29266863 TI - Does nebulized hypertonic saline shorten hospitalization in young children with acute viral wheezing? AB - BACKGROUND: Although previous studies have shown benefits of nebulized hypertonic saline (HS) for improving airway clearance and shortening hospitalization in infants with bronchiolitis, prospective blinded studies in preschool children with acute viral wheezing are limited. OBJECTIVES: To determine nebulized 3% HS efficacy in young children admitted with acute viral wheezing. METHODS: This double-blind, randomized controlled trial was conducted in children aged 6 months to 5 years admitted with acute viral wheezing from July 1st to December 31st 2016. Patients were randomized to receive inhalation of 2.5 mg salbutamol dissolved in either 3% HS or normal saline (NS). Clinical data, asthma clinical severity score, and length of hospital stay (LOS) were recorded. RESULTS: A total of 47 patients were enrolled (22 in HS and 25 in NS) without significant differences in demographic data and baseline clinical scores. Median LOS and median time of oxygen therapy were significantly shorter in HS than NS group: 48 versus 72 h, P = 0.021 and 36 versus 72 h, P = 0.025, respectively. HS patients had significantly improved asthma clinical severity scores, respiratory rates and oxygen saturation at 12 h compared to NS group (P-value 0.042, 0.032, and 0.043). There were no adverse events. CONCLUSION: In children under 5 years admitted with acute viral wheezing, nebulized hypertonic saline/salbutamol significantly shortened hospital stay length, time of oxygen therapy, and improved asthma clinical severity score faster than normal saline/salbutamol. PMID- 29266860 TI - Human bocavirus and human metapneumovirus in hospitalized children with lower respiratory tract illness in Changsha, China. AB - BACKGROUND: Lower respiratory tract illness is a major cause of morbidity and mortality in children worldwide, however, information about the epidemiological and clinical characteristics of LRTIs caused by HMPV and HBoV in China is limited. OBJECTIVES: Human bocavirus (HBoV) and human metapneumovirus (HMPV) are two important viruses for children with lower respiratory tract infections (LRTI). We aimed to assay the correlation between viral load and clinical characteristics of HBoV and HMPV with LRTI in Changsha, China. METHODS: Nasopharyngeal aspirates (NPAs) from children with LRTI were collected. Real-time PCR was used to screen HBoV and HMPV. Analyses were performed using SPSS 16.0 software. RESULTS: Pneumonia was the most frequent diagnosis. There was no significant difference between HBoV- and HMPV-positive patients in age (P = .506) or hospitalization duration (P = .280); 24.1% and 18.2% were positive for HBoV and HMPV. HBoV infections peaked in summer (32.2%), and HMPV infections peaked in winter (28.9%). The HBoV-positive patients had a shorter hospitalization duration than the HBoV-negative patients (P = .021), and the HMPV-positive patients had a higher prevalence of fever than the HMPV-negative patients (P = .002). The HBoV viral load was significantly higher among patients aged <1 year (P = .006). The mean HBoV and HMPV viral loads were not significantly different between patients with single infections and coinfections. Patients infected with HBoV only were older than those coinfected with HBoV and other respiratory viruses (P = .005). No significant difference was found in the clinical characteristics of patients infected with HMPV only and those coinfected with HMPV and other respiratory viruses. CONCLUSION: Pneumonia was the most frequent diagnosis caused by HBoV and HMPV. Neither HBoV nor HMPV viral load was correlated with disease severity. PMID- 29266864 TI - Quantitative CT scans of lung parenchymal pathology in premature infants ages 0-6 years. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common, heterogeneous disease in premature infants. We hypothesized that quantitative CT techniques could assess lung parenchymal heterogeneity in BPD patients across a broad age range and demonstrate how pathologies change over time. METHODS: A cross-sectional, retrospective study of children age 0-6 years with non-contrast chest CT scans was conducted. BPD subjects met NICHD/NHLBI diagnostic criteria for BPD and were excluded for congenital lung/airway abnormalities or other known/suspected pulmonary diagnoses; control subjects were not premature and had normal CT scan findings. Radiologic opacities, lucencies, and spatial heterogeneity were quantified via: 1) thresholding using CT-attenuation (HU); 2) manual segmentation; and 3) Ochiai reader-scoring system. Clinical outcomes included BPD severity by NICHD/NHLBI criteria, respiratory support at NICU discharge, wheezing, and respiratory exacerbations. RESULTS: Heterogeneity (standard deviation) of lung attenuation in BPD was significantly greater than in controls (difference 36.4 HU [26.1-46.7 HU], P < 0.001); the difference between the groups decreased 0.58 HU per month of age (0.08-1.07 HU per month, P = 0.02). BPD patients had greater amounts of opacities and lucencies than controls except with automated quantification of lucencies. Cross-sectionally, lucencies per Ochiai score and opacities per manual segmentation decreased with time. No approach measured a statistically significant relationship to BPD clinical severity. CONCLUSIONS: Opacities, lucencies, and overall heterogeneity of lungs via quantitative CT can distinguish BPD patients from healthy controls, and these abnormalities decrease with age across BPD patients. Defining BPD severity by clinical outcomes such as respiratory support at several time points (vs a single time point, per current guidelines) may be meaningful. PMID- 29266866 TI - Pregnancy leisure physical activity and children's neurodevelopment: a narrative review. AB - : In recent years, interest in the relation between maternal physical activity during pregnancy and children's neurocognitive development has been growing. Several observational studies and clinical trials have analysed this relation and they differ in the findings, especially for children's language-related skills and IQ. Physical activity assessment, amount of physical activity and the test used for measuring children's cognition could affect this relation, as well as other factors that should be considered. This article will review the evidence on the effects of physical activity during pregnancy on children's different cognitive domains. TWEETABLE ABSTRACT: Leisure physical during pregnancy positively affects offspring's general intelligence and language skills. PMID- 29266865 TI - Survival analysis of patients with advanced non-small cell lung cancer receiving tyrosine kinase inhibitor (TKI) treatment: A multi-center retrospective study. AB - BACKGROUND: The study was conducted to assess differences in overall survival (OS) in patients with non-small cell lung cancer (NSCLC) receiving different treatment modalities of tyrosine kinase inhibitors (TKIs). METHODS: A total of 463 NSCLC patients receiving TKI treatment were included. OS was compared according to treatment timing in all patients, the elderly, and patients positive for EGFR mutations. RESULTS: One hundred and seventy two patients received TKIs as first-line treatment, 220 as second-line, and 67 as third-line. The results between the three groups were not statistically significant: the one, two, and three-year OS rates were: 55.3%, 22.3%, and 11.3% (first-line); 59.6%, 27.8%, and 14.9% (second-line); and 53.8%, 41.3%, and 29.5% (third-line), respectively (P = 0.095). Results between the three groups of elderly patients were also not statistically significant (P = 0.469). The one and two-year OS rates in EGFR mutation-positive patients receiving first-line treatment were 48% and 17.5%, respectively. The one, two, and three-year OS rates of patients receiving second line treatment were: 54.2%, 30.3%, and 20.2%, respectively. There were no statistically significant differences between the groups with EGFR mutations receiving first-line or second-line treatment. Thirteen EGFR mutation-positive patients received third-line TKI treatment for a median duration of 7 months. Their one and two-year OS rates were 69.8% and 58.2%, respectively, which were higher than in the other two groups (P = 0.015). CONCLUSION: Three lines of TKI therapy can prolong survival in NSCLC patients. Elderly patients can benefit from TKI therapy. EGFR mutation-positive patients can benefit from second-line or third-line TKI therapy. PMID- 29266867 TI - Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia. AB - Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL), one of the most common and aggressive forms of haematological malignancies. However, TKI resistance has remained an unsolved issue. In this study, we investigate the impact of adding arsenic trioxide (ATO) on the action of Dasatinib, a second generation TKI, in Ph+ ALL. We show that ATO cooperates with Dasatinib in both TKI-sensitive and resistant Ph+ ALL cell lines to increase apoptosis and we unravel the underlying mechanisms. Indeed, combining ATO and Dasatinib leads to severe cell apoptosis by activating the UPR apoptotic IRE1/JNK/PUMA axis, while neutralizing the UPR ATF4-dependent anti-apoptotic axis, activated by ATO alone. Additionally, ATO and Dasatinib in combination repress the expression of several genes, which we previously showed to be associated with shorter survival probability in ALL patients. Overall these data support the use of ATO in combination with Dasatinib as a novel therapeutic regimen for Ph+ ALL patients. PMID- 29266868 TI - Serum concentration of anti-Mullerian hormone is not associated with semen quality. AB - Impaired semen quality is frequent in Western countries and is the main reason or contributing reason in up to 50% of cases of couple infertility. Male factor infertility is mainly determined by examination of semen samples according to the World Health Organization's 2010 guidelines. AMH has both autocrine and paracrine properties through a direct effect via the AMH type II receptor and is therefore thought to be involved in spermatogenesis. We aimed to study the association between the serum concentration of AMH and semen quality in a cross-sectional study including 970 young Danish men from the general population. All participants provided a semen sample, had a blood sample drawn, underwent a physical examination, and answered a questionnaire including information on lifestyle and medical history. Serum concentrations of reproductive hormones [AMH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), calculated free T, oestradiol (E2) and inhibin B] and semen parameters (semen volume, sperm concentration, and percentages of motile and morphologically normal spermatozoa) were determined. We found no association between serum AMH and semen quality, except for a significant (p = 0.011) trend for lower percentage of normal morphology with higher AMH. AMH quartile was positively associated with serum inhibin B (p < 0.001), inhibin B/FSH ratio (p < 0.001) and T/E2 ratio (0.016), and negatively associated with FSH (p = 0.004), LH (p = 0.005) and E2 (p = 0.028). There was no association between AMH quartile and T, calculated free T or total T/LH ratio. In conclusion, serum AMH is not useful as a marker of semen quality, and semen analysis using WHO criteria is still the golden standard in the evaluation of the infertile man. PMID- 29266869 TI - Hypertonic saline inhalations in bronchiolitis-A cumulative meta-analysis. AB - We undertook a cumulative meta-analysis for the efficacy of hypertonic saline (HS) compared to normal saline (NS) inhalations or no inhalations as controls in bronchiolitis. We performed literature searches from PubMed, Scopus, and by hand search until 20 June 2017. We accepted published randomized controlled trials of HS inhalations in children with bronchiolitis aged <24 months. We evaluated the differences between treatment group with HS and control group without HS inhalations for the length-of-stay in hospital (LOS) by cumulative mean difference (MD) and in hospitalization rate by cumulative risk ratio (RR). We identified 18 studies including 2102 children treated in hospital, and the cumulative MD in LOS was -0.471 days (95% confidence interval [CI] -0.765 to 0.177, Higgins heterogeneity test [I2 ] 72.9%). The cumulative MD reduced in more recently published papers. In studies with the upper age limit of 12 months, the cumulative MD was -0.408 days (95%CI -0.733 to -0.083) without any important heterogeneity (I2 = 0%). If only studies with a very low risk of bias were included, the cumulative MD was 0.034 (95%CI -0.361 to 0.293) without any important heterogeneity (I2 = 0%). We identified eight studies including 1834 children in the outpatient setting, and the cumulative risk ratio for hospitalization was 0.771 (95%CI 0.619-0.959, I2 55.8%). In conclusion, HS inhalations offered only limited clinical benefits, though the differences between HS and control groups were statistically significant. The heterogeneity between the studies was substantial. Further studies are warranted with consistent definitions of bronchiolitis and comparable research frames. PMID- 29266870 TI - Thermodynamic enantioseparation behavior of phenylthiohydantoin-amino acid derivatives in supercritical fluid chromatography on polysaccharide chiral stationary phases. AB - Thirteen pairs of enantiomers belonging to the same structural family (phenylthiohydantoin-amino acids) were analyzed on two polysaccharide chiral stationary phases, namely, tris-(3,5-dimethylphenylcarbamate) of amylose (Chiralpak AD-H) or cellulose (Chiralcel OD-H) in supercritical fluid chromatography with a carbon dioxide/methanol mobile phase (90:10 v/v). Five different temperatures (5, 10, 20, 30, 40 degrees C) were applied to evaluate the thermodynamic behavior of these enantioseparations. On the cellulose stationary phase, the retention, and separation trends were most similar among the set of probe analytes, suggesting that the chiral cavities in this stationary phase have little diversity, or that all analytes accessed the same cavities. Conversely, the retention and separation trends on the amylose phase were much more diverse, and could be related to structural differences among the set of probe analytes (carbon chain length in the amino acid residue, secondary amine in proline, existence of covalent rings, or formation of pseudo-rings via intramolecular hydrogen bonds). The large variability of behaviors on the amylose phase suggests that the chiral-binding sites in this chiral stationary phase have more variety than on the cellulose phase, and that the analytes did access different cavities. PMID- 29266871 TI - Artificial neural network model to distinguish follicular adenoma from follicular carcinoma on fine needle aspiration of thyroid. AB - BACKGROUND: To distinguish follicular adenoma (FA) and follicular carcinoma (FC) of thyroid in fine needle aspiration cytology (FNAC) is a challenging problem. AIMS AND OBJECTIVES: In this article, we attempted to build an artificial neural network (ANN) model from the cytological and morphometric features of the FNAC smears of thyroid to distinguish FA from FC. MATERIAL AND METHODS: The cytological features and morphometric analysis were done on the FNAC smears of histology proven cases of FA (26) and FC (31). The cytological features were analysed semi-quantitatively by two independent observers (RS and PD). These data were used to make an ANN model to differentiate FA versus FC on FNAC material. The performance of this ANN model was assessed by analysing the confusion matrix and receiving operator curve. RESULT: There were 39 cases in training set, 9 cases each in validation and test sets. In the test group, ANN model successfully distinguished all cases (9/9) of FA and FC. The area under receiver operating curve was 1. CONCLUSION: The present ANN model is efficient to diagnose follicular adenoma and carcinoma cases on cytology smears without any error. In future, this ANN model will be able to diagnose follicular adenoma and carcinoma cases on thyroid aspirate. This study has immense potential in future. This is an open ended ANN model and more parameters and more cases can be included to make the model much stronger. PMID- 29266872 TI - Facile Synthesis of Lipid-Perfluorocarbon Nanoemulsion Coated with Silica Shell as an Ultrasound Imaging Agent. AB - A novel organic/inorganic hybrid nanovesicle as an ultrasound imaging agent is synthesized via facile emulsion and silica deposition methods. This nanovesicle, hyaluronate (HA)-docetaxel (DTX)/perfluoro-n-pentane (PFP)@SNC, consists of an encapsulated liquid PFP core, loaded DTX, and an HA-decorated silica shell. The HA-DTX/PFP@SNC has a narrow size distribution of 274.5 +/- 3.25 nm, a negative zeta potential of -11.6 +/- 0.47 mV, and an entrapment efficiency of 86.70% +/- 1.42%. HA-DTX/PFP@SNC possesses an ultrasound (US)-triggered drug release and a temperature-dependent size change behavior. Compared with DTX/PFP@soybean phosphatidylcholine (SPC), which has no silica shell, the HA-DTX/PFP@SNC is more stable under various conditions. The MTT assay indicates that the blank HA PFP@SNC vehicle has no cytotoxicity to A549 cells. Furthermore, due to the HA mediated tumor-targeting ability, the HA-DTX/PFP@SNC shows obvious cytotoxicity to A549 cells. In vitro and in vivo US imaging results indicate that HA DTX/PFP@SNC has a stronger and more durable echo signal than DTX/PFP@SPC. Moreover, the in vivo echo signal of HA-DTX/PFP@SNC is stronger than that of DTX/PFP@SNC due to the HA-mediated tumor targeting. Therefore, this novel organic/inorganic hybrid vesicle is a US contrast agent candidate. PMID- 29266873 TI - Retracted: Activities of carbohydrate-metabolism enzymes in pre-drought primed wheat plants under drought stress during grain filling. AB - : Abid M, Tian Z, Hu J, Ullah A, Cui Y, Ali S, Jiang S, Zahoor R, Fan Y, Dong J and Dai T Activities of carbohydrate-metabolism enzymes in pre-drought primed wheat plants under drought stress during grain filling. J Integr Plant Biol Accepted Author Manuscript. doi:10.1111/jipb.12628 The above article from Journal of Integrative Plant Biology, published online on 20 December, 2017, in Wiley Online Library (wileyonlinelibrary.com) as Accepted Article, has been withdrawn by agreement among the authors, the journal Editors-in-Chief and John Wiley & Sons Australia, Ltd on behalf of the JIPB Board, after noticing an overlap of a figure from a previously published article, from the same laboratory. REFERENCE: Abid M, Tian Z, Hu J, Ullah A, Cui Y, Ali S, Jiang S, Zahoor R, Fan Y, Dong J and Dai T Activities of carbohydrate-metabolism enzymes in pre-drought primed wheat plants under drought stress during grain filling. J Integr Plant Biol Accepted Author Manuscript. doi:10.1111/jipb.12628. PMID- 29266874 TI - Recurrent swelling of the ear. PMID- 29266875 TI - Collagen nanofibre anisotropy induces myotube differentiation and acetylcholine receptor clustering. AB - To create musculoskeletal tissue scaffolds for functional integration into host tissue, myotubes must be properly aligned with native tissue and spur the formation of neuromuscular junctions. However, our understanding of myoblast differentiation in response to structural alignment is incomplete. To examine how substrate anisotropy mediates myotube differentiation, we studied C2C12 myoblasts grown on aligned collagen substrates in the presence or absence of agrin. Myoblasts grown on microfluidically patterned collagen substrates demonstrated increased multinucleated myotubes and nicotinic acetylcholine receptor (AChR) clusters. However, agrin treatment did not synergistically increase differentiation of myoblasts seeded on these patterned collagen substrates. Myoblasts grown on aligned electrospun collagen nanofibres also demonstrated increased formation of multinucleated myotubes and AChR clusters, and agrin treatment did not increase differentiation of these cells. Using fluorescently labelled collagen nanofibres, we found that AChR clustered in cells grown on nanofibres with significantly higher anisotropy and that this clustering was eliminated with agrin treatment. Interestingly, anisotropy of substrate had no effect on the localization of AChRs along the myotube, suggesting that additional signalling pathways determine the specific location of AChRs along individual myotubes. Taken together, our results suggest a novel role for fibre anisotropy in myotube differentiation, specifically AChR clustering, and that anisotropy may guide differentiation by activating similar pathways to agrin. Our data suggest that agrin treatment is not necessary for differentiation and maturation of myoblasts into myotubes when myoblasts are grown on aligned collagen substrates. PMID- 29266876 TI - Pressure injury identification, measurement, coding, and reporting: Key challenges and opportunities. AB - Pressure injury (PI) rates are a commonly used indicator of performance of health care facilities, both in acute and subacute settings. However, measuring PI rates in an accurate and reproducible fashion has been challenging. The consequences of poor measurement may include failure to identify poorly performing institutions or incorrect accusations of poor quality care. In this article, we describe the main challenges in identification, coding, and reporting of PIs. Issues include inconsistent identification of PIs at the time of admission, variations in the intensity of PI detection, and differing approaches to coding and the adjustment for differing risks amongst different patient population. These are compounded by differences in the epidemiological approach because rates will differ according to whether patients are surveyed cross-sectionally (eg, on a set day per month) or if the survey is undertaken at discharge. In some cases, financial incentives may also influence PI reporting. We also discuss potential strategies for improving data collection and benchmarking as an aid to reducing PI prevalence. PMID- 29266877 TI - Grafts for Peyronie's disease: a comprehensive review. AB - The difficulty implicit in combining all the characteristics that an ideal patch to treat Peyronie's disease with a lengthening procedure should have, together with the challenges of comparing results from different series, means that the ideal patch has yet to be determined. Our objective with this review was to determine whether any given patch type is preferable to the others based on the evaluation of the results of published studies. A systematic search of the literature was conducted from PubMed until December 2016. Articles reporting basic research, animal research, reviews or meta-analyses and studies in children were eliminated. Series with patients undergoing some kind of other surgical intervention were only included if results were reported separately. Case reports and series of five patients were excluded. Five variables were selected to evaluate the results: number of patients, follow-up period, straightening rate, shortening rate and post-operative ED rate. For this purpose, 69 papers were included for review, and the outcomes of the use of autologous dermis, tunica vaginalis, dura mater, fascia, saphenous vein, tunica albuginea, buccal mucosa, porcine intestinal submucosa, pericardium, TachoSil(r) and synthetic materials were presented and analysed separately. The different series published are extremely variable and heterogeneous in terms of the number of patients included, patient selection, follow-up periods, and in the measurement and interpretation of the outcomes analysed. Given these facts, it is not possible to draw any definitive conclusion, homogeneous, prospective studies using validated tools are required to determine which the ideal graft is. PMID- 29266878 TI - Software and package applicating for network meta-analysis: A usage-based comparative study. AB - OBJECTIVE: To compare and analyze the characteristics and functions of software applications for network meta-analysis (NMA). METHODS: PubMed, EMbase, The Cochrane Library, the official websites of Bayesian inference Using Gibbs Sampling (BUGS), Stata and R, and Google were searched to collect the software and packages for performing NMA; software and packages published up to March 2016 were included. After collecting the software, packages, and their user guides, we used the software and packages to calculate a typical example. All characteristics, functions, and computed results were compared and analyzed. RESULTS: Ten types of software were included, including programming and non programming software. They were developed mainly based on Bayesian or frequentist theory. Most types of software have the characteristics of easy operation, easy mastery, exact calculation, or excellent graphing. However, there was no single software that performed accurate calculations with superior graphing; this could only be achieved through the combination of two or more types of software. CONCLUSION: This study suggests that the user should choose the appropriate software according to personal programming basis, operational habits, and financial ability. Then, the choice of the combination of BUGS and R (or Stata) software to perform the NMA is considered. PMID- 29266879 TI - Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis: A Randomized Clinical Trial. AB - OBJECTIVE: To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long-term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA). METHODS: A total of 24,081 patients with OA or RA who had a moderate or high risk for CV disease were enrolled internationally into a double-blind randomized controlled trial. Interventions included celecoxib at a dosage of 100-200 mg twice daily, ibuprofen at a dosage of 600-800 mg 3 times daily, or naproxen at a dosage of 375-500 mg twice daily. The main outcomes were the first occurrence of a major adverse CV event, GI event, or renal event, and mortality. RESULTS: In the subgroup of patients with OA, the risk of a major adverse CV event was significantly reduced when celecoxib was compared with ibuprofen (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.72-0.99), but no significant difference was observed when celecoxib was compared with naproxen. In the RA subgroup, comparisons of celecoxib versus ibuprofen and celecoxib versus naproxen for the risk of major adverse CV events revealed HRs of 1.06 (95% CI 0.69-1.63) and 1.22 (95% CI 0.78-1.92), respectively. In the OA subgroup, comparisons of celecoxib versus ibuprofen for the risk of GI events showed an HR of 0.68 (95% CI 0.51 0.91), and a comparison of celecoxib versus naproxen showed an HR of 0.73 (95% CI 0.55-0.98). Duplicate comparisons in patients with RA revealed HRs of 0.48 (95% CI 0.22-1.07) and 0.54 (95% CI 0.24-1.24), respectively. In patients with OA, a comparison of celecoxib versus ibuprofen for the risk of renal events showed an HR of 0.58 (95% CI 0.40-0.82). In patients with RA, celecoxib treatment was associated with significantly lower mortality compared with naproxen treatment (HR 0.47, 95% CI 0.25-0.88). CONCLUSION: Treatment with celecoxib at approved dosages conferred a similar or lower risk of CV, GI, and renal adverse events compared with treatment with ibuprofen or naproxen in patients with OA and patients with RA. PMID- 29266880 TI - The highs and lows of wheezing: A review of the most popular adventitious lung sound. AB - Wheezing is the most widely reported adventitious lung sound in the English language. It is recognized by health professionals as well as by lay people, although often with a different meaning. Wheezing is an indicator of airway obstruction and therefore of interest particularly for the assessment of young children and in other situations where objective documentation of lung function is not generally available. This review summarizes our current understanding of mechanisms producing wheeze, its subjective perception and description, its objective measurement, and visualization, and its relevance in clinical practice. PMID- 29266881 TI - Study of Endochondral Ossification in Human Fetalcartilage Anlagen of Metacarpals: Comparative Morphology of Mineral Deposition in Cartilage and in the Periosteal Bone Matrix. AB - The progression of mineral phase deposition in hypertrophic cartilage and periosteal bone matrix was studied in human metacarpals primary ossification centers before vascular invasion began. This study aimed to provide a morphologic/morphometric comparative analysis of the calcification process in cartilage and periosteal osteoid used as models of endochondral ossification. Thin, sequential sections from the same paraffin inclusions of metacarpal anlagen (gestational age between the 20th and 22nd weeks) were examined with light microscopy and scanning electron microscopy, either stained or heat deproteinated. This process enabled the analysis of corresponding fields using the different methods. From the initial CaPO4 nucleation in cartilage matrix, calcification progressed increasing the size of focal, globular, randomly distributed deposits (size range 0.5-5 um), followed by aggregation into polycyclic clusters and finally forming a dense, compact mass of calcified cartilage. At the same time, the early osteoid calcification was characterized by a fine granular pattern (size range 0.1-0.5 um), which was soon compacted in the layer of the first periosteal lamella. Scanning electron microscopy of heat deproteinated sections revealed a rod-like hydroxyapatite crystallite pattern, with only size differences between the early globular deposits of the two calcifying matrices. The morphology of the early calcium deposits was similar in both cartilage and osteoid, with variations in size and density only. However, integration of the reported data with the actual hypotheses of the mechanisms of Ca concentration suggested that ion transport was linked to the progression of the chondrocyte maturation cycle (with recall of H2 O from the matrix) in cartilage, while ions transport was an active process through the cell membrane in osteoid. Other considered factors were the collagen type specificity and the matrix fibrillar texture. Anat Rec, 301:571-580, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29266882 TI - Large-Vessel Dilatation in Giant Cell Arteritis: A Different Subset of Disease? AB - OBJECTIVE: To compare patients with large-vessel giant cell arteritis (LV-GCA) characterized by wall thickening, stenosis, and/or occlusion of subclavian arteries to those with subclavian dilatation. METHODS: For the purposes of the present retrospective study, 2 different subsets of LV-GCA were identified and compared from an established cohort of patients with radiographic evidence of subclavian artery vasculitis secondary to GCA: LV-GCA with wall thickening, stenosis, and/or occlusion of subclavian arteries (Group 1), and LV-GCA with dilatation of subclavian arteries without wall thickening or stenotic changes (Group 2). RESULTS: The study included 109 patients in Group 1 and 11 in Group 2. Large-vessel involvement secondary to GCA was diagnosed significantly later in patients from Group 2 compared to those from Group 1 (median 15.3 versus 0.0 months; P = 0.010). Compared to patients from Group 1, those from Group 2 were more frequently male (17% versus 45%; P = 0.027), ever smokers (42% versus 73%; P = 0.048), and more frequently had a history of coronary artery disease (11% versus 36%; P = 0.018). At LV-GCA diagnosis, 10 of the 11 patients (91%) from Group 2 had aortic dilatation compared to 13 of 109 patients (12%) from Group 1 (P < 0.001). During the followup period, the prevalence of aortic aneurysm was significantly higher in patients from Group 2 compared with those from Group 1 (64% versus 7% at 5 years; P < 0.001). CONCLUSION: Two different subsets of LV GCA were identified. Given the strong association between subclavian artery dilatation and aortic aneurysm, such patients should be evaluated and monitored carefully for aortic dilatation. PMID- 29266883 TI - [The Guigou family and the treatment of hypertrophic pyloric stenosis in Spain]. PMID- 29266884 TI - [Morgagni-Larrey anterior diaphragmatic hernias. Review of 13 cases]. AB - OBJECTIVE: A review of anterior congenital diaphragmatic hernias (CDH) treated at our center, analysis of our experience and evolution in the surgical technique in pediatric patients over the last 15 years. MATERIAL AND METHODS: A retrospective descriptive study of patients of our center with anterior CDH (Morgagni, Larrey and Morgagni-Larrey) between 2000 and 2015, through a systematic review of clinical records. The studied variables were: age at diagnosis, age at treatment, diagnostic methods, symptoms, surgical technique, evolution, complications and relapses. Posterior CDH (Bochdalek) and patients older than 14 years old were excluded. RESULTS: 13 patients (8 females) with anterior diaphragmatic hernia. Mean age at diagnosis was 29.4 months (range fetal age 4 months-14 years old) and mean age at surgery 18.5 m (range 1 day-14 years). Three left hernias (Larrey hernia) and n= 2central hernias (Morgagni-Larrey). Two patients were diagnosed prenatally, the rest of them were casual diagnoses. Symptoms: n= 6 asymptomatic, n= 4respiratory symptoms, n= 1abdominal pain, n= 1both symptoms and n= 1 hydrops fetalis. In all cases, a chest X-ray was performed, CT in n= 5 cases and US in other n= 5 patients. The surgical approach was laparoscopic in n= 7 (1 conversion due to bleeding), thoracoscopic in n= 1 (requiring conversion to laparotomy due to technical difficulty), thoracotomy in n= 1patients and laparotomy in n= 4. Prosthetic patches were necessary in n= 2 patients. During the follow-up (3.9 years, range: 1-8), there were n= 2 recurrences (laparoscopy and thoracotomy) and n= 1 exitus 2 years after surgery, due to pathology not associated with diaphragmatic hernia. CONCLUSIONS: The minimally invasive approach is considered of choice in the literature. Our group considers that most patients with anterior CDH should be considered for a laparoscopic repair. The laparoscopic approach is easily reproducible and the conversion rate is low when it is performed by expert surgeons. However, the low prevalence of this pathology would require comparative and long-term multicenter studies to obtain statistically significant conclusions. PMID- 29266885 TI - [Functional endoscopic evaluation of swallowing in infants with deglutition disorders]. AB - BACKGROUND: Functional endoscopic evaluation of swallowing (FEES) is a recognized method for Deglutition Disorders (DD) in adults, with anecdotal experience in children, obtaining not conclusive results. OBJECTIVE: To compare the accuracy of test FEES in infants with high suspicion of altered DD seen in a third level hospital with the gold standard Videofluoroscopic (VF). PATIENTS, MATERIAL AND METHODS: The results and findings by FEES and VF of 66 children with clinical diagnosis of DD were compared. STATISTICAL ANALYSIS: An estimate of the sensitivity and specificity of FEES was performed. As well as calculating positive predictive value (PPV), negative predictive value (NPV) and likelihood ratios. RESULTS: 60 patients enrolled, 4 and FEES showed high sensitivity to identify the presence of aspiration and penetration (9 98%) and high specificity for the arrest of spillage and waste (94% and 95%). Gastroesophageal reflux to make the diagnosis of DD with FEES had a sensitivity of 80% and specificity of 84%. Spill and penetration had the highest agreement with respect to the gold standard of 0.81. CONCLUSIONS: FEES in infants diagnosed with DD had a sensitivity of 80.8% and specificity 85.3%. 0696 concordance regarding to the VFD in the diagnosis of DD, and to identify suction stroke had a kappa of 0815. PMID- 29266886 TI - [Is there an ideal patient for transumbilical laparoscopic assisted appendectomy?] AB - OBJECTIVES: To identify the factors that lead to postoperative morbidity in acute appendicitis patients treated using a TULAA (Transumbilical laparoscopic assisted appendectomy) approach. MATERIAL AND METHODS: Retrospective review of patients treated through a TULAA approach between 2007 and 2014. Data concerning the location of the appendix, need for conversion, appendiceal abscess or perforation, surgical time and other complications were collected. Student's T test and Chi-squared test were used for statistical analysis. RESULTS: A total of 111 appendectomies underwent TULAA. The average operating time was 79 minutes (45 150). Nonperforated appendicitis was found in 90% of patients with 10% having perforated appendicitis or appendiceal abscess. In 35,13% of cases, additional trocars were used, usually when the appendix was in a retrocecal position (89,5%). When the appendix was found in a pelvic or ileal position, a need for extra trocars decreased to 25.9% (p< 0.05). The surgery was converted to open surgery in 6,3% of the cases. The appendix in a retrocecal position had a conversion rate of 20,8% compared to 2,3% of cases with an appendix in a pelvic location (p< 0.05). A total of 3,6% reported postoperative wound infection, possibly caused by perforation of the appendix during extraction (p< 0.05). All the perforated appendixes were considered complicated appendixes. CONCLUSIONS: The retrocecal location of the appendix is associated with the need to install additional trocars or conversion to open surgery. The TULAA approach is ideal for patients with nonperforated acute appendicitis in a pelvic or ileal location. PMID- 29266887 TI - [Functional outcomes in postsurgery for Hirschsprung's disease]. AB - OBJECTIVE: To analyze functional outcomes of patients operated for Hirschsprung's disease (HD). METHODS AND MATERIAL: Retrospective study of patients with HD (2000 2014). We analyzed surgical technique, age at diagnostic and treatment, amount of resected bowel, complications and their influence on functional outcomes. RESULTS: Of the 44 diagnosed with HD, 37 were operated in our center. Men 29 (78.4%). With associated pathology 7 (18.9%), and 5 (13.5%) made their debut with enterocolitis. Diagnostic average age 1.04 (0.0 to 7.1 years) and operation average age 1.4 (0.3 to 9.3 years). We did transanal endorectal pull-through (TERPT) in 17 (45.9%) patients and transabdominal approach (TAB) in 20 (54.1%). Received postoperative dilations 8 (21.6%) patients. Functional outcomes were evaluated at an average age of 9.6 (4.7-15.7years) incontinence/soiling were found in 6/28 (21.4%) and constipation in 5/28 (17.9%). The highest rate of incontinence/ soiling was present in 41.7 % TERPT vs. 6.2% TAB (p= 0,036). However, the average age at follow-up in patients with incontinence/soiling was 5.9 +/- 1.3 years old, less than the 10,6 +/- 3.2 years in the ones without incontinence/soiling (p< 0,001). We found that the 5 cases of constipation arose in patients with TAB (p= 0, 044), and likewise all were operated under 1 year of age. CONCLUSION: Despite the well known benefits of the TERPT over the TAB, we found a greater degree of incontinence/soiling in the TERPT, which could be explained by a less follow up, since incontinence/soiling improves with age. On the other hand there is a higher rate of constipation in the TAB that lasts in time. PMID- 29266888 TI - [Complications in the conservative managemennt of splenic rupture]. AB - INTRODUCTION: Management of splenic rupture in haemodynamically stable children is non-surgical treatment. However, complications can occur during follow-up. Objective: to study the frequency, evolution and treatment of complications of conservative treatment of splenic rupture. Secondary objective: to evaluate the results of the American Pediatric Surgical Association (APSA) clinical guideline in conservative treatment. MATERIAL AND METHODS: Retrospective study of patients with abdominal trauma between 2010-2016. We included children under 15 years of age with splenic injury after blunt abdominal trauma. Demographic variables, mechanism and degree of injury of American Association for the Surgery of Trauma were studied in the sample. The complications, the time of onset and their treatment were analyzed. The treatment was based on the recommendations of the APSA with the exception of ultrasound follow-up. In case of complications and according to the clinical and characteristics, embolization was indicated. RESULTS: Twenty-eight patients were attended, 21 males (75%). The median age was 8.35 years (6.28-11.35). Seven patients (25%) presented complications: two arteriovenous fistula (AVF), three pseudo-aneurysms and two hemorrhages. The median time to diagnosis of complications was 5.67 days (P25 4- P75 5.75). Embolization was performed in two patients with pseudo-aneurysm. Another patient underwent emergency splenectomy for rebleeding. The rest of the complications resolved spontaneously. CONCLUSIONS: In splenic rupture, unlike APSA, ultrasound monitoring is useful to rule out early complications. PMID- 29266889 TI - [Button vesicostomy in newborn: an alternative of classical cutaneous vesicostomy]. AB - PURPOUSE: In newborn and infant with functional and/or anatomical lower urinary tract obstruction, the goals of vesicostomy are to achieve a low pressure bladder, an effective bladder drainage and to prevent urinary tract infection and sepsis. Nonetheless, classical vesicostomy is not free from complications. The aim is to describe a surgical technique of button vesicostomy as an alternative of cutaneous vesicostomy. MATERIAL AND METHODS: 13 newborn and infant, age between 14 and 60 days (median 20 days), twelve male and one female, underwent button vesicostomy. Twelve patients were neurologically normal and one with neurogenic bladder. Surgical technique of button vesicostomy differs from the classical one; it does not require bladder cupula mobilization, the botton is inserted into the bladder at the urachus insertion without suturing the bladder mucosa to the skin, creating a vesico-cutaneous fistula. RESULTS: Button vesicostomy was found to be safe and effective in 96%. Stabilization of upper urinary tracts was achieved in all cases. Botton vesicostomy has made it possible to undergo intermittent catheterization through the button before closure of the vesicostomy, as well as performing standard urodynamic studies through the urethra to evaluate bladder function during follow-up and providing objective data for proper undiversion. There were no complications. Vesicostomy was closed at a median age of twenty months, combined with reconstructive procedures, when necessary. CONCLUSIONS: Button vesicostomy has improved the outcome of the classical vesicostomy. It provides an efficient way for lowering the bladder pressure in the absence of complications, making possible to perform urodynamic studies; the evaluation of bladder function is essential prior to the undiversion. PMID- 29266890 TI - [Management of recurrent urethrocutaneous fistula after hypospadias surgery in pediatric patients: initial experience with dermal regeneration sheet Integra]. AB - OBJECTIVE: To present our initial experience using a dermal regeneration sheet as an urethral cover in the repair of recurrent urethrocutaneous fistulae in pediatric patients. METHODS: Since May 2016 to March a total of 8 fistulaes were repaired using this new technique. We performed the ddissection of the fistulous tract and posterior closure of the urethral defect. A dermal regeneration sheet was used to cover the urethral suture. Finally a rotational flap was performed to avoid overlap sutures. RESULTS: During the follow-up (average 6 months), one patient presented in the immediate postoperative period infection of the surgical wound. This patient presented recurrence of the fistula. 88% of the patients included presented a good evolution with no other complications. CONCLUSIONS: In our initial experience the new technique seems easy, safe and effective in the management of the recurrent urethrocutaneous fistulae in pediatric patients. More studies are needed to prove these results. PMID- 29266891 TI - [Clinical and immunohistochemical correlation of balanitis xerotica obliterans]. AB - AIM: Balanitis xerotica obliterans (BXO) is a disease of the skin and mucosa of male genitals of unknown etiology that may affect children of any age. It has a low incidence (9-19%) and in adults is considered a potential premalignant lesion. The aim of our study is to establish the incidence of BXO in our center and to determine its correlation between the clinical and immunohistochemical (IHC) findings. METHODS: Prospective cohort including all children < 14 years with foreskin pathology that required a circumcision between 2014-2016. Statistical analysis of the clinical characteristics, histological and IHC findings searching for inflammatory response, premalignant lesions and microbiological findings. RESULTS: A total of 176 boys with phimosis had circumcision with a mean age of 7 +/- 3 years (Range 2-14). Presurgical diagnosis of BXO was suspected in 28.4% (n= 50) whereas the AP confirmed a total of 29.5% (n= 53) with a very good interobserver concordance (kappa= 0.81: p< 0.01). Previous treatment with corticoids in BXO was found in 63.5% (n= 33/52). Meatal stenosis was found in 7.69% (n= 4/52) requiring meatal/urethral dilations. Patients with BXO had a T-Lymphocytes CD3+ mediated inflammatory response with a positive correlation between tumor suppressing protein (p53) expression and chronic inflammation. CONCLUSIONS: BXO is a chronic inflammatory disease mediated by T-lymphocytes with an incidence greater than previously reported. Surgeons' criterion has a very good concordance with the AP findings. The elevation of p53 in children with BXO may indicate a plausible malignant potential that may require a surgical treatment (circumcision) and an adequate follow-up. PMID- 29266892 TI - [Psychoprophylaxis in elective paediatric general surgery: does audiovisual tools improve the perioperative anxiety in children and their families?] AB - AIM OF THE STUDY: Surgery is considered a stressful experience for children and their families who undergo elective procedures. Different tools have been developed to improve perioperative anxiety. Our objective is to demonstrate if the audiovisual psychoprophylaxis reduces anxiety linked to paediatric surgery. METHODS: A randomized prospective case-control study was carried out in children aged 4-15 who underwent surgery in a Paediatric Surgery Department. We excluded patients with surgical backgrounds, sever illness or non-elective procedures. Simple randomization was performed and cases watched a video before being admitted, under medical supervision. Trait and state anxiety levels were measured using the STAI-Y2, STAI-Y2, STAI-C tests and VAS in children under 6-years-old, at admission and discharge. RESULTS: 100 patients (50 cases/50 controls) were included, mean age at diagnosis was 7.98 and 7.32 respectively. Orchiopexy was the most frequent surgery performed in both groups. Anxiety state levels from parents were lower in the Cases Group (36.06 vs 39.93 p= 0.09 in fathers, 38.78 vs 40.34 p= 0.43 in mothers). At discharge, anxiety levels in children aged > 6 were statistically significant among cases (26.84 vs 32.96, p< 0.05). CONCLUSIONS: The use of audiovisual psychoprophylaxis tools shows a clinically relevant improvement in perioperative anxiety, both in children and their parents. Our results are similar to those reported by other authors supporting these tools as beneficial strategy for the family. PMID- 29266894 TI - DEBRIDING WOUNDS TO REDUCE BIOBURDEN. AB - Approximately 60-90% of chronic wounds have bioburden, which is associated with non-viable tissue in the wound bed and is often difficult to detect with the naked eye (Harries et al. 2016). PMID- 29266893 TI - Is the risk of preeclampsia higher in donor oocyte pregnancies? A systematic review and meta-analysis. AB - OBJECTIVE: Preeclampsia (PE) occurs in 4.6% of pregnancies worldwide. The social phenomenon of increasing maternal age has raised the demand for donor oocytes. Egg donation has allowed women with poor ovarian reserve, premature ovarian failure, genetic disorders or surgical menopause to get pregnant. Recipients provide a unique model of immune response because of the differences in the genetic makeup of mothers and fetuses. In PE, immune tolerance may be impaired as a result of having non-autologous eggs implanted. Egg donation is a highly successful assisted reproductive technology, despite the significant number of issues arising from the implantation of non-autologous eggs. This study aimed to determine whether there is an association between egg donation and preeclampsia. METHODS: A systematic review of the literature available in PubMed and Google Scholar was carried out from January of 1995 to August of 2016 using the terms 'oocyte donation, preeclampsia', 'oocyte donation, in vitro fertilization, preeclampsia', 'oocyte donation, preeclampsia, outcomes pregnancies', 'oocyte donation, obstetric outcome.' Only six retrospective cohort studies met the selection criteria. RESULTS: The meta-analysis revealed a statistically significant association between egg donation and onset of preeclampsia (OR 4.50; 95% CI: 3.28-6.19; p<0.0001). CONCLUSION: Oocyte donation is associated with increased risk of preeclampsia in singleton pregnancies. Therefore, it is crucial to properly record and assess this finding when egg donation is the chosen assisted reproductive technology to attain pregnancy. PMID- 29266895 TI - NURSING AND MIDWIFERY STUDENTS TEACHING INFECTION CONTROL IN INDONESIA. AB - Morbidity, mortality and quality of life are impacted on by healthcare-associated infections (HAI) which are preventable. According to the World Health Organization 2016), in developing countries, around 10% of patients will contract HAI. PMID- 29266897 TI - STANDARD PRECAUTIONS BUT NO STANDARD ADHERENCE. AB - Infection Prevention and Control (IPC) measures are the foundation of best practice by healthcare workers for their own safety and that of their patients, yet low adherence rates place all parties at risk. PMID- 29266896 TI - Review on the role of glutathione on oxidative stress and infertility. AB - Infertility is a global health problem and it is one of the most stressful conditions amongst married couples. Even though not lethal, it has been described as a radical life changing problem that carries with it significant psychological trauma. Infertility can be caused by various problems and sometimes it is not possible to establish a cause. Oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) and protective antioxidants, influences the entire reproductive lifespan of men and women. ROS can modulate cellular functions, and oxidative stress can disturb the intracellular milieu, resulting in diseased cells or endanger cell survival. Under normal conditions, antioxidants act to oppose ROS production, scavenging existing free radicals and promoting the repair of ROS-induced damage to cell structures. At controlled levels, oxidative stress facilitates some physiological reproductive functions but at higher levels it is implicated in pathological processes in the reproductive tract that contribute to infertility and poor pregnancy outcomes. As high levels of reactive oxygen species and low antioxidant status have been implicated in conditions contributing to infertility, treatment based on strategies to boost the exhausted antioxidant defense of the reproductive microenvironment is intuitive. Glutathione is a natural body antioxidant, which helps preserve all other antioxidants. It is present in both the male and female gametes and its level varies widely. This study reviews the role oxidative stress plays in both male and female infertility, and the antioxidant action of glutathione on infertility. PMID- 29266898 TI - Preimplantation genetic diagnosis for a patient with multiple endocrine neoplasia type 1: case report. AB - Preimplantation genetic diagnosis was carried out for embryonic analysis in a patient with multiple endocrine neoplasia type 1 (MEN1). This is a rare autosomal dominant cancer syndrome and the patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues, associated with germline and somatic inactivating mutations in the MEN1 gene. This case report documents a successful preimplantation genetic diagnosis (PGD) involving a couple at-risk for MEN1 syndrome, with a birth of a healthy infant. The couple underwent a cycle of controlled ovarian stimulation and intracytoplasmic sperm injection (ICSI). Embryos were biopsied at the blastocyst stage and cryopreserved; we used PCR based DNA analysis for PGD testing. Only one of the five embryos analyzed for MEN1 syndrome was unaffected. This embryo was thawed and transferred following endometrial preparation. After positive betaHCG test; clinical pregnancy was confirmed by ultrasound, and a healthy infant was born. PGD for single gene disorders has been an emerging therapeutic tool for couples who are at risk of passing a genetic disease on to their offspring. PMID- 29266899 TI - IGNITING THE POTENTIAL OF WOUND CARE CHAMPIONS. AB - Melbourne Health is celebrating the 13th year of a wound care champion program that has transformed 85 ward nurses into a unique group of Wound Resource Nurses (WReNs) to meet the challenges and demands of implementing evidence based wound care practices. PMID- 29266900 TI - USING POSITIVE CLINICAL LEADERSHIP TO SUPPORT A CULTURE OF PRESSURE INJURY PREVENTION. AB - The Royal Melbourne Hospital (RMH) is an 800 bed tertiary referral service within metropolitan Melbourne. While the hospital acquired pressure injury (HAPI) incidence rate is low (2.5%), there is still work to be done in this area. PMID- 29266901 TI - POTENTIAL TO REDUCE URINARY TRACT INFECTIONS WITH THE USE OF BLADDER SCANNERS IN MATERNITY CARE. AB - The National Medical Research Council Australia website states that 20% of hospital acquired infections are urinary tract infections (UTIs). This percentage is derived from a study involving 75,694 participants, undertaken in England, Wales, Northern Ireland and the Republic of Ireland and of the reported UTIs, 40 57% are caused by urinary catheters (Smyth et al. 2008). PMID- 29266902 TI - PERINEAL WOUND CARE: EDUCATION AND TRAINING IN AUSTRALIA. AB - In Australia, approximately 75% of women who have a vaginal birth will sustain some form of perineal trauma (AIHW 2013); and over half of perineal injuries will require suturing. PMID- 29266903 TI - IMPROVING INFECTION PREVENTION AND CONTROL PRACTICES IN A CULTURALLY, LINGUISTICALLY AND SPIRITUALLY DIVERSE ENVIRONMENT. AB - Atoifi Adventist Hospital (AAH) in the Solomon Islands serves a population of 80,000 people, many living in small remote villages. Atoifi is situated on the east side of the island of Malaita in the East Kwaio region. Kwaio is one of 12 language groups on Malaita and most people engage in the subsistence economy. PMID- 29266904 TI - STOP THE CYCLE OF CONTAMINATION AND DEATH. AB - Pressure ulcers (PUs) are a serious adverse event for patients that could be prevented (Thomas, 2001). Immobility and the resulting unrelieved pressure (Sharp and McLaws, 2006; Gefen et al. 2008) on muscle tissue overlying bony prominences is thought to be a major risk factor for deep tissue injury (Gefen et al. 2008). PMID- 29266905 TI - Diagnosis and management of group A streptococcal pharyngitis and associated complications [digest]. AB - Although group A Streptococcus (GAS) pharyngitis is the most common cause of bacterial pharyngitis in children and adolescents, many viral and bacterial infections mimic the symptoms of GAS pharyngitis. Emergency clinicians must recognize the symptomatology of GAS pharyngitis and use appropriate means of diagnosis and treatment to promote good antibiotic stewardship. This issue reviews the signs and symptoms of GAS pharyngitis, as well as associated complications, and provides recommendations for appropriate treatment that focuses on reducing the severity and duration of symptoms, reducing the incidence of nonsuppurative complications, and reducing transmission. [Points & Pearls is a digest of Pediatric Emergency Medicine Practice]. PMID- 29266906 TI - CATHETER ASSOCIATED URINARY TRACT INFECTIONS (CAUTIS): A RESEARCH UPDATE. AB - Infections associated with indwelling urinary catheters (IDCs) are one of the most frequently reported healthcare associated infections (Elvy and Colville 2009). Approximately 26% of patients in Australian hospitals receive a catheter while on admission (Gardner et al 2014). PMID- 29266914 TI - Activity of Serotonin 5-HT1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties. AB - Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A receptor ligands (+/ )8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (+/-)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A receptor-mediated. In the forced swim test, F15599, F13714, and (+/-)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (+/-)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5 HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders. PMID- 29266915 TI - Nanoscale Carbon Modified alpha-MnO2 Nanowires: Highly Active and Stable Oxygen Reduction Electrocatalysts with Low Carbon Content. AB - Carbon-coated alpha-MnO2 nanowires (C-MnO2 NWs) were prepared from alpha-MnO2 NWs by a two-step sucrose coating and pyrolysis method. This method resulted in the formation of a thin, porous, low mass-percentage amorphous carbon coating (<5 nm, <=1.2 wt % C) on the nanowire with an increase in single-nanowire electronic conductivity of roughly 5 orders of magnitude (alpha-MnO2, 3.2 * 10-6 S cm-1; C MnO2, 0.52 S cm-1) and an increase in surface Mn3+ (average oxidation state: alpha-MnO2, 3.88; C-MnO2, 3.66) while suppressing a phase change to Mn3O4 at high temperature. The enhanced physical and electronic properties of the C-MnO2 NWs enriched surface Mn3+ and high conductivity-are manifested in the electrocatalytic activity toward the oxygen reduction reaction (ORR), where a 13 fold increase in specific activity (alpha-MnO2, 0.13 A m-2; C-MnO2, 1.70 A m-2) and 6-fold decrease in charge transfer resistance (alpha-MnO2, 6.2 kOmega; C MnO2, 0.9 kOmega) were observed relative to the precursor alpha-MnO2 NWs. The C MnO2 NWs, composed of ~99 wt % MnO2 and ~1 wt % carbon coating, also demonstrated an ORR onset potential within 20 mV of commercial 20% Pt/C and a chronoamperometric current/stability equal to or greater than 20% Pt/C at high overpotential (0.4 V vs RHE) and high temperature (60 degrees C) with no additional conductive carbon. PMID- 29266916 TI - A Conductive Binder for High-Performance Sn Electrodes in Lithium-Ion Batteries. AB - Tin (Sn) has been widely studied as a promising anode material for high-energy and high-power-density Li-ion batteries owing to its high specific capacity. In this work, a water-soluble conductive polymer is studied as a binder for nanosized Sn anodes. Unlike conventional binders, this conductive polymer formed a conductive network, which maintained the mechanical integrity during the repeated charge and discharge processes despite the inevitable Sn particle pulverization. The resultant Sn anode without conductive additives showed a specific capacity of 593 mA h g-1 after 600 cycles at the current density of 500 mA g-1, exhibiting better cycling stability as well as rate performance compared to Sn anodes with conventional binders. Furthermore, it was also found that the conductive binder enhanced the formation of stable solid electrolyte interphase (SEI) layers. PMID- 29266917 TI - On-Particle Rolling Circle Amplification-Based Core-Satellite Magnetic Superstructures for MicroRNA Detection. AB - Benefiting from the specially tailored properties of the building blocks as well as of the scaffolds, DNA-assembled core-satellite superstructures have gained increasing interest in drug delivery, imaging, and biosensing. The load of satellites plays a vital role in core-satellite superstructures, and it determines the signal intensity in response to a biological/physical stimulation/actuation. Herein, for the first time, we utilize on-particle rolling circle amplification (RCA) to prepare rapidly responsive core-satellite magnetic superstructures with a high load of magnetic nanoparticle (MNP) satellites. Combined with duplex-specific nuclease-assisted target recycling, the proposed magnetic superstructures hold great promise in sensitive and rapid microRNA detection. The long single-stranded DNA produced by RCA serving as the scaffold of the core-satellite superstructure can be hydrolyzed by duplex-specific nuclease in the presence of target microRNA, resulting in a release of MNPs that can be quantified in an optomagnetic sensor. The proposed biosensor has a simple mix-separate-measure strategy. For let-7b detection, the proposed biosensor offers a wide linear detection range of approximately 5 orders of magnitude with a detection sensitivity of 1 fM. Moreover, it has the capability to discriminate single-nucleotide mismatches and to detect let-7b in cell extracts and serum, thus showing considerable potential for clinical applications. PMID- 29266918 TI - Chemical Oxidation of Polymer Electrodes for Redox Active Devices: Stabilization through Interfacial Interactions. AB - To achieve optimal performance in a conjugated polymer-based electrochemical device, i.e. for a supercapacitor to reach full depth of discharge or for an electrochromic device (ECD) to achieve maximum contrast, the two electrodes must be in different oxidation states when the device is assembled. Here, we evaluate the use of chemical oxidation as a scalable postprocessing method to adjust the redox state of polymer-coated electrodes. We evaluate how the extent of oxidation depends on both the redox properties of the conjugated polymer and on the choice of chemical oxidant, and how these parameters affect the functionality of the film. Comparing Ag(I) and Fe(III) oxidants, we find that it is not the oxidizing power that determines the extent of doping but rather the redox potentials of the polymers, with the more easily oxidized polymers doping to a higher extent. Because the polarity and surface energy of the polymer changes upon oxidation, we also show how a phosphonic acid surface pre-treatment improves interfacial adhesion between the polymer and a transparent oxide electrode (ITO). Finally, as a proof of principle, we demonstrate how chemical oxidation of the organic counter electrode a minimally color changing dioxypyrrole polymer enhances the device contrast of an ECD, confirming that this approach is a promising route toward high-throughput manufacturing of ECDs and other polymer-based electrochemical devices. PMID- 29266919 TI - Grafting of Bioactive Polymers with Various Architectures: A Versatile Tool for Preparing Antibacterial Infection and Biocompatible Surfaces. AB - The aim of this Research Article is to present three different techniques of poly(sodium styrene sulfonate) (polyNaSS) covalent grafting onto titanium (Ti) surfaces and study the influence of their architecture on biological response. Two of them are "grafting from" techniques requiring an activation step either by thermal or UV irradiation. The third method is a "grafting to" technique involving an anchorage molecule onto which polyNaSS synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization is clicked. The advantage of the "grafting to" technique when compared to the "grafting from" technique is the ability to control the architecture and length of the grafted polymers on the Ti surface and their influence on the biological responses. This investigation compares the effect of the three different grafting processes on the in vitro biological responses of bacteria and osteoblasts. Overall outcomes of this investigation confirmed the significance of the sulfonate functional groups on the biological responses, regardless of the grafting method. In addition, results showed that the architecture and distribution of grafted polyNaSS on Ti surfaces alter the intensity of the bacteria response mediated by fibronectin. PMID- 29266920 TI - Application of High-Throughput Seebeck Microprobe Measurements on Thermoelectric Half-Heusler Thin Film Combinatorial Material Libraries. AB - In view of the variety and complexity of thermoelectric (TE) material systems, combinatorial approaches to materials development come to the fore for identifying new promising compounds. The success of this approach is related to the availability and reliability of high-throughput characterization methods for identifying interrelations between materials structures and properties within the composition spread libraries. A meaningful characterization starts with determination of the Seebeck coefficient as a major feature of TE materials. Its measurement, and hence the accuracy and detectability of promising material compositions, may be strongly affected by thermal and electrical measurement conditions. This work illustrates the interrelated effects of the substrate material, the layer thickness, and spatial property distributions of thin film composition spread libraries, which are studied experimentally by local thermopower scans by means of the Potential and Seebeck Microprobe (PSM). The study is complemented by numerical evaluation. Material libraries of the half Heusler compound system Ti-Ni-Sn were deposited on selected substrates (Si, AlN, Al2O3) by magnetron sputtering. Assuming homogeneous properties of a film, significant decrease of the detected thermopower Sm can be expected on substrates with higher thermal conductivity, yielding an underestimation of materials thermopower between 15% and 50%, according to FEM (finite element methods) simulations. Thermally poor conducting substrates provide a better accuracy with thermopower underestimates lower than 8%, but suffer from a lower spatial resolution. According to FEM simulations, local scanning of sharp thermopower peaks on lowly conductive substrates is linked to an additional deviation of the measured thermopower of up to 70% compared to homogeneous films, which is 66% higher than for corresponding cases on substrates with higher thermal conductivity of this study. PMID- 29266921 TI - Polymer-Templated LiFePO4/C Nanonetworks as High-Performance Cathode Materials for Lithium-Ion Batteries. AB - Lithium iron phosphate (LFP) is currently one of the main cathode materials used in lithium-ion batteries due to its safety, relatively low cost, and exceptional cycle life. To overcome its poor ionic and electrical conductivities, LFP is often nanostructured, and its surface is coated with conductive carbon (LFP/C). Here, we demonstrate a sol-gel based synthesis procedure that utilizes a block copolymer (BCP) as a templating agent and a homopolymer as an additional carbon source. The high-molecular-weight BCP produces self-assembled aggregates with the precursor-sol on the 10 nm scale, stabilizing the LFP structure during crystallization at high temperatures. This results in a LFP nanonetwork consisting of interconnected ~10 nm-sized particles covered by a uniform carbon coating that displays a high rate performance and an excellent cycle life. Our "one-pot" method is facile and scalable for use in established battery production methodologies. PMID- 29266922 TI - Selective Electrochemical Reduction of Carbon Dioxide Using Cu Based Metal Organic Framework for CO2 Capture. AB - The conversion efficiency and product selectivity of the electroreduction of carbon dioxide have been largely limited by the low CO2 solubility in aqueous solution. To relieve this problem, Cu3(BTC)2 (Cu-MOF) as CO2 capture agent was introduced into a carbon paper based gas diffusion electrode (GDE) in this study. The faradaic efficiencies (FEs) of CH4 on GDE with Cu-MOF weight ratio in the range of 7.5-10% are 2-3-fold higher than that of GDE without Cu-MOF addition under negative potentials (-2.3 to -2.5 V vs SCE), and the FE of the competitive hydrogen evolution reaction (HER) is reduced to 30%. This work paves the way to develop GDE with high catalytic activity for ERC. PMID- 29266923 TI - Ionic Liquid-Assisted Synthesis of Mesoporous Carbons with Surface-Enriched Nitrogen for the Hydrogen Evolution Reaction. AB - Heteroatom-doped carbon materials are promising metal-free catalysts for the hydrogen evolution reaction (HER) at low voltage with high durability. However, many of the active sites introduced by heteroatom doping are hardly accessible within the bulk carbon structure and consequently contribute little to the catalytic activity. Here we report a facile ionic liquid-assisted method for synthesizing mesoporous nitrogen-doped carbons, enabling enrichment of nitrogen atoms at the pore surface, demonstrated by X-ray photoelectron spectroscopy (XPS) and temperature-programmed desorption of carbon dioxide (CO2-TPD). The resulting metal-free nitrogen-doped mesoporous carbons exhibit a remarkable electrocatalytic activity in HER. The accessible and efficient utilization of nitrogen atoms is responsible for the superior HER catalytic activity. PMID- 29266924 TI - Spatiotemporal Image Correlation Analysis for 3D Flow Field Mapping in Microfluidic Devices. AB - Microfluidic devices reproducing 3D networks are particularly valuable for nanomedicine applications such as tissue engineering and active cell sorting. There is however a gap in the possibility to measure how the flow evolves in such 3D structures. We show here that it is possible to map 3D flows in complex microchannel networks by combining wide field illumination to image correlation approaches. For this purpose, we have derived the spatiotemporal image correlation analysis of time stacks of single-plane illumination microscopy images. From the detailed analytical and numerical analysis of the resulting model, we developed a fitting method that allows us to measure, besides the in plane velocity, the out-of-plane velocity component down to vz ? 65 MUm/s. We have applied this method successfully to the 3D reconstruction of flows in microchannel networks with planar and 3D ramifications. These different network architectures have been realized by exploiting the great prototyping ability of a 3D printer, whose precision can reach few tens of micrometers, coupled to poly dimethyl-siloxane soft-printing lithography. PMID- 29266925 TI - Single Nanochannel-Aptamer-Based Biosensor for Ultrasensitive and Selective Cocaine Detection. AB - Ultrasensitive and selective detection of molecules at nano or sub-nanomolar level is very important for many areas such as early diagnosis and drug testing. Herein, we report a high-sensitive cocaine sensor based on a single nanochannel coupled with DNA aptamers. The single nanochannel-aptamer-based biosensor can recognize cocaine molecules with an excellent sensitivity and good selectivity. A linear relationship between target cocaine concentration and output ionic current is obtained in a wide concentration range of cocaine from 1 nM to 10 MUM. The cocaine sensor also shows a detection limit down to 1 nM. This study provides a new avenue to develop new nanochannel-aptamer-based biosensors for rapid and ultratrace detection of a variety of illicit drugs. PMID- 29266926 TI - A Caged Enkephalin Optimized for Simultaneously Probing Mu and Delta Opioid Receptors. AB - Physiological responses to the opioid neuropeptide enkephalin often involve both mu and delta opioid receptors. To facilitate quantitative studies into opioid signaling, we previously developed a caged [Leu5]-enkephalin that responds to ultraviolet irradiation, but its residual activity at delta receptors confounds experiments that involve both receptors. To reduce residual activity, we evaluated side-chain, N-terminus, and backbone caging sites and further incorporated the dimethoxy-nitrobenzyl moiety to improve sensitivity to ultraviolet light-emitting diodes (LEDs). Residual activity was characterized using an in vitro functional assay, and the power dependence and kinetics of the uncaging response to 355 nm laser irradiation were assayed using electrophysiological recordings of mu opioid receptor-mediated potassium currents in brain slices of rat locus coeruleus. These experiments identified N-MNVOC-LE as an optimal compound. Using ultraviolet LED illumination to photoactivate N MNVOC-LE in the CA1 region of hippocampus, we found that enkephalin engages both mu and delta opioid receptors to suppress inhibitory synaptic transmission. PMID- 29266927 TI - Frequency-Based Analysis of Gramicidin A Nanopores Enabling Detection of Small Molecules with Picomolar Sensitivity. AB - Methods to detect low concentrations of small molecules are useful for a wide range of analytical problems including the development of clinical assays, the study of complex biological systems, and the detection of biological warfare agents. This paper describes a semisynthetic ion channel platform capable of detecting small molecule analytes with picomolar sensitivity. Our methodology exploits the transient nature of ion channels formed from gramicidin A (gA) nanopores and the frequency of observed single channel events as a function of concentration of free gA molecules that reversibly dimerize in a bilayer membrane. We initially use a protein (here, a monoclonal antibody) to sequester the ion channel activity of a C-terminally modified gA derivative. When a small molecule analyte is introduced to the electrical recording medium, it competitively binds to the protein and liberates the gA derivative, restoring its single ion channel activity. We found that monitoring the frequency of gA channel events makes it possible to detect picomolar concentrations of small molecule in solution. In part, due to the digital on/off nature of frequency-based analysis, this approach is 103 times more sensitive than measuring macroscopic membrane ion flux through gA channels as a basis for detection. This novel methodology, therefore, significantly improves the limit of detection of nanopore-based sensors for small molecule analytes, which has the potential for incorporation into miniaturized and low cost devices that could complement current established assays. PMID- 29266928 TI - Unimolecular Logic Gate with Classical Input by Single Gold Atoms. AB - By a combination of solution and on-surface chemistry, we synthesized an asymmetric starphene molecule with two long anthracenyl input branches and a short naphthyl output branch on the Au(111) surface. Starting from this molecule, we could demonstrate the working principle of a single molecule NAND logic gate by selectively contacting single gold atoms by atomic manipulation to the longer branches of the molecule. The logical input "1" ("0") is defined by the interaction (noninteraction) of a gold atom with one of the input branches. The output is measured by scanning tunneling spectroscopy following the shift in energy of the electronic tunneling resonances at the end of the short branch of the molecule. PMID- 29266929 TI - Locating Large, Flexible Ligands on Proteins. AB - Many biologically important ligands of proteins are large, flexible, and in many cases charged molecules that bind to extended regions on the protein surface. It is infeasible or expensive to locate such ligands on proteins with standard methods such as docking or molecular dynamics (MD) simulation. The alternative approach proposed here is scanning of a spatial and angular grid around the protein with smaller fragments of the large ligand. Energy values for complete grids can be computed efficiently with a well-known fast Fourier transform accelerated algorithm and a physically meaningful interaction model. We show that the approach can readily incorporate flexibility of the protein and ligand. The energy grids (EGs) resulting from the ligand fragment scans can be transformed into probability distributions and then directly compared to probability distributions estimated from MD simulations and experimental structural data. We test the approach on a diverse set of complexes between proteins and large, flexible ligands, including a complex of sonic hedgehog protein and heparin, three heparin sulfate substrates or nonsubstrates of an epimerase, a multibranched supramolecular ligand that stabilizes a protein-peptide complex, a flexible zwitterionic ligand that binds to a surface basin of a Kringle domain, and binding of ATP to a flexible site of an ion channel. In all cases, the EG approach gives results that are in good agreement with experimental data or MD simulations. PMID- 29266930 TI - Characterizing Hydration Properties Based on the Orientational Structure of Interfacial Water Molecules. AB - In this work, we present a general computational method for characterizing the molecular structure of liquid water interfaces as sampled from atomistic simulations. With this method, the interfacial structure is quantified based on the statistical analysis of the orientational configurations of interfacial water molecules. The method can be applied to generate position dependent maps of the hydration properties of heterogeneous surfaces. We present an application to the characterization of surface hydrophobicity, which we use to analyze simulations of a hydrated protein. We demonstrate that this approach is capable of revealing microscopic details of the collective dynamics of a protein hydration shell. PMID- 29266931 TI - New Angles on Standard Force Fields: Toward a General Approach for Treating Atomic-Level Anisotropy. AB - Nearly all standard force fields employ the "sum-of-spheres" approximation, which models intermolecular interactions purely in terms of interatomic distances. Nonetheless, atoms in molecules can have significantly nonspherical shapes, leading to interatomic interaction energies with strong orientation dependencies. Neglecting this "atomic-level anisotropy" can lead to significant errors in predicting interaction energies. Herein, we propose a simple, transferable, and computationally efficient model (MASTIFF) whereby atomic-level orientation dependence can be incorporated into ab initio intermolecular force fields. MASTIFF includes anisotropic exchange-repulsion, charge penetration, and dispersion effects, in conjunction with a standard treatment of anisotropic long range (multipolar) electrostatics. To validate our approach, we benchmark MASTIFF against various sum-of-spheres models over a large library of intermolecular interactions between small organic molecules. MASTIFF achieves quantitative accuracy, with respect to both high-level electronic structure theory and experiment, thus showing promise as a basis for "next-generation" force field development. PMID- 29266933 TI - UV Photodissociation Mass Spectrometry Accurately Localize Sites of Backbone Deuteration in Peptides. AB - Hydrogen/deuterium exchange mass spectrometry (HDX-MS) is now a routinely used technique to inform on protein structure, dynamics, and interactions. Localizing the incorporated deuterium content on a single residue basis increases the spatial resolution of this technique enabling detailed structural analysis. Here, we investigate the use of ultraviolet photodissociation (UVPD) at 213 nm to measure deuterium levels at single residue resolution in HDX-MS experiments. Using a selectively labeled peptide, we show that UVPD occurs without H/D scrambling as the peptide probe accurately retains its solution-phase deuterium labeling pattern. Our results indicate that UVPD provides an attractive alternative to electron mediated dissociation for increasing the spatial resolution of the HDX-MS experiment, capable of yielding high fragmentation efficiency, high fragment ion diversity, and low precursor ion charge-state dependency. PMID- 29266932 TI - Real-Time In-Cell Nuclear Magnetic Resonance: Ribosome-Targeted Antibiotics Modulate Quinary Protein Interactions. AB - How ribosome antibiotics affect a wide range of biochemical pathways is not well understood; changes in RNA-mediated protein quinary interactions and consequent activity inside the crowded cytosol may provide one possible mechanism. We developed real-time (RT) in-cell nuclear magnetic resonance (NMR) spectroscopy to monitor temporal changes in protein quinary structure, for >=24 h, in response to external and internal stimuli. RT in-cell NMR consists of a bioreactor containing gel-encapsulated cells inside a 5 mm NMR tube, a gravity siphon for continuous exchange of medium, and a horizontal drip irrigation system to supply nutrients to the cells during the experiment. We showed that adding antibiotics that bind to the small ribosomal subunit results in more extensive quinary interactions between thioredoxin and mRNA. The results substantiate the idea that RNA-mediated modulation of quinary protein interactions may provide the physical basis for ribosome inhibition and other regulatory pathways. PMID- 29266935 TI - All the Ways To Have Substituted Nanothreads. AB - We describe a general, symmetry-conditioned way of enumerating isomers of saturated singly substituted one-dimensional nanothreads of the (CH)5E and (CH)5CR type, where E is a heteroatom and R is a substituent. Four nanothreads - so-called tube (3,0), polytwistane, the zipper polymer, and polymer I, are treated in detail. The methodology, combining symmetry arguments and computer based enumeration, is generally applicable to isomerism problems in polymers. PMID- 29266934 TI - Impact of Bi3+ Heterovalent Doping in Organic-Inorganic Metal Halide Perovskite Crystals. AB - Intrinsic organic-inorganic metal halide perovskites (OIHP) based semiconductors have shown wide applications in optoelectronic devices. There have been several attempts to incorporate heterovalent metal (e.g., Bi3+) ions in the perovskites in an attempt to induce electronic doping and increase the charge carrier density in the semiconductor. It has been reported that inclusion of Bi3+ decreases the band gap of the material considerably. However, contrary to the earlier conclusions, despite a clear change in the appearance of the crystal as observed by eye, here we show that the band gap of MAPbBr3 crystals does not change due the presence of Bi3+ in the growth solution. An increased density of states in the band gap and use of very thick samples for transmission measurements, erroneously give the impression of a band gap shift. These sub band gap states also act as nonradiative recombination centers in the crystals. PMID- 29266936 TI - Suppressing Ion Transfer Enables Versatile Measurements of Electrochemical Surface Area for Intrinsic Activity Comparisons. AB - Correlating the current/voltage response of an electrode to the intrinsic properties of the active material requires knowledge of the electrochemically active surface area (ECSA), a parameter that is often unknown and overlooked, particularly for highly nanostructured electrodes. Here we demonstrate the power of nonaqueous electrochemical double layer capacitance (DLC) to provide reasonable estimates of the ECSA across 17 diverse materials spanning metals, conductive oxides, and chalcogenides. Whereas data recorded in aqueous electrolytes generate a wide range of areal specific capacitance values (7-63 MUF/real cm2), nearly all materials examined display an areal specific capacitance of 11 +/- 5 MUF/real cm2 when measured in weakly coordinating KPF6/MeCN electrolytes. By minimizing ion transfer reactions that convolute accurate DLC measurements, we establish a robust methodology for quantifying ECSA, enabling more accurate structure-function correlations. PMID- 29266937 TI - Cyclin-Dependent Kinase 8: A New Hope in Targeted Cancer Therapy? AB - Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating transcription either through its association with the Mediator complex or by phosphorylating transcription factors. Myriads of genetic and biochemical studies have established CDK8 as a key oncogenic driver in many cancers. Specifically, CDK8 mediated activation of oncogenic Wnt-beta-catenin signaling, transcription of estrogen-inducible genes, and suppression of super enhancer-associated genes contributes to oncogenesis in colorectal, breast, and hematological malignancies, respectively. However, while most research supports the role of CDK8 as an oncogene, other work has raised the possibility of its contrary function. The diverse biological functions of CDK8 and its seemingly context-specific roles in different types of cancers have spurred a great amount of interest and perhaps an even greater amount of controversy in the development of CDK8 inhibitors as potential cancer therapeutic agents. Herein, we review the latest landscape of CDK8 biology and its involvement in carcinogenesis. We dissect current efforts in discovering CDK8 inhibitors and attempt to provide an outlook at the future of CDK8-targeted cancer therapies. PMID- 29266938 TI - Stabilization of Metastable Thermoelectric Crystalline Phases by Tuning the Glass Composition in the Cu-As-Te System. AB - Recrystallization of amorphous compounds can lead to the stabilization of metastable crystalline phases, which offers an interesting way to unveil novel binary or ternary compounds and control the transport properties of the obtained glass ceramics. Here, we report on a systematic study of the Cu-As-Te glassy system and show that under specific synthesis conditions using the spark-plasma sintering technique, the alpha-As2Te3 and beta-As2Te3 binary phases and the previously unreported AsTe3 phase can be selectively crystallized within an amorphous matrix. The microstructures and transport properties of three different glass ceramics, each of them containing one of these phases with roughly the same crystalline fraction (~30% in volume), were investigated in detail by means of X ray diffraction, scanning electron microscopy, neutron thermodiffraction, Raman scattering (experimental and lattice-dynamics calculations), and transport property measurements. The physical properties of the glass ceramics are compared with those of both the parent glasses and the pure crystalline phases that could be successfully synthesized. SEM images coupled with Raman spectroscopy evidence a "coast-to-island" or dendriticlike microstructure with microsized crystallites. The presence of the crystallized phase results in a significant decrease in the electrical resistivity while maintaining the thermal conductivity to low values. This study demonstrates that new compounds with interesting transport properties can be obtained by recrystallization, which in turn provides a tuning parameter for the transport properties of the parent glasses. PMID- 29266939 TI - A Structural Model of a P450-Ferredoxin Complex from Orientation-Selective Double Electron-Electron Resonance Spectroscopy. AB - Cytochrome P450 (CYP) monooxygenases catalyze the oxidation of chemically inert carbon-hydrogen bonds in diverse endogenous and exogenous organic compounds by atmospheric oxygen. This C-H bond oxy-functionalization activity has huge potential in biotechnological applications. Class I CYPs receive the two electrons required for oxygen activation from NAD(P)H via a ferredoxin reductase and ferredoxin. The interaction of Class I CYPs with their cognate ferredoxin is specific. In order to reconstitute the activity of diverse CYPs, structural characterization of CYP-ferredoxin complexes is necessary, but little structural information is available. Here we report a structural model of such a complex (CYP199A2-HaPux) in frozen solution derived from distance and orientation restraints gathered by the EPR technique of orientation-selective double electron electron resonance (os-DEER). The long-lived oscillations in the os-DEER spectra were well modeled by a single orientation of the CYP199A2-HaPux complex. The structure is different from the two known Class I CYP-Fdx structures: CYP11A1-Adx and CYP101A1-Pdx. At the protein interface, HaPux residues in the [Fe2S2] cluster binding loop and the alpha3 helix and the C-terminus residue interact with CYP199A2 residues in the proximal loop and the C helix. These residue contacts are consistent with biochemical data on CYP199A2-ferredoxin binding and electron transfer. Electron-tunneling calculations indicate an efficient electron-transfer pathway from the [Fe2S2] cluster to the heme. This new structural model of a CYP Fdx complex provides the basis for tailoring CYP enzymes for which the cognate ferredoxin is not known, to accept electrons from HaPux and display monooxygenase activity. PMID- 29266940 TI - Reagent for Introducing Base-Stabilized Phosphorus Atoms into Organic and Inorganic Compounds. AB - The cyclic alkyl(amino) carbene (cAAC) stabilized monoanionic phosphorus atom in the form of lithium phosphinidene [cAACPLi(THF)2]2 (1) has been isolated as a molecular species and characterized by single crystal X-ray structure analysis. Furthermore, the structure and bonding of compound 1 has been investigated by theoretical methods. The utilization of the lithium phosphinidene as a phosphorus transfer reagent for a wide range of organic and inorganic substrates has been investigated. Herein, we report on the preparation of fascinating compounds containing P-C, P-Si, P-Ge, and P-P bonds using a single step with a base stabilized phosphorus atom. PMID- 29266942 TI - Using Two-Dimensional Correlation Size Exclusion Chromatography (2D-CoSEC) and EEM-PARAFAC to Explore the Heterogeneous Adsorption Behavior of Humic Substances on Nanoparticles with Respect to Molecular Sizes. AB - The adsorption behaviors of different constituents within bulk humic substances (HS) on two nanoparticles, TiO2 and ZnO, were examined by using two-dimensional correlation size exclusion chromatography (2D-CoSEC) and excitation emission matrix-parallel factor analysis (EEM-PARAFAC), which separated bulk HS into different size fractions and fluorescent components, respectively. Subtle changes in the size distributions of HS with increasing adsorbents were successfully identified and tracked via the 2D-CoSEC. From adsorption isotherm experiments, three different HS constituent groups with respect to sizes and fluorescence features were identified by the 2D-CoSEC and EEM-PARAFAC, respectively. The chromatographically separated HS size groups presented dissimilar adsorption behaviors in terms of adsorption affinity and isotherm nonlinearity. The sequence orders of adsorption, interpreted from the 2D-CoSEC, was consistent with those of the isotherm model parameters individually calculated for different HS size subfractions, signifying the promising application of 2D-CoSEC in obtaining an insight into the heterogeneous adsorption of HS in terms of molecular sizes. EEM PARAFAC results also supported the major finding of the 2D-CoSEC as shown by the preferential adsorption of the fluorescent components associated with large molecular sizes. PMID- 29266941 TI - Amphiphilic Alginates for Marine Antifouling Applications. AB - Amphiphilic polymers are promising candidates for novel fouling-release coatings for marine applications. We grafted amphiphilic alginates with fluorinated side chains to glass and silicon substrates and characterized the obtained films by contact angle goniometry, spectroscopic ellipsometry, XPS, and ATR-FTIR. The potential to inhibit protein attachment was tested against four different proteins, and intermediate fluorine loadings showed the strongest reduction with respect to hydrophobic, aliphatic controls. A similar trend was observed in dynamic attachment experiments using Navicula perminuta diatoms and settlement experiments with zoospores of the green algae Ulva linza. The results indicate that amphiphilic alginates are promising natural and renewable biomacromolecules that could be included in future protective coating technologies. PMID- 29266943 TI - "Seriously Sweet": Acesulfame K Exhibits Selective Inhibition Using Alternative Binding Modes in Carbonic Anhydrase Isoforms. AB - Human carbonic anhydrase IX (CA IX) is upregulated in neoplastic tissues; as such, it is studied as a drug target for anticancer chemotherapy. Inhibition of CA IX has been shown to be therapeutically favorable in terms of reducing tumor growth. Previously, saccharin, a commonly used artificial sweetener, has been observed to selectively inhibit CA IX over other CA isoforms. In this study, X ray crystallography showed acesulfame potassium (Ace K) binding directly to the catalytic zinc in CA IX (mimic) and through a bridging water in CA II. This modulation in binding is reflected in the binding constants, with Ace K inhibiting CA IX but not other CA isoforms. Hence, this study establishes the potential of Ace K (an FDA approved food additive) as a lead compound in the design and development of CA IX specific inhibitors. PMID- 29266944 TI - Bending Carbon Nanoforms for Supramolecular Recognition: A Topological Study on Hemifullerene-Based Aggregates. AB - Buckybowls have risen as appealing fullerene fragment derivatives. Their intrinsic curvature has been exploited in the generation of host-guest supramolecular assemblies, not only through concave-convex complementarity but also through less-known concave-concave staggered arrangements. Whereas the stabilization of bowl-in-bowl dispositions has been ascribed to efficient pi-pi forces together with favorable dipole-dipole interactions, a detailed analysis on the forces guiding the formation of the staggered arrangements is missing so far. Herein, we present a thorough theoretical characterization of bowl-in-bowl vs staggered hemifullerene-based homodimers and heterodimers with the electron-donor truxTTF molecule, as test cases, under the density functional theory and by means of chemical bonding techniques. Our results clearly reveal strong and localized noncovalent signatures, together with an enhanced orbital interaction, associated with CH-pi and sulfur-mediated interactions governing the staggered formation. Bending the fullerene fragment is demonstrated to favor the stabilization in both homo- and heterodimers, in good accord with the depletion in the pi-electron density calculated upon increasing the buckybowl curvature. The optimal buckybowl curvature for the highest interaction energy is, however, dependent on the type of supramolecular assembly (bowl-in-bowl vs staggered) and the concave region to which hemifullerene approaches truxTTF. Interestingly, two regimes are found as a function of buckybowl curvature for hemifullerene homodimers: bowl-in-bowl dispositions are calculated more stable at low curvatures whereas staggered dimers prevail for highly curved buckybowls. Our results highlight the potential of discrete CH-pi and sulfur-mediated interactions to generate unconventional staggered supramolecular arrangements toward the development of a new and unexplored host-guest chemistry. PMID- 29266945 TI - Activation of H2 by Gadolinium Cation (Gd+): Bond Energy of GdH+ and Mechanistic Insights from Guided Ion Beam and Theoretical Studies. AB - The energy-dependent reactions of the lanthanide gadolinium cation (Gd+) with H2, D2, and HD are investigated using guided ion beam tandem mass spectrometry. From analysis of the resulting endothermic product ion cross sections, the 0 K bond dissociation energy for GdH+ is measured to be 2.18 +/- 0.07 eV. Theoretical calculations on GdH+ are performed for comparison with the experimental thermochemistry and generally appear to overestimate the experimental GdH+ bond dissociation energy. The branching ratio of the products in the HD reaction suggests that Gd+ reacts primarily via a statistical insertion mechanism to form the hydride product ion with contributions from direct mechanisms. Relaxed potential energy surfaces for GdH2+ are computed and are consistent with the availability of both statistical and direct reaction pathways. The reactivity and hydride bond energy for Gd+ is compared with previous results for the group three metal cations, Sc+ and Y+, and the lanthanides, La+ and Lu+, and periodic trends are discussed. PMID- 29266946 TI - Photosensitization Versus Photocyclization: Competitive Reactions of Phenylphenalenone in Its Role as Phytoanticipins in Plant Defense Strategies. AB - Phenalenone (PN) derivatives are involved in plant defense strategies, producing molecular singlet oxygen in a photosensitization process. Many experimental and theoretical studies determined that PN can performe this process with a quantum yield close to 1. However, it has been observed that the efficiency of some of its derivatives is much lower. This is the case of 9-phenylphenalenone (9-PhPN). To elucidate the factors that determine the different photochemistry of PN and its derivate 9-PhPN, we developed a complete active space self-consistent field/multi-configurational second-order perturbation theory study where several deactivation paths through the lowest excited states were explored. We found that the characteristics of the low-lying excited states are similar for both PN and 9 PhPN in the areas near the geometry of excitation. Consequently, the first processes that take place immediately after absorption are possible in both systems, including the population of the triplet state responsible for oxygen sensitization. However, 9-PhPN can also undergo cyclization by a bond formation between the carbonyl oxygen and a carbon atom of the phenyl substituent. This process competes favorably with population of triplet states and is responsible for the decrease of the quantum yield of oxygen sensitization in 9-PhPN relative to PN. PMID- 29266947 TI - Beryllium Bonding in the Light of Modern Quantum Chemical Topology Tools. AB - We apply several modern quantum chemical topology (QCT) tools to explore the chemical bonding in well established beryllium bonds. By using the interacting quantum atoms (IQA) approach together with electron distribution functions (EDF) and the natural adaptive orbitals (NAdOs) picture, we show that, in agreement with orbital-based analyses, the interaction in simple sigma and pi complexes formed by BeX2 (X = H, F, Cl) with water, ammonia, ethylene, and acetylene is dominated by electrostatic terms, albeit covalent contributions cannot be ignored. Our detailed analysis proves that several sigma back-donation channels are relevant in these dimers, actually controlling the conformational preference in the pi adducts. A number of one-electron beryllium bonds are also studied. Orbital invariant real space arguments clearly show that the role of covalency and charge transfer cannot be ignored. PMID- 29266948 TI - Isotope Effects on Nuclear Magnetic Shielding in Molecular Hydrogen. AB - The secondary isotope shifts of six molecular hydrogen isotopologues (H2, D2, T2, HD, HT, and DT) were measured using gas-phase nuclear magnetic resonance spectroscopy. It was found that these isotope shifts are in satisfying agreement with performed ab initio quantum chemistry computations. However, there is a small systematic discrepancy between results of experiments and computations, i.e., the magnitudes of computed shifts are approximately 10% larger than those obtained from the experiments. This indicates that computations performed using the Born-Oppenheimer approximation are not sufficient for reproducing quantitatively the experimentally determined secondary isotope shifts of molecular hydrogen. PMID- 29266949 TI - Temperature-Dependent Intramolecular Spin Coupling Interactions of a Flexible Bridged Nitronyl Nitroxide Biradical in Solution. AB - A biradical consisting of two nitronyl nitroxide (NN) radicals bridged by diphenyl-hexaethylene glycol chain [phenyl-O-(CH2CH2O)6-phenyl (GBN1)] was synthesized and investigated using electron paramagnetic resonance (EPR) spectroscopy in solution at different temperature ranges. The reversible temperature dependence behavior of spin coupling exchange is comprehensively reflected by the different lifetime of conformations due to a tumbling motion of the flexible hexaethylene glycol chain. The influences of different solvent on the exchange interactions between the radical entities are described by a two conformational model, which was, for the first time, applied for di-NN molecule and revealed the thermodynamic parameters enthalpy and entropy (DeltaH and DeltaS) of the conformational changes. The positive value of enthalpy indicates lower energy of the stretched form (as calculated) compared to the bent form. The transition enthalpy in polar MeCN is larger than in toluene and the positive entropy sign indicates more chain conformation options in the bent state. The magnetic properties of this molecule were investigated in solid state by magnetization studies and EPR spectroscopy. PMID- 29266950 TI - Engineering Dirac Materials: Metamorphic InAs1-xSbx/InAs1-ySby Superlattices with Ultralow Bandgap. AB - Quasiparticles with Dirac-type dispersion can be observed in nearly gapless bulk semiconductors alloys in which the bandgap is controlled through the material composition. We demonstrate that the Dirac dispersion can be realized in short period InAs1-xSbx/InAs1-ySby metamorphic superlattices with the bandgap tuned to zero by adjusting the superlattice period and layer strain. The new material has anisotropic carrier dispersion: the carrier energy associated with the in-plane motion is proportional to the wave vector and characterized by the Fermi velocity vF, and the dispersion corresponding to the motion in the growth direction is quadratic. Experimental estimate of the Fermi velocity gives vF = 6.7 * 105 m/s. Remarkably, the Fermi velocity in this system can be controlled by varying the overlap between electron and hole states in the superlattice. Extreme design flexibility makes the short-period metamorphic InAs1-xSbx/InAs1-ySby superlattice a new prospective platform for studying the effects of charge-carrier chirality and topologically nontrivial states in structures with the inverted bandgaps. PMID- 29266951 TI - Tuning the Doping Types in Graphene Sheets by N Monoelement. AB - The doping types of graphene sheets are generally tuned by different dopants with either three or five valence electrons. As a five-valence-electrons element, however, nitrogen dopants in graphene sheets have several substitutional geometries. So far, their distinct effects on electronic properties predicted by theoretical calculations have not been well identified. Here, we demonstrate that the doping types of graphene can be tuned by N monoelement under proper growth conditions using chemical vapor deposition (CVD), characterized by combining scanning tunneling microscopy/spectroscopy, X-ray/ultraviolet photoelectron spectroscopy, Hall effect measurement, Raman spectroscopy, and density functional theory calculations. We find that a relatively low partial pressure of CH4 (mixing with NH3) can lead to the growth of dominant pyridinic N substitutions in graphene, in contrast with the growth of dominant graphitic N substitutions under a higher partial pressure of CH4. Our results unambiguously confirm that the pyridinic N leads to the p-type doping, and the graphitic N leads to the n-type doping. Interestingly, we also find that the pyridinic N and the graphitic N are preferentially separated in different domains. Our findings shed light on continuously tuning the doping level of graphene monolayers by using N monoelement, which can be very convenient for growth of functional structures in graphene sheets. PMID- 29266952 TI - Charge Separation in Donor-C60 Complexes with Real-Time Green Functions: The Importance of Nonlocal Correlations. AB - We use the nonequilibrium Green function (NEGF) method to perform real-time simulations of the ultrafast electron dynamics of photoexcited donor-C60 complexes modeled by a Pariser-Parr-Pople Hamiltonian. The NEGF results are compared to mean-field Hartree-Fock (HF) calculations to disentangle the role of correlations. Initial benchmarking against numerically highly accurate time dependent density matrix renormalization group calculations verifies the accuracy of NEGF. We then find that charge-transfer (CT) excitons partially decay into charge separated (CS) states if dynamical nonlocal correlation corrections are included. This CS process occurs in ~10 fs after photoexcitation. In contrast, the probability of exciton recombination is almost 100% in HF simulations. These results are largely unaffected by nuclear vibrations; the latter become however essential whenever level misalignment hinders the CT process. The robust nature of our findings indicates that ultrafast CS driven by correlation-induced decoherence may occur in many organic nanoscale systems, but it will only be correctly predicted by theoretical treatments that include time-nonlocal correlations. PMID- 29266953 TI - N-Heterocyclic Carbene-Catalyzed Umpolung of beta,gamma-Unsaturated 1,2 Diketones. AB - The umpolung of beta,gamma-unsaturated diketones through N-heterocyclic carbene catalysis is described, which allows access to a variety of highly functionalized bicyclic cyclohexene-beta-lactones and 1,3,4-triaryl benzenes. An unprecedented reaction pattern involving the catalytic formation of nucleophilic O-acylated homoenolate intermediate is proposed. A diverse set of transformations on the product further showed the synthetic potential of this protocol. PMID- 29266954 TI - Near-Field Enhanced Photochemistry of Single Molecules in a Scanning Tunneling Microscope Junction. AB - Optical near-field excitation of metallic nanostructures can be used to enhance photochemical reactions. The enhancement under visible light illumination is of particular interest because it can facilitate the use of sunlight to promote photocatalytic chemical and energy conversion. However, few studies have yet addressed optical near-field induced chemistry, in particular at the single molecule level. In this Letter, we report the near-field enhanced tautomerization of porphycene on a Cu(111) surface in a scanning tunneling microscope (STM) junction. The light-induced tautomerization is mediated by photogenerated carriers in the Cu substrate. It is revealed that the reaction cross section is significantly enhanced in the presence of a Au tip compared to the far-field induced process. The strong enhancement occurs in the red and near-infrared spectral range for Au tips, whereas a W tip shows a much weaker enhancement, suggesting that excitation of the localized plasmon resonance contributes to the process. Additionally, using the precise tip-surface distance control of the STM, the near-field enhanced tautomerization is examined in and out of the tunneling regime. Our results suggest that the enhancement is attributed to the increased carrier generation rate via decay of the excited near-field in the STM junction. Additionally, optically excited tunneling electrons also contribute to the process in the tunneling regime. PMID- 29266955 TI - An Experimental Approach to Systematically Probe Charge Inversion in Nanofluidic Channels. AB - Charge inversion of the surfaces of nanofluidic channels occurs in systems with high-surface charge and/or highly charged ions and is of particular interest because of applications in biological and energy conversion systems. However, the details of such charge inversion have not been clearly elucidated. Specifically, although we can experimentally and theoretically show charge inversion, understanding at what conditions charge inversion occurs, as well how much the charge-inverting ions change the surface, are not known. Here, we show a novel experimental approach for uniquely finding both the zeta-potential and adsorption time of charge inverting ions in aqueous nanofluidic systems. PMID- 29266956 TI - Anomalous Properties of Lys Residues Buried in the Hydrophobic Interior of a Protein Revealed with 15N-Detect NMR Spectroscopy. AB - Ionizable residues buried in hydrophobic environments in proteins are essential for many fundamental biochemical processes. These residues titrate with anomalous pKa values that are challenging to reproduce with structure-based calculations owing to the conformational reorganization coupled to their ionization. Detailed characterization of this conformational reorganization is of interest; unfortunately, the properties of buried Lys residues are difficult to study experimentally. Here we demonstrate the utility of 15N NMR spectroscopy to gain insight into the protonation state, state of hydration and conformational dynamics of the Nzeta amino group of buried Lys residues. The experiments were applied to five variants of staphylococcal nuclease, with internal Lys residues that titrate with pKa values ranging from 6.2 to 8.1. Direct detection of buried Lys residues with these NMR spectroscopy methods will enable correlation between thermodynamic and structural data as well as unprecedented examination of how conformational transitions coupled to their ionization affect their pKa values. PMID- 29266957 TI - Strategy for Modeling the Infrared Spectra of Ion-Containing Water Drops. AB - Hydrated ions are ubiquitous in environmental and biological media. Understanding the perturbation exerted by an ion on the water hydrogen bond network is possible in the nanodrop regime by recording vibrational spectra in the O-H bond stretching region. This has been achieved experimentally in recent years by forming gaseous ions containing tens to hundreds of water molecules and recording their infrared photodissociation spectra. In this paper, we demonstrate the capabilities of a modeling strategy based on an extension of the AMOEBA polarizable force field to implement water atomic charge fluctuations along with those of intramolecular structure along the dynamics. This supplementary flexibility of nonbonded interactions improves the description of the hydrogen bond network and, therefore, the spectroscopic response. Finite temperature IR spectra are obtained from molecular dynamics simulations by computing the Fourier transform of the dipole moment autocorrelation function. Simulations of 1-2 ns are required for extensive sampling in order to reproduce the experimental spectra. Furthermore, bands are assigned with the driven molecular dynamics approach. This method package is shown to compare successfully with experimental spectra for 11 ions in water drops containing 36-100 water molecules. In particular, band frequency shifts of the free O-H stretching modes at the cluster surface are well reproduced as a function of both ion charge and drop size. PMID- 29266958 TI - Molecular Recognition, Conformational Behavior, and Spectral Characteristics of Oxatub[4]arene Macrocycle. AB - In the present work, we analyze molecular recognition behavior of synthetic hydroxylated oxatub[4]arene (TA4) receptor toward the methyl viologen in different redox states. The supramolecular binding of methyl viologen guest toward TA4 macrocyclic scaffold has been studied employing the dispersion corrected omegaB97X-D based density functional theory. The methyl viologen in dicationic and neutral forms revealed distinct features in electronic, 1H nuclear magnetic resonance, and infrared spectra. Quantum theory of atoms in molecules in conjunction with the noncovalent interaction reduced density gradient in real space have been used as tools to characterize the underlying host-guest binding. PMID- 29266959 TI - Self-Assembly-Triggered Cis-to-Trans Conversion of Azobenzene Compounds. AB - Cis-to-trans transition of azobenzene compounds usually occurs under appropriate light irradiation or slow thermal relaxation, and one can hardly obtain complete cis-to-trans transition of azos due to the overlap of the n-pi* transition of the trans and the cis isomers. We show that by viewing the photostationary state as a chemical equilibrium between the cis and trans isomers, triggered self-assembly of the trans isomers can promote the cis-to-trans transition, and trans azos with spectrum-grade purity can even be achieved using an elegantly designed coordinating azo. This work establishes a new paradigm for manipulating the cis to-trans transition of azo compounds, which may inspire designs for various azo based advanced materials. PMID- 29266960 TI - FLECS Technology for High-Throughput Single-Cell Force Biology and Screening. AB - Dr. Ivan Pushkarsky from the Department of Bioengineering at UCLA and Forcyte Biotechnologies, Inc. was awarded The President's Innovation Award at the Annual Society of Biomolecular Imaging and Informatics meeting held in San Diego, September 2017. All cell types produce mechanical forces to serve important physiological roles. Since aberrant force-generating phenotypes directly lead to disease, cellular force-generation mechanisms are high-value targets for new therapies. Despite knowledge of their significance in disease, drug developers have had limited access to force-generating cellular phenotypes, especially in the context of high-throughput screening. To serve this valuable need, we have developed a platform microtechnology called "FLECS" that can acquire robust contractility data from 1000s of uniformly patterned single cells simultaneously and seamlessly integrates with the 96- and 384-well plate formats to facilitate large-scale drug screens. This perspective discusses the challenges facing existing laboratory methods for measuring cellular force in the context of drug discovery. It then provides an overview of the FLECS platform, describes how it was designed to overcome many of these challenges, and discusses some exciting work already accomplished with FLECS. It concludes by highlighting the platform nature of the technology and the potential value that it promises for a myriad of drug development efforts. PMID- 29266961 TI - Qualitative and Quantitative Analyses of the Dynamic and Static Stabilizers of the Medial Elbow: An Anatomic Study. AB - BACKGROUND: The anterior bundle of the medial ulnar collateral ligament (UCL) and the forearm flexors provide primary static and dynamic stability to valgus stress of the elbow in overhead-throwing athletes. Quantitative anatomic relationships between the dynamic and static stabilizers have not been described. PURPOSE: To perform qualitative and quantitative anatomic evaluations of the medial elbow-UCL complex with specific attention to pertinent osseous and soft tissue landmarks. STUDY DESIGN: Descriptive laboratory study. METHODS: Ten nonpaired, fresh-frozen human cadaveric elbows (mean age, 54.1 years [range, 42-64 years]; all male) were utilized for this study. Quantitative analysis was performed with a 3-dimensional coordinate measuring device to quantify the location of pertinent bony landmarks and tendon and ligament footprints on the humerus, ulna, and radius. RESULTS: The anterior bundle of the UCL attached 8.5 mm (95% CI, 6.9-10.0) distal and 7.8 mm (95% CI, 6.6-9.1) lateral to the medial epicondyle, 1.5 mm (95% CI, 0.5-2.5) distal to the sublime tubercle, and 7.3 mm (95% CI, 6.1-8.5) distal to the joint line on the ulna along the ulnar ridge. The flexor digitorum superficialis (FDS) ulnar tendinous insertion was closely related and interposed within the anterior bundle of the UCL, overlapping with 45.6% (95% CI, 38.1-53.6) of the length of the anterior bundle of the UCL. The flexor carpi ulnaris (FCU) attached 1.9 mm (95% CI, 0.8-2.9) posterior and 1.3 mm (95% CI, 0.6-3.2) proximal to the sublime tubercle and overlapped with 20.9% (95% CI, 7.2-34.5) of the area of the distal footprint of the anterior bundle of the UCL. CONCLUSION: The anterior bundle of the UCL had consistent attachment points relative to the medial epicondyle and sublime tubercle. The ulnar limb of the FDS and FCU tendons demonstrated consistent insertions onto the ulnar attachment of the anterior bundle of the UCL. These anatomic relationships are important to consider when evaluating distal UCL tears both operatively and nonoperatively. Excessive stripping of the sublime tubercle should be avoided during UCL reconstruction to prevent violation of these tendinous attachments. CLINICAL RELEVANCE: The findings of this study enhance the understanding of valgus restraint in throwing athletes and provide insight into the difference in nonoperative outcomes between proximal and distal tears of the UCL. PMID- 29266962 TI - Pulmonary Rehabilitation, an Update: Clinical Phenotypes and Effect of Comorbidities and Echocardiographic Abnormalities. PMID- 29266963 TI - Adenolipoma of the Bronchus. A Rare Entity. PMID- 29266964 TI - Nutrition and sarcopenia: A review of the evidence of nutritional influences. AB - Prevention of age related decline in muscle mass and strength is a key strategy to keeping physical capacity in older age and allowing independent living. To emerge preventive strategies, a better understanding is required of life style factors that impacts on sarcopenia. However, since muscle mass and strength in later life depend on both the rate of muscle loss and the peak achieved in early life, attempts to prevent sarcopenia also require considering diet through the life course and the potential benefits of early interventions. Optimizing diet and nutrition status during the life may be an important strategy to preventing sarcopenia and enhancing physical ability in older age. PMID- 29266965 TI - Intensified Therapy with Inhaled Corticosteroids and Long-Acting beta2-Agonists at the Onset of Upper Respiratory Tract Infection to Prevent Chronic Obstructive Pulmonary Disease Exacerbations. A Multicenter, Randomized, Double-Blind, Placebo controlled Trial. AB - RATIONALE: The efficacy of intensified combination therapy with inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) at the onset of upper respiratory tract infection (URTI) symptoms in chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVES: To evaluate whether intensified combination therapy with ICS/LABA, at the onset of URTI symptoms, decreases the incidence of COPD exacerbation occurring within 21 days of the URTI. METHODS: A total of 450 patients with stable, moderate to very severe COPD, were included in this investigator-initiated and -driven, double-blind, randomized, placebo controlled study. At inclusion, patients were assigned to open-labeled low maintenance dose ICS/LABA. Each patient was randomized either to intensified-dose ICS/LABA or placebo and instructed to start using this medication only in case of a URTI, at the onset of symptoms, twice daily, for 10 days. MEASUREMENTS AND MAIN RESULTS: The incidence of any exacerbation following a URTI was not significantly decreased in the ICS/LABA group, as compared with placebo (14.6% vs. 16.2%; hazard ratio, 0.77; 95% confidence interval, 0.46-1.33; P = 0.321) but the risk of severe exacerbation was decreased by 72% (hazard ratio, 0.28; 95% confidence interval, 0.11-0.74%; P = 0.010). In the stratified analysis, effect size was modified by disease severity, fractional exhaled nitric oxide, and the body mass index-airflow obstruction-dyspnea, and exercise score. Compared with the stable period, evidence of at least one virus was significantly more common at URTI, 10 days after URTI, and at exacerbation. CONCLUSIONS: Intensified combination therapy with ICS/LABA for 10 days at URTI onset did not decrease the incidence of any COPD exacerbation but prevented severe exacerbation. Patients with more severe disease had a significant risk reduction for any exacerbation. Clinical trial registered with www.isrctn.com (ISRCTN45572998). PMID- 29266966 TI - Cardiovascular Outcomes after a Respiratory Tract Infection among Adults with Non Cystic Fibrosis Bronchiectasis: A General Population-based Study. AB - RATIONALE: Studies suggest that adults with bronchiectasis are at increased risk of cardiovascular comorbidities. OBJECTIVES: We aimed to quantify the relative risk of incident cardiovascular events after a respiratory tract infection among adults with bronchiectasis. METHODS: Using UK electronic primary care records, we conducted a within-person comparison using the self-controlled case series method. We calculated the relative risk of first-time cardiovascular events (either first myocardial infarction or stroke) after a respiratory tract infection compared with the individual's baseline risk. RESULTS: Our cohort consisted of 895 adult men and women with non-cystic fibrosis bronchiectasis with a first myocardial infarction or stroke and at least one respiratory tract infection. There was an increased rate of first-time cardiovascular events in the 91-day period after a respiratory tract infection (incidence rate ratio, 1.56; 95% confidence interval, 1.20-2.02). The rate of a first cardiovascular event was highest in the first 3 days after a respiratory tract infection (incidence rate ratio, 2.73; 95% confidence interval, 1.41-5.27). CONCLUSIONS: These data suggest that respiratory tract infections are strongly associated with a transient increased risk of first-time myocardial infarction or stroke among people with bronchiectasis. As respiratory tract infections are six times more common in people with bronchiectasis than the general population, the increased risk has a disproportionately greater impact in these individuals. These findings may have implications for including cardiovascular risk modifications in airway infection treatment pathways in this population. PMID- 29266967 TI - Screening and Diagnosis of Monoclonal Gammopathies: An International Survey of Laboratory Practice. AB - CONTEXT: - Serum tests used for the screening and diagnosis of monoclonal gammopathies include serum protein electrophoresis (SPE; agarose gel or capillary zone), immunofixation (IFE) and immunosubtraction capillary electrophoresis, serum free light chains, quantitative immunoglobulins, and heavy/light-chain combinations. Urine protein electrophoresis and urine IFE may also be used to identify Bence-Jones proteinuria. OBJECTIVE: - To assess current laboratory practice for monoclonal gammopathy testing. DESIGN: - In April 2016, a voluntary questionnaire was distributed to 923 laboratories participating in a protein electrophoresis proficiency testing survey. RESULTS: - Seven hundred seventy-four laboratories from 38 countries and regions completed the questionnaire (83.9% response rate; 774 of 923). The majority of participants (68.6%; 520 of 758) used agarose gel electrophoresis as their SPE method, whereas 31.4% (238 of 758) used capillary zone electrophoresis. The most common test approaches used in screening were SPE with reflex to IFE/immunosubtraction capillary electrophoresis (39.3%; 299 of 760); SPE only (19.1%; 145 of 760); SPE and IFE or immunosubtraction capillary electrophoresis (13.9%; 106 of 760); and SPE with IFE, serum free light chain, and quantitative immunoglobulins (11.8%; 90 of 760). Only 39.8% (305 of 767) of laboratories offered panel testing for ordering convenience. Although SPE was used by most laboratories in diagnosing new cases of myeloma, when laboratories reported the primary test used to follow patients with monoclonal gammopathy, only 55.7% (403 of 724) chose SPE, with the next most common selections being IFE (18.9%; 137 of 724), serum free light chain (11.7%; 85 of 724), and immunosubtraction capillary electrophoresis (2.1%; 15 of 724). CONCLUSIONS: - Ordering and testing practices for the screening and diagnosis of monoclonal gammopathy vary widely across laboratories. Improving utilization management and report content, as well as recognition and development of laboratory-directed testing guidelines, may serve to enhance the clinical value of testing. PMID- 29266968 TI - Ex Vivo Confocal Fluorescence Microscopy for Rapid Evaluation of Tissues in Surgical Pathology Practice. AB - CONTEXT: - Optical imaging techniques are currently available for imaging tissues without the need for any type of extensive tissue preparation. There are several applications for their potential use in surgical pathology practice. OBJECTIVE: - To evaluate the feasibility of using a confocal fluorescence microscopy (CFM) platform for ex vivo examination of tissues obtained from surgical resections of breast, lung, kidney, and liver. DESIGN: - Tissue fragments (0.5-1.0 cm) were immersed in 0.6 mM acridine orange for 6 seconds and imaged using a CFM platform at a 488-nm wavelength. The imaged tissues were subsequently fixed in formalin and processed routinely to generate hematoxylin-eosin-stained tissue sections. Mosaics of the grayscale CFM images were studied at different magnifications for recognition of the tissue and were compared with conventional histopathologic examination of hematoxylin-eosin tissue sections. RESULTS: - We imaged 55 tissue fragments obtained from 16 breast (29%), 18 lung (33%), 14 kidney (25%), and 7 liver (13%) surgical excision specimens. Acridine orange labeled the nuclei, creating the contrast between nucleus and cytoplasm and thereby recapitulating the tissue architecture. We could obtain CFM images of good quality within 5 to 10 minutes that allowed recognition of the cytomorphologic details for categorization of the imaged tissue and were similar to histologic examination of hematoxylin-eosin tissue sections. CONCLUSIONS: - The ease and speed of acquisition of CFM images together with the resolution and resemblance of the CFM images to hematoxylin-eosin sections suggest that the CFM platform has excellent potential for use in surgical pathology practice. PMID- 29266969 TI - Environmental Dissemination of Multidrug Methicillin-Resistant Staphylococcus sciuri After Application of Manure from Commercial Swine Production Systems. AB - The deposition of manure originating from food animal farms in the environment can lead to the dissemination of antimicrobial-resistant (AMR) bacterial foodborne pathogens, thereby potentially impacting human health. The objective of our study was to determine the dissemination of multidrug methicillin-resistant Staphylococcus sciuri (MDR-MRSS) in the environment after land application of manure on commercial swine farms. A total of 400 environmental samples (40 manure and 360 soil) were collected after repeated sampling from four commercial swine farms located in North Carolina (n = 1) and Iowa (n = 3) in the United States. At each farm, we collected 10 manure and 40 soil samples (20 samples before and after 2 h of manure application) from four plots (five soil samples/plot) on day 0. Subsequently, 20 soil samples were collected on day 7, 14, and 21 from the same plots. A total of 67 (16.75%) MRSS were isolated from the 400 samples. The prevalence in soil and manure was 13.33% (48/360) and 47.5% (19/40), respectively. Prevalence was highest in the soil samples collected after 2 h of manure application on day 0 and decreased subsequently on 7, 14, and 21 days. Antimicrobial susceptibility testing was done against a panel of 12 antibiotics. A majority of S. sciuri isolates exhibited resistance against ampicillin (AMP; 95.5%), penicillin (PEN; 95.5%), clindamycin (CLI; 95.5%), cefoxitin (FOX; 92.5%), ceftiofur (XNL; 92.5%), tetracycline (TET; 86.56%), and erythromycin (ERY; 50.74%). The MDR pattern AMP FOX CLI PEN TET XNL (n = 24; 35.8%) was the most commonly observed. We detected multiple AMR genes, including mecA, aac(6'), Ie-aph(2")Ia, tetM, tetK, mphC, ermA, ermB, and ermC. Pulsed-field gel electrophoresis clustered isolates from different sample collection days from the same farm into one group. Overall, our study identifies swine manure as an important reservoir of MDR-MRSS and highlights its dissemination in the environment upon spreading of manure. PMID- 29266970 TI - Comparison of Depression and Burnout Levels of Mothers of Children with Attention Deficit Hyperactivity Disorder Before and After Treatment. AB - OBJECTIVE: This study aimed to compare the depression and burnout levels of mothers of children having attention-deficit/hyperactivity disorder (ADHD) between the child's pre- and posttreatment periods. METHOD: The study sample consisted of 40 children aged between 4 and 10 years and their mothers. Initially, 40 cases participated, but during the follow-up, 19 cases dropped out. The Beck Depression Inventory (BDI), the Maslach Burnout Inventory (MBI), and the Turgay DSM-IV Based Child and Adolescent Behaviour Disorders Screening and Rating Scale (T-DSM-IV-S) were used. RESULTS: Among the mothers, posttreatment BDI scores, MBI-emotional exhaustion, and personal accomplishment were significantly lower than the pretreatment scores. In the treatment's second month, all T-DSM-IV S subscale scores showed a statistically significant decrease. CONCLUSIONS: It was concluded that treatment of children with ADHD would have a favorable impact on their mothers' depressive symptoms, which would consequently decrease negative parental attitudes, hence reducing the risk of behavioral disorder in children with ADHD and exerting a positive effect on their treatment. PMID- 29266972 TI - Well-being in elderly long-term care residents with chronic mental disorder: a systematic review. AB - OBJECTIVES: One of the most important objectives of care for older long-term care residents with chronic mental disorders is to facilitate well-being. This review provides an overview of research literature on well-being in this population. METHOD: A systematic review was conducted using Pubmed, PsycINFO and PsycARTICLES for all studies up until March 2016. Three reviewers independently assessed the eligibility of the publications and made a selection. RESULTS: From a total of 720 unique search results, ten studies were deemed eligible. Specialized care, specifically the presence of mental health-workers was associated with increased well-being outcomes. Perceived amount of personal freedom was also related to higher well-being, whereas stigmatization and depression were related to reduced well-being. Size of residence, single or group-accommodation or moving to another locationdid not, however, seem to have an impact on well-being. CONCLUSION: Specialized care, aimed at psychiatric disorders and extra attention for depressed residents are useful tools to promote well-being. Additionally, themes like personal freedom and stigmatization should be taken into consideration in the care for older long-term care residents with chronic mental disorder. However, as very little research has been conducted on this topic, conclusions should be interpreted with caution. More research is highly desirable. PMID- 29266971 TI - Expression of the Chemokine Receptor CXCR3 Correlates with Dendritic Cell Recruitment and Prognosis in Gastric Cancer. AB - AIM: The aim of this study was to investigate whether CXCR3 expression is associated with: infiltration of dendritic cells (DCs) and CD4+ and CD8+ tumor infiltrating lymphocytes (TILs); various clinical features; and overall survival (OS) of patients diagnosed with gastric cancer (GC). MATERIALS AND METHODS: The study included 169 GC specimens and 91 corresponding paracancerous tissues. Immunohistochemistry was conducted to determine the expression of CXCR3 and the presence of DCs and CD4+ and CD8+ TILs. Statistical analyses were done using SPSS 17.0 software. RESULTS: CXCR3 expression in GC tissues was significantly higher than in paracancerous tissues (p < 0.001). Higher CXCR3 expression was associated with increased DC and both CD8+ and CD4+ TIL infiltration (p = 0.003, p = 0.008, and p = 0.016, respectively). In contrast, low CXCR3 expression was correlated with greater tumor invasion depth, III/IV TNM stage, lymph node metastasis, and more poorly differentiated tumor cells in GC patients (p = 0.001, p = 0.005, p = 0.037, and p = 0.004, respectively). Univariate analysis indicated that patients with high CXCR3 expression and high DC and CD8+ TIL infiltration had longer OS (log-rank test, p < 0.001, p = 0.018, and p = 0.001, respectively). Univariate and multivariate analyses indicated that CXCR3 expression was an independent prognostic factor for OS (p < 0.001, in both cases). CONCLUSION: The results of this study indicate that CXCR3 overexpression in GC is associated with increased DC and TIL infiltration and improved OS, and thus could be further exploited as a biomarker of favorable prognosis and a therapeutic target in GC. PMID- 29266973 TI - Investigational opioid antagonists for treating opioid-induced bowel dysfunction. AB - INTRODUCTION: Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC. Areas covered: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued. Expert opinion: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients' quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature. PMID- 29266974 TI - Modulation of Fatty Acids and Interleukin-6 in Glioma Cells by South American Tea Extracts and their Phenolic Compounds. AB - Dietary phenolic compounds are plant metabolites with beneficial effects on the central nervous system. Thus, our aim was to identify anti-inflammatory compounds from South American plants on glia, which regulates neuro-immune response. The compounds were extracted from Lantana grisebachii (LG), Aspidosperma quebracho blanco (AQB), and Ilex paraguariensis (IP) teas and identified by HPLC-DAD-MS. Extracts (0-200 ug/ml) were tested on human T98-G and rat C6 glioma lines. Cellular viability (by the resazurin assay), fatty acid profile (by gas chromatography) and pro-inflammatory interleukin-6 release (IL-6 by ELISA) were determined. Data were analyzed by partial least-square regression to discriminate bioactive compounds. Twenty-one compounds were determined in LG, mainly iridoids, which were linked to omega-3 and omega-6 polyunsaturated fatty acids, but not to IL-6 release. Thirty-one compounds were found in AQB, mostly hydroxybenzoic derivatives, which were positively related to IL-6 release. Twenty-three compounds were identified in IP, including caffeoylquinic derivatives and mainly chlorogenic acid. They increased the omega-7 palmitoleic fatty acid, which was related to IL-6 decrease. These results enhances phytochemical knowledge of widely available plants, and suggest the lipid-related anti-inflammatory activity of IP phenolic compounds, which give nutritional relevance to the tea. PMID- 29266975 TI - Cognitive dysfunction predicts worse health-related quality of life for older stroke survivors: a nationwide population-based survey in Taiwan. AB - OBJECTIVES: This study investigated the associations of cognitive status with specific/overall health-related quality of life (HRQoL) in older stroke survivors in Taiwan. METHOD: A subsample of 592 older stroke survivors in a nationwide population-based survey of cognitive-dysfunction prevalencewas analyzed. HRQoL was assessed using the EuroQol five-dimension questionnaire (EQ-5D). RESULTS: Stroke survivors with dementia were 5.60 times more likely to have mobility problems, 12.20 times to have self-care problems, 16.61 times to have problems in usual activities, 4.31 times to have pain/discomfort, and 3.28 times to have anxiety/depression than stroke survivors with normal cognitive function. Stroke survivors with mild cognitive dysfunction (MCD) were 2.57 times more likely to have mobility problems, 3.17 times to have self-care problems, 3.31 times to have problems in usual activities, 2.11 times to have pain/discomfort, and 2.35 times to have anxiety/depression than those with normal cognitive function. Both dementia (b = -15.13, p < .001) and MCD (b = -6.24, p < .001) significantly contributed to lower EQ-5D VAS; both dementia (b = -.15, p < .001) and MCD (b = .10, p < .001) significantly contributed to lower EQ-5D index. CONCLUSION: Dementia and MCD strongly predicted worse overall and specific HRQoL dimensions, especially self-care and usual activities for older stroke survivors. PMID- 29266976 TI - Characteristics Associated with Drug Prescription and Compliance Among Young Children with Autism Spectrum Disorder. AB - OBJECTIVES: Psychotropic drugs are prescribed to people with autism spectrum disorder (ASD) usually as a means to alleviate comorbidities associated with the disorder. However, despite the uncertainty regarding the efficacy of these treatments for ASD, their prevalence is continuously increasing. The goal of this study was to understand the characteristics associated with drug prescription and compliance among young children with ASD. MATERIALS AND METHODS: We studied patterns of drug utilization in a population-based sample of 211 young children with ASD in Southern Israel. Data regarding drug prescription and compliance (percentage of purchased drugs out of total prescriptions) were acquired from the electronic records of these patients. Compliance rates (CRs) were calculated as percentage of purchased drugs of the total number of prescriptions. RESULTS: A total of 122 prescriptions were made for 75 children in our sample. Drug prescription was significantly associated with the severity of ASD and the types of comorbidity (p < 0.05). Atypical antipsychotic drugs were the most prevalent drugs (49 children; 23.2%), followed by stimulants (28 children; 13.2%) and first generation antipsychotic drugs (16 children; 7.6%). The average CR in our sample was 75% +/- 3% with about half of the children demonstrating full compliance, and less than fifth of them not complying at all with their drug prescription. CR had a positively linear association with ASD severity at a marginal statistical significance of p = 0.06. No other variables were statistically associated with drug compliance in our study. CONCLUSIONS: Our results highlight the significant effect of ASD severity on both the prescription and CRs of drugs among young children with ASD. Further examination of drug utilization for longer periods and larger samples will help confirming our findings and test the effects of other variables on these pharmaceutical parameters. PMID- 29266977 TI - Interactions Between PPARG and AGTR1 Gene Polymorphisms on the Risk of Hypertension in Chinese Han Population. AB - AIMS: To explore the interactions between PPARG and AGTR1 polymorphisms and their associations with hypertension in the Chinese Han population. METHODS: Seven single nucleotide polymorphisms (SNPs) of the PPARG gene and five SNPs of the AGTR1 gene were selected and genotyped in 1591 unrelated Chinese Han adults. The SNPAssoc package of R was used to analyze the associations between the selected SNPs and hypertension. The potential gene-gene interactions between PPARG and AGTR1 genes were tested by model-based multifactor dimensionality reduction (MB MDR). RESULTS: The frequencies of the C allele of rs3856806 and the G allele of rs13433696 in the PPARG gene were significantly lower in hypertensive subjects, whereas the A allele of rs9817428 in the PPARG gene was much higher in hypertensives. In addition, individuals with T allele of rs2933249 in the AGTR1 gene displayed a significantly decreased risk of hypertension. MB-MDR analyses suggested that the two-locus model (rs9817428 and rs2933249) and the three-locus model (rs9817428, rs3856806, and rs2933249) were significantly associated with a decreased risk of hypertension. Moreover, among the eight SNPs not individually associated with hypertension (rs12631819, rs2920502, rs1175543, and rs2972164 in the PPARG gene, and rs2638360, rs1492100, rs5182, and rs275646 in the AGTR1 gene), the two-locus model involving rs12631819 and rs5182 demonstrated increased susceptibility to hypertension, and the five-locus model involving rs12631819, rs2920502, rs2972164, rs5182, and rs2638360 demonstrated a significantly decreased risk of hypertension. CONCLUSION: Polymorphisms in both the PPARG and AGTR1 genes were found to be significantly associated with hypertension. Moreover, there were significant gene-gene interactions identified between the PPARG and AGTR1 genes in relation to hypertension susceptibility in the Chinese Han population. PMID- 29266978 TI - Prognostic and Clinicopathological Significance of BAP1 Protein Expression in Different Types of Cancer-A Meta-Analysis. AB - BACKGROUND AND AIMS: The prognostic value of BRCA1-associated protein 1 (BAP1) expression in different cancer types remains controversial. The aim of this study was to identify the prognostic and clinicopathological significance of BAP1 gene expression. MATERIALS AND METHODS: The PubMed, Web of Science, and Embase databases were searched comprehensively for relevant studies. The pooled effects were calculated to investigate the association of BAP1 expression with cancer prognosis and clinicopathological features. The chi2 and I2 tests were performed to evaluate heterogeneity among the enrolled articles. If the p > 0.05 and I2 < 50%, a fixed-effects model was applied; and if the p < 0.05 and I2 > 50%, we used a random-effects model. RESULTS: A total of 26 studies covering 8043 patients were included in the meta-analysis. The correlation between BAP1 expression and patient survival was evaluated for 10 different cancer types. The pooled hazard ratio (HR) of BAP1 expression and overall survival (OS) was 0.83 (95% confidence interval [CI]: 0.61-1.12) with heterogeneity (I2 = 85.8%, p < 0.001), which indicated that the expression of BAP1 had no obvious impact on patient survival in the all-cancer cohort. However, subgroup analyses indicated that cancer type, rather than other parameters (geographic region, detection method, sample size, or comparison method), lead to this heterogeneity. BAP1 expression was a favorable predicative factor for OS in clear cell renal cell carcinoma (HR = 0.57, 95% CI: 0.47-0.69), non-small cell lung cancer (HR = 0.55, 95% CI: 0.32 0.96), and uveal melanoma (HR = 0.41, 95% CI: 0.27-0.62), while high expression of BAP1 was associated with poorer outcome in malignant pleural mesothelioma (HR = 2.03, 95% CI: 1.67-2.47). CONCLUSION: Our study revealed that BAP1 expression tends to have different prognostic values in different cancer types. Clinically, BAP1 may serve as a promising marker for prognostic prediction for certain cancer types. PMID- 29266979 TI - Aspiration and Corticosteroid Injection. PMID- 29266980 TI - Souped Up for Health. PMID- 29266981 TI - Court of Dreams. AB - This article was written in May 1992, after Magic Johnson announced he had tested positive for the human immunodeficiency virus that causes AIDS and was retiring from the Los Angeles Lakers. Since then, Johnson played in the 1992 Summer Olympic Games and, after a brief return to the Lakers, permanently retired from the NBA. PMID- 29266983 TI - scanning sports. PMID- 29266984 TI - Patellofemoral Syndrome. PMID- 29266985 TI - Does iron increase heart-attack risk? PMID- 29266987 TI - QuikQuiz. PMID- 29266986 TI - Does Exercise Intensity Matter? AB - To improve health, more physicians and exercise specialists now encourage people to exercise on a regular basis. For the average person, many experts say that exercise intensity is not an issue. Just getting people off the couch is the first step towards improved health. However, for the already active patient interested in improving performance, intensity is an important consideration. PMID- 29266988 TI - Snowboarding Injuries. AB - In brief The authors studied data from 415 injured snowboarders to determine injury patterns. Injuries were evenly distributed between upper and lower extremities, and 41% were fractures. The wrist was the most common injury site. Snowboarders wearing hard-shell boots were more likely to injure their knees; those wearing soft boots, their ankles. In a nonstatistical comparison, snowboarders' injury rates were similar to Alpine skiers', but boarders were more likely than skiers to injure their upper extremities. PMID- 29266990 TI - editor's notes. PMID- 29266989 TI - pearls. PMID- 29266991 TI - Relieving Painful 'Shin Splints'. AB - In brief Shin splints, or more precisely, medial tibial stress syndrome (MTSS), are painful and troublesome. Despite treatment or activity modification, they often recur. Distinguishing MTSS, the most common running overuse injury, from other overuse injuries can help focus treatment, which starts conservatively. Recommending activity modification, ice massage, NSAIDs, and stretching is a good first step. Patients who don't respond to treatment may need additional diagnostic workup and more restrictive activity guidelines. PMID- 29266992 TI - Acromioclavicular Injuries. AB - In brief Injuries to the acromioclavicular (AC) joint commonly occur among athletes. Dislocations are usually visually apparent, but sprains require a directed physical exam to determine the extent of damage to the AC joint. To rule out fractures, radiographs should be part of the diagnostic work-up. A review of the literature examines the controversy over surgical and nonsurgical methods to treat AC dislocations. Treatment, even for some of the more severe injuries, is conservative and includes ice, immobilization, and, occasionally, attempts at closed reduction. PMID- 29266993 TI - Preventing, Diagnosing, and Treating Cold Urticaria. AB - In brief While most cases of cold urticaria are mild and characterized only by pruritus, severe anaphylactic reaction is possible. Our patient, a healthy male runner, experienced intermittent and sometimes severe pruritus and severe urticaria after running in the cold. Avoiding cold air and cold water or using prophylactic medications that suppress the release of mast cell mediators has proved modestly successful in preventing and treating cold urticaria. Patients who develop cold urticaria often improve with time. PMID- 29266994 TI - Heart Rates in Boat Racers. AB - Six healthy, normotensive, experienced boat racers had high heart rates during races even though their work load was small, and the rates did not decrease with more experience. PMID- 29266995 TI - Olympic Drug Testing: Improvements Without Progress. AB - Twenty years ago the International Olympic Committee decided to protect athletes from themselves by testing for drug use. Since then like Topsy-or Frankenstein Olympic drug testing just grew. PMID- 29266996 TI - Running Therapy: Organized and Moving. AB - Thaddeus Kostrubala was always in the vanguard of running therapy, a loosely defined but effective way to deal with mental illness. Now he's started an academy of its practitioners. PMID- 29266997 TI - brief reports. PMID- 29266998 TI - Ankle Reconditioning with TNS. PMID- 29266999 TI - The Limits to Training. PMID- 29267001 TI - a need to know. PMID- 29267000 TI - How Competition Affects Elite Women Swimmers. AB - How does a strong motivation to win affect women after the days of competition are over? Ten years later, these swimmers say it contributed positively to their social health. PMID- 29267003 TI - scanning sports. PMID- 29267004 TI - The Way to the Will. PMID- 29267005 TI - Runner's Knee. AB - A systematic approach to knee problems by anatomical location of symptoms helps the physician make a specific diagnosis. The aim is to keep the runner running, so treatment is conservative whenever possible. PMID- 29267006 TI - Rescue Service for Powerboat Racing. AB - This rescue team for powerboat racing combines the skills of a physician, scuba divers, Red Cross volunteers, amateur radio operators, and the local boat club. PMID- 29267007 TI - A Comparison of Judo and Aikido Injuries. AB - Judo and aikido use similar techniques, so players may suffer similar injuries. But because judo is competitive, its injury rate may be higher. PMID- 29267008 TI - Sudden Drowning Syndrome. AB - Many drownings result from ignorance or misinformation-not only on the part of outdoorsmen, but also of rescue personnel. This article clears up some of the myths surrounding this problem. PMID- 29267009 TI - letters. PMID- 29267010 TI - Anemia in Cutaneous Malignant Melanoma: Low Blood Hemoglobin Level is Associated with Nodal Involvement, Metastatic Disease, and Worse Survival. AB - Anemia is common in cancer patients and also affects survival. However, its clinical role and prognostic significance remains unknown in cutaneous melanoma patients (CMPs). The aim of this study was to determine the clinical significance of blood hemoglobin levels in CMPs. Of 446 CMPs were enrolled into this study and were investigated retrospectively. The median value of hemoglobin levels was 13.4 g/dL (7.9-17.4 g/dL). The female patients (P < 0.001) and those with nodular histology (P = 0.040), elevated erythrocyte sedimentation rate (P < 0.001), higher serum lactate dehydrogenase (P < 0.001), lymph node involvement (P = 0.018), and metastatic disease (P < 0.001) had more likely low hemoglobin concentrations compared with other CMPs. However, serum hemoglobin levels were not significantly associated with age, anatomic localization, and various pathological features including Breslow depth, mitotic rate, and ulceration. We found that hemoglobin levels were significantly associated with outcome; the patients with low hemoglobin concentrations had worse survival than other CMPs (P < 0.001). On multivariate analyses, however, hemoglobin level lost its significance, thus, it was not found independently associated with the outcome. In conclusion, low blood hemoglobin concentration is associated with nodal involvement and metastatic disease. Although anemia in diagnosis was not an independent prognostic factor for survival in CMPs, it was associated with poor prognostic factors. PMID- 29267013 TI - Pearls. PMID- 29267011 TI - Everyone Is a Protagonist: Residue Conformational Preferences in High-Resolution Protein Structures. AB - In many structural bioinformatics problems, there is a broad range of unanswered questions about protein dynamics and amino acid properties. Proteins are not strictly static objects, but rather populate ensembles of conformations. One way to understand these particularities is to analyze the information available in experimental databases. The Ramachandran plot, despite being more than half a century old, remains an utterly useful tool in the study of protein conformation. Based on its assumptions, we inspected a large data set (11,130 protein structures, amounting to 5,255,768 residues) and discriminated the conformational preferences of each residue type regarding their secondary structure participation. These data were studied for phi [Formula: see text], psi [Formula: see text], and side chain chi [Formula: see text] angles, being presented in non Ramachandranian plots. In the largest analysis of protein conformation made so far, we propose an original plot to depict conformational preferences in relation to different secondary structure elements. Despite confirming previous observations, our results strongly support a unique character for each residue type, whereas also reinforcing the observation that side chains have a major contribution to secondary structure and, by consequence, on protein conformation. This information can be further used in the development of more robust methods and computational strategies for structural bioinformatics problems. PMID- 29267014 TI - The Lowdown on Carbo Loading. PMID- 29267015 TI - A (nasal) strip of status. PMID- 29267016 TI - Overuse Injuries of the Elbow. AB - In brief Sports-related overuse injuries brief of the elbow occur most often in people involved in throwing and racket sports. Common injuries include medial and lateral epicondylitis, radial tunnel syndrome, ulnar nerve entrapment, triceps and biceps tendinitis, and conditions related to valgus extension overload: ulnar collateral ligament tears, lateral compartment osteochondral injuries, and posterior olecranon impingement. Accurate diagnosis requires an understanding of elbow anatomy and a careful physical examination. Most of these injuries respond to activity modification, nonsteroidal anti-inflammatory drugs, and a directed rehabilitation program. Surgical intervention, however, is occasionally necessary. PMID- 29267017 TI - Exercise Challenge for Exercise-Induced Bronchospasm. AB - In brief For assessing symptoms of exercise-induced asthma in active young people, the exercise challenge test has advantages over the therapeutic trial: It can be used to specifically confirm the presence of exercise-induced bronchospasm, evaluate pharmacologic control, and help improve compliance. Knowing how to interpret and use the test results helps physicians expedite effective treatment, whether the physician performs the test in the office or refers the patient to a specialty lab. PMID- 29267018 TI - Exercise-Induced Renal and Electrolyte Changes. AB - In brief The metabolic stress of exercise brief can impair the kidneys' ability to maintain volume and electrolyte homeostasis. Minor abnormalities in renal function and plasma electrolyte composition, such as hypovolemia, electrolyte loss, hyperkalemia, and lactic acidosis, may result. In addition, direct and hormonal effects of exercise on the kidneys can lead to proteinuria or hematuria. Rarely, the effects of exercise on the kidneys can be life-threatening, as with heatstroke or rhabdomyolysis. Optimal care not only includes expedient diagnosis and treatment, but also educating the patient about adequate hydration and other preventive measures. PMID- 29267019 TI - Advanced Cardiac Life Support. AB - In brief Changes in the advanced car-brief diac life support guidelines in-elude a new classification system for interventions, training in the use of automated defibrillators, and required early defibrillation for ventricular fibrillation. The algorithms for treating ventricular fibrillation and pulseless ventricular tachycardia, pulseless electrical activity, and asystole are reviewed. Cardiac arrest caused by special circumstances-hypothermia, near drowning, trauma, and electrical injuries-presents additional treatment considerations. PMID- 29267020 TI - Drug Test the High School Band. PMID- 29267021 TI - Foot Pain After a Basketball Rebound. PMID- 29267022 TI - Use Your Head to Choose a Bike Helmet. PMID- 29267023 TI - Forum. PMID- 29267024 TI - CME Self Test. PMID- 29267025 TI - Plasma Fatty Acids as Surrogate for Prostate Levels. AB - Inconsistent results from epidemiologic studies of circulating fatty acids and prostate cancer risk may be partly due to use of blood concentrations as surrogate biomarkers of prostate tissue concentrations. To determine whether blood concentrations reflect prostate tissue fatty acid profiles, we evaluated associations between phospholipid fatty acid (PLFA) profiles measured in plasma and prostate tissue from 20 patients who underwent prostatectomy. For each patient, three prostate tissue specimens varying in size and location were collected. Correlations were calculated between a) tissue specimens by size ( <= 20 mg, > 20 mg); b) individual tissue samples [Intraclass Correlation Coefficient (ICC)]; and c) plasma and mean tissue PLFA concentrations. PLFA concentrations from <= 20 mg and > 20 mg tissues were nearly identical. For most PLFAs, intra individual correlations between tissue specimens were moderate to strong (linoleic acid = 0.66, eicosapentaenoic acid = 0.96), with only one ICC below 0.50 (trans-fatty acid 18:2, ICC = 0.28). Most correlations of mean tissue and plasma concentrations were moderate to strong (alpha-linoleic acid = 0.47, eicosapentaenoic acid = 0.93). PLFA concentrations are largely homogeneous within the prostate and can be reliably measured in small quantities of tissue. The overall strong correlations between plasma and tissue suggest that for most individual PLFAs, plasma concentrations are adequate surrogate markers of prostate tissue concentrations. PMID- 29267026 TI - Reply to "The Meaning of Personal Accomplishment and Burnout in Radiology". PMID- 29267027 TI - Medicolegal-Malpractice and Ethical Issues in RadiologyCan a Radiologist Delegate the Informed Consent Process to a Nonphysician Assistant? PMID- 29267028 TI - Correction. PMID- 29267029 TI - Scientific Integrity: Challenges in the Electronic Era. PMID- 29267030 TI - Reply to "Differential Diagnosis of Pancreatic Calcifications". PMID- 29267031 TI - The Meaning of Personal Accomplishment and Burnout in Radiology. PMID- 29267033 TI - Schooner Cruises: Unpredictable Adventures on the High Seas. AB - Cruises on 19th-century schooners are for those who can do without air conditioning, hot showers, and maids-and don't mind perhaps hauling up an anchor or grabbing a line. PMID- 29267032 TI - Differential Diagnosis of Pancreatic Calcifications. PMID- 29267034 TI - Eye Injuries in Squash and Racquetball Players: An Update. AB - In brief From the summer of 1978 to May 1981 there were 154 eye injuries from squash and 91 from racquetball reported to the eye surgeons of Canada. The ball caused 90% of the most serious racquetball injuries and 67% of those in squash. Fifty-two players reported eye injuries that occurred while wearing open eye guards. Only two injuries occurred involving protectors with plastic in front of the eye. Players who wear prescription lenses are particularly at risk during play, because the glasses cannot withstand balls and rackets traveling at speeds of up to 127 mph. PMID- 29267036 TI - Out of the Mind, Into the Muscles. PMID- 29267035 TI - Performance of Eye Protectors for Squash and Racquetball. AB - In brief Although squash and racquetball eye protectors are available and many people wear them, eye injuries still exist. The authors studied the ability of the 13 eye protectors currently available in Canada to protect the players' eyes. The eye guards were mounted on a headform, and balls were thrown at it at speeds from 50 to 100 mph. This was recorded on high-speed film that was analyzed to determine ball speed, lens or frame deformation, and damage during impact. Eye contact with protectors having lenses was confirmed only once in 54 impacts. All 17 hits to the open eye guards produced ball-eye contact. The authors suggest that standards for eye protectors should be established. PMID- 29267037 TI - Selecting a Running Shoe. PMID- 29267040 TI - Medical Problems in Ballet. AB - In brief Although many problems in young ballet dancers are related to anatomical structure, these panelists point out that good early training is essential. For instance, turning out from the hip instead of the knee would prevent most knee injuries. Ironically, the best training is available to the dancers who need it the least-the professionals. The panelists also discuss back and foot problems, ankle injury, scoliosis, and diet. Dancers often avoid physicians because they ask them to stop dancing. Physicians should adopt the role of educator and develop rapport with dancers. PMID- 29267039 TI - Fat: Understanding the 'Enemy'. PMID- 29267038 TI - Nutritional Intake and Hematological Parameters in Endurance Runners. AB - In brief This study of the nutritional intake and hematological parameters in 52 middle-distance and distance runners at Simon Fraser University showed that the mean energy intake was 3,020 kcal a day for men and 2,026 kcal a day for women. The women's mean iron intake was 12.5 mg a day, which is below the recommended daily intake of 14 mg a day. The men's intake was adequate at 18.5 mg a day. Although mean hemoglobin levels were 14.8 gm/100 ml for men and 13.3 gm/100 ml for women, 29% of the men and 82% of the women had plasma ferritin concentrations at risk for iron deficiency. PMID- 29267041 TI - scanning sports. PMID- 29267042 TI - The Scuba Regulator as a Resuscitator for In-Water Rescue Breathing. AB - In brief Basically, scuba rescue techniques involve bringing the victim to the surface, establishing flotation, initiating ventilation with the mouth-to-mouth or mouth-to-snorkel method, and continuing rescue breathing while towing the victim to safety. This article describes a rescue method using selected scuba regulators for in-water breathing. The authors emphasize that only regulators tested to have appropriate pressure are safe to use. They describe how to test regulators and list rules for safe rescue using the regulator. Students should be exposed to as many rescue methods as possible and select the most appropriate for each situation. PMID- 29267043 TI - Why Burden Exercise With the Natural Label? PMID- 29267044 TI - Exercise for Prevention of Osteoporosis: A Review. AB - In brief This paper reports some of the current research about the effects of physical activity on bone mineral and its implications in preventing osteoporosis. For men, bone mineral loss does not usually present a problem until about the eighth decade, but some women may lose 30% of their bone mineral mass by age 70. Although physical activity is only one of many factors in osteoporosis, it is clear that bone atrophy occurs when activity is lacking and that bone hypertrophy occurs when sufficient physical activity is present. PMID- 29267045 TI - Friction Blisters. AB - In brief Friction blisters are caused by excess frictional trauma to areas of the skin with a thick horny layer and a tight attachment to underlying structures. A moist and/or warm environment promotes blister formation. Blisters are treated by early aspiration of the fluid and by protecting the blister roof. Preventive measures include properly fitting shoes that are broken in slowly, protective padding over potential sites of blister formation, and using drying foot powders and nonslip insoles. Predisposing factors such as certain biomechanical foot defects require correction of the underlying defect and protective padding of blister-prone areas. PMID- 29267046 TI - brief reports. PMID- 29267047 TI - Air Pollution: Adverse Effects on Athletic Performance. AB - Airborne pollutants can have significant objective and subjective effects on athletes and can cause substantial decrements in their performance. PMID- 29267048 TI - letters. PMID- 29267049 TI - Nutritional Concerns For the Dancer. AB - It seems reasonable that dancers would follow a balanced diet to meet the demands of their profession. However, many do not associate energy from food with quality performances. PMID- 29267051 TI - Predicted Impact of the Food and Drug Administration's Menu-Labeling Regulations on Restaurants in 4 New Jersey Cities. AB - OBJECTIVES: To determine the proportion of restaurants that will be required to post calorie information under the Food and Drug Administration's menu-labeling regulations in 4 New Jersey cities. METHODS: We classified geocoded 2014 data on 1753 restaurant outlets in accordance with the Food and Drug Administration's guidelines, which will require restaurants with 20 or more locations nationwide to post calorie information. We used multivariate logistic regression analyses to assess the association between menu-labeling requirements and census tract characteristics. RESULTS: Only 17.6% of restaurants will be affected by menu labeling; restaurants in higher-income tracts have higher odds than do restaurants in lower-income tracts (odds ratio [OR] = 1.55; P = .02). Restaurants in non-Hispanic Black (OR = 1.62; P = .02) and mixed race/ethnicity (OR = 1.44; P = .05) tracts have higher odds than do restaurants in non-Hispanic White tracts of being affected. CONCLUSIONS: Additional strategies are needed to help consumers make healthy choices at restaurants not affected by the menu-labeling law. These findings have implications for designing implementation strategies for the law and for evaluating its impact. PMID- 29267052 TI - Inequality in Utilization of Dental Services: A Systematic Review and Meta analysis. AB - BACKGROUND: Dental diseases are among the most prevalent conditions worldwide, with universal access to dental care being one key to tackling them. Systematic quantification of inequalities in dental service utilization is needed to identify where these are most pronounced, assess factors underlying the inequalities, and evaluate changes in inequalities with time. OBJECTIVES: To evaluate the presence and extent of inequalities in dental services utilization. SEARCH METHODS: We performed a systematic review and meta-analysis by searching 3 electronic databases (MEDLINE, Embase, Cochrane Central Database), covering the period from January 2005 to April 2017. SELECTION CRITERIA: We included observational studies investigating the association between regular dental service utilization and sex, ethnicity, place of living, educational or income or occupational position, or insurance coverage status. Two reviewers undertook independent screening of studies and made decisions by consensus. DATA COLLECTION AND ANALYSIS: Our primary outcome was the presence and extent of inequalities in dental service utilization, measured as relative estimates (usually odds ratios [ORs]) comparing different (high and low utilization) groups. We performed random effects meta-analysis and subgroup analyses by region, and we used meta regression to assess whether and how associations changed with time. MAIN RESULTS: A total of 117 studies met the inclusion criteria. On the basis of 7 830 810 participants, dental services utilization was lower in male than female participants (OR = 0.85; 95% confidence interval [CI] = 0.74, 0.95; P < .001); ethnic minorities or immigrants than ethnic majorities or natives (OR = 0.71; 95% CI = 0.59, 0.82; P < .001); those living in rural than those living in urban places (OR = 0.87; 95% CI = 0.76, 0.97; P = .011); those with lower than higher educational position (OR = 0.61; 95% CI = 0.55, 0.68; P < .001) or income (OR = 0.66; 95% CI = 0.54, 0.79; P < .001); and among those without insurance coverage status than those with such status (OR = 0.58; 95% CI = 0.49, 0.68; P < .001). Occupational status (OR = 0.95; 95% CI = 0.81, 1.09; P = .356) had no significant impact on utilization. The observed inequalities did not significantly change over the assessed 12-year period and were universally present. AUTHORS' CONCLUSIONS: Inequalities in dental service utilization are both considerable and globally consistent. Public Health Implications. The observed inequalities in dental services utilization can be assumed to significantly cause or aggravate existing dental health inequalities. Policymakers should address the physical, socioeconomic, or psychological causes underlying the inequalities in utilization. PMID- 29267053 TI - Elevated Blood Lead Levels by Length of Time From Resettlement to Health Screening in Kentucky Refugee Children. AB - OBJECTIVES: To examine elevated blood lead levels (EBLLs) in refugee children by postrelocation duration with control for several covariates. METHODS: We assessed EBLLs (>= 5ug/dL) between 2012 and 2016 of children younger than 15 years (n = 1950) by the duration of resettlement to health screening by using logistic regression, with control for potential confounders (gender, region of birth, age of housing, and intestinal infestation) in a cross-sectional study. RESULTS: Prevalence of EBLLs was 11.2%. Length of time from resettlement to health screening was inversely associated with EBLLs (tertile 2 unadjusted odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.56, 1.12; tertile 3 OR = 0.62; 95% CI = 0.42, 0.90; tertile 2 adjusted odds ratio [AOR] = 0.62; 95% CI = 0.39, 0.97; tertile 3 AOR = 0.57; 95% CI = 0.34, 0.93). There was a significant interaction between intestinal infestation and age of housing (P < .003), indicating significant risk in the joint exposure of intestinal infestation (a pica proxy) and age of house. CONCLUSIONS: Elevated blood lead levels were reduced with increasing length of time of resettlement in unadjusted and adjusted models. Improved housing, early education, and effective safe-house inspections may be necessary to address EBLLs in refugees. PMID- 29267054 TI - Various Types of Arthritis in the United States: Prevalence and Age-Related Trends From 1999 to 2014. AB - OBJECTIVES: To determine the prevalence trends of osteoarthritis (OA), rheumatoid arthritis (RA), and other types of arthritis in the United States from 1999 to 2014. METHODS: We analyzed data on 43 706 community-dwelling adults aged 20 years and older who participated in the 1999-2014 National Health and Nutrition Examination Surveys. We accounted for survey design and sampling weights so that estimates were nationally representative. We assessed temporal trends in age standardized arthritis prevalence by using joinpoint regression. RESULTS: Age adjusted prevalence of arthritis was 24.7% (OA = 9.7%; RA = 4.2%; other arthritis = 2.8%; "don't know" type = 8.0%). Prevalence of OA increased from 6.6% to 14.3%, whereas RA prevalence decreased from 5.9% to 3.8%. Increase in OA prevalence was significant in both genders; in non-Hispanic Whites, non-Hispanic Blacks, and Hispanics; and in people with high socioeconomic status. Decrease in RA prevalence was more pronounced in men, non-Hispanic Blacks, and participants with low income or obesity. CONCLUSIONS: Between 1999 and 2014, nearly one quarter of American adults reported arthritis. The prevalence of OA has more than doubled over time, whereas RA prevalence has declined. PMID- 29267055 TI - Social Impact Bonds as a Funding Method for Health and Social Programs: Potential Areas of Concern. AB - Social Impact Bonds (SIBs) represent a new way to finance social service and health promotion programs whereby different types of investors provide an upfront investment of capital. If a given program meets predetermined criteria for a successful outcome, the government pays back investors with interest. Introduced in the United Kingdom in 2010, SIBs have since been implemented in the United States and across Europe, with some uptake in other jurisdictions. We identify and explore selected areas of concern related to SIBs, drawing from literature examining market-based reforms to health and social services and the evolution of the SIB funding mechanism. These areas of concern include increased costs to governments, restricted program scope, fragmented policymaking, undermining of public-sector service provision, mischaracterization of the root causes of social problems, and entrenchment of systemically produced vulnerabilities. We argue that it is essential to consider the long-term, aggregate, and contextualized effects of SIBs in order to evaluate their potential to contribute to public health. We conclude that such evaluations must explore the assumptions underlying the "common sense" arguments often used in support of SIBs. PMID- 29267056 TI - Completion of Requirements in Iowa's Medicaid Expansion Premium Disincentive Program, 2014-2015. AB - OBJECTIVES: To evaluate rates of member compliance with Iowa's Medicaid expansion premium disincentive program. METHODS: We used 2014 to 2015 Iowa Medicaid data to construct rolling 12-month cohorts of Wellness Plan and Marketplace Choice members (Iowa's 2 Medicaid expansion waiver programs for individuals <= 100% and 101%-138% of the federal poverty level, respectively), calculated completion rates for required activities (i.e., wellness examinations and health risk assessments), and identified factors associated with program compliance. RESULTS: Overall, 18.5% of Wellness Plan and 12.5% of Marketplace Choice members completed both activities (P < .001). From 2014 to 2015, completion rates for both activities decreased for Wellness Plan members but increased for Marketplace Choice members. Members who were younger, male, or non-White were less likely to complete required activities. CONCLUSIONS: Approximately 81% of Wellness Plan members and 87% of Marketplace Choice members failed to comply with program requirements and should have been subject to paying premiums the following year or face disenrollment. Disparities in completion rates may exacerbate disparities in insurance coverage and health outcomes. Public Health Implications. As states consider establishing Medicaid premium disincentive programs, they should anticipate challenges to successful implementation. PMID- 29267057 TI - Effects of Alcohol Interventions on Other Drug Use in the Cherokee Nation. AB - OBJECTIVES: To evaluate effects of 2 alcohol prevention interventions-Communities Mobilizing for Change on Alcohol (CMCA), a community organizing intervention designed to reduce youth alcohol access, and CONNECT, an individual-level screening and brief intervention approach-on other drug use outcomes. METHODS: We conducted a community intervention trial with quarterly surveys over 3 years (2012-2015) of high school students living within the jurisdictional service area of the Cherokee Nation in Oklahoma. We used generalized estimating equations and linear probability models to examine intervention spillover effects on other drug use. RESULTS: We found significant reductions in drug use other than alcohol attributable to CMCA and CONNECT. CMCA was associated with a 35% reduction in chewing tobacco use, a 39% reduction in marijuana use, and a 48% reduction in prescription drug misuse. CONNECT was associated with a 26% reduction in marijuana use and a 31% reduction in prescription drug misuse. CONCLUSIONS: Nonalcohol drug use was consistently reduced as a result of 2 theoretically and operationally distinct alcohol prevention strategies. Evaluations of alcohol prevention efforts should continue to include other drug use to understand the broader effects of such interventions. PMID- 29267058 TI - Effect of Medicaid Expansions of 2014 on Overall and Early-Stage Cancer Diagnoses. AB - OBJECTIVES: To determine whether the 2014 Medicaid expansions facilitated by the Affordable Care Act affected overall and early-stage cancer diagnosis for nonelderly adults. METHODS: We used Surveillance, Epidemiology, and End Results Cancer Registry data from 2010 through 2014 to estimate a difference-in differences model of cancer diagnosis rates, both overall and by stage, comparing changes in county-level diagnosis rates in US states that expanded Medicaid in 2014 with those that did not expand Medicaid. RESULTS: Among the 611 counties in this study, Medicaid expansion was associated with an increase in overall cancer diagnoses of 13.8 per 100 000 population (95% confidence interval [CI] = 0.7, 26.9), or 3.4%. Medicaid expansion was also associated with an increase in early stage diagnoses of 15.4 per 100 000 population (95% CI = 5.4, 25.3), or 6.4%. There was no detectable impact on late-stage diagnoses. CONCLUSIONS: In their first year, the 2014 Medicaid expansions were associated with an increase in cancer diagnosis, particularly at the early stage, in the working-age population. Public Health Implications. Expanding public health insurance may be an avenue for improving cancer detection, which is associated with improved patient outcomes, including reduced mortality. PMID- 29267059 TI - Hearing Aid Acquisition in Chinese Older Adults With Hearing Loss. AB - OBJECTIVES: To investigate the prevalence and associated factors of hearing aid acquisition in Chinese older adults. METHODS: We obtained data from a population based survey on ear and hearing disorders, which was conducted in 4 provinces of China in 2014 to 2015. Trained examiners conducted pure tone audiometry and audiologists further ascertained for hearing loss. We relied on hearing conditions and audiologists' recommendations to identify 1503 participants who needed to wear hearing aids. RESULTS: Among those 1503 participants, the estimated prevalence of hearing aid acquisition was 6.5% (95% confidence interval = 5.3%, 7.8%). Urban residency, having severe hearing loss, understanding hearing aid function, and receiving a hearing test in the past 12 months were associated with elevated prevalence of hearing aid acquisition. The top-3 reported reasons for not acquiring a hearing aid were not understanding its function (25.4%), not needing it (22.3%), and not being able to afford it (21.3%). CONCLUSIONS: Hearing aid use, as a widespread rehabilitation and treatment of hearing loss, remains a big challenge in China. Apart from providing low-cost hearing aids, more efforts should focus on improving hearing knowledge and disseminating information about hearing aid function among older adults. PMID- 29267060 TI - Opioid Crisis: No Easy Fix to Its Social and Economic Determinants. AB - The accepted wisdom about the US overdose crisis singles out prescribing as the causative vector. Although drug supply is a key factor, we posit that the crisis is fundamentally fueled by economic and social upheaval, its etiology closely linked to the role of opioids as a refuge from physical and psychological trauma, concentrated disadvantage, isolation, and hopelessness. Overreliance on opioid medications is emblematic of a health care system that incentivizes quick, simplistic answers to complex physical and mental health needs. In an analogous way, simplistic measures to cut access to opioids offer illusory solutions to this multidimensional societal challenge. We trace the crisis' trajectory through the intertwined use of opioid analgesics, heroin, and fentanyl analogs, and we urge engaging the structural determinants lens to address this formidable public health emergency. A broad focus on suffering should guide both patient- and community-level interventions. PMID- 29267062 TI - Cost-Related Medication Nonadherence for Older Adults Participating in SNAP, 2013 2015. AB - OBJECTIVES: To estimate the impact of Supplemental Nutrition Assistance Program (SNAP) participation on cost-related medication nonadherence (CRN) for older adults in the United States, with a particular focus on those who are food insecure and those threatened by hunger. METHODS: We used propensity score matching to create matched intervention and comparison groups of SNAP-eligible US adults aged 60 years and older with data from the 2013-2015 National Health Interview Survey. Intervention group participants were identified on the basis of self-reported SNAP participation in the past year. RESULTS: SNAP participants were 4.8 percentage points less likely to engage in CRN than eligible nonparticipants (P < .01). The effect of SNAP is about twice as large for older adults threatened by hunger (9.1 percentage points; P < .01), and considerable even for those who are food insecure (7.4 percentage points; P < .05). CONCLUSIONS: Findings point to a spillover "income effect" as SNAP may help older adults better afford their medications, conceivably by reducing out-of-pocket food expenditures. When prescribing treatment plans, health systems and payers have a vested interest in connecting older patients to SNAP and other resources that may help address barriers to care. PMID- 29267061 TI - Increases in Acute Hepatitis C Virus Infection Related to a Growing Opioid Epidemic and Associated Injection Drug Use, United States, 2004 to 2014. AB - OBJECTIVES: To compare US trends in rates of injection drug use (IDU), specifically opioid injection, with national trends in the incidence of acute HCV infection to assess whether these events correlated over time. METHODS: We calculated the annual incidence rate and demographic and risk characteristics of reported cases of acute HCV infection using surveillance data from 2004 to 2014 and the annual percentage of admissions to substance use disorder treatment facilities reporting IDU for the same time period by type of drug injected and demographic characteristics. We then tested for trends. RESULTS: The annual incidence rate of acute HCV infection increased more than 2-fold (from 0.3 to 0.7 cases/100 000) from 2004 to 2014, with significant increases among select demographic subgroups. Admissions for substance use disorder attributed to injection of heroin and prescription opioid analgesics increased significantly, with an almost 4-fold increase in prescription opioid analgesic injection. Significant increases in opioid injection mirrored those for reported cases of acute HCV infection among demographic subgroups. CONCLUSIONS: These findings strongly suggest that the national increase in acute HCV infection is related to the country's opioid epidemic and associated increases in IDU. PMID- 29267063 TI - Mortality Among Confirmed Lassa Fever Cases During the 2015-2016 Outbreak in Nigeria. AB - OBJECTIVES: To determine factors associated with mortality among confirmed Lassa fever cases. METHODS: We reviewed line lists and clinical records of laboratory confirmed cases of Lassa fever during the 2016 outbreak in Nigeria to determine factors associated with mortality. We activated an incident command system to coordinate response. RESULTS: We documented 47 cases, 28 of whom died (case fatality rate [CFR] = 59.6%; mean age 31.4 years; SD = +/-18.4 years). The youngest and the oldest were the most likely to die, with 100% mortality in those aged 5 years or younger and those aged 55 years or older. Patients who commenced ribavirin were more likely to survive (odds ratio [OR] = 0.1; 95% confidence interval [CI] = 0.03, 0.50). Fatality rates went from 100% (wave 1) through 69% (wave 2) to 31% (wave 3; chi2 for linear trend: P < .01). Patients admitted to a health care center before incident command system activation were more likely to die (OR = 4.4; 95% CI = 1.1, 17.6). The only pregnant patient in the study died postpartum. CONCLUSIONS: Effective, coordinated response reduces mortality from public health events. Attention to vulnerable groups during disasters is essential. Public Health Implications. Activating an incident command system improves the outcome of disasters in resource-constrained settings. PMID- 29267064 TI - Sustained Reduction in Chlamydia Infections Following a School-Based Screening: Detroit, 2010-2015. AB - We describe school-based screening events in four Detroit, Michigan public high schools. To examine trends, we analyzed Chlamydia trachomatis data from 2010 to 2015. Prevalence of C. trachomatis decreased significantly (P < .01): from 10.24% to 6.27%. Future school-based screening events may bring about similar results if the program is instituted in a high-prevalence area and can achieve high student participation. PMID- 29267066 TI - Effect of the Affordable Care Act on Breastfeeding Outcomes. AB - OBJECTIVES: To assess how the 2012 Affordable Care Act (ACA) policy change, which required most private health insurance plans to cover lactation-support services and breastfeeding equipment (without cost-sharing), affected breastfeeding outcomes. METHODS: We used a regression-adjusted difference-in-differences approach with cross-sectional observational data from the US National Immunization Survey from 2008 to 2014 to estimate the effect of the ACA policy change on breastfeeding outcomes, including initiation, duration, and age at first formula feeding. The sample included children aged 19 to 23 months covered by private health insurance or Medicaid. RESULTS: The ACA policy change was associated with an increase in breastfeeding duration by 10% (0.57 months; P = .007) and duration of exclusive breastfeeding by 21% (0.74 months; P = .001) among the eligible population. Results indicate no significant effects on breastfeeding initiation and age at first formula feeding. CONCLUSIONS: Reducing barriers to receiving support services and breastfeeding equipment shows promise as part of a broader effort to encourage breastfeeding, particularly the duration of breastfeeding and the amount of time before formula supplementation. PMID- 29267065 TI - Impact of Dual Use of Department of Veterans Affairs and Medicare Part D Drug Benefits on Potentially Unsafe Opioid Use. AB - OBJECTIVES: To estimate the prevalence and consequences of receiving prescription opioids from both the Department of Veterans Affairs (VA) and Medicare Part D. METHODS: Among US veterans enrolled in both VA and Part D filling 1 or more opioid prescriptions in 2012 (n = 539 473), we calculated 3 opioid safety measures using morphine milligram equivalents (MME): (1) proportion receiving greater than 100 MME for 1 or more days, (2) mean days receiving greater than 100 MME, and (3) proportion receiving greater than 120 MME for 90 consecutive days. We compared these measures by opioid source. RESULTS: Overall, 135 643 (25.1%) veterans received opioids from VA only, 332 630 (61.7%) from Part D only, and 71 200 (13.2%) from both. The dual-use group was more likely than the VA-only group to receive greater than 100 MME for 1 or more days (34.3% vs 10.9%; adjusted risk ratio [ARR] = 3.0; 95% confidence interval [CI] = 2.9, 3.1), have more days with greater than 100 MME (42.5 vs 16.9 days; adjusted difference = 16.4 days; 95% CI = 15.7, 17.2), and to receive greater than 120 MME for 90 consecutive days (7.8% vs 3.1%; ARR = 2.2; 95% CI = 2.1, 2.3). CONCLUSIONS: Among veterans dually enrolled in VA and Medicare Part D, dual use of opioids was associated with more than 2 to 3 times the risk of high-dose opioid exposure. PMID- 29267068 TI - Rainbow: Cleveland's Teaching Clinic. AB - Education and prevention across the whole spectrum of sportsmedicine are the goals of Cleveland's nine-year-old Rainbow Sports Medicine Center. PMID- 29267067 TI - Trends in Illicit Cigarette Use in Brazil Estimated From Legal Sales, 2012-2016. AB - OBJECTIVES: To estimate the proportions of illicit cigarette consumption in Brazil from 2012 to 2016, a period of sharp increases in cigarette taxes. METHODS: We used an approach based on legal sales provided by the Secretariat of Federal Revenues and self-reported consumption data from an annually conducted telephone survey (VIGITEL) to estimate the changes over time in illegal cigarette use in Brazil. For that purpose, we also used available information on the proportion of illegal cigarette consumption from a nationwide household survey conducted in 2013 to calculate a constant proportion of underreporting from VIGITEL in relation to total consumption and sales in Brazil. RESULTS: There was an increase in the estimated proportion of illicit cigarette use from 2012 to 2013 (from 28.6% to 32.3%), then a decrease from 2013 to 2014 (32.3% to 28.8%), and then a sustained trend of increase from 2014 to 2016 (28.8% to 42.8%). CONCLUSIONS: Novel and feasible approaches to estimate changes over time in the illegal market are important for helping the effective implementation of tobacco excise tax policy. PMID- 29267069 TI - letters. PMID- 29267070 TI - brief reports. PMID- 29267071 TI - a need to know. PMID- 29267076 TI - Equipment Update: Penn State's Foldable Rigid Stretcher. AB - Because moving a player improperly can compound a head or neck injury, the authors designed and built a foldable rigid stretcher with an adjustable traction bar. PMID- 29267074 TI - Take a Week Off. PMID- 29267075 TI - Databank Sweepstakes. PMID- 29267077 TI - The Shoe Rating Game. AB - Manufacturers, retailers, researchers, and publishers reacted strongly to this year's shoe ratings. Amid charges and credibility gaps, one thing is clear: there is no such thing as the perfect shoe. PMID- 29267079 TI - Rehabilitating Chondromalacia Patellae. PMID- 29267078 TI - Misuse of Strength Development Programs in Athletic Training. AB - Athletes often overemphasize strength and ignore speed, timing, balance, and other skills that would improve performance. The author recommends specificity of training and activities that build rotational strength. PMID- 29267080 TI - Exercise-Induced Muscle Soreness. AB - The cause of acute exercise-induced muscle soreness-ischemia-has been clearly defined, but the cause of delayed muscle soreness is more elusive. The author believes irritated connective tissue is the villain. PMID- 29267081 TI - scanning sports. PMID- 29267082 TI - Catastrophic Head and Neck Injuries. AB - Improved conditioning, a helmet standard, and rules forbidding butt blocking and face tackling account for the lowest incidence of football head and neck injuries in 18 years. PMID- 29267083 TI - Heart Rate Response of High School Basketball Officials. AB - The men who officiate high school basketball games are true weekend athletes. They work at sedentary jobs during the week and get their exercise Friday and Saturday on the court. PMID- 29267084 TI - The Racquetball Pro: A Physiological Profile. AB - Racquetball will soon overtake tennis as the nation's No. 1 participation sport. This study suggests that it is an effective way to achieve fitness. PMID- 29267085 TI - Diet, Fitness, and Athletic Performance. AB - The coaches and trainers surveyed had up-to-date information about water replacement, but they were woefully uninformed about quick energy drinks and the role of protein. PMID- 29267086 TI - Case Report: Ruptured Spleen in a College Football Player. AB - This athlete had a subcapsular splenic tear even though laboratory blood studies showed little change. The physician's high index of suspicion led to diagnosis with computerized tomography. PMID- 29267087 TI - Preadolescent Training-How Young Is Too Young? AB - Youngsters are undertaking rigorous training programs at earlier and earlier ages, and not everyone is happy about it. PMID- 29267088 TI - Case Report: 40 Years of Fitness. AB - Few autopsy studies have been done to verify the relationship between coronary heart disease and exercise. George Life's medical history seems to support the theory that there is an inverse relationship between the two. PMID- 29267089 TI - a need to know. PMID- 29267090 TI - Sports Medicine in Australia: A Tale of Two Clinics. AB - Australian sports medicine is characterized by a modern national institute to train and test athletes and a private clinic where the emphasis is on aggressive injury rehabilitation. PMID- 29267091 TI - Is There Safety in Numbers? PMID- 29267092 TI - Exotic Fishing Grounds: A Lure Even for Nonanglers. AB - From Scotland to the northern lands of the midnight sun, these idyllic salmon and trout spots are a midsummer-night's dream. PMID- 29267093 TI - The Mitral Valve Prolapse Syndrome in Athletes. AB - In brief The mitral valve prolapse syndrome is prevalent in apparently normal people, including athletes. Symptoms, when present, range from chest pain and palpitations to anxiety neurosis. The typical finding on auscultation of the heart is a midsystolic click and/or a mid-to-late systolic high-frequency murmur. Cardiac arrhythmias are common and often do not require therapy. The exercise ECG shows ST segment depression in up to one fourth of patients. When drug therapy is necessary, beta blockers are usually selected. The overall prognosis is excellent. Sudden death, infectious endocarditis, and cerebral thromboembolic events are relatively rare. PMID- 29267094 TI - NFL Players vs Owners: A Medical Care Tug-of-War. AB - A fight for control over NFL medical care looms when the players' union and management negotiate a new contract. PMID- 29267095 TI - letters. PMID- 29267096 TI - Flexibility as a Predictor of Knee Injuries in College Football Players. AB - In brief The ligamentous laxity testing scores and knee injuries of football players from three colleges were compared and statistically analyzed. Since no correlation was found between laxity test scores and knee injuries, the tests have no apparent predictive value. PMID- 29267097 TI - brief reports. PMID- 29267098 TI - Ballet Injuries. AB - In brief Only in the last five years has medical care for ballet injuries received more than perfunctory professional interest, although ballet companies in other countries have long had regular medical attention. Most ballet injuries are to the foot, ankle, knee, thigh, hip, spine, and related muscles. Dance masters emphasize that injuries occur because of faulty technique and that any cure is only temporary unless the fault is corrected. Injured dancers are impatient to return to classes or performance because of intense competition and a short career span. Permitting the dancer to do as many of the ballet exercises as possible without further injury will alleviate anxiety and promote cooperation from the dancer. PMID- 29267099 TI - Extremity Elevation Unit. PMID- 29267100 TI - Professional Golfers and the Price They Pay. AB - In brief Professional golfers' injuries are usually related to their swings. A wide variety of acute and chronic injuries have been reported, including carpal fractures, ulnar and median nerve neuropathies, tendinitis, skin rashes, and eye injuries. There have been two deaths. In this study questionnaires were mailed to 500 professional golfers, and 226 were returned. During their careers 103 men and 87 women were injured, an average of two injuries per player. The left wrist, lower back, and left hand were most commonly injured. Repetitive practice swings caused the most injuries in both men and women. PMID- 29267101 TI - Designing a Safe, Sound Exercise Program. PMID- 29267103 TI - Peaking for Life. PMID- 29267104 TI - Olympic Sports Medicine: New Foundation for the Future? AB - Critics have said the US Olympic sports medicine program has no focus and few practical contributions. New ideas and new staff may get the program off and running. PMID- 29267102 TI - Thought Processes and Emotions in Sport. AB - In brief The mental approach to sport is much more important than most athletes realize. Mental processes must be trained just as sports skills, and they take time to develop. Various methods for dealing with psychological problems that appear before, during, and after competitive events include relaxation techniques, mental preparation, and positive self-evaluation. Sport psychologists can help athletes improve the psychological processes associated with successful athletic performance, but few are available in the United States at this time because the field is new. However, physicians and trainers have contact with many athletes and can listen to and help them with these problems. PMID- 29267105 TI - scanning sports. PMID- 29267106 TI - Christine Wells: Asking the Right Questions. AB - Arizona exercise physiologist Chris Wells is highly regarded by her students and her peers for her research on homeostasis, adaptation to heat stress, and the effect of gender on athletic performance. PMID- 29267109 TI - names and faces. PMID- 29267110 TI - Does Lifting Weights Harm a Prepubescent Athlete? AB - It may be tempting for prepubescent athletes to imitate their elders who lift weights for strength and to improve performance. Physicians and coaches disagree on the long-term effects. PMID- 29267108 TI - Effect of a Supplement on Dietary Intakes of Female Collegiate Swimmers. AB - In brief This study describes the diets of female swimmers and assesses the effects of a liquid supplement. The self-selected diets provided more than the recommended dietary allowances (RDA) of food energy and six nutrients and less than the RDAs of vitamin D and iron. Consumption of the liquid dietary supplement increased the intake of all nutrients except cholesterol and increased the frequency of food intake. More frequent food consumption may improve performance by increasing alertness, avoiding hunger discomfort, and decreasing the rate of lipogenesis. A liquid dietary supplement is one way to improve the nutritional quality of athletes' diets and increase the frequency of food consumption. PMID- 29267111 TI - Something New for '82. PMID- 29267112 TI - Volar Plate Injuries. AB - In brief The common "jammed finger" occurs at the proximal interphalangeal (PIP) joint and is too often minimized by the coach and player and inadequately treated by the physician. Unless appropriately diagnosed and treated, volar plate injuries at that joint may result in permanent limitation of motion. The volar plate can be injured when the athlete misses a Frisbee throw or a basketball pass, because these activities force hyperextension of the PIP joint and tear the volar plate away from its insertion. The authors discuss the functional anatomy of the PIP joint, the mechanism of injury, treatment, possible complications, and rehabilitation. PMID- 29267113 TI - Effects of a YMCA Starter Fitness Program. AB - In brief This paper reports the findings of the effect of an eight-week starter fitness program on the first 1,362 people enrolled in it. The subjects were tested for cardiorespiratory fitness, body fat and weight, [Formula: see text]O2 max, muscular strength and endurance, and flexibility, using the YMCA physical fitness test battery before the program started and after eight weeks of training. The classes met for one hour, three times a week. Both men and women reduced body weight, body fat, and resting heart rate, and increased [Formula: see text]O2 max, flexibility, and muscular strength and endurance. Improved fitness was related to compliance and whether the subject or his company paid for the program. PMID- 29267114 TI - B15: Myth or Miracle? AB - In brief B15, a mixture of calcium gluconate and N, N-Dimethylglycine (DMG), is widely used by amateur and professional athletes because they believe it lowers blood lactic acid, stabilizes blood sugar during exercise, and reduces the effects of fatigue. In general, Russian studies report increased oxygen efficiency, but they are not properly controlled. Some American studies support the claims of reduced lactic acid and increased performance, but others show no measurable effects. The authors say further studies are needed, but it is illegal to sell B15 as a dietary supplement or a drug. PMID- 29267115 TI - brief reports. PMID- 29267117 TI - Screening for Mitral Valve Prolapse. PMID- 29267118 TI - American Academy of Pediatrics. PMID- 29267120 TI - Hotel Exercise Facilities Help Travelers Stay Fit. AB - Hotel managers are discovering that exercises facilities-from complete health clubs to jogging trails-will attract business and pleasure travelers. PMID- 29267119 TI - letters. PMID- 29267121 TI - scanning sports. PMID- 29267122 TI - Skiing in Colorado: Changes in the Status Snow. AB - Nature changed the snow conditions and aged the ski population in Colorado, so resort owners retaliated with snow-making machines and more intermediate trails. PMID- 29267123 TI - Figure Skating: What Do We Know About It? AB - In brief: Despite its long history, there has been very little systematic study of figure skating. Successful skaters and coaches have passed on ideas, traditions, and opinions to their followers with the idea that what once produced good results must be the correct approach. Skaters are significantly shorter, lighter, and leaner than their sedentary counterparts and have a rather low percent body fat. Their cardiovascular fitness levels are 50% to 60% higher than those of sedentary people of the same age, but far less than those of endurance athletes. PMID- 29267124 TI - Foot Orthoses in Ski Boots. AB - In brief: Orthoses can be used inside downhill ski boots to aid in parallel skiing. Small degrees of imbalance become significant when they affect the skier's posture and ability to turn. The author explains how orthoses, cants between the boot and the ski, and posts correct biomechanical deformities including tibial varus and valgus, subtalar varus, forefoot varus and valgus, and leg-length discrepancies. He advises skiers whose feet hurt to find a good podiatrist and a reliable ski boot fitter. PMID- 29267125 TI - Exercise Sport Playfully. PMID- 29267126 TI - Exercising Safely in Winter. PMID- 29267127 TI - Injuries in Competitive Figure Skaters. AB - In brief This study determined the nature and incidence of skating injuries in 19 high-level competitors ranging from 11 to 19 years old. The subjects completed a one-page questionnaire on their skating history, warm-up routine, medical problems, and skating injuries, and they were examined for anatomical malalignment, strength, flexibility, and evidence of injury. Most injuries were from overuse, but there were few serious injuries for the large number of hours they spent training, and the incidence of injury compares favorably with other sports. The authors say the low incidence may be related to the stretching exercises that the skaters performed. PMID- 29267128 TI - Correction to: Rosano et al., Cardiovascular disease in women, is it different to men? The role of sex hormones. PMID- 29267129 TI - Vaccine Hesitancy and Online Information: The Influence of Digital Networks. AB - AIMS: This article analyzes the digital childhood vaccination information network for vaccine-hesitant parents. The goal of this study was to explore the structure and influence of vaccine-hesitant content online by generating a database and network analysis of vaccine-relevant content. METHOD: We used Media Cloud, a searchable big-data platform of over 550 million stories from 50,000 media sources, for quantitative and qualitative study of an online media sample based on keyword selection. We generated a hyperlink network map and measured indegree centrality of the sources and vaccine sentiment for a random sample of 450 stories. RESULTS: 28,122 publications from 4,817 sources met inclusion criteria. Clustered communities formed based on shared hyperlinks; communities tended to link within, not among, each other. The plurality of information was provaccine (46.44%, 95% confidence interval [39.86%, 53.20%]). The most influential sources were in the health community (National Institutes of Health, Centers for Disease Control and Prevention) or mainstream media ( New York Times); some user generated sources also had strong influence and were provaccine (Wikipedia). The vaccine-hesitant community rarely interacted with provaccine content and simultaneously used primary provaccine content within vaccine-hesitant narratives. CONCLUSION: The sentiment of the overall conversation was consistent with scientific evidence. These findings demonstrate an online environment where scientific evidence online drives vaccine information outside of the vaccine hesitant community but is also prominently used and misused within the robust vaccine-hesitant community. Future communication efforts should take current context into account; more information may not prevent vaccine hesitancy. PMID- 29267130 TI - Measurement of Metastasis in the Follow-Up of Localized Prostate Cancer. PMID- 29267131 TI - Reply to Y. Zhu et al. PMID- 29267132 TI - Regulation of Excitatory Amino Acid Transmission in the Retina: Studies on Neuroprotection. AB - Excitotoxicity occurs in neurons due to the accumulation of excitatory amino acids such as glutamate in the synaptic and extrasynaptic locations. In the retina, excessive glutamate concentrations trigger a neurotoxic cascade involving several mechanisms, including the elevation of intracellular calcium (Ca2+) and the activation of alpha-amino-3-hydroxy 5-methyl-4-iso-xazole-propionic acid/kainate (AMPA/KA) and N-methyl-d-aspartate (NMDA) receptors leading to retinal degeneration. Both ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) are present in the mammalian retina. Indeed, due to the abundant expression of GluRs, the mammalian retina is highly susceptible to excitotoxic neurodegeneration. Excitotoxicity has been postulated to present a common downstream mechanism for several stimuli, including hypoglycemia, hypoxia, ischemia, and chronic neurodegenerative diseases. Experimental approaches to the study of neuroprotection in the retina have utilized insults that trigger hypoxia, hypoglycemia, or excitotoxicity. Using these experimental approaches, the neuroprotective potential of GluR agents, including the NMDA receptor modulators (MK801, ifenprodil, memantine); AMPA/KA receptor antagonist (CNQX); Group II and III mGluR agonists (LY354740, quisqualate); and Ca2+-channel blockers (diltiazem, lomerizine, verapamil, omega conotoxin), and others (pituitary adenylate cyclase activating polypeptide, neuropeptide Y, acetylcholine receptor agonists) have been elucidated. In addition to corroborating the exocytotic role of excitatory amino acids in retinal degeneration, these studies affirm that multiple mechanism/s contribute to the prevention of damage caused by excitotoxicity in the retina. Therefore, it is feasible that several pathways are involved in protecting the retina from toxic insults in ocular neurodegenerative conditions such as glaucoma and retinal ischemia. Furthermore, these experimental models are viable tools for evaluating therapeutic candidates in ocular neuropathies. PMID- 29267133 TI - Enhanced biogas production from anaerobic co-digestion of pig slurry and horse manure with mechanical pre-treatment. AB - Enhanced biogas production from anaerobic co-digestion of pig slurry and horse manure with mechanical pre-treatment. In this study, co-digestion of horse manure and pig slurry was investigated in a continuously stirred tank reactor, with a mechanical pre-treatment. Experiments were conducted at 37 degrees C, with hydraulic retention times of 23 days and increasing shares of horse manure, corresponding to different horse manure to pig slurry ratios (HM:PS) equal to 0:100, 10:90, 13:87 and 20:80, in terms of percentage of inlet volatile solids (%VS inlet). The results show that the best synergetic effect between the microbial consortia of pig slurry and the high Carbon to Nitrogen ratio (C/N) of horse manure is obtained for the mixture of 20:80%VS inlet, yielding the highest specific methane production (SMP = 142.6 L kgTCOD-1) and the highest soluble chemical oxygen demand (SCOD) reduction (68.5%), due to the high volatile dissolved solids content and soluble chemical oxygen demand to total chemical oxygen demand ratio (SCOD/TCOD). Thus, co-digestion of horse manure and pig slurry is shown to be a promising approach for biogas production and as a waste treatment solution. Furthermore, the analysis provides a methodology for the pre treatment of these substrates and to investigate into the best combination for improved biogas production. PMID- 29267134 TI - Candida tropicalis Isolates from Mexican Republic Exhibit High Susceptibility to Bleomycin and Variable Susceptibility to Hydrogen Peroxide. AB - Candida sp. are found as part of the commensal flora in humans but can cause invasive candidiasis in patients with severe underlying disease, especially cancer patients. These patients are frequently subjected to nonsurgical anticancer treatments such as ionizing radiation and anticancer drugs, which kill proliferating human cells by damaging DNA but also affect the microbiota of the patient. C. tropicalis, an emerging fungal pathogen, is associated with high mortality rates of cancer patients especially in tropical regions. In this study, we have investigated the in vitro susceptibility of 38 C. tropicalis clinical isolates from several Mexican hospitals to chronic treatments with several DNA damaging agents, including oxidizing compounds and anticancer drugs. C. tropicalis isolates displayed a high variability in their susceptibility to hydrogen peroxide (H2O2) while showing a high susceptibility to bleomycin (BLM), an anticancer drug that causes double-strand breaks in DNA. This contrasted with the moderate-to-high resistance exhibited by several C. albicans laboratory strains. At least for the C. tropicalis reference strain MYA3404, this susceptibility was hardly modified by the presence of serum. Our results open the possibility of using susceptibility to BLM to differentiate between C. tropicalis and C. albicans; however, analysis of a larger number of isolates is required. The use of BLM for prevention of C. tropicalis infections in neutropenic patients with cancer should be also evaluated. Finally, the variable susceptibility to H2O2 might be due to allelic variation of the histone acetyl-transferase complex which modulates the induction kinetics of H2O2-induced genes in C. tropicalis. PMID- 29267135 TI - Enhanced ozonation degradation of petroleum refinery wastewater in the presence of oxide nanocatalysts. AB - The catalytic activity of Mn2O3, FeOOH and CeO2 nanoparticles was evaluated in the treatment of a synthetic petroleum refinery wastewater (SPRW) using O3 in a discontinuous reactor at 25 degrees C and pH 5.5. The mineralization and partial chemical oxidation rates of SPRW using these metal oxides are in the same order of magnitude, and the catalytic activity in the mineralization of SPRW decreased in the order Mn2O3 > CeO2 > FeOOH. The mineralized fraction progressively increased with time in the catalytic process while in the non-catalytic process it remained constant. The effect of the operational conditions on the mineralization and partial chemical oxidation rates using Mn2O3 was investigated in detail. The mineralization rate was found to be lower than the partial oxidation rate due to the formation of partially oxidized by-products, and this is dependent on the solids dosage and pH. An investigation of the mechanism demonstrated that the enhancement effect could be attributed to the introduction of the manganese oxide nanoparticles, which could promote the utilization of O3 and/or enhance the formation of free radicals (*OH, *O2H and *O2-) on the solid surface and further accelerate the degradation of the organic compounds present in the wastewater. PMID- 29267136 TI - Occurrence of glyphosate and AMPA residues in soy-based infant formula sold in Brazil. AB - Glyphosate is an herbicide widely used in the world, being applied in several crops, among them soybeans. Recently, glyphosate and its metabolite aminomethylphosphonic acid (AMPA) have been identified as possible contributors to the emergence of various diseases such as autism, Parkinson's and Alzheimer's diseases, as well as cancer. The child population-consuming cereal-based foods is the most exposed to the effects of pesticides because of their developmental phase and they have a higher food intake per kilogram of body weight than adults. The presence of glyphosate and AMPA residues in soy-based infant formulas was evaluated during the years 2012-2017, totalising 105 analyses carried out on 10 commercial brands from different batches. Glyphosate and AMPA were determined by liquid chromatography with fluorescence detection after derivatisation reaction. The method was validated and showed accuracy and precision with a limit of quantification (LOQ) of 0.02 mg kg-1. Among those samples that contained levels above the LOQ, the variation of glyphosate residues was from 0.03 mg kg-1 to 1.08 mg kg-1 and for AMPA residues was from 0.02 mg kg-1 to 0.17 mg kg-1. This is the first scientific communication about glyphosate and AMPA contamination in soy based infant formula in Brazil, The study was conducted under good laboratory practice (GLP) and supported by good scientific practice. PMID- 29267137 TI - Characterization of Isolates Associated with Emergence of OXA-48-Producing Klebsiella pneumoniae in Croatia. AB - Here, we report a retrospective study conducted to elucidate emergence, epidemiology, and molecular mechanisms of resistance underlying the early spread of OXA-48 carbapenemase-producing Enterobacteriaceae in Croatia. Retrospective screening for OXA-48 producers was performed on a collection of 296 nonrepetitive, carbapenem-nonsusceptible enterobacterial isolates collected from January 2011 to December 2012 from 40 participating centers in Croatia. Antimicrobial susceptibility profiles and production of carbapenemases were assessed phenotypically. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing were used for epidemiological analysis. Resistance genes were characterized by polymerase chain reaction (PCR) and sequencing. Plasmid localization of blaOXA-48 in isolates and transconjugants was investigated by S1 PFGE and Southern hybridization. PCR mapping was used for identification of genetic platform surrounding blaOXA-48. Out of 296 carbapenem-nonsusceptible isolates, blaOXA-48 gene was detected in 12 Klebsiella pneumoniae isolates. All OXA-48-producing isolates showed varying resistance to carbapenems and 11 were multidrug resistant. All coproduced additional beta-lactamases, including CTX-M 15, which was detected in eight isolates. Isolates were delineated in five clonal types by PFGE corresponding to five sequence types (STs) assigned ST15, ST16, ST37, ST528, and ST1418. All OXA-48 isolates conjugated successfully and other resistance determinants were not cotransferred. blaOXA-48 was carried on a ~60 kb IncL/M plasmid and was detected within Tn1999.2 composite transposon. OXA-48, a class D carbapenemase, is emerging as a potentially significant contributor among carbapenem-resistant Enterobacteriaceae in Croatia, alongside class A and B carbapenemases. Polyclonal genetic background of K. pneumoniae isolates carrying ~60 kb incL/M plasmid indicates that dissemination of the blaOXA48 gene is not driven exclusively by the spread of a single clone. PMID- 29267139 TI - Robust new NIRS coupled with multivariate methods for the detection and quantification of tallow adulteration in clarified butter samples. AB - Cows' butterfat may be adulterated with animal fat materials like tallow which causes increased serum cholesterol and triglycerides levels upon consumption. There is no reliable technique to detect and quantify tallow adulteration in butter samples in a feasible way. In this study a highly sensitive near-infrared (NIR) spectroscopy combined with chemometric methods was developed to detect as well as quantify the level of tallow adulterant in clarified butter samples. For this investigation the pure clarified butter samples were intentionally adulterated with tallow at the following percentage levels: 1%, 3%, 5%, 7%, 9%, 11%, 13%, 15%, 17% and 20% (wt/wt). Altogether 99 clarified butter samples were used including nine pure samples (un-adulterated clarified butter) and 90 clarified butter samples adulterated with tallow. Each sample was analysed by using NIR spectroscopy in the reflection mode in the range 10,000-4000 cm-1, at 2 cm-1 resolution and using the transflectance sample accessory which provided a total path length of 0.5 mm. Chemometric models including principal components analysis (PCA), partial least-squares discriminant analysis (PLSDA), and partial least-squares regressions (PLSR) were applied for statistical treatment of the obtained NIR spectral data. The PLSDA model was employed to differentiate pure butter samples from those adulterated with tallow. The employed model was then externally cross-validated by using a test set which included 30% of the total butter samples. The excellent performance of the model was proved by the low RMSEP value of 1.537% and the high correlation factor of 0.95. This newly developed method is robust, non-destructive, highly sensitive, and economical with very minor sample preparation and good ability to quantify less than 1.5% of tallow adulteration in clarified butter samples. PMID- 29267138 TI - Ocular Distribution and Pharmacokinetics of Lifitegrast in Pigmented Rabbits and Mass Balance in Beagle Dogs. AB - PURPOSE: Lifitegrast is approved in the United States for the treatment of dry eye disease (DED). We assessed lifitegrast's ocular distribution/pharmacokinetic profile in rabbits, and 14C-lifitegrast mass balance/excretion in dogs. METHODS: Female pigmented rabbits received a single topical ocular dose of lifitegrast (Formulation No. 1, n = 25; No. 2, n = 25) per eye twice daily (target, 1.75 mg/eye/dose). Blood/ocular tissues were collected on day 5. Beagle dogs received single intravenous (n = 10; target, 3 mg, 262 MUCi/animal) and ocular (n = 8, target, 3 mg, 30 MUCi/eye) doses of 14C-lifitegrast (~8 weeks between doses). Blood, excreta, and cage rinse/wipes were collected. Concentrations were measured by mass spectrometry/liquid scintillation counting. Pharmacokinetic analyses (noncompartmental) included maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 8 h (AUC0-8). RESULTS: In rabbits, lifitegrast Cmax and AUC0-8 were similar between formulations. Cmax was highest in ocular anterior segment tissues: 5,190-14,200 ng/g [conjunctiva (palpebral/bulbar), cornea, anterior sclera]. Posterior segment tissues had lower concentrations (0-826 ng/g). AUC0-8 followed a similar trend. Plasma concentrations were low (Cmax <18 ng/mL). Tissue/plasma tmax was ~0.25-1 h. In dogs, after intravenous/ocular doses, 14C-lifitegrast was eliminated primarily through feces. Excreted radioactivity was mainly unchanged lifitegrast. CONCLUSIONS: High exposure of lifitegrast in rabbit ocular anterior segment tissues and low exposure in posterior segment tissues/plasma suggests that lifitegrast reaches target tissues for DED treatment, with low potential for off target systemic/ocular effects. Excretion of unchanged 14C-lifitegrast suggests minimal drug metabolism in vivo. This is consistent with lifitegrast clinical trial efficacy/safety data. PMID- 29267140 TI - Human Wharton's Jelly-Derived Stem Cells Display a Distinct Immunomodulatory and Proregenerative Transcriptional Signature Compared to Bone Marrow-Derived Stem Cells. AB - Mesenchymal stromal cells (MSCs) are multipotent stem cells with immunosuppressive and trophic support functions. While MSCs from different sources frequently display a similar appearance in culture, they often show differences in their surface marker and gene expression profiles. Although bone marrow is considered the "gold standard" tissue to isolate classical MSCs (BM MSC), MSC-like cells are currently also derived from more easily accessible extra embryonic tissues such as the umbilical cord. In this study, we defined the best way to isolate MSCs from the Wharton's jelly of the human umbilical cord (WJ-MSC) and assessed the mesenchymal and immunological phenotype of BM-MSC and WJ-MSC. Moreover, the gene expression profile of established WJ-MSC cultures was compared to two different bone marrow-derived stem cell populations (BM-MSC and multipotent adult progenitor cells or MAPC(r)). We observed that explant culturing of Wharton's jelly matrix is superior to collagenase tissue digestion for obtaining mesenchymal-like cells, with explant isolated cells displaying increased expansion potential. While being phenotypically similar to adult MSCs, WJ-MSC show a different gene expression profile. Gene ontology analysis revealed that genes associated with cell adhesion, proliferation, and immune system functioning are enriched in WJ-MSC. In vivo transplantation confirms their immune modulatory effect on T cells, similar to BM-MSC and MAPC. Furthermore, WJ-MSC intrinsically overexpress genes involved in neurotrophic support and their secretome induces neuronal maturation of SH-SY5Y neuroblastoma cells to a greater extent than BM-MSC. This signature makes WJ-MSC an attractive candidate for cell based therapy in neurodegenerative and immune-mediated central nervous system disorders such as multiple sclerosis, Parkinson's disease, or amyotrophic lateral sclerosis. PMID- 29267141 TI - "God is the giver and taker of life": Muslim beliefs and attitudes regarding assisted suicide and euthanasia. AB - In the context of the Belgian debates on end-of-life care, the views of Muslims remain understudied. The aim of this article is twofold. First, we seek to document the relation between contemporary normative Muslim ideas on assisted suicide and voluntary euthanasia on the one hand and real-world views and attitudes of Muslims living in Belgium on the other hand. Second, we aim to identify whether a shift is observable in the views and attitudes regarding active termination of life between first- and second-generation Muslims. We have observed that when dealing with these bioethical issues, both first- and second generation Muslims adopt a theological line of reasoning similar to the one that can be found in normative Islamic views. We have found an absolute rejection of every act that deliberately terminates life, based upon the unconditional belief in an afterlife and in God's sovereign power over life and death. PMID- 29267142 TI - Influence of social and neighborhood contexts on smoking cessation among urban minorities. AB - A range of individual, social, and neighborhood factors influence the smoking related health inequities of urban minorities. Yet little is known about how these factors interact to influence smoking behaviors, including cessation. Hierarchical linear modeling was used to estimate the variance in cessation service utilization among a sample of primarily African American adults accounted for by individual, social, and neighborhood factors. Findings showed individual and social factors were important predictors of cessation service utilization. Social contexts have significant effects on smoking cessation service use, and social influences were more significant predictors of cessation service use than neighborhood factors. PMID- 29267143 TI - "And then, nothing": Alzheimer's archives and the good (enough) death. AB - This paper focuses on the author's mother, a subject whose ageing process was speeded and whose morality was challenged by the myriad and unpredictable effects of Alzheimer's disease. Using an archive of recorded conversations, the paper examines some of the existential questions with which the mother grappled until she lost the ability to speak. It considers these late ethical expressions in the context of her earlier political activism, marks her brief obsession with the possibility of assisted dying, and concludes by assessing the relative "goodness" of her very recent death in some of the terms that she herself established. PMID- 29267144 TI - Low Graft Attenuation at Unenhanced CT: Association with 1-Month Mortality or Graft Failure after Liver Transplantation. AB - Purpose To investigate whether low graft attenuation at unenhanced computed tomography (CT) is associated with 1-month mortality or graft failure after liver transplant and determine its diagnostic performance. Materials and Methods Included were 663 recipients who underwent CT imaging within 7 days after liver transplant between December 2014 and August 2016. Initial poor function (IPF) was diagnosed by using a combination of laboratory values within 7 days after liver transplant and subdivided patients into primary and secondary IPF. At 1 month after the operation, mortality and graft failure or survival in recipients was categorized. Two radiologists who were blinded to clinical data retrospectively and independently evaluated graft attenuation on unenhanced CT images (high or isoattenuation, graft attenuation greater than or equal to that of spleen; low, graft attenuation less than that of spleen). The interobserver agreement was evaluated by using intraclass correlation coefficient and kappa statics. Incidence of low graft attenuation between recipients with IPF and those with normal function was compared by using chi2 test. The relationship between graft attenuation and outcome in primary and secondary IPF was evaluated by using log rank test. Results Of 663 recipients, 114 had IPF (80 primary; 34 secondary). After 1 month, 11 had graft failure or died, whereas 652 survived. Low graft attenuation was more common in patients with IPF than in normal-function patients (P < .001). In the primary group (those without identifiable cause), 15 patients had low graft attenuation, which led to mortality or graft failure within 1 month in seven of those patients. No recipient with high or isoattenuation had 1-month mortality or graft failure (P < .001). The secondary group (those with identifiable cause) showed no significant association between graft attenuation and 1-month mortality and graft failure (P = .181). Values of low graft attenuation for 1-month mortality and graft failure in primary IPF were positive predictive value, 46.7%; negative predictive value, 100%; sensitivity, 100%; specificity, 89.0%; and accuracy, 90.0%. There was excellent interobserver agreement in the assessment of graft attenuation (intraclass correlation coefficient, 0.957; kappa = 1.00). Conclusion Low graft attenuation can be associated with 1-month mortality or graft failure in liver graft recipients with primary IPF. (c) RSNA, 2017. PMID- 29267145 TI - Improving Arterial Spin Labeling by Using Deep Learning. AB - Purpose To develop a deep learning algorithm that generates arterial spin labeling (ASL) perfusion images with higher accuracy and robustness by using a smaller number of subtraction images. Materials and Methods For ASL image generation from pair-wise subtraction, we used a convolutional neural network (CNN) as a deep learning algorithm. The ground truth perfusion images were generated by averaging six or seven pairwise subtraction images acquired with (a) conventional pseudocontinuous arterial spin labeling from seven healthy subjects or (b) Hadamard-encoded pseudocontinuous ASL from 114 patients with various diseases. CNNs were trained to generate perfusion images from a smaller number (two or three) of subtraction images and evaluated by means of cross-validation. CNNs from the patient data sets were also tested on 26 separate stroke data sets. CNNs were compared with the conventional averaging method in terms of mean square error and radiologic score by using a paired t test and/or Wilcoxon signed-rank test. Results Mean square errors were approximately 40% lower than those of the conventional averaging method for the cross-validation with the healthy subjects and patients and the separate test with the patients who had experienced a stroke (P < .001). Region-of-interest analysis in stroke regions showed that cerebral blood flow maps from CNN (mean +/- standard deviation, 19.7 mL per 100 g/min +/- 9.7) had smaller mean square errors than those determined with the conventional averaging method (43.2 +/- 29.8) (P < .001). Radiologic scoring demonstrated that CNNs suppressed noise and motion and/or segmentation artifacts better than the conventional averaging method did (P < .001). Conclusion CNNs provided superior perfusion image quality and more accurate perfusion measurement compared with those of the conventional averaging method for generation of ASL images from pair wise subtraction images. (c) RSNA, 2017. PMID- 29267146 TI - Obligate Overdiagnosis Due to Mammographic Screening: A Direct Estimate for U.S. Women. AB - Purpose To determine obligate overdiagnosis rates, defined as the percentage of women diagnosed with screen-detected breast cancer who die of causes other than breast cancer prior to clinical presentation of that cancer, for ductal carcinoma in situ (DCIS), invasive breast cancer, and all breast cancers. Materials and Methods Age-specific all-cause mortality rates from the Human Mortality Database, age-specific breast cancer incidence and mortality rates from Surveillance, Epidemiology, and End Results data, and estimates of mean lead times and lead time distributions from breast cancer screening trials are used to estimate obligate (or type 1) overdiagnosis rates for DCIS, invasive breast cancer, and all breast cancers (DCIS plus invasive) for U.S. women undergoing screening mammography. Mortality rates by age are used to estimate the number of women who die of causes other than breast cancer during the lead time afforded by screening mammography. Resulting age-dependent overdiagnosis rates, along with screen detected breast cancer incidence by age, are used to estimate type 1 overdiagnosis rates for the U.S. screening population. Results Obligate overdiagnosis rates depend strongly on the age at which a woman is screened, ranging from less than 1% at age 40 years to 30%, 21%, and 22.5% at age 80 years for DCIS, invasive breast cancer, and all breast cancers, respectively. Type 1 overdiagnosis rates among screened women in the United States are estimated to be 9% for DCIS and approximately 7% for both invasive breast cancer and all breast cancers. Screening of women ages 40-49 years (or premenopausal women, as determined from patient history, starting at age 40 years) adds little to obligate overdiagnosis rates (0.15% for DCIS and less than 0.1% for invasive breast cancer and all breast cancers). Conclusion Type 1 overdiagnosis rates increase rapidly with age at screening. Obligate overdiagnosis occurs in 9% of DCIS and approximately 7% of both invasive breast cancer and all breast cancers in the U.S. mammographic screening population, with screening of women ages 40-49 years (or premenopausal women starting at age 40 years) making a negligible contribution of 0.15% to obligate overdiagnosis of DCIS and a contribution of less than 0.1% to the obligate overdiagnosis rates of invasive breast cancer and all breast cancers. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29267147 TI - Structural Organization of 6B9 Molecule, a Monoclonal Antibody Against Lycopene. AB - Full cDNA and corresponding amino acid (AA) sequences of 6B9 monoclonal antibody (mAb) against lycopene was obtained using Step-Out RACE technology. Variable (V) and constant (C) regions were identified. The light chain of 6B9 contained 238 AA IgM with the highest level of identity (0.93) to both the anti-VEGF receptor antibody and anti-collagen type II FAb CIIC1. The heavy chain was composed of 634 AA with a high identity (0.9) to the Ig mu chain C region. Potential posttranslational modification regions in both chains were identified alongside with disulfide bond sites. The obtained information can be used for making chimeric constructs containing 6B9 mAb (or its fragments) and lycopene, a powerful carotenoid with antioxidant as well as antiproliferating properties, which can be implemented in the treatment of an aggressive form of prostate cancer and possibly other malignancies. PMID- 29267148 TI - Prokaryotic Expression of Hepatitis C Virus-NS3 Protein and Preparation of a Monoclonal Antibody. AB - Hepatitis C virus (HCV) is a significant health threat that has been extensively investigated worldwide. Improving the sensitivity and specificity of laboratory tests for screening and early diagnosis of HCV in a relevant population is an effective measure to control the spread of HCV. To build a more reliable diagnostic method for HCV, we expressed gene fragments of HCV-NS3 linked to a carrier, pET28a, and then transformed this vector into Escherichia. coli. The produced recombinant NS3 protein with a molecular weight of 38 kDa, which was purified through Ni-chelating affinity chromatography, was used to immunize BALB/C mice, which generated a serum antibody titer of 1:160,000 against the immunogen. Three positive monoclonal isolates (2A5, 2A6, and 5B12) were screened and established. Western blot and enzyme-linked immunosorbent assay (ELISA) results of these monoclonal cells show that each could specifically recognize the recombinant protein. Antibodies 2A5 and 2A6 were developed into an ELISA sandwich antibody pair for the recombinant protein. The detection sensitivity of our developed ELISA was 1.6 ng/mL, with a linear range of 2.5-80 ng/mL (R2 = 0.998). Serum NS3 ELISA results show that the average value in the healthy group, liver disease group, and hepatitis C group was 3.71, 7.28, and 13.11 ng/mL, respectively. The positive rates of HCV-NS3 protein in the liver disease group and hepatitis C group was 17.2% and 41.7%, respectively. Detection of HCV-NS3 antigen can be used as an auxiliary test for anti-HCV antibody detection, thus reducing leakage detection and providing a reliable basis for clinical practice. PMID- 29267149 TI - Preparation of a Monoclonal Antibody Against gD Protein of Bovine Herpesvirus I. AB - The two DNA fragments encoding predicted main antigenic regions, aa 20-160 and aa 257-344 on gD protein of bovine herpesvirus-1 (BoHV-1) were tandem-cloned into the vector pET28a. The recombinant His-tagged Delta gD1-Delta gD2 was expressed in Escherichia coli BL21(DE3)pLysS by induction with 0.5 mM isopropyl-1-thio-beta D-galactoside (IPTG) and Western blot analysis demonstrated that the recombinant His-tagged Delta gD1-Delta gD2 reacted with the positive serum against BoHV-1. A monoclonal antibody (MAb), designated as 2B6, was prepared by fusion of SP2/0 myeloma cells with splenocytes from a female 8-week-old BALB/c mouse immunized with purified His-tagged Delta gD1-Delta gD2 protein with the addition of Freund's adjuvant. The titer of the ascitic fluid triggered by hybridoma cells secreting MAb 2B6 was 1:2.5 * 108 and the subtype of MAb 2B6 was IgG 2a/kappa. MAb 2B6 positively recognized with BoHV-1 infected Madin-Darby bovine kidney cells by an indirect fluorescent antibody assay. Moreover, MAb 2B6 showed 1:160 viral neutralizing activity using 60% plaque reduction assay. Therefore, this work suggested that MAb 2B6 has potential in the diagnosis of bovine respiratory disease complex associated with BoHV-1 and function analysis. PMID- 29267151 TI - Erratum: Predicting Ascospore Release of Monilinia vaccinii-corymbosi of Blueberry with Machine Learning. PMID- 29267153 TI - Follower Jealousy at Work: A Test of Vecchio's Model of Antecedents and Consequences of Jealousy. AB - The present study tests the validity of Robert P. Vecchio's seminal work on antecedents and consequences of jealousy. Specifically, we examine whether antecedents such as in-group status, supervisory considerateness, and supervisory differentiation of subordinates are associated with jealousy. In addition, we examine whether jealousy is associated with the outcome variable of social loafing. Leaders (n = 73) and their followers (n = 303) working in business organizations in Norway contributed data. Multilevel analyses showed that a high quality working relationship with one's supervisor was inversely related to reports of jealousy. In addition, supervisors who displayed high levels of considerateness, for example, by providing followers with positive emotional support, were better able to reduce subordinate jealousy. This is a novel observation since previous research failed to demonstrate such a relationship. Finally, jealousy was positively associated with social loafing, suggesting that jealous followers engaged in an active counterproductive resistance response. The present study contributes to the extant literature by identifying unexamined antecedents of jealousy and a dysfunctional behavioral response to jealousy in the form of social loafing in the workplace. PMID- 29267150 TI - Association of beta-hCG Surveillance with Emotional, Reproductive, and Sexual Health in Women Treated for Gestational Trophoblastic Neoplasia. AB - BACKGROUND: To assess the emotional, reproductive, sexual health, and relationship concerns of women treated for gestational trophoblastic neoplasia (GTN) and examine associations with beta-hCG surveillance. METHODS: This institutional review board approved study surveyed GTN survivors (n = 51) who received treatment from 1996 to 2008. Fifty-one women, including those actively followed or formerly treated, were surveyed. The survey consisted of background/medical information, the Reproductive Concerns Scale, the Female Sexual Function Index, an item from the Abbreviated Dyadic Adjustment Scale, the Center for Epidemiologic Studies-Depression scale, the Menopausal Symptom Checklist, the Impact of Life Events Scale, and exploratory items. RESULTS: Mean age at diagnosis was 37.1 years; 41.6 years at study enrollment. Twenty-seven patients (56%) expressed worry about treatment harm and 30 (60%) about recurrence. Twenty percent reported significant depressive symptomatology. Mild cancer-related distress, reproductive concerns, sexual dysfunction, and bothersome menopausal symptoms were noted. Nineteen patients (40%) rated their beta-hCG surveillance worry as "high." Among patients who attempted conception after treatment, 3 of 12 (25%) succeeded in the beta-hCG high-worry group versus 13 of 19 (68%) in the beta-hCG low-worry group. Survivors with high beta-hCG worry had greater reproductive concerns than those with low worry (p = 0.002) and reported less sexual desire (p = 0.025). There was no difference in the number of low-worry versus high-worry participants in active surveillance (p = 0.09). CONCLUSION: Our study suggests that cancer-specific distress, sexual health, and reproductive concerns continue to impact women years after treatment. High worry about beta-hCG surveillance is negatively associated with the emotional well being of GTN survivors and possibly influences reproductive attempts and success. PMID- 29267154 TI - Implementation of Multisetting Interventions to Address Childhood Obesity in Diverse, Lower-Income Communities: CDC's Childhood Obesity Research Demonstration Projects. PMID- 29267155 TI - Best Practices and Barriers to Obesity Prevention in Head Start: Differences Between Director and Teacher Perceptions. AB - INTRODUCTION: Practices and barriers to promoting healthy eating and physical activity at Head Start centers may influence children's energy balance behaviors. We examined differences between directors' and teachers' perspectives on best practices and barriers to promoting healthy eating and physical activity in Head Start centers. METHODS: We conducted a cross-sectional study of directors (n = 23) and teachers (n = 113) at 23 Head Start centers participating in the baseline assessment of the Texas Childhood Obesity Research Demonstration study. Participants completed surveys about practices and barriers to promoting healthy eating and physical activity. Multilevel regression models examined differences between director and teacher responses. RESULTS: More than half of directors and teachers reported meeting most best practices related to nutrition and physical activity; few directors or teachers (<25%) reported conducting physical activity for more than 60 minutes a day, and less than 40% of teachers helped children attend to satiety cues. Significantly more directors than teachers reported meeting 2 nutrition-related best practices: "Teachers rarely eat less healthy foods (especially sweets, salty snacks, and sugary drinks) in front of children" and "Teachers talk to children about trying/enjoying new foods" (P < .05). No barrier to healthy eating or physical activity was reported by more than 25% of directors or teachers. Significantly more teachers than directors reported barriers to healthy eating, citing lack of food service staff support, limited time, and insufficient funds (P < .05). CONCLUSION: More barriers to healthy eating were reported than were barriers to physical activity indicating that more support may be needed for healthy eating. Differences between responses of directors and teachers may have implications for future assessments of implementation of best practices and barriers to implementation related to nutrition and physical activity in early care and education centers. PMID- 29267156 TI - Strategies to Recruit a Diverse Low-Income Population to Child Weight Management Programs From Primary Care Practices. AB - PURPOSE AND OBJECTIVES: Primary care practices can be used to engage children and families in weight management programs. The Texas Childhood Obesity Research Demonstration (TX CORD) study targeted patients at 12 primary care practices in diverse and low-income areas of Houston, Texas, and Austin, Texas for recruitment to a trial of weight management programs. This article describes recruitment strategies developed to benefit both families and health care practices and the modification of electronic health records (EHRs) to reflect recruitment outcomes. INTERVENTION APPROACH: To facilitate family participation, materials and programs were provided in English and Spanish, and programs were conducted in convenient locations. To support health care practices, EHRs and print materials were provided to facilitate obesity recognition, screening, and study referral. We provided brief training for providers and their office staffs that covered screening patients for obesity, empathetic communication, obesity billing coding, and use of counseling materials. EVALUATION METHODS: We collected EHR data from 2012 through 2014, including demographics, weight, and height, for all patients aged 2 to 12 years who were seen in the 12 provider practices during the study's recruitment phase. The data of patients with a body mass index (BMI) at or above the 85th percentile were compared with the same data for patients who were referred to the study and patients who enrolled in the study. We also examined reasons that patients referred to the study declined to participate. RESULTS: Overall, 26% of 7,845 patients with a BMI at or above the 85th percentile were referred to the study, and 27% of referred patients enrolled. Enrollment among patients with a BMI at or above the 85th percentile was associated with being Hispanic and with more severe obesity than with patients of other races/ethnicities or less severe obesity, respectively. Among families of children aged 2 to 5 years who were referred, 20% enrolled, compared with 30% of families of older children (>5 y to 12 y). Referral rates varied widely among the 12 primary care practices, and referral rates were not associated with EHR modifications. IMPLICATIONS FOR PUBLIC HEALTH: Engagement and recruitment strategies for enrolling families in primary care practice in weight management programs should be strengthened. Further study of factors associated with referral and enrollment, better systems for EHR tools, and data on provider and office adherence to study protocols should be examined. EHRs can track referral and enrollment to capture outcomes of recruitment efforts. PMID- 29267157 TI - Association Between Consumption of Sugar-Sweetened Beverages and Sociodemographic Characteristics Among Mississippi Adults. AB - INTRODUCTION: The consumption of sugar-sweetened beverages (SSBs) is linked to excessive weight gain, diabetes, and risk of cardiovascular disease. We examined the association between SSB consumption and sociodemographic characteristics among Mississippi adults. METHODS: We used data from the 2012 Mississippi Behavioral Risk Factor Surveillance System, which collected information on SSB consumption from 7,485 respondents. We used logistic regression models to calculate adjusted prevalence ratios (APRs) and 95% confidence intervals (CIs) for characteristics associated with SSB consumption. RESULTS: In 2012, 40.8% of Mississippi adults reported consuming at least one SSB daily. The likelihood of consuming SSBs at least once daily among respondents aged 18 to 34 years was 2.81 times higher (APR, 2.81; 95% CI, 2.49-3.18) than among those aged 65 years or older. The prevalence among men was 20% higher (APR, 1.20; 95% CI, 1.11-1.30) than among women and 23% higher (APR, 1.23; 95% CI, 1.13-1.35) among black respondents than among white respondents. The prevalence among respondents with less than a high school education was 25% higher (APR, 1.25; 95% CI, 1.11-1.41) than among those who with more than a high school education and 33% higher (APR, 1.33; 95% CI, 1.16-1.52) among those with an annual household income of less than $20,000 than among those with an income of $50,000 or more. CONCLUSION: Among Mississippi adults, age, sex, race, education level, and income are associated with an increased likelihood of SSB consumption. Findings highlight the need for policies and interventions to address SSB consumption and promote alternatives to SSBs among Mississippians. PMID- 29267158 TI - Arthroscopic autologous chondrocyte implantation in the hip for the treatment of full-thickness cartilage defects - A case series of 29 patients and review of the literature. AB - PURPOSE: Current literature indicates that the appropriate treatment of articular cartilage defects has significant influence on the postoperative outcome after hip arthroscopy. In the hip, arthroscopic treatment of cartilage defects is technically challenging, especially the autologous chondrocyte implantation/matrix-associated autologous chondrocyte implantation (ACI/MACI) procedures. The purpose of this prospective study was to introduce two injectable MACI products with self-adherent properties. Furthermore, we report short-term outcome and review the current literature. METHODS: Full-thickness cartilage defects of 29 patients caused by the femoroacetabular impingement (FAI) were treated arthroscopically with an injectable MACI product in a two-step surgical procedure. The patient-related outcome was assessed with International Hip Outcome Tool (iHOT33), Euro-Quol group score (EQ-5D) and Non-Arthritic-Hip-Score (NAHS) at baseline, six weeks, six, 12 and 24 months. RESULTS: Twenty-nine out of 46 patients (27 male/two female) with a mean age of 30.3 years (range 18-45 years) and an average defect size of 2.21 cm2 were available for follow-up after a mean of 19 months (range 6-24 months). All defects were located on the acetabulum International Cartilage Repair Society (ICRS) grade 3A-3D (nine 3A; eleven 3B; six 3C; three 3D). Twenty-six patients had associated labral pathology (23 repair 1-5 anchors; three partial trimming). Twenty-seven defects were caused by the FAI (20 CAM, six combined, one Pincer), two cases were of traumatic cause. An overall statistically significant improvement was observed for all assessment scores at an average follow-up of 19 months. CONCLUSION: In this study, we present short-term data of new arthroscopic injectable matrix-associated, autologous chondrocyte implants as a treatment option for full-thickness cartilage defects of the hip. All patient-administered assessment scores demonstrated an increase in activity level, quality of life and reduction of pain after a 19-month follow-up. Further randomized controlled trails (RCTs) with comparison of natural history, bone marrow stimulation techniques and MACI of the hip have to approve the results in long-term follow-up. PMID- 29267159 TI - Dominance of the Enterocytozoon bieneusi genotype BEB6 in red deer (Cervus elaphus) and Siberian roe deer (Capreolus pygargus) in China and a brief literature review. AB - Enterocytozoon bieneusi is the most frequently diagnosed microsporidian species in humans and is also found in a wide range of animals. It is considered to be an important but neglected zoonotic pathogen. With the development of deer bred in captivity, the number of deer has been increasing in recent years in China and there are more people involved in this work. The aims of this study were to determine prevalence and genotypes of E. bieneusi in red deer (Cervus elaphus) and Siberian roe deer (Capreolus pygargus), and to assess their potential zoonotic transmission. A total of 122 fecal specimens were collected from 104 red deer and 18 roe deer from three deer farms in Heilongjiang and Jilin Provinces, China. Enterocytozoon bieneusi was detected and genotyped by PCR and sequencing of the internal transcribed spacer (ITS) region of the rRNA gene. The average infection rate was 8.2% (10/122), with 7.7% (8/104) for red deer and 11.1% (2/18) for roe deer. Two genotypes were identified: a known genotype BEB6 (n = 9) and a novel genotype named HLJD-VI (n = 1). This is the first report of E. bieneusi infection in Siberian roe deer. The fact that genotype BEB6 was detected previously in one human case of microsporidiosis, and that genotype HLJD-VI fell into zoonotic group 1, suggest the possibility of transmission to humans. A brief review of E. bieneusi genotypes in deer worldwide shows that 40 genotypes have been found in seven deer species, with genotype BEB6 being predominant. PMID- 29267160 TI - Near-Field Inductive-Coupling Link to Power a Three-Dimensional Millimeter-Size Antenna for Brain Implantable Medical Devices. AB - OBJECTIVE: Near-field inductive-coupling link can establish a reliable power source to a batteryless implantable medical device based on Faraday's law of induction. METHODS: In this paper, the design, modeling, and experimental verification of an inductive-coupling link between an off-body loop antenna and a 0.9 three-dimensional (3-D) bowtie brain implantable antenna is presented. To ensure reliability of the design, the implantable antenna is embedded in the cerebral spinal fluid of a realistic human head model. Exposure, temperature, and propagation simulations of the near electromagnetic fields in a frequency dispersive head model were carried out to comply with the IEEE safety standards. Concertedly, a fabrication process for the implantable antenna is proposed, which can be extended to devise and miniaturize different 3-D geometric shapes. RESULTS: The performance of the proposed inductive link was tested in a biological environment; in vitro measurements of the fabricated prototypes were carried in a pig's head and piglet. The measurements of the link gain demonstrated in the pig's head and in piglet. SIGNIFICANCE: The in vitro measurement results showed that the proposed 3-D implantable antenna is suitable for integration with a miniaturized batteryless brain implantable medical device (BIMD). PMID- 29267162 TI - Correction: Caregiver Input to Optimize the Design of a Pediatric Care Planning Guide for Rehabilitation: Descriptive Study. AB - [This corrects the article DOI: 10.2196/rehab.7566.]. PMID- 29267163 TI - Metadata Correction: Brain Activation in Response to Personalized Behavioral and Physiological Feedback From Self-Monitoring Technology: Pilot Study. AB - [This corrects the article DOI: 10.2196/jmir.8890.]. PMID- 29267161 TI - In Vivo Superresolution Imaging of Neuronal Structure in the Mouse Brain. AB - OBJECTIVE: this study proposes and evaluates a technique for in vivo deep-tissue superresolution imaging in the light-scattering mouse brain at up to a 3.5 Hz 2-D imaging rate with a 21*21 MUm2 field of view. METHODS: we combine the deep-tissue penetration and high imaging speed of resonant laser scanning two-photon (2P) microscopy with the superresolution ability of patterned excitation microscopy. Using high-frequency intensity modulation of the scanned two-photon excitation beam, we generate patterned illumination at the imaging plane. Using the principles of structured illumination, the high-frequency components in the collected images are then used to reconstruct images with an approximate twofold increase in optical resolution. RESULTS: using our technique, resonant 2P superresolution patterned excitation reconstruction microscopy, we demonstrate our ability to investigate nanoscopic neuronal architecture in the cerebral cortex of the mouse brain at a depth of 120 MUm in vivo and 210 MUm ex vivo with a resolution of 119 nm. This technique optimizes the combination of speed and depth for improved in vivo imaging in the rodent neocortex. CONCLUSION: this study demonstrates a potentially useful technique for superresolution in vivo investigations in the rodent brain in deep tissue, creating a platform for investigating nanoscopic neuronal dynamics. SIGNIFICANCE: this technique optimizes the combination of speed and depth for improved superresolution in vivo imaging in the rodent neocortex. PMID- 29267164 TI - A new ELISA for autoantibodies to steroid 21-hydroxylase. AB - BACKGROUND: A new ELISA for autoantibodies to steroid 21-hydroxylase (21-OH Ab) is described. METHODS: In the assay test sample autoantibodies form a bridge between 21-OH coated onto the plate well and liquid phase 21-OH-biotin. Bound 21 OH-biotin is detected by the addition of streptavidin peroxidase and colorogenic peroxidase substrate. RESULTS: Of 100 samples from patients with autoimmune Addison's disease, 86 (86%) were positive for 21-OH Ab ELISA whereas 84 (84%) were positive in an immunoprecipitation assay based on 125I-labeled 21-OH. Six (0.6%) of 928 healthy adult blood donors and 1 (2.0%) of 49 adult patients with type 1 diabetes mellitus (T1DM) were positive by ELISA. No samples from adult patients with Graves' disease (GD; n=50), celiac disease (n=29), systemic lupus erythematosis (n=9) or rheumatoid arthritis (n=20) were positive by ELISA. However, 2/51 (3.9%) children with GD, 3/69 (4.3%) children with Hashimoto's thyroiditis (HT) and 3/119 (2.5%) children with T1DM alone or associated with autoimmune thyroid disorders were ELISA positive. CONCLUSIONS: The new assay should be useful for screening patients known to be at increased risk of developing clinical autoimmune Addison's disease, in particular children with HT, GD and/or T1DM. PMID- 29267165 TI - Comparison between blood gas analyzer and central laboratory analyzer for the determination of electrolytes in patients with acute respiratory acidosis. PMID- 29267166 TI - Assessment of in vitro stability: a call for harmonization across studies. PMID- 29267167 TI - Creation of the Swiss group of Pharmacogenomics and personalised Therapy (SPT). PMID- 29267168 TI - Amla (Emblica officinalis) improves hepatic and renal oxidative stress and the inflammatory response in hypothyroid female wistar rats fed with a high-fat diet. AB - BACKGROUND: We investigated the protective effects of amla (Emblica officinalis) on the pathogenesis of oxidative stress (OS) and inflammatory response in hypothyroid rats fed with a high-fat diet (HFD) as an experimental model of hypothyroidism (HT) with obesity. METHODS: A total of 80 female wistar rats (5 months-old) were divided into eight different groups. Propylthiouracil (PTU) and HFD were used to induce the experimental HT and obesity, respectively. The euthyroid and hypothyroid rats were fed either normal chow or HFD with and without amla extract (AE, 100 mg/kg bw/day) for 6 weeks. The blood and tissues, liver and kidney OS and inflammatory parameters were studied using appropriate biochemical and molecular techniques. RESULTS: PTU and HFD per se caused OS and inflammatory response as evidenced by increased plasma MDA, TNF-alpha, CRP and GPx in association with decreased levels of TAS and reduced glutathione (GSH). The proteomic analysis revealed that the expressions of pERK, pP38, TNF-alpha, IL6, COX2 and NOX-4 were up-regulated in the liver and kidney of these rats. In addition, all these metabolic derangements were further augmented when HT was followed by the addition of HFD. This suggested that there was a synergism between HT and the intake of HFD on the development of OS and inflammatory response. CONCLUSIONS: The treatment with amla fruit extract significantly restored the redox imbalance and inflammatory signaling and ameliorated OS and inflammatory response, suggesting the use of this natural compound as an alternative remedy or adjuvant for the management of metabolic complications concomitant with HT. PMID- 29267169 TI - Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor. AB - BACKGROUND: Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. CASE PRESENTATION: In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769 1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. CONCLUSIONS: Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management. PMID- 29267170 TI - WHO 2006 Child Growth Standards overestimate short stature and underestimate overweight in Japanese children. AB - BACKGROUND: It is unclear whether the World Health Organization (WHO) 2006 Child Growth Standards are applicable to East Asian populations. We investigated the applicability of the WHO standards of length/height and weight to a cohort representing middle-class children in Japan. METHODS: A cohort of children aged 0 5 years (3430 boys, 3025 girls) in the Tokyo Child Care Center Survey consecutively recruited from 2007 to 2013 were studied. Age- and sex-specific z scores of length/height, weight and weight for length/height were calculated relative to either the WHO standards or the Japanese 2000 Growth References (nationally representative cross sectional survey data). RESULTS: Compared with the WHO standards, Japanese children at birth, 1, 3, 5 years were shorter (length/height standard deviation score [SDS] -0.26, -0.82, -0.81, -0.63 for boys, and -0.15, -0.67, -0.84, -0.62 for girls, respectively) and lighter (weight SDS -0.62, -0.36, -0.34, -0.42 for boys and -0.60, -0.17, -0.29, -0.43 for girls, respectively). Weight for length/height showed smaller differences at various length/height points (SDS -0.05 to 0.15 for boys, 0.01 to 0.29 for girls, respectively). CONCLUSIONS: Adoption of the WHO standards would substantially alter the prevalence of short stature, underweight and overweight in Japanese children 0-5 years of age. These findings advocate the use of the national references in Japan. PMID- 29267171 TI - Clinical outcome in a series of pediatric patients with congenital generalized lipodystrophies treated with dietary therapy. AB - BACKGROUND: Congenital generalized lipodystrophy (CGL) produces clinical features with severe metabolic consequences. Research has focused on measuring the response to the drugs. Nevertheless, there are no studies on the response to dietary therapy. The aim of this study was to show the clinical response to early nutritional intervention to modify or reverse metabolic effects in pediatric patients with CGL. METHODS: A retrospective study was conducted on patients with CGL followed up between January 2003 and June 2017. After diagnosis, patients were indicated a diet with a total calorie intake according to the reference daily intake (RDI), without fast sugars. Clinical feature and laboratory tests (insulin, glucose, A1C, lipid panel, liver and kidney function tests), and complementary studies (abdominal ultrasonography, echocardiogram), at the first visit and during follow-up were recorded. Statistics, version 10, was used for analysis. RESULTS: Eight patients were included. The median age at the first visit was 1.1 years (range, 0.28-9.9 years) and the median time of follow-up was 3.9 years (range, 0.4-9.47 years). The median initial triglyceride level was 516 mg/dL (range, 327-3590 mg/dL) p=0.014; median low-density lipoprotein (LDL) was 157 mg/dL (range, 94-370 mg/dL) p=0.03; median glycemia was 84 mg/dL (range, 63 126 mg/dL) p=0.02; median insulin was 28.84 uUI/mL (range, 3.9-116); median homeostatic model assessment-insulin resistance (HOMA-IR) was 5.3 (range, 1.21 23.2). After 3-6 months of diet, the median percentage of triglyceride decrease was 79.5% (range, 47-97%), LDL 44% (range, 20.5-59%), glycemia 8.8% (range, 0 53.1%), insulin 67.8% (range, 0-92.8%) p=0.02 and HOMA-IR was 81.5% (range, 50 98%) p=0.05. As of the last follow-up visit, in none of the patients, liver ultrasonography or echocardiogram had deteriorated. CONCLUSIONS: In these pediatric patients with CGL, a diet adjusted to RDI with restriction of fast sugars led to a marked improvement in metabolic parameters. PMID- 29267173 TI - Watch out for congenital Zika syndrome in non-endemic regions. AB - Zika virus (ZIKV), first discovered in 1947, is the most recent member of the TORCH family. It usually causes an asymptomatic or mildly symptomatic disease in infected adults but can lead to severe brain abnormalities in fetuses who are infected in utero by vertical transmission of the virus through the placenta. The constellation of these fetal/neonatal abnormalities is named as congenital Zika syndrome (CZS). Although horizontal transmission of ZIKV is largely dependent on the presence of the vector (i.e. Aedes mosquitoes), women residing in non-endemic areas are still at risk of acquiring the infection once they travel to an endemic region or have unprotected sexual contact with an infected male. Therefore, it is important for physicians practicing in non-endemic regions to be familiar with the clinical and neuroimaging manifestations of CZS and to consider this diagnosis as a potential etiology for congenital microcephaly and other fetal central nervous system abnormalities. PMID- 29267172 TI - Early onset preeclampsia is associated with an elevated mean platelet volume (MPV) and a greater rise in MPV from time of booking compared with pregnant controls: results of the CAPE study. AB - OBJECTIVE: To characterise Mean platelet volume (MPV) in patients with early onset preeclampsia (EOPE) and unaffected controls from time of first antenatal visit until the postpartum. MATERIALS AND METHODS: Retrospective secondary analysis of an observational study in an Irish tertiary referral centre with 9000 deliveries annually. The MPV of 27 women with EOPE was compared to 19 unaffected controls. The inclusion criteria for the disease state was the development of EOPE defined by the National Institute for Health and Care Excellence (NICE) guideline, as new onset hypertension presenting after 20 weeks and prior to 34 weeks with significant proteinuria. Between October 2013 and July 2015 we recruited 27 women with EOPE and 19 pregnant controls. Statistical analysis was performed using paired T-test of Mann-Whitney test where appropriate and a P value <0.05 was deemed significant. RESULTS: At time of diagnosis and late in the third trimester MPV was significantly increased to 9.0 (+/-0.3) fL in cases of EOPE in comparison to 8.5 (+/-0.6) fL in normotensive controls (P<0.05). There was no significant difference during the first trimester or postpartum when comparing the MPV in EOPE to controls. CONCLUSION: Despite an increased MPV at time of diagnosis of EOPE this study did not demonstrate a potential use for increased MPV as a first trimester screening tool. PMID- 29267174 TI - A poor long-term neurological prognosis is associated with abnormal cord insertion in severe growth-restricted fetuses. AB - OBJECTIVE: To clarify and compare if the neurological outcomes of fetal growth restriction (FGR) cases with abnormal cord insertion (CI) are associated with a higher risk of a poor neurological outcome in subjects aged 3 years or less versus those with normal CI. METHODS: A multicenter retrospective cohort study was conducted among patients with a birth weight lower than the 3rd percentile, based on the standard reference values for Japanese subjects after 22 weeks' gestation, who were treated at a consortium of nine perinatal centers in Japan between June 2005 and March 2011. Patients whose birth weights were less than the 3rd percentile and whose neurological outcomes from birth to 3 years of age could be checked from their medical records were analyzed. The relationship between abnormal CI and neurological outcomes was analyzed. Univariate and multivariate models of multivariate logistic regression were employed to estimate the raw and odds ratio (OR) with 95% confidence intervals comparing marginal (MCI) and velamentous cord insertion (VCI) to normal CI. RESULTS: Among 365 neonates, 63 cases of MCI and 14 cases of VCI were observed. After excluding 24 cases with neonatal or infant death from the total FGR population, the assessment of the outcomes of the infants aged 3 years or younger showed the following rates of neurological complications: 7.3% (n=25) for cerebral palsy, 8.8% (n=30) for developmental disorders, 16.7% (n=57) for small-for-gestational-age short stature (SGA), 0.6% (n=2) for impaired hearing, 0.9% (n=3) for epilepsy, 1.2% (n=4). The ORs (95% confidence intervals) based on multivariate analysis were as follows: cerebral palsy=10.1 (2.4-41.5) in the VCI group and 4.3 (1.6-11.9) in the MCI group, developmental disorders=6.7 (1.7-26) in the VCI group and 3.9 (1.1-14.2) in the single umbilical artery (SUA) group, 5.1 (1.4-18.7) for birth weight <1000 g and 2.8 (1.2-6.7) for placental weight <200 g. CONCLUSIONS: The present results indicate that growth-restricted fetuses diagnosed with a birth weight below the 3rd percentile exhibiting abnormal umbilical CI are at a high risk for poor neurological outcomes, including cerebral palsy and/or developmental disorders. PMID- 29267175 TI - Risk factors and classification of stillbirth in a Middle Eastern population: a retrospective study. AB - OBJECTIVE: To estimate the incidence of stillbirth, explore the associated maternal and fetal factors and to evaluate the most appropriate classification of stillbirth for a multiethnic population. METHODS: This is a retrospective population-based study of stillbirth in a large tertiary unit. Data of each stillbirth with a gestational age >/=24 weeks in the year 2015 were collected from electronic medical records and analyzed. RESULTS: The stillbirth rate for our multiethnic population is 7.81 per 1000 births. Maternal medical factors comprised 52.4% in which the rates of hypertensive disorders, diabetes and other medical disorders were 22.5%, 20.8% and 8.3%, respectively. The most common fetal factor was intrauterine growth restriction (IUGR) (22.5%) followed by congenital anomalies (21.6%). All cases were categorized using the Wigglesworth, Aberdeen, Tulip, ReCoDe and International Classification of Diseases-perinatal mortality (ICD-PM) classifications and the rates of unclassified stillbirths were 59.2%, 46.6%, 16.6%, 11.6% and 7.5%, respectively. An autopsy was performed in 9.1% of cases reflecting local religious and cultural sensitivities. CONCLUSION: This study highlighted the modifiable risk factors among the Middle Eastern population. The most appropriate classification was the ICD-PM. The low rates of autopsy prevented a detailed evaluation of stillbirths, therefore it is suggested that a minimally invasive autopsy [postmortem magnetic resonance imaging (MRI)] may improve the quality of care. PMID- 29267176 TI - Maternal and neonatal vitamin D deficiency and transient tachypnea of the newborn in full term neonates. AB - AIM: To investigate the association between maternal and neonatal serum 25 hydroxyvitamin D (25-OHD) levels and development of transient tachypnea of the newborn (TTN) in full term infants. METHODS: This was a prospective case-control study carried out on 30 neonates with TTN and their mothers and 30 control neonates and their mothers. Levels of 25-OHD were measured in maternal and neonatal blood samples that were obtained in the first 12-24 h of postnatal age. RESULTS: Both maternal and neonatal 25-OHD levels in the TTN group were significantly lower compared to the control group (P=0.0001). A negative correlation was observed between neonatal 25-OHD level and average hospital stay (P=0.0001). CONCLUSION: We observed that lower maternal and neonatal vitamin 25 OHD levels were associated with TTN development in full term infants. PMID- 29267177 TI - Air pollution and public health: the challenges for Delhi, India. AB - Mitigating the impact of pollution on human health worldwide is important to limit the morbidity and mortality arising from exposure to its effect. The level and type of pollutants vary in different urban and rural settings. Here, we explored the extent of air pollution and its impacts on human health in the megacity of Delhi (India) through a review of the published literature. The study aims at describing the extent of air pollution in Delhi, the magnitude of health problems due to air pollution and the risk relationship between air pollution and associated health effects. We found 234 published articles in the PubMed search. The search showed that the extent of air pollution in Delhi has been described by various researchers from about 1986 onwards. We synthesized the findings and discuss them at length with respect to reported values, their possible interpretations and any limitations of the methodology. The chemical composition of ambient air pollution is also discussed. Further, we discuss the magnitude of health problem with respect to chronic obstructive pulmonary diseases (COPD), bronchial asthma and other illnesses. The results of the literature search showed that data has been collected in last 28 years on ambient air quality in Delhi, though it lacks a scientific continuity, consistency of locations and variations in parameters chosen for reporting. As a result, it is difficult to construct a spatiotemporal picture of the air pollution status in Delhi over time. The number of sites from where data have been collected varied widely across studies and methods used for data collection is also non-uniform. Even the parameters studied are varied, as some studies focused on particulate matter <=10 MUm in aerodynamic diameter (PM10) and those <=2.5 MUm in aerodynamic diameter (PM2.5), and others on suspended particulate matter (SPM) and respirable suspended particulate matter (RSPM). Similarly, the locations of data collection have varied widely. Some of the sites were at busy traffic intersections, some on the terraces of offices and residential houses and others in university campuses or airports. As a result, the key question of the extent of pollution and its distribution across various parts of the city could be inferred. None of the studies or a combination of them could present a complete picture of the burden of diseases like COPD, bronchial asthma and other allergic conditions attributable to pollution in Delhi. Neither could it be established what fraction of the burden of the above diseases is attributable to ambient air pollution, given that other factors like tobacco smoke and indoor air pollution are also contributors to the causation of such diseases. In our discussion, we highlight the knowledge gaps and in the conclusion, we suggested what research can be undertaken to fill the these research gaps. PMID- 29267178 TI - Applications of stem cell-derived exosomes in tissue engineering and neurological diseases. AB - Exosomes are extracellular vesicles with diameters of 30-100 nm that are key for intercellular communication. Almost all types of cell, including dendritic cells, T cells, mast cells, epithelial cells, neuronal cells, adipocytes, mesenchymal stem cells, and platelets, can release exosomes. Exosomes are present in human body fluids, such as urine, amniotic fluid, malignant ascites, synovial fluid, breast milk, cerebrospinal fluid, semen, saliva, and blood. Exosomes have biological functions in immune response, antigen presentation, intercellular communication, and RNA and protein transfer. This review provides a brief overview of the origin, morphological characteristics, enrichment and identification methods, biological functions, and applications in tissue engineering and neurological diseases of exosomes. PMID- 29267179 TI - Transitional Care Experience in Home Health: Exposing Students to Care Transitions Through Scenarios and Simulation. AB - Chronically ill older adults are at risk for avoidable adverse events especially during care transitions, the transfer to one care setting or one level of care to another. Because of the expected increase in the older adult population, increased demand for transitional care is anticipated. Despite the consistent call for expanded competencies in care transitions, nursing education has not incorporated these concepts into nursing curricula. To fill this gap, Villanova University developed patient care scenarios and simulations incorporating standardized patients to demonstrate the needs, risks, and potential complications associated with transitioning patients from acute care to home. PMID- 29267180 TI - Finding Positive Results with a New Focus on End-of-Life Content in an Associate Degree Nursing Program. AB - The end-of-life lecture has historically led to an emotionally difficult day for first-semester nursing students. The instructor implemented a few small changes to update the end-of-life lecture content, and as a result, positive outcomes were found. The purpose of this project was to provide a positive end-of-life experience for first-semester nursing students. A variety of small changes were implemented to achieve this goal. PMID- 29267181 TI - Building Reflection with Word Clouds for Online RN to BSN Students. AB - Reflection allows students to integrate learning with their personal context, developing deeper knowledge and promoting critical thinking. Word clouds help students develop themes/concepts beyond traditional methods, introducing visual aspects to an online learning environment. Students created word clouds and captions, then responded to those created by peers for a weekly discussion assignment. Students indicated overwhelming support for the use of word clouds to develop deeper understanding of the subject matter. This reflection assignment could be utilized in asynchronous, online undergraduate nursing courses for creative methods of building reflection and developing knowledge for the undergraduate RN to BSN student. PMID- 29267182 TI - Exposing the bidirectional effects of alcohol on coagulation in trauma: Impaired clot formation and decreased fibrinolysis in rotational thromboelastometry. AB - BACKGROUND: Alcohol has been associated with altered viscoelastic testing in trauma, indicative of impaired coagulation. Such alterations, however, show no correlation to coagulopathy-related outcomes. Other data suggest that alcohol may inhibit fibrinolysis. We sought to clarify these mechanisms after traumatic injury using thromboelastometry (ROTEM), hypothesizing that alcohol-related clot formation impairment may be counter-balanced by inhibited fibrinolysis. METHODS: Laboratory, demographic, clinical, and outcome data were prospectively collected from 406 critically injured trauma patients at a Level I trauma center. ROTEM and standard coagulation measures were conducted in parallel. Univariate comparisons were performed by alcohol level (EtOH), with subsequent regression analysis. RESULTS: Among 274 (58%) patients with detectable EtOH, median EtOH was 229 mg/dL. These patients were primarily bluntly injured and had lower GCS (p < 0.05) than EtOH-negative patients, but had similar admission pH and injury severity (p = NS). EtOH-positive patients had prolonged ROTEM clotting time and rate of clot formation time (CFT/alpha); they also had decreased fibrinolysis (max lysis %; all p < 0.05). In linear regression, for every 100 mg/dL increase in EtOH, clotting time increased by 13 seconds and fibrinolysis decreased by 1.5% (both p < 0.05). However, EtOH was not an independent predictor of transfusion requirements or mortality. In high-EtOH patients with coagulopathic ROTEM tracings, transfusion rates were significantly lower than expected, relative to EtOH-negative patients with similar ROTEM findings. CONCLUSION: As assayed by ROTEM, alcohol appears to have a bidirectional effect on coagulation in trauma, both impairing initial clot formation and inhibiting fibrinolysis. This balancing of mechanisms may explain lack of correlation between altered ROTEM and coagulopathy-related outcomes. Viscoelastic testing should be used with caution in intoxicated trauma patients. LEVEL OF EVIDENCE: Epidemiological study, level III. PMID- 29267183 TI - The effects of cryopreserved red blood cell transfusion on tissue oxygenation in obese trauma patients. AB - BACKGROUND: Low tissue oxygenation (StO2) is associated with poor outcomes in obese trauma patients. A novel treatment could be the transfusion of cryopreserved packed red blood cells (CPRBCs), which the in vitro biochemical profile favors red blood cell (RBC) function. We hypothesized that CPRBC transfusion improves StO2 in obese trauma patients. METHODS: Two hundred forty three trauma patients at five Level I trauma centers who required RBC transfusion were randomized to receive one to two units of liquid packed RBCs (LPRBCs) or CPRBCs. Demographics, injury severity, StO2, outcomes, and biomarkers of RBC function were compared in nonobese (body mass index [BMI] < 30) and obese (BMI >= 30) patients. StO2 was also compared between obese patients with BMI of 30 to 34.9 and BMI >= 35. StO2 was normalized and expressed as % change after RBC transfusion. A p value less than 0.05 indicated significance. RESULTS: Patients with BMI less than 30 (n = 141) and BMI of 30 or greater (n = 102) had similar Injury Severity Score, Glasgow Coma Scale, and baseline StO2. Plasma levels of free hemoglobin, an index of RBC lysis, were lower in obese patients after CPRBC (125 [72-259] MUg/mL) versus LPRBC transfusion (230 [178-388] MUg/mL; p < 0.05). StO2 was similar in nonobese patients regardless of transfusion type, but improved in obese patients who received CPRBCs (104 +/- 1%) versus LPRPCs (99 +/- 1%, p < 0.05; 8 hours after transfusion). Subanalysis showed improved StO2 after CPRBC transfusion was specific to BMI of 35 or greater, starting 5 hours after transfusion (p < 0.05 vs. LPRBCs). CPRBCs did not improve clinical outcomes in either group. CONCLUSION: CPRBC transfusion is associated with increased StO2 and lower free hemoglobin levels in obese trauma patients, but did not improve clinical outcomes. Future studies are needed to determine if CPRBC transfusion in obese patients attenuates hemolysis to improve StO2. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 29267184 TI - Measuring US Army medical evacuation: Metrics for performance improvement. AB - BACKGROUND: The US Army medical evacuation (MEDEVAC) community has maintained a reputation for high levels of success in transporting casualties from the point of injury to definitive care. This work served as a demonstration project to advance a model of quality assurance surveillance and medical direction for prehospital MEDEVAC providers within the Joint Trauma System. METHODS: A retrospective interrupted time series analysis using prospectively collected data was performed as a process improvement project. Records were reviewed during two distinct periods: 2009 and 2014 to 2015. MEDEVAC records were matched to outcomes data available in the Department of Defense Trauma Registry. Abstracted deidentified data were reviewed for specific outcomes, procedures, and processes of care. Descriptive statistics were applied as appropriate. RESULTS: A total of 1,008 patients were included in this study. Nine quality assurance metrics were assessed. These metrics were: airway management, management of hypoxemia, compliance with a blood transfusion protocol, interventions for hypotensive patients, quality of battlefield analgesia, temperature measurement and interventions, proportion of traumatic brain injury (TBI) patients with hypoxemia and/or hypotension, proportion of traumatic brain injury patients with an appropriate assessment, and proportion of missing data. Overall survival in the subset of patients with outcomes data available in the Department of Defense Trauma Registry was 97.5%. CONCLUSION: The data analyzed for this study suggest overall high compliance with established tactical combat casualty care guidelines. In the present study, nearly 7% of patients had at least one documented oxygen saturation of less than 90%, and 13% of these patients had no documentation of any intervention for hypoxemia, indicating a need for training focus on airway management for hypoxemia. Advances in battlefield analgesia continued to evolve over the period when data for this study was collected. Given the inherent high-risk, high-acuity nature of prehospital advanced life support and emphasis on the use of nonphysician practitioners in an out-of-hospital setting, the need for ongoing medical oversight and quality improvement assessment is crucial. LEVEL OF EVIDENCE: Care management, level IV. PMID- 29267185 TI - Re: Three versus four-factor prothrombin complex concentrates for "factor-based" resuscitation in a porcine hemorrhagic shock model. PMID- 29267186 TI - Cytotoxicity of the Defensive Secretion from the Medicinal Insect Blaps rynchopetera. AB - Blaps rynchopetera Fairmaire has long been used as a folk medicine by the Yi and Bai ethnic groups in China to treat fever, cough, gastritis, boils, and tumors. In the present study, the cytotoxicity of the defensive secretion (TDS) of B. rynchopetera against AGS Caco-2, HepG2 U251 and Bel-7402 was tested, and the results revealed that TDS had potent cytotoxicity against testing cells with IC50 values of 45.8, 17.4, 53.6, 98.4 and 23.4 MUg/mL, respectively. Gas chromatography-mass spectrometry (GC-MS) analysis was employed to clarify the cytotoxic constituents in TDS of B. rynchopetera and five volatile compounds, including 2-ethyl-2,5-cyclohexadiene-1,4-dione (3, 31.00%), 1-tridecene (5, 28.02%), 2-methyl-2,5-cyclohexadiene-1,4-dione (2, 22.86%), hydroquinone (4, 1.33%), and p-benzoquinone (1, 1.01%), were identified. Chemical constituent investigation on TDS further supported the presence of 5 above compounds. A cytotoxic assay indicated that compounds 1, 2, 3 and 4 exhibited significant cytotoxicity against the testing cell lines, implying that benzoquinones and hydroquinone played important roles in the cytotoxicity of TDS of B. rynchopetera. TDS is a cytotoxic natural material and further studies investigating mechanisms and inhibitory activities on other cell lines is warranted. PMID- 29267187 TI - Application of a General Computer Algorithm Based on the Group-Additivity Method for the Calculation of Two Molecular Descriptors at Both Ends of Dilution: Liquid Viscosity and Activity Coefficient in Water at Infinite Dilution. AB - The application of a commonly used computer algorithm based on the group additivity method for the calculation of the liquid viscosity coefficient at 293.15 K and the activity coefficient at infinite dilution in water at 298.15 K of organic molecules is presented. The method is based on the complete breakdown of the molecules into their constituting atoms, further subdividing them by their immediate neighborhood. A fast Gauss-Seidel fitting method using experimental data from literature is applied for the calculation of the atom groups' contributions. Plausibility tests have been carried out on each of the calculations using a ten-fold cross-validation procedure which confirms the excellent predictive quality of the method. The goodness of fit (Q2) and the standard deviation (sigma) of the cross-validation calculations for the viscosity coefficient, expressed as log(eta), was 0.9728 and 0.11, respectively, for 413 test molecules, and for the activity coefficient log(gamma)infinity the corresponding values were 0.9736 and 0.31, respectively, for 621 test compounds. The present approach has proven its versatility in that it enabled the simultaneous evaluation of the liquid viscosity of normal organic compounds as well as of ionic liquids. PMID- 29267190 TI - 2017: A Fruitful Year for Pharmaceuticals. AB - First of all, let me wish you a healthy and wonderful year in 2018 [...]. PMID- 29267188 TI - Magnetic Nanoparticles in the Central Nervous System: Targeting Principles, Applications and Safety Issues. AB - One of the most challenging goals in pharmacological research is overcoming the Blood Brain Barrier (BBB) to deliver drugs to the Central Nervous System (CNS). The use of physical means, such as steady and alternating magnetic fields to drive nanocarriers with proper magnetic characteristics may prove to be a useful strategy. The present review aims at providing an up-to-date picture of the applications of magnetic-driven nanotheranostics agents to the CNS. Although well consolidated on physical ground, some of the techniques described herein are still under investigation on in vitro or in silico models, while others have already entered in-or are close to-clinical validation. The review provides a concise overview of the physical principles underlying the behavior of magnetic nanoparticles (MNPs) interacting with an external magnetic field. Thereafter we describe the physiological pathways by which a substance can reach the brain from the bloodstream and then we focus on those MNP applications that aim at a nondestructive crossing of the BBB such as static magnetic fields to facilitate the passage of drugs and alternating magnetic fields to increment BBB permeability by magnetic heating. In conclusion, we briefly cite the most notable biomedical applications of MNPs and some relevant remarks about their safety and potential toxicity. PMID- 29267191 TI - Development and Application of Eddy Current Sensor Arrays for Process Integrated Inspection of Carbon Fibre Preforms. AB - This publication presents the realisation of a sensor concept, which is based on eddy current testing, to detect textile defects during preforming of semi finished carbon fibre parts. The presented system has the potential for 100% control of manufactured carbon fibre based components, allowing the immediate exclusion of defective parts from further process steps. The core innovation of this system is given by the high degree of process integration, which has not been implemented in the state of the art. The publication presents the functional principle of the sensor that is based on half-transmission probes as well as the signals that can be gained by its application. Furthermore, a method to determine the optimum sensor resolution is presented as well as the sensor housing and its integration in the preforming process. PMID- 29267189 TI - Neuroprotective, Neurogenic, and Amyloid Beta Reducing Effect of a Novel Alpha 2 Adrenoblocker, Mesedin, on Astroglia and Neuronal Progenitors upon Hypoxia and Glutamate Exposure. AB - Locus coeruleus-noradrenergic system dysfunction is known to contribute to the progression of Alzheimer's disease (AD). Besides a variety of reports showing the involvement of norepinephrine and its receptor systems in cognition, amyloid beta (Abeta) metabolism, neuroinflammation, and neurogenesis, little is known about the contribution of the specific receptors to these actions. Here, we investigated the neurogenic and neuroprotective properties of a new alpha2 adrenoblocker, mesedin, in astroglial primary cultures (APC) from C57BL/6 and 3*Tg-AD mice. Our results demonstrate that mesedin rescues neuronal precursors and young neurons, and reduces the lactate dehydrogenase (LDH) release from astroglia under hypoxic and normoxic conditions. Mesedin also increased choline acetyltransferase, postsynaptic density marker 95 (PSD95), and Abeta-degrading enzyme neprilysin in the wild type APC, while in the 3*Tg-AD APC exposed to glutamate, it decreased the intracellular content of Abeta and enhanced the survival of synaptophysin-positive astroglia and neurons. These effects in APC can at least partially be attributed to the mesedin's ability of increasing the expression of Interleukine(IL)-10, which is a potent anti-inflammatory, neuroprotective neurogenic, and Abeta metabolism enhancing factor. In summary, our data identify the neurogenic, neuroprotective, and anti-amyloidogenic action of mesedin in APC. Further in vivo studies are needed to estimate the therapeutic value of mesedin for AD. PMID- 29267193 TI - Screen-Printed Electrode Modified by Bismuth /Fe3O4 Nanoparticle/Ionic Liquid Composite Using Internal Standard Normalization for Accurate Determination of Cd(II) in Soil. AB - The quality and safety of agricultural products are threatened by heavy metal ions in soil, which can be absorbed by the crops, and then accumulated in the human body through the food chain. In this paper, we report a low-cost and easy to-use screen-printed electrode (SPE) for cadmium ion (Cd(II)) detection based on differential pulse voltammetry (DPV), which decorated with ionic liquid (IL), magnetite nanoparticle (Fe3O4), and deposited a bismuth film (Bi). The characteristics of Bi/Fe3O4/ILSPE were investigated using scanning electron microscopy, cyclic voltammetry, impedance spectroscopy, and linear sweep voltammetry. We found that the sensitivity of SPE was improved dramatically after functionalized with Bi/Fe3O4/IL. Under optimized conditions, the concentrations of Cd(II) are linear with current responses in a range from 0.5 to 40 ug/L with the lowest detection limit of 0.05 ug/L (S/N = 3). Additionally, the internal standard normalization (ISN) was used to process the response signals of Bi/Fe3O4/ILSPE and established a new linear equation. For detecting three different Cd(II) concentrations, the root-mean-square error using ISN (0.25) is lower than linear method (0.36). Finally, the proposed electrode was applied to trace Cd(II) in soil samples with the recovery in the range from 91.77 to 107.83%. PMID- 29267192 TI - l-Acetylcarnitine: A Mechanistically Distinctive and Potentially Rapid-Acting Antidepressant Drug. AB - Current therapy of mood disorders has several limitations. Although a high number of drugs are clinically available, as of today, nearly two-thirds of individuals do not achieve full symptomatic remission after treatment with conventional antidepressants. Moreover, several weeks of drug treatment are usually required to obtain clinical effects, a limitation that has considerable clinical implications, ranging from high suicide risk to reduced compliance. The characteristic lag time in classical antidepressant effectiveness has given great impulse to the search for novel therapeutics with more rapid effects. l acetylcarnitine (LAC), a small molecule of growing interest for its pharmacological properties, is currently marketed for treatment of neuropathic pain. Recent preclinical and clinical data suggested that LAC may exert antidepressant effects with a more rapid onset than conventional drugs. Herein, we review data supporting LAC antidepressant activity and its distinctive mechanisms of action compared with monoaminergic antidepressants. Furthermore, we discuss the unique pharmacological properties of LAC that allow us to look at this molecule as representative of next generation antidepressants with a safe profile. PMID- 29267195 TI - Development of Highly Repellent Silica Particles for Protection of Hemp Shiv Used as Insulation Materials. AB - New bio-materials have recently gained interest for use in insulation panels in walls, but wider adoption by the building industry is hindered by their intrinsic properties. The fact that such materials are mainly composed of cellulose makes them combustible, and their hydrophilic surface presents a high water uptake, which would lead to faster biodegradation. A hydrophobic treatment with silica particles was successfully synthesised via Stober process, characterised, and deposited on hemp shiv. The surface of hemp shiv coated several times with 45 and 120 nm particles were uniformly covered, as well as extensively water repellent. Those samples could withstand in humidity chamber without loss of their hydrophobic property and no sign of mould growth after 72 h of exposure. PMID- 29267194 TI - The In Vitro Impact of the Herbicide Roundup on Human Sperm Motility and Sperm Mitochondria. AB - Toxicants, such as herbicides, have been hypothesized to affect sperm parameters. The most common method of exposure to herbicides is through spraying or diet. The aim of the present study was to investigate the effect of direct exposure of sperm to 1 mg/L of the herbicide Roundup on sperm motility and mitochondrial integrity. Sperm samples from 66 healthy men who were seeking semen analysis were investigated after written informed consent was taken. Semen analysis was performed according to the World Health Organization guidelines (WHO, 2010). Mitochondrial integrity was assessed through mitochondrial staining using a mitochondria-specific dye, which is exclusively incorporated into functionally active mitochondria. A quantity of 1 mg/L of Roundup was found to exert a deleterious effect on sperm's progressive motility, after 1 h of incubation (mean difference between treated and control samples = 11.2%) in comparison with the effect after three hours of incubation (mean difference = 6.33%, p < 0.05), while the relative incorporation of the mitochondrial dye in mitochondria of the mid piece region of Roundup-treated spermatozoa was significantly reduced compared to relative controls at the first hour of incubation, indicating mitochondrial dysfunction by Roundup. Our results indicate that the direct exposure of semen samples to the active constituent of the herbicide Roundup at the relatively low concentration of 1 mg/L has adverse effects on sperm motility, and this may be related to the observed reduction in mitochondrial staining. PMID- 29267196 TI - Zno Micro/Nanostructures Grown on Sapphire Substrates Using Low-Temperature Vapor Trapped Thermal Chemical Vapor Deposition: Structural and Optical Properties. AB - In this research, the Zn(C5H7O2)2.xH2O-based growth of ZnO micro/nanostructures in a low temperature, vapor-trapped chemical vapor deposition system was attempted to optimize structural and optical properties for potential biomedical applications. By trapping in-flow gas molecules and Zinc vapor inside a chamber tube by partially obstructing a chamber outlet, a high pressure condition can be achieved, and this experimental setup has the advantages of ease of synthesis, being a low temperature process, and cost effectiveness. Empirically, the growth process proceeded under a chamber condition of an atmospheric pressure of 730 torr, a controlled volume flow rate of input gas, N2/O2, of 500/500 Standard Cubic Centimeters per Minute (SCCM), and a designated oven temperature of 500 degrees C. Specifically, the dependence of structural and optical properties of the structures on growth duration and spatially dependent temperature were investigated utilizing scanning electron microscopy, X-ray diffraction (XRD), photoluminescence (PL), and ultraviolet-visible transmission spectroscopy. The experimental results indicate that the grown thin film observed with hexagonal structures and higher structural uniformity enables more prominent structural and optical signatures. XRD spectra present the dominant peaks along crystal planes of (002) and (101) as the main direction of crystallization. In addition, while the structures excited with laser wavelength of 325 nm emit a signature radiation around 380 nm, an ultraviolet lamp with a wavelength of 254 nm revealed distinctive photoluminescence peaks at 363.96 nm and 403.52 nm, elucidating different degrees of structural correlation as functions of growth duration and the spatial gradient of temperature. Transmittance spectra of the structures illustrate typical variation in the wavelength range of 200 nm to 400 nm, and its structural correlation is less significant when compared with PL. PMID- 29267197 TI - Receptor-Like Kinase LYK9 in Pisum sativum L. Is the CERK1-Like Receptor that Controls Both Plant Immunity and AM Symbiosis Development. AB - Plants are able to discriminate and respond to structurally related chitooligosaccharide (CO) signals from pathogenic and symbiotic fungi. In model plants Arabidopsis thaliana and Oryza sativa LysM-receptor like kinases (LysM RLK) AtCERK1 and OsCERK1 (chitin elicitor receptor kinase 1) were shown to be involved in response to CO signals. Based on phylogenetic analysis, the pea Pisum sativum L. LysM-RLK PsLYK9 was chosen as a possible candidate given its role on the CERK1-like receptor. The knockdown regulation of the PsLyk9 gene by RNA interference led to increased susceptibility to fungal pathogen Fusarium culmorum. Transcript levels of PsPAL2, PsPR10 defense-response genes were significantly reduced in PsLyk9 RNAi roots. PsLYK9's involvement in recognizing short-chain COs as most numerous signals of arbuscular mycorrhizal (AM) fungi, was also evaluated. In transgenic roots with PsLyk9 knockdown treated with short chain CO5, downregulation of AM symbiosis marker genes (PsDELLA3, PsNSP2, PsDWARF27) was observed. These results clearly indicate that PsLYK9 appears to be involved in the perception of COs and subsequent signal transduction in pea roots. It allows us to conclude that PsLYK9 is the most likely CERK1-like receptor in pea to be involved in the control of plant immunity and AM symbiosis formation. PMID- 29267198 TI - Water Quality and Brain Function. AB - In the United States, regulations are in place to ensure the quality of drinking water. Such precautions are intended to safeguard the health of the population. However, regulatory guidelines may at times fail to achieve their purpose. This may be due to lack of sufficient data regarding the health hazards of chronic low dose exposure to contaminants or the introduction of new substances that pose a health hazard risk that has yet to be identified. In this review, examples of different sources of contaminants in drinking water will be discussed, followed by an evaluation of some select individual toxicants with known adverse neurological impact. The ability of mixtures to potentially cause additive, synergistic, or antagonistic neurotoxic responses will be briefly addressed. The last section of the review will provide examples of select mechanisms by which different classes of contaminants may lead to neurological impairments. The main objective of this review is to bring to light the importance of considering trace amounts of chemicals in the drinking water and potential brain abnormalities. There is continued need for toxicology studies to better understand negative consequences of trace amounts of toxins and although it is beyond the scope of this brief overview it is hoped that the review will underscore the paucity of studies focused on determining how long-term exposure to minute levels of contaminants in drinking water may pose a significant health hazard. PMID- 29267199 TI - Evidence for Anti-Pseudogymnoascus destructans (Pd) Activity of Propolis. AB - White-nose syndrome (WNS) in bats, caused by Pseudogymnoascus destructans (Pd), is a cutaneous infection that has devastated North American bat populations since 2007. At present, there is no effective method for controlling this disease. Here, we evaluated the effect of propolis against Pd in vitro. Using Sabouraud dextrose agar (SDA) medium, approximately 1.7 * 107 conidia spores of the Pd strain M3906-2/mL were spread on each plate and grown to form a consistent lawn. A Kirby-Bauer disk diffusion assay was employed using different concentrations of propolis (1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%), in plates incubated at 8 degrees C and 15 degrees C. At 8 degrees C and 15 degrees C, as the concentration of propolis increased, there was an increasing zone of inhibition (ZOI), reaching the highest degree at 10% and 25% concentrations, respectively. A germule suppression assay showed a similar effect on Pd conidia germination. A MALDI-TOF-MS analysis of propolis revealed multiple constituents with a potential anti-Pd activity, including cinnamic acid, p-coumaric acid, and dihydrochalcones, which could be further tested for their individual effects. Our study suggests that propolis or its individual constituents might be suitable products against Pd. PMID- 29267200 TI - High Incidence and Levels of Ochratoxin A in Wines Sourced from the United States. AB - Ochratoxin A (OTA) is one of the most prevalent mycotoxin contaminants of food crops. Among the agricultural products consequently contaminated by OTA is wine. In the present study, a sample of wines sourced from the United States was assessed for OTA. Wines were primarily analyzed by high-performance liquid chromatography with fluorescence detection (HPLC-FD) coupled to a liquid-liquid extraction (LLE) technique which was developed and validated as a simplified sample preparation approach. More than 85% of the wines evaluated were found to contain OTA, at levels above the limit-of-detection (LOD = 0.1 ug L-1), and 76% were above the limit-of-quantitation (LOQ = 0.3 ug L-1) for the LLE/HPLC-FD method. More than two-thirds of the wines above the LOQ were found to exceed 1 ug L-1. Complementary analysis by HPLC coupled to tandem mass spectrometry (HPLC MS/MS) confirmed OTA in 74% of the OTA-positive wines (i.e., >LOQ by HPLC-FD). Overall, both the occurrence and measured levels of OTA were generally high, specifically relative to previous assessments of OTA in wine, and two of the wines were above the only current (European Union) regulatory limit of two parts per-billion (ppb, ~2 ug L-1). Possible trends with respect to geographical region and/or growing climate are noted. As the first assessment of U.S. wines in more than a decade, the overall high occurrence and levels of OTA in wine, and possible geographic and climatic trends, point to a need for regular surveillance of wines, as well as investigation of the relevant contributors to OTA occurrence toward mitigating contamination and exposure risks. PMID- 29267202 TI - The Fate of Glyphosate and AMPA in a Freshwater Endorheic Basin: An Ecotoxicological Risk Assessment. AB - Glyphosate is the most widely used herbicide worldwide. However, there are some uncertain aspects with respect to its environmental fate. To evaluate the existence and distribution of this pesticide and its metabolite, aminomethylphosphonic acid (AMPA), their presence in fresh water, sediment, and suspended particulate matter (SPM) was measured in samples collected in a river running across a large city and through areas with intensive and extensive agriculture. The aquatic risk associated to the occurrence of these compounds was estimated using the hazard quotient (HQ) calculation for water and sediment. From the analyzed samples, overall 35% contained glyphosate, AMPA, or both compounds. Concentrations of the analytes were spread in different percentages depending on the environmental matrices considered, with levels ranging from 12 to 20 times higher for glyphosate and AMPA in sediment and SPM, as compared with the levels found in water. The most polluted area was situated within a green belt zone of the city; while in second place were sites located in areas of extensive agriculture. Aquatic organisms inhabiting areas both inside and outside agricultural areas are threatened by water glyphosate concentrations. Benthic organisms inside the greenbelt zone and inside the lower basin are threatened by the concentrations of glyphosate in sediment. Even when the concentrations measured in water were below the levels of concern for wildlife, results showed the risk of agricultural practices to aquatic biota. An update of the limits established for freshwater biota protection is needed. PMID- 29267201 TI - Telomere Biology and Thoracic Aortic Aneurysm. AB - Ascending aortic aneurysms are mostly asymptomatic and present a great risk of aortic dissection or perforation. Consequently, ascending aortic aneurysms are a source of lethality with increased age. Biological aging results in progressive attrition of telomeres, which are the repetitive DNA sequences at the end of chromosomes. These telomeres play an important role in protection of genomic DNA from end-to-end fusions. Telomere maintenance and telomere attrition-associated senescence of endothelial and smooth muscle cells have been indicated to be part of the pathogenesis of degenerative vascular diseases. This systematic review provides an overview of telomeres, telomere-associated proteins and telomerase to the formation and progression of aneurysms of the thoracic ascending aorta. A better understanding of telomere regulation in the vascular pathology might provide new therapeutic approaches. Measurements of telomere length and telomerase activity could be potential prognostic biomarkers for increased risk of death in elderly patients suffering from an aortic aneurysm. PMID- 29267204 TI - Climate Change and Health under the Shared Socioeconomic Pathway Framework. AB - A growing body of literature addresses how climate change is likely to have substantial and generally adverse effects on population health and health systems around the world. These effects are likely to vary within and between countries and, importantly, will vary depending on different socioeconomic development patterns. Transitioning to a more resilient and sustainable world to prepare for and manage the effects of climate change is likely to result in better health outcomes. Sustained fossil fuel development will likely result in continued high burdens of preventable conditions, such as undernutrition, malaria, and diarrheal diseases. Using a new set of socioeconomic development trajectories, the Shared Socioeconomic Pathways (SSPs), along with the World Health Organization's Operational Framework for Building Climate Resilient Health Systems, we extend existing storylines to illustrate how various aspects of health systems are likely to be affected under each SSP. We also discuss the implications of our findings on how the burden of mortality and the achievement of health-related Sustainable Development Goal targets are likely to vary under different SSPs. PMID- 29267203 TI - Telomerase Inhibitors from Natural Products and Their Anticancer Potential. AB - Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy-a hallmark of cancer-and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design. PMID- 29267205 TI - Disturbed Glucose Metabolism in Rat Neurons Exposed to Cerebrospinal Fluid Obtained from Multiple Sclerosis Subjects. AB - Axonal damage is widely accepted as a major cause of permanent functional disability in Multiple Sclerosis (MS). In relapsing-remitting MS, there is a possibility of remyelination by myelin producing cells and restoration of neurological function. The purpose of this study was to delineate the pathophysiological mechanisms underpinning axonal injury through hitherto unknown factors present in cerebrospinal fluid (CSF) that may regulate axonal damage, remyelinate the axon and make functional recovery possible. We employed primary cultures of rat unmyelinated cerebellar granule neurons and treated them with CSF obtained from MS and Neuromyelitis optica (NMO) patients. We performed microarray gene expression profiling to study changes in gene expression in treated neurons as compared to controls. Additionally, we determined the influence of gene-gene interaction upon the whole metabolic network in our experimental conditions using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) program. Our findings revealed the downregulated expression of genes involved in glucose metabolism in MS-derived CSF-treated neurons and upregulated expression of genes in NMO-derived CSF-treated neurons. We conclude that factors in the CSF of these patients caused a perturbation in metabolic gene(s) expression and suggest that MS appears to be linked with metabolic deformity. PMID- 29267206 TI - JNK, p38, ERK, and SGK1 Inhibitors in Cancer. AB - Mitogen-activated protein kinases (MAP kinases) are a family of kinases that regulates a range of biological processes implicated in the response to growth factors like latelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and stress, such as ultraviolet irradiation, heat shock, and osmotic shock. The MAP kinase family consists of four major subfamilies of related proteins (extracellular regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and extracellular regulated kinase 5 (ERK5)) and regulates numerous cellular activities, such as apoptosis, gene expression, mitosis, differentiation, and immune responses. The deregulation of these kinases is shown to be involved in human diseases, such as cancer, immune diseases, inflammation, and neurodegenerative disorders. The awareness of the therapeutic potential of the inhibition of MAP kinases led to a thorough search for small-molecule inhibitors. Here, we discuss some of the most well-known MAP kinase inhibitors and their use in cancer research. PMID- 29267207 TI - Designing Smart Biomaterials for Tissue Engineering. AB - The engineering of human tissues to cure diseases is an interdisciplinary and a very attractive field of research both in academia and the biotechnology industrial sector. Three-dimensional (3D) biomaterial scaffolds can play a critical role in the development of new tissue morphogenesis via interacting with human cells. Although simple polymeric biomaterials can provide mechanical and physical properties required for tissue development, insufficient biomimetic property and lack of interactions with human progenitor cells remain problematic for the promotion of functional tissue formation. Therefore, the developments of advanced functional biomaterials that respond to stimulus could be the next choice to generate smart 3D biomimetic scaffolds, actively interacting with human stem cells and progenitors along with structural integrity to form functional tissue within a short period. To date, smart biomaterials are designed to interact with biological systems for a wide range of biomedical applications, from the delivery of bioactive molecules and cell adhesion mediators to cellular functioning for the engineering of functional tissues to treat diseases. PMID- 29267208 TI - Pituitary Gonadotropins, Prolactin and Growth Hormone Differentially Regulate AQP1 Expression in the Porcine Ovarian Follicular Cells. AB - The present in vitro study analyzed whether the hormones that affect the ovarian follicular steroidogenesis process also participate in the regulation of AQP1 mRNA and protein expression. Granulosa (Gc) and theca cells (Tc) of medium and large porcine ovarian follicles were exposed to follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and growth hormone (GH) for 24 h in separated cells and co-cultures of these cells. Real-time PCR, Western blotting, immunofluorescence and volumetric analysis were then performed. Gonadotropins, PRL and GH had a stimulatory impact on AQP1 mRNA and protein expression in Gc and Tc of medium and large ovarian cells. Moreover, swelling assays, in response to a hypotonic environment, demonstrated the functional presence of AQPs in porcine Gc and Tc. Immunofluorescence analysis showed that AQP1 protein was mainly localized in the perinuclear region of the cytoplasm, endosomes and cell membranes of Gc and Tc from medium and large follicles. It seems possible that AQP1 present in Gc and Tc cells may be implicated not only in the regulation of water homeostasis required for follicle development but also in cell proliferation and migration. PMID- 29267209 TI - Variability of MMP/TIMP and TGF-beta1 Receptors throughout the Clinical Progression of Chronic Venous Disease. AB - Chronic venous disease (CVeD) is a prevalent condition with a significant socioeconomic burden, yet the pathophysiology is only just beginning to be understood. Previous studies concerning the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs)) within the varicose vein wall are inconsistent and disregard clinical progression. Moreover, it is highly plausible that MMP and TIMP expression/activity is affected by transforming growth factor (TGF)-beta1 and its signaling receptors (TGFbetaRs) expression/activity in the vein wall. A case-control study was undertaken to analyze genetic and immunohistochemical differences between healthy (n = 13) and CVeD (early stages: n = 19; advanced stages: n = 12) great saphenous vein samples. Samples were grouped based on anatomic harvest site and subjected to quantitative polymerase chain reaction for MMP1, MMP2, MMP8, MMP9, MMP12, MMP13, TIMP1, TIMP2, TIMP3, TIMP4, TGFbetaR1, TGFbetaR2, and TGFbetaR3 gene expression analysis, and then to immunohistochemistry for immunolocalization of MMP2, TIMP2, and TGFbetaR2. Decreased gene expression of MMP12, TIMP2, TIMP3, TIMP4, and TGFbetaR2 was found in varicose veins when compared to controls. Regarding CVeD clinical progression, two facts arose: results across anatomical regions were uneven; decreased gene expression of MMP9 and TGFbetaR3 and increased gene expression of MMP2 and TIMP3 were found in advanced clinical stages. Most immunohistochemistry results for tunica intima were coherent with qPCR results. In conclusion, decreased expression of TGFbetaRs might suggest a reduction in TGF-beta1 participation in the MMP/TIMP imbalance throughout CVeD progression. Further studies about molecular events in the varicose vein wall are required and should take into consideration the venous anatomical region and CVeD clinical progression. PMID- 29267210 TI - Structural Differences between the Lignin-Carbohydrate Complexes (LCCs) from 2- and 24-Month-Old Bamboo (Neosinocalamus affinis). AB - The lignin-carbohydrate complex (LCC) was isolated from milled wood lignin of 2- and 24-month-old crude bamboo (Neosinocalamus affinis) culms using acetic acid (AcOH) and then characterized. The results have shown that the LCC preparation from 2-month-old bamboo (L2) exhibited a slightly lower molecular weight than the LCC preparation from the 24-month-old bamboo (L24). Further studies using Fourier transform infrared spectroscopy (FT-IR) and heteronuclear single quantum coherence (2D-HSQC) NMR spectra analyses indicate that the LCC preparations included glucuronoarabinoxylan and G-S-H lignin-type with G>S>>H. The content of the S lignin units of LCC in the mature bamboo was always higher than in the young bamboo. Combined with sugar composition analysis, the contents of phenyl glycoside and ether linkages in the L24 preparation were higher than in the L2 preparation; however, there was a reverse relationship of ester LCC bonds in L2 and L24. Lignin-xylan was the main type of LCC linkage in bamboo LCCs. Lignin lignin linkages in the LCC preparations included beta-beta, beta-5 and beta-1 carbon-to-carbon, as well as beta-O-4 ether linkages, but beta-1 linkages were not present in L2. PMID- 29267212 TI - The Screening of Anticholinergic Accumulation by Traditional Chinese Medicine. AB - Many Western drugs can give rise to serious side effects due to their ability to bind to acetylcholine receptors in the brain. This aggravates when they are combined, which is known as anticholinergic accumulation (AA). Some bioactives in Traditional Chinese Medicine (TCM) are known to block acetylcholine receptors and thus potentially cause AA. The AA of TCM was screened by quantifying the displacement of [3H] pirenzepine on acetylcholine receptors in a rat brain homogenate. We used a new unit to express AA, namely the Total Atropine Equivalents (TOAT). The TOAT of various herbs used in TCM was very diverse and even negative for some herbs. This is indicative for the broadness of the pallet of ingredients used in TCM. Three TCM formulas were screened for AA: Ma Huang Decotion (MHD), Antiasthma Simplified Herbal Medicine intervention (ASHMI), and Yu Ping Feng San (YPFS). The TOAT of ASHMI was indicative for an additive effect of herbs used in it. Nevertheless, it can be calculated that one dose of ASHMI is probably too low to cause AA. The TOAT of YPFS was practically zero. This points to a protective interaction of AA. Remarkably, MHD gave a negative TOAT, indicating that the binding to the acetylcholine receptors was increased, which also circumvents AA. In conclusion, our results indicate that TCM is not prone to give AA and support that there is an intricate interaction between the various bioactives in TCM to cure diseases with minimal side effects. PMID- 29267211 TI - Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? AB - Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed. PMID- 29267213 TI - Praeruptorin A Inhibits Human Cervical Cancer Cell Growth and Invasion by Suppressing MMP-2 Expression and ERK1/2 Signaling. AB - Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of HeLa and SiHa cells, induced cell cycle arrest at G0/G1 phase, upregulated Rb, p16, p21 and p27 proteins and downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins. PA also significantly reduced expression of matrix metalloproteinase-2 (MMP-2) and increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). In addition, PA suppressed ERK1/2 activation and increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregulation of TIMP-2. PA treatment inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation, MMP-2 expression, cellular migration, and invasion of HeLa cells. Our findings are the first to demonstrate the activity of PA against cervical cancer cells, and suggest this agent has promise as a therapeutic agent in treatment of human cervical cancer. PMID- 29267215 TI - Impact of Glycerol as Carbon Source onto Specific Sugar and Inducer Uptake Rates and Inclusion Body Productivity in E. coli BL21(DE3). AB - The Gram-negative bacterium E. coli is the host of choice for a multitude of used recombinant proteins. Generally, cultivation is easy, media are cheap, and a high product titer can be obtained. However, harsh induction procedures using isopropyl beta-d-1 thiogalactopyranoside as inducer are often referred to cause stress reactions, leading to a phenomenon known as "metabolic" or "product burden". These high expressions of recombinant proteins mainly result in decreased growth rates and cell lysis at elevated induction times. Therefore, approaches tend to use "soft" or "tunable" induction with lactose and reduce the stress level of the production host. The usage of glucose as energy source in combination with lactose as induction reagent causes catabolite repression effects on lactose uptake kinetics and as a consequence reduced product titer. Glycerol-as an alternative carbon source-is already known to have positive impact on product formation when coupled with glucose and lactose in auto-induction systems, and has been referred to show no signs of repression when cultivated with lactose concomitantly. In recent research activities, the impact of different products on the lactose uptake using glucose as carbon source was highlighted, and a mechanistic model for glucose-lactose induction systems showed correlations between specific substrate uptake rate for glucose or glycerol (qs,C) and the maximum specific lactose uptake rate (qs,lac,max). In this study, we investigated the mechanistic of glycerol uptake when using the inducer lactose. We were able to show that a product-producing strain has significantly higher inducer uptake rates when being compared to a non-producer strain. Additionally, it was shown that glycerol has beneficial effects on viability of cells and on productivity of the recombinant protein compared to glucose. PMID- 29267214 TI - Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight. AB - Monoterpenes belong to the terpenoids class of natural products and are bio synthesized through the mevalonic acid pathway. Their small molecular weight coupled with high non-polar nature make them the most abundant components of essential oils which are often considered to have some general antioxidant and antimicrobial effects at fairly high concentrations. These compounds are however reported to have antidiabetic effects in recent years. Thanks to the ingenious biosynthetic machinery of nature, they also display a fair degree of structural complexity/diversity for further consideration in structure-activity studies. In the present communication, the merit of monoterpenes as antidiabetic agents is scrutinized by assessing recent in vitro and in vivo studies reported in the scientific literature. Both the aglycones and glycosides of these compounds of rather small structural size appear to display antidiabetic along with antiobesity and lipid lowering effects. The diversity of these effects vis-a-vis their structures and mechanisms of actions are discussed. Some key pharmacological targets include the insulin signaling pathways and/or the associated PI3K-AKT (protein kinase B), peroxisome proliferator activated receptor-gamma (PPARgamma), glucose transporter-4 (GLUT4) and adenosine monophosphate-activated protein kinase (AMPK) pathways; proinflammatory cytokines and the NF-kappaB pathway; glycogenolysis and gluconeogenesis in the liver; glucagon-like-1 receptor (GLP-1R); among others. PMID- 29267217 TI - Chronic Monosodium Glutamate Administration Induced Hyperalgesia in Mice. AB - Monosodium glutamate (MSG) is a widely used food additive. Although it is generally considered safe, some questions regarding the impact of its use on general health have arisen. Several reports correlate MSG consumption with a series of unwanted reactions, including headaches and mechanical sensitivity in pericranial muscles. Endogenous glutamate plays a significant role in nociceptive processing, this neurotransmitter being associated with hyperalgesia and central sensitization. One of the mechanisms underlying these phenomena is the stimulation of Ca2+/calmodulin sensitive nitric oxide synthase, and a subsequent increase in nitric oxide production. This molecule is a key player in nociceptive processing, with implications in acute and chronic pain states. Our purpose was to investigate the effect of this food additive on the nociceptive threshold when given orally to mice. Hot-plate and formalin tests were used to assess nociceptive behaviour. We also tried to determine if a correlation between chronic administration of MSG and variations in central nitric oxide (NO) concentration could be established. We found that a dose of 300 mg/kg MSG given for 21 days reduces the pain threshold and is associated with a significant increase in brain NO level. The implications of these findings on food additive drug interaction, and on pain perception in healthy humans, as well as in those suffering from affections involving chronic pain, are still to be investigated. PMID- 29267216 TI - Epigallocatechin-3-Gallate Suppresses Human Herpesvirus 8 Replication and Induces ROS Leading to Apoptosis and Autophagy in Primary Effusion Lymphoma Cells. AB - Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to induce cell death in cancer cells. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by human herpesvirus 8 (HHV8). In this study, we examined the role of EGCG on PEL cells in cell death and HHV8 replication. We performed trypan blue exclusion assay to assess the cell viability of PEL cells, flow cytometry analysis to examine the cell cycle distribution and reactive oxygen species (ROS) generation, caspase-3 activity to assay apoptosis, acridine orange staining to determine autophagy, and immunoblotting to detect the protein levels involved in apoptosis and autophagy as well as mitogen activated protein kinases (MAPKs) activation upon EGCG treatment. The expression of the HHV8 lytic gene was determined by luciferase reporter assay and reverse transcription-PCR, and viral progeny production was determined by PCR. Results revealed that EGCG induced cell death and ROS generation in PEL cells in a dose-dependent manner. N acetylcysteine (NAC) inhibited the EGCG-induced ROS and rescued the cell from EGCG-induced cell death. Even though EGCG induced ROS generation in PEL cells, it reduced the production of progeny virus from PEL cells without causing HHV8 reactivation. These results suggest that EGCG may represent a novel strategy for the treatment of HHV8 infection and HHV8-associated lymphomas. PMID- 29267218 TI - Age-Related Differences of Maximum Phonation Time in Patients after Cardiac Surgery. AB - Background and aims: Maximum phonation time (MPT), which is related to respiratory function, is widely used to evaluate maximum vocal capabilities, because its use is non-invasive, quick, and inexpensive. We aimed to examine differences in MPT by age, following recovery phase II cardiac rehabilitation (CR). Methods: This longitudinal observational study assessed 50 consecutive cardiac patients who were divided into the middle-aged group (<65 years, n = 29) and older-aged group (>=65 years, n = 21). MPTs were measured at 1 and 3 months after cardiac surgery, and were compared. Results: The duration of MPT increased more significantly from month 1 to month 3 in the middle-aged group (19.2 +/- 7.8 to 27.1 +/- 11.6 s, p < 0.001) than in the older-aged group (12.6 +/- 3.5 to 17.9 +/- 6.0 s, p < 0.001). However, no statistically significant difference occurred in the % change of MPT from 1 month to 3 months after cardiac surgery between the middle-aged group and older-aged group, respectively (41.1% vs. 42.1%). In addition, there were no significant interactions of MPT in the two groups for 1 versus 3 months (F = 1.65, p = 0.20). Conclusion: Following phase II, CR improved MPT for all cardiac surgery patients. PMID- 29267219 TI - Assessing the Health of LiFePO4 Traction Batteries through Monotonic Echo State Networks. AB - A soft sensor is presented that approximates certain health parameters of automotive rechargeable batteries from on-vehicle measurements of current and voltage. The sensor is based on a model of the open circuit voltage curve. This last model is implemented through monotonic neural networks and estimate over potentials arising from the evolution in time of the Lithium concentration in the electrodes of the battery. The proposed soft sensor is able to exploit the information contained in operational records of the vehicle better than the alternatives, this being particularly true when the charge or discharge currents are between moderate and high. The accuracy of the neural model has been compared to different alternatives, including data-driven statistical models, first principle-based models, fuzzy observers and other recurrent neural networks with different topologies. It is concluded that monotonic echo state networks can outperform well established first-principle models. The algorithms have been validated with automotive Li-FePO4 cells. PMID- 29267220 TI - Galangin Reduces the Loss of Dopaminergic Neurons in an LPS-Evoked Model of Parkinson's Disease in Rats. AB - Parkinson's disease (PD) is caused by the loss of dopaminergic (DA) neurons in the midbrain substantia nigra (SN). Neuroinflammation, which is marked by microglial activation, plays a very important role in the pathogenesis of PD. Pro inflammatory mediators produced by activated microglia could damage DA neurons. Hence, the inhibition of microglial activation may provide a new approach for treating PD. Galangin has been shown to inhibit inflammation in a variety of diseases, but not PD. In this study, we aimed to investigate the anti inflammatory effect of galangin and the underlying mechanisms in Lipopolysaccharide (LPS) induced PD models. We first examined the protective effect of galangin in the LPS-induced PD rat model. Specifically, we investigated the effects on motor dysfunction, microglial activation, and the loss of DA neurons. Then, galangin was used to detect the impact on the inflammatory responses and inflammatory signaling pathways in LPS-induced BV-2 cells. The in vivo results showed that galangin dose-dependently attenuates the activation of microglia, the loss of DA neurons, and motor dysfunction. In vitro, galangin markedly inhibited LPS-induced expression of tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta), cyclooxygenase 2 (COX-2), and induced nitric oxide synthase (iNOS) via associating with the phosphorylation of c-JUN N-terminal Kinase (JNK), p38, protein kinase B (AKT), and nuclear factor kappaB (NF-kappaB) p65. Collectively, the results indicated that galangin has a role in protecting DA neurons by inhibiting microglial activation. PMID- 29267221 TI - Effect of Age on Blood Glucose and Plasma Insulin, Glucagon, Ghrelin, CCK, GIP, and GLP-1 Responses to Whey Protein Ingestion. AB - Protein-rich supplements are used widely to prevent and manage undernutrition in older people. We have previously shown that healthy older, compared to younger, adults have less suppression of energy intake by whey protein-although the effects of age on appetite-related gut hormones are largely unknown. The aim of this study was to determine and compare the acute effects of whey protein loads on blood glucose and plasma gut hormone concentrations in older and younger adults. Sixteen healthy older (eight men, eight women; mean +/- SEM: age: 72 +/- 1 years; body mass index: 25 +/- 1 kg/m2) and 16 younger (eight men, eight women; 24 +/- 1 years; 23 +/- 0.4 kg/m2) adults were studied on three occasions in which they ingested 30 g (120 kcal) or 70 g (280 kcal) whey protein, or a flavored water control drink (~2 kcal). At regular intervals over 180 min, blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were measured. Plasma ghrelin was dose-dependently suppressed and insulin, glucagon, CCK, GIP, and GLP-1 concentrations were dose-dependently increased by the whey protein ingestion, while blood glucose concentrations were comparable during all study days. The stimulation of plasma CCK and GIP concentrations was greater in older than younger adults. In conclusion, orally ingested whey protein resulted in load dependent gut hormone responses, which were greater for plasma CCK and GIP in older compared to younger adults. PMID- 29267222 TI - Tectus niloticus (Tegulidae, Gastropod) as a Novel Vector of Ciguatera Poisoning: Detection of Pacific Ciguatoxins in Toxic Samples from Nuku Hiva Island (French Polynesia). AB - Ciguatera fish poisoning (CFP) is a foodborne disease caused by the consumption of seafood (fish and marine invertebrates) contaminated with ciguatoxins (CTXs) produced by dinoflagellates in the genus Gambierdiscus. The report of a CFP-like mass-poisoning outbreak following the consumption of Tectus niloticus (Tegulidae, Gastropod) from Anaho Bay on Nuku Hiva Island (Marquesas archipelago, French Polynesia) prompted field investigations to assess the presence of CTXs in T. niloticus. Samples were collected from Anaho Bay, 1, 6 and 28 months after this poisoning outbreak, as well as in Taiohae and Taipivai bays. Toxicity analysis using the neuroblastoma cell-based assay (CBA-N2a) detected the presence of CTXs only in Anaho Bay T. niloticus samples. This is consistent with qPCR results on window screen samples indicating the presence of Gambierdiscus communities dominated by the species G. polynesiensis in Anaho Bay. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses revealed that P-CTX-3B was the major congener, followed by P-CTX-3C, P-CTX-4A and P-CTX-4B in toxic samples. Between July 2014 and November 2016, toxin content in T. niloticus progressively decreased, but was consistently above the safety limit recommended for human consumption. This study confirms for the first time T. niloticus as a novel vector of CFP in French Polynesia. PMID- 29267223 TI - Vitamin E (alpha- and gamma-Tocopherol) Levels in the Community: Distribution, Clinical and Biochemical Correlates, and Association with Dietary Patterns. AB - Little is known about the distribution and determinants of circulating vitamin E levels in a German population. In this cross-sectional study we assessed the distribution of both alpha- and gamma-tocopherol levels, identified their clinical and biochemical correlates, and assessed their relationships with a priori and a posteriori derived dietary patterns. Plasma alpha- and gamma tocopherol concentrations were measured using high performance liquid chromatography (HPLC) with fluorescence detection in 641 individuals (mean-age: 61 years; 40.6% women). Correlates of both markers were determined using linear regression with backward selection. Using a validated food-frequency questionnaire (FFQ), an a priori defined vitamin E-rich dietary pattern was constructed, and three a posteriori derived dietary patterns were identified by principal component analysis. Each pattern was related to alpha- and gamma tocopherol levels using linear regression. Median concentrations of alpha- and gamma-tocopherol were 31.54 MUmol/L and 1.35 umol/L, respectively. 57.6% of participants had alpha-tocopherol levels >30 umol/L. Triglycerides, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol, and vitamin E supplementation were identified as correlates of vitamin E levels. After excluding supplement users, a dietary pattern rich in meat, bread, fats, potatoes, and sugar/confectionery was inversely related to alpha-tocopherol levels (beta, -0.032, SE = 0.016; p = 0.047). Prospective studies are warranted to evaluate the actual impact of the reported findings in terms of nutrition and health outcomes. PMID- 29267224 TI - Care Model Design for E-Health: Integration of Point-of-Care Testing at Dutch General Practices. AB - Point-of-care testing (POCT)-laboratory tests performed with new mobile devices and online technologies outside of the central laboratory-is rapidly outpacing the traditional laboratory test market, growing at a rate of 12 to 15% each year. POCT impacts the diagnostic process of care providers by yielding high efficiency benefits in terms of turnaround time and related quality improvements in the reduction of errors. However, the implementation of this disruptive eHealth technology requires the integration and transformation of diagnostic services across the boundaries of healthcare organizations. Research has revealed both advantages and barriers of POCT implementations, yet to date, there is no business model for the integration of POCT within general practice. The aim of this article is to contribute with a design for a care model that enables the integration of POCT in primary healthcare. In this research, we used a design modelling toolkit for data collection at five general practices. Through an iterative design process, we modelled the actors and value transactions, and designed an optimized care model for the dynamic integration of POCTs into the GP's network of care delivery. The care model design will have a direct bearing on improving the integration of POCT through the connectivity and norm guidelines between the general practice, the POC technology, and the diagnostic centre. PMID- 29267226 TI - Sperm Quality during Storage Is Not Affected by the Presence of Antibiotics in EquiPlus Semen Extender but Is Improved by Single Layer Centrifugation. AB - Contamination of semen with bacteria arises during semen collection and handling. This bacterial contamination is typically controlled by adding antibiotics to semen extenders but intensive usage of antibiotics can lead to the development of bacterial resistance and may be detrimental to sperm quality. The objective of this study was to determine the effects of antibiotics in a semen extender on sperm quality and to investigate the effects of removal of bacteria by modified Single Layer Centrifugation (MSLC) through a colloid. Semen was collected from six adult pony stallions (three ejaculates per male). Aliquots of extended semen were used for MSLC with Equicoll, resulting in four treatment groups: control and MSLC in extender with antibiotics (CA and SA, respectively); control and MSLC in extender without antibiotics (CW and SW, respectively). Sperm motility, membrane integrity, mitochondrial membrane potential and chromatin integrity were evaluated daily by computer-assisted sperm analysis (CASA) and flow cytometry. There were no differences in sperm quality between CA and CW, or between SA and SW, although progressive motility was negatively correlated to total bacterial counts at 0 h. However, MSLC groups showed higher mean total motility (P < 0.001), progressive motility (P < 0.05), membrane integrity (P < 0.0001) and mitochondrial membrane potential (P < 0.05), as well as better chromatin integrity (P < 0.05), than controls. Sperm quality remained higher in the MSLC groups than controls throughout storage. These results indicate that sperm quality was not adversely affected by the presence of antibiotics but was improved considerably by MSLC. PMID- 29267227 TI - Stimulation and Neuromodulation in the Treatment of Epilepsy. AB - Invasive brain stimulation technologies are allowing the improvement of multiple neurological diseases that were non-manageable in the past. Nowadays, this technology is widely used for movement disorders and is undergoing multiple clinical and basic science research for development of new applications. Epilepsy is one of the conditions that can benefit from these emerging technologies. The objective of this manuscript is to review literature about historical background, current principles and outcomes of available modalities of neuromodulation and deep brain stimulation in epilepsy patients. PMID- 29267228 TI - Energetic Di- and Trinitromethylpyridines: Synthesis and Characterization. AB - Pyridine derivatives based on the addition of trinitromethyl functional groups were synthesized by the reaction of N2O4 with the corresponding pyridinecarboxaldoximes, then they were converted into dinitromethylide hydrazinium salts. These energetic compounds were fully characterized by IR and NMR spectroscopy, elemental analysis, differential scanning calorimetry (DSC), and X-ray crystallography. These pyridine derivatives have good densities, positive enthalpies of formation, and acceptable sensitivity values. Theoretical calculations carried out using Gaussian 03 and EXPLO5 programs demonstrated good to excellent detonation velocities and pressures. Each of these compounds is superior in performance to TNT, while 2,6-bis(trinitromethyl)pyridine (D = 8700 m.s-1, P = 33.2 GPa) shows comparable detonation performance to that of RDX, but its thermal stability is too low, making it inferior to RDX. PMID- 29267225 TI - HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment. AB - Going back to their discovery in the early 1980s, both the Human T-cell Leukemia virus type-1 (HTLV-1) and the Human Immunodeficiency Virus type-1 (HIV-1) greatly fascinated the virology scene, not only because they were the first human retroviruses discovered, but also because they were associated with fatal diseases in the human population. In almost four decades of scientific research, both viruses have had different fates, HTLV-1 being often upstaged by HIV-1. However, although being very close in terms of genome organization, cellular tropism, and viral replication, HIV-1 and HTLV-1 are not completely commutable in terms of treatment, especially because of the opposite fate of the cells they infect: death versus immortalization, respectively. Nowadays, the antiretroviral therapies developed to treat HIV-1 infected individuals and to limit HIV-1 spread among the human population have a poor or no effect on HTLV-1 infected individuals, and thus, do not prevent the development of HTLV-1-associated diseases, which still lack highly efficient treatments. The present review mainly focuses on the course of HTLV-1 infection, from the initial infection of the host to diseases development and associated treatments, but also investigates HIV 1/HTLV-1 co-infection events and their impact on diseases development. PMID- 29267229 TI - Synthesis of Non-Racemic Pyrazolines and Pyrazolidines by [3+2] Cycloadditions of Azomethine Imines. AB - Asymmetric [3+2] cycloadditions of azomethine imines comprise a useful synthetic tool for the construction of pyrazole derivatives with a variable degree of saturation and up to three stereogenic centers. As analogues of pyrrolidines and imidazolidines that are abundant among natural products, pyrazoline and pyrazolidine derivatives represent attractive synthetic targets due to their extensive applications in the chemical and medicinal industries. Following the increased understanding of the mechanistic aspect of metal-catalyzed and organocatalyzed [3+2] cycloadditions of 1,3-dipoles gained over recent years, significant strides have been taken to design and develop new protocols that proceed efficiently under mild synthetic conditions and duly benefit from superior functional group tolerance and selectivity. In this review, we represent the current state of the art in this field and detailed methods for the synthesis of non-racemic pyrazolines and pyrazolidines via [3+2] metal and organocatalyzed transformations reported since the seminal work of Kobayashi et al. and Fu et al. in 2002 and 2003 up to the end of year 2017. PMID- 29267230 TI - An Implantable Wireless Neural Interface System for Simultaneous Recording and Stimulation of Peripheral Nerve with a Single Cuff Electrode. AB - Recently, implantable devices have become widely used in neural prostheses because they eliminate endemic drawbacks of conventional percutaneous neural interface systems. However, there are still several issues to be considered: low efficiency wireless power transmission; wireless data communication over restricted operating distance with high power consumption; and limited functionality, working either as a neural signal recorder or as a stimulator. To overcome these issues, we suggest a novel implantable wireless neural interface system for simultaneous neural signal recording and stimulation using a single cuff electrode. By using widely available commercial off-the-shelf (COTS) components, an easily reconfigurable implantable wireless neural interface system was implemented into one compact module. The implantable device includes a wireless power consortium (WPC)-compliant power transmission circuit, a medical implant communication service (MICS)-band-based radio link and a cuff-electrode path controller for simultaneous neural signal recording and stimulation. During in vivo experiments with rabbit models, the implantable device successfully recorded and stimulated the tibial and peroneal nerves while communicating with the external device. The proposed system can be modified for various implantable medical devices, especially such as closed-loop control based implantable neural prostheses requiring neural signal recording and stimulation at the same time. PMID- 29267231 TI - Antinociceptive and Antibacterial Properties of Anthocyanins and Flavonols from Fruits of Black and Non-Black Mulberries. AB - Anthocyanins and flavones are important pigments responsible for the coloration of fruits. Mulberry fruit is rich in anthocyanins and flavonols, which have multiple uses in traditional Chinese medicine. The antinociceptive and antibacterial activities of total flavonoids (TF) from black mulberry (MnTF, TF of Morus nigra) and non-black mulberry (MmTF, TF of Morus mongolica; and MazTF, TF of Morus alba 'Zhenzhubai') fruits were studied. MnTF was rich in anthocyanins (11.3 mg/g) and flavonols (0.7 mg/g) identified by ultra-performance liquid chromatography-tunable ultraviolet/mass single-quadrupole detection (UPLC TUV/QDa). Comparatively, MmTF and MazTF had low flavonol contents and MazTF had no anthocyanins. MnTF showed significantly higher antinociceptive and antibacterial activities toward Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus than MmTF and MazTF. MnTF inhibited the expression of interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), phospho-p65 (p-p65) and phospho-IkappaBalpha (p-IkappaBalpha), and increased interleukin 10 (IL-10). Additionally, mice tests showed that cyanidin-3-O-glucoside (C3G), rutin (Ru) and isoquercetin (IQ) were the main active ingredients in the antinociceptive process. Stronger antinociceptive effect of MnTF was correlated with its high content of anthocyanins and flavonols and its inhibitory effects on proinflammatory cytokines, iNOS and nuclear factor-kappaB (NF-kappaB) pathway related proteins. PMID- 29267232 TI - Measuring Liquid-Level Utilizing Wedge Wave. AB - A new technique for measuring liquid-level utilizing wedge wave is presented and demonstrated through FEM simulation and a corresponding experiment. The velocities of wedge waves in the air and the water, and the sensitivities for the measurement, are compared with the simulation and the results obtained in the experiments. Combining the simulation and the measurement theory, it is verified that the foundation framework for the methods is available. The liquid-level sensing is carried out using the aluminum waveguide with a 30 degrees wedge in the water. The liquid-level is proportional to the traveling time of the mode 1 wedge wave. The standard deviations and the uncertainties of the measurement are 0.65 mm and 0.21 mm using interface echo, and 0.39 mm and 0.12 mm utilized by end echo, which are smaller than the industry standard of 1.5 mm. The measurement resolutions are 7.68 MUm using the interface echo, which is the smallest among all the guided acoustic wave-based liquid-level sensing. PMID- 29267234 TI - Implementation of Wi-Fi Signal Sampling on an Android Smartphone for Indoor Positioning Systems. AB - Collecting and maintaining radio fingerprint for wireless indoor positioning systems involves considerable time and labor. We have proposed the quick radio fingerprint collection (QRFC) algorithm which employed the built-in accelerometer of Android smartphones to implement step detection in order to assist in collecting radio fingerprints. In the present study, we divided the algorithm into moving sampling (MS) and stepped MS (SMS), and describe the implementation of both algorithms and their comparison. Technical details and common errors concerning the use of Android smartphones to collect Wi-Fi radio beacons were surveyed and discussed. The results of signal sampling experiments performed in a hallway measuring 54 m in length showed that in terms of the amount of time required to complete collection of access point (AP) signals, static sampling (SS; a traditional procedure for collecting Wi-Fi signals) took at least 2 h, whereas MS and SMS took approximately 150 and 300 s, respectively. Notably, AP signals obtained through MS and SMS were comparable to those obtained through SS in terms of the distribution of received signal strength indicator (RSSI) and positioning accuracy. Therefore, MS and SMS are recommended instead of SS as signal sampling procedures for indoor positioning algorithms. PMID- 29267233 TI - Carbapenem Resistance: A Review. AB - Carbapenem resistance is a major and an on-going public health problem globally. It occurs mainly among Gram-negative pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, and may be intrinsic or mediated by transferable carbapenemase-encoding genes. This type of resistance genes are already widespread in certain parts of the world, particularly Europe, Asia and South America, while the situation in other places such as sub-Saharan Africa is not well documented. In this paper, we provide an in-depth review of carbapenem resistance providing up-to-date information on the subject. PMID- 29267235 TI - Relationship between Telomere Length, Genetic Traits and Environmental/Occupational Exposures in Bladder Cancer Risk by Structural Equation Modelling. AB - : Background: Telomere length (TL) maintenance plays an important role in bladder cancer (BC) and prognosis. However the manifold influence of everyday life exposures and genetic traits on leucocyte TL (LTL), is not fully elucidated. Methods: Within the framework of a hospital-based case (n = 96)/control (n = 94) study (all Caucasian males), we investigated the extent to which LTL and BC risk were modulated by genetic polymorphisms and environmental and occupational exposures. Data on lifetime smoking, alcohol and coffee drinking, dietary habits and occupational exposures, pointing to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) were collected. Structural equation modelling (SEM) analysis appraised this complex relationships. Results: The SEM analysis indicates negative direct links (p < 0.05) between LTL with age, DNA adducts, alcohol and NAT2, and positive ones with coffee, MPO and XRCC3; and between BC risk (p < 0.01) with cigarettes, cumulative exposure to AAs and coffee, while are negative with LTL and age. There was evidence of indirect effects (p < 0.05) on BC risk, probably via LTL reduction, by age and NAT2 (positive link), MPO and XRCC3 (negative link). CONCLUSIONS: Our study supports evidence that LTL attrition is a critical event in BC. The new finding that LTL erosion depends on some preventable everyday life exposures genetically modulated, opens new perspectives in BC prevention. PMID- 29267238 TI - Upgrading the Performance of Cholesteric Liquid Crystal Lasers: Improvement Margins and Limitations. AB - The topic of cholesteric-liquid-crystal lasers is a rapidly expanding research area in the field of soft-matter photonics. The increasing interest in this field is due to the high versatility that these lasers may possibly present and the prospects of giving rise to new miniaturized devices. However, further improvements in their operation capabilities are still required for potential applications. In this paper, we critically analyze the main strategies proposed up to now to optimize their performance. We show theoretically and experimentally that possible innovations in the device structure cannot produce lasers with threshold energies below a certain limit. This limit is determined by the light scattering and absorption losses inside the liquid crystal. Even assuming the case of samples free of defects and perfectly non-absorbing, an intrinsic light scattering, typical of mesogens, still remains. Numerical estimates of the thresholds indicate that these lasers could hardly be driven by compact light sources such as current electroluminescent or light-emitting diodes. Since the improvement possibilities regarding cell architecture seem to be exhausted, the advance must come from the use of new dye molecules. These molecules should show enhanced emission cross-sections and be efficiently integrable within the mesogenic solvent. In addition, the fluorescent systems must present very small quantum yields to triplet states if continuous-wave lasing is sought. In this respect, quantum dots are an alternative to explore for further investigations. PMID- 29267237 TI - Recyclable Keggin Heteropolyacids as an Environmentally Benign Catalyst for the Synthesis of New 2-Benzoylamino-N-phenyl-benzamide Derivatives under Microwave Irradiations at Solvent-Free Conditions and the Evaluation of Biological Activity. AB - 2-Benzoylamino-N-phenyl-benzamide derivatives (5a-h) were prepared from 2-phenyl 3,1-(4H)-benzoxazin-4-one 3 and substituted anilines 4a-h in the presence of a Keggin-type heteropolyacids series (H3PW12O40.13H2O; H4SiW12O40.13H2O; H4SiMo12O40.13H2O; and H3PMo12O40.13H2O) as catalysts without solvent and under microwave irradiation. We found that the use of H3PW12O40.13H2O acid coupled to microwave irradiation allowed obtaining a high-yielding reaction with a short time. The compound structures were established by 1H-NMR and 13C-NMR. The antibacterial and antifungal activities of the synthesized compounds exhibited an inhibition of the growth of bacteria and fungi. PMID- 29267236 TI - Biological Implications of Differential Expression of Mitochondrial-Shaping Proteins in Parkinson's Disease. AB - It has long been accepted that mitochondrial function and morphology is affected in Parkinson's disease, and that mitochondrial function can be directly related to its morphology. So far, mitochondrial morphological alterations studies, in the context of this neurodegenerative disease, have been performed through microscopic methodologies. The goal of the present work is to address if the modifications in the mitochondrial-shaping proteins occurring in this disorder have implications in other cellular pathways, which might constitute important pathways for the disease progression. To do so, we conducted a novel approach through a thorough exploration of the available proteomics-based studies in the context of Parkinson's disease. The analysis provided insight into the altered biological pathways affected by changes in the expression of mitochondrial shaping proteins via different bioinformatic tools. Unexpectedly, we observed that the mitochondrial-shaping proteins altered in the context of Parkinson's disease are, in the vast majority, related to the organization of the mitochondrial cristae. Conversely, in the studies that have resorted to microscopy-based techniques, the most widely reported alteration in the context of this disorder is mitochondria fragmentation. Cristae membrane organization is pivotal for mitochondrial ATP production, and changes in their morphology have a direct impact on the organization and function of the oxidative phosphorylation (OXPHOS) complexes. To understand which biological processes are affected by the alteration of these proteins we analyzed the binding partners of the mitochondrial-shaping proteins that were found altered in Parkinson's disease. We showed that the binding partners fall into seven different cellular components, which include mitochondria, proteasome, and endoplasmic reticulum (ER), amongst others. It is noteworthy that, by evaluating the biological process in which these modified proteins are involved, we showed that they are related to the production and metabolism of ATP, immune response, cytoskeleton alteration, and oxidative stress, amongst others. In summary, with our bioinformatics approach using the data on the modified proteins in Parkinson's disease patients, we were able to relate the alteration of mitochondrial-shaping proteins to modifications of crucial cellular pathways affected in this disease. PMID- 29267239 TI - Osteointegration of Porous Poly-epsilon-Caprolactone-Coated and Previtalised Magnesium Implants in Critically Sized Calvarial Bone Defects in the Mouse Model. AB - Metallic biomaterials are widely used in maxillofacial surgery. While titanium is presumed to be the gold standard, magnesium-based implants are a current topic of interest and investigation due to their biocompatible, osteoconductive and degradable properties. This study investigates the effects of poly-epsilon caprolactone-coated and previtalised magnesium implants on osteointegration within murine calvarial bone defects: After setting a 3 mm * 3 mm defect into the calvaria of 40 BALB/c mice the animals were treated with poly-epsilon caprolactone-coated porous magnesium implants (without previtalisation or previtalised with either osteoblasts or adipose derived mesenchymal stem cells), porous Ti6Al4V implants or without any implant. To evaluate bone formation and implant degradation, micro-computertomographic scans were performed at day 0, 28, 56 and 84 after surgery. Additionally, histological thin sections were prepared and evaluated histomorphometrically. The outcomes revealed no significant differences within the differently treated groups regarding bone formation and the amount of osteoid. While the implant degradation resulted in implant shifting, both implant geometry and previtalisation appeared to have positive effects on vascularisation. Although adjustments in degradation behaviour and implant fixation are indicated, this study still considers magnesium as a promising alternative to titanium-based implants in maxillofacial surgery in future. PMID- 29267241 TI - Analytical Expressions for Numerical Characterization of Semiconductors per Comparison with Luminescence. AB - Luminescence is one of the most important characterisation tools of semiconductor materials and devices. Recently, a very efficient analytical set of equations has been applied to explain optical properties of dilute semiconductor materials, with an emphasis on the evolution of peak luminescence gain with temperature and its relation to sample quality. This paper summarizes important steps of the derivation of these expressions that have not been presented before and delivers a theoretical framework that can used to apply exactly solvable Hamiltonians for realistic studies of luminescence in various systems. PMID- 29267240 TI - Persistent Threats by Persistent Pollutants: Chemical Nature, Concerns and Future Policy Regarding PCBs-What Are We Heading For? AB - Polychlorinated biphenyl (PCB)-contaminated sites around the world affect human health for many years, showing long latency periods of health effects. The impact of the different PCB congeners on human health should not be underestimated, as they are ubiquitous, stable molecules and reactive in biological tissues, leading to neurological, endocrine, genetic, and systemic adverse effects in the human body. Moreover, bioaccumulation of these compounds in fatty tissues of animals (e.g., fish and mammals) and in soils/sediments, results in chronic exposure to these substances. Efficient destruction methods are important to decontaminate polluted sites worldwide. This paper provides an in-depth overview of (i) the history and accidents with PCBs in the 20th century, (ii) the mechanisms that are responsible for the hazardous effects of PCBs, and (iii) the current policy regarding PCB control and decontamination. Contemporary impacts on human health of historical incidents are discussed next to an up to date overview of the health effects caused by PCBs and their mechanisms. Methods to decontaminate sites are reviewed. Steps which lead to a policy of banning the production and distribution of PCBs are overviewed in a context of preventing future accidents and harm to the environment and human health. PMID- 29267242 TI - High Affinity Binding of Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1) to Lu/BCAM Adhesion Glycoprotein. AB - The protein toxin Cytotoxic Necrotizing Factor 1 (CNF1) is a major virulence factor of pathogenic Escherichia coli strains. It belongs to a family of single chain AB-toxins, which enter mammalian cells by receptor-mediated endocytosis. Recently, we identified the Lutheran (Lu) adhesion glycoprotein/basal cell adhesion molecule (BCAM) as a cellular receptor for CNF1. Here, we identified the Ig-like domain 2 of Lu/BCAM as main interaction site of the toxin by direct protein-protein interaction and competition studies. Using surface plasmon resonance, we showed a high affinity CNF-Lu/BCAM interaction with a KD of 2.8 nM. Furthermore, we performed small-angle X-ray scattering to define the molecular envelope of the Lu/BCAM-CNF1 complex, suggesting a 6:1 ratio of Lu/BCAM to CNF1 in the receptor-toxin complex. This study leads to a deeper understanding of the interaction between CNF1 and Lu/BCAM, and presents novel opportunities for the development of future anti-toxin strategies. PMID- 29267243 TI - Anticoagulants Influence the Performance of In Vitro Assays Intended for Characterization of Nanotechnology-Based Formulations. AB - The preclinical safety assessment of novel nanotechnology-based drug products frequently relies on in vitro assays, especially during the early stages of product development, due to the limited quantities of nanomaterials available for such studies. The majority of immunological tests require donor blood. To enable such tests one has to prevent the blood from coagulating, which is usually achieved by the addition of an anticoagulant into blood collection tubes. Heparin, ethylene diamine tetraacetic acid (EDTA), and citrate are the most commonly used anticoagulants. Novel anticoagulants such as hirudin are also available but are not broadly used. Despite the notion that certain anticoagulants may influence assay performance, a systematic comparison between traditional and novel anticoagulants in the in vitro assays intended for immunological characterization of nanotechnology-based formulations is currently not available. We compared hirudin-anticoagulated blood with its traditional counterparts in the standardized immunological assay cascade, and found that the type of anticoagulant did not influence the performance of the hemolysis assay. However, hirudin was more optimal for the complement activation and leukocyte proliferation assays, while traditional anticoagulants citrate and heparin were more appropriate for the coagulation and cytokine secretion assays. The results also suggest that traditional immunological controls such as lipopolysaccharide (LPS ) are not reliable for understanding the role of anticoagulant in the assay performance. We observed differences in the test results between hirudin and traditional anticoagulant-prepared blood for nanomaterials at the time when no such effects were seen with traditional controls. It is, therefore, important to recognize the advantages and limitations of each anticoagulant and consider individual nanoparticles on a case-by-case basis. PMID- 29267244 TI - Numerical Modelling of Effects of Biphasic Layers of Corrosion Products to the Degradation of Magnesium Metal In Vitro. AB - Magnesium (Mg) is becoming increasingly popular for orthopaedic implant materials. Its mechanical properties are closer to bone than other implant materials, allowing for more natural healing under stresses experienced during recovery. Being biodegradable, it also eliminates the requirement of further surgery to remove the hardware. However, Mg rapidly corrodes in clinically relevant aqueous environments, compromising its use. This problem can be addressed by alloying the Mg, but challenges remain at optimising the properties of the material for clinical use. In this paper, we present a mathematical model to provide a systematic means of quantitatively predicting Mg corrosion in aqueous environments, providing a means of informing standardisation of in vitro investigation of Mg alloy corrosion to determine implant design parameters. The model describes corrosion through reactions with water, to produce magnesium hydroxide Mg(OH) 2 , and subsequently with carbon dioxide to form magnesium carbonate MgCO 3 . The corrosion products produce distinct protective layers around the magnesium block that are modelled as porous media. The resulting model of advection-diffusion equations with multiple moving boundaries was solved numerically using asymptotic expansions to deal with singular cases. The model has few free parameters, and it is shown that these can be tuned to predict a full range of corrosion rates, reflecting differences between pure magnesium or magnesium alloys. Data from practicable in vitro experiments can be used to calibrate the model's free parameters, from which model simulations using in vivo relevant geometries provide a cheap first step in optimising Mg-based implant materials. PMID- 29267245 TI - Comparative Study between Direct and Pseudomorphic Transformation of Rice Husk Ash into MFI-Type Zeolite. AB - Pre-shaped mesoporous amorphous rice husk ash (RHA) and MCM-41 derived from RHA as a silica source were transformed into MFI-type zeolites using two different structure-directing agents. Tetrapropylammonium hydroxide (TPAOH) was utilized as an alkali source for silica dissolution and structure control during the direct transformation of RHA into zeolite. A monopropylamine (PA)-containing alkaline solution (NaOH) was used for the pseudomorphic transformation of RHA or MCM-41 into zeolite. The hydrothermal conversion of RHA or MCM-41 into MFI-type zeolites was investigated as a function of reaction time at 175 degrees C. With PA as template, the crystallization took place inside and on the outer surface of RHA or MCM-41 without losing the original shape of the initial silica sources, while TPAOH led to the formation of conventional MFI-type zeolite crystals due to the complete dissolution of RHA. The final products were characterized by X-ray diffraction, nitrogen adsorption, scanning electron microscopy, and optical emission spectroscopy. PMID- 29267246 TI - 4,5-Dimethoxy-2-nitrobenzohydrazides and 1-(1-Benzylpiperidin-4-yl)ethan-1-ones as Potential Antioxidant/Cholinergic Endowed Small Molecule Leads. AB - The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimer's disease (AD). We differentiate "poly active" agents from "multi-target" ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available. PMID- 29267247 TI - Landsat-Derived Estimates of Mangrove Extents in the Sierra Leone Coastal Landscape Complex during 1990-2016. AB - This study provides the first assessment of decadal changes in mangrove extents in Sierra Leone. While significant advances have been made in mangrove mapping using remote sensing, no study has documented long-term changes in mangrove extents in Sierra Leone-one of the most vulnerable countries in West Africa. Such understanding is critical for devising regional management strategies that can support local livelihoods. We utilize multi-date Landsat data and cloud computational techniques to quantify spatiotemporal changes in land cover, with focus on mangrove ecosystems, for 1990-2016 along the coast of Sierra Leone. We specifically focus on four estuaries-Scarcies, Sierra Leone, Yawri Bay, and Sherbro. We relied on the k-means approach for an unsupervised classification, and validated the classified map from 2016 using ground truth data collected from Sentinel-2 and high-resolution images and during field research (accuracy: 95%). Our findings indicate that the Scarcies river estuary witnessed the greatest mangrove loss since 1990 (45%), while the Sierra Leone river estuary experienced mangrove gain over the last 26 years (22%). Overall, the Sierra Leone coast lost 25% of its mangroves between 1990 and 2016, with the lowest coverage in 2000, during the period of civil war (1991-2002). However, natural mangrove dynamics, as supported by field observations, indicate the potential for regeneration and sustainability under carefully constructed management strategies. PMID- 29267248 TI - Fibre Bragg Gratings for the Monitoring of Wooden Structures. AB - The aim of this work was to develop and validate an experimental methodology suitable for analysing on-site the behaviour of fibre-reinforced wooden structures. The proposed measurement method is based on the application of fibre Bragg grating (FBG) strain sensors. An analysis of adhesive behaviour was performed preliminarily, which provided indications for choosing the type of adhesive and for the fibre bonding length in accordance with the volume of measurement. The first series of tests was carried out on wood samples to verify the coupling between the measuring sensor and the wood support when the latter is subject to mechanical stresses. The second investigation was done on site to test the behaviour of a historical wood floor before and after reinforcement by means of a series of tests performed using optical fibres with the Bragg grating. The optical fibre system measurements were compared to those obtained using a laser vibrometer, a measurement system of proven stability and precision. The comparison makes it possible to confirm the validity of the results and the reliability of the system for the monitoring of historic wooden structures. PMID- 29267249 TI - Dynamic Gesture Recognition with a Terahertz Radar Based on Range Profile Sequences and Doppler Signatures. AB - The frequency of terahertz radar ranges from 0.1 THz to 10 THz, which is higher than that of microwaves. Multi-modal signals, including high-resolution range profile (HRRP) and Doppler signatures, can be acquired by the terahertz radar system. These two kinds of information are commonly used in automatic target recognition; however, dynamic gesture recognition is rarely discussed in the terahertz regime. In this paper, a dynamic gesture recognition system using a terahertz radar is proposed, based on multi-modal signals. The HRRP sequences and Doppler signatures were first achieved from the radar echoes. Considering the electromagnetic scattering characteristics, a feature extraction model is designed using location parameter estimation of scattering centers. Dynamic Time Warping (DTW) extended to multi-modal signals is used to accomplish the classifications. Ten types of gesture signals, collected from a terahertz radar, are applied to validate the analysis and the recognition system. The results of the experiment indicate that the recognition rate reaches more than 91%. This research verifies the potential applications of dynamic gesture recognition using a terahertz radar. PMID- 29267250 TI - The Effect of Resveratrol on Cell Viability in the Burkitt's Lymphoma Cell Line Ramos. AB - Resveratrol is a polyphenolic natural compound produced by a variety of crops. Currently, resveratrol is considered a multi-target anti-cancer agent with pleiotropic activity, including the ability to prevent the proliferation of malignant cells by inhibiting angiogenesis and curtailing invasive and metastatic factors in many cancer models. However, the molecular mechanisms mediating resveratrol-specific effects on lymphoma cells remain unknown. To begin tackling this question, we treated the Burkitt's lymphoma cell line Ramos with resveratrol and assessed cell survival and gene expression. Our results suggest that resveratrol shows a significant anti-proliferative and pro-apoptotic activity on Ramos cells, inducing the DNA damage response, DNA repairing, and modulating the expression of several genes that regulate the apoptotic process and their proliferative activity. PMID- 29267252 TI - A Support Vector Learning-Based Particle Filter Scheme for Target Localization in Communication-Constrained Underwater Acoustic Sensor Networks. AB - Target localization, which aims to estimate the location of an unknown target, is one of the key issues in applications of underwater acoustic sensor networks (UASNs). However, the constrained property of an underwater environment, such as restricted communication capacity of sensor nodes and sensing noises, makes target localization a challenging problem. This paper relies on fractional sensor nodes to formulate a support vector learning-based particle filter algorithm for the localization problem in communication-constrained underwater acoustic sensor networks. A node-selection strategy is exploited to pick fractional sensor nodes with short-distance pattern to participate in the sensing process at each time frame. Subsequently, we propose a least-square support vector regression (LSSVR) based observation function, through which an iterative regression strategy is used to deal with the distorted data caused by sensing noises, to improve the observation accuracy. At the same time, we integrate the observation to formulate the likelihood function, which effectively update the weights of particles. Thus, the particle effectiveness is enhanced to avoid "particle degeneracy" problem and improve localization accuracy. In order to validate the performance of the proposed localization algorithm, two different noise scenarios are investigated. The simulation results show that the proposed localization algorithm can efficiently improve the localization accuracy. In addition, the node-selection strategy can effectively select the subset of sensor nodes to improve the communication efficiency of the sensor network. PMID- 29267251 TI - Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model. AB - The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites hydroxybupropion, threohydrobupropion and erythrohydrobupropion-based on a mixed "bottom-up" and "top-down" approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (Cmax) area under the concentration-time curve (AUC) values and Cmax and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and Cmax ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory metabolites. PMID- 29267253 TI - Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue. AB - Brain tumor glioblastoma has no clear molecular signature and there is no effective therapy. In rodents, the intracellular distribution of the cyclic AMP (cAMP)-dependent protein kinase (Protein kinase A, PKA) R2Alpha subunit was previously shown to differentiate tumor cells from healthy brain cells. Now, we aim to validate this observation in human tumors. The distribution of regulatory (R1 and R2) and catalytic subunits of PKA was examined via immunohistochemistry and Western blot in primary cell cultures and biopsies from 11 glioblastoma patients. Data were compared with information obtained from 17 other different tumor samples. The R1 subunit was clearly detectable only in some samples. The catalytic subunit was variably distributed in the different tumors. Similar to rodent tumors, all human glioblastoma specimens showed perinuclear R2 distribution in the Golgi area, while it was undetectable outside the tumor. To test the effect of targeting PKA as a therapeutic strategy, the intracellular cyclic AMP concentration was modulated with different agents in four human glioblastoma cell lines. A significant increase in cell death was detected after increasing cAMP levels or modulating PKA activity. These data raise the possibility of targeting the PKA intracellular pathway for the development of diagnostic and/or therapeutic tools for human glioblastoma. PMID- 29267254 TI - Transcriptomic Studies of the Effect of nod Gene-Inducing Molecules in Rhizobia: Different Weapons, One Purpose. AB - Simultaneous quantification of transcripts of the whole bacterial genome allows the analysis of the global transcriptional response under changing conditions. RNA-seq and microarrays are the most used techniques to measure these transcriptomic changes, and both complement each other in transcriptome profiling. In this review, we exhaustively compiled the symbiosis-related transcriptomic reports (microarrays and RNA sequencing) carried out hitherto in rhizobia. This review is specially focused on transcriptomic changes that takes place when five rhizobial species, Bradyrhizobium japonicum (=diazoefficiens) USDA 110, Rhizobium leguminosarum biovar viciae 3841, Rhizobium tropici CIAT 899, Sinorhizobium (=Ensifer) meliloti 1021 and S. fredii HH103, recognize inducing flavonoids, plant-exuded phenolic compounds that activate the biosynthesis and export of Nod factors (NF) in all analysed rhizobia. Interestingly, our global transcriptomic comparison also indicates that each rhizobial species possesses its own arsenal of molecular weapons accompanying the set of NF in order to establish a successful interaction with host legumes. PMID- 29267255 TI - Over a Decade of recA and tly Gene Sequence Typing of the Skin Bacterium Propionibacterium acnes: What Have We Learnt? AB - The Gram-positive, anaerobic bacterium Propionibacterium acnes forms part of the normal microbiota on human skin and mucosal surfaces. While normally associated with skin health, P. acnes is also an opportunistic pathogen linked with a range of human infections and clinical conditions. Over the last decade, our knowledge of the intraspecies phylogenetics and taxonomy of this bacterium has increased tremendously due to the introduction of DNA typing schemes based on single and multiple gene loci, as well as whole genomes. Furthermore, this work has led to the identification of specific lineages associated with skin health and human disease. In this review we will look back at the introduction of DNA sequence typing of P. acnes based on recA and tly loci, and then describe how these methods provided a basic understanding of the population genetic structure of the bacterium, and even helped characterize the grapevine-associated lineage of P. acnes, known as P. acnes type Zappe, which appears to have undergone a host switch from humans-to-plants. Particular limitations of recA and tly sequence typing will also be presented, as well as a detailed discussion of more recent, higher resolution, DNA-based methods to type P. acnes and investigate its evolutionary history in greater detail. PMID- 29267257 TI - Antimicrobial Furoquinoline Alkaloids from Vepris lecomteana (Pierre) Cheek & T. Heller (Rutaceae). AB - Three new prenylated furoquinoline alkaloids named lecomtequinoline A (1), B (2), and C (3), together with the known compounds anhydroevoxine (4), evoxine (5), dictamnine (6), N-methylflindersine (7), evoxanthine (8), hesperidin, lupeol, beta-sitosterol, stigmasterol, beta-sitosterol-3-O-beta-d-glucopyranoside, stearic acid, and myristyl alcohol, were isolated by bioassay-guided fractionation of the methanolic extracts of leaves and stem of Vepris lecomteana. The structures of compounds were determined by spectroscopic methods (NMR, MS, UV, and IR) and by comparison with previously reported data. Crude extracts of leaves and stem displayed high antimicrobial activity, with Minimum Inhibitory Concentration (MIC) (values of 10.1-16.5 and 10.2-20.5 ug/mL, respectively, against Escherichia coli, Bacillus subtilis, Pseudomonas agarici, Micrococcus luteus, and Staphylococcus warneri, while compounds 1-6 showed values ranging from 11.1 to 18.7 ug/mL or were inactive, suggesting synergistic effect. The extracts may find application in crude drug preparations in Western Africa where Vepris lecomteana is endemic, subject to negative toxicity results in vivo. PMID- 29267258 TI - Plasma Long Non-Coding RNA (lncRNA) GAS5 is a New Biomarker for Coronary Artery Disease. AB - Our study aimed to investigate the diagnostic value of long non-coding RNA (lncRNA) GAS5 for coronary artery disease (CAD) and to explore the mechanism of the role of GAS5 in CAD. A total of 30 patients with CAD were selected from January 2015 to January 2017 in The First Hospital of Tianmen. In addition, 30 healthy individuals were selected as a control group, and patients with various other types of cardiovascular diseases were also selected. Expression of GAS5 in plasma of all participants was detected by quantitative real-time PCR. Receiver operating characteristic (ROC) curve analysis was performed to investigate the diagnostic value of GAS5 for CAD. Levels of mammalian target of rapamycin (mTOR) and phospho-mTOR (p-mTOR) in human primary coronary artery endothelial cells (HCAECs) were detected by western blotting. Compared with normal healthy people, expression level of lncRNA Novlnc6 was significantly reduced in patients with CAD and diabetes mellitus, but not in patients with other types of cardiovascular diseases, such as hypertension, abnormal aortic aneurysm, viral myocarditis. In addition, the expression level of GAS5 was significantly lower in patients with CAD compared to patients with diabetes mellitus. ROC curve analysis showed that GAS5 may serve as a promising biomarker for CAD. GAS5 knockdown and overexpression showed no significant effect on the level of mTOR) in HCAECs. However, GAS5 knockdown significantly increased the level of phospho-mTOR (p mTOR), and GAS5 overexpression significantly decreased the level of p-mTOR. Treatment with mTOR inhibitor and activator showed no significant effect on expression of GAS5 in HCAECs. GAS5 plays a role as upstream regulator of the mTOR pathway to participate in the development of CAD. GAS5 was specifically downregulated in patients with CAD, and it may serve as a promising biomarker for CAD. PMID- 29267259 TI - Update: Providing Quality Family Planning Services - Recommendations from CDC and the U.S. Office of Population Affairs, 2017. AB - In April 2014, CDC published "Providing Quality Family Planning Services: Recommendations of CDC and the U.S. Office of Population Affairs" (QFP), which describes the scope of services that should be offered in a family planning visit and how to provide those services (e.g., periodicity of screening, which persons are in need of services, etc.) (1). The sections in QFP include the following: Determining the Client's Need for Services; Contraceptive Services; Pregnancy Testing and Counseling; Clients Who Want to Become Pregnant; Basic Infertility Services; Preconception Health Services; Sexually Transmitted Disease Services; and Related Preventive Health Services. In addition, the QFP includes an appendix entitled Screening Services for Which Evidence Does Not Support Screening. PMID- 29267256 TI - Real Time Analysis of Bioanalytes in Healthcare, Food, Zoology and Botany. AB - The growing demand for real time analysis of bioanalytes has spurred development in the field of wearable technology to offer non-invasive data collection at a low cost. The manufacturing processes for creating these sensing systems vary significantly by the material used, the type of sensors needed and the subject of study as well. The methods predominantly involve stretchable electronic sensors to monitor targets and transmit data mainly through flexible wires or short-range wireless communication devices. Capable of conformal contact, the application of wearable technology goes beyond the healthcare to fields of food, zoology and botany. With a brief review of wearable technology and its applications to various fields, we believe this mini review would be of interest to the reader in broad fields of materials, sensor development and areas where wearable sensors can provide data that are not available elsewhere. PMID- 29267261 TI - QuickStats: Percentage of Adults Aged >=18 Years with Any Hearing Loss,* by State - National Health Interview Survey,? 2014-2016. AB - Overall, 15.9% of U.S. adults aged >=18 years had any hearing loss during 2014 2016. The prevalence of any hearing loss was lowest in New Jersey (10.6%), Connecticut (11.0%), Maryland (11.0%), California (12.3%), New York (12.6%), and the District of Columbia (8.6%). The prevalence of any hearing loss was highest in West Virginia (24.7%), Oregon (24.6%), Montana (23.8%), Idaho (23.1%), and Wyoming (22.3%). PMID- 29267262 TI - Erratum: Vol. 66, No. 32. PMID- 29267260 TI - Prevalence of Obesity Among Adults, by Household Income and Education - United States, 2011-2014. AB - Studies have suggested that obesity prevalence varies by income and educational level, although patterns might differ between high-income and low-income countries (1-3). Previous analyses of U.S. data have shown that the prevalence of obesity varied by income and education, but results were not consistent by sex and race/Hispanic origin (4). Using data from the National Health and Nutrition Examination Survey (NHANES), CDC analyzed obesity prevalence among adults (aged >=20 years) by three levels of household income, based on percentage (<=130%, >130% to <=350%, and >350%) of the federal poverty level (FPL) and individual education level (high school graduate or less, some college, and college graduate). During 2011-2014, the age-adjusted prevalence of obesity among adults was lower in the highest income group (31.2%) than the other groups (40.8% [>130% to <=350%] and 39.0% [<=130%]). The age-adjusted prevalence of obesity among college graduates was lower (27.8%) than among those with some college (40.6%) and those who were high school graduates or less (40.0%). The patterns were not consistent across all sex and racial/Hispanic origin subgroups. Continued progress is needed to achieve the Healthy People 2020 targets of reducing age adjusted obesity prevalence to <30.5% and reducing disparities (5). PMID- 29267263 TI - CDC Grand Rounds: National Amyotrophic Lateral Sclerosis (ALS) Registry Impact, Challenges, and Future Directions. AB - Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a rapidly progressive fatal neurologic disease. Currently, there is no cure for ALS and the available treatments only extend life by an average of a few months. The majority of ALS patients die within 2-5 years of diagnosis, though survival time varies depending on disease progression (1,2). For approximately 10% of patients, ALS is familial, meaning it and has a genetic component; the remaining 90% have sporadic ALS, where etiology is unknown, but might be linked to environmental factors such as chemical exposures (e.g., heavy metals, pesticides) and occupational history (3). PMID- 29267264 TI - Notes from the Field: Use of Asynchronous Video Directly Observed Therapy for Treatment of Tuberculosis and Latent Tuberculosis Infection in a Long-Term-Care Facility - Puerto Rico, 2016-2017. PMID- 29267265 TI - Prevalence and Disparities in Tobacco Product Use Among American Indians/Alaska Natives - United States, 2010-2015. AB - An overarching goal of Healthy People 2020 is to achieve health equity, eliminate disparities, and improve health among all groups.* Although significant progress has been made in reducing overall commercial tobacco product use,? disparities persist, with American Indians or Alaska Natives (AI/ANs) having one of the highest prevalences of cigarette smoking among all racial/ethnic groups (1,2). Variations in cigarette smoking among AI/ANs have been documented by sex and geographic location (3), but not by other sociodemographic characteristics. Furthermore, few data exist on use of tobacco products other than cigarettes among AI/ANs (4). CDC analyzed self-reported current (past 30-day) use of five tobacco product types among AI/AN adults from the 2010-2015 National Survey on Drug Use and Health (NSDUH); results were compared with six other racial/ethnic groups (Hispanic; non-Hispanic white [white]; non-Hispanic black [black]; non Hispanic Native Hawaiian or other Pacific Islander [NHOPI]; non-Hispanic Asian [Asian]; and non-Hispanic multirace [multirace]). Prevalence of current tobacco product use was significantly higher among AI/ANs than among non-AI/ANs combined for any tobacco product, cigarettes, roll-your-own tobacco, pipes, and smokeless tobacco. Among AI/ANs, prevalence of current use of any tobacco product was higher among males, persons aged 18-25 years, those with less than a high school diploma, those with annual family income <$20,000, those who lived below the federal poverty level, and those who were never married. Addressing the social determinants of health and providing evidence-based, population-level, and culturally appropriate tobacco control interventions could help reduce tobacco product use and eliminate disparities in tobacco product use among AI/ANs (1). PMID- 29267267 TI - Metaphors matter: from biobank to a library of medical information. PMID- 29267266 TI - CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve. AB - PURPOSE: Fragile X premutation (PM) carriers may experience difficulties conceiving a child probably due to fragile X-associated diminished ovarian reserve (FXDOR). We investigated which subgroups of carriers with a PM are at higher risk of FXDOR, and whether the number of AGG interruptions within the repeat sequence further ameliorates the risk. METHODS: We compared markers of ovarian reserve, including anti-Mullerian hormone, antral follicle count, and number of oocytes retrieved between different subgroups of patients with a PM. RESULTS: We found that carriers with midrange repeats size (70-90 CGG) demonstrate significantly lower ovarian reserve. Additionally, the number of AGG interruptions directly correlated with parameters of ovarian reserve. Patients with longer uninterrupted CGG repeats post-AGG interruptions had the lowest ovarian reserve. CONCLUSION: This study connects AGG interruptions and certain CGG repeat length to reduced ovarian reserve in carriers with a PM. A possible explanation for our findings is the proposed gonadotoxicity of the FMR1 transcripts. Reduction of AGG interruptions could increase the likelihood that secondary RNA structures in the FMR1 messenger RNA are formed, which could cause cell dysfunction within the ovaries. These findings may provide women with guidance regarding their fertility potential and accordingly assist with their family planning. PMID- 29267268 TI - Will buffer zones around schools in agricultural areas be adequate to protect children from the potential adverse effects of pesticide exposure? AB - California has proposed limiting agricultural pesticide use within 0.4 km of schools and childcare facilities. However, the 0.4-km buffer may not be appropriate for all pesticides because of differing toxicities, fate, and application methods. Living near pesticide use has been associated with poorer birth outcomes, neurodevelopment, and respiratory function in children. More research about exposures in schools, childcare facilities, and homes is needed. Despite incomplete science, this regulation is an important step to reduce potential exposures to children. The most vulnerable exposure period may be in utero, and future regulations should also aim to reduce exposures to pregnant women. PMID- 29267269 TI - Role of depression in secondary prevention of Chinese coronary heart disease patients receiving percutaneous coronary intervention. AB - INTRODUCTION: Coronary heart disease (CHD) patients who have undergone percutaneous coronary intervention (PCI) have higher rates of depression than the general population. However, few researchers have assessed the impact of depression on the secondary prevention of CHD in China. OBJECTIVE: The main purpose of this investigation was to explore the relationship between depression and secondary prevention of CHD in Chinese patients after PCI. METHODS: This descriptive, cross-sectional one-site study recruited both elective and emergency PCI patients one year after discharge. Data from 1934 patients were collected in the clinic using questionnaires and medical history records between August 2013 and September 2015. Depression was evaluated by the 9-item Patient Health Questionnaire. Secondary prevention of CHD was compared between depression and non-depression groups. RESULTS: We found that depression affected secondary prevention of CHD in the following aspects: lipid levels, blood glucose levels, smoking status, physical activity, BMI, and rates of medication use. CONCLUSIONS: Depressive patients with CHD are at increased risk of not achieving the lifestyle and risk factor control goals recommended in the 2006 AHA guidelines. Screening should focus on patients after PCI because treating depression can improve outcomes by improving secondary prevention of CHD. PMID- 29267270 TI - The added value of a family-centered approach to optimize infants' social emotional development: A quasi-experimental study. AB - OBJECTIVE: Family-centered care (FCC) has been related to positive healthcare outcomes in pediatric care. Our aim was to assess whether an FCC approach also leads to better and earlier identification of social-emotional problems and less child psychosocial problems at age 18 months. METHODS: In a quasi-experimental study within routine well-child care in the Netherlands, we compared those regions in which an FCC approach was implemented (FCC-JointStart) to those regions with "care-as-usual" (CAU), including all children. In all regions, professionals performed well-child visits (2-18 months) and assessed social emotional problems, or risks developing these, by rating outcomes of assessments as "not optimal" or as "a problem." We compared FCC-JointStart and CAU regarding the rates of newly identified (risks for) social-emotional problems, the pace of identification over time, and the child's psychosocial wellbeing at eighteen months as measured by the Child Behavior Checklist (CBCL). For participants that received extra care, we compared FCC-JointStart and CAU regarding the severity of parent-reported problems. Parents were blinded, professionals were not. RESULTS: 5658 parents (68%) agreed to participate in the study. In the FCC-JointStart group, risks were identified more frequently, though differences were small (24.7% versus 22.0%, odds ratio (95%-confidence interval) adjusted for confounders: 1.44 (0.96; 2.18), Phi = .03). Risks were also identified earlier (p = .008), and additional care was provided to more severe cases than in CAU. Effect sizes r ranged from 0.17 (PSBC) to 0.22 (FAD). CBCL scores at 18 months did not differ between groups. CONCLUSIONS: FFC-JointStart may contribute to more and earlier identification of risks for social-emotional problems and of families that need additional care, but not to fewer child psychosocial problems at age 18 months. TRIAL REGISTRATION: Netherlands Trial Register NTR2681. PMID- 29267272 TI - When enough data are not enough to enact policy: The failure to ban chlorpyrifos. AB - Strong evidence now supports the notion that organophosphate pesticides damage the fetal brain and produce cognitive and behavioral dysfunction through multiple mechanisms, including thyroid disruption. A regulatory ban was proposed, but actions to end the use of one such pesticide, chlorpyrifos, in agriculture were recently stopped by the Environmental Protection Agency under false scientific pretenses. This manuscript describes the costs and consequences of this policy failure and notes how this case study is emblematic of a broader dismissal of scientific evidence and attacks on scientific norms. Scientists have a responsibility to rebut and decry these serious challenges to human health and scientific integrity. PMID- 29267271 TI - Aged interleukin-10tm1Cgn chronically inflamed mice have substantially reduced fat mass, metabolic rate, and adipokines. AB - Interleukin 10tm1Cgn (IL 10tm) mice have been utilized as a model of chronic inflammation and declining health span because of their propensity to develop chronic activation in NFkB pathways, skeletal muscle and cardiac changes, and mitochondrial dysfunction. We hypothesized that older IL 10tm frail mice would have alterations similar to frail, older humans in measured parameters of glucose metabolism, oxygen consumption (VO2), respiratory quotient (RQ), spontaneous locomotor activity, body composition and plasma adipokine levels. To test this hypothesis, we investigated these metabolic parameters in cohorts of 3, 10, and 20 month old IL 10tm female mice and age and gender matched C57Bl/6 mice. Insulin sensitivity, glucose homeostasis, locomotor activity and RQ were not significantly altered between the two strains of mice. Interestingly, old IL 10tm mice had significantly decreased VO2 when normalized by lean mass, but not when normalized by fat mass or the lean/fat mass ratio. NMR based body composition analysis and dissection weights show that fat mass is decreased with age in IL 10tm mice compared to controls. Further, plasma adiponectin and leptin were also decreased in IL 10tm.These findings suggest that frailty observed in this mouse model of chronic inflammation may in part be driven by alterations in fat mass, hormone secretion and energy metabolism. PMID- 29267274 TI - Kozeny-Carman theory for modeling of porous granular structures saturation with emulsion during imbibition process. AB - The issue discussed in the current publication is a process of emulsions penetration in the granular media driven by the capillary force. The research work focuses on the study of rate and height of multiphase liquids penetration in a porous bed. Changes of the medium porosity and saturation level occurring as a result of pores obstruction by the droplets of an inner phase, were considered. The surfactant-stabilized emulsions with the different dispersed phase concentrations were investigated applying a classical wicking test. The modified version of Kozeny-Carman theory was proposed in order to describe the observed imbibition process in porous structures composed of spherical grains. This approach allowed to predict transport of emulsions considering an effect of bed saturation and porosity changes. In practice, the introduced concept can be appropriable in the numerous industries and scientific fields to predict the imbibition process of the multiphase liquids in granular structures regarding variation of the investigated bed permeability. PMID- 29267273 TI - Mechanistic modeling quantifies the influence of tumor growth kinetics on the response to anti-angiogenic treatment. AB - Tumors exploit angiogenesis, the formation of new blood vessels from pre-existing vasculature, in order to obtain nutrients required for continued growth and proliferation. Targeting factors that regulate angiogenesis, including the potent promoter vascular endothelial growth factor (VEGF), is therefore an attractive strategy for inhibiting tumor growth. Computational modeling can be used to identify tumor-specific properties that influence the response to anti-angiogenic strategies. Here, we build on our previous systems biology model of VEGF transport and kinetics in tumor-bearing mice to include a tumor compartment whose volume depends on the "angiogenic signal" produced when VEGF binds to its receptors on tumor endothelial cells. We trained and validated the model using published in vivo measurements of xenograft tumor volume, producing a model that accurately predicts the tumor's response to anti-angiogenic treatment. We applied the model to investigate how tumor growth kinetics influence the response to anti angiogenic treatment targeting VEGF. Based on multivariate regression analysis, we found that certain intrinsic kinetic parameters that characterize the growth of tumors could successfully predict response to anti-VEGF treatment, the reduction in tumor volume. Lastly, we use the trained model to predict the response to anti-VEGF therapy for tumors expressing different levels of VEGF receptors. The model predicts that certain tumors are more sensitive to treatment than others, and the response to treatment shows a nonlinear dependence on the VEGF receptor expression. Overall, this model is a useful tool for predicting how tumors will respond to anti-VEGF treatment, and it complements pre-clinical in vivo mouse studies. PMID- 29267275 TI - Size, skills, and suffrage: Motivated distortions in perceived formidability of political leaders. AB - Research shows that perception of physical size and status are positively associated. The current study was developed to replicate and extend earlier research on height perceptions of political leaders, indicating that supporters perceive their leaders as taller than non-supporters do, and winners are perceived as taller after the elections, while losers are perceived as shorter after the elections (winner/loser effects). Individuals use greater height and strength as indications of greater physical formidability. We hypothesized that in-group leaders' height and strength, but not weight, would be overestimated more compared to out-group leaders', and that this status-size association is not only driven by dominance, but also by prestige. We also tested whether previously found gender effects in estimates were due to using one's own height as an anchor, and we used an improved methodological approach by relying on multiple measurements of physical formidability and a within-subject design for testing winner/loser effects. The results of a two-part longitudinal study (self-selected sample via voting advice website; NWave1 = 2,011; NWave2 = 322) suggest that estimated physical formidability of political leaders is affected by motivated perception, as prestige was positively associated with estimated formidability, and in-group leaders were estimated more formidable than out-group leaders. We conclude that distortions in judged formidability related to social status are the result of motivated social perception in order to promote group functioning and leadership. Although we did not replicate a winner-effect (greater estimations of formidability after winning the elections), we did find some evidence for a loser-effect. Earlier suggestions that men make larger estimations than women because of their own larger body size are not supported. Implications for theory and future research are discussed. PMID- 29267276 TI - Quantifying the burden of vampire bat rabies in Peruvian livestock. AB - BACKGROUND: Knowledge of infectious disease burden is necessary to appropriately allocate resources for prevention and control. In Latin America, rabies is among the most important zoonoses for human health and agriculture, but the burden of disease attributed to its main reservoir, the common vampire bat (Desmodus rotundus), remains uncertain. METHODOLOGY/PRINCIPAL FINDINGS: We used questionnaires to quantify under-reporting of livestock deaths across 40 agricultural communities with differing access to health resources and epidemiological histories of vampire bat rabies (VBR) in the regions of Apurimac, Ayacucho and Cusco in southern Peru. Farmers who believed VBR was absent from their communities were one third as likely to report livestock deaths from disease as those who believed VBR was present, and under-reporting increased with distance from reporting offices. Using generalized mixed-effect models that captured spatial autocorrelation in reporting, we project 4.6 (95% CI: 4.4-8.2) rabies cases per reported case and identify geographic areas with potentially greater VBR burden than indicated by official reports. Spatially-corrected models estimate 505-724 cattle deaths from VBR in our study area during 2014 (421-444 deaths/100,000 cattle), costing US$121,797-171,992. Cost benefit analysis favoured vaccinating all cattle over the current practice of partial vaccination or halting vaccination all together. CONCLUSIONS: Our study represents the first estimate of the burden of VBR in Latin America to incorporate data on reporting rates. We confirm the long-suspected cost of VBR to small-scale farmers and show that vaccinating livestock is a cost-effective solution to mitigate the burden of VBR. More generally, results highlight that ignoring geographic variation in access to health resources can bias estimates of disease burden and risk. PMID- 29267277 TI - Development and evaluation of an anti-rabies virus phosphoprotein-specific monoclonal antibody for detection of rabies neutralizing antibodies using RFFIT. AB - BACKGROUND: Rabies is a major public health problem with a fatality rate close to 100%; however, complete prevention can be achieved through pre- or post-exposure prophylaxis. The rapid fluorescent focus inhibition test (RFFIT) is one of the recommended testing methods to determine the production of neutralizing antibodies after vaccination. Here, we report the development of a new monoclonal antibody (mAb) designed to react specifically with Rabies virus (RABV) phosphoprotein (P protein), and the evaluation of its applicability to the RFFIT and its effectiveness as a diagnostic reagent for human rabies. METHODOLOGY/PRINCIPAL FINDINGS: The mAb KGH P 16B8 was produced to target the P protein of the Korean KGH RABV strain. An indirect immunofluorescence assay (IFA) was conducted to detect various strains of RABV in various cell lines. Alexa conjugated KGH P 16B8 (16B8-Alexa) was developed for the RFFIT. The IFA test could detect RABV up to a 1:2,500 dilution, with a detection limit comparable to that of a commercial diagnostic reagent. The sensitivity, specificity, positive predictive value, and negative predictive value of the RFFIT using 16B8-Alexa in 414 clinical specimens were 98.67%, 99.47%, 99.55%, and 98.42%, respectively. The results of the RFFIT with 16B8-Alexa were strongly correlated with those obtained using an existing commercial diagnostic reagent (r = 0.995, p<0.001). CONCLUSIONS/SIGNIFICANCE: The mAb developed in this study shows high sensitivity and specificity, confirming its clinical utility with the RFFIT to measure the rabies neutralizing antibody titer and establish a diagnosis in human. Thus, 16B8 Alexa is expected to serve as an alternative diagnostic reagent that is widely accessible, with potentially broad applications beyond those of the RFFIT in Korea. Further studies with 16B8-Alexa should provide insight into the immunological mechanism of the P protein of Korean RABV. PMID- 29267278 TI - Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naive individual during the 2016 outbreak in Miami, FL. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus of significant public health concern. In the summer of 2016, ZIKV was first detected in the contiguous United States. Here we present one of the first cases of a locally acquired ZIKV infection in a dengue-naive individual. We collected blood from a female with a maculopapular rash at day (D) 5 and D7 post onset of symptoms (POS) and we continued weekly blood draws out to D148 POS. To establish the ontogeny of the immune response against ZIKV, lymphocytes and plasma were analyzed in a longitudinal fashion. The plasmablast response peaked at D7 POS (19.6% of CD19+ B cells) and was undetectable by D15 POS. ZIKV-specific IgM was present at D5 POS, peaked between D15 and D21 POS, and subsequently decreased. The ZIKV-specific IgG response, however, was not detected until D15 POS and continued to increase after that. Interestingly, even though the patient had never been infected with dengue virus (DENV), cross-reactive IgM and IgG binding against each of the four DENV serotypes could be detected. The highest plasma neutralization activity against ZIKV peaked between D15 and D21 POS, and even though DENV binding antibodies were present in the plasma of the patient, there was neither neutralization nor antibody dependent enhancement (ADE) of DENV. Interestingly, ADE against ZIKV arose at D48 POS and continued until the end of the study. CD4+ and CD8+ T-cells recognized ZIKV-NS2A and ZIKV-E, respectively. The tetramer positive CD8+ T-cell response peaked at D21 POS with elevated levels persisting for months. In summary, this is the first study to establish the timing of the ontogeny of the immune response against ZIKV. PMID- 29267279 TI - Unlinking the methylome pattern from nucleotide sequence, revealed by large-scale in vivo genome engineering and methylome editing in medaka fish. AB - The heavily methylated vertebrate genomes are punctuated by stretches of poorly methylated DNA sequences that usually mark gene regulatory regions. It is known that the methylation state of these regions confers transcriptional control over their associated genes. Given its governance on the transcriptome, cellular functions and identity, genome-wide DNA methylation pattern is tightly regulated and evidently predefined. However, how is the methylation pattern determined in vivo remains enigmatic. Based on in silico and in vitro evidence, recent studies proposed that the regional hypomethylated state is primarily determined by local DNA sequence, e.g., high CpG density and presence of specific transcription factor binding sites. Nonetheless, the dependency of DNA methylation on nucleotide sequence has not been carefully validated in vertebrates in vivo. Herein, with the use of medaka (Oryzias latipes) as a model, the sequence dependency of DNA methylation was intensively tested in vivo. Our statistical modeling confirmed the strong statistical association between nucleotide sequence pattern and methylation state in the medaka genome. However, by manipulating the methylation state of a number of genomic sequences and reintegrating them into medaka embryos, we demonstrated that artificially conferred DNA methylation states were predominantly and robustly maintained in vivo, regardless of their sequences and endogenous states. This feature was also observed in the medaka transgene that had passed across generations. Thus, despite the observed statistical association, nucleotide sequence was unable to autonomously determine its own methylation state in medaka in vivo. Our results apparently argue against the notion of the governance on the DNA methylation by nucleotide sequence, but instead suggest the involvement of other epigenetic factors in defining and maintaining the DNA methylation landscape. Further investigation in other vertebrate models in vivo will be needed for the generalization of our observations made in medaka. PMID- 29267281 TI - Deep Reads: How I learnt to love population genetics. PMID- 29267280 TI - Elucidating the impact of low doses of nano-formulated benznidazole in acute experimental Chagas disease. AB - BACKGROUND: Chagas disease is a neglected parasitic infection caused by the protozoan Trypanosoma cruzi (T. cruzi) that affects more than 6 million people, mainly in Latin America. Benznidazole is still the drug of choice in many countries to treat it in spite of its dosage regimen and adverse side effects such as such as allergic dermatitis, peripheral neuropathy and anorexia. Thus, novel, safer, and more efficacious treatments for such neglected infection are urgently required. METHODOLOGY: In this study, the efficacy of orally administered low doses of benznidazole (BNZ) nanoparticles was evaluated during the acute phase in mice infected with T. cruzi Nicaragua (TcN) that were immunosuppressed during the chronic stage of the disease. Moreover, the production of T. cruzi-specific antibodies, cardiac tissue inflammation and reactive oxygen species generation by Vero cells treated with both BNZ nanoparticles (BNZ-nps) and raw BNZ (R-BNZ) were also evaluated. PRINCIPAL FINDINGS: T. cruzi infected mice treated with 10, 25 or 50 mg/kg/day of BNZ-nps survived until euthanasia (92 days post infection (dpi)), while only 15% of infected untreated mice survived until the end of the experiment. PCR analysis of blood samples taken after induction of immunosuppression showed that a dosage of 25 mg/kg/day rendered 40% of the mice PCR-negative. The histological analysis of heart tissue showed a significant decrease in inflammation after treatments with 25 and 50 mg/kg/day, while a similar inflammatory damage was observed in both infected mice treated with R-BNZ (50 mg/kg/day) and untreated mice. In addition, only BNZ-nps treated mice led to lower levels of T. cruzi-specific antibodies to 50-100%. Finally, mammalian Vero cells treated with BNZ-nps or R-BNZ lead to a significant increase in ROS production. CONCLUSIONS: Based on these findings, this research highlights the in-vitro/in-vivo efficacy of nanoformulated BNZ against T. cruzi acute infections in immunosuppressed and non-immunosuppressed mice and provides further evidence for the optimization of dosage regimens to treat Chagas disease. PMID- 29267282 TI - Ten failings in global neglected tropical diseases control. PMID- 29267283 TI - FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas. AB - Lung cancer remains one of the most prominent public health challenges, accounting for the highest incidence and mortality among all human cancers. While pulmonary invasive mucinous adenocarcinoma (PIMA) is one of the most aggressive types of non-small cell lung cancer, transcriptional drivers of PIMA remain poorly understood. In the present study, we found that Forkhead box M1 transcription factor (FOXM1) is highly expressed in human PIMAs and associated with increased extracellular mucin deposition and the loss of NKX2.1. To examine consequences of FOXM1 expression in tumor cells in vivo, we employed an inducible, transgenic mouse model to express an activated FOXM1 transcript in urethane-induced benign lung adenomas. FOXM1 accelerated tumor growth, induced progression from benign adenomas to invasive, metastatic adenocarcinomas, and induced SOX2, a marker of poorly differentiated tumor cells. Adenocarcinomas in FOXM1 transgenic mice expressed increased MUC5B and MUC5AC, and reduced NKX2.1, which are characteristics of mucinous adenocarcinomas. Expression of FOXM1 in KrasG12D transgenic mice increased the mucinous phenotype in KrasG12D-driven lung tumors. Anterior Gradient 2 (AGR2), an oncogene critical for intracellular processing and packaging of mucins, was increased in mouse and human PIMAs and was associated with FOXM1. FOXM1 directly bound to and transcriptionally activated human AGR2 gene promoter via the -257/-247 bp region. Finally, using orthotopic xenografts we demonstrated that inhibition of either FOXM1 or AGR2 in human PIMAs inhibited mucinous characteristics, and reduced tumor growth and invasion. Altogether, FOXM1 is necessary and sufficient to induce mucinous phenotypes in lung tumor cells in vivo. PMID- 29267284 TI - Theoretical perspectives on central chemosensitivity: CO2/H+-sensitive neurons in the locus coeruleus. AB - Central chemoreceptors are highly sensitive neurons that respond to changes in pH and CO2 levels. An increase in CO2/H+ typically reflects a rise in the firing rate of these neurons, which stimulates an increase in ventilation. Here, we present an ionic current model that reproduces the basic electrophysiological activity of individual CO2/H+-sensitive neurons from the locus coeruleus (LC). We used this model to explore chemoreceptor discharge patterns in response to electrical and chemical stimuli. The modeled neurons showed both stimulus-evoked activity and spontaneous activity under physiological parameters. Neuronal responses to electrical and chemical stimulation showed specific firing patterns of spike frequency adaptation, postinhibitory rebound, and post-stimulation recovery. Conversely, the response to chemical stimulation alone (based on physiological CO2/H+ changes), in the absence of external depolarizing stimulation, showed no signs of postinhibitory rebound or post-stimulation recovery, and no depolarizing sag. A sensitivity analysis for the firing-rate response to the different stimuli revealed that the contribution of an applied stimulus current exceeded that of the chemical signals. The firing-rate response increased indefinitely with injected depolarizing current, but reached saturation with chemical stimuli. Our computational model reproduced the regular pacemaker like spiking pattern, action potential shape, and most of the membrane properties that characterize CO2/H+-sensitive neurons from the locus coeruleus. This validates the model and highlights its potential as a tool for studying the cellular mechanisms underlying the altered central chemosensitivity present in a variety of disorders such as sudden infant death syndrome, depression, and anxiety. In addition, the model results suggest that small external electrical signals play a greater role in determining the chemosensitive response to changes in CO2/H+ than previously thought. This highlights the importance of considering electrical synaptic transmission in studies of intrinsic chemosensitivity. PMID- 29267286 TI - Saccades are phase-locked to alpha oscillations in the occipital and medial temporal lobe during successful memory encoding. AB - Efficient sampling of visual information requires a coordination of eye movements and ongoing brain oscillations. Using intracranial and magnetoencephalography (MEG) recordings, we show that saccades are locked to the phase of visual alpha oscillations and that this coordination is related to successful mnemonic encoding of visual scenes. Furthermore, parahippocampal and retrosplenial cortex involvement in this coordination reflects effective vision-to-memory mapping, highlighting the importance of neural oscillations for the interaction between visual and memory domains. PMID- 29267285 TI - Binding of high mobility group A proteins to the mammalian genome occurs as a function of AT-content. AB - Genomic location can inform on potential function and recruitment signals for chromatin-associated proteins. High mobility group (Hmg) proteins are of similar size as histones with Hmga1 and Hmga2 being particularly abundant in replicating normal tissues and in cancerous cells. While several roles for Hmga proteins have been proposed we lack a comprehensive description of their genomic location as a function of chromatin, DNA sequence and functional domains. Here we report such a characterization in mouse embryonic stem cells in which we introduce biotin tagged constructs of wild-type and DNA-binding domain mutants. Comparative analysis of the genome-wide distribution of Hmga proteins reveals pervasive binding, a feature that critically depends on a functional DNA-binding domain and which is shared by both Hmga proteins. Assessment of the underlying queues instructive for this binding modality identifies AT richness, defined as high frequency of A or T bases, as the major criterion for local binding. Additionally, we show that other chromatin states such as those linked to cis regulatory regions have little impact on Hmga binding both in stem and differentiated cells. As a consequence, Hmga proteins are preferentially found at AT-rich regions such as constitutively heterochromatic regions but are absent from enhancers and promoters arguing for a limited role in regulating individual genes. In line with this model, we show that genetic deletion of Hmga proteins in stem cells causes limited transcriptional effects and that binding is conserved in neuronal progenitors. Overall our comparative study describing the in vivo binding modality of Hmga1 and Hmga2 identifies the proteins' preference for AT rich DNA genome-wide and argues against a suggested function of Hmga at regulatory regions. Instead we discover pervasive binding with enrichment at regions of higher AT content irrespective of local variation in chromatin modifications. PMID- 29267287 TI - Mutational analysis of Rift Valley fever phlebovirus nucleocapsid protein indicates novel conserved, functional amino acids. AB - Rift Valley fever phlebovirus (RVFV; Phenuiviridae, Phlebovirus) is an important mosquito-borne pathogen of both humans and ruminants. The RVFV genome is composed of tripartite, single stranded, negative or ambisense RNAs. The small (S) segment encodes both the nucleocapsid protein (N) and the non-structural protein (NSs). The N protein is responsible for the formation of the viral ribonucleoprotein (RNP) complexes, which are essential in the virus life cycle and for the transcription and replication of the viral genome. There is currently limited knowledge surrounding the roles of the RVFV nucleocapsid protein in viral infection other than its key functions: N protein multimerisation, encapsidation of the RNA genome and interactions with the RNA-dependent RNA polymerase, L. By bioinformatic comparison of the N sequences of fourteen phleboviruses, mutational analysis, minigenome assays and packaging assays, we have further characterised the RVFV N protein. Amino acids P11 and F149 in RVFV N play an essential role in the function of RNPs and are neither associated with N protein multimerisation nor known nucleocapsid protein functions and may have additional roles in the virus life cycle. Amino acid Y30 exhibited increased minigenome activity despite reduced RNA binding capacity. Additionally, we have determined that the N terminal arm of N protein is not involved in N-L interactions. Elucidating the fundamental processes that involve the nucleocapsid protein will add to our understanding of this important viral protein and may influence future studies in the development of novel antiviral strategies. PMID- 29267288 TI - Exploration of workforce changes in integrated chronic care: Findings from an interactive and emergent research design. AB - INTRODUCTION: Integrated care interventions introduced in response to the increased demand for long-term care entail profound changes to the health workforce. This exploratory study aims to provide an overview of the workforce changes implemented as part of integrated chronic care interventions. METHODS: An interactive and emergent research design was used consisting of a literature review, qualitative expert questionnaires and case reports. We defined integrated care as interventions targeting at least two of the six Chronic Care Model components. Workforce changes were defined as those changes experienced by clinical and non-clinical staff responsible for public and individual health intervention. RESULTS: Seven workforce changes were identified: (1) nurse involvement, (2) multidisciplinary staff, (3) multidisciplinary protocols/pathways, (4) provider training, (5) case manager/care coordinator, (6) team meetings, and (7) new positions. Most interventions included more than one of these workforce changes. CONCLUSION: The results of this study provide detailed insights into the current implementation of workforce changes in integrated care interventions and thereby pave the way for further investigations into the relative effectiveness of different workforce changes within the scope of complex interventions. Advancing knowledge in this area is essential for fostering health systems' capacity to cope with the challenges related to the current demographic and epidemiological trends. PMID- 29267289 TI - Ovarian carcinoma glyco-antigen targeted by human IgM antibody. AB - Epithelial Ovarian Cancer (EOC) cells expression of a novel carbohydrate antigen was defined using a human VH4-34 encoded IgM monoclonal antibody (mAb216). MAb216 binds to a poly N-acetyllactosamine epitope expressed on B cells and kills normal and malignant B cells in vitro and in vivo. EOC patient ascites and EOC cell lines were used to study the anti tumor effect of mAb216. Various assays were used to characterize the epitope and demonstrate antibody-mediated binding and cytotoxicity in EOC. Drug and antibody combination effects were determined by calculating the combination index values using the Chou and Talalay method. MAb216 displays direct antibody mediated cytotoxicity on a population of human EOC tumor and ascites samples and EOC cell lines, which express high amounts of poly N-acetyllactosamine epitope, carried by CD147/CD98. Eighty four percent of patient samples, including platin resistant, had a tumor population that bound the monoclonal antibody. The binding pattern of mAb216 and mechanism of cytotoxicity was similar to that seen on normal and malignant B cells with unique general membrane disruption and "pore" formation. In vitro incubation with mAb216 and cisplatin enhanced killing of OVCAR3 cell line. In EOC cell lines percent cytotoxicity correlated with percent expression of epitope. Although in vitro data shows specific EOC cytotoxicity, for possible treatment of EOC MAb216 would need to be evaluated in a clinical trial with or without chemotherapy. PMID- 29267290 TI - Organization and characterization of genetic regions in Bacillus subtilis subsp. krictiensis ATCC55079 associated with the biosynthesis of iturin and surfactin compounds. AB - Bacillus subtilis subsp. krictiensis ATCC55079 produces the cyclic lipopeptide antibiotics iturin A-F as well as several surfactins. Here, we analyzed and characterized the biosynthetic genes associated with iturin and surfactin production in this strain. We aligned the sequences of each iturin and surfactin synthetase ORF obtained from a genomic library screen and next generation sequencing. The resulting 37,249-bp and 37,645-bp sequences associated with iturin and surfactin production, respectively, contained several ORFs that are predicted to encode proteins involved in iturin and surfactin biosynthesis. These ORFs showed higher sequence homologies with the respective iturin and surfactin synthetase genes of B. methylotrophicus CAU B946 than with those of B. subtilis RB14 and B. subtilis ATCC6633. Moreover, comparative analysis of the secondary metabolites produced by the wild-type and surfactin-less mutant (with a spectinomycin resistance cassette inserted into the srfAB gene within the putative surfactin gene region) strains demonstrated that the mutant strain showed significantly higher antifungal activity against Fusarium oxysporum than the wild-type strain. In addition, the wild-type strain-specific surfactin high performance liquid chromatography (HPLC) peaks were not observed in the surfactin less mutant strain. In contrast, the iturin A peak detected by HPLC and liquid chromatography-mass spectrometry (LC/MS) in the surfactin-less mutant strain was 30% greater than that in the wild-type strain. These results suggested that the gene cluster we identified is involved in surfactin biosynthesis, and the biosynthetic pathways for iturin and surfactin in Bacillus strains producing both iturin and surfactin may utilize a common pathway. PMID- 29267291 TI - Utility of quick sepsis-related organ failure assessment (qSOFA) to predict outcome in patients with pneumonia. AB - BACKGROUND: Despite on-going advances in medical treatment, the burden of disease of pneumonia remains high. We aimed to determine the association of the qSOFA score with in-hospital mortality, length of hospitalisation, and admission to the intensive care unit (ICU) in patients with pneumonia. Further, in a subgroup analysis, the outcomes were compared for qSOFA in comparison to other risk scores, including the CURB-65 and SIRS scores. METHODS: In a retrospective analysis, admission data from the ED of the Bern University Hospital, Switzerland, were screened to identify patients admitted for pneumonia. In addition to clinical characteristics, qSOFA and CURB-65 scores and SIRS criteria were assessed and evaluated with respect to the defined study outcomes. RESULTS: 527 patients (median age 66 IQR 50-76) were included in this study. The overall in-hospital mortality was 13.3% (n = 70); 22.0% (n = 116) were transferred to the ICU. The median length of hospitalisation was 7 days (IQR 4-12). In comparison to qSOFA-negative patients, qSOFA-positive patients had increased odds ratios for in hospital mortality (OR 2.6, 95%:1.4, 4.7, p<0.001) and ICU admission (3.5, 95% CI: 2.0. 5.8, p<0.001) and an increased length of stay (p<0.001). For ICU admission, the specificity of qSOPA-positivity (>=2) was 82.1% and sensitivity 43.0%. For in-hospital mortality, the specificity of qSOPA-positivity (<=2) was 88.9% and sensitivity 24.4%. In the subgroup analysis (n = 366). The area under the receiver operating curve for ICU admission was higher for qSOFA than for the CURB-65 score (p = 0.013). The evaluated scores did not differ significantly in their prognostication of in-hospital mortality (p>0.05). CONCLUSIONS: The qSOFA score is associated with in-hospital mortality, ICU admission and length of hospitalisation in ED patients with pneumonia. Subgroup analysis revealed that qSOFA is superior to CURB-65 in respect to prognostication of ICU admission. PMID- 29267292 TI - Time to development of adverse drug reactions and associated factors among adult HIV positive patients on antiretroviral treatment in Bahir Dar City, Northwest Ethiopia. AB - BACKGROUND: Adverse drug reactions (ADRs) are harmful and unintended reactions to medicines given at standard doses. Although the antiretroviral treatment (ART) changed the global HIV epidemic significantly, it's associated adverse events is huge. Therefore, investigating the rate and development of ADRs of ART provides vital information for monitoring risks. METHODS: Retrospective study was conducted among patients on ART from July1/2011-June 30/2016 at Felege Hiwot referral hospital. Data were collected using checklist and document review. The p value and hazard ratio with its confidence interval was used to show presence and strength of association. RESULTS: A total of 602 subjects were studied. The rate of occurrence of major ADRs was 4.3/100PY. Patients with no formal and completed primary education were at higher risk of developing ADRs compared to those with higher level education [AHR = 8, 95% CI: 2.53-25.20, AHR = 4.9, 95% CI: 1.65 14.44]. The risks of ADRs among patients working in NGOs were more than four times compared to those in governmental organizations [AHR = 4.3, 95% CI: 1.42 13.31]. The risks of ADRs in WHO clinical stage II, III and IV were much higher than in stage I [AHR = 4, 95% CI: 1.33-11.93, AHR = 5.3, 95% CI: 2.02-13.79 and AHR = 7, 95% CI: 2.51-20.10] respectively. Moreover, patients didn't receive OI prophylaxis were more three times at risk of ADRs compared to those received [AHR = 3.2, 95% CI: 1.47-7.08]. CONCLUSIONS: Most of the ADRs cases were occurred within a year after initiation of ART. Educational status, occupation, advanced clinical stage and OI prophylaxis therapy were predictors ADRs. Continuous counseling for non-educated patients and clients in clinical stage II and above, and patients didn't take OI prophylaxis need to get close follow up to prevent the associated ADRs by the concerned parties. PMID- 29267293 TI - Development of machine-vision system for gap inspection of muskmelon grafted seedlings. AB - Grafting robots have been developed in the world, but some auxiliary works such as gap-inspecting for grafted seedlings still need to be done by human. An machine-vision system of gap inspection for grafted muskmelon seedlings was developed in this study. The image acquiring system consists of a CCD camera, a lens and a front white lighting source. The image of inspected gap was processed and analyzed by software of HALCON 12.0. The recognition algorithm for the system is based on principle of deformable template matching. A template should be created from an image of qualified grafted seedling gap. Then the gap image of the grafted seedling will be compared with the created template to determine their matching degree. Based on the similarity between the gap image of grafted seedling and the template, the matching degree will be 0 to 1. The less similar for the grafted seedling gap with the template the smaller of matching degree. Thirdly, the gap will be output as qualified or unqualified. If the matching degree of grafted seedling gap and the template is less than 0.58, or there is no match is found, the gap will be judged as unqualified; otherwise the gap will be qualified. Finally, 100 muskmelon seedlings were grafted and inspected to test the gap inspection system. Results showed that the gap inspection machine-vision system could recognize the gap qualification correctly as 98% of human vision. And the inspection speed of this system can reach 15 seedlings.min-1. The gap inspection process in grafting can be fully automated with this developed machine vision system, and the gap inspection system will be a key step of a fully automatic grafting robots. PMID- 29267294 TI - Internal wave turbulence at a biologically rich Mid-Atlantic seamount. AB - The turbulence regime near the crest of a biologically rich seamount of the Mid Atlantic Ridge southwest of the Azores was registered in high spatial and temporal resolution. Internal tides and their higher harmonics dominate the internal wave motions, producing considerable shear-induced turbulent mixing in layers of 10-50 m thickness. This interior mixing of about 100 times open-ocean interior values is observed both at a high-resolution temperature sensor mooring site at the crest, 770 m water depth being nearly 400 m below the top of the seamount, and a CTD-yoyo site at the slope off the crest 400 m horizontally away, 880 m water depth. Only at the mooring site, additionally two times higher turbulence is observed near the bottom, associated with highly non-linear wave breaking. The highest abundance of epifauna, notably sponges, are observed just below the crest and 100 m down the eastern slope (700-800 m) in a cross-ridge video-camera transect. This sponge belt is located in a water layer of depressed oxygen levels (saturation 63+/-2%) with a local minimum centered around 700 m. Turbulent mixing supplies oxygen to this region from above and below and is expected to mix nutrients away from this biodegraded layer towards the depth of highest abundance of macrofauna. PMID- 29267295 TI - Visual perception affected by motivation and alertness controlled by a noninvasive brain-computer interface. AB - The influence of motivation and alertness on brain activity associated with visual perception was studied experimentally using the Necker cube, which ambiguity was controlled by the contrast of its ribs. The wavelet analysis of recorded multichannel electroencephalograms (EEG) allowed us to distinguish two different scenarios while the brain processed the ambiguous stimulus. The first scenario is characterized by a particular destruction of alpha rhythm (8-12 Hz) with a simultaneous increase in beta-wave activity (20-30 Hz), whereas in the second scenario, the beta rhythm is not well pronounced while the alpha-wave energy remains unchanged. The experiments were carried out with a group of financially motivated subjects and another group of unpaid volunteers. It was found that the first scenario occurred mainly in the motivated group. This can be explained by the increased alertness of the motivated subjects. The prevalence of the first scenario was also observed in a group of subjects to whom images with higher ambiguity were presented. We believe that the revealed scenarios can occur not only during the perception of bistable images, but also in other perceptual tasks requiring decision making. The obtained results may have important applications for monitoring and controlling human alertness in situations which need substantial attention. On the base of the obtained results we built a brain computer interface to estimate and control the degree of alertness in real time. PMID- 29267297 TI - Adaptations of an RNA virus to increasing thermal stress. AB - Environments can change in incremental fashions, where a shift from one state to another occurs over multiple organismal generations. The rate of the environmental change is expected to influence how and how well populations adapt to the final environmental state. We used a model system, the lytic RNA bacteriophage Phi6, to investigate this question empirically. We evolved viruses for thermostability by exposing them to heat shocks that increased to a maximum temperature at different rates. We observed increases in the ability of many heat shocked populations to survive high temperature heat shocks. On their first exposure to the highest temperature, populations that experienced a gradual increase in temperature had higher average survival than populations that experienced a rapid temperature increase. However, at the end of the experiment, neither the survival of populations at the highest temperature nor the number of mutations per population varied significantly according to the rate of thermal change. We also evaluated mutations from the endpoint populations for their effects on viral thermostability and growth. As expected, some mutations did increase viral thermostability. However, other mutations decreased thermostability but increased growth rate, suggesting that benefits of an increased replication rate may have sometimes outweighed the benefits of enhanced thermostability. Our study highlights the importance of considering the effects of multiple selective pressures, even in environments where a single factor changes. PMID- 29267296 TI - Association of physical capacity with heart rate variability based on a short duration measurement of resting pulse rate in older adults with obesity. AB - BACKGROUND: Obesity can limit physical capacity and lower physical activity levels in elderly people. Low physical activity levels may be mediated by autonomic dysfunction with decreased heart rate variability (HRV). However, the relationship between autonomic dysfunction and low physical capability remains unclear. This cross-sectional study investigated the association of low physical capability with HRV in older adults with obesity. MATERIALS AND METHODS: We recruited 231 old man and 210 old women with a mean (range) age of 65.5 (51-78) and 62.9 (52-76) years, respectively. Physical capability was measured using mobility tasks, including functional reach, single-leg stance (SLS), gait speed (GS), timed up and go, and timed chair rise (TCR), and the scores on these tasks were merged and transformed into a global physical capability score (GPCS). HRV was measured using a 7-min resting pulse-based technique, and the time- and frequency-domain indices of HRV were obtained including standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences at rest (rMSSD), and high-frequency (HF) power. All HRV indices were natural log (ln) transformed for analysis. Participants were divided into high, moderate, and low physical-capability groups according to their physical performance. Multivariate analysis of covariance was performed to test differences in HRV indices among physical-capability groups with participants' characteristics serving as covariates. A stepwise regression model was established to identify the determinants of HRV indices. We used hierarchical regression analysis to identify the association of the GPCS with HRV indices. RESULTS: In both men and women, the low physical-capability group exhibited significantly increased heart rate (P <0.05) and decreased HRV in terms of a decreased ln[SDNN] (P <0.001), ln[rMSSD] (P <0.05) and ln[HF] (P <0.05), compared with the high physical capability group. GS positively predicted ln[SDNN], whereas SLS, GS, and TCR were determinants of ln[HF], regardless of gender. The GPCS in older men and women independently accounted for 29.9% (P <0.001) and 23.7% (P <0.001), respectively, in variance in ln[SDNN]. CONCLUSIONS: A low physical-capability level is an independent determinant of decreased HRV in older adults with obesity. PMID- 29267299 TI - SCM: A method to improve network service layout efficiency with network evolution. AB - Network services are an important component of the Internet, which are used to expand network functions for third-party developers. Network function virtualization (NFV) can improve the speed and flexibility of network service deployment. However, with the evolution of the network, network service layout may become inefficient. Regarding this problem, this paper proposes a service chain migration (SCM) method with the framework of "software defined network + network function virtualization" (SDN+NFV), which migrates service chains to adapt to network evolution and improves the efficiency of the network service layout. SCM is modeled as an integer linear programming problem and resolved via particle swarm optimization. An SCM prototype system is designed based on an SDN controller. Experiments demonstrate that SCM could reduce the network traffic cost and energy consumption efficiently. PMID- 29267298 TI - Distinct virulence of Rift Valley fever phlebovirus strains from different genetic lineages in a mouse model. AB - Rift Valley fever phlebovirus (RVFV) causes high rates of abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or blindness in humans. Viral transmission occurs via mosquito vectors in endemic areas, which necessitates regular vaccination of susceptible livestock animals to prevent the RVF outbreaks. Although ZH501 strain has been used as a challenge strain for past vaccine efficacy studies, further characterization of other RVFV strains is important to optimize ruminant and nonhuman primate RVFV challenge models. This study aimed to characterize the virulence of wild-type RVFV strains belonging to different genetic lineages in outbred CD1 mice. Mice were intraperitoneally infected with 1x103 PFU of wild-type ZH501, Kenya 9800523, Kenya 90058, Saudi Arabia 200010911, OS1, OS7, SA75, Entebbe, or SA51 strains. Among them, mice infected with SA51, Entebbe, or OS7 strain showed rapid dissemination of virus in livers and peracute necrotic hepatitis at 2-3 dpi. Recombinant SA51 (rSA51) and Zinga (rZinga) strains were recovered by reverse genetics, and their virulence was also tested in CD1 mice. The rSA51 strain reproduced peracute RVF disease in mice, whereas the rZinga strain showed a similar virulence with that of rZH501 strain. This study showed that RVFV strains in different genetic lineages display distinct virulence in outbred mice. Importantly, since wild-type RVFV strains contain defective-interfering RNA or various genetic subpopulations during passage from original viral isolations, recombinant RVFV strains generated by reverse genetics will be better suitable for reproducible challenge studies for vaccine development as well as pathological studies. PMID- 29267300 TI - The optimal number of personnel for good quality of chest compressions: A prospective randomized parallel manikin trial. AB - BACKGROUND: Long durational chest compression (CC) deteriorates cardiopulmonary resuscitation (CPR) quality. The appropriate number of CC personnel for minimizing rescuer's fatigue is mostly unknown. OBJECTIVE: We determined the optimal number of personnel needed for 30-min CPR in a rescue-team. METHODS: We conducted a randomized, manikin trial on healthcare providers. We divided them into Groups A to D according to the assigned different rest period to each group between the 2 min CCs. Groups A, B, C, and D performed CCs at 2, 4, 6, and 8 min rest period. All participants performed CCs for 30 min with a different rest period; participants allocated to Groups A, B, C, and D performed, eight, five, four, and three cycles, respectively. We compared a quality change of CCs among these groups to investigate how the assigned rest period affects the maintenance of CC quality during the 30-min CPR. RESULTS: This study involved 143 participants (male 58 [41%]; mean age, 24 years,) for the evaluation. As participants had less rest periods, the quality of their CCs such as sufficient depth ratio declined over 30-min CPR. A significant decrease in the sufficient CC depth ratio was observed in the second to the last cycle as compared to the first cycle. (median changes; A: -4%, B: -3%, C: 0%, and D: 0% p < 0.01). CONCLUSIONS: A 6 min rest period after 2 min CC is vital in order to sustain the quality of CC during a 30-min CPR cycle. At least four personnel may be needed to reduce rescuer's fatigue for a 30-min CPR cycle when the team consists of men and women. PMID- 29267301 TI - Presenting information on regulation values improves the public's sense of safety: Perceived mercury risk in fish and shellfish and its effects on consumption intention. AB - Risk communication aims to promote health and understanding through information exchange; however, explanations regarding the basis of regulation values for the public are insufficient. Moreover, it is unclear how information presentation affects the public's sense of safety and their consumption intentions. We first investigated the relationship between perception of mercury-risk in fish and shellfish and individual attributes and knowledge. We then examined how presenting information on regulation values and primary factors regarding perception affected sense of safety toward regulations and food-consumption intentions. An online survey was conducted with Japanese individuals (N = 1148). Respondents were randomly assigned to one of three groups based on the presentation level of regulation values. People who frequently consumed tuna had a high perception of dread risk of mercury. This suggests that the dread risk perception of mercury does not determine tuna-type consumption behavior; rather, individuals' consumption behavior determines dread risk perception of mercury. Among those with high tuna-type consumption, those receiving information that a safety factor of 10 times had been considered showed a significantly greater sense of safety than did the group that was not presented with information on regulation values (odds ratio (95% confidence interval): 2.04 (1.18-3.53), p < 0.05). However, presentation of regulation values showed a weak but significantly positive correlation with excessive intake of tuna-type fish (odds ratio: 2.95 (0.93-9.32), p < 0.10). Presenting the information on regulation values increases sense of safety; however, it may also lead to excessive intake. PMID- 29267302 TI - Efficacy and safety of selective glucocorticoid receptor modulators in comparison to glucocorticoids in arthritis, a systematic review. AB - BACKGROUND: Long-term treatment with glucocorticoids (GCs) plays an important role in the management of arthritis patients, although the efficacy/safety balance is unfavorable. Alternatives with less (severe) adverse effects but with good efficacy are needed. Selective GC receptor modulators (SGRMs) are designed to engage the GC receptor with dissociative characteristics: transactivation of genes, which is mainly responsible for unwanted effects, is less strong while trans-repression of genes, reducing inflammation, is maintained. It is expected that SGRMs thus have a better efficacy/safety balance than GCs. A systematic review providing an overview of the evidence in arthritis is lacking. OBJECTIVE: To systematically review the current literature on efficacy and safety of oral SGRMs in comparison to GCs in arthritis. METHODS: A search was performed in Medline, Embase and the Cochrane Library, from inception dates of databases until May 2017. Experimental studies involving animal arthritis models or human material of arthritis patients, as well as clinical studies in arthritis patients were included, provided they reported original data. All types of arthritis were included. Data was extracted on the SGRM studied and on the GC used as reference standard; the design or setting of the study was extracted as well as the efficacy and safety results. RESULTS: A total of 207 articles was retrieved of which 17 articles were eligible for our analysis. Two studies concerned randomized controlled trials (RCT), five studies were pre-clinical studies using human material, and 10 studies involved pre-clinical animal models (acute and/or chronic arthritis induced in mice or rats). PF-04171327, the only compound investigated in a clinical trial setting, had a better efficacy/safety balance compared to GCs: better clinical anti-inflammatory efficacy and similar safety. CONCLUSION: Studies assessing both efficacy and safety of SGRMs are scarce. There is limited evidence for dissociation of anti-inflammatory and metabolic effects of the SGRMs studied. Development of many SGRMs is haltered in a preclinical phase. One SGRM showed a better clinical efficacy/safety balance. PMID- 29267303 TI - Early dystrophin loss is coincident with the transition of compensated cardiac hypertrophy to heart failure. AB - Hypertension causes cardiac hypertrophy, one of the most important risk factors for heart failure (HF). Despite the importance of cardiac hypertrophy as a risk factor for the development of HF, not all hypertrophied hearts will ultimately fail. Alterations of cytoskeletal and sarcolemma-associated proteins are considered markers cardiac remodeling during HF. Dystrophin provides mechanical stability to the plasma membrane through its interactions with the actin cytoskeleton and, indirectly, to extracellular matrix proteins. This study was undertaken to evaluate dystrophin and calpain-1 in the transition from compensated cardiac hypertrophy to HF. Wistar rats were subjected to abdominal aorta constriction and killed at 30, 60 and 90 days post surgery (dps). Cardiac function and blood pressure were evaluated. The hearts were collected and Western blotting and immunofluorescence performed for dystrophin, calpain-1, alpha-fodrin and calpastatin. Statistical analyses were performed and considered significant when p<0.05. After 90 dps, 70% of the animals showed hypertrophic hearts (HH) and 30% hypertrophic+dilated hearts (HD). Systolic and diastolic functions were preserved at 30 and 60 dps, however, decreased in the HD group. Blood pressure, cardiomyocyte diameter and collagen content were increased at all time points. Dystrophin expression was lightly increased at 30 and 60 dps and HH group. HD group showed decreased expression of dystrophin and calpastatin and increased expression of calpain-1 and alpha-fodrin fragments. The first signals of dystrophin reduction were observed as early as 60 dps. In conclusion, some hearts present a distinct molecular pattern at an early stage of the disease; this pattern could provide an opportunity to identify these failure-prone hearts during the development of the cardiac disease. We showed that decreased expression of dystrophin and increased expression of calpains are coincident and could work as possible therapeutic targets to prevent heart failure as a consequence of cardiac hypertrophy. PMID- 29267304 TI - Prevalence of paediatric chronic suppurative otitis media and hearing impairment in rural Malawi: A cross-sectional survey. AB - OBJECTIVE: To estimate the prevalence of World Health Organization-defined chronic suppurative otitis media (CSOM) and mild hearing impairment in a population representative sample of school-entry age children in rural Malawi. A secondary objective was to explore factors associated with CSOM in this population. METHODS: We performed a community-based cross-sectional study of children aged 4-6 years in Chikhwawa District, Southern Malawi, utilising a village-level cluster design. Participants underwent a structured clinical assessment, including video-otoscopy and screening audiometry. Diagnoses were made remotely by two otolaryngologists who independently reviewed clinical data and images collected in the field. Hearing impairment was classified as failure to hear a pure tone of 25dB or greater at 1, 2 or 4kHz. RESULTS: We recruited 281 children across 10 clusters. The prevalence estimates of CSOM, unilateral hearing impairment and bilateral hearing impairment were 5.4% (95%CI 2.2-8.6), 24.5% (95%CI 16.3-30.0), and 12.5% (95%CI 6.2-16.9) respectively. Middle ear disease was seen in 46.9% of children with hearing impairment. A trend towards increased risk of CSOM was observed with sleeping in a house with >2 other children. INTERPRETATION: We found a high burden of middle ear disease and preventable hearing impairment in our sample of school-entry age children in rural Malawi. There are important public health implications of these findings as CSOM and hearing impairment can affect educational outcomes, and may impact subsequent development. The identification and management of middle ear disease and hearing impairment represent major unmet needs in this population. PMID- 29267305 TI - A quantitative evaluation of multiple biokinetic models using an assembled water phantom: A feasibility study. AB - This study examined the feasibility of quantitatively evaluating multiple biokinetic models and established the validity of the different compartment models using an assembled water phantom. Most commercialized phantoms are made to survey the imaging system since this is essential to increase the diagnostic accuracy for quality assurance. In contrast, few customized phantoms are specifically made to represent multi-compartment biokinetic models. This is because the complicated calculations as defined to solve the biokinetic models and the time-consuming verifications of the obtained solutions are impeded greatly the progress over the past decade. Nevertheless, in this work, five biokinetic models were separately defined by five groups of simultaneous differential equations to obtain the time-dependent radioactive concentration changes inside the water phantom. The water phantom was assembled by seven acrylic boxes in four different sizes, and the boxes were linked to varying combinations of hoses to signify the multiple biokinetic models from the biomedical perspective. The boxes that were connected by hoses were then regarded as a closed water loop with only one infusion and drain. 129.1+/-24.2 MBq of Tc 99m labeled methylene diphosphonate (MDP) solution was thoroughly infused into the water boxes before gamma scanning; then the water was replaced with de ionized water to simulate the biological removal rate among the boxes. The water was driven by an automatic infusion pump at 6.7 c.c./min, while the biological half-life of the four different-sized boxes (64, 144, 252, and 612 c.c.) was 4.8, 10.7, 18.8, and 45.5 min, respectively. The five models of derived time-dependent concentrations for the boxes were estimated either by a self-developed program run in MATLAB or by scanning via a gamma camera facility. Either agreement or disagreement between the practical scanning and the theoretical prediction in five models was thoroughly discussed. The derived biokinetic model represented the metabolic mechanism in the human body and helped to solidify the internal circulatory system into concert with numerical verification. PMID- 29267306 TI - Clinical and economic impact of antibiotic resistance in developing countries: A systematic review and meta-analysis. AB - INTRODUCTION: Despite evidence of the high prevalence of antibiotic resistant infections in developing countries, studies on the clinical and economic impact of antibiotic resistance (ABR) to inform interventions to contain its emergence and spread are limited. The aim of this study was to analyze the published literature on the clinical and economic implications of ABR in developing countries. METHODS: A systematic search was carried out in Medline via PubMed and Web of Sciences and included studies published from January 01, 2000 to December 09, 2016. All papers were considered and a quality assessment was performed using the Newcastle-Ottawa quality assessment scale (NOS). RESULTS: Of 27 033 papers identified, 40 studies met the strict inclusion and exclusion criteria and were finally included in the qualitative and quantitative analysis. Mortality was associated with resistant bacteria, and statistical significance was evident with an odds ratio (OR) 2.828 (95%CI, 2.231-3.584; p = 0.000). ESKAPE pathogens was associated with the highest risk of mortality and with high statistical significance (OR 3.217; 95%CIs; 2.395-4.321; p = 0.001). Eight studies showed that ABR, and especially antibiotic-resistant ESKAPE bacteria significantly increased health care costs. CONCLUSION: ABR is associated with a high mortality risk and increased economic costs with ESKAPE pathogens implicated as the main cause of increased mortality. Patients with non-communicable disease co morbidities were identified as high-risk populations. PMID- 29267307 TI - Robust moving-blocker scatter correction for cone-beam computed tomography using multiple-view information. AB - Scatter contamination is one of the main sources of decreasing the image quality in cone-beam computed tomography (CBCT). The moving blocker method is economic and effective for scatter correction (SC), which can simultaneously estimate scatter and reconstruct the complete volume within the field of view (FOV) from a single CBCT scan. However, at the regions with large intensity transition in the projection images along the axial blocker moving direction, the estimation of scatter signal from blocked regions in a single projection view can produce large error and cause significant artifacts in reconstructed images and null the usability of these regions. Furthermore, blocker edge detection error can significantly deteriorate both primary signal and scatter signal estimation and lead to unacceptable reconstruction results. In this study, we propose to use the adjacent multi-view projection images to jointly estimate scatter signal more accurately. In return, the more accurately estimated scatter signal can be utilized to detect blocker edges more accurately for greatly improved robustness of moving-blocker based SC. The experimental results using a Catphan phantom and an anthropomorphic pelvis phantom CBCT data show that the new method can effectively suppress the estimation errors of scatter signal in the fast signal transition regions and is able to correct the blocker detection errors. This development will expand the utility of moving-blocker based SC for the target with sharp intensity changes in the projection images and provide the needed robustness for its clinical translation. PMID- 29267308 TI - Risk salience of a novel virus: US population risk perception, knowledge, and receptivity to public health interventions regarding the Zika virus prior to local transmission. AB - BACKGROUND: As the incidence of Zika infection accelerated in Central and South American countries from November 2015 through April 2016, U.S. public health officials developed vector control and risk communication strategies to address mosquito-borne and sexual modes of transmission. This study reports upon U.S. perceptions of the Zika virus prior to domestic transmission, and analyzes the association of socio-economic, political, knowledge and risk factors with population receptivity to selected behavioral, environmental, and clinical intervention strategies. METHODS: A representative sample of 1,233 U.S. residents was drawn from address-based telephone and mobile phone lists, including an oversample of 208 women of child-bearing age living in five U.S. southern states. Data were collected between April and June, 2016, and weighted to represent U.S. population distributions. RESULTS: Overall, 78% of the U.S. population was aware of Zika prior to domestic transmission. Those unaware of the novel virus were more likely to be younger, lower income, and of Hispanic ethnicity. Among those aware of Zika, over half would delay pregnancy for a year or more in response to public health warnings; approximately one third agreed with a possible vector control strategy of targeted indoor spraying by the government; and nearly two thirds agreed that the government should make pregnancy-termination services available to women who learn their fetus had a Zika-related birth defect. Receptivity to these public health interventions varied by age, risk perception, and knowledge of the virus. CONCLUSION: Risk salience and population receptivity to public health interventions targeting a novel virus can be conditioned on pre existing characteristics in the event of an emerging infectious disease. Risk communicators should consider targeted strategies to encourage adoption of behavioral, environmental, and clinical interventions. PMID- 29267309 TI - Serum adiponectin levels are associated with worse cognitive function in postmenopausal women. AB - INTRODUCTION: Adiponectin may be a biomarker of cognitive impairment stage, and its clinical progression. In this study we aimed to evaluate the relationship between serum adiponectin levels and cognitive performances in menopausal women, and whether serum adiponectin levels may be differently associated with cognitive performances as compared to overweight/obese subjects. METHODS: We enrolled 188 post-menopausal women, divided into two groups: obese/overweight group (n = 96) and normal weight group (n = 92). After a clinical examination, and laboratory measurements, we assessed cognitive functions by Montreal Cognitive Assessment test (MoCA). RESULTS: A significant and greater decrease in executive/visuo spatial and in attention functions occurred in obese/overweight group as compared to normal weight group (p< 0.001). A significant positive relationship between serum adiponectin levels, and MoCA Global cognitive function was found. MoCA executive, and MoCA attention functions significantly and positively correlated with serum adiponectin levels. BMI, WHR, and serum adiponectin levels were independently associated with MoCA Global cognitive function, but only serum adiponectin levels were independently associated with MoCA attention. CONCLUSION: A significant positive association may exist between serum adiponectin levels, and better cognitive function in postmenopausal status. The major determinant of attentional capacity was just serum adiponectin levels, and dosage of serum adiponectin levels may be early serum marker of cognitive decline. Therefore, serum adiponectin level has to be used, as early biomarker, to detect cognitive decline, and to support an early prevention. PMID- 29267311 TI - Who's there? - First morphological and DNA barcoding catalogue of the shallow Hawai'ian sponge fauna. AB - The sponge fauna has been largely overlooked in the Archipelago of Hawai'i, notwithstanding the paramount role of this taxon in marine ecosystems. The lack of knowledge about Porifera populations inhabiting the Hawai'ian reefs limits the development of ecological studies aimed at understanding the functioning of these marine systems. Consequently, this project addresses this gap by describing the most representative sponge species in the shallow waters of the enigmatic bay of Kane'ohe Bay, in O'ahu Island. A total of 30 species (28 demosponges and two calcareous sponges) living associated to the reef structures are here reported. Six of these species are new records to the Hawai'ian Porifera catalogue and are suspected to be recent introductions to these islands. Morphological descriptions of the voucher specimens are provided, along with sequencing data of two partitions involving the mitochondrial cytochrome oxidase subunit 1 (COI) marker and a fragment covering partial (18S and 28S) and full (ITS-1, 5.8S and ITS-2) nuclear ribosomal genes. Species delimitations based on genetic distances were calculated to valitate how taxonomic assignments from DNA barcoding aligned with morphological identifications. Of the 60 sequences submitted to GenBank ~88% are the first sequencing records for the corresponding species and genetic marker. This work compiles the first catalogue combining morphological characters with DNA barcoding of Hawai'ian sponges, and contributes to the repository of public databases through the Sponge Barcoding Project initiative. PMID- 29267310 TI - Impact of diabetes on gingival wound healing via oxidative stress. AB - The aim of this study is to investigate the mechanisms linking high glucose to gingival wound healing. Bilateral wounds were created in the palatal gingiva adjacent to maxillary molars of control rats and rats with streptozotocin-induced diabetes. After evaluating postsurgical wound closure by digital imaging, the maxillae including wounds were resected for histological examinations. mRNA expressions of angiogenesis, inflammation, and oxidative stress markers in the surgical sites were quantified by real-time polymerase chain reaction. Primary fibroblast culture from the gingiva of both rats was performed in high glucose and normal medium. In vitro wound healing and cell proliferation assays were performed. Oxidative stress marker mRNA expressions and reactive oxygen species production were measured. Insulin resistance was evaluated via PI3K/Akt and MAPK/Erk signaling following insulin stimulation using Western blotting. To clarify oxidative stress involvement in high glucose culture and cells of diabetic rats, cells underwent N-acetyl-L-cysteine treatment; subsequent Akt activity was measured. Wound healing in diabetic rats was significantly delayed compared with that in control rats. Nox1, Nox2, Nox4, p-47, and tumor necrosis factor-alpha mRNA levels were significantly higher at baseline in diabetic rats than in control rats. In vitro study showed that cell proliferation and migration significantly decreased in diabetic and high glucose culture groups compared with control groups. Nox1, Nox2, Nox4, and p47 expressions and reactive oxygen species production were significantly higher in diabetic and high glucose culture groups than in control groups. Akt phosphorylation decreased in the high glucose groups compared with the control groups. Erk1/2 phosphorylation increased in the high glucose groups, with or without insulin treatment, compared with the control groups. Impaired Akt phosphorylation partially normalized after antioxidant N acetyl-L-cysteine treatment. Thus, delayed gingival wound healing in diabetic rats occurred because of impaired fibroblast proliferation and migration. Fibroblast dysfunction may occur owing to high glucose-induced insulin resistance via oxidative stress. PMID- 29267312 TI - Instantaneous simulation of fluids and particles in complex microfluidic devices. AB - Microfluidics researchers are increasingly using computer simulation in many different aspects of their research. However, these simulations are often computationally intensive: simulating the behavior of a simple microfluidic chip can take hours to complete on typical computing hardware, and even powerful workstations can lack the computational capabilities needed to simulate more complex chips. This slows the development of new microfluidic chips for new applications. To address this issue, we present a microfluidic simulation method that can simulate the behavior of fluids and particles in some typical microfluidic chips instantaneously (in around one second). Our method decomposes the chip into its primary components: channels and intersections. The behavior of fluid in each channel is determined by leveraging analogies with electronic circuits, and the behavior of fluid and particles in each intersection is determined by querying a database containing nearly 100,000 pre-simulated channel intersections. While constructing this database takes a nontrivial amount of computation time, once built, this database can be queried to determine the behavior of fluids and particles in a given intersection in a fraction of a second. Using this approach, the behavior of a microfluidic chip can be simulated in just one second on a standard laptop computer, without any noticeable degradation in the accuracy of the simulation. While our current technique has some constraints on the designs of the chips it can simulate (namely, T- or cross shaped intersections, 90 degree channel turns, a fixed channel width, fluid flow rates between 0 and 2 cm/s, and particles with diameters between 1 and 20 microns), we provide several strategies for increasing the range of possible chip designs that can be simulated using our technique. As a proof of concept, we show that our simulation method can instantaneously simulate the paths followed by particles in both simple and complex microfluidic chips, with results that are essentially indistinguishable from simulations that took hours or even days to complete using conventional approaches. PMID- 29267313 TI - Application of MIKE SHE to study the impact of coal mining on river runoff in Gujiao mining area, Shanxi, China. AB - Coal mining is one of the core industries that contribute to the economic development of a country but deteriorate the environment. Being the primary source of energy, coal has become essential to meet the energy demand of a country. It is excavated by both opencast and underground mining methods and affects the environment, especially hydrological cycle, by discharging huge amounts of mine water. Natural hydrological processes have been well known to be vulnerable to human activities, especially large scale mining activities, which inevitably generate surface cracks and subsidence. It is therefore valuable to assess the impact of mining on river runoff for the sustainable development of regional economy. In this paper, the impact of coal mining on river runoff is assessed in one of the national key coal mining sites, Gujiao mining area, Shanxi Province, China. The characteristics of water cycle are described, the similarities and differences of runoff formation are analyzed in both coal mining and pre-mining periods. The integrated distributed hydrological model named MIKE SHE is employed to simulate and evaluate the influence of coal mining on river runoff. The study shows that mining one ton of raw coal leads to the reduction of river runoff by 2.87 m3 between 1981 and 2008, of which the surface runoff decreases by 0.24 m3 and the baseflow by 2.63 m3. The reduction degree of river runoff for mining one ton of raw coal shows an increasing trend over years. The current study also reveals that large scale coal mining initiates the formation of surface cracks and subsidence, which intercepts overland flow and enhances precipitation infiltration. Together with mine drainage, the natural hydrological processes and the stream flows have been altered and the river run off has been greatly reduced. PMID- 29267315 TI - A logic-based dynamic modeling approach to explicate the evolution of the central dogma of molecular biology. AB - It is nearly half a century past the age of the introduction of the Central Dogma (CD) of molecular biology. This biological axiom has been developed and currently appears to be all the more complex. In this study, we modified CD by adding further species to the CD information flow and mathematically expressed CD within a dynamic framework by using Boolean network based on its present-day and 1965 editions. We show that the enhancement of the Dogma not only now entails a higher level of complexity, but it also shows a higher level of robustness, thus far more consistent with the nature of biological systems. Using this mathematical modeling approach, we put forward a logic-based expression of our conceptual view of molecular biology. Finally, we show that such biological concepts can be converted into dynamic mathematical models using a logic-based approach and thus may be useful as a framework for improving static conceptual models in biology. PMID- 29267314 TI - Mapping of quantitative trait loci for grain yield and its components in a US popular winter wheat TAM 111 using 90K SNPs. AB - Stable quantitative trait loci (QTL) are important for deployment in marker assisted selection in wheat (Triticum aestivum L.) and other crops. We reported QTL discovery in wheat using a population of 217 recombinant inbred lines and multiple statistical approach including multi-environment, multi-trait and epistatic interactions analysis. We detected nine consistent QTL linked to different traits on chromosomes 1A, 2A, 2B, 5A, 5B, 6A, 6B and 7A. Grain yield QTL were detected on chromosomes 2B.1 and 5B across three or four models of GenStat, MapQTL, and QTLNetwork while the QTL on chromosomes 5A.1, 6A.2, and 7A.1 were only significant with yield from one or two models. The phenotypic variation explained (PVE) by the QTL on 2B.1 ranged from 3.3-25.1% based on single and multi-environment models in GenStat and was pleiotropic or co-located with maturity (days to heading) and yield related traits (test weight, thousand kernel weight, harvest index). The QTL on 5B at 211 cM had PVE range of 1.8-9.3% and had no significant pleiotropic effects. Other consistent QTL detected in this study were linked to yield related traits and agronomic traits. The QTL on 1A was consistent for the number of spikes m-2 across environments and all the four analysis models with a PVE range of 5.8-8.6%. QTL for kernels spike-1 were found in chromosomes 1A, 2A.1, 2B.1, 6A.2, and 7A.1 with PVE ranged from 5.6-12.8% while QTL for thousand kernel weight were located on chromosomes 1A, 2B.1, 5A.1, 6A.2, 6B.1 and 7A.1 with PVEranged from 2.7-19.5%. Among the consistent QTL, five QTL had significant epistatic interactions (additive * additive) at least for one trait and none revealed significant additive * additive * environment interactions. Comparative analysis revealed that the region within the confidence interval of the QTL on 5B from 211.4-244.2 cM is also linked to genes for aspartate-semialdehyde dehydrogenase, splicing regulatory glutamine/lysine-rich protein 1 isoform X1, and UDP-glucose 6-dehydrogenase 1-like isoform X1. The stable QTL could be important for further validation, high throughput SNP development, and marker-assisted selection (MAS) in wheat. PMID- 29267316 TI - Detecting protein folding by thermal fluctuations of microcantilevers. AB - The accurate characterization of proteins in both their native and denatured states is essential to effectively understand protein function, folding and stability. As a proof of concept, a micro rheological method is applied, based on the characterization of thermal fluctuations of a micro cantilever immersed in a bovine serum albumin solution, to assess changes in the viscosity associated with modifications in the protein's structure under the denaturant effect of urea. Through modeling the power spectrum density of the cantilever's fluctuations over a broad frequency band, it is possible to implement a fitting procedure to accurately determine the viscosity of the fluid, even at low volumes. Increases in viscosity during the denaturant process are identified using the assumption that the protein is a hard sphere, with a hydrodynamic radius that increases during unfolding. This is modeled accordingly through the Einstein-Batchelor formula. The Einstein-Batchelor formula estimates are verified through dynamic light scattering, which measures the hydrodynamic radius of proteins. Thus, this methodology is proven to be suitable for the study of protein folding in samples of small size at vanishing shear stresses. PMID- 29267317 TI - Assessing the feasibility of confocal laser endomicroscopy in solitary pulmonary nodules for different part of the lungs, using either 0.6 or 1.4 mm probes. AB - BACKGROUND: Malignant solitary pulmonary nodules (SPN) have become more prevalent, with upper lobes predilection. Probe-based confocal laser endomicroscopy (pCLE) provides in-vivo imaging of SPN. However, the stiffness of the 1mm confocal probe (AlveoFlex) causes difficult accessibility to the upper lobes. A thinner 600MUm probe designed for bile duct exploration (CholangioFlex) has the potential to reach the upper lobes. OBJECTIVES: To examine the accessibility of malignant SPNs in all segments of the lungs using either the 0.6mm or 1.4 mm probe and to assess the quality and inter observer interpretation of SPN confocal imaging obtained from either miniprobes. METHODS: Radial(r)-EBUS was used to locate and sample the SPN. In-vivo pCLE analysis of the SPN was performed using either CholangioFlex (apical and posterior segments of the upper lobes) or AlveoFlex (other segments) introduced into the guide sheath before sampling. pCLE features were compared between the two probes. RESULTS: Fourty eight patients with malignant SPN were included (NCT01931579). The diagnostic accuracy for lung cancer using r-EBUS coupled with pCLE imaging was 79.2%. All the SPNs were successfully explored with either one of the probes (19 and 29 subjects for CholangioFlex and AlveoFlex, respectively). A specific solid pattern in the SPN was found in 30 pCLE explorations. Comparison between the two probes found no differences in the axial fibers thickness, cell size and specific solid pattern in the nodules. Extra-alveolar microvessel size appeared larger using CholangioFlex suggesting less compression effect. The kappa test for interobserver agreement for the identification of solid pattern was 0.74 (p = 0.001). CONCLUSION: This study demonstrates that pCLE imaging of SPNs is achievable in all segments of both lungs using either the 0.6mm or 1.4mm miniprobe. PMID- 29267318 TI - Bazedoxifene and conjugated estrogen combination maintains metabolic homeostasis and benefits liver health. AB - The bazedoxifene and conjugated estrogens (CE+BZA) combination has been shown to prevent visceral adiposity and weight gain after ovariectomy. However, its impact on the liver transcriptomes associated with prevention of hepatosteatosis is yet to be determined. In the present study, we use liver transcriptomics and plasma metabolomics analysis to characterize the effects of various estrogens on liver. The CE+BZA combination was very effective at preventing ovariectomy-induced weight gain in mice fed a high-fat diet (HFD). In CE+BZA treated animals, liver weight and hepatic lipid deposition were significantly lower than in Vehicle (Veh) treated animals. Additionally, CE+BZA induced unique liver transcriptome and plasma metabolome profiles compared to estradiol, conjugated estrogens alone, and bazedoxifene alone. Blood plasma metabolite analysis identified several metabolites similar to and distinct from other estrogen treatments. Integrated pathway analysis showed that gene networks that were associated with inflammation, reactive oxygen species pathway and lipid metabolism and their relevant metabolites were regulated significantly by CE+BZA treatment. Thus, long term CE+BZA treatment modulated hepatic metabolic gene networks and their associated metabolites and improves hepatic health without stimulating the uterus. PMID- 29267319 TI - Burden of disease attributed to ambient air pollution in Thailand: A GIS-based approach. AB - BACKGROUND: Growing urbanisation and population requiring enhanced electricity generation as well as the increasing numbers of fossil fuel in Thailand pose important challenges to air quality management which impacts on the health of the population. Mortality attributed to ambient air pollution is one of the sustainable development goals (SDGs). We estimated the spatial pattern of mortality burden attributable to selected ambient air pollution in 2009 based on the empirical evidence in Thailand. METHODS: We estimated the burden of disease attributable to ambient air pollution based on the comparative risk assessment (CRA) framework developed by the World Health Organization (WHO) and the Global Burden of Disease study (GBD). We integrated geographical information systems (GIS)-based exposure assessments into spatial interpolation models to estimate ambient air pollutant concentrations, the population distribution of exposure and the concentration-response (CR) relationship to quantify ambient air pollution exposure and associated mortality. We obtained air quality data from the Pollution Control Department (PCD) of Thailand surface air pollution monitoring network sources and estimated the CR relationship between relative risk (RR) and concentration of air pollutants from the epidemiological literature. RESULTS: We estimated 650-38,410 ambient air pollution-related fatalities and 160-5,982 fatalities that could have been avoided with a 20 reduction in ambient air pollutant concentrations. The summation of population-attributable fraction (PAF) of the disease burden for all-causes mortality in adults due to NO2 and PM2.5 were the highest among all air pollutants at 10% and 7.5%, respectively. The PAF summation of PM2.5 for lung cancer and cardiovascular disease were 16.8% and 14.6% respectively and the PAF summations of mortality attributable to PM10 was 3.4% for all-causes mortality, 1.7% for respiratory and 3.8% for cardiovascular mortality, while the PAF summation of mortality attributable to NO2 was 7.8% for respiratory mortality in Thailand. CONCLUSION: Mortality due to ambient air pollution in Thailand varies across the country. Geographical distribution estimates can identify high exposure areas for planners and policy-makers. Our results suggest that the benefits of a 20% reduction in ambient air pollution concentration could prevent up to 25% of avoidable fatalities each year in all causes, respiratory and cardiovascular categories. Furthermore, our findings can provide guidelines for future epidemiological investigations and policy decisions to achieve the SDGs. PMID- 29267320 TI - The impact of visceral adipose tissue as best predictor for difficult colonoscopy and the clinical utility of a long small-caliber scope as rescue. AB - BACKGROUND: There have been many reports about a variety of factors associated with incomplete colonoscopy or difficult colonoscopy with long cecal intubation time (CIT). The aim of this retrospective study was to analyze the factors related to difficult colonoscopy under conscious sedation and demonstrate the clinical utility of a small-caliber scope as rescue by using the data from a large number of subjects who underwent health check-ups. METHODS: Consecutive 1036 cases over a 12-month period (April 2015 to March 2016) were enrolled and 619 subjects were divided into two groups: Easy colonoscopy (CS) Group (CIT <= 10 min); Difficult CS Group (CIT > 10 min or incomplete colonoscopy by a standard scope). The two groups were compared by subjects and colonoscopy characteristics with univariate analysis followed by multivariate logistic regression analysis. Reasons for incomplete colonoscopy were also assessed. RESULTS: Cecal intubation rate increased from 97.9% to 99.9% (1007/1008) by the rescue scope. Main reasons for incomplete colonoscopy were tortuosity in the left hemicolon (38%), redundancy in the right hemicolon (29%), pain (19%) and fixation (14%). Moreover, 95% (20/21) of rescue colonoscopies were completed without additional sedation. Higher BMI (21 kg/m2 <= BMI) and intermediate visceral adipose tissue (VAT) (75 cm2 <= VAT < 150 cm2) were significantly associated with easy CS (80.7% vs 19.3%, P = 0.004; 56.3% vs 43.7%, P = 0.001) by univariate analysis. Age, gender, and VAT, not BMI, were independently associated with difficult colonoscopy by multivariate analysis (OR (95% CI), P: 0.964 (0.942, 0.985), 0.001; 1.845 (1.101, 3.091), 0.020; 2.347 (1.395, 3.951), 0.001). Subgroup analysis by gender also showed VAT as the best predictor for both genders. CONCLUSION: Difficult colonoscopy was significantly associated with advancing age, female gender and, lower (< 75 cm2) or higher (150 cm2 <=) VAT. These subjects may benefit from having complete and more comfortable colonoscopy examinations by using the small caliber scope rather than the standard scope. PMID- 29267321 TI - Light spectrum modifies the utilization pattern of energy sources in Pseudomonas sp. DR 5-09. AB - Despite the overruling impact of light in the phyllosphere, little is known regarding the influence of light spectra on non-phototrophic bacteria colonizing the leaf surface. We developed an in vitro method to study phenotypic profile responses of bacterial pure cultures to different bands of the visible light spectrum using monochromatic (blue: 460 nm; red: 660 nm) and polychromatic (white: 350-990 nm) LEDs, by modification and optimization of a protocol for the Phenotype MicroArrayTM technique (Biolog Inc., CA, USA). The new protocol revealed high reproducibility of substrate utilization under all conditions tested. Challenging the non-phototrophic bacterium Pseudomonas sp. DR 5-09 with white, blue, and red light demonstrated that all light treatments affected the respiratory profile differently, with blue LED having the most decisive impact on substrate utilization by impairing respiration of 140 substrates. The respiratory activity was decreased on 23 and 42 substrates under red and white LEDs, respectively, while utilization of one, 16, and 20 substrates increased in the presence of red, blue, and white LEDs, respectively. Interestingly, on four substrates contrasting utilization patterns were found when the bacterium was exposed to different light spectra. Although non-phototrophic bacteria do not rely directly on light as an energy source, Pseudomonas sp. DR 5-09 changed its respiratory activity on various substrates differently when exposed to different lights. Thus, ability to sense and distinguish between different wavelengths even within the visible light spectrum must exist, and leads to differential regulation of substrate usage. With these results, we hypothesize that different light spectra might be a hitherto neglected key stimulus for changes in microbial lifestyle and habits of substrate usage by non-phototrophic phyllospheric microbiota, and thus might essentially stratify leaf microbiota composition and diversity. PMID- 29267322 TI - Characterization of Salmonella enterica isolates causing bacteremia in Lima, Peru, using multiple typing methods. AB - In this study, different molecular typing tools were applied to characterize 95 Salmonella enterica blood isolates collected between 2008 and 2013 from patients at nine public hospitals in Lima, Peru. Combined results of multiplex PCR serotyping, two- and seven-loci multilocus sequence typing (MLST) schemes, serotyping, IS200 amplification and RAPD fingerprints, showed that these infections were caused by eight different serovars: Enteritidis, Typhimurium, Typhi, Choleraesuis, Dublin, Paratyphi A, Paratyphi B and Infantis. Among these, Enteritidis, Typhimurium and Typhi were the most prevalent, representing 45, 36 and 11% of the isolates, respectively. Most isolates (74%) were not resistant to ten primarily used antimicrobial drugs; however, 37% of the strains showed intermediate susceptibility to ciprofloxacin (ISC). Antimicrobial resistance integrons were carried by one Dublin (dfra1 and aadA1) and two Infantis (aadA1) isolates. The two Infantis isolates were multidrug resistant and harbored a large megaplasmid. Amplification of spvC and spvRA regions showed that all Enteritidis (n = 42), Typhimurium (n = 34), Choleraesuis (n = 3) and Dublin (n = 1) isolates carried the Salmonella virulence plasmid (pSV). We conclude that the classic serotyping method can be substituted by the multiplex PCR and, when necessary, sequencing of only one or two loci of the MLST scheme is a valuable tool to confirm the results. The effectiveness and feasibility of different typing tools is discussed. PMID- 29267323 TI - Evaluation of the EGFR polymorphism R497K in two cohorts of neoadjuvantly treated breast cancer patients. AB - Pathological response of breast cancer to neoadjuvant chemotherapy (NAC) presents great variability, and new prognostic biomarkers are needed. Our aim was to evaluate the association of the epidermal growth factor receptor gene (EGFR) polymorphism R497K (rs2227983) with prognostic features and clinical outcomes of breast cancer, including the pathological response to NAC and the recurrence-free survival (RFS). Tumoral complete response (tCR) was defined by no remaining invasive cancer in the excised breast, whereas pathological complete response (pCR) was defined by no remaining invasive cancer both in the excised breast and lymph nodes. Two independent cohorts were analyzed: one from Brazil (INCA, n = 288) and one from The Netherlands (NKI-AVL, n = 255). In the INCA cohort, the variant (Lys-containing) genotypes were significantly associated with lower proportion of tCR (ORadj = 0.92; 95%CI = 0.85-0.99), whereas in the NKI-AVL cohort they were associated with tumor grade 3 (p = 0.035) and with triple negative subtype (p = 0.032), but not with clinical outcomes. Such distinct prognostic associations may have arisen due to different neoadjuvant protocols (p < 0.001), or to lower age at diagnosis (p < 0.001) and higher proportion of tumor grade 3 (p = 0.018) at the NKI-AVL cohort. Moreover, NKI-AVL patients achieved better proportion of pCR (21.2% vs 8.3%, p < 0.001) and better RFS (HRadj = 0.48; 95% adjCI = 0.26-0.86) than patients from INCA. In conclusion, large scale studies comprehending different populations are needed to evaluate the impact of genome variants on breast cancer outcomes. PMID- 29267324 TI - Traditional Chinese medicine for knee osteoarthritis: An overview of systematic review. AB - BACKGROUND: Traditional Chinese medicine (TCM) has been accepted as a complementary therapy for knee osteoarthritis. However, the efficacy and safety of the intervention were still conflicting and uncertain. Meanwhile, the quality of methodology and evidence in the field was unknown. OBJECTIVE: To summarize the characteristics and critically evaluate the quality of methodology, as well as the evidence of systematic reviews (SRs) on TCM for knee osteoarthritis. METHODS: Five electronic databases were searched from inception to April 2016. The methodological quality of the included studies was assessed by AMSTAR and ROBIS. The quality of the evidence was determined using the GRADE approach. RESULTS: Ten SRs were included. The conclusions suggest that TCM provides potential benefits for patients with knee osteoarthritis. These benefits include pain relief, functional improvement, and presence of few adverse events. Limitations of the methodological quality mainly included the lack of a-priori protocol or protocol registration and incomprehensive literature search. A list of excluded studies was also not provided. The overall quality of evidence in the SRs was poor, ranging from "very low" to "low," mainly because of the serious risk of bias of original trials, inconsistencies, and imprecision in the outcomes. CONCLUSIONS: TCM generally appears to be effective for knee osteoarthritis treatment. However, the evidence is not robust enough because of the methodological flaws in SRs. Hence, these conclusions on available SRs should be treated with caution for clinical practice. PMID- 29267325 TI - Maternal obesity in the ewe increases cardiac ventricular expression of glucocorticoid receptors, proinflammatory cytokines and fibrosis in adult male offspring. AB - Obesity during human pregnancy predisposes offspring to obesity and cardiovascular disease in postnatal life. In a sheep model of maternal overnutrition/obesity we have previously reported myocardial inflammation and fibrosis, as well as cardiac dysfunction in late term fetuses, in association with chronically elevated blood cortisol. Significant research has suggested a link between elevated glucocorticoid exposure in utero and hypertension and cardiovascular disease postnatally. Here we examined the effects of maternal obesity on myocardial inflammation and fibrosis of their adult offspring. Adult male offspring from control (CON) mothers fed 100% of National Research Council (NRC) recommendations (n = 6) and male offspring from obese mothers (MO) fed 150% NRC (n = 6), were put on a 12-week ad libitum feeding challenge then necropsied. At necropsy, plasma cortisol and left and right ventricular thickness were markedly increased (P<0.05) in adult male MO offspring. Myocardial collagen content and collagen-crosslinking were greater (P<0.05) in MO offspring compared to CON offspring in association with increased mRNA and protein expression of glucocorticoid receptors (GR). No group difference was found in myocardial mineralocorticoids receptor (MR) protein expression. Further, mRNA expression for the proinflammatory cytokines: cluster of differentiation (CD)-68, transforming growth factor (TGF)-beta1, and tumor necrosis factor (TNF)-alpha were increased (P < 0.05), and protein expression of CD-68, TGF-beta1, and TNF-alpha tended to increase (P<0.10) in MO vs. CON offspring. These data provide evidence for MO induced programming of elevated plasma cortisol and myocardial inflammation and fibrosis in adult offspring potentially through increased GR. PMID- 29267326 TI - The role of chemical antifouling defence in the invasion success of Sargassum muticum: A comparison of native and invasive brown algae. AB - Competition and fouling defence are important traits that may facilitate invasions by non-indigenous species. The 'novel weapons hypothesis' (NWH) predicts that the invasive success of exotic species is closely linked to the possession of chemical defence compounds that the recipient community in the new range is not adapted to. In order to assess whether chemical defence traits contribute to invasion success, anti-bacterial, anti-quorum sensing, anti-diatom, anti-larval and anti-algal properties were investigated for the following algae: a) the invasive brown alga Sargassum muticum from both, its native (Japan) and invasive (Germany) range, b) the two non- or weak invasive species Sargassum fusiforme and Sargassum horneri from Japan, and c) Fucus vesiculosus, a native brown alga from Germany. Crude and surface extracts and lipid fractions of active extracts were tested against common fouling organisms and zygotes of a dominant competing brown alga. Extracts of the native brown alga F. vesiculosus inhibited more bacterial strains (75%) than any of the Sargassum spp. (17 to 29%). However, Sargassum spp. from Japan exhibited the strongest settlement inhibition against the diatom Cylindrotheca closterium, larvae of the bryozoan Bugula neritina and zygotes of the brown alga F. vesiculosus. Overall, extracts of S. muticum from the invasive range were less active compared to those of the native range suggesting an adaptation to lower fouling pressure and competition in the new range resulting in a shift of resource allocation from costly chemical defence to reproduction and growth. Non-invasive Sargassum spp. from Japan was equally defended against fouling and competitors like S. muticum from Japan indicating a necessity to include these species in European monitoring programs. The variable antifouling activity of surface and crude extracts highlights the importance to use both for an initial screening for antifouling activity. PMID- 29267327 TI - Completeness and overlap in open access systems: Search engines, aggregate institutional repositories and physics-related open sources. AB - This study examines the completeness and overlap of coverage in physics of six open access scholarly communication systems, including two search engines (Google Scholar and Microsoft Academic), two aggregate institutional repositories (OAIster and OpenDOAR), and two physics-related open sources (arXiv.org and Astrophysics Data System). The 2001-2013 Nobel Laureates in Physics served as the sample. Bibliographic records of their publications were retrieved and downloaded from each system, and a computer program was developed to perform the analytical tasks of sorting, comparison, elimination, aggregation and statistical calculations. Quantitative analyses and cross-referencing were performed to determine the completeness and overlap of the system coverage of the six open access systems. The results may enable scholars to select an appropriate open access system as an efficient scholarly communication channel, and academic institutions may build institutional repositories or independently create citation index systems in the future. Suggestions on indicators and tools for academic assessment are presented based on the comprehensiveness assessment of each system. PMID- 29267328 TI - Estimation of genomic prediction accuracy from reference populations with varying degrees of relationship. AB - Genomic prediction is emerging in a wide range of fields including animal and plant breeding, risk prediction in human precision medicine and forensic. It is desirable to establish a theoretical framework for genomic prediction accuracy when the reference data consists of information sources with varying degrees of relationship to the target individuals. A reference set can contain both close and distant relatives as well as 'unrelated' individuals from the wider population in the genomic prediction. The various sources of information were modeled as different populations with different effective population sizes (Ne). Both the effective number of chromosome segments (Me) and Ne are considered to be a function of the data used for prediction. We validate our theory with analyses of simulated as well as real data, and illustrate that the variation in genomic relationships with the target is a predictor of the information content of the reference set. With a similar amount of data available for each source, we show that close relatives can have a substantially larger effect on genomic prediction accuracy than lesser related individuals. We also illustrate that when prediction relies on closer relatives, there is less improvement in prediction accuracy with an increase in training data or marker panel density. We release software that can estimate the expected prediction accuracy and power when combining different reference sources with various degrees of relationship to the target, which is useful when planning genomic prediction (before or after collecting data) in animal, plant and human genetics. PMID- 29267329 TI - Topological and kinetic determinants of the modal matrices of dynamic models of metabolism. AB - Large-scale kinetic models of metabolism are becoming increasingly comprehensive and accurate. A key challenge is to understand the biochemical basis of the dynamic properties of these models. Linear analysis methods are well-established as useful tools for characterizing the dynamic response of metabolic networks. Central to linear analysis methods are two key matrices: the Jacobian matrix (J) and the modal matrix (M-1) arising from its eigendecomposition. The modal matrix M-1 contains dynamically independent motions of the kinetic model near a reference state, and it is sparse in practice for metabolic networks. However, connecting the structure of M-1 to the kinetic properties of the underlying reactions is non-trivial. In this study, we analyze the relationship between J, M 1, and the kinetic properties of the underlying network for kinetic models of metabolism. Specifically, we describe the origin of mode sparsity structure based on features of the network stoichiometric matrix S and the reaction kinetic gradient matrix G. First, we show that due to the scaling of kinetic parameters in real networks, diagonal dominance occurs in a substantial fraction of the rows of J, resulting in simple modal structures with clear biological interpretations. Then, we show that more complicated modes originate from topologically-connected reactions that have similar reaction elasticities in G. These elasticities represent dynamic equilibrium balances within reactions and are key determinants of modal structure. The work presented should prove useful towards obtaining an understanding of the dynamics of kinetic models of metabolism, which are rooted in the network structure and the kinetic properties of reactions. PMID- 29267330 TI - Mortality among the homeless: Causes and meteorological relationships. AB - BACKGROUND: The homeless constitute a subpopulation particularly exposed to atmospheric conditions, which, in the temperate climate zone, can result in both cold and heat stress leading to the increased mortality hazard. Environmental conditions have become a significant independent risk factor for mortality from specific causes, including circulatory or respiratory diseases. It is known that this group is particularly prone to some addictions, has a shorter life span, its members often die of different causes than those of the general population and may be especially vulnerable to the influence of weather conditions. MATERIALS AND METHODS: The retrospective analysis is based on data concerning 615 homeless people, out of which 176 died in the analyzed period (2010-2016). Data for the study was collected in the city of Olsztyn, located in north-east Poland, temperate climatic zone of transitional type. To characterize weather conditions, meteorological data including daily minimum and maximum temperatures and the Universal Thermal Climate Index (UTCI) were used. RESULTS: The average life span of a homeless person was shorter by about 17.5 years than that recorded for the general population. The average age at death of a homeless male was 56.27 years old (SD 10.38), and 52.00 years old (SD 9.85) of a homeless female. The most frequent causes of death were circulatory system diseases (33.80%). A large number of deaths were attributable to smoking (47.18%), whereas a small number was caused by infectious diseases, while a relatively large proportion of deaths were due to tuberculosis (2.15%). Most deaths occurred in the conditions of cold stress (of different intensity). Deaths caused by hypothermia were thirteen-fold more frequently recorded among the homeless than for the general population. A relative risk of death for a homeless person even in moderate cold stress conditions is higher (RR = 1.84) than in thermoneutral conditions. CONCLUSIONS: Our results indicate excessive mortality among the homeless as well as the weak and rather typical influence of atmospheric conditions on mortality rates in this subpopulation, except for a greater risk of cold related deaths than in the general population. UTCI may serve as a useful tool to predict death risk in this group of people. PMID- 29267332 TI - Construction of an SNP-based high-density linkage map for flax (Linum usitatissimum L.) using specific length amplified fragment sequencing (SLAF-seq) technology. AB - Flax is an important crop for oil and fiber, however, no high-density genetic maps have been reported for this species. Specific length amplified fragment sequencing (SLAF-seq) is a high-resolution strategy for large scale de novo discovery and genotyping of single nucleotide polymorphisms. In this study, SLAF seq was employed to develop SNP markers in an F2 population to construct a high density genetic map for flax. In total, 196.29 million paired-end reads were obtained. The average sequencing depth was 25.08 in male parent, 32.17 in the female parent, and 9.64 in each F2 progeny. In total, 389,288 polymorphic SLAFs were detected, from which 260,380 polymorphic SNPs were developed. After filtering, 4,638 SNPs were found suitable for genetic map construction. The final genetic map included 4,145 SNP markers on 15 linkage groups and was 2,632.94 cM in length, with an average distance of 0.64 cM between adjacent markers. To our knowledge, this map is the densest SNP-based genetic map for flax. The SNP markers and genetic map reported in here will serve as a foundation for the fine mapping of quantitative trait loci (QTLs), map-based gene cloning and marker assisted selection (MAS) for flax. PMID- 29267331 TI - Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates. AB - Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. We investigated immunogenicity and protective efficacy of a multi-antigen (MA) universal influenza DNA vaccine consisting of HA, M2, and NP antigens in cynomolgus macaques. Following challenge with a heterologous pandemic H1N1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. The MA DNA vaccine induced robust serum and mucosal antibody responses but these high antibody titers were not broadly neutralizing. In contrast, the vaccine induced broadly-reactive NP specific T cell responses that cross-reacted with the challenge virus and inversely correlated with lower viral loads and inflammation. These results demonstrate that a MA DNA vaccine that induces strong cross-reactive T cell responses can, independent of neutralizing antibody, mediate significant cross-protection in a nonhuman primate model and further supports development as an effective approach to induce broad protection against circulating and emerging influenza strains. PMID- 29267333 TI - Potentially preventable visits to the emergency department in older adults: Results from a national survey in Italy. AB - BACKGROUND: Despite older adults use emergency department more appropriately than other age groups, there is a significant share of admissions that can be considered potentially preventable. OBJECTIVE: To identify socio-demographic characteristics and health care resources use of older adults admitted to emergency department for a potentially preventable visit. DESIGN: Data come from the Multipurpose Survey "Health conditions and use of health services", edition 2012-2013. A stratified multi-stage probability design was used to select a sample using municipal lists of households. SUBJECT: 50474 community dwelling Italians were interviewed. In this analysis, 27003 subjects aged 65 years or older were considered. METHODS: Potentially preventable visits were defined as an emergency department visit that did not result in inpatient admission. Independent variables were classified based on the socio-behavioral model of Andersen-Newman. Descriptive statistics and a logistic regression model were developed. RESULTS: In the twelve months before the interview 3872 subjects (14.3%) had at least one potentially preventable visit. Factors associated with an increased risk of a potentially preventable visit were older age (75-84 years: OR 1.096, CI 1.001-1.199; 85+years: OR 1.022, CI 1.071-1.391), at least one hospital admission (OR 3.869, IC 3.547-4.221), to waive a visit (OR 1.188, CI 1.017-1.389) or an exam (OR 1.300, CI 1.077-1.570). Factors associated with a lower risk were female gender (OR 0.893, CI 0.819-0.975), area of residence (Center: OR 0.850; CI 0.766-0.943; Islands: OR 0.617, CI 0.539-0.706, South: OR 0.560; CI 0.505-0.622), private paid assistance (OR 0.761, CI 0.602-0.962); a better health-related quality of life (PCS score 46-54: OR 0.744, CI 0.659-0.841; PCS score >55: OR 0.746, CI 0.644-0.865). CONCLUSIONS: Our study identified several characteristics associated with an increased risk of potentially preventable visits to the emergency department. This might allow the development of specific interventions to prevent the access of at risk subjects to the emergency department. PMID- 29267334 TI - Effectiveness of eHealth interventions for reducing mental health conditions in employees: A systematic review and meta-analysis. AB - BACKGROUND: Many organisations promote eHealth applications as a feasible, low cost method of addressing mental ill-health and stress amongst their employees. However, there are good reasons why the efficacy identified in clinical or other samples may not generalize to employees, and many Apps are being developed specifically for this group. The aim of this paper is to conduct the first comprehensive systematic review and meta-analysis evaluating the evidence for the effectiveness and examine the relative efficacy of different types of eHealth interventions for employees. METHODS: Systematic searches were conducted for relevant articles published from 1975 until November 17, 2016, of trials of eHealth mental health interventions (App or web-based) focused on the mental health of employees. The quality and bias of all identified studies was assessed. We extracted means and standard deviations from published reports, comparing the difference in effect sizes (Hedge's g) in standardized mental health outcomes. We meta-analysed these using a random effects model, stratified by length of follow up, intervention type, and whether the intervention was universal (unselected) or targeted to selected groups e.g. "stressed". RESULTS: 23 controlled trials of eHealth interventions were identified which overall suggested a small positive effect at both post intervention (g = 0.24, 95% CI 0.13 to 0.35) and follow up (g = 0.23, 95% CI 0.03 to 0.42). There were differential short term effects seen between the intervention types whereby Mindfulness based interventions (g = 0.60, 95% CI 0.34 to 0.85, n = 6) showed larger effects than the Cognitive Behaviour Therapy (CBT) based (g = 0.15, 95% CI 0.02 to 0.29, n = 11) and Stress Management based (g = 0.17, 95%CI -0.01 to 0.34, n = 6) interventions. The Stress Management interventions however differed by whether delivered to universal or targeted groups with a moderately large effect size at both post-intervention (g = 0.64, 95% CI 0.54 to 0.85) and follow-up (g = 0.69, 95% CI 0.06 to 1.33) in targeted groups, but no effect in unselected groups. INTERPRETATION: There is reasonable evidence that eHealth interventions delivered to employees may reduce mental health and stress symptoms post intervention and still have a benefit, although reduced at follow-up. Despite the enthusiasm in the corporate world for such approaches, employers and other organisations should be aware not all such interventions are equal, many lack evidence, and achieving the best outcomes depends upon providing the right type of intervention to the correct population. PMID- 29267335 TI - QTL mapping for benzoxazinoid content, preharvest sprouting, alpha-amylase activity, and leaf rust resistance in rye (Secale cereale L.). AB - Mapping population of recombinant inbred lines (RILs) representing 541 * Ot1-3 cross exhibited wide variations of benzoxazinoid (BX) content in leaves and roots, brown rust resistance, alpha-amylase activity in the grain, and resistance to preharvest sprouting. QTL mapping of major BX species using a DArT-based map revealed a complex genetic architecture underlying the production of these main secondary metabolites engaged in stress and allelopathy responses. The synthesis of BX in leaves and roots was found to be regulated by different QTL. The QTL for the BX content, rust resistance, alpha-amylase activity, and preharvest sprouting partially overlapped; this points to their common genetic regulation by a definite subset of genes. Only one QTL for BX located on chromosome 7R coincided with the loci of the ScBx genes, which were mapped as two clusters on chromosomes 5RS (Bx3-Bx5) and 7R (Bx1-Bx2). The QTL common for several BX species, rust resistance, preharvest sprouting, and alpha-amylase activity are interesting objects for further exploration aimed at developing common markers for these important agronomic traits. PMID- 29267336 TI - 2-aminoethoxydiphenyl borate provides an anti-oxidative effect and mediates cardioprotection during ischemia reperfusion in mice. AB - Excessive levels of reactive oxygen species (ROS) and impaired Ca2+ homeostasis play central roles in the development of multiple cardiac pathologies, including cell death during ischemia-reperfusion (I/R) injury. In several organs, treatment with 2-aminoethoxydiphenyl borate (2-APB) was shown to have protective effects, generally believed to be due to Ca2+ channel inhibition. However, the mechanism of 2-APB-induced cardioprotection has not been fully investigated. Herein we investigated the protective effects of 2-APB treatment against cardiac pathogenesis and deciphered the underlying mechanisms. In neonatal rat cardiomyocytes, treatment with 2-APB was shown to prevent hydrogen peroxide (H2O2) -induced cell death by inhibiting the increase in intracellular Ca2+ levels. However, no 2-APB-sensitive channel blocker inhibited H2O2-induced cell death and a direct reaction between 2-APB and H2O2 was detected by 1H-NMR, suggesting that 2-APB chemically scavenges extracellular ROS and provides cytoprotection. In a mouse I/R model, treatment with 2-APB led to a considerable reduction in the infarct size after I/R, which was accompanied by the reduction in ROS levels and neutrophil infiltration, indicating that the anti-oxidative properties of 2-APB plays an important role in the prevention of I/R injury in vivo as well. Taken together, present results indicate that 2-APB treatment induces cardioprotection and prevents ROS-induced cardiomyocyte death, at least partially, by the direct scavenging of extracellular ROS. Therefore, administration of 2-APB may represent a promising therapeutic strategy for the treatment of ROS-related cardiac pathology including I/R injury. PMID- 29267337 TI - Effect of TET inhibitor on bovine parthenogenetic embryo development. AB - DNA demethylation catalysed by the ten-eleven translocation (TET) protein is an important step during extensive global epigenetic reprogramming in mammals. However, whether TET proteins play a key role in DNA demethylation during the development of bovine pre-implanted embryos is still unclear. In this study, we utilized dimethyloxallyl glycine (DMOG), a small-molecule inhibitor of the TET protein, to impede the enzymatic activity of TET and explore subsequent effects on bovine parthenogenetic embryo development. We first detected the expression of the TET family, consisting of TET1, TET2 and TET3, in bovine MII stage oocytes and found that TET3 is more highly expressed than TET1 and TET2. Treatment with 1 mM DMOG increased 5mC levels (30.4% vs 79.8% at the 8-cell stage for satellite I, 25.3% vs 40.6% at the 8-cell stage for alpha-satellite, 20.5% vs 73.5% at the blastocyst stage for satellite I and 16.6% vs 30.0% at the blastocyst stage for alpha-satellite) at every bovine parthenogenetic embryo developmental stage. At the same time, DNA methylation level of satellite DNA and pluripotency gene promoters increased significantly. Real-time PCR analysis results indicated that the transcription levels of NANOG and OCT-4 decreased in the DMOG-treated group. Furthermore, TET inhibition negatively affected blastocyst formation, resulting in a decline in the blastocyst rate (17.1 +/- 1.3% vs 24.1 +/- 0.6%); however, the percentage of apoptotic cells was significantly increased according to the results of a TUNEL assay. Additionally, expression levels of the apoptosis related gene BAX were up-regulated, while the expression of BCL-2 was down regulated. In conclusion, these results support that TET plays important roles in bovine parthenogenetic embryo development by influencing DNA methylation reprogramming, gene expression and apoptosis. PMID- 29267338 TI - Alarmingly high prevalence of hypertension and pre-hypertension in North India results from a large cross-sectional STEPS survey. AB - OBJECTIVES: The study was primarily aimed at estimating the prevalence of hypertension and pre-hypertension and the risk factors of hypertension in the North Indian state of Punjab. It also aimed at assessing the magnitude of undiagnosed cases of hypertension in the community and ascertaining the blood pressure control status of those on treatment. METHODS: A non-communicable disease risk factor survey (based on WHO-STEPS approach) was done in the state of Punjab, India in a multistage stratified sample of 5127 individuals. The study subjects were administered the WHO STEPS-questionnaire and also underwent anthropometric and blood pressure measurements. RESULTS: Overall prevalence of HTN among the study participants was found out to be 40.1% (95% CI: 38.8-41.5%) whereas prevalence of pre-hypertension, isolated diastolic and isolated systolic hypertension were 40.8% (39.5-42.2%), 9.2% (8.4-10.0%) and 6.5% (5.9-7.2%) respectively. Age group (45-69 years), male gender, social group, marital status, alcohol use, obesity and salt intake (> = 5 gms/day) were the risk factors significantly associated with HTN. Among all persons with HTN, only 30.1% were known case of HTN or on treatment, among whom nearly 61% had controlled blood pressure. Patients with uncontrolled BP were more frequently male, obese patients, with sedentary lifestyle and patients with diabetes. CONCLUSIONS: The study reported alarmingly high prevalence of hypertension, especially of undiagnosed or untreated cases amongst the adult population, a significant proportion of whom have uncontrolled blood pressure levels. This indicates the need for systematic screening and awareness program to identify the undiagnosed cases in the community and offer early treatment and regular follow up. PMID- 29267339 TI - Integrated self-regulating resistive heating for isothermal nucleic acid amplification tests (NAAT) in Lab-on-a-Chip (LoC) devices. AB - Isothermal nucleic acid amplification tests (NAAT) in a Lab-on-a-Chip (LoC) format promise to bring high-accuracy, non-instrumented rapid tests to the point of care. Reliable rapid tests for infectious diseases allow for early diagnosis and treatment, which in turn enables better containment of potential outbreaks and fewer complications. A critical component to LoC NAATs is the heating element, as all NAAT protocols require incubation at elevated temperatures. We propose a cheap, integrated, self-regulating resistive heating solution that uses 2xAAA alkaline batteries as the power source, can maintain temperatures in the 60 63 degrees C range for at least 25 minutes, and reaches the target range from room temperature in 5 minutes. 4 heating element samples with different electrical characteristics were evaluated in a thermal mock-up for a LoC NAAT device. An optimal heating element candidate was chosen based on temperature profiling. The optimal candidate was further evaluated by thermal modelling via finite element analysis of heat transfer and demonstrated suitable for isothermal nucleic acid amplification. PMID- 29267341 TI - Optogenetic conditioning of paradigm and pattern discrimination in the rat somatosensory system. AB - The rodent whisker-barrel cortical system is a model for studying somatosensory discrimination at high spatiotemporal precision. Here, we applied optogenetics to produce somatosensory inputs in the whisker area using one of transgenic rat lines, W-TChR2V4, which expresses channelrhodopsin-2 (ChR2) in the mechanoreceptive nerve endings around whisker follicles. An awake W-TChR2V4 rat was head-fixed and irradiated by blue LED light on the whisker area with a paradigm conditioned with a reward. The Go task was designed so the rat is allowed to receive a reward, when it licked the nozzle within 5 s after photostimulation. The No-go task was designed so as the rat has to withhold licking for at least 5 s to obtain a reward after photostimulation. The Go-task conditioning was established within 1 hr of training with a reduction in the reaction time and increase of the success rate. To investigate the relationship between the spatiotemporal pattern of sensory inputs and the behavioral output, we designed a multi-optical fiber system that irradiates the whisker area at 9 spots in a 3*3 matrix. Although the Go-task conditioning was established using synchronous irradiation of 9 spots, the success rate was decreased with an increase of the reaction time for the asynchronous irradiation. After conditioning to the Go task, the rat responded to the blue LED flash irradiated on the barrel cortex, where many neurons also express ChR2, or photostimulation of the contralateral whisker area with a similar reaction time and success rate. Synchronous activation of the peripheral mechanoreceptive nerves is suggested to drive a neural circuit in the somatosensory cortex that efficiently couples with the decision. Our optogenetic system would enable the precise evaluation of the psychophysical values, such as the reaction time and success rate, to gain some insight into the brain mechanisms underlying conditioned behaviors. PMID- 29267340 TI - Clinical predictors of outcome in patients with inflammatory dilated cardiomyopathy. AB - OBJECTIVES: The study objectives were to identify predictors of outcome in patients with inflammatory dilated cardiomyopathy (DCMi). METHODS: From 2004 to 2008, 55 patients with biopsy-proven DCMi were identified and followed up for 58.2+/-19.8 months. Predictors of outcome were identified in a multivariable analysis with a Cox proportional hazards analysis. The primary endpoint was a composite of death, heart transplantation and hospitalization for heart failure or ventricular arrhythmias. RESULTS: For the primary endpoint, a QTc interval >440msec (HR 2.84; 95% CI 1.03-7.87; p = 0.044), a glomerular filtration rate (GFR) <60ml/min/1.73m2 (HR 3.19; 95% CI 1.35-7.51; p = 0.008) and worsening of NYHA classification during follow-up (HR 2.48; 95% CI 1.01-6.10; p = 0.048) were univariate predictors, whereas left ventricular ejection fraction at baseline, NYHA class at entry, atrial fibrillation, treatment with digitalis or viral genome detection were not significantly related to outcome. After multivariable analysis, a GFR <60ml/min/1.73m2 (HR 3.04; 95% CI 1.21-7.66; p = 0.018) remained a predictor of adverse outcome. CONCLUSIONS: In patients with DCMi, a prolonged QTc interval >440msec, a GFR<60ml/min/1.73m2 and worsening of NYHA classification during follow-up were univariate predictors of adverse prognosis. In contrast, NYHA classification at baseline, left ventricular ejection fraction, atrial fibrillation, treatment with digitalis or viral genome detection were not related to outcome. After multivariable analysis, a GFR <60ml/min/1.73m2 remained independently associated with adverse outcome. PMID- 29267343 TI - Optimal shortening of uniform covering arrays. AB - Software test suites based on the concept of interaction testing are very useful for testing software components in an economical way. Test suites of this kind may be created using mathematical objects called covering arrays. A covering array, denoted by CA(N; t, k, v), is an N * k array over [Formula: see text] with the property that every N * t sub-array covers all t-tuples of [Formula: see text] at least once. Covering arrays can be used to test systems in which failures occur as a result of interactions among components or subsystems. They are often used in areas such as hardware Trojan detection, software testing, and network design. Because system testing is expensive, it is critical to reduce the amount of testing required. This paper addresses the Optimal Shortening of Covering ARrays (OSCAR) problem, an optimization problem whose objective is to construct, from an existing covering array matrix of uniform level, an array with dimensions of (N - delta) * (k - Delta) such that the number of missing t-tuples is minimized. Two applications of the OSCAR problem are (a) to produce smaller covering arrays from larger ones and (b) to obtain quasi-covering arrays (covering arrays in which the number of missing t-tuples is small) to be used as input to a meta-heuristic algorithm that produces covering arrays. In addition, it is proven that the OSCAR problem is NP-complete, and twelve different algorithms are proposed to solve it. An experiment was performed on 62 problem instances, and the results demonstrate the effectiveness of solving the OSCAR problem to facilitate the construction of new covering arrays. PMID- 29267342 TI - Adenovirus platform enhances transduction efficiency of human mesenchymal stem cells: An opportunity for cellular carriers of targeted TRAIL-based TR3 biologics in ovarian cancer. AB - Clinical application of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based cancer therapeutics has not reached optimal potencies in part due to inadequate drug stability and inefficiencies in cancer-selective drug delivery. As such, innovative strategies regarding drug design and delivery are of utmost importance to achieve improved treatment results. With our current study, we aimed at exploring the groundwork for a two-stage targeting concept, which is based on the intrinsic tumor homing capacity of mesenchymal stem cells (MSCs) as cellular drug factories for the in situ production of our newly designed and biomarker-targeted TRAIL-based TR3 therapeutics. Since MSCs are primary cells, capable in vitro of only a limited number of cell divisions, identification of suitable strategies for their efficient genetic manipulation is of critical importance. We chose adenoviral (Ad) vectors as a transduction vehicle due to its ability to infect dividing and non-dividing cells and because of their limited restrictions regarding the packaging capacity of their genetic payload. In order to enhance the transduction efficacy of MSCs using Ad5 wild type-based vectors, we tested a variety of fiber knob modifications on a panel of patient-derived MSC lines established from adipose tissue. We identified Ad5pK7, an Ad5 vector containing a polylysine fiber knob modification, exhibiting the highest transduction rates across a panel of 16 patient-derived MSC lines. We further demonstrated that MSCs could be efficiently transduced with an Ad5pK7 vector containing membrane-anchored and secreted TR3 expression units, including the MUC16 (CA125)-targeted variant Meso64-TR3. In both in vitro and in vivo experiments, MSC-derived Meso64-TR3 was far more potent on MUC16-expressing ovarian cancer compared to its non-targeted TR3 counterpart. Our findings thus provide the foundation to initiate further preclinical investigations on MSC mediated treatment options in ovarian cancer using biomarker-targeted TR3-based biologics. PMID- 29267344 TI - Perceptual training to improve hip fracture identification in conventional radiographs. AB - Diagnosing certain fractures in conventional radiographs can be a difficult task, usually taking years to master. Typically, students are trained ad-hoc, in a primarily-rule based fashion. Our study investigated whether students can more rapidly learn to diagnose proximal neck of femur fractures via perceptual training, without having to learn an explicit set of rules. One hundred and thirty-nine students with no prior medical or radiology training were shown a sequence of plain film X-ray images of the right hip and for each image were asked to indicate whether a fracture was present. Students were told if they were correct and the location of any fracture, if present. No other feedback was given. The more able students achieved the same level of accuracy as board certified radiologists at identifying hip fractures in less than an hour of training. Surprisingly, perceptual learning was reduced when the training set was constructed to over-represent the types of images participants found more difficult to categorise. Conversely, repeating training images did not reduce post-training performance relative to showing an equivalent number of unique images. Perceptual training is an effective way of helping novices learn to identify hip fractures in X-ray images and should supplement the current education programme for students. PMID- 29267345 TI - Wikipedia as a gateway to biomedical research: The relative distribution and use of citations in the English Wikipedia. AB - Wikipedia is a gateway to knowledge. However, the extent to which this gateway ends at Wikipedia or continues via supporting citations is unknown. Wikipedia's gateway functionality has implications for information design and education, notably in medicine. This study aims to establish benchmarks for the relative distribution and referral (click) rate of citations-as indicated by presence of a Digital Object Identifier (DOI)-from Wikipedia, with a focus on medical citations. DOIs referred from the English Wikipedia in August 2016 were obtained from Crossref.org. Next, based on a DOI's presence on a WikiProject Medicine page, all DOIs in Wikipedia were categorized as medical (WP:MED) or non-medical (non-WP:MED). Using this categorization, referred DOIs were classified as WP:MED, non-WP:MED, or BOTH, meaning the DOI may have been referred from either category. Data were analyzed using descriptive and inferential statistics. Out of 5.2 million Wikipedia pages, 4.42% (n = 229,857) included at least one DOI. 68,870 were identified as WP:MED, with 22.14% (n = 15,250) featuring one or more DOIs. WP:MED pages featured on average 8.88 DOI citations per page, whereas non-WP:MED pages had on average 4.28 DOI citations. For DOIs only on WP:MED pages, a DOI was referred every 2,283 pageviews and for non-WP:MED pages every 2,467 pageviews. DOIs from BOTH pages accounted for 12% (n = 58,475). The referral of DOI citations found in BOTH could not be assigned to WP:MED or non-WP:MED, as the page from which the referral was made was not provided with the data. While these results cannot provide evidence of greater citation referral from WP:MED than non WP:MED, they do provide benchmarks to assess strategies for changing referral patterns. These changes might include editors adopting new methods for designing and presenting citations or the introduction of teaching strategies that address the value of consulting citations as a tool for extending learning. PMID- 29267346 TI - Metabolomic profiling and stable isotope labelling of Trichomonas vaginalis and Tritrichomonas foetus reveal major differences in amino acid metabolism including the production of 2-hydroxyisocaproic acid, cystathionine and S-methylcysteine. AB - Trichomonas vaginalis and Tritrichomonas foetus are pathogens that parasitise, respectively, human and bovine urogenital tracts causing disease. Using LC-MS, reference metabolomic profiles were obtained for both species and stable isotope labelling with D-[U-13C6] glucose was used to analyse central carbon metabolism. This facilitated a comparison of the metabolic pathways of T. vaginalis and T. foetus, extending earlier targeted biochemical studies. 43 metabolites, whose identities were confirmed by comparison of their retention times with authentic standards, occurred at more than 3-fold difference in peak intensity between T. vaginalis and T. foetus. 18 metabolites that were removed from or released into the medium during growth also showed more than 3-fold difference between the species. Major differences were observed in cysteine and methionine metabolism in which homocysteine, produced as a bi-product of trans-methylation, is catabolised by methionine gamma-lyase in T. vaginalis but converted to cystathionine in T. foetus. Both species synthesise methylthioadenosine by an unusual mechanism, but it is not used as a substrate for methionine recycling. T. vaginalis also produces and exports high levels of S-methylcysteine, whereas only negligible levels were found in T. foetus which maintains significantly higher intracellular levels of cysteine. 13C-labeling confirmed that both cysteine and S methylcysteine are synthesised by T. vaginalis; S-methylcysteine can be generated by recombinant T. vaginalis cysteine synthase using phosphoserine and methanethiol. T. foetus contained higher levels of ornithine and citrulline than T. vaginalis and exported increased levels of putrescine, suggesting greater flux through the arginine dihydrolase pathway. T. vaginalis produced and exported hydroxy acid derivatives of certain amino acids, particularly 2-hydroxyisocaproic acid derived from leucine, whereas negligible levels of these metabolites occurred in T. foetus. PMID- 29267347 TI - Dynamic of HIV-testing after arrival in France for migrants from sub-Saharan Africa: The role of both health and social care systems. AB - OBJECTIVE: HIV testing is an important tool in the management of the HIV epidemic among key populations. We aimed to explore the dynamic of first-time HIV testing in France for sub-Saharan migrants after their arrival. METHODS: ANRS-Parcours is a retrospective life-event survey conducted from 2012 to 2013 in healthcare facilities in the Paris region, among 926 sub-Saharan HIV-infected migrants and 763 non-infected migrants. After describing the time to first HIV test in France and associated circumstances, we performed a discrete-time logistic regression to analyze the influence of socioeconomic position, contact with the healthcare system and sexual behaviors, on first-time HIV testing in France in migrants who arrived after 2000. RESULTS: Median first-time HIV testing occurred during the second year spent in France for non-infected men and women in both groups, and during the first year for men of the HIV group. The probability of testing increased with hospitalization and pregnancy for women of both groups. For non infected men unemployment and absence of a residence permit were associated with an increased probability of HIV testing [respectively, OR = 2.2 (1.2-4.1) and OR = 2.0 (1.1-3.5)]. Unemployment was also associated with an increased probability of first-time HIV-testing for women of the HIV group [OR: 1.7 (1.0-2.7)]. Occasional and multiple sexual relationships were associated with an increased probability of first-time testing only for HIV-infected women [OR: 2.2 (1.2-4.0) and OR = 2.4 (1.3-4.6)]. CONCLUSION: Access to first HIV testing in France is promoted by contact with the health care system and is facilitated for unemployed and undocumented migrants after arrival.However, testing should be offered more systematically and repeated in order to reduce time between HIV infection and diagnosis, especially for deprived people which are particularly vulnerable regarding HIV infection. PMID- 29267348 TI - Analysis of polypharmacy effects in older patients using Japanese Adverse Drug Event Report database. AB - Population aging is a global phenomenon, and choosing appropriate medical care for the elderly is critical. Polypharmacy is suspected to increase the risk of adverse events (AEs) in older patients. We examined the AE profiles associated with polypharmacy and aging using the Japanese Adverse Drug Event Report (JADER) database. We attempted to mitigate the effect of patient-related factors using a multiple-logistic regression technique and data subsetting. We selected case reports for AEs as specified in the Medical Dictionary for Regulatory Activities (MedDRA). The association between polypharmacy and "renal disorder" or "hepatic disorder" was evaluated using reporting odds ratio (ROR) and adjusted for covariates using multiple-logistic regression. For renal disorder, advanced polypharmacy showed higher adjusted RORs, because the value of administered drugs group [1.82 (1.76-1.88), >= 10] was higher than that of the number of administered drugs group [1.27 (1.24-1.31), 5-9]. The lower limit of the 95% confidence interval (CI) of adjusted ROR for age (>= 60 years) was > 1 for renal disorder. For hepatic disorder, the adjusted RORs were as follows: 1.17 (1.14 1.20) for the number of administered drugs group (5-9) and 1.14 (1.11-1.18) for the number of administered drugs group (>= 10). The adjusted RORs of hepatic disorder compared to those of renal disorder had lower adjusted RORs related to the increase in the number of administered drugs. Therefore, elderly individuals should be closely monitored for the occurrence of renal disorder when they are subjected to polypharmacy. This approach might apply to the simultaneous evaluation of the AE risk of polypharmacy and aging. PMID- 29267349 TI - Extraction optimization, purification and characterization of polysaccharides from the seed coat of black soybean. AB - In this study, the extraction of water-soluble polysaccharides from the seed coat of black soybean (BSCP) was investigated and optimized. A response surface methodology based on a Box-Behnken design (BBD) was used to optimize the extraction conditions as follows: extraction temperature, 100 degrees C; ratio of water to material, 22.3 mL/g; and extraction time, 133.2 min. Under these conditions, the experimental yield of polysaccharides was 10.56%, which was consistent with the predictive yield. A novel galactomannan, BSCP-1, with a molecular weight of 7.55 * 105 Da determined by high-performance gel permeation chromatography, was isolated from the black soybean seed coat. Through gas chromatography-mass spectrometry analysis, BSCP-1 was identified as a galactomannan consisting of galactose, mannose and rhamnose in a molar ratio of 6.01:3.56:1.00. Cytotoxicity against the human gastric carcinoma cancer cell line was also determined. PMID- 29267350 TI - What is a good result after clubfoot treatment? A Delphi-based consensus on success by regional clubfoot trainers from across Africa. AB - BACKGROUND: Congenital talipes equino-varus (CTEV), also known as clubfoot, is one of the most common congenital musculoskeletal malformations. Despite this, considerable variation exists in the measurement of deformity correction and outcome evaluation. This study aims to determine the criteria for successful clubfoot correction using the Ponseti technique in low resource settings through Africa. METHODS: Using the Delphi method, 18 experienced clubfoot practitioners and trainers from ten countries in Africa ranked the importance of 22 criteria to define an 'acceptable or good clubfoot correction' at the end of bracing with the Ponseti technique. A 10cm visual analogue scale was used. They repeated the rating with the results of the mean scores and standard deviation of the first test provided. The consistency among trainers was determined with the intra-class correlation coefficient (ICC). From the original 22 criteria, ten criteria with a mean score >7 and SD <2 were identified and were rated through a second Delphi round by 17 different clubfoot treatment trainers from 11 countries in Africa. The final definition consisted of all statements that achieved strong agreement, a mean score of >9 and SD<1.5. RESULTS: The consensus definition of a successfully treated clubfoot includes: (1) a plantigrade foot, (2) the ability to wear a normal shoe, (3) no pain, and (4) the parent is satisfied. Participants demonstrated good consistency in rating these final criteria (ICC 0.88; 0.74,0.97). CONCLUSIONS: The consistency of Ponseti technique trainers from Africa in rating criteria for a successful outcome of clubfoot management was good. The consensus definition includes basic physical assessment, footwear use, pain and parent satisfaction. PMID- 29267351 TI - The role of cinnamon as a modulator of the expression of genes related to antioxidant activity and lipid metabolism of laying quails. AB - Since cinnamon has vitamins and minerals in addition to antioxidants compounds in its chemical composition studies have shown the potential of cinnamon supplementation on some important characteristics in the performance of birds. Thus, this study was conducted under the hypothesis that the inclusion of cinnamon in the laying quail diet could influence the performance of the birds through the expression of genes related to antioxidant activity and lipid metabolism. To test this hypothesis, 144 Japanese quail (Coturnix japonica) with an initial age of 18 weeks and average weight of 133g were distributed in a completely randomized design with two treatments: no cinnamon supplementation (NCS-control group) and with supplementation of 9g/kg of cinnamon powder (CPS). The experiment lasted for 84 days. At the end of the experimental period, six animals from each treatment were euthanized by cervical dislocation, blood was collected and organs weighed. Liver tissue was collected for gene expression and biochemical analyses. We observed a significant effect of cinnamon inclusion on the weight of the pancreas (P = 0.0418), intestine (P = 0.0209) and ovary (P = 0.0389). Lower weights of the pancreas and intestine, and a higher ovary weight was observed in birds receiving the CPS diet. Quails fed with cinnamon supplementation also had better feed conversion per egg mass (2.426 g /g, P = 0.0126), and higher triglyceride (1516.60 mg/dL, P = 0.0207), uric acid (7.40 mg/dL, P = 0.0003) and VLDL (300.40 mg/dL, P = 0.0252) contents. A decreased content of thiobarbituric acid reactive substances (TBARS) and lower catalase activity was observed in the liver of quails from the CPS diet (0.086 nmoles/mg PTN, and 2.304 H2O2/min/mg PTN, respectively). Quails from the CPS group presented significantly greater expression of FAS (fatty acid synthase, 36,03 AU), ACC (Acetyl-CoA Carboxylase, 31.33 AU), APOAI (apolipoprotein A-I, 803,9 AU), ESR2 (estrogen receptor 2, 0.73 AU) SOD (superoxide dismutase, 4,933.9 AU) and GPx7 (glutathione peroxidase 7, 9.756 AU) than quails from the control group. These results allow us to suggest that cinnamon powder supplementation in the diet of laying quails can promote balance in the metabolism and better performance through the modulation of antioxidant activity and the expression of genes related to lipid metabolism. PMID- 29267352 TI - Urinary exosomal viral microRNA as a marker of BK virus nephropathy in kidney transplant recipients. AB - OBJECTIVE: Bkv-miR-B1-5p, one of the microRNAs encoded by BK virus, was recently reported to be elevated in the blood among the patients with BK virus nephropathy (BKVN). Urinary exosome was suggested to be a possible source of biomarker for kidney diseases, but it was unknown whether it could contain viral microRNA as well as human microRNAs. The aim of this study was to evaluate whether urinary exosomal BK viral microRNA were expressed during replication and could be used to diagnose BKVN in kidney transplant recipients. MATERIALS AND METHODS: In a cross sectional multicenter study, we collected and analyzed 458 graft biopsies from 385 kidney transplant recipients. Urine samples were collected at the time of graft biopsy, and microRNAs in urinary exosome were measured once. For 13 patients with BKVN and 67 age, sex-matched kidney transplant recipients, we measured BK viral microRNA B1-5p, 3p and human microRNA-16 in urinary exosomal fraction and compared the diagnostic value with BK viral load in plasma and urine. RESULTS: Pathology proven BKVN was diagnosed in 13 patients (2.8%). High levels of bkv-miR-B1-5p and bkv-miR-B1-3p were shown in all patients with BKVN. Meanwhile, plasma BK viral load assay (cut-off value of >= 4.0 log10 copies/mL) showed false negative in 3 cases and urinary BK viral load assay (cut-off value of >= 7.0 log10 copies/mL) showed false negative in 1 case among these 13 patients. The receiver operator characteristics curve analysis for bkv-miR-B1-5p and bkv-miR-B1-5p/miR-16 showed excellent discriminative power for the diagnosis of BKVN, with area under the curve values of 0.989 and 0.985, respectively. CONCLUSIONS: This study suggests that urinary exosomal bkv-miR-B1-5p and bkv-miR B1-5p/miR-16 could be surrogate markers for the diagnosis of BKVN. PMID- 29267353 TI - Degradation of RNA during lysis of Escherichia coli cells in agarose plugs breaks the chromosome. AB - The nucleoid of Escherichia coli comprises DNA, nucleoid associated proteins (NAPs) and RNA, whose role is unclear. We found that lysing bacterial cells embedded in agarose plugs in the presence of RNases caused massive fragmentation of the chromosomal DNA. This RNase-induced chromosomal fragmentation (RiCF) was completely dependent on the presence of RNase around lysing cells, while the maximal chromosomal breakage required fast cell lysis. Cell lysis in plugs without RNAse made the chromosomal DNA resistant to subsequent RNAse treatment. RiCF was not influenced by changes in the DNA supercoiling, but was influenced by growth temperature or age of the culture. RiCF was partially dependent on H-NS, histone-like nucleoid structuring- and global transcription regulator protein. The hupAB deletion of heat-unstable nucleoid protein (HU) caused increase in spontaneous fragmentation that was further increased when combined with deletions in two non-coding RNAs, nc1 and nc5. RiCF was completely dependent upon endonuclease I, a periplasmic deoxyribonuclease that is normally found inhibited by cellular RNA. Unlike RiCF, the spontaneous fragmentation in hupAB nc1 nc5 quadruple mutant was resistant to deletion of endonuclease I. RiCF-like phenomenon was observed without addition of RNase to agarose plugs if EDTA was significantly reduced during cell lysis. Addition of RNase under this condition was synergistic, breaking chromosomes into pieces too small to be retained by the pulsed field gels. RNase-independent fragmentation was qualitatively and quantitatively comparable to RiCF and was partially mediated by endonuclease I. PMID- 29267354 TI - Salmonella Typhimurium PagP- and UgtL-dependent resistance to antimicrobial peptides contributes to the gut colonization. AB - Mucosal barrier formed by cationic antimicrobial peptides (CAMPs) is believed to be crucial for host protection from pathogenic gut infection. However, some pathogens can develop resistance to the CAMPs to survive in hosts. Salmonella enterica is a common cause of acute diarrhea. During the course of this disease, the pathogen must continuously colonize the gut lumen, which contains CAMPs. However, it is incompletely understood whether the resistance of Salmonella strains to CAMPs contributes to the development of gut infections. PhoPQ two component system-dependent lipid A modifications confer resistance to CAMPs in S. enterica serovar Typhimurium. Therefore, we introduced mutations into the PhoPQ regulated genes in an S. Typhimurium strain, obtaining pagP ugtL and pmrA mutant strains. Each mutant strain demonstrated a distinct spectrum of the resistance to CAMPs. Using streptomycin mouse model for Salmonella diarrhea, we show that the pagP ugtL, but not pmrA, mutant strain had a gut colonization defect. Furthermore, the pagP ugtL, but not pmrA, mutant strain had decreased outer membrane integrity and susceptibility to magainin 2, an alpha-helical CAMP. Taken together, the PagP- and UgtL-dependent resistance to CAMPs was demonstrated to contribute to sustained colonization in the gut. This may be due to the robust outer membrane of S. Typhimurium, inducing the resistance to alpha-helical CAMPs such as alpha-defensins. Our findings indicate that the development of resistance to CAMPs is required for the S. Typhimurium gut infection. PMID- 29267355 TI - Health-related quality of life of subjects with Barrett's esophagus in a Chinese population. AB - AIM: The aim of this study was to investigate health-related quality of life (HRQoL) of a Chinese population with Barrett's esophagus (BE). METHODS: Data from subjects with BE from a single hospital were prospectively collected from October 2012 to December 2014. The exclusion criteria included total esophagectomy, severe cardiopulmonary deficiency, malignancy, or other unsuitable conditions for scope. All the enrolled cases were asked to complete the Reflux Disease Questionnaire (RDQ), the short form-12, (SF-12), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: In total, 139 subjects were enrolled, and the mean age of the cases was 61.85 years old. Most subjects had short-segment BE (SSBE) (92.8%) and non-dysplastic BE tissue (94.2%). The mean physical and mental composite scores, PCS and MCS, of SF-12 were 44.14 and 45.53, respectively. The SF-12 scores in BE individuals were similar in men and women, elderly and non elderly, LSBE and SSBE, coexisting EE and no-EE, and dysplastic and non dysplastic. The appearance of reflux symptoms tended to decrease SF-12 scores in affected individuals, especially heartburn. The rates of anxiety and depression accounted for 25.2% and 17.3% of these cases, respectively. CONCLUSION: Our study found HRQoL in BE patients was strongly associated with presentation of reflux symptoms. PMID- 29267356 TI - Evaluating the effectiveness of conservation and development investments in reducing deforestation and fires in Ankeniheny-Zahemena Corridor, Madagascar. AB - Forest conservation and REDD+ projects invest millions of dollars each year to reduce local communities' dependence on forests and prevent forest loss and degradation. However, to date, there is limited evidence on whether these investments are effective at delivering conservation outcomes. We explored the relationships between 600+ small-scale conservation and development investments that occurred from 2007 to 2014 and conservation outcomes (deforestation rates and fire detections) within Ankeniheny-Zahamena Corridor in Madagascar using linear fixed effects panel regressions. We derived annual changes in forest cover and fires from satellite remote sensing. We found a statistically significant correlation between presence of any investment and reduced deforestation rates in 2010 and 2011 -years with accelerated deforestation elsewhere in the study area. This result indicated investments abated deforestation rates during times of political instability and lack of governance following a 2009 coup in Madagascar. We also found a statistically significant relationship between presence of any investment and reduced fire detections in the study area, suggesting investments had an impact on reducing burning of forest for agriculture. For both outcomes (i.e., deforestation rates and fire detections), we found that more dollars invested led to greater conservation outcomes (i.e. fewer fires or less deforestation), particularly when funding was sustained for one to two years. Our findings suggest that conservation and development investments can reduce deforestation and fire incidence, but also highlight the many challenges and complexities in assessing relationships between investments and conservation outcomes in a dynamic landscape and a volatile political context. PMID- 29267357 TI - Climate change versus deforestation: Implications for tree species distribution in the dry forests of southern Ecuador. AB - Seasonally dry forests in the neotropics are heavily threatened by a combination of human disturbances and climate change; however, the severity of these threats is seldom contrasted. This study aims to quantify and compare the effects of deforestation and climate change on the natural spatial ranges of 17 characteristic tree species of southern Ecuador dry deciduous forests, which are heavily fragmented and support high levels of endemism as part of the Tumbesian ecoregion. We used 660 plant records to generate species distribution models and land-cover data to project species ranges for two time frames: a simulated deforestation scenario from 2008 to 2014 with native forest to anthropogenic land use conversion, and an extreme climate change scenario (CCSM4.0, RCP 8.5) for 2050, which assumed zero change from human activities. To assess both potential threats, we compared the estimated annual rates of species loss (i.e., range shifts) affecting each species. Deforestation loss for all species averaged approximately 71 km2/year, while potential climate-attributed loss was almost 21 km2/year. Moreover, annual area loss rates due to deforestation were significantly higher than those attributed to climate-change (P < 0.01). However, projections into the future scenario show evidence of diverging displacement patterns, indicating the potential formation of novel ecosystems, which is consistent with other species assemblage predictions as result of climate change. Furthermore, we provide recommendations for management and conservation, prioritizing the most threatened species such as Albizia multiflora, Ceiba trichistandra, and Cochlospermum vitifolium. PMID- 29267358 TI - Comparison of computer systems and ranking criteria for automatic melanoma detection in dermoscopic images. AB - Melanoma is the deadliest form of skin cancer, and early detection is crucial for patient survival. Computer systems can assist in melanoma detection, but are not widespread in clinical practice. In 2016, an open challenge in classification of dermoscopic images of skin lesions was announced. A training set of 900 images with corresponding class labels and semi-automatic/manual segmentation masks was released for the challenge. An independent test set of 379 images, of which 75 were of melanomas, was used to rank the participants. This article demonstrates the impact of ranking criteria, segmentation method and classifier, and highlights the clinical perspective. We compare five different measures for diagnostic accuracy by analysing the resulting ranking of the computer systems in the challenge. Choice of performance measure had great impact on the ranking. Systems that were ranked among the top three for one measure, dropped to the bottom half when changing performance measure. Nevus Doctor, a computer system previously developed by the authors, was used to participate in the challenge, and investigate the impact of segmentation and classifier. The diagnostic accuracy when using an automatic versus the semi-automatic/manual segmentation is investigated. The unexpected small impact of segmentation method suggests that improvements of the automatic segmentation method w.r.t. resemblance to semi automatic/manual segmentation will not improve diagnostic accuracy substantially. A small set of similar classification algorithms are used to investigate the impact of classifier on the diagnostic accuracy. The variability in diagnostic accuracy for different classifier algorithms was larger than the variability for segmentation methods, and suggests a focus for future investigations. From a clinical perspective, the misclassification of a melanoma as benign has far greater cost than the misclassification of a benign lesion. For computer systems to have clinical impact, their performance should be ranked by a high-sensitivity measure. PMID- 29267359 TI - SIRT2 gene has a classic SRE element, is a downstream target of serum response factor and is likely activated during serum stimulation. AB - The sirtuin proteins are an evolutionarily conserved family of NAD+-dependent deacetylases that regulate various cellular functions. Among the seven sirtuins, SIRT2 is predominantly found in the cytoplasm, and is present in a wide range of tissues. Recent studies indicate that SIRT2 plays an important role in metabolic homeostasis. Several studies indicate that SIRT2 is upregulated under serum deprivation conditions. Since the serum response factor gene usually responds rapidly to serum deprivation and/or serum restoration following deprivation, we hypothesized that a common mechanism may serve to regulate both SIRT2 and SRF during serum stimulation. Using a bioinformatics approach, we searched the SRF binding motif in the SIRT2 gene, and found one classic CArG element (CCATAATAGG) in the SIRT2 gene promoter, which was bound to SRF in the electrophoretic mobility shift assay (EMSA). Serum deprivation induced SIRT2 expression, while SRF and the SRF binding protein, p49/STRAP, repressed SIRT2 gene expression. SIRT2 gene expression was also repressed by the Rho/SRF inhibitor, CCG-1423. These data demonstrate that the classic SRE element in the SIRT2 gene promoter region is functional and therefore, SIRT2 gene is a downstream target of the Rho/SRF signaling pathway. The increased expression of SRF that was observed in the aged heart may affect SIRT2 gene expression and contribute to altered metabolic status in senescence. PMID- 29267360 TI - Stacked competitive networks for noise reduction in low-dose CT. AB - Since absorption of X-ray radiation has the possibility of inducing cancerous, genetic and other diseases to patients, researches usually attempt to reduce the radiation dose. However, reduction of the radiation dose associated with CT scans will unavoidably increase the severity of noise and artifacts, which can seriously affect diagnostic confidence. Due to the outstanding performance of deep neural networks in image processing, in this paper, we proposed a Stacked Competitive Network (SCN) approach to noise reduction, which stacks several successive Competitive Blocks (CB). The carefully handcrafted design of the competitive blocks was inspired by the idea of multi-scale processing and improvement the network's capacity. Qualitative and quantitative evaluations demonstrate the competitive performance of the proposed method in noise suppression, structural preservation, and lesion detection. PMID- 29267361 TI - Intestinal tract is an important organ for lowering serum uric acid in rats. AB - The kidney was recognized as a dominant organ for uric acid excretion. The main aim of the study demonstrated intestinal tract was an even more important organ for serum uric acid (SUA) lowering. Sprague-Dawley rats were treated normally or with antibiotics, uric acid, adenine, or inosine of the same molar dose orally or intraperitoneally for 5 days. Rat's intestinal tract was equally divided into 20 segments except the cecum. Uric acid in serum and intestinal segment juice was assayed. Total RNA in the initial intestinal tract and at the end ileum was extracted and sequenced. Protein expression of xanthine dehydrogenase (XDH) and urate oxidase (UOX) was tested by Western blot analysis. The effect of oral UOX in lowering SUA was investigated in model rats treated with adenine and an inhibitor of uric oxidase for 5 days. SUA in the normal rats was 20.93+/-6.98 MUg/ml, and total uric acid in the intestinal juice was 308.27+/-16.37 MUg, which is two times more than the total SUA. The uric acid was very low in stomach juice, and attained maximum in the juice of the first segment (duodenum) and then declined all the way till the intestinal end. The level of uric acid in the initial intestinal tissue was very high, where XDH and most of the proteins associated with bicarbonate secretion were up-regulated. In addition, SUA was decreased by oral UOX in model rats. The results suggested that intestinal juice was an important pool for uric acid, and intestinal tract was an important organ for SUA lowering. The uric acid distribution was associated with uric acid synthesis and secretion in the upper intestinal tract, and reclamation in the lower. PMID- 29267362 TI - Reasons for encounter and health problems managed by general practitioners in the rural areas of Beijing, China: A cross-sectional study. AB - OBJECTIVE: The purpose of this study was to describe the patients' reasons for encounter (RFE) and health problems managed by general practitioners (GPs) in the rural areas of Beijing to provide evidences for health services planning and GPs training. METHODS: This study was conducted at 14 community health service centers (CHSCs) in 6 suburban districts of Beijing, using a multistage sampling method. A total of 100 GPs was selected from the study sites. A self-designed data collection form was developed on the basis of Subjective-Objective Assessment-Plan (SOAP), including patient characteristics, RFEs, health problems, interventions, and consultation length. Each GP recorded and coded their 100 consecutive patients' RFEs and health problems with the International Classification of Primary Care, 2nd version (ICPC-2). Descriptive statistics were employed to describe the distribution of RFE and health problems. Student t-test and analysis of variance were used to compare the differences of mean number of RFE or health problems per encounter by patient characteristics. RESULTS: A total of 10,000 patient encounters with 13,705 RFEs and 15,460 health problems were recorded. The RFEs and health problems were mainly distributed in respiratory, circulatory, musculoskeletal, endocrine, metabolic and nutritional, and digestive systems. Cough and hypertension were the most common RFE and health problem, respectively. With increased ages, the mean number of RFEs decreased and the mean number of health problems increased. Patients with Beijing medical insurance had less RFEs and more health problems than those in other cities (p<0.001). Patients who had visited the CHSC previously and signed contracts with the GP team had more health problems than those who had not (p<0.001). CONCLUSIONS: These findings present a view of patients' demands and work contents of GPs in Beijing rural areas and can provide reference for health services planning and GPs training. PMID- 29267363 TI - RNA-Seq differential expression analysis: An extended review and a software tool. AB - The correct identification of differentially expressed genes (DEGs) between specific conditions is a key in the understanding phenotypic variation. High throughput transcriptome sequencing (RNA-Seq) has become the main option for these studies. Thus, the number of methods and softwares for differential expression analysis from RNA-Seq data also increased rapidly. However, there is no consensus about the most appropriate pipeline or protocol for identifying differentially expressed genes from RNA-Seq data. This work presents an extended review on the topic that includes the evaluation of six methods of mapping reads, including pseudo-alignment and quasi-mapping and nine methods of differential expression analysis from RNA-Seq data. The adopted methods were evaluated based on real RNA-Seq data, using qRT-PCR data as reference (gold-standard). As part of the results, we developed a software that performs all the analysis presented in this work, which is freely available at https://github.com/costasilvati/consexpression. The results indicated that mapping methods have minimal impact on the final DEGs analysis, considering that adopted data have an annotated reference genome. Regarding the adopted experimental model, the DEGs identification methods that have more consistent results were the limma+voom, NOIseq and DESeq2. Additionally, the consensus among five DEGs identification methods guarantees a list of DEGs with great accuracy, indicating that the combination of different methods can produce more suitable results. The consensus option is also included for use in the available software. PMID- 29267364 TI - Accounting for tourism benefits in marine reserve design. AB - Marine reserve design often considers potential benefits to conservation and/or fisheries but typically ignores potential revenues generated through tourism. Since tourism can be the main source of economic benefits for many marine reserves worldwide, ignoring tourism objectives in the design process might lead to sub-optimal outcomes. To incorporate tourism benefits into marine reserve design, we develop a bioeconomic model that tracks tourism and fisheries revenues through time for different management options and location characteristics. Results from the model show that accounting for tourism benefits will ultimately motivate greater ocean protection. Our findings demonstrate that marine reserves are part of the optimal economic solution even in situations with optimal fisheries management and low tourism value relative to fisheries. The extent of optimal protection depends on specific location characteristics, such as tourism potential and other local amenities, and the species recreational divers care about. Additionally, as tourism value increases, optimal reserve area also increases. Finally, we demonstrate how tradeoffs between the two services depend on location attributes and management of the fishery outside marine reserve borders. Understanding when unavoidable tradeoffs will arise helps identify those situations where communities must choose between competing interests. PMID- 29267366 TI - Comparative transcriptome analyses reveal the genetic basis underlying the immune function of three amphibians' skin. AB - Skin as the first barrier against external invasions plays an essential role for the survival of amphibians on land. Understanding the genetic basis of skin function is significant in revealing the mechanisms underlying immunity of amphibians. In this study, we de novo sequenced and comparatively analyzed skin transcriptomes from three different amphibian species, Andrias davidianus, Bufo gargarizans, and Rana nigromaculata Hallowell. Functional classification of unigenes in each amphibian showed high accordance, with the most represented GO terms and KEGG pathways related to basic biological processes, such as binding and metabolism and immune system. As for the unigenes, GO and KEGG distributions of conserved orthologs in each species were similar, with the predominantly enriched pathways including RNA polymerase, nucleotide metabolism, and defense. The positively selected orthologs in each amphibian were also similar, which were primarily involved in stimulus response, cell metabolic, membrane, and catalytic activity. Furthermore, a total of 50 antimicrobial peptides from 26 different categories were identified in the three amphibians, and one of these showed high efficiency in inhibiting the growth of different bacteria. Our understanding of innate immune function of amphibian skin has increased basis on the immune related unigenes, pathways, and antimicrobial peptides in amphibians. PMID- 29267367 TI - A portable optical reader and wall projector towards enumeration of bio conjugated beads or cells. AB - Measurement of the height of a packed column of cells or beads, which can be direclty related to the number of cells or beads present in a chamber, is an important step in a number of diagnostic assays. For example, haematocrit measurements may rapidly identify anemia or polycthemia. Recently, user-friendly and cost-efficient Lab-on-a-Chip devices have been developed towards isolating and counting cell sub-populations for diagnostic purposes. In this work, we present a low-cost optical module for estimating the filling level of packed magnetic beads within a Lab-on-a-Chip device. The module is compatible with a previously introduced, disposable microfluidic chip for rapid determination of CD4+ cell counts. The device is a simple optical microscope module is manufactured by 3D printing. An objective lens directly interrogates the height of packed beads which are efficiently isolated on the finger-actuated chip. Optionally, an inexpensive, battery-powered Light Emitting Diode may project a shadow of the microfluidic chip at approximately 50-fold magnification onto a nearby surface. The reader is calibrated with the filling levels of known concentrations of paramagnetic beads within the finger actuated chip. Results in direct and projector mode are compared to measurements from a conventional, inverted white-light microscope. All three read-out methods indicate a maximum variation of 6.5% between methods. PMID- 29267365 TI - Germ-line and somatic EPHA2 coding variants in lens aging and cataract. AB - Rare germ-line mutations in the coding regions of the human EPHA2 gene (EPHA2) have been associated with inherited forms of pediatric cataract, whereas, frequent, non-coding, single nucleotide variants (SNVs) have been associated with age-related cataract. Here we sought to determine if germ-line EPHA2 coding SNVs were associated with age-related cataract in a case-control DNA panel (> 50 years) and if somatic EPHA2 coding SNVs were associated with lens aging and/or cataract in a post-mortem lens DNA panel (> 48 years). Micro-fluidic PCR amplification followed by targeted amplicon (exon) next-generation (deep) sequencing of EPHA2 (17-exons) afforded high read-depth coverage (1000x) for > 82% of reads in the cataract case-control panel (161 cases, 64 controls) and > 70% of reads in the post-mortem lens panel (35 clear lens pairs, 22 cataract lens pairs). Novel and reference (known) missense SNVs in EPHA2 that were predicted in silico to be functionally damaging were found in both cases and controls from the age-related cataract panel at variant allele frequencies (VAFs) consistent with germ-line transmission (VAF > 20%). Similarly, both novel and reference missense SNVs in EPHA2 were found in the post-mortem lens panel at VAFs consistent with a somatic origin (VAF > 3%). The majority of SNVs found in the cataract case control panel and post-mortem lens panel were transitions and many occurred at di pyrimidine sites that are susceptible to ultraviolet (UV) radiation induced mutation. These data suggest that novel germ-line (blood) and somatic (lens) coding SNVs in EPHA2 that are predicted to be functionally deleterious occur in adults over 50 years of age. However, both types of EPHA2 coding variants were present at comparable levels in individuals with or without age-related cataract making simple genotype-phenotype correlations inconclusive. PMID- 29267368 TI - Management of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation (ECMO): An observational cohort study. AB - BACKGROUND: Intracranial hemorrhage (ICH) is a common complication in adults treated with extracorporeal membrane oxygenation (ECMO). The aim of this study was to identify predictors of outcome and investigate intervention strategies following ICH development in ECMO-treated adult patients. METHODS: We conducted a retrospective review of adult patients (>=18 years) who developed an ICH during ECMO treatment at the Karolinska University Hospital (Stockholm, Sweden) between September 2005 and May 2017. Outcome was assessed by 30-day mortality and Glasgow Outcome Scale (GOS) after 6 months. The statistical analysis was supplemented by a case series of patients who were surgically treated for an ICH. RESULTS: Sixty five patients developed an ICH during ECMO treatment. 30-day mortality was 74% (n = 48), and was significantly associated with low level of consciousness at ICH diagnosis (p = 0.036), presence of intraparenchymal hematoma (IPH) (p = 0.049), IPH volume (p = 0.002), presence of intraventricular hemorrhage (p = 0.001), subarachnoid hemorrhage Fisher grade (p<0.001), hydrocephalus (p<0.001), midline shift (p = 0.026) and absent basal cisterns (p<0.001). Among the 30-day survivors (n = 17), 63% (n = 10) had favorable neurological outcome (GOS 4-5) after six months. Five patients were surgically treated for their ICH, some with dire hemorrhagic consequences, however one patient made a complete recovery. CONCLUSIONS: ICH in adult ECMO patients is associated with a high mortality rate. Outcome predictors can help to identify patients where ICH treatment is indicated. Treating a patient with an ICH during ECMO represents an intricate balance between pro- and anticoagulatory demands. Furthermore, surgical treatment is associated with several risks but may be indicated in life-threatening lesions. Prospective studies are warranted. PMID- 29267369 TI - A novel cell exclusion zone assay with a barrier made from room temperature vulcanizing silicone rubber. AB - OBJECTIVE: To examine the usefulness of room temperature vulcanizing (RTV) silicone rubber as a barrier material for cell exclusion zone assays. METHODS: We created barriers using three types of RTV silicone rubber with differing viscosities. We then assessed the adherence of these barriers to culture dishes and their ease of removal from the dishes. We tested the effect of the newly created barriers on the extracellular matrix (ECM) protein fibronectin by attaching and then removing them from fibronectin-coated culture dishes. We also conducted cell exclusion zone assays with MIO-M1 cells using this new barrier in order to measure cell migration. We used real time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining to measure the effect of fibronectin on MIO-M1 cell migration and the effect of migration (with fibronectin coating) on basic fibroblast growth factor (bFGF) expression in MIO-M1 cells. RESULTS: Of the three types of RTV silicon rubber tested, KE-3495-T was the best in terms of adherence to the dish and ease of removal from the dish. When barrier attachment and removal tests were performed, this rubber type did not have an effect on the fibronectin that coated the dish. In the cell exclusion assay, removal of the barrier revealed that a cell-free area with a distinct margin had been created, which allowed us to conduct a quantitative assessment of migration. Fibronectin significantly promoted the migration of MIO-M1 cells (P = 0.02). In addition, both real time RT-PCR and immunohistological staining indicated that bFGF expression in migrating MIO-M1 cells was significantly higher than that in non-migrating cells (P = 0.03). CONCLUSIONS: RTV silicone rubber can be used to create an effective barrier in cell exclusion zone assays and allows simple and low-cost multi-parametric analysis of cell migration. PMID- 29267370 TI - Competitive cation binding computations of proton balance for reactions of the phosphagen and glycolytic energy systems within skeletal muscle. AB - Limited research and data has been published for the H+ coefficients for the metabolites and reactions involved in non-mitochondrial energy metabolism. The purpose of this investigation was to compute the fractional binding of H+, K+, Na+ and Mg2+ to 21 metabolites of skeletal muscle non-mitochondrial energy metabolism, resulting in 104 different metabolite-cation complexes. Fractional binding of H+ to these metabolite-cation complexes were applied to 17 reactions of skeletal muscle non-mitochondrial energy metabolism, and 8 conditions of the glycolytic pathway based on the source of substrate (glycogen vs. glucose), completeness of glycolytic flux, and the end-point of pyruvate vs. lactate. For pH conditions of 6.0 and 7.0, respectively, H+ coefficients (-'ve values = H+ release) for the creatine kinase, adenylate kinase, AMP deaminase and ATPase reactions were 0.8 and 0.97, -0.13 and -0.02, 1.2 and 1.09, and -0.01 and -0.66, respectively. The glycolytic pathway is net H+ releasing, regardless of lactate production, which consumes 1 H+. For glycolysis fueled by glycogen and ending in either pyruvate or lactate, H+ coefficients for pH 6.0 and 7.0 were -3.97 and 2.01 (pyruvate), and -1.96 and -0.01 (lactate), respectively. When starting with glucose, the same conditions result in H+ coefficients of -3.98 and -2.67, and 1.97 and -0.67, respectively. The most H+ releasing reaction of glycolysis is the glyceraldehyde-3-phosphate dehydrogenase reaction, with H+ coefficients for pH 6.0 and 7.0 of -1.58 and -0.76, respectively. Incomplete flux of substrate through glycolysis would increase net H+ release due to the absence of the pyruvate kinase and lactate dehydrogenase reactions, which collectively result in H+ coefficients for pH 6.0 and 7.0 of 1.35 and 1.88, respectively. The data presented provide an extensive reference source for academics and researchers to accurately profile the balance of protons for all metabolites and reactions of non-mitochondrial energy metabolism, and reveal the greater role of glycolysis in net H+ release than previously assumed. The data can also be used to improve the understanding of the cause of metabolic acidosis, and reveal mechanistic connections between H+ release within and from muscle and the electrochemical neutrality concepts that further refine acid-base balance in biological solutions. PMID- 29267371 TI - Population study evaluating fracture risk among patients with chronic osteomyelitis. AB - BACKGROUND: Studies investigating the fracture risk in patients with chronic osteomyelitis (COM) limited to case reports. This study evaluated the association between COM and subsequent fracture risk using population-based data. METHODS: A subset claims data of the Taiwan National Health Insurance was used to identify 7,147 patients with COM newly diagnosed in 1999-2005 without fracture history and 28,588 general population controls, frequency matched by sex, age and diagnosis date. The incident fractures was measured by the end of 2013. RESULTS: The incidence density of fracture was 1.94-fold greater in the COM cohort than in controls (21.5 vs. 11.1 per 1000 person-years), with the adjusted hazard ratio (HR) of 1.81 (95% CI: 1.67-1.95) for COM patients compared to controls after controlling for sex, age, and comorbidities of diabetes, osteoporosis, depression and end-stage renal disease in Cox proportional hazards regression. The fracture risk increased with age and women were at greater risk than men. The fracture incidence increased substantially in those with osteoporosis, 40.2 per 1000 person-years in COM patients. Site specific analysis showed a higher portion of incident fractures for lower limbs, 52.7% in COM cohort and 46.3% in controls. CONCLUSION: Findings in this 15-year follow-up observation support our hypothesis that patients with COM are at an elevated risk of subsequent fracture. COM patients and the elderly deserve adequate consultation and awareness for fracture prevention. PMID- 29267373 TI - Combinations of genetic variants associated with bipolar disorder. AB - The main objective of the study was to find genetic variants that in combination are significantly associated with bipolar disorder. In previous studies of bipolar disorder, combinations of three and four single nucleotide polymorphisms (SNP) genotypes taken from 803 SNPs were analyzed, and five clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of ten SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the five previous clusters were identified in the genomes of 266 or 44% of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome.The SNP genotypes in the smaller combinations were the normal homozygote, heterozygote or variant homozygote. In the combinations containing 10 SNP genotypes almost all the genotypes were the normal homozygote. Such a finding may indicate that accumulation in the genome of combinations containing few SNP genotypes may be a risk factor for bipolar disorder when those combinations contain relatively many rare SNP genotypes, whereas combinations need to contain many SNP genotypes to be a risk factor when most of the SNP genotypes are the normal homozygote. PMID- 29267374 TI - Association of toll-like receptors polymorphism and intrauterine transmission of cytomegalovirus. AB - BACKGROUND: Congenital Cytomegalovirus (CMV) is a very common intrauterine infection which can cause severe developmental disabilities. Transmission of the virus to the fetus occurs in only 40% of primarily infected women. The probability of intrauterine transmission is higher when infection occurs during the second trimester of pregnancy than in the first trimester. The Toll-like receptors (TLRs) protein family plays a key role in both innate immune response to CMV infections and in normal pregnancy. Specific single nucleotide polymorphisms (SNPs) in TLRs can affect CMV infections and maternal-fetal interface expression. Therefore, TLR SNPs could be involved in intrauterine transmission determination. STUDY AIM: To establish a correlation between TLR2 (rs4696480, rs3804100, rs1898830), TLR3 (rs3775291) and TLR7(rs179008) SNPs with CMV intrauterine transmission during the first and second trimester. METHODS: SNPs of 83 pregnant women with primary CMV were analyzed by Real-Time PCR and PCR RFLP assay and compared to intrauterine transmission state. RESULTS: Women bearing the GG genotype in the rs1898830 TLR2 SNP who were infected with CMV during the second trimester did not transmit the virus to the fetus. Likewise, in the co-dominant or recessive models of this SNP, a significant association was found between the genotypes and CMV intrauterine transmission. In all cohort women or in women infected during the first trimester, no such associations were found between the tested SNPs and intrauterine transmission of the virus. CONCLUSION: Women bearing the GG genotype in the rs1898830 SNP, who are infected with CMV during the second trimester of pregnancy, have a low likelihood of transmitting the virus to the fetus. PMID- 29267372 TI - Cardiac-specific ablation of the E3 ubiquitin ligase Mdm2 leads to oxidative stress, broad mitochondrial deficiency and early death. AB - The maintenance of normal heart function requires proper control of protein turnover. The ubiquitin-proteasome system is a principal regulator of protein degradation. Mdm2 is the main E3 ubiquitin ligase for p53 in mitotic cells thereby regulating cellular growth, DNA repair, oxidative stress and apoptosis. However, which of these Mdm2-related activities are preserved in differentiated cardiomyocytes has yet to be determined. We sought to elucidate the role of Mdm2 in the control of normal heart function. We observed markedly reduced Mdm2 mRNA levels accompanied by highly elevated p53 protein expression in the hearts of wild type mice subjected to myocardial infarction or trans-aortic banding. Accordingly, we generated conditional cardiac-specific Mdm2 gene knockout (Mdm2f/f;mcm) mice. In adulthood, Mdm2f/f;mcm mice developed spontaneous cardiac hypertrophy, left ventricular dysfunction with early mortality post-tamoxifen. A decreased polyubiquitination of myocardial p53 was observed, leading to its stabilization and activation, in the absence of acute stress. In addition, transcriptomic analysis of Mdm2-deficient hearts revealed that there is an induction of E2f1 and c-Myc mRNA levels with reduced expression of the Pgc 1a/Ppara/Esrrb/g axis and Pink1. This was associated with a significant degree of cardiomyocyte apoptosis, and an inhibition of redox homeostasis and mitochondrial bioenergetics. All these processes are early, Mdm2-associated events and contribute to the development of pathological hypertrophy. Our genetic and biochemical data support a role for Mdm2 in cardiac growth control through the regulation of p53, the Pgc-1 family of transcriptional coactivators and the pivotal antioxidant Pink1. PMID- 29267375 TI - Breakthrough seizures-Further analysis of the Standard versus New Antiepileptic Drugs (SANAD) study. AB - OBJECTIVES: To develop prognostic models for risk of a breakthrough seizure, risk of seizure recurrence after a breakthrough seizure, and likelihood of achieving 12-month remission following a breakthrough seizure. A breakthrough seizure is one that occurs following at least 12 months remission whilst on treatment. METHODS: We analysed data from the SANAD study. This long-term randomised trial compared treatments for participants with newly diagnosed epilepsy. Multivariable Cox models investigated how clinical factors affect the probability of each outcome. Best fitting multivariable models were produced with variable reduction by Akaike's Information Criterion. Risks associated with combinations of risk factors were calculated from each multivariable model. RESULTS: Significant factors in the multivariable model for risk of a breakthrough seizure following 12-month remission were number of tonic-clonic seizures by achievement of 12 month remission, time taken to achieve 12-month remission, and neurological insult. Significant factors in the model for risk of seizure recurrence following a breakthrough seizure were total number of drugs attempted to achieve 12-month remission, time to achieve 12-month remission prior to breakthrough seizure, and breakthrough seizure treatment decision. Significant factors in the model for likelihood of achieving 12-month remission after a breakthrough seizure were gender, age at breakthrough seizure, time to achieve 12-month remission prior to breakthrough, and breakthrough seizure treatment decision. CONCLUSIONS: This is the first analysis to consider risk of a breakthrough seizure and subsequent outcomes. The described models can be used to identify people most likely to have a breakthrough seizure, a seizure recurrence following a breakthrough seizure, and to achieve 12-month remission following a breakthrough seizure. The results suggest that focussing on achieving 12-month remission swiftly represents the best therapeutic aim to reduce the risk of a breakthrough seizure and subsequent negative outcomes. This will aid individual patient risk stratification and the design of future epilepsy trials. PMID- 29267376 TI - Few long-term consequences after prolonged maternal separation in female Wistar rats. AB - Environmental factors during the early-life period are known to have long-term consequences for the adult phenotype. An intimate interplay between genes and environment shape the individual and may affect vulnerability for psychopathology in a sex-dependent manner. A rodent maternal separation model was here used to study the long-term effects of different early-life rearing conditions on adult behavior, HPA axis activity and long-term voluntary alcohol intake in female rats. Litters were subjected to 15 min (MS15) or 360 min (MS360) of daily maternal separation during postnatal day 1-21. In adulthood, the behavioral profiles were investigated using the multivariate concentric square fieldTM (MCSF) test or examined for HPA axis reactivity by cat-odor exposure with subsequent characterization of voluntary alcohol intake and associated changes in HPA axis activity. Adult female MS360 offspring showed mostly no, or only minor, effects on behavior, HPA axis reactivity and long-term alcohol intake relative to MS15. Instead, more pronounced effects were found dependent on changes in the natural hormonal cycle or by the choice of animal supplier. However, changes were revealed in corticosterone load after long-term alcohol access, as females subjected to MS360 had higher concentrations of fecal corticosterone. The present findings are in line with and expand on previous studies on the long-term effects of maternal separation in female rats with regard to behavior, HPA axis activity and voluntary alcohol intake. It can also be a window into further studies detailing how early-life experiences interact with other risk and protective factors to impact the adult phenotype and how possible sex differences play a role. PMID- 29267377 TI - Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition. AB - Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth. PMID- 29267379 TI - Correction: HBV infection in untreated HIV-infected adults in Maputo, Mozambique. AB - [This corrects the article DOI: 10.1371/journal.pone.0181836.]. PMID- 29267378 TI - The immunological mechanisms that control pneumococcal carriage. AB - Colonization of the human nasopharynx by pneumococcus is extremely common and is both the primary reservoir for transmission and a prerequisite for disease. Current vaccines targeting the polysaccharide capsule effectively prevent colonization, conferring herd protection within vaccinated communities. However, these vaccines cover only a subset of all circulating pneumococcal strains, and serotype replacement has been observed. Given the success of pneumococcal conjugate vaccine (PCV) in preventing colonization in unvaccinated adults within vaccinated communities, reducing nasopharyngeal colonization has become an outcome of interest for novel vaccines. Here, we discuss the immunological mechanisms that control nasopharyngeal colonization, with an emphasis on findings from human studies. Increased understanding of these immunological mechanisms is required to identify correlates of protection against colonization that will facilitate the early testing and design of novel vaccines. PMID- 29267380 TI - Fiber type-specific afferent nerve activity induced by transient contractions of rat bladder smooth muscle in pathological states. AB - Bladder smooth muscle shows spontaneous phasic contractions, which undergo a variety of abnormal changes depending on pathological conditions. How abnormal contractions affect the activity of bladder afferent nerves remains to be fully tested. In this study, we examined the relationship between transient increases in bladder pressure, representing transient contraction of bladder smooth muscle, and spiking patterns of bladder afferent fibers of the L6 dorsal root, in rat pathological models. All recordings were performed at a bladder pressure of approximately 10 cmH2O by maintaining the degree of bladder filling. In the cyclophosphamide-induced model, both Adelta and C fibers showed increased sensitivity to transient bladder pressure increases. In the prostaglandin E2 induced model, Adelta fibers, but not C fibers, specifically showed overexcitation that was time-locked with transient bladder pressure increases. These fiber type-specific changes in nerve spike patterns may underlie the symptoms of urinary bladder diseases. PMID- 29267382 TI - Stably expressed APOBEC3H forms a barrier for cross-species transmission of simian immunodeficiency virus of chimpanzee to humans. AB - APOBEC3s (A3s) are potent restriction factors of human immunodeficiency virus type 1/simian immunodeficiency viruses (HIV-1/SIV), and can repress cross-species transmissions of lentiviruses. HIV-1 originated from a zoonotic infection of SIV of chimpanzee (SIVcpz) to humans. However, the impact of human A3s on the replication of SIVcpz remains unclear. By using novel SIVcpz reporter viruses, we identified that human APOBEC3B (A3B) and APOBEC3H (A3H) haplotype II strongly reduced the infectivity of SIVcpz, because both of them are resistant to SIVcpz Vifs. We further demonstrated that human A3H inhibited SIVcpz by deaminase dependent as well independent mechanisms. In addition, other stably expressed human A3H haplotypes and splice variants showed strong antiviral activity against SIVcpz. Moreover, most SIV and HIV lineage Vif proteins could degrade chimpanzee A3H, but no Vifs from SIVcpz and SIV of gorilla (SIVgor) lineages antagonized human A3H haplotype II. Expression of human A3H hapII in human T cells efficiently blocked the spreading replication of SIVcpz. The spreading replication of SIVcpz was also restricted by stable A3H in human PBMCs. Thus, we speculate that stably expressed human A3H protects humans against the cross species transmission of SIVcpz and that SIVcpz spillover to humans may have started in individuals that harbor haplotypes of unstable A3H proteins. PMID- 29267384 TI - Correction: Past alcohol consumption and incident atrial fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0185228.]. PMID- 29267381 TI - Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains. AB - A fundamental role of the Hsp90 and Cdc37 chaperones in mediating conformational development and activation of diverse protein kinase clients is essential in signal transduction. There has been increasing evidence that the Hsp90-Cdc37 system executes its chaperoning duties by recognizing conformational instability of kinase clients and modulating their folding landscapes. The recent cryo electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex has provided a framework for dissecting regulatory principles underlying differentiation and recruitment of protein kinase clients to the chaperone machinery. In this work, we have combined atomistic simulations with protein stability and network-based rigidity decomposition analyses to characterize dynamic factors underlying allosteric mechanism of the chaperone-kinase cycle and identify regulatory hotspots that control client recognition. Through comprehensive characterization of conformational dynamics and systematic identification of stabilization centers in the unbound and client- bound Hsp90 forms, we have simulated key stages of the allosteric mechanism, in which Hsp90 binding can induce instability and partial unfolding of Cdk4 client. Conformational landscapes of the Hsp90 and Cdk4 structures suggested that client binding can trigger coordinated dynamic changes and induce global rigidification of the Hsp90 inter-domain regions that is coupled with a concomitant increase in conformational flexibility of the kinase client. This process is allosteric in nature and can involve reciprocal dynamic exchanges that exert global effect on stability of the Hsp90 dimer, while promoting client instability. The network-based rigidity analysis and emulation of thermal unfolding of the Cdk4-cyclin D complex and Hsp90-Cdc37-Cdk4 complex revealed weak spots of kinase instability that are present in the native Cdk4 structure and are targeted by the chaperone during client recruitment. Our findings suggested that this mechanism may be exploited by the Hsp90-Cdc37 chaperone to recruit and protect intrinsically dynamic kinase clients from degradation. The results of this investigation are discussed and interpreted in the context of diverse experimental data, offering new insights into mechanisms of chaperone regulation and binding. PMID- 29267383 TI - On the validity and consistency of misjudgment of stepping ability in young and older adults. AB - Disparities between perceived and actual physical abilities have been shown in older adults and may lead to balance loss or falls. However, it is unclear whether one's misjudgment is an inherent trait and thus consistent across different tasks, and whether this misjudgment is age-related. We measured the degree of misjudgment in young and older adults on four different stepping tasks; stepping over a raised bar, crossing a declining cord by stepping over it at a self-selected height, crossing a virtual river by stepping over it at a self selected width, and making a recovery step after release from an inclined position. Before comparison, we carefully checked the validity of the different tasks to determine the misjudgment. No substantial differences were found in the amplitude of the misjudgment between the age groups, and the degree of misjudgment did not transfer across different stepping tasks. However, since only one task (i.e., stepping over a raised bar) met our criteria for validly assessing one's misjudgment, it remains unclear whether the degree of misjudgment is task-specific or an inherent trait. These findings stress the importance of testing the construct validity of the task, prior to the examination of the misjudgment of stepping ability. PMID- 29267385 TI - Correction: Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors. AB - [This corrects the article DOI: 10.1371/journal.pone.0177683.]. PMID- 29267386 TI - High-frequency conductive hearing loss as a diagnostic test for incomplete ossicular discontinuity in non-cholesteatomatous chronic suppurative otitis media. AB - Chronic suppurative otitis media, with or without cholesteatoma, may lead to erosion of the ossicles and discontinuity of the ossicular chain. In incomplete ossicular discontinuity (IOD), partial erosion of the ossicles occurs, but some sound transmission is noted throughout the ossicular chain. High-frequency conductive hearing loss (HfCHL) has been considered a hallmark of incomplete ossicular discontinuity. This study aims to evaluate the use of HfCHL as a preoperative predictor of IOD in patients with non-cholesteatomatous chronic suppurative otitis media. The HfCHL test was defined as the preoperative air-bone gap (ABG) at 4 kHz minus the average of the ABG at 0.25 and 0.5 kHz. The test was applied in 328 patients before surgery and compared to intraoperative findings as the gold standard. At surgery, 201 (61.3%) patients had an intact ossicular chain, 44 (13.4%) had a complete ossicular discontinuity, and 83 (25.3%) exhibited an IOD. The best cutoff level was calculated as 10 dB. The HfCHL test to diagnose IOD had a sensitivity of 83% and a specificity of 92% with a post test probability of 78% and a likelihood ratio of 10.2. We concluded that the HfCHL test is highly effective in predicting IOD in patients with non cholesteatomatous chronic suppurative otitis media and that it should be used routinely as a screening test prior to surgery. PMID- 29267387 TI - Identification of double-yolked duck egg using computer vision. AB - The double-yolked (DY) egg is quite popular in some Asian countries because it is considered as a sign of good luck, however, the double yolk is one of the reasons why these eggs fail to hatch. The usage of automatic methods for identifying DY eggs can increase the efficiency in the poultry industry by decreasing egg loss during incubation or improving sale proceeds. In this study, two methods for DY duck egg identification were developed by using computer vision technology. Transmittance images of DY and single-yolked (SY) duck eggs were acquired by a CCD camera to identify them according to their shape features. The Fisher's linear discriminant (FLD) model equipped with a set of normalized Fourier descriptors (NFDs) extracted from the acquired images and the convolutional neural network (CNN) model using primary preprocessed images were built to recognize duck egg yolk types. The classification accuracies of the FLD model for SY and DY eggs were 100% and 93.2% respectively, while the classification accuracies of the CNN model for SY and DY eggs were 98% and 98.8% respectively. The CNN-based algorithm took about 0.12 s to recognize one sample image, which was slightly faster than the FLD-based (about 0.20 s). Finally, this work compared two classification methods and provided the better method for DY egg identification. PMID- 29267388 TI - Poverty and disability in low- and middle-income countries: A systematic review. AB - INTRODUCTION: Disability and poverty are believed to operate in a cycle, with each reinforcing the other. While agreement on the existence of a link is strong, robust empirical evidence substantiating and describing this potential association is lacking. Consequently, a systematic review was undertaken to explore the relationship between disability and economic poverty, with a focus on the situation in low and middle income countries (LMICs). METHODS: Ten electronic databases were searched to retrieve studies of any epidemiological design, published between 1990-March 2016 with data comparing the level of poverty between people with and without disabilities in LMICs (World Bank classifications). Poverty was defined using economic measures (e.g. assets, income), while disability included both broad assessments (e.g. self-reported functional or activity limitations) and specific impairments/disorders. Data extracted included: measures of association between disability and poverty, population characteristics and study characteristics. Proportions of studies finding positive, negative, null or mixed associations between poverty and disability were then disaggregated by population and study characteristics. RESULTS: From the 15,500 records retrieved and screened, 150 studies were included in the final sample. Almost half of included studies were conducted in China, India or Brazil (n = 70, 47%). Most studies were cross-sectional in design (n = 124, 83%), focussed on specific impairment types (n = 115, 77%) and used income as the measure for economic poverty (n = 82, 55%). 122 studies (81%) found evidence of a positive association between disability and a poverty marker. This relationship persisted when results were disaggregated by gender, measure of poverty used and impairment types. By country income group at the time of data collection, the proportion of country-level analyses with a positive association increased with the rising income level, with 59% of low-income, 67% of lower middle and 72% of upper-middle income countries finding a positive relationship. By age group, the proportion of studies reporting a positive association between disability and poverty was lowest for older adults and highest for working-age adults (69% vs. 86%). CONCLUSIONS: There is strong evidence for a link between disability and poverty in LMICs and an urgent need for further research and programmatic/policy action to break the cycle. PMID- 29267389 TI - An effective assessment method of spinal flexibility to predict the initial in orthosis correction on the patients with adolescent idiopathic scoliosis (AIS). AB - BACKGROUND: Spinal flexibility is an essential parameter for clinical decision making on the patients with adolescent idiopathic scoliosis (AIS). Various methods are proposed to assess spinal flexibility, but which assessment method is more effective to predict the effect of orthotic treatment is unclear. OBJECTIVE: To investigate an effective assessment method of spinal flexibility to predict the initial in-orthosis correction, among the supine, prone, sitting with lateral bending and prone with lateral bending positions. METHODS: Thirty-five patients with AIS (mean Cobb angle: 28 degrees +/- 7 degrees ; mean age: 12 +/- 2 years; Risser sign: 0-2) were recruited. Before orthosis fitting, spinal flexibility was assessed by an ultrasound system in 4 positions (apart from standing) including supine, prone, sitting with lateral bending and prone with lateral bending. After orthosis fitting, the initial in-orthosis correction was routinely assessed by whole spine standing radiograph. Comparisons and correlation analyses were performed between the spinal flexibility in the 4 positions and the initial in orthosis correction. RESULTS: The mean in-orthosis correction was 41% while the mean curve correction (spinal flexibility) in the 4 studied positions were 40% (supine), 42% (prone), 127% (prone with lateral bending) and 143% (sitting with lateral bending). The correlation coefficients between initial in-orthosis correction and curve correction (spinal flexibility) in the 4 studied positions were r = 0.66 (supine), r = 0.75 (prone), r = 0.03 (prone with lateral bending) and r = 0.04 (sitting with lateral bending). CONCLUSIONS: The spinal flexibility in the prone position is the closest to and most correlated with the initial in orthosis correction among the 4 studied positions. Thus, the prone position could be an effective method to predict the initial effect of orthotic treatment on the patients with AIS. PMID- 29267390 TI - Association of Marek's Disease induced immunosuppression with activation of a novel regulatory T cells in chickens. AB - Marek's Disease Virus (MDV) is an alphaherpesvirus that infects chickens, transforms CD4+ T cells and causes deadly lymphomas. In addition, MDV induces immunosuppression early during infection by inducing cell death of the infected lymphocytes, and potentially due to activation of regulatory T (Treg)-cells. Furthermore, immunosuppression also occurs during the transformation phase of the disease; however, it is still unknown how the disease can suppress immune response prior or after lymphoma formation. Here, we demonstrated that chicken TGF-beta+ Treg cells are found in different lymphoid tissues, with the highest levels found in the gut-associated lymphoid tissue (cecal tonsil: CT), fostering an immune-privileged microenvironment exerted by TGF-beta. Surprisingly, significantly higher frequencies of TGF-beta+ Treg cells are found in the spleens of MDV-susceptible chicken lines compared to the resistant line, suggesting an association between TGF-beta+ Treg cells and host susceptibility to lymphoma formation. Experimental infection with a virulent MDV elevated the levels of TGF beta+ Treg cells in the lungs as early as 4 days post infection, and during the transformation phase of the disease in the spleens. In contrast to TGF-beta+ Treg cells, the levels of CD4+CD25+ T cells remained unchanged during the infection and transformation phase of the disease. Furthermore, our results demonstrate that the induction of TGF-beta+ Treg cells is associated with pathogenesis of the disease, as the vaccine strain of MDV did not induce TGF-beta+ Treg cells. Similar to human haematopoietic malignant cells, MDV-induced lymphoma cells expressed high levels of TGF-beta but very low levels of TGF-beta receptor I and II genes. The results confirm that COX-2/ PGE2 pathway is involved in immunosuppression induced by MDV-lymphoma cells. Taken together, our results revealed a novel TGF-beta+ Treg subset in chickens that is activated during MDV infection and tumour formation. PMID- 29267391 TI - EAG response and behavioral orientation of Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae) to synthetic host-associated volatiles. AB - Dastarcus helophoroides Fairmaire (Coleoptera: Bothrideridae) is an effective predatory beetle of larvae and pupae of several cerambycid beetles including Monochamus alternatus and Anoplophora glabripennis. Electroantennography (EAG) and a dynamic two-choice olfactometer were respectively used to measure the antennal and behavioral responses of both sexes to selected volatile compounds. Female and male D. helophoroides exhibited similar EAG and behavioral responses. Significant dose-dependent EAG responses in both sexes were elicited by nonanal, octanal, cis-3-hexenol, 3-carene, (R)-(+)-alpha-pinene, (S)-(-)-alpha-pinene, (R) (+)-limonene and (S)-(-)-limonene. Female and male beetles were repelled at high concentration by cis-3-hexenol and (S)-(-)-limonene, respectively. Both sexes of D. helophoroides were significantly attracted to nonanal, cis-3-hexenol, 3-carene and (R)-(+)-limonene even at low concentrations. These compounds might be used either individually or in mixtures for developing biological control methods to attract this predatory beetle into forest stands threatened by cerambycid beetles. PMID- 29267393 TI - Correction: A cluster-randomized controlled study to evaluate a team coaching concept for improving teamwork and patient-centeredness in rehabilitation teams. AB - [This corrects the article DOI: 10.1371/journal.pone.0180171.]. PMID- 29267392 TI - A paradigm shift: The mitoproteomes of procyclic and bloodstream Trypanosoma brucei are comparably complex. PMID- 29267394 TI - Correction: D-galactose-induced brain ageing model: A systematic review and meta analysis on cognitive outcomes and oxidative stress indices. AB - [This corrects the article DOI: 10.1371/journal.pone.0184122.]. PMID- 29267395 TI - Variability of ultraplankton composition and distribution in an oligotrophic coastal ecosystem of the NW Mediterranean Sea derived from a two-year survey at the single cell level. AB - Ultraplankton [heterotrophic prokaryotes and ultraphytoplankton (<10 MUm)] were monitored weekly over two years (2009 & 2010) in a coastal area of the NW Mediterranean Sea. Six clusters were differentiated by flow cytometry on the basis of their optical properties, two heterotrophic prokaryote (HP) subgroups labelled LNA and HNA (low and high nucleic acid content respectively), Prochlorococcus, Synechococcus, autotrophic picoeukaryotes and nanoeukaryotes. HP represented an important component of the microbial assemblage over the survey with relatively small abundance variation through seasons. The carbon biomass ratio HP/ultraphytoplankton averaged 0.45, however this ratio exceeded 1 during spring. Ultraphytoplankton biomass made about 50% of the total autotrophic carbon estimates but this contribution increased up to 97% and 67% during the 2009 and 2010 spring periods respectively. Within ultraphytoplankton, nanoeukaryote represent the most important ultraphytoplankton group in terms of autotrophic carbon biomass (up to 70%). Picoeukaryote maximum abundance occurred in winter. Synechococcus was the most abundant population (maximum 1.2 x 10 5 cells cm-3) particularly in spring where it represented up to 54% of ultraphytoplankton carbon biomass. The warmer winter-spring temperatures and the lengthening of the stratification period created a favorable situation for the earlier appearance of Synechococcus and its persistence throughout summer, paralleling Prochlorococcus development. Prochlorococcus was dominant over summer and autumn with concentrations up to 1.0 * 10 5 cells cm-3. While the abundance of Synechococcus throughout survey was of the same order as that reported in western Mediterranean Sea, Prochlorococcus was more abundant and similar to the more typical oligotrophic and warm waters. The abundance variation of the ultraplankton components through the survey was relatable to variations in the hydrological and nutrient conditions. PMID- 29267396 TI - Users' thoughts and opinions about a self-regulation-based eHealth intervention targeting physical activity and the intake of fruit and vegetables: A qualitative study. AB - PURPOSE: EHealth interventions are effective in changing health behaviours, such as increasing physical activity and altering dietary habits, but suffer from high attrition rates. In order to create interventions that are adapted to end-users, in-depth investigations about their opinions and preferences are required. As opinions and preferences may vary for different target groups, we explored these in two groups: the general population and a clinical sample. METHODS: Twenty adults from the general population (mean age = 42.65, 11 women) and twenty adults with type 2 diabetes (mean age = 64.30, 12 women) performed 'MyPlan 1.0', which is a self-regulation-based eHealth intervention designed to increase physical activity and the intake of fruit and vegetables in the general population. The opinions and preferences of end-users were explored using a think aloud procedure and a questionnaire. During a home visit, participants were invited to think aloud while performing 'MyPlan 1.0'. The thoughts were transcribed verbatim and inductive thematic analysis was applied. RESULTS: Both groups had similar opinions regarding health behaviours and 'MyPlan 1.0'. Participants generally liked the website, but often experienced it as time-consuming. Furthermore, they regularly mentioned that a mobile application would be useful to remind them about their goals on a daily basis. Finally, users' ideas about how to pursue health behaviours often hindered them to correctly use the website. CONCLUSIONS: Although originally created for the general population, 'MyPlan 1.0' can also be used in adults with type 2 diabetes. Nevertheless, more adaptations are needed to make the eHealth intervention more convenient and less time-consuming. Furthermore, users' ideas regarding a healthy lifestyle should be taken into account when designing online interventions. PMID- 29267397 TI - Metagenomic analysis of soil and freshwater from zoo agricultural area with organic fertilization. AB - Microbial communities drive biogeochemical cycles in agricultural areas by decomposing organic materials and converting essential nutrients. Organic amendments improve soil quality by increasing the load of essential nutrients and enhancing the productivity. Additionally, fresh water used for irrigation can affect soil quality of agricultural soils, mainly due to the presence of microbial contaminants and pathogens. In this study, we investigated how microbial communities in irrigation water might contribute to the microbial diversity and function of soil. Whole-metagenomic sequencing approaches were used to investigate the taxonomic and the functional profiles of microbial communities present in fresh water used for irrigation, and in soil from a vegetable crop, which received fertilization with organic compost made from animal carcasses. The taxonomic analysis revealed that the most abundant genera were Polynucleobacter (~8% relative abundance) and Bacillus (~10%) in fresh water and soil from the vegetable crop, respectively. Low abundance (0.38%) of cyanobacterial groups were identified. Based on functional gene prediction, denitrification appears to be an important process in the soil community analysed here. Conversely, genes for nitrogen fixation were abundant in freshwater, indicating that the N-fixation plays a crucial role in this particular ecosystem. Moreover, pathogenicity islands, antibiotic resistance and potential virulence related genes were identified in both samples, but no toxigenic genes were detected. This study provides a better understanding of the community structure of an area under strong agricultural activity with regular irrigation and fertilization with an organic compost made from animal carcasses. Additionally, the use of a metagenomic approach to investigate fresh water quality proved to be a relevant method to evaluate its use in an agricultural ecosystem. PMID- 29267398 TI - Annexin A5 reduces early plaque formation in ApoE -/- mice. AB - Annexin A5 (AnxA5) exerts anti-inflammatory, anticoagulant and anti-apoptotic effects through its binding to cell surface expressed phosphatidylserine. We previously showed that AnxA5 can stabilize advanced atherosclerotic plaques by reducing macrophage infiltration. We now investigated the effects of AnxA5 administration on the onset of atherosclerosis development. Eight-week-old ApoE-/ mice were fed a western diet while being administered AnxA5 or control (M1234) for a total of 6 weeks. AnxA5 administration reduced plaque size in the aortic root as well as the aortic arch by 36% and 55% respectively. As determined by immunohistochemistry, administration of AnxA5 further stabilized plaque by reducing macrophage content and increasing smooth muscle cell content. Furthermore, the pre-treatment of HUVEC's with AnxA5 reduced monocyte adhesion under flow-conditions. Finally, AnxA5 administration results in a trend to reduced cell death more pronounced in the aortic arch than the aortic root. In conclusion, treatment with AnxA5 before the onset of atherosclerosis reduces plaque formation in a murine model of atherosclerosis in part by reducing apoptotic rates further to its beneficial effect on macrophage infiltration and activation. PMID- 29267400 TI - Correction: The association between environmental exposures during childhood and the subsequent development of Crohn's disease: A score analysis approach. AB - [This corrects the article DOI: 10.1371/journal.pone.0171742.]. PMID- 29267401 TI - Distinct fitness costs associated with the knockdown of RNAi pathway genes in western corn rootworm adults. AB - RNA interference (RNAi) based approaches can potentially be used to control insect pests. These approaches may depend on the usage of microRNA (miRNA) or double stranded RNA (dsRNA) mediated gene knockdown, which likely involves proteins that regulate these pathways, such as Argonaute 1 (Ago1), Argonaute 2 (Ago2), Dicer 1 (Dcr1), Dicer 2 (Dcr2), and Drosha in insects. We previously performed functional characterization of Ago2 and Dcr2 of western corn rootworm (WCR), Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae) and observed that knockdown of Ago2 and Dcr2 ameliorated the lethal effect induced by the dsRNA-mediated knockdown of an essential gene in WCR, thereby confirming the involvement of Ago2 and Dcr2 in the dsRNA pathway. In the current study, we identified and characterized additional members of the Argonaute and Dicer gene families, namely Ago1, Ago3, Aubergine, and Dcr1, in a previously developed WCR transcriptome. We also identified a Drosha homolog in the same transcriptome. We evaluated the impacts on WCR adult fitness associated with the dsRNA-mediated knockdown of Ago1, Ago2, Dcr1, Dcr2, and Drosha genes. Among these putative RNAi pathway genes, only the knockdown of Ago1 incurred significant fitness costs such as reduced survival and oviposition rate, as well as decreased egg viability. The present study, to our knowledge, represents the first report showing that Ago1 is critical to the survival of insect adults. Our findings suggest that Ago1 plays an essential role in broader life stages of an insect than previously thought. Importantly, since fitness costs were not observed, downregulation or loss of function of RNAi pathway genes such as Ago2 or Dcr2 may confer resistance to pest control measures that rely on the normal functions of these genes. However, the precise roles of these genes under field conditions (i.e., in the presence of possible viral pathogens) requires further investigation. PMID- 29267399 TI - Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. AB - Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit gamma-C receptor cytokine (IL-15)-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of gamma-C cytokine (IL-2, IL-7 and IL-15) ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies. PMID- 29267403 TI - Changes in vegetation phenology on the Mongolian Plateau and their climatic determinants. AB - Climate change affects the timing of phenological events, such as the start, end, and length of the growing season of vegetation. A better understanding of how the phenology responded to climatic determinants is important in order to better anticipate future climate-ecosystem interactions. We examined the changes of three phenological events for the Mongolian Plateau and their climatic determinants. To do so, we derived three phenological metrics from remotely sensed vegetation indices and associated these with climate data for the period of 1982 to 2011. The results suggested that the start of the growing season advanced by 0.10 days yr-1, the end was delayed by 0.11 days yr-1, and the length of the growing season expanded by 6.3 days during the period from 1982 to 2011. The delayed end and extended length of the growing season were observed consistently in grassland, forest, and shrubland, while the earlier start was only observed in grassland. Partial correlation analysis between the phenological events and the climate variables revealed that higher temperature was associated with an earlier start of the growing season, and both temperature and precipitation contributed to the later ending. Overall, our findings suggest that climate change will substantially alter the vegetation phenology in the grasslands of the Mongolian Plateau, and likely also in biomes with similar environmental conditions, such as other semi-arid steppe regions. PMID- 29267402 TI - The role of microbial amyloid in neurodegeneration. AB - It has become apparent that the intestinal microbiota orchestrates important aspects of our metabolism, immunity, and development. Recent work has demonstrated that the microbiota also influences brain function in healthy and diseased individuals. Of great interest are reports that intestinal bacteria play a role in the pathogenic cascade of both Parkinson and Alzheimer diseases. These neurodegenerative disorders both involve misfolding of endogenous proteins that spreads from one region of the body to another in a manner analogous to prions. The mechanisms of how the microbiota influences or is correlated with disease require elaboration. Microbial proteins or metabolites may influence neurodegeneration through the promotion of amyloid formation by human proteins or by enhancing inflammatory responses to endogenous neuronal amyloids. We review the current knowledge concerning bacterial amyloids and their potential to influence cerebral amyloid aggregation and neuroinflammation. We propose the term "mapranosis" to describe the process of microbiota-associated proteopathy and neuroinflammation. The study of amyloid proteins made by the microbiota and their influence on health and disease is in its infancy. This is a promising area for therapeutic intervention because there are many ways to alter our microbial partners and their products, including amyloid proteins. PMID- 29267406 TI - Needle aspiration should be considered as primary intervention option for stable patients with spontaneous pneumothorax. PMID- 29267405 TI - Maternal depressive symptoms during and after pregnancy are associated with attention-deficit/hyperactivity disorder symptoms in their 3- to 6-year-old children. AB - Maternal depressive symptoms during pregnancy have been associated with child behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD) in early childhood. However, it remains unclear if depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain times, and if maternal depressive symptoms after pregnancy add to or mediate any prenatal effects. 1,779 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Mothers filled in the Center of Epidemiological Studies Depression Scale biweekly from 12+0-13+6 to 38+0-39+6 weeks+days of gestation or delivery, and the Beck Depression Inventory-II and the Conners' Hyperactivity Index at the child's age of 3 to 6 years (mean 3.8 years, standard deviation [SD] 0.5). Maternal depressive symptoms were highly stable throughout pregnancy, and children of mothers with consistently high depressive symptoms showed higher average levels (mean difference = 0.46 SD units, 95% Confidence Interval [CI] 0.36, 0.56, p < 0.001 compared to the low group), and proportion (32.1% vs. 14.7%) and odds (odds ratio = 2.80, 95% CI 2.20, 3.57, p < 0.001) of clinically significant ADHD symptoms. These associations were not explained by the effects of maternal depressive symptoms after pregnancy, which both added to and partially mediated the prenatal effects. Maternal depressive symptoms throughout pregnancy are associated with increased ADHD symptomatology in young children. Maternal depressive symptoms after pregnancy add to, but only partially mediate, the prenatal effects. Preventive interventions suited for the pregnancy period may benefit both maternal and offspring mental health. PMID- 29267407 TI - Commentary: Brain, Mind, World: Predictive Coding, Neo-Kantianism, and Transcendental Idealism. PMID- 29267404 TI - Unilateral nephrectomy diminishes ischemic acute kidney injury through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses. AB - While unilateral nephrectomy (UNx) is suggested to protect against ischemia reperfusion injury (IRI) in the remaining kidney, the mechanisms underlying this protection remain to be elucidated. In this study, functional MRI was employed in a renal IRI rat model to reveal global and regional changes in renal filtration, perfusion, oxygenation and sodium handling, and microarray and pathway analyses were conducted to identify protective molecular mechanisms. Wistar rats were randomized to either UNx or sham UNx immediately prior to 37 minutes of unilateral renal artery clamping or sham operation under sevoflurane anesthesia. MRI was performed 24 hours after reperfusion. Blood and renal tissue were harvested. RNA was isolated for microarray analysis and QPCR validation of gene expression results. The perfusion (T1 value) was significantly enhanced in the medulla of the post-ischemic kidney following UNx. UNx decreased the expression of fibrogenic genes, i.a. Col1a1, Fn1 and Tgfb1 in the post-ischemic kidney. This was associated with a marked decrease in markers of activated myofibroblasts (Acta2/alpha-Sma and Cdh11) and macrophages (Ccr2). This was most likely facilitated by down-regulation of Pdgfra, thus inhibiting pericyte-myofibroblast differentiation, chemokine production (Ccl2/Mcp1) and macrophage infiltration. UNx reduced ischemic histopathologic injury. UNx may exert renoprotective effects against IRI through increased perfusion in the renal medulla and alleviation of the acute pro-inflammatory and pro-fibrotic responses possibly through decreased myofibroblast activation. The identified pathways involved may serve as potential therapeutic targets and should be taken into account in experimental models of IRI. PMID- 29267408 TI - Standard or networked meta-analyses in assessing the best option for neo-adjuvant therapy in resectable oesophageal cancer: chemotherapy or chemo-radiotherapy? PMID- 29267409 TI - ? PMID- 29267410 TI - [Employment of People with Mental Disorders in Terms of the Policies Developed by the European and International Institutions]. AB - Objectives The aim of this article is to present an overview of the reflections led by various European and international organizations on the employment of people with mental disorders.Methods This study is based on data from websites of international organizations and interviews taken place with a disability specialist at the International Labour Organisation (ILO) and members of the European Commission.Results Unlike the French law of 11 February 2005 which refers expressly to psychic disability, this notion is not explicitly dedicated by various European and international legal rules. However, these standards like the United Nations Convention on the Rights of Persons with Disabilities have adopted the contemporary model which presents disability as the result of an interaction between person and environment. Thus they acknowledge that disabled people include people suffering from mental disorders because in the person's environment, a psychiatric impairment could lead to limitations of activities or restrictions of social participation that constitute a situation of disability of psychiatric origin. Therefore, the legal mechanisms often do not provide appropriate answers to the characteristics of psychiatric disability.Besides, negative attitudes, stereotypes and discrimination towards people with a psychiatric disability are still observed in the workplace, in spite of intensified anti-discrimination legislation.This study inventories the different proposals to remedy to substantial barriers to the employment of people with a psychiatric condition. In the European Union's strategy for increasing the employment of these persons, particular consideration is given to put forward a series of key recommendations to improve practices of reasonable accommodation in the workplace. Nonetheless, it must be emphasized that it is necessary to conceive adequate measures in order to take into account the changeability and the unpredictability of mental disorders. Indeed, situations of psychiatric disability require flexibility and reactivity more than any other situation of disability. The discrimination experienced by people with a psychiatric disability is likely to continue as long as specific responses are not implemented. In this perspective, ILO highlights a number of best practices addressing the challenges of psychiatric disabled people's employment. That is why a disability network was created to share knowledge. The great added value of this network is the opportunity to share best practices between companies, best practices between countries in order to increase the ability to include people with mental disorders. Focus is put on strategies to combat discrimination in employment, by raising awareness, exploring measures and good practices to improve mental health in the workplace.Conclusion Finally, this study shows similar challenges in the prevention of the mental health and the issue of the psychiatric handicap, including to remedy to the insufficient attention paid to provide reasonable accommodation to persons with mental disorders. PMID- 29267411 TI - [The Costs of Mental Disorders in the Workplace: Can They Be Decreased?] AB - Objectives The World Economic Forum estimated that, by 2030, global costs of mental disorders are projected to reach US$6.0 trillion; about two thirds of these costs will be attributed to lost productivity related to disability. This brief article discusses factors that are related to the costs of mental illness in the workplace, identifies some of the workplace elements which could be targeted to reduce costs and explores examples of types of workplace interventions that can reduce costs.Methods We summarize the results of a Canadian research program using economic analyses to understand the costs of work disability related to mental disorders and cost-effective interventions.Results There are at least two main approaches to decrease the costs of mental disorders in the workplace. The first approach could be to decrease the prevalence of mental disorders among workers or the incidence of sickness absences. A second approach would be to increase access to treatment by addressing barriers to treatment. Both can have significant impacts to decrease costs.Conclusions Treatment can help workers experience mental disorders have higher productivity than they would have otherwise. By creating supportive workplace cultures through management training, organizations can potentially see a return through decreased sickness absences and higher productivity. PMID- 29267412 TI - [Mental Disorders and Reasonable Accommodation at Work: The Potential of Quebec Law]. AB - Objectives Being able to work constitutes a powerful social integration vector for those suffering from mental health disorders, while also providing therapeutic benefits for them. Yet, despite some advances in this regard, such persons are still denied employment. The obstacles to their full workforce integration reside in the prejudices surrounding the disorders affecting them and the need to adapt tasks to their needs and abilities. The International Convention on the Rights of Persons with Disabilities, adopted by the United Nations in 2006, points out that disability results from the interaction between persons with impairments and attitudinal and environmental barriers that hinder their full and effective participation in society on the basis of equality with others. It stresses the importance of the right to work of persons with disabilities and, in particular, the implementation of reasonable accommodation for these persons in all workplaces. From this perspective, this article aims to explore the impacts of the legal obligation of accommodation.Methods In Canada, the fundamental rights approach and, in particular, the obligation for reasonable accommodation with regard to handicapped workers, has been well established in case law since the mid 1980s. This obligation is of a constitutional nature and its extended range is limited only by the proof of undue hardship. It thus forcefully prompts labour markets to take into consideration the needs and capacities of disabled workers. Through a study of Quebec case law, this article looks at the potential of the duty to accommodate with regard to promoting access to and retention of employment among people with mental disorders.Results The study found that the duty to accommodate imposes an innovative approach that takes into account the particular situation of the disabled person and involves the participation of all stakeholders. Accommodation allows employees to maintain an employment relationship despite repeated absences caused by illness, thus enabling them to do their work. Employers must provide adjustments relating to working time and allow gradual return when necessary. Moreover, the accommodation may involve changing the work itself or its psychosocial aspects.Conclusion By implementing measures to change the psychosocial work environment, accommodation not only promotes access to and retention of employment among people with mental disorders, but also opens the way to first stage prevention for the benefit of all. PMID- 29267413 TI - [Employment and Recovery Process]. AB - Objectives It is widely acknowledged and confirmed by research that there is a close relationship between work and recovery from a mental illness. The aim of this article is to discuss different aspects of the relationship between these two concepts.Methods The discussion is based on a synthesis of the relevant literature in two domains: the benefits of employment for people living with a mental illness and their contributions to the recovery process, and the specification of the recovery paradigm and of the recovery-oriented practices.Results The recovery paradigm may be characterized by some main shifts in the vision of people living with a mental illness and of their future, with consequences on how to support these people, and in particular how to conceive their vocational rehabilitation. One of the first shifts is that it is possible for a large majority of these people to recover, to return to active and social life, to consider a favourable future. This possibility, which gives rise to hope and a high expectation, should now be the priority objective of supporting practices, which implies a renewal of these practices. A second shift is that this possibility of recovery does not necessarily require a complete and prior reduction of the mental disorders. The recovery approach, by giving priority to commitment to an active and social life, supports vocational reintegration as a priority. This new approach to practices and services should be considered at two levels: in the design and organization of services, which must be redefined according to the primary objectives and the values of recovery, but also at the individual level, in the accompanying posture, which should be based on the values of recovery. In vocational rehabilitation, Individual Placement and Support (IPS) is recognized as an evidence-based practice and its principles are well defined. There is a striking convergence between the underlying principles of IPS programs and the principles of the recovery-oriented practices, but the shift in the accompanying individual posture is better specified by the recovery oriented practice literature.A number of research focuses on the different ways by which employment contribute to the recovery process. We rely on existing qualitative meta-synthesis of these studies, to present the factors contributing to the recovery process according to the relevant main dimensions.Conclusion In the current French context of development of effective professional integration practices, based on the Place and train model, it is important to stress that these practices must be also recovery-oriented, which implies not only a new design of vocational services but also to adopt a new attitude for supporting people in the process of work integration. PMID- 29267414 TI - [Cognitive Functioning and Work Outcome Among People with Schizophrenia Spectrum Disorder: The Contribution of the International Classification of Functioning]. AB - Objectives Cognitive impairment can be a barrier to employment of people with a schizophrenia spectrum disorder (SSD). However, other factors have also been identified as potentially hindering work integration and job tenure. But the links between all these factors remain unknown. The objective of this article is to propound an integrative model, using the International Classification of Functioning (ICF), of how cognitive impairment associated with SSD is related to other factors involved in difficulties in work integration and job tenure.Methods The description of the theoretical framework of the ICF enables to organize these factors in a comprehensive model. Then, a review of recent literature allows us to identify factors associated with employment of people with SSD, and to see the link between cognitive functioning and other factors.Results Most of reviewed studies find moderate correlations or no correlation between cognitive impairments and work integration or job tenure. Stronger correlations were nevertheless found between cognitive factors and work behavior or performance. Considering other factors, like personal or environmental factors, and the framework of the ICF, a comprehensive view of the vocational rehabilitation for people with SSD is developed. Interactions between some personal (e.g. self efficacy or self esteem) and environmental (e.g. job coach or layout of workstation) factors may influence the translation of cognitive difficulties into work participation restrictions.Conclusion Vocational rehabilitation programs should further consider the complexity of interactions between cognitive, personal and environmental factors, and how they impact work functioning. As defined in ICF, activity limitations may represent an interesting mediator between cognitive variables and work functioning. Future research should be conducted to bring a better understanding of these patterns of interactions. PMID- 29267415 TI - [A Group Cognitive-Behavioural Intervention to Prevent Depression Relapse in Individuals Having Recently Returned to Work: Protocol and Feasibility]. AB - Workplace depression is one of the major causes for sick leave and loss of productivity at work. Many studies have investigated factors predicting return to work for people with depression, including studies evaluating return to work programs and organizational factors. Yet, a paucity of studies have targeted the prevention of depressive relapses at work, even though more than half of those having had a depression will have a depressive relapse in the near future.Objectives This article describes a research protocol involving a novel group intervention based on cognitive behavioural principles with the aim to optimize return to work and diminish risk of depressive relapses.Method This pilot study follows a randomized controlled trial design, with half the participants (N=25) receiving the group intervention and the other half (N=25) receiving usual services. The theoretical and empirical underpinnings of the intervention are described, along with a detailed presentation of the intervention and of the study's objectives. The group intervention consists of 8 sessions whereby Cognitive behavioural therapy (CBT) principles and techniques are applied to the following themes: (1) Coping with stress at work; (2) Recognizing and modifying my dysfunctional beliefs linked to work; (3) Overcoming obstacles linked to work functioning and maintaining work; (4) Negotiating needed work adjustments with the support of the immediate supervisor; (5) Finding my strengths and competencies related to work; (6) Accepting criticism and asserting myself appropriately at work; (7) Uncovering my best coping strategies for work.Results Qualitative information pertaining to the first two cohorts' participants' subjective appreciation of the group experience revealed that the intervention was perceived as very useful by all, with group support, namely harmony and interpersonal support, as well as CBT strategies being mentioned specifically.Conclusion Finally, the potential relevance of the group intervention will be brought forward. PMID- 29267416 TI - [A Model of Support System for the Professional Insertion of People with Psychological Disability]. AB - Objectives Psychosocial rehabilitation, particularly work integration, is currently a public health preoccupation, as evidenced by recent publications on this topic and the development of new professional insertion program. This article aims to present a French health facility focused on psychosocial rehabilitation of persons in state of psychic disability, in order to highlight its specific programs of professional insertion.Methods After a brief remind about the theoretical foundations of psychosocial rehabilitation, psychic disability and recovery, we present the means used by our healthcare facility, illustrating our remarks with 2 case studies.Results Our rehabilitation programs demonstrate the need of a multidisciplinary in interventions, the need for multiplicity in proposals of activities, the importance of self-determination, of healthcare professionals in management of the public admitted in our healthcare facility, and the importance of fighting the stigma caused by mental disorders.Conclusion Our programs need to be placed in the French context, in which persist stigmatization towards persons with psychiatric disorders, and huge barriers to employment. PMID- 29267417 TI - [Towards an Understanding of Stigma: What is the Stereotype Associated with Schizophrenia]. AB - Objectives Stigmatization of people suffering from schizophrenia spectrum disorder relies on the existence of a stereotype which is associated with a social category, here schizophrenia. The short report's aim is to briefly synthesize the recent literature about the content of the stereotype associated with schizophrenia, and to suggest some perspectives for future studies, on the basis of recent advances in the domain.Methods First, we present the theoretical concepts of stigma and stereotype. Second, we propose a brief synthesis of the recently published articles focusing on the content of schizophrenia stereotype in the general population, in English and in French.Results The stereotype associated with mental illness is clearly negative. The most common model in the literature assumes 4 factors in the content of stereotype: attribution of responsibility in the condition, dangerousness, poor prognosis, unpredictability and incompetence in social roles. If the stereotype could vary among countries, it is clearly associated with desire for social distance and discrimination. The stereotype also varies among mental illnesses. Compared with bipolar disorders and autism, schizophrenia focuses the most negative aspects of mental illness stereotype, especially in terms of dangerousness and social distance.Conclusion The study of stereotype, though rapidly growing, still raises questions about the validity of commonly used models in the psychiatric literature, and may benefit from further specific studies. Social psychology models and methods appear to be a promising perspective. The production of data, useful for users, families as well as for professionals may require multidisciplinarity for future projects. PMID- 29267418 TI - [Representations of Mental Disorders and Employment Fit Perceived by Employers of the Regular Labour Market in France]. AB - Introduction People with mental disorders face stigma and discriminatory hiring practices in the competitive labour market. This study on employers' representations of mental disorders provides knowledge regarding the specifics of their negative perceptions for this population, which appears to be an important barrier to their inclusion in the workplace. Heilman's lack of fit model (1983) enabled to show that recruiters seek to match the characteristics they perceive in candidates with those they deem necessary to succeed in the organization. A lack of fit between the two components-candidates and the selection criteria would explain the non-selection of the applicant. This psychological process can be applied to the recruitment of people with psychiatric disabilities.Objectives The goal of this study was to identify employers' representations towards mental disorder in general and in the workplace particularly, as well as to determine the prerequisites for hiring this population. As such, this would allow to better understand the psychological processes involved in the exclusion of people with psychiatric disabilities.Method In a qualitative study, 29 semi-structured interviews were conducted with employers and HR Department representatives of organizations in France that were under the French legal obligation to hire people with a disability (organizations having more than 20 employees). We used the free association technique to identify representational contents concerning mental disorder. Qualitative data on the essential prerequisites for recruitment were collected through open-ended questions. The data were processed by a categorical content analysis conducted independently by three researchers. The structure of the representation was identified by distinguishing the components of the central nucleus from those of the peripheral nucleus according to the two criteria of the method of Moliner (1994): the index of popularity of each element and the co-occurrence between each element of the representation.Results Results revealed negative representations of people with mental disorders, focusing on social deviance and harm to society, believing that people with mental disorders would have non-standard skills and behaviours and would be socially disruptive and burdensome, particularly in the workplace. The analysis of the prerequisites for hiring persons with psychiatric disabilities showed how these representations towards mental disorders are barriers for their recruitment, mainly linked to a perceived lack of employment fit.Conclusion Future avenues of research and actions are suggested. They are as follows: learning, education on mental disorders, training and specific techniques to reduce organizational stakeholders' stereotypes and prejudice. Also, supporting stakeholders for the inclusion of people with mental disorders in the workplace appears fundamental, especially by improving recruitment and integration practises. PMID- 29267419 TI - [Supervisors and Employment Counselors in Messidor Transitional Social Firms Supporting People with Psychiatric Disability to Gain Competitive Employment]. AB - Objectives Some programs have been developed in France for helping people with a psychiatric disability to get competitive employment, especially prevocational programs such as transitional social firms. However, these programs have not been studied until now. Studies on supported employment programs (evidence-based practices) conducted in other countries demonstrated that variation of work outcomes is due, among other factors, to employment specialists' competencies. These results highlight the need for describing more specifically the work of the two professionals, employment counselors and supervisors, working in transitional social firms in order to better understand their role, tasks and competencies. Therefore, the objective of this study aims at describing the roles, tasks and competencies of these two professionals working in transitional social firms, to better understand how they support people with psychiatric disability for eventually obtaining competitive employment.Methods A qualitative method was used to describe roles, tasks and competencies of employment counselors and supervisors working in the transitional social firms of the Messidor's association (7 regions). In sum, 24 individual interviews with employment counselors and supervisors of these social firms as well as 7 focus groups with the two types of professionals, were conducted.Results This study allowed to define the work of the two professionals (role and tasks) and a list of 110 competencies for employment counselors as well as 155 competencies for supervisors working in these transitional social firms, emerged from qualitative analyses. This "double support" has been defined as a complementary approach helping workers to change their own perceptions, becoming more confident in their work abilities, and thus helping them to gain competitive employment. On the one hand, the employment counselor supports each worker in developing strategies and actions to reach competitive employment, and put in place "job development skills" to coordinate his role with key stakeholders (e.g. psychiatrist, employers) involved in the work integration of people with severe mental disorders. On the other hand, the supervisor is following each worker all day long, training and helping them to overcome potential difficulties regarding the work to do, and building confidence and self-esteem in the workers under their supervision, which are all key elements to gain competitive employment.Conclusion Clinical implications are suggested regarding the recruitment of professionals working in transitional social firms, and thus improving work outcomes for people with a severe mental illness. PMID- 29267420 TI - [Return to Work Strategies of Employees who Experienced Depression: Employers and HR's Perspectives]. AB - Major depression is one of the leading causes of work disability across the world. In Canada, the lifetime prevalence of depression varies from 10 to 12%. Depression impacts not only the employee who is often stigmatized and can lose his professional identity, but also has consequences on colleagues and supervisors in organizations. In the literature, four models are described from which employers and managers use in their organizations to make decisions regarding the work disability of employees on sick leave: biomedical, financial management, personnel management, and organizational development. These models can also be supported by economic, legal and ethical interests. Even though these models are essential to better understand the decision of employers and HR regarding work disability, information remains scarce regarding the concrete strategies used by these stakeholders to facilitate the return to work for employees on sick leave due to depression.Objectives the aim of this paper is to document, considering employers' and human resources' perspectives, the best strategies to put in place to facilitate the return to work of employees on sick leave due to depression.Method This study was part of a larger study carried out in Canada to assess factors influencing the return to work after a depression related sick leave, taking into account the viewpoint of four types of stakeholders: employers/human resources, supervisors, unions and people diagnosed with depression. 219 employers (68.5%) and human resources directors (31.5%) from 82.6% organizations having more than 100 employees accepted to answer a telephone semi-structured interview. The question of interest in this study is: In your opinion, what are the best strategies to help an employee who has had a depression to return to work? Coding was influenced by empirical findings and theories related to psychosocial risk factors that the authors use in their respective disciplines as well as return to work principles/steps mentioned in the literature. The main objective was to keep all the strategies mentioned by participants, and analyzing them with major principles of return to work.Results 24 return to work strategies spread on six principles emerged: 1) Contact with the employee during his sick leave (10 strategies); 2) Evaluate and plan the return to work without precipitating it (6); 3) Training for managers and colleagues regarding mental health in the workplace (4); 4) Concertation between key return to work stakeholders (4); 5) Progressive return to work with work accommodations (4); 6) Health and work follow-up regarding the employee (6).Conclusion These six principles including 34 strategies are usually related to the timeframe process of the return to work, though they can be implemented sometimes in parallel. This possible overlap reinforces the idea to consider the return to work as sustainable in order to prevent potential relapses and improve the performance at work. Next steps will be to systematically implement these principles and strategies in organizations in order to evaluate their impact on return to work of employees on sick leave due to depression. PMID- 29267421 TI - [The Relationship between Workaholism, Burnout and Personality: A Literature Review]. AB - Objectives This paper reviews and summarizes the literature on personality traits associated with workaholism and burnout, using the Five Factors Model (FFM) of personality.Methods We searched among PsycINFO Database and Google Scholar web search engine to identify relevant articles and studies on workaholism, burnout and personality.Results The first part of this paper defines each concept individually, focussing on personal, environmental and organizational factors associated with workaholism and burnout. We also explore the impact on family, social and professional life. In the second part, results suggest that neuroticism, a personality trait, is associated with workaholism and burnout. Conscientiousness, agreeableness and extraversion also appear to have a significant but specific effects on burnout and workaholism.Conclusion It appears desirable for personal and organizational health, to explore specific factors of work-related illness, like personality traits. Implications for employee well being and organizational health are discussed. PMID- 29267422 TI - [Psychoeducational Group Intervention for Parents of Adolescents with an Eating Disorders: Feasibility and Satisfaction]. AB - Parental involvement is recommended and essential in the treatment of eating disorders in adolescence. This role is certainly difficult to accomplish and requires guidance.Objective This article aims to describe the implementation of a psychoeducational group intervention for parents of teenagers consulting for eating disorders in a regional hospital in the province of Quebec, and the results of a satisfaction survey.Method The intervention is mainly based on the principles of the Maudsley approach. Additional information on physical activity and the disorder maintenance cycle was added. It consisted of 2 meetings of 2 hours, and was offered to 36 parents divided in 5 cohorts. Their level of satisfaction was then assessed.Results The intervention was feasible and parents have expressed overall high satisfaction with the services they received.Conclusion This type of intervention has proven to be feasible, acceptable and valued. PMID- 29267423 TI - [Interprofessional Collaboration as a Modality to Resolve Therapeutic Impasses in Child Psychiatry: A Review]. AB - Child and adolescent intervention in child psychiatric clinics generates a high risk of therapeutic impasses for clinicians. Among the factors that contribute to this situation are the increasing severity of the problems of young people who are referred to psychiatric clinics and the obligation for professionals to collaborate with various actors surrounding the patient. This literature review explores the possibility that an intervention targeting indicators of interprofessional collaboration can help resolved the therapeutic impasses encountered by professionals working in child psychiatry. The article begins with a description of the impasse in therapeutic clinical child psychiatry. It then introduces a broad look at research about interprofessional collaboration and its effects on mental health service delivery. Finally, it examines the structuring model of the interprofessional collaboration process of D'Amour et al. in order to highlight the indicators that may be related to the resolution of clinical therapeutic impasses in child psychiatry. This review examines the possible interventions that could be done when targeting indicators of D'Amour et al.'s interprofessional collaboration model in order to improve therapeutic impasses resolution. A promising direction for future research which could contribute to therapeutic impasses resolution in child psychiatry is proposed. PMID- 29267424 TI - [Iron Man: Between Confusion of Identity and Addiction to Technology]. AB - The fascination surrounding a successful artwork is linked to the fact it faces the viewer to unknown aspects of his/her own psychic life. The same applies to the comics Iron Man. Behind the armour is hiding a man caught up in the traumatic incidences of life. The hero demonstrates a psychic weakness which, despite being deep, is, however, showing universal aspects.The analysis of his misfortunes reveals a narcissistic disorder. The article intends to set out the identity confusion the Marvel's protagonist is trapped in while highlighting the addictive troublesome linking him to his high-tech armour. This article also seeks to attest the fact the symbiosis between Tony Stark and Iron Man is anticipating the evolution of our behaviour with regard to new technologies.To this end, the authors are recalling the episodes of the series. Through the analysis of the confrontational dialogue the hero is maintaining with his iron armour, they explore how the internal experiment related to the sense of identity disorder is figured out. Thus, going through the key moments of the saga, the authors raise the ambiguity of his hero. The metapsychological analysis of the actions undertaken by Iron Man reflects a little-known facet of his personality, revealing a character more tormented than he really looks. However, the point is not to "treat" a fictional man, but to observe how he can help us to understand the internal behaviour of our patients, and also our own.The Faustian drama this comic leads to is hence understood as a living testimony of our own psychic conflicts. Furthermore, the analysis gives rise to a questioning as to the risk of identity confusion the technological progress can create at a time when the Human is more and more depending on the machines he creates himself. PMID- 29267425 TI - Translation and adaptation to Brazilian Portuguese of the Lymphedema Rating Scale in Head and Neck Cancer. AB - OBJECTIVE: Translate to brazilian portuguese, culturally adapt and test the rating and classification scales of cervicofacial lymphedema of the MD Anderson Cancer Center Head and Neck Lymphedema Protocol (MDACC HNL) in patients undergoing treatment for head and neck cancer. METHODS: The process followed international guidelines and translation stages by two head and neck surgeons, and back translation independently by two native Americans. The test of final version was based on the evaluation of 18 patients by one speech pathologist and one physical therapist who applied the scales in Portuguese. RESULTS: The translation of the three scales was carried out independently and the translators reached a consensus for the final version. Minor modifications were made by translating two terms into the Assessment of the Face. Versions of back translation were similar to each other. The instrument was successfully applied to patients independently. CONCLUSION: The translation and cultural adaptation of the assessment and rating scale of the cervicofacial lymphedema of the MD Anderson Cancer Center Head and Neck Lymphedema Protocol to the Brazilian Portuguese were successful. PMID- 29267426 TI - Scores TISS-28 versus NEMS to size the nursing team in a pediatric intensive care unit. AB - OBJECTIVE: To estimate the workload and size the nursing team using the scales TISS-28 and NEMS in a pediatric intensive care unit. METHODS: An observational prospective study with a quantitative approach was conducted at the pediatric intensive care unit of a university hospital from Jan 1st, 2009 to Dec 31st, 2009. All children who remained hospitalized for more than 8 hours were included, with length of stay of 4 hours in case of death. Clinical data were collected and the Paediatric Index of Mortality 2 and the scores TISS-28 and NEMS were determined. The TISS-28 and NEMS were converted into working hours of the nursing team and sizing complied with the parameters of the Brazilian Federal Nursing Council. Pearson's correlation and the Bland-Altman model were used to verify the association and agreement between the instruments. RESULTS: A total of 459 children were included, totaling 3,409 observations. The average values for the TISS-28 and NEMS were 20.8+/-8 and 25.2+/-8.7 points, respectively. The nursing workload was 11 hours by TISS-28 and 13.3 hours by NEMS. The estimated number of professionals by TISS-28 and NEMS was 29.6 and 35.8 professionals, respectively. The TISS-28 and NEMS showed adequate correlation and agreement. CONCLUSION: Time spent in nursing activities and team sizing reflected by the NEMS were significantly greater when compared to the TISS-28. PMID- 29267427 TI - Metabolic investigation in patients with nephrolithiasis. AB - OBJECTIVE: To evaluate the prevalence of metabolic disorders associated with nephrolithiasis in a female population. METHODS: A retrospective study on 1,737 patients with evidence of recent formation of renal stones, being 54% females. The laboratory investigation consisted of at least two samples of blood and 24 hour urine to assess calcium, uric acid, citrate and creatinine levels, qualitative cystinuria, urinary pH following fasting and 12-hour water restriction, urine culture, serum creatinine and parathyroid hormone. RESULTS: The most frequent alterations were hypercalciuria (40.9%), urinary tract infection (23.2%), hypocitraturia (22.4%), low urinary volume (20.5%) and hyperuricosuria (16%). CONCLUSION: The most frequent metabolic alterations in females were hypocitraturia, urinary tract infection, low urinary volume and hyperuricosuria. PMID- 29267428 TI - Obesity, sarcopenia, sarcopenic obesity and reduced mobility in Brazilian older people aged 80 years and over. AB - OBJECTIVE: To analyze which abnormalities in body composition (obesity, sarcopenia or sarcopenic obesity) are related to reduced mobility in older people aged 80 years and older. METHODS: The sample included 116 subjects aged 80 years and older. The body composition was measured using dual-energy X-ray absorptiometry (DXA) and mobility was assessed by motor tests. The chi2 test was used to analyze the proportion of older people with sarcopenia, obesity and sarcopenic obesity based on sex as well as to indicate an association between obesity, sarcopenia, sarcopenic obesity and mobility. Binary logistic regression, adjusted for the variables (sex and osteoarticular diseases), was used to express the magnitude of these associations. One-way analysis of variance was used to compare the mobility of four groups (Normal, Obesity, Sarcopenia and Sarcopenic Obesity). RESULTS: The Sarcopenia Group had lower performance in the lower limbs strength test and in sum of two tests compared with Obesity and Normal Groups. Older people with sarcopenia had higher chance of reduced mobility (OR: 3.44; 95%CI: 1.12-10.52). CONCLUSION: Older people aged 80 years and older with sarcopenia have more chance for reduction in mobility. PMID- 29267429 TI - Description and evaluation of experimental models for uterine transplantation in pigs. AB - OBJECTIVE: To evaluate the technique of uterine transplantation and the use of drugs used in the process of immunosuppression. METHODS: We included 12 sows, and immunosuppression was performed with minimal doses of cyclosporine, and cross match was done to exclude the possibility of blood incompatibility. Hysterectomy was performed in the donor under general anesthesia, with the removal of the aorta and inferior vena cava in monobloc, and anastomosis of these vessels was made in the recipient. RESULTS: Six experiments were performed, and on the immediate postoperative period, five animals had good reperfusion. However, on the seventh postoperative day, histological analysis showed rejection in five animals. CONCLUSION: The experimental model of uterine transplantation is feasible, but monitoring doses of immunosuppressants is pivotal to prevent rejection episodes. PMID- 29267430 TI - A review of data in medical request and the patient questionnaire for magnetic resonance evaluation of silicone breast implants. AB - OBJECTIVE: To analyze the quality and quantity of data in the questionnaires and in request forms for magnetic resonance imaging. METHODS: This retrospective study was conducted with data from 300 medical records. The research used the following data from the questionnaires: patient age, reason for the magnetic resonance imaging, reason for placing the breast implant, report of any signs or symptoms, time elapsed since surgery to place the current breast implant, replacement implant surgery, chemotherapy, and/or radiation therapy treatments. From the magnetic resonance imaging request forms, information about the breast implant, the implant placement surgery, patient clinical information and ordering physician specialty were verified. RESULTS: The mean age of patients was 48.8 years, and the mean time elapsed since breast implant surgery was 5 years. A total of 60% of women in the sample were submitted to aesthetic surgery, while 23.7% were submitted to chemotherapy and/or radiation therapy. In the request forms, 23.7% of physicians added some piece of information about the patient, whereas 2.3% of them informed the type of implant and 5.2% informed about the surgery. CONCLUSION: The amount of information in the magnetic resonance imaging request forms is very limited, and this may hinder quality of radiological reports. Institutional and technological measures should be implemented to encourage the requesting physicians and radiologists to share information. PMID- 29267431 TI - Aspects of images in magnetic resonance of liver tumors treated with transarterial selective internal radiotherapy with yttrium-90. AB - Transarterial selective internal radiation therapy with yttrium-90, also known as radioembolization, is a therapy based on the administration of resin or glass microspheres loaded with the radioisotope yttrium-90, via selective arterial catheterization of tumor-feeding vessels. It is classified as a type of locoregional therapy and its main goal is to treat patients with primary or secondary hepatic lesions that are unresectable and not responsive to other therapies. Since it is a new technology still restricted to very few hospitals in Brazil, but used in patients throughout the country, it is necessary to demonstrate the main aspects of hepatic lesions treated with selective internal radiation therapy found in magnetic resonance imaging, and to make specific considerations on interpretation of these images. The objective of this report is to demonstrate the main aspects of magnetic resonance imaging of unresectable primary or secondary hepatic lesions, in patients submitted to transarterial selective internal radiation therapy. PMID- 29267432 TI - Acne fulminans. AB - Acne fulminans is a rare and severe variant of acne. In Brazilian medical journals, cases are infrequently reported, confirming its rarity. We followed five young male patients with this severe variant of cutaneous lesions, accompanied by also severe systemic symptoms: fever, anorexia, weight loss, and arthralgia. All had a good response to corticosteroids (prednisone), but had significant scarring. PMID- 29267433 TI - Acquired lymphangiomas mimicking multiple hallux warts. AB - Lymphangioma is an uncommon benign vascular tumour that involves lymphatic vessels. It can be acquired or, most frequently, congenital. The acquired form presents with dilated lymphatic channels due to an obstruction. These lesions have no risk of malignant transformation, but they have a high rate of recurrence whether removed. We present a case of a 52-year-old woman with acquired lymphangiomas mimicking warts. She came to our observation for some keratotic lesions on her feet. Clinically, we found three warts on the sole of her left foot, but we also noticed the presence of swelling and papillomatous wart-like papules on both halluces. The hallux papules were studied by performing an excisional biopsy and were found to be lymphangiomas. PMID- 29267434 TI - Acute renal failure in a patient with epidermolysis bullosa acquisita. AB - Epidermolysis bullosa acquisita is a severe autoimmune subepidermal bullous disease. In this report, we described for the first time a patient with epidermolysis bullosa acquisita who developed acute renal failure. There is a possibility that epidermolysis bullosa acquisita and acute renal failure's pathogenesis shared some common autoimmune pathways. Moreover, acute blood volume reduction may be another cause of prerenal kidney failure. Further studies are needed to verify our hypothesis. PMID- 29267435 TI - Ashy dermatosis with involvement of mucous membranes. AB - Ashy dermatosis is a rare condition, of unknown aetiology, in which mucous membranes are typically spared. The authors report the case of a 57-year-old female with a history of asymptomatic gray-bluish macules located on the trunk and oral mucosa. There were no relief changes on examination. Skin biopsies from the oral mucosa and trunk were performed and both were compatible with ashy dermatosis. The patient started treatment with oral clofazimine but due to the absence of clinical improvement the drug was discontinued three months later. This case report illustrates an atypical case of ashy dermatosis owing to the involvement of mucous membranes, which is rarely described in the literature. PMID- 29267436 TI - Association of amyloidosis cutis dyschromica and familial Mediterranean fever. AB - Amyloidosis cutis dyschromica is a rare type of primary cutaneous amyloidosis characterized by reticulate hyper-pigmentation with discrete hypopigmented macules. Up to date, about 50 cases of amyloidosis cutis dyschromica have been reported and the majority are familial cases of Asian ethnicity. Various diseases, particularly autoimmune diseases such as systemic sclerosis and systemic lupus erythematosus, have been associated with amyloidosis cutis dyschromica. Herein, we report a case of amyloidosis cutis dyschromica accompanying familial Mediterranean fever with a delayed diagnosis of 40 years. To the best of our knowledge, this is the first report of the association of amyloidosis cutis dyschromica and familial mediterranean fever. PMID- 29267437 TI - Atypical Kaposi's sarcoma in young inmunocompetent patient. AB - Kaposi's sarcoma is a rare tumor associated with human herpes virus 8 (HHV-8) infection. Four main clinical subtypes have been described. This study reports on a form of KS in an HIV negative and immunocompetent middle-aged man. The only remarkable factor is that he has sex with other men. This form of Kaposi's sarcoma is rare. It occurs more in younger patients than in the classic form, is limited to the skin, and is associated with a good prognosis. The means of transmission of the virus is through saliva in oroanal or orogenital sexual practices. Mechanisms of tumor development are still not well known. Given the possible increased number of this variant, it would be interesting to extend this study. PMID- 29267438 TI - Bilateral clear cell acanthoma of the areola and nipple: good response to topical corticosteroids. AB - : Clear cell acanthoma is a rare, epidermal tumor not common in the area of the nipples; indeed, the literature describes only 8 cases, all showing unilateral presentation. We here report the first case of bilateral clear cell acanthoma with good response to topical corticosteroids. CASE REPORT: A sixteen-year old girl presented with 2 excrescent, fleshy, and exudative tumor masses in both nipples and areola mammae. A biopsy was conducted and confirmed clear cell acanthoma histopathologically. Treatment with strong corticosteroids resulted in rapid improvement and resolution. After one year of follow-up, the patient developed atopic dermatitis. DISCUSSION: We describe the first case of bilateral clear cell acanthoma localized in the nipple/areola that resolved with powerful corticosteroids, suggesting a reactive etiology of the lesion. PMID- 29267439 TI - Blue nevus with satellitosis: case report and literature review. AB - Blue nevus is a benign melanocytic lesion, typically asymptomatic and of unknown etiology. Many histological subtypes are recognized, the most commons being: common blue nevus, cellular blue nevus, and combined blue nevus. New rare variants have been described in the literature, with emphasis on eruptive blue nevus, plaque, agminate, linear, with satellitosis, disseminated, familial and targetoid. The diagnosis of blue nevus usually presents no difficulties, however, the presence of structures such as irregular edges or satellitosis, are highly suggestive of malignancy, and the differential diagnosis with malignant blue nevus and melanoma with peripheral spread should be considered. We report a case of blue nevus with satellitosis in a 15-year-old female patient. PMID- 29267440 TI - Bullous pemphigoid associated with milia, increased serum IgE, autoantibodies against desmogleins, and refractory treatment in a young patient. AB - Bullous pemphigoid is a blistering autoimmune disease characterized by two hemidesmosomal proteins (anti-BP180 and 230). Pemphigus, by contrast, is characterized by two autoantibodies (anti-desmoglein 1 and 3). Coexistence of autoantibodies of bullous pemphigoid and pemphigus in a patient is rare. A 25 year-old male patient was admitted to our hospital, reporting a 3-month history of multiple papules, vesicles, and erosions over an extensive erythema on the entire body. Laboratory tests showed high levels of serum IgE, anti-BP180 antibodies, and anti-desmoglein 1 and 3. Histopathologic and immunopathologic features were characterized by bullous pemphigoid. No improvement was seen with systemic corticosteroid therapy, however, pulse corticosteriod therapy combined with methylprednisolone, immunosuppressants, immunomodulators, and plasmapheresis led to the recovery of his condition with numerous milia. PMID- 29267441 TI - Bullous systemic lupus erythematosus in a 10-year-old child. AB - Bullous systemic lupus erythematosus (BSLE) is a rare autoimmune subepidermal blistering disease, with few cases described in childhood. It has different clinical-pathological features. We report a case of BSLE in a 10-year-old child with systemic lupus erythematosus, treated with prednisone and hydroxychloroquine. There was complete remission with dapsone, with no recurrence of skin lesions throughout one year of follow-up. We highlight the rarity and early age of occurrence. PMID- 29267442 TI - Congenital Langerhans cell histiocytosis: a good prognosis disease? AB - Langerhans cell histiocytosis is rare and more frequent in children. The skin is affected in 50% of the cases and is the only site in 10%. Its course varies from self-limited and localized forms to severe multisystemic forms. Congenital cases are usually exclusively cutaneous and self-limited, with spontaneous remission in months. This study presents a rare congenital case, initially restricted to the skin, with subsequent dissemination and fatal outcome. A male newborn presented congenital disseminated erythematous scaly lesions. The biopsy was conclusive for Langerhans cell histiocytosis. The patient evolved into the multisystemic form in weeks, when chemotherapy was started, according to the LCH-2009 protocol; however, the patient was refractory to treatment and died. PMID- 29267443 TI - Congenital plaque-like glomangioma: report of two cases. AB - Glomus tumors are rare hamartomas that originate from the glomus body. These tumors can be divided into solitary and multiple, the latter also known as glomangioma. We report the case of two patients with a rare variety of glomangioma called congenital plaque-like glomangioma. It presents as numerous red to bluish compressible papules, that increase in size in proportion with the weight and height growth of the child. Diagnostic confirmation is with histopathology and the treatment is surgical. PMID- 29267444 TI - Cutaneous metastases in a patient with no previous diagnosis of cancer: diagnostic challenge. AB - On rare occasions, skin lesions are the first local of metastatic manifestation of internal malignancies. In case of no previous diagnosis of these tumors, the approach of suspicious skin lesions becomes a challenge, especially in differentiating cutaneous metastases and adnexal primary neoplasms. Currently, besides epidemiologic, dermoscopic and histopathologic aspects, the evaluation also integrates immunohistochemical exams and cell markers such as p40 and p63, highly specific for skin metastases. This article describes the case of cutaneous metastases as the sole obvious sign of breast cancer in a previously asymptomatic woman. The diagnosis was made by the finding of neoplastic cells in the dermis and immunohistochemistry compatible with ductal carcinoma. PMID- 29267445 TI - Cutaneous myeloid sarcoma associated with chronic myeloid leukemia. AB - Myeloid sarcoma is an extramedullary tumor of malignant myeloid cells often associated with acute myeloid leukemia, chronic myeloproliferative disorders and myelodysplastic syndromes. The skin is one of the most commonly affected sites. We report a rare case of cutaneous myeloid sarcoma associated with chronic myeloid leukemia. PMID- 29267446 TI - Cutaneous polyarteritis nodosa causing refractory skin deformation and pigmentation as sequel. AB - A 39-year-old woman presented with prominent and painful livedo reticularis lesions spreading on her upper and lower extremities. Histopathologically, the small-to medium-sized arteries in the deep dermis and subcutis showed necrotizing vasculitis with cellular infiltration, suggesting cutaneous polyarteritis nodosa. The serum levels of inflammatory markers normalized with aspirin 100mg/day and prednisolone 10mg/day within 2 months, and there was no other skin or organ involvement over 18 months of follow up. However, serious refractory skin depressions and pigmentation remained after two years of treatment. This suggests the importance of early and aggressive therapy for cutaneous polyarteritis nodosa to prevent unsightly skin sequel, as well as control of disease activity. PMID- 29267447 TI - Cutaneous manifestations of Churg-Strauss syndrome: key to diagnosis. AB - Churg-Strauss syndrome is a rare systemic vasculitis characterized by asthma and other allergy symptoms as well as eosinophilia and necrotizing vasculitis involving small and medium-sized vessels. Its prevalence in the general population ranges from 1-3 cases per million a year, varying according to the population studied. The authors describe a case of a female patient affected by the disease with important systemic manifestations and not very florid skin lesions. PMID- 29267448 TI - Deferasirox-induced urticarial vasculitis in a patient with myelodysplastic syndrome. AB - Deferasirox is an iron chelator agent used in the treatment of diseases with iron overload, such as thalassemia and myelodysplastic syndrome. Although the majority of adverse reactions of deferasirox involve gastrointestinal symptoms and increase in serum creatinine and transaminases, skin rashes, such as maculopapular and urticarial eruptions, have also been reported. This study reports a case of myelodysplastic syndrome with urticarial vasculitis due to deferasirox therapy. Drug eruption was been confirmed by means of a challenge test, together with histopathological and clinical findings. To the best of our knowledge, we report the first case of deferasirox-induced urticarial vasculitis. Physicians should be aware of the possibility of urticarial vasculitis on deferasirox therapy and the fact that the discontinuation of the drug generally results in improvement. PMID- 29267449 TI - Diffuse cutaneous melanosis: rare complication of metastatic melanoma. AB - Diffuse cutaneous melanosis is a rare complication of metastatic melanoma related to a worse prognosis. There are few cases reported in the literature. Its pathogenesis has not been completely elucidated, although studies have suggested certain mechanisms for its occurrence. It is clinically manifested as a blue-gray discoloration of the skin and mucous membranes in a cephalo caudal progression and usually associated with melanuria. Skin and mucosa histopathology reveals only the presence of melanophages in the dermis, mainly perivascular, and free interstitial melanin. We report the case of a 68-year-old male with metastatic melanoma, diffuse hyperpigmentation of the skin and melanuria. PMID- 29267450 TI - Eosinophilic annular erythema in adults: report of two cases and review of the literature. AB - We herein report two cases of eosinophilic annular erythema in adults, which is rare. In both patients, lesions developed rapidly in few days and were located mainly on the trunk, buttocks, and extremities. Diagnosis was histopathological, with typical features including acute dermal inflammatory infiltrate with abundant eosinophils. One of the patients recurred after treatment on three occasions and finally cured spontaneously. The second patient recurred once and was then successfully treated with topical clobetasol. Clinical and histopathological features of eosinophilic annular erythema in adults have rarely been reported. A review of the literature and discussion of relationship with Wells syndrome are also included. PMID- 29267451 TI - Disseminated cryptococcosis with skin lesions: report of a case series. AB - Cryptococcosis is a common fungal infection in immunocompromised patients, caused by genus Cryptococcus, presenting with meningitis, pneumonia, and skin lesions. Cutaneous presentation can be varied, but specifically in solid organ transplant recipients (iatrogenically immunocompromised), cryptococcosis should always be considered in the differential diagnosis of cellulitis-like lesions, since the delay in diagnosis leads to worse prognosis and fatal outcome. We report four cases of cryptococcosis with cutaneous manifestation not only for its rarity, but also to emphasize the important role of the dermatologist in the diagnosis of this disease. PMID- 29267452 TI - Folliculotropic mycosis fungoides: challenging clinical, histopathological and immunohistochemical diagnosis. AB - Mycosis fungoides is a cutaneous T-cell lymphoma with various clinical and pathological presentations. Early lesions are nonspecific, which hinders early diagnosis. The folliculotropic subtype is manifested as acneiform lesions, follicular papules or erythematous plaques mainly on the face, neck and upper trunk. Histopathology shows dense lymphocytic infiltrate surrounding and infiltrating the hair follicles. A case of difficult histopathological diagnosis with florid and unusual skin lesions mainly on the face is reported. PMID- 29267453 TI - Frontal fibrosing alopecia and extrafacial lichen planus pigmentosum in a caucasian woman. AB - We present the case of a 72-year-old Caucasian woman with frontal fibrosing alopecia of one year's duration. Eighteen months later, she presented with sudden hyperpigmentation on the submental area, neck and upper chest. Histopathological examination was consistent with lichen planus pigmentosus. This is the report of a unique case of a FFA and extrafacial lichen planus pigmentosus. PMID- 29267454 TI - Frontal fibrosing alopecia and lichen planus pigmentosus: diagnosis and therapeutic challenge. AB - Frontal fibrosing alopecia is a variant of lichen planopilaris with marginal progressive hair loss on the scalp, eyebrows and axillae. We report a case of frontal fibrosing alopecia and lichen planus pigmentosus in a postmenopausal woman, that started with alopecia on the eyebrows and then on the frontoparietal region, with periocular and cervical hyperpigmentation of difficult management. The condition was controlled with systemic corticosteroid therapy and finasteride. Lichen planus pigmentosus is an uncommon variant of lichen planus frequently associated with frontal fibrosing alopecia in darker phototipes. It should be considered in patients affected by scarring alopecia with a pattern of lichen planopilaris and areas of skin hyperpigmentation revealing perifollicular hyperpigmentation refractory to multiple treatments. This case illustrates diagnostic and therapeutic challenge in face of scarring alopecia and perifollicular hyperpigmentation. PMID- 29267455 TI - Granuloma annulare treated with narrowband UVB phototherapy. AB - Granuloma annulare is a benign cutaneous inflammatory disease, whose lesions have spontaneous improvement in two years in 50% of cases, but there is recurrence in 40% of patients. Treatment may be topical, intralesional or systemic. The use of phototherapy with narrowband UVB is highlighted, whose mechanism of action in this disease is still unclear, probably related to the inhibition of T lymphocytes. Herein, a case of a disseminated granuloma annulare of difficult therapeutic management is described. It was treated with narrowband UVB phototherapy twice a week for six months, with good clinical improvement, being a good low-risk therapeutic option and that, in this case, provided quick and satisfactory response. PMID- 29267456 TI - Guillain-Barre syndrome in a patient on adalimumab for the treatment of psoriasis. AB - The use of TNF-alpha inhibitors for the treatment of moderate to severe psoriasis and psoriatic arthritis is increasingly more frequent. The authors report a case of Guillain-Barre syndrome as a late manifestation of the treatment with adalimumab. Although unusual, this is relevant for professionals who prescribe biologic drugs. We also stress the importance of investigating the past and family medical history regarding demyelinating diseases before starting treatment. PMID- 29267457 TI - Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report and implications of early onset. AB - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant manifestation of cutaneous and uterine leiomyomas together with renal cancer due to autosomal dominant germline mutations of fumarate hydratase gene. A twenty-year-old female patient presented with type-II segmental piloleiomyoma and increased menstruation due to uterine leiomyomas, with a history of bilateral nephrectomy performed at 13 and 16 years of age for type 2 papillary renal cell carcinoma. This case represents one of the very early onsets of hereditary leiomyomatosis and renal cell carcinoma syndrome. As genetic anticipation for renal cancer is a well-documented entity for HLRCC syndrome, early recognition is crucial for both the patient and her family in order to provide appropriate counseling and initiation of surveillance. PMID- 29267458 TI - Hyperpigmentation as a peculiar presentation of mycosis fungoides. AB - Hyperpigmented mycosis fungoides is an extremely rare subtype of mycosis fungoides. It presents as multiple pigmented macules and patches without poikilodermatous changes and characterized by a CD8+ phenotype on immunohistochemistry. This report describes a typical case of hyperpigmented mycosis fungoides in a 62-year-old woman, who presented with a 7-year history of multiple hyperpigmented macules and patches on the trunk and right leg with progression over this half a year. Histology and immunohistochemical staining of skin samples confirmed the diagnosis of mycosis fungoides. She received psoralen plus ultraviolet A (PUVA) therapy. After an 8-week treatment, the erythematous changes cleared without recurrence during a 6-month follow-up period. An intractable hyperpigmented patch should raise the clinical suspicion of mycosis fungoides with sequential skin biopsy. PMID- 29267459 TI - Kissing nevus of the penis: a case report and dermatoscopic findings. AB - Divided nevus, also known as kissing nevus, is a rare variant of congenital melanocytic nevi in which there are two adjacent nevi in areas of the body that undergo embryonic cleavage. The original description of this type of lesion was on the eyelid. The location on the penis is even rarer, with only 17 case reports in the literature so far, and only one of them described the dermoscopic findings. We report the case of a patient with divided nevus of the penis and its clinical, dermoscopic and histopathological features. PMID- 29267460 TI - Lymphocytoma cutis on the inguinal region: report of a rare case of benign lymphoproliferative disorder. AB - Lymphocytoma cutis, or benign reactive lymphoid hyperplasia, is an inflammatory skin lesion that mimics clinically and histologically malignant lymphoma. Most cases are idiopathic, but they may also be triggered by multiple factors, such as insect bites, tattoos, injections and herpes zoster. Clinically, the lesions are erythematous, soft papules, plaques or nodules, usually located on the upper limbs and face. The diagnosis is mainly based on histopathology and immunohistochemistry. Corticosteroid injections, cryosurgery, PUVA therapy, radiotherapy and surgery can be therapeutic options in cases requiring immediate treatment. To demonstrate an atypical presentation of this tumor, a case lymphocytoma skin on the groin will be reported, describing its diagnosis and treatment. PMID- 29267461 TI - Melanoma in situ and syringoma: a rare collision tumor. Clinical-pathological report of a case. AB - Collision or contiguous tumors, defined as two or more distinct tumors occurring at one site, are often an unexpected finding and may represent a diagnostic challenge, as clinical and histological presentations do not always coincide. Various combinations of collision tumors have been described with respect to melanocytic lesions, with the most frequently reported being the combination of nevus and basal cell carcinoma. We present an unusual case on the nose involving a melanoma in situ and a clinically-inapparent syringoma, which, to the best of our knowledge, is the first report of this combination. PMID- 29267462 TI - Metastatic Crohn's disease despite infliximab therapy. AB - Metastatic Crohn's disease is a rare extraintestinal manifestation of Crohn's disease. It is characterized by polymorphic skin lesions formed by non-caseating granulomas located on anatomical sites distant from the gastrointestinal tract. We report a rare case of metastatic Crohn's disease, simultaneously displaying multiple clinically heterogeneous cutaneous lesions, in a patient with previously diagnosed Crohn's disease in remission due to anti-TNF-alpha use. This case highlights the need for high clinical suspicion and early biopsy in the setting of a patient with Crohn's disease and persistent skin lesions, even under biologic therapy. Furthermore, it reinforces the need of monitoring of the serum level of infliximab, increasing the dose in case it is low or undetectable. PMID- 29267463 TI - Oral manifestation of histoplasmosis on the palate. AB - This case report describes an uncommon manifestation of histoplasmosis on the soft palate. The importance of appropriate treatment and follow-up in complex cases is emphasized, especially in patients with chronic diseases. Oral lesions may occur as multiple, granular and painful ulcers, as well as verrucous growths. Lesions may also be deep, with infiltrative edges and erythematous or with white areas, accompanied by local lymphadenopathy, resembling a carcinoma on clinical examination. In this sense, a fast and accurate diagnosis is essential to the success of treatment of oral histoplasmosis. PMID- 29267464 TI - Oral plasmablastic lymphoma as the first manifestation of AIDS. AB - Plasmablastic lymphoma is a non-Hodgkin lymphoma characterized by its plasmacytic differentiation and predilection for the oral cavity. It is among the lymphomas most commonly associated with AIDS. This report details a case of a HIV-positive patient with a 1-month history of an exophytic mass in the gingival area of the upper left quadrant. The diagnosis of plasmablastic lymphoma was made based on its histopathological and immunophenotypical features. She was treated with chemotherapy followed by autologous hematopoietic stem cell transplantation. Despite complete resolution of the lesion, the patient died of cardiorespiratory arrest. This case illustrates plasmablastic lymphoma as the first clinical manifestation of AIDS, highlighting the importance of differentiating between a potentially malignant lesion and other pathologic processes. PMID- 29267466 TI - Pemphigus foliaceus with pustular presentation in a patient with psoriasis. AB - Pemphigus foliaceus is a chronic autoimmune disease of the skin, clinically characterized by scaly and crusty cutaneous erosions involving the seborrheic areas. The patient can eventually become erythrodermic. There are reports of atypical cases of pemphigus foliaceus with pustules and neutrophils, and clinical differentiation from generalized pustular psoriasis of von Zumbusch is difficult. We report the case of a 55-year-old man with a history of psoriasis vulgaris that has developed pemphigus foliaceus with pustules, triggered by withdrawal of systemic corticosteroids. This is the first report associating this atypical form of pemphigus with psoriasis, suggesting that an overlap with generalized pustular psoriasis can occur. PMID- 29267465 TI - Osteoma cutis: rare painful tumor in atypical location. AB - Osteoma cutis or cutaneous ossification is a rare entity characterized by the formation of bone in the skin. We present an isolated primary osteoma cutis located on the palm, an atypical location. PMID- 29267467 TI - Periorbital leiomyosarcoma treated by means of conventional surgery and frontal myocutaneous flap. AB - Cutaneous leiomyosarcoma is a rare neoplasia, and its periorbital presentation is rather uncommon. We present a case of a male patient who was surgically treated, with the reconstruction performed with a frontal myocutaneous flap. The patient has been followed up for one year with adequate oncologic control and good aesthetic outcome. PMID- 29267468 TI - Porokeratotic eccrine and hair follicle nevus: a report of two cases and review of the literature. AB - Porokeratotic eccrine and hair follicle nevus is a very rare non-hereditary disorder of keratinization with eccrine and hair follicle involvement with only 9 cases described in the literature. In 2009 the term porokeratotic anexial ostial nevus was proposed to comprehend porokeratotic eccrine and hair follicle nevus and a related and more common process without follicular involvement: porokeratotic eccrine ostial and dermal duct nevus Recent findings suggest that both entities may be produced by a mutation in GJB2 gene, which is associated to KID syndrome. Herein we report 2 cases of porokeratotic eccrine and hair follicle nevus and review the existing cases in the Spanish and English literature. PMID- 29267469 TI - Pretibial dystrophic epidermolysis bullosa. AB - Epidermolysis bullosa is a group of mechano-bullous genetic disorders caused by mutations in the genes encoding structural proteins of the skin. Dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene encoding collagen VII, the main constituent of anchoring fibrils. In this group, there are autosomal dominant and recessive inheritances. The pre-tibial form is characterized by the presence of blisters, milia, atrophic scars and lesions similar to lichen planus. The diagnosis is clinical and laboratory and subtypes are distinguished by means of immunohistochemical and ultrastructural studies, in addition to genetic differentiation. Electron microscopy and immunomapping are used in the diagnosis. PMID- 29267470 TI - Pyoderma gangrenosum associated with left iliac vein compression syndrome: presentation of difficult diagnosis. AB - Pyoderma gangrenosum is a rare neutrophilic dermatosis of unknown etiology, of which the most frequent clinical manifestations are ulcers. The diagnosis difficulty is, among other things, to rule out other causes of ulcers, since it is considered a diagnosis of exclusion. Skin ulcerations may also occur in the iliac vein compression syndrome, which, like pyoderma gangrenosum, mainly affects young women. Because they have such similar characteristics, the presence of vascular disease may hinder the diagnosis of concurrent pyoderma gangrenosum. Because of the clinical relevance of ulcerated lesions and scars, the early diagnosis and treatment of this condition is considered extremely important. We report a case in which the two diseases were associated, hampering the diagnosis of pyoderma gangrenosum. PMID- 29267471 TI - Reconstruction of surgical defect of the dorsum of the hand. AB - In some cases, keratoacanthomas can be indistinguishable from squamous cell carcinoma, making the gold standard treatment surgical excision with histopathological evaluation. The surgical defects created on the back of the hand can be challenging to repair. We describe the use of bilateral rotation flap as an option in this area, and discuss the indications and contraindications of some of the possible surgical techniques for reconstruction of the dorsum of the hand. PMID- 29267472 TI - Red nodule on the face with "spontaneous" regression. AB - Pseudolymphomatous folliculitis is a rare entity included among the cutaneous pseudolymphomas. A 32-year-old man, with an unremarkable medical history, presented with a two-month history of an asymptomatic solitary nodule on his left cheek. Histopathological examination demonstrated a dense nodular and diffuse dermal lymphocytic infiltrate with numerous histiocytes and dendritic cells that surrounded hypertrophic hair follicles. Pseudolymphomatous folliculitis commonly presents in the fourth decade of life, with no sex predominance, as an asymptomatic, rapidly growing and solitary red dome-shaped nodule on the face. It has a benign clinical course as the lesions usually resolve with surgical excision or regress spontaneously after incisional biopsy. Although there is no report of pseudolymphomatous folliculitis progressing into lymphoma in the literature, follow-up of these patients is recommended. PMID- 29267473 TI - Sarcoidal granulomatous reaction due to tattoos: report of two cases. AB - Numerous infectious, inflammatory and neoplastic complications secondary to tattoo placement have been reported in the literature. Within inflammatory complications sarcoidal granulomatous reactions have been described. We report two cases, a 55-year-old woman with yellowish infiltrated plaques on bilateral ciliary region, 16 years after the placement of a permanent tattoo in the eyebrows, and a 20-year-old tattoo artist who developed orange papules on 3 of his tattoos. Histopathology in both cases confirmed diagnosis of sarcoidal granulomatous reaction due to tattoo pigment. PMID- 29267474 TI - "String of pearls pattern": report of three cases of non clear-cell acanthoma. AB - The coiled and dotted vessels in a serpiginous arrangement or "string of pearls" is considered a classical vascular pattern associated with clear cell acanthoma. We present three cases of epidermal tumors different from clear cell acanthoma that have the same "string of pearls" vascular pattern. Even though most authors keep considering the "string of pearls" vascular pattern an almost pathognomonic sign of clear-cell acanthoma, the cases presented here suggest that some other epidermal tumors can also show this pattern. PMID- 29267475 TI - The importance of direct immunofluorescence in pemphigus herpetiformis diagnosis. AB - Pemphigus herpetiformis is an autoimmune bullous disease, that combines clinical features of dermatitis herpetiformis and linear IgA bullous dermatosis and immunological characteristics of pemphigus, which makes this disease peculiar and this diagnosis rarely suspected in the first evaluation of the patient. The reported case is of a patient with clinically bullous disease similar to dermatitis herpetiformis, whose multiple biopsies were inconclusive, and only after direct immunofluorescence with a pemphigus pattern (intraepidermal intercellular pattern) the confirmation of the diagnosis was possible. PMID- 29267476 TI - Trigeminal trophic syndrome simulating rodent ulcer basal cell carcinoma: a new clinico-dermoscopic approach. AB - Trigeminal trophic syndrome is an uncommon cause of facial ulcers, that affects the sensitive area of the trigeminal nerve. We present the case of an 84-year-old patient with ulcerated facial trigeminal trophic syndrome, and report the development of a clinico-dermoscopic approach for his clinical examination. The value of this model for the diagnosis of facial ulcers suspected to be a rodent ulcer basal cell carcinoma is suggested. PMID- 29267477 TI - Tunneled island flaps in facial defects reconstruction. AB - The reconstruction of facial surgical defects is usually challenging for the dermatologic surgeon. Three different cases of facial defects in which tunneled island flaps were used are reported. In 2 cases, wide defects involving the nasal dorsum and ala were repaired using a nasolabial island flap tunneled through the lateral side of the nose. A tunneled island glabellar flap was used for medial canthus reconstruction in the third case. Despite complex pedicle dissection and frequent trapdoor deformation, tunneled island flaps allow reconstruction of wide defects in a single-staged procedure, camouflaging the scar of the donor area in boundaries of cosmetic units and preserving the facial central symmetry. PMID- 29267478 TI - Unique autosomal recessive variant of palmoplantar keratoderma associated with hearing loss not caused by known mutations. AB - Inherited Palmoplantar Keratodermas are rare disorders of genodermatosis that are conventionally regarded as autosomal dominant in inheritance with extensive clinical and genetic heterogeneity. This is the first report of a unique autosomal recessive Inherited Palmoplantar keratoderma -sensorineural hearing loss syndrome which has not been reported before in 3 siblings of a large consanguineous family. The patients presented unique clinical features that were different from other known Inherited Palmoplantar Keratodermas -hearing loss syndromes. Mutations in GJB2 or GJB6 and the mitochondrial A7445G mutation, known to be the major causes of diverse Inherited Palmoplantar Keratodermas -hearing loss syndromes were not detected by Sanger sequencing. Moreover, the pathogenic mutation could not be identified using whole exome sequencing. Other known Inherited Palmoplantar keratoderma syndromes were excluded based on both clinical criteria and genetic analysis. PMID- 29267479 TI - Usefulness of the subunit principle in nasal reconstruction. AB - The subunit principle in nasal reconstruction proposed the concept of reconstructing the specific topographic subunits that were identified as dorsum, tip, columella, the paired alae, sidewalls, and soft triangles. In patients with more than 50% of subunit loss, removing the remaining portion of the subunit and reconstructing the entire subunit may yield better results. The placement of incisions along the borders of the subunits minimizes scar lines. Furthermore, as trapdoor contraction occurs, the entire restored subunit bulges in a way that mimics the normal contour of a nasal tip, dorsum or ala. Two cases of nasal reconstruction that followed this important principle are described. PMID- 29267480 TI - Wooly hair nevus. AB - Woolly hair nevus is a rare condition characterized by a structural anomaly of the hair, restricted to certain areas of the scalp. The hair becomes coiled and slightly hypopigmented. The term woolly hair refers to changes that affect all the scalp and has a hereditary character. We present a case of woolly hair nevus, that developed at the age of 2 years, associated with dental diastema and verrucous epidermal nevus. PMID- 29267481 TI - Zoon vulvitis. AB - Zoon vulvitis or vulvitis chronica plasmacellularis is a rare, chronic benign inflammation of the vulvar mucosa, diagnosed histologically, with variable therapeutic responses. It is important to be diagnosed because it mimics the presentation of other genital conditions, such as lichen planus and squamous cell carcinoma, which require specific treatment. We report a case of a female patient with three asymptomatic shallow ulcers on the labia minora. Laboratory tests ruled out infectious diseases and the biopsy was consistent with Zoon Vulvitis. PMID- 29267482 TI - AMB warns against the use of electronic nicotine delivery devices: Electronic and heated cigarettes. PMID- 29267483 TI - Inflammatory arthritis or osteoarthritis of the knee - Efficacy of intra-joint infiltration of methylprednisolone acetate versus triamcinolone acetonide or triamcinolone hexacetonide. PMID- 29267484 TI - Implications for public health of the religiosity-longevity relation. AB - A growing body of scientific studies has demonstrated a consistently positive association between religious-spiritual (R/S) involvement and beneficial effects on physical health, culminating with increased longevity. This protective effect on the mortality risk is not only statistically significant but also clinically relevant. The mechanisms involved in this association include psycho-neuro endocrine-immune pathways, greater adherence to healthy behaviors and diverse social factors. Public health strategies could better explore this association. This can be done on an individual (health professionals adopting simple measures) or institutional scale (health institutions joining religious organizations). Some evidence suggests that the benefits of R/S to health and longevity would be more present in populations from more religious regions. In this sense, the Americas (Latin and North) are privileged places for the exploration of this association, compared to regions where there is certain indifference about R/S practices. Exploring this interface can improve the supply and usage of health care, especially for marginalized populations. To achieve this, health professionals, religious leaders and policy makers need to work together. PMID- 29267485 TI - Algorithms for monitoring warfarin use: Results from Delphi Method. AB - Warfarin stands as the most prescribed oral anticoagulant. New oral anticoagulants have been approved recently; however, their use is limited and the reversibility techniques of the anticoagulation effect are little known. Thus, our study's purpose was to develop algorithms for therapeutic monitoring of patients taking warfarin based on the opinion of physicians who prescribe this medicine in their clinical practice. The development of the algorithm was performed in two stages, namely: (i) literature review and (ii) algorithm evaluation by physicians using a Delphi Method. Based on the articles analyzed, two algorithms were developed: "Recommendations for the use of warfarin in anticoagulation therapy" and "Recommendations for the use of warfarin in anticoagulation therapy: dose adjustment and bleeding control." Later, these algorithms were analyzed by 19 medical doctors that responded to the invitation and agreed to participate in the study. Of these, 16 responded to the first round, 11 to the second and eight to the third round. A 70% consensus or higher was reached for most issues and at least 50% for six questions. We were able to develop algorithms to monitor the use of warfarin by physicians using a Delphi Method. The proposed method is inexpensive and involves the participation of specialists, and it has proved adequate for the intended purpose. Further studies are needed to validate these algorithms, enabling them to be used in clinical practice. PMID- 29267486 TI - Neuroendocrine tumors: An epidemiological study of 250 cases at a tertiary hospital. AB - OBJECTIVE: To compare the frequency of neuroendocrine tumors in our service with that reported in the literature considering age, gender, location, degree of differentiation and increase in incidence by means of a retrospective study. METHOD: Search of variables from a database of neuroendocrine tumor cases diagnosed at the Department of Pathological Sciences, Hospital da Santa Casa de Sao Paulo over the past 10 years, relating them to epidemiological data such as gender, age, distribution across organs, most-used immunohistochemical markers and presence or absence of either lymph node or distant metastases. RESULTS: In all, 250 cases were reviewed, 133 involving females, predominantly in the 61-70 age range. The lung was the most frequent site, followed by the stomach. CD56, synaptophysin and chromogranin were the immunohistochemical markers used most often and to a lesser extent Ki67, a marker of cell proliferation that indicates a higher or lower degree of histological malignancy. Metastases, either in lymph nodes and/or distant sites, were found in 44 cases (17.6%). CONCLUSION: The results were largely consistent with those in the literature, including age group, gender and location. Most metastases originated from high-grade tumors, with high Ki67 levels and greater impairment of the liver. However, only 36.4% of the cases had Ki67 index. Reevaluation of the Ki67 proliferative index using image analysis in doubtful cases will allow for a correlation between progression and prognosis. PMID- 29267487 TI - Obstructive sleep apnea syndrome among obese individuals: A cross-sectional study. AB - INTRODUCTION: The obstructive sleep apnea syndrome (OSAS) is a respiratory illness, characterized by recurrent episodes of apnea and hypopnea, leading to reduction or cessation of the airflow. Obesity is one of the major risk factors for the development of OSAS. To help in the diagnosis of this disease, easily applicable and low-cost questionnaries were developed, such as the Berlin Questionnaire (BQ). OBJECTIVE: To evaluate the efficacy of the BQ for the screening of OSAS among candidates to bariatric surgery in a multidisciplinary preoperative program. METHOD: This is an observational, descriptive and cross sectional study which evaluated obese individuals that were being prepared for bariatric surgery by means of the BQ. RESULTS: BQ was able to detect that minimal variations in the body mass index, neck circumference and hip-to-waist ratio lead to changes in the risk to develop OSAS; the higher the values of these variables, the higher the risk for OSAS development. CONCLUSION: BQ was an efficient and reliable tool to demonstrate the high risk for OSAS development in individual with obesity. PMID- 29267488 TI - Systemic arterial hypertension, blood pressure levels and associated factors in schoolchildren. AB - INTRODUCTION: Hypertension is a major public health problem in contemporary times and it has high prevalence throughout the world. OBJECTIVE: To investigate the situation of Systemic Arterial Hypertension in schoolchildren aged 6 to 10 years in Divinopolis/MG-Brazil and associated factors. METHOD: This is a cross sectional, epidemiological, descriptive and analytical study, whose population was children aged 6 to 10 years enrolled in public schools in Divinopolis-MG Brazil. Data collection was conducted from October 2014 to May 2015. Multivariate linear regressions were used to test associations between blood pressure, socioeconomic, anthropometric, dietary and physical activity. RESULTS: The prevalence of hypertension was 15.2% in a sample of 284 children and mean values of systolic blood pressure of 101.7 (+/-13.2) mmHg and diastolic blood pressure of 66.0 (+/-11.2) mmHg. The body fat percentage showed significant differences between the genders, with 24.2 and 26.2%, respectively for boys and girls. Significant associations were made between blood pressure levels, body weight, body mass index, waist circumference, body fat percentage, consumption of yogurt, beef /chicken, beans, pizza, sandwich and some behaviors variables. CONCLUSION: The presented data show important aspects of school profile in the age range 6-10 years, especially related to the behavior of blood pressure. PMID- 29267489 TI - Sexual function, anxiety and depression in women with benign breast disease. A case-control study. AB - INTRODUCTION: Sexual dysfunction is highly prevalent, affecting 40% of the female population. The incidence of such dysfunction is known to be higher among women with malignant breast disease and in patients with depression or anxiety. However, there are few data regarding the prevalence of sexual dysfunction among women with benign breast disease (BBD). OBJECTIVE: To evaluate the incidence of sexual dysfunction, depression and anxiety among women with BBD, in comparison with that observed for healthy women. METHOD: We evaluated the incidence of sexual dysfunction in 60 patients with benign breast disease (fibroadenomas, breast cysts, breast pain and phyllodes tumor) and 69 healthy women (control group). Participants completed the Sexual Quotient Questionnaire for Females (SQQ F), the Beck Depression Inventory and the Beck Anxiety Inventory. Statistical analysis revealed that depression and anxiety were comparable between BBD and control groups (10.3 vs. 20.3% and 38.7 vs. 34.3%, respectively, p>0.05). The mean SQQ-F score (65.6+/-22.7 vs. 70.1+/-16.8; p>0.05) and sexual dysfunction (33.3 vs. 25.4%; p=0.324) were similar between BBD and control groups. CONCLUSION: We found no differences between women with BBD and healthy women in terms of the incidence of sexual dysfunction, anxiety and depression. Nevertheless, given the high prevalence of this condition, it is important to assess sexual quality of life, as well as overall quality of life, in women with BBD. PMID- 29267490 TI - Knockout of p16INK4a promotes aggregative growth of dermal papilla cells. AB - OBJECTIVE: Dermal papilla cells (DPCs) are located in the hair follicles and play an important role in hair growth. These cells have the ability to induce hair follicle formation when they display aggregative behavior. DPCs derived from the androgenetic alopecia (AGA) area undergo premature senescence in vitro, associated with p16INK4a expression. The aim of the current study was to investigate the expression of p16INK4a in aggregative and non-aggregative DPCs and the effect of p16INK4a down-regulation in these cells by adenovirus-mediated RNA interference (RNAi). METHOD: DPCs were isolated and cultured from healthy human scalp. p16INK4a gene and protein were detected in aggregative and non aggregative cells. Expression of p16INK4a in DPCs was silenced by infection with rAd5-CDKN1A-1p2shRNA. Cell fate was monitored after infection. The growth of cells was measured by MTT assay. Cell cycle was evaluated by flow cytometry (FCM). RESULTS: DPCs were isolated by digestion and showed aggregative behavior for six passages. The expression of p16INK4a showed a clear upward trend in non aggregative cells when compared with aggregative group. p16INK4a expression was silenced by rAd5-CDKN1A-1p2shRNA (p<0.05). The p16INK4a-silenced cells grew more rapidly and exhibited a trend towards aggregative growth. There was an increase in the proportion of cells in G1 phase, while those in S phase were reduced after p16INK4a gene silencing (p<0.05). CONCLUSION: Our results suggest that p16INK4a plays an important role in the premature senescence and aggregative behavior of DPCs. These observations can lead to novel therapeutic strategies for treatment of AGA. PMID- 29267491 TI - Cancer care network: Structure analysis of enabled services. AB - INTRODUCTION: Cancer has now become part of the agenda of health managers, prompting them to consider new models of system organization. OBJECTIVE: To study the cancer care network of the Brazilian public health system (SUS, in the Portuguese acronym) in the state of Sao Paulo by analyzing the structure of the installed and enabled network for treatment and its characteristics. METHOD: A single, integrated case study. We used secondary data from the following sources: Datasus, Inca, RHC and CNES, and primary data from official documents from the Reference Committee on Oncology of the State of Sao Paulo. We used the official guidelines to able services from the National Health Department to make comparison. RESULTS: According to the CNES, in April, 2013 there were 72 cancer care services authorized by SUS in the state of Sao Paulo. Using the population criterion, the state had one service enabled for every 581,961 inhabitants, in an unequal distribution throughout the 17 health care regions. In terms of available structure and services, 80% of the hospitals were compliant for cancer surgery, 31% for chemotherapy and 74% for radiotherapy. In terms of minimum production, only 13% of hospitals were compliant with cancer surgery, 42% with chemotherapy and 14% with radiotherapy. CONCLUSION: The installed network proved to have sufficient size and structure to meet the demand from new cancer cases. However, there were both regional differences, as well as a wide variation in productivity between services, which probably had an impact on patient access. PMID- 29267492 TI - Oral corticosteroids for asthma exacerbations might be associated with adrenal suppression: Are physicians aware of that? AB - INTRODUCTION: Oral corticosteroids (OCS) are a mainstay of treatment for asthma exacerbations, and short-term OCS courses were generally considered to be safe. Nevertheless, frequent short-term OCS courses could lead to hypothalamic pituitary-adrenal (HPA) axis dysfunction. Our study aimed at investigating the integrity of the HPA axis in children with persistent asthma or recurrent wheezing at the beginning of an inhaled corticosteroids (ICS) trial. METHOD: Morning basal cortisol was assessed just before the beginning of ICS, and 30, 60, and 90 days later, using Immulite(r) Siemens Medical Solutions Diagnostic chemiluminescent enzyme immunoassay (Los Angeles, USA; 2006). RESULTS: In all, 140 children (0.3-15 years old) with persistent asthma or recurrent wheezing have been evaluated and 40% of them reported short-term OCS courses for up to 30 days before evaluation. Out of these, 12.5% had biochemical adrenal suppression but showed adrenal recovery during a three-month ICS trial treatment. No significant differences were observed among children with or without adrenal suppression, neither in the number of days free of OCS treatment before cortisol evaluation (p=0.29) nor in the last OCS course duration (p=0.20). The number of short-term OCS courses reported in the year preceding the cortisol evaluation was also not different (p=0.89). CONCLUSION: Short-term systemic courses of corticosteroids at conventional doses can put children at risk of HPA axis dysfunction. ICS treatment does not impair adrenal recovery from occurring. Health practitioners should be aware of the risk of a blunted cortisol response upon exposure to stress during the follow-up of patients with persistent asthma or recurrent wheezing. PMID- 29267493 TI - Changes in serum cardiac myosin light chain 1 levels in children with fulminant myocarditis during continuous blood purification. AB - OBJECTIVE: To investigate the changes in serum cardiac myosin light chain 1 (CMLC 1) levels in children with fulminant myocarditis (FM) during continuous blood purification (CBP), as well as to analyze its correlation with other laboratory indexes. METHOD: Twenty-four (24) children with FM who underwent CBP were enrolled. Before and during treatment (48 and 72 hours after treatment, or death), the optical density value of serum CMLC-1 was measured using enzyme linked immunosorbent assay, and then the serum CMLC-1 concentration was calculated. The correlations between CMLC-1 OD value change and laboratory indexes including creatine kinase-MB (CK-MB), troponin, myohemoglobin and N terminal pro-brain natriuretic peptide (NT-proBNP) were analyzed. RESULTS: The serum CMLC-1 concentration significantly increased in the children with FM and decreased obviously during CBP therapy. In the same period, the change of CMLC-1 concentration were positively correlated with creatine kinase-MB (r=0.528), troponin (r=0.726), myohemoglobin (r=0.702), and NT-proBNP levels (r=0.589). CONCLUSION: The serum CMLC-1 concentration increases significantly in children with FM, but CBP therapy can effectively control this increase. PMID- 29267494 TI - Arterial stiffness and 25-hydroxyvitamin D levels in chronic kidney disease patients. AB - OBJECTIVE: Arterial stiffness refers to arterial wall rigidity, particularly developing in central vessels. Arterial stiffness increases in early stage chronic kidney disease (CKD), and it is a strong predictor of cardiovascular and all cause mortality. Vitamin D has beneficial effects on blood pressure, vascular endothelial function and arterial stiffness. 25-hydroxyvitamin D (25(OH)D) deficiency is quite common worldwide and in the CKD population. We aimed to evaluate the prevalence of 25(OH)D deficiency and its relation with arterial stiffness in CKD. METHOD: Our study included 101 patients (51 male, 50 female), with stages 3B-5 CKD not on dialysis. A single-cuff arteriograph device (Mobil-O Graph) was used to evaluate arterial stiffness parameters of pulse wave velocity (PWV) and augmentation index (Alx@75). The patients were divided into two groups: group I vitamin D non-deficient [25(OH)D > 15 ng/mL] and group II vitamin D deficient [25(OH)D <= 15 ng/mL]. RESULTS: Overall, the mean 25(OH)D level was 14.1+/-7.9 ng/mL and 70 patients (69.4%) were vitamin D deficient. The mean Alx@75 value was significantly higher in group II (28.6+/-10.8% vs. 23.3+/-13.5%, p=0.038). PWV was higher in group II, but the difference was not significant. Group II exhibited significantly lower serum albumin (p<0.001), hemoglobin (p=0.005), calcium (p=0.041) and estimated glomerular filtration rate (eGFR) (p=0.041), but significantly higher 24-hour proteinuria (p=0.011) and more females (p=0.006). Vitamin D was negatively correlated with Alx@75 augmentation pressure, parathyroid hormone, proteinuria and body mass index, and positively correlated with albumin, hemoglobin, eGFR, calcium and transferrin. 25(OH)D was independently associated with Alx@75 (beta=-0.469, p=0.001) and albumin (beta=0.447, p=0.002). CONCLUSION: In CKD patients 25(OH)D deficiency was common, particularly in females. Level of 25(OH)D was independently associated with Alx@75. PMID- 29267495 TI - The importance of legislative measures on tobacco control in Brazil. AB - INTRODUCTION: In the tobacco control program, educational, socioeconomic, ecological and legislative actions should be planned. Legislative actions should include the federal, state and municipal spheres, have a primarily preventive purpose and federal reach. OBJECTIVE: Survey of bills presented in both legislative houses at federal level, House of Representatives and Senate (which together form the National Congress) and the resulting laws. METHOD: In the period from 1965 to 2015, 254 bills were filed with the House of Representatives and, from 1971 to 2015, 68 others were presented to the Senate. RESULTS: In the House of Representatives, of the 254 bills, 68.9% were archived/rejected/returned, 14.9% did not have a result, 12.2% are currently being processed/analyzed by commissions, 2.0% refer to the inclusion of amendments/law annexes, 1.2% were transformed into legal norm/proposition of origin and 0.8% were transformed into laws. In the Senate, of the 68 bills, 19.1% were filed, 33.8% did not have a result, 4.4% were currently being processed, and 42.7% referred to changes in the law. Anti--tobacco actions were more prevalent in the periods 1979-1984 by the AMB, 1985-2007 by MS/INCA, and in 2008-2015 by the ACT. CONCLUSION: Tobacco control legislation has progressed constantly, with the provocation of legislators from both Houses triggered by the MS/INCA and civil entities committed to smoking control, such as a number of non-governmental organizations (especially the AMB and the ACT). PMID- 29267496 TI - T cell subsets and immunoglobulin G levels are associated with the infection status of systemic lupus erythematosus patients. AB - Systemic lupus erythematosus (SLE) is a chronic, autoimmune disorder that affects nearly all organs and tissues. As knowledge about the mechanism of SLE has increased, some immunosuppressive agents have become routinely used in clinical care, and infections have become one of the direct causes of mortality in SLE patients. To identify the risk factors indicative of infection in SLE patients, a case control study of our hospital's medical records between 2011 and 2013 was performed. We reviewed the records of 117 SLE patients with infection and 61 SLE patients without infection. Changes in the levels of T cell subsets, immunoglobulin G (IgG), complement C3, complement C4, globulin, and anti-double stranded DNA (anti-ds-DNA) were detected. CD4+ and CD4+/CD8+ T cell levels were significantly lower and CD8+ T cell levels were significantly greater in SLE patients with infection than in SLE patients without infection. Additionally, the concentrations of IgG in SLE patients with infection were significantly lower than those in SLE patients without infection. However, complement C3, complement C4, globulin, and anti-ds-DNA levels were not significantly different in SLE patients with and without infection. Therefore, clinical testing for T cell subsets and IgG is potentially useful for identifying the presence of infection in SLE patients and for distinguishing a lupus flare from an acute infection. PMID- 29267497 TI - Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats. AB - Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects. PMID- 29267499 TI - Production and characterization of a biosurfactant produced by Streptomyces sp. DPUA 1559 isolated from lichens of the Amazon region. AB - Surfactants are amphipathic compounds containing both hydrophilic and hydrophobic groups, capable to lower the surface or interfacial tension. Considering the advantages of the use of biosurfactants produced by microorganisms, the aim of this paper was to develop and characterize a biosurfactant produced by Streptomyces sp. DPUA1559 isolated from lichens of the Amazon region. The microorganism was cultured in a mineral medium containing 1% residual frying soybean oil as the carbon source. The kinetics of biosurfactant production was accompanied by reducing the surface tension of the culture medium from 60 to values around 27.14 mN/m, and by the emulsification index, which showed the efficiency of the biosurfactant as an emulsifier of hydrophobic compounds. The yield of the isolated biosurfactant was 1.74 g/L, in addition to the excellent capability of reducing the surface tension (25.34 mN/m), as observed from the central composite rotational design when the biosurfactant was produced at pH 8.5 at 28 degrees C. The critical micelle concentration of the biosurfactant was determined as 0.01 g/mL. The biosurfactant showed thermal and pH stability regarding the surface tension reduction, and tolerance under high salt concentrations. The isolated biosurfactant showed no toxicity to the micro crustacean Artemia salina, and to the seeds of lettuce (Lactuca sativa L.) and cabbage (Brassica oleracea L.). The biochemistry characterization of the biosurfactant showed a single protein band, an acid character and a molecular weight around 14.3 kDa, suggesting its glycoproteic nature. The results are promising for the industrial application of this new biosurfactant. PMID- 29267498 TI - Ginsenoside Rg1 protects human renal tubular epithelial cells from lipopolysaccharide-induced apoptosis and inflammation damage. AB - Ginsenoside Rg1, one of the most notable active components of Panax ginseng, has been widely reported to exert anti-inflammatory actions. This study aimed to reveal whether ginsenoside Rg1 also exhibits beneficial roles against lipopolysaccharide (LPS)-induced apoptosis and inflammation in human renal tubular epithelial cells, and to evaluate the potential role of the component on tubulointerstitial nephritis treatment. HK-2 cells were treated with various doses of ginsenoside Rg1 (0, 50, 100, 150, and 200 MUM) in the absence or presence of 5 MUg/mL LPS. Thereafter, CCK-8 assay, flow cytometry, western blot, migration assay, reactive oxygen species (ROS) assay, and ELISA were carried out to respectively assess cell viability, apoptosis, migration, ROS activity, and the release of inflammatory cytokines. As a result, ginsenoside Rg1 protected HK 2 cells from LPS-induced injury, as cell viability was increased, cell apoptosis was decreased, and the release of MCP-1, IL-1beta, IL-6, and TNF-alpha was reduced. Ginsenoside Rg1 functioned to HK-2 cells in a dose-dependent manner, and the 150 MUM dose exhibited the most protective functions. Ginsenoside Rg1 had no significant impact on cell migration and ROS activity, while it alleviated LPS induced ROS release and migration impairment. Furthermore, the down-regulations of p-PI3K, p-AKT, and up-regulations of PTEN, p-IkappaBalpha, p-p65, Bcl-3 induced by LPS were recovered to some extent after ginsenoside Rg1 treatment. In conclusion, ginsenoside Rg1 protects HK-2 cells against LPS-induced inflammation and apoptosis via activation of the PI3K/AKT pathway and suppression of NF-kappaB pathway. PMID- 29267500 TI - Quality of life and adherence to treatment in early-treated Brazilian phenylketonuria pediatric patients. AB - Early dietary treatment of phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, results in normal cognitive development. Although health-related quality of life (HRQoL) of PKU patients has been reported as unaffected in high-income countries, there are scarce data concerning HRQoL and adherence to treatment of PKU children and adolescents from Brazil. The present study compared HRQoL scores in core dimensions of Brazilian early-treated PKU pediatric patients with those of a reference population, and explored possible relationships between adherence to treatment and HRQoL. Early-treated PKU pediatric patient HRQoL was evaluated by self- and parent-proxy reports of the Pediatric Quality of Life Inventory (PedsQL) core scales. Adherence to treatment was evaluated by median Phe levels and percentage of results within the therapeutic target range in two periods. Means for total and core scales scores of PedsQL self- and parent proxy-reports of PKU patients were significantly lower than their respective means for controls. Adequacy of median Phe concentrations and the mean percentage of values in the target range fell substantially from the first year of life to the last year of this study. There was no significant difference in mean total and core scale scores for self- and parent proxy-reports between patients with adequate and those with inadequate median Phe concentrations. The harmful consequences for intellectual capacity caused by poor adherence to dietary treatment could explain the observed decrease in all HRQoL scales, especially in school functioning. Healthcare system and financial difficulties may also have influenced negatively all HRQoL dimensions. PMID- 29267501 TI - Effectiveness of preoperative decolonization with nasal povidone iodine in Chinese patients undergoing elective orthopedic surgery: a prospective cross sectional study. AB - Staphylococcus aureus colonization in the nares of patients undergoing elective orthopedic surgery increases the potential risk of surgical site infections. Methicillin-resistant S. aureus (MRSA) has gained recognition as a pathogen that is no longer only just a hospital-acquired pathogen. Patients positive for MRSA are associated with higher rates of morbidity and mortality following infection. MRSA is commonly found in the nares, and methicillin-sensitive S. aureus (MSSA) is even more prevalent. Recently, studies have determined that screening for this pathogen prior to surgery and diminishing staphylococcal infections at the surgical site will dramatically reduce surgical site infections. A nasal mupirocin treatment is shown to significantly reduce the colonization of the pathogen. However, this treatment is expensive and is currently not available in China. Thus, in this study, we first sought to determine the prevalence of MSSA/MSRA in patients undergoing elective orthopedic surgery in northern China, and then, we treated the positive patients with a nasal povidone-iodine swab. Here, we demonstrate a successful reduction in the colonization of S. aureus. We propose that this treatment could serve as a cost-effective means of eradicating this pathogen in patients undergoing elective orthopedic surgery, which might reduce the rate of surgical site infections. PMID- 29267502 TI - Mechanism of hif-1alpha mediated hypoxia-induced permeability changes in bladder endothelial cells. AB - This study aimed to investigate the mechanism of hypoxia-inducible factor-1 alpha (HIF-1alpha) mediated hypoxia-induced permeability changes in bladder endothelial cells. Models of in vitro hypoxic cell culture of bladder cancer, bladder cancer cells with low HIF-1alpha expression and HIF-1alpha RNA interference (RNAi) expression vector were established. Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to detect the expression of HIF 1alpha and vascular endothelial growth factor (VEGF) in each group. Bladder cell permeability was determined. Results showed that protein and mRNA expression of HIF-1alpha and VEGF at 3 and 12 h of hypoxia were significantly higher than normal control (P<0.05), and peaked at 12 h. HIF-1alpha and VEGF expression in the hypoxic group and hypoxic+3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC 1) group were significantly higher than normal control (P<0.05), while expression in the hypoxic+YC-1 group was significantly lower than the hypoxic group (P<0.05). Bladder cell permeability in the hypoxic and hypoxic+YC-1 group were significantly increased compared to normal control (P<0.05), while in the hypoxic+YC-1 group was significantly decreased compared to the hypoxic group (P<0.05). Most of the cells in the stably transfected HIF-1alpha RNAi expression vector pcDNA6.2-GW/EmGFP-miR-siHIF-1alpha expressed green fluorescence protein (GFP) under fluorescence microscope. pcDNA6.2-GW/EmGFP-miR-siHIF-1alpha could significantly inhibit HIF-1alpha gene expression (P<0.05). HIF-1alpha and VEGF expression in the hypoxic group and siHIF-1alpha hypoxic group were significantly higher than normal group (P<0.05), while expression in the siHIF-1alpha hypoxic group was significantly lower than the hypoxic group (P<0.05). Findings suggest that HIF-1alpha is an important factor in the increase of bladder cancer cell permeability. PMID- 29267503 TI - Long non-coding RNA LINC00261 sensitizes human colon cancer cells to cisplatin therapy. AB - Colon cancer is one of the most common digestive tumors. The present study aimed to explore the functional role, as well as the underlying mechanism of long non coding RNA LINC00261 in colon cancer. Expression of LINC00261 was analyzed in colon cancer cell lines and human normal cell lines. Acquired resistance cell lines were then built and the acquired resistance efficiency was detected by evaluating cell viability. Thereafter, the effects of LINC00261 overexpression on cisplatin-resistant colon cancer cells were measured, as well as cell apoptosis, viability, migration, and invasion. Subsequently, we investigated the interaction of LINC00261 and beta-catenin. The results showed that the LINC00261 gene was down-regulated in colon cancer cell lines and tissues, and in cisplatin-resistant cells. LINC00261 overexpression might relieve cisplatin resistance of colon cancer cells via promoting cell apoptosis, and inhibiting cell viability, migration, and invasion. Moreover, LINC00261 might down-regulate nuclear beta catenin through restraining beta-catenin from cytoplasm into nuclei or it could also promote beta-catenin degradation and inhibit activation of Wnt pathway. Finally, LINC00261 reduced cisplatin resistance of colon cancer in vivo and enhanced the anti-colon cancer effect of cisplatin through reducing tumor volume and weight. PMID- 29267504 TI - Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly. AB - Pituitary adenomas account for 10-15% of primary intracranial tumors. Growth hormone (GH)-secreting adenomas account for 13% of all pituitary adenomas and cause acromegaly. These tumors can be aggressive, invade surrounding structures and are highly recurrent. The objective of this study was to evaluate E-cadherin, Slug and neural cell adhesion molecule (NCAM) expression in GH-secreting pituitary adenomas and its relationship to tumor invasiveness. A cross-sectional study of patients who underwent hypophysectomy due to GH-secreting pituitary adenoma from April 2007 to December 2014 was carried out. The medical records were reviewed to collect clinical data. Immediately after surgery, tumor samples were frozen in liquid nitrogen and stored in a biofreezer at -80 degrees C for assessment of E-cadherin 1 (CDH1), SLUG (SNAI2), and NCAM (NCAM1) by real-time PCR. The samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis of E-cadherin and NCAM. Thirty-five patients with acromegaly were included in the study. Of these, 65.7% had invasive tumors. Immunohistochemically, E-cadherin was expressed in 96.7% of patients, and NCAM in 80% of patients. There was no statistically significant relationship between tumor grade or invasiveness and immunohistochemical expression of these markers. Regarding gene expression, 50% of cases expressed CDH1, none expressed SNAI2, and 53.3% expressed NCAM1. There was no statistically significant relationship between tumor grade or invasiveness and gene expression of CDH1, SNAI2, and NCAM1. The absence of Slug overexpression and of E-cadherin and NCAM suppression suggests that expression of these markers is not associated with tumor invasiveness in GH-secreting pituitary adenomas. PMID- 29267505 TI - Therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis. AB - Caspase recruitment domain-containing protein 9 (Card9) is located upstream of the nuclear factor kappa B (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK) inflammatory pathways. This study investigated the therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis (SAP). SAP was induced by a retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats (n=54), which were then treated with pioglitazone. Blood and pancreatic tissues were harvested at 3, 6, and 12 h after SAP induction. Pancreatic pathological damage was evaluated by hematoxylin and eosin staining. Serum amylase, serum pro-inflammatory cytokines, and pancreatic myeloperoxidase (MPO) activities were determined by enzyme-linked immunosorbent assay. The expression of Card9 mRNA and protein in pancreatic tissues was detected by real-time polymerase chain reaction and western blotting. Pioglitazone had a therapeutic effect in treating rats with SAP by decreasing the level of amylase activity, ameliorating pancreatic histological damage, decreasing serum pro-inflammatory cytokine levels and tissue MPO activity, and downregulating the expression of NF-kappaB, p38MAPK, and Card9 mRNAs and proteins (P<0.05). The present study demonstrated that the inhibition of Card9 expression could reduce the severity of SAP. Card9 has a role in the pathogenic mechanism of SAP. PMID- 29267506 TI - Comparison of Arndt-endobronchial blocker plus laryngeal mask airway with left sided double-lumen endobronchial tube in one-lung ventilation in thoracic surgery in the morbidly obese. AB - This study aimed to evaluate the feasibility and performance of Arndt endobronchial blocker (Arndt) combined with laryngeal mask airway (LMA) compared with left-sided double-lumen endobronchial tube (L-DLT) in morbidly obese patients in one-lung ventilation (OLV). In a prospective, randomized double-blind controlled clinical trial, 80 morbidly obese patients (ASA I-III, aged 20-70) undergoing general anesthesia for elective thoracic surgeries were randomly allocated into groups Arndt (n=40) and L-DLT (n=40). In group Arndt, a LMATM Proseal was placed followed by an Arndt-endobronchial blocker. In group L-DLT, patients were intubated with a left-sided double-lumen endotracheal tube. Primary endpoints were the airway establishment, ease of insertion, oxygenation, lung collapse and surgical field exposure. Results showed similar ease of airway establishment and tube/device insertion between the two groups. Oxygen arterial pressure (PaO2) of patients in the Arndt group was significantly higher than L DLT (154+/-46 vs 105+/-52 mmHg; P<0.05). Quality of lung collapse and surgical field exposure in the Arndt group was significantly better than L-DLT (effective rate 100 vs 90%; P<0.05). Duration of surgery and anesthesia were significantly shorter in the Arndt group (2.4+/-1.7 vs 3.1+/-1.8 and 2.8+/-1.9 vs 3.8+/-1.8 h, respectively; P<0.05). Incidence of hoarseness of voice and incidence and severity of throat pain at the post-anesthesia care unit and 12, 24, 48, and 72 h after surgery were significantly lower in the Arndt group (P<0.05). Findings suggested that Arndt-endobronchial blocker combined with LMA can serve as a promising alternative for morbidly obese patients in OLV in thoracic surgery. PMID- 29267507 TI - Two novel Mg(II)-based and Zn(II)-based complexes: inhibiting growth of human liver cancer cells. AB - Two new Mg(II)-based and Zn(II)-based coordination polymers, {[Mg3(BTB)(DMA)4](DMA)2}n (1, H3BTB=1,3,5-benzenetrisbenzoic acid, DMA=N,N dimethylacetamide) and {(H2NMe2)2[Zn3(BTB)2(OH)(Im)](DMF)9(MeOH)7}n (2, Im=imidazole, DMF=N,N-dimethylformamide), have been successfully synthesized and structurally characterized under solvothermal conditions. 1 contains a linear [Mg3(COO)6] cluster that connected by the fully deprotonated BTB3- ligands to give a kgd-type 2D bilayer structure; 2 represents a microporous 3D pillar layered system based on the binuclear Zn units and pillared Im ligands, which shows a (3,5)-connected hms topological net. In addition, in vitro anticancer activities of compounds 1 and 2 on 4 human liver cancer cells (HB611, HHCC, BEL 7405 and SMMC-7721) were determined. PMID- 29267508 TI - Characterization of air-liquid interface culture of A549 alveolar epithelial cells. AB - Alveolar epithelia play an essential role in maintaining the integrity and homeostasis of lungs, in which alveolar epithelial type II cells (AECII) are a cell type with stem cell potential for epithelial injury repair and regeneration. However, mechanisms behind the physiological and pathological roles of alveolar epithelia in human lungs remain largely unknown, partially owing to the difficulty of isolation and culture of primary human AECII cells. In the present study, we aimed to characterize alveolar epithelia generated from A549 lung adenocarcinoma cells that were cultured in an air-liquid interface (ALI) state. Morphological analysis demonstrated that A549 cells could reconstitute epithelial layers in ALI cultures as evaluated by histochemistry staining and electronic microscopy. Immunofluorescent staining further revealed an expression of alveolar epithelial type I cell (AECI) markers aquaporin-5 protein (AQP-5), and AECII cell marker surfactant protein C (SPC) in subpopulations of ALI cultured cells. Importantly, molecular analysis further revealed the expression of AQP-5, SPC, thyroid transcription factor-1, zonula occludens-1 and Mucin 5B in A549 ALI cultures as determined by both immunoblotting and quantitative RT-PCR assay. These results suggest that the ALI culture of A549 cells can partially mimic the property of alveolar epithelia, which may be a feasible and alternative model for investigating roles and mechanisms of alveolar epithelia in vitro. PMID- 29267509 TI - Clinical correlates of loss of insight in bipolar depression. AB - INTRODUCTION: Affective state may influence insight, especially regarding mania. Nevertheless, studies have so far suggested that depression seems not to significantly impair insight. To the best of our knowledge, this study pioneers the evaluation of how insight variations in bipolar depression correlate with clinical variables. METHOD: A group of 165 bipolar patients, 52 of whom had depressive episodes according to DSM-5 criteria, were followed during a year. All patients underwent clinical assessment, and insight was evaluated through the Insight Scale for Affective Disorders (ISAD). Repeated-measures ANOVA was calculated comparing scores on the four ISAD factors (insight into symptoms, the condition itself, self-esteem and social relationships) in order to investigate differences in insight according to different objects. Correlational analysis explored which clinical symptoms were linked to reduced insight. RESULTS: Worse total insight correlated with suicide attempt/ideation and fewer subsyndromal manic symptoms such as mood elevation, increased energy and sexual interest. Worse self-esteem insight was associated with not only suicide ideation/attempt but also with activity reduction and psychomotor retardation. Worse symptom insight also correlated with psychomotor retardation. Better insight into having an affective disorder was associated with more intense hypochondria symptoms. Finally, worse insight into having an illness was associated with psychotic episodes. CONCLUSION: Our study found that symptoms other than psychosis - suicide ideation, psychomotor retardation and reduction of activity and work - correlate with insight impairment in bipolar depression. PMID- 29267510 TI - Clinical and familial profile of bipolar disorder with and without obsessive compulsive disorder: an Indian study. AB - INTRODUCTION: Comorbid obsessive-compulsive disorder (OCD) is common in bipolar disorder (BD). Clinical characteristics, functionality and familial pattern of this comorbidity are largely understudied. OBJECTIVE: To assess clinical profile, familial loading of psychiatric disorders and level of functioning in remitted BD patients who have comorbid OCD and to compare results with those of remitted BD patients without OCD. METHODS: Remitted BD-I subjects were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders, Global Assessment of Functioning Scale (GAF), Hamilton Depression Rating Scale (HDRS), Young Mania Rating Scale (YMRS), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Family Interview for Genetic Studies (FIGS). BD patients with and without OCD were compared. Group differences were analyzed using the chi-square test and the independent samples t test. Values <0.05 were considered statistically significant. RESULTS: Of the 90 remitted BD-I patients, 35.5% (n=32) had obsessive-compulsive symptoms/OCD. The BD-OCD group showed significantly lower GAF scores, higher rates of suicidal attempts, hospitalizations, manic and depressive episodes compared to the group with BD only (p<0.05). In addition, first and second-degree relatives had higher rates of BD-OCD and OCD, but not of BD. CONCLUSIONS: BD-OCD is characterized by more severe BD, more dysfunction and higher familial loading of BD-OCD and OCD. Larger studies involving relatives of probands will help to confirm our findings and to delineate nosological status of BD-OCD comorbidity. PMID- 29267511 TI - Accuracy of the 15-item Geriatric Depression Scale (GDS-15) in a community dwelling oldest-old sample: the Pieta Study. AB - INTRODUCTION: Late-life depression (LLD) is common, but remains underdiagnosed. Validated screening tools for use with the oldest-old in clinical practice are still lacking, particularly in developing countries. OBJECTIVES: To evaluate the accuracy of a screening tool for LLD in a community-dwelling oldest-old sample. METHODS: We evaluated 457 community-dwelling elderly subjects, aged >=75 years and without dementia, with the Geriatric Depression Scale (GDS-15). Depression diagnosis was established according to DSM-IV criteria following a structured psychiatric interview with the Mini International Neuropsychiatric Interview (MINI). RESULTS: Fifty-two individuals (11.4%) were diagnosed with major depression. The area under the receiver operating characteristic (ROC) curve was 0.908 (p<0.001). Using a cut-off score of 5/6 (not depressed/depressed), 84 (18.4%) subjects were considered depressed by the GDS-15 (kappa coefficient = 53.8%, p<0.001). The 4/5 cut-off point achieved the best combination of sensitivity (86.5%) and specificity (82.7%) (Youden's index = 0.692), with robust negative (0.9802) and reasonable positive predictive values (0.3819). CONCLUSION: GDS-15 showed good accuracy as a screening tool for major depression in this community-based sample of low-educated oldest-old individuals. Our findings support the use of the 4/5 cut-off score, which showed the best diagnostic capacity. PMID- 29267512 TI - Salivary cortisol during memory encoding in pregnancy predicts postpartum depressive symptoms: a longitudinal study. AB - INTRODUCTION: Postpartum depression (PPD) is a common disorder that substantially decreases quality of life for both mother and child. In this longitudinal study, we investigated whether emotional memory, salivary cortisol (sCORT) or alpha amylase during pregnancy predict postpartum depressive symptoms. METHODS: Forty four pregnant women (14 euthymic women with a diagnosis of major depressive disorder [MDD] and 30 healthy women) between the ages of 19 and 37 years (mean age = 29.5+/-4.1 years) were longitudinally assessed in the 2nd trimester of pregnancy (12-22 weeks of gestational age) and again at 14-17 weeks postpartum. Depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: Follow-ups were completed for 41 women (7% attrition). Postpartum EPDS scores were predicted by sCORT collected immediately after an incidental encoding memory task during pregnancy (b=-0.78, t -2.14, p=0.04). Postpartum EPDS scores were not predicted by positive (p=0.27) or negative (p=0.85) emotional memory. CONCLUSIONS: The results of this study indicate that higher levels of sCORT during a memory encoding task in the 2nd trimester of pregnancy are associated with lower postpartum EPDS scores. While the hypothalamus-pituitary-adrenal (HPA) axis has long been associated with the neurobiology of MDD, the role of the HPA axis in perinatal depression deserves more attention. PMID- 29267513 TI - Hepatitis C: clinical and biological features related to different forms of cocaine use. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is related with several liver diseases such as cirrhosis and hepatocellular carcinomas, leading to more than 0.5 million deaths every year and to a great global burden. It is known that injection drug users show a high prevalence of HCV infection, being considered a risk group for this disease. Cocaine users seem to be in greater risk than other drug users, and several hypotheses for this association are being studied. AIM: To review data on HCV infection in cocaine users, taking into consideration the relevance of the different routes of drug administration and other risk behaviors. METHODS: This was a narrative review performed in the main scientific databases. RESULTS AND CONCLUSION: Data suggest that cocaine use could be associated with HCV infection due to the specificities of cocaine consumption pattern, even in those subjects who do not inject drugs, in addition to other risky behaviors, such as tattooing and unprotected sex. Injectable cocaine users seem to be more susceptible to contamination than users who do not inject drugs. However, evidence is pointing to the possibility of infection by sharing drug paraphernalia other than syringes. Moreover, specific immune system impairments caused by cocaine use are also being linked with HCV infection susceptibility, persistence and increased pathological effects. PMID- 29267514 TI - Lowering blood pressure is a priority in Brazil and worldwide. PMID- 29267515 TI - Prevalence of thyroid autoantibodies in patients with systematic autoimmune rheumatic diseases. Cross-sectional study. AB - BACKGROUND: Thyroid autoimmunity is more common in patients with rheumatic diseases than in healthy populations. The degree of association seems subject to influence from patients' geographical location. Here, we aimed to ascertain the prevalence of thyroid autoantibodies in a cohort of patients with systemic rheumatic disease and the degree of association between its presence and inflammatory activity. DESIGN AND SETTING: Cross-sectional observational study in a rheumatology unit. METHODS: 301 patients with systemic lupus erythematosus (SLE), 210 with rheumatoid arthritis (RA), 58 with scleroderma (SSc) and 80 with spondyloarthritis (SpA) were studied regarding thyroid function (TSH and T4), anti-thyroglobulin (TgAb) and anti-thyroperoxidase (TPOab) and compared with 141 healthy controls. Disease activity in patients with rheumatic disease was assessed through appropriate indexes. RESULTS: There were more antithyroid antibodies in SLE patients with hypothyroidism (P = 0.01; odds ratio, OR 2.7; 95% confidence interval, CI: 1.20-6.26) and in those without hypothyroidism (P = 0.06; OR 2.4; 95% CI: 1.28-4.55) than in controls. SSc patients also showed: P = 0.03 both with antithyroid antibodies and hypothyroidism (OR 3.4; 95% CI: 1.06 10.80) and without hypothyroidism (OR 3.1; 95% CI: 1.11-0.13). RA and SpA patients had the same prevalence as controls (P not significant). Presence of autoantibodies with and without hypothyroidism was not associated with the activity or functional indexes evaluated. CONCLUSION: SLE and SSc were associated with higher prevalence of thyroid autoantibodies in patients with and without hypothyroidism, unlike SpA and RA. There was no link between thyroid autoantibody presence and disease activity or functional impairment. PMID- 29267516 TI - A study of pulmonary function in end-stage renal disease patients on hemodialysis: a cross-sectional study. AB - BACKGROUND: The aim here was to study acute effects of hemodialysis among end stage renal disease (ESRD) patients. DESIGN AND SETTING: Prospective study in tertiary-level care center. METHODS: Fifty ESRD patients undergoing hemodialysis were studied. Spirometric pulmonary function tests were performed before and after four-hour hemodialysis sessions. RESULTS: The patients' average age was 45.8 +/- 10.0 years; 64% were males and 64% had normal body mass index. Anemia (94%) and hypoalbuminemia (72%) were common. Diabetes mellitus (68%), hypertension (34%) and coronary artery disease (18%) were major comorbidities. Forty-five patients (90%) had been on hemodialysis for six months to three years. The patients' pre-dialysis mean forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were below normal: 45.8 +/- 24.9% and 43.5 +/- 25.9% of predicted, respectively. After hemodialysis, these increased significantly, to 51.1 +/- 23.4% and 49.3 +/- 25.5% of predicted, respectively (P < 0.01). The increase in mean FEV1/FVC, from 97.8 +/- 20.8% to 99.3 +/- 20.1% of predicted, was not significant (P > 0.05). The pre-dialysis mean forced expiratory flow 25 75% was 50.1 +/- 31% and increased significantly, to 56.3 +/- 31.6% of predicted (P < 0.05). The mean peak expiratory flow was below normal (43.8 +/- 30.7%) and increased significantly, to 49.1 +/- 29.9% of predicted (P < 0.05). Males and females showed similar directions of change after hemodialysis. CONCLUSIONS: Pulmonary function abnormalities are common among ESRD patients. Comparison of pre and post-hemodialysis parameters showed significant improvements, but normal predicted values were still not achieved. PMID- 29267517 TI - What do Cochrane systematic reviews say about probiotics as preventive interventions? AB - BACKGROUND: Probiotics have been used for a range of clinical situations and their use is strongly encouraged by the media worldwide. This study identified and summarized all Cochrane systematic reviews about the preventive effects of probiotics in clinical practice. DESIGN AND SETTING: Review of systematic reviews, conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de Sao Paulo (Unifesp). METHODS: We included all Cochrane reviews on any probiotics when they were used as preventive interventions and compared with no intervention, placebo or any other pharmacological or non-pharmacological intervention. RESULTS: 17 Cochrane systematic reviews fulfilled our inclusion criteria and were summarized in this report. None of the reviews included in the present study provided high-quality evidence for any outcome. The benefits from use of probiotics included decreased incidence of antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea; decreased incidence of upper respiratory tract infections and duration of episodes; decreased need for antibiotics and absences from school due to colds; and decreased incidence of ventilator-associated pneumonia. Probiotics seem to decrease the incidence of gestational diabetes mellitus, birthweight, risk of vaginal infection and incidence of eczema. CONCLUSION: Despite the marketing and the benefits associated with probiotics, there is little scientific evidence supporting the use of probiotics. None of the reviews provided any high quality evidence for prevention of illnesses through use of probiotics. More trials are needed to gain better knowledge of probiotics and to confirm when their use is beneficial and cost-effective. PMID- 29267518 TI - Chronic Periodontitis and RANKL/OPG Ratio in Peri-Implant Mucosae Inflammation. AB - tHistory of chronic periodontitis (CP) is a risk factor for oseointegration failure. The osteoclastogenesis system (RANK, RANKL and OPG) is critical for bone homeostatic control. We investigated the levels of OPG and RANKL in peri-implant tissues from volunteers with and without a history of CP and their association with mucosae inflammation. This is a single-blind case-contro study. Diagnosis of a history of CP and peri-implant examination was performed on 46 volunteers, divided into control (without history of CP, n=26) and CP group (with history of CP, n=20). Gingival biopsies were harvested during implant exposure. Quantitative PCR evaluated OPG/RANKL mRNA expressions. OPG and RANKL proteins were analyzed by western blot and immunohistochemistry assay. The chi-square test analyzed the significance of nominal variables between groups while continuous variables were analyzed by T-test or Mann-Whitney test, after Shapiro-Wilk test evaluation. The 2-DeltaDeltaCT Livak method calculation evaluated the gene expression. Values of p<0.05 were considered statistically significant. Volunteers with CP history had 23 times higher chance of developing mucosae inflammation. High mucosae levels of RANKL (p=0.04) and RANKL/OPG (p=0.001) mRNA expressions were observed in CP group. CP volunteers showed increased RANKL protein levels in opposition to decreased OPG expression. Even without active periodontitis, volunteers with a history of CP had elevated gingival levels of RANKL/OPG and higher correlation with peri-implant mucosae inflammation and implant loss. PMID- 29267520 TI - How to Select a Questionnaire with a Good Methodological Quality? AB - In the last decades, several instruments have been used to evaluate the impact of oral health problems on the oral health-related quality of life (OHRQoL) of individuals. However, some instruments lack thorough methodological validation or present conceptual differences that hinder comparisons with instruments. Thus, it can be difficult to clinicians and researchers to select a questionnaire that accurately reflect what are really meaningful to individuals. This short communication aimed to discuss the importance of use an appropriate checklist to select an instrument with a good methodological quality. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was developed to provide tools for evidence-based instrument selection. The COSMIN checklist comprises ten boxes that evaluate whether a study meets the standard for good methodological quality and two additional boxes to meet studies that use the Item Response Theory method and general requirements for results generalization, resulting in four steps to be followed. In this way, it is required at least some expertise in psychometrics or clinimetrics to a wide ranging use of this checklist. The COSMIN applications include its use to ensure the standardization of cross-cultural adaptations and safer comparisons between measurement studies and evaluation of methodological quality of systematic reviews of measurement properties. Also, it can be used by students when training about measurement properties and by editors and reviewers when revising manuscripts on this topic. The popularization of COSMIN checklist is therefore necessary to improve the selection and evaluation of health measurement instruments. PMID- 29267519 TI - Preemptive and Postoperative Medication Protocols for Root Coverage Combined with Connective Tissue Graft. AB - This trial evaluated the preemptive and postoperative effect of dexamethasone and ibuprofen on prevention of pain/discomfort, edema and interference in daily life in patients undergoing root coverage combined with subepithelial connective tissue graft (CAF + CTG). Twenty patients were randomly assigned as follows: NSAID Group: 400mg Ibuprofen 60 min preemptive + 400mg Ibuprofen postoperative; or SAID Group: 4mg Dexamethasone 60 min preemptive + 4mg Dexamethasone postoperative. The postoperative medication was administered 8 and 16 h post surgery. Each patient received questionnaires based on a numeric scale (101-point numeric scale rate [NRS-101]) and multiple choice questions (four-point verbal rating scale [VRS-4]) about trans-operative pain/discomfort, hourly for 8 h after surgery and once a day for three days. A Visual Analogue Scale (VAS) for edema and interference in daily life during the 1st, 2nd, 3rd and 7th day was also answered. The degree of anxiety was rated statistically by the Chi-square test. The Mann-Whitney and Friedman tests were used for the other questionnaires. The surgery time and number of analgesic pills consumed were compared using Student's t-test. Patients who used dexamethasone presented a trend toward less pain when compared to individuals who ingested ibuprofen, with a significant difference observed 3 h after the procedure (p<0.05). The use of dexamethasone also promoted less edema until the 2nd day and lower interference in daily life on the third day when compared with ibuprofen (p<0.05). We concluded that the use of dexamethasone as a preemptive and postoperative medication was more suitable as a drug therapeutic protocol for CAF + CTG. PMID- 29267521 TI - Retention System and Splinting on Morse Taper Implants in the Posterior Maxilla by 3D Finite Element Analysis. AB - The purpose of this study was to evaluate different retention systems (cement- or screw-retained) and crown designs (non-splinted or splinted) of fixed implant supported restorations, in terms of stress distributions in implants/components and bone tissue, by 3-dimensional (3D) finite element analysis. Four 3D models were simulated with the InVesalius, Rhinoceros 3D, and SolidWorks programs. Models were made of type III bone from the posterior maxillary area. Models included three 4.0-mm-diameter Morse taper (MT) implants with different lengths, which supported metal-ceramic crowns. Models were processed by the Femap and NeiNastran programs, using an axial force of 400 N and oblique force of 200 N. Results were visualized as the von Mises stress and maximum principal stress (sigmamax). Under axial loading, there was no difference in the distribution of stress in implants/components between retention systems and splinted crowns; however, in oblique loading, cemented prostheses showed better stress distribution than screwed prostheses, whereas splinted crowns tended to reduce stress in the implant of the first molar. In the bone tissue cemented prostheses showed better stress distribution in bone tissue than screwed prostheses under axial and oblique loading. The splinted design only had an effect in the screwed prosthesis, with no influence in the cemented prosthesis. Cemented prostheses on MT implants showed more favorable stress distributions in implants/components and bone tissue. Splinting was favorable for stress distribution only for screwed prostheses under oblique loading. PMID- 29267522 TI - Three-Dimensional Finite Element Analysis of Varying Diameter and Connection Type in Implants with High Crown-Implant Ratio. AB - The aim of this study was to evaluate the effect of varying the diameter, connection type and loading on stress distribution in the cortical bone for implants with a high crown-implant ratio. Six 3D models were simulated with the InVesalius, Rhinoceros 3D 4.0 and SolidWorks 2011 software programs. Models were composed of bone from the posterior mandibular region; they included an implant of 8.5 mm length, diameter O 3.75 mm or O 5.00 mm and connection types such as external hexagon (EH), internal hexagon (IH) and Morse taper (MT). Models were processed using the Femap 11.2 and NeiNastran 11.0 programs and by using an axial force of 200 N and oblique force of 100 N. Results were recorded in terms of the maximum principal stress. Oblique loading showed high stress in the cortical bone compared to that shown by axial loading. The results showed that implants with a wide diameter showed more favorable stress distribution in the cortical bone region than regular diameter, regardless of the connection type. Morse taper implants showed better stress distribution compared to other connection types, especially in the oblique loading. Thus, oblique loading showed higher stress concentration in cortical bone tissue when compared with axial loading. Wide diameter implant was favorable for improved stress distribution in the cortical bone region, while Morse taper implants showed lower stress concentration than other connections. PMID- 29267523 TI - MMP2 and MMP9 are Associated with Apical Periodontitis Progression and Might be Modulated by TLR2 and MyD88. AB - The aim of this study was to evaluate the expression of MMP2 and MMP9 during apical periodontitis (AP) progression in TLR2 (TLR2 KO) and in MyD88 (MyD88 KO) knockout mice compared to wild type (WT) mice. AP was induced in mandibular first molars of TLR2 KO (n= 18), MyD88 KO (n= 18), and WT mice (n= 18). After 7, 21, and 42 days, the animals were euthanized and the jaws were dissected and subjected to histotechnical processing. Subsequent sections were stained by immunohistochemistry and evaluated for detection of MMP2 and MMP9. Statistical analysis of the semi-quantitative analysis of immunohistochemistry was performed using chi-square test (alpha = 0.05). In the initial periods of AP progression, an increased expression of MMP9 in the TLR2 KO and MyD88 KO mice was observed. In the final periods of AP progression, a reduction of MMP2 expression and an increase of MMP9 expression in the TLR2 KO mice were observed. MMP2 and MMP9 production was modulated for TLR2 and MyD88 during apical periodontitis progression. PMID- 29267524 TI - Pentaerythritol Tetrasalicylate in the Chemical Composition of Root Canal Sealers. AB - The aim of this study was to synthesize and evaluate physicochemical properties of a new salicylate derivative in experimental calcium-based root canal sealers. Two salicylate derivatives were synthesized for the transesterification reaction of methyl salicylate with two different alcohols (1,3-butylenoglicol disalicylate BD and pentaerythritol tetrasalicylate -PT) in molar ratio 1:3 and 1:6, respectively. The products (BD and PT), were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance spectroscopy (RMN). Calcium-based experimental sealers were prepared with the same catalyst paste (60% of MTA, 39% of n-ethyl-o-toluenesulfonamide, and 1% titanium dioxide) and four different concentrations of BD and PT in the base pastes (40/0 - control, 35/5, 30/10 and 20/20) with 60% of bismuth oxide. The experimental sealers were evaluated for setting time, solubility (24 h, 7, 14 and 30 days), diametral tensile strength and Young's Modulus. Data were analyzed by one- or two-way ANOVA with Tukey's test (p<0.05). The addition of PT reduced the materials setting time. After 24 h the sealer 40/0 and 35/5 had higher solubility, and after 14 and 28 days the sealer 20/20 showed the lowest solubility (p<0.05). After 7 days the sealer 20/20 stabilized its solubility. The sealer 40/0 presented the highest values and the 20/20 presented the lowest values of diametral tensile strength and Young's modulus (p<0.05). The addition of PT to calcium-based root canal sealers provides benefits to the setting time and solubility. PMID- 29267525 TI - Apically extruded debris in filling removal of curved canals using 3 NiTi systems and hand files. AB - The aim of this study was to assess the amount of apically extruded debris during filling removal with WaveOne Gold (WOG), ProTaper Universal Retreatment (PTR), D RaCe Retreatment (DRR) or hand files (HF), to compare the working time during filling removal, and to describe failures of NiTi instruments. Forty mesiobuccal roots of maxillary first molars were prepared with WOG Primary, obturated and divided into 4 groups (n=10), according to the instruments used: WOG, PTR, DRR or HF. Distilled water was used as irrigant and the extruded debris were collected in Eppendorf tubes and dried. The amount of extruded debris was determined by subtracting the final from the initial weight. The time of filling removal for each canal was recorded and the instruments used were analyzed pre and post operatively by SEM. Kruskal-Wallis and Dunn's test analyzed extruded debris data and ANOVA, followed by Tukey's test, compared the working time data (a=0.05). Instrument deformation and fracture were described. WOG produced significantly less debris compared with HF and DRR (p<0.05), and similar to PTR (p>0.05). HF, PTR and DRR showed no significant difference (p>0.05). Working time in HF group was significantly higher than others (p<0.05). SEM analyses showed, from the 18 instruments evaluated, 3 fractures and 10 deformations. All instruments tested caused debris extrusion. WOG was associated with less extrusion than DRR and HF. Filling removal with HF was slower than with the other instruments. All NiTi systems presented fracture and deformation. PMID- 29267526 TI - Effect of Grinding and Multi-Stimuli Aging on the Fatigue Strength of a Y-TZP Ceramic. AB - This study aimed to investigate the effect of grinding and multi-stimuli aging on the fatigue strength, surface topography and the phase transformation of Y-TZP ceramic. Discs were manufactured according to ISO-6872:2008 for biaxial flexure testing (diameter: 15 mm; thickness: 1.2 mm) and randomly assigned considering two factors "grinding" and "aging": C- control (as-sintered); CA- control + aging; G- ground; GA- ground + aging. Grinding was carried out with coarse diamond burs under water-cooling. Aging protocols consisted of: autoclave (134 degrees C, 2 bars pressure, 20 hours), followed by storage for 365 days (samples were kept untouched at room temperature), and by mechanical cycling (106 cycles by 20 Hz under a load of 50% from the biaxial flexure monotonic tests). Flexural fatigue strengths (20,000 cycles; 6 Hz) were determined under sinusoidal cyclic loading using staircase approach. Additionally, surface topography analysis by FE SEM and phase transformation analysis by X-ray Diffractometry were performed. Dixon and Mood methodology was used to analyze the fatigue strength data. Grinding promotes alterations of topographical pattern, while aging apparently did not alter it. Grinding triggered t-m phase transformation without impacting the fatigue strength of the Y-TZP ceramic; and aging promoted an intense t-m transformation that resulted in a toughening mechanism leading to higher fatigue strength for as-sintered condition, and a tendency of increase for ground condition (C < CA; G = GA). It concludes that grinding and aging procedures did not affect deleteriously the fatigue strength of the evaluated Y-TZP ceramic, although, it promotes surface topography alterations, except to aging, and t-m phase transformation. PMID- 29267527 TI - Bond Strength and Cytotoxicity of a Universal Adhesive According to the Hybridization Strategies to Dentin. AB - This study evaluated application protocol (etch-and-rinse/ER and self-etching/SE) and dentin wettability (wet and dry) on microtensile bond strength (MUTBS) and transdentinal cytotoxicity of ScotchbondTM Universal (SU) adhesive system. The MUTBS values and fracture mode were registered 24 h after adhesive system application and resin composite block build-up (n=5). For analysis of transdentinal cytotoxicity, odontoblast-like MDPC-23 cells were seeded on pulpal surface of dentin discs (0.4 mm thick) adapted to artificial pulp chambers (n=8). The adhesive system was applied to occlusal surface, followed by 24-h incubation time. Cell viability (Alamar Blue) and morphology (SEM) were assessed. Adper Single Bond 2 and Clearfil SE Bond were used as positive controls of the ER and SE application protocols, respectively. No treatment was performed on negative control (NC) group. Data were analyzed by ANOVA and Tukey's tests (alpha=5%). Higher MUTBS values were found for ER mode in comparison with SE protocol (p<0.05). Dentin wettability had no effect on bond strength of SU in both the ER and SE techniques (p>0.05). Most fractures involved hybrid layer and/or adhesive layer. Neither variable prevented the intense toxic effects of adhesive systems on MDPC-23 cultured cells, since intense reduction in cell viability (+/-88%) and severe alterations in cell morphology were observed for all groups compared to NC, with no differences among them (p>0.05). Therefore, it was concluded that application of SU following the ER protocol had better adhesive performance. However, this adhesive system featured intense transdentinal cytotoxicity to pulp cells, regardless of application protocol and dentin wettability. PMID- 29267528 TI - One Abutment at One Time Concept for Platform-Switched Morse Implants: Systematic Review and Meta-Analysis. AB - The aim of this systematic review and meta-analysis was to compare the peri implant vertical bone loss of immediate loading of implant crowns using the one abutment at one time (AOT) protocol and implants with abutment removal (AR). This systematic review with meta-analysis was reported according to the PRISMA statement, with guidance from the Cochrane Collaboration Handbook. A total of 103 publications were identified in the PubMed database and reference lists of examined articles. After the screening of titles and abstracts, the eligibility of eight full-text articles was assessed. Five studies published between 2010 and 2015 were included in the meta-analysis. There was less peri-implant vertical bone loss at implants using an AOT protocol than at implants using AR protocol (WMD -0.19, 95% CI -0.26 to -0.13; p<0.0001; random-effects model). In conclusion, the use of the AOT protocol with platform-switched Morse implants results in less bone loss than do AR procedures, but this effect may not be clinically relevant. The preservation of marginal bone level achieved with the AOT protocol may not enhance the aesthetics. These results should be interpreted with caution. PMID- 29267529 TI - Effect of Ceramic Interposition and Post-activation Times on Knoop Hardness of Different Shades of Resin Cement. AB - The aim of this study was to evaluate Knoop hardness of different shades of a resin cement light-cured directly or through ceramic discs, measured 15 min or 24 h after light exposure, and at different depths. Specimens of a commercial resin cement (Variolink Veneer) in seven shades, were fabricated in an elastomeric mold, covered with a mylar strip, a 0.7 mm thick ceramic disc (IPS e.max Press) was placed and the cement was light-activated for 20 s using a blue LED (Radii Cal). The cured resin cement specimens were transversely wet-flattened to their middle portion and microhardness (Knoop) values were recorded at 15 min after light exposure and after deionized water storage at 37 oC for 24 h. Five indentations were made in the cross-sectional area at 100 and 700 MUm depths from the top surface. Ten specimens were made for each test conditions. Data were submitted to ANOVA split-plot design (shade, post-cure time, mode of activation and depth), followed by Tukey post hoc test (alpha=0.05). Significant differences for shade (p<0.0001), mode of activation (p<0.001), post-cure time (p<0.0001) and depth (p<0.0001) were detected. No significant interactions (p>0.05) were found, except for shade x post-cure time (p<0.0045) and mode of activation x post-cure time (p<0.0003). Resin cement shade has a significant effect on Knoop hardness. Indirect activation through a ceramic material reduced significantly Knoop hardness. Hardness Knoop significantly increased after 24 h in all cements shades compared to values obtained after 15 min. Resin cement depth significantly reduced Knoop hardness. PMID- 29267530 TI - Influence of Photoinitiator on Accelerated Artificial Aging and Bond Strength of Experimental Resin Cements. AB - The goal of this study was to evaluate in vitro the effect of the photoinitiator phenylpropanedione (PPD), alone or combined with camphorquinone (CQ), on color stability of photoactivated resin cements and their bond strength to ceramics using a micro-shear test. Four resin cements were used: a commercial brand cement (RelyX Veneer(r)) and 3 experimental cements with different types and concentration of photoinitiators. For color analysis, ceramic discs were cemented on bovine dentin specimens to simulate indirect restorations (n=8) and were exposed to UV for 120 h and tested for color alteration using a reflectance spectrophotometer and the CIEL*a*b* system. Data were analyzed by Anova and Tukey's test at 5% significance level. The color test results did not present statistically significant difference for the ?E for all the studied cements, neither for ?L, ?a and ?b. For the bond strength, all the studied cements showed statistically significant differences to each other, with the highest result for the RelyX Veneer(r) (29.07 MPa) cement, followed by the cement with CQ (21.74 MPa) and CQ+PPD (19.09 MPa) cement; the lowest result was obtained by the cement using only PPD as a photoinitiator (13.99 MPa). So, based on the studied parameters, PPD was not advantageous as photoinitiator of resin cements, because it showed a low value of bond strength to the ceramics and no superior color stability. PMID- 29267532 TI - Influence of Zingiber officinale Extract on Push-Out Bond Strength of Glass-Fiber Post. AB - The aim of this study was to evaluate in vitro the influence of 20% glycolic ginger extract on the bond strength of glass-fiber post cemented with etch-and rinse or self-etching resin cement. Forty-eight bovine roots were standardized (17+/-0.5 mm) and randomly divided into two groups, according to irrigant used during biomechanical preparation: NaOCl: 1% sodium hypochlorite and GEN: 20% glycolic ginger extract. Root canal was prepared and randomly assigned to one of two subgroups (n=12), according to luting protocol: self-etching (RelyX U200) and etch-and-rinse (RelyX ARC). After 48 h, the roots were sectioned perpendicularly (4 in cervical third and 3 in middle third) and submitted to push-out bond strength test (50 kgf load cell, 1.0 mm/min). Failure mode was analyzed in SEM and stereomicroscopy. Data were analyzed by three-way ANOVA and Tukey tests (p<0.05). ANOVA revealed that there were no significant differences between U200 (2.01+/-0.17)B and ARC (1.93+/-0.12)B in GEN group, and at the cervical third for both irrigants, 2.69+/-0.16A and 2.54+/-0.17A, respectively. Middle third showed lower bond strength than cervical third, regardless the irrigant. Overall, the cervical third regardless the irrigant employed and the association between NaOCl and ARC, presented better adhesive performance. PMID- 29267531 TI - Impact of 35% Hydrogen Peroxide on Color and Translucency Changes in Enamel and Dentin. AB - This study evaluated the effects of tooth bleaching with high-concentration of hydrogen peroxide on alterations of translucency parameter (TP) and color of dentin and enamel. The crown of five human molars was sectioned into four slices parallel to buccal surface. The dentin of external slices containing buccal/ lingual enamel was fully removed with diamond bur; while these slices were used to assess alterations on enamel. Alterations on dentin were assessed into the center of internal slices. The color of specimens was measured over white and black backgrounds using a spectrophotometer (CieL*a*b) at baseline, allowing to calculate the TP by difference between the color measured over each background. Specimens were submitted to three 15-min applications of 35% hydrogen peroxide followed by their storage in water for one-week. Afterwards, the color measurements were repeated at both backgrounds. Color (?L, ?a, ?b and ?E) and translucency (?TP) changes were calculated and data individually analyzed by T test (alpha = 0.05). Influence of hard tissue and assessment time on each color parameter was also analyzed by 2-way repeated measure ANOVA (alpha = 0.05). Tooth bleaching resulted in increased lightness for the enamel, whereas no alteration on this parameter occurred for dentin. No difference between the tooth hard tissues was observed regards the other color parameters and ?E. A slightly reduction on TP was observed only for the enamel. In conclusion, 35% hydrogen peroxide caused similar color and translucency changes on dentin and enamel. PMID- 29267533 TI - Cemento-Osseous Dysplasias: Imaging Features Based on Cone Beam Computed Tomography Scans. AB - Imaging exams have important role in diagnosis of cemento-osseous dysplasia (COD). Cone beam computed tomography (CBCT) stands out for allowing three dimensional image evaluation. This study aimed to assess the prevalence of cases diagnosed as COD on CBCT scans, as well identify the main imaging features related to these lesions. An analysis was performed in a database containing 22,400 radiological reports, in which all cases showing some type of COD were initially selected. These CBCT exams were reevaluated to confirm the radiographic diagnosis and determine the prevalence and distribution of the types of COD with regard to gender, age and preferred location, while describing its most common imaging aspects. Data were presented using descriptive analyses. There were 82 cases diagnosed as COD in the CBCT images (prevalence of 0.4%). The distribution of patients was 11 (13.4%) male and 71 (86.6%) female, with a mean age of 49.8 years (age-range 17-85 years). There were 47 (57.3%) cases of periapical COD, 23 (28%) of focal COD and 12 (14.6%) of florid COD. The mandible was more affected than the maxilla. In most cases, the lesions were mixed or hyperdense. All COD had well-defined limits and there were no cases of tooth displacement. In conclusion, periapical COD was the most common type and the most affected bone was the mandible. Imaging evaluation is critical for diagnosis and dentists should bear in mind all possible radiographic presentations of COD in order to prevent misleading diagnoses and consequently, inadequate treatments. PMID- 29267534 TI - Intracranial aneurysm and arachnoid cyst: just a coincidence? A case report. AB - CONTEXT: Presence of an arachnoid cyst and a non-ruptured intracystic brain aneurysm is extremely rare. The aim of this paper was to describe a case of a patient with an arachnoid cyst and a non-ruptured aneurysm inside it. Clinical, surgical and radiological data were analyzed and the literature was reviewed. CASE REPORT: A patient complained of chronic headache. She was diagnosed as having a temporal arachnoid cyst and a non-ruptured middle cerebral artery aneurysm inside it. Surgery was performed to clip the aneurysm and fenestrate the cyst. CONCLUSIONS: This report raises awareness about the importance of intracranial vascular investigation in patients with arachnoid cysts and brain hemorrhage. PMID- 29267536 TI - Hepatitis C: evaluation of outcomes and georeferencing of cases in Santa Cruz do Sul, Brazil, between 2002 and 2015. A cross-sectional study. AB - BACKGROUND: Hepatitis C virus infection is one of the main causes of chronic liver disease, with high death rates. The aim here was to analyze case outcomes, sociodemographic and clinical characteristics and spatial distribution among patients diagnosed with hepatitis C in the city of Santa Cruz do Sul (RS), Brazil. DESIGN AND SETTING: Cross-sectional study on 200 cases of hepatitis C in Santa Cruz do Sul that were notified between 2002 and 2015. METHODS: Secondary data including sociodemographic and clinical variables and type of outcome (death, follow-up, abandonment or clinical cure) were gathered. The spatial distribution analysis on hepatitis C virus cases according to outcome was based on information regarding residential address. RESULTS: 58.5% of the patients were 41 years of age and over, 67% were males and 92.5% had the chronic form of the disease. The most frequent transmission route was illicit drug injection (29%); 15.1% of the patients presented coinfection with the human immunodeficiency virus (HIV). Regarding outcomes, 31% achieved clinical cure, 10% died and 20% abandoned follow-up. The cases studied were mainly located in regions of the city characterized by lower socioeconomic status, with high frequency of places used for drug trafficking. CONCLUSION: The population consisted of adults aged 41 years and over, mostly with chronic hepatitis C. The most common transmission routes were illicit drug injection and blood transfusions. There were high rates of HIV coinfection and abandonment of disease monitoring and predominance of cases in neighborhoods with low socioeconomic status. PMID- 29267537 TI - Bilateral subconjunctival hemorrhage secondary to abciximab use: case report. AB - CONTEXT: There are no reports on cases of subconjunctival hemorrhage due to use of glycoprotein IIb/IIIa inhibitors. In this report, we present the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab. CASE REPORT: A 40-year-old male patient underwent coronary angiography after acute anterior myocardial infarction and a coronary stent was placed. Abciximab was added to the therapy because of stent thrombosis. Bilateral subconjunctival hemorrhage was observed after the administration of the abciximab treatment. We treated our patient by stopping abciximab and administering artificial tears. CONCLUSION: For the first time in the literature, we presented the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab, which was managed conservatively. PMID- 29267535 TI - C-reactive protein/albumin ratio is associated with lung function among children/adolescents with cystic fibrosis: a three-year longitudinal study. AB - BACKGROUND: Chronic lung infections, inflammation and depletion of nutritional status are considered to be prognostic indicators of morbidity in patients with cystic fibrosis. The aim of this study was to investigate the association between inflammatory markers and lung function, nutritional status and morbidity among children/adolescents with cystic fibrosis. DESIGN AND SETTINGS: Prospective three year longitudinal study conducted in an outpatient clinic in southern Brazil. METHODS: Children/adolescents aged 1-15 years with cystic fibrosis were enrolled. Nutritional status was determined from weight-to-length and body mass index-to age z-scores and was classified as acceptable, at risk or nutritional failure. Tumor necrosis factor-alpha, interleukin-1beta, myeloperoxidase, C-reactive protein and C-reactive protein/albumin ratio were analyzed. Lung function was evaluated based on the forced expiratory volume in the first second and morbidity according to the number of hospitalizations for pulmonary exacerbation and infections by Pseudomonas aeruginosa. Lung function, nutritional status and morbidity were the outcomes. Odds ratios and 95% confidence intervals were to evaluate the effect of baseline inflammatory markers on the clinical outcomes after three years of follow-up and p-values < 0.05 were considered significant. RESULTS: We evaluated 38 children/adolescents with cystic fibrosis: 55% female; median age (with interquartile range), 3.75 years (2.71-7.00). Children/adolescents with high C-reactive protein/albumin ratio at baseline had odds of 18 (P = 0.018) of presenting forced expiratory volume in the first second <= 70% after three years. The other inflammatory markers were not associated with the outcomes. CONCLUSION: C-reactive protein/albumin ratio was associated with forced expiratory volume in the first second <= 70% after three years. PMID- 29267538 TI - Cross-sectional study on the association between frailty and violence against community-dwelling elderly people in Brazil. AB - BACKGROUND: The physical, emotional and cognitive limitations that may be present in the aging process, coupled with family unpreparedness, may lead to greater dependence among the elderly. This favors development of frailty syndrome and greater levels of violence against the elderly. The objective here was to analyze the association between violence against the elderly and frailty; and the geographic distribution of violence against the elderly according to the presence of frailty syndrome. DESIGN AND SETTING: Cross-sectional study on 705 community dwelling elderly people in Uberaba (MG), Brazil. METHODS: The Fried frailty phenotype and conflict tactics scale were used. Data were analyzed using descriptive statistics, the chi-square test and a logistic regression model. The intensity of the events and the relationship between clusters of violence and frailty status were assessed by means of kernel estimation. RESULTS: The adjusted analysis indicated that pre-frailty and frailty were associated with physical and verbal aggression (odds ratio, OR = 1.51; 95% confidence interval, CI: 1.04-2.19; OR = 2.12; 95% CI: 1.29-3.47), frailty was associated with physical aggression (OR = 2.48; 95% CI: 1.25-4.94) and pre-frailty and frailty were associated with verbal aggression (OR = 1.48; 95% CI: 1.03-2.15; OR = 2.15; 95% CI: 1.31-3.52), respectively. Regardless of frailty status and its relationship with violence, clusters of occurrences were larger in similar regions in the southeastern part of the municipality; but superimposition of overlays relating to aggression showed that for frail individuals the clusters were smaller than for non-frail and pre-frail individuals. CONCLUSIONS: The condition of frailty was associated with greater chances of violence against the elderly. PMID- 29267540 TI - Survival outcome among patients with Ewing's sarcoma of bones and joints: a population-based cohort study. AB - BACKGROUND: The aim here was to elucidate the current survival condition of patients diagnosed with Ewing's sarcoma of the bones and joints and determine independent risk factors associated with the prognosis. DESIGN AND SETTING: Retrospective cohort study based on the Surveillance, Epidemiology and End Results (SEER) database in the United States. METHODS: We identified 397 patients who were diagnosed with Ewing's sarcoma of the bones and joints between January 2004 and December 2013. The multivariate Cox proportional hazards model was used to determine factors associated with the risk of death by adjusting for various factors. RESULTS: The one, two and five-year disease-specific survival rates were 89.08%, 78.08% and 62.47%, respectively. The factors related to death were age (>= 18 years versus < 18 years; hazard ratio, HR = 1.77; 95% confidence interval, CI: 1.38-2.31); tumor site (extremity versus spine and pelvis; HR = 2.03; 95% CI: 1.31-2.62); tumor size (> 10 cm versus <= 10 cm; HR = 1.78; 95% CI: 1.34-2.56); and type of treatment (surgery alone versus radiotherapy with surgery; HR = 0.51; 95% CI: 0.38-0.89; or radiotherapy alone versus radiotherapy with surgery; HR = 1.61; 95% CI: 1.10-2.39; or no treatment versus radiotherapy with surgery; HR = 1.86; 95% CI: 1.23, 2.58). CONCLUSIONS: Patients with Ewing's sarcoma showed poor survival in situations of age >= 18 years, tumor size > 10 cm, receiving radiotherapy alone and receiving no treatment. Patients undergoing surgery alone had better survival. PMID- 29267539 TI - Prevalence of electrocardiographic abnormalities in primary care patients according to sex and age group. A retrospective observational study. AB - BACKGROUND: Knowledge of the prevalence of electrocardiographic abnormalities in a population is useful for interpreting the findings. The aim here was to assess the prevalence of electrocardiographic abnormalities and self-reported comorbidities and cardiovascular risk factors according to sex and age group among Brazilian primary care patients. DESIGN AND SETTING: Observational retrospective study on consecutive primary care patients in 658 cities in the state of Minas Gerais, Brazil, whose digital electrocardiograms (ECGs) were sent for analysis to the team of the Telehealth Network of Minas Gerais (TNMG). METHODS: All ECGs analyzed by the TNMG team in 2011 were included. Clinical data were self-reported and electrocardiographic abnormalities were stratified according to sex and age group. RESULTS: A total of 264,324 patients underwent ECG examinations. Comorbidities and cardiovascular risk factors were more frequent among women, except for smoking. Atrial fibrillation and flutter, premature beats, intraventricular blocks, complete right bundle branch block and left ventricular hypertrophy were more frequent among men, and nonspecific ventricular repolarization abnormalities and complete left bundle branch block among women. CONCLUSION: Electrocardiographic abnormalities were relatively common findings, even in the younger age groups. The prevalence of electrocardiographic abnormalities increased with age and was higher among men in all age groups, although women had higher frequency of self-reported comorbidities. PMID- 29267541 TI - Quality of life and anxiety in women with breast cancer before and after treatment. AB - OBJECTIVES: to determine the quality of life and anxiety in patients with breast cancer and the changes they experience after treatments. METHOD: prospective study. Breast cancer statistics (n=339, confidence=95%, accuracy= +/- 5.32%). The quality of life questionnaires (QLQ) used were QLQ C-30 and QLQ Br23, and the State-Trait Anxiety Inventory (STAI) was used for anxiety. A multivariate analysis was performed to identify variables associated with baseline quality of life and anxiety as well as pre- and post-treatment differences. Authorization was obtained from the Ethics Committee, and informed consent was provided by all patients. RESULTS: the baseline quality of life dimensions with the lowest score were future prospects (46.0/100) and sexual enjoyment (55.7/100). The dimensions with the highest score were body image (94.2/100) and role (93.3/100). The most disturbing symptoms were insomnia, fatigue and concern about hair loss. After treatment, the dimensions of physical function, role, body image, financial concerns and symptomatology worsened, whereas emotional function and future prospects improved. Severe anxiety presented as a state (48.6%) and as a trait (18.2%). The highest baseline state anxiety was associated with married-widowed status and anxiolytic medication. The greatest trait anxiety was associated with an inactive work situation, anxiolytic medication, breast swelling and advanced stage at diagnosis. After treatment, anxiety significantly decreased. CONCLUSIONS: After treatment, the quality of life score was positively modified, while state and trait anxiety decreased. PMID- 29267542 TI - Cultural adaptation and reliability of the General Comfort Questionnaire for chronic renal patients in Brazil. AB - OBJECTIVE: to make the cultural adaptation and evaluate the reliability of the Brazilian version of the General Comfort Questionnaire for chronic hemodialytic renal patients. METHOD: methodological study with the following steps: translation; consensus among judges; back-translation; validation of equivalence (semantic, idiomatic, experimental and conceptual) by 12 judges; and pre-test with 80 chronic renal patients on hemodialysis. Reliability was checked through measures of internal consistency (Cronbach's alpha). RESULTS: the overall consensus of the instrument had 94.3% of equivalence. Twenty-one items of the instrument were modified. Of these, only two needed semantic and idiomatic changes. The other 19 underwent few modifications, such as reversing words in the sentence and replacing some corresponding synonym terms. The Cronbach's alpha was 0.80, indicating optimal internal consistency. In the application, the total score ranged from 116 to 172 points (M = 151.66; SD = +/- 12.60). CONCLUSION: the validation of the Portuguese version of the instrument represents one additional resource to be made available to nephrologist nurses; it will aid in directing the decision-making so that the nursing interventions be performed according to the level of comfort and domain, either physical, socio-cultural, environmental or psycho-spiritual. The tool was named in Portuguese: General Comfort Questionnaire - Brazilian version. PMID- 29267543 TI - Interaction between professionals and cancer survivors in the context of Brazilian and Canadian care. AB - OBJECTIVE: analyze cancer survivors' reports about their communication with health professional team members and describe the similarities and differences in interactional patterns between Brazilian and Canadian health care contexts. METHOD: This study adopted a qualitative health research approach to secondary analysis, using interpretive description as the methodology, allowing us to elaborate a new research question and look at the primary data from a different perspective. There were in total eighteen participants; all of them were adults and elderly diagnosed with urologic cancer. After being organized and read, the data sets were classified into categories, and an analytic process was performed through inductive thematic analysis. RESULTS: This resulted in three categories of findings which we have framed as: Communication between professional and survivor; The symptoms, the doubts, the questions; and Actions and reaction. CONCLUSION: This comparative study allowed us to bring to the attention of health professionals, especially nurses, findings regarding effective communication, humanization and empathy, supporting both inside and outside support groups, giving pieces of advice, and advocating for the survivor as is necessary. The study also showed the importance of self-development of these professionals as they fight for better quality in the health system for their patients. PMID- 29267544 TI - Conceptual and operational definitions of the components of the nursing diagnosis Acute Pain (00132). AB - OBJECTIVE: to develop the operational and conceptual definitions of the defining characteristics and related factors of the nursing diagnosis Acute Pain (00132) for nonverbal critically ill patients. METHOD: integrative literature review in the databases/libraries: Medical Literature Analysis and Retrieval System Online (MEDLINE via Pubmed), Cochrane Library, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Latin American & Caribbean Health Sciences Literature (LILACS). RESULTS: 799 results were found in the literature, of which 80 studies were selected for full text reading and 16 were used in the elaboration of definitions for the 17 defining characteristics and three related factors of the nursing diagnosis. The gray literature, ie, thesis, dissertations, books, guidelines and dictionary was also explored to ensure the robustness needed to clarify the topics not covered by the studies. CONCLUSION: the definitions aim to facilitate the identification of the nursing diagnosis for nonverbal critically ill patients and to support future teaching and research on the nursing diagnosis of Acute Pain (00132). PMID- 29267545 TI - Risk classification priorities in an emergency unit and outcomes of the service provided. AB - OBJECTIVE: to check the association of the proposed priorities of the institutional protocol of risk classification with the outcomes and evaluate the profile of the care provided in an emergency unit. METHOD: observational epidemiological study based on data from the computerized files of a Reference Emergency Unit. Care provided to adults was evaluated regarding risk classification and outcomes (death, hospitalization and hospital discharge) based on the information recorded in the emergency bulletin. RESULTS: the mean age of the 97,099 registered patients was 43.4 years; 81.5% cases were spontaneous demand; 41.2% had been classified as green, 15.3% yellow, 3.7% blue, 3% red and 36.and 9% had not received a classification; 90.2% of the patients had been discharged, 9.4% hospitalized and 0.4% had died. Among patients who were discharged, 14.7% had been classified as yellow or red, 13.6% green or blue, and 1.8% as blue or green. CONCLUSION: the protocol of risk classification showed good sensitivity to predict serious situations that can progress to death or hospitalization. PMID- 29267546 TI - Validation of the MISSCARE-BRASIL survey - A tool to assess missed nursing care. AB - OBJECTIVE: to analyze the metric validity and reliability properties of the MISSCARE-BRASIL survey. METHOD: methodological research conducted by assessing construct validity and reliability via confirmatory factor analysis, known-groups validation, convergent construct validation, analysis of internal consistency and test-retest reliability. The sample consisted of 330 nursing professionals, of whom 86 participated in the retest phase. RESULTS: of the 330 participants, 39.7% were aides, 33% technicians, 20.9% nurses, and 6.4% nurses with administrative roles. Confirmatory factorial analysis demonstrated that the Brazilian Portuguese version of the instrument is adequately adjusted to the dimensional structure the scale authors originally proposed. The correlation between "satisfaction with position/role" and "satisfaction with teamwork" and the survey's missed care variables was moderate (Spearman's coefficient =0.35; p<0.001). The results of the Student's t-test indicated known-group validity. Professionals from closed units reported lower levels of missed care in comparison with the other units. The reliability showed a strong correlation, with the exception of "institutional management/leadership style" (intraclass correlation coefficient (ICC)=0.15; p=0.04). The internal consistency was adequate (Cronbach's alpha was greater than 0.70). CONCLUSION: the MISSCARE-BRASIL was valid and reliable in the group studied. The application of the MISSCARE-BRASIL can contribute to identifying solutions for missed nursing care. PMID- 29267547 TI - Comparison of education group strategies and home visits in type 2 diabetes mellitus: clinical trial. AB - OBJECTIVE: to compare the adherence and empowerment of patients with type 2 diabetes mellitus for self-care practices and glycemic control in group education strategies and home visits. METHOD: Clinical trial with ten randomized clusters, performed with 238 patients with type 2 diabetes mellitus distributed in group education, home visit, and control group. Socio-demographic data, glycated hemoglobin and those obtained from the self-care and empowerment questionnaires were collected. Statistical analysis was performed separately by educational strategy. RESULTS: the mean age of the patients was 57.8 years old (SD = 9.4 years old), with a predominantly female participation (66.4%). Both strategies presented similar results regarding adherence to self-care practices and patient empowerment. There was also a reduction in glycated hemoglobin levels; however, only in the education group, the difference presented statistical significance (p <0.001). CONCLUSION: the strategies were effective; however, group education presented better glycemic control results in relation to the home visit. International registry: NCT02132338 and national: RBR-92j38t in the clinical trials registry. PMID- 29267548 TI - Actions of the fall prevention protocol: mapping with the classification of nursing interventions. AB - OBJECTIVE: to analyze the correspondence between the actions contained in the fall prevention protocol of the Ministry of Health and the Nursing Interventions Classification (NIC) by a cross-mapping. METHOD: this is a descriptive study carried out in four stages: protocol survey, identification of NIC interventions related to nursing diagnosis, the risk of falls, cross-mapping, and validation of the mapping from the Delphi technique. RESULTS: there were 51 actions identified in the protocol and 42 interventions in the NIC. Two rounds of mapping evaluation were carried out by the experts. There were 47 protocol actions corresponding to 25 NIC interventions. The NIC interventions that presented the highest correspondence with protocol actions were: fall prevention, environmental-safety control, and risk identification. Regarding the classification of similarity and comprehensiveness of the 47 actions of the protocol mapped, 44.7% were considered more detailed and specific than the NIC, 29.8% less specific than the NIC and 25.5% were classified as similar in significance to the NIC. CONCLUSION: most of the actions contained in the protocol are more specific and detailed, however, the NIC contemplates a greater diversity of interventions and may base a review of the protocol to increase actions related to falls prevention.. PMID- 29267549 TI - The year 2017 and the four-yearly evaluation of the Stricto Sensu Graduate Programs: investments and actions to continued progress. PMID- 29267550 TI - Multiorganic resections in gastric cancer. PMID- 29267551 TI - Corona Mortis: anatomical and surgical description on 60 cadaveric hemipelvises. AB - OBJECTIVE: to report the prevalence of arterial corona mortis and to describe its surgical and clinical applicabilities. METHODS: We dissected 60 hemipelvises (50 men and 10 women) fixed in a 10% formalin solution for the purpose of gathering information on corona mortis. We measured the caliber and length of the obturator artery and its anastomotic branch with the aid of a digital caliper and submitted the data to statistical analyzes and comparisons with the GraphPad Prism 6 software. RESULTS: arterial corona mortis was present in 45% of the studied sample. The most common origin of the obturator artery was the internal iliac artery; however, there was one exceptional case in which it originated from the femoral artery. The caliber of the anastomotic branch was on average 2.7mm, whereas the caliber of the obturator artery was 2.6mm. CONCLUSION: the vascular connections between the obturator, internal iliac, external iliac and inferior epigastric arterial systems are relatively common over the upper pubic branch. The diameter and a trajectory of the anastomotic artery may vary. Thus, iatrogenic lesions and pelvic and acetabular fractures can result in severe bleeding that puts the patient's life at risk. PMID- 29267552 TI - Risk factors associated with complications of acute appendicitis. AB - OBJECTIVE: to identify the main risk factors associated with the development of complications in patients with acute appendicitis. METHODS: we conducted a case control study of 402 patients with acute appendicitis hospitalized in a secondary hospital, divided into two groups: the control group, with 373 patients who progressed without postoperative complications (Group 1) and the study group, with 29 patients who presented complications (Group 2). We evaluated demographic data, signs and symptoms of the disease, imaging tests and hospitalization data. RESULTS: factors associated with complications were fever, radiological and sonographic changes, abrupt positive decompression and diarrhea. Migration of pain, nausea, vomiting and abrupt positive decompression were the findings that were significantly more frequent in both groups (p = 0.05). The duration of signs and symptoms in days in group 2 was significantly higher than in group 1, with a median of three days for the group with complications (p = 0.05). CONCLUSION: alterations in imaging, fever, diarrhea, positive abrupt decompression, duration of symptoms and lower age are associated with a higher frequency of complications in acute appendicitis, which reinforces the importance of anamnesis, physical examination and indication of complementary exams in the approach of these patients. PMID- 29267553 TI - Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer: a randomized, double-blind clinical trial. AB - OBJECTIVE: to evaluate the effect of perioperative administration of symbiotics on the incidence of surgical wound infection in patients undergoing surgery for colorectal cancer. METHODS: We conducted a randomized clinical trial with colorectal cancer patients undergoing elective surgery, randomly assigned to receive symbiotics or placebo for five days prior to the surgical procedure and for 14 days after surgery. We studied 91 patients, 49 in the symbiotics group (Lactobacillus acidophilus 108 to 109 CFU, Lactobacillus rhamnosus 108 to 109 CFU, Lactobacillus casei 108 to 109 CFU, Bifi dobacterium 108 to 109 CFU and fructo-oligosaccharide (FOS) 6g) and 42 in the placebo group. RESULTS: surgical site infection occurred in one (2%) patient in the symbiotics group and in nine (21.4%) patients in the control group (p=0.002). There were three cases of intraabdominal abscess and four cases of pneumonia in the control group, whereas we observed no infections in patients receiving symbiotics (p=0.001). CONCLUSION: the perioperative administration of symbiotics significantly reduced postoperative infection rates in patients with colorectal cancer. Additional studies are needed to confirm the role of symbiotics in the surgical treatment of colorectal cancer. PMID- 29267554 TI - Brief hospitalization protocol for pressure ulcer surgical treatment: outpatient care and one-stage reconstruction. AB - OBJECTIVE: to evaluate a brief hospitalization protocol for the treatment of pressure ulcers, proposed by the Complex Wound Group of Clinical Hospital of University of Sao Paulo Medical School, particularly in regard to selection of patients, hospitalization time, cutaneous covering, complications and sore recurrence. METHODS: retrospective cohort of 20 consecutive patients with 25 pressure lesions Grade IV. All patients were ambulatorily prepared and were hospitalized for surgical one time procedure for pressure lesion closing. RESULTS: in total, 27 flaps were performed to close 25 wounds. Three patients showed minor dehiscence (11.1%). There was no recurrence during the post-surgical follow-up period. No patient suffered a new surgery and no flap showed partial or total necrosis. Median time of hospitalization was 3.6 days (2-6 days) and median follow-up was 91 months (2-28 months). All patients maintained their lesions closed, and there was no recurrence during follow-up. CONCLUSION: the brief hospitalization protocol was considered adequate for the resolution of pressure wounds, showing an average time of hospitalization of 3.6 days and rate of minor surgical wound dehiscence of 11.1%. PMID- 29267555 TI - Deaths from abdominal trauma: analysis of 1888 forensic autopsies. AB - OBJECTIVE: to evaluate the epidemiological profile of deaths due to abdominal trauma at the Forensic Medicine Institute of Belo Horizonte, MG - Brazil. METHODS: we conducted a retrospective study of the reports of deaths due to abdominal trauma autopsied from 2006 to 2011. RESULTS: we analyzed 1.888 necropsy reports related to abdominal trauma. Penetrating trauma was more common than blunt one and gunshot wounds were more prevalent than stab wounds. Most of the individuals were male, brown-skinned, single and occupationally active. The median age was 34 years. The abdominal organs most injured in the penetrating trauma were the liver and the intestines, and in blunt trauma, the liver and the spleen. Homicide was the most prevalent circumstance of death, followed by traffic accidents, and almost half of the cases were referred to the Forensic Medicine Institute by a health unit. The blood alcohol test was positive in a third of the necropsies where it was performed. Cocaine and marijuana were the most commonly found substances in toxicology studies. CONCLUSION: in this sample. there was a predominance of penetrating abdominal trauma in young, brown and single men, the liver being the most injured organ. PMID- 29267556 TI - Comparison between isolated serial clinical examination and computed tomography for stab wounds in the anterior abdominal wall. AB - OBJECTIVE: to compare abdominal computer tomography (CT) with isolated serial clinical exam (SCE) in the management of anterior abdominal stab wounds. METHODS: randomized prospective study performed at Hospital de Pronto Socorro de Porto Alegre involving patients with anterior abdominal stab wounds without indication of immediate laparotomy; patients were divided in two groups: CT group and SCE group, In the SCE group, patients were followed up with serial clinical exam every 6 hours, Patients of CT group were submitted to abdominal computer tomography after initial evaluation. RESULTS: 66 patients were studied and 33 were included in each group, Of total, six were submitted to surgery, three of each group, In the SCE group, patients submitted to surgery in media waited 12 hours from arrival to diagnosis without any non-therapeutic surgeries, The remaining 30 patients of this group were discharged from hospital after 24 hours of observation, In the CT group, three patients showed alteration at CT and were submitted to laparotomy, one non-therapeutic, The others were discharged from hospital after 24 hours of observation, Abdominal computer tomography had a positive predictive value (PPV) of 67% and negative predictive value (NPV) of 100%, with 96% of accuracy, Isolated serial clinical exam showed PPV and NPV of 100% and 100% of accuracy. CONCLUSION: selective management of anterior abdominal stabs is safe, when a rigorous selection of patients is observed, Isolated serial clinical exam may be performed without computer tomography, without increase of hospitalization time or morbidity, reducing costs, exposure to radiation, mortality and morbidity and non-therapeutic laparotomies. PMID- 29267557 TI - Intravitreal injection of polysorbate 80: a functional and morphological study. AB - OBJECTIVE: to determine the functional and morphological effects at rabbits retina of PS80 concentration used in the preparation of intravitreal drugs. METHODS: eleven New Zealand rabbits received a intravitreal injection of 0.1ml of PS80. As control, the contralateral eye of each rabbit received the same volume of saline. Electroretinography was performed according to a modified protocol, as well as biomicroscopy and retina mapping before injection and seven and ten days after. Animals were euthanized in the 30th day and the retinas were analyzed by light microscopy. RESULTS: eyes injected with PS80 did not present clinical signs of intraocular inflammation. Electroretinography did not show any alteration of extent and implicit time of a and b waves at scotopic and photopic conditions. There were no morphological alterations of retinas at light microscopy. CONCLUSION: intravitreal injection of PS80 in the used concentration for intravitreal drug preparations do not cause any functional or morphological alterations of rabbit retinas. These results suggest that PS80 is not toxic to rabbit retinas and may be safely used in the preparation of new lipophilic drugs for intravitreal injection. PMID- 29267558 TI - Identification of the sentinel lymph node using hemosiderin in locally advanced breast cancer. AB - OBJECTIVE: to verify the agreement rate in the identification of sentinel lymph node using an autologous marker rich in hemosiderin and 99 Technetium (Tc99) in patients with locally advanced breast cancer. METHODS: clinical trial phase 1, prospective, non-randomized, of 18 patients with breast cancer and clinically negative axilla stages T2=4cm, T3 and T4. Patients were submitted to sub-areolar injection of hemosiderin 48 hours prior to sentinel biopsy surgery, and the identification rate was compared at intraoperative period to the gold standard marker Tc99. Agreement between methods was determined by Kappa index. RESULTS: identification rate of sentinel lymph node was 88.9%, with a medium of two sentinel lymph nodes per patients. The study identified sentinel lymph nodes stained by hemosiderin in 83.3% patients (n=15), and, compared to Tc99 identification, the agreement rate was 94.4%. CONCLUSION: autologous marker rich in hemosiderin was effective to identify sentinel lymph nodes in locally advanced breast cancer patients. PMID- 29267559 TI - Can renal stone size and the use of the nephrolithometric system increase the efficacy of predicting the risk of failure of percutaneous nephrolithotripsy? AB - OBJECTIVE: to verify the association of success rate of percutaneous lithotripsy, Guy score and size of the stone. METHODS: one hundred patients submitted to percutaneous nephrolithotripsy were evaluated. All stones were classified according to Guy Score. Patient free of stone was considered when residual fragments were <=2mm. RESULTS: according to guy Score, 54% were score 1 (Group 1), 18% score 2 (Group 2), 15% score 3 (Group 3), and 13% score 4 (Group 4). Success was observed in 77.77% in Group 1, 27.77% in group 2, 26.6% in Group 3, and 7.69% in Group 4. In patients with Guy score 1, there was statistical significance of prediction of free stone rate when evaluated according to the size of the stone. Among groups 2, 3 and 4 there was no statistical significance, but it was observed a trend in relation to stone size, the bigger the higher the chance of residual fragments. CONCLUSION: nephrolithometry by Guy Score and size of the stone are single predictors of success of percutaneous nephrolithotripsy. Stone size may influence success rate of patients with Guy Score 1. PMID- 29267560 TI - Ruling out intra-abdominal injuries in blunt trauma patients using clinical criteria and abdominal ultrasound. AB - OBJECTIVE: to identify victims of blunt abdominal trauma in which intra-abdominal injuries can be excluded by clinical criteria and by complete abdominal ultrasonography. METHODS: retrospective analysis of victims of blunt trauma in which the following clinical variables were analyzed: hemodynamic stability, normal neurologic exam at admission, normal physical exam of the chest at admission, normal abdomen and pelvis physical exam at admission and absence of distracting lesions (Abbreviated Injury Scale >2 at skull, thorax and/or extremities). The ultrasound results were then studied in the group of patients with all clinical variables evaluated. RESULTS: we studied 5536 victims of blunt trauma. Intra-abdominal lesions with AIS>1 were identified in 144 (2.6%); in patients with hemodynamic stability they were present in 86 (2%); in those with hemodynamic stability and normal neurological exam at admission in 50 (1.8%); in patients with hemodynamic stability and normal neurological and chest physical exam at admission, in 39 (1.5%); in those with hemodynamic stability, normal neurological, chest, abdominal and pelvic physical exam at admission, in 12 (0.5%); in patients with hemodynamic stability, normal neurological, chest, abdominal and pelvic physical exam at admission, and absence of distracting lesions, only two (0.1%) had intra-abdominal lesions. Among those with all clinical variables, 693 had normal total abdominal ultrasound, and, within this group, there were no identified intra-abdominal lesions. CONCLUSION: when all clinical criteria and total abdominal ultrasound are associated, it is possible to identify a group of victims of blunt trauma with low chance of significant intra-abdominal lesions. PMID- 29267561 TI - ACERTO guidelines of perioperative nutritional interventions in elective general surgery. AB - OBJECTIVE: to present recommendations based on the ACERTO Project (Acceleration of Total Post-Operative Recovery) and supported by evidence related to perioperative nutritional care in General Surgery elective procedures. METHODS: review of relevant literature from 2006 to 2016, based on a search conducted in the main databases, with the purpose of answering guiding questions previously formulated by specialists, within each theme of this guideline. We preferably used randomized controlled trials, systematic reviews and meta-analyzes but also selected some cohort studies. We contextualized each recommendation-guiding question to determine the quality of the evidence and the strength of this recommendation (GRADE). This material was sent to authors using an open online questionnaire. After receiving the answers, we formalized the consensus for each recommendation of this guideline. RESULTS: the level of evidence and the degree of recommendation for each item is presented in text form, followed by a summary of the evidence found. CONCLUSION: this guideline reflects the recommendations of the group of specialists of the Brazilian College of Surgeons, the Brazilian Society of Parenteral and Enteral Nutrition and the ACERTO Project for nutritional interventions in the perioperative period of Elective General Surgery. The prescription of these recommendations can accelerate the postoperative recovery of patients submitted to elective general surgery, with decrease in morbidity, length of stay and rehospitalization, and consequently, of costs. PMID- 29267562 TI - Can reducing the number of stitches compromise the outcome of laparoscopic Burch surgery in the treatment of stress urinary incontinence? Systematic review and meta-analysis. AB - The retropubic colposuspension in the treatment of stress urinary incontinence has been rescued with the laparoscopic route. Some authors have reduced the number of stitches, from two to one, due to the difficulty of suturing by this route. To what extent can this modification compromise outcome? To answer this question, we performed a systematic review and meta-analysis on the MEDLINE/PubMed and LILACS/SciELO databases between 1990 and 2015. We included randomized clinical trials, cohort studies and case-control series comparing laparoscopic versus open Burch, and two versus one stitch in laparoscopic Burch, with a minimum follow-up of one year. Fourteen studies compared laparoscopic versus open Burch, in which we found no differences between the two techniques using one stitch (Relative Risk - RR - of 0.94, 95% CI 0.79-1.11) and two stitches (RR of 1.03, 95% CI 0.97-1.10). Only one study compared one stitch versus two stitches in laparoscopic Burch, with cure rates of 68% versus 87%, respectively (p-value= 0.02). We did not identify differences when compared open technique with two stitches versus laparoscopic with one stitch and open technique with two stitches versus laparoscopic with two. The study comparing one versus two laparoscopic stitches demonstrated superior results with the latter. Although there is no robust evidence, when Burch surgery is performed laparoscopically, the use of two stitches seems to be the best option. PMID- 29267563 TI - Tumor lamination in mediastinal giant tumors. AB - Mediastinum tumors may grow slowly and reach giant proportions without symptoms, hindering surgical removal. Tumor big dimensions difficult surgical maneuvers, with risk of uncontrollable bleeding and prejudice to surrounding structures. It may be necessary the use of exceptional measures such as venous-venous circulatory deviation, pre-operatory embolization and total extracorporeal circulation. We describe the technique of tumor lamination that allows for complete or almost complete resection of such tumors that in many occasions are not resectable. The description is based on the results of four patients treated with mediastinum giant tumors. PMID- 29267564 TI - Punch grafts to treat lower limb intractable sores. AB - Lower limb recurrent ulcers, usually caused by prolonged decubitus, trauma, diabetes or burns, may not heal with conventional clinical or surgical treatment. Frequently, laminated skin grafts do not integrate with the recipient layer, and the only alternatives are neighbor microsurgical flaps. These have higher morbidity and create secondary defects, to be corrected with skin grafts, when fasciocutaneous or miocutaneous segments are removed for the treatment of the primary defect. We describe the non-conventional use of punch grafts in the treatment of lower limb ulcers, when conventional skin laminated graft failed, without the use of flaps. Since this is a very successful technique, its use should be considered as a valuable alternative for the treatment of recurrent lower limb ulcers. It is a simple and easy-learned technique that may be used by different surgeons, even in remote places without correct specialized hospital facilities. PMID- 29267565 TI - Erratum: A proposal of Brazilian Society of Surgical Oncology for standardizing cytoreductive surgery plus hypertermic intraperitoneal chemotherapy procedures in Brazil: pseudomixoma peritonei, appendiceal tumors and malignant peritoneal mesothelioma. AB - [This corrects the article doi: 10.1590/0100-69912017005016]. PMID- 29267566 TI - How to evaluate and acknowledge a scientific journal peer reviewer: a proposed index to measure the performance of reviewers. PMID- 29267567 TI - Tarsal platform show after upper eyelid blepharoplasty with or without brassiere sutures. AB - PURPOSE: Increased tarsal platform show (TPS) and decreased brow fat span (BFS) are associated with favorable results in women undergoing cosmetic blepharoplasty. We conducted a study to evaluate the efficacy of upper blepharoplasty with or without a technique (brassiere sutures) to increase TPS and decrease BFS. METHODS: This is a prospective, randomized, comparative, case series study of 100 eyelids (50 consecutive women patients) treated with cosmetic upper blepharoplasty performed by a single surgeon. Patients were randomized to receive traditional upper blepharoplasty with a single running suture skin closure versus orbicularis oculi muscle fixation to the periosteum (brassiere sutures) prior to skin closure. Data on patient age, duration of follow-up, complications, and treatment were analyzed. The mean TPS, mean BFS, and mean TPS/BFS ratio were measured at three anatomic landmarks before and after surgery. RESULTS: Fifty-six eyelids (28 patients) were treated with traditional single suture blepharoplasty, and 44 eyelids (22 patients) had brassiere sutures. In both groups, paired t-tests indicate significant differences between preoperative and postoperative evaluations (p<0.05) for eyelid parameters in each location. However, when TPS, BFS, and TPS/BFS ratio were compared between groups with two way ANOVA, there were no statistically significant differences (p>0.05). CONCLUSIONS: Brassiere sutures during upper blepharoplasty and traditional blepharoplasty were associated with postoperative increase in TPS, decrease in BFS, and increase in TPS/BFS, without statistically significant differences between these surgeries. PMID- 29267568 TI - Quality of the ophthalmological service to outpatients of the public and private healthcare systems. AB - PURPOSE: To compare perceptions of the quality of ophthalmological services offered to outpatients from the public healthcare system to those from the private healthcare system, and to determine which measures are seen as necessary and a priority for improving the quality of care. METHODS: This was a prospective observational study on 200 patients, 101 and 99 of whom were from the public and private healthcare systems, respectively. All patients underwent an ophthalmological examination at an ophthalmology hospital in Belo Horizonte, Minas Gerais, Brazil. Personal interviews were conducted using two structured questionnaires adapted from the modified SERVQUAL scale. RESULTS: Overall, patients from the private healthcare system were significantly more dissatisfied than those from the public healthcare system. In both systems, reliability was considered to be the most important determinant of quality, and it presented the highest level of dissatisfaction. Satisfaction with the public healthcare system was significantly greater than that with the private healthcare system in terms of the tangibles, reliability, responsiveness, and assurance determinants of the SERVQUAL scale. CONCLUSIONS: Institutions must plan, execute, evaluate, and monitor measures that seek to improve the overall patient satisfaction with the quality of services provided, particularly in the private healthcare system, and special attention must be paid to reliability in both healthcare systems. The identification and monitoring of the quality of healthcare services through the periodic use of the SERVQUAL scale may provide healthcare managers with information so that they can identify, plan, and monitor necessary and priority measures. This could be a key strategy for improving the quality of outpatient health services in the public and private systems. PMID- 29267569 TI - Intermittent exotropia surgery: results in different age groups. AB - PURPOSE: To report the outcomes in patients undergoing surgical correction of intermittent exotropia and to compare the age at surgery to motor and sensory success. METHODS: This was a retrospective cohort study. The results of patients with intermittent exotropia treated with surgery over a 4-year period were reviewed. Patients were divided into two groups based on age at first surgery (<4 years vs. >=4 years), and motor and sensory outcomes were compared between the two groups. RESULTS: One hundred thirty-six patients were evaluated, with 67 and 51 patients undergoing surgery before and after the age of 4 years, respectively. The mean age at surgery was 6.8 +/- 2.6 years. The reoperation rate for the patients who underwent surgery before 4 years of age was 48% versus 42% for the ones who underwent surgery after this age (p=0.93). Postoperative stereopsis showed an inverse linear association with age at surgery (p<0.001). For each month younger at the time of surgery, there was 0.69 s of arc worsening in the Titmus test. Conversely, when we separately analyzed the patients in whom the first postoperative alignment was esotropic vs. orthophoric/exotropic, we found no correlation between the immediate postoperative alignment in the first week and sensory outcome at the last visit. CONCLUSIONS: When indicated, patients with intermittent exotropia can be operated upon safely under 4 years of age, and may even present better motor results than older patients. Postoperative stereoacuity in younger children revealed to be worse than in older children; however, this result is unlikely to be due to inadequate age for surgery, but rather, immaturity for performing the stereopsis test. PMID- 29267570 TI - Refractive errors in children and adolescents in Bucaramanga (Colombia). AB - PURPOSE: The aim of this study was to establish the frequency of refractive errors in children and adolescents aged between 8 and 17 years old, living in the metropolitan area of Bucaramanga (Colombia). METHODS: This study was a secondary analysis of two descriptive cross-sectional studies that applied sociodemographic surveys and assessed visual acuity and refraction. Ametropias were classified as myopic errors, hyperopic errors, and mixed astigmatism. Eyes were considered emmetropic if none of these classifications were made. The data were collated using free software and analyzed with STATA/IC 11.2. RESULTS: One thousand two hundred twenty-eight individuals were included in this study. Girls showed a higher rate of ametropia than boys. Hyperopic refractive errors were present in 23.1% of the subjects, and myopic errors in 11.2%. Only 0.2% of the eyes had high myopia (<=-6.00 D). Mixed astigmatism and anisometropia were uncommon, and myopia frequency increased with age. There were statistically significant steeper keratometric readings in myopic compared to hyperopic eyes. CONCLUSIONS: The frequency of refractive errors that we found of 36.7% is moderate compared to the global data. The rates and parameters statistically differed by sex and age groups. Our findings are useful for establishing refractive error rate benchmarks in low-middle-income countries and as a baseline for following their variation by sociodemographic factors. PMID- 29267571 TI - In vivo OCT assessment of anterior segment central axial lengths with accommodation. AB - PURPOSE: To assess changes in anatomic structures in the anterior eye segment in terms of axial lengths with accommodation via optical coherence tomography. METHODS: In this observational study, 25 eyes of 25 healthy adults were examined using the Visante(r) omni optical coherence tomography system. Central corneal thickness, anterior chamber depth, central lens thickness, and anterior segment length were assessed. The evaluated parameters were obtained with accommodation using different stimulus vergences, namely 0.0, -1.0, -2.0, and -3.0 D. Variation of these parameters was compared among different levels of accommodation. RESULTS: Central corneal thickness was not altered at any stimulus vergence during accommodation (p>0.05). Conversely, anterior chamber depth was significantly reduced (p<0.05), whereas central lens thickness was significantly increased (p<0.05). Anterior segment length also increased with accommodation (p<0.05), indicating backward movement of the posterior pole. CONCLUSIONS: There are significant variations in anterior segment lengths that occur with accommodation. Studying these changes will provide useful information regarding the accommodation mechanism that can improve our understanding of this process and facilitate clinical decision-making by practitioners. PMID- 29267573 TI - A comparison of two conjunctival rotation autograft techniques in primary pterygium surgery. AB - PURPOSE: To compare the effects of 90 degrees and 180 degrees conjunctival rotational autograft (CRA) techniques used in primary pterygium surgery. METHODS: Forty-five patients were included in this retrospective study. Visual acuity (VA), corneal topography, and auto-refractometer measurements, as well as detailed biomicroscopic examinations, were performed preoperatively and postoperatively. During surgery, the pterygium tissue was excised then rotated 90 degrees in Group 1 and180 degrees in Group 2, after which it was sutured to the bare sclera. Pterygium recurrence was defined as corneal invasion >=1 mm. RESULTS: Group 1 consisted of 21 patients with a mean age of 45.1 +/- 11.8 years, while Group 2 comprised 24 patients with a mean age of 47.9 +/- 13.8 years. The pterygia in Group 1 were graded as more advanced than those in Group 2. A similar number of recurrences were observed in Group 1 (14.3%) and in Group 2 (16.7%). There was no statistically significant difference in terms of the preoperative and postoperative VA and astigmatism values between the two groups. There was a statistically significant improvement in the postoperative VA and astigmatism values in Group 1 and in the postoperative astigmatism values in Group 2. Although postoperative redness was more common in Group 1, no statistically significant difference was found between the groups. CONCLUSION: BothCRA techniques can be successful in patients for whom it is desirable to avoid a conjunctival autograft and for patients without high cosmetic expectations. PMID- 29267572 TI - Algorithm for dry eye disease diagnosis in individuals infected with human T-cell lymphotropic virus type 1. AB - PURPOSE: To evaluate the accuracy of lacrimal film tests and propose an algorithm for the diagnosis of dry eye disease in individuals infected with human T-cell lymphotropic virus type 1. METHODS: Ninety-six patients infected with human T cell lymphotropic virus type 1 were enrolled in the study. To assess clinical complaints, patients completed the Ocular Surface Disease Index questionnaire. To evaluate lacrimal film quality, patients underwent the tear breakup time test, Schirmer I test, and Rose Bengal staining. Dry eye disease was diagnosed when at least two of the three test results were abnormal. The sensitivity, specificity, positive and negative predictive values, and overall accuracy of the questionnaire as well as of each test alone and combined in parallel and in series were determined. RESULTS: The most sensitive test was the tear breakup time test (98%), whereas the most specific was the Schirmer I test (100%). Rose Bengal staining had the highest overall accuracy (88.64%), whereas the Ocular Surface Disease Index had the lowest overall accuracy (62.65%). The tear breakup time test, Schirmer I test, and Ocular Surface Disease Index combined in parallel showed increased sensitivity and decreased specificity for all tests. In contrast, when combined in series, these tests demonstrated increased specificity and decreased sensitivity. CONCLUSION: This study shows the need to use multiple tests to evaluate tear film quality and include a symptom questionnaire as part of the diagnostic algorithm for dry eye disease. PMID- 29267574 TI - Repeatability and reproducibility of automatic segmentation of retinal layers in healthy subjects using Spectralis optical coherence tomography. AB - PURPOSE: To evaluate the repeatability and reproducibility of automatic segmentation in healthy subjects using a Spectralis optical coherence tomography (OCT) system. METHODS: A total of 60 eyes from 60 patients were included in this prospective study. Spectral-domain optical coherence tomography images were generated using the Spectralis OCT system. An automated algorithm was used to segment the macular retina into nine layers and evaluate the thickness of each layer in the foveal, inner, and outer Early Treatment Diabetic Retinopathy Study (ETDRS) subfield rings. The eyes were imaged three times by an examiner to assess intraobserver repeatability and imaged once by a second examiner to assess interobserver reproducibility. The first scan was used for reference, whereas the second and third scans were collected using the device's follow-up mode. Intraclass correlation coefficients (ICCs) of repeatability and reproducibility were analyzed. RESULTS: The examiners achieved high repeatability and reproducibility for all parameters. Good agreement was found for all parameters in all ETDRS subdivisions with an ICC of >0.96 for all measurements. CONCLUSION: It is possible to obtain cross-sections from the same location using the device's follow-up mode, making it virtually impossible to distinguish between repeated measurements taken with the device by different examiners. PMID- 29267575 TI - An innovation in glaucoma surgery: XEN45 gel stent implantation. AB - PURPOSE: To report follow-up data for patients who underwent XEN45 gel stent implantation, a new method of minimally invasive glaucoma surgery. METHODS: Fifteen eyes in fifteen patients who underwent XEN45 gel stent implantation surgery were investigated in the study. All patients were examined preoperatively and at the following postoperative time points: 1 day; 1 and 2 weeks; and 1, 2, 3, 6, and 12 months. Intraocular pressure (IOP) was measured via Goldmann applanation tonometry. Combined surgical procedures (XEN45 + phacoemulsification + intraocular lens) were performed in patients who that had cataracts in addition to glaucoma. RESULTS: The mean IOP values were significantly lower than the preoperative values at all postoperative visits (p<0.001). In two patients, the IOP exceeded 20 mmHg 12 months after surgery. These IOP increases were controlled by medical therapy, and none of the patients needed another surgical procedure. CONCLUSION: XEN45 gel stent implantation is a minimally invasive glaucoma surgery that ensures the effective reduction of IOP. This new treatment modality also avoids the destructive complications encountered in other invasive surgical procedures. However, further studies with greater numbers of patients and longer follow-up periods are needed to clarify certain points. PMID- 29267576 TI - Comparison of linear measurements of optic cup-to-disk ratio obtained with RTVue OCT and digital retinography. AB - PURPOSE: To compare the linear measurements of the optic disk cup obtained using RTVue optical coherence tomography (OCT) with those obtained using digital retinography. METHODS: This is a cross-sectional study performed with digital retinography and RTVue OCT images from patients with glaucoma or patients suspected of glaucoma. In color retinography, the greatest horizontal and vertical diameters of the optic disk starting from the inner edge of the Elschnig ring were obtained using a pachymeter with a grade of 0.01 mm. In OCT, the delineation of the optic nerve was obtained automatically from the horizontal and vertical cup results. RESULTS: One hundred eyes from 100 subjects with a mean age of 60.1 +/- 15.7 years were included. Of these, 79 were the right eye and 21 the left eye, with 61 men and 39 women. The mean horizontal cup obtained with OCT was 0.91 +/- 0.10, while that obtained with retinography was 0.79 +/- 0.11 (p<0.01). CONCLUSIONS: There was poor agreement between the evaluated methods in the measurements of optic disk cup excavations. Measurements obtained automatically with OCT RTVue were higher but were significantly correlated with measurements obtained manually with digital retinography. Poor agreement of the optic disk parameters between the two imaging devices was noted. PMID- 29267577 TI - Evolution of optic nerve and retina alterations in a child with indirect traumatic neuropathy as assessed by optical coherence tomography. AB - Herein, we describe the case of a 4-year-old child with indirect traumatic optic neuropathy and serial changes of the optic nerve head and retinal nerve fiber layer (RNFL) documented using optical coherence tomography (OCT). Visual acuity improved despite progressive RNFL thinning and optic disc pallor. We concluded that OCT may be useful for monitoring axonal loss but may not predict the final visual outcome. PMID- 29267578 TI - Trocar-assisted intrascleral sutureless fixation of a dislocated three-piece sulcus intraocular lens. AB - Trocar-assisted intraocular lens (IOL) reposition surgery using a scleral fixation method was performed for a patient with a dislocated sulcus IOL. Two 3 mm-long scleral tunnels 2 mm from and parallel to the limbus were formed using a 23-gauge vitrectomy trocar transconjunctivally entering the sclera at an angle of approximately 10 degrees . Haptics were collected using a 23-gauge serrated retinal forceps entering from the trocar cannula and externalized from the scleral tunnels together with the trocar. The same procedure was applied for the other haptic. Both haptics were pushed into the scleral tunnel and a transconjunctival secure 10-0 nylon suture was placed at the scleral tunnel entry site around the haptic. Sutures were removed 1 week later. No complications occurred intraoperatively or postoperatively. At a 10-month follow-up, IOL was stabilized. IOL reposition surgery using the trocar-assisted IOL scleral fixation method is a viable alternative to intrascleral fixation surgery. PMID- 29267579 TI - An unusual presentation of ocular rosacea. AB - Rosacea is a chronic, progressive disease of unknown cause affecting the eye and the facial skin. Ocular rosacea is often underdiagnosed if the ophthalmologist does not inspect the patient's face adequately during the ocular examination. Severe ocular complications and blindness can occur if the treatment is delayed because of non-diagnosis of the rosacea. Here, we present a case of ocular rosacea in a 78-year-old Caucasian woman. Based on the ocular lesions, which preceded cutaneous involvement, she was misdiagnosed as having ocular cicatricial pemphigoid initially. This case emphasizes the difficulty in diagnosis when ocular findings precede those of skin manifestations, and rosacea should be kept in mind in the differential diagnosis of chronic cicatrizing conjunctivitis. PMID- 29267580 TI - Conjunctival tattoo: report on an emerging body modification trend. AB - We report the case of a patient who received conjunctival tattooing for cosmetic purposes with associated complications. A 28-year-old male experienced severe ocular pain after undergoing conjunctival tattooing. Slit-lamp examination revealed blue deposits over the conjunctiva in association with intense conjunctival edema and a 4+ anterior chamber cellular reaction. The patient underwent clinical treatments to control ocular inflammation. Two months after the injury, the patient was still in follow-up to ensure that any further complications were managed and documented. This unusual case of conjunctival tattooing resulted in conjunctival edema and anterior uveitis. Because of the increasing popularity of eyeball tattooing, the potentially severe complications of this procedure may become more common. PMID- 29267581 TI - Teleophthalmology: where are we now? AB - Information and communication technology has rapidly reached diverse aspects of modern life, including medicine and health-related matters. Aiming to improve teaching, research, and health care delivery for geographic or economic reasons, telemedicine is an ascending trend. Teleophthalmology might be one of the most challenging applications of telemedicine given its need for standardized and high definition digital images. However, technological advances are enhancing information transmission continuously and expanding the potential of teleophthalmology. In this review, we investigate the evolution and current status of teleophthalmology, describe its use in different areas, and explore its applicability. Although teleophthalmology is not a replacement for traditional eye care and still faces challenges for adequate implementation, it represents an effective care delivery method, facilitating appropriate and timely distribution of service especially in remote and/or underdeveloped regions. PMID- 29267582 TI - Optimizing literature search in systematic reviews: is MEDLINE sufficient for identifying effect studies on corneal properties and glaucoma? PMID- 29267584 TI - Evaluation of a Cryptococcal antigen Lateral Flow Assay in serum and cerebrospinal fluid for rapid diagnosis of cryptococcosis in Colombia. AB - A Lateral Flow Assay to detect cryptococcal antigen (CrAg(r) LFA) in serum and cerebrospinal fluid for the rapid diagnosis of cryptococcosis was evaluated. A retrospective validation was performed. Sensitivity and specificity of the CrAg(r) LFA was 100%. High concordance (kappa index=1.0) between Cryptococcal Antigen Latex Agglutination System (CALAS(r)) and CrAg(r) LFA was observed. CrAg(r) LFA showed higher analytical sensitivity for detecting low concentrations of cryptococcal antigen. PMID- 29267583 TI - Identification and antifungal susceptibility of Candida species isolated from the urine of patients in a university hospital in Brazil. AB - The aim of this study was to identify Candida spp. isolated from candiduria episodes at a tertiary hospital in the Midwest region of Brazil, and to determine their susceptibility profiles to antifungal compounds. From May 2011 to April 2012, Candida spp. isolated from 106 adult patients with candiduria admitted to the University Hospital of the Federal University of Mato Grosso do Sul were evaluated. Both, species identification and susceptibility testing with fluconazole-FLC, voriconazole-VRC, and amphotericin B-AmB were carried out using the Vitek 2. To discriminate species of the C. parapsilosis complex, a RAPD-PCR technique using the RPO2 primer was performed. From the total of 106 isolates, 42 (39.6%) C. albicans and 64 (60.4%) Candida non-albicans (CNA) - 33 C. tropicalis, 18 C. glabrata, 5 C. krusei, 4 C. parapsilosis sensu stricto, 2 C. kefyr, 1 C. lusitaniae, and 1 C. guilliermondii were identified. All isolates were susceptible to AmB and VRC, whereas all C. glabrata isolates presented either resistance (5.6%) or dose-dependent susceptibility (94.4%) to FLC. The study of Candida spp. and their resistance profiles may help in tailoring more efficient therapeutic strategies for candiduria. PMID- 29267585 TI - Occurrence and antimicrobial susceptibility of thermophilic Campylobacter species isolated from healthy children attending municipal care centers in Southern Ecuador. AB - The prevalence and antimicrobial susceptibility of Campylobacter jejuni and C. coli strains in healthy, well-nourished children of middle socioeconomic level from Southern Ecuador were determined. Among the 127 children studied, 17 (13.4%) harbored Campylobacter sp. corresponding to C. jejuni (7.1%) and C. coli (6.3%) with a higher concentration of C. jejuni among boys (8.6%) and C. coli (8.8%) among girls. C. jejuni showed high resistance to nalidixic acid and ciprofloxacin (77.8%), but susceptibility to all other antimicrobials tested. C. coli strains showed resistance to more antibiotics than C. jejuni strains including resistance to nalidixic acid (75%), ciprofloxacin (75%), erythromycin (12.5%) and ampicillin (28.6), but susceptible to gentamicin and amoxicillin/clavulanic acid. PMID- 29267586 TI - The magnitude of syphilis: from prevalence to vertical transmission. AB - INTRODUCTION: In 2013, the World Health Organization (WHO) reported that 1.9 million pregnant women were infected with syphilis worldwide, of which 66.5% had adverse fetal effects in cases of untreated syphilis. Congenital syphilis contributes significantly to infant mortality, accounting for 305,000 perinatal deaths worldwide annually. AIM: To estimate the prevalence of syphilis in parturients, the incidence of congenital syphilis and the vertical transmission rate. MATERIAL AND METHODS: a cross-sectional study with data collected from 2041 parturients who had undergone treatment between 2012 and 2014 in the maternity section of the Pedro Ernesto Hospital of the State University of Rio de Janeiro, in the metropolitan area of Rio de Janeiro. The inclusion criterion was positive VDRL and treponemal test in a hospital environment. RESULTS: the prevalence of syphilis in pregnant women was 4.1% in 2012, 3.1% in 2013 and 5% in 2014, with official reporting of 15.6%, 25.0% and 48.1%, respectively. The incidence of congenital syphilis (CS) was 22/1,000 in live births (LB) in 2012; 17/1,000 LB in 2013 and 44.8/1,000 LB in 2014. CS underreporting during the period was 6.7%. Vertical transmission occurred in 65.8% of infants from infected mothers. It was concluded that, in 34.6% of the CS cases, maternal VDRL titers were = 1/4. CONCLUSION: Results demonstrate the magnitude of the disease, fragility of the reporting system in the assessment of the actual prevalence, impact on perinatal outcomes, and they are a warning about the real situation of syphilis, which is still underestimated in the State. PMID- 29267587 TI - Characterization of Leptospira isolates from humans and the environment in Uruguay. AB - Laboratory diagnosis of human leptospirosis usually relies on indirect methods exploring specific immune response. Isolation and identification of the involved strains are cumbersome, but can provide biological resources for pathogenic studies and relevant information for guiding prevention and control measures. The aim of the research we are hereby reporting was the characterization of Leptospira isolates obtained from humans and the environment in Uruguay. Blood cultures were performed from early samples of 302 Uruguayan patients, mainly rural workers, and from 36 water samples taken from their living or working environments. Eight human isolates and seven environmental isolates were obtained and analyzed by end point Polymerase Chain Reaction (PCR), Multilocus Variable Number of Tandem Repeat Analysis (MLVA) and other molecular methods. Human isolates corresponded to several serogroups and serovars of Leptospira interrogans and Leptospira kirschneri species, probably reflecting the infection with similar involved Leptospira species and serovars of an extended animal reservoir in rural settings of the country, mostly dedicated to meat and dairy production. Culture-positive patients were older than usually affected workers, and presented signs and symptoms of severe illness. A high organic and circulating bacterial burden may explain an easier positive result from these workers' samples. Environmental isolates were mainly identified as Leptospira biflexa strains, with a single L. meyeri isolate of uncertain significance. PMID- 29267588 TI - Prevalence of Human T-lymphotropic virus type 1 and 2 among blood donors in Manaus, Amazonas State, Brazil. AB - INTRODUCTION: Human T-lymphotropic virus type 1 and 2 (HTLV-1/2) is endemic in Brazil, but few studies have investigated the seroprevalence of HTLV and its subtypes among blood donors in the capital city Manaus, Amazonas State, Brazil. AIM: To estimate the seroprevalence of HTLV-1/2 and to identify circulating subtypes among blood donors in Manaus. MATERIALS AND METHODS: Blood donors (2001 2003) were screened for HTLV-1/2 antibodies by ELISA. Positive results were confirmed and subtyped by Western blot assays. Prevalence rates were calculated and compared with demographic data. RESULTS: Among the 87,402 individuals screened, 116 (0.13%) were seropositive for HTLV-1/2. A second sample (76/116) was collected and retested by HTLV-1/2 ELISA, of which only 41/76 were positive. Western blot confirmed HTLV infection in 24/41 retested blood donors [HTLV-1 (n=16), HTLV-2 (n=5) and HTLV-untypable (n=3)]. DISCUSSION: HTLV-1 and HTLV-2 are prevalent among blood donors in Manaus. However, additional studies are needed to comprehend the epidemiology of HTLV-1/2 in Amazonas not only to understand the pathophysiology of the disease providing adequate medical assistance, but also to reduce or block virus transmission. PMID- 29267589 TI - Quality of life in Brazilian patients with treated or untreated chronic hepatitis C. AB - INTRODUCTION: Multiple factors negatively affect the quality of life of patients infected with hepatitis C virus. This study aims to evaluate the effect of pharmacological treatment on the quality of life of these individuals. METHODS: This is a cross-sectional study conducted in two Southern Brazilian centers that used two instruments (a generic and a specific one) for measuring the quality of life in patients with chronic hepatitis C: the Short Form-36 (SF-36); and the Chronic Liver Disease Questionnaire (CLDQ) for liver disease. We included patients from two centers without any treatment (control group), or receiving medication (peginterferon + ribavirin +/- telaprevir or boceprevir, i.e., respectively, dual, and triple therapies). RESULTS: One hundred and forty-seven patients were included. Patients under treatment (n = 86) had a lower score in 7 of the 8 SF-36 domains, with statistical significance (p<0.05) only for the emotional function domain. Patients who were not treated (n = 58) had higher scores in 4 of the 6 (p<0.05) CLDQ domains. A comparison of patients, receiving dual or triple therapies for both questionnaires, was only significant in the Vitality domain from CLDQ. CONCLUSIONS: Treatment can affect the subjective perception of patients regarding quality of life. Due to the complexity of the disease, each patient must be evaluated in multiple dimensions. Thus, the results may be useful for understanding the patient's perceptions during treatment, and it can also serve as a reference for care instructions. PMID- 29267590 TI - Intestinal parasitic infections among expatriate workers in various occupations in Sharjah, United Arab Emirates. AB - Intestinal parasitic infections are prevalent throughout many countries. This study aimed to determine the prevalence of intestinal parasite carriers among 21,347 expatriate workers, including food handlers and housemaids attending the public health center laboratory in Sharjah, UAE. Stool sample collection was performed throughout the period between January and December 2013. All samples were examined microscopically. Demographic data were also obtained and analyzed. Intestinal parasites were found in 3.3% (708/21,347) of the studied samples (single and multiple infections). Among positive samples, six hundred and eighty three samples (96.5%) were positive for a single parasite: Giardia lamblia (257; 36.3%) and Entamoeba histolytica/Entamoeba dispar (220; 31.1%), respectively, whereas mono-infections with helminths accounted for 206 (29.1%) of the samples. Infection rates with single worms were: Ascaris lumbricoides (84; 11.9%), Hookworm (34; 4.8%), Trichuris trichiura (33; 4.7%), Taenia spp. (27; 3.81%), Strongyloides stercoralis (13; 1.8%), Hymenolepis nana (13; 1.8%), and Enterobius vermicularis (2; 0.28%), respectively. Infections were significantly associated with gender (x2 = 14.18; p = 0.002) with males as the most commonly infected with both groups of intestinal parasites (protozoa and helminths). A strong statistical association was noted correlating the parasite occurrence with certain nationalities (x2= 49.5, p <0.001). Furthermore, the study has also found a strong statistical correlation between parasite occurrence and occupation (x2= 15.60; p = 0.029). Multiple infections were not common (3.5% of the positive samples), although one individual (0.14%) had four helminth species, concurrently. These findings emphasized that food handlers with different pathogenic parasitic organisms may pose a significant health risk to the public. PMID- 29267591 TI - Subdural empyema caused by Peptostreptococcus sp.: a complication of acute pharyngitis. AB - Subdural Empyema (ESD) is the collection of purulent fluid that develops between the exterior "dura mater" layer and the middle "arachnoid mater" layer that covers the brain. ESD can be caused by a primary infection located in the paranasal sinuses. In many aerobic and/or anaerobic bacterial cases, hearing or traumatic processes serve as the causative agent. This report presents pharyngitis in a young girl which later developed into a subdural empyema caused by the bacteria Peptostreptococcus sp. The report emphasizes the correct clinical valuation of pharyngitis as a risk factor for developing subdural empyema in children. PMID- 29267592 TI - Bacteria arise at the border of mycoplasma-infected HeLa cells, containing cytoplasm with either malformed cytosol, mitochondria and endoplasmic reticulum or tightly adjoined smooth vacuoles. AB - A study with transmission electron microscopy of mycoplasma-contaminated HeLa cells using five cell donors referred to as donors A, B, C, D and E, observations are herein presented. Experiments performed with cells from donors B, C and D, revealed the presence of Mycoplasma hyorhinis after PCR and sequencing experiments. Bacteria probably originated from a cytoplasm with compacted tiny granular particles replacing the normal cytosol territories, or from the contact with the cytoplasm through a clear semi-solid material. The compact granularity (CG) of the cytoplasm was crossed by stripes of smooth and rough endoplasmic reticulum cisternae. Among apparently normal mitochondria, it was noted, in variable proportions, mitochondria with crista-delimited lucent central regions that expand to and occupied the interior of a crista-less organelle, which can undergo fission. Other components of the scenarios of mycoplasma-induced cell demolition are villus-like structures with associated 80-200 nm vesicles and a clear, flexible semi-solid, process-sensitive substance that we named jam-like material. This material coated the cytoplasmic surface, its recesses, irregular protrusions and detached cytoplasmic fragments. It also cushioned forming bacteria. Cyst-like structures were often present in the cytoplasm. Cells, mainly apoptotic, exhibiting ample cytoplasmic sectors with characteristic net-like profile due to adjoined vacuoles, as well as ovoid or elongated profiles, consistently appeared in all cells from the last four cell donors. These cells were named "modified host cells" because bacteria arose in the vacuoles. The possibility that, in some samples, there was infection and/or coinfection of the host cell by another organism(s) cannot be ruled out. PMID- 29267593 TI - Molluscicidal effect of Euphorbia umbellata (Pax) Bruyns latex on Biomphalaria glabrata, Schistosoma mansoni host snail. AB - Euphorbia umbellata (Pax) Bruyns is an easily cultivated shrub, with occurrence in the tropical regions of the American and African continents. Chemical studies have revealed that the latex of this plant is rich in terpene compounds, which are highly toxic to snails Biomphalaria glabrata (Basommatophora: Planorbidae). The aim of this study was to evaluate the chemical composition and molluscicidal activity of the latex produced by E. umbellata, as well as the safety of its application in aquatic environments. The concentration of latex that killed 90% of the exposed snails after 24 h exposure (LC90) was 3.69 mg/L. Toxicity bioassays using Danio rerio (zebrafish) revealed that these animals were less susceptible to latex than planorbids. However, it is important to perform other toxicity tests to ensure the feasibility of using latex to control populations of mollusks that contribute to schistosomiasis transmission. A phytochemical screening performed with the E. umbellata latex identified the triterpenoid and coumarin class. Further studies are warranted to isolate, identify, and test the active compounds of E. umbellata latex in B. glabrata. PMID- 29267594 TI - Intestinal symptoms and Blastocystis load in schoolchildren of Paranagua Bay, Parana, Brazil. AB - The symptomatology of Blastocystis cannot be attributed to any particular subtype, although can be related to a high Blastocystis infection load. One stool sample from each of 217 schoolchildren of Vale de Sol Paranagua Bay (Parana, Brazil) was collected. Three milliliters of each fixed stool sample were processed applying the formalin-ether concentration technique. After obtaining the overall prevalence of intestinal parasites, quantification was carried out in Blastocystis positive samples. A total of 75/217 (34.6%) children suffered from intestinal symptoms (abdominal pain and/or persistent diarrhea), of whom 41.3% (31/75) presented moderate/heavy Blastocystis load with a statistically significant risk to present intestinal symptoms (OR 0.039 [0.006-0.15]; p<0.001) Moreover, those symptomatic schoolchildren monoparasitized only by Blastocystis (10/75, 13.3%), and those polyparasitized by Blastocystis with other non pathogenic species (15/75, 20%) with moderate/heavy loads, also entail a statistically significant risk of intestinal symptomatology, both in monoparasitism (12%, OR 0.10 [0.004-0.63]; p=0.021) and in polyparasitism with a non-pathogenic parasite (18.6%, OR 0.059 [0.002-0.35]; p=0.001). For the first time in Brazil, using data from schoolchildren of Paranagua Bay, we demonstrated that moderate/ heavy loads of Blastocystis could be related to intestinal symptoms. PMID- 29267595 TI - Intestinal parasitism among waste pickers in Mato Grosso do Sul, Midwest Brazil. AB - The purpose of this study was to estimate the prevalence of intestinal parasites in both cooperative-affiliated and independent waste pickers operating at the municipal sanitary landfill in Campo Grande, Mato Grosso do Sul, Brazil, and associate these findings with hemoglobin, eosinophils, vitamin A and C levels and interleukin 5 and 10 (IL-5 and IL-10) production. Biological samples were collected, in addition to clinical, epidemiological, and sociodemographic data. Stool analyzes were based on sedimentation by centrifugation and on spontaneous sedimentation. High-performance liquid chromatography was used to determine vitamin A and C levels. ELISA was employed to quantify interleukins. Intestinal parasites were found in 29 of the 66 subjects assessed (43.9%). Endolimax nana (22.7%), Entamoeba coli (21.1%), Giardia lamblia (6.1%), Entamoeba histolytica/E. dispar (4.5%), and Ascaris lumbricoides (4.5%) were the most prevalent species. Pathogenic parasites were detected in 11 individuals (16.7%). Hypovitaminoses A and C were detected in 19.6% (13/66) and 98.4% (65/66) of subjects, respectively. IL-5 and IL-10 production was observed in 21 (31.8%) and 32 (48.4%) subjects, respectively. Infection with pathogenic intestinal parasites was not a cause of vitamin A and C deficiency or IL-5 and IL-10 production among these workers. PMID- 29267596 TI - Waterfowl as the main reservoir of avian influenza A (H5N6) virus in wet markets. PMID- 29267597 TI - Low bone mineral density among HIV-infected patients in Brazil. AB - Decrease in bone mineral density (BMD) has been a complication among people living with HIV/AIDS. To investigate the prevalence of osteopenia/osteoporosis among HIV-infected people living in Sao Paulo city, we studied 108 HIV-infected patients (79 men and 29 women). We extracted data from patients' medical records and BMD was measured by dual-energy X-ray absorptiometry (DXA). Median age of participants was 42 years (interquartile range [IQR] 36-48 years), and the median time since HIV diagnosis was 4.01 years (IQR 2-11 years). Patients had acquired HIV primarily by the sexual route (men who have sex with men 44%, heterosexual 49%). Median age, duration of HIV infection, duration of ART and CD4 nadir were similar for men and women. Plasma viral load was undetectable for 53 patients (49%). Median CD4 T cell count was 399 cells/uL (IQR 247 - 568). Twenty five patients (23%) had LBMD, and there was no statistically significant difference between men and women (<-1). The associated risk factors for LBMD were older age (>= 50 years old) and smoking with a RR of 3.87 and 2.80, respectively. Thus, despite the lack of statistically significant relationship between the use of ART and LBMD or between duration of ART and LBMD, these factors should be addressed in larger studies. PMID- 29267598 TI - Association between seroprevalence of IgG anti-Toxoplasma gondii and risk factors for infection among pregnant women in Climerio de Oliveira Maternity, Salvador, Bahia, Brazil. AB - Maternal Toxoplasma gondii (T. gondii) infection can lead to spontaneous abortion, fetal malformation, and numerous sequelae in the newborn, including visual and hearing impairment. T. gondii serology was determined in pregnant women and their newborns who were referred to Climerio de Oliveira Maternity, Federal University of Bahia, and the possible associations with the risk factors for maternal infection were investigated. This cross-sectional study was conducted from January to December 2014 and included 712 pregnant women, aged 15 to 49 years, and 235 newborns. Seroprevalence was determined by the detection of T. gondii-specific immunoglobulin (Ig) M (IgM) and IgG antibodies using enzyme linked immunoassay. In addition, mothers completed a questionnaire that focused on socioeconomic aspects, and survey data were tabulated using the SPSS statistical software program (version 21.0 for Windows). The seroprevalence rate for specific IgG antibodies was 51% (362) among mothers and 93% (219) among neonates. All the mothers and their newborns were negative for specific-IgM antibodies. Higher age group and lower maternal education were the only risk factors statistically associated with the presence of specific IgG. In summary, high levels of specific IgG antibodies were observed in pregnant women. The knowledge of risk factors for toxoplasmosis can help in the orientation of newly pregnant women. PMID- 29267599 TI - American tegumentary leishmaniasis: epidemiological and molecular characterization of prevalent Leishmania species in the State of Tocantins, Brazil, 2011-2015. AB - Determination of the epidemiological profile of the American tegumentary leishmaniasis (ATL) and identification of Leishmania species that are prevalent in the State of Tocantins were carried out through a retrospective and descriptive study based on data reported in SINAN, in the period from 2011 to 2015. Molecular techniques such as PCR-RFLP and PCR-G6PD to amplify Leishmania DNA were performed on stored on Giemsa-stained slides from lesion scarifications of ATL patients who were amastigote-positive by the direct microscopic examination. There were 1,434 ATL cases in Tocantins reported in this period. The highest incidence was reported in men aged over 60 years, rural residents, the most affected ethnic group was mixed ethnicity (mixed black and white) and the ones with lower education. The predominant clinical form was cutaneous, being diagnosed mainly by laboratory methods. Pentavalent antimonial was effective in resolving cases. The predominant species found in 271 analyzed samples from 32 municipalities located in 8 different health regions of Tocantins was Leishmania (Viannia) braziliensis. Identifying the epidemiological profile and characterizing the Leishmania spp species on regional level is essential to establish control and prevention behaviors, minimizing the number of cases and treatment resistance, recurrence and evolution to mucosal forms. PMID- 29267601 TI - Impact of a provider training program on the treatment of children with autism spectrum disorder at psychosocial care units in Brazil. AB - OBJECTIVE: To develop, implement, and verify the impact of a training program for health care providers working with children with autism spectrum disorder (ASD) in psychosocial care centers for children and adolescents (Centro de Atencao Psicossocial a Infancia e a Adolescencia - CAPSi) in Sao Paulo, Brazil. METHODS: This quasi-experimental study was conducted with 14 professionals from four CAPSi units. The training program consisted of six phases: 1) pre-intervention observation; 2) meeting with staff to assess the main needs of the training program; 3) developing materials for training and evaluation; 4) meetings to discuss program implementation; 5) a final meeting for case discussion and evaluation; and 6) distance supervision. Three measures were used to evaluate the training program: i) the Knowledge, Attitudes, and Practices (KAP) questionnaire; ii) videos containing questions designed to assess program comprehension; and iii) a satisfaction survey. RESULTS: Thirteen videos were produced to as visual aids for use during the training program, and a further 26 videos were developed to evaluate it. The program was well evaluated by the participants. The video responses and KAP questionnaire scores suggest that staff knowledge and attitudes improved after training. CONCLUSION: The positive findings of this study suggest that the tested training program is feasible for use with multidisciplinary teams working in the CAPSi environment. PMID- 29267600 TI - HIF-1alpha and infectious diseases: a new frontier for the development of new therapies. AB - The aim of this review is to show the significant role of HIF-1alpha in inflammatory and infectious diseases. Hypoxia is a physiological characteristic of a wide range of diseases from cancer to infection. Cellular hypoxia is sensed by oxygen-sensitive hydrolase enzymes, which control the protein stability of hypoxia-inducible factor alpha 1 (HIF-1alpha) transcription factors. When stabilized, HIF-1alpha binds with its cofactors to HIF-responsive elements (HREs) in the promoters of target genes to organize a broad ranging transcriptional program in response to the hypoxic environment. HIF-1alpha also plays a regulatory function in response to a diversity of molecular signals of infection and inflammation even under normoxic conditions. HIF-1alpha is stimulated by pro inflammatory cytokines, growth factors and a wide range of infections. Its induction is a general element of the host response to infection. In this review, we also discuss recent advances in knowledge on HIF-1alpha and inflammatory responses, as well as its direct influence in infectious diseases caused by bacteria, virus, protozoan parasites and fungi. PMID- 29267602 TI - Conceptions and practices of an integrative treatment for substance use disorders involving Amazonian medicine: traditional healers' perspectives. AB - OBJECTIVE: The harmful use of psychoactive substances represents one of today's largest public health problems. Yet, in spite of its global relevance, current treatment for substance use disorders (SUDs) is still not entirely successful. The purpose of this study was to investigate alternative treatments and conceptions from traditional Amazonian medicine adapted to SUDs. METHODS: We conducted semi-structured interviews with 13 practicing experts at a well established addiction treatment center in the Peruvian Amazon and performed qualitative content analysis on the collected data. Main categories were deductively defined and corresponding subcategories inductively developed. RESULTS: Our findings revealed characteristic features and consequences, causes and antecedents, and treatment methods of SUDs as the main categories. Overall, concepts of disease etiology bore resemblance with contemporary biopsychosocial models of SUDs. The Amazonian therapeutic means however differed markedly from current Western ones. The main methods involved dietary retreats, healing ceremonies, and purging rituals. The integral application of Amazonian methods, as well as their traditional implementation according to prescribed ritual protocols, were emphasized by the experts as crucial for efficacy and safety of treatment delivery. CONCLUSION: We suggest further scientific attention to these therapies, including clinical studies, for which our results provide conceptual underpinnings. Findings from this research expand the cross-cultural understanding of SUDs and, in the long run, may enhance its treatment options. PMID- 29267603 TI - Introducing care management to Brazil's alcohol and substance use disorder population. AB - Brazil has a sizable alcohol and substance use disorder (ASUD) population, yet there are considerable gaps in treatment access and retention. ASUD, a chronic medical condition, is highly comorbid with medical and behavioral health disorders. This indicates a need for more targeted interventions in order to achieve health care integration (a major goal of Brazil's health care system). Care management - that is, the organization of patient care by an institution - is a viable strategy to engage individuals with ASUD who might benefit from treatment but are not aware of or do not use the available resources, as well as to help maintain patients in treatment. Care management is considered an essential supplement to the treatment of chronic disease. The objective of this article is to discuss the applicability of care management for the treatment of ASUD within the public health care system in Brazil. We describe models of care management that have been adopted internationally and identify the feasibility and advantages for its adoption in Brazil. PMID- 29267604 TI - Profile and costs involved in long-term compulsory hospitalization of psychiatric patients. AB - OBJECTIVE: Involuntary hospitalization for acute psychiatry cases can be acceptable when there is potential harm. However, there are few reasons for a patient committed on these grounds to stay in an institution for a long period. The objective of the present study was to identify the profile and costs of compulsory hospitalizations over 20 days in a public psychiatric hospital in the coastal region of the state of Sao Paulo. METHODS: Retrospective data were collected from the medical records of 1,064 patients admitted between July 2013 and June 2016 from an intensive mental healthcare unit in Santos, state of Sao Paulo, Brazil. RESULTS: Records were found of 527 patients who had been hospitalized for at least 21 days during the study period. Long-term hospitalization related to judicial mandates represented 5.9% of the total sample. These patients stayed in the hospital for an average period of 142 days, while patients hospitalized for any other reason stayed an average period of 35 days (p < 0.001). The cost of a long-term court-ordered hospitalization averaged US$ 21,311 per patient. CONCLUSION: Judicial mandate has been an important reason for the long-term hospitalization of chronic psychiatric patients in Santos, Brazil. PMID- 29267605 TI - The Brazilian Cardiac Surgery, Although it has High International Prestige, Never Performed a Great "Trial". PMID- 29267606 TI - Pre-validation Study of the Brazilian Version of the Disruptions in Surgery Index (DiSI) as a Safety Tool in Cardiothoracic Surgery. AB - INTRODUCTION: Most risk stratification scores used in surgery do not include external and non-technical factors as predictors of morbidity and mortality. OBJECTIVE: The present study aimed to translate and adapt transculturally the Brazilian version of the Disruptions in Surgery Index (DiSI) questionnaire, which was developed to capture the self-perception of each member of the surgical team regarding the disruptions that may contribute to error and obstruction of safe surgical flow. METHODS: A universalist approach was adopted to evaluate the conceptual equivalence of items and semantics, which included the following stages: (1) translation of the questionnaire into Portuguese; (2) back translation into English; (3) panel of experts to draft the preliminary version; and (4) pre-test for evaluation of verbal comprehension by the target population of 43 professionals working in cardiothoracic surgery. RESULTS: The questionnaire was translated into Portuguese and its final version with 29 items obtained 89.6% approval from the panel of experts. The target population evaluated all items as easy to understand. The mean overall clarity and verbal comprehension observed in the pre-test reached 4.48 +/- 0.16 out of the maximum value of 5 on the psychometric Likert scale. CONCLUSION: Based on the methodology used, the experts' analysis and the results of the pre-test, it is concluded that the essential stages of translation and cross-cultural adaptation of DiSI to the Portuguese language were satisfactorily fulfilled in this study. PMID- 29267607 TI - B-Type Natriuretic Peptide as a Predictor of Short-Term Mortality in On-Pump Coronary Artery Bypass Grafting. AB - OBJECTIVE: The present study refers to a determination of the preoperative B-type natriuretic peptide is a predictor of short-term all-cause mortality in patients undergoing on-pump coronary artery bypass graft surgeries. METHODS: Two hundred and twenty-one patients undergoing on-pump coronary artery bypass graft surgeries were evaluated prospectively during a 30-day postoperative follow-up period. Serum B-type natriuretic peptide concentration was measured without a 24-hour period prior to the surgical procedure and the value obtained was correlated with a short-term all-cause mortality. RESULTS: Data analysis showed that all-cause mortality rates were equal to 9.5% in 30 days. Accuracy analysis by the receiver operating characteristic curve found an ideal cut-off value of B-type natriuretic peptide equal to 150 pg/mL in relation to mortality (AUC=0.82, 95% CI=0.71-0.87, P<0.001). Multivariate analysis showed that B-type natriuretic peptide value greater than or equal to 150 pg/mL (P=0.030, HR=3.99, 95% CI=1.14-13.98) was an independent predictor of all-cause mortality in a 30-day follow-up period. CONCLUSION: Preoperative serum B-type natriuretic peptide concentration is an independent predictor of short-term all-cause mortality in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. PMID- 29267608 TI - The Evaluation of Nosocomial Infections in Pediatric Patients with Extracorporeal Membrane Oxygenation Support. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) has become a standard technique over the past few decades in intensive care unit (ICU). OBJECTIVE: A review of pediatric patients who received ECMO support in the pediatric cardiac ICU was conducted to determine the incidence, risk factors and causal organisms related to acquired infections and assess the survival rates of ECMO patients with nosocomial infections. METHODS: Sixty-six patients who received ECMO support in the pediatric cardiac ICU between January 2011 and June 2014 were included in the study. Demographic, echocardiographic, hemodynamic features and surgical procedures were reviewed. RESULTS: Sixty-six patients received a total of 292.5 days of venoarterial ECMO support. Sixty were postoperative patients. Forty-five patients were weaned from ECMO support with an ECMO survival rate of 68.2%. The rate of infection was 116.2/1000 ECMO days. Prolonged ICU stay, duration of ventilation and ECMO were found associated with development of nosocomial infection and only the duration of ECMO was an independent risk factor for nosocomial infections in ECMO patients. CONCLUSION: The correction of the underlying process leading to ECMO support and shortening the length of ECMO duration together with stricter application of ECMO indications would improve the infection incidence and hospital surveillance of the patient group. PMID- 29267609 TI - Hypothyroidism is a Risk Factor for Atrial Fibrillation after Coronary Artery Bypass Graft. AB - INTRODUCTION: Few reports in the world have shown a differential effect of hypothyroidism in relation to morbidity and mortality following cardiac surgery. OBJECTIVE: To determine the association between preoperative hypothyroidism, composite and disaggregated outcomes of mortality and complications in patients undergoing first-time isolated myocardial revascularization surgery. METHODS: Historical cohort of patients undergoing myocardial revascularization between January 2008 and December 2014, with 626 patients included for evaluation of the composite and disaggregated outcomes of in-hospital mortality and complications (atrial fibrillation, surgical site infection and reoperation due to bleeding). A logistic regression model was used to determine the association between hypothyroidism and the onset of those outcomes. RESULTS: Cohort of 1696 eligible patients for the study, with 1.8 mortality. Median age, female gender and prevalence of arterial hypertension were all significantly higher among hypothyroid patients. No differences were found in other preoperative or intraoperative characteristics. Hypothyroidism was associated with the presence of the composite outcome, RR 1.6 (1.04-2.4) and atrial fibrillation 1.9 (1.05 3.8). No association with mortality, infections or reoperation due to bleeding was found. CONCLUSION: Hypothyroidism is a disease that affects females predominantly and does not determine the presence of other comorbidities. Hypothyroidism is a risk factor for the onset of postoperative fibrillation in patients undergoing myocardial revascularization surgery. Postoperative care protocols focused on the prevention of these complications in this type of patients must be instituted. PMID- 29267610 TI - Validation of Four Prediction Scores for Cardiac Surgery-Associated Acute Kidney Injury in Chinese Patients. AB - OBJECTIVE: To assess the clinical value of four models for the prediction of cardiac surgery-associated acute kidney injury (CSA-AKI) and severe AKI which renal replacement therapy was needed (RRT-AKI) in Chinese patients. METHODS: 1587 patients who underwent cardiac surgery in the department of cardiac surgery in the Zhongshan Hospital, Fudan University, between January 2013 and December 2013 were enrolled in this research. Evaluating the predicting value for cardiac surgery-associated AKI (AKICS score) and RRT-AKI (Cleveland score, SRI and Mehta score) by Hosmer-Lemeshow goodness-of-fit test for the calibration and area under receiver operating characteristic curve (AUROC) for the discrimination. RESULTS: Based on 2012 KDIGO (Kidney Disease: Improving Global Outcomes) AKI definition, the incidence of AKI and RRT-AKI was 37.4% (594/1587) and 1.1% (18/1587), respectively. The mortality of AKI and RRT-AKI was 6.1% (36/594) and 66.7% (12/18), respectively, while the total mortality was 2.8% (44/1587). The discrimination (AUROC=0.610) for the prediction of CSA-AKI of AKICS was low, while the calibration (x2=7.55, P=0.109) was fair. For the prediction of RRT-AKI, the discrimination of Cleveland score (AUROC=0.684), Mehta score (AUROC=0.708) and SRI (AUROC=0.622) were not good; while the calibration of them were fair (Cleveland score x2=1.918, P=0.166; Mehta score x2=9.209, P=0.238; SRI x2=2.976, P=0.271). CONCLUSION: In our single-center study, based upon valve surgery dominant and less diabetes mellitus patients, according to KDIGO AKI definition, the predictive value of the four models, combining discrimination and calibration, for respective primary event, were not convincible. PMID- 29267611 TI - Comparison of Arterial Repair through the Suture, Suture with Fibrin or Cyanoacrylate Adhesive in Ex-Vivo Porcine Aortic Segment. AB - INTRODUCTION: Tissue adhesives can be used as adjacent to sutures to drop or avoid bleeding in cardiovascular operations. OBJECTIVE: To verify the efficiency of fibrin and cyanoacrylate adhesive to seal arterial sutures and if the adhesives penetrate through suture line to the inner of arteries. METHODS: 20 abdominal aorta segments of pigs were divided into two groups according to the adhesive which would be used as adjacent to the suture. In every arterial segment an arteriotomy was done, followed by a conventional artery closure. Afterwards a colloidal fluid was injected inside the arterial segment with a simultaneous intravascular pressure monitoring up to a fluid leakage through the suture. This procedure was repeated after application of one of the adhesives on the suture in order to check if the bursting pressure increases. The inner aorta segments also were analyzed in order to check if there was intraluminal adhesive penetration. RESULTS: In Suture 1 group, the mean arterial pressure sustained by the arterial suture reached 86+/-5.35 mmHg and after the fibrin adhesive application reached 104+/-11.96 (P<0.002). In the Suture 2 group, the mean arterial pressure sustained by the suture reached 83+/-2.67 mmHg and after the cyanoacrylate adhesive application reached 152+/-14.58 mmHg (P<0.002). Intraluminal adhesive penetration has not been noticed. CONCLUSION: There was a significant rise in the bursting pressure when tissue adhesives were used as adjacent to arterial suture, and this rise was higher if the cyanoacrylate adhesive was used. In addition, the adhesives do not penetrate through the suture line into the arteries. PMID- 29267612 TI - Analysis of Dyssynchrony and Ventricular Function in Right Univentricular Stimulation at Different Positions. AB - INTRODUCTION: Chronic stimulation of the right ventricle with pacemaker is associated with ventricular dyssynchrony and loss of contractility, even in subjects without previous dysfunction. In these patients, there is a debate of which pacing site is less associated with loss of ventricular function. OBJECTIVE: To compare pacemaker-induced dyssynchrony among different pacing sites in right ventricular stimulation. METHODS: Cross-sectional study of outpatients with right ventricle stimulation higher than 80% and preserved left ventricular ejection fraction. Pacing lead position (apical, medial septum or free wall) was assessed through chest X-rays. Every patient underwent echocardiogram to evaluate for dyssynchrony according to CARE-HF criteria: aortic pre-ejection time, interventricular delay and septum/posterior wall delay on M mode. RESULTS: Forty patients were included. Fifty-two percent had apical electrode position, 42% mid septum and 6% free wall. Mean QRS time 148.97+/-15.52 milliseconds. A weak correlation between the mean QRS width and pre-aortic ejection time (r=0.32; P=0.04) was found. No difference in QRS width among the positions could be noted. Intraventricular delay was lower in apical patients against mid septal (34.4+/ 17.2 vs. 54.3+/-19.1 P<0.05) - no difference with those electrode on the free wall. No difference was noted in the pre-aortic ejection time (P=0.9). CONCLUSION: Apical pacing showed a lower interventricular conduction delay when compared to medial septum site. Our findings suggest that apical pacing dyssynchrony is not ubiquitous, as previously thought, and that it should remain an option for lead placement. PMID- 29267613 TI - Subcutaneous Implantable Cardioverter Defibrillator: Early Experience. AB - INTRODUCTION: The implantable cardioverter defibrillator had been increasing the survival of patients at high risk for sudden cardiac death. The subcutaneous implantable cardioverter defibrillator was developed to mitigate the complications inherent to lead placement into cardiovascular system. OBJECTIVE: To report the initial experience of 18 consecutive cases of subcutaneous implantable cardioverter defibrillator implantation showing the indications, potential pitfalls and perioperative complications. METHODS: Between September 2016 and March 2017, 18 patients with indication for primary and secondary prevention of sudden cardiac death, with no concomitant indication for artificial cardiac pacing, were included. RESULTS: The implantation of the subcutaneous implantable cardioverter defibrillator successfully performed in 18 patients. It was difficult to place the subcutaneous lead at the parasternal line in two patients. One patient returned a week after the procedure complaining about an increase in pain intensity at pulse generator pocket site, which was associated with edema, temperature rising and hyperemia. Two patients took antialgic medication for five days after surgery. A reintervention was necessary in one patient to replace the lead in order to correct inappropriate shocks caused by myopotential oversensing. CONCLUSION: In our initial experience, although the subcutaneous implantable cardioverter defibrillator implantation is a less invasive, simple-accomplishment procedure, it resulted in a bloodier surgery perhaps requiring an operative care different from the conventional. Inappropriate shock by oversensing is a reality in this system, which should be overcame in order not to become a limiting issue for its indication. PMID- 29267614 TI - The Outcomes of Superior Cavopulmonary Connection Operation: a Single Center Experience. AB - INTRODUCTION: The superior cavopulmonary connection operation is one of the stages of the palliative surgical management for patients with functionally single ventricle. After surviving this stage, the patients are potential candidates for the final palliative procedure: the Fontan operation. OBJECTIVES: This study aimed to analyze the outcomes of superior cavopulmonary connection operations in our center and to identify factors affecting the survival and the progression to Fontan stage. METHODS: The outcomes of 161 patients were retrospectively analyzed after undergoing superior cavopulmonary connection operation in our center between 2005 and 2015. RESULTS: The early mortality rate was 2.5%. Five (3.1%) patients underwent takedown of the superior cavopulmonary connection. The rate of exclusion from the Fontan stage was 8.3%. Statistical analysis revealed that elevated mean pulmonary artery pressure preoperatively and the prior palliation with pulmonary artery banding were risk factors for both early mortality and takedown; however, the age, the morphology of the single ventricle and the type of operation were not considered risk factors. CONCLUSION: The superior cavopulmonary connection operation can be performed with low rate mortality and morbidity; however, the elevated mean pulmonary artery pressure preoperatively and the prior pulmonary artery banding are associated with poor outcomes. PMID- 29267615 TI - The Left Atrial Appendage Revised. AB - Nonvalvular atrial fibrillation is associated with a 4- to 5-fold strokes increase and may be responsible for 15% to 20% of all strokes in the elderly. In this scenario, the left atrial appendage thrombus would be the associated with 90% of cases. The use of anticoagulants, percutaneous devices, and the left atrial appendage surgical exclusion is still an open discussion. For left atrial appendage procedures, relevant anatomic spatial relationships have to be emphasized, besides the chance of the normal physiological functioning would be eliminated with the proceedings. There are evidences that the left atrial appendage closure during routine cardiac surgery is significantly associated with an increased risk of early postoperative atrial fibrillation. Therefore, the purpose of this review is to focus basic aspects for continuous medical education. In summary, the rationale of this text is to emphasize anatomical and pharmacological aspects involved in the simple surgical exclusion of left atrial appendage under cardiopulmonary bypass. There are several operative techniques, but to conclude this revision it will present one of them based on the discussed basic sciences. PMID- 29267616 TI - Neuroprotective Anesthesia Regimen and Intensive Management for Pediatric Cardiac Surgery with Cardiopulmonary Bypass: a Review and Initial Experience. AB - This article describes our proposal for routine anesthesia, intraoperative medical management, cerebral and physiological monitoring during pediatric cardiac surgery with cardiopulmonary bypass that intend to provide appropriate anesthesia (analgesia, hypnosis), neuroprotection, adequate cerebral and systemic oxygen supply, and preventing against drugs neurotoxicity. A concise retrospective data is presented. PMID- 29267617 TI - Relationship between Brain Natriuretic Peptide and Recurrence of Atrial Fibrillation after Successful Electrical Cardioversion: an Updated Meta-Analysis. AB - OBJECTIVE: To investigate the relationship between brain natriuretic peptide and recurrence of atrial fibrillation after successful electrical cardioversion. METHODS: Medline and Embase databases were used to identify publications evaluating BNP/N-Terminal (NT)-proBNP levels in association with atrial fibrillation recurrence after successful electrical cardioversion. Nineteen studies that fulfilled the specified criteria of our analysis were found. RESULTS: Baseline BNP/NT-proBNP levels of the atrial fibrillation recurrence group were significantly higher than those of the sinus rhythm maintaining group (SMD -0.70, CI [-0.82, -0.58]). CONCLUSION: Our analysis suggests that low BNP/NT proBNP levels are associated with sinus rhythm maintenance, and baseline BNP/NT proBNP concentrations may be a predictor of atrial fibrillation recurrence after successful electrical cardioversion. PMID- 29267618 TI - Spontaneous Left Anterior Descending Coronary Artery Dissection Requiring Coronary Artery Bypass Surgery. AB - INTRODUCTION: Spontaneous coronary artery dissection is a sudden separation between the layers of a coronary artery wall, non-iatrogenic or trauma related, that has been recognized as an important cause of myocardial infarction. OBJECTIVE: To report an emblematic case, in terms of angiographic images, clinical presentation and predisposing factors, whose clinical management failure led to surgical intervention. METHODS: A previously healthy 48-year-old male farmer was admitted to the emergency room complaining of anterior chest pain described as "tearing", which started after physical exertion. Anterior wall ST segment depression was observed in the electrocardiogram and troponin levels were increased. The patient then underwent coronary catheterization. Angiography showed a tortuous left anterior descending coronary artery with a dissection line involving proximal and middle segments, resulting in mild to moderate luminal stenosis. At first, a conservative approach was chosen. Control cardiac catheterization, 3 months later, showed dissection progression to the distal segment. RESULTS: The patient was referred to surgical treatment. Internal thoracic artery and a great saphenous vein graft were used to revascularize the target vessels. He had an uneventful postoperative course. CONCLUSION: In this report, we describe a typical clinical manifestation of an uncommon cause of acute myocardial infarction. The dissection was started by an extreme physical effort, which is a known triggering factor. Management of these cases is always challenging because there are no evidence-based therapies or guideline-based recomendations. PMID- 29267619 TI - Embolization by Bullet Dislodged from the Heart. AB - Embolization by a dislodged projectile is a rare complication that may occur in cases of gunshot cardiac injuries. We report a case of a firearm projectile cardiac injury that evolved, with dislocation of the projectile during cardiac surgery, into embolization of the right external carotid artery. PMID- 29267620 TI - A Rare Cause of Left Ventricular Assist Device (LVAD) Obstruction: Left Atrial Dissection. AB - Left atrial dissection is a rare factor that may cause left ventricular assist device obstruction. Prompt diagnosis and surgical repair are essential. This case report describes our experience and a successful surgical management in a patient after HeartMate 3 implantation and mitral valve inflow obstruction due to a left atrial dissection. PMID- 29267621 TI - Stent-Graft Relining in a Patient with Acute Aortic Aneurysm and a Completely Migrated Endograft. AB - Stent-graft migration and type I endoleaks are associated with a higher rate of reintervention and increased mortality and morbidity. This article describes a patient presented with an infrarenal aortic stent-graft which had migrated into the aortic sac with loss of all aortic neck attachment. The acutely expanding abdominal aortic aneurysm was treated by placing a second modular endograft within and above the migrated stentgraft. The patient returned 36 months later, with features of an acute myocardial infarction, severe bilateral lower limb ischemia, and renal failure. He was too ill for intervention and demised within 48 hours. PMID- 29267622 TI - Humanitarian Missions: a Call for Action and Impact from Cardiovascular Surgeons. PMID- 29267624 TI - The Freedom of Clinicians and the Art of the Impossible. PMID- 29267623 TI - Cardiac Autonomic Modulation - The Search for an Ultimate Technique. PMID- 29267625 TI - 2017 Guidelines for Arterial Hypertension Management in Primary Health Care in Portuguese Language Countries. PMID- 29267626 TI - Pericardial Parietal Mesothelial Cells: Source of the Angiotensin-Converting Enzyme of the Bovine Pericardial Fluid. AB - BACKGROUND: Angiotensin II (Ang II), the primary effector hormone of the renin angiotensin system (RAS), acts systemically or locally, being produced by the action of angiotensin-converting-enzyme (ACE) on angiotensin I. Although several tissue RASs, such as cardiac RAS, have been described, little is known about the presence of an RAS in the pericardial fluid and its possible sources. Locally produced Ang II has paracrine and autocrine effects, inducing left ventricular hypertrophy, fibrosis, heart failure and cardiac dysfunction. Because of the difficulties inherent in human pericardial fluid collection, appropriate experimental models are useful to obtain data regarding the characteristics of the pericardial fluid and surrounding tissues. OBJECTIVES: To evidence the presence of constituents of the Ang II production paths in bovine pericardial fluid and parietal pericardium. METHODS: Albumin-free crude extracts of bovine pericardial fluid, immunoprecipitated with anti-ACE antibody, were submitted to electrophoresis (SDS-PAGE) and gels stained with coomassie blue. Duplicates of gels were probed with anti-ACE antibody. In the pericardial membranes, ACE was detected by use of immunofluorescence. RESULTS: Immunodetection on nitrocellulose membranes showed a 146-KDa ACE isoform in the bovine pericardial fluid. On the pericardial membrane sections, ACE was immunolocalized in the mesothelial layer. CONCLUSIONS: The ACE isoform in the bovine pericardial fluid and parietal pericardium should account at least partially for the production of Ang II in the pericardial space, and should be considered when assessing the cardiac RAS. PMID- 29267627 TI - Comparison of Secondary Prevention Status between Percutaneous Coronary Intervention and Coronary Artery Bypass Patients. AB - BACKGROUND: Data are scarce regarding disparities in cardiovascular risk factor management between patients treated with percutaneous coronary intervention (PCI) and those treated with coronary artery bypass grafting (CABG). OBJECTIVE: Whether the goal achievement rates of cardiovascular risk factors were different between PCI and CABG patients. METHODS: We retrospectively reviewed the data retrieved from a clinical record database of patients admitted to Beijing Anzhen Hospital between January 1, 2014, and December 31, 2014, who underwent PCI or CABG. RESULTS: Compared with the CABG group, low-density lipoprotein cholesterol (LDL C) < 1.8 mmol/L (28.6% vs. 24.7%; p < 0.01), LDL-C < 2.07 mmol/L (43.5% vs. 39.4%; p < 0.01) and blood pressure (BP) < 140/90 mm Hg (85.6% vs. 77.7%; p < 0.01) goal achievement rates were significantly higher in the PCI group. Compared with patients >= 60 years old: patients < 60 years old had better BP < 140/90 mm Hg goal achievement rates (87.7% vs. 84.4%; p < 0.01) in the PCI group, and better fasting blood-glucose (FBG) < 7 mmol/L (79.4% vs.72.0%; p < 0.01) and HbA1c < 7% (79.4% vs. 70.1%; p < 0.01) goal achievement rates in the CABG group. Compared with females: males had better LDL-C < 2.07 mmol/L (24.7% vs. 28.5%; p < 0.01), FBG < 7 mmol/L (71.8% vs.75.2%; p < 0.01) and HbA1c < 7% (70.4% vs. 74.1%; p < 0.01) goal achievement rates in the PCI group. CONCLUSION: Patients in the PCI group were generally more likely than those in the CABG group to achieve LDL C < 1.8 mmol/L and BP goals. The control of cardiovascular risk factors differed between patients >= 60 years old and < 60 years old. Female patients were less likely to achieve LDL-C, FBG and HbA1c goals. PMID- 29267628 TI - Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases. AB - Phytosterols are bioactive compounds found in foods of plant origin, which can be divided into plant sterols and plant stanols. Clinical studies consistently indicate that the intake of phytosterols (2 g/day) is associated with a significant reduction (8-10%) in levels of low-density lipoprotein cholesterol (LDL-cholesterol). Thus, several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels. As the typical western diet contains only about 300 mg/day of phytosterols, foods enriched with phytosterols are usually used to achieve the recommended intake. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. This review aims to address the evidence available in the literature on the relationship between phytosterols and risk of cardiovascular disease. PMID- 29267629 TI - Limitations in the Diagnosis of Noncompaction Cardiomyopathy by Echocardiography. PMID- 29267630 TI - Case 6/2017 - Extensive Giant Left Coronary Artery Aneurysm Due to Kawasaki Vasculitis in Asymptomatic 48-Year-Old Man. PMID- 29267631 TI - Combined Mitral and Aortic Valvar Bioprosthesis Transcatheter Transapical Implant: First Description in Brazil. PMID- 29267632 TI - Transcatheter Aortic Valve Implantation with Embolic Protection System in a Patient with Left Ventricle Apical Thrombus. PMID- 29267633 TI - Association between SYNTAX Score and Coronary Collateral CirculationReplyInterarterial coronary anastomoses: occurrence in normal hearts and in certain pathologic conditionsThe human coronary collateral circulationCoronary collateral circulation in patients with chronic coronary total occlusion; its relationship with cardiac risk markers and SYNTAX score. PMID- 29267634 TI - Erratum. AB - [This corrects the article doi: 10.5935/abc.20170121]. PMID- 29267635 TI - [The meaning of statistical significance: comments to Martinez-Ferrer and colleagues]. PMID- 29267636 TI - [Vaccination during surveillance stage in children with cancer]. PMID- 29267637 TI - [Equity, validity and reliability of the National Examination for Candidates to Medical Residences (ENARM): opportunities for improvement]. PMID- 29267638 TI - [Legislation and public health in France]. PMID- 29267639 TI - [Congenital syphilis prevalence in three public hospitals in Baja California, Mexico, 2012-2015]. PMID- 29267640 TI - [Prevalence of antimicrobial use among hospitalized patients in non-critical areas in a university hospital in Mexico]. PMID- 29267641 TI - [Latin American scientific production in health economics, 2005-2014]. PMID- 29267642 TI - [Decreasing the use of physical tests as indicators of health in the educational context]. PMID- 29267643 TI - [Environmental pollution and air pollutants' historical data repositories in Peru]. PMID- 29267644 TI - [Predictive validity of the abridged Family Medicine Knowledge and Attitudes Questionnaire]. PMID- 29267645 TI - [Self-medication in people with recent illness who do not seek care and its association with places where they ask for help]. PMID- 29267646 TI - [Financial sustainability and excellence in Chilean public health care]. PMID- 29267647 TI - Energy, added sugar, and saturated fat contributions of taxed beverages and foods in Mexico. AB - OBJECTIVE: To estimate the dietary contribution of taxed beverages and foods. MATERIALS AND METHODS: Using 24-hour diet recall data from the Ensanut 2012 (n=10 096), we estimated the contribution of the items which were taxed in 2014 to the total energy, added sugar, and saturated fat intakes in the entire sample and by sociodemographic characteristics. RESULTS: The contributions for energy, added sugar, and saturated fat were found to be 5.5, 38.1, and 0.4%, respectively, for the taxed beverages, and 14.4, 23.8, and 21.4%, respectively, for the taxed foods. Children and adolescents (vs. adults), medium and high socioeconomic status (vs. low), urban area (vs. rural), and North and Center region (vs. South) had higher energy contribution of taxed beverages and foods. The energy contribution was similar between males and females. CONCLUSIONS: These taxes covered an important proportion of Mexicans' diet and therefore have the potential to improve it meaningfully. PMID- 29267648 TI - Vitamin D status by sociodemographic factors and body mass index in Mexican women at reproductive age. AB - OBJECTIVE: To describe the prevalence of Vitamin D deficiency (VDD) and insufficiency (VDI), and the main dietary sources of vitamin D (VD) in a probabilistic sample of Mexican women at reproductive age participating in Ensanut 2012, stratified by sociodemographic factors and body mass index (BMI) categories. MATERIALS AND METHODS: Serum concentrations of 25-hydroxyvitamin-D(25 OH-D) were determined using an ELISA technique in 4162 women participants of Ensanut 2012 and classified as VDD, VDI or optimal VD status. Sociodemographic, anthropometric and dietary data were also collected. The association between VDD/VDI and sociodemographic and anthropometry factors was assessed adjusting for potential confounders through an estimation of a multinomial logistic regression model. RESULTS: The prevalence of VDD was 36.8%, and that of VDI was 49.8%. The mean dietary intake of VD was 2.56 MUg/d. The relative risk ratio (RRR) of VDD or VDI was calculated by a multinomial logistic regression model in 4162 women. The RRR of VDD or VDI were significantly higher in women with overweight (RRR: 1.85 and 1.44, p<0.05), obesity (RRR: 2.94 and 1.93, p<0.001), urban dwelling (RRR:1.68 and 1.31, p<0.06), belonging to the 3rd tertile of income (RRR: 5.32 and 2.22, p<0.001), or of indigenous ethnicity (RRR: 2.86 and 1.70, p<0.05), respectively. CONCLUSION: The high prevalence of VDD/VDI in Mexican women calls for stronger actions from the health authorities, strengthtening the actual policy of food supplementation and recommending a reasonable amount of sun exposure. PMID- 29267649 TI - [Modifications of the superoxide anion level in breast milk by the intake of flavonoids and carotenoids]. AB - OBJECTIVE: To associate the intake of flavonoids and carotenoids with the breast milk level of superoxide anion, as an oxidative stress marker. MATERIALS AND METHODS: 100 women from Cordoba (Argentina), who breastfed within the first postpartum 6 months, were studied during the 2013-2015 period, by evaluating their sanitary data, food intake and anion level in milk with multiple logistic regression. RESULTS: The intake of flavonoids, provitamin A carotenoids and non provitamin carotenoids was 72 (61) mg/d, 1813 (1 657) ug/d y 5427 (3 664) ug/d, respectively. The anion was associated with the intake of flavanols (OR=1.081; CI95 1.001-1.167) y flavanones (OR=1.025; CI95 1.001-1.048). This effect was not seen with other flavonoids and carotenoids. CONCLUSIONS: Intake of flavanols and flavanones increases milk oxidation risk, which is relevant to develop diet recommendations. PMID- 29267650 TI - Micronuclei and nuclear anomalies in Mexico's indigenous population. AB - OBJECTIVE: To determine the number of micronuclei and nuclear anomalies in Mexico's indigenous population. MATERIALS AND METHODS: One hundred twenty indigenous individuals were evaluated, including thirty from the ethnicities Cora, Huichol, Tarahumara and Tepehuano. The number of micronuclei (MN) and any nuclear abnormality (NA) in oral mucosa cells, including cells with nuclear buds, binucleated cells, cells with karyolysis, karyorrhetic, condensed chromatin and pyknotic cells were determined for each participant. RESULTS: Tepehuano and Tarahumaras showed the greatest damage to DNA. The Tepehuano group presented the highest number of MN and NA, this being a significant difference (p < 0.05) compared with the rest of the studied groups. This group also presented the highest herbicide exposure (46.7%). In relation to the smoking and drinking habits, these were more frequent in the Tarahumara group (33.3 and 50% respectively). CONCLUSION: The ethnic diversity, habits and customs may influence the DNA nuclear integrity in the Amerindian groups. PMID- 29267651 TI - CYP1A1, CYP1B1, GSTM1 and GSTT1 genetic variants and breast cancer risk in Mexican women. AB - OBJECTIVE: To evaluate if variants in the genes CYP1A1 (T3801C and A4889G), CYP1B1 (G119T), GSTM1 (indel) and GSTT1 (indel) are associated with breast cancer (BC) among Mexican women. MATERIALS AND METHODS: 952 incident cases with histologically confirmed BC were matched by age (+/- 5 years) and zone of residence with 998 healthy population controls. Genetic variants in genes CYP1A1, CYP1B1, GSTM1 and GSTT1were genotyped by allelic discrimination and multiplex PCR. In a subsample of women, 105 markers for ancestry were determined. RESULTS: An increased BC risk, independent of other BC risk factors, was observed among carriers of CYP1B1 G119T genotype (T/T vs. G/G: OR=1.9; 95%CI 1.4-2.5). CONCLUSION: Our results support the existence of genetic susceptibility for BC conferred by CYP1B1 G119T variant among Mexican women. PMID- 29267652 TI - Dietary determinants of urinary molybdenum levels in Mexican women: a pilot study. AB - OBJECTIVE: This study determined the main dietary sources of urinary molybdenum (Mo) concentrations in a sample of 124 pregnant women in Mexico. MATERIALS AND METHODS: Dietary data was collected during pregnancy, through a semi-qualitative food frequency questionnaire, with information of 84 foods. Urine Mo levels were determined by atomic absorption spectrometry, for at least two trimesters of pregnancy. The associations with Mo levels were estimated by generalized mixed effect regression models. RESULTS: Between 5.8 to 12.7% of the samples were above the 95th percentile of urinary Mo distribution reported by National Health and Nutrition Examination Survey (NHANES) 2009-2010 for women (151 MUg/L and 148 MUg/g creatinine). After bootstrap resampling was conducted, women with high consumption of hot peppers (beta=1.34MUg/g; 95% CI: 1.00-1.80; p= 0.05) had marginally higher urinary Mo concentration levels, creatinine adjusted, compared to women with low-consumption. CONCLUSION.: Hot chili pepper consumption may contribute to body burden Mo levels in this population. PMID- 29267653 TI - [Knowledge about pregnancy risk and self-efficacy in adolescent males: parental support and school factors]. AB - OBJECTIVE: To identify the association between knowledge about pregnancy risk and self-efficacy in condom use with parental support and school factors in adolescent men. MATERIALS AND METHODS: Cross-sectional study with 448 students in Puebla and Morelos. Two logistic models were adjusted. RESULTS: Knowledge about pregnancy risk is associated with communication about sexuality between parents and sons (OR = 2.45, 95%CI 1.35-4.47), satisfaction with school (OR=2.18, 95%CI 1.15-4.13), if teachers talk about gender equity frequently/very frequently (OR=1.69, 95%CI 1.06-2.67) and with age (OR=1.77, 95%CI 1.26-2.50). Self-efficacy in condom use is statistical related with communication about sexuality between parents and sons (OR=1.80, 95%CI 1.01-3.20), satisfaction with school (OR=2.60, 95%CI 1.42-4.77), belong to middle socioeconomic level (OR=1.82, 95%CI 1.07-3.11) and live in a community with a high degree of marginalization (OR=0.47, 95%CI 0.30-0.73). CONCLUSIONS: To study family and school support, considering the influence of the social environment, allows a greater understanding of skills acquisition for a preventive sexual behavior, in males during early adolescence. PMID- 29267654 TI - [Contraception in Mexican adolescents in upper secondary schools: use and unmet needs]. AB - OBJECTIVE: To describe sexual behavior and contraceptive use in adolescent students. MATERIALS AND METHODS: National representative survey in upper secondary schools in Mexico 2014. Logistic regressions identify the factors associated with contraceptive use and unmet needs for contraception (UNC). RESULTS: For male adolescents, non-contraceptive use in the last sexual relation is associated with non-contraceptive use in the sexual debut (OR=11.5; IC95%:5.6,23.4) and not recognizing effective contraceptive methods (OR=2.4;IC95%:1.04,5.5). For female adolescents, non-contraceptive use is associated with non-contraceptive use in sexual debut (OR=4.5;IC95%:2.3,8.4) and low self-efficacy towards condom use and negotiation (OR=3.1; IC95%:1.1,8.2). UNC were associated with insecure attitudes towards condom use and negotiation (OR=3.5;IC95%:1.3,9.4), non-contraceptive use in sexual debut (OR=9.0;IC95%:2.5,32.4) and use of alcohol or drugs during sexual relations (OR=3.0;IC95%:1.1,8.1). CONCLUSIONS: Strategies to ensure contraceptive use from sexual debut onwards are required, promoting self-efficacy and safe sex practices among adolescents. PMID- 29267655 TI - [Legal health services of abortion in Uruguay. Strategies of the primary health care public services]. AB - OBJECTIVE: To analyze the strategies developed by the health centers to implement the law of legal abortion (LA) in public services of the primary care in Montevideo, Uruguay. MATERIALS AND METHODS: A qualitative research was conducted combining techniques of document analysis, self-administered questionnaires to key informants, and in-depth interviews with directors of health centers. A simple summative index of accessibility to abortion services was built. RESULTS: The law approved in Uruguay in 2012 demanded the development of a strategy to promote women's accessibility to LA in the public primary care system. The services failed to fully implement the strategy, due to institutional barriers. CONCLUSION: Despite the wide availability of LA services in primary care and that they are an integral part of sexual and reproductive health benefits, there is an important barrier to their use in the number of gynecologists that appeal to conscientious objection. PMID- 29267656 TI - [Analysis of health expenditure efficiency in countries of Latin America and the Caribbean]. AB - OBJECTIVE: To compare the efficiency levels of health expenditure in 25 countries in Latin America and the Caribbean. MATERIALS AND METHODS: The methodology of stochastic frontier analysis was applied to estimate the efficiency scores of the countries, using data from years 1995, 2000, 2005, 2010, 2012. Two output variables were considered, life expectancy at birth and infant mortality. In the latter case, determinants of inefficiency were analyzed. RESULTS: The average efficiency level of the region using life expectancy is higher than when using infant mortality. CONCLUSIONS: Results suggest that countries can still improve the use of resources. Guiding the expenditure policy towards immunization programs and ensuring births take place in the presence of trained staff are efficient ways to save neonates. PMID- 29267657 TI - [Regulatory elements on marijuana, for the effective population health protection]. AB - When discussing the public health approach to the use of marijuana, the complexity of rigorous regulatory interventions for population protection is omitted. Using the experience of governments where these practices already exist, regulation is introduced as an essential public health function, spelling out seven purposes for controlling marijuana. The technical elements of institutional capacity -including the technical and financial capacity- and of governance that must be covered by any rigorous regulation of its use are detailed below. The difficulty of regulating psychoactive substances is addressed when considering the capacity to control other legal substances manifested with their increased consumption. It is concluded that for an effective regulation of marijuana, the need for strengthening the institutional and governance aspects of the regulatory authority should not be minimized. PMID- 29267658 TI - How has dental pulp stem cells isolation been conducted? A scoping review. AB - The objective of this study was to realize a scoping review the literature in order to identify the profile of DPSCs isolation and analyze the possible risk factors that could change the native behavior of these cells. An initial search was conducted using the following MeSH terms: "(dental pulp stem cell [MeSH])"; "(dental pulp [MeSH])" AND "(stem cell [MeSH])"; "("dental pulp stem cell" [MeSH]")". The electronic search was done without date restriction up to and including April 2014, in PubMed, Scopus, Scielo and ISI Web of Knowledge databases. Studies were submitted to inclusion and exclusion criteria and 222 articles were included. Data showed that over the past 15 years many studies have been conducted using DPSCs. However this is the first systematic review regarding the isolation of stem cell, and more specifically of dental pulp stem cells. The isolation of dental pulp stem cells showed great variability, hampering the development of standard protocols to achieve in vitro dental pulp stem cells with similar characteristics. This scoping review combined, for the first time, the methodologies used for dental pulp stem isolation, highlighting the most frequently used. PMID- 29267659 TI - P-glycoprotein expression in oral lichen planus. AB - Oral lichen planus (OLP) is a stress induced inflammatory condition with malignant potency. The mdr1 (multidrug resistance) is a stress gene overexpressed in cancerous conditions and its translated form, the p-glycoprotein efflux transporter is usually overexpressed with chemotherapy, leading to chemoresistance. OLP, a lesion with carcinogenic potency, is broadly classified into the asymptomatic reticular form and the aggressive erosive form. The objective of the study was to verify the expression level of p-glycoprotein in antifungal-treated and untreated reticular OLP, in untreated erosive OLP and erosive OLP patients treated with corticosteroid. Semi-quantitative reverse transcriptase polymerase chain reaction (SQ-RTPCR) and ELISA were performed on biopsy tissue samples to evaluate the mdr1 mRNA and protein expression of p glycoprotein, respectively. The present study shows for the first time that mdr1 mRNA as well as its translated form p-glycoprotein are overexpressed in OLP subjects compared to healthy individuals. This overexpression is significantly higher in erosive than in reticular OLP patients, further confirming that the erosive form has higher risk for multidrug resistance. A higher expression is also observed in corticosteroid-treated erosive cases than similar untreated ones. The gradation of expression is in conformity with severity of the disease. PMID- 29267660 TI - Reclassification and treatment of odontogenic keratocysts: A cohort study. AB - The odontogenic keratocyst (OKC) is a recurrent cyst that has been recently reclassified from an odontogenic tumor to an odontogenic cyst. The aim of the present study was to investigate its treatment and address issues related to its association with nevoid basal cell carcinoma syndrome (NBCCS). Lesions from the cohort of patients included in the present study consisted of 40 OKCs, of which 27 lesions were treated by enucleation (GE) and 13 underwent decompression (GD). Complementary treatment occurred in 38 (95%) lesions, of which 10 underwent isolated peripheral ostectomy (GO) and 28 underwent peripheral ostectomy combined with Carnoy's solution (GC). Thirteen lesions were associated with NBCCS (GS), while the others (n=27) were non-syndromic lesions (GnS). The recurrence-free periods (RFP) in the sample groups were compared using the Kaplan-Meier function and log-rank test at a significance level of 5% (p < 0.05) and were used to calculate the cumulative risk of recurrence (CRR) in each postoperative year. During the follow-up period, which had a mean of 43.5 months (range: 12-102 months), six (15%) recurrences were diagnosed. There was no significant difference among the RFP for the compared groups (p > 0.05) or increased CRR for the decompression (15.4%) over five years. Application of Carnoy's solution did not increase the efficacy of the peripheral ostectomy, but was related to a CRR of 0% for the syndromic lesions over five years. Therefore, 1) decompression did not increase the recurrence risk; 2) peripheral ostectomy demonstrated a similar efficacy as the combination with Carnoy's solution; 3) the association of NBCCS did not seem to significantly influence OKC recurrence; and 4) syndromic lesions seem to behave in the same manner as non-syndromic lesions when submitted to complementary treatments. PMID- 29267661 TI - Is there correlation between polymerization shrinkage, gap formation, and void in bulk fill composites? A MUCT study. AB - This in vitro study aimed to evaluate the volume of polymerization shrinkage (VS), gap (VG), and void (VV) using computerized microtomography (MUCT) in bulk fill resin composites and conventional class I restorations, and to establish a correlation between these factors. Class I cavities (4 x 5 x 4 mm), C-factor = 4.2, were performed on caries-free human third molars and randomly divided into five groups (n = 6): FSI (Filtek Supreme XTE incremental insertion); FSS [(Filtek Supreme XTE single insertion(SI)]; TBF [(Tetric Bulk Fill: SI and manual filling (MF)]; SFM (Sonic Fill: SI/MF); and SFS (SonicFill: SI and sonic filling). The teeth were scanned and analyzed by MUCT at T0, after filling the cavity with resin, and at T1, after polymerization for VG and VV, and for VS (T1-T0). There was statistically significant difference in VS in MUCT for the FSI and FSS groups and between SFS and FSS as well as some difference in VV for FSI and bulk fill resin composites and no difference in VG between the conventional technique and bulk fill composites. Bulk fill resin composites presented similar VS and gap formation to those of incrementally inserted conventional resin composites. There is a moderate and weak positive correlation between polymerization shrinkage and gap formation and void, respectively. The final gap formation was more dependent on the initial gap than on polymerization shrinkage or void volume. PMID- 29267662 TI - Materials used for indirect pulp treatment in primary teeth: a mixed treatment comparisons meta-analysis. AB - This study aimed to systematically review the literature to address the question regarding the influence of different materials in the clinical and radiographic success of indirect pulp treatment in primary teeth. A literature search was carried out for articles published prior to January 2017 in PubMed/MEDLINE, CENTRAL, Scopus, TRIP and ClinicalTrials databases; relevant articles included randomized clinical trials that compared materials used for indirect pulp treatment in primary teeth. Two reviewers independently selected the studies and extracted the data. The effects of each material on the outcome (clinical and radiographic failures) were analyzed using a mixed treatment comparisons meta analysis. The ranking of treatments according to their probability of being the best choice was also calculated. From 1,088 potentially eligible studies, 11 were selected for full-text analysis, and 4 were included in the meta-analysis. In all papers, calcium hydroxide liner was used as the control group versus an adhesive system, resin-modified glass ionomer cement or placebo. The follow-up period ranged from 24 to 48 months, with dropout rates of 0-25.7%. The material type did not significantly affect the risk of failure of the indirect pulp treatment. However, calcium hydroxide presented a higher probability of failure. In conclusion, there is no scientific evidence showing the superiority of any material used for indirect pulp treatment in primary teeth. PMID- 29267663 TI - Oral health assessment for users of marijuana and cocaine/crack substances. AB - The objective of this study was to assess the oral health status of users of illicit drugs such as marijuana and cocaine/crack and compare it with individuals not using these chemical substances. Questionnaires were applied to 35 illicit drugs users to gather information on demographic status, general health, and use of drugs. Then, a clinical assessment of the oral health condition was performed to collect data on decayed, missing and filled teeth (DMFT) index, salivary flow rate (SFR), and mucosal lesions. The control group was composed of 35 non-illicit drug users. In the experimental group, 91.43% were males, 80% were smokers, and 42.85% were alcoholics. Cocaine was the most common drug used (77.15%), followed by marijuana (68.6%), and crack (51.4%). The average DMFT index was 9.8 and the SFR was reduced in 60% of subjects. Mucosal alterations were detected, but no potentially malignant disorders or oral cancer were diagnosed. Compared to control group, significantly higher values for gender (40%, p = 0.0001), smoking (22.86%) and heavy drinking (5.7%) habits (p = 0.0001), SFR (31.4%; p = 0.0308), and oral lesions (p = 0.0488) were found for the experimental group, although significantly higher values were found in the control group for DMFT index (p = 0.0148). It can be concluded that the use of illicit drugs contributed to an increased prevalence of oral mucosa lesions. In addition, a decline on SFR and a reduced DMFT index was observed for illicit drug users. PMID- 29267664 TI - Treg and Th17 cells in inflammatory periapical disease: a systematic review. AB - The process involved in periapical lesions, which occur as an outcome of pulpal necrosis, is regulated by the immune system including regulatory T cells (Treg) and T helper 17 cell (Th17) responses. The objective of this study was to conduct a frequency systematic review to determine the presence of Treg/Th17 responses and the influence of these cells in the progression of chronic inflammatory periapical lesions in humans. A systematic computerized search was carried out in Pubmed, Medline, Web of Science and Scopus electronic databases from their date of inception through the first week of May 2017. In addition, the reference lists of the included articles and the grey literature were hand-searched. Articles that evaluated the presence and influence of Treg/Th17 in the progression of human periapical lesions were included. Study selection and the quality assessment of the included articles (using the Newcastle-Ottawa scale) were carried out by two authors. Fifty-seven titles/abstracts were screened and eight studies met the eligibility criteria and were included in this systematic review. The included studies showed large variation in the type of periapical lesion assessed, mean age, age range, type of experiment and findings regarding the participation of Th17 and Treg in the status of inflammatory periapical lesions. The studies showed the involvement of Treg in the modulation of the inflammatory response in radicular cysts and periapical granulomas. This systematic review highlights the relationship between Treg and Th17 acting in a subtle balance inhibiting or promoting the progression of human periapical lesions. PMID- 29267665 TI - Biostimulatory effects of simvastatin on MDPC-23 odontoblast-like cells. AB - The aim of this study was to evaluate the bioactivity and cytocompatibility of simvastatin (SV) applied to MDPC-23 odontoblast-like cells. For this purpose, MDPC-23 cells were seeded in 96-well plates and submitted to treatments with 0.01 or 0.1 MUM of SV for 24 h, 72 h or continuously throughout the experimental protocol. The negative control group (NC) was maintained in DMEM. Cell viability (MTT), ALP activity (thymolphthalein monophosphate), and mineralized matrix deposition (alizarin red) were analyzed at several time points. The data were submitted to ANOVA and Tukey's test (alpha = 0.05). Although cell viability was observed in the groups treated with SV, these groups did not differ from the NC up to 7 days. There was a reduction in cell viability for the groups treated with 0.1 MUM of SV for 72 h, and submitted to continuous mode after 14 days. A significant increase in ALP activity occurred in the group treated with 0.01 MUM of SV for 24 h, compared with the NC; however, only the group treated with 0.1 MUM of SV in continuous mode reduced the ALP activity, in comparison with the NC. After 14 days, only continuous treatment with 0.1 MUM of SV did not differ from NC, whereas the other experimental groups showed increased mineralized matrix deposition. Thus, it was concluded that low concentrations of simvastatin were bioactive and cytocompatible when applied for short periods to cultured MDPC-23 odontoblast-like cells. PMID- 29267666 TI - Health-related quality of life of patients with squamous cell carcinoma: a comparison according to tumor location. AB - The aim of this study was to evaluate the health-related quality of life (QOL) of patients with squamous cell carcinoma (SCC) according to tumor location. The sample consisted of 27 patients with primary SCC in the oral cavity (n = 15), pharynx (n = 7), and larynx (n = 5) who were undergoing cancer treatment at the Cancer Hospital of Londrina, regardless of age, sex, clinical stage, and type of antineoplastic treatment. Health-related QOL was evaluated using the 30-item Cancer-Quality of Life Questionnaire (QLQ-C30), the 35-item Head and Neck Cancer Quality of Life Questionnaire (QLQ-HN35), and the University of Washington Quality of Life Questionnaire (UW-QOL). These questionnaires were administered individually to each patient before ambulatory care. Sociodemographic data (age and sex) and clinical data (T stage, tumor location, and type of antineoplastic treatment) were collected from the patients' medical records. Scores were compared according to tumor location using the chi-squared test and one-way analysis of variance (p < 0.05). No score differed significantly according to tumor location. It can be concluded that the health-related QOL of patients with SCC was not influenced by tumor location. PMID- 29267667 TI - Analysis of CD57+ natural killer cells and CD8+ T lymphocytes in periapical granulomas and radicular cysts. AB - The aim of this study was to compare the number of CD57+ natural killer (NK) cells and CD8+ T lymphocytes between periapical granulomas (PGs) and radicular cysts (RCs). Twenty-fives cases of PGs and 25 of RCs were submitted to histological analysis and immunohistochemistry using anti-CD57 and anti-CD8 biomarkers. Positive cells were counted in 10 fields (400* magnification) and the median value was calculated for each case. Statistical tests were used to evaluate differences in the number of CD57+ NK cells and CD8+ T lymphocytes according to type of lesion, intensity of the infiltrate and thickness of the lining epithelium. The number of CD57+ NK cells and CD8+ T lymphocytes was higher in PGs than in RCs (p = 0.129 and p = 0.541, respectively). Comparison of the number of CD57+ NK cells in atrophic and hyperplastic epithelium revealed a larger number of cells in the atrophic epithelium (p = 0.042). A larger number of CD57+ NK cells and CD8+ T lymphocytes were observed in grade III infiltrates compared to grade I/II (p = 0.145 and p = 0.725, respectively). CD8+ T lymphocytes were more prevalent than CD57+ NK cells in most cases when PGs and RCs were analyzed separately or in combination (p < 0.0001). CD57+ NK cells and CD8+ T lymphocytes play a key role in antiviral defense and the presence of these cells supports evidence suggesting the participation of these microorganisms in the pathogenesis of PGs and RCs. The response mediated by CD8+ T lymphocytes was more frequent, indicating greater participation of the adaptive immunity in these chronic lesions. PMID- 29267668 TI - The analgesic effect of photobiomodulation therapy (830 nm) on the masticatory muscles: a randomized, double-blind study. AB - This study assesses the efficacy of photobiomodulation therapy (830 nm) for myalgia treatment of masticatory muscles. Sixty patients with muscular myalgia were selected and randomly allocated into 2 groups (n=30): Group A comprised patients given a placebo (control), and Group B consisted of those undergoing photobiomodulation therapy (PBMT). PBMT and placebo were applied bilaterally to specific points on the masseter and temporal muscles. Referred pain elicited by palpation and maximum mouth opening were measured before (EV1) and after (EV2) the treatments. The data were analyzed using statistical tests, considering a significance level of 5%. No significant differences in range were observed for active or passive mouth opening (p >= 0.05). Comparing the final outcomes (EV1 EV2) of both treatments, statistical significance was verified for total pain in the right masseter muscle (p = 0.001) and total pain (p = 0.005). In EV2, significant differences in pain reported with palpation were found between Groups A and B for the following: left posterior temporal muscle (p = 0.025), left superior masseter muscle (p = 0.036), inferior masseter muscle (p = 0.021), total pain (left side) (p = 0.009), total masseter muscle (left side) (p = 0.014), total temporal (left side) (p = 0.024), and total pain (p = 0.035). We concluded that PBMT (830 nm) reduces pain in algic points, but does not influence the extent of mouth opening in patients with myalgia. PMID- 29267669 TI - Culture-dependent approaches to explore the prevalence of root canal pathogens from endodontic infections. AB - Endodontic infections are considered to be caused by the presence of various microorganisms within the root canal system. Recognition of this microbiota contributes to the successful treatment of infected root canals. This study investigated the microorganisms associated with primary and secondary endodontic infections via culture methods, biochemical tests, and molecular approaches in an Iranian population. Microbial specimens were collected from 36 patients with primary endodontic infection and 14 patients with a history of root canal therapy. Advanced microbiological culture techniques were used to isolate microbiota; subsequently, biochemical tests and 16S ribosomal RNA gene sequencing were performed to identify the microorganisms. Within the total 218 cultivable isolates, Veillonella parvula (20.6%) was found to occur with the highest frequency in primary endodontic infection, followed by Porphyromonas gingivalis (14.1%), and Aggregatibacter actinomycetemcomitans (9.2%). Enterococcus faecalis (36.6%) was the most predominant microorganism in secondary endodontic infections, followed by Candida albicans, Propionibacterium acnes, and V. parvula with frequencies of 20%, 2%, and 2%, respectively. It was concluded that V. parvula and E. faecalis was most frequently found in primary and secondary endodontic infections, respectively. PMID- 29267670 TI - Microtensile bond strength of CAD/CAM materials to dentin under different adhesive strategies. AB - The present study aimed to evaluate the microtensile bond strength (MUTBS) of novel computer-aided design/computer-aided manufacturing (CAD/CAM) restorative materials to dentin using different adhesive strategies. Thirty-two crowns were milled using CAD/CAM materials (Vita Mark II as control, Vita Suprinity, Vita Enamic and Lava Ultimate) and luted to dentin using different resin cements (RelyX ARC, RelyX Unicem 2 and RelyX Ultimate). The specimens were stored in 100% relative humidity at 37 degrees C for 24 h and sectioned. The samples (n = 16) with cross-sectional areas of approximately 0.90 mm2, were submitted to a MUTBS test in a universal testing machine with a crosshead speed of 0.5 mm/min. The samples were analyzed with SEM to determinate the failure mode. According to 2 way ANOVA and Tukey's test (alpha=0.05), the interaction effect (material x luting strategy) was significant (p=0.001). Regardless of the luting strategy, a higher MUTBS was obtained with Lava Ultimate and Vita Enamic, which were significantly different from Vita Mark II and Vita Suprinity (p<0.05). For Vita Mark II, Vita Suprinity, Vita Enamic, and Lava Ultimate, the MUTBS obtained with RelyX Unicem 2 was not significantly different from that obtained with RelyX ARC or RelyX Ultimate. All groups obtained at least three types of failure. The adhesive strategy with self-adhesive resin cement was comparable to conventional resin cement with total-etch or self-etch adhesive techniques in the bond of novel CAD/CAM materials to dentin. PMID- 29267671 TI - Gingival crevicular fluid oxidative stress level in patients with periodontal disease and hyperlipidemia. AB - This study aimed to assess the impact of hyperlipidemia on healthy and diseased periodontal tissue by evaluating oxidative stress biomarkers in gingival crevicular fluid (GCF). Clinical periodontal parameters and blood serum lipid, GCF malondialdehyde (MDA), protein carbonyl (PC), and total antioxidant capacity (TAOC) levels were evaluated in six age and sex-matched groups (n = 15 each) of normolipidemic and hyperlipidemic individuals as follows: normolipidemic + periodontally healthy (H), normolipidemic + gingivitis (G), normolipidemic + chronic periodontitis (CP), hyperlipidemic + periodontally healthy (HH), hyperlipidemic + gingivitis (HG), and hyperlipidemic + CP (HCP). GCF MDA, and PC levels varied among groups, with patients with periodontitis having the highest MDA and PC levels [CP > G > H (p < 0.01) and HCP > HG > HH (p < 0.01)] and the lowest TAOC levels [CP < G < H (p < 0.01) and HCP < HG < HH (p < 0.01)]. Furthermore, paired comparisons showed MDA and PC levels to be higher and TAOC levels to be lower in HCP compared with NCP (p < 0.01). In patients with hyperlipidemia, GCF, MDA, and PC levels positively correlated with clinical assessments and serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) levels and negatively correlated with serum high density lipoprotein cholesterol (HDL) levels, whereas GCF TAOC levels negatively correlated with clinical assessments and serum TG, TC, and LDL levels, but positively correlated with serum HDL levels (p < 0.01). In normolipidemic patients, GCF, MDA, and PC levels positively correlated with clinical assessments and serum TG levels and negatively correlated with serum HDL levels, whereas GCF TAOC levels negatively correlated with clinical assessments and serum TG levels and positively correlated with serum HDL levels (p < 0.01). In conclusion, abnormal serum lipid subfractions could be considered a risk factor for enhancing oxidative stress in GCF in the presence of periodontal disease. PMID- 29267672 TI - Correlation and comparative analysis of the CPQ8-10 and child-OIDP indexes for dental caries and malocclusion. AB - The aim of this study was to evaluate the correlation between the Child Perceptions Questionnaire 8 to 10 (CPQ8-10) and child-Oral Impact on Daily Performances (child-OIDP) indexes according to their total and item scores, as well as assess the discriminative validity of these assessment tools regarding dental caries and malocclusion among schoolchildren. A sample of 300 children aged between 8 and 10 years answered the questionnaires in two distinct steps. First, half of the sample (G1 = 150) answered the CPQ8-10 and the other half (G2 = 150) answered the child-OIDP. A week after, G1 answered the child-OIDP and G2 answered the CPQ8-10. Dental Aesthetic Index and WHO criteria were used to categorize malocclusion and dental caries, respectively. Descriptive analysis, Spearman's correlation and Mann-Whitney test were performed in this study. The CPQ8-10 and child-OIDP demonstrated a statistically significant and moderate correlation between their total scores. Regarding the discriminative validity, CPQ8-10 demonstrated a significant association between the "emotional status" daily activity and dental caries, and between the "eating", "sleeping", and "studying" daily activities and malocclusion. Concerning the child-OIDP, a significant difference was found only between the "social contact" activity and presence of dental caries. Both instruments were not capable of distinguishing children with and without dental caries and/or malocclusion by their total scores. However, the instruments were able to discriminate between children with and without those oral disorders in different dimensions. Thus, the CPQ8-10 and the child-OIDP demonstrated a different capacity to assess the impact on OHRQoL among schoolchildren. PMID- 29267673 TI - Effect of CRABP2 on the proliferation and odontoblastic differentiation of hDPSCs. AB - Cellular retinoic acid-binding protein 2 (CRABP2) has been detected in several organs during embryonic development. Recent studies have demonstrated that CRABP2 plays important roles in the retinoic acid, beta-catenin and Notch signaling pathways, as well as in the interaction between epithelial and mesenchymal cells, which are important for human dental pulp stem cells (hDPSCs) and tooth development. In the present study, the expression of CRABP2 during mouse molar development and the role of CRABP2 in hDPSC odontoblastic differentiation were evaluated. CRABP2 was gradually decreased during the development of the first maxillary molar, which exhibited the same trend as the expression of CRABP2 during the odontoblastic induction of hDPSCs. CRABP2 knockdown inhibited the proliferative ability of hDPSCs, while it enhanced odontoblastic differentiation via promoting mineralization nodule formation and upregulating the activity of alkaline phosphatase and the expression of mineralization-related genes. The present study uncovered a novel function of CRABP2 in hDPSCs. Our data suggest that CRABP2 may act as a regulator during the proliferation and differentiation of hDPSCs. PMID- 29267674 TI - Comparison of two methods of irrigant agitation in the removal of residual filling material in retreatment. AB - The aim of this study was to compare the efficacy of passive ultrasonic irrigation and EasyClean for removing residual filling material in retreatment. Twenty-two maxillary lateral incisors with apical curvature were instrumented with ProTaper files and filled with Endofill using the lateral compactation technique. Removal of filling material was performed with Reciproc, Mtwo and ProDesign Logic 50/.01 files. The teeth were inserted in a silicone mould, which was placed in a metal muffle, and split to visualize the residual filling material. The samples were divided into two groups (n = 11) according to the irrigation protocol: Passive ultrasonic irrigation (PUI group) with 3 activations of 20 seconds and EasyClean (Easy Equipamentos Odontologicos, Belo Horizonte, Brazil) (EC group) used in continuous rotation with 3 activations of 20 seconds, both using NaOCl and EDTA. Environmental scanning electron microscopic images of the apical, middle, and cervical thirds were taken before and after the irrigant activation. The Kappa test was used to determine interexaminer agreement. Statistical analysis was performed using Kruskal-Wallis, Mann-Whitney, and Wilcoxon tests (p < 0.05). PUI and EC improved the removal of remnant filling material in all root canal thirds (p < 0.05). PUI and EC presented similar performance in the final step of retreatment (p > 0.05). No significant difference was observed in the removal of filling material in the apical, middle, and cervical thirds in both groups (p > 0.05). EasyClean in continuous rotary motion is useful in retreatment and was shown to be as effective as ultrasonic activation in the removal of remnant filling material. PMID- 29267675 TI - Effectiveness of different final irrigation techniques and placement of endodontic sealer into dentinal tubules. AB - The aim of this study was to compare two irrigation techniques and four devices for endodontic sealer placement into the dentinal tubules. Ninety-nine single rooted human teeth were instrumented and allocated to either the control (CO) (n=11) or experimental groups according to the irrigation method: syringe and NaveTip needle (NT) (n=44), and EndoActivator (EA) (n=44). These groups were subdivided according to sealer placement into K-File (KF), lentulo spiral (LS), Easy Clean (EC), and EndoActivator (EA) subgroups. Moreover, the distances of 5 mm and 2 mm from the apex were analyzed. The teeth were obturated with AH Plus and GuttaCore X3. Analyses were performed by scanning electron microscopy associated to cathodoluminescence. The percentage and maximum depth of sealer penetration were measured. Data were evaluated by three-way analysis of variance (ANOVA) and Games-Howell test (p<0.05). EA was superior to NT in percentage of sealer penetration. EC was significantly superior to EA (subgroup) for sealer penetration, and both improved the percentage of sealer penetration when compared to LS. Better sealer penetration was observed at the distance of 5 mm from the apex. Sealer penetration into the dentinal tubules was significantly improved by sonic irrigant activation. PMID- 29267676 TI - Determinants of oral self-care in the Brazilian adult population: a national cross-sectional study. AB - This study aims to investigate variables related to adherence to oral self-care in the Brazilian adult population. It is an exploratory study, using secondary data from a population-based survey on a representative sample of the adult population of the entire Brazilian territory (n=60202). The sample was selected using a multiple stage approach. The oral self-care indicator was defined by grouping the variables: periodicity of dentist appointments, use of dental floss, toothbrush and toothpaste, frequency of brushing and replacement of the toothbrush. The scores obtained from the indicator were categorized into adequate, partially adequate, and inadequate care. Statistical analysis consisted of dimensionality reduction, and oral self-care-related variables were submitted to logistic regression. The variables mostly related to inadequate or partially adequate oral self-care were: illiteracy (OR = 11.20, OR = 4.81), low educational level (OR = 3.50, OR = 1.96), negative oral health self-concept (OR=3.73, OR=1.74), absence of natural teeth (OR = 4.98, OR=2.60), edentulous lower arch (OR = 3.09; _____), number of missing upper teeth (OR=1.14, OR=1.05), absence of health insurance (OR=2.23, OR=2.07), sedentary lifestyle (OR=2.77, OR=1.51), and smoking (OR=2.18, OR=1.40). It was concluded that the individual's level of education is one of the main factors for adherence to adequate oral self-care, followed by level of oral health self-concept and tooth loss. Likewise, lifestyle also bears a significant influence. PMID- 29267677 TI - [Validation of the theoretical logical model for food and nutritional surveillance in primary care]. AB - The aim of this study was to describe the stages in the development and results of the validation of the theoretical logical model for food and nutritional surveillance in primary healthcare (PHC). This was a descriptive and exploratory study that involved 20 specialists in food and nutrition, including researchers, policymakers, health professionals, and users based on a consensus technique in two rounds. Participants classified the structural components needed for food and nutritional surveillance and the respective expected results according to pertinence and relevance. The items were defined as consensus when they reached more than 80% agreement among participants, confirmed by the analysis of the median and interval between the first and third quartiles. The results reflect the validated content of the matrices organized according to four technical components: strategic planning, administrative planning, management and organization of practices, and monitoring and evaluation. The structure and necessary processes for conducting food and nutritional surveillance activities in PHC and the expected short-, medium-, and long-term results were described in the theoretical logical model. The validation of the theory of functioning of the intervention met its objective of increasing the content and construct validity and support the analytical generalization of the case-studies method, a strategy adopted to evaluate the implementation of food and nutritional surveillance in a specified context, in addition to creating a space for dialogue between the theory and its critique by involving different stakeholders in the evaluation, as well as providing a useful management tool. PMID- 29267678 TI - Differences and similarities in women living and not living with HIV: contributions by the GENIH study to sexual and reproductive healthcare. AB - This quantitative study in the city of Sao Paulo, Brazil, compared contexts of social vulnerability and sexual and reproductive behavior in a sample of 975 women living with HIV/AIDS (WLHIV) and 1,003 women not living with HIV, the latter recruited among users of the primary healthcare system. WLHIV experienced situations of greater vulnerability that potentially increased their risk of HIV infection and unplanned pregnancy and abortion. Compared to women users of the primary healthcare system, WLHIV reported higher rates of drug use, sex for money, exposure to intimate partner violence, difficulties in access to services for prevention and early diagnosis, unplanned pregnancies, induced abortion, and teenage pregnancy. A considerable number of the women users of the primary healthcare system shared these same experiences, but at lower rates. The identification of contexts of vulnerability and the integration of HIV testing services with sexual and reproductive health services should constitute lines of care for these women, both in specialized and primary care services. PMID- 29267679 TI - [Norbert Elias on the phenomenology of aging and death]. AB - This study focuses on the contribution by German sociologist Norbert Elias (1897 1990) to the theme of aging and death. A reading of Elias' work allows reconsidering his analyses and perspectives on the thresholds of aging and death in societies with different demographic histories. Norbert Elias addressed these issues in The Loneliness of the Dying, published in 1982 in Germany and with an expanded version in 1985 in England. The author delves into his own experience with aging as inspiration for constructing his work, referring to his personal history and career as a social scientist, dialoguing with both the social and human sciences and with knowledge in the field of health. Elias endeavors to understand how the aging body is experienced and represented by the elderly person and how younger people grasp the processes and stages of advancing age. His thinking is attuned to the multiplicity of metaphors and meanings on finitude, on processes of aging and rites of passage in "younger" societies or more demographically "mature" ones. These are the concerns and inquiries of Norbert Elias that we will reflect on, in dialogue with his studies on finitude or the final moments of existence. PMID- 29267680 TI - Severe intimate partner physical violence as a risk factor for inadequate cervical cancer screening. AB - With the aim of assessing the occurrence of severe intimate partner physical violence as a risk factor for inadequate screening of uterine cervical cancer, a case-control study was performed with a multidimensional questionnaire in a sample of 640 users of the Family Health Strategy in the Municipality of Nova Iguacu, Rio de Janeiro State, Brazil. Cases were defined as women who had not had a cervical cytology test in the previous three years. The results showed that severe physical violence against the woman (adjustedOR = 2.2; 95%CI: 1.1-4.4) and co-occurrence of the event in the couple (adjustedOR = 3.8; 95%CI: 1.4-9.8) were risk factors for inadequate screening. Alcohol abuse by the woman was an effect modifier for not having the test among victims of violence (adjustedOR = 10.2; 95%CI: 1.8-56.4) and in cases of co-occurrence of violence (adjustedOR = 8.5; 95%CI: 1.4-50.7). In addition to known causal factors for intimate partner violence, the results point to a risk association between women's exposure to abuse and inadequate screening. The findings call for an expanded view of women's absenteeism from screening, since this indicator can represent unmet demands not readily detected by health teams. PMID- 29267681 TI - [Bullying of emos in Mexico City: an ethnographic analysis]. AB - The article describes the beliefs that have fueled violence by various groups against male and female "emos" in Mexico City. This was an ethnographic study from 2012 to 2015 based on 24 in-depth interviews with young students enrolled in public universities in Mexico City in 2008. The study focused primarily on emos (10), but also included young people that described themselves as punks (6), darks (5), and rockers (3). The findings suggest that bullying of emos is deeply rooted in gender beliefs, particularly hegemonic notions of masculinity. The study highlights the fact that bullying is perpetrated not only by other youth, but also occurs in the family and school settings, where the violence is taken for granted as a legitimate construct associated with the idea of discipline in school. The strategies used by these young people to resist bullying suggest reflexive attitudes towards their historical, scholastic, and family contexts. They are able to reaffirm their collective demand for the right to education and diversity in university classes, but the situation calls for policies to prevent bullying, especially in the university community. PMID- 29267682 TI - Links between family farming and the National School Feeding Program in Brazil: comments on the article by Schwartzman et al. PMID- 29267683 TI - The world is taking inspiration from the National School Feeding Program, but can Brazil maintain the progress? PMID- 29267684 TI - Background and elements of the linkage between the Brazilian school feeding program and family farming. AB - Since 2009, legislation of the National School Feeding Program of Brazil (PNAE) institutionalizes its linkage with family farming as it establishes the requirement that at least 30% out of the total financial resources allocated by the federal government to the states and municipalities for school feeding must be used in the purchase of products directly from this sector. This study analyzes the process of drafting this legislation, focusing on the elements related to the procurement from family farming, through a historical contextualization, and it also presents a graphical representation with the main elements of this linkage: its objectives, target population, actions implemented and expected results. Actors involved with the drafting of the legislation were interviewed. The analyses show that the procurement from family farming is a far reaching initiative in terms of the concept, execution and results. It has also showed that a strong articulation between the actors and institutions of the different sectors involved is critical to its success. The education, agriculture, planning, procurement and civil society sectors should work articulately at national, state and local level. The results of this study demonstrate that initiatives like this, of institutional procurement from family farming, which are currently being implemented in several countries, constitute as an important strategy of food and nutrition security, for the fulfillment of the human right to adequate food and the promotion of long-term sustainable development. PMID- 29267685 TI - [Characterization of access to normal childbirth care in Bahia State, Brazil, based on graph theory]. AB - Origin-destination flow is a phenomenon that can be modeled as a network. Graph theory is a mathematical tool to characterize a network and thus allows studying the topological properties and temporal and spatial development of a set of related elements. The article aims to estimate the topological evolution of an inter-municipal network of normal deliveries. We selected the admissions for normal deliveries in the Hospital Information System of the Brazilian Unified National Health System, from 2008 to 2014, for women residing in Bahia State, Brazil. The following indices were applied: entry degree (from how many municipalities the women came for childbirth), exit degree (to how many municipalities they left), entry flow (how many women came), exit flow (how many women left), and the mean size of the exit edge (distance traveled). Analyses between macro-regions used the following indicators: proportion of normal deliveries performed outside the municipality of residence and mean size of the exit edge. The results indicate an increase in deliveries performed outside the municipality of residence, in addition to the persistence of concentration of deliveries in the hub municipalities in the Health Regions, and an increase in the distance between the municipality of residence and the municipality where the delivery took place. The organization of networks for normal childbirth poses an on-going challenge. It is important to analyze the flow of women for childbirth care in order to support the establishment of inter-municipal references to guarantee safe labor and childbirth. In conclusion, it is necessary to develop a regionalized network to meet the demand by pregnant women in the territory with universal and equitable coverage. PMID- 29267686 TI - [Contributions and challenges associated with bodily practices and meditation for health promotion in the public primary care system in the city of Sao Paulo, Brazil]. AB - The article presents an analysis of contributions and challenges associated with bodily practices and meditation for health promotion in the public primary care system. The qualitative study was developed in 16 healthcare units in the city of Sao Paulo, Brazil, using interviews with 29 health professionals and 36 practitioners of bodily practices and meditation, including participant observation of 31 practices such as Tai Chi, Lian Gong, Qigong, Yoga, Capoeira, Dance, Meditation, Relaxation, Mindfulness, and Body Awareness. There was an improvement in joint pain, mobility, balance, memory, depression, and anxiety, besides greater ease in coping with chronic conditions. Such contributions are related to favoring practitioners' autonomy, building health references through self-awareness; the combination of health promotion and therapeutic care in the approaches; and support for access to cultural goods and community spaces. The challenges identified here were precarious integration with the supply of other health services, lack of supervision and evaluation, and the predominance of a health-sector culture. PMID- 29267687 TI - [Relationship between dietary consumption of vitamins and minerals, body mass index, and waist circumference: a population-based study of adults in southern Brazil]. AB - The study's objective was to investigate the association between inadequate dietary consumption of micronutrients and indicators of general and abdominal obesity. Cross-sectional analysis of the second wave of the EpiFloripa Adults longitudinal study, including 1,222 individuals, aged 22-63 years and residing in Florianopolis, Santa Catarina State, Southern Brazil. Food consumption data was obtained from two 24-hour food recalls, and habitual consumption and prevalence rates of inadequate consumption of calcium, iron, zinc, and vitamins A, C, D, and E were estimated according to the Institute of Medicine and National Research Council guidelines. General obesity was defined based on the body mass index (BMI) values and abdominal obesity was based on waist circumference (WC) values. For most of the micronutrients investigated (calcium and vitamins A, C, D, and E), consumption levels were below the recommendations, with high prevalence of inadequate consumption in the sample as a whole. Only inadequate vitamin C intake was higher among obese individuals (general or abdominal). In addition, there was an inverse association between lower consumption of calcium and iron and higher BMI and WC, and between lower consumption of vitamins A and D and higher WC levels (beta = -0.92cm; 95%CI: -1.76; -0.08 and beta = -0.69 cm; 95%CI: -1.32; 0.06, respectively), especially in young adults. The study showed an inverse association between inadequate dietary consumption of micronutrients and general and abdominal obesity in a sample of adults in Southern Brazil. PMID- 29267688 TI - There is need to continue the direct procurement from family farming by the Brazilian National School Feeding Program. PMID- 29267689 TI - Budgetary impact of diagnostic tests for visceral leishmaniasis in Brazil. AB - The aim of the present study was to estimate the financial costs of the incorporation and/or replacement of diagnostic tests for human visceral leishmaniasis (VL) in Brazil. The analysis was conducted from the perspective of the Brazilian Unified National Health System (SUS) over a period of three years. Six diagnostic tests were evaluated: the indirect immunofluorescence antibody test (IFAT), the IT LEISH rapid test, the parasitological examination of bone marrow aspirate, the direct agglutination test (DAT-LPC) standardized in the Clinical Research Laboratory, Rene Rachou Institute of the Oswaldo Cruz Foundation, the Kalazar Detect rapid test, and polymerase chain reaction (PCR). The assumptions used were the number of suspected cases of VL reported to the Brazilian Ministry of Health in 2014 and the direct cost of diagnostic tests. The costs to diagnose suspected cases of VL over three years using the IFAT and the DAT-LPC were estimated at USD 280,979.91 and USD 121,371.48, respectively. The analysis indicated that compared with the use of the IFAT, the incorporation of the DAT-LPC into the SUS would result in savings of USD 159,608.43. With regard to the budgetary impact of rapid tests, the use of IT LEISH resulted in savings of USD 21.708,72 over three years. Compared with a parasitological examination, diagnosis using PCR resulted in savings of USD 3,125,068.92 over three years. In this study, the replacement of the IFAT with the DAT-LPC proved financially advantageous. In addition, the replacement of the Kalazar Detect rapid test with the IT LEISH in 2015 was economically valuable, and the replacement of parasitological examination with PCR was indicated. PMID- 29267690 TI - [Family odysseys: the search for infant mental health care]. AB - The aim was to analyze the peregrination of families of children treated in a Center for Psychosocial Care for Children and Adolescents in their search for mental health care. The study included participant observations at the clinic and focus groups with the children's families. The qualitative study used institutional analysis as the theoretical and methodological reference, and the material was discussed in light of the approach to psychosocial care. The families' search in the face of the child's psychological distress is a prime indicator for assessing strengths and weaknesses in building the network of care, and for revealing the families' understanding of their children's mental health problems and treatments. The study found contradictory forces at play in daily care, demonstrating both the provider's transformative force and occasionally the user's crystallization and maintenance. In this sense, the hegemonic model - disease-centered, fragmenting patients and their care - has been challenged by the instituting force that proposes to reposition the patient and incorporate psychological distress as part of overall health, linking services and actions in a model of care. Despite the tangled maze that families face in their peregrination for care, strides have been made in psychosocial care, while highlighting challenges. Such progress has been anchored in relational technologies (shelter, bonding, trust, and accountability) with the various actors involved in the care. PMID- 29267691 TI - Prevalence and risk factors for latent tuberculosis infection among primary health care workers in Brazil. AB - Health care workers (HCW) are at increased risk of latent tuberculosis infection (LTBI) from occupational exposure to Mycobacterium tuberculosis. The objective was to determine the prevalence of and risk factors for LTBI among primary HCW in five Brazilian cities. We conducted a cross-sectional study, from 2011 to 2013, among primary HCW, using a structured questionnaire and an evaluated for LTBI using the Quantiferon-TB Gold in-tube test. The magnitude of the associations was assessed using hierarchical logistic regression models. Among 708 HCW, the LTBI prevalence was 27% (n = 196; 95%CI: 24%-31%). We found that the following factors were positively associated with LTBI in primary HCW: age > 50 years (OR = 2.94; 95%CI: 1.44-5.99), absence of a BCG scar (OR = 2.10; 95%CI: 1.28-3.43), self reported ex-smoker status (OR = 1.80; 95%CI: 1.04-3.11), being a nurse (OR = 2.97; 95%CI: 1.13-7.83), being a nurse technician (OR = 3.10; 95%CI: 1.26-7.60), being a community health agent (OR = 2.60; 95%CI: 1.06-6.40), and irregular use of N95 masks (OR = 2.51; 95%CI: 1.11-5.98). In contrast, HCWs who do not work in health care facilities with a TB control program were less likely to have LTBI (OR = 0.66; 95%CI: 0.45-0.97). This study demonstrated a substantial occupational risk of LTBI among primary HCW in Brazil. The Brazilian TB control program, as well as local programs, need to target these high-risk HCW with education, as well as with better personal protective equipment to prevent acquisition of new TB infection. PMID- 29267692 TI - [Coverage of assessment of nutritional status in the Brazilian Food and Nutritional Surveillance System, 2008-2013]. AB - This study aims to describe and analyze nationwide coverage of the assessment of nutritional status in the user population of public health services recorded in Brazil's Online Food and Nutritional Surveillance System SISVAN) from 2008 to 2013. This was an ecological study of secondary data from information systems. The indicators were: percentages of registration in and utilization of the system; total coverage and coverage of data from the Bolsa Familia Program, corrected according to the user population of the Brazilian Unified National Health System SUS) and described according to the states of Brazil and Federal District, major geographic regions, and/or life cycle phases. The analysis used descriptive statistics, linear regression for estimation of temporal variation, and Spearman's correlation between total coverage and social, demographic, and health variables. From 2008 to 2013, more than 99% of Brazil's municipalities counties) had individuals enrolled and monitored in the system, and the highest frequencies and total variations in coverage appeared in the Northeast and North. Nationwide coverage ranged from 9.78% to 14.92%, with a statistically significant upward trend. The largest volume of data was for children and adolescents. The Bolsa Familia Program's share of data in SISVAN increased from 57.17% to 85.78%. The municipal human development index and per capita gross domestic product in the states were inversely correlated with coverage, and family health teams were directly correlated. The results indicate persistently low coverage for a system that is intended to be universal. The study showed a significant increase in coverage during the period analyzed and revealed factors related to this increase. PMID- 29267693 TI - [Femicide in Porto Alegre, Rio Grande do Sul State, Brazil: gender iniquities in dying]. AB - Femicide is the murder of women as the result of gender inequalities. It is the most extreme form of violence against women. The theoretical and methodological frame of reference used in this study was patriarchy theory and critical discourse analysis. We analyzed the discourses from 64 police inquiries categorized as femicides in Porto Alegre, Rio Grande do Sul State, Brazil, from 2006 to 2010. The victims were mostly poor young women living in outlying areas of the city with high rates of prostitution and women murdered by the drug traffic, deaths not routinely classified as femicides by the police. Many inquiries were shelved for purported lack of evidence, and many other cases were not even started. The discourse in the police reports often demeaned and blamed the victims, although some criticized the inequalities between men and women and identified the lethal effects of male chauvinism. Police inquiries are important sources for studying femicide in society, adding abundant information on the crimes' victims, perpetrators, and scenarios. PMID- 29267694 TI - [Quality of care for labor and childbirth in a public hospital network in a Brazilian state capital: patient satisfaction]. AB - The study assessed the quality of care for labor and childbirth in the public hospital system in the city of Recife, Pernambuco State, Brazil, according to the mothers' satisfaction, using a cross-sectional exploratory study in all the public hospitals in the network, grouped according to type of hospital management and interviews with 1,000 mothers. Quality of care was measured according to management strata and the following dimensions of quality: reception; respect for individual rights; prenatal and childbirth care; and ambience. The results' significance was analyzed with the Pearson and Friedman chi-square test. There was high prenatal coverage, not linked to childbirth care, and intense migration of deliveries. Waiting time for care by the healthcare team was long, the proportion of vaginal deliveries in the municipal maternity services was 80%, and only 16% of the deliveries included skin-to-skin contact with the newborn; breastfeeding occurred in the birthing room in 11% of the deliveries. Among the various management modalities, the charitable hospital rated highest. The target dimension showed significant differences, with higher satisfaction rates for the following: respect (88.2%), kindness (86.7%), physicians' work (85.2%), and trust in the healthcare staff (84.3%). The highest rates of dissatisfaction were for: temperature on the ward (62.2%), possibility of lodging complaints (48.1%), quantity and quality of hospital clothing and bedding (49.2%), and privacy (43%). Despite positive strides, the findings show the need for reorganization of obstetric care policy, with regionalization, regulation, consolidation of networks of care, and interventions in the healthcare setting, aimed at consolidating the humanization of care. PMID- 29267695 TI - Perceived Stress Scale: confirmatory factor analysis of the PSS14 and PSS10 versions in two samples of pregnant women from the BRISA cohort. AB - This study aimed to assess the dimensional structure, reliability, convergent validity, discriminant validity, and scalability of the Perceived Stress Scale (PSS). The sample consisted of 1,447 pregnant women in Sao Luis (Maranhao State) and 1,400 in Ribeirao Preto (Sao Paulo State), Brazil. The 14 and 10-item versions of the scale were assessed using confirmatory factor analysis, using weighted least squares means and variance (WLSMV). In both cities, the two-factor models (positive factors, measuring resilience to stressful situations, and negative factors, measuring stressful situations) showed better fit than the single-factor models. The two-factor models for the complete (PSS14) and reduced scale (PSS10) showed good internal consistency (Cronbach's alpha >= 0.70). All the factor loadings were >= 0.50, except for items 8 and 12 of the negative dimension and item 13 of the positive dimension. The correlations between both dimensions of stress and psychological violence showed the expected magnitude (0.46-0.59), providing evidence of an adequate convergent construct validity. The correlations between the scales' positive and negative dimensions were around 0.74-0.78, less than 0.85, which suggests adequate discriminant validity. Extracted mean variance and scalability were slightly higher for PSS10 than for PSS14. The results were consistent in both cities. In conclusion, the single factor solution is not recommended for assessing stress in pregnant women. The reduced, 10-item two-factor scale appears to be more appropriate for measuring perceived stress in pregnant women. PMID- 29267696 TI - [Does time spent traveling to regional hub cities to receive healthcare influence mortality in small towns in Rio Grande do Sul State, Brazil?] AB - The current study aims to determine whether the time spent travelling to regional hub cities to receive healthcare affects mortality from avoidable causes and the standardized crude mortality rate in towns with up to 5,000 inhabitants in Rio Grande do Sul State, Brazil. Without adjusting for control variables, the longest time spent to reach cities with 100,000 inhabitants or more was associated with an increase in both rates. However, while the pattern in the avoidable mortality rate was similar after including controls, the standardized crude mortality rate reversed its signal. This suggests that if other socioeconomic and healthcare characteristics are kept constant, the distance to reference cities is associated with both a reduction in deaths from avoidable causes and an increase in other causes of death. PMID- 29267697 TI - Training activities at CSP: the rewarding experience with the internship program in science publishing in 2017. PMID- 29267698 TI - Learning the art of science publishing. PMID- 29267699 TI - Update and extension of the Brazil SimSmoke model to estimate the health impact of cigarette smoking by pregnant women in Brazil. AB - A previous application of the Brazil SimSmoke tobacco control policy simulation model was used to show the effect of policies implemented between 1989 and 2010 on smoking-attributable deaths (SADs). In this study, we updated and further validated the Brazil SimSmoke model to incorporate policies implemented since 2011 (e.g., a new tax structure with the purpose of increasing revenues/real prices). In addition, we extended the model to estimate smoking-attributable maternal and child health outcomes (MCHOs), such as placenta praevia, placental abruption, preterm birth, low birth weight, and sudden infant death syndrome, to show the role of tobacco control in achieving the Millennium Development Goals. Using data on population, births, smoking, policies, and prevalence of MCHOs, the model is used to assess the effect on both premature deaths and MCHOs of tobacco control policies implemented in Brazil in the last 25 years relative to a counterfactual of policies kept at 1989 levels. Smoking prevalence in Brazil has fallen by an additional 17% for males (16%-19%) and 19% for females (14%-24%) between 2011 and 2015. As a result of the policies implemented since 1989, 7.5 million (6.4-8.5) deaths among adults aged 18 years or older are projected to be averted by 2050. Current policies are also estimated to reduce a cumulative total of 0.9 million (0.4-2.4) adverse MCHOs by 2050. Our findings show the benefits of tobacco control in reducing both SADs and smoking-attributable MCHOs at population level. These benefits may be used to better inform policy makers in low and middle income countries about allocating resources towards tobacco control policies in this important area. PMID- 29267700 TI - EDITORIAL. PMID- 29267701 TI - Right to the city, right to health: what are the interconnections? AB - Right to health intertwines with right to the city: guaranteed access to healthy urban spaces reduces inequities among the population, so that disadvantaged groups can also enjoy positive urbanization effects. In this sense, interconnection between right to the city and right to health promotes equity. This article seeks to explore the interconnection between right to the city and right to health on the basis of an integrative review guided by the question 'What knowledge about right to the city and right to health has been produced in the light of equity?' For this purpose, we analyzed evidence available in the literature indexed in PubMed/Medline, Lilacs, and SciELO between 1986 and 2016. Over this three-decade span, we identified the presence of different degrees of right to the city and right to health in the formulation of policies and in social movement agendas. Formulations regarding population growth moved away from the rights agenda, but in a later phase of democratic consolidation, the fight for rights to health re-emerged. In a third moment of the political visibility of excluded geographical spaces and multiple identity agendas, the struggle to ensure everyone's right to the city came on strong in the game. PMID- 29267702 TI - The universalization of rights and the promotion of equity: the case of the health of the black population. AB - This article takes the field of "health of the black population" as an object to problematize some tensions and possibilities existing around the operationalization of the concepts of universality and equity in public policies and no debate about the right to the city. The question that mobilizes it is: how to articulate the search for the universalization of rights with demands mobilized by specific groups in an unequal society. In order to respond, to approve the debates and the resistances surrounding the institutionalization of the National Policy of Integral Health of the Black Population and its relation with the prerogatives of the Unified Health System. The result is a critique of the universalization/targeting and recognition/distribution and pointing to a dialectical approach. Categories that consider a mediation between singularity, particularity and universality. PMID- 29267703 TI - Legislative vulnerability of minority groups. AB - Minorities are in an inferior position in society and therefore vulnerable in many aspects. This study analyzes legislative vulnerability and aims to categorize as "weak" or "strong" the protection conferred by law to the following minorities: elderly, disabled, LGBT, Indians, women, children/ adolescents and black people. In order to do so, it was developed a documental research in 30 federal laws in which legal provisions were searched to protect minorities. Next, the articles were organized in the following categories: civil, criminal, administrative, labor and procedural, to be analyzed afterwards. Legal protection was considered "strong" when there were legal provisions that observed the five categories and "weak" when it did not meet this criterion. It was noted that six groups have "strong" legislative protection, which elides the assertion that minorities are outside the law. The exception is the LGBT group, whose legislative protection is weak. In addition, consecrating rights through laws strengthens the institutional channels for minorities to demand their rights. Finally, it was observed that the legislative protection granted tominorities is not homogeneous but rather discriminatory, and there is an interference by the majority group in the rights regulation of vulnerable groups. PMID- 29267704 TI - The right to the city and International Urban Agendas: a document analysis. AB - Considering social, economic and demographic issues, living in the city implies inadequate living conditions, social exclusion, inequities and other problems to the population. At the same time, the city is a setting of cultural, social and affective production. As a result, there is a need to reflect on the right to the city and its relationship with promoting the health of its inhabitants. To that effect, urban agendas have been developed to address the city's ambiguity. This paper aims to analyze four of these agendas through the lenses of Health Promotion. A qualitative document review approach was conducted on urban agendas proposed by international organizations and applied to the Brazilian context: Healthy Cities, Sustainable Cities, Smart Cities and Educating Cities. Results indicate some level of effort by the analyzed agendas to assume social participation, intersectoriality and the territory as central to addressing exclusion and inequities. However, more in-depth discussions are required on each of these concepts. We conclude that urban agendas can contribute greatly toward consolidating the right to the city, provided that their underpinning concepts are critically comprehended. PMID- 29267705 TI - Who are they, what do they talk about and who listens to the poor? AB - The right to a dignified life for all requires overcoming the challenges imposed on the most vulnerable groups, and poverty is one of the oldest and most devastating phenomena. Listening to them is essential to create remediating opportunities. This study aims to identify characteristics of this listening in the context of health promotion and the Sustainable Development Goals - SDGs, an international effort to support the fight against poverty, among others. In an integrative review of literature, conducted through the search terms of Poverty, Right to the City, Equity Policy and Identification of Poverty, 86 studies that listened to vulnerable groups, such as women, children, adolescents, adults, the elderly, families and drug users, all poor and low-skilled workers were analyzed. Each strategy shown was related to one or more SDGs. The recurrent strategies in the studies analyzed were increased social protection and spaces to listen to vulnerable groups, as well as public policies that enabled the fight against poverty. Equity must be thought of in the context of comprehensive and universalizing rights policies, overcoming fragmented and focal policies that fail to address the structural causes of poverty and human exploitation. PMID- 29267706 TI - Photovoice as a listening mode: subsidies for the promotion of equity. AB - Health Promotion observations of patients from a Rehabilitation Center in rural Sao Paulo evidenced that these people faced difficulties in dealing with their physical limitations when these prevented them from working. This study aimed to broaden listening methods to facilitate dialogue with people in situations of physical frailty and removal from their work activities, using Photovoice, a participatory research-action method, as a tool and Health Promotion's theoretical framework. Images captured and reports that accompanied them consisted of the material of this study. Two thematic categories stood out: the expert decision; and physical condition: vanity, power and hope. Labor activity is perceived as a determinant of individuals' introduction in their environment and defines their role in the family and in the social field. Faced with disability, they feel deprived of their identity, vulnerable and without future prospects of social reintegration, an individual and familiar misfit process, but without social visibility and with negative consequences for global health is observed. Photovoice proved to be effective in apprehending perceptions and stimulating debate, providing essential inputs to promote equity in socially disadvantaged groups. PMID- 29267707 TI - Healthier Saire: a intersectorial policy as a turning point for local equity. AB - Public health studies see intersectoriality as a strategy to promote equity in addressing the social determinants of health. The municipality of Saire, a member of the Healthy Pernambuco Municipalities Network (RPMS), stands out for its adoption of an intersectorial policy, named A Healthier Saire. This present study examines how this policy has promoted local equity. It was a case study using a timeline to record critical events, analysis of documents, interviews and participant observation. Actor-Network Theory (ANT) was used as a theoretical reference, and showed how adoption of the municipal policy had been central in promoting local empowerment and equity. The results, based on the timeline, demonstrate that initially it was necessary to obtain a cognitive translation, conducted through the direct influence and responsibility of the RPMS, which facilitated a second, strategic translation, with the construction of a policy anchored on the municipal program - which is currently being translated logistically into concrete actions directed towards equity. Key factors in this process for promoting local equity were: the role of strategic leadership; the value given to training; and the retention and use of structures that had previously been built. PMID- 29267708 TI - Health Academies Program and the promotion of physical activity in the city: the experience of Belo Horizonte, Minas Gerais state, Brazil. AB - The objectives of this study were to describe the history and evaluation methodology of the Brazilian Health Academy Program (PAS) in Belo Horizonte, MG and discuss it as an experience of health promotion and equity. Data from 4,048 non-users (2008-09) and 402 users (2014-15) were analyzed from two cross sectional surveys. Socio-demographic profile and level of physical activity were described for both groups. Social interaction, satisfaction with life, quality of life, and social organization in the neighborhood were compared between < 3 and >= 3 monthly minimum wages income and conducted only for women aged 40 years and older . Chi-square test of Person was performed (p <= 0.05). Prevalence of leisure-time physical activity among non-users was of 30.2% and users of 53.7%. Better perception of quality of life, positive satisfaction with life, greater social interactions and participation in the neighborhood were observed among women with higher income compared to their counterparts (p < 0.001). In turn, for all evaluated constructs, users reported better perception of the lower income group. The PAS has opportunized physical activity to the vulnerable population and seems to act on other outcomes besides the lifestyle. PMID- 29267709 TI - Evaluation matrix for health promotion programs in socially vulnerable territories. AB - Health promotion has a set of strategies for advancing health and reducing inequalities. However, evaluating the effectiveness of health promotion programs has been a challenge. This paper shows the development and application of the Evaluation Matrix, constructed with qualitative-quantitative and multidimensional indicators supported by public policies targeting socially vulnerable territories. This is a cross-sectional study with the implementation of a health promotion program in order to develop an Evaluation Matrix to be applied in two distinct socio-environmentally vulnerable areas. The Evaluation Matrix proved to be easily applicable and enabled the detection of strengths and weaknesses of health promotion programs applied in different territories. The participation of managers, teams, population and multiple sectors of society was decisive for the success of the program. Furthermore, community health workers stood out as essential stakeholders due to their linkages with the population. Contributions include a tool and methodology for evaluating health promotion programs to be applied in different territories and modified according to the territory. PMID- 29267710 TI - [Socio-environmental vulnerability index: a methodological proposal based on the case of Rio de Janeiro, Brazil]. AB - The term vulnerability has been more frequently used in several studies, striving to better understand the specificities and needs of different population groups. The scope of this study was to identify, characterize and analyze populations in situations of socio-environmental vulnerability in Rio de Janeiro city, consolidating social, economic, environmental, health and public security indicators in a synthesis index - the Socio-Environmental Vulnerability Index. The data sources used were the IBGE-2010 Demographic Census, the Geo-Rio Foundation and the Public Security Institute of the state of Rio de Janeiro. The methodology integrated Multicriteria Decision Analysis into a Geographic Information System. According to our results, the socio-environmental vulnerability in Rio de Janeiro city is aggravated by risk situations and environmental degradation. Those aspects are accentuated by the population density in shantytown areas, where the most disadvantaged strata exist in a process of environmental and urban exclusion. The study makes it possible to locate spatially vulnerable areas, emphasizing the importance of these tools to guide resource allocation, formulation and implementation of more effective public policies. PMID- 29267711 TI - Participatory diagnosis to identify health problems in a socially vulnerable community. AB - The Health Promotion paradigm led to the acknowledgment of health due to factors linked to the social, political and economic contexts. In Brazil, health inequities are one of the most striking features of the health situation, challenging the effectiveness of intersectoral policies. This study aimed to understand the perception of socially vulnerable community dwellers of the problems that interfere with the health conditions and the coping strategies used. The methodology consisted of a participatory research based on the participatory diagnosis conducted with 31 key informants from the community studied in Fortaleza, Ceara, Brazil. As a result, participants evidenced that the community has health issues due to weak intersectoral actions (infrastructure, public safety, basic sanitation, garbage collection, among others) and that they seek to address them through social mobilization actions and institutional support. Thus, Participatory Diagnosis is thought to increase social involvement with health promotion and problem solving and contributes to ensuring the right to the city to all its residents. PMID- 29267712 TI - Participatory construction of the State Health Promotion Policy: a case from Minas Gerais, Brazil. AB - Minas Gerais started the development of the Minas Gerais Health Promotion Policy (POEPS-MG) based on the review of the National Health Promotion Policy (PNPS). This is a case report based on the documentary analysis of the material produced in the 38 workshops with a participation of 1.157 members across the State. The first workshop was intrasectoral and took place at the State Health Secretariat (SDH-MG). The second was an intersectoral workshop with the participation of several State Health Secretariats of Minas Gerais. The final workshop counted on the participation of State Regional Technical References. Another 35 workshops were developed in the 28 State Regional Administrations. Results were systematized and consolidated from the Analytical Matrix used in the PNPS, generating the base document of the POEPS-MG. It is important to highlight that, the specific regional requirements identified during the Policy's construction process reinforce the enriching moments of developing in an innovative, democratic and participative way actions that may provide some meanings to Health Promotion in the State of Minas Gerais. The State Policy seeks to bring life to the PNPS, adapting it to the reality of the territory and strengthening it - with the assurance of budgetary resources. PMID- 29267713 TI - Social participation in Primary Health Care towards the 2030 Agenda. AB - Listening to society is an ethical reference to respond to its legitimate needs and aspirations. Considering as presuppositions the social participation and the right to the city, which are part of the 2030 Agenda, this study sought to recognize the voice of users that evaluated PHC services and their attributes. This descriptive and cross-sectional study used national ministerial evaluation data, outlining a region with 323 teams in 80 municipalities in the state of Sao Paulo and 1,272 users heard by authors. Users were mostly female, over 51 years old, with low income and schooling, eliciting challenges to population aging and selective care. Around 93% were 20 minutes away from health services and opening on Saturdays (43%) and at night (38%) would facilitate access. Some 60% were received without scheduling and 62% did not consider services prepared for urgent care. Some 85% received Community Health Workers and 40% other professionals, suggesting disparities in the incorporation of the territory to the care production process. In line with National Primary Health Care Policy and what is recommended by international conferences, social participation was recognized as a way to address the multiple aspects in the construction of universal health. PMID- 29267714 TI - Reflecting on twenty years of Masculinities: an interview with Raewyn Connell. AB - Raewyn Connell is very well known for her work on social theory and gender studies, and more specifically on masculinities. She was one of the founders of masculinities research and her 1995 book Masculinities is considered one of the most important references on the topic. Connell's concept of hegemonic masculinity has been particularly influential and has attracted much debate. She has written extensively about its applications to education, health, and violence prevention. Our conversation was about her trajectory as an intellectual, her commitment to gender justice, and the development of her work from Australia to the global scale. PMID- 29267715 TI - Pendulum migration and healthcare in border area. AB - This article aims to reflect about the importance and the potential impact of pendulum migration in the pursuance for healthcare, and, specifically, about the peculiarity of this kind of mobility in border areas. It describes the context in which the pendulum migration is inserted for the modification of the urban space in the 20th century, makes initial comments about legal aspects of the theme in health sector, and describes the reality of the Brazil-Argentina-Paraguay triple border as an important location of pendulum migration for the pursuance of healthcare as an illustrative fact. In this way, hypotheses are formulated about the causes of the pendulum migration impact on patient's health like the effect of the distance covered from home to healthcare facilities, and organizational aspects related to healthcare like the uncertainty about having or not health assistance due to international mobility. It concludes that this kind of mobility is very common in the pursuance of healthcare despite the traditional approach to the theme mentioning only work or study. Besides that, it is very important to study its impact on health and to include this theme on the cross border healthcare debate. PMID- 29267716 TI - [Interdisciplinarity as a strategy for the prevention of systemic arterial hypertension in children: a systematic review]. AB - Researches that developed interdisciplinary actions in schools seeking to modify the arteial pressure levels or salt and/or sodium consumption by children were analyzed. Studies available on the PubMed, ScienceDirect and Lilacs databases, associating the keywords: intervention study, nutrition intervention, schoolchildren, school health, blood pressure, sodium and salt were included. The research included articles from the last 15 years, in Portuguese, English and Spanish, which had preschool or school children as participants. With respect to the change of the blood pressure levels, 7 studies with positive and significant results and 6 without variation were identified. In terms of modification of the ingestion of food with high salt and/or sodium content, 4 studies revealed positive and significant results, and only one was unsuccessful. The conclusions drawn are that the interventions that use nutritional education combined with physical activities prevail in the literature. However, these actions proved to be more effective when implemented over a long period of time. PMID- 29267717 TI - IgM ELISA for leptospirosis diagnosis: a systematic review and meta-analysis. AB - A systematic review with meta-analysis was performed to estimate the accuracy of IgM ELISA for Leptospirosis diagnosis. A search of Medline, Lilacs, Embase, Cochrane Central Register of Controlled Trials and Grey literature (Google Scholar and British Library) was conducted. The medical subject headings (MeSHs) and the words "leptospirosis", "human leptospirosis" and "IgM ELISA" were used. Fifty-two studies were analyzed, which included 10,775 samples. The pooled sensitivity of all the studies was 86% (CI 95%, 85%-87%) and specificity was 90% (CI 95%, 89%-91%). In studies of the acute phase, the sensitivity and specificity were 84% (CI 95%, 82%-85%) and 91% (CI 95%, 90%-91%), respectively. In conclusion, IgM ELISA is sensitive for use as an initial screen for leptospiral infections. PMID- 29267718 TI - [Alcohol consumption and physical violence among adolescents: which is the predictor?] AB - The scope of this integrative review was to investigate the association between alcohol consumption and physical violence in the literature, with an emphasis on identifying the predictor between them. A search was conducted in the Lilacs, Medline and SciELO databases, adopting "violence," "alcohool drinking" and "adolescent" as descriptors. It included articles published between 2005 and 2014 that analyzed the association between alcohol consumption and physical violence using multivariate analysis. Of the total of 1667 articles located, 29 met the inclusion criteria. Alcohol consumption was investigated more as a predictor of involvement in physical violence when the teenager is the perpetrator or the victim of violence, with a significant association found in 19 studies. However, when victimization was investigated as a predictor (7 studies), most of these (6) revealed no significant association with the intake of alcoholic beverages. The consumption of alcohol has proven to be the predictor of physical violence for both the teen perpetrator and for the adolescent victim of violence. However, having been the victim of violence in childhood and adolescence may also lead adolescents to alcohol consumption. PMID- 29267719 TI - Race/skin color and mental health disorders in Brazil: a systematic review of the literature. AB - : Mental health disorders contribute a significant burden to society. This systematic literature review aims to summarize the current state of the literature on race/skin color and mental health disorders in Brazil. METHODS: PubMed and Lilacs were searched using descriptors for mental health disorders (depression, anxiety, Common Mental Disorders, psychiatric morbidity, etc.) and race to find studies conducted in Brazil. Studies of non-population groups, that did not analyze race/skin color, or for which the mental disorder was not the object of study were excluded. After evaluation of quality, 14 articles were selected for inclusion. There was an overall higher prevalence of mental health disorders in non-Whites. Of the six multivariate analyses that found statistically significant results, five indicated a greater prevalence or odds of mental health disorder in non-Whites compared to Whites (measure of association between 1.18-1.85). This review identified the trend in the literature regarding the association between race and mental health disorders. However, important difficulties complicate the comparability of the studies, principally in function of the differences in the mental health disorders studied, the method of categorizing race/skin color, and the screening tools used in the studies analyzed. PMID- 29267720 TI - [Lesbian reproductive practices: reflections on genetics and health]. AB - The relationship between science, technology and capital, which are intrinsic to Reproductive Technologies (RT), makes them a possibility of reproductive choice and an alternative for lesbians who wish to have children. The article seeks to reflect on the projects formulated based on the statements of lesbian couples who had used or had plans to use RT. Interviews were conducted with eight couples of women with ages between 26 and 45, all self-declared Caucasians, who had completed higher education and were living in the Greater Sao Paulo region between 2010 and 2011. The results reveal the preference of the respondents for donor sperm originating from a sperm bank and also the importance placed on information on the family history of health of the donor. A noteworthy finding is the interest in importing from an American sperm bank, because of an alleged limited availability of samples in Brazil and the fact that they provide more information about the donors. Thus, while RT enable non-biological parenting, genetics is considered important thereby contributing to the medicalization of parenthood. PMID- 29267721 TI - Risk and protective factors for chronic diseases in adults: a population-based study. AB - The article describes the relative frequency ok of risk and protective behaviors for chronic non-communicable diseases (NCDs) in adults residing in Vicosa, Brazil. A cross-section-al population-based study including 1,226 adults living in the municipality. We used a structured questionnaire containing questions sociodemographic and behavioral The risk and protection factors evaluated were: smoking, physical activity, excessive consumption of alcohol and food consumption. The proportion of risk and protection factors was calculated in the total population, according to gender, education and socioeconomic status. The studied population has a high frequency of risk factors for NCDs, such as excessive consumption of alcoholic beverages, habit of consuming whole milk, habit of eating meat with visible fat, regular consumption of soft drinks and 78.5% did not achieve the minimum recommendation for physical activity in leisure time. With regard to protective factors, 86.2% of the population reported regular consumption of fruits and vegetables, and 73%, of beans. It was found the highest frequency of risk factors in among males, in younger people and middle socioeconomic status. This population has an urgent need for public policy of municipal planning to change this current scenario. PMID- 29267722 TI - Overweight and obesity are not associated to high blood pressure in young people sport practitioners. AB - The aim of this study was to analyze the association between overweight and obesity with high blood pressure (HBP) according to sports practice in young people. Took part in this study 636 young people aged 10 to 17 years of Londrina, Parana State, Brazil. Sex, age, parental education, sedentary behavior, sports practice, nutritional status and blood pressure were analysed. Poisson regression was used to estimate the prevalence ratio (PR) and 95% confidence intervals. Overweight and obesity young people showed higher prevalence of HBP compared to eutrophics when analysed the total sample (25,7 e 29,5 vs 15,2%) and non sport practitioners (29,7 e 33,3 vs 15,1%), which did not occur with sports practitioners (17,1 e 18,2 vs 15,5%). Positive associations were found between overweight and obesity with HBP in total sample (PR = 1,60, 1,02-2,52 and 1,93, 1,15-3,25) and on non sport practitioners (RP = 1,80, 1,05-3,14 and 2,15, 1,10 4,16). For young people sports practitioners were not found associations between overweight and obesity with HBP (PR = 1,01, 0,36-2,82 and 1,09, 0,48-2,48). Weight excess was not associated with HBP in young people sports practitioners, suggesting cardiovascular protection in young people with overweight and obesity. PMID- 29267723 TI - Sedentary behavior based on screen time: prevalence and associated sociodemographic factors in adolescents. AB - The aim of this study to estimate the prevalence of sedentary behavior based on screen time (>= 2-hour day) and to identify the association with sociodemographic factors among adolescents in a city in southern Brazil. This is an epidemiological survey of school-based cross-sectional study with students aged 14-19 years in the city of Sao Jose/SC - Brazil. Self-administered questionnaire was used, containing information sociodemographic, level of physical activity and about screen time. Descriptive statistics were performed, and odds ratios were estimated using binary logistic regression and 95% confidence level. The prevalence of excess screen time was 86.37% followed by computer use (55.24%), TV use (51.56%) and Videogame use (15.35%). Boys had higher prevalence of excessive video game use. Those of skin color different from white and mothers who studied less than eight years were more likely to watch too much TV, and those of low economic level were more likely of having excessive screen time. Girls of skin color different from white were more likely to watch too much TV, and those aged 14-16 years were more likely to have videogame use time and total time screen above recommended. PMID- 29267724 TI - Women's knowledge of methods for secondary prevention of breast cancer. AB - The objective of this study was to evaluate women's knowledge of methods for screening breast cancer. The study was done on a population of women aged 18 or over in the city of Rio Grande between April and November 2011. Interviewers used questionnaires on all of the women at selected households. Models were developed for every type of screening (self-examination of breasts, mammography, and clinical exams) that were analyzed through the use of Poisson regression. Out of the 1596 women interviewed, 1355 reported self-examination, 456, mammography, and only 191, clinical examination of the breast, performed by a health professional, as important for the prevention of breast cancer. White women with 11 years or more worth of schooling had a greater probability of having mammography exams and clinical examinations as methods for screening. We noted, linked to the aforementioned, that there was a linear tendency whereby there was a greater probability for those with high incomes to undergo one of the above interventions. The study noted that there was a need for more detailed information aimed at the population on prevention methods in order to avoid late diagnosis. We noted that non-white women with little education and on low incomes showed less knowledge of clinical examination methods and mammographies. PMID- 29267725 TI - Impact of first sexual intercourse on the sexual and reproductive life of young people in a capital city of the Brazilian Northeast. AB - This study aimed to analyze the repercussion of first sexual intercourse on the number of pregnancies and partners of teenagers with obstetric history in Teresina (PI), Brazil. This is a cross-sectional study with 464 young women selected by accidental sampling who gave birth at 15-19 years of age in the first four months of 2006 in six maternity hospitals of the municipality. Primary data was collected from May to December 2008 at the participants' homes after tracking them in the hospital medical records. The univariate and bivariate analysis were performed by descriptive statistics and Pearson's Correlation Coefficient Test or T-test, respectively. Tukey's post hoc test was used as post hoc test and significant variables on the bivariate analysis (p < 0.05) were also included in the multifactor analysis of variance model. Schooling (p < 0,001) and menarche's age (p < 0,001) influenced the age of first sexual intercourse and this, in turn, showed significant negative correlation (p < 0.01) with the number of partners and pregnancies of young women. Thus, the earlier the young women start sexual activity, the higher the number of pregnancies and sexual partners until the moment of their reproductive life. Thus, early first sexual intercourse had a negative repercussion on these variables. PMID- 29267726 TI - Factors associated with tuberculosis retreatment in priority districts of Maranhao, Brazil. AB - This study investigated factors associated with cases of tuberculosis retreatment due to relapse and readmission after treatment abandonment. This is an analytical cross-sectional study type of cases reported in the Information System for Notifiable Diseases in priority municipalities in the State of Maranhao, from January 2005 to December 2010. A logistic regression model was used to identify the association. Patients aged between 40 and 59 years (OR = 1.49, p = 0.029) with a pulmonary clinical form (OR = 2.79, p = 0.016) were more likely to incur relapse. Readmissions after abandonment were more likely in males (OR = 1.53, p = 0.046), aged between 20 and 39 years (OR = 1.65, p = 0.007), with less than eight years of schooling (OR = 2.01, p = 0.037) and with alcohol dependence (OR=1.66, p = 0.037), which showed a higher probability of another abandonment (OR = 5.96, p < 0.001). These data reinforce the need for strategies aimed at this group, such as increased supervised treatment, intensified active search, post-discharge follow-up and health education action. PMID- 29267727 TI - [Hospitalization for infectious diseases, parasitism and nutritional evolution of children attended in public child day care centers]. AB - The scope of this article is to analyze the influence of hospitalizations by infectious diseases (diarrhea and pneumonia) and parasitism in nutritional evolution, over the period of a year, among children enrolled in municipal public day care centers. Mothers of children in a cohort were asked about previous hospitalization due to diarrhea and pneumonia, as well as in relation to the elimination of worms, during the period of one year of attendance at day care centers. Anthropometrics were measured at each visit. An adjusted model to examine the relationship between infections experienced and growth outcomes (weight and height) was applied. In a subset analysis of 269 children followed up at every visit over the course of 12 months, hospitalization due to pneumonia and parasite infection were associated with decelerated growth in weight and height. Parasitic infection and pneumonia were associated with growth impairment in terms of weight and height. PMID- 29267728 TI - [Anthropometric indicators as predictors in determining frailty in elderly people]. AB - The scope of this article is to analyze anthropometric indicators as predictors in determining frailty in elderly people. This is a cross-sectional, family-based and analytical study. The survey was composed of 316 elderly subjects. The association between the anthropometric markers and frailty was tested using the Logistic Regression technique. However, the power of frailty diagnosis using anthropometric markers and the identification of the best cutoff points were evaluated using the parameters provided by the Receiver Operating Characteristic (ROC) curve. The anthropometric indicators of nutritional status: calf circumference, body mass index and corrected arm-muscle area are inversely associated with frailty. Thus, an increase in the values of these indicators is a protective factor against this syndrome. Analyzing body mass index and calf circumference simultaneously in order to perform a simpler screening for frail elderly people is recommended, as these indicators show good sensitivity and are easier to measure. PMID- 29267729 TI - Distribution of pulmonary tuberculosis in Rio de Janeiro (Brazil): a spatial analysis. AB - The aim of this study was to analyze the spatial distribution of the tuberculosis endemic in Rio de Janeiro State from 2002 to 2011. A retrospective study was conducted in the state of Rio de Janeiro from 2002 to 2011. Spatial analysis techniques were used to describe the distribution of tuberculosis incidence in the state. Multilevel Poisson regression model was used to access the relationship of tuberculosis and the following factors: "sex", "age-group" and "diagnostic year" (individual-level factors). Demographic density and municipality were also included in the model as contextual-level factors. A reduction in endemic tuberculosis was observed over the years. The highest incidence rates were concentrated on the south coast of the state, covering Rio de Janeiro City (capital) and neighboring cities. We detected a significant clustering of high TB incidence rates on the south coast of the state and a cluster of low incidence in the northeastern region of state. The risk of tuberculosis was higher in early 2000s, in males and in 40-59 age group. Metropolitan regions are important risk areas for the spread of tuberculosis. These findings could be used to plan control measures according to the characteristics of each region. PMID- 29267730 TI - [The use of dental services on a regular basis in the population of Montes Claros in the State of Minas Gerais, Brazil]. AB - The use of dental services on a regular basis by residents of Montes Claros (MG) was assessed, as well as related aspects. Cross-sectional study was conducted with a complex probabilistic sample by conglomerates. Logistic regression was used (OR/CI95%) with a significance level of 5. Of the 2582 study participants, 761 required and obtained access to the services for less than a year. Of these, 262 (35.8%) used the services in a regular/routine manner. The use of dental services on a regular basis was greatest among individuals in the age group ">= 18 <= 37"; with schooling "equal to or greater than 9 years"; who classified their oral health, general health and appearance of teeth and gums as "excellent/good"; who reported no pain" on teeth and gums over the last six months; They reported that the "assistance provider had adequate skills"; that they "always/often" received information about oral hygiene and diet/nutrition. In addition, this use was lower among those who rated the time to ask questions about the dental problem or treatment as "regular/bad/terrible." The conclusion drawn is that the use of dental services on a regular basis was relatively low, being associated with personal traits, subjective health conditions and characteristics related to the services. PMID- 29267731 TI - Construction and validation of educational video for the guidance of parents of children regarding clean intermittent catheterization. AB - OBJECTIVE: To construct and validate an educational video for the guidance of parents of children who require clean intermittent catheterization. METHOD: Methodological study, developed in two stages: construction and validation of the video was performed by experienced judges from March to December 2016. The construction of the technology had the Theory of Adaptation as theoretical reference. For the data analysis, the intraclass correlation index was used. RESULTS: The first version of the video was 12 minutes, after validation the replacement of technical terms by colloquial language, dynamism in dialogues and the mention of handwashing before assembling the material was recommended. With regard to total reliability, the intraclass correlation coefficient for all the categories evaluated was 0.768, considered reasonable. In the evaluation of language clarity, relevance to practice and theoretical relevance, the results were 0.745, 0.771 and 0.777, respectively, considered reasonable, with p<0.0001. CONCLUSION: The educational video was valid regarding appearance and content, with potential to mediate educational practices in hospital and outpatient settings. PMID- 29267732 TI - Impact of urinary incontinence types on women's quality of life. AB - OBJECTIVE: To identify the most frequent type of urinary incontinence in women assisted in two outpatient clinics of urogynecology, and to compare general and specific quality of life among the different types of incontinence measured through validated questionnaires. METHOD: Cross-sectional study conducted at the urogynecology outpatient clinic. The following questionnaires were used for quality of life assessment: Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), International Consultation Incontinence Questionnaire Short-Form (ICIQ-SF), King's Health Questionnaire (KHQ), and Pelvic Organ Prolapse Incontinence Sexual Questionnaire (PISQ-12). RESULTS: The study included 556 women. Mixed Urinary Incontinence was the most frequent type (n=348/62.6%), followed by Stress Urinary Incontinence (n=173/31.1%) and Urge Urinary Incontinence (n=35/6.3%). Women with mixed urinary incontinence had greater impact on the general (SF-36) and specific quality of life (KHQ and ICIQ-SF) compared to the others (p<0.05). In the evaluation of sexual function (PISQ-12), there was no difference between groups (p=0.28). CONCLUSION: All types of urinary incontinence interfere both in the general and specific quality of life, but women with mixed urinary incontinence are the most affected. PMID- 29267733 TI - The behavior of practicing sports among nursing students. AB - OBJECTIVE: Analyzing the frequency patterns of practicing sports, the stages of change phases and the pros and cons of decision-making balance in nursing students related to gender and which year of study they are in. METHOD: A cross sectional, descriptive and exploratory study. RESULTS: 535 students of both genders participated in the study. An analysis of the results revealed that 27.6% of the students did not present any frequency of practicing sports; 55.3% of the students did not have a consistent or continuous habit of practicing sports; students overall exhibited a non-existing frequency of practicing sports at similar levels throughout the study cycle; male students presented similar percentages in their positioning in the precontemplation and contemplation stages throughout the study cycle; and throughout all the stages of change phases students showed higher values for pros over cons related to practicing sports. CONCLUSION: The results reinforce the relevance for implementing mechanisms for promoting and monitoring nursing students' involvement and regular participation in practicing sports. PMID- 29267734 TI - Characterization of hygiene habits and environments in children's care homes. AB - OBJECTIVE: Identify the hygiene habits of children and caregivers in order to prevent and control infectious diseases in care environments in Bogota, Colombia, as well as characterize the surface bacteria in these environments. METHOD: Instruments were designed, validated and applied to evaluate healthy habits, with samples taken from surfaces in kitchens, bathrooms, halls, mats, and tools in 230 locations. Th e isolated bacteria were classifi ed using automated methodologies. RESULTS: A total of 699 bacteria were isolated, with the largest growth percentage found in kitchens (36%). Th ese results are contrary to what was observed, where most of the kitchens appeared to be clean. In the survey, 93% of the caregivers reported washing their hands before handling food, and 23% said they used personal protection items when handling food. CONCLUSION: There is a need for monitoring and interventions in hygiene and care habits in environments that care for children. PMID- 29267735 TI - Organizational barriers to the availability and insertion of intrauterine devices in Primary Health Care Services. AB - OBJECTIVE: To identify organizational barriers to IUD availability in Primary Health Care services from the perspective of women's health coordinators. METHOD: This is a quantitative study carried out with women's health officials from the municipalities of the southern macro region of Minas Gerais, Brazil, with an on line completion of a structured instrument and a descriptive data analysis. RESULTS: 79 technicians participated in the study. Among the municipalities, 15.2% do not provide IUDs and 8.3% do not refer women to other services, 53.7% do not provide IUDs at basic health units. Among those who provide the IUD, 68.7% do not have a specific protocol and 10.5% do not adopt pregnancy as a condition that makes it impossible to insert the IUD, and 80.6% adopt unnecessary conditions, such as vaginal infection. As a criterion for IUD access, 86.5% referred to a medical prescription, 71.6% required exams, 44.6% were over 18 years of age and 24.4% participation in groups, none based on scientific evidence. Only the doctor inserted the IUD. CONCLUSION: Problems in the access to the IUD were identified due to organizational barriers to its availability and insertion, such as the lack of availability of the method or the excess of unnecessary criteria to make it available. PMID- 29267736 TI - Quality of the leader-member relationship and the organizational commitment of nurses. AB - OBJECTIVE: To understand the perception of the quality of leadership relationships and the organizational commitment of nurses, and to analyze the influence of this relationship quality. METHOD: Cross-sectional and correlational study, with a quantitative approach, using a non-probability convenience sampling with 408 nurses. The data were collected through questionnaires at Central Hospital in Lisbon, between January and March 2013. The statistical analysis of the data was carried out using IBM(r) SPSS(r) Statistics 19 software. RESULTS: Three hundred forty-two questionnaires were considered valid. The quality of the leadership relationship was satisfactory, and the nurses were poorly committed to the organization. The quality of the leadership relationship was statistically correlated with organizational commitment: there was found a moderate association to affective commitment (rs=0.42, p<0.05), a low association with the normative commitment (rs=0.37, p<0.05), and a very low association with the calculative commitment (rs=0.14, p<0.05). CONCLUSION: Leadership exerts influence on organizational commitment. An opportunity to improve the quality of the leadership relationship between nurses and their leaders was found, with the consequent possibility of developing organizational commitment. PMID- 29267737 TI - Adherence to self-care practices and empowerment of people with diabetes mellitus: a randomized clinical trial. AB - OBJECTIVE: To evaluate adherence to self-care and glycemic control and empowerment of people with diabetes mellitus in group education. METHOD: Cluster randomized clinical trial, with participants with type 2 diabetes mellitus. All people in the sample were linked to Family Health Strategy Units from Divinopolis, state of Minas Gerais, Brazil, during 2014 and 2015. Data regarding adherence to self-care practices, empowerment and glycated hemoglobin were collected for comparison of groups in the baseline and of intergroup results before and after interventions. The chosen level of significance was 0.05. RESULTS: The sample had 183 people, with 72 in the intervention group and 111 in the control group. A statistically significant decrease (< 0.001) in the value of glycated hemoglobin and an increase in the scores of adherence to self-care and empowerment scales were found for participants in the intervention group (< 0.001). CONCLUSION: Group education caused an increase in the scores of the scales of adherence to self-care practices and empowerment, in addition to an improvement in glycemic levels, as shown by glycated hemoglobin results. Brazilian Registry of Clinical Trials: RBR-92j38t. PMID- 29267738 TI - Evaluation of the directly observed therapy for treating tuberculosis according to the dimensions of policy transfer. AB - OBJECTIVE: To evaluate the directly observed therapy for treating tuberculosis in the Primary Health Care Service according to the dimensions of policy transfer. METHOD: Descriptive study, conducted with professionals from Basic Health Units in the city of Sao Paulo, SP state. The interviews were conducted from May to July/2016, using a validated, self-administered instrument with 39 items on a five-point Likert scale. The variables were organized in the dimensions: information, knowledge and innovation. The mean of the responses was calculated: the means between four and five were classified as adequate, between two and a half and three and a half as fair, and between one and two as inadequate. RESULTS: 112 health professionals participated in the study. In the dimension of information, participation of the community in the treatment was considered fair. In the dimension of knowledge, the treatment routine in the unit and the participation of the professionals in trainings were classified as fair. In the dimension of innovation, the unit infrastructure, the use of community resources and the creation of strategies to promote patient adherence were evaluated as fair. The other variables were adequate. CONCLUSION: The transfer of the directly observed therapy for treating tuberculosis in the Primary Health Care assessed has been occurring gradually and successfully. PMID- 29267739 TI - Medication incidents in an outpatient emergency service: documental analysis. AB - OBJECTIVE: To characterize medication incidents occurred in an outpatient emergency service. METHOD: Descriptive, documental, retrospective and quantitative research. The International Classification for Patient Safety was the theoretical reference for the construction of the instrument used to collect and analyze the data from 119 notification and investigation forms of incidents occurred in 2014 in a teaching hospital. Data were collected twice, compared, corrected and transcribed to an Excel worksheet. The SPSS 19.0 Software and the non-parametric Mann-Whitney test were used in the analysis; p<0.05 indicated statistical significance. RESULTS: A total of 142 incidents were analyzed, most of them involving the nursing team; 93.7% were avoidable; one-third involved high alert medications; the majority involved parenteral administration. Harm was rare but proportional to the time elapsed for error detection. Management failures prevailed, especially omission. CONCLUSION: Most of the incidents analyzed were characterized as potentially harmful and avoidable, with emphasis on personnel factors as contributors. PMID- 29267740 TI - Factors associated with HIV prevalence in a prison population. AB - OBJECTIVE: To analyze HIV prevalence and associated factors in inmates in a prison in a state in the Northeast region of Brazil. METHOD: Epidemiological, cross-sectional study carried out with prisoners. Interviews were conducted using a form and a rapid test for the diagnosis. Bivariate and multivariate hypothesis testing, with a simple logistic ratio (unadjusted odds ratio) and multiple ratio (adjusted odds ratio) were applied. Significance level was set at p<=0.05. RESULTS: A total of 2,131 inmates participated in the study. The HIV prevalence was 1.0%. Seropositive individuals were mostly Afro-American; their marital status was predominantly single/separated/widower. The mean age was of 31.3 years, and the mean educational level was 6.29 years. There was a link between the HIV virus and the variables: selection of partners based on physical attributes and vaginal sexual intercourse. CONCLUSION: Tackling the HIV infection represents a major challenge for prison and sanitary authorities, considering that the issues related to the HIV context inside and outside the prison environment are interconnected and, therefore, demands coordinated action. PMID- 29267741 TI - Motivational interviewing in the social support of caregivers of patients with breast cancer in chemotherapy. AB - OBJECTIVE: To evaluate the effects of motivational interviewing for the change of social support behavior of caregivers of breast cancer patients in chemotherapy. METHOD: A quasi-experimental study conducted with women in chemotherapy for breast cancer and their respective caregivers. The intervention of Brief Motivational Interviewing was applied to the caregivers indicated by patients in four individual sessions with weekly intervals and duration of 30 minutes each. The social support behavior was evaluated by women before and after the intervention through the Social Support Scale. RESULTS: Eighteen women and 18 caregivers participated in the study. The social support of women was higher for both the emotional and the instrumental dimensions of the Social Support Scale after the intervention of Brief Motivational Interviewing with caregivers. These findings contribute to the clinical practice of several professional categories in the use of low-cost intervention strategies for improvement of the quality of life during and after treatment of women with breast cancer. CONCLUSION: The intervention positively promoted behavioral change by improving the social support provided by caregivers to breast cancer patients undergoing chemotherapy. PMID- 29267742 TI - Chronicity and use of health services: peer education of the School of Patients. AB - OBJECTIVE: To evaluate the impact of the training strategy of the Escuela de Pacientes (School of Patients) on the use of health services among people with chronic diseases. METHOD: Quantitative design study of pretest and posttest evaluation with a population of 3,350 chronic patients of the Escuela de Pacientes (Andalusia, 2013-2015). A questionnaire adapted from the Stanford University was used. It measured the self-perceived health, number of health visits, and level of trust and communication with health personnel. A descriptive and bivariate study, a correlation study and a pretest/posttest net gain analysis were performed. RESULTS: Participation of 964 patients (28.8% of the population), of which 18.8% were men, mean age 56 years. Training increased trust in Primary Care (PC) and Hospital Care (HC) professionals (0.44 and 0.65 points), medical visits decreased by 25%, and hospital admissions fell by 51% with statistically significant differences by sex and disease. The correlation index between trust in professionals and use of health services was -0.215. CONCLUSION: The training strategy had a positive impact on the use of health services and trust in health professionals, and were identified areas of improvement from which recommendations are established. PMID- 29267743 TI - Socio-spatial inequalities related to tuberculosis in the city of Itaborai, Rio de Janeiro. AB - INTRODUCTION: Tuberculosis remains as a global public health problem and its occurrence and distribution is associated with social inequalities. Itaborai is among the priority Brazilian municipalities for tuberculosis control. The study aimed to combine social indicators into a composite indicator to measure differences in living conditions of the population in Itaborai, as well as evidence of health inequalities related to tuberculosis. METHODS: An ecological study, with spatial analysis of tuberculosis and its relation to socioeconomic and demographic status of households. Data were obtained from individuals declared in the Mortality Information System (SIM), notified in the Notification of Injury Information System - SINAN or Tuberculosis Special Treatment Information System - SITETB from 2007 to 2013. RESULTS: Evidence indicates association between sociodemographic inequalities and occurrence of tuberculosis in the population. Findings point to a lower percentage of healing and a higher percentage of abandonment and death in areas with high social vulnerability, with a relative risk over twice as high than that found in areas of lower vulnerability. CONCLUSION: The study showed strong evidence that the influence of unequal sociodemographic conditions have a negative impact on health conditions of the population in Itaborai. PMID- 29267744 TI - Consistency evaluation of values of weight, height, and body mass index in Food Intake and Physical Activity of School Children: the quality control of data entry in the computerized system. AB - INTRODUCTION: The quality control of data entry in computerized questionnaires is an important step in the validation of new instruments. The study assessed the consistency of recorded weight and height on the Food Intake and Physical Activity of School Children (Web-CAAFE) between repeated measures and against directly measured data. METHODS: Students from the 2nd to the 5th grade (n = 390) had their weight and height directly measured and then filled out the Web-CAAFE. A subsample (n = 92) filled out the Web-CAAFE twice, three hours apart. The analysis included hierarchical linear regression, mixed linear regression model, to evaluate the bias, and intraclass correlation coefficient (ICC), to assess consistency. Univariate linear regression assessed the effect of gender, reading/writing performance, and computer/internet use and possession on residuals of fixed and random effects. RESULTS: The Web-CAAFE showed high values of ICC between repeated measures (body weight = 0.996, height = 0.937, body mass index - BMI = 0.972), and regarding the checked measures (body weight = 0.962, height = 0.882, BMI = 0.828). The difference between means of body weight, height, and BMI directly measured and recorded was 208 g, -2 mm, and 0.238 kg/m2, respectively, indicating slight BMI underestimation due to underestimation of weight and overestimation of height. This trend was related to body weight and age. CONCLUSION: Height and weight data entered in the Web-CAAFE by children were highly correlated with direct measurements and with the repeated entry. The bias found was similar to validation studies of self-reported weight and height in comparison to direct measurements. PMID- 29267745 TI - Prevalence of body weight excess in undergraduate students: analysis of repeated surveys. AB - OBJECTIVE: To compare the prevalence of excess of body weight between the surveys conducted in the years 2010, 2012 and 2014, in college students from the same institution. METHODS: Three cross-sectional surveys were carried out in representative samples of students of a public institution. The excess of body weight was estimated by the body mass index and compared between the surveys, using the chi2 test for linear trend, in each of the categories: sociodemographic, link with the university and health-related behaviors. RESULTS: There were 1,069, 1,074 and 1,031 participants in the surveys in 2010, 2012 and 2014, respectively. Between surveys, the prevalence of overweight increased in men (2010: 30.1%; 2014: 36.4%), but not in women. There was an increased prevalence of excess body weight for the categories of sociodemographic variables link with the university and health-related behaviors in men and women. CONCLUSION: An increasing prevalence of excess body weight in college students was observed in the surveys. The conduction of interventions aimed at maintaining body weight is essential in order to avoid possible diseases associated with the concentrations of fat in inadequate levels. PMID- 29267746 TI - Factors associated with risk of malnutrition in the elderly in south-eastern Brazil. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence of malnutrition risk and its association with socioeconomic, behavioral, and health characteristics in the community-dwelling elderly. METHODS: A cross-sectional study with individuals aged >= 60 years. Nutritional status was evaluated using the Mini Nutritional Assessment. Socioeconomic, behavioral, and health information was also collected from all participants. The association between each variable and the risk of malnutrition was calculated and adjusted using Poisson hierarchical regression. RESULTS: The initial sample consisted of 3,101 elderly people, of whom 28.3% (95%CI 25.3 - 31.4%) were at risk of malnutrition. The multivariate analysis showed that the risk of malnutrition was significantly higher in women without formal education, who did not live with a partner, and identified as black-skinned. The risk of malnutrition was twice as high in individuals with no family income as compared to those who earned at least three minimum wages. Smokers were also more likely to be at risk of malnutrition than individuals who had never smoked. Participants suffering from kidney, respiratory or heart disease were at higher risk of malnutrition than those with no history of such illnesses. CONCLUSION: These findings could be used to help in the development of health policies and in the establishment of adequate programs aimed at reducing the risk of malnutrition in this population. PMID- 29267747 TI - The influence of meal and food markets in fruit and vegetable consumption among adults in the city of Sao Paulo. AB - INTRODUCTION: Despite the increased consumption of fruits and vegetables in the Brazilian population, a great proportion of people do not meet the recommendations. Purchasing sites associated with fruit and vegetable consumption has not been widely explored. OBJECTIVE: To explore the association between fruit and vegetable purchasing and consumption sites and the consumption of these foods among adults living in the city of Sao Paulo, Brazil. METHODS: Cross-sectional study with 2 thousand individuals living in the city of Sao Paulo, aged between 20 and 59 years, participants of the "Obesogenic Environment Study in Sao Paulo". The outcome was fruit and vegetable consumption measured by weekly consumption. Exposure variables included purchasing sites (supermarkets, open-air food markets, fruit and vegetable specialized markets, and corner stores) and consumption sites (full service restaurants and fast food restaurants). RESULTS: The sample comprises women (52.3%) aged between 25 and 34 years (30.2%), with at least 8 years of schooling (42.8%) receiving 2 to 5 minimum wages (34.6%). Demographic and socioeconomic variables showed association with regular consumption of fruits and vegetables (p < 0.05). The regular consumption of meals in full service restaurant was associated with vegetables consumption. The regular consumption of meals in fast-food restaurants was not associated with vegetables consumption. Food purchasing sites were not associated with fruit or vegetable consumption. CONCLUSION: The choice of restaurant type was associated with vegetable consumption. In the studied population, food purchasing sites were not associated with fruit or vegetable consumption. PMID- 29267748 TI - Simultaneity of behavioral risk factors for cardiovascular disease in university students. AB - OBJECTIVE: To analyze the prevalence and factors associated with clustering of four behavioral risk factors - physical inactivity, high fat intake, harmful use of alcohol and tobacco use - for cardiovascular diseases (CVD) among undergraduate students from Universidade Federal do Rio Grande, Rio Grande, Rio Grande do Sul, Brazil. METHODS: Cross-sectional study. Socio-demographic variables, breakfast habits, satisfaction with body image, body mass index, and self-perceived general health were analyzed. The outcome evaluated was simultaneity of risk factors for CVD. Crude and adjusted analyses were carried out, stratified by gender, using ordinal logistic regression, extracting odds ratio with respective 95% confidence intervals (95%CI) and p values. RESULTS: The sample was composed of 1,123 students (response rate: 66.0%); of these, 24.7% had two or more risk factors. In the adjusted analysis, the variables intermediate maternal education, absence of breakfast habit, and poor or regular self perceived general health was significantly associated (p < 0.05) with the outcomes. CONCLUSION: The results indicate an important prevalence of two or more simultaneous risk factors among undergraduate students. It was possible to outline which groups are more susceptible to more risk factors. The association between absence of breakfast habit and poor/regular self-perceived general health are highlighted. PMID- 29267749 TI - Factors associated with adherence and persistence to hormonal therapy in women with breast cancer. AB - INTRODUCTION: Hormonal therapy in breast cancer is essential to the transition from active treatment to care survival, because it improves long-term survival and provides a better quality of life. reducing hospital costs as well. However, adherence and persistence in the recommended treatment are important to achieve the desirable results. METHODOLOGY: This is a cohort retrospective study of 182 women on hormonal treatment identified at a high complexity oncology unit, in the southeastern region of Brazil, and followed-up until 2014. We performed a bivariate analysis to analyze the factors associated with adherence and we conducted the multivariate Cox regression to identify variables associated with discontinuity of treatment over time. RESULTS: Overall adherence was 85.2% and persistence was 45.4% at the end of 5 years. No association was found between the studied independent variables and adherence. Women with advanced stage (HR = 2.24; 95% confidence interval 1.45 - 3.45), who did not undergo surgery (HR = 3.46; 95%CI 2.00 - 5.97), and with three or more hospitalizations (HR = 6.06; 95%CI 2.53 - 14.54) exhibited increased risk of discontinuity. DISCUSSION: The variables associated with persistence reflect the relation between the highest disease severity and the discontinuity of adjuvant hormonal treatment. CONCLUSION: Despite the high adherence level, there is a progressive increase in non-persistence among women on hormonal therapy, influenced by characteristics related to disease severity, which contributes to an inadequate therapeutic response. PMID- 29267750 TI - Inequality in iron sulfate supplementation among pregnant women in Southern Brazil. AB - INTRODUCTION: The use of ferrous sulfate is recommended for all pregnant women from the 20th week of gestation to the 3rd month after delivery. OBJECTIVE: To evaluate the coverage of ferrous sulfate among pregnant women and differentials according to demographic and socioeconomic variables. METHOD: A cross-sectional population-based study with women who had children in Rio Grande, Rio Grande do Sul, Brazil, from January 1st to December 31st, 2013. Ferrous sulfate coverage was assessed according to maternal age, schooling, family income, and type of prenatal care. Statistical analysis included Pearson's chi2 test and Poisson regression. RESULTS: 2,685 postpartum women (97% of the total) were interviewed and the ferrous sulfate coverage was 63%. The largest relative differences were between the extreme maternal schooling groups (50%) and the type of medical care in prenatal care (72%). Women aged between 13 and 19 years were significantly associated with the use of supplement (RP = 1.16; 95%CI 1.08 - 1.25) when compared to women aged >= 30 years. Those who used the public service in prenatal care were more strongly associated with the outcome when compared to those who used the private system (PR = 1.61; 95%CI 1.49 - 1.74). CONCLUSION: Considering that there are unusual situations in the health sector in which disadvantaged groups are privileged, these findings are rare and indicate the presence of inequality in a way that is opposite to what was expected. The supplement should consider all women, especially older women, with higher education and better socioeconomic status. PMID- 29267751 TI - The implantation of the Surveillance System for Non-communicable Diseases in Brazil, 2003 to 2015: successes and challenges. AB - OBJECTIVE: To describe the implantation of the Surveillance System for Noncommunicable Diseases (NCDs) in the Unified Health System (Sistema Unico de Saude) and the challenges in maintaining it. METHODS: A literature review was carried out the information contained in federal government directives between 2003 and 2015 was consulted. RESULTS: A comprehensive risk and protection factor surveillance system was implemented. It is capable of producing information and providing evidence to monitor changes in the health behavior of the population. Among the advances cited are the organization of epidemiological surveys, such as the Surveillance System for Risk Factors and Protection for NCD (Sistema de Vigilancia de Fatores de Risco e Protecao para DCNT - Vigitel), the National School Health Survey (Pesquisa Nacional de Saude do Escolar - PeNSE), and the National Health Survey (Pesquisa Nacional de Saude) from 2013, which enabled the most extensive health diagnosis of the Brazilian population. In 2011, the NCD National Plan 2011-2022 established targets for reducing risk factors and NCD mortality. CONCLUSION: The information gathered from the NCD surveillance system can support the implementation of sectoral and intersectorial strategies, which will result in the implementation of the Brazilian Strategic Action Plan for the prevention and control of NCDs, as well as the monitoring and evaluation of their results periodically. Finally, it can be a very important tool to help Brazil achieve the goals proposed by the 2030 Agenda for Sustainable Development and the Global Plan to Tackling NCDs. PMID- 29267752 TI - Maternal socioeconomic factors and adverse perinatal outcomes in two birth cohorts, 1997/98 and 2010, in Sao Luis, Brazil. AB - : Several studies have identified social inequalities in low birth weight (LBW), preterm birth (PTB), and intrauterine growth restriction (IUGR), which, in recent years, have diminished or disappeared in certain locations. OBJECTIVES: Estimate the LBW, PTB, and IUGR rates in Sao Luis, Maranhao, Brazil, in 2010, and check for associations between socioeconomic factors and these indicators. METHODS: This study is based on a birth cohort performed in Sao Luis. It included 5,051 singleton hospital births in 2010. The chi-square test was used for proportion comparisons, while simple and multiple Poisson regression models with robust error variance were used to estimate relative risks. RESULTS: LBW, PTB and IUGR rates were 7.5, 12.2, and 10.3% respectively. LBW was higher in low-income families, while PTB and IUGR were not associated with socioeconomic factors. CONCLUSION: The absence or weak association of these indicators with social inequality point to improvements in health care and/or in social conditions in Sao Luis. PMID- 29267754 TI - Analysis of the epidemiological situation of leprosy in an endemic area in Brazil: spatial distribution in the periods 2001 - 2003 and 2010 - 2012. AB - INTRODUCTION: In Brazil, the spatial distribution of leprosy is heterogeneous. Areas with high transmission of the disease remain in the North, Center-west and Northeast. Areas with high transmission of the disease remain in the Northern, Central-Western and Northeastern regions of the country. OBJECTIVE: to describe the spatial distribution of leprosy in municipalities with high risk of transmission, in the periods from 2001 - 2003 and 2010 - 2012. METHODS: This was an ecological study using data from the Notifiable Diseases Information System (SINAN). They included all municipalities in the states of Mato Grosso, Tocantins, Rondonia, Para and Maranhao. The following leprosy indicators were calculated per 100,000 inhabitants: incidence rate of leprosy, incidence rate in children aged less than 15 years and rate of new cases with grade 2 disabilities. The spatial scan statistic was used to detect significant clusters (p <= 0.05) in the study area. RESULTS: In the period 2001 - 2003, the scan spatial statistics identified 44 significant clusters for the leprosy incidence rate, and 42 significant clusters in the period 2010 - 2012. In the period 2001 - 2003, it was possible to identify 20 significant clusters to the incidence rate in children aged less than 15, and 14 significant clusters in the period 2010 - 2012. For the rate of new cases with grade 2 disability, the scan statistics identified 19 significant clusters in the period 2001 - 2003, and 14 significant clusters in the period 2010 - 2012. CONCLUSIONS: Despite the reduction in the detection of leprosy cases, there is a need intensify disease control actions, especially in the clusters identified. PMID- 29267753 TI - Perception of neighborhood safety and screen time in adolescents from Curitiba, Brazil. AB - OBJECTIVE: To analyze the association between perceptions of neighborhood safety (PNS) and screen time among adolescents and to assess the moderating effects of sex, age and socioeconomic status. METHODS: A cross-sectional study with school survey was conducted in Curitiba, Brazil. First, six schools (three public and three private) were intentionally selected. Next, one class within each educational level (from the sixth year of elementary school to the third year of high school) was randomly selected. PNS was assessed using a NEWS-Y scale, and daily screen time was defined as the time spent watching TV/videos/DVDs, playing video games and using the Internet. Multinomial logistic regression models were used to test the association between PNS and screen time, adjusting for the confounding variables. RESULTS: The sample included 776 adolescents (boys and girls), aged between 11 and 18 years old. Perceived crime was associated with time playing video games among older teenagers (p < 0.05). Pedestrian and traffic safety was inversely associated with time playing video games among adolescents with high socioeconomic status (p < 0.05). CONCLUSION: The association between PNS and screen time is complex among adolescents and varies according to sociodemographic variables and the screen time outcome (TV/videos/DVDs, video games and the Internet). PMID- 29267755 TI - Primary health care as assessed by health professionals: comparison of the traditional model versus the Family Health Strategy. AB - INTRODUCTION: The Family Health Strategy (FHS) should be first-contact care in the Brazilian Health System. However, Primary Health Care (PHC) still encompasses two models: the FHS and the traditional health care facilities. The expansion of the FHS has been slow and heterogeneous in many cities, rendering a comparative evaluation of key quality-related elements of PHC models crucial. OBJECTIVE: To compare the performance of PHC models as perceived by health professionals. METHODS: A cross-sectional study involving managers and health professionals from PHC of a medium-size city in South-eastern Brazil. Data were collected by applying the Primary Care Assessment Tool. The performance was estimated through primary health care indexes (general and partial PHCI by attributes). Univariate polytomous logistic regression was performed to compare care model performances according to their attributes. Strength of association was estimated by odds ratio with 95% confidence interval. RESULTS: Three managers and 81 health professionals participated in the study. The FHS had a better index rating than the traditional care model for general PHCI and for the attributes longitudinality, comprehensiveness, family focus and professional level. CONCLUSION: Although the FHS attained higher scores compared to the traditional model, it has not yet achieved the performance expected. This scenario points to the need for increased FHS cover and quality improvements at the existing units. PMID- 29267756 TI - A spatial analysis of urban transit accidents assisted by Emergency Mobile Care Services: an analysis of space and time. AB - INTRODUCTION: Urban transit accident are a global public health problem. The objective of this study was to describe the profile of the victims and the occurrences of urban transit accidents attended to by emergency mobile care services (Servico de Atendimento Movel de Urgencia- SAMU) in Recife, and their distribution based on spatial analysis. METHODOLOGY: An ecological study, developed through secondary data from emergency mobile care services in Recife, referring to the total number of occurrences of urban transit accidents attended to from January 1 to June 30, 2015. The spatial analysis was performed using the Moran index. RESULTS: Basic support units performed most of the emergency services (89.2%). Among the victims, there was a predominance of males (76.8%) and an age group of 20 - 29 years old (31.5%). Collisions were responsible for 59.9% of the transit accidents, and motorcycles for 61.6% of the accidents among all means of transportation. Friday was the day that showed the highest risk for treatment, and there was a concentration of events between 6:00 am - 8:59am and 6:00pm - 8:59pm. The MoranMap identified critical areas where calls came from traffic accidents during the period analyzed. DISCUSSION: The records of the mobile service from the spatial analysis are an important source of information for health surveillance. CONCLUSION: The spatial analysis of urban transit accidents identified regions with a positive spatial correlation, providing subsidies to the logistical planning of emergency mobile care services. This study is groundbreaking in that it offers such information about the region. PMID- 29267758 TI - CORRECTION. AB - [This corrects the article doi: 10.1590/1980-5497201600040004] [This corrects the article doi: 10.1590/1980-5497201600030001] [This corrects the article doi: 10.1590/S1415-790X2012000400015]. PMID- 29267757 TI - Space-temporal analysis of Chagas disease and its environmental and demographic risk factors in the municipality of Barcarena, Para, Brazil. AB - INTRODUCTION: Chagas disease is a parasitosis considered a serious problem of public health. In the municipality of Barcarena, Para, from 2007 to 2014, occurred the highest prevalence of this disease in Brazil. OBJECTIVE: To analyze the disease distribution related to epidemiological, environmental and demographic variables, in the area and period of the study. METHODS: Epidemiological and demographic data of Barcarena Health Department and satellite images from the National Institute For Space Research (INPE) were used. The deforestation data were obtained through satellite image classification, using artificial neural network. The statistical significance was done with the chi2 test, and the spatial dependence tests among the variables were done using Kernel and Moran techniques. RESULTS: The epidemiological curve indicated a disease seasonal pattern. The major percentage of the cases were in male, brown skin color, adult, illiterate, urban areas and with probable oral contamination. It was confirmed the spatial dependence of the disease cases with the different types of deforestation identified in the municipality, as well as agglomerations of cases in urban and rural areas. Discussion: The disease distribution did not occur homogeneously, possibly due to the municipality demographic dynamics, with intense migratory flows that generates the deforestation. CONCLUSION: Different relationships among the variables studied and the occurrence of the disease in the municipality were observed. The technologies used were satisfactory to construct the disease epidemiological scenarios. PMID- 29267759 TI - [The Evaluation of Health Programs and Interventions Within the Framework of Budgetary Health Programs]. PMID- 29267760 TI - [Payment by performance to improve the nutritional status of children: impact of budget support agreements in three peruvian regions with a high prevalence of chronic malnutrition in children in 2010-2014]. AB - : To estimate the impact of a payment scheme by performance, known as a budget support agreement, applied by the government in three regions in Peru with the highest rates of chronic malnutrition (CM) in children in 2008-Apurimac, Ayacucho, and Huancavelica-on indicators of health service coverage (immunization, childhood growth and development, and iron supplementation) and the nutritional status of children (malnutrition, anemia, and diarrhea). These agreements were used to transfer resources to the budgets of these regions with the condition of fulfilling management commitments and coverage goals with a view toward improving the nutritional status of children. METHODS: Based on data from the Demographic and Family Health Survey conducted from 2008 to 2014, evolution of the indicators in a sample of children residing in the areas where the support programs were signed was compared to that of a control sample in the period in which the agreements were in force and in the subsequent years to estimate differences in the impact of this support strategy. RESULTS: There was a positive impact of the programs on the increase in vaccination coverage provided by the basic health system and rotavirus vaccination, which consequently reduced the rates of diarrhea and malnutrition. CONCLUSIONS: The scheme was effective in increasing the vaccination coverage and reducing CM but did not seem to improve the coverage of other benefits, including childhood growth and iron supplementation to children and mothers. PMID- 29267761 TI - [Cost-Fffectiveness of Two Antiviral Therapies for Chronic Hepatitis B in Peru: Entecavir and Tenofovir]. AB - OBJETIVES: To compare in terms of cost-effectiveness to entecavir (ETV) and tenofovir (TDF) in the treatment of hepatitis B virus (HBV) in public hospitals in Peru. MATERIALS AND METHODS: We structured a Markov model. We define effectiveness adjusted life years for quality (QALY). We include the direct costs of treatment in soles from the perspective of the Ministry of Health of Peru. We estimate the relationship between cost and effectiveness ratios (ICER). We performed sensitivity analyzes considering a range of willingness to pay (WTP) from one to three times the Gross Domestic Product (GDP) per capita, and a tornado analysis regarding Monetary Net Profit (BMN) or ICER. RESULTS: Treatment with TDF is more effective and less expensive than ETV. The ETV had a cost per QALY of PEN 4482, and PEN 1526 TDF. The PTO maintains a progressively larger with increasing WTP BMN. The discount rate was the only variable with a significant effect on model uncertainty. CONCLUSION: Treatment with TDF is more cost effective than ETV in public hospitals in Peru. PMID- 29267762 TI - [Impact evaluation of educational-motivational intervention "Como Jugando" to prevent obesity in school children of Cercado de Lima: results in the first year]. AB - OBJECTIVE: To determine the impact of the educational-motivational intervention "Como jugando" on the body mass index (BMI), knowledge on nutrition, physical activity levels, and eating patterns in students from the first to fourth grades of four educational institutions (EIs) of Cercado de Lima after the first year of the intervention. MATERIALS AND METHODS: This was a quasi-experimental, controlled study. BMI, knowledge on nutrition, frequency of food consumption, and level of physical activity were evaluated. The "Como jugando" program included playful and experiential activities for school children and involved both teachers and parents. The impact was estimated by applying the McNemar test for related samples and regression models for the analysis of differences in adjusted variables related to children and their mothers. RESULTS: The study included 696 school children from two experimental EIs and two control EIs. The Z-score for BMI and the prevalence of obesity did not vary during the study period. The intervention improved the knowledge of nutrition [odds ratio (OR): 1.46; 95% confidence interval (CI): 1.17-1.81], reduced the likelihood of poor levels of physical activity (OR: 0.63; 95% CI: 0.46-0.87), and improved the consumption patterns for all food categories except vegetables in the intervention group. CONCLUSIONS: The "Como jugando" intervention, in the first year of implementation, did not reduce the Z-score for BMI but improved the knowledge of nutrition, reduced the probability of poor levels of physical activity, and maintained or increased the consumption of fruits, sugar-free water, packaged juices, and sweet and savory cookies. Therefore, the "Como jugando" intervention should be better studied in order to estimate its impact on biological indicators. PMID- 29267763 TI - [The Role of Media-Based Surveillance System for Public Health Events in Peru]. AB - OBJECTIVES: The objective of this study was to describe events and outbreaks identified by Media-Based Surveillance System for Public Health Events between 2013 and 2015. Further, to determine the percentage of events or outbreaks that were not identifing by regular surveillance systems. MATERIALS AND METHODS: We analyzed the data collected from Media-Based Surveillance System for Public Health Events of the National Center for Epidemiology and Disease Control. This surveillance system records news from the written media, radio, television, and Internet in Peru on a daily basis; classifies them according to the type of event; determines whether the event was registered, investigated, and confirmed; and evaluates whether the news was alarmist, informative, or educational. RESULTS: Overall, 49.4% of the events reported had not been identified by epidemiological surveillance systems at the local, regional, or national level. In addition, 17.4% of the analyzed news was alarmist. CONCLUSION: This type of surveillance has a high potential to identify outbreaks and/or health events not identified by regular surveillance systems and should thus be strengthened. In addition, the results of this tool may help to improve decision-making. PMID- 29267764 TI - [Perceived stress and intention to migrate to the interior of peru among physicians and nurses who reside in Lima: exploratory analysis of the national survey of satisfaction of users in health, 2015]. AB - OBJECTIVES.: To identify the frequency of intention to migrate to the interior of Peru (IMIP) and assess the association between perceived stress (PS) and IMIP among physicians and nurses residing in metropolitan Lima in 2015. MATERIALS AND METHODS. : This was a secondary analysis of data obtained from the National Survey of Satisfaction of Users in Health (Encuesta Nacional de Satisfaccion de Usuarios en Salud-ENSUSALUD) in 2015. Only professionals residing in Metropolitan Lima were included for the analysis. IMIP was defined as the intention to work in a geographical region other than Lima. PS was measured using the 14-question perceived stress scale validated in Spanish. Logistic regression was used to evaluate this association; the measure of association was the odds ratio (OR) with the 95% confidence interval (95% CI). RESULTS. : Data from 796 professionals were analyzed, 54.8% of whom were nurses. The average age was 45.2 years; 4.9% (37) of the participants had IMIP, 64.9% (24) of whom were nurses. The results of multivariate logistic regression analysis indicated an association between higher PS and IMIP (OR: 1.31, 95% CI: 1.07-1.60). CONCLUSIONS.: The IMIP was reported by one of every 20 professionals and was associated with higher PS in the study group. PMID- 29267765 TI - [Social Representations Related to Anemia in Children Under Three years in Awajun and Wampis Communities of Peru]. AB - OBJECTIVES: To understand the social representations of the Awajun and Wampis communities related to the symptoms and treatment of anemia in children younger than 3 years, as well as the relationship of these representations with the symbolism, constructs, and type of diet of these populations. MATERIALS AND METHODS: This qualitative study was conducted from June to August 2015 in the districts of Rio Santiago, Cenepa, and Nieva (Amazon region, Peru), and included in-depth interviews (IDIs) of health personnel, community authorities, parents, and focus groups (FGs) for mothers. RESULTS: A total of 38 IDIs and 13 FGs were conducted. The evaluated populations had limited awareness about anemia and health personnel, but anemia with symptoms were correlated with social representations and cultural manifestations. This behavior was reflected in the parents' choice of treatments that were not necessarily the same as those indicated by the health personnel, and these social groups preferred the consumption of certain foods that were considered to cure the "putsumat". Visiting a health care center or using micronutrients was not their first treatment option. CONCLUSIONS: Social representations and traditional practices still exist, and include interpretative systems in health, disease, and disease management. The logic, meaning, and coherence of these practices depend on the cultural group considered. The "putsumat" or "putsuju" is an interpretive model for anemia, and the symptoms in children include pallor, thinness, and fatigue; this model is based on the cultural system of the Awajun and Wampis populations. PMID- 29267766 TI - [Molecular characterization of pathogenic bacteria of the respiratory tract in peruvian patients with cystic fibrosis]. AB - OBJECTIVES.: To molecularly characterize the pathogenic bacteria of the respiratory tract isolated from patients with cystic fibrosis (CF) in Peru. MATERIALS AND METHODS.: Bacterial communities cultured from sputum samples of pediatric and adult patients with CF admitted to the Edgardo Rebagliati Martins National Hospital and the National Institute of Child Health were characterized. Standard microbiological techniques were used for bacterial culture, and gene sequencing of 16S rRNA and matrix-assisted laser desorption ionization time-of flight (MALDI-TOF) mass spectrometry and tandem MALDI-TOF mass spectrometry (MALDI TOF/TOF) were used for molecular characterization. RESULTS.: Seventeen bacterial strains were characterized by 16S rRNA sequencing, and the identified pathogenic bacteria were Pseudomonas aeruginosa (31.5%), Staphylococcus aureus (12.6%), Pseudomonas spp. (11.8%), and Klebsiella oxytoca (3.1%). MALDI-TOF analysis generated a series of spectra representative of each isolated bacterial species, whereas MALDI TOF/TOF analysis identified the peptides and proteins of the most common strains and provided data on pathogenicity and sensitivity to antibiotics. CONCLUSIONS.: The primary pathogenic microorganisms found in the respiratory tract of patients with CF in Peru were the same as those found in other countries. This study is the first to perform 16S rRNA sequencing as well as MALDI-TOF and MALDI-TOF/TOF analysis of the bacterial pathogens circulating in Peru. The inclusion of proteomic analysis further allowed for the identification of native microorganisms involved in CF. PMID- 29267767 TI - [Effect of the Industrial Nanoparticles TiO 2 , SiO 2 and ZnO on Cell Viability and Gene Expression in Red Bone Marrow of Mus Musculus]. AB - OBJECTIVES: To evaluate the effect of ZnO, TiO2 and SiO2 nanoparticles on cell viability and expression of the interleukin 7, interleukin 3, and granulocyte macrophage colony stimulating factor (GM-CSF) genes in Mus musculus. MATERIAL AND METHODS: Red bone marrow was extracted from five Balb/c mice for the analysis of cell viability using the MTT test. The mice were divided into two groups of five each: one group was inoculated intraperitoneally with 0.5, 1.0, 2.5, 5.0, and 10 mg/kg of ZnO and SiO2 nanoparticles, respectively, and the other group was inoculated with 5.0, 10.0, 15.0, 20.0, and 25 mg/kg of TiO2 nanoparticles, respectively. Thirty hours later, RNA was extracted from the red bone marrow of the mice in both groups for gene expression analysis using quantitative PCR and RT-PCR. RESULTS: ZnO and SiO2 nanoparticles reduced cell viability in a dose dependent manner by 37% and 26%, respectively, starting at a dose of 1 mg/kg. TiO2 nanoparticles at 5 mg/kg and 10 mg/kg reduced the gene expression of interleukins 7 and 3 by 55.3% and 70.2%, respectively, and SiO2 nanoparticles caused the greatest decrease (91%) in the expression of GM-CSF. ZnO nanoparticles reduced the expression of GM-CSF starting at doses of 20 mg/kg and 25 mg/kg. CONCLUSIONS: ZnO, SiO2 and TiO2 nanoparticles affect cell viability and gene expression in the mouse bone marrow. PMID- 29267768 TI - [Evaluation of economic expenditure related to human hydatidosis in Junin, Peru]. AB - The objective of the present study was to calculate the economic loss caused by the treatment of human hydatidosis. For this purpose, a cost analysis of the cases reported in the Junin region of Peru in 2013 was conducted. The total cost (direct and indirect) per patient assisted by the Ministry of Health (Ministerio de Salud-Minsa), the social security system (EsSalud), and private health care was 1,220, 3,051, and 4,090 US dollars (USD), respectively. The mean annual loss considering the number of health care services for uncomplicated cases of human hydatidosis was USD 24,542 in Minsa, USD 369,292 in EsSalud, and USD 130,566 in private health care. Overall, the rate of loss of human productivity was a small proportion. Our findings indicate that hydatidosis imposes a heavy economic burden in the Junin region of Peru. PMID- 29267769 TI - [Dietetic Determinants of Zinc Consumption in Stunted Children Under Five in Maya Communities From Guatemala]. AB - The objective of the study was to identify the elements from feeding patterns that influence the intake and bioavailability of zinc in stunted children (SC) 1 5 years from Maya communities living in Huehuetenango, Guatemala. This descriptive, cross-sectional study was performed in 138 stunted children aged 1-5 years. It was applied: an inventory of zinc food sources availability, a Food Frequency Questionnaire, a questionnaire about living conditions. anthropometrics measurements and information on food intake habits, and information about disease prevalence. Twenty-eight food sources of zinc were available for consumption (54% low and 7% high zinc bioavailability). The consumption of foods with high bioavailability was low, while the antagonistic foods were high. On average the daily zinc consumption in diet 3 mg (95% CI: 2.65-3.35). Only 14.5% of the children met the zinc requirements, and 2.9% reached the daily recommendation. Episodes of diarrhea and respiratory infections were observed 15 days before the visit, in 29.71% and 45.6% of children, respectively. Most of children have a diet that does not cover the daily requirement. PMID- 29267770 TI - [Diagnostic performance of the indirect immunofluorescence test for the detection of antibodies against HTLV-1]. AB - The objective of the study was to determine the diagnostic yield of the indirect immunofluorescence (IFI) test for the detection of antibodies against HTLV-1. A diagnostic test evaluation study was performed. HTLV-1-infected MT2 cells and HTLV-1-uninfected K-562 cells were cultured; then these cells were impregnated and fixed in sheets for immunofluorescence and faced to Peruvian sera. A total of 155 sera (80 HTLV-1-positive sera and 75 sera positive for other diseases) from the Peruvian Instituto Nacional de Salud were used. In addition, the parameters of repeatability (intra-laboratory) and reproducibility (in laboratories of the Peruvian coast, mountains and jungle) of the test were evaluated. The IFI test detected the presence of antibodies against HTLV-1 reaching a sensitivity of 98.75% (95% CI: 95.69 - 100.00%), a specificity of 98.67% (95% CI: 95.40 - 100.00%) and the Kappa index was 0.975. There were no false positives or false negatives; however, one undetermined result and one non-specific result were obtained. The test showed 100% qualitative agreement when performing the repeatability and reproducibility. The results obtained are comparable to the reference test. Therefore, the IFI test had a good diagnostic performance and would be useful for the confirmation of HTLV-1. PMID- 29267771 TI - [Viral Hepatitis Infection Markers Among Blood Donor in a National Hospital of Metropolitan Lima]. AB - The aim of the study was to determine the frequency of infection markers for hepatitis B and hepatitis C and to identify associated factors in blood donors. The study was carried out using data obtained from blood donor medical records collected in a public hospital in Lima. Of 28,263 individuals analyzed between 2012 and 2015, 0.6% (n=156) were reactive for HBsAg; 5.2% (n=1,465), for anti HBc; and 0.8% (n=232), for anti-HVC. Positive results for HBsAg (p=0.319) and anti-HVC (p=0.037) were more common in voluntary donors. For HBsAg and anti-HBc, positive results were more common in individuals aged 50 years or older. The number of voluntary donors was higher among individuals younger than 20 years (p<0.001). The study indicates that reactivity to hepatitis infection markers is associated with voluntary donation and the age group of blood donors. PMID- 29267772 TI - [Clinical and prognostic characteristics of the molecular subtypes of breast cancer determined by immunohistochemistry. Arequipa, Peru]. AB - The objective of this study was to determine the clinical and prognostic characteristics of breast carcinomas according to the molecular subtype using immunohistochemical markers. The study included 280 women with unilateral breast cancer enrolled from 2009 to 2012. The carcinomas were classified into four subtypes based on immunohistochemical findings: luminal A, luminal B, HER2, and triple negative. The Kaplan-Meier test was used to determine the effect of histological type and molecular subtype on overall survival. Our results indicated that the most common breast carcinoma subtype was luminal A (105 cases, 37.5%), followed by luminal B (88 cases, 31.4%), HER2 (46 cases, 16.4%), and triple negative (41 cases, 14.6%). Luminal carcinomas were well-differentiated in most cases, without involvement of the axillary lymph nodes, and showed a similar tumor size and stage. In contrast, HER2 and triple-negative tumors were poorly differentiated in most cases, with axillary node involvement, and were associated with decreased overall survival. PMID- 29267773 TI - [Associated Factors to non-use of Formal Health Services in the Peruvian Population: Analysis of the National Household Survey (ENAHO) 2015]. AB - The aim of the study was to estimate the prevalence of non-use of health services (NUHS) and its associated factors using the National Household Survey (ENAHO 2015). The participants were defined as NUHS if they have presented any symptoms, discomfort, illness, relapse of chronic illness or accident during the last month and did not go to the health services. 35036 participants were analyzed; the prevalence of NUHS was 53,9%. NUHS was higher in the coastal region (adjusted Prevalence Ratio [aPR]=1.24;95%CI:1.17-1.31), highlands (aPR=1.38; 95%CI: 1.31 1.46) and jungle (aPR=1.25,95%CI:1.18-1.33) compared to Lima. Likewise, there were a higher prevalence of NUHS in participants without health insurance (aPR=1.59;95%CI:1.52-1.66) and those affiliated to Ministry of Health insurance (aPR=1.16;95%CI:1.11-1.22) compared to those affiliated to Social Security. More than half of the participants suffered from NUHS, which was associated with geographical and health system conditions. It is required evidenced-informed public policies to improve this situation. PMID- 29267774 TI - [Update on tegumentary leishmaniasis and carrion's disease vectors in Peru]. AB - Among approximately 190 species of Lutzomyia in Peru, only a small number have been identified as vectors of tegumentary leishmaniasis in Western and inter Andean valleys. These include L. peruensis, L. verrucarum, L. tejadai, L. ayacuchensis, and L. pescei. In the Amazon region, L. yuilli yuilli, L. chagasi, L. davisi, and L. auraensis are naturally infected, among the subgenera Leishmania and Viannia. L. auraensis is newly reported as a potential vector of leishmaniasis in neotropical regions. Among the primary and most widely distributed vectors of human bartonellosis or Carrion's disease, L. verrucarum and L. peruensis are predominant in the Andean regions of northern, central, and southern Peru. Other potential vectors of Carrion's disease are L. serrana in the Monzon Valley, Huamalies, and Huanuco; L. pescei in Apurimac and Cusco; and L. robusta and L. maranonensis in Jaen, San Ignacio, and Utcubamba provinces, and the high forests of Peru. Because of the high prevalence of leishmaniasis and bartonellosis outside of known endemic areas in Peru, it is necessary to update data and distribution maps of these disease vectors. This may improve both prevention and control measures. Existing information about sandfly vectors in Peru is also provided in this article. PMID- 29267775 TI - [Self-Knowledge, Adherence to Treatment, and Control of Arterial Hypertension in Peru: a Narrative Review]. AB - This non-systematic bibliographic review examines the published Peruvian medical literature on arterial hypertension (HTN) as of December 2016. The results were divided into three thematic areas: self-knowledge, adherence to treatment, and control. We identified 197 articles, although only 15 were used for the analysis. Despite improvement in recent years, we found that the level of self-knowledge about HTN is poor. The level is better in urban areas, but is generally worse than in other Latin American cities. Moreover, despite improvement, HTN control is insufficient and worse than in other Latin American countries. Finally, adherence to treatment may be worse in the provinces. PMID- 29267776 TI - [Research on near-miss maternal mortality in Latin America]. AB - The near miss approach in obstetrics represents an opportunity to understand the role that structural, psychosocial and cultural determinants play in the critical obstetric experiences of women who, at the risk of death, saved their lives. This article shows the results of a narrative and critical review of the studies that have been developed from this approach in Latin America in the last 6 years. Seven international databases and 19 different journals were reviewed, originating in 7 countries. It was found that there is little production around the subject and predominated the clinical approximations referring to the diagnostic and therapeutic procedures used with this population. The predominant paradigm is positivist and most are descriptive, retrospective and cross sectional, ranging from secondary sources of information (archives, records). It is urgent to carry out research from this approach with women, recovering the experiences they have experienced in the critical episode. PMID- 29267777 TI - [Health Surveys: Essentials Tools in the Monitoring and Evaluation of the Budgetary Programs]. AB - This article analyzes the use of health surveys in the monitoring and evaluation of the Budgetary Programs. From its beginnings in 2008, in Peru, the Budget for Results (PpR) has meant not only a modification of the organization of the State budget, but a shift towards a perspective based on scientific evidence that prioritizes the results in the population and the necessary goods and services. National health surveys have played a relevant role, since they provide population information at the product and results level, information that has also supported the changes in the management cycle of State interventions, under a structure in which the availability of information constitutes the best input for decision making. Finally, it presents the considerations that must be taken into account for the adequate use of the information that comes from health surveys and the complementarity that it requires of other sources of information, so as to facilitate the integral approach in the monitoring and evaluation of the chain of results of budgetary programs in health. Surveys are important tools for monitoring and evaluating budget programs, their detailed knowledge allows them to improve their use in decision-making. PMID- 29267778 TI - [Evaluation of budget design and execution, an instrument of performance-based budgeting: some experiences applied to health]. AB - Since 2008, the evaluation of budget design and execution (EDEP for its acronym in Spanish) - one of the evaluations tools developed by the Peruvian Ministry of Economy and Finance (MEF) as part of the implementation of Performance Budgeting- seek to provide reliable information about design coherence and progress in the implementation of public interventions, in order to improve their management and make informed budget decisions. The EDEP methodology includes preparing an evaluation report and defining a matrix of commitments to improve performance. Commitments are defined based on the recommendation of the EDEP. The EDEP seeks to correct exiting problems in public programs and optimize their results. MEF tracks the fulfillment of these commitments and links together the analysis of public budget requests and the progress of these commitments. Now, almost 10 years after its implementation, 57 EDEP have been carried out in different sectors and 07 of them are related to health interventions such as: the comprehensive health system, vaccination service, normal births, acute respiratory infections and acute diarrheal diseases, among others. Beyond the discrepancies in the application of this tool, the EDEP and its matrix of commitments have allowed the use of the results of the evaluations and have become a mechanism to generate useful information to improve the public services. PMID- 29267779 TI - [Effects of social programs on indigent population health: Evidence from results based budgeting's impact evaluations to social programs in Peru]. AB - This article describes the experience of the MEF's impact evaluation management as one of the RBB instruments and documents the design and results obtained from three impact evaluations of the most emblematic government social programs. The Service of Visiting Families (SAF) of the National Program "Cuna Mas", conditional cash transfer Program "JUNTOS" and National Program "Pension 65" focusing on objective population's health the outcomes. Among the main results, it was found the SAF generated improvements in cognitive and communication development in children, but had no impact on mothers' child care practices or children's nutritional status. In the case of JUNTOS, there were increases in per capita spending, food expenditure, decreases in severity and poverty gap, increases in school attendance and reductions of school dropout. However, no significant results were found in most indicators of prenatal health, child health, or chronic malnutrition. In the case of Pension 65, there were increases in household consumption and improvements in elderly's emotional health (depression, self valoration); but there was no evidence of increases in the use of health services by the elderly or improvements in their physical health. Therefore, it is recommended that such programs boost their designs and inter sectoral coordination with MINSA and subnational institutions, in order to improve contents of healthy practices and child care, and optimize the provision of health and education services, in order to meet the demands of their users. PMID- 29267780 TI - [From scientific research to health policy design: the experience of iodine deficiency elimination in Peru]. AB - Scientific research is an essential public health function, enabling recognition of problems that compromise health and facilitating solutions. Research is essential to formulate health policy at a national level. There has been significant but inconsistent overall progress, due to economic conditions in low- and middle-income countries. An example that illustrates this situation is the investigation of iodine deficiency (ID) in Peru, and the application of the results for development of a public health program. The research demonstrated persistent ID, which causes fetal brain damage and subsequent mental retardation. The use of iodinated oil to prevent and treat ID was shown to have an immediate and long-term effect, and confirmed that urinary concentration of iodine was the best indicator of iodine intake. These results were accepted by the Ministry of Health, and the National Program for the Control of Endemic Goiter and Cretinism was created in 1983, achieving virtual elimination of ID by 1995. PMID- 29267781 TI - [Integrated mobile health systems: Role of socio-cultural factors and the socio technical systems approach]. AB - This paper discusses the role of socio-cultural factors in strengthening integrated mobile health systems. Emphasis is placed on the importance that any initiative in mobile health should consider the analysis of socio-cultural factors during the process of the development and implementation of programs and research interventions. The socio-cultural and socio-technical approach also consider the human factor and considers the conditions of the environment and the context beyond the technological resources of the mobile health system and the infrastructure that supports it. Methodologies such as observational studies, focus groups, and in-depth interviews should be included ideally in any mobile health study. We also present a case study in the north area of Lima (Peru), adapting the Community-Based Participatory Research platform that is based on a socio-technical approach and evaluates the socio-cultural approach with the objective to optimize the diagnosis process of tuberculosis using mobile health. PMID- 29267782 TI - [Diffuse large B-cell lymphoma: a single disease?] AB - Non-Hodgkin's lymphomas are common and comprise a heterogeneous group of neoplasms, with diffuse large B-cell lymphoma (DLBCL) accounting for more than 60% of cases. Moreover, DLBCL presents with a variety of clinical characteristics, genetic profiles, and therapeutic responses. We aimed to improve progression-free survival, total survival, and objective results in an DLBCL subgroup. However, another subgroup demonstrated poor responses. Therefore, it is necessary to design treatment programs based on clinical, immunohistochemical, and genetic profiles, grouping cases properly to identify correct therapeutic modalities for each lymphoma subtype. Currently, these neoplasms are classified as high- and low-risk lymphomas, and therapeutic regimens are being developed to complement conventional R-CHOP, such as R-DA-EPOCH, R2CHOP, IR-CHOP, VR-CHOP, and eveRCHOP, which are expected to improve outcomes. PMID- 29267783 TI - [Primary orbital cystic tumor: A case of hydatidosis in a child]. AB - Primary orbital cystic tumors caused by Echinococcus granulosus are rare. As this parasite is endemic in Peru, we report the case of a 10-year-old girl from a rural area of Huancavelica, who presented with progressive and irreducible axial proptosis of the right eye and loss of vision. Orbital tomographic images demonstrated a tumor mass with a cystic appearance. Serologic tests were negative. The patient underwent surgical resection, and histopathologic analysis revealed anhistic membranes, corresponding to hydatid cysts. During one year of follow-up, no evidence of local or systemic recurrence was observed. In conclusion, orbital hydatidosis should be considered in the differential diagnosis of a cystic orbital tumor in pediatric patients, especially if the patient is from an endemic area. PMID- 29267784 TI - [Epidemic and endemic mortality according to causes and sanitary conditions in mid-nineteenth century Lima, Peru]. AB - In mid-19th century Lima, Peru, death had various causes. Nonetheless, epidemics raised greater concern among the population and authorities. The highest number of deaths was due to endemic diseases caused by poor sanitary conditions. However, as these were accepted as routine deaths, they were ignored. PMID- 29267785 TI - [Rapid Progression of Chronic Kidney Disease in the Peruvian Population]. PMID- 29267786 TI - [Rapid progression of chronic kidney disease in the peruvian population - reply]. PMID- 29267787 TI - [Food and Processed Food Labelling: An Instrument Needed for Alimentary Education]. PMID- 29267788 TI - [Chromosomal microarray analysis in peruvian children with delayed psychomotor development or intellectual disability]. PMID- 29267789 TI - Landslide hazard mapping, DNA damage induced by sucrose and the biotechnology potential of sponge-associated bacteria communities. PMID- 29267790 TI - Potentially mobile of heavy metals on the surface sediments in tropical hyper saline and positive estuaries. AB - Estuarine sediments represent important pools of trace metals, released from both anthropogenic and natural sources. Fluctuations in the water column physicochemical conditions, on the other hand, may transfer metals from solid to liquid compartment and resulting in contamination of the surrounding environment. The present research was carried out to evaluate the weakly bounded heavy metal levels in tropical hyper-saline and positive estuaries, in order to quantify its potentially availability. The monitoring includes five metals (Cd, Cr, Cu, Pb, Zn) and cover nine estuaries in Rio Grande do Norte state/Brazil, including four hypersaline and five true estuaries. 50 surface sediment samples were collected in each estuary. At the same time, organic matter concentrations were evaluated in order to help explaining possible local variations in heavy metal levels. Organic matter results (0.7% - 7.3%) suggest the positive Potengi estuary as the most critical environmental quality situation. On the other hand, according to heavy metals levels, both Conchas and Potengi estuaries registered the higher concentrations of Cr. The highest concentrations were observed in the hyper saline estuaries, with the exception of the Zn. The present study revealed that the watershed occupation has significantly influenced the heavy metal concentrations in the estuaries. PMID- 29267791 TI - Conservation of geosites as a tool to protect geoheritage: the inventory of Ceara Central Domain, Borborema Province - NE/Brazil. AB - The Ceara Central Domain, in the northern Borborema Province/NE Brazil, encompasses important geological records (geosites) which allow understanding a relevant period of the Earth's evolution, mainly associated to Neoproterozoic Brazilian/Pan-African Cycle and West Gondwana amalgamation, besides Neoarchean to Ordovician records. The presented geoheritage inventory aims to characterise the geosites with scientific relevance of Ceara Central Domain. By applying a method for large areas, the final selection resulted in eight geological frameworks represented by 52 geosites documented in a single database. This is the first step for a geoconservation strategy based on systematic inventories, statutory protection, geoethical behaviour and awareness about scientific, educational and/or cultural relevance of geosites. PMID- 29267792 TI - High consumption of sucrose induces DNA damage in male Wistar rats. AB - The purpose of this study was to determine the effects of the high consumption of sucrose on the levels of DNA damage in blood, hippocampus and bone marrow of rats. Male Wistar rats were treated for 4 months with sucrose (10% for 60 initial days and 34% for the following 60 days) in drinking water, and then, glycemia and glycated hemoglobin (A1C) were measured. Levels of DNA damage in blood and hippocampus were evaluated by the comet assay. The micronucleus test was used to evaluate chromosomal damages in the bone marrow. The sucrose treatment significantly increased (p<0.01) the serum glucose levels (~20%) and A1C (~60%). The level of primary DNA damage was significantly increased (p<0.05) in hippocampal cells (~60%) but not in peripheral blood leukocytes (p>0.05). Additionally, it was observed a significative increase (p<0.05) in the markers of chromosomal breaks/losses in bone marrow, as indicated by the micronucleus test. This is the first study that evaluated DNA damage induced by high sucrose concentration in the hippocampus and bone marrow of rats. Sucrose-induced DNA damage was observed in both tissues. However, the mechanism of sucrose toxicity on DNA remains unknown. PMID- 29267794 TI - Palynological analysis of Dennstaedtiaceae taxa from the Paranaense Phytogeografic Province that produce monolete spores and its systematic implications (I): Blotiella lindeniana , Histiopteris incisa and Paesia glandulosa. AB - The genera of Dennstaedtiaceae have sporophytes with very different morphological characteristics between each other, and this feature has made difficult the systematic circumscription of the family. This reason makes necessary the study of new characters that allow a better understanding of the relations within the group. The spore morphology and wall structure of Blotiella lindeniana, Histiopteris incisa and Paesia glandulosa from the Paranaense Phytogeographic Province were studied using light microscope, and scanning and transmission electron microscope. The exospore has two layers and, according to the species, the exospore surface bears pila, echinae, verrucae, bacula and tubercles. The perispore has two or three layers and its surface is psilate, baculate or rugulate. The variability found in the sculpture of the spores and their stratification and ultrastructure of perispore reflects the morphological differences observed in the sporophyte of the species studied. Additionally, while the stratification and ultrastructure of the exospore is shared by the Dennstaedtiaceae species, their ornamentation could be a character to distinguish species into the clade "hypolepidoide". The finding of spores with similar characteristics in phylogenetically unrelated families allows us to suggest that palynological features do not have an evolutionary value to establish relationships between groups above the genus level. PMID- 29267793 TI - 6-Gingerol inhibits hair cycle via induction of MMP2 and MMP9 expression. AB - 6-Gingerol is the major active constituent of ginger. In the current study, we aimed to investigate the mechanisms underlying the effects of 6-Gingerol on hair growth. Mice were randomly divided into five groups; after hair depilation (day 0), mice were treated with saline, or different concentrations of 6-Gingerol for 11 days. The histomorphological characteristics of the growing hair follicles were examined after hematoxylin and eosin staining. The results indicated that 6 Gingerol significantly suppressed hair growth compared with that in the control group. And choose the concentration of 6-Gingerol at 1 mg/mL to treated with mice. Moreover, 6-Gingerol (1 mg/mL) significantly reduced hair re-growth ratio, hair follicle number, and hair follicle length, which were associated with increased expression of MMP2 and MMP9. Furthermore, the growth factors, such as EGF, KGF, VEGF, IGF-1 and TGF-beta participate in the hair follicle cycle regulation and regulate hair growth. We then measured the concentrations of them using ELISA assays, and the results showed that 6-Gingerol decreased EGF, KGF, VEGF, and IGF-1 concentrations, and increased TGF-beta concentration. Thus, this study showed that 6-Gingerol might act as a hair growth suppressive drug via induction of MMP2 and MMP9 expression, which could interfere with the hair cycle. PMID- 29267795 TI - Can nearby eutrophic reservoirs sustain a differentiated biodiversity of planktonic microcrustaceans in a tropical semiarid basin? AB - This paper aims to compare alpha and beta diversities of planktonic microcrustaceans from three reservoirs located nearby in a tropical semiarid basin. Our hypothesis was that alpha and beta diversities of the community are different, although the ecosystems are located close to each other. We carried out two sampling campaigns: dry and rainy seasons. The sampling of microcrustaceans and environmental variables (dissolved oxygen, chlorophyll a and nutrient) was performed at twelve stations and were distributed throughout the three zones (river, transition, and lacustrine), using a plankton net (45 um). The reservoirs showed different uses and types of nitrogen predominance: Cachoeira (supply/nitrate), Borborema (sewage/ammonia) and Saco (aquaculture/ammonia). Seventeen species were recorded whose richness was assessed as particularly specific to each one of the studied reservoirs. Seasonally, both reservoirs with high anthropogenic alteration showed greater richness in the dry season. The three reservoirs located in a same basin showed different richness and composition, but the diversity did not differ between the zones of the reservoirs. Although communities are close to each other, their composition and richness were found to be distinct for each reservoir. This may be in response to the peculiar particularities, such as nitrogen sources and the different uses. PMID- 29267796 TI - Cytogenetics and Molecular Genetic Analysis of Chimerism in Marmosets (Callithrix: Primates). AB - The birth of fraternal twins is a characteristic frequently observed in callitrichids. Cytogenetic studies have demonstrated hematopoietic chimerism in marmosets with the occurrence of two cell lines 2n=46,XX/46,XY in females and males co-twins, without phenotypic changes. Amplification by PCR have also been used to verify the presence of the SRY gene in female chimaeras. Our aim was to verify the occurrence of chimerism in Callithrix sp. individuals considered as hybrids according to their intermediate phenotypes between C. jacchus and C. penicillata. Blood samples from 37 Callithrix sp. individuals were collected. Hematopoietic chimerism 2n=46,XX/46,XY was detected by cytogenetic analysis in five individuals, three males and two females. A fragment of approximately 200bp of the SRY gene was amplified in seven females with normal external genitalia. The percentage of 32% of chimeric individuals detected in the present study is similar to that observed for pure specimens of Callithrix. These data suggests that hybridization probably does not interfere with the occurrence of twin gestation, nor of chimerism. Although cytogenetics is the main tool to identify the two cell lineages present in cases of chimerism, the amplification of the SRY gene by PCR has proved to be more efficient to identify the Y chromosome in cases of chimeric female marmoset. PMID- 29267797 TI - Chemical Composition and Antibacterial Activity of the Essential Oil of Vitex agnus-castus L. (Lamiaceae). AB - Abnormal multiplication of oral bacteria causes dental caries and dental plaque. These diseases continue to be major public health concerns worldwide, mainly in developing countries. In this study, the chemical composition and antimicrobial activity of the essential oil of Vitex agnus-castus leaves (VAC-EO) collected in the North of Brazil against a representative panel of cariogenic bacteria were investigated. The antimicrobial activity of VAC-EO was evaluated in terms of its minimum inhibitory concentration (MIC) values by using the broth microdilution method in 96-well microplates. The chemical constituents of VAC-EO were identified by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). VAC-EO displayed some activity against all the investigated oral pathogens; MIC values ranged from 15.6 to 200 MUg/mL. VAC-EO had promising activity against Streptococcus mutans (MIC= 15.6 MUg/mL), Lactobacillus casei (MIC= 15.6 MUg/mL), and Streptococcus mitis (MIC= 31.2 MUg/mL). The compounds 1,8 cineole (23.8%), (E)-beta-farnesene (14.6%), (E)-caryophyllene (12.5%), sabinene (11.4%), and alpha-terpinyl acetate (7.7%) were the major chemical constituents of VAC-EO. VAC-EO displays antimicrobial activity against cariogenic bacteria. The efficacy of VAC-EO against S. mutans is noteworthy and should be further investigated. PMID- 29267798 TI - Perception, knowledge and attitudes of Brazilian orthodontists on the treatment of Class II malocclusions. AB - The present study aimed to assess the perception and knowledge of Brazilian orthodontists on the ideal moment to treat Class II malocclusions. Questionnaires with open, semi-open and close questions were sent by e-mail to 1653 Brazilian orthodontists. These orthodontists were registered in the Brazilian Association of Orthodontics and Dentofacial Orthopedics (ABOR). One-hundred and three (9.86%) Orthodontists replied to the questionnaires. Most of them were males (60.5%) with specialization as the highest level of professional qualification (59.9%). Most of the orthodontists (51%) reported preference for treating Class II malocclusions in late mixed dentition, followed by the early mixed dentition (29%). The age range between 10 and 12 years old figured as the most prevalent in patients searching for treatment (42.7%). Most of the patients searching for treatment were females (69.7%). Preferences for functional orthopedic appliances were reported by 35% of the orthodontists. Brazilian orthodontists revealed a trend for treating patients with Class II malocclusions in the late mixed dentition. Female patients aged from 10 to 12 years old represented the majority of patients that search for orthodontic treatment. Functional orthopedic appliances were preferred by Brazilian orthodontists for treating Class II malocclusions. PMID- 29267799 TI - Life-long Maternal Cafeteria Diet Promotes Tissue-Specific Morphological Changes in Male Offspring Adult Rats. AB - Here, we evaluated whether the exposure of rats to a cafeteria diet pre- and/or post-weaning, alters histological characteristics in the White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and liver of adult male offspring. Female Wistar rats were divided into Control (CTL; fed on standard rodent chow) and Cafeteria (CAF; fed with the cafeteria diet throughout life, including pregnancy and lactation). After birth, only male offspring (F1) were maintained and received the CTL or CAF diets; originating four experimental groups: CTL-CTLF1; CTL-CAFF1; CAF-CTLF1; CAF-CAFF1. Data of biometrics, metabolic parameters, liver, BAT and WAT histology were assessed and integrated using the Principal Component Analysis (PCA). According to PCA analysis worse metabolic and biometric characteristics in adulthood are associated with the post-weaning CAF diet compared to pre and post weaning CAF diet. Thus, the CTL-CAFF1 group showed obesity, higher deposition of fat in the liver and BAT and high fasting plasma levels of glucose, triglycerides and cholesterol. Interestingly, the association between pre and post-weaning CAF diet attenuated the obesity and improved the plasma levels of glucose and triglycerides compared to CTL-CAFF1 without avoiding the higher lipid accumulation in BAT and in liver, suggesting that the impact of maternal CAF diet is tissue-specific. PMID- 29267800 TI - Evaluation of the impact of pharmaceutical care for tuberculosis patients in a Secondary Referral Outpatient Clinic, Minas Gerais, Brazil. AB - Pharmaceutical care is a professional practice seeking the responsible provision of drug therapy by identifying, resolving, and preventing Drug-Related Problems (DRP). The study aims to describe and evaluate the impact of pharmaceutical care given to patients being treated for tuberculosis (TB). Study concurrent, longitudinal, prospective conducted during pharmaceutical care in the TB outpatient clinic, Clinical Hospital, Federal University of Minas Gerais during the period August 2009 to July 2012. The Pharmacotherapy Workup proposed by Cipolle et al. (2004) was used. Statistical analyses were performed by X2 or Fisher exact test, as appropriate. A total of 62 patients were followed up, and 128 drug-related problems (DRP) were identified: 69.5% related to safety, 13.3% to effectiveness, 12.5% to indication, and 4.7% to treatment adherence, and 62.1% of the DRP were resolved. A total of 115 pharmaceutical interventions were performed. The impact of pharmaceutical care was satisfactory for 73.9% of patients with a resolution rate of 77%. There was a greater impact on pharmaceutical care (index >= 0.50) for those patients who were not smokers (p <0.05). The impact of pharmaceutical care was important, so the pharmacist should work alongside the multidisciplinary team to monitor treatment and perform interventions. PMID- 29267801 TI - Gas exchange and antioxidant activity in seedlings of C opaifera langsdorffii Desf. under different water conditions. AB - The aim of this study was to evaluate gas exchange, efficiency of the photosynthetic apparatus, and antioxidant activity in Copaifera langsdorffii Desf. The seedlings were cultivated under different conditions of water availability, in order to improve the utilization efficiency of available water resources. The seedlings were cultivated in four different water retention capacities (WRC- 25%, 50%, 75%, and 100%), and evaluated at four different time (T- 30, 60, 90, and 120 days). During the experimental period, seedlings presented the highest values for carboxylation efficiency of Rubisco (A/Ci), intrinsic water use efficiency (IWUE = A/gs), chlorophyll index, and stomatal opening, when grown in the substrate with 75% WRC, but the stomatal index (SI) was less the 25% WRC. The efficiency of photosystem II was not significantly altered by the treatments. Comparison between the extreme treatments in terms of water availability, represented by 25% and 100% WRC, represent stress conditions for the species. Water availability causes a high activity of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase) in the plant. PMID- 29267802 TI - Thidiazuron (TDZ) increases fruit set and yield of 'Hosui' and 'Packham's Triumph' pear trees. AB - The low fruit set is one of the main factors leading to poor yield of pear orchards in Brazil. The exogenous application of thidiazuron (TDZ) and aminoethoxyvinilglycine (AVG) has shown promising results in some pear cultivars and other temperate fruit trees. The objective of this study was to evaluate the effect of TDZ and AVG on fruit set, yield, and fruit quality of 'Hosui' and 'Packham's Triumph' pears. The study was performed in a commercial orchard located in Sao Joaquim, SC. Plant material consisted of 'Hosui' and 'Packham's Triumph' pear trees grafted on Pyrus calleryana. Treatments consisted on different rates of TDZ (0 mg L-1, 20 mg L-1, 40 mg L-1 and 60 mg L-1) sprayed at full bloom for both cultivars. An additional treatment of AVG 60 mg L-1 was sprayed one week after full bloom in 'Hosui'. The fruit set, number of fruit per tree, yield, fruit weight, seed number, and fruit quality attributes were assessed. Fruit set and yield of both cultivars are consistently increased by TDZ, within the rates of 20 to 60 mg L-1. Besides, its application increased fruit size of 'Hosui' and did not negatively affect fruit quality attributes of both cultivars. PMID- 29267803 TI - Dynamic Analysis of the Temperature and the Concentration Profiles of an Industrial Rotary Kiln Used in Clinker Production. AB - Cement is one of the most used building materials in the world. The process of cement production involves numerous and complex reactions that occur under different temperatures. Thus, there is great interest in the optimization of cement manufacturing. Clinker production is one of the main steps of cement production and it occurs inside the kiln. In this paper, the dry process of clinker production is analysed in a rotary kiln that operates in counter flow. The main phenomena involved in clinker production is as follows: free residual water evaporation of raw material, decomposition of magnesium carbonate, decarbonation, formation of C3A and C4AF, formation of dicalcium silicate, and formation of tricalcium silicate. The main objective of this study was to propose a mathematical model that realistically describes the temperature profile and the concentration of clinker components in a real rotary kiln. In addition, the influence of different speeds of inlet gas and solids in the system was analysed. The mathematical model is composed of partial differential equations. The model was implemented in Mathcad (available at CCA/UFES) and solved using industrial input data. The proposal model is satisfactory to describe the temperature and concentration profiles of a real rotary kiln. PMID- 29267804 TI - Uniqueness Properties of The Solution of The Inverse Problem for The Sturm Liouville Equation With Discontinuous Leading Coefficient. AB - The present paper studies uniqueness properties of the solution of the inverse problem for the Sturm-Liouville equation with discontinuous leading coefficient and the separated boundary conditions. It is proved that the considered boundary value is uniquely reconstructed, i.e. the potential function of the equation and the constants in the boundary conditions are uniquely determined by given Weyl function or by the given spectral data. PMID- 29267805 TI - Periodic complex map germs and foliations. AB - In this paper we study topological and analytical conditions on the orbits of a germ of diffeomorphism in the complex plane in order to obtain periodicity. In particular, we give a simple proof of a finiteness criteria for groups of analytic diffeomorphisms, stated in Brochero Martinez 2003. As an application, we derive some consequences about the integrability of complex vector fields in dimension three in a neighborhood of a singular point. PMID- 29267806 TI - Qualitative research: where do we stand now? PMID- 29267807 TI - Processes and challenges of the interaction betweeen research and policy from the perspective of researchers. AB - Evidence-informed policies can produce social and economic impacts and equity and health benefits. Interaction between researchers in politics depends on the interests of social stakeholders and favorable political environments. This paper seeks to understand the meanings and researchers' perspectives of interaction processes between scientists and decision-makers that would influence the research impact on the health policy. This is a qualitative content analysis study conducted in 2014 to identify the core meanings and relationships between research and politics. The paper builds on the RAPID program approach of the Overseas Development Institute. Fourteen researchers who conducted maternal and neonatal morbidity and mortality studies sponsored by the Health Ministry were interviewed. Researchers focused on the production of knowledge, strengthening of research capacities and dissemination of results. On some occasions, researchers also participated in the definition of clinical care policies and performance of health services. They pointed to barriers to interact and produce an impact on politics due to tensions in the political, economic and social context, as well as to institutional and organizational changes in the health sector and to the academic evaluation system. PMID- 29267808 TI - Assessment of perceptions of clinical management in courses oriented by competency. AB - The study aims to assess perceptions of mastery of abilities in clinical management in participants of courses oriented by competency and based on active methodologies of teaching and learning, before and after the offered training process. Three conceptual frameworks were utilized: clinical management, expectation of auto-efficacy, and the holistic concept of competency. Methodologically, an electronic instrument was made available to students of the training courses, adapted to the Likert scale, in two stages: before the courses were undertaken and after their completion. The group of subjects that participated simultaneously in both stages was comprised of 825 trainees. Average, mean, standard deviation, and the Wilcoxon test were utilized in the analysis. Generally, in terms of findings, the perception of mastery of abilities in clinical management increased after the courses, proving a positive contribution of the training process of the students. Among other aspects of their results, it is concluded that the educational initiatives studied, oriented by competency and based in active methodologies of teaching and learning, can obtain the increase in perception of their participants regarding the mastery of abilities present in the competency profile, confirming the study's hypothesis. PMID- 29267809 TI - Health pact: approaches and collisions in the federal arena. AB - This article analyze the institutional construction process of the Health Pact, consolidated in 2006 and that expresses an incremental evolution of the regulatory framework of federative relationships in Brazilian National Health System. Even considering that such process has developed in a federative parity arena ( CIT) it is assumed the general hypothesis of Brazilian literature about federalism that suggests the Federal Government dominant role in the formulation of social policies. Using an institutionalist approach, focusing on the relationship between Federalism and Public Policy it was done a qualitative study starting from semi-structured interviews with managers and consultants who participated in the process and analyzing the minutes of meetings from CIT between 2004-2012. The results indicate: the federal government held the formulation initiative, but there was reasonable influence of sub national governments; the long discussions period reflected a high degree of dissent between the federated entities; as a result, the question of financing was transferred to a political commitment for expansion of funding sources to be assumed by the three spheres of government; the Health Pact did not change the dynamics federative relations regarding the frame of regional health care networks. PMID- 29267810 TI - [Emergence of the nursing model transmitted in Spanish universities: an analytical approach through Grounded Theory]. AB - The scope of this paper was to ascertain the meaning of the term "nursing" among teaching nurses at Spanish universities. The research was qualitative, and the strategy used was analytical induction. Sampling was theoretical and focused on the selection of extreme cases and the data collection technique was in-depth interviews. The analysis was carried out using the specific Grounded Theory technique. Strategies were established to ensure credibility, portability, confirmability and auditability. Based on the analysis of the data, three categories were identified that responded to the planned objective: it is a "human activity linked to motherhood," a "vocation to help others that some people have" and an "activity that takes care of the needs of others respecting their identity." It can be concluded that in Spanish universities a model of nurse is being transmitted where the proper role of care is inherent to the feminine gender and the vocation of service to others that some people have. This is the reason why the Spanish Royal Academy (RAE) only identifies the role of technical assistance to medicine as a professional element of nursing. PMID- 29267811 TI - Learning with High Fidelity Simulation. AB - The High-Fidelity Simulation is a fundamental pedagogical method in the nursing student's teaching-learning process. An exploratory and descriptive study was performed by using a qualitative approach in order to understand the Nursing Degree course students' perception about the contribution of the Simulated High Fidelity Practice for clinical competence learning. The self-filling questionnaire, composed of open questions and the technique of content analysis for the treatment of narrative material according to Bardin, was used. With the clinical scenario development, we emphasize the nursing students' perception in the learning of professional competences in three domains with greater focus in the field of care delivery and management. It was concluded that the High fidelity Simulation is a fundamental pillar in the nursing students training, which reinforces the existing pedagogical practice. We stress the need to reformulate the scenarios in order to achieve a better learning balance in the different dimensions of their professional competences and to develop evaluation tools. PMID- 29267812 TI - [Promoting a healthy diet in childhood: weaknesses in the context of Primary Health Care]. AB - This paper reports the experience of the incorporation of perceptions of social actors in the investigation of the weaknesses of the process of implementation of programs that aim to promote a healthy diet in childhood. It involves qualitative research carried out in a medium-sized Brazilian municipality in which the participants were nurses and community health agents. The data were collected through semi-structured questionnaires as well as focus groups. The findings indicated that the quality and continuity of actions to promote a healthy diet were limited due to the precarious working conditions, hence the strong demand for adequate orientation due to the unfavorable context where child health is concerned. Although the reality of peripheral countries points to an incipience in program evaluation, the incorporation of qualitative investigation broadened by the perspective of the participants may constitute an important tool of participation and social responsibility. This minimizes political effects and verticalized and discontinuous actions, helping the generation of opportune and adequate information for the understanding of the different local contexts and social experiences. PMID- 29267813 TI - Faculty teaching skills perceived by medical students of a university of the Brazilian Amazon region. AB - The National Curriculum Guidelines for achieving a medical degree value active teaching methodologies and the application of new teaching skills in the current setting. In this context, we consider that evaluation of teachers by students is an important tool for the development of education. Therefore, we aimed to identify students perceptions about the skills of medical school faculty of the Federal University of Amapa (UNIFAP) through the implementation of a cross sectional and qualitative research from four focus group sessions, attended by 28 volunteer students from the first, second and third year of the course. Sessions were recorded and the content was analyzed in two stages using the Wordle.net platform and Bardin technique. Focal groups discussed five main topics: faculty teaching skills; academic planning; faculty skills evaluation by students; theory practice integration and the teaching-learning process. In general, it was observed that all the students had similar ideas, but those with more years in the course showed greater mastery of subjects. Worth highlighting were the need to improve essential aspects of medical training and the importance of constant evaluation of this process. PMID- 29267814 TI - Reporting child violence, health care flows and work process of primary health care professionals. AB - This study aimed to analyze the flows of the network of children's protection against violence regarding reporting and decisions made. This is a qualitative research based on the Theory of Praxis Interpretation of Community Health Nursing - TIPESC, proposed by Egry, which seeks nursing intervention through a dynamic and participative methodology. Data were collected through official documents and interviews with Primary Health Care professionals in three health facilities of a Brazilian city and analyzed through Dialectical Hermeneutics and the Flowchart Analyzing the Care Model of a Health Service. Results point to the difficulties and weaknesses of the care network in addressing issues, the need for intersectoral actions and the training of professionals to deal with situations of violence. In conclusion, strategies must be adopted to increase the capacity of monitoring and follow-up of reported cases, to provide qualified training of workers and organize the health network, with a view to offering a sufficient number of quality care services and to receive contributions from professionals to address violence against children. PMID- 29267815 TI - Domestic violence against women, public policies and community health workers in Brazilian Primary Health Care. AB - Domestic violence creates multiple harms for women's health and is a 'wicked problem' for health professionals and public health systems. Brazil recently approved public policies to manage and care for women victims of domestic violence. Facing these policies, this study aimed to explore how domestic violence against women is usually managed in Brazilian primary health care, by investigating a basic health unit and its family health strategy. We adopted qualitative ethnographic research methods with thematic analysis of emergent categories, interrogating data with gender theory and emergent Brazilian collective health theory. Field research was conducted in a local basic health unit and the territory for which it is responsible, in Southern Brazil. The study revealed: 1) a yawning gap between public health policies for domestic violence against women at the federal level and its practical application at local/decentralized levels, which can leave both professionals and women unsafe; 2) the key role of local community health workers, paraprofessional health promotion agents, who aim to promote dialogue between women experiencing violence, health care professionals and the health care system. PMID- 29267816 TI - [The National Health Promotion Policy: an evaluability assessment in a health region in Brazil]. AB - The National Health Promotion Policy (PNPS) is based on the broadened concept of health and presents the promotion of health as a set of strategies and ways of promoting health, both individually and collectively with responsibilities for the three federated entities. The scope of this study was to develop an evaluability assessment of the PNPS. It is a qualitative-based evaluability assessment conducted in a health region in the Brazilian Northeast in the year 2013. Participants in the study were 18 key informants directly involved in PNPS implementation, of which eight are municipal health secretaries, six are coordinators of primary health care, two are coordinators of epidemiological surveillance, a general regional coordinator and a regional primary care coordinator. The semi-structured interview and the legal documents of the policy were used for gathering information from 2006 to 2012. The construction of the logical model made it possible to reflect on the possible influences of the context on the PNPS implementation. The results showed that PNPS is not yet sufficiently established in the health region and pointed to the need to incorporate specific monitoring and evaluation instruments for this policy. PMID- 29267817 TI - Most common oral manifestations in pediatric patients HIV positive and the effect of highly active antiretroviral therapy. AB - This integrative literature review aims to identify the main oral lesions affecting pediatric patients with HIV, and describe the effect of highly active antiretroviral therapy (HAART) on these injuries, comparing it to antiretroviral therapy (ART). A search was conducted in PubMed and Scielo databases, following predetermined inclusion and exclusion criteria. 19 papers were selected and the main information on the prevalence and frequency of oral manifestations in HIV positive pediatric patients and effect of therapy applied were extracted. The most frequent injuries were oral candidiasis, gingivitis, parotid gland enlargement and linear gingival erythema. The use of HAART shown to reduce the prevalence of oral manifestations in pediatric patients with HIV and be more effective than ART. The findings of this study suggest that the most frequent oral manifestation in HIV-infected children is oral candidiasis, followed by changes such as gingivitis and enlargement parotid glands. The use of HAART appears to reduce the prevalence of these oral lesions, showing more effective results than ART. PMID- 29267818 TI - [Bullying and psychoactive substance use during adolescence: a systematic review]. AB - Bullying and psychoactive substance abuse are prevalent phenomena among adolescents and identified as health problems that may jeopardise the development of all those involved. This systematic review of the literature aims to identify the extent to which involvement in bullying and psychoactive substance use during adolescence are associated, as well as check for differences regarding the social roles of bullying. From the search for empirical articles published between January 2009 and December 2014 in seven electronic databases, 585 records were identified. After the criteria for inclusion and exclusion were applied, the remaining 40 studies were analyzed based on the design, characteristics of the sample and results of the relationship between bullying and psychoactive substance use. Most studies are quantitative and cross-sectional, and they showed mixed samples of boys and girls in the school environment, which was the place where the phenomena are studied by preference. The association between the perpetration of bullying and psychoactive substance use for adolescents of both sexes is revealed. In relation to victimization by bullying, it was not possible to determine the direction and characterization of the relationship with psychoactive substance use. PMID- 29267819 TI - Working processes of professionals at Psychosocial Care Centers (CAPS): an integrative review. AB - This is an integrative review of the literature on the working processes of professionals staffing the Psychosocial Care Centers (CAPS), reflecting on service practices, in particular social reinsertion of service users from the bio psychosocial perspective. The literature review aims to show how working processes are being developed by CAPS professionals, and the repercussions for service users. This literature review used the Lilacs, SciELO and PubMed databases in Portuguese, English and Spanish, selecting 57 articles that were analyzed and organized using an Excel spreadsheet. This study revealed shortcomings in the amount and quality of physical, human and material resources, a fragile mental health network, and dissonances in the care provided to users and their families, reducing the quality of the working processes. The outcomes mentioned most often were intake, unique therapeutic project and territory as dissonant components of the de-institutionalization proposal. This work combines the experience and knowledge of professionals across the country, with score to guide the re-direction of care practices. PMID- 29267820 TI - Bayesian model and spatial analysis of oral and oropharynx cancer mortality in Minas Gerais, Brazil. AB - The objective of this study was to determine of oral and oropharynx cancer mortality rate and the results were analyzed by applying the Spatial Analysis of Empirical Bayesian Model. To this end, we used the information contained in the International Classification of Diseases (ICD-10), Chapter II, Category C00 to C14 and Brazilian Mortality Information System (SIM) of Minas Gerais State. Descriptive statistics were observed and the gross rate of mortality was calculated for each municipality. Then Empirical Bayesian estimators were applied. The results showed that, in 2012, in the state of Minas Gerais, were registered 769 deaths of patients with cancer of oral and oropharynx, with 607 (78.96%) men and 162 (21.04%) women. There was a wide variation in spatial distribution of crude mortality rate and were identified agglomeration in the South, Central and North more accurately by Bayesian Estimator Global and Local Model. Through Bayesian models was possible to map the spatial clustering of deaths from oral cancer more accurately, and with the application of the method of spatial epidemiology, it was possible to obtain more accurate results and provide subsidies to reduce the number of deaths from this type of cancer. PMID- 29267821 TI - [Patient safety culture in three Brazilian hospitals with different types of management]. AB - The scope of the study was to evaluate patient safety culture and associated factors in Brazilian hospitals with different types of management, namely federal, state and private hospitals. The design was cross-sectional and observational. A survey of 1576 professionals at three hospitals of Rio Grande do Norte state was performed using the Hospital Survey on Patient Safety Culture adapted for Brazil, which measures 12 dimensions of safety culture. Perceptions are described by attributing a general result (Range 0-10) and the percentage of positive responses to estimate their strengths and weaknesses. The response rate was 13.6% (n= 215). The patient safety coefficient was between 7 and 10 for 78.1% of the respondents, whereby the highest average grade was attributed to the private hospital (8.32). It has been estimated that the type of hospital management, unit service, position and number of adverse event notifications are associated with the overall patient safety grade (p <0.001). Only the private hospital had strengths in the dimensions analyzed, while the weaknesses appeared in all the hospitals. PMID- 29267822 TI - Prevalence of signs and symptoms of temporomandibular disorders in college preparatory students: associations with emotional factors, parafunctional habits, and impact on quality of life. AB - The aim of this study was to evaluate the prevalence of temporomandibular disorders (TMD) signs and symptoms, its correlation with gender, parafunctional habits, emotional stress, anxiety, and depression and its impact on oral health related quality of life (OHRQL) in college preparatory students at public and private institutions in Joao Pessoa, Paraiba (PB). The sample consisted of 303 students. Presence of TMD symptoms was determined by an anamnesis questionnaire containing questions related to the presence of parafunctional habits and emotional stress. A simplified clinical evaluation protocol was used. Anxiety and depression were determined with the Hospital Anxiety and Depression (HAD) scale and the OHRQL using the short version contained in the Oral Health Impact Profile (OHIP-14). The Chi-square, Fisher Exact, Mann Whitney, and Kruskal-Wallis tests were performed. Presence of signs and symptoms of TMD was statistically associated (p <= 0,05) with female gender, parafunctional habits, emotional stress, and anxiety, and represented greater impairment of the OHRQL. The physical pain domain was the most affected. The increased prevalence of signs and symptoms of TMD among college preparatory students indicates that there is a need for education and clarification among teachers and students to improve early diagnosis and to prevent the problem. PMID- 29267823 TI - Indicators for teenager's oral health's surveillance. AB - The existence of a few indicators that could guide the evaluation of oral health surveillance in the primary health care attention, mainly in adolescence life cycle, raised the realization of this study. To develop indicators to this end, it was conducted: document analysis to guide the development of a logic model and selection of data to compose indicators. This selection and validation of the logic model were performed by a group of four experts that, from the perspective of the modified Delphi method, analyzed if the model illustrated the activities, results and expected impact of a primary oral health service to enable the adolescents oral health surveillance and assigned points (0-10) to each data proposed. Then, those data judged important by the consensus of experts (media>=7; standard deviation <3) were used to construct indicators. After individual analysis and group discussions, the logical model and 36 of the 48 data, initially proposed, were consensually important, resulting in 26 indicators. The indicators matrix intends to be a situational diagnostic tool to assess, plan and manage health actions to adolescents, but it can be used in other life cycles by its adaptation. PMID- 29267824 TI - Association between burnout syndrome, harmful use of alcohol and smoking in nursing in the ICU of a university hospital. AB - The article aims to determine the presence of burnout syndrome among professionals in the field of Nursing in the Intensive Care Unit in a university hospital and a possible association with consumption of alcohol and tobacco. Participants were 160 nursing professionals from 04 intensive care unit of a university hospital in the period from March 2013 to February 2014. We used a structured questionnaire, plus the smoking history, Maslach Burnout Inventory, Alcohol Use Disorders Identification Test, Fagerstrom Dependence Questionnaire and the measurement of carbon monoxide. We used Fisher's chi-square or Fisher exact test. Syndrome was found in 34 professionals, most of them female, married and young adults. 18 professionals reported being smokers. 6,4% of Nursing Assistants, 50% Practical Nurses and Nurses 71,4% drank moderate; 5,4% Nursing Assistant and 14,3% Nurses scored default risk drinking and only 01 Practical Nurses had possible alcohol dependence. There was a positive association of the syndrome with smoking in 01 ICU. Final considerations: Hospital Intensive Care services need assistance from the managers of services for the purpose of caring for the health of their caregivers. PMID- 29267825 TI - Analysis of new drugs registered in Brazil in view of the Unified Health System and the disease burden. AB - The most important aspect of a new drug in terms of public health is its therapeutic value and benefit it provides for the patient and for the society. The aim of this study was to analyze new drugs registered in Brazil between 2003 and 2013 with respect to Pharmaceutical Assistance programs within the Brazilian health system and to the disease burden in the country. In our retrospective cohort study, new drugs registered in Brazil were identified through document analysis of databases and publicly available documents from National Health Surveillance Agency. The data on disease burden in Brazil was obtained from the Global Burden of Disease Study 2012, published by the World Health Organization. The level of therapeutic innovation was determined using the Motola algorithm. Although a total of 159 new medicines were used in the cohort, only 28 (17.6%) were classified as important therapeutic innovations. There is a disproportionate relationship between the percentage of new drugs and the burden of disease, with an under-representation of drugs for infectious respiratory diseases, heart disease, and digestive diseases. Incentive strategies for research and development of medicines should be prioritized to reduce the disparity regarding the burden of disease and to help develop innovative medicines necessary to improve health throughout the country. PMID- 29267826 TI - National Registry of Health Facilities: data reliability evidence. AB - This study compared the reliability of a data group registered in the secondary databases of the National Registry of Health Facilities. A survey was conducted in 2,777 with hospitals to achieve this objective. Visited hospitals provided information on equipment, geographic location, operating status and number of beds. Regarding matching data between visited hospitals and the National Registry, it can be noted that the operating status was updated in 89% of cases, the number of beds in 44%, 82% had the correct amount of equipment and 63% had accurate geographic coordinates. These findings point to a good reliability of information from the National Registry of Health Facilities, regarding the compared categories, excepting for data on the number of registered beds and for some equipment. As a further development of this work, we stress the need to discuss strategies and incentives to improve the reliability of data that still have inconsistencies, in order to improve the instruments used to formulate public policies. PMID- 29267827 TI - Tuberculosis mortality trend in the state of Parana, Brazil - 1998-2012. AB - The objective was to analyze the trend in tuberculosis mortality in Parana from 1998 to 2012, according to healthcare macro-region-al, gender and age. Ecological study of time series data with the system of the Unified System Mortality Information Health (SIM/SUS). Trend analysis of standardized mortality rates was performed by linear regression segmented identifying the points with the change trend. There were 847 deaths of residents in Parana in the period. The trend was initially declining to state, with subsequent significant increase only for the macro-regional East. Mortality from tuberculosis showed growing trend for the age groups 20-39 years and 40-49 years and for males. The growing trend in tuberculosis mortality was observed from 2010 is a warning to managers honing the service at different levels of health care. PMID- 29267828 TI - [Inequalities in dental care during the life course of young people: a cohort study]. AB - The scope of this study was to investigate dental care from the life course perspective and its determinant factors among young people in the city of Sobral, State of Ceara, Brazil. A cohort study was conducted with waves in 2000, 2006 and 2012 with 482 young people aged between 17 and 21 years. Two outcomes were investigated: immediate dental care and the lack of dental care, based on the dental trajectory in relation to restorative treatment. Socioeconomic conditions and recourse to oral health services and actions in the three waves investigated were used as independent variables. It was found that low socioeconomic status throughout life presented itself as a risk factor for lack of dental care and the inverse effect was observed with immediate dental care. Participation in groups of teenagers was also related to dental care, as well as receiving information on oral health. This study revealed the presence of inequalities in dental care throughout the life course of the population assessed. PMID- 29267829 TI - [Empowerment, stress vulnerability and burnout among Portuguese nursing staff]. AB - The work environment in Portuguese hospitals, characterized by economic cutbacks, can lead to higher levels of burnout experienced by nursing staff. Furthermore, vulnerability to stress can negatively affect the perception of burnout in the workplace. However, structural empowerment is an organizational process that can prevent and decrease burnout among nurses. Consequently, the aim of the study was to examine to what extent structural empowerment and vulnerability to stress can play a predictive role in core burnout in a sample of Portuguese nurses. A convenience sample of 297 nursing staff members from Portuguese hospitals was used in this study. Core burnout was negatively and significantly related to all the dimensions of structural empowerment, and it was positively and significantly related to vulnerability to stress. Regression models showed that core burnout was significantly predicted by access to funds, access to opportunities and vulnerability to stress. Organizational administrations must make every effort in designing interventions focused on structural empowerment, as well as interventions focused on individual interventions that enhance skills for coping with stress. PMID- 29267830 TI - [Discomfort associated with dental extraction surgery and development of a questionnaire (QCirDental). Part I: Impacts and internal consistency]. AB - The scope of this study was to develop and validate a questionnaire (QCirDental) to measure the impacts associated with dental extraction surgery. The QCirDental questionnaire was developed in two steps; (1) question and item generation and selection, and (2) pretest of the questionnaire with evaluation of the its measurement properties (internal consistency and responsiveness). The sample was composed of 123 patients. None of the patients had any difficulty in understanding the QCirDental. The instrument was found to have excellent internal consistency with Cronbach's alpha reliability coefficient of 0.83. The principal component analysis (Kaiser-Meyer-Olkin Measure of Sampling Adequacy 0,72 and Bartlett's Test of Sphericity with p < 0.001) showed six (6) dimensions explaining 67.5% of the variance. The QCirDental presented excellent internal consistency, being a questionnaire that is easy to read and understand with adequate semantic and content validity. More than 80% of the patients who underwent dental extraction reported some degree of discomfort within the perioperative period which highlights the necessity to assess the quality of care and impacts of dental extraction surgery. PMID- 29267831 TI - Variables related to suicide attempt in a Spanish province over a three-year period (2009-2011). AB - The aim was to identify and describe socio demographic and clinical variables in individuals who have made a suicide attempt. An analysis of electronically stored records on persons admitted to the emergency departments of a northern health district during the period 2009-2011 for mental disorders was conducted. The records of 826 patients (30.1% of the total), where 485 (58.7%) were female, aged between 14 and 94 years (M = 49.3; SD = 12.7), were selected. This amounted to 412 individuals (49.9%) who had made a suicide attempt, and were compared with others without prior suicide attempt. A binary logistic regression analysis was performed to examine the strongest predictors of suicide attempt. The results show that the risk of making a suicide attempt increases with age, those most at risk being aged 34 to 53 years (p < 0.01; OR = 6.99), female (p < 0.05; OR = 2.70) and unemployed (p < 0.05; OR = 4.98). The most predictive psychopathological diagnoses for suicide attempt were anxiety disorders (p < 0.01; OR = 3.95) and impulse control disorders/addictions (p < 0.01; OR = 3.76). The importance of creating specific risk and protection profiles when implementing contextualized health policies on suicide attempt prevention is discussed. PMID- 29267832 TI - Factors associated with absences from orthodontic treatment at a dental specialty center. AB - : The aim of this study was to identify the factors associated with the users failing to keep orthodontic treatment appointments (absences), in three regional dental specialty centers (CEO-R) located in the State of Ceara. METHODOLOGY: This was a cross-sectional epidemiological study with secondary data source of 3 CEO R, from which 237 medical records of complete orthodontic treatments were examined, with 8.283 appointments and 2.665 (32.17%) missing appointments. Data collection was standardized by an electronic questionnaire.. Factors associated with users missing appointments were calculated by means of absence rates and thematic maps were constructed based on distributions of the geographical pattern of occurrence. To evaluate the association between the outcome variable (absence from treatment) and the independent variables (sex, age, breakage of appliance, change of professional, income and place of user's residence) multiple logistic regression analysis was used with p <= 0.05. RESULTS: There were high absence rates for both city headquarters and non-headquarter CEO-Rs. The variable change of professional showed statistical significance, in relation to the number of absences. CONCLUSION: The highest number of absences was associated with change of professional. PMID- 29267833 TI - Needs and dynamics of the Primary Healthcare workforce in Brazil. AB - Primary care and the healthcare workforce can be considered the greatest challenges of SUS (Sistema Unico de Saude), principally in recent decades. This article aims to describe the growth and regional distribution of the professions requiring higher education registered in the primary healthcare units. This descriptive study with a quantitative approach is concerned with the 14 accredited professions in the five major regions of Brazil from 2008 to 2013. The data was collected from the national database of the Ministry of Health. Among the professional categories with the greatest rates of national growth are physical education teachers, nutritionists, occupational therapists, physiotherapists, and pharmacists. In the North region of Brazil, physiotherapy, social work, and speech therapy stand out as having the greatest growth rates; in the Northeast, physical education, physiotherapy, and occupational therapy; and in the Center-West, nutrition and physiotherapy; in the Southeast, nutrition and pharmacology; and physical education showed prominent growth in the South. The major losses occurred in the professions of biologist and veterinary doctors in all regions. In general, the professional categories that comprise the Family Health Support Nuclei, NASF, demonstrate greater growth rates than nurses and doctors. PMID- 29267834 TI - Association between the risk of alcohol use and unprotected sex in adolescents in a city in the southern region of Brazil. AB - This paper aims to analyze alcohol abuse and unprotected sex and the association between them in students in a city in the southern region of Brazil. This is a cross-sectional study using a quantitative approach with 590 secondary school students from two public schools. Regarding alcohol use, 14% scored from eight to 40 in The Alcohol Use Disorders Identification Test (AUDIT), which means, at least, a risky drinking behavior, with higher rate among boys. Moreover, 31.1% indulged themselves in binge drinking, which means drinking six or more doses according to AUDIT; and even among those who are low- risk drinkers, 21.1% had this drinking pattern. Regarding sexual behavior, young boys started sexual life earlier and the kind of relationship more referred to by them is one with no commitment; boys have uncommitted relationships, while girls have more relationships with commitment. In relation to the results of the association between alcohol use and sexual intercourse, 47.3% stated alcohol use before having sex, and those who started sexual activity got more drunk and had higher scores in the AUDIT. New studies are recommended regarding the association between both behaviors in Brazil, considering that the causal relationship is not clear and shows several explanation models. PMID- 29267835 TI - Noise in early childhood education institutions. AB - High sound pressure levels have been observed in schools, and its interference in the health of children and teachers it was taken to analyze these levels in childhood education centers serving children aged zero to six years, investigate the staff's perceptions concerning noise exposure and identify the auditory conditions of these workers and the occurrence of diseases. The study was conducted in ten institutions employing 320 workers. Sound pressure levels were measured according to the technical norms; employees completed a questionnaire on the perception of noise and underwent auditory evaluation. There was high sound pressure level and differences between institutions, situations and places. Most employees are considered exposed to noise with attention and concentration difficulties, anxiety and headache. About 30% of employees had bilateral sensorineural hearing loss in specific frequency. The sound pressure levels found can affect children's learning and the health of all. The employees also perceived elevated levels of noise and indicated some possible negative aspects in their work routine. Actions to improve the acoustic comfort in these institutions will be discussed with the management teams. PMID- 29267836 TI - Oral Health in the Family Health Strategy: analysis of articles published in the period 2004-2014. AB - This study aimed to conduct an integrative review of scientific literature on the topic of Oral Health in the Family Health Strategy in the period 2004-2014. Articles published in national and international journals (n = 141) were consulted and selected from the electronic Library the Scientific Electronic Library Online (SciELO) and from electronic databases PubMed, Lilacs, BBO and Cochrane. The implementation process of oral health teams in the Family Health Strategy was the most frequent thematic variable (18%) of the 15 variables identified. The Northeast was the Brazilian macro-region where the largest number of published articles originated (n = 61). The studies were predominantly quantitative, and the highest number of publications occurred in 2010 (n = 26). We concluded that there is an increasing interest in investigating the context of oral health implementation in the Family Health Strategy, with particular emphasis on theme categories related to the micro-process work and the redefinition of professional identities arising from multidisciplinary work in primary care. PMID- 29267837 TI - [Divergent estimates of falls among the elderly: an epidemiological debate based on the conceptual characteristics]. PMID- 29267838 TI - The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC. PMID- 29267839 TI - A special issue on TGF-beta signaling: regulation, crosstalk, and biology. PMID- 29267840 TI - Accurate identification of hospital admissions from care homes; development and validation of an automated algorithm. AB - Background: measuring the complex needs of care home residents is crucial for resource allocation. Hospital patient administration systems (PAS) may not accurately identify admissions from care homes. Objective: to develop and validate an accurate, practical method of identifying care home resident hospital admission using routinely collected PAS data. Method: admissions data between 2011 and 2012 (n = 103,105) to an acute Trust were modelled to develop an automated tool which compared the hospital PAS address details with the Care Quality Commission's (CQC) database, producing a likelihood of care home residency. This tool and the Nuffield method (CQC postcode match only) were validated against a manual check of a random sample of admissions (n = 2,000). A dataset from a separate Trust was analysed to assess generalisability. Results: the hospital PAS was inaccurate; none of the admissions from a care home identified on manual check had a care home source of admission recorded on the PAS. Both methods performed well; the automated tool had a higher positive predictive value than the Nuffield method (100% 95% confidence interval (CI) 98.23-100% versus 87.10% 95%CI 82.28-91.00%), meaning those coded as care home residents were more likely to actually be from a care home. Our automated tool had a high level of agreement 99.2% with the second Trust's data (Kappa 0.86 P < 0.001). Conclusions: care home status is not routinely or accurately captured. Automated matching offers an accurate, repeatable, scalable method to identify care home residency and could be used as a tool to benchmark how care home residents use acute hospital resources across the National Health Service. PMID- 29267841 TI - Corrigendum: Consumption of Alcoholic Energy Drinks Is Associated with Work related Injury or Disease Among Manual Workers in Taiwan. PMID- 29267842 TI - Hemolysis in In-Date RBC Concentrates. AB - Objectives: Hemolysis is one of the most prominent changes that occur during the liquid storage of RBCs in additive solution (AS), but most studies have measured hemolysis only on day 42. Methods: Prestorage leukoreduced RBCs in AS-1 and AS-3 were studied, one group on day 42 and a second group between day 0 and day 40. Each product was sampled for direct measurement of supernatant hemoglobin and hematocrit. Results: Ninety day 42 and 218 day 7 to day 39 RBCs showed a mean +/- SD supernatant hemoglobin of 75 +/- 100 vs 25.5 +/- 16 mg/dL respectively (P < .01). Supernatant hemoglobin correlated weakly with storage age (r = 0.2, P < .01) but more strongly with hematocrit (r = 0.4, P < .01). Conclusions: There are minimal differences in supernatant hemoglobin until the final days of liquid storage when some high hematocrit RBCs show excessive hemolysis. PMID- 29267843 TI - Cost Analysis of Operating an Anatomic Pathology Laboratory in a Middle-Income Country. AB - Objective: To examine the cost of operating an anatomic pathology laboratory in a teaching hospital in Malaysia. Once the cost is determined, compare it with the costs of operating other laboratories in the same hospital, and operating anatomic pathology laboratories in other countries. Methods: Cost and workload data were obtained from hospital records for 2015. Time allocation of staff between laboratory testing and other activities was determined using assumptions from published workload studies. Results: The laboratory received 20,093 cases for testing in 2015, and total expenditures were US $1.20 million, ie, $61.97 per case. The anatomic pathology laboratory accounted for 5.2% of the laboratory budget at the hospital, compared to 64.3% for the clinical laboratory and 30.5% for the microbiology laboratory. We provide comparisons to a similar laboratory in the United States. Conclusions: Anatomic pathology is more costly than other hospital laboratories due to the labor-intensive work, but is essential, particularly for cancer diagnoses and treatment. PMID- 29267845 TI - Concurrent cisplatin and radiotherapy versus cetuximab and radiotherapy, an unsolved problem. PMID- 29267844 TI - Nalmefene attenuates malignant potential in colorectal cancer cell via inhibition of opioid receptor. AB - Morphine is postulated a risk factor in promoting tumor growth and metastasis during the preoperative period, and high glycolysis of tumor cells is proved to accelerate tumor progression. In this study, we investigated whether nalmefene, an opioid receptor inhibitor, could inhibit CT26 colon cancer cell growth through influencing cell glycolysis. CCK8 and transwell migration assays showed that nalmefene inhibited CT26 cells viability and migration in a concentration dependent manner. Extracellular acidification rate and oxygen consumption rate showed that nalmefene inhibited glycolysis of CT26 cells. Moreover, western blot analysis and quantitative real-time PCR revealed that nalmefene decreased the expressions of enzymes related to glycolysis. Flow cytometry results revealed that intracellular calcium (Ca2+) level was changed by nalmefene, western blot analysis showed that nalmefene decreased calmodulin expression and calcium/calmodulin dependent protein kinases II (CaMK II) phosphorylation, thus inhibiting the serine/threonine kinase (AKT)-glycogen synthase kinase-3beta (GSK 3beta) pathway. Furthermore, the effects of KN93, an inhibitor of CaMK II, were similar to the effects of nalmefene, and the anti-tumor effect of nalmefene could be counteracted by morphine. In conclusion, the anti-tumor effect of nalmefene may be achieved by inhibiting opioid receptor and down-regulating calmodulin expression and CaMK II phosphorylation, thus inhibiting AKT-GSK-3beta pathway and the glycolysis of CT26 cells. PMID- 29267846 TI - Root hairs increase rhizosphere extension and carbon input to soil. AB - Background and Aims: Although it is commonly accepted that root exudation enhances plant-microbial interactions in the rhizosphere, experimental data on the spatial distribution of exudates are scarce. Our hypothesis was that root hairs exude organic substances to enlarge the rhizosphere farther from the root surface. Methods: Barley (Hordeum vulgare 'Pallas' - wild type) and its root hairless mutant (brb) were grown in rhizoboxes and labelled with 14CO2. A filter paper was placed on the soil surface to capture, image and quantify root exudates. Key Results: Plants with root hairs allocated more carbon (C) to roots (wild type: 13 %; brb: 8 % of assimilated 14C) and to rhizosheaths (wild type: 1.2 %; brb: 0.2 %), while hairless plants allocated more C to shoots (wild type: 65 %; brb: 75 %). Root hairs increased the radial rhizosphere extension three fold, from 0.5 to 1.5 mm. Total exudation on filter paper was three times greater for wild type plants compared to the hairless mutant. Conclusion: Root hairs increase exudation and spatial rhizosphere extension, which probably enhance rhizosphere interactions and nutrient cycling in larger soil volumes. Root hairs may therefore be beneficial to plants under nutrient-limiting conditions. The greater C allocation below ground in the presence of root hairs may additionally foster C sequestration. PMID- 29267847 TI - Adjusting for bias introduced by instrumental variable estimation in the Cox proportional hazards model. AB - Instrumental variable (IV) methods are widely used for estimating average treatment effects in the presence of unmeasured confounders. However, the capability of existing IV procedures, and most notably the two-stage residual inclusion (2SRI) algorithm recommended for use in non-linear contexts, to account for unmeasured confounders in the Cox proportional hazard model is unclear. We show that instrumenting an endogenous treatment induces an unmeasured covariate, referred to as an individual frailty in survival analysis parlance, which if not accounted for leads to bias. We propose a new procedure that augments 2SRI with an individual frailty and prove that it is consistent under certain conditions. The finite sample-size behavior is studied across a broad set of conditions via Monte Carlo simulations. Finally, the proposed methodology is used to estimate the average effect of carotid endarterectomy versus carotid stenting on the mortality of patients suffering from carotid artery disease. Results suggest that the 2SRI-frailty estimator generally reduces the bias of both point and interval estimators compared to traditional 2SRI. PMID- 29267848 TI - ProbAnnoWeb and ProbAnnoPy: probabilistic annotation and gap-filling of metabolic reconstructions. AB - Summary: Gap-filling is a necessary step to produce quality genome-scale metabolic reconstructions capable of flux-balance simulation. Most available gap filling tools use an organism-agnostic approach, where reactions are selected from a database to fill gaps without consideration of the target organism. Conversely, our likelihood based gap-filling with probabilistic annotations selects candidate reactions based on a likelihood score derived specifically from the target organism's genome. Here, we present two new implementations of probabilistic annotation and likelihood based gap-filling: a web service called ProbAnnoWeb, and a standalone python package called ProbAnnoPy. Availability and implementation: Our tools are available as a web service with no installation needed (ProbAnnoWeb) at probannoweb.systemsbiology.net, and as a local python package implementation (ProbAnnoPy) at github.com/PriceLab/probannopy. Contact: evangelos.simeonidis@systemsbiology.org or nathan.price@systemsbiology.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29267849 TI - Role of calcium-sensing receptor in regulating spontaneous activation of postovulatory aging rat oocytes. AB - Mechanisms for postovulatory aging (POA) of oocytes and for spontaneous activation (SA) of rat oocytes are largely unknown. Expression of calcium-sensing receptor (CaSR) in rat oocytes and its role in POA remain unexplored. In this study, expression of CaSR in rat oocytes aging for different times was detected by immunofluorescence microscopy, and western blotting and the role of CaSR in POA was determined by observing the effects of regulating its activity on SA susceptibility and cytoplasmic calcium levels. The results showed that CaSR was expressed in rat oocytes. Oocytes recovered 19 h post human chorionic gonadotropin (hCG) injection were more susceptible to SA and expressed more functional CaSR than oocytes recovered 13 h after hCG injection, although both expressed the same level of total CaSR protein. Treatment with CaSR antagonist significantly suppressed cytoplasmic calcium elevation and SA of oocytes. Activation of Na-Ca2+ exchanger with NaCl inhibited SA to a greater extent than suppression of CaSR with NPS-2143, suggesting that calcium sources other than CaSR-controlled channels contributed to the elevation of cytoplasmic calcium. Treatment with T- or L-type calcium channel blockers significantly reduced SA. Suppression of all calcium channels tested reduced SA to minimum. It is concluded that the level of CaSR functional dimer protein, but not that of the total CaSR protein, was positively correlated with the SA susceptibility during POA of rat oocytes confirming that CaSR is involved in POA regulation. Blocking multiple calcium channels might be a better choice for efficient control of SA in rat oocytes. PMID- 29267850 TI - Rcupcake: an R package for querying and analyzing biomedical data through the BD2K PIC-SURE RESTful API. AB - Motivation: In the era of big data and precision medicine, the number of databases containing clinical, environmental, self-reported and biochemical variables is increasing exponentially. Enabling the experts to focus on their research questions rather than on computational data management, access and analysis is one of the most significant challenges nowadays. Results: We present Rcupcake, an R package that contains a variety of functions for leveraging different databases through the BD2K PIC-SURE RESTful API and facilitating its query, analysis and interpretation. The package offers a variety of analysis and visualization tools, including the study of the phenotype co-occurrence and prevalence, according to multiple layers of data, such as phenome, exposome or genome. Availability and implementation: The package is implemented in R and is available under Mozilla v2 license from GitHub (https://github.com/hms dbmi/Rcupcake). Two reproducible case studies are also available (https://github.com/hms-dbmi/Rcupcake-case studies/blob/master/SSCcaseStudy_v01.ipynb, https://github.com/hms-dbmi/Rcupcake case-studies/blob/master/NHANEScaseStudy_v01.ipynb). Contact: paul_avillach@hms.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29267851 TI - Sequential feature selection and inference using multi-variate random forests. AB - Motivation: Random forest (RF) has become a widely popular prediction generating mechanism. Its strength lies in its flexibility, interpretability and ability to handle large number of features, typically larger than the sample size. However, this methodology is of limited use if one wishes to identify statistically significant features. Several ranking schemes are available that provide information on the relative importance of the features, but there is a paucity of general inferential mechanism, particularly in a multi-variate set up. We use the conditional inference tree framework to generate a RF where features are deleted sequentially based on explicit hypothesis testing. The resulting sequential algorithm offers an inferentially justifiable, but model-free, variable selection procedure. Significant features are then used to generate predictive RF. An added advantage of our methodology is that both variable selection and prediction are based on conditional inference framework and hence are coherent. Results: We illustrate the performance of our Sequential Multi-Response Feature Selection approach through simulation studies and finally apply this methodology on Genomics of Drug Sensitivity for Cancer dataset to identify genetic characteristics that significantly impact drug sensitivities. Significant set of predictors obtained from our method are further validated from biological perspective. Availability and implementation: https://github.com/jomayer/SMuRF. Contact: souparno.ghosh@ttu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29267852 TI - Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells. PMID- 29267853 TI - Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. AB - Aims: Several techniques have been utilized for the ablation of persistent (P) and long-standing persistent (LsP) atrial fibrillation (AF); however, the best approach of substrate ablation remains poorly defined. This study aims to examine the impact of ablation approach on outcomes associated with P or LsP AF ablation by conducting a meta-analysis and regression on contemporary literature. Methods and results: A systematic literature review was conducted up to 29 July 2015 for scientific literature reporting on outcomes associated with P or LsP AF ablation. One hundred and thirteen studies reported outcomes in a total of 18 657 patients undergoing various ablation approaches for the treatment of P-LsP AF between 2001 and 2015. The point efficacy estimate of a single-AF ablation procedure without the use of anti-arrhythmic drugs was 43% (95% CI; 39-47%). Multiple procedures and/or the use of anti-arrhythmic drugs increase success to 69% (95% CI; 66-71%). Meta-regression revealed that ablation technique (P < 0.001) and left atrial size (P = 0.02) were predictive of single procedure, drug-free success. The addition of extra-pulmonary substrate approaches was associated with declining efficacy when compared to a pulmonary vein ablation alone. Conclusion: The efficacy of a single-AF ablation procedure for P or LsP AF is 43%; however, can be increased to 69% with the use of multiple procedures and/or anti-arrhythmic drugs. Current literature supports the finding that pulmonary vein antrum ablation/isolation is at least equivalently efficacious to other contemporary P-LsP ablation strategies. PMID- 29267854 TI - Draft genome of the milu (Elaphurus davidianus). AB - Background: Milu, also known as Pere David's deer (Elaphurus davidianus), was widely distributed in East Asia but recently experienced a severe bottleneck. Only 18 survived by the end of the 19th century, and the current population of 4500 individuals was propagated from just 11 kept by the 11th British Duke of Bedford. This species is known for its distinguishable appearance, the driving force behind which is still a mystery. To aid efforts to explore these phenomena, we constructed a draft genome of the species. Findings: In total, we generated 321.86 gigabases (Gb) of raw DNA sequence from whole-genome sequencing of a male milu deer using an Illumina HiSeq 2000 platform. Assembly yielded a final genome with a scaffold N50 size of 3.03 megabases (Mb) and a total length of 2.52 Gb. Moreover, we identified 20 125 protein-coding genes and 988.1 Mb of repetitive sequences. In addition, homology-based searches detected 280 rRNA, 1335 miRNA, 1441 snRNA, and 893 tRNA sequences in the milu genome. The divergence time between E. davidianus and Bos taurus was estimated to be about 28.20 million years ago (Mya). We identified 167 species-specific genes and 293 expanded gene families in the milu lineage. Conclusions: We report the first reference genome of milu, which will provide a valuable resource for studying the species' demographic history of severe bottleneck and the genetic mechanism(s) of special phenotypic evolution. PMID- 29267855 TI - BS-virus-finder: virus integration calling using bisulfite sequencing data. AB - Background: DNA methylation plays a key role in the regulation of gene expression and carcinogenesis. Bisulfite sequencing studies mainly focus on calling single nucleotide polymorphism, different methylation region, and find allele-specific DNA methylation. Until now, only a few software tools have focused on virus integration using bisulfite sequencing data. Findings: We have developed a new and easy-to-use software tool, named BS-virus-finder (BSVF, RRID:SCR_015727), to detect viral integration breakpoints in whole human genomes. The tool is hosted at https://github.com/BGI-SZ/BSVF. Conclusions: BS-virus-finder demonstrates high sensitivity and specificity. It is useful in epigenetic studies and to reveal the relationship between viral integration and DNA methylation. BS-virus-finder is the first software tool to detect virus integration loci by using bisulfite sequencing data. PMID- 29267856 TI - Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters-patient-centered end points in trials of maintenance therapy. AB - Background: Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methods: HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. Results: There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI - 0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366 404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P < 0.0001). Median time to second line chemotherapy was 19.7 months with PZ and 15.0 months with P [hazard ratio (HR) 0.72, 95% CI 0.69-0.86, P = 0.0001]. Conclusions: There were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. Clinical Trials Registration Number: NCT00866697. PMID- 29267858 TI - Hybrid-denovo: a de novo OTU-picking pipeline integrating single-end and paired end 16S sequence tags. AB - Background: Illumina paired-end sequencing has been increasingly popular for 16S rRNA gene-based microbiota profiling. It provides higher phylogenetic resolution than single-end reads due to a longer read length. However, the reverse read (R2) often has significant low base quality, and a large proportion of R2s will be discarded after quality control, resulting in a mixture of paired-end and single end reads. A typical 16S analysis pipeline usually processes either paired-end or single-end reads but not a mixture. Thus, the quantification accuracy and statistical power will be reduced due to the loss of a large amount of reads. As a result, rare taxa may not be detectable with the paired-end approach, or low taxonomic resolution will result in a single-end approach. Results: To have both the higher phylogenetic resolution provided by paired-end reads and the higher sequence coverage by single-end reads, we propose a novel OTU-picking pipeline, hybrid-denovo, that can process a hybrid of single-end and paired-end reads. Using high-quality paired-end reads as a gold standard, we show that hybrid denovo achieved the highest correlation with the gold standard and performed better than the approaches based on paired-end or single-end reads in terms of quantifying the microbial diversity and taxonomic abundances. By applying our method to a rheumatoid arthritis (RA) data set, we demonstrated that hybrid denovo captured more microbial diversity and identified more RA-associated taxa than a paired-end or single-end approach. Conclusions: Hybrid-denovo utilizes both paired-end and single-end 16S sequencing reads and is recommended for 16S rRNA gene targeted paired-end sequencing data. PMID- 29267857 TI - A hybrid-hierarchical genome assembly strategy to sequence the invasive golden mussel, Limnoperna fortunei. AB - Background: For more than 25 years, the golden mussel, Limnoperna fortunei, has aggressively invaded South American freshwaters, having travelled more than 5000 km upstream across 5 countries. Along the way, the golden mussel has outcompeted native species and economically harmed aquaculture, hydroelectric powers, and ship transit. We have sequenced the complete genome of the golden mussel to understand the molecular basis of its invasiveness and search for ways to control it. Findings: We assembled the 1.6-Gb genome into 20 548 scaffolds with an N50 length of 312 Kb using a hybrid and hierarchical assembly strategy from short and long DNA reads and transcriptomes. A total of 60 717 coding genes were inferred from a customized transcriptome-trained AUGUSTUS run. We also compared predicted protein sets with those of complete molluscan genomes, revealing an exacerbation of protein-binding domains in L. fortunei. Conclusions: We built one of the best bivalve genome assemblies available using a cost-effective approach using Illumina paired-end, mate-paired, and PacBio long reads. We expect that the continuous and careful annotation of L. fortunei's genome will contribute to the investigation of bivalve genetics, evolution, and invasiveness, as well as to the development of biotechnological tools for aquatic pest control. PMID- 29267859 TI - Accurate prediction of personalized olfactory perception from large-scale chemoinformatic features. AB - Background: The olfactory stimulus-percept problem has been studied for more than a century, yet it is still hard to precisely predict the odor given the large scale chemoinformatic features of an odorant molecule. A major challenge is that the perceived qualities vary greatly among individuals due to different genetic and cultural backgrounds. Moreover, the combinatorial interactions between multiple odorant receptors and diverse molecules significantly complicate the olfaction prediction. Many attempts have been made to establish structure-odor relationships for intensity and pleasantness, but no models are available to predict the personalized multi-odor attributes of molecules. In this study, we describe our winning algorithm for predicting individual and population perceptual responses to various odorants in the DREAM Olfaction Prediction Challenge. Results: We find that random forest model consisting of multiple decision trees is well suited to this prediction problem, given the large feature spaces and high variability of perceptual ratings among individuals. Integrating both population and individual perceptions into our model effectively reduces the influence of noise and outliers. By analyzing the importance of each chemical feature, we find that a small set of low- and nondegenerative features is sufficient for accurate prediction. Conclusions: Our random forest model successfully predicts personalized odor attributes of structurally diverse molecules. This model together with the top discriminative features has the potential to extend our understanding of olfactory perception mechanisms and provide an alternative for rational odorant design. PMID- 29267860 TI - The Effect of Implant Type on Nipple Position Geometry and Aesthetics Following Tissue Expander Reconstruction After Nipple Sparing Mastectomy. AB - Background: While recent studies have reported modest to no difference in breast aesthetics for shaped and round implant types in breast augmentations, the anatomy and biomechanics in the setting of breast reconstruction is different. Objectives: Accordingly, we endeavored to evaluate whether two implant types impacted nipple position and aesthetic features in prosthetic breast reconstruction. Methods: A retrospective chart review was carried out on patients who underwent nipple-sparing mastectomy (NSM) with immediate tissue expander breast reconstruction. Patients were divided into two cohorts: smooth round implants and textured shaped implants. Postoperative photographs were evaluated to assess nipple displacement vis-a-vis a vector of maximal projection and aesthetic outcome for features of breast shape. Results: Of 102 breasts meeting the inclusion criteria, 41 had tissue expander-implant reconstruction with anatomical shaped implants, and 61 had reconstruction with smooth round implants. The shaped implant cohort had less nipple deviation from the point of maximal projection (3.69 +/- 6.24 vs 7.52 +/- 10.50; P < 0.0001). Graded semi quantitative aesthetic scores were also higher (4.04 +/- 0.67 vs 3.72 +/- 0.93; P = 0.0044) in the shaped implants than in the round cohort. Conclusions: Unlike breast augmentation, there is a paucity of overlying breast tissue and larger dissected spaces in prosthetic breast reconstruction. Our analysis suggests that in this setting, textured anatomic implants result in less nipple deviation from the point of maximum projection and improved aesthetic outcomes compared to round implants. When considering implant choice in NSM reconstruction, the manifold risks of shaped textured implants must thus be informed by potential aesthetic benefits with respect to shape and enhanced nipple sensation. Level of Evidence 4: PMID- 29267861 TI - Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer. AB - Background: Androgens are generally immunosuppressive, and men with untreated hypogonadism are at increased risk for autoimmune conditions. To date, there has been no evidence linking androgen deprivation therapy (ADT) to autoimmune diseases, including rheumatoid arthritis (RA). We investigated the association between ADT and RA in patients with prostate cancer. Patients and methods: We identified 105 303 men age 66 years or older who were diagnosed with stages I-III prostate cancer from 1992 through 2006 using the Surveillance, Epidemiology, and End Results-Medicare linked database, excluding patients with a history of RA. chi2 test was used to compare 5-year Kaplan-Meier rates of RA diagnoses. Competing risk Cox regression using inverse probability of treatment weighting was utilized to examine the association between pharmacologic ADT and diagnosis of RA. Results: The 43% of patients (N = 44 785) who received ADT experienced a higher 5-year rate of RA diagnoses compared with men who did not (5.4% versus 4.4%, P < 0.001). Receipt of any ADT was associated with a 23% increased risk of being diagnosed with RA (hazard ratio 1.23, 95% confidence interval 1.09-1.40, P = 0.001). The risk of being diagnosed with RA increased with a longer duration of ADT, from 19% with 1-6 months and 29% with 7-12 months to 33% with >=13 months (Ptrend < 0.001). Conclusions: Consistent with the immunosuppressive properties of androgens, we demonstrated for the first time that ADT was associated with an elevated risk of being diagnosed with RA in this large cohort of elderly men with prostate cancer. The risk was higher with a longer duration of ADT. Linking ADT to an increased risk of being diagnosed with an autoimmune condition adds to mounting evidence of the adverse effects of ADT that should prompt physicians to thoughtfully weigh its risks and benefits. PMID- 29267862 TI - Bioinformatics in the Netherlands: the value of a nationwide community. PMID- 29267864 TI - Commentary on: Biceps Augmentation Using Solid Silicone Implants. PMID- 29267863 TI - Phase I-II clinical trial design: a state-of-the-art paradigm for dose finding. AB - Background: Conventional phase I algorithms for finding a phase-2 recommended dose (P2RD) based on toxicity alone is problematic because the maximum tolerated dose (MTD) is not necessarily the optimal dose with the most desirable risk benefit trade-off. Moreover, the increasingly common practice of treating an expansion cohort at a chosen MTD has undesirable consequences that may not be obvious. Patients and methods: We review the phase I-II paradigm and the EffTox design, which utilizes both efficacy and toxicity to choose optimal doses for successive patient cohorts and find the optimal P2RD. We conduct a computer simulation study to compare the performance of the EffTox design with the traditional 3 + 3 design and the continuous reassessment method. Results: By accounting for the risk-benefit trade-off, the EffTox phase I-II design overcomes the limitations of conventional toxicity-based phase I designs. Numerical simulations show that the EffTox design has higher probabilities of identifying the optimal dose and treats more patients at the optimal dose. Conclusions: Phase I-II designs, such as the EffTox design, provide a coherent and efficient approach to finding the optimal P2RD by explicitly accounting for risk-benefit trade-offs underlying medical decisions. PMID- 29267865 TI - Serum Lipids in Association With Type 2 Diabetes Risk and Prevalence in a Chinese Population. AB - Context: We previously reported an association between lysophosphatidylinositol (LPI) (16:1) and risk for type 2 diabetes in a Chinese population using an untargeted analysis. Objective: To examine the overall associations of LPIs and their related metabolites, such as nonesterified fatty acids (NEFAs) and acylcarnitines, with incident and prevalent type 2 diabetes using a targeted approach. Design and Setting: A case-control study was nested within the Singapore Chinese Health Study. Cases and controls were individually matched by age, sex, and date of blood collection. We used both liquid and gas chromatography tandem mass spectrometry to measure serum metabolite levels at baseline, including 8 LPIs, 19 NEFAs, and 34 acylcarnitines. Conditional logistic regression models were used to estimate the associations between metabolites and diabetes risk. Participants: Participants included 160 incident and 144 prevalent cases with type 2 diabetes and 304 controls. Main Outcome Measure: Incident and prevalent type 2 diabetes. Results: On the basis of a false discovery rate <0.1, we identified 37 metabolites associated with prevalent type 2 diabetes, including 7 LPIs, 18 NEFAs, and 12 acylcarnitines, and 11 metabolites associated with incident type 2 diabetes, including 2 LPIs and 9 NEFAs. Two metabolites, LPI (16:1) and dihomo-gamma-linolenic acid, showed independent associations with incident type 2 diabetes and significantly enhanced the risk prediction. Conclusions: We found several LPIs and NEFAs that were associated with risk for type 2 diabetes and may improve our understanding of the pathogenesis. The findings suggest that lipid profiles could aid in diabetes risk assessment in Chinese populations. PMID- 29267867 TI - The benefit of pacemaker therapy in patients with neurally mediated syncope and documented asystole: a meta-analysis of implantable loop recorder studies. AB - Aim: Although the efficacy of cardiac pacing in patients with neurally mediated syncope (NMS) and documented asystole is established, a more robust point estimate of the benefit, which is not possible with any individual study, is lacking. Methods and results: We undertook a meta-analysis of individual participant data from four studies that reported follow-up data on syncope recurrence with cardiac pacing in patients with NMS who had had an electrocardiographic (ECG) documentation of an asystolic event by means of implantable loop recorder (ILR). Of a total of 1046 patients, who had ILR implanted, 383 (36.6%) patients had an ECG documentation of a diagnostic event during mean follow-up of 13 +/- 10 months. Of these, 201 (52%) patients, corresponding to 19.2% of the total ILRs, had an asystolic event of 12.8 +/- 11.0 s duration documented and met the criteria for pacemaker therapy. Follow-up was available in 121 (60%) of those patients with asystolic events. Syncope recurred after pacing in 18 (14.9%) patients with an actuarial rate of 13% [95% confidence interval (CI) +/-6] at 1 year, 21% (95%CI +/-10) at 2 years, and 24% (95%CI +/ 11) at 3 years. On multivariable Cox regression analysis, positive tilt test response was the only significant predictor of syncope recurrence with a hazard ratio (95% CI) of 4.3 (1.4-13). On the contrary, type of asystolic event (sinus arrest or atrioventricular block), prodrome, cardiac abnormalities, number and duration of history of syncope, age, and gender were not predictors of recurrence of syncope. Conclusion: A long asystolic pause, suitable for pacemaker therapy, was found in one of five patients with ILR. After pacemaker implantation, most of these patients remained free of syncope recurrence for up to 3 years. The benefit of pacemaker was greater in patients with negative tilt test. PMID- 29267866 TI - The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy. AB - Background: Immunotherapy has increasingly become a staple in cancer treatment. However, substantial limitations in the durability of response highlight the need for more rational therapeutic combinations. The aim of this study is to investigate how to make tumor cells more sensitive to T-cell-based cancer immunotherapy. Methods: Two pairs of melanoma patient-derived tumor cell lines and their autologous tumor-infiltrating lymphocytes were utilized in a high throughput screen of 850 compounds to identify bioactive agents that could be used in combinatorial strategies to improve T-cell-mediated killing of tumor cells. RNAi, overexpression, and gene expression analyses were utilized to identify the mechanism underlying the effect of Topoisomerase I (Top1) inhibitors on T-cell-mediated killing. Using a syngeneic mouse model (n = 5 per group), the antitumor efficacy of the combination of a clinically relevant Top1 inhibitor, liposomal irinotecan (MM-398), with immune checkpoint inhibitors was also assessed. All statistical tests were two-sided. Results: We found that Top1 inhibitors increased the sensitivity of patient-derived melanoma cell lines (n = 7) to T-cell-mediated cytotoxicity (P < .001, Dunnett's test). This enhancement is mediated by TP53INP1, whose overexpression increased the susceptibility of melanoma cell lines to T-cell cytotoxicity (2549 cell line: P = .009, unpaired t test), whereas its knockdown impeded T-cell killing of Top1 inhibitor-treated melanoma cells (2549 cell line: P < .001, unpaired t test). In vivo, greater tumor control was achieved with MM-398 in combination with alpha-PD-L1 or alpha PD1 (P < .001, Tukey's test). Prolonged survival was also observed in tumor bearing mice treated with MM-398 in combination with alpha-PD-L1 (P = .002, log rank test) or alpha-PD1 (P = .008, log-rank test). Conclusions: We demonstrated that Top1 inhibitors can improve the antitumor efficacy of cancer immunotherapy, thus providing the basis for developing novel strategies using Top1 inhibitors to augment the efficacy of immunotherapy. PMID- 29267868 TI - Biceps Augmentation Using Solid Silicone Implants. AB - Background: Biceps augmentation using solid silicone implants has been increasingly requested in recent years despite a paucity of literature evaluating the safety and efficacy of this procedure. Objectives: The purpose of this study was to provide information about complications, surgical planning, and aesthetic outcomes of biceps augmentation. Methods: A retrospective chart review was conducted for patients undergoing solid silicone biceps augmentation in the author's practice from April 2011 through May 2016. Collected data were analyzed to assess the indications for surgery, quantity of complications, and need for surgical revision, and to evaluate aesthetic outcome. Results: Twenty-one male patients were included in the study. The mean age was 42.6 years and the mean follow up was 7.1 months. Indications for surgery include a desire to increase biceps size (n = 16), and correction of biceps deformity after biceps tendon rupture (n = 5). Eight patients underwent subfascial implant placement and 13 submuscular implant placement. Complications occurred in 10 patients (48%) including asymmetry (n = 4), seroma (n = 3), surgical site infection (SSI) (n = 1), cellulitis (n = 1), and hematoma (n = 1). The overall reoperation rate was 23.8%. Implant malposition occurred in 3 of the 8 (38%) of subfascial implant placement patients. Complications requiring revision surgery were higher for subfascial implants 37.5% vs 15.4% for submuscular. Conclusions: Biceps augmentation with a solid silicone implant can increase upper arm volume and correct asymmetry and deformity resulting from muscle injury. Submuscular biceps implant placement is recommended over subfascial insertion to avoid implant malposition. Level of Evidence 4: PMID- 29267869 TI - Effect of perioperative blood transfusion on the long-term survival of patients undergoing esophagectomy for esophageal cancer: a systematic review and meta analysis. AB - Perioperative blood transfusion has been linked to poorer long-term survival in patients undergoing esophagectomy, presumably due to its potential immunomodulatory effects. This review aims to summarize existing evidence relating to the influence of blood transfusion on long-term survival following esophagectomy for esophageal cancer. A systematic literature search (up to February 2017) was conducted for studies reporting the effects of perioperative blood transfusion on survival following esophagectomy for esophageal cancer. Meta analysis was used to summate survival outcomes. Twenty observational studies met the criteria for inclusion. Eighteen of these studies compared the outcomes of patients who received allogenic blood transfusion to patients who did not receive this intervention. Meta-analysis of outcomes revealed that allogenic blood transfusion significantly reduced long-term survival (HR = 1.49; 95% CI 1.26 to 1.76; P < 0.001). There appeared to be a dose-related response with patients who received >=3 units of blood having lower long-term survival compared to patient who received between 0 and 2 units (HR = 1.59; 95% CI 1.31 to 1.93; P < 0.001). Two studies comparing patients who received allogenic versus autologous blood transfusion showed superior survival in the latter group. Factors associated with the requirement for perioperative blood transfusion included: intraoperative blood loss; preoperative hemoglobin; operative approach; operative time, and; presences of advanced disease. These findings indicate that perioperative blood transfusion is associated with significantly worse long-term survival in patients undergoing esophagectomy for esophageal cancer. Autologous donation of blood, meticulous intraoperative hemostasis, and avoidance of unnecessary transfusions may prevent additional deaths attributed to this intervention. PMID- 29267870 TI - Commentary on: Liposuction-Augmentation Mammaplasty. PMID- 29267871 TI - Expanding Existing Antimicrobial Stewardship Programs in Pediatrics: What Comes Next. AB - The prevalence of pediatric antimicrobial stewardship programs (ASPs) is increasing in acute care facilities across the United States. Over the past several years, the evidence base used to inform effective stewardship practices has expanded, and regulatory interest in stewardship programs has increased. Here, we review approaches for established, hospital-based pediatric ASPs to adapt and report standardized metrics, broaden their reach to specialized populations, expand to undertake novel stewardship initiatives, and implement rapid diagnostics to continue their evolution in improving antimicrobial use and patient outcomes. PMID- 29267872 TI - At the Origin of a Worldwide Invasion: Unraveling the Genetic Makeup of the Caribbean Bridgehead Populations of the Dengue Vector Aedes aegypti. AB - Human-driven global environmental changes have considerably increased the risk of biological invasions, especially the spread of human parasites and their vectors. Among exotic species that have major impacts on public health, the dengue fever mosquito Aedes aegypti originating from Africa has spread worldwide during the last three centuries. Although considerable progress has been recently made in understanding the history of this invasion, the respective roles of human and abiotic factors in shaping patterns of genetic diversity remain largely unexplored. Using a genome-wide sample of genetic variants (3,530 ddRAD SNPs), we analyzed the genetic structure of Ae. aegypti populations in the Caribbean, the first introduced territories in the Americas. Fourteen populations were sampled in Guyane and in four islands of the Antilles that differ in climatic conditions, intensity of urbanization, and vector control history. The genetic diversity in the Caribbean was low (He = 0.14-0.17), as compared with a single African collection from Benin (He = 0.26) and site-frequency spectrum analysis detected an ancient bottleneck dating back ~300 years ago, supporting a founder event during the introduction of Ae. aegypti. Evidence for a more recent bottleneck may be related to the eradication program undertaken on the American continent in the 1950s. Among 12 loci detected as FST-outliers, two were located in candidate genes for insecticide resistance (cytochrome P450 and voltage-gated sodium channel). Genome-environment association tests identified additional loci associated with human density and/or deltamethrin resistance. Our results highlight the high impact of human pressures on the demographic history and genetic variation of Ae. aegypti Caribbean populations. PMID- 29267874 TI - Fixed choice design and augmented fixed choice design for network data with missing observations. AB - The statistical analysis of social networks is increasingly used to understand social processes and patterns. The association between social relationships and individual behaviors is of particular interest to sociologists, psychologists, and public health researchers. Several recent network studies make use of the fixed choice design (FCD), which induces missing edges in the network data. Because of the complex dependence structure inherent in networks, missing data can pose very difficult problems for valid statistical inference. In this article, we introduce novel methods for accounting for the FCD censoring and introduce a new survey design, which we call the augmented fixed choice design (AFCD). The AFCD adds considerable information to analyses without unduly burdening the survey respondent, resulting in improvements over the FCD, and other existing estimators. We demonstrate this new method through simulation studies and an analysis of alcohol use in a network of undergraduate students living in a residence hall. PMID- 29267873 TI - Mitochondrial targeted peptides preserve mitochondrial organization and decrease reversible myocardial changes in early swine metabolic syndrome. AB - Aims: The mechanisms responsible for cardiac damage in the early stages of metabolic syndrome (MetS) remain unknown. Mitochondria are intimately associated with cellular myofibrils, with the cytoskeleton functioning as a linkage coordinator, and closely associated to the calcium release sites of the sarcoplasmic reticulum (SR). We hypothesized that early MetS is characterized by mitochondria-related myocardial damage, associated with altered cytoskeletal mitochondria-SR interaction. Methods and results: Domestic pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondrial-targeted peptide elamipretide (ELAM; 0.1 mg/kg SC q.d), or Lean controls (n = 6/group). Cardiac remodeling and function were assessed by fast comuted tomography. Myocardial mitochondrial structure, SR-mitochondria interaction, calcium handling, cytoskeletal proteins, oxidative stress, and apoptosis were studied ex-vivo. MetS pigs developed hyperlipidemia, hypertension, and insulin resistance, yet cardiac function was preserved. MetS-induced mitochondrial disorganization, decreased (C18:2)4 cardiolipin, disrupted ATP/ADP balance, and decreased cytochrome-c oxidase (COX)-IV activity. MetS also increased mitochondrial hydrogen peroxide (H2O2) production, decreased nicotinamide adenine dinucleotide phosphate (NADPH)/NADP and GSH/GSSG, and decreased myocardial desmin and beta2 tubulin immunoreactivity, and impaired SR mitochondrial interaction and mitochondrial calcium handling, eliciting myocardial oxidative stress and apoptosis. ELAM improved mitochondrial organization and cardiolipin species profile, restored ATP/ADP ratio and COX-IV activity, decreased H202 production, and improved generation of NADPH and GSH. ELAM also improved cytoskeletal-mitochondria-SR interaction and mitochondrial calcium handling, attenuating oxidative stress, and apoptosis. Conclusions: Disorganization of cardiomyocyte cytoskeletal-mitochondria-SR network is associated with cardiac reversible changes in early MetS, preceding overt cardiac dysfunction. These findings may introduce novel therapeutic targets for blunting cardiac damage in early MetS. PMID- 29267875 TI - Response to "Comments on 'Nonsurgical Medical Penile Girth Augmentation: Experience-Based Recommendations'". PMID- 29267876 TI - A coarse-grained model for DNA origami. AB - Modeling tools provide a valuable support for DNA origami design. However, current solutions have limited application for conformational analysis of the designs. In this work we present a tool for a thorough study of DNA origami structure and dynamics. The tool is based on a novel coarse-grained model dedicated to geometry optimization and conformational analysis of DNA origami. We explored the ability of the model to predict dynamic behavior, global shapes, and fine details of two single-layer systems designed in hexagonal and square lattices using atomic force microscopy, Forster resonance energy transfer spectroscopy, and all-atom molecular dynamic simulations for validation of the results. We also examined the performance of the model for multilayer systems by simulation of DNA origami with published cryo-electron microscopy and atomic force microscopy structures. A good agreement between the simulated and experimental data makes the model suitable for conformational analysis of DNA origami objects. The tool is available at http://vsb.fbb.msu.ru/cosm as a web service and as a standalone version. PMID- 29267877 TI - GIGI-Quick: a fast approach to impute missing genotypes in genome-wide association family data. AB - Summary: Genome-wide association studies have become common over the last ten years, with a shift towards targeting rare variants, especially in pedigree-data. Despite lower costs, sequencing for rare variants still remains expensive. To have a relatively large sample with acceptable cost, imputation approaches may be used, such as GIGI for pedigree data. GIGI is an imputation method that handles large pedigrees and is particularly good for rare variant imputation. GIGI requires a subset of individuals in a pedigree to be fully sequenced, while other individuals are sequenced only at relevant markers. The imputation will infer the missing genotypes at untyped markers. Running GIGI on large pedigrees for large numbers of markers can be very time consuming. We present GIGI-Quick as a method to efficiently split GIGI's input, run GIGI in parallel and efficiently merge the output to reduce the runtime with the number of cores. This allows obtaining imputation results faster, and therefore all subsequent association analyses. Availability and and implementation: GIGI-Quick is open source and publicly available via: https://cse-git.qcri.org/Imputation/GIGI-Quick. Contact: msaad@hbku.edu.qa. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29267878 TI - Computational identification of micro-structural variations and their proteogenomic consequences in cancer. AB - Motivation: Rapid advancement in high throughput genome and transcriptome sequencing (HTS) and mass spectrometry (MS) technologies has enabled the acquisition of the genomic, transcriptomic and proteomic data from the same tissue sample. We introduce a computational framework, ProTIE, to integratively analyze all three types of omics data for a complete molecular profile of a tissue sample. Our framework features MiStrVar, a novel algorithmic method to identify micro structural variants (microSVs) on genomic HTS data. Coupled with deFuse, a popular gene fusion detection method we developed earlier, MiStrVar can accurately profile structurally aberrant transcripts in tumors. Given the breakpoints obtained by MiStrVar and deFuse, our framework can then identify all relevant peptides that span the breakpoint junctions and match them with unique proteomic signatures. Observing structural aberrations in all three types of omics data validates their presence in the tumor samples. Results: We have applied our framework to all The Cancer Genome Atlas (TCGA) breast cancer Whole Genome Sequencing (WGS) and/or RNA-Seq datasets, spanning all four major subtypes, for which proteomics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) have been released. A recent study on this dataset focusing on SNVs has reported many that lead to novel peptides. Complementing and significantly broadening this study, we detected 244 novel peptides from 432 candidate genomic or transcriptomic sequence aberrations. Many of the fusions and microSVs we discovered have not been reported in the literature. Interestingly, the vast majority of these translated aberrations, fusions in particular, were private, demonstrating the extensive inter-genomic heterogeneity present in breast cancer. Many of these aberrations also have matching out-of-frame downstream peptides, potentially indicating novel protein sequence and structure. Availability and implementation: MiStrVar is available for download at https://bitbucket.org/compbio/mistrvar, and ProTIE is available at https://bitbucket.org/compbio/protie. Contact: cenksahi@indiana.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29267879 TI - Osteoarthritis: the genesis of pain. AB - OA is a painful joint disease that predominantly affects the elderly. Pain is the primary symptom of OA, and it can present as either intermittent or constant. OA pain mechanisms are complex and have only recently been determined. Both peripheral and central processes are involved in creating the OA pain experience, making targeted therapy problematic. Nociceptive, inflammatory and neuropathic pains are all known to occur in OA, but to varying degrees in a patient- and time specific manner. A better understanding of these multifactorial components of OA pain will lead to the development of more effective and safer pain treatments. PMID- 29267881 TI - Identification and chemical characterization of N-acyl-homoserine lactone quorum sensing signals across sponge species and time. AB - Marine sponges form symbiotic relationships with complex microbial communities, yet little is known about the mechanisms by which these microbes regulate their behavior through gene expression. Many bacterial communities regulate gene expression using chemical signaling termed quorum sensing. While a few previous studies have shown presence of N-acyl-homoserine lactone (AHL)-based quorum sensing in marine sponges, the chemical identity of AHL signals has been published for only two sponge species. In this study, we screened for AHLs in extracts from 15 sponge species (109 specimens in total) from the Mediterranean and Red Sea, using a wide-range AHL biosensor. This is the first time that AHL presence was examined over time in sponges. We detected the presence of AHL in 46% of the sponge species and found that AHL signals differ for certain sponge species in time and across sponge individuals. Furthermore, for the Mediterranean sponge species Sarcotragus fasciculatus, we identified 14 different AHLs. The constant presence of specific AHL molecules in all specimens, together with varying signaling molecules between the different specimens, makes Sa. fasciculatus a good model to further investigate the function of quorum sensing in sponge-associated bacteria. This study extends the knowledge of AHL-based quorum sensing in marine sponges. PMID- 29267880 TI - Decreasing Use of Radioactive Iodine for Low-Risk Thyroid Cancer in California, 1999 to 2015. AB - Context: Routine radioactive iodine (RAI) ablation for low-risk differentiated thyroid cancer (DTC) is not supported by current practice guidelines. Objective: To assess recent stage-specific trends in use of RAI ablation. Design, Setting, and Patients: Retrospective study of patients with DTC (1999 to 2015) identified from the California Cancer Registry. Statistical analysis included standardized differences, P values, and multivariable analyses using RAI as the predictor variable. Main Outcome Measures: Trends and drivers of RAI ablation for low-risk DTC. Results: Of 46,906 patients with DTC who underwent near-total or total thyroidectomy [mean age 48.2 +/- 15.5 (standard deviation) years, 77% female), 25,457 (54%) received RAI. The proportion of patients with regional/distant disease who received RAI remained stable at 68%. Use of RAI for patients with localized disease (no extrathyroidal extension, lymph node, or distant metastases) decreased from 55% (1999) to 30% (2015), with the most substantial change occurring in tumors <1 cm (39% to 11%). The rate also decreased for localized tumors between 1 and 2 cm (62% to 34%) and 2 and 4 cm (67% to 49%) and remained stable at 59% for tumors >4 cm. In multivariable analyses, patients with localized disease were less likely to receive RAI if they were >65 years old [odds ratio (OR) 0.77, 95% confidence interval (CI): 0.71 to 0.83], had tumors <1 cm (OR 0.33, 95% CI: 0.31 to 0.35), or were treated in an academic hospital (OR 0.71, 95% CI: 0.67 to 0.75). Conclusions: The rate of RAI ablation decreased over time, mainly attributable to decreased use for localized DTCs <2 cm. Many patients with low-risk DTC still receive RAI unnecessarily. PMID- 29267882 TI - The immune checkpoint molecule VISTA regulates allergen-specific Th2-mediated immune responses. AB - V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint receptor and ligand that regulates T-cell activation. We investigated the functional involvement of VISTA in Th2 cell-mediated immune responses using an ovalbumin (OVA)-induced allergic asthma model. Treatment with an anti-VISTA monoclonal antibody (mAb) during allergen sensitization increased the production of antibodies, including total IgE, OVA-specific IgG1 and IgG2a and allergen specific IL-5 and IL-13; it also increased the expression of IL-13 by splenic CD4+ T cells. However, treatment with the anti-VISTA mAb during sensitization did not accelerate asthmatic responses, including airway hyper-responsiveness (AHR) or the number of eosinophils in bronchoalveolar lavage (BAL) fluid. In contrast, treatment with the anti-VISTA mAb during allergen challenge significantly augmented AHR and BAL fluid eosinophilia. This treatment also increased the production of IL-5 and IL-13 in BAL fluid and the expression of IL-13 by CD4+ T cells in draining lymph nodes. These results suggest that VISTA is involved in the regulation of Th2 cell generation and Th2 cell-mediated antibody production and regulates asthmatic responses, especially in the effector phase. PMID- 29267883 TI - Distinct features of C/N balance regulation in Prochlorococcus sp. strain MIT9313. AB - The abundance and significant contribution to global primary production of the marine cyanobacterium Prochlorococcus have made it one of the main models in marine ecology. Several conditions known to cause strong effects on the regulation of N-related enzymes in other cyanobacteria lacked such effect in Prochlorococcus. Prochlorococcus sp. strain MIT9313 is one of the most early branching strains among the members of this genus. In order to further understand the C/N control system in this cyanobacterium, we studied the effect of the absence of three key elements in the ocean, namely N, P and Fe, as well as the effect of inhibitors of the N assimilation or photosynthesis on the N metabolism of this strain. Furthermore, we focused our work in the effect of ageing, as the age of cultures has clear effects on the regulation of some enzymes in Prochlorococcus. To reach this goal, expression of the main three regulators involved in N assimilation in cyanobacteria, namely ntcA, glnB and pipX, as well as that of icd (encoding for isocitrate dehydrogenase) were analysed. Our results show that the control of the main proteins involved in the C/N balance in strain MIT9313 differs from other model Prochlorococcus strains. PMID- 29267884 TI - GlycoDomainViewer: a bioinformatics tool for contextual exploration of glycoproteomes. AB - The GlycoDomainViewer is a bioinformatic tool to aid in the mining of glycoproteomic datasets from different sources and facilitate incorporation of glycosylation into studies of protein structure and function. We present a version 2.0 of GlycoDomainViewer incorporating a number of advanced features, which enhances visibility and accessibility of the wealth of glycoproteomic data being generated. The GlycoDomainViewer enables visual exploration of glycoproteomic data, incorporating information from recent N- and O-glycoproteome studies on human and animal cell lines and some organs and body fluids. The initial data comprises sites of glycosylation for N-linked, O-GalNAc, O-Fucose, O Xyl, O-Mannose (in both human and yeast) and cytosolic O-GlcNAc type. The data made available via this tool will be regularly updated to improve the coverage of known glycosylation sites and datasets, reflecting the advances currently being made in characterization of glycoproteomes. The tool is available at https://glycodomain.glycomics.ku.dk. PMID- 29267885 TI - Two-step interrogation then recognition of DNA binding site by Integration Host Factor: an architectural DNA-bending protein. AB - The dynamics and mechanism of how site-specific DNA-bending proteins initially interrogate potential binding sites prior to recognition have remained elusive for most systems. Here we present these dynamics for Integration Host factor (IHF), a nucleoid-associated architectural protein, using a MUs-resolved T-jump approach. Our studies show two distinct DNA-bending steps during site recognition by IHF. While the faster (~100 MUs) step is unaffected by changes in DNA or protein sequence that alter affinity by >100-fold, the slower (1-10 ms) step is accelerated ~5-fold when mismatches are introduced at DNA sites that are sharply kinked in the specific complex. The amplitudes of the fast phase increase when the specific complex is destabilized and decrease with increasing [salt], which increases specificity. Taken together, these results indicate that the fast phase is non-specific DNA bending while the slow phase, which responds only to changes in DNA flexibility at the kink sites, is specific DNA kinking during site recognition. Notably, the timescales for the fast phase overlap with one dimensional diffusion times measured for several proteins on DNA, suggesting that these dynamics reflect partial DNA bending during interrogation of potential binding sites by IHF as it scans DNA. PMID- 29267887 TI - Snake fangs: 3D morphological and mechanical analysis by microCT, simulation, and physical compression testing. AB - This Data Note provides data from an experimental campaign to analyse the detailed internal and external morphology and mechanical properties of venomous snake fangs. The aim of the experimental campaign was to investigate the evolutionary development of 3 fang phenotypes and investigate their mechanical behaviour. The study involved the use of load simulations to compare maximum Von Mises stress values when a load is applied to the tip of the fang. The conclusions of this study have been published elsewhere, but in this data note we extend the analysis, providing morphological comparisons including details such as curvature comparisons, thickness, etc. Physical compression results of individual fangs, though reported in the original paper, were also extended here by calculating the effective elastic modulus of the entire snake fang structure including internal cavities for the first time. This elastic modulus of the entire fang is significantly lower than the locally measured values previously reported from indentation experiments, highlighting the possibility that the elastic modulus is higher on the surface than in the rest of the material. The micro-computed tomography (microCT) data are presented both in image stacks and in the form of STL files, which simplifies the handling of the data and allows its re-use for future morphological studies. These fangs might also serve as bio inspiration for future hypodermic needles. PMID- 29267886 TI - Refined sgRNA efficacy prediction improves large- and small-scale CRISPR-Cas9 applications. AB - Genome editing with the CRISPR-Cas9 system has enabled unprecedented efficacy for reverse genetics and gene correction approaches. While off-target effects have been successfully tackled, the effort to eliminate variability in sgRNA efficacies-which affect experimental sensitivity-is in its infancy. To address this issue, studies have analyzed the molecular features of highly active sgRNAs, but independent cross-validation is lacking. Utilizing fluorescent reporter knock out assays with verification at selected endogenous loci, we experimentally quantified the target efficacies of 430 sgRNAs. Based on this dataset we tested the predictive value of five recently-established prediction algorithms. Our analysis revealed a moderate correlation (r = 0.04 to r = 0.20) between the predicted and measured activity of the sgRNAs, and modest concordance between the different algorithms. We uncovered a strong PAM-distal GC-content-dependent activity, which enabled the exclusion of inactive sgRNAs. By deriving nine additional predictive features we generated a linear model-based discrete system for the efficient selection (r = 0.4) of effective sgRNAs (CRISPRater). We proved our algorithms' efficacy on small and large external datasets, and provide a versatile combined on- and off-target sgRNA scanning platform. Altogether, our study highlights current issues and efforts in sgRNA efficacy prediction, and provides an easily-applicable discrete system for selecting efficient sgRNAs. PMID- 29267889 TI - Number of patients needed to prescribe statins in primary cardiovascular prevention: mirage and reality. AB - Background: Number of patients needed to treat (NNT) with a statin in primary prevention of coronary heart disease (CHD) is often misinterpreted because this single statistic averages results from heterogeneous studies. Objective: To provide estimates of the number of individuals needed to be prescribed a statin to prevent one CHD event accounting for their level of CHD risk and for persistence to treatment. Methods: A post hoc analysis was conducted based on a Cochrane review on statins for the primary prevention of cardiovascular diseases. Five-year NNTs were calculated separately from randomized clinical trials (RCTs), including 'lower' and 'higher' risk populations (CHD mean event rates of 3.7 and 14.4 per 1000 person-years, respectively). NNTs were adjusted for 5-year persistence to treatment using a value of 65%. Results: Persistence-adjusted 5 year NNTs to prevent one CHD for the lower and higher CHD risk categories were 146 [95% confidence interval (CI): 117-211] and 53 (95% CI: 39-88) respectively, values 25% and 15% higher than their unadjusted counterpart (117, 95% CI: 94-167 and 46, 95% CI: 34-78). Conclusions: Five-year NNTs for statins to prevent a first CHD is almost three times higher in those at lower versus higher risk populations. Reporting combined results from RCTs including subjects at different cardiovascular risks should be avoided. Individualizing the risk of CHD should orient family physicians and their patients in their choice of preventive approaches and generate more realistic expectations about compliance and outcomes. PMID- 29267888 TI - Improvement of Vip3Aa16 Toxin Production and Efficiency Through Nitrous Acid and UV Mutagenesis of Bacillus thuringiensis (Bacillales: Bacillaceae). AB - Bacillus thuringiensis Berliner (Bacillales: Bacillaceae) strain BUPM95 was known by the efficiency of its vegetative insecticidal protein (Vip3Aa16) against different Lepidoptera such as Spodoptera littoralis (Lepidoptera: Noctuidae). To overcome the problem of the low quantities of Vip3 proteins secreted by B. thuringiensis strains in the culture supernatant, classical mutagenesis of vegetative cells of BUPM95 strain was operated using nitrous acid and UV rays. The survivors were screened on the basis of their hemolytic activity and classified in three groups: unaffected, overproducing, and hypo-producing mutants. Using different mutants improved in their hemolytic activity, the supernatants showed an improved toxicity toward S. littoralis larvae (83.33-100% of mortality) compared with the wild-type supernatant (76%). After Vip3 protein quantification in the different supernatants, bioassays against S. littoralis larvae demonstrated that mutants M62, M43, and M76 were improved in the efficiency of their toxin as demonstrated by the lower values of LC50 and LC90 compared with the wild-type Vip3Aa16 protein. However, M26 and M73 mutants were improved in the toxin quantities produced in the supernatant. The improvement of the production and the efficiency of B. thuringiensis Vip3 toxins should contribute to a significant reduction of the production costs of these very interesting B. thuringineis proteins and facilitate the use of these toxins in the pest control management. PMID- 29267890 TI - Response to "The Micromort Concept and its Applicability to Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) Risk Assessment". PMID- 29267891 TI - Infections caused by Scedosporium/Lomentospora species: Clinical and microbiological findings in 21 cases. AB - The clinical and microbiological characteristics of infections caused by Scedosporium/ Lomentospora species in 21 patients are described. We searched retrospectively the records for Scedosporium/ Lomentospora species seen at the University Hospital Virgen de las Nieves from 2006 to 2017. Out of them, 16 were male; mean age at diagnosis was 57.8 (+/-SD 15) years; all patients had risk factors for fungal infection such as corticosteroids and/or immunosuppressive treatment in 18 (85.7%) patients, pulmonary diseases in seven (33.3%) cases, hematological malignancies in six (28.5%), and organ transplantation in three (14.2%) patients. Most patients had infection in the lung/pleura (17/80.9%); cough was present in 12 patients and dyspnea in another 12, and the mean interval until diagnosis was 13.6 days. The most frequent species was S. apiospermum/S. boydii in 14 patients (66.6%), followed by L. prolificans in seven. The diagnosis was obtained from sputum in 12 (57.1%) cases, followed by pleural fluid and bronchoalveolar lavage in two of each. The most frequently used antifungals were voriconazole and amphotericin B, but combination of more than one antifungal drug was only used in three patients. Ten patients were cured, and six patients died as a consequence of the infection; three patients had chronic infection. In general, infections caused by Scedosporium/Lomentospora species are rare, serious, and difficult to diagnose and treat, having a high index or mortality especially in those caused by L. prolificans. PMID- 29267893 TI - Crossover is not associated with faster trial accrual. PMID- 29267892 TI - Diverse Streptococcus pneumoniae Strains Drive a Mucosal-Associated Invariant T Cell Response Through Major Histocompatibility Complex class I-Related Molecule Dependent and Cytokine-Driven Pathways. AB - Mucosal-associated invariant T (MAIT) cells represent an innate T-cell population that can recognize ligands generated by the microbial riboflavin synthesis pathway, presented via the major histocompatibility complex class I-related molecule (MR1). Streptococcus pneumoniae is a major human pathogen that is also associated with commensal carriage; thus, host control at the mucosal interface is critical. The recognition of pneumococci by MAIT cells has not been defined nor have the genomics and transcriptomics of the riboflavin operon. We observed robust recognition of pneumococci by MAIT cells, using both MR1-dependent and MR1 independent pathways. The pathway used was dependent on the antigen-presenting cell. The riboflavin operon was highly conserved across a range of 571 pneumococci from 39 countries, dating back to 1916, and different versions of the riboflavin operon were also identified in related Streptococcus species. These data indicate an important functional relationship between MAIT cells and pneumococci. PMID- 29267894 TI - ASJ's Position on Publishing Papers That Discuss Off-Label Product Usage. PMID- 29267896 TI - Commentary on: The Effect of Implant Type on Nipple Position Geometry and Aesthetics Following Tissue Expander Reconstruction After Nipple Sparing Mastectomy. PMID- 29267895 TI - Differences in Virological and Immunological Risk Factors for Non-Hodgkin and Hodgkin Lymphoma. AB - Background: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are increased in populations with immune dysfunction, including people living with HIV; however, there is little evidence for to what degree immunological and virological factors differently affect NHL and HL risk. Methods: Data from the Data Collection on Adverse events of Anti-HIV Drugs Study cohort were analyzed to identify independent risk factors for NHL and HL using hazard ratios (HRs), focusing on current and cumulative area under the curve (AUC) measures of immunological and virological status. Variables with different associations with NHL and HL were identified using marginal Cox models. All statistical tests were two-sided. Results: Among 41 420 people followed for 337 020 person-years, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] = 1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI = 0.38 to 0.52). Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 <100 vs > 599 cells/mm3 = 8.08, 95% CI = 5.63 to 11.61; HL = 4.58, 95% CI = 2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs < 50 copies/mL = 1.97, 95% CI = 1.50 to 2.59) and higher AUC of HIV-VL (aHR of NHL for highest vs lowest quintile = 2.91, 95% CI = 1.92 to 4.41) were associated with NHL only. Both current and AUC of HIV-VL were factors that had different associations with NHL and HL, where the hazard ratio for NHL was progressively higher than for HL with increasing HIV-VL category. Lower current CD4 cell count had a strong but similar association with both NHL and HL. Conclusions: CD4 depletion increased risk of both types of lymphomas while current and accumulated HIV-VL was associated with NHL only. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk. PMID- 29267897 TI - Microsurgical Endoscope-Assisted Gravity-Aided Transfalcine Approach for Contralateral Metastatic Deep Medial Cortical Tumors. PMID- 29267898 TI - A polymorphic MYC response element in KBTBD11 influences colorectal cancer risk, especially in interaction with an MYC-regulated SNP rs6983267. AB - Background: MYC is a well-established cancer driver gene regulating the expression of numerous genes, indicating that polymorphisms in MYC response elements could affect tumorigenesis through altering MYC regulation. We performed integrative multistage study to evaluate the effects of variants in MYC response elements and colorectal cancer (CRC) risk. Patients and methods: We systematically integrated ChIP-Seq, DNase-Seq and transcription factor motif data to screen variants with potential ability to affect the MYC binding affinity. Then, we conducted a two-stage case-control study, totally consisting of 4830 CRC cases and 4759 controls in Chinese population to identify risk polymorphisms and interactions. The effects of risk variants were confirmed by functional assays in CRC LoVo, SW480 and HCT15 cells. Results: We identified a novel polymorphism rs11777210 in KBTBD11 significantly associated with CRC susceptibility (P = 2.43 * 10-12). Notably, we observed a significant interaction between rs11777210 and MYC nearby rs6983267 (P-multi = 0.003, P-add = 0.005), subjects carrying rs6983267 GG and rs11777210 CC genotypes showing higher susceptibility to CRC (2.83-fold) than those carrying rs6983267 TT and rs11777210 TT genotypes. We further demonstrated that rs6983267 T > G increased MYC expression, and MYC bound to and negatively regulated KBTBD11 expression when the rs11777210 C risk allele was present. KBTBD11 was downregulated in tumor tissues, and KBTBD11 knockdown promoted cell proliferation and inhibited cell apoptosis. Conclusion: The rs11777210 is a potential predictive biomarker of CRC susceptibility, and KBTBD11 functions as a putative tumor suppressor in tumorigenesis. Our study highlighted the high CRC risk of people carrying rs6983267 G and rs11777210 C alleles, and provided possible biological mechanism of the interaction. PMID- 29267899 TI - Delimiting Strategic Zones for the Development of Fall Armyworm (Lepidoptera: Noctuidae) on Corn in the State of Florida. AB - The fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), cannot survive prolonged periods of freezing temperatures, thereby limiting where it can overwinter in North America. Climate change is anticipated to reduce the frequency of freeze days in Florida over the decades, with the potential consequence of a significant expansion of the overwintering range, whose northern limit in North America was assessed between 27 and 28 degrees N in the last century. To assess this possibility, the development of the fall armyworm on corn leaves, one of the main host plants in the United States, was determined at five constant temperatures ranging from 14 to 30 degrees C. Based on the development time, the thermal constant and the lower threshold temperature were used to estimate the number of generations of fall armyworm at 42 locations in the state of Florida, from 2006 to 2016. Maps were constructed to provide a visual description of the interpolated data, using GIS (Geographic Information System). The highest number of generations was observed in the counties farther south, an area that showed the highest temperatures during the years and plays a strategic role in maintaining fall armyworm populations in corn fields. Additionally, we conclude that in the absence of freeze periods, the northern limit for fall armyworm overwintering should be between 28 and 29 degrees N. PMID- 29267901 TI - Physiological responses to heat stress in two genetically distinct chicken inbred lines. AB - High ambient temperature is one of the most important environmental factors negatively impacting poultry production and health. Genetics is an important contributor in mitigating the stress response to heat. Two genetically distinct highly inbred lines of similar body size (Leghorn and Fayoumi) were characterized for phenotypic differences in response to heat. At 14 days of age, birds were exposed to 38 degrees C with 50% humidity for 4 hours, then 35 degrees C until the conclusion of the experiment. Non-treated individuals were kept at 29.4 degrees C for the first week and then 25 degrees C throughout the experiment. Birds in the heat-stress group were inoculated at day (d) 21 with Newcastle disease virus (NDV) La Sota strain to investigate the effects of heat stress and NDV infection. Thirteen blood parameters were measured using the iSTAT blood analyzer at three stages: 4 h, 6 d, and 9 d post heat-stress treatment, representing acute heat (AH) exposure, chronic heat (CH1) exposure, and chronic heat exposure after virus infection (CH2), respectively. Most blood parameters were significantly changed with heat stress in Leghorns at AH and in Fayoumis at CH1 and CH2. The Leghorn line had significant acute responses with disrupted acid base balance and metabolic disorders. The heat-resilient Fayoumis maintained a relatively well-balanced acid-base balance. The current study provides the comprehensive profile of biomarker signatures in blood associated with heat tolerance and suggests that PO2, TCO2, HCO3, and base excess can be served as potential biomarkers that can be used to genetically improve heat tolerance in poultry. PMID- 29267900 TI - Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project. AB - Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257). Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals. Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient physician communication and balance risk in colorectal cancer trials. PMID- 29267903 TI - Depression screening and management in primary care. PMID- 29267902 TI - Identification of active denitrifiers by DNA-stable isotope probing and amplicon sequencing reveals Betaproteobacteria as responsible for attenuation of nitrate contamination in a low impacted aquifer. AB - Groundwater reservoirs constitute important freshwater resources. However, these ecosystems are highly vulnerable to contamination and have to rely on the resident microbiota to attenuate the impact of this contamination. Nitrate is one of the main contaminants found in groundwater, and denitrification is the main process that removes the compound. In this study, the response to nutrient load on indigenous microbial communities in groundwater from a low impacted aquifer in Uruguay was evaluated. Denitrification rates were measured in groundwater samples from three different sites with nitrate, acetate and pyrite amendments. Results showed that denitrification is feasible under in situ nitrate and electron donor concentrations, although the lack of readily available organic energy source would limit the attenuation of higher nitrate concentrations. DNA-stable isotope probing, combined with amplicon sequencing of 16S rRNA, nirS and nirK genes, was used to identify the active denitrifiers. Members of the phylum Betaproteobacteria were the dominant denitrifiers in two of three sites, with different families being observed; members of the genus Vogesella (Neisseriaceae) were key denitrifiers at one site, while the genera Dechloromonas (Rhodocyclaceae) and Comamonas (Comamonadaceae) were the main denitrifiers detected at the other sites. PMID- 29267904 TI - Oral Contraceptive Management in Aesthetic Surgery: A Survey of Current Practice Trends. AB - Background: Oral contraceptive pills (OCPs) are currently used by approximately 16% of all women aged 15 to 44 in the United States and have been used by 80% of all sexually active women at some point in their lives. However, no guidelines exist for discontinuation of OCP therapy before or after elective cosmetic surgery. Objectives: The aim of this study is to establish current practice trends regarding perioperative OCP management in aesthetic surgery. Methods: An eight-item online survey was distributed to members of the American Society of Plastic Surgeons (ASPS). Survey results were analyzed to determine if surgeons' practice setting, years of experience, annual cosmetic volume, or types of cosmetic procedures performed affected their perioperative management of OCPs. Results: A total of 220 questionnaires were collected (11.9% response rate). Only 31.8% of surgeons reported any discontinuation of OCPs pre- or postoperatively. Among physicians, 7.3% reported only preoperative discontinuation, 24.5% reported OCP discontinuation both pre- and postoperatively, and 0.0% of physicians reported discontinuation of OCPs only postoperatively. There was no statistically significant difference between the percentage of surgeons in academic practice who discontinue OCPs perioperatively (P = 0.335). There was no statistical significance towards overall years in practice (P = 0.152). There were no significant differences between the three groups in the number of cosmetic procedures performed annually or percentage breakdown of procedures performed. Conclusions: Despite OCP therapy being a known risk factor for venous thromboembolic events, a majority of surgeons performing cosmetic surgery do not routinely recommend perioperative cessation. PMID- 29267905 TI - Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection. AB - Objective: To investigate maintenance of rituximab (RTX) in RA patients re treated with reduced doses compared with standard dose in a real life setting. Methods: The Autoimmunity and Rituximab (AIR) registry is a nationwide prospective observational cohort investigating the long-term safety and efficacy of RTX in RA. The present study included patients from the AIR registry that have been re-treated with RTX after a first course of RTX standard dose (1000 mg * 2). Two groups were defined according to dose of RTX of the first retreatment course (i.e. second course): standard dose group and reduced dose group. Five years' maintenance and rate of serious infections of the retreatment period were compared between standard dose and reduced dose groups. Analyses used the inverse probability of treatment weighting propensity score adjusted method. Results: Among the 1986 patients from the AIR registry, 1278 were included, 1093 (85.5%) treated with standard dose and 185 (14.5%) with reduced doses. Maintenance of RTX at 5 years in the standard and reduced groups was 55.5 and 53.8%, respectively, and did not significantly differ between groups in adjusted analyses (hazard ratio = 1.03; 95% CI: 0.81, 1.30), but the cumulative RTX dose received for retreatment [1.4 (0.6) vs 2.3 (1.0) g/year, P < 0.001] and the rate of serious infections were significantly lower in the reduced dose group (adjusted hazard ratio = 0.50; 95% CI: 0.27, 0.92; P = 0.02). Conclusion: Use of reduced doses of RTX for retreatment did not alter the maintenance of RTX at 5 years in RA patients, but allowed a 39% total dose reduction and a lower rate of serious infections. PMID- 29267906 TI - Taxonomic affinity, habitat and seed mass strongly predict seed desiccation response: a boosted regression trees analysis based on 17 539 species. AB - Background and Aims: Seed desiccation response plays an important role in plant regeneration ecology, and has significant implications for species conservation. The majority of seed plants produce desiccation-tolerant (orthodox) seeds, whilst comparatively few produce desiccation-sensitive (recalcitrant) seeds that are unable to survive dehydration, and which cannot be conserved in traditional seed banks. This study develops a set of models to predict seed desiccation response in unstudied species. Methods: Taxonomy, trait, location and climate data were compiled to form a global data set of 17 539 species. Three boosted regression trees models were then developed to predict species' seed desiccation responses based on habitat and trait information for the species, and the seed desiccation responses of close relatives (either members of the same genus, family or order, depending on the model). Ten-fold cross-validation was used to test model predictive success. The utility of the models was then demonstrated by predicting seed desiccation response for two floras: Ecuador, and Britain and Ireland. Key Results: The three models had varying success rates for identifying the desiccation-sensitive species: 89 % for the genus-level model, 79 % for the family-level model and 60 % for the order-level model. The most important predictor variables were the seed desiccation responses of a species' relatives, seed mass and annual precipitation. It is predicted that 10 % of seed plants from Ecuador and 1.2 % of those from Britain and Ireland produce desiccation-sensitive seeds. Due to data availability, prediction accuracy is likely to be higher for the British and Irish flora, where it is estimated that a desiccation-sensitive species had a 96.7 % chance of being correctly identified, compared with 80.8 % in the Ecuador flora. Conclusions: These models can utilize existing data to predict species' likely seed desiccation responses, providing a gap-filling tool for global studies of plant traits, as well as critical decision-making support for plant conservation activities. PMID- 29267907 TI - miRNA limits MAP kinase-mediated immunity: optimization of plant fitness. PMID- 29267908 TI - Pandemic Zika: A Formidable Challenge to Medicine and Public Health. PMID- 29267909 TI - Modes of Transmission of Zika Virus. AB - For >60 years, Zika virus (ZIKV) has been recognized as an arthropod-borne virus with Aedes species mosquitoes as the primary vector. However in the past 10 years, multiple alternative routes of ZIKV transmission have been identified. We review the available data on vector and non-vector-borne modes of transmission and interventions undertaken, to date, to reduce the risk of human infection through these routes. Although much has been learned during the outbreak in the Americas on the underlying mechanisms and pathogenesis of non-vector-borne ZIKV infections, significant gaps remain in our understanding of the relative incidence of, and risk from, these modes compared to mosquito transmission. Additional research is urgently needed on the risk, pathogenesis, and effectiveness of measures to mitigate non-vector-borne ZIKV transmission. PMID- 29267910 TI - Zika Virus Mosquito Vectors: Competence, Biology, and Vector Control. AB - Zika virus (ZIKV) (Flaviviridae, Flavivirus) has become one of the most medically important mosquito-borne viruses because of its ability to cause microcephaly in utero and Guillain-Barre syndrome in adults. This virus emerged from its sylvatic cycle in Africa to cause an outbreak in Yap, Federated States of Micronesia in 2007, French Polynesia in 2014, and most recently South America in 2015. The rapid expansion of ZIKV in the Americas largely has been due to the biology and behavior of its vector, Aedes aegypti. Other arboviruses transmitted by Ae. aegypti include the 2 flaviviruses dengue virus and yellow fever virus and the alphavirus chikungunya virus, which are also (re)emerging viruses in the Americas. This mosquito vector is highly domesticated, living in close association with humans in urban households. Its eggs are desiccation resistant, and the larvae develop rapidly in subtropical and tropical environments. Climate warming is facilitating range expansion of Ae. aegypti, adding to the threat this mosquito poses to human health, especially in light of the difficulty controlling it. Aedes albopictus, another highly invasive arbovirus vector that has only been implicated in one country (Gabon), is an important vector of ZIKV, but because of its wide geographic distribution may become a more important vector in the future. This article discusses the historical background of ZIKV and the biology and ecology of these 2 vectors. PMID- 29267911 TI - Small Molecules and Antibodies for Zika Therapy. AB - Zika virus (ZIKV) infection during pregnancy can cause devastating congenital abnormities or fetal demise. Zika virus infection could also cause Guillain-Barre syndrome in adults. Mosquito control, vaccine, and therapeutics are 3 potential, effective means to prevent ZIKV infection. Here we review the current status of ZIKV drug discovery. Both small molecule inhibitors and therapeutic antibodies have been identified, some of which have shown promising efficacy in mouse models. Most inhibitors were identified through screening US Food and Drug Administration-approved drugs and clinical trial compounds; however, none of them were potent enough to justify a ZIKV clinical trial. Such a repurposing approach has also been pursued for dengue therapy, with several compounds tested in clinical trials showing no clinical benefits. Because pregnant women are the main target population for ZIKV treatment, therapeutic candidates could be developed through a 2-stage path. The first stage should demonstrate safety and efficacy in nonpregnant patients. Once efficacy has been demonstrated in nonpregnant patients, the candidates should be rapidly advanced to stage 2 for safety and efficacy evaluation in pregnant patients. The 2-stage developmental path is supported by previous results from trials with other viral infections that showed that treatment of pregnant women with antiviral drugs or hyperimmunoglobulins significantly reduced congenital abnormalities in neonates. PMID- 29267913 TI - Clinical Development Strategies and Considerations for Zika Vaccine Licensure. AB - The Zika outbreak that began in 2015 has spread from Brazil to countries across the Western Hemisphere including the United States, presenting global public health challenges that call for the expedited development and availability of preventive vaccines to protect against Zika virus disease. While the general principles guiding the nonclinical and clinical development for Zika vaccines are the same as those of other preventive vaccines, unique considerations apply, in particular if development occurs during a public health emergency. Furthermore, incomplete information about the pathogenesis of Zika virus disease and the mechanism by which candidate preventive vaccines potentially may confer protection presents additional challenges to their clinical development. Nevertheless, definition of clinical development strategies to enable sound regulatory assessment, with a goal toward licensure is critical for these products. This article will provide an overview of the regulatory considerations for the clinical development and licensure of Zika vaccine candidates including a discussion of clinical study designs, approaches to demonstrate vaccine effectiveness, and regulatory pathways to licensure. PMID- 29267912 TI - Pathogenesis of Non-Zika Congenital Viral Infections. AB - A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 from South and Central America and the Caribbean. Although the full spectrum of ZIKV infection of the newborn has yet to be determined, other maternal viral infections resulting in transmission to the fetus provide instructive lessons that can be applied to the prospective evaluation of individuals with ZIKV infection. This review focuses on those other congenital infections, including rubella, congenital cytomegalovirus, human immunodeficiency virus, hepatitis B virus, and neonatal herpes simplex virus, from which lessons for the evaluation of ZIKV in the newborn can be applied. PMID- 29267914 TI - Epidemiology of Zika Virus Infection. AB - Long known to be endemic in Africa and Southeast Asia and a rare cause of acute febrile illness, Zika virus (ZIKAV) arose from obscurity when an Asian genotype ZIKAV caused an outbreak of mild febrile illness in 2007 in Yap State, Federated States of Micronesia. Subsequent viral spread in the Pacific led to a large outbreak in French Polynesia commencing in 2013. After its recognition in the Americas through March 2017, the Pan American Health Organization has received reports of >750000 suspected and laboratory-confirmed cases of autochthonous ZIKAV transmission. Outbreaks in most countries in the Americas peaked in early to mid-2016. Increased surveillance in several Southeast Asian counties has led to increased case recognition, including an outbreak in Singapore, and the first reports of birth defects linked to ZIKAV in the region. As of April 2017, the World Health Organization reported 84 countries or territories with current or previous ZIKAV transmission. PMID- 29267915 TI - Quantifying Zika: Advancing the Epidemiology of Zika With Quantitative Models. AB - When Zika virus (ZIKV) emerged in the Americas, little was known about its biology, pathogenesis, and transmission potential, and the scope of the epidemic was largely hidden, owing to generally mild infections and no established surveillance systems. Surges in congenital defects and Guillain-Barre syndrome alerted the world to the danger of ZIKV. In the context of limited data, quantitative models were critical in reducing uncertainties and guiding the global ZIKV response. Here, we review some of the models used to assess the risk of ZIKV-associated severe outcomes, the potential speed and size of ZIKV epidemics, and the geographic distribution of ZIKV risk. These models provide important insights and highlight significant unresolved questions related to ZIKV and other emerging pathogens. PMID- 29267916 TI - Zika Virus Infection in Pregnancy: Maternal, Fetal, and Neonatal Considerations. AB - An infection with the Zika virus (ZIKV) is usually mild, with nonspecific symptoms and most often asymptomatic. However, because of its causal relationship with severe congenital malformations, the ZIKV epidemic became an imperative for mobilization, renewed strategies for vector control, and biomedical research. A congenital Zika syndrome (CZS) has been characterized with 5 distinctive features that focus on brain development abnormalities (including microcephaly and brain calcifications), retinal manifestations, and defects on extremities including congenital contractures and hypertonia. The CZS could be just "the tip of the iceberg", pending the documentation of a spectrum of disease that could manifest later in life, from mild dysfunction to severe disease. It will be a matter of time for neurodevelopmental abnormalities, learning disabilities, and other unknown but yet-to-be-described outcomes to be associated with intrauterine ZIKV infection. In addition, ZIKV infection during pregnancy has been associated with other adverse outcomes. Reports mostly include ZIKV-affected pregnancies, and it will be difficult to clearly establish causality without appropriate control groups. We are summarizing some of the known or reported consequences of such infection during pregnancy. Women of reproductive age and particularly pregnant women are the most vulnerable to the adverse consequences of the ZIKV epidemic. Vector control programs need to be expanded to curtail new infections. Research is needed to develop safe and effective treatments, a preventive or therapeutic vaccine, and specific and sensitive tests and to diagnose and identify correlates of long-term immunity. Vaccines and treatments should be safe to be used in pregnancy. To do nothing would allow thousands of pregnant women to expose their fetuses to an infection that causes birth defects and other problems. Prenatal diagnosis technology development is necessary to be able to predict or diagnose adverse fetal outcomes related to ZIKV. Moreover, these tests should be used in a manner similar to the testing/screening method for neural tube defects and common chromosomal anomalies during prenatal care. PMID- 29267917 TI - History and Emergence of Zika Virus. AB - Zika virus was discovered in East Africa in 1947 by the Rockefeller Foundation during investigations on the ecology of yellow fever. Although it was subsequently shown to have widespread distribution in Africa and Asia, it was not known to cause epidemics until 2007. This paper describes the history of the virus discovery, emergence and evolution as an epidemic virus, and the its evolving clinical spectrum. PMID- 29267918 TI - Zika Virus Vaccine Development. AB - The emergence of Zika virus in Brazil and its association with microcephaly and Guillain-Barre syndrome led to accelerated vaccine development efforts. Based on prior flavivirus vaccine development programs, knowledge of flavivirus particle structure, definition of E dimers as the key antigenic target, and deep understanding of neutralizing mechanisms, multiple vaccine strategies have advanced to the stage of clinical evaluation with unprecedented speed. These include nucleic acid (DNA and messenger RNA), whole-inactivated virus, live attenuated or chimeric virus, and protein or viruslike particle vaccines. Within a year from the declaration by the World Health Organization of Zika virus as a Public Health Emergency of International Concern, multiple vaccine candidates entered clinical trials, now totaling 7 products with an additional 40-plus candidate vaccines in preclinical development. The rapid progress in vaccine development demonstrates the capacity of governments, public health organizations, and the scientific community to respond to pandemic threats when sufficient prior knowledge exists, emergency funding is made available, and interagency cooperation is achieved and serves as a paradigm for preparing for future emerging infectious diseases. PMID- 29267920 TI - Zika Vaccines: Role for Controlled Human Infection. AB - Zika virus (ZIKV), a previously little known arbovirus, caused an unprecedented outbreak in Latin America and the Caribbean throughout 2015 and 2016. The virus has been associated with the congenital Zika syndrome (CZS), which can occur with maternal ZIKV infection during any trimester and can result from asymptomatic infection. There is concern that even low levels of viremia can result in CZS, meaning an effective vaccine will need to induce very high levels of protection. Controlled human infection models (CHIMs), in which subjects are infected with a pathogen of interest, have been used to down-select vaccine candidates and have provided efficacy data in support of vaccine licensure.A ZIKV CHIM could be instrumental in determining which of the many ZIKV vaccine candidates provides the highest degree of protection and should be advanced in clinical development. The development of a ZIKV CHIM is not without challenges. The ZIKV, unlike other flaviviruses, is sexually and mosquito-transmitted, and an increase in the incidence of Guillain-Barre syndrome was reported in some countries during the ZIKV outbreak. These obstacles can be overcome with thoughtful study design to ensure maximal risk mitigation. If successful, a ZIKV CHIM could de-risk and accelerate ZIKV vaccine development. PMID- 29267919 TI - Small-Animal Models of Zika Virus. AB - Zika virus (ZIKV) infection can result in serious consequences, including severe congenital manifestations, persistent infection in the testes, and neurologic sequelae. After a pandemic emergence, the virus has spread to much of North and South America and has been introduced to many countries outside of ZIKV-endemic areas as infected travelers return to their home countries. Rodent models have been important in gaining a better understanding of the wide range of disease etiologies associated with ZIKV infection and for the initial phase of developing countermeasures to prevent or treat viral infections. We discuss herein the advantages and disadvantages of small-animal models that have been developed to replicate various aspects of disease associated with ZIKV infection. PMID- 29267921 TI - Zika Virus and Future Research Directions. AB - There was a dramatic upsurge in research activity after the recognition of Zika virus (ZIKV) transmission in South America in 2015 and its causal relationship to devastating anomalies in newborn infants. Progress in this area required a community of arbovirologists poised to refocus their research efforts and rapidly characterize the features of ZIKV transmission and infection through diverse multidisciplinary collaborations. Significant gaps remain in our knowledge of the natural history of ZIKV infection, its effects on neurodevelopment, modes and risk of transmission, and its interrelationship with other arbovirus infections. Development of effective countermeasures, such as therapeutics and an effective vaccine, are also research priorities. Lessons learned from our research response to ZIKV may help public health officials plan for the next emerging infectious disease threat.The last 18 months have witnessed one of the most rapid and coordinated research responses against an emerging disease to date. Zika virus, a pathogen that has been known since 1947 but poorly studied until recently because it was believed to only cause a mild infection, has rapidly become the object of intense investigation by the international research community since the link between infection and severe congenital disease was announced by Brazilian authorities in November 2015. According to PubMed, the total number of ZIKV related publications skyrocketed from 117 in 2015 to 3253 in August of 2017. This supplement summarizes the tremendous progress that has been made since 2015 to elucidate the biology of this virus, its various disease manifestations in humans and animals, the diverse routes by which it is transmitted, and the role of various mosquito vectors in the recent outbreaks. In addition, several efforts have been initiated to develop new diagnostics, therapeutics, vaccines, and vector control strategies to better detect, treat, and prevent this important infection. There are 3 factors that contributed to the rapid progress in ZIKV research: (1) the availability of dedicated funding for ZIKV research; (2) the prior existence of both flavivirologists and maternal-child health researchers who were poised to tackle this new public health challenge; and (3) the high level of coordination and collaboration between different research agencies worldwide.Despite the significant progress, many significant questions remain to be addressed to accelerate the development of effective ZIKV countermeasures and increase our preparedness against this significant public health threat. Some of the most pressing scientific gaps that need to be addressed to advance the field are summarized below. PMID- 29267922 TI - Diagnosis of Zika Virus Infections: Challenges and Opportunities. AB - Accurate diagnosis of Zika virus (ZIKV) infections has become a pressing need for the effective prevention and control of the epidemic. The findings that ZIKV infections are associated with birth defects and neurologic disease, and that the virus can be sexually transmitted, accentuate the need for accurate diagnostic testing for different applications new to the arbovirus field. Antibody response to related flaviviruses has long been known to be cross-reactive, and antibody detection of ZIKV is nonspecific in populations previously exposed to any of the four dengue viruses or West Nile virus, or vaccinated against yellow fever virus. Therefore, the diagnosis of ZIKV infections has increasingly depended on detection by nucleic acid tests. During the recent epidemic, tests authorized for emergency use have been utilized by public health laboratories and the commercial sector, but a more dependable and responsive diagnostic testing has yet to be developed. PMID- 29267923 TI - Neurological Implications of Zika Virus Infection in Adults. AB - The 2015-2016 epidemic of Zika virus (ZIKV) in the Americas and the Caribbean was associated with an unprecedented burden of neurological disease among adults. Clinically, Guillain-Barre syndrome (GBS) predominated among regions affected by the ZIKV epidemic, but the spectrum of neurological disease in the adults appears broader as cases of encephalopathy, encephalitis, meningitis, myelitis, and seizures have also been reported. A para-infectious temporal profile of ZIKV associated GBS (ZIKV-GBS) has been described in clinical studies, which may suggest a direct viral neuropathic effect. However, ZIKV neuropathogenesis has not yet been fully understood. Mechanisms for ZIKV-GBS and other neurological syndromes have been hypothesized, such as adaptive viral genetic changes, immunological interactions with other circulating flaviviruses, and host and factors. This review summarizes the current evidence on ZIKV-associated neurological complications in the adults. PMID- 29267924 TI - Humoral Immune Responses Against Zika Virus Infection and the Importance of Preexisting Flavivirus Immunity. AB - The recent emergence of Zika virus (ZIKV) in the western hemisphere has been linked to Guillain-Barre syndrome, congenital microcephaly, and devastating ophthalmologic and neurologic developmental abnormalities. The vast geographic spread and adverse disease outcomes of the 2015-2016 epidemic have elevated ZIKV from a previously understudied virus to one of substantial public health interest worldwide. Recent efforts to dissect immunological responses to ZIKV have provided significant insights into the functional quality and antigenic targets of ZIKV-induced B-cell responses. Several groups have demonstrated immunological cross-reactivity between ZIKV and other flaviviruses and have identified antibodies capable of both cross-neutralization, as well as antibody-dependent enhancement (ADE) of ZIKV infection. However, the impact of preexisting flavivirus immunity on ZIKV pathogenesis, the generation of protective responses, and in utero transmission of ZIKV infection remain unclear. Given the widespread endemicity of DENV in the areas most effected by the current ZIKV outbreak, the possibility of ADE is especially concerning and may pose unique challenges to the development and deployment of safe and immunogenic ZIKV vaccines. Here, we review current literature pertaining to ZIKV-induced B-cell responses and humoral cross reactivity and discuss relevant considerations for the development of vaccines and therapeutics against ZIKV. PMID- 29267925 TI - Zika Virus Structure, Maturation, and Receptors. AB - The emergence of Zika virus (ZIKV) as a major public health threat has focused research on understanding virus biology and developing a suite of strategies for disease intervention. Recent advances in cryoelectron microscopy have accelerated structure-function studies of flaviviruses and of ZIKV in particular. Structures of the mature and immature ZIKV have demonstrated its similarity with other known flaviviruses such as dengue and West Nile viruses. However, ZIKV's unique pathobiology demands an explanation of how its structure, although similar to its flavivirus relatives, is sufficiently unique to address questions of receptor specificity, transmission, and antigenicity. Progress in defining the immunodominant epitopes and how neutralizing antibodies bind to them will provide great insight as vaccines progress through clinical trials. Identification of host receptors will substantially illuminate the interesting ZIKV tropism and provide insights into pathogenesis. Although the answers to all of these questions are not yet available, rapid progress in combining structural biology with other techniques is revealing the similarities and the differences in virion structure and function between ZIKV and related flaviviruses. PMID- 29267926 TI - Nonhuman Primate Models of Zika Virus Infection, Immunity, and Therapeutic Development. AB - Zika virus is a re-emerging flavivirus transmitted primarily by arthropod vectors. The recent devastating outbreak of Zika virus in Brazil was preceded by the slow global encroachment of this virus over many decades. To date, significant research efforts are underway to understand the spread and the unique pathogenesis of this virus; with the intent to rapidly develop vaccines and therapeutics. Several model systems have emerged to study Zika. This review will focus on the use of nonhuman primates to model Zika infection. PMID- 29267928 TI - Cost-effectiveness of tobacco control policies and programmes targeting adolescents: a systematic review. AB - Background: Consistent evidence shows the importance of preventing smoking at young ages, when health behaviours are formed, with long-term consequences on health and survival. Although tobacco control policies and programmes targeting adolescents are widely promoted, the cost-effectiveness of such interventions has not been systematically documented. We performed a systematic review on the cost effectiveness of policies and programmes preventing tobacco consumption targeting adolescents. Methods: We systematically reviewed literature on the (i) cost and effectiveness of (ii) prevention policies targeting (iii) smoking by (iv) adolescents. PubMed, Web of Science, Cochrane, CEA-TUFTS, Health Economic Evaluations, Wiley Online Library, Centre for Reviews and Dissemination Database, the National Institute for Health and Care Excellence and Google Scholar databases were used, and Google search engine was used for other grey literature review. Results: We obtained 793 full-text papers and 19 grey literature documents, from which 16 studies fulfilled the inclusion criteria. Of these, only one was published in the last 5 years, and 15 were performed in high-income countries. Eight analyzed the cost-effectiveness of school-based programmes, five focused on media campaigns and three on legal bans. Policies and programmes were found to be cost-effective in all studies, and both effective and cost-saving in about half of the studies. Conclusions: Evidence is scarce and relatively obsolete, and rarely focused on the evaluation of legal bans. Moreover, no comparisons have been made between different interventions or across different contexts and implementation levels. However, all studies conclude that smoking prevention policies and programmes amongst adolescents are greatly worth their costs. PMID- 29267927 TI - VaDiR: an integrated approach to Variant Detection in RNA. AB - Background: Advances in next-generation DNA sequencing technologies are now enabling detailed characterization of sequence variations in cancer genomes. With whole-genome sequencing, variations in coding and non-coding sequences can be discovered. But the cost associated with it is currently limiting its general use in research. Whole-exome sequencing is used to characterize sequence variations in coding regions, but the cost associated with capture reagents and biases in capture rate limit its full use in research. Additional limitations include uncertainty in assigning the functional significance of the mutations when these mutations are observed in the non-coding region or in genes that are not expressed in cancer tissue. Results: We investigated the feasibility of uncovering mutations from expressed genes using RNA sequencing datasets with a method called Variant Detection in RNA(VaDiR) that integrates 3 variant callers, namely: SNPiR, RVBoost, and MuTect2. The combination of all 3 methods, which we called Tier 1 variants, produced the highest precision with true positive mutations from RNA-seq that could be validated at the DNA level. We also found that the integration of Tier 1 variants with those called by MuTect2 and SNPiR produced the highest recall with acceptable precision. Finally, we observed a higher rate of mutation discovery in genes that are expressed at higher levels. Conclusions: Our method, VaDiR, provides a possibility of uncovering mutations from RNA sequencing datasets that could be useful in further functional analysis. In addition, our approach allows orthogonal validation of DNA-based mutation discovery by providing complementary sequence variation analysis from paired RNA/DNA sequencing datasets. PMID- 29267929 TI - Floral heterochrony promotes flexibility of reproductive strategies in the morphologically homogeneous genus Eugenia (Myrtaceae). AB - Background and Aims: Comparative floral ontogeny represents a valuable tool to understand angiosperm evolution. Such an approach may elucidate subtle changes in development that discretely modify floral architecture and underlie reproductive lability in groups with superficial homogeneous morphology. This study presents a comparative survey of floral development in Eugenia (Myrtaceae), one of the largest genera of angiosperms, and shows how previously undocumented ontogenetic trends help to explain the evolution of its megadiversity in contrast to its apparent flower uniformity. Methods: Using scanning electron microscopy, selected steps of the floral ontogeny of a model species (Eugenia punicifolia) are described and compared with 20 further species representing all ten major clades in the Eugenia phylogenetic tree. Additional floral trait data are contrasted for correlation analysis and character reconstructions performed against the Myrtaceae phylogenetic tree. Key results: Eugenia flowers show similar organ arrangement patterns: radially symmetrical, (most commonly) tetramerous flowers with variable numbers of stamens and ovules. Despite a similar general organization, heterochrony is evident from size differences between tissues and structures at similar developmental stages. These differences underlie variable levels of investment in protection, subtle modifications to symmetry, herkogamic effects and independent androecium and gynoecium variation, producing a wide spectrum of floral display and contributing to fluctuations in fitness. During Eugenia's bud development, the hypanthium (as defined here) is completely covered by stamen primordia, unusual in other Myrtaceae. This is the likely plesiomorphic state for Myrteae and may have represented a key evolutionary novelty in the tribe. Conclusions: Floral evolution in Eugenia depends on heterochronic patterns rather than changes in complexity to promote flexibility in floral strategies. The successful early establishment of Myrteae, previously mainly linked to the key innovation of fleshy fruit, may also have benefitted from changes in flower structure. PMID- 29267930 TI - Green Toxicology-Know Early About and Avoid Toxic Product Liabilities. AB - Toxicology uniquely among the life sciences relies largely on methods which are more than 40-years old. Over the last 3 decades with more or less success some additions to and few replacements in this toolbox took place, mainly as alternatives to animal testing. The acceptance of such new approaches faces the needs of formal validation and the conservative attitude toward change in safety assessments. Only recently, there is growing awareness that the same alternative methods, especially in silico and in vitro tools can also much earlier and before validation inform decision-taking in the product life cycle. As similar thoughts developed in the context of Green Chemistry, the term of Green Toxicology was coined to describe this change in approach. Here, the current developments in the alternative field, especially computational and more organo-typic cell cultures are reviewed, as they lend themselves to front-loaded chemical safety assessments. The initiatives of the Center for Alternatives to Animal Testing Green Toxicology Collaboration are presented. They aim first of all for forming a community to promote this concept and then for a cultural change in companies with the necessary training of chemists, product stewards and later regulators. PMID- 29267931 TI - Comments on "Nonsurgical Medical Penile Girth Augmentation: Experience-Based Recommendations". PMID- 29267932 TI - Is osteoarthritis one disease or a collection of many? AB - OA is a multifaceted and heterogeneous syndrome that may be amenable to tailored treatment. There has been an increasing focus within the OA research community on the identification of meaningful OA phenotypes with potential implications for prognosis and treatment. Experimental and clinical data combined with sophisticated statistical approaches have been used to characterize and define phenotypes from the symptomatic and structural perspectives. An improved understanding of the existing phenotypes based on underlying disease mechanisms may shed light on the distinct entities that make up the disease. This narrative review provides an updated summary of the most recent advances in this field as well as limitations from previous approaches that can be addressed in future studies. PMID- 29267933 TI - Effect of Low-Oxygen Conditions Created by Modified Atmosphere Packaging on Radiation Tolerance in Drosophila suzukii (Diptera: Drosophilidae) in Sweet Cherries. AB - Modified atmosphere packaging (MAP) creates a low-oxygen (O2) environment that can increase the shelf life of fresh produce by decreasing respiration and the growth of pathogens. Low oxygen may also increase insect tolerance to irradiation (IR), and the use of MAP with products treated by IR to control quarantine pests before export may inadvertently compromise treatment efficacy. Spotted wing drosophila, Drosophila suzukii Matsumura (Diptera: Drosophilidae) is a quarantine pest of stone and small fruits and a potential target for postharvest IR treatment. The effect of low oxygen generated by MAP at ambient temperatures on the radiation tolerance of D. suzukii infesting sweet cherries was examined. Early pupal stage D. suzukii were inserted into ripe sweet cherries and treated by 1) MAP + IR, 2) IR alone, 3) MAP alone, or 4) no MAP and no IR and held for adult emergence. Three types of commercially available MAP products were tested that produced different oxygen concentrations between 3 and 15%, and a sublethal radiation dose (60 Gy) was used to allow comparisons between the treatments. Xtend PP61 bags (3.2-4.8% O2), Xtend PP71 bags (5.4-8.6% O2), and Xtend PP53 bags (13.6-15.4% O2) did not enhance survivorship to the adult stage in D. suzukii pupae irradiated at 60 Gy in sweet cherries. MAP use should not compromise phytosanitary IR treatment against D. suzukii in exported sweet cherries or other fruit. PMID- 29267934 TI - Impacted and transmigrant mandibular canines. PMID- 29267935 TI - To be serrate or pinnate: diverse leaf forms of yarrows (Achillea) are linked to differential expression patterns of NAM genes. AB - Background and Aims: To understand the link between species diversity and phenotype developmental evolution is an important issue in evolutionary biology. Yarrows in the genus Achillea (Asteraceae) show a great diversity in leaf serrate or pinnate dissection patterns. In Arabidopsis thaliana, the development of leaf serration requires the activity of the transcription factor CUC2. Does this regulator also work for leaf dissections of the Asteraceae plants? If so, how do the conserved regulatory 'tools' work differently to produce diverse leaf forms? Methods: Seedling leaf morphology was observed, and morphogenesis of leaf serration or lobes was examined by scanning electron microscopy (SEM). NAM genes, orthologues of arabidopsis CUC2, were isolated from A. acuminata with serrate leaves and A. asiatica with three-pinnatisect leaves, respectively. By means of whole-mount in situ mRNA hybridization and two quantitative gene expression assays, the droplet digital PCR (ddPCR) and quantitative real-time PCR (qPCR), expression patterns of the NAM genes during leaf dissection development were checked in both species for comparison. Key Results: For both species, the development of leaf dissection initiated when a leaf blade was about 300-400 um long. In A. acuminata, in situ hybridization showed NAM expression signals at leaf margins where teeth are growing, or later on, in the sinuses of the teeth, whilst in A. asiatica, hybridization signals appear not only on leaf margins but further on the margins of leaf lobes. Both ddPCR and qPCR revealed a continuous decline of AacNAM expression from the early to the late developmental stages of a single leaf of A. acuminata, whereas a relatively long maintenance and fluctuation of AasNAM expression was seen in a leaf of A. asiatica. Conclusions: Differential spatiotemporal patterns of NAM expression were found between the two yarrow species during development of leaf dissection. This study provides the first evidence for NAM activity in the development of leaf dissection of the Asteraceae plants, and demonstrates that leaf form diversity is correlated to the altered NAM expression dynamic. PMID- 29267936 TI - Effects of Energy Reserves and Diet on Glassy-Winged Sharpshooter Egg Maturation. AB - The glassy-winged sharpshooter is an invasive insect capable of transmitting the plant pathogen Xylella fastidiosa. As rates of pathogen spread are a function of vector abundance, identification of factors contributing to glassy-winged sharpshooter egg production will aid in predicting population growth. Here, effects of stored energy reserves and adult diet on glassy-winged sharpshooter egg maturation were evaluated. To estimate energy reserves available to adult females at the beginning of feeding assays, residuals from a regression of wet weight on size were used. Analysis of a subset of females sacrificed at the beginning of feeding assays, demonstrated that females with a positive residual wet weight had higher lipid content and carried more eggs than females with a negative residual wet weight. To evaluate effects of diet and energy reserves on egg maturation, energy reserves available to females entering feeding assays on cowpea and grapevine were estimated. For females held on cowpea, residual wet weight and quantity of excreta produced over a 6-d feeding period affected egg production. In contrast, for females held on grapevine, only residual wet weight affected egg production. Comparison of cowpea and grapevine xylem sap determined that eight amino acids were more concentrated in xylem sap from cowpea than from grapevine. Collectively, the results suggest that glassy-winged sharpshooter population growth within crop monocultures will not depend solely on the nutritional quality of the specific crop for producing mature eggs but also on the quantity of energy reserves accumulated by females prior to entering that crop habitat. PMID- 29267937 TI - Interim monitoring for non-inferiority trials: minimizing patient exposure to inferior therapies. AB - The goal of a non-inferiority randomized trial is to demonstrate that an experimental treatment is not unacceptably worse than a standard treatment. The experimental treatment is known to have less toxicity or other quality-of-life benefits when compared with the standard treatment, so that a small decrement in efficacy would be acceptable. Interim monitoring of randomized trials is used to stop trials early if the conclusions of the trial become definitive early. In the context of a non-inferiority trial, of special interest is stopping a trial early when the experimental treatment is inferior to the standard treatment. Methods for performing interim monitoring of non-inferiority trials are reviewed for their ability to minimize patient exposure to inferior experimental treatments. Examples of trials from the literature are discussed along with a computer simulation of a simple non-inferiority monitoring rule. Interim monitoring for non-inferiority trials is shown to substantially reduce the exposure of patients to inferior therapies when, in fact, the experimental treatment is inferior to the standard treatment. Interim monitoring rules typically used in superiority trials may be sub-optimal for non-inferiority trials, and may unnecessarily expose patients to inferior therapies. Examples of trials with inferior experimental arms and trials with sub-optimal monitoring rules are given. Appropriate interim monitoring of non-inferiority trials can reduce the exposure of patients to inferior therapies when the experimental treatment is inferior to the standard treatment. PMID- 29267938 TI - Conflict with Mothers and Siblings During Caregiving: Differential Costs for Black and White Adult Children. AB - Objectives: Family conflict has been found to play a role in caregivers' psychological well-being; however, few studies have considered race differences in the prevalence and consequences of caregiving conflict. In this paper, we use mixed-methods to examine differences in the experiences of conflict among Black and White adult children caring for mothers. Methods: Quantitative and qualitative data were collected from 279 adult-child caregivers (213 White; 66 Black). Results: Multilevel modeling revealed that conflict with mothers predicted depressive symptoms among Black, but not White caregivers, whereas there were not statistically significant race differences in the effects of conflict with siblings. However within-model tests showed stronger effects of conflict with mothers than siblings for Black caregivers, and stronger effects of conflict with siblings than mothers for White caregivers. Qualitative data revealed that Black caregivers' conflict with mothers resulted from their inability to meet their mothers' needs, inducing concern and sadness. White children's conflict stemmed from mothers' resistance to unwanted assistance and requests for support that children considered excessive, evoking irritation and frustration. Discussion: This study highlights ways in which the experiences of caregivers reflect broader patterns of differences between Black and White families in both intergenerational cohesion and health disparities in midlife. PMID- 29267939 TI - Psychometric Properties of the Problem Areas in Diabetes: Teen and Parent of Teen Versions. AB - Objective: This study adds to the literature on the psychometric properties of the Problem Areas in Diabetes-Teen (PAID-T) and Parent (P-PAID-T) Versions. It also aims to shorten the measures of diabetes-specific distress, determine construct validity, and establish cutoff scores. Methods: Data are from two independent studies (N = 1,265). Adolescent-caregiver dyads completed measures of emotional distress, diabetes strengths, hemoglobin A1c, blood glucose checks, and average blood glucose. Exploratory and confirmatory factor analyses assessed factor structures for each measure. Correlational analyses provided support for concurrent validity. Receiver-operating characteristic curves identified cutoff scores based on clinically meaningful groups identified with latent profile analysis. Results: Analyses supported a 14-item PAID-T and a 15-item P-PAID-T, with preliminary cutoff scores >=44 and >=54, respectively. Measures were associated with emotional and health outcomes as hypothesized. Conclusions: The PAID-T and P-PAID-T are valid, reliable, and useful measures of diabetes-specific distress for teenagers with type 1 diabetes and parents of teenagers. PMID- 29267940 TI - The Effects of Metacognition-Oriented Social Skills Training on Psychosocial Outcome in Schizophrenia-Spectrum Disorders: A Randomized Controlled Trial. AB - A pilot study of the effects of metacognition-oriented social skills training (MOSST) on social functioning in patients with schizophrenia spectrum disorders (SSDs) reported promising results. The main purpose of the current trial was to compare the effectiveness and potential benefits of MOSST vs conventional social skills training (SST). Single-blind randomized controlled trial with 2 groups of patients aged 18-65 with SSDs on partial hospitalization. Participants were randomly assigned (1:1) to receive 16 group sessions with MOSST or conventional SST, both in addition to standard care, over 4 months, with a 6-month follow-up. Psychosocial functioning, metacognition, and symptom outcomes were measured by blind assessors. Statistical analyses used mixed models to estimate treatment effects in each postrandomization time point. Thirty-six patients were randomly assigned to the MOSST group and 33 patients to the conventional SST group. Between-group differences were significant in favor of MOSST on Social and Occupational Functioning Assessment Scale (SOFAS) and Personal and Social Performance Scale (PSP) total scores at post-treatment and follow-up. Concerning PSP subscales, there were significant between-group differences in favor of MOSST at follow-up on socially useful activities, personal and social relationships, and disturbing and aggressive behaviors. Metacognition only improved following MOSST group. For people with SDDs, MOSST appears to have short- and long-term beneficial effects on social functioning and symptoms. Further studies are required to replicate the current results in other samples. PMID- 29267941 TI - Protein and membrane trafficking routes in plants: conventional or unconventional? PMID- 29267944 TI - The Micromort Concept and its Applicability to Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) Risk Assessment. PMID- 29267945 TI - Commentary on: Surgical Site Irrigation in Plastic Surgery: What is Essential? PMID- 29267943 TI - Hemodynamics Associated With Intracerebral Arteriovenous Malformations: The Effects of Treatment Modalities. AB - The understanding of the physiology of cerebral arteriovenous malformations (AVMs) continues to expand. Knowledge of the hemodynamics of blood flow associated with AVMs is also progressing as imaging and treatment modalities advance. The authors present a comprehensive literature review that reveals the physical hemodynamics of AVMs, and the effect that various treatment modalities have on AVM hemodynamics and the surrounding cortex and vasculature. The authors discuss feeding arteries, flow through the nidus, venous outflow, and the relative effects of radiosurgical monotherapy, endovascular embolization alone, and combined microsurgical treatments. The hemodynamics associated with intracranial AVMs is complex and likely changes over time with changes in the physical morphology and angioarchitecture of the lesions. Hemodynamic change may be even more of a factor as it pertains to the vast array of single and multimodal treatment options available. An understanding of AVM hemodynamics associated with differing treatment modalities can affect treatment strategies and should be considered for optimal clinical outcomes. PMID- 29267942 TI - A Genome Resequencing-Based Genetic Map Reveals the Recombination Landscape of an Outbred Parasitic Nematode in the Presence of Polyploidy and Polyandry. AB - The parasitic nematode Haemonchus contortus is an economically and clinically important pathogen of small ruminants, and a model system for understanding the mechanisms and evolution of traits such as anthelmintic resistance. Anthelmintic resistance is widespread and is a major threat to the sustainability of livestock agriculture globally; however, little is known about the genome architecture and parameters such as recombination that will ultimately influence the rate at which resistance may evolve and spread. Here, we performed a genetic cross between two divergent strains of H. contortus, and subsequently used whole-genome resequencing of a female worm and her brood to identify the distribution of genome-wide variation that characterizes these strains. Using a novel bioinformatic approach to identify variants that segregate as expected in a pseudotestcross, we characterized linkage groups and estimated genetic distances between markers to generate a chromosome-scale F1 genetic map. We exploited this map to reveal the recombination landscape, the first for any helminth species, demonstrating extensive variation in recombination rate within and between chromosomes. Analyses of these data also revealed the extent of polyandry, whereby at least eight males were found to have contributed to the genetic variation of the progeny analyzed. Triploid offspring were also identified, which we hypothesize are the result of nondisjunction during female meiosis or polyspermy. These results expand our knowledge of the genetics of parasitic helminths and the unusual life-history of H. contortus, and enhance ongoing efforts to understand the genetic basis of resistance to the drugs used to control these worms and for related species that infect livestock and humans throughout the world. This study also demonstrates the feasibility of using whole genome resequencing data to directly construct a genetic map in a single generation cross from a noninbred nonmodel organism with a complex lifecycle. PMID- 29267946 TI - Association of Lower Cardiovagal Tone and Baroreflex Sensitivity With Higher Liver Fat Content Early in Type 2 Diabetes. AB - Context: Cardiovascular autonomic neuropathy (CAN) diagnosed by diminished heart rate variability (HRV) is prevalent and carries an increased risk of mortality in patients with diabetes and chronic liver diseases. Objective: To determine whether lower HRV is associated with increased liver fat content in recent-onset diabetes. Design: Cross-sectional study. Setting: German Diabetes Study (GDS), Dusseldorf, Germany. Participants: Individuals with type 1 diabetes (n = 97) or type 2 diabetes (n = 109) with known diabetes duration <=1 year and two age- and sex-matched glucose-tolerant control groups from the GDS baseline cohort. Main Outcome Measures: Four time and frequency domain HRV indices each were measured over 3 hours during a hyperinsulinemic-euglycemic clamp, whereas spontaneous cross-correlation baroreflex sensitivity (xBRS) was computed over 5 minutes. Hepatic fat content was determined by 1H magnetic resonance spectroscopy, and values >5.56% were defined as hepatic steatosis. Results: Hepatic steatosis was observed in 52% and 5% of patients with type 2 and type 1 diabetes, respectively. After adjustment for sex, age, body mass index, smoking, diabetes duration, hemoglobin A1c, M-value, and triglycerides, all four vagus-mediated time domain HRV indices, three of four frequency domain indices, and xBRS were inversely associated with liver fat content in participants with type 2 diabetes (all P < 0.05) but not in the group with type 1 diabetes. Conclusions: Both lower cardiovagal tone and baroreflex sensitivity are strongly associated with prevalent hepatic steatosis in patients with recent-onset type 2 as opposed to type 1 diabetes, suggesting a role for hepatic steatosis in the early development of parasympathetic CAN in type 2 diabetes. PMID- 29267947 TI - ART, Stoffenmanager, and TRA: A Systematic Comparison of Exposure Estimates Using the TREXMO Translation System. AB - Several occupational exposure models are recommended under the EU's REACH legislation. Due to limited availability of high-quality exposure data, their validation is an ongoing process. It was shown, however, that different models may calculate significantly different estimates and thus lead to potentially dangerous conclusions about chemical risk. In this paper, the between-model translation rules defined in TREXMO were used to generate 319000 different in silico exposure situations in ART, Stoffenmanager, and ECETOC TRA v3. The three models' estimates were computed and the correlation and consistency between them were investigated. The best correlated pair was Stoffenmanager-ART (R, 0.52 0.90), whereas the ART-TRA and Stoffenmanager-TRA correlations were either lower (R, 0.36-0.69) or no correlation was found. Consistency varied significantly according to different exposure types (e.g. vapour versus dust) or settings (near field versus far-field and indoors versus outdoors). The percentages of generated situations for which estimates differed by more than a factor of 100 ranged from 14 to 97%, 37 to 99%, and 1 to 68% for Stoffenmanager-ART, TRA-ART, and TRA Stoffenmanager, respectively. Overall, the models were more consistent for vapours than for dusts and solids, near-fields than for far-fields, and indoor than for outdoor exposure. Multiple linear regression analyses evidenced the relationship between the models' parameters and the relative differences between the models' predictions. The relative difference can be used to estimate the consistency between the models. Furthermore, the study showed that the tiered approach is not generally applicable to all exposure situations. These findings emphasize the need for a multiple-model approach to assessing critical exposure scenarios under REACH. Moreover, in combination with occupational exposure measurements, they might also be used for future studies to improve prediction accuracy. PMID- 29267948 TI - Relationship Between Exposure to Second-Hand Smoke in the Workplace and Occupational Injury in the Republic of Korea. AB - Background: Most studies in the field of smoking exposure in the workplace linked to occupational safety have only focused on active smoking. Few studies have reported that exposure to second-hand smoke in the workplace is a possible factor increasing the risk of occupational injury without considering occupational characteristics. The aim of this study was to determine the association between occupational injury and level of exposure to second-hand smoke at the workplace among Korean workers, after taking into account occupational characteristics. Method: Using data from the third Korean Working Conditions Survey, levels of exposure to second-hand smoke were categorized as none, moderate, and high. We investigated the influence of exposure to second-hand smoke on occupational injury using logistic regression analysis with stratification by sex, smoking status, smoke-free policy in the workplace, and occupational characteristics. Occupational characteristics (occupational classification, working schedule, length of working day, and co-exposure to occupational hazards in the workplace) were stratified and analyzed using logistic regression models to estimate the risk of occupational injury linked to exposure to second-hand smoke. Results: Among all participants, there was a significant dose-dependent association between risk of occupational injury and level of exposure level to second-hand smoke. After stratification by sex and smoking status, there was a significant association between risk of occupational injury and exposure level to second-hand smoke. Moreover, there was a significant relationship between exposure to second hand smoke in the workplace and occupational injury, depending on the smoking free policy at workplace (odds ratio [OR] in completely non-smoking workplace, 4.23; OR in non-smoking workplace with separate smoking area, 2.98; OR in smoking workplace 2.84). Additionally, there was a significant relationship between risk of occupational injury and exposure to second-hand smoke after stratification by occupational classification, working schedule, long working hours, and co exposure to hazards in the workplace. Discussion: There was a dose-response relationship between occupational injury and exposure to second-hand smoke, even after stratification to reduce the impact of various potential confounders and after taking into account occupational characteristics. These findings provide greater insight into the effects of exposure to second-hand smoke on the working population and may direct further research and policy-making in this field. PMID- 29267950 TI - Low diagnostic yield of non-invasive testing in patients with suspected coronary artery disease: results from a large unselected hospital-based sample. AB - Aims: Stable angina is the most common presentation of heart disease and has a good prognosis. With declining coronary artery disease (CAD), rates a diagnostic approach balancing costs and benefits is a challenge, particularly in women. This study describes the real-life diagnostic workup in a large hospital to explore whether the diagnostic approach may be improved. Methods and results: We identified 4028 patients free of CAD, referred for and assessed with non-invasive (NIT) or invasive test for stable suspected CAD in 2012-15. In both the sexes, the majority (>85%) presented with chest pain as primary symptom. Women had more non-angina (60.2 vs. 54.5%) and less typical angina (8.2 vs. 11.8%, P < 0.001). Despite a mean pretest probability of 20.9% in women and 45.1% in men (P < 0.001), only 69 (3.1%) women and 190 men (10.4%) were diagnosed with obstructive CAD. In all, 93% underwent a NIT and 80% of these were normal. Among the 1238 men and 1595 women with non-angina or dyspnoea, only 6.1% and 2.9%, respectively, had positive NIT. After multiple adjustments, women remained less likely to have positive NIT [odds ratio (OR) 0.42 95% confidence interval (95% CI 0.32-0.56)] and given a positive test also less likely to have obstructive CAD [OR 0.30 (0.17 0.52)]. The C-statistics for predicting positive NIT was 0.77 (0.72-0.82) in women and 0.77 (0.74-0.80) in men. Conclusion: These data confirm the very low diagnostic yield of non-invasive and invasive assessment of CAD in current clinical practice, particularly in women and in patients with atypical symptoms. Data call for a more rational approach to avoid unnecessary testing. PMID- 29267949 TI - Normal interventricular differences in tissue architecture underlie right ventricular susceptibility to conduction abnormalities in a mouse model of Brugada syndrome. AB - Aims: Loss-of-function of the cardiac sodium channel NaV1.5 is a common feature of Brugada syndrome. Arrhythmias arise preferentially from the right ventricle (RV) despite equivalent NaV1.5 downregulation in the left ventricle (LV). The reasons for increased RV sensitivity to NaV1.5 loss-of-function mutations remain unclear. Because ventricular electrical activation occurs predominantly in the transmural axis, we compare RV and LV transmural electrophysiology to determine the underlying cause of the asymmetrical conduction abnormalities in Scn5a haploinsufficient mice (Scn5a+/-). Methods and results: Optical mapping and two photon microscopy in isolated-perfused mouse hearts demonstrated equivalent depression of transmural conduction velocity (CV) in the LV and RV of Scn5a+/- vs. wild-type littermates. Only RV transmural conduction was further impaired when challenged with increased pacing frequencies. Epicardial dispersion of activation and beat-to-beat variation in activation time were increased only in the RV of Scn5a+/- hearts. Analysis of confocal and histological images revealed larger intramural clefts between cardiomyocyte layers in the RV vs. LV, independent of genotype. Acute sodium current inhibition in wild type hearts using tetrodotoxin reproduced beat-to-beat activation variability and frequency dependent CV slowing in the RV only, with the LV unaffected. The influence of clefts on conduction was examined using a two-dimensional monodomain computational model. When peak sodium channel conductance was reduced to 50% of normal the presence of clefts between cardiomyocyte layers reproduced the activation variability and conduction phenotype observed experimentally. Conclusions: Normal structural heterogeneities present in the RV are responsible for increased vulnerability to conduction slowing in the presence of reduced sodium channel function. Heterogeneous conduction slowing seen in the RV will predispose to functional block and the initiation of re-entrant ventricular arrhythmias. PMID- 29267951 TI - German healthcare professionals' perspective on implementing recommendations about polypharmacy in general practice: a qualitative study. AB - Background: Key recommendations for the management of patients with polypharmacy are structured medication counselling (SMC), medication lists and systematic medication reviews. Objective: The aim of this study was to identify determinants (hindering and facilitating factors) for the implementation of the recommendations in general practice. Methods: This study was linked to a tailored intervention aimed at improving the implementation of the recommendations in German general practice. Interviews and focus groups with different healthcare professionals were carried out in the design phase and after delivery of the intervention. The material from both data collections was analysed separately in a content analytical approach resulting in two sets of categories. For this study, the subcategories of both sets were assigned to the Tailoring Interventions for Chronic Diseases (TICD) checklist, a comprehensive framework of determinants of practice. Results: Interviews with 24 general practitioners (GPs), 4 other medical specialists, 1 pharmacist, 3 nurses and 6 medical assistants as well as 2 mixed focus groups with 17 professionals were conducted. We identified 93 determinants: 29 referred to medication counselling, 21 to the use of medication lists, 20 to medications reviews and 23 to all recommendations. The determinants were related to all 7 main domains and to 25 of the 57 subdomains on the TICD checklist including guideline factors, patient factors, individual healthcare professional factors, social, political and legal factors, incentives and resources, and capacity for organizational change. Conclusion: While many interventions to improve polypharmacy focus on the provision of pharmacological knowledge, a much wider range of domains need to be addressed, such as communication skills, patient involvement and practice organization. PMID- 29267952 TI - Impacted and transmigrant mandibular canines incidence, aetiology, and treatment: a systematic review. PMID- 29267955 TI - Topical Vancomycin Reduces Surgical-Site Infections After Craniotomy: A Prospective, Controlled Study. AB - BACKGROUND: Surgical-site infections (SSIs) are an important cause of morbidity and mortality in neurosurgical patients. Topical antibiotics are one potential method to reduce the incidence of these infections. OBJECTIVE: To examine the efficacy of topical vancomycin applied within the wound during craniotomy in a large prospective cohort study at a major academic center. METHODS: Three hundred fifty-five patients were studied prospectively in this cohort study; 205 patients received 1 g of topical vancomycin powder in the subgaleal space while 150 matched control patients did not. Patients otherwise received identical care. The primary outcome variable was SSI rate factored by cohort. Secondary analysis examined cost savings from vancomycin usage estimated from hospital costs associated with SSI in craniotomy patients. RESULTS: The addition of topical vancomycin was associated with a significantly lower rate of SSI than standard of care alone (0.49% [1/205] vs 6% [9/150], P = .002). Based on the costs of revision surgery for infections, topical vancomycin usage was estimated to save $1367 446 per 1000 craniotomy patients. No adverse reactions occurred. CONCLUSION: Topical vancomycin is a safe, effective, and cost-saving measure to prevent SSIs following craniotomy. These results have broad implications for standard of care in craniotomy. PMID- 29267953 TI - A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation. AB - Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality. PMID- 29267954 TI - High diagnostic accuracy of histone H4-IgG autoantibodies in systemic lupus erythematosus. AB - Objective: Diagnosis of SLE relies on the detection of autoantibodies. We aimed to assess the diagnostic potential of histone H4 and H2A variant antibodies in SLE. Methods: IgG-autoantibodies to histones H4 (HIST1H4A), H2A type 2-A (HIST2H2AA3) and H2A type 2-C (HIST2H2AC) were measured along with a standard antibody (SA) set including SSA, SSB, Sm, U1-RNP and RPLP2 in a multiplex magnetic microsphere-based assay in 153 SLE patients [85% female, 41 (13.5) years] and 81 healthy controls [77% female, 43.3 (12.4) years]. Receiver operating characteristic analysis was performed to assess diagnostic performance of individual markers. Logistic regression analysis was performed on a random split of samples to determine the additional value of histone antibodies in comparison with SA by likelihood ratio test and determination of diagnostic accuracy in the remaining validation samples. Results: Microsphere-based assay showed good interclass correlation (mean 0.85, range 0.73-0.99) and diagnostic performance in receiver operating characteristic analysis (area under the curve (AUC) range 84.8-93.2) compared with routine assay for SA parameters. HIST1H4A IgG was the marker with the best individual diagnostic performance for SLE vs healthy (AUC 0.97, sensitivity 95% at 90% specificity). HIST1H4A-IgG was an independent significant predictor for the diagnosis of SLE in multivariate modelling (P < 0.0001), and significantly improved prediction of SLE over SA parameters alone (residual deviance 45.9 vs 97.1, P = 4.3 * 10-11). Diagnostic accuracy in the training and validation samples was 89 and 86% for SA, and 95 and 89% with the addition of HIST1H4A-IgG. Conclusion: HIST1H4A-IgG antibodies improve diagnostic accuracy for SLE vs healthy. PMID- 29267956 TI - Abundance and diversity of aerobic heterotrophic microorganisms and their interaction with cyanobacteria in the oxic layer of an intertidal hypersaline cyanobacterial mat. AB - Aerobic heterotrophic microorganisms (AH) play a significant role in carbon cycling in cyanobacterial mats; however, little is known about their abundance, diversity and interaction with cyanobacteria. Using catalyzed reporter deposition fluorescence in situ hybridization (CARD-FISH), bacterial counts in the mat's oxic layer reached a mean of 2.23 +/- 0.4 * 1010 cells g-1. Cultivation of AH yielded strains belonging to Actinobacteria, Bacteroidetes, Firmicutes, Gammaproteobacteria and Haloarchaea. 16S rRNA bacterial sequences retrieved from the mat's oxic layer were related to Bacteroidetes, Chloroflexi and Proteobacteria, whereas archaeal sequences belonged to Crenarchaeota and Haloarchaea. Monocultures of cyanobacteria from the same mat were associated with different AH, although Bacteroidetes were found in most cultures. CARD-FISH showed that Bacteroidetes- and Chloroflexi-related bacteria were closely associated with filaments of Microcoleus chthonoplastes. The growth of an axenic culture of M. chthonoplastes PCC7420 was stimulated on the addition of a filtrate obtained from a non-axenic Microcoleus culture and containing only AH and released substances. In contrast, a similar filtrate from a non-axenic Cyanothece related culture killed Cyanothece PCC 7418. We conclude that a diverse community of AH exist in close association with cyanobacteria in microbial mats and the interactions between AH and cyanobacteria are species-specific and involve the release of substances. PMID- 29267957 TI - Multivariate generalized linear model for genetic pleiotropy. AB - When a single gene influences more than one trait, known as pleiotropy, it is important to detect pleiotropy to improve the biological understanding of a gene. This can lead to improved screening, diagnosis, and treatment of diseases. Yet, most current multivariate methods to evaluate pleiotropy test the null hypothesis that none of the traits are associated with a variant; departures from the null could be driven by just one associated trait. A formal test of pleiotropy should assume a null hypothesis that one or fewer traits are associated with a genetic variant. We recently developed statistical methods to analyze pleiotropy for quantitative traits having a multivariate normal distribution. We now extend this approach to traits that can be modeled by generalized linear models, such as analysis of binary, ordinal, or quantitative traits, or a mixture of these types of traits. Based on methods from estimating equations, we developed a new test for pleiotropy. We then extended the testing framework to a sequential approach to test the null hypothesis that $k+1$ traits are associated, given that the null of $k$ associated traits was rejected. This provides a testing framework to determine the number of traits associated with a genetic variant, as well as which traits, while accounting for correlations among the traits. By simulations, we illustrate the Type-I error rate and power of our new methods, describe how they are influenced by sample size, the number of traits, and the trait correlations, and apply the new methods to a genome-wide association study of multivariate traits measuring symptoms of major depression. Our new approach provides a quantitative assessment of pleiotropy, enhancing current analytic practice. PMID- 29267958 TI - Regional Brain Tissue Changes and Associations with Disease Severity in Children with Sleep Disordered Breathing. AB - Study Objectives: Children with sleep-disordered breathing (SDB) exhibit behavioral, cognitive, and autonomic deficits, suggestive of neural injury. We assessed whether the tissue alterations resulted from acute or chronic processes, and if alterations correlated with disease severity. Methods: Brain tissue integrity was examined with mean diffusivity (MD) (3.0-Tesla scanner) in 20 non snoring controls (mean age+/-sem, 12.2+/-0.6y; 10 male) and 18 children with SDB (12.3+/-0.7y; 11 male). Sleep, cognitive, and behavioral measures were compared between groups following overnight polysomnography using Student's t-tests. Whole brain MD maps were realigned and averaged, normalized, smoothed, and compared between groups using ANCOVA (covariates; age, gender, and socioeconomic status). Partial correlations were calculated between whole-brain smoothed MD maps and obstructive apnea hypopnea indices (OAHI). Results: Age, gender, and sleep variables did not differ between groups. The SDB group showed higher OAHI, body mass indices, and systolic blood pressure. Significantly reduced MD values (acute changes) appeared in the hippocampus, insula, thalamus, temporal and occipital cortices, and cerebellum, but were increased (chronic damage) in the frontal and prefrontal cortices in the SDB group over controls. Both positive and negative correlations appeared with extent of tissue changes and disease severity. Externalizing and Total Problem Behaviors were significantly higher in SDB children. Verbal, performance and total IQ scores trended lower, and behavioral scores trended higher. Conclusions: Pediatric SDB is accompanied by predominantly acute brain changes in areas that regulate autonomic, cognitive, and mood functions, and chronic changes in frontal cortices essential for behavioral control. Interventions need to be keyed to address acute vs chronic injury. PMID- 29267959 TI - Gender differences in limited duty time for lower limb injury. AB - Background: Among active-duty military personnel, lower limb musculoskeletal injuries and related conditions (injuries) frequently arise as unintended consequences of physical training. These injuries are particularly common among women. The practical impact of such injuries on temporary military occupational disability has not been estimated with precision on a large scale. Aims: To determine the proportion of service time compromised by limited duty days attributable to lower limb injuries, characterize the time affected by these limitations in terms of specific lower limb region and compare the limited duty time between male and female soldiers. Methods: Administrative data and individual limited duty assignments (profiles) were obtained for active-duty US Army personnel who served in 2014. Lower limb injury-related profiles were used to calculate the percent of person-time requiring duty limitations by gender and body region. Results: The study group was 568 753 soldiers of whom 14% were women. Nearly 13% of service days for active-duty US Army soldiers required limited duty for lower limb injuries during 2014. Knee injuries were responsible for 45% of those days. Within integrated military occupations, female soldiers experienced 27-57% more time on limited duty for lower limb injuries compared with men. Conclusions: The substantial amount of limited duty for lower limb musculoskeletal injuries among soldiers highlights the need for improvement in training-related injury screening, prevention and timely treatment with particular attention to knee injuries. The excessive impact of lower limb injuries on female soldiers' occupational functions should be a surveillance priority in the current environment of expanding gender-integrated training. PMID- 29267960 TI - Shift of hindgut microbiota and microbial short chain fatty acids profiles in dairy calves from birth to pre-weaning. AB - This study aimed to characterize mucosa- and digesta-associated microbiota in the hindgut (cecum, colon and rectum) of newborn (NB, n = 6), day 7 (n = 6), day 21 (n = 6) and day 42 (n = 6) Holstein bull calves using amplicon sequencing. The hindgut microbiota was diverse at birth, and mucosa-attached microbial community had higher individual variation than that of digesta-associated community. In total, 16 phyla were identified with Firmicutes, Bacteroidetes and Proteobacteria being the dominant microbial taxa in the hindgut. Quantitative real-time PCR analysis showed a significant age effect on the proportion of mucosa-attached Escherichia coli, Bifidobacterium, Clostridium cluster XIVa and Faecalibacterium prausnitzii. Especially, high abundance of mucosa-associated Escherichia was detected during the first week of life, suggesting higher chance of the pathogenic infection during this stage. The relative abundances of predicted microbial genes involved in amino acid metabolism, carbohydrate metabolism and energy metabolism were enriched, indicating the importance of hindgut microbiota in fermentation during the pre-weaned period. Moreover, the significant correlation between short-chain fatty acid concentration and mucosa-attached carbohydrate utilizing (Coprococcus 1, Blautia, Lachnospiraceae NC2004 group, etc.) and health-related bacteria (Escherichia-Shigella and Salmonella) suggests the importance of hindgut microbiota in the fermentation and health of dairy calves during pre-weaned period. PMID- 29267961 TI - Relating High Insecticide Residues in Larval Breeding Habitats in Urban Residential Areas to the Selection of Pyrethroid Resistance in Anopheles gambiae s.l. (Diptera: Culicidae) in Akim Oda, Ghana. AB - The main objective of this study was to assess insecticide contamination in Anopheles breeding habitats in urban residential areas and pyrethroid susceptibility status of mosquitoes found in the habitats. A larval survey was conducted in Akim Oda between July and October 2016. The larvae that were reared to adult were used for susceptibility test against four different pyrethroid insecticides (deltamethrin 0.05%, permethrin 0.75%, cyfluthrin 0.15%, and etofenprox 0.5%). Gas chromatography was used to analyze pesticide residues in water collected from the breeding habitats. High levels of permethrin and deltamethrin plus traces of several organochlorine and organophosphate insecticides were detected in the larval-breeding habitats. None of the four pyrethroid insecticides caused more than 10% mortality. Anopheles coluzzii Coetzee & Wilkerson dominated in the study area with high frequency of kdr mutation (93.5%). We report for the first time in Ghana, high levels of pyrethroid insecticides contamination in Anopheles breeding habitats in urban residential areas where there are no major agricultural activities. The contamination is suspected to be the major cause of pyrethroid resistance in the Anopheles species. Improper disposal of old insecticide-treated net and other domestic insecticides and the use of herbicides are suspected to be the source of insecticide contamination. PMID- 29267962 TI - Diagnosis of superficial esophageal squamous cell carcinoma invasion depth before endoscopic submucosal dissection. AB - Endoscopic submucosal dissection (ESD) is a widely accepted procedure for superficial esophageal squamous cell carcinoma (SESCC) limited to the epithelium or lamina propria mucosae (EP/LPM). We aimed to compare the efficacy of endoscopic ultrasonography (EUS) and magnifying endoscopy with narrow band imaging (ME-NBI) for predicting the tumor invasion depth in patients with SESCC. Specifically, we evaluated the ability of these examinations to distinguish EP/LPM from SESCC invading the muscularis mucosae or superficial submucosa (MM/SM1) and more deeply invasive lesions before ESD.We retrospectively analyzed a database of all patients with SESCC who had undergone both EUS and ME-NBI for pretreatment staging and ESD resection at Hiroshima University Hospital between September 2007 and June 2015. The clinicopathologic characteristics of SESCCs were classified according to the Japanese Classification of Esophageal Cancer.A total of 174 lesions in 174 patients were included: 124 (71%) EP/LPMs, 35 (20%) MM/SM1s, and 15 (9%) SESCCs invading the mid submucosae (SM2). The sensitivity of EUS and of ME-NBI in distinguishing EP/LPM from MM/SM1 and more invasive lesions was 72% and 83%, respectively. The accuracy of EUS and ME-NBI in distinguishing EP/LPM from MM/SM1 and more invasive lesions was 70% and 82%, respectively. Sensitivity and accuracy of ME-NBI in distinguishing EP/LPM from MM/SM1 and more deeply invasive SESCCs is significantly higher than those of EUS (P = 0.048 and P = 0.017, respectively).ME-NBI may be more useful than EUS for the determination of SESCC invasion depth before ESD. PMID- 29267963 TI - Impact of the Asian Chestnut Gall Wasp, Dryocosmus kuriphilus (Hymenoptera, Cynipidae), on the Chestnut Component of Honey in the Southern Swiss Alps. AB - The Asian chestnut gall wasp (ACGW; Dryocosmus kuriphilus Yasumatsu, Hymenoptera, Cynipidae) is considered as one of the most dangerous pests of the genus Castanea. In southern Switzerland, repeated heavy ACGW attacks prevented chestnut trees from vegetating normally for years before the arrival and spread of the biological control agent Torymus sinensis (Kamijo, Hymenoptera, Torymidae). This resulted in a greatly reduced green biomass and flower production. In this paper, we analyze the impact of such an ecosystem alteration of the environment on the composition of produced honey. Six beekeepers were chosen from sites with different densities of chestnut trees, each of which providing series of honey samples from 2010 to 2016. We determined the chestnut component in the honeys via a combined chemical and sensory approach, and correlated the obtained results with the degree of yearly ACGW-induced crown damage and weather conditions during the period in question in the surrounding chestnut stands. The chestnut component in the analyzed honey sample series showed a strong correlation with the degree of ACGW-induced crown damage, whereas meteorological conditions of the corresponding year had a very marginal effect. Decreases in the chestnut component of the honey were statistically significant starting from a ACGW infestation level of 30%. PMID- 29267964 TI - Biomedical informatics and data science: evolving fields with significant overlap. PMID- 29267965 TI - ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion. AB - Recent studies have reported the emerging role of microRNAs (miRNAs) in human cancers. We systematically characterized miRNA expression and editing in the human brain, which displays the highest number of A-to-I RNA editing sites among human tissues, and in de novo glioblastoma brain cancer. We identified 299 miRNAs altered in their expression and 24 miRNAs differently edited in human brain compared to glioblastoma tissues. We focused on the editing site within the miR 589-3p seed. MiR-589-3p is a unique miRNA almost fully edited (~100%) in normal brain and with a consistent editing decrease in glioblastoma. The edited version of miR-589-3p inhibits glioblastoma cell proliferation, migration and invasion, while the unedited version boosts cell proliferation and motility/invasion, thus being a potential cancer-promoting factor. We demonstrated that the editing of this miRNA is mediated by ADAR2, and retargets miR-589-3p from the tumor suppressor PCDH9 to ADAM12, which codes for the metalloproteinase 12 promoting glioblastoma invasion. Overall, our study dissects the role of a unique brain specific editing site within miR-589-3p, with important anticancer features, and highlights the importance of RNA editing as an essential player not only for diversifying the genomic message but also for correcting not-tolerable/critical genomic coding sites. PMID- 29267966 TI - Release and Decay Kinetics of Copeptin vs AVP in Response to Osmotic Alterations in Healthy Volunteers. AB - Context: Copeptin is the C-terminal fragment of the arginine vasopressin (AVP) prohormone whose measurement is more robust than that of AVP. Similar release and clearance characteristics have been suggested promoting copeptin as a surrogate marker. Objective: To characterize the physiology of osmotically regulated copeptin release and its half-life in direct comparison with plasma AVP. Design: Ninety-one healthy volunteers underwent a standardized three-phase test protocol including (1) osmotic stimulation into the hypertonic range by hypertonic-saline infusion followed by osmotic suppression via (2) oral water load and (3) subsequent glucose infusion. Plasma copeptin, AVP, serum sodium, and osmolality levels were measured in regular intervals. Results: In phase 1, an increase in median osmotic pressure [289 (286; 291) to 311 (309; 314) mOsm/kg H2O] caused similar release kinetics of plasma copeptin [4 (3.1; 6) to 29.3 (18.6; 48.2) pmol/L] and AVP [1 (0.7; 1.6) to 10.3 (6.8; 18.8) pg/mL]. Subsequent osmotic suppression to 298 (295; 301) mOsm/kg at the end of phase 3 revealed markedly different decay kinetics between both peptides-an estimated initial half-life of copeptin being approximately 2 times longer than that of AVP (26 vs 12 minutes). Conclusion: Copeptin is released in equimolar amounts with AVP in response to osmotic stimulation, suggesting its high potential as an AVP surrogate for differentiation of osmotic disorders. Furthermore, we here describe the decay kinetics of copeptin in response to osmotic depression enabling to identify a half-life for copeptin in direct comparison with AVP. PMID- 29267967 TI - FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis. AB - FRMPD4 (FERM and PDZ Domain Containing 4) is a neural scaffolding protein that interacts with PSD-95 to positively regulate dendritic spine morphogenesis, and with mGluR1/5 and Homer to regulate mGluR1/5 signaling. We report the genetic and functional characterization of 4 FRMPD4 deleterious mutations that cause a new X linked intellectual disability (ID) syndrome. These mutations were found to be associated with ID in ten affected male patients from four unrelated families, following an apparent X-linked mode of inheritance. Mutations include deletion of an entire coding exon, a nonsense mutation, a frame-shift mutation resulting in premature termination of translation, and a missense mutation involving a highly conserved amino acid residue neighboring FRMPD4-FERM domain. Clinical features of these patients consisted of moderate to severe ID, language delay and seizures alongside with behavioral and/or psychiatric disturbances. In-depth functional studies showed that a frame-shift mutation, FRMPD4p.Cys618ValfsX8, results in a disruption of FRMPD4 binding with PSD-95 and HOMER1, and a failure to increase spine density in transfected hippocampal neurons. Behavioral studies of frmpd4-KO mice identified hippocampus-dependent spatial learning and memory deficits in Morris Water Maze test. These findings point to an important role of FRMPD4 in normal cognitive development and function in humans and mice, and support the hypothesis that FRMPD4 mutations cause ID by disrupting dendritic spine morphogenesis in glutamatergic neurons. PMID- 29267969 TI - Erratum to: "Genomic Displacement and Shift of the Hybrid Zone in the Japanese Fire-Bellied Newt". PMID- 29267968 TI - Seasonality of Colaspis crinicornis (Coleoptera: Chrysomelidae) and its Injury Potential to Corn in Southeastern Nebraska. AB - Colaspis crinicornis Schaeffer (Coleoptera: Chrysomelidae) primarily occurs in the Great Plains, United States. Although C. crinicornis has historically been considered a non-pest and is rarely found in agricultural systems, population densities of this species have been increasing in corn, Zea mays L., and soybean, Glycine max (L.) Merrill, over the last decade in southeastern Nebraska. As part of a comprehensive project to understand the life history and pest potential of C. crinicornis, a field study was conducted to: understand adult seasonality of C. crinicornis using emergence cages and whole-plant-count sampling in cornfields and sweep-net sampling in soybean fields; confirm voltinism and the overwintering stage; and evaluate the potential of larvae to cause economic injury to corn roots. Data indicate that C. crinicornis is univoltine in southeastern Nebraska and overwinters as medium-large larvae at least 20 cm deep in the soil. Adults were present from June through August with peak emergence in July. The C. crinicornis lifecycle is similar to related Colaspis species. Root injury to corn was minor at population densities encountered in the field, and therefore, C. crinicornis is unlikely to cause economic loss. C. crinicornis may be an example of an insect species that has exploited open niches in crops that have been created by changes in agricultural and pest management practices. The lifecycle and polyphagous nature of the insect, annual crop rotation, the shift to minimum tillage, and replacement of insecticides with Bacillus thuringiensis Berliner (Bt) traits may have collectively facilitated establishment and increased survival in agroecosystems. PMID- 29267970 TI - Value Relativism and Perspective Taking are Two Distinct Facets of Wisdom-Related Knowledge. AB - Objectives: There has been mixed evidence for age differences in wisdom-related knowledge across the adult life span. This study investigated two potential moderators of the link between age and wisdom-related knowledge: the wisdom criteria and the wisdom tasks. Method: To test these moderators, 40 younger and 40 older participants completed four wisdom tasks differing in context-richness. Independent trained raters coded the resulting think-aloud protocols in terms of value relativism, as defined in the Berlin wisdom paradigm, and perspective taking, as defined by Grossmann. Results: The type of task did not show any main or interaction effects on the present two wisdom criteria. However, age differences in the two wisdom criteria were multidirectional: whereas perspective taking did not differ by age group, value relativism was lower in older than younger adults. In addition, value relativism, but not perspective taking, was related to measures of fluid and crystallized intelligence, whereas perspective taking, but not value relativism, was related to a measure of life investment. Discussion: This study provides evidence for the idea that value relativism and perspective taking are two distinct facets of wisdom-related knowledge. Implications for future age-comparative research interested in wisdom are discussed. PMID- 29267971 TI - Perfluorocarbon solutions limit tubular epithelial cell injury and promote CD133+ kidney progenitor differentiation: potential use in renal assist devices for sepsis-associated acute kidney injury and multiple organ failure. AB - Background: The renal assist device (RAD) is a blood purification system containing viable renal tubular epithelial cells (TECs) that has been proposed for the treatment of acute kidney injury (AKI) and multiple organ failure. Perfluorocarbons (PFCs) are oxygen carriers used for organ preservation in transplantation. The aim of this study was to investigate the effect of PFCs on hypoxia- and sepsis-induced TEC injury and on renal CD133+ progenitor differentiation in a microenvironment similar to the RAD. Methods: TECs were seeded in a polysulphone hollow fibre under hypoxia or cultured with plasma from 10 patients with sepsis-associated AKI in the presence or absence of PFCs and were tested for cytotoxicity (XTT assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay, caspases, enzyme-linked immunosorbent assay, Fas/Fas Ligand pathway activation), mitochondrial activity, cell polarity [transepithelial electrical resistance (TEER)] and adenosine triphosphate production. The effect of PFCs on proliferation and differentiation of human CD133+ progenitors was also studied. Results: In the presence of PFCs, TECs seeded into the polysulphone hollow fibre showed increased viability and expression of insulin-like growth factor 1, hepatocyte growth factor and macrophage-stimulating protein. Plasma from septic patients induced TEC apoptosis, disruption of oxidative metabolism, alteration of cell polarity and albumin uptake, down-regulation of the tight junction protein ZO-1 and the endocytic receptor megalin on the TEC surface. These detrimental effects were significantly reduced by PFCs. Moreover, PFCs induced CD133+ renal progenitor cell proliferation and differentiation towards an epithelial/tubular-like phenotype. Conclusions: PFCs improved the viability and metabolic function of TECs seeded within a polysulphone hollow fibre and subjected to plasma from septic AKI patients. Additionally, PFCs promoted differentiation towards a tubular/epithelial phenotype of CD133+ renal progenitor cells. PMID- 29267972 TI - THiCweed: fast, sensitive detection of sequence features by clustering big datasets. AB - We present THiCweed, a new approach to analyzing transcription factor binding data from high-throughput chromatin immunoprecipitation-sequencing (ChIP-seq) experiments. THiCweed clusters bound regions based on sequence similarity using a divisive hierarchical clustering approach based on sequence similarity within sliding windows, while exploring both strands. ThiCweed is specially geared toward data containing mixtures of motifs, which present a challenge to traditional motif-finders. Our implementation is significantly faster than standard motif-finding programs, able to process 30 000 peaks in 1-2 h, on a single CPU core of a desktop computer. On synthetic data containing mixtures of motifs it is as accurate or more accurate than all other tested programs. THiCweed performs best with large 'window' sizes (>=50 bp), much longer than typical binding sites (7-15 bp). On real data it successfully recovers literature motifs, but also uncovers complex sequence characteristics in flanking DNA, variant motifs and secondary motifs even when they occur in <5% of the input, all of which appear biologically relevant. We also find recurring sequence patterns across diverse ChIP-seq datasets, possibly related to chromatin architecture and looping. THiCweed thus goes beyond traditional motif finding to give new insights into genomic transcription factor-binding complexity. PMID- 29267973 TI - Adult Craniopharyngioma: Case Series, Systematic Review, and Meta-Analysis. AB - BACKGROUND: The optimal therapeutic approach for adult craniopharyngioma remains controversial. Some advocate for gross total resection (GTR), while others advocate for subtotal resection followed by adjuvant radiotherapy (STR + XRT). OBJECTIVE: To conduct a systematic review and meta-analysis assessing the rate of recurrence in the follow-up of 3 yr in adult craniopharyngioma stratified by extent of resection and presence of adjuvant radiotherapy. METHODS: MEDLINE (1946 July 1, 2016) and EMBASE (1980-June 30, 2016) were systematically reviewed. From1975 to 2013, 33 patients were treated with initial surgical resection for adult onset craniopharyngioma at our center and were reviewed for inclusion in this study. RESULTS: Data from 22 patients were available for inclusion as a case series in the systematic review. Eligible studies (n = 21) were identified from the literature in addition to a case series of our institutional experience. Three groups were available for analysis: GTR, STR + XRT, and STR. The rates of recurrence were 17%, 27%, and 45%, respectively. The risk of developing recurrence was significant for GTR vs STR (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.15-0.38) and STR + XRT vs STR (OR: 0.20, 95% CI: 0.10-0.41). Risk of recurrence after GTR vs STR + XRT did not reach significance (OR: 0.63, 95% CI: 0.33-1.24, P = .18). CONCLUSION: This is the first and largest systematic review focusing on the rate of recurrence in adult craniopharyngioma. Although the rates of recurrence are favoring GTR, difference in risk of recurrence did not reach significance. This study provides guidance to clinicians and directions for future research with the need to stratify outcomes per treatment modalities. PMID- 29267974 TI - Molecular identification of goose (Anser cygnoide) suppressor ubiquitin-specific protease 18 (USP18) and the effects of goose IFN and TMUV on its comparative transcripts. AB - Ubiquitin-specific protease 18 (USP18) is known as an inhibition factor and has been associated with the innate immune response to pathogens. USP18 is the only deconjugating protease with specificity for interferon-stimulated gene 15 (ISG15), which is supposed to be missing in birds. To analyze the efficacy of goose USP18 (goUSP18) against Tembusu virus (TMUV) infection, we first cloned USP18 homologous cDNA from TMUV infected geese. The coding sequence was 1131 bp, and the deduced amino acid sequence shared conserved motifs with its homologues. Tissue-specific expression has shown that goUSP18 transcripts are strongly expressed in the spleen and liver of adult geese, as well as in the pancreas of goslings. Moreover, the goUSP18 transcripts were induced by goose interferons (goIFN) in goose embryo fibroblasts (GEF) and by TLR ligands in peripheral blood mononuclear cells (PBMC). Notably, goUSP18 transcripts were highly up-regulated by TMUV infection compared to the basal level in uninfected birds. Taken together, these results suggested that goUSP18 was involved in host innate immunity against TMUV infection. PMID- 29267975 TI - The New Possibilities in Early Diagnosis of Preeclampsia by Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor in 16-20 Weeks Gestation. AB - Background: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are used in diagnosing preeclampsia (PE), but their potential in early prediction in pregnant women at 16 to 20 weeks gestation (WG) has remained unexplored. Methods: We retrospectively measured serum levels of sFlt-1 and PlGF in 120 pregnant women at 16 to 20 WG. Among these women, 16 had early-onset PE and 23 had late-onset PE. Results: Compared with normal pregnancy values, in the serum of women in whom PE later developed, sFlt-1 values increased (P <.001), values of PlGF decreased (P = .001), and the sFlt-1/PlGF ratio increased (P <.001) as early as 16 to 20 WG. Receiver operating characteristic (ROC) curve analysis for the sFlt-1/PlGF ratio at 16 to 20 WG showed an area under the curve (AUC) value of 0.863 (95% confidence interval [CI], 0.788-0.918), P <.001, sensitivity of 74.4%, and specificity of 86.6% for PE in general; and AUC of 0.970 (95% CI, 0.913-0.994), P <.001, sensitivity of 100%, and specificity of 81.5% for early-onset PE only. Also, we determined the 5th and 95th percentiles for sFlt-1, PlGF, and sFlt-1/PlGF ratio values of healthy pregnant women. Conclusion: sFlt-1 and PlGF and, in particular, the sFlt-1/PlGF ratio can detect PE as early as 16 to 20 WG-as long as 10 to 15 weeks before PE onset. PMID- 29267976 TI - Accuracy of genetic code translation and its orthogonal corruption by aminoglycosides and Mg2+ ions. AB - We studied the effects of aminoglycosides and changing Mg2+ ion concentration on the accuracy of initial codon selection by aminoacyl-tRNA in ternary complex with elongation factor Tu and GTP (T3) on mRNA programmed ribosomes. Aminoglycosides decrease the accuracy by changing the equilibrium constants of 'monitoring bases' A1492, A1493 and G530 in 16S rRNA in favor of their 'activated' state by large, aminoglycoside-specific factors, which are the same for cognate and near-cognate codons. Increasing Mg2+ concentration decreases the accuracy by slowing dissociation of T3 from its initial codon- and aminoglycoside-independent binding state on the ribosome. The distinct accuracy-corrupting mechanisms for aminoglycosides and Mg2+ ions prompted us to re-interpret previous biochemical experiments and functional implications of existing high resolution ribosome structures. We estimate the upper thermodynamic limit to the accuracy, the 'intrinsic selectivity' of the ribosome. We conclude that aminoglycosides do not alter the intrinsic selectivity but reduce the fraction of it that is expressed as the accuracy of initial selection. We suggest that induced fit increases the accuracy and speed of codon reading at unaltered intrinsic selectivity of the ribosome. PMID- 29267978 TI - Methodological Innovations in Gerontology: Advances in Psychosocial Research. PMID- 29267977 TI - Sequence-dependent response of DNA to torsional stress: a potential biological regulation mechanism. AB - Torsional restraints on DNA change in time and space during the life of the cell and are an integral part of processes such as gene expression, DNA repair and packaging. The mechanical behavior of DNA under torsional stress has been studied on a mesoscopic scale, but little is known concerning its response at the level of individual base pairs and the effects of base pair composition. To answer this question, we have developed a geometrical restraint that can accurately control the total twist of a DNA segment during all-atom molecular dynamics simulations. By applying this restraint to four different DNA oligomers, we are able to show that DNA responds to both under- and overtwisting in a very heterogeneous manner. Certain base pair steps, in specific sequence environments, are able to absorb most of the torsional stress, leaving other steps close to their relaxed conformation. This heterogeneity also affects the local torsional modulus of DNA. These findings suggest that modifying torsional stress on DNA could act as a modulator for protein binding via the heterogeneous changes in local DNA structure. PMID- 29267979 TI - Mother-infant sleep patterns and parental functioning of room-sharing and solitary sleeping families: a longitudinal study from 3 to 18 months. AB - Study Objectives: To examine longitudinally differences in (a) objective and subjective sleep patterns and (b) parenting functioning (i.e., maternal emotional distress, maternal separation anxiety and parental involvement in infant care( between room-sharing and solitary sleeping mother-infant dyads. Methods: Maternal and infant sleep, sleeping arrangements and parental functioning were assessed at three (N=146), six (N=141), twelve (N=135), and eighteen (N=130) months postpartum. Maternal and infant sleep were assessed with actigraphy and sleep diaries for 5 nights. Questionnaires were used to assess sleeping arrangements, nighttime breastfeeding, and parental functioning. Results: Persistent room sharing mothers (i.e., sharing a room with the infant on at least three assessment points) had significantly lower actigraphy-based sleep percent, lower longest sleep periods and more night-wakings than persistent solitary sleeping mothers. For infants, differences in actigraphic sleep were found only in longest sleep period, although mothers of persistent room-sharing infants reported more infant night-wakings than mothers of persistent solitary sleeping infants. The trajectories of maternal and infant sleep in both room-sharing and solitary sleeping groups demonstrated that sleep became more consolidated with time. Group differences indicated higher maternal separation anxiety and lower paternal overall and nighttime involvement in infant caregiving in room-sharing families compared to solitary-sleeping families. Conclusions: The findings are discussed in light of the latest American Academy of Pediatrics recommendation to room share until 12 months postpartum. Although no causal effects can be inferred from this study, maternal sleep quality and certain parenting characteristics seem to be important factors to consider when parents consult about sleeping arrangements. PMID- 29267980 TI - The trophic life cycle stage of Pneumocystis species induces protective adaptive responses without inflammation-mediated progression to pneumonia. AB - Pneumocystis species are fungal pathogens that cause pneumonia in immunocompromised hosts. Lung damage during Pneumocystis pneumonia is predominately due to the inflammatory immune response. Pneumocystis species have a biphasic life cycle. Optimal innate immune responses to Pneumocystis species are dependent on stimulation with the cyst life cycle stage. Conversely, the trophic life cycle stage broadly suppresses proinflammatory responses to multiple pathogen-associated molecular patterns (PAMPs), including beta-1,3-glucan. Little is known about the contribution of these life cycle stages to the development of protective adaptive responses to Pneumocystis infection. Here we report that CD4+ T cells primed in the presence of trophic forms are sufficient to mediate clearance of trophic forms and cysts. In addition, primary infection with trophic forms is sufficient to prime B-cell memory responses capable of clearing a secondary infection with Pneumocystis following CD4+ T cell depletion. While trophic forms are sufficient for initiation of adaptive immune responses in immunocompetent mice, infection of immunocompromised recombination-activating gene 2 knockout (RAG2-/-) mice with trophic forms in the absence of cysts does not lead to the severe weight loss and infiltration of innate immune cells associated with the development of Pneumocystis pneumonia. PMID- 29267981 TI - Enhanced spontaneous DNA twisting/bending fluctuations unveiled by fluorescence lifetime distributions promote mismatch recognition by the Rad4 nucleotide excision repair complex. AB - Rad4/XPC recognizes diverse DNA lesions including ultraviolet-photolesions and carcinogen-DNA adducts, initiating nucleotide excision repair. Studies have suggested that Rad4/XPC senses lesion-induced helix-destabilization to flip out nucleotides from damaged DNA sites. However, characterizing how DNA deformability and/or distortions impact recognition has been challenging. Here, using fluorescence lifetime measurements empowered by a maximum entropy algorithm, we mapped the conformational heterogeneities of artificially destabilized mismatched DNA substrates of varying Rad4-binding specificities. The conformational distributions, as probed by FRET between a cytosine-analog pair exquisitely sensitive to DNA twisting/bending, reveal a direct connection between intrinsic DNA deformability and Rad4 recognition. High-specificity CCC/CCC mismatch, free in solution, sampled a strikingly broad range of conformations from B-DNA-like to highly distorted conformations that resembled those observed with Rad4 bound; the extent of these distortions increased with bound Rad4 and with temperature. Conversely, the non-specific TAT/TAT mismatch had a homogeneous, B-DNA-like conformation. Molecular dynamics simulations also revealed a wide distribution of conformations for CCC/CCC, complementing experimental findings. We propose that intrinsic deformability promotes Rad4 damage recognition, perhaps by stalling a diffusing protein and/or facilitating 'conformational capture' of pre-distorted damaged sites. Surprisingly, even mismatched DNA specifically bound to Rad4 remains highly dynamic, a feature that may reflect the versatility of Rad4/XPC to recognize many structurally dissimilar lesions. PMID- 29267982 TI - Determination of Protein Haptenation by Chemical Sensitizers Within the Complexity of the Human Skin Proteome. AB - Skin sensitization associated with the development of allergic contact dermatitis occurs via a number of specific key events at the cellular level. The molecular initiating event (MIE), the first in the sequence of these events, occurs after exposure of the skin to an electrophilic chemical, causing the irreversible haptenation of proteins within skin. Characterization of this MIE is a key step in elucidating the skin sensitization adverse outcome pathway and is essential to providing parameters for mathematical models to predict the capacity of a chemical to cause sensitization. As a first step to addressing this challenge, we have exposed complex protein lysates from a keratinocyte cell line and human skin tissue with a range of well characterized sensitizers, including dinitrochlorobenzene, 5-chloro-2-methylisothiazol-3-one, cinnamaldehyde, and the non (or weak) sensitizer 6-methyl coumarin. Using a novel stable isotope labeling approach combined with ion mobility-assisted data independent mass spectrometry (HDMSE), we have characterized the haptenome for these sensitizers. Although a significant proportion of highly abundant proteins were haptenated, we also observed the haptenation of low abundant proteins by all 3 of the chemical sensitizers tested, indicating that within a complex protein background, protein abundance is not the sole determinant driving haptenation, highlighting a relationship to tertiary protein structure and the amino acid specificity of these chemical sensitizers and sensitizer potency. PMID- 29267983 TI - Comparison of HbA2, E, F and Red Cell Parameters in Homozygous HbE With and Without alpha0-Thalassemia Trait. AB - Objectives: To compare levels of HbA2, HbE, HbF, and red cell parameters (total Hb, PCV, MCV, and MCH) and also determine their appropriated cut-off points for initial discrimination between homozygous HbE with and without alpha0-thalassemia trait. Methods: Hb analysis results from capillary electrophoresis (CE) and red cell parameters of homozygous HbE without alpha0-thalassemia trait (n = 41) and with alpha0-thalassemia trait (n = 17) were reviewed. Results: The MCV, MCH, and HbE of homozygous HbE with alpha0-thalassemia trait were significantly lower than those of homozygous HbE without alpha0-thalassemia, while HbA2 levels of the former were significantly higher than those of the latter. HbA2 at a cut-off point of 5.3% had 69.0% efficiency in discrimination between the 2 groups. It could also reduce 56.1% of homozygous HbE samples for alpha0-thalassemia testing. Conclusions: The elevated HbA2 >=5.3% is a useful marker for initial discrimination between homozygous HbE with and without alpha0-thalassemia trait. PMID- 29267984 TI - Dad 'never said much' but... Young Men and Great War Veterans in Day-to-Day-Life in Interwar Britain. AB - This article explores whether, how, and what young men in interwar Britain heard about the Great War from its veterans. Oral histories are used to enable the first detailed examination of the hitherto largely unexplored topic of the intergenerational transmission of representations of the Great War in interwar Britain. It shows that although many veterans were reticent about their war experiences, young men heard about Great War experiences from veterans more frequently than has previously been acknowledged. What they heard was heterogeneous, like representations in popular culture, but tended to emphasize positive and rewarding elements of wartime service rather than disillusion. While veterans' narratives could be fleeting and ephemeral, this examination of their character shows they should be considered an important component of the wider body of representations of the Great War in interwar popular culture through which young men might 'know' about the Great War. As well as examining what young men heard, consideration is given to alternative ways that young men learned about familial service, and to what triggered veterans' narratives and why some remained silent. Reasons for the trope of the silent veteran are suggested, and its strength in contemporary popular memory is illustrated in discussion of the 'discomposure' it could cause some interviewees. PMID- 29267985 TI - Echocardiographic features of post-transcatheter aortic valve implantation thrombosis and endocarditis. AB - BACKGROUND: Transcatheter heart valve thrombosis (THV-t) and endocarditis (THV-e) are relevant complications after transcatheter aortic valve implantation (TAVI). Transcatheter heart valve (THV) dysfunction definition is mostly based on Doppler (stenosis/regurgitation) without considering leaflets characteristics. PURPOSE: To evaluate the additional diagnostic value of leaflets echocardiographic features over Doppler when prosthetic valve complication is suspected. METHODS: Among 621 post-TAVI patients, 128 cases with probable valve complication were identified. THV-t was finally diagnosed in 13 patients (10%) and THV-e in 8 (6%), while the remaining 107 (84%) had no definitive diagnosis of thrombosis/endocarditis (THV-no). We analyzed at 2 time points (baseline and follow-up) both traditional Doppler parameters and leaflets morpho-functional features. RESULTS: Both Doppler and leaflets parameters showed high sensitivity (sensitivity 92%) and low specificity (ranging from specificity 32% to 74%) in detecting THV-t. Interestingly, the combination of mean aortic pressure gradient >=20 mm Hg and leaflet thickening significantly improved the specificity of echocardiography for diagnosis of THV thrombosis (specificity 94%). On the other hand, echocardiographic diagnosis of THV endocarditis remained limited by very low sensitivity despite showing high specificity. CONCLUSIONS: The combination of Doppler and leaflets parameters can improve the echocardiographic diagnosis of THV thrombosis in post-TAVI patients with suspicious symptoms, via a significant increase in the overall test specificity. This would potentially allow more rational gatekeeping to more expensive/invasive diagnostic examinations (eg, CT scan) or therapeutic trials (eg, unnecessary anticoagulation). PMID- 29267986 TI - Accurate High-Pressure Measurements of Carbon Monoxide's Electrical Properties. AB - Accurate measurements of carbon monoxide's electrical properties were carried out at high pressure for the first time enabling stringent comparisons with theoretical values calculated ab initio. Dielectric permittivity measurements were conducted utilising a microwave re-entrant cavity resonator over the temperature range from (255 to 313) K and at pressures up to 8 MPa with a relative combined expanded uncertainty (k=2) less than or equal to 52 ppm. The new data enable carbon monoxide's molar polarizability to be correlated within 0.5 %, significantly improving upon existing literature data, which have a relative scatter of about 10 %. The measured molecular polarizability and electric dipole moment of carbon monoxide were determined to be 2.176*10-40 C2 m2 J-1 and 0.107 D. Literature values from ab initio calculations for these properties are within 0.28 % and 3.9 %, respectively, of the measured quantities. Moreover, our measurement of the electric dipole moment at finite temperature agrees within 2.2 % with the value derived from accurate spectroscopic measurements for the ground rovibrational state. The second dielectric virial coefficient of carbon monoxide was determined experimentally for the first time to be bepsilon =(1.015+/-0.044) cm3 mol-1 , which compares reasonably with ab initio estimates. PMID- 29267987 TI - Mono-Substituted Hydrocarbon Diastereomer Combinations Reveal Stapled Peptides with High Structural Fidelity. AB - Modified peptides, such as stapled peptides, which replicate the structure of alpha-helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (alphaSyn, Cks1 and CK1alpha) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution-phase models for the optimised peptides were generated using NMR-derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide. PMID- 29267988 TI - Respiratory muscle training for multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system, affecting approximately 2.5 million people worldwide. People with MS may experience limitations in muscular strength and endurance - including the respiratory muscles, affecting functional performance and exercise capacity. Respiratory muscle weakness can also lead to diminished performance on coughing, which may result in (aspiration) pneumonia or even acute ventilatory failure, complications that frequently cause death in MS. Training of the respiratory muscles might improve respiratory function and cough efficacy. OBJECTIVES: To assess the effects of respiratory muscle training versus any other type of training or no training for respiratory muscle function, pulmonary function and clinical outcomes in people with MS. SEARCH METHODS: We searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (3 February 2017), which contains trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, LILACS and the trial registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform. Two authors independently screened records yielded by the search, handsearched reference lists of review articles and primary studies, checked trial registers for protocols, and contacted experts in the field to identify further published or unpublished trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that investigated the efficacy of respiratory muscle training versus any control in people with MS. DATA COLLECTION AND ANALYSIS: One reviewer extracted study characteristics and study data from included RCTs, and two other reviewers independently cross checked all extracted data. Two review authors independently assessed risk of bias with the Cochrane 'Risk of bias' assessment tool. When at least two RCTs provided data for the same type of outcome, we performed meta-analyses. We assessed the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included six RCTs, comprising 195 participants with MS. Two RCTs investigated inspiratory muscle training with a threshold device; three RCTs, expiratory muscle training with a threshold device; and one RCT, regular breathing exercises. Eighteen participants (~ 10%) dropped out; trials reported no serious adverse events.We pooled and analyzed data of 5 trials (N=137) for both inspiratory and expiratory muscle training, using a fixed-effect model for all but one outcome. Compared to no active control, meta-analysis showed that inspiratory muscle training resulted in no significant difference in maximal inspiratory pressure (mean difference (MD) 6.50 cmH2O, 95% confidence interval (CI) -7.39 to 20.38, P = 0.36, I2 = 0%) or maximal expiratory pressure (MD -8.22 cmH2O, 95% CI -26.20 to 9.77, P = 0.37, I2 = 0%), but there was a significant benefit on the predicted maximal inspiratory pressure (MD 20.92 cmH2O, 95% CI 6.03 to 35.81, P = 0.006, I2 = 18%). Meta-analysis with a random-effects model failed to show a significant difference in predicted maximal expiratory pressure (MD 5.86 cmH2O, 95% CI -10.63 to 22.35, P = 0.49, I2 = 55%). These studies did not report outcomes for health-related quality of life.Three RCTS compared expiratory muscle training versus no active control or sham training. Under a fixed-effect model, meta-analysis failed to show a significant difference between groups with regard to maximal expiratory pressure (MD 8.33 cmH2O, 95% CI -0.93 to 17.59, P = 0.18, I2 = 42%) or maximal inspiratory pressure (MD 3.54 cmH2O, 95% CI -5.04 to 12.12, P = 0.42, I2 = 41%). One trial assessed quality of life, finding no differences between groups.For all predetermined secondary outcomes, such as forced expiratory volume, forced vital capacity and peak flow pooling was not possible. However, two trials on inspiratory muscle training assessed fatigue using the Fatigue Severity Scale (range of scores 0-56 ), finding no difference between groups (MD, -0.28 points, 95% CI-0.95 to 0.39, P = 0.42, I2 = 0%). Due to the low number of studies included, we could not perform cumulative meta-analysis or subgroup analyses. It was not possible to perform a meta-analysis for adverse events, no serious adverse were mentioned in any of the included trials.The quality of evidence was low for all outcomes because of limitations in design and implementation as well as imprecision of results. AUTHORS' CONCLUSIONS: This review provides low-quality evidence that resistive inspiratory muscle training with a resistive threshold device is moderately effective postintervention for improving predicted maximal inspiratory pressure in people with mild to moderate MS, whereas expiratory muscle training showed no significant effects. The sustainability of the favourable effect of inspiratory muscle training is unclear, as is the impact of the observed effects on quality of life. PMID- 29267989 TI - School dental screening programmes for oral health. AB - BACKGROUND: School dental screening refers to visual inspection of children's oral cavity in a school setting followed by making parents aware of their child's current oral health status and treatment needs. Screening at school intends to identify children at an earlier stage than symptomatic disease presentation, hence prompting preventive and therapeutic oral health care for the children. This review evaluates the effectiveness of school dental screening in improving oral health status. OBJECTIVES: To assess the effectiveness of school dental screening programmes on overall oral health status and use of dental services. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 15 March 2017), the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Register of Studies, to 15 March 2017), MEDLINE Ovid (1946 to 15 March 2017), and Embase Ovid (15 September 2016 to 15 March 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Centralised Search Project to identify all clinical trials and add them to CENTRAL. SELECTION CRITERIA: We included randomised controlled trials (RCTs) (cluster or parallel) that evaluated school dental screening compared with no intervention or with one type of screening compared with another. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six trials (four were cluster-RCTs) with 19,498 children who were 4 to 15 years of age. Four trials were conducted in the UK and two were based in India. We assessed two trials to be at low risk of bias, one trial to be at high risk of bias and three trials to be at unclear risk of bias.None of the six trials reported the proportion of children with untreated caries or other oral diseases.Four trials evaluated traditional screening versus no screening. We performed a meta-analysis for the outcome 'dental attendance' and found an inconclusive result with high heterogeneity. The heterogeneity was found it to be, in part, due to study design (three cluster-RCTs and one individual-level RCT). Due to the inconsistency, we downgraded the evidence to 'very low certainty' and are unable to draw conclusions about this comparison.Two cluster RCTs (both four-arm trials) evaluated criteria-based screening versus no screening and showed a pooled effect estimate of RR 1.07 (95% CI 0.99 to 1.16), suggesting a possible benefit for screening (low-certainty evidence). There was no evidence of a difference when criteria-based screening was compared to traditional screening (RR 1.01, 95% CI 0.94 to 1.08) (very low-certainty evidence).In one trial, a specific (personalised) referral letter was compared to a non-specific one. Results favoured the specific referral letter with an effect estimate of RR 1.39 (95% CI 1.09 to 1.77) for attendance at general dentist services and effect estimate of RR 1.90 (95% CI 1.18 to 3.06) for attendance at specialist orthodontist services (low-certainty evidence).One trial compared screening supplemented with motivation to screening alone. Dental attendance was more likely after screening supplemented with motivation, with an effect estimate of RR 3.08 (95% CI 2.57 to 3.71) (low-certainty evidence).None of the trials had long-term follow-up to ascertain the lasting effects of school dental screening.None of the trials reported cost-effectiveness and adverse events. AUTHORS' CONCLUSIONS: The trials included in this review evaluated short-term effects of screening, assessing follow-up periods of three to eight months. We found very low certainty evidence that was insufficient to allow us to draw conclusions about whether there is a role for traditional school dental screening in improving dental attendance. For criteria-based screening, we found low certainty evidence that it may improve dental attendance when compared to no screening. However, when compared to traditional screening there was no evidence of a difference in dental attendance (very low-certainty evidence).We found low certainty evidence to conclude that personalised or specific referral letters improve dental attendance when compared to non-specific counterparts. We also found low-certainty evidence that screening supplemented with motivation (oral health education and offer of free treatment) improves dental attendance in comparison to screening alone.We did not find any trials addressing cost effectiveness and adverse effects of school dental screening. PMID- 29267990 TI - Right unilateral electroconvulsive therapy does not cause more cognitive impairment than pharmacologic treatment in treatment-resistant bipolar depression: A 6-month randomized controlled trial follow-up study. AB - OBJECTIVES: Electroconvulsive therapy is an effective treatment for bipolar depression, but there are concerns about whether it causes long-term neurocognitive impairment. METHODS: In this multicenter randomized controlled trial, in-patients with treatment-resistant bipolar depression were randomized to either algorithm-based pharmacologic treatment or right unilateral electroconvulsive therapy. After the 6-week treatment period, all of the patients received maintenance pharmacotherapy as recommended by their clinician guided by a relevant treatment algorithm. Patients were assessed at baseline and at 6 months. Neurocognitive functions were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and autobiographical memory consistency was assessed using the Autobiographical Memory Interview-Short Form. RESULTS: Seventy-three patients entered the trial, of whom 51 and 26 completed neurocognitive assessments at baseline and 6 months, respectively. The MATRICS Consensus Cognitive Battery composite score improved by 4.1 points in both groups (P = .042) from baseline to 6 months (from 40.8 to 44.9 and from 41.9 to 46.0 in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively). The Autobiographical Memory Interview-Short Form consistency scores were reduced in both groups (72.3% vs 64.3% in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively; P = .085). CONCLUSIONS: This study did not find that right unilateral electroconvulsive therapy caused long term impairment in neurocognitive functions compared to algorithm-based pharmacologic treatment in bipolar depression as measured using standard neuropsychological tests, but due to the low number of patients in the study the results should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00664976. PMID- 29267992 TI - The effects of age on pulse wave velocity in untreated hypertension. AB - Increased arterial stiffness is an important determinant of cardiovascular risk, able to predict morbidity and mortality, and closely associated with ageing and blood pressure. The aims of this study were: (1) To determine the age-dependent reference pulse wave velocity (PWV), and compare it with values from hypertensive patients, and (2) to evaluate the impact of isolated and untreated hypertension on arterial stiffness. A total of 1079 patients were enrolled and divided into a control group (NT) of asymptomatic normotensive patients and a group of asymptomatic hypertensive patients (HT). Blood pressure, carotid-femoral PWV, and body mass index were measured in each subject, whose blood was drawn for laboratory tests. Aortic mean PWV in the NT group was 6.85 +/- 1.66 m/s, which increased linearly (R2 = 0.62; P < .05) with age. In patients over 50 years of age, PWV was significantly higher than in younger patients (8.35 vs 5.92 m/s, respectively, P < .001). This significant difference persisted when observing male and female patients separately. In the hypertensive group, mean PWV value was 8.04 +/- 1.8 m/s (range 4.5-15.8 m/s) and increased (R2 = 0.243; P < .05) with age. The PWV increase in HT was significantly higher (0.93 m/s per decade, P < .001) than in NT (0.44 m/s per decade). Our study provides normal values of PVW per decade, and shows that these values increase with age, especially after 50 years of age, particularly in HT patients. This stiffness growth rate may be responsible for increased cardiovascular risk in both groups. PMID- 29267991 TI - Extraction of mean emotional tone from face arrays in social anxiety disorder. AB - BACKGROUND: Social anxiety disorder (SAD) is characterized by intense fear when facing a crowd. Processing biases of crowd-related information have been suggested as contributing to the etiology and maintenance of the disorder. Here we tested whether patients with SAD display aberrant patterns of extracting the mean emotional tone from sets of faces. METHODS: Twenty-one participants with SAD and 24 unanxious control participants had to determine the average emotion expression of sets of six different morphed faces ranging from happy to angry. In 20% of trials the six faces were randomly sampled from the entire happy-angry range. The remaining 80% of trials, considered the critical trials, had an emotional outlier: five faces were sampled from one-half of the emotional range, whereas the sixth face was sampled from the opposite emotional range. RESULTS: Participants with SAD were less accurate than controls in extracting the mean emotional tone from sets of faces. Unanxious participants underweighted negative outliers and overweighed positive outliers when extracting the mean, whereas participants with SAD exhibited no such biases. CONCLUSIONS: Results suggest a possible mechanism associated with the anxiety experienced by socially anxious individuals when facing a crowd. PMID- 29267993 TI - Hopelessness as a Predictor of Suicide Ideation in Depressed Male and Female Adolescent Youth. AB - We examined hopelessness as a predictor of suicide ideation in depressed youth after acute medication treatment. A total of 158 depressed adolescents were administered the Children's Depression Rating Scale-Revised (CDRS-R) and Columbia Suicide Severity Rating Scale (C-SSRS) as part of a larger battery at baseline and at weekly visits across 6 weeks of acute fluoxetine treatment. The Beck Hopelessness Scale (BHS) was administered at baseline and week 6. A negative binomial regression model via a generalized estimating equation analysis of repeated measures was used to estimate suicide ideation over the 6 weeks of acute treatment from baseline measure of hopelessness. Depression severity and gender were included as covariates in the model. The negative binomial analysis was also conducted separately for the sample of males and females (in a gender-stratified analysis). Mean CDRS-R total scores were 60.30 +/- 8.93 at baseline and 34.65 +/- 10.41 at week 6. Mean baseline and week 6 BHS scores were 9.57 +/- 5.51 and 5.59 +/- 5.38, respectively. Per the C-SSRS, 43.04% and 83.54% reported having no suicide ideation at baseline and at week 6, respectively. The analyses revealed that baseline hopelessness was positively related to suicide ideation over treatment (p = .0027), independent of changes in depression severity. This significant finding persisted only for females (p = .0024). These results indicate the importance of early identification of hopelessness. PMID- 29267995 TI - Sexual and Relationship Satisfaction associated with Shifts in Dyadic Trajectories of Depressive Symptoms in German Couples across Four Years. AB - Depression is a pervasive mental health concern; thus, it is important to identify modifiable factors associated with reducing depressive symptoms across time. Using 1,876 heterosexual couples assessed annually across 4 years from the Panel Analysis of Intimate Relationships and Family Dynamics (Pairfam) study, time-varying covariate growth models tested if sexual and relationship satisfaction were linked with shifts in trajectories of depressive symptoms across time. For both men and women, higher sexual and relationship satisfaction scores were significantly associated with decreasing their own depressive symptom trajectories, but only relationship satisfaction was linked with their partners' depressive symptom trajectories. Potential clinical implications include the treatment of depressive symptoms by making changes across time in their own relationship satisfaction and sexual satisfaction. PMID- 29267994 TI - A bundled quality improvement program to standardize clinical blood pressure measurement in primary care. AB - We evaluated use of a program to improve blood pressure measurement at 6 primary care clinics over a 6-month period. The program consisted of automated devices, clinical training, and support for systems change. Unannounced audits and electronic medical records provided evaluation data. Clinics used devices in 81.0% of encounters and used them as intended in 71.6% of encounters, but implementation fidelity varied. Intervention site systolic and diastolic blood pressure with terminal digit "0" decreased from 32.1% and 33.7% to 11.1% and 11.3%, respectively. Improvement occurred uniformly, regardless of sites' adherence to the measurement protocol. Providers rechecked blood pressure measurements less often post-intervention (from 23.5% to 8.1% of visits overall). Providers at sites with high protocol adherence were less likely to recheck measurements than those at low adherence sites. Comparison sites exhibited no change in terminal digit preference or repeat measurements. This study demonstrates that clinics can apply a pragmatic intervention to improve blood pressure measurement. Additional refinement may improve implementation fidelity. PMID- 29267996 TI - Incident reporting in dentistry: Clinical supervisor's awareness, practice and perceived barriers. AB - BACKGROUND: The significance of patient safety and risk management in dentistry has surfaced as dental settings bear delicate procedures carried out by teams utilising numerous devices and tools in complex environments. AIM AND OBJECTIVES: Our aim is to assess awareness, practice, attitude and perceived barriers of reporting incidents amongst dental clinical supervisors working at dental colleges in Riyadh, Saudi Arabia. The objectives are as follows: (i) Determine if correlations exist between socio-demographic data and supervisors' awareness, practice, attitude and perceived barriers. (ii) Identify most common perceived barriers. MATERIALS AND METHODS: An online questionnaire was sent to the 450 clinical supervisors working at five dental colleges of Riyadh. The collected data included items assessing the awareness, practice and attitude of reporting students' incidents along with the perceived barriers. RESULTS: A response rate of (60.1% n = 264 of 450) was established. The majority of the respondents (62.9% n = 166) were aware of the incident reporting policy. Yet, only (35.4% n = 93) of them had completed an incident reporting form before. Most of the participants (90.5% n = 239) agreed on the necessity of reporting student's incidents, but only (67.0% n = 177) agreed on the necessity of reporting well-handled incidents. The possible negative relationship with students was the most agreed on barrier to reporting. CONCLUSION: This study shows that certain demographics of supervisors had significant relationship with their awareness, attitude, perceived barriers and practice. Awareness of the policy and form was linked to the increase in supervisors' practice, although they tend to report verbally rather than in writing. The possible negative relationship with students was the most common perceived barrier. PMID- 29267997 TI - Painful erythematous skin nodules in a kidney transplant recipient. PMID- 29267998 TI - Waterborne disease outbreaks associated with environmental and undetermined exposures to water - United States, 2013-2014. PMID- 29267999 TI - Novel Role of Calcineurin Inhibitors in Curbing T Cells' Sweet Tooth. PMID- 29268000 TI - Human Cell Atlas Poised to Transform Our Understanding of Organs. PMID- 29268001 TI - Erratum. PMID- 29268002 TI - Erratum. PMID- 29268003 TI - Is "early intervention" in bipolar disorder what it claims to be? AB - BACKGROUND: The notion of early intervention is understandably appealing for conditions such as bipolar disorder (BD), a chronic life-long illness that increases risk of suicide and diminishes quality of life. It is purported that intervening early in the course of the illness with suitable interventions could substantially alter the trajectory of BD and improve outcomes. However, while there are obvious benefits to the prompt commencement of treatment, it is important to consider the gaps in our understanding regarding the aetiopathogenesis of bipolar disorder-upon which the paradigm of early intervention is predicated. METHODS: A literature search was undertaken using recognized search engines: PubMed, PsycINFO Medline, and Scopus, along with auxiliary manual searches. RESULTS: This review first examines how the unpredictable nature of BD creates substantial difficulties when determining an optimal therapeutic target for early intervention. Second, the challenges with identifying appropriate populations and apposite times for early intervention strategies is discussed. Finally, the risks associated with intervening early are examined, highlighting the potential harmful effects of initiating medication. CONCLUSION: Early intervention for BD is a potentially useful strategy that warrants investigation, but until the emergence and trajectory of the illness are definitive, and a clear view of key targets is achieved, a more conservative approach to treating nascent BD and its antecedent symptoms is needed. PMID- 29268004 TI - Levels of interleukin-6 and high-sensitivity C-reactive protein reflecting mania severity in bipolar disorder. PMID- 29268005 TI - Verbigeration: An overlooked symptom of a "forgotten syndrome"? PMID- 29268006 TI - Predictors of long-term distress in female partners of men diagnosed with prostate cancer. AB - OBJECTIVE: Female partners of men with prostate cancer (PCa) experience heightened psychological distress; however, long-term distress for this group is not well described. We examined partner's psychological and cancer-specific distress over 2 years and predictors of change. METHODS: A cohort of 427 female partners (63% response; mean age 62.6 y) of PCa survivors completed baseline (2-4 y post-PCa treatment) assessments of anxiety, depression, and cancer-specific distress and were followed up at 6, 12, 18, and 24 months. Caregiver burden, threat and challenge appraisal, self-efficacy, and dyadic adjustment were assessed as potential predictors of distress. RESULTS: Over time, 23% to 25% of women reported anxiety; 8% to 11% depression; 5% to 6% high cancer-specific distress. Higher caregiver burden and more threat appraisals were associated with increased distress, anxiety, depression, and cancer-specific distress over time. Higher dyadic adjustment over time and more challenge appraisals at 24 months were associated with less distress, anxiety, and depression. Increased partner self-efficacy was associated with lower distress and depression at baseline. CONCLUSIONS: A substantial subgroup of partners experience ongoing anxiety, with depression less prevalent but also persistent. Caregiver burden, partner self efficacy, threat, and challenge appraisals present as potential supportive care targets. PMID- 29268007 TI - Thermodynamic Justification for the Parabolic Model for Reactivity Indicators with Respect to Electron Number and a Rigorous Definition for the Electrophilicity: The Essential Role Played by the Electronic Entropy. AB - The temperature-dependence of the Helmholtz free energy with respect to the number of electrons is analyzed within the framework of the Grand Canonical Ensemble. At the zero-temperature limit, the Helmholtz free energy behaves as a Heaviside function of the number of electrons; however, as the temperature increases, the profile smoothens and exhibits a minimum value at noninteger positive values of the fractional electronic charge. We show that the exact average electronic energy as a function of the number of electrons does not display this feature at any temperature, since this behavior is solely due to the electronic entropy. Our mathematical analysis thus indicates that the widely used parabolic interpolation model should not be viewed as an approximation for the average electronic energy, but for the dependence of the Helmholtz free energy upon the number of electrons, and this analysis is corroborated by numerical results. Finally, an electrophilicity index is defined for the Helmholtz free energy showing that, for a given chemical species, there exists a temperature value for which this quantity is equivalent to the electrophilicity index defined within the parabolic interpolation of the electronic energy as a function of the number of electrons. Our formulation suggests that the convexity property of the energy versus the number of electrons together with the entropic contribution does not allow for an analogous nucleophilicity index to be defined. PMID- 29268008 TI - The 3D Structure of Human DP Prostaglandin G-Protein-Coupled Receptor Bound to Cyclopentanoindole Antagonist, Predicted Using the DuplexBiHelix Modification of the GEnSeMBLE Method. AB - Prostaglandins play a critical physiological role in both cardiovascular and immune systems, acting through their interactions with 9 prostanoid G protein coupled receptors (GPCRs). These receptors are important therapeutic targets for a variety of diseases including arthritis, allergies, type 2 diabetes, and cancer. The DP prostaglandin receptor is of interest because it has unique structural and physiological properties. Most notably, DP does not have the 3-6 ionic lock common to Class A GPCRs. However, the lack of X-ray structures for any of the 9 prostaglandin GPCRs hampers the application of structure-based drug design methods to develop more selective and active medications to specific receptors. We predict here 3D structures for the DP prostaglandin GPCR, based on the GEnSeMBLE complete sampling with hierarchical scoring (CS-HS) methodology. This involves evaluating the energy of 13 trillion packings to finally select the best 20 that are stable enough to be relevant for binding to antagonists, agonists, and modulators. To validate the predicted structures, we predict the binding site for the Merck cyclopentanoindole (CPI) selective antagonist docked to DP. We find that the CPI binds vertically in the 1-2-7 binding pocket, interacting favorably with residues R3107.40 and K762.54 with additional interactions with S3137.43, S3167.46, S191.35, etc. This binding site differs significantly from that of antagonists to known Class A GPCRs where the ligand binds in the 3-4-5-6 region. We find that the predicted binding site leads to reasonable agreement with experimental Structure-Activity Relationship (SAR). We suggest additional mutation experiments including K762.54, E1293.49, L1233.43, M2706.40, F2746.44 to further validate the structure, function, and activation mechanism of receptors in the prostaglandin family. Our structures and binding sites are largely consistent and improve upon the predictions by Li et al. ( J. Am. Chem. Soc. 2007 , 129 ( 35 ), 10720 ) that used our earlier MembStruk prediction methodology. PMID- 29268009 TI - Reduction Responsive Nanovesicles Derived from Novel alpha-Tocopheryl-Lipoic Acid Conjugates for Efficacious Drug Delivery to Sensitive and Drug Resistant Cancer Cells. AB - Two novel alpha-tocopheryl-lipoic acid conjugates (TL1 and TL2) were synthesized for the anticancer drug, doxorubicin (DOX), delivery. Both conjugates were able to form stable nanovesicles. The critical aggregation concentration (CAC) was determined using 4-(N,N-dimethylamino)cinnamaldehyde (DMACA) as a fluorescence probe. Formation of highly packed nanovesicles was characterized by 1,6-diphenyl 1,3,5-hexatriene (DPH) fluorescence anisotropy and microviscosity measurements. The morphologies of nanovesicles were visualized by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The response of nanovesicles to reducing environment of cells was probed by the addition of dithiothreitol (DTT), which was followed by the increase in the hydrodynamic diameter under dynamic light scattering (DLS) measurements. The encapsulation efficiency of a commonly used anticancer drug, doxorubicin (DOX), in nanovesicles was found to be ~60% and ~55% for TL1 and TL2, respectively (TL1-DOX and TL2-DOX). Also, the cumulative drug (DOX) release from DOX-encapsulated nanovesicles in response to biological reducing agent glutathione (GSH) was ~50% and ~40% for TL1-DOX and TL2 DOX, respectively, over a period of 10 h. Both TL1-DOX and TL2-DOX delivered the anticancer drug, doxorubicin (DOX), across the DOX-sensitive and DOX-resistant HeLa (HeLa-DOXR) cells in an efficient manner and significantly more efficaciously than the drug alone treatments, especially in HeLa-DOXR cells. The nanovesicle mediated DOX treatment also showed significantly higher cell death when compared to DOX alone treatment in HeLa-DOXR cells. Blood compatibility of the nanovesicles was supported from clotting time, hemolysis, and red blood cell (RBC) aggregation experiments for their potential in vivo applications. Concisely, we present biocompatible and responsive nanovesicles for efficacious drug delivery to drug-sensitive and drug-resistant cancer cells. PMID- 29268010 TI - Characterizing Bonding Patterns in Diradicals and Triradicals by Density-Based Wave Function Analysis: A Uniform Approach. AB - Density-based wave function analysis enables unambiguous comparisons of the electronic structure computed by different methods and removes ambiguity of orbital choices. We use this tool to investigate the performance of different spin-flip methods for several prototypical diradicals and triradicals. In contrast to previous calibration studies that focused on energy gaps between high and low spin-states, we focus on the properties of the underlying wave functions, such as the number of effectively unpaired electrons. Comparison of different density functional and wave function theory results provides insight into the performance of the different methods when applied to strongly correlated systems such as polyradicals. We show that canonical molecular orbitals for species like large copper-containing diradicals fail to correctly represent the underlying electronic structure due to highly non-Koopmans character, while density-based analysis of the same wave function delivers a clear picture of the bonding pattern. PMID- 29268011 TI - Dye Tool Box for a Fluorescence Enhancement Immunoassay. AB - Immunochemical analytical methods are very successful in clinical diagnostics and are nowadays also emerging in the control of food as well as monitoring of environmental issues. Among the different immunoassays, luminescence based formats are characterized by their outstanding sensitivity making this format especially attractive for future applications. The need for multiparameter detection capabilities calls for a tool box of dye labels in order to transduce the biochemical reaction into an optically detectable signal. Here, in a multiparameter approach each analyte may be detected by a different dye with a unique emission color (covering the blue to red spectral range) or a unique luminescence decay kinetics. In the case of a competitive immunoassay format for each of the different dye labels an individual antibody would be needed. In the present paper a slightly modified approach is presented using a 7-aminocoumarin unit as the basic antigen against which highly specific antibodies were generated. Leaving the epitope region in the dyes unchanged but introducing a side group in positon 3 of the coumarin system allowed us to tune the optical properties of the coumarin dyes without the necessity of new antibody generation. Upon modification of the parent coumarin unit the full spectral range from blue to deep red was accessed. In the manuscript the photophysical characterization of the coumarin derivatives and their corresponding immunocomplexes with two highly specific antibodies is presented. The coumarin dyes and their immunocomplexes were characterized by steady-state and time-resolved absorption as well as emission spectroscopy. Moreover, fluorescence depolarization measurements were carried out to complement the data stressing the different binding modes of the two antibodies. The binding modes were evaluated using the photophysics of 7 aminocoumarins and how it was affected in the respective immunocomplexes, namely, the formation of the intramolecular charge transfer (ICT) as well as the twisted intramolecular charge transfer (TICT). In contrast to other antibody-dye pairs reported a distinct fluorescence enhancement upon formation of the antibody-dye complex up to a factor of 50 was found. Because of the easy emission color tuning by tailoring the coumarin substitution for the antigen binding in nonrelevant position 3 of the parent molecule, a dye tool box is on hand which can be used in the construction of competitive multiparameter fluorescence enhancement immunoassays (FenIA). PMID- 29268012 TI - Comparison of Additive and Polarizable Models with Explicit Treatment of Long Range Lennard-Jones Interactions Using Alkane Simulations. AB - Long-range Lennard-Jones (LJ) interactions have a significant impact on the structural and thermodynamic properties of nonpolar systems. While several methods have been introduced for the treatment of long-range LJ interactions in molecular dynamics (MD) simulations, increased accuracy and extended applicability is required for anisotropic systems such as lipid bilayers. The recently refined Lennard-Jones particle-mesh Ewald (LJ-PME) method extends the particle-mesh Ewald (PME) method to long-range LJ interactions and is suitable for use with anisotropic systems. Implementation of LJ-PME with the CHARMM36 (C36) additive and CHARMM Drude polarizable force fields improves agreement with experiment for density, isothermal compressibility, surface tension, viscosity, translational diffusion, and 13C T1 relaxation times of pure alkanes. Trends in the temperature dependence of the density and isothermal compressibility of hexadecane are also improved. While the C36 additive force field with LJ-PME remains a useful model for liquid alkanes, the Drude polarizable force field with LJ-PME is more accurate for nearly all quantities considered. LJ-PME is also preferable to the isotropic long-range correction for hexadecane because the molecular order extends to nearly 20 A, well beyond the usual 10-12 A cutoffs used in most simulations. PMID- 29268013 TI - Halogen-Adatom Mediated Phase Transition of Two-Dimensional Molecular Self Assembly on a Metal Surface. AB - Construction of tunable and robust two-dimensional (2D) molecular arrays with desirable lattices and functionalities over a macroscopic scale relies on spontaneous and reversible noncovalent interactions between suitable molecules as building blocks. Halogen bonding, with active tunability of direction, strength, and length, is ideal for tailoring supramolecular structures. Herein, by combining low-temperature scanning tunneling microscopy and systematic first principles calculations, we demonstrate novel halogen bonding involving single halogen atoms and phase engineering in 2D molecular self-assembly. On the Au(111) surface, we observed catalyzed dehalogenation of hexabromobenzene (HBB) molecules, during which negatively charged bromine adatoms (Brdelta-) were generated and participated in assembly via unique C-Brdelta+...Brdelta- interaction, drastically different from HBB assembly on a chemically inert graphene substrate. We successfully mapped out different phases of the assembled superstructure, including densely packed hexagonal, tetragonal, dimer chain, and expanded hexagonal lattices at room temperature, 60 degrees C, 90 degrees C, and 110 degrees C, respectively, and the critical role of Brdelta- in regulating lattice characteristics was highlighted. Our results show promise for manipulating the interplay between noncovalent interactions and catalytic reactions for future development of molecular nanoelectronics and 2D crystal engineering. PMID- 29268014 TI - Conical Torch: The Next-Generation Inductively Coupled Plasma Source for Spectrochemical Analysis. AB - A completely new ICP torch for optical/mass spectrometry is introduced with a conical geometry leading to significant reduction in gas and power consumption. As a new holistic methodology, the torch has been designed on the basis of fluid flow patterns, heat transfer, plasma physics, and analytical performance. Computer simulations, capable of accounting for magneto-hydrodynamic effects, have been used to optimize torch geometry. The result is a "conical" torch with up to 70% reduction in argon flow and more than 4 times power density compared with traditional "cylindrical" torches. Based on experimental measurements, these features lead to a stable plasma with 1000-1700K higher excitation/rotational temperature and a 5-fold increase in electron number density compared to common torches. Interferences from easily ionizable elements (e.g., Na) are also observed to be minimized due to 3 times higher robustness (Mg II/Mg I ratio). Eventually, analytical parameters including detection limits for multielement analysis indicate comparable/better performance of the new torch in comparison with conventional torches. PMID- 29268015 TI - Counterion-Release Entropy Governs the Inhibition of Serum Proteins by Polyelectrolyte Drugs. AB - Dendritic polyelectrolytes constitute high potential drugs and carrier systems for biomedical purposes. Still, their biomolecular interaction modes, in particular those determining the binding affinity to proteins, have not been rationalized. We study the interaction of the drug candidate dendritic polyglycerol sulfate (dPGS) with serum proteins using isothermal titration calorimetry (ITC) interpreted and complemented with molecular computer simulations. Lysozyme is first studied as a well-defined model protein to verify theoretical concepts, which are then applied to the important cell adhesion protein family of selectins. We demonstrate that the driving force of the strong complexation, leading to a distinct protein corona, originates mainly from the release of only a few condensed counterions from the dPGS upon binding. The binding constant shows a surprisingly weak dependence on dPGS size (and bare charge) which can be understood by colloidal charge-renormalization effects and by the fact that the magnitude of the dominating counterion-release mechanism almost exclusively depends on the interfacial charge structure of the protein specific binding patch. Our findings explain the high selectivity of P- and L selectins over E-selectin for dPGS to act as a highly anti-inflammatory drug. The entire analysis demonstrates that the interaction of proteins with charged polymeric drugs can be predicted by simulations with unprecedented accuracy. Thus, our results open new perspectives for the rational design of charged polymeric drugs and carrier systems. PMID- 29268016 TI - Detection of Curvature-Radius-Dependent Interfacial pH/Polarity for Amphiphilic Self-Assemblies: Positive versus Negative Curvature. AB - It is possible that a defined curvature at the membrane interface controls its pH/polarity to exhibit specific bioactivity. By utilizing an interface interacting spiro-rhodamine pH probe and the Schiff base polarity probe, we have shown that the pH deviation from the bulk phase to the interface (DeltapH)/interfacial dielectric constant (kappa(i)) for amphiphilic self assemblies can be regulated by the curvature geometry (positive/negative) and its radius. According to 1H NMR and fluorescence anisotropy investigations, the probes selectively interact with an anionic interfacial Stern layer. The DeltapH/kappa(i) values for the Stern layer are estimated by UV-vis absorption and fluorescence studies. For the anionic sodium bis-2-ethylhexyl-sulfosuccinate (AOT) inverted micellar (IM) negative interface, the highly restricted water and proton penetration into the Stern layer owing to tight surfactant packing or a reduced water-exposed headgroup area may be responsible for the much lower DeltapH ~ -0.45 and kappa(i) ~ 28 in comparison to ~-2.35 and ~44, respectively, for the anionic sodium dodecyl sulfate (SDS) micellar positive interface with a close similar Stern layer. With increasing AOT IM water-pool radius (1.7-9.5 nm) or [water]/[AOT] ratio ( w0) (8.0-43.0), the DeltapH and kappa(i) increase maximally up to ~-1.22 and ~45, respectively, due to a greater water-exposed headgroup area. However, the unchanged DeltapH ~ -0.65 and kappa(i) ~ 53.0 within radii ~3.5-8.0 nm for the positive interface of a mixed Triton X-100 (TX-100)/SDS (4:1) micelle justify its packing flexibility. Interestingly, the continuously increasing DeltapH trend for IM up to its largest possible water-pool radius of ~9.5 nm may rationalize the increase in DeltapH (~-1.4 to -1.6) with the change in the curvature radii (~15 to 50 nm) for sodium 1,2-dimyristoyl- sn-glycero-3 phosphorylglycerol (DMPG)/1,2-dimyristoyl- sn-glycero-3-phosphocholine (DMPC) (2:1) large unilamellar vesicles (LUV) owing to its negative interface. Whereas, similar to the micellar positive interface, the unchanged DeltapH at the positive LUV interface was confirmed by fluorescence microscopic studies with giant unilamellar vesicles of identical lipids composition. The present study offers a unique and simple method of monitoring the curvature-radius-dependent interfacial pH/polarity for biologically related membranes. PMID- 29268017 TI - Controlled Electrochemical Intercalation of Graphene/h-BN van der Waals Heterostructures. AB - Electrochemical intercalation is a powerful method for tuning the electronic properties of layered solids. In this work, we report an electrochemical strategy to controllably intercalate lithium ions into a series of van der Waals (vdW) heterostructures built by sandwiching graphene between hexagonal boron nitride (h BN). We demonstrate that encapsulating graphene with h-BN eliminates parasitic surface side reactions while simultaneously creating a new heterointerface that permits intercalation between the atomically thin layers. To monitor the electrochemical process, we employ the Hall effect to precisely monitor the intercalation reaction. We also simultaneously probe the spectroscopic and electrical transport properties of the resulting intercalation compounds at different stages of intercalation. We achieve the highest carrier density >5 * 1013 cm2 with mobility >103 cm2/(V s) in the most heavily intercalated samples, where Shubnikov-de Haas quantum oscillations are observed at low temperatures. These results set the stage for further studies that employ intercalation in modifying properties of vdW heterostructures. PMID- 29268018 TI - Time-Resolved Tracking of Separately Internalized Neuropeptide Y2 Receptors by Two-Color Pulse-Chase. AB - Internalization and intracellular trafficking of G protein-coupled receptors (GPCR) plays an important role in the signal transduction. These processes are often highly dynamic and take place rapidly. In the past 10 years, it became obvious that internalized GPCRs are also capable of signaling via arrestin or heterotrimeric G proteins within the endosomal compartment. Real-time imaging of receptors in living cells can help to evaluate the temporal and spatial localization. We achieved a two-color pulse-chase labeling approach, which allowed the tracking of the human neuropeptide Y2 receptor (hY2R) in the same cell at different times. The ability to visualize the internalization pathway of two separately labeled and separately stimulated subsets of hY2R in a time resolved manner revealed a rapid trafficking. Fusion of the two hY2R subsets was already observed 10 min after stimulation in the early endosomal compartment without subsequent separation of the fused receptor populations. The results demonstrate that the cells do not discriminate between receptors that were stimulated and internalized at different time points. PMID- 29268019 TI - High Mobility Group Box-1 (HMGb1): Current Wisdom and Advancement as a Potential Drug Target. AB - High mobility group box-1 (HMGb1) protein, a nuclear non-histone protein that is released or secreted from the cell in response to damage or stress, is a sentinel for the immune system that plays a critical role in cell survival/death pathways. This review highlights key features of the endogenous danger-associated molecular pattern (DAMP) protein, HMGb1 in the innate inflammatory response along with various cofactors and receptors that regulate its downstream effects. The evidence demonstrating increased levels of HMGb1 in human inflammatory diseases and conditions is presented, along with a summary of current small molecule or peptide-like antagonists proven to specifically target HMGb1. Additionally, we delineate the measures needed toward validating this protein as a clinically relevant biomarker or bioindicator and as a relevant drug target. PMID- 29268021 TI - Three-Dimensional Macroporous Co-Embedded N-Doped Carbon Interweaving with Carbon Nanotubes as Excellent Bifunctional Catalysts for Zn-Air Batteries. AB - Highly efficient noble metal-free bifunctional catalysts for expediting the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) in metal-air batteries or fuel cells are still challenging and imperative. In this work, we report a facile and scalable method for syntheizing three-dimensional (3D) macroporous Co-embedded N-doped carbon interconnecting with in situ growth carbon nanotubes (CNTs). The as-synthesized material exhibits great electrocatalytic performance for ORR with an onset potential of 0.901 V vs RHE as well as a high limited current density of 4.83 mA/cm2 in an alkaline electrolyte under a rotation speed of 1600 rpm at 5 mV/s. Furthermore, this 3D porous carbon also shows good electrocatalytic performance for OER in an alkaline electrolyte. This high electrocatalytic performance is mainly attributed to its large specific surface area and highly conductive CNTs and the synergistic effect between Co active species and the carbon framework. The result of a two-electrode Zn-air battery based on this carbon material achieves a peak density of 163 mW/cm2 at a voltage of 0.63 V, indicating the great potential of the catalyst for battery application. PMID- 29268020 TI - Intermolecular Anti-Markovnikov Hydroamination of Unactivated Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer. AB - Here we report a catalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated alkenes using primary and secondary sulfonamides. These reactions occur at room temperature under visible light irradiation and are jointly catalyzed by an iridium(III) photocatalyst, a dialkyl phosphate base, and a thiol hydrogen atom donor. Reaction outcomes are consistent with the intermediacy of an N-centered sulfonamidyl radical generated via proton-coupled electron transfer activation of the sulfonamide N-H bond. Studies outlining the synthetic scope (>60 examples) and mechanistic features of the reaction are presented. PMID- 29268022 TI - The Effect of Corticosteroid Injection Into Rotator Interval for Early Frozen Shoulder: A Randomized Controlled Trial. AB - BACKGROUND: Corticosteroid injection is a common treatment for frozen shoulder, but controversy still exists regarding the injection site with the best outcome. HYPOTHESIS: To treat the frozen shoulder in the freezing stage with corticosteroid injection, a single injection into the rotator interval (RI) could yield better effects in terms of improvement in pain, passive range of motion (ROM), and function than would an injection into the intra-articular (IA) or subacromial (SA) space. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with primary frozen shoulder in the freezing stage were randomized into 3 groups: RI injection, IA injection, or SA injection with corticosteroid. Clinical outcomes were documented at baseline and at 4, 8, and 12 weeks after intervention, including visual analog scale (VAS) for pain; passive ROM measurements, including external rotation, internal rotation, forward flexion, and abduction; and evaluation with the Disability of Arm, Hand, and Shoulder (DASH) score and Constant score. RESULTS: There were no significant differences in the basic properties of the 3 groups (27 in RI group, 24 in IA group, and 26 in SA group) before injection. Improvements in pain VAS, passive ROM, Constant score, and DASH score were faster and significant in the RI group from 4 weeks after injection, followed by those in the IA group. Passive ROM decreased and DASH score did not change significantly in the SA group, although pain VAS and Constant score improved significantly. CONCLUSION: To treat frozen shoulder in the freezing stage with corticosteroid injection, a single injection into the RI yielded better effects in terms of improvement in pain, passive ROM, and function than did injections into the IA or SA space. PMID- 29268023 TI - Whole-genome sequencing reveals the extent of heterozygosity in a preferentially self-fertilizing hermaphroditic vertebrate. AB - The mangrove rivulus, Kryptolebias marmoratus, is one of only two self fertilizing hermaphroditic fish species and inhabits mangrove forests. While selfing can be advantageous, it reduces heterozygosity and decreases genetic diversity. Studies using microsatellites found that there are variable levels of selfing among populations of K. marmoratus, but overall, there is a low rate of outcrossing and, therefore, low heterozygosity. In this study, we used whole genome data to assess the levels of heterozygosity in different lineages of the mangrove rivulus and infer the phylogenetic relationships among those lineages. We sequenced whole genomes from 15 lineages that were completely homozygous at microsatellite loci and used single nucleotide polymorphisms (SNPs) to determine heterozygosity levels. More variation was uncovered than in studies using microsatellite data because of the resolution of full genome sequencing data. Moreover, missense polymorphisms were found most often in genes associated with immune function and reproduction. Inferred phylogenetic relationships suggest that lineages largely group by their geographic distribution. The use of whole genome data provided further insight into genetic diversity in this unique species. Although this study was limited by the number of lineages that were available, these data suggest that there is previously undescribed variation within lineages of K. marmoratus that could have functional consequences and (or) inform us about the limits to selfing (e.g., genetic load, accumulation of deleterious mutations) and selection that might favor the maintenance of heterozygosity. These results highlight the need to sequence additional individuals within and among lineages. PMID- 29268024 TI - Anterolateral Knee Extra-articular Stabilizers: A Robotic Study Comparing Anterolateral Ligament Reconstruction and Modified Lemaire Lateral Extra articular Tenodesis. AB - BACKGROUND: Persistent clinical instability after anterior cruciate ligament (ACL) reconstruction may be associated with injury to the anterolateral structures and has led to renewed interest in anterolateral extra-articular procedures. The influence of these procedures on knee kinematics is controversial. Purpose/Hypothesis: The purpose was to investigate the biomechanical properties of anatomic anterolateral ligament (ALL) reconstruction and a modified Lemaire procedure (lateral extra-articular tenodesis [LET]) in combination with ACL reconstruction as compared with isolated ACL reconstruction in the setting of deficient anterolateral structures (ALL and Kaplan fibers). It was hypothesized that both techniques would reduce tibial internal rotation when combined with ACL reconstruction in the setting of anterolateral structure deficiency. STUDY DESIGN: Controlled laboratory study. METHODS: A 6 degrees of freedom robotic system was used to assess tibial internal rotation, a simulated pivot-shift test, and anterior tibial translation in 10 paired fresh-frozen cadaveric knees. The following states were tested: intact; sectioned ACL, ALL, and Kaplan fibers; ACL reconstruction; and an anterolateral extra-articular procedure (various configurations of ALL reconstruction and LET). Knees within a pair were randomly assigned to either ALL reconstruction or LET with a graft tension of 20 N and a randomly assigned fixation angle (30 degrees or 70 degrees ). ALL reconstruction was then repeated and secured with a graft tension of 40 N. RESULTS: In the setting of deficient anterolateral structures, ACL reconstruction was associated with significantly increased residual laxity for tibial internal rotation (up to 4 degrees ) and anterior translation (up to 2 mm) laxity as compared with the intact state. The addition of ALL reconstruction or LET after ACL reconstruction significantly reduced tibial internal rotation in most testing scenarios to values lower than the intact state (ie, overconstraint). Significantly greater reduction in laxity with internal rotation and pivot-shift testing was found with the LET procedure than ALL reconstruction when compared with the intact state. Combined with ACL reconstruction alone, both extra articular procedures restored anterior tibial translation to values not significantly different from the intact state with most testing scenarios (usually within 1 mm). CONCLUSION: Residual laxity was identified after isolated ACL reconstruction in the setting of ALL and Kaplan fiber deficiency, and the combination of ACL reconstruction in this setting with either ALL reconstruction or the modified Lemaire LET procedure resulted in significant reductions in tibiofemoral motion at most knee flexion angles, although overconstraint was also identified. ALL reconstruction and LET restored anterior tibial translation to intact values with most testing states. CLINICAL RELEVANCE: ALL reconstruction and lateral extra-articular tenodesis have been described in combination with intra-articular ACL reconstruction to address rotational laxity. This study demonstrated that both procedures resulted in significant reductions of tibial internal rotation versus the intact state independent of graft tension or fixation angle, although anterior tibial translation was generally restored to intact values. The influence of overconstraint with anterolateral knee reconstruction procedures has not been fully evaluated in the clinical setting and warrants continued evaluation based on the findings of this biomechanical study. PMID- 29268025 TI - Reply to Shah et al.: Mitochondrial Dysfunction in Bronchopulmonary Dysplasia. PMID- 29268026 TI - Hip Arthroscopic Surgery With Labral Preservation and Capsular Plication in Patients With Borderline Hip Dysplasia: Minimum 5-Year Patient-Reported Outcomes. AB - BACKGROUND: The arthroscopic management of hip dysplasia has been controversial and has historically demonstrated mixed results. Studies on patients with borderline dysplasia, emphasizing the importance of the labrum and capsule as secondary stabilizers, have shown improvement in patient-reported outcomes (PROs). Purpose/Hypothesis: The purpose was to assess whether the results of hip arthroscopic surgery with labral preservation and concurrent capsular plication in patients with borderline hip dysplasia have lasting, positive outcomes at a minimum 5-year follow-up. It was hypothesized that with careful patient selection, outcomes would be favorable. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data were prospectively collected and retrospectively reviewed for patients aged <40 years who underwent hip arthroscopic surgery for intra-articular abnormalities. Inclusion criteria included lateral center-edge angle (LCEA) between 18 degrees and 25 degrees , concurrent capsular plication and labral preservation, and minimum 5-year follow-up. Exclusion criteria were severe dysplasia (LCEA <=18 degrees ), Tonnis grade >=2, pre-existing childhood hip conditions, or prior hip surgery. PRO scores including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and Hip Outcome Score Sport Specific Subscale (HOS-SSS) and the visual analog scale (VAS) score for pain were collected preoperatively, at 3 months, and annually thereafter. Complications and revisions were recorded. RESULTS: Twenty-five hips (24 patients) met the inclusion criteria. Twenty-one hips (19 patients, 84%) were available for follow up. The mean age at surgery was 22.9 years. The mean preoperative LCEA and Tonnis angle were 21.7 degrees (range, 18 degrees to 24 degrees ) and 6.9 degrees (range, -1 degrees to 16 degrees ), respectively. The mean follow-up was 68.8 months. The mean mHHS increased from 70.3 to 85.9 ( P < .0001), the mean NAHS from 68.3 to 87.3 ( P < .0001), and the mean HOS-SSS from 52.1 to 70.8 ( P = .0002). The mean VAS score improved from 5.6 to 1.8 ( P < .0001). Four hips (19%) required secondary arthroscopic procedures, all of which resulted in improved PRO scores at latest follow-up. No patient required conversion to total hip arthroplasty. CONCLUSION: While periacetabular osteotomy remains the standard for treating true acetabular dysplasia, hip arthroscopy may provide a safe and durable means of managing intra-articular abnormalities in the setting of borderline acetabular dysplasia at midterm follow-up. These procedures should be performed by surgeons with expertise in advanced arthroscopic techniques, using strict patient selection criteria, with emphasis on labral preservation and capsular plication. PMID- 29268027 TI - Recent developments in our understanding of the implications of traditional African medicine on drug metabolism. AB - INTRODUCTION: The use of traditional herbal medicines has become increasingly popular globally, but in some countries, it is the main or sometimes even the only healthcare service available in the most rural areas. This is especially true for Africa where herbal medicines form a key component of traditional medicinal practices and there is access to a diversity of medicinal plants. Although many benefits have been derived from the use of traditional herbal medicines, many concerns are associated with their use of which herb-drug interactions have been identified to have a rising impact on patient treatment outcome. One type of pharmacokinetic interaction involves the modulation of drug metabolizing enzymes, which may result in enhanced or reduced bioavailability of co-administered drugs. Areas covered: This review highlights the current information available on drug metabolism-associated information with regards to traditional African medicines related to some of the most prevalent diseases burdening the African continent. Expert opinion: It is clear from previous studies that enzyme modulation by traditional African medicines plays a significant role in the pharmacokinetics of some co-administered drugs, but more research is needed to provide detailed information on these interactions, specifically for treatment of prevalent diseases such as tuberculosis and hypertension. PMID- 29268028 TI - Different strategies to kill the host presented by Metarhizium anisopliae and Beauveria bassiana. AB - Studies conducted over the last decades have shown the potential of entomopathogenic fungi for the biocontrol of some insect pests. Entomopathogenic fungi infect their host through the cuticle, so they do not need to be ingested to be effective. These fungi also secrete secondary metabolites and proteins that are toxic to insect pests. In this context, we analyzed the pathogenicity of Metarhizium anisopliae (Metschn.) strains IBCB 384 and IBCB 425 and Beauveria bassiana (Bals.-Criv.) Vuill. strains E 1764 and E 3158 against Galleria mellonella (Linn.) larvae, during pre-invasion and post-invasion phases. The results showed M. anisopliae, especially strain IBCB 384, was most virulent in the pre-invasion phase against G. mellonella, whereas B. bassiana, especially strain E 1764, was most virulent in the post-invasion phase. During in vivo development and in the production of toxic serum, B. bassiana E 3158 was the most virulent. Different fungal growth (or toxin) strategies were observed for studied strains. Metarhizium anisopliae IBCB 425 prioritizes the growth strategy, whereas strain IBCB 384 and B. bassiana strains E 1764 and E 3158 have a toxic strategy. All strains have pathogenicity against G. mellonella, indicating their possible use for biocontrol. PMID- 29268029 TI - Mitochondrial Dysfunction in Bronchopulmonary Dysplasia. PMID- 29268030 TI - Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung. AB - The complement system plays a critical role in immune responses against pathogens. However, its identity and regulation in the lung are not fully understood. This study aimed to explore the role of tripartite motif protein (TRIM) 72 in regulating complement receptor (CR) of the Ig superfamily (CRIg) in alveolar macrophage (AM) and innate immunity of the lung. Imaging, absorbance quantification, and flow cytometry were used to evaluate in vitro and in vivo AM phagocytosis with normal, or altered, TRIM72 expression. Pulldown, coimmunoprecipitation, and gradient binding assays were applied to examine TRIM72 and CRIg interaction. A pneumonia model was established by intratracheal injection of Pseudomonas aeruginosa. Mortality, lung bacterial burden, and cytokine levels in BAL fluid and lung tissues were examined. Our data show that TRIM72 inhibited CR-mediated phagocytosis, and release of TRIM72 inhibition led to increased AM phagocytosis. Biochemical assays identified CRIg as a binding partner of TRIM72, and TRIM72 inhibited formation of the CRIg-phagosome. Genetic ablation of TRIM72 led to improved pathogen clearance, reduced cytokine storm, and improved survival in murine models of severe pneumonia, specificity of which was confirmed by adoptive transfer of wild-type or TRIM72KO AMs to AM-depleted TRIM72KO mice. TRIM72 overexpression promoted bacteria-induced NF-kappaB activation in murine alveolar macrophage cells. Our data revealed a quiescent, noninflammatory bacterial clearance mechanism in the lung via AM CRIg, which is suppressed by TRIM72. In vivo data suggest that targeted suppression of TRIM72 in AM may be an effective measure to treat fatal pulmonary bacterial infections. PMID- 29268031 TI - Modified sprint interval training protocols: physiological and psychological responses to 4 weeks of training. AB - Sprint interval training (SIT) protocols involving brief (<=15 s) work bouts improve aerobic and anaerobic performance, highlighting peak speed generation as a potentially important adaptive stimulus. To determine the physiological and psychological effects of reducing the SIT work bout duration, while maintaining total exercise and recovery time, 43 healthy males (n = 27) and females (n = 16) trained for 4 weeks (3 times/week) using one of the following running SIT protocols: (i) 30:240 (n = 11; 4-6 * 30-s bouts, 4 min rest); (ii) 15:120 (n = 11; 8-12 * 15-s bouts, 2 min rest); (iii) 5:40 (n = 12; 24-36 * 5-s bouts, 40 s rest); or (iv) served as a nonexercising control (n = 9). Protocols were matched for total work (2-3 min) and rest (16-24 min) durations, as well as the work-to rest ratio (1:8 s). Pre- and post-training measures included a graded maximal oxygen consumption test, a 5-km time trial, and a 30-s maximal sprint test. Self efficacy, enjoyment, and intentions were assessed following the last training session. Training improved maximal oxygen consumption (5.5%; P = 0.006) and time trial performance (5.2%; P = 0.039), with a main effect of time for peak speed (1.7%; P = 0.042), time to peak speed (25%; P < 0.001), and body fat percentage (1.4%; P < 0.001) that appeared to be driven by the training. There were no group effects for self-efficacy (P = 0.926), enjoyment (P = 0.249), or intentions to perform SIT 3 (P = 0.533) or 5 (P = 0.951) times/week. This study effectively demonstrated that the repeated generation of peak speed during brief SIT work bouts sufficiently stimulates adaptive mechanisms promoting increases in aerobic and anaerobic capacity. PMID- 29268032 TI - Pharmacodynamics and common drug-drug interactions of the third-generation antiepileptic drugs. AB - INTRODUCTION: Anticonvulsants that belong to the third generation are considered as 'newer' antiepileptic drugs, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam, rufinamide and stiripentol. Areas covered: This article reviews pharmacodynamics (i.e. mechanisms of action) and clinically relevant drug drug interactions of the third-generation antiepileptic drugs. Expert opinion: Newer antiepileptic drugs have mechanisms of action which are not shared with the first and the second generation anticonvulsants, like inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation. New mechanisms of action increase chances of controlling forms of epilepsy resistant to older anticonvulsants. Important advantage of the third-generation anticonvulsants could be their little propensity for interactions with both antiepileptic and other drugs observed until now, making prescribing much easier and safer. However, this may change with new studies specifically designed to discover drug-drug interactions. Although the third-generation antiepileptic drugs enlarged therapeutic palette against epilepsy, 20-30% of patients with epilepsy is still treatment-resistant and need new pharmacological approach. There is great need to explore all molecular targets that may directly or indirectly be involved in generation of seizures, so a number of candidate compounds for even newer anticonvulsants could be generated. PMID- 29268033 TI - The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration. AB - Although the pathogenesis of Parkinson's disease (PD) remains unclear, mutations in leucine-rich repeat kinase 2 (Lrrk2) are among the major causes of familial PD. Most of these mutations disrupt Lrrk2 kinase and (or) GTPase domain function, resulting in neuronal degeneration. However, the signal pathways underlying Lrrk2 induced neuronal degeneration are not fully understood. There is an expanding body of evidence that suggests a link between Lrrk2 function and MAP kinase (MAPK) cascades. To further investigate this link in vivo, genetic RNAi screens of the MAPK pathways were performed in a Drosophila model to identify genetic modifier(s) that can suppress G2019S-Lrrk2-induced PD-like phenotypes. The results revealed that the knockdown of hemipterous (hep, or JNKK) increased fly survival time, improved locomotor function, and reduced loss of dopaminergic neurons in G2019S-Lrrk2 transgenic flies. Expression of the dominant-negative allele of JNK (JNK-DN), a kinase that is downstream of hep in G2019S-Lrrk2 transgenic flies, elicited a similar effect. Moreover, treatment with the JNK inhibitor SP600125 partially reversed the G2019S-Lrrk2-induced loss of dopaminergic neurons. These results indicate that the hep pathway plays an important role in Lrrk2-linked Parkinsonism in flies. These studies provide new insights into the molecular mechanisms underlying Lrrk2-linked PD pathogenesis and aid in identifying potential therapeutic targets. PMID- 29268034 TI - Genome-wide searches and molecular analyses highlight the unique evolutionary path of flavone synthase I (FNSI) in Apiaceae. AB - Flavone synthase is a key enzyme for flavone biosynthesis and is encoded by two gene families: flavone synthase I (FNSI) and flavone synthase II (FNSII). FNSII is widely distributed in plants, while FNSI has been reported in rice (Oryza sativa) and seven species of Apiaceae. FNSI has likely evolved from the duplication of flavanone 3beta-hydroxylase (F3H). In this study, we used multiple bioinformatics tools to identify putative FNSI and F3H genes from 42 publicly available genome and transcriptome datasets. Results showed that rice FNSI does not share a common ancestral sequence with other known FNSI genes and that FNSI is absent from species outside of Apiaceae. Positive selection site identification analysis revealed that four sites within the FNSI tree branches of Apiaceae evolved under significant positive selection. The putative F3H genes identified in this study provide a valuable resource for further function analysis of flavone synthase. PMID- 29268035 TI - Safety and efficacy of long-term treatment with teneligliptin: Interim analysis of a post-marketing surveillance of more than 10,000 Japanese patients with type 2 diabetes mellitus. AB - BACKGROUND: This post-marketing surveillance examined the safety and efficacy of long-term teneligliptin therapy in Japanese patients. RESEARCH DESIGN AND METHODS: We report interim results (cut-off date: 28 June 2017) of a 3-year PMS undertaken in subjects with type 2 diabetes mellitus (T2DM). Survey items included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. A subgroup analysis was also performed across three age groups (<65 years; 65 to <75 years; >=75 years). Main outcome measures were incidence of ADRs, laboratory variables, and change in glycated hemoglobin (HbA1c) from baseline over time. RESULTS: Of 11,677 patients registered, data from 10,532 patients (6,338 males/4,194 females) were analyzed for the safety analysis set; the median administration period was 731 days. Overall, ADRs and serious ADRs were reported in 364 (3.46%) and 91 patients (0.86%), respectively. The most common ADRs were all hypoglycemia (0.32%), constipation (0.27%), and hepatic function abnormal (0.24%). No change in mean body weight occurred, and a reduction in mean HbA1c was observed until 2 years. The safety and efficacy profiles did not differ markedly among the three age groups. CONCLUSIONS: These interim results show that teneligliptin was well tolerated and improved hyperglycemia in Japanese patients with T2DM in clinical practice. PMID- 29268036 TI - Nitric Oxide-Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease. AB - Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling. PMID- 29268037 TI - The Efficacy of Platelet-Rich Plasma on Tendon and Ligament Healing: A Systematic Review and Meta-analysis With Bias Assessment. AB - BACKGROUND: There has been a surge in high-level studies investigating platelet rich plasma (PRP) for tendon and ligament injuries. A number of meta-analyses have been published, but few studies have focused exclusively on tendon and ligament injuries. PURPOSE: To perform a meta-analysis assessing the ability of PRP to reduce pain in patients with tendon and ligament injuries. STUDY DESIGN: Systematic review and meta-analysis. METHODS: This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search of the literature was carried out in April 2017 using electronic databases PubMed, MEDLINE, and the Cochrane Library. Only level 1 studies were included. Platelet and leukocyte count, injection volume, kit used, participant age/sex, comparator, and activating agent used were recorded. The short-term and long-term efficacy of PRP was assessed using the visual analog scale (VAS) to measure pain intensity. Injury subgroups (rotator cuff, tendinopathy, anterior cruciate ligament, and lateral epicondylitis) were evaluated. Funnel plots and the Egger test were used to screen for publication bias, and sensitivity analysis was performed to evaluate the effect of potential outliers by removing studies one at a time. RESULTS: Thirty-seven articles were included in this review, 21 (1031 participants) of which could be included in the quantitative analysis. The majority of studies published investigated rotator cuff injuries (38.1%) or lateral epicondylitis (38.1%). Seventeen studies (844 participants) reported short-term VAS data, and 14 studies (771 participants) reported long-term VAS data. Overall, long-term follow-up results showed significantly less pain in the PRP group compared with the control group (weighted mean difference [WMD], -0.84; 95% CI, -1.23 to -0.44; P < .01). Patients treated with PRP for rotator cuff injuries (WMD, -0.53; 95% CI, -0.98 to -0.09; P = .02) and lateral epicondylitis (WMD, -1.39; 95% CI, -2.49 to -0.29; P = .01) reported significantly less pain in the long term. Substantial heterogeneity was reported at baseline ( I2 = 72.0%; P < .01), short-term follow up ( I2 = 72.5%; P < .01), long-term follow-up ( I2 = 76.1%; P < .01), and overall ( I2 = 75.8%; P < .01). The funnel plot appeared to be asymmetric, with some missingness at the lower right portion of the plot suggesting possible publication bias. CONCLUSION: This review shows that PRP may reduce pain associated with lateral epicondylitis and rotator cuff injuries. PMID- 29268038 TI - The Winged Scapula. AB - In brief Winging of the scapula most brief commonly results when trauma or overuse injures the long thoracic nerve. However, as these two case studies illustrate, the diagnosis might not be initially obvious, and the etiology can be overlooked. Scapular winging may have an unusual cause. Thus, when the mechanism of injury is not clear, a careful workup is particularly critical. Although most cases of long thoracic neuropathy resolve with conservative treatment, surgery is sometimes needed. Most active individuals can return to full activity. PMID- 29268039 TI - Emergency Removal of Football Helmets. AB - In brief when a football player has a brief suspected head or neck injury, when and how to remove the football helmet become critical issues. Protocols differ; however, the National Collegiate Athletic Association guidelines, which state that the helmet should only be removed on the field under very special circumstances, are appropriate. An understanding of the technologically advanced design and tight fit of modern football helmets will help guide medical personnel through each step of the helmet removal process. PMID- 29268040 TI - Getting Rid of a Pain in the Neck. PMID- 29268042 TI - Patient Adviser. PMID- 29268041 TI - Medicolegal Challenges of Advising At-Risk Patients. AB - In brief The case of a talented baseball pitcher who has Marfan's syndrome sets the stage for an examination of the medicolegal issues posed by athletes at risk for sudden death. The medical literature is somewhat unclear whether sports participation is unsafe for all individuals with Marfan's syndrome. Legal precedent has established guidelines on the "right to participate" and on informed consent. For medical and legal reasons, physicians need to establish appropriate risk management and informed consent procedures. PMID- 29268043 TI - Forum. PMID- 29268044 TI - A Stretching Primer. PMID- 29268045 TI - What's Brewing With Caffeine? PMID- 29268046 TI - Sports Injury Look-Alikes. AB - In brief Sports medicine physicians see brief overuse, chronic, or recurrent injuries in athletes every day. However, some patients who have symptoms consistent with these injuries actually have underlying disease. Three case studies examine athletes who initially seemed to have overuse syndromes or recurrent chronic injuries. The eventual diagnoses were rheumatoid arthritis, systemic lupus erythematosus, and gout. PMID- 29268047 TI - Coming Soon: SPORTSMEDICINE on Disk. PMID- 29268049 TI - QuikQuiz. PMID- 29268048 TI - How to Manage Herpes in Active Patients. AB - Oral herpetic lesions are painful, disfiguring, and highly contagious. The key for physicians is recognizing these lesions and helping patients minimize the risk of transmission and recurring infections. Active patients, especially those in contact sports, should know how to treat recurrent infections as soon as they feel prodromes. PMID- 29268052 TI - Scanning Sports. PMID- 29268050 TI - Pearls. PMID- 29268053 TI - Factors associated with colostrum quality in individual cows from dairy herds in the Waikato region of New Zealand. AB - AIMS: To examine associations between various cow-level factors and quality of first-milking colostrum (measured as Brix), and to evaluate herd-level associations between vaccination against calf diarrhoea and colostrum quality, in cows from dairy herds in the Waikato region of New Zealand. METHODS: A single colostrum sample was collected, by complete udder evacuation, from each of 20 cows from 29 dairy herds in the Waikato region of New Zealand during the 2016 spring calving period. Vaccination pre-partum with a calf diarrhoea vaccine was used in 15 herds. Each colostrum sample was tested using a digital Brix refractometer. The body condition score of each cow was recorded at the time of sample collection and farmers provided records of clinical mastitis and facial eczema from the previous 12 months, as well as the age and breed of cows. Associations between cow-level variables in non-vaccinated herds and Brix were examined using a multivariable linear mixed model and estimated marginal means obtained for different categories. RESULTS: Mean Brix of 281 samples from cows in non-vaccinated herds was 18.7 (SD 0.26)%; 63/281 (22.4%) samples had Brix >=22% and 152/281 (54.1%) had Brix >=18%. Mean Brix of colostrum samples from cows aged >=6 years (20.2 (95% CI=19.1-21.2)%) was higher than for samples from 2-year-old cows (18.6 (95% CI=17.3-19.9)%) (p=0.005). Colostrum that was collected at the first milking on the day of calving had higher Brix (20.0 (95% CI=19.1-20.9)%) than colostrum collected from cows that calved the previous day (17.5 (95% CI=16.5-18.4)%) (p<0.001). Mean Brix of colostrum samples from cows which produced >=8 L (18.2 (95% CI=17.1-19.2)%) tended to be lower than from cows which produced <8 L first-milking colostrum (19.1 (95% CI=18.3-20.0)%) (p=0.08). Among vaccinating herds, 9/15 (60%) had >=60% colostrum samples with Brix >=18% compared with 4/14 (29%) of non-vaccinating herds (p=0.04). CONCLUSIONS AND CLINICAL RELEVANCE: Colostrum quality, as measured by Brix, was associated with the total volume of first-milking colostrum, interval from calving to colostrum collection and cow age. Vaccination against calf diarrhoea was associated with a higher proportion of colostrum samples with adequate Brix. Careful selection of colostrum donor cows should ensure newborn calves are fed adequate quality colostrum which should be beneficial in preventing failure of passive transfer of IgG. Testing of colostrum from individual cows with a Brix refractometer is advocated for the selection of colostrum for feeding newborn calves. PMID- 29268054 TI - Pharmacological management of cystic fibrosis related diabetes. AB - INTRODUCTION: There are limited data from randomized clinical trials to guide optimal options for pharmacological treatment of cystic fibrosis related diabetes (CFRD). Current guidelines recommend insulin as the only treatment option for CFRD. Areas covered: Current guidelines for screening, diagnosis and pharmacological agents for treatment of impaired glucose tolerance and CFRD in patients with cystic fibrosis are reviewed. Insights from clinical studies examining the role of insulin therapy in CFRD are presented. Expert commentary: CFRD is the most common extra pulmonary complication of cystic fibrosis, and is primarily related to insulin insufficiency. Insulin is the treatment of choice for CFRD. Insulin treatment is associated with improvement in glycemic control, nutritional status and lung function. Current data does not support use of oral hypoglycemic agents for treatment of CFRD. PMID- 29268055 TI - Continuous 900-megahertz electromagnetic field applied in middle and late adolescence causes qualitative and quantitative changes in the ovarian morphology, tissue and blood biochemistry of the rat. AB - PURPOSE: The purpose of this study was to use histological and biochemical methods in order to evaluate changes taking place in the ovarian of rats exposed to the effect of a 900-megahertz (MHz) electromagnetic field (EMF) in middle and late adolescence. MATERIALS AND METHODS: Twenty-four 34-d-old female Sprague Dawley rats were assigned equally to control, sham and EMF groups. EMF group rats were exposed to the effect of a 900-MHz EMF for 1 h a day, at the same time every day between postnatal days 35 and 59, while inside an EMF cage. Sham group rats were kept inside the EMF cage for the same time between postnatal days 35 and 59 without being exposed to any EMF effect. At the end of the study, rats' ovarian were removed and blood specimens were taken. Right ovarium tissues were subjected to routine histological procedures and stained with hematoxylin and eosin, periodic acid shift and Masson's trichrome. Follicles were counted in ovarian sections stained with hematoxylin and eosin. The TUNEL method was used to evaluate apoptosis. Left ovarian tissue and blood specimens were investigated biochemically. RESULTS: Histopathological examination of EMF group ovarian tissue revealed thinning in the zona granulosa and theca layers, shrinking in granulosa cells, reduced mitotic activity and leukocyte infiltration in the follicles and stroma. Secondary follicle numbers in the EMF group were significantly lower than in the other groups. In terms of biochemistry, EMF and sham group superoxide dismutase, catalase and anti-Mullerian hormone levels and EMF group 3 nitrotyrosine values increased significantly compared to the control group. EMF and sham group serum catalase and 8-hydroxy-deoxiguanosine values increased significantly compared to the control group, and EMF group total oxidant status and oxidative stress index values were significantly higher compared to the sham and control groups. CONCLUSIONS: A total of 900-MHz EMF applied in middle and late adolescence may cause changes in the morphology and biochemistry of the rat ovarium. PMID- 29268056 TI - Radioprotective effect of atorvastatin against ionizing radiation-induced nephrotoxicity in mice. AB - PURPOSE: Kidneys are exposed to ionizing radiation during radiotherapy in patients with abdominal malignancy. The aim of this study is to investigate the protective effect of atorvastatin (ATV) against ionizing radiation-induced nephrotoxicity in mice. MATERIALS AND METHODS: Sixty male BALB/c mice were randomly divided into six groups (10 mice per group); control, irradiation (IR), IR plus ATV (10, 20 and 50 mg/kg) and only ATV (50 mg/kg). ATV groups received ATV for seven days via oral gavage before exposure to IR. Animals were exposed to 2 Gy whole body of X-ray on day 8. After exposure to IR, biochemical, histological and immunohistological assays were performed. RESULTS: ATV significantly decreased the level of oxidative stress biomarkers in irradiated mice in comparison with IR alone. A significant reduction in the urea and creatinine levels was observed in ATV plus IR group compared to IR alone. Tubular degeneration, glomerular atrophy, interstitial expansion and fibrosis were observed in irradiated mice. Tubular degeneration and atrophy in the kidneys of IR plus ATV group were less than IR group. In addition, pre-treated animal with ATV significantly showed reduction in caspase-3 immunoreactivity. CONCLUSION: ATV has significant protective effect against radiation-induced nephrotoxicity in mice and is a promising medication for protection of patients during radiotherapy. PMID- 29268057 TI - [Fresh Wind at Acta Medica Portuguesa]. PMID- 29268058 TI - Atopic Dermatitis: The New Therapeutic Revolution in Dermatology. PMID- 29268059 TI - [Analysis of the Cochrane Review: Omega-3 Fatty Acids for the Treatment of Dementia. Cochrane Database Syst Rev. 2016;4:CD009002.] AB - Dietary supplementation with omega-3 polyunsaturated fatty acids from fish and plant sources is commonly prescribed as a non-farmacological alternative to improve brain functions and slow down the progression of dementia. This use is mostly based on findings of preclinical studies which established the role of omega-3 polyunsaturated fatty acids in the development and integrity of the brain, as well as epidemiological research that found evidence of malnutrition in patients with dementia. This Cochrane systematic review included three randomized, placebo-controlled trials at low risk of bias, in which omega-3 polyunsaturated fatty acids were administered to people with mild to moderate Alzheimer's disease in the form of supplements. Of the main results of this systematic review we highlight the lack of convincing evidence for the efficacy of omega-3 polyunsaturated fatty acids supplementation in the treatment of patients with Alzheimer's disease, as well as the low frequency of reported adverse events, with a comparable overall frequency between omega-3 polyunsaturated fatty acids and the placebo groups. The effects on other populations with dementia remain unclear. This paper aims to summarize and discuss the main results and conclusions of this systematic review, as well as its implications for the daily clinical practice. PMID- 29268060 TI - [In the Child's Best Interest: The Contribution of Child and Adolescent Psychiatry]. AB - INTRODUCTION: Child and Adolescent Forensic Psychiatry involves a multidisciplinary assessment at the courts' requested to assist them in the process of justice delivery. MATERIAL AND METHODS: Retrospective study which included 233 forensic requests to two child and adolescent psychiatrists from Coimbra's HP-CHUC Child and Adolescent Psychiatry Department between 1998 and 2012. RESULTS: Biographic, psychopathology, social and family aspects were analyzed. The response time throughout the process, the origin and nature of the request's and the type of process which originated the request were also assessed. The authors identified the involved professionals and whether they needed to go to court. When there were questions, they evaluated the capacity to answer them, the forensic difficulties and solutions found, and the presence of recommendations. DISCUSSION: The obtained results met the clinical experience and literature regarding demography and psychopathology. As for the difficulties, there were a number of aspects which could be improved by both parts, aiming to ameliorate the articulation between Health and Justice. CONCLUSION: With this study it was possible to reflect on the authors forensic practice, in order to develop a closer partnership with the courts to promote the real 'best interests' of children/adolescents and their families. PMID- 29268061 TI - [Pain Management, Local Infection, Satisfaction, Adverse Effects and Residual Pain after Major Open Abdominal Surgery: Epidural versus Continuous Wound Infusion (PAMA Trial)]. AB - INTRODUCTION: The Management of postoperative pain after abdominal surgery is a major challenge to the anesthesiologist. The optimization of postoperative analgesia improves prognosis contributing also to patient satisfaction and reducing morbidity and mortality. The aim of this randomized control study is to perform the comparative analysis in terms of effectiveness of an unconventional and still poorly technique implemented, continuous wound infusion, and the currently most applied and gold standard technique, epidural analgesia, in the postoperative period after abdominal surgery. MATERIAL AND METHODS: Fifty patients, previously subjected to abdominal surgery by median laparotomy with xifo-pubic incision were randomized to receive postoperative analgesia via epidural (n = 25) or via continuous wound infusion (n = 25) during 48 hours. The primary outcome was analysis of pain at rest (< 4/10 numerical pain scale) after 24 hours postoperatively. Scores of pain at six, 12 and 48 hours and three months after surgery were also evaluated, as well as the incidence of adverse effects 48 hours postoperatively. RESULTS: The proportion of patients with successful control of postoperative pain was 84% against 60% with epidural analgesia and continuous wound infusion, respectively. Within the continuous wound infusion group with uncontrolled pain, all patients rated the pain below 6/10 24 hours postoperatively. The incidence of nausea, vomiting, pruritus or ileus was lower in the continuous wound infusion group, with statistically significant results for recovery of intestinal function. There was one case of systemic local anesthetic toxicity with an episode of frequent ventricular extrasystoles without hemodynamic instability, which ceased after suspension of continuous epidural infusion of local anesthetic. DISCUSSION: This study suggests that continuous wound infusion is the technique with most efficacy and safety, being even better than epidural analgesia in postoperative pain control after major abdominal surgery. This technique is associated with better analgesia, lower incidence of side effects, high level of satisfaction and no residual pain, contributing to enhanced recovery. CONCLUSION: Continuous wound infusion is an effective technique, which should be implemented for analgesia after major abdominal surgery, with advantages when compared with epidural analgesia, especially low incidence of adverse effects. Registration: Trial not registered. PMID- 29268062 TI - Reliability, Stability and Validity of the Brazilian Adaptation of the Oliveira Questionnaire on Low Back Pain in Young People. AB - INTRODUCTION: The objective of this study was to adapt the Brazilian version, and verify the validity, reliability and internal consistency of the Oliveira questionnaire on low back pain in young people. MATERIAL AND METHODS: The questionnaire was translated from European Portuguese into Brazilian Portuguese by means of translation and re-translation. The validity of the contents was determined by experts who analyzed the clarity and pertinence of the questions. Fifteen young people aged 15 to 18 took part in the pre-test step (qualitative analysis), 40 in the test-retest (reliability) and 679 in the evaluation of internal consistency. The intra-class correlation coefficient and Spearman's correlation coefficient were used in the reliability analysis (test-retest), and Cronbach's alpha to determine the internal consistency (stability). RESULTS: In the translation phase the questionnaire was modified and considered suitable, observing similarity and equivalence of the two versions. After being corrected by the experts in the validation of the contents, the instrument was considered suitable and valid, and in the pre-test, the young people suggested some modifications to make the questionnaire more succinct. With respect to reliability, the values for the intra-class correlation coefficient were between 0.512 - acceptable and 1 - excellent and Spearman's correlation coefficient varied between 0.525 and 1, classifying the instrument as reproducible. The internal consistency was considered acceptable with a 0.757 Cronbach's alpha. DISCUSSION: The Oliveira questionnaire was choosen since it has been used in several Portuguese studies; moreover, it addresses the need to raise data regarding low back pain and associated risk factors. CONCLUSIONS: The Brazilian version of the Oliveira questionnaire on low back pain in young people showed valid and reliable cultural adaptation, with good reliability and stability. PMID- 29268063 TI - Medical Training Experience and Expectations Regarding Future Medical Practice of Medical Students at the University of Cape Verde. AB - INTRODUCTION: Cape Verde is a small insular developing state. Its first experience of undergraduate medical education began in October 2015. The purpose of this paper is to describe and analyze the professional expectations and profile of the first class of medical students at the University of Cape Verde. MATERIAL AND METHODS: A piloted, standardized questionnaire, with closed and open ended questions, was distributed to registered medical students attending classes on the day of the survey. All data were analyzed using SPSS. RESULTS: Students decided to study medicine in their mid-teens with relatives and friends having had significant influence over their decisions. Other major reasons for choosing medical training include "to take care of other people", "fascination for the subject matters of medicine" and "I have always wanted to". The degree of feminization of the student population is extremely high (20/25; 80.0%). Medical students are in general satisfied with the training program, and have expectations that the training received will allow them to be good professionals. Nevertheless, they consider the course too theoretical. Medical students know that this represents an opportunity for them to contribute to public welfare. Nonetheless, their expectations are to combine public sector practice with private work. Medical students come mostly from Santiago Island where the Capital of the Country is located. They still do not know about their future area of specialization. But all of those who want to specialize want to do so abroad. They mostly expect to follow hospital careers rather than health administration or family and community medicine. DISCUSSION: This study contributes to the growing body of knowledge about medical students' difficulties and expectations regarding medical schools or curriculums in lusophone countries. The decision to invest in the training of local physicians is justified by the need to be less dependent on foreigners. Local postgraduate medical training programs are already considered a priority for the immediate future. CONCLUSION: Cape Verde is pursuing a bold strategy to deal with a shortage of medical doctors. The problems experienced by medical students provide an important insight to help the new medical school to provide a better learning environment for students. The fact that students are not sure about their future area of specialization is an opportunity to guide them towards the areas of the health system with pressing needs. The current feminization of the medical workforce will be sustained with the profile of the present intake, hence the need to take this into account in workforce planning. PMID- 29268064 TI - [The Experience of a Protocol for the Management of Pediatric Minor Head Injury: A Three Years Longitudinal Study]. AB - INTRODUCTION: Head injury is common in children, with mostly being minor and not resulting in intracranial injury. Computerized tomography head scan is the preferred exam, but implies exposure to radiation; the indications for computerized tomography head scan in minor injuries are not consensual. An expectant approach is a good option in most cases. The aim was to compare the patients hospitalized and subjected to computerized tomography head scan with patients hospitalized but not subjected to computerized tomography head scan in order to assess the safety of our institution's practice protocol. MATERIAL AND METHODS: Analytical longitudinal retrospective study, during three years, including patients younger than 15 years of age with minor head injury, admitted for in hospital surveillance through a paediatric emergency room. We defined two study groups: group A (hospitalized with computerized tomography head scan) and group B (hospitalized without computerized tomography head scan). RESULTS: Study sample consisting of 206 patients: 81 (39%) group A and 125 (61%) group B. Symptoms, including vomiting, were more frequent in group B (91% and 61% vs 75% and 35%, p < 0.05); large scalp hematoma and palpable fracture in group A (11% and 12% vs 0%, p < 0.05). We performed computerized tomography head scan in 39% of the study patients (children with red flags in the physical examination or unfavourable course during hospitalization); 43% had traumatic brain injury (29 patients had fracture, 18 patients had intracranial injury). Three patients underwent neurosurgery. We did not register deaths, readmissions or neurologic sequelae. DISCUSSION: Significant intracranial injury was infrequent. The hospitalization and surveillance of children and adolescents with symptomatic minor head injury, without red flags in the physical examination, did not seem to result in additional risks. CONCLUSION: The careful selection of patients for computerized tomography head scan enabled a decrease in the number of these exams and the exposure to ionizing radiation. PMID- 29268065 TI - [Stapedo-Vestibular Ankylosis: Retrospective Study of Five Cases in Sao Tome e Principe]. AB - INTRODUCTION: Otosclerosis is a common form of conductive hearing loss characterized by abnormal bone remodeling exclusively in the otic capsule. The prevalence of otosclerosis varies in racial populations and is described as being rare in black African populations. In this paper we aim to report five cases of clinical, and surgically confirmed, otosclerosis in black individuals, in Sao Tome and Principe. MATERIAL AND METHODS: Since February 2011, Ear, Nose and Throat consultations and surgeries specialty have been carried out at Dr. Ayres de Menezes Hospital in cooperation with the project 'Health for all'. A retrospective analysis was undertaken of the records of all patients subjected either to stapedectomy or partial stapedectomy until February 2014. Information regarding clinical presentation, audiometric data and surgery reports was recorded. RESULTS: Five adult patients underwent stapedectomy or partial stapedectomy. All of them presented with normal otoscopy, conductive or mixed hearing loss on audiogram and normal tympanometry with absent stapedial reflexes. None of the patients had signs of infection or history of head trauma. Three cases showed improvement in the air-bone gap after surgery. The other two were lost to follow-up. DISCUSSION: We documented and surgically confirmed five cases of clinical otosclerosis in this population. A thematic review was carried out and concluded that, despite being described as a rare event in this race, available literature on this topic is not enough to state that there is lower prevalence of otosclerosis amongst the African population. CONCLUSION: Even if not common, otosclerosis cannot be disregarded as a possible cause for conductive hearing loss among the population of Sao Tome and Principe. PMID- 29268066 TI - [Vitamin B12 Deficiency in Type 2 Diabetes Mellitus]. AB - INTRODUCTION: Type 2 diabetes mellitus is a common disease, affecting up to 13.1% of the Portuguese population. In addition to the known micro and macrovascular complications, drug side effects constitute a major concern, leading to changes in the treatment guidelines, which favor safety over efficacy. Metformin is the first-line pharmacological treatment for most patients with type 2 diabetes mellitus; however, it has been associated with vitamin B12 deficiency in up to 30% of treated patients. The authors describe the prevalence of vitamin B12 deficiency in a diabetic population and explore the possible underlying factors. MATERIAL AND METHODS: Retrospective, observational study. Clinical and laboratory data of type 2 diabetes mellitus patients whose vitamin B12 status was evaluated in the last decade (2005 - 2016) were analyzed. Patients with known malabsorptive syndromes or having undergone bariatric surgery were excluded from the study. Statistical analysis of the data was done and the results were considered statistically significant at p values < 0.05. RESULTS: The study included a total of 1007 patients (58% women) with a mean age of 66.4 +/- 12.2 years and 11 +/- 10.4 years of type 2 diabetes mellitus duration. These patients had a high prevalence of complications: diabetic renal disease 47.7%, neuropathy 9.2%, retinopathy 14.9%, coronary artery disease 8.4%, cerebrovascular disease 10.9%, and peripheral arterial disease 5.5%. Vitamin B12 deficiency (< 174 ng / dL) was present in 21.4% of the population and this subgroup was older (68.4 vs 65.8 years, p = 0.006), had a longer type 2 diabetes mellitus duration (13.35 vs 10.36 years; p = 0.001), higher prevalence of retinopathy (20.9% vs 13.3%; p = 0.005) and thyroid dysfunction (34% vs 23.7%; p = 0.002). Vitamin B12 deficiency was also more frequent in patients treated with metformin (24.7% vs 15.8%; p = 0.017), antiplatelet agents (25.4% vs 16.2%, p < 0.001), and calcium channel blockers (26.8% vs 18.2%; p = 0.001). After adjustment for possible confounders, the variables associated with B12 deficiency were: metformin, hypothyroidism, age and type 2 diabetes mellitus duration. DISCUSSION: Despite the retrospective design, the results report a high prevalence of vitamin B12 deficiency in the type 2 diabetic population. This study also demonstrates that the B12 deficiency risk is higher in older people, with longer diabetes mellitus duration, hypothyroidism and treated with metformin. CONCLUSION: Further studies are needed to identify the risk factors for the B12 deficit. The recognition of these variables will contribute to optimize the screening and prevention of the B12 deficiency in type 2 diabetes mellitus. PMID- 29268067 TI - Partial Red Blood Cell Exchange in Children and Young Patients with Sickle Cell Disease: Manual Versus Automated Procedure. AB - INTRODUCTION: The benefits of manual versus automated red blood cell exchange have rarely been documented and studies in young sickle cell disease patients are scarce. We aim to describe and compare our experience in these two procedures. MATERIAL AND METHODS: Young patients (<= 21 years old) who underwent manual- or automated-red blood cell exchange for prevention or treatment of sickle cell disease complications were included. Clinical, technical and hematological data were prospectively recorded and analyzed. RESULTS: Ninety-four red blood cell exchange sessions were performed over a period of 68 months, including 57 manual and 37 automated, 63 for chronic complications prevention, 30 for acute complications and one in the pre-operative setting. Mean decrease in sickle hemoglobin levels was higher in automated-red blood cell exchange (p < 0.001) and permitted a higher sickle hemoglobin level decrease per volume removed (p < 0.001), while hemoglobin and hematocrit remained stable. Ferritin levels on chronic patients decreased 54%. Most frequent concern was catheter outflow obstruction on manual-red blood cell exchange and access alarm on automated-red blood cell exchange. No major complication or alloimunization was recorded. DISCUSSION: Automated-red blood cell exchange decreased sickle hemoglobin levels more efficiently than manual procedure in the setting of acute and chronic complications of sickle cell disease, with minor technical concerns mainly due to vascular access. The threshold of sickle hemoglobin should be individualized for clinical and hematological goals. In our cohort of young patients, the need for an acceptable venous access was a limiting factor, but iron-overload was avoided. CONCLUSION: Automated red blood cell exchange is safe and well tolerated. It permits a higher sickle hemoglobin removal efficacy, better volume status control and iron-overload avoidance. PMID- 29268068 TI - Building a Maternal and Newborn Care Training Programme for Health-Care Professionals in Guinea-Bissau. AB - INTRODUCTION: The Integrated Programme of Maternal and Child Health aims to reduce maternal and child mortality in Guinea-Bissau. The purpose of this article is to share our experience in building a training programme on maternal and newborn care for health-care professionals in Guinea-Bissau. MATERIAL AND METHODS: Regional directors of the four target areas chose a group of staff who provide prenatal and childbirth care to attend the course (12 to 15 trainees per region). In each region, 15 highly interactive and practical sessions were scheduled over eight weeks. The trainees' summative and reactive assessment was obtained using a multiple choice questionnaire (final test) and an anonymous survey, respectively. RESULTS: Attendees included 25 nurses, 17 midwives and 14 doctors. About two thirds had five years' practice or less. Test median scores were higher among trainees with two to nine years of practice (54.4% to 60.9%), as compared to those with a year or less (47.8%) or 10 or more years (45.7%). Pedagogical variables were rated as 'good' or 'very good' by 91% to 95% of the attendees. DISCUSSION: Use of an interactive and practical pedagogical methodology produced positive results and was crucial to tailoring the training to local needs. However, adapting the syllabus according to professional categories and experiences should be considered. CONCLUSION: Our results warrant further development and evaluation of training programmes on maternal and neonatal care in Guinea-Bissau. PMID- 29268069 TI - [Premature Atherosclerosis in HIV-Infected Pediatric Patients: Literature Review and Clinical Approach]. AB - Human immunodeficiency virus infected children and adolescents are a pediatric group with increased risk of premature cardiovascular disease. The virus itself, the antiretroviral therapy and the lifestyle establish a complex interplay of factors that promotes an accelerated atherosclerosis. This process is probably mediated by dyslipidaemia, dysregulation of glucose metabolism, lipodystrophy, inflammation, endothelial dysfunction and a prothrombotic state. The clinical approach to this population in terms of cardiovascular prevention is mainly based on efficient treatment of the infection, reduction of the modifiable risk factors and promotion of lifestyle changes. PMID- 29268070 TI - Hepatic Angiosarcoma Masquerading as Hemangioma: A Challenging Differential Diagnosis. AB - Hemangiomas are usually diagnosed based on ultrasound findings. The presence of symptoms, rapid growth or atipical imagiological findings should make us consider other diagnoses, including malignant tumors such as angiosarcomas. We describe the case of a previously healthy 46-year-old female without a history of exposure to carcinogens who presented with abdominal pain for two months. Diagnostic work up revealed elevated gamma-glutamyl transferase and lactate dehydrogenase levels. Abdominal ultrasound described a large nodular lesion in the right lobe of the liver described as a hemangioma. One month later, a computed tomography-scan was made and revealed the same lesion, which had grown from 13.5 to 20 cm, maintaining typical imaging characteristics of a hemangioma. A right hepatectomy was performed and pathology revealed an angiosarcoma. After surgery, a positron emission tomography-computed tomography scan showed hepatic and bone metastasis. The patient started taxane-based chemotherapy and lumbar palliative radiotherapy, but died 10 months after surgery. This case shows how difficult it is to diagnose hepatic angiosarcoma relying only on imaging findings. Two abdominal computed tomography -scans were performed and none suggested this diagnosis. Angiosarcoma is a very aggressive tumour with an adverse prognosis. Surgery is the only curative treatment available. However, it is rarely feasible due to unresectable disease or distant metastasis. PMID- 29268071 TI - Methemoglobinemia After Paracetamol Ingestion: A Case Report. AB - Methemoglobinemia is a potentially fatal condition, mainly acquired after intoxication by certain drugs. To this date, only three cases associated with paracetamol have been reported. This case report describes a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis who was self medicated with acetaminophen for seven days (at a daily dose of 3 g); the patient went to the hospital after noticing the appearance of a diffuse brownish skin tone, without other symptoms. Arterial blood analysis revealed an increase in methemoglobin levels, with biochemistry showing an increase in total bilirubin and alanine aminotransferase. Paracetamol was discontinued and on reassessment nine days after the onset of symptoms the patient had a clear improvement in her skin color, with normalization of methemoglobin levels. PMID- 29268072 TI - Metastase Vulvar do Carcinoma de Celulas Escamosas do Colo do Utero. PMID- 29268073 TI - Sexual transmission of Zika virus: a literature review. AB - Zika virus is an emerging health threat worldwide. A member of the yellow fever virus family, it is primarily spread by mosquitoes of the Aedes (Stegomyia) genus. Unusually for a mosquito-borne virus, sexual spread has also been reported; with cases of male-to-female, female-to-male and male-to-male sexual transmission all now published in the scientific literature, in both symptomatic and asymptomatic infection. Female-to-female sexual transmission has not yet been reported, but is biologically plausible. The extent of the effect of sexual transmission on the spread of Zika virus around the world is not well characterised, but has particular relevance to travellers to and from non-endemic regions, and assisted reproduction services. PMID- 29268074 TI - Gay men's chemsex survival stories. AB - : Background Chemsex (the combined use of drugs and sexual experiences) by men who have sex with men is associated with the transmission of sexually transmissible infections and blood-borne viruses, but psychosocial factors associated with chemsex engagement and remission remain unidentified. In the present study we considered how do gay men self-identify a chemsex problem and remain chemsex free? METHODS: Using a life course perspective, the present qualitative interview study examined participants' reflections to discern pathways in and out of chemsex engagement. Six participants (aged >=18 years) were drawn from a cohort of men who had completed the tailored therapeutic Structured Weekend Antidote Program. Transcripts were analysed using a Labovian narrative analysis framework. RESULTS: Each man identified a multiplicity of incidents and feelings that contributed to their engagement in chemsex, and engagement in chemsex was connected to participants' identity development and desire to belong to a gay community. Underlying individual accounts, a common narrative suggested a process through which chemsex journeys were perceived as spiralling from exciting and self-exploratory incidents into an out-of-control, high-risk activity that was isolating and prompted engagement with therapy. Despite seeking therapeutic engagement, participants expressed uncertainty about maintaining a gay future without chemsex. CONCLUSIONS: Chemsex was associated with a positive gay identity gain, which explained the ambivalence participants expressed in maintaining a gay future without chemsex despite their awareness of negative consequences. This is significant for understanding both why chemsex pathways may prove attractive and why they may be so difficult to leave. PMID- 29268075 TI - Intensive sex partying with gamma-hydroxybutyrate: factors associated with using gamma-hydroxybutyrate for chemsex among Australian gay and bisexual men - results from the Flux Study. AB - : Background Gamma-hydroxybutyrate (GHB) use among gay and bisexual men (GBM) has increased in recent years. It is commonly cited as a sexual-enhancement drug. There is, however, little evidence for factors associated with GHB use or the consequences of its use among GBM. AIM: Factors associated with GHB use, its relationship to sexual risk behaviour, and the contexts, consequences, and motivations for its use were examined. METHODS: The Following Lives Undergoing Change (Flux) Study is an online prospective observational study of Australian GBM. At baseline, a total of 3190 GBM provided details about their use of GHB. Data on frequency, methods, pleasures and consequences of their drug use, alongside key demographic variables were collected. RESULTS: Mean age was 35.0 years. One in five men (19.5%) had a history of GHB use and 5.4% reported use within the past 6 months, with 2.7% having used it monthly or more frequently. Overdose had been experienced by 14.7%, this was more common among men who used GHB at least monthly. Being HIV-positive, having more gay friends, greater social engagement with gay men who use drugs, a greater number of sexual partners, group sex, and condomless anal intercourse with casual partners were independently associated with GHB use in the past 6 months. Greater social engagement with gay men who use drugs and group sex were independently associated with at least monthly use. More frequent GHB use was independently associated with experiencing overdose among GHB users. CONCLUSION: Most men used GHB infrequently and it was often used explicitly to enhance sexual experiences, often in the context of intensive sex partying. Men who used GHB frequently, were at greater risk of overdose and other negative health outcomes. GHB use should be considered alongside other drugs that have been implicated in sexual risk behaviour and HIV transmission. Harm-reduction interventions need to consider the particular impact of frequent GHB use. PMID- 29268076 TI - Crouzon Syndrome: A Case Series of Craniomaxillofacial Distraction Osteogenesis for Functional Rehabilitation. AB - Crouzon syndrome (CS) is the most common craniosynostosis syndrome and requires a comprehensive management strategy for the optimization of care and functional rehabilitation. This report presents a case series of 6 pediatric patients diagnosed with CS who were treated with distraction osteogenesis (DO) to treat serious functional issues involving severe orbital proptosis, an obstructed nasopharyngeal airway, and increased intracranial pressure (ICP). Three boy and 3 girls were 8 months to 6 years old at the time of the operation. The mean skeletal advancement was 16.1 mm (range, 10 to 27 mm) with a mean follow-up of 31.7 months (range, 13 to 48 months). Reasonable and successful outcomes were achieved in most patients as evidenced by adequate eye protection, absence of signs and symptoms of increased ICP, and tracheostomy tube decannulation except in 1 patient. Complications were difficult fixation of external stabilizing pins in the distraction device (n = 1) and related to surgery (n = 4). Although DO can be considered very technical and can have potentially serious complications, the technique produces favorable functional and clinical outcomes in treating severe CS. PMID- 29268077 TI - Big Data and the Big Questions Surrounding Vesicoureteral Reflux Management. PMID- 29268078 TI - Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease. AB - INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information. METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change. RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317. DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity. PMID- 29268080 TI - Strategies for identification of mutations induced by carbon-ion beam irradiation in Arabidopsis thaliana by whole genome re-sequencing. AB - Heavy-ion beam irradiation is a powerful physical mutagen that has been used to create numerous mutant materials in plants. These materials are an essential resource for functional genomics research in the post-genome era. The advent of Next-Generation Sequencing (NGS) technology has promoted the study of functional genomics and molecular breeding. A wealth of information can be gathered from whole genome re-sequencing; however, understanding the molecular mutation profile at genome wide, as well as identifying causal genes for a given phenotype are big challenging issues for researchers. The huge outputs created by NGS make it difficult to capture key information. It is worthy to explore an effective and efficient data-sieving strategy for mutation scanning at whole genome scale. Re sequencing data from one laboratory wild type (Columbia) and eleven M3Arabidopsis thaliana lines derived from carbon-ion beam irradiation were used in present study. Both the number and different combinations of samples used for analysis affected the sieving results. The result indicated that using six samples was sufficient to filter out the shared mutation (background interference) sites as well as to identify the true mutation sites in the whole genome. The final number of candidate mutation sites could be further narrowed down by combining traditional rough map-based cloning. Our results demonstrated the feasibility of a parallel sequencing analysis as an efficient tool for the identification of mutations induced by carbon-ion beam irradiation. For the first time, we presented different analysis strategies for handling massive parallel sequencing data sets to detect the mutations induced by carbon-ion beam irradiation in Arabidopsis thaliana with low false-positive rate, as well as to identify the causative nucleotide changes responsible for a mutant phenotype. PMID- 29268079 TI - Midlife cardiovascular health and 20-year cognitive decline: Atherosclerosis Risk in Communities Study results. AB - INTRODUCTION: The aim was to examine associations between midlife cardiovascular health (CVH) and 20-year cognitive decline among blacks and whites. METHODS: Midlife CVH metrics (American Heart Association's Life's Simple 7) were calculated and examined in relation to midlife and 20-year change in cognitive function among 13,270 whites and blacks from the Atherosclerosis Risk in Communities Cohort Study. We used linear mixed models to estimate adjusted associations of midlife CVH with midlife cognitive status and change. RESULTS: Higher midlife (Life's Simple 7) scores and individual metrics, particularly blood pressure and glucose, were associated with better midlife cognition and reduced 20-year decline. Midlife CVH 20-year neuroprotection was more pronounced among whites than blacks. DISCUSSION: Better midlife CVH was associated with higher midlife and reduced decline in cognitive function 20 years later. However, the benefits of midlife CVH on cognition were stronger for whites than for blacks. Our findings suggest that improved midlife CVH may promote enduring cognitive health. PMID- 29268081 TI - The unique two-component tail sheath of giant Pseudomonas phage PaBG. AB - Myoviridae bacteriophages have a special contractile tail machine that facilitates high viral infection efficiency. The major component of this machine is a tail sheath that contracts during infection, allowing delivery of viral DNA into the host cell. Tail sheaths of Myoviridae phages are composed of multiple copies of individual proteins. The giant Pseudomonas aeruginosa phage PaBG is notable in its possession of two tail sheath proteins. These tail sheath proteins are encoded by orf 76 and 204, which were cloned and expressed individually and together in Escherichia coli. We demonstrate that only co-expression of both genes results in efficient assembly of thermostable and proteolytically resistant polysheaths composed of gp76 and gp204 with approximately 1:1 stoichiometry. Both gp76 and gp204 have been identified as structural components of the virion particle. We conclude that during PaBG morphogenesis in vivo two proteins, gp76 and gp204, assemble the tail sheath. PMID- 29268082 TI - Localization to detergent-resistant membranes and HIV-1 core entry inhibition correlate with HIV-1 restriction by SERINC5. AB - SERINC5(S5) is a multi-span transmembrane protein that potently blocks the infectivity of HIV-1 produced by human T-cells. The ability of S5 to restrict infectivity correlates with its presence in the virion, but the exact mechanism by which S5 restricts HIV-1 is unknown. Here we tested whether the core from HIV 1 virions containing S5 is delivered to the cytoplasm. Using the "fate of the capsid" assay, we demonstrated that the viral core of S5-restricted HIV-1 does not reach the cytoplasm of target cells, suggesting a block in the delivery of the core to the cytoplasm. In agreement with evidence suggesting that the viral determinants for S5 restriction map to the envelope of HIV-1, we observed that S5 induces conformational changes to the HIV-1 envelope. Further, we demonstrated that S5 localizes to detergent-resistant membranes (DRMs), as has been shown previously for the HIV-1 envelope in producer cells. In order to identify the determinants of S5 restriction, we explored the ability of all human SERINC proteins to restrict HIV-1. In contrast to human S5, we observed that human SERINC2(S2) did not restrict HIV-1, and was inefficiently incorporated into HIV-1 virions when compared to S5. Experiments using S5-S2 chimeric proteins revealed two functional domains for restriction: one necessary for S5 incorporation into virions, which does not seem to be necessary for restriction, and a second one necessary to change the HIV-1 envelope conformation, localize to DRMs, and block infection. PMID- 29268083 TI - High rejection reverse osmosis membrane for removal of N-nitrosamines and their precursors. AB - Direct potable reuse is becoming a feasible option to cope with water shortages. It requires more stringent water quality assurance than indirect potable reuse. Thus, the development of a high-rejection reverse osmosis (RO) membrane for the removal of one of the most challenging chemicals in potable reuse - N nitrosodimethylamine (NDMA) - ensures further system confidence in reclaimed water quality. This study aimed to achieve over 90% removal of NDMA by modifying three commercial and one prototype RO membrane using heat treatment. Application of heat treatment to a prototype membrane resulted in a record high removal of 92% (1.1-log) of NDMA. Heat treatment reduced conductivity rejection and permeability, while secondary amines, selected as N-nitrosamine precursors, were still well rejected (>98%) regardless of RO membrane type. This study also demonstrated the highly stable separation performance of the heat-treated prototype membrane under conditions of varying feed temperature and permeate flux. Fouling propensity of the prototype membrane was lower than a commercial RO membrane. This study identified a need to develop highly selective RO membranes with high permeability to ensure the feasibility of using these membranes at full scale. PMID- 29268084 TI - Characterization of dissolved organic nitrogen in leachate from a newly established and fertilized turfgrass. AB - Understanding the mechanisms of nitrogen (N) retention and loss from fertilized urban turfgrass is critical to develop practices that mitigate N transport and protect water quality in urban ecosystems. We investigated the fate of N in lysimeters sodded with St. Augustine turfgrass and amended with labeled 15N from either ammonium sulfate or urea. Fourier transform ion cyclotron resonance mass spectroscopy (FTICR-MS) was employed to identify various biomolecular classes in the leached dissolved organic N (DON) from one lysimeter for each treatment and the control. Mean DON concentrations, over 92 days, were 88, 94, and 94% of total N in the leachate from the control, urea, and ammonium sulfate treatments, respectively. Isotopic analysis showed that <3% of N in the leachate originated from newly applied N fertilizer, suggesting that the remainder of the N in the leachate was derived from the lysimeter soil or sod biomass pools. The 15N fertilizer recovery was greatest in soil (44-48%), followed by sod+thatch (18 33%), grass clippings (10-13%), and leachate (<3%). Despite isotopic evidence of little contribution of N from fertilizers in the leachate, a fraction of ammonium sulfate fertilizer was recovered as DON in the leachate, likely after uptake and conversion of inorganic fertilizer to organic plant exudates and/or microbial byproducts. FTICR-MS identified N-bearing organic molecular formulas in the leachate from urea and ammonium sulfate treatments, providing evidence of N leaching from newly established turfgrass of DON compounds in a range of biomolecular compositions such as lipid-, protein-, carbohydrate-, and lignin like molecules. PMID- 29268085 TI - Expression of succinate dehydrogenase and fumarase genes in maize leaves is mediated by cryptochrome. AB - Blue light inhibits succinate dehydrogenase and fumarase enzyme activity and gene expression in green leaves of maize (Zea mays L.). Irradiation of maize plants by blue light resulted in the transient decrease of transcripts of genes Sdh1-2 and Sdh2-3 encoding correspondingly the flavoprotein and iron-sulfur protein subunits of succinate dehydrogenase, and of Fum1 encoding the mitochondrial form of fumarase. The blue light effect was probably mediated by transcription factors COP1 and HY5, with the expression of the latter increased upon blue light treatment. This was accompanied by a decrease in the expression of COP1, presumably involved in proteasome degradation of HY5. It was also demonstrated that calcium ions do not participate in this process. PMID- 29268086 TI - Abscisic acid is involved in aromatic ester biosynthesis related with ethylene in green apples. AB - The production of aromatic volatiles such as esters during the ripening process in climacteric fruits is known to be controlled by ethylene. However, we here show that abscisic acid (ABA) application accelerated the onset of short-chain ester production (hexyl propionate, ethyl-2-methyl butyrate) and the expression of biosynthesis genes (MdAAT2 and MdBCAT1) during ripening of 'Orin' apple. ABA application also promoted the production of ethylene, and caused ethylene peak shifts correlated with the expression of ethylene synthesis genes (MdACS1/3 and MdACO1), suggesting that ABA may act jointly with ethylene as a positive regulator at the ripening stage of 'Orin' apple. Additionally, endogenous levels and expression of biosynthesis (MdNCED1) and signal transduction genes (MdABF2 like) of ABA increased towards ripening. Finally, the localization of the putative MdABF2-like protein binding element, AREB/ABF, was observed in the 5' upstream region of MdACS1/3 and MdACO1. PMID- 29268087 TI - Agrobacterial tumors interfere with nodulation and demonstrate the expression of nodulation-induced CLE genes in pea. AB - CLAVATA (CLV) system including CLV1-like kinase and CLE-peptides is the part of the AON (autoregulation of nodulation) that controls nodule number in legume plants. Moreover, CLV system plays a key role in meristems, where it regulates the expression of WOX genes in organizing centers. Recently, we found that WOX5 homolog in pea is also expressed in nodules and in tumors induced by Agrobacterium tumefaciens. Based on this, we hypothesized that both nodules and agrobacterial tumors may be regulated by and may trigger the same components of AON, including the same WOX and CLV genes. Here, we found that pea plants with agrobacterial tumors induced prior to rhizobial inoculation had reduced the number of nodules. This effect was absent in pea sym29 mutant defective in CLV1 like kinase, the key component of AON. That suggests that agrobacterial tumors may produce a signal activating CLV1-like kinase and thereby decrease the nodule number. Since CLE peptides are known to act upstream of CLV1-like kinase, expression analysis of CLE genes has been performed both in developing nodules and tumors. Overall, 45 CLE genes were identified, and among them nine nodulation induced CLEs were found in pea. In agrobacterial tumors, no expression of nodule specific CLE genes the homologues of which inhibit nodulation in other legumes was observed. However, increased expression of two other nodulation-induced CLE genes was observed in agrobacterial tumors, suggesting that CLE genes are expressed in tumors that may still contribute to autoregulatory processes suppressing nodulation. PMID- 29268088 TI - Layers of Neuroscience. AB - In a patch of cortex, laminae connect to different parts of the brain. Huber et al. (2017) demonstrate the ability of human neuroimaging to derive laminar information flow between brain regions, paving the way for human neuroscience applications. PMID- 29268089 TI - United Again: STING and the Police. AB - Neuroinflammation is a common feature of aging and neurodegeneration. In this issue of Neuron, Mathur et al. (2017) report that the antiviral drug Ganciclovir induces an interferon type I response in microglia through activation of the STING pathway, inhibiting inflammation and leading to protection in a model of multiple sclerosis. PMID- 29268090 TI - The Locomotion Tug-of-War: Cholinergic and Dopaminergic Interactions Outside the Striatum. AB - In this issue of Neuron, Moehle et al. (2017) demonstrate that presynaptic muscarinic receptors counteract the effects of dopamine in an output nucleus of the basal ganglia. They provide intracellular, anatomical, and network-level mechanisms for this cholinergic-dopaminergic interplay. PMID- 29268091 TI - Zooming Out of Single Neurons Reveals Structure in Mnemonic Representations. AB - In this issue of Neuron, Rossi-Pool et al. (2017) show that the complex and heterogeneous response profiles of individual neurons in the dorsal premotor cortex during comparison of tactile temporal patterns can be understood in terms of two robust activity patterns that emerge across the population. PMID- 29268092 TI - An International Laboratory for Systems and Computational Neuroscience. AB - The neural basis of decision-making has been elusive and involves the coordinated activity of multiple brain structures. This NeuroView, by the International Brain Laboratory (IBL), discusses their efforts to develop a standardized mouse decision-making behavior, to make coordinated measurements of neural activity across the mouse brain, and to use theory and analyses to uncover the neural computations that support decision-making. PMID- 29268093 TI - Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits. AB - Ethanol is one of the most commonly abused drugs. Although environmental and genetic factors contribute to the etiology of alcohol use disorders, it is ethanol's actions in the brain that explain (1) acute ethanol-related behavioral changes, such as stimulant followed by depressant effects, and (2) chronic changes in behavior, including escalated use, tolerance, compulsive seeking, and dependence. Our knowledge of ethanol use and abuse thus relies on understanding its effects on the brain. Scientists have employed both bottom-up and top-down approaches, building from molecular targets to behavioral analyses and vice versa, respectively. This review highlights current progress in the field, focusing on recent and emerging molecular, cellular, and circuit effects of the drug that impact ethanol-related behaviors. The focus of the field is now on pinpointing which molecular effects in specific neurons within a brain region contribute to behavioral changes across the course of acute and chronic ethanol exposure. PMID- 29268096 TI - Activation of the STING-Dependent Type I Interferon Response Reduces Microglial Reactivity and Neuroinflammation. AB - Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNbeta, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation. PMID- 29268095 TI - The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement. AB - The brain transforms the need for water into the desire to drink, but how this transformation is performed remains unknown. Here we describe the motivational mechanism by which the forebrain thirst circuit drives drinking. We show that thirst-promoting subfornical organ neurons are negatively reinforcing and that this negative-valence signal is transmitted along projections to the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO). We then identify molecularly defined cell types within the OVLT and MnPO that are activated by fluid imbalance and show that stimulation of these neurons is sufficient to drive drinking, cardiovascular responses, and negative reinforcement. Finally, we demonstrate that the thirst signal exits these regions through at least three parallel pathways and show that these projections dissociate the cardiovascular and behavioral responses to fluid imbalance. These findings reveal a distributed thirst circuit that motivates drinking by the common mechanism of drive reduction. PMID- 29268094 TI - White Matter Plasticity in the Adult Brain. AB - The study of brain plasticity has tended to focus on the synapse, where well described activity-dependent mechanisms are known to play a key role in learning and memory. However, it is becoming increasingly clear that plasticity occurs beyond the synapse. This review focuses on the emerging concept of white matter plasticity. For example, there is growing evidence, both from animal studies and from human neuroimaging, that activity-dependent regulation of myelin may play a role in learning. This previously overlooked phenomenon may provide a complementary but powerful route through which experience shapes the brain. PMID- 29268097 TI - Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence. AB - Altered brain energy homeostasis is a key adaptation occurring in the cocaine addicted brain, but the effect of cocaine on the fundamental source of energy, mitochondria, is unknown. We demonstrate an increase of dynamin-related protein-1 (Drp1), the mitochondrial fission mediator, in nucleus accumbens (NAc) after repeated cocaine exposure and in cocaine-dependent individuals. Mdivi-1, a demonstrated fission inhibitor, blunts cocaine seeking and locomotor sensitization, while blocking c-Fos induction and excitatory input onto dopamine receptor-1 (D1) containing NAc medium spiny neurons (MSNs). Drp1 and fission promoting Drp1 are increased in D1-MSNs, consistent with increased smaller mitochondria in D1-MSN dendrites after repeated cocaine. Knockdown of Drp1 in D1 MSNs blocks drug seeking after cocaine self-administration, while enhancing the fission promoting Drp1 enhances seeking after long-term abstinence from cocaine. We demonstrate a role for altered mitochondrial fission in the NAc, during early cocaine abstinence, suggesting potential therapeutic treatment of disrupting mitochondrial fission in cocaine addiction. PMID- 29268100 TI - Phase-space topography characterization of nonlinear ultrasound waveforms. AB - Fundamental understanding of ultrasound interaction with material discontinuities having closed interfaces has many engineering applications such as nondestructive evaluation of defects like kissing bonds and cracks in critical structural and mechanical components. In this paper, to analyze the acoustic field nonlinearities due to defects with closed interfaces, the use of a common technique in nonlinear physics, based on a phase-space topography construction of ultrasound waveform, is proposed. The central idea is to complement the "time" and "frequency" domain analyses with the "phase-space" domain analysis of nonlinear ultrasound waveforms. A nonlinear time series method known as pseudo phase-space topography construction is used to construct equivalent phase-space portrait of measured ultrasound waveforms. Several nonlinear models are considered to numerically simulate nonlinear ultrasound waveforms. The phase space response of the simulated waveforms is shown to provide different topographic information, while the frequency domain shows similar spectral behavior. Thus, model classification can be substantially enhanced in the phase space domain. Experimental results on high strength aluminum samples show that the phase-space transformation provides a unique detection and classification capabilities. The Poincare map of the phase-space domain is also used to better understand the nonlinear behavior of ultrasound waveforms. It is shown that the analysis of ultrasound nonlinearities is more convenient and informative in the phase-space domain than in the frequency domain. PMID- 29268098 TI - Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor. AB - Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M4) to oppose cAMP-dependent dopamine receptor subtype 1 (D1) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D1-mediated activation of motor activity. These studies provide important new insights into the unique role of M4 in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output. PMID- 29268101 TI - Developmental selenium exposure and health risk in daily foodstuffs: A systematic review and meta-analysis. AB - Selenium (Se) is a trace mineral and an essential nutrient of vital importance to human health in trace amounts. It acts as an antioxidant in both humans and animals, immunomodulator and also involved in the control of specific endocrine pathways. The aim of this work is to provide a brief knowledge on selenium content in daily used various foodstuffs, nutritional requirement and its various health consequences. In general, fruits and vegetables contain low content of selenium, with some exceptions. Selenium level in meat, eggs, poultry and seafood is usually high. For most countries, cereals, legumes, and derivatives are the major donors to the dietary selenium intake. Low level of selenium has been related with higher mortality risk, dysfunction of an immune system, and mental failure. Selenium supplementation or higher selenium content has antiviral outcomes and is necessary for effective reproduction of male and female, also decreases the threat of chronic disease (autoimmune thyroid). Generally, some advantages of higher content of selenium have been shown in various potential studies regarding lung, colorectal, prostate and bladder cancers risk, nevertheless results depicted from different trials have been diverse, which perhaps indicates the evidence that supplementation will merely grant advantage if the intakes of a nutrient is deficient. In conclusion, the over-all people should be advised against the usage of Se supplements for prevention of cardiovascular, hepatopathies, or cancer diseases, as advantages of Se supplements are still ambiguous, and their haphazard usage could result in an increased Se toxicity risk. The associations among Se intake/status and health, or disease risk, are complicated and need exposition to notify medical practice, to improve dietary recommendations, and to develop adequate communal health guidelines. PMID- 29268099 TI - Distinct Inhibitory Circuits Orchestrate Cortical beta and gamma Band Oscillations. AB - Distinct subtypes of inhibitory interneuron are known to shape diverse rhythmic activities in the cortex, but how they interact to orchestrate specific band activity remains largely unknown. By recording optogenetically tagged interneurons of specific subtypes in the primary visual cortex of behaving mice, we show that spiking of somatostatin (SOM)- and parvalbumin (PV)-expressing interneurons preferentially correlates with cortical beta and gamma band oscillations, respectively. Suppression of SOM cell spiking reduces the spontaneous low-frequency band (<30-Hz) oscillations and selectively reduces visually induced enhancement of beta oscillation. In comparison, suppressing PV cell activity elevates the synchronization of spontaneous activity across a broad frequency range and further precludes visually induced changes in beta and gamma oscillations. Rhythmic activation of SOM and PV cells in the local circuit entrains resonant activity in the narrow 5- to 30-Hz band and the wide 20- to 80 Hz band, respectively. Together, these findings reveal differential and cooperative roles of SOM and PV inhibitory neurons in orchestrating specific cortical oscillations. PMID- 29268102 TI - Application of electrochemical advanced oxidation to bisphenol A degradation in water. Effect of sulfate and chloride ions. AB - Electrochemical oxidation with electrogenerated H2O2 (EO- H2O2), electro-Fenton (EF), photoelectro-Fenton (PEF) and solar PEF (SPEF) have been applied to mineralize bisphenol A solutions in 0.050 M Na2SO4 or 0.008 M NaCl + 0.047 M Na2SO4 at pH 3.0. The assays were performed in an undivided cell with a boron doped diamond (BDD) anode and an air-diffusion cathode for continuous H2O2 production. The PEF and SPEF processes yielded almost total mineralization due to the potent synergistic action of generated hydroxyl radicals and active chlorine, in conjunction with the photolytic action of UV radiation. The higher intensity of UV rays from sunlight explained the superior oxidation ability of SPEF. The effect of applied current density was studied in all treatments, whereas the role of bisphenol A concentration was examined in PEF. Bisphenol A abatement followed a pseudo-first-order kinetics, which was very quick in SPEF since UV light favored a large production of hydroxyl radicals from Fenton's reaction. Eight non chlorinated and six chlorinated aromatics were identified as primary products in the chloride matrix. Ketomalonic, tartronic, maleic and oxalic acids were detected as final short-chain aliphatic carboxylic acids. The large stability of Fe(III)-oxalate complexes in EF compared to their fast photomineralization in PEF and PEF accounted for by the superior oxidation power of the latter processes. PMID- 29268103 TI - Effects of three veterinary antibiotics and their binary mixtures on two green alga species. AB - The individual and combined toxicities of chlortetracycline (CTC), oxytetracycline (OTC) and enrofloxacin (ENF) have been examined in two green algae representative of the freshwater environment, the international standard strain Pseudokichneriella subcapitata and the native strain Ankistrodesmus fusiformis. The toxicities of the three antibiotics and their mixtures were similar in both strains, although low concentrations of ENF and CTC + ENF were more toxic in A. fusiformis than in the standard strain. The toxicological interactions of binary mixtures were predicted using the two classical models of additivity: Concentration Addition (CA) and Independent Action (IA), and compared to the experimentally determined toxicities over a range of concentrations between 0.1 and 10 mg L-1. The CA model predicted the inhibition of algal growth in the three mixtures in P. subcapitata, and in the CTC + OTC and CTC + ENF mixtures in A. fusiformis. However, this model underestimated the experimental results obtained in the OTC + ENF mixture in A. fusiformis. The IA model did not predict the experimental toxicological effects of the three mixtures in either strain. The sum of the toxic units (TU) for the mixtures was calculated. According to these values, the binary mixtures CTC + ENF and OTC + ENF showed an additive effect, and the CTC + OTC mixture showed antagonism in P. subcapitata, whereas the three mixtures showed synergistic effects in A. fusiformis. Although A. fusiformis was isolated from a polluted river, it showed a similar sensitivity with respect to P. subcapitata when it was exposed to binary mixtures of antibiotics. PMID- 29268104 TI - Impact of sludge treatments on the extractability and fate of acetyl sulfamethoxazole residues in amended soils. AB - Sludge recycled in agriculture may bring antibiotics into cropped soils. The nature, total amount, and availability of the antibiotics in soil partly depend on the sludge treatments. Our paper compares the fate of N-acetyl sulfamethoxazole (AC-SMX) residues between soils incubated with the same sludge but submitted to different processes before being added in soil. The fate of 14C AC-SMX residues was studied in mixtures of soil and sludges at different treatment levels: 1) activated and 2) centrifuged sludges, both enriched with 14C AC-SMX, and 3) limed and 4) heat-dried sludges obtained by treating the previously contaminated centrifuged sludge. The evolution of the extractability of 14C residues (CaCl2, methanol) and their mineralization were followed during 119 days. More than 80% of the initial 14C-activity was no longer extractable after 14 days, except in soil with limed sludge. Liming and drying the centrifuged sludge decreased the mineralized 14C fraction from 5.7-6.4% to 1.2 1.8% and consequently, the corresponding soils contained more 14C residues after 119 days. Although 14C residues were more CaCl2-extractable in soil with limed sludge, they seemed to be poorly bioavailable for biodegradation. For all solid sludges, the mineralization rate of 14C-AC-SMX residues was strongly correlated to that of sludge organic carbon, with a coefficient three times lower for the limed and dried sludges than for the centrifuged sludge after 14 days. PMID- 29268105 TI - Are postural adjustments during reaching related to walking development in typically developing infants and infants at risk of cerebral palsy? AB - BACKGROUND: In typical development, postural adjustments during reaching change in the second half of infancy, including increasing rates of direction-specific adjustments. These changes are absent or different in infants at risk of cerebral palsy (CP). To discover whether these changes are related to acquisition of independent walking, we studied postural adjustments during reaching in infants before and after they learned to walk. METHODS: Ten typically developing (TD) infants and 11 infants at very high risk (VHR) of CP were assessed before and after they learned to walk. Reaching movements were elicited during supported sitting, while surface electromyography was recorded of arm, neck, and trunk muscles. Percentages of direction-specific adjustments (first level of control), and recruitment patterns and anticipatory activation (second level of control) were calculated. RESULTS: In both groups, postural adjustments during reaching were similar before and after acquisition of independent walking. Direction specificity increased with age in typically developing infants but not in VHR infants. CONCLUSION: Increasing age rather than the transition to independent walking is associated with increasing direction-specificity of TD-infants during reaching while sitting, while infants at very high risk of CP show no increase in direction-specificity, suggesting that they gradually grow into a postural deficit. PMID- 29268107 TI - Engineering microbial communities using thermodynamic principles and electrical interfaces. AB - Microbial communities present the next research frontier. We argue here that understanding and engineering microbial communities requires a holistic view that considers not only species-species, but also species-environment interactions, and feedbacks between ecological and evolutionary dynamics (eco-evo feedbacks). Due this multi-level nature of interactions, we predict that approaches aimed soley at altering specific species populations in a community (through strain enrichment or inhibition), would only have a transient impact, and species environment and eco-evo feedbacks would eventually drive the microbial community to its original state. We propose a higher-level engineering approach that is based on thermodynamics of microbial growth, and that considers specifically microbial redox biochemistry. Within this approach, the emphasis is on enforcing specific environmental conditions onto the community. These are expected to generate higher-level thermodynamic bounds onto the system, which the community structure and function can then adapt to. We believe that the resulting end-state can be ecologically and evolutionarily stable, mimicking the natural states of complex communities. Toward designing the exact nature of the environmental enforcement, thermodynamics and redox biochemistry can act as coarse-grained principles, while the use of electrodes-as electron providing or accepting redox agents-can provide implementation with spatiotemporal control. PMID- 29268108 TI - Bullying victimization experiences among middle and high school adolescents: Traditional bullying, discriminatory harassment, and cybervictimization. AB - The objectives of the current study were to estimate the prevalence of nine types of bullying victimization among adolescents in Grades 7 to 12, and examine how these experiences vary according to gender and school grade. Data were drawn from the Manitoba Youth Health Survey. The sample size was N = 64 174 and included boys and girls from Grades 7 to 12. Nine types of bullying victimization were assessed. Gender and grade differences were noted with girls being more to likely than boys to report six types of victimization. The odds of bullying victimization were higher in Grades 8 to 12 compared to Grade 7. Effective anti bullying intervention strategies need to address a range of victimization types and should consider gender and school grade. Interventions should start before Grade 7 and continue until the end of Grade 12. PMID- 29268109 TI - Perception of intelligibility and qualities of non-native accented speakers. AB - PURPOSE: To provide effective treatment to clients, speech-language pathologists must be understood, and be perceived to demonstrate the personal qualities necessary for therapeutic practice (e.g., resourcefulness and empathy). One factor that could interfere with the listener's perception of non-native speech is the speaker's accent. The current study explored the relationship between how accurately listeners could understand non-native speech and their perceptions of personal attributes of the speaker. Additionally, this study investigated how listeners' familiarity and experience with other languages may influence their perceptions of non-native accented speech. METHODS: Through an online survey, native monolingual and bilingual English listeners rated four non-native accents (i.e., Spanish, Chinese, Russian, and Indian) on perceived intelligibility and perceived personal qualities (i.e., professionalism, intelligence, resourcefulness, empathy, and patience) necessary for speech-language pathologists. RESULTS: The results indicated significant relationships between the perception of intelligibility and the perception of personal qualities (i.e., professionalism, intelligence, and resourcefulness) attributed to non-native speakers. However, these findings were not supported for the Chinese accent. Bilingual listeners judged the non-native speech as more intelligible in comparison to monolingual listeners. No significant differences were found in the ratings between bilingual listeners who share the same language background as the speaker and other bilingual listeners. CONCLUSIONS: Based on the current findings, greater perception of intelligibility was the key to promoting a positive perception of personal qualities such as professionalism, intelligence, and resourcefulness, important for speech-language pathologists. The current study found evidence to support the claim that bilinguals have a greater ability in understanding non-native accented speech compared to monolingual listeners. The results, however, did not confirm an advantage for bilingual listeners sharing the same language backgrounds with the non-native speaker over other bilingual listeners. PMID- 29268106 TI - Food components with antifibrotic activity and implications in prevention of liver disease. AB - Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components. PMID- 29268110 TI - Growth, reproduction and biochemical toxicity of chlorantraniliprole in soil on earthworms (Eisenia fetida). AB - Diamide insecticides have become the fourth most commonly used insecticide class in the world. Chlorantraniliprole (CAP) is a first-generation diamide insecticide with broad application potential. In this experiment, the eco-toxicity of CAP in soil at 0.1, 1.0, 5.0 and 10.0mg/kg on earthworms (Eisenia fetida) was evaluated during a 42 d exposure. More specifically, the environmental fate and transport of CAP between soil and earthworms was monitored during the exposure period. The present results indicated that the CAP contents of 0.1, 1.0, 5.0 and 10.0mg/kg treatments decreased to no more than 20% in the soil after 42 d of exposure. The accumulation of CAP in earthworms was 0.03, 0.58, 4.28 and 7.21mg/kg earthworm (FW) at 0.1, 1.0, 5.0 and 10.0mg/kg after 42 d of exposure. At 0.1mg/kg and 1.0mg/kg, CAP had no effect on earthworms during the exposure period. The weight of earthworms was significantly reduced at 5.0 and 10.0mg/kg at 28 and 42 days after CAP application. After the 14th day, CAP induced excess production of reactive oxygen species (ROS) at 5.0 and 10.0mg/kg, resulting in oxidative damage to biomacromolecules. We believe that CAP has a high risk potential for earthworms when used at 5.0 and 10.0mg/kg. PMID- 29268111 TI - Assessing the potential phytotoxicity of digestate from winery wastes. AB - In this study, digestate from winery wastes was investigated focusing on phytotoxicity using macrophytes and evaluating the potential contribution of ammonium and copper. Spreading of digestate on soil could represent a suitable approach to recycle nutrients and organic matter, creating an on site circular economy. In this study, digestate quality was evaluated considering both chemical physical characteristics and biological toxicity applying germination test. The effluent did not meet the entire amendment quality standard defined by Italian law (Decree 75/2010 germination index > 60% with solution of 30% v/v of digestate), but bio-stimulation was observed at low doses (3.15-6.25% v/v) for S. alba and S. saccharatum. The beneficial concentration agreed with Nitrate Directive dose and suggested that limited addition of digestate could have several positive effects on soil characteristics and on crop growth. Specific test using ammonium and copper solutions showed that these pollutants were not directly correlated to observed phytotoxicity. PMID- 29268112 TI - Biodegradation and detoxification of chlorimuron-ethyl by Enterobacter ludwigii sp. CE-1. AB - The application of the herbicide chlorimuron-ethyl has a lasting toxic effect on some succession crops. Here, a bacterium capable of utilizing chlorimuron-ethyl as the sole source of nitrogen was isolated from the contaminated soil and was identified as Enterobacter ludwigii sp. CE-1, and its detoxification and degradation of the herbicide were then examined. The biodegradation of chlorimuron-ethyl by the isolate CE-1 was significantly accelerated with increasing concentration (1-10mg/l) and temperature (20-40 degrees C). The optimal pH for the degradation of chlorimuron-ethyl by the isolate CE-1 was pH 7.0. A pathway for the biodegradation of chlorimuron-ethyl by the isolate CE-1 was proposed, in which it could be first converted into 2-amino-4-chloro-6 methoxypyrimidine and an intermediate product by the cleavage of the sulfonylurea bridge and then transformed into saccharin via hydrolysis and amidation. The plant height and fresh weight of corn that had been incubated in nutrient solution containing 0.2mg/l of chlorimuron-ethyl significantly recovered to 83.9% and 83.1% compared with those in the uninoculated control, although the root growth inhibition of chlorimuron-ethyl could not be alleviated after inoculation for 14 d. The results indicate that the isolate CE-1 is a promising bacterial resource for the biodegradation and detoxification of chlorimuron-ethyl. PMID- 29268113 TI - Usefulness of RTL-W1 and OLCAB-e3 fish cell lines and multiple endpoint measurements for toxicity evaluation of unknown or complex mixture of chemicals. AB - Fish are currently used for the assessment of chemical toxicity. The REACh regulation and the European directive on the protection of animals used for scientific purposes both recommend the use of methods other than animal testing. In view of this, fish cell lines are increasingly used to provide fast and reliable toxic and ecotoxic data on new chemicals. The sensitivity of the Rainbow trout liver cell line RTL-W1 and Japanese medaka embryos cell line OLCAB-e3 were used with different toxicity endpoints, namely cytotoxicity, EROD activity, ROS production and DNA damage for various classes of pollutants displaying different modes of action but also with complex environmental mixtures. Toxicity tests were coupled with chemical analysis to quantify the chemical concentrations in cell cultures. Differences in sensitivity were found between fish cell lines. MTT reduction assay revealed that OLCAB-e3 cells were more sensitive than RTL-W1 cells. On the contrary, RTL-W1 gave higher response levels for the Fpg-modified comet assay and ROS assay. The OLCAB-e3 cell line did not express EROD activity unlike RTL-W1. This study highlights the capacity of the two different fish cell lines to measure the toxicity of individual toxicants but also environmental mixtures. Then, results obtained here illustrate the interest of using different cell lines and toxicity endpoints to assess the toxicity of complex or unknown mixture of chemicals. PMID- 29268114 TI - Selenium poisoning of fish by coal ash wastewater in Herrington Lake, Kentucky. AB - Selenium pollution from the E.W. Brown Electric Generating Station was investigated in Herrington Lake, KY. Coal ash wastewater is discharged as surface water overflow from ash disposal ponds into the lake via a National Pollutant Discharge Elimination System permit issued by the Kentucky Division of Water, but the permit does not restrict or limit the amount of selenium released. Unpermitted discharges occur from seeps and drainage through leaks in ash pond dams. Together, these discharges have resulted in selenium concentrations in water, sediment, benthic macroinvertebrates, and fish that are 2-9 times the level that is toxic for fish reproduction and survival. A large proportion (12.2%, or 25 times background) of juvenile largemouth bass (Micropterus salmoides, the only species examined) exhibited spinal and/or craniofacial malformations that are consistent with selenium poisoning. Teratogenic Deformity Index values indicated a 3.05% population-level impact on the bass fishery, with total selenium-induced mortality (including pre-swimup mortality) estimated to be in excess of 25% per year. These findings confirm that coal ash discharges into Herrington Lake are contributing selenium to the Lake that is poisoning fish. PMID- 29268115 TI - Application of magnetic ionomer for development of very fast and highly efficient uptake of triazo dye Direct Blue 71 form different water samples. AB - This research focuses on removing Direct Blue 71 (DB 71) from aqueous solution in an efficient and very fast route by ionic liquid mediated gamma-Fe2O3 magnetic ionomer. 2-hydroxyethylammonium sulphonate immobilized on gamma-Fe2O3 nanoparticles (gamma-Fe2O3-2-HEAS) was used for this purpose. The influence of shaking time, medium pH, the concentration of sorbent and NaNO3 on removal was evaluated to greatly influence removal extent. The optimal removal conditions were determined by response surface methodology based on the four-variable central composite design to obtain maximum removal efficiency and determine the significance and interaction effect of the variables on the removal of target triazo dye. The results have shown that an amount of 98.2% as % removal under the optimum conditions. The adsorption kinetics and isotherms were well fitted to a pseudo-second order model and Freundlich model, respectively. Based on these models, the maximum dye adsorption capacity (Qm) of 47.60mgg-1 was obtained. Finally, the proposed nano-adsorbent was applied satisfactorily for removal of target triazo dye from different water samples. PMID- 29268116 TI - Effects of bamboo biochar on soybean root nodulation in multi-elements contaminated soils. AB - Improvements in plant physiological performance by means of biochar application in soils contaminated by multi-elements are determinants of agroecosystem functioning. This study analyzed the effects of bamboo-derived biochar on root nodulation and plant growth in a moderately acidic Andosol (pH = 5.56) contaminated with multi-elements during a 70-day investigation of soybean growth. Bamboo biochar that had been pyrolyzed at a temperature below 500 degrees C was applied to soils at three different and moderately high rates (5%, 10%, and 15%, w/w). Biochar amendment beyond 5% stimulated root nodulation as well as soybean growth. The nodule weight per root system was significantly enhanced by 186% and 243% over the control at the 10% and 15% addition rates, respectively. The primary explanation for these stimulatory effects was attributed to an increase in the K and Mo supplies for plant uptake that was induced by the biochar application, whereas the increased availability of P contributed to a lesser extent. Leaf CO2 assimilation rate was slightly enhanced at the highest application rate, but this enhancement was not associated with an increase in biomass. The incorporation of biochar into the soil reduced extractable-NH4NO3 Cd, Cu, Mn, Ni, and Zn, but not Pb, regardless of the application dose. This change was accompanied by a significant (P < 0.05) suppression of the uptake od trace elements in soybean shoots at the optimum application rate (10%); the degree of reduction followed this order: Pb>Mn>Cd>Zn>Cu>Ni. The increase in soil pH and the diffusion/adsorption of trace elements onto the biochar may have contributed to the lowering of the concentration of trace elements in the soil as well as in soybean shoots. PMID- 29268117 TI - Identification of a cytochrome P450 gene in the earthworm Eisenia fetida and its mRNA expression under enrofloxacin stress. AB - Cytochrome P450 (CYP450) enzymes are a family of hemoproteins primarily responsible for detoxification functions. Earthworms have been used as a bioindicator of soil pollution in numerous studies, but no CYP450 gene has so far been cloned. RT-PCR and RACE-PCR were employed to construct and sequence the CYP450 gene DNA from the extracted mRNA in the earthworm Eisenia fetida. The cloned gene (EW1) has an open reading frame of 477bp. The 3'-terminal region contained both the consensus and the signature sequences characteristic of CYP450. It was closely related to the CYP450 gene from the flatworm genus Opisthorchis felineus with 87% homology. The predicted structure of the putative protein was 97% homologous to human CYP450 family 27. This gene has been deposited in GenBank (accession no. KM881474). Earthworms (E. fetida) were then exposed to 1, 10, 100, and 500mgkg-1 enrofloxacin in soils to explore the mRNA expression by real time qPCR. The effect of enrofloxacin on mRNA expression levels of EW1 exhibited a marked hormesis pattern across the enrofloxacin dose range tested. This is believed to be the first reported CYP450 gene in earthworms, with reference value for molecular studies on detoxification processes in earthworms. PMID- 29268118 TI - Cadmium induced changes in Solidago chilensis Meyen (Asteraceae) grown on organically fertilized soil with reference to mycorrhizae, metabolism, anatomy and ultrastructure. AB - Solidago chilensis Meyen (Asteraceae) is a medicinal important plant with few studies on nutrition and metabolism and none information on cadmium phytotoxicity. The objective of this study was to investigate Cd induced responses on the growth and metabolism in S. chilensis and on arbuscular mycorrhiza (AM). The experiment was carried out in a greenhouse, consisting of a 5 * 4 factorial with five doses of manure (0, 3.5, 7, 14 and 21gdm-3) and four doses of cadmium (0, 25, 50 and 75mgdm-3) applied to a Dystrophic Ultisol. After 250 days of plant cultivation, biomass, nutrient content, photosynthetic rate, guaiacol peroxidase activity, mycorrhizal colonization, glomalin content, anatomical and ultrastucture were evaluated. Plants were significantly affected by interaction of manure and Cd doses with anatomical, ultrastructural, physiological and nutritional modifications. Manure applied into Cd contaminated soil significantly improved mycorrhizal colonization and glomalin production. The highest organic manure dose (21gdm-3) alleviated toxicity symptoms of Cd on S. chilensis. PMID- 29268119 TI - The progestin norethisterone affects thyroid hormone-dependent metamorphosis of Xenopus laevis tadpoles at environmentally relevant concentrations. AB - Previously, levonorgestrel (LNG) has been shown to be an endocrine disruptor of the amphibian thyroid system. In the present study, we investigated whether anti thyroidal effects are a common property of progestins other than LNG. Premetamorphic Xenopus laevis tadpoles were exposed to norethisterone (NET) and dienogest DIE (each at 0.1-10nM) and LNG (10nM) until completion of metamorphosis. LNG and NET at all concentrations caused a significant developmental retardation whereas DIE did not impair time to metamorphosis. In LNG and 10nM NET exposed animals, tsh mRNA levels increased considerably later than the developmental delay occurred and thyroid histopathology showed no signs of TSH-hyperstimulation. Instead, thyroid glands from these treatments appeared inactive in producing thyroid hormones. Thyroidal transcript levels of dio2 and dio3 were increased by treatments with LNG and NET at 1nM and 10nM, whereas iyd mRNA was reduced by LNG and 10nM NET. Expression of slc5alpha5 was not changed by any treatment. Effects of DIE differed from those induced by LNG and NET. No developmental delay was measurable; however, tshbeta and dio2 mRNAs were increased in pituitary glands of tadpoles exposed to 1.0nM and 10nM DIE. Thyroid histopathology displayed no abnormalities and thyroidal mRNA expression of the genes analyzed (slc5alpha5, iyd, dio2, dio3) was not changed by DIE. Overall, our results provide evidence that the anti-thyroidal effects already known from LNG are also present in another progestin, namely NET, even at environmentally relevant concentrations. In conclusion we suggest that progestins do not only pose an environmental risk in terms of their impact on reproductive success of aquatic vertebrates, but also with respect to their anti-thyroidal properties affecting amphibian metamorphosis. PMID- 29268120 TI - Experimental exposure of blue mussels (Mytilus galloprovincialis) to high levels of benzo[a]pyrene and possible implications for human health. AB - Polycyclic aromatic hydrocarbons (PAHs) are lipophilic compounds able to accumulate in the food chain. Mussels showed to bioaccumulate contaminants, such as PAHs, so that recurrent consumption of such contaminated food represents a risk for human health. This study was aimed to elucidate if acute exposure of Mediterranean blue mussel (Mytilus galloprovincialis), a bivalve of great economic importance in several countries, to a PAH, benzo[a]pyrene (B[a]P), at doses able to induce cytochrome P450 1A (CYP1A) and pathological changes in mussel gills, can produce accumulation in soft tissue. We explored the cytotoxic effects (cell viability, DNA laddering, and glutathione levels) of in vitro exposure of human peripheral blood mononuclear cells (PBMCs) to organic extracts obtained from blue mussels previously exposed for 12 and 72h via water to B[a]P (0.5-1mg/L). In our experimental conditions, B[a]P induced CYP1A induction and morphological changes in mussel gills and a significant B[a]P accumulation in soft tissue. Conversely, exposing PBMCs to organic extracts obtained from contaminated mussels, resulted in a significant reduction of cell viability and cell glutathione content, and in an increase in DNA laddering. This confirms that consumption of mussels from B[a]P polluted waters might affect human health. Our data lead us to suggest that CYP1A activity in mussel gills may be useful (more than the amount of detected PAHs in the mussel edible tissue) as a marker in assessment of risk for health of consumers exposed to PAHs through ingestion of shellfish. PMID- 29268121 TI - Age-dependent alterations of glucose clearance and homeostasis are temporally separated and modulated by dietary fat. AB - Diet- and age-dependent changes in glucose regulation in mice occur, but the temporal development, mechanisms and influence of dietary fat source remain to be defined. We followed metabolic changes in three groups of mice including a low fat diet (LFD) reference group and two high-fat, high-sucrose diets based on either fish oil (FOD) or soybean oil (SOD), rich in omega3- and omega6 polyunsaturated fatty acids, respectively, to closely monitor the age-dependent development in glucose regulation in both obese (SOD-fed) and lean (LFD- and FOD fed) mice. We assessed glucose homeostasis and glucose clearance at week 8, 12, 16, 24, 31, and 39 and performed an insulin tolerance test at week 40. We further analyzed correlations between the gut microbiota and key metabolic parameters. Interestingly, alterations in glucose homeostasis and glucose clearance were temporally separated, while 16S ribosomal gene amplicon sequencing revealed that gut microbial alterations formed correlation clusters with fat mass and either glucose homeostasis or glucose clearance, but rarely both. Importantly, effective glucose clearance was maintained in FOD- and even increased in LFD-fed mice, whereas SOD-fed mice rapidly developed impaired glucose clearance followed by a gradual improvement from week 8 to week 39. All groups had similar responses to insulin 40 weeks post diet initiation despite severe nonalcoholic steatohepatitis in SOD-fed mice. We conclude that age-related alterations in glucose regulation may occur in both lean and obese mice and are modulated by dietary fat as indicated by the sustained metabolic homeostasis observed in mice fed omega3 polyunsaturated fatty acids. PMID- 29268123 TI - Laparoscopic posterior rectopexy (Well's procedure) for full-thickness rectal prolapse following laparoscopic repair of an anorectal malformation: A case report. AB - INTRODUCTION: Intractable full-thickness rectal prolapse (IRP) unresponsive to conservative treatment remains a major problem after anorectoplasty for high or intermediate anorectal malformation (ARM). Surgical management must aim for a permanent fixation of the rectum to the presacral fascia. While in children with IRP following ARM repair the optimal procedure has not been established yet, laparoscopic posterior mesh-rectopexy (Well's procedure) has demonstrated efficacy in adults. PRESENTATION OF CASE: A male infant with intermediate ARM received laparoscopic-assisted anorectal pull-through at the age of 4 months. Three months later he developed mucosal prolapse and received multimodal conservative treatment. Because of progression into a full-thickness RP with ulcerations, the parents opted for surgical management. Well's procedure was performed at the age of 4 years. Using four ports, the rectum was circumferentially mobilized down to the pelvic floor and pulled inside. A 5 * 5 cm prolene mesh was tacked to the sacrum, enveloped posteriorly 270 degrees around the rectum, fixed with interrupted prolene sutures on both edges and carefully covered with peritoneum. Any redundant external mucosa was excised from a perineal approach. There were no intra- and postoperative complications. Within 1.5 years of follow-up the boy had voluntary bowel movements and was toilet trained. No prolapse recurrence could be observed nor provoked. DISCUSSION: We present the first pediatric case of IRP secondary to laparoscopic ARM repair which has been successfully treated by combined Well's procedure and perineal mucosal resection. CONCLUSION: Well's procedure is a successful technique and should be further explored in children with ARM and IRP. PMID- 29268122 TI - Resveratrol and pinostilbene confer neuroprotection against aging-related deficits through an ERK1/2-dependent mechanism. AB - Age-related declines in motor function may be due, in part, to an increase in oxidative stress in the aging brain leading to dopamine (DA) neuronal cell death. In this study, we examined the neuroprotective effects of natural antioxidants resveratrol and pinostilbene against age-related DAergic cell death and motor dysfunction using SH-SY5Y neuroblastoma cells and young, middle-aged, and old male C57BL/6 mice. Resveratrol and pinostilbene protected SH-SY5Y cells from a DA induced decrease in cell viability. Dietary supplementation with resveratrol and pinostilbene inhibited the decline of motor function observed with age. While DA and its metabolites (DOPAC and HVA), dopamine transporter, and tyrosine hydroxylase levels remain unchanged during aging or treatment, resveratrol and pinostilbene increased ERK1/2 activation in vitro and in vivo in an age-dependent manner. Inhibition of ERK1/2 in SH-SY5Y cells decreased the protective effects of both compounds. These data suggest that resveratrol and pinostilbene alleviate age-related motor decline via the promotion of DA neuronal survival and activation of the ERK1/2 pathways. PMID- 29268124 TI - Surgical case series of multiple aneurysms: A single-centre experience of 16 years. AB - INTRODUCTION: Multiple aneurysms are present in 10% in patients with intracranial aneurysms. An analysis of the literature, focusing on the different treatments, and a description of our experience are performed. PRESENTATION OF CASE SERIES: A surgical series with multiple intracranial aneurysms from 2000 to 2016, describing demographic, radiological and clinical features, is showed. In all patients a pre- and post-operative angiography was performed and surgical treatment, based on accurate indications, provided good outcomes in most cases. DISCUSSION: Successful treatment of multiple intracranial aneurysms can be achieved by an interdisciplinary approach and the main factors influencing surgical treatment are discussed. CONCLUSIONS: Surgery always remains a definitive treatment and, considering intrinsic lesional features and patient's characteristics, it offers good results for intracranial multiple aneurysms. PMID- 29268125 TI - Discordant correlation of breast adenoid cystic carcinoma on imaging and pathology: A case report and literature review on surgical management. AB - INTRODUCTION: Adenoid cystic carcinomas (ACC) of the breast are extremely rare tumours, accounting for <0.1% of newly diagnosed breast cancer cases. Little data exist regarding the correlation of radiological findings with histology of this rare subtype. To our knowledge, gross size discrepancy between the 2 modalities has not been reported. We describe a case of ACC with appreciable size discordance between imaging and pathology report. PRESENTATION OF CASE: A 71 years old lady presented with a painless right breast lump of a few months duration. Clinical examination revealed a 1.5 cm right breast upper outer quadrant mass. Axillary and systemic examinations were unremarkable. Mammogram showed an asymmetric density in the right upper outer quadrant which corresponded to a suspicious nodule measuring about 2 cm on the ultrasound. Ultrasound of the axilla showed an indeterminate right lymph node. Core needle biopsy of the right breast nodule showed ACC while the lymph node biopsy was non- metastatic. Staging scans did not reveal any definite distant metastasis. Her naso-endoscopy and MRI of the neck were normal. She underwent a right mastectomy and sentinel lymph node biopsy. Final histology returned as a grade II 55 mm ACC. Lympho-vascular invasion was absent. The tumour was triple negative for Estrogen receptor (ER), Progesterone receptor (PR) and Human epidermal receptor 2 (HER 2). Sentinel lymph node biopsy was negative for metastasis. She recovered well but declined adjuvant chemotherapy and radiation therapy. She is currently well 6 months post operation. DISCUSSION: ACC is an extremely rare subtype, therefore there are limited reports in literature on its imaging and pathological characteristics. Of this sparse data, there was no mention that there might be a big size discrepancy between the 2 modalities. This appreciable discrepancy has implications for pre operative planning and the choice of breast surgery. It will be useful if the pathological extent of ACC could be determined more accurately radiologically. However, there are no distinctive imaging characteristics for ACC. ACC can appear as a smooth round mass similar to that of a benign mass or as an irregular mass on mammogram. On ultrasound, ACC often manifested as a hypo- echoic heterogeneous mass with minimal vascularity on Doppler imaging and may have an indistinct margin. MRI has a higher sensitivity than mammogram and ultrasound in determining the true extent of the tumour, but there remains little data on its usefulness in ACC. CONCLUSION: ACC can be extensively infiltrative and present much larger than its radiological size, as reported in our case. Use of better imaging modalities judiciously, in these cases, are needed to more accurately predict the true pathological size of ACC to prevent inadequate surgery. PMID- 29268126 TI - Pain management in spine surgery. PMID- 29268127 TI - Design, synthesis and biological evaluation of 1, 4-dihydro indeno[1,2-c] pyrazole linked oxindole analogues as potential anticancer agents targeting tubulin and inducing p53 dependent apoptosis. AB - A series of 1, 4-dihydroindeno-[1,2-c] pyrazole linked oxindole conjugates have been synthesized by using Knoevenagel condensation method and further evaluated for their antiproliferative activity against HeLa, A549 and MDA-MB-231 human cancer cell lines along with HEK-293 (normal human embryonic kidney cells). Among the derivatives, compounds 12a, 12b, and 12d showed excellent cytotoxicity with IC50 values ranging between 1.33 to 4.33 MUM. Furthermore, detailed biological assays showed that there was accumulation of mitotic cells in G2/M phase, disruption of microtubule network and increase in the G2/M checkpoint proteins (Cyclin B1 and CDK1). Moreover, compound 12d with IC50 value of 1.33 MUM showed significant upregulation of tumor suppressor proteins like p53, p21 and pro apoptotic Bax. The molecular docking analysis demonstrated that these congeners occupy the colchicine binding pocket of the tubulin. PMID- 29268128 TI - 2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study. AB - Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (Pi/PPi) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4 thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies. PMID- 29268129 TI - Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity. AB - A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced beta-amyloid (Abeta) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation. PMID- 29268130 TI - Design and characterization of alpha-lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors. AB - Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, alpha-lipoic acid, the naturally-occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of alpha-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, 1c displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC50 value of 3.14 +/- 0.58 MUM and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy. PMID- 29268131 TI - Antagonists of the adenosine A2A receptor based on a 2-arylbenzoxazole scaffold: Investigation of the C5- and C7-positions to enhance affinity. AB - We have recently reported a series of 2-furoyl-benzoxazoles as potential A2A adenosine receptor (A2AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hA2AR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hA2AR, we explored the C5- and C7-position of hits 1 and 2 based on docking studies. These modifications led to compounds with nanomolar-range affinity (e.g. 6a, Ki = 40 nM) and high antagonist activity (e.g. 6a, IC50 = 70.6 nM). Selected compounds also exhibited interesting in vitro DMPK (Drug Metabolism and Pharmacokinetics) properties including high solubility and low cytotoxicity. Therefore, the benzoxazole ring appears as a highly effective scaffold for the design of new A2A antagonists. PMID- 29268132 TI - 4-arylamidobenzyl substituted 5-bromomethylene-2(5H)-furanones for chronic bacterial infection. AB - Bacterial quorum-sensing (QS) can cause bacterial biofilm formation, thus induce antibiotic resistance and inflammation in chronic bacterial infections. A series of novel 4-arylamidobenzyl substituted 5-bromomethylene-2(5H)-furanones were designed by introducing of brominated furanones into rosiglitazone skeleton, and their potential application in the treatment of chronic bacterial infection was evaluated with regard to their disruption of quorum sensing and anti-inflammatory activities in vitro as well as in animal infection model. Compound 2e displayed both potent QS inhibitory activity and anti-inflammatory activity. Further mechanism studies revealed that the biological effects of 2e and 2k could be attributed, at least in part, to their interaction with PPARgamma, and consequent suppression of the activation of NF-kappaB and MAPK cascades. Importantly, pretreatment with 2e significantly protects mice from lethal-dose LPS challenge. Thus, these data suggest that the dual effective derivative 2e may serve as a valuable candidate for the treatment of chronic bacterial infection. PMID- 29268133 TI - Targeting pattern-recognition receptors to discover new small molecule immune modulators. AB - Pattern recognition receptors (PRRs) are key immune receptors of the innate immune system, which recognize the conserved pathogen-associated molecular patterns (PAMPs) of the invading pathogens. Compared to the adaptive immune receptors, PRRs have three distinguishing features, viz., universal expression, fast response and recognizing many kinds of microbes. Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and NOD-like receptors (NLRs) recognize viral nucleic acid/bacterial fragments and trigger anti-microbial innate immune responses. Upon recognition of their ligand species, PRRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in the activation of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and interferon regulatory factors (IRFs) that control the transcription of genes encoding pro-inflammatory factors including type I interferon and other inflammatory cytokines, which are critical for eliminating the potential threat to the host. Here, we summarize the effects of small molecule regulators acting on signaling pathways initiated by TLR, RLR and NLR as well as their influence on innate and adaptive immune responses leading to therapy. PMID- 29268134 TI - Emimycin and its nucleoside derivatives: Synthesis and antiviral activity. AB - The synthesis of emimycin, 5-substituted emimycin analogues and the corresponding ribo- and 2'-deoxyribonucleoside derivatives is described. Emimycin, its 5 substituted congeners and the ribonucleoside derivatives are completely devoid of antiviral activity against RNA viruses. In contrast, some of the 2'-deoxyribosyl emimycin derivatives are potent inhibitors of the replication of herpes simplex virus-1 and varicella-zoster virus, lacking cytotoxicity. PMID- 29268135 TI - Transmission scanning electron microscopy: Defect observations and image simulations. AB - The new capabilities of a FEG scanning electron microscope (SEM) equipped with a scanning transmission electron microscopy (STEM) detector for defect characterization have been studied in parallel with transmission electron microscopy (TEM) imaging. Stacking faults and dislocations have been characterized in strontium titanate, a polycrystalline nickel-base superalloy and a single crystal cobalt-base material. Imaging modes that are similar to conventional TEM (CTEM) bright field (BF) and dark field (DF) and STEM are explored, and some of the differences due to the different accelerating voltages highlighted. Defect images have been simulated for the transmission scanning electron microscopy (TSEM) configuration using a scattering matrix formulation, and diffraction contrast in the SEM is discussed in comparison to TEM. Interference effects associated with conventional TEM, such as thickness fringes and bending contours are significantly reduced in TSEM by using a convergent probe, similar to a STEM imaging modality, enabling individual defects to be imaged clearly even in high dislocation density regions. Beyond this, TSEM provides significant advantages for high throughput and dynamic in-situ characterization. PMID- 29268136 TI - Fine tuning an aberration corrected ADF-STEM. AB - Aberration correctors offer greatly enhanced resolution in electron microscopes, however can require dramatically more complicated adjustments. A method of computer adjustment of a probe forming aberration corrector in a Scanning Transmission Electron Microscope (STEM) is proposed and analyzed using image simulation. This method works directly with the image and should work well with crystalline specimens. It does not have a significant dependence on post specimen lens aberrations. PMID- 29268137 TI - Selective distortion of body image by asynchronous visuotactile stimulation. AB - In the rubber hand illusion (RHI), a rubber hand is felt as being part of one's body. This illusion is evoked by providing synchronous visuotactile stimulation to the fake and real hands. Asynchronous visuotactile stimulation is known not to produce such an illusion of ownership, being commonly used as the control condition. Here we explored the impact of synchronous and asynchronous visuotactile stimulation on the body image. We combined the induction of the RHI with a quantitative test for the internal representation of body metrics (i.e., the positions of key fiducial points on the body relative to each other). We found a significant recalibration of the upper/lower arm lengths following asynchronous visuotactile stimulation. In particular, we observed a selective elongation of the lower arm, a distortion typical of deafferentation. Conversely, synchronous visuotactile stimulation did not alter the estimation of the arm segments' length. Our findings are consistent with a dynamic internal representation of body image that is continuously updated based on incoming multisensory information. Furthermore, the use of asynchronous multisensory stimulation as a neutral condition should be reconsidered since it introduces changes in the body image. PMID- 29268138 TI - TUG1 knockdown ameliorates atherosclerosis via up-regulating the expression of miR-133a target gene FGF1. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have been revealed to participate in the pathological events associated with atherosclerosis. However, the exact role of lncRNA taurine-up-regulated gene 1 (TUG1) and its possible molecular mechanism in atherosclerosis remain unidentified. METHODS: High-fat diet (HFD)-treated ApoE /- mice were used as an in vivo model of atherosclerosis. Ox-LDL-induced macrophages and vascular smooth muscle cells (VSMCs) were employed as cell models of atherosclerosis. qRT-PCR was performed to detect the expression of TUG1 and miR-133a. Serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were analyzed by commercially available enzyme kits. Oil red O and hematoxylin and eosin (H&E) staining were conducted to examine atherosclerotic lesion. Luciferase reporter assay combined with RNA immunoprecipitation (RIP) was applied to confirm the interaction between TUG1, miR-133a and FGF1. Cell proliferation ability was determined by Cell Counting Kit-8 (CCK-8) assay and trypan blue dye exclusion test. Cell apoptosis was evaluated with TUNEL assay. Expression and production of inflammatory cytokines was measured with western blot and ELISA analysis. RESULTS: TUG1 expression was up-regulated in HFD-treated ApoE-/- mice, as well as in ox-LDL-induced RAW264.7 and MOVAS cells. TUG1 knockdown inhibited hyperlipidemia, decreased inflammatory response, and attenuated atherosclerotic lesion in HFD-treated ApoE-/- mice. TUG1 could function as a molecular sponge of miR-133a to suppress its expression. TUG1 overexpression accelerated cell growth, improved inflammatory factor expression, and inhibited apoptosis in ox-LDL stimulated RAW264.7 and MOVAS cells, while this effect was abated after transfection with miR-133 mimic. Moreover, fibroblast growth factor 1 (FGF1) was identified as a direct target of miR-133a. Restored expression of FGF1 overturned the effect of miR-133a on cell proliferation, inflammatory factor secretion and apoptosis in ox-LDL-treated RAW264.7 and MOVAS cells. Finally, TUG1 was revealed to up-regulate FGF1 expression by sponging miR-133a. CONCLUSION: TUG1 knockdown ameliorates atherosclerosis by modulating FGF1 via miR-133a, raising the possibility of targeting TUG1 as an atheroprotective therapeutic strategy. PMID- 29268139 TI - A randomised phase II trial of docetaxel versus docetaxel plus carboplatin in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial. AB - BACKGROUND: Docetaxel is standard first-line chemotherapy for patients with metastatic castration-resistant prostate carcinoma (mCRPC). Docetaxel re challenge has never been tested in a prospective randomised controlled study. As some studies support the addition of carboplatin to docetaxel, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel re-treatment in docetaxel pre-treated mCRPC patients. METHODS: Patients with mCRPC with a progression-free interval of >=3 months after initial docetaxel treatment were randomised between docetaxel 75 mg/m2 or docetaxel 60 mg/m2 plus carboplatin AUC4. The primary end-point was progression-free survival (PFS; PSA/RECIST). RESULTS: Owing to insufficient recruitment, the study was discontinued early after inclusion of 75 patients (targeted 150) PFS and overall survival (OS) were comparable between both groups (median PFS 12.7 months (95% CI 9.9-17.5 months) with docetaxel monotherapy and 11.7 months (95% CI 8.5-21.0 months) with combination therapy (p = 0.98); OS 18.5 months (95% CI 11.8-24.5 months) versus 18.9 months (95% CI 16.0-23.7 months) (p = 0.79). An interim analysis (SEQTEST) showed that the null hypothesis could already be excepted, and no significant difference between both study arms was expected if inclusion would be completed. The incidence of grade 3-4 infections and gastrointestinal side effects was numerical higher in the carboplatin arm (p = 0.056). CONCLUSION: This early terminated study suggests no benefit from the addition of carboplatin to docetaxel re-treatment in patients with mCRPC, whereas the combination resulted in more toxicity. Re-treatment with docetaxel monotherapy appears to be feasible, save and effective for patients with mCRPC and an initial good response to docetaxel. TRIAL REGISTRATION: NTR3070. PMID- 29268140 TI - Alterations in comprehensive geriatric assessment decrease survival of elderly patients with cancer. AB - INTRODUCTION: A comprehensive geriatric assessment (CGA) evaluating several domains of health is recommended for elderly patients with cancer. Effects of altered domains on the risk of death in this population need to be clarified. The aim of this study was to estimate the independent association of each CGA domain to overall survival (OS). METHOD: Patients included in the ONCODAGE cohort completed a CGA at baseline. Cox models (one per domain) estimated the hazard ratio (HR) of death for each CGA domain. Directed Acyclic Graphs (DAGs) selected specific sets of adjustment factors for each model. RESULTS: The analysis included 1264 patients (mean age: 78 years, women: 70%). Median follow-up was 5.2 years, and 446 patients died. Each altered domain had a detrimental effect on survival, sometimes dependent on gender, age, education or time from inclusion. Nutritional status had a time-varying effect, with higher mortality rates if altered only within the first 3 years of follow-up. In case of altered mobility, the risk of death was higher only for the youngest patients and, in case of altered autonomy, only for the youngest women. An altered neurological state led to higher mortality rates; this effect increased with the level of education. Patients with altered psychological status or more than four comorbidities at baseline had also higher mortality rates. CONCLUSIONS: Patients with an altered CGA domain have a higher risk of death than those without any alteration. The effect of some alterations is different in some subgroups or at a given time of the treatments. PMID- 29268141 TI - Multiple ligand binding sites regulate the Hedgehog signal transducer Smoothened in vertebrates. AB - The Hedgehog (Hh) pathway plays a central role in the development of multicellular organisms, guiding cell differentiation, proliferation and survival. While many components of the vertebrate pathway were discovered two decades ago, the mechanism by which the Hh signal is transmitted across the plasma membrane remains mysterious. This fundamental task in signalling is carried out by Smoothened (SMO), a human oncoprotein and validated cancer drug target that is a member of the G-protein coupled receptor protein family. Recent structural and functional studies have advanced our mechanistic understanding of SMO activation, revealing its unique regulation by two separable but allosterically-linked ligand-binding sites. Unexpectedly, these studies have nominated cellular cholesterol as having an instructive role in SMO signalling. PMID- 29268142 TI - Tumor acidity activating multifunctional nanoplatform for NIR-mediated multiple enhanced photodynamic and photothermal tumor therapy. AB - The study reports a multifunctional nanoplatform based on mesoporous silica coated gold nanorod (AuNR@MSN) to overcome biological barriers associating with nanocarrier for multiple enhanced photodynamic therapy (PDT) and photothermal therapy (PPT). Indocyanine green (ICG) was loaded into AuNR@MSN and end-capped with beta-cyclodextrin (beta-CD). Then, a peptide RLA ([RLARLAR]2) with plasma membrane permeability and mitochondria-targeting capacity was anchored to AuNR@MSN via host-gust interaction. Subsequently, a charge-reversible polymer was introduced to endow stealth property. When the nanoplatform extravasates to tumor tissue, the weak acidity in tumor microenvironment could induce the dissociation of charge-reversible polymer and re-exposure of RLA peptide. Such a pH-mediated transition could facilitate the targeted accumulation of the nanoplatform in mitochondria. Upon singular 808 nm laser irradiation, the nanoplatform displayed enhanced PDT effect through the generation of reactive oxygen species (ROS) mediated by the local electric field of AuNR, plasmonic photothermal effect, and leakage of endogenous ROS by mitochondrion-targeted PDT. Meanwhile, local hyperthermia was generated by both ICG and AuNR for PPT. The in vitro and in vivo experiments demonstrated that the composite nanoplatform had good antitumor effect with minimal side effect. This work provides new insight into the development of new phototherapeutics for oncotherapy. PMID- 29268143 TI - Regeneration of cortical tissue from brain injury by implantation of defined molecular gradient of semaphorin 3A. AB - Despite great efforts in the exploration of therapeutic strategies for treating brain injuries, it is still challenging to regenerate neural tissues and to restore the lost function within an injured brain. In this report, we employed a tissue engineering approach to regenerate cortical tissue from brain injury by implantation of defined semaphorin 3A (Sema3A) gradient packaged in a hydrogel based device. Over a thirty-day recovery period, the implanted Sema3A gradient was sufficient to induce substantial migration of neural progenitor cells to the hydrogel and to promote differentiation of these cells for neuroregeneration at the injury site. As revealed by molecular characterization and RNA transcriptome analysis, the regenerated tissues induced by Sema3A gradient exhibited significant similarity to normal cortical tissues. Many genes associated with neuronal migration and stem cell differentiation were significantly up-regulated. In addition, our result suggested a crosstalk between Sema3A and Wnt/beta-catenin pathways in course of induced brain regeneration. This study demonstrated an innovative strategy to regenerate brain tissue after traumatic injury by controlling the in vivo chemotactic environment with unprecedented sophistication, and also resolved new insights about Sema3A's role in adult neurogenesis. PMID- 29268144 TI - Multifunctional hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release for enhanced tumor suppression. AB - Therapeutic efficacy of conventional single PEGylated polymeric micelles is significantly reduced by limited endocytosis and intracellular drug release. To improve drug delivery efficiency, poly (ethylene glycol)-block-poly (l-lactic acid)/(Arg-Gly-Asp-Phe)-poly (aminoethyl ethylene phosphate)-block-poly (l-lactic acid) (PEG-PLLA/RGDF-PAEEP-PLLA) hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release are developed. The optimized hybrid micelles with 6 wt % of RGDF have favorable in vitro and in vivo activities. The hybrid micelles could temporarily shield the targeting efficacy of RGDF at pH 7.4 due to the steric effect exerted by concealment of RGDF peptides in the PEG corona, which strongly decreases the clearance by mononuclear phagocyte system and consequently improves the tumor accumulation. Inside the solid tumor with a lower acidic pH, the hybrid micelles restore the active tumor targeting property with exposed RGDF on the surface of the micelles because of the increased protonation and stretching degree of PAEEP blocks. RGDF-mediated endocytosis improves the tumor cell uptake. The hybrid micelles would also enhance intracellular drug release because of the hydrolysis of the acid/phosphatase sensitivity of PAEEP blocks in endo/lysosome. Systemic administration of the hybrid micelles significantly inhibits tumor growth by 96% due to the integration of enhanced circulation time, tumor accumulation, cell uptake and intracellular drug release. PMID- 29268145 TI - The WNT7B protein promotes the migration and differentiation of human dental pulp cells partly through WNT/beta-catenin and c-Jun N-terminal kinase signalling pathways. AB - OBJECTIVE: The aim of this study is to investigate the role of the WNT7B protein in the migration and differentiation of human dental pulp cells (HDPCs). DESIGN: The effect of recombinant human WNT7B (rhWNT7B) on the proliferation and migration of HDPCs was evaluated by 5-ethynyl-2'-deoxyuridine (EdU), immunofluorescence staining of Ki67, flow cytometry and scratch assay; the differentiation of HDPCs was measured by alkaline phosphatase (ALP) staining, alizarin red staining, ALP activity, qPCR and western blot. The activation of the WNT/beta-catenin (WNT/beta-catenin) and c-Jun N-terminal kinase (JNK) pathways was analysed by western blot, immunocytochemistry and dual luciferase assays. XAV939 and SP600125,the inhibitors of the WNT/beta-catenin and JNK pathways, were further applied to verify the mechanism. RESULTS: rhWNT7B repressed the proliferation but did not affect the apoptosis of HDPCs. In the presence of rhWNT7B, ALP and alizarin red staining were increased substantially in the HDPCs with osteogenic induction; the gene expression of Runx2 and Col1 in HDPCs was quite elevated compared with that induced in osteogenic medium without WNT7B measured by qPCR; The ALP activity was also increased with rhWNT7B stimulation in HDPCs after 7-day odontogenic culture; Western blot revealed that the expression of dentin sialophosphoprotein (DSPP) of HDPCs was up-regulated significantly with the addition of WNT7B as well. Further study showed that rhWNT7B activated the WNT/beta-catenin and JNK signalling pathways in the differentiation of HDPCs. XAV939 and SP600125 can partly offset the effect of the WNT7B-induced differentiation of HDPCs. CONCLUSION: WNT7B promoted the differentiation of HDPCs partly through the WNT/beta-catenin and JNK signalling pathways. PMID- 29268147 TI - Association between lumbopelvic pain and pelvic floor dysfunction in women: A cross sectional study. AB - BACKGROUND: The prevalence, cost and disability associated with lumbopelvic pain continues to rise despite the range of available therapeutic interventions, indicating a deficiency in current approaches. A literature base highlighting a correlation between lumbopelvic pain and pelvic floor function is developing; however, the features that characterize this correlation have yet to be fully established. PURPOSE: The purpose of this study was to determine the prevalence and characteristics of pelvic floor muscle function among women with lumbopelvic pain. METHODS: A cross-sectional study was conducted on non-pregnant women presenting with lumbopelvic pain to one of seven outpatient orthopaedic clinics in Canada. Potential participants underwent a screening process to assess for pelvic floor muscle dysfunction. RESULTS: A total of 182 women were recruited and 97 were excluded, leaving 85 participants (n = 85). Of these, 95.3% were determined to have some form of pelvic floor dysfunction. Specifically, 71% of the participants had pelvic floor muscle tenderness, 66% had pelvic floor weakness and 41% were found to have a pelvic organ prolapse. Participants with combined low back pain and pelvic girdle pain presented with higher levels of disability and increased characteristics of pelvic floor dysfunction. CONCLUSIONS: Our findings corroborate and extend recent research supporting the hypothesis that a high proportion of pelvic floor muscle dysfunction is present among women with lumbopelvic pain. Specifically, increased pelvic floor muscle pressure-pain sensitivity represented the most frequent characteristic, the clinical implications of which require further study. PMID- 29268146 TI - Mobile contingency management as an adjunctive treatment for co-morbid cannabis use disorder and cigarette smoking. AB - INTRODUCTION: Cannabis is the most widely used illicit drug in the U.S. with 19.8 million current users. Population-based data indicate that almost all cannabis users (90%) have a lifetime history of tobacco smoking and the majority (74%) currently smoke tobacco. Among cannabis users, smoking tobacco is associated with increased frequency of cannabis use, increased morbidity, and poorer cannabis cessation outcomes. There is a lack of research, however, focused on addressing cessation of both substances simultaneously. The purpose of the current pilot study was to evaluate the feasibility and acceptability of a multi-component tobacco/cannabis abstinence treatment. METHODS: Five participants completed Abstinence Reinforcement Therapy, an intervention that included five sessions of cognitive-behavioral telephone counseling for tobacco/cannabis, pharmacotherapy for smoking cessation, and five weeks of mobile contingency management to remain abstinent from tobacco and cannabis. RESULTS: Feasibility of recruitment, retention and treatment completion was high. Satisfaction with the treatment was also high. CONCLUSION: Results support the feasibility and acceptability of this approach with dual cannabis and tobacco users and suggest that further research examining the efficacy of this approach is warranted. PMID- 29268148 TI - A chip-based rapid genotyping assay to discriminate between rhinovirus species A, B and C. AB - BACKGROUND: Human rhinoviruses (RVs) are increasingly associated with severe disease of the respiratory tract. Multiple studies highlighted the clinical significance of different RV species; RV-C is linked to asthma exacerbations and increased disease severity in children, whereas RV-B seems to correlate with milder disease. OBJECTIVES: Current typing strategies for differentiation of RV species are time consuming and require extensive equipment. Here we present a novel genotyping tool to discriminate RV species A, B and C. STUDY DESIGN: The method encompasses a VP4/VP2 polymerase chain reaction (PCR), followed by hybridization of the product on a macro array with probes covering RV-A, B, and C, produced by Chipron as custom array. Validation was performed with respiratory specimens submitted for diagnostic evaluation to the Academic Medical Center. A selection of RV PCR-positive samples genotyped based on VP4/VP2 sequencing was evaluated. Diagnostic performance was tested on respiratory samples positive for RV in an in-house multiplex respiratory PCR from January 2016 to January 2017. In house primers and additional genotype-specific primers were used for sequencing to investigate array-negative and array-double-positive samples. RESULTS: The majority of samples pretyped RVs (n = 135) were classified correctly, except for one that was assigned RV-C instead of RV-A, and 3 samples tested negative. The array gave four double-positive results; the presence of more than one genotype was confirmed in two samples. In 173/187 (92.5%) RV-positive tested patient samples from 2016, the test resulted in a designated species. RV species A was identified in 109 specimens (58.3%), RV-B in 26 (13.9%), and RV-C in 56 (29.9%) samples. Sequencing of the probe region of 14 (7.6%) negative samples revealed up to 3 mismatches to the probes for 12 samples; in 2 cases no PCR product was generated. Notably, in 18 samples the chip detected more than one species, of which 16 were confirmed by sequencing. DISCUSSION: The Chipron LCD RV array provides a fast and highly sensitive method for discrimination between rhinovirus species, and has the power to detect dual infections. PMID- 29268149 TI - Effects of digestate recirculation on a two-stage anaerobic digestion system, particularly focusing on metabolite correlation analysis. AB - Single-stage (S-N treatment) and two-stage anaerobic digestion with (T-R treatment) and without digestate recirculation (T-N treatment) for methane production using food waste (FW) were comparatively evaluated to examine the effects of digestate recirculation on anaerobic digestion (AD). Digestate recirculation positively affected the methane yield and organic loading rate (OLR). Metabolite correlation analysis revealed that a systematic hydrolysis degree of greater than 75% is crucial to achieve the complete recoverable yield of methane from FW. Digestate recirculation also markedly increased the system alkalinity, maintaining an optimum pH for methanogens. However, the ammonium accumulated by T-R treatment would destroy the metabolic balance between the hydrolytic bacteria and methanogens, especially at a critical OLR. Therefore, the appropriate control of two-stage AD systems with digestate recirculation is limited not only to OLR regulation but also to the prevention of ammonium accumulation. PMID- 29268150 TI - Beneficial synergistic effect on bio-oil production from co-liquefaction of sewage sludge and lignocellulosic biomass. AB - Co-liquefaction of municipal sewage sludge (MSS) and lignocellulosic biomass such as rice straw or wood sawdust at different mixing ratios and the characterization of the obtained bio-oil and bio-char were investigated. Synergistic effects were found during co-processing of MSS with biomass for production of bio-oil with higher yield and better fuel properties than those from individual feedstock. The co-liquefaction of MSS/rice straw (4/4, wt) increased the bio-oil yield from 22.74% (bio-oil yield from liquefaction of MSS individually) or 23.67% (rice straw) to 32.45%. Comparable increase on bio-oil yield was also observed for MSS/wood sawdust mixtures (2/6, wt). The bio-oils produced from MSS/biomass mixtures were mainly composed of esters and phenols with lower boiling points (degradation temperatures) than those from individual feedstock (identified with higher heavy bio-oil fractions). These synergistic effects were probably resulted from the interactions between the intermittent products of MSS and those of biomass during processing. PMID- 29268151 TI - Microwave-assisted acid pretreatment of alkali lignin: Effect on characteristics and pyrolysis behavior. AB - This study performed microwave-assisted acid pretreatment on pure lignin. The effects of microwave temperature, microwave time, and hydrochloric acid concentration on characteristics and pyrolysis behavior of lignin were examined. Results of ultimate analysis revealed better properties of all pretreated samples than those of raw lignin. Fourier transform infrared spectroscopy analysis showed breakage of betaO4 bond and aliphatic side chain, decrease in OH groups, and formation of CO groups in pretreatment. Microwave temperature exerted more significant influence on lignin structure. Thermal stability of treated lignin was improved and insensitive to short microwave time and acid concentration under mild conditions. Resulting from improved alkyl-phenols and decreased alkoxy phenols, microwave-assisted acid pretreatment of lignin yielded bio-oil with excellent quality. Total yield of phenols in pyrolysis vapors (200 degrees C) improved to 14.15%, whereas that of guaiacols decreased to 22.36%. This study shows that microwave-assisted acid pretreatment is a promising technology for lignin conversion. PMID- 29268152 TI - Self-reported executive function and hoarding in adults with obsessive-compulsive disorder. AB - BACKGROUND: Hoarding behavior may distinguish a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Little is known about the relationship between executive dysfunction and hoarding in individuals with OCD. METHODS: The study sample included 431 adults diagnosed with DSM-IV OCD. Participants were assessed by clinicians for Axis I disorders, personality disorders, indecision, and hoarding. Executive functioning domains were evaluated using a self-report instrument, the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). We compared scores on these domains in the 143 hoarding and 288 non-hoarding participants, separately in men and women. We used logistic regression to evaluate relationships between executive function scores and hoarding, and correlation and linear regression analyses to evaluate relationships between executive function scores and hoarding severity, in women. RESULTS: In men, the hoarding group had a significantly higher mean score than the non-hoarding group only on the shift dimension. In contrast, in women, the hoarding group had higher mean scores on the shift scale and all metacognition dimensions, i.e., those that assess the ability to systematically solve problems via planning and organization. The relationships in women between hoarding and scores on initiating tasks, planning/organizing, organization of materials, and the metacognition index were independent of other clinical features. Furthermore, the severity of hoarding in women correlated most strongly with metacognition dimensions. CONCLUSIONS: Self-reported deficits in planning and organization are associated with the occurrence and severity of hoarding in women, but not men, with OCD. This may have implications for elucidating the etiology of, and developing effective treatments for, hoarding in OCD. PMID- 29268153 TI - Current prevalence, comorbidity and associated factors for symptoms of depression and generalised anxiety in the Lagos State Mental Health Survey (LSMHS), Nigeria. AB - BACKGROUND: Depression and anxiety are very prevalent, highly co-morbid, burdensome with huge treatment gaps in low and middle-income countries (LMICs). This study aimed to estimate the current prevalence of symptoms of depression and generalised anxiety, examine co-morbid conditions and associated sociodemographic factors in Lagos state, Nigeria. METHODS: A face to face household survey completed by 11,246 adult participants (age 18-75years). Clinically significant symptoms of depression, generalised anxiety and somatic symptoms were assessed using the specific modules of the Patient Health Questionnaire (PHQ) respectively. Alcohol use, substance use and disability were assessed with the Alcohol Use Disorders Identification Test-short form (AUDIT-C), the Mini International Neuropsychiatric Interview (M.I.N.I) and the WHO Disability Assessment Schedule (WHODAS 2.0) respectively. RESULTS: The mean age was 36.75 (sd 12.3) years and there were 6525 (58.0%) females. The weighted current prevalence of symptoms of depression, generalised anxiety and combined depression/generalised anxiety were 5.5% (se 0.3), 3.5% (se 0.2) and 1.2% (se 0.1) respectively. About 20.9% of all cases of depressive symptoms have co morbidity with symptoms of generalised anxiety. Symptoms of depression and generalised anxiety had high co-morbidity with somatic symptoms, alcohol use problems and disability but not substance use disorders. Being female, not married (especially separated/divorced or widowed) and unemployment were significantly associated with presence of either symptoms of depression or generalised anxiety. CONCLUSION: Our findings suggest that despite the popularity of cross-national surveys, there is need for individual countries and states to generate complimentary local data to plan effective local response to close the huge treatment gap for common mental disorders. PMID- 29268154 TI - Subthreshold autism spectrum disorder in patients with eating disorders. AB - AIM: Increasingly data suggest a possible overlap between psychopathological manifestations of eating disorders (EDs) and autism spectrum disorders (ASD). The aim of the present study was to assess the presence of subthreshold autism spectrum symptoms, by means of a recently validated instrument, in a sample of participants with EDs, particularly comparing participants with or without binge eating behaviours. METHODS: 138 participants meeting DSM-5 criteria for EDs and 160 healthy control participants (HCs), were recruited at 3 Italian University Departments of Psychiatry and assessed by the SCID-5, the Adult Autism Subthreshold Spectrum (AdAS Spectrum) and the Eating Disorders Inventory, version 2 (EDI-2). ED participants included: 46 with restrictive anorexia (AN-R); 24 with binge-purging type of Anorexia Nervosa (AN-BP); 34 with Bulimia Nervosa (BN) and 34 with Binge Eating Disorder (BED). The sample was split in two groups: participants with binge eating behaviours (BEB), in which were included participants with AN-BP, BN and BED, and participants with restrictive behaviours (AN-R). RESULTS: participants with EDs showed significantly higher AdAS Spectrum total scores than HCs. Moreover, EDs participants showed significantly higher scores on all AdAS Spectrum domains with the exception of Non verbal communication and Hyper-Hypo reactivity to sensory input for AN-BP participants, and Childhood/Adolescence domain for AN-BP and BED participants. Participants with AN-R scored significantly higher than participants with BEB on the AdAS Spectrum total score, and on the Inflexibility and adherence to routine and Restricted interest/rumination AdAS Spectrum domain scores. Significant correlations emerged between the Interpersonal distrust EDI-2 sub-scale and the Non verbal communication and the Restricted interest and rumination AdAS Spectrum domains; as well as between the Social insecurity EDI-2 sub-scale and the Inflexibility and adherence to routine and Restricted interest and rumination domains in participants with EDs. CONCLUSIONS: Our data corroborate the presence of higher subthreshold autism spectrum symptoms among ED participants with respect to HCs, with particularly higher levels among restrictive participants. Relevant correlations between subthreshold autism spectrum symptoms and EDI-2 Subscale also emerged. PMID- 29268155 TI - Lymphoblast-derived integration-free ISRM-CON9 iPS cell line from a 75year old female. AB - Human lymphoblast cells were used to generate integration-free induced pluripotent stem cells (iPSCs) employing episomal-based plasmids expressing OCT4, SOX2, NANOG, LIN28, c-MYC and L-MYC. The derived iPSCs were defined as pluripotent based on (i) expression of pluripotency-associated markers, (ii) embryoid body-based differentiation into cell types representative of the three germ layers and (iii) the similarity between the transcriptomes of the iPSC line and the human embryonic stem cell line H1 with a Pearson correlation of 0.95. PMID- 29268156 TI - Derivation of human iPSC line NCCSi002-A from umbilical cord blood (UCB) CD34+cells of donor from Indian ethnicity. AB - We discuss the reprogramming of CD34+ cells isolated from UCB of a healthy female child of Indian ethnicity. The CD34+cells were nucleofected using episomal vectors expressing Oct4, Sox2, L-Myc, Klf4, Lin28 and p53DD (negative mutation in p53). The colonies were stained for alkaline phosphatase and evaluated for pluripotency marker expression by PCR, immunofluorescence and flow-cytometry. The safety of cells was confirmed by absence of plasmid in subsequent passages by PCR. G-banded karyotype demonstrated a stable genome. The ability of tri-lineage differentiation was confirmed by specific marker expression by immunofluorescence invitro and teratoma formation invivo. PMID- 29268157 TI - Quantifying regional consumption-based health impacts attributable to ambient air pollution in China. AB - Serious air pollution has caused about one million premature deaths per year in China recently. Besides cross-border atmospheric transport of air pollution, trade also relocates pollution and related health impacts across China as a result of the spatial separation between consumption and production. This study proposes an approach for calculating the health impacts of emissions due to a region's consumption based on a multidisciplinary methodology coupling economic, atmospheric, and epidemiological models. These analyses were performed for China's Beijing and Hebei provinces. It was found that these provinces' consumption-based premature deaths attributable to ambient PM2.5 were respectively 22,500 and 49,700, which were 23% higher and 37% lower than the numbers solely within their boundaries in 2007. The difference between the effects of trade and trade-related emissions on premature deaths attributable to air pollution in a region has also been clarified. The results illustrate the large and broad impact of domestic trade on regional air quality and the need for comprehensive consideration of supply chains in designing policy to mitigate the negative health impacts of air pollution across China. PMID- 29268158 TI - The influence of specific atmospheric circulation types on PM10-bound benzo(a)pyrene inhalation related lung cancer risk in Barcelona, Spain. AB - Benzo(a)pyrene (BaP) is a Polycyclic Aromatic Hydrocarbon (PAH) well known for its carcinogenic effects. In this study, BaP levels in daily PM10 samples collected at 8 stations in Barcelona (Spain), during the years 2013-2015, were analyzed in relation to distinct atmospheric circulation patterns. Our objective was to estimate the BaP inhalation related Lung Cancer Risk (LCR) in connection with the prevailing synoptic conditions. Air masses were also analyzed in order to examine the possibility of transboundary BaP contributions. The influence of high pressure anticyclonic systems caused a sharp increase of PM10-bound BaP concentrations in all stations due to recirculation and accumulation of polluted air, whilst the calculated BaP inhalation related LCR values implied a potential health risk from BaP exposure and were not recommendable primarily at central heavily trafficked sites. However the LCR remained below the upper limit posed by United States Environmental Protection Agency (US EPA), even under the most stagnant atmospheric conditions. The elaboration of backward air mass trajectories with Concentration Weighted Trajectory (CWT) algorithm indicated that combustion emissions in Spain, France and the industrialized Northern coast of Algeria are potential contributors to the PM10-bound BaP concentrations measured in Barcelona. PMID- 29268159 TI - Presence of diphenyl phosphate and aryl-phosphate flame retardants in indoor dust from different microenvironments in Spain and the Netherlands and estimation of human exposure. AB - Phosphate flame retardants (PFRs) are ubiquitous chemicals in the indoor environment. Diphenyl phosphate (DPHP) is a major metabolite and a common biomarker of aryl-PFRs. Since it is used as a chemical additive and it is a common impurity of aryl-PFRs as well as a degradation product, its presence in indoor dust as an additional source of exposure should not be easily ruled out. In this study, DPHP (and TPHP) are measured in indoor dust in samples collected in Spain and in the Netherlands (n=80). Additionally, the presence of other emerging aryl-PFRs was monitored by target screening. TPHP and DPHP were present in all samples in the ranges 169-142,459ng/g and 106-79,661ng/g, respectively. DPHP concentrations were strongly correlated to the TPHP levels (r=0.90, p<0.01), suggesting that DPHP could be present as degradation product of TPHP or other aryl-PFRs. Estimated exposures for adults and toddlers in Spain to TPHP and DPHP via dust ingestion (country for which the number of samples was higher) were much lower than the estimated reference dose (US EPA) for TPHP. However, other routes of exposure may contribute to the overall internal exposure (diet, dermal contact with dust/consumer products and inhalation of indoor air). The estimated urinary DPHP levels for adults and toddlers in Spain (0.002-0.032ng/mL) as a result of dust ingestion were low in comparison with the reported levels, indicating a low contribution of this source of contamination to the overall DPHP exposure. Other aryl-PFRs, namely cresyl diphenyl phosphate (CDP), resorcinol bis(diphenyl phosphate) (RDP), 2-ethylhexyl diphenyl phosphate (EDPHP), isodecyl diphenyl phosphate (IDP) and bisphenol A bis(diphenyl phosphate) (BDP), were all detected in indoor dust, however, with lower frequency. PMID- 29268161 TI - Improvement of biosurfactant production by Wickerhamomyces anomalus CCMA 0358 and its potential application in bioremediation. AB - In this work, biosurfactant production by Wickerhamomyces anomalus CCMA 0358 was increased through the development of an optimized culture medium using response surface methodology. The optimized culture medium contained yeast extract (4.64 g/L), ammonium sulfate (4.22 g/L), glucose (1.39 g/L) and olive oil (10 g/L). Biosurfactant production using this medium was validated both in flasks and bioreactor, and the surface tension was reduced from 49.0 mN/m up to 31.4 mN/m and 29.3 mN/m, respectively. In both cases, the highest biosurfactant production was achieved after 24 h of growth. W. anomalus CCMA 0358 demonstrated to be a fast biosurfactant producer (24 h) as compared to other yeast strains previously reported (144-240 h). The produced biosurfactant remained stable at high temperature (121 degrees C), NaCl concentrations as high as 300 g/L, and pH values between 6 and 12. The crude biosurfactant allowed the recovery of 20% of crude oil from contaminated sand, being a promising candidate for application in bioremediation or in the petroleum industry. PMID- 29268160 TI - Distribution, variability, and predictors of urinary bisphenol A levels in 50 North Carolina adults over a six-week monitoring period. AB - Bisphenol A (BPA) is commonly manufactured to make polycarbonate plastics and epoxy resins for use in consumer products and packaged goods. BPA has been found in several different types of environmental media (e.g., food, dust, and air). Many cross-sectional studies have frequently detected BPA concentrations in adult urine samples. However, limited data are available on the temporal variability and important predictors of urinary BPA concentrations in adults. In this work, the major objectives were to: 1) quantify BPA levels in duplicate-diet solid food, drinking water, hard floor surface wipe, and urine samples (first-morning void [FMV], bedtime, and 24-h) collected from adults over a six-week monitoring period; 2) determine the temporal variability of urinary BPA levels using concentration, specific gravity (SG) adjusted, creatinine (CR) adjusted, and excretion rate values, and; 3) examine associations between available study factors and urinary BPA concentrations. In 2009-2011, a convenience sample of 50 adults was recruited from residential settings in North Carolina. The participants completed diaries and collected samples during weeks 1, 2, and/or 6 of a six-week monitoring period. BPA was detected in 38%, 4%, and 99% of the solid food (n=775), drinking water (n=50), and surface wipe samples (n=138), respectively. Total BPA (free plus conjugated) was detected in 98% of the 2477 urine samples. Median urinary BPA levels were 2.07ng/mL, 2.20ng/mL-SG, 2.29ng/mg, and 2.31ng/min for concentration, SG-adjusted, CR-adjusted, and excretion rate values, respectively. The intraclass correlation coefficient (ICC) estimates for BPA showed poor reproducibility (<=0.35) for all urine sample types and methods over a day, week, and six weeks. CR-adjusted bedtime voids collected over six weeks required the fewest, realistic number of samples (n=11) to obtain a reliable biomarker estimate (ICC=0.80). Results of linear mixed-effects models showed that sex, race, season, and CR-level were all significant predictors (p<0.05) of the adults' urinary BPA concentrations. BPA levels in the solid food and surface wipe samples did not contribute significantly to the participants' urinary BPA concentrations. However, a significant positive relationship was observed between solid food intake and urine-based estimates of BPA dose, when aggregated over 24-h periods. Ingestion of BPA via solid food explained only about 20% of the total dose (at the median of the dose distribution), suggesting that these adults were likely exposed to other major unknown (non-dietary) sources of BPA in their everyday environments. PMID- 29268162 TI - Activation of persulfate by irradiated laterite for removal of fluoroquinolones in multi-component systems. AB - Although several emerging contaminants (e.g. fluoro(quinolones) (FQs)) have been simultaneously detected in environmental systems, there is very limited information on their elimination from contaminated waters in multi-component systems. In this study, removal of three FQs including flumequine (FLU), ciprofloxacin (CIP) and norfloxacin (NOR) were investigated in single and mixture systems, using natural laterite soil and persulfate (PS) under UVA irradiation. Both sorption and oxidation reactions contribute to the removal of FQs from aqueous phase, whereas quenching experiments showed that SO4- is mainly responsible for the FQs oxidation. The kinetic rate constants can be ranked as follows: CIP > NOR > FLU, regardless of whether the compound was alone or in mixture. The higher degradation rate constant of CIP relative to those of NOR and FLU could be explained by the high reactivity of SO4- radical with cyclopropane ring containing compounds. Fall in oxidation performance was observed in synthetic wastewater, probably due to sulfate radical scavenging by wastewater components. However, degradation rate constants of CIP in wastewater remains unchanged in mixture systems as compared to single ones. This environmentally friendly remediation technology may appear as a promising way for the removal of fluoroquinolone antibiotics from multi-contaminated waters. PMID- 29268163 TI - Considering quality of life in end-of-life decisions for severely disabled children. AB - BACKGROUND: End-of-life decisions (EoLDs) are very difficult to make. How parents and physicians incorporate quality of life (QoL) considerations into their end-of life decision making (EoLDM) for children with profound intellectual and multiple disabilities (PIMD) remains unknown. AIMS: To determine which elements contribute to QoL according to parents and physicians, how QoL is incorporated into EoLDM and how parents and physicians discuss QoL considerations in the Netherlands. METHODS: Semi-structured interviews were conducted with the physicians and parents of 14 children with PIMD for whom an EoLD had been made within the past two years. RESULTS: Parents and physicians agreed on the main elements that contribute to QoL in children with PIMD. The way in which QoL was incorporated differed slightly for different types of decisions. Parents and physicians rarely discussed elements contributing to the child's QoL when making EoLDS. CONCLUSIONS: and Implications Although QoL was highly important during EoLDM for children with PIMD, parents and physicians did not fully explore the elements that contribute to the child's QoL when they made EoLDs. We recommend the development of a communication tool that will help parents and physicians discuss elements that contribute to QoL and the consequences these elements have for upcoming decisions. PMID- 29268164 TI - Enhanced bioelectricity generation of air-cathode buffer-free microbial fuel cells through short-term anolyte pH adjustment. AB - Short-term initial anolyte pH adjustment can relieve the performance deterioration of the single-chamber air-cathode buffer-free microbial fuel cell (BFMFC) caused by anolyte acidification. Adjusting the initial anolyte pH to 9 in 5 running cycles is the optimum strategy. The relative abundance of the electrochemically active Geobacter in the KCl-pH9-MFC anode biofilm increased from 59.01% to 75.13% after the short-term adjustment. The maximum power density (Pmax) of the KCl-pH9-MFC was elevated from 316.4mW.m-2 to 511.6mW.m-2, which was comparable with that of the PBS-MFC. And, after the short-term adjusting, new equilibrium between the anolyte pH and the anode biofilm electrochemical activity has been established in the BFMFC, which ensured the sustainability of the improved bioelectricity generation performance. PMID- 29268165 TI - Depressive symptoms in patients with an implantable cardioverter defibrillator: Does treatment expectations play a role? AB - OBJECTIVE: Patients with an implantable cardioverter defibrillator (ICD) and co morbid depression are at greater risk of poor quality of life and premature death. We examined if treatment expectations predict depressive symptoms 12months post implant. METHODS: First-time implant patients from the WEBCARE study (n=177; 83.1% men) completed the EXPECTations towards ICD therapy questionnaire and the Type D Scale at baseline, and the Patient Health Questionnaire at baseline and 12months. RESULTS: Using hierarchical linear regression with 3 models, we identified the following independent predictors of 12-months depressive symptoms: Model 1: Negative treatment expectations (beta=0.202; p=0.020) and baseline depression (beta=0.376; p<0.0001). Model 2: Baseline depression (beta=0.350; p<0.0001) and Type D personality (beta=0.162; p=0.042); negative treatment expectations was borderline significant (beta=0.169; p=0.051). Model 3: Baseline depression (beta=0.353; p<0.0001) and negative treatment expectations (beta=0.180; p=0.043); Type D personality was not significant (beta=0.150; p=0.067), adjusting for positive treatment expectations, heart failure, sex, and shocks during follow-up. The models accounted for 22.2%, 24.1%, and 23.3% of the variance in 12-months depressive symptoms, respectively. CONCLUSION: Further research is warranted to explore the role of treatment expectations at the time of implant and its overlap with personality as a determinant of depression in patients with an ICD. PMID- 29268166 TI - Prevalence, correlates and outcomes of insomnia in patients with first episode psychosis from a tertiary psychiatric institution in Singapore. AB - OBJECTIVES: The study aimed to evaluate the prevalence of insomnia in patients with first episode psychosis (FEP) and to explore the relationship between insomnia and socio-demographic and clinical variables as well as quality of life (QOL) and functioning in Singapore. METHODS: Data on sleep, smoking, alcohol habits, QOL and socio-demographics were collected from 280 FEP patients who were enrolled in the Early Psychosis Intervention Programme (EPIP) within 3months of joining the programme. Multiple logistic regression analyses were performed to determine the socio-demographic and clinical correlates of insomnia. The association of insomnia with QOL as well as functioning was examined using multiple linear regression analyses. RESULTS: The prevalence of clinical insomnia was 22.6%. Older age and higher dosage of antipsychotic medication were significantly associated with a lower risk of insomnia while hazardous alcohol use, current smoking and a longer duration of untreated psychosis were significantly associated with a higher risk of insomnia. Insomnia was associated with significant decreases in all QOL domains assessed in the study even after adjusting for confounders. CONCLUSIONS: FEP patients with insomnia must be screened for hazardous alcohol use and smoking. Patients must be referred concurrently for treatment of insomnia, smoking cessation as well as brief intervention for hazardous alcohol use when needed. PMID- 29268167 TI - Suicidal ideation among adults with cardiovascular disease: The National Health and Nutrition Examination Survey. AB - OBJECTIVE: Previous studies have shown a possible link between cardiovascular disease (CVD) and suicidal ideation (SI). However, limited information exists regarding the association between different subtypes of CVD and SI and the role of depression. METHODS: Data were used from the National Health and Nutrition Examination Survey for cycles 2009-2010 and 2011-2012. SI was assessed by item 9 of the Patient Health Questionnaire 9. Data regarding sociodemographic factors, and comorbid conditions were collected and examined as potential correlates. Logistic regression analyses were used to examine the relationship between CVD and subtypes and suicidal ideation. RESULTS: Among a total of 11,678 participants, suicidal ideation was significantly higher among patients with CVD compared to participants without a history of CVD (5.4% vs 3.6%, P<0.001). A subset of patients with CVD with a history of congestive heart failure (CHF) and prior myocardial infarction (MI) had the highest percentage of SI (10.6%). The association between CVD and SI remained significant after adjusting for baseline characteristics and associated comorbidities including depression (OR 1.40, 95% CI 1.10-2.09, P=0.006). CONCLUSION: CVD is an independent risk factor for SI. The identification of a subset of patients with CVD at greatest risk of SI underlines the importance of screening in this vulnerable population. PMID- 29268168 TI - Conserved FcgammaR- glycan discriminates between fucosylated and afucosylated IgG in humans and mice. AB - The binding strength between IgG and FcgammaR is influenced by the composition of the N-linked glycan at position N297 in the Fc-domain of IgG. Particularly, afucosylation increases the binding affinity of human IgG1 to human FcgammaRIIIa up to ~20 fold, and additional galactosylation of the afucosylated IgG increases the affinity up to ~40 fold. The increase in affinity for afucosylated IgG has previously been shown to depend on direct carbohydrate-carbohydrate interactions between the IgG-Fc glycan with an N-linked glycan at position 162 unique to hFcgammaRIIIa and hFcgammaRIIIb. Here we report that the N162 glycosylation site is also found in the orthologous mouse FcgammaR, mFcgammaRIV. The N162-glycan in mFcgammaRIV was also responsible for enhancing the binding to mouse IgG with reduced fucose similar to hFcgammaRIIIa. However, unlike hFcgammaRIIIa, mFcgammaRIV did not bind more avidly to IgG with increased galactose and reduced fucose. Overall, these results suggest the N162-glycan in the human FcgammaRIII family and its orthologous mouse FcgammaRIV to be functionally conserved. PMID- 29268170 TI - Evaluation of the "non-epileptic" patient in a tertiary center epilepsy clinic. AB - PURPOSE: The epilepsy clinic at the Montreal Neurological Institute receives a high volume of referrals. Despite most patients assessed in the clinic eventually being diagnosed with epilepsy, other disorders causing alteration of consciousness or paroxystic symptoms that could be misdiagnosed as seizures are seen frequently. The incidence and clinical characteristics of such patients have not yet been determined. We aimed to determine the proportion and clinical characteristics of patients referred to our epilepsy clinic who had a final diagnosis other than epilepsy. METHODS: We performed a retrospective chart analysis of consecutive patient referrals to the epilepsy clinic from January 2013 to January 2015, inclusively. RESULTS: Four hundred four patient referrals were evaluated, 106 (or 26%) had a final diagnosis other than epilepsy. Referrals came primarily from general practitioners and nonneurology specialists. Although most patients had a normal routine electroencephalography (EEG) prior to the clinic visit, sleep-deprived EEG and cardiac investigations were rarely performed. Patients received a final diagnosis other than epilepsy after 1 to 2 visits in 92% of cases and with minimal paraclinical investigations. Prolonged video-EEG recording was required in 27% of patients. The most common diagnoses were syncope (33%), psychiatric symptoms (20%), followed by migraine (10%), and psychogenic nonepileptic seizures (9%). CONCLUSIONS: A significant proportion of patients seen in our tertiary care epilepsy clinic is in fact, not patients with epilepsy. Enhanced knowledge of these differential diagnosis and important anamnesis components to rule out seizures will help improve guidelines for referral to Epilepsy clinic and cost-effectively optimize the use of paraclinical investigations. PMID- 29268169 TI - The first MICCAI challenge on PET tumor segmentation. AB - INTRODUCTION: Automatic functional volume segmentation in PET images is a challenge that has been addressed using a large array of methods. A major limitation for the field has been the lack of a benchmark dataset that would allow direct comparison of the results in the various publications. In the present work, we describe a comparison of recent methods on a large dataset following recommendations by the American Association of Physicists in Medicine (AAPM) task group (TG) 211, which was carried out within a MICCAI (Medical Image Computing and Computer Assisted Intervention) challenge. MATERIALS AND METHODS: Organization and funding was provided by France Life Imaging (FLI). A dataset of 176 images combining simulated, phantom and clinical images was assembled. A website allowed the participants to register and download training data (n = 19). Challengers then submitted encapsulated pipelines on an online platform that autonomously ran the algorithms on the testing data (n = 157) and evaluated the results. The methods were ranked according to the arithmetic mean of sensitivity and positive predictive value. RESULTS: Sixteen teams registered but only four provided manuscripts and pipeline(s) for a total of 10 methods. In addition, results using two thresholds and the Fuzzy Locally Adaptive Bayesian (FLAB) were generated. All competing methods except one performed with median accuracy above 0.8. The method with the highest score was the convolutional neural network-based segmentation, which significantly outperformed 9 out of 12 of the other methods, but not the improved K-Means, Gaussian Model Mixture and Fuzzy C-Means methods. CONCLUSION: The most rigorous comparative study of PET segmentation algorithms to date was carried out using a dataset that is the largest used in such studies so far. The hierarchy amongst the methods in terms of accuracy did not depend strongly on the subset of datasets or the metrics (or combination of metrics). All the methods submitted by the challengers except one demonstrated good performance with median accuracy scores above 0.8. PMID- 29268171 TI - DNA damage and oxidative stress induced by imidacloprid exposure in different tissues of the Neotropical fish Prochilodus lineatus. AB - Imidacloprid (IMI), a systemic neonicotinoid insecticide widely used in worldwide scale, is reported in freshwater bodies. Nevertheless, there is a lack of information about IMI sublethal effects on freshwater fish. Thus, the aim of this study was to identify the potential hazard of this insecticide to the South American fish Prochilodus lineatus exposed for 120 h to four IMI concentrations (1.25, 12.5, 125, and 1250 MUg L-1). A set of biochemical, genotoxic and physiological biomarkers were evaluated in different organs of the fish. IMI exposure induced significant changes in the enzymatic profiles of P. lineatus, with alterations in the activity of biotransformation and antioxidant enzymes in different tissues. Redox balance of the tissues was affected, since oxidative damage such as lipoperoxidation (LPO) and protein carbonylation (PCC) were evidenced in the liver, gills, kidney and brain of fish exposed to different IMI concentrations. Fish exposed to all IMI concentrations showed decreased blood glucose indicating an increase of energetic demand. DNA damage was evidenced by the comet test, in the erythrocytes of fish all the concentrations evaluated. We integrated these results in the Integrated Biomarker Response (IBR) index, which evidenced that the organs most affected by IMI exposure were the liver and kidney, followed by the gills. Our results highlight the importance of investigating different target tissues after IMI exposure and show the sublethal effects of IMI in some of them; they also warn to the possible consequences that fish living in freshwater ecosystems can suffer due to IMI exposure. PMID- 29268172 TI - Comparative sorption isotherms and removal studies for Pb(II) by physical and thermochemical modification of low-cost agro-wastes from Tanzania. AB - Corn and rice husks, agro-wastes available in large quantities in Tanzania, were used to remove Pb2+ from aqueous solution. Husks were used in raw form, pyrolyzed form, and chemically modified form. Material characterization was carried out using the BET method, FTIR spectroscopy, SEM, pHPZC, and cation exchange capacity analysis. Langmuir, Freundlich, Dubinin-Radushkevich (D-R), and Temkin isotherms were used to elucidate Pb2+ sorption mechanisms. The surface area and cation exchange capacity (CEC) of untreated and chemically treated biochars were significantly higher than that of raw husks. Sorption data for Pb2+ for all biosorbents fit the Freundlich and D-R models well with high R2 values. Most of the synthesized biosorbents in this study indicated >90% for Pb2+ removal, with the ZnCl2-treated corn husk biochar sorption capacities ranking highest in all modeling results. Surface morphological features (e.g., micropores and fissures) and acidic and unsaturated functional groups may have significantly contributed to the observed Pb2+ removal efficiencies. PMID- 29268173 TI - Simultaneous removal of ciprofloxacin, norfloxacin, sulfamethoxazole by co producing oxidative enzymes system of Phanerochaete chrysosporium and Pycnoporus sanguineus. AB - Pycnoporus sanguineus could remove 98.5% ciprofloxacin (CIP), 96.4% norfloxacin (NOR), 100% sulfamethoxazole (SMX), and 100% their mixture through biotransformation within 2 d, while Phanerochaete chrysosporium could only remove 64.5% CIP, 73.2% NOR, and 63.3% SMX through biosorption and biotransformation within 8 d, respectively. The efficiencies of antibiotic bioremoval under co culture were more than that under the pure culture of P. chrysosporium but less than that under the pure culture of P. sanguineus. However, only 2% CIP and 3% NOR under co-culture were detected in the mycelia. In vitro enzymatic degradation and in vivo cytochrome P450 inhibition experiments revealed that laccase and cytochrome P450 could play roles in the removal of above all antibiotics, while manganese peroxidase could only play role in SMX removal. Transformation products of CIP and NOR under the pure culture of P. chrysosporium could be assigned to three different reaction pathways: (i) defluorination or dehydration, (ii) decarboxylation, and (iii) oxidation of the piperazinyl substituent. Additionally, other pathways, (iv) monohydroxylation, and (v) demethylation or deethylation at position N1 also occurred under the co-culture and pure culture of P. sanguineus. Antibacterial activity of antibiotics could be eliminated after treatments with pure and co-culture of P. chrysosporium and P. sanguineus. The cytotoxicity of the metabolites of SMX and NOR under co-culture was lower than that under the pure culture of P. sanguineus, indicating co-culture is a more environmentally friendly strategy to eliminate SMX and NOR. PMID- 29268174 TI - Polychlorinated biphenyls, indicators of thyroid function and thyroid autoantibodies in the Anniston Community Health Survey I (ACHS-I). AB - In this study, we examined associations between serum concentrations of 35 polychlorinated biphenyl (PCB) congeners, pesticides, and indicators of thyroid function in participants of the Anniston Community Health Survey (ACHS). Study subjects lived in the vicinity of a former PCB production facility and had PCB concentrations 2 to 3 times higher than similar age and race groups from the general population. We investigated associations among serum levels of thyroid hormones (thyroxin [T4], free thyroxin [fT4], triiodothyronine [T3], thyroid stimulation hormone [TSH]) and auto-antibodies (thyroglobulin antibody [TgAb] or thyroperoxidase antibody [TPOAb]) and combined indicators of thyroid function with the sum of PCBs, varying PCB groups, individual PCB congeners, and 8 pesticides. Logistic and linear regression models were adjusted for log10 transformed total lipids, age, sex, ethnicity, BMI, smoking, and family history of thyroid disease. We also performed analyses stratified by ethnicity and sex. Linear regression showed inverse associations between TT3 and thyroid-like PCBs (sum of PCBs 28, 52, 74, 101, 105, and 118; p = .0004), two pesticides (hexachlorobenzene, and pp'-DDE), and individual congeners (PCBs 74, 105). Null associations were observed between PCBs, pesticides, TSH, TT4, and fT4. Logistic regression analyses did not provide support for TT3 findings and found no association with other thyroid hormones, antibodies, or combined indicator of thyroid function. These results suggest there is little evidence that these chemicals have any major clinical effect on thyroid function in this highly PCB exposed population. PMID- 29268175 TI - Background electrolytes and pH effects on selenate adsorption using iron impregnated granular activated carbon and surface binding mechanisms. AB - Iron-impregnated granular activated carbon (Fe-GAC) has been shown effective for selenite adsorptive removal from aqueous solutions, but similar effectiveness was not observed with selenate. This study examined the effects of background electrolytes and pH on selenate adsorption on to Fe-GAC, and surface bindings to elucidate the selenate adsorption mechanisms. The decrease magnitude of selenate adsorption capacity under three background electrolytes followed the order: LiCl > NaCl > KCl, as ionic strength increased from 0.01 to 0.1 M. Larger adsorption capacity differences among the three electrolytes were observed under the higher ionic strengths (0.05 and 0.1 M) than those under 0.01 M. Multiplet peak fittings of high resolution X-ray photoelectron spectra for O1s and Fe2p3/2 indicated the presence of iron (III) on adsorbent surface. pH variations during the adsorbent preparation within 3-8 in NaCl solutions did not cause appreciable changes in the iron redox state and composition. Raman spectra showed the formation of both monodentate and bidentate inner sphere complexes under pHs <7 and a mixture of outer sphere and inner sphere complexes at pH 8. These results explained the lower selenate adsorption under alkaline conditions. Mechanisms for monodentate and bidentate formations and a stable six-member ring structure were proposed. Two strategies were recommended for modifying Fe-GAC preparation procedure to enhance the selenate adsorption: (1) mixed-metal oxide coatings to increase the point of zero charge (pHzpc); and (2) ferrous iron coating to initially reduce selenate followed by selenite adsorption. PMID- 29268176 TI - Deciphering physio-biochemical, yield, and nutritional quality attributes of water-stressed radish (Raphanus sativus L.) plants grown from Zn-Lys primed seeds. AB - Water shortage appears to be expedited under the current climate change scenario worldwide. The present work was aimed to investigate the effects of zinc-chelated lysine (Zn-Lys) on germination and yield of water stressed radish plants. The research was comprised of two studies where the effect of Zn-Lys seed priming on germination attributes under PEG-induced water stress was investigated in the first experiment. In the second experiment, growth, physio-biochemical, and yield responses of water-stressed radish plants raised from Zn-Lys primed seeds were recorded. The seeds pre-conditioned with 0, 1.5, 3, 4.5, or 6 mg kg-1 of Zn-Lys was grown in petri-dishes and pots. Priming treatments significantly improved the germination attributes under water stress. Plants raised from primed seeds exhibited significant improvements in plant biomass production, leaf photosynthetic pigments, final root yield, and nutritional quality. Furthermore, the activities of superoxide dismutase (SOD) and peroxidase (POD) were increased, while the melondialdehyde (MDA) content decreased. Root flavonoids, ascorbic acid, carotenoids, protein, carbohydrates, fiber and lysine content were significantly improved due to Zn-Lys seed priming, both under water-stressed and non-stressed conditions. Moreover, plant's mineral nutrients such as K and Ca as well as Mg, Fe, P, and Zn of final harvested roots were also improved due to Zn Lys seed priming. Overall, for the induction of drought tolerance and nutritional quality, Zn-Lys regimes of 3 and 4.5 mg kg-1 were most effective. It can be inferred that the Zn-Lys priming maintained a potential balance of nutrient uptake and translocation by preventing drought-induced lipid peroxidation of membranes. PMID- 29268177 TI - Exposure to the environmentally-persistent insecticide chlordecone induces detoxification genes and causes polyp bail-out in the coral P. damicornis. AB - Marine ecosystems are both stressed and threatened by pesticides that are used on land. Nevertheless, research on the impact of pesticides on coral reefs and the underlying mechanisms is still in its infancy. The insecticide chlordecone is a persistent organic pollutant with carcinogenic effects in rats and mice. Chlordecone has been detected in diverse marine organisms in the Caribbean, but unexpectedly, also in French Polynesia. We combined transcriptomic and morphologic analyses of analyses the response of the coral Pocillopora damicornis to chlordecone stress. We compared chlordecone stress with thermal stress to determine a chlordecone-specific response. We found eight transcripts related to the P450-1A or P450-3A families that were specifically overexpressed in response to chlordecone. There was also sequential overexpression of transcripts involved in apoptosis and degradation of cellular matrix proteins. Finally, we report the first observation of chlordecone-induced P. damicornis polyp bail-out. Altogether, these results strongly suggest that apoptosis and expression of genes belonging to the cathepsin family are sequentially regulated processes leading to coenosarc dissociation and loss. PMID- 29268178 TI - Determination of priority and other hazardous substances in football fields of synthetic turf by gas chromatography-mass spectrometry: A health and environmental concern. AB - Due to the high concern generated in the last years about the safety of recycled tire rubber used for recreational sports surfaces, this study aims at evaluating the presence of forty organic compounds including polycyclic aromatic hydrocarbons (PAHs), phthalates, adipates, vulcanisation additives and antioxidants in recycled tire crumb of synthetic turf football fields. Ultrasound Assisted Extraction (UAE) was successfully employed to extract the target compounds from the crumb rubber, and analysis was performed by gas chromatography mass spectrometry (GC-MS). The transfer of the target chemicals from the crumb rubber to the runoff water and to the air above the rubber surface has also been evaluated employing solid-phase microextraction (SPME). Samples from fifteen football fields were analysed, and the results revealed the presence of 24 of the 40 target compounds, including 14 of the 16 EPA PAHs, with total concentrations up to 50 MUg g-1. Heavy metals such as Cd, Cr and Pb were also found. A partial transfer of organic compounds to the air and runoff water was also demonstrated. The analysis of rain water collected directly from the football field, showed the presence of a high number of the target compounds at concentrations reaching above 100 MUg L-1. The environmental risk arising from the burning of crumb rubber tires has been assessed, as well, analysing the crumb rubber, and the air and water in contact with this material, showing a substantial increase both of the number and concentration of the hazardous chemicals. PMID- 29268179 TI - Consequences of contamination on the interactions between phytoplankton and bacterioplankton. AB - Sediment resuspension can provoke strong water enrichment in nutrients, contaminants, and microorganisms. Microcosm incubations were performed in triplicate for 96 h, with lagoon and offshore waters incubated either with sediment elutriate or with an artificial mixture of contaminants issued from sediment resuspension. Sediment elutriate provoked a strong increase in microbial biomass, with little effects on the phytoplankton and bacterioplankton community structures. Among the pool of contaminants released, few were clearly identified as structuring factors of phytoplankton and bacterioplankton communities, namely simazine, Cu, Sn, Ni, and Cr. Effects were more pronounced in the offshore waters, suggesting a relative tolerance of the lagoon microbial communities to contamination. The impacts of contamination on the microbial community structure were direct or indirect, depending on the nature and the strength of the interactions between phytoplankton and bacterioplankton. PMID- 29268180 TI - Influence of indoor environmental factors on mass transfer parameters and concentrations of semi-volatile organic compounds. AB - Semi-volatile organic compounds (SVOCs) in indoor environments can partition among the gas phase, airborne particles, settled dust, and available surfaces. The mass transfer parameters of SVOCs, such as the mass transfer coefficient and the partition coefficient, are influenced by indoor environmental factors. Subsequently, indoor SVOC concentrations and thus occupant exposure can vary depending on environmental factors. In this review, the influence of six environmental factors, i.e., indoor temperature, humidity, ventilation, airborne particle concentration, source loading factor, and reactive chemistry, on the mass transfer parameters and indoor concentrations of SVOCs was analyzed and tentatively quantified. The results show that all mass transfer parameters vary depending on environmental factors. These variations are mostly characterized by empirical equations, particularly for humidity. Theoretical calculations of these parameters based on mass transfer mechanisms are available only for the emission of SVOCs from source surfaces when airborne particles are not present. All mass transfer parameters depend on the temperature. Humidity influences the partition of SVOCs among different phases and is associated with phthalate hydrolysis. Ventilation has a combined effect with the airborne particle concentration on SVOC emission and their mass transfer among different phases. Indoor chemical reactions can produce or eliminate SVOCs slowly. To better model the dynamic SVOC concentration indoors, the present review suggests studying the combined effect of environmental factors in real indoor environments. Moreover, interactions between indoor environmental factors and human activities and their influence on SVOC mass transfer processes should be considered. PMID- 29268181 TI - Degradation of atrazine by electrochemically activated persulfate using BDD anode: Role of radicals and influencing factors. AB - A novel advanced oxidation process using boron-doped diamond (BDD) anode to activate persulfate (PS) with low concentration of electrolyte was systematically investigated in this study. Compared to direct electrochemical oxidation of atrazine (ATZ) using BDD anode, the addition and activation of PS significantly declined the demand for electrolytes. It was confirmed by scavenger experiments that both radical and non-radical oxidation occurred in this system. Degradation of ATZ was enhanced with the increase of current density and dosage of PS, and decrease of initial pH. However, the increase of current density can also lead to the decrease of current efficiency, then increase of energy consumption. Besides, the inhibitory effect of anions on the degradation of ATZ followed the order of HCO3->H2PO4->NO3-, while the presence of Cl- accelerated the degradation of ATZ. Furthermore, the degradation products mainly resulting from de-alkylation, de chlorination, and hydroxylation were detected. Due to the distinctive preference to ethyl group in BDD/PS system, the formation of deethyl-atrazine was quicker than that of deisopropyl-atrazine. The study aims to provide a comprehensive understanding on the potential application of BDD/PS system in water treatment. PMID- 29268182 TI - Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder. AB - Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in metyrapone effects on delta power sleep, and no significant metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties. PMID- 29268183 TI - Treatment of landfill leachate biochemical effluent using the nano-Fe3O4/Na2S2O8 system: Oxidation performance, wastewater spectral analysis, and activator characterization. AB - Nano-Fe3O4 was used as heterogeneous catalyst to activate Na2S2O8 for the generation of the sulfate radicals (SO4-) to oxidize the residual pollutants in landfill leachate biochemical effluent. The oxidation performance, wastewater spectral analysis and activator characterization were discussed. Oxidation experimental result shows that nano-Fe3O4 has obvious catalytic effect on Na2S2O8 and can significantly enhance the oxidation efficiencies of Na2S2O8 on landfill leachate biochemical effluent, with COD and color removals above 63% and 95%, respectively. Based on the analyses of three-dimensional excitation emission matrix fluorescence spectrum (3DEEM), ultraviolet-visible spectra (UV-vis), and Fourier Transform infrared spectroscopy (FTIR) of wastewater samples before and after treatment, it can be concluded that the pollution level of dissolved organic matter (DOM) declined and that the humic acid (HA) fractions were efficiently degraded into small molecules of fulvic acid (FA) fractions with less weight and stable structure. Compared to the raw wastewater sample, the aromaticity and substituent groups of the DOM were lessened in the treated wastewater sample. Moreover, the main structure of the organics and functional groups were changed by the Fe3O4/Na2S2O8 system, with substantial decrease of conjugated double bonds. The micro morphology of nano-Fe3O4 was characterized before and after reaction by the methods of scanning electron microscope spectra (SEM), X-ray diffraction pattern (XRD), and X-ray photoelectron spectroscopy (XPS). The XRD pattern analysis showed that nano-Fe3O4 was oxidized into r-Fe2O3 and that the particle size of it also became smaller after reaction. XPS was employed to analyze the content and iron valence on the nano-Fe3O4 surface, and it can be found that the ratio of Fe3+/Fe2+ decreased from 1.8 before reaction to 0.8 after reaction. From the SEM analysis after the treatment, it was determined that the spacing between nano-Fe3O4 was increased, but in turn, the particles decreased in diameter. PMID- 29268184 TI - Improved river continuity facilitates fishes' abilities to track future environmental changes. AB - Barriers represent one of the largest anthropogenic impacts on the ecological status of rivers, and they also potentially restrict fishes' ability to respond to future environmental changes. Thus, river management aims to restore the longitudinal connectivity of rivers to allow continuous migration and movement of water, sediments and biota. However, it is often unclear whether the targeted barriers are also those most relevant for fish species, particularly to track future habitat shifts caused by environmental change. In this study, we applied species distribution models and the GIS-based fish dispersal model FIDIMO to evaluate the impacts of barriers (e.g. weirs and dams) on the dispersal of 17 native fish species in the European River Elbe with a particular focus on climate and land use-induced habitat shifts. Specifically, we compared three scenarios of longitudinal connectivity: (i) current longitudinal connectivity, (ii) connectivity improvements as planned by river managers for 2021 and (iii) a reference with full longitudinal connectivity. The models indicated that barriers restricted the movement of two modeled fish species on average, thus impeding fishes' abilities to track future habitat shifts. Moreover, the number of species affected by barriers increased downstream. For the River Elbe, our results suggest that river management has most likely identified the most relevant barriers in respect to the modeled species and future environmental change. We emphasize that river management and barrier prioritization must thoroughly consider species-specific movement and dispersal abilities, as well as the specific spatial arrangement of barriers in the river system in relation to the spatial distribution of species' populations and suitable habitats. PMID- 29268185 TI - Sexual attraction and the nonmedical use of opioids and sedative drugs among Chinese adolescents. AB - OBJECTIVE: The nonmedical use of prescription drugs (NMUPD) is attracting public attention. We aimed to explore the association between sexual attraction and NMUPD among Chinese adolescents. METHOD: A school-based survey was conducted in seven Chinese provinces, and a multi-stage stratified cluster sampling method was used in this study. A total of 150,822 students from seven Chinese provinces completed the questionnaire; the response rate was 95.93%. All data were collected between November 2014 and January 2015. RESULTS: Overall, 8.8%, 4.4%, and 2.2% of the students reported lifetime, past-year, and past-month NMUPD, respectively. Compared with heterosexual students (8.2%), sexual minority and unsure students were more likely to report lifetime NMUPD (14.4% and 10.0%, respectively; chi2 = 244.34, P < 0.001). In addition, sexual minority and unsure students were more likely to admit past-year and past-month use of NMUPD. After adjusting for social demographics and lifestyle covariates, sexual minority and unsure students were at an increased risk of lifetime NMUPD (adjusted odds ratio [AOR] = 1.68, 95% confidence interval [CI] = 1.54-1.83 and AOR = 1.33, 95% CI = 1.26-1.41, respectively). CONCLUSIONS: Our study suggested that sexual minority and unsure adolescents have a higher risk of NMUPD. Moreover, our study suggested that sexual minority and unsure students are more likely to both try and continue to use prescription drugs. Further studies focusing on the mechanism of substance abuse and appropriate interventions among sexual minority and unsure adolescents are warranted. PMID- 29268186 TI - Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies. AB - The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)-based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy. PMID- 29268187 TI - Evanescent wave aptasensor for continuous and online aminoglycoside antibiotics detection based on target binding facilitated fluorescence quenching. AB - The biosensors capable for on-site continuous and online monitoring of pollutants in environment are highly desired due to their practical importance and convenience. The group specific detection of pollutants is especially attractive due to the diversity of environmental pollutants. Here we devise an evanescent wave aptasensor based on target binding facilitated fluorescence quenching (FQ EWA) for the online continuous and group-specific detection of aminoglycoside antibiotics (AMGAs). In FQ-EWA, a fluorophore labeled DNA aptamer selected against kanamycin was used for both the target recognition in solution and signal transduction on optical fiber of EWA. The aptamers form multiple-strand complex (M-Apt) in the absence of AMGAs. The binding between AMGA and the aptamer disrupts M-Apt and leads to the formation of AMGA -aptamer complex (AMGA-Apt). The photo-induced electron transfer between the fluorophore and AMGA partially quenches the fluorescence of AMGA-Apt. The structure-selective absorption of AMGA Apt over M-Apt on the graphene oxide further quenches the fluorescence of AMGA Apt. Meanwhile, the unbound aptamers in solution assemble with the unlabeled aptamers immobilized on the fiber to form M-Apt. The amount of M-Apt on the fiber is inversely proportional to the concentration of AMGAs, enabling the signal-off detection of AMGAs from 200nM to 200MUM with a detection limit of 26nM. The whole detection process is carried out in an online mode without any offline operation, providing a great benefit for system automation and miniaturization. FQ-EWA also shows great surface regeneration capability and enables the continuous detection more than 60 times. PMID- 29268188 TI - A dual-functional microfluidic chip for on-line detection of interleukin-8 based on rolling circle amplification. AB - Interleukin 8 (IL-8), also known as C-X-C motif ligand 8(CXCL8), is a proinflammatory chemokine functioned in neutrophil chemotaxis and activation. And it plays an important role in the process of glioma stem-like cell vascularization in the latest research. Herein, a dual-function microfluidic biosensor based on rolling circle amplification (RCA) was fabricated for cell culture and online IL-8 detection. A microfluidic chip was designed with two high passages connected by the vertical channels. One of the channels with immobilized capture antibody was prepared for IL-8 detection and another channel for cell culture. Immunoassays were achieved by a sandwich structure consisting of antibodies, IL-8, and aptamers. Signal amplification was mainly due to RCA and biotin-streptavidin linkage. The linear range for IL-8 was 7.5 -120pgmL-1 in this assay. Moreover, the developed method was successfully applied to detect the IL-8 in tumor-derived endothelial cells (TDEC) and Human Umbilical Vein Endothelial cells (HUVEC) under chemical hypoxia condition. Semi-quantitative detection of IL 8 consumption in HUVEC cells in low oxygen condition was also achieved. These results were in statistical agreement with those obtained by commercial assay of enzyme-linked immunoassay kit (ELISA). The microfluidic chip based biosensor reported hereby has a large prospect in the basic research and clinical diagnosis of cancer stem cell. PMID- 29268189 TI - Kaempferol inhibits the migration and invasion of rheumatoid arthritis fibroblast like synoviocytes by blocking activation of the MAPK pathway. AB - In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) play an essential role in cartilage destruction. Aggressive migration and invasion by FLSs significantly affect RA pathology. Kaempferol has been shown to inhibit cancer cell migration and invasion. However, the effects of kaempferol on RA FLSs have not been investigated. Our study aimed to determine the effects of kaempferol on RA both in vitro and in vivo. In vitro, cell migration and invasion were measured using scratch assays and the Boyden chamber method, respectively. The cytoskeletal reorganization of RA FLSs was evaluated by immunofluorescence staining. Matrix metalloproteinase (MMP) levels were measured by real-time PCR, and protein expression levels were measured by western blotting. In vivo, the effects of kaempferol were evaluated in mice with CIA. The results showed that kaempferol reduced migration, invasion and MMP expression in RA FLSs. In addition, we demonstrated that kaempferol inhibited reorganization of the actin cytoskeleton during cell migration. Moreover, kaempferol dramatically suppressed tumor necrosis factor (TNF)-alpha-induced MAPK activation without affecting the expression of TNF-alpha receptors. We also demonstrated that kaempferol attenuated the severity of arthritis in mice with CIA. Taken together, these results suggested that kaempferol inhibits the migration and invasion of FLSs in RA by blocking MAPK pathway activation without affecting the expression of TNF alpha receptors. PMID- 29268190 TI - Mogroside IVE attenuates experimental liver fibrosis in mice and inhibits HSC activation through downregulating TLR4-mediated pathways. AB - Liver fibrosis has been emphasized as a serious threat to human health. There is currently no effective clinical drug treatment. Although mogrosides (MGs) have extensive pharmacological effects with minimal toxicity, their effects on liver function, inflammation, matrix metalloproteinases and hepatic stellate cell (HSC) activation remain to be researched. In the current study, we investigated whether mogroside IVE (MGIVE), a main compound isolated from MGs, provided protection against liver fibrosis in mice. MGIVE (25mg/kg) significantly reduced carbon tetrachloride (CCl4)-induced inflammatory infiltration, pro-inflammatory cytokine release, and myeloperioxide (MPO) activity, as well as improved liver function in CCl4-treated mice. Additionally, MGIVE also significantly impaired CCl4-induced increases in liver fibrotic marker expression, such as collagen type I and hypoxia inducible factor-1alpha (HIF-1alpha). Further investigation indicated that the possible molecular target of MGIVE is the toll-like receptor 4 (TLR4) mediated pathway, and MGIVE treatment significantly prevented CCl4-induced transforming growth factor-beta1 (TGF-beta1) overexpression and the phosphorylation of mitogen activated protein kinase (MAPK) in vivo. In vitro tests of HSCs or RAW 264.7 cells challenged with TGF-beta1 or lipopolysaccharide (LPS) demonstrated that TLR4 expression partly mediated the anti-fibrotic effects of MGIVE. In conclusion, supplementation with MGIVE may attenuate liver fibrosis through inhibiting the TLR4 signaling pathway, including MyD88 and MAPKs, as well as HIF-1alpha. MGIVE may act as a therapeutic potential drug for the treatment of liver fibrosis via the TLR4/HIF-1alpha cohort signaling pathway. PMID- 29268191 TI - The cysteinyl leukotriene receptor 1 (CysLT1R) antagonist montelukast suppresses matrix metalloproteinase-13 expression induced by lipopolysaccharide. AB - Bacterial products such as LPS are critical factors responsible for bone destruction. MMP-13, a member of the matrix metalloproteinase family, plays a critical role in the proteolytic degradation of extracellular matrix components, which includes collagen fibrils in the bone matrix. Montelukast is a selective cysteinyl leukotrienes receptor 1 (cysLT1R) antagonist used clinically for the treatment of asthma, as it reduces eosinophilic inflammation in airways. This study aims to explore the role of montelukast in regulating MMP-13 expression induced by LPS in osteoblasts. Our results indicate that LPS stimulated cysLT1R expression in mouse MC3T3-E1 osteoblasts in a dose- and time-dependent manner. Notably, LPS-induced up-regulation of MMP-13 was ameliorated by treatment with montelukast in a dose-dependent manner. Furthermore, treatment with montelukast stimulated the expression of SOCS3, an inhibitor of MMP-13. Silencing of SOCS3 abolished the inhibitory effects of montelukast on MMP-13 expression. Mechanistically, we found that montelukast suppressed LPS-induced nuclear translocation of NF-kappaB p65 as well as NF-kappaB transcriptional activity by inhibiting the phosphorylation and degradation of IkappaBalpha. These data suggest that montelukast can modulate inflammatory events in bone diseases. PMID- 29268192 TI - Interleukin-37 alleviates airway inflammation and remodeling in asthma via inhibiting the activation of NF-kappaB and STAT3 signalings. AB - Asthma is a common respiratory inflammatory disorder disease of childhood, and airway smooth muscle cells (ASMCs) play an important role in this disease. Recently, studies have found that interleukin (IL)-37 inhibits allergic airway inflammation of asthmatic mouse models. The aim of this study was to investigate the exact mechanism of IL-37 in asthma. In this study, we found recombinant human IL-37 protein significantly reduced ovalbumin (OVA)-induced airway hyperresponsiveness, inflammatory cell infiltration, the epithelial-mesenchymal transition (EMT) process, and levels of IL-4, IL-6 and IL-13, but increased interferon (IFN)-gamma expression. Moreover, IL-37 treatment remarkably inhibited transforming growth factor (TGF)-beta1-induced cell proliferation, migration, EMT, and inflammatory response in ASMCs. IL-37 notably upregulated IkappaB expression and downregulated levels of NF-kappaB p65, phospho-NF-kappaB p65, STAT3 and phospho-STAT3 both in OVA-induced mice and in TGF-beta1-stimulated ASMCs. The effects of IL-37 on TGF-beta1-induced ASMCs were abrogated by STAT3 upregulation. Additionally, PDTC, a NF-kappaB inhibitor, showed the similar effects as IL-37 in ASMCs. In conclusion, IL-37 may alleviate airway inflammation and remodeling in asthma through suppressing the activation of NF-kappaB and STAT3. PMID- 29268193 TI - Building a state space for song learning. AB - The songbird system has shed light on how the brain produces precisely timed behavioral sequences, and how the brain implements reinforcement learning (RL). RL is a powerful strategy for learning what action to produce in each state, but requires a unique representation of the states involved in the task. Songbird RL circuitry is thought to operate using a representation of each moment within song syllables, consistent with the sparse sequential bursting of neurons in premotor cortical nucleus HVC. However, such sparse sequences are not present in very young birds, which sing highly variable syllables of random lengths. Here, we review and expand upon a model for how the songbird brain could construct latent sequences to support RL, in light of new data elucidating connections between HVC and auditory cortical areas. We hypothesize that learning occurs via four distinct plasticity processes: 1) formation of 'tutor memory' sequences in auditory areas; 2) formation of appropriately-timed latent HVC sequences, seeded by inputs from auditory areas spontaneously replaying the tutor song; 3) strengthening, during spontaneous replay, of connections from HVC to auditory neurons of corresponding timing in the 'tutor memory' sequence, aligning auditory and motor representations for subsequent song evaluation; and 4) strengthening of connections from premotor neurons to motor output neurons that produce the desired sounds, via well-described song RL circuitry. PMID- 29268194 TI - A protocol for studying the interaction between small-molecular drug and DNA using microdialysis sampling integrated with chemiluminescent detection. AB - It is of great significance to understand how drug molecules interact with DNA, which is one of the most important aspects of biological investigations in drug discovery at molecular level. Herein, with the model of ractopamine and calf thymus DNA (ct-DNA), a protocol using microdialysis (MD) sampling integrated with flow injection (FI)-chemiluminescent (CL) detection was developed for studying the interaction between small-molecular drug and DNA. After incubating ractopamine with ct-DNA, unbound ractopamine was on-line sampled using a MD probe, followed by being introduced into a FI-CL system for quantitation. The detected concentrations of unbound ractopamine were calibrated with the recovery of the MD probe, and then treated with Klotz analysis and Scatchard analysis to acquire the binding parameters. The MD probe exhibited a mean recovery of 27.3% for ractopamine sampling under the optimal conditions. The binding constants obtained by Klotz analysis and Scatchard analysis were 3.8 * 106 M-1 and 3.9 * 106 M-1, respectively, showing negligible difference. Ractopamine was estimated to have only one type of binding site on ct-DNA. The obtained results demonstrated that the protocol using on-line MD sampling integrated with FI-CL detection is a simple and reliable technique platform for studying the interaction between small-molecular drug and DNA. PMID- 29268195 TI - Development and validation of a bioanalytical method for quantification of LNA-i miR-221, a 13-mer oligonucleotide, in rat plasma using LC-MS/MS. AB - LNA-i-miR-221, a 13-mer oligonucleotide, is a new miR-221 inhibitor that could be used as a novel drug for multiple myeloma. Herein, an ion-pair reversed phase liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantification of LNA-i-miR-221 in rat plasma. Plasma samples were prepared with an initial phenol/chloroform/isoamyl alcohol liquid-liquid extraction followed by a solid phase extraction. Chromatographic separation was performed with a gradient system on a HALO C18 column using hexafluoro-2-propanol/triethylamine buffer and methanol as mobile phase at a flow rate of 0.4 mL/min. Under these conditions LNA-i-miR-221 and the analogue internal standard are co-eluted at 1.2 min. The detection was carried out in multiple reaction monitoring (MRM) mode using a negative electrospray ionization (ESI) interface. The assay showed a good linearity within the calibration range 10-10000 ng/mL. The precision, accuracy, and recovery values were found to be <15% (<20% at LLOQ), 100 +/- 15%, and 97.6-103.7%, respectively. This method was successfully applied to measure the concentrations of LNA-i-miR-221 in plasma samples following the intravenous administration during a 4-week toxicity study in rats. PMID- 29268196 TI - pth moment exponential stability of stochastic memristor-based bidirectional associative memory (BAM) neural networks with time delays. AB - Stochastic memristor-based bidirectional associative memory (BAM) neural networks with time delays play an increasingly important role in the design and implementation of neural network systems. Under the framework of Filippov solutions, the issues of the pth moment exponential stability of stochastic memristor-based BAM neural networks are investigated. By using the stochastic stability theory, Ito's differential formula and Young inequality, the criteria are derived. Meanwhile, with Lyapunov approach and Cauchy-Schwarz inequality, we derive some sufficient conditions for the mean square exponential stability of the above systems. The obtained results improve and extend previous works on memristor-based or usual neural networks dynamical systems. Four numerical examples are provided to illustrate the effectiveness of the proposed results. PMID- 29268197 TI - Fixed-time stabilization of impulsive Cohen-Grossberg BAM neural networks. AB - This article is concerned with the fixed-time stabilization for impulsive Cohen Grossberg BAM neural networks via two different controllers. By using a novel constructive approach based on some comparison techniques for differential inequalities, an improvement theorem of fixed-time stability for impulsive dynamical systems is established. In addition, based on the fixed-time stability theorem of impulsive dynamical systems, two different control protocols are designed to ensure the fixed-time stabilization of impulsive Cohen-Grossberg BAM neural networks, which include and extend the earlier works. Finally, two simulations examples are provided to illustrate the validity of the proposed theoretical results. PMID- 29268198 TI - Baccalaureate nursing students' perspectives of peer tutoring in simulation laboratory, a Q methodology study. AB - OBJECTIVES: The study aim was to identify the perceived perspectives of baccalaureate nursing students toward the peer tutoring in the simulation laboratory. Insight into the nursing students' experiences and baseline data related to their perception of peer tutoring will assist to improve nursing education. DESIGN: Q methodology was applied to explore the students' perspectives of peer tutoring in the simulation laboratory. PARTICIPANTS: A convenience P-sample of 40 baccalaureate nursing students was used. METHOD: Fifty eight selected Q statements from each participant were classified into the shape of a normal distribution using an 11-point bipolar scale form with a range from 5 to +5. PQ Method software analyzed the collected data. RESULTS: Three discrete factors emerged: Factor I ("Facilitate or empower" knowledge acquisition), Factor II ("Safety Net" Support environment), and Factor III ("Mentoring" learn how to learn). CONCLUSIONS: The findings of this study support and indicate that peer tutoring is an effective supplementary strategy to promote baccalaureate students' knowledge acquisition, establishing a supportive safety net and facilitating their abilities to learn in the simulation laboratory. PMID- 29268199 TI - Predictors of dysphagia in critically injured patients with neck trauma. AB - PURPOSE: Trauma patients admitted to the intensive care unit (ICU) are at heightened risk for oropharyngeal dysphagia and pulmonary aspiration. Timely and appropriate referrals for dysphagia may reduce mortality rates and hospital readmissions. This study sought to identify predictors of dysphagia in a large cohort of patients with multiple traumatic injuries. METHODS: The Trauma Registry Database was queried for admissions at a level 1 trauma center from 2012 to 2016 who underwent instrumental swallowing evaluations. Relevant demographics, injuries, and interventions known to be associated with dysphagia were collected. The Dysphagia Outcome and Severity Scale (DOSS) was utilized to define severity of dysphagia. Regression analyses were performed to identify predictors of dysphagia. RESULTS: Two hundred and sixty two patients met criteria. Multivariate analyses found injury severity (p<0.01), tracheostomy (p<0.05), TBI (p<0.05), and cervical spinal bracing (p<0.001) to be predictors of dysphagia development. Furthermore, length of ICU stay (p<0.01) and cervical spinal bracing (p<0.01) were associated with a greater severity of dysphagia. CONCLUSIONS: Oropharyngeal dysphagia is a common complication in trauma patients. Our results propose a set of predictors that should be considered when identifying critically injured patients at risk for dysphagia. PMID- 29268200 TI - Anti-aging factor, serum alpha-Klotho, as a marker of acute physiological stress, and a predictor of ICU mortality, in patients with septic shock. AB - PURPOSE: Genetic deletions decreasing serum alpha-Klotho (alpha-KL) have been associated with rapid aging, multi-organ failure and increased mortality in experimental sepsis. We hypothesized that lower alpha-KL obtained at the onset of septic shock correlates with higher mortality. MATERIALS AND METHODS: Prospective cohort of 104 adult patients with septic shock. Alpha-KL was measured via ELISA on serum collected on the day of enrollment (within 72h from the onset of shock). Relationship between alpha-KL and clinical outcome measures was evaluated in uni- and multi-variable models. RESULTS: Median (IQR) alpha-KL was 816 (1020.4) pg/mL and demonstrated a bimodal distribution with two distinct populations, Cohort A [n=97, median alpha-KL 789.3 (767.1)] and Cohort B [n=7, median alpha-KL 4365.1(1374.4), >1.5 IQR greater than Cohort A]. Within Cohort A, ICU non survivors had significantly higher serum alpha-KL compared to survivors as well as significantly higher APACHE II and SOFA scores, rates of mechanical ventilation, and serum BUN, creatinine, calcium, phosphorus and lactate (all p<=0.05). Serum alpha-KL>=1005, the highest tertile, was an independent predictor of ICU mortality when controlling for co-variates (p=0.028, 95% CI 1.143-11.136). CONCLUSIONS: Elevated serum alpha-KL in patients with septic shock is independently associated with higher mortality. Further studies are needed to corroborate these findings. PMID- 29268201 TI - The novel organic mononitrate NDHP attenuates hypertension and endothelial dysfunction in hypertensive rats. AB - RATIONALE: Development and progression of cardiovascular diseases, including hypertension, are often associated with impaired nitric oxide synthase (NOS) function and nitric oxide (NO) deficiency. Current treatment strategies to restore NO bioavailability with organic nitrates are hampered by undesirable side effects and development of tolerance. In this study, we evaluated NO release capability and cardiovascular effects of the newly synthesized organic nitrate 1, 3-bis (hexyloxy) propan-2-yl nitrate (NDHP). METHODS: A combination of in vitro and in vivo approaches was utilized to assess acute effects of NDHP on NO release, vascular reactivity and blood pressure. The therapeutic value of chronic NDHP treatment was assessed in an experimental model of angiotensin II-induced hypertension in combination with NOS inhibition. RESULTS: NDHP mediates NO formation in both cell-free system and small resistance arteries, a process which is catalyzed by xanthine oxidoreductase. NDHP-induced vasorelaxation is endothelium independent and mediated by NO release and modulation of potassium channels. Reduction of blood pressure following acute intravenous infusion of NDHP was more pronounced in hypertensive rats (two-kidney-one-clip model) than in normotensive sham-operated rats. Toxicological tests did not reveal any harmful effects following treatment with high doses of NDHP. Finally, chronic treatment with NDHP significantly attenuated the development of hypertension and endothelial dysfunction in rats with chronic NOS inhibition and angiotensin II infusion. CONCLUSION: Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease. PMID- 29268203 TI - The state of knowledge about the relationship between 5-HTTLPR, stress, and depression. PMID- 29268204 TI - Animal-assisted intervention for individuals with cognitive impairment: A meta analysis of randomized controlled trials and quasi-randomized controlled trials. AB - The aim of this meta-analysis was to systematically examine the efficacy of animal-assisted intervention (AAI) for cognitive impairment patients. PubMed, Embase, the Cochrane library, PsycINFO, and Web of Science databases were searched up to June 2017 to collect studies related to AAI conducted in patients with cognitive impairment. Five randomized controlled trials (RCTs) and five quasi-randomized controlled trials (quasi-RCTs) involving 413 participants were included. Compared with control groups, AAI groups exhibited significantly fewer behavioral and psychological symptoms of dementia (BPSD), especially depression and agitation. In both the short and long term, AAI had beneficial effects on BPSD in cognitive impairment patients. However, no significant improvements were found in daily living activities, quality of life or cognitive score. The present meta-analysis showed that AAI can be effective in reducing BPSD in patients with cognitive impairment. PMID- 29268202 TI - iNOS polymorphism modulates iNOS/NO expression via impaired antioxidant and ROS content in P. vivax and P. falciparum infection. AB - Nitric oxide (NO) has dicotomic influence on modulating host-parasite interplay, synchronizing physiological orchestrations and diagnostic potential; instigated us to investigate the plausible association and genetic regulation among NO level, components of oxidative stress, iNOS polymorphisms and risk of malaria. Here, we experimentally elucidate that iNOS promoter polymorphisms are associated with risk of malaria; employing mutation specific genotyping, functional interplay using western blot and RT-PCR, quantitative estimation of NO, total antioxidant content (TAC) and reactive oxygen species (ROS). Genotyping revealed significantly associated risk of P. vivax (adjusted OR = 1.92 and 1.72) and P. falciparum (adjusted OR = 1.68 and 1.75) infection with SNP at iNOS-954G/C and iNOS-1173C/T positions, respectively; though vivax showed higher risk of infection. Intriguingly, mutation and infection specific differential upregulation of iNOS expression/NO level was observed and found to be significantly associated with mutant genotypes. Moreover, P. vivax showed pronounced iNOS protein (2.4 fold) and mRNA (2.5 fold) expression relative to healthy subjects. Furthermore, TAC and ROS were significantly decreased in infection; and differentially decreased in mutant genotypes. Our findings endorse polymorphic regulation of iNOS expression, altered oxidant-antioxidant components and evidences of risk association as the hallmark of malaria pathogenesis. iNOS/NO may serve as potential diagnostic marker in assessing clinical malaria. PMID- 29268205 TI - The stress response HPA-axis hormone, glucocorticoid, reduces cellular SKA complex gene expression. AB - The Spindle- and Kinetochore-Associated (SKA) complex has been proven to be involved in many human mental behavioral disorders. Glucocorticoid, a hypothalamic-pituitary-adrenal (HPA) axis hormone, is a critical mediator of stress response in neurons. However, the underlying mechanisms of glucocorticoid's effects on human neuronal cells remain unclear. This study demonstrates that increased extracellular glucocorticoid levels significantly reduce neuronal cell SKA complex genes' expression levels, followed by altered neuronal cell viability and neurite development. The results suggest that the abnormality of this HPA-axis hormone could impact the neuronal cell functions through the alternation of SKA complex functions, which might induce cell death. PMID- 29268206 TI - Efficacy of bright light therapy in bipolar depression. AB - For 30 years, bright light therapy (BLT) has been considered as an effective, well-tolerated treatment for seasonal affective disorder (SAD). Because of low response rates, new treatment strategies are needed for bipolar depression (BD), which resembles SAD in certain respects. Few placebo-controlled studies of BLT efficacy have been carried out for BD. Accordingly, this study evaluates the efficacy and safety of BLT as an add-on treatment for BD. Thirty-two BD outpatients were randomly assigned to BLT (10000lx) or dim light (DL, < 500lx). During a two-week period, light was administered each morning for 30min. The Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale assessed clinical outcome, and the UKU Side Effects Rating Scale evaluated side effects. No significant difference was observed in baseline depression scores in the two groups. Response rates for BLT and DL were 81% and 19%, and remission rates were 44% and 12.5%, respectively. Analyses showed statistically significant reductions in depression scores for the BLT group compared with the DL group on all scales. Side effects were similar in both groups, with headache as the most common side effect. The results suggest that BLT is an effective and safe add-on treatment for BD. PMID- 29268207 TI - Trauma characteristics and sleep impairment among trauma-exposed children. AB - Trauma-related sleep difficulties are quite common and their functional and clinical importance are increasingly recognized. High rates of sleep problems have been documented among trauma-exposed adults, particularly those diagnosed with posttraumatic stress disorder (PTSD); however, research with trauma-exposed children is relatively limited. Research specifically with child samples is critical due to the numerous developmental and functional implications that may result from sleep impairment. Characteristics of the traumatic event may play a key role in understanding sleep difficulties, yet, these associations are not well understood among trauma-exposed children. The current study therefore investigated whether aspects of the traumatic event (i.e., type, nature, chronicity, age of onset, removal from home, and complex trauma) were related to higher levels of sleep disturbances among 276 treatment-seeking children ages 6 18 years (M = 10.88, SD = 3.39; 63.4% female; 62.7% Black). Sleep problems were common in this sample. Domestic and community violence exposure were associated with higher levels of select sleep difficulties, as were interpersonal trauma, chronic trauma, a trauma that began early in life, and complex trauma. Nonetheless, type of trauma and characteristics of the traumatic event were largely unrelated to sleep problems on either caregiver's or children's reports. Removal from the home was not linked with sleep impairment. Although findings signify the relevance of sleep disturbances among trauma-exposed children, trauma characteristics may have limited influence on sleep problems. PMID- 29268208 TI - Citrinin as an accessory establishment factor of P. expansum for the colonization of apples. AB - Penicillium expansum is the causal agent of blue mold decay of apples. This fungal species can produce the two important mycotoxins patulin and citrinin. It was previously shown that patulin represents a colonization factor for the infection of apples. No definitive information about the importance of citrinin for the colonization of apples is currently available. The pksCT gene of the citrinin cluster codes for the citrinin polyketide synthase. Mutants of P. expansum in which the pksCT was inactivated showed a drastic decrease in the citrinin production. In addition, the pksCT mutants were also reduced in the ability to colonize apples. Externally added citrinin restored the capacity of the mutants to colonize apples roughly to that of the wild type. A kinetic analysis of the expression of the two respective pks genes of patulin (patK) and citrinin (pksCT) revealed that both genes are highly expressed in the first phase during the colonization process. The production of patulin in the apple matrix coincides with the expression of the patK gene. Almost no citrinin could be identified analytically during the first phase but only at a later stage of the colonization. It could be demonstrated that citrinin is degraded in apples and can tightly be bound to pectin. Overall the results suggest that citrinin may have an accessory function for the establishment of the colonization guided by other factors. PMID- 29268209 TI - Design and characterization of crotamine-functionalized gold nanoparticles. AB - This paper describes the development of a facile and environmentally friendly strategy for supporting crotamine on gold nanoparticles (GNPs). Our approach was based on the covalent binding interaction between the cell penetrating peptide crotamine, which is a snake venom polypeptide with preference to penetrate dividing cells, and a polyethylene glycol (PEG) ligand, which is a nontoxic, water-soluble and easily obtainable commercial polymer. Crotamine was derivatized with ortho-pyridyldisulfide-polyethyleneglycol-N-hydroxysuccinimide (OPSS-PEG SVA) cross-linker to produce OPSS-PEG-crotamine as the surface modifier of GNP. OPSS-PEG-SVA can serve not only as a surface modifier, but also as a stabilizing agent for GNPs. The successful PEGylation of the nanoparticles was demonstrated using different physicochemical techniques, while the grafting densities of the PEG ligands and crotamine on the surface of the nanoparticles were estimated using a combination of electron microscopy and mass spectrometry analysis. In vitro assays confirmed the internalization of these GNPs, into living HeLa cells. The results described herein suggest that our approach may serve as a simple platform for the synthesis of GNPs decorated with crotamine with well-defined morphologies and uniform dispersion, opening new roads for crotamine biomedical applications. PMID- 29268210 TI - The in vitro and in vivo biocompatibility evaluation of electrospun recombinant spider silk protein/PCL/gelatin for small caliber vascular tissue engineering scaffolds. AB - Recombinant spider silk protein (pNSR32) and gelatin (Gt) were demonstrated to enhance cytocompatibility of electrospun pNSR32/PCL/Gt scaffold. However, its potential pro-inflammatory effects and interactions with tissue and blood are unknown. In this study, the physicochemical properties and in vitro and in vivo biocompatibility of such scaffolds were evaluated. The results showed that the pNSR32/PCL/Gt scaffold possessed larger average fiber diameters, wider fiber diameter distribution and faster degradation rate than that of pNSR32/PCL and PCL scaffolds. The addition of pNSR32 and Gt had little influence on the hemolysis and plasma re-calcification time, but prolonged kinetic clotting time and reduced the platelet adhesion. The Il-6 and Tnf-alpha mRNA expression levels were up regulated in macrophages seeded on the PCL and pNSR32/PCL scaffolds. The lowest release of IL-6 and TNF-alpha appeared in the pNSR32/PCL/Gt scaffold. Histological results revealed that the PCL and pNSR32/PCL scaffolds elicited severe host tissue responses after implantation, while prominent ingrowth of host cells were observed in the pNSR32/PCL and pNSR32/PCL/Gt scaffolds. The comet assay and bone marrow micronucleus test demonstrated that the pNSR32/PCL/Gt scaffold did not increase the frequency of DNA damage or bone marrow micronucleus. In short, this study confirmed that the pNSR32/PCL/Gt scaffold exhibited better blood and tissue compatibility than pNSR32/PCL and PCL scaffolds. No induction of genotoxicity and inflammatory factor releases makes the pNSR32/PCL/Gt scaffold a good candidate for engineering small diameter vascular tissue. PMID- 29268211 TI - Orally-dissolving film for sublingual and buccal delivery of ropinirole. AB - Ropinirole is a very important treatment option for Parkinson's disease (PD), a major threat to the aging population. However, this drug undergoes extensive first-pass metabolism, resulting in a low oral bioavailability. Moreover, the necessity of frequent administration due to the short half-life of ropinirole may jeopardize patient compliance. Indeed, taking this drug in solid oral dosage forms (e.g. Tablet) can be a challenge because of the tremor, rigidity, limited mobility, and impaired drug absorption experienced by PD patients. In light of these, there is a pressing need to devise formulations for the delivery of ropinirole that allow simple and easy administration and fast drug action, as well as avoidance of first-pass metabolism and overcoming the challenge of impaired absorption due to gastrointestinal dysfunctions, etc. Herein, we seek to overcome all these challenges via sublingual or buccal delivery of orally dissolving films. Accordingly, we aimed to fabricate and characterize orally dissolving films of ropinirole and assess their in vivo pharmacokinetics after sublingual and buccal administration. The ropinirole oral film was non-toxic and exhibited fast disintegration and dissolution and was physically stable for at least 28 days. Upon buccal/sublingual administration of the oral films, ropinirole reached the systemic circulation within 15 min and bioavailability was significantly improved, which may be attributable to avoidance of first-pass metabolism via absorption through the oral cavity. In conclusion, our ropinirole oral film improved bioavailability after sublingual or buccal administration. This formulation potentially overcomes biopharmaceutical challenges and provide a convenient means of administration of ropinirole or other anti-PD drugs. PMID- 29268212 TI - Sensitive and uniform detection using Surface-Enhanced Raman Scattering: Influence of colloidal-droplets evaporation based on Au-Ag alloy nanourchins. AB - Surface Enhanced Raman Scattering (SERS) has been developed into a powerful vibrational spectroscopy technique for chemical detection. However, the fabrication of colloidal droplets-based SERS substrates with well reproducibility and uniformity still remains challenging. In this paper, colloidal suspensions of hollow Au-Ag alloy nanourchins (HAAA-NUs) and Au nanoparticles (Au NPs) with different morphologies were employed as SERS-active substrates. After evaporation of colloidal suspensions, we evaluated the SERS performance based on the following features: "Coffee Ring Effects", adsorption processes of probe molecule and colloidal NPs, spin coating and morphologies of suspended NPs. The results demonstrated that SERS signals could be enhanced enormously in the marginal region of Coffee Ring patterns. The limit of detection (LOD) for amaranth molecule would be reached 10-8 M. Moreover, by combining the droplets evaporation of HAAA-NUs suspensions with spin coating, the relative standard deviation (RSD) could be down to 3.5%, showing excellent reproducibility. The investigation here would provide a simple, practical and portable SERS detection method with excellent signal uniformity. PMID- 29268213 TI - Antimicrobial activity of T4 bacteriophage conjugated indium tin oxide surfaces. AB - We report the antimicrobial activity of bare and surface functionalized indium tin oxide (ITO) conjugated with T4 bacteriophage towards E. coli. A ~ 103-fold reduction (99.9%) in the bacterial concentration was achieved within 2 h exposure of E. coli to the bare as well as the amine, carboxylic and methyl functionalized ITO/T4 surfaces. Despite the known differences in bacteriophage loading of these ITO/T4 systems, the almost identical extent of antimicrobial activity of all of the ITO/T4 systems resulted from the release of a comparable amount of infective T4 from the systems. As anticipated, a single dose of immobilized bacteriophage was sufficient to eliminate further surge of bacterial population. Upon the 2 h eradication of the '1st batch' of E. coli population, all of the ITO/T4 systems, each system with 102-fold more suspended bacteriophage (due to propagation of the phage at the expense of the '1st batch' E. coli death), reduced the '2nd batch' of E. coli concentration by ~104-fold in just 30 min, suggesting the potential of immobilized bacteriophage systems as solution to the issues of antimicrobial agent depletion. All of the ITO/T4 systems maintained their antimicrobial activity in the presence of model food components. The antimicrobial activity was however, affected by pH; at pH 5 whereby the bacteria's growth was physiologically inhibited, generally no reduction in E. coli concentration was detected. The present work provides an understanding of the mode of antimicrobial activity exhibited by an immobilized bacteriophage based substrate and demonstrates efficacy in the presence of food components. PMID- 29268214 TI - Continuous monitoring of radon gas as a tool to understand air dynamics in the cave of Altamira (Cantabria, Spain). AB - The use of radon as an atmospheric tracer in the Altamira Cave over the past 30years has provided relevant information about gaseous exchanges between the Polychromes Room, the adjoining Chambers inside the cave, and the outside atmosphere. The relatively simple physico-chemical behaviour of radon gas provides a marked advantage over other tracer gases that are usually present in high concentrations in hypogeous environments, such as CO2. Two types of continuous radon measurement were undertaken. The first involves active detectors located in the Hall and Polychromes Room, which provide radon concentration values at 1-hour intervals. In addition, nuclear solid track etched detectors (CR 39) are used in every chamber of the cave over 14-day exposure periods, providing average radon concentrations. In this paper we show some of the specific degassing and recharge events identified by anomalous variations in the concentration of radon gas in the Polychromes Room. In addition, we update knowledge regarding the degree of connection between chambers inside the cave and with the outside atmosphere. We verify that the connection between the Polychromes Room and the rest of the cave has been drastically reduced by the installation of the second closure in 2008. Except for point exchanges with the Crossing zone generated by a negative temperature gradient in that direction, the atmosphere of the Polychromes Room remains stable, or else it exchanges matter with the outside atmosphere through the karst interface. The role of radon as a tracer is demonstrated to be valid both to reflect seasonal cycles of degassing and recharge, and to analyse shorter (daily) period fluctuations. PMID- 29268215 TI - Negligent and intentional fires in Portugal: Spatial distribution characterization. AB - In the European context, Portugal is the country with the highest number of wildfires and the second with more burnt area. The vast majority of these events are of human origin, whether caused by accident, negligence or arson, reason why it is particularly important to know the regime of these wildfires for forest and wildfire management activities. The study focuses on the most recent years of 2001-2014, when wildfire ignition's coordinates are known, and aims to identify and characterize the wildfire incidence spatial patterns of variability as well as their main drivers. After grouping wildfires with human cause into negligent and intentional, we studied their spatial distribution in terms of normalized number of wildfires (NNF) and burnt area (NBA) in the five Nomenclature of Territorial Units for Statistics II regions of mainland Portugal. Results disclose an uneven spatial distribution of the fire incidence, characterized by a south-north gradient, much higher values in Norte region and more evident for intentional than for negligent wildfires. Human and biophysical drivers strongly influence NNF and NBA, at regional and national scales. Distribution patterns at regional scale, for negligent and intentional wildfires are quite different from entire mainland and all wildfires. Drivers' influence is higher for intentional than for negligent wildfires, for southern than for northern regions and for NBA than for NNF. The leading drivers of NNF are distance to roads (d) population density (pd) and altitude (h) while of NBA are h, d, slope and pd, and this influence is higher for intentional than for negligent wildfires. PMID- 29268216 TI - Relationships among satisfaction, noise perception, and use of urban green spaces. PMID- 29268217 TI - Dicarboxylic acids and levoglucosan in aerosols from Indo-Gangetic Plain: Inferences from day night variability during wintertime. AB - This study assesses daytime and nighttime atmospheric abundance and molecular distribution of dicarboxylic acids (DCA: C2-C10) and biomass burning tracers (levoglucosan and biomass burning derived potassium: K+BB) in PM10 (particulate matter with aerodynamic diameter<=10MUm) from an urban location, Kanpur (in central Indo-Gangetic Plain: IGP) during wintertime (December 2015-February 2016). In this study, PM10 varied from 130 to 242 and 175-388MUgm-3 during daytime and nighttime, respectively. The average ratios of OC/EC (day: 12.3; night: 9.3) and WSOC/OC (day: 0.74; night: 0.48) were relatively high during daytime (OC: organic carbon; EC: elemental carbon; WSOC: water-soluble organic carbon). Strong linear correlations (R2>=0.6; p<0.05) of OC with levoglucosan and K+BB suggest biomass burning emission as predominant source of organic aerosols over the IGP. The measured concentrations of total DCA (SigmaC2-C10) showed pronounced diurnal variability with a higher concentration during nighttime (2510+/-1025ngm-3) as compared to that in daytime (1499+/-562ngm-3). Concentrations of oxalic acid (C2), succinic acid (C4) and malonic acid (C3) were predominantly high as compared to other congeners of DCA (C2-C10) over central IGP. Relatively higher mass fraction (73.4%) of C2 in total DCA during nighttime than that in daytime (61.5%) indicates role of secondary organic aerosols (SOAs) formation involving aqueous-phase chemistry. Strong linear correlations of C2 with C3 and C4 plausibly suggest that C2 can have predominant formation pathways via decomposition of higher congeners of DCA. Overall, strong linear correlations of C2 with levoglucosan and sulphate suggest that biomass burning emission and secondary transformations are predominant sources of DCA over IGP during wintertime. PMID- 29268218 TI - Municipal wastewater spiramycin removal by conventional treatments and heterogeneous photocatalysis. AB - This study assessed the effects and removal options of the macrolide spiramycin, currently used for both in human and veterinary medicine- with a special focus on advanced oxidation processes based on heterogeneous TiO2_assisted photocatalysis. Spiramycin real concentrations were investigated on a seasonal basis in a municipal wastewater treatment plant (up to 35MUgL-1), while its removal kinetics were studied considering both aqueous solutions and real wastewater samples, including by-products toxicity assessment. High variability of spiramycin removal by activated sludge treatments (from 9% (wintertime) to >99.9% (summertime)) was observed on a seasonal basis. Preliminary results showed that a total spiramycin removal (>99.9%) is achieved with 0.1gL-1 of TiO2 in aqueous solution after 80min. Integrated toxicity showed residual slight acute effects in the photocatalytic treated solutions, independently from the amount of TiO2 used, and could be linked to the presence of intermediate compounds. Photolysis of wastewater samples collected after activated sludge treatment during summer season (SPY 5MUgL-1) allowed a full SPY removal after 80min. When photocatalysis with 0.1gL-1 of TiO2 was carried out in wastewater samples collected in winter season (SPY 30MUgL-1) after AS treatment, SPY removal was up to 91% after 80min. PMID- 29268219 TI - Spatial exposure-hazard and landscape models for assessing the impact of GM crops on non-target organisms. AB - The cultivation of Genetically Modified (GM) crops may have substantial impacts on populations of non-target organisms (NTOs) in agroecosystems. These impacts should be assessed at larger spatial scales than the cultivated field, and, as landscape-scale experiments are difficult, if not impossible, modelling approaches are needed to address landscape risk management. We present an original stochastic and spatially explicit modelling framework for assessing the risk at the landscape level. We use techniques from spatial statistics for simulating simplified landscapes made up of (aggregated or non-aggregated) GM fields, neutral fields and NTO's habitat areas. The dispersal of toxic pollen grains is obtained by convolving the emission of GM plants and validated dispersal kernel functions while the locations of exposed individuals are drawn from a point process. By taking into account the adherence of the ambient pollen on plants, the loss of pollen due to climatic events, and, an experimentally validated mortality-dose function we predict risk maps and provide a distribution giving how the risk varies within exposed individuals in the landscape. Then, we consider the impact of the Bt maize on Inachis io in worst-case scenarii where exposed individuals are located in the vicinity of GM fields and pollen shedding overlaps with larval emergence. We perform a Global Sensitivity Analysis (GSA) to explore numerically how our input parameters influence the risk. Our results confirm the important effects of pollen emission and loss. Most interestingly they highlight that the optimal spatial distribution of GM fields that mitigates the risk depends on our knowledge of the habitats of NTOs, and finally, moderate the influence of the dispersal kernel function. PMID- 29268220 TI - Improving representation of riparian vegetation shading in a regional stream temperature model using LiDAR data. AB - Modelling river temperature at the catchment scale is needed to understand how aquatic communities may adapt to current and projected climate change. In small and medium rivers, riparian vegetation can greatly reduce maximum water temperature by providing shade. It is thus important that river temperature models are able to correctly characterise the impact of this riparian shading. In this study, we describe the use of a spatially-explicit method using LiDAR derived data for computing the riparian shading on direct and diffuse solar radiation. The resulting data are used in the T-NET one-dimensional stream temperature model to simulate water temperature from August 2007 to July 2014 for 270km of the Loir River, an indirect tributary of the Loire River (France). Validation is achieved with 4 temperature monitoring stations spread along the Loir River. The vegetation characterised with the LiDAR approach provides a cooling effect on maximum daily temperature (Tmax) ranging from 3.0 degrees C (upstream) to 1.3 degrees C (downstream) in late August 2009. Compared to two other riparian shading routines that are less computationally-intensive, the use of our LiDAR-based methodology improves the bias of Tmax simulated by the T-NET model by 0.62 degrees C on average between April and September. However, difference between the shading routines reaches up to 2 degrees C (monthly average) at the upstream-most station. Standard deviation of errors on Tmax is not improved. Computing the impact of riparian vegetation at the hourly timescale using reach-averaged parameters provides results close to the LiDAR-based approach, as long as it is supplied with accurate vegetation cover data. Improving the quality of riparian vegetation data should therefore be a priority to increase the accuracy of stream temperature modelling at the regional scale. PMID- 29268221 TI - The occurrence and fate of PAHs over multiple years in a wastewater treatment plant of Harbin, Northeast China. AB - The occurrence and fate of polycyclic aromatic hydrocarbons (PAHs) were investigated in wastewater, sludge and surrounding air from the wastewater treatment plant (WWTP) in Harbin, Northeast China. The concentration of total PAHs in the influent, effluent and sludge were 4080ng/L, 864ng/L and 8200ng/gdw, respectively. The total concentration of PAHs showed a trend of first rising, and then decreasing over years in the influent, effluent and sludge, which was in agreement with the usage of coal and oil in Harbin. The level of PAHs was 26 560ng/m3 in air from site 1 (the top of the A/O tank), 62-608ng/m3 in air from site 2 (the vicinity of the WWTP) and 61-686ng/m3 in air from site 3 (the urban district of Harbin). In the influent and effluent, the mean concentration of PAHs followed the sequence of summer>winter>autumn>spring, while the sequence was winter>summer>autumn>spring in sludge and air. Rainfall may be the main reason for higher contamination in summer. Coal fired central heating and indoor dust may be reasons for higher PAHs in winter. The mean removal efficiency of total PAHs was approximately 85% (20% of which was adsorbed onto sludge, and 65% volatilized into air or degraded by biodegradation), and 15% of PAHs were discharged through the effluent. There was approximately 6240kg of PAHs imported into the WWTP every year, 1005kg discharged into the Songhua River through the effluent, and 327kg absorbed onto sludge and the rest was degraded or volatilized into air. PCA was applied to identify the sources of PAHs for both heating and non-heating seasons. In general, coal combustion was the main source of PAHs during the heating season and vehicle exhaust was the main source of PAHs during the non-heating season. PMID- 29268222 TI - Levels, patterns, trends and significance of polychlorinated naphthalenes (PCNs) in Great Lakes fish. AB - Polychlorinated naphthalenes (PCNs) were introduced to market about a century ago and their production is thought to have ceased by the early 1980s. However, relatively limited knowledge exists on their abundance in the edible portion of a variety of Great Lakes fish to aid in understanding their potential risk to human consumers. We studied levels, patterns, trends and significance of PCNs in a total 470 fillet samples of 18 fish species collected from the Canadian waters of the Great Lakes between 2006 and 2013. A limited comparison of fillet and wholebody concentrations in Carp and Bullhead was also conducted. The ?PCN ranged from 0.006-6.7ng/g wet weight (ww) and 0.15-190ng/g lipid weight (lw) with the dominant congeners being PCN-52/60 (34%), -42 (21%) and -66/67 (15%). The concentrations spatially varied in the order of the Detroit River>Lakes Erie>Ontario>Huron>Superior. PCN-66/67 was the dominating congener contributing on average 76-80% of toxic equivalent concentration (TEQPCN). Contribution of TEQPCN to TEQTotal (TEQDioxins+Furans+dioxin-likePCBs+PCNs) was mostly <15%, especially at higher TEQTotal, and PCB-126 remains the major congener contributing to TEQTotal. The congener pattern suggests that impurities in PCB formulations and thereby historical PCB contamination, instead of unintentional releases from industrial thermal processes, could be an important source of PCNs in Great Lakes fish. A limited temporal change analysis indicated declines in the levels of PCN-66/67 between 2006 and 2012, complemented by previously reported decrease in PCNs in Lake Ontario Lake Trout between 1979 and 2004. The whole body concentrations were 1.4-3.2 fold higher than the corresponding fillets of Carp and Bullhead. Overall, the study results suggest that only targeted monitoring of PCNs in Great Lakes fish, especially at the Detroit River, Lake Erie and Lake Ontario, is necessary to assess continued future improvements of this group of contaminants of concern. PMID- 29268223 TI - Impact of the biomass burning on methane variability during dry years in the Amazon measured from an aircraft and the AIRS sensor. AB - The present study examines the spatiotemporal variability and interrelations of the atmospheric methane (CH4), carbon monoxide (CO) and biomass burning (BB) outbreaks retrieved from satellite data over the Amazon region during the 2003 2012 period. In the climatological context, we found consistent seasonal cycles of BB outbreaks and CO in the Amazon, both variables showing a peak during the dry season. The dominant CO variability mode features the largest positive loadings in the southern Amazon, and describes the interannual CO variations related to BB outbreaks along the deforestation arc during the dry season. In line with CO variability and BB outbreaks, the results show strong correspondence with the spatiotemporal variability of CH4 in the southern Amazon during years of intense drought. Indeed, the areas with the largest positive CH4 anomalies in southern Amazon overlap the areas with high BB outbreaks and positive CO anomalies. The analyses also showed that high (low) BB outbreaks in the southern Amazon occur during dry (wet) years. In consequence, the interannual climate variability modulates the BB outbreaks in the southern Amazon, which in turn have considerable impacts on CO and CH4 interannual variability in the region. Therefore, the BB outbreaks might play a major role in modulating the CH4 and CO variations, at least in the southern Amazon. This study also provides a comparison between the estimate of satellite and aircraft measurements for the CH4 over the southern Amazon, which indicates relatively small differences from the aircraft measurements in the lower troposphere, with errors ranging from 0.18% to 1.76%. PMID- 29268224 TI - Whether hurricane Katrina impacted trace metal and dioxin depositional histories in marshes of St. Louis Bay, Mississippi. AB - Salt marsh sediments generally undergo steady accumulation over time and thus are widely used to reconstruct the depositional histories of various anthropogenic contaminants derived from atmospheric and fluvial sources. Major hurricanes can significantly affect coastal landscapes by eroding and re-distributing sediment. Thus, each major hurricane can leave distinct signals in coastal wetland sediments. On the other hand, early-diagenetic remobilization of Fe and Mn in organic rich marsh sediment is a common phenomenon. However, remobilization of Fe and Mn across the redox boundary can induce remobilization of other trace elements and thus can disturb their depositional histories. Four short (~1m) sediment cores were collected from the fringing marshes of St. Louis Bay, Mississippi (located ~30km east of Hurricane Katrina's track) during 2010-2011 to investigate possible impacts of Hurricane Katrina (2005), and early-diagenetic remobilization of Fe and Mn, on trace metal and dioxin depositional histories in these sediments. Results from 210Pb, 137Cs, stable Cs, particulate organic carbon (POC), sediment bulk density and grain size indicate significant impact of hurricane event layers on anthropogenic stable Cs, while deposition profiles of V, Ni and Cr are impacted by Fe and Mn remobilization to a limited extent. PMID- 29268225 TI - Key microbial taxa in the rhizosphere of sorghum and sunflower grown in crop rotation. AB - Microbes are key determinants of plant health and productivity. Previous studies have characterized the rhizosphere microbiomes of numerous plant species, but little information is available on how rhizosphere microbial communities change over time under crop rotation systems. Here, we document microbial communities in the rhizosphere of sorghum and sunflower (at seedling, flowering and senescence stages) grown in crop rotation in four different soils under field conditions. A comprehensive 16S rRNA-based amplicon sequencing survey revealed that the differences in alpha-diversity between rhizosphere and bulk soils changed over time. Sorghum rhizosphere soil microbial diversity at flowering and senescence were more diverse than bulk soils, whereas the microbial diversity of sunflower rhizosphere soils at flowering were less diverse with respect to bulk soils. Sampling time was also important in explaining the variation in microbial community composition in soils grown with both crops. Temporal changes observed in the rhizosphere microbiome were both plant-driven and due to seasonal changes in the bulk soil biota. Several individual taxa were relatively more abundant in the rhizosphere and/or found to be important in maintaining rhizosphere microbial networks. Interestingly, some of these taxa showed similar patterns at different sampling times, suggesting that the same organisms may play the same functional/structural role at different plant growth stages and in different crops. Overall, we have identified prominent microbial taxa that might be used to develop microbiome-based strategies for improving the yield and productivity of sorghum and sunflower. PMID- 29268226 TI - Spatial patterns and temporal variations of six criteria air pollutants during 2015 to 2017 in the city clusters of Sichuan Basin, China. AB - Spatiotemporal variations of six criteria air pollutants and influencing factors in the city clusters of Sichuan Basin were studied based on real-time hourly concentrations of PM2.5 (the particles with diameters smaller than 2.5MUm), PM10 (the particles with diameters smaller than 10MUm), SO2, NO2, CO and O3 and routine meteorological data during the years from 2015 to 2017. The Sichuan Basin was further categorized into four regions: West, south, northeast Sichuan Basin (WSB, SSB and NESB) and plateau of west Sichuan Basin (PWSB) to better understand regional air pollution characteristics. Heavy air pollution was mainly induced by high PM2.5 or ozone concentrations in the cities clusters of Sichuan Basin. The compound air pollution characteristics existed in WSB with simultaneously high concentrations of PM2.5 and ozone, while PM2.5 concentrations in SSB were the highest among the four regions and especially in the city of Zigong with maximum PM2.5 concentration of 109.3MUgm-3 in winter. The MDA8 (daily maximum 8-hour average surface O3 concentrations) more frequently exceeded CAAQS (Chinese Ambient Air Quality Standards) Grade I and II standards in Ziyang, Guang'an and Liangshan than the other cities maybe due to joint effects of industry emissions and regional transportation from surrounding cities. Annual (diurnal) variations of the pollutants with the exception of ozone showed "U" (flat "W") shape, while the ozone exhibited the opposite trends inside Sichuan Basin (WSB, SSB and NESB). Ozone pollution was more dependent on vehicle emissions inside Sichuan Basin, and industry had more important effects on ozone in the cities of PWSB with less vehicles. Severe ozone pollution can be formed easily under the weather conditions of high temperature, long sunshine duration and low RH (relative humidity) inside Sichuan Basin. High ozone concentrations in winter in PWSB may be partly transported from the other surrounding cities. PMID- 29268227 TI - Environmental factors associated with blood lead among newcomer women from South and East Asia in the Greater Toronto Area. AB - BACKGROUND: Newcomers bring with them histories of environmental exposure in their home countries and may have different sources of lead (Pb) exposure compared to other residents of their adopted country. AIMS: To describe past and current factors associated with Pb exposure and blood Pb among South and East Asian newcomer women of reproductive age in the Greater Toronto Area (GTA), Ontario, Canada. METHODS: In collaboration with public health units and community organizations a community-based research model was utilized by recruiting peer researchers to assist in all aspects of the study. Blood samples were taken and phone interviews were conducted. Canadian Health Measures Survey (CHMS) cycles 1, 2, and 3 data was used to contextualize the distribution blood Pb levels. Multiple regression was applied to log-transformed blood lead measurements, using a hierarchical model building process. RESULTS: In total, 211 participants were recruited from Bangladesh, China, India, Pakistan and Sri Lanka. The distribution of the blood Pb varied by country of origin, and higher blood Pb values were found above 75th percentile compared to the CHMS. Distal factors significantly influencing blood Pb concentrations related to life history, such as duration of stay in Canada (RR=0.91; 95% CI 0.86-0.97), living near agricultural fields (RR=0.78; 95% CI 0.62-0.93), and country of origin. Proximal factors with significant contribution were use of cosmetics, traditional remedies, and smoking cigarettes. RECOMMENDATIONS: Different past and current exposures may be important in various newcomer populations, informing international stakeholders, public health agencies, and primary care practitioners to adapt health education and exposure reduction programs to consider pre- and post-migration factors. PMID- 29268229 TI - Fatigue and damage of porcine pars interarticularis during asymmetric loading. AB - If the articular facets of the vertebra grow in an asymmetric manner, the developed bone geometry causes an asymmetry of loading. When the loading environment is altered by way of increased activity, the likelihood of acquiring a stress fracture may be increased. The combination of geometric asymmetry and increased activity is hypothesised to be the precursor to the stress fracture under investigation in this study, spondylolysis. This vertebral defect is an acquired fracture with 7% prevalence in the paediatric population. This value increases to 21% among athletes who participate in hyperextension sports. Tests were carried out on porcine lumbar vertebrae, on which the effect of facet angle asymmetry was simulated by offsetting the load laterally by 7mm from the mid point. Strain in the vertebral laminae was recorded using six 3-element stacked rosette strain gauges placed bilaterally. Specimens were loaded cyclically at a rate of 2Hz. Fatigue cycles; strain, creep, secant modulus and hysteresis were measured. The principal conclusions of this paper are that differences in facet angle lead to an asymmetry of loading in the facet joints; this in turn leads to an initial increase in strain on the side with the more coronally orientated facet. The strain amplitude, which is the driving force for crack propagation, is greater on this side at all times up to fracture, the significance of this can be observed in the increased steady state creep rate (p = 0.036) and the increase in yielding and toughening mechanisms taking place, quantified by the force displacement hysteresis (p = 0.026). PMID- 29268228 TI - Oil sands tailings pond sediment toxicity to early life stages of northern pike (Esox lucius). AB - The Athabasca River in Alberta flows through natural sources of eroding oil sands bitumen and oil sands mining operations that may result in low level contamination of surface waters. Northern pike (Esox lucius) are apex predators and important food and game fish species native to the Athabasca River system. This species has the potential to be exposed to both natural and anthropogenic sources of contamination from oil sands related materials throughout its life cycle. Pike are difficult to rear in the laboratory and little information exists on the toxicity of oil sands related materials to this key indigenous fish species. In this study, the potential effects of two sediment samples collected from different areas of one tailings pond in the Athabasca oil sands area are assessed in a daily renewal bioassay on early life stages of northern pike. Gametes were collected from spawning wild pike captured from a reference site outside of the oil sands area. Fertilized eggs were exposed to control water or increasing concentrations of tailings pond sediments for 21days, coinciding with initiation of exogenous feeding and completion of yolk absorption. Developing fish were examined for survival and changes in body weight, length, and development. Embryos exhibited increased developmental abnormalities and decreased growth and survival with increasing sediment concentration. Both sediment samples had similar levels of naphthenic acids and similar types of PAHs, with alkylated PAHs dominating. However, concentrations of total and alkylated PAHs differed between sediment samples and were related to increasing developmental abnormalities and decreased growth and survival. This is consistent with developmental changes observed with exposure to PAHs in other fish species. These results provide information on the effects of tailings pond sediments comprising mixtures of PAHs and alkylated PAHs on the development and survival of a key species in the northern aquatic ecosystem. PMID- 29268230 TI - Morphological changes of cerebellar substructures in temporal lobe epilepsy: A complex phenomenon, not mere atrophy. AB - PURPOSE: To evaluate cerebellar volume changes in temporal lobe epilepsy (TLE) patients in greater detail. We aimed to determine which discrete substructures significantly differ in patients with TLE compared to controls and the nature of this difference. Correlations with age at epilepsy onset, epilepsy duration, seizure frequency, and total number of antiepileptic drugs (AED) in the patient's history were studied. We analyzed the potential association between cerebellar atrophy and epilepsy surgery outcome. METHODS: Study participants were 36 TLE patients; 22 hippocampal sclerosis (HS) only and 38 healthy controls. All patients later underwent temporal lobe resection. All subjects were examined using 1.5T MRI. Cerebellar volume was adjusted for total intracranial volume, age, and gender, and measured using voxel-based morphometry. Cerebellar substructures were defined using the AAL atlas. Data processing was performed automatically. Separate analyses for HS only subset were performed. RESULTS: Total cerebellar gray matter volume (GMV) appeared non-significantly smaller in epilepsy patients. Within the substructures, the GMV of the selected vermian segments were significantly larger in patients. The GMV of the whole cerebellum and of all individual cerebellar substructures non-significantly decreased with increasing complex partial seizure frequency and total number of AEDs in the patient's history. Total cerebellar GMV was significantly smaller in patients with persistent seizures after epilepsy surgery than in seizure-free patients. CONCLUSION: Cerebellar atrophy is a complex phenomenon, the character of changes differs significantly within the cerebellar substructures. Total cerebellar GMV reduction is associated with worse outcome of temporal lobe resection. PMID- 29268231 TI - Oligothiophene-based colorimetric and ratiometric fluorescence dual-channel cyanide chemosensor: Sensing ability, TD-DFT calculations and its application as an efficient solid state sensor. AB - An oligothiophene-based colorimetric and ratiometric fluorescence dual-channel cyanide chemosensor 3 T-2CN was reported. Sensor 3 T-2CN showed both naked-eye recognition and ratiometric fluorescence response for CN- with an excellent selectivity and high sensitivity. The sensing mechanism based on the nucleophilic attack of CN- on the vinyl CC bond has been successfully confirmed by the optical measurements, 1H NMR titration, FT-IR spectra as well as the DFT/TD-DFT calculations. Moreover, the detection limit was calculated to be 0.19MUM, which is much lower than the maximum permission concentration in drinking water (1.9MUM). Importantly, test strips (filter paper and TLC plates) containing 3 T 2CN were fabricated, which could act as a practical and efficient solid state optical sensor for CN- in field measurements. PMID- 29268232 TI - A novel fluorescein-based "turn-on" probe for the detection of hydrazine and its application in living cells. AB - We constructed a novel probe for hydrazine detection based on ICT and PET mechanism. Phthalimide and acetyl ester groups were used as the recognition units. Addition of hydrazine produced a turn-on fluorescence at 525nm along with the fluorescent color change from dark to yellow. The probe could selectively detect hydrazine over other related interfering species. The detection limit of the probe for hydrazine was calculated to be 0.057MUM which was lower than the EPA standard (0.320MUM). Furthermore, the probe could also be applied for the imaging of hydrazine in living cells. PMID- 29268233 TI - Temperature- and pressure-dependent infrared spectroscopy of 1-butyl-3 methylimidazolium trifluoromethanesulfonate: A dipolar coupling theory analysis. AB - Continued growth and development of ionic liquids requires a thorough understanding of how cation and anion molecular structure defines the liquid structure of the materials as well as the various properties that make them technologically useful. Infrared spectroscopy is frequently used to assess molecular-level interactions among the cations and anions of ionic liquids because the intramolecular vibrational modes of the ions are sensitive to the local potential energy environments in which they reside. Thus, different interaction modes among the ions may lead to different spectroscopic signatures in the vibrational spectra. Charge organization present in ionic liquids, such as 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([C4mim]CF3SO3), is frequently modeled in terms of a quasicrystalline structure. Highly structured quasilattices enable the dynamic coupling of vibrationally-induced dipole moments to produce optical dispersion and transverse optical-longitudinal optical (TO-LO) splitting of vibrational modes of the ionic liquid. According to dipolar coupling theory, the degree of TO-LO splitting is predicted to have a linear dependence on the number density of the ionic liquid. Both temperature and pressure will affect the number density of the ionic liquid and, therefore, the amount of TO-LO splitting for this mode. Therefore, we test these relationships through temperature- and pressure-dependent FT-IR spectroscopic studies of [C4mim]CF3SO3, focusing on the totally symmetric SO stretching mode for the anion, nus(SO3). Increased temperature decreases the amount of TO-LO splitting for nus(SO3), whereas elevated pressure is found to increase the amount of band splitting. In both cases, the experimental observations follow the general predictions of dipolar coupling theory, thereby supporting the quasilattice model for this ionic liquid. PMID- 29268234 TI - Environment dependent enhanced photoluminescence and Boolean logic gates like behavior of Bi2O3 and Ag:Bi2O3 nanostructures. AB - In the evolution of nanotechnology research for smart and precise sensor fabrication, here we report the implementation of simple logic gate operations performing by luminescent nanostructures in biomolecule environment based on photoluminescence (PL) technique. This present work deals with the luminescence property of alpha-Bi2O3 and Ag modified alpha-Bi2O3 nanostructures for d-glucose and Bovine serum albumin (BSA) sensing applications. These nanostructures are prepared by simple co-precipitation method and their morphology are examined using transmission electron microscope (TEM). We explore the PL characteristics of the prepared nanostructures and observe their change in PL intensity in the presence of d-glucose and BSA molecules. Enhancement in PL intensity is observed in the presence of d-glucose and BSA. Based on the PL response of prepared nanostructures in the biomolecule environment, we demonstrate biophotonic logic gates including YES, PASS 0, OR and INHIBIT gates. PMID- 29268235 TI - Highly selective apo-arginase based method for sensitive enzymatic assay of manganese (II) and cobalt (II) ions. AB - A novel enzymatic method of manganese (II) and cobalt (II) ions assay, based on using apo-enzyme of Mn2+-dependent recombinant arginase I (arginase) and 2,3 butanedione monoxime (DMO) as a chemical reagent is proposed. The principle of the method is the evaluation of the activity of L-arginine-hydrolyzing of arginase holoenzyme after the specific binding of Mn2+ or Co2+ with apo-arginase. Urea, which is the product of enzymatic hydrolysis of L-arginine (Arg), reacts with DMO and the resulted compound is detected by both fluorometry and visual spectrophotometry. Thus, the content of metal ions in the tested samples can be determined by measuring the level of urea generated after enzymatic hydrolysis of Arg by reconstructed arginase holoenzyme in the presence of tested metal ions. The linearity range of the fluorometric apo-arginase-DMO method in the case of Mn2+ assay is from 4pM to 1.10nM with a limit of detection of 1pM Mn2+, whereas the linearity range of the present method in the case of Co2+ assay is from 8pM to 45nM with a limit of detection of 2.5pM Co2+. The proposed method being highly sensitive, selective, valid and low-cost, may be useful to monitor Mn2+ and Co2+ content in clinical laboratories, food industry and environmental control service. PMID- 29268236 TI - Mechanisms of epithelial thickening due to IL-1 signalling blockade and TNF-alpha administration differ during wound repair and regeneration. AB - IL-1 and TNF-alpha are always present during wound repair, but their pleiotropic and synergistic effects are incompletely understood. In this work, we evaluated the role of IL-1 in wound repair, and examined whether TNF-alpha administration impaired scarless wound repair. First, we characterised wound repair in outbred CD-1 mice according to age and sex in an ear punch wound model. Then, we examined the effects of Interleukin 1 receptor antagonist (IL-1ra) and TNF-alpha placement inside ear wounds by means of loaded Heparin beads in young and middle-aged male and female mice. Wounds in middle-aged females repaired with scarless characteristics, whereas those in young males showed fibrotic scarring. Rather than improving wound repair in young males, IL-1 signalling blockade increased epithelial thickness and IL-1beta and TNF-alpha expression, and diminished epidermal apoptosis. TNF-alpha impaired wound repair in middle-aged females, which exhibited acanthosis and overexpression of IL-1, but no change in apoptosis. These findings suggest that this mechanism of epidermal thickening differs from that observed in IL1-ra-treated animals. PMID- 29268237 TI - How accurate is visual determination of foot strike pattern and pronation assessment. AB - Nowadays, choosing adequate running shoes is very difficult, due to the high number of different designs. Nevertheless, shoes have two main characteristics to fit runners' technique and morphology: drop and arch support. Retailers' advices are usually based on the visual assessment of the customer's running technique. Such method is subjective and requires an experimented examiner while objective methods require expensive material, such as 3D motion system and pressure insoles. Therefore, the aim of this study was to determine the accuracy of foot strike pattern and pronation assessment using video cameras, compared to a gold standard motion tracking system and pressure insoles. 34 subjects had to run at 8, 12 and 16 Km/h shod and 12 Km/h barefoot during 30 s trials on a treadmill. Agreement between foot strike pattern assessment methods was between 88% and 92%. For pronation, agreement on assessment methods was between 42% and 56%. The results obtained indicate a good accuracy on foot strike pattern assessment, and a high difficulty to determine pronation with enough accuracy. There is therefore a need to develop new tools for the assessment of runner's pronation. PMID- 29268238 TI - The impact of OxyContin reformulation at the Sydney Medically Supervised Injecting Centre: Pros and cons. PMID- 29268239 TI - Effect of ageing and time since first heroin and cocaine use on mortality from external and natural causes in a Spanish cohort of drug users. AB - BACKGROUND: We aimed to assess the effect of ageing and time since first heroin/cocaine use on cause-specific mortality risk and age disparities in excess mortality among heroin (HUs) and cocaine users (CUs) in Spain. METHODS: A cohort of 15,305 HUs and 11,905 CUs aged 15-49 starting drug treatment during 1997-2007 in Madrid and Barcelona was followed until December 2008. Effects of ageing and time since first heroin/cocaine use were estimated using a competing risk Cox model and the relative and absolute excess mortality compared to the general population through directly age-sex standardized rate ratios (SRRs) and differences (SRDs), respectively. RESULTS: Mortality risk from natural causes increased with time since first heroin use, whereas that from overdose declined after having peaked in the first quinquennium. Significant effects of time since first cocaine use were not identified, although fatal overdose risk seemed higher in CUs after five years. Mortality risk from natural causes (HUs and CUs), injuries (HUs), and overdoses (CUs) increased with age, the latter without reaching statistical significance. Crude mortality rates from overdoses and injuries remained very high at age 40-59 among both HUs (595 and 217 deaths/100,000 person-years, respectively) and CUs (191 and 88 deaths/100,000 person-years). SRDs from all and natural causes were much higher at age 40-59 than 15-29 in both HUs (2134 vs. 834 deaths/100,000 person-years) and CUs (927 vs. 221 deaths/100,000 person-years), while the opposite occurred with SRRs. CONCLUSION: The high mortality risk among HUs and CUs at all ages from both external and natural causes, and increased SRDs with ageing, suggest that high level healthcare and harm reduction services should be established early and maintained throughout the lifetime of these populations. PMID- 29268240 TI - UBE2C is involved in the functions of ECRG4 on esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal cancerrelated gene 4 (ECRG4) is down-regulated in esophageal squamous-cell carcinoma (ESCC) and inhibits the tumorigenicity of ESCC cells. Ubiquitin conjugating enzyme E2 (UBE2C), an E2 ubiquitin-conjugating enzyme, is upregulated in numerous human cancers, including ESCC. METHODS: mRNA and protein expression was determined by real-time PCR and western blotting analysis, respectively. Cell apoptosis was assessed by Annexin V-fluorescein isothiocyanate staining and flow cytometry analysis. RESULTS: By analyzing previous quantitative proteomics data on EC9706 cells, we found that UBE2C was significantly down-regulated in ECRG4 overexpressed cells. Western blotting analysis validated the proteomics results in both EC9706 and EC-18 cells. In addition, Pearson's correlation analysis demonstrated a negative correlation between the mRNA levels of ECRG4 and UBE2C in ESCC tissues. Then, we found that Nuclear Factor-kappaB (NF-kappaB) inhibitor, pyrriolidine-dithiocarbamate (PDTC), could inhibit NF-kappaB p65 nuclear translocation and UBE2C expression, which was partially reversed by ECRG4 silence. More importantly, UBE2C knockdown in TE-1 cells significantly inhibited cell proliferation and induced cell apoptosis, which was partially reversed by ECRG4 knockdown. CONCLUSIONS: ECRG4 down regulated UBE2C expression in ESCC cells via NF-kappaB signaling. UBE2C was involved in the anti-proliferative and pro-apoptotic functions of ECRG4 in ESCC cells. PMID- 29268241 TI - Potential effect of spermidine on GABA, dopamine, acetylcholinesterase, oxidative stress and proinflammatory cytokines to diminish ketamine-induced psychotic symptoms in rats. AB - Ketamine, N-methyl-d-aspartate receptor antagonist has been implanted in such behavioural and biochemical alterations in animals similar to human psychosis. Spermidine, a biogenic polyamine, involved in various cellular functions in living organisms, on the contrary possess NMDA receptor agonistic effect. Therefore, we aimed to study the effect of spermidine (10 and 20 mg/kg, i.p.) in ketamine (50 mg/kg, i.p.) induced psychotic symptoms using various behavioural animal models. Biochemical assays were done to confirm the molecular pathways associated with spermidine and psychosis. Spermidine was significant to alleviate the ketamine-induced psychotic symptoms as indicated by decrease in locomotor activity in actophotometer, stereotypic behaviours, immobility duration in force swim test and latency to climb the pole in pole climb avoidance test. Interestingly, spermidine significantly decreased acetylcholinesterase (AChE) activity, serum tumor necrosis factor (TNF-alpha), dopamine and malondialdehyde (MDA) level while increased gamma-amino butyric acid and reduced glutathione (GSH) level in different regions of brain. Spermidine did not produce cataleptic effect on bar test at lower dose, but at the higher dose its cataleptic effect was similar to haloperidol. Based on behavioural and biochemical results, present study revealed spermidine as a promising antipsychotic biomolecule, however, its cataleptic effect at higher doses must be ruled out before use in clinical settings. PMID- 29268242 TI - STAT3 aggravates TGF-beta1-induced hepatic epithelial-to-mesenchymal transition and migration. AB - Signal transducer and activator of transcription 3 (STAT3) has been shown to affect epithelial-to-mesenchymal transition (EMT) in cancers. We investigated the underlying molecular mechanisms of STAT3 crosstalk with Snail-Smad3/transforming growth factor (TGF)-beta1 signaling pathways during the EMT in hepatocellular carcinoma (HCC). STAT3 and TGF-beta1 expressions are examined in liver tissues of HCC patients and rats. The effect of IL-6/ STAT3 crosstalk with Snail-Smad3/TGF beta1 on EMT, carcinogenesis, migration and invasion are tested in vitro and in vivo. Phosphorylation of STAT3 and TGF-beta1 proteins are universally high and positively co-expressed in HCC tissues from human and rats. Hepatic lower p-STAT3 proteins are related to earlier tumor stages in HCC patients. AG490 (a JAK2 specific inhibitor) treatment could reduce tumor numbers and sizes depending on suppression of STAT3 signaling in HCC rats. TGF-beta1 could induce EMT along with an E-cadherin decrease, while vimentin, Snail, p-Smad2/3, and p-STAT3/STAT3 increase in HepG2. SIS3 (a specific inhibitor of Smad3) could markedly inhibit Snail, Vim and p-STAT3 along with blocking phosphorylation of Smad3, but E cadherin could be activated in HepG2. IL-6 activates STAT3 signaling and then has cascading consequences for activating Snail-Smad3/TGF-beta1 and vimentin as well as migration and invasion in liver cancer cells. In contrast, AG490 has an effect that inhibits phosphorylation of STAT3, lowers Snail-p-Smad3 protein levels, decreases TGF-beta1-related PAI-1 promoter activation and then reduces migration or invasion of liver cancer cells. STAT3 functions as a positive regulator to activate TGF-beta1-induced EMT and metastasis of HCC. STAT3 and the Snail Smad3/TGF-beta1 signaling pathways synergistically augment EMT and migration in HCC. PMID- 29268243 TI - Orphan G protein-coupled receptors: The role in CNS disorders. AB - There are various types of receptors in the central nervous system (CNS). G protein-coupled receptors (GPCRs) have the highest expression with a wide range of physiological functions. A newer sub group of these receptors namely orphan GPCRs have been discovered. GPR3, GPR6, GPR17, GPR26, GPR37, GPR39, GPR40, GPR50, GPR52, GPR54, GPR55, GPR85, GPR88, GPR103, and GPR139 are the selected orphan GPCRs for this article. Their roles in the central nervous system have not been understood well so far. However, recent studies show that they may have very important functions in the CNS. Hence, in the present study, we reviewed most recent findings regarding the physiological roles of the selected orphan GPCRs in the CNS. After a brief presentation of each receptor, considering the results from genetic and pharmacological manipulation of the receptors, their roles in the pathophysiology of different diseases and disorders including anxiety, depression, schizophrenia, epilepsy, Alzheimer's disease, Parkinson's disease, and substance abuse will be discussed. At present, our knowledge regarding the role of GPCRs in the brain is very limited. However, previous limited studies show that orphan GPCRs have an important place in psychopharmacology and these receptors are potential new targets for the treatment of major CNS diseases. PMID- 29268244 TI - Peanut testa extracts possessing histone deacetylase inhibitory activity induce apoptosis in cholangiocarcinoma cells. AB - Previous studies demonstrated that peanut testa extracts (KK4 and ICG15042) containing natural histone deacetylase (HDAC) inhibitors inhibited the growth of several human cancer cell lines via apoptosis induction. The aims of this study were to investigate the anti-proliferative effects and the mechanism(s) responsible for apoptosis induction mediated by these peanut testa extracts in human cholangiocarcinoma cell lines (KKU-M214 and KKU-100). The anti proliferative effects were assessed by MTT assay. Apoptotic cell death and cell cycle arrest were analyzed by flow cytometry. The caspase activities were studied using colorimetric caspase activity assay and western blot analysis. Our results revealed that KK4 and ICG15042 extracts inhibited cell proliferation of both KKU M214 and KKU-100 cells in a dose- and time-dependent manner, with IC50 values of 38.28 +/- 0.29 (KK4), 43.91 +/- 1.94 (ICG15042) MUg/mL for KKU-M214 and 78.40 +/- 1.74 (KK4), 82.77 +/- 0.94 (ICG15042) MUg/mL for KKU-100 at 72 h. Apoptosis induction by these peanut testa extracts were observed in both KKU-M214 and KKU 100 cells in a concentration-dependent manner. Moreover, the percentage of cells in the sub-G1 phase was significantly increased in both KKU-M214 and KKU-100 cells. Cell cycle arrest was not observed in other cell cycle phases. Activation of caspases 8 and 3 were apparent integral parts of apoptosis induction in both cells. Both peanut testa extracts also caused down-regulation of p53, p21, Bcl-2 and pERK1/2 protein expression in these cells. These results suggest that peanut testa extracts may be potential anti-cancer agents for cholangiocarcinoma chemoprevention or chemotherapy. PMID- 29268245 TI - Ameliorative effect of pumpkin seed oil against emamectin induced toxicity in mice. AB - The current study was conducted to evaluate the toxic effects of emamectin insecticide in mice and the possible protective effect of pumpkin seed oil. Treated mice received emamectin benzoate in the diet at 75-ppm for 8 weeks, while another group of animals received emamectin in addition to pumpkin seed oil at a dose of 4 ml/kg. Biochemical analysis of MDA, DNA fragmentation, GSH, CAT and SOD was performed in liver, kidney and brain as oxidant/antioxidant biomarkers. In addition, gene expression of CYP2E1 and Mgst1 and histopathological alterations in these organs were evaluated. Emamectin administration induced oxidative stress in liver and kidney evidenced by elevated levels of MDA and percentage of DNA fragmentation with suppression of GSH level and CAT and SOD activities. Brain showed increase of MDA level with inhibition of SOD activity. Relative expressions of CYP2E1 and Mgst1 genes were significantly elevated in both liver and kidney. Emamectin produced several histopathological changes in liver, kidney and brain. Co-administration of pumpkin seed oil produced considerable protection of liver and kidney and complete protection of brain. In conclusion, pumpkin seed oil has valuable value in ameliorating the toxic insult produced by emamectin in mice. PMID- 29268246 TI - Analysis of monoamine oxidase (MAO) enzymatic activity by high-performance liquid chromatography-diode array detection combined with an assay of oxidation with a peroxidase and its application to MAO inhibitors from foods and plants. AB - Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of biogenic amines and neurotransmitters and produce ammonia, aldehydes, and hydrogen peroxide which is involved in oxidative processes. Inhibitors of MAO-A and -B isozymes are useful as antidepressants and neuroprotectants. The assays of MAO usually measure amine oxidation products or hydrogen peroxide by spectrophotometric techniques. Those assays are often compromised by interfering compounds resulting in poor results. This research describes a new method that combines in the same assay the oxidative deamination of kynuramine to 4 hydroxyquinoline analyzed by HPLC-DAD with the oxidation of tetramethylbenzidine (TMB) (or Amplex Rex) by horseradish peroxidase (HRP) in presence of hydrogen peroxide. The new method was applied to study the inhibition of human MAO-A and B by bioactive compounds including beta-carboline alkaloids and flavonoids occurring in foods and plants. As determined by HPLC-DAD, beta-carbolines, methylene blue, kaempferol and clorgyline inhibited MAO-A and methylene blue, 5 nitroindazole, norharman and deprenyl inhibited MAO-B, and all of them inhibited the oxidation of TMB in the same extent. The flavonoids catechin and cyanidin were not inhibitors of MAO by HPLC-DAD but highly inhibited the oxidation of TMB (or Amplex Red) by peroxidase whereas quercetin and resveratrol were moderate inhibitors of MAO-A by HPLC-DAD, but inhibited the peroxidase assay in a higher level. For some phenolic compounds, using the peroxidase-coupled assay to measure MAO activity led to mistaken results. The new method permits to discern between true inhibitors of MAO from those that are antioxidants and which interfere with peroxidase assays but do not inhibit MAO. For true inhibitors of MAO, inhibition as determined by HPLC-DAD correlated well with inhibition of the oxidation of TMB and this approach can be used to assess the in vitro antioxidant activity (less hydrogen peroxide production) resulting from MAO inhibition. PMID- 29268247 TI - Experimental Inhibition of Periostin Attenuates Kidney Fibrosis. AB - BACKGROUND: Periostin is responsible for tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been shown to contribute to fibrosis in chronic kidney disease. We investigated the role of periostin and the effect of periostin blockade in renal fibrogenesis. METHODS: We investigated the function of periostin in vivo in wild-type and periostin-null mice (Postn-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct cells from the wild-type and Postn-KO mice were used. RESULTS: Periostin expression was strongly induced by UUO in the wild-type mice. UUO induced renal fibrosis and morphological changes in the obstructed kidney of wild-type mice, whereas global knockout of periostin reduced fibrosis induced by UUO and improved kidney structure. Fibrosis- and inflammation-related mRNA were significantly induced in the wild-type mice and were decreased in the Postn-KO mice. Additionally, alpha-smooth muscle actin expression was increased following the administration of recombinant periostin in vitro. The effect of periostin blockade was examined using 2 methods. The integrin blockade peptide decreased fibrosis-related gene expression in in vitro experiments. Anti-periostin polyclonal antibody attenuated renal fibrosis induced by UUO through changes in transforming growth factor-beta signaling and the inflammatory and apoptotic pathways. CONCLUSION: Periostin is a marker of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade effectively attenuated renal fibrogenesis. Thus, periostin inhibition may be a therapeutic strategy for the amelioration of renal disease progression. PMID- 29268248 TI - Gender-Specific Antenatal Growth Reference Charts in Monochorionic Twins. AB - OBJECTIVE: To create antenatal gender-specific reference growth charts in uncomplicated monochorionic diamniotic twins. MATERIALS AND METHODS: This is a prospective longitudinal study in which uncomplicated monochorionic (MC) twin pregnancies were included from 23 + 4 weeks of gestation onwards. Estimated fetal weight (EFW) and biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) were evaluated in both fetuses every 2 weeks using standardized methodology. Maternal and fetal complications were excluded. Charts were fitted for each biometric parameter and EFW in relation to gestational age and fetal gender using multilevel mixed models. RESULTS: The final analysis included a total of 456 ultrasound examinations in 62 MC twins, with a mean of 7 scans per pregnancy (range 5-8). The mean as well as 5th and 95th percentiles of each biometric parameter and EFW were adjusted in relation to gender and gestational age between 24 and 37 weeks of gestation. Male fetuses have higher reference values than females, and the disparity is larger in the upper centiles of the distribution. DISCUSSION: We provide gender-specific reference growth charts for MC twins. We suggest that these charts will improve prenatal MC twin assessment and surveillance, with a more accurate classification of normal or growth-restricted fetuses adjusted per sex. PMID- 29268249 TI - Prenatal Diagnosis of Trisomy 2p due to Terminal 2p Duplication including Interstitial Telomeric Sequences. AB - We report on a prenatally diagnosed unusual case of inverted terminal duplication of the short arm of chromosome 2, leading to interstitial telomeric sequences (ITSs) and partial trisomy 2p. To our knowledge, there are only 4 further cases of pure partial trisomy 2p reported prenatally. Here, the mother was referred at 22 weeks of gestation for isolated fetal congenital heart malformation at ultrasound. The karyotype of amniotic fluid cells displayed a large duplication of the short arm of chromosome 2 that was further investigated by array-CGH, which detected a 1-copy gain of 43.75 Mb in chromosome 2 at 2p21p25.3. FISH confirmed the presence of an inverted duplication in the short arm of chromosome 2 involving the region 2p21pter and revealed the presence of ITSs at the breakpoint in chromosome 2p21. This report contributes to the prenatal description of the syndrome. We also discuss the possible mechanisms leading to this duplication and the formation of ITSs which are rarely described in constitutional rearrangements. PMID- 29268250 TI - Psychometric Properties of the MyotonPRO in Dementia Patients with Paratonia. AB - BACKGROUND: Paratonia is a distinctive form of hypertonia, causing loss of functional mobility in early stages of dementia to severe high muscle tone and pain in the late stages. For assessing and evaluating therapeutic interventions, objective instruments are required. OBJECTIVE: Determine the psychometric properties of the MyotonPRO, a portable device that objectively measures muscle properties, in dementia patients with paratonia. METHODS: Muscle properties were assessed with the MyotonPRO by 2 assessors within one session and repeated by the main researcher after 30 min and again after 6 months. Receiver operating characteristic curves were constructed for all MyotonPRO outcomes to discriminate between participants with (n = 70) and without paratonia (n = 82). In the participants with paratonia, correlation coefficients were established between the MyotonPRO outcomes and the Modified Ashworth Scale for paratonia (MAS-P) and muscle palpation. In participants with paratonia, reliability (intraclass correlation coefficient) and agreement values (standard error of measurement and minimal detectable change) were established. Longitudinal outcome from participants with paratonia throughout the study (n = 48) was used to establish the sensitivity for change (correlation coefficient) and responsiveness (minimal clinical important difference). RESULTS: Included were 152 participants with dementia (mean [standard deviation] age of 83.5 [98.2]). The area under the curve ranged from 0.60 to 0.67 indicating the MyotonPRO is able to differentiate between participants with and without paratonia. The MyotonPRO explained 10-18% of the MAS-P score and 8-14% of the palpation score. Interclass correlation coefficients for interrater reliability ranged from 0.57 to 0.75 and from 0.54 to 0.71 for intrarater. The best agreement values were found for tone, elasticity, and stiffness. The change between baseline and 6 months in the MyotonPRO outcomes explained 8-13% of the change in the MAS-P scores. The minimal clinically important difference values were all smaller than the measurement error. CONCLUSION: The MyotonPRO is potentially applicable for cross-sectional studies between groups of paratonia patients and appears less suitable to measure intraindividual changes in paratonia. Because of the inherent variability in movement resistance in paratonia, the outcomes from the MyotonPRO should be interpreted with care; therefore, future research should focus on additional guidelines to increase the clinical interpretation and improving reproducibility. PMID- 29268251 TI - Long Noncoding RNA Linc00152 Functions as a Tumor Propellant in Pan-Cancer. AB - BACKGROUND/AIMS: The oncogenic role of linc00152 in pan-cancer is unclear. METHODS: In this study, RNA-Seq of 33 breast specimens was performed, and the expression of linc00152 was validated by qPCR using 50 paired breast cancer tissues and adjacent normal tissues. This result combined with the expression of linc00152 in pan-cancer was revalidated by Gene Expression Omnibus and The Cancer Genome Atlas data. Next, the oncogenic roles of linc00152 in view of prognosis, chemoresistance, genomic and epigenetic regulation, including DNA methylation and histone modification, potential biological function enrichment, and basic molecular function in pan-cancer, were also evaluated in vitro and in vivo. RESULTS: Linc00152 is upregulated in pan-cancer, especially in progressive cancer, and the high expression of linc00152 may lead to a worse prognosis and chemoresistance in pan-cancer patients. Amplification, DNA hypomethylation, promoter-like lncRNA characteristics and super-enhancer regulation are the drivers that lead to the upregulation of linc00152 in pan-cancer. Meanwhile, linc00152 was involved in cancer-related pathways, infection and immune response associated pathways by enriched analysis using TCGA data. Finally, linc00152 was confirmed to promote the proliferation, migration and invasion in MDA-MB-231, SGC 7901 and 786-O. Moreover, RIP and RNA pull-down assays indicated that linc00152 can bind to EZH2 directly. CONCLUSION: All of the results indicated that linc00152 acted as an oncogenic propellant from various perspectives, and it may be an effective therapy target in pan-cancer. PMID- 29268253 TI - Title Page / Table of Contents / Policy Statement. PMID- 29268252 TI - Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress. AB - BACKGROUND: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV) possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. METHODS: The ApoE-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67), senescence (p16INK4a), oxidant (NADPH oxidase 4, NOX4) and antioxidant (superoxide dismutase, SOD) were observed by immunofluorescence staining. RESULTS: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE-/- mice. However, the decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS) in ApoE-/- mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE /- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16INK4a in the hearts of ApoE-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. CONCLUSION: AST IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress. PMID- 29268255 TI - Meeting the Iron Needs of Low and Very Low Birth Weight Infants. AB - Low birth weight (LBW), defined as a birth weight of <2,500 g, affects 16% of all newborns and is a risk factor for impaired neurodevelopment as well as adverse cardiovascular and metabolic outcomes, including hypertension. LBW infants include both term, small for gestational age infants and preterm infants. Most LBW infants have only marginally LBW (2,000-2,500 g). Recent advances in neonatal care have significantly improved the survival of very LBW (VLBW) infants (<1,500 g). LBW infants are at high risk of iron deficiency due to low iron stores at birth and higher iron requirements due to rapid growth. Using a factorial approach, iron requirements of LBW infants have been estimated to be 1-2 mg/kg/day, which is much higher than the requirements of term, normal birth weight infants, who need almost no dietary iron during the first 6 months of life. In VLBW infants, blood losses and blood transfusions related to neonatal intensive care, as well as erythropoietin treatment, will greatly influence iron status and iron requirements. The timing of umbilical cord clamping at birth is of great importance for the amount of blood transfused from the placenta to the newborn and thereby total body iron. Delayed cord clamping of LBW infants is associated with less need for blood transfusion, less intraventricular hemorrhage, and less necrotizing enterocolitis. Randomized controlled trials have shown that an iron intake of 1-3 mg/kg/day (1-2 mg for marginally LBW and 2-3 mg for VLBW) is needed to effectively prevent iron deficiency. There is some recent evidence that these levels of iron intake will prevent some of the negative health consequences associated with LBW, especially behavioral problems and other neurodevelopmental outcomes and possibly even hypertension. However, it is also important to avoid excessive iron intakes which have been associated with adverse effects in LBW infants. PMID- 29268254 TI - Iron Nutriture of the Fetus, Neonate, Infant, and Child. AB - Iron is a key nutrient and is essential for the developing fetus, neonate, infant, and child. Iron requirements are high during early stages of life because it is critically important for the production of new red blood cells and muscle cells as well as brain development. Neonates, infants, and children obtain iron from dietary sources including breast milk (lactoferrin) and heme- and non-heme containing foods. Iron deficiency (ID) is the most common micronutrient deficiency in children and pregnant women worldwide. ID and iron deficiency anemia (IDA) can affect growth and energy levels as well as motor and cognitive performance in the developing child. The fetus is completely dependent on maternal iron crossing through the placenta and, although it is generally well protected against deficiency at birth, ID in mothers can increase the risk of ID and IDA in their children as early as 4 months. This review will discuss the uses of iron, iron requirements, and the sources of iron from conception through childhood. In addition, it will describe the prevalence and clinical manifestations of ID and IDA in children and discuss recommendations for iron supplementation of children and pregnant women. PMID- 29268256 TI - Iron and Cognitive Development: What Is the Evidence? AB - The theoretical irreversible damage that iron deficiency and iron deficiency anemia can exert on child development makes a compelling argument for action to alleviate the burden. However, a critical analysis of evidence from iron interventions in early life is necessary to determine whether and how iron interventions improve cognitive outcomes. Key iron interventions used in clinical and public health practice include oral iron supplementation and, in young children, iron-containing multiple micronutrient powders. This article examines the evidence to answer 4 main questions. (1) Does antenatal iron supplementation influence long-term child cognitive development? (2) Does oral iron supplementation in preschool children improve short-term cognitive development? (3) Does oral iron supplementation in older children improve cognitive development? And (4), can provision of iron harm cognitive development? Early trials indicated benefit from parenteral iron in young children regardless of anemia status. There also appears to be evidence for benefit using oral iron treatment on cognitive performance in anemic primary school children. However, antenatal and early childhood oral iron intervention studies show inconsistent effects on early and long-term childhood cognitive outcomes. These data suggest either that (a) effects from oral iron on cognitive development in young children are small or nonexistent or that (b) heterogeneity between trials and the low quality of many studies make assessment of effect difficult. Importantly, few large, placebo-controlled trials in under-2-year-old children in low-income settings assessing effects of iron interventions on cognition have been performed; high-quality, placebo-controlled, adequately powered trials of universal iron interventions on cognitive performance in young children are urgently needed to justify policies of universal iron intervention in this group. PMID- 29268257 TI - Editorial. PMID- 29268258 TI - Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism. AB - The fact that humans must balance their need for iron against its potential for causing harm has been known for several centuries, but the molecular mechanisms by which we achieve this feat have only been revealed in the last 2 decades. Chief amongst these is the discovery of the master-regulatory liver-derived hormone hepcidin. By switching off ferroportin in enterocytes and macrophages, hepcidin exerts fine control over both iron absorption and its distribution among tissues. Hepcidin expression is downregulated by low iron status and active erythropoiesis and upregulated by iron overload and infection and/or inflammation. The latter mechanism explains the etiology of the anemia of chronic infection. Pharmaceutical companies are actively developing hepcidin agonists and antagonists to combat iron overload and anemia, respectively. In a global health context the discovery of hepcidin shines a new light on the world's most prevalent micronutrient problem; iron deficiency and its consequent anemia. It is now apparent that humans are not poorly designed to absorb dietary iron, but rather are exerting a tonic downregulation of iron absorption to protect themselves against infection. These new insights suggest that interventions to reduce infections and inflammation will be at least as effective as dietary interventions and that the latter will not succeed without the former. PMID- 29268259 TI - Systemic Venous Drainage Is Associated with an Unfavorable Prenatal Behavior in Fetal Bronchopulmonary Sequestration. AB - OBJECTIVE: This study aimed to determine the significance of the venous drainage pattern of bronchopulmonary sequestration (BPS) in the prenatal course. METHODS: The venous drainage pattern of fetuses with BPS was determined with high definition flow and confirmed by postnatal three-dimensional computed tomography angiography scan or autopsy. The volume of BPS lesions during gestation was recorded by the three-dimensional ultrasonographic Virtual Organ Computer-Aided Analysis software. The relationship between venous drainage pattern and prenatal characteristics was determined. RESULTS: Seventy-one fetuses were enrolled: 35 with systemic venous drainage (SVD) and 36 with pulmonary venous drainage (PVD). The volumes of BPS lesions significantly increased from the middle second trimester to the later second trimester in the SVD group. A marked decrease from the later second trimester to the third trimester was observed in the PVD group. The incidences of associated anomalies, hydrops, and polyhydramnios in the SVD group were 14.2, 23.3, and 33.3%, respectively, significantly higher than those in the PVD group (0, 0, and 5.6%, respectively). CONCLUSIONS: Our data indicate that SVD is correlated with a higher risk of associated anomalies and an unfavorable prenatal course in fetal BPS. Identification of the venous drainage pattern is of clinical significance in predicting the prenatal behavior of fetal BPS. PMID- 29268260 TI - Decreased Fronto-Parietal and Increased Default Mode Network Activation is Associated with Subtle Cognitive Deficits in Elderly Controls. AB - BACKGROUND: Cognitive functions progressively deteriorate during aging and neurodegenerative diseases. The present study aims at investigating differences in working memory performance as well as functional brain changes during the earliest stages of cognitive decline in health elderly individuals. METHODS: 62 elderly individuals (41 females), including 41 controls (35 females) and 21 middle cognitive impairment subjects (6 females), underwent neuropsychological assessment at baseline and an fMRI examination in a N-back paradigm contrasting 2 back vs. 0-back condition. Upon a 18 months follow-up, we identified stable controls (sCON) with preserved cognition and deteriorating controls (dCON) with 1SD decrease of performances in at least two neuropsychological tests. Data analyses included accuracy and reaction time (RT) for the 2-back condition and general linear model (GLM) for the fMRI sequence. RESULTS: At the behavioral level, sCON and dCON performed better than MCI in terms of accuracy and reaction time. At the brain level, functional differences in regions of the fronto parietal network (FPN) and of the Default Mode Network (DFM) were observed. Significantly lower neural activations in the bilateral inferior and middle frontal gyri were found in MCI versus both dCON / sCON and for dCON versus sCON. Significantly increased activations in the anterior cingulate cortex and posterior cingulate cortex and bilateral insula were found in MCI versus both dCON / sCON and in dCON versus sCON. CONCLUSION: The present study suggests that brain functional changes in FPN and DMN anticipate differences in cognitive performance in healthy elderly individuals with subsequent subtle cognitive decline. PMID- 29268261 TI - Difference between Methods for Estimation of Basal Metabolic Rate and Body Composition in Pediatric Patients with Osteogenesis Imperfecta. AB - BACKGROUND/AIMS: Osteogenesis Imperfecta (OI) is a bone disease characterized by bone fragility, deformities, and multiple fractures. The aim of this study was to compare the different methods of measuring the basal metabolic rate (BMR) and body composition (BC) in pediatric patients with OI. METHODS: This cross sectional study included 52 individuals with a median age of 9 (5.25-12.7) years. BMR was calculated by bioelectrical impedance analyses (BIA), predictive values according to age from the World Health Organization (WHO), a kcal/cm formula, and indirect calorimetry (IC). BC was assessed using the anthropometric calculation of percentage body fat (%BF) and lean mass (kg), BIA, and dual-energy X-ray absorptiometry (DEXA). Agreement among the methods was assessed using the Bland Altman technique. RESULTS: IC estimates of BMR were greater than BIA and lower than values obtained using the WHO and kcal/cm methods. Better agreement was observed using the WHO values for mild forms of OI and the kcal/cm formula for moderate-to-severe forms. For BC, DEXA estimates of %BF were higher and the lean mass was lower than the values obtained using BIA and anthropometry. Neither method agreed with the DEXA method results. CONCLUSIONS: Significant differences exist among the various methods used for measuring BMR and BC with regard to phenotypic differences between OI types. PMID- 29268262 TI - Low- versus High-Dose and Early versus Late Parenteral Amino-Acid Administration in Very-Low-Birth-Weight Infants: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Providing parenteral amino acids to very-low-birth-weight infants during the first weeks of life is critical for adequate growth and neurodevelopment. However, there is no consensus about what dose is appropriate or when to initiate supplementation. As a result, daily practice varies among neonatal intensive care units. The objective of our study was to determine the effects of early parenteral amino-acid supplementation (within 24 h of birth) versus later initiation and high dose (>3.0 g/kg/day) versus a lower dose on growth and morbidities. METHODS: A systematic review and meta-analysis of publications identified by searching PubMed, EMBASE, and Cochrane databases was conducted. Randomized controlled studies were eligible if information on growth was available. RESULTS: The search identified 14 studies. No differences were observed in growth or morbidity after early or high-dose amino-acid supplementation, but for several outcomes, meta-analysis was not possible due to study heterogeneity. Initiation of amino acids within the first 24 h of life appeared to be safe and well tolerated, and leads more rapidly to a positive nitrogen balance. CONCLUSIONS: Administering a high dose (>3.0 g/kg/day) or an early dose (<=24 h) of parenteral amino acids is safe and well tolerated but does not offer significant benefits on growth. Further large-scale randomized controlled trials in preterm infants are needed to study the effects of early and high-dose amino acids on growth and morbidity more consistently and extensively. PMID- 29268263 TI - Renal PGC1alpha May Be Associated with Recovery after Delayed Graft Function. AB - BACKGROUND: Delayed renal graft function (DGF) contributes to the determination of length of hospitalization, risk of acute rejection, and graft loss. Existing tools aid the diagnosis of specific DGF etiologies such as antibody-mediated rejection, but markers of recovery have been elusive. The peroxisome proliferator gamma co-activator-1-alpha (PGC1alpha) is highly expressed in the renal tubule, regulates mitochondrial biogenesis, and promotes recovery from experimental acute kidney injury. OBJECTIVES: We aimed to determine the association between renal allograft PGC1alpha expression and recovery from delayed graft function. METHODS: We retrospectively analyzed patients undergoing renal transplantation at a single center from January 1, 2008 to June 30, 2014. PGC1alpha expression was assessed by immunostaining and ultrastructural characteristics by transmission electron microscopy. Of 34 patients who underwent renal biopsy for DGF within 30 days of transplant, 21 were included for analysis. RESULTS: Low PGC1alpha expression was associated with a significantly longer time on dialysis after transplant (median of 35.5 vs. 16 days, p < 0.05) and a significantly higher serum creatinine (sCr) at 4 weeks after transplantation among those who discontinued dialysis (5 vs. 1.65 mg/dL, p < 0.0001). Low PGC1alpha expression was not associated with higher sCr at 12 weeks after transplantation. Ultrastructural characteristics including apical membrane blebbing and necrotic luminal debris were not informative regarding clinical outcomes. CONCLUSIONS: These data suggest that higher PGC1alpha expression is associated with faster and more complete recovery from DGF. Mitochondrial biogenesis may be a therapeutic target for DGF. Larger studies are needed to validate these findings. PMID- 29268264 TI - Progressive Reduction in Myocyte Autophagy After Myocardial Infarction in Rabbits: Association with Oxidative Stress and Left Ventricular Remodeling. AB - BACKGROUND/AIMS: The alterations in myocyte autophagy after myocardial infarction (MI) and the underlying mechanisms have not been fully understood. In this study, we investigated the temporal changes of myocyte autophagy in the remote non infarcted myocardium in rabbits after MI and the relationships between alterations of myocyte autophagy and left ventricular (LV) remodeling and myocardial oxidative stress. METHODS: Rabbits were assigned to MI or sham operation. Rabbits with MI or sham were randomly assigned to receive chloroquine, an autophagy inhibitor, antioxidant vitamins C and E or placebo for 4 weeks. H9C2 cardiomyocytes were subjected to hypoxia or hydrogen peroxide (H2O2) treatment. RESULTS: MI rabbits exhibited progressive increases of LV end-diastolic dimension (EDD), and decreases of LV fractional shortening (FS) and dP/dt over 8 weeks. Myocyte autophagy assessed by the scores of LC3 and Beclin1 expression was progressively decreased at 1, 4 and 8 weeks after MI. The ratio of LC3 II/I and Beclin1 and Atg5 proteins were also decreased at 4 weeks after MI. There was a negative correlation between autophagy and LV EDD and a positive correlation between autophagy and LV FS and dP/dt. The autophagy inhibitor chloroquine worsened LV remodeling after MI. Decreased myocyte autophagy was associated with increased myocardial 4-hydroxynonenal. Antioxidant vitamins C and E prevented the decrease in myocyte autophagy after MI. In cultured H9C2 cardiomyocytes, the LC3 II/I ratio was decreased at 4 and 8 h after exposure to hypoxia, and the change was associated with increased 8-hydroxy-2-deoxyguanosine. A low concentration of H2O2 decreased the LC3 II/I ratio. CONCLUSION: Progressive reduction in myocyte autophagy in the remote non-infarcted myocardium was associated with myocardial oxidative stress and LV remodeling after MI. Antioxidants prevented the reduction in myocyte autophagy after MI, suggesting that oxidative stress mediates reduction in myocyte autophagy that contributes to post-MI remodeling. PMID- 29268265 TI - Halo Sign and Eosinophilia: What Is Your Diagnosis? AB - Blood eosinophilia associated with transient and migrating nodules with a halo sign on chest computed tomography scan should suggest larva migrans related to toxocariasis or ascaris suum. PMID- 29268266 TI - Vanishing Immunoglobulins: The Formation of Pauci-Immune Lesions in Myeloperoxidase-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. PMID- 29268267 TI - Nine-Year Outcome of Ranibizumab Monotherapy for Choroidal Neovascularization Secondary to Pathologic Myopia. AB - PURPOSE: The aim of this study was to evaluate the 9-year outcome of ranibizumab monotherapy for myopic choroidal neovascularization (mCNV). METHODS: This was a retrospective, nonrandomized, multicentric study to evaluate the long-term outcomes of mCNV treated with ranibizumab monotherapy for at least 9 years according to a strict pro re nata regimen. RESULTS: Seventeen eyes of 17 patients (12 women, mean age 57.9 +/- 7.7 years) were included. The mean follow-up period was 112.4 +/- 3.9 months (range 108-120). The mean difference in best-corrected visual acuity (BCVA) from baseline to the last follow-up was +1.2 +/- 15.6 ETDRS letters (p = 0.004, between initial vs. 12 and 24 months). The mean total number of intravitreal injections for each patient was 1.24 +/- 1.70 per year (range 2 25). No systemic adverse reactions related to the drug treatment were detected during the 9-year follow-up period. CONCLUSIONS: Long-term ranibizumab monotherapy treatment induces unchanged or better BCVA compared to baseline after a 9-year treatment in almost all eyes. PMID- 29268268 TI - Expressions and Regulatory Effects of P38/ERK/JNK Mapks in the Adipogenic Trans Differentiation of C2C12 Myoblasts. AB - BACKGROUND/AIMS: Myoblasts and muscle satellite cells have the potential to transdifferentiate into adipocytes or adipocyte-like cells. Previous studies suggest that mitogen-activated protein kinase (MAPK) is critical to adipogenic trans-differentiation of muscle cells. ERK1/2, P38 and JNK are three major MAPK family members; their activation and regulatory functions during adipogenic trans differentiation of myoblasts are investigated. METHODS: C2C12 myoblasts were cultured and induced for adipogenic trans-differentiation. Activation patterns of MAPKs were assayed using protein microarray and Western blot. Three specific MAPK blockers, U0126, SB20358 and SP600125, were used to block ERK1/2, P38 and JNK during trans-differentiation. Cellular adipogenesis was measured using staining and morphological observations of cells and expression changes in adipogenic genes. RESULTS: Inhibitors reduced phosphorylation of corresponding MAPK and produced unique cellular effects. Suppressing P38 promoted adipogenic trans differentiation and intensified adipolytic metabolism in differentiated cells. However, inhibition of ERK1/2 had the opposite effects on adipogenesis and no effect on adipolysis. Blocking JNK weakly blocked trans-differentiation but stimulated adipolysis and induced apoptosis. CONCLUSION: Three MAPKs participate in the regulation of myoblast adipogenic trans-differentiation by controlling adipogenic and adipolysis metabolism. PMID- 29268269 TI - Optical Coherence Tomography Angiography in Healthy Subjects and Diabetic Patients. AB - Fluorescein angiography and indocyanine green angiography provide information about the normal retinal and choroidal vascular perfusion. They allow the evaluation of different diseases and increase the capability to define and diagnose several pathological conditions. Fluorescein angio graphy is the "gold standard" in imaging the retinal vascular bed and its changes, although not all the different layers of the capillary network can be visualized in a bidimensional examination. Optical coherence tomography angiography allows a depth-resolved visualization of the retinal and choroidal microvasculature, by calculating the difference (decorrelation) between static and nonstatic tissue. Given that the main moving elements in the eye fundus are contained in vessels, determining a vascular decorrelation signal permits a three-dimensional visualization of the retinal and choroidal vascular network without the administration of an intravenous dye. Moreover, a complete morphofunctional assessment may help in defining both the origin and the clinical activity of different vascular diseases such as diabetic retinopathy. PMID- 29268270 TI - Fatal Overdoses of Opioids in Israel 2005-2014. AB - AIMS: To explore previously unreported rates and trends in opioid-related mortality in Israel, 2005-2014. METHODS: Data was obtained from the national database on causes of death. Drug poisoning deaths were divided into opioid related deaths and deaths related to other drugs according to International Classification of Diseases (ICD)-10 code of underlying cause, and included drug poisoning of accidental, intentional or undetermined intent. Age-adjusted rates were calculated per 100,000 population. Rate ratios were calculated and a logistic model constructed to compare the risk of opioid-related deaths in both halves of the decade (2006-2009 and 2009-2013) and between various demographic groups. RESULTS: While age-adjusted rates of deaths related to other drugs remained relatively stable, rates of opioid-related deaths significantly decreased during this period across all groups. During the study period, the number of opioid-related deaths in Israel declined from 1.3 to 0.3 per 100,000. Opioid-related deaths were more common among men, young adults and immigrants from the Former Soviet Union. CONCLUSIONS: Rates of opioid-related deaths in Israel were low compared to those reported in the United States and United Kingdom. In addition, the decline in opioid-related deaths in Israel is contrary to trends observed in the United States and United Kingdom. Factors that may contribute to these differences are discussed. PMID- 29268271 TI - Cognitive Functioning in Formerly Opioid-Dependent Adults after At Least 1 Year of Abstinence: A Naturalistic Study. AB - This study is an evaluation of cognitive functioning in formerly opioid-dependent adults after at least 1 year of abstinence. Participants (45 formerly opioid dependent patients, referred to as abstainers, and 45 matched healthy controls) completed a structured screening and subsequent cognitive test battery covering intelligence, learning and memory, attention, and executive functions. Many cognitive functions were comparable between long-term abstainers and healthy controls, and we found few relevant differences. Long-term abstainers seem to have subtle deficits in recognition performance. Based on our and earlier findings, opioid maintenance treatment may be seen as relatively safe with respect to cognitive dysfunction and cognitive functioning is of great relevance for the rehabilitation and daily functioning of substance-dependent people. PMID- 29268272 TI - Is Social Network a Protective Factor for Cognitive Impairment in US Chinese Older Adults? Findings from the PINE Study. AB - BACKGROUND: Social network has been identified as a protective factor for cognitive impairment. However, the relationship between social network and global and subdomains of cognitive function remains unclear. OBJECTIVE: This study aims to provide an analytic framework to examine quantity, composition, and quality of social network and investigate the association between social network, global cognition, and cognitive domains among US Chinese older adults. METHODS: Data were derived from the Population Study of Chinese Elderly (PINE), a community engaged, population-based epidemiological study of US Chinese older adults aged 60 and above in the greater Chicago area, with a sample size of 3,157. Social network was assessed by network size, volume of contact, proportion kin, proportion female, proportion co-resident, and emotional closeness. Cognitive function was evaluated by global cognition, episodic memory, executive function, working memory, and Chinese Mini-Mental State Examination (C-MMSE). Linear regression and quantile regression were performed. RESULTS: Every 1-point increase in network size (b = 0.048, p < 0.001) and volume of contact (b = 0.049, p < 0.01) and every 1-point decrease in proportion kin (b = -0.240, p < 0.01) and proportion co-resident (b = -0.099, p < 0.05) were associated with higher level of global cognition. Similar trends were observed in specific cognitive domains, including episodic memory, working memory, executive function, and C-MMSE. However, emotional closeness was only significantly associated with C-MMSE (b = 0.076, p < 0.01). Social network has differential effects on female versus male older adults. CONCLUSION: This study found that social network dimensions have different relationships with global and domains of cognitive function. Quantitative and structural aspects of social network were essential to maintain an optimal level of cognitive function. Qualitative aspects of social network were protective factors for C-MMSE. It is necessary for public health practitioners to consider interventions that enhance different aspects of older adults' social network. PMID- 29268273 TI - Retinol and Betacarotene Status in Mother-Infant Dyads and Associations between Them. AB - BACKGROUND/AIMS: Assessing the diet and biochemical indicators of vitamin A deficiency (VAD) in high-risk populations is crucial in cases where this deficiency is mainly caused by chronically inadequate intake. This study aimed to determine the retinol and betacarotene status in mother-infant dyads, and to evaluate the associations between them. METHODS: Umbilical cord serum, maternal serum, and colostrum were collected from 134 healthy mothers living in a risk region for VAD. Vitamin A and betacarotene were quantified by liquid chromatography, and dietary information was collected using a food frequency questionnaire. RESULTS: Although the overall mean intakes of vitamin A and betacarotene were considered adequate, 16% of the women had insufficient intake. Mean retinol levels were also adequate, yet low levels were diagnosed in about 8% of the mothers, based on maternal serum and colostrum, and in 16% of the cord serum samples. Retinol and betacarotene were positively associated in cord serum (p = 0.004), maternal serum (p = 0.041), and colostrum (p < 0.001) but was not associated with dietary intake. CONCLUSIONS: A diagnosis of adequacy based on mean biochemical and dietary data of this population in fact masks the marginal vitamin A status presented by mothers and children. PMID- 29268275 TI - Reply to the Letter by Hall Entitled "ILUVIEN in Diabetic Macular Edema: The Choice of Second-Line Corticosteroid Should Be Left to the Clinical Judgement of the Treating Physician". PMID- 29268274 TI - Relations of Changes in Serum Carcinoembryonic Antigen Levels before and after Neoadjuvant Chemoradiotherapy and after Surgery to Histologic Response and Outcomes in Patients with Locally Advanced Rectal Cancer. AB - OBJECTIVES: The histologic response to neoadjuvant chemoradiotherapy (nCRT) has been intimately related to outcomes in locally advanced rectal cancer. Serum carcinoembryonic antigen (CEA) levels change after nCRT and after surgery as compared with before nCRT. METHODS: The subjects were 149 patients with locally advanced rectal cancer who received nCRT between 2005 and 2013. The patients were divided into 4 groups according to the serum CEA levels: group 1, 55 patients with negative serum CEA levels before nCRT; group 2, 41 patients with positive serum CEA levels before nCRT that became negative after nCRT; group 3, 37 patients with positive serum CEA levels after nCRT that became negative after surgery; and group 4, 16 patients with positive serum CEA levels after nCRT as well as after surgery. RESULTS: Pathological complete response, T downstaging, and tumor shrinkage were significantly higher in group 1 than in other groups. Disease-free survival was significantly poorer in group 4. The lack of a decrease in the serum CEA level in group 4 was most likely attributed to the persistence of micrometastases outside the resection field. CONCLUSIONS: Changes in serum CEA levels measured before nCRT, after nCRT, and after surgery can be used to reliably predict the histologic response to nCRT and outcomes. PMID- 29268276 TI - Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress. AB - BACKGROUND/AIMS: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. METHODS: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. RESULTS: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. CONCLUSION: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment. PMID- 29268280 TI - Different Phenotypes of Mild Nonproliferative Diabetic Retinopathy with Different Risks for Development of Macular Edema (C-TRACER Study). AB - PURPOSE: To evaluate diabetic retinopathy (DR) progression in patients with diabetes mellitus type 2 in 2 populations of different ethnicity. METHODS: A prospective observational study was designed to follow eyes/patients with mild nonproliferative DR, for 2 years or until the development of central-involved macular edema (CIME), in 2 centers from different regions of the world. A total of 205 eyes/patients fulfilled the inclusion/exclusion criteria and were included in this study. Ophthalmological examinations, fundus photography with RetmarkerDR analysis, and optical coherence tomography were performed at baseline and at 6, 12 and 24 months. RESULTS: Of the 158 eyes/patients that completed this study, 24 eyes developed CIME and 134 eyes were present at the last study visit. Eighty eight eyes (56.4%) were classified as phenotype A, 49 (31.4%) as phenotype B, and 19 (12.2%) as phenotype C. Phenotype A is associated with a very low risk for development of CIME in comparison with phenotypes B and C. The OR for development of CIME was 19.0 for phenotype B and 25.1 for phenotype C. CONCLUSION: Eyes in the initial stages of DR show different phenotypes with different risks of progression to ME. The phenotypes associated with increased risks of progression show different distributions in patients of different ethnicities. PMID- 29268287 TI - Video Comment on Javier Aranda-Hernandez et al. PMID- 29268281 TI - Oncogenic Human Papillomavirus: Application of CRISPR/Cas9 Therapeutic Strategies for Cervical Cancer. AB - Oncogenic human papillomaviruses (HPVs) cause different types of cancer especially cervical cancer. HPV-associated carcinogenesis provides a classical model system for clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) based cancer therapies since the viral oncogenes E6 and E7 are exclusively expressed in cancerous cells. Sequence-specific gene knockdown/knockout using CRISPR/Cas9 shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, CRISPR/Cas9-based targeting therapy requires further validation of its efficacy in vitro and in vivo to eliminate the potential off target effects, necessitates verification of the delivery vehicles and the combinatory use of conventional therapies with CRISPR/Cas9 to ensure the feasibility and safety. In this review we discuss the potential of combining CRISPR/Cas9 with other treatment options as therapies for oncogenic HPVs associated carcinogenesis. and present our assessment of the promising path to the development of CRISPR/Cas9 therapeutic strategies for clinical settings. PMID- 29268288 TI - Video Comment on Vinay Dhir et al. PMID- 29268289 TI - Video Comment on Harutoshi Sugiyama et al. PMID- 29268290 TI - Video Comment on David J. Tate et al. PMID- 29268291 TI - Foreword. PMID- 29268293 TI - Colonoscopy quality: measuring the patient experience. PMID- 29268294 TI - Non-lifting colorectal neoplasia - shall we CAST it away? PMID- 29268295 TI - Does the double-opening submucosal tunneling endoscopic resection technique really work for submucosal tumors in the esophagus and gastric fundus near the cardia? PMID- 29268296 TI - Reply to Li & Linghu. PMID- 29268297 TI - [French comment on article Hot avulsion may be effective as salvage treatment for focal Barrett's esophagus remaining after endoscopic therapy for dysplasia or early cancer: a preliminary study]. PMID- 29268298 TI - [French comment on article Increased postprandial glucagon-like peptide-1 (GLP-1) production after endoscopic gastrointestinal bypass using the Cousin lumen apposing stent in a porcine model]. PMID- 29268299 TI - [French comment on article Feasibility of a complete pancreatobiliary linear endoscopic ultrasound examination from the stomach]. PMID- 29268300 TI - [French comment on article Transpancreatic precut papillotomy versus double guidewire technique in difficult biliary cannulation: prospective randomized study]. PMID- 29268301 TI - [French comment on article A new composite measure of colonoscopy: the Performance Indicator of Colonic Intubation (PICI)]. PMID- 29268302 TI - [French comment on article Cold-forceps avulsion with adjuvant snare-tip soft coagulation (CAST) is an effective and safe strategy for the management of non lifting large laterally spreading colonic lesions]. PMID- 29268303 TI - Perilla extract improves frequent urination in spontaneously hypertensive rats with enhancement of the urothelial presence and anti-inflammatory effects. AB - OBJECTIVE: To investigate the effects of perilla extract on urinary symptoms in spontaneously hypertensive rats as a model of spontaneous overactive bladder. METHODS: Spontaneously hypertensive rats were randomly divided into two groups and fed either a control diet or a perilla extract-containing diet. Cystometry, gene expression and histological analyses were carried out to evaluate the effects of perilla extract after 2-week feeding of either the control or the perilla extract diet. The expression of inflammation-related genes in the human urothelial cell line HT-1376 and the normal human bladder epithelial cell was measured after the treatment with perillaldehyde, the main component of perilla extract, or perillic acid, the final metabolite of perillaldehyde. RESULTS: A significant 27% increase in the micturition interval and decreased expression of nerve growth factor, tumor necrosis factor-alpha, interleukin-1beta and transient receptor potential V1 were observed in the perilla group compared with the control group. The level of uroplakin 3A was 40% higher in the perilla group than in the control group. The urothelium in the control group was thin or defective, but it was almost completely intact in the perilla group. Perillaldehyde and perillic acid suppressed the induction of nerve growth factor and tumor necrosis factor-alpha by interleukin-1beta in HT-1376 and normal human bladder epithelial cells. CONCLUSIONS: The present findings suggest that perilla extract improves frequent urination, and this improvement seems to be mediated, at least in part, by enhancement of the urothelial presence and by the anti-inflammatory effects of perilla. PMID- 29268304 TI - Get SET: aligning anatomy demonstrator programmes with Surgical Education and Training selection criteria. AB - BACKGROUND: Prevocational doctors aspiring to surgical careers are commonly recruited as anatomy demonstrators for undergraduate and graduate medical programmes. Entry into Surgical Education and Training (SET) is highly competitive and a unique opportunity exists to align anatomy demonstrator programmes with the selection criteria and core competencies of SET programmes. This study used a qualitative approach to (i) determine what criteria applicants for SET are assessed on and (ii) identify criteria that could be aligned with and enhanced by an anatomy demonstrator programme. METHODS: The selection guidelines of all nine surgical specialties for the 2017 intake of SET trainees were analysed using qualitative content analysis methodology. RESULTS: The Royal Australasian College of Surgeons adopted a holistic approach to trainee selection that assessed both discipline-specific and discipline-independent skills. Qualitative content analysis identified eight categories of key selection criteria: medical expertise, scholarly activity, professional identity, interpersonal skills, integrity, self-management, insight and self-awareness and community involvement. The structured curriculum vitae was heavily weighted towards discipline-specific skills, such as medical expertise and scholarly activity. Insufficient information was available to determine the weighting of selection criteria assessed by the structured referee reports or interviews. CONCLUSION: Anatomy demonstrator programmes provide prevocational doctors with unique opportunities to develop surgical skills and competencies in a non clinical setting. Constructively aligned anatomy demonstrator programmes may be particularly beneficial for prevocational doctors seeking to improve their anatomical knowledge, teaching skills or scholarly activity. PMID- 29268306 TI - Intra-adrenal corticotropin in bilateral macronodular adrenal hyperplasia: Report of two Japanese cases. PMID- 29268305 TI - Cervical spine traumatic epidural haematomas: Incidence and characteristics. AB - OBJECTIVE: Cervical spine traumatic epidural haematomas (CSTEH) can cause potentially devastating neurological deficits if not promptly identified. Study aims were to determine the incidence, characteristics and outcomes for patients with CSTEH. METHODS: A retrospective study was performed at a tertiary hospital with an adult Level 1 Trauma Centre on all consecutive patients diagnosed with CSTEH over a 4 year period. Medical record review was undertaken for all patients with the diagnoses of CSTEH to identify patient characteristics including age, mechanism of injury and co-morbid conditions. Additional data was extracted regarding radiology interpretation, surgical interventions, thromboembolic chemoprophylaxis use, discharge disposition and neurological outcomes. RESULTS: A total of 27 888 patients were admitted with traumatic injuries between 1 July 2010 and 30 June 2014, of which 1916 patients sustained cervical spine injuries. The incidence of CSTEH was 0.6% among all trauma patients and 9.1% among patients with any cervical spine injury. Of those with CSTEH, 89 patients (50.9%) had neurological deficits consistent with the anatomical location of the epidural haematoma. Magnetic resonance imaging diagnosed CSTEH in 132 patients (75.4%), of whom 23 patients (13.1%) had normal computed tomography cervical spine imaging. Among the patients diagnosed with CSTEH, 13 (7.4%) died and 78 (44.6%) required cervical spine surgical decompressions. CONCLUSION: This study shows a high incidence of CSTEH among trauma patients. CSTEH is associated with significant morbidity and mortality. High clinical vigilance is required to allow the request and acquisition of urgent magnetic resonance imaging to diagnose CSTEH as the entity is often not evident on initial cervical spine computed tomography investigations. PMID- 29268307 TI - Scottish healthcare student's perceptions of an interprofessional ward simulation: An exploratory, descriptive study. AB - The most memorable learning occurs during placement. Simulated interprofessional learning is a logical learning opportunity to help healthcare professionals work beyond their professional silos. In this qualitative study, we investigated the perceived learning of students from six health professions (adult nursing, diagnostic radiography, occupational therapy, physiotherapy, dietetics, and pharmacy) from their participation in a 45 min interprofessional ward simulation. Semistructured focus groups were undertaken, and data were analyzed using framework analysis. Two overarching themes were evident, each of which had subthemes: (i) the ward simulation as an interprofessional education opportunity (subthemes: reality of situations and interactions); and (ii) the perceived learning achieved (subthemes: professional roles, priorities, respect, communication, teamwork, and quality of care). The results indicated that a short interprofessional ward simulation, unsupported by additional learning opportunities or directed study, is a useful and engaging interprofessional learning opportunity. Students appear to have learnt important key messages central to the interprofessional education curricula to help develop practitioners who can effectively work together as an interprofessional team, and that this learning is partly due to simulation allowing things to go wrong. PMID- 29268308 TI - Preoperative malnutrition and prognosis after neoadjuvant chemotherapy followed by subsequent esophagectomy. PMID- 29268309 TI - Exosome-derived microRNAs in cancer progression: angel or devil? PMID- 29268310 TI - Micropapillary lung adenocarcinoma and micrometastasis. PMID- 29268311 TI - Surgical strategy for tetralogy of Fallot with abnormal coronary arteries. PMID- 29268312 TI - Treatment of uncomplicated acute type B aortic dissection in the endovascular era: is it time for a paradigm shift? PMID- 29268313 TI - From Barcelona to New York: 15 years of transition of sepsis performance improvement. PMID- 29268314 TI - Clinical prediction models: a fashion or a necessity in medicine? PMID- 29268315 TI - Endovascular repair or best medical treatment: what is the optimal management of uncomplicated Type-B acute aortic dissection? PMID- 29268316 TI - Pneumothorax management-chest drain or needle aspiration? PMID- 29268317 TI - The NeoRes trial: questioning the benefit of radiation therapy as part of neoadjuvant therapy for esophageal adenocarcinoma. PMID- 29268318 TI - Molecular mechanisms of pathological tumor transformation and their clinical implications: predictors of pulmonary adenocarcinoma transformation into small cell carcinoma. PMID- 29268319 TI - Endoluminal vs. extraluminal cardiomyotomy for oesophageal achalasia. PMID- 29268320 TI - ASCEND-5: too little too late? PMID- 29268321 TI - The role of an immune checkpoint score in resected non-small cell lung cancer patients' prognosis. PMID- 29268322 TI - Mechanical ventilation in brain injured patients: seeing the forest for the trees. PMID- 29268323 TI - The dawning of perioperative care in esophageal cancer. PMID- 29268324 TI - Rethinking the role of postoperative critical care in an inequitable world. PMID- 29268325 TI - Video assisted thoracic surgery vs. thoracotomy regarding postoperative chronic pain. PMID- 29268326 TI - Is segmentectomy indicative for small-sized non-small cell lung cancer in the basal segments with a small ground-glass opacity component? PMID- 29268327 TI - Should age be a criterion for intensive care unit admission in cancer patients? Still an issue of uncertainty. PMID- 29268328 TI - Under-treatment of small cell lung cancer: the case for surgical resection. PMID- 29268329 TI - What comes after the Early Goal Directed Therapy for sepsis era? PMID- 29268330 TI - Is chest tube drainage losing ground in management of patients with spontaneous pneumothorax? PMID- 29268331 TI - Genomic lesions drive the metastasis of esophageal squamous cell carcinoma. PMID- 29268332 TI - Comments on the trial of cisplatin and etoposide plus thoracic radiotherapy followed by nivolumab or placebo for locally advanced non-small cell lung cancer (RTOG 3505). PMID- 29268333 TI - Outcomes with moderate aortic stenosis and impaired left ventricular function: prelude to a randomized trial? PMID- 29268334 TI - Essential signaling in NF2 loss-related tumours: the therapeutic potential of CRL4DCAF1 and mTOR combined inhibition. PMID- 29268335 TI - Obstructive sleep apnea-Hypertension link: almost there? PMID- 29268336 TI - Fluid resuscitation targeting sepsis-induced cardiovascular dysfunction: severity of disease as effect modifier. PMID- 29268337 TI - Editorial on pain following thoracic surgery. PMID- 29268338 TI - Circulating tumor cells in lung cancer: cluster circulating tumor cells as hybrid epithelial-mesenchymal transition/mesenchymal-epithelial transition (E/M). PMID- 29268339 TI - The search continues: neuroprotection for all neonates with hypoxic-ischemic encephalopathy. PMID- 29268340 TI - Pleural recurrences of thymoma: role and effectiveness of intrathoracic chemohyperthermia. PMID- 29268341 TI - The challenge of co-existent moderate aortic stenosis and left ventricular systolic impairment. PMID- 29268342 TI - Challenging decision: ICU admission of critically ill elderly solid tumor patients. PMID- 29268343 TI - While size matters-advanced "Radiomics" remain promising for the clinical management of ground glass opacities. PMID- 29268344 TI - Prophylactic cranial irradiation for stage IV small cell lung cancer, live longer or reduce morbidity of brain metastases? PMID- 29268345 TI - Surgery for limited-stage small cell lung cancer: ready for prime-time? PMID- 29268346 TI - Gender and cardiovascular impact of obstructive sleep apnea: work in progress! PMID- 29268347 TI - Editorial: pleural recurrence of thymoma-what is the value of intra-thoracic chemo-hyperthermia? PMID- 29268348 TI - Editorial comment on the RESPOND study. PMID- 29268349 TI - Moderate aortic valve stenosis in patients with left ventricular systolic dysfunction-insights on prognosis and the potential role of early aortic valve replacement. PMID- 29268350 TI - Is it still time for meta-analyses in operable esophageal cancers, or rather for a change of paradigm? PMID- 29268351 TI - Early oral nutrition plays an active role in enhanced recovery after minimally invasive esophagectomy. PMID- 29268352 TI - Atezolizumab in advanced non-small cell lung cancer. PMID- 29268353 TI - Assessment of pulmonary vascular response to exercise with Doppler echocardiography: state of the art? PMID- 29268354 TI - Extranodal extension of nodal metastasis is the main prognostic moderator in squamous cell carcinoma of the esophagus after neoadjuvant chemoradiotherapy. PMID- 29268355 TI - Viewing the big picture on small cell lung cancer. PMID- 29268356 TI - Are beta blockers still necessary for all survivors of acute myocardial infarction? PMID- 29268357 TI - Mediastinal germ cell tumors: new therapeutic insights. PMID- 29268358 TI - Histologic subtype component predicts lymph node micrometastasis and prognosis in patients with stage I lung adenocarcinoma. PMID- 29268359 TI - Adjuvant chemotherapy following trimodality therapy for esophageal carcinoma-Is the evidence sufficient? PMID- 29268360 TI - Effectiveness of catheter ablation of atrial fibrillation: are we at the dawn of a new era? PMID- 29268361 TI - The first randomized controlled trial on early versus late oral feeding after minimally invasive esophagectomy and the ongoing quest for more evidence. PMID- 29268362 TI - VELUCT, a long non-coding RNA with an important cellular function despite low abundance. PMID- 29268363 TI - Thermal ablation for the treatment of primary and secondary pulmonary malignancies. PMID- 29268364 TI - Editorial on "Can CT-PET and endoscopic assessment post-neoadjuvant chemoradiotherapy predict residual disease in esophageal cancer". PMID- 29268365 TI - Simulation-based training for handling extracorporeal membrane oxygenation emergencies. PMID- 29268367 TI - New histological classification and staging of thymic malignancies: ITMIG consensus statements and the 8th TNM staging system. PMID- 29268366 TI - The current status of antiplatelet therapy in patients undergoing transcatheter aortic valve implantation. PMID- 29268368 TI - The future of achalasia therapy: expanding the minimally invasive armamentarium and risk of secondary gastroesophageal reflux. PMID- 29268369 TI - Non-intubated tracheal surgery: is it worthwhile? PMID- 29268370 TI - Awake minimal invasive carinal resection-tightrope walking in thoracic surgery? PMID- 29268371 TI - Confronting the fundamental challenges of airway surgery: a paradigm shift is practically upon us. PMID- 29268372 TI - The printed trachea. PMID- 29268373 TI - Repair of large airway defects with bioprosthetic materials. PMID- 29268374 TI - Reoperation for hemostasis within 24 hours can get a better short-term outcome when indicated after lung cancer surgery. AB - Background: Postoperative hemorrhage after lung cancer surgery is a potentially fatal complication. This study aimed to investigate the indications and timing of reoperation for postoperative hemorrhage after lung cancer surgery. Methods: We identified all patients who underwent lung resection and mediastinal lymph node dissection for lung cancer between October 2001 and September 2015 at Sichuan Cancer Hospital, identifying 57 who had undergone reoperation for hemostasis. The records of these 57 patients were reviewed and analyzed. Results: The most common postoperative hemorrhage site was the separation surface of the original pleural adhesions (29.8%). The median time interval between the initial operation and reoperation was 12 hours (range, 2-432 hours), and most patients (77.2%) underwent reoperation within 24 hours. The overall morbidity and mortality rates of reoperation were 50.9% and 5.3%, respectively. The morbidity rates of the early reoperation group (<=24 hours) and the late reoperation group were 43.2% and 77.0%, respectively, which were significantly different (P=0.033). The mortality rates of the early reoperation group and the late reoperation group were 0 and 23.1%, respectively, which were also significantly different (P=0.010). Conclusions: Once indications of reoperation for postoperative hemorrhage after lung cancer surgery are identified, reoperation within 24 hours after the initial operation can get a better short-term outcome. PMID- 29268375 TI - Surgical management of acquired tracheo/bronchoesophageal fistula associated with esophageal diverticulum. AB - Background: The reports on acquired tracheoesophageal fistulas (TEFs) or bronchoesophageal fistulas (BEFs) associated with traction esophageal diverticula (TED) are rare. Here, we present our experience of six cases. Methods: Between Jan. 2015 and Jun. 2016, 6 patients were admitted to our department for TEF/BEFs combined with esophageal diverticula. Clinical data of the 6 patients were retrospectively reviewed. Results: All orifices of TEF/BEF in the esophagus side opened at the diverticula wall. The orifices in the airway side were 2 at the carina and 4 at the right intermediate bronchus. All six patients received the same intervention: a limited diverticulectomy with the fistula resection was done in the esophagus; separate layers of repair were performed for the defect in the esophagus; the muscle flap interposition was used in all six cases. All postoperative courses were uneventful. No recurrence fistula and symptomatic diverticula occurred. The airway and esophagus were patency during a median of 9 month follow-up. Conclusions: Acquired TEF/BEFs caused by esophageal diverticula can be treated successfully by surgery. A limited diverticulectomy is sufficient to ensure enough esophagus remodeling. Keywords: Tracheo/bronchoesophageal fistula (TEF/BEF); esophagus diverticulum; acquired. PMID- 29268376 TI - C-reactive protein for the early prediction of anastomotic leak after esophagectomy in both neoadjuvant and non-neoadjuvant therapy case: a propensity score matching analysis. AB - Background: Anastomotic leak is one of most significant causes of mortality after esophagectomy. Therefore, it is clinically valuable to detect anastomotic leak early after esophagectomy in esophageal cancer. The purpose of this study is to investigate the associations between routine postoperative laboratory findings and anastomotic leak and to analyze the laboratory findings to find out an independent predictive marker for anastomotic leak. In addition, this study compares cases treated with neoadjuvant therapy (NT) and those without (non-NT). Methods: We retrospectively assessed the medical records of 201 consecutive cases that met this study's criteria from January 2009 to December 2016. All patients underwent curative and complete esophagectomy for intra-thoracic esophageal cancer. We compiled and analyzed routine laboratory findings from the day before surgery to the eighth postoperative day on a daily basis. Routine laboratory tests consisted of 26 separate tests, including complete blood cell counts, blood chemistries, as well as erythrocyte sedimentation rate and C-reactive protein (CRP). Barium esophagogram with chest computed tomography (CT) was performed on the seventh postoperative day to evaluate the presence of an anastomotic leak. Results: A total of 45 of 201 patients underwent NT. Anastomotic leaks were found in 23 (11.4%) of 201 patients (8 patients in NT and 15 patients in non-NT). White blood cell (WBC) from the second postoperative day (P=0.031, P=0.006, P=0.007, P=0.007, P=0.041, and P=0.003, respectively) and CRP from the third postoperative day (P=0.012, P<0.001, P=0.014, P<0.001, P=0.001, and P=0.006, respectively) were associated with anastomotic leak in non-NT; however, only CRP on the third, fifth, sixth, and seventh postoperative days (P=0.041, P=0.037, P=0.002, and P=0.003, respectively) was associated with anastomotic leak in NT. The CRP level on the third postoperative day was a significant independent predictive marker of anastomotic leak (P=0.041, odd ratio (OR) 1.056, 95% confidential interval (CI): 1.002-1.113) and had a significant diagnostic cutoff value for the development of anastomotic leak (non-NT: cutoff value 17.12 mg/dL, sensitivity 69.2%, specificity 78.1%, P<0.001, area 0.822; NT: cutoff value 16.42 mg/dL, sensitivity 80.0%, specificity 70.0%, P=0.042, area 0.7104). Conclusions: There were divergent laboratory findings reflective of anastomotic leak between patients who underwent NT and those who did not. The CRP level on the third postoperative day had a significant cutoff value for early detection of anastomotic leak after esophagectomy in both NT and non-NT groups. PMID- 29268377 TI - Peroxisome proliferator-activated receptor-gamma in induced sputum is correlated with MMP-9/TIMP-1 imbalance and formation of emphysema in COPD patients. AB - Background: The development of chronic obstructive pulmonary disease (COPD) is modulated by the symmetry of matrix metalloproteinases (MMPs) and the counter acting tissue inhibitors of metalloproteinases (TIMPs). We investigated the interaction between peroxisome proliferator-activated receptor gamma (PPARgamma) expression and the imbalance of MMP-9/TIMP-1 in the induced sputum of stable COPD patients. Methods: Sixty-six stable COPD patients were enrolled and the induced sputum samples were gathered. The correlation between PPARgamma and other index, including MMP-9, TIMP-1, pulmonary function and the index of emphysema-the percentage of low attenuation area (LAA%), was analyzed. Results: PPARgamma and TIMP-1 concentrations were decreased and the concentration of MMP-9 and the ratio of MMP9/TIMP1 were enhanced in the induced sputum of COPD patients, compared to the healthy controls. Among COPD patients, those with worse lung function or patients with emphysema exhibited increased MMP-9 expression with decreased TIMP 1 and PPARgamma expression. Besides, the concentration of PPARgamma of the induced sputum was correlated with the forced expiratory volume in one second percentage (FEV1%) positively and the expression of TIMP-1; while it was negatively correlated with the residual volume (RV), RV/total lung capacity (TLC), LAA%, and MMP-9 expression. Conclusions: Our findings reveal the protective role of PPARgamma in the maintenance of the dynamic balance of MMP 9/TIMP-1 in COPD, thus providing evidence on which to base the potential COPD treatment. PMID- 29268378 TI - A multi-center retrospective study of single-port versus multi-port video assisted thoracoscopic lobectomy and anatomic segmentectomy. AB - Background: To assess the feasibility and perioperative outcomes of single-port (SP) and multi-port (MP) approaches for video-assisted thoracoscopic surgery (VATS) lobectomy and anatomical segmentectomy. Methods: Retrospective data from 458 patients who received VATS lobectomy or anatomical segmentectomy at Shanghai Chest Hospital, Korea University Guro Hospital, Affiliated Hospital of National Taiwan University, University of Hong Kong Queen Mary Hospital and Shenzhen Hospital were collected. Patients were divided into SP group and MP group according to the surgical approach. Perioperative factors such as operation time, blood loss during surgery, conversion rate, the number and stations of lymph nodes harvested, postoperative chest tube drainage time, postoperative hospitalization time, perioperative morbidity and mortality, and pain scores during the first 3 days after surgery were compared between the two groups. Results: There were no differences in the number (P=0.278) and stations (P=0.564) of lymph nodes harvested, postoperative morbidity (P=0.414) or mortality(P=0.246), and pain score on the third day (P=0.630) after surgery between the two groups. The SP group had a longer operation time (P=0.042) and greater intraoperative blood loss (P<0.001), but the conversion rate was even higher in the MP group (P=0.018). Patients in the SP group had shorter chest tube removal time (P=0.012) and postoperative hospitalization time (P=0.005). Pain scores were lower on the first (P=0.014) and second (P=0.006) day after surgery in the SP group. Conclusions: SP VATS lobectomy and anatomical segmentectomy is technologically more demanding than MP VATS. It can be safe and feasible in the hands of experienced surgeons, with comparable preoperative outcomes to MP VATS, but less pain in the early postoperative period. PMID- 29268379 TI - Age and blood transfusion: relationship and prognostic implications in cardiac surgery. AB - Background: Red blood cell (RBC) transfusion is a well-known predictor of acute kidney injury (AKI) and death after cardiac surgery. This study aimed to define the relationship between age and the need for RBC. Methods: Study population included 1,765 consecutive patients undergoing on-pump procedures from 2013 to 2015. The relationship between RBC transfusion and both survival and AKI, and any interaction with age was estimated. A propensity score for the likelihood to receive RBC transfusion was calculated using multivariate logistic regression analysis to adjust for the effect of confounding factors. A logistic estimation curve was developed to investigate the interaction between this score and age. Results: Patients receiving RBC transfusions had more comorbidities irrespective of age. Elderly patients underwent transfusion more often than younger patients with a 1.3-fold increase in the relative risk for transfusion. Age did not independently predict the need for RBC. AKI and mortality rates were significantly higher in transfused subsets irrespective of age. Conclusions: Comorbidity profile and not age per se confers an increased risk of transfusion. PMID- 29268380 TI - Incidence and risk factors of iatrogenic pneumothorax after thoracentesis in emergency department settings. AB - Background: There is a lack of data regarding the incidence and associated factors of pneumothorax following thoracentesis conducted in emergency department (ED) settings. The present study aims to determine the incidence of pneumothorax following thoracentesis in ED settings and evaluate the association of specific demographics, clinical, and procedure factors with thoracentesis-related pneumothorax. Methods: We retrospectively reviewed the medical records of 3,067 thoracentesis cases in the ED of a tertiary care, university-affiliated hospital between January 2009 and December 2014. To evaluate the factors associated with the occurrence of pneumothorax following thoracentesis, matched controls were used with a case to control ratio of 1:5. Results: Of the 3,067 cases that received thoracentesis, 19 cases of pneumothorax were observed (0.62%). Patients with pneumothorax had significantly lower weight and body mass index (BMI) than those without pneumothorax (51.0 vs. 61.2 kg, 20.0 vs. 22.6; P<0.001, respectively). In the multivariate logistic regression analysis, being underweight, defined as a BMI of <18.5 [OR, 5.2 (95% CI, 1.3-21.2); P=0.021] was significantly associated with the occurrence of pneumothorax. Conclusions: The incidence of pneumothorax following thoracentesis was very low in the present study. However, clinicians should be aware of the risk of pneumothorax in underweight patients during thoracentesis. Further prospective studies are required to clarify the results of the present study. PMID- 29268381 TI - Circulating microRNA-34 family low expression correlates with poor prognosis in patients with non-small cell lung cancer. AB - Background: To evaluate the association of plasma miR-34a/b/c expressions with the clinicopathological properties and the prognosis in non-small cell lung cancer (NSCLC) patients. Methods: A total of 196 NSCLC patients were recruited in the study. Plasma sample and tumor tissue sample were collected. Total RNA was extracted from plasma and tissue samples, and microR-34a/b/c expression was evaluated by real-time polymerase chain reaction (PCR). Results: MiR-34a and miR 34c in plasma were positively associated with that in tumor tissue (P<0.001 and P=0.001, respectively). Plasma miR-34a expression was negatively correlated with lymph node metastasis (P=0.002), also tissue miR-34a expression was negatively associated with lymph node metastasis (P=0.018). Furthermore, plasma miR-34a high expression was correlated with prolonged disease-free survival (DFS) (P=0.011) and overall survival (OS) (P=0.011) compared to low expression, and plasma miR 34c high expression could predict longer DFS (P=0.038) than low expression, while no correlation of plasma miR-34b with DFS and OS was discovered. In terms of tissue sample, worse DFS was associated with miR-34a (P=0.002) and miR-34c (P=0.032) low expressions compared with high expressions, and miR-34a (P<0.001), as well as miR-34c (P=0.003) high expressions were associated with longer OS than low expressions. Plasma miR-34a was correlated with prolonged DFS and OS in univariate Cox model, while it could not independently predict DFS and OS of NSCLC patients in multivariate Cox model. Conclusions: In conclusion, circulating miR-34a and miR-34c might be served as novel prognostic biomarkers in NSCLC patients. PMID- 29268382 TI - Prognostic role of a comprehensive geriatric assessment on the management of elderly patients with advanced non-small cell lung cancer (NSCLC): a pooled analysis of two prospective phase II trials by the GFPC Group. AB - Background: The prognostic role of a comprehensive geriatric assessment (CGA) on the management of elderly patients with advanced-stage non-small cell lung cancer (NSCLC) remains to be established. The objective of this analysis was to determine the prognostic role of each CGA domain on overall survival (OS) among elderly patients with advanced-stage NSCLC. Methods: We pooled individual data from two prospective, randomized phases II trials in patients over 65 years old with advanced-stage NSCLC, who were considered fit (0405 trial) or no-fit (0505 trial) based on a CGA. Both trials compared first-line chemotherapy followed by second-line erlotinib with the reverse strategy in terms of progression-free survival (PFS) and OS. Factors prognostic of OS were sought by using the Kaplan Meier method and the log rank test for univariate analysis, and a Cox model for multivariate analysis. Results: Analysis performed on 194 patients (mean age: 77 years, male gender: 70%, never- or ex-smokers: 56%) showed, in univariate analysis that performance status (PS), smoking status, Charlson, simplified Charlson, nutritional scores, and a mobility score were prognostics of OS. In multivariate analysis, PS [HR: 1.4 (1.02-1.9), P=0.04] and the Charlson score [HR: 1.46 (1.07-1.99), P=0.02] were independently prognostic of OS, while the nutritional score [HR: 0.69 (0.46-1.04), P=0.07] and the mobility score [HR: 0.25 (0.06-1.01), P=0.06] were close to significance. Conclusions: PS and comorbidities appear to be the main predictors of OS in elderly advanced NSCLC patients selected on the basis of CGA. PMID- 29268383 TI - Long-term adherence to continuous positive airway pressure in patients with rapid eye movement-only obstructive sleep apnea: a prospective cohort study. AB - Background: Obstructive sleep apnea (OSA) during rapid eye movement (REM) sleep is a special form of OSA that occurs predominantly during REM sleep. No study has assessed the long-term adherence to continuous positive airway pressure (CPAP) among patients with REM-only OSA. To objectively assess the long-term adherence to CPAP therapy among patients with REM-predominant (REM-only) OSA. Methods: This was a prospective observational cohort study that included consecutive patients who were diagnosed with OSA. Patients were divided into the following two groups: (I) REM-only OSA [an apnea hypopnea index (AHI) of >=5, with a REM-AHI/NREM-AHI of >2, an NREM-AHI of <15, and a minimum of 15 min of REM-sleep duration], and (II) non-stage specific OSA. Follow-up was performed at 1, 6 and 12 months after the initiation of CPAP-therapy. Results: The study included 175 patients; 30 met the criteria for REM-only OSA, and the remaining patients constituted the non stage specific OSA group. The number of hours of CPAP use per day was significantly lower in the REM-only OSA group at 1, 6 and 12 months compared to the non-stage specific OSA group. At 12 months, the number of hours used per day was 3.8+/-1.8 and 5.1+/-2.1 hours in the REM-only and non-stage specific OSA groups, respectively (P=0.003). Approximately 80% of the enrolled participants in both groups were still using CPAP at the end of the study; 23.3% of REM-only OSA patients met the criteria for good adherence (>4 hours/day), and 56.7% met the criteria for partial adherence. Conclusions: CPAP adherence is lower among patients with REM-only OSA compared to patients with non-stage specific OSA. PMID- 29268384 TI - Impact of pregabalin on early phase post-thoracotomy pain compared with epidural analgesia. AB - Background: The purpose of this randomized study was to compare the effects of pregabalin with epidural analgesia on early phase post-thoracotomy pain. Methods: This study was conducted on 90 adult patients who underwent thoracotomy. Patients were randomly divided into two groups, an epidural analgesia group, where 45 patients received 0.2% ropivacaine hydrochloride and fentanyl through a thoracic epidural catheter, and a pregabalin group, where 45 patients received 75 mg pregabalin orally twice daily. Both groups were also administered orally with celecoxib along with each treatment. Numerical rating scale (NRS) and sleep interference rate (SIR) were evaluated on the first day, third day, and fifth day after surgery. Anesthetic induction time, operation time, recovery time, the use of additional analgesic drugs and adverse effects were also examined. Results: NRS and SIR were significantly lower in the pregabalin group at all time points (P<0.05). The number of patients requiring additional analgesic drugs within 24 hours after surgery showed no difference between the two groups; however, the number was significantly decreased in the pregabalin group after post-operative day 1 (P<0.001). Adverse effects including pneumonia, dysuria, constipation and nausea were identified among many patients in the epidural analgesia group (P<0.05). Operation time and recovery time were the same for both groups, while the epidural analgesia group showed a significantly longer anesthetic induction time (P<0.001). Conclusions: Pregabalin is considered to be a safe and effective treatment method which is an alternative to epidural analgesia for acute post thoracotomy pain. PMID- 29268385 TI - Macrolide-resistant Mycoplasma pneumoniae prevalence and clinical aspects in adult patients with community-acquired pneumonia in China: a prospective multicenter surveillance study. AB - Background: Drug resistant Mycoplasma pneumoniae (MP) is a rising issue in the management of community-acquired pneumonia (CAP). Epidemiological monitoring is essential for identifying resistant patterns of MP isolates against various antibiotics in adult CAP patients. Methods: This is a prospectively designed multicenter study conducted on adult patients with CAP visiting six teaching hospitals in the cities of Beijing, Shanghai and Guangzhou between September 2010 and June 2012. Results: A total of 520 adult patients (mean age: 45.7+/-26.2 years) with CAP visiting teaching hospitals in the cities of Beijing, Shanghai and Guangzhou were included. Of the 520 patients, only 75 (14.42%) were confirmed MP positive by means of culture and real-time PCR methods. Quinolones were the most common initially prescribed antimicrobial, followed by beta-lactams and beta lactams plus quinolones. Macrolide resistance was as high as 80% and 72% against erythromycin (ERY) and azithromycin (AZM) respectively, which were associated with the A2063G transition mutation in domain V of the 23S ribosomal RNA (rRNA) gene. Six strains with mild to moderate ERY-resistant level were still susceptible to AZM. Tetracycline (TET), minocycline (MIN) and quinolones [moxifloxacin (MOX) and fluoroquinolones] had no signs of resistance. Conclusions: High resistance was observed with macrolides, whereas, none of the MP strains were resistant to fluoroquinolones and TET. Hence, macrolide resistant MP (MRMP)_infections could be well treated with fluoroquinolones. However, few isolated strains had minimal inhibitory concentration (MIC) values on the edge of resistance to quinolones, alarming a quinolone-resistant MP in the near future. PMID- 29268386 TI - The prognosis of invasive adenocarcinoma presenting as ground-glass opacity on chest computed tomography after sublobar resection. AB - Background: Ground-glass opacity (GGO) on chest computed tomography (CT) is generally associated with non-invasive or minimally invasive adenocarcinoma (MIA). However, many instances of GGO are diagnosed as invasive adenocarcinoma. The purpose of this study is to analyse the histopathologic characteristics of invasive adenocarcinoma presenting as GGO and the prognosis after sublobar resection. Methods: We conducted a retrospective chart review of 191 patients who were treated for stage I non-small cell lung cancer presenting as a GGO predominant tumour upon CT and who underwent curative resection. We analysed the histologic subtypes and components of invasive adenocarcinomas presenting as GGO predominant tumours. We also compared the 5-year recurrence-free survival (RFS) of invasive adenocarcinomas presenting as GGO-predominant in patients undergoing sublobar resection or lobectomy. Results: Of 191 GGO-predominant tumour patients, 97 patients had adenocarcinoma in situ (AIS) or MIA, and 94 patients had invasive adenocarcinoma. In the analysis of the histologic component of invasive adenocarcinoma presenting as GGO, the mean rate of the lepidic component was 47.4%, that of the acinar component was 42.1%, and that of the papillary component was 7.3%. Micropapillary and solid components were nearly absent. The 5 year RFS rates of sublobar resection and lobectomy were both 100%. Conclusions: Invasive components such as acinar and papillary components can also be seen as GGO tumours on chest CT. After the sublobar resection of GGO-predominant tumours, a good prognosis can be expected, even if the tumour is an invasive adenocarcinoma such as the acinar or papillary subtypes. PMID- 29268387 TI - Physiological rules for the heart, lungs and other pressure-based organs. AB - Background: The adherence of the heart to physical laws, such as Laplace's Law, may act as a measure of the organ's relative efficiency. Allometric relationships were investigated to assess the heart's efficiency concerning end-diastolic and end-systolic volumes, cardiac pressurization energy, cardiac output and mass. Methods: Data to generate allometric relationships was obtained using a literature search, identifying heart and lung data across different mammalian and bird species. Statistical analysis was carried out using ordinary least squares (OLS) estimation. Results: Near isometric relationships exist between body mass and seven parameters indicating no "efficiency of size" with scaling of the heart, and size-matching of the heart to the lungs and whole body. Even though there was equal efficiency in pressurization energy generation, cardiac output was maximally efficient in small mammals <10 kg and birds; the human heart reached only 71% efficiency. This loss in cardiac efficiency with increasing body mass can be explained by the aortic cross-section that scales following the three quarter allometry law, compared to end-systolic and end-diastolic volumes that scale isometrically. The heart is therefore throttled by a relatively small aorta at large body size. Conclusions: Mammalian and avian hearts operate at similar efficiencies, demonstrating a high degree of symmorphosis, however cardiac output efficiency decreases in larger animals due to a relatively negative aortic cross section allometry. This work has a myriad of potential applications including explaining cardiac dysfunction in athletes, patient-prosthesis mismatch in aortic valve replacement and why heavy exercise is associated with a worse prognosis than mild or moderate exercise. PMID- 29268388 TI - Study on the role of transient receptor potential C6 channels in esophageal squamous cell carcinoma radiosensitivity. AB - Background: To study the effect of transient receptor potential C6 (TRPC6) channels on esophageal squamous cell carcinoma (ESCC) cell lines Eca109 cell cycle and to confirm whether TRPC6 channel is candidate radiosensitivity in vitro and in vivo. Methods: We chose Eca109 cell line with a strong TRPC6 channels expression. Cell cycle was investigated after TRPC6 channel inhibitor SKF96365 treated with a 5 uM concentration. According to the results of cell cycle, radiation was performed. CCK-8 test was used to test the cell proliferation. Then we performed the same study in vivo. Total of 40 male nude mice were randomly divided into four groups as follows: SKF96365, radio, combined radio-SKF96365 and control. In SKF96365 group, 20 mg/kg 5 uM SKF96365 was injected into the abdominal cavity of the nude mice at day 5-11. In radiation group, the nude mice received radiotherapy 2 Gy per day at day 7-11. In combined radio-SKF96365 group, 20 mg/kg 5 uM SKF96365 was injected into the abdominal cavity of the nude mice at day 5-11 and 2 Gy radiotherapy was delivered to the tumor site at day 7-11. In control group, nude mice were injected saline into the abdominal cavity at day 5 11. General states of health were observed, the tumor size in volume was measured with calipers two times every week. Six weeks after seeding, mice were sacrificed by neck-break. The tumor size was measured in volume with caliper and in weigh with scale. Results: Treatment with SKF96365 substantially increased the percentage of Eca109 cells in the G2/M phase and reduced that in G0/G1 phase in a time-dependent manner. Most of the cells (85.26%), 24 h after SKF96365 treatment were arrested in the G2/M phase. CCK-8 test showed that Eca109 ESCC cells received both SKF96365 and radiation showed the worst ability of cell proliferation. The same result was obtained in vivo. Nude mice received combined radio-SKF96365 showed the smallest tumor size and volume. Conclusions: TRPC6 plays an important role in development of esophageal cancer, and SKF96365 may increase the sensitivity of radiotherapy. TRPC6 may become a new radiotherapy target in esophageal cancer. PMID- 29268389 TI - Effects of Nuss procedure on thoracic scoliosis in patients with pectus excavatum. AB - Background: The objectives of this study are to investigate the association between pectus excavatum (PE) and thoracic scoliosis (TS) and to analyze the effects of the Nuss procedure on the thoracic spinal curvature in patients with PE. Methods: A total of 468 patients who underwent the Nuss procedure and pectus bar removal for PE from March 2011 to January 2015 were assessed and included into the present study. Results: TS prevalence was 9.4% pre-correctively and 9.8% post-correctively. There was a positive correlation between age and Cobb angle (CA), pre-correctively and post-correctively (both, P<0.001). The late correction group (LG, age >=10 years) had a higher CA and more frequent TS than the early correction group (EG, age <10 years) (pre-correction: CA 6.3+/-4.9 degrees vs. 4.5+/-3.8 degrees , P<0.001, TS P<0.001; post-correction: 7.6+/-7.2 degrees vs. 4.1+/-3.3 degrees , P<0.001, TS P<0.001). The post-corrective changes in CA were different according to the time of correction (decreased in EG: 4.5+/-3.8 degrees vs. 4.1+/-3.3 degrees , P=0.078; increased in LG: 6.3+/-4.9 degrees vs. 7.6+/ 7.2 degrees , P=0.002). In patients with pre-corrective TS, CA after correction was decreased (post-correctively 11.9+/-10.0 degrees vs. pre-correctively 13.9+/ 6.0 degrees , P=0.090). In addition, post-corrective CA was significantly decreased in EG (pre-correction 13.9+/-7.4 degrees vs. post-correction 6.6+/-8.1 degrees , P<0.001). However, post-corrective CA was increased in LG (pre correction 13.8+/-4.5 degrees vs. post-correction 16.7+/-9.2 degrees , P=0.053). The number of patients with TS after correction was decreased in EG (P=0.194) and significantly increased in LG (P=0.028). There were both pre-corrective and post corrective predictive factors for TS (Pre-corrective: age P<0.001, severity P=0.016, and BMI P=0.046; post-corrective: age at the time of correction P<0.001, weight P=0.046, and pre-corrective CA P<0.001). Conclusions: The Nuss procedure had some significant effects on the thoracic spinal curvature, with early correction able to reduce TS in patients with PE. PMID- 29268390 TI - Could thymomectomy be a reasonable option for non-myasthenic thymoma patients? AB - Background: Complete resection is the mainstay of treatment for thymoma, but few studies have investigated the extent of resection on normal thymus. Extended thymectomy is considered the treatment of choice for myasthenic patients with thymoma, while the optimal therapy for non-myasthenic patients is still a matter of debate. The aim of this retrospective study was to compare extended thymectomy vs. thymomectomy in non-myasthenic thymoma patients for (I) oncological outcome, (II) multicentric thymoma occurrence and (III) postoperative myasthenia gravis (MG) development. Methods: A retrospective comparative study was conducted on 92 non-myasthenic patients with completely resected thymoma, according to the extent of resection: extended thymectomy (70 patients) vs. R0-mediastinal thymomectomy (22 patients). Clinical and pathological characteristics, oncological outcome and postoperative MG occurrence were compared between the two study groups. Results: We did not observe any significant differences in gender, age, symptomology, preoperative chemotherapy, histology, tumour size, adjuvant therapy or complications. There were no recorded postoperative mortalities. Stage distribution was different between the two groups: similar percentages of early stage thymoma for both groups were present, but there was a prevalence of stage III for extended thymectomy and stage IV for thymomectomy (P<0.01). At a median follow-up of 77.4 months (range 1-255 months), no statistically significant differences were recorded in local recurrence (P=0.396), thymoma related deaths (P=0.504), multicentric thymoma occurrence (P=0.742) and postoperative MG development (P=0.343). A high preoperative anti-acetylcholine receptor antibodies (ARAb) serum titer assay was statistically correlated with postoperative MG occurrence (r=0.49, P<0.05). Conclusions: Thymomectomy appears to be a valid treatment option for non-myasthenic thymoma patients, as this procedure was associated to the same 5-year oncological results, compared to extended thymectomy, for both stage I-II small thymomas and patients with giant unilateral masses, as well as advanced diseases. Moreover, thymomectomy was not associated to an increased rate of postoperative MG. PMID- 29268391 TI - What is difficult about doing video-assisted thoracic surgery (VATS)? A retrospective study comparing VATS anatomical resection and conversion to thoracotomy for lung cancer in a university-based hospital. AB - Background: To analyze causes and clinical outcomes of conversion to thoracotomy during video-assisted thoracic surgery (VATS) anatomical resection for patients with non-small cell lung cancer. Methods: A total of 245 consecutive pulmonary resections were performed from January 2013 to July 2016 at Chungbuk National University Hospital. Patients who underwent curative, anatomical resection for lung cancer were included in the study. Preoperative basal characteristics, functional factors, radiologic findings and clinical outcomes were compared between converted and non-converted patients. Results: Of the 245 patients, 91 (benign disease) and 17 (non-anatomical resection) were excluded from the study. Of the 137 remaining patients, 51 (37%) who received anatomical resection via VATS and 38 (28%) via conversion to thoracotomy were included in the study, but 48 (35%) with planned thoracotomy were excluded. Gender, previous medical history, American Society of Anesthesiologists (ASA) score, body mass index (BMI) and forced expiratory volume for 1 second (FEV1) were not different between the two groups. However, age (P<0.01), enlarged lymph node by chest computed tomography (P=0.04), lesion fluorodeoxyglucose (FDG) uptake except main mass by positron emission tomography with computed tomography (P=0.01) (P<0.01), and tumor location (P=0.03) were significantly different between groups. Multivariate analysis showed patient age [odds ratio (OR), 1.06; P=0.04] and tumor location (OR, 2.71; P=0.03) were predicted conversion to thoracotomy. Converted patients showed a trend for longer duration of thoracic drainage, longer hospital stays and higher blood loss, but operation time (P<0.01) was the only statistically different factor between patient groups. Conclusions: Elderly patients, in particular if their lung mass was located in the middle or lower lobe, may be likely to convert to thoracotomy during VATS anatomical resection for lung cancer. These factors can help determine surgical approach, especially when surgeons are not familiar with VATS. PMID- 29268392 TI - Clinical analyses on salvage lymphadenectomy through cervical incision for patients with cervical and cervicothoracic recurrences after esophagectomy. AB - Background: Locoregional recurrences are often observed after esophagectomy with lymphadenectomy. The treatment strategy for these patients has not been established completely. The purpose of this study was to evaluate the prognosis of salvage lymphadenectomy through the cervical incision for cervical and cervicothoracic recurrences. Methods: We retrospectively reviewed patients underwent initial esophagectomy and then salvage lymphadenectomy in Fudan University Shanghai Cancer Center during July 2006 and September 2016. Survival curve was calculated by Kaplan-Meier method. Prognostic factors for post-salvage lymphadenectomy overall survival (PSL-OS) were identified by univariate and multivariate analyses. Results: The median disease-free survival (DFS) was 8 months. The median PSL-OS was 40 months (95% CI: 8.850-71.150). The 1-, 2-, 3- and 5-year PSL-OS rate were 87%, 58%, 52% and 41%, respectively. Univariate and multivariate analyses confirmed the initial TNM stage was the only independent prognostic factor for PSL-OS (P=0.000 by log-rank test, P=0.009 by Cox hazards model, HR 3.999, 95% CI: 1.413-11.316) among these patients. Conclusions: PSL survival could be considerable for patients with early initial tumor stage. Prospective studies are warranted to clarify the value of salvage lymphadenectomy. PMID- 29268393 TI - The long-term outcome of adjuvant hypofractionated radiotherapy and conventional fractionated radiotherapy after breast-conserving surgery for early breast cancer: a prospective analysis of 107 cases. AB - Background: This study aimed to evaluate the long-term outcomes of hypofractionated and conventional fractionated radiotherapy after breast conserving surgery in patients with early-stage breast cancer. In addition, cosmetic and delayed toxic effects in the breast were also investigated. Methods: A total of 107 female patients were recruited and randomly classified into the hypofractionated radiotherapy (HF) group (53 participants) and the conventional fractioned radiotherapy (CF) group (54 participants). The HF group was subjected to the following treatments: whole-breast irradiation (+/- irradiation of the infra-supraclavicular region) at 42.56 Gy/16 fractions + tumor bed boost at 7.98 Gy/3 fractions. The CF group received the following treatments: whole-breast irradiation (+/- irradiation of the infra-supraclavicular region) at 50 Gy/25 fractions + tumor bed boost at 10 Gy/5 fractions. Results: The 10-year local recurrence (LR) rate, tumor-specific survival rate, disease-free survival rate, and overall survival rate of the HF and CF groups were 9.6% vs. 7.9% (P=0.712); 88.1% vs. 90.1% (P=0.738); 81.1% vs. 82.9% (P=0.792); and 86.5% vs. 88.5% (P=0.748), respectively. The 10-year rates of patients with good or excellent cosmetic results in the HF and CF groups were 72.7% vs. 67.4% (P=0.581), respectively. The 10-year rates of patients with delayed toxicity-free effects in the skin and the rates of patients with toxicity-free subcutaneous tissues in the HF and CF groups were 70.5% vs. 65.2% (P=0.595) and 52.3% vs. 47.8% (P=0.673), respectively. Conclusions: Hypofractionated and CF showed comparable long-term efficacy, cosmetic effects, and delayed toxic effects. Hence, HF may be used as an alternative to conventional fractionated radiotherapy. PMID- 29268394 TI - Management of occult malignant pleural disease firstly detected at thoracotomy for non-small cell lung cancer patients. AB - Background: The current study was to investigate the risk factors of occult malignant pleural disease (MPD) detected at thoracotomy and the outcomes of surgical intervention for these non-small cell lung cancer (NSCLC) patients with or without MPD. Methods: We reviewed 2,093 consecutive NSCLC patients who underwent thoracotomy from January 2006 to January 2015. We used univariate and multivariate statistics to analyze the associations between clinicopathological variables and occurrence of occult MPD. Survival probability was estimated by the Kaplan-Meier method. Results: 5.26% (110/2,093) MPD was observed for these NSCLC patients with 28% of 5-year estimated survival rate. Age <=50 (P=0.055), high CEA level (P=0.006), advanced N stage (P=0.005), adenocarcinoma (P=0.001) and pleural invasion (P=0.041) were detected to be independent risk factors for the occult MPD. Combination of these five factors, 0.756 of area under curve (AUC) was shown by the integrated prediction model test. Based on the optimal cut-off value (risk score =2.795), low-risk patients have better prognosis than the high-risk patients (median survival time 61.4 months vs. not reached, P<0.001; 5-year survival 71.8% vs. 51.1%, P<0.001). Significantly, 49.0 months/31.7% and 29.4 months/19.5% of the median survival time/5-year survival rate were found for the occult MPD 110 patients receiving primary lesion resection and open-close surgery, respectively (P=0.037). Conclusions: We summarized that a new prediction model including 5-risk factors of age, carcinoembryonic antigen (CEA), N stage, adenocarcinoma and pleural invasion was provided to diagnose MPD for the NSCLC patients and primary lesion resection greatly contributed for these MPD patients. PMID- 29268395 TI - SYNTAX score may predict the severity of atherosclerosis of the ascending aorta. AB - Background: The objective of this study was to investigate the association of the coronary SYNTAX score with the degree of atherosclerosis of the ascending aorta in patients who underwent coronary artery bypass grafting (CABG). Methods: A total of 152 patients (mean age 65 years, 66% male) were analyzed who underwent isolated CABG with both SYNTAX score and the intraoperative 5-point scale grading of the severity of atherosclerosis in the ascending aorta available. The patient were stratified into low, intermediate, and high SYNTAX score groups [<=22 (n=36), 22-33 (n=42), and >=33 (n=76)]. Results: The mean SYNTAX score was 31+/ 11. Patient demographics and comorbidity were comparable in each group. The prevalence of severe atherosclerosis (Grade >=III) in the ascending aorta was 17.5% (n=27) in the whole population and was different in each group with higher prevalence in higher score groups (8.3% vs. 9.5% vs. 26.3%, P=0.018). After adjusting for age, sex and other relevant comorbidity, SYNTAX score remained a predictor of severe atherosclerosis [adjusted OR 1.63, 95% CI: 1.01-2.62, P=0.046 (per 10 point increase); adjusted OR 5.20, 95% CI: 1.15-23.5, P=0.032 (high vs. low score)]. Conclusions: SYNTAX score was associated with the severity of atherosclerosis in the ascending aorta. Patients with high scores have a 5 times higher chance of severe disease compared to patients with low scores and should warrant preoperative and intraoperative comprehensive assessment of the ascending aorta. PMID- 29268396 TI - Anterior fissureless uniport vs. posterior intra-fissure triple-port thoracoscopic right upper lobectomy: a propensity-matched study. AB - Background: This study aimed to assess the efficiency of anterior fissureless uniport (AFU) thoracoscopic lobectomy for early stage right upper non-small cell lung cancer (NSCLC). Methods: Between June 2014 and Dec 2016, 162 consecutive NSCLC patients who underwent thoracoscopic right upper lobectomy (RUL) by AFU approach (AFU group, n=65) or posterior intra-fissure triple-port dissection (PIFT group, n=97) were enrolled. A propensity-matched analysis was used to compare perioperative outcomes, safety and efficiency between the two groups. Results: Propensity matching produced 40 pairs in this retrospective study. During the operation, lobectomy took less time in the AFU group compared with the PIFT group, while no statistical differences in mediastinal lymphadenectomy time, intraoperative blood loss, and total of lymph nodes harvested were found between the two groups. Postoperatively, length of hospital stay (LOS) and time of postoperative air leak were significantly reduced in AFU group than in PIFT group. However, the overall complication rate and volume of pleural effusion drainage within 48 h were similar. Compared with the PIFT group, visual analogue scale (VAS) of 3 postoperative days in AFU group was slighter. Conclusions: In RUL, AFU thoracoscopic approach is safe, efficient and easily maneuverable, which would reduce the duration of lobectomy, LOS and time of postoperative air leak. Postoperative pain is also mild. PMID- 29268397 TI - Epidemiology, microbiology and treatment implications in adult patients hospitalized with pneumonia in different regions of China: a retrospective study. AB - Background: Data describing epidemiology, clinical outcomes and treatment patterns, of hospitalised patients with pneumonia in China are limited. We aimed to describe such information among adult pneumonia patients in southern and northern China. Methods: We retrospectively reviewed electronic medical records of pneumonia patients aged >=18 years, hospitalized between 2008 and 2013 at Guangdong Provincial Hospital of Chinese Medicine (n=3,636), southern China, and between 2010 and 2014 at Peking University People's Hospital, Beijing (n=1,689), northern China, in order to collect data on patient demographics, microbiology, clinical outcomes and treatment and resistance patterns. Results: The mean (SD) age of patients was 60.0 (21.4) and 64.4 (18.4) years in Guangdong and Beijing, respectively. Mean length of hospital stay was 12.1 and 20.8 days, and overall mortality was 2.9% and 8.0%, respectively. Gram-negative bacilli were most frequently isolated, predominantly Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Infection with these bacteria was associated with unfavourable clinical outcomes, and the antibiotic resistance among these bacteria increased between 2008-2010 and 2011-2013 in both regions of China. The treatment and choice of antibiotics slightly varied between the two regions based on the susceptible pathogens identified among their populations. Conclusions: Of the pathogens identified, Staphylococcus aureus infection (particularly the methicillin-resistant S. aureus) was associated with poor clinical outcomes; however antibiotic resistance among S. aureus generally decreased during the study data collection periods. Also, disease severity was greater in Beijing as compared with Guangdong, and this may be associated with higher microbiological diagnosis rate and higher frequency of initial antibiotic modification among Beijing populations. PMID- 29268398 TI - Perception of circadian variation of symptoms in Chinese patients with chronic obstructive pulmonary disease. AB - Background: Although, the variable pattern of asthmatic symptoms is well recognized, little is known about the respiratory symptoms variability in patients of chronic obstructive pulmonary disease (COPD). The present study evaluated the variability of the respiratory symptoms in a day and their influence on the daily activities in a cohort of Chinese COPD patients. Methods: An observational cross-sectional study was conducted in 11 medical centers of China. Participants were outpatient >=40 years old with stable COPD, post bronchodilator forced expiratory volume in 1 second (FEV1) <80% predicted. Overall, data of 1,032 eligible patients were valid for final analysis. Results: Mean post bronchodilator FEV1 (predicted %) was 46.5%. Cough, expectoration and dyspnea were the most commonly observed symptoms (73.6%, 68.8% and 61.4%, respectively). Daily symptom variability was experienced by 50.2% of symptomatic patients. The wake up time in the morning was the worst and the most troublesome time during the day (39.3%), followed by the nighttime (21.3%). The morning activities were most affected by COPD symptoms. Multivariate analyses revealed that COPD assessment test (CAT) scores was the only factor correlated with patients' symptom variability [odds ratio (OR) =0.463, P<0.0001]. Conclusions: Patient-perceived symptoms vary during the day in Chinese COPD patients. They experience the greatest increase in respiratory symptoms early in the morning. This variation should be considered as a potential new target in the long-term COPD management. PMID- 29268400 TI - Lymph node involvement according to lung adenocarcinoma subtypes: lymph node involvement is influenced by lung adenocarcinoma subtypes. AB - Backgrounds: Invasive adenocarcinoma subtypes are known to be associated with prognosis; however, the underlying reason remains unclear. To find out the reason, we investigated the possible influence of lymph node (LN) involvement by the constituent histologic subtypes in the tumor and clarified the different prognosis according to the predominant histologic subtypes in the tumor and LN. Methods: A total of 97 consecutive patients who underwent surgical resection for lung invasive adenocarcinoma between February 2009 and December 2015 were included. We analyzed the associations of the histologic subtypes between the tumor and LN and disease-free survival (DFS) according to the histologic subtypes and predicted the histologic subtype in LN involvement using the component ratio of the predominant histologic subtype in the tumor. A P value <0.05 was considered statistically significant. Results: Acinar and papillary subtypes occupied the majority of the predominant histological subtypes (tumor 73.2%, LN 71.1%). The tumor showed significantly more constituent histologic subtypes than LN (P<0.001). Micropapillary and solid predominant subtype were more common in poorer differentiation (tumor P<0.001, LN P=0.001). The predominant histologic subtype in the tumor was not the same as that in LN and micropapillary and solid predominant subtypes were significantly more prone to LN involvement than other subtypes (P<0.001). Regarding the predominant histologic subtypes in the tumor, there was no significant difference in DFS between micropapillary and solid predominant subtypes and other subtypes. However, regarding the predominant histologic subtypes in LN, micropapillary and solid predominant subtypes had significantly lower DFS than other subtypes (P=0.010). Solid predominant subtype had a significant cutoff value for prediction of the predominant histologic subtype in LN using the component ratio of the predominant histologic subtype in the tumor (cutoff value 12.5%, sensitivity 70.0%, specificity 82.4%, area 0.775, P<0.001). Conclusions: The present study presented a possible reason of discrepancies in outcomes according to the lung adenocarcinoma constituent subtypes. Micropapillary and solid predominant subtypes had poorer prognosis than other subtypes, which might be explained by being more prone to LN involvement. PMID- 29268399 TI - Evaluation of surgical approaches to anatomical segmentectomies: the transition to minimal invasive surgery improves hospital outcomes. AB - Background: We aim to evaluate the transition process from open to video-assisted thoracoscopic surgery (VATS) anatomical segmentectomies in a regional thoracic surgical unit. Methods: In a retrospective study from January 2013 to December 2015, we identified all anatomical segmentectomies performed in our unit. Pre, peri and postoperative data were compared between the three years (2013, 2014 and 2015) and according to operative approach. Thoracotomy after VATS intraoperative biopsy was considered a conversion for the purposes of the study. Results: A total of 86 consecutive cases [56 females and 30 males, median age 70 years (range, 43 to 83 years); median FEV1 of 78% predicted (range, 41% to 126%)] were included. There was a significant change in the surgical approach with time. Fifty-two cases underwent VATS (73% via single-port) and 34 open surgeries, including nine conversions. There were no postoperative deaths in the VATS group and one in the open group. Operative outcomes were similar over time with no haemorrhagic events, equivalent R1 resection and nodal stations explored in all lymph node positive patients. In node negative cases however, open surgery was associated with more extensive mediastinal exploration. Patients in 2015 had a shorter hospital stay in comparison to those in previous years [median 4 days (range, 1-15 days) vs. median 6 days (range, 3-27 days), P=0.01]. There were no differences in the incidence of complications or readmissions to hospital over time. Conclusions: The transition over a short period of time from open to single port VATS segmentectomy has allowed us to significantly reduce postoperative hospital stay without compromising operative or postoperative outcomes. PMID- 29268401 TI - Chemoradiotherapy for unresectable cases of thymic epithelial tumors: a retrospective study. AB - Background: Because of the rarity of thymic epithelial tumors (TETs), there is no treatment for managing unresectable tumors that is supported by a high level of evidence. We present here the clinical outcomes of concurrent or sequential chemoradiotherapy for patients with unresectable TETs. Methods: We collated records for 215 patients with TETs who were treated at our institution and focused on the 20 patients who underwent chemoradiotherapy without curative intent surgical resection. Results: Six patients with thymoma (4%) and 14 patients with thymic carcinoma (19%) were treated with chemoradiotherapy. Six received concurrent therapy, and platinum-containing regimens were administered to 16 patients. The survival of patients with thymic carcinoma was poorer than that of patients with thymoma [median overall survival (OS), 64.1 and 31.4 months, respectively; P=0.059]. No significant difference in survival was observed between patients treated concurrently and sequentially (48.5 vs. 38.2 months, respectively, P=0.83) or between patients treated with platinum containing regimens and other regimens (43.5 and 53.8 months, respectively, P=0.25). Conclusions: Chemoradiotherapy for unresectable TETs can be beneficial, especially when administrated concurrently. Patients for concurrent chemoradiotherapy should be chosen carefully because of its effectiveness and toxicity. PMID- 29268402 TI - ALK and ROS1 rearrangements, coexistence and treatment in epidermal growth factor receptor-wild type lung adenocarcinoma: a multicenter study of 732 cases. AB - Background: Anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangements represent two most frequent fusion targets in lung adenocarcinoma. Our study was intended to explore the clinicopathological characteristics, coexistence and treatment of ALK/ROS1-rearranged patients of lung adenocarcinoma without epidermal growth factor receptor (EGFR) mutation. Methods: Patients with wild-type EGFR mutation were screened for ALK/ROS1 at four domestic hospitals. ALK/ROS1 rearrangements were detected by reverse transcription-polymerase chain reaction (RT-PCR). Progression-free survival (PFS) curve was plotted with the Kaplan-Meier method. Results: Among 732 eligible cases, ALK and ROS1 rearrangements were detected in 89 (12.2%) and 32 (4.4%) patients respectively. One patient harbored coexisting ALK/ROS1 fusion. Both ALK and ROS1-positive phenotypes were predominantly detected in younger non-smokers. More ALK/ROS1 rearranged patients were correlated with the expressions of TTF1, napsin A and solid predominant adenocarcinoma subtype. Thirty-three ALK and six ROS1 rearrangement patients received crizotinib treatment at an advanced stage. The median PFS was 9.5 months for ALK-positive patients and it was not attained in ROS1-rearranged counterparts. Conclusions: The frequency of ALK and ROS1 rearrangements is elevated in EGFR-wild-type patients and the phenomenon of coexisting ALK/ROS1 has remained extremely rare. The rearrangements of ALK/ROS1 are correlated with age, smoking status, expressions of TTF1 & napsin A and solid predominant adenocarcinoma subtype. PMID- 29268403 TI - Comparison of clinical and radiological characteristics between anaplastic lymphoma kinase rearrangement and epidermal growth factor receptor mutation in treatment naive advanced lung adenocarcinoma. AB - Background: Gene analysis could not be performed in all patients, especially in advanced non-small cell lung cancer (NSCLC). We aimed to find some clinical futures and CT or FDG-PET characteristics, which could be combined to help distinguish anaplastic lymphoma kinase (ALK) rearrangement form epidermal growth factor receptor (EGFR) mutations in treatment naive advanced lung adenocarcinoma of Chinese patients. Methods: We retrospectively reviewed clinical and radiological characteristics of 145 patients with treatment naive advanced lung adenocarcinoma. The one-way ANOVA, the Mann-Whitney test, chi-square test and logistic regression were used for comparison between patients with ALK rearrangement and those with EGFR mutation. Results: Among 145 patients with advanced lung adenocarcinoma, only six patients had both ALK rearrangement and EGFR mutation, the sample size was too small to analysis. Univariate analysis revealed that patients with ALK rearrangement were younger (P=0.001) and with lower serum carcinoembryonic antigen (CEA) level (P=0.008) than those with EGFR mutation. More of tumors with ALK rearrangement were well defined (P=0.023) and have bubble lucency (P=0.026) compared with those with EGFR mutation (P=0.026). Lymphadenopathy was seen more frequently in patients with ALK rearrangement (P=0.167). Twenty-six patients received FDG-PET/CT, among this population, lesion standardized uptake values (SUV) >6.95 and lymph nodes SUVmax >6.25 were more often seen in ALK rearrangement group (P=0.011, both). In multivariate analysis, patients younger than 50 years (RR =9.878, 95% CI: 2.318-42.090, P=0.002), with lower CEA level than 4.95 ug/L (RR =8.166, 95% CI: 1.085-31.983, P=0.003) and without brain metastasis (RR =7.304, 95% CI: 1.099-48.558, P=0.040) were more likely to be ALK rearrangement than EGFR mutation. Tumor diameter less than 36 mm were prone to be EGFR mutation (RR =0.078, 95% CI: 0.017-0.356, P=0.001). Conclusions: Treatment naive advanced lung adenocarcinomas with ALK rearrangement were more likely to have younger age, lower serum CEA level, larger tumor volume, well defined tumor border, and non-brain metastasis than those with EGFR mutation. Bubble lucency and higher FDG uptake of lesion and lymph nodes may help distinguish ALK rearrangement from EGFR mutation in the absence of genetic analysis. PMID- 29268404 TI - No compensatory lung growth after resection in a one-year follow-up cohort of patients with lung cancer. AB - Background: As compensatory lung growth after lung resection has been studied in animals of various ages and in one case report in a young adult, it has not been studied in a cohort of adults operated for lung cancer. Methods: A prospective study including patients with lung cancer was conducted over two years. Parenchymal mass was calculated using computed tomography before (M0) and at 3 and 12 months (M3 and M12) after surgery. Respiratory function was estimated by plethysmography and CO/NO lung transfer (DLCO and DLNO). Pulmonary capillary blood volume (Vc) and membrane conductance for CO (DmCO) were calculated. Insulin like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) plasma concentrations were measured simultaneously. Results: Forty-nine patients underwent a pneumonectomy (N=12) or a lobectomy (N=37) thirty two completed the protocol. Among all patients, from M3 to M12 the masses of the operated lungs (239+/-58 to 238+/-72 g in the lobectomy group) and of the non operated lungs (393+/-84 to 377+/-68 g) did not change. Adjusted by the alveolar volume (VA), DLNO/VA decreased transiently by 7% at M3, returning towards the M0 value at M12. Both Vc and DmCO increased slightly between M3 and M12. IGF-1 and IGFBP-3 concentrations did not change at M3, IGF-1 decreased significantly from M3 to M12. Conclusions: Compensatory lung growth did not occur over one year after lung surgery. The lung function data could suggest a slight recruitment or distension of capillaries owing to the likely hemodynamic alterations. An angiogenesis process is unlikely. PMID- 29268405 TI - CT angiography for diagnosis and subcategorization of unroofed coronary sinus syndrome. AB - Background: To evaluate the role of CT angiography (CTA) in the diagnosis and subcategorization of unroofed coronary sinus syndrome (URCS). Methods: We retrospectively analyzed 46 URCS patients diagnosed by CTA. Based on the defect location and size of coronary sinus (CS), URCS was divided into four types: complete defect as type I, partial defect of proximal CS as type II, partial defect of distal CS as type III, partial defect in which a communication occurs between CS and left atrial as type IV. According to presence of left superior vena cava (LSVC), all types were divided into 2 subtypes as a and b. All 46 patients underwent echocardiography. Results: According to subcategorization of URCS by CTA, type I was observed in 23 cases (Ia 7, Ib 16), type II in 10 cases (IIa 3, IIb 7), type III in 12 cases (IIIa 3, IIIb 9), and type IV in 1 case classified as IVb subtype. In these 46 cases, 21 were detected by echocardiography as URCS (46%). The sensitivity of echocardiography in detecting URCS was significantly lower compared with cardiac CTA (P<0.05). In type I patients, the mean CS diameter indexed to body surface area (CS index) was larger than other types (P<0.05). Thirty patients were successfully treated by surgery and the diagnosis of URCS was confirmed by operative findings. Among them, data were available in 22 cases for analysis; and patients with types I, II and IIIa differ significantly from those with types IIIb and IV (P<0.05) with respect to surgical repair. Conclusions: CTA and imaging reconstruction can provide excellent anatomical delineation of the heart, great vessels, and CS, and allows for precise diagnosis of URCS. This CTA classification scheme of URCS is simple and easy to use, and has important clinical implications for diagnosis and treatment. PMID- 29268406 TI - Diffuse alveolar haemorrhage with predominant upper lung lobe involvement associated with congestive heart failure: a case series. AB - Background: Diffuse alveolar haemorrhage (DAH) may accompany or complicate various diseases with different pathophysiology. The diagnosis of DAH, especially when presenting as diffuse non-resolving and predominantly upper lobe lung consolidations, is particularly difficult in patients with cardiac disease. Methods: We retrospectively reviewed seven cases of DAH with predominant upper lobe involvement in the setting of acute or acute-on-chronic congestive heart failure (CHF). Results: In general, time from onset till diagnostic confirmation of DAH was long. Chest CT scan mostly confirmed diffuse lung infiltrates without preferential side location but with typical cortical sparing in all patients. Echocardiography showed presence of some degree of mitral valve insufficiency in all subjects. Conclusions: Diagnosis of DAH presenting as non-resolving upper lobe densities, accompanying CHF remains cumbersome but may be suggested indirectly by the presence of cortical sparing and mitral valve insufficiency. The latter may play a crucial role in the development of DAH. PMID- 29268407 TI - The involvement of the laminin-integrin alpha7beta1 signaling pathway in mechanical ventilation-induced pulmonary fibrosis. AB - Introduction: The central objective of the study was to determine the possibility and potential mechanism by which the laminin-integrin alpha7beta1 signaling pathway acts on mechanical ventilation (MV)-induced pulmonary fibrosis in a rat model. Methods: Fibrosis rat models were established via the mechanical injury method. Ninety rats were recruited and divided into the normal, low tidal volume (LVT), huge VT (HVT), Arg-Gly-Asp-Ser (RGDS), LVT + RGDS and HVT + RGDS groups. On day 0, 3, and 7 after model establishment, the pulmonary hydroxyproline content was measured using alkaline hydrolysis and the pulmonary index was also calculated. All rats in each group were executed on day 0, 3 and 7. The histopathological changes detected in the left pulmonary tissues were observed using hematoxylin-eosin (HE) and Masson staining methods. Discussion: The mRNA and protein expressions of Wnt-5A, beta-catenin, E-cadherin and Collagen I in the Wnt/beta-catenin signaling pathway were detected using both reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting methods. Immunohistochemistry was employed to detect the fibronectin (FN) expression in the pulmonary tissues on the 7th day. All indexes in the RGDS and LVT + RGDS groups indicated no explicit differences compared with the normal group. In the LVT, HVT, HVT + RGDS groups, the respective weights of the rats and the expression of E-cadherin on the 7th day exhibited decreases, however the pulmonary index, hydroxyproline, pulmonary alveolar inflammation, pulmonary fibrosis, FN expression, and protein expressions of Wnt-5A, beta-catenin, and Collagen I all displayed increased levels (all P<0.05). The index changes detected in the HVT group were the most blatant results observed in the study. The rat pulmonary index on the 7th day, hydroxyproline (HYP), pulmonary alveolar inflammation, pulmonary fibrosis, FN expression, and protein expressions of Wnt 5A, beta-catenin, and type I-collagen were all down-regulated, in contrast the expression of E-cadherin was up-regulated in the LVT + RGDS and HVT + RGDS groups in comparison with the LVT and HVT groups, respectively (all P<0.05). Conclusions: The findings of the study suggested that RGDS could act to block the laminin-integrin alpha7beta1-signaling pathway, ultimately contributing to the inhibition of the progression of MV-induced pulmonary fibrosis. PMID- 29268408 TI - Pulmonary manifestations of Q fever: analysis of 38 patients. AB - Background: Lung involvement in both acute and chronic Q fever is not well described with only a few reported cases of pseudotumor or pulmonary fibrosis in chronic Q fever. The aim of this study was to better understand the pulmonary manifestations of Q fever. Methods: We conducted a retrospective cohort study of patients with diagnosis of Q fever at Mayo Clinic Rochester. A total of 69 patients were initially identified between 2001 and 2014. Thirty-eight patients were included in this study as 3 were pediatric patients, 20 did not meet serologic criteria for Q fever, and 8 did not have imaging available at time of initial diagnosis. Descriptive analysis was conducted using JMP software. Results: The median age was 57 years [interquartile range (IQR) 43, 62], 84% from the Midwest, and 13% worked in an occupation involving animals. The most common presentation was fevers (61%). Respiratory symptoms, such as cough, were noted in only 4 patients (11%). Twelve patients (29%) had abnormal imaging studies attributed to Q fever. Three patients (25%) with acute Q fever had findings of consolidation, lymphadenopathy, pleural effusions, and nonspecific pulmonary nodules. Radiographic findings of chronic Q fever were seen in 9 patients (75%) and included consolidation, ground-glass opacities, pleural effusions, lymphadenopathy, pulmonary edema, and lung pseudotumor. Conclusions: Our results demonstrate that pulmonary manifestations are uncommon in Q fever but include cough and consolidation for acute Q fever and radiographic findings of pulmonary edema with pleural effusions, consolidation, and pseudotumor in those with chronic Q fever. PMID- 29268409 TI - Early identification of patients at risk for acute respiratory distress syndrome among severe pneumonia: a retrospective cohort study. AB - Background: Severe pneumonia is the predominant cause for acute respiratory distress syndrome (ARDS). Identification of ARDS from patients with severe pneumonia remains a significant clinical problem due to the overlap of clinical presentations and symptoms. Early recognition of risks for ARDS from severe pneumonia is of great clinical value. Methods: From April 2014 to December 2015, patients with severe pneumonia at admission were retrieved from the hospital database, of which ARDS developed within 7 days were further identified. We compared the demographic and clinical characteristics at admission between severe pneumonia patients with and without ARDS development, followed by analysis of potential predictors for ARDS development and mortality. Multivariate logistic regression and receiver operating characteristic (ROC) curves were performed to screen independent risk factors and identify their sensitivity in predicting ARDS development and prognosis. Results: Compared with severe pneumonia without ARDS development, patients with ARDS development had shorter disease duration before admission, higher lung injury score (LIS), serum fibrinogen (FiB), and positive end-expiratory pressure (PEEP), lower Marshall score, sequential organ failure assessment score and proportion of cardiovascular and gastrointestinal diseases, but similar mortality. Serum FiB >5.15 g/L [adjusted odds ratio (OR) 1.893, 95% confidence interval (CI): 1.141-3.142, P=0.014] and PEEP >6.5 cmH2O (adjusted OR 1.651, 95% CI: 1.218-2.237, P=0.001) were independent predictors for ARDS development with a sensitivity of 58.3% and 87.5%, respectively, and pH <7.35 (adjusted OR 0.832, 95% CI: 0.702-0.985, P=0.033) was an independent risk factor for ARDS mortality with a sensitivity of 95.2%. Conclusions: ARDS development risk could be early recognized by PEEP >6.5 cmH2O and serum FiB >5.15 g/L in severe pneumonia patients, and pH <7.35 is a reliable prognostic factor in predicting ARDS mortality risk. PMID- 29268410 TI - Predictors of arterial desaturation during intubation: a nested case-control study of airway management-part I. AB - Background: Arterial desaturations experienced during endotracheal intubation (ETI) may lead to poor outcomes. Thus, our primary aim was to identify predictors of arterial desaturation (pulse oximetry <90%) during the peri-intubation period and to assess outcomes of those who developed arterial hypoxemia. Methods: Adult patients admitted to a medical and/or surgical intensive care unit (ICU) over the time period of January 1st 2013 through December 31st 2014 who required ETI were included. Only the first intubation was captured. Arterial desaturation was defined as pulse oximetry readings of <90% (hypoxemia) in the immediate peri intubation period. Patients were then grouped in cases (those who developed desaturation) and controls (those who did not develop this complication). Results: The final cohort included 420 patients. Arterial desaturations occurred in 74 (18%) patients. When adjusting for significant predictors on univariate analysis and known predictors of a difficult airway, only acute respiratory failure (OR 2.38; 95% CI: 1.15-4.93; P=0.02) and provider training level (OR 7.12; 95% CI: 1.65-30.67; P=0.016) remained significant. Higher pulse oximetry readings prior to intubation was found to be protective on multivariate analysis (OR 0.92; 95% CI: 0.89-0.96; P<0.01; per one percent increase). Conclusions: Patients who were intubated for acute respiratory failure and those who were intubated by junior level trainees had increased odds of experiencing arterial desaturation in the peri-intubation period. Patients experiencing arterial desaturation had lower pulse oximetry readings prior to intubation suggesting a possible delay at intubation. PMID- 29268411 TI - Perioperative factors associated with 1-year mortality after lung transplantation: a single-center experience in Korea. AB - Background: Most studies about the risk factors of 1-year mortality after lung transplantation were performed on non-Asians. This study aimed to evaluate the perioperative factors related to the 1-year mortality after lung transplantation in Korea. Methods: Sixty-eight consecutive patients who underwent lung transplantation without preoperative extracorporeal membrane oxygenation treatment at 1 tertiary hospital in South Korea between October 24, 2012, and October 16, 2015, were analyzed retrospectively. Results: Forty-four patients (64.7%) lived for >1 year after lung transplantation. The median age of all patients was 55 years (range, 16-75 years), and men accounted for 57.4%. The major cause of lung transplantation was idiopathic pulmonary fibrosis (48.5%); the other causes were interstitial lung disease related to connective tissue disease (17.6%) and bronchiolitis obliterans after stem cell transplantation (14.7%). In univariate analysis, higher median age (52 vs. 61.5 years, P<0.001), male sex (45.5% vs. 79.2%, P=0.007), lower preoperative albumin level (<3 g/dL) (22.7% vs. 45.8%, P=0.049), need for renal replacement therapy (RRT) after surgery (4.5% vs. 37.5%, P=0.001), and postoperative delta neutrophil index (DNI) >5.5 higher than the preoperative DNI (22.7% vs. 70.8%, P<0.001) were significantly related to 1-year mortality. After adjustments, old age, postoperative increased DNI, and need for RRT after transplantation were the independent perioperative risk factors for 1-year mortality after lung transplantation. Conclusions: Recipients with advanced age should be carefully selected, and patients who need RRT or with increased DNI after transplantation should be managed accordingly. PMID- 29268412 TI - Tumor-stroma ratio (TSR) in non-small cell lung cancer (NSCLC) patients after lung resection is a prognostic factor for survival. AB - Background: In recent years, the tumor-stroma ratio (TSR) has been considered to a new and independent predictive variable for the prognosis of some kinds of neoplasms. The objective of this study was to assess the prognostic significance of the TSR in non-small cell lung cancer (NSCLC). Methods: A cohort of 261 NSCLC patients who underwent radical surgery of lung cancer were included in the present study. Two independent observers visually estimated the TSR on hematoxylin-eosin (H&E) stained tissue pathological slices. According to the proportion of stroma >=50% or <50%, We separate the patients into two groups: those with stroma-poor and those with stroma-rich tumors. Results: Both univariate and multivariate analyses disclosed that the TSR was associated with overall survival (OS) [hazard ratio (HR), 1.741; 95% confidence intervals (CI), 1.040-2.913 and HR, 1.904; 95% CI, 1.132-3.202, respectively]. The HR values for disease-free survival (DFS) were 1.795 (95% CI, 1.073-3.005) and 2.034 (95% CI, 1.210-3.420). The OS and DFS of patients with stroma-poor tumors were better than those with stroma-rich tumors. Conclusions: These results demonstrated that the TSR is a new prognostic factor for NSCLC. Stroma-poor tumors were associated with longer disease-free period and better prognosis than were stroma-rich tumors in NSCLC patients. The TSR may contribute to the development of individualized treatment for NSCLC in the future. PMID- 29268413 TI - Chest tube drainage versus needle aspiration for primary spontaneous pneumothorax: which is better? AB - Background: Needle aspiration and chest tube drainages are two main treatments for primary spontaneous pneumothorax (PSP). However, the application of needle aspiration or chest tube drainages has not reached a consensus. The aim of this study is to compare the needle aspiration with chest tube drainages in patients suffering with PSP and therefore help offer suggestions for clinical practice. Methods: We searched literatures from PubMed, OVID and Web of Science from their inception to June 30, 2017. Continuous and dichotomous outcomes were expressed by weight mean difference (WMD) and risk ratio (RR) respectively, and each with 95% confidence intervals (CIs). We used the fixed effect or random effect model to perform quantitative synthesis. Results: A total of 6 RCTs recruiting 458 participants were included in our analysis. On the basis of the six studies, our results indicated that compared with chest tube drainage applying needle aspiration shortened the hospital stay (WMD: -1.67 days; 95% CI: -2.25 to 1.08; P<0.001) and decreased hospitalization rate (RR: 0.40; 95% CI: 0.22-0.75; P=0.004). However, there was no difference regarding immediate success rate (RR: 1.01; 95% CI: 0.70-1.46; P=0.96) and one-year recurrence rate (RR: 0.89; 95% CI: 0.58-1.38; P=0.61). Conclusions: In the light of this present research, it is necessary to apply needle aspiration into treating PSP to reduce hospitalization rate and shorten hospital stay. However, the two treatments have no significant difference with respect to immediate success rate, one-year recurrence rate, one week success rate, three-month recurrence rate or complication rate. PMID- 29268414 TI - Percutaneous thermal ablation for stage IA non-small cell lung cancer: long-term follow-up. AB - Background: Surgical resection is the most effective curative therapy for non small cell lung cancer (NSCLC). However, many patients are unable to tolerate resection secondary to poor reserve or comorbid disease. Radiofrequency ablation (RFA) and microwave ablation (MWA) are methods of percutaneous thermal ablation that can be used to treat medically inoperable patients with NSCLC. We present long-term outcomes following thermal ablation of stage IA NSCLC from a single center. Methods: Patients with stage IA NSCLC and factors precluding resection who underwent RFA or MWA from July 2005 to September 2009 were studied. CT and PET-CT scans were performed at 3 and 6 month intervals, respectively, for first 24 months of follow-up. Factors associated with local progression (LP) and overall survival (OS) were analyzed. Results: Twenty-one patients underwent 21 RFA and 4 MWA for a total of 25 ablations. Fifteen patients had T1a and six patients had T1b tumors. Mean follow-up was 42 months, median survival was 39 months, and OS at three years was 52%. There was no significant difference in median survival between T1a nodules and T1b nodules (36 vs. 39 months, P=0.29) or for RFA and MWA (36 vs. 50 months, P=0.80). Ten patients had LP (47.6%), at a median time of 35 months. There was no significant difference in LP between T1a and T1b tumors (22 vs. 35 months, P=0.94) or RFA and MWA (35 vs. 17 months, P=0.18). Median OS with LP was 32 months compared to 39 months without LP (P=0.68). Three patients underwent repeat ablations. Mean time to LP following repeat ablation was 14.75 months. One patient had two repeat ablations and was disease free at 40-month follow-up. Conclusions: Thermal ablation effectively treated or controlled stage IA NSCLC in medically inoperable patients. Three-year OS exceeded 50%, and LP did not affect OS. Therefore, thermal ablation is a viable option for medically inoperable patients with early stage NSCLC. PMID- 29268415 TI - Optimal managements of stage IIIA (N2) non-small cell lung cancer patients: a population-based survival analysis. AB - Background: This study aimed to investigate the optimal management of stage IIIA (cN2) non-small cell lung cancer (NSCLC) patients and determine potential predictive factors. Methods: We extracted patients diagnosed as NSCLC stage IIIA (cN2) between 2004 and 2011 from Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients given different clinical managements by Kaplan-Meier method. Other variables such as age, sex and tumor size were analyzed to explore the factors associated with outcomes. Results: A total of 98,700 IIIA-cN2 NSCLC patients were identified from SEER database. Survival of patients treated with surgery was better than that of patients treated by radiotherapy alone (P<0.001). Radiation prior to surgery significantly improved the survival in comparison with surgery alone (P<0.001). In the subgroups of OS analysis, age >65 (P=0.902), adenocarcinoma (P=0.279), tumor size <=3 cm (P=0.170), well differentiated (P=0.360) patients, preoperative radiotherapy improved survival insignificantly compared with surgery alone. Conclusions: Preoperative radiation with surgery had the most encouraging survival outcomes in stage IIIA-cN2 NSCLC patients compared with radiation or surgery alone. No significant outcome improvement was shown between postoperative radiotherapy (PORT) and surgery alone. PMID- 29268416 TI - Uniportal video-assisted lobectomy through a posterior approach. AB - We propose a technique of uniportal VATS lobectomy using a posterior approach. The main differences of our technique versus standard anterior uniportal VATS are the following: (I) the surgical incision is performed in the auscultatory triangle instead of in the posterior axillary line and (II) the surgeon is placed posteriorly to the patient rather than anteriorly. For thoracic surgeons who are familiar with posterolateral thoracotomy, our technique allows to replicate the same maneuvers performed in the open approach. This strategy was applied with success in 19 consecutive patients for anatomical resection of neoplastic (n=17) and benign (n=2) diseases. PMID- 29268417 TI - Adjuvant treatment of non-small cell lung cancer: focus on targeted therapy. AB - In patients with completely resected stage II-IIIA non-small cell lung cancer (NSCLC), adjuvant platinum-based chemotherapy is associated with a modest, albeit significant, improvement in survival of approximately 5% at 5 years. However, regardless of whether adjuvant chemotherapy has been administered or not, the 5 year survival of these patients remains poor. In recent years, the discovery of targetable gene alterations such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements has revolutionized the therapeutic approach to advanced NSCLC, owing to the introduction for clinical use of selective tyrosine kinase inhibitors (TKIs). The outstanding activity shown by EGFR- and ALK-TKIs in advanced NSCLC patients with EGFR mutations or ALK rearrangements, respectively, leads to the logical question of what role these agents may have if used in the adjuvant setting. In the present review we will discuss the emerging data that support the potential benefit of targeted therapy as adjuvant treatment of patients with completely resected NSCLC, and summarize the ongoing clinical trials which will eventually address this issue. PMID- 29268418 TI - Advancements in mechanical circulatory support for patients in acute and chronic heart failure. AB - Cardiogenic shock (CS) continues to have high mortality and morbidity despite advances in pharmacological, mechanical, and reperfusion approaches to treatment. When CS is refractory to medical therapy, percutaneous mechanical circulatory support (MCS) should be considered. Acute MCS devices, ranging from intra-aortic balloon pumps (IABPs) to percutaneous temporary ventricular assist devices (VAD) to extracorporeal membrane oxygenation (ECMO), can aid, restore, or maintain appropriate tissue perfusion before the development of irreversible end-organ damage. Technology has improved patient survival to recovery from CS, but in patients whom cardiac recovery does not occur, acute MCS can be effectively utilized as a bridge to long-term MCS devices and/or heart transplantation. Heart transplantation has been limited by donor heart availability, leading to a greater role of left ventricular assist device (LVAD) support. In patients with biventricular failure that are ineligible for LVAD implantation, further advancements in the total artificial heart (TAH) may allow for improved survival compared to medical therapy alone. In this review, we discuss the current state of acute and durable MCS, ongoing advances in LVADs and TAH devices, improved methods of durable MCS implantation and patient selection, and future MCS developments in this dynamic field that may allow for optimization of HF treatment. PMID- 29268419 TI - Pathophysiology and classification of primary graft dysfunction after lung transplantation. AB - The term primary graft dysfunction (PGD) incorporates a continuum of disease severity from moderate to severe acute lung injury (ALI) within 72 h of lung transplantation. It represents the most significant obstacle to achieving good early post-transplant outcomes, but is also associated with increased incidence of bronchiolitis obliterans syndrome (BOS) subsequently. PGD is characterised histologically by diffuse alveolar damage, but is graded on clinical grounds with a combination of PaO2/FiO2 (P/F) and the presence of radiographic infiltrates, with 0 being absence of disease and 3 being severe PGD. The aetiology is multifactorial but commonly results from severe ischaemia-reperfusion injury (IRI), with tissue-resident macrophages largely responsible for stimulating a secondary 'wave' of neutrophils and lymphocytes that produce severe and widespread tissue damage. Donor history, recipient health and operative factors may all potentially contribute to the likelihood of PGD development. Work that aims to minimise the incidence of PGD in ongoing, with techniques such as ex vivo perfusion of donor lungs showing promise both in research and in clinical studies. This review will summarise the current clinical status of PGD before going on to discuss its pathophysiology, current therapies available and future directions for clinical management of PGD. PMID- 29268421 TI - Initial experience of medical pleuroscopy via the peel-away introducer of the indwelling pleural catheter using a thin bronchoscope. AB - We present a case series describing a modified technique of combining medical Pleuroscopy (MP) and indwelling pleural catheter (IPC) placement for obtaining pleural biopsies and managing recurrent pleural effusions. The unique feature of this technique is the introduction of a thin bronchoscope through the peel-away introducer of IPC to obtain pleural biopsies thus avoiding a bigger incision followed by placement of IPC. This procedure was performed on nine patients in an outpatient setting. A regular flexible bronchoscopy forceps was used to obtain pleural biopsies in eight out of nine patients and only one patient could not tolerate the procedure due to marginal respiratory status. A diagnosis of malignancy was successfully obtained in six patients, one patient had biopsy findings of chronic inflammation and one patient had necrotic debris and rare atypical cells despite having visible pleural lesions. No procedure related patient complications were noted. PMID- 29268422 TI - Design of interventional studies in thoracic surgery. AB - Interventional studies differ from observational studies in that one or more specific interventions are evaluated. Randomized controlled trials remain the gold standard for interventional studies and can take different forms. In surgical studies, the three types of randomized controlled trials most commonly encountered are: (I) trials that compare two different medical treatments for patients undergoing surgery; (II) trials that evaluate two different surgical techniques and (III) studies that compare surgery vs. non-operative management. When an intervention is to be evaluated but a randomized controlled trial is not feasible, alternative interventional study designs may be considered. PMID- 29268420 TI - A neuroanatomical framework for the central modulation of respiratory sensory processing and cough by the periaqueductal grey. AB - Sensory information arising from the airways is processed in a distributed brain network that encodes for the discriminative and affective components of the resultant sensations. These higher brain networks in turn regulate descending motor control circuits that can both promote or suppress behavioural responses. Here we explore the existence of possible descending neural control pathways that regulate airway afferent processing in the brainstem, analogous to the endogenous descending analgesia system described for noxious somatosensation processing and placebo analgesia. A key component of this circuitry is the midbrain periaqueductal grey, a region of the brainstem recently highlighted for its altered activity in patients with chronic cough. Understanding the nature and plasticity of descending neural control may help identify novel central therapeutic targets to alleviate the neuronal hypersensitivity underpinning many symptoms of respiratory disease. PMID- 29268424 TI - Using the confidence interval confidently. AB - Biomedical research is seldom done with entire populations but rather with samples drawn from a population. Although we work with samples, our goal is to describe and draw inferences regarding the underlying population. It is possible to use a sample statistic and estimates of error in the sample to get a fair idea of the population parameter, not as a single value, but as a range of values. This range is the confidence interval (CI) which is estimated on the basis of a desired confidence level. Calculation of the CI of a sample statistic takes the general form: CI = Point estimate +/- Margin of error, where the margin of error is given by the product of a critical value (z) derived from the standard normal curve and the standard error of point estimate. Calculation of the standard error varies depending on whether the sample statistic of interest is a mean, proportion, odds ratio (OR), and so on. The factors affecting the width of the CI include the desired confidence level, the sample size and the variability in the sample. Although the 95% CI is most often used in biomedical research, a CI can be calculated for any level of confidence. A 99% CI will be wider than 95% CI for the same sample. Conflict between clinical importance and statistical significance is an important issue in biomedical research. Clinical importance is best inferred by looking at the effect size, that is how much is the actual change or difference. However, statistical significance in terms of P only suggests whether there is any difference in probability terms. Use of the CI supplements the P value by providing an estimate of actual clinical effect. Of late, clinical trials are being designed specifically as superiority, non inferiority or equivalence studies. The conclusions from these alternative trial designs are based on CI values rather than the P value from intergroup comparison. PMID- 29268423 TI - Truths, lies, and statistics. AB - Distribution of valuable research discoveries are needed for the continual advancement of patient care. Publication and subsequent reliance of false study results would be detrimental for patient care. Unfortunately, research misconduct may originate from many sources. While there is evidence of ongoing research misconduct in all it's forms, it is challenging to identify the actual occurrence of research misconduct, which is especially true for misconduct in clinical trials. Research misconduct is challenging to measure and there are few studies reporting the prevalence or underlying causes of research misconduct among biomedical researchers. Reported prevalence estimates of misconduct are probably underestimates, and range from 0.3% to 4.9%. There have been efforts to measure the prevalence of research misconduct; however, the relatively few published studies are not freely comparable because of varying characterizations of research misconduct and the methods used for data collection. There are some signs which may point to an increased possibility of research misconduct, however there is a need for continued self-policing by biomedical researchers. There are existing resources to assist in ensuring appropriate statistical methods and preventing other types of research fraud. These included the "Statistical Analyses and Methods in the Published Literature", also known as the SAMPL guidelines, which help scientists determine the appropriate method of reporting various statistical methods; the "Strengthening Analytical Thinking for Observational Studies", or the STRATOS, which emphases on execution and interpretation of results; and the Committee on Publication Ethics (COPE), which was created in 1997 to deliver guidance about publication ethics. COPE has a sequence of views and strategies grounded in the values of honesty and accuracy. PMID- 29268425 TI - The biostatistical minimum. AB - Every day in our clinical practice, probability and statistics are used for a broad variety of actions, including the explanation of levels of risk to patients, the access to clinical guidelines, the understanding of research publications, and the writing of investigation papers for analysing numerical data and treatments options. Therefore, an unintentional statistical misconduct may originate from many sources. It is often difficult to detect, and little is known regarding the prevalence or underlying causes of research misconduct among biomedical researchers. The improvements in teaching statistics to thoracic surgeons should improve the thoughtful of statistical concepts and should reduce the incidence of fallacies. The Biostatistical basis should comprise the aspect of the Biostatistics that surgeons should be aware of correctly interpreting in their research findings: the understanding of p-values, confidence intervals, Student's t-tests, Z test, chi-square goodness of fit, ANOVA tables, and basic statistical models (linear or logistic regression). The understanding of Biostatistics is essential to all thoracic surgeons, and it is not unaware since most received some statistics lessons in their training. The Statistic Corner of the Journal of Thoracic Diseases kept the emphasis on Biostatistical methods to applies and when. Thus, various authors wrote about the analyses of several types of outcomes variables, the analyses of study design, the measures of association and impact, and the general strategies for the statistical analyses. Deceptively, these Statistic Corner articles have only scratched the surface. Nonetheless, we hope that had provided a stimulus to enhance the skills to interpret Biostatistics. PMID- 29268426 TI - The global alliance against chronic respiratory diseases Portugal: 10 years of experience. PMID- 29268427 TI - The value of learning surface ECG in the 21st century. PMID- 29268428 TI - Thoracoscopic resection of a huge mediastinal cystic lymphangioma. AB - Mediastinal cystic lymphangioma is an extremely uncommon benign tumor. The patients with mediastinal cystic lymphangioma are often misdiagnosed because of no specific symptoms. The cysts usually are incidentally found and preoperative diagnosis is difficult due to their atypical appearance on imaging studies. Most cases are diagnosed during or after the operation. Moreover, the standard surgical approach for resection has not yet been well established. We report a case of an adult patient with a giant mediastinal cystic lymphangioma that was successfully resected by video-assisted thoracoscopic surgery (VATS). This case report shows that resection by VATS is feasible when mediastinal cystic tumor is suspected, even if they are huge, and that VATS may be an alternative to open thoracotomy to treat mediastinal cystic lymphangioma. PMID- 29268429 TI - Successful treatment with afatinib for pancreatic metastasis of lung adenocarcinoma: a case report. AB - Metastatic lung cancer of the pancreas is rare and optimal treatment protocols have not been determined. An asymptomatic 53-year-old man with primary lung cancer underwent a right lower lobectomy and was diagnosed with acinar adenocarcinoma, pT2bN2M0 stage IIIA. An epidermal growth factor receptor (EGFR) mutation (exon 19 deletion L747-A750insP) was detected in the primary tumor. Adjuvant platinum-based chemotherapy was administered. The patient's serum carcinoembryonic antigen (CEA) level had increased to 38.6 ng/mL 32 months after surgery, and positron emission tomography-computed tomography (PET-CT) revealed a 2.5-cm, hypermetabolic nodule in the pancreatic body. Using endoscopic ultrasound guided fine-needle aspiration (EUS-FNA), the nodule was pathologically diagnosed as a pancreatic metastasis of lung adenocarcinoma. The EGFR status of the pancreatic metastasis was confirmed to be the same as that of the primary lung tumor. The patient started afatinib therapy and his serum CEA level immediately decreased and remained at approximately the reference limit. On a follow-up PET CT scan after 10 months of treatment with afatinib, the metastatic nodule in the pancreas had disappeared and no accumulation of fluorine-18-deoxyglucose (FDG) was detected. To the best of our knowledge, this is the first reported case of a complete response of pancreatic metastatic lung adenocarcinoma to EGFR-tyrosine kinase inhibitors (TKIs). PMID- 29268430 TI - Hemangioma originating from the main pulmonary artery. AB - In this study, we report the case of a 42-year-old female patient who was diagnosed with hemangioma in the pericardium connected to the main pulmonary artery. Chest CT revealed a hypodense, well-marginated, mass-like lesion, probably connected to the main pulmonary artery, and multiple heterogeneous attenuations were seen with contrast enhancement. The tumor was resected using conventional extracorporeal circulation for complete resection involving the main pulmonary artery wall. Pathologic examination revealed hemangioma. Because main pulmonary originated hemangioma is extremely rare, examination of these cases provides much needed data to further our understanding of this disease. We herein report such a case. PMID- 29268431 TI - Bronchopulmonary infection by Lophomonas blattarum in a pediatric patient after hematopoietic progenitor cell transplantation: first report in Mexico. AB - Lophomonas blattarum is a multiflagellated protozoon which parasitizes the gut of termites and cockroaches. Although L. blattarum infection is rare, it can affect lung, maxillary sinuses and genitourinary tract. The presentation of bronchopulmonary lophomonas includes nonspecific symptoms such as fever, cough and dyspnea. Diagnosis is based on identification of living protozoan forms in fresh samples from respiratory secretions (bronchoalveolar lavage). We report the case of a 2-year-old male with a history of severe combined immunodeficiency (T-, B-, NK-), post-hematopoietic stem cell transplant and full immune reconstitution 12 months following a successful transplant who thereafter presented lophomonas. PMID- 29268432 TI - Bronchial lumen is the safer route for an airway exchange catheter in double lumen tube replacement: preventable complication in airway management for thoracic surgery. AB - There is no current consensus on which lumen an airway exchange catheter (AEC) should be passed through in double-lumen endotracheal tube (DLT) to exchange for a single-lumen endotracheal tube (SLT) after thoracic surgery. We report an unusual case to provide possible solution on this issue. A 71-year-old man with lung adenocarcinoma had an event of a broken exchange catheter used during a DLT replacement with a SLT, after a video-assisted thoracic surgery. The exchange catheter was impinged at the distal tracheal lumen and snapped during manipulation. All three segments of the catheter were retrieved without further airway compromises. Placement of airway tube exchanger into the tracheal lumen of double-lumen tube is a potential contributing factor of the unusual complication. We suggest an exchange catheter be inserted into the bronchial lumen in optimal depth with the adjunct of video laryngoscope, as the safe method for double-lumen tube exchange. PMID- 29268433 TI - Chondroblastoma of the rib in a 47-year-old man: a case report with a systematic review of literature. AB - Chondroblastoma is an uncommon benign bone tumour arising typically in the epiphysis. Few cases of chondroblastoma of the rib have been reported in the literature. We describe a case of chondroblastoma of a 47-year-old man located in the body of the IX right rib. The patient presented a moderate right thoracic pain with an apparently palpable mass. Computed tomography (CT) scan showed a well-defined oval 49 mm * 43 mm lesion with the lytic bone destruction of the rib. A surgical resection was performed with an excellent outcome and no recurrence after 4-year follow-up. We also conducted a systematic review of literature where we evidenced that chondroblastoma could affect people of all age, but it's most common in children and young adult. Surgical resection constitutes the treatment of choice. PMID- 29268435 TI - Professor Hiroyuki Oizumi: how to identify the intersegmental plane. PMID- 29268434 TI - Successful repair of thoracic outlet syndrome in a growing young patient due to posterior sternoclavicular joint dislocation. AB - Posterior sternoclavicular dislocation is an extremely rare injury, usually related to heavy trauma, such as a traffic accident. The anatomical proximity of vital mediastinal structures often discourages a closed reduction during emergency situations. In this case report, we present a 17-year-old male patient who was admitted to our emergency department after having fallen down a flight of stairs five days previously. He was eventually found to have thoracic outlet syndrome. Chest computed tomography (CT) and shoulder magnetic resonance imaging (MRI) showed a posterior dislocation of the right clavicular head with all sternoclavicular joint ligaments ruptured; a hematoma around the clavicular shaft; compression of the right brachiocephalic, subclavian, and internal jugular veins; compression of the brachial plexus; and the right hemopneumothorax. Emergent open reduction with sutures and simultaneous plate stabilization was conducted for the posterior sternoclavicular dislocation, and thoracic outlet syndrome was completely resolved by the seventh postoperative day. The plate was removed six months after the open reduction. Complete range of motion in the shoulder and no pain were achieved without any complications. Unlike other techniques, this technique, using both sutures reduction and simultaneous plate stabilization, will offer excellent results, especially in a growing, young patient. PMID- 29268436 TI - Interview with Prof. Gilbert Massard: multifarious ways to elevate thoracic surgery education. PMID- 29268437 TI - Interview with Team Captains of the postgraduate symposium-Master Cup in the 25th Meeting of the ESTS. PMID- 29268438 TI - Prof. Boris Sepesi: patient-personalized treatment is the best treatment. PMID- 29268439 TI - Interview with Prof. Pier Luigi Filosso during the 25th Meeting of the European Society of Thoracic Surgeons (ESTS). PMID- 29268440 TI - Pre-embedding subcutaneous suture for chest-tube insertion in uniportal video assisted thoracoscopic surgery. PMID- 29268441 TI - Diagnostic implication of fibrin degradation products and D-dimer in aortic dissection-author's reply. PMID- 29268442 TI - The role and potential mechanisms of long non-coding RNA in small cell lung cancer. PMID- 29268443 TI - Esophageal resection after neoadjuvant therapy: understanding the limitations of large database analyses. PMID- 29268444 TI - Tumor spread through air spaces (STAS): a call for more evidence. PMID- 29268445 TI - Robotic-assisted right upper lobectomy: with the further research, robot-assisted thoracic surgery (RATS) will be better in future. PMID- 29268446 TI - Robotic left lower lobectomy: our experience. PMID- 29268447 TI - Robotic-assisted thoracoscopic surgery: cost and lymph node dissection. PMID- 29268448 TI - Robotic-assisted thoracoscopic segmentectomy: there is a long way to go. PMID- 29268449 TI - Robotic thoracic surgery: S1+2 segmentectomy of the left upper lobe: advantage of robotic assisted thoracic surgery. PMID- 29268450 TI - Robotic-assisted McKeown esophagectomy: a safe and reliable method. PMID- 29268451 TI - Erratum to nodal management and upstaging of disease: initial results from the Italian VATS Lobectomy Registry. AB - [This corrects the article DOI: 10.21037/jtd.2017.06.12.]. PMID- 29268452 TI - Natriuretic peptide-guided versus clinically guided therapy for chronic heart failure: careful expert clinical management can remove need for biomarker tailored dosing adjustment. PMID- 29268453 TI - Admitting an elderly patient with solid tumor in the intensive care unit: what do we have to look for? PMID- 29268454 TI - Editorial on "Transcription factor SPZ1 promotes TWIST-mediated epithelial mesenchymal transition and oncogenesis in human liver cancer". PMID- 29268455 TI - The role of sublobar resections in the treatment of early stage non-small cell lung cancer-still awaiting evidence. PMID- 29268456 TI - The step forward for VA ECMO: left ventricular unloading! PMID- 29268457 TI - Central sleep apnea during continuous positive airway pressure therapy in obstructive sleep apnea patients: from the compliance to adaptation, maladaptation and reflexes. PMID- 29268458 TI - Prophylactic cranial irradiation or no prophylactic cranial irradiation in metastatic small cell lung cancer: is it a relevant question once again? PMID- 29268459 TI - Transcriptional programs of tumor infiltrating T-cells provide insight into mechanisms of immune response and new targets for immunotherapy. PMID- 29268460 TI - The new classifications for thymic epithelial tumors: benefits and problems. PMID- 29268461 TI - Complete mediastinal lymph node dissection versus systematic lymph node sampling in surgical treatment of non-small cell lung cancer: do we have the answer? PMID- 29268462 TI - Not like breast cancer, but like breast cancer: micrometastasis and micropapillary structure in lung cancer. PMID- 29268463 TI - Reaping Wnt after calming Hippo: Wnt and Hippo signaling cross paths in lung cancer. PMID- 29268464 TI - Tumor epithelial tumors: do we expect a brighter or a grey future? PMID- 29268465 TI - Emergent central sleep apnea during CPAP therapy-clinical implications. PMID- 29268466 TI - Early stage small cell lung cancer: very rare, but a surgical disease! PMID- 29268467 TI - KEYNOTE-010: flash of a supernova (immune-checkpoint inhibitors) in second-line non-small cell lung cancer. PMID- 29268468 TI - Routine beta-blocker administration following acute myocardial infarction: why still an unsolved issue? PMID- 29268469 TI - Surgical risk models: how they contribute to improvement of our treatments? PMID- 29268470 TI - Tumor-associated macrophages-additional effectors at anti-PD-1/PD-L1 therapy? PMID- 29268471 TI - Do we still need pharmacological stress ulcer prophylaxis at the ICU? PMID- 29268472 TI - Seeing is believing: visualization of pulmonary vein gaps using ultra-high resolution electroanatomic mapping. PMID- 29268473 TI - EGFR tyrosine kinase inhibitors as first-line therapy in advanced EGFR mutation positive non-small cell lung cancer: strategies to improve clinical outcome. PMID- 29268474 TI - Role of the modern radiotherapy in the postoperative setting for esophageal cancer. PMID- 29268475 TI - Pulmonary nodules and mini-invasive lung resection: do we have the right "tool" for their intraoperative localization? PMID- 29268476 TI - Coronary artery disease and myocardial revascularization in patients undergoing transcatheter aortic valve replacement. PMID- 29268477 TI - Percutaneous patent foramen ovale closure for cryptogenic stroke: learning from clinical trial and error. PMID- 29268478 TI - The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy. PMID- 29268479 TI - Surgery compared to stereotactic body radiation therapy for early-stage non-small cell lung cancer: better, equivalent or worse? PMID- 29268480 TI - What is the optimal adjuvant therapy for T3N0 lung cancer invading the chest wall? PMID- 29268481 TI - Timing of invasive strategy in patients with non-ST-segment elevation acute coronary syndrome and effect on clinical outcomes. PMID- 29268482 TI - The role of Piccolo in cancer treatment: relationship with EGFR and related therapies, and a marker for new targeted therapies. PMID- 29268483 TI - Establishing the entity of neonatal acute respiratory distress syndrome. PMID- 29268484 TI - Intratumoral heterogeneity and biomarkers for transformation into small cell lung carcinomas from lung adenocarcinomas. PMID- 29268485 TI - Antithrombotic treatment following transcatheter valve replacement: current considerations. PMID- 29268486 TI - Antithrombotic therapy after transcatheter aortic valve implantation: a new piece of the still unresolved puzzle. PMID- 29268487 TI - Are specialized pro-resolving mediators promising therapeutic agents for severe bronchial asthma? PMID- 29268488 TI - Extracapsular lymph node involvement in patients with esophageal cancer treated with neoadjuvant chemoradiation therapy followed by surgery: the closer you look, the less you see. PMID- 29268489 TI - The extracorporeal membrane oxygenation (ECMO) high-fidelity simulator: the best complementary tool to learn the technique. PMID- 29268490 TI - Looking for sputum biomarkers in lung cancer secondary prevention: where are we now? PMID- 29268491 TI - Role of intrapulmonary lymph node retrieval for pathological examination in resectable non-small cell lung cancer. PMID- 29268492 TI - High-fidelity simulation for extracorporeal membrane oxygenation training, utile or futile? PMID- 29268493 TI - Pathologic N1 disease in lung cancer: the segmental and subsegmental lymph nodes. PMID- 29268494 TI - Vaccine against PCSK9: the natural strategy from passive to active immunization for the prevention of atherosclerosis. PMID- 29268495 TI - Exosomes: recruits for tumour surveillance? PMID- 29268496 TI - Tumor microenvironment as a potential source of clinical biomarkers in non-small cell lung cancer: can we use enemy territory at our advantage? PMID- 29268497 TI - Heparin versus bivalirudin for percutaneous coronary intervention: has the debate come to an end? PMID- 29268498 TI - Sputum-based DNA methylation biomarkers to guide lung cancer screening decisions. PMID- 29268499 TI - Minimally invasive resection and reconstruction of the intrathoracic trachea and carina. PMID- 29268500 TI - The price of innovation: a primer on high risk, high reward surgery. PMID- 29268501 TI - Restrictive ventilatory impairment is associated with poor outcome in patients with cT1aN0M0 peripheral squamous cell carcinoma of the lung. AB - Background: Patients with squamous cell carcinoma (SqCC) of the lung sometimes have a comorbid pulmonary disease such as pulmonary emphysema or an interstitial lung disease (ILD), both of which negatively affect patient outcome. The aim of this study was to determine the outcome of patients in a multicenter database who underwent surgery for cT1aN0M0 peripheral SqCC lung cancer. Methods: The medical records of a total of 228 eligible patients from seven institutions were reviewed to evaluate the impact of concomitant impaired pulmonary function and other clinicopathological factors on overall survival (OS) and relapse-free survival (RFS). Results: Six patients with positive or unclear tumor margins were excluded. Of the 222 remaining study patients, 42 (18.9%) and 97 (43.7%) patients were found to have coexisting restrictive or obstructive ventilatory impairment, respectively. Over a median follow-up period of 30.6 months, the 5-year OS and RFS were 69.0% and 62.6%, respectively. By multivariate analysis, ILDs identified on high-resolution computed tomography (HRCT), pulmonary function test results indicating a restrictive ventilatory impairment, and wedge resection were found to be independent risk factors for poor OS. An increased level of serum squamous cell carcinoma antigen (SCC-Ag) (>1.5 ng/mL) and the same risk factors for poor OS were independent risk factors for recurrence. Among patients who underwent anatomical lung resection (lobectomy and segmentectomy, n=173), a restrictive ventilatory impairment was an independent risk factor for poor OS, and increased serum SCC-Ag level, ILDs on HRCT, and restrictive ventilatory impairment were independent risk factors for poor RFS by multivariate analysis. Factors such as visceral pleural invasion, and lymphatic or vascular invasion were not significantly associated with outcome. Conclusions: A restrictive ventilatory impairment negatively affects the outcome of patients with cT1aN0M0 peripheral SqCC lung cancer. PMID- 29268502 TI - Short and long-term results of sternectomy for sternal tumours. AB - Background: We analyzed our experience in sternal resections (SRs) for primary or secondary neoplasm focusing on technical aspects of reconstruction, post operative outcomes and long term survival. Methods: From January 2005 to December 2015, 36 patients (24 males, 67%) underwent surgical excision of primary (chondrosarcoma n=18 patients, 50%; osteosarcoma n=2, 6%; Ewing sarcoma n=1, 3%; other n=2, 6%) or secondary (breast cancer n=7, 19%; kidney carcinoma n=2, 6%) sternal tumour. We performed n=30 partial sternectomy and n=6 total sternectomy with en-bloc resection of the sternocostal cartilages in all patient and extended resection in 7 patients. Stability was obtained with prosthetic material, rigid and non-rigid and a muscular flap: rigid material [Strasbourg Thoracic Osteosynthesis System (STRATOS), MedXpert GmbH] and muscle flap n=11 (30.6%); polytetrafluoroethylene patch and muscle flap n=6 (16.7%); muscle flap alone n=19 (52.8%). Results: The 30-day mortality rate was 0, overall complication rate was 19%. The median ICU stay was 1.5 days and mean hospital stay was 10.6+/-5.9 days. We obtained a complete (R0) resection in all patients. Overall survival (OS) at 5 and 10 years were 59% and 40%; in the group of primary neoplasm OS rate at 5 and 10 years was 79% and 54%. Disease free survival (DFS) rate at 5 years was 61%. Higher grading was identified as negative prognostic factor. Conclusions: Wide radical resections of anterior chest wall are basilar in a multimodality treatment for primary or metastatic neoplasm of the sternum. Stabilization with titanium bars and clips provides rigidity of chest wall with good functional results. PMID- 29268503 TI - Postoperative pain in thoracic surgery: re-evaluating the benefits of VATS when coupled with epidural analgesia. AB - Background: In order to evaluate the reduced postoperative pain of complete video assisted thoracoscopic surgery (cVATS), a study was conducted to compare acute postoperative pain between cVATS and open thoracotomy employing continuous epidural analgesia (EA). Methods: A total of 62 patients, 49 males and 13 females with a mean age of 54.8 years, who had undergone thoracic surgery at our institution from November 2013 to June 2015 were enrolled in this study. We statistically investigated differences in the intensity of postoperative pain between cVATS with or without EA and between cVATS and open thoracotomy under EA. The degree of pain was measured using a visual analog scale, nine times for three days after the surgery. Results: The mean postoperative pain scores were stronger in the cVATS without EA group than in the group treated with EA at every single observation point, although there were no significant differences. When employing EA, no significant differences were found between cVATS and open thoracotomy. Conclusions: The use of EA may overshadow the benefits of using cVATS over open thoracotomy. PMID- 29268504 TI - The methylation state of VDR gene in pulmonary tuberculosis patients. AB - Background: Our previous study suggested that the methylation of vitamin D receptor (VDR) gene affected its expression and the defense against tuberculosis (TB) infection in vitro. In this study, we further investigated the methylation level of VDR gene in pulmonary TB patients. Methods: The consecutive TB patients who were admitted into our department from January 2013 to January 2015 were recruited. The potential methylation sites analyzed in this study included 16 CpG sites. The amplification of bisulfite modified genomic DNA was ligated to pUC18-T vector and the positive clone of blue-white selection was sequenced to analyze the methylation state of VDR gene. Results: This study had samples of 27 TB patients and 30 healthy controls. TB patients were in the hyper-methylation state compared to the healthy controls. The significant differences between TB patients and healthy controls were detected in 7 of these 16 CpG sites. The mRNA expression of AKT, GSK3betaand FOXO1 decreased in TB patients compared to that of healthy controls. Conclusions: Our study contributes to supplying more evidences that the methylation level of VDR gene affects the progression of TB. PMID- 29268505 TI - Long-term survival after surgery for pulmonary metastases from colorectal cancer: an observational cohort study. AB - Background: Evidence for pulmonary metastasectomy following colorectal cancer (CRC) is scarce. The aim of the study was to investigate long-term survival and identify prognostic factors to aid patient selection. Methods: We included all patients who underwent pulmonary resections for CRC metastases between January 01, 2004 and December 31, 2015 in a population-based cohort study. The primary outcome measure was all-cause mortality and was ascertained from Swedish national registers. The Kaplan-Meier estimator was used to calculate cumulative survival. We used Cox regression for estimation of hazard ratios (HR) and 95% confidence intervals (CI) for the association between patient characteristics and survival. Results: We included 184 patients. The number of procedures per year increased from 1 in 2004 to 34 in 2015. During a median follow-up time of 3.2 years, 36% (66/184) patients died. Overall survival at 5 years was 60% (95% CI: 50-68%) and was significantly lower compared to an age- and gender-matched Swedish population. Carcinoembryonic antigen (CEA) level was identified as a prognostic factor for mortality in the age and sex-adjusted analysis (HR, 2.46; 95% CI: 1.15 5.26, P=0.020). Conclusions: We found a steady increase in the number of pulmonary metastasectomies after CRC during the study period. We identified prethoracotomy CEA level as a prognostic factor for long-term survival, which was consistent with prior reports. The 5-year overall survival rate in our study was 60%, which was high in comparison with prior reports. Although our results indicated that current patient selection criteria were reasonable, definitive evidence of efficacy is pending. PMID- 29268506 TI - A meta-analysis of late outcomes of mitral valve repair in patients with rheumatic heart disease. AB - Background: Rheumatic heart disease (RHD) is a predominant health concern in developing countries. The aim of this meta-analysis was to evaluate the outcomes of mitral valve (MV) repair in patients with RHD, and identify predictors that may postoperatively affect treatment outcome. Methods: A meta-analysis of eligible studies assessing patients undergoing MV repair with RHD and reporting the outcomes of MV repair, including 30-day mortality and long-term follow-up survival, MV reoperation rate and postoperative adverse events. Relevant English articles were searched up to 1 March, 2017 in Web of Science, PubMed, Google Scholar, Cochrane Library, EmBase, Elsevier, and Science Direct. Selected studies should meet all inclusion criteria, and underwent data extraction. Results: A total of ten studies with 2,770 patients met all inclusion criteria, and were selected for assessment. Pooled analysis showed that 30-day mortality in patients with rheumatic MV disease after MV repair surgery was 1.9%, 95% confidence interval (CI) (0.8-2.9%); long-term survival was 97.3%, 95% CI (95.9-98.6%), and a freedom from reoperation rate of 93.6%, 95% CI (91.4-95.9%) was obtained; freedom from adverse events was 97.5%, 95% CI (95.2-99.8%). Conclusions: The outcome of rheumatic MV repair is outstanding in terms of low early mortality, high long-term survival and freedom from valve-related complications, which may be very common in patients after rheumatic MV replacement; meanwhile, MV reoperation rate after initial surgery is acceptable. Surgeons may try to repair MV in RHD when it is feasible. PMID- 29268507 TI - Doxycycline attenuates paraquat-induced pulmonary fibrosis by downregulating the TGF-beta signaling pathway. AB - Background: Paraquat (PQ) is a highly efficient herbicide that remains widely used in agriculture. However, the inappropriate application of this herbicide may cause multiple organ injuries including pulmonary injury. In this study, we report that doxycycline (Doxy) treats PQ-induced pulmonary fibrosis (PF). Methods: Mice with PQ-induced PF were treated with different doses of Doxy by intragastric administration. Human lung cancer cell line A549 pre-treated with TGF-beta1 (5 ng/mL) were treated with Doxy hydrochloride (3.4 uM). Results: PF was observed from day 28 in PQ-treated group and Doxy treatments significantly reduced pulmonary coefficient, histopathological score and collagen content in a dose-dependent manner. Doxy can inhibit the expression levels of plasma inflammation cytokines at day 28 after modeling and reduced inflammatory response at early stage of PQ-induced lung injury. Immunohistochemical staining assay and proteomic analysis indicated that Doxy could restore ectopic epithelial mesenchymal transition (EMT) induced by PQ-treatment by regulating numerous TGF beta signaling related proteins. Conclusions: The findings suggest that Doxy can restore the balance of epithelial-mesenchymal cells and attenuate PQ-induced PF by downregulating the TGF-beta signaling pathway. PMID- 29268508 TI - Volume doubling time of lung adenocarcinomas considering epidermal growth factor receptor mutation status of exon 19 and 21: three-dimensional volumetric evaluation. AB - Background: The current study was to investigate the volume doubling time (VDT) of lung adenocarcinomas considering epidermal growth factor receptor (EGFR) mutation status of exon 19 and 21, when compared with EGFR wide type. Methods: Eighty-eight patients with pathologically proven adenocarcinomas, which underwent two or more computed tomography (CT) scans spared by 25 or more days, were included. EGFR mutations at exons 19 and 21 were determined using amplification refractory mutation system and all patients were divided into three groups-EGFR wide type group, EGFR mutation in exon 19 and 21 groups. Three-dimensional manual segmentations for all tumors were performed on first and latest follow-up CT scans; subsequently, VDTs were calculated and compared among three groups. Clinicopathoradiologic characters were also collected for subgroup analysis. Results: EGFR mutations occurred in 49 (55.7%) patients, 19 in exon 19 and 30 in exon 21, respectively. The median VDT of all patients (33 men, 55 women; median age, 62 years) was 214 days (range, -4,092 to 10,920 days). Highly differentiated adenocarcinomas (median, 408 days) demonstrated longer VDT than those moderately (median, 172 days) or poorly (median, 144 days) differentiated (P=0.04). The VDT distribution was similar among EGFR wide type group (median, 207 days), EGFR mutation in exon 19 group (median, 288 days) and exon 21 group (median, 144 days) (P=0.21). In subgroup analysis, the median VDT of adenocarcinomas with EGFR mutation in exon 19 was longer than that of EGFR wide type for males (P=0.03) or patients without spiculation sign in chest CT (P=0.04). Totally 24 adenocarcinomas presented negative VDTs, most of which tended to be stable. Positive VDT values were used for all median description. Conclusions: Overall VDT of lung adenocarcinomas seems not affected by EGFR mutation status. Researches with large population are warranted for further study. PMID- 29268509 TI - Urban particulate matter triggers lung inflammation via the ROS-MAPK-NF-kappaB signaling pathway. AB - Background: Particulate matter (PM) is a high risk factor for various respiratory diseases and triggers an inflammatory response in lung tissues. However, the molecular mechanism of the PM-induced inflammatory response is incompletely understood. Methods: Human bronchial epithelial cells (HBECs) were treated with the urban PM 1649b for assessment of the inflammatory response. The intracellular level of reactive oxygen species (ROS) was measured by flow cytometry. PM activated signaling pathways were addressed with specific inhibitors. In vivo, the C57 mice model of PM-induced acute lung inflammation was established with intratracheal instillation of PM for 2 consecutive days. The oxidant stress in lung tissues was assessed with dihydroethidium (DHE) staining, and malondialdehyde (MDA) activity and hydrogen peroxide (H2O2) assays. The histopathologic changes in lung tissues and number of inflammatory cells in bronchoalveolar lavage fluid (BALF) were examined. Expression of pro-inflammatory cytokines in BALF was measured by ELISA. Results: PM increased the expression of interleukin (IL)-1beta, IL-6, IL-8, matrix metalloproteinase (MMP)-9 and cyclooxygenase (COX)-2 in a dose-dependent manner. ROS generation and activation of MAPK (ERK, JNK, p38 MAPK) and NF-kappaB pathways were detected in PM-exposed HBECs. Pretreatment with N-acetylcysteine (NAC) led to the inflammatory response, ROS level and activation of the MAPK and NF-kappaB pathways to be attenuated. Blockade of ERK, JNK or p38 MAPK pathway with specific inhibitor prevented the release of pro-inflammatory cytokines and activation of the NF-kappaB pathway. Inhibition of the NF-kappaB pathway reduced the expression of pro-inflammatory cytokines. In vivo, PM exposure increased oxidant stress in lung tissues, infiltration of inflammatory cells around PM in lung tissues, the number of total cells and inflammatory cells in BALF, and the concentrations of IL-1beta, IL-6, IL-8 and MMP-9 in BALF, all of which were reversed partially upon NAC treatment. Conclusions: PM exposure enhanced the airway inflammatory response significantly through ROS-mediated activation of MAPK (ERK, JNK, p38 MAPK) and downstream NF kappaB signaling pathways. Oxidative stress appeared to be the key regulator for PM-induced lung inflammation. These results suggested the molecular mechanism of lung inflammation caused by PM. PMID- 29268510 TI - Clinical implications of differentiating between types of post-tracheostomy tracheal stenosis. AB - Background: Post-tracheostomy tracheal stenosis (PTTS) can be divided into four types according to stenosis mechanism and site: subglottic, stoma, cuff, and tip granuloma. However, there is little information available regarding clinical differences among types of PTTS; therefore, we evaluated the clinical differences between these types. Methods: We retrospectively evaluated 99 PTTS patients who underwent interventional bronchoscopy between 2004 and 2014. Patients were divided into two groups according to pathophysiological similarities as follows: subglottic or stoma type (n=59) and cuff or tip type (n=40). Results: There were no differences in baseline characteristics between groups. However, silicone stents were more frequently needed in patients with subglottic or stoma type stenosis (76%) than those with cuff or tip type stenosis (55%, P=0.031) to maintain airway patency. On the contrary, permanent tracheostomy was more frequently performed in patients with cuff or tip type stenosis (50%) than those with subglottic or stoma type stenosis (19%, P=0.002). Finally, successful removal of the tracheostomy tube without surgery and procedure- or disease related mortality were more frequently achieved in patients with subglottic or stoma type stenosis (71%) than those with cuff or tip type stenosis (45%, P=0.012). Conclusions: Although there were no significant differences in baseline characteristics between PTTS types, patients with subglottic or stoma type stenosis had more favorable outcomes than those with cuff or tip type stenosis. Therefore, it could be important to distinguish between types of PTTS when assessing prognosis. PMID- 29268511 TI - Replacement of calcified ascending aorta in patients undergoing aortic valve replacement. AB - Background: Aortic stenosis (AS) with an extensively calcified ascending aorta is a growing indication for transcatheter aortic valve implantation (TAVI) because aortic manipulation during surgical aortic valve replacement (AVR) is unsafe in these patients. The aim of this study was to evaluate the outcomes of AVR plus ascending aorta replacement (AAR) in patients with severe AS and a heavily calcified ascending aorta. Methods: From 2004 to 2014, a total of 32 patients with severe AS and extensive aortic calcification underwent concomitant first time AVR and AAR (AVR + AAR). The mean patient age was 74+/-7 (range, 59-87) years, and 7 (22%) patients were octogenarians. The mean logistic EuroSCORE was 21.4%+/-19.0% (range, 3.3-68.2%). Arterial cannulae were placed at the ascending aorta (n=26, 81%), aortic arch (n=5, 16%), or axillary artery (n=1, 3%). The aorta was not clamped, and circulatory arrest was used in all patients. One-to many (1:n) propensity score matching between the study population (AVR + AAR, n=29) and control group (isolated AVR for severe AS, n=433) was performed. Results: There was no early mortality in the study population. Postoperative neurologic complications included a minor stroke, which resolved without sequelae at discharge, and a transient ischemic attack. The 5-year survival rate was 83%+/ 9%. In the propensity score-matched comparison, 5-year survival was not significantly different between groups; 81%+/-10% in the AVR + AAR group vs. 87%+/-2% in the isolated AVR group (P=0.950). Conclusions: Surgical AVR with AAR in AS patients with calcified ascending aortas led to acceptable early and late outcomes. Although the applications for TAVI are growing, a surgical approach may be an alternative option for relatively younger patients with severely calcified aorta. PMID- 29268512 TI - Comprehensive investigation of clinicopathologic features, oncogenic driver mutations and immunohistochemical markers in peripheral lung squamous cell carcinoma. AB - Background: Although the majority of lung squamous cell carcinomas (SQCC) arise in central airways, the prevalence of peripheral (p) SQCC is increasing. This study aimed to have a comprehensive investigation of clinicopathologic features, status of common driver mutations and immunophenotypes of p-SQCC compared to central (c) SQCC. Methods: A total of 261 p-SQCC were compared to 444 c-SQCC for clinicopathologic characteristics. Comprehensive mutational analysis of EGFR, KRAS, HER2, BRAF, PIK3CA, DDR2, AKT1, ALK, ROS1, RET and FGFRs were performed. TTF1, CK7, Napsin A and PE10 protein expression were analyzed through immunohistochemistry (IHC). TTF1, CK7, CK8, SPA and TP63 gene expression levels were measured by quantitative real-time PCR. Results: Compared to c-SQCC, p-SQCC were associated with female (14.2% vs. 4.5%, P<0.001), never-smokers (22.6% vs. 13.3%, P=0.001), older age at diagnosis (64.9 vs. 59.5 years, P<0.001) and lower pathologic stage (P<0.001). The frequency of EGFR mutations was significantly higher in p-SQCC than c-SQCC (6.2% vs. 2.2%, P=0.040). Positive protein expression of TTF1 (P=0.010) and CK7 (P=0.001) was significantly more prevalent in p-SQCC. p-SQCC had significantly higher gene expression of SPA (P=0.003), whereas c-SQCC showed higher gene expression of TP63 (P=0.028). Conclusions: Lung p-SQCC had distinctive clinicopathologic characteristics and molecular features compared to c-SQCC, but showed some similarity with adenocarcinoma (ADC). PMID- 29268513 TI - The impact of extreme obesity on outcomes after left ventricular assist device implantation. AB - Background: The association between extreme body mass index (BMI) and outcomes in left ventricular assist device (LVAD) patients has not been well established. With the commercial use of LVADs a larger number of patients with a BMI >40 have undergone device implantation. The purpose of this study was to evaluate the short and long-term outcomes of LVAD patients with extreme obesity. Methods: A retrospective review of all patients (n=383) at our center who received a LVAD as primary implant between 2005-2015 was performed. Demographics, preoperative laboratory values, and postoperative outcomes were analyzed. Patients were divided into three groups based on BMI (kg/m2) classification (group 1: <=25; group 2: 25 to 35; group 3: >=35) and compared using one-way analysis of variance (ANOVA), Kruskal-Wallis and Chi-squared analysis as appropriate. Results: Comparison of postoperative outcomes demonstrated an increased risk of respiratory failure and right ventricular (RV) failure in patients with a BMI >=35 (range, 35-59). Length of stay, sternal infection, driveline/pocket infection, systemic infection, GI-bleeding, and neurological events within the first year of device therapy were not related to BMI. Survival at 30-day, 1- and 2-year was not significantly different among the three groups. The group with the smallest BMI demonstrated an increased risk for re-operative bleeding. Conclusions: Despite an increased risk of early morbidity in patients with extreme obesity, long term survival was not significantly different between the BMI groups. Careful consideration is recommended when evaluating patients with an excessive BMI for LVAD therapy although it should not be a contraindication for device placement. PMID- 29268514 TI - Pneumonectomy is safe and effective for non-small cell lung cancer following induction therapy. AB - Background: Uncertainty surrounds the safety and efficacy of pneumonectomy in the setting of induction chemoradiation for non-small cell lung cancer (NSCLC). We sought to evaluate fifteen years of experience with pneumonectomy with and without induction therapy. Methods: Over a 15-year period [1999-2014], data were extracted from medical records of patients undergoing pneumonectomy for NSCLC. Primary outcomes were 5-year overall survival and mortality at 30, 60 and 90 days following operation. Morbidity data was also reviewed. Statistical comparisons were performed using the Chi-Square test. Kaplan-Meier curves were compared using the log rank test. Significance was defined as a P value less than 0.05. Patients with a prior cancer history, bilateral lung nodules and oligometastatic disease at presentation were excluded. Results: After exclusion criteria were applied, 240 patients were analyzed and 137 (57%) underwent induction therapy prior to pneumonectomy. Five-year overall survival was 38.5%. Mortality at 90 days was 7.94%. There was no statistically significant difference in perioperative mortality with the addition of induction therapy. In fact, in the subset of patients with N2 disease (n=65), induction therapy was associated with improved 5 year overall survival (10.7% vs. 32.7%, P=0.014). Thirty-five percent of patients with N2 disease exhibited a complete response in the nodal basin following induction therapy; however, this did not confer a statistically significant overall or disease-free survival benefit. Conclusions: Pneumonectomy can safely be performed in the setting of induction chemoradiation. In patients with N2 disease, induction therapy may confer a survival benefit when the surgery can be done with limited morbidity and mortality. PMID- 29268515 TI - Impact of major video-assisted thoracoscopic surgery on care quality. AB - Background: The objective of this study was to investigate the impact of a program of major video-assisted surgery on care quality in a Unit of Thoracic Surgery. Methods: A descriptive comparative study was conducted of 793 major thoracic procedures performed between 2009 and 2012. Quality indicators and hospital performance before [2009-2010] and after (2011 and 2012) the implementation of the program. Results: The incidence of surgical complications decreased significantly from 6.32%/7.88% (2009/2010, respectively) to 1.87%/1.67% (2011/2012, respectively) [95% CI for 7.08% (4.20-9.96%); 95% CI for 1.76% (0.44 3.08%) P<0.001, respectively]. The mean hospital stay was reduced from 8.5/7.8 days in 2009/2010, respectively, to 6.3/5.8 days in 2011/2012, respectively. Mortality rates were 0.57%, 0.60%, 0.93% and 0.43% in 2009, 2010, 2011, and 2012, respectively (P=0.624, 95% CI: -0.6, 0.7). The percentages of emergency readmissions in 2009/2010 were 1.16%/1.23%, respectively vs. 2.80%/0.84% in 2011/2012. Conclusions: The implementation of the video-assisted thoracic surgery (VATS) program in the unit of Thoracic Surgery Care resulted in a significant improvement in care quality, with a reduction of length of hospital stay, but without any changes in mortality or the percentage of readmissions at 30 post operative days. PMID- 29268516 TI - Prognostic significance and role in TNM stage of tumor deposits in esophageal cancer. AB - Background: Tumor deposits (TDs) are now observed in esophageal cancer (EC), but the role of TDs is seldom elucidated. This study aimed to research the prognostic significance and the role of TDs in EC. The patients with primary EC, who had undergone curative esophagectomy in West China Hospital from May 2005 to May 2011 were retrospectively enrolled. Methods: The prognosis and clinicopathological traits were compared between tumor deposits positive (TDP) and tumor deposits negative (TDN) groups in all patients and TNM 0-IV stages respectively. Results: In our study, 1,044 patients were enrolled, with 948 (90.8%) in TDN group and 96 (9.2%) in TDP group. TDP group had significantly more advanced EC and worse prognosis (all P<0.001) than TDN group in all patients, TNM II stage and TNM III stage. The prognosis of TDP group in TNM II stage was significantly worse than TDN patients in TNM III stage (P<0.001), and the worst prognosis was always found in patients with at least one TD regardless of the number of metastatic lymph node is. Conclusions: Patients in TDP subgroup had more advanced EC and worse prognosis than those in TDN subgroup. It might be more reasonable to be regarded as an indicator of stage migration in EC. PMID- 29268517 TI - Post-traumatic acute thoracic aortic injury (TAI)-a single center experience. AB - Background: We assess the effectiveness and our experience in emergency thoracic endovascular aortic repair (TEVAR) in patients with post-traumatic acute thoracic aortic injury (TAI) and associated multiorgan trauma. TAI is a life-threatening condition. It usually results from a sudden deceleration caused by vehicle accident, a fall or some other misfortune. Techniques of endovascular aortic repair have become promising methods to treat emergent TAI. Methods: Since 2007, 114 patients with thoracic aorta pathologies have been treated by TEVAR. Our study involved 15 (incl. 14 men) of them (13%) who underwent stent graft implantation for post-traumatic either aortic rupture or pseudoaneurysm. The procedural access was limited to small skin incision in one groin and percutaneous puncture of the contralateral femoral artery. We evaluated technical success, early and long-term mortality, complication rate of procedure and throughout clinical and instrumental follow-up. Results: Technical success rate was 100%. All patients survived the endovascular interventions. No additional procedures or conversions to open surgery were necessary. After the operation, none of the patients had symptoms of stroke or spinal cord ischemia (SCI). No serious stent-graft-related adverse events such as endoleak, infection or migration were noted during follow-up period that ranged from 6 to 108 months. Conclusions: In our department, techniques of TEVAR with stentgraft implantation have become methods of choice in treatment of traumatic TAIs since they have enabled to minimize operational risk, particularly in unstable multitrauma patients in severe clinical status. TEVAR for TAI performed in emergency settings provide favorable long-term results. PMID- 29268518 TI - Short-term inpatient-based high-intensive pulmonary rehabilitation for lung cancer patients: is it feasible and effective? AB - Background: This study was conducted to develop a preoperative in-hospital short term rehabilitation program for surgical lung cancer patients, and investigate its feasibility, potential cost benefit and effectiveness on outcome measures including reduction of postoperative pulmonary complications (PPCs) and postoperative length of stay. Methods: A 7-day inpatient-based high-intensive rehabilitation regimen was performed between March 01, 2014 and June 30, 2015. It was combined with inspiratory muscles training (IMT) and aerobic endurance training and was tested in an enriched cohort study with 939 lung cancer patients undergoing lobectomy in a regional thoracic unit. Results: Finally, 939 patients were divided into pulmonary rehabilitation (PR) group (n=197) and non-PR (NPR) group (n=742), according to whether they received the 7-day preoperative in hospital systematic rehabilitation. The PR group had a shorter total length of stay (14.7+/-4.0 vs. 16.7+/-6.2 days, P<0.001) as well as postoperative length of stay (6.2+/-3.3 vs. 8.3+/-5.6 days, P<0.001) than the NPR group. Lower incidences of total PPCs (18.3%, 36/197 vs. 26.1%, 194/742, P=0.022), pneumonia (11.2%, 22/197 vs. 17.3%, 128/742, P=0.024) and atelectasis (6.6%, 13/197 vs. 12.3%, 91/742, P=0.038) were found in the PR group compared with NPR group. Meanwhile, a multivariable analysis of risk to PPCs, atelectasis and pneumonia, revealed that the PR intervention was the independent risk factor of the occurrence of the PPCs (OR =0.57, 95% CI: 0.47 to 0.93, P=0.033) and atelectasis (OR =0.49, 95% CI: 0.26 to 0.91, P=0.024). Conclusions: The study showed the effectiveness of this systematic and high-intensive PR combining IMT and aerobic exercise in reductions of the length of stay and occurrence of PPCs without increase in in-hospital cost, suggesting the potential of this rehabilitation pattern as a practicable strategy performed preoperatively in surgical lung cancer patients. PMID- 29268519 TI - Spontaneous ventilation anesthesia combined with uniportal and tubeless thoracoscopic lung biopsy in selected patients with interstitial lung diseases. AB - Background: The current guidelines emphasize the significant role of video assisted thoracic surgical lung biopsy (VATS-LB) for a definite diagnosis of interstitial lung diseases (ILD), but they also encourage physicians to maintain the balance between the surgical benefits as well as risks. Both spontaneous ventilation video-assisted thoracic surgery (VATS) and uniportal VATS have emerged as remarkable progresses in VATS. We combined these two types of VATS and refined them to uniportal spontaneous ventilation VATS without urinary catheterization and chest tube drainage [uniportal and tubeless VATS (UT-VATS)] to perform LB in selected patients with ILD. Methods: From January 2014 to May 2015, 43 patients were included in the study. The surgical data was retrospectively analyzed. Results: The mean diffusion capacity for carbon monoxide (DLCO) of patients was 57.6%+/-13.0%, forced vital capacity (FVC) was 73.1%+/-17.0%. There was no 30-day mortality. No patient required a switch to intubated anesthesia. The mean age was 49.6+/-10.7 years. The general median operative duration was 22+/-5 minutes, with 25+/-3 minutes for multiple specimens and 15+/-2 minutes for single specimen, respectively. Intra-operative conversion to 2-portal VATS followed by chest tube drainage and urinary catheterization occurred in 3 (7.0%) patients due to extensive pleural adhesion, and postoperative chest tube insertion was documented in 1 (2.3%) patient due to subcutaneous emphysema. No postoperative mechanical ventilation was noted. Precise histopathological diagnosis was achieved in 38 (88.4%) patients. Conclusions: Uniportal and tubeless thoracoscopic LB using spontaneous ventilation anesthesia can be considered a feasible and safe operation method for selected patients with ILD. PMID- 29268520 TI - Rhinovirus is associated with severe adult community-acquired pneumonia in China. AB - Background: Human rhinovirus (HRV) is one of the most common viral etiologies detected in community-acquired pneumonia (CAP) adult cases. However, few is known about the characteristics of HRV-associated CAP. To describe the clinical features of HRV-associated CAP in immunocompetent adults admitted to multiple medical centers in mainland China over a 2-year period. Methods: A total of 383 patients admitted to hospitals for CAP were enrolled from 46 medical centers in mainland China between January 2013 and December 2014. Multiplex real-time polymerase chain reaction (RT-PCR) assays for viral detection and DNA-based quantitative loop-mediated isothermal amplification (qLAMP) assays for bacterial detection were implemented to all lower respiratory tract specimens obtained from the patients. Twenty-eight cases (28/383, 7.3%) revealed HRV-positive PCR results. Patients with bronchoalveolar lavage (BAL) HRV-positive PCR results (n=20) were further enrolled and divided into two groups depending on the status of bacterial co-infection (viral group, n=12; viral-Bacterial group, n=8). Demographic, clinical and microbiological data were reviewed and compared in detail. Results: Cases with HRV-infection were remarkably correlated with respiratory failure (14/20) and most of them (13/14) received mechanical ventilation. Fever (17/20), productive cough (15/20) and dyspnea (6/20) were common symptoms while flu-like symptoms were rarely observed in the cohort. Streptococcus pneumoniae (3/8), Klebsiella pneumoniae (3/8) and Mycoplasma pneumoniae (2/8) were most frequently identified bacterium in the viral-bacterial group. Compared with the viral group, higher incidence of septic shock (3/8 vs. 1/12, P=0.255), longer ICU length of stay (LOS) (10.0 vs. 6.5 days, P=0.686), longer hospital LOS (18.5 vs. 13.0 days, P=0.208) and higher 28-day mortality (2/8 vs. 2/12, P=1) were observed in the Viral-Bacterial group, although without statistically significant difference. Conclusions: HRV is a common etiology in CAP among China adults, especially in severe CAP. Clinicians should be vigilant considering of the poor outcome. Highly qualified multiplex PCR techniques with invasive sampling are needed to increase the detection rate. PMID- 29268522 TI - Pneumonectomy in pulmonary metastasis. AB - Background: The risk of complication following pneumonectomy is high; therefore, the decision to perform pneumonectomy should be carefully evaluated. A retrospective multicenter study of patients with metastatic lung tumors who underwent pneumonectomy was conducted. Methods: The database from the Metastatic Lung Tumor Study Group of Japan was retrospectively reviewed. Between 1984 and 2013, 4,742 patients underwent pulmonary metastasectomy. Of the 4,742 patients, 55 patients (1.16%) who underwent pneumonectomy were analyzed, and their survival parameters and prognostic factors were evaluated. Results: Of the 55 patients who underwent pneumonectomy, 34 patients were male and 21 patients were female. The primary tumor sites were colorectal in 28 patients, head and neck in 12 patients, bone in three patients, bladder in three patients, and other regions in nine patients (breast, uterus, liver, soft tissues in two patients, respectively, and pancreas in one patient). The overall 5-year survival rate of patients following pneumonectomy was 28.9%. The rate was significantly lower than that of patients who underwent other metastasectomy which had an overall 5-year survival rate of 53.4% (P<0.001). There were 3 hospital mortalities (3/55, 5.45%). Univariate analysis revealed that patients 55 years old or older (P=0.016) and patients who had lymph node metastasis (P=0.032) were significant predictors of poor prognosis. Multivariate analysis indicated that the age group 55 years old or older was an independent prognostic factor (P=0.040). Conclusions: The indication of pneumonectomy should be carefully reviewed, especially for patients 55 years old or older, however characteristics of each primary organ should also be considered. PMID- 29268521 TI - Stereotactic body radiotherapy (SBRT) for pulmonary metastases from renal cell carcinoma-a multicenter analysis of the German working group "Stereotactic Radiotherapy". AB - Background: Renal cell carcinoma (RCC) is traditionally considered to be radioresistant. Radiotherapy response rates are believed to improve with hypofractionated, high dose stereotactic body radiotherapy (SBRT). However, limited data exist regarding the role of SBRT in the treatment of pulmonary metastases. Methods: The working group "Stereotactic Radiotherapy" of the German Society of Radiation Oncology analyzed its multi-institutional database of more than 700 patients who received SBRT for pulmonary metastases. Treatment was performed at 10 centers between 2001 and 2016. Patients with metastatic RCC were included in the study. Tumor characteristics, treatment details, and follow-up data including survival, local control (LC), distant metastases, and toxicity were evaluated. Results: A total of 46 RCC patients treated with SBRT for 67 lung metastases were identified, who received a median total biologically effective dose (BEDiso) at planning target volume (PTV) isocenter of 117.0 Gy (range, 48.0 189.0 Gy). A median fractional dose of 20.8 Gy at isocenter (range, 6.0-37.9 Gy) was administered in a median number of 3 fractions (1-8 fractions). After a median follow-up time of 28.3 months for all patients, 1- and 3-year LC rates were 98.1% and 91.9%, with corresponding 1- and 3-year overall survival (OS) of 84.3% and 43.8%, respectively. Pulmonary metastases treated with BEDiso >=130 Gy showed a trend for superior LC (P=0.054). OS was significantly improved in both uni- and multivariate analysis for patients with higher Karnofsky performance scale, lower maximum pulmonary metastasis diameter and lack of post-SBRT systemic therapy due to progression (P=0.014; P=0.049; P=0.006). Only mild acute and late toxicity was reported. Conclusions: SBRT for pulmonary metastases from RCC was associated with low treatment-associated toxicity, promising survival, and excellent LC, especially in those patients receiving a BEDiso >=130 Gy. PMID- 29268523 TI - Characteristics of coronary microcirculatory function in patients with Takotsubo syndrome. AB - Background: Takotsubo syndrome (TS) is a recently described cardiac syndrome whose pathogenesis is still unclear. We investigated the characteristics of coronary microcirculatory function in patients with TS through the analysis of the TIMI frame count (TFC) compared to normal subjects and with to subjects with microvascular angina (MA). Methods: We enrolled 71 TS patients (F:M =69:2, mean age of 65.27+/-9.53 years), 70 controls (F:M =34:36, mean age of 56.63+/-13.5 years) and 71 patients with MA, (F:M =69:2, mean age of 65.9+/-9.2 years). The assessment of the microcirculation was carried out through the TFC. Results: microcirculation was significantly altered in patients with TS compared with healthy controls [left anterior descending coronary artery (LAD) 25.16+/-6.91 vs. 17.30+/-3.76, P<0.001; circumflex artery (CX) 25.48+/-6.10 vs. 17.05+/-4.60, P<0.001; right coronary artery (RCA) 26.43+/-8.95 vs. 15.74+/-4.27, P<0.001, average TFC in TS 25.70+/-5.34 vs. 16,70+/-3.26, P<0.001). A TFC >20 frames was able to discriminate TS patients from controls with a specificity of 88.57% and sensitivity of 85.92% (AUC 0.927, P<0.0001). Microvascular dysfunction was diffuse in TS as well as in MA and slightly more severe in this last (mean TFC in MA 28.25+/-9.3 vs. 25.7+/-5.34 in TS, P<0.046). Conclusions: Coronary microcirculation in TS patients is diffuse and milder compared to MA patients. Cut-off values >20 frames discriminate between patients with normal microcirculation and patients with TS. PMID- 29268524 TI - Reference values for spirometry in Chinese aged 4-80 years. AB - Background: Although there are over 1.34 billion Chinese in the world, nationwide spirometric reference values for Chinese are unavailable, which is usually based on Caucasian conversion. The aim of this study was to establish spirometric reference values for Chinese with a national wide sample. Methods: We enrolled healthy non-smokers in 24 centers in Northeast, North, Northwest, Southwest, South, East and Central China from January 2007 to June 2010. Spirometry was performed according to American Thoracic Society and European Respiratory Society guidelines. Reference equations were established using the Lambda-Mu-Sigma (LMS) method for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF) and maximal midexpiratory flow (MMEF). Popular Caucasian reference values adjusted with ethnic conversion factors were validated with Chinese measured spirometry data. The present study also compared with other published Chinese equations for spirometry. Results: A total of 7,115 eligible individuals aged 4 to 80 years (50.9% females) were recruited. Reference equations against age and height by gender were established, including predicted values and lower limits of normal (LLNs). Validated with Chinese data, the mean percentage differences of Caucasian reference values adjusted with ethnic conversion factors were -10.2% to 1.8%, and the percentages of total subjects under LLNs were 0.1% to 8.9%. Compared with this study, the percentage differences of previous Chinese studies ranged from -17.8% to 11.4%, which were found to significantly overestimate or underestimate lung function. Conclusions: This study established new reference values for better interpretation of spirometry in Chinese aged 4 to 80 years, while Caucasian references with adjustment were inappropriate for Chinese. PMID- 29268525 TI - Elevated pretreatment serum lactate dehydrogenase level predicts inferior overall survival and disease-free survival after resection of thymic carcinoma. AB - Background: The prognostic significance of serum lactate dehydrogenase (LDH) level in thymic carcinoma (TC) remains unclear. Therefore, we evaluated the role of pretreatment serum LDH level in the prognosis for TC in this study. Methods: Sixty consecutive surgical patients were analyzed in this study with pathologic confirmed TC in Sun Yat-sen University Cancer Center from June 1996 to June 2014. Results: The cut-off value of LDH was 210.50 IU/L. In both univariate analysis and multivariable analysis, only pretreatment serum LDH level (P=0.027) and pathological Masaoka stage (P=0.041) were associated with overall survival (OS). In univariate analysis, pretreatment serum LDH level, tumor size, postoperative radiotherapy (PORT) and pathological Masaoka stage were associated with disease free survival (DFS) (all P<0.050). Multivariable analysis showed that LDH level (P=0.001), PORT (P=0.001) and pathological Masaoka stage (P=0.038) were independently prognostic factors of DFS. This study also revealed that male patients and larger tumor size had a significantly higher rate of elevated pretreatment serum LDH level than in the other groups. Conclusions: In conclusion, pretreatment serum LDH level was an independent prognosis factor of OS and DFS for patients with TC. PMID- 29268526 TI - Long-term outcomes of stage I NSCLC (<=3 cm) patients following segmentectomy are equivalent to lobectomy under analogous extent of lymph node removal: a PSM based analysis. AB - Background: Segmentectomy has the advantage of less complications, but might have less lymph node sampling and higher risk of recurrence. We aimed to compare treatment outcome between two surgical options, and explore the effect of regional lymph node removal on the prognostic difference. Methods: We retrospectively analyzed data of stage I non-small cell lung cancer (NSCLC) (<=3 cm in size) patients who underwent either segmentectomy, or lobectomy, collected from the Surveillance, Epidemiology and End Results (SEER) database, from 2003 to 2013. The primary endpoints were overall survival (OS) and lung cancer-specific survival (LCSS). We also collected data from Shandong Provincial Hospital as validation. Results: Ultimately 1,156 patients treated by segmentectomy and 17,748 patients treated by lobectomy from SEER database were included in the analysis. Overall, segmentectomy was inferior to lobectomy in terms of OS [hazard ratio (HR): 1.316 (1.186-1.461), P<0.001] and LCSS [HR: 1.310 (1.142-1.504), P<0.001]. When the removal of regional lymph nodes (LN) was taken into consideration, no significant difference was found in OS and LCSS, in any Scope of Regional Lymph Node Surgery layer (0, 1-3, more than 3, and biopsy/sentinel layer, all P>0.05). After propensity score matching (PSM), there was no difference between segmentectomy and lobectomy in OS [HR: 1.081 (0.937-1.248), P=0.286] and LCSS [HR: 1.039 (0.861-1.253), P=0.692]. Only sex, age, histology, summary stage, differentiation, tumor size, and radiation still remained as independent prognostic factors for both OS and LCSS. For validation part, there was no significantly prognostic difference between lobectomy and sublobectomy group in overall (P=0.132) and each regional LN removed layer (0, 1-3, more than 3 layers: all P>0.05). Conclusions: Segmentectomy with proper lymph node resection or sampling could be a good alternative to lobectomy. PMID- 29268527 TI - Coated expandable metal stents are effective irrespective of airway pathology. AB - Background: Tracheobronchial stents are a treatment option for inoperable benign or malignant tracheobronchial stenosis (TBS) or postoperative bronchopleural fistulas (POBPF). The present study evaluated the outcomes of patients with TBS and POBPF who were treated by placement of recent generation, fully covered, self expanding metallic stents (SEMS) and determined stent efficacy relative to airway pathology. Methods: From January 2009 to January 2016, 68 patients with TBS or POBPF underwent rigid bronchoscopy, laser/mechanical debridement and placement of fully covered SEMS. Eighteen patients had benign stenosis, 38 had malignant stenosis, and 12 patients had POBPF. Results: Seventy-four SEMS were successfully placed in 68 patients. There were no perioperative deaths. Stent-related complications occurred in 20 (29.4%) patients: granulation tissue formation [TBS group, 10.7% (n=6); POBPF group, 8.3% (n=1)]; stent fracture [TBS group, 5.4% (n=3); POBF group, 8.3% (n=1)], stent migration [TBS group, 7.1% (n=4); POBF group, 0% (n=0)], severe secretions not removable by flexible bronchoscopy [TBS group, 7.1% (n=4); POBF group, 8.3% (n=1)]. No stent migration was observed in the POBPF group. Four patients (7.1%) in the TBS group had stent migration requiring stent replacement. After stenting, all TBS patients had a Hugh-Jones classification score improvement >=1 grade and 42 patients (75%) had an improvement >=2 grades. Logistic regression analysis showed that the disease (stenosis vs. fistula) did not influence the occurrence of stent complications [OR 0.96, 95% confidence interval (CI): 0.71-1.13, P=0.13]. Conclusions: Fully covered SEMS are effective and provide a versatile treatment option for patients with inoperable TBS and POBPF. PMID- 29268528 TI - Simple covering technique in thoracoscopic bullectomy for spontaneous pneumothorax. AB - Reduced-port thoracoscopic surgery for pneumothorax has been well reported. However, the optimum method for preventing postoperative recurrence in reduced port thoracoscopic bullectomy remains unclear. We investigated ways to improve the covering technique with reduced-port thoracoscopic bullectomy for spontaneous pneumothorax. From April to December 2016, we performed a simple covering technique with reduced-port thoracoscopic bullectomy on six patients and evaluated the surgical results and patient outcomes. All of the patients were successfully treated with the simple covering technique, and none had a postoperative ipsilateral recurrence of pneumothorax. Our method is a simple and easy technique involving the wide reinforcement of the staple line and may be effective in reducing the risk of postoperative recurrence in reduced-port thoracoscopic bullectomy. PMID- 29268529 TI - A useful method to keep azygos arch in minimally invasive resection of esophageal leiomyoma. AB - Lifting azygos arch with a prolene line is a useful way to keep azygos arch in minimally invasive resection of esophageal leiomyoma without affecting surgical exposure and operative procedure. PMID- 29268530 TI - Uniportal video assisted thoracic surgery with 2 cm skin incision for right middle lobectomy with systematic lymphadenectomy. AB - Today, video-assisted thoracic surgery (VATS) was very popular and more and more common, which could be carried out at all levels of medical centers, most of which used multiple-ports VATS techniques. However, uniportal VATS was more difficult technique compared with multiple-ports VATS, and was not yet completely universal. Uniportal port VATS with 2 cm incision was more difficult surgery, and asked the surgeon to master more surgical techniques and good collaborations with each other, however, which not only could reduce the postoperative pain and skin numbness but supply cosmetology and psychological comfort for patients. To reduce unnecessary damage to patients, we minimized the incision to 2 cm. Therefore, we called it precise uniportal port VATS technique in our surgical center and introduced it here. PMID- 29268531 TI - Prevention of cardiac herniation and left artery descending obstruction in cases of extensive surgical pericardial window procedure. AB - The thoracotomy approach for pericardial window surgery was shown to be more effective at preventing effusion recurrence and the need for repeat surgery. However, cardiac herniation remains a common complication after extensive pericardial excision. This technical note describes a simple and effective technique to prevent potential heart herniation through the pericardial window and at the same time to avoid potential obstruction of the left artery descending. PMID- 29268532 TI - Clinical consensus of emergency airway management. AB - Airway management is a common and key method to maintain and improve external respiration function of patients. Emergency physicians need a more appropriate guide to airway management. We concisely concluded current circumstances of Chinese emergency airway management. Then, we raised four principles: (I) priority to ventilation and oxygenation; (II) evaluation before intubation; (III) higher level of preparation (de-escalation); (IV) simplest (and least potentially harmful) form of intubation. We raised "CHANNEL" flow to direct initial emergency airway management and an algorithm was showed for emergency physicians understanding key points of airway management and further making medical decision. Finally, we introduced pharmacology of airway management. PMID- 29268534 TI - Airway stent complications: the role of follow-up bronchoscopy as a surveillance method. AB - Background: Airway stenting has become an integral part of the therapeutic endoscopic management of obstructive benign and malignant central airway diseases. Despite increased use of airway stents and frequent stent-associated complications, no clear guidelines for surveillance and maintenance exist. This study aim is to elucidate predictive factors associated with development of stent complications, as well as an optimal surveillance period for follow-up bronchoscopy for early detection and possible prevention of stent-associated complications. Methods: Retrospective cohort study of all patients who underwent airway stent placements at our institution from April 2010 to December 2013 for benign and malignant airway diseases. Metallic, silicone (straight, Y stent, T tube) and hybrid stents were included in the study. Stent complications were analyzed at the time of follow-up bronchoscopy performed four to six weeks after initial stent placement or earlier if patients became symptomatic. Results: The study included 134 patients of which 147 stents were placed. Follow-up bronchoscopy was performed in 94 patients. Symptomatic status at the time of follow-up bronchoscopy was not associated with stent complications [odds ratio (OR) =1.88; 95% CI: 0.79-4.45; P=0.15]. Patient age, sex, indication for stent placement, and stent location, were not associated with development of complications (all P>0.05). Compared to all other stents, hybrid stents were more likely to migrate (OR =6.60; 95% CI: 2.16-20.2; P=0.001) or obstruct by secretions (OR =2.53; 95% CI: 1.10-5.84; P=0.03). There were no complications associated with surveillance bronchoscopy. Conclusions: Surveillance bronchoscopy within 4 to 6 weeks of stent placement may be useful for early detection of complications and their subsequent management, regardless of symptomatic status and indication for stent placement. Prospective multicenter studies are needed to compare optimal surveillance methods and the impact on patient mortality, morbidity and healthcare costs. PMID- 29268536 TI - Massive pulmonary embolism causing large T-wave inversion and QT prolongation. AB - We present a case of massive pulmonary embolism where the electrocardiogram (ECG) demonstrated transient T-wave inversion and marked QT-prolongation. The pathomechanism and clinical significance of these changes are discussed. PMID- 29268535 TI - Persistent air leaks: a review with an emphasis on bronchoscopic management. AB - Persistent air leak (PAL) is a cause of significant morbidity in patients who have undergone lung surgery and those with significant parenchymal lung disease suffering from a pneumothorax. Its management can be complex and challenging. Although conservative treatment with chest drain and observation is usually effective, other invasive techniques are needed when conservative treatment fails. Surgical management and medical pleurodesis have long been the usual treatments for PAL. More recently numerous bronchoscopic procedures have been introduced to treat PAL in those patients who are poor candidates for surgery or who decline surgery. These techniques include bronchoscopic use of sealants, sclerosants, and various types of implanted devices. Recently, removable one-way valves have been developed that are able to be placed bronchoscopically in the affected airways, ameliorating air-leaks in patients who are not candidates for surgery. Future comparative trials are needed to refine our understanding of the indications, effectiveness, and complications of bronchoscopic techniques for treating PAL. The following article will review the basic principles of management of PAL particularly focusing on bronchoscopic techniques. PMID- 29268537 TI - Different QRS morphologies in a dual-chamber pacemaker: what is the mechanism? AB - A 12-lead electrocardiogram (ECG) of a dual-chamber pacemaker with different paced QRS morphologies is presented. Such an observation is usually made when there are different degrees of fusion, in association with the intrinsic rhythm in the presence of spontaneous changes of the stimulation mode of the pacemaker. PMID- 29268538 TI - GARD, a new way to battle with chronic respiratory diseases, from disease oriented programmes to global partnership. AB - Initiated by World Health Organization (WHO) Global Chronic Respiratory Disease (CRD)-oriented programmes, Global Initiative on Asthma (GINA), GOLD-Global Initiative for Chronic Obstructive Pulmonary Disease (COPD), Allergic Rhinitis and its Impact on Asthma (ARIA), and Practical Approach to Lung Health (PAL) have catalyzed creation of the Global Alliance Against CRD (GARD). Forty-five countries sharing GARD's goal to reduce the burden of CRD joint GARD. In 20 countries with reliable death estimates, CRD mortality has been analyzed in 2000, 2005, 2010 and 2015. Dramatic decline in CRD mortality is seen in Kyrgyzstan, Netherlands, Italy and Republic of Korea (69%, 55%, 48%, and 48%). Positive trend in COPD mortality is seen for Lithuania (36% decline) and Spain (21%). In France, Japan, Mexico, Romania and Costa Rica, positive trend for asthma mortality is obvious from 2000 to 2015 from about 40% in France and Romania, 50% and Mexico and Czech Republic, 65% in Japan and 69% in Belgium. In Costa Rica zero asthma mortality was registered in 2015. In Czechia and Belgium decline is seen from 2000 to 2005, which then stabilized in Czech Republic and went further down in Belgium. In Finland initially, low asthma mortality remains practically unchanged with slight decline in 2015. In other countries analyzed, we did not see any positive trend in CRD mortality. In all countries with positive CRD dynamic WHO introduced activities remained active, they have been taken into local guidelines and practice and supported national authorities in implementing these evidence based guidelines. Before GARD launch WHO initiated activities produced a good basis for further GARD movement and by 2010 we see a visible positive trend in CRD mortality in success countries. By 2015 when WHO noncommunicable disease (NCD) Global Action Plan 2013-2020 rollouts globally dramatic decline in total CRD mortality and particularly in Asthma and COPD mortality became obvious. Global disease oriented programmes, national and international partnerships combined with the Global NCD Action Plan most probable produce a positive synergistic effect on the mortality from CRD. PMID- 29268533 TI - Chinese Guideline on allergen immunotherapy for allergic rhinitis. AB - The present document is based on a consensus reached by a panel of experts from Chinese Society of Allergy (CSA) and Chinese Allergic Rhinitis Collaborative Research Group (C2AR2G). Allergen immunotherapy (AIT), has increasingly been used as a treatment for allergic rhinitis (AR) globally, as it has been shown to provide a long-term effect in improving nasal and ocular symptoms, reducing medication need, and improving quality of life. AIT is currently the only curative intervention that can potentially modify the immune system in individuals suffering from AR and prevent the development of new sensitization and the progression of disease from AR to asthma. Although the use of AIT is becoming more acceptable in China, to date no AR immunotherapy guideline from China is available for use by the international community. This document has thus been produced and covers the main aspects of AIT undertaken in China; including selection of patients for AIT, the allergen extracts available on the Chinese market, schedules and doses of allergen employed in different routes of AIT, assessment of effect and safety, patients' administration and follow-up, and management of adverse reactions. The Chinese guideline for AR immunotherapy will thus serve as a reference point by doctors, healthcare professionals and organizations involved in the AIT of AR in China. Moreover, this guideline will serve as a source of information for the international community on AIT treatment strategies employed in China. PMID- 29268539 TI - Infectious pleural effusion status and treatment progress. AB - Pleural cavity infection continuously seriously threatens human health with continuous medical progress. From the perspective of pathophysiology, it can be divided into three stages: exudative stage, fibrin exudation and pus formation stage, and organization stage. Due to the pathogenic bacteria difference of pleural cavity infection and pulmonary infection, it is very important for disease treatment to analyze the bacteria and biochemical characteristics of the infectious pleural effusion. Most prognoses of patients have been relatively good, while for some patients, the complicated parapneumonic effusion or empyema could be evolved. Antibiotic treatment and sufficient drainage are the foundation for this treatment. No evidence can support the routine use of a fibrin agent. However, it has been reported that the plasminogen activator and deoxyribonuclease can be recommended to be applied in the pleural cavity. In case of failure on conservative medical treatment, operative treatment can be applied such as thoracoscopy and pleural decortication. According to the clinical characteristics of these patients, it is a key to research prognosis, as well as early evaluation and stratification, in the future. PMID- 29268540 TI - Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age. AB - Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial lung disease (ILD) and carries a worse prognosis than many cancers. Until recently, there were no active treatment options available for patients with IPF, meaning palliation or lung transplantation in selected patients were the only options. The management of IPF has changed dramatically over the last decade with the advent of two antifibrotic agents; pirfenidone and nintedanib. These new agents have been shown to reduce decline in lung function and pirfenidone has been shown to reduce mortality. The changing landscape of IPF diagnosis and management present a number of issues that may be encountered including management of side effects related to antifibrotic therapy. This article aims to give an overview of the holistic approach to the management of patients with IPF, including antifibrotic management, symptom management and the invaluable role of the ILD specialist nurse. PMID- 29268542 TI - Preface to 2017 focused issue: Quantitative Imaging of Thoracic Diseases. PMID- 29268543 TI - Texture analysis of CT imaging for assessment of esophageal squamous cancer aggressiveness. AB - Background: To explore the role of texture analysis of computed tomography (CT) images in preoperative assessment of esophageal squamous cell carcinoma (ESCC) aggressiveness. Methods: Seventy-three patients with pathologically confirmed ESCC underwent unenhanced and contrast enhanced CT imaging preoperatively. Texture analysis was performed on unenhanced and contrast enhanced CT images, respectively. Six CT texture parameters were obtained. One-way analysis of variance or independent-samples t-test (normality), independent-samples Kruskal Wallis test or Mann-Whitney U test (non-normality), binary Logistic regression analysis (multivariable), Spearman correlation test, receiver operating characteristic (ROC) curve analysis and intraclass correlation coefficient (ICC) were used for statistical analyses. Results: Kurtosis was an independent predictor for T stages (T1-2 vs. T3-4) as well as overall stages (I-II vs. III IV) based on unenhanced CT images, while entropy was an independent predictor for T stages (T1-2 vs. T3-4), lymph node metastasis (N- vs. N+) and overall stages (I/II vs. III/IV). Skew and kurtosis based on unenhanced CT images showed significant differences among N stages (N0, N1, N2 and N3) as well as 90th percentile based on contrast enhanced CT images. In correlation with T stage of ESCC, kurtosis and entropy significantly correlated with T stage both on unenhanced and contrast enhanced CT images. Reversely, entropy and 90th percentile based on contrast enhanced CT images showed significant correlations with N stage (r: 0.526, 0.265; both P<0.05), as well as overall stage (r: 0.562, 0.315; both P<0.05). For identifying ESCC with different T stages (T1-2 vs. T3 4), lymph node metastasis (N- vs. N+) and overall stages (I/II vs. III/IV), entropy based on contrast enhanced CT images, showed good performance with area under ROC curve area under curve (AUC) of 0.637, 0.815 and 0.778, respectively. Conclusions: Texture analysis of CT images held great potential in differentiating different T, N and overall stages of ESCC preoperatively, while failed to assess the differentiation degrees. PMID- 29268541 TI - Molecular targets in aortic aneurysm for establishing novel management paradigms. AB - Aortic aneurysm (AA) is a lethal disease and presents a large challenge for surgeons in the clinic. Although surgical management remains the major choice of AA, operative mortality remains high. With advances in understanding of the mechanisms of AAs, molecular targets, such as matrix metalloproteinases (MMPs), D dimer, and inflammation markers, including C-reactive protein, interleukins and phagocytes, are important in the pathology of development of AA. These markers may become important for improving the diagnostic quality and provide more therapeutic choices for treatment of AA. Although these new markers require long term trials before they can be translated into the clinic, they can still be helpful in determining new directions. The main aim of this review is to discuss the current findings of molecular targets in progression of AA and discuss the potential application of these new targets for managing this disease. PMID- 29268544 TI - Combined CT angiography of the aorta and craniocervical artery: a new imaging protocol for assessment of acute type A aortic dissection. AB - Background: To investigate the feasibility of combined computed tomography angiography (CTA) of the aorta and craniocervical artery in acute type A aortic dissection (ATAAD) and the value of incremental craniocervical information. Methods: Combined CTA of head, neck and aorta was performed in patients with suspected aortic dissection and 243 ATAAD patients were analyzed. The image quality and radiation dose were assessed. Valuable craniocervical CTA findings were determined for further surgical analysis. Results: The mean dose-length product (DLP) was 314.11+/-29.31 mGy.cm. The image quality of craniocervical arteries were 100% diagnostic. Intimal flap involving carotid arteries was detected in 47% of patients, and significant stenosis of true lumen was observed in 60% of common carotid arteries (CCAs). Hypodensity and hypoplasia/occlusion of carotid arteries were also detected and apprised surgeons. The tortuosity of carotid artery was found in 90.9% of patients. Bilateral antegrade selective cerebral perfusion (ASCP) was performed in 21.1% of aortic arch surgery based on 7 hemodynamic variation types of the circle of Willis (CW) determined by cranial CTA information. Conclusions: A combined CTA of head, neck and aorta is feasible with low radiation dose and diagnostic image quality. Incremental information on craniocervical pathology and anatomy may be useful for surgery repair of ATAAD. PMID- 29268545 TI - The impact of chemotherapy on persistent ground-glass nodules in patients with lung adenocarcinoma. AB - Backgrounds: To evaluate the response of persistent ground glass nodules (GGNs) in patients with lung adenocarcinoma treated with platinum-based chemotherapy on computed tomography (CT). Methods: We retrospectively studied patients with GGNs that met the following criteria: (I) GGNs found in patients with lung adenocarcinoma, which persist for more than 3 months; (II) patients treated with platinum-based (cisplatin or carboplatin) chemotherapy for at least 2 cycles; (III) ground glass proportion !Y50%. For each patient, if more than two CTs satisfied the inclusion criteria, then the baseline and last CTs were used for analysis, defined as CT1 and CT2. A total of 91 persistent pulmonary GGNs in 51 patients fulfilled the inclusion criteria. We defined growth as a nodule !Y2 mm increase in diameter or showing up a solid portion. GGN response to therapy was assessed and compared with the baseline CT. Differences in CT findings were analyzed using a paired t-test and Pearson |O2 test. Results: Between 2010 and 2015, 25 of the 51 (49%) were male and 26 of the 51 (51%) were female. The average age at time of detection of a GGN was 63.8 (range, 36-84) years. Mean follow-up duration was 24.1!A17.9 months. During the follow-up periods, on a per nodule basis, 94.5% of GGNs (n=86) remained unchanged in size. Only 5.5% GGNs (n=5) in 5 patients increased in size. The nodules CT feature in each lung adenocarcinoma clinical stage show no difference. No significant difference was found in the size, attenuation, volume, and mass of GGN between baseline and post treatment measurements, regardless of the type of chemotherapy (P>0.05). Conclusions: The clinical course of GGNs in patients with lung adenocarcinoma is predominantly indolent, and platinum-based chemotherapy may have no effect on the growth of persistent GGNs. PMID- 29268546 TI - Logistic regression analysis and a risk prediction model of pneumothorax after CT guided needle biopsy. AB - Background: Pneumothorax is the most common complication of computed tomography (CT)-guided needle biopsy. The purpose of this study was to investigate independent risk factors of pneumothorax, other than emphysema, after CT-guided needle biopsy and to establish a risk prediction model. Methods: A total of 864 cases of CT-guided needle biopsy with an 18-gauge cutting needle were enrolled in this study. The relevant risk factors associated with pneumothorax included age, sex, emphysema, short-axis size of the lesion, depth of the lesion, body position, and the number of pleural punctures. Several independent risk factors of pneumothorax were found, and a predictive model for pneumothorax was established using univariate and multivariate logistic regression analyses. Results: Pneumothorax occurred in 31.4% (271/864) of cases. Univariate analysis showed that significant risk factors of pneumothorax included age, emphysema, small lesion size, no contact between the lesion and the pleura, prone or lateral body position, and multiple punctures. Independent risk factors of pneumothorax in the multivariate logistic regression analysis included emphysema (P=0.000), no contact between the lesion and the pleura (P=0.000), prone or lateral body position (P=0.002), and the number of pleural punctures (P=0.000). The sensitivity, specificity, and accuracy of the predictive model for pneumothorax were 56.8%, 79.6%, and 72.5%, respectively. Conclusions: Pneumothorax is a common complication of CT-guided lung biopsy. Independent risk factors of pneumothorax include emphysema, no contact between the lesion and the pleura, and prone or lateral body position. The predictive model developed in this study was highly accurate in predicting the incidence of pneumothorax. PMID- 29268547 TI - Preliminary study on the diagnostic value of single-source dual-energy CT in diagnosing cervical lymph node metastasis of thyroid carcinoma. AB - Background: To investigate the value of single-source dual-energy spectral CT imaging in improving the accuracy of preoperative diagnosis of lymph node metastasis of thyroid carcinoma. Methods: Thirty-four thyroid carcinoma patients were enrolled and received spectral CT scanning before thyroidectomy and cervical lymph node dissection surgery. Iodine-based material decomposition (MD) images and 101 sets of monochromatic images from 40 to 140 keV were reconstructed after CT scans. The iodine concentrations (IC) of lymph nodes were measured on the MD images and was normalized to that of common carotid artery to obtain the normalized iodine concentration (NIC). The CT number of lymph nodes as function of photon energy was measured on the 101 sets of images to generate a spectral HU curve and to calculate its slope lambdaHU. The measurements between the metastatic and non-metastatic lymph nodes were statistically compared and receiver operating characteristic (ROC) curves were used to determine the optimal thresholds of these measurements for diagnosing lymph nodes metastasis. Results: There were 136 lymph nodes that were pathologically confirmed. Among them, 102 (75%) were metastatic and 34 (25%) were non-metastatic. The IC, NIC and the slope lambdaHU of the metastatic lymph nodes were 3.93+/-1.58 mg/mL, 0.70+/-0.55 and 4.63+/-1.91, respectively. These values were statistically higher than the respective values of 1.77+/-0.71 mg/mL, 0.29+/-0.16 and 2.19+/-0.91 for the non metastatic lymph nodes (all P<0.001). ROC analysis determined the optimal diagnostic threshold for IC as 2.56 mg/mL, with the sensitivity, specificity and accuracy of 83.3%, 91.2% and 85.3%, respectively. The optimal threshold for NIC was 0.289, with the sensitivity, specificity and accuracy of 96.1%, 76.5% and 91.2%, respectively. The optimal threshold for the spectral curve slope lambdaHU was 2.692, with the sensitivity, specificity and accuracy of 88.2%, 82.4% and 86.8%, respectively. Conclusions: The measurements obtained in dual-energy spectral CT improve the sensitivity and accuracy for preoperatively diagnosing lymph node metastasis in thyroid carcinoma. PMID- 29268548 TI - Ultrasound-guided percutaneous microwave ablation for benign breast lesions: evaluated by contrast-enhanced ultrasound combined with magnetic resonance imaging. AB - Background: Minimally invasive ablative techniques in the treatment of breast tumor has become popularly in recent years. Methods: We analyzed gray-scale and contrast-enhanced ultrasound (CEUS) features of 205 microwave ablated breast benign lesions from 182 consecutive patients, compared with magnetic resonance imaging (MRI) and histopathology findings. The follow-up was implemented at 3, 6 and 12 months after the ablation treatment. Results: Before the MWA, the mean of largest diameter and volume of the lesions were 14.41+/-6.54 and 3,224+/-961 mm3, respectively. However, those of the lesions respectively were 8.48+/-6.30 and 2,116+/-732 mm3 one year after the treatment. The longest diameter and the volume of the ablative lesions were gradually decreased 3, 6 or 12 months after the MWA. 44 (/205, 21.5%) ablative lesions were disappeared one year after the MWA. One hundred and forty-two (/205, 69.3%) ablative lesions presented a hypoechoic halo surrounding it on gray-scale US after the MWA. The success rate of the MWA treatment in the benign breast lesion was 87.32% and 82.93% evaluated by CEUS and enhanced MRI, respectively. During the ablation, no patient had serious complications, such as hemorrhage, serious pain and fat necrosis, etc. Conclusions: Microwave ablation was a safe and efficient method in the treatment of the benign breast tumors. CEUS and enhanced MRI could accurately assess whether the MWA treatment is effective. PMID- 29268549 TI - Comparison of sonographic characteristics of primary thyroid lymphoma and anaplastic thyroid carcinoma. AB - Background: Although primary thyroid lymphoma (PTL) and anaplastic thyroid carcinoma (ATC) both account for a rare portion of the morbidity of all thyroid malignancies, the therapeutic methods and prognosis for these two diseases are different. The purpose of this study was to investigate the sonographic characteristics of PTL and ATC and to compare the sonographic findings of PTL and ATC. Methods: The study included 42 patients with histopathologically proven PTL (n=27) and ATC (n=15). The Clinical characteristics and sonographic findings were retrospectively reviewed and compared between the two groups. Results: The mean age of patients with ATC was not significantly different from that in patients with PTL (P=0.601). The female-to-male ratio of patients with ATC was significantly lower than that of patients with PTL (P=0.029). Both PTL and ATC commonly present as a relatively large, solid mass on sonography with compressive symptoms, in which hoarseness was seen more frequently in ATC group (66.7%) than in PTL group (14.8%) (P=0.001). There is no significant difference in thyroid size, nodular size, margin, shape, echo texture, echogenicity, cystic change, vascularity and local invasion on sonography between ATC and PTL groups. Echogenic strands, markedly hypoechoic and enhanced posterior echo were seen more frequently in PTL group (92.6%, 92.6%, and 85.2%, respectively) than those in ATC group (6.7%, 60.0%, and 33.3%, respectively) (P<0.05), and calcification was seen more frequently in ATC group (80.0%) than in PTL group (0%) (P<0.001). Three ultrasound patterns were observed for PTL including diffuse type (25.9%), nodular type (48.2%) and mixed type (25.9%), while all ATC cases presented with nodular type (100.0%). Associated Hashimoto's thyroiditis occurred more frequently in PTL group (59.3%) than in ATC group (20.0%) (P=0.023). Conclusions: Certain sonographic features as a markedly hypoechogenicity, the presence of an enhanced posterior echo and linear echogenic strands, lack of calcification and associated Hashimoto's thyroiditis were valuable for distinguishing PTL from ATC. In contrast, heterogeneous echogenicity, uncircumscribed margin, irregular shape, and vascular pattern were not specific features for differential diagnosis. PMID- 29268550 TI - CT findings of pulmonary nocardiosis: a report of 9 cases. AB - Background: Pulmonary nocardiosis often occurs among immunocompromised patients, especially in those with impaired cell immunity related to AIDS and transplant. As the number of patients receiving transplant, the occurrence of pulmonary nocardiosis may also increase. Radiologic characteristics of this entity have not been well documented. In present study, CT findings of clinical confirmed pulmonary nocardiosis were retrospectively reviewed in order to understand CT features of pulmonary nocardiosis. Methods: Electronic databases of Shenzhen People's Hospital, Shenzhen, China, and the Third People's Hospital of Longgang District, Shenzhen, China were searched for patients with definitive diagnosis of pulmonary nocardiosis and available CT images. Nine patients were founded and they were included in this retrospective analysis. Clinical presentations at diagnosis and related medical history were recorded. CT images were retrospectively reviewed by two radiologists in consensus. Results: The patients consisted of seven men and two women with a median age of 47 years (range, 20-73 years). There were three immunocompromised patients and six immunocompetent patients. The latter included two patients had history of bronchiectasis. The symptoms at the diagnosis were nonspecific of fever, cough, sputum, dyspnea, chest pain, and hemoptysis. CT findings included: lung consolidation (n=8) with cavitation in three cases and foci of decreased enhancement in one patient who had contrast-enhanced CT, nodules/masses (n=6) with cavitation in two patients, ground-glass opacity (n=4), centrilobular nodules (n=4), pleural effusion (n=4), bronchiectasis (n=4), interlobular septal thickening (n=3), interlobular reticular opacity (n=3), lymph node enlargement (n=2), halo sign (n=2) and mucoid impaction (n=1). Conclusions: Lung consolidation and nodules/masses are the most common findings, but CT findings of pulmonary nocardiosis are diverse and nonspecific. In some clinical background, such as immunocompromised patients or with some underlying lung diseases, consolidation or nodules/masses with cavitation may suggest the possibility of pulmonary nocardiosis. PMID- 29268551 TI - Evaluation of supplementary diagnostic value of contrast-enhanced ultrasound for lymph node puncture biopsy. AB - Background: Contrast enhanced ultrasound (CEUS) is an effective way to evaluate the distribution of micro vessels in organs with little invasiveness. The qualitative evaluation and differential diagnosis of lymph node is essential for a number of clinical situations, including appropriate examination selection, oncologic staging, therapy and prognosis beyond diagnosis itself. The purpose of this study is to investigate the contribution of characterization of cervical lymphadenopathies on CEUS as an indication for lymph node puncture biopsy. Methods: Records of 157 lymph nodes from 103 patients who had undergone CEUS examination were studied retrospectively, and enhancement patterns and characteristics were evaluated. The diagnoses obtained by means of core-needle biopsy examination or surgical removal, or patients were closely followed-up for at least 6 months. Of the lymph nodes examined, 94 were benign (48 lymphadenitis and 46 tuberculosis) and 63 were malignant (55 metastases and 8 lymphomas). The vascular characterization of lymph nodes was compared with results obtained by pathologic examination. Results: The study using CEUS showed 55 (54.5%) cases of "peripheral" enhancement in group A and 47 (83.9%) cases of "hilar normal or activated" in group B. Inhomogeneous "spotted or cycle-like" enhancement in the equilibrium phase was seen in 80 (79.2%) cases of group A and only 11 (19.6%) cases of group B. The specificity, sensitivity and accuracy of CEUS examination result as an indication for puncture biopsy were 80.4%, 81.2% and 80.9%, respectively. Conclusions: Centripetal perfusion in the early arterial phase or inhomogeneous spotted or cycle-like enhancement in the equilibrium phase of the cervical lymph nodes during CEUS can be used as an indication for core-needle biopsy with a high degree of accuracy. Conversely, for lymph nodes with more variable appearances, surgical removal or closely followed-up of nodes may be more appropriate. PMID- 29268552 TI - Complete thoracoscopic excision of an infected bronchogenic cyst due to mediastinitis. AB - Because bronchogenic cysts can result in infection, further complications due to compression of adjacent organs or malignant transformation, symptomatic and complicated bronchogenic cysts are usually surgically removed. However, surgical excision can be hazardous or incomplete because of dense adhesion to surrounding vital organs as a consequence of severe inflammation. Herein, we report a rare case of infected bronchogenic cyst caused by mediastinitis and we describe how a surgical approach using video-assisted thoracoscopic surgery (VATS) should be considered for treatment, even among patients with complicated bronchogenic cysts. PMID- 29268553 TI - A laceration of left internal mammary artery caused by an amateur golfer's swing. AB - We report the rare case of a patient presenting with a spontaneous laceration of left internal mammary artery (LIMA) after playing golf. The patient had no specific history except for cardiac surgery, and there were no results that caused bleeding on preoperative examination. A computed tomography (CT) scan of the chest demonstrated an anterior mediastinal hematoma and a left hemothorax with active extravasation close to LIMA. Through thoracotomy, hematoma evacuation and clipping for lacerated artery were performed. The patient was discharged in stable condition on the sixteenth postoperative day. This is the first reported case of a spontaneous laceration of internal mammary artery (IMA) after playing golf. PMID- 29268554 TI - Crizotinib plus radiotherapy in brain oligoprogressive NSCLC ROS1 rearranged and PD-L1 strong. AB - ROS1+ patients represent a unique molecular subset of non-small cell lung cancer (NSCLC). Early phase clinical trials have shown a high response rate to crizotinib in these patients. We describe a case of an 18 years old woman, never smoker, with NSCLC ROS1+ and miliary brain metastases treated with crizotinib and radiotherapy. From October 2014 to June 2015 the Patient was treated with crizotinib. The first intracranial time to progression (IT-TTP) occurred after 7 months; the patient underwent stereotactic radiosurgery (SRS) and continued TKI treatment. The second IT-TTP appeared after 16 months. A continued response in the chest was observed for all the 23 months of crizotinib treatment. At the progression, we assessed programmed death ligand 1 (PD-L1) expression by immunohistochemistry, that resulted highly expressed. Our report indicates that the integration of crizotinib with local treatments should be considered in ROS1 NSCLC patients experiencing oligometastatic progression. Moreover, this case is an example of PD-L1 strong in oncogene addicted patients. PMID- 29268555 TI - Robot-assisted Ivor-Lewis esophagectomy with intrathoracic robot-sewn anastomosis. AB - This video clip demonstrated a performance of robot-assisted Ivor-Lewis esophagectomy with intrathoracic robot-sewn anastomosis. The patient had an esophageal mass located approximately 33 cm away from incisor, and robot-assisted Ivor-Lewis esophagectomy was applied for him. Importantly, a double-layer esophago-gastric anastomosis was made by robotic hand-sewn suture. Our early experience demonstrated that the robot-sewn intrathoracic anastomosis is feasible and safe with a lower complication rate and the absence of anastomotic leakage. PMID- 29268556 TI - Disseminated intravascular coagulopathy caused by type II endoleak after endovascular aneurysm repair in severe aortic stenosis. AB - A 72-year-old man with severe aortic stenosis (AS) presented with a type II endoleak after endovascular aneurysm repair (EVAR). Laboratory findings were consistent with disseminated intravascular coagulopathy (DIC) with thrombocytopenia. The platelet count increased slightly after aortic valve replacement but fully recovered with the reversal of DIC after surgical repair of the type II endoleak. PMID- 29268557 TI - Completion pneumonectomy after fenestration for empyema due to nontuberculous mycobacteriosis associated with destroyed lung as a result of cancer surgery. AB - Long-term follow-up of post-operative lung cancer patients indicates that some patients develop lung complications. Destroyed lung cannot be ignored because it predisposes the patient to recurrent infection. We report a case of thoracic empyema with bronchopleural fistula that developed in lung tissue damaged due to cancer surgery and associated with an infection of Mycobacterium gordonae (M. gordonae); a class of bacterium responsible for nontuberculous mycobacterial infection. The patient's cancer did not recur after surgery and followed a typical course that began with sub-pleural cystitis followed by repeated infection. We performed fenestration because the patient developed fistulous empyema and the infection became difficult to control using antibiotics. The patient then underwent a radical pleuropneumonectomy and his postoperative course was excellent. Thus, in cases of impaired lung function due to cancer surgery and where pharmacologic control of infection is challenging, we suggest that radical surgical intervention should be considered. PMID- 29268558 TI - Use of veno-arterial extracorporeal membrane oxygenation in a case of tracheal injury repair in a patient with severe relapsing polychondritis. AB - Tracheobronchial malacia occurs in 50% of patients with relapsing polychondritis (RP), and is often managed with stent insertion. While severe complications have been described after silicone tracheal stent insertion, there are few reports describing tracheal injury in patients with RP. We present a case of tracheal perforation secondary to Dumon(r) stent manipulation in a patient with RP. The tracheal injury was successfully repaired with a silicone Y-stent inserted via right thoracotomy using veno-arterial extracorporeal membrane oxygenation (VA ECMO) for ventilatory support. It is safe and feasible to introduce a silicone Y stent through a thoracotomy for a tracheal trauma in combination with VA-ECMO support. PMID- 29268559 TI - Dysphagia in the aging cardiovascular patient. AB - Dysphagia is not a normal process of aging. Dysphagia aortica refers to external compression of the distal esophagus from an enlarged, ectatic or aneurysmal thoracic aorta leading to mechanical obstruction of the food bolus. It is a rare cause of dysphagia seen in the older population and predisposing risk factors include female gender, short stature, and kyphosis. We selected the case of an octogenarian with a significant cardiovascular history presenting with dysphagia where the diagnosis of dysphagia aortica was delayed but ultimately identified. Although rare, we urge and remind a high index of suspicion for clinicians treating this patient population. PMID- 29268560 TI - One-stage surgery in combination with thoracic endovascular grafting and resection of T4 lung cancer invading the thoracic aorta and spine. AB - A novel strategy of one-stage surgery in combination with thoracic endovascular grafting and resection for T4 lung cancer invading the thoracic aorta and spine is described. A 56-year-old man with locally advanced lung cancer infiltrating the aortic wall and spine underwent neoadjuvant chemotherapy and thoracic irradiation, followed by en bloc resection of the aortic wall and spine with thoracic endovascular grafting. He developed postoperative chylothorax, but there were no stent graft-related events. After 3 months, computed tomography (CT) did not show aortic stent graft stenosis, migration, or deformation. PMID- 29268561 TI - Pulmonary inflammatory myofibroblastic tumor with TPM4-ALK translocation. AB - A 35-year-old woman with shortness of breath and cough was referred to our hospital and agreed to receive therapy for lung tumor in our hospital. Based on the findings from a bronchoscopic biopsy, she was suspected of having pulmonary inflammatory myofibroblastic tumor (IMT), but a correct diagnosis was not indicated. Right upper wedge lobectomy was performed. The findings of a pathological examination of the permanent surgical resected tissue, the ultimate diagnosis was pulmonary IMT. The immunohistochemistry of ALK using the intercalated antibody-enhanced polymer (iAEP) method was positive. We extracted the RNA from frozen surgical resected tumor tissue and proved the tropomyosin alpha-4 chain (TPM4)-ALK by 5' rapid amplification of cDNA end (5' RACE) and reverse transcription polymerase chain reaction. The preoperative bronchial biopsy specimen was also found to be positive for anti-ALK immunohistochemistry with the iAEP method. A molecular therapeutic drug may be useful as personalized therapy for tumors with ALK translocation as oncogenic drivers. We should examine the ALK protein expression and translocation in cases of lung cancer and IMT using an adequate ALK immunohistochemistry system. We experienced a case of pulmonary IMT with TPM4-ALK translocation. PMID- 29268562 TI - Video-assisted thoracoscopic surgery right upper lobectomy in a situs inversus totalis patient. AB - Situs inversus totalis (SIT) is a rare congenital disease, with an adult incidence rate ranging from approximately 1:5,000 to 1:10,000. SIT with lung cancer is rarely reported. Most surgeons have no clinical experience with SIT. We reported the experience of a patient with SIT combined with right upper lung cancer, who underwent video-assisted thoracoscopic surgery (VATS), and provide useful information for the reader to deal with this rare situation. PMID- 29268563 TI - Routine aortic valve replacement followed by a myriad of complications: role of 3D printing in a difficult cardiac surgical case. AB - Aortic valve replacement (AVR) is a routine cardiac surgical intervention that is rarely associated with severe complications. In this report, we present a complex and unique case following AVR in a middle-aged woman. We show the growing necessity for a strong cooperation between interventional cardiologists and cardiac surgeons, together with the emerging role of cardiac tomography based three-dimensional printing technique in planning and executing precision surgery within the chest. PMID- 29268564 TI - The lung cancer research career of Prof. Ramon Rami-Porta: passion, vision and reflection. PMID- 29268565 TI - Bioresorbable stents: quo vantis? PMID- 29268566 TI - CCR6 Is a Predicting Biomarker of Radiosensitivity and Potential Target of Radiosensitization in Rectal Cancer. AB - PURPOSE: This study aimed to explore the functions and mechanisms of C-C motif chemokine receptor 6 (CCR6), a gene associated with progression and metastasis of colorectal cancer (CRC), in radiosensitivity of rectal cancer (RC). Materials and Methods: RNA sequencing and immunohistochemical analysis on CCR6 expression were performed in pretreatment tissues of RC patients exhibiting different therapeutic effects of radiotherapy. Colonogenic survival assay was conducted in different CRC cell lines to assess their radiosensitivity. And the impact of CCR6 expression on radiosensitivity was validated through RNA interference. The DNA damage repair (DDR) abilities of cell lines with different CCR6 expression were evaluated through immunofluorescence-based gammaH2AX quantification. RESULTS: The CCR6 mRNA level was higher in patients without pathologic complete remission (pCR) than in those with pCR (fold changed, 2.11; p=0.004). High-level expression of CCR6 protein was more common in the bad responders than in the good responders (76.3% vs. 37.5%, p < 0.001). The CRC cell lines with higher CCR6 expression (LoVo and sw480) appeared to be more radioresistant, compared with the sw620 cell line which had lower CCR6 expression. CCR6 knockdown made the LoVo cells more sensitive to ionizing radiation (sensitization enhancement ratio, 1.738; p < 0.001), and decreased their DDR efficiency. CONCLUSION: CCR6 might affect the RC radiosensitivity through DDR process. These findings supported CCR6 as a predicting biomarker of radiosensitivity and a potential target of radiosensitization for RC patients. PMID- 29268567 TI - Lifestyle Risk Prediction Model for Prostate Cancer in a Korean Population. AB - PURPOSE: The use of prostate-specific antigen as a biomarker for prostate cancer (PC) has been controversial and is, therefore, not used by many countries in their national health screening programs. The biological characteristics of PC in East Asians including Koreans and Japanese are different from those in the Western populations. Potential lifestyle risk factors for PC were evaluated with the aim of developing a risk prediction model. Materials and Methods: A total of 1,179,172 Korean men who were cancer free from 1996 to 1997, had taken a physical examination, and completed a lifestyle questionnaire, were enrolled in our study to predict their risk for PC for the next eight years, using the Cox proportional hazards model. The model's performance was evaluated using the C-statistic and Hosmer-Lemeshow type chi-square statistics. RESULTS: The risk prediction model studied age, height, body mass index, glucose levels, family history of cancer, the frequency of meat consumption, alcohol consumption, smoking status, and physical activity, which were all significant risk factors in a univariate analysis. The model performed very well (C statistic, 0.887; 95% confidence interval, 0.879 to 0.895) and estimated an elevated PC risk in patients who did not consume alcohol or smoke, compared to heavy alcohol consumers (hazard ratio [HR], 0.78) and current smokers (HR, 0.73) (p < 0.001). CONCLUSION: This model can be used for identifying Korean and other East Asian men who are at a high risk for developing PC, as well as for cancer screening and developing preventive health strategies. PMID- 29268568 TI - Prognosis of Pancreatic Cancer Patients with Synchronous or Metachronous Malignancies from Other Organs Is Better than Those with Pancreatic Cancer Only. AB - PURPOSE: Pancreatic cancer associated double primary tumors are rare and their clinicopathologic characteristics are not well elucidated. Materials and Methods: Clinicopathologic factors of 1,352 primary pancreatic cancers with or without associated double primary tumors were evaluated. RESULTS: Of resected primary pancreatic cancers, 113 (8.4%) had associated double primary tumors, including 26 stomach, 25 colorectal, 18 lung, and 13 thyroid cancers. The median interval between the diagnoses of pancreatic cancer and associated double primary tumors was 0.5 months. Overall survival (OS) of pancreatic cancer patients with associated double primary tumors was longer than those with pancreatic cancer only (median, 23.1 months vs. 17.0 months, p=0.002). Patients whose pancreatic cancers were resected before the diagnosis of metachronous tumors had a better OS than patients whose pancreatic cancer resected after the diagnosis of metachronous tumors (48.9 months and 13.5 months, p=0.001) or those whose pancreatic cancers were resected synchronously with non-pancreas tumors (19.1 months, p=0.043). The OS of pancreatic cancer patients with stomach (33.9 months, p=0.032) and thyroid (117.8 months, p=0.049) cancers was significantly better than those with pancreas cancer only (17.0 months). CONCLUSION: About 8% of resected pancreatic cancers had associated double primary tumors, and those from the colorectum, stomach, lung, and thyroid were common. Patients whose pancreatic cancer was resected before the diagnosis of metachronous tumors had better OS than those resected after the diagnosis of metachronous tumors or those resected synchronously. PMID- 29268569 TI - Effect of diets with different energy and lipase levels on performance, digestibility and carcass trait in broilers. AB - Objective: A 28-d trial was conducted to evaluate the effect of diets with different energy and lipase levels on performance, nutrient digestibility, serum profiles, gut health, and carcass quality in broilers. METHODS: A total of 720 one-day-old male Ross 308 broilers (45.4+/-0.5 g) were randomly assigned to one of the following four treatments: i) RET, reduced energy treatment (metabolizable energy = 2,950 and 3,100 kcal/kg for starter and finisher diet), ii) BDT, basal diet treatment (metabolizable energy = 3,050 and 3,200 kcal/kg for starter and finisher diet, iii) RET015, RET+0.15 g/kg lipase, and iv) RET03, RET+0.3 g/kg lipase. There were 10 replications (cages) per treatment with 18 birds per cage. RESULTS: During d 1 to 14, broilers fed BDT, RET015, and RET03 diets had higher (p<0.05) body weight gain than those fed RET diet. During d 1 to 14, 15 to 28 and the overall experiment, feed conversion ratio in RET03 treatment was lower (p<0.05) compared with RET treatment. On d 14, the apparent total tract digestibility (ATTD) of dry matter (DM), ether extract (EE), and gross energy in RET03 treatment was higher (p<0.05) than those in RET treatment, while the ATTD of N was increased (p<0.05) by RET03 treatment. On d 28, broilers fed RET03 diet had higher (p<0.05) ATTD of DM than those fed RET and RET015 diets, while the ATTD of EE in BDT and RET03 treatments was increased (p<0.05) compared with RET and RET015 treatments. Broilers fed RET03 diet had higher villus height (VH) and VH:crypt depth (CD) ratio than those fed RET and BDT diets. The activity of pancreatic lipase in BDT and RET03 treatments was higher (p<0.05) than that in RET treatment. CONCLUSION: Taken together, lipase supplementation (3,000 U/kg feed) increased growth performance, nutrient digestibility, VH, VH:CD ratio and lipase activity, but decreased triglyceride, low-density lipoprotein cholesterol and the abdominal fat percentage in broilers fed reduced energy diet. PMID- 29268570 TI - Effects of zinc sources and levels of zinc amino acid complex on growth performance, hematological and biochemical parameters in weanling pigs. AB - Objective: The objective of the study was to investigate the effects of zinc amino acid complex (ZnAA) on growth performance, hematological and biochemical parameters in weanling pigs. METHODS: In Exp. 1, a total of 216 Duroc*Landrace*Large White weanling pigs were assigned randomly to 6 dietary treatments. Each treatment had 6 replicates (pens) with 6 pigs each. The diets were corn-soybean meal based with supplementation of 0, 20, 40, 80, 120 mg Zn/kg from ZnAA or 40 mg Zn/kg from feed-grade zinc sulfate. The experiment lasted 42 days. In Exp. 2, a total of 180 weanling pigs were assigned randomly to 3 dietary treatments supplemented with 0, 80, or 800 mg Zn/kg from ZnAA. RESULTS: In Exp. 1, pigs fed 40 to 80 mg Zn/kg from ZnAA had higher (p<0.05) average daily gain (ADG) than the unsupplemented group during d 0 to 14. During d 0 to 42, the pigs fed 20 to 120 mg Zn/kg from ZnAA had increased (p<0.05) ADG. Pigs fed 20 to 120 mg/kg Zn from ZnAA had lower feed:gain (p<0.05), increased the activity of serum Cu-Zn superoxide dismutase on d 14, and increased serum Zn levels on d 42 (p<0.05). In Exp. 2, pigs fed diets with 800 mg Zn/kg had increased average daily feed intake during d 15 to 28 (p<0.05) compared to the unsupplemented group. During d 0 to 28, the pigs fed supplemental Zn had increased ADG (p<0.05). On d 14 and d 28, pigs fed supplemental Zn had higher the serum alkaline phosphatase activities (p<0.05). No significant differences were observed in the hematological parameters and organ indices. CONCLUSION: Supplementation with 20 to 80 mg/kg Zn from ZnAA improved the growth performance in weaned pigs. The piglets can tolerate up to 800 mg/kg Zn from ZnAA with limited potential health effects. PMID- 29268571 TI - Effects of dietary supplementation of lipid-coated zinc oxide on intestinal mucosal morphology and expression of the genes associated with growth and immune function in weanling pigs. AB - OBJECTIVE: The present study was conducted to investigate the effects of a lipid coated zinc oxide (ZnO) supplement Shield Zn (SZ) at the sub-pharmacological concentration on intestinal morphology and gene expression in weanling pigs, with an aim to gain insights into the mechanism of actions for SZ. METHODS: Forty 22 day-old weanling pigs were fed a nursery diet supplemented with 100 or 2,500 mg Zn/kg with uncoated ZnO (negative control [NC] or positive control [PC], respectively), 100, 200, or 400 mg Zn/kg with SZ for 14 days and their intestinal tissues were taken for histological and molecular biological examinations. The villus height (VH) and crypt depth (CD) of the intestinal mucosa were measured microscopically following preparation of the tissue specimen; expression of the genes associated with growth and immune function was determined using the real time quantitative polymerase chain reaction. RESULTS: There was no difference in daily gain, gain:feed, and diarrhea score between the SZ group and either of NC and PC. The VH and VH:CD ratio were less for the SZ group vs NC in the jejunum and duodenum, respectively (p<0.05). The jejunal mucosal mRNA levels of insulin like growth factor (IGF-I) and interleukin (IL)-10 regressed and tended to regress (p = 0.053) on the SZ concentration with a positive coefficient, respectively, whereas the IL-6 mRNA level regressed on the SZ concentration with a negative coefficient. The mRNA levels of IGF-I, zonula occludens protein-1, tumor necrosis factor-alpha, IL-6, and IL-10 did not differ between the SZ group and either of NC and PC; the occludin and transforming growth factor-beta1 mRNA levels were lower for the SZ group than for PC. CONCLUSION: The present results are interpreted to suggest that dietary ZnO provided by SZ may play a role in intestinal mucosal growth and immune function by modulating the expression of IGF I, IL-6, and IL-10 genes. PMID- 29268572 TI - Relationship between water-holding capacity and intramuscular fat content in Japanese commercial pork loin. AB - OBJECTIVE: The relationship between water-holding capacity (WHC) and intermuscular fat (IMF) was studied in Japanese commercial pork. METHODS: Longissimus muscles of pigs (n = 62), obtained from two meat packing plants, were analyzed for IMF content, moisture content, drip loss, cooking loss, and pH. Pairwise relationships among these traits were determined using correlation analyses. RESULTS: IMF content was significantly correlated with moisture content (r = -0.88; p<0.01) and pH (r = 0.32; p<0.05), but not with drip loss (r = -0.23; p = 0.07) or cooking loss (r = -0.10; p = 0.42). In contrast, drip loss was significantly (and negatively) correlated with pH (r = -0.57; p<0.01). CONCLUSION: IMF content was not significantly correlated with WHC in pork, and so ultimately, we consider pH to be one of the most important factors influencing WHC in pork meat. PMID- 29268573 TI - Reversibility and safety of KISS1 metastasis suppressor gene vaccine in immunocastration of ram lambs. AB - OBJECTIVE: The aim of this study was to investigate the reversibility and safety of KISS1 metastasis suppressor (KISS1) gene vaccine in immunocastration. METHODS: Six eight-week old ram lambs were randomly divided into vaccinated and control groups. The vaccine (1 mg/ram lamb) was injected at weeks 0, 3, and 6 of the study. Blood samples were collected from the jugular vein before primary immunization and at weeks 2, 4, 6, 10, 14, 22, and 30 after primary immunization. All ram lambs were slaughtered at 38 weeks of age, and samples were collected. RESULTS: The specific anti-KISS1 antibody titers in vaccinated animals were significantly higher and the serum testosterone level was significantly lower than those in the control groups from week 4 to 14 after primary immunization (p<0.05). No significant difference was observed at weeks 22 and 30 after the primary immunization. Similar results were also found for scrotal circumference, testicular weight, length, breadth, and spermatogenesis in seminiferous tubules in week 30 after primary immunization. KS (KISS1-hepatitis B surface antigen S) fusion fragment of KISS1 gene vaccine was not detected in host cell genomic DNA of 9 tissues of the vaccinated ram lambs by polymerase chain reaction. CONCLUSION: The effects of KISS1 gene vaccine in immunocastration were reversible and no integration events were recorded. PMID- 29268574 TI - Nutrient variations from swine manure to agricultural land. AB - OBJECTIVE: Swine manure in Korea is separated into solid and liquid phases which are composted separately and then applied on land. The nutrient accumulation in soil has been a big issue in Korea but the basic investigation about nutrient input on arable land has not been achieved in detail. Within the nutrient production from livestock at the national level, most values are calculated by multiplication of the number of animals with the excreta unit per animal. However, the actual amount of nutrients from swine manure may be totally different with the nutrients applied to soil since livestock breeding systems are not the same with each country. METHODS: This study investigated 15 farms producing solid compost and 14 farms producing liquid compost. Composting for solid phase used the Turning+Aeration (TA) or Turning (T) only methods, while liquid phase aeration composting was achieved by continuous (CA), intermittent (IA), or no aeration (NA). Three scenarios were constructed for investigating solid compost: i) farm investigation, ii) reference study, and iii) theoretical P changes (DeltaP = 0), whereas an experiment for water evaporation was conducted for analyzing liquid compost. RESULTS: In farm investigation, weight loss rates of 62% and 63% were obtained for TA and T, respectively, while evaporation rates for liquid compost were 8.75, 7.27, and 5.14 L/m2.d for CA, IA, and NA, respectively. Farm investigation provided with the combined nutrient load (solid+liquid) of VS, N, and P of 117.6, 7.2, and 2.7 kg/head.yr. Nutrient load calculated from farm investigation is about two times higher than the calculated with reference documents. CONCLUSION: The nutrient loading coefficients from one swine (solid+liquid) were (volatile solids, 0.79; nitrogen, 0.53; phosphorus, 0.71) with nutrient loss of 21%, 47%, and 29%, respectively. The nutrient count from livestock manure using the excretion unit has probably been overestimated without consideration of the nutrient loss. PMID- 29268575 TI - The differences between copper sulfate and tribasic copper chloride on growth performance, redox status, deposition in tissues of pigs, and excretion in feces. AB - OBJECTIVE: The objective of this experiment was to compare the effects of adding 130 mg/kg Cu from either copper sulfate (CS) or tribasic copper chloride (TBCC) on growth performance, mineral deposition in tissues, and the excretion in feces of pigs as well as changes in the mineral contents in tissues and feces when the supplemental Cu level was decreased from 130 mg/kg to 10 mg/kg. METHODS: A total of 72 pigs (32.6+/-1.2 kg) were randomly assigned to a CS diet or a TBCC diet with 6 pens per treatment. The trial lasted 102 d and included 3 phases (phase 1, 1 to 30 d; phase 2, 31 to 81 d; and phase 3, 82 to 102 d). The supplemental levels of Cu in the 2 treatments were 130 mg/kg in phase 1 and 2 and 10 mg/kg in phase 3. RESULTS: The results showed that pigs fed the CS diet tended to have higher average daily gain than pigs fed the TBCC diet during d 1 to 81 (p<0.10). Compared with CS, TBCC increased the activities of aspartate transaminase (AST), ceruloplasmin, and superoxide dismutase in serum on d 30 (p<0.05). The TBCC decreased the Cu level in the liver on d 81 (p<0.05) and increased the Mn level in the liver on d 102 (p<0.05). The concentration of Cu in feces sharply decreased when the supplemental Cu level in diet changed from 130 mg/kg to 10 mg/kg in both diets (p<0.05). CONCLUSION: The result suggested that TBCC and CS had no significant difference on growth performance but TBCC had higher activities of AST and antioxidant enzymes and lower liver Cu than CS when pigs fed diets with 130 mg Cu/kg diet. PMID- 29268576 TI - Applications of capacitation status for litter size enhancement in various pig breeds. AB - OBJECTIVE: Several studies have reported the development of new molecular methods for the prognosis and diagnosis of male fertility based on biomarkers aimed at overcoming the limitations of conventional male fertility analysis tools. However, further studies are needed for the field application of these methods. Therefore, alternative methods based on existing semen analysis methods are required to improve production efficiency in the animal industry. METHODS: we examined the possibility of improving litter size in various pig breeds using combined Hoechst 33258/chlortetracycline fluorescence (H33258/CTC) staining. The correlation between field fertility and capacitation status by combined H33258/CTC staining in different ejaculates spermatozoa (n = 3) from an individual boar (20 Landrace, 20 Yorkshire, and 20 Duroc) was evaluated as well as overall accuracy. RESULTS: The acrosome reacted (AR) pattern after capacitation (%) was positively correlated with the litter size of Landrace, Yorkshire, and Duroc pigs and the overall accuracy was 75%, 75%, and 70% in Landrace, Yorkshire, and Duroc pigs, respectively. The difference (Delta) in AR pattern before and after capacitation was positively correlated with the litter size of Landrace, Yorkshire, and Duroc pigs and the overall accuracy was 80%, 65%, and 55% in Landrace, Yorkshire, and Duroc pigs, respectively. However, the difference (Delta) in capacitated (B) pattern before and after capacitation was negatively correlated with the litter size of Landrace pigs and the overall accuracy was 75%. Moreover, average litter size was significantly altered according to different combined H33258/CTC staining parameters. CONCLUSION: These results show that combined H33258/CTC staining may be used to predict male fertility in various breeds. However, the selection of specific efficiency combined H33258/CTC staining parameters requires further consideration. Taken together, these findings suggest that combined H33258/CTC staining may constitute an alternative method for predicting male fertility until such time as fertility related biomarkers are further validated. PMID- 29268577 TI - Acidification of pig slurry effects on ammonia and nitrous oxide emissions, nitrate leaching, and perennial ryegrass regrowth as estimated by 15N-urea flux. AB - OBJECTIVE: The present study aimed to assess the nitrogen (N) use efficiency of acidified pig slurry for regrowth yield and its environmental impacts on perennial ryegrass swards. METHODS: The pH of digested pig slurry was adjusted to 5.0 or 7.0 by the addition of sulfuric acid and untreated as a control. The pig slurry urea of each treatment was labeled with 15N urea and applied at a rate of 200 kg N/ha immediately after cutting. Soil and herbage samples were collected at 7, 14, and 56 d of regrowth. The flux of pig slurry-N to regrowth yield and soil N mineralization were analyzed, and N losses via NH3, N2O emission and NO3- leaching were also estimated. RESULTS: The pH level of the applied slurry did not have a significant effect on herbage yield or N content of herbage at the end of regrowth, whereas the amount of N derived from pig slurry urea (NdfSU) was higher in both herbage and soils in pH-controlled plots. The NH4+-N content and the amount of N derived from slurry urea into soil NH4+ fraction (NdfSU-NH4+) was significantly higher in in the pH 5 plot, whereas NO3- and NdfSU-NO3- were lower than in control plots over the entire regrowth period. Nitrification of NH4+-N was delayed in soil amended with acidified slurry. Compared to non-pH-controlled pig slurry (i.e. control plots), application of acidified slurry reduced NH3 emissions by 78.1%, N2O emissions by 78.9% and NO3- leaching by 17.81% over the course of the experiment. CONCLUSION: Our results suggest that pig slurry acidification may represent an effective means of minimizing hazardous environmental impacts without depressing regrowth yield. PMID- 29268578 TI - L-lysine and L-arginine inhibit the oxidation of lipids and proteins of emulsion sausage by chelating iron ion and scavenging radical. AB - OBJECTIVE: To evaluate the effects of L-lysine (Lys)/L-arginine (Arg) on lipid and protein oxidation of emulsion sausage during storage and its possible mechanism. METHODS: Four samples were prepared based on the presence or absence of additional sodium isoascorbate, Lys, or Arg: sample A (control), sample B (0.05 g of sodium isoascorbate), sample C (0.4 g of Lys), and sample D (0.4 g of Arg). Peroxide value (POV), thiobarbituric reactive substances (TBARS), protein carbonyls and thiols were measured. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical-scavenging, ferrous ion-chelating ability were also measured. RESULTS: Compared with the control, the sample treated with sodium isoascorbate, Lys or Arg had significantly lower POV during the initial 20 days, TBARS during the initial 15 days. Protein carbonyls were significantly lower compared Sample B, C, and D with A during the later storage (10 to 25 days); basically, protein thiols became lower during storage when the samples were treated with sodium isoascorbate, Lys, or Arg. Both Lys and Arg had weak reducing power but strong ferrous ion-chelating activity and DPPH radical- and hydroxyl radical-scavenging activity. CONCLUSION: Both Lys and Arg effectively inhibited the oxidation of lipids and proteins in emulsion sausage by scavenging free radicals and chelating ferrous ions. The results obtained may be favorable for the prevention of lipid and protein oxidation during processing and storage of meat products. PMID- 29268579 TI - Circular RNA expression profiles in the porcine liver of two distinct phenotype pig breeds. AB - OBJECTIVE: An experiment was conducted to identify and characterize the circular RNA expression and metabolic characteristics in the liver of Jinhua pigs and Landrace pigs. METHODS: Three Jinhua pigs and three Landrace pigs respectively at 70-day were slaughtered to collect the liver tissue samples. Immediately after slaughter, blood samples were taken to detect serum biochemical indicators. Total RNA extracted from liver tissue samples were used to prepare the library and then sequence on HiSeq 2500. Bioinformatic methods were employed to analyze sequence data to identify the circRNAs and predict the potential roles of differentially expressed circRNAs between the two breeds. RESULTS: Significant differences in physiological and biochemical traits were observed between growing Jinhua and Landrace pigs. We identified 84,864 circRNA candidates in two breeds and 366 circRNAs were detected as significantly differentially expressed. Their host genes are involved in lipid biosynthetic and metabolic processes according to the gene ontology analysis and associated with metabolic pathways. CONCLUSION: Our research represents the first description of circRNA profiles in the porcine liver from two divergent phenotype pigs. The predicted miRNA-circRNA interaction provides important basis for miRNA-circRNA relationships in the porcine liver. These data expand the repertories of porcine circRNA and are conducive to understanding the possible molecular mechanisms involved in miRNA and circRNA. Our study provides basic data for further research of the biological functions of circRNAs in the porcine liver. PMID- 29268580 TI - Multi-resistance strategy for viral diseases and in vitro short hairpin RNA verification method in pigs. AB - OBJECTIVE: Foot and mouth disease (FMD) and porcine reproductive and respiratory syndrome (PRRS) are major diseases that interrupt porcine production. Because they are viral diseases, vaccinations are of only limited effectiveness in preventing outbreaks. To establish an alternative multi-resistant strategy against FMD virus (FMDV) and PRRS virus (PRRSV), the present study introduced two genetic modification techniques to porcine cells. METHODS: First, cluster of differentiation 163 (CD163), the PRRSV viral receptor, was edited with the clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 technique. The CD163 gene sequences of edited cells and control cells differed. Second, short hairpin RNA (shRNAs) were integrated into the cells. The shRNAs, targeting the 3D gene of FMDV and the open reading frame 7 (ORF7) gene of PRRSV, were transferred into fibroblasts. We also developed an in vitro shRNA verification method with a target gene expression vector. RESULTS: shRNA activity was confirmed in vitro with vectors that expressed the 3D and ORF7 genes in the cells. Cells containing shRNAs showed lower transcript levels than cells with only the expression vectors. The shRNAs were integrated into CD163-edited cells to combine the two techniques, and the viral genes were suppressed in these cells. CONCLUSION: We established a multi-resistant strategy against viral diseases and an in vitro shRNA verification method. PMID- 29268581 TI - Luteinizing hormone beta gene polymorphism and its effect on semen quality traits and luteinizing hormone concentrations in Murrah buffalo bulls. AB - Objective: Present investigation was aimed to study the Single Nucleotide Variants of the luteinizing hormone beta (LHbeta) gene and to analyze their association with the semen quality (fresh and post-thawed frozen semen) and luteinizing hormone (LH) concentrations in Murrah buffalo bulls. METHODS: Polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) and Sanger sequencing method is used to study genetic variability in LHbeta gene. LH assay was carried out using enzyme-linked immunosorbent assay method. A fixed general linear model was used to analyze association of single nucleotide polymorphism (SNP) of LHbeta gene with semen quality in 109 and LH concentrations in 80 Murrah bulls. RESULTS: LHbeta gene was found to be polymorphic. Total six SNPs were identified in LHbeta gene g C356090A, g C356113T, g A356701G, g G355869A, g G356330C, and g G356606T. Single Stranded Conformational Polymorphism variants of pattern 2 of exon 1+pattern 2 of exon 2+pattern 1 of exon 3 had highly significant (p<0.01) effect on sperm concentration (million/mL), percent mass motility, acrosome integrity and membrane integrity in fresh and frozen semen whereas significant (p<0.05) effect was observed on percent live spermatozoa. SSCP variants of pattern 2 of exon 1+pattern 2 of exon 2+pattern 1 of exon 3 had highly significant (p<0.01) effect on luteinizing hormone concentrations too. CONCLUSION: The observed association between SSCP variants of LHbeta gene with semen quality parameters and LH concentrations indicated the possibilities of using LHbeta as a candidate gene for identification of markers for semen quality traits and LH concentrations in Murrah buffaloes. PMID- 29268582 TI - Low incubation temperature successfully supports the in vitro bovine oocyte maturation and subsequent development of embryos. AB - OBJECTIVE: The aim of this study was to compare the effects of 36.5 degrees C and 38.5 degrees C incubation temperatures on the maturation of bovine oocytes and developmental competence of embryos. METHODS: In experiment 1, oocytes were maturated in bicarbonate-buffered TCM-199 for 22 hours in a humidified atmosphere of 5% CO2 in the air at either 36.5 degrees C or 38.5 degrees C and nuclear maturation status were determined. In experiment 2, in vitro fertilized oocytes were allocated randomly into synthetic oviductal fluid medium with or without a mixture of 1 mM L-glutathione reduced and 1,500 IU superoxide dismutase and cultured in a humidified atmosphere of 5% CO2, 5% O2, and 90% N2 in the air at 38.5 degrees C for 8 days. RESULTS: There were no significant differences between incubation temperatures in terms of oocyte maturation parameters such as cumulus expansion, first polar body extrusion and nuclear maturation. Incubation temperatures during in vitro maturation had no effects on developmental competence of embryos, but supplementation of antioxidants increased (p< 0.05) developmental competence of the embryos. Blastocysts from oocytes matured at 38.5 degrees C had comparatively higher inner cell mass, but low overall and trophectoderm cell numbers (p<0.05). CONCLUSION: The results of present study showed that maturation of bovine oocytes at 36.5 degrees C may provide a suitable thermal environment for nuclear maturation and subsequent embryo development. PMID- 29268583 TI - Effects of first feed intake time on growth performance, nutrient apparent metabolic rate and intestinal digestive enzyme activities in broilers. AB - OBJECTIVE: This experiment studied the effects of first feed intake time post hatch on growth performance, nutrient apparent metabolic rate and intestinal digestive enzyme activities in broilers. METHODS: Two thousand five hundred and twenty LingNan Yellow broilers were randomly allotted to seven treatments with six replicates of 60 each. The only experimental factor was the first feed intake time which was 18, 24, 30, 36, 42, 48, and 54 hours after hatching. The whole experiment lasted for 21 days. RESULTS: During the whole period, the 30 h treatment had the best body weight and average daily gain (p<0.05), followed by the 24 h group performance optimization. Also, the 30 h group was observed to have the best apparent metabolic rate for ether extract (p<0.05) and crude protein (p<0.05) and the highest activities of amylase, lipase and trypsin in small intestine. And the 24 h group was second only to the 30 h group in terms of the above two measures. CONCLUSION: These results indicated that the appropriate first feeding time of LingNan Yellow broilers was 24 to 30 hours after hatching. PMID- 29268584 TI - Comparison among methods of effective energy evaluation of corn silage for beef cattle. AB - OBJECTIVE: This study was conducted to compare different methods on effective energy evaluation of corn silage for beef cattle. METHODS: Twenty Wandong bulls (Chinese indigenous yellow cattle) with initial body weight of 281+/-15.6 kg, were assigned to 1 of 5 dietary treatments with 4 animals per treatment in a randomized complete block design. Five dietary treatments included group 1 with corn silage only diet, group 2 with corn silage-concentrate basal diet (BD) and 3 groups with 3 test diets, which were the BD partly substituted by corn silage at 10%, 30%, and 60%. The total collection digestion trial was conducted for 5 d for each block after a 10-d adaptation period, and then an open-circuit respiratory cage was used to measure the gas exchange of each animal in a consecutive 4-d period. RESULTS: The direct method-derived metabolizable energy and net energy of corn silage were 8.86 and 5.15 MJ/kg dry matter (DM), expressed as net energy requirement for maintenance and gain were 5.28 and 2.90 MJ/kg DM, respectively; the corresponding regression method-derived estimates were 8.96, 5.34, 5.37, and 2.98 MJ/kg DM, respectively. The direct method-derived estimates were not different (p>0.05) from those obtained using the regression method. Using substitution method, the nutrient apparent digestibility and effective energy values of corn silage varied with the increased corn silage substitution ratio (p<0.05). In addition, the corn silage estimates at the substitution ratio of 30% were similar to those estimated by direct and regression methods. CONCLUSION: In determining the energy value of corn silage using substitution method, there was a discrepancy between different substitution ratios, and the substitution ratio of 30% was more appropriate than 10% or 60% in the current study. The regression method based on multiple point substitution was more appropriate than single point substitution on energy evaluation of feedstuffs for beef cattle. PMID- 29268585 TI - Analysis of cross-population differentiation between Thoroughbred and Jeju horses. AB - Objective: This study was intended to identify genes positively selected in Thoroughbred horses (THBs) that potentially contribute to their running performances. METHODS: The genomes of THB and Jeju horses (JH, Korean native horse) were compared to identify genes positively selected in THB. We performed cross-population extended haplotype homozygosity (XP-EHH) and cross-population composite likelihood ratio test (XP-CLR) statistical methods for our analysis using whole genome resequencing data of 14 THB and 6 JH. RESULTS: We identified 98 (XP-EHH) and 200 (XP-CLR) genes that are under positive selection in THB. Gene enrichment analysis identified 72 gene ontology biological process (GO BP) terms. The genes and GO BP terms explained some of THB's characteristics such as immunity, energy metabolism and eye size and function related to running performances. GO BP terms that play key roles in several cell signaling mechanisms, which affected ocular size and visual functions were identified. GO BP term Eye photoreceptor cell differentiation is among the terms annotated presumed to affect eye size. CONCLUSION: Our analysis revealed some positively selected candidate genes in THB related to their racing performances. The genes detected are related to the immunity, ocular size and function, and energy metabolism. PMID- 29268587 TI - Effects of cashew nut testa levels as an alternative to wheat bran in gestating sow diets. AB - OBJECTIVE: This study was conducted to evaluate the effects of dietary cashew nut testa (CNT) as an alternative feed ingredient to wheat bran on reproductive performance, litter performance, milk composition, and blood profiles of gestating sows. METHODS: Forth multiparous sows (Yorkshire*Landrace) were fed experimental diets starting at 35 days of pregnancy and an initial average body weight (BW) of 211.53+/-8.86 kg. Each sow was assigned to a treatment based on BW, backfat thickness (BF) and parity with 10 sows per treatment. Treatments were as follows: i) corn-soybean meal based diet with 6% of wheat bran (C0); ii) basal diet with 2% of CNT and 4% of wheat bran (C2); iii) basal diet with 4% of CNT and 2% of wheat bran (C4); and iv) basal diet with 6% of CNT (C6). RESULTS: There were no statistically significant differences in BW and BF of gestating sows throughout the experimental period. However, changes in BF (p = 0.09) and the daily feed intake of sows (p = 0.09) tended to linearly increase during the lactation period. The weaning to estrus interval (WEI) showed a quadratic response to CNT treatment (p = 0.02), and the C2 diet showed the shortest WEI. Litter birth weight (p = 0.04) and piglet birth weight (p = 0.06) were linearly decreased with increase in CNT. Furthermore, there had no significant differences in piglet weight and litter weight in 21 day. Insulin concentration at day 70 of gestation was linearly reduced with increasing CNT level in diets (p = 0.03). CONCLUSION: When 6% CNT replaced wheat bran in gestating sow diets, there were no negative effects on sow performance, but litter birth weight and piglet birth weight were decreased when CNT level increased in gestating sow diets. PMID- 29268586 TI - Immunomodulatory effects of phytogenics in chickens and pigs - A review. AB - Environmental stressors like pathogens and toxins may depress the animal immune system through invasion of the gastrointestinal tract (GIT) tract, where they may impair performance and production, as well as lead to increased mortality rates. Therefore, protection of the GIT tract and improving animal health are top priorities in animal production. Being natural-sourced materials, phytochemicals are potential feed additives possessing multiple functions, including: anti inflammatory, anti-fungal, anti-viral and antioxidative properties. This paper focuses on immunity-related physiological parameters regulated by phytochemicals, such as carvacrol, cinnamaldehyde, curcumin, and thymol; many studies have proven that these phytochemicals can improve animal performance and production. On the molecular level, the impact of inflammatory gene expression on underlying mechanisms was also examined, as were the effects of environmental stimuli and phytochemicals in initiating nuclear factor kappa B and mitogen-activated protein kinases signaling pathways and improving health conditions. PMID- 29268588 TI - Effects of feeding different varieties of faba bean (Vicia faba L.) straws with concentrate supplement on feed intake, digestibility, body weight gain and carcass characteristics of Arsi-Bale sheep. AB - Objective: A study was conducted to evaluate the varietal differences among faba bean straws and also to assess the potentials of faba bean straws supplemented with concentrate fed at the rate 70% straws and 30% concentrate mixture on feed intake, digestibility, body weight gain and carcass characteristics of the animals. METHODS: Forty yearling Arsi-Bale sheep with initial body weight of 19.85+/-0.29 kg (mean+/- standard deviation) were grouped in a randomized complete block design into eight blocks of five animals each based on their initial body weight. Straws included in the study were from Mosisa (T1M), Walki (T2W), Degaga (T3D), Shallo (T4S), and local (T5L) varieties of faba bean and concentrate (2:1 ratio of wheat bran to "noug" seed cake). The experiment consisted of seven days of digestibility and 90 days of feeding trials followed by evaluation of carcass parameters at the end. RESULTS: Local variety had lower (p<0.05) in grain and straw yield compared to improved varieties but higher in crude protein, metabolizable energy contents and in vitro organic matter digestibility. The apparent digestibility of dry matter and crude protein of sheep fed Walki and Mosisa straws were higher than (p<0.05) straws from Shallo varieties. Sheep fed Walki straw had greater (p<0.05) dry matter intake, average daily gain and feed conversion efficiency than sheep fed local and Shallo straws. Slaughter body weight and empty body weight were higher (p<0.05) for sheep fed Mosisa and Walki straws as compared to sheep fed Shallo straws. Apart from this, the other carcass components were not affected (p>0.05) by variety of the faba bean straws. CONCLUSION: There is significant varietal differences between faba bean straws both in quality and quantity. Similarly, significant variation was observed in feed intake, digestibility, body weight gain and feed conversion efficiency among sheep fed different straws of faba bean varieties with concentrate supplement. Based on these results, Walki and Mosisa varieties could be recommended as pulse crop rotation with cereals in the study area. PMID- 29268589 TI - Correlation between blood, physiological and behavioral parameters in beef calves under heat stress. AB - OBJECTIVE: The performance, health, and behaviour of cattle can be strongly affected by climate. The objective of this study was to determine the effect of heat stress on blood parameters, blood proteins (haptoglobin [Hp]; heat shock protein 70 [HSP70]), rectal temperature (RT), heart rate (HR) and rumination time in Korean native beef calves. METHODS: Thirty-two Korean native beef calves were randomly assigned to 8 groups with 4 animals per group. They were kept in environmental condition with temperature-humidity index (THI) ranging from 70.01 to 87.72 in temperature-humidity controlled chamber for 7 days. RESULTS: Their HR, RT, and serum cortisol and HSP70 levels were increased (p<0.05) in high THI compared to those at low THI. But, serum Hp level was decreased (p<0.05) in high THI compared to these at low THI. In addition, HR, RT, serum cortisol and HSP70 were positively correlated with THI (R2 = 0.8368, p<0.01; R2 = 0.6162, p<0.01; R2 = 0.581, p<0.01; R2 = 0.2241, p = 0.0062, respectively). There was also positive association between HR and cortisol (R2 = 0.4697, p<0.01). Similarly, RT and cortisol were positively associated (R2 = 0.4581, p<0.01). But, THI and HR were negatively correlated with Hp (R2 = 0.2157, p = 0.02; R2 = 0.3362, p = 0.003). Hematology and metabolites results were different among treatment groups. Standing position was higher (p<0.05) in the high THI group compared to that in the low THI group. CONCLUSION: Based on these results, it can be concluded that HR, RT, blood parameters (Cortisol, HSP70, Hp) and standing position are closely associated with heat stress. These parameters can be consolidated to develop THI chart for Korean native beef calves. PMID- 29268590 TI - Morphological defects of sperm and their association with motility, fertility, and hatchability in four Korean native chicken breeds. AB - Objective: This study was conducted to compare morphological defects, viability, motility (MOT), fertility (F), and hatchability (H) in four Korean native chicken breeds (KNCBs), and to evaluate whether defective segments of spermatozoa are associated with MOT, F, and H. METHODS: Four KNCBs, including Korean Ogye (KO), Hwangbong (HB), Hyunin Black (HH), and Hoengseong Yakdak (HY) were used. White Leghorn (WL) was used as a control. Nine cocks from each breed were randomly assigned into three groups. Semen was collected by abdominal massage method. Eosin-nigrosin staining method was used to identify live-dead spermatozoa. Different segments and specific morphological defects of spermatozoa were identified using 4', 6-diamidino-2-phenylidole and MitoTracker Red CMXRos. F and H rates were evaluated following artificial insemination (AI). RESULTS: KO had the highest MOT rate compared to HY. Viable normal sperm rates of KO and HH were high and comparable with WL. HY spermatozoa had the highest viable abnormal sperm (VAS) or morphological defect rate followed by HB. Likewise, HB spermatozoa had the highest dead sperm (dead) rate compared to KO, HY, and WL. Bent, coiled, detached, broken, and knotted were common identified specific morphological defects for all breeds. Most morphological defects were at the head and tail in all breeds. VAS showed strong negative correlation with MOT (r = -0.697) and F (r = -0.609). Similarly, defective tail was negatively correlated with MOT (r = 0.587), F (r = -0.797), and H (r = -0.448). The F and H rates of KO and WL were comparable. CONCLUSION: These data indicate that most identified specific morphological defects are at the head and tail. VAS and defective tail were associated with poor motility, F, and H. KNCBs showed more morphological defects than WL. Finally, these results will facilitate successful AI and semen cryopreservation. PMID- 29268591 TI - A genome-wide association study of social genetic effects in Landrace pigs. AB - OBJECTIVE: The genetic effects of an individual on the phenotypes of its social partners, such as its pen mates, are known as social genetic effects. This study aims to identify the candidate genes for social (pen-mates') average daily gain (ADG) in pigs by using the genome-wide association approach. METHODS: Social ADG (sADG) was the average ADG of unrelated pen-mates (strangers). We used the phenotype data (16,802 records) after correcting for batch (week), sex, pen, number of strangers (1 to 7 pigs) in the pen, full-sib rate (0% to 80%) within pen, and age at the end of the test. A total of 1,041 pigs from Landrace breeds were genotyped using the Illumina PorcineSNP60 v2 BeadChip panel, which comprised 61,565 single nucleotide polymorphism (SNP) markers. After quality control, 909 individuals and 39,837 markers remained for sADG in genome-wide association study. RESULTS: We detected five new SNPs, all on chromosome 6, which have not been associated with social ADG or other growth traits to date. One SNP was inside the prostaglandin F2alpha receptor (PTGFR) gene, another SNP was located 22 kb upstream of gene interferon-induced protein 44 (IFI44), and the last three SNPs were between 161 kb and 191 kb upstream of the EGF latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) gene. PTGFR, IFI44, and ELTD1 were never associated with social interaction and social genetic effects in any of the previous studies. CONCLUSION: The identification of several genomic regions, and candidate genes associated with social genetic effects reported here, could contribute to a better understanding of the genetic basis of interaction traits for ADG. In conclusion, we suggest that the PTGFR, IFI44, and ELTD1 may be used as a molecular marker for sADG, although their functional effect was not defined yet. Thus, it will be of interest to execute association studies in those genes. PMID- 29268593 TI - Multiple Neuroendocrine Tumors in Stomach and Duodenum in a Multiple Endocrine Neoplasia Type 1 Patient. AB - A 67-year-old woman with a history of subtotal parathyroidectomy, distal pancreatectomy, and total splenectomy 23 years prior underwent surgical gastric resection for neuroendocrine tumors of the stomach and duodenum. Meticulous examination of the entire stomach and duodenum revealed multiple scattered, minute neuroendocrine tumors. To the best of our knowledge, this is the first case report of a patient diagnosed with gastroduodenal neuroendocrine tumors associated with multiple endocrine neoplasia type 1 (MEN 1) in whom complete histologic mapping of the whole gastrectomy specimen was performed. The presence of MEN 1-associated neuroendocrine tumors in the stomach is very rare, but should be considered in patients diagnosed with MEN 1 who present with a new tumor in the stomach. PMID- 29268592 TI - The effects of low-protein diets and protease supplementation on broiler chickens in a hot and humid tropical environment. AB - Objective: This experiment was conducted to investigate the effects of dietary crude protein (CP) level and exogenous protease supplementation on growth performance, serum metabolites, carcass traits, small intestinal morphology and endogenous protease activity in broiler chickens reared under a tropical climate. METHODS: A total of 480 day-old male broiler chicks were randomly assigned to eight dietary treatments in a 4*2 factorial arrangement. The main effects were CP level (21.0%, 19.7%, 18.5%, or 17.2% from 1 to 21 days and 19.0%, 17.9%, 16.7%, or 15.6% from 22 to 35 days) and protease enzyme supplementation (0 ppm or 500 ppm). All experimental diets were fortified with synthetic feed-grade lysine, methionine, threonine and tryptophan to provide the minimum amino acid recommended levels for Cobb 500. RESULTS: Reducing dietary CP linearly reduced (p<0.05) growth performance, serum albumin, total protein, and carcass traits and increased (p<0.05) serum triglycerides and abdominal fat. There was no consistent effect of reducing dietary CP on morphological parameters of the intestine and on the pancreatic and intestinal endogenous protease activity (p>0.05). Protease supplementation improved (p<0.05) feed conversion ratio, body weight gain, carcass yield and intestinal absorptive surface area. CONCLUSION: Protease supplementation, as measured by growth performance, intestinal morphology and carcass yield, may alleviate the detrimental effects of low protein diets in broiler chickens. PMID- 29268594 TI - Aberrant CD3 Expression in a Relapsed Plasma Cell Neoplasm. PMID- 29268596 TI - The use of fully covered self-expanding metal stents for benign biliary etiologies: are we getting it right? PMID- 29268595 TI - Microbiota, a key player in alcoholic liver disease. AB - Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. Only 20% of heavy alcohol consumers develop alcoholic liver cirrhosis. The intestinal microbiota (IM) has been recently identified as a key player in the severity of liver injury in ALD. Common features of ALD include a decrease of gut epithelial tight junction protein expression, mucin production, and antimicrobial peptide levels. This disruption of the gut barrier, which is a prerequisite for ALD, leads to the passage of bacterial products into the blood stream (endotoxemia). Moreover, metabolites produced by bacteria, such as short chain fatty acids, volatile organic compounds (VOS), and bile acids (BA), are involved in ALD pathology. Probiotic treatment, IM transplantation, or the consumption of dietary fiber, such as pectin, which all alter the ratio of bacterial species, have been shown to improve liver injury in animal models of ALD and to be associated with an improvement in gut barrier function. Although the connections between the microbiota and the host in ALD are well established, the underlying mechanisms are still an active area of research. Targeting the microbiome through the use of prebiotic, probiotic, and postbiotic modalities could be an attractive new approach to manage ALD. PMID- 29268597 TI - Recent perspectives of pediatric rhinitis. AB - Rhinitis is a common global disorder, which impacts on the quality of life of the sufferer and caregivers. We searched the electronic database PubMed for preclinical as well as clinical controlled trials reporting various outcomes, developments as well as latest perspectives with regard to management of pediatric rhinitis. It was observed clearly that multiple factors are responsible for its prevalence. The important ones are genetic factors, environmental factors, role of allergens, viral attacks and possible effects of nutrition. The present review article summarizes the current knowledge on the early childhood rhinitis; in particular, on the prevalence rates, phenotypes, associated co morbidities, and risk factors. PMID- 29268598 TI - The influence of dexmedetomidine on the emergence agitation of pediatric patients after the operations of sense organs under general anesthesia using sevoflurane. AB - BACKGROUND: We investigated the influence of dexmedetomidine on the emergence agitation of pediatric patients after ophthalmologic operation under general anesthesia using sevoflurane. METHODS: We selected 90 patients that were administered pediatric ophthalmologic operation for the study. The patients were randomly divided into 3 groups according to the administration way of drugs, i.e. the normal saline group (Group S, n = 30), the midazolam group (Group M, n = 30) and the dexmedetomidine group (Group D, n = 30). For all patients, anesthesia induction was performed using sevoflurane before anesthesia, and the anesthesia was maintained in the operation with a combination of sevoflurane and remifentanil; laryngeal mask airway (LMA) was used for assisted ventilation. 10 minutes before the end of operation, 15mL of 0.9% normal saline, 0.05mg/kg of midazolam and 0.5MUg/kg of dexmedetomidine were administered to Group S, Group M and Group D, respectively. After the operation, we observed the awakening time, time of the LMA removal as well as the recovery time in the post anesthesia care unit (PACU) of patients in all three groups. We evaluated the postoperative condition of sedation and agitation of the patients using Ramsay sedation scale, 5-point scale and pediatric anesthesia emergence deliriums scale (PAED) and performed statistical analysis. RESULTS: In the comparisons of awakening time, time of the LMA removal as well as the recovery time, we found that Group M was the longest sequentially followed by Group D and Group S with statistically significant differences (P < 0.05). While the comparison of the scores of Ramsay sedation scale revealed that Group D scored highest followed by Group M and Group S with statistically significant differences (P < 0.05), both of the comparisons of the scores of 5-point scale and PAED scale showed that Group D scored the lowest, followed by Group M and Group S in sequence with statistically significant differences (P < 0.05). CONCLUSIONS: Dexmedetomidine can significantly lower the incidence of emergence agitation of pediatric patients after the ophthalmologic operation under sevoflurane anesthesia. PMID- 29268599 TI - Boron Nitride Quantum Dots as Efficient Coreactant for Enhanced Electrochemiluminescence of Ruthenium(II) Tris(2,2'-bipyridyl). AB - In the present work, an enhanced and stable anodic electrochemiluminescence (ECL) was observed from a suspension of boron nitride quantum dots (BNQDs) and Ru(bpy)32+, which had a 400-fold enhancement compared with individual Ru(bpy)32+. Interestingly, different from the previous research on BNQDs as a type of optical probe, BNQDs were demonstrated as an efficient coreactant of Ru(bpy)32+-based ECL for the first time and confirmed by collecting the ECL spectra. The amino-bearing groups and the electrocatalytic effect of the BNQDs endowed them as potential coreactants for ECL of Ru(bpy)32+, and the possible mechanism of the electrode surface reaction was discussed. Several factors including electrode material, the pH of the buffer solution, and the amount of BNQDs were investigated and also further confirmed the role of the BNQDs in the proposed Ru(bpy)32+/BNQDs system. On the basis of the quenching effect between the excited state of Ru(bpy)32+ and the oxidation form of DA in the ECL system of Ru(bpy)32+/BNQDs, the ECL sensing platform for DA was successfully established. The proposed ECL system with the outstanding ECL efficiency may hold great potential in the bioanlysis because of the biocompatibility and good stability of BNQDs. PMID- 29268600 TI - Evaporation of Nanosuspensions on Substrates with Different Hydrophobicity. AB - Liquid drop evaporation on surfaces is present in many industrial and medical applications, e.g., printed electronics, spraying of pesticides, DNA mapping, etc. Despite this strong interest, a theoretical description of the dynamic of the evaporation of complex liquid mixtures and nanosuspensions is still lacking. Indeed, one of the aspects that have not been included in the current theoretical descriptions is the competition between the kinetics of evaporation and the adsorption of surfactants and/or particles at the liquid/vapor and liquid/solid interfaces. Materials formed by an electrically isolating solid on which a patterned conducting layer was formed by the deposits left after drop evaporation have been considered as very promising for building electrical circuits on flexible plastic substrates. In this work, we have done an exhaustive study of the evaporation of nanosuspensions of latex and hydrophobized silver nanoparticles on four substrates of different hydrophobicity. The advancing and receding contact angles as well as the time dependence of the volume of the droplets have been measured over a broad range of particle concentrations. Also, mixtures of silver particles and a surfactant, commonly used in industrial printing, have been examined. Furthermore, the adsorption kinetics at both the air/liquid and solid/liquid interfaces have been measured. Whereas the latex particles do not adsorb at the solid/liquid and only slightly reduce the surface tension, the silver particles strongly adsorb at both interfaces. The experimental results of the evaporation process were compared with the predictions of the theory of Semenov et al. (Evaporation of Sessile Water Droplets: Universal Behavior in the Presence of Contact Angle Hysteresis. Colloids Surf. Physicochem. Eng. Asp. 2011, 391 (1-3), 135-144) and showed surprisingly good agreement despite that the theory was developed for pure liquids. The morphology of the deposits left by the droplets after total evaporation was studied by scanning electronic microscopy, and the effects of the substrate, the particle nature, and their concentrations on these patterns are discussed. PMID- 29268601 TI - A New Class of Metal-Cyclam-Based Zirconium Metal-Organic Frameworks for CO2 Adsorption and Chemical Fixation. AB - Metal-organic frameworks (MOFs) have shown great promise in catalysis, mainly due to their high content of active centers, large internal surface areas, tunable pore size, and versatile chemical functionalities. However, it is a challenge to rationally design and construct MOFs that can serve as highly stable and reusable heterogeneous catalysts. Here two new robust 3D porous metal-cyclam-based zirconium MOFs, denoted VPI-100 (Cu) and VPI-100 (Ni), have been prepared by a modulated synthetic strategy. The frameworks are assembled by eight-connected Zr6 clusters and metallocyclams as organic linkers. Importantly, the cyclam core has accessible axial coordination sites for guest interactions and maintains the electronic properties exhibited by the parent cyclam ring. The VPI-100 MOFs exhibit excellent chemical stability in various organic and aqueous solvents over a wide pH range and show high CO2 uptake capacity (up to ~9.83 wt% adsorption at 273 K under 1 atm). Moreover, VPI-100 MOFs demonstrate some of the highest reported catalytic activity values (turnover frequency and conversion efficiency) among Zr-based MOFs for the chemical fixation of CO2 with epoxides, including sterically hindered epoxides. The MOFs, which bear dual catalytic sites (Zr and Cu/Ni), enable chemistry not possible with the cyclam ligand under the same conditions and can be used as recoverable stable heterogeneous catalysts without losing performance. PMID- 29268602 TI - Multiple Conformational States Contribute to the 3D Structure of a Glucan Decasaccharide: A Combined SAXS and MD Simulation Study. AB - The inherent flexibility of carbohydrates is dependent on stereochemical arrangements, and characterization of their influence and importance will give insight into the three-dimensional structure and dynamics. In this study, a beta (1->4)/beta-(1->3)-linked glucosyl decasaccharide is experimentally investigated by synchrotron small-angle X-ray scattering from which its radius of gyration (Rg) is obtained. Molecular dynamics (MD) simulations of the decasaccharide show four populated states at each glycosidic linkage, namely, syn- and anti conformations. The calculated Rg values from the MD simulation reveal that in addition to syn-conformers the presence of anti-psi conformational states is required to reproduce experimental scattering data, unveiling inherent glycosidic linkage flexibility. The CHARMM36 force field for carbohydrates thus describes the conformational flexibility of the decasaccharide very well and captures the conceptual importance that anti-conformers are to be anticipated at glycosidic linkages of carbohydrates. PMID- 29268603 TI - Transmission Electron Microscopy Reveals Deposition of Metal Oxide Coatings onto Metal-Organic Frameworks. AB - Postsynthetic strategies for modifying metal-organic frameworks (MOFs) have proven to be an incredibly powerful approach for expanding the scope and functionality of these materials. Previously, we reported on the postsynthetic exchange (PSE) of metal ions and ligands in the University of Oslo (UiO) series of MOFs. Detailed characterization by several analytical methods, most notably inductively coupled plasma mass spectrometry and transmission electron microscopy reveal that metal ion deposition on the surface of these MOFs occurs in the form of nanoscale metal oxides, rather than yielding exchanged metal sites within the MOFs, as was previously reported. By contrast, these combined analytical methods do confirm that ligand-based PSE can occur in these MOFs. These findings provide new insight into the postsynthetic manipulation of MOF materials, highlight the importance of rigorously characterizing these materials to correctly assign their composition and structure, and provide a new route to making hybrid solids with a MOF@metal oxide architecture. PMID- 29268604 TI - Tellurium: Fast Electrical and Atomic Transport along the Weak Interaction Direction. AB - In anisotropic materials, the electrical and atomic transport along the weak interaction direction is usually much slower than that along the chemical bond direction. However, Te, an important semiconductor composed of helical atomic chains, exhibits nearly isotropic electrical transport between intrachain and interchain directions. Using first-principles calculations to study bulk and few layer Te, we show that this isotropy is related to similar effective masses and potentials for charge carriers along different transport directions, benefiting from the delocalization of the lone-pair electrons. This delocalization also enhances the interchain binding, and thus facilitates diffusion of vacancies and interstitial atoms across the chains, which together with the fast intrachain diffusion enable rapid self-healing of these defects at low temperature. Interestingly, the interstitial atoms diffuse along the chain via a concerted rotation mechanism. Our work reveals the unconventional properties underlying the superior performance of Te while providing insight into the transport in anisotropic materials. PMID- 29268605 TI - Magnetically Coated Bioabsorbable Stents for Renormalization of Arterial Vessel Walls after Stent Implantation. AB - The insertion of a stent in diseased arteries is a common endovascular procedure that can be compromised by the development of short- and long-term inflammatory responses leading to restenosis and thrombosis, respectively. While treatment with drugs, either systemic or localized, has decreased the incidence of restenosis and thrombosis these complications persist and are associated with a high mortality in those that present with stent thrombosis. We reasoned that if stents could be made to undergo accelerated endothelialization in the deployed region, then such an approach would further decrease the occurrence of stent thrombosis and restenosis thereby improving clinical outcomes. Toward that objective, the first step necessitated efficient capture of progenitor stem cells, which eventually would become the new endothelium. To achieve this objective, we engineered intrinsic ferromagnetism within nonmagnetizable, biodegradable magnesium (Mg) bare metal stents. Mg stents were coated with biodegradable polylactide (PLA) polymer embedding magnetizable iron-platinum (FePt) alloy nanoparticles, nanomagnetic particles, nMags, which increased the surface area and hence magnetization of the stent. nMags uniformly distributed on stents enabled capture, under flow, up to 50 mL/min, of systemically injected iron-oxide-labeled (IO-labeled) progenitor stem cells. Critical parameters enhancing capture efficiency were optimized, and we demonstrated the generality of the approach by showing that nMag-coated stents can capture different cell types. Our work is a potential paradigm shift in engineering stents because implants are rendered as tissue in the body, and this "natural stealthiness" reduces or eliminates issues associated with pro-inflammatory immune responses postimplantation. PMID- 29268606 TI - Cascade Oxidation/Halogenoaminocyclization Reaction of Trifluoromethylated Homoallylic N-Acylhydrazines: Metal-free Synthesis of CF3-Substituted Pyrazolines. AB - An efficient and practical cascade oxidation/halogenoaminocyclization of trifluoromethylated homoallylic N-acylhydrazines is developed. The protocol enables an efficient access to various biologically interesting CF3-containing pyrazoline compounds from readily accessible trifluoromethylated homoallylic N acylhydrazines in good to excellent yields under mild conditions without any other additives or catalysts. The produced pyrazoline compounds can be further manipulated to other more complicated derivatives through transformation of residual halogen atom. PMID- 29268607 TI - Highly Oriented Nanowire Thin Films with Anisotropic Optical Properties Driven by the Simultaneous Influence of Surface Templating and Shear Forces. AB - The functional properties of nanoparticle thin films depend strongly on the arrangement of the nanoparticles within the material. In particular, anisotropic optoelectronic properties can be achieved through the aligned assembly of 1D nanomaterials such as silver nanowires (AgNWs). However, the control of the hierarchical organization of these nanoscale building blocks across multiple length scales and over large areas is still a challenge. Here, we show that the oriented deposition of AgNWs using grazing incidence spraying of the nano-object suspensions on a substrate comprising parallel surface wrinkles readily produces highly oriented monolayer thin films on macroscopic areas (>5 * 5 mm2). The use of textured substrates enhances the degree of ordering as compared to flat ones and increases the area over which AgNWs are oriented. The resulting microscopic linear arrangement of AgNWs evaluated by scanning electron microscopy (SEM) reflects in a pronounced macroscopic optical anisotropy measured by conventional polarized UV-vis-NIR spectroscopy. The enhanced ordering obtained when spraying is done in the same direction as the wrinkles makes this approach more robust against small rotational offsets during preparation. On the contrary, the templating effect of the wrinkle topography can even dominate the shear-driven alignment when spraying is performed perpendicular to the wrinkles: the concomitant but opposing influence of topographic confinement (alignment along the wrinkles) and of spray-induced shear forces (orientation along the spraying direction) lead to films in which the predominant orientation of AgNWs gradually changes from one direction to its perpendicular one over the same substrate in a single processing step. This demonstrates that exploiting the subtle balance between shear forces and substrate-nanowire interactions mediated by wrinkles offers a new way to control the self-assembly of nanoparticles into more complex patterns. PMID- 29268608 TI - Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein. AB - S119 was a top hit from an ultrahigh throughput screen performed to identify novel inhibitors of influenza virus replication. It showed a potent antiviral effect (50% inhibitory concentration, IC50 = 20 nM) and no detectable cytotoxicity (50% cytotoxic concentration, CC50 > 500 MUM) to yield a selectivity index greater than 25 000. Upon investigation, we found that S119 selected for resistant viruses carrying mutations in the viral nucleoprotein (NP). These resistance mutations highlight a likely S119 binding site overlapping with but not identical to that found for the compound nucleozin. Mechanism of action studies revealed that S119 affects both the oligomerization state and cellular localization of the NP protein which has an impact on viral transcription, replication, and protein expression. Through a hit-to-lead structure-activity relationship (SAR) study, we found an analog of S119, named S119-8, which had increased breadth of inhibition against influenza A and B viruses accompanied by only a small loss in potency. Finally, in vitro viral inhibition assays showed a synergistic relationship between S119-8 and oseltamivir when they were combined, indicating the potential for future drug cocktails. PMID- 29268609 TI - Mol2vec: Unsupervised Machine Learning Approach with Chemical Intuition. AB - Inspired by natural language processing techniques, we here introduce Mol2vec, which is an unsupervised machine learning approach to learn vector representations of molecular substructures. Like the Word2vec models, where vectors of closely related words are in close proximity in the vector space, Mol2vec learns vector representations of molecular substructures that point in similar directions for chemically related substructures. Compounds can finally be encoded as vectors by summing the vectors of the individual substructures and, for instance, be fed into supervised machine learning approaches to predict compound properties. The underlying substructure vector embeddings are obtained by training an unsupervised machine learning approach on a so-called corpus of compounds that consists of all available chemical matter. The resulting Mol2vec model is pretrained once, yields dense vector representations, and overcomes drawbacks of common compound feature representations such as sparseness and bit collisions. The prediction capabilities are demonstrated on several compound property and bioactivity data sets and compared with results obtained for Morgan fingerprints as a reference compound representation. Mol2vec can be easily combined with ProtVec, which employs the same Word2vec concept on protein sequences, resulting in a proteochemometric approach that is alignment independent and thus can also be easily used for proteins with low sequence similarities. PMID- 29268611 TI - Atom Pair Contribution Method: Fast and General Procedure To Predict Molecular Formation Enthalpies. AB - An atom pair contribution (APC) model aimed at predicting the gas-phase formation enthalpy (DeltafH degrees ) of molecules is reported. In contrast to bond contribution (BC) or group contribution (GC) methods, it relies on increments associated with pairs of bonded and geminal atoms along with 15 structural corrections. Another distinctive feature of the present APC method is the large amount of experimental and high-level theoretical data specially compiled in this work to fit and validate the model (2671 entries). Unlike GC methods, the present APC model has wide applicability with the number of adjustable parameters limited to 68. Although it requires only a structural formula as input and involves only back-of-the-envelope calculations, it is more reliable than state-of-the-art quantitative structure-property relationship methods, popular semiempirical Hamiltonians, and even low-level density functional theory approaches based on gradient-corrected functionals. It is therefore a valuable tool for fast screening applications or whenever chemical accuracy is not necessary. PMID- 29268612 TI - A Facile Ion-Doping Strategy To Regulate Tumor Microenvironments for Enhanced Multimodal Tumor Theranostics. AB - Integration of multiple therapeutic/diagnostic modalities into a single system holds great promise to improve theranostic efficiency for tumors, but still remains a technical challenge. Herein, we report a new multimodal theranostic nanoconstruct based on Fe-doped polydiaminopyridine nanofusiforms, built easily and on a large scale, which can dual-regulate intracellular oxygen and glutathione levels, transport iron ions, and simultaneously be used for thermal imaging and magnetic resonance imaging. Co-loading of dihydroartemisinin and methylene blue generates a superior multifunctional theranostic agent with enhanced photochemotherapy efficiency and biodegradability, leading to almost complete destruction of tumors with near-infrared light irradiation. This represents an attractive route to develop multimodal anticancer theranostics. PMID- 29268610 TI - Driving Protein Conformational Changes with Light: Photoinduced Structural Rearrangement in a Heterobimetallic Oxidase. AB - The heterobimetallic R2lox protein binds both manganese and iron ions in a site selective fashion and activates oxygen, ultimately performing C-H bond oxidation to generate a tyrosine-valine cross-link near the active site. In this work, we demonstrate that, following assembly, R2lox undergoes photoinduced changes to the active site geometry and metal coordination motif. Through spectroscopic, structural, and mass spectrometric characterization, the photoconverted species is found to consist of a tyrosinate-bound iron center following light-induced decarboxylation of a coordinating glutamate residue and cleavage of the tyrosine valine cross-link. This process occurs with high quantum efficiencies (Phi = 3%) using violet and near-ultraviolet light, suggesting that the photodecarboxylation is initiated via ligand-to-metal charge transfer excitation. Site-directed mutagenesis and structural analysis suggest that the cross-linked tyrosine-162 is the coordinating residue. One primary product is observed following irradiation, indicating potential use of this class of proteins, which contains a putative substrate channel, for controlled photoinduced decarboxylation processes, with relevance for in vivo functionality of R2lox as well as application in environmental remediation. PMID- 29268613 TI - Precisely Tuning Helical Twisting Power via Photoisomerization Kinetics of Dopants in Chiral Nematic Liquid Crystals. AB - It has been paid much attention to improve the helical twisting power (beta) of dopants in chiral nematic liquid crystals (CLCs); however, the correlations between the beta value and the molecular structures as well as the interaction with nematic LCs are far from clear. In this work, a series of reversibly photo switchable axially chiral dopants with different lengths of alkyl or alkoxyl substituent groups have been successfully synthesized through nucleophilic substitution and the thiol-ene click reaction. Then, the effect of miscibility between these dopants and nematic LCs on the beta values, as well as the time dependent decay/growth of the beta values upon irradiations, has been investigated. The theoretical Teas solubility parameter shows that the miscibility between dopants and nematic LCs decreases with increasing of the length of substituent groups from dopant 1 to dopant 4. The beta value of chiral dopants in nematic LCs decreases from dopant 1 to dopant 4 both at the visible light photostationary state (PSS) and at the UV PSS after UV irradiation. With increasing of the length of substituent groups, the photoisomerization rate constant of dopants increases for trans-cis transformation upon UV irradiation and decreases for the reverse process upon visible light irradiation either in isotropic ethyl acetate or in anisotropic LCs, although the constant in ethyl acetate is several times larger than the corresponding value in LCs. Also, the color of the CLCs could be tuned upon light irradiations. These results enable the precise tuning of the pitch and selective reflection wavelength/color of CLCs, which paves the way to the applications in electro-optic devices, information storage, high-tech anticounterfeit, and so forth. PMID- 29268615 TI - RESPEC Incorporates Residue Specificity and the Ligand Effect into the Elastic Network Model. AB - RESPEC is a new framework that introduces residue specificity into elastic network modeling (ENM) to successfully render intact protein-ligand complexes as well as apo proteins. This framework establishes a broader application of coarse graining idea via describing (i) a coarse-grained residue/node through its heavy atoms as virtual nodes, (ii) an effective B-factor for such a node, directly obtained from the experimental data, and (iii) a node-node interaction by a cumulative distance-dependent force constant. RESPEC improves the level of correlations with B-factors after optimizing the parameters of the model. In the absence of ligands, the mean correlations exceed 0.72, which is higher than the classical ENM results, based on a diverse set of proteins. Global modes satisfactorily describe the conformational transitions for apo structures. When the ligands are included at atomistic resolution in RESPEC calculations, mean correlation values exceed 0.9 over the same data set. PMID- 29268617 TI - Sensors in China. PMID- 29268618 TI - Understanding the impact of diet and nutrition on symptoms of Tourette syndrome: A scoping review. AB - Anecdotal reports frequently suggest some dietary involvement in the maintenance of tics in children with Tourette syndrome (TS). This scoping review aimed to (1) understand the possible influence of diet as a trigger of tics and (2) map out the existing studies documenting dietary interventions in children with TS. Current evidence suggests no single diet to benefit individuals with TS. However, reports from parents of children with TS suggest that certain allergens in food may exacerbate tic-related symptoms. For example, an increase in tics has been related to the consumption of caffeine and refined sugar. Moreover, oligoantigenic diets and sugar-free diets have been identified as significantly reducing tics. More research is urgently needed to develop more accurate guidance for parents and children with TS, as many have reported using dietary and nutritional supplements, despite the lack of evidence detailing any benefits, side effects and recommended doses. PMID- 29268614 TI - Cyclopropanations via Heme Carbenes: Basic Mechanism and Effects of Carbene Substituent, Protein Axial Ligand, and Porphyrin Substitution. AB - Catalytic carbene transfer to olefins is a useful approach to synthesize cyclopropanes, which are key structural motifs in many drugs and biologically active natural products. While catalytic methods for olefin cyclopropanation have largely relied on rare transition-metal-based catalysts, recent studies have demonstrated the promise and synthetic value of iron-based heme-containing proteins for promoting these reactions with excellent catalytic activity and selectivity. Despite this progress, the mechanism of iron-porphyrin and hemoprotein-catalyzed olefin cyclopropanation has remained largely unknown. Using a combination of quantum chemical calculations and experimental mechanistic analyses, the present study shows for the first time that the increasingly useful C?C functionalizations mediated by heme carbenes feature an FeII-based, nonradical, concerted nonsynchronous mechanism, with early transition state character. This mechanism differs from the FeIV-based, radical, stepwise mechanism of heme-dependent monooxygenases. Furthermore, the effects of the carbene substituent, metal coordinating axial ligand, and porphyrin substituent on the reactivity of the heme carbenes was systematically investigated, providing a basis for explaining experimental reactivity results and defining strategies for future catalyst development. Our results especially suggest the potential value of electron-deficient porphyrin ligands for increasing the electrophilicity and thus the reactivity of the heme carbene. Metal-free reactions were also studied to reveal temperature and carbene substituent effects on catalytic vs noncatalytic reactions. This study sheds new light into the mechanism of iron porphyrin and hemoprotein-catalyzed cyclopropanation reactions and it is expected to facilitate future efforts toward sustainable carbene transfer catalysis using these systems. PMID- 29268619 TI - Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA Phase III study design. AB - Treatment for relapsed/refractory multiple myeloma (RRMM) remains an unmet need. Isatuximab, an anti-CD38 monoclonal antibody has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRMM. Here, we describe the design of the Phase III ICARIA-MM study (NCT02990338) which will evaluate isatuximab in combination with pomalidomide (Pom) and low-dose dexamethasone (dex) (Pom/dex) versus Pom/dex alone in RRMM. Patients will be randomized in a 1:1 ratio. The primary endpoint is progression-free survival. Response will be determined by an independent response review committee using IMWG criteria (2016) and safety will be assessed throughout. Approximately 300 patients (150 in each arm) are expected to enroll. The first patient was recruited in January 2017 and accrual is ongoing. PMID- 29268620 TI - Clinical and Biochemical Outcomes Following EEG Neurofeedback Training in Traumatic Brain Injury in the Context of Spontaneous Recovery. AB - : It has been found that reduction of posttraumatic stress symptoms is positively associated with the reduction of postconcussive symptoms. Cortisol is commonly used as a biomarker of stress. Understanding the role of posttraumatic stress and cortisol in symptom reduction has implication for neuropsychological rehabilitation particularly in the context of spontaneous recovery. OBJECTIVE: The aim of the research was to study the effectiveness of EEG neurofeedback training on clinical symptoms, perceived stress, and cortisol in traumatic brain injury (TBI) patients in the context of spontaneous recovery. METHODS: The design was an experimental longitudinal design with the pre-post comparison. The sample comprised 60 patients with the diagnosis of TBI-30 patients in the neurofeedback training (NFT) group and 30 patients in the treatment as usual group (TAU) group. Half of the patients were recruited within 6 months of injury to study the role of spontaneous recovery and the other half were recruited in the 12 to 18 months postinjury phase. Alpha-theta training was given to the NFT group over 20 sessions. Pre and post comparisons were made on clinical symptom rating, perceived stress, and serum cortisol levels. RESULTS: The results indicate significant differences in symptom reporting and perceived stress between the NFT and TAU groups. Significant differences were also seen in cortisol levels with implications for the acute recovery phase. CONCLUSION: Alpha-theta NFT has a beneficial effect on symptom reduction as well as perceived stress. It also has a beneficial effect on levels of serum cortisol, corroborating these findings. PMID- 29268621 TI - Evaluating Cell Metabolism Through Autofluorescence Imaging of NAD(P)H and FAD. AB - SIGNIFICANCE: Optical imaging using the endogenous fluorescence of metabolic cofactors has enabled nondestructive examination of dynamic changes in cell and tissue function both in vitro and in vivo. Quantifying NAD(P)H and FAD fluorescence through an optical redox ratio and fluorescence lifetime imaging (FLIM) provides sensitivity to the relative balance between oxidative phosphorylation and glucose catabolism. Since its introduction decades ago, the use of NAD(P)H imaging has expanded to include applications involving almost every major tissue type and a variety of pathologies. Recent Advances: This review focuses on the use of two-photon excited fluorescence and NAD(P)H fluorescence lifetime techniques in cancer, neuroscience, tissue engineering, and other biomedical applications over the last 5 years. In a variety of cancer models, NAD(P)H fluorescence intensity and lifetime measurements demonstrate a sensitivity to the Warburg effect, suggesting potential for early detection or high-throughput drug screening. The sensitivity to the biosynthetic demands of stem cell differentiation and tissue repair processes indicates the range of applications for this imaging technology may be broad. CRITICAL ISSUES: As the number of applications for these fluorescence imaging techniques expand, identifying and characterizing additional intrinsic fluorophores and chromophores present in vivo will be vital to accurately measure and interpret metabolic outcomes. Understanding the full capabilities and limitations of FLIM will also be key to future advances. FUTURE DIRECTIONS: Future work is needed to evaluate whether a combination of different biochemical and structural outcomes using these imaging techniques can provide complementary information regarding the utilization of specific metabolic pathways. Antioxid. Redox Signal. 00, 000-000. PMID- 29268622 TI - Relationships Between Youth Sports Participation and Mental Health in Young Adulthood Among Finnish Males. AB - PURPOSE: To examine whether retrospectively assessed sports participation (SP) and competitive sports (CS) at the age of 12 years is associated with mental health and health behavior in young adulthood among males. DESIGN: A cross sectional study using self-administered questionnaires. SETTING: Conducted prior to compulsory military refresher training course in Finland allowing geographically representative sample of Finnish young men. PARTICIPANTS: Six hundred eighty males aged between 20 and 35 years. MEASURES: Mental well-being was measured with the short version of Warwick-Edinburgh Mental Well-Being Scale and mental distress with 5 items of The Short Form Helalth Survey (SF-36) scale. ANALYSIS: Binary logistic regression models. RESULTS: Sports participation at the age of 12 was associated with better mental health in young adulthood, with both mental well-being (odds ratio [OR] = 1.86, 95% confidence interval 1.11-3.11) and mental distress (OR = 0.61, 0.41-0.90). Age, years of education, and current physical activity were controlled. Higher level of intensity of SP and the level of CS in childhood were associated with lower level of mental distress in adulthood. No association was found between the level of CS in childhood and mental well-being in adulthood. Further, youth SP seemed to be a risk factor for increased alcohol consumption and use of snuff in adulthood. CONCLUSIONS: Despite negative outcomes related to health behavior, the findings provide support for the association between youth SP and positive mental health outcomes in adulthood among males. PMID- 29268623 TI - Anti-sFlt-1 Therapy Preserves Lung Alveolar and Vascular Growth in Antenatal Models of Bronchopulmonary Dysplasia. AB - RATIONALE: Pregnancies complicated by antenatal stress, including preeclampsia (PE) and chorioamnionitis (CA), increase the risk for bronchopulmonary dysplasia (BPD) in preterm infants, but biologic mechanisms linking prenatal factors with BPD are uncertain. Levels of sFlt-1 (soluble fms-like tyrosine kinase 1), an endogenous antagonist to VEGF (vascular endothelial growth factor), are increased in amniotic fluid and maternal blood in PE and associated with CA. OBJECTIVES: Because impaired VEGF signaling has been implicated in the pathogenesis of BPD, we hypothesized that fetal exposure to sFlt-1 decreases lung growth and causes abnormal lung structure and pulmonary hypertension during infancy. METHODS: To test this hypothesis, we studied the effects of anti-sFlt-1 monoclonal antibody (mAb) treatment on lung growth in two established antenatal models of BPD that mimic PE and CA induced by intraamniotic (i.a.) injections of sFlt-1 or endotoxin, respectively. In experimental PE, mAb was administered by three different approaches, including antenatal treatment by either i.a. instillation or maternal uterine artery infusion, or by postnatal intraperitoneal injections. RESULTS: With each strategy, mAb therapy improved infant lung structure as assessed by radial alveolar count, vessel density, right ventricular hypertrophy, and lung function. As found in the PE model, the adverse lung effects of i.a. endotoxin were also reduced by antenatal or postnatal mAb therapy. CONCLUSIONS: We conclude that treatment with anti-sFlt-1 mAb preserves lung structure and function and prevents right ventricular hypertrophy in two rat models of BPD of antenatal stress and speculate that early mAb therapy may provide a novel strategy for the prevention of BPD. PMID- 29268624 TI - Insulin Concentration in Vials Randomly Purchased in Pharmacies in the United States: Considerable Loss in the Cold Supply Chain. AB - The insulin content in vials/cartridges should be 95 U/ml upon release. No independent confirmation of insulin concentration is available when purchased in the pharmacy (end of the cold supply chain). We quantitatively measured intact insulin in randomly acquired multidose human insulin vials by standard analytical methods. Eighteen 10 ml vials from two manufacturers (M1 and M2) were randomly acquired. The intact insulin concentration ranged from 13.9 to 94.2 U/ml, mean 40.2 U/ml. No vial met the minimum standard of 95 U/ml. These results imply the cold supply chain impacts insulin concentrations to a larger extent than anticipated. Patients are paying high prices for insulin and should expect to receive insulin vials with adequate insulin content in return. PMID- 29268625 TI - Using population-based routinely collected data from the Sentinel Stroke National Audit Programme to investigate factors associated with discharge to care home after rehabilitation. AB - OBJECTIVES: We investigated factors associated with Care Home (CH) discharge following stroke using routinely collected data in unselected patients and assessed the relevance of previous research findings to such patients seen in routine clinical practice. DESIGN: Retrospective analysis of data from the Sentinel Stroke National Audit Programme using univariate analysis and logistic regression. SETTING: A large acute and rehabilitation UK stroke unit with access to early supported discharge. SUBJECTS: All patients with stroke treated from 1 January 2014 to 1 January 2017. MAIN MEASURES: National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). RESULTS: Of 2584 patients (median age 78 years, interquartile range (IQR) 69-86; 50.6% male; 86.7% infarcts; median admission NIHSS 4, IQR 2-9), 401 (15.5%) died in hospital and 203 patients (7.9%) were permanently discharged to CH for the first time. Most had pre-discharge mRS scores of 4/5. Factors (odds ratios; 95% confidence intervals) associated with CH discharge included age (1.07; 1.05-1.10), incontinence (11.5; 7.13-19.25), dysphagia (2.13; 1.39-3.29), severe weakness (1.93; 1.28-2.92), pneumonia (1.68; 1.13-2.50), urinary tract infection (UTI) (1.70; 1.04-2.75) and depression (1.65; 1.00-2.72). In a subgroup of all patients with a pre-discharge mRS of 4/5, age (1.04; 1.02-1.06), incontinence (4.87; 2.39 11.02), UTI (2.0; 1.09-3.71) and pneumonia (1.59; 1.02-2.50) were the only factors associated with CH discharge. CONCLUSION: Potentially modifiable variables like incontinence, UTI and pneumonia were associated with CH discharge, particularly in the severely disabled. PMID- 29268626 TI - Suicide at Very Advanced Age - The Extremes of the Gender Paradox. PMID- 29268627 TI - Barriers to the Prevention of Suicide in Nursing Homes. AB - BACKGROUND: The suicide rate in older people is high. Gatekeeper training is recommended for at-risk populations in the detection and management of suicidal residents in nursing homes. AIMS: This study focuses on how caregivers in nursing homes consider suicide in older people from a social perspective, and to what extent these social representations are an obstacle to the prevention of suicide. METHOD: This study is both observational and qualitative, and is based on semi directed one-to-one interviews with caregivers. RESULTS: We met with 18 caregivers from three nursing homes in 2015. We show that the social representations of caregivers working in nursing homes are essentially identical to those of the general population and those found in other studies on paramedics. Suicide is seen as an expression of autonomy, a response to the suffering associated with aging and the living conditions imposed on older people in our society, particularly in nursing homes. LIMITATIONS: Our study highlights the problems inherent to the position of caregiver, in which we can observe a conflict between professional missions and personal ideology. CONCLUSION: This study confirms the need to continue training on suicide prevention in nursing homes. PMID- 29268629 TI - Vesico-Uterine Fistula after TURB in pregnancy, a rare cause of genitourinary fistula. PMID- 29268630 TI - Thiazole Orange as an Alternative to Antibody Binding for Detecting Triple helical DNA in Heterochromatin of Drosophila and Rhynchosciara. AB - The standard method for detecting triple-stranded DNA over the last 1.5 decades has been immune detection using antibodies raised against non-canonical nucleic acid structures. Many fluorescent dyes bind differentially to nucleic acids and often exhibit distinctive staining patterns along metaphase chromosomes dependent upon features, including binding to the major and minor DNA grooves, level of chromatin compaction, nucleotide specificity, and level of dye stacking. Relatively recently, the fluorochrome Thiazole Orange (TO) was shown to preferentially bind to triplex DNA in gels. Here, we demonstrate that TO also detects triplex DNA in salivary gland chromosomes of Drosophila melanogaster and Rhynchosciara americana identical in location and specificity to observations using antibodies. This finding may enable triple-stranded DNA investigations to be carried out on a much broader and reproducible scale than hitherto possible using antibodies, where a frequently encountered problem is the difference in detection specificity and sensitivity between one antibody and another. PMID- 29268631 TI - Regression of Lingual Lymphatic Vessels in Sodium-restricted Mice. AB - Lymphatic vessel networks can expand and regress, with consequences for interstitial fluid drainage and nutrient supply to tissues, inflammation, and tumor spread. A diet high in sodium stimulates hyperplasia of cutaneous lymphatic capillaries. We hypothesized that dietary sodium restriction would have the opposite effect, shrinking lymphatic capillaries in the tongue. Lingual lymphatic capillary density and size was significantly reduced in mice fed a low-sodium diet (0.03%) for 3 weeks compared with control-fed mice. Blood vessel density was unchanged. Despite lymphatic capillary shrinkage, lingual edema was not observed. The effect on lymphatic capillaries was reversible, as lymphatic density and size in the tongue were restored by 3 weeks on a control diet. Lymphatic hyperplasia induced by a high-sodium diet is dependent on infiltrating macrophages. However, lingual CD68+ macrophage density was unchanged by sodium deficiency, indicating that distinct mechanisms may mediate lymphatic regression. Further studies are needed to test whether dietary sodium restriction is an effective, non-invasive co-therapy for oral cancer. PMID- 29268632 TI - Medical students and professionalism - Do the hidden curriculum and current role models fail our future doctors? AB - PURPOSE: Formal medical curricula aim to promote professionalism through learning from lectures, interactive tutorials and simulations. We report an exploratory voting exercise, conducted within a new integrated professional teaching module, examining the likely influence on students' knowledge and perceptions of truth telling. METHODS: Responses were collected from cohorts of final year students over a six-year period. Students were asked to pick between two responses to a standardized clinical vignette, firstly the response that they personally thought was the more desirable action, and subsequently the response they believed would most likely result in the context of everyday real-life clinical practice. RESULTS: The difference (proportional change) in voting for "avoid full disclosure" from vote 1 (more desirable action) to vote 2 (likely real-life response) was 50% (95% CI: 36-64%, p < 0.001) favoring avoidance of full disclosure. CONCLUSIONS: This finding highlights a substantial inconsistency between the knowledge taught by the formal curriculum, and the perception generated by the hidden curriculum. Medical Schools should develop strategies to manage the hidden curriculum, prepare clinical teachers to be good role models, and prepare students to be discerning about the hidden curriculum and when choosing role models. PMID- 29268633 TI - Amyotrophic lateral sclerosis and food intake. AB - OBJECTIVE: To verify if specific foods and nutrients could be risk factors or protective factors for amyotrophic lateral sclerosis (ALS). METHODS: Patients with newly diagnosed ALS from three Italian administrative regions were included. For each patient, a healthy control, matched for age (+/-5 years), sex and administrative region of residence, was selected by a general practitioner. Cases and controls were interviewed by a trained investigator who filled a validated and reproducible food-frequency questionnaire. Daily intake of macronutrients, micronutrients, fatty acids, and total energy were estimated using an Italian food composition database. RESULTS: Two hundred and twelve cases and 212 controls were included. A risk reduction was found for coffee and tea (odds ratios (OR) = 0.29, 95% CI 0.14-0.60), whole bread (OR = 0.55, 95% CI 0.31-0.99), raw vegetables (OR = 0.25, 95% CI 0.13-0.52) and citrus fruits (OR = 0.49, 95% CI 0.25-0.97). A risk increase was observed for red meat (OR = 2.96, 95% CI 1.46 5.99) and pork and processed meat (OR = 3.87, 95% CI 1.86-8.07). An increased risk was found for total protein (OR = 2.96, 95% CI 1.08-8.10), animal protein (OR = 2.91, 95% CI 1.33-6.38), sodium (OR = 3.96, 95% CI 1.45-10.84), zinc (OR = 2.78, 95% CI 1.01-7.83) and glutamic acid (OR = 3.63, 95% CI 1.08-12.2). CONCLUSIONS: Some foods/nutrients may be risk factors and others protective factors for ALS. PMID- 29268634 TI - On-line biofilm strength detection in cross-flow membrane filtration systems. AB - A fluid dynamic gauging (FDG) technique was used for on-line and in situ measurements of Pseudomonas aeruginosa PAO1 biofilm thickness and strength on flat sheet polyethersulphone membranes. The measurements are the first to be successfully conducted in a membrane cross-flow filtration system under constant permeation. In addition, FDG was used to demonstrate the removal behaviour of biofilms through local biofilm strength and removal energy estimation, which other conventional measurements such as flux and TMP cannot provide. The findings suggest that FDG can provide valuable additional information related to biofilm properties that have not been measured by other monitoring methods. PMID- 29268635 TI - Nicotine exposure suppresses hyperinsulinemia and improves endothelial dysfunction mediators independent of corticosteroids in insulin-resistant oral contraceptive-treated female rats. AB - Estrogen-progestin oral contraceptives (COC) or tobacco smoking has been associated with hypertension and endothelial dysfunction resulting in increased risk of cardiovascular diseases (CVD). Contrasting effects of nicotine exposure on endothelial function have been reported. The effect of non-smoking nicotine exposure on endothelial dysfunction during COC treatment remains to be fully elucidated. We therefore, sought to determine the effects of nicotine exposure during COC treatment on endothelial dysfunction mediators and circulating corticosteroids. Female Wistar rats aged 10 weeks were given (po) vehicle, nicotine (1.0 mg/kg) with or without COC steroids (1.0 ug ethinylestradiol and 5.0 ug levonorgestrel) daily for 6 weeks. Nicotine exposure caused 113.3% increase in insulinemia whereas COC treatment led to 76.9% increased insulinemia compared with control. Furthermore, COC treatment or nicotine exposure led to glucose deregulation, insulin resistance, reduced nitric oxide bioavailability, elevated plasminogen activator inhibitor-1, uric acid, oxidative stress, atherogenic dyslipidemia, and corticosteroids. However, COC + NIC treatment led to 41.2% decrease in insulemina compared with COC-treated rats. Furthermore, all other alterations were alleviated by nicotine exposure in COC-treated female rats with the exception of corticosteroids. PMID- 29268636 TI - Management of diabetes using herbal extracts: review. AB - Diabetes is a group of metabolic diseases characterised by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage and dysfunction of many organs. Diabetes caused 1.5 million deaths in 2012, with hyperglycemia causing an additional 2.2 million deaths, as it is associated with increased risk of cardiovascular and other diseases. Various types of plants have been used for several centuries worldwide not only as dietary supplements but also as traditional treatment regimens for many diseases. So far, a large number of traditionally claimed plant medicine has been tested for diabetes and some of them showed a promising therapeutic potential. The main focus of this review is to describe what we know to date of herbal extracts, along with their glucose lowering mechanisms, which are either through insulin-mimicking activity, enhanced beta-cells regeneration, or glucose uptake. PMID- 29268637 TI - The pharmacological treatment of bronchiectasis. AB - INTRODUCTION: Until recently considered as a minor health problem, the role of bronchiectasis is now increasingly recognized. New specific drugs are being approved for treatment of bronchiectasis. Possibly they will offer better perspectives to bronchiectatic subjects with evolving course. Areas covered: We provide an overview of aetiopathogenesis, clinics and non-pharmacological management, extending the topic of pharmacological treatment. Present therapies were extrapolated from other chronic lung diseases, but newer promising specific drugs are being awaited. Therapy aims at improving mobilisation of bronchial secretions and, if any, reversing airflow obstruction. Antibiotics are indicated to treat exacerbations, eradicate or reduce sputum bacterial load. Expert commentary: Over the last years evidence is mounted that bronchiectatic subjects with accelerated course of disease should be referred to secondary and tertiary centres. This requires increased awareness on the role and the frequency of bronchiectasis in primary care. Long-term continuous or cyclical use of antibiotics is recommended to stabilize or improve the course of evolving disease. Macrolides are a currently preferred option. Inhaled antibiotics are gaining importance and are the object of ongoing research interest. Practical challenges of inhaled antibiotic treatment remain the need of defining the best therapeutic regimen and optimizing true adherence. PMID- 29268638 TI - Pharmacokinetic/pharmacodynamic profile of reslizumab in asthma. AB - INTRODUCTION: Allergic asthma is a Th2-driven inflammatory process characterized by the infiltration of eosinophils into the airways. IL-5 is a key trigger for eosinophil expansion and release from the bone marrow and plays a crucial role in the entire life span of eosinophils from differentiation to maturation and survival. IL-5 can be considered among the most obvious targets to selectively inhibit eosinophilic airway inflammation. Areas covered: The preclinical and clinical development of reslizumab, a humanized mAb against IL-5 that has been developed to block IL-5 bioactivity and reduce biologically available IL-5, are described with a particular focus on its pharmacodynamics (PK)/pharmacokinetic (PD) profile. Expert opinion: Although pivotal trials have documented that reslizumab can be recommended as add-on therapy for the treatment of patients with severe eosinophilic asthma, there is still important information that is lacking and some PK and PD properties of reslizumab are still not fully understood. PMID- 29268639 TI - Elevated circulating heat shock protein 70 and its antibody concentrations in chronic spontaneous urticaria. AB - Heat shock proteins (Hsp) play a complex role in cytoprotection, inflammation, and function of the immune system. They may be involved in pathogenesis of various diseases. Our aim was to determine circulating Hsp70 and anti-Hsp70 antibodies concentrations in patients with chronic spontaneous urticaria (CSU). Concentrations of Hsp70 in plasma and anti-Hsp70 antibodies in serum as well as serum C-reactive protein (CRP) were measured in CSU patients and in the controls. Plasma Hsp70 concentrations were significantly higher in CSU (all) and mild CSU patients as compared with the controls. Moderate-severe CSU patients tended to show higher Hsp70 concentration as compared with the controls, but not with mild activity of the disease. There were no significant differences in Hsp70 concentration between moderate-severe and mild CSU patients. Serum anti-Hsp70 antibodies concentrations were significantly higher in CSU (all) and mild CSU in comparison to the controls. Association was observed between anti-Hsp70 antibodies and increased CRP concentration; however, no correlation between anti Hsp70 and Hsp70 concentrations was seen in the patients. It seems that up regulation of Hsp70 in CSU may induce marked increase in anti-Hsp70 antibodies production, which are accompanied by parallel changes in CRP concentration. We suggest that Hsp may be released in CSU in response to stressful stimuli, such as inflammation. PMID- 29268640 TI - miR-199a-5p inhibits proliferation and induces apoptosis in hemangioma cells through targeting HIF1A. AB - MicroRNAs (miRNAs) exhibit a crucial role in the regulation of angiogenesis and tumor progression, of which miR-199a-5p (miR-199a) has been reported to function as a tumor suppressor in multiple malignancies. However, the precise mechanisms underlying miR-199a in hemangiomas (HAs) remain elusive. In this study, we found that miR-199a had low expression level, while proliferating cell nuclear antigen (PCNA) had high expression level in proliferating-phase HAs compared with the involuting-phase HAs and normal tissues. Spearman correlation analysis revealed the negative correlation of miR-199a with PCNA expression in proliferating-phase HAs. In vitro experiments showed that restoration of miR-199a suppressed cell proliferation capability and induced cell apoptosis in HA-derived endothelial cells (HDEC) and CRL-2586 EOMA cells, followed with decreased PCNA expression and increased cleaved caspase-3 expression, but miR-199a inhibitor reversed these effects. Furthermore, HIF1A was identified as a target of miR-199a and had negative correlation with miR-199a expression in proliferating-phase HAs. Overexpression of HIF1A attenuated the anti-proliferation effect of miR-199a mimic in HAs cells. Taken together, our findings demonstrate that miR-199a may inhibit proliferation and induce apoptosis in HAs cells via targeting HIF1A and provide a potential therapeutic target for HAs. PMID- 29268641 TI - ? PMID- 29268642 TI - ? PMID- 29268643 TI - ? PMID- 29268644 TI - ? PMID- 29268645 TI - ? PMID- 29268646 TI - ? PMID- 29268647 TI - ? PMID- 29268648 TI - ? PMID- 29268649 TI - ? PMID- 29268650 TI - ? PMID- 29268651 TI - Serum leptin level across different phases of menstrual cycle in normal weight and overweight/obese females. AB - We compared serum leptin levels during various phases of menstrual cycle and its correlation with serum estradiol between normal weight and overweight/obese young females. Fifty-six young females with normal menstrual cycle were grouped into 26 normal weight and 30 overweight/obese subjects. Serum leptin and estradiol levels were measured during early follicular, pre-ovulatory and luteal phases of menstrual cycle in both groups using ELISA technique. Serum leptin levels were significantly different across different phases of menstrual cycle with a steady increment from follicular phase (9.97 +/- 5.48 ng/dl) through pre-ovulatory phase (11.58 +/- 6.49 ng/dl) with their peaks in luteal phase (12.52 +/- 6.39 ng/dl, p < .001). Same pattern of change during menstrual phases was observed when the normal weight and overweight/obese group were analyzed separately. Serum leptin levels were significantly higher in overweight/obese group compared to normal weight subjects. In any of the study groups, leptin levels were not found to be correlated with estradiol level during different phases of menstrual cycle. PMID- 29268652 TI - Vaginal delivery among women who underwent labor induction with vaginal dinoprostone (PGE2) insert: a retrospective study of 1656 women in China. AB - OBJECTIVE: This study aimed to qualify relevant factors for vaginal delivery among women who underwent labor induction with vaginal dinoprostone (PGE2) insert in a Chinese tertiary maternity hospital. MATERIAL AND METHODS: A retrospective study was conducted in Hubei Maternal and Child Health Hospital. A total of 1656 pregnancies that underwent labor induction with vaginal dinoprostone insert between January and August 2016 were finally included in this study. Data were analyzed using univariate and multivariable regression modeling. RESULTS: Of 1656 women with PGE2-induced labor at term, 396 (23.91%) gave birth by cesarean section, 1260 (76.09%) had a vaginal delivery among which 921 (55.61%) delivered vaginally within 24 h. Multivariable regression analysis showed that maternal age (p < .001, OR = 0.89, 95%CI 0.85-0.93), parity (multiparous versus nulliparous, p < .001, OR = 8.74, 95%CI 4.36-17.50), baseline fetal heart rate (p = .009, OR = 0.98, 95%CI 0.96-0.99), and birth weight (p < .001, OR = 0.37, 95%CI 0.28-0.51) were significantly correlated with vaginal delivery. Moreover, body mass index (p < .001, OR = 1.11, 95%CI 1.05-1.19), parity (multiparous versus nulliparous, p < .001, OR = 6.57, 95%CI 2.37-18.23), baseline fetal heart rate (p = .004, OR = 0.96, 95%CI 0.94-0.99), and birth weight (p < .001, OR = 0.34, 95%CI 0.21-0.54) were independent predictors of vaginal delivery within 24-h. CONCLUSIONS: Our findings suggested a vaginal delivery rate of 76.09% when dinoprostone vaginal insert was used for labor induction, which was markedly higher than the overall annual vaginal delivery rate of 65.1% in China during 2014. Maternal age, parity, baseline fetal heart rate, and birth weight were significant factors for vaginal delivery. This study enables us to better understand the efficiency of dinoprostone and the potential predictors of vaginal delivery in dinoprostone induced labor, which may be helpful to guide the clinical use of dinoprostone and therefore provide better service clinically. PMID- 29268653 TI - Characterization of methylthioadenosin phosphorylase (MTAP) expression in colorectal cancer. AB - PURPOSE: Tumour seriously affects people's quality of life. Colorectal cancer is a refractory tumour in digestive tract tumors. In colorectal cancer, gene expression abnormalities is the main reason for its incidence, we mainly focus on the molecular mechanism of MTAP in the development of colorectal cancer. METHODS: The tumour tissue and its adjacent tissue samples of 50 patients with colorectal cancer were screened from July 2011 to February 2015, and the expression of MTAP was detected. Cell lines that overexpress MTAP and low expression of MTAP were constructed in colorectal cancer cell lines. The cell proliferation, invasion and migration was detected in the cells with different expression levels of MTAP. Immunohistochemistry was used to detect the expression of MTAP in liver metastasis and to investigate its clinical significance. And statistics of clinical significance. RESULTS: Q-PCR results showed that the expression of MTAP in colorectal cancer cell lines were significantly higher than that normal human colonic myofibroblasts cell line. Cell proliferation test results showed that cell proliferation was accelerated when MTAP was overexpression, cell invasion and migration were simultaneously accelerated. The expression of MTAP in primary liver was positively correlated with metastatic disease in patients with liver metastatic colorectal cancer via EMT. CONCLUSIONS: MTAP accelerates the growth and metastasis of colorectal cancer through EMT. PMID- 29268655 TI - Corrigendum. AB - Alves, E., Magano, R., Amorim, M., Nogueira, C., & Silva, S. (2016). Factors influencing parent reports of facilitators and barriers to human milk supply in neonatal intensive care units. Journal of Human Lactation, 32(4), 695-703. (Original DOI: 10.1177/0890334416664071) On page 696, data were incorrectly reported in the sentence, "Among the 126 families eligible for the study, 122 (98.6%) agreed to participate, including 120 mothers and 91 fathers (Figure 1)." The corrected sentence is provided below: Among the 126 families eligible for the study, 122 (96.8%) agreed to participate, including 120 mothers and 91 fathers (Figure 1). PMID- 29268654 TI - Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials. AB - BACKGROUND: Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials. METHODS: The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation. RESULTS: To date, participants from two phase I studies and two effectiveness trials have participated in MTN-016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit. CONCLUSION: In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion. PMID- 29268656 TI - Outcomes of High-Frequency Gastric Electric Stimulation for the Treatment of Severe, Medically Refractory Gastroparesis in Finland. AB - BACKGROUND AND AIMS: Severe, medically uncontrollable gastroparesis is a rare entity, which can be treated using a high-frequency gastric electric stimulator implanted surgically. Previous follow-ups have proven positive outcomes with gastric electric stimulator in patients with gastroparesis. The aim of this study was to evaluate the efficacy and safety of gastric electric stimulator in patients, in whom gastroparesis could not be controlled by conservative means in our country. MATERIALS AND METHODS: This is a retrospective multi-center cohort comprising all patients who had been implanted gastric electric stimulator for severe, medically refractory gastroparesis during 2007-2015 in Finland. RESULTS: Fourteen patients underwent implantation of gastric electrical stimulator without any postoperative complications. Laparoscopic approach was used in 13 patients (93%). Prior implantation, all patients needed frequent hospitalization for parenteral feeding, 13 had severe nausea, 11 had severe vomiting, 10 had notable weight loss, and 6 had frequent abdominal pain. After operation, none of the patients required parenteral feeding, 11 patients (79%) gained median of 5.1 kg in weight (P < 0.01), and symptoms were relieved markedly in 8 and partially in 3 patients (79%). Of partial responders, two continued to experience occasional vomiting and one mild nausea. Five patients needed medication for gastroparesis after the operation. One patient did not get any relief of symptoms, but gained 6 kg in weight. No major late complications occurred. CONCLUSION: Gastric electrical stimulator seems to improve the nutritional status and give clear relief of the symptoms of severe, medically uncontrollable gastroparesis. Given the low number of operations, gastric electrical stimulator seems to be underused in Finland. PMID- 29268658 TI - 'I'm more aware of my HIV risk than anything else': syndemics of syphilis and HIV among gay men in Winnipeg. AB - Despite decreased rates of HIV infection in Winnipeg, syphilis incidence continues to rise. Communities of men who have sex with men shoulder much of this burden of illness. This qualitative study aimed to better understand the co evolution of HIV and syphilis in Winnipeg through a series of interviews with gay men. Eighteen individuals were recruited through advertising in sexual health centres and through subsequent snowball sampling. Thematic interpretive analysis and inductive reasoning were used to find individual and shared group meanings. We found that HIV formed the contextual ground on which sexual decision-making was made, with three main themes emerging during interviews: 1) bacterial STI transience being contrasted against HIV permanence; 2) syphilis being 'dirty' versus HIV carrying significant stigma, though being spared the label of uncleanliness; and 3) the role of pleasure and intimacy in sexual health decision making. Based on these findings, we recommend further exploration to develop more effective strategies around syphilis prevention, in particular with regards to the longer-term illness ramifications and its relationship to HIV transmission. PMID- 29268657 TI - Identification and characterization of circular RNAs in the silkworm midgut following Bombyx mori cytoplasmic polyhedrosis virus infection. AB - The pathogenesis of Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) infection is unclear, although accumulating evidence indicates that circular RNAs (circRNAs), which act as competing endogenous RNAs or positive regulators, play important roles in regulating gene expression in eukaryotes and, thus, may play a role in BmCPV infections. To explore the expression and biological functions of circRNAs in the silkworm midgut following BmCPV infection, silkworm circRNA expression profiles of normal midgut tissue (control) and BmCPV-infected midgut tissue (test) were determined using high-through sequencing. A total of 9,753 and 7,475circRNAs were detected from the control and test samples, respectively. The two samples shared 6,085 circRNAs, while 646 and 737 circRNAs were expressed specifically in the control and test samples, respectively. A total of 3,638 circRNAs were shown to be differentially expressed, and 400 circRNAs were substantially differentially expressed with a fold-change >= 2.0 (p< 0.05 and a false discover rate < 0.05), of which 294 were up-regulated and 106 were down regulated following infection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to determine the principal functions of the substantially differentially regulated genes. circRNA-miRNA interaction networks were constructed based on a correlation analysis between the differentially expressed circRNAs and the nature of their microRNA (miRNA) binding sites. The network inferred that 13 miRNAs interacting with 193 circRNAs were among the 300 most abundant relationships. bmo-miR-3389-5p, bmo-miR-745-3p, and bmo-miR-3262 were related to 30, 34, and 34 circRNAs, respectively. circRNA_8115, circRNA_9444, circRNA_4553, circRNA_0827, and circRNA_6649 contained six, five, four, four, and four miRNA binding sites, respectively. We further found that alternative circularization of circRNAs is a common feature in silkworms and that the junction sites of many silkworm circRNAs are flanked by canonical GT/AG splicing signals. Our study is the first to show the circRNA response to virus infection. Thus, it provides a novel perspective on circRNA miRNA interactions during BmCPV pathogenesis, and it lays the foundation for future research of the potential roles of circRNAs in BmCPV pathogenesis. PMID- 29268659 TI - Impact of ethical factors on job satisfaction among Korean nurses. AB - BACKGROUND: Although numerous studies on job satisfaction among nurses have been conducted, there is a lack of research considering the ethical perspectives of leadership and organizational climate in job satisfaction. OBJECTIVE: The purpose of this study was to clarify the impact of the ethical climate and ethical leadership as perceived by nurses on job satisfaction in South Korea. RESEARCH DESIGN: A descriptive and correlational study was conducted with a convenience sample of 263 nurses from four general hospitals in South Korea. Ethical considerations: This study was approved by the Institute Review Board of Hallym University before data collection. RESULTS: Job satisfaction was positively correlated with ethical climate and ethical leadership. The ethical climate in relationship with hospitals and people orientation leadership were influential factors in the level of job satisfaction among nurses. DISCUSSION: Organizations in the nursing environment should pay attention to improving the ethical climate with acceptable ethical norms in the workplace and nurse leaders should respect, support and genuinely care about their nurses in ethical concerns. PMID- 29268660 TI - Intersectional identities and dilemmas in interactions with healthcare professionals: an interpretative phenomenological analysis of British Muslim gay men. AB - Individual interviews were conducted with six self-identified Muslim gay men living in London focusing on their experience of health service use. Transcripts were analysed using interpretative phenomenological analysis. Analysis identified two major themes: the close(d) community and self-management with healthcare professionals, detailing participants' concerns regarding the risks of disclosing sexuality; and the authentic identity - 'you're either a Muslim or you're gay, you can't be both' - which delineated notions of incommensurate identity. Analysis highlights the need for health practitioners to have insight into the complexity of intersectional identities, identity disclosure dynamics and the negative consequences of assumptions made, be these heteronormative or faith related. PMID- 29268661 TI - Abstracts of ISOBM 2017 Congress for Tumor Marker Publication. PMID- 29268662 TI - The Voices That Influence HIV-Positive Mothers' Breastfeeding Practices in an Urban, Ghanaian Society. AB - BACKGROUND: The World Health Organization recommends that HIV-positive mothers should breastfeed for at least 1 year. There are people in the lives of these mothers who influence their decisions. Research aim: The aim was to explore the role of social persuasion in the decision-making processes of HIV-positive breastfeeding mothers. METHODS: A qualitative, exploratory research design was employed ( N = 13). Participants were recruited from a public hospital in the Greater Accra Region of Ghana. One-on-one interviews were recorded and transcribed verbatim, and the contents of the transcripts were analyzed for emerging themes. RESULTS: The perspectives of spouses, health workers, counselors, and siblings about breastfeeding affect the breastfeeding practices of mothers living with HIV in Ghana. Most of the women had negative experiences with their midwives. Because of complex social and cultural influences, the opinions of spouses, health professionals, siblings, and members of the communities in which breastfeeding mothers with HIV live influence breastfeeding practices. CONCLUSION: This study described HIV-positive, breastfeeding mothers' perceptions of the role played by spouses, health professionals, siblings, and the community in breastfeeding decisions and practices. Influential people in the lives of breastfeeding mothers with HIV should be involved during interventions by HIV counselors to promote breastfeeding practices. PMID- 29268663 TI - A "matter of communication": A new classification to compare and evaluate telehealth and telemedicine interventions and understand their effectiveness as a communication process. AB - This article attempts to define functions and applications of telemedicine and telehealth in order to achieve a simplified and comprehensive taxonomy. This may be used as a tool to evaluate their efficacy and to address health policies from the perspective of the centrality of information in the healthcare. Starting from a lexical frame, telemedicine or telehealth is conceived as a communication means and their action as a communication process. As a performance, the communication is related to the health outcome. Three functions ( telemetry, telephasis, and telepraxis) and nine applications are identified. Understanding the mechanisms of telemedicine and telehealth effectiveness is crucial for a value-driven healthcare system. This new classification-focusing on the end effect of telemedicine and telehealth and on the type of interactions between involved actors-moves toward a new and simplified methodology to compare different studies and practices, design future researches, classify new technologies and guide their development, and finally address health policies and the healthcare provision. PMID- 29268664 TI - Molecular docking, QSAR and ADMET based mining of natural compounds against prime targets of HIV. AB - AIDS is one of the multifaceted diseases and this underlying complexity hampers its complete cure. The toxicity of existing drugs and emergence of multidrug resistant virus makes the treatment worse. Development of effective, safe and low cost anti-HIV drugs is among the top global priority. Exploration of natural resources may give ray of hope to develop new anti-HIV leads. Among the various therapeutic targets for HIV treatment, reverse transcriptase, protease, integrase, GP120, and ribonuclease are the prime focus. In the present study, we predicted potential plant-derived natural molecules for HIV treatment using computational approach, i.e. molecular docking, quantitative structure activity relationship (QSAR), and ADMET studies. Receptor-ligand binding studies were performed using three different software for precise prediction - Discovery studio 4.0, Schrodinger and Molegrow virtual docker. Docking scores revealed that Mulberrosides, Anolignans, Curcumin and Chebulic acid are promising candidates that bind with multi targets of HIV, while Neo-andrographolide, Nimbolide and Punigluconin were target-specific candidates. Subsequently, QSAR was performed using biologically proved compounds which predicted the biological activity of compounds. We identified Anolignans, Curcumin, Mulberrosides, Chebulic acid and Neo-andrographolide as potential natural molecules for HIV treatment from results of molecular docking and 3D-QSAR. In silico ADMET studies showed drug-likeness of these lead molecules. Structure similarities of identified lead molecules were compared with identified marketed drugs by superimposing both the molecules. Using in silico studies, we have identified few best fit molecules of natural origin against identified targets which may give new drugs to combat HIV infection after wet lab validation. PMID- 29268665 TI - Gastrointestinal Complications After Surgical Correction of Neuromuscular Scoliosis: A Retrospective Cohort Study. AB - STUDY DESIGN: A retrospective cohort study of consecutively operated neuromuscular scoliosis patients. BACKGROUND AND AIM: Surgical correction of neuromuscular scoliosis can be complicated by early gastrointestinal complications, but data on the extent and severity of them is scarce. The aim of the study was to determine the incidence, course, and risk factors of gastrointestinal complications after neuromuscular scoliosis correction. MATERIAL AND METHODS: Ninety-one patients (<21 years of age) were consecutively operated on for neuropathic neuromuscular scoliosis during 2000-2011. Patients who developed marked postoperative gastrointestinal complications were identified and clinical, operative, and radiographic records, death certificates, and post mortem reports were examined. RESULTS: The average age at surgery was 14.5 (SD 2.9) and follow-up time was 4.9 (SD 2.3) years. Gastrointestinal complications occurred in 12 (13%) patients and included prolonged paralytic ileus (7%, 6/91), dysphagia (7%, 6/91), and gastroparesis (1%, 1/91). Hospital stay was 22 (SD 11) days in patients with gastrointestinal complications and 16 (SD 20) days in non complicated patients (p = 0.005). Dysphagia required permanent feeding gastrostomy in one patient whereas other complications were transient and none caused death. The risk factors for postoperative gastrointestinal complications were preoperative main curve correction <30% in traction/bending radiographs (Relative Risk (RR) = 28 (95% Confidence Interval (CI) 4.4-180); p < 0.001), preoperative main curve >90 degrees (RR = 5.5 (95% CI 1.3-23); p = 0.020), disturbance in intraoperative spinal cord monitoring (RR = 6.0 (95% CI 1.1-34); p = 0.043), and intravenous opioid medication over 5 days postoperatively (RR = 7.9 (95% CI 1.8-35), p = 0.006). CONCLUSION: Gastrointestinal complications occurred in 13% of patients after neuromuscular scoliosis correction. Marked gastrointestinal complications extended postoperative hospitalization period, but they were transient in majority (92%) of cases and none caused death. Rigid scoliosis was the most significant risk factor for gastrointestinal complications. Gastrointestinal complications appear to be less frequent after posterior only spinal fusion with total pedicle screw instrumentation and Ponte osteotomies. PMID- 29268666 TI - Feasibility of a Clinical Pathway With Early Oral Intake and Discharge for Laparoscopic Gastrectomy. AB - BACKGROUND AND AIMS: Although some studies have reported the safety of early oral intake after gastrectomy, it still remains controversial. This study focused on the feasibility of a clinical pathway with early oral intake and discharge setting for exclusively laparoscopic distal gastrectomy. MATERIALS AND METHODS: A clinical pathway was applied to 403 patients until December 2014. In the protocol, patients are allowed to take a sip of water and a soft diet on the first and second days after the operation, respectively, and the discharge day is set as the fifth to seventh day after the operation. Clinicopathological variables were prospectively collected, and risk factors for discharge variances were analyzed. RESULTS: The completion rate of the clinical pathway was 76.9%. There were five re-admissions (1.2%). The overall morbidity rate was 18% ( n = 72), and major complications (Clavien-Dindo IIIa or greater) occurred in 13 patients (3%). Complications were the causes for discharge variances in 68 cases (73%), while the attending surgeons' judgment was the cause in 25 cases (27%). On multivariate analysis, age (odds ratio = 2.23, 95% confidence interval = 1.38 3.60, p = 0.001) and operative time (odds ratio = 2.38, 95% confidence interval = 1.45-3.98, p = 0.001) were independent risk factors for discharge variances. CONCLUSION: A high completion rate of a clinical pathway with early oral intake and discharge setting for laparoscopic distal gastrectomy was achievable with an acceptably low re-admission rate. Laparoscopic distal gastrectomy is recommended as a first step for a clinical pathway with an early oral intake and discharge protocol. PMID- 29268668 TI - Clinical/research abstracts accepted for presentation at AAFP Conference 2017. PMID- 29268667 TI - Measuring the Effects of an Animal-Assisted Intervention for Pediatric Oncology Patients and Their Parents: A Multisite Randomized Controlled Trial [Formula: see text]. AB - OBJECTIVE: This multicenter, parallel-group, randomized trial examined the effects of an animal-assisted intervention on the stress, anxiety, and health related quality of life for children diagnosed with cancer and their parents. METHOD: Newly diagnosed patients, aged 3 to 17 years (n = 106), were randomized to receive either standard care plus regular visits from a therapy dog (intervention group), or standard care only (control group). Data were collected at set points over 4 months of the child's treatment. Measures included the State Trait Anxiety InventoryTM, Pediatric Quality of Life Inventory, Pediatric Inventory for Parents, and child blood pressure and heart rate. All instruments were completed by the child and/or his/her parent(s). RESULTS: Children in both groups experienced a significant reduction in state anxiety ( P < .001). Parents in the intervention group showed significantly decreased parenting stress ( P = .008), with no changes in stress among parents in the control group. However, no significant differences between groups over time on any measures were observed. CONCLUSIONS: Animal-assisted interventions may provide certain benefits for parents and families during the initial stages of pediatric cancer treatment. PMID- 29268669 TI - In pursuit of better care, compassion and understanding of cats globally. PMID- 29268671 TI - At the Boundaries of Misattribution. AB - Priming effects in the Affect Misattribution Procedure (AMP) have been explained by a misattribution of prime-related affect to neutral targets. However, the measure has been criticized for being susceptible to intentional use of prime features in judgments of the targets. To isolate the contribution of unintentional processes, the present research expanded on the finding that positive affect can be misattributed to familiarity (i.e., positivity-familiarity effect). To the extent that prime-valence is deemed irrelevant for judgments of target-familiarity, positivity-familiarity effects in the AMP could potentially rule out intentional use of the primes. Seven experiments collectively suggest that prime-valence influences judgments of target-familiarity in the AMP, but only when the task context does not suggest a normatively accurate response to the familiarity-judgment task. Relations of positivity-familiarity effects to self-reported use of prime-valence revealed mixed results regarding the role of intentional processes. Implications for the AMP and misattribution effects are discussed. PMID- 29268672 TI - You Are Right! AB - In the social Simon task, two participants perform a spatial compatibility task together, each of them responding to only one stimulus (e.g., one participant reacts to red, the other to green stimuli). Participants show joint spatial compatibility effects (SCEs), that is, they respond faster when their go-stimulus appears on their half of the screen. Effects are absent when the same go/no-go task is performed without a coactor. Joint SCEs were originally explained in terms of shared task representations, but recent research suggests that effects result from spatial response coding: in joint go/no-go tasks, participants perceive themselves as the right/left participant operating a right/left response key. While previous research showed that the spatial alignment of keys and seats influences the effect, the present research demonstrates that merely instructing participants to be the right/left participant operating a right/left response key instead of labeling participants and keys with arbitrary numbers substantially increases joint SCEs. PMID- 29268673 TI - Can Methodological Considerations Challenge the Dissociation of the Perceptual and Motor Inhibitory Processes? AB - Using an original conflict task paradigm, Nassauer and Halperin (2003) argued that inhibition ability can be classified into two distinct perceptual and motor inhibitory processes. The current study examined the robustness of this paradigm by raising two major methodological points: the amount of information that needs to be processed and the task order (fixed vs. random). Sixty young adults performed the original or modified tasks. Overall, a decrease in the amount of information had the effect of removing the stimulus conflict on some subtests. Therefore, no more inhibition performance could be assessed. Even if the findings can be interpreted as a change in response-related complexity that relates reaction time performance to the informational processing load, the discrepancies in terms of the amount of information originally designed are necessary to induce inhibitory conflicts. Additionally, unlike previous recommendations, the fixed task order initially adopted cannot be considered an essential methodological requirement. PMID- 29268675 TI - The Role of Visual Distractors in the Simon Effect. AB - The Simon effect lies on the automatic generation of a stimulus spatial code, which, however, is not relevant for performing the task. Results typically show faster performance when stimulus and response locations correspond, rather than when they do not. Considering reaction time distributions, two types of Simon effect have been individuated, which are thought to depend on different mechanisms: visuomotor activation versus cognitive translation of spatial codes. The present study aimed to investigate whether the presence of a distractor, which affects the allocation of attentional resources and, thus, the time needed to generate the spatial code, changes the nature of the Simon effect. In four experiments, we manipulated the presence and the characteristics of the distractor. Findings extend previous evidence regarding the distinction between visuomotor activation and cognitive translation of spatial stimulus codes in a Simon task. They are discussed with reference to the attentional model of the Simon effect. PMID- 29268676 TI - The Role of Representation Strength of the Prime in Subliminal Visuomotor Priming. AB - This study investigated the role of representation strength of the prime in subliminal visuomotor priming in two experiments. Prime/target compatibility (compatible and incompatible) and preposed object type (jumbled lines, strong masking; and rectangular outlines, weak masking) were manipulated in Experiment 1. A significant negative compatibility effect (NCE) was observed in the rectangle condition, whereas no compatibility effect was found in the line condition. However, when a new variable, prime duration, was introduced in Experiment 2, the NCE was reversed with an increase in the prime duration in the rectangle condition, whereas the NCE was maintained in the line condition. This result is consistent with the claim that increasing the prime duration causes the prime representation to be too strong for inhibition in the rectangle condition but strong enough to reliably trigger inhibition in the line condition. The findings demonstrated that prime representation has a causal role in subliminal visuomotor priming. PMID- 29268678 TI - Inflammatory Pathways and Parturition. PMID- 29268677 TI - Not all Anchors Weigh Equally. AB - The anchoring bias is a reliable effect wherein a person's judgments are affected by initially presented information, but it is unknown specifically why this effect occurs. Research examining this bias suggests that elements of both numeric and semantic priming may be involved. To examine this, the present research used a phenomenon wherein people treat numeric information presented differently in Arabic numeral or verbal formats. We presented participants with one of many forms of an anchor that represented the same value (e.g., twelve hundred or 1,200). Thus, we could examine how a concept's meaning and its absolute numeric value affect anchoring. Experiments 1 and 2 showed that people respond to Arabic and verbal anchors differently. Experiment 3 showed that these differences occurred largely because people tend to think of numbers in digit format. This suggests that one's conceptual understanding of the anchored information matters more than its strict numeric value. PMID- 29268679 TI - Estimation of pH effect on the structure and stability of kinase domain of human integrin-linked kinase. AB - Integrin-linked kinase (ILK) is an evolutionarily conserved Ser/Thr protein kinase, involved in many physiological functions such as signal transduction, actin rearrangement, cell proliferation, migration, polarisation, angiogenesis and apoptosis. An increased expression of ILK is associated with different cancers and thus considered as an attractive target for cancer therapy. We have successfully cloned, expressed and purified the kinase domain (193-446 residues) of ILK. To see the effect of pH on the structure and conformation, we performed circular diachroism, fluorescence and absorbance measurements in a wide range of pH conditions. We observed that within the range of pH 7.5-11.0, ILK193-446 maintains its both secondary and tertiary structures. While visible aggregates were observed under the acidic pH 2.0-5.5 conditions, in order to complement these observations, we have performed molecular dynamics simulations of this kinase domain by mimicking diverse pH conditions which enabled us to see conformational preferences of the protein under such conditions. A significant correlation between the spectroscopic and molecular dynamics simulation was observed. These findings are useful to understand the conformation of ILK protein under certain pH condition which may be further implicated in the drug design and discovery. PMID- 29268680 TI - Modification of the N-Terminus of a Calcium Carbonate Precipitating Peptide Affects Calcium Carbonate Mineralization. AB - BACKGROUND: A core sequence (the 9 C-terminal residues) of calcification associated peptide (CAP- 1) isolated from the exoskeleton of the red swamp crayfish was previously shown to control calcium carbonate precipitation with chitin. In addition, a modified core sequence in which the phosphorylated serine at the N terminus is replaced with serine exhibits was also previously shown to alter precipitation characteristics with chitin. OBJECTIVES: We focused on calcium carbonate precipitation and attempted to elucidate aspects of the mechanism underlying mineralization. We attempted to evaluate in detail the effects of modifying the N-terminus in the core sequence on calcium carbonate mineralization without chitin. METHODS: The peptide modifications included phosphorylation, dephosphorylation, and a free or acetylated Nterminus. The peptides were synthesized manually on Wang resin using the DIPCI-DMAP method for the first residue, and Fmoc solid phase peptide synthesis with HBTU-HOBt for the subsequent residues. Prior to calcium carbonate precipitation, calcium carbonate was suspended in MilliQ water. Carbon dioxide gas was bubbled into the stirred suspension, then the remaining solid CaCO3 was removed by filtration. The concentration of calcium ions in the solution was determined by standard titration with ethylenediaminetetraacetate. Calcium carbonate precipitation was conducted in a micro tube for 3 h at 37 degrees C. We used the micro-scale techniques AFM (atomic force microscopy) and TEM (transmission electron microscopy), and the macro-scale techniques chelate titration, HPLC, gel filtration, CD (circular dichroism) and DLS (dynamic light scattering). RESULTS: We determined the morphologies of the calcium carbonate deposits using AFM and TEM. The pS peptide provided the best control of the shape and size of the calcium carbonate round particles. The acetylated peptides (Ac-S and Ac-pS) provided bigger particles with various shapes. S peptide provided a mixture of bigger particles and amorphous particles. We verified these findings using DLS. All the peptide samples produced nanostructures of the expected size in agreement with the AFM and TEM results. We estimated the abilities of these peptides to precipitate calcium carbonate by determining the residual calcium hydrogen carbonate concentration by standard titration with ethylenediaminetetraacetate after calcium carbonate precipitation. The Ac-pS peptide showed the lowest residual calcium hydrogen carbonate concentration whereas the S peptide showed the highest, suggesting that the precipitating activities of these peptides towards calcium carbonate correlated with peptide net charge. Then the gel filtration results showed a large oligomer peak and a small oligomer/monomer peak for all peptide samples in agreement with the AFM, TEM and DLS results. CD measurements showed that all the peptides formed random-coil-like structures. Thus, we used both macro- and micro-observation techniques such as chelate titration, DLS, AFM and TEM to show that the calcium carbonate precipitating activities of four derivatives of the core sequence of CAP-1 may correlate with the peptide net charge. CONCLUSION: These peptides mainly act as a catalyst rather than as a binder or component of the calcium carbonate deposits (as a template). On the other hand, the morphologies of the calcium carbonate deposits appeared to be dependent on the ability of the peptide to assemble and act as a template. Consequently, elucidating the relationship between peptide sequence and the ability of the peptide to assemble would be indispensable for controlling precipitate morphologies in the near future. This knowledge would provide important clues for elucidating the relationship between peptide sequence and mineralization ability, including deposit morphology and precipitating activity, for use in nanobiochemistry and materials chemistry research. PMID- 29268681 TI - Utilization of Proteins and Peptides to Create Organic-Hydroxyapatite Hybrids. AB - BACKGROUND: Various types of proteins play important roles in the biomineralization of hydroxyapatite (HAp, Ca10(PO4)6(OH)2). The resulting organic HAp nanohybrids have highlyorganized hierarchical structures that show unique morphological, structural, and mechanical properties. By mimicking the biomineralization process, organic-HAp hybrid materials have been created by utilizing proteins and peptides. OBJECTIVES: In this review, firstly the roles of proteins in HAp mineralization in vivo are briefly explained. Recent progresses in the creation of organic-HAp hybrids through the utilization of proteins and peptides are then described. RESULTS: Roles of collagen and amelogenin on the formation of bones and teeth were explained. Then, recent advances, including those by the authors, in the creation of organic-HAp hybrids through the utilization of these proteins, their derivatives, and synthetic peptides, including engineering- isolated ones, were reviewed. CONCLUSION: Organic-HAp hybrid materials have been intensively created by utilizing proteins and peptides. Among them, engineering-isolated or rationally designed peptides and their derivatives represent future promising building components for organic-HAp hybrids with precise hierarchical structures. Not only the excellent functions of the resultant hybrids materials, but also the creation of materials by biomimetic synthetic processes at a low cost and environmental burden are important for sustainable industrial development. PMID- 29268682 TI - A Review of Computational Drug Repositioning Approaches. AB - Computational drug repositioning emerges as a new idea of drug discovery and development. Contrary to conventional routines, computational drug repositioning encompasses low risk and high safety. Some successful cases demonstrated its advantage. Therefore, a large number of computational drug repositioning approaches have been developed over the past decades. We summarized briefly these methods and classified them into target-based, gene-expression-based, phenome based and multi-omics-based categories according to strategies of drug repositioning. We reviewed some representatives of computational drug repositioning methods in each category, with emphasis on detail of techniques and finally discussed developing trends of computational drug repositioning. PMID- 29268683 TI - Promoting Inter-/Intra- Cellular Process of Nanomedicine through its Physicochemical Properties Optimization. AB - BACKGROUND: Nanomedicine, which is defined as application of nanoparticles in medicine, has offered new hopes for overcoming the drawbacks appeared in traditional chemotherapy. The size of nanomedicine normally in the range from 1 to 200 nm endows its potential applications in cancer therapy. But in clinics, there is still a gap between the in vitro physicochemical properties and the cellular level performance. METHOD: The physicochemical properties include size, shape, surface chemistry, surface topology, and surface properties strongly affect nanomedicine inter-/intra-cellular efficiency. Herein, this article reviews effects of physicochemical properties of nanomedicine on the cellular endocytosis and intracellular route. And strategies of nanomedicine optimization are also discussed from different perspectives. RESULTS: On the one hand, not as that of the traditional small molecular agents, the cellular endocytosis pathway and efficiency of nanomedicine is related to its size, structure and surface properties. On the other hand, the intracellular conditions also affect the intracellular route of nanomedicine. CONCLUSION: Nanomedicine of different scale size is internalized through different pathways. While different sensitivities to intracellular conditions determined by physicochemical properties of nanomedicine will lead to different cellular consumption. So, both the properties of nanomedicine and the intracellular conditions play important roles in cellular metabolism. Consequently, nanocarriers finely engineered as the above principles can provide practical solution to the problems appeared in cellular level for promoting traditional cancer therapy. PMID- 29268684 TI - Transdermal Delivery of Compounds with Different Lipophilicity and Molecular Weight from W/O Microemulsions Analyzed by UPLC-QTOF/ MS and LC-MS/MS. AB - OBJECTIVE: The aim of this study was to develop a novel W/O microemulsion for a natural extract of Wen-Luo-Tong (WLT) containing mainly icariin, hydroxysafflor yellow A (HSYA) and gallic acid to be applied to skin as a potential treatment for peripheral neuropathy. METHODS: The oil phase was selected on the basis of affinity with the surfactant and co-surfactant. Pseudo-ternary diagrams were constructed to optimize microemulsions and finally stability studies were performed on the selected formulations. Droplet sizes were analyzed by using a zetasizer and were found to be within the desired range. Selected microemulsions with acceptable viscosities, containing 5%, 8% and 10% of water extract solution, were used for in vitro skin penetration studies using Franz diffusion cells and excised rat skin. New LC-MS/MS and UPLC-Q-TOF/MS methods were employed for quantitative and qualitative analysis. RESULTS: The optimized formulation (ME-4) consisting of 10% (w/w) water extract solution, 60% isopropyl myristate, 30%(w/w) Smix: Propylene glycol (5:2) significantly increased the cumulative permeated amounts of HSYA, icariin and gallic acid compared with the water extract solution controls. CONCLUSION: This novel formulation also increased the number of components penetrating rat skin. Ten components were detected in the Franz cell receptor solution using a UPLC-Q-TOF/MS system after the application of formulation ME-4 for 24h on the skin in vitro. However, only one component was detected after applying the control. Therefore, the microemulsion ME-4 was selected for future in vivo pharmacodynamic studies. PMID- 29268685 TI - Effect of Binary Organic Solvents Together with Emulsifier on Particle Size and In vitro Behavior of Paclitaxel-Encapsulated Polymeric Lipid Nanoparticles. AB - BACKGROUND: Biodegradable nanoparticles with diameters between 100 nm and 500 nm are of great interest in the contexts of targeted delivery. OBJECTIVE: The present work provides a review concerning the effect of binary organic solvents together with emulsifier on particle size as well as the influence of particle size on the in vitro drug release and uptake behavior. METHODS: The polymeric lipid nanoparticles (PLNs) with different particle sizes were prepared by using binary solvent dispersion method. Various formulation parameters such as binary organic solvent composition and emulsifier types were evaluated on the basis of their effects on particle size and size distribution. PLNs had a strong dependency on the surface tension, intrinsic viscosity and volatilization rate of binary organic solvents and the hydrophilicity/hydrophobicity of emulsifiers. Acetone-methanol system together with pluronic F68 as emulsifier was proved to obtain the smallest particle size. Then the PLNs with different particle sizes were used to investigate how particle size at nanoscale affects interacted with tumor cells. RESULTS: As particle size got smaller, cellular uptake increased in tumor cells and PLNs with particle size of ~120 nm had the highest cellular uptake and fastest release rate. The paclitaxel (PTX)-loaded PLNs showed a size dependent inhibition of tumor cell growth, which was commonly influenced by cellular uptake and PTX release. CONCLUSION: The PLNs would provide a useful means to further elucidate roles of particle size on delivery system of hydrophobic drugs. PMID- 29268686 TI - Carbon Nanotubes: Classification, Method of Preparation and Pharmaceutical Application. AB - Nanoscience and nanotechnology are emerging areas in the pharmaceutical sciences and the need of modernizing world. Nanoscience is the world of atoms, macromolecular assemblies, macromolecules, quantum dots, and molecules. Nanoscience is the study, and understanding control of phenomena and manipulation of material at the nanoscale. Carbon nanotubes are a tube like material mainly made up of carbon. Only carbon nanotubes are the macromolecules of graphite consisting of sheets of carbon, which is weaved into the cylinder. Graphite sheets look like a hexagonal in shape Nano carbon tubes are about 2 millimetres long and these are one hundred times as stiff as steel. The arrangement of atom in a carbon nanotube is in a form of hexagonal as like as graphite. Carrying capacity of carbon nanotube is 1000 times higher than that of copper thermal stability of it is 4000k, it can be semiconducting or metallic, depending on their diameter and chirality of the atom. These carbon nanotubes having various classifications like single walled CNT's, Multiwalled CNT's, Nano horns, Nano buds, polymerized single walled nanotubes. The review is more focused towards the methods of preparation of nanotubes and their general various applications in pharmacy and medicine along with toxicity. These carbon Nano tubes can be prepared by using various methods with successful ease or application in pharmaceuticals, i.e. gas storage, adsorption, catalyst supported, delivery of drug through targeted system, electrochemistry, bio sensing, fuel cell, photodynamic cells, etc. CNT's are advanced technology in the era of nanotechnology in pharmaceutical sciences which are more emphasizing on patient's compliance and safety. Possessing a broad area of application along with targeted drug delivery. The Scientists are still exploring the various applications of it. PMID- 29268687 TI - Evolution of Host Target Cell Specificity During HIV-1 Infection. AB - BACKGROUND: Many details of HIV-1 molecular virology have been translated into lifesaving antiviral drugs. Yet, we have an incomplete understanding of the cells in which HIV-1 replicates in untreated individuals and persists in during antiretroviral therapy. METHODS: In this review we discuss how viral entry phenotypes have been characterized and the insights they have revealed about the target cells supporting HIV-1 replication. In addition, we will examine whether some HIV-1 variants have the ability to enter cells lacking CD4 (such as astrocytes) and the role that trans-infection plays in HIV-1 replication. RESULTS: HIV-1 entry into a target cell is determined by whether the viral receptor (CD4) and the coreceptor (CCR5 or CXCR4) are expressed on that cell. Sustained HIV-1 replication in a cell type can produce viral lineages that are tuned to the CD4 density and coreceptor expressed on those cells; a fact that allows us to use Env protein entry phenotypes to infer information about the cells in which a viral lineage has been replicating and adapting. CONCLUSION: We now recognize that HIV-1 variants can be divided into three classes representing the primary target cells of HIV-1; R5 T cell-tropic variants that are adapted to entering memory CD4+ T cells, X4 T cell-tropic variants that are adapted to entering naive CD4+ T cells and Mtropic variants that are adapted to entering macrophages and possibly other cells that express low levels of CD4. While much progress has been made, the relative contribution that infection of different cell subsets makes to viral pathogenesis and persistence is still being unraveled. PMID- 29268688 TI - Probing Structural Variation and Dynamics in the HIV-1 Env Fusion Glycoprotein. AB - BACKGROUND: Recent advances in structural characterization of the HIV envelope glycoprotein (Env) have provided a high-resolution glimpse of the architecture of this target for neutralizing antibodies and the machinery responsible for mediating receptor binding and membrane fusion. These structures primarily capture the detailed organization of the receptor-naive, prefusion conformation of Env, but under native solution conditions Env is highly dynamic, sampling multiple conformational states as well as exhibiting local protein flexibility. METHODS: Special emphasis is placed on the use of biophysical methods, including single-molecule fluorescence microscopy and hydrogen/deuterium-exchange mass spectrometry. RESULTS: Using novel biophysical approaches, striking isolate specific differences in Env's dynamic profile have been revealed that appear to underlie phenotypic differences of the viral isolates such as neutralization sensitivity and CD4 receptor reactivity. CONCLUSION: Structural studies are complemented by novel biophysical investigations that enable visualization of the dynamics of HIV-1 Env under native conditions. These approaches will also enable us to gain new insights into the mechanisms of action of antibodies and drugs. PMID- 29268689 TI - Basics in Endoscopic Ultrasound Part 2: EUS-guided Sampling and Therapeutic Applications. AB - BACKGROUND: Endoscopic ultrasound (EUS) has been used in the clinical arena for almost 35 years and it is now well-integrated in everyday hospital practice. METHOD: We conducted a systematic review of the available English-language articles. OBJECTIVE: The purpose of this review is to summarize the relevant applications of operative EUS. RESULTS: More than 5000 scientific papers published in the literature have demonstrated its high accuracy for the diagnosis and staging of a variety of benign and malignant conditions. The main indications of operative EUS, both diagnostic and therapeutic, are related to its ability to combine ultrasound imaging and safe and effective needle insertion into lesions originating from the gut wall and from organs nearby. In addition, technologic advancements of echoendoscopes with a therapeutic working-channel have allowed to perform several EUS-guided interventions, i.e. celiac plexus neurolysis, drainage of fluid collections, drainage of dilated biliary and pancreatic ducts, and vascular interventions. PMID- 29268690 TI - Reduced Lipocalin 2 Expression Contributes to Vincristine Resistance in Human Colon Cancer Cells. AB - BACKGROUND: Vincristine (VCR) resistance can lead to cancer chemotherapy failure. Although changes in gene expression are responsible for drug resistance, the specific identities and roles of these genes remain unclear. OBJECTIVE: In this study, we aimed to identify differentially expressed genes and mechanisms of VCR resistance in colorectal cancer (CRC) cells. METHODS: A VCR-resistant CRC cell line (HCT-8/VCR) was established, and differentially expressed proteins between HCT-8 and HCT-8/VCR cells were screened using a human cytokine array; the results were confirmed by reverse transcription polymerase chain reaction and Western blotting. Furthermore, differentially expressed proteins were downregulated using siRNA, and cell proliferation and apoptosis were assessed by Cell Counting Kit-8 assay and flow cytometry, respectively. RESULTS: Compared with HCT-8 CRC cells, HCT-8/VCR cells showed downregulation of lipocalin 2 (LCN2). We found that siRNA mediated downregulation of LCN2 in HCT-8 cells significantly increased VCR resistance. Furthermore, when we downregulated LCN2, we observed significant decreases in apoptosis, but no significant effect on cell cycle. CONCLUSION: Overall, these results demonstrate that LCN2 plays an important role in VCR resistance and is a potential therapeutic target for this disease. PMID- 29268691 TI - Mambalgins, the Venom-origin Peptides as a Potentially Novel Group of Analgesics: Mini Review. AB - BACKGROUND: Despite a wide variety of current analgesia regimens, chronic pain is an incredibly difficult condition to treat. Its pathophysiology, initiation, development and course involve a range of different receptors and transmitters. The acid-sensing ion channels (ASICs) are being attributed to an increasingly larger significance in pain aetiology. Over the last few years, the mechanism of ASICs action, influence of their antagonists/agonists and clinical applications have been well described. However, the importance of this protein is significantly larger, not only from the perspective of pain management, but also in psychiatry of addiction or fear. Recently discovered peptides from three finger toxin group, called mambalgins (isolated from Dendroaspis polylepis polylepsis) exhibit potent analgesic mechanisms of action on ASICs in animal model. AIMS & METHODS: The article reviews current knowledge in the field of mambalgins and assesses their potential analgesic application, based on the recent experimental evidence. RESULTS: The mambalgins seem to decrease the intensity of the inflammatory, neuropathic and mechanic pain. This has been demonstrated in animal studies of different pain models, including carrageenan- induced inflammatory pain, chronic constrictive injury-induced neuropathic pain and thermal pain. The mechanism of mambalgin action is not clearly defined, but it is suspected that they bind directly to the pH-sensitive region of the ASIC. CONCLUSION: In this short review, we attempted to summarise the current knowledge about mambalgins and their potential applications as a new substance in searching for the ideal analgesia without common side effects of the other drug groups. PMID- 29268692 TI - Literature Evidence and ARRIVE Assessment on Neuroprotective Effects of Flavonols in Neurodegenerative Diseases' Models. AB - BACKGROUND AND OBJECTIVE: This paper was based on a literature search of PubMed and Scielo databases using the keywords "Flavonoids, Neuroprotection, Quercetin, Rutin, Isoquercitrin, Alzheimer, Parkinson, Huntington" and combinations of all the words. METHOD: We collected relevant publications, during the period of 2000 to 2016, emphasizing in vivo and in vitro studies with neurological assessment of flavonol's potentials, as well as classifying studies according to evidence levels, in order to elucidate evidence-based literature and its application on clinical research. In addition, we highlight the importance of flavonols in modern research fields, indicating their neuroprotective potential and use thereof as preventive and therapeutic treatment of numerous neurodegenerative disease. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, represent worldwide a major health problem with great financial impact. They are multifactorial diseases, hallmarked by similar pathogenesis that covers conditions such as oxidative stress, formation of free radicals, abnormal protein dynamics (degradation and aggregation), mitochondrial dysfunction, lipid peroxidation and cellular death or senescence. Flavonols are polyphenolic compounds, widely distributed in the plant kingdom and found in high concentrations in vegetables, fruits and teas. Their neuroprotective effects are mainly related to their antioxidant, anti-proliferative and anti-inflammatory properties. CONCLUSION: It was this paper's intention to contribute with an evidence analysis of recent studies approaching neuroprotective effects of flavonols and the potential to conduct human clinical studies. PMID- 29268693 TI - Advances in Therapies of Cerebellar Disorders: Immune-mediated Ataxias. AB - The identification of an increasing number of immune mediated ataxias suggests that the cerebellum is often a target organ for autoimmune insults. The diagnosis of immune mediated ataxias remains challenging as there is significant clinical overlap between immune mediated and other forms of ataxia. Furthermore the classification of immune mediated ataxias requires further clarification particularly for those ataxias where no specific antigenic trigger and associated antibodies have been identified. Recognition of immune mediated ataxias remains imperative as therapeutic interventions can often be effective, although given the relative rarity of this entity, large-scale treatment trials may not be feasible. This review will discuss advances in therapies for immune mediated ataxias based on what is currently available in the literature. PMID- 29268694 TI - Origins and biogeography of the Anolis crassulus subgroup (Squamata: Dactyloidae) in the highlands of Nuclear Central America. AB - BACKGROUND: Recent studies have begun to reveal the complex evolutionary and biogeographic histories of mainland anoles in Central America, but the origins and relationships of many taxa remain poorly understood. One such group is the Anolis (Norops) crassulus species subgroup, which contains ten morphologically similar highland taxa, the majority of which have restricted distributions. The nominal taxon A. crassulus has a disjunct distribution from Chiapas, Mexico, through Guatemala, in the highlands of El Salvador, and in the Chortis Highlands of Honduras. We test the relationships of these species using multiple mitochondrial and nuclear loci in concatenated and multispecies coalescent frameworks, in an effort to both resolve long-standing taxonomic confusion and present new insights into the evolution and biogeography of these taxa. RESULTS: Sequences of multiple mitochondrial and nuclear loci were generated for eight of the ten species of the Anolis crassulus species subgroup. We analyzed phylogenetic relationships and estimated divergence times and ancestral ranges of the subgroup, recovering a monophyletic subgroup within Anolis. Within the nominal taxon Anolis crassulus, we recovered multiple genetically distinct lineages corresponding to allopatric populations, and show that the Chortis Highland lineage split from the others over 13 MYA. Additionally, distinct mitochondrial lineages are present within the taxa A. heteropholidotus and A. morazani, and importantly, samples of A. crassulus and A. sminthus previously used in major anole phylogenetic analyses are not recovered as conspecific with those taxa. We infer a Chortis Highland origin for the ancestor of this subgroup, and estimate cladogenesis of this subgroup began approximately 22 MYA. CONCLUSIONS: Our results provide new insights into the evolution, biogeography, and timing of diversification of the Anolis crassulus species subgroup. The disjunctly distributed Anolis crassulus sensu lato represents several morphologically conserved, molecularly distinct anoles, and several other species in the subgroup contain multiple isolated lineages. PMID- 29268695 TI - An integrated meta-analysis approach to identifying medications with potential to alter breast cancer risk through connectivity mapping. AB - BACKGROUND: Gene expression connectivity mapping has gained much popularity in recent years with a number of successful applications in biomedical research testifying its utility and promise. A major application of connectivity mapping is the identification of small molecule compounds capable of inhibiting a disease state. In this study, we are additionally interested in small molecule compounds that may enhance a disease state or increase the risk of developing that disease. Using breast cancer as a case study, we aim to develop and test a methodology for identifying commonly prescribed drugs that may have a suppressing or inducing effect on the target disease (breast cancer). RESULTS: We obtained from public data repositories a collection of breast cancer gene expression datasets with over 7000 patients. An integrated meta-analysis approach to gene expression connectivity mapping was developed, which involved unified processing and normalization of raw gene expression data, systematic removal of batch effects, and multiple runs of balanced sampling for differential expression analysis. Differentially expressed genes stringently selected were used to construct multiple non-joint gene signatures representing the same biological state. Remarkably these non-joint gene signatures retrieved from connectivity mapping separate lists of candidate drugs with significant overlaps, providing high confidence in their predicted effects on breast cancers. Of particular note, among the top 26 compounds identified as inversely connected to the breast cancer gene signatures, 14 of them are known anti-cancer drugs. CONCLUSIONS: A few candidate drugs with potential to enhance breast cancer or increase the risk of the disease were also identified; further investigation on a large population is required to firmly establish their effects on breast cancer risks. This work thus provides a novel approach and an applicable example for identifying medications with potential to alter cancer risks through gene expression connectivity mapping. PMID- 29268696 TI - Stereoscopic processing of crossed and uncrossed disparities in the human visual cortex. AB - BACKGROUND: Binocular disparity provides a powerful cue for depth perception in a stereoscopic environment. Despite increasing knowledge of the cortical areas that process disparity from neuroimaging studies, the neural mechanism underlying disparity sign processing [crossed disparity (CD)/uncrossed disparity (UD)] is still poorly understood. In the present study, functional magnetic resonance imaging (fMRI) was used to explore different neural features that are relevant to disparity-sign processing. METHODS: We performed an fMRI experiment on 27 right handed healthy human volunteers by using both general linear model (GLM) and multi-voxel pattern analysis (MVPA) methods. First, GLM was used to determine the cortical areas that displayed different responses to different disparity signs. Second, MVPA was used to determine how the cortical areas discriminate different disparity signs. RESULTS: The GLM analysis results indicated that shapes with UD induced significantly stronger activity in the sub-region (LO) of the lateral occipital cortex (LOC) than those with CD. The results of MVPA based on region of interest indicated that areas V3d and V3A displayed higher accuracy in the discrimination of crossed and uncrossed disparities than LOC. The results of searchlight-based MVPA indicated that the dorsal visual cortex showed significantly higher prediction accuracy than the ventral visual cortex and the sub-region LO of LOC showed high accuracy in the discrimination of crossed and uncrossed disparities. CONCLUSIONS: The results may suggest the dorsal visual areas are more discriminative to the disparity signs than the ventral visual areas although they are not sensitive to the disparity sign processing. Moreover, the LO in the ventral visual cortex is relevant to the recognition of shapes with different disparity signs and discriminative to the disparity sign. PMID- 29268697 TI - Comparative transcriptome and proteome profiling of two Citrus sinensis cultivars during fruit development and ripening. AB - BACKGROUND: Transcriptome and proteome analyses on fruit pulp from the blood orange 'Zaohong' and the navel orange 'twenty-first century' were performed to study Citrus sinensis quality-related molecular changes during consecutive developmental periods, including young fruit, fruit-coloring onset and fruit delayed-harvest for two months, during which fruit remained on the trees. RESULTS: The time-course analysis for the fruit developmental periods indicated a complex, dynamic gene expression pattern, with the numbers of differentially expressed genes (DEGs) between the two cultivars being 119, 426 and 904 at the three continuous stages tested during fruit development and ripening. The continuous increase in total soluble solids over the course of fruit development was correlated with up-regulated sucrose phosphate synthase (SPS) transcription levels in both cultivars. Eleven differentially expressed genes between the two cultivars involved in the flavonoid pathway were significantly enriched at the onset of the fruit-coloring stage when anthocyanins were detected in blood orange alone. Among 5185 proteins, 65 up-regulated and 29 down-regulated proteins were co-expressed with their cognate mRNAs with significant transcription and protein expression levels when the fruits from the two cultivars were compared at the fruit delayed-harvest stage. Additionally, important genes participating in the gamma-aminobutyric acid (GABA) shunt were activated in blood orange at two significant expression levels in the fruit delayed-harvest stage. Thus, organic acids in fruit continuously decreased during this stage. CONCLUSIONS: This research was the first to provide a more comprehensive understanding of the differentially expressed genes involved in anthocyanin, sucrose and citrate metabolism at the transcriptome and proteome levels in C. sinensis, especially during the fruit delayed-harvest stage. PMID- 29268698 TI - High neutrophil-to-lymphocyte ratios confer poor prognoses in patients with small cell lung cancer. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily obtained from routine blood tests. We investigated the associations of the NLR and PLR with the clinical parameters and prognoses of small cell lung cancer (SCLC) patients. METHODS: Pre-treatment clinical and laboratory data from 139 patients with SCLC were retrospectively studied with univariate analyses. The NLR and PLR values were divided into two separate groups: high NLR (>4.55, n = 32) vs low NLR (<=4.55, n = 107) and high PLR (>148, n = 63) vs low PLR (<=148, n = 76). Kaplan-Meier survival analyses and Cox proportional hazard models were used to examine the effects of NLR and PLR on overall survival. RESULTS: Chi-square analyses revealed significant associations of high NLR with tumour stage, hepatic metastasis, radiotherapy and chemotherapy and significant associations of high PLR with tumour stage, bone and hepatic metastases, exposure to cooking oil fumes, and chemotherapy. Mann-Whitney U tests demonstrated an association of high NLR with smoking exposure, and high NLR and high PLR were correlated with several laboratory parameters. Kaplan-Meier analyses revealed that high NLR and high PLR conferred poor prognoses for SCLC patients. Moreover, multivariate analysis demonstrated that NLR, tumour stage, and hepatic metastasis were independent prognostic factors for survival. In this study, we found that NLR and PLR were associated with several factors that reflect the inflammatory (white blood cell count, WBC; lactate dehydrogenase, LDH) and nutritional (albumin, ALB; haemoglobin, HB; and cholesterol) status of SCLC patients at diagnosis. CONCLUSIONS: NLR is an independent prognostic factor and can be used to predict the mortality risk of SCLC patients. PMID- 29268699 TI - Acacia hydaspica ethyl acetate extract protects against cisplatin-induced DNA damage, oxidative stress and testicular injuries in adult male rats. AB - BACKGROUND: Cisplatin (CP), an effective anticancer agent, carries the risk of impairing testicular function leading to infertility. The present study aimed at evaluating the protective effect of A. hydaspica ethyl acetate extract (AHE) against CP-induced oxidative stress and testicular injuries in rats. METHODS: Rats were divided into six groups (n = 6). Group I (control), group II (CP single dose on day 16). Group III received AHE for 21 days. Group IV (CP + AHE; post- treatment group). Group V (AHE + CP; pre-treatment group) and group VI (CP + Sily). RESULTS: CP treatment reduced serum testosterone (T), LH and FSH, decreased the activity level of antioxidant enzymes while increased the concentration of oxidative stress markers, i.e. thiobarbituric acid reactive substances (TBARS), H2O2 and nitric oxide (NO) along with corresponding DNA damages. Furthermore, CP induced adverse morphological changes in testis of rats including reduced epithelial height and tubular diameter, increased luminal diameter with impaired spermatogenesis. Pre and post-treatment with AHE reduced the side effects of CP in testis tissues through improvement in the reproductive hormonal secretions, enzymatic activities, histological and DNA damage parameters. Pretreatment seems to be more effective and equivalent to silymarin group in reversing the CP deleterious effects as compared to post-treatment. CONCLUSION: The results demonstrated that A. hydaspica treatment in CP-induced testicular toxicity augments the antioxidants defense mechanism, reverted the level of fertility hormones, suppressed the histomorphological alterations and DNA damages and thus provides the evidence that it may have a therapeutic role in free radical mediated diseases. PMID- 29268700 TI - Examining the online approaches used by hospitals in Sydney, Australia to inform patients about healthcare associated infections and infection prevention strategies. AB - BACKGROUND: Provision of information plays a critical role in supporting patients to be engaged or empowered to be involved with infection prevention measures in hospitals. This explorative study evaluated the suitability, readability and accessibility of information on healthcare associated infections (HCAIs) and infection prevention strategies targeted at patients from the websites of 19 acute care public hospitals in Sydney, Australia. METHODS: We included hospitals with greater than 200 beds in the sample. We examined online information targeted at patients on HCAIs and infection prevention and compared it using the Suitability Assessment of Material (SAM) and Simple Measure of Gobbledygook (SMOG) readability formulas for suitability, readability and accessibility. RESULTS: Thirty-six webpages were identified as being relevant and containing information about HCAIs or infection prevention. Based on the SAM/SMOG scores, only three webpages were found to be 'superior'. Many of the webpages scored poorly in content, literacy, graphics, learning stimulation and cultural appropriateness. In comparison, most of the webpages scored well in the layout and typography. The majority (97%) of the materials were written at a level higher than the recommended reading grade level. Lastly, the websites scored poorly on the ability to locate the information easily, as messages about HCAIs/infection prevention were usually embedded into other topics. CONCLUSION: While providing information online is only one approach to delivering messages about infection prevention, it is becoming increasingly important in today's technology society. Hospitals are neglecting to use best practices when designing their online resources and current websites are difficult to navigate. The findings point to the need to review patient information on HCAIs regarding suitability, readability and accessibility. PMID- 29268701 TI - Multiple Score Comparison: a network meta-analysis approach to comparison and external validation of prognostic scores. AB - BACKGROUND: Prediction models and prognostic scores have been increasingly popular in both clinical practice and clinical research settings, for example to aid in risk-based decision making or control for confounding. In many medical fields, a large number of prognostic scores are available, but practitioners may find it difficult to choose between them due to lack of external validation as well as lack of comparisons between them. METHODS: Borrowing methodology from network meta-analysis, we describe an approach to Multiple Score Comparison meta analysis (MSC) which permits concurrent external validation and comparisons of prognostic scores using individual patient data (IPD) arising from a large-scale international collaboration. We describe the challenges in adapting network meta analysis to the MSC setting, for instance the need to explicitly include correlations between the scores on a cohort level, and how to deal with many multi-score studies. We propose first using IPD to make cohort-level aggregate discrimination or calibration scores, comparing all to a common comparator. Then, standard network meta-analysis techniques can be applied, taking care to consider correlation structures in cohorts with multiple scores. Transitivity, consistency and heterogeneity are also examined. RESULTS: We provide a clinical application, comparing prognostic scores for 3-year mortality in patients with chronic obstructive pulmonary disease using data from a large-scale collaborative initiative. We focus on the discriminative properties of the prognostic scores. Our results show clear differences in performance, with ADO and eBODE showing higher discrimination with respect to mortality than other considered scores. The assumptions of transitivity and local and global consistency were not violated. Heterogeneity was small. CONCLUSIONS: We applied a network meta-analytic methodology to externally validate and concurrently compare the prognostic properties of clinical scores. Our large-scale external validation indicates that the scores with the best discriminative properties to predict 3 year mortality in patients with COPD are ADO and eBODE. PMID- 29268702 TI - Assessing and improving organizational readiness to implement substance use disorder treatment in primary care: findings from the SUMMIT study. AB - BACKGROUND: Millions of people with substance use disorders (SUDs) need, but do not receive, treatment. Delivering SUD treatment in primary care settings could increase access to treatment because most people visit their primary care doctors at least once a year, but evidence-based SUD treatments are underutilized in primary care settings. We used an organizational readiness intervention comprised of a cluster of implementation strategies to prepare a federally qualified health center to deliver SUD screening and evidence-based treatments (extended-release injectable naltrexone (XR-NTX) for alcohol use disorders, buprenorphine/naloxone (BUP/NX) for opioid use disorders and a brief motivational interviewing/cognitive behavioral -based psychotherapy for both disorders). This article reports the effects of the intervention on key implementation outcomes. METHODS: To assess changes in organizational readiness we conducted pre- and post-intervention surveys with prescribing medical providers, behavioral health providers and general clinic staff (N = 69). We report on changes in implementation outcomes: acceptability, perceptions of appropriateness and feasibility, and intention to adopt the evidence-based treatments. We used Wilcoxon signed rank tests to analyze pre- to post-intervention changes. RESULTS: After 18 months, prescribing medical providers agreed more that XR-NTX was easier to use for patients with alcohol use disorders than before the intervention, but their opinions about the effectiveness and ease of use of BUP/NX for patients with opioid use disorders did not improve. Prescribing medical providers also felt more strongly after the intervention that XR-NTX for alcohol use disorders was compatible with current practices. Opinions of general clinic staff about the appropriateness of SUD treatment in primary care improved significantly. CONCLUSIONS: Consistent with implementation theory, we found that an organizational readiness implementation intervention enhanced perceptions in some domains of practice acceptability and appropriateness. Further research will assess whether these factors, which focus on individual staff readiness, change over time and ultimately predict adoption of SUD treatments in primary care. PMID- 29268703 TI - Bone marrow-derived mesenchymal stem cells induced by inflammatory cytokines produce angiogenetic factors and promote prostate cancer growth. AB - BACKGROUND: Prostate is susceptible to infection and pro-inflammatory agents in a man's whole life. Chronic inflammation might play important roles in the development and progression of prostate cancer. Mesenchymal stem cells (MSCs) are often recruited to the tumor microenvironment due to local inflammation. We have asked whether stimulation of MSCs by pro-inflammatory cytokines could promote prostate tumor growth. The current study investigated the possible involvement of MSCs stimulated by pro-inflammatory cytokines in promotion and angiogenesis of prostate cancer through relative pathway in vitro and in vivo. METHODS: A syngeneic mouse model of C57 was established. The murine prostate cancer cells (RM-1) mixing with MSCs treated with tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) or vehicle were subcutaneously injected into C57 mice. Tumor volume of C57 mouse model was estimated and serum level of platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) was test by Enzyme-linked Immunosorbent Assay (ELISA). A hen egg test-chorioallantoic membrane (HET-CAM) assay was applied to test the effect of conditioned media of stimulated MSCs in chorioallantoic membrane angiogenesis. Short interfering RNA (siRNA) knocked down either hypoxia-inducible factor-1alpha (HIF-1alpha) or nuclear factor-erythroid-2-related factor 2 (NRF2) were employed. mRNA of PDGF and VEGF in MSCs, as well as NRF2 and HIF-1alpha was test by Real time polymerase chain reaction (PCR) analyses. Protein expression levels of PDGF and VEGF from conditioned medium, NRF2, HIF-1alpha, as well as PDGF and VEGF in MSCs were detected by Western blot analysis. RESULTS: MSCs treated with TNF-alpha and IFN gamma promote tumor growth in C57 syngeneic mouse model, correlating with increased serum level of PDGF, VEGF. HET-CAM assay shows the angiogenic effect of conditioned medium of MSCs pre-treated with the pro-inflammatory cytokines. mRNA and protein levels of two pro-angiogenic factors (PDGF and VEGF) and key hypoxia regulators (HIF-1alpha and NRF2) in MSCs were induced after MSCs' pretreatment. siRNA knockdown either HIF-1alpha or NRF2 results reduction of PDGF and VEGF expression. CONCLUSIONS: MSCs stimulated by pro-inflammatory cytokines increase the expression of PDGF and VEGF via the NRF2-HIF-1alpha pathway and accelerate prostate cancer growth in mice. PMID- 29268704 TI - Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon? AB - BACKGROUND: Hepatitis B virus (HBV) chronic infection affects up to 240 million people in the world and it is a common cause of cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) plays an essential role in HBV persistence and replication. Current pharmacological treatment with nucleos(t)ide analogues (NA) may suppress HBV replication with little or no impact on cccDNA, hence lifelong treatment is required in the vast majority of patients. Clearances of intrahepatic cccDNA and/or HBsAg are critical endpoints for future antiviral therapy in chronic HBV. Recent promising developments targeting different molecular HBV life cycle steps are being pre-clinically tested or have moved forward in early clinical trials. METHODS: We review the current state of the art of these pharmacological developments, mainly focusing on efficacy and safety results, which are expected to lay the ground for future HBV eradication. An inclusive literature search on new treatments of HBV using the following electronic databases: Pubmed/MEDLINE, AMED, CINAHL and the Cochrane Central Register of Controlled Trials. Full-text manuscripts and abstracts published over the last 12 years, from 2005 to March 2011 were reviewed for relevance and reference lists were crosschecked for additional applicable studies regarding new HBV antiviral treatment. RESULTS: HBV entry inhibitors, HBV core inhibitors, HBV cccDNA transcripts RNA interference, HBV cell apoptosis inducers, HBV RNA, viral proteins and DNA knock down agents, HBV release inhibitors, anti sense nucleosides, exogenous interferon stimulation, interferon response stimulation and HBV therapeutic vaccines were reviewed. CONCLUSION: This review will provide readers with an updated vision of current and foreseeable therapeutic developments in chronic hepatitis B. PMID- 29268705 TI - Identification of tRNA nucleoside modification genes critical for stress response and development in rice and Arabidopsis. AB - BACKGROUND: Modification of nucleosides on transfer RNA (tRNA) is important either for correct mRNA decoding process or for tRNA structural stabilization. Nucleoside methylations catalyzed by MTase (methyltransferase) are the most common type among all tRNA nucleoside modifications. Although tRNA modified nucleosides and modification enzymes have been extensively studied in prokaryotic systems, similar research remains preliminary in higher plants, especially in crop species, such as rice (Oryza sativa). Rice is a monocot model plant as well as an important cereal crop, and stress tolerance and yield are of great importance for rice breeding. RESULTS: In this study, we investigated how the composition and abundance of tRNA modified nucleosides could change in response to drought, salt and cold stress, as well as in different tissues during the whole growth season in two model plants-O. sativa and Arabidopsis thaliana. Twenty two and 20 MTase candidate genes were identified in rice and Arabidopsis, respectively, by protein sequence homology and conserved domain analysis. Four methylated nucleosides, Am, Cm, m1A and m7G, were found to be very important in stress response both in rice and Arabidopsis. Additionally, three nucleosides,Gm, m5U and m5C, were involved in plant development. Hierarchical clustering analysis revealed consistency on Am, Cm, m1A and m7G MTase candidate genes, and the abundance of the corresponding nucleoside under stress conditions. The same is true for Gm, m5U and m5C modifications and corresponding methylation genes in different tissues during different developmental stages. CONCLUSIONS: We identified candidate genes for various tRNA modified nucleosides in rice and Arabidopsis, especially on MTases for methylated nucleosides. Based on bioinformatics analysis, nucleoside abundance assessments and gene expression profiling, we propose four methylated nucleosides (Am, Cm, m1A and m7G) that are critical for stress response in rice and Arabidopsis, and three methylated nucleosides (Gm, m5U and m5C) that might be important during development. PMID- 29268706 TI - N-glycosylation of serum proteins for the assessment of patients with IgD multiple myeloma. AB - BACKGROUND: Because glycosylation is one of the most common post-translational modifications of proteins and because changes in glycosylation have been shown to have a significant correlation with the development of many cancer types, we investigated the serum N-glycome used to diagnose, stage and evaluate the pathological outcomes in IgD multiple myeloma. METHODS: Serum samples were available for 20 patients with IgD multiple myeloma, 41 patients with light chain multiple myeloma and 42 healthy control subjects. Serum N-glycans were released and analysed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis. RESULTS: Characteristic changes were revealed in the serum N glycome of IgD myeloma. In particular, three N-glycans (NG1(6)A2F, Peak3; NG1(3)A2F, Peak4; NA2FB, Peak7) showed increased clinical value. The best area under the ROC curve of NG1(6)A2F to diagnose IgD myeloma was 0.981, with a 95.0% sensitivity and 95.2% specificity, and that of NG1(3)A2F was 0.936, with a 95.0% sensitivity and 78.6% specificity. The best area under the ROC curve of NA2FB/NG1(3)A2F to differentially diagnose IgD myeloma versus light chain myeloma was 0.744, with a 95.3% sensitivity and 50.0% specificity. The level of NG1(3)A2F was correlated with the international staging system, while the higher abundance of NA2FB presented in IgD myeloma was predictive of a shorter progression-free survival. CONCLUSIONS: The advent of serum N-glycan signatures may play a role in the diagnosis, staging and prognosis of IgD myeloma and will serve as the foundation for a precision medicine approach to this rare subtype of multiple myeloma. PMID- 29268707 TI - Does being physically active prevent future disability in older people? Attenuated effects when taking time-dependent confounders into account. AB - BACKGROUND: Causal experimental evidence that physical activity prevents disability in older people is sparse. Being physically active has nonetheless been shown to be associated with disability-free survival in observational studies. Observational studies are, however, prone to bias introduced by time dependent confounding. Time-dependent confounding occurs when an exposure (e.g. being physically active at some time-point) potentially affects the future status of a confounder (such as depression sometime later), and both variables have an effect on latter outcome (i.e. disability). "Conventional" analysis with e.g. Cox regression is the mainstay when analyzing longitudinal observational studies. Unfortunately, it does not provide unbiased estimates in the presence of time dependent confounding. Marginal structural models (MSM) - a relatively new class of causal models - have the potential to adequately account for time-dependent confounding. Here we analyze the effect of older people being physically active on disability, in a large long-term observational study. We address time dependent confounding by using marginal structural models and provide a non technical practical demonstration of how to implement this type of modeling. METHODS: Data is from 639 elderly individuals ascertained in the European multi center Leukoaraiosis and Disability study (LADIS), followed-up yearly over a period of three years. We estimated the effect of self-reported physical activity on the probability to transit to instrumental disability in the presence of a large set of potential confounders. We compare the results of "conventional" modeling approaches to those estimated using marginal structural models, highlighting discrepancies. RESULTS: A "conventional" Cox-regression-like adjustment for salient baseline confounders signals a significant risk reduction under physical activity for later instrumental disability (OR 0.62, 95% CI 0.44 0.90). However, given MSM estimation, the effect is attenuated towards null (OR 1.00, 95% CI 0.57-1.76). CONCLUSIONS: Contrary to most reports, we did not find that physical activity in older people prevents future instrumental disability, when taking time-dependent confounding into account. This result may be due to the characteristics our particular study population. It is, however, also conceivable that previous evidence neglected the effect of this type of bias. We suggest that analysts of longitudinal observational studies consider marginal structural models as a further modeling approach. PMID- 29268708 TI - Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC. AB - BACKGROUND: The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim. METHODS: The patients were treated with the vaccine at 1 * 106, 1 * 107and the maximum dose 8 * 107 at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life. RESULTS: The vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-alpha and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients'quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence. CONCLUSIONS: We provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients' quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial. PMID- 29268709 TI - Negative correlation between rates of molecular evolution and flowering cycles in temperate woody bamboos revealed by plastid phylogenomics. AB - BACKGROUND: Heterogeneous rates of molecular evolution are universal across the tree of life, posing challenges for phylogenetic inference. The temperate woody bamboos (tribe Arundinarieae, Poaceae) are noted for their extremely slow molecular evolutionary rates, supposedly caused by their mysterious monocarpic reproduction. However, the correlation between substitution rates and flowering cycles has not been formally tested. RESULTS: Here we present 15 newly sequenced plastid genomes of temperate woody bamboos, including the first genomes ever sequenced from Madagascar representatives. A data matrix of 46 plastid genomes representing all 12 lineages of Arundinarieae was assembled for phylogenetic and molecular evolutionary analyses. We conducted phylogenetic analyses using different sequences (e.g., coding and noncoding) combined with different data partitioning schemes, revealing conflicting relationships involving internodes among several lineages. A great difference in branch lengths were observed among the major lineages, and topological inconsistency could be attributed to long branch attraction (LBA). Using clock model-fitting by maximum likelihood and Bayesian approaches, we furthermore demonstrated extensive rate variation among these major lineages. Rate accelerations mainly occurred for the isolated lineages with limited species diversification, totaling 11 rate shifts during the tribe's evolution. Using linear regression analysis, we found a negative correlation between rates of molecular evolution and flowering cycles for Arundinarieae, notwithstanding that the correlation maybe insignificant when taking the phylogenetic structure into account. CONCLUSIONS: Using the temperate woody bamboos as an example, we found further evidence that rate heterogeneity is universal in plants, suggesting that this will pose a challenge for phylogenetic reconstruction of bamboos. The bamboos with longer flowering cycles tend to evolve more slowly than those with shorter flowering cycles, in accordance with a putative generation time effect. PMID- 29268710 TI - Follow-up of iatrogenic aorto-coronary "Dunning" dissections by cardiac computed tomography imaging. AB - BACKGROUND: Iatrogenic aorto-coronary dissections following percutaneous coronary interventions (PCI) represent a rare but potentially life threatening complication. This restrospective and observational study aims to describe our in house experience for timely diagnostics and therapy including cardiovascular imaging to follow-up securely high-risk patients with Dunning dissections. METHODS: Dunning dissections (DD) occurred during clinical routine PCIs, which were indicated according to current ESC guidelines. Diagnostic assessment, treatment and follow-up were based on coronary angiography with PCI or conservative treatment and cardiac computed tomography (cCTA) imaging. RESULTS: A total of eight patients with iatrogenic DD were included. Median age was 69 years (IQR 65.8-74.5). Patients revealed a coronary multi-vessel-disease in 75% with a median SYNTAX-II-score of 35.3 (IQR 30.2-41.2). The most common type of DD was type III (50%), followed by type I (38%) and type II (13%). In most patients (88%) the DD involved the right coronary arterial ostium. 63% were treated by PCI, the remaining patients were treated conservatively. 88% of patients received at least one cCTA within 2 days, 50% were additionally followed-up by cCTA within a median of 6 months (range: 4-8 months) without any residual. CONCLUSION: Independently of the type of DD (I-III) it was demonstrated that cCTA represents a valuable imaging modality for detection and follow-up of patients with DDs. PMID- 29268711 TI - "I am a person but I am not a person": experiences of women living with obstetric fistula in the central region of Malawi. AB - BACKGROUND: The consequences of living with obstetric fistula are multifaceted and very devastating for women, especially those living in poor resource settings. Due to uncontrollable leakages of urine and/or feces, the condition leaves women with peeling of skin on their private parts, and the wetness and smell subject them to stigmatization, ridicule, shame and social isolation. We sought to gain a deeper understanding of lived experiences of women with obstetric fistula in Malawi, in order to recommend interventions that would both prevent new cases of obstetric fistula as well as improve the quality of life for those already affected. METHODS: We conducted semi-structured interviews with 25 women with obstetric fistula at Bwaila Fistula Care Center in Lilongwe and in its surrounding districts. We interviewed twenty women at Bwaila Fistula Care Center; five additional women were identified through snowball sampling and were interviewed in their homes. We also interviewed twenty family members. To analyze the data, we used thematic analysis. Data were categorized using Nvivo 10. Goffman's theory of stigma was used to inform the data analysis. RESULTS: All the women in this study were living a socially restricted and disrupted life due to a fear of involuntary disclosure and embarrassment. Therefore, "anticipated" as opposed to "enacted" stigma was especially prevalent among the participants. Many lost their positive self-image due to incontinence and smell. As a way to avoid shame and embarrassment, these women avoided public gatherings; such as markets, church, funerals and weddings, thus losing part of their social identity. Participants had limited knowledge about their condition. CONCLUSION: The anticipation of stigma by women in this study consequently limited their social lives. This fear of stigma might have arisen from previous knowledge of social norms concerning bowel and bladder control, which do not take into account an illness like obstetric fistula. This misconception might have also arisen from lack of knowledge about causes of the condition itself. There is need therefore to create awareness and educate women and their communities about the causes of obstetric fistula, its prevention and treatment, which may help to prevent fistula as well as reduce all dimensions of stigma, and consequently increase dignity and quality of life for these women. PMID- 29268712 TI - Retinal capillary rarefaction in patients with untreated mild-moderate hypertension. AB - BACKGROUND: Microvascular rarefaction influences peripheral vascular resistance, perfusion and metabolism by affecting blood pressure and flow pattern. In hypertension microvascular rarefaction has been described in experimental animal studies as well as in capillaroscopy of skin and biopsies of muscle tissue in patients. Retinal circulation mirrors cerebral microcirculation and allows non invasive investigations. We compared capillary rarefaction of retinal vessels in hypertensive versus normotensive subjects. METHODS: In this study retinal capillary rarefaction in 70 patients with long time (more than 67 month of disease duration) and 64 patients with short time hypertension stage 1 or 2 has been compared to 55 healthy control subjects, who participated in clinical trials in our Clinical Research Center ( www.clinicaltrials.gov : NCT01318395, NCT00627952, NCT00152698, NCT01319344). Retinal vascular parameters have been measured non-invasively and in vivo in perfusion image by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). Capillary rarefaction was assessed by capillary area (CapA) (in pixel-number) and intercapillary distance (ICD) (in MUm). Additionally retinal capillary flow (RCF) was measured. RESULTS: ICD was greater in the long time hypertensive group compared to healthy individuals (24.2 +/- 6.3 MUm vs 20.1 +/- 4.2 MUm, p = 0.001) and compared to short time hypertensive patients (22.2 +/- 5.2 MUm, p = 0.020). Long time hypertensive patients showed less CapA compared to healthy people (1462 +/- 690 vs 1821 +/- 652, p = 0.005). Accordingly, RCF was significantly lower in the long time hypertensive group compared to the healthy control group (282 +/- 70 AU vs 314 +/ 60 AU, p = 0.032). Our data indicate a lower level of retinal capillary density in hypertensive patients, especially in those with long time hypertension. CONCLUSION: Patients with hypertension stage 1 or 2 showed retinal capillary rarefaction in comparison to healthy normotensive subjects. Retinal capillary rarefaction was intensified with duration of disease. PMID- 29268713 TI - The analysis of relationship between selected sociodemografic factors and disorders of speech organs in Parkinson's patients. AB - BACKGROUND: Evaluation of speech disorders in PD taking into account sociodemographic conditions is not frequent. This paper aims to establish correlations between articulation disorders in PD patients and factors such as the patients' sex, age, education and residence. METHODS: The study included 92 patients with idiopathic PD diagnosed by means of multiple neurological examinations, biochemical tests, MRI and CT scanning carried out in accordance with the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria. A speech and language test involved the assessment of the mobility of the speech organs as well as the reflexes inside the oral cavity. Frenchay Dysarthria Assessment was applied for an objective evaluation of dysarthria. RESULTS: The study revealed the existence of significant relationship between the functionality of articulators in PD patients and their education and residence. Big city dwellers demonstrated lower incidence of disorders within speech organs, particularly those affecting mobility of the soft palate while eating. Disorders of moderate intensity were more frequently found in subjects living in villages. Subjects with a university education displayed better position of the lips at rest and better performance of both lips and the mandible while speaking. CONCLUSIONS: Abnormal functioning of the articulatory organs was observed more frequently in PD patients residing in rural areas than in those inhabiting urban areas. As for education, our cohort university graduates displayed a better position of the lips at rest and better performance of the lips and jaw during speaking than those with secondary and vocational education. PMID- 29268714 TI - Purification of nanogram-range immunoprecipitated DNA in ChIP-seq application. AB - BACKGROUND: Chromatin immunoprecipitation-sequencing (ChIP-seq) is a widely used epigenetic approach for investigating genome-wide protein-DNA interactions in cells and tissues. The approach has been relatively well established but several key steps still require further improvement. As a part of the procedure, immnoprecipitated DNA must undergo purification and library preparation for subsequent high-throughput sequencing. Current ChIP protocols typically yield nanogram quantities of immunoprecipitated DNA mainly depending on the target of interest and starting chromatin input amount. However, little information exists on the performance of reagents used for the purification of such minute amounts of immunoprecipitated DNA in ChIP elution buffer and their effects on ChIP-seq data. Here, we compared DNA recovery, library preparation efficiency, and ChIP seq results obtained with several commercial DNA purification reagents applied to 1 ng ChIP DNA and also investigated the impact of conditions under which ChIP DNA is stored. RESULTS: We compared DNA recovery of ten commercial DNA purification reagents and phenol/chloroform extraction from 1 to 50 ng of immunopreciptated DNA in ChIP elution buffer. The recovery yield was significantly different with 1 ng of DNA while similar in higher DNA amounts. We also observed that the low nanogram range of purified DNA is prone to loss during storage depending on the type of polypropylene tube used. The immunoprecipitated DNA equivalent to 1 ng of purified DNA was subject to DNA purification and library preparation to evaluate the performance of four better performing purification reagents in ChIP-seq applications. Quantification of library DNAs indicated the selected purification kits have a negligible impact on the efficiency of library preparation. The resulting ChIP-seq data were comparable with the dataset generated by ENCODE consortium and were highly correlated between the data from different purification reagents. CONCLUSIONS: This study provides comparative data on commercial DNA purification reagents applied to nanogram-range immunopreciptated ChIP DNA and evidence for the importance of storage conditions of low nanogram range purified DNA. We verified consistent high performance of a subset of the tested reagents. These results will facilitate the improvement of ChIP-seq methodology for low-input applications. PMID- 29268715 TI - Super-delta: a new differential gene expression analysis procedure with robust data normalization. AB - BACKGROUND: Normalization is an important data preparation step in gene expression analyses, designed to remove various systematic noise. Sample variance is greatly reduced after normalization, hence the power of subsequent statistical analyses is likely to increase. On the other hand, variance reduction is made possible by borrowing information across all genes, including differentially expressed genes (DEGs) and outliers, which will inevitably introduce some bias. This bias typically inflates type I error; and can reduce statistical power in certain situations. In this study we propose a new differential expression analysis pipeline, dubbed as super-delta, that consists of a multivariate extension of the global normalization and a modified t-test. A robust procedure is designed to minimize the bias introduced by DEGs in the normalization step. The modified t-test is derived based on asymptotic theory for hypothesis testing that suitably pairs with the proposed robust normalization. RESULTS: We first compared super-delta with four commonly used normalization methods: global, median-IQR, quantile, and cyclic loess normalization in simulation studies. Super delta was shown to have better statistical power with tighter control of type I error rate than its competitors. In many cases, the performance of super-delta is close to that of an oracle test in which datasets without technical noise were used. We then applied all methods to a collection of gene expression datasets on breast cancer patients who received neoadjuvant chemotherapy. While there is a substantial overlap of the DEGs identified by all of them, super-delta were able to identify comparatively more DEGs than its competitors. Downstream gene set enrichment analysis confirmed that all these methods selected largely consistent pathways. Detailed investigations on the relatively small differences showed that pathways identified by super-delta have better connections to breast cancer than other methods. CONCLUSIONS: As a new pipeline, super-delta provides new insights to the area of differential gene expression analysis. Solid theoretical foundation supports its asymptotic unbiasedness and technical noise-free properties. Implementation on real and simulated datasets demonstrates its decent performance compared with state-of-art procedures. It also has the potential of expansion to be incorporated with other data type and/or more general between group comparison problems. PMID- 29268716 TI - Utilization and efficacy of second-line targeted therapy in metastatic renal cell carcinoma: data from a national registry. AB - BACKGROUND: It is well known that patient characteristics and survival outcomes in randomized trials may not necessarily be similar to those in real-life clinical practice. The aim of the present study was to analyse second line treatment strategies in the real-world practice and to estimate the outcomes of patients treated with second-line targeted therapy for metastatic renal cell carcinoma (mRCC). METHODS: This is a retrospective, registry-based study using data from the national registry of targeted therapies for mRCC. The RENIS registry contains data on 3049 patients who started the therapy with at least one targeted agent before 31 December, 2014. Of these patients, 1029 had a record of at least two different targeted therapies and sufficient data for analysis. Survival analysis was carried out using the Kaplan-Meier method. Statistical significance of differences in survival between subgroups was assessed using the log-rank test. RESULTS: The median overall survival from the start of second-line treatment was 17.0 months (95% confidence interval [CI] 14.5-19.5 months), 17.1 months (95% CI 14.5-19.8), and 15.4 months (95% CI 11.0-19.7) for second-line everolimus, sorafenib, and sunitinib, respectively. Patients receiving second line everolimus were older at the start of second-line treatment, more likely to have metachronous disease, and less likely to be previously treated with cytokines or to continue to third-line treatment than patients treated with second-line sunitinib or sorafenib. Progression-free survival (PFS) correlated with PFS on first-line treatment only for everolimus. CONCLUSIONS: In this retrospective study, no significant differences in survival were observed between the cohorts treated with different second-line agents including everolimus, sorafenib, and sunitinib. PMID- 29268717 TI - Functional characterization of soybean strigolactone biosynthesis and signaling genes in Arabidopsis MAX mutants and GmMAX3 in soybean nodulation. AB - BACKGROUND: Strigolactones (SLs) play important roles in controlling root growth, shoot branching, and plant-symbionts interaction. Despite the importance, the components of SL biosynthesis and signaling have not been unequivocally explored in soybean. RESULTS: Here we identified the putative components of SL synthetic enzymes and signaling proteins in soybean genome. Soybean genome contains conserved MORE AXILLARY BRANCHING (MAX) orthologs, GmMAX1s, GmMAX2s, GmMAX3s, and GmMAX4s. The tissue expression patterns are coincident with SL synthesis in roots and signaling in other tissues under normal conditions. GmMAX1a, GmMAX2a, GmMAX3b, and GmMAX4a expression in their Arabidopsis orthologs' mutants not only restored most characteristic phenotypes, such as shoot branching and shoot height, leaf shape, primary root length, and root hair growth, but also restored the significantly changed hormone contents, such as reduced JA and ABA contents in all mutant leaves, but increased auxin levels in atmax1, atmax3 and atmax4 mutants. Overexpression of these GmMAXs also altered the hormone contents in wild type Arabidopsis. GmMAX3b was further characterized in soybean nodulation with overexpression and knockdown transgenic hairy roots. GmMAX3b overexpression (GmMAX3b-OE) lines exhibited increased nodule number while GmMAX3b knockdown (GmMAX3b-KD) decreased the nodule number in transgenic hairy roots. The expression levels of several key nodulation genes were also altered in GmMAX3b transgenic hairy roots. GmMAX3b overexpression hairy roots had reduced ABA, but increased JA levels, with no significantly changed auxin content, while the contrast changes were observed in GmMAX3b-KD lines. Global gene expression in GmMAX3b-OE or GmMAX3b-KD hairy roots also revealed that altered expression of GmMAX3b in soybean hairy roots changed several subsets of genes involved in hormone biosynthesis and signaling and transcriptional regulation of nodulation processes. CONCLUSIONS: This study not only revealed the conservation of SL biosynthesis and signaling in soybean, but also showed possible interactions between SL and other hormone synthesis and signaling during controlling plant development and soybean nodulation. GmMAX3b-mediated SL biosynthesis and signaling may be involved in soybean nodulation by affecting both root hair formation and its interaction with rhizobia. PMID- 29268718 TI - Elevation of tumour markers TGF-beta, M2-PK, OV-6 and AFP in hepatocellular carcinoma (HCC)-induced rats and their suppression by microalgae Chlorella vulgaris. AB - BACKGROUND: Chlorella vulgaris (ChV), a unicellular green algae has been reported to have anticancer and antioxidant effects. The aim of this study was to determine the chemopreventive effect of ChV on liver cancer induced rats by determining the level and expression of several liver tumour markers. METHODS: Male Wistar rats (200-250 g) were divided into 4 groups according to the diet given: control group (normal diet), ChV group with three different doses (50, 150 and 300 mg/kg body weight), liver cancer- induced group (choline deficient diet + 0.1% ethionine in drinking water or CDE group), and the treatment group (CDE group treated with three different doses of ChV). Rats were killed at 0, 4, 8 and 12 weeks of experiment and blood and tissue samples were taken from all groups for the determination of tumour markers expression alpha-fetoprotein (AFP), transforming growth factor-beta (TGF-beta), M2-pyruvate kinase (M2-PK) and specific antigen for oval cells (OV-6). RESULTS: Serum level of TGF-beta increased significantly (p < 0.05) in CDE rats. However, ChV at all doses managed to decrease (p < 0.05) its levels to control values. Expressions of liver tumour markers AFP, TGF-beta, M2-PK and OV-6 were significantly higher (p < 0.05) in tissues of CDE rats when compared to control showing an increased number of cancer cells during hepatocarcinogenesis. ChV at all doses reduced their expressions significantly (p < 0.05). CONCLUSIONS: Chlorella vulgaris has chemopreventive effect by downregulating the expression of tumour markers M2-PK, OV-6, AFP and TGF-beta, in HCC-induced rats. PMID- 29268719 TI - The effectiveness of a primary care nursing-led dietary intervention for prediabetes: a mixed methods pilot study. AB - BACKGROUND: Primary care nurse-led prediabetes interventions are seldom reported. We examined the implementation and feasibility of a 6-month multilevel primary care nurse-led prediabetes lifestyle intervention compared with current practice in patients with prediabetes, with weight and glycated haemoglobin (HbA1c) as outcomes. METHODS: This study used a convergent mixed methods design involving a 6-month pragmatic non-randomised pilot study with a qualitative process evaluation, and was conducted in two neighbouring provincial cities in New Zealand, with indigenous Maori populations comprising 18.2% and 23.0%, respectively. Participants were non-pregnant adults aged <= 70 years with newly diagnosed prediabetes (HbA1c 41-49 mmol/mol), body mass index (BMI) >= 25 kg/m2 and not prescribed Metformin. A structured dietary intervention tool delivered by primary care nurses with visits at baseline, 2-3 weeks, 3 months and 6 months was implemented in four intervention practices. Four control practices continued to provide usual care. Primary quantitative outcome measures were weight and HbA1c. Linear and quantile regression models were used to compare each outcome between the two groups at follow-up. Qualitative data included: observations of nurse training sessions and steering group meetings; document review; semi-structured interviews with a purposive sample of key informants (n = 17) and intervention patients (n = 20). Thematic analysis was used. RESULTS: One hundred fifty-seven patients with prediabetes enrolled (85 intervention, 72 control), 47.8% female and 31.2% Maori. Co-morbidities were common, particularly hypertension (49.7%), dyslipidaemia (40.1%) and gout (15.9%). Baseline and 6 month measures were available for 91% control and 79% intervention participants. After adjustment, the intervention group lost a mean 1.3 kg more than the control group (p < 0.001). Mean HbA1c, BMI and waist circumference decreased in the intervention group and increased in the control group, but differences were not statistically significant. Implementation fidelity was high, and it was feasible to implement the intervention in busy general practice settings. The intervention was highly acceptable to both patients and key stakeholders, especially primary care nurses. CONCLUSIONS: Study findings confirm the feasibility and acceptability of primary care nurses providing structured dietary advice to patients with prediabetes in busy general practice settings. The small but potentially beneficial mean weight loss among the intervention group supports further investigation. TRIAL REGISTRATION: ANZCTR ACTRN12615000806561 . Registered 3 August 2015 (Retrospectively registered). PMID- 29268720 TI - Falls efficacy, postural balance, and risk for falls in older adults with falls related emergency department visits: prospective cohort study. AB - BACKGROUND: Risk for falls in older adults has been associated with falls efficacy (self-perceived confidence in performing daily physical activities) and postural balance, but available evidence is limited and mixed. We examined the interaction between falls efficacy and postural balance and its association with future falls. We also investigated the association between falls efficacy and gait decline. METHODS: Falls efficacy, measured by the Modified Falls Efficacy Scale (MFES), and standing postural balance, measured using computerized posturography on a balance board, were obtained from 247 older adults with a falls-related emergency department visit. Six-month prospective fall rate and habitual gait speed at 6 months post baseline assessment were also measured. RESULTS: In multivariable proportional odds analyses adjusted for potential confounders, falls efficacy modified the association between postural balance and fall risk (interaction P = 0.014): increasing falls efficacy accentuated the increased fall risk related to poor postural balance. Low baseline falls efficacy was strongly predictive of worse gait speed (0.11 m/s [0.06 to 0.16] slower gait speed per IQR decrease in MFES; P < 0.001). CONCLUSION: Older adults with high falls efficacy but poor postural balance were at greater risk for falls than those with low falls efficacy; however, low baseline falls efficacy was strongly associated with worse gait function at follow-up. Further research into these subgroups of older adults is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01713543 . PMID- 29268721 TI - The development of CHAMP: a checklist for the appraisal of moderators and predictors. AB - BACKGROUND: Personalized healthcare relies on the identification of factors explaining why individuals respond differently to the same intervention. Analyses identifying such factors, so called predictors and moderators, have their own set of assumptions and limitations which, when violated, can result in misleading claims, and incorrect actions. The aim of this study was to develop a checklist for critically appraising the results of predictor and moderator analyses by combining recommendations from published guidelines and experts in the field. METHODS: Candidate criteria for the checklist were retrieved through systematic searches of the literature. These criteria were evaluated for appropriateness using a Delphi procedure. Two Delphi rounds yielded a pilot checklist, which was tested on a set of papers included in a systematic review on reinforced home based palliative care. The results of the pilot informed a third Delphi round, which served to finalize the checklist. RESULTS: Forty-nine appraisal criteria were identified in the literature. Feedback was obtained from fourteen experts from (bio)statistics, epidemiology and other associated fields elicited via three Delphi rounds. Additional feedback from other researchers was collected in a pilot test. The final version of our checklist included seventeen criteria, covering the design (e.g. a priori plausibility), analysis (e.g. use of interaction tests) and results (e.g. complete reporting) of moderator and predictor analysis, together with the transferability of the results (e.g. clinical importance). There are criteria both for individual papers and for bodies of evidence. CONCLUSIONS: The proposed checklist can be used for critical appraisal of reported moderator and predictor effects, as assessed in randomized or non-randomized studies using individual participant or aggregate data. This checklist is accompanied by a user's guide to facilitate implementation. Its future use across a wide variety of research domains and study types will provide insights about its usability and feasibility. PMID- 29268722 TI - Comparison of biannual ultrasonography and annual non-contrast liver magnetic resonance imaging as surveillance tools for hepatocellular carcinoma in patients with liver cirrhosis (MAGNUS-HCC): a study protocol. AB - BACKGROUND: Ultrasonography (US) is recommended as a standard surveillance tool for patients with a high risk of developing hepatocellular carcinoma (HCC). However, the low sensitivity of US for small HCC can lead to surveillance failure, resulting in advanced stage tumor presentations. For the early detection of HCC in high-risk patients and to improve survival and prognosis, a new efficient imaging tool with a high sensitivity for HCC detection is needed. The purpose of this study is to evaluate and compare the feasibility and efficacy of non-contrast magnetic resonance imaging (MRI) with US as a surveillance tool for HCC in patients with liver cirrhosis. METHODS: MAGNUS-HCC is a prospective, multicenter clinical trial with a crossover design for a single arm of patients. This study was approved by six Institutional Review Boards, and informed consent was obtained from all participants. All patients will undergo liver US every 6 months and non-contrast liver MRI every 12 months during a follow-up period of 3 years. If a focal liver lesion suspected of harboring HCC is detected, dynamic liver computed tomography (CT) will be performed to confirm the diagnosis. After the last surveillance round, patients without suspicion of HCC or who are not diagnosed with HCC will be evaluated with a dynamic liver CT to exclude false negative findings. The primary endpoint is to compare the rate of detection of HCC by US examinations performed at 6-month intervals with that of yearly non contrast liver MRI studies during a 3-year follow-up. The secondary endpoint is the survival of the patients who developed HCC within the 3-year follow-up period. DISCUSSION: MAGNUS-HCC is the first study to compare the feasibility of non-contrast MRI with US as a surveillance tool for the detection of HCC in high risk patients. We anticipate that the evidence presented in this study will establish the efficacy of non-contrast MRI as a surveillance tool for HCC in high risk patients. TRIAL REGISTRATION: The date of trial registration ( NCT02551250 ) in this study was September 15, 2015, and follow-up is still ongoing. PMID- 29268723 TI - Lifetime prevalence of suicidal ideation among men who have sex with men: a meta analysis. AB - BACKGROUND: Suicide is a leading cause of death among men who have sex with men (MSM) and suicidal ideation may put individuals at higher risk of suicide. A great disparity of lifetime prevalence of suicidal ideation among MSM was observed across studies, indicating the importance of a reliable estimation of the pooled lifetime prevalence. However, the only one published meta-analysis estimating the pooled lifetime prevalence of suicidal ideation among MSM was conducted in 2008 with only 2 eligible studies. Subsequently, there was a rapid increase of publications about lifetime suicidal ideation among MSM, suggesting that an update on the pooled lifetime prevalence of suicidal ideation among MSM was necessary. Therefore, this study aimed to update the estimation of the pooled lifetime prevalence of suicidal ideation among MSM. METHODS: Electronic databases of PubMed, CINAHL, Scopus (social science), Embase and PsycInfo were searched until September 2017 to identify relevant studies. Cross-sectional studies exploring the lifetime prevalence of suicidal ideation among MSM were enrolled. Heterogeneity was evaluated using the Cochran Q test and quantified using the I 2 statistic. The possibility of publication bias was assessed using both Begg's rank test and Egger's linear test, and an Egger's funnel plot for asymmetry was presented. Subgroup analyses were performed according to the geographic area, sample source and HIV status. RESULTS: Nineteen studies with a total of 26,667 MSM were included, of which 9374 were identified with suicidal ideation. A high degree of heterogeneity (P <= 0.001, I 2 =99.2%) was observed among the eligible studies, with the reported prevalence ranging from 13.18 to 55.80%. The pooled lifetime prevalence of suicidal ideation among MSM by a random effects model was 34.97% (95% confidence interval: 28.35%-41.90%). Both the Begg's rank test and Egger's linear test indicated low possibility of publication bias. Subgroup analyses showed that the lifetime prevalence of suicidal ideation among MSM differed significantly by geographic area, sample source and HIV status (P < 0.05). CONCLUSIONS: The high pooled lifetime prevalence of suicidal ideation among MSM found in this meta-analysis significantly underscores the importance of early assessment of suicidal ideation among MSM, as well as the need for strengthening the psychological interventions. PMID- 29268724 TI - Surgical treatment of ankle fracture with or without deltoid ligament repair: a comparative study. AB - BACKGROUND: Deltoid ligament (DL) rupture is commonly seen in clinical practice; however the need to explore and surgically repair it is still in debate. The objective of the current study is to compare the outcomes of surgical treatment of ankle fracture with or without DL repair. METHODS: Between 2009 and 2015, Seventy-four ankle fractures with DL rupture were identified and followed. Twenty patients were treated with surgical repair of the DL, while 54 were not. The pre- and post-operative medial clear space (MCS) were measured and the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and visual analogue scale (VAS) were used for functional evaluation. According to the radiological malreduction of MCS, the odds ratio (OR) and 95% confidence interval (CI) for each potential relative factor were calculated. RESULTS: The mean followup time was 53.7 months. The mean MCS preoperatively, postoperatively, and at last followup time were 8.7 +/- 2.4 (range, 6.2-14.8) mm, 3.7 +/- 0.9 (range, 2.6-6.4) mm, 3.6 +/- 1.0 (range, 2.6-6.8) mm, respectively. The mean AOFAS score was 86.4 +/- 8.1 (range, 52-100) points, and the mean VAS was 1.4 +/- 1.4 (range, 0-7) points. During followup, 14.9% (11/74) cases were found to be malreduced (MCS>5 mm), and 5.4% (4/74) went on to failure. Surgical repair of DL can significantly decrease the postoperative MCS (P<0.05), and can also decrease the malreduction rate (P<0.05). AO/OTA type-C ankle fractures showed a positive correlation with malreduction (OR = 4.38, P = 0.03). In this type of injury, surgical repair of the DL can significantly decrease the malreduction rate (P<0.05). No significant difference was found between the AO/OTA type-B fracture with or without DL repair. CONCLUSIONS: Surgical repair of the DL is helpful in decreasing the postoperative MCS and malreduction rate, especially for the AO/OTA type-C ankle fractures. PMID- 29268725 TI - Visual symptoms associated with refractive errors among Thangka artists of Kathmandu valley. AB - BACKGROUND: Prolong near work, especially among people with uncorrected refractive error is considered a potential source of visual symptoms. The present study aims to determine the visual symptoms and the association of those with refractive errors among Thangka artists. METHODS: In a descriptive cross sectional study, 242 (46.1%) participants of 525 thangka artists examined, with age ranged between 16 years to 39 years which comprised of 112 participants with significant refractive errors and 130 absolutely emmetropic participants, were enrolled from six Thangka painting schools. The visual symptoms were assessed using a structured questionnaire consisting of nine items and scoring from 0 to 6 consecutive scales. The eye examination included detailed anterior and posterior segment examination, objective and subjective refraction, and assessment of heterophoria, vergence and accommodation. Symptoms were presented in percentage and median. Variation in distribution of participants and symptoms was analysed using the Kruskal Wallis test for mean, and the correlation with the Pearson correlation coefficient. A significance level of 0.05 was applied for 95% confidence interval. The majority of participants (65.1%) among refractive error group (REG) were above the age of 30 years, with a male predominance (61.6%), compared to the participants in the normal cohort group (NCG), where majority of them (72.3%) were below 30 years of age (72.3%) and female (51.5%). RESULT: Overall, the visual symptoms are high among Thangka artists. However, blurred vision (p = 0.003) and dry eye (p = 0.004) are higher among the REG than the NCG. Females have slightly higher symptoms than males. Most of the symptoms, such as sore/aching eye (p = 0.003), feeling dry (p = 0.005) and blurred vision (p = 0.02) are significantly associated with astigmatism. CONCLUSION: Thangka artists present with significant proportion of refractive error and visual symptoms, especially among females. The most commonly reported symptoms are blurred vision, dry eye and watering of the eye. The visual symptoms are more correlated with astigmatism. PMID- 29268727 TI - Correction to: More than visual literacy: art and the enhancement of tolerance for ambiguity and empathy. AB - CORRECTION: Following publication of the original article [1], the authors reported that the corrections they had requested for Table 3 had not been implemented, and that the title for Table 2 included an unnecessary indication for remark/reference ("a" in a superscript font) at the end of the title. Also, the affiliation of the authors had not been clearly stated: it should read 'Faculty of Medicine, Bar-Ilan University, Safed Campus, P.O.Box 1589, Safed, Israel'. PMID- 29268726 TI - Hierarchizing caries risk factors among first-year university students in Nice (France): a cross-sectional study. AB - BACKGROUND: The purpose of this study was to rank the risk factors for dental caries among first-year university students in Nice (France). METHODS: All first year students are required to undergo a compulsory preventive medical examination. Among these students, volunteers were offered a dental visit. Information was collected through an interview followed by an oral examination. We assessed the volunteers' oral hygiene habits (daily toothbrushing frequency, type of toothbrush used, frequency of toothbrush replacement, place of toothpaste purchase, and flossing), daily health-related behaviors (number of main daily meals, daily sugary intakes, smoking, alcohol consumption, consumption of cannabis or other drugs), oral-health-related behaviors (self-reported oral health, dental visits during the past year, reason for the last dental consultation, and failure to seek dental care due to financial reasons), and oral health issues (dental crowding, oral hygiene, presence of caries, presence of pit and fissure sealant remnants). The dependent variable was the presence of at least one untreated carious lesion. The data were subjected to univariate analyses to select explanatory variables, and subsequently, a logistic regression was performed. RESULTS: Six hundred twenty-nine students aged 18.8+/-1.6 years were enrolled in this study. The sex ratio was 0.72, with a strong predominance of the female gender. Only 59.3% of the students had never experienced dental caries, while 22.4% had already undergone restorative procedures and did not have any carious lesion at the time of the examination, and 11.6% presented with carious lesions and had never been treated by a dentist. Lastly, 6.7% had carious lesions despite evidence of prior restorative procedures. The multivariate analysis revealed the following pejorative risk factors: failure to seek dental care due to financial reasons (OR:3.06, 95% CI: 1.40-6.70), poor oral hygiene revealed during the oral examination (OR:2.59, 95% CI: 1.60-4.20), and poor self reported oral health (OR:2.43, 95% CI: 1.24-4.77). Conversely, the analysis revealed the following protective factors: preventive visits to the dentist (OR:0.63, 95% CI: 0.41-0.99), the use of an electric toothbrush (OR:0.36, 95% CI: 0.17-0.77), and sealant remnants (OR:0.22, 95% CI: 0.05-0.97). CONCLUSIONS: The highest-ranking caries risk factor for the study population was the financial barrier. PMID- 29268728 TI - Triweekly administration of parathyroid hormone (1-34) accelerates bone healing in a rat refractory fracture model. AB - BACKGROUND: Some reports have shown that intermittent parathyroid hormone (PTH) (1-34) treatment for patients with delayed union or nonunion have led to successful healing. In this study, we investigated whether systemic intermittent administration of PTH (1-34) has a beneficial effect on bone healing in a rat refractory fracture model. METHODS: We created a refractory femoral fracture model in 32 rats with periosteal cauterization that leads to atrophic nonunion at 8 weeks after surgery. Half the rats received subcutaneous intermittent human PTH (1-34) injections at a dosage of 100 MUg/kg, thrice a week for 8 weeks. The other half received the vehicle only. At 8 weeks after fracture, radiographic, histological and mechanical assessments were performed. RESULTS: Radiographic assessments showed that the union rate was significantly higher in the PTH group than in the control group (P < 0.05). The degree of fracture repair as scored using the Allen grading system in histological assessment was significantly greater in the PTH group than in the control group (P < 0.05). The ultimate stress and stiffness measurements were significantly greater in the PTH group than in the control group (p < 0.05). CONCLUSIONS: We demonstrated that triweekly administration of PTH (1-34) increased union rate and accelerated bone healing in a rat refractory fracture model, suggesting that systemic administration of PTH (1-34) could become a novel and useful therapy for accelerating fracture healing in patients at high risk of delayed union or nonunion. PMID- 29268729 TI - Strengthening medical training programmes by focusing on professional transitions: a national bridging programme to prepare medical school graduates for their role as medical interns in Botswana. AB - BACKGROUND: The improvement of existing medical training programmes in resource constrained settings is seen as key to addressing the challenge of retaining medical graduates trained at considerable cost both in-country and abroad. In Botswana, the establishment of the national Medical Internship Training Programme (MIT) in 2014 was a first step in efforts to promote retention through the expansion and standardization of internship training, but MIT faces a major challenge related to variability between incoming trainees due to factors such as their completion of undergraduate medical training in different settings. To address this challenge, in August 2016 we piloted a bridging programme for foreign and locally trained medical graduates that aimed to facilitate their transition into internship training. This study aimed to describe the programme and evaluate its impact on the participants' self-rated perceptions of their knowledge, experience, clinical skills, and familiarity with Botswana's healthcare system. METHODS: We conducted a national, intensive, two-week programme designed to facilitate the transition from medical student to intern and to prepare all incoming interns for their work in Botswana's health system. Participants included all interns entering in August 2016. Formats included lectures, workshops, simulations, discussions, and reflection-oriented activities. The Kellogg Foundation Outcomes Logic Model was used to evaluate the programme, and participants self-rated their knowledge, skills, and attitudes across each of the programme objectives on paired questionnaires before and after participation. RESULTS: 48/54 participants (89%) provided paired data. Participants reported a high degree of satisfaction with the programme (mean 4.2/5). Self-rated preparedness improved after participation (mean 3.2 versus 3.7, p < 0.001), as did confidence across 18/19 knowledge/skill domains, suggesting that participants felt that the programme prepared them for their internship training. Exploratory analysis revealed that 20/25 participants (80%) reporting either no effect or a negative effect following participation had rated themselves "extremely" or "quite" prepared beforehand, suggesting the programme grounded expectations for interns who initially were overconfident. In contrast, no interns who had initially rated themselves "moderately" or "somewhat" prepared reported a decline in their self-rated sense of preparedness. Interns commented on the benefits of learning about roles/responsibilities, interacting with clinicians from Botswana's healthcare sectors, and the sense of community the programme engendered. CONCLUSIONS: This programme was feasible to implement and was well-received by participants. Overall, participants perceived an enhancement of their knowledge, skills, and expectations about their role in Botswana's health system after completion of the programme. Our results are likely to be of interest to educators dedicated to training, professional transitions, and career pathways in similar settings in the region and beyond. PMID- 29268730 TI - Academic detailers' and general practitioners' views and experiences of their academic detailing visits to improve the quality of analgesic use: process evaluation alongside a pragmatic cluster randomized controlled trial. AB - BACKGROUND: Continuous medical education strategies, including academic detailing (AD), have mixed effects on the quality of prescribing in general practice. Alongside a cluster-randomized controlled trial (cRCT) to assess the effectiveness of AD visits (on appropriate prescribing of analgesics for chronic pain in osteoarthritis) by Farmaka, an independent drug information center, we performed a process evaluation to identify possible barriers and success factors to improve these AD visits, both from the perspective of the academic detailers delivering the visits and the general practitioners (GPs) receiving them. METHODS: We performed semi-structured interviews with 20 GPs who participated in the cRCT and 13 academic detailers. The interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: GPs viewed AD visits as a practical and useful CME strategy, that is less time consuming than other CME activities, and the visitors as providers of objective and independent information relevant to their daily practice with whom they can have meaningful discussion. Academic detailers saw themselves as content experts, mainly informing GPs about the topic and not emphasizing on behavior change. Both GPs and academic detailers believed that the AD visits could have better interaction and discussion if performed in small groups. According to the GPs, the visits on analgesic use provided some new and relevant information as well as clarifying some misconceptions. They increased awareness of the disadvantages of particular non-steroidal anti inflammatory drugs and of the lower doses of paracetamol that should be prescribed for chronic use, which may have changed their beliefs and/or attitudes towards more appropriate prescribing for osteoarthritis. However, the transfer of knowledge into practice was seen as not so straightforward. CONCLUSIONS: GPs view AD visits as a credible and interesting way of CME that enhances their knowledge and increases reflection on their prescribing behavior. PMID- 29268731 TI - The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis. AB - BACKGROUND: Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens. METHODS: We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline. RESULTS: Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = -0.76; -0.98 to -0.53, 95% CI, P < 0.00001, and SMD = 0.36; -0.63 to -0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while >=5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2-4 injection subgroups. CONCLUSION: Overall, 2-4 and >=5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens. PMID- 29268732 TI - Nutritional status, exclusive breastfeeding and management of acute respiratory illness and diarrhea in the first 6 months of life in infants from two regions of Indonesia. AB - BACKGROUND: Infant morbidity and mortality rates remain high in Indonesia, with acute respiratory illnesses (ARI) and diarrhea the leading two health problems in children under 5 years. We aimed to describe the nutritional status, feeding practice and case management of ARI and diarrhea of infants from two regions of Indonesia during the first 6 months of life. METHODS: This study was an observational study conducted in parallel to an immunogenicity and efficacy trial of an oral rotavirus vaccine (RV3-BB) in the Klaten and Yogyakarta regions, Indonesia. Mothers were interviewed at 3 time points: within the first 6 days of their infant's life, and at 8-10 and 22-24 weeks of age. Questions asked included pregnancy history, infant nutritional status, feeding status and health of infants within up to 2 weeks prior to the assessment. RESULTS: Between February 2013 and January 2014, 233 mother-infant pairs were recruited. 60% (136/223) of infants were exclusively breastfed (EBF) until 6 months of age with the strongest support for EBF reported by mothers themselves 70% (101/223) and 25% (36/223) from their partners. At 6 months, 6% (14/223) of infants were underweight and severely underweight; 4% (8/ 223) wasted and severely wasted; and 12% (28/223) were stunted and severely stunted. Non-recommended medication use was high, with 54% (21/39) of infants with reported cough within 2 weeks of an assessment receiving cough medication, 70% (27 /39) an antihistamine, 26% (10/39) a mucolytic and 15% (6 /39) an oral bronchodilator. At age 22-24 week, infants with reported diarrhea within 2 weeks of an assessment had low use of oral rehydration solutions (ORS) (3/21;14%) and zinc therapy (2/ 21;10%). CONCLUSION: In this unique observational study, breastfeeding rates of 60% at 6 months were below the Indonesian national target of >75%. Adherence to WHO guidelines for management of ARI and diarrhea was poor, with high use of non-recommended cough medications and oral bronchodilators in the first 6 months of life and low use of ORS and zinc therapy. Ongoing education of primary health care workers and parents regarding management of common illness is needed in Indonesia. PMID- 29268733 TI - Future access and improvement of industrial lactic acid bacteria cultures. AB - Industrial fermentations based on micro-organisms such as the lactic acid bacteria (LAB) play an important role in several industries globally and represent multi-billion Euro/dollar businesses. LAB provide a natural way to produce safe, sustainable, and environmentally friendly products for a variety of industries. Product innovation is a key requirement for these industries to survive and grow globally. However, the development of new products may be affected by two man-made constraints; the Nagoya Protocol on benefit sharing and the opposition to the use of modern biotechnology for strain improvement. An expert workshop was held in Amsterdam, May 10-11, 2017 to discuss these challenges; a number of conclusions and recommendations were formulated and will be presented herein. PMID- 29268736 TI - Q&A: Why use synchrotron x-ray tomography for multi-scale connectome mapping? AB - To understand how information flows and is used in the human brain, we must map neural structures at all levels, providing visualizations similar to those of Google Earth for continents, countries, cities, and streets. Unfortunately, the imaging and processing techniques currently used in connectomics projects cannot achieve complete mapping for the brains of large animals within the timespan of a typical research career. However, feasible improvements in x-ray imaging would change this situation. This Q&A discusses synchrotron x-ray tomography, an exciting new approach for in situ mapping of whole-brain wiring diagrams at multiple levels of spatial resolution. PMID- 29268735 TI - Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia reperfusion injury and enhance reconditioning of donor lungs after circulatory death. AB - BACKGROUND: Lung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs. METHODS: C57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 degrees C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs. RESULTS: Lungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-alpha, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL 17 and macrophage-produced HMGB1 and TNF-alpha after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-alpha/HMGB1 cytomix. CONCLUSIONS: These results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post transplant IR injury as well as rehabilitation of DCD lungs. PMID- 29268734 TI - Outer membrane protein folding from an energy landscape perspective. AB - The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. How OMPs fold into this crowded environment remains an open question. Here, we review current knowledge about OMP folding mechanisms in vitro and discuss how the need to fold to a stable native state has shaped their folding energy landscapes. We also highlight the role of chaperones and the beta-barrel assembly machinery (BAM) in assisting OMP folding in vivo and discuss proposed mechanisms by which this fascinating machinery may catalyse OMP folding. PMID- 29268737 TI - Prevalence and determinants of polypharmacy in Switzerland: data from the CoLaus study. AB - BACKGROUND: Polypharmacy is a frequent condition, but its prevalence and determinants in the Swiss mid-aged population are unknown. We aimed to evaluate the prevalence and determinants of polypharmacy in a large Swiss mid-aged population-based sample. METHODS: Data from 4938 participants of the CoLaus study (53% women, age range 40-81 years) were collected between 2009 and 2012. Polypharmacy was defined by the regular use of five or more drugs. RESULTS: Polypharmacy was reported by 580 participants [11.8%, 95% confidence interval (10.9; 12.6)]. Participants on polypharmacy were significantly older (mean +/- standard deviation: 66.0 +/- 9.1 vs. 56.6 +/- 10.1 years), more frequently obese (35.9% vs. 14.7%), of lower education (66.6% vs. 50.7%) and former smokers (46.7% vs. 36.4%) than participants not on polypharmacy. These findings were confirmed by multivariate analysis: odds ratio and (95% confidence interval) for age groups 50-64 and 65-81 relative to 40-49 years: 2.90 (2.04; 4.12) and 10.3 (7.26; 14.5), respectively, p for trend < 0.001; for low relative to high education: 1.56 (1.17; 2.07); for overweight and obese relative to normal weight participants: 2.09 (1.65; 2.66) and 4.38 (3.39; 5.66), respectively, p for trend < 0.001; for former and current relative to never smokers: 1.42 (1.14, 1.75) and 1.63 (1.25, 2.12), respectively, p for trend < 0.001. CONCLUSION: One out of nine participants of our sample is on polypharmacy. Increasing age, body mass index, smoking and lower education independently increase the likelihood of being on polypharmacy. PMID- 29268738 TI - Models and analyses to understand threats to polio eradication. AB - To achieve complete polio eradication, the live oral poliovirus vaccine (OPV) currently used must be phased out after the end of wild poliovirus transmission. However, poorly understood threats may arise when OPV use is stopped. To counter these threats, better models than those currently available are needed. Two articles recently published in BMC Medicine address these issues. Mercer et al. (BMC Med 15:180, 2017) developed a statistical model analysis of polio case data and characteristics of cases occurring in several districts in Pakistan to inform resource allocation decisions. Nevertheless, despite having the potential to accelerate the elimination of polio cases, their analyses are unlikely to advance our understanding OPV cessation threats. McCarthy et al. (BMC Med 15:175, 2017) explored one such threat, namely the emergence and transmission of serotype 2 circulating vaccine derived poliovirus (cVDPV2) after OPV2 cessation, and found that the risk of persistent spread of cVDPV2 to new areas increases rapidly 1-5 years after OPV2 cessation. Thus, recently developed models and analysis methods have the potential to guide the required steps to surpass these threats. 'Big data' scientists could help with this; however, datasets covering all eradication efforts should be made readily available.Please see related articles: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0937-y and https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0941-2 . PMID- 29268739 TI - Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression. AB - BACKGROUND: Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium. METHODS: Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls. RESULTS: In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate < 0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA < 0.001). CONCLUSION: We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non invasive biomarker in COPD. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008). PMID- 29268740 TI - An elevated plus-maze in mixed reality for studying human anxiety-related behavior. AB - BACKGROUND: A dearth of laboratory tests to study actual human approach-avoidance behavior has complicated translational research on anxiety. The elevated plus maze (EPM) is the gold standard to assess approach-avoidance behavior in rodents. METHODS: Here, we translated the EPM to humans using mixed reality through a combination of virtual and real-world elements. In two validation studies, we observed participants' anxiety on a behavioral, physiological, and subjective level. RESULTS: Participants reported higher anxiety on open arms, avoided open arms, and showed an activation of endogenous stress systems. Participants' with high anxiety exhibited higher avoidance. Moreover, open arm avoidance was moderately predicted by participants' acrophobia and sensation seeking, with opposing influences. In a randomized, double blind, placebo controlled experiment, GABAergic stimulation decreased avoidance of open arms while alpha-2 adrenergic antagonism increased avoidance. CONCLUSION: These findings demonstrate cross-species validity of open arm avoidance as a translational measure of anxiety. We thus introduce the first ecologically valid assay to track actual human approach-avoidance behavior under laboratory conditions. PMID- 29268742 TI - Factors associated with junior doctors' decisions to apply for general practice training programmes in the UK: secondary analysis of data from the UKMED project. AB - BACKGROUND: The UK, like many high-income countries, is experiencing a worsening shortfall of general practitioners (GPs) alongside an increasing demand for their services. At the same time, factors influencing junior doctors' decisions to apply for GP training are only partially understood and research in this area has been hampered by the difficulties in connecting the datasets that map the journey from student to qualified GP. The UK Medical Education Database (UKMED) has been established to ameliorate this problem by linking institutional data across the spectrum of medical education from school to specialty training. Our study aimed to use UKMED to investigate which demographic and educational factors are associated with junior doctors' decisions to apply for GP training. METHODS: Study data, provided by the UKMED Development Group and accessed remotely, contained longitudinal educational and sociodemographic information on all doctors who entered UK medical schools in the 2007/2008 academic year and who made first-time specialty training applications in 2015. We used multivariable logistic regression models to investigate two binary outcomes, namely (1) application to GP training, possibly alongside applications to other specialties, and (2) application solely to GP training. RESULTS: Of 7634 doctors in the sample, 43% applied to GP training possibly alongside other specialities and 26% applied solely to GP training. The odds of applying to GP training were associated with particular demographic factors (being female, non-white or secondary educated in the UK increased the odds of application) and educational factors (non-graduate entry, intercalation and above-median academic performance during medical school all decreased the odds of application). After adjusting for these factors, both the medical school and the foundation school attended were independently associated with the odds of applying to GP training. CONCLUSIONS: Our findings suggest that the supply and demand imbalance in UK primary care might be improved by (1) efforts to attract greater numbers of female, non-white and UK secondary-educated students into medical schools, and (2) targeting resources at medical and foundation schools that deliver doctors likely to fill significant gaps in the workforce. Further research is required to better understand inter-school differences and to develop strategies to improve recruitment of GP trainees. PMID- 29268741 TI - The Toll pathway underlies host sexual dimorphism in resistance to both Gram negative and Gram-positive bacteria in mated Drosophila. AB - BACKGROUND: Host sexual dimorphism is being increasingly recognized to generate strong differences in the outcome of infectious disease, but the mechanisms underlying immunological differences between males and females remain poorly characterized. Here, we used Drosophila melanogaster to assess and dissect sexual dimorphism in the innate response to systemic bacterial infection. RESULTS: We demonstrated sexual dimorphism in susceptibility to infection by a broad spectrum of Gram-positive and Gram-negative bacteria. We found that both virgin and mated females are more susceptible than mated males to most, but not all, infections. We investigated in more detail the lower resistance of females to infection with Providencia rettgeri, a Gram-negative bacterium that naturally infects D. melanogaster. We found that females have a higher number of phagocytes than males and that ablation of hemocytes does not eliminate the dimorphism in resistance to P. rettgeri, so the observed dimorphism does not stem from differences in the cellular response. The Imd pathway is critical for the production of antimicrobial peptides in response to Gram-negative bacteria, but mutants for Imd signaling continued to exhibit dimorphism even though both sexes showed strongly reduced resistance. Instead, we found that the Toll pathway is responsible for the dimorphism in resistance. The Toll pathway is dimorphic in genome-wide constitutive gene expression and in induced response to infection. Toll signaling is dimorphic in both constitutive signaling and in induced activation in response to P. rettgeri infection. The dimorphism in pathway activation can be specifically attributed to Persephone-mediated immune stimulation, by which the Toll pathway is triggered in response to pathogen-derived virulence factors. We additionally found that, in absence of Toll signaling, males become more susceptible than females to the Gram-positive Enterococcus faecalis. This reversal in susceptibility between male and female Toll pathway mutants compared to wildtype hosts highlights the key role of the Toll pathway in D. melanogaster sexual dimorphism in resistance to infection. CONCLUSION: Altogether, our data demonstrate that Toll pathway activity differs between male and female D. melanogaster in response to bacterial infection, thus identifying innate immune signaling as a determinant of sexual immune dimorphism. PMID- 29268743 TI - Patient safety incident reports related to traditional Japanese Kampo medicines: medication errors and adverse drug events in a university hospital for a ten-year period. AB - BACKGROUND: Kampo medicine is traditional Japanese medicine, which originated in ancient traditional Chinese medicine, but was introduced and developed uniquely in Japan. Today, Kampo medicines are integrated into the Japanese national health care system. Incident reporting systems are currently being widely used to collect information about patient safety incidents that occur in hospitals. However, no investigations have been conducted regarding patient safety incident reports related to Kampo medicines. The aim of this study was to survey and analyse incident reports related to Kampo medicines in a Japanese university hospital to improve future patient safety. METHODS: We selected incident reports related to Kampo medicines filed in Toyama University Hospital from May 2007 to April 2017, and investigated them in terms of medication errors and adverse drug events. RESULTS: Out of 21,324 total incident reports filed in the 10-year survey period, we discovered 108 Kampo medicine-related incident reports. However, five cases were redundantly reported; thus, the number of actual incidents was 103. Of those, 99 incidents were classified as medication errors (77 administration errors, 15 dispensing errors, and 7 prescribing errors), and four were adverse drug events, namely Kampo medicine-induced interstitial pneumonia. The Kampo medicine (crude drug) that was thought to induce interstitial pneumonia in all four cases was Scutellariae Radix, which is consistent with past reports. According to the incident severity classification system recommended by the National University Hospital Council of Japan, of the 99 medication errors, 10 incidents were classified as level 0 (an error occurred, but the patient was not affected) and 89 incidents were level 1 (an error occurred that affected the patient, but did not cause harm). Of the four adverse drug events, two incidents were classified as level 2 (patient was transiently harmed, but required no treatment), and two incidents were level 3b (patient was transiently harmed and required substantial treatment). CONCLUSIONS: There are many patient safety issues related to Kampo medicines. Patient safety awareness should be raised to prevent medication errors, especially administration errors, and adverse drug events in Kampo medicine. PMID- 29268744 TI - Situational awareness within objective structured clinical examination stations in undergraduate medical training - a literature search. AB - BACKGROUND: Medical students may not be able to identify the essential elements of situational awareness (SA) necessary for clinical reasoning. Recent studies suggest that students have little insight into cognitive processing and SA in clinical scenarios. Objective Structured Clinical Examinations (OSCEs) could be used to assess certain elements of situational awareness. The purpose of this paper is to review the literature with a view to identifying whether levels of SA based on Endsley's model can be assessed utilising OSCEs during undergraduate medical training. METHODS: A systematic search was performed pertaining to SA and OSCEs, to identify studies published between January 1975 (first paper describing an OSCE) and February 2017, in peer reviewed international journals published in English. PUBMED, EMBASE, PsycINFO Ovid and SCOPUS were searched for papers that described the assessment of SA using OSCEs among undergraduate medical students. Key search terms included "objective structured clinical examination", "objective structured clinical assessment" or "OSCE" and "non-technical skills", "sense making", "clinical reasoning", "perception", "comprehension", "projection", "situation awareness", "situational awareness" and "situation assessment". Boolean operators (AND, OR) were used as conjunctions to narrow the search strategy, resulting in the limitation of papers relevant to the research interest. Areas of interest were elements of SA that can be assessed by these examinations. RESULTS: The initial search of the literature retrieved 1127 publications. Upon removal of duplicates and papers relating to nursing, paramedical disciplines, pharmacy and veterinary education by title, abstract or full text, 11 articles were eligible for inclusion as related to the assessment of elements of SA in undergraduate medical students. DISCUSSION: Review of the literature suggests that whole-task OSCEs enable the evaluation of SA associated with clinical reasoning skills. If they address the levels of SA, these OSCEs can provide supportive feedback and strengthen educational measures associated with higher diagnostic accuracy and reasoning abilities. CONCLUSION: Based on the findings, the early exposure of medical students to SA is recommended, utilising OSCEs to evaluate and facilitate SA in dynamic environments. PMID- 29268745 TI - Comparison of tolerance of four bacterial nanocellulose-producing strains to lignocellulose-derived inhibitors. AB - BACKGROUND: Through pretreatment and enzymatic saccharification lignocellulosic biomass has great potential as a low-cost feedstock for production of bacterial nanocellulose (BNC), a high value-added microbial product, but inhibitors formed during pretreatment remain challenging. In this study, the tolerance to lignocellulose-derived inhibitors of three new BNC-producing strains were compared to that of Komagataeibacter xylinus ATCC 23770. Inhibitors studied included furan aldehydes (furfural and 5-hydroxymethylfurfural) and phenolic compounds (coniferyl aldehyde and vanillin). The performance of the four strains in the presence and absence of the inhibitors was assessed using static cultures, and their capability to convert inhibitors by oxidation and reduction was analyzed. RESULTS: Although two of the new strains were more sensitive than ATCC 23770 to furan aldehydes, one of the new strains showed superior resistance to both furan aldehydes and phenols, and also displayed high volumetric BNC yield (up to 14.78 +/- 0.43 g/L) and high BNC yield on consumed sugar (0.59 +/- 0.02 g/g). The inhibitors were oxidized and/or reduced by the strains to be less toxic. The four strains exhibited strong similarities with regard to predominant bioconversion products from the inhibitors, but displayed different capacity to convert the inhibitors, which may be related to the differences in inhibitor tolerance. CONCLUSIONS: This investigation provides information on different performance of four BNC-producing strains in the presence of lignocellulose derived inhibitors. The results will be of benefit to the selection of more suitable strains for utilization of lignocellulosics in the process of BNC production. PMID- 29268746 TI - School workers' knowledge, attitude and behaviour related to use of Toombak: a cross sectional study from Khartoum state, Sudan. AB - BACKGROUND: Toombak is a form of smokeless tobacco (SLT) that is locally made and consumed in Sudan and contains several carcinogenic elements. Use of Toombak has been etiologically linked to various oral diseases including oral cancer. This study aimed to obtain baseline information about the Toombak use among Sudanese school workers, as well as their knowledge about Toombak related health hazards and attitude towards their role in Toombak control. In addition, this study assessed the availability and effectiveness of control policies and preventive practices in the schools. METHODS: A cross-sectional school-based study using one stage stratified random sampling procedure; four schools were selected randomly from each of seven localities. A total of 239 school workers' were recruited (census) from the selected schools in Khartoum State, Sudan. RESULTS: Of the school workers, 63% (147) were <=40 years, half were females and 79.2% (187) were teachers. A total of 9.6% (22) school workers confirmed ever use of Toombak and the percentage of daily users amounted to 64.7% (11). Moreover, 76.2% (16) of ever Toombak users were >=40 years and all of them were males (p < 0.001). Most of the school workers reported good knowledge, positive attitude towards their role in Toombak control and good preventive practice. Female school workers were more likely to report positive attitude towards their role in Toombak control (p < 05), and to report good knowledge. Those reporting good preventive practice in schools reported good knowledge more than two times than their counterpart (p < 0.001). Age was the strongest predictor of ever Toombak use among school workers (p < .001). CONCLUSIONS: The use of Toombak among school workers was associated with poor knowledge, negative attitude towards their role in Toombak control and poor preventive practice, Therefore, school workers use of Toombak may reduce their motivation and use of their potential in the prevention of a major health problem caused by Toombak use and affects their role model behaviour. On the other hand, school workers engagement with preventive practices in schools' was associated with good knowledge which in turn empowers their positive attitude towards their role in Toombak control. PMID- 29268747 TI - Alarming prevalence and clustering of modifiable noncommunicable disease risk factors among adults in Bhutan: a nationwide cross-sectional community survey. AB - BACKGROUND: Bhutan is currently facing a double burden of non-communicable (NCDs) and communicable diseases, with rising trends of NCDs. The 2014 STEPS survey identified high prevalence of several NCD risk factors; however, associations with socio-demographic characteristics as well as clustering of risk factors were not assessed. This study aimed to determine the distribution and clustering of modifiable NCD risk factors among adults in Bhutan and their demographic and social determinants. METHODS: This was secondary analysis of data from NCD Risk Factors WHO STEPS Survey 2014 in Bhutan. A weighted analysis was conducted to calculate the prevalence of NCD risk factors, and associations were explored using weighted log-binomial regression models. RESULTS: This study included 2822 Bhutanese aged 18-69 years; 52% were 18-39 years, 62% were female, and 69% were rural resident. Prevalence of high salt intake, unhealthy diet and tobacco use were 99, 67 and 25% respectively. Raised blood pressure was the commonest (36%) modifiable biological risk factor followed by overweight (33%). The median NCD risk factors per person was 3 (Inter Quartile Range: 2-4); 52.5%% had > = 3 risk factors. A statistically significant difference was found between male vs. female in alcohol consumption(aPR 0.71, 95% CI: 0.53-0.97), low physical activity(aPR 2.06, 95% CI: 1.54-2.75), impaired fasting glycaemia(aPR 1.24, 95% CI: 1.01 1.52), and being overweight(aPR 1.46, 95% CI: 1.31-1.63). Low physical activity was more common among those with secondary and above education level vs. those without any formal education(aPR 1.71, 95% CI: 1.24-2.35), and among those residing in urban areas vs. those in rural(aPR 3.43, 95% CI: 2.27-5.18). Older participants and urban residents were more likely to have > = 3 NCD risk factors compared to younger(aPR 1.46, 95% CI: 1.35-1.58) and rural residents(aPR 1.21, 95% CI: 1.10-1.32). CONCLUSION: Lifestyle modifications at the population level are urgently required in Bhutan as several NCD risk factors such as high salt intake, unhealthy diet, overweight, and high blood pressure were alarmingly high and frequently clustered. Moreover there is a need to consider policy and socio political and economic factors that have undermined global and national progress to address the rise of NCDs and their risk factors in Bhutan as elsewhere. PMID- 29268748 TI - Patient and surgical factors affecting procedure duration and revision risk due to deep infection in primary total knee arthroplasty. AB - BACKGROUND: The aim of this study was to assess which patient and procedure factors affected both the risk of infection as well as procedure duration. Additionally, to assess if procedure duration affected the revision risk due to deep infection in total knee arthroplasty (TKA) patients and in a subgroup of low risk patients. METHODS: 28,262 primary TKA with 311 revisions due to deep infection were included from the Norwegian Arthroplasty Register (NAR) and analysed from primary surgery from 2005 until 31st December 2015 with a 1 and 4 year follow up. The risk of revision due to deep infection was calculated in a multivariable Cox regression model including patient and procedure related risk factors, assessing Hazard Ratio (HR) with 95% confidence interval (CI). RESULTS: Multivariate analysis showed statistically significant associations with revision due to deep infection and increased procedure duration for male patients, ASA3+ (American Society of Anesthesiologists) and perioperative complications. Procedure duration >=110 min (75 percentile) had a higher risk of deep infection compared to duration <75 min (25 percentile), in the unadjusted analysis (HR = 1.8, 95% CI 1.3-2.5, p = 0.001) and in the adjusted analysis (HR = 1.5, 95% CI 1.0-2.1, p = 0.03). For low-risk patients, procedure duration did not increase the risk of infection. CONCLUSION: Male patients, ASA 3+ patients and perioperative complications were risk factors both for longer procedure duration and for deep infection revisions. Patients with a high degree of comorbidity, defined as ASA3+, are at risk of infection with longer procedure durations. The occurrence of perioperative complications potentially leading to a more complex and lengthy procedure was associated with a higher risk of infection. Long procedure duration in itself seems to have minor impact on infection since we found no association in the low-risk patient. PMID- 29268749 TI - Process-oriented evaluation of an international faculty development program for Asian developing countries: a qualitative study. AB - BACKGROUND: Non-English-speaking developing countries in Southeast Asia have been provided only limited opportunities for faculty development in the education of health professions. Although there exist a few programs that have been shown to be effective, they are frequently presented with few explanations on how and why the programs work due to their outcome-oriented nature. This study explores the process of the Lee Jong-Wook Fellowship for Health Professional Education, an international faculty development program designed for capacity building of educators of health professions in Southeast Asian developing countries. METHODS: Fellows were from Cambodia, Myanmar, and Laos. Qualitative data were collected from two types of semi-structured interviews - group and individual. Thematic analysis was conducted to explore the factors related to the effectiveness of the program, framed by four components of faculty development, which included context, facilitators, program, and participants. RESULTS: From the thematic analysis, the authors identified a total of 12 themes in the four components of faculty development. In the context domain, the resource-poor setting, a culture that puts emphasis on hierarchy and seniority, and educational environment depending on individual commitment rather than broad consensus emerged as key factors. In the facilitators domain, their teaching methods and materials, mutual understanding between teacher and learner, and collaboration between facilitators mainly influenced the learning during the fellowship. In the program domain, the key advantages of the fellowship program were its applicability to the workplace of the fellows and enough allowed time for practice and reflection. Finally, in the participants domain, Fellows valued their heterogeneity of composition and recognized cognitive as well as non-cognitive attributes of the participants as essential. CONCLUSIONS: This process-oriented evaluation reveals the diverse factors that contributed to achieving the intended outcomes of the fellowship. Although much evidence from best practices in faculty development are still valid, the findings suggest that the selection strategies, learning environment, and English communication should be given more consideration when organizing a program targeting these people and cultures. A comprehensive understanding of the process would contribute to developing tailored strategies for educators of health professions in developing countries in similar settings. PMID- 29268750 TI - Discriminative ability of quality of life measures in multiple sclerosis. AB - BACKGROUND: Though many people with multiple sclerosis (MS) have comorbidities, the use of generic and disease-specific health related quality of life (HRQOL) scales to discriminate the effects of comorbidity has not been established. The utility of these scales to discriminate differences between persons with varying levels of disability is also unknown. METHODS: Using online questionnaires, a convenience sample of Albertans with MS was recruited between July 2011 and March 2013. Participants completed demographic questions, a validated comorbidity questionnaire, a self-reported disability scale, and the following HRQOL scales: the Short Form (SF)-36, SF-6D, Health Utilities Index-Mark III (HUI-III), and Multiple Sclerosis Quality of Life-54 (MSQOL-54). The ability of each HRQOL scale to distinguish between comorbidity groups was assessed using a one-way analysis of covariance, adjusting for age, sex, disease course, and disability level. RESULTS: Five hundred sixty three participants completed all relevant questionnaires. All HRQOL measures distinguished between persons with or without depression, while none were able to distinguish between participants with or without hypertension, thyroid disease, irritable bowel syndrome, or osteoporosis. The SF-36 physical scale, SF-6D, HUI-III, and MSQOL-54 physical scales were able to distinguish between all disability groups, though the HUI-III was better able to distinguish between individuals with moderate versus severe disability. CONCLUSIONS: Disease-specific measures would discriminate better between those with and without comorbidities than generic-specific measures and the HUI-III would discriminate best between persons with differing severities of disability. Generic or disease-specific measures may be useful in future studies examining the effects of comorbidity in MS and the effects of treatment of comorbidities in MS. PMID- 29268751 TI - Exposure to ambient air pollution and calcification of the mitral annulus and aortic valve: the multi-ethnic study of atherosclerosis (MESA). AB - BACKGROUND: Long-term exposure to high ambient air pollution has been associated with coronary artery calcium (CAC), a marker of cardiovascular disease (CVD). Calcifications of left-sided heart valves are also markers of CVD risk. We investigated whether air pollution was associated with valvular calcification and its progression. METHODS: We studied 6253 MESA participants aged 45-84 years who underwent two cardiac CT scans 2.5 years apart to quantify aortic valve calcium (AVC) and mitral annular calcium (MAC). CAC was included for the same timeframe for comparison with AVC/MAC. Ambient particulate matter <2.5 MUm (PM2.5) and oxides of nitrogen (NOx) concentrations were predicted from residence-specific spatio-temporal models. RESULTS: The mean age (SD) of the study sample was 62 (10) years, 39% were white, 27% black, 22% Hispanic, and 12% Chinese. The prevalence of AVC and MAC at baseline were 13% and 9% respectively, compared to 50% prevalence of CAC. The adjusted prevalence ratios of AVC and MAC for each 5 MUg/m3 higher PM2.5 was 1.19 (95% CI 0.87, 1.62) and 1.20 (0.81, 1.77) respectively, and for CAC was 1.14 (1.01, 1.27). Over 2.5 years, the mean change in Agatston units/year for each 5 MUg/m3 higher PM2.5 concentration was 0.29 ( 5.05, 5.63) for AVC and 4.38 (-9.13, 17.88) for MAC, compared to 8.66 (0.61, 16.71) for CAC. We found no significant associations of NOx with AVC and MAC. CONCLUSION: Our findings suggest a trend towards increased 2.5-year progression of MAC with exposure to outdoor PM2.5, although this association could not be confirmed. Additional well-powered studies with longer periods of follow-up are needed to further study associations of air pollution with valvular calcium. TRIAL REGISTRATION: Although MESA is not a clinical trial, this cohort is registered at ClinicalTrials.gov Identifier: NCT00005487; Date of registration May 25, 2000. PMID- 29268752 TI - Prostate cancer small non-coding RNA transcriptome in Arabs. AB - BACKGROUND: Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Small non-coding RNAs (sRNAs), particularly microRNAs (miRNAs), regulate several cellular processes and have an important role in many human malignancies including PCa. We assessed the sRNA profiles associated with PCa in Arabs, a population that has rarely been studied. METHODS: We used next generation sequencing technology to obtain the entire sRNA transcriptome of primary prostate tumor formalin-fixed paraffin-embedded tissues, and their paired non-tumor tissues, collected from Bedouin patients (Qatari and Saudi). The miRNA and the target gene expression were evaluated by real-time quantitative PCR. miRNA KEGG pathway and miRNA target genes were subsequently analyzed by starBase and TargetScan software. RESULTS: Different expression patterns of several sRNA and miRNA editing were revealed between PCa tumor and their paired non-tumor tissues. Our study identified four miRNAs that are strongly associated with prostate cancer, which have not been reported previously. Differentially expressed miRNAs significantly affect various biological pathways, such as cell cycle, endocytosis, adherence junction and pathways involved in cancer. Prediction of potential targets for the identified miRNAs indicates the overexpression of KRAS, BCL2 and down-regulation of PTEN in PCa tumor tissues. CONCLUSION: These miRNAs, newly associated with prostate cancer, may represent not only markers for the increased risk of PCa in Arabs, but may also reflect the clinical and pathological diversity as well as the ethno specific heterogeneity of prostate cancer. PMID- 29268753 TI - Innovations in the quantitative virus outgrowth assay and its use in clinical trials. AB - A robust measure of the size of the latent HIV reservoir is essential to quantifying the effect of interventions designed to deplete the pool of reactivatable, replication competent proviruses. In addition to the ability to measure a biologically relevant parameter, any assay designed to be used in a clinical trial needs to be reproducible and scalable. The need to quantify the number of resting CD4+ T cells capable of releasing infectious virus has led to the development of the quantitative viral outgrowth assay (VOA). The assay as originally described has a number of features that limit its scalability for use in clinical trials; however recent developments reducing the time and manpower requirements of the assay, while importantly improving reproducibility mean that it is becoming much more practical for it to enter into more widespread use. This review describes the background to VOA development and the practical issues that they present in utilising them in clinical trials. It describes the innovations that have made their usage more practical and the limitations that still exist. PMID- 29268754 TI - A Mokken analysis of the literacy in musculoskeletal problems questionnaire. AB - BACKGROUND: Limited health literacy is known to impact on medication adherence, hospital readmission and potentially poorer health outcomes. The literature on the health literacy of those with musculoskeletal conditions suggests greater functional limitations and increased pain levels. There are a number of measures of health literacy. One that specifically relates to musculoskeletal complaints is the Literacy in Musculoskeletal Problems (LiMP) questionnaire. The LiMP contains 9 multiple choice items that cover anatomy, musculoskeletal conditions and the diagnosis of musculoskeletal complaints. The aim of the study was to evaluate the dimensionality and internal structure of the LiMP in patients attending for osteopathy care at a student-led clinic, as a potential measure of musculoskeletal health literacy. METHOD: Three hundred and sixty-one (n = 361) new patients attending the Victoria University Osteopathy Clinic completed the LiMP and a demographic and health information questionnaire prior to their initial consultation. Mokken scale analysis, a nonparametric item response theory approach, was used to evaluate the dimensionality and structure of the LiMP in this population, to ascertain whether the questionnaire was measuring a single latent construct - musculoskeletal health literacy. McDonald's omega and Cronbach's alpha were calculated as the reliability estimations. The relationship between the LiMP and a single item screen of health literacy was also undertaken. RESULTS: The 9 items on the LiMP did not form a Mokken scale and the reliability estimations were below an acceptable level (alpha and omega <0.45). LiMP items 5 and 8 were more likely to be answered correctly by those with higher health literacy (p < 0.05), however the effect sizes were small (<0.20). CONCLUSION: Calculation of a total score for the LiMP, as advocated by the original authors, is not supported based on data in the present study. Further research is required to explore the relationship of the LiMP items to demographic and clinical data, and to other broader measures of health literacy. Further research may also develop a health literacy measure that is specific to patients seeking manual therapy care for musculoskeletal complaints. PMID- 29268756 TI - The effect of kidney function on the urate lowering effect and safety of increasing allopurinol above doses based on creatinine clearance: a post hoc analysis of a randomized controlled trial. AB - BACKGROUND: The use of allopurinol in people with chronic kidney disease (CKD) remains one of the most controversial areas in gout management. The aim of this study was to determine the effect of baseline kidney function on safety and efficacy of allopurinol dose escalation to achieve serum urate (SU) <6 mg/dl. METHODS: We undertook a post hoc analysis of a 24-month allopurinol dose escalation treat-to-target SU randomized controlled trial, in which 183 people with gout were randomized to continue current dose allopurinol for 12 months and then enter the dose escalation phase or to begin allopurinol dose escalation immediately. Allopurinol was increased monthly until SU was <6 mg/dl. The effect of baseline kidney function on urate lowering and adverse effects was investigated. RESULTS: Irrespective of randomization, there was no difference in the percentage of those with creatinine clearance (CrCL) <30 ml/min who achieved SU <6 mg/dl at the final visit compared to those with CrCL >=30 to <60 ml/min and those with CrCL >=60 ml/min, with percentages of 64.3% vs. 76.4% vs. 75.0%, respectively (p = 0.65). The mean allopurinol dose at month 24 was significantly lower in those with CrCL <30 ml/min as compared to those with CrCL >=30 to <60 ml/min or CrCL >=60 ml/min (mean (SD) 250 (43), 365 (22), and 460 (19) mg/day, respectively (p < 0.001)). Adverse events were similar among groups. CONCLUSIONS: Allopurinol is effective at lowering urate even though and accepting that there were small numbers of participants with CrCL <30 ml/min, these data indicate that allopurinol dose escalation to target SU is safe in people with severe CKD. The dose required to achieve target urate is higher in those with better kidney function. TRIAL REGISTRATION: Australian and New Zealand Clinical trials Registry, ACTRN12611000845932 . Registered on 10 August 2011. PMID- 29268755 TI - Sub-chronic inhalation of lead oxide nanoparticles revealed their broad distribution and tissue-specific subcellular localization in target organs. AB - BACKGROUND: Lead is well known environmental pollutant, which can cause toxic effects in multiple organ systems. However, the influence of lead oxide nanoparticles, frequently emitted to the environment by high temperature technological processes, is still concealed. Therefore, we investigate lead oxide nanoparticle distribution through the body upon their entry into lungs and determine the microscopic and ultramicroscopic changes caused by the nanoparticles in primary and secondary target organs. METHODS: Adult female mice (ICR strain) were continuously exposed to lead oxide nanoparticles (PbO-NPs) with an average concentration approximately 106 particles/cm3 for 6 weeks (24 h/day, 7 days/week). At the end of the exposure period, lung, brain, liver, kidney, spleen, and blood were collected for chemical, histological, immunohistochemical and electron microscopic analyses. RESULTS: Lead content was found to be the highest in the kidney and lungs, followed by the liver and spleen; the smallest content of lead was found in brain. Nanoparticles were located in all analysed tissues and their highest number was found in the lung and liver. Kidney, spleen and brain contained lower number of nanoparticles, being about the same in all three organs. Lungs of animals exposed to lead oxide nanoparticles exhibited hyperaemia, small areas of atelectasis, alveolar emphysema, focal acute catarrhal bronchiolitis and also haemostasis with presence of siderophages in some animals. Nanoparticles were located in phagosomes or formed clusters within cytoplasmic vesicles. In the liver, lead oxide nanoparticle exposure caused hepatic remodeling with enlargement and hydropic degeneration of hepatocytes, centrilobular hypertrophy of hepatocytes with karyomegaly, areas of hepatic necrosis, occasional periportal inflammation, and extensive accumulation of lipid droplets. Nanoparticles were accumulated within mitochondria and peroxisomes forming aggregates enveloped by an electron-dense mitochondrial matrix. Only in some kidney samples, we observed areas of inflammatory infiltrates around renal corpuscles, tubules or vessels in the cortex. Lead oxide nanoparticles were dispersed in the cytoplasm, but not within cell organelles. There were no significant morphological changes in the spleen as a secondary target organ. Thus, pathological changes correlated with the amount of nanoparticles found in cells rather than with the concentration of lead in a given organ. CONCLUSIONS: Sub-chronic exposure to lead oxide nanoparticles has profound negative effects at both cellular and tissue levels. Notably, the fate and arrangement of lead oxide nanoparticles were dependent on the type of organs. PMID- 29268757 TI - A national cohort study on pediatric Behcet's disease: cross-sectional data from an Italian registry. AB - BACKGROUND: Behcet's disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about 25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD. METHODS: We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behcet's Disease. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria. RESULTS: The study included 110 patients (62 M, 48F). Average age at onset was 8.34+/-4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn't fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-alpha and anti-IL-1) to treat severe organ involvement. CONCLUSIONS: Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population. PMID- 29268758 TI - Promoting deceased organ and tissue donation registration in family physician waiting rooms (RegisterNow-1 trial): study protocol for a pragmatic, stepped wedge, cluster randomized controlled registry. AB - BACKGROUND: There is a worldwide shortage of organs available for transplant, leading to preventable mortality associated with end-stage organ disease. While most citizens in many countries with an intent-to-donate "opt-in" system support organ donation, registration rates remain low. In Canada, most Canadians support organ donation but less than 25% in most provinces have registered their desire to donate their organs when they die. The family physician office is a promising yet underused setting in which to promote organ donor registration and address known barriers and enablers to registering for deceased organ and tissue donation. We developed a protocol to evaluate an intervention to promote registration for organ and tissue donation in family physician waiting rooms. METHODS/DESIGN: This protocol describes a planned, stepped-wedge, cluster randomized registry trial in six family physician offices in Ontario, Canada to evaluate the effectiveness of reception staff providing patients with a pamphlet that addresses barriers and enablers to registration including a description of how to register for organ donation. An Internet-enabled tablet will also be provided in waiting rooms so that interested patients can register while waiting for their appointments. Family physicians and reception staff will be provided with training and/or materials to support any conversations about organ donation with their patients. Following a 2-week control period, the six offices will cross sequentially into the intervention arm in randomized sequence at 2-week intervals until all offices deliver the intervention. The primary outcome will be the proportion of patients visiting the office who are registered organ donors 7 days following their office visit. We will evaluate this outcome using routinely collected registry data from provincial administrative databases. A post-trial qualitative evaluation process will assess the experiences of reception staff and family physicians with the intervention and the stepped-wedge trial design. DISCUSSION: Promoting registration for organ donation in family physician offices is a potentially useful strategy for increasing registration for organ donation. Increased registration may ultimately help to increase the number of organs available for transplant. The results of this trial will provide important preliminary data on the effectiveness of using family physician offices to promote registration for organ donation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03213171 . Registered on 11 July 2017. PMID- 29268759 TI - Comparison of the efficacy of three topical antiseptic solutions for the prevention of catheter colonization: a multicenter randomized controlled study. AB - BACKGROUND: To compare the efficacy of three antiseptic solutions [0.5%, and 1.0% alcohol/chlorhexidine gluconate (CHG), and 10% aqueous povidone-iodine (PVI)] for the prevention of intravascular catheter colonization, we conducted a randomized controlled trial in patients from 16 intensive care units in Japan. METHODS: Adult patients undergoing central venous or arterial catheter insertions were randomized to have one of three antiseptic solutions applied during catheter insertion and dressing changes. The primary endpoint was the incidence of catheter colonization, and the secondary endpoint was the incidence of catheter related bloodstream infections (CRBSI). RESULTS: Of 1132 catheters randomized, 796 (70%) were included in the full analysis set. Catheter-tip colonization incidence was 3.7, 3.9, and 10.5 events per 1000 catheter-days in 0.5% CHG, 1% CHG, and PVI groups, respectively (p = 0.03). Pairwise comparisons of catheter colonization between groups showed a significantly higher catheter colonization risk in the PVI group (0.5% CHG vs. PVI: hazard ratio, HR 0.33 [95% confidence interval, CI 0.12-0.95], p = 0.04; 1.0% CHG vs. PVI: HR 0.35 [95% CI 0.13-0.93], p = 0.04). Sensitivity analyses including all patients by multiple imputations showed consistent quantitative conclusions (0.5% CHG vs. PVI: HR 0.34, p = 0.03; 1.0% CHG vs. PVI: HR 0.35, p = 0.04). No significant differences were observed in the incidence of CRBSI between groups. CONCLUSIONS: Both 0.5% and 1.0% alcohol CHG are superior to 10% aqueous PVI for the prevention of intravascular catheter colonization. TRIAL REGISTRATION: Japanese Primary Registries Network; No.: UMIN000008725 Registered on 1 September 2012. PMID- 29268760 TI - Copeptin in acute decompensation of liver cirrhosis: relationship with acute-on chronic liver failure and short-term survival. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterized by the presence of acute decompensation (AD) of cirrhosis, organ failure, and high short term mortality rates. Hemodynamic dysfunction and activation of endogenous vasoconstrictor systems are thought to contribute to the pathogenesis of ACLF. We explored whether copeptin, a surrogate marker of arginine vasopressin, is a potential marker of outcome in patients admitted for AD or ACLF and whether it might be of additional value to conventional prognostic scoring systems in these patients. METHODS: All 779 patients hospitalized for AD of cirrhosis from the CANONIC database with at least one serum sample available for copeptin measurement were included. Presence of ACLF was defined according to the CLIF consortium organ failure (CLIF-C OF) score. Serum copeptin was measured in samples collected at days 0-2, 3-7, 8-14, 15-21, and 22-28 when available. Competing-risk regression analysis was applied to evaluate the impact of serum copeptin and laboratory and clinical data on short-term survival. RESULTS: Serum copeptin concentration was found to be significantly higher in patients with ACLF compared with those without ACLF at days 0-2 (33 (14-64) vs. 11 (4-26) pmol/L; p < 0.001). Serum copeptin at admission was shown to be a predictor of mortality independently of MELD and CLIF-C OF scores. Moreover, baseline serum copeptin was found to be predictive of ACLF development within 28 days of follow-up. CONCLUSIONS: ACLF is associated with significantly higher serum copeptin concentrations at hospital admission compared with those with traditional AD. Copeptin is independently associated with short-term survival and ACLF development in patients admitted for AD or ACLF. PMID- 29268761 TI - Quantification of mitral regurgitation in patients with hypertrophic cardiomyopathy using aortic and pulmonary flow data: impacts of left ventricular outflow tract obstruction and different left ventricular segmentation methods. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging in patients with hypertrophic cardiomyopathy (HCM) enables the assessment of not only left ventricular (LV) hypertrophy and scarring but also the severity of mitral regurgitation. CMR assessment of mitral regurgitation is primarily based on the difference between LV stroke volume (LVSV) and aortic forward flow (Ao) measured using the phase-contrast (PC) technique. However, LV outflow tract (LVOT) obstruction causing turbulent, non-laminar flow in the ascending aorta may impact the accuracy of aortic flow quantification, leading to false conclusions regarding mitral regurgitation severity. Thus, we decided to quantify mitral regurgitation in patients with HCM using Ao or, alternatively, main pulmonary artery forward flow (MPA) for mitral regurgitation volume (MRvol) calculations. METHODS: The analysis included 143 prospectively recruited subjects with HCM and 15 controls. MRvol was calculated as the difference between LVSV computed with either the inclusion (LVSVincl) or exclusion (LVSVexcl) of papillary muscles and trabeculations from the blood pool and either Ao (MRvolAoi or MRvolAoe) or MPA (MRvolMPAi or MRvolMPAe). The presence or absence of LVOT obstruction was determined based on Doppler echocardiography findings. RESULTS: MRvolAoi was higher than MRvolMPAi in HCM patients with LVOT obstruction [47.0 ml, interquartile range (IQR) = 31.5-60.0 vs. 35.5 ml, IQR = 26.0-51.0; p < 0.0001] but not in non-obstructive HCM patients (23.0 ml, IQR = 16.0-32.0 vs. 24.0 ml, IQR = 15.3-32.0; p = 0.26) or controls (18.0 ml, IQR = 14.3-21.8 vs. 20.0 ml, IQR = 14.3-22.0; p = 0.89). In contrast to controls and HCM patients without LVOT obstruction, in HCM patients with LVOT obstruction, aortic flow-based MRvol (MRvolAoi) was higher than pulmonary-based findings (MRvolMPAi) (bias = 9.5 ml; limits of agreement: -11.7-30.7 with a difference of 47 ml in the extreme case). The differences between aortic-based and pulmonary-based MRvol values calculated using LVSVexcl mirrored those derived using LVSVincl. However, MRvol values calculated using LVSVexcl were lower in all the groups analyzed (HCM with LVOT obstruction, HCM without LVOT obstruction, and controls) and with all methods of MRvol quantification used (p <= 0.0001 for all comparisons). CONCLUSIONS: In HCM patients, LVOT obstruction significantly affects the estimation of aortic flow, leading to its underestimation and, consequently, to higher MRvol values than those obtained with MPA-based MRvol calculations. PMID- 29268762 TI - Methylation patterns in serum DNA for early identification of disseminated breast cancer. AB - BACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3-6 and 6-12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC. CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent. PMID- 29268763 TI - Interaction of the epigenetic integrator UHRF1 with the MYST domain of TIP60 inside the cell. AB - BACKGROUND: The nuclear epigenetic integrator UHRF1 is known to play a key role with DNMT1 in maintaining the DNA methylation patterns during cell division. Among UHRF1 partners, TIP60 takes part in epigenetic regulations through its acetyltransferase activity. Both proteins are involved in multiple cellular functions such as chromatin remodeling, DNA damage repair and regulation of stability and activity of other proteins. The aim of this work was to investigate the interaction between UHRF1 and TIP60 in order to elucidate the dialogue between these two proteins. METHODS: Biochemical (immunoprecipitation and pull down assays) and microscopic (confocal and fluorescence lifetime imaging microscopy; FLIM) techniques were used to analyze the interaction between TIP60 and UHRF1 in vitro and in vivo. Global methylation levels were assessed by using a specific kit. The results were statistically analyzed using Graphpad prism and Origin. RESULTS: Our study shows that UHRF1, TIP60 and DNMT1 were found in the same epigenetic macro-molecular complex. In vitro pull-down assay showed that deletion of either the zinc finger in MYST domain or deletion of whole MYST domain from TIP60 significantly reduced its interaction with UHRF1. Confocal and FLIM microscopy showed that UHRF1 co-localized with TIP60 in the nucleus and confirmed that both proteins interacted together through the MYST domain of TIP60. Moreover, overexpression of TIP60 reduced the DNA methylation levels in HeLa cells along with downregulation of UHRF1 and DNMT1. CONCLUSION: Our data demonstrate for the first time that TIP60 through its MYST domain directly interacts with UHRF1 which might be of high interest for the development of novel oncogenic inhibitors targeting this interaction. PMID- 29268764 TI - Additive effect of tDCS combined with Peripheral Electrical Stimulation to an exercise program in pain control in knee osteoarthritis: study protocol for a randomized controlled trial. AB - BACKGROUND: Knee osteoarthritis (OA) has been linked to maladaptive plasticity in the brain, which may contribute to chronic pain. Neuromodulatory approaches, such as Transcranial Direct Current Stimulation (tDCS) and Peripheral Electrical Stimulation (PES), have been used therapeutically to counteract brain maladaptive plasticity. However, it is currently unclear whether these neuromodulatory techniques enhance the benefits of exercise when administered together. Therefore, this protocol aims to investigate whether the addition of tDCS combined or not with PES enhances the effects of a land-based strengthening exercise program in patients with knee OA. METHODS: Patients with knee OA (n = 80) will undertake a structured exercise program for five consecutive days. In addition, they will be randomized into four subgroups receiving either active anodal tDCS and sham PES (group 1; n = 20), sham tDCS and active PES (group 2, n = 20), sham tDCS and PES (group 3, n = 20), or active tDCS and PES (group 4, n = 20) for 20 min/day for five consecutive days just prior to commencement of the exercise program. The primary outcomes will be subjective pain intensity (VAS) and related function (WOMAC). Secondary outcomes will include quality of life (SF 36), anxiety and depression symptoms (HAD), self-perception of improvement, pressure pain thresholds over the knee, quadriceps strength, and quadriceps electromyographic activity during maximum knee extension voluntary contraction. We will also investigate cortical excitability using transcranial magnetic stimulation. Outcome measures will be assessed at baseline, 1 month after, before any intervention, after 5 days of intervention, and at 1 month post exercise intervention. DISCUSSION: The motor cortex becomes less responsive in knee OA because of poorly adapted plastic changes, which can impede exercise therapy benefits. Adding tDCS and/or PES may help to counteract those maladaptive plastic changes and improve the benefits of exercises, and the combination of both neuromodulatory techniques must have a higher magnitude of effect. TRIAL REGISTRATION: Brazilian Registry on Clinical Trials (ReBEC) - Effects of electrical stimulation over the skull and tight together with exercises for knee OA; protocol number RBR-9D7C7B. TRIAL REGISTRATION: ID: RBR-9D7C7B . Registered on 29 February 2016. PMID- 29268766 TI - Human papillomavirus detection using the Abbott RealTime high-risk HPV tests compared with conventional nested PCR coupled to high-throughput sequencing of amplification products in cervical smear specimens from a Gabonese female population. AB - BACKGROUND: Cervical cancer is the fourth most common malignancy in women worldwide. However, screening with human papillomavirus (HPV) molecular tests holds promise for reducing cervical cancer incidence and mortality in low- and middle-income countries. The performance of the Abbott RealTime High-Risk HPV test (AbRT) was evaluated in 83 cervical smear specimens and compared with a conventional nested PCR coupled to high-throughput sequencing (HTS) to identify the amplicons. RESULTS: The AbRT assay detected at least one HPV genotype in 44.57% of women regardless of the grade of cervical abnormalities. Except for one case, good concordance was observed for the genotypes detected with the AbRT assay in the high-risk HPV category determined with HTS of the amplicon generated by conventional nested PCR. CONCLUSIONS: The AbRT test is an easy and reliable molecular tool and was as sensitive as conventional nested PCR in cervical smear specimens for detection HPVs associated with high-grade lesions. Moreover, sequencing amplicons using an HTS approach effectively identified the genotype of the hrHPV identified with the AbRT test. PMID- 29268765 TI - From forensic epigenetics to forensic epigenomics: broadening DNA investigative intelligence. AB - Human genetic variation is a major resource in forensics, but does not allow all forensically relevant questions to be answered. Some questions may instead be addressable via epigenomics, as the epigenome acts as an interphase between the fixed genome and the dynamic environment. We envision future forensic applications of DNA methylation analysis that will broaden DNA-based forensic intelligence. Together with genetic prediction of appearance and biogeographic ancestry, epigenomic lifestyle prediction is expected to increase the ability of police to find unknown perpetrators of crime who are not identifiable using current forensic DNA profiling. PMID- 29268767 TI - Non-invasive test using palmitate in patients with suspected fatty acid oxidation defects: disease-specific acylcarnitine patterns can help to establish the diagnosis. AB - BACKGROUND: The aim of the present study was to establish a non-invasive, fast and robust enzymatic assay to confirm fatty acid oxidation defects (FAOD) in humans following informative newborn-screening or for selective screening of patients suspected to suffer from FAOD. MATERIAL/METHODS: The reliability of this method was tested in whole blood from FAOD patients with specific enzymatic defects. Whole blood samples were assayed in 30 medium chain- (MCADD, age 0 to 17 years), 6 very long chain- (VLCADD, age 0 to 4 years), 6 long chain hydroxy- (LCHAD, age 1 to 6 years), 3 short chain- (SCADD, age 10 to 13 years) acyl-CoA dehydrogenase- and 2 primary carnitine transporter deficiencies (CTD, age 3 to 5 years). Additionally, 26 healthy children (age 0 to 17 years) served as controls. Whole blood samples were incubated with stable end-labeled palmitate; labeled acylcarnitines were analyzed by tandem mass spectrometry and compared with controls and between patient groups (Mann-Whitney Rank Sum Test). Concentrations of specific labeled acylcarnitine metabolites were compared between particular underlying MCADD- (ANOVA), VLCADD- and LCHADD- genetic variants (descriptive data analysis). RESULTS: 11 different acylcarnitines were analyzed. MCADD- (C8-, C10 carnitine, C8/C10- and C8/C4-carnitine), VLCADD- (C12-, C14:1-, C14:2-carnitine, C14:1/C12- and C14:2/C12-carnitine), LCHADD (C16-OH-carnitine) as well as CTD- deficiency (sum of all acylcarnitines) samples could be clearly identified and separated from control values as well as other FAOD, whereas the sum of all acylcarnitines was not conclusive between FAOD samples. Furthermore, C4- (SCADD), C14- (VLCADD) and C14-OH-carnitines (LCHADD) were discriminating between the FAOD groups. Metabolic parameters did not differ significantly between underlying MCADD variants; similar results could be observed for VLCADD- and LCHADD- variants. CONCLUSION: This functional method in whole blood samples is relatively simple, non-invasive and little time consuming. It allows to identify MCADD-, VLCADD-, LCHADD- and carnitine transporter deficiencies. The genetic phenotypes of one enzyme defect did not result in differing acylcarnitine patterns in MCADD, VLCADD or LCHADD in vitro. PMID- 29268768 TI - CX3CL1 promotes MMP-3 production via the CX3CR1, c-Raf, MEK, ERK, and NF-kappaB signaling pathway in osteoarthritis synovial fibroblasts. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that affects the cartilage, synovium, and subchondral bone and is the leading cause of disability in older populations. Specific diagnostic biomarkers are lacking; hence, treatment options for OA are limited. Synovial inflammation is very common in OA joints and has been associated with both OA's symptoms and pathogenesis. Confirming the role of the synovium in OA pathogenesis is a promising strategy for mitigating the symptoms and progression of OA. CX3CL1 is the only member of the CX3C class of chemokines that combines the properties of chemoattractants and adhesion molecules. CX3CL1 levels in the synovium and serum were both discovered to be positively associated with OA pathogenesis. CX3CL1 and its receptor CX3CR1 belong to a family of G protein-coupled receptors. Matrix metalloproteinases (MMPs), which are responsible for matrix degradation, play a crucial role in OA progression. The relationship between CX3CL1 and MMPs in the pathophysiology of OA is still unclear. METHODS: CX3CL1-induced MMP-3 production was assessed with quantitative real-time PCR and ELISA. The mechanisms of action of CX3CL1 in different signaling pathways were studied using western blot analysis, quantitative real-time PCR and ELISA. Neutralization antibodies of integrin were achieved to block the CX3CR1 signaling pathway. Luciferase assays were used to study NF-kappaB promoter activity. RESULTS: We investigated the signaling pathway involved in CX3CL1-induced MMP-3 production in osteoarthritis synovial fibroblasts (OASFs). CX3CL1 was found to induce MMP-3 production in a concentration-dependent and time-dependent manner. Using pharmacological inhibitors and CX3CR1 small interfering RNA to block CX3CR1 revealed that the CX3CR1 receptor was involved in the CX3CL1-mediated upregulation of MMP-3. CX3CL1 mediated MMP-3 production was attenuated by c-Raf inhibitors (GW5074) and MEK/ERK inhibitors (PD98059 and U0126). The OASFs were stimulated using CX3CL1-activated p65 phosphorylation. CONCLUSIONS: Our results demonstrate that CX3CL1 activates c Raf, MEK, ERK, and NF-kappaB on the MMP-3 promoter through CX3CR1, thus contributing to cartilage destruction during OA. PMID- 29268770 TI - Structure based drug discovery for designing leads for the non-toxic metabolic targets in multi drug resistant Mycobacterium tuberculosis. AB - BACKGROUND: The problem of drug resistance and bacterial persistence in tuberculosis is a cause of global alarm. Although, the UN's Sustainable Development Goals for 2030 has targeted a Tb free world, the treatment gap exists and only a few new drug candidates are in the pipeline. In spite of large information from medicinal chemistry to 'omics' data, there has been a little effort from pharmaceutical companies to generate pipelines for the development of novel drug candidates against the multi drug resistant Mycobacterium tuberculosis. METHODS: In the present study, we describe an integrated methodology; utilizing systems level information to optimize ligand selection to lower the failure rates at the pre-clinical and clinical levels. In the present study, metabolic targets (Rv2763c, Rv3247c, Rv1094, Rv3607c, Rv3048c, Rv2965c, Rv2361c, Rv0865, Rv0321, Rv0098, Rv0390, Rv3588c, Rv2244, Rv2465c and Rv2607) in M. tuberculosis, identified using our previous Systems Biology and data-intensive genome level analysis, have been used to design potential lead molecules, which are likely to be non-toxic. Various in silico drug discovery tools have been utilized to generate small molecular leads for each of the 15 targets with available crystal structures. RESULTS: The present study resulted in identification of 20 novel lead molecules including 4 FDA approved drugs (droxidropa, tetroxoprim, domperidone and nemonapride) which can be further taken for drug repurposing. This comprehensive integrated methodology, with both experimental and in silico approaches, has the potential to not only tackle the MDR form of Mtb but also the most important persister population of the bacterium, with a potential to reduce the failures in the Tb drug discovery. CONCLUSION: We propose an integrated approach of systems and structural biology for identifying targets that address the high attrition rate issue in lead identification and drug development We expect that this system level analysis will be applicable for identification of drug candidates to other pathogenic organisms as well. PMID- 29268769 TI - Systems serology: profiling vaccine induced humoral immunity against HIV. AB - The results of the RV144 HIV vaccine, in combination with several recent non human primate vaccine studies continue to highlight the potentially protective role of non-neutralizing Fc functional antibodies in HIV vaccine design. For many currently licensed vaccines, assays that detect antigen-specific antibody titers or neutralization levels have been used as a correlate of protection. However, antibodies can confer protection through multiple other mechanisms beyond neutralization, or mechanisms which are not dependent on total antibody titers. Alternative strategies that allow us to further understand the precise mechanisms by which antibodies confer protection against HIV and other infectious pathogens is vitally important for the development of future vaccines. Systems serology aims to comprehensively survey a diverse array of antibody features and functions, in order to simultaneously examine the mechanisms behind and distinguish the most important antibody features required for protection, thus identifying key targets for future experimental vaccine testing. This review will focus on the technical aspects required for the application of Systems serology and summarizes the recent advances provided by application of this systemic analytical approach. PMID- 29268771 TI - Monocyte-derived tissue transglutaminase in multiple sclerosis patients: reflecting an anti-inflammatory status and function of the cells? AB - BACKGROUND: Leukocyte infiltration into the central nervous system is an important feature of multiple sclerosis (MS) pathology. Among the infiltrating cells, monocytes comprise the largest population and are considered to play a dual role in the course of the disease. The enzyme tissue transglutaminase (TG2), produced by monocytes, plays a central role in monocyte adhesion/migration in animal models of MS. In the present study, we questioned whether TG2 expression is altered in monocytes from MS patients compared to healthy control (HC) subjects. Moreover, we determined the inflammatory status of these TG2-expressing monocytes, what inflammatory factor regulates TG2 expression, and whether TG2 can functionally contribute to their adhesion/migration processes. METHODS: Primary human monocytes from MS patients and HC subjects were collected, RNA isolated and subjected to qPCR analysis. Human THP-1 monocytes were lentivirally transduced with TG2 siRNA or control and treated with various cytokines. Subsequently, mRNA levels of inflammatory factors, adhesion properties, and activity of RhoA were analyzed in interleukin (IL)-4-treated monocytes. RESULTS: TG2 mRNA levels are significantly increased in monocytes derived from MS patients compared to HC subjects. In addition, correlation analyses indicated that TG2-expressing cells display a more anti-inflammatory, migratory profile in MS patients. Using THP-1 monocytes, we observed that IL-4 is a major trigger of TG2 expression in these cells. Furthermore, knockdown of TG2 expression leads to a pro-inflammatory profile and reduced adhesion/migration properties of IL-4-treated monocytes. CONCLUSIONS: TG2-expressing monocytes in MS patients have a more anti inflammatory profile. Furthermore, TG2 mediates IL-4-induced anti-inflammatory status in THP-1 monocytes, adhesion, and cytoskeletal rearrangement in vitro. We thus propose that IL-4 upregulates TG2 expression in monocytes of MS patients, driving them into an anti-inflammatory status. PMID- 29268772 TI - A functional role of LEFTY during progesterone therapy for endometrial carcinoma. AB - BACKGROUND: The left-right determination factor (LEFTY) is a novel member of the TGF-beta/Smad2 pathway and belongs to the premenstrual/menstrual repertoire in human endometrium, but little is known about its functional role in endometrial carcinomas (Em Cas). Herein, we focused on LEFTY expression and its association with progesterone therapy in Em Cas. METHODS: Regulation and function of LEFTY, as well as its associated molecules including Smad2, ovarian hormone receptors, GSK-3beta, and cell cycle-related factors, were assessed using clinical samples and cell lines of Em Cas. RESULTS: In clinical samples, LEFTY expression was positively correlated with estrogen receptor-alpha, but not progesterone receptor (PR), status, and was inversely related to phosphorylated (p) Smad2, cyclin A2, and Ki-67 levels. During progesterone therapy, expression of LEFTY, pSmad2, and pGSK-3beta showed stepwise increases, with significant correlations to morphological changes toward secretory features and decreased Ki-67 values. In Ishikawa cells, an Em Ca cell line that expresses PR, progesterone treatment reduced proliferation and induced increased expression of LEFTY and pGSK-3beta, although LEFTY promoter regions were inhibited by transfection of PR. Moreover, inhibition of GSK-3beta resulted in increased LEFTY expression through a decrease in its ubiquitinated form, suggesting posttranslational regulation of LEFTY protein via GSK-3beta suppression in response to progesterone. In addition, overexpression or knockdown of LEFTY led to suppression or enhancement of Smad2 dependent cyclin A2 expression, respectively. CONCLUSION: Upregulation of LEFTY may serve as a useful clinical marker for the therapeutic effects of progesterone for Em Cas, leading to inhibition of tumor cell proliferation through alteration in Smad2-dependent transcription of cyclin A2. PMID- 29268773 TI - Phytochemical and pharmacological investigation of Spiraea chamaedryfolia: a contribution to the chemotaxonomy of Spiraea genus. AB - OBJECTIVE: Diterpene alkaloids are secondary plant metabolites and chemotaxonomical markers with a strong biological activity. These compounds are characteristic for the Ranunculaceae family, while their occurrence in other taxa is rare. Several species of the Spiraea genus (Rosaceae) are examples of this rarity. Screening Spiraea species for alkaloid content is a chemotaxonomical approach to clarify the classification and phylogeny of the genus. Novel pharmacological findings make further investigations of Spiraea diterpene alkaloids promising. RESULTS: Seven Spiraea species were screened for diterpene alkaloids. Phytochemical and pharmacological investigations were performed on Spiraea chamaedryfolia, the species found to contain diterpene alkaloids. Its alkaloid-rich fractions were found to exert a remarkable xanthine-oxidase inhibitory activity and a moderate antibacterial activity. The alkaloid distribution within the root was clarified by microscopic techniques. PMID- 29268774 TI - MicroRNA-135a regulates NHE9 to inhibit proliferation and migration of glioblastoma cells. AB - BACKGROUND: Glioblastoma multiformae (GBM) is the most aggressive type of malignant brain tumor with complex molecular profile. Overexpression of Na+/H+ Exchanger isoform 9 (NHE9) promotes tumor progression and correlates positively with insensitivity to radiochemotherapy and poor prognosis. However, molecular mechanisms responsible for increase in NHE9 levels beyond a critical threshold have not been identified. METHODS: Bioinformatics analysis, luciferase reporter assays, real-time PCR and western blotting were conducted to examine the expression profiles and identify microRNAs (miRNA) that target NHE9. Cell proliferation and migration assays were conducted in U87 glioblastoma cells to determine the consequence of miRNA mediated targeting of NHE9. Endosomal pH measurements, immunofluorescence microscopy and surface biotinylation experiments were conducted to characterize the mechanistic basis of regulation. RESULTS: We show that microRNA 135a (miR-135a) targets NHE9 to downregulate its expression in U87 cells. MiR-135a levels are significantly lower in glioblastoma cells compared to normal brain tissue. Downregulation of NHE9 expression by miR-135a affects proliferative and migratory capacity of U87 cells. Selectively increasing NHE9 expression in these cells restored their ability to proliferate and migrate. We demonstrate that miR-135a takes a two-pronged approach affecting epidermal growth factor receptors (EGFRs) to suppress tumor cell growth and migration. EGFR activity is a potent stimulator of oncogenic signaling. While miR-135a targets EGFR transcripts to decrease the total number of receptors made, by targeting NHE9 it routes the few EGFRs made away from the plasma membrane to dampen oncogenic signaling. NHE9 is localized to sorting endosomes in glioblastoma cells where it alkalinizes the endosome lumen by leaking protons. Downregulation of NHE9 expression by miR-135a acidifies sorting endosomes limiting EGFR trafficking to the glioblastoma cell membrane. CONCLUSIONS: We propose downregulation of miR 135a as a potential mechanism underlying the high NHE9 expression observed in subset of glioblastomas. Future studies should explore miR-135a as a potential therapeutic for glioblastomas with NHE9 overexpression. PMID- 29268775 TI - Initial blood pH during cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients: a multicenter observational registry-based study. AB - BACKGROUND: When an out-of-hospital cardiac arrest (OHCA) patient receives cardiopulmonary resuscitation (CPR) in the emergency department (ED), blood laboratory test results can be obtained by using point-of-care testing during CPR. In the present study, the relationship between blood laboratory test results during CPR and outcomes of OHCA patients was investigated. METHODS: This study was a multicenter retrospective analysis of prospective registered data that included 2716 OHCA patients. Data from the EDs of three university hospitals in different areas were collected from January 2009 to December 2014. Univariate and multivariable analyses were conducted to elucidate the factors associated with survival to discharge and neurological outcomes. A final analysis was conducted by including patients who had no prehospital return of spontaneous circulation and those who underwent rapid blood laboratory examination during CPR. RESULTS: Overall, 2229 OHCA patients were included in the final analysis. Among them, the rate of survival to discharge and a good Cerebral Performance Categories Scale score were 14% and 4.4%, respectively. The pH level was independently related to survival to hospital discharge (adjusted OR 6.287, 95% CI 2.601-15.197; p < 0.001) and good neurological recovery (adjusted OR 15.395, 95% CI 3.439-68.911; p < 0.001). None of the neurologically intact patients had low pH levels (< 6.8) or excessive potassium levels (> 8.5 mEq/L) during CPR. CONCLUSIONS: Among the blood laboratory test results during CPR of OHCA patients, pH and potassium levels were observed as independent factors associated with survival to hospital discharge, and pH level was considered as an independent factor related to neurological recovery. PMID- 29268776 TI - External quality assessment of malaria microscopy diagnosis among public health facilities in West Amhara Region, Ethiopia. AB - OBJECTIVE: To evaluate the importance of external quality assessment program on malaria microscopic diagnosis. RESULTS: A total of 3148 slides were collected in 4 consecutive external quality assessment rounds and blindly rechecked at Amhara Public Health Institute. The average agreement between health facility and APHI slide readers was 96.6%. The percent agreement for parasite detection and species identification for P. falciparum became improved in four consecutive EQA rounds from 93.88 to 99.24% and 92.67 to 97.35% respectively. The rates of false positive and false negative were also dramatically decreased in each round from 10.5 to 0.79% and 2.14 to 0.74% respectively. Therefore, we recommend that malaria EQA program should maintain and expand in all malaria diagnostic health facilities in the region to provide accurate and reliable malaria microscopic service. PMID- 29268777 TI - Breast metastasis from squamous cell carcinoma of the oropharynx: a case report. AB - BACKGROUND: Breast metastases from extramammary tumors are extremely rare, the most common primary tumors being contralateral breast carcinoma, followed by lung, gynecological, gastrointestinal, melanoma, and hematological cancers. Only a few cases deriving from head and neck squamous cell carcinoma have been reported in the literature to date. CASE PRESENTATION: We report a case of a 47 year-old Caucasian woman who presented to our hospital with a solitary breast lesion in the right upper external quadrant associated with multiple bone and visceral metastases. Two years before, she had undergone radical resection of a squamous cell carcinoma of the oropharynx (stage pT2, pN1), which was followed by adjuvant radiotherapy. Breast ultrasound showed a hypoechogenic tumor lesion of 4 cm in the right upper external quadrant that was associated with multiple axillary and infra-/supraclavicular adenopathies. A positron emission tomographic scan documented multiple visceral and bone metastases with a single hypermetabolic lesion of the right breast. The results of histology and immunohistochemistry were consistent with a metastasis from a squamous cell carcinoma. The patient died of acute respiratory insufficiency 1 month after her breast metastasis diagnosis and before starting any systemic antitumoral treatment. CONCLUSIONS: Although breast metastases are extremely rare, they should be considered in any patient with a history of cancer and confirmed by histology and immunohistochemistry because they are very difficult to distinguish from other primary breast tumors based only on clinical and radiological features. There are no standardized treatment guidelines for breast metastasis management. Surgery and radiotherapy can play a role in symptom palliation, but they do not have any relevant impact on survival, the prognosis being poor, with an estimated overall survival less than 1 year from diagnosis. PMID- 29268778 TI - Correction to: Effect of genetic ancestry to the risk of susceptibility to gastric cancer in a mixed population of the Brazilian Amazon. AB - Following publication of the original article [1], the authors requested a correction to the name of one of the co-authors. The correct name Marianne Rodrigues Fernandes, not Marianne Fernandes Rodrigues. PMID- 29268779 TI - Effect of fresh frozen plasma on the in vitro activation of U937 monocytes: a potential role for the age of blood donors and their underlying cytokine profile. AB - BACKGROUND: Fresh frozen plasma (FFP) administration may increase the risk of nosocomial infections in parallel with the development of immune modulation. This could be driven by soluble mediators, possibly influencing the in vitro activation of human U937 monocyte cells, in a manner dependent on the age of the donors. METHODS: FFP donors were stratified into groups of 19-30 years, 31-40 years or 41-50 years, and U937 cells were cultured with FFP (alone or plus lipopolysaccharide-LPS) for 24 h. Both in FFP and supernatants, TNF, IL-1beta, IL 6, and IL-10 levels were measured by ELISA. Additionally, CD11B, TLR2, and CASP3 gene expression were measured by qtPCR in U937 cells. Total phagocytic activity was also assayed. RESULTS: Elevated IL-10, but low TNF and IL-1beta levels were measured in FFP from individuals aged 19-40 years, whereas in individuals aged 41 50 years FFP were characterized by equalized TNF and IL-10 levels. Elevated IL-6 levels were found in all FFP samples, especially in those from the oldest individuals. FFP stimulation was associated with striking modifications in cytokine production in an age-dependent way. Exposure to FFP attenuates the response to LPS. TLR2 and CD11B expression were enhanced regardless of the age of plasma donors, although CASP3 expression was increased only when FFP from individuals aged 19-40 years were tested. Phagocytosis decreased after exposure to FFP regardless of donor age. CONCLUSION: Our results suggest that soluble mediators in FFP may modulate the functioning of monocytes. Interestingly, this effect appears to be partially influenced by the age of donors. PMID- 29268780 TI - Seasonal, spatial, and maternal effects on gut microbiome in wild red squirrels. AB - BACKGROUND: Our understanding of gut microbiota has been limited primarily to findings from human and laboratory animals, but what shapes the gut microbiota in nature remains largely unknown. To fill this gap, we conducted a comprehensive study of gut microbiota of a well-studied North American red squirrel (Tamiasciurus hudsonicus) population. Red squirrels are territorial, solitary, and live in a highly seasonal environment and therefore represent a very attractive system to study factors that drive the temporal and spatial dynamics of gut microbiota. RESULT: For the first time, this study revealed significant spatial patterns of gut microbiota within a host population, suggesting limited dispersal could play a role in shaping and maintaining the structure of gut microbial communities. We also found a remarkable seasonal rhythm in red squirrel's gut microbial composition manifested by a tradeoff between relative abundance of two genera Oscillospira and Corpococcus and clearly associated with seasonal variation in diet availability. Our results show that in nature, environmental factors exert a much stronger influence on gut microbiota than host associated factors including age and sex. Despite strong environmental effects, we found clear evidence of individuality and maternal effects, but host genetics did not seem to be a significant driver of the gut microbial communities in red squirrels. CONCLUSION: Taken together, the results of this study emphasize the importance of external ecological factors rather than host attributes in driving temporal and spatial patterns of gut microbiota in natural environment. PMID- 29268781 TI - Wild eel microbiome reveals that skin mucus of fish could be a natural niche for aquatic mucosal pathogen evolution. AB - BACKGROUND: Fish skin mucosal surfaces (SMS) are quite similar in composition and function to some mammalian MS and, in consequence, could constitute an adequate niche for the evolution of mucosal aquatic pathogens in natural environments. We aimed to test this hypothesis by searching for metagenomic and genomic evidences in the SMS-microbiome of a model fish species (Anguilla Anguilla or eel), from different ecosystems (four natural environments of different water salinity and one eel farm) as well as the water microbiome (W-microbiome) surrounding the host. RESULTS: Remarkably, potentially pathogenic Vibrio monopolized wild eel SMS microbiome from natural ecosystems, Vibrio anguillarum/Vibrio vulnificus and Vibrio cholerae/Vibrio metoecus being the most abundant ones in SMS from estuary and lake, respectively. Functions encoded in the SMS-microbiome differed significantly from those in the W-microbiome and allowed us to predict that successful mucus colonizers should have specific genes for (i) attachment (mainly by forming biofilms), (ii) bacterial competence and communication, and (iii) resistance to mucosal innate immunity, predators (amoeba), and heavy metals/drugs. In addition, we found several mobile genetic elements (mainly integrative conjugative elements) as well as a series of evidences suggesting that bacteria exchange DNA in SMS. Further, we isolated and sequenced a V. metoecus strain from SMS. This isolate shares pathogenicity islands with V. cholerae O1 from intestinal infections that are absent in the rest of sequenced V. metoecus strains, all of them from water and extra-intestinal infections. CONCLUSIONS: We have obtained metagenomic and genomic evidence in favor of the hypothesis on the role of fish mucosal surfaces as a specialized habitat selecting microbes capable of colonizing and persisting on other comparable mucosal surfaces, e.g., the human intestine. PMID- 29268782 TI - Overexpressed HSF1 cancer signature genes cluster in human chromosome 8q. AB - BACKGROUND: HSF1 (heat shock factor 1) is a transcription factor that is found to facilitate malignant cancer development and proliferation. In cancer cells, HSF1 mediates a set of genes distinct from heat shock that contributes to malignancy. This set of genes is known as the HSF1 Cancer Signature genes or simply HSF1 CanSig genes. HSF1-CanSig genes function and operate differently than typical cancer-causing genes, yet it is involved in fundamental oncogenic processes. RESULTS: By utilizing expression data from 9241 cancer patients, we identified that human chromosome 8q21-24 is a location hotspot for the most frequently overexpressed HSF1-CanSig genes. Intriguingly, the strength of the HSF1 cancer program correlates with the number of overexpressed HSF1-CanSig genes in 8q, illuminating the essential role of HSF1 in mediating gene expression in different cancers. Chromosome 8q21-24 is found under selective pressure in preserving gene order as it exhibits strong synteny among human, mouse, rat, and bovine, although the biological significance remains unknown. Statistical modeling, hierarchical clustering, and gene ontology-based pathway analyses indicate crosstalk between HSF1-mediated responses and pre-mRNA 3' processing in cancers. CONCLUSIONS: Our results confirm the unique role of chromosome 8q mediated by the master regulator HSF1 in cancer cases. Additionally, this study highlights the connection between cellular processes triggered by HSF1 and pre-mRNA 3' processing in cancers. PMID- 29268783 TI - Prognostic value of preoperative prognostic nutritional index and its associations with systemic inflammatory response markers in patients with stage III colon cancer. AB - BACKGROUND: The prognostic nutritional index (PNI) has been widely applied for predicting survival outcomes of patients with various malignant tumors. Although a low PNI predicts poor prognosis in patients with colorectal cancer after tumor resection, the prognostic value remains unknown in patients with stage III colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy. This study aimed to investigate the prognostic value of PNI in patients with stage III colon cancer. METHODS: Medical records of 274 consecutive patients with stage III colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and December 2013 were reviewed. The optimal PNI cutoff value was determined using receiver operating characteristic (ROC) curve analysis. The associations of PNI with systemic inflammatory response markers, including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) level, and clinicopathologic characteristics were assessed using the Chi square or Fisher's exact test. Correlation analysis was performed using Spearman's correlation coefficient. Disease-free survival (DFS) and overall survival (OS) stratified by PNI were analyzed using Kaplan-Meier method and log-rank test, and prognostic factors were identified by Cox regression analyses. RESULTS: The preoperative PNI was positively correlated with LMR (r = 0.483, P < 0.001) and negatively correlated with NLR (r = - 0.441, P < 0.001), PLR (r = - 0.607, P < 0.001), and CRP level (r = - 0.333, P < 0.001). A low PNI (<= 49.22) was significantly associated with short OS and DFS in patients with stage IIIC colon cancer but not in patients with stage IIIA/IIIB colon cancer. In addition, patients with a low PNI achieved a longer OS and DFS after being treated with 6-8 cycles of adjuvant chemotherapy than did those with < 6 cycles. Multivariate analyses revealed that PNI was independently associated with DFS (hazard ratios 2.001; 95% confidence interval 1.157-3.462; P = 0.013). CONCLUSION: The present study identified preoperative PNI as a valuable predictor for survival outcomes in patients with stage III colon cancer receiving curative tumor resection followed by adjuvant chemotherapy. PMID- 29268784 TI - 68Ga PSMA-11 PET with CT urography protocol in the initial staging and biochemical relapse of prostate cancer. AB - BACKGROUND: 68Ga-labelled prostate specific membrane antigen (PSMA) ligand PET/CT is a promising modality in primary staging (PS) and biochemical relapse (BCR) of prostate cancer (PC). However, pelvic nodes or local recurrences can be difficult to differentiate from radioactive urine. CT urography (CT-U) is an established method, which allows assessment of urological malignancies. The study presents a novel protocol of 68Ga-PSMA-11 PET/CT-U in PS and BCR of PC. METHODS: A retrospective review of PSMA PET/CT-U preformed on 57 consecutive patients with prostate cancer. Fifty mL of IV contrast was administered 10 min (range 8-15) before the CT component of a combined PET/CT study, acquired approximately 60 min (range 40-85) after administration of 166 MBq (range 91-246) of 68Ga-PSMA-11. PET and PET/CT-U were reviewed by two nuclear medicine physicians and CT-U by a radiologist. First, PET images were reviewed independently followed by PET/CT-U images. Foci of activity which could not unequivocally be assessed as disease or urinary activity were recorded. PET/CT-U was considered of potential benefit in final interpretation when the equivocal focal activity in PET images corresponded to opacified ureter, bladder, prostate bed, seminal vesicles, or urethra. Student's T test and Pearson's correlation coefficient was used for assessment of variables including lymph node size and standardized uptake value. RESULTS: Overall 50 PSMA PET/CT-U studies were performed for BCR and 7 for PS. Median PSA with BCR and PS were 2.0 +/- 11.4 ng/ml (0.06-57.3 ng/ml) and 18 +/- 35.3 ng/ml (6.8-100 ng/ml), respectively. The median Gleason-score for both groups was 7 (range 6-10). In BCR group, PSMA PET was reported positive in 36 (72%) patients, CT-U in 11(22%) patients and PET/CT-U in 33 (66%) patients. In PS group, PSMA PET detected the primary site in all seven patients, of which one patient with metastatic nodal disease had negative CT finding. Of 40 equivocal foci (27/57 patients) on PET, 11 foci (10/57 patients, 17.5%) were localized to enhanced urine on PET/CT-U, hence considered of potential benefit in interpretation. Of those, 3 foci (3 patients) were solitary sites of activity on PSMA imaging including two local and one nodal site and 4 foci (3 patients) were in different nodal fields. CONCLUSIONS: PET/CT-U protocol is a practical approach and may assist in interpretation of 68Ga-PSMA-11 imaging by delineation of the contrast opacified genitourinary system and matching focal PSMA activity with urinary contrast. PMID- 29268785 TI - Prevalence of bovine subclinical mastitis and isolation of its major causes in Bishoftu Town, Ethiopia. AB - OBJECTIVE: A cross-sectional study was conducted from November 2015 to March 2016 to estimate the prevalence, to assess the risk factors and to isolate the major etiological agent of subclinical mastitis in Bishoftu town. The study was conducted on 262 cross breed lactating cows selected from 12 intensively managed dairy farms. California mastitis test (CMT) and bacteriological culture methods were used as diagnostic tools. RESULT: From 262 cows examined, 105 (40.1%) and from 1048 quarters examined, 170 (16.1%) were positive for sub-clinical mastitis using CMT. All CMT positive samples were cultured for etiological agent identification. From 170 samples cultured, 153 were positive for known subclinical mastitis pathogens. The dominant bacteria isolated were Staphylococcus species from these Staphylococcus aureus (44.9%) was the major one followed by Streptococcus spp. (25.3%) and other gram negative enteric bacteria, Escherichia coli (8.8%). Age, body condition score, milk yield, and number of parity were considered as potential risk factors; among these, age and number of parity have statistically significance association with the occurrence of subclinical mastitis (P < 0.05) both in the CMT and the bacteriological tests. PMID- 29268786 TI - Does being a retired or employed caregiver affect the association between behaviours in Alzheimer's disease and caregivers' health-related quality-of-life? AB - OBJECTIVE: We examined whether caregivers' employment status (i.e., retired or employed) might modify the association between the behaviours of persons with Alzheimer's disease (PwAD) and caregivers' health-related quality-of-life (HRQoL). Data came from a cross-sectional study of the primary informal caregivers of 200 persons with mild or moderate Alzheimer's disease. Caregivers completed the EQ-5D-3L to rate their HRQoL and generate health utility scores, and the Dementia Behaviour Disturbance Scale (DBDS) to assess the degree to which PwAD exhibited each of 28 behaviours. Caregivers' health utility scores were regressed on overall DBDS scores, with caregiver employment status (retired, employed) treated as an effect modifier and confounder in separate regression models. We also controlled for age, sex, income, education, caregivers' relationship to the PwAD, and whether caregivers gave up paid employment/cut down working hours to care for PwAD. RESULTS: Effect modification by caregiver employment status is possible, with the inverse association between DBDS score and health utility score largely existing for retired versus employed caregivers. Research using larger samples and longitudinal data would further inform this area of inquiry. PMID- 29268787 TI - Salmonella enterica serovar Choleraesuis vector delivering SaoA antigen confers protection against Streptococcus suis serotypes 2 and 7 in mice and pigs. AB - Streptococcus suis is one of the major pathogens that cause economic losses in the swine industry worldwide. However, current bacterins only provide limited prophylactic protection in the field. An ideal vaccine against S. suis should protect pigs against the clinical diseases caused by multiple serotypes, or at least protect against the dominant serotype in a given geographic region. A new recombinant Salmonella enterica serotype Choleraesuis vaccine vector, rSC0011, that is based on the regulated delayed attenuation system and regulated delayed antigen synthesis system, was developed recently. In this study, an improved recombinant attenuated Salmonella Choleraesuis vector, rSC0016, was developed by incorporating a sopB mutation to ensure adequate safety and maximal immunogenicity. In the spleens of mice, rSC0016 colonized less than rSC0011. rSC0016 and rSC0011 colonized similarly in Peyer's patches of mice. The recombinant vaccine rSC0016(pS-SaoA) induced stronger cellular, humoral, and mucosal immune responses in mice and swine against SaoA, a conserved surface protein that is present in many S. suis serotypes, than did rSC0011(pS-SaoA) without sopB or rSC0018(pS-SaoA), which is an avirulent, chemically attenuated vaccine strain. rSC0016(pS-SaoA) provided 100% protection against S. suis serotype 2 in mice and pigs, and full cross-protection against SS7 in pigs. This new vaccine vector provides a foundation for the development of a universal vaccine against multiple serotypes of S. suis in pigs. PMID- 29268788 TI - Prevalence and associated factors influencing stunting in children aged 2-5 years in the Gaza Strip-Palestine: a cross-sectional study. AB - BACKGROUND: Stunting continues to be a major public health problem in developing countries. It is one of the most important risk factors for morbidity and mortality during childhood. In Palestine, it is another health problem, which adds to the catastrophic issues in the region. This study aimed to determine the prevalence of stunting and its associated factors among preschool children in the Gaza Strip. METHODS: A cross-sectional study design was conducted in the Gaza Strip. A total of 357 children aged 2-5 years and their mothers aged 18-50 years were recruited. A multistage cluster sampling was used in the selection of the study participants from three geographical areas in the Gaza Strip: Jabalia refugee camp, El Remal urban area, and Al Qarara rural area. A structured questionnaire was used for face- to -face interviews with the respective child's mother to collect sociodemographic information and feeding practice. Anthropometric measurements for children were taken to classify height-for-age (HAZ), while maternal height was measured as well. Descriptive and binary logistic regression analyses were applied to determine the prevalence and associated factors with stunting. RESULTS: The total prevalence of stunting in this study was 19.6%, with the highest prevalence being (22.6%) in Jabalia refugee camp. It turns out that shorter mothers had increased the odds of stunting in preschool children in the Gaza Strip. Children born to mothers whose height was 1.55-1.60 m or <1.55 m were more likely to be stunted (p = 0. 008), or (p < 0.001), respectively, than children born to mothers whose height was >1.60 m. Moreover, parental consanguinity increased the risk of stunted children (p = 0. 015). CONCLUSIONS: This study showed the prevalence of stunting was of alarming magnitude in the Gaza Strip. Our results also demonstrated that parental consanguinity and short maternal stature were associated with stunting. Culturally appropriate interventions and appropriate strategies should be implemented to discourage these types of marriages. Policy makers must also raise awareness of the importance of the prevention and control of nutritional problems to combat stunting among children in the Gaza Strip. PMID- 29268790 TI - OptPipe - a pipeline for optimizing metabolic engineering targets. AB - BACKGROUND: We propose OptPipe - a Pipeline for Optimizing Metabolic Engineering Targets, based on a consensus approach. The method generates consensus hypotheses for metabolic engineering applications by combining several optimization solutions obtained from distinct algorithms. The solutions are ranked according to several objectives, such as biomass and target production, by using the rank product tests corrected for multiple comparisons. RESULTS: OptPipe was applied in a genome-scale model of Corynebacterium glutamicum for maximizing malonyl-CoA, which is a valuable precursor for many phenolic compounds. In vivo experimental validation confirmed increased malonyl-CoA level in case of DeltasdhCAB deletion, as predicted in silico. CONCLUSIONS: A method was developed to combine the optimization solutions provided by common knockout prediction procedures and rank the suggested mutants according to the expected growth rate, production and a new adaptability measure. The implementation of the pipeline along with the complete documentation is freely available at https://github.com/AndrasHartmann/OptPipe . PMID- 29268789 TI - The malaria testing and treatment landscape in Kenya: results from a nationally representative survey among the public and private sector in 2016. AB - BACKGROUND: Since 2004, Kenya's national malaria treatment guidelines have stipulated artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria, and since 2014, confirmatory diagnosis of malaria in all cases before treatment has been recommended. A number of strategies to support national guidelines have been implemented in the public and private sectors in recent years. A nationally-representative malaria outlet survey, implemented across four epidemiological zones, was conducted between June and August 2016 to provide practical evidence to inform strategies and policies in Kenya towards achieving national malaria control goals. RESULTS: A total of 17,852 outlets were screened and 2271 outlets were eligible and interviewed. 78.3% of all screened public health facilities stocked both malaria diagnostic testing and quality-assured ACT (QAACT). Sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy was available in 70% of public health facilities in endemic areas where it is recommended for treatment. SP was rarely found in the public sector outside of the endemic areas (< 0.5%). The anti malaria stocking private sector had lower levels of QAACT (46.7%) and malaria blood testing (20.8%) availability but accounted for majority of anti-malarial distribution (70.6% of the national market share). More than 40% of anti malarials were distributed by unregistered pharmacies (37.3%) and general retailers (7.1%). QAACT accounted for 58.2% of the total anti-malarial market share, while market share for non-QAACT was 15.8% and for SP, 24.8%. In endemic areas, 74.9% of anti-malarials distributed were QAACT. Elsewhere, QAACT market share was 49.4% in the endemic-prone areas, 33.2% in seasonal-transmission areas and 37.9% in low-risk areas. CONCLUSION: Although public sector availability of QAACT and malaria diagnosis is relatively high, there is a gap in availability of both testing and treatment that must be addressed. The private sector in Kenya, where the majority of anti-malarials are distributed, is also critical for achieving universal coverage with appropriate malaria case management. There is need for a renewed commitment and effective strategies to ensure access to affordable QAACT and confirmatory testing in the private sector, and should consider how to address malaria case management among informal providers responsible for a substantial proportion of the anti-malarial market share. PMID- 29268791 TI - A novel Ffu fusion system for secretory expression of heterologous proteins in Escherichia coli. AB - BACKGROUND: The high level of excretion and rapid folding ability of beta fructofuranosidase (beta-FFase) in Escherichia coli has suggested that beta-FFase from Arthrobacter arilaitensis NJEM01 can be developed as a fusion partner. METHODS: Based on the modified Wilkinson and Harrison algorithm and the preliminary verification of the solubility-enhancing ability of beta-FFase truncations, three beta-FFase truncations (i.e., Ffu209, Ffu217, and Ffu312) with a native signal peptide were selected as novel Ffu fusion tags. Four difficult-to express protein models; i.e., CARDS TX, VEGFR-2, RVs and Omp85 were used in the assessment of Ffu fusion tags. RESULTS: The expression levels and solubility of each protein were markedly enhanced by the Ffu fusion system. Each protein had a favorable Ffu tag. The Ffu fusion tags performed preferably when compared with the well-known fusion tags MBP and NusA. Strikingly, it was confirmed that Ffu fusion proteins were secreted into the periplasm by the periplasmic analysis and N-amino acid sequence analysis. Further, efficient excretion of HV3 with defined anti-thrombin activity was obtained when it was fused with the Ffu312 tag. Moreover, HV3 remained soluble and demonstrated notable anti-thrombin activity after the removal of the Ffu312 tag by enterokinase. CONCLUSIONS: Observations from this work not only complements fusion technologies, but also develops a novel and effective secretory system to solve key issues that include inclusion bodies and degradation when expressing heterologous proteins in E. coli, especially for proteins that require disulfide bond formation, eukaryotic secreted proteins, and membrane-associated proteins. PMID- 29268792 TI - Individual diseases or clustering of health conditions? Association between multiple chronic diseases and health-related quality of life in adults. AB - BACKGROUND: Chronic diseases are highly prevalent and cluster in individuals (multimorbidity). This study investigated the association between multimorbidity and Health-Related Quality of Life (HRQoL), assessing the combination of chronic diseases highly correlated with this outcome. METHODS: We conducted a household survey in 2015 in a random sample of 2912 South Australian adults (48.9 +/- 18.1 years; 50.9% females), obtaining information on sociodemographics, lifestyle, and 17 chronic conditions clustered in four different groups (metabolic, cardiovascular, gastrointestinal, and musculoskeletal). Information on physical (PCS) and mental components scores (MCS) of HRQoL were assessed using the SF-12 questionnaire. Multivariable linear regression models considering individual diseases (mutually adjusted) and clusters within- and between-groups were used to test the associations. RESULTS: Only 41% of the sample was negative for all the investigated diseases. The most prevalent conditions were osteoarthritis, obesity and hypertension, which affected one in every four individuals. PCS was markedly lower among those reporting stroke, heart failure, and osteoarthritis, but they were not associated with MCS. Direct-trend relationships were observed between the number of chronic conditions (clusters within- and between-groups) and PCS, but not with MCS. The strongest association with PCS was for musculoskeletal conditions (difference between those affected by 2+ conditions and those free of these conditions -6.7 95%CI -8.5;-5.4), and lower PCS were observed in any combination of clusters between-group including musculoskeletal diseases. CONCLUSION: In the context of multimorbidity, musculoskeletal diseases are a key determinant group of PCS, amplifying the association of other chronic conditions on physical but not on mental health. PMID- 29268794 TI - Multivariable regression analysis of list experiment data on abortion: results from a large, randomly-selected population based study in Liberia. AB - BACKGROUND: The list experiment is a promising measurement tool for eliciting truthful responses to stigmatized or sensitive health behaviors. However, investigators may be hesitant to adopt the method due to previously untestable assumptions and the perceived inability to conduct multivariable analysis. With a recently developed statistical test that can detect the presence of a design effect - the absence of which is a central assumption of the list experiment method - we sought to test the validity of a list experiment conducted on self reported abortion in Liberia. We also aim to introduce recently developed multivariable regression estimators for the analysis of list experiment data, to explore relationships between respondent characteristics and having had an abortion - an important component of understanding the experiences of women who have abortions. METHODS: To test the null hypothesis of no design effect in the Liberian list experiment data, we calculated the percentage of each respondent "type," characterized by response to the control items, and compared these percentages across treatment and control groups with a Bonferroni-adjusted alpha criterion. We then implemented two least squares and two maximum likelihood models (four total), each representing different bias-variance trade-offs, to estimate the association between respondent characteristics and abortion. RESULTS: We find no clear evidence of a design effect in list experiment data from Liberia (p = 0.18), affirming the first key assumption of the method. Multivariable analyses suggest a negative association between education and history of abortion. The retrospective nature of measuring lifetime experience of abortion, however, complicates interpretation of results, as the timing and safety of a respondent's abortion may have influenced her ability to pursue an education. CONCLUSION: Our work demonstrates that multivariable analyses, as well as statistical testing of a key design assumption, are possible with list experiment data, although with important limitations when considering lifetime measures. We outline how to implement this methodology with list experiment data in future research. PMID- 29268793 TI - Selection strategy of phage-displayed immunogens based on an in vitro evaluation of the Th1 response of PBMCs and their potential use as a vaccine against Leishmania infantum infection. AB - BACKGROUND: The development of a vaccine for the prevention of visceral leishmaniasis (VL) still represents a significant unmet medical need. A human vaccine can be found if one takes into consideration that many people living in endemic areas of disease are infected but do not develop active VL, including those subjects with subclinical or asymptomatic infection. METHODS: In this study, a phage display was used to select phage-exposed peptides that were specific to immunoglobulin G (IgG) antibodies from asymptomatic and symptomatic VL patients, separating them from non-infected subjects. Phage clones presenting valid peptide sequences were selected and used as stimuli of peripheral blood mononuclear cells (PBMCs) obtained from both patients' groups and controls. Those with higher interferon-gamma (IFN-gamma)/interleukin (IL)-10 ratios were further selected for vaccination tests. RESULTS: Among 17 evaluated clones, two were selected, B1 and D11, and used to immunize BALB/c mice in an attempt to further validate their in vivo protective efficacy against Leishmania infantum infection. Both clones induced partial protection against the parasite challenge, which was evidenced by the reduction of parasitism in the evaluated organs, a process mediated by a specific T helper (Th)1 immune response. CONCLUSIONS: To the best of our knowledge, this study is the first to use a rational strategy based on in vitro stimulation of human PBMCs with selected phage-displayed clones to obtain new immunogens against VL. PMID- 29268795 TI - Disease evolution in mixed connective tissue disease: results from a long-term nationwide prospective cohort study. AB - BACKGROUND: The phenotypic stability of mixed connective tissue disease (MCTD) is not clear, and knowledge about disease activity and remission is scarce. We aimed to establish the occurrence of evolution from MCTD to another defined rheumatic condition, and the prevalence and durability of remission after long-term observation. METHODS: In this large population-based prospective observational MCTD cohort study (N = 118), disease conversion was defined by the development of new auto-antibodies and clinical features compliant with another well-defined rheumatic condition. Remission was defined by a combination of systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K) of 0 and European League Against Rheumatism scleroderma trials and research (EUSTAR) activity index <2.5. Predictors of phenotypic stability and disease remission were assessed by logistic regression. RESULTS: Among 118 patients, 14 (12%) developed another well defined rheumatic condition other than MCTD after mean disease duration of 17 (SD 9) years. Puffy hands predicted a stable MCTD phenotype in univariable regression analysis (OR 7, CI 2-27, P = .010). Disease activity defined by SLEDAI-2 K, decreased gradually across the observation period and > 90% of patients had EUSTAR activity index <2.5. There were 13% patients in remission throughout the whole mean observation period of 7 (SD 2) years. The strongest predictor of remission was percentage of predicted higher forced vital capacity. CONCLUSIONS: Our results strengthen the view of MCTD as a relatively stable disease entity. Long-term remission in MCTD is not frequent; however, the low SLEDAI-2 K and EUSTAR scores during the observation period suggests that the disease runs a milder course than systemic lupus erythematosus and systemic sclerosis. PMID- 29268796 TI - The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer. AB - BACKGROUND: Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence. METHODS: We analyzed 699 cancerous and non-cancerous tissues using a methylation array or reduced representation bisulfite sequencing to discover the most specific OC methylation patterns. A three-DNA-methylation-serum-marker panel was developed using targeted ultra-high coverage bisulfite sequencing in 151 women and validated in 250 women with various conditions, particularly in those associated with high CA125 levels (endometriosis and other benign pelvic masses), serial samples from 25 patients undergoing neoadjuvant chemotherapy, and a nested case control study of 172 UKCTOCS control arm participants which included serum samples up to two years before OC diagnosis. RESULTS: The cell-free DNA amount and average fragment size in the serum samples was up to ten times higher than average published values (based on samples that were immediately processed) due to leakage of DNA from white blood cells owing to delayed time to serum separation. Despite this, the marker panel discriminated high grade serous OC patients from healthy women or patients with a benign pelvic mass with specificity/sensitivity of 90.7% (95% confidence interval [CI] = 84.3-94.8%) and 41.4% (95% CI = 24.1-60.9%), respectively. Levels of all three markers plummeted after exposure to chemotherapy and correctly identified 78% and 86% responders and non-responders (Fisher's exact test, p = 0.04), respectively, which was superior to a CA125 cut off of 35 IU/mL (20% and 75%). 57.9% (95% CI 34.0-78.9%) of women who developed OC within two years of sample collection were identified with a specificity of 88.1% (95% CI = 77.3-94.3%). Sensitivity and specificity improved further when specifically analyzing CA125 negative samples only (63.6% and 87.5%, respectively). CONCLUSIONS: Our data suggest that DNA methylation patterns in cell-free DNA have the potential to detect a proportion of OCs up to two years in advance of diagnosis and may potentially guide personalized treatment. The prospective use of novel collection vials, which stabilize blood cells and reduce background DNA contamination in serum/plasma samples, will facilitate clinical implementation of liquid biopsy analyses. PMID- 29268797 TI - The unresolved problem of beta-2 microglobulin amyloid deposits in the intervertebral discs of long-term dialysis patients. AB - BACKGROUND: Dialysis-related destructive spondyloarthropathy caused by beta-2 microglobulin (beta2M) amyloid deposits in intervertebral discs is a major burden for patients undergoing long-term dialysis. This study aimed to quantify the presence of beta2M amyloid deposits in the intervertebral disc tissue of such patients and analyze whether there was a significant correlation between beta2M accumulation and the duration of dialysis. METHODS: Two groups of patients who had undergone surgery for degenerative spinal pathologies were selected: the dialysis group (n = 29) with long-term dialysis and the control group (n = 10) with no renal impairment. Tissue sections were prepared from specimens of intervertebral disc tissue obtained during spinal surgery and analyzed via histological staining, including immunohistochemistry (IHC) and Congo red. RESULTS: There was a statistically significant multifold increase of beta2M expression in the disc tissue of long-term dialysis patients when compared to non dialysis patients, as shown by both IHC (0.019 +/- 0.023 MUm2 vs. 0.00020 +/- 0.00033 MUm2, respectively; p = 0.012) and Congo red staining (0.027 +/- 0.041 MUm2 vs. 9.240 * 10-5 +/- 5.261 * 10-5 MUm2, respectively; p = 0.047). We also note a moderate strength positive correlation between the duration of dialysis and positive IHC (r = 0.39; p = 0.015) and Congo-red staining (r = 0.42; p = 0.007). CONCLUSIONS: The problem of beta2M amyloidosis in long-term dialysis patients remains unresolved even with predominant use of high-flux dialysis membranes. This highlights the insufficiency of current dialysis modalities to effectively filter beta2M. PMID- 29268798 TI - Impact of I/D polymorphism of angiotensin-converting enzyme (ACE) gene on myocardial infarction susceptibility among young Moroccan patients. AB - OBJECTIVE: Our case-control study aimed to access the potential association of insertion/deletion (I/D) ACE (angiotensin converting enzyme) gene polymorphism with myocardial infarction (MI) risk of occurrence among a sample of Moroccan patients, especially young ones. RESULTS: Distribution of I/D ACE gene variant among cases vs controls, showed that healthy controls carried out higher frequency of wild type allele I compared to cases (23.5% vs 21.79% respectively), when cases were carrying higher frequency of mutant allele D (78.21% vs 76.5% for controls). Patients were-after this- divided into two groups of < 45 and > 55 years of age, to investigate whether or not younger patients carried out higher frequency of the mutant allele D, than older ones. As expected, < 45 years old patients carried out more DD genotype than older ones (68.9% vs 54.6% respectively), and higher frequency of mutant allele D (81.08% vs 75% respectively). Besides, a tendency to a positive association was found under the recessive genetic transmission model (OR [95% CI] = 1.85 [0.93-3.69], P = 0.08), suggesting that the I/D ACE polymorphism may be associated with MI occurrence among younger patients (< 45 years of age). PMID- 29268800 TI - Dietary soya protein improves intra-myocardial lipid deposition and altered glucose metabolism in a hypertensive, dyslipidaemic, insulin-resistant rat model. AB - This study investigates the effects of replacing dietary casein by soya protein on the underlying mechanisms involved in the impaired metabolic fate of glucose and lipid metabolisms in the heart of dyslipidaemic rats chronically fed (8 months) a sucrose-rich (62.5 %) diet (SRD). To test this hypothesis, Wistar rats were fed an SRD for 4 months. From months 4 to 8, half the animals continued with the SRD and the other half were fed an SRD in which casein was substituted by soya. The control group received a diet with maize starch as the carbohydrate source. Compared with the SRD-fed group, the following results were obtained. First, soya protein significantly (P<0.001) reduced the plasma NEFA levels and normalised dyslipidaemia and glucose homoeostasis, improving insulin resistance. The protein levels of fatty acid translocase at basal state and under insulin stimulation and the protein levels and activity of muscle-type carnitine palmitoyltransferase 1 were normalised. Second, a significant (P<0.001) reduction of TAG, long-chain acyl CoA and diacylglycerol levels was observed in the heart muscle. Third, soya protein significantly increased (P<0.01) GLUT4 protein level under insulin stimulation and normalised glucose phosphorylation and oxidation. A reduction of phosphorylated AMP protein kinase protein level was recorded without changes in uncoupling protein 2 and PPARalpha. Fourth, hydroxyproline concentration decreased in the left ventricle and hypertension was normalised. The new information provided shows the beneficial effects of soya protein upon the altered pathways of glucose and lipid metabolism in the heart muscle of this rat model. PMID- 29268799 TI - Risk factors for bone loss in patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs. AB - OBJECTIVE: Osteoporosis is a complication of rheumatoid arthritis. We examined the risk factors for bone loss in rheumatoid arthritis patients receiving biological disease-modifying anti-rheumatic drugs. Lumbar spine and femoral neck bone mineral density was measured at two time points in 153 patients with rheumatoid arthritis managed with biological disease-modifying anti-rheumatic drugs. We examined patients' variables to identify risk factors for least significant reduction of bone mineral density. RESULTS: Least significant reduction of lumbar spine bone mineral density (<= - 2.4%) was seen in 13.1% of patients. Least significant reduction of femoral neck bone mineral density (<= - 1.9%) was seen in 34.0% of patients. Multiple logistic regression analysis showed that a risk factor for least significant reduction of the lumbar spine was high dose methylprednisolone use. Multiple regression analysis showed that a risk factor for least significant reduction of the femoral neck was short disease duration. Our findings showed that a risk factor for femoral neck bone mineral density reduction was a short disease duration. These findings suggest that rheumatoid arthritis patients receiving treatment with biological disease modifying anti-rheumatic drugs may benefit from earlier osteoporosis treatments to prevent femoral neck bone loss. PMID- 29268801 TI - Is user involvement a reality or a dream in LMICs - as well as in the rest of the world? PMID- 29268802 TI - 'Welzijn op Recept' (Social Prescribing): a helping hand in re-establishing social contacts - an explorative qualitative study. AB - 'Welzijn op Recept' is an intervention in which primary care providers refer patients with psychosocial problems to a community well-being organisation. Welzijn op Recept has been helping participants in the town of Nieuwegein, the Netherlands for more than three years. An impact study was carried out from September to December 2014. The qualitative study aimed to determine what happens in the chain of the social prescription and what changes the participant experiences in terms of social participation. The participants in this study were selected by the well-being coaches. A total of 10 semi-structured in-depth interviews were conducted. This study has shown that the participants had confidence in their referral to the community well-being organisation. The well being coaches constitute a link between primary care providers, patients and the community well-being organisation. Participants have explicitly indicated that they experienced an increase in their own strength, self-confidence, self reliance and the number of social contacts, and stated that they are experiencing better health. A point of special interest in the current programme is the planning of structured follow-up interviews after starting up an activity. PMID- 29268803 TI - Genomic dissection and prediction of feed intake and residual feed intake traits using a longitudinal model in F2 chickens. AB - Feed efficiency traits (FETs) are important economic indicators in poultry production. Because feed intake (FI) is a time-dependent variable, longitudinal models can provide insights into the genetic basis of FET variation over time. It is expected that the application of longitudinal models as part of genome-wide association (GWA) and genomic selection (i.e. genome-wide selection (GS)) studies will lead to an increase in accuracy of selection. Thus, the objectives of this study were to evaluate the accuracy of estimated breeding values (EBVs) based on pedigree as well as high-density single nucleotide polymorphism (SNP) genotypes, and to conduct a GWA study on longitudinal FI and residual feed intake (RFI) in a total of 312 chickens with phenotype and genotype in the F2 population. The GWA and GS studies reported in this paper were conducted using beta-spline random regression models for FI and RFI traits in a chicken F2 population, with FI and BW recorded for each bird weekly between 2 and 10 weeks of age. A single SNP regression approach was used on spline coefficients for weekly FI and RFI traits, with results showing that two significant SNPs for FI occur in the synuclein (SNCAIP) gene. Results also show that these regions are significantly associated with the spline coefficients (q 2) for 5- and 6-week-old birds, while GWA study results showed no SNP association with RFI in F2 chickens. Estimated breeding value predictions obtained using a pedigree-based best linear unbiased prediction (ABLUP) model were then compared with predictions based on genomic best linear unbiased prediction (GBLUP). The accuracy was measured as correlation between genomic EBV and EBV with the phenotypic value corrected for fixed effects divided by the square root of heritability. The regression of observed on predicted values was used to estimate bias of methods. Results show that prediction accuracies using GBLUP and ABLUP for the FI measured from 2nd to 10th week were between 0.06 and 0.46 and 0.03 and 0.37, respectively. These results demonstrate that genomic methods are able to increase the accuracy of predicted breeding values at later ages on the basis of both traits, and indicate that use of a longitudinal model can improve selection accuracy for the trajectory of traits in F2 chickens when compared with conventional methods. PMID- 29268804 TI - Morphological, biometrical and molecular characterization of Archaeopsylla erinacei (Bouche, 1835). AB - In the present work, we carried out a morphological, biometrical and molecular study of the species Archaeopsylla erinacei (Bouche, 1835) and their subspecies: Archaeopsylla erinacei erinacei (Bouche, 1835) and Archaeopsylla erinacei maura (Jordan & Rothschild, 1912) isolated from hedgehogs (Erinaceus europaeus) from different geographical regions (Seville and Corse). We have found morphological differences in females of A. erinacei from the same geographical origin that did not correspond with molecular differences. We suggest that some morphological characters traditionally used to discriminate females of both subspecies should be revised as well as we set the total length of the spermatheca as a valid criterion in order to discriminate between both subspecies. The Internal Transcribed Spacers 1 and 2 (ITS1, ITS2) and partial 18S rRNA gene, and partial cytochrome c-oxidase 1 (cox1) and cytochrome b (cytb) mtDNA gene sequences were determined to clarify the taxonomic status of these taxa and to assess intra specific and intra-population similarity. In addition, a phylogenetic analysis with other species of fleas using Bayesian and Maximum Likelihood analysis was performed. All molecular markers used, except 18S, showed molecular differences between populations corresponding with geographical origins. Thus, based on the phylogenetic and molecular study of two nuclear markers (ITS1, ITS2) and two mitochondrial markers (cox1 and cytb), as well as concatenated sequences of both subspecies, we reported the existence of two geographical genetic lineages in A. erinacei corresponding with two different subspecies: A. e. erinacei (Corse, France) and A. e. maura (Seville, Spain), that could be discriminated by polymerase chain reaction-linked random-fragment-length polymorphism. PMID- 29268805 TI - Suboptimal infant and young child feeding practices among internally displaced persons during conflict in eastern Ukraine. AB - OBJECTIVE: To determine current status, areas for improvement and effect of conflict on infant and young child feeding (IYCF) practices among internally displaced persons (IDP) in eastern Ukraine. DESIGN: Cross-sectional household survey, June 2015. SETTING: Kharkiv, Dnipropetrovsk and Zaporizhia oblasts (Ukrainian administrative divisions) bordering conflict area in Ukraine. SUBJECTS: Randomly selected IDP households with children aged <2 years registered with local non-governmental organizations. Questions based on the WHO IYCF assessment questionnaire were asked for 477 children. Mid-upper arm circumference was measured in 411 children aged 6-23 months. RESULTS: Exclusive breast-feeding prevalence for infants aged <6 months was 25.8 (95 % CI 15.8, 38.0) %. Percentage of mothers continuing breast-feeding when their child was aged 1 and 2 years was 53.5 (95 % CI 43.2, 63.6) % and 20.6 (95 % CI 11.5, 32.7) %, respectively. Bottle feeding was common for children aged <2 years (68.1 %; 95 % CI 63.7, 72.3 %). Almost all infants aged 6-8 months received solid foods (98.6 %; 95 % CI 88.5, 99.9 %). Mothers who discontinued breast-feeding before their infant was 6 months old more often listed stress related to conflict as their primary reason for discontinuation (45.7 %) compared with mothers who discontinued breast-feeding when their child was aged 6-23 months (14.3 %; P<0.0001). CONCLUSIONS: To mitigate the effects of conflict and improve child health, humanitarian action is needed focused on helping mothers cope with stress related to conflict and displacement while supporting women to adhere to recommended IYCF practices if possible and providing appropriate support to women when adherence is not feasible. PMID- 29268806 TI - Effect of the dietary delivery matrix on vitamin D3 bioavailability and bone mineralisation in vitamin-D3-deficient growing male rats. AB - This study assessed bioavailability and utilisation of vitamin D3 in two feeding trials using young, growing Sprague-Dawley male rats. Trial one fed animals standard AIN-93G diet (casein protein) containing no vitamin D3 and goat or cow skimmed milk supplemented with vitamin D3. Trial two fed animals modified dairy free AIN-93G diet (egg albumin) containing no vitamin D3 and goat or cow skimmed or full-fat milk supplemented with vitamin D3. Control groups received AIN-93G diets with or without vitamin D, and water. At 8 weeks of age, blood samples were collected for vitamin and mineral analysis, and femurs and spines were collected for assessment of bone mineralisation and strength. In both trials, analyses showed differences in bioavailability of vitamin D3, with ratios of serum 25 hydroxyvitamin D3 to vitamin D3 intake more than 2-fold higher in groups drinking supplemented milk compared with groups fed supplemented solid food. Bone mineralisation was higher in groups drinking supplemented milk compared with groups fed supplemented solid food, for both trials (P<0.05). There was no difference in the parameters tested between skimmed milk and full-fat milk or between cow milk and goat milk. Comparison of the two trials suggested that dietary protein source promoted bone mineralisation in a growing rat model: modified AIN-93G with egg albumin produced lower bone mineralisation compared with standard AIN-93G with casein. Overall, this study showed that effects of vitamin D3 deficiency in solid diets were reversed by offering milk supplemented with vitamin D3, and suggests that using milk as a vehicle to deliver vitamin D is advantageous. PMID- 29268807 TI - Energy intake in short bowel syndrome: assessment by 24-h dietary recalls compared with the doubly labelled water method. AB - Short bowel syndrome (SBS) represents a serious intestinal absorption disorder, and patients may be prone to severe malnutrition. Dietetic therapy is critically important both for immediate prognosis and successful long-term rehabilitation. To maintain energy balance, an accurate assessment of energy intake is required. Our objective was to compare energy intake (EI) assessed by 24-h dietary recalls (EIrecall), a standard clinical assessment, with the total energy expenditure measured by the doubly labelled water (TEEdlw) method in SBS patients and matched controls. A total of twenty-two participants (eleven each in the SBS and control groups (CG), six female and five male) were evaluated; CG were matched to SBS patients on the basis of age, BMI and sex. TEE was measured by DLW and compared with EI determined by four 24-h dietary recalls using the USDA Automated Multiple Pass Method. Bland-Altman plots and paired Student's t test were used to compare EIrecall with TEEdlw (P<0.05). Participants' mean age was 53 (sd 8) years. TEEdlw (7.85 (SD 1.16) MJ/d, 0.14 (SD 0.02) MJ/kg per d) was significantly lower (P=0.014) compared with EIrecall (11.07 (SD 3.45) MJ/d, 0.21 (SD 0.08) MJ/kg per d) in the SBS group. On the other hand, in the CG group TEEdlw (10.02 (SD 1.86) MJ/d, 0.18 (SD 0.03) MJ/kg per d) was significantly higher (P=0.001) compared with EIrecall (7.19 (SD 1.68) MJ/d, 0.13 (SD 0.03) MJ/kg per d). In SBS patients, reported EI is higher than DLW-measured EI. Therefore, providing or prescribing energetic intake based on EIrecall without accounting for potential malabsorption related losses can compromise the energy needs in SBS patients and affect nutritional status in the long term. PMID- 29268808 TI - Urban and rural dietary patterns are associated with anthropometric and biochemical indicators of nutritional status of adolescent Mozambican girls. AB - OBJECTIVE: The objective of the present study was to explore whether dietary patterns (DP) are associated with nutritional status indicators among adolescent Mozambican girls. Design/Setting/Subjects In this population-based cross sectional study we used the FFQ data of 547 girls aged 14-19 years from Central Mozambique to derive dietary patterns by means of principal component analysis. We used two-level linear regression models to examine the associations between the DP and anthropometric and biochemical indicators of nutritional status. RESULTS: We identified three DP: 'Urban bread and fats', 'Rural meat and vegetables' and 'Rural cassava and coconut'. The 'Urban bread and fats' DP was positively associated with BMI-for-age Z-score (BMIZ), mid-upper arm circumference (MUAC), triceps skinfold (P for all<0.001) and blood Hb (P=0.025). A negative association was observed between the 'Urban bread and fats' DP and serum folate (P<0.001). The 'Rural meat and vegetables' DP and the 'Rural cassava and coconut' DP were associated negatively with BMIZ, MUAC and triceps skinfold (P for all<0.05), but the 'Rural meat and vegetables' DP was associated positively with serum ferritin (P=0.007). CONCLUSIONS: Urban and rural DP were associated with nutritional status indicators. In a low-resource setting, urban diets may promote body fat storage and blood Hb concentrations but compromise serum folate concentration. It is important to continue valuing the traditional, rural foods that are high in folate. PMID- 29268809 TI - Prevalence of personality disorders in patients with fibromyalgia: a brief review. AB - Fibromyalgia (FM) is a complex musculoskeletal pain disorder characterized by widespread pain, fatigue, and other functional symptoms. Patients with FM are frequently affected by psychiatric disorders. Clinicians typically observe certain personality characteristics or traits associated with FM, but there is still a lack of studies about personality disorders (PDs) in patients with FM. Aim of our brief review is to summarize the literature to date on prevalence of PDs in FM. We searched the PubMed electronic database for all articles up to 1 February 2017, and identified a number of reports about prevalence of PDs in patients with FM. Most of studies show that the proportion of PDs diagnosed in patients with FM appears far greater than that found in the general population. We suggest that is very useful to evaluate PDs in patients with FM systematically, in order to improve the understanding, assessment, and treatment of this clinical condition. PMID- 29268810 TI - Genetic correlations between yield traits or days open measured in cows and semen production traits measured in bulls. AB - We used a bivariate animal model to investigate the genetic correlations between yield traits or days open (DO) as characters measured in cows and semen production traits as characters measured in bulls. Lactation records of 305-day milk, fat, and protein yields, and DO, from 386 809 first-lactation Holstein cows in Hokkaido, Japan, that calved between 2008 and 2014 were used. Semen production records were collected between 2005 and 2014 and included volume per ejaculate (VOL), sperm concentration (CON), number of sperm per ejaculate (NUM), progressive motility index of sperm (MOT), and MOT after freeze-thawing (A-MOT). Number of sperm per ejaculate was log-transformed into a NUM score (NUMS). A total of 30 373 semen production records from 1196 bulls were obtained. The pedigree file used for analysing the records was involving 885 345 animals. Heritability was estimated for VOL (0.42), CON (0.12), NUMS (0.37), MOT (0.08), and A-MOT (0.11). Weak and negative genetic correlations were recorded between yield traits measured in cows and VOL, CON or NUMS measured in bulls. Moderate and negative genetic correlations were obtained between DO and MOT (-0.42) or A MOT (-0.43). Selection focused on MOT or A-MOT measured in bulls may therefore improve DO measured in cows. PMID- 29268811 TI - Childhood adversity and cognitive function in schizophrenia spectrum disorders and healthy controls: evidence for an association between neglect and social cognition. AB - BACKGROUND: Childhood adversity is associated with cognitive impairments in schizophrenia. However, findings to date are inconsistent and little is known about the relationship between social cognition and childhood trauma. We investigated the relationship between childhood abuse and neglect and cognitive function in patients with a first-episode of schizophrenia or schizophreniform disorder (n = 56) and matched healthy controls (n = 52). To the best of our knowledge, this is the first study assessing this relationship in patients and controls exposed to similarly high levels of trauma. METHODS: Pearson correlational coefficients were used to assess correlations between Childhood Trauma Questionnaire abuse and neglect scores and cognition. For the MCCB domains displaying significant (p < 0.05) correlations, within group hierarchical linear regression, was done to assess whether abuse and neglect were significant predictors of cognition after controlling for the effect of education. RESULTS: Patients and controls reported similarly high levels of abuse and neglect. Cognitive performance was poorer for patients compared with controls for all cognitive domains except working memory and social cognition. After controlling for education, exposure to childhood neglect remained a significant predictor of impairment in social cognition in both patients and controls. Neglect was also a significant predictor of poorer verbal learning in patients and of attention/vigilance in controls. However, childhood abuse did not significantly predict cognitive impairments in either patients or controls. CONCLUSION: These findings are cross sectional and do not infer causality. Nonetheless, they indicate that associations between one type of childhood adversity (i.e. neglect) and social cognition are present and are not illness-specific. PMID- 29268813 TI - Attitudes of medical doctors and nurses towards the role of the nurses in the primary care unit in Italy. AB - : AimAim of the present study was to assess the knowledge of the potential role of nurses in the primary care setting and to analyse the attitudes towards their utilization by nurses and General Practitioners (GPs) in a region of Italy. BACKGROUND: Nowadays, in Italy, the role of the nurse in primary care is still under-recognized and most primary care medical offices are managed individually by a physician. METHODS: The study consists of a questionnaire-based cross sectional survey carried out in Piedmont, Italy, between February and September 2015.FindingsWe included 105 participants, 57 nurses and 48 physicians. The presence of a nurse working together with the GP was defined as 'useful' by 54.4% of nurses (versus 60.4% of physicians), as 'essential' by 45.6% of nurses (versus 25.0% of physicians), as 'marginal' by no nurses (versus 14.6% of physicians) and as 'unimportant' by none (P=0.002). Thus, physicians seemed to be less favorable towards a full collaboration and power-sharing with nurses. Furthermore, GPs and nurses showed a different attitude towards the role of nurses in primary care: while nurses highlighted their clinical value, physicians tended rather to recognize them a 'supportive' role. Moreover, only 20.8% of the physicians interviewed stated that they worked with a nurse. At the multivariate analysis, the age class resulted to be a significant predictor of the perception that the presence of a nurse working with the GP is essential: participants >50 years had an OR of 0.03 (P=0.028). Although the primary care organization appears still largely based on a traditional physician-centric care model, the positive attitude of nurses and young GPs towards a more collaborative model of primary care might represent a promising starting point. PMID- 29268814 TI - Genetic parameters for stayability to consecutive calvings in Zebu cattle. AB - Longer-lived cows tend to be more profitable and the stayability trait is a selection criterion correlated to longevity. An alternative to the traditional approach to evaluate stayability is its definition based on consecutive calvings, whose main advantage is the more accurate evaluation of young bulls. However, no study using this alternative approach has been conducted for Zebu breeds. Therefore, the objective of this study was to compare linear random regression models to fit stayability to consecutive calvings of Guzera, Nelore and Tabapua cows and to estimate genetic parameters for this trait in the respective breeds. Data up to the eighth calving were used. The models included the fixed effects of age at first calving and year-season of birth of the cow and the random effects of contemporary group, additive genetic, permanent environmental and residual. Random regressions were modeled by orthogonal Legendre polynomials of order 1 to 4 (2 to 5 coefficients) for contemporary group, additive genetic and permanent environmental effects. Using Deviance Information Criterion as the selection criterion, the model with 4 regression coefficients for each effect was the most adequate for the Nelore and Tabapua breeds and the model with 5 coefficients is recommended for the Guzera breed. For Guzera, heritabilities ranged from 0.05 to 0.08, showing a quadratic trend with a peak between the fourth and sixth calving. For the Nelore and Tabapua breeds, the estimates ranged from 0.03 to 0.07 and from 0.03 to 0.08, respectively, and increased with increasing calving number. The additive genetic correlations exhibited a similar trend among breeds and were higher for stayability between closer calvings. Even between more distant calvings (second v. eighth), stayability showed a moderate to high genetic correlation, which was 0.77, 0.57 and 0.79 for the Guzera, Nelore and Tabapua breeds, respectively. For Guzera, when the models with 4 or 5 regression coefficients were compared, the rank correlations between predicted breeding values for the intercept were always higher than 0.99, indicating the possibility of practical application of the least parameterized model. In conclusion, the model with 4 random regression coefficients is recommended for the genetic evaluation of stayability to consecutive calvings in Zebu cattle. PMID- 29268815 TI - Added sugars and sugar-sweetened beverage consumption, dietary carbohydrate index and depression risk in the Seguimiento Universidad de Navarra (SUN) Project. AB - The association between added sugars or sugar-sweetened beverage consumption and the risk of depression, as well as the role of carbohydrate quality in depression risk, remains unclear. Among 15 546 Spanish university graduates from the Seguimiento Universidad de Navarra (SUN) prospective cohort study, diet was assessed with a validated 136-item semi-quantitative FFQ at baseline and at 10 year follow-up. Cumulative average consumption of added sugars, sweetened drinks and an overall carbohydrate quality index (CQI) were calculated. A better CQI was associated with higher whole-grain consumption and fibre intake and lower glycaemic index and consumption of solid (instead of liquid) carbohydrates. Clinical diagnoses of depression during follow-up were classified as incident cases. Multivariable time-dependent Cox regression models were used to estimate hazard ratios (HR) of depression according to consumption of added sugars, sweetened drinks and CQI. We observed 769 incident cases of depression. Participants in the highest quartile of added sugars consumption showed a significant increment in the risk of depression (HR=1.35; 95 % CI 1.09, 1.67, P=0.034), whereas those in the highest quartile of CQI (upper quartile of the CQI) showed a relative risk reduction of 30 % compared with those in the lowest quartile of the CQI (HR=0.70; 95 % CI 0.56, 0.88). No significant association between sugar-sweetened beverage consumption and depression risk was found. Higher added sugars and lower quality of carbohydrate consumption were associated with depression risk in the SUN Cohort. Further studies are necessary to confirm the reported results. PMID- 29268812 TI - Norovirus transmission dynamics: a modelling review. AB - Norovirus is one of the leading causes of viral gastroenteritis worldwide and responsible for substantial morbidity, mortality and healthcare costs. To further understanding of the epidemiology and control of norovirus, there has been much recent interest in describing the transmission dynamics of norovirus through mathematical models. In this study, we review the current modelling approaches for norovirus transmission. We examine the data and methods used to estimate these models that vary structurally and parametrically between different epidemiological contexts. Many of the existing studies at population level have focused on the same case notification dataset, whereas models from outbreak settings are highly specific and difficult to generalise. In this review, we explore the consistency in the description of norovirus transmission dynamics and the robustness of parameter estimates between studies. In particular, we find that there is considerable variability in estimates of key parameters such as the basic reproduction number, which may mean that the effort required to control norovirus at the population level may currently be underestimated. PMID- 29268816 TI - WITHDRAWN: Epigenetic silence of HOTAIR contributes to the metastasis of pancreatic cancer via targeting miR-138. AB - Ahead of Print article withdrawn by publisher. PMID- 29268817 TI - MYBL2 Is Targeted by miR-143-3p and Regulates Breast Cancer Cell Proliferation and Apoptosis. AB - Breast cancer remains a public health issue on a global scale. The present study aimed to explore the functional role of MYB proto-oncogene like 2 (MYBL2) in breast cancer, as well as underlying mechanisms. The regulatory relationship between miR-143-3p and MYBL2 was analyzed, and the effects of dysregulation of miR-143-3p and MYBL2 on cell proliferation and apoptosis were investigated. The results showed that MYBL2 and miR-143-3p were inversely expressed in breast cancer tissues and cells: MYBL2 was highly expressed, whereas miR-143-3p was lowly expressed. MYBL2 was confirmed as a target gene of miR-143-3p. Suppression of MYBL2 inhibited proliferation and induced apoptosis of breast cancer cells, which was similar to the effects of overexpression of miR-143-3p. Our findings reveal that MYBL2 is targeted by miR-143-3p and regulates breast cancer cell proliferation and apoptosis. PMID- 29268819 TI - Psychometric Testing of the Persian Version of the Perceived Perioperative Competence Scale-Revised. AB - The clinical competence of nursing students in operating room (OR) is an important issue in nursing education. The purpose of this study was to evaluate the psychometric properties of the Persian Perceived Perioperative Competence Scale-Revised (PPCS-R) instrument. This cross-sectional study was conducted across 12 universities in Iran. The psychometric properties and factor structure of the PPCS-R for OR students was examined. Based on the results of factor analysis, seven items were removed from the original version of the scale. The fitness indices of the Persian scale include comparative fit index (CFI) = .90, goodness-of-fit-index (GFI) = .86, adjusted goodness-of-fit index (AGFI) = .90, normed fit index (NFI) = .84, and root mean square error of approximation (RMSEA) = .04. High validity and reliability indicated the scale's value for measuring perceived perioperative competence of Iranian OR students. PMID- 29268818 TI - miR-188 Inhibits Glioma Cell Proliferation and Cell Cycle Progression Through Targeting beta-Catenin. AB - MicroRNAs (miRNAs) play important roles in several human cancers. Although miR 188 has been suggested to function as a tumor repressor in cancers, its precise role in glioma and the molecular mechanism remain unknown. In the present study, we investigated the effect of miR-188 on glioma and explored its relevant mechanisms. We found that the expression of miR-188 is dramatically downregulated in glioma tissues and cell lines. Subsequent investigation revealed that miR-188 expression was inversely correlated with beta-catenin expression in glioma tissue samples. Using a luciferase reporter assay, beta-catenin was determined to be a direct target of miR-188. Overexpression of miR-188 reduced beta-catenin expression at both the mRNA and protein levels, and inhibition of miR-188 increased beta-catenin expression. Moreover, we found that overexpression of miR 188 suppressed glioma cell proliferation and cell cycle G1-S transition, whereas inhibition of miR-188 promoted glioma cell proliferation. Importantly, silencing beta-catenin recapitulated the cellular and molecular effects seen upon miR-188 overexpression, which included inhibiting glioma cell proliferation and G1-S transition. Taken together, our results demonstrated that miR-188 inhibits glioma cell proliferation by targeting beta-catenin, representing an effective therapeutic strategy for glioma. PMID- 29268820 TI - The Inter-Rater Reliability of the Observation Instrument for Assessing Pain in Elderly With Dementia: An Investigation in the Long-Term Care Setting. AB - BACKGROUND AND PURPOSE: The Observation Instrument for Assessing Pain in Elderly With Dementia (BISAD) was developed in Germany. The instrument demonstrated high inter-rater reliability values for the original French version. So far, there are no results to that effect in the Austrian long-term care setting available. The objective of this study was to investigate agreement and inter-rater reliability of BISAD in residents with dementia. METHODS: A quantitative multicenter descriptive cross-sectional design with a convenience sample of 71 residents. RESULTS: Analysis of all eight items demonstrated fair to moderate concordance. Absolute agreement of the total value was 25.32%. Subtotals of the observation before mobilization was 52.11%, and during mobilization 32.39%. CONCLUSION: The reliability analysis shows that the items are less reliable. Currently, BISAD does not make a reliable contribution to clinical decision making in the tested setting. PMID- 29268821 TI - Development and Psychometric Evaluation of the Nurses' Compassion Fatigue Inventory. AB - BACKGROUND AND PURPOSE: Many efforts have been made so far to measure compassion fatigue (CF). There is no specific, precise, and comprehensive tool for CF measurement among nurses. This study aimed at developing and evaluating the psychometric properties of the Nurses' Compassion Fatigue Inventory (NCFI). METHODS: This methodological study was made in 3 consecutive phases: the hybrid concept analysis, the item pool generation, the psychometric validation. RESULTS: The initial item pool contained 98 items. The psychometric properties were examined and exploratory factor analysis revealed a 6-factor structure. NCFI contained 35 items. The Cronbach's alpha, intra-class correlation coefficient (ICC), and standard error of measurement (SEM) were 0.940, 0.935, and 7.6, respectively. CONCLUSION: The NCFI has acceptable reliability and validity. It can be easily used by nursing researchers and managers and even hospital nurses. PMID- 29268822 TI - Psychometric Evaluation of the Persian Translation of the Thalassemia-Specific Quality of Life Questionnaire. AB - BACKGROUND AND PURPOSE: There is no Persian scale for assessing the quality of life of patients with thalassemia major. Thus, this study was conducted to translate and validate the 36-item thalassemia-specific Transfusion-Dependent Quality of Life (TranQoL) questionnaire. METHODS: The questionnaire was first translated into Persian and then was backward-translated into English. Afterward, panels of experts commented on the Persian translation, and then its face validity was confirmed and content validity index (CVI) and content validity ratio (CVR) were calculated. The factorial structure and the reliability of the translated questionnaire were assessed using exploratory factor analysis (EFA) and internal consistency method, respectively. RESULTS: The CVI and CVR of the questionnaire were .95 and .84, respectively. Five items were deleted during EFA, and 9 factors were extracted from the 31 remaining items. The reliability of the questionnaire was confirmed through a Cronbach's alpha coefficient of .9. CONCLUSION: The Persian translation of the TranQoL questionnaire is highly reliable and valid, and thus, it can be used as a specific measure for assessing the quality of life among patients with thalassemia. PMID- 29268823 TI - Guest Editorial. PMID- 29268824 TI - The Psychometric Properties of the World Health Organization Quality of Life BREF Among Thai Women Who Have Experienced Intimate Partner Violence. AB - BACKGROUND AND PURPOSE: The World Health Organization Quality of Life BREF (WHOQOL-BREF) has been used in various populations and cultures. However, its psychometric properties are unknown among women who experienced intimate partner violence (WIPV). This study aimed to explore the reliability and validity of the WHOQOL-BREF among Thai WIPV. METHODS: Two hundred eighty-four female patients receiving care at a northeast hospital in Thailand responded to the WHOQOL-BREF and intimate partner violence (IPV) questions. Exploratory factor and consistency analyses were applied. RESULTS: Different from the original study, this study generated 5 factors, 1 of which is Medical Care Needs. The resulting scale and subscales showed good reliability and construct validity. CONCLUSION: The 5 factor scale can be used among WIPV by health care professionals to assess their quality of life (QOL) and appropriately address their needs. PMID- 29268825 TI - Development and Psychometric Evaluation of the Nurses Professional Values Scale 3. AB - BACKGROUND AND PURPOSE: The Nurses Professional Values Scale-3 (NPVS-3) is an instrument derived from the American Nurses Association Code designed to measure nurses' professional values. The purpose of this study was to examine its psychometric properties. METHODS: A random sample of 1,139 baccalaureate nursing students, graduate nursing students, and practicing nurses participated. The 28 item Likert-scale instrument was subjected to exploratory and confirmatory factor analysis. Principal components analysis with varimax rotation and Kaiser normalization resulted in a 3-factor solution. RESULTS: Findings supported internal consistency reliability of 3 factors with alpha coefficients from .80 to .91 and total scale coefficient of .94. Construct validity was supported with a factor loading range of .31-.95 across 3 factors-Caring, Activism, Professionalism. CONCLUSION: NPVS-3 is a psychometrically sound instrument that can be used by nursing researchers, educators, administrators, and practitioners. PMID- 29268826 TI - An Evaluation of the Psychometric Properties of the Behavior Change Strategies for Healthy Eating Scale. AB - BACKGROUND AND PURPOSE: The Behavior Change Strategies for Healthy Eating Scale (BCSHES) has potentially broad implications for use by researchers, practitioners, and educators across various medical and allied health professions. To date, however, the psychometric properties of the BCSHES have not been rigorously evaluated, potentially limiting its use. The purpose of this study was to thoroughly evaluate the psychometric properties of the BCSHES. METHODS: The Rasch Rating Scale Model was used to analyze BCSHES data on a sample of 191 graduate/professional program students. RESULTS: Messick's framework for construct validity was used to discern validity evidence, which noted the BCSHES possessed very strong psychometric properties and is capable of yielding valid and reliable scores. CONCLUSIONS: Use of the scale is encouraged, where appropriate. PMID- 29268827 TI - Construct Validity of the Portuguese Version of the Wagnild and Young Resilience Scale. AB - BACKGROUND AND PURPOSE: This study aims to validate the resilience scale developed by Wagnild and Young for the Portuguese population. METHODS: The instrument validation was conducted with a sample of 313 adults attending the Higher Institute of Educational Sciences, of which 62.3% were female and 37.7% male, between 18 and 58 years old. RESULTS: Three factors were decided upon: life satisfaction, planning-discipline, and independence, and there was a positive average correlation between the three factors. The confirmatory factor analysis showed excellent comparative fit index and root mean square error of approximation values, so we conclude that the model has an excellent fit. Also, Cronbach's alpha coefficient used for internal consistency values reported good values. CONCLUSIONS: Overall, the key global indicators of the model's fit and reliability analysis express their quality for Portuguese population. PMID- 29268828 TI - Testing Nursing Competence: Validity and Reliability of the Nursing Performance Profile. AB - BACKGROUND AND PURPOSE: There is growing evidence that simulation testing is appropriate for assessing nursing competence. We compiled evidence on the validity and reliability of the Nursing Performance Profile (NPP) method for assessing competence. METHODS: Participants (N = 67) each completed 3 high fidelity simulation tests; raters (N = 31) scored the videotaped tests using a 41 item competency rating instrument. RESULTS: The test identified areas of practice breakdown and distinguished among subgroups differing in age, education, and simulation experience. Supervisor assessments were positively correlated, r = .31. Self-assessments were uncorrelated, r = .07. Interrater agreement ranged from 93% to 100%. Test-retest reliability ranged from r = .57 to .69. CONCLUSIONS: The NPP can be used to assess competence and make decisions supporting public safety. PMID- 29268829 TI - Rasch Analysis of Lebanese Nurses' Responses to the Occupational Fatigue Exhaustion Recovery Scale. AB - BACKGROUND AND PURPOSE: The purpose of our methodological study was to explore the psychometric properties of Occupational Fatigue Exhaustion Recovery (OFER) subscales. METHODS: Rasch analyses of 366 Lebanese registered nurses' responses to the Chronic Fatigue (CF), Acute Fatigue (AF), and Intershift Recovery (IR) subscales. RESULTS: Disordered rating categories, response dependence, and possible differential item functioning (DIF). The data were a better fit to a 3 dimensional Rasch rating scale model; difference, chi2 = 104, df = 12, p = .01; unidimensional Akaike information criterion (AIC) = 11,925; multidimensional AIC = 11,821. CONCLUSION: Multidimensional analysis confirmed that the CF and AF subscales have sufficient reliability for use in exploratory studies of fatigue with English-speaking respondents in the Eastern Mediterranean region. An Arabic version of OFER subscales is required to facilitate future studies in Lebanon and the region. Norm values are reported to facilitate international comparisons. PMID- 29268830 TI - Reliability and Validity of the Center for Epidemiologic Studies Depression Scale in a Population-Based Cohort of Middle-Aged U.S. Adults. AB - BACKGROUND AND PURPOSE: Globally, depressive symptoms are a leading contributor to years lived with disability. The Center for Epidemiological Studies-Depression (CES-D) scale has been used extensively to quantify depression; yet, its psychometric properties remain contentious. This study examined the reliability and factor structure of the CES-D in the MacArthur Foundation's Midlife in the United States Study (MIDUS), a nationally representative cohort study of noninstitutionalized, English-speaking adults aged 24-74 years. METHODS: Internal consistency (Cronbach's alpha) and confirmatory factor analysis (CFA) were used to examine the reliability and factor structure of the CES-D. RESULTS: There were 1,233 participants who were included in the analysis (mean age = 57.3 years [SD = 11.5], 56.7% female). Cronbach's alpha of .90 was observed. The 4-factor model had the best model fit. CONCLUSIONS: High internal consistency was demonstrated alongside a replication of the original 4-factor structure. Continued use of the CES-D in noninstitutionalized populations is warranted. PMID- 29268831 TI - Maltese Translation and Adaptation of Champion's Health Belief Model Scale and the Revised Illness Perception Questionnaire for Breast Screening Among Maltese Women. AB - BACKGROUND AND PURPOSE: Translating, adapting, and piloting Champion's Health Belief Model Scale for Mammography Screening (CHBMS-MS) and Revised Illness Perception Questionnaire (IPQ-R) among Maltese women. METHODS: The Maltese questionnaire (Maltese Breast Screening Questionnaire [MBSQ]) was developed through 9 steps. Bilingual women (n = 15) completed MBSQ at 2 time points. RESULTS: During forward-backward translations (Steps 1-4), 4 English controversial terms were raised. Twelve experts agreed on terminologies during adaptation process (Step 5). Following face validity (n = 6; Step 6), 3 items were deleted. Following reconciliation (Step 7) and proofreading (Step 8), MBSQ consisted of 121 items. Pilot testing (Step 9) showed positive correlation (CHBMS MS = .87, IPQ-R = .85; p < .001); high Cronbach's alpha (CHBMS-MS = .93, IPQ-R = .92); overall acceptable internal consistency (CHBMS-MS = .69-.83, IPQ-R = .75 .93); and acceptable test-retest reliability correlations: CHBMS-MS (Maltese = .62-.76; English = .61-.84), IPQ-R (Maltese=.63-.82; English = .61-.91; p < .001). CONCLUSIONS: Maltese and English scale items demonstrated high reliability and validity preliminary values. PMID- 29268832 TI - Inter-Rater Reliability and User-Friendliness of the Delirium Observation Screening Scale. AB - BACKGROUND AND PURPOSE: Delirium is a common and often unrecognized complication of hospitalized elderly patients. Currently, there is no evidence for inter-rater reliability studies between registered nurses in the literature. Furthermore, the user-friendliness of the Delirium Observation Screening Scale (DOSS) has not been tested in Austria. METHODS: A quantitative cross-sectional design with a convenience sample of 141 patients and 36 nurses in an Austrian hospital. RESULTS: Analysis of rater-agreement and inter-rater reliability on item level, total score as well as category of delirium risk demonstrated very high agreement. In contrast, no or only fair kappa coefficient were determined. The user-friendliness of the scale was partially satisfactory. CONCLUSIONS: The very high absolute agreement speaks for the reliability of DOSS although the kappa paradox became obvious. The results of the presented study relate only to the tested setting. PMID- 29268833 TI - Assessment of Basic Knowledge About Alzheimer's Disease Among Older Rural Residents: A Pilot Test of a New Measure. AB - BACKGROUND AND PURPOSE: Underserved rural populations face a higher risk of Alzheimer's disease (AD), yet studies investigating AD knowledge in this population are lacking. The purpose of this research was to develop an AD basic knowledge measure that is appropriate for use with underserved populations. METHOD: A content domain map, content validity index, and cognitive interviews were used in developing the first version of the basic knowledge of Alzheimer's disease (BKAD; Study 1). Reliability and validity of the measure in this descriptive study were examined using Rasch modeling and tests for construct, concurrent, and discriminate validity (Study 2). Multiple regression was employed to examine AD knowledge predictors. RESULTS: Findings included that the BKAD instrument discriminated well between persons with varied education levels. Psychometric analysis yielded important information to guide revision of the BKAD measure. CONCLUSION: The BKAD measure shows promise in meeting the need for a culturally relevant measure to assess basic Alzheimer's disease knowledge in underserved rural populations. PMID- 29268834 TI - Reliability and Validity Testing of the MotionWatch 8 in Older Adults. AB - BACKGROUND AND PURPOSE: The purpose of this pilot study was to test the reliability and validity of the MotionWatch 8 with older adults. METHODS: Participants wore the MotionWatch 8 for 3 days, completed a diary of activities and the Borg Rating of Perceived Exertion (RPE) scale. RESULTS: Evidence of reliability and validity was supported because there was no difference in daily level of activity and that recorded physical activity matched the activity counts. There was a significant difference in Borg RPE scale scores between the sedentary group (Borg RPE scale = 8.6, SD = 3.0) and those with some level of activity (Borg RPE scale = 9.9, SD = 2.3; F = 5.72, p = .02). CONCLUSION: The findings provide preliminary support for the reliability and validity of the MotionWatch 8 when used with older adults. PMID- 29268835 TI - Predictive Validity of the Brazilian Portuguese Version of the Family Questionnaire for Relapse in Patients With Schizophrenia. AB - BACKGROUND AND PURPOSE: The Family Questionnaire-Brazilian Portuguese Version (FQ BPV) has been preliminarily validated in the Brazilian population. This study assessed the predictive validity of the FQ-BPV for relapse in patients with schizophrenia. METHODS: Ninety-four dyads (patients with schizophrenia and their relatives) were recruited from three mental health clinics. Expressed emotion was assessed using the FQ-BPV. Presence of relapse was assessed at 6-, 9-, 12-, and 18-month follow-ups and analyzed through logistic regressions. RESULTS: The critical comments (CC) domain of the FQ-BPV was statistically significant at 18 months. However, the model was not sufficiently robust to classify individuals correctly into relapse or no relapse categories. CONCLUSION: The FQ-BPV did not predict relapse well and we cannot recommend it for that purpose in Brazil without further studies. PMID- 29268836 TI - Characterization of Hydrolysis Kinetics in Staged Anaerobic Digestion of Wastewater Treatment Sludge. AB - The hydrolysis of mixed primary and secondary sludges in two-stage anaerobic digestion was evaluated and compared with conventional single-stage digestion, using various temperature-phased configurations of M1-M2, M1-T3, T1-T2, and T1 M3. A dual hydrolysis model best described the hydrolysis in all tests. This model was also able to consistently estimate the readily and slowly fractions of particulate chemical oxygen demand (COD) of raw sludge used in the tests. The hydrolysis kinetic coefficients (Khyd_s and Khyd_r) estimated for the mesophilic digesters were significantly greater in the short hydraulic retention time (HRT) M1 digester than those of the extended HRT digesters. Conversely, at thermophilic temperatures only Khyd_r was greater in short HRT T1 digester when compared to the extended HRT digesters. The increased Khyd_r and reduced Khyd_s values due to staging effect were explained with surface reaction models and endogenous decay. The temperature dependency of Khyd_s and Khyd_r was also explored in the staged digesters. PMID- 29268837 TI - Thermogravimetric Analysis of Textile Dyeing Sludge (TDS) in N2/CO2/O2 Atmospheres and its Combustion Model with Coal. AB - The combustion characteristics of textile dyeing sludge (TDS) in N2/O2, CO2/O2, and N2/CO2 atmospheres, and blends of TDS with coal were analyzed using TGA (thermogravimetric analysis). Results showed that the replacement of N2 by CO2 resulted in negative effects on the combustion and pyrolysis of TDS. Comparing N2/O2 and CO2/O2 atmospheres, combustion of TDS was easier in a N2/O2 atmosphere, but the residual mass after TDS pyrolysis in pure CO2 was less than that in N2 by approximately 4.51%. When the proportion of TDS was 30-50% in the blends of coal with TDS, a synergistic interaction clearly occurred, and it significantly promoted combustion. In considering different combustion parameters, the optimal proportion of TDS may be between 20-30%. The activation energy Ea value decreased from 155.6 kJ/mol to 53.35 kJ/mol with an increasing TDS proportion from 0% to 50%, and it rapidly decreased when the TDS proportion was below 20%. PMID- 29268838 TI - Impacts of SRT on Particle Size Distribution and Reactor Performance in Activated Sludge Processes. AB - Particle size distribution of the particulates is an essential characteristic of the wastewater quality. Particle size of activated sludge flocs may affect key sludge handling processes including sedimentation, thickening, digestion, and dewatering. This study evaluated the effects of solids retention time (SRT) on particle size distribution, sludge settleability, effluent turbidity, and removals of chemical oxygen demand (COD) and -N in a lab-scale Modified Ludzak-Ettinger (MLE) reactor and an integrated fixed film activated sludge (IFAS) reactor. This study also surveyed particle size distribution profile of five full-scale water resource recovery facilities (WRRFs), including high purity oxygen (HPO), step-feed nitrification/denitrification (NDN), and MLE NDN processes. This study provides direct evidence of the effects of SRT on particle size distribution and sludge settleability in lab-scale reactors and full-scale WRRFs. PMID- 29268839 TI - Environmental Evaluation of Soil Salinity with Various Watering Technologies Assessment. AB - The purpose of this study is to develop mathematical tools for evaluating the level of environmental safety of various watering technologies. A set of indicators, was developed with regard to the natural factors, the nature of the man-induced load, degradation type, and characteristics of the disruption of humification conditions. Thermal and physical characteristics of the soil, the state of its surface, and meteorological factors, including air temperature, relative humidity, precipitation, wind speed, solar radiation, etc. were studied with a view to determining the heat and air exchange in the soil. An environmental evaluation of the methods for saline land development was conducted with regard to the heat and moisture supply. This tool can be used to determine the level of environmental safety of soil salinization during the environmental evaluation of the investigation of soil salinity with various watering technologies. PMID- 29268840 TI - Characterizations of Polysulfone/Ferrihydrite Mixed Matrix Membranes for Water/Wastewater Treatment. AB - This study aimed to investigate the effects of ferrihydrite (Fh) nanoparticle loading on the physicochemical properties of polysulfone (PSf) membranes fabricated via the phase inversion method. The morphologies and physicochemical properties of prepared Fh and PSf/Fh mixed matrix membranes (MMMs) were characterized using transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), Fourier transmission infra-red (FTIR), scanning electron microscopy (SEM), atomic force microscopy (AFM), pure water flux analysis, contact angle measurement, and membrane porosity analysis. FTIR study indicated that a new O-H band was formed when Fh was added into the membrane matrix. SEM analysis showed the formation of typical asymmetric membrane structures with elongated fingerlike and looser porous layers. Increasing the loading of Fh significantly enhanced membrane pure water flux from 230.2 L/m2*h (M-Fh 0%) to 726.6 L/m2*h (M-Fh 15.3%), attributed to the improved membranes structures, membranes wettability, surface roughness, and overall porosity. The findings suggest incorporation of Fh into PSf membranes improves physicochemical properties of the membranes which are applicable for water/wastewater treatment. PMID- 29268841 TI - Application of Fuzzy Set/Qualitative Comparative Analysis to Public Participation Projects in Support of the EU Water Framework Directive. AB - This study analyzes the level of satisfaction of stakeholders in the public participation process (PPP) of water resources management, which is mandatory according to the EU Water Framework Directive (WFD). The methodology uses a fuzzy set/qualitative comparative analysis (fsQCA), which allows the identification of a combination of factors that lead to the outcome that is stakeholders' satisfaction. It allows dealing with uncertain environments due to the heterogeneous nature of stakeholders and factors. The considered causes range from environmental objectives pursued, actual capacity of efficiently carrying out those objectives, socioeconomic development of the region, level of involvement and means of participation of the stakeholders engaged in the PPP, and alternative policies and measures that should be performed. Results support the argument that different causal paths explain the stakeholders' satisfaction. The methodology may help in the implementation of the WFD and conflict resolution since it leads to greater fairness, social equity, and consensus among stakeholders. PMID- 29268842 TI - Metal Speciation in the Rivers Around Potchefstroom Based on Seasonality. AB - About 44 surface water samples were collected in the wet and dry seasons around mining areas near the city of Potchefstroom in South Africa, and physicochemical parameters were analyzed to assess the speciation of pollutants and impact on dispersion potential. It was found that concentrations of the trace elements measured decreased significantly during the dry season. High concentrations of trace elements during the wet season were correlated to high effluents from anthropogenic sources which were flowing into the surface water. Aqueous metal speciation in both seasons was conducted using the PHREEQC geochemical modelling code. The seasonal variation of species observed was due to changes in the physicochemical quality of water between the two seasons. Collected data indicated that high percentages of Ca and Mg were present as free hydrate species, whereas the Fe, Cd, As, and U were mostly present as carbonate or hydroxide species. PMID- 29268843 TI - Clinical effectiveness and cost-effectiveness of issuing longer versus shorter duration (3-month vs. 28-day) prescriptions in patients with chronic conditions: systematic review and economic modelling. AB - BACKGROUND: To reduce expenditure on, and wastage of, drugs, some commissioners have encouraged general practitioners to issue shorter prescriptions, typically 28 days in length; however, the evidence base for this recommendation is uncertain. OBJECTIVE: To evaluate the evidence of the clinical effectiveness and cost-effectiveness of shorter versus longer prescriptions for people with stable chronic conditions treated in primary care. DESIGN/DATA SOURCES: The design of the study comprised three elements. First, a systematic review comparing 28-day prescriptions with longer prescriptions in patients with chronic conditions treated in primary care, evaluating any relevant clinical outcomes, adherence to treatment, costs and cost-effectiveness. Databases searched included MEDLINE (PubMed), EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Cochrane Central Register of Controlled Trials. Searches were from database inception to October 2015 (updated search to June 2016 in PubMed). Second, a cost analysis of medication wastage associated with < 60-day and >= 60 day prescriptions for five patient cohorts over an 11-year period from the Clinical Practice Research Datalink. Third, a decision model adapting three existing models to predict costs and effects of differing adherence levels associated with 28-day versus 3-month prescriptions in three clinical scenarios. REVIEW METHODS: In the systematic review, from 15,257 unique citations, 54 full text papers were reviewed and 16 studies were included, five of which were abstracts and one of which was an extended conference abstract. None was a randomised controlled trial: 11 were retrospective cohort studies, three were cross-sectional surveys and two were cost studies. No information on health outcomes was available. RESULTS: An exploratory meta-analysis based on six retrospective cohort studies suggested that lower adherence was associated with 28-day prescriptions (standardised mean difference -0.45, 95% confidence interval -0.65 to -0.26). The cost analysis showed that a statistically significant increase in medication waste was associated with longer prescription lengths. However, when accounting for dispensing fees and prescriber time, longer prescriptions were found to be cost saving compared with shorter prescriptions. Prescriber time was the largest component of the calculated cost savings to the NHS. The decision modelling suggested that, in all three clinical scenarios, longer prescription lengths were associated with lower costs and higher quality adjusted life-years. LIMITATIONS: The available evidence was found to be at a moderate to serious risk of bias. All of the studies were conducted in the USA, which was a cause for concern in terms of generalisability to the UK. No evidence of the direct impact of prescription length on health outcomes was found. The cost study could investigate prescriptions issued only; it could not assess patient adherence to those prescriptions. Additionally, the cost study was based on products issued only and did not account for underlying patient diagnoses. A lack of good-quality evidence affected our decision modelling strategy. CONCLUSIONS: Although the quality of the evidence was poor, this study found that longer prescriptions may be less costly overall, and may be associated with better adherence than 28-day prescriptions in patients with chronic conditions being treated in primary care. FUTURE WORK: There is a need to more reliably evaluate the impact of differing prescription lengths on adherence, on patient health outcomes and on total costs to the NHS. The priority should be to identify patients with particular conditions or characteristics who should receive shorter or longer prescriptions. To determine the need for any further research, an expected value of perfect information analysis should be performed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027042. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29268844 TI - [KAT6B promotes LPS-triggered IL-6 production via enhancing recruitment of H3K23 acetylation to IL-6 promoter region]. AB - Objective To explore the regulatory role of lysine acetyltransferase 6B (KAT6B) in lipopolysaccharide(LPS)-triggered interleukin 6 (IL-6) production in macrophages and the mechanism. Methods Real-time quantitative PCR (qRT-PCR) was performed to detect and quantitate KAT6B mRNA level in mouse peritoneal macrophages and RAW264.7 cells under LPS stimulation for 0, 2, 4, 6 hours. RNA interference technology was used to knock down the expression of KAT6B in peritoneal macrophages, the expression of IL-6 in LPS-stimulated murine macrophages was detected by qRT-PCR at the mRNA level and ELISA at the protein level; meanwhile, the levels of IL-6 mRNA and protein were tested by the same means in RAW264.7 cells with over-expressed KAT6B. The transfection efficiency and signal pathway activation were examined by Western blot analysis. Dual luciferase reporter assay was used to investigate the role of KAT6B in IL-6 transcription. Chromatin immunoprecipitation (ChIP) was done to evaluate the effect of KAT6B on the recruitment of acetylation of histone 3 lysine 23 (H3K23ac) within IL-6 promoter region. Results LPS stimulation up-regulated KAT6B expression in both peritoneal macrophages and RAW264.7 cells. Silence of KAT6B suppressed LPS-induced IL-6 production in murine peritoneal macrophages, overexpression of V5-KAT6B promoted the production of LPS-triggered IL-6 in RAW264.7 cells. The change of KAT6B level did not affect the activity of NF kappaBp65 and MAPK induced by LPS. KAT6B increased the recruitment of H3K23ac on IL-6 gene DNA promoter. Conclusion KAT6B can enhance LPS-triggered IL-6 production by promoting the recruitment of H3K23ac to IL-6 gene promoter region. PMID- 29268845 TI - [Inhibitory effect and mechanism of tofacitinib on the secretion of cytokines by T cells in human peripheral blood]. AB - Objective To study the inhibitory effect of tofacitinib on the production of cytokines by T cells in human peripheral blood and its mechanism. Methods Peripheral blood mononuclear cells (PBMCs) and purified T cells were cultured and stimulated with anti-CD3 plus anti-CD28 antibodies in the presence or absence of tofacitinib (0.5 MUmol/L). The levels of interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and interleukin 2 (IL-2) in the culture supernatants were detected by ELISA, and the expressions of activated molecules CD69 and CD25 on the surface of CD4+ and CD8+ T cells, the production of cytokines and the phosphorylation of signal transducers and transcriptional activators STAT1, STAT3, STAT4 in T cells were examined by flow cytometry. At the same time, the proliferation and apoptosis of T cells were observed by 5- (and 6 ) carboxyfluorescein diacetate succinimidyl ester (CFSE) staining and the flow cy tometry with annexin V-FITC/PI, respectively. Results Tofacitinib inhibited the production of IFN-gamma, TNF-alpha and the expression of CD25 on T cells from the peripheral blood. In addition, the proliferation and the phosphorylation of STAT1, STAT3, STAT4 by T cells were also depressed. However, tofacitinib had no effect on the secretion of IL-2, the expression of CD69 and the apoptosis of T cells. Conclusion Tofacitinib can inhibit the secretion of IFN-gamma and TNF alpha by T cells in the peripheral blood, and its mechanism might be related to the inhibitory effect of tofacitinib on the activation, proliferation and signal transduction in T cells. PMID- 29268846 TI - [Optimization and evaluation of an inflammatory cell model in LPS-stimulated PMA differentiated THP-1 cells]. AB - Objective To develop an optimal inflammatory cell model from lipopolysaccharide (LPS)-stimulated phorbol ester (PMA)-differentiated THP-1 cells, and investigate its response to anti-inflammatory agent phosphodiesterase inhibitor rolipram. Methods THP-1 cells were differentiated by PMA and stimulated by LPS to release inflammatory factors in cell supernatants, like tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6), which were detected by ELISA. The doses and durations of both PMA and LPS treatment were optimized to develop the inflammatory cell model. Rolipram was added along with LPS after PMA differentiation to assess the response of cells to the anti-inflammatory agent. Results THP-1 cells showed no significant differences in cell morphology between PMA treatment for 24 hours and for 48 hours, but significantly high levels of TNF alpha and IL-6 were released under LPS treatment. TNF-alpha level increased significantly after the differentiation by PMA at 100 ng/mL in comparison with that at 50 ng/mL, and it increased in a LPS dose-depended manner untill a plateau at 0.2 MUg/mL LPS; the secretion level of IL-6 increased remarkably when THP-1 cells were induced by PMA at 100 ng/mL and stimulated by LPS>=1 MUg/mL. The inflammatory cell model made using PMA at 100 ng/mL and LPS at 0.5 MUg/mL was more sensitive to the anti-inflammatory agent rolipram, compared with that by 0.1 MUg/mL LPS. Conclusion PMA at 100 ng/mL was selected for the differentiation of THP-1 cells with the enhanced responsiveness to LPS stimulation; THP-1 cells by the induction of PMA at 100 ng/mL coupled with the stimulation of LPS at no less than 0.2 MUg/mL was an optimal inflammatory cell model for significant secretion of TNF-alpha and IL-6, which was sensitive to the action of anti-inflammatory agents. PMID- 29268847 TI - [The therapeutic effect and its mechanism of adiponectin on ApoE-/- mice with atherosclerosis]. AB - Objective To analyze the role of adiponectin (APN) in the treatment of ApoE-/- mice with atherosclerosis (AS) and its possible mechanism. Methods Twenty male ApoE-/- mice were enrolled to establish AS model with high-fat diet, and then randomly divided into control group (saline, intraperitoneal injection, 4 weeks) and APN-treated group (25 MUg/d, intraperitoneal injection, 4 weeks). HE staining, immunohistochemistry, ELISA, immunofluorescence, reverse transcription PCR and Western blotting were performed to analyze the effect of APN on ApoE-/- mice and the changes of related signaling pathways. Results Compared with the control group, the APN-treated group had smaller atheroma macular areas and lower levels of inflammatory cytokines (IL-8 and TNF-alpha) in blood vessels. The APN treated group had less inflammatory cell infiltration in perivascular adipose tissues than those of the control group. The APN-treated group had lower levels of CD86 and IL-1beta, but higher levels of CD206 and IL-10 in perivascular adipose tissues than those of the control group. Western blot analysis showed that APN treatment significantly increased the expression of p-STAT6 in perivascular adipose tissues as compared with that of the control group. Conclusion APN has a definitely therapeutic effect on ApoE-/- mice, and the possible mechanism may be associated with the induced macrophage polarization through STST6 signal in perivascular adipose tissues. PMID- 29268848 TI - [Paeoniflorin ameliorates liver injury of MRL/lpr mice through inhibition of NF kappaB pathway]. AB - Objective To investigate the effects of paeoniflorin (PF) on liver injury of MRL/lpr mice and its underlying mechanisms. Methods The research included 10 normal control C57BL/6 mice and 40 MRL/lpr mice. MRL/lpr mice were randomly assigned equally to a blank control group, a dexamethasone (1.5 mg/kg) group, and two PF (20, 40 mg/kg) groups. The serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) were tested with microplate assay. Inflammatory cytokines in the serum and liver were also detected using ELISA. Liver pathological changes were observed using HE staining. The protein levels of receptor interacting protein140 (RIP140), Toll-like receptor 4 (TLR4), p-NF kappaBp65, NF-kappaBp65, p-IkappaBalpha and IkappaBalpha in the liver were detected by Western blot analysis. Results PF significantly decreased the serum levels of AST and ALT, obviously decreased the expressions of the inflammatory cytokines IL-1beta, IL-6 and TNF-alpha in the serum and liver, alleviated liver pathological changes and inhibited the expressions of RIP140, TLR4, p-NF kappaBp65, p-IkappaBalpha proteins in the MRL/lpr mice. Conclusion PF has protective effects against liver injury in MRL/lpr mice by inhibiting NF-kappaB pathway. PMID- 29268849 TI - [The mechanism of oxLDL/beta2GPI/anti-beta2GPI antibody complex promoting the expression of adhesion molecules in HUVECs]. AB - Objective To investigate the effect of oxidative low-density lipoprotein/beta2 glycoprotein I/anti-beta2 glycoprotein I antibody (oxLDL/beta2GPI/anti-beta2GPI Ab) complex on the expressions of adhesion molecules in human umbilical vein endothelial cells (HUVECs), and the role of Toll-like receptor 4 (TLR4) signaling pathway during this process. Methods HUVECs were stimulated with simple medium, oxLDL, oxLDL/beta2GPI complex, oxLDL/anti-beta2GPI-Ab complex, oxLDL/beta2GPI/anti-beta2GPI-Ab complex and LPS separately, and then the total mRNA and protein were collected. The mRNA and protein expressions of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) were detected by real-time quantitative PCR and Western blotting, respectively. Pre-treatment method was applied to explore the influence of TLR4 antagonist TAK-242 (5 MUmol/L) and p38MAPK antagonist SB203580 (10 MUmol/L) on the expressions of adhesion molecules in HUVECs. THP-1 cell adhesion test was employed to evaluate the effect of oxLDL/beta2GPI/anti-beta2GPI-Ab complex on the ability of attracting monocytes of HUVECs. Results Compared with simple medium, oxLDL/beta2GPI/anti-beta2GPI-Ab complex obviously upregulated the expressions of ICAM-1, VCAM-1 and vWF in HUVECs and promoted the adhesion of THP-1 cells to HUVECs. In addition, these effects were inhibited by the pre-treatment of TAK-242 or SB203580. Conclusion OxLDL/beta2GPI/anti-beta2GPI-Ab complex could up-regulate the expressions of adhesion molecules in HUVECs and promote the adhesion of THP-1 cells to HUVECs, in which TLR4 and p38 MAPK were closely involved. PMID- 29268850 TI - [AMPK over-expression inhibits proliferation, matrix synthesis and inflammation response of glomerular mesangial cells in pristine-induced lupus mice]. AB - Objective To explore the effects of AMP-activated protein kinase (AMPK) over expression on the proliferation, matrix synthesis and inflammatory cytokine production in glomerular mesangial cells from pristane-induced systemic lupus erythematosus (SLE) mice. Methods C57BL/6 mice were randomly divided into control group and model group. The SLE mouse model was established by the treatment with pristane. The levels of autoantibodies were detected by ELISA. The primary glomerular mesangial cells were isolated from the mice of the control and model groups. The primary glomerular mesangial cells of the model mice were divided into model subgroup, empty vector subgroup and over-expression subgroup. The pEGFP-C1-vector and pEGFP-C1-MPK were transferred into the cells of the empty vector and over-expression subgroups, respectively. The expression of AMPK was tested by Western blotting. After AMPK was successfully over-expressed, cell apoptosis was detected by flow cytometry. The expressions of AMPK, cyclin D1, proliferating cell nuclear antigen (PCNA), P21, P27, fibronectin (FN), collagen IV (Col4), interleukin 6 (IL-6) and interleukin 1beta (IL-1beta) were measured by Western blotting. Results The levels of serum dsDNA IgG, dsDNA IgM, Sm IgG, Sm IgM significantly increased in the model group compared with the control group, indicating that the mouse model used in this study successfully imitated the pathological process of SLE. In addition, over-expression of AMPK promoted the apoptosis of mesangial cells from the SLE mice. Moreover, the expressions of cyclin D1, PCNA, P21, FN, Col4, IL-6 and IL-1beta were markedly depressed, whereas the level of P27 protein was raised in these cells after AMPK over expression. Conclusion AMPK over-expression can inhibit the cell proliferation, matrix synthesis and inflammatory response of mesangial cells in pristane-induced SLE mice. PMID- 29268851 TI - [Penehyclidine hydrochloride attenuates LPS-induced acute lung injury in rats]. AB - Objective To study the protective effect of penehyclidine hydrochloride (PHCD) against acute lung injury induced by lipopolysaccharide (LPS) in rats. Methods 36 Sprague Dawley (SD) rats were randomly divided into control group, LPS-induced shock group (LPS group), and PHCD treated group (PHCD group). Rat shock model was prepared by intraperitoneal injection of LPS (5 mg/kg). The rats of PHCD group were treated with PHCD (1.0 mg/kg) by caudal vein injection. Rat blood gas analysis was performed 6 hours after the injection. Lung wet/dry mass ratio (W/D) was detected after the rats were sacrificed. The levels of tumor necrosis factor alpha (TNF-alpha), interleukin 8 (IL-8), and IL-6 in bronchoalveolar lavage fluid (BALF) were tested by ELISA. The lung tissue inflammation was observed by HE staining. The expression of inducible nitric oxide synthase (iNOS) was detected by real-time quantitative PCR and Western blot analysis. Results Compared with the control group, lung W/D and blood lactate acid (LAC) increased significantly in the LPS group, while the blood pH and the arterial oxygen partial pressure (PaO2) decreased markedly. The levels of TNF-alpha, IL-8 and IL-6 significantly increased in lung BALF of the LPS-induced rats, and the expression of iNOS increased significantly. HE staining showed that LPS treatment caused pulmonary edema, congestion and inflammatory cell infiltration. After PHCD treatment, lung W/D and LAC were reduced; the pH and PaO2 were elevated compared with LPS-induced rats; the levels of TNF-alpha, IL-8 and IL-6 in BALF were evidently down regulated; the expression of iNOS decreased obviously. HE staining showed that the lung inflammation was attenuated by PHCD treatment. Conclusion PHCD attenuates lung injury by inhibiting LPS-induced lung inflammation. PMID- 29268852 TI - [Distributions of H3K27me3 and its modification enzymes in different tissues of mice]. AB - Objective To investigate the levels of trimethylated histone 3 at lysine residue 27 (H3K27me3) and its modification enzymes Zeste gene enhancer homolog 2 (EZH2), lysine-specific demethylase 6B (Kdm6B/JMJD3) and lysine-specific demethylase 6A (Kdm6A/UTX) in tissues and organs of 7-day and 2-month postnatal mice. Methods Immunohistochemistry was used to detect the expressions of H3K27me3 and its modification enzymes EZH2, JMJD3 and UTX in the brain, salivary glands, back fat, thymus, lung, heart, stomach, intestines, liver, testes, and skin of 7-day and 2 month mice. Real-time quantitative PCR was used to confirm the results. The relationships between H3K27me3 and its modification enzymes were analyzed statistically. Results Immunohistochemistry showed H3K27me3 persistently present in all examined tissues of 7-day and 2-month mice. EZH2 was persistently expressed in the brain, heart, liver, and skin of 7-day and 2-month mice, but only expressed in the salivary glands, adipose tissues, thymus, lung, intestines, and testes of 2-month mice. JMJD3 was expressed in the brain, salivary glands, adipose tissues, lung, heart, stomach, intestines, testes, skin of 7-day mice, but was not expressed in the lung, adipose tissues and stomach of 2-month mice. UTX was expressed in the brain, salivary glands, adipose tissues, lung, heart, testes, skin of 7-day mice, but only expressed in the testes of 2-month mice. Most mRNA of H3K27 modification enzymes were moderately or highly expressed as their immunohistochemical results were positive. Conclusion There was H3K27me3 persistently present in the all examined tissues at different stages. EZH2 was mostly expressed in the brain, salivary glands, adipose tissues, thymus, lung, heart, intestines, liver, testes and skin of 2-month-old mice. JMJD3 and UTX were mostly expressed in the brain, salivary glands, adipose tissues, lung, heart, skin and testes of 7-day-old mice. No significant association was found between the distribution of H3K27me3 and the expression of EZH2. There was also no obvious inverse distribution relationship between H3K27me3 and JMJD3 or UTX. Moreover, there was no negative relationship between the distribution of EZH2, JMJD3 and UTX. These results suggest that EZH2, JMJD3 and UTX may play important roles in many tissues of mice after birth. The levels of H3K27me3 and its modified enzymes may be controlled by multiple factors in vivo to fulfill complex physiological functions. PMID- 29268853 TI - [Triperygium wilfordii multiglucoside ameliorates kidney damage in diabetic rats by inhibiting the expressions of MBL and MASP2]. AB - Objective To explore the effect of Triperygium wilfordii multiglucoside (TWM) on the expressions of mannose-binding lectin (MBL) and mannan-binding lectin serine peptidase 2 (MASP2) in the kidney of diabetic rats, and discuss the protective role of TWM in diabetic nephropathy and its possible mechanism. Methods Forty five male SD rats were randomly assigned into model group (n=35) and normal control group (n=10). Rats in the normal control group were fed with regular diet, while those in the model group were fed with high-fat high-sugar diet and given an intraperitoneal injection of 40 mg/kg streptozotocin (STZ) six weeks later. The successfully induced type 2 diabetic rat models (n=33) were then randomized into DM group (n=16) and TWM treatment group (n=17) treated with TWM [10 mg/(kg.d)] for eight weeks. At the end of 14th week, the levels of blood sugar, 24-hour urine protein, serum creatinine and blood urea nitrogen were measured. Renal pathological changes were examined with PAS staining. MBL-A and MASP2 expressions were detected by immunohistochemistry in the renal tissues. The expressions of MBL1, MASP2, NF-kappaB and MCP-1 mRNAs were semi-quantified by real-time PCR. The expressions of MBL-A, MASP2, NF-kappaB and MCP-1 proteins were determined by Western blotting. Results Compared with the diabetic group, the levels of serum creatinine, blood urea nitrogen, 24-hour urine protein decreased, renal histopathology was improved, the expressions of MBL, MASP2, NF-kappaB and MCP-1 mRNAs and proteins were reduced in the TWM group. Correlation analysis showed that the expression of MBL was positively correlated with MASP2, NF kappaB, MCP-1 and 24-hour urine protein. Conclusion MBL and MASP2 are over expressed in the kidney of diabetic rats. TWM can ameliorate kidney damage in diabetic rats and delay the development of diabetic nephropathy by inhibiting the expressions of MBL and MASP2. PMID- 29268854 TI - [Knockdown of TRAIL-DR5 gene inhibits autophagy of ER-positive MCF-7 breast cancer cells induced by SAHA]. AB - Objective To clarify the regulation role of tumor necrosis factor-related apoptosis inducing ligand-death receptor 5 (TRAIL-DR5) in cell autophagy induced by suberoylanilidehydroxamic acid (SAHA) in ER-positive breast cancer cell MCF-7. Methods The logarithmic growth phase of MCF-7 cells were divided into control group, SAHA treatment group, TRAIL-DR5 siRNA group and SAHA combined with TRAIL DR5 siRNA treatment group. Western blotting was used to verify the results of TRAIL-DR5 gene silencing. Real-time quantitative PCR was performed to detect the mRNA levels of autophagy-related gene 9B (ATG9B), microtubule-associated protein 1 light chain 3A (LC3A) and LC3B in the different groups. The expressions of beclin-1, ATG3, ATG5, ATG7, ATG12, ATG16, ATG4A, ATG4B, ATG9B, LC3II, cathepsin B (CTSB) in the breast cancer cells were detected by Western blotting. The level of CTSB in the breast cancer cell culture supernatant was analyzed by ELISA. Immunofluorescence cytochemical staining was used to determine the expression and distribution of LC3II in the breast cancer cells. Results TRAIL-DR5 siRNA transfection significantly decreased the levels of TRAIL-DR5 in MCF-7 cells. After the knock-down of TRAIL-DR5 gene in MCF-7, the mRNA and protein levels of the autophagy-related factors in breast cancer cells markedly decreased, and the protein level of CTSB also decreased. After SAHA treatment of MCF-7 cells, the level of LC3II increased; when knockdown of TRAIL-DR5 receptor, LC3II level was significantly lower than that in the SAHA-alone-treated cells. Conclusion Down regulating the TRAIL-DR5 gene can inhibit cell autophagy induced by SAHA in ER positive MCF-7 breast cancer cells. PMID- 29268855 TI - [Y-27632 protects H9c2 cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy pathway]. AB - Objective To investigate the protective effect of preconditioning with Rho-kinase inhibitor Y-27632 on H9c2 cardiomyocytes against hypoxia/reoxygenation (H/R) injury, and explore its underlying mechanism. Methods H9c2 cardiomyocytes were divided into normal group, H/R group, Y-27632 group and Y-27632 plus 3 methyladenine (Y-27632/3-MA) group. The cells of the normal group were cultured with 950 mL/L air and 50 mL/L CO2 at 37DegreesCelsius for 6 hours. The cells of the H/R group were pretreated with hypoxia (940 mL/L N2, 10 mL/L O2, 50 mL/L CO2) for 3 hours, followed by 3-hour reoxygenation (950 mL/L air, 50 mL/L CO2). The cells of the Y-27632 group were preconditioned with 10 MUmol//L of Rho-kinase inhibitor Y-27632 for 1 hour followed by H/R treatment as the H/R group did. The cells in the Y-27632/3-MA group were preconditioned with 10 MUmol//L of Y- 27632 and 5 mmol/L of autophagy inhibitor 3-MA for 1 hour before H/R treatment. After the treatments, CCK-8 assay was used to detect cell survival rate and chemical colorimetry was used to detect lactate dehydrogenase (LDH) activity. Cell apoptosis was measured by flow cytometry. The protein levels of phosphorylation myosin light chain (p-MLC) and beclin 1 were analyzed by Western blot analysis. Results After Y-27632 pretreatment, the survival rate of H9c2 cells were improved; the LDH activity, the apoptosis rate and the protein level of p-MLC were reduced; and the level of beclin 1 was raised. However, in the Y-27632/3-MA group, the anti-apoptotic effect on H9c2 cells was significantly attenuated, the protein level of p-MLC increased and the level of beclin 1 decreased. Conclusion Preconditioning with Y-27632 can alleviate H/R-induced myocardium injury through inhibiting Rho-kinase and promoting autophagy pathway. PMID- 29268856 TI - [microRNA-139 suppresses proliferation of hepatocellular carcinoma cells by silencing of B cell translocation gene 3]. AB - Objective To determine the role of miR-139 in the development of hepatocellular carcinoma (HCC) and to preliminarily clarify the underlying mechanism. Methods CCK-8 assay was performed to investigate the effect of miR-139 on HCC cell proliferation. Four databases, TargetScan, MiRanda, Clip-seq and miRDB, in combination with literature review, were used to predict the downstream pathways and specifically the potential targets of miR-139. The predicted targets were then verified by Western blot analysis and luciferase reporter assay. Results CCK 8 assay confirmed that miR-139 suppressed the proliferation of HCC cells. By the comparisons between the four databases and the review of literatures, a total of five genes (ICK, BTG3, DCBLD2, EIF4G2 and HNRNPF) were predicted as potential targets of miR-139. Western blot and luciferase reporter assay validated that miR 139 could directly inhibit the expression of BTG3 in HCC cells. Conclusion miR 139 can repress the proliferation of HCC cells via directly inhibiting the expression of BTG3. PMID- 29268857 TI - [Expression and activity identification of APOBEC3A-HBc fusion protein]. AB - Objective To construct the expression vector of the fusion protein of apolipoprotain B mRNA editing enzyme catalytic polypeptide-like 3A (APOBEC3A) and hepatitis B virus core proteins (HBc) with different sequences, and identify its expression, intracellular localization and cytosine deamination activity. Methods The APOBEC3A gene and the coding sequence of HBc and four kinds of truncated HBc containing C-termimal domain were amplified by PCR. The APOBEC3A with full-length HBc antigen or four kinds of truncated HBc were cloned into a eukaryotic expression vector pcDNA3.0 by In-Fusion method, and confirmed by DNA sequencing. The recombinants were then transfected into HEK293T cells. The expression and localization of the fusion proteins were detected by Western blotting and immunofluorescence cytochemistry. The cytosine deamination activity was analyzed by electrophoresis on a urea denaturing polyacrylamide gel. Results Five kinds of fusion protein were expressed in HEK293T cells successfully, and the expression of the vectors containing the truncated HBc were higher than that of the APOBEC3A HBc vector containing the full-length HBc. The fusion protein of APOBEC3A-HBc was mainly expressed in the cytoplasm of HEK293T cells, and the fusion proteins of APOBEC3A-HBc144S, APOBEC3A-HBc144E, APOBEC3A-HBc144AAA, APOBEC3A-HBc144A were expressed mainly in the nuclei of HEK293T cells. The cytosine deamination activity of the fusion proteins containing the truncated HBc was higher than that of the fusion protein APOBEC3A-HBc. Conclusion The fusion protein expression vectors of APOBEC3A and HBc with different lengths and sequences have been constructed successfully. The expressing ability, intracellular localization and cytosine deamination activity are obviously different between the fusion protein APOBEC3A-HBc and the fusion proteins containing the truncated HBc. PMID- 29268858 TI - [Establishment of an iRFP and luciferase dual-color fluorescence-traced hepatocellular carcinoma transplantation model in nude mice]. AB - Objective To establish a hepatocellular carcinoma xenograft model in nude mice which could stably express gene and be monitored dynamically. Methods We first constructed the lentiviral particles containing luciferase (Luc) and near infrared fluorescent protein (iRFP) and puromycin resistance gene, and then transduced them into the HepG2 hepatoma cells. The cell line stably expressing Luc and iRFP genes were screened and inoculated into nude mice to establish xenograft tumor model. Tumor growth was monitored using in vivo imaging system. HE staining and immunohistochemistry were used to evaluate the pathological features and tumorigenic ability. Results HepG2 cells stably expressing iRFP and Luc were obtained; with the engineered cell line, xenograft model was successfully established with the features of proper tumor developing time and high rate of tumor formation as well as typical pathological features as showed by HE staining and immunohistochemistry. Conclusion Hepatocellular carcinoma model in nude mice with the features of stable gene expression and dynamical monitoring has been established successfully with the HepG2-iRFP-Luc cell line. PMID- 29268859 TI - [Optimization of culture of fetal rat cardiomyocytes in vitro]. AB - Objective To explore the optimal method for in vitro cultivation of SD fetal rat cardiomyocytes. Methods Cardiomyocytes of SD fetal rats from pregnant rats on gestational day 19 were obtained by digesting cardiac tissues with 0.8 g/L trypsin and 0.4 g/L collagenase II. With differential centrifugation and different animal serums (bovine fetal serum or horse serum), we tried to look for the optimal culture conditions. The morphology and beat frequency of cardiomyocytes were observed under an inverted phase-contrast microscope. In addition, the expressions of alpha-sarcomeric actinin (alpha-SA) and cardiac troponin I (cTnI) in the cultured cardiomyocytes were detected by immunofluorescence staining to identify cardiomyocytes and the purity of these cells after 24, 48, 72 and 96 hours of cultivation. Results After 24 hours of cultivation, we had seen a majority of adherent cells and a few of suspension cells, and also seen some pulsating cardiomyocytes. The positive rates of alpha SA and cTnI in the cardiomyocytes of the horse serum-cultured group were obviously higher than those in the bovine fetal serum-cultured group after 48, 72 and 96 hours of cultivation. Conclusion Co-digestion with trypsin and collagenaseII in combination with horse serum cultivation are easier to cultivate fetal rat cardiomyocytes. PMID- 29268860 TI - [Intramuscular injection of lentivirus-mediated EPAS1 gene improves hind limb ischemia and its mechanism in a rat model of peripheral artery vascular disease]. AB - Objective To investigate the effect of over-expressed endothelial Per-Arnt-Sim domain protein 1 (EPAS1) on peripheral arterial disease (PAD) in a rat model. Methods PAD rat model was established by external iliac artery ligation followed by lentivirus-mediated EPAS1 gene injection into rat right adductor magnus. The models were evaluated by quantitative analysis of gait disturbance. The changes of blood flow in the posterior extremity of the rats were detected using laser Doppler. The expressions of EPAS1, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) mRNAs were tested by real-time quantitative PCR. The expression of alpha-smooth muscle actin (alphaSMA) was detected by immunohistochemical staining. Results Compared with lenti-EGFP group, rat hind limb function and circulation got recovered obviously 7 days after lenti-EPAS1 injection. The mRNA expressions of EPAS1, HGF, bFGF, and VEGF were up-regulated in the lenti-EPAS1-treated sites.The expression of alphaSMA showed an obvious increase in the lenti-EPAS1-treated muscles. Conclusion Over-expressed lenti-EPAS1 can promote angiogenesis via the up-regulation of EPAS1-related angiogenic factors in the muscles of the affected hind limb and reduce gait disturbance. PMID- 29268861 TI - [Expressions of gastrin and apoptosis-associated proteins involved in mitochondrial pathway in gastric cancer tissues and the clinical significance]. AB - Objective To investigate the expressions and correlations of gastrin and apoptosis-associated proteins involved in mitochondrial apoptotic pathway in gastric cancer tissues, and explore their clinicopathological characteristics. Methods The tissue chip technology and immunohistochemistry (IHC) were used to detect the expressions of gastrin and apoptosis-associated proteins (Bcl2, caspase-9 and caspase-3) in human gastric cancer tissues and their paracancerous tissues. The correlations of these markers and their clinicopathological characteristics were analyzed using Spearman rank correlation analysis and Chi square test. Results The expressions of gastrin and Bcl2 in gastric cancer tissues were significantly higher than those in the corresponding paracancerous tissues, whereas the expressions of caspase-9 and caspase-3 in gastric cancer tissues was significantly lower than those in the corresponding tissues. There was a significant positive correlation between the expressions of gastrin and Bcl2 in gastric cancer tissues (r=0.237). The expression of gastrin was associated with tumor position, and the expression of Bcl2 was associated with tumor size, TNM stage and lymph node metastasis. Conclusion Gastrin and Bcl2 are highly expressed in gastric cancer tissues, and they are correlated with the clinicopathologic features. PMID- 29268863 TI - Retraction notice to Polar and apolar extra virgin olive oil and leaf extracts as a promising anti-inflammatory natural treatment for osteoarthritis. ACTHIS_119_4 (2017) 407-416. PMID- 29268864 TI - The Temin Effect. PMID- 29268865 TI - Spontaneous Rupture of an Iris Stromal Cyst. PMID- 29268862 TI - EGF receptor signaling, phosphorylation, ubiquitylation and endocytosis in tumors in vivo. AB - Despite a well-established role for the epidermal growth factor receptor (EGFR) in tumorigenesis, EGFR activities and endocytosis in tumors in vivo have not been studied. We labeled endogenous EGFR with GFP by genome-editing of human oral squamous cell carcinoma cells, which were used to examine EGFR-GFP behavior in mouse tumor xenografts in vivo. Intravital multiphoton imaging, confocal imaging of cryosections and biochemical analysis revealed that localization and trafficking patterns, as well as levels of phosphorylation and ubiquitylation of EGFR in tumors in vivo closely resemble patterns and levels observed in the same cells treated with 20-200 pM EGF in vitro. Consistent with the prediction of low ligand concentrations in tumors, EGFR endocytosis was kinase-dependent and blocked by inhibitors of clathrin-mediated internalization; and EGFR activity was insensitive to Cbl overexpression. Collectively, our data suggest that a small pool of active EGFRs is sufficient to drive tumorigenesis by signaling primarily through the Ras-MAPK pathway. PMID- 29268866 TI - Rhegmatogenous Retinal Detachment after Pediatric Cataract Surgery. PMID- 29268867 TI - Acute Annular Outer Retinopathy. PMID- 29268868 TI - Large Area of Myelinated Retinal Nerve Fibers. PMID- 29268869 TI - Splitting the Lumps: The Importance of Phenotyping Drusen. PMID- 29268870 TI - Conjunctival Stromal Tumor. PMID- 29268871 TI - Re: Singh et al.: Nepafenac 0.3% after cataract surgery in patients with diabetic retinopathy: results of 2 randomized phase 3 studies (Ophthalmology. 2017;124:776 785). PMID- 29268872 TI - Reply. PMID- 29268873 TI - Re: Singh et al.: Nepafenac 0.3% after cataract surgery in patients with diabetic retinopathy: results of 2 randomized phase 3 studies (Ophthalmology. 2017;124:776 785). PMID- 29268874 TI - Reply. PMID- 29268875 TI - Re: Maggio et al.: Vitreomacular adhesion and the risk of neovascular age-related macular degeneration (Ophthalmology. 2017;124:657-666). PMID- 29268876 TI - Reply. PMID- 29268877 TI - Re: Singh et al.: Nepafenac 0.3% after cataract surgery in patients with diabetic retinopathy: result of 2 randomized phase 3 studies (Ophthalmology. 2017;124:776 785). PMID- 29268878 TI - Reply. PMID- 29268879 TI - Decision Science Can Help Policymakers to Identify and Evaluate Policies to Treat Opioid Use Disorder Among Pregnant Women. PMID- 29268880 TI - Intracoronary Optical Coherence Tomography 2018: Current Status and Future Directions. AB - The advent of intravascular imaging has been a significant advancement in visualization of coronary arteries, particularly with optical coherence tomography (OCT) that allows for high-resolution imaging of intraluminal and transmural coronary structures. Accumulating data support a clinical role for OCT in a multitude of clinical scenarios, including assessing the natural history of atherosclerosis and modulating effects of therapies, mechanisms of acute coronary syndromes, mechanistic insights into the effects of novel interventional devices, and optimization of percutaneous coronary intervention. In this state-of-the-art review, we provide an overview of the published data on the clinical utility of OCT, highlighting the areas that need further investigation and the current barriers for further adoption of OCT in interventional cardiology practice. PMID- 29268882 TI - Should We Just Go With the Flow? PMID- 29268883 TI - Physiological Predictors of Acute Coronary Syndromes: Emerging Insights From the Plaque to the Vulnerable Patient. AB - In this review, the authors explore the evolving evidence linking physiological assessment of coronary artery disease with plaque progression and vulnerability. Reducing adverse clinical events remains the ultimate goal for diagnostic tests, and this review highlights evidence supporting the prognostic value of physiological metrics in predicting outcomes. Historical and contemporary studies support synergy among lesion severity, ischemia, plaque vulnerability, and patient prognosis. Ischemia contributes to clinical events through association with plaque burden, but this review addresses the emerging concept that it associates with atherothrombosis via disturbed lesion hemodynamics. Biomechanical pathophysiological forces including endothelial shear stress-the frictional force generated by blood flow on the vessel wall-are increasingly linked with atherogenesis, vulnerable plaque morphology, and platelet and leukocyte activation. The authors conclude by transitioning from the model of the vulnerable plaque to the concept of the "vulnerable patient," looking more broadly at physiological contributors to Virchow's triad underpinning acute coronary syndrome. PMID- 29268881 TI - Fractional Flow Reserve/Instantaneous Wave-Free Ratio Discordance in Angiographically Intermediate Coronary Stenoses: An Analysis Using Doppler Derived Coronary Flow Measurements. AB - OBJECTIVES: The study sought to determine the coronary flow characteristics of angiographically intermediate stenoses classified as discordant by fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR). BACKGROUND: Discordance between FFR and iFR occurs in up to 20% of cases. No comparisons have been reported between the coronary flow characteristics of FFR/iFR discordant and angiographically unobstructed vessels. METHODS: Baseline and hyperemic coronary flow velocity and coronary flow reserve (CFR) were compared across 5 vessel groups: FFR+/iFR+ (108 vessels, n = 91), FFR-/iFR+ (28 vessels, n = 24), FFR+/iFR (22 vessels, n = 22), FFR-/iFR- (208 vessels, n = 154), and an unobstructed vessel group (201 vessels, n = 153), in a post hoc analysis of the largest combined pressure and Doppler flow velocity registry (IDEAL [Iberian-Dutch English] collaborators study). RESULTS: FFR disagreed with iFR in 14% (50 of 366). Baseline flow velocity was similar across all 5 vessel groups, including the unobstructed vessel group (p = 0.34 for variance). In FFR+/iFR- discordants, hyperemic flow velocity and CFR were similar to both FFR-/iFR- and unobstructed groups; 37.6 (interquartile range [IQR]: 26.1 to 50.4) cm/s vs. 40.0 [IQR: 29.7 to 52.3] cm/s and 42.2 [IQR: 33.8 to 53.2] cm/s and CFR 2.36 [IQR: 1.93 to 2.81] vs. 2.41 [IQR: 1.84 to 2.94] and 2.50 [IQR: 2.11 to 3.17], respectively (p > 0.05 for all). In FFR-/iFR+ discordants, hyperemic flow velocity, and CFR were similar to the FFR+/iFR+ group; 28.2 (IQR: 20.5 to 39.7) cm/s versus 23.5 (IQR: 16.4 to 34.9) cm/s and CFR 1.44 (IQR: 1.29 to 1.85) versus 1.39 (IQR: 1.06 to 1.88), respectively (p > 0.05 for all). CONCLUSIONS: FFR/iFR disagreement was explained by differences in hyperemic coronary flow velocity. Furthermore, coronary stenoses classified as FFR+/iFR- demonstrated similar coronary flow characteristics to angiographically unobstructed vessels. PMID- 29268885 TI - An Unresolved Question: Antiplatelet Treatment Driven by Platelet Function in ST Segment Elevation Myocardial Infarction Patients. PMID- 29268884 TI - Observational Study of Platelet Reactivity in Patients Presenting With ST-Segment Elevation Myocardial Infarction Due to Coronary Stent Thrombosis Undergoing Primary Percutaneous Coronary Intervention: Results From the European PREvention of Stent Thrombosis by an Interdisciplinary Global European Effort Registry. AB - OBJECTIVES: High platelet reactivity (HPR) was studied in patients presenting with ST-segment elevation myocardial infarction (STEMI) due to stent thrombosis (ST) undergoing immediate percutaneous coronary intervention (PCI). BACKGROUND: HPR on P2Y12 inhibitors (HPR-ADP) is frequently observed in stable patients who have experienced ST. The HPR rates in patients presenting with ST for immediate PCI are unknown. METHODS: Consecutive patients presenting with definite ST were included in a multicenter ST registry. Platelet reactivity was measured before immediate PCI with the VerifyNow P2Y12 or Aspirin assay. RESULTS: Platelet reactivity was measured in 129 ST patients presenting with STEMI undergoing immediate PCI. HPR-ADP was observed in 76% of the patients, and HPR on aspirin (HPR-AA) was observed in 13% of the patients. HPR rates were similar in patients who were on maintenance P2Y12 inhibitor or aspirin since stent placement versus those without these medications. In addition, HPR-ADP was similar in patients loaded with a P2Y12 inhibitor shortly before immediate PCI versus those who were not. In contrast, HPR-AA trended to be lower in patients loaded with aspirin as compared with those not loaded. CONCLUSIONS: Approximately 3 out of 4 ST patients with STEMI undergoing immediate PCI had HPR-ADP, and 13% had HPR-AA. Whether patients were on maintenance antiplatelet therapy while developing ST or loaded with P2Y12 inhibitors shortly before undergoing immediate PCI had no influence on the HPR rates. This raises concerns that the majority of patients with ST have suboptimal platelet inhibition undergoing immediate PCI. PMID- 29268886 TI - Benefit of Switching Dual Antiplatelet Therapy After Acute Coronary Syndrome According to On-Treatment Platelet Reactivity: The TOPIC-VASP Pre-Specified Analysis of the TOPIC Randomized Study. AB - OBJECTIVES: This study sought to evaluate the impact of initial platelet reactivity on the benefit of switched strategy. BACKGROUND: TOPIC (Timing Of Platelet Inhibition after acute Coronary Syndrome) study suggested that switched dual antiplatelet therapy (DAPT) could improve net clinical benefit after acute coronary syndrome by preventing bleeding. METHODS: Acute coronary syndrome patients, 1 month after coronary stenting and event free, were randomly assigned to aspirin and clopidogrel (switched DAPT) or continuation of drug regimen (unchanged DAPT). All patients underwent platelet function testing at this time and were classified as low on-treatment platelet reactivity (LTPR) (platelet reactivity index vasodilator-stimulated phosphoprotein <=20%) or non-LTPR (platelet reactivity index vasodilator-stimulated phosphoprotein >20%). The primary endpoint aimed to evaluate the impact of platelet reactivity on clinical outcomes and benefit of switched DAPT strategy. RESULTS: A total of 645 patients were included, 305 (47%) of whom were classified as LTPR. LTPR patients were less often diabetic (p = 0.01), had lower body mass index (p < 0.01), and were more often on ticagrelor (p < 0.01). Patients defined as LTPR and randomized to unchanged DAPT were at the highest risk of primary endpoint occurrence (31%; p < 0.01). Conversely, in the switched arm, LTPR patients had no significant difference in primary outcome incidence compared with non-LTPR patients (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.40 to 1.49; p = 0.45). The switched strategy was associated with important reduction in primary endpoint incidence in LTPR patients (HR: 0.29; 95% CI: 0.17 to 0.51; p < 0.01) and only numerically lower incidence in non-LTPR patients (HR: 0.79; 95% CI: 0.46 to 1.35; p = 0.39). CONCLUSIONS: Switched DAPT was superior regardless of initial platelet reactivity but the benefit was greater in LTPR patients. Indeed, the switched strategy was highly effective in this group, which had impaired prognosis with unchanged DAPT but similar prognosis after switching. PMID- 29268887 TI - De-Escalation of Platelet P2Y12 Receptor Inhibiting Therapy After Percutaneous Coronary Intervention: Does One Size Fit All? PMID- 29268888 TI - The Metamorphosis of ST-Segment Elevation Myocardial Infarction Programs: The Changing Role of the Interventional Cardiologist and its Manpower Implications. PMID- 29268889 TI - 40 Years of Percutaneous Coronary Intervention: A Historical Remark on the Development and Evolution of Guidewire Technology. PMID- 29268890 TI - 40 Years of Percutaneous Coronary Intervention: A Historical Remark on the Development of the Monorail Technique. PMID- 29268891 TI - Mechanisms of Orbital Versus Rotational Atherectomy Plaque Modification in Severely Calcified Lesions Assessed by Optical Coherence Tomography. PMID- 29268892 TI - The Year of Special Anniversaries: Tin, Crystal, Silver, and Ruby. PMID- 29268893 TI - Overlapping Foot and Ankle Surgery. PMID- 29268894 TI - Determination of Pathogens in Postoperative Wound Infection After Surgically Reduced Calcaneal Fractures and Implications for Prophylaxis and Treatment. AB - High rates of postoperative wound infection (POWI) have been reported after surgery for calcaneal fractures. This is a retrospective cohort study to determine the causative pathogens of these infections and subsequent treatment strategies. In addition, microbacterial growth from superficial wound swabs and deep fluid or tissue cultures were compared. Patients with a unilateral surgically treated calcaneal fracture during a 15-year period were included. Patient, fracture, and surgical characteristics were collected from the electronic medical records. An infection was categorized as deep or superficial using the Centers for Disease Control and Prevention criteria. Secondary outcomes were wound edge necrosis and wound dehiscence. The collection of culture swabs, their results, and treatment strategies were documented. Of 357 patients, 92 (26%) developed a POWI; 55 (60%) deep and 37 (40%) superficial. The most frequent causative pathogens were Enterobacteriaceae and Staphylococcus aureus. Of the 55 patients with deep infection, 31 (56%) were treated with intravenous antibiotics and surgical debridement, 2 (4%) with intravenous antibiotics, and 22 (40%) with implant removal. In 33 of 92 patients (36%) with a POWI, both superficial and deep cultures were obtained, with a microorganism not cultured from the superficial swab 13 (39%) times. In conclusion, we found that one quarter of patients with operative calcaneal fracture treatment developed a POWI, mainly caused by Enterobacteriaceae or S. aureus. Physicians should not rely on the results of superficially obtained cultures for adequate treatment of deep infection. Because the spectrum of sensitivity profiles varies greatly between hospitals and countries, we recommend empiric antibiotic treatment of both gram positive and gram-negative microorganisms on suspicion of deep infection. PMID- 29268895 TI - A Perifascial Areolar Tissue Graft With Topical Administration of Basic Fibroblast Growth Factor for Treatment of Complex Wounds With Exposed Tendons and/or Bones. AB - The management of wounds with tendon and/or bone exposure is challenging because of the insufficient blood supply to the wound bed. We describe our experience with 19 patients using a perifascial areolar tissue (PAT) graft with topical administration of basic fibroblast growth factor (bFGF) in the treatment of complex wounds with exposed tendons and/or bones in the extremities. Using a PAT graft is minimally invasive and technically easy, and the donor site is relatively preserved. However, PAT grafts for the treatment of a complex wound with large areas of exposed tendons and/or bones have sometimes failed to survive because of insufficient vascularization of the wound bed. Therefore, topical administration of bFGF, which promotes angiogenesis, was added to the graft. All grafts showed good graft survival and successfully covered the tendons and bones. Topical administration of bFGF accelerated vascularization in the PAT graft and facilitated wound healing by increasing the blood supply to the wound bed and achieved success with the PAT graft. In conclusion, using a PAT graft with topical administration of bFGF is a suitable option for the treatment of complex wounds with a large proportion of exposed tendons and/or bones. With minimal damage to the tissues near the wound, the PAT graft can be a useful option for limb salvage and could become a valuable tool for reconstructive surgeons. PMID- 29268896 TI - Effect of Mechanical Axis Correction on Outcomes of Hallux Valgus Surgery. AB - A new method of mechanical axis planning has recently been suggested to aid in corrective surgery for hallux valgus (HV) deformity, which aims to identify the ideal position for the first metatarsal after correction. We investigated the influence of the mechanical axis angle (MAA) correction on the outcomes of corrective HV surgery. We reviewed 50 radiographs to identify the "normal" MAA range within the population. We also reviewed the medical records of 100 patients who had undergone scarf osteotomy at our institution from January 2011 to December 2013. These patients were segregated into 2 groups according to their postoperative MAA: those within the normal range (normal group) and those outside this range (outlier group). We compared the pre- and postoperative functional scores between the 2 groups using statistical analysis. The normal MAA range within our population was 12.5 degrees +/- 0.8 degrees (range 11.0 degrees to 14.3 degrees ). We found that the physical component summary score of the short form 36-item health survey was significantly poorer for the outlier group at 6 and 24 months postoperatively compared with the normal group, although the other postoperative scores were comparable. Surgical correction of the MAA to the normal range of the patient population can be recommended because it provides improved quality of life. However, further studies are required to investigate the influence of MAA planning on other standardized foot and ankle scores. PMID- 29268897 TI - Fifth Metatarsal Osteotomies for Treatment of Bunionette Deformity: A Meta Analysis of Angle Correction and Clinical Condition. AB - We assessed which type of osteotomy would be most suited for correcting an increased fourth to fifth intermetatarsal angle (IMA) and metatarsophalangeal angle (MPA) and would have the best results regarding the clinical condition and satisfaction. The study design was a systematic review and meta-analysis. The main outcome measures were the IMA, MPA, and American Orthopaedic Foot and Ankle Society Lesser Metatarsophalangeal-Interphalangeal scale and satisfaction scores. A systematic search was performed in Medline, Embase, Cochrane, SPORTdiscus, and CINAHL up to September 2016. Prospective and retrospective studies that had evaluated the outcomes of fifth metatarsal osteotomies to correct a bunionette deformity at all patient ages were included. The outcomes were determined from clinical or radiographic evaluations. The search yielded 28 studies suitable for inclusion in our meta-analysis. All groups of osteotomies achieved significant IMA changes, with proximal osteotomies resulting in significantly greater changes than diaphyseal or distal osteotomies. The overall effect of osteotomies on the MPA was of a significant reduction. Proximal and diaphyseal osteotomies both resulted in significant differences in MPA correction compared with distal osteotomies. The incidence of major complications was the least in the distal osteotomy group. The overall mean success rate of bunionette surgery was 93%. The patients were most satisfied with proximal osteotomies, followed by distal and diaphyseal osteotomies (100% and 92%, respectively). In conclusion, every type of osteotomy has the capability of significantly reducing the fourth to fifth IMA and MPA. The fewest complications occurred with distal osteotomies, and the greatest satisfaction score was achieved with proximal osteotomies. However, only 1 study evaluated these results for proximal osteotomies. Distal osteotomies resulted in a high satisfaction rate and were the most represented osteotomy in our meta-analysis. Thus, when major IMA and MPA reduction is not required, the distal osteotomy could be the treatment of choice owing to its low complication rate. PMID- 29268898 TI - Measuring Recovery After Ankle Fractures: A Systematic Review of the Psychometric Properties of Scoring Systems. AB - Recovery after ankle fractures places a considerable burden on patients both short and long term. Numerous tools called patient-reported outcome measures (PROMs) have been developed to measure the outcome of ankle fractures. They can assist clinicians to measure the effect, guide intervention, and assess the rate of recovery. We identified and evaluated the psychometric properties of PROMs used in the assessment of ankle fractures. In a systematic search, we examined 4 databases from inception to December 4, 2016. Search terms included ankle fracture, ankle pain, disability, gait, questionnaire, and PROMs. Reference lists were also examined. The inclusion criteria were English studies and adult populations. The psychometric properties of the identified PROMs were examined, including internal consistency, test-retest reliability, validity, floor-ceiling effects, and minimally important clinical differences. We identified 22 PROMs relating to ankle pain and disability. Only 5 were specifically used for ankle fractures. The 36-item short-form health survey and short musculoskeletal functional assessment reported floor-ceiling effects, and the lower extremity functional scale reported good responsiveness and content validity, although these are not tools specifically related to ankle fractures. The ankle-fracture outcome of rehabilitation measure (A-FORM) and the Olerud and Molander questionnaire were ankle fracture specific and assessed for internal consistency and validity. Clinicians should use the most appropriate PROM to evaluate patients' recovery from ankle fractures. The A-FORM currently has the most appropriate evidence supporting its use as a PROM for ankle fracture management and rehabilitation. PMID- 29268899 TI - Expanded Age Indication for Ponseti Method for Correction of Congenital Idiopathic Talipes Equinovarus: A Systematic Review. AB - The deformity known as congenital idiopathic talipes equinovarus (CTEV) is probably the most common (1 to 2 in 1000 live births) congenital orthopedic condition requiring intensive treatment. With the perception that the treatment of idiopathic CTEV by extensive soft tissue release is often complicated by stiffness, recurrence, and the need for additional procedures, the minimally invasive Ponseti method has been accepted as the first line of treatment, which has achieved excellent results globally. The Ponseti method has achieved excellent results in children with idiopathic CTEV aged <=2 years. However, the upper age limit for the Ponseti treatment has not yet been defined. We reviewed the published data to determine the efficacy of the Ponseti method in older children with neglected CTEV. PMID- 29268900 TI - Suture-Button Fixation and Mini-Open Anterior Inferior Tibiofibular Ligament Augmentation Using Suture Tape for Tibiofibular Syndesmosis Injuries. AB - Tibiofibular fixation using suture-button implants is an optional method for the surgical treatment of syndesmosis injuries. Although good clinical outcomes have been reported, inadequate stability between the tibia and fibula has also been documented. Thus, suture-button fixation is not considered the reference standard. For surgical treatment of lateral ligament injuries of the ankle, good treatment outcomes have also been reported with ligament augmentation using nonabsorbable suture tape. Ligament augmentation tape with suture-button fixation could also be promising for improved treatment outcomes in syndesmosis injuries. We describe suture-button fixation together with mini-open anterior inferior tibiofibular ligament augmentation using suture tape for treatment of syndesmosis injuries. PMID- 29268901 TI - Split Peroneus Longus Free Tendon Autograft Transplantation for the Treatment of Neglected Extensor Hallucis Longus Tendon Laceration: A Case Report. AB - A neglected laceration of the extensor hallucis longus (EHL) tendon is rare. Retraction of the tendon ends often occurs when a laceration is neglected, leading to a substantial tendon deficit. A paucity of case reports is available describing the treatment of EHL laceration with a large area of gap secondary to retraction. Therefore, the treatment recommendations are limited. We present the case of a neglected EHL tendon laceration with a 10.5-cm gap in a healthy 22-year old female. The EHL tendon laceration was repaired using a split peroneus longus tendon autograft that, to the best of our knowledge, has not been previously reported. At the 3-year follow-up evaluation, the patient retained full function of her hallux and was free of symptoms. PMID- 29268902 TI - Does First Ray Amputation in Diabetic Patients Influence Gait and Quality of Life? AB - It has recently been suggested that first ray amputation in diabetic patients with serious foot complications can prolong bipedal ambulatory status, and reduce morbidity and mortality. However, no data are available on gait analysis and quality of life after this procedure. In the present case-control study (6 amputee and 6 nonamputee diabetics, 6 healthy non-diabetic), a sample of amputee diabetic patients were evaluated and compared with a sample of nonamputee diabetic patients and a group of age-matched healthy subjects. Gait biomechanics, quality of life, and pain were evaluated. Compared with the other 2 groups, amputee patients displayed a lower walking speed and greater variability and lower ankle, knee, and hip range of motion values. They also tended to have a more flexed hip profile. Pain and lower quality of life were related to worsening biomechanical data. Our study results have shown that gait biomechanics in diabetic patients with first ray amputation are abnormal, probably owing to the severity of diabetes and the absence of the push-off phase provided by the hallux. Tailored orthotics and rehabilitation programs and a specific pain management program should be considered to improve the gait and quality of life of diabetic patients with first ray amputation. PMID- 29268903 TI - Fixation Strength of Polyetheretherketone Sheath-and-Bullet Device for Soft Tissue Repair in the Foot and Ankle. AB - Tendon transfers are often performed in the foot and ankle. Recently, interference screws have been a popular choice owing to their ease of use and fixation strength. Considering the benefits, one disadvantage of such devices is laceration of the soft tissues by the implant threads during placement that potentially weaken the structural integrity of the grafts. A shape memory polyetheretherketone bullet-in-sheath tenodesis device uses circumferential compression, eliminating potential damage from thread rotation and maintaining the soft tissue orientation of the graft. The aim of this study was to determine the pullout strength and failure mode for this device in both a synthetic bone analogue and porcine bone models. Thirteen mature bovine extensor tendons were secured into ten 4.0 * 4.0 * 4.0-cm cubes of 15-pound per cubic foot solid rigid polyurethane foam bone analogue models or 3 porcine femoral condyles using the 5 * 20-mm polyetheretherketone soft tissue anchor. The bullet-in-sheath device demonstrated a mean pullout of 280.84 N in the bone analog models and 419.47 N in the porcine bone models. (p = .001). The bullet-in-sheath design preserved the integrity of the tendon graft, and none of the implants dislodged from their original position. PMID- 29268904 TI - Novel Elastic Syndesmosis Hook Plate Fixation Versus Routine Screw Fixation for Syndesmosis Injury. AB - Unstable external-rotation type ankle fractures with concomitant syndesmosis injury commonly occur. Syndesmosis screw fixation has long been regarded as a reference standard treatment for syndesmosis injury. However, its complications and biomechanical disadvantages have become controversial; thus, we designed a novel elastic syndesmosis hook plate (ESHP) that combines the features of both rigidity and flexibility. The purpose of the present study was to introduce this new method and compare its clinical outcomes with those of routine screw fixation. We randomized 25 patients to the screw fixation group and ESHP group. The average follow-up period was 12 months. The clinical outcomes included malreduction or loss of reduction, overall complications, and function. During the follow-up period, 3 cases (25%) of malreduction were found in screw fixation group on postoperative computed tomography. In the ESHP group, only 1 patient (7.69%) had a narrowed anterior gap between the distal tibia and fibula. However, the difference in the malreduction rate between the 2 groups was not significant statistically (p = .32). The overall complication rate in the ESHP group was lower than that in the screw group, although no significant differences were found between the 2 groups. The mean visual analog scale scores in the ESHP and screw groups were 1.46 +/- 1.33 and 2.42 +/- 2.07, respectively. The average dorsiflexion range of motion in both groups was satisfactory (14.77 degrees versus 12.83 degrees ; p = .16). However, a statistically significant difference was found in the plantarflexion range of motion between the 2 groups (p < .05). In addition, the ESHP group had an earlier time to return to work (p < .05). The ESHP fixation construct can stably fix syndesmosis, retain the physiologic micromotion function of the syndesmosis, and results in fewer complications compared with routine syndesmosis screw fixation for syndesmotic instability. In conclusion, our results have shown ESHP to be a viable method for treatment of syndesmosis instability. PMID- 29268905 TI - Does Total Ankle Arthroplasty Belong in the Comprehensive Care for Joint Replacement? AB - The Comprehensive Care for Joint Replacement (CJR) model seeks to lower costs and improve quality for primary lower extremity joint replacements. This includes total ankle arthroplasty (TAA), which is performed far less frequently than total hip (THA) and knee (TKA) arthroplasty. We used the SPARCS database to identify 537 TAA and 239,053 elective primary THA or TKA procedures from 2009 to 2014, excluding hip fractures. Compared with THA and TKA, TAA had a shorter mean length of stay (2.2 versus 3.2 days), greater mean cost ($20,817 versus $17,613), lower rate of disposition to nursing and rehabilitation facilities (17% versus 52%), and lower rate of 90-day readmission (4.9% versus 5.8%). In multivariable adjusted regression models of TAA versus THA and TKA, length of stay was 30% shorter (p < .001), costs were 14% greater (p < .001), and risk of disposition to nursing and rehabilitation facilities was 86% lower (p < .001), with no significant difference in 90-day readmission (p = .957). Patients undergoing TAA had different patterns of short-term resource usage compared with patients undergoing THA and TKA, most notably higher short-term costs. The economic viability of TAA is threatened by alternative payment models that reimburse hospitals for TAA at the same rate as THA and TKA. PMID- 29268906 TI - Evaluation of Midterm Results of the Panta Nail: An Active Compression Tibiotalocalcaneal Arthrodesis Device. AB - A tibiotalocalcaneal intramedullary rod is a powerful construct often reserved for difficult and salvage cases. The Panta Nail (Integra LifeSciences, Plainsboro, NJ) is a second-generation rod that offers active axial compression compared with previous rod designs. We characterized our experience with this device and identified factors associated with nonunion. We retrospectively identified 19 patients receiving the Panta Nail during a 4-year period with a mean follow-up period of 16 months. We used a consecutive series approach toward inclusion. Fusion, asymptomatic fibrous union, or nonunion was determined for each ankle and subtalar joint as the primary endpoint. Patients were grouped as follows: group A, successful outcome; group B, successful outcome after dynamization; group C, no successful outcome. Secondary data were tested for association with the probability of first-attempt fusion. The Panta Nail resulted in a first-attempt fusion rate of 65% at the ankle and subtalar joints. With implementation of dynamization (31% of cases) at an average of 28 weeks after insertion (groups A and B), the bony fusion rate was 88% and 77% at the ankle and subtalar joint, respectively. Inclusion of 3 asymptomatic fibrous unions with final visual analog scale scores <4 (1 ankle; 2 subtalar) as successful outcomes resulted in 94% and 88% success rates for the ankle and subtalar joints (groups A and B). Salvaged total ankle arthroplasties with the Panta Nail device as a subgroup had an 83% fusion rate, with a 50% dynamization rate. No predictors of nonunion were found. The Panta Nail is a second-generation tibiotalocalcaneal arthrodesis device capable of providing good success rates for fusion. Also, dynamization is an appropriate and frequent augmentation method. PMID- 29268907 TI - Improving the Consent Process in Foot and Ankle Surgery With the Use of Personalized Patient Literature. AB - A patient-specific letter was introduced to the consent process to observe the effect, if any, on information recall and satisfaction for patients undergoing elective foot and ankle surgery. The patients attending the clinic were written a personalized letter-this was a simple personalized letter that outlined their treatment options, the proposed management plan, likely treatment course, and the benefits, risks, and likely period required for recovery. The personalized letter system was compared with the 2 existing methods of consent process: signing for consent at their outpatient encounter at which they were scheduled for surgery and a separate consent clinic without the personalized letter. A total of 111 patients (87 females, 24 males) undergoing elective foot and ankle surgery were assessed on the day of surgery for recall of the procedure, risks, postoperative course, and satisfaction with the consent process. Patients receiving a personalized letter recalled more than those who had attended a routine preoperative consent clinic visit and significantly more than those who had provided consent at their last clinic visit. Patient satisfaction with the consent process was also greater in the personalized group. Our results suggest that the consent process is improved using routine preoperative consent clinics and, most notably, with patient-specific information to improve patient recall and satisfaction. PMID- 29268908 TI - Posterior Inferior Tibiofibular Ligament Release to Achieve Anatomic Reduction of Posterior Malleolar Fractures. AB - We assessed the clinical and radiographic outcomes of posterior inferior tibiofibular ligament (PITFL) release to achieve anatomic reduction of posterior malleolar fractures (PMFs). Nineteen PMFs (>25% of tibial plafond) that could not be reduced after anatomic reduction of distal fibula fractures were managed by PITFL release. The syndesmosis was stressed intraoperatively and by 2 surgeons unaware of the postoperative measurements to increase reliability. The pre- and postoperative fracture gaps and articular step-offs were measured on lateral radiographs of all patients and computed tomography (CT) scans of 12. Tibiofibular clear space and overlap measures at the final follow-up visit were used to evaluate postoperative syndesmotic stability. Postoperative function was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) scale score. The mean pre- and postoperative fracture gap and step-off of the PMFs was 4.9 mm and 0.4 mm and 2.8 mm and 0.4 mm, respectively. On CT scan, the mean pre- and postoperative fracture gap and step-off was 5.2 mm and 0.5 mm and 3.3 mm and 0.6 mm, respectively. The preoperative and final follow-up tibiofibular clear space and overlap did not differ significantly. The mean follow-up period was 26.7 months, and the mean AOFAS scale score was 90.6 points at the final follow up. Direct visualization and reduction of PMFs through PITFL release led to satisfactory clinical and radiographic outcomes without causing ankle instability. PMID- 29268909 TI - Radiographic Assessment of Fibular Length Variance: The Case for "Fibula Minus". AB - Given the high prevalence of ankle fractures and morbidity of malalignment after fixation, an appropriate anatomic relationship between the distal fibula and adjacent tibia and talus is important. The tip of the lateral malleolus of the fibula has often been described to be at the level of the lateral talar process. However, no studies to date have examined the relationship of the distal fibular tip to the lateral process of the talus. We assessed 66 weightbearing mortise radiographs for variability of the distal fibular tip in relation to the lateral process of the talus. The subjects were all skeletally mature, with a mean age of 45.3 +/- 14.6 years. We used a paired t test with a null hypothesis that the true mean difference in the distance from the distal fibula to the lateral process was equal to 0. The mean distance of the distal tip of the fibula was 0.257 +/- 0.127 cm proximal to the tip of the lateral process of the talus. The 95% confidence interval was 0.226 to 0.288. Of the 66 subjects, 65 had the distal tip of the fibula proximal to the lateral process of the talus, corresponding to a negative fibular variance. In the remaining subject, the distal tip of the fibula was at the same level of the tip as the lateral process of the talus. The distal tip of the fibula is most commonly not at the level of the talus lateral process, as often described in published reports. Instead, it has a variance analogous to the relationship between the lengths of the ulna compared with the radius. The distal tip of the fibula in our study was more often proximal to the tip of the lateral process of the talus and can be described as a negative fibular variance, or "fibula minus." PMID- 29268910 TI - Biomechanical Comparison of Fixation With a Single Screw Versus Two Kirschner Wires in Distal Chevron Osteotomies of the First Metatarsal: A Cadaver Study. AB - Distal chevron osteotomy is a common procedure for surgical correction of hallux valgus. Osteosynthesis with 1 screw or 2 Kirschner wires has been commonly used. We compared the stability of the 2 techniques in distal chevron osteotomy. Sixteen first metatarsals from fresh-frozen human cadaver feet (9 different cadaveric specimens) were used. A standardized distal chevron osteotomy was performed. One first metatarsal from each pair was assigned to group 1 (3.5-mm cortical screw; n = 8) and one to group 2 (two 1.6-mm Kirschner wires; n = 8). Using a materials testing machine, the head of the first metatarsals was loaded in 2 different configurations (cantilever and physiologic) in succession. In the cantilever configuration, the relative stiffness of the osteosynthesis compared with intact bone was 59% +/- 27% in group 1 and 68% +/- 18% in group 2 (p = .50). In the physiologic configuration, it was 38% +/- 25% in group 1 and 35% +/- 7% in group 2 (p = .75). The failure strength in the cantilever configuration was 187 +/- 105 N in group 1 and 259 +/- 71 N in group 2 (p = .21). No statistically significant differences were found in stability between the 2 techniques. The use of 1 screw or 2 Kirschner wires had no significant differences in their biomechanical loading capacity for osteosynthesis in distal chevron osteotomies for treatment of hallux valgus. PMID- 29268911 TI - Update of the Society for Vascular Surgery abdominal aortic aneurysm guidelines. PMID- 29268913 TI - Invited commentary. PMID- 29268912 TI - Select early type IA endoleaks after endovascular aneurysm repair will resolve without secondary intervention. AB - OBJECTIVE: Although it is traditionally considered ominous, the natural history of early proximal attachment site endoleaks (IA) after endovascular aneurysm repair (EVAR) is not well known. Our aim was to identify risk factors for persistent type IA endoleaks and to determine their effect on long-term outcomes after EVAR. METHODS: All patients who underwent infrarenal EVAR at a single institution between 1998 and 2015 were identified. Preoperative axial imaging and intraoperative arteriograms were reviewed, and those patients with a type IA endoleak were further studied. Aneurysm features were characterized by two reviewers and were studied for predictors of persistent endoleaks at the conclusion of the case. Patient records and the Social Security Death Index were used to record 1-year and overall survival. RESULTS: We identified 1484 EVARs, 122 (8%) of which were complicated by a type IA endoleak on arteriography after graft deployment, with a median follow-up of 4 years. The majority of patients underwent additional ballooning of the proximal site (52 [43%]) or placement of an aortic cuff (47 [39%]); 30 patients (25%) received a Palmaz stent, and four patients were treated with coils or anchors. At case end, only 43 (35%) of the type IA endoleaks remained; at 1 month, only 16 endoleaks persisted (13%), and only six persisted at 1 year (6%). In multivariable analysis, the only independent predictor of persistence of type IA endoleak at the conclusion of the case was the presence of extensive neck calcifications (odds ratio [OR], 9.9; 95% confidence interval [CI], 1.4-67.9; P = .02). Thirteen patients (11%) underwent reintervention for type IA endoleaks, with a time frame ranging from 3 days postoperatively to 11 years. There were three patients (2.4%) who experienced aneurysm rupture. Postoperative type IA endoleak was associated with lower survival at 1 year (79% vs 91%; relative risk, 2.5; 95% CI, 1.1-5.4; P = .02), but it did not affect long-term survival (log-rank, P = .45). Both an increase in aneurysm sac size and failure of the endoleak to resolve by case end were independent predictors of a need for reintervention (growth: OR, 8.3; 95% CI, 2.2 31.6; P < .01; persistent endoleak: OR, 7.6; 95% CI, 1.8-31.5; P < .01). A persistent type IA endoleak was not independently associated with an increase in sac size on surveillance imaging (P = .28). CONCLUSIONS: Aneurysm rupture secondary to persistent type IA endoleak is rare, and most will resolve within 1 year. Extensive neck calcification is the only independent predictor of persistent type IA endoleak, and an increase in sac size warrants reintervention. These data suggest that select early persistent type IA endoleaks can be safely observed. PMID- 29268914 TI - Invited commentary. PMID- 29268915 TI - Invited commentary. PMID- 29268916 TI - The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. AB - BACKGROUND: Decision-making related to the care of patients with an abdominal aortic aneurysm (AAA) is complex. Aneurysms present with varying risks of rupture, and patient-specific factors influence anticipated life expectancy, operative risk, and need to intervene. Careful attention to the choice of operative strategy along with optimal treatment of medical comorbidities is critical to achieving excellent outcomes. Moreover, appropriate postoperative surveillance is necessary to minimize subsequent aneurysm-related death or morbidity. METHODS: The committee made specific practice recommendations using the Grading of Recommendations Assessment, Development, and Evaluation system. Three systematic reviews were conducted to support this guideline. Two focused on evaluating the best modalities and optimal frequency for surveillance after endovascular aneurysm repair (EVAR). A third focused on identifying the best available evidence on the diagnosis and management of AAA. Specific areas of focus included (1) general approach to the patient, (2) treatment of the patient with an AAA, (3) anesthetic considerations and perioperative management, (4) postoperative and long-term management, and (5) cost and economic considerations. RESULTS: Along with providing guidance regarding the management of patients throughout the continuum of care, we have revised a number of prior recommendations and addressed a number of new areas of significance. New guidelines are provided for the surveillance of patients with an AAA, including recommended surveillance imaging at 12-month intervals for patients with an AAA of 4.0 to 4.9 cm in diameter. We recommend endovascular repair as the preferred method of treatment for ruptured aneurysms. Incorporating knowledge gained through the Vascular Quality Initiative and other regional quality collaboratives, we suggest that the Vascular Quality Initiative mortality risk score be used for mutual decision-making with patients considering aneurysm repair. We also suggest that elective EVAR be limited to hospitals with a documented mortality and conversion rate to open surgical repair of 2% or less and that perform at least 10 EVAR cases each year. We also suggest that elective open aneurysm repair be limited to hospitals with a documented mortality of 5% or less and that perform at least 10 open aortic operations of any type each year. To encourage the development of effective systems of care that would lead to improved outcomes for those patients undergoing emergent repair, we suggest a door-to-intervention time of <90 minutes, based on a framework of 30-30-30 minutes, for the management of the patient with a ruptured aneurysm. We recommend treatment of type I and III endoleaks as well as of type II endoleaks with aneurysm expansion but recommend continued surveillance of type II endoleaks not associated with aneurysm expansion. Whereas antibiotic prophylaxis is recommended for patients with an aortic prosthesis before any dental procedure involving the manipulation of the gingival or periapical region of teeth or perforation of the oral mucosa, antibiotic prophylaxis is not recommended before respiratory tract procedures, gastrointestinal or genitourinary procedures, and dermatologic or musculoskeletal procedures unless the potential for infection exists or the patient is immunocompromised. Increased utilization of color duplex ultrasound is suggested for postoperative surveillance after EVAR in the absence of endoleak or aneurysm expansion. CONCLUSIONS: Important new recommendations are provided for the care of patients with an AAA, including suggestions to improve mutual decision-making between the treating physician and the patients and their families as well as a number of new strategies to enhance perioperative outcomes for patients undergoing elective and emergent repair. Areas of uncertainty are highlighted that would benefit from further investigation in addition to existing limitations in diagnostic tests, pharmacologic agents, intraoperative tools, and devices. PMID- 29268918 TI - Invited commentary. PMID- 29268917 TI - Isolated iliac vascular injuries and outcome of repair versus ligation of isolated iliac vein injury. AB - OBJECTIVE: The incidence of morbidity and mortality for iliac vascular injuries in the literature are likely overestimated owing to associated injuries. Data for isolated iliac vascular injuries are very limited. No large studies have reported the incidence of morbidity for repair versus ligation of isolated iliac vein injuries. METHODS: Patients in the National Trauma Data Bank (NTDB; 2007-2012) with at least one iliac vascular injury were analyzed. Isolated iliac vessels were defined as cases with Abbreviated Injury Scale severity score of greater than 3 for extraabdominal injuries and an Organ Injury Scale grade of greater than 3 for intraabdominal injuries. RESULTS: Overall, 6262 iliac vascular injuries (2809 penetrating, 3453 blunt) were identified in 271,076 patients with abdominal trauma (2.3%). There were 3379 patients (1841 penetrating, 1538 blunt) with isolated iliac vascular injuries (1.2%) and 557 patients (514 penetrating, 43 blunt) with combined iliac artery and vein injuries (0.2%). The 30-day mortality rate was 16.5% for isolated iliac vein injury, 19.3% for isolated iliac artery injury, and 48.7% for combined isolated iliac artery and vein injury. The 30-day mortality rate was 23.4% for isolated iliac vascular injuries compared with 39.0% for nonisolated iliac vascular injuries (P < .001). Patients with isolated iliac vein injuries had morbidity rates of deep venous thrombosis (repair, 14.6%; ligation, 14.1%; P = .875), pulmonary embolism (repair, 1.8%; ligation, 0.5%; P = .38), fasciotomy (repair, 9.3%; ligation, 14.6%; P = .094), amputation (repair, 1.8%; ligation, 2.6%; P = .738), acute kidney injury (repair, 5.8%; ligation, 4.7%; P = .627). Multivariate logistic regression demonstrated that ligation of isolated iliac vein injuries had an odds ratio of 2.2 for mortality compared with repair (95% confidence interval, 1.08-4.66). CONCLUSIONS: Isolated iliac vascular injuries are associated with a high incidence of mortality, especially for combined venous and arterial injury, but mortality is significantly lower than in patients with nonisolated iliac vascular injuries. In patients with isolated iliac vein injuries, mortality was higher in patients who underwent ligation compared with repair; however, the rates of deep venous thrombosis, pulmonary embolism, fasciotomy, amputation, and acute kidney injury were not different between the treatment groups. These data lend credence to the assessment that repair of iliac vein injuries is preferable to ligation whenever feasible. PMID- 29268919 TI - Invited commentary. PMID- 29268920 TI - Unusual mesenteric revascularization. PMID- 29268921 TI - What is an MIPS APM? PMID- 29268923 TI - Approximate Truth. PMID- 29268922 TI - Comparison of Different Diastolic Resting Indexes to iFR: Are They All Equal? AB - BACKGROUND: Pressure measurement for the duration of the wave-free period (WFP) is considered essential for resting-state physiological assessment of coronary stenosis severity using the instantaneous wave-free ratio (iFR). OBJECTIVES: The aim of this study was to compare other diastolic resting indexes to iFR. METHODS: In the population of the VERIFY2 (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography) study, iFR calculated by proprietary software (Volcano Harvest, Volcano Corporation, Rancho Cordova, California) was compared with the ratio of resting distal coronary pressure and aortic pressure during the complete duration of diastole (dPR), 25% to 75% of diastole (dPR25-75), and midpoint of diastole (dPRmid), along with Matlab calculated iFR (iFRmatlab) and iFR-like indexes shortening the length of the WFP by 50 and 100 ms (iFR-50ms and iFR-100ms), respectively. Mutual differences, Spearman correlations, area under the curve values from receiver-operating characteristic analyses, and diagnostic performance with respect to iFR and fractional flow reserve (FFR) were calculated for all indexes. RESULTS: Median iFR in 197 patients with 257 vessels was 0.91 with an interquartile range of 0.87 to 0.95. The mutual differences (+/- SD) with iFR were 0.006 +/- 0.011 (dPR), 0.001 +/- 0.007 (dPR25-75), 0.001 +/- 0.008 (dPRmid), 0.005 +/- 0.009 (iFRmatlab), 0.003 +/- 0.008 (iFR-50ms), and 0.001 +/- 0.009 (iFR-100ms). Correlations for all indexes with iFR were >0.99 (p < 0.001 for all). Area under the curve values for predicting iFR were >0.99 for all indexes as well. Diagnostic accuracy compared with FFR was 76% to 77% for all indexes including iFR. CONCLUSIONS: All diastolic resting indexes tested were identical to iFR, both numerically and with respect to their agreement with FFR. A numerically equal value to iFR can be determined without restriction to the WFP. Cutoff values, guidelines, and clinical recommendations for iFR can therefore be extended to these other indexes. (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography [VERIFY2]; NCT02377310). PMID- 29268924 TI - Association of Elevated NT-proBNP With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) is considered a marker that is expressed in response to myocardial strain and possibly fibrosis. However, the relationship to myocardial fibrosis in a community-based population is unknown. OBJECTIVES: The authors evaluated the relationship between cardiac magnetic resonance (CMR) measures of fibrosis and NT proBNP levels in the MESA (Multi-Ethnic Study of Atherosclerosis) study. METHODS: A total of 1,334 participants (52% white, 23% black, 11% Chinese, 14% Hispanic, and 52% men with a mean age of 67.6 years) at 6 sites had both serum NT-proBNP measurements and CMR with T1 mapping of indices of fibrosis at 1.5 T. Univariate and multivariable regression analyses adjusting for demographics, cardiovascular risk factors, and left ventricular (LV) mass were performed to examine the association of log NT-proBNP with CMR T1 mapping indices. RESULTS: In the fully adjusted model, each 1-SD increment (0.44 pg/ml) of log NT-proBNP was associated with a 0.62% increment in extracellular volume fraction (p < 0.001), 0.011 increment in partition coefficient (p < 0.001), and 4.7-ms increment in native T1 (p = 0.001). Results remained unchanged after excluding individuals with clinical cardiovascular disease or late gadolinium enhancement (n = 167), and after replacing LV mass by LV end-diastolic volume in the regression models. CONCLUSIONS: Elevated NT-proBNP is related to subclinical fibrosis in a community based setting. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487). PMID- 29268925 TI - NT-proBNP and Myocardial Fibrosis: The Invisible Link Between Health and Disease. PMID- 29268926 TI - Self-Expanding Transcatheter Aortic Valve System for Symptomatic High-Risk Patients With Severe Aortic Stenosis. AB - BACKGROUND: The CENTERA transcatheter heart valve (THV) is a low-profile, self expanding nitinol valve made from bovine pericardial tissue that is 14-F compatible with a motorized delivery system allowing for repositionability. OBJECTIVES: The pivotal study evaluated safety and efficacy of this THV in high surgical-risk study patients with severe symptomatic aortic stenosis. METHODS: Implantations were completed in 23 centers. Clinical and echocardiographic outcomes were assessed at baseline, discharge, and 30 days. Major events were adjudicated by an independent clinical events committee. Echocardiograms and computed tomography scans were reviewed by core laboratories. The primary endpoint was all-cause mortality at 30 days. RESULTS: Between March 25, 2015 and July 5, 2016, 203 patients with severe symptomatic aortic stenosis and increased surgical risk, as determined by the heart team, were treated by transfemoral THV implantation (age 82.7 +/- 5.5 years, 67.5% female, 68.0% New York Heart Association functional class III/IV). At 30 days, mortality was 1%, disabling stroke occurred in 2.5% of patients, and New York Heart Association functional class I/II was observed in 93.0% of patients. Effective orifice area increased from 0.71 +/- 0.20 cm2 to 1.88 +/- 0.43 cm2 (p < 0.001). Mean aortic transvalvular gradient decreased from 40.5 +/- 13.2 mm Hg to 7.2 +/- 2.8 mm Hg at 30 days post-procedure (p < 0.001). Paravalvular aortic regurgitation at 30 days was moderate or higher in 0.6% of patients. A new permanent pacemaker was implanted in 4.5% of patients receiving the THV (4.9% for patients at risk). CONCLUSIONS: The herein described THV is safe and effective at 30 days with low mortality, significant improvements in hemodynamic outcomes, and low incidence of adverse events. Of particular interest is the low incidence of permanent pacemaker implantations. (Safety and Performance Study of the Edwards CENTERA-EU Self-Expanding Transcatheter Heart Valve [CENTERA-2]; NCT02458560). PMID- 29268927 TI - New Valves May Overcome Weaknesses of Transcatheter Aortic Valve Replacement. PMID- 29268928 TI - Structure and Function of the Left Atrium and Left Atrial Appendage: AF and Stroke Implications. AB - Atrial fibrillation (AF) and stroke are important major health problems that share common risk factors and frequently coexist. Left atrial (LA) remodeling is an important underlying substrate for AF and stroke. LA dilation and dysfunction form a prothrombotic milieu characterized by blood stasis and endothelial dysfunction. In addition, alterations of the atrial cardiomyocytes, increase of noncollagen deposits in the interstitial space and fibrosis, favor the occurrence of re-entry that predisposes to AF. Eventually, AF further impairs LA function and promotes LA remodeling, closing a self-perpetuating vicious circle. Multimodality imaging provides a comprehensive evaluation of several aspects of LA remodeling and offers several parameters to identify patients at risk of AF and stroke. How multimodality imaging can be integrated in clinical management of patients at risk of AF and stroke is the focus of the present review paper. PMID- 29268930 TI - Madame President. PMID- 29268929 TI - Fontan-Associated Liver Disease: Proceedings from the American College of Cardiology Stakeholders Meeting, October 1 to 2, 2015, Washington DC. AB - Over the past decade, as the majority of patients with single ventricle anatomy who have undergone the Fontan operation reach adulthood, a newly recognized disease process, Fontan-associated liver disease (FALD), has emerged. FALD is an extracardiac complication that may lead to substantial comorbid disease and premature mortality. The risk factors, pathophysiology, longitudinal consequences, and therapeutic options related to FALD remain poorly defined. Although we recognize that Fontan circulatory properties are associated with extracardiac organ dysfunction, numerous gaps in our understanding of the nature of this relationship exist. Such extracardiac manifestations, in addition to other late complications of the circulation, can significantly affect quality of life and healthcare use. Therefore, to initiate a formal evaluation of FALD, the American College of Cardiology (ACC) sponsored a stakeholders meeting on October 1 to 2, 2015, in Washington, DC. The goal of the meeting was to bring together subspecialty experts in the fields of adult and pediatric hepatology, congenital cardiology (adult congenital and pediatric cardiology), heart failure/transplant, epidemiology, and cardiothoracic surgery, as well as patient advocates, patients, parents of children and young adults who have had the Fontan procedure, and research organizations and societies to discuss the current state of FALD. Topics included gaps in knowledge, optimal care, research opportunities and barriers, and sound practices to guide providers, patients, and families. This report summarizes findings from the stakeholders meeting and seeks to establish a platform for understanding and addressing FALD. PMID- 29268931 TI - Crescendo Skin Sympathetic Nerve Activity and Ventricular Arrhythmia. PMID- 29268932 TI - Trimethylamine-N-oxide and Heart Failure With Reduced Versus Preserved Ejection Fraction. PMID- 29268933 TI - Clinical, Radiographic, and Microbiologic Features of Infective Endocarditis in Patients With Hypertrophic Cardiomyopathy. AB - Infective endocarditis (IE) is an infection of the inner lining of the heart with high morbidity and mortality despite medical and surgical advancements in recent decades. Hypertrophic cardiomyopathy (HC) is one of several medical conditions that have been linked to an increased risk of IE, but there is a paucity of data on this association. We therefore sought to define the clinical phenotype of IE in patients with HC at a single tertiary care center. A retrospective cohort of 30 adult patients with HC diagnosed with IE between January 1, 2006 and December 31, 2016 at Mayo Clinic Rochester were identified. Similar rates of aortic (n = 14) and mitral (n = 16) valve involvement by IE were noted (47% vs 53%). This finding persisted even in patients with left-ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. Symptomatic embolic complications occurred in 10 cases (33%). Surgical intervention was performed in 11 cases (37%). One-year mortality was remarkably low at 7%. In conclusion, in the largest single-center cohort of IE complicating HC, there were similar rates of both mitral and aortic valve involvement regardless of the presence of left ventricular outflow tract obstruction, which is contrary to a long-standing tenet regarding the association of HC and IE. Moreover, no "high risk" IE subset was identified based on HC-related parameters. PMID- 29268934 TI - Iatrogenic Atrial Septal Defect After Percutaneous Mitral Valve Repair With the MitraClip System. AB - This study examines the incidence of iatrogenic atrial septal defect (iASD) after the MitraClip procedure and its influence on echocardiographic and clinical outcomes. We examined 96 patients who underwent a successful MitraClip procedure and who also had baseline and 1-year postprocedure transthoracic echocardiograms. At 1-year follow-up, iASD were observed in 24% of cases. Compared with the patients without iASD, the patients with iASD had a larger right atrium and greater severity of tricuspid regurgitation (TR) at baseline. After the MitraClip procedure, mitral regurgitation lessened significantly in both groups. Although right atrial area and right ventricular diameters increased significantly in patients with iASD (25.3 +/- 8.0 to 28.3 +/- 9.5 cm2, 39.7 +/- 7.1 to 42.2 +/- 8.1 mm, p <0.05 for both comparisons), these variables did not change in patients without iASD. In addition, patients with iASD had worse TR at follow-up. The incidence of stroke was comparable between the 2 groups during 1-year follow-up (4.3% vs 4.1%). However, patients with iASD had a markedly higher re hospitalization rate for heart failure (26% vs 2.7%, p <0.05). In conclusion, iASD occurred in 24% of patients who underwent the MitraClip therapy and the presence of iASD was associated with right-sided heart enlargement, worse TR, and a higher re-hospitalization rate for heart failure. PMID- 29268935 TI - Frequency of Guideline-Based Statin Therapy in Adults With Congenital Heart Disease. AB - We aimed to evaluate atherosclerotic cardiovascular disease (ASCVD) risk estimates and guideline-based statin use for primary prevention of ASCVD in adults with congenital heart disease (ACHD). This was a case-controlled, retrospective study of 248 cases and 744 age- and gender-matched controls at a tertiary care referral center. ASCVD risk scores were calculated and used to assess indication for statin treatment for primary prevention per the 2013 American College of Cardiology and American Heart Association guideline on assessment of cardiovascular risk. There were no differences in average 10-year ASCVD risk scores between ACHD cases (4.6% +/- 6.6%) and matched controls (5.1% +/- 6.7%, p = 0.32). ACHD cases had lower total cholesterol (183 +/- 38 vs 192.6 +/- 35.3 mg/dL, p < 0.001) and were less likely to smoke (8.1% vs 14.6%, p = 0.008), yet had lower high density lipoprotein (52.6 +/- 17.2 vs 55.3 +/- 17.1 mg/dL, p = 0.03) and higher hypertension rates (38.7% vs 28.5%, p = 0.003). However, only 42.3% ACHD cases with a primary prevention statin indication were appropriately prescribed therapy as compared with 59.0% of controls (p = 0.04). In conclusion, ACHD cases have a similar 10-year ASCVD risk score than age- and gender-matched peers, but ACHD cases are less likely than their peers to be prescribed statin therapy for primary prevention per guideline-based recommendations. PMID- 29268936 TI - Comparison of Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Chronic Kidney Disease. AB - There are few data comparing outcomes of transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) in patients with chronic kidney disease. In this retrospective cohort study using the National Inpatient Sample 2011 to 2014, we included a total of 2,820 TAVI and 4,054 SAVR procedures, representative of 14,039 TAVI and 19,835 SAVR procedures nationally. Co-primary outcomes were in-hospital mortality, acute kidney injury (AKI), dialysis requiring AKI, and postoperative stroke. In multivariate analysis, TAVI was associated with a lower in-hospital mortality (odds ratio [OR] 0.47, 95% confidence interval [CI] 0.32 to 0.69, p < 0.001), rates of AKI (OR 0.18, 95% CI 0.14 to 0.22, p < 0.001), dialysis-requiring AKI (OR 0.30, 95% CI 0.20 to 0.44, p < 0.001), and postoperative stroke (OR 0.27, 95% CI 0.13 to 0.53, p < 0.001) compared with SAVR. In 1001 propensity-matched pairs of TAVI and SAVR procedures, TAVI was associated with lower in-hospital mortality (OR 0.67, 95% CI 0.45 to 0.99, p = 0.047) rates of AKI (OR 0.39, 95% CI 0.32 to 0.46, p < 0.001), dialysis requiring AKI (OR 0.53, 95% CI 0.35 to 0.81, p < 0.001), postoperative stroke (OR 0.46, 95% CI 0.20 to 0.98, p = 0.045), significantly shorter length of stay (OR 0.35, 95% CI 0.29 to 0.42, p < 0.001), and nonsignificant difference in cost (OR 1.05, 95% CI 0.88 to 1.26, p = 0.57) compared with SAVR. In conclusion, TAVI may be a preferable approach to SAVR in patients with severe aortic stenosis in the setting of chronic kidney disease. PMID- 29268937 TI - Relation of Lifestyle Factors and Life's Simple 7 Score to Temporal Reduction in Troponin Levels Measured by a High-Sensitivity Assay (from the Atherosclerosis Risk in Communities Study). AB - The impact of lifestyle-related factors on temporal decreases in high-sensitivity cardiac troponin T (hs-cTnT), possibly reflecting reversal of subclinical myocardial damage, has not been evaluated in a community-based setting. We measured hs-cTnT twice, 6 years apart, in 9,256 participants from the Atherosclerosis Risk in Communities (ARIC) Study who were free from baseline cardiovascular disease. We used Poisson and multinomial regression to evaluate the associations of cigarette smoking, alcohol consumption, body mass index, healthy diet score, physical activity, and Life's Simple 7 (LS7) score (a composite measure of lifestyle-related health factors) with 6-year decreases in hs-cTnT. Of the 3,017 patients with detectable baseline hs-cTnT (>=5 ng/L), 2,418 (80%) remained detectable, whereas 599 (20%) had undetectable levels (<5 ng/L) at the 6-year follow-up visit. Patients with a body mass index of <30 kg/m2, adherence to American Heart Association's physical activity guidelines, and average or optimal LS7 scores were more likely to improve from a detectable to an undetectable hs-cTnT level during follow-up. There was a robust association between optimal LS7 score and temporal hs-cTnT reduction (relative risk 1.64, 95% confidence interval 1.11 to 2.42, for baseline >=5 ng/L and for follow-up <5 ng/L). A greater duration of exposure to average or optimal LS7 score was also associated with increased likelihood of temporal hs-cTnT reduction (p-trend <0.001). In conclusion, we found that lifestyle factors and the LS7 score were associated with reversal of subclinical myocardial damage. In conclusion, our results support the growing evidence that hs-cTnT levels change in response to lifestyle modifications and hs-cTnT may serve as a useful dynamic surrogate for monitoring cardiovascular risk. PMID- 29268938 TI - What birthweight percentile is associated with optimal perinatal mortality and childhood education outcomes? AB - BACKGROUND: Small for gestational age, defined as birthweight <10th percentile for gestational age, is known to be associated with clinically meaningful impairments in health and development. The effects of variation within the normal range of birthweight percentile on perinatal mortality and childhood education remain less well defined. OBJECTIVE: We sought to quantify the association among birthweight percentile, perinatal mortality, and educational outcomes and to determine the optimal birthweight percentile for those outcomes in Aboriginal and non-Aboriginal Australian children. STUDY DESIGN: This was a retrospective cohort study. Perinatal data for all children born in the Northern Territory, Australia, from 1999 through 2008 were linked to measures of educational attainment at age 8 9 years. Multivariable analysis was used to determine the optimal birthweight percentile for low perinatal mortality and high reading and numeracy scores. RESULTS: The birth cohort contained 35,239 births (42% Aboriginal), of which 11,214 had linked and valid education records. Median birthweight percentile was 29.2 in Aboriginal infants and 44.0 in non-Aboriginal infants. The odds of perinatal mortality decreased by 4% with each 1-percentile increase birthweight percentile overall (adjusted odds ratio, 0.96; P = .000) and lowest mortality rates were at the 61st and 78th percentile in Aboriginal and non-Aboriginal infants, respectively. Although birthweights <10th percentile were associated with greatly increased odds of perinatal mortality, the increased risk extended well beyond this cut-off. Birthweight percentile was also positively correlated with scores in reading (P = .000) and numeracy (P = .000). In non-Aboriginal children, reading and numeracy scores peaked at the 66th percentile, but for Aboriginal children there was continuous benefit with increasing birthweight percentile. Birthweight percentile explained 1% of the variation in education outcomes, with much greater variation explained by other perinatal and sociodemographic factors. CONCLUSION: Birthweights between the 50th-93rd percentiles were most consistently associated with both low perinatal mortality and high reading and numeracy scores, suggesting that small for gestational age does not sufficiently capture the risks associated with variation in fetal growth. Our data indicate that the effect of birthweight percentile accounts for 1% of variation in perinatal and education outcomes. PMID- 29268939 TI - Step-by-step training in basic laparoscopic skills using two-way web conferencing software for remote coaching: A multicenter randomized controlled study. AB - BACKGROUND: Despite its advantages, few trainees outside of North America have access to simulation training. We hypothesized that a stepwise training method using tele-mentoring system would be an efficient technique for training in basic laparoscopic skills. METHODS: Residents were randomized into two groups and trained to proficiency in intracorporeal suturing. The stepwise group (SG) practiced the task step-by-step, while the other group practiced comprehensively (CG). Each participant received weekly coaching via two-way web conferencing software. The duration of the coaching sessions and self-practice time were compared between the two groups. RESULTS: Twenty residents from 15 institutions participated, and all achieved proficiency. Coaching sessions using tele mentoring system were completed without difficulties. The SG required significantly shorter coaching time per session than the CG (p = .002). There was no significant difference in self-practice time. CONCLUSIONS: The stepwise training method with the tele-mentoring system appears to make efficient use of surgical trainees' and trainers' time. PMID- 29268940 TI - Hospital readmission after distal pancreatectomy is predicted by specific intra- and post-operative factors. AB - BACKGROUND: Distal pancreatectomy (DP) continues to carry a significant risk of morbidity resulting in hospital readmissions and increased costs. Prognostic factors predicting 30-day readmission after DP were evaluated. METHODS: Data were collected from 946 patients undergoing DP at the University of Verona Hospital Trust and the Massachusetts General Hospital between 2004 and 2014. Patients were divided into a derivation and a validation cohort. RESULTS: The 30-day readmission rate was 13.9%. Predictors of readmission were age over 60 years (OR 1.8), intraoperative transfusions (OR 2.02), CR-POPF (OR 2.4), abdominal abscesses (OR 3.9), and urinary tract infections (OR 5.9). The score generated by the derivation cohort was validated identifying three different categories with a progressively increased risk for readmission. CONCLUSION: One out of seven patients undergoing DP will be readmitted within 30 days of discharge. Comorbidities seems not to affect the risk. A 10-point score predicts the risk of 30-days readmission. PMID- 29268941 TI - High suspicion US pattern on the ATA guidelines, not cytologic diagnosis, may be a predicting marker of lymph node metastasis in patients with classical papillary thyroid carcinoma. AB - BACKGROUND: To evaluate the utility of ultrasound (US) patterns based on the 2015 American Thyroid Association (ATA) guidelines and cytologic diagnosis of the Bethesda System for Reporting Thyroid Cytopathology as predicting markers for lymph node metastasis (LNM) in classical papillary thyroid carcinoma (PTC). METHODS: A retrospective analysis of 657 patients with classical PTC who underwent ultrasound-guided fine-needle aspiration (US-FNA) and surgery were included in this study. The associations between LNM and the US features or the Bethesda System for Reporting Thyroid Cytopathology were evaluated. RESULTS: Multivariate logistic regression analysis showed that the high suspicion US pattern was independently associated with LNM (odds ratio = 3.081; 95% confidence interval = 1.515-6.262; P = .002). And the Bethesda category was not significantly associated with LNM (P = .056). CONCLUSIONS: The high suspicion US pattern of the 2015 ATA guidelines, not cytologic diagnosis, could be a predicting marker of LNM in patients with classical PTC. PMID- 29268942 TI - Development and implementation of a virtual reality laparoscopic colorectal training curriculum. AB - BACKGROUND: Contemporary surgical training can be compromised by fewer practical opportunities. Simulation can fill this gap to optimize skills' development and progress monitoring. A structured virtual reality (VR) laparoscopic sigmoid colectomy curriculum is constructed and its validity and outcomes assessed. METHODS: Parameters and thresholds were defined by analysing the performance of six expert surgeons completing the relevant module on the LAP Mentor simulator. Fourteen surgical trainees followed the curriculum, performance being recorded and analysed. Evidence of validity was assessed. RESULTS: Time to complete procedure, number of movements of right and left instrument, and total path length of right and left instrument movements demonstrated evidence of validity and clear learning curves, with a median of 14 attempts needed to complete the curriculum. CONCLUSIONS: A structured curriculum is proposed for training in laparoscopic sigmoid colectomy in a VR environment based on objective metrics in addition to expert consensus. Validity has been demonstrated for some key metrics. PMID- 29268943 TI - An interactive model of auditory-motor speech perception. AB - Mounting evidence indicates a role in perceptual decoding of speech for the dorsal auditory stream connecting between temporal auditory and frontal-parietal articulatory areas. The activation time course in auditory, somatosensory and motor regions during speech processing is seldom taken into account in models of speech perception. We critically review the literature with a focus on temporal information, and contrast between three alternative models of auditory-motor speech processing: parallel, hierarchical, and interactive. We argue that electrophysiological and transcranial magnetic stimulation studies support the interactive model. The findings reveal that auditory and somatomotor areas are engaged almost simultaneously, before 100 ms. There is also evidence of early interactions between auditory and motor areas. We propose a new interactive model of auditory-motor speech perception in which auditory and articulatory somatomotor areas are connected from early stages of speech processing. We also discuss how attention and other factors can affect the timing and strength of auditory-motor interactions and propose directions for future research. PMID- 29268944 TI - Instruments for detection and screening of cognitive impairment for older adults in primary care settings: A review. AB - The Patient Protection and Affordable Care Act requires evaluation for cognitive impairment as part of the Annual Wellness Visit (AWV). Nurses and nurse practitioners in primary care are in a good position to incorporate brief cognitive screens into the AWV. Early recognition of cognitive problems allows clinicians and patients the opportunity to discuss any new or ongoing concerns about cognition, address possible reversible causes, or refer for further evaluation. It should be noted that some patients may prefer not to explore for cognitive impairment. Numerous brief cognitive screens have been developed for primary care, with no one screen being appropriate for all patients or clinicians. This review examines the psychometric properties, usefulness, and limitations of both patient and informant brief (under five minutes) cognitive screens endorsed by the Alzheimer's, National Institute of Aging (NIA), and Gerontological Society (GSA) workgroups, plus a recently developed brief version of the standard MoCA. PMID- 29268945 TI - Editorial Comment. PMID- 29268946 TI - Reply. PMID- 29268947 TI - The Design and Assessment of a Multiparametric Model for the Dysphonia Severity Index for Persian-speaking Populations. AB - OBJECTIVES: In instrumental voice assessment, multiparametric models reflect the multidimensional nature of voice and are therefore better than models that reflect only a single dimension of voice. The Dysphonia Severity Index (DSI) is one of the most common multiparametric models. In voice assessment, race, language, and structural and physiological features affect the acoustic, aerodynamic, and voice range profile measures. Given these differences, this study was conducted to design and evaluate a multiparametric and objective model for assessing the severity of dysphonia in Persian-speaking populations. MATERIAL AND METHODS: This study examined 300 participants with several types of dysphonia (104 women and 196 men) and 100 healthy individuals (63 women and 37 men). Five acoustic parameters, three aerodynamic parameters, and seven voice range profile parameters were measured for designing the model. Perceptual evaluation was performed using the grade, roughness, breathiness, asthenia, strain scale. The logistic regression analysis was used to determine the factors affecting the DSI and each component's coefficient. RESULTS: Of the 15 parameters assessed, shimmer, vital capacity, semitone range, and voice onset time of /pa/ remained in the model with their coefficients. This section presents the DSI model for the examined population. The discriminant analysis showed that this combination corresponds to 47.8 of the perceptual assessment: DSI = 0.289 (shimmer) + 0.0001 (VC) - 0.059 (STR) - 13.278 (VOT_Pa). CONCLUSION: In this study, the DSI corresponded to the physiological, linguistic, and racial characteristics of the Persian-speaking population with or without voice disorder. PMID- 29268949 TI - Atezolizumab for platinum-treated metastatic urothelial carcinoma. PMID- 29268948 TI - Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open label, phase 3 randomised controlled trial. AB - BACKGROUND: Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. METHODS: We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged >=18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 75 mg/m2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs >=5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. FINDINGS: Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11.1 months [95% CI 8.6-15.5; n=116] vs 10.6 months [8.4-12.2; n=118]; stratified hazard ratio [HR] 0.87, 95% CI 0.63-1.21; p=0.41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15.9 months [95% CI 10.4 to not estimable] vs 8.3 months [5.6-13.2]; HR 0.57, 95% CI 0.26-1.26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). INTERPRETATION: Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. FUNDING: F Hoffmann-La Roche, Genentech. PMID- 29268951 TI - Effective treatment of restless legs syndrome by safinamide in Parkinson's disease patients. PMID- 29268950 TI - Osteosarcoma arising in fibrous dysplasia, confirmed by mutational analysis of GNAS gene. AB - Malignancy arising in fibrous dysplasia (FD) is rare. Approximately 100 cases have been reported so far, and osteosarcoma is the most common malignancy. We report a case of osteosarcoma in a 33-year-old Japanese man with monostotic FD of the right proximal femur from the age of 16 years. Histologically, relatively well-differentiated osteosarcoma was found in the FD lesion. Immunohistochemically, the FD was negative for p53 or MDM2, and the MIB-1 index was less than 1%, whereas the osteosarcoma was positive for both p53 and MDM2, and the MIB-1 index was up to 15%. The FD and osteosarcoma were negative for CDK4. Fluorescent in situ hybridization assay showed no amplification of the MDM2 gene, indicating that the osteosarcoma was a conventional osteosarcoma, not an intraosseous well-differentiated type. The original cell of malignancy in FD is unclear. Malignancy can be potentially derived from dysplastic cells in the area of the FD or cells in the adjacent normal tissues. GNAS gene mutation has recently been reported for fibrous dysplasia and the mutation is highly specific to fibrous dysplasia among fibro-osseous lesions including osteosarcoma. In this case, point mutations of GNAS were found in the FD and osteosarcoma but not in the adjacent normal tissues, suggesting that osteosarcoma was derived from the spindle cells of FD. This is the first report to clearly show that osteosarcoma is derived from the spindle cells in fibrous dysplasia (FD). PMID- 29268952 TI - The dynamic of cellulase activity of fungi inhabiting organic municipal solid waste. AB - The study dealt with to identified and screened out potential cellulase producing fungal strains. All the indigenous fungal strains were developed on carboxymethyl cellulose (CMC) mandel media at 30 degrees C for 3-4 days to examine their congo red cellulase activity. It was found from the primary screening test result that only four isolates Trichoderma viride, Aspergillus niger, Aspergillus fumigatus and Fusarium oxysporum were shown large zone formation that meant they have great potential cellulase activity. Among these, Trichoderma viride and Aspergillus niger strains were showed highest enzymatic activity during the secondary screening, while Trichoderma viride generated the highest protein (89.51 MUg/ml). Furthermore, these potential fungal strains will be useful for the organic municipal solid waste degradation. PMID- 29268953 TI - Exploring repositioning movements in sitting with 'at risk' groups using accelerometry and interface pressure mapping technologies. AB - BACKGROUND: Despite high quality guidelines underpinning pressure ulcer care (NPUAP/EPUAP/PPPIA, 2014), pressure ulceration still poses a significant financial impact on health care services in treatment and staff costs as well as having a profound effect on the health and quality of life of individuals experiencing them. Repositioning is a key preventative technique recommended by occupational therapists and other health care professionals. The frequency and quality of repositioning movements performed by individuals, however, can be difficult to determine. This paper explores the use of technology in monitoring repositioning movements in sitting. OBJECTIVE: To explore the outputs of technologies such as interface pressure mapping systems and accelerometers in enabling the therapist to accurately monitor seated behaviour and enhance practice through targeted interventions to prevent sitting acquired pressure ulceration. METHOD: Reviewing the findings of two recent research studies with 'at risk' cohorts (spinal cord injury; elderly orthopaedic), using accelerometry and seated interface pressures, this paper will highlight how useful this technology is in clinical practice to monitor weight shifts and repositioning behaviours. RESULT: Both studies illustrated that the majority of individuals did not adhere to the frequency or magnitude of movements currently recommended to redistribute seating interface pressures. When repositioning was performed it was ineffective in reducing seated pressures. CONCLUSION: In an era of personalised medicine, technology has an important role to play in providing the service user, caregivers and healthcare staff with important biofeedback information about seated behaviours, particularly those that minimise the risk of developing sitting acquired pressure ulcers. This information can augment occupational therapists' clinical decision-making in maximising active pressure ulcer prevention. PMID- 29268954 TI - E-Mailed Conference Synopses as a Tool for Resident and Faculty Development. AB - OBJECTIVE: This study aims to investigate the utility and success of daily conference synopses emails ("Daily Dispatches") sent to surgical attending physicians, fellows, and residents to foster resident and faculty development. DESIGN: Emails were distributed by the surgical residency program director (PD), summarizing each day of a surgical conference. Two prospective electronic surveys were administered to surgical residents, fellows, and attending surgeons to evaluate the value of this Daily Dispatch method. SETTING: Institutional; Medstar Georgetown University Hospital, Department of Surgery, Washington, DC. PARTICIPANTS: Email synopses were sent to surgical attendings, fellows and residents. Pilot survey was distributed to 60 participants, main survey sent to 74 participants. RESULTS: The response rate for the pilot survey was 41.6% (25/60). When asked about the mode of delivery, 96% of respondents wanted to maintain the email medium when compared to a lecture, paper handout, or the use of social media. The response rate for the main survey was 31.1% (23/74). Almost all (91%) respondents reported reading the emails. Within this group, 70% "agreed" or "strongly agreed" that the emails were useful. Furthermore, 90% reported learning "at least one new thing" and 80% confirmed these "emails provide meaningful content they would not otherwise obtain". CONCLUSION: Individualized daily synopsis emails highlighting relevant content provided meaningful information from conferences to non-attendees. The emails were well received and useful. Daily Dispatches meet an important need in dissemination of information traditionally gathered only by the rate-limiting step of conference attendance. PMID- 29268956 TI - On accuracy and precision of flowmeters used for oxygen therapy in a veterinary teaching hospital. AB - OBJECTIVE: To determine the accuracy and precision of flowmeters used for oxygen therapy in a veterinary teaching hospital. STUDY DESIGN: An observational study. METHODS: A total of 50 flowmeters used for oxygen therapy were evaluated using Defender 530 gas flow analyzers to measure flow. For each flowmeter, a minimum of seven flow settings were tested in random order and in triplicate. Flow measured at ambient conditions was converted to standardized flow specifications (21.1 degrees C and 760 mmHg) and analyzed using general linear mixed models. Flowmeters were considered accurate at a given flow setting when the targeted mean flow was within the corresponding 95% confidence interval. Precision of flow was characterized based on the magnitude of variance component estimates. RESULTS: Flowmeters of 1.0, 3.5 and 8.0 L minute-1 were considered accurate across flow settings corresponding to their capacity range. Flowmeters of 7.0 and 15.0 L minute-1 were accurate at flow settings <=2.0 L minute-1. For flow settings >=3.0 L minute-1, average oxygen flow was consistently below reference values. Precision varied with the capacity of the flowmeter, ranked by decreasing precision as 1.0 > 3.5 > 8.0 > 7.0 > 15.0 L minute-1. CONCLUSIONS AND CLINICAL RELEVANCE: A flowmeter of the smallest maximum capacity within the desired flow range is more appropriate for smaller patients where accurate, precise flow delivery is needed. Although 15.0 L minute-1 flowmeters were accurate at flow settings <=2.0 L minute-1, the graduated increments do not allow exact flow settings <0.5 L minute-1. Flowmeters of 15 L minute-1 capacity should be useful for high-flow oxygen delivery for which accuracy and precision are not critical. PMID- 29268955 TI - Residential proximity to high-density poultry operations associated with campylobacteriosis and infectious diarrhea. AB - Poultry carry zoonotic bacteria that can cause gastroenteritis in humans. Environmental transmission of pathogens from poultry operations may increase gastrointestinal infection risk in surrounding communities. To evaluate associations between residential proximity to high-density poultry operations and individual-level diarrheal illnesses, we conducted a nested case-control study among 514,488 patients in Pennsylvania (2006-2015). Using electronic health records, we identified cases of five gastrointestinal outcomes: three pathogen specific infections, including Escherichia coli (n = 1425), Campylobacter (n = 567), and Salmonella (n = 781); infectious diarrhea (n = 781); and non-specific diarrhea (2012-2015; n = 28,201). We estimated an inverse-distance squared activity metric for poultry operations based on farm and patient addresses. Patients in the second and fourth (versus first) quartiles of the poultry operation activity metric had increased odds of Campylobacter (AOR [CI], Q2: 1.36 [1.01, 1.82]; Q3: 1.38 [0.98, 1.96]; Q4: 1.75 [1.31, 2.33]). Patients in the second, third, and fourth quartiles had increased odds of infectious diarrhea (Q2: 1.76 [1.29, 2.39]; Q3: 1.76 [1.09, 2.85]; Q4: 1.60 [1.12, 2.30]). Stratification revealed stronger relations of fourth quartile and both Campylobacter and infectious diarrhea in townships, the most rural community type in the study geography. Increasing extreme rainfall in the week prior to diagnosis strengthened fourth quartile Campylobacter associations. The poultry operation activity metric was largely unassociated with E. coli, Salmonella, and non-specific diarrhea. Findings suggest high-density poultry operations may be associated with campylobacteriosis and infectious diarrhea in nearby communities, highlighting additional public health concerns of industrial agriculture. PMID- 29268957 TI - Use of alpha2-Adrenergic Agonists to Improve Surgical Field Visibility in Endoscopy Sinus Surgery: A Systematic Review of Randomised Controlled Trials. AB - PURPOSE: We assessed the evidence for the use of alpha2-adrenergic agonists (A2AAs) in bleeding control and field quality in endoscopic sinus surgery. METHODS: We systematically reviewed randomized clinical trials (RCTs) assessing A2AAs in endoscopic sinus surgery. Abstracts were reviewed by 2 investigators for eligibility, and selected articles were fully reviewed. Data on study design, population, A2AA drug and control groups, bleeding and surgical field quality outcomes, and adverse effects were extracted and synthesized. FINDINGS: A total of 13 RCTs that included 896 individuals (7 double-blind trials, 5 single-blind trials, and 1 open-label trial) were selected that assessed the efficacy of clonidine (6 RCTs, 407 patients), dexmedetomidine (6 RCT, 423 patients), or both (1 RCT, 66 patients). Clonidine was compared with placebo (3 RCTs), midazolam (1 RCT), and remifentanil (2 RCTs). Dexmedetomidine was compared with esmolol (2 RCTs), remifentanil (2 RCTs), nitroglycerin and esmolol (1 RCT), and magnesium sulfate (1 RCT). Clonidine and dexmedetomidine were compared in 1 RCT. Clonidine reduced the proportion of individuals with an impaired surgical field by 23% vs placebo (number needed to treat = 4). Clonidine was better than midazolam and remifentanil in 2 trials, and dexmedetomidine was better than magnesium sulfate and esmolol in 2 trials but was not superior to esmolol, remifentanil, or nitroglycerin in 4 trials. Dexmedetomidine produced significantly better differences in bleeding outcomes versus clonidine. Adverse events were infrequent and mainly caused by hypotension or bradycardia. IMPLICATIONS: RCTs consistently report that A2AAs reduce bleeding and improve surgical field quality during endoscopic sinus surgery. Adverse event reporting was often omitted in RCTs. Well designed RCTs with appropriate sample sizes are desirable to identify the best A2AAs and confirm their potential effects on clinical outcomes. PMID- 29268958 TI - DNA methylation dynamics in aging: how far are we from understanding the mechanisms? AB - DNA methylation is currently the most promising molecular marker for monitoring aging and predicting life expectancy. However, the mechanisms underlying age related DNA methylation changes remain mostly undiscovered. Here we discuss the current knowledge of the dynamic nature of DNA epigenome landscape in mammals, and propose putative molecular mechanisms for aging-associated DNA epigenetic changes. Specifically, we describe age-related variations of methylcytosine and its oxidative derivatives in relation to the dynamics of chromatin structure, histone post-translational modifications and their modulators. Finally, we are proposing a conceptual framework that could explain the complex nature of the effects of age on DNA methylation patterns. This combines the accumulation of DNA methylation noise and also all of the predictable, site-specific DNA methylation changes. Gathering information in this area would pave the way for future investigation aimed at establishing a possible causative role of epigenetic mechanisms in aging. PMID- 29268959 TI - Danazol as First-Line Therapy for Myelodysplastic Syndrome. AB - BACKGROUND: Allogeneic stem cell transplantation (ASCT) represents the only option with a potential cure rate of 30% to 50% in myelodysplastic syndrome (MDS); however, < 5% of patients are optimal candidates for this management. Therapeutic options are limited in patients unsuitable for ASCT. Evidence that androgens might be beneficial in MDS is controversial. We aimed to document the clinical outcomes of patients diagnosed with MDS treated with danazol as first line therapy. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed in our center with MDS according to the World Health Organization 2008 criteria and treated with danazol between 2005 and 2015. Response was defined according to international working group criteria. RESULTS: We included 42 patients treated exclusively with danazol. Median dose was 400 mg/d (range, 100 600 mg/d). Median follow-up was 12 (range, 3-76) months. Twenty-four of these patients (60%) achieved clinical response. Median overall survival was 24 months (95% confidence interval, 5.1-42). Responders were older than nonresponders (P = .025) and had higher baseline hemoglobin concentration (P = .009). No patients discontinued danazol because of toxicity. Fifteen patients died (35.7%) and 5 progressed to acute myeloid leukemia. CONCLUSION: Danazol as first-line therapy is an acceptable treatment option with low side effects for patients with MDS who cannot receive ASCT. PMID- 29268960 TI - Efficiency of PacBio long read correction by 2nd generation Illumina sequencing. AB - Long sequencing reads offer unprecedented opportunities in analysis and reconstruction of complex genomic regions. However, the gain in sequence length is often traded for quality. Therefore, recently several approaches have been proposed (e.g. higher sequencing coverage, hybrid assembly or sequence correction) to enhance the quality of long sequencing reads. A simple and cost effective approach includes use of the high quality 2nd generation sequencing data to improve the quality of long reads. We designed a dedicated testing procedure and selected universal programs for long read correction, which provide as the output sequences that can be used in further genomic and transcriptomic studies. Our results show that HALC is the best choice for correction of long PacBio reads, when both, read size and quality, are the main focus of the analysis. However, the tested tools show some unexpected behaviors, including read trimming and fragmentation. PMID- 29268961 TI - QSdpR: Viral quasispecies reconstruction via correlation clustering. AB - RNA viruses are characterized by high mutation rates that give rise to populations of closely related genomes, known as viral quasispecies. Underlying heterogeneity enables the quasispecies to adapt to changing conditions and proliferate over the course of an infection. Determining genetic diversity of a virus (i.e., inferring haplotypes and their proportions in the population) is essential for understanding its mutation patterns, and for effective drug developments. Here, we present QSdpR, a method and software for the reconstruction of quasispecies from short sequencing reads. The reconstruction is achieved by solving a correlation clustering problem on a read-similarity graph and the results of the clustering are used to estimate frequencies of sub species; the number of sub-species is determined using pseudo F index. Extensive tests on both synthetic datasets and experimental HIV-1 and Zika virus data demonstrate that QSdpR compares favorably to existing methods in terms of various performance metrics. PMID- 29268962 TI - piRNA analysis framework from small RNA-Seq data by a novel cluster prediction tool - PILFER. AB - With the increasing number of studies focusing on PIWI-interacting RNA (piRNAs), it is now pertinent to develop efficient tools dedicated towards piRNA analysis. We have developed a novel cluster prediction tool called PILFER (PIrna cLuster FindER), which can accurately predict piRNA clusters from small RNA sequencing data. PILFER is an open source, easy to use tool, and can be executed even on a personal computer with minimum resources. It uses a sliding-window mechanism by integrating the expression of the reads along with the spatial information to predict the piRNA clusters. We have additionally defined a piRNA analysis pipeline incorporating PILFER to detect and annotate piRNAs and their clusters from raw small RNA sequencing data and implemented it on publicly available data from healthy germline and somatic tissues. We compared PILFER with other existing piRNA cluster prediction tools and found it to be statistically more accurate and superior in many aspects such as the robustness of PILFER clusters is higher and memory efficiency is more. Overall, PILFER provides a fast and accurate solution to piRNA cluster prediction. PMID- 29268963 TI - Management of Hemophilic Cysts and Pseudotumors of the Hand in Bleeding Disorders: A Case Series. AB - PURPOSE: Hemophilic cysts and pseudotumors (HCPTs) of the hand are rare and are secondary to bleeding disorders such as hemophilia A and B. This is a report of our experience in the management of this rare condition. PATIENTS AND METHODS: Seven male patients with hemophilia A presenting with progressive swelling of the hand were treated between 2004 and 2013 at a tertiary referral hospital. All patients had clotting factor replacement based on our previously reported protocol. The age of the patients ranged from 3 to 49 years (median age, 19 years). RESULTS: Four patients had soft tissue hemophilic cysts and 3 had bony hemophilic pseudotumors. Two patients had traumatic pseudoaneurysm of the ulnar artery in addition to the cysts. The soft tissue cysts required surgical excision in 3 patients under factor cover as per the protocol. The bony lesions were initially managed nonsurgically by factor replacement, but 2 patients failed to respond and required amputation of the fingers. The ulnar artery aneurysm was excised and artery ligated in 1 patient and the artery was vein grafted owing to poor hand perfusion in 1. CONCLUSIONS: Based on our observations in the management of HCPTs of the hand and the existing literature, we conclude that the soft tissue cysts require surgical excision along with factor replacement and distal bony lesions smaller than 3 cm respond to factor replacement. Larger bony lesions require surgical treatment. Treatment of hemophilic cysts and pseudotumors should be undertaken only in centers with a major hematology backup. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 29268964 TI - Natural compounds and extracts from Mexican medicinal plants with anti leishmaniasis activity: An update. AB - Leishmaniasis is considered as an emerging, uncontrolled disease and is endemic in 98 countries. Annually, about 2 million cases of cutaneous and 500000 cases of visceral-type leishmaniasis are recorded and 60000 persons died from the disease. In Mexico, cutaneous leishmaniasis is known as chiclero's ulcer and is reported in 22 states, it is considered as a health problem. For its treatment, pentavalent antimonial drugs are administered. These drugs cause severe side effects, are costly. Drug-resistant cases have been reported and have been developing for over 70 years. One alternative to the drugs that are currently available is to find active molecules in medicinal plants. Dihydrocorynantheine, corynantheine and corynantheidine are active against Leishmania major, while harmane, pleiocarpin, buchtienin, luteolin and quercetin are active against Leishmania donovani. In Mexico, about 20 medicinal plants have been evaluated against Leishmania mexicana, among which the most active are Tridax procumbens, Lonchocarpus xuul and Pentalinon andrieuxii. From these plants, active compounds with IC50 <= 30 MUg/mL or MUM have been isolated, such as 3(S)-16,17 didehydrofalcarinol or Oxylipin, cholestra-4,20,24-trien-3-one or pentalinosterol, 24-methylcholest-4-24(28)-dien-3-one, cholest-4-en-3-one, 6,7 dihydroneridie-none, neridienone, cholest-5,20,24-trien-3beta-ol, and isocordoin. Today, only pentalinonsterol has been synthesized and assayed in the visceral leishmaniasis experimental model using BALB/c mice infected with Leishmania donovani. Liposome formulation of this compound administered by intravenous route at 2.5 mg/kg showed a significant reduction of parasite load in mouse liver and spleen. PMID- 29268965 TI - Antioxidants: Friend or foe? AB - Reactive oxygen species are the intermediates that are formed during the normal metabolic process which are effectively neutralized by the antioxidant system of the body. Any imbalance in this neutralization process causes oxidative stress which has been implicated as one of the cause in diseases such as Alzheimer's disease, cardiovascular disorders, cancer etc. Research has enabled the use of antioxidants as therapeutic agents in the treatment of various diseases. Literature also puts forth the negative effects of using antioxidants in the treatment of diseases. This review is a compilation of both the beneficial and detrimental effects of use of antioxidants in the treatment of diseases such as cancer, cardiovascular diseases, diabetes and oral diseases. PMID- 29268966 TI - Comparative molecular docking studies of lupeol and lupenone isolated from Pueraria lobata that inhibits BACE1: Probable remedies for Alzheimer's disease. AB - OBJECTIVE: To discover lead lupane triterpenoid's potential isolated from Pueraria lobata roots against beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which serve as a rate limiting step in amyloid beta (Abeta) production altering the course of Alzheimer's disease. In addition, enzyme kinetics study and molecular docking were conducted to establish the inhibition type and structure activity relationship. METHODS: A systematic study of 70% ethanolic P. lobata root extract was employed to identify its BACE1 inhibitory potential. Further, BACE1 inhibitory potential of two lupane terpenoids, yielded from ethanolic extract, was assessed. In order to determine their inhibition mode, Lineweaver-Burk plots and Michaelis-Menten model for BACE1 was performed. AutoDock 4.2 program in addition determined the molecular interaction of BACE1 with isolated terpenoids. RESULTS: Considering the inhibitory potential of 70% ethanolic extract of P. lobata against BACE1 (IC50 = 80.35 MUg/mL), lupeol and lupenone were subsequently isolated and exhibited notable or moderate BACE1 inhibitory activity with IC50 values of 5.12 and 62.98 MUmol/L, respectively, as compared to the positive control quercetin (IC50 = 21.28 MUmol/L). The enzyme kinetics study enabled us to identify both compounds as competitive inhibitors, where lupeol displayed a very potent inhibition against BACE1 with low inhibition constant (Ki) value of 1.43 MUmol/L, signifying greater binding affinity. In order to understand the binding mechanism and structure-activity relationship of two triterpene-based BACE1 inhibitors, we employed computer aided docking studies which evidently revealed that hydroxyl group of lupeol formed two hydrogen bonds with the ASP32 (catalytic aspartic residue) and SER35 residues of BACE1 with the binding energy of (-8.2 kcal/mol), while the ketone group of lupenone did not form any hydrogen bonds with BACE1 giving evidence for less binding affinity. These results in turn have predicted the dependence of the inhibitory activity in the presence of hydroxyl group which has provided a new basis for BACE1 blockade. CONCLUSIONS: Our results have successfully explored the molecular mechanism of lupane triterpenoids via BACE1 inhibition, suggesting that lupeol in particular could be utilized as a useful therapeutic and preventive agent to mitigate Alzheimer's disease. PMID- 29268967 TI - Rescue effects of aqueous seed extracts of Foeniculum vulgare and Carum carvi against cadmium-induced hepatic, renal and gonadal damage in female albino rats. AB - OBJECTIVE: To investigate the protective effects of aqueous seed extracts of fennel "Foeniculum vulgare" (FVE) and caraway "Carum carvi" (CCE) on liver, kidney and reproductive organs in female rats against cadmium chloride (CC) intoxication. METHODS: A total of 36 adult female rats were divided into six groups, six in each group. Control group (fed normal diet), CC-treated group (50 mg CC/kg diet), CCE-treated group (150 mg CCE/kg diet), CCE + CC group, FVE (150 mg/kg diet) and FVE + CC. One month later, all rats were sacrificed and all samples were collected at proestrus phase. RESULTS: The toxic effects of CC were confirmed biochemically by significant increase of serum concentration of liver enzymes (P < 0.05), and creatinine (P < 0.001). Moreover, CC increased significantly the serum level of malondialdehyde (MDA) and decreased the total antioxidant capacity (TAC) (P < 0.001). In addition, serum concentrations of estrogen, progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly decreased (P < 0.01). Histopathologically, CC treated group revealed marked pathological changes in renal, hepatic, ovarian and uterine tissues. All toxic findings observed in liver and kidney with CC treatment were found to be ameliorated markedly after co-treatments with FVE or CCE. Furthermore, co-treatment of FVE with CC improved significantly all studied reproductive parameters (P < 0.01). CONCLUSIONS: Both FVE and CCE could be used as efficient treatments for liver and kidney against CC intoxication. Moreover, FVE could be utilized as a potent treatment to protect and improve female fertility from cadmium intoxication. PMID- 29268968 TI - Phytochemical analysis and biological activities of Hertia cheirifolia L. roots extracts. AB - OBJECTIVE: To test the antioxidant, antimicrobial and alpha-glucosidase inhibitory activities of the roots extracts from Hertia cheirifolia (H. cheirifolia) L. METHODS: Total phenolics and total flavonoids content of the different extracts were determined by colorimetric methods and reverse phase high performance liquid chromatography (RP-HPLC) was performed to identify various chemical components. The different extracts were evaluated for antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis-3 ethylenebenzothiozoline-6-sulfonic acid (ABTS+) and beta-carotene bleaching tests and alpha-glucosidase inhibitory properties. The antimicrobial activity was carried out in vitro by the broth dilution method. RESULTS: Trans-cinnamic acid, rutin hydrate, naringin and quercetin were the main compounds of the ethyl acetate extract from H. cheirifolia L. This extract has significant scavenging activity to decrease free radicals especially for DPPH and ABTS radicals. As well as, the ethyl acetate extract exhibited an antimicrobial property against bacterial strains. Bacillus licheniformis and Salmonella enterica were the most sensitive strains with minimum inhibitory concentration values of 0.156 mg/mL. CONCLUSION: The ethyl acetate extract was found to be selectively antioxidant and antimicrobial. PMID- 29268969 TI - Bacteriocin-like inhibitory substance (BLIS) activity of Streptococcus macedonicus MBF10-2 and its synergistic action in combination with antibiotics. AB - OBJECTIVE: To characterize the bacteriocin-like inhibitory-substances (BLIS) activity of Streptococcus macedonicus MBF10-2 [named BLIS(MBF10-2)], a bacteriocinogenic strain isolated from an Indonesian tofu byproduct. METHODS: BLIS(MBF10-2) was obtained by culturing the bacterium, and standard deferred antagonism assays were used to demonstrate its activity. The antibacterial testing of fractions collected by filtration using 3-30 kDa cut-off membrane sizes were carried out by performing well diffusion method. RESULTS: The growth of Micrococcus luteus, Streptococcus pyogenes, Lactococcus lactis, Leuconostoc mesenteroides and Weissella confusa were inhibited by BLIS(MBF10-2). Interestingly, BLIS-containing fractions obtained from sequential application on ultrafiltration membranes indicated that this bacterium Streptococcus macedonicus MBF10-2 could produces at least two antimicrobial peptides activities, one of which is likely to be a lantibiotic peptide. Potential synergistic activity against certain Gram-positive (but not Gram-negative) species when partnered with antibiotics (ampicillin, tetracycline or kanamycin) were observed. CONCLUSION: Combination of some BLIS(MBF10-2) active fractions with antibiotics (ampicillin, tetracycline or kanamycin) could demonstrate synergistic activities against certain Gram-positive species. PMID- 29268970 TI - Pharmacological evaluation of smooth muscle relaxant and cardiac-modulation potential of Phyla nodiflora in ex-vivo and in-vivo experiments. AB - OBJECTIVE: To investigate the pharmacological basis of its uses of Phyla nodiflora (P. nodiflora) for the treatment of anomalies predominantly by smooth muscle containing tissues such as gastrointestinal/vascular/broncho spasm and cardiovascular modulation. METHODS: The crude hydroalcoholic extract of P. nodiflora (Pn.Cr) and its fractions were evaluated on isolated rabbit jejunum, rat trachea, aorta and atrium. To access the contractile or relaxant effects of testing materials, the tissues were mounted in isolated organ bath and responses were recorded with transducers coupled with data acquisition system. BALB/c mice were challenged with castor oil for the assessment of in-vivo antidiarrheal activity. Normotensive rats were used for in-vivo hypotensive study. RESULTS: Hydroalcoholic extract of Pn.Cr at variable concentrations inhibited the natural spontaneous rhythm and 80 mmol/L K+ mediated contractions in isolated segment of jejunum with EC50 values of 3.18 and 1.91 mg/mL respectively. Verapamil, a Ca2+ channel blocker, demonstrated akin pattern in jejunum and therefore possibly suggesting calcium blocking activity. On isolated rat tracheal tissue, Pn.Cr showed relaxation of high-K+ and carbachol mediated contractions (EC50 values: 1.24 and 2.42 mg/mL). Pn.Cr treatment relaxed the rat aortic ring in a cumulative doses with high-K+ and phenylephrine-induced contractions (EC50 values 0.25 and 0.92 mg/mL). Activity based fractionation of Pn.Cr showed that dichloromethane fraction was more potent for relaxing the tissues spasm compared to aqueous fraction. In-vivo experiments, significant protection by Pn.Cr (P < 0.05) was observed in castor oil-induced diarrhea (50-500 mg/kg) whereas hypotensive effect in anesthetized rats was seen at the dose range of 1-10 mg/kg of Pn.Cr (P < 0.05). CONCLUSION: This study suggests the blockage of calcium channel in the smooth muscles as a pharmacological application to make usage of P. nodiflora in the management of diarrhea, asthma and hypotensive effect. PMID- 29268971 TI - Antibiofilm activity of alpha-mangostin extracted from Garcinia mangostana L. against Staphylococcus aureus. AB - OBJECTIVE: To isolate alpha-mangostin (AMG) from the peels of mangosteen (Garcinia mangostana L.), grown in Vietnam, and to investigate antibiofilm activity of this compound against three Staphylococcus aureus (S. aureus) strains, one of which was methicillin-resistant S. aureus (MRSA) and the other two strains were methicillin-sensitive S. aureus (MSSA). METHODS: AMG in n-hexane fraction was isolated on a silica gel column and chemically analyzed by HPLC and NMR. The antibiofilm activity of this compound was investigated by using a 96 well plate model for the formation of biofilms. Biofilm biomass was quantified using crystal violet. The viability of cells was observed under confocal microscopy using LIVE/DEAD BacLight stains. Biofilm composition was determined using specific chemical and enzyme tests for polysaccharide, protein and DNA. Membrane-damaging activity was assayed by measuring the hemolysis of human red blood cells in presence of AMG. RESULTS: The results indicated that the isolated AMG, with a purity that exceeded 98%, had minimal inhibitory concentrations in the range of 4.6-9.2 MUmol/L for the three strains tested. Interestingly, the MSSA strains were more sensitive to AMG than the MRSA strain. Minimal bactericidal concentrations were 2-fold higher than the minimal inhibitory concentration values for the three strains, indicating that AMG was a bactericidal compound. AMG also prevented biofilm formation effectively, albeit that again the MRSA strain was the most resistant. Interestingly, biofilms of the MRSA strain contained protein as a main component of the extracellular matrix, whereas this was polysaccharide in the MSSA strains. This might relate to the resistance of the MRSA 252 strain to AMG. Assays using human red blood cells indicated that AMG caused significant membrane damage with 50% of cell lysis occurred at concentration of about 36 MUmol/L. CONCLUSIONS: Our results provide evidence that the isolated AMG has inhibitory activity against biofilm formation by S. aureus, including MRSA. Thus, isolated AMG proposes a high potential to develop a novel phytopharmaceutical for the treatment of MRSA. PMID- 29268972 TI - Some pathogenic characters of paratyphoid Salmonella enterica strains isolated from poultry. AB - OBJECTIVE: To investigate some pathogenic characters of Salmonella enterica strains isolated from poultry. METHODS: Twenty-three genetically distinct Salmonella enterica strains, of different serovars and pulsotype, were examined for virulence traits. Resistance to gastric acid environment was estimated by measuring the percentage of survived bacterial cells after exposure for 2 h to a synthetic gastric juice. Strains were analyzed with PCR for the presence of the following virulence genes: mgtC and rhuM located on SPI-3, sopB and pipB located on SPI-5, Salmonella virulence plasmid (spv) R (spvR), spvB and spvC located on Salmonella plasmid virulence and sodCI, sopE, and gipA located on prophage. Finally, resistance to 21 antibiotics was tested with Kirby-Bauer method. RESULTS: A percentage of 82.60% of strains were resistant to gastric environment after induction and 60.87% of the strains exhibited constitutive resistance too. Nineteen different virulence profiles were detected. The phage related genes sodCI and sopE and the plasmid mediated operon spvR, spvB and spvC (spvRBC) were detected in 82.60%, 47.82% and 52.17% of strains, respectively. Typhimurium and Enteritidis strains showed the highest number of virulence genes. Twenty-one different antibiotic resistance profiles were obtained and two isolates (Typhimurium and Enteritidis) resulted sensible to all the tested molecules. The ampicillin, streptomycin, sulfonamide and tetracycline resistance profile was detected in seven isolates (30.43%). CONCLUSION: Our results show that paratyphoid Salmonella strains with several characters of pathogenicity, that may be cause of severe pathology in animals and humans, are circulating among poultry. PMID- 29268973 TI - Faunal data and envenomation emergency first aid of cone snails (Conus spp.) in Qeshm Island, the Persian Gulf. AB - OBJECTIVE: To investigate the fauna of a highly venomous marine species group, the cone snails (Family Conidae), in the shores of Qeshm Island, of evaluating the possibility of envenomation in the area and summarize recommendations for emergency first aid. METHODS: Shores surrounding Qeshm Island were surveyed to collect cone snails during cold (February and March) and warm (May and June) seasons of 2017. Collected snails were identified to the species level. Abundance and species richness were estimated in shores of different structures, including muddy and sandy-rocky shores. Also, the most updated medical literature was reviewed to summarize related emergency first aid. RESULTS: Three cone snail species were recorded from southern sandy-rocky shores of the Island, in decreasing order of abundance, included crowned cone (Conus coronatus) (65%), feathered cone (Conus pennaceus) (28%), and frigid cone (Conus frigidus) (7%). Abundance of these species were significantly higher in cold season compared to the warm season (P < 0.05). No cone snails were recorded along the northern muddy shores of the Island. CONCLUSIONS: Envenomation can cause various symptoms ranging from minor local pain to systemic paralysis and death due to respiratory failure. We recommend an awareness programme for the seashore visiting public. PMID- 29268974 TI - Regulating effect of glycyrrhetinic acid on bronchial asthma smooth muscle proliferation and apoptosis as well as inflammatory factor expression through ERK1/2 signaling pathway. AB - OBJECTIVE: To study the influence of glycyrrhetinic acid (GA) on bronchial asthma (BA) smooth muscle proliferation and apoptosis as well as inflammatory factor expression and its molecular mechanism. METHODS: Male SD guinea pigs were selected and made into asthma models, bronchial asthma smooth muscle cells were cultured and divided into BA group, GA group and GA + LM group that were treated with serum-free RPMI1640 culture medium, serum-free RPMI1640 culture medium containing 50 ng/mL glycyrrhetinic acid, serum-free RPMI1640 culture medium containing 50 ng/mL glycyrrhetinic acid and 100 ng/mL LM22B-10 respectively; normal guinea pigs were collected and bronchial smooth muscle cells were cultured as control group. The cell proliferation activity as well as the expression of proliferation and apoptosis genes, inflammatory factors and p-ERK1/2 was determined. RESULTS: Proliferation activity value and mRNA expression of Bcl-2, TNF-alpha, IL-4, IL-6, YKL-40, protein expression of p-ERK1/2 of airway smooth muscle cell in BA group were significantly higher than those of control group while mRNA expression levels of Bax, caspase-9 as well as caspase-3 were significantly lower than that of control group (P < 0.05); proliferation activity value and mRNA expression of Bcl-2, TNF-alpha, IL-4, IL-6, YKL-40, protein expression of p-ERK1/2 of airway smooth muscle cell in GA group were significantly lower than those of BA group (P < 0.05) while the mRNA expression levels of Bax, caspase-9 as well as caspase-3 were significantly higher than those of BA group (P < 0.05); proliferation activity value and mRNA expression of Bcl-2, TNF-alpha, IL-4, IL-6, YKL-40 of airway smooth muscle cell in GA + LM group were significantly higher than those of GA group (P < 0.05) while mRNA expression levels of Bax, caspase-9 as well as caspase-3 were significantly lower that of GA group (P < 0.05). CONCLUSION: GA can inhibit the proliferation of bronchial smooth muscle cells and reduce the expression of inflammatory factors by inhibiting the phosphorylation of ERK1/2. PMID- 29268975 TI - Development of a mouse model of arecoline-induced oral mucosal fibrosis. AB - OBJECTIVE: To develop a BALB/c mouse model of oral submucous fibrosis (OSF) induced by arecoline and to exhibit an accumulation of collagen and angiogenesis changes. METHODS: BALB/c mice were randomly assigned to either the control (distilled water) or experimental group (arecoline) (n = 40). Eight mice from each group were sacrificed every 4 weeks since 8 weeks post treatment. Changes in histopathologic features, levels of collagen type I and collagen type III, and angiogenesis were measured. RESULTS: In the 8th week, epithelium atrophy, collagen cumulation and micrangium pathologic changes in the lamina propria were observed in the oral mucosa. In the 20th week, hyaline degeneration of the connective tissues was observed on the tongue and palate mucosa. The angiogenesis and collagen type I changed significantly as the diseases advanced (P < 0.05); however, collagen type III was not statistically different. CONCLUSIONS: An OSF model involving mice can be rapidly induced by drinking a high-dose of arecoline. OSF angiogenic changes in mice primarily decrease and collagen accumulation is mainly collagen type I. PMID- 29268976 TI - Expression of vimentin and glial fibrillary acidic protein in central nervous system development of rats. AB - OBJECTIVE: To investigate the distribution and contents of vimentin (Vim) and glial fibrillary acidic protein (GFAP) immunoreactivities in the central nervous system (CNS) of normal newborn, adult and aged rats. METHODS: In this study, thirty healthy and normal Sprague-Dawley rats were simply classified into three groups: Newborn (7 days aged), adult (5 months aged) and aged (24 months aged) rats. Brains and spinal cord were dissected and cut into frozen sections. The expression of Vim and GFAP in CNS were detected by confocal immunofluorescence. RESULTS: In each group, Vim was expressed in all the regions of CNS including the hippocampal, cerebral cortex, the third ventricle and spinal cord, and the expression was highest in neuron-like cell of newborn rats, while Vim was mainly expressed in cell bodies in adult and aged rats. GFAP was expressed in all the regions of CNS including the hippocampal, cerebral cortex, the third ventricle and spinal cord, and the expression was in astrocytes of aged rats. In the third ventricle, Vim was detected in all groups, and only observed in neuron-like cells of newborn. Meanwhile, the GFAP expression showed no significant differences between adult and aged rats in this region. The co-localization of Vim and GFAP were mainly observed in hippocampus and cerebral cortex of newborn, but this co localization was found in the third ventricle of the rats in all groups. CONCLUSION: Our data demonstrate for the first time that the expression of Vim and GFAP in the rat's CNS during development. This data may provide a foundation for the further mechanistic studies of these two main intermediate filaments during development of CNS. PMID- 29268977 TI - Reverse effect of curcumin on CDDP-induced drug-resistance via Keap1/p62-Nrf2 signaling in A549/CDDP cell. AB - OBJECTIVE: To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway. METHODS: A drug-resistant cell model was established by exposing A549/CDDP cell to 2 MUg/mL CDDP. A549/CDDP cell was treated with 20 MUg/mL CDDP and 10 MUM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed. RESULTS: CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin. CONCLUSIONS: The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell. Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch. PMID- 29268978 TI - Electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure. AB - OBJECTIVE: To investigate the electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure. METHODS: Guinea pigs model of iron deficiency anemia complicated with chronic heart failure in 10 guinea pigs of the experimental group was made by feeding a low iron diet, pure water and subcutaneous injection of isoproterenol. The control group consisting of 11 guinea pigs was given normal food, normal water and injected with normal saline. The left ventricular outflow tract model specimen was also prepared. The standard microelectrode technique was used to observe electrophysiological changes of autonomic cells in the outflow tract of left ventricular heart failure complicated with iron deficiency anemia in guinea pig model. The indicators of observation were maximal diastolic potential, action potential amplitude, 0 phase maximal depolarization velocity, 4 phase automatic depolarization velocity, repolarization 50% and 90%, and spontaneous discharge frequency. RESULTS: Compared with the control group, 4 phase automatic depolarization velocity, spontaneous discharge frequency and 0 phase maximal depolarization velocity decreased significantly (P < 0.01) and action potential amplitude reduced (P < 0.01) in model group. Moreover, repolarization 50% and 90% increased (P < 0.01). CONCLUSIONS: There are electrophysiological abnormalities of the left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with heart failure. PMID- 29268979 TI - Polyphenolic content, in vitro antioxidant activity and chemical composition of extract from Nephelium lappaceum L. (Mexican rambutan) husk. AB - OBJECTIVE: To determinate the recovery of total polyphenolic compounds content, in vitro antioxidant activity and HPLC/ESI/MS characterization of extract from Nephelium lappaceum L. (Mexican rambutan). METHODS: The rambutan husk extract was obtained by aqueous extraction and a polyphenolic fraction was recovered using Amberlite XAD-16. The total polyphenolic compounds content was determined by the Folin Ciocalteu and butanol-HCI methods. In vitro antioxidant activity was performed using ABTS and ferric reducing antioxidant power methods. RESULTS: Mexican rambutan husk showed a total polyphenolic content of 582 mg/g and an evident antioxidant activity by ABTS and ferric reducing antioxidant power analysis. The HPLC/ESI/MS assay allowed the identification of 13 compounds, most of which belong to ellagitannins. Geraniin, corilagin and ellagic acid were present in the sample; the mineral composition was also evaluated. CONCLUSIONS: Rambutan husk cultivated in Mexico is a promising source for the recovery of added value bioactive compounds with antioxidant activity, which have potential applications as bioactive antioxidant agents for the treatment of diseases. PMID- 29268980 TI - Influenza H3N2 Vaccines: Recent Challenges. AB - H3N2-subtype influenza A viruses are major causes of seasonal influenza epidemics. Emerging H3N2 variants require the annual adjustment of the vaccine strain. Recently, studies addressing the reduced effectiveness of current H3N2 vaccines have identified production-related substitutions in the viral hemagglutinin antigen as a possible cause for reduced vaccine efficacy. PMID- 29268981 TI - Do Archaea Need an Origin of Replication? AB - Chromosomal DNA replication starts at a specific region called an origin of replication. Until recently, all organisms were thought to require origins to replicate their chromosomes. It was recently discovered that some archaeal species do not utilize origins of replication under laboratory growth conditions. PMID- 29268983 TI - Young Male With Chest Pain. PMID- 29268984 TI - Chest Pain in a Patient With a Left Bundle Branch Block. PMID- 29268982 TI - Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. AB - Viruses from the Coronaviridae, Togaviridae, and Hepeviridae families all contain genes that encode a conserved protein domain, called a macrodomain; however, the role of this domain during infection has remained enigmatic. The recent discovery that mammalian macrodomain proteins enzymatically remove ADP-ribose, a common post-translation modification, from proteins has led to an outburst of studies describing both the enzymatic activity and function of viral macrodomains. These new studies have defined these domains as de-ADP-ribosylating enzymes, which indicates that these viruses have evolved to counteract antiviral ADP ribosylation, likely mediated by poly-ADP-ribose polymerases (PARPs). Here, we comprehensively review this rapidly expanding field, describing the structures and enzymatic activities of viral macrodomains, and discussing their roles in viral replication and pathogenesis. PMID- 29268985 TI - The End. PMID- 29268986 TI - Who We Miss. PMID- 29268987 TI - Greater Love Than That. PMID- 29268988 TI - It May Come as No Shock: Cardioversion of Atrial Fibrillation and Atrial Flutter With Ibutilide: January 2018 Annals of Emergency Medicine Journal Club. PMID- 29268989 TI - Man With Bulging Blisters. PMID- 29268990 TI - Young Woman With Black Spot on Foot. PMID- 29268991 TI - Sensitivity of the Ottawa 3DY Scale for Assessment of Cognitive Impairment of Older Emergency Department Patients. PMID- 29268992 TI - In reply. PMID- 29268993 TI - In Response to Geiderman. PMID- 29268994 TI - The Path to Falling in Love With Emergency Medicine Again. PMID- 29268995 TI - Young Man With Left Arm Pain and Swelling. PMID- 29268996 TI - Young Child in Respiratory Distress. PMID- 29268997 TI - What to Do After You Cut: Recommendations for Abscess Management in the Emergency Setting. PMID- 29268998 TI - Commentary. PMID- 29268999 TI - Correction. PMID- 29269000 TI - Elderly Male With Shortness of Breath. PMID- 29269001 TI - Elderly Woman With Vomiting. PMID- 29269002 TI - Evaluation of the kinetic energy of the torso by magneto-inertial measurement unit during the sit-to-stand movement. AB - Sit-to-stand tests are used in geriatrics as a qualitative issue in order to evaluate motor control and stability. In terms of measured indicators, it is traditionally the duration of the task that is reported, however it appears that the use of the kinetic energy as a new quantitative criterion allows getting a better understanding of musculoskeletal deficits of elderly subjects. The aim of this study was to determine the feasibility to obtain the measure of kinetic energy using magneto-inertial measurement units (MIMU) during sit-to-stand movements at various paces. 26 healthy subjects contributed to this investigation. Measured results were compared to a marker-based motion capture using the correlation coefficient and the normalized root mean square error (nRMSE). nRMSE were below 10% and correlation coefficients were over 0.97. In addition, errors on the mean kinetic energy were also investigated using Bland Altman 95% limits of agreement (0.63 J-0.77 J), RMSE (0.29 J-0.38 J) and correlation coefficient (0.96-0.98). The results obtained highlighted that the method based on MIMU data could be an alternative to optoelectronic data acquisition to assess the kinetic energy of the torso during the sit-to-stand test, suggesting this method as being a promising alternative to determine kinetic energy during the sit-to-stand movement. PMID- 29269003 TI - Analysis of a swimmer's hand and forearm in impulsive start from rest using computational fluid dynamics in unsteady flow conditions. AB - The propulsive forces generated by the hands and arms of swimmers have so far been determined essentially by quasi-steady approaches. This study aims to quantify the temporal dependence of the hydrodynamic forces for a simple translation movement: an impulsive start from rest. The study, carried out in unsteady numerical simulation, couples the calculation of the lift and the drag on an expert swimmer hand-forearm model with visualizations of the flow and flow vortex structure analysis. The results of these simulations show that the hand and forearm hydrodynamic forces should be studied from an unsteady approach because the quasi-steady model is inadequate. It also appears that the delayed stall effect generates higher circulatory forces during a short translation at high angle of attack than forces calculated under steady state conditions. During this phase the hand force coefficients are approximately twice as large as those of the forearm. The total force coefficients are highest for angles of attack between 40 degrees and 60 degrees . For the same angle of attack, the forces produced when the leading edge is the thumb side are slightly greater than those produced when the leading edge is the little finger side. PMID- 29269004 TI - Redefining pulmonary hypertension. PMID- 29269005 TI - Neutrophils: Homing in on the myeloid mechanisms of metastasis. AB - The metastasis cascade is complex and comprises several stages including local invasion into surrounding tissue, intravasation and survival of tumour cells in the circulation, and extravasation and colonisation of a distant site. It is increasingly clear that these processes are driven not only by signals within the tumour cells, but are also profoundly influenced by stromal cells and signals in the tumour microenvironment. Amongst the many cell types within the tumour microenvironment, immune cells such as lymphocytes, macrophages and neutrophils play a prominent role in tumour development and progression. Neutrophils, however, have only recently emerged as important players, particularly in metastasis. Here we review the current evidence suggesting a multi-faceted role for neutrophils in the metastatic cascade. PMID- 29269006 TI - Measurement Under the Microscope: High Variability and Limited Construct Validity in Emergency Department Patient-Experience Scores. AB - STUDY OBJECTIVE: We evaluate variability and construct validity in commercially generated patient-experience survey data in a large sample of US emergency departments (EDs). METHODS: We used Press Ganey patient-experience data from a national emergency medicine group from 2012 to 2015 across 42 facilities and 242 physicians. We estimated variability as month-to-month changes in percentile scores and through intraclass correlations. Construct validity was assessed with linear regression analysis for monthly facility- and physician-level percentile scores. RESULTS: A total of 1,758 facility-months and 10,328 physician-months of data were included. Across facility-months, 40.8% had greater than 10 points of percentile change, 14.7% changed greater than 20 points, and 4.4% changed greater than 30. Across physician-months, 31.9% changed greater than 20 points, 21.5% changed greater than 30, and 13.6% changed greater than 40. Intraclass correlation estimates demonstrated similar variability; however, this was reduced as data were aggregated over fixed time increments. For facility-level construct validity, several facility factors predicted higher scores: teaching status; more older, male, and discharged patients without Medicaid insurance; lower patient volume; less requirement for physician night coverage; and shorter lengths of stay for discharged patients. For physician-level construct validity, younger physician age, participating in satisfaction training, increasing relative value units per visit, more commercially insured patients, higher computed tomography or magnetic resonance imaging use, working during less crowded times, and fewer night shifts predicted higher scores. CONCLUSION: In this sample, both physician- and facility-level patient-experience data varied greatly month to month, with physician variability being considerably higher. Facility-level scores have greater construct validity than physician-level ones. Optimizing data gathering may reduce variability in ED patient-experience data and better inform decisionmaking, quality measurement, and pay for performance. PMID- 29269007 TI - Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non-Small Cell Lung Cancer. AB - INTRODUCTION: Patients with brain metastases (BMs) arising from EGFR-mutated and anaplastic lymphoma kinase gene (ALK)-rearranged NSCLC have a favorable prognosis compared with patients with non-oncogene-addicted NSCLC, emphasizing the importance of minimizing toxicities such as the cognitive sequelae of whole brain radiation therapy (WBRT). Although radiosurgery without WBRT is the preferred strategy for one to three BMs, this paradigm remains controversial for patients with multiple BMs. METHODS: We reviewed the cases of patients with EGFR-mutated and ALK-rearranged NSCLC presenting to our cancer center between 2008 and 2017 and included only patients receiving treatment to four or more BMs in a single radiosurgery session. RESULTS: We identified 35 patients with a median follow-up of 4.1 years. The maximum number of BMs treated in a single radiosurgery session ranged from four to 26 (median number of BM treated per radiosurgery course: 6), and in total over all courses the number ranged from four to 47 (median: 10). The median survival was 3.0 years (4.2 for ALK-rearranged NSCLC; 2.4 for EGFR-mutated NSCLC) from the diagnosis of BM, and survival was comparable regardless of number of radiosurgery courses, number of BMs treated in total, or number of BMs treated in a single radiosurgery session. The mean hippocampal and whole-brain doses were exceedingly low even for patients receiving treatment to more than 10 BMs (1.2 and 0.8 Gy, respectively). Radiosurgery was well tolerated overall and the 5-year rate of freedom from neurologic death was 84%. The 5-year rate of freedom from WBRT was 97%. CONCLUSIONS: Radiosurgery for multiple BMs is controversial, yet patients with EGFR-mutated and ALK-rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene-addicted NSCLC with four or more BMs. PMID- 29269008 TI - Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells Define the Response of Different Subsets of Non-Small Cell Lung Cancer to PD-1/PD L1 Blockade Immunotherapy. AB - INTRODUCTION: Inhibition of programmed cell death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1 expression in tumor cells with treatment outcomes has been reported in many pivotal trials; however, the relationship remains unclear. Here, we demonstrate that those patients with both high density of PD-1-positive CD8 and PD-L1 positive CD4-positive CD25-positive (PD-1hi PD-L1hi) regulatory T cells (Tregs) have a better response to PD1/PD-L1 blockade. METHODS: In our study between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood samples and fresh tumor specimens were collected for study. Of these, 42 large (10-mm3) fresh tumor specimens were obtained from surgical procedures and checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4, and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small biopsy specimens from patients who received immunotherapy (pembrolizumab or nivolumab) were analyzed by immunohistochemistry and IF. The correlation between flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank correlation test; the primary end point was progression-free survival. For the PD 1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells were cultured (1*105 per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by anti-PD-1 and anti-PD-L1 was measured by a conventional 51Cr release assay. RESULTS: We first identified a population of high-PD-L1-expressing CD25-positive CD4-positive T cells (PD-L1hi Tregs) in the tumor microenvironment. The frequency of PD-L1hi Tregs was higher in tumor tissue (mean 48.6 +/- 14.3% in CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 +/- 10.2% in CD25 positive CD3-positive CD4-positive T cells) and normal tissue (mean 38.6 +/- 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as determined by flow cytometry. The frequency of PD-L1hi Tregs was positively correlated with PD 1-positive CD8 in Tregs. In addition, the TILs from these patients (PD-1hi PD L1hi) showed PD-1/PD-L1 pathway dependence and could induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The patients with PD-L1-positive NSCLC with PD-1hi PD-L1hi TILs showed a better clinical outcome than those with a low frequency of PD-1hi CD8 or PD-L1hi Tregs (median progression-free survival not reached versus 2 months). CONCLUSIONS: Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC. PMID- 29269009 TI - Prognostic Model for Resected Squamous Cell Lung Cancer: External Multicenter Validation and Propensity Score Analysis exploring the Impact of Adjuvant and Neoadjuvant Treatment. AB - INTRODUCTION: We developed one of the first clinicopathological prognostic nomograms for resected squamous cell lung cancer (SQLC). Herein, we validate the model in a larger multicenter cohort and we explore the impact of adjuvant and neoadjuvant treatment (ANT). METHODS: Patients with resected SQLC from January 2002 to December 2012 in six institutions were eligible. Each patient was assigned a prognostic score based on the clinicopathological factors included in the model (age, T descriptor according to seventh edition of the TNM classification, lymph node status, and grading). Kaplan-Meier analysis for disease-free survival, cancer-specific survival (CSS), and overall survival was performed according to a three-class risk model. Harrell's C-statistics were adopted for model validation. The effect of ANT was adjusted with propensity score. RESULTS: Data on 1375 patients were gathered (median age, 68 years; male sex, 86.8%; T descriptor 1 or 2 versus 3 or 4, 71.7% versus 24.9%; nodes negative versus positive, 53.4% versus 46.6%; and grading of 1 or 2 versus 3, 35.0% versus 41.1%). Data for survival analysis were available for 1097 patients. With a median follow-up of 55 months, patients at low risk had a significantly longer disease-free survival than did patients at intermediate risk (hazard ratio [HR] = 1.67, 95% confidence interval [CI]: 1.40-2.01) and patients at high risk (HR = 2.46, 95% CI: 1.90-3.19); they also had a significantly longer CSS (HR = 2.46, 95% CI: 1.80-3.36 versus HR = 4.30, 95% CI: 2.92-6.33) and overall survival (HR = 1.79, 95% CI: 1.48-2.17 versus HR = 2.33, 95% CI: 1.76-3.07). A trend in favor of ANT was observed for intermediate-risk/high-risk patients, particularly for CSS (p = 0.06 [5-year CSS 72.7% versus 60.8%]). CONCLUSIONS: A model based on a combination of easily available clinicopathological factors effectively stratifies patients with resected SQLC into three risk classes. PMID- 29269010 TI - Molecular cloning and analysis of the full-length aciniform spidroin gene from Araneus ventricosus. AB - Orb-web spiders produce more than seven different protein-based silks/glues by specialized abdominal glands for different uses. Prey-wrapping silk is secreted by aciniform glands for wrapping prey and forming the inner layer of egg case, and is almost twice as tough as other silks because of high strength and extensibility. So far, only two complete gene sequences have been obtained for aciniform spidroins (AcSp1). Here we describe the AcSp1 full-length gene sequence from the spider species Araneus ventricosus, using a long-distance PCR (LD-PCR) approach. The full-length AcSp1 gene is a single enormous exon of 10,338 bp in size, and the predicted protein sequence is 3445 amino acids long and consists of a conserved nonrepetitive N-terminal domain, a central predominantly repetitive region composed of fifteen repeat units, and a conserved nonrepetitive C-terminal domain. PMID- 29269011 TI - Specific binding of trivalent metal ions to lambda-carrageenan. AB - Carrageenans are a family of sulphated cell wall polysaccharides extracted from seaweeds and are widely used in different industrial sectors. Relative to kappa carrageenan (kappa-car) and iota-carrageenan (iota-car), the ionic binding behavior of lambda-carrageenan (lambda-car) is far less studied. In this work, the interaction and binding behavior between lambda-car and metal ions of different valency (Na+, K+, Mg2+, Ca2+, Fe2+, Fe3+, Al3+, Cr3+) have been investigated. In contrast to the non-specific interaction of the monovalent and divalent cations, specific binding has been identified between lambda-car and Fe3+/Al3+. The specific binding could lead to either precipitation or gelation of lambda-car, depending on the way of introducing Fe3+/Al3+ ions. Fe3+ and Al3+ exhibit the same binding stoichiometry of [M3+]/[repeating unit] = 1.0, with the former having a relatively larger binding constant. Cr3+, though having very similar physical properties with Fe3+/Al3+, is incapable of binding specifically to Cr3+. The phenomena could not be interpreted in terms of counterion condensation, and are rather attributable to a mechanism in which hexa coordination of Fe3+/Al3+ and entropy-driven cation dehydration play crucial roles in driving the binding of the trivalent metal ions to lambda-car. PMID- 29269012 TI - Chitosan/nanohydroxyapatite composite based scallop shells as an efficient adsorbent for mercuric ions: Static and dynamic adsorption studies. AB - Chitosan/nanohydroxyapatite composites based on scallop shells (CP12, CP14 and CP21) were prepared with different chitosan: nanohydroxyapatite ratios (1:2, 1:4 and 2:1, respectively). Nanohydroxyapatite (P), chitosan(C) and their composites were characterized by means of TGA, XRD, N2 adsorption/desorption analysis, SEM, Zeta potential and FTIR. The BET surface area ranged between 189 and 512 m2/g. Static adsorption of Hg+2 was tested for the effect of adsorbent dosage, pH, time and initial Hg+2 concentrations indicating that maximum static adsorption capacity was confirmed by CP12 (111.6 mg/g). Static adsorption well fitted with Langmuir adsorption isotherm and Pseudo-second order kinetic models. CP12 was selected for dynamic adsorption of Hg+2 considering the effect of bed height, flow rate and the effect of Hg+2 concentrations. Maximum dynamic adsorption capacity was confirmed at bed height of 3 cm, 2.0 mL/min flow rate and 300 mg/L as Hg+2 concentration with breakthrough time (tb) and exhaustion time (te) of 9 and 21 h. Yoon-Nelson and Thomas models best described the experimental Hg+2 breakthrough curve model. After static adsorption, EDTA solution confirmed the maximum desorption efficiency. The validity of CP12 was tested through three cycles of column dynamic adsorption-desorption. PMID- 29269013 TI - The novel Group A Streptococcus antigen SpnA combined with bead-based immunoassay technology improves streptococcal serology for the diagnosis of acute rheumatic fever. AB - OBJECTIVES: Streptococcal serology provides evidence of prior Group A Streptococcus (GAS) exposure, crucial to the diagnosis of acute rheumatic fever (ARF) and post-streptococcal glomerulonephritis. However, current tests, which measure anti-streptolysin-O and anti-DNaseB antibodies, are limited by false positives in GAS endemic settings, and incompatible methodology requiring the two tests to be run in parallel. The objective was to improve streptococcal serology by combining the novel GAS antigen, SpnA, with streptolysin-O and DNaseB in a contemporary, bead-based immunoassay. METHODS: Recombinant streptolysin-O, DNAseB and SpnA were conjugated to polystyrene beads with unique fluorescence positions so antibody binding to all three antigens could be detected simultaneously by cytometric bead array. Multiplex assays were run on sera collected in three groups: ARF; ethnically matched healthy children; and healthy adults. RESULTS: The ability of the antigens to detect a previous GAS exposure in ARF was assessed using the 80th centile of the healthy children group as cut-off (upper limit of normal). SpnA had the highest sensitivity at 88%, compared with 75% for streptolysin-O and 56% for DNaseB. CONCLUSIONS: SpnA has favorable immunokinetics for streptococcal serology, and can be combined with anti-streptolysin-O and anti DNaseB in a multiplex format to improve efficiency and accuracy. PMID- 29269014 TI - Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene. AB - Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30 s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis. Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient's younger years. PMID- 29269015 TI - Reinforcing mitochondrial functions in aging brain: An insight into Parkinson's disease therapeutics. AB - Mitochondria, the powerhouse of the neural cells in the brain, are also the seat of certain essential gene signaling pathways that control neuronal functions. Deterioration of mitochondrial functions has been widely reported in normal aging as well as in a spectrum of age-associated neurological diseases, including Parkinson's disease (PD). Evidences accumulated in the recent past provide not only advanced information on the causes of mitochondrial bioenergetics defects and redox imbalance in PD brains, but also much insight into mitochondrial biogenesis, quality control of mitochondrial proteins, and genes, which regulate intra- and extra-mitochondrial signaling that control the general health of neural cells. The mitochondrial quality control machinery is affected in aging and especially in PD, thus affecting intraneuronal protein transport and degradation, which are primarily responsible for accumulation of misfolded proteins and mitochondrial damage in sporadic as well as familial PD. Essentially we considered in the first half of this review, mitochondria-based targets such as mitochondrial oxidative stress and mitochondrial quality control pathways in PD, relevance of mitochondrial DNA mutations, mitophagy, mitochondrial proteases, mitochondrial flux, and finally mitochondria-based therapies possible for PD. Therapeutic aspects are considered in the later half and mitochondria-targeted antioxidant therapy, mitophagy enhancers, mitochondrial biogenesis boasters, mitochondrial dynamics modulators, and gene-based therapeutic approaches are discussed. The present review is a critical assessment of this information to distinguish some exemplary mitochondrial therapeutic targets, and provides a utilitarian perception of some avenues for therapeutic designs on identified mitochondrial targets for PD, a very incapacitating disorder of the geriatric population, world over. PMID- 29269016 TI - Functional changes in vascular reactivity to adenosine receptor activation in type I diabetic mice. AB - Activation of adenosine receptors has been implicated in several biological functions, including cardiovascular and renal function. Diabetes causes morphological and functional changes in the vasculature, resulting in abnormal responses to various stimuli. Recent studies have suggested that adenosine receptor expression and signaling are altered in disease states such as hypertension, diabetes. Using a streptozotocin (STZ) mouse model of type I diabetes (T1D), we investigated the functional changes in aorta and resistance mesenteric arteries to adenosine receptor agonist activation in T1D. Organ baths and DMT wire myographs were used for muscle tension measurements in isolated vascular rings, and western blotting was used for protein analysis. Concentration response curves to selective adenosine receptor agonists, including CCPA (A1 receptor agonist), Cl-IBMECA (A3 receptor agonist), CGS-21680 (A2A receptor agonist), and BAY 60-6583 (A2B receptor agonist), were performed. We found that diabetes did not affect adenosine receptor agonist-mediated relaxation or contraction in mesenteric arteries. However, aortas from diabetic mice exhibited a significant decrease (P < 0.05) in A1 receptor-mediated vasoconstriction. In addition, the aortas from STZ-treated mice exhibited an increase in phenylephrine mediated contraction (EC50 7.40 +/- 0.08 in STZ vs 6.89 +/- 0.14 in vehicle; P < 0.05), while relaxation to A2A receptor agonists (CGS-21680) tended to decrease in aortas from the STZ-treated group (not statistically significant). Our data suggest that changes in adenosine receptor(s) vascular reactivity in T1D is tissue specific, and the decrease in A1 receptor-mediated aortic contraction could be a compensatory mechanism to counterbalance the increased adrenergic vascular contractility observed in aortas from diabetic mice. PMID- 29269017 TI - PAC-1 and its derivative WF-210 Inhibit Angiogenesis by inhibiting VEGF/VEGFR pathway. AB - Procaspase Activating Compound-1 (PAC-1) and its derivative WF-210 induce apoptosis in cancer cells by activating procaspase-3 to caspase-3. The aim of this study was to extend current knowledge about the mechanisms of PAC-1 and WF 210, particularly about their effects on tumor angiogenesis. PAC-1 and WF-210 restrained VEGF-induced human umbilical vascular endothelial cells (HUVECs) proliferation, invasion, and tube formation. PAC-1 and WF-210 abrogated VEGF induced vessel sprouting from rat aortic rings and inhibited vascular formation in the Matrigel plug assay. PAC-1 and WF-210 suppressed phosphorylation of VEGFR2 and its downstream protein kinases c-Src, FAK, and AKT in both HUVECs and U-87 cells. When given to mice bearing subcutaneous or orthotopic xenograft, PAC-1 and WF-210 inhibited the tumor growth and tumor angiogenesis. Further tests showed that PAC-1 and WF-210 inhibited stemness and induced autophagy flux of U-87 cells. This study revealed mechanisms of PAC-1 and WF-210 other than inducing apoptosis, which provides additional support for their using in the clinic. PMID- 29269018 TI - Secoisolariciresinol diglucoside inhibits adipogenesis through the AMPK pathway. AB - Flaxseeds are used to treat metabolic diseases such as type 2 diabetes, fatty liver, hyperlipidemia and obesity. Secoisolariciresinol diglucoside (SDG) is a main substance of lignan which belongs to the phytoestrogen family and exists abundantly in flaxseeds. In this study, SDG reduced the body weight and size of adipose tissue, and decreased protein expressions of peroxisome proliferator activated receptor gamma (PPARgamma) and CCAAT-enhancer-binding protein alpha (C/EBPalpha) in the high fat diet-fed-induced obese mice model. In the vitro study, we examined the anti-adipogenic effect of SDG during differentiation of 3T3-L1 cells into adipocytes. 3T3-L1 preadipocytes were differentiated and treated with various concentrations of SDG. Oil Red O staining was done to measure the quantity of lipid contents. As a result, SDG reduced lipid accumulation and decreased the expressions of adipogenic-related genes such as adipocyte fatty-acid-binding protein 2, adiponectin, and resistin. SDG also decreased the mRNA and protein levels of PPARgamma and C/EBPalpha. Furthermore, phosphorylation levels of AMP-activated protein kinase alpha (AMPK alpha) and its upstream activator, liver kinase B1, were significantly increased by SDG in 3T3 L1 cells. These results suggest that SDG inhibits adipogenesis by activating AMPKalpha, suggesting it could be an attractive therapeutic candidate for the treatment of obesity. PMID- 29269019 TI - Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury. AB - Accumulating evidence suggests that activated factor X (FXa), a key coagulation factor, plays an important role in the development of vascular inflammation through activation of many cell types. Here, we investigated whether pharmacological blockade of FXa attenuates neointima formation after wire mediated vascular injury. Transluminal femoral artery injury was induced in C57BL/6 mice by inserting a straight wire. Rivaroxaban (5mg/kg/day), a direct FXa inhibitor, was administered from one week before surgery until killed. At four weeks after surgery, rivaroxaban significantly attenuated neointima formation in the injured arteries compared with control (P<0.01). Plasma lipid levels and blood pressure were similar between the rivaroxaban-treated group and non-treated group. Quantitative RT-PCR analyses demonstrated that rivaroxaban reduced the expression of inflammatory molecules (e.g., IL-1beta and TNF-alpha) in injured arteries at seven days after surgery (P<0.05, respectively). In vitro experiments using mouse peritoneal macrophages demonstrated that FXa increased the expression of inflammatory molecules (e.g., IL-1beta and TNF-alpha), which was blocked in the presence of rivaroxaban (P<0.05). Also, in vitro experiments using rat vascular smooth muscle cells (VSMC) demonstrated that FXa promoted both proliferation and migration of this cell type (P<0.05), which were blocked in the presence of rivaroxaban. Inhibition of FXa by rivaroxaban attenuates neointima formation after wire-mediated vascular injury through inhibition of inflammatory activation of macrophages and VSMC. PMID- 29269021 TI - No difference in knowledge obtained from infographic or plain language summary of a Cochrane systematic review: three randomized controlled trials. AB - OBJECTIVES: The aim of this study was to test the usefulness of an infographic in the translation of knowledge about health information from a Cochrane systematic review to lay and professional populations in comparison to a plain language summary (PLS) and scientific abstract (SA). STUDY DESIGN AND SETTING: We conducted three parallel randomized trials with university students (n = 171), consumers (n = 99), and doctors (n = 64), to examine the effect of different summary formats of a Cochrane systematic review on the knowledge about health information presented in the review, reading experience, and perceived user friendliness. In the trials involving students and doctors, an infographic was compared to a PLS and a SA, while in those with consumers, an infographic was compared to a PLS. RESULTS: We found no difference in knowledge between the infographic and the text-based PLS in any of the trials or in the whole participant sample. All three participant groups preferred the infographic and gave it higher ratings for reading experience (d = 0.48 in the overall sample) and user-friendliness (d = 0.46 in the overall sample). CONCLUSION: Although the infographic format was perceived as more enjoyable for reading, it was not better than a traditional, text-based PLS in the translation of knowledge about findings from a Cochrane systematic review. PMID- 29269022 TI - Photoactivated CRY1 and phyB Interact Directly with AUX/IAA Proteins to Inhibit Auxin Signaling in Arabidopsis. AB - Light is a key environmental cue that inhibits hypocotyl cell elongation through the blue and red/far-red light photoreceptors cryptochrome- and phytochrome mediated pathways in Arabidopsis. In contrast, as a pivotal endogenous phytohormone auxin promotes hypocotyl elongation through the auxin receptors TIR1/AFBs-mediated degradation of AUX/IAA proteins (AUX/IAAs). However, the molecular mechanisms underlying the antagonistic interaction of light and auxin signaling remain unclear. Here, we report that light inhibits auxin signaling through stabilization of AUX/IAAs by blue and red light-dependent interactions of cryptochrome 1 (CRY1) and phytochrome B with AUX/IAAs, respectively. Blue light triggered interactions of CRY1 with AUX/IAAs inhibit the associations of TIR1 with AUX/IAAs, leading to the repression of auxin-induced degradation of these proteins. Our results indicate that photoreceptors share AUX/IAAs with auxin receptors as the same direct downstream signaling components. We propose that antagonistic regulation of AUX/IAA protein stability by photoreceptors and auxin receptors allows plants to balance light and auxin signals to optimize their growth. PMID- 29269020 TI - TCR Signaling: Mechanisms of Initiation and Propagation. AB - The mechanisms by which a T cell detects antigen using its T cell antigen receptor (TCR) are crucial to our understanding of immunity and the harnessing of T cells therapeutically. A hallmark of the T cell response is the ability of T cells to quantitatively respond to antigenic ligands derived from pathogens while remaining inert to similar ligands derived from host tissues. Recent studies have revealed exciting properties of the TCR and the behaviors of its signaling effectors that are used to detect and discriminate between antigens. Here we highlight these recent findings, focusing on the proximal TCR signaling molecules Zap70, Lck, and LAT, to provide mechanistic models and insights into the exquisite sensitivity and specificity of the TCR. PMID- 29269023 TI - Rice Interploidy Crosses Disrupt Epigenetic Regulation, Gene Expression, and Seed Development. AB - Seed development in angiosperms requires a 2:1 maternal-to-paternal genome ratio (2m:1p) in the endosperm. When the ratio is disrupted, the seed development is impaired. Rice interploidy crosses result in endosperm failures, but the underlying molecular mechanisms remain unclear. Here, we report that the defective endosperm in rice interploidy crosses was associated with nonadditive expression of small RNAs and protein-coding genes. Interestingly, 24-nt small interfering RNAs were enriched in the 5' and 3' flanking sequences of nonadditively expressed genes in the interploidy crosses and were negatively associated with the expression of imprinted genes. Furthermore, some PRC2 family genes and DNA methylation-related genes including OsMET1b and OsCMT3a were upregulated in the 2*4 cross (pollinating a diploid "mother" with a tetraploid "father") but repressed in the reciprocal cross. These different epigenetic effects could lead to precocious or delayed cellularization during endosperm development. Notably, many endosperm-preferred genes, including starch metabolic and storage protein genes during grain filling, were found to be associated with DNA methylation or H3K27me3, which are repressed in both 2*4 and 4*2 crosses. WUSCHEL homeobox2 (WOX2)-like (WOX2L), an endosperm-preferred gene, was expressed specifically in the rice endosperm, in contrast to WOX2 expression in the Arabidopsis embryo. Disruption of WOX2L in transgenic rice by CRISPR/Cas9 mediated gene editing blocked starch and protein accumulation, resulting in seed abortion. In addition to gene repression, disrupting epigenetic process in the interploidy crosses also induced expression of stress-responsive genes. Thus, maintaining the 2m:1p genome ratio in the endosperm is essential for normal grain development in rice and other cereal crops. PMID- 29269024 TI - Posterior Fibular Groove Deepening Procedure With Low-Profile Screw Fixation of Fibrocartilaginous Flap for Chronic Peroneal Tendon Dislocation. AB - Chronic peroneal tendon dislocation is an uncommon disorder that frequently presents with concomitant pathology. Posterior fibular groove deepening and retinaculum repair have been increasing in popularity for treatment of peroneal tendon dislocations. The purpose of the present study was to introduce a posterior fibular groove deepening procedure using low-profile snap-off screws to securely and simply fix the fibrocartilaginous flap to facilitate faster rehabilitation and to assess the clinical outcomes of patients with chronic peroneal tendon dislocation and associated pathologic features. In the present retrospective case series, 34 ankles in 34 patients underwent the fibular groove deepening procedure using low-profile screws with superior peroneal retinaculum repair. The clinical outcomes were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale and patient subjective satisfaction rate. The time of return to recreational and sports activities was also assessed. Weightbearing ankle radiographs were evaluated to assess the stability of the flap by checking the screws. The mean follow-up period was 47.96 (range 12 to 142) months. The mean AOFAS scale score for all patients improved from 69.96 +/- 13.14 to 87.72 +/- 10.13 at the last follow-up examination (p < .001). Overall, 85.3% of patients subjectively rated their operative outcomes as excellent or good. The 18 (52.9%) patients with an isolated peroneal tendon dislocation had a faster return to recreational or sports activities than the 16 (47.1%) patients with concomitant pathologic features (2.95 +/- 0.19 versus 4.14 +/- 1.34 months; p = .002). No patient experienced residual dislocation, screw loosening, or irritation from the screws. The fibular groove deepening procedure using low-profile screws is be a simple procedure that offers rigid fixation. This leads to relatively fast rehabilitation and resumption of recreational or sports activities. PMID- 29269025 TI - First Metatarsophalangeal Joint Arthrodesis: Does the Addition of a Lag Screw to a Dorsal Locking Plate Influence Union Rate and/or Final Alignment after Fusion. AB - First metatarsophalangeal (MTP-1) joint fusion is a reliable method for the correction of various deformities, including hallux valgus and hallux rigidus. Ideal constructs provide high rates of fusion in the desired alignment. The present study examined the union rates and the change in dorsiflexion angle during the follow-up period in patients who had undergone MTP-1 fusion with a dorsal locking plate and a lag screw compared with patients who had undergone fusion with a dorsal locking plate alone. We performed a retrospective review of 99 feet undergoing MTP-1 fusion. The joints were fused using either a dorsal locking plate alone or a lag screw plus a dorsal locking plate. Union was determined radiographically during the follow-up period. Suspected nonunions were confirmed by computed tomography. The dorsiflexion angles were radiographically measured at the first postoperative visit and at the final follow-up visit. Of the 99 feet, 36 (36.4%) were in the lag screw plus dorsal plate group and 63 (63.6%) in the dorsal plate group. The mean follow-up period was 12.9 (range 12 to 33.5) months. The dorsal plate plus lag screw group had a significantly lower change in the mean dorsiflexion angle (0.57 degrees +/- 5.01 degrees ) during the postoperative period compared with the dorsal plate group (6.73 degrees +/- 7.07 degrees ). The addition of a lag screw to a dorsal locking plate for MTP-1 arthrodesis might offer improved stability of the joint in the sagittal plane over time compared with a dorsal plate alone. PMID- 29269026 TI - The role of working memory capacity in cardiovascular monitoring of cognitive workload. AB - Cardiovascular measures have been found to be sensitive to task onset and offset, but are less sensitive to adjacent levels of increasing cognitive workload. A potential confound in the literature is the disregard of individual differences in cardiovascular reactivity. In particular, the individuals' working memory capacity (WMC) is likely to play a role in cardiovascular reactivity to workload. A total of 98 university students performed four cognitive tasks that varied in their level of workload. The operation span (OSPAN) task was used to measure the participants' WMC. A variety of cardiovascular measures were gathered in real time during the experiment. Derived measures of blood pressure regulation were also calculated. In line with what was hypothesized, cardiovascular measures detected workload onset and offset but did not consistently distinguish between the individual task levels. Furthermore, a significant interaction between workload levels and WMC showed that cardiovascular profile varied depending on WMC scores. In addition, WMC negatively predicted subjective ratings of task difficulty as well as task performance, with subjective estimation of task difficulty and error increasing as WMC decreased. The results suggest that WMC may play a critical role in determining how individuals react to increased cognitive workload. PMID- 29269027 TI - Reasons to Be Nervous about Flukicide Discovery. AB - The majority of anthelmintics dysregulate neuromuscular function, a fact most prominent for drugs against nematode parasites. In contrast to the strong knowledge base for nematode neurobiology, resource and tool deficits have prevented similar advances in flatworm parasites since those driven by bioimaging, immunocytochemistry, and neuropeptide biochemistry 20-30 years ago. However, recent developments are encouraging a renaissance in liver fluke neurobiology that can now support flukicide discovery. Emerging data promote neuromuscular signalling components, and especially G protein-coupled receptors (GPCRs), as next-generation targets. Here, we summarise these data and expose some of the new opportunities to accelerate progress towards GPCR-targeted flukicides for Fasciola hepatica. PMID- 29269028 TI - Targeting Plasmodium Proteases to Block Malaria Parasite Escape and Entry. AB - Proliferation of malaria parasites in a host requires mechanisms to spread between red blood cells (RBCs). We discuss here the implications for biology and antimalarial drug development of companion studies that establish the requirement of two Plasmodium spp. proteases of the plasmepsin family in parasite egress from, and invasion into, RBCs. PMID- 29269029 TI - Primary Care Provider Perceptions and Practices Regarding Dosing Units for Oral Liquid Medications. AB - INTRODUCTION: To prevent errors, health care professional and safety organizations recommend using milliliters (mL) alone for oral liquid medication dosing instructions and devices. In 2018, for federal incentives under the Quality Payment Program, one requirement is for electronic health records to automatically use mL alone whenever oral liquid medications are prescribed. Current perceptions and practices of primary care providers (PCPs) regarding dosing units for oral liquid medications were assessed. METHODS: Pediatricians, family practitioners, nurse practitioners, and internists participating in the 2015 DocStyles Web-based survey were asked about their perceptions and practices regarding dosing units for oral liquid medications. RESULTS: Three fifths of PCPs (59.0%) reported that using mL alone is safest for dosing oral liquid medications; however, nearly three quarters (72.0%) thought that patients/caregivers prefer instructions that include spoon-based units. Within each specialty, fewer PCPs reported they would prescribe using mL alone than reported that using mL alone is safest (P < .0001 for all). Among PCPs who think milliliter-only dosing is safest, those who perceived patients/caregivers prefer including spoon-based units were less likely to prescribe using mL alone (odds ratio 0.45, 95% confidence interval 0.34-0.59). Pediatricians were more likely than other PCPs to report that it is safest to use mL alone (80.8% vs 54.7%) and that they would use mL alone when prescribing (56.8% vs 30.9%) (P < .0001 for both). CONCLUSIONS: Because less than two thirds of pediatricians and one third of other PCPs would use mL alone in dosing instructions, additional education to encourage prescribing and communicating with patients/caregivers using mL alone may be needed. PMID- 29269030 TI - Enhancing Resident Education and Optimizing Care for Children With Special Health Care Needs in Resident Continuity Clinics. PMID- 29269031 TI - When Residents Let Conscience Be Their Guide: Professional Development and Educational Opportunity. AB - Residency is a time of professional identity formation. During this time, residents may first be exposed to conflicts between professional duties and personal beliefs which may lead to a request for a conscience-based exemption. Faculty, whether the supervising attending or the program director, have an important role in the professional and ethical development of residents by acknowledging and supporting residents as they encounter these potential conflicts. In this paper, we highlight three areas of unique issues that arise within the context of residency training programs when a resident makes a request to be excused from clinical duties based on personal conscience: namely, the maintenance of educational standards, the burdens that may be placed on colleagues, and the responsibility for faculty to foster the professional development of ethically sensitive pediatricians. PMID- 29269032 TI - Saving Ourselves, Our Patients, and Our Profession: Making the Case for Narrative Competence in Pediatrics. PMID- 29269033 TI - Effects of pH on nano-bubble stability and transport in saturated porous media. AB - An understanding of nano-scale bubble (NB) transport in porous media is important for potential application of NBs in soil/groundwater remediation. It is expected that the solution chemistry of NB water highly influences the surface characteristics of NBs and porous media and the interaction between them, thus affecting the stability and transport characteristics of NB. In this study, in addition to stability experiments, one-dimensional column transport experiments using glass beads were conducted to investigate the effects of pH on the NB transport behavior. The results showed that the NBs were more stable under higher pH. Column transport experiments revealed that entrapment of NBs, especially larger ones, was enhanced in lower-pH water, likely suggesting pH-dependent NB attachment and physical straining, both of which are also probably influenced by bubble size. Although relatively smaller NBs were released after switching the eluting fluid to one with lower ionic strength, most of the NBs in lower-pH water were still retained in the porous media even altering the chemical condition. PMID- 29269034 TI - Melanin deposition ruled out as cause of color changes in the red-eared sliders (Trachemys scripta elegans). AB - Animal coloration primarily depends on the presence of pigments and the mixing ratio of eumelanin and pheomelanin. The color of red-eared slider's carapace varies with age, from an olive green to a yellow green, and then to a yellow brown in juveniles, generally. The purpose of the present study was to investigate whether this color change is related to the difference in melanin expression. Melanin deposition levels were examined in the carapace, skin, eye and muscle of the three color-types using hematoxylin and eosin staining. Moreover, the full-length coding sequence (CDS) of red-eared slider turtle melanin biosynthesis regulatory genes TYR, TYRP1, MITF and SLC24A5 were cloned, sequenced and quantitatively analyzed. Both histological view of melanin deposition and quantitative real-time PCR test of melanin-regulated gene expressions showed that there are significant differences among different tissues of red-eared slider, but no significant difference among different color-types, indicating that melanin deposition is not associated with ontogenetic color change in the carapace of red-eared slider. This study initially explore the melanin deposition and the mRNA expression of melanin biosynthesis regulatory genes in red-eared slider, which serve as a foundation for further insight into the pigmentation patterns and the mechanism of body color change in turtles. PMID- 29269035 TI - Diversity in membrane composition is associated with variation in thermoregulatory capacity in hymenopterans. AB - Thermoregulatory capacity varies widely among bees and wasps, but the cellular physiology required to support such thermogenic ability remains unclear. Studies conducted on ectothermic species living in varying temperature show that cellular membrane composition is adjusted to remain functional, a process named homeoviscous adaptation. We show that the fatty acid composition of flight muscle membranes varies with thermogenic capacity in species of bees and wasps. The relative abundance of palmitate (16:0) and linoleate (18:2) decreased, while oleate (18:1) increased with increasing thoracic temperature. Species selected for the study varied over ten-fold in body mass, which in turn affected species thoracic temperature and their fatty acids profile. Nevertheless, all analyses conducted show that thoracic temperature is the main driver of flight muscle membrane composition in hymenopterans with diverse thermoregulatory capacity. These findings are in line with the predictions based on the homeoviscous adaptation hypothesis and further show that thermogenic strategy used by insect species impacts cellular membrane composition. PMID- 29269036 TI - Artificial intelligence in fracture detection: transfer learning from deep convolutional neural networks. AB - AIM: To identify the extent to which transfer learning from deep convolutional neural networks (CNNs), pre-trained on non-medical images, can be used for automated fracture detection on plain radiographs. MATERIALS AND METHODS: The top layer of the Inception v3 network was re-trained using lateral wrist radiographs to produce a model for the classification of new studies as either "fracture" or "no fracture". The model was trained on a total of 11,112 images, after an eightfold data augmentation technique, from an initial set of 1,389 radiographs (695 "fracture" and 694 "no fracture"). The training data set was split 80:10:10 into training, validation, and test groups, respectively. An additional 100 wrist radiographs, comprising 50 "fracture" and 50 "no fracture" images, were used for final testing and statistical analysis. RESULTS: The area under the receiver operator characteristic curve (AUC) for this test was 0.954. Setting the diagnostic cut-off at a threshold designed to maximise both sensitivity and specificity resulted in values of 0.9 and 0.88, respectively. CONCLUSION: The AUC scores for this test were comparable to state-of-the-art providing proof of concept for transfer learning from CNNs in fracture detection on plain radiographs. This was achieved using only a moderate sample size. This technique is largely transferable, and therefore, has many potential applications in medical imaging, which may lead to significant improvements in workflow productivity and in clinical risk reduction. PMID- 29269037 TI - Reproducibility of apparent diffusion coefficient measurements evaluated with different workstations. AB - AIM: To evaluate apparent diffusion coefficient (ADC) measurements of breast lesions on different computer platforms to address post-processing influences on ADC measurement reproducibility. MATERIALS AND METHODS: One hundred biopsy-proven breast lesions were included in this prospective study. MRI examination was performed at 3 T using standard sequences and an echo planar diffusion-weighted imaging sequence with b-values of 0 and 850 s/mm2. The images were reviewed by two radiologists in consensus. Regions of interest were placed manually within the lesion, following its contour. Care was taken to exclude adjacent normal tissue or necrotic tissue and cystic components within the lesion. The mean ADC value was measured for each lesion on two different platforms: On the MRI workstation that came with the scanner and on a commercially available DICOM (digital imaging and communication in medicine) viewer. Agreement between workstation measurements was evaluated using intraclass correlation coefficient and Bland-Altman plots. RESULTS: Fifty-nine malignant and 41 benign lesions were analysed. Of the benign lesions, 28 were mass lesions and 13 were non-mass-like enhancements. In addition, 46 of the malignant lesions were masses and 13 were non-mass-like enhancements. Agreement between the two workstation measurements was high (intraclass correlation coefficients=0.981). Using Bland-Altman plots, no systematic differences were identified between workstations. Limits of agreement ranged between a minimum of -0.071*10-3 mm2/s and a maximum of 0.102*10 3 mm2/s. CONCLUSION: ADC measurements are reproducible among the workstations considered in this study. PMID- 29269038 TI - Characterisation of meta-analytical functional connectivity in progressive supranuclear palsy. AB - AIM: To characterise the meta-analytical functional connectivity patterns in progressive supranuclear palsy (PSP) and compare them to idiopathic Parkinson's disease (IPD). MATERIALS AND METHODS: It was previously reported that PSP and IPD showed distinct regions of brain atrophy based on voxel-based morphometry (VBM) meta-analysis. Using these regions as seeds, healthy control data were referenced to create and statistically compare meta-analytical functional connectivity maps of PSP and IPD. RESULTS: Some overlap was noted between the two diseases, including within the thalamus, striatum, and prefrontal cortex; however, the PSP seeds demonstrated more extensive functional co-activity throughout the brain, particularly within the midbrain, precentral gyrus, parietal cortex, basal ganglia, and cerebellum. CONCLUSION: These findings may help guide future longitudinal studies in the development of new functional imaging biomarkers for diagnosis and assessing treatment response. PMID- 29269039 TI - Automatic Detection of Acromegaly From Facial Photographs Using Machine Learning Methods. AB - BACKGROUND: Automatic early detection of acromegaly is theoretically possible from facial photographs, which can lessen the prevalence and increase the cure probability. METHODS: In this study, several popular machine learning algorithms were used to train a retrospective development dataset consisting of 527 acromegaly patients and 596 normal subjects. We firstly used OpenCV to detect the face bounding rectangle box, and then cropped and resized it to the same pixel dimensions. From the detected faces, locations of facial landmarks which were the potential clinical indicators were extracted. Frontalization was then adopted to synthesize frontal facing views to improve the performance. Several popular machine learning methods including LM, KNN, SVM, RT, CNN, and EM were used to automatically identify acromegaly from the detected facial photographs, extracted facial landmarks, and synthesized frontal faces. The trained models were evaluated using a separate dataset, of which half were diagnosed as acromegaly by growth hormone suppression test. RESULTS: The best result of our proposed methods showed a PPV of 96%, a NPV of 95%, a sensitivity of 96% and a specificity of 96%. CONCLUSIONS: Artificial intelligence can automatically early detect acromegaly with a high sensitivity and specificity. PMID- 29269040 TI - Transcriptomics and Targeted Proteomics Analysis to Gain Insights Into the Immune control Mechanisms of HIV-1 Infected Elite Controllers. AB - A small subset of HIV-1 infected individuals, the "Elite Controllers" (EC), can control viral replication and restrain progression to immunodeficiency without antiretroviral therapy (ART). In this study, a cross-sectional transcriptomics and targeted proteomics analysis were performed in a well-defined Swedish cohort of untreated EC (n=19), treatment naive patients with viremia (VP, n=32) and HIV 1-negative healthy controls (HC, n=23). The blood transcriptome identified 151 protein-coding genes that were differentially expressed (DE) in VP compared to EC. Genes like CXCR6 and SIGLEC1 were downregulated in EC compared to VP. A definite distinction in gene expression between males and females among all patient-groups were observed. The gene expression profile between female EC and the healthy females was similar but did differ between male EC and healthy males. At targeted proteomics analysis, 90% (29/32) of VPs clustered together while EC and HC clustered separately from VP. Among the soluble factors, 33 were distinctive to be statistically significant (False discovery rate=0.02). Cell surface receptor signaling pathway, programmed cell death, response to cytokine and cytokine-mediated signaling seem to synergistically play an essential role in HIV-1 control in EC. PMID- 29269041 TI - Passive Transfer of Immune Sera Induced by a Zika Virus-Like Particle Vaccine Protects AG129 Mice Against Lethal Zika Virus Challenge. AB - Zika virus (ZIKV) poses a serious public health threat due to its association with birth defects in developing fetuses and Guillain-Barre Syndrome in adults. We are developing a ZIKV vaccine based on virus-like particles (VLPs) generated in transiently transfected HEK293 cells. The genetic construct consists of the prM and envelope structural protein genes of ZIKV placed downstream from a heterologous signal sequence. To better understand the humoral responses and correlates of protection (CoP) induced by the VLP vaccine, we evaluated VLP immunogenicity with and without alum in immune-competent mice (C57Bl/6 x Balb/c) and observed efficient induction of neutralizing antibody as well as a dose sparing effect of alum. To assess the efficacy of the immune sera, we performed passive transfer experiments in AG129 mice. Mice that received the immune sera prior to ZIKV infection demonstrated significantly reduced viral replication as measured by viral RNA levels in the blood and remained healthy, whereas control mice succumbed to infection. The results underscore the protective effect of the antibody responses elicited by this ZIKV VLP vaccine candidate. These studies will help define optimal vaccine formulations, contribute to translational efforts in developing a vaccine for clinical development, and assist in the definition of immunologic CoP. PMID- 29269044 TI - Bispecific antibodies for cancer therapy: A review. AB - The ability to produce monoclonal antibodies with defined and distinct specificities has resulted in a vast spectrum of therapeutic monoclonal antibodies including bispecific antibodies (BsAbs). Several types of BsAbs have been produced but the most well-known of these are trispecific antibodies (TrAbs or TrioMabs) and bispecific T cell engager antibodies (BiTE). TrAbs have two variable segments for antigen binding and an Fc component to recruit immune cells. Catumaxomab is a TrAb that has orphan drug status from the Food and Drug Administration (FDA) for EpCam positive gastric and ovarian tumors and was previously approved by the European Medicinal Agency (EMA) for the same indication. One arm of catumaxomab binds to EpCAM, the other binds to CD3 on T cells and the Fc portion recruits immune cells. Catumaxomab is no longer being produced by the manufacturer due to logistic considerations and hence not available in the European market. Blinatumomab is a BiTE that comprises of two variable segments only with one arm binding to CD19 and the other binding to CD3. Blinatumomab has been approved for relapsed or refractory B-cell precursor ALL in adults and children by the FDA. There are over 50 bispecific antibodies currently on clinical trials for various malignancies and the hope is that in the future many of these, with better understanding of principles and techniques of production, will provide treatment options for many different types of cancer. PMID- 29269043 TI - Impact of Eurycoma longifolia extract on DNA integrity, lipid peroxidation, and functional parameters in chilled and cryopreserved bull sperm. AB - This study aims to assess the effect of Eurycoma longifolia aqueous extract on chilled and cryopreserved quality of bull sperm. Semen samples were obtained from four Simmental-Brangus. Each sample was divided into two fractions: the first fraction was used for chilling the semen, and the second fraction was used for the freezing process. Both fractions were extended with Tris-egg yolk extender supplemented with 0.0, 0.25, 0.5, 1.0, 2.5, 5.0, and 7.5 mg/ml Eurycoma longifolia aqueous extract. The diluted chilled fraction was chilled at 5 degrees C for 6 days, whereas the frozen-thawed fraction was frozen in liquid nitrogen. Data revealed that 1 mg/ml E. longifolia aqueous extract yielded significantly (p < .05) higher sperm motility, morphology, viability, and sperm membrane integrity compared with the control group and other treated groups in chilled semen evaluation. For cryopreserved sperm, a significant difference (p < .05) in sperm motility, viability, sperm membrane integrity, DNA integrity, and lipid peroxidation was observed between 5 mg/ml E. longifolia aqueous extract and other treated and control groups. However, no significant difference in the percentage of sperm exhibiting normal sperm morphology was observed among the groups. In conclusion, the addition of 0.25 and 1 mg/ml E. langifolia extract to chilled semen and 5 mg/ml E. longifolia aqueous extract to cryopreserved sperm into Tris-egg yolk extender helps in maintaining superior quality of bull spermatozoa during chilling and freezing. PMID- 29269042 TI - HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss. The protein HtrA1 is enriched in retinal pigment epithelial (RPE) cells isolated from AMD patients and in drusen deposits. However, it is poorly understood how increased levels of HtrA1 affect the physiological function of the RPE at the intracellular level. Here, we developed hfRPE (human fetal retinal pigment epithelial) cell culture model where cells fully differentiated into a polarized functional monolayer. In this model, we fine-tuned the cellular levels of HtrA1 by targeted overexpression. Our data show that HtrA1 enzymatic activity leads to intracellular degradation of tubulin with a corresponding reduction in the number of microtubules, and consequently to an altered mechanical cell phenotype. HtrA1 overexpression further leads to impaired apical processes and decreased phagocytosis, an essential function for photoreceptor survival. These cellular alterations correlate with the AMD phenotype and thus highlight HtrA1 as an intracellular target for therapeutic interventions towards AMD treatment. PMID- 29269046 TI - TGF-beta1 up-regulates cadherin-11 expression through Snail: A potential mechanism for human trophoblast cell differentiation. AB - Cadherins are transmembrane proteins that mediate cell-cell adhesion by promoting the formation of adherens junctions. The regulated expression of cadherins is thought to play important roles in both normal and diseased placental development. Cadherin-11, also known as OB-cadherin, is expressed in human placenta and has been shown to be involved in regulation of trophoblast cell differentiation. We have demonstrated that transforming growth factor-beta1 (TGF beta1) promotes human trophoblast cell differentiation. In addition, cadherin-11 can be up-regulated by TGF-beta1 treatment. However, the underlying molecular mechanisms that mediate TGF-beta1-induced cadherin-11 expression remain unknown. In this study, we demonstrate that TGF-beta1 up-regulates cadherin-11 expression in human trophoblast cells. TGF-beta1 treatment activates SMAD2/3 signaling pathways. Knockdown of SMAD2 or SMAD3 attenuates the stimulatory effect of TGF beta1 on cadherin-11 expression. In addition, the transcription factors, Snail and Slug, are up-regulated by the TGF-beta1 treatment. Interestingly, only knockdown of Snail abolishes the TGF-beta1-induced up-regulation of cadherin-11 expression. Our results suggest that TGFbeta1-SMAD2/3-Snail signaling could contribute to the human trophoblast cell differentiation by up-regulating cadherin-11 expression. PMID- 29269045 TI - Adolescent Access to Care and Risk of Early Mother-to-Child HIV Transmission. AB - PURPOSE: Adolescent females aged 15-19 account for 62% of new HIV infections and give birth to 16 million infants annually. We quantify the risk of early mother to-child transmission (MTCT) of HIV among adolescents enrolled in nationally representative MTCT surveillance studies in South Africa. METHODS: Data from 4,814 adolescent (<=19 years) and 25,453 adult (>=20 years) mothers and their infants aged 4-8 weeks were analyzed. These data were gathered during three nationally representative, cross-sectional, facility-based surveys, conducted in 2010, 2011-2012, and 2012-2013. All infants were tested for HIV antibody (enzyme immunoassay), to determine HIV exposure. Enzyme immunoassay-positive infants or those born to self-reported HIV-positive mothers were tested for HIV infection (total nucleic acid polymerase chain reaction). Maternal HIV positivity was inferred from infant HIV antibody positivity. All analyses were weighted for sample realization and population live births. RESULTS: Adolescent mothers, compared with adult mothers, have almost three times less planned pregnancies 14.4% (95% confidence interval [CI]: 12.5-16.5) versus 43.9% (95% CI: 42.0-45.9) in 2010 and 15.2% (95% CI: 13.0-17.9) versus 42.8% (95% CI: 40.9-44.6) in 2012 2013 (p < .0001), less prevention of MTCT uptake (odds ratio [OR] in favor of adult mothers = 3.36, 95% CI: 2.95-3.83), and higher early MTCT (adjusted OR = 3.0, 95% CI: 1.1-8.0), respectively. Gestational age at first antenatal care booking was the only significant predictor of early MTCT among adolescents. CONCLUSIONS: Interventions that appeal to adolescents and initiate sexual and reproductive health care early should be tested in low- and middle-income settings to reduce differential service uptake and infant outcomes between adolescent and adult mothers. PMID- 29269047 TI - Coordinated regulation of hepatic FoxO1, PGC-1alpha and SREBP-1c facilitates insulin action and resistance. AB - : Type 2 diabetes is characterized by insulin resistance, hyperinsulinemia and hepatic overproduction of glucose and lipids. Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c; this pathway is hyperactivated in insulin-resistant states. Insulin suppresses gluconeogenic enzyme expression by Akt-dependent phosphorylation/inactivation of FoxO1 and PGC 1alpha; this pathway is impaired in insulin-resistant states by aPKC excess, which displaces Akt from scaffolding-protein WD40/ProF, where Akt phosphorylates/inhibits FoxO1. But how PGC-1alpha and FoxO1 are coordinated in insulin action and resistance is uncertain. Here, in normal mice, we found, along with Akt and aPKC, insulin increased PGC-1alpha association with WD40/ProF by an aPKC-dependent mechanism. However, in insulin-resistant high-fat-fed mice, like FoxO1, PGC-1alpha phosphorylation was impaired by aPKC-mediated displacement of Akt from WD40/ProF, as aPKC inhibition diminished its association with WD40/ProF, and simultaneously restored Akt association with WD40/ProF and phosphorylation/inhibition of both PGC-1alpha and FoxO1. Moreover, in high-fat fed mice, in addition to activity, PGC-1alpha expression was increased, not only by FoxO1 activation, but also, as found in human hepatocytes, by a mechanism requiring aPKC and SREBP-1c, which also increased expression and activity of PKC iota. In high-fat-fed mice, inhibition of hepatic aPKC, not only restored Akt association with WD40/ProF and FoxO1/PGC-1alpha phosphorylation, but also diminished expression of SREBP-1c, PGC-1alpha, PKC-iota and gluconeogenic and lipogenic enzymes, and corrected glucose intolerance and hyperlipidemia. CONCLUSION: Insulin suppression of gluconeogenic enzyme expression is facilitated by coordinated inactivation of FoxO1 and PGC-1alpha by WD40/ProF-associated Akt; but this coordination also increases vulnerability to aPKC hyperactivity, which is abetted by SREBP-1c-induced increases in PGC-1alpha and PKC-iota. PMID- 29269048 TI - Determinants of cholesterol efflux capacity in humans. AB - High-density lipoproteins (HDL) play an important role in the reverse cholesterol transport (RCT) pathway, contributing to the efflux of excess cellular cholesterol. However, the classic hypothesis that raising HDL-cholesterol (HDL-C) concentrations reduces cardiovascular disease (CVD) risk has been challenged by recent intervention studies. Nowadays, improving cholesterol efflux capacity of HDL particles is considered to be a better target for the prevention of CVD. We will first briefly summarize assays that have been developed in order to quantify HDL-mediated cholesterol efflux from macrophages. However, the main purpose of this review is to discuss factors and ABC-transporters that are associated with HDL-mediated cholesterol efflux, such as HDL particle characteristics (i.e. HDL size and composition), subjects' characteristics (i.e. gender, BMI and age), HDL C raising drugs, lifestyle, genetic background, as well as acute and low-grade systemic inflammation. Results suggested that factors associated with small HDL particles efficiently promote cholesterol efflux via the ABCA1 transporter. This appears to contradict findings from epidemiological studies suggesting that in particular large HDL2 particles are related to a reduced CVD risk. It is therefore essential not only to understand targets to increase cholesterol efflux capacity, but also to prove causality between cholesterol efflux capacity and the prevention of CVD risk. PMID- 29269049 TI - A Systematic Review of Transcendent States Across Meditation and Contemplative Traditions. AB - BACKGROUND: Across cultures and throughout history, transcendent states achieved through meditative practices have been reported. The practices to attain transcendent states vary from transcendental meditation to yoga to contemplative prayer, to other various forms of sitting meditation. While these transcendent states are ascribed many different terms, those who experience them describe a similar unitive, ineffable state of consciousness. Despite the common description, few studies have systematically examined transcendent states during meditation. OBJECTIVES: The objectives of this systematic review were to: 1) characterize studies evaluating transcendent states associated with meditation in any tradition; 2) qualitatively describe physiological and phenomenological outcomes collected during transcendent states and; 3) evaluate the quality of these studies using the Quality Assessment Tool. METHODS: Medline, PsycINFO, CINAHL, AltHealthWatch, AMED, and the Institute of Noetic Science Meditation Library were searched for relevant papers in any language. Included studies required adult participants and the collection of outcomes before, during, or after a reported transcendent state associated with meditation. RESULTS: Twenty five studies with a total of 672 combined participants were included in the final review. Participants were mostly male (61%; average age 39 +/- 11 years) with 12.7 +/- 6.6 (median 12.6; range 2-40) average years of meditation practice. A variety of meditation traditions were represented: (Buddhist; Christian; Mixed (practitioners from multiple traditions); Vedic: Transcendental Meditation and Yoga). The mean quality score was 67 +/- 13 (100 highest score possible). Subjective phenomenology and the objective outcomes of electroencephalography (EEG), electrocardiography, electromyography, electrooculogram, event-related potentials, functional magnetic resonance imaging, magnetoencephalography, respiration, and skin conductance and response were measured. Transcendent states were most consistently associated with slowed breathing, respiratory suspension, reduced muscle activity and EEG alpha blocking with external stimuli, and increased EEG alpha power, EEG coherence, and functional neural connectivity. The transcendent state is described as being in a state of relaxed wakefulness in a phenomenologically different space-time. Heterogeneity between studies precluded any formal meta-analysis and thus, conclusions about outcomes are qualitative and preliminary. CONCLUSIONS: Future research is warranted into transcendent states during meditation using more refined phenomenological tools and consistent methods and outcome evaluation. PMID- 29269050 TI - Sustained anti-inflammatory effects of TGF-beta1 on microglia/macrophages. AB - Ischemic brain injuries caused release of damage-associated molecular patterns (DAMPs) that activate microglia/macrophages (MG/MPs) by binding to Toll-like receptors. Using middle cerebral artery transiently occluded rats, we confirmed that MG/MPs expressed inducible nitric oxide synthase (iNOS) on 3days after reperfusion (dpr) in ischemic rat brain. iNOS expression almost disappeared on 7dpr when transforming growth factor-beta1 (TGF-beta1) expression was robustly increased. After transient incubation with TGF-beta1 for 24h, rat primary microglial cells were incubated with lipopolysaccharide (LPS) and released NO level was measured. The NO release was persistently suppressed even 72h after removal of TGF-beta1. The sustained TGF-beta1 effects were not attributable to microglia-derived endogenous TGF-beta1, as revealed by TGF-beta1 knockdown and in vitro quantification studies. Then, boiled supernatants prepared from ischemic brain tissues showed the similar sustained inhibitory effects on LPS-treated microglial cells that were prevented by the TGF-beta1 receptor-selective blocker SB525334. After incubation with TGF-beta1 for 24h and its subsequent removal, LPS induced phosphorylation of IkappaB kinases (IKKs), IkappaB degradation, and NFkappaB nuclear translocation were inhibited in a sustained manner. SB525334 abolished all these effects of TGF-beta1. In consistent with the in vitro results, phosphorylated IKK-immunoreactivity was abundant in MG/MPs in ischemic brain lesion on 3dpr, whereas it was almost disappeared on 7dpr. The findings suggest that abundantly produced TGF-beta1 in ischemic brain displays sustained anti-inflammatory effects on microglial cells by persistently inhibiting endogenous Toll-like receptor ligand-induced IkappaB degradation. PMID- 29269051 TI - Relationship between receptor occupancy and the antinociceptive effect of mu opioid receptor agonists in male rats. AB - The analgesic mechanisms of mu opioid receptor (MOR) agonists, including receptor occupancy at the site of action, are not completely understood. The aims of the present study were to evaluate: (i) receptor occupancy in the rat brain after administration of MOR agonists; (ii) the relationship between occupancy and the antinociceptive effect. Morphine (2 or 4 mg/kg) or oxycodone (1 or 3 mg/kg) was subcutaneously administered to rats. The antinociceptive effect of these drugs was measured by the hot-plate test. MOR occupancy in the thalamus was assessed by conducting an ex vivo receptor binding assay using [3H] [D-Ala2, N-MePhe4, Gly ol]-enkephalin, followed by autoradiographic analysis. Both drugs produced antinociception in a dose-dependent manner, and these effects disappeared after the time point at which the maximal effect was elicited. Thalamic MOR occupancy was observed in a dose-dependent manner at the time point at which maximal antinociception was elicited, and relatively low occupancy was observed when the antinociceptive effect was decreasing. Good correlation between thalamic MOR occupancy and the antinociceptive effect was observed. These findings provide direct evidence for the receptor occupancy of MOR agonists at the site of action and its relationship with the analgesic effect. PMID- 29269052 TI - Electrophysiological study on sensory nerve activity from the submandibular salivary gland in rats. AB - To evaluate the role of afferent information from the salivary gland, we analyzed the neural activity of the sensory nerve innervating the submandibular gland in anesthetized rats. The sensory nerves running through the parasympathetic nerve supply responded to mechanical pressure applied to the surface of the main duct and the body of the gland, whilst those in the sympathetic nerve supply responded only to the body of the gland. The sensory nerves in the sympathetic and parasympathetic nerve routes responded to pressure in the duct system produced by a retrograde injection of saline into the main duct. The threshold pressure for production of afferent discharges was higher than the maximum secretory pressure evoked by electrical stimulation of the parasympathetic secretory nerve. The retrograde ductal injection of drugs related to the inflammatory process (capsaicin and bradykinin) evoked intense multi-unit discharges in the sensory nerves of both routes. The sensory nerve in the sympathetic route was responsive to ligation of the artery to the gland. These results suggest that sensory nerves in the sympathetic and parasympathetic routes mainly conduct noxious information, and that those in the sympathetic route are responsive to ischemia and may control blood flow of the gland. PMID- 29269053 TI - First genome report on novel sequence types of Neisseria meningitidis: ST12777 and ST12778. AB - OBJECTIVES: Neisseria meningitidis is an important causative agent of meningitis and/or sepsis with high morbidity and mortality. Baseline genome data on N. meningitidis, especially from developing countries such as India, are lacking. This study aimed to investigate the whole genome sequences of N. meningitidis isolates from a tertiary care centre in India. METHODS: Whole-genome sequencing was performed using an Ion TorrentTM Personal Genome MachineTM (PGM) with 400-bp chemistry. Data were assembled de novo using SPAdes Genome Assembler v.5.0.0.0. Sequence annotation was performed through PATRIC, RAST and the NCBI PGAAP server. Downstream analysis of the isolates was performed using the Center for Genomic Epidemiology databases for antimicrobial resistance genes and sequence types. Virulence factors and CRISPR were analysed using the PubMLST database and CRISPRFinder, respectively. RESULTS: This study reports the whole genome shotgun sequences of eight N. meningitidis isolates from bloodstream infections. The genome data revealed two novel sequence types (ST12777 and ST12778), along with ST11, ST437 and ST6928. The virulence profile of the isolates matched their sequence types. All isolates were negative for plasmid-mediated resistance genes. CONCLUSIONS: To the best of our knowledge, this is the first report of ST11 and ST437 N. meningitidis isolates in India along with two novel sequence types (ST12777 and ST12778). These results indicate that the sequence types circulating in India are diverse and require continuous monitoring. Further studies strengthening the genome data on N. meningitidis are required to understand the prevalence, spread, exact resistance and virulence mechanisms along with serotypes. PMID- 29269054 TI - Repeated blood transfusions: Identification of a novel culprit of early graft failure in children. AB - BACKGROUND: The attrition of right ventricle to pulmonary artery (RV-PA) grafts has been attributed in part to the body's immunologic response. We hypothesized that antibodies developed through blood transfusion, directed against the grafts, may result in accelerated degeneration and the need for re-intervention. METHODS: This is a population-based study of the province of Quebec. We included children born between January 1, 1987 to December 31, 2006 who were diagnosed with a cono truncal anomaly and had an RV-PA graft. The patients were followed for transfusion exposure and RV-PA graft re-intervention. Time to re-intervention in those exposed versus non-exposed was analyzed using Cox regression. Analysis was done in two time periods, before and after the calendar year 2000, given the change in blood preparation in the province of Quebec. RESULTS: There were 413 patients who met the inclusion criteria of a cono-truncal disorder. Of the whole study population, 69% received a blood transfusion. Cox regression analysis showed that among patients who had the initial graft performed (n=181) before year 2000, having 2 or more blood transfusion was associated with an nearly tripled risk of a re-intervention comparing to no blood transfusion (hazard ratio of 2.88; 95% confidence interval 1.05-7.91). In patients who had the initial graft performed after year 2000 (n=232), the associated risk increase was 7-fold (hazard ratio of 7.01; 95% confidence interval 3.06-16.02). Kaplan-Meier analyses confirmed the significant difference in the re-intervention free survival probabilities between those who received 2 or more blood product transfusion and those who did not as well: prior to year 2000 (67.9% vs. 88.0% at 5years, p=0.0201) as well as after year 2000 (39.7% vs. 82.8% at 5years, p<0.0001). CONCLUSION: In this population-based analysis, repeated blood product transfusion was associated with a significant increased risk of a need for RV-PA graft re intervention. This data strongly suggest that repeated blood transfusion may adversely impact graft longevity. PMID- 29269055 TI - Ideal cardiovascular health score at the ELSA-Brasil baseline and its association with sociodemographic characteristics. AB - BACKGROUND: The American Heart Association's ideal cardiovascular health (ICH) define criteria for seven metrics, four classified as lifestyle factors (diet, physical activity, smoking and body-mass index) and four classified as health factors (smoking, blood pressure, fasting plasma glucose and total cholesterol). We aimed to analyze ICH scores at the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment and the associations with sociodemographic characteristics (age, sex, race, educational level, and family income). METHODS: We analyzed 13,356 ELSA-Brasil participants without cardiovascular disease using quasi-Poisson regression models to study the association between the ICH score and sociodemographic characteristics. RESULTS: Mean ICH scores were 2.5+/-1.3. Only 1047 (7.8%) participants had 5 or more ICH metrics. In adjusted models, age 65-74years was associated with lower ICH scores (-35.4%; 95% confidence interval [CI]: -37.6% to -33.1%) compared to age 35 44years. Women had higher ICH scores compared to men (+13.8%; 95%CI: +11.8% to +15.7%), mainly due to differences in the health factor ICH metrics. Participants of Black race had lower ICH scores compared to those of White race (-9.4%; 95%CI: -11.8% to -7.0%). Individuals with less than high school education had lower ICH scores than college-educated individuals (-17.2%; 95%CI: -20.0% to -14.2%). Low (<1245 USD) family income was also associated with lower ICH scores compared to those with high (>=3320 USD) family income (-4.4%, 95%CI: -7.2% to -1.6%). CONCLUSIONS: We found a low proportion of individuals with 5 or more ICH metrics. Age, sex, race, educational level and income were associated with ICH scores. PMID- 29269056 TI - The myocardial bright signal: The arrhythmogenic link between function and myocardial fibrosis. PMID- 29269057 TI - Enhancement of colon carcinogenesis by the combination of indole-3 carbinol and synbiotics in hemin-fed rats. AB - The risk of developing colorectal cancer (CRC) could be associated with red and processed meat intake. Experimental data supports that hemin iron, found abundantly in red meat, promotes CRC in mice and rats, while indole-3 carbinol (I3C) and synbiotics (syn) exert anti-carcinogenic activities in most studies of colon carcinogenesis. This study aimed to investigate the modifying effects of I3C and syn (inulin + Bifidobacterium lactis), given separately or together, on dimethylhidrazine (DMH)-induced colon carcinogenesis in hemin-fed rats. All animals were given four subcutaneous DMH injections and then, two weeks after carcinogen exposure, they began a basal diet containing hemin, hemin + I3C, hemin + syn, or hemin + I3C + syn for 23 weeks. The combination of I3C + syn significantly increased fecal water genotoxicity, tumor volume and invasiveness when compared to the hemin-fed control group. The groups fed I3C or syn alone had a significant reduction in the number of preneoplastic aberrant crypt foci (ACF) lesions compared to the hemin-fed group. Dietary I3C also reduced fecal water genotoxicity. Gene expression analysis of colorectal tumors demonstrated that the combination of dietary I3C + syn increased transcript levels for Raf1 and decreased tumor progression and invasiveness related to the genes Cdh1 and Appl1. This analysis also revealed that the Tnf and Cdh1 genes were significantly up- and down-regulated, respectively, in tumors of rats that received I3C, in comparison with the hemin-fed group. These findings reveal that the joint administration of I3C and syn enhanced the development of colon tumors induced by DMH in hemin-fed rats, while they potentially reduced ACF development when given alone. PMID- 29269058 TI - Proteomics and phosphoproteomics analysis of liver in male rats exposed to bisphenol A: Mechanism of hepatotoxicity and biomarker discovery. AB - Bisphenol A (BPA), discovered to be an artificial estrogen, has been shown to leach from some containers and mediate oxidative damage to cells and tissues and to be involved in reproductive disorders, obesity, diabetes, and liver dysfunction. In the current study, we investigated the effects of oral chronic exposure to low dose of BPA (0.5 mg kg-1) on the protein and phosphoprotein expression profiles in male Wistar rat liver using a gel-based proteomics approach based on two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization mass spectrometry identification. Our results showed that BPA exposure affected the levels of proteins and phosphoproteins involved in diverse biological processes associated with hepatotoxicity, fatty liver, and carcinoma. Moreover, we analyzed the effects of BPA on oxidative stress by assessing levels of malondialdehyde (MDA), a marker of lipid peroxidation, and reduced glutathione (GSH), a non-enzymatic antioxidant agent, in the liver. As expected BPA induced oxidative stress indicated by increased levels of MDA and decreased GSH content in the liver. In conclusion, chronic oral exposure of rats to BPA leads to increased oxidative stress in the liver and major alterations in the liver proteome and phosphoproteome, which may contribute to the pathophysiology of liver diseases. PMID- 29269059 TI - Trace determination of carbamate pesticides in medicinal plants by a fluorescent technique. AB - The safety issue of using carbamate pesticides in medicinal plants (MPs) has been a global concern and hence attracted attention of many researchers to develop analytical tools for trace pesticides detection. Derived from the fluorescence based techniques, a rapid, convenient and efficient method for the detection of three carbamate pesticides, including carbofuran, aldicarb and methomyl has been developed by using core-shell QDs. By optimizing experimental parameters, the system demonstrated high detection sensitivities for the investigated carbamates, with the lowest detectable concentrations less than 0.05 MUM. The molecular docking study indicated that the selected carbamate pesticides bound to the catalytic active site of acetylcholinesterase via pi-pi or H-pi interactions, which also revealed the potential mechanism of the differences in inhibition strength among the three pesticides on AChE. Moreover, in order to investigate the applicability and reliability of the proposed method for the pesticide analysis in real sample with complex matrix, the matrix effects of eight common MPs have been systematically explored. These findings suggested that this technique was a simple, sensitive and reliable method for rapid determination of carbamate pesticides in real samples, especially those with complex matrices like MPs, vegetables, fruits, and other agricultural crops. PMID- 29269060 TI - Genotoxicity and antioxidant activity of five Agrimonia and Filipendula species plant extracts evaluated by comet and micronucleus assays in human lymphocytes and Ames Salmonella/microsome test. AB - The species of Agrimonia and Filipendula have been traditionally used in folk medicine as anti-inflammatory herbs. This study extends the knowledge on bioactivities of F. palmata, A. eupatoria, A. procera, F. ulmaria and F. vulgaris by comprehensive characterization of their methanolic extracts. Antioxidant properties of extracts were evaluated by DPPH* (2,2-diphenyl-1-picrylhydrazyl), ABTS*+ 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) scavenging and oxygen radical absorbance capacities (ORAC). Genotoxicity of extracts was tested using alkaline single-cell gel electrophoresis (comet) and cytokinesis-block micronucleus assays in human lymphocytes in vitro and the Ames Salmonella/microsome test. All investigated Agrimonia and Filipendula extracts possessed strong antioxidant activity, which was comparable with that of a standard antioxidant trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thirty five compounds belonging to the classes of phenolic acids, flavonoids, phenylpropanoids and ellagitanins were detected by ultra-performance liquid chromatography - mass spectrometry (UPLC-Q-TOF-MS). Agrimonia and Filipendula extracts induced an increase in a DNA damage in the comet assay expressed as mean percentage of DNA in the comet tail. However, these extracts did not produce reverse mutation in bacterial cells in the Ames test and were not genotoxic in the micronucleus test. However, a slight though significant decrease of nuclear division index values was determined. In general, this study proved that Agrimonia and Filipendula species are a good source of bioactive compounds; their extracts may be classified as non-mutagenic and non-clastogenic in vitro under conditions of the current study. Consequently, the plants may be a promising material for nutraceuticals and natural medicines. PMID- 29269061 TI - Is hydrogen sulfide a potential novel therapy to prevent renal damage during ureteral obstruction? AB - In prolonged complete unilateral ureteral obstruction, reduced renal blood flow places the kidney in a state of ischemia, which can cause tubular injury and inflammation. Infiltrating inflammatory cells release transforming growth factor beta 1, which is a cytokine that initiates fibrosis through the epithelial mesenchymal-transition pathway. Persistent fibrosis can lead to irreversible renal injury and loss of function. While surgical intervention can remove the obstruction, relief of obstruction may not fully reverse renal injury. Additionally, patients often encounter long wait-times between initial consultation and medical intervention, resulting in the accumulation of renal injury that may cause permanent dysfunction. Currently, accepted pharmacological therapies to mitigate the symptoms of ureteral obstruction include acetaminophen, cyclooxygenase-inhibitors, non-steroidal anti-inflammatory medications, opioids and alpha-receptor blockers. However, there is no evidence that they mitigate renal injury. Therefore, identifying potential therapies that could be administered during obstruction may help to improve renal function following decompression. Evidence suggests that endogenously produced gasotransmitters can exhibit anti-inflammatory and antioxidant effects. Nitric oxide, carbon monoxide, and hydrogen sulfide have been identified as gasotransmitters and have been shown to have cytoprotective effects in various models of tissue injury. Studies have shown that treatment with sodium hydrogen sulfide (a hydrogen sulfide donor salt) mitigated transforming growth factor beta 1 expression, oxidative stress, fibrosis, and inflammation associated with urinary obstruction. More recently, the use of more directed hydrogen sulfide donor molecules, such as GYY4137, has led to significant decreases in inflammation, fibrosis, and expression of epithelial mesenchymal transition markers following urinary obstruction. Taken together, these findings suggest that hydrogen sulfide may be a novel potential therapy against renal injury caused by urinary obstruction. This review will highlight the existing literature about the pathogenesis and treatment of renal damage caused by chronic urinary obstruction and propose novel upcoming strategies that could improve patient outcomes. PMID- 29269062 TI - Subarachnoid Trabeculae: A Comprehensive Review of Their Embryology, Histology, Morphology, and Surgical Significance. AB - INTRODUCTION: Brain is suspended in cerebrospinal fluid (CSF)-filled subarachnoid space by subarachnoid trabeculae (SAT), which are collagen-reinforced columns stretching between the arachnoid and pia maters. Much neuroanatomic research has been focused on the subarachnoid cisterns and arachnoid matter but reported data on the SAT are limited. This study provides a comprehensive review of subarachnoid trabeculae, including their embryology, histology, morphologic variations, and surgical significance. METHODS: A literature search was conducted with no date restrictions in PubMed, Medline, EMBASE, Wiley Online Library, Cochrane, and Research Gate. Terms for the search included but were not limited to subarachnoid trabeculae, subarachnoid trabecular membrane, arachnoid mater, subarachnoid trabeculae embryology, subarachnoid trabeculae histology, and morphology. Articles with a high likelihood of bias, any study published in nonpopular journals (not indexed in PubMed or MEDLINE), and studies with conflicting data were excluded. RESULTS: A total of 1113 articles were retrieved. Of these, 110 articles including 19 book chapters, 58 original articles, 31 review articles, and 2 case reports met our inclusion criteria. CONCLUSIONS: SAT provide mechanical support to neurovascular structures through cell-to-cell interconnections and specific junctions between the pia and arachnoid maters. They vary widely in appearance and configuration among different parts of the brain. The complex network of SAT is inhomogeneous and mainly located in the vicinity of blood vessels. Microsurgical procedures should be performed with great care, and sharp rather than blunt trabecular dissection is recommended because of the close relationship to neurovascular structures. The significance of SAT for cerebrospinal fluid flow and hydrocephalus is to be determined. PMID- 29269063 TI - Carotid-Carotid Artery Crossover Bypass with a Synthetic Vascular Graft for Symptomatic Type 1A Common Carotid Artery Occlusion. AB - OBJECTIVE: To investigate the effect of carotid-carotid artery crossover bypass with a synthetic vascular graft for symptomatic type 1A common carotid artery occlusion (CCAO). METHODS: A retrospective analysis was conducted of patients with symptomatic type 1A CCAO who underwent carotid-carotid artery crossover bypass surgery via a retropharyngeal route with a synthetic vascular graft in the Department of Neurosurgery at our hospital. Preoperative demographic data, surgical complications, incidence of stroke during follow-up, and other clinical data were summarized. RESULTS: Between 2011 and 2016, carotid-carotid artery crossover bypass was performed with a synthetic vascular graft in 4 patients with type 1A CCAO. The mean patient age was 63.3 years (range, 49-69 years). Clinical symptoms included dizziness, amaurosis fugax, persistent limb numbness, and transient ischemic attack. In all 4 patients, postoperative computed tomography angiography showed internal carotid artery thickening due to successful bypass, whereas computed tomography perfusion showed improved postoperative cerebral perfusion on the side of the lesion. The sole perioperative complication was a complaint of foreign body sensation on swallowing in 1 patient. The mean duration of follow-up was 40.3 months (range, 14-77 months), during which no newly occurred cerebral ischemia or synthetic vascular graft occlusion was observed. CONCLUSIONS: Carotid-carotid artery crossover bypass with a synthetic vascular graft is a safe and effective therapeutic approach for patients with symptomatic type 1A CCAO. However, studies with larger series are needed to enable more precise conclusions. PMID- 29269064 TI - Computed Tomography Evaluation of the Correspondence Between the Arcuate Eminence and the Superior Semicircular Canal. AB - BACKGROUND: The arcuate eminence (AE) has been traditionally used in middle cranial fossa (MCF) surgery as a guide to accurate location of the superior semicircular canal (SSC) deep within the temporal bone. However, the anatomic relationship between the AE and SSC is controversial. We evaluated the anatomic coincidence between the AE and the SSC in the MCF surface. Distances between the most relevant anatomic structures in the MCF and prevalence of SSC dehiscence were measured. METHODS: We analyzed 75 (150 sides) 0.75-mm slice thickness temporal bone computed tomography scans and classified the AE and SSC relationship as coincident and noncoincident. Radiologic findings were reported independently in a blind fashion by 2 authors. Data were presented as mean +/- SD or frequency and percentage. Student t test or an unequal variance t test was used. Interobserver agreement among readings was assessed using kappa statistic for categorical variables and intraclass Kendall tau-a correlations for continuous measures. P < 0.05 was considered to indicate statistical significance. RESULTS: The AE matched the SSC in only 31.3% of cases. The AE could be localized as lateral as 11.6 mm from the SSC. It was impossible to identify the AE in 33 scans (22.0%). SSC dehiscence was found in 5 cases (3.3%). A few millimeters separated most analyzed landmarks, and a wide variability in secondary measurements was observed. CONCLUSIONS: The AE does not systematically overlie the SSC and should not be routinely used as a reference to reach this structure in MCF surgery. PMID- 29269065 TI - Frontolateral Approach Combined with Endoscopic Endonasal Extradural Posterior Clinoidectomy to the Upper Clival Region: Anatomic and Feasibility Study. AB - BACKGROUND: Surgical management of lesions located in the upper clival region is challenging. Complex open transcranial approaches have been used to reach surgical targets in these areas. The frontotemporozygomatic approach combined with an intradural posterior clinoidectomy has been proposed as the most reliable route to manage such lesions. We investigated combining a minimally invasive endoscopic endonasal extradural posterior clinoidectomy (EPC) with a standard frontolateral approach to expand the working area within the upper clival region. METHODS: Investigators dissected 10 human cadaveric heads at the Laboratory of Surgical NeuroAnatomy of the University of Barcelona. The heads were positioned to simulate a supine position, enabling the simultaneous use of both endonasal and frontolateral routes. The dissections were divided into 3 steps-standard frontolateral approach, EPC, and re-evaluation of the frontolateral route-aiming to compare the surgical exposure before and after EPC. RESULTS: After EPC, through the frontolateral pathway it was possible to improve visualization and working angles to the interpeduncular fossa and retrosellar and upper clival regions. Increase in extension of the carotid-oculomotor window was 7 mm and 10 mm before and after the posterior clinoidectomy, respectively. CONCLUSIONS: EPC provided extra working space for the frontolateral approach to the upper clival area with 42.8% expansion of the carotid-oculomotor triangle. Surgical series are needed to demonstrate clinical advantages and disadvantages of this novel combined approach. PMID- 29269066 TI - In Reply to "A Reply to Commentaries on: Surgical and Teaching Mission to Mongolia: Experience and Lessons". PMID- 29269067 TI - Microsurgical Removal of Snagged Stent Retriever During Endovascular Embolectomy for Acute Ischemic Stroke. AB - BACKGROUND: Catheter-based endovascular thrombectomy has gained popularity for use in patients with acute large-vessel occlusion; however, various complications have been reported. Herein, we present a unique, serious procedure-related complication. CASE DESCRIPTION: A 91-year-old woman with acute middle cerebral artery (MCA) occlusion underwent endovascular thrombectomy with a stent retriever, but the device could not be retrieved from the horizontal segment of MCA during the procedure. Subsequently, she underwent emergency craniotomy. The lodged stent was extracted with microforceps using a counter-stretch of the vessels, so as not to avulse the perforating arteries. The stent device was retrieved uneventfully through a sheath introducer that was inserted through the femoral artery. Postprocedural indocyanine green video angiography showed complete recanalization of the MCA and internal cerebral artery. CONCLUSIONS: This is a rare case in which successful open surgery was performed to retrieve a snagged stent retriever, with successful recanalization of the large cerebral artery occlusion. PMID- 29269068 TI - Multimodal Treatment of Intracranial Aneurysms in Children: Clinical Case Series and Review of the Literature. AB - BACKGROUND: The management of intracranial aneurysms in the pediatric population presents unique challenges. Cases are rare and tend to be of higher complexity compared with aneurysms in adults. Outcomes in long-term follow-up are not well characterized. Here we present illustrative case examples to demonstrate key concepts in managing these lesions in the context of the modern neurovascular era. METHODS: Four institutional databases of neurovascular procedures from 2012 to 2017 were reviewed. Patients <18 years old who underwent treatment for intracranial aneurysms were included. Patient characteristics, aneurysm details, treatment information, and angiographic and clinical outcomes were recorded. RESULTS: Ten cases of intracranial aneurysms in 9 children were identified. Management included direct clipping, trapping and bypass, endovascular coil embolization, endovascular vessel sacrifice, and flow diversion. CONCLUSIONS: The management of intracranial aneurysms in pediatric patients requires special considerations, from the diagnostic phase to treatment methods and follow-up regimen. These are ideally considered by a multidisciplinary team, with expertise from pediatric neurosurgeons, cerebrovascular neurosurgeons, and neurointerventionalists. PMID- 29269069 TI - Massive Brain Swelling and Death After Cranioplasty: A Systematic Review. AB - BACKGROUND: Although cranioplasty is a common procedure, it may cause a variety of complications. Massive brain swelling after cranioplasty (MBSC) is an unusual complication that has been reported more frequently in recent years. Most of the existing information about this condition is speculative and the cause remains unclear. METHODS: A PubMed and Scopus search adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed to include studies reporting patients with MBSC. Different information was analyzed in these cases to describe the characteristics and identify risk factors for MBSC. RESULTS: The search yielded 19 articles with a total of 26 patients. All studies were case reports and small case series. In most patients, preoperative intracranial hypotension and a considerable degree of sinking of skin flap were identified; this was the only constant finding observed in these cases. In addition, we propose a grading system to estimate the degree of preoperative sinking of skin flap and an algorithm with recommendations to decrease the incidence of MBSC. CONCLUSIONS: MBSC is an unusual, highly lethal, and probably underreported condition. The information gathered in this review indicates that MBSC occurs secondary to a cascade of pathologic events triggered by the bone flap implantation. This evidence suggests that the primary pathologic change is a sudden increase in the intracranial pressure acting on a brain chronically exposed to intracranial hypotension. PMID- 29269070 TI - Infection Rate after Cranial Neurosurgical Procedures: A Prospective Single Center Study. AB - OBJECTIVE: To determine infection rate (IR) and to identify modifiable risk factors (RF) in cranial neurosurgery in a neurosurgical department for tertiary referral as part of an infection control surveillance to reduce surgical site infections (SSI). METHODS: A prospective SSI incidence cohort study from February 2013 to January 2014 was performed in a tertiary-care neurosurgical teaching hospital and referral center. All consecutive adults undergoing any cranial neurosurgical procedure were included. Data were collected by a trained member of the infection control staff during the twice-weekly visits of the hospitalized patients. Follow-up was 30 days (procedures without implant) and 1 year (procedures involving permanent implants). SSI was diagnosed according to criteria of CDC. RESULTS: A total of 317 patients undergoing 333 index procedures were included. The median age was 61 years (range, 17-91 years) and 46% were female. Survival in patients with completed follow-up was 76% (196/258). Overall, IR was 7.2% (24/333 index procedures); in 96% (23/24), a neurosurgical implant was involved. The IR of extraventricular drainage (EVD) was 12.5% (13.1/1000 EVD days). The main causative pathogens were Staphylococcus aureus followed by coagulase-negative staphylococci and Propionibacterium acnes. Independent RF for neurosurgical SSI were EVD as part of the index operation and body mass index >25 kg/m2. CONCLUSIONS: IR was in accordance with recent prospective single-center studies (reported IR between 1.6% and 9%). EVD placement was identified as the strongest modifiable RF for SSI in cranial neurosurgical procedures. The need for standard infection control procedures for the insertion and maintenance of EVDs to avoid their contamination is reinforced. PMID- 29269071 TI - Diffuse Idiopathic Hyperostosis Manifesting as Dysphagia and Bilateral Cord Paralysis: A Case Report and Literature Review. AB - BACKGROUND: Diffuse idiopathic hyperostosis (DISH) is characterized by calcifications affecting mainly the spinal anterior longitudinal ligament. This disease is mainly asymptomatic but cervical osteophytes can sometimes cause dysphagia (DISHphagia), hoarseness, and even dyspnea. CASE DESCRIPTION: We report, for the first time in the medical literature, a case of a 76-year-old patient with DISH causing an important dysphagia as well as bilateral vocal cord paralysis causing critical dyspnea. The patient was surgically treated by anterior resection of the osteophytes and application of bone wax, with significant clinical improvement and no radiologic recurrence after 2 years of follow-up. DISCUSSION AND CONCLUSION: A thorough literature review didn't yield any article reporting on bilateral vocal cord paralysis caused by DISH. Management of this condition is typically multidisciplinary, and treatment of cervical osteophyte-associated dysphagia or respiratory compromise is primarily medical, after performing necessary tests to rule out other causes of dysphagia. Surgical intervention is warranted when medical treatment fails, when there is weight loss, a significant airway compromise or sleeping alterations. A treatment algorithm is proposed in the end of this review for symptomatic anterior osteophytes caused by DISH in the mobile cervical spine. PMID- 29269072 TI - Bacillaceae-derived peptide antibiotics since 2000. AB - Members of the Bacillaceae family, including Bacillus spp., Brevibacillus spp., Paenibacillus spp., Aneurinibacillus sp., and Halobacillus sp., are an important source of structurally diverse classes of short peptides of ~ 30 residues or fewer possessing peculiar and rapid killing activity against various pathogens. Additionally, many have unique structures that enhance resistance to hydrolysis by proteases, and these are ideal therapeutic tools and potential alternatives to current antibiotics. The need for novel antibiotic lead compounds is urgent, and this review summarises 119 Bacillaceae compounds published since 2000, including 12 surfactin-like lipopeptides, 16 iturinic lipopeptides, fengycin C, 33 other cyclic lipopeptides, 26 linear lipopeptides, two thiopeptides, four 2,5 diketopiperazines, 20 typical cyclic peptides, and five standard linear peptides. The current and potential therapeutic applications of these peptides, including structure, antibacterial, antifungal, and antiviral activities, are discussed. PMID- 29269073 TI - [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice. AB - We have previously shown that following oral delivery in dodecyl maltoside (DDM), [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, improved energy balance and glucose homeostasis in genetically obese/diabetic mouse models. More recently, we have provided immunohistochemical evidence indicating that these synthetic peptide leptin mimetics cross the blood-brain barrier and concentrate in the area of the arcuate nucleus of the hypothalamus in normal C57BL/6J and Swiss Webster mice, in genetically obese ob/ob mice, and in diet-induced obese (DIO) mice. In the present study, we describe the effects of oral delivery of [D Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control in diet-induced (DIO) mice, a non-genetic rodent model of obesity and its associated insulin resistance, which more closely recapitulates common obesity and diabetes in humans. Male C57BL/6J and DIO mice, 17, 20, and 28 weeks of age, were maintained on a low-fat or high fat diet and given vehicle (DDM) alone or [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in DDM by oral gavage for 12 or 14 days. Body weight gain, food and water intake, fasting blood glucose, oral glucose tolerance, and serum insulin levels were measured. Our data indicate that (1) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 restore glucose tolerance in male DIO mice maintained on a high-fat diet to levels comparable to those of non-obese C57BL/6J wild-type mice of the same age and sex maintained on a low-fat diet; and (2) the influence of [D-Leu-4]-OB3 and MA-[D Leu-4]-OB3 on glycemic control appears to be independent of their effects on energy balance. These results suggest that [D-Leu-4]-OB3 and/or MA-[D-Leu-4]-OB3 may have application to the management of the majority of cases of common obesity in humans, a state characterized at least in part, by leptin resistance resulting from a defect in leptin transport across the blood-brain barrier. They further suggest that these small molecule synthetic peptide leptin mimetics, through their influence on glycemic control, may prevent the pre-diabetic state associated with most cases of common obesity from escalating into overt type 2 diabetes mellitus. PMID- 29269074 TI - Role of orexin-1 receptors in the dorsal hippocampus (CA1 region) in expression and extinction of the morphine-induced conditioned place preference in the rats. AB - Orexinergic system is involved in reward processing and drug addiction. Objectives here, we investigated the effect of intra-hippocampal CA1 administration of orexin-1 receptor (OX1r) antagonist on the expression, and extinction of morphine-induced place preference in rats. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Two experimental plots were designed; SB334867 as a selective OX1r antagonist was dissolved in 12% DMSO, prepared in solutions with different concentrations (3, 30, and 300 nM), and microinjected into the CA1 and some neighboring regions (0.5 MUl/side), bilaterally. CPP score and locomotor activity were recorded during the CPP test. Results demonstrated that intra-CA1 administration of the OX1r antagonist attenuates the expression of morphine induced CPP. Furthermore, higher concentrations of SB334867 facilitated the extinction period of morphine-induced CPP and reduced its latency. Nevertheless, solely administration of DMSO did not have any influence on the CPP scores and locomotion in both phases. Our findings suggest that OX1rs in the CA1 region of the hippocampus are involved in the expression of morphine CPP. Moreover, blockade of OX1rs could facilitate extinction and may extinguish the ability of drug-related cues. It seems that the antagonist might be considered as a propitious therapeutic agent in suppressing drug-seeking behaviors. PMID- 29269075 TI - Docetaxel promotes the generation of anti-tumorigenic human macrophages. AB - The taxanes Docetaxel and Paclitaxel are two of the standard chemotherapies for patients with metastatic breast cancer. The functional effect of Docetaxel and Paclitaxel on human innate immune cells of the myeloid lineage is not well established, nor is the effects these agents have on differentiation of monocytes into macrophages and dendritic cells. Therefore, the aim with this project was to determine the effects of Docetaxel and Paclitaxel on primary human monocyte differentiation, activation and function. For this purpose, primary human monocytes were isolated from healthy donors and cultured with or without Docetaxel and Paclitaxel. We found that Docetaxel promoted the differentiation of primary human monocytes into pro-inflammatory macrophages with an M1 phenotype and an ability to present antigens to T cells. Monocytes treated with Docetaxel also displayed an elevated secretion of IL-8 and IL-1beta, but did not promote generation of monocytic myeloid-derived suppressor cells. In conclusion, Docetaxel appears to have an immune stimulatory effect that would be beneficial for an anti-tumorigenic type of immune response, whereas Paclitaxel seems to have less effect on myeloid cells. PMID- 29269077 TI - Incidental Bony Changes on Infant Chest Radiograph. PMID- 29269076 TI - Bifacial effects of engineering tumour cell-derived exosomes on human natural killer cells. AB - Extracellular vesicles (EVs) are nano vesicular structures that are secreted by almost all kinds of cells. Exosomes are small EVs derived from endosomes, with a diameter between 30-100nm. Tumour-derived exosomes carry many molecules and factors from tumour cells. These exosomes are recognized and taken up by immunocytes. However, tumour-derived exosomes can not only suppress immune cell functions but also help tumours escape immune surveillance in the tumour microenvironment. The present work investigated the effect of exosomes derived from genetical modified K562 cells (GMK cells), which express IL-15, IL-18 and 4 1BBL (TNFSF9) on their surface. The results showed that these GME exosomes, carrying IL-15, IL-18 and 4-1BBL proteins similar to their host cells, could activate NK cells, increase the cytotoxicity of NK cells on some tumour cells in a short treatment (4h) and promote NK cells proliferation. However, with an extended treatment time (48h), these exosomes could inhibite the cytotoxicity of NK cells by inhibiting activated receptor expression on NK cells. These results indicated the bifacial effects of GMK exosomes on NK cells, which will be helpful to explore the possibility of using transformed exosomes as an anti-tumour immune vaccine or a therapeutic tool in future. PMID- 29269078 TI - Hypovolemic Shock Caused by Angiotensin-Converting Enzyme Inhibitor-Induced Visceral Angioedema: A Case Series and A Simple Method to Diagnose this Complication in the Emergency Department. AB - BACKGROUND: Visceral angioedema is a rarely reported side effect of angiotensin converting-enzyme inhibitors (ACEI). Because signs and symptoms tend to be nonspecific, the diagnosis is difficult to make, especially in the emergency department (ED). CASE REPORT: We describe 2 patients presenting with signs of hypovolemic shock, in which the diagnosis of ACEI-induced visceral angioedema was made in the ED. We surmise that patients with abdominal pain, who present with hypovolemic shock and are taking medications that can predispose to angioedema, may have this complication if their hemoglobin level is elevated compared with their previous levels. An abdominal computed tomography scan, if it does not identify any other significant etiology, will increase the probability that ACEI induced visceral angioedema is the diagnosis when there is nonspecific bowel wall thickening or edema. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Identification of ACEI-induced visceral angioedema in the ED will avoid prolonged admissions, unnecessary procedures, and future recurrences. PMID- 29269079 TI - Point-of-Care Ultrasound Diagnosis of Proximal Hamstring Rupture. AB - BACKGROUND: Acute proximal hamstring ruptures can be a diagnostic challenge in the emergency department. The revealing sign of large posterior thigh ecchymosis is typically not yet present; the physical examination is limited due to pain, radiographs can be unremarkable, and definitive testing with magnetic resonance imaging is not practical. These avulsions are often misdiagnosed as hamstring strains and treated conservatively. The diagnosis is made after failed treatment, often months after the injury. Surgical repair at that time can be technically challenging and higher risk due to tendon retraction and adhesion of the tendon stump to the sciatic nerve. CASE REPORTS: The first case illustrates an example of how delay in diagnosis can occur in both emergency medicine and outpatient primary care settings. It also shows complications and morbidity potential for patients who warrant and do not receive timely surgical repair. The second case illustrates physical examination findings obtainable during the acute setting, and the use of point-of-care ultrasound (POCUS) in facilitating an expedited diagnosis and treatment plan. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Timely diagnosis of hamstring rupture is paramount to optimize patient outcomes for this serious injury. The best results are obtained with surgical repair within 3-6 weeks of injury. POCUS evaluation can aid significantly in the timely diagnosis of this injury. If the POCUS examination raises clinical concern for a proximal hamstring rupture, this may allow for earlier diagnosis and definitive treatment of proximal hamstring rupture. PMID- 29269080 TI - Normal Anal Examination After Penetration: A Case Report. AB - BACKGROUND: Physical findings are rare after anal penetration. Furthermore, children delay in disclosing or are reticent to discuss penetration. CASE REPORT: A 12-year-old boy presented to medical care multiple times over a several-week period complaining of abdominal pain, bloody diarrhea, and poor appetite. On colonoscopy, he was found to have a cylindrical foreign body (measuring 7 cm tall and 7 cm in diameter) in his rectum, which had been present for at least 2 weeks. He initially denied knowing how the object got into his rectum and later stated that he inserted it himself out of curiosity. One week after the object was removed, follow-up examination using video colposcopy revealed a completely normal anal examination; the patient had a normal anal examination despite known anal penetration and removal of the object. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Children can have a normal anal examination despite anal penetration, and do not always disclose anal penetration. The aforementioned concepts can be applied to situations related to child sexual abuse in the emergency department, where physical examinations are frequently normal and children delay in disclosing the abuse. When there is concern for sexual abuse, even in the absence of a disclosure or examination findings, patients should be referred for a child abuse pediatrics evaluation if available. PMID- 29269081 TI - Diagnosis of Simultaneous Acute Ruptures of the Anterior Cruciate Ligament and Posterior Cruciate Ligament Using Point-of-Care Ultrasound in the Emergency Department. AB - BACKGROUND: Patients with acute anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injuries from sport-related activities are frequently seen in the emergency department (ED). However, knee instability tests are known to show variable sensitivity and specificity. These tests would also have limited functionality in patients with severe pain and swelling in the knee. CASE REPORT: A 19-year-old female judo player presented to the ED with severe left knee pain. She had abruptly twisted her left knee while she was shoulder-throwing her opponent. She complained of severe pain and refused physical examination of the knee injury; as a result, evaluation of knee instability could not be performed. However, a point-of-care ultrasound helped in making a prompt and accurate diagnosis of simultaneous, complete rupture and partial ruptures of the ACL and PCL, respectively. The ultrasound findings correlated well with the magnetic resonance imaging images in the assessment of the combined ACL-PCL ruptures. The patient underwent simultaneous arthroscopic ACL and PCL reconstruction with a hamstring tendon autograft and was discharged. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Point-of-care ultrasound imaging of the knee in trauma patients may be helpful for diagnosis of ACL and PCL injuries by augmenting findings of physical examinations in patients with severe pain and swelling in the knee. Ultimately, it may lead to more accurate diagnosis and treatment plans in knee trauma patients. PMID- 29269082 TI - Emphysematous Esophagitis and Gastritis Due to Ingestion of Concentrated Hydrogen Peroxide. PMID- 29269083 TI - Intravenous Flecainide for Emergency Department Management of Acute Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most commonly encountered dysrhythmia in the emergency department, and its prevalence is increasing. A substantial proportion of these patients have recent-onset AF (<48 h). The poor prognosis associated with AF is being increasingly recognized, and there is some evidence for better outcomes in younger patients with recent-onset AF when sinus rhythm is restored. Flecainide is recommended in the latest international guidelines for cardioversion of recent-onset AF, but its safety and efficacy relative to other recommended agents are unclear. OBJECTIVE: Our aim was to clarify the Level 1 evidence for the use of i.v. flecainide in acute AF. METHODS: We performed a systematic review and meta-analysis of the literature. Medline, Ovid, Embase, and Cochrane Central databases were searched for relevant studies. Only randomized controlled trials (RCTs) of i.v. flecainide for acute conversion of recent-onset AF were selected for meta-analysis. RESULTS: Four hundred and three studies were screened, of which 11 RCTs were eligible for meta-analysis. Flecainide had high efficacy for cardioversion within 2 h (number needed to treat [NNT] = 1.8). Efficacy was superior to propafenone, amiodarone, procainamide, ibutilide, and sotalol (NNT = 4.3). There was no statistically significant difference in pro dysrhythmia compared to these anti-dysrhythmics or placebo. CONCLUSIONS: Intravenous flecainide cardioversion could be a safe and effective option for emergency physicians to restore sinus rhythm in selected patients with acute AF. PMID- 29269085 TI - Evaluation of the hypothesis that phasic dopamine constitutes a cached-value signal. AB - The phasic dopamine error signal is currently argued to be synonymous with the prediction error in Sutton and Barto (1987, 1998) model-free reinforcement learning algorithm (Schultz et al., 1997). This theory argues that phasic dopamine reflects a cached-value signal that endows reward-predictive cues with the scalar value inherent in reward. Such an interpretation does not envision a role for dopamine in more complex cognitive representations between events which underlie many forms of associative learning, restricting the role dopamine can play in learning. The cached-value hypothesis of dopamine makes three concrete predictions about when a phasic dopamine response should be seen and what types of learning this signal should be able to promote. We discuss these predictions in light of recent evidence which we believe provide particularly strong tests of their validity. In doing so, we find that while the phasic dopamine signal conforms to a cached-value account in some circumstances, other evidence demonstrate that this signal is not restricted to a model-free cached-value reinforcement learning signal. In light of this evidence, we argue that the phasic dopamine signal functions more generally to signal violations of expectancies to drive real-world associations between events. PMID- 29269086 TI - KISS1 tumor suppressor restricts angiogenesis of breast cancer brain metastases and sensitizes them to oncolytic virotherapy in vitro. AB - KISS1 tumor suppressor protein regulates cancer cell invasion via MMP9 metalloproteinase. Downregulation of KISS1 gene expression promotes progression of breast cancer and melanoma, resulting in the development of distant metastases. In the current study, we investigated whether restoration of KISS1 expression in KISS1-deficient human metastatic breast cancer cells holds potential as an advanced anticancer strategy. To this end we engineered an infectivity-enhanced conditionally-replicative human adenovirus type 5 encoding KISS1 as an "arming" transgene in the Ad5 E3 region for an ectopic KISS1 expression in transduced cancer cells. The oncolytic potential of the vector was examined using brain-invading metastatic clones of CN34 and MDA-MB-231 breast cancer cells, which supported high levels of AdKISS1 replication, correlating with a robust CRAd-mediated cytotoxicity. Secretion of cellular factors responsible for tumor angiogenesis, cell-to-cell communication and anti-tumoral immune responses upon KISS1 expression in breast cancer cells was analyzed by a RayBiotech Kiloplex Quantibody array. Overall, our results indicate that KISS1 transgene expression provides an important benefit for CRAd-mediated cytotoxicity in breast cancer cells and holds potential as an anticancer treatment in conjunction with oncolytic virotherapy of breast and other metastatic cancers. PMID- 29269087 TI - Postoperative narcotic use is associated with development of clinically relevant pancreatic fistulas after distal pancreatectomy. AB - BACKGROUND: Various strategies to decrease postoperative pancreatic fistula after a distal pancreatectomy have proved unsuccessful. Because narcotics can cause spasm of the sphincter of Oddi and thereby increase pressure within the pancreatic duct stump, we hypothesized that increased narcotic use would be associated with increased occurrence of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. METHODS: Retrospective analysis of consecutive distal pancreatectomies (2011-2016) was performed. Postoperative narcotic use was calculated in morphine equivalents. Postoperative pancreatic fistula was graded according to the International Study Group on Pancreatic Surgery. Perioperative variables were evaluated using multivariate logistic regression with clinically relevant postoperative pancreatic fistula as the dependent outcome. RESULTS: In the study, 310 distal pancreatectomies were analyzed (61% robotic, 20% open, 19% laparoscopic). Average age was 62 (53% female), and median total dose of morphine equivalents was 424 mg (interquartile range 242-768). Clinically relevant postoperative pancreatic fistula occurred in 21.6%. Clinically relevant postoperative pancreatic fistula and not clinically relevant postoperative pancreatic fistula cohorts were similar in most demographics and operative variables, but clinically relevant postoperative pancreatic fistula patients had fewer stapled transections (80 vs 90%, P=.025), less pancreatic cancers (11 vs 35%, P<.001), and greater median total morphine equivalents (577 vs 403 mg, P < .009). On univariate analysis, clinically relevant postoperative pancreatic fistula was associated with body mass index, nonstapled transection, suture ligation of the PD, a nonpancreatic cancer pathology, prophylactic octreotide, and total morphine equivalents >424 (cohort median). On multivariate analysis, only pancreatic cancer pathology was protective against a clinically relevant postoperative pancreatic fistula (odds ratio 0.24, confidence interval, 0.10-0.50, P=.001), while increasing total morphine equivalents were predictive of a clinically relevant postoperative pancreatic fistula (odds ratio 1.13, confidence interval, 1.01-1.27, P=.035) with a 13% increased risk for every approximate ~100 mg increase in total morphine equivalents. CONCLUSION: In this retrospective analysis, postoperative narcotic use was associated with the development of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. Limiting narcotic use may be one of the few available mitigating strategies against the development of a clinically relevant postoperative pancreatic fistula after distal pancreatectomy. PMID- 29269088 TI - Would a good screening test increase the effectiveness of border screening for influenza control? PMID- 29269089 TI - Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment. PMID- 29269090 TI - Assessment and modelling of antibacterial combination regimens. AB - BACKGROUND: The increasing global prevalence of multidrug-resistant bacteria is forcing clinicians to prescribe combination antibiotic regimens to treat serious infections. Currently, the joint activity of a combination is quantified by comparing the observed and expected effects using a reference model. These reference models make different assumptions and interpretations of synergy. They fail to: (i) account for multiple bacterial subpopulations with differing susceptibilities; (ii) quantify or interpret the explicit interaction (synergy/antagonism) mechanisms; and (iii) accommodate spontaneous mutations. AIMS: To develop better study designs, mathematical models, metrics and pharmacodynamic analyses to assist with the identification of highly active combinations that are translatable to the clinical context to address the mounting antibiotic resistance threat. SOURCES: PubMed, references of identified studies and reviews, and personal experience when evidence was lacking. CONTENT: We reviewed metrics and approaches for quantifying the joint activity of the combination. The first example is using experimental data from an in vitro checkerboard synergy panel to develop and illustrate a less model-dependent method for assessing combination regimens. In the second example a pharmacokinetic/pharmacodynamic model was developed using mechanism-based mathematical modelling and monotherapy and combination therapy data obtained from an in vitro hollow fibre infection model evaluating linezolid and rifampin regimens against Mycobacterium tuberculosis. IMPLICATIONS: Mechanism-based mathematical approach provides an excellent platform for describing the time course of effect while taking into account the mechanisms of different antibiotics and differing pathogen susceptibilities. This approach allows for the future integration of 'omics' data describing host-pathogen interactions, that will provide a systems-level understanding of the underlying infectious process, and enable the design of effective combination therapies. PMID- 29269091 TI - Impact of Staphylococcus aureus phenotype and genotype on the clinical characteristics and outcome of infective endocarditis. A multicentre, longitudinal, prospective, observational study. AB - OBJECTIVE: We aimed to evaluate the impact of Staphylococcus aureus phenotype (vancomycin MIC) and genotype (agr group, clonal complex CC) on the prognosis and clinical characteristics of infective endocarditis (IE). METHODS: We performed a multicentre, longitudinal, prospective, observational study (June 2013 to March 2016) in 15 Spanish hospitals. Two hundred and thirteen consecutive adults (>=18 years) with a definite diagnosis of S. aureus IE were included. Primary outcome was death during hospital stay. Main secondary end points were persistent bacteraemia, sepsis/septic shock, peripheral embolism and osteoarticular involvement. RESULTS: Overall in-hospital mortality was 37% (n = 72). Independent risk factors for death were age-adjusted Charlson co-morbidity index (OR 1.20; 95% CI 1.08-1.34), congestive heart failure (OR 3.60; 95% CI 1.72-7.50), symptomatic central nervous system complication (OR 3.17; 95% CI 1.41-7.11) and severe sepsis/septic shock (OR 4.41; 95% CI 2.18-8.96). In the subgroup of methicillin-susceptible S. aureus IE (n = 173), independent risk factors for death were the age-adjusted Charlson co-morbidity index (OR 1.17; 95% CI 1.03 1.31), congestive heart failure (OR 3.39; 95% CI 1.51-7.64), new conduction abnormality (OR 4.42; 95% CI 1.27-15.34), severe sepsis/septic shock (OR 5.76; 95% CI 2.57-12.89) and agr group III (OR 0.27; 0.10-0.75). Vancomycin MIC >=1.5 mg/L was not independently associated with death during hospital nor was it related to secondary end points. No other genotype variables were independently associated with in-hospital death. CONCLUSIONS: This is the first prospective study to assess the impact of S. aureus phenotype and genotype. Phenotype and genotype provided no additional predictive value beyond conventional clinical characteristics. No evidence was found to justify therapeutic decisions based on vancomycin MIC for either methicillin-resistant or methicillin-susceptible S. aureus. PMID- 29269092 TI - How to: diagnose infection caused by Clostridium difficile. AB - BACKGROUND: Clostridium difficile is recognized as the major agent responsible for nosocomial diarrhoea. In the context of recent increase in the incidence and severity of C. difficile infections (CDI), an accurate diagnosis is essential for optimal treatment and prevention, but continues to be challenging. AIMS: The present article reviews each key step of CDI diagnosis including stool selection, methods and strategies used, and interpretation of the results. SOURCES: The most recent guidelines for CDI diagnosis published by scientific societies were reviewed. CONTENT: CDI diagnosis is based on clinical presentation and laboratory tests confirming the presence of toxigenic strain or toxins in stools. Stool selection is crucial and can be improved by implementing rejection criteria and a strict policy for appropriate testing. Multiple laboratory tests detecting different targets (free toxin or presence of a potentially toxigenic strain) are commercially available. However, none of these tests combine high sensitivity and specificity to diagnose CDI, low hands-on time and low cost. An optimized diagnosis can be achieved by implementing a two- or three-step algorithm. Algorithms currently recommended by the ESCMID comprise a screening test with high sensitivity followed by a more specific test to detect free toxins. Presence of free toxins in stools has been shown to better correlate with severe outcome whereas nucleic acid amplification tests may lead to an over-diagnosis by detecting asymptomatic carriers of a toxigenic strain. IMPLICATION: To date, no single test can accurately diagnose CDI. Guidelines from the ESCMID recommend a two- or three-step algorithm for optimal CDI detection. PMID- 29269093 TI - ESTRO ACROP: Technology for precision small animal radiotherapy research: Optimal use and challenges. AB - Many radiotherapy research centers have recently installed novel research platforms enabling the investigation of the radiation response of tumors and normal tissues in small animal models, possibly in combination with other treatment modalities. Many more research institutes are expected to follow in the coming years. These novel platforms are capable of mimicking human radiotherapy more closely than older technology. To facilitate the optimal use of these novel integrated precision irradiators and various small animal imaging devices, and to maximize the impact of the associated research, the ESTRO committee on coordinating guidelines ACROP (Advisory Committee in Radiation Oncology Practice) has commissioned a report to review the state of the art of the technology used in this new field of research, and to issue recommendations. This report discusses the combination of precision irradiation systems, small animal imaging (CT, MRI, PET, SPECT, bioluminescence) systems, image registration, treatment planning, and data processing. It also provides guidelines for reporting on studies. PMID- 29269094 TI - Prospect of robotic assistance for fully automated brachytherapy seed placement into skull base: Experimental validation in phantom and cadaver. AB - BACKGROUND AND PURPOSE: To investigate the feasibility and accuracy of robot assisted brachytherapy for skull base tumours. MATERIAL AND METHODS: A custom robot system was tested on both phantom and cadaveric specimen. Cone beam CT (CBCT) images were transferred to the graphical user interface (GUI) for planning trajectories and the data were sent to the robot control unit. Following registration, the puncture needle was inserted into the target by the robot under navigation guidance, and seeds were implanted. Placement error was instantly displayed on the GUI; the result was verified after postoperative image scanning. RESULTS: A total of 150 seeds (100 for phantom experiments, 50 for cadaveric studies) were deposited by the robot system. In phantom experiments the mean placement error was 0.57 +/- 0.21 mm (measured by the navigation system) vs. 1.41 +/- 0.38 mm (measured by image fusion) (p < 0.001); in cadaveric studies the corresponding figures were 0.60 +/- 0.30 mm vs. 2.48 +/- 0.32 mm (p < 0.001). There was no significant difference for comparison of accuracy test in phantom experiments (p = 0.173) as well as in cadaveric studies (p = 0.354). Accuracy was better in the phantom experiment than in cadaveric studies (p < 0.001). CONCLUSIONS: The performance of robot-assisted skull base brachytherapy is feasible and accurate. Dosimetric coverage will need to be demonstrated in further studies. PMID- 29269095 TI - A critical review of recent clinical practice guidelines on management of cryptorchidism. AB - BACKGROUND/PURPOSE: Limited efforts have been made in assessing the qualities of clinical practice guidelines (CPGs) on cryptorchidism (UDT). This appraisal aims to determine the quality of recent CPGs on the management of UDT. METHODS: After systematic literature search, all English-based CPGs providing recommendations for the management of UDT from 2012 to 2017 were reviewed. Using the AGREE II (Appraisal of Guidelines and Research Evaluation) instrument, eligible CPGs were independently appraised by 5 reviewers. Domain scores were calculated and summarized. Intraclass coefficient (ICC) was used to assess for interrater reliability. RESULTS: Five CPGs from Agency for Healthcare Research and Quality (AHRQ), American Urological Association (AUA), British Association of Pediatric Surgeons/British Association of Urologic Surgeons (BAPS/BAUS), Canadian Urological Association (CUA), and European Association of Urology/European Society for Pediatric Urology (EAU/ESPU) were assessed. There was a solid agreement (ICC: 0.749) among the 5 reviewers (p<0.001). Most recommendations for diagnostic and treatment approaches were consistent across CPGs. For most guidelines, the domains of 'clarity of presentation,' 'scope and purpose,' 'stakeholder involvement,' and 'rigor of development' were high, while 'applicability' was low. CONCLUSION: Most guidelines on UDT score high in the AGREE II domains and have consistent recommendations. To improve the 'applicability' domain, future guidelines should improve on aspects that facilitate implementation of the recommendations. TYPE OF STUDY: Systematic review. LEVEL OF EVIDENCE: V (based on the lowest level of evidence utilized by the assessed guidelines). PMID- 29269096 TI - Reallocating Accelerometer-Assessed Sedentary Time to Light or Moderate- to Vigorous-Intensity Physical Activity Reduces Frailty Levels in Older Adults: An Isotemporal Substitution Approach in the TSHA Study. AB - INTRODUCTION: The effects of replacing sedentary time with light or moderate- to vigorous-intensity physical activity on frailty are not well known. AIM: To examine the mutually independent associations of sedentary time (ST), light intensity physical activity (LPA), and moderate- to vigorous-intensity physical activity (MVPA) with frailty status in older adults. METHODS: A total of 628 people aged >=65 years from the Toledo Study of Healthy Aging (TSHA) participated in this cross-sectional study. Frailty was measured using the Frailty Trait Scale. Hip-worn accelerometers were used to capture objective measurements of ST, LPA, and MVPA. Linear regression and isotemporal substitution analyses were used to examine associations of ST, LPA, and MVPA with frailty status. Analyses were also stratified by comorbidity. RESULTS: In single and partition models, LPA and MVPA were negatively associated with frailty. Time in sedentary behavior was not associated with frailty in these models. In the isotemporal substitution models, replacing 30 minutes/d of ST with MVPA was associated with a decrease in frailty [beta -2.460; 95% confidence interval (CI): -3.782, -1.139]. In contrast, replacing ST with LPA was not associated with favorable effects on this outcome. However, when the models were stratified by comorbidity, replacing ST with MVPA had the greatest effect on frailty in both the comorbidity (beta -2.556; 95% CI: 4.451, -0.661) and the no comorbidity group (beta -2.535; 95% CI: -4.343, 0.726). Moreover, the favorable effects of LPA in people with comorbidities was found when replacing 30 minutes/d of ST with LPA (beta -0.568; 95% CI: -1.050, 0.086). CONCLUSIONS: Substituting ST with MVPA is associated with theoretical positive effects on frailty. People with comorbidity may also benefit from replacing ST with LPA, which may have important clinical implications in order to decrease the levels of physical frailty. PMID- 29269097 TI - Heuristics and biases in cardiovascular disease prevention: How can we improve communication about risk, benefits and harms? AB - OBJECTIVE: Cardiovascular disease (CVD) prevention guidelines recommend medication based on the probability of a heart attack/stroke in the next 5-10 years. However, heuristics and biases make risk communication challenging for doctors. This study explored how patients interpret personalised CVD risk results presented in varying formats and timeframes. METHODS: GPs recruited 25 patients with CVD risk factors and varying medication history. Participants were asked to 'think aloud' while using two CVD risk calculators that present probabilistic risk in different ways, within a semi-structured interview. Transcribed audio recordings were coded using Framework Analysis. RESULTS: Key themes were: 1) numbers lack meaning without a reference point; 2) risk results need to be both credible and novel; 3) selective attention to intervention effects. Risk categories (low/moderate/high) provided meaningful context, but short-term risk results were not credible if they didn't match expectations. Colour-coded icon arrays showing the effect of age and interventions were seen as novel and motivating. Those on medication focused on benefits, while others focused on harms. CONCLUSION: CVD risk formats need to be tailored to patient expectations and experiences in order to counteract heuristics and biases. PRACTICE IMPLICATIONS: Doctors need access to multiple CVD risk formats to communicate effectively about CVD prevention. PMID- 29269098 TI - Hyperkeratotic nail dystrophy. PMID- 29269099 TI - Acute mediastinitis as a rare complication of an infectious mononucleosis. PMID- 29269100 TI - Long-term Progression of Type 1 Neovascularization in Age-related Macular Degeneration Using Optical Coherence Tomography Angiography. AB - PURPOSE: To analyze the long-term growth patterns of type 1 neovascularization (NV) in eyes with age-related macular degeneration (AMD) receiving anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Retrospective cohort study. METHODS: Patients were enrolled from 2 eye centers and underwent optical coherence tomography angiography (OCTA) imaging with follow-up greater than 1 year. Choroidal neovascularization (CNV) was manually segmented on OCTA images and compared between time points. CNV growth was subdivided into 3 categories based on OCTA area measurement: CNV doubling, modest growth of less than 50%, and shrinkage. These growth rates were correlated with OCTA morphologic features. RESULTS: Forty-one eyes were analyzed. Mean CNV area was 1.60 +/- 1.84 mm2 at baseline and 1.80 +/- 1.84 mm2 at 1 year. Thirty-three eyes (80%) displayed an increase in CNV area at 1 year with a mean increase of 0.20 +/- 0.38 mm2 (P = .001). Eleven eyes (27%) underwent CNV doubling, 19 eyes (46%) illustrated modest growth, and 6 (15%) showed shrinkage. Anatomic features including a capillary fringe (odds ratio [OR] = 5.3, P = .036) and immature lesion morphology (OR = 4.2, P = .015) were significantly associated with CNV doubling. CNV growth occurred in 3 predominant patterns: "symmetric" growth, "asymmetric" growth, and "finger-like projections," which reflected the orientation of expansion of CNV. "Symmetric" and "asymmetric" growth together correlated with greater frequency of CNV doubling (OR = 15, P = .0048). CONCLUSION: OCTA provides noninvasive measurement of the area of neovascular lesions in AMD. Sustained growth of type 1 NV can be identified in the majority of lesions (80%) that display characteristic patterns of progression despite ongoing anti-VEGF therapy. PMID- 29269101 TI - Mutations responsible for alcohol tolerance in the mutant of Synechococcus elongatus PCC 7942 (SY1043) obtained by single-cell screening system. AB - The production of alcohols directly from carbon dioxide by engineered cyanobacteria is an attractive technology for a sustainable future. Enhanced tolerance to the produced alcohols would be a desirable feature of the engineered cyanobacterial strains with higher alcohol productivity. We have recently obtained the mutant strains of Synechococcus elongatus PCC 7942 with higher tolerance to isopropanol using a single-cell screening system (Arai et al., Biotechnol. Bioeng., 114, 1771-1778, 2017). Among the mutant strains, SY1043 showed the highest isopropanol tolerance. Interestingly, SY1043 also showed higher tolerance to other alcohols such as ethanol and 1-butanol, however, the mechanisms involved in enhancing this alcohol tolerance were unclear. To reveal the alcohol tolerance mechanism of SY1043, we investigated the relationship between alcohol tolerance and four mutations found in SY1043 by genome resequencing analysis. Isopropanol tolerance was enhanced by amino acid substitution (Leu285Pro) in a hypothetical protein encoded by Synpcc7942_0180 of the wild type strain TA1297. TA4135, into which this mutation was introduced, showed a same tendency of tolerance to other alcohols (ethanol and 1-butanol). PMID- 29269102 TI - Epithelial membrane protein 3 (Emp3) downregulates induction and function of cytotoxic T lymphocytes by macrophages via TNF-alpha production. AB - Tetraspanin membrane protein, epithelial membrane protein 3 (Emp3), is expressed in lymphoid tissues. Herein, we have examined the Emp3 in antigen presenting cell (APC) function in the CD8+ cytotoxic T lymphocytes (CTLs) induction. Emp3 overexpressing RAW264.7 macrophage cell line derived from BALB/c mice reduced anti-C57BL/6 alloreactive CTL induction, while Emp3-knockdown RAW264.7 enhanced it compared with parent RAW267.4. Emp3-overexpressing RAW264.7 inhibited, but Emp3-knockdown RAW264.7 augmented, CD8+ T cell proliferation, interferon-gamma secretion, IL-2 consumption, and IL-2Ralpha expression on CD8+ T cells. The supernatant from co-culture with Emp3-overexpressing RAW264.7 contained higher amount of TNF-alpha, and TNF- alpha neutralization significantly restored all these inhibitions and the alloreactive CTL induction. These results suggest that Emp3 in allogeneic APCs possesses the inhibitory function of alloreactive CTL induction by downregulation of IL-2Ralpha expression CD8+ T cells via an increase in TNF-alpha production. This demonstrates a novel mechanism for regulating CTL induction by Emp3 in APCs through TNF-alpha production. PMID- 29269103 TI - Dynamic elastic response prostheses alter approach angles and ground reaction forces but not leg stiffness during a start-stop task. AB - In a dynamic elastic response prosthesis (DERP), spring-like properties aim to replace the loss of musculature and soft tissues and optimise dynamic movement biomechanics, yet higher intact limb (IL) loading exists. It is unknown how amputees wearing a DERP will perform in start-stop movements and how altering the prosthetic stiffness will influence the performance and loading. This study assessed movement dynamics through comparisons in spatiotemporal, kinematic and kinetic variables and leg stiffness of intact, prosthetic and control limbs. The effect of prosthetic stiffness on movement dynamics was also determined. Eleven male unilateral transtibial amputees performed a start-stop task with one DERP set at two different stiffness - Prescribed and Stiffer. Eleven control participants performed the movement with the dominant limb. Kinematic and kinetic data were collected by a twelve-camera motion capture system synchronised with a Kistler force platform. Selected variables were compared between intact, prosthetic and control limbs, and against prosthetic stiffness using ANOVA and effect size. Pearson's Correlation was used to analyse relationship between leg stiffness and prosthetic deflection. Amputees showed a more horizontal approach to the bound during the start-stop movement, with lower horizontal velocities and a longer stance time on the IL compared to controls. In both stiffness conditions, the IL showed selected higher anteroposterior and vertical forces and impulses when compared to the controls. Leg stiffness was not significantly different between limbs as a result of the interplay between angle swept and magnitude of force, even with the change in prosthetic stiffness. A main effect for prosthetic stiffness was found only in higher impact forces of the prosthetic limb and more horizontal touchdown angles of the IL when using the prescribed DERP. In conclusion, amputees achieve the movement with a horizontal approach when compared to controls which may reflect difficulty of movement initiation with a DERP and a difficulty in performing the movement dynamically. The forces and impulses of the IL were high compared to control limbs. The consistent leg stiffness implies compensation strategies through other joints. PMID- 29269105 TI - Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling. AB - Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects. PMID- 29269104 TI - Dengue virus induced changes in Ca2+ homeostasis in human hepatic cells that favor the viral replicative cycle. AB - The role of Ca2+ during dengue virus (DENV) replication is unknown; thus, changes in Ca2+ homeostasis in DENV infected human hepatic HepG2 and Huh-7 cells were analyzed. Infected HepG2 cells, but not Huh-7 cells, showed a significant increase in plasma membrane permeability to Ca2+, while both cell lines showed marked reduced levels of Ca2+ stored in the endoplasmic reticulum. While the expression levels of STIM1 and ORAI1 showed no changes, STIM1 and ORAI1 were shown to co-localized in infected cells, indicating activation of the store operated Ca2+ entry (SOCE) pathway. Finally, manipulation in the infected cells of the intra and extracellular Ca2+ levels by chelators (BAPTA-AM and EGTA), SOC inhibitor (SKF96365), IP3 Receptor antagonist (2APB) or increase of extracellular [Ca2+], significantly reduced DENV yield, but not vesicular stomatitis virus yield, used as a control. These results show that DENV infection alters cell Ca2+ homeostasis and that such changes favor viral replication. PMID- 29269106 TI - Letter to Editor regarding "Characterizing and predicting rates of delirium across general hospital settings". PMID- 29269107 TI - Evidence for cervical muscle morphometric changes on magnetic resonance images after whiplash: A systematic review and meta-analysis. AB - INTRODUCTION: Morphometric changes to cervical musculature in whiplash associated disorder have been reported in several studies with varying results. However, the evidence is not clear because only a limited number of cohorts have been studied and one cohort has been reported in multiple publications. The aim of this study was to assess the evidence for cervical muscle morphometric changes on magnetic resonance (MR) images after whiplash using a systematic review with meta analysis. MATERIALS AND METHODS: PubMed, MEDLINE and Cochrane Library were searched without language restriction using combinations of the MeSH terms "muscles", "whiplash injuries", and "magnetic resonance imaging". Studies of acute and chronic whiplash were included if they compared whiplash and control cervical spine muscle morphometry measurements from MR images. The search identified 380 studies. After screening, eight studies describing five cohorts (one acute, three chronic, one both acute and chronic) met the inclusion criteria. Participant characteristics and outcome measures were extracted using a standard extraction format. Quality of eligible studies was assessed using the Newcastle-Ottawa Scale. Muscle cross-sectional area (CSA) and fat infiltrate (MFI) for acute and chronic whiplash cohorts were compared using mean difference and 95% confidence intervals. Meta-analysis models were created when data from more than two eligible cohorts was available, using inverse-variance random effects models (RevMan5 version 5.3.5). RESULTS: Quality assessment was uniformly good but only two studies blinded the assessor. Analysis of the acute cohorts revealed no consensus with respect to CSA. MFI was not measured in the acute cohorts. Analysis of the chronic cohorts revealed CSA is probably increased in some muscles after whiplash but there is insufficient evidence to confirm whether MFI is also increased. Because the available data were limited, meta-analyses of only multifidus were performed. In chronic whiplash multifidus CSA was significantly increased at C5 (Z = 3.51, p < 0.01) and C6 (Z = 2.66, p < 0.01); and MFI was significantly increased at C7 only (Z = 2.52, p < 0.01) but the heterogeneity was unacceptably high (I2 = 83%). CONCLUSIONS: The strength of the evidence for cervical muscle morphometric changes on MR images after whiplash is inconsistent for CSA and MFI. Future study designs should be standardised with quantification of three-dimensional muscle morphometry. PMID- 29269108 TI - Reply letter to: Comments on "Solid pseudopapillary neoplasm of the pancreas: Management and long-term outcome". PMID- 29269109 TI - Pre-operative evaluation prior to soft tissue sarcoma excision - Why can't we get it right? AB - BACKGROUND: To define the association between an appropriate pre-operative workup (pre-operative advanced imaging studies, diagnostic biopsy) and incomplete soft tissue sarcoma (STS) excision. PATIENTS AND METHODS: This was a retrospective review of 397 consecutive patient records (2000-2008), looking at primary site advanced imaging (MRI or CT) and diagnostic biopsy procedures completed prior to the initial attempt at definitive surgical excision. Downstream effects of an inadequate pre-operative workup were also evaluated, including time to referral to a sarcoma multi-disciplinary care team and perceived alteration of surgical care in order to obtain a complete excision of the altered sarcoma bed. RESULTS: Thirty-eight percent (149/397) of soft tissue sarcomas identified underwent an incomplete excision prior to referral. A significant difference in the incidence of pre-operative primary site advanced imaging (91% vs. 42%, p < 0.001) and a pre operative diagnostic biopsy (85% vs. 16%, p < 0.001) was found between the wide excision group and incomplete excision groups. Pre-operative biopsy (p < 0.001), tumor size >5 cm (p < 0.001), and a referral from an orthopaedic surgeon (p < 0.02) were all associated with reduced risk of incomplete excision in multivariate analysis. Seventy-four percent of patients in the incomplete excision group required an alteration in their definitive wide margin surgical resection, including rotational muscle flap coverage (37%), free flap coverage (11%), or amputation (11%). CONCLUSION: A minority of patients referred following incomplete excision of a STS had undergone an appropriate pre-operative workup prior to referral, leading to increased long-term morbidity following definitive re-excision. Education efforts to heighten awareness of suspicious soft tissue lesions remain vital. PMID- 29269110 TI - Subcutaneous implant breast reconstruction: the importance of objectively assessing the outcomes. PMID- 29269112 TI - Review of follow-up requirements of low-risk squamous cell carcinomas after surgical excision. PMID- 29269111 TI - Cell lines as models for the study of Cry toxins from Bacillus thuringiensis. AB - Cell lines have been use extensively for the study of the mode of action of different pore forming toxins produced by different bacterial species. Bacillus thuringiensis Cry toxins are not the exception and their mechanism of action has been analyzed in different cell lines. Here we review the data obtained with different cell lines, including those that are naturally susceptible to the three domain Cry toxins (3d-Cry) and other non-susceptible cell lines that have been transformed with 3d-Cry toxin binding molecules cloned from the susceptible insects. The effects on Cry toxin action after expressing different insect gut proteins, such as glycosyl-phosphatidyl-inositol (GPI) anchored proteins (like alkaline phosphatase (ALP) aminopeptidase (APN)), or trans-membrane proteins (like cadherin (CAD) or ATP-binding cassette subfamily C member 2 (ABCC2) transporter) in cell lines showed that, with few exceptions, expression of GPI anchored proteins do not correlated with increased susceptibility to the toxin, while the expression of CAD or ABCC2 proteins correlated with induced susceptibility to Cry toxins in the transformed cells lines. Also, that the co expression of CAD and ABCC2 transporter induced a synergistic effect in the toxicity of 3d-Cry toxins. Overall the data show that in susceptible cell lines, the 3d-Cry toxins induce pore formation that correlates with toxicity. However, the intracellular responses remain controversial since it was shown that the same 3d-Cry toxin in different cell lines activated different responses such as adenylate cyclase-PKA death response or apoptosis. Parasporins are Cry toxins that are toxic to cancer cell lines that have structural similarities with the insecticidal Cry toxins. They belong to the 3d-Cry toxin or to MTX-like Cry toxin families but also show important differences with the insecticidal Cry proteins. Some parasporins are pore-forming toxins, and some activate apoptosis. In this review we summarized the results of the different studies about the Cry toxins mode of action using cultured cell lines and discuss their relation with the studies performed in insect larvae. PMID- 29269113 TI - Long-term functional outcome of tibial osteomyelitis reconstruction with free tissue transfer. PMID- 29269114 TI - Local morbidity from red-bellied black snake (Pseudechis porphyriacus, Elapidae) envenoming: Two cases and a brief review of management. AB - The red-bellied black snake (Pseudechis porphyriacus, Elapidae) is one of several species of venomous snakes most commonly implicated in human and domestic animal envenoming in Australia. Human systemic envenoming can present with myotoxicity that may include myoglobinuria; hemoglobinuria and intravascular hemolysis; thrombocytopenia, anticoagulant coagulopathy, and, rarely, mild cranial nerve palsies. Pseudechis porphyriacus envenoming can also feature significant local morbidity such as ecchymoses, bleeding, pain and necrosis. Some envenomed patients may develop progressive thickness necrosis independent of secondary infection, and occasionally require surgical debridement. Uncommonly, some digital envenoming may cause more severe deeper tissue pathology that justifies dermotomy and/or distal phalangeal amputation. Presented are two patients with significant local morbidity from P. porphyriacus envenoming. An 18-month old girl received a protracted envenoming on her right foot, while a 38-year old male professional zoologist was envenomed on the third digit of his right hand. Each patient experienced myotoxicity, one had anticoagulant coagulopathy, and both developed clinically significant local morbidity including persistent bleeding, ecchymoses, local necrosis and pain; each required extensive treatment and variably prolonged admission. Noted also were transiently elevated D-dimer with low-normal or normal fibrinogen levels. The progressive necrosis and subsequent chronic pathologic changes with ischemia of the latter patient's digit eventually required a dermotomy and amputation of the distal phalanx. The pediatric patient did not require extensive wound debridement, but experienced prolonged difficulty in ambulation because of slowly resolving wound discomfort. Factors that may contribute to the severity of local morbidity of P. porphyriacus envenoming are considered, and management of envenoming by this taxon is briefly reviewed. PMID- 29269115 TI - Elimination of eosinophils using anti-IL-5 receptor alpha antibodies effectively suppresses IL-33-mediated pulmonary arterial hypertrophy. AB - Interleukin (IL)-5 is a critical regulator of eosinophils and a therapeutic target for asthma. The administration of anti-IL-5 or anti-IL-5 receptor (IL-5R) antibodies has been shown to reduce eosinophil counts and ameliorate asthmatic symptoms in studies on animal models of allergy as well as in human clinical trials. In order to explore other potential clinical uses of IL-5R antibodies, we used an animal model of IL-33-mediated pulmonary arterial hypertrophy. We first generated chimeric monoclonal antibodies against the mouse IL-5 receptor alpha chain (IL-5Ralpha), which comprised an Fc region from human IgG1 and a Fab region from a previously established anti-mouse IL-5Ralpha monoclonal antibody. To investigate the role of antibody-dependent cell-mediated cytotoxicity (ADCC), chimeric antibodies that lacked ADCC were prepared. These antibodies recognized IL-5Ralpha to the same extent as the ADCC-sufficient antibodies. Administration of chimeric antibodies with ADCC resulted in the elimination of eosinophils from the lung and thus suppressed the development of arterial hypertrophy. This effect was attenuated in mice treated with antibodies lacking ADCC. Taken together, the results of this study provided a potential use for anti-IL-5Ralpha antibodies in the treatment of arterial hypertrophy, which leads to pulmonary hypertension. PMID- 29269118 TI - Characterization of 3D embryonic C57BL/6 and A/J mouse midbrain micromass in vitro culture systems for developmental neurotoxicity testing. AB - In vitro micromass culture systems have been proposed as an alternative method for developmental toxicity assessment to reduce the need for resource-intensive in vivo toxicity testing. In this study, a three-dimensional in vitro embryonic mouse midbrain culture system is characterized in two mouse strains to facilitate gene x environment considerations. Gestational day (GD) 11 C57BL/6 or GD 12 A/J mouse midbrain cells were isolated and cultured in high-density micromass format for 22days in vitro (DIV). Hematoxylin intensity and protein content revealed that neuronal differentiation increases linearly over time in both C57BL/6 and A/J cultures. Protein expression showed time-dependent proliferation markers (PCNA) increased significantly between DIV 4-6 compared to DIV 1. Early and late differentiation markers (e.g. beta-tubulin III and NMDAE1) were expressed between DIV 6-8 and DIV 8-15, respectively. Immunohistochemistry and protein expression results for proliferation and differentiation markers were concordant. Protein expression patterns for the two mouse strain micromass systems were similar. This study characterizes a novel method for investigating early neurogenesis and may be used to characterize neurodevelopmental toxicity in vitro. Our findings show how the use of different mouse strains in neurodevelopmental studies may extend test systems for gene and environment interaction studies. PMID- 29269117 TI - Age at injury and genotype modify acute inflammatory and neurofilament-light responses to mild CHIMERA traumatic brain injury in wild-type and APP/PS1 mice. AB - Peak incidence of traumatic brain injury (TBI) occurs in both young and old individuals, and older age at injury is associated with worse outcome and poorer recovery. Moderate-severe TBI is a reported risk factor for dementia, including Alzheimer's disease (AD), but whether mild TBI (mTBI) alters AD pathogenesis is not clear. To delineate how age at injury and predisposition to amyloid formation affect the acute response to mTBI, we used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of TBI to induce two mild injuries in wild-type (WT) and APP/PS1 mice at either 6 or 13months of age and assessed behavioural, histological and biochemical changes up to 14days post injury. Age at injury did not alter acute behavioural responses to mTBI, including measures of neurological status, motor performance, spatial memory, fear, or anxiety, in either strain. Young APP/PS1 mice showed a subtle and transient increase in diffuse Abeta deposits after injury, whereas old APP/PS1 mice showed decreased amyloid deposits, without significant alterations in total soluble or insoluble Abeta levels at either age. Age at injury and genotype showed complex responses with respect to microglial and cytokine outcomes, where post-injury neuroinflammation is increased in old WT mice but attenuated in old APP/PS1 mice. Intriguingly, silver staining confirmed axonal damage in both strains and ages, yet only young WT and APP/PS1 mice showed neurofilament positive axonal swellings after mTBI, as this response was almost entirely attenuated in old mice. Plasma neurofilament-light levels were significantly elevated after injury only in young APP/PS1 mice. This study suggests that mild TBI has minimal effects on Abeta metabolism, but that age and genotype can each modify acute outcomes related to white matter injury. PMID- 29269116 TI - Epigenetic regulation in medulloblastoma. AB - Medulloblastoma is the most common malignant childhood brain tumor. The heterogeneous tumors are classified into four subgroups based on transcription profiles. Recent developments in genome-wide sequencing techniques have rapidly advanced the understanding of these tumors. The high percentages of somatic alterations of genes encoding chromatin regulators in all subgroups suggest that epigenetic deregulation is a major driver of medulloblastoma. In this report, we review the current understanding of epigenetic regulation in medulloblastoma with a focus on the functional studies of chromatin regulators in the initiation and progression of specific subgroups of medulloblastoma. We also discuss the potential usage of epigenetic inhibitors for medulloblastoma treatment. PMID- 29269119 TI - An exploratory clinical study to determine the utility of heart rate variability analysis in the assessment of dosha imbalance. AB - The present study is a comparison of the data of spectral analysis of heart rate variability with clinical evaluation of pathological state of doshas. The calculated cardiointervalography values are combined into three integral indexes, which according to the authors' opinion reflect the influence on heart rhythm of vata, pitta and kapha, the regulation systems of the body known as doshas in Ayurveda. Seven gross dosha imbalances were assessed to test the agreement between the two methods in this study. Heart Rate Variability (HRV) spectral data was collected from 42 participants to make the comparison with the clinical assessment of dosha imbalance. Clinical method of dosha assessment and method of calculating integral indexes by cardiointervalography data showed substantial agreement by Kappa coefficient statistic (k = 0.78) in assessment of gross dosha imbalance. The results of the data generated from this pilot study warrant further studies to rigorously validate the algorithms of HRV analysis in understanding dosha imbalance in Ayurvedic clinical practice and research settings. PMID- 29269121 TI - Corrigendum to "Biglycan is a novel binding partner of fibroblast growth factor receptor 3c (FGFR3c) in the human testis" [Mol. Cell Endocrinol.] 399 (2015) 235 243. PMID- 29269120 TI - Mouse Metanephric Mesenchymal Cell-Derived Angioblasts Undergo Vasculogenesis in Three-Dimensional Culture. AB - In vitro models for the investigation of renal vascular development are limited. We previously showed that isolated metanephric mesenchymal (MM) and ureteric bud (UB) cells grown in three-dimensional (3D) matrices formed organoids that consisted of primitive vascular structures surrounding a polarized epithelium. Here, we examined the potential of two principal effectors of vasculogenesis, vascular endothelial growth factor A (VEGF-A), and platelet-derived growth factor B chain (PDGF-BB), to stimulate MM cell differentiation. The results showed that MM cells possess angioblast characteristics by expressing phenotypic markers for endothelial and mesenchymal cells. UB cells synthesize VEGF-A and PDGF-BB proteins and RNA, whereas the MM cells express the respective cognate receptors, supporting their role in directional induction of vasculogenesis. VEGF-A stimulated proliferation of MM cells in monolayer and in 3D sponges but did not affect MM cell migration, organization, or vasculogenesis. However, PDGF-BB stimulated MM cell proliferation, migration, and vasculogenesis in monolayer and organization of the cells into primitive capillary-like assemblies in 3D sea sponge scaffolds in vitro. A role for PDGF-BB in vasculogenesis in the 3D MM/UB co-culture system was validated by direct interference with PDGF-BB or PDGF receptor-beta cell interactions to implicate PDGF-BB as a primary effector of MM cell vasculogenesis. Thus, MM cells resemble early renal angioblasts that may provide an ideal platform for the investigation of renal vasculogenesis in vitro. PMID- 29269122 TI - Reduced estimated glomerular filtration rate is associated with depressive symptoms in elder Chinese: A population-based cross-sectional study. AB - Depression has been associated with chronic kidney disease (CKD). However, few studies have examined whether such association exist in average older individuals with mild to moderate reduced kidney function. This study investigated the association between reduced estimated glomerular filtration rate (eGFR) and depressive symptoms in Chinese older population. Data was obtained from the Rugao Longevity and Ageing Study conducted in Jiangsu, China. Cockcroft-Gault (CG) equation was used to calculate eGFR. Depressive symptoms were defined by using Chinese version of 15-item Geriatric Depression Scale (GDS-15). The prevalence of depressive symptoms was 9.9% among 1749 elderly participants aged 70-84 years. Many elderly had a mild to moderate reduced renal function (84.3%, 57.1% in stage2 CKD and 27.2% in stage3 CKD, respectively). The overall GDS-15 score showed an upward trend with decreasing of eGFR (p < 0.05). Furthermore, a moderate decline of eGFR (in stage3 CKD) was significantly associated with increased risk of depressive symptoms even after adjusting for confounders (OR = 1.71, 95%CI 1.05-2.77, P = 0.03). Elder had no depressive symptoms if their eGFR was normal or mildly reduced. Our results suggest that a moderate decrease of eGFR (stage3 CKD) was independently associated with depressive symptoms in general Chinese elderly. PMID- 29269123 TI - The relationship between immunogenic red blood cell antigens and Human Immunodeficiency Virus infection. AB - INTRODUCTION: Evidence suggests that red cell antigens may act as receptors for viruses and bacteria and therefore could be associated with HIV infection. Previous studies have been controversial and therefore the aim of this exploratory study was to analyse the expression of immunogenic red cell antigens in HIV-seropositive individuals and to compare the results to negative donors from South Africa. METHODS: The expression of ABO, Rh, Kell and Duffy antigens from 119 HIV-seropositive patients was compared to 317 HIV-seronegative blood donors. Nucleic acid amplification testing and PCR were used to determine the HIV status and the ID-Gel Card Technology was used to determine the blood group antigen profile. RESULTS: There was no significant difference in the expression of A, B, AB, Duffy or Kel antigens between the two groups but significantly lower numbers of HIV+ individuals were O Rh Negative (p = ,0.0001). Analysis of those with a Duffy null phenotype revealed a significantly higher incidence of blood type A RH1-Positive, Dce/R0r and B RH1-Positive, DcEe/R2r within the HIV seropositive group (p = < 0.05). None of the HIV-seropositive individuals were O RH1-Negative, dce/rr. CONCLUSION: In conclusion these initial findings have demonstrated a decreased incidence of blood type O Rh1-negative in HIV + individuals which suggests that red blood cell antigens may play an important role in susceptibility to HIV infection. The relationship between red cell antigens and HIV infection however remains complex and therefore larger studies are required to confirm these results. PMID- 29269124 TI - Mesonephric proliferations of the female genital tract. AB - The mesonephric (Wolffian) duct regresses in females during embryological development. Remnants of this duct may persist typically along the lateral walls of the cervix, vagina, adnexa, and uterine corpus. These mesonephric epithelia may expand into hyperplastic proliferations and rarely form neoplasms. The spectrum of morphology, immunophenotype, clinical presentation, and molecular characteristics of mesonephric lesions is reviewed, with attention to distinction from entities in the differential diagnosis. PMID- 29269125 TI - Targeted molecular profiling reveals genetic heterogeneity of poromas and porocarcinomas. AB - The genetic landscape of rare benign tumours and their malignant counterparts is still largely unexplored. While recent work showed that mutant HRAS is present in subsets of poromas and porocarcinomas, a more comprehensive genetic view on these rare adnexal neoplasms is lacking. Using high-coverage next generation sequencing, we investigated the mutational profile of 50 cancer-related genes in 12 cases (six poromas and six porocarcinomas). Non-synonymous mutations were found in two-thirds of both poromas and porocarcinomas. Hotspot HRAS mutations were identified in two poromas (p.G13R and p.Q61R) and one porocarcinoma (p.G13C). While in poromas only few cases showed single mutated genes, porocarcinomas showed greater genetic heterogeneity with up to six mutated genes per case. Recurrent TP53 mutations were found in all porocarcinomas that harboured mutated genes. Non-recurrent mutations in porocarcinomas were found in several additional tumour suppressors (RB1, APC, CDKN2A, and PTEN), and genes implicated in PI3K-AKT and MAPK signalling pathways (ABL1, PDGFRA, PIK3CA, HRAS, and RET). UV-associated mutations were found in TP53, APC, CDKN2A, PTEN, and RET. In conclusion, our study confirms and extends the spectrum of genetic lesions in poromas and porocarcinomas. While poromas exhibited only few mutations, which did not involve TP53, the majority of porocarcinomas harboured UV-mediated mutations in TP53 with some of these cases showing considerable genetic heterogeneity that may be clinically exploitable. PMID- 29269126 TI - Single-Institution Propensity-Matched Study to Evaluate the Psychological Effect of Minimally Invasive Interval Debulking Surgery Versus Standard Laparotomic Treatment: From Body to Mind and Back. AB - STUDY OBJECTIVE: To further investigate the psycho-oncologic effect of minimally invasive surgery comparing patients submitted to minimally invasive interval debulking surgery (MI-IDS) with a balanced population treated by standard laparotomy (L-IDS). DESIGN: Single-institution propensity-matched study (Canadian Task Force classification II-2). SETTING: Division of Gynecologic Oncology, "Policlinico A. Gemelli" Foundation, Rome, Italy. PATIENTS: The investigational arm included 30 patients with advanced ovarian cancer treated with MI-IDS, whereas the control arm included a consecutive series of 30 patients with advanced ovarian cancer submitted to L-IDS. For every patient preoperative data were collected to assess the response to neoadjuvant chemotherapy. Perioperative data were also recorded. INTERVENTIONS: A General Well-Being Schedule (GWBS) and a clinical assessment of body uneasiness, the Body Uneasiness Test, were administered by a psycho-oncologist immediately before IDS and within 30 days after surgery to evaluate the psychological burden in both groups. MEASUREMENT AND MAIN RESULTS: Both groups were matched as closely as possible. No statistical differences were registered in terms of surgical procedures and residual tumor. A significantly longer median operative time in patients was counterbalanced by more favorable estimated blood loss and median length of stay and time to chemotherapy. No statistically significant differences were registered in terms of postoperative complications. Starting from a substantially homogenous psychological condition, psychometric evaluation underlined statistically significant differences in favor of MI-IDS. The mean GWBS score was 64.17 +/- 11.77 in patients and 54.15 +/- 14.76 in control subjects, with a statistically significant difference between the 2 groups (p = .004). CONCLUSION: MI-IDS seems to play an important role in the quality of life and oncologic outcomes. Even if presented data testified a further evolutionary step in oncologic patient care, more experience with larger groups of patients is desirable to deeply investigate and assess our results. PMID- 29269127 TI - Round Ligament Adenomyoma. PMID- 29269128 TI - Pharmacological interactions of monoclonal antibodies. AB - The pharmacological interactions of biological agents are not well known. Because biologic agents are not metabolised by cytochrome P450 (CYP) enzymes and do not interact with cell membrane transporters, it is generally perceived that they are free from interactions with small molecule drugs. However, the clearance of biological agents varies depending on the modulation of the immune response or by either increasing or reducing the expression of target cells of the biological agents, which can occur through the action of multiple synthetic chemical agents. Furthermore, some biological agents may modify the metabolism of chemical drugs through their effects on the expression of P450 system enzymes.. In this review, we will provide an outline of the pharmacokinetics properties and pharmacologic interactions of biological drugs, focusing on monoclonal antibodies, and how these can interact with chemical synthesis molecules. We believe knowledge of them is important for clinicians and affects multiple clinical specialties. PMID- 29269129 TI - Insight in the biology of Chlamydia-related bacteria. AB - The Chlamydiales order is composed of obligate intracellular bacteria and includes the Chlamydiaceae family and several family-level lineages called Chlamydia-related bacteria. In this review we will highlight the conserved and distinct biological features between these two groups. We will show how a better characterization of Chlamydia-related bacteria may increase our understanding on the Chlamydiales order evolution, and may help identifying new therapeutic targets to treat chlamydial infections. PMID- 29269130 TI - Combination treatment of celecoxib and ciprofloxacin attenuates live S. aureus induced oxidative damage and inflammation in murine microglia via regulation of cytokine balance. AB - Microglial activation is the most common phenomenon in S. aureus induced brain abscesses as well as other common neurodegenerative diseases. The main objective of this study is to reduce the microglial inflammation with effective bacterial elimination. Ciprofloxacin and celecoxib were used in combination to regulate S. aureus induced oxidative stress and inflammation in primary murine microglial cells. Our results showed that combination treatment effectively killed viable S. aureus and reduced the inflammatory consequences. It can be concluded that lower production of pro-inflammatory cytokines and higher anti-inflammatory IL-10 level may be responsible for microglial polarization switching from pro-inflammatory M1 to anti-inflammatory M2. PMID- 29269131 TI - Technical Performance Score Predicts Partial/Transitional Atrioventricular Septal Defect Outcomes. AB - BACKGROUND: Repair of partial or transitional atrioventricular septal defects (P/TAVSDs) has excellent outcomes; however, late reinterventions remain a concern. Technical performance score (TPS) measures residua after repair and has been associated with early/mid-term outcomes after congenital cardiac operation. Our study investigates TPS as a predictor of outcomes after P/TAVSD repair. METHODS: This was a single-center retrospective review of P/TAVSD repair from July 2000 to November 2015. Intraoperative and discharge TPS were assigned based on echocardiographic criteria: class 1, no residua; class 2, minor residua; and class 3, major residua or reintervention for major residua. Intensive care unit (ICU) hospital length of stay and reintervention after discharge were analyzed with Cox regression. RESULTS: In our cohort, 124 partial (68%) and 59 transitional (32%) AVSDs underwent repair. Median age was 1.5 years (interquartile range [IQR]: 0.6 to 3.8 years), median weight was 9.7 kg (IQR: 6.6 to 14.1 kg), and 96 (52%) were female. Twenty patients (11%) required reintervention after discharge. On multivariable modeling, patients with TPS class 3 spent more days in the ICU (hazard ratio [HR] 0.33, 95% confidence interval [CI]: 0.19 to 0.58, p < 0.001) and hospital (HR 0.33, 95% CI: 0.19 to 0.57, p < 0.001) and had shorter time to reintervention after discharge (HR 8.76, 95% CI: 1.03 to 74.7, p = 0.047). CONCLUSIONS: Major residua, that is TPS class 3, were a predictor of in-hospital outcomes and unplanned reinterventions after discharge, with left atrioventricular valve regurgitation being the strongest predictor. Use of TPS as a tool for residual lesions may identify patients predisposed to prolonged ICU hospital stay and reinterventions after discharge, providing feedback on areas in need of improvement in technique and identification of patients who warrant closer follow-up. PMID- 29269132 TI - Broad activity of diphenyleneiodonium analogues against Mycobacterium tuberculosis, malaria parasites and bacterial pathogens. AB - In this study, a structure-activity relationship (SAR) compound series based on the NDH-2 inhibitor diphenyleneiodonium (DPI) was synthesised. Compounds were evaluated primarily for in vitro efficacy against Gram-positive and Gram-negative bacteria, commonly responsible for nosocomial and community acquired infections. In addition, we also assessed the activity of these compounds against Mycobacterium tuberculosis (Tuberculosis) and Plasmodium spp. (Malaria). This led to the discovery of highly potent compounds active against bacterial pathogens and malaria parasites in the low nanomolar range, several of which were significantly less toxic to mammalian cells. PMID- 29269133 TI - Removal notice to "Subcutaneous injections of aluminum at vaccine adjuvant levels activate innate immune genes in mouse brain that are homologous with biomarkers of autism" [Journal of Inorganic Biochemistry 177 (2017) 39-54]. PMID- 29269134 TI - AsBIC8 -8th Asia/Pacific Biological Inorganic Chemistry Conference. PMID- 29269135 TI - Deciphering the potential of baicalin as an antiviral agent for Chikungunya virus infection. AB - The past decade has seen the re-emergence of Chikungunya virus (CHIKV) as a major global health threat, affecting millions around the world. Although fatal infections are rare among infected patients, the occurrence of long-lasting polyarthralgia has a significant impact on patients' quality of lives and ability to work. These issues were the stimuli for this study to determine the potential of baicalin, a bioflavonoid, as the novel antiviral compound against CHIKV. It was found that baicalin was well tolerated by Vero, BHK-21 and HEK 293T cells with maximal nontoxic doses >600 MUM, ~ 350 MUM and ~110 MUM, respectively. Antiviral assays indicated that baicalin was the most effective inhibitor when tested for its direct virucidal activity with EC50 ~ 7 MUM, followed by inhibition of virus entry into the host cell, attachment of virus particle to cellular receptors and finally intracellular replication of viral RNA genome. In silico analysis using molecular docking demonstrated close interactions between baicalin and CHIKV envelope protein with considerably strong binding affinity of 9.7 kcal/mol. qRT-PCR analysis revealed that baicalin had the greatest effect on the synthesis of viral negative stand RNA with EC50 ~ 0.4 MUM followed by the inhibition of synthesis of positive-strand genomic (EC50 ~ 13 MUM) and subgenomic RNAs (EC50 ~ 14 MUM). These readings indicate that the compound efficiently inhibits replicase complexes formation but is a less potent inhibitor of existing replicase complexes. Coherent with this hypothesis, the use of recombinant CHIKV replicons harboring Renilla luciferase marker showed that replication of corresponding replicon RNAs was only slightly downregulated at higher doses of baicalin, with EC50 > 100 MUM. Immunofluorescence and western blotting experiments demonstrated dose-dependent inhibition of expression of different viral proteins. It was also observed that levels of important protein markers for cellular autophagy (LC3) and apoptosis (Bax) were reduced in baicalin treatment groups as compared with untreated virus infected controls. In summary, given its low toxicity and high efficacy against CHIKV, baicalin has great potential to be developed as the novel antiviral compound for CHIKV. In vivo studies to evaluate its activity in a more complexed system represent a necessary step for future analysis. PMID- 29269136 TI - Managing people with diabetes during the cancer palliation in the era of simultaneous care. AB - Managing people with diabetes and cancer during palliation constitutes a daunting challenge. Cancer, diabetes and treatment toxicity could be seen as a "Bermuda Triangle" for physician and health care professionals in general. Based on literature review, the present paper stresses the distinctive aspects that diabetes and cancer together involve and bring out. Considering the simultaneous care approach as the basement of our perspective, we explore the areas of palliative intervention for which the specific features of persons with diabetes and cancer emerge: pain manifestation and treatment, response to opioids, psychosocial and communication aspects, infection-related susceptibility and complications. The overall impact of suffering that these two diseases in association involve requires new awareness and a cultural attitude towards new network based approaches in order to strengthen the person-centered health care in this field. PMID- 29269137 TI - Mapping glenohumeral laxity: effect of capsule tension and abduction in cadaveric shoulders. AB - BACKGROUND: Shoulder capsular plication aims to restore the passive stabilization of the glenohumeral capsule; however, high reported recurrence rates warrant concern. Improving our understanding of the clinical laxity assessment across 2 dimensions, capsular integrity and shoulder position, can help toward the standardization of clinical tools. Our objectives were to test and describe glenohumeral laxity across 5 capsular tension levels and 4 humeral position levels and describe tension-position interplay. METHODS: We tested 14 dissected cadavers for glenohumeral laxity in 5 directions: anterior, posterior, and inferior translation, and internal and external axial rotation. Laxity was recorded across capsule tension (baseline, stretched, 5 mm, 10 mm, and 15 mm of plication) and position (0 degrees , 20 degrees , 40 degrees , 60 degrees of scapular abduction). Repeated-measures analysis of variance with post hoc contrasts tested the effect of tension, position, and composite tension * position on laxity. RESULTS: Capsule tension, position, and composite interplay had a statistically significant, although unequal, effect on laxity in each direction. Laxity was consistently overconstrained in 15-mm plication and was overall greatest in 20 degrees and lowest in 60 degrees . Restoration occurred most in 10 mm, but this depended on the position. The composite effect was significant for external and internal rotation and inferior laxity, but laxity at the middle range (20 degrees or 40 degrees ) was different than at the end range (0 degrees or 60 degrees ) for all directions. CONCLUSIONS: On average, laxity was restored to baseline tension after 10-mm plication, but this determination varied depending on shoulder position. Middle-range laxity behaved differently than end-range laxity across plication tensions. This information is useful in understanding the unstable shoulder as well as for standardizing clinical laxity assessment. PMID- 29269138 TI - Shoulder strength value differences between genders and age groups. AB - BACKGROUND: The strength of a normal shoulder differs according to gender and decreases with age. Therefore, the Constant score, which is a shoulder function measurement tool that allocates 25% of the final score to strength, differs from the absolute values but likely reflects a normal shoulder. To compare group results, a normalized Constant score is needed, and the first step to achieving normalization involves statistically establishing the gender differences and age related decline. In this investigation, we sought to verify the gender difference and age-related decline in strength. METHODS: We obtained a randomized representative sample of the general population in a small to medium-sized Spanish city. We then invited this population to participate in our study, and we measured their shoulder strength. We performed a statistical analysis with a power of 80% and a P value < .05. RESULTS: We observed a statistically significant difference between the genders and a statistically significant decline with age. CONCLUSION: To the best of our knowledge, this is the first investigation to study a representative sample of the general population from which conclusions can be drawn regarding Constant score normalization. PMID- 29269139 TI - Importance of latissimus dorsi muscle preservation for shoulder function after scapulectomy. AB - BACKGROUND: Scapulectomy is an inevitable treatment for sarcomas of the scapula. This procedure is unavoidable because it reduces the local recurrence rate but can impair shoulder movements and affect the activities of daily living. This study investigated the factors influencing functional outcomes after scapulectomy. MATERIALS AND METHODS: The clinical results of 8 patients (5 males, 3 females) who were diagnosed with primary or metastatic sarcomas of the scapula were retrospectively reviewed. The mean age was 49 years (range, 11-86 years). We examined the correlation between the type of excision of the scapula (total, subtotal, or partial) and postoperative functional outcomes according to the Musculoskeletal Tumor Society (MSTS) score. In partial excision, the glenohumeral joint was preserved; in subtotal excision, the glenoid was completely resected and some bony components were preserved; and in total excision, the entire bony component of the scapula was resected. The average follow-up period was 55 months (range, 9-142 months). RESULTS: The partial, subtotal, and total excision groups had mean functional scores of 96.7%, 76.7%, and 62.2%, respectively. Although the mean functional scores were lower in patients who underwent total and subtotal excisions, 3 patients in whom the latissimus dorsi muscle was preserved had better function (mean MSTS score, 76.7%) than the 2 patients in whom it was not preserved (mean MSTS score, 55.0%). CONCLUSION: These results suggest that the latissimus dorsi muscle, along with the deltoid and pectoralis major muscles, is one of the stabilizers of the proximal humerus after scapulectomy. PMID- 29269140 TI - Long-term outcomes of humeral head replacement for the treatment of osteoarthritis; a report of 44 arthroplasties with minimum 10-year follow-up. AB - BACKGROUND: Studies have demonstrated mixed results after humeral head replacement (HHR) for osteoarthritis at short- and medium-term follow-up intervals. The purpose of this study was to investigate the long-term outcomes (minimum 10 years) of HHR for the treatment of osteoarthritis. METHODS: This study included 44 shoulders in 42 patients who had been followed up for a minimum of 10 years, at a mean clinical follow-up of 17 years (range, 10-30 years). Of this group, 31 shoulders had radiographic follow-up beyond 5 years, at a mean of 11.1 years (range, 5-21 years). RESULTS: Patients experienced significant pain relief postoperatively that was maintained during the long-term follow-up (P < .01), with a subgroup of 11 patients reporting persistent moderate or severe pain. Patients maintained increases in shoulder abduction (<.01), external rotation (<.01) and modified Neer scores (<.01). Ten of 44 (22.7%) shoulders underwent revision surgery, predominantly for glenoid arthrosis (n = 9). In the 25 shoulders with 5 years of radiographic follow-up, Kaplan-Meier survival analysis demonstrated moderate to severe glenoid erosion in 50% at 5 years, which increased to 59% at 15 years and 88% at 20 years. CONCLUSIONS: HHR remains a successful operation for osteoarthritis at long-term follow-up. However, there is a substantive subgroup with continuing pain and a high rate of glenoid bone erosion after 10 years. Surgeons should carefully consider patients' needs and desires when judging the indications for HHR. PMID- 29269141 TI - Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia. AB - The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42 degrees C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42 degrees C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37 degrees C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. ~5%ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo. PMID- 29269142 TI - Crossing the blood-brain barrier with nanoparticles. AB - The blood-brain barrier (BBB) is one of the most essential protection mechanisms in the central nervous system (CNS). It selectively allows individual molecules such as small lipid-soluble molecules to pass through the capillary endothelial membrane while limiting the passage of pathogens or toxins. However, this protection mechanism is also a major obstacle during disease state since it dramatically hinders the drug delivery. In recent years, various tactics have been applied to assist drugs to cross the BBB including osmotic disruption of the BBB and chemical modification of prodrugs. Additionally, nanoparticles (NPs) mediated drug delivery is emerging as an effective and non-invasive system to treat cerebral diseases. In this review, we will summarize and analyze the advances in the drug delivery across the BBB using various NPs in the last decade. The NPs will cover both traditional and novel nanocarriers. The traditional nanocarriers consist of poly(butylcyanoacrylate), poly(lactic-co glycolic acid), poly(lactic acid) NPs, liposomes and inorganic systems. In the meanwhile, novel nanocarriers such as carbon quantum dots with their recent applications in drug delivery will also be introduced. In terms of significance, this review clearly depicts the BBB structure and comprehensively describes various NPs-mediated drug delivery systems according to different NPs species. Also, the BBB penetration mechanisms are concluded in general, emphasized and investigated in each drug delivery system. PMID- 29269143 TI - Organogels, promising drug delivery systems: an update of state-of-the-art and recent applications. PMID- 29269144 TI - The feasibility of an encapsulated cell approach in an animal deafness model. AB - For patients with profound hearing loss a cochlear implant (CI) is the only treatment today. The function of a CI depends in part of the function and survival of the remaining spiral ganglion neurons (SGN). It is well known from animal models that inner ear infusion of neurotrophic factors prevents SGN degeneration and maintains electrical responsiveness in deafened animals. The purpose with this study was to investigate the effects of a novel encapsulated cell (EC) device releasing neurotrophic factors in the deafened guinea pig. The results showed that an EC device releasing glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) implanted for four weeks in deafened guinea pigs significantly preserved the SGNs and maintained their electrical responsiveness. There was a significant difference between BDNF and GDNF in favour of GDNF. This study, demonstrating positive structural and functional effects in the deafened inner ear, suggests that an implanted EC device releasing biologically protective substances offers a feasible approach for treating progressive hearing impairment. PMID- 29269145 TI - Identification and quantification of linear and branched isomers of perfluorooctanoic and perfluorooctane sulfonic acids in contaminated groundwater in the veneto region. AB - Perfluoroalkylated acids (PFAAs) are ubiquitous xenobiotic substances characterized by high persistency, bioaccumulation potential and toxicity. They have generated global concern because of their widespread presence both in water and biota compartments. In the past four years, alarming levels of these pollutants have been found in both surface and groundwater collected in an area covering more than 150 square kilometers in the south-western part of the province of Vicenza (Veneto region, Italy). One of the sources of the contamination recognized by local authorities is a fluorochemicals production plant that produced PFAAs since late sixties by electrochemical fluorination involving the obtainment of a complex mixture of linear and branched isomers. Branched isomers account for a significant part of total long chain homologues (22%-35%). Because of the potential threat to public health and the absence of specific limits set for these pollutants by Directive 98/83/EC, local authorities have established the following performance limits for drinking water: 90 ng L-1 for PFOA + PFOS, (reduced to 40 ng L-1 in the most contaminated municipalities), 30 ng L-1 for PFOS and 300 ng L-1 for the sum of all other PFAAs. Given the non negligible incidence of branched isomers, it appears very important to correctly identify and quantify their contribution to total PFAAs. A liquid chromatography electrospray ionization tandem spectrometry LC-MS/MS method, coupled with solid phase extraction, was developed to identify and quantify 25 PFAAs including six branched isomers of PFOS and four branched isomers of PFOA. Expanded uncertainty, recovery and precision were determined and found to agree with the reference EPA method 537:2009. The quantification limit is comprised in the 1-5 ng L-1 range. PMID- 29269146 TI - Dual polyhedral oligomeric silsesquioxanes polymerization approach to mutually mediated separation mechanisms of hybrid monolithic stationary and mobile phases towards small molecules. AB - Hybrid monolithic stationary phase based HPLC is a typical example of practices in separation science. In this study, we developed a dual polyhedral oligomeric silsesquioxanes (POSS) polymerization approach to the preparation of a hybrid monolithic stationary phase of tri-porous structure and various surface chemistry. N-phenylaminopropyl-POSS (PA-POSS) and glycidyl-POSS (EP-POSS) were exemplified to demonstrate effective mutually-mediated separation mechanisms of the hybrid monolithic stationary phase and mobile phase towards diverse small molecules. PA-POSS and EP-POSS can be the monomer and/or crosslinker each other. They were polymerized via the epoxy-ring opening reaction to form the poly[(PA POSS)-(EP-POSS)] (polyPOSS) monolithic stationary phase of 110.6/164.6 A3 micropore (as a cube/ball), 10 nm mesopore and 0.95 MUm macropore with the native siloxane cage and remaining phenyl/epoxy as well as chemically generated positive chargeable tertiary phenylamine and hydrophilic hydroxyl groups. Such pore structure and surface chemistry allow us to perform the effective separation of targeted small molecules, such as alkylbenzenes and alkylbenzene ketones, nucleic acid bases and amino acids, as well as phenols and phenolic acids, under reversed phase, HILIC and mixed mode (polarity, size-exclusion and hydrogen-bonding) by just changing the molar ratio of POSS-precursors, and the composition and pH of a mobile phase as well. We believe that the approach developed herein can be extended to fabricate other kinds of hybrid monolithic stationary phases that are suitable for the separation of biomacromolecules and chiral molecules when choosing the existed POSS and/or designing new POSS with the substituted pendant groups of different physicochemical properties. PMID- 29269147 TI - Effect-directed analysis via hyphenated high-performance thin-layer chromatography for bioanalytical profiling of sunflower leaves. AB - High-performance thin-layer chromatography (HPTLC) coupled with effect-directed analysis was used for non-targeted screening of sunflower leaf extract for components exhibiting antioxidant, antibacterial and/or cholinesterase enzyme inhibitory effects. The active compounds were characterized by HPTLC-electrospray ionization-high resolution mass spectrometry (ESI-HRMS) and HPTLC-Direct Analysis in Real Time (DART)-MS/MS. The latter ambient ionization technique (less soft than ESI) resulted in oxidation and fragmentation products and characteristic fragment ions. NMR spectroscopy after targeted isolation via preparative normal phase flash chromatography and semi-preparative reversed phase high-performance liquid chromatography supported the identification of two diterpenes to be (-) kaur-16-en-19-oic acid and 15-alpha-angeloyloxy-ent-kaur-16-en-19-oic acid. Both compounds found to be multi-potent as they inhibited acetylcholinesterase and butyrylcholinesterase and showed antibacterial effects against Gram-positive Bacillus subtilis and Gram-negative Aliivibrio fischeri bacteria. Kaurenoic acid was also active against the Gram-negative pepper pathogenic Xanthomonas euvesicatoria bacteria. PMID- 29269148 TI - [Factor XIII-guided treatment algorithm reduces blood transfusion in burn surgery]. AB - BACKGROUND AND OBJECTIVES: Major burn surgery causes large hemorrhage and coagulation dysfunction. Treatment algorithms guided by ROTEM(r) and factor VIIa reduce the need for blood products, but there is no evidence regarding factor XIII. Factor XIII deficiency changes clot stability and decreases wound healing. This study evaluates the efficacy and safety of factor XIII correction and its repercussion on transfusion requirements in burn surgery. METHODS: Randomized retrospective study with 40 patients undergoing surgery at the Burn Unit, allocated into Group A those with factor XIII assessment (n = 20), and Group B, those without assessment (n = 20). Erythrocyte transfusion was guided by a hemoglobin trigger of 10g.dL-1 and the other blood products by routine coagulation and ROTEM(r) tests. Analysis of blood product consumption included units of erythrocytes, fresh frozen plasma, platelets, and fibrinogen. The coagulation biomarker analysis compared the pre- and post-operative values. RESULTS AND CONCLUSIONS: Group A (with factor XIII study) and Group B had identical total body surface area burned. All patients in Group A had a preoperative factor XIII deficiency, whose correction significantly reduced units of erythrocyte concentrate transfusion (1.95 vs. 4.05, p = 0.001). Pre- and post operative coagulation biomarkers were similar between groups, revealing that routine coagulation tests did not identify factor XIII deficiency. There were no recorded thromboembolic events. Correction of factor XIII deficiency in burn surgery proved to be safe and effective for reducing perioperative transfusion of erythrocyte units. PMID- 29269149 TI - Does platelet-rich fibrin increase the stability of implants in the posterior of the maxilla? A split-mouth randomized clinical trial. AB - The effect of platelet-rich fibrin (PRF) on bone healing around dental implants in areas of poor bone quality has not been studied. The aim of this study was to evaluate the stability of implants placed in the posterior maxilla, with or without the use of PRF, during the healing period. A split-mouth randomized clinical trial was performed. Twenty patients with missing teeth in the molar region of the maxilla, requiring bilateral implants, were included. PRF was used on one side (group 1); no PRF was used on the other (group 2). Implant stability was assessed by resonance frequency analysis (RFA) at 2, 4, and 6 weeks after placement. At 2 weeks, the mean ISQ was 60.60+/-3.42 in group 1 and 58.25+/-3.64 in group 2; at 4 weeks it was 70.30+/-3.36 in group 1 and 67.15+/-4.33 in group 2; at 6 weeks it was 78.45+/-3.36 in group 1 and 76.15+/-2.94 in group 2. Significant differences in RFA were found between the groups at 2 weeks (P=0.04), 4 weeks (P=0.014), and 6 weeks (P=0.027) after placement. The study results suggest that the use of PRF may enhance the post-insertion stability of dental implants placed in the posterior maxilla during the healing period. PMID- 29269150 TI - No lyse no wash flow cytometry for maximizing minimal sample preparation. AB - Red blood cell lysis is an integral part of many flow cytometry protocols. It's potential to cause artifacts has been known for decades, but lysis free sample preparation has failed to replace lysis in most applications. Studies of various lysing protocols on cell losses and effects on phenotypic markers and cell function began early in the history of immunophenotyping and continue to this day. Opportunities to combine live cell response and functional assessment with phenotyping have sparked increasing interest in no lyse no wash protocols, with minimizing sample preparation effects on the cell biology as the primary goal. No lyse no wash protocols reduce sample handling and are procedurally less complex than lysis protocols, but the impact of keeping intact red blood cells that grossly outnumber the target white blood cells, must be understood to fully take advantage of this simplicity. Presented here are theories and methods for executing and interpreting no lyse no wash assays in whole blood. Methods for distinguishing white blood cells and platelets from red blood cells and improving scatter data by combining 405 nm and 488 nm side scatter are shown. Methods for assessing white blood cell light scattering profiles for individual instruments and sample treatments are discussed within the context of example profiles for no lysis and hypotonic and ammonium chloride lysis treatments. The utility of overcoming no lyse no wash scatter and fluorescence background limitations using alternate scatter and fluorescence thresholding strategies is also discussed in the context of application examples. PMID- 29269151 TI - Cell sorting of various cell types from mouse and human skeletal muscle. AB - Muscle stem cells or satellite cells are required for skeletal muscle regeneration. It has been shown that the satellite cell microenvironment, including neighboring cells such as endothelial cells, macrophages or fibroblasts are essential for complete and efficient regeneration. A deficient behavior of these cells compromises regeneration. Therefore, there is a strong interest in understanding the cellular and molecular interactions at work between these cell types during muscle regeneration. Fluorescence-activated cell sorting allows to isolate these four cell types at different time points of regeneration, for further high throughput or behavioral experiments. We present here a method for the concomitant isolation of 4 cell types present in the regenerating skeletal muscle: muscle stem cells, endothelial cells, fibro-adipogenic precursor cells and macrophages. PMID- 29269152 TI - Percutaneous angioplasty versus atherectomy for treatment of symptomatic infra popliteal arterial disease. AB - BACKGROUND: Outcomes for debulking by atherectomy (ATH) for adjunctive treatment of below the knee (BTK) symptomatic arterial disease compared to percutaneous transluminal angioplasty alone (PTA) are unclear. METHODS: MEDLINE, EMBASE, PubMed and the Cochrane Central Register of Controlled Trials were queried from between 2000 and 2017 including studies comparing PTA alone to PTA-ATH. Random effect meta-analysis model was used to pool the data across the studies. Study endpoints included: vessel dissection, residual stenosis (<30%), mortality at 12months and amputation rates at 1 and 12months. RESULTS: A total of 2587 patients (72.9years; 63% male) were included from 4 studies (2 prospective, one of which was randomized, and 2 retrospective) comparing PTA alone to ATH-PTA in patients with symptomatic infra-popliteal disease. There was no significant difference between the two approaches in terms of vessel dissection [OR 3.73 with 95% CI 0.83 to 16.64, p=0.08] or residual stenosis [OR 0.41 with 95% CI 0.11 to 1.60, p=0.18]. Clinical outcomes did not differ in terms of 12month mortality [OR 3.47 with 95% CI 0.15 to 81.37, p=0.44], or limb amputation at 1month [OR 1.23 with 95% CI 0.91 to 1.67, p=0.18] or 12months [OR: 1.02 with 95% CI 0.83 to 1.26, p=0.83]. CONCLUSION: In patients undergoing (BTK) intervention, PTA alone and ATH PTA was associated with similar outcomes in terms of vessel dissection and residual stenosis, mortality at 12months, and limb amputation at 1 or 12months. PMID- 29269153 TI - About European guidelines for heart failure 2016. PMID- 29269154 TI - Physical stability of API/polymer-blend amorphous solid dispersions. AB - The preparation of amorphous solid dispersions (ASDs) is a well-established strategy for formulating active pharmaceutical ingredients by embedding them in excipients, usually amorphous polymers. Different polymers can be combined for designing ASDs with desired properties like an optimized dissolution behavior. One important criterion for the development of ASD compositions is the physical stability. In this work, the physical stability of API/polymer-blend ASDs was investigated by thermodynamic modeling and stability studies. Amorphous naproxen (NAP) and acetaminophen (APAP) were embedded in blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and either poly(vinylpyrrolidone) (PVP) or poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64). Parameters for modeling the API solubility in the blends and the glass-transition temperature curves of the water-free systems with Perturbed-Chain Statistical Associating Fluid Theory and Kwei equation, respectively, were correlated to experimental data. The phase behavior for standardized storage conditions (0%, 60% and 75% relative humidity (RH)) was predicted and compared to six months-long stability studies. According to modeling and experimental results, the physical stability was reduced with increasing HPMCAS content and increasing RH. This trend was observed for all investigated systems, with both APIs (NAP and APAP) and both polymer blends (PVP/HPMCAS and PVPVA64/HPMCAS). PC-SAFT and the Kwei equation turned out to be suitable tools for modeling and predicting the physical stability of the investigated API/polymer-blends ASDs. PMID- 29269156 TI - Declining measles antibodies in the era of elimination: Australia's experience. AB - BACKGROUND: Australia is one of only a few countries with a long-standing and consistent serosurveillance program. We conducted a national serosurvey in 2012 2013 to estimate population seroprevalence of measles-specific IgG and the effective reproduction number, R, and compare the results with the three previous serosurveys (1996-1999, 2002 and 2007) to examine trends following a decade of sustained measles control. METHODS: 2729 residual sera from 1 to 49 year olds were tested using the Enzygnost anti-measles IgG enzyme immunoassay (EIA). All sera in the equivocal range by EIA on re-testing and a random sample of low positive and negative sera were later tested by a microneutralisation assay. R was calculated from weighted estimates of the proportion seronegative by age using a previously developed contact matrix. RESULTS: In the 2012-13 serosurvey, anti-measles IgG seropositivity for 1-49 year olds was 80.8% (95% CI: 79.4-82.3%) and 8.9% (95% CI: 7.8-10.0%) had equivocal antibody levels. The increasing proportion of seronegative and equivocal individuals in age groups 10-39 years continued a trend seen in previous serosurveys. There was also an increase in equivocal results among 2-4 and 5-9 year old children, >90% of whom were recently vaccinated. R increased from 0.57 in 1999 to above the epidemic threshold of 1 in 2012-13 (R = 1.7). All 20 EIA negative sera, 238/241 (98.8%) equivocal sera, and 89/92 (96.7%) low positive sera had a titre <10 (negative) in the measles microneutralisation assay. CONCLUSIONS: A number of countries with sustained measles control have now demonstrated that measles-specific IgG antibodies decline with time since vaccination. As there is good epidemiologic evidence of population-level protection, the implications of declining measles-specific IgG antibody levels for maintaining measles elimination are unclear. Novel studies to determine correlates of protection against measles transmission and disease in the post-elimination era are needed to help answer this question. PMID- 29269155 TI - A simple and rapid approach to develop recombinant avian herpesvirus vectored vaccines using CRISPR/Cas9 system. AB - Herpesvirus of turkeys (HVT) has been successfully used as live vaccine against Marek's disease (MD) worldwide for more than 40 years either alone or in combination with other serotypes. HVT is also widely used as a vector platform for generation of recombinant vaccines against a number of avian diseases such as infectious bursal disease (IBD), Newcastle disease (ND) and avian influenza (AI) using conventional recombination methods or recombineering tools on cloned viral genomes. In the present study, we describe the application of CRISPR/Cas9-based genome editing as a rapid and efficient method of generating HVT recombinants expressing VP2 protein of IBDV. This approach offers an efficient method to introduce other viral antigens into the HVT genome for rapid development of recombinant vaccines. PMID- 29269157 TI - Self-assembling protein nanoparticles with built-in flagellin domains increases protective efficacy of a Plasmodium falciparum based vaccine. AB - To eliminate the problems associated with the use of extraneous adjuvants we have designed a Self-Assembling Protein Nanoparticle (SAPN) containing epitopes from the Plasmodium falciparum circumsporozoite protein (PfCSP) (designated FMP014) and portions of the TLR5 agonist flagellin (designated FMP014D0D1) as an intrinsic adjuvant. By combining different molar ratios of FMP014 to FMP014D0D1 monomers before self-assembly, we generated multiple nanoparticles and investigated their biophysical characteristics, immunogenicity and protective efficacy. Immunization with the construct formulated with the ratio 58:2 of FMP014 to FMP014D0D1 had the highest protective efficacy against a challenge with a transgenic P. berghei sporozoite expressing PfCSP. Increasing the proportion of flagellin per particle resulted in an inverse relationship with levels of both antibody titers and protection. The cytokine profiles of the various immunization groups were evaluated and quantitative amounts of the cytokines IL-2, IFN-gamma, IL-12/p70 (Th1); IL4, IL5 (Th2); TNF-alpha, IL1beta, IL-6, KC/GRO (pro inflammatory), and IL-10 (immunomodulatory) were measured. The relationship of the cytokines to each other revealed a strong immunomodulatory effect depending on the proportion of flagellin in the construct. Our results demonstrate that SAPNs with flagellin may be a promising strategy for the development and delivery of a safe vaccine for infectious diseases. PMID- 29269158 TI - Assessing determinants of the intention to accept a pertussis cocooning vaccination: A survey among healthcare workers in maternity and paediatric care. AB - OBJECTIVE: To assess the intention to accept a pertussis cocooning vaccination and to examine the determinants that influence this intention among healthcare workers (HCWs) in maternity and paediatric care. DESIGN: Cross-sectional survey. SETTING: Maternity assistants, midwives, and paediatric nurses in the Netherlands. METHODS: We developed a 123-item questionnaire based on a literature review and the Reasoned Action Approach (a social cognitive model of behaviour). We used the questionnaire to explore the determinants of intention to accept pertussis cocooning vaccination among the HCW groups. We also assessed the behavioural beliefs underlying HCWs' attitudes towards pertussis cocooning. We used correlation and regression analyses to assess univariate and multivariate associations in the study variables. RESULTS: Altogether, 486 maternity assistants, 320 midwives, and 200 paediatric nurses completed the questionnaire; 45%-63% reported their intentions to accept pertussis vaccination. Attitude, anticipated affect regarding non-acceptance, and decisional uncertainty were uniquely associated with the intention to accept a pertussis vaccination. The respondents' attitude towards pertussis cocooning vaccination was further explained by their general vaccination beliefs, agreement with a policy advice to vaccinate HCWs, the perceived cost-benefit ratio, and the perceived personal responsibility to prevent pertussis in patients. CONCLUSION: About half of the participating HCWs reported their intentions to accept a pertussis cocooning vaccination. Attitude, anticipated affect regarding non-acceptance, and decisional uncertainty came forward as the most important determinants of intention. This study helps build the evidence base describing the determinants of the intention to accept a pertussis cocooning vaccination among HCWs. PMID- 29269159 TI - The anti-caries effects of dental adhesive resin influenced by the position of functional groups in quaternary ammonium monomers. AB - OBJECTIVES: A new quaternary ammonium monomer (QAM), triethylaminododecyl acrylate (TEADDA) was synthesized, in which the position of the functional groups was different from that of dimethylaminododecyl methacrylate (DMADDM). The objectives were to: (1) investigate the effect of the changed position of the functional groups on the mechanical properties, anti-biofilm activity and biocompatibility of adhesive resin, and (2) study the anti-bacterial mechanism of QAM to improve the performance of the adhesive system modified by QAM. METHODS: TEADDA and DMADDM were added into adhesives. Microtensile bond strength and surface charge density were measured. Multi-species biofilms were incubated on specimens for 16h, 48h and 72h and analyzed via MTT assay, lactic acid measurement and confocal laser scanning microscopy. The ratio of different species of bacteria was measured by real-time polymerase chain reaction. Cytotoxicity and biocompatibility were analyzed by eluents cytotoxicity test and histological images of H&E staining via an animal study in rats. RESULTS: The mass fraction of TEDDA allowed to be added into adhesive was higher than that of DMADDM. However, even 10% TEADDA did not yield a strong anti-biofilm effect on biofilm growth, lactic acid production and bacteria compositions. TEADDA added into adhesives showed better mechanical properties but weaker anti-bacterial effect. There was no significant difference on cytotoxicity and biocompatibility between DMADDM and TEADDA. SIGNIFICANCE: The study could be helpful for the investigation of the anti-caries mechanism of QAMs, the design of new QAMs and the improvement of the anti-caries activity of the modified dental materials. PMID- 29269160 TI - The influence of esmolol on septic shock and sepsis: A meta-analysis of randomized controlled studies. AB - BACKGROUND: Esmolol may have some potential in treating septic shock and sepsis. However, the results remain controversial. We conduct a systematic review and meta-analysis to explore the efficacy of esmolol in patients with septic shock and sepsis. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases are systematically searched. Randomized controlled trials (RCTs) assessing the efficacy of esmolol for septic shock and sepsis are included. Two investigators independently search articles, extract data, and assess the quality of included studies. Meta-analysis is performed using the random-effect model. RESULTS: Five RCTs are included in the meta-analysis. Overall, compared with control intervention in septic patients, esmolol intervention is found to significantly increase survival rate (risk ratio (RR)=2.06; 95% confidence interval (CI)=1.52 to 2.79; P=0.006), decrease heart rate (Standard Mean difference (Std. MD)=-2.43; 95% CI=-4.13 to -0.72; P=0.005) and TnI (Std. MD= 1.91; 95% CI=-2.39 to -1.43; P<0.00001), but has no significant impact on mean arterial pressure (MAP) (Std. MD=0.11; 95% CI=-0.21 to 0.44; P=0.49), central venous pressure (CVP) (Std. MD=-0.11; 95% CI=-0.50 to 0.28; P=0.58) and central venous oxygen saturation (ScvO2) (Std. MD=1.87; 95% CI=-1.53 to 5.26; P=0.28). CONCLUSIONS: Esmolol treatment may be able to improve survival rate, and reduce heart rate and TnI, but has no influence on MAP, CVP and ScvO2 in patients with septic shock and sepsis. PMID- 29269161 TI - Three times a charm... a case of repeat appendicitis status post two prior appendectomies. AB - BACKGROUND: Appendicitis is defined as the bacterial proliferation and inflammation of the vermiform appendix, typically caused by a fecalith . There have been a few cases reported in the literature of recurrent appendicitis status post an appendectomy, however there has been no reported case of a recurrence status post two prior appendectomies. We would like to present the first case of recurrent appendicitis status post two prior appendectomies. CASE REPORT: A 32year old otherwise healthy male presented to the ER on 8/27 with right lower quadrant pain and no other symptoms. His initial triage vital signs were within normal limits. Of note patient had an appendectomy on 8/15/17 and a repeat appendectomy on 8/22/17 for recurrent appendicitis. Other than the RLQ abdominal pain, the patient's review of systems and physical examination were unremarkable. Patient's WBC was 7.5 and lactate was 1.4. A CT of the abdomen/pelvis showed a 1.3cm inflamed appendix. Patient was admitted to the Surgery service on IVF and IV antibiotics. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Appendicitis should continue to be on an emergency physician's differential for a patient with RLQ pain even when the patient has had a prior appendectomy. Appropriate management in the ER can lead to improved treatment, timely surgical consultations and decreased complications. PMID- 29269162 TI - Echocardiography in cardiac arrest: An emergency medicine review. AB - INTRODUCTION: Cardiac arrest management primarily focuses on optimal chest compressions and early defibrillation for shockable cardiac rhythms. Non shockable rhythms such as pulseless electrical activity (PEA) and asystole present challenges in management. Point-of-care ultrasound (POCUS) in cardiac arrest is promising. OBJECTIVES: This review provides a focused assessment of POCUS in cardiac arrest, with an overview of transthoracic (TTE) and transesophageal echocardiogram (TEE), uses in arrest, and literature support. DISCUSSION: Cardiac arrest can be distinguished between shockable and non shockable rhythms, with management varying based on the rhythm. POCUS provides a diagnostic and prognostic tool in the emergency department (ED), which may improve accuracy in clinical decision-making. Several protocols incorporate POCUS based on different cardiac views. TTE includes parasternal long axis, parasternal short axis, apical 4-chamber, and subxiphoid views, which may be used in cardiac arrest for diagnosis of underlying cause and potential prognostication. TEE is conducted by inserting the probe into the esophagus of intubated patients, with several studies evaluating its use in cardiac arrest. It is associated with few adverse effects, while allowing continued compressions (and evaluation of those compressions) and not interrupting resuscitation efforts. CONCLUSIONS: POCUS is a valuable diagnostic and prognostic tool in cardiac arrest, with recent literature supporting its diagnostic ability. TTE can guide resuscitation efforts dependent on the rhythm, though TTE should not interrupt other resuscitation measures. TEE can be useful during arrest, but further studies based in the ED are needed. PMID- 29269163 TI - Non-traditional risk factors for atherosclerotic disease: A review for emergency physicians. AB - INTRODUCTION: Acute coronary syndrome (ACS) is a life-threatening disease frequently managed in the Emergency Department (ED). Risk factors such as age, hypertension, diabetes mellitus, obesity, and smoking are classically associated with atherosclerosis and ACS. OBJECTIVE: This review evaluates non-traditional risk factors for atherosclerotic disease and seeks to inform physicians of their potential danger, particularly in vulnerable patient populations. DISCUSSION: Traditional risk factors are commonly utilized in the evaluation of patients with concern for ACS and acute myocardial infarction (AMI), though these may not be as useful for individual patient assessment. Heart disease accounts for a significant number of deaths in the U.S. Awareness of disease presentation and risk factors is important; however, several non-traditional risk factors are associated with atherosclerosis. Vasculitides, as well as immunologic medications used to treat these patients, increase atherosclerosis. Specific types of cancer and some therapies used to treat cancer are associated with atherosclerosis development and cardiovascular disease (CVD). Heavy alcohol use increases atherosclerosis and risk of AMI. Pregnancy also increases risk of AMI. Patients with HIV develop atherosclerosis at higher rates, and antiretroviral therapy predisposes patients to early development of coronary disease. Infections such as pneumonia and sepsis, associated with elevated inflammation, increase rate of ACS events during illness and throughout the one-year period after diagnosis of infection. CONCLUSIONS: Several non-traditional factors are associated with increased risk of atherosclerosis and ACS. Knowledge of these risk factors is important in the ED to minimize the potential of missing ACS. PMID- 29269164 TI - [Self-inflicted burns in our burns center between 2011 and 2016]. AB - The prevalence of immolation by fire in France is uncertain. We carried out a retrospective epidemiological study on immolations between 2011 and 2016 at the burn treatment centre at the hopital Saint-Louis in Paris. We studied the prevalence and characteristics of patients entering hospital for this reason. Between 2011 and 2016, a total of 1098 patients were hospitalized in the centre, of which 50 were admitted for immolation, i.e. five percent of the hospitalized population. The average age at entry was 46 years, and they were mostly men (62%). All but one was a suicide attempt. The average total burn area was 34.5%, and the average length of stay in the centre was 53 days. The products used for the immolation were mostly white spirit, alcohol or gasoline. Nine (18%) out of the 50 patients died, burned at 62.5% on average. A psychiatric history was reported in 35 patients and 21 had previously attempted suicide; nine patients were chronic alcoholics and four were drug addicts. The most frequently reported reasons for the suicide attempt were sentimental breakdown, death of a relative or financial problem. The prevalence of immolation in our study is very low compared to that found in developing countries. The majority of our cohort is composed of patients with a history of psychiatric disorders. The history of attempted suicide is also a major risk factor for committing suicidal acts by immolation. Prevention measures should be implemented to reduce this risk. PMID- 29269165 TI - Protontherapy of head and neck paragangliomas: A monocentric study. AB - PURPOSE: The aim of this study was to assess efficacy and safety of proton beam therapy of paragangliomas of the head and neck, rare benign tumours developed close to crucial structures such as cranial nerves and vascular tissues. PATIENTS AND METHODS: Ten patients with a paraganglioma of the head and neck were treated from 2001 to 2014 with image-guided proton therapy. Neurological and ear nose throat symptoms were collected in addition to audiometric testing, before and after the treatment. Acute and late toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v4. RESULTS: Median age at diagnosis was 52.6years (range: 18.2-65.8years). Proton therapy was the exclusive treatment in six patients and four patients had a postoperative radiotherapy. Median dose was 50.4Gy relative biological effectiveness (RBE; range: 45.0 67.0Gy). With a median follow-up of 24.6months (range: 6.7-46.2 months), local tumour control rate was 100% (stable, n=10). No upper grade 2 acute toxicity was reported. To the latest news, seven patients had controlled symptoms (improved, n=1, stabilized, n=6). One patient out of seven with initial tinnitus had a decrease in his symptoms, while the six other patients had a sustained stabilization. CONCLUSION: Proton beam therapy is an effective and well-tolerated treatment modality of skull base paragangliomas, with documented functional benefit. A longer follow-up is planned in order to assess local control and long term toxicities. PMID- 29269166 TI - A qualitative, interprofessional analysis of barriers to and facilitators of implementation of the Department of Veterans Affairs' Clostridium difficile prevention bundle using a human factors engineering approach. AB - BACKGROUND: Clostridium difficile infection (CDI) is increasingly prevalent, severe, and costly. Adherence to infection prevention practices remains suboptimal. More effective strategies to implement guidelines and evidence are needed. METHODS: Interprofessional focus groups consisting of physicians, resident physicians, nurses, and health technicians were conducted for a quality improvement project evaluating adherence to the Department of Veterans Affairs' (VA) nationally mandated C difficile prevention bundle. Qualitative analysis with a visual matrix display identified barrier and facilitator themes guided by the Systems Engineering Initiative for Patient Safety model, a human factors engineering approach. RESULTS: Several themes, encompassing both barriers and facilitators to bundle adherence, emerged. Rapid turnaround time of C difficile polymerase chain reaction testing was a facilitator of timely diagnosis. Too few, poorly located, and cluttered sinks were barriers to appropriate hand hygiene. Patient care workload and the time-consuming process of contact isolation precautions were also barriers to adherence. Multiple work system components serve as barriers to and facilitators of adherence to the VA CDI prevention bundle among an interprofessional group of health care workers. Organizational factors appear to significantly influence bundle adherence. CONCLUSION: Interprofessional perspectives are needed to identify barriers to and facilitators of bundle implementation, which is a necessary first step to address adherence to bundled infection prevention practices. PMID- 29269167 TI - The development of hand hygiene compliance imperatives in an emergency department. AB - BACKGROUND: Monitoring results showing poor hand hygiene compliance in a major, busy emergency department prompted a quality improvement initiative to improve hand hygiene compliance. PURPOSE: To identify, remove, and reduce barriers to hand hygiene compliance in an emergency department. METHODS: A barrier identification tool was used to identify key barriers and opportunities associated with hand hygiene compliance. Hand hygiene imperatives were developed and agreed on with clinicians, and a framework for monitoring and improving hand hygiene compliance was developed. RESULTS: Barriers to compliance were ambiguity about when to clean hands, the pace and urgency of work in some areas of the department, which left little time for hand hygiene and environmental and operational issues. Sore hands were a problem for some staff. Expectations of compliance were agreed on with staff, and changes were made to remove barriers. A monitoring tool was designed to monitor progress. Gradual improvement occurred in all areas, except in emergency situations, which require further improvement work. CONCLUSIONS: The context of care and barriers to compliance should be reflected in hand hygiene expectations and monitoring. In the emergency department, the requirement to deliver urgent live-saving care can supersede conventional hand hygiene expectations. PMID- 29269168 TI - External electrical cardioversion of persistent atrial fibrillation in a patient with a MicraTM Transcatheter Pacing System. AB - We report a case of a 85-year old woman with a preexisting Transcatheter Pacing System (TPS) (MicraTM VR, Fa. Medtronic, Inc., Minneapolis, MN, USA) undergoing several external electrical cardioversions (CV) for symptomatic persistent atrial fibrillation (persAF). Due to bradycardia in the setting of atrial fibrillation a right apical TPS implantation was performed earlier. Four weeks prior to presentation at our facility an unsuccessful CV with a maximum biphasic energy level of 360J was performed, after which amiodarone was initiated. At the time of presentation three shocks with 100 J, 200 J and 360 J were delivered without sustained restoration of a stable sinus rhythm. Patches were in an anterior posterior position. No complications and no significant changes in device parameters in comparison to the pre-acquired values were observed. To our knowledge, this is the first case report of an external CV in a patient with a TPS. External CV in patients with a preexisting TPS seems to be safe and feasible. PMID- 29269169 TI - Parental presence or absence during paediatric burn wound care procedures. AB - AIM: Differing views on benefits and disadvantages of parental presence during their child's wound care after burn injury leave the topic surrounded by controversies. This study aimed to describe and explain parents' experiences of their presence or absence during wound care. METHODS: Shortly after the burn event, 22 semi-structured interviews were conducted with parents of children (0 16 years old) that underwent hospitalization in one of the three Dutch burn centers. Eighteen of these parents also participated in follow-up interviews three to six months after discharge. Interviews were analyzed using grounded theory methodology. RESULTS: Analyses resulted in themes that were integrated into a model, summarizing key aspects of parental presence during wound care. These aspects include parental cognitions and emotions (e.g., shared distress during wound care), parental abilities and needs (e.g., controlling own emotions, being responsive, and gaining overall control) and the role of burn care professionals. CONCLUSION: Findings emphasize the distressing nature of wound care procedures. Despite the distress, parents expressed their preference to be present. The abilities to control their own emotions and to be responsive to the child's needs were considered beneficial for both the child and the parent. Importantly, being present increased a sense of control in parents that helped them to cope with the situation. For parents not present, the professional was the intermediary to provide information about the healing process that helped parents to deal with the situation. In sum, the proposed model provides avenues for professionals to assess parents' abilities and needs on a daily basis and to adequately support the child and parent during wound care. PMID- 29269170 TI - [Transparency and replicability of nursing intervention studies in long-term care: A selective literature review]. AB - BACKGROUND AND OBJECTIVE: The development and evaluation of interventions in long term care is time-consuming and expensive due to their complexity. To ensure reproducibility and successful implementation, these interventions must be described and published in a comprehensible and qualitative manner. The aim of this study is to analyze intervention studies from the inpatient long-term care setting with regard to their completeness, reporting quality, transparency and thus reproducibility. METHOD: The completeness and the reporting quality of the interventions described in the publications were examined in the context of a selective literature review by means of intervention studies from the long-term care setting (n=22). To this end, the Template for Intervention Description and Replication (TIDieR) checklist and the Criteria for Reporting the Development and Evaluation of Complex Interventions in Healthcare 2 (CReDECI2-DE) list were used. Transparency criteria included study registration and access to study protocols. RESULTS: The TIDieR checklist examination revealed that only three studies contained all the information necessary; the CReDECI2 test provided a complete description for only one study. Frequent shortcomings were observed concerning the information on modifications and titrations for the study participants and the location. Protocols were available for eight studies, 14 studies were registered. CONCLUSIONS: In terms of science, this means that the reproducibility of scientific findings is limited, which is why they cannot provide secure knowledge. As a result, the practical benefit to be derived from published studies that are accessible to decision-makers is limited as well. As far as publishers are concerned they should pay more attention to the completeness, registration and availability of materials. PMID- 29269171 TI - [Report from an ongoing research project: The Cologne Research and Development Network (CoRe-Net) and the value-based approach to healthcare]. AB - With the BMBF's funding program "Structural Development in Health Services Research" the Cologne Research and Development Network CoRe-Net is being set up by various partners from both clinical practice and health services research. The network focuses on the further development of healthcare according to the concept of learning organizations. On the basis of three research projects, the Cologne network CoRe-Net aims to establish itself in a sustainable manner and analyze healthcare delivery for two vulnerable patient groups. The two groups include a) deceased patients in Cologne and b) people suffering from heart disease and an associated mental comorbidity. The Cologne network CoRe-Net is based on M.E. Porter's value-based healthcare approach. PMID- 29269172 TI - Pneumatosis cystoides intestinalis. PMID- 29269173 TI - Cost-utility analysis of fracture risk assessment using microRNAs compared with standard tools and no monitoring in the Austrian female population. AB - BACKGROUND: Osteoporosis poses an immense burden to the society in terms of morbidity, mortality and financial cost. To reduce this burden, it is essential to accurately assess the individual patient's fracture risk and, where indicated, to initiate appropriate treatment that reduces fracture probability. Current screening and monitoring approaches include utilization of FRAX(r), a web-based country-specific fracture risk assessment tool, and bone mineral density measurement by Dual Energy X-ray Absorptiometry (DXA). Recently, microRNAs have been recognized as important regulators of bone physiology and potential biomarkers for fracture risk assessment and monitoring. A fracture risk assessment tool based on microRNAs (osteomiRTM test) is currently being developed. The aim of this study was to estimate the cost-effectiveness of fracture risk screening, monitoring, and resulting treatment decisions for the Austrian female population using the osteomiRTM test compared with DXA, with FRAX(r), or with no screening/monitoring. METHODS: A cost-utility-model was developed to simulate long-term consequences of Austrian women from age 50 over lifetime or death with respect to osteoporosis. Markov-modelling techniques were used to calculate health state transitions of fracture incidence according to risk groups (high, intermediate, low). High-risk patients receive medical treatment. Probabilities were derived via systematic-literature-review; direct costs (2015, ?) from published sources from the payer's perspective. Results evaluate the incremental cost-effectiveness ratios (ICER) for osteomiRTM against the comparators, gains or losses of fractures, life years (LYs), quality-adjusted life years (QALYs), and direct costs. QALYs, life years (LYs) and costs were discounted (3% p.a). RESULTS: Fracture risk assessment and monitoring using the osteomiRTM test reduces fracture incidence compared with no monitoring, DXA alone, or FRAX(r) alone. In the per-patient analysis, the ICER/QALY of osteomiRTM vs. no-monitoring was 13,103 ?, vs. FRAX(r) 37,813 ?, and vs. DXA -19,605 ?, indicating that costs can be saved while gaining QALYs. Considering the total cohort over lifetime, the osteomiRTM test can avoid 57,919 fractures compared with DXA, 31,285 fractures compared with FRAX(r) and 133,394 fractures compared with no monitoring. Sensitivity analysis confirmed the robustness of these findings. CONCLUSION: Fracture risk assessment and monitoring using the osteomiRTM test dominates DXA-strategy and constitutes a cost-effective alternative to FRAX(r), and no-monitoring, respectively. PMID- 29269174 TI - Substance P restores normal skin architecture and reduces epidermal infiltration of sensory nerve fiber in TNCB-induced atopic dermatitis-like lesions in NC/Nga mice. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus and eczematous lesion. Substance P (SP) is an 11-amino-acid endogenous neuropeptide that belongs to the tachykinin family and several reports recently have supported the anti-inflammatory and tissue repairing roles of SP. OBJECTIVE: In this study, we investigated whether SP can improve AD symptoms, especially the impaired skin barrier function, in 2, 4, 6 trinitrochlorobenzene (TNCB)-induced chronic dermatitis of NC/Nga mice or not. METHOD: AD-like dermatitis was induced in NC/Nga mice by repeated sensitization with TNCB for 5 weeks. The experimental group designations and topical treatments were as follows: vehicle group (AD-VE); SP group (AD-SP); and SP with NK1R antagonist CP99994 (AD-SP-A) group. Histological analysis was performed to evaluate epidermal differentiation, dermal integrity, and epidermal nerve innervation in AD-like lesions. The skin barrier functions and pruritus of NC/Nga mice were evaluated by measuring transepidermal water loss (TEWL) and scratching behavior, respectively. RESULT: Topical SP treatment resulted in significant down regulation of Ki67 and the abnormal-type keratins (K) K6, K16, and K17, restoration of filaggrin and claudin-1, marked reduction of TEWL, and restoration of basement membrane and dermal collagen deposition, even under continuous sensitization of low dose TNCB. In addition, SP significantly reduced innervation of itch-evoking nerve fibers, gelatinase activity and nerve growth factor (NGF) expression in the epidermis but upregulated semaphorin-3A (Sema3A) expression in the epidermis, along with reduced scratching behavior in TNCB-treated NC/Nga mice. All of these effects were completely reversed by co-treatment with the NK1R antagonist CP99994. In cultured human keratinocytes, SP treatment reduced expression of TGF-alpha, but upregulated TGF-beta and Sema3A. CONCLUSION: Topically administered SP can restore normal skin barrier function, reduce epidermal infiltration of itch-evoking nerve fibers in the AD-like skin lesions, and alleviate scratching behavior. Thus, SP may be proposed as a potential medication for chronic dermatitis and AD. PMID- 29269175 TI - [Lung cancer in HIV-infected patients]. AB - Until 1996, AIDS was the leading cause of deaths from HIV infection. In 2010, because of introduction of powerful antiretroviral therapies, AIDS represented less than 25% of deaths. Cancer has become the leading cause of death in this population, and, because of smoking and immunosuppression, lung cancer risk is more important than in general population. Furthermore, treatment is more difficult, due to potential interactions between antiretroviral and anticancer therapies, to comorbidities and to tumor aggressiveness. Research will focus on molecular biology, immunotherapies and lung cancer screening in order to improve survival of HIV patients with lung cancer. For all these reasons, HIV patients must be included in clinical trials. PMID- 29269177 TI - Adhesive arachnoiditis secondary to the use of intrathecal liposoluble contrast. PMID- 29269176 TI - [Hot topics in 2017 in oncology and hematology. A selection by the editorial board of Bulletin du Cancer]. AB - Actuality was dense in 2017 for oncology and hematology. The editorial board of the Bulletin du Cancer proposes a selection of key data distinguishing four trends: precision medicine, immunotherapy, focus on early stages and global management of metastatic disease. A summary of results which have been published or presented in congresses is proposed and the impact on daily practices is discussed. PMID- 29269178 TI - Invisible, but necessary. PMID- 29269179 TI - Lordosis facilitated by GPER-1 receptor activation involves GnRH-1, progestin and estrogen receptors in estrogen-primed rats. AB - The present study assessed the participation of membrane G-protein coupled estrogen receptor 1 (GPER-1) and gonadotropin releasing hormone 1 (GnRH-1) receptor in the display of lordosis induced by intracerebroventricular (icv) administration of G1, a GPER-1 agonist, and by unesterified 17beta-estradiol (free E2). In addition, we assessed the participation of both estrogen and progestin receptors in the lordosis behavior induced by G1 in ovariectomized (OVX), E2-benzoate (EB)-primed rats. In Experiment 1, icv injection of G1 induced lordosis behavior at 120 and 240min. In Experiment 2, icv injection of the GPER-1 antagonist G15 significantly reduced lordosis behavior induced by either G1 or free E2. In addition, Antide, a GnRH-1 receptor antagonist, significantly depressed G1 facilitation of lordosis behavior in OVX, EB-primed rats. Similarly, icv injection of Antide blocked the stimulatory effect of E2 on lordosis behavior. In Experiment 3, systemic injection of either tamoxifen or RU486 significantly reduced lordosis behavior induced by icv administration of G1 in OVX, EB-primed rats. The results suggest that GnRH release activates both estrogen and progestin receptors and that this activation is important in the chain of events leading to the display of lordosis behavior in response to activation of GPER-1 in estrogen-primed rats. PMID- 29269180 TI - The usefulness of high temporal resolution breast MRI sequences. PMID- 29269181 TI - Effect of 24-Hour Bed Rest versus Early Ambulation on Headache after Spinal Anesthesia: Systematic Review and Meta-analysis. AB - OBJECTIVES: We performed a systematic review of the evidence for the effectiveness of bed rest after dural puncture to update current evidence on the topic. DESIGN: The design was a systematic review and meta-analysis. DATA SOURCES: We searched 10 electronic databases in English (Medline, CINAHL, EMBASE, and the Cochrane Controlled Trial Register) and Korean (KISS, KMBASE, NDSL, and RISS) using the terms "post-dural puncture headache," "spinal anesthesia," "epidural anesthesia," and "bed rest" to identify reports discussing the effectiveness of bed rest in preventing post-dural puncture headache (PDPH) after spinal anesthesia from 1980 to 2014. Review/Analysis Methods: Original studies such as randomized and nonrandomized controlled trials, where participants were allocated to an intervention or control group, were included. A total of eight studies that met the inclusion criteria were independently reviewed and encoded by two review authors. To ensure the quality of the eight studies, levels of risk of bias were assessed by two different researchers. The main outcome was the prevalence of PDPH. RESULTS: The included studies indicated that PDPH prevalence did not differ between the group assigned to 24 hours of bed rest and the group assigned to early ambulation. In subgroup analysis, the effect size of clinical factors (severity of headache, day of onset, and needle gauge) and the study characteristics (language and sample size) did not differ between groups. CONCLUSION: This meta-analysis of studies suggested that long-term bed rest after spinal anesthesia may not be effective in preventing PDPH. PMID- 29269182 TI - Detection of Intra-Articular Screw Penetration of Proximal Humerus Fractures: Is Postoperative Computed Tomography the Necessary Imaging Modality? AB - RATIONALE AND OBJECTIVE: Screw penetration is the common complication of proximal humerus fractures treated with locking plates. This study compared postoperative plain radiography to computed tomography (CT) for their abilities in determining screw penetration, and was to evaluate whether advanced imaging modalities (two dimensional [2D] CT; three-dimensional [3D] CT) could increase surgeons' level of confidence regarding their diagnoses. MATERIALS AND METHODS: Two observers reviewed radiological images of 134 patients who sustained proximal humerus fractures treated with locking plates. The observers were asked to answer two questions: (1) Is there screw penetrating into glenohumeral joint for this patient (Yes/No)? and (2) On a scale from 0 to 10, how confident are you about this diagnosis: (0-10) (0 = not at all confident; 10 = very confident)? Three evaluations were performed: (1) plain radiography alone, (2) radiography and 2D CT 4 weeks later, and (3) radiography in combination with 2D and 3D CT after that. This process was then repeated for intraobserver analysis. RESULTS: CT obtained almost perfect interobserver and intraobserver agreement (0.818-0.961), which was higher than radiography (0.377-0.655). For incidence of screw penetration, the significant difference was found between radiographs and CT images (P <.0125), but not between 2D and 3D CT images (P > .05). For confidence of diagnosis, the differences between imaging modalities were significant (all P <.001). CONCLUSIONS: We suggest that postoperative CT scans (especially 3D CT images) should be used to evaluate the intra-articular screw penetration of proximal humerus fractures, especially when surgeons have not enough confidence in determining screw penetration using radiography alone. PMID- 29269183 TI - A new technique for encapsulated filtration blebs: Vitrector assisted cystectomy. PMID- 29269184 TI - [Serious video games in pediatrics]. AB - Playing video games has been associated with several negative effects in children. However, serious games, which are video games designed for a primary purpose other than pure entertainment, should not be neglected by pediatricians. In the field of public health, some serious games are a means to decrease drug consumption and improve sexual health behavior in adolescents. In schools, serious games can be used to change students' perception of the disease of one of their classmates, or to train students on basic life support. Serious games are also used with patients: they can distract them from a painful procedure, increase their compliance to treatments, or participate in their rehabilitation. Finally, serious games allow healthcare professionals to train on the management of various medical situations without risk. For every field of application, this review presents the rationale of the use of video games, followed by concrete examples of video games and the results of their scientific evaluation. PMID- 29269185 TI - [Tools and techniques to improve the oral health of children with autism]. AB - Autism spectrum disorder (ASD) is a life-long heterogeneous psychiatric disorder, characterized by impaired social interaction and communication, and the presence of repetitive and stereotyped behaviors as well as restricted interests. These features have an impact on the oral health of these individuals: high risk of dental caries, poorer periodontal status, and bruxism are often described. Children with ASD often provide limited collaboration with medical procedures, particularly those considered invasive such as dental care. Children with ASD are prone to agitation, self-injury, and emotional dysregulation; they can also present hypersensitivity to sensory input. These features make it difficult for professionals to examine and treat children with ASD; they interfere with dental care and constitute a barrier to it. Most of them are treated under general anesthesia or sedation. Therefore, children with ASD present a challenge for the dental community. Adapted and specific strategies are required to allow individuals with ASD to go beyond the barriers of dental care. Different tools and techniques of evidence-based practice can be considered: visual pedagogy, behavioral approaches, and numeric devices can be used. Pediatricians have a key role in the oral care of children with autism. The aim of this article is to present the oral health associated with ASD, to set out the possible ways to improve oral health, to enable the practitioner to detect problems, to raise awareness, and to help patients and their families in their care pathway. PMID- 29269186 TI - Effects of vortioxetine on biomarkers associated with glutamatergic activity in an SSRI insensitive model of depression in female rats. AB - The aim of this study was to investigate the antidepressant activity of vortioxetine in a tryptophan (TRP) depletion female rat model of depression and compare it to that of paroxetine using doses that fully occupy the serotonin transporter (SERT). We evaluated the effects of vortioxetine on potential biomarkers associated with TRP depletion including serum aldosterone, corticosterone and IL-6 levels together with indirect indicators of glutamate neurotransmission. Female Sprague-Dawley rats were randomized to control, low TRP, low TRP/paroxetine or low TRP/vortioxetine groups. Vortioxetine and paroxetine were administered via diet (10mg/kg/day) and drinking water (10mg/kg/day) respectively for 14days. Vortioxetine but not paroxetine reversed TRP depletion-induced depressive-like behavior. Vortioxetine reduced TRP depletion-induced increases of serum corticosterone, aldosterone, IL-6 and N methyl-d-aspartate and alpha7-nicotinic acetylcholine receptor expression in the amygdala and hippocampus, respectively. Paroxetine demonstrated little effect except a reduction of aldosterone. Vortioxetine but not paroxetine reversed TRP depletion-induced reductions of serum and brain kynurenic acid. In conclusion, vortioxetine, but not paroxetine, enabled reversals of TRP depletion-induced changes of depression-like behavior and markers of glutamatergic activity. These observations support the hypothesis that vortioxetine's antidepressant activity may involve mechanisms beyond SERT inhibition. PMID- 29269187 TI - Attention deficit hyperactivity disorder symptoms in patients with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a chronic life-threatening disease. In patients who suffer from chronic disease, Attention Deficit Hyperactivity Disorder (ADHD) is associated with functional impairment that can affect adherence to treatment and consequently influence prognosis. METHODS: CF patients filled in the ADHD Rating Scale (ADHD-RS) adapted to the DSM5 and were assessed on a continuous performance task (MOXO-CPT), a standardized-computerized test designed to evaluate several domains of attention. RESULTS: Of the 175 patients (99 males), 18% presented ADHD symptoms, according to ADHD-RS; 16% in the younger group (<18years), and 18.9% in the adult group. The male to female ratio was 3:1 in children and 1:1 in adults. CONCLUSIONS: The occurrence of ADHD symptoms in patients with CF is substantially higher than in the general population and should be recognized as a co-morbidity of CF. As ADHD can impair adherence to therapy, further research is needed to investigate the effect of ADHD therapy on adherence. PMID- 29269188 TI - Malaria in Children. AB - Malaria remains widespread throughout the planet and increasing global travel continues to lead to imported cases of malaria in travelers, including children. This article provides an overview of pediatric malaria, including its epidemiology, clinical features, diagnosis, treatment, and prevention in travelers. PMID- 29269190 TI - Current Concepts in the Evaluation and Management of Bronchiolitis. AB - Bronchiolitis is a lower respiratory tract illness caused by viral infection in children 2 years of age and younger, frequently associated with wheezing on physical examination. It is a common cause of hospitalization, particularly in patients with risk factors for more serious disease. The diagnosis can be made based on clinical signs and symptoms alone, and care is generally supportive with a focus on safely doing less for symptomatic children. Bronchodilators, systemic steroids, and other therapies have been shown to have no significant effect on hospitalization rates, length of stay, or symptom duration. PMID- 29269191 TI - Management of Ebola Virus Disease in Children. AB - The West African outbreak of 2013 to 2016 was the largest Ebola epidemic in history. With tens of thousands of patients treated during this outbreak, much was learned about how to optimize clinical care for children with Ebola. In anticipation of inevitable future outbreaks, a firsthand summary of the major aspects of pediatric Ebola case management in austere settings is presented. Emphasis is on early and aggressive critical care, including fluid resuscitation, electrolyte repletion, antimicrobial therapy, and nutritional supplementation. PMID- 29269189 TI - Pediatric Community-Acquired Pneumonia in the United States: Changing Epidemiology, Diagnostic and Therapeutic Challenges, and Areas for Future Research. AB - Community-acquired pneumonia (CAP) is one of the most common serious infections in childhood. This review focuses on pediatric CAP in the United States and other industrialized nations, specifically highlighting the changing epidemiology of CAP, diagnostic and therapeutic challenges, and areas for further research. PMID- 29269192 TI - New Developments in Rapid Diagnostic Testing for Children. AB - The advent of new diagnostics assays for Group A Streptococcus, influenza, and respiratory syncytial virus now provide rapid results with increased sensitivity and specificity. Molecular testing is no longer confined to the walls of the laboratory, but moving to the patient in the form of point-of-care tests. In addition, multiplex syndromic panels are allowing broad testing of pathogens associated with a single clinical presentation. This article focuses specifically on rapid diagnostic tests for pathogens most affecting children. Rapid and accurate pathogen detection in children may result in decreased time to optimal antimicrobial treatment and improved patient outcomes. PMID- 29269193 TI - Low CD4 cells and viral co-infection increase the risk of VaIN: Use of SCCA1 and Ki67 as diagno-prognostic biomarkers. AB - This study evaluated the correlation of SCCA1, Ki67 and CD4 cell expressions and classified vaginal smears in individuals co-infected with Human immunodeficiency virus (HIV), Herpes simplex virus 2 (HSV2), Epstein Barr virus (EBV) and Human Papilloma virus (HPV). This crossectional study included 173 participants within the age range of 20-70 years. Vaginal smears were stained by Papanicolaou technique and classified into high-grade squamous cell intraepithelial lesion (HSIL), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells of undetermined significance (ASCUS) and negative for intraepithelial lesion (NIL). Presence of immunoglobulin M and G antibodies for EBV, HIV, HPV and HSV2, and SCCA1 and Ki67 antigens were determined by ELISA method. Result showed that biomarkers SCCA1 had higher sensitivity (87.5%) to vaginal lesions when compared with Ki67 which had a sensitivity of 70.8% (p > .01). Assays revealed viral co infections of 96.0% and 16.8% in smears positive and negative for vaginal lesions, respectively (p < .01) with HIV, HSV2 and EBV as the most prevalent type of co-infection (36%). The findings of this study suggest that low CD4 cells and viral co-infection could increase the risk of developing vaginal lesions. This study also suggests that SCCA1 and Ki67 could be used as diagnostic and prognostic biomarkers for vaginal intraepithelial neoplasia (VaIN). PMID- 29269194 TI - [Lemierre's syndrome: Diagnosis, exploration, treatment]. AB - Lemierre's syndrome is a rare and severe sepsis that can rapidly lead to a life threatening condition in the absence of early management. This syndrome described at the beginning of the 20th century combines oropharyngeal infection complicated with septic thrombosis of the internal jugular vein and septic emboli predominantly pulmonary. Fusobacterium necrophorum, anaerobic germ, Gram negative bacillus is the main germ in this "necrobacillosis". The diagnosis is should be confirmed precociously with cervicothoracic CT-scan, reference exam, and bacteriological examinations (especially in atypical forms). Its management consists of an emergency antibiotic treatment, combining a third-generation cephalosporin or a betalactam with metronidazole, anticoagulant therapy to be reserved for high-risk situations related to thrombosis. Surgical treatment may be required. PMID- 29269195 TI - Forecasting Faces in the Cortex: Comment on 'High-Level Prediction Signals in a Low-Level Area of the Macaque Face-Processing Hierarchy', by Schwiedrzik and Freiwald, Neuron (2017). AB - Although theories of predictive coding in the brain abound, we lack key pieces of neuronal data to support these theories. Recently, Schwiedrzik and Freiwald found neurophysiological evidence for predictive codes throughout the face-processing hierarchy in macaque cortex. We highlight how these data enhance our knowledge of cortical information processing, and the impact of this more broadly. PMID- 29269196 TI - Heterozygous Deletion Impacting SMARCAD1 in the Original Kindred with Absent Dermatoglyphs and Associated Features (Baird, 1964). AB - In 1964, Baird described a family with adermatoglyphia, facial milia, and skin fragility. Using whole exome sequencing, genotyping, and Sanger sequencing, we identified a 116-kb heterozygous deletion involving exons 1-9 of SMARCAD1 in descendants of this kindred. This contrasts with point mutations within exon 9 in all other reported families. PMID- 29269197 TI - Understanding the Burden of Pediatric Gastrointestinal Diseases-Does a Look From the Perspective of Inpatient Administrative Databases Help? PMID- 29269198 TI - Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes. AB - OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap. PMID- 29269199 TI - A Mixed Lipid Emulsion for Prevention of Parenteral Nutrition Associated Cholestasis in Extremely Low Birth Weight Infants: A Randomized Clinical Trial. AB - OBJECTIVES: To examine whether a mixed lipid emulsion reduces the incidence of parenteral nutrition associated cholestasis (PNAC) in extremely low birth weight (ELBW, <1000 g) infants. STUDY DESIGN: This double-blind randomized trial of 230 ELBW infants (June 2012-October 2015) was performed at a single level IV neonatal intensive care unit. Patients received either a mixed lipid emulsion composed of soybean oil, medium chain triglycerides, olive oil, and fish oil-(intervention) or a soybean oil-based lipid emulsion (control) for parenteral nutrition. The primary outcome measure was PNAC (conjugated bilirubin >1.5 mg/dL [25 umol/L] at 2 consecutive measurements). The study was powered to detect a reduction of PNAC from 25% to 10%. RESULTS: Reasons for noneligibility of 274 infants screened were refusal to participate (n = 16), death (n = 10), withdrawal of treatment (n = 5), higher order multiples (n = 9), and parents not available for consent (n = 4). Intention to treat analysis was carried out in 223 infants (7 infants excluded after randomization). Parenteral nutrition associated cholestasis was 11 of 110 (10.1%) in the intervention and 18 of 113 (15.9%) in the control group (P = .20). Multivariable analyses showed no statistically significant difference in the intention to treat (aOR 0.428, 95% CI 0.155-1.187; P = .10) or per protocol population (aOR 0.457, 95% CI 0.155-1.347; P = .16). There was no statistically significant effect on any other neonatal morbidity. CONCLUSIONS: The incidence of parenteral nutrition associated cholestasis was not significantly reduced using a mixed lipid emulsion in ELBW infants. TRIAL REGISTRATION: ClinicalTrials.govNCT01585935. PMID- 29269200 TI - Genetic spectrum of low density lipoprotein receptor gene variations in South Indian population. AB - BACKGROUND: Low density lipoprotein receptor (LDLR) is a membrane bound receptor maintaining cholesterol homeostasis along with Apolipoprotein B (APOB), Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and other genes of lipid metabolism. Any pathogenic variation in these genes alters the function of the receptor and leads to Familial Hypercholesterolemia (FH) and other cardiovascular diseases. OBJECTIVE: This study was aimed at screening the LDLR, APOB and PCSK9 genes in Hypercholesterolemic patients to define the genetic spectrum of FH in Indian population. METHODS: Familial Hypercholesterolemia patients (n=78) of South Indian Tamil population with LDL cholesterol and Total cholesterol levels above 4.9mmol/l and 7.5mmol/l with family history of Myocardial infarction were involved. DNA was isolated by organic extraction method from blood samples and LDLR, APOB and PCSK9 gene exons were amplified using primers that cover exon intron boundaries. The amplicons were screened using High Resolution Melt (HRM) Analysis and the screened samples were sequenced after purification. RESULTS: This study reports 20 variations in South Indian population for the first time. In this set of variations 9 are novel variations which are reported for the first time, 11 were reported in other studies also. The in silico analysis for all the variations detected in this study were done to predict the probabilistic effect in pathogenicity of FH. CONCLUSION: This study adds 9 novel variations and 11 recurrent variations to the spectrum of LDLR gene mutations in Indian population. All these variations are reported for the first time in Indian population. This spectrum of variations was different from the variations of previous Indian reports. PMID- 29269201 TI - Point-of-care creatinine testing in patients receiving contrast-enhanced computed tomography scan. AB - BACKGROUND: The aim of this study was to evaluate the creatinine assay on the ABL800 FLEX(c) blood gas analyzer for the screening of pre-existing renal impairment before radiographic contrast administration in the emergency department (ED), by comparing it with standard practice using central laboratory blood testing. METHODS: The evaluation comprised two elements. The first, conducted in the central laboratory, focused on the analytical performance of the ABL800 creatinine assay. This included assessment of imprecision and accuracy by comparison with central laboratory standard creatinine assay. We also compared ABL 800 estimated glomerular filtration rate (eGFR) and 99mTc-DTPA measured GFR (mGFR). The second part, conducted in ED sought to determine the impact that implementation of the creatinine at the point-of-care (POC) has on the timeframe in which ED patients are submitted for computed tomography scan (CT). RESULTS: The ABL800 enzymatic creatinine assay met the National Kidney Disease Education Program acceptance criteria for imprecision and showed good agreement with the isotope dilution mass spectrometry-traceable Roche enzymatic assay used in the central laboratory. Furthermore, ABL800 eGFR was in total agreement with mGFR by a reference method. The implementation of POC testing creatinine in the ED significantly reduced patient waiting times for contrast enhanced CT (1.73[0.75 3.01] vs 2.57 [1.53-3.48] hours, for period with and without ABL800 respectively, p=0.04). CONCLUSION: The ABL800 assay is comparable with central laboratory reference method in terms of analytical performance and superior in terms of turnaround time. Implementation of creatinine at POC reduces delay results, potentially allowing ED clinical staff to make more rapid clinical decisions and reduce patient waiting time. PMID- 29269202 TI - AGR2 diagnostic value in nasopharyngeal carcinoma prognosis. AB - BACKGROUND: Anterior Gradient (AGR) 2 concentration increases in the serum of tumor patients, and their diagnostic and prognostic significances were evaluated in some tumors. The previous works showed that AGR2 high express in nasopharyngeal carcinoma (NPC) biopsy tissues. However, whether AGR2 serves as a diagnostic and prognostic marker for NPC remains unclear. METHODS: 42 healthy volunteers, 34 breast cancer patients and 124 NPC patients were enrolled into this study, and the serum samples were collected from these healthy volunteers, breast cancer patients and NPC patients. Concomitantly, 79 frozen nasopharyngeal specimens consisted of 65 NPC tissues and 14 normal nasopharyngeal tissues were enrolled in the observation. The enzyme linked immunosorbent assay (ELISA) was used to estimate AGR2 concentration in the serum samples, and AGR2 mRNA expressions in the frozen tissue samples were detected by real time RT-PCR. RESULTS: The real time RT-PCR results showed that AGR2 mRNA level was increased in NPC tissues compared with the normal nasopharyngeal tissues (p<0.05). The ELISA data showed that AGR2 concentration in NPC serum was significantly higher in NPC patient serums than that in the health population (p<0.05). And, AGR2 expression showed a correlation with tumor node metastasis (TNM) grade (p<0.05) and Recurrence (p<0.05). Moreover, the cumulative survival rate of patients with high concentration of AGR2 was significantly lower than that of patients with low concentration of AGR2 (p<0.05), and the cumulative hazard rate of patients with high concentration of AGR2 was significantly higher than that with low concentration of AGR2 (p<0.05). CONCLUSION: Serum AGR2 can be used as a serum marker for clinical prognosis of nasopharyngeal carcinoma. However, serum AGR2 levels could not provide advantages in clinical practice for the differential diagnosis of cancer. PMID- 29269204 TI - Intraoperative baseline oxygen consumption as a prognostic factor in emergency open abdominal surgery: Methodological issues. PMID- 29269203 TI - DEPIVIH 2: Use of three HIV testing methods in French primary care settings - ELISA laboratory screening versus two rapid point-of-care HIV tests. AB - OBJECTIVE: The primary endpoint was to evaluate the use of HIV testing methods by French primary care providers: Elisa laboratory screening, instant result HIV diagnostic test and rapid result HIV diagnostic test. The secondary endpoints were the population screening rate of unknown HIV status consulting during the study period, reasons for screening and for choosing the specific screening method, the investigators' satisfaction with the rapid diagnostic test (RDT) and problems encountered. PATIENTS AND METHODS: National prospective interventional study with French family physicians (FP) from December 2013 to December 2014. FPs enrolled all consenting adults consulting for an HIV screening test during a 6 month period: the choice was an Elisa laboratory test or one of the two RDTs. RESULTS: During the study period, 43 FPs included 981 patients. HIV screening was performed for the first time for 31.6% of patients; 767 (78.2%) Elisa laboratory test prescriptions and 214 (21.8%) RDTs were performed, leading to a screening rate of 1.3%. For 120 (15.7%) of the Elisa laboratory tests, the result was not reported and six RDTs were not valid. Nine patients were diagnosed as HIV infected (0.9%): five with Elisa laboratory test and four with RDT. Almost 90% of FPs were willing to keep on using RDTs in their daily practice. CONCLUSION: In general practice, RDTs may be an important additional tool to traditional HIV screening. They could account for one in five tests prescribed in this context. PMID- 29269205 TI - Response. PMID- 29269206 TI - Reduced insulin sensitivity may be related to less striatal glutamate: An 1H-MRS study in healthy non-obese humans. AB - Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using 1H-MRS, we measured levels of several neurometabolites in the striatum and dorsolateral prefrontal cortex (DLPFC) of seventeen healthy non obese persons (9 female, mean age: 28.35 +/- 9.53). Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. We hypothesized that %S would be positively related with levels of Glu and Glu + glutamine (Glx) in the striatum. Exploratory analyses were also conducted between other fasting markers of metabolic health and neurometabolites measured with 1H-MRS. In the right striatum, %S was positively correlated with levels of Glu (r(15) = .49, p = .04) and Glx (r(15) = .50, p = .04). In the left striatum, there was a trend positive correlation between %S and Glu (r(15) = .46, p = .06), but not Glx levels (r(15) = .20, p = .44). The relationships between %S and striatal Glu levels remained after controlling for age, sex, and BMI (right: r(12) = .73, beta = .52, t = 2.55, p = .03; left: (r(12) = .63, beta = .53, t = 2.25, p = .04) These preliminary findings suggest that %S may be related to markers of glutamatergic functioning in the striatum of healthy non-obese persons. These findings warrant replication in larger samples and extension into neuropsychiatric populations where altered striatal DA, Glu, and %S are implicated. PMID- 29269207 TI - Patient-reported health-related quality of life for men treated with low-dose rate prostate brachytherapy as monotherapy with 125-iodine, 103-palladium, or 131 cesium: Results of a prospective phase II study. AB - PURPOSE: To compare quality of life (QoL) after brachytherapy with one of the three approved radioactive isotopes. METHODS AND MATERIALS: Patients with mostly favorable intermediate-risk prostate cancer were treated on this prospective phase II trial with brachytherapy as monotherapy, without hormonal therapy. QoL was recorded at baseline and each follow-up by using the Expanded Prostate Cancer Index Composite instrument. The minimal clinically important difference was defined as half the standard deviation of the baseline score for each domain. Mixed effect models were used to compare the different isotopes, and time-driven activity-based costing was used to compute costs. RESULTS: From 2006 to 2013, 300 patients were treated with iodine-125 (I-125, n = 98, prescribed dose [PD] = 145 Gy), palladium-103 (Pd-103, n = 102, PD = 125 Gy), or cesium-131 (Cs-131, n = 100, PD = 115 Gy). Median age was 64.9 years. Median follow-up time was 5.1 years for the entire cohort, and 7.1, 4.8 and 3.3 years for I-125, Pd-103, and Cs-131 groups, respectively. All three isotope groups showed an initial drop in QoL at first follow-up, which gradually improved over the first 2 years for urinary and bowel domains. QoL profiles were similar between I-125 and Pd-103, whereas Cs-131 showed a statistically significant decrease in QoL regarding bowel and sexual function at 12 months compared with Pd-103. However, these differences did not reach the minimal clinically important difference. Compared with I-125, the use of Pd-103 or Cs-131 resulted in cost increases of 18% and 34% respectively. CONCLUSIONS: The three different isotopes produced a similar QoL profile. Statistically significant differences favored Pd-103/I-125 over Cs-131 for bowel and sexual QoL, but this did not reach clinical significance. PMID- 29269208 TI - Bright Light as a Preventive Intervention for Depression in Late-Life: A Pilot Study on Feasibility, Acceptability, and Symptom Improvement. AB - OBJECTIVES: We examined the feasibility and acceptability of a portable bright light intervention and its impact on sleep disturbance and depressive symptoms in older adults. METHODS: One-arm prevention intervention pilot study of the Re Timer (Re-Timer Pty Ltd, Adelaide, Australia) bright light device (worn 30 minutes daily for 2 weeks) in 1 older adults (age 65 + years) with subsyndromal symptoms of depression and poor sleep quality. Participants were assessed on intervention acceptability and adherence, depressive symptoms (Patient Health Questionnaire- 9), and sleep (Pittsburgh Sleep Quality Index, Insomnia Severity Index, actigraphy and daily diary reports). RESULTS: The Re-Timer device was rated positively by participants, and, on average, participants only missed 1 day of utilization. Although depressive symptoms declined and self-reported sleep improved, improvement was seen largely before the start of intervention. CONCLUSIONS: An effective preventive intervention that is targeted towards a high risk group of older adults has the potential to reduce distress and costly health service use. PMID- 29269209 TI - Finding Meaning during Times of Anguish in Later Life. PMID- 29269210 TI - Peripersonal space boundary in schizotypy and schizophrenia. PMID- 29269211 TI - Endoscopic pharyngolaryngoplasty: A case report. AB - INTRODUCTION: Any technique that allows decannulation of tracheostomy-dependent patients relieves their discomfort and reduces health costs. CASE REPORT: We present the case of a 70-year-old tracheostomy-dependent patient with pharyngolaryngeal stenosis and a history of radiation therapy for laryngeal cancer in remission for 13years and multiple decannulation failures. Endoscopic pharyngolaryngoplasty was performed using reconstructive transoral laser microsurgery techniques, allowing permanent decannulation. Endoscopic sutures secured by clips were performed to remodel the pharyngolarynx and prevent recurrence of synechiae. DISCUSSION: Endoscopic surgery of the pharynx and larynx was initially developed for resection of small tumours. Reconstructive transoral laser microsurgery has been developed more recently. One of the objectives of this surgery is to reconstruct the pharyngolarynx to treat functional sequelae following surgery and/or radiation therapy for head and neck cancer. It allows reconstruction of the upper airways to restore mouth breathing in tracheostomy dependent patients, thereby facilitating permanent decannulation. PMID- 29269212 TI - Synthesis of pentacyclic iminosugars with constrained butterfly-like conformation and their HIV-RT inhibitory activity. AB - Novel pentacyclic iminosugars 1 and 2 with the constrained butterfly-like conformation were first synthesized by the key intramolecular click reaction from the tricyclic iminosugars fused benzo[e][1,3]thiazin-4-one 3 and 4. The pentacyclic iminosugar was constructed by fusing both benzo[e][1,3]thiazin-4-one and triazolo[5,1-c][1,4]oxazepine scaffolds. Their structures were determined by their 1H, 13C NMR, and HRMS (ESI) spectra and X-ray. The pentacyclic iminosugars 1(a-c), 2(a-b) and their corresponding protected precursors 13(a-c) and 14(a-b) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds could effectively inhibit RT activity. Among them, compound 13c was the best one with the IC50 value of RT inhibitory activity of 0.69 MUM. Structure-activity relationship analysis suggested that the improvement of the hydrophilicity of the pentacycles was of benefit to their anti HIV RT activity. PMID- 29269213 TI - Quantitative determination of linking number differences between circular polynucleosomes and histone H1-bound circular polynucleosomes. AB - With the aim of discovering contribution of histone H1 to linking number changes of DNA, determination of linking number differences between histone H1-free circular polynucleosomes and histone H1-bound circular polynucleosomes was carried out during our investigations. Our results showed that on average, binding of ~11.5 histone H1 molecules causes one linking number change in circular polynucleosomes in the presence of 1.5 mM spermidine. When concentrations of spermidine decreases or increases, these linking number differences decrease significantly. It is therefore evident that linking number changes caused by histone H1 are spermidine concentration-dependent. PMID- 29269215 TI - Small molecule SUMOylation activators are novel neuroprotective agents. AB - Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson's disease, Alzheimer's disease, and stroke. PMID- 29269214 TI - Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates. AB - Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug - paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC. PMID- 29269216 TI - Effects of newly synthetized isoquinoline derivatives on rat uterine contractility and ROCK II activity. AB - Protein kinases have an important role in signal transduction in the cellular system via protein phosphorylation. RhoA activated Rho-kinases have a pivotal role in the regulation of smooth muscle contraction. ROCK I and ROCK II phosphorylate myosin-phosphatase and myosin-kinase, which induces contraction in the myometrium. Several studies have investigated the affinity of isoquinoline alkaloids (HA-1077, H1152P) to Rho-kinases, and these compounds notably inhibited the Ca2+-independent process. We measured the efficiency of 25 original, newly synthesized isoquinoline derivatives for the Rho-kinase activity using Rho associated kinase activity assay and determined their effects on the non pregnant, 20-day pregnant and parturient rat myometrial contraction in vitro. The IC50 values of 11 from among the 25 derivatives were significantly lower on the oxytocin-induced non-pregnant rat uterine contraction compared with Y-27632 and fasudil, although their maximal inhibitory effects were weaker than those of Y 27632 and fasudil. We measured the effects of 11 isoquinoline molecules with significant IC50 values on ROCK II activity. We found two isoquinolines out of 11 compounds (218 and 852) which decreased the active ROCK II level similarly as Y 27632. Then we found that 218 and 852 relaxed the 20th-day pregnant and parturient rat uterus with greater potency as compared with fasudil. The majority of the synthesized isoquinoline derivatives have uterus relaxant effects and two of them significantly suppress the Rho-kinase mediated myosin light chain phosphorylation. Our results may suggest that the isoquinoline structure has a promising prospect for the development of new and effective inhibitors of uterine contractions in preterm birth. PMID- 29269217 TI - An In Vivo Perspective of the Role(s) of the Alternative Oxidase Pathway. AB - Despite intense research on the in vitro characterization of regulatory factors modulating the alternative oxidase (AOX) pathway, the regulation of its activity in vivo is still not fully understood. Advances concerning in vivo regulation of AOX based on the oxygen-isotope fractionation technique are reviewed, and regulatory factors that merit future research are highlighted. In addition, we review and discuss the main biological functions assigned to the plant AOX, and suggest future experiments involving in vivo activity measurements to test different hypothesized physiological roles. PMID- 29269219 TI - Impact of para-aortic recurrence risk-guided intensity-modulated radiotherapy in locally advanced cervical cancer with positive pelvic lymph nodes. AB - OBJECTIVES: A previous study has suggested the benefit of sub-renal vein radiotherapy (SRVRT) for pelvic lymph node (PLN)-positive cervical cancer. In order to better select patients for SRVRT, this study aimed to evaluate the value of a risk-based radiation field based on PLN location and number in PLN-positive cervical cancer. METHODS: We reviewed 198 patients with FIGO stage IB2-IVA cervical cancer, positive PLNs, and negative para-aortic lymph nodes (PALNs) from 2004 to 2015 at two tertiary centers. All patients underwent pelvic radiotherapy (PRT) or SRVRT with IMRT. The SRVRT extended the PRT field cranially to the level of the left renal vein. The prescribed doses were 45-50.4Gy in 1.8Gy per fraction. RESULTS: Overall, 118 and 80 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage, common iliac PLNs, and number of PLNs. The median follow-up was 63months (range: 7-151months). PALN failure was experienced by 28 patients (23.7%) in the PRT group and 1 patient (1.3%) in the SRVRT group (p<0.001). Compared with PRT, SRVRT significantly improved 5-year PALN recurrence-free survival (56.8% vs. 100%, p<0.001) and cancer-specific survival (56.5% vs. 93.9%, p<0.001) among patients with common iliac PLNs or >=3 PLNs. No significant differences were observed in these outcomes among patients with PLNs below the common iliac bifurcation and 1 2 PLNs. The SRVRT did not increase severe toxicities. CONCLUSIONS: Risk-based radiation field based on PLN location and number could optimize outcomes for PLN positive cervical cancer. PMID- 29269218 TI - Temporal and SUMO-specific SUMOylation contribute to the dynamics of Polo-like kinase 1 (PLK1) and spindle integrity during mouse oocyte meiosis. AB - During mammalian meiosis, Polo-like kinase 1 (PLK1) is essential during cell cycle progression. In oocyte maturation, PLK1 expression is well characterized but timing of posttranslational modifications regulating its activity and subcellular localization are less clear. Small ubiquitin-related modifier (SUMO) posttranslational modifier proteins have been detected in mammalian gametes but their precise function during gametogenesis is largely unknown. In the present paper we report for mouse oocytes that both PLK1 and phosphorylated PLK1 undergo SUMOylation in meiosis II (MII) oocytes using immunocytochemistry, immunoprecipitation and in vitro SUMOylation assays. At MII, PLK1 is phosphorylated at threonine-210 and serine-137. MII oocyte PLK1 and phosphorylated PLK1 undergo SUMOylation by SUMO-1, -2 and -3 as shown by individual in vitro assays. Using these assays, forms of phosphorylated PLK1 normalized to PLK1 increased significantly and correlated with SUMOylated PLK1 levels. During meiotic progression and maturation, SUMO-1-SUMOylation of PLK1 is involved in spindle formation whereas SUMO-2/3-SUMOylation may regulate PLK1 activity at kinetochore-spindle attachment sites. Microtubule integrity is required for PLK1 localization with SUMO-1 but not with SUMO-2/3. Inhibition of SUMOylation disrupts proper meiotic bipolar spindle organization and spindle kinetochore attachment. The data show that both temporal and SUMO-specific SUMOylation play important roles in orchestrating functional dynamics of PLK1 during mouse oocyte meiosis, including subcellular compartmentalization. PMID- 29269221 TI - Campaign-Once Again Streptokinase Trials (COAST) in Acute Ischemic Stroke. PMID- 29269220 TI - The Kentucky Appalachian Stroke Registry (KApSR). AB - BACKGROUND: The population of rural Kentucky and West Virginia has a disproportionately high incidence of stroke and stroke risk factors. The Kentucky Appalachian Stroke Registry (KApSR) is a novel registry of stroke patients developed to collect demographic and clinical data in real time from these patients' electronic health records. OBJECTIVE: We describe the development of this novel registry and test it for ability to provide the information necessary to identify care gaps and direct clinical management. METHODS: The KApSR was developed as described in this article. To assess utility in patient care, we developed a "Diabetes Quality Assurance Dashboard" by cross-referencing patients in the registry with a diagnosis of ischemic cerebrovascular disease with patients that were tested for hemoglobin A1c (HbA1c) levels, patients with HbA1c levels diagnostic for diabetes mellitus (DM), and patients with an elevated HbA1c that were formally diagnosed with DM. RESULTS: For the 1008 patients treated for ischemic cerebrovascular disease in the year studied, 859 (85%) had their HbA1c tested. Of those, 281 had levels of 6.5 or greater, although only 261 (93%) were discharged with a formal diagnosis of DM. CONCLUSIONS: The KApSR has practical value as a tool to assess a large population of patients quickly for care quality and for research purposes. PMID- 29269222 TI - Letter to the Editor regarding "Comparison of Rates of Growth between Unruptured and Ruptured Aneurysms Using Magnetic Resonance Angiography". PMID- 29269223 TI - Dengue death tolls: A nightmare for Khyber Pakhtunkhwa, Pakistan. PMID- 29269224 TI - Concurrent prediction of ground reaction forces and moments and tibiofemoral contact forces during walking using musculoskeletal modelling. AB - Ground reaction forces and moments (GRFs and GRMs) measured from force plates in a gait laboratory are usually used as the input conditions to predict the knee joint forces and moments via musculoskeletal (MSK) multibody dynamics (MBD) model. However, the measurements of the GRFs and GRMs data rely on force plates and sometimes are limited by the difficulty in some patient's gait patterns (e.g. treadmill gait). In addition, the force plate calibration error may influence the prediction accuracy of the MSK model. In this study, a prediction method of the GRFs and GRMs based on elastic contact element was integrated into a subject specific MSK MBD modelling framework of total knee arthroplasty (TKA), and the GRFs and GRMs and knee contact forces (KCFs) during walking were predicted simultaneously with reasonable accuracy. The ground reaction forces and moments were predicted with an average root mean square errors (RMSEs) of 0.021 body weight (BW), 0.014 BW and 0.089 BW in the antero-posterior, medio-lateral and vertical directions and 0.005 BW*body height (BH), 0.011 BW*BH, 0.004 BW*BH in the sagittal, frontal and transverse planes, respectively. Meanwhile, the medial, lateral and total tibiofemoral (TF) contact forces were predicted by the developed MSK model with RMSEs of 0.025-0.032 BW, 0.018-0.022 BW, and 0.089-0.132 BW, respectively. The accuracy of the predicted medial TF contact force was improved by 12% using the present method. The proposed method can extend the application of the MSK model of TKA and is valuable for understanding the in vivo knee biomechanics and tribological conditions without the force plate data. PMID- 29269226 TI - Effects of pre- and neonatal undernutrition on the kyphotic response and c-Fos activity in the caudal periaqueductal gray of primiparous lactating Wistar rats. AB - In rodents, the most representative component of maternal behavior that meets the purpose of newborn nutrition is the kyphotic posture. During this posture, the mother maintains a unique environment for the protection, thermal regulation and breast-feeding of the progeny. The aim of this study was to investigate possible deficiencies in the kyphotic posture of adult lactating dams with pre- and neonatal undernutrition evoked by their own pups suckling in a home-cage situation. Wistar dams that had been previously exposed to perinatal undernutrition were mated at 90days of age, and pregnancy was confirmed by vaginal smears. Before testing if the perinatal underfed dam affected behavior, pups were removed (4h), and both the maternal response and the kyphotic posture were video-recorded (1h) and analyzed at 4 and 12days of lactation. Pre- and post test litter weight gain was obtained. To immunostain the caudal periaqueductal gray, the litter was separated from their dams 24h before suckling stimulation. The results showed that underfed dams significantly reduced the duration of high kyphosis by choosing unconventional postures (prone and partial kyphosis). The body weight of the F1 offspring was significantly reduced, and the underfed F0 dams showed reduced c-Fos immunostaining at the caudal periaqueductal gray. The findings showed that early underfed dams have deficiencies in the mechanisms underlying the kyphosis, possibly because the pups' cues to evoke this posture were suboptimal and/or because the dam expressed deficient nursing. The results suggest that the abnormal kyphotic posture may affect the mother-litter bonds and have long-term effects on neonatal brain functions. PMID- 29269225 TI - A surface-based approach to determine key spatial parameters of the acetabulum in a standardized pelvic coordinate system. AB - Accurately determining the spatial relationship between the pelvis and acetabulum is challenging due to their inherently complex three-dimensional (3D) anatomy. A standardized 3D pelvic coordinate system (PCS) and the precise assessment of acetabular orientation would enable the relationship to be determined. We present a surface-based method to establish a reliable PCS and develop software for semi automatic measurement of acetabular spatial parameters. Vertices on the acetabular rim were manually extracted as an eigenpoint set after 3D models were imported into the software. A reliable PCS consisting of the anterior pelvic plane, midsagittal pelvic plane, and transverse pelvic plane was then computed by iteration on mesh data. A spatial circle was fitted as a succinct description of the acetabular rim. Finally, a series of mutual spatial parameters between the pelvis and acetabulum were determined semi-automatically, including the center of rotation, radius, and acetabular orientation. Pelvic models were reconstructed based on high-resolution computed tomography images. Inter- and intra-rater correlations for measurements of mutual spatial parameters were almost perfect, showing our method affords very reproducible measurements. The approach will thus be useful for analyzing anatomic data and has potential applications for preoperative planning in individuals receiving total hip arthroplasty. PMID- 29269227 TI - Site-Seeing: Hereditary Hemorrhagic Telangiectasia with Native-Valve Endocarditis. PMID- 29269228 TI - The Deficit of Nutrition Education of Physicians. AB - Globally, death rates from cardiovascular disease are increasing, rising 41% between 1990 and 2013, and are often attributed, at least in part, to poor diet quality. With urbanization, economic development, and mass marketing, global dietary patterns have become more Westernized to include more sugar-sweetened beverages, highly processed foods, animal-based foods, and fewer fruits and vegetables, which has contributed to increasing cardiovascular disease globally. In this paper, we will examine the trends occurring globally in the realm of nutrition and cardiovascular disease prevention and also present new data that international nutrition knowledge amongst cardiovascular disease providers is limited. In turn, this lack of knowledge has resulted in less patient education and counseling, which is having profound effects on cardiovascular disease prevention efforts worldwide. PMID- 29269229 TI - Central Nervous System Lupus During Pregnancy Accompanied by Hypothermia. PMID- 29269230 TI - Inflammation and Cardiovascular Disease Risk: A Case Study of HIV and Inflammatory Joint Disease. AB - The epidemiologic data associating infection and inflammation with increased risk of cardiovascular disease is well established. Patients with chronically upregulated inflammatory pathways, such as those with HIV and inflammatory joint diseases, often have a risk of future cardiovascular risk that is similar to or higher than patients with diabetes. Thus, it is of heightened importance for clinicians to consider the cardiovascular risk of patients with these conditions. HIV and inflammatory joint diseases are archetypal examples of how inflammatory disorders contribute to vascular disease and provide illustrative lessons that can be leveraged in the prevention of cardiovascular disease. Managing chronic inflammatory diseases calls for a multifaceted approach to evaluation and treatment of suboptimal lifestyle habits, accurate estimation of cardiovascular disease risk with potential upwards recalibration due to chronic inflammation, and more intensive treatment of risk factors because current tools often underestimate the risk in this population. This approach is further supported by the recently published CANTOS trial demonstrating that reducing inflammation can serve as a therapeutic target among persons with residual inflammatory risk for cardiovascular disease. PMID- 29269231 TI - (19alphaH)-lupane and (9betaH)-lanostane triterpenes from Euphorbia helioscopia trigger apoptosis of tumor cell. AB - Chemical investigation of Euphorbia helioscopia resulted in the identification of seven new triterpenes named euphorbatrine A-G (1-7), including two (19alphaH) lupane (1-2) and three (9betaH)-lanostane (4-6), which are very rare metabolites from plants. Their structures were elucidated by extensive spectroscopic analysis, X-ray crystallography and chemical methods. Compounds 5 and 6 triggered apoptosis of Hela-/- cell with EC50 values of 1.59+/-0.25 and 26.48+/-0.78MUM, respectively. PMID- 29269232 TI - Chromanopyrones and a flavone from Hypericum monogynum. AB - Six new compounds, including three pyrone derivatives (2-4), one new flavone (5), and two new naturally-occurring compounds (1 and 6), together with 16 known compounds were isolated from the leaves and twigs of Hypericum monogynum. In addition, compounds 2-4 are racemates. Their structures and absolute configurations were determined on the basis of extensive analysis of spectroscopic data and ECD calculation. All compounds were evaluated for the inhibitory effects on alpha-glucosidase, compounds 1, 5, and 7 showed moderate inhibitory activities with IC50 values of 161.46, 257.78, and 11.54MUg/ml, respectively. Compound 8 exhibited weak anti-oxidant activity with IC50 value of 12.55MUg/ml. PMID- 29269233 TI - An efficient synthesis and antifungal evaluation of natural product streptochlorin and its analogues. AB - Streptochlorin, a small indole alkaloid isolated from marine Streptomyces sp., exhibits a wide range of potent biological activities. An efficient and economic synthetic protocol for streptochlorin has been developed and validated, 4 steps from indole in a total yield of 45%, and further applied for the synthesis of its analogues. Biological testing showed that most of the target compounds exhibited potential antifungal activity in the primary assays, especially compounds 6, 7 and 9c were the most active ones, representing effective activity against the phytopathogenic fungi screened in preliminary test and might be explored for the study of mode of action in the future. PMID- 29269234 TI - New chlorinated diphenyl ethers and xanthones from a deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001. AB - Seven new compounds, including four new chlorinated diphenyl ethers, namely chrysines A-D (1-4), one new dichlorinated xanthone, chrysoxanthone (5), dichloroorcinol (6), and one new benzeneacetic acid derivative, 3-isopentyl-4 hydroxy phenylacetic acid methyl ester (7), along with fourteen known compounds (8-21), were isolated from a deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001. Their structures were determined by extensive spectroscopic methods and X-ray single-crystal diffraction analysis. All of the isolated compounds (1 21) were evaluated for their alpha-glucosidase inhibitory activity using PNPG method. Among them, nine compounds (2, 3, 5, 6, 8, 9, 13, 17, and 18) exhibited inhibitory activity against alpha-glucosidase with IC50 values of 0.35, 0.20, 0.04, 0.16, 0.15, 0.09, 0.14, 0.14, and 0.12mM, respectively (IC50 0.28mM for the positive control acarbose). PMID- 29269235 TI - Antitrypanosomal activity and evaluation of the mechanism of action of diterpenes from aerial parts of Baccharis retusa (Asteraceae). AB - Baccharis retusa, a medicinal Brazilian plant from Asteraceae, has been used in Brazilian folk medicine to treatment of several illnesses, including parasitic diseases. Bioactivity-guided fractionation of the n-hexane extract from the aerial parts of B. retusa resulted in the isolation and characterization of three active related diterpenes: ent-15beta-senecioyl-oxy-kaur-16-en-19-oic acid (1), ent-kaur-16-en-19-oic (2) and ent-16-oxo-17-nor-kauran-19-oic (3) acids. The structures of isolated compounds were defined by spectroscopic analysis, including NMR and HRESIMS. Antitrypanosomal activity of 1-3 was performed against cell-derived trypomastigotes using the colorimetric resazurin assay. The obtained results demonstrated that isolated compounds displayed a reduced toxicity against NCTC cells and were effective against the trypomastigote forms of T. cruzi with IC50 values of 3.8MUM (1), 75.3MUM (2) and 44.2MUM (3). Additionally, compound 3 displayed activity against amastigote forms of T. cruzi with IC50 of 83.2MUM. Compound 1 displayed the highest selectivity index (SI) when considered the trypomastigote forms, and its effect in the plasma membrane of parasite was evaluated using the fluorescent probe SYTOX Green. A considerable permeabilization (57%) in the membrane of the parasite was observed when compared to the untreated trypomastigotes. These data demonstrate, for the first time, the antitrypanosomal activity and mechanism of action of 1 and related compounds 2 and 3, obtained from aerial parts of B. retusa. PMID- 29269236 TI - Synthesis of tigogenin MeON-Neoglycosides and their antitumor activity. AB - To discover new potent cytotoxic steroidal saponins, a series of tigogenin neoglycosides were synthesized via oxyamine neoglycosylation for the first time. The preliminary bioassays for their in vitro antitumor activities against five human cancer cell lines (A375, A-549, HCT-116, HepG2 and MCF-7) were conducted. The results revealed a sugar-dependent activity profile of their cytotoxicity, the glycoconjugation converted the non-active tigogenin to the most potential product Tg29 ((3R)-N-methoxyamino-tigogenin-beta-2-deoxy-d-galactoside) with IC50 value of 2.7MUM and 4.6MUM against HepG2 and MCF-7 cells respectively. And the 3R tigogenin neoglycosides exhibited enhanced antitumor activity while the 3S tigogenin almost showed no activity. Among the five cell lines, HepG2 and MCF-7 cells showed more sensitive cytotoxic responses to the products. Therefore, the neoglycosylation could be a promising strategy for the synthesis of antitumor steroidal saponins and it also proved the essential role of carbohydrate moiety of steroidal saponins in the biological activity. PMID- 29269237 TI - Three-centre evaluation of laboratory Clostridium difficile detection algorithms and the EntericBio(r) realtime C. difficile assay. AB - The comparatively high cost of laboratory detection methods for Clostridium difficile infection (CDI) coupled to a low prevalence rate has resulted in testing algorithms that use cheaper and relatively sensitive screening methods, followed by more specific confirmatory methods. The aim of this prospectively conducted study from two centres in the UK, and one in the Republic of Ireland was to determine the efficacy of the EntericBio(r) realtime C. difficile Assay (EBCD) for the detection of toxigenic C. difficile in stool samples. The EBCD was compared to the in-use testing methods for Clostridium difficile (CD) detection in each centre. In the two UK centres, the EBCD was compared to the C.diff Quik Chek Complete(r) kit (Techlab), and discrepancies were tested further using The Xpert(r)C. difficile PCR assay (Cepheid) and PCR ribotyping after cultivation using the spore culture method, respectively. In the Irish centre, EBCD comparison was to an algorithm of C. DIFF CHEKTM-60 test (Techlab) for screening followed by C. difficile Premier TM Toxins A&B assay (Meridian Bioscience(r)) in the case of positive results; discrepancies were tested using the Xpert(r)C. difficile PCR assay. In a retrospective analysis of data, a total of 947 stool samples were tested, of which eight (0.8%) proved inhibitory to the EBCD assay. Of the 939 valid tests conducted, reported sensitivities of the EBCD were 94.7%, 100% and 97.9%, respectively; specificities were 99.6%, 100% and 100%, respectively; positive predictive values were 94.7%, 100% and 100%, respectively, and negative predictive values were 99.6%, 100% and 99.8%, respectively. The CD positivity rates in the current study ranged between 6.6% and 8.2%. PMID- 29269238 TI - The sheath of Waldeyer is not a specific anatomical trait of the ureterovesical junction. AB - The function of the ureterovesical junction depends upon a peculiar structure, the adventitial fibromuscular sheath of Waldeyer, which coats the distal end of the ureter. The origin of the smooth muscle of Waldeyer's sheath (WS) is disputed. Evidence points more likely to an ureteral one. In this regard we hypothesized the WS is not specific to the distal ureter but is rather a common trait. We therefore aimed at exploring whether or not the proximal ureter is provided with a similar adventitial fibromuscular coat. We performed an immunohistochemical study on human samples of proximal ureter resulted after nephrectomies in ten patients. We applied myoid immunohistochemical markers: alpha-smooth muscle actin (alpha-SMA), desmin, and heavy chain of smooth muscle myosin (SMM) which labeled additional adventitial smooth muscle bundles, a discontinuous inner circular one applied on the muscular coat, and outer longitudinal cords specifically located on one side of the ureter, as is the case for WS. Moreover, the lamina propria myoid deep layer showed isolated smooth muscle fibers and spindle-shaped stromal cells with telocyte morphology. Our results support the idea that WS may not be a specific structure of the distal ureter, instead being just a common anatomical characteristic of the ureter. PMID- 29269239 TI - Emergent coronary angiography post arrest-Do observational studies provide enough evidence for strong recommendations? PMID- 29269240 TI - Exosomes from mesenchymal stromal cells enhance imatinib-induced apoptosis in human leukemia cells via activation of caspase signaling pathway. AB - BACKGROUND AIMS: Imatinib (IM), a tyrosine kinase inhibitor targeting the BCR-ABL oncoprotein, remains a major therapeutic strategy for patients with chronic myelogenous leukemia (CML). However, IM resistance is still a challenge in the treatment of CML. Recently, it was reported that exosomes (Exo) were involved in drug resistance. Therefore, the present study investigated whether Exo secreted by human umbilical cord mesenchymal stromal cells (hUC-MSC-Exo) affected the sensitivity of K562 cells to IM. METHODS: hUC-MSC-Exo were isolated and identified. K562 cells were then treated or not with IM (1 umol/L) in combination with hUC-MSC-Exo (50 ug/mL). Cell viability and apoptosis were determined by cell counting kit 8 (CCK-8) and annexin V/propidium iodide (PI) double staining, respectively. Apoptotic proteins, caspase and their cleaved forms were detected by Western blot. RESULTS: It was shown that hUC-MSC-Exo alone had no effect on cell viability and apoptosis of K562 cells. However, hUC-MSC-Exo promoted IM induced cell viability inhibition and apoptosis. Moreover, hUC-MSC-Exo enhanced the increased Bax expression and the decreased Bcl-2 expression that were induced by IM. Compared with IM alone, caspase-9 and caspase-3 were further activated by combination of hUC-MSC-Exo with IM. Finally, the effects of hUC-MSC-Exo on K562 cells could be reversed by pretreatment of K562 cells with caspase inhibitor Z VAD-FMK (30 umol/L) DISCUSSION: These results indicate that hUC-MSC-Exo enhanced the sensitivity of K562 cells to IM via activation of caspase signaling pathway. Therefore, combining IM with hUC-MSC-Exo could be a promising approach to improve the efficacy of CML treatment. PMID- 29269241 TI - Multiple system atrophy: Building a global community - 30years of advocacy efforts. AB - Multiple system atrophy (MSA) is a rare, progressive and ultimately fatal neurodegenerative disease with no known cause and no available disease modifying treatment. Known previously by various names including Shy-Drager Syndrome, olivopontocerebellar atrophy (OPCA) and striatonigral degeneration, MSA can be classified simultaneously as a movement disorder, an autonomic disorder, a cerebellar ataxia and an atypical parkinsonian disorder. Despite scholarly attempts to better describe the disease, awareness among medical practitioners about multiple system atrophy as a diagnostic possibility has been slow to catch on. As a result, patients often go undiagnosed for many years or are largely misdiagnosed as Parkinson's disease. The non-homogeneous clinical presentation of MSA and years of confusing nomenclature have all contributed to a lack of awareness of the disease among healthcare professionals as well as the public. This lack of awareness has amplified the unmet needs of MSA patients and other stakeholders. Since the 1980s there has been a growing advocacy effort directed at this rare disease from advocacy groups, grassroots supporters, healthcare professionals and research networks. These stakeholders are beginning to unite their efforts and attack the disease from a global perspective in the hopes of improving outcomes for MSA patients in the future. PMID- 29269242 TI - A historical snapshot of Ixodes scapularis-borne pathogens in New Jersey ticks reflects a changing disease landscape. AB - Historical specimens, when available, can provide new insight into the distribution and evolution of pathogens that may not be discernible from more recent samples. We used ticks collected from hunter-killed white-tailed deer in New Jersey in 2002 to examine the prevalence and distribution of four pathogens transmitted by Ixodes scapularis, the blacklegged tick. Infection with Borrelia burgdorferi sensu stricto, Babesia microti, and Anaplasma phagocytophilum (the agents of Lyme disease, human babesiosis, and human granulocytic anaplasmosis, respectively) was highest in the Coastal Plain and lowest in the northwestern Skylands region. These patterns correspond well with the historically observed northward expansion of I. scapularis within New Jersey and the comparatively recent increase in human cases of these pathogens in the northern part of the state. Additionally, we provide evidence that Borrelia miyamotoi, a relatively new emerging pathogen and agent of relapsing fever, was widespread (though not common) throughout the state in 2002. Our findings highlight the need for enhanced awareness of tick-borne diseases other than Lyme and implementation of large-scale tick surveillance in endemic regions. PMID- 29269243 TI - Quality Improvement Project to Increase Patients' Knowledge About Their Impending Procedures During the Consent Process. PMID- 29269244 TI - Comparison Between Manual Auditing and a Natural Language Process With Machine Learning Algorithm to Evaluate Faculty Use of Standardized Reports in Radiology. AB - PURPOSE: When implementing or monitoring department-sanctioned standardized radiology reports, feedback about individual faculty performance has been shown to be a useful driver of faculty compliance. Most commonly, these data are derived from manual audit, which can be both time-consuming and subject to sampling error. The purpose of this study was to evaluate whether a software program using natural language processing and machine learning could accurately audit radiologist compliance with the use of standardized reports compared with performed manual audits. METHODS: Radiology reports from a 1-month period were loaded into such a software program, and faculty compliance with use of standardized reports was calculated. For that same period, manual audits were performed (25 reports audited for each of 42 faculty members). The mean compliance rates calculated by automated auditing were then compared with the confidence interval of the mean rate by manual audit. RESULTS: The mean compliance rate for use of standardized reports as determined by manual audit was 91.2% with a confidence interval between 89.3% and 92.8%. The mean compliance rate calculated by automated auditing was 92.0%, within that confidence interval. CONCLUSION: This study shows that by use of natural language processing and machine learning algorithms, an automated analysis can accurately define whether reports are compliant with use of standardized report templates and language, compared with manual audits. This may avoid significant labor costs related to conducting the manual auditing process. PMID- 29269245 TI - Critical role of ROCK2 activity in facilitating mucosal CD4+ T cell activation in inflammatory bowel disease. AB - Rho-associated kinase (ROCK) has been found to be involved in the pathogenesis of a variety of autoimmune diseases, but the role of ROCK in inflammatory bowel disease (IBD) is still elusive. In this study, we demonstrated that the levels of ROCK2, but not ROCK1, activity were significantly upregulated in peripheral blood mononuclear cells (PBMC) and inflamed mucosa from IBD patients using a ROCK activity assay, and that ROCK2 activity in intestinal mucosa was positively correlated with disease severity. Stimulation with TNF markedly upregulated ROCK2 activity in IBD CD4+ T cells through NF-kappaB signaling. Blockade of ROCK2 activity using Slx-2119 significantly suppressed proinflammatory cytokines in inflamed mucosa from IBD patients including IFX-unresponsive CD patients, and inhibited IBD CD4+ T cells to differentiate into Th1 and Th17 cells through downregulating phosphorylated Stat1 and Stat3, but promoted Treg cell differentiation through upregulating phosphorylated Stat5. Furthermore, oral administration of Slx-2119 markedly ameliorated intestinal mucosal inflammation in TNBS-induced colitis in mice and decreased proinflammatory cytokines productions in inflamed colon. Our data indicate that ROCK2 plays a critical role in inducing mucosal T cell activation and inflammatory responses in IBD and that inhibition of ROCK2 activity might serve as a novel therapeutic approach in the management of IBD. PMID- 29269246 TI - Screening, nutritional optimization and purification for phytase produced by Enterobacter aerogenes and its role in enhancement of hydrocarbons degradation and biofilm inhibition. AB - In this study, a novel isolate of Enterobacter aerogenes isolated from contaminated soils with hydrocarbons had extracellular phytate-degrading activity. Enterobacter aerogenes isolates were identified by biochemical tests and confirmed by16S rRNA gene products (amplified size 211bp) for genotypic detection. The phytase activity was reached to maximum activity when this isolate was cultivated under the optimal conditions which consisted of using minimal salt medium containing 1%(w/v) rice bran as a sole source for carbon and 2% (w/v) yeast extract at pH 5.5 and temperature of 50 degrees C for 48 h. The phytase had purified to homogeneity by 50% ammonium sulphate precipitation, ion exchange and gel filtration chromatography with 75.7 fold of purification and a yield of 30.35%. The purified phytase is a single peptide with approximate molecular mass of 42 kDa as assessed by SDS-PAGE. The highest degradative ability by Enterobacter aerogenes of black oil, white oil and used engine oil had observed after 72 h of incubation. Rapid degradation of black oil and used engine oil had also observed while slow degradation of white oilat all time of incubation. The purified phytase inhibited biofilm formation ability in a dose-dependent manner for all Gram-negative and Gram-positive biofilm-forming bacteria and a significant difference in cell surface hydrophobicity was observed after exposure of planktonic cells to phytase for hour. The hydrolyzing effect of phytase released by Enterobacter aerogenes for complex salts of phosphorus that are insoluble in the soil led to increase of phosphorus concentrations and enhanced the ability of Enterobacter aerogenes to degrade a specific hydrocarbon in contaminated soil so that the phytase has a promising application in bioremediation of contaminated soils with hydrocarbons. PMID- 29269247 TI - Development and validation of a Weight-Specific Health Literacy Instrument (WSHLI). AB - OBJECTIVE: Develop/validate a weight-specific health literacy instrument. METHODS: The development of weight-specific health literacy measurement consisted of seven phases: (a) a literature review; (b) consultation with weight management experts; (c) generation of an item pool; (d) selection of items via the Delphi method; (e) pilot testing; (f) a national survey; and (g) examination of the psychometric properties of the results. RESULTS: A random sample of 362 Taiwanese adults completed the face-toface survey. The results of factor analysis indicated reasonable good fit of a 2-factor model (chi2/df=1.1, p=0.18; RMSEA=0.02, CFI=0.99, TLI=0.99). Construct validity testing showed that the both factors were significantly correlated with s-MHLS (gamma=0.71, p<0.001; gamma=0.22, p<0.001), comprehension (gamma=0.32, p<0.001: gamma=0.10, p<0.05), and writing (gamma=0.44, p<0.001: gamma=0.11, p<0.05). Predictive validity testing showed that the first factor had significant correlations with weight management efficacy (gamma=0.16, p<0.001), and three weight management behaviors. The second factor was significantly correlated with weight management efficacy (gamma=0.11, p<0.05) but not with the 3 weight management behaviors. CONCLUSIONS: On the basis of the psychometric results, we conclude that the final version of Weight-Specific Health Literacy Instrument (WSHLI) includes the 13 items. It is a valid and reliable tool for weight management research and evaluation in Mandarin Chinese speaking populations. PMID- 29269248 TI - Generation and characterization of a fowl adenovirus 9 dual-site expression vector. AB - Fowl adenoviruses (FAdVs) are widely considered as excellent platforms for vaccine development and gene therapy. We improved on our right-end partial TR-2 deleted or a left-end 2.3 kb deleted vectors by developing a single, dual-site delivery vector. We demonstrated that, in addition to ORF11, the right end ORF17 is also dispensable. To further improve the capacity and flexibility of the FAdV 9 based vector system, we generated an infectious recombinant FAdV-9 dual-site expression clone lacking 1.9 kb of the left end and replaced with mCherry under the control of a native promoter, and 3.6 kb of the right-end replaced with an EGFP expression cassette. Five intermediate FAdmid clones were successfully constructed: a) pFAdV-9Delta0-2RED (mCherry replacing the left end 2.2 kb ORF0 to 2); b) pFAdV-9RED (mCherry replacing the left end 1.9 kb ORF1 to 2); c) pFAdV 9Delta17 (deletion of ORF17 and 393 bp downstream untranslated region); d) pFAdV 9GFP (EGFP expression cassette replacing the right end 3.6 kb) and e) pFAdV-9Dual (both mCherry in the left end and the EGFP expression cassette in the right end of our vector). Our novel FAdV-9 dual-site vaccine vector, produced infectious virus and expressed either one or both mCherry and EGFP. PMID- 29269249 TI - Engineering the chloroplast of Chlamydomonas reinhardtii to express the recombinant PfCelTOS-Il2 antigen-adjuvant fusion protein. AB - Malaria is an infectious disease having a large negative impact on economic growth. Vaccines are considered as a novel strategy to reduce the burden of malaria. Malaria parasite has a complex life cycle and attempts are being made to develop vaccines that target each stage of the life cycle. Oral vaccines seem to be more feasible to implement in poor countries, since they are relatively inexpensive, needle-free administrated, mostly stable at non-refrigerated conditions and painless. By using recombinant technology, suitable oral hosts could serve as antigen delivering vehicles in developing oral vaccines. Chlamydomonas reinhardtii offers beneficial attributes as oral recombinant protein expression platform. Moreover, C. reinhardtii chloroplast is an attractive platform for expressing malaria antigens because it is capable of folding complex proteins, including those requiring disulfide bond formation, while lacking the ability to glycosylate proteins; a valuable quality of any malaria protein expression system, since the Plasmodium parasite lacks N-linked glycosylation machinery. As a first step towards developing an oral vaccine candidate against malaria, here, we expressed a fusion protein consisting of PfCelTOS, a candidate for pre-erythrocytic and transmission-blocking vaccines, fused to human interleukin-2 (IL-2) as vaccine adjuvant in the chloroplast of C. reinhardtii. The effect of light and media on recombinant protein production and cell growth was then studied. Results demonstrated that expressed recombinant proteins accumulate as a soluble, properly folded and functional protein within algal chloroplasts. Moreover, results showed that the highest cell density can be achieved using mixotrophy mode. However, protein accumulation appears to be favored by cultivating in TAP medium in low light. PMID- 29269250 TI - Surgical outcomes following rectus muscle plication versus resection combined with antagonist muscle recession for basic horizontal strabismus. AB - PURPOSE: To evaluate change in ocular alignment and surgical success of rectus muscle plication versus resection when coupled with antagonist muscle recession for basic esodeviations and exodeviations. METHODS: The medical records of consecutive patients with basic horizontal strabismus who underwent a rectus muscle plication or resection combined with a known amount of antagonist muscle recession from January 2009-June 2016 by one surgeon were reviewed retrospectively. Changes in ocular alignment and surgical success at 4-16 weeks after surgery and reoperation rates for plication compared to resection were assessed. Success was defined as undercorrection of <=10Delta and overcorrection of <=4Delta at distance. RESULTS: A total of 162 patients with basic esotropia (88 lateral rectus muscle plications; 74 lateral rectus resections) and 60 patients with basic exotropia (31 medial rectus muscle plications; 29 medial rectus resections) were included. Success rates at 4-16 weeks after surgery were 95.5% for lateral rectus plication, 89.2% for lateral rectus resection, 77.4% for medial rectus plication, and 96.6% for medial rectus resection. No significant differences were found when analyzing the change in ocular alignment between the plication and resection groups for patients with either basic esotropia or basic exotropia. Reoperation rates were low for all groups (range, 3.2%-5.4%) during a follow-up period of 4 weeks to 72 months. CONCLUSIONS: Horizontal rectus muscle plication produced similar changes in ocular alignment and surgical success compared to rectus muscle resection at 4-16 weeks after surgery when coupled with comparable amounts of antagonist muscle recession. PMID- 29269251 TI - The emerging role of obesity in short-acting hormonal contraceptive effectiveness. PMID- 29269252 TI - Factors associated with nonadherence to instructions for using the Nestorone(r)/ethinyl estradiol contraceptive vaginal ring. AB - OBJECTIVES: We sought to identify factors associated with nonadherence to instructions for using a novel contraceptive providing 1 year of protection. STUDY DESIGN: Data from a multicountry Phase 3 trial of the Nestorone(r) (segesterone acetate)/ethinyl estradiol (NES/EE) contraceptive vaginal ring (CVR) were analyzed. Participants were instructed to use the CVR over 13 cycles and follow a 21/7 regimen. Their reports of CVR removals >2 h outside scheduled removal periods served as a proxy for nonadherence. We used multivariate logistic regression to determine factors associated with such use. RESULTS: Of 905 participants, 120 (13%) reported CVR removals >2 h. Removals for washing [odds ratio (OR) 3.96, 95% confidence interval (CI) 2.50-6.27] or sexual intercourse (OR 3.19, 95% CI 2.03-4.99), and finding CVR insertion difficult (OR 2.80, 95% CI 1.36-5.80) were factors associated with removals >2 h. Lower educational attainment also predicted ring removal >2 h (OR 3.23, 95% CI 1.55-6.75). Women residing in Europe or Australia were less likely to remove the ring for >2 h compared with women in the United States (OR 0.44, 95% CI 0.24-0.83 and OR 0.13, 95% CI 0.02-0.98, respectively). Participants who reported removals >2 h were more likely to discontinue CVR use (OR 1.93, 95% CI 1.24-2.95), report dissatisfaction (OR 2.20, 95% CI 1.32-3.69) and become pregnant during the study (OR 4.07, 95% CI 1.58-10.50). CONCLUSIONS: Removing the CVR for washing and removing it before intercourse are factors associated with nonadherence to ring use. These are important topics for counseling women who are considering or using vaginal rings, including the NES/EE CVR. IMPLICATIONS: Findings from this study may be useful in guiding counseling for current and prospective vaginal ring users. Anticipatory guidance should focus on how the ring feels in the vagina and during sex. Asking about ring removals may help identify women who are at increased risk for having an unplanned pregnancy. PMID- 29269253 TI - Podophyllotoxin derivatives as an excellent anticancer aspirant for future chemotherapy: A key current imminent needs. AB - Cancer is one of the leading groups of threatened caused by abnormal state cell growth and second leading diseases involved in the major global death. To treat this, research looking for promising anticancer drugs from natural resource, or synthesized novel molecules by diverse group of scientists worldwide. Currently, drugs get into clinical practices and showing side effects with target actions which in turn leading to multidrug resistance unknowingly. Podophyllotoxin, a naturally occurring lignan and with hybrids have become one of the most attractive subjects due to their broad spectrum of pharmacological activities. Podophyllotoxin derivatives have been the centre of attention of extensive chemical amendment and pharmacological investigation in modern decades. Mainly, the innovation of the semi-synthetic anticancer drugs etoposide and teniposide has stimulated prolonged research interest in this structural phenotype. The present review focuses mainly onnew anticancer drugs from podophyllotoxin analogs, mechanism of action and their structure-activity relationships (SAR) as potential anticancer candidates for future discovery of suitable drug candidates. PMID- 29269254 TI - Bombesin/oligoarginine fusion peptides for gastrin releasing peptide receptor (GRPR) targeted gene delivery. AB - The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin peptide ligand (BBN(6-14)), to selectively target the gastrin releasing peptide receptor (GRPR); oligoarginine peptides (hexa- (R6) and nona-arginine (R9)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6-14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3. PMID- 29269255 TI - Immunoproteasome inhibition and bioactivity of thiasyrbactins. AB - A family of macrodilactam natural products, the syrbactins, are known proteasome inhibitors. A small group of syrbactin analogs was prepared with a sulfur-for carbon substitution to enhance synthetic accessibility and facilitate modulation of their solubility. Two of these compounds surprisingly proved to be inhibitors of the trypsin-like catalytic site, including of the immunoproteasome. Their bound and free conformations suggest special properties of the thiasyrbactin ring are responsible for this unusual preference, which may be exploited to develop drug-like immunoproteasome inhibitors. These compounds show greater selectivity than earlier compounds used to infer phenotypes of immunoproteasome inhibition, like ONX-0914. PMID- 29269256 TI - 5-HT1A and 5-HT2A receptors affinity, docking studies and pharmacological evaluation of a series of 8-acetyl-7-hydroxy-4-methylcoumarin derivatives. AB - In this work we describe the synthesis, docking studies and biological evaluation of a focused library of novel arylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4 methylcoumarin. The new compounds were screened for their 5-HT1A and 5-HT2A receptor affinity. Among the evaluated compounds, six displayed high affinities to 5-HT1A receptors (4a-0.9 nM, 6a-0.5 nM, 10a-0.6 nM, 3b-0.9 nM, 6b-1.5 nM, 10b 1 nM). Compound 6a and 10a bearing a bromo- or methoxy- substituent in ortho position of the piperazine phenyl ring, were identified as potent antagonists of the 5-HT1A receptors. In the tail suspension test, mice injected with 6a showed a dose-dependent increase in depressive-like behavior that was related to a decrease in locomotor activity. Compound 10a did not decrease or prolong immobility time nor did it affect home cage activity. Molecular docking studies using 5-HT1A and 5-HT2A homology models revealed structural basis of the high affinity of ortho-substituted derivatives and subtle changes in amino acid interactions patterns depending on the length of the alkyl linker. PMID- 29269257 TI - Multifocal occurrence of intraoral isolated MS in a patient without leukemic presentation: A case report and literature review. AB - Myeloid sarcoma (MS), also referred to as chloroma or granulocytic sarcoma, is a rare extramedullary malignant tumor composed of immature myeloid cells. MS usually occurs with acute myelocytic leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome or as a recurrence of acute myelocytic leukemia; however, MS may occasionally present as isolated, without current or previous peripheral blood or bone marrow involvement. Oral and maxillofacial MS, especially isolated, is extremely rare, and the clinical manifestations are diverse and usually nonspecific. Here, we report a rare case of isolated nonleukemic MS involving the gingivae, the mucosa of the left maxillary edentulous region, and the adjacent hard palate. The pertinent literature was also reviewed to provide additional clarification on the clinicopathologic characteristics, differential diagnosis, treatment regimens, and prognosis of oral and maxillofacial isolated MS. PMID- 29269258 TI - Differential expression of STAT-3 in subtypes of oral lichen planus: a preliminary study. AB - OBJECTIVE: This study aimed to examine the expression of signaling transduction proteins and their possible correlation with different clinical subtypes of oral lichen planus (OLP). STUDY DESIGN: We examined the immunoexpression and phosphorylation status of 21 signaling transduction proteins of OLP (n = 10) and normal groups (n = 8) using PathScan analysis. Using immunohistochemistry, we detected expression of STAT-3 and p38 MAPK in tissues of OLP (n = 40) and normal controls (n = 10). RESULTS: PathScan analysis showed that STAT-3 (Ser727) expression in normal control (N), reticular OLP (R-OLP) and erosive OLP (E-OLP) group was gradually elevated (R-OLP vs N, P = .001; E-OLP vs N, P < .001; E-OLP vs R-OLP, P = .002). Immunohistochemistry showed that STAT-3 expression in the epithelium of normal control, reticular OLP and erosive OLP was consistent with PathScan analysis (R-OLP vs N, P < .001; E-OLP vs N, P < .001; E-OLP vs R-OLP, P = .036). Both PathScan (P = .012) and immunohistochemistry (P < .001) showed that, p38 MAPK expression was significantly higher in OLP compared with normal controls. However, a significant difference was not seen between the reticular OLP and erosive OLP groups. CONCLUSIONS: Our results indicate that STAT-3 may be involved in OLP development and progression and account for different clinical manifestations. PMID- 29269259 TI - Thermosensitive chitosan/phosphate hydrogel-composites fortified with Ag versus Ag@Pd for biomedical applications. AB - INTRODUCTION: Thermo-responsive hydrogels are promising biomedical systems as their gelation is triggered by temperature changes. Greenly synthesized noble metallic nanoparticles are a growing research area assessing their potential applications in nanomedicine. MATERIALS AND METHODS: Chitosan/phosphate thermosensitive gels were successfully achieved. The developed composite scaffolds were functionalized with the greenly synthesized Ag or Ag@Pd targeting improved bactericidal activity and biocompatibility performance. The physicochemical characterization was assessed through TGA, DSC, FESEM, HRTEM, XRD and FTIR. Bactericidal activities were tested against gram- positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa. Their biodegradability upon DMEM immersion was followed up to seven days through measuring ionic concentrations of Ca, P, Ag and Pd successively. KEY FINDINGS: The newly developed phosphatic layers over the scaffold surfaces post-immersion assessed their osteogenic ability. Further, their promising and differentiated bactericidal activities due to the noble metals incorporation were proved. Cytotoxicity assessment demonstrated their high biocompatibility since no toxic effect was recorded. SIGNIFICANCE: Consequently, they can be successfully and directly applied in biomedical and dental surgeries. PMID- 29269260 TI - Peptidyl-prolyl isomerase Pin1 deficiency attenuates angiotensin II-induced abdominal aortic aneurysm formation in ApoE-/- mice. AB - Peptidyl-prolyl isomerase Pin1 has been reported to be associated with endothelial dysfunction. However, the role of smooth muscle Pin1 in the vascular system remains unclear. Here, we examined the potential function of Pin1 in smooth muscle cells (SMCs) and its contribution to abdominal aortic aneurysm (AAA) pathogenesis. The level of Pin1 expression was found to be elevated in human AAA tissues and mainly localized to SMCs. We constructed smooth muscle specific Pin1 knockout mice to explore the role of this protein in AAA formation and to elucidate the underlying mechanisms. AAA formation and elastin degradation were hindered by Pin1 depletion in the angiotensin II-induced mouse model. Pin1 depletion reversed the angiotensin II-induced pro-inflammatory and synthetic SMC phenotype switching via the nuclear factor (NF)-kappaB p65/Klf4 axis. Moreover, Pin1 depletion inhibited the angiotensin II-induced matrix metalloprotease activities. Mechanically, Pin1 deficiency destabilized NF-kappaB p65 by promoting its polyubiquitylation. Further, we found STAT1/3 bound to the Pin1 promoter, revealing that activation of STAT1/3 was responsible for the increased expression of Pin1 under angiotensin II stimulation. Thus, these results suggest that Pin1 regulates pro-inflammatory and synthetic SMC phenotype switching and could be a novel therapeutic target to limit AAA pathogenesis. PMID- 29269261 TI - Reassessing the Role of Hox Genes during Vertebrate Development and Evolution. AB - Since their discovery Hox genes have been at the core of the established models explaining the development and evolution of the vertebrate body plan as well as its paired appendages. Recent work brought new light to their role in the patterning processes along the main body axis. These studies show that Hox genes do not control the basic layout of the vertebrate body plan but carry out region specific patterning instructions loaded on the derivatives of axial progenitors by Hox-independent processes. Furthermore, the finding that Hox clusters are embedded in functional chromatin domains, which critically impacts their expression, has significantly altered our understanding of the mechanisms of Hox gene regulation. This new conceptual framework has broadened our understanding of both limb development and the evolution of vertebrate paired appendages. PMID- 29269262 TI - Translocator protein (18kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy. AB - Prior studies indicated that neuroinflammation might play a role in the pathophysiology of major depressive disorder (MDD). The purpose of this study was to examine changes in a microglial marker in the brain of patients with MDD during cognitive-behavioral therapy (CBT) and supportive psychotherapy (SPT). Participants were newly diagnosed patients with MDD receiving CBT (n=20) or SPT (n=20) who were compared with 20 healthy control subjects. We used [18F]-FEPPA positron emission tomography (PET) to examine translocator protein total distribution volume (TSPO VT), a marker of microglial density and inflammation. Patients were scanned before and after CBT and SPT. Before therapy, TSPO VT was significantly elevated in neocortical grey matter, frontal cortex, temporal cortex, and hippocampus in MDD relative to the control subjects. In the CBT group, but not in the SPT group, TSPO VT was significantly reduced during the treatment period. Reductions in TSPO VT were correlated with the amelioration of depressive symptoms. This correlation was consistent in the hippocampus in both CBT and SPT groups. In conclusion, CBT, when it reduced symptoms, also decreased TSPO VT. Efficient psychosocial interventions were accompanied by the normalization of a glial marker in the brain of patients with MDD, which may indicate reduced pro-inflammatory activity. PMID- 29269263 TI - Improved detectability of sex steroids from frozen sections of breast cancer tissue using GC-triple quadrupole-MS. AB - Sex steroids in clinical endocrinology have been mainly investigated with peripheral blood and urine samples, while there is limited information regarding the local levels within tissues. To improve analytical properties of sex steroids from trace amounts of tissue samples, two-phase extractive ethoxycarbonlyation and subsequent pentafluoropropionyl derivatization coupled to gas chromatography tandem mass spectrometry (GC-MS/MS) was developed. The optimized analytical conditions led to excellent chromatographic separation of 15 estrogens, 6 androgens, and 2 progestins. The quantitative results were calculated based on in house control samples as the steroid-free tissues, and the precision and accuracy were 4.2%-26.8% and 90.8%-116.4%, respectively. The on-column limit of quantification was from 180 fg to 0.5 pg for androgens and estrogens, and 1.25 pg for progestins, which were found to be linear (r2 > 0.990). The validated method was then applied to quantify 7 sex steroids from three 100-MUm-thick frozen breast tissue slices from postmenopausal patients with breast cancer. This is the first report on the improved GC-MS/MS method for the detection of androgens and pregnenolone from breast cancer tissues, and it can be a useful technique to measure the local levels of sex steroids, thus, enhancing our understanding of the pathophysiological significances of steroidogenesis. PMID- 29269264 TI - Peptidoglycan recognition proteins in hematophagous arthropods. AB - Hematophagous arthropods are medically important disease vectors that transmit a variety of pathogens. Unlike mammals that employ both innate and adaptive immunity to clear invading pathogens, these vectors rely mainly on an innate immune system to combat pathogens. Peptidoglycan recognition proteins (PGRPs) are important components of innate immune signaling pathways and are responsible for recognizing microbe-associated molecular patterns (MAMPs), thus regulating host immune interactions with both harmful and helpful microbes. Here we review a number of recent studies in different vectors that address the function of PGRPs in immune regulation. Further, we discuss the variation of PGRPs between vectors and Drosophila. PMID- 29269265 TI - Shared motherhood IVF: high delivery rates in a large study of treatments for lesbian couples using partner-donated eggs. AB - Shared motherhood IVF treatment is becoming increasingly accepted among assisted reproductive techique practitioners and patients in Europe, although data on its overall efficiency remain scarce. This 6-year retrospective study from a single, private, UK HFEA-regulated centre included consecutive lesbian couples (n = 121) undergoing shared motherhood IVF treatment (141 cycles). Recipients were more parous and had undergone more previous intrauterine insemination and IVF treatments than donor partners, who had slightly higher ovarian reserve markers than recipients. Indications in most cycles (60%) were non-medical. Most (79%) egg-providers were stimulated with gonadotrophin releasing hormone antagonist protocol, and no moderate or severe cases of ovarian hyperstimulation syndrome (OHSS) arose. A total of 172 fresh and vitrified-warmed embryo transfers were carried out: 70% at the blastocyst-stage and 58% involved a single embryo. Cumulative live birth rate per receiver was 60% (72/120), and twin delivery rate was 14% (10/72). Perinatal outcome parameters were better for singleton than twin pregnancies, although the latter also achieved generally favourable outcomes. No significant difference in cumulative outcomes were found between synchronized and non-synchronized cycles. Shared motherhood IVF combines ovarian stimulation with single blastocyst transfer to provide a safe and effective treatment modality offering reassuring obstetrical and perinatal outcomes. PMID- 29269266 TI - Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L malate:quinone oxidoreductase, a potential drug target. AB - Plasmodium falciparum is an apicomplexan parasite that causes the most severe malaria in humans. Due to a lack of effective vaccines and emerging of drug resistance parasites, development of drugs with novel mechanisms of action and few side effects are imperative. To this end, ideal drug targets are those essential to parasite viability as well as absent in their mammalian hosts. The mitochondrial electron transport chain (ETC) of P. falciparum is one source of such potential targets because enzymes, such as L-malate:quinone oxidoreductase (PfMQO), in this pathway are absent humans. PfMQO catalyzes the oxidation of L malate to oxaloacetate and the simultaneous reduction of ubiquinone to ubiquinol. It is a membrane protein, involved in three pathways (ETC, the tricarboxylic acid cycle and the fumarate cycle) and has been shown to be essential for parasite survival, at least, in the intra-erythrocytic asexual stage. These findings indicate that PfMQO would be a valuable drug target for development of antimalarial with novel mechanism of action. Up to this point in time, difficulty in producing active recombinant mitochondrial MQO has hampered biochemical characterization and targeted drug discovery with MQO. Here we report for the first time recombinant PfMQO overexpressed in bacterial membrane and the first biochemical study. Furthermore, about 113 compounds, consisting of ubiquinone binding site inhibitors and antiparasitic agents, were screened resulting in the discovery of ferulenol as a potent PfMQO inhibitor. Finally, ferulenol was shown to inhibit parasite growth and showed strong synergism in combination with atovaquone, a well-described anti-malarial and bc1 complex inhibitor. PMID- 29269268 TI - The impact of mechanically stimulated muscle-derived stromal cells on aged skeletal muscle. AB - Perivascular stromal cells, including mesenchymal stem/stromal cells (MSCs), secrete paracrine factor in response to exercise training that can facilitate improvements in muscle remodeling. This study was designed to test the capacity for muscle-resident MSCs (mMSCs) isolated from young mice to release regenerative proteins in response to mechanical strain in vitro, and subsequently determine the extent to which strain-stimulated mMSCs can enhance skeletal muscle and cognitive performance in a mouse model of uncomplicated aging. Protein arrays confirmed a robust increase in protein release at 24h following an acute bout of mechanical strain in vitro (10%, 1Hz, 5h) compared to non-strain controls. Aged (24month old), C57BL/6 mice were provided bilateral intramuscular injection of saline, non-strain control mMSCs, or mMSCs subjected to a single bout of mechanical strain in vitro (4*104). No significant changes were observed in muscle weight, myofiber size, maximal force, or satellite cell quantity at 1 or 4wks between groups. Peripheral perfusion was significantly increased in muscle at 4wks post-mMSC injection (p<0.05), yet no difference was noted between control and preconditioned mMSCs. Intramuscular injection of preconditioned mMSCs increased the number of new neurons and astrocytes in the dentate gyrus of the hippocampus compared to both control groups (p<0.05), with a trend toward an increase in water maze performance noted (p=0.07). Results from this study demonstrate that acute injection of exogenously stimulated muscle-resident stromal cells do not robustly impact aged muscle structure and function, yet increase the survival of new neurons in the hippocampus. PMID- 29269267 TI - Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III. AB - A marked stimulation of complex II enzymatic activity was detected in cybrids bearing a homoplasmic MTCYB microdeletion causing disruption of both the activity and the assembly of complex III, but not in cybrids harbouring another MTCYB mutation affecting only the complex III activity. Moreover, complex II stimulation was associated with SDHA subunit tyrosine phosphorylation. Despite the lack of detectable hydrogen peroxide production, up-regulation of the levels of mitochondrial antioxidant defenses revealed a significant redox unbalance. This effect was also supported by the finding that treatment with N acetylcysteine dampened the complex II stimulation, SDHA subunit tyrosine phosphorylation, and levels of antioxidant enzymes. In the absence of complex III, the cellular amount of succinate, but not fumarate, was markedly increased, indicating that enhanced activity of complex II is hampered due to the blockage of respiratory electron flow. Thus, we propose that complex II phosphorylation and stimulation of its activity represent a molecular mechanism triggered by perturbation of mitochondrial redox homeostasis due to severe dysfunction of respiratory complexes. Depending on the site and nature of the damage, complex II stimulation can either bypass the energetic deficit as an efficient compensatory mechanism, or be ineffectual, leaving cells to rely on glycolysis for survival. PMID- 29269269 TI - Deep Convolutional Neural Network Analysis of Flow Imaging Microscopy Data to Classify Subvisible Particles in Protein Formulations. AB - Flow-imaging microscopy (FIM) is commonly used to characterize subvisible particles in therapeutic protein formulations. Although pharmaceutical companies often collect large repositories of FIM images of protein therapeutic products, current state-of-the-art methods for analyzing these images rely on low dimensional lists of "morphological features" to characterize particles that ignore much of the information encoded in the existing image databases. Deep convolutional neural networks (sometimes referred to as "CNNs or ConvNets") have demonstrated the ability to extract predictive information from raw macroscopic image data without requiring the selection or specification of "morphological features" in a variety of tasks. However, the inherent heterogeneity of protein therapeutics and optical phenomena associated with subvisible FIM particle measurements introduces new challenges regarding the application of ConvNets to FIM image analysis. We demonstrate a supervised learning technique leveraging ConvNets to extract information from raw images in order to predict the process conditions or stress states (freeze-thawing, mechanical shaking, etc.) that produced a variety of different protein particles. We demonstrate that our new classifier, in combination with a "data pooling" strategy, can nearly perfectly differentiate between protein formulations in a variety of scenarios of relevance to protein therapeutics quality control and process monitoring using as few as 20 particles imaged via FIM. PMID- 29269270 TI - A Measurement and Modeling Study of Hair Partition of Neutral, Cationic, and Anionic Chemicals. AB - Various neutral, cationic, and anionic chemicals contained in hair care products can be absorbed into hair fiber to modulate physicochemical properties such as color, strength, style, and volume. For environmental safety, there is also an interest in understanding hair absorption to wide chemical pollutants. There have been very limited studies on the absorption properties of chemicals into hair. Here, an experimental and modeling study has been carried out for the hair-water partition of a range of neutral, cationic, and anionic chemicals at different pH. The data showed that hair-water partition not only depends on the hydrophobicity of the chemical but also the pH. The partition of cationic chemicals to hair increased with pH, and this is due to their electrostatic interaction with hair increased from repulsion to attraction. For anionic chemicals, their hair-water partition coefficients decreased with increasing pH due to their electrostatic interaction with hair decreased from attraction to repulsion. Increase in pH did not change the partition of neutral chemicals significantly. Based on the new physicochemical insight of the pH effect on hair-water partition, a new quantitative structure property relationship model has been proposed, taking into account of both the hydrophobic interaction and electrostatic interaction of chemical with hair fiber. PMID- 29269271 TI - Evaluation of Hydrogen Exchange Mass Spectrometry as a Stability-Indicating Method for Formulation Excipient Screening for an IgG4 Monoclonal Antibody. AB - Antibodies are molecules that exhibit diverse conformational changes on different timescales, and there is ongoing interest to better understand the relationship between antibody conformational dynamics and storage stability. Physical stability data for an IgG4 monoclonal antibody (mAb-D) were gathered through traditional forced degradation (temperature and stirring stresses) and accelerated stability studies, in the presence of different additives and solution conditions, as measured by differential scanning calorimetry, size exclusion chromatography, and microflow imaging. The results were correlated with hydrogen exchange mass spectrometry (HX-MS) data gathered for mAb-D in the same formulations. Certain parameters of the HX-MS data, including hydrogen exchange in specific peptide segments in the CH2 domain, were found to correlate with stabilization and destabilization of additives on mAb-D during thermal stress. No such correlations between mAb physical stability and HX-MS readouts were observed under agitation stress. These results demonstrate that HX-MS can be set up as a streamlined methodology (using minimal material and focusing on key peptide segments at key time points) to screen excipients for their ability to physically stabilize mAbs. However, useful correlations between HX-MS and either accelerated or real-time stability studies will be dependent on a particular mAb's degradation pathway(s) and the type of stresses used. PMID- 29269272 TI - Sacrococcygeal Teratoma Presenting with Vaginal Discharge and Polyp in an Infant. AB - BACKGROUND: Sacrococcygeal teratoma accounts for the most common solid tumor in neonates. Because of improved technology, 50%-70% of cases can be diagnosed antenatally during routine ultrasound screenings. If not diagnosed antenatally, clinical findings at birth are distinct in most cases including a palpable or visible mass. CASE: We report an unusual case of a 1-year-old girl who presented with persistent vaginal discharge leading to diagnosis of a mucosal polypoid lesion of the vagina, ultimately revealing a hidden sacrococcygeal teratoma. SUMMARY AND CONCLUSION: We suggest thorough investigation of all infants who present with purulent discharge and recurrent vaginal mass; sacrococcygeal teratoma should routinely be considered as a differential diagnosis. PMID- 29269273 TI - Direct Leverage for Reducing the Femoral Head in Total Hip Arthroplasty Without Femoral Shortening Osteotomy for Crowe Type 3 to 4 Dysplasia of the Hip. AB - BACKGROUND: A number of methods for reduction in high hip dislocation in total hip arthroplasty (THA) are time-consuming and laborious, and require great surgical skills. This study aimed to introduce a new reduction technique to achieve rapid, safe, and easy reduction in high hip dislocation. METHODS: We retrospectively reviewed 74 THA patients (82 hips; 44 women, 30 men) with severe hip dysplasia who underwent direct leverage using a Hohmann retractor into the anatomical acetabulum without femoral shortening osteotomy between September 2007 and January 2014. Forty-nine hips were classified as Crowe III and 33 hips were classified as Crowe IV. The mean follow-up period was 5.1 years (range 2-8). RESULTS: Mean Harris Hip Score increased from 42.1 (range 24-71) before surgery to 89.9 (range 76-100) at final follow-up examination. The legs were lengthened by a mean of 3.0 cm (range 1.1-5.5) and 2.5 cm (range 1.1-3.5) in Crowe III hips and 3.6 cm (range 1.9-5.5) in Crowe IV hips postoperatively. The average leg length discrepancy at the final follow-up examination was 0.4 cm (standard deviation 0.5 cm). One greater trochanteric fracture occurred during the hip reduction process. One patient developed femoral nerve palsies and recovered completely at 3 weeks postoperatively. CONCLUSION: Direct leverage using the Hohmann retractor for the reduction in high hip dislocation in THA without femoral shortening osteotomy is simple, safe, and effective. PMID- 29269274 TI - Engineered cell and tissue models of pulmonary fibrosis. AB - Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3years' post-diagnosis. Treatments for IPF are limited to two FDA approved drugs, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis. PMID- 29269275 TI - Standardization of immunotherapy adverse events in patient information leaflets and development of an interface terminology for outpatients' monitoring. AB - INTRODUCTION: Immunotherapy is effective for treating cancer, but it is also associated with a wide spectrum of adverse events. In order to detect them early, the patients need to be monitored at home, between the therapy administrations, e.g., by asking them to report outcomes, usually including symptoms and quality of life measures. For the collected data to be reusable, the symptoms need to be in a standardized form. The aim of this study is to explore the standardization of the information contained in the patient information leaflets (PILs) of immunotherapy drugs, by creating an interface terminology of immunotherapy related adverse events, which should support a consistent collection of symptoms from the patients. METHODS: PILs contain a significant amount of information in free text, but they mix patient-reportable and clinically assessable events. We extracted a list of patient-reportable adverse events, mapped them to reference terminologies and compared the mapping results to choose the best-performing reference terminology. RESULTS: The PILs standardization led to the extraction of 151 symptoms and 424 terms, including both preferred terms and synonyms in English and Italian. Among the reference terminologies we considered, SNOMED CT allowed us to map all concepts and became, hence, the main reference terminology for the resulting interface terminology. A preliminary validation on the PIL of a new immunotherapy drug showed that our interface terminology already contained all the mentioned symptoms. CONCLUSION: PILs provide a valuable source for determining adverse events. The resulting interface terminology includes Italian and English terms for patient-reportable adverse events for five immunotherapy drugs representative of their category. Further work will be undertaken to evaluate the usability of the interface terminology and the patients' experience and satisfaction with the proposed terms, made available for example through an app, as well as its effectiveness on data quality and quality of care. PMID- 29269276 TI - The Japanese Angelica acutiloba root and yokukansan increase hippocampal acetylcholine level, prevent apoptosis and improve memory in a rat model of repeated cerebral ischemia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Japanese Angelica acutiloba root (Angelica root) is included in several Kampo medicines including Yokukansan (YKS). Angelica root and YKS are used for the treatment of a variety of psychological and neurodegenerative disorders. Development of safe and effective therapeutic agents against cerebrovascular disorders will improve the treatment of patients with dementia. AIM OF THE STUDY: The effect of Angelica root and YKS on ischemia impaired memory has not yet been fully investigated. The present study investigated whether Angelica root is also involved in memory improving and neuroprotective effect of YKS in a model of cerebrovascular ischemia. MATERIALS AND METHODS: Male Wistar rats grouped into sham rats received saline, and other three groups subjected to repeated cerebral ischemia induced by 4-vessel occlusion (4-VO), received a 7-day oral administration of either saline, Angelica root or YKS. Memory was evaluated by eight-arm radial maze task. Acetylcholine release (ACh) in the dorsal hippocampus was investigated by microdialysis-HPLC. Apoptosis was determined by terminal deoxynucleotidyl transferase (TdT)-mediated fluorescein-deoxyuridine triphosphate (dUTP) nick-end labeling. RESULTS: Ischemia induced apoptosis, reduced release of ACh, and impaired the memory (increased error choices and decreased correct choices). Angelica root and YKS improved the memory deficits, upregulated the release of ACh and prevented 4-VO-induced hippocampal apoptosis. CONCLUSION: The dual ACh-increasing and neuroprotective effect of Angelica root could make it a promising therapeutic agent useful for the treatment of symptoms of cerebrovascular dementia. Angelica root could be one of the components contributing to the memory-improving and neuroprotective effects of YKS. PMID- 29269277 TI - Comprehensive Genomic Profiling of Malignant Effusions in Patients with Metastatic Lung Adenocarcinoma. AB - Cytology samples are increasingly used for comprehensive molecular testing. Although fine-needle aspirates are adequate substrates for high-throughput sequencing, the suitability of malignant body fluids remains largely unexplored. We investigated the adequacy and utility of performing targeted next-generation sequencing (NGS) on malignant effusions from patients with metastatic lung adenocarcinoma. Thirty-two effusion samples submitted for hybrid capture-based NGS using a clinically validated solid tumor genotyping panel were examined. All cases showed >=5% tumor cellularity; however, 28 (88%) provided sufficient DNA for NGS (>=1 ng/MUL). The sequencing reads showed satisfactory quality control statistics, and the variant allele frequencies were correlated with tumor cellularity. Furthermore, pathogenic or likely pathogenic genomic alterations were identified in 26 of 28 samples (93%), whereas clinically actionable alterations were present in 18 (64%). Notably, nine patients had additional molecular testing performed on preceding or subsequent biopsy specimens, and the results across multiple samples were compared. In two patients, the NGS-based fluid analysis identified clinically actionable alterations that were not detected by other hotspot testing. In four patients treated with tyrosine kinase inhibitors, malignant fluid sequencing confirmed driver alterations from prior testing and revealed new resistance mechanisms. Hence, given adequate DNA input and tumor cellularity, comprehensive genomic profiling of malignant effusions may be used to establish mutational status at diagnosis and inform treatment resistance during targeted therapy. PMID- 29269278 TI - The History and Impact of Molecular Coding Changes on Coverage and Reimbursement of Molecular Diagnostic Tests: Transition from Stacking Codes to the Current Molecular Code Set Including Genomic Sequencing Procedures. AB - Changes in coding and coverage generate an uncertain reimbursement environment for molecular pathology laboratories. We analyzed our experience with two representative molecular oncology tests: a T-cell receptor (TCR) beta rearrangement test and a large (467-gene) cancer next-generation sequencing panel, the Columbia Combined Cancer Panel (CCCP). Before 2013, the TCR beta test was coded using stacked current procedural terminology codes and subsequently transitioned to a tier 1 code. CCCP was coded using a combination of tier 1 and 2 codes until 2015, when a new Genomic Sequencing Procedure code was adopted. A decrease in reimbursement of 61% was observed for the TCR beta test on moving from stacking to tier 1 codes. No initial increase in total rejection rate was observed, but a subsequent increase in rejection rates in 2015 and 2016 was noted. The CCCP test showed a similar decrease (48%) in reimbursement after adoption of the new Genomic Sequencing Procedure code and was accompanied by a sharp increase in rejection rates both on implementation of the new code and over time. Changes in coding can result in substantial decreases in reimbursement. This may be a barrier to patient access because of the high cost of molecular diagnostics. Revisions to the molecular code set will continue. These findings help laboratories and manufacturers prepare for the financial impact and advocate appropriately. PMID- 29269279 TI - Evaluation of a Urine-Based Rapid Molecular Diagnostic Test with Potential to Be Used at Point-of-Care for Pulmonary Tuberculosis: Cape Town Cohort. AB - Tuberculosis (TB) diagnosis among sputum-scarce patients is time consuming. Thus, a nonsputum diagnostic alternative is urgently needed. The Mycobacterium tuberculosis-specific transrenal (Tr) DNA from urine is a potential target for TB diagnostics. In this study, a new urine-based Tr-DNA molecular assay was evaluated for diagnosis of pulmonary tuberculosis among 428 adults suspected of having pulmonary TB (164 HIV positive, 263 HIV negative) from Cape Town, South Africa. Tr-DNA was isolated from 4 mL of EDTA urine, and a rapid, double stranded, primer-based PCR method was performed targeting the Mycobacterium tuberculosis-specific direct repeat region. Each Tr-DNA eluate was tested in triplicate using an automated molecular analyzer with controls included in each test. With liquid culture used as the gold standard, the Tr-DNA assay showed sensitivity of 42.9% (n = 75/175; 95% CI, 35.4%-50.5%) and specificity of 88.6% (n = 210/237; 95% CI, 83.9%-92.4%). Among HIV-infected patients with TB, sensitivity and specificity were 45.2% and 89.0%, respectively. The combination of smear microscopy and Tr-DNA increased the sensitivity to 83.8% (smear microscopy alone, 75.1%), with 96.6% specificity. This study indicates that Tr DNA has a moderate specificity with low sensitivity for diagnosis of pulmonary TB. Despite low sensitivity, this diagnostic test may have potential in combination with smear microscopy to support TB diagnosis in HIV-endemic regions, where sputum-scarce patients are common. PMID- 29269280 TI - Conventional and Single-Molecule Targeted Sequencing Method for Specific Variant Detection in IKBKG while Bypassing the IKBKGP1 Pseudogene. AB - In addition to Sanger sequencing, next-generation sequencing of gene panels and exomes has emerged as a standard diagnostic tool in many laboratories. However, these captures can miss regions, have poor efficiency, or capture pseudogenes, which hamper proper diagnoses. One such example is the primary immunodeficiency associated gene IKBKG. Its pseudogene IKBKGP1 makes traditional capture methods aspecific. We therefore developed a long-range PCR method to efficiently target IKBKG, as well as two associated genes (IRAK4 and MYD88), while bypassing the IKBKGP1 pseudogene. Sequencing accuracy was evaluated using both conventional short-read technology and a newer long-read, single-molecule sequencer. Different mapping and variant calling options were evaluated in their capability to bypass the pseudogene using both sequencing platforms. Based on these evaluations, we determined a robust diagnostic application for unambiguous sequencing and variant calling in IKBKG, IRAK4, and MYD88. This method allows rapid identification of selected primary immunodeficiency diseases in patients suffering from life threatening invasive pyogenic bacterial infections. PMID- 29269281 TI - Autonomic Arousal as a Mechanism of the Persistence of Nocebo Hyperalgesia. AB - : Placebo and nocebo mechanisms can lead to clinically significant modulation of pain. Although learning is considered to be the broad mechanism underlying placebo analgesia as well as nocebo hyperalgesia, critical differences have emerged in their specific mechanisms. One of the most interesting of these is that whereas placebo analgesia seems to be relatively short-lived, nocebo hyperalgesia appears more resistant to extinction, often persisting indefinitely. The current study examined why nocebo hyperalgesia persists longer than placebo analgesia. Sixty healthy volunteers were randomized to receive placebo conditioning, nocebo conditioning, or no conditioning using an experimental pain model with surreptitious decreases (placebo group) and increases (nocebo group) in pain stimulation paired with sham treatment during training. Pain was then assessed in a test phase with and without the sham treatment at equal pain stimulation. The conditioning procedure successfully induced placebo analgesia as well as nocebo hyperalgesia in the relevant groups, with nocebo hyperalgesia outlasting placebo analgesia, confirming nocebo hyperalgesia's resistance to extinction. Most interestingly, nocebo treatment led to heightened anticipatory anxiety ratings and autonomic arousal. Further, autonomic arousal completely mediated the effect of nocebo versus placebo training on extinction, suggesting that heightened autonomic arousal may be an important mechanism in the persistence of nocebo hyperalgesia. PERSPECTIVE: Heightened anticipatory anxiety in the form of elevated autonomic arousal may explain why nocebo hyperalgesia persists relative to placebo analgesia. As such, interventions that reduce anticipatory anxiety could reduce the burden of persistent nocebo hyperalgesia. PMID- 29269282 TI - Treatment of WEEE industrial wastewaters: Removal of yttrium and zinc by means of micellar enhanced ultra filtration. AB - In this paper, the efficiency of micellar enhanced ultrafiltration technique (MEUF) was tested for the removal of yttrium and zinc ions from synthetic industrial liquid wastes. UF membranes (monotubular ceramic membranes of 210 kDa and 1 kDa molecular weight cut-off) were used with adding an anionic surfactant, sodium dodecyl sulfate (SDS). A two - level full factorial design was performed in order to evaluate the effect of molecular weight cut-off, sodium dodecyl sulfate concentration and pressure on the permeate flux and rejection yields. It was found that the single factors presented the largest influence on the permeate flux: the membrane pore size and the pressure had positive effect, instead the SDS had negative effect. Regarding the metal rejection yields the main relevant factors were the membrane pore size with a negative effect, followed by the surfactant concentration with a positive effect. The effect of the pressure seemed to be almost negligible, for zinc removal experiments had a positive effect in the interactions with the surfactant and membrane pore size. The results showed that very good removal percentages up to 99% were achieved for both metals under the following conditions: 1 kDa membrane MWCO, in the presence of the surfactant at a concentration above CMC independently of the investigated pressure. PMID- 29269283 TI - Supercritical water gasification of landfill leachate for hydrogen production in the presence and absence of alkali catalyst. AB - Gasification of landfill leachate in supercritical water using batch-type reactor is investigated. Alkali such as NaOH, KOH, K2CO3, Na2CO3 is used as catalyst. The effect of temperature (380-500 degrees C), retention time (5-25 min), landfill leachate concentration (1595 mg L-1-15,225 mg L-1), catalyst adding amount (1-10 wt%) on hydrogen mole fraction, hydrogen yield, carbon gasification rate, COD, TOC, TN removal efficiency are investigated. The results showed that gaseous products mainly contained hydrogen, methane, carbon dioxide and carbon monoxide without addition of catalyst. However, the main gaseous products are hydrogen and methane with addition of NaOH, KOH, K2CO3, Na2CO3. In the absence of alkali catalyst, the effect of temperature on landfill leachate gasification is positive. Hydrogen mole fraction, hydrogen yield, carbon gasification ratio increase with temperature, which maximum value being 55.6%, 107.15 mol kg-1, 71.96% is obtained at 500 degrees C, respectively. Higher raw landfill leachate concentration leads to lower hydrogen production and carbon gasification rate. The suitable retention time is suggested to be 15 min for higher hydrogen production and carbon gasification rate. COD, TOC and TN removal efficiency also increase with increase of temperature, decrease of landfill leachate concentration. In the presence of catalyst, the hydrogen production is obviously promoted by addition of alkali catalyst. the effect of catalysts on hydrogen production is in the following order: NaOH > KOH > Na2CO3 > K2CO3. The maximum hydrogen mole fraction and hydrogen yield being 74.40%, 70.05 mol kg-1 is obtained with adding amount of 5 wt% NaOH at 450 degrees C, 28 MPa, 15 min. PMID- 29269284 TI - Effect of temperature and organic loading rate on siphon-driven self-agitated anaerobic digestion performance for food waste treatment. AB - The effects of organic loading rate (OLR) and operating temperature on the performance of siphon-driven self-agitated anaerobic reactor (SDSAR) in an on site food waste (FW) treatment system were investigated. Two reactors were operated in parallel for comparison between mesophilic condition (35 +/- 1 degrees C) and thermophilic condition (55 +/- 1 degrees C). With HRT above 15 d and OLR below 4.8 kg-COD/m3/d, relatively high COD removal in the range of 84.5 92.3% was obtained in both reactors. The limits of the loading capacity of the mesophilic SDSAR were observed when OLR was further increased to 7.3 kg-COD/m3/d by shortening HRT. Blocking and gas production reduction occurred and COD removal decreased sharply to 75.9% in the mesophilic reactor. In contrast, the thermophilic reactor can be operated at this OLR with satisfactory COD removal and biogas production. Furthermore, at OLR of 14.4 kg-COD/m3/d, the COD removal was maintained as high as 87.5% in the thermophilic reactor. The conversion of influent COD to methane was maintained above 80% at all the OLR applied in both reactors. The results of this study indicated that thermophilic SDSAR is preferred for the on-site FW treatment. PMID- 29269285 TI - Design and analysis of siloxanes removal by adsorption from landfill gas for waste-to-energy processes. AB - Separation of volatile methyl siloxanes from landfill gas using fixed adsorption beds was modeled with the objective of identifying appropriate technology and the economics associated with this purification step. A general adsorption model assuming plug flow and radial symmetry was developed and used to conduct a parametric sweep of 162 unique cases. The varied parameters were adsorbent type (activated carbon and silica gel), bed height (3.05-9.15 m/10-30 ft), inlet siloxane concentration (5-15 mg/m3), moisture content (0-100% relative humidity at STP or RH), and siloxane tolerance limit (0.094-9.4 mg/m3) that correlated to three distinct energy conversion technologies (electricity production using engines or fuels cells or catalytic conversion to liquid hydrocarbon fuels). Due to the detrimental effect of RH on siloxane absorption, the maximum allowable moisture content of LFG before purification is 50% RH and moisture removal processes are also required. The design calculations using a selected case study show that the adsorption bed height required needed for 6 months minimum breakthrough time for catalytic fuel production is twice that for engine applications. Fuel cell applications require 3 times the bed height compared to engine applications. However, the purification costs amounted to 94%, 16% and 52% of recovered product value for engine, liquefaction, and fuel cell applications, respectively indicating the need for a high value product to justify purification costs. The approaches and conclusions can be extended to specific process conditions for landfill gas purification and to other processes that use biogas produced from waste as a feedstock. PMID- 29269286 TI - Editorial commentary: Targeting TYMP for cardiovascular disease: How far are we? PMID- 29269287 TI - Editorial commentary: Mathematical modeling as a tool to elucidate fundamental principles in cardiac electrophysiology. PMID- 29269288 TI - Identification of immune-related genes in gill cells of Japanese eels (Anguilla japonica) in adaptation to water salinity changes. AB - The changes in ambient salinity influence ion and water homeostasis, hormones secretion, and immune response in fish gills. The physiological functions of hormones and ion transporters in the regulation of gill-osmoregulation have been widely studied, however the modulation of immune response under salinity changes is not determined. Using transcriptome sequencing, we obtained a comprehensive profile of osmo-responsive genes in gill cells of Japanese eel (Anguilla japonica). Herein, we applied bioinformatics analysis to identify the immune related genes that were significantly higher expressed in gill pavement cells (PVCs) and mitochondrial-rich cells (MRCs) in freshwater (FW) than seawater (SW) adapted fish. We validated the data using the real-time qPCR, which showed a high correlation between the RNA-seq and real-time qPCR data. In addition, the immunohistochemistry results confirmed the changes of the expression of selected immune-related genes, including C-reactive protein (CRP) in PVCs, toll-like receptor 2 (TLR2) in MRCs and interleukin-1 receptor type 2 (IL-1R2) in both PVCs and MRCs. Collectively our results demonstrated that those immune-related genes respond to salinity changes, and might trigger related special signaling pathways and network. This study provides new insights into the impacts of ambient salinity changes on adaptive immune response in fish gill cells. PMID- 29269289 TI - Identification and analysis of an MKK4 homologue in response to the nucleus grafting operation and antigens in the pearl oyster, Pinctada fucata. AB - The mitogen-activated protein kinase kinase 4 (MKK4) is a key component of the c Jun N-terminal kinase (JNK) signaling pathway and regulates multiple cellular activities. However, little is known about the roles of this kinase in pearl oyster. In this study, we identified an MKK4 homologue in Pinctada fucata by using a transcriptome database. Sequence analysis and protein structure prediction showed that PfMKK4 is highly conserved to MKK4 from other vertebrate and invertebrate species. Phylogenetic analysis revealed that PfMKK4 has the closest relationship with that from Crassostrea gigas. QPCR was used to investigate expression profiles in different healthy adult tissues and developmental stages of P. fucata. We found that PfMKK4 was ubiquitously expressed in all tissues and developmental stages examined except for in D-shaped larvae. Gene expression analysis suggested that PfMKK4 is involved in the response to the nucleus insertion operation. Lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid [poly(I:C)] stimulation in vivo reduced PfMKK4 mRNA expression at 6 h, 48 h and 48 h, 72 h, respectively. LPS and poly(I:C) induced PfMKK4 phosphorylation in a primary mantle cell culture. These results contribute to better understanding of the potential role played by PfMKK4 in protecting the pearl oyster from injury caused by grafting or disease. PMID- 29269290 TI - Pancreatic inflammation and atrophy are not associated with pancreatic cancer concomitant with intraductal papillary mucinous neoplasm. AB - BACKGROUND: Inflammation-induced carcinogenesis in pancreatic ductal adenocarcinoma (PDAC) has been reported; however, its involvement in PDAC with intraductal papillary mucinous neoplasm (IPMN) remains unclear. We herein investigated the relationship between pancreatic atrophy and inflammation and the incidence of PDAC concomitant with IPMN. METHODS: This study included 178 consecutive patients who underwent surgical resection for PDAC with IPMN (N = 21) and IPMN (N = 157) between April 2001 and October 2016. A multivariable logistic regression analysis was conducted to assess the relationship between pancreatic inflammation and atrophy and the incidence of PDAC concomitant with IPMN, with adjustments for clinical characteristics and imaging features. Pathological pancreatic inflammation and atrophy were evaluated in resected specimens. RESULTS: High degrees of pancreatic inflammation and atrophy were not associated with the incidence of PDAC with IPMN (multivariable odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.07 to 3.33, P = .52, adjusted by clinical characteristics, OR = 0.9, 95% CI = 0.10 to 5.86, P = .91, adjusted by imaging studies; OR = 0.2, 95% CI = 0.009 to 1.31, P = .10, adjusted by clinical characteristics, OR = 0.2, 95% CI = 0.01 to 1.43, P = .12, adjusted by imaging studies, respectively). CONCLUSIONS: Pancreatic inflammation and atrophy were not associated with pancreatic cancer concomitant with IPMN. PMID- 29269291 TI - Novice nurses' perceptions of acute situations - A phenomenographic study. AB - BACKGROUND: Today's nurses face complex patient challenges and increased patient acuity. Novice nurses may feel unprepared for some of the tasks facing them. In order to prevent adverse events and improve patient outcomes, the management of acute situations has been identified as an area needing attention. Despite this, it is not yet clear what novice nurses themselves perceive as an acute situation. Therefore, the aim of this study is to describe novice nurses' perceptions of acute situations. METHOD: The study has a qualitative, descriptive design with a phenomenographic approach. Semi-structured interviews were conducted with twelve novice nurses, with less than a year of working experience, about their perceptions of acute situations. RESULTS: Acute situations are perceived as situations that occur suddenly, that involve shortage of time, or that generate a sense of insufficient personal competence. When acute situations arise, nurses experience a feeling of overwhelming responsibility. Acute situations involve not only deteriorating patient health but can also include challenging interpersonal relations or deficiencies in organisational procedures. CONCLUSION: An acute situation, as perceived by novice nurses, contains significantly more than medical manifestations related to the patient, a prominent perception being that interpersonal relations are crucial for appropriate management. PMID- 29269292 TI - Identification of Cep169-interacting proteins and the in vivo modification sites of Cep169 via proteomic analysis. AB - Cep169 is a microtubule plus-end tracking and centrosomal protein that interacts with CDK5RAP2. Cep169 is known to regulate microtubule dynamics and stability; however, its other cellular functions remain largely elusive. In this study, we identified novel Cep169-interacting proteins from HeLa cell extracts. Proteomic analysis via LC-MS/MS helped to identify approximately 400 novel Cep169 interacting proteins, including centrosomal proteins, cilium proteins, microtubule-associating proteins, and several E3 ubiquitin ligases. In addition, we identified in vivo posttranslational modification sites of Cep169, namely, 27 phosphorylation sites, five methylation sites, and four ubiquitination sites. Of these, 14 phosphorylated residues corresponding to the consensus Cdk phosphorylation sites may be required for Cdk1-mediated dissociation of Cep169 from the centrosome during mitosis and Cdk regulation during the G1/S phase. Furthermore, siRNA-induced Cep169 depletion was found to inhibit the growth of RPE1 cells. Our findings suggest that Cep169 regulates cell growth by interacting with multiple proteins. PMID- 29269293 TI - Activation of macrophages by a laccase-polymerized polyphenol is dependent on phosphorylation of Rac1. AB - Various physiologically active effects of polymerized polyphenols have been reported. In this study, we synthesized a polymerized polyphenol (mL2a-pCA) by polymerizing caffeic acid using mutant Agaricus brasiliensis laccase and analyzed its physiological activity and mechanism of action. We found that mL2a-pCA induced morphological changes and the production of cytokines and chemokines in C3H/HeN mouse-derived resident peritoneal macrophages in vitro. The mechanisms of action of polymerized polyphenols on in vitro mouse resident peritoneal cells have not been characterized in detail previously. Herein, we report that the mL2a pCA-induced production of interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) in C3H/HeN mouse-derived resident peritoneal cells was inhibited by treatment with the Rac1 inhibitor NSC23766 trihydrochloride. In addition, we found that mL2a-pCA activated the phosphorylation Rac1. Taken together, the results show that mL2a-pCA induced macrophage activation via Rac1 phosphorylation dependent pathways. PMID- 29269294 TI - Oxidative stress induced necroptosis activation is involved in the pathogenesis of hyperoxic acute lung injury. AB - Necroptosis has been found to be involved in the pathogenesis of some lung diseases, but its role in hyperoxic acute lung injury (HALI) is still unclear. This study aimed to investigate contribution of necroptosis to the pathogenesis of HALI induced by hyperbaric hyperoxia exposure in a rat model. Rats were divided into control group, HALI group, Nec-1 (necroptosis inhibitor) group and edaravone group. Rats were exposed to pure oxygen at 250 kPa for 6 h to induce HALI. At 30 min before hyperoxia exposure, rats were intraperitoneally injected with Nec-1 or edaravone, and sacrificed at 24 h after hyperoxia exposure. Lung injury was evaluated by histology, lung water to dry ratio (W/D) and bronchoalveolar lavage fluid (BALF) biochemistry; the serum and plasma oxidative stress, expression of RIP1, RIP3 and MLKL, and interaction between RIP1 and RIP3 were determined. Results showed hyperoxia exposure significantly caused damage to lung and increased necroptotic cells and the expression of RIP1, RIP3 and MLKL. Edaravone pre-treatment not only inhibited the oxidative stress in HALI, but also reduced necroptotic cells, decreased the expression of RIP1, RIP3 and MLKL and improved lung pathology. Nec-1 pretreatment inhibited necroptosis and improved lung pathology, but had little influence on oxidative stress. This study suggests hyperoxia exposure induces oxidative stress may activate necroptosis, involving in the pathology of HALI, and strategies targeting necroptosis may become promising treatments for HALI. PMID- 29269295 TI - FGFR1 is essential for N-acetyl-seryl-aspartyl-lysyl-proline regulation of mitochondrial dynamics by upregulating microRNA let-7b-5p. AB - Fibroblast growth factor receptor (FGFR) 1 plays a key role in endothelial homeostasis by inducing microRNA (miR) let-7. Our previous paper showed that anti fibrotic effects of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) were associated with restoring diabetes-suppressed expression of FGFR1 and miR let-7, the key contributor of mitochondrial biogenesis, which is regulated by mitochondrial membrane GTPase proteins (MFN2 and OPA1). Here, we found that the FGFR1 signaling pathway was critical for AcSDKP in maintaining endothelial mitochondrial biogenesis through induction of miR let-7b-5p. In endothelial cells, AcSDKP restored the triple cytokines (TGF-beta2, interleukin-1beta, tumor necrosis factor-alpha)-suppressed miR let-7b-5p and protein levels of the mitochondrial membrane GTPase. This effect of AcSDKP was lost with either fibroblast growth factor receptor substrate 2 (FRS2) siRNA or neutralizing FGFR1 treated cells. Similarly, AcSDKP had no effect on the miR let-7b-5p inhibitor suppressed GTPase levels in endothelial cells. In addition, a miR let-7b-5p mimic restored the levels of FRS2 siRNA-reduced GTPases in endothelial cells. These findings were also confirmed using MitoTracker Green and an immunofluorescence assay. Our results demonstrated that the AcSDKP-FGFR1 signaling pathway is critical for maintaining mitochondrial dynamics by control of miR let-7b-5p in endothelial cells. PMID- 29269296 TI - Influence of glucocorticoids on time-of-day-dependent variations in IgE-, histamine-, and platelet-activating factor-mediated systemic anaphylaxis in different mouse strains. AB - A time-of-day-dependent variation in IgE-mediated passive systemic anaphylaxis was previously reported in ICR mice. In the present study, we investigated time of-day-dependent variations in IgE-, histamine-, and platelet-activating factor (PAF)-mediated systemic anaphylaxis in C57BL/6, BALB/c, and NC/Nga mice at 9:00 h and 21:00 h, and evaluated the potential influence of glucocorticoids (GCs) on these variations. We found significant time-of-day-dependent variations in IgE mediated systemic anaphylaxis in C57BL/6 mice, and in histamine- and PAF-mediated systemic anaphylaxis in BALB/c mice. Significant daily variations in IgE-, histamine-, and PAF-mediated systemic anaphylaxis were not observed in NC/Nga mice. Pretreatment with dexamethasone and adrenalectomy abolished the daily variations in IgE-mediated systemic anaphylaxis in C57BL/6 mice and in PAF mediated systemic anaphylaxis in BALB/c mice, suggesting that GCs from adrenal glands are pivotal in regulating these variations. In contrast, pretreatment with dexamethasone and adrenalectomy did not abolish the daily variation in histamine mediated systemic anaphylaxis in BALB/c mice, suggesting that GC-independent and adrenal gland-independent mechanisms are important for the variation. The present study demonstrated that time-of-day-dependent variations in systemic anaphylaxis differed among inbred mouse strains and with anaphylaxis-inducing substances. Thus, mouse strains, time of experiment, and anaphylaxis-inducing substances used must be considered to obtain appropriate experimental results. PMID- 29269297 TI - Inhibitory activity of linarin on osteoclastogenesis through receptor activator of nuclear factor kappaB ligand-induced NF-kappaB pathway. AB - Linarin, a natural flavonoid glycoside widely found in plants, has been reported to possess anti-inflammation, neuroprotection and osteogenic properties. However, its impact on osteoclast remains unclear. In the present study, the effects of linarin on osteoclastogenesis and its underlying molecular mechanisms of action were investigated. Using the culture systems of osteoclasts derived from bone marrow macrophages (BMMs), we found that linarin dose-dependently inhibited osteoclasts formation and bone resorptive activity. The Cell Counting Kit-8 test displayed that the viability of cells was not influenced by linarin at doses up to 10 MUg/mL. In addition, linarin downregulated osteoclast-related genes expression, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAP), osteoclast-associated receptor (OSCAR) and c-Fos, as shown by quantitative real time polymerase chain reaction (RT-qPCR). Western blot analysis further showed that linarin inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced nuclear factor kappa B (NF-kappaB) p65 and NFATc1 activity. The present findings show that linarin exerted a potent inhibitory effect on osteoclastogenesis through RANKL-induced NF kappaB signaling pathway. In conclusion, the results suggest that linarin has anti-osteoclastic effects and may serve as potential modulatory agents for the prevention and treatment of bone loss-associated diseases. PMID- 29269298 TI - Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression. AB - OBJECTIVE: Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. METHODS: Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 MUg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1beta, and interleukin (IL)-1beta in pancreatic tissue was detected by Western blot and real-time PCR. RESULTS: Dexmedetomidine at 20 MUg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 MUg/kg significantly down regulated the expression of NLRP3, pro-IL-1beta, and IL-1beta in pancreatic tissue, but up-regulated the expression of NET in both mouse models. CONCLUSION: Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression. PMID- 29269299 TI - Toll-like receptor 2 activation implicated in oral squamous cell carcinoma development. AB - Recent studies have revealed that Toll-like receptors (TLRs) are highly expressed and activated in many types of cancer. Physiologically, TLR2 recognizes bacteria and other microorganisms in the oral cavity; however, the role of TLR2 in oral squamous cell carcinoma (OSCC) is unclear. In this study, we demonstrated that TLR2 is highly expressed in OSCC in comparison with adjacent non-malignant tissue. TLR2 was also expressed in OSCC-derived cell lines, and its expression was activated by ligands derived from bacteria and mycoplasma. Furthermore, to elucidate the mechanism of OSCC progression via TLR2 signal transduction, we focused on microRNAs (miRNAs) that are induced by TLR2 activation. Interestingly, ligand activation of TLR2 induced the expression of miR-146a and we found that downregulation of caspase recruitment domain-containing protein 10 (CARD10) mRNA in OSCC-derived cell lines. Moreover, knockdown of CARD10 induced resistance to cisplatin-induced apoptosis in OSCC cells. These findings suggest that the activation of TLR2 by bacterial components can enhance the progression of OSCC and may be implicated in acquired resistance to cisplatin-induced apoptosis through regulation of the miR-146a pathway. PMID- 29269300 TI - MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7. AB - Tyrosine kinase inhibitors (TKIs) exert potent therapeutic efficacy in non-small cell lung cancers (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations. However, a major impediment for the effective treatment is the development of drug resistance. Some evidence supports a role for miRNAs in modulating NSCLC TKIs resistance. Here we show that miR-181a is significantly up regulated in gefitinib-resistant cells compared with gefitinib-sensitive cells. Upregulation of miR-181a caused resistance of gefitinib, whereas downregulation of miR-181a sensitized NSCLC cells to gefitinib. Furthermore, the miR-181a plasma levels were significantly increased in acquired gefitinib resistant NSCLC patients compared with the plasma levels prior to gefitinib treatment in each patient. Bioinformatics analysis and luciferase reporter assay showed that growth arrest-specific 7 (GAS7) was a direct target gene of miR-181a. A significant inverse correlation between the expression of miR-181a and GAS7 was identified in NSCLC tissues. Downregulation of GAS7 expression could antagonize gefitinib re sensitivity in PC9GR mediated by knockdown of miR-181a via AKT/ERK pathways and epithelial-to-mesenchymal transition markers. Additionally, GAS7 expression was downregulated in a large cohort of NSCLC patients, and a high mRNA level of GAS7 was associated with improved overall survival. Collectively, our findings provide a novel basis for using miR-181a/GAS7-based therapeutic strategies to reverse gefitinib resistance in NSCLC. PMID- 29269301 TI - FBXO2, a novel marker for metastasis in human gastric cancer. AB - FBXO2 belongs to the F-box family of proteins, is a cytoplasmic protein and ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins. Recently published studies indicate that other members of the F-box family, such as SKP2 and FBXW7, are involved in the development of gastric cancer. The role of FBXO2 in the process of tumorigenesis, including gastric cancer, is still unknown. In this study, we show that the level of FBXO2 is highly correlated with lymph node metastasis, and that overall survival (OS) of patients with high FBXO2 expression is significantly shorter than patients with low FBXO2 expression. FBXO2 promoted the proliferation and migration of human gastric cancer cells, whereas knockdown of FBXO2 by siRNA led to a decrease in those activities. Down regulating FBXO2 reduced epithelial-mesenchymal transition (EMT) in gastric cancer cells, with increased expression of E-cadherin and decreased expression of N-cadherin and vimentin. In summary, our findings suggest that FBXO2-regulated EMT led to carcinogenicity in gastric cancer and may be a novel target in the diagnosis and treatment of gastric cancer. PMID- 29269302 TI - Depressive symptoms in people with disabilities; secondary analysis of cross sectional data from the United Kingdom and Greece. AB - BACKGROUND: Evidence suggests there is an association between depressive symptoms and disability. OBJECTIVE/HYPOTHESIS: The objective of this study was to examine whether people with disabilities in the United Kingdom and Greece face more depressive symptoms than people without disabilities. The hypothesis was that people with disabilities in both countries are more likely to experience depressive symptoms. METHODS: We used data from the 2014 European Health Interview Survey (wave 2). After performing principal-component factor analysis, we carried out logistic regressions, in order to investigate differences in depressive symptoms between people with and without disabilities, and examine the factors affecting depressive symptoms for people with disabilities. RESULTS: People with disabilities in the UK were 2.8 times more likely to experience depressive symptoms compared to people without disabilities (95% C.I.: 2.51-3.05, p < .001), while in Greece, they were 2.2 times more likely to do so (95% C.I.: 1.90-2.64, p < .001). Our findings regarding people with disabilities showed that women, older people (in Greece), unemployed and inactive people (in Greece), and better-educated people (in the UK) were more likely to experience depressive symptoms. Married people, older people (in the UK), people living in densely populated areas (in Greece), people who assessed their health as 'average' or 'good', and people who enjoyed social support (in Greece) were less likely to face depressive symptoms. CONCLUSIONS: Due to population-ageing and higher incidence of depressive symptoms in disabled people, it is important that policies are put in place to address the mental health needs of this population. PMID- 29269303 TI - Disabilities moderate the association between neighbourhood urbanity and cognitive health: Results from the Irish longitudinal study on ageing. AB - BACKGROUND: Geographical variations in cognitive health have been extensively explored, but the evidence on adult individuals with disabilities is inconclusive. While urban living is suggested as more cognitively stimulating than rural dwelling in epidemiological research, both rurality and urbanity can present barriers that may negatively impact cognitive health, the former due to limited accessibility to stimulation, and the latter because presenting environmental stressors. OBJECTIVE: To bridge this gap in the literature, we investigated geographical variations in multiple cognitive skills in adult age based on neighbourhood urbanity and having disabilities. METHODS: Data on global cognition, memory, speed of processing and executive functions, as well as reported functional limitations, was taken from 4127 individuals aged 50 + participating in the first wave of The Irish Longitudinal Study on Ageing (TILDA). Neighbourhood urbanity was measured using Census data on population density. Multivariate regression analyses controlled for socio-demographic, health and lifestyle covariates. RESULTS: Residence in medium-high densely populated areas was significantly associated with better cognitive performance across all measures, after controlling for covariates. However, having disabilities was linked to worse global cognitive functioning (MoCA, p = .005), immediate recall (p = .022) and executive functions (CTT2, p = .009) in the least and most densely populated areas. CONCLUSIONS: Living in urbanised areas may provide more mental stimulation than rural places; however, functional limitations moderate this association, suggesting potential environmental challenges both in rural and urban areas. Considering both individual and environmental circumstances can enrich investigations of geographical variations in cognitive health. PMID- 29269304 TI - Gaze perception induces early attention orienting effects in occipito-parietal regions. AB - Other's eye gaze is a powerful attention orienting cue that can change our perception of objects in the environment. Here, we seek to characterize the influence of attention orienting by eye gaze on the neural processing of visual targets. We used a Posner-like cueing paradigm to investigate with magnetoencephalography the brain responses associated with target processing. We analyzed the cerebral sources of the evoked responses to visual targets that were validly or invalidly cued by eye gaze. The effect of attention orienting was reflected in faster reaction times to valid than invalid targets. At the brain level, we showed an early influence of attention orienting by gaze with enhanced brain responses for invalid relative to valid targets. This influence was maximum contra-laterally to the target, with a right hemisphere dominance. Responses to targets presented in the left visual field were modulated between 91 and 400ms in the right posterior parietal and occipital cortices. Responses to targets presented in the right visual field were modulated between 174 and 218ms in the left superior parietal cortex. Our results confirm previous EEG studies that demonstrated early influence of attention orienting by gaze on target processing and provide evidence for the sources of this effect in occipito-parietal regions. This early influence may reflect the first stage of the perceptual changes induced by social attention. PMID- 29269305 TI - Planning versus comprehension in turn-taking: Fast responders show reduced anticipatory processing of the question. AB - Rapid response latencies in conversation suggest that responders start planning before the ongoing turn is finished. Indeed, an earlier EEG study suggests that listeners start planning their responses to questions as soon as they can (Bogels et al., 2015a). The present study aimed to (1) replicate this early planning effect and (2) investigate whether such early response planning incurs a cost on participants' concurrent comprehension of the ongoing turn. During the experiment participants answered questions from a confederate partner. To address aim (1), the questions were designed such that response planning could start either early or late in the turn. Our results largely replicate Bogels et al. (2015a), showing a large positive ERP effect and an oscillatory alpha/beta reduction right after participants could have first started planning their verbal response, again suggesting an early start of response planning. To address aim (2), the confederate's questions also contained either an expected word or an unexpected one to elicit a differential N400 effect, either before or after the start of response planning. We hypothesized an attenuated N400 effect after response planning had started. In contrast, the N400 effects before and after planning did not differ. There was, however, a positive correlation between participants' response time and their N400 effect size after planning had started; quick responders showed a smaller N400 effect, suggesting reduced attention to comprehension and possibly reduced anticipatory processing. We conclude that early response planning can indeed impact comprehension processing. PMID- 29269306 TI - Dopaminergic medication shifts the balance between going and stopping in Parkinson's disease. AB - The present behavioral study delineates the impact of Parkinson's disease (PD) and of dopaminergic medication on action control over voluntary behavior. Previous studies reported either prolonged responding or stopping latencies in PD compared to healthy controls (HC). Few studies investigated the effects of dopaminergic medication on these processes concurrently. We administered a stop change task, an extended version of the stop task, that required (i) speeded responding to a go signal (i.e., going), (ii) inhibiting ongoing motor responses (i.e., stopping), and (iii) changing to an alternative response. PD performance (n = 33) was collected once during regular dopaminergic medication conditions (On state) and once after a medication washout period (Off state). A group of age matched HC (n = 21) performed the stop-change task once. Response latencies to go signals were comparable between HC and PD Off, indicative of unimpaired going. Compared to HC, PD Off showed prolonged stopping latencies. Within the clinical group, stopping latencies significantly improved after taking dopaminergic medication. Interestingly, the shorter stopping latencies observed in the On state were paralleled by longer response latencies to go signals. The degree of the inhibition improvement observed in the medication state was correlated with the degree of response slowing. Change RT did not vary between groups or between medication states. These patterns of results are discussed in terms of a tradeoff between going versus stopping of motor responses in PD patients. Shifts of this tradeoff seem to be driven by dopaminergic medication, which has potential clinical implications. PMID- 29269307 TI - Asymmetries in initiation of aiming movements in schizophrenia. AB - Several studies have reported motor symptoms in schizophrenia (SCZ), in some cases describing asymmetries in their manifestation. To date, biases were mainly reported for sequential movements, and the hypothesis was raised of a dopamine related hemispheric imbalance. Aim of this research is to better characterize asymmetries in movement initiation in SCZ by exploring single actions. Fourteen SCZ patients and fourteen healthy subjects were recruited. On a trial-by-trial basis, participants were instructed to reach for one of eight possible targets. Measures of movement initiation and execution were collected. Starting point, target and moving limb were systematically varied to check for asymmetric responses. Results showed that SCZ patients, besides being overall slower than controls, additionally presented with a bias affecting both the moving hand and the side from which movements were initiated. This finding is discussed in relation to hemispheric lateralization in motor control. PMID- 29269308 TI - PKCdelta-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity. AB - Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCdelta expression out of PKC isoforms. PKCdelta co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCdelta. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCdelta. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCdelta, genetic inhibitions of PKCdelta [i.e., PKCdelta knockout mice (KO) and PKCdelta antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCdelta is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCdelta or p47phox, is important for dopaminergic protection against MA insult. PMID- 29269309 TI - NADPH oxidase 4 and endothelial nitric oxide synthase contribute to endothelial dysfunction mediated by histone methylations in metabolic memory. AB - "Metabolic memory" is identified as a phenomenon that transient hyperglycemia can be remembered by vasculature for quite a long term even after reestablishment of normoglycemia. NADPH oxidases (Noxs) and endothelial nitric oxide synthase (eNOS) are important enzymatic sources of reactive oxygen species (ROS) in diabetic vasculature. The aim of this study is to explore the roles of epigenetics and ROS derived from Noxs and eNOS in the metabolic memory. In this study, we demonstrated that vascular ROS was continuously activated in endothelium induced by transient high glucose, as well as sustained vascular endothelial dysfunction. The Nox4 and uncoupled eNOS are the major sources of ROS, while inhibition of Nox4 and eNOS significantly attenuated oxidative stress and almost recovered the endothelial function in metabolic memory. Furthermore, the aberrant histone methylation (H3K4me1, H3K9me2, and H3K9me3) at promoters of Nox4 and eNOS are the main causes for the persistent up-regulation of these two genes. Modifying the histone methylation could reduce the expression levels of Nox4 and eNOS, thus obviously attenuating endothelial dysfunction. These results indicate that histone methylation of Nox4 and eNOS play a key role in metabolic memory and may be the potential intervention targets for metabolic memory. PMID- 29269310 TI - Methylglyoxal displays colorectal cancer-promoting properties in the murine models of azoxymethane and CT26 isografts. AB - Methylglyoxal (MG), a highly reactive carbonyl species (RCS) with pro-oxidant and proinflammatory properties, may be a colon tumor-promoting factor in food and biological systems. In the present study, we found that consumption of MG significantly deteriorated azoxymethane (AOM)-induced colonic preneoplastic lesions in ICR mice, in which biomarkers of oxidative stress and inflammation within the body and feces induced by MG-fueled carbonyl stress may have played important roles. Interestingly, exposure to MG also led to increases in the serum low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio and fecal bile acid levels in mice, which may be critical factors involved in MG-induced colonic lesions. Additionally, MG treatment (50mg/kg body weight (BW); intraperitoneally) promoted tumor growth of CT26 isografts in mice partly by carbonyl stress-evoked protumorigenic responses, including low-grade inflammation and oxidative stress. Furthermore, primary tumor cells isolated from mice with MG-induced CT26 isografts had greater proliferative and migratory activities as well as stem-like properties compared to those isolated from the vehicle controls. Excitingly, enhanced expression or activation of proteins that modulate cell survival, proliferation, or migration/invasion was also observed in those cells. In conclusion, it is conceivable that MG-induced carbonyl stress may be the pivotal promoter involved in colon cancer progression. PMID- 29269311 TI - Biomechanical evaluation of C1 lateral mass and C2 translaminar bicortical screws in atlantoaxial fixation: an in vitro human cadaveric study. AB - BACKGROUND CONTEXT: Atlantoaxial fixation with C1 lateral mass-C2 translaminar bicortical (C1LM-C2TB) screws has been reported to afford good stability with the least risk of injury to vertebral artery. However, no comparative in vitro studies have been conducted to evaluate the biomechanical stability of this method. PURPOSE: This study aimed to compare in vitro biomechanics of fixation with C1LM-C2TB with fixation with C1 lateral mass-C2 translaminar unicortical screws (C1LM-C2TU) and with C1 lateral mass-C2 pedicle screws (C1LM-C2PS). STUDY DESIGN: This is an in vitro biomechanical study. METHODS: Fifteen fresh-frozen human cadaveric cervical spines (C1-C3) were tested after destabilization by transverse-alar-apical ligament disruption. Instrumentation was performed with three fixation constructs: C1LM-C2PS, C1LM-C2TU, and C1LM-C2TB. Flexion, extension, lateral bending, and axial rotation were tested. Range of motion and neutral zone pre-fatigue and post-fatigue values were measured. RESULTS: No significant differences were observed in flexion-extension among the three groups. However, C1LM-C2TB fixation was superior to C1LM-C2TU fixation in lateral bending and axial rotation. CONCLUSION: C2 translaminar bicortical screws are biomechanically superior to C2TU screws for fixation of the atlantoaxial complex, and it is equivalent to C2PS fixation. C2 translaminar bicortical screws or C2PS should be preferred over C2TU screws. PMID- 29269312 TI - Fabrication of polycaprolactone-silanated beta-tricalcium phosphate-heparan sulfate scaffolds for spinal fusion applications. AB - BACKGROUND CONTEXT: Interbody spinal fusion relies on the use of external fixation and the placement of a fusion cage filled with graft materials (scaffolds) without regard for their mechanical performance. Stability at the fusion site is instead reliant on fixation hardware combined with a selected cage. Ideally, scaffolds placed into the cage should both support the formation of new bone and contribute to the mechanical stability at the fusion site. PURPOSE: We recently developed a scaffold consisting of silane-modified PCL-TCP (PCL-siTCP) with mechanical properties that can withstand the higher loads generated in the spine. To ensure the scaffold more closely mimicked the bone matrix, we incorporated collagen (Col) and a heparan sulfate glycosaminoglycan sugar (HS3) with increased affinity for heparin-binding proteins such as bone morphogenetic protein-2 (BMP-2). The osteostimulatory characteristic of this novel device delivering exogenous BMP2 was assessed in vitro and in vivo as a prelude to future spinal fusion studies with this device. STUDY DESIGN/SETTING: A combination of cell-free assays (BMP2 release), progenitor cell-based assays (BMP2 bioactivity, cell proliferation and differentiation), and rodent ectopic bone formation assays was used to assess the osteostimulatory characteristics of the PCL-siTCP-based scaffolds. MATERIALS AND METHODS: Freshly prepared rat mesenchymal stem cells were used to determine reparative cell proliferation and differentiation on the PCL-siTCP-based scaffolds over a 28-day period in vitro. The bioactivity of BMP2 released from the scaffolds was assessed on progenitor cells over a 28-day period using ALP activity assays and release kinetics as determined by enzyme-linked immunosorbent assay. For ectopic bone formation, intramuscular placement of scaffolds into Sprague Dawley rats (female, 4 weeks old, 120-150 g) was achieved in five animals, each receiving four treatments randomized for location along the limb. The four groups tested were (1) PCL siTCP/Col (5-mm diameter*1-mm thickness), PCL-siTCP/Col/BMP2 (5 ug), (3) PCL siTCP/Col/HS3 (25 ug), and (4) PCL-siTCP/Col/HS3/BMP2 (25 and 5 ug, respectively). Bone formation was evaluated at 8 weeks post implantation by microcomputed tomography (uCT) and histology. RESULTS: Progenitor cell-based assays (proliferation, mRNA transcripts, and ALP activity) confirmed that BMP2 released from PCL-siTCP/Col/HS3 scaffolds increased ALP expression and mRNA levels of the osteogenic biomarkers Runx2, Col1a2, ALP, and bone gla protein osteocalcin compared with devices without HS3. When the PCL-siTCP/Col/HS3/BMP2 scaffolds were implanted into rat hamstring muscle, increased bone formation (as determined by two-dimensional and three-dimensional uCTs and histologic analyses) was observed compared with scaffolds lacking BMP2. More consistent increases in the amount of ectopic bone were observed for the PCL-siTCP/Col/HS3/BMP2 implants compared with PCL-siTCP/Col/BMP2. Also, increased mineralizing tissue within the pores of the scaffold was seen with modified-tetrachrome histology, a result confirmed by uCT, and a modest but detectable increase in both the number and the thickness of ectopic bone structures were observed with the PCL siTCP/Col/HS3/BMP2 implants. CONCLUSIONS: The combination of PCL siTCP/Col/HS3/BMP2 thus represents a promising avenue for further development as a bone graft alternative for spinal fusion surgery. PMID- 29269313 TI - No Significant Association Between Proton Pump Inhibitor Use and Risk of Stroke After Adjustment for Lifestyle Factors and Indication. AB - BACKGROUND & AIMS: Proton pump inhibitors (PPI) are among the top 10 most prescribed medications worldwide. We investigated the association between PPI use and ischemic stroke. METHODS: We collected data on 68,514 women (mean age, 65 +/- 7 years) enrolled in the Nurses' Health Study since 2000 and 28,989 men (mean age, 69 +/- 8 years) in the Health Professionals Follow-up Study since 2004, without a history of stroke. We used Cox proportional hazards models to examine the association between risk of incident stroke and PPI use among participants. The primary end point was first incident stroke. RESULTS: In the 2 cohorts, we documented 2599 incident strokes (2037 in women and 562 in men) over a 12-year period, encompassing 949,330 person-years. After adjustment for established risk factors for stroke, PPI use was associated with a significant increase in risk of ischemic stroke (hazard ratio, 1.18; 95% confidence interval, 1.02-1.37). The association was reduced after we adjusted for potential indications for PPI use, including history of peptic ulcer disease, gastroesophageal reflux disease, or gastrointestinal bleeding, and prior use of histamine-2 receptor antagonist therapy (hazard ratio, 1.08; 95% confidence interval, 0.91-1.27). Regular PPI use was not associated with increased risk of stroke overall or hemorrhagic stroke. CONCLUSIONS: In an analysis of data from the Nurses' Health Study and the Health Professionals Follow-up Study, we did not find a significant association between PPI use and ischemic stroke, after accounting for indications for PPI use. Prior reports of an increased risk of stroke may be due to residual confounding related to chronic conditions associated with PPI use. PMID- 29269314 TI - Membrane fluidization by alcohols inhibits DesK-DesR signalling in Bacillus subtilis. AB - After cold shock, the Bacillus subtilis desaturase Des introduces double bonds into the fatty acids of existing membrane phospholipids. The synthesis of Des is regulated exclusively by the two-component system DesK/DesR; DesK serves as a sensor of the state of the membrane and triggers Des synthesis after a decrease in membrane fluidity. The aim of our work is to investigate the biophysical changes in the membrane that are able to affect the DesK signalling state. Using linear alcohols (ethanol, propanol, butanol, hexanol, octanol) and benzyl alcohol, we were able to suppress Des synthesis after a temperature downshift. The changes in the biophysical properties of the membrane caused by alcohol addition were followed using membrane fluorescent probes and differential scanning calorimetry. We found that the membrane fluidization induced by alcohols was reflected in an increased hydration at the lipid-water interface. This is associated with a decrease in DesK activity. The addition of alcohol mimics a temperature increase, which can be measured isothermically by fluorescence anisotropy. The effect of alcohols on the membrane periphery is in line with the concept of the mechanism by which two hydrophilic motifs located at opposite ends of the transmembrane region of DesK, which work as a molecular caliper, sense temperature-dependent variations in membrane properties. PMID- 29269315 TI - Inorganic mercury and cadmium induce rigidity in eukaryotic lipid extracts while mercury also ruptures red blood cells. AB - Hg and Cd are non-essential toxic heavy metals that bioaccumulate in the tissues of living systems but less is known about their interactions with Eukaryotic lipid bilayers. Microscopy experiments showed that Hg and Cd changed the cell morphology of rabbit erythrocytes while Hg also induced cell rupture. As membranes are one of the first available targets, our study aimed to better understand metal-lipid interactions that could lead to toxic effects. Fluorescence spectroscopy (Laurdan Generalized Polarization) and dynamic light scattering were used to analyze metal-induced changes in membrane fluidity and the size of liposomes composed of Brain (Porcine), Liver (Bovine), Heart (Bovine) and Yeast (S. cerevisiae) lipid extracts. Under physiological chloride and pH levels, Hg irreversibly cleaves plasmalogens resulting in an increase in membrane rigidity. These lipids are enriched in Brain, Heart and Erythrocyte membranes and are important in signalling and the protection against oxidative stress. Interestingly, Hg had a heavily reduced effect on the plasmalogen-free Yeast extract membrane. In contrast, Cd induced rigidity by targeting negatively charged phosphatidic acid, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and cardiolipin in these extracts. Metal-induced liposome aggregation depended on the proportion of negatively charged lipids/plasmalogen and even the order of metal addition. Our results show that data from model systems correlate with trends observed in complex biological extracts and red blood cells and serve as a predictive tool for analyzing metal-lipid interactions. The determination of the specific lipid targets for Hg and Cd provides new insights how these metals exert toxic effects on cell membranes. PMID- 29269316 TI - Emotion-driven impulsiveness and snack food consumption of European adolescents: Results from the I.Family study. AB - We aimed to investigate the association between emotion-driven impulsiveness and snack food consumption in 1039 European adolescents aged 12-18 years. During the cross-sectional examination in 2013/2014, complete information was collected on: emotion-driven impulsiveness (using the negative urgency subscale from the Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency (UPPS-P) Impulsive Behaviour Scale) and snacking behaviour operationalised as 1) consumption frequency of daily snacks, 2) consumption frequency of energy-dense snacks (both measured using Food Frequency Questionnaire) and 3) usual energy intake of food consumed per snacking occasion in calories. The latter was measured using online self-administered 24-h dietary recalls and was estimated based on the National Cancer Institute (NCI) Method. Anthropometric variables were measured and BMI z-score (zBMI) calculated. Age, sex, highest education level of the family and country of residence were assessed using a questionnaire. Mixed-effect regression analyses were separately conducted for each snacking behaviour outcome with emotion-driven impulsiveness as the exposure. After controlling for zBMI, age, sex, country and socioeconomic status, emotion-driven impulsiveness was positively associated with daily consumption frequency of snacks (beta = 0.07, 95% Confidence Interval (CI) [0.02, 0.12]) and consumption frequency of energy-dense snacks (beta = 0.25, 95% CI [0.19, 0.31]), but not with usual energy intake of food per snacking (beta = 2.52, 95% CI [-0.55, 5.59]). Adolescents with a stronger emotion-driven impulsiveness tendency reported a higher snacking frequency and specifically more energy-dense snacks, whereas the energy intake of snack food seemed less important. These findings have implications for obesity prevention and treatment as they indicate the importance of targeting emotion-driven impulsiveness as a strategy to avoid excessive snacking. PMID- 29269317 TI - Cysteinyl leukotriene receptor 1 expression identifies a subset of neutrophils during the antiviral response that contributes to postviral atopic airway disease. AB - BACKGROUND: Viral respiratory tract infections increase the risk of development and exacerbation of atopic disease. Previously, we demonstrated the requirement for a neutrophil (PMN) subset expressing CD49d to drive development of postviral atopic airway disease in mice. OBJECTIVE: We sought to determine whether human CD49d+ PMNs are present in the nasal mucosa during acute viral respiratory tract infections and further characterize this PMN subset in human subjects and mice. METHODS: Sixty subjects (5-50 years old) were enrolled within 4 days of acute onset of upper respiratory symptoms. Nasal lavage for flow cytometry and nasal swabs for viral PCR were performed at enrollment and during convalescence. The Sendai virus mouse model was used to investigate the phenotype and functional relevance of CD49d+ PMNs. RESULTS: CD49d+ PMN frequency was significantly higher in nasal lavage fluid during acute respiratory symptoms in all subjects (2.9% vs 1.0%, n = 42, P < .001). In mice CD49d+ PMNs represented a "proatopic" neutrophil subset that expressed cysteinyl leukotriene receptor 1 (CysLTR1) and produced TNF, CCL2, and CCL5. Inhibition of CysLTR1 signaling in the first days of a viral respiratory tract infection was sufficient to reduce accumulation of CD49d+ PMNs in the lungs and development of postviral atopic airway disease. Similar to the mouse, human CD49d+ PMNs isolated from nasal lavage fluid during a viral respiratory tract infection expressed CysLTR1. CONCLUSION: CD49d and CysLTR1 coexpressing PMNs are present during symptoms of an acute viral respiratory tract infection in human subjects. Further study is needed to examine selective targeting of proatopic neutrophils as a potential therapeutic strategy to prevent development of postviral atopic airway disease. PMID- 29269318 TI - A comprehensive study on automated muscle segmentation for assessing fat infiltration in neuromuscular diseases. AB - Severity and progression of degenerative neuromuscular diseases can be sensitively captured by evaluating the fat infiltration of muscle tissue in T1 weighted MRI scans of human limbs. For computing the fat fraction, the original muscle needs to be first separated from other tissue. Five conceptionally different approaches were investigated and evaluated with respect to the segmentation of muscles of human thighs. Besides a rather basic thresholding approach, local (level set) as well as global (graph cut) energy-minimizing segmentation approaches with and without a shape prior energy term were examined. For experimental evaluations, a dataset containing 37 subjects was divided into four classes according to the degree of fat infiltration. Results show that the choice of the best method depends on the severity of fat infiltration. In severe cases, the best results were obtained with shape prior based graph cuts, whereas in marginal cases thresholding was sufficient. With the best approach, the worst case error in fat fraction computation was always below 11% and on average between 2% for tissue showing no fat infiltrations and 6% for heavily infiltrated tissue. The obtained Dice similarity coefficients, measuring the segmentation quality, were on average between 0.85 and 0.92. Although segmentation of heavily infiltrated muscle tissue is extremely difficult, an approach for reasonably segmenting these image data was identified. Especially the negative impact on the calculated fat fraction can be reduced significantly. PMID- 29269320 TI - Random forest feature selection, fusion and ensemble strategy: Combining multiple morphological MRI measures to discriminate among healhy elderly, MCI, cMCI and alzheimer's disease patients: From the alzheimer's disease neuroimaging initiative (ADNI) database. AB - BACKGROUND: In the era of computer-assisted diagnostic tools for various brain diseases, Alzheimer's disease (AD) covers a large percentage of neuroimaging research, with the main scope being its use in daily practice. However, there has been no study attempting to simultaneously discriminate among Healthy Controls (HC), early mild cognitive impairment (MCI), late MCI (cMCI) and stable AD, using features derived from a single modality, namely MRI. NEW METHOD: Based on preprocessed MRI images from the organizers of a neuroimaging challenge,3 we attempted to quantify the prediction accuracy of multiple morphological MRI features to simultaneously discriminate among HC, MCI, cMCI and AD. We explored the efficacy of a novel scheme that includes multiple feature selections via Random Forest from subsets of the whole set of features (e.g. whole set, left/right hemisphere etc.), Random Forest classification using a fusion approach and ensemble classification via majority voting. From the ADNI database, 60 HC, 60 MCI, 60 cMCI and 60 CE were used as a training set with known labels. An extra dataset of 160 subjects (HC: 40, MCI: 40, cMCI: 40 and AD: 40) was used as an external blind validation dataset to evaluate the proposed machine learning scheme. RESULTS: In the second blind dataset, we succeeded in a four-class classification of 61.9% by combining MRI-based features with a Random Forest based Ensemble Strategy. We achieved the best classification accuracy of all teams that participated in this neuroimaging competition. COMPARISON WITH EXISTING METHOD(S): The results demonstrate the effectiveness of the proposed scheme to simultaneously discriminate among four groups using morphological MRI features for the very first time in the literature. CONCLUSIONS: Hence, the proposed machine learning scheme can be used to define single and multi-modal biomarkers for AD. PMID- 29269319 TI - The dynamic nature of fear engrams in the basolateral amygdala. AB - Great progress has been made in our understanding of how so-called memory engrams in the brain enable the storage and retrieval of memories. This has led to the realization that across the lifetime of an animal, the spatial and temporal properties of a memory engram are not fixed, but instead are subjected to dynamic modifications that can be both dependent and independent on additional experiences. The dynamic nature of engrams is especially relevant in the case of fear memories, whose contributions to an animal's evolutionary fitness depend on a delicate balance of stability and flexibility. Though fear memories have the potential to last a lifetime, their expression also needs to be properly tuned to prevent maladaptive behavior, such as seen in patients with post-traumatic stress disorder. To achieve this balance, fear engrams are subjected to complex spatiotemporal dynamics, making them informative examples of the "dynamic engram". In this review, we discuss the current understanding of the dynamic nature of fear engrams in the basolateral amygdala, a brain region that plays a central role in fear memory encoding and expression. We propose that this understanding can be further advanced by studying how fast dynamics, such as oscillatory circuit activity, support the storage and retrieval of fear engrams that can be stable over long time intervals. PMID- 29269321 TI - Development of glucocorticoid resistance over one year among mothers of children newly diagnosed with cancer. AB - Chronic distress associates with peripheral release of cortisol and a parallel upregulation of innate inflammation. Typically, cortisol functions to down regulate inflammatory processes. However, in the context of chronic stress, it is hypothesized that glucocorticoid receptors within immune cells become less sensitive to the anti-inflammatory effects of cortisol, resulting in increased systemic inflammation. Caring for a child newly diagnosed with cancer is a particularly provocative chronic stressor. Here, we examine evidence for the development of cellular resistance to glucocorticoids among 120 mothers (Aged 18 56 years; 86% Caucasian) across the 12 months following their child's new diagnosis with cancer. Measures of psychological distress, interleukin (IL)-6, and glucocorticoid resistance (GCR) were assessed 1, 6, and 12 months after the diagnosis. A latent factor for distress was derived from the covariation among symptoms of anxiety, depression, and post-traumatic stress. Latent change score models revealed a significant positive association between change in distress and change in GCR from 0 to 6 months, and 6 months-1 year. This finding provides initial evidence for a longitudinal association between change in maternal distress and change in GCR from the onset of a chronic stressor through one year. Although levels of IL-6 increased during the first six months after the child's diagnosis, the magnitude of this change was not related to change in distress or change in GCR. Given the possible health consequences of reduced immune sensitivity to glucocorticoids, future work should further explore this stress response and its clinical significance. PMID- 29269322 TI - Drug transport mechanisms and in vitro release kinetics of vancomycin encapsulated chitosan-alginate polyelectrolyte microparticles as a controlled drug delivery system. AB - In this study, chitosan-alginate polyelectrolyte microparticles containing the antibiotic, vancomycin chloride were prepared using the ionotropic gelation (coacervation) technique. In vitro release and drug transport mechanisms were studied concerning the chitosan only and alginate only microparticles as a control group. Further, the effect of porosity on the drug transport mechanism was also studied for chitosan-alginate mixed particles produced by lyophilizing in contrast to the air-dried non-porous particles. According to the in vitro release data, alginate only and chitosan only microparticles showed burst release and prolonged release respectively. Chitosan-alginate lyophilized microparticles showed the best-controlled release of vancomycin with the average release of 22MUg per day for 14days. Also, when increasing alginate concentration there was no increase in the release rate of vancomycin. The release data of all the microparticles were treated with Ritger-Peppas, Higuchi, Peppas-Sahlin, zero order, and first-order kinetic models. The best fit was observed with Peppas Sahlin model, indicating the drug transport mechanism was controlled by both Fickian diffusion and case II relaxations. Also, Fickian diffusion dominates the drug transport mechanism of all air-dried samples during the study period. However, the Fickian contribution was gradually reducing with time. Porosity significantly effects the drug transport mechanism as case II relaxation dominates after day 10 of the lyophilized microparticles. PMID- 29269323 TI - Analysis of over 1500 triatomine vectors from across the US, predominantly Texas, for Trypanosoma cruzi infection and discrete typing units. AB - Across the Americas, triatomine insects harbor diverse strains of Trypanosoma cruzi (T. cruzi), agent of Chagas disease. Geographic patterns of vector infection and parasite strain associations, especially in vectors encountered by the public, may be useful in assessing entomological risk, but are largely unknown across the US. We collected Triatoma spp. from across the US (mainly Texas), in part using a citizen science initiative, and amplified T. cruzi DNA to determine infection prevalence and parasite discrete typing units (DTUs). We found 54.4% infection prevalence in 1510 triatomines of 6 species; prevalence in adult T. gerstaeckeri (63.3%; n=897) and T. lecticularia (66.7%; n=66) was greater than in T. sanguisuga (47.6%; n=315), T. indictiva (47.8% n=67), T. rubida (14.1%; n=64), and T. protracta (10.5%; n=19). The odds of infection in adults were 9.73 times higher than in nymphs (95% CI 4.46-25.83). PCR of the spliced leader intergenic region (SL-IR) and/or the putative lathosterol/episterol oxidase TcSC5D gene revealed exclusively T. cruzi DTUs TcI and TcIV; 5.5% of T. cruzi-positive samples were not successfully typed. T. gerstaeckeri (n=548) were more frequently infected with TcI (53.9%) than TcIV (34.4%), and 11.9% showed mixed TcI/TcIV infections. In contrast, T. sanguisuga (n=135) were more frequently infected with TcIV (79.3%) than TcI (15.6%), and 5.2% showed mixed infections. Relative abundance of parasite DTUs varied spatially, with both TcI and TcIV co-circulating in vectors in central Texas, while TcIV predominated in northern Texas. Given prior findings implicating TcI in human disease and TcI and TcIV in animal disease in the US, knowledge of spatial distribution of T. cruzi infection and DTUs in vectors is important to understanding public and veterinary health risk of T. cruzi infection. PMID- 29269324 TI - Delivery of microRNA-1 inhibitor by dendrimer-based nanovector: An early targeting therapy for myocardial infarction in mice. AB - Myocardial infarction (MI), known to be rapidly progressed and fatal, necessitates a timely and effective intervention particularly within golden 24 h. The crux is to develop a therapeutic agent that can early target the infarct site with integrated therapeutic capacity. Finding the AT1 receptor being most over expressed at 24 h after MI, we developed a nanovector (AT1-PEG-DGL) anchored with AT1 targeting peptide, and simultaneously armed it with specific microRNA-1 inhibitor (AMO-1) to attenuate cardiomyocyte apoptosis. In vivo imaging after IV administration demonstrated that AT1-PEG-DGL quickly accumulated in the MI heart during the desired early period, significantly outperforming the control group without AT1 targeting. Most importantly, a pronounced in-vivo anti-apoptosis effect was observed upon a single IV injection. Apoptotic cell death in the infarct border zone was significantly decreased and the myocardial infarct size was reduced by 64.1% as compared with that in MI control group, promising for early MI treatment. PMID- 29269326 TI - Assessment of meniscus with adiabatic T1rho and T2rho relaxation time in asymptomatic subjects and patients with mild osteoarthritis: a feasibility study. AB - OBJECTIVE: To investigate the ability of magnetic resonance imaging (MRI) adiabatic relaxation times in the rotating frame (adiabatic T1rho and T2rho) to detect structural alterations in meniscus tissue of mild OA patients and asymptomatic volunteers. METHOD: MR images of 24 subjects (age range: 50-67 years, 12 male), including 12 patients with mild osteoarthritis (OA) (Kellgren Lawrence (KL) = 1, 2) and 12 asymptomatic volunteers, were acquired using a 3 T clinical MRI system. Morphological assessment was performed using semiquantitative MRI OA Knee Score (MOAKS). Adiabatic T1rho and T2rho (AdT1rho, AdT2rho) relaxation time maps were calculated in regions of interest (ROIs) containing medial and lateral horns of menisci. The median relaxation time values of the ROIs were compared between subjects classified based on radiographic findings and MOAKS evaluations. RESULTS: MOAKS assessment of patients and volunteers indicated the presence of meniscal and cartilage lesions in both groups. For the combined cohort group, prolonged AdT1rho was observed in the posterior horn of the medial meniscus (PHMED) in subjects with MOAKS meniscal tear (P < 0.05). AdT2rho was statistically significantly longer in PHMED of subjects with MOAKS full-thickness cartilage loss (P < 0.05). After adjusting for multiple comparisons, differences in medians of observed AdT1rho and AdT2rho values between mild OA patients and asymptomatic volunteers did not reach statistical significance. CONCLUSION: AdT1rho and AdT2rho measurements have the potential to identify changes in structural composition of meniscus tissue associated with meniscal tear and cartilage loss in a cohort group of mild OA patients and asymptomatic volunteers. PMID- 29269325 TI - Efficacy, immunogenicity, and safety of a 9-valent human papillomavirus vaccine in Latin American girls, boys, and young women. AB - BACKGROUND: A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. METHODS: Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16-26 years, and an immunogenicity and safety study in girls and boys aged 9-15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. RESULTS: The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. CONCLUSIONS: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden. PMID- 29269327 TI - Sagittal alignment and mobility of the thoracolumbar spine are associated with radiographic progression of secondary hip osteoarthritis. AB - OBJECTIVE: To identify predictors of radiographic progression of hip osteoarthritis (OA) over 12 months among functional hip impairments and spinal alignment and mobility. DESIGN: Fifty female patients with secondary hip OA, excluding those with end-stage hip OA, participated in this prospective cohort study. Joint space width (JSW) of the hip was measured at baseline and 12 months later. With radiographic progression of hip OA over 12 months (>0.5 mm in JSW) as dependent variable, logistic regression analyses were performed to identify predictors for hip OA progression among functional impairments of the hip and spine with and without adjustment for age, body mass index (BMI), and minimum JSW at baseline. The independent variables were hip pain, Harris hip score (HHS), hip morphological parameters, hip passive range of motion (ROM) and muscle strength, and alignment and mobility of the thoracolumbar spine at baseline. RESULTS: Twenty-one (42.0%) patients demonstrated radiographic progression of hip OA. Multivariable logistic regression analysis showed that larger anterior inclination of the spine in standing position (adjusted OR [95% CI], 1.37 [1.04 1.80]; P = 0.028) and less thoracolumbar spine mobility (adjusted OR [95% CI], 0.96 [0.92-0.99]; P = 0.037) at baseline were statistically significantly associated with radiographic progression of hip OA, even after adjustment for age, BMI, and minimum JSW. CONCLUSIONS: The findings suggest that spinal alignment and mobility should be considered when assessing risk and designing preventive intervention for radiographic progression of secondary hip OA. PMID- 29269328 TI - Health care resource use, health care expenditures and absenteeism costs associated with osteoarthritis in US healthcare system. AB - OBJECTIVES: We determined incremental health care resource utilization, incremental health care expenditures, incremental absenteeism, and incremental absenteeism costs associated with osteoarthritis. DESIGN: Medical Expenditure Panel Survey (MEPS) for 2011 was used as data source. Individuals 18 years or older and employed during 2011 were eligible for inclusion in the sample for analyses. Individuals with osteoarthritis were identified based on ICD-9-CM codes. Incremental health care resource utilization included annual hospitalization, hospital days, emergency room visits and outpatient visits. Incremental health expenditures included annual inpatient, outpatient, emergency room, medications, miscellaneous and annual total expenditures. RESULTS: Of the total sample, 1354 were diagnosed with osteoarthritis, and compared to non osteoarthritis individuals. Incremental resource utilization, expenditures, absenteeism and absenteeism costs were estimated using regression models, adjusting for age, gender, sex, region, marital status, insurance coverage, comorbidities, anxiety, asthma, hypertension and hyperlipidemia. Regression models revealed incremental mean annual resource use associated with osteoarthritis of 0.07 hospitalizations, equal to 70 additional hospitalizations per 100 osteoarthritic patients annually, and 3.63 outpatient visits, equal to 363 additional visits per 100 osteoarthritic patients annually. Mean annual incremental total expenditures associated with osteoarthritis were $2046. Annually, mean incremental expenditures were largest for inpatient expenditures at $826, followed by mean incremental outpatient expenditures of $659, and mean incremental medication expenditures of $325. Mean annual incremental absenteeism was 2.2 days and mean annual incremental absenteeism costs were $715.74. Total direct expenditures were estimated at $41.7 billion. CONCLUSION: Osteoarthritis was associated with significant incremental health care resource utilization, expenditures, absenteeism and absenteeism costs. PMID- 29269329 TI - Perception of ABC (asymmetry, borders, and color) parameters in the screening for melanoma: Model exercise with experienced dermatologists. PMID- 29269330 TI - Nitric oxide-releasing injectable hydrogels with high antibacterial activity through in situ formation of peroxynitrite. AB - : Nitric oxide (NO) is an endogenous molecule with many critical biological functions that depend on its concentration. At high levels, NO provides broad spectrum antibacterial effects through both its pathogen inhibition and killing abilities. However, its short half-life has been a great challenge to its clinical application in pharmaceutical forms. In this study, we incorporated the NO donor S-nitrosothiolated gelatin (GelSNO) into injectable gelatin-based hydrogels (GHs) to controllably release NO. Under catalysis by horseradish peroxidase, H2O2 oxidizes phenol moieties functionalized on gelatin to quickly form phenol-phenol crosslinks that encapsulate GelSNO. Through thermal, visible light, and oxidizing agent-driven mechanisms, NO is released from the GH/GelSNO hydrogels. By varying the GelSNO concentration, the release of NO was controllable in a wide range, 0.054-2.050 MUmol/mL, for up to 14 days. In addition, NO release was fine-tunable as a function of H2O2 concentration. Notably, the in situ formation of peroxynitrite (ONOO-) that produces potent antibacterial effects originated from H2O2 residues and nitrous acid formed by NO and oxygen in aqueous solution. The Kirby-Bauer method indicated that there was an inhibition zone against both Escherichia coli and Staphylococcus aureus incubated with GH/GelSNO hydrogels. The AlarmaBlue assay showed that E. coli and S. aureus were completely killed at NO concentrations of 0.39 and 0.58 MUmol/mL. Cytotoxicity tests of GH/GelSNO hydrogels on human dermal fibroblasts at the indicated bactericidal NO concentrations induced no cell toxicity. In summary, GH/GelSNO hydrogels may provide a new platform for topical delivery of NO in treating wound infections and for various biomedical applications. STATEMENT OF SIGNIFICANCE: NO is an effective antibacterial agent even in cases of antibiotic resistant bacteria. Moreover, its intermediate, peroxynitrite, has been reported to have a much higher ability to kill bacteria. In this study, we utilized injectable GH/GelSNO hydrogels formed by HRP/H2O2 reaction not only to control NO release but also to generate peroxynitrite in situ from released NO and H2O2 residues. The GH/GelSNO hydrogels showed significant antibacterial ability on both gram-positive and negative bacteria, while no cytotoxicity was induced on human dermal fibroblasts. In addition, their tunable chemico-physical properties and controllable NO release within a wide range but narrow scale will make the hydrogels useful in various biomedical applications. PMID- 29269332 TI - Ultrastructural organization of elastic fibres in the partition boundaries of the annulus fibrosus within the intervertebral disc. AB - : The relationship between elastic fibre disorders and disc degeneration, aging and progression of spine deformity have been discussed in a small number of studies. However, the clinical relevance of elastic fibres in the annulus fibrosus (AF) of the disc is poorly understood. Ultrastructural visualization of elastic fibres is an important step towards understanding their structure function relationship. In our previous studies, a novel technique for visualization of elastic fibres across the AF was presented and their ultrastructural organization in intra- and inter-lamellar regions was compared. Using the same novel technique in the present study, the ultrastructural organization of elastic fibres in the partition boundaries (PBs), which are located between adjacent collagen bundles, is presented for the first time. Visualization of elastic fibres in the PBs in control and partially digested (digested) samples was compared, and their orientation in two different cutting planes (transverse and oblique) were discussed. The ultrastructural analysis revealed that elastic fibres in PBs were a well-organized dense and complex network having different size and shape. Adjacent collagen bundles in a cross section (CS) lamella appear to be connected to each other, where elastic fibres in the PBs were merged in parallel or penetrated into the collagen bundles. There was no significant difference in directional coherency coefficient of elastic fibres between the two different cutting planes (p = .35). The present study revealed that a continuous network of elastic fibres may provide disc integrity by connecting adjacent bundles of CS lamellae together. Compared to our previous studies, the density of the elastic fibre network in PBs was lower, and fibre orientation was similar to the intra-lamellar space and inter-lamellar matrix. STATEMENT OF SIGNIFICANCE: A detailed ultrastructural study in the partition boundaries of the annulus fibrosus within the disc revealed a well-organized elastic fibre network with a complex ultrastructure. The continuous network of elastic fibres may provide disc integrity by connecting adjacent bundles of cross section lamellae together. The density of the elastic fibre network in PBs was lower, and fibre orientation was similar to the intra-lamellar space and the inter-lamellar matrix. PMID- 29269331 TI - A bio-based pro-antimicrobial polymer network via degradable acetal linkages. AB - : The synthesis of a fully degradable, bio-based, sustained release, pro antimicrobial polymer network comprised of degradable acetals (PANDA) is reported. The active antimicrobial agent - p-anisaldehyde (pA) (an extract from star anise) - was converted into a UV curable acetal containing pro-antimicrobial monomer and subsequently photopolymerized into a homogenous thiol-ene network. Under neutral to acidic conditions (pH < 8), the PANDAs undergo surface erosion and exhibit sustained release of pA over 38 days. The release of pA from PANDAs was shown to be effective against both bacterial and fungal pathogens. From a combination of confocal microscopy and transmission electron microscopy, we observed that the released pA disrupts the cell membrane. Additionally, we demonstrated that PANDAs have minimal cytotoxicity towards both epithelial cells and macrophages. Although a model platform, these results point to promising pathways for the design of fully degradable sustained-release antimicrobial systems with potential applications in agriculture, pharmaceuticals, cosmetics, household/personal care, and food industries. STATEMENT OF SIGNIFICANCE: With the increasing number of patients prescribed immunosuppressants coupled with the rise in antibiotic resistance - life-threatening microbial infections are a looming global threat. With limited success within the antibiotic pipeline, nature-based essential oils (EOs) are being investigated for their multimodal effectiveness against microbes. Despite the promising potential of EOs, difficulties in their encapsulation, limited water solubility, and high volatility limit their use. Various studies have shown that covalent attachment of these EO derivatives to polymers can mitigate these limitations. The current study presents the synthesis of a fully-degradable, sustained release, cytocompatible, pro-antimicrobial acetal network derived from p-anisaldehyde. This polymer network design provides a pathway toward application-specific EO releasing materials with quantitative encapsulation efficiencies, sustained release, and broad-spectrum antimicrobial activity. PMID- 29269333 TI - Microchannel system for rate-controlled, sequential, and pH-responsive drug delivery. AB - : Controlled delivery of drug at a constant rate, in a sequential order, or responsive to environment conditions has been pursued for a long time to enhance the efficacy of therapeutic molecules and to minimize side effects of highly potent drugs. However, achieving such delicately-controlled delivery of a drug molecule is non-trivial and still remains a challenge. We propose the use of microchannels to control the rate, sequence, and pH-responsiveness of drug delivery for high precision and predictability. In this study, we introduce elementary drug delivery units consisting of micro-reservoirs and microchannels that have variations in their lengths, widths, numbers, and straightness. The release study demonstrates that the release rates of model drugs can be modulated by the design of microchannels. Finite element modeling of drug release predicts the performance of the drug delivery units with high accuracy. The possibility of sequential drug delivery is also demonstrated using biodegradable polymer plug in microchannels. Finally, pH-responsive delivery of drugs in microfluidic units is also discussed and demonstrated via cell viability tests. STATEMENT OF SIGNIFICANCE: In this work, we developed microchannel-based drug delivery devices whose release rate could be accurately calculated and controlled by design of microchannel geometry. Although there have been many advances in microfabricated drug delivery systems, in particular, reservoir-based systems, no systematic investigation has been made to utilize the release channels. In our work, an equivalent electrical circuit concept was applied to the microfluidic systems for more detailed design and analysis. A microfluidic channel was regarded as an electrical resistor; their diffusion/electrical flux could be tuned with geometric factors such as length, width, a number of channel/resistor and their connections. Furthermore, from delivery rate control using channel geometry, multifunctional channel-based release systems for sequential and pH-responsive were demonstrated. PMID- 29269334 TI - CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. AB - : Traditional electrospun nanofiber membranes were incapable of promoting cellular infiltration due to its intrinsic property (e.g., dense structure and small pore size) limiting their use in tissue regeneration. Herein, we report a simple and novel approach for expanding traditional nanofiber membranes from two dimensional to three-dimensional (3D) with controlled thickness and porosity via depressurization of subcritical CO2 fluid. The expanded 3D nanofiber scaffolds formed layered structures and simultaneously maintained the aligned nanotopographic cues. The 3D scaffolds also retained the fluorescent intensity of encapsulated coumarin 6 and the antibacterial activity of encapsulated antimicrobial peptide LL-37. In addition, the expanded 3D nanofiber scaffolds with arrayed holes can significantly promote cellular infiltration and neotissue formation after subcutaneous implantation compared to traditional nanofiber membranes. Such scaffolds also significantly increased the blood vessel formation and the ratio of M2/M1 macrophages after subcutaneous implantation for 2 and 4 weeks compared to traditional nanofiber membranes. Together, the presented method holds great potential in the fabrication of functional 3D nanofiber scaffolds for various applications including engineering 3D in vitro tissue models, antimicrobial wound dressing, and repairing/regenerating tissues in vivo. STATEMENT OF SIGNIFICANCE: Electrospun nanofibers have been widely used in regenerative medicine due to its biomimicry property. However, most of studies are limited to the use of 2D electrospun nanofiber membranes. To the best of our knowledge, this article is the first instance of the transformation of traditional electrospun nanofiber membranes from 2D to 3D via depressurization of subcritical CO2 fluid. This method eliminates many issues associated with previous approaches such as necessitating the use of aqueous solutions and chemical reactions, multiple-step process, loss of the activity of encapsulated biological molecules, and unable to expand electrospun nanofiber mats made of hydrophilic polymers. Results indicate that these CO2 expanded nanofiber scaffolds can maintain the activity of encapsulated biological molecules. Further, the CO2 expanded nanofiber scaffolds with arrayed holes can greatly promote cellular infiltration, neovascularization, and positive host response after subcutaneous implantation in rats. The current work is the first study elucidating such a simple and novel strategy for fabrication of 3D nanofiber scaffolds. PMID- 29269336 TI - Connected Health Devices for Health Care in French General Medicine Practice: Cross-Sectional Study. AB - BACKGROUND: The integration of Connected Health Devices (CHDs) is growing within mobile health (mHealth) and telemedicine, encouraged by institutions and industries. The idea is to improve lifestyle habits and health behaviors as a preventive goal in an aging population with fewer physicians available. However, their ill-defined place in health care does not promote their use in current medical practice. OBJECTIVE: The primary objective of this study was to quantify CHDs' use rate by general practitioners (GPs). A secondary objective was to evaluate their benefits and limitations in usual care. METHODS: A cross-sectional study through an Internet-based survey was addressed to French GPs via regional medical unions and continuous education agencies, supplemented with an informative website, from March 2015 to July 2015. Surveys where either the form was insufficiently filled or the main question was left unanswered were excluded from the study. RESULTS: A total of 1084 answers were analyzed, of which 19.46% (211/1084, 95% CI 17.1-21.8) GPs used CHDs, and 10.15% (110/1084, 95% CI 8.5 12.1) prescribed a CHD. CHD users statistically prescribed more CHDs (7.38% [80/1084] in the user group vs 2.86% [31/1084] in nonusers; P<.001) and were more likely to use them in the future. Major interests in their utilization were in patient monitoring for 84.96% (921/1084) and patient education for 75.83% (822/1084), especially for diabetes (89.67%, 972/1084) and hypertension (84.13%, 912/1084). Generated data had to be managed securely by the patient primarily for 85.79% (930/1084) of the GPs. CHDs had to not constrain GPs outside clinical consultation, nor restrain their time for 75.83% (822/1084). Additional actors in patient care were not desired for 79.98% (867/1084) of the GPs. Questions about data management issues and technical difficulties were raised. CONCLUSIONS: CHDs are little used by French GPs and even less prescribed to their patients, as only a few GPs use these tools. Their benefits as tools of patient empowerment, although expected, remain to be demonstrated in real-life setups. PMID- 29269335 TI - Uterine Artery Flow and Offspring Growth in Long-Evans Rats following Maternal Exposure to Ozone during Implantation. AB - BACKGROUND: Epidemiological studies suggest that increased ozone exposure during gestation may compromise fetal growth. In particular, the implantation stage of pregnancy is considered a key window of susceptibility for this outcome. OBJECTIVES: The main goals of this study were to investigate the effects of short term ozone inhalation during implantation on fetal growth outcomes and to explore the potential for alterations in uterine arterial flow as a contributing mechanism. METHODS: Pregnant Long-Evans rats were exposed to filtered air, 0.4 ppm ozone, or 0.8 ppm ozone for 4 h/d during implantation, on gestation days (GD) 5 and 6. Tail cuff blood pressure and uterine artery Doppler ultrasound were measured on GD 15, 19, and 21. To assess whether peri-implantation ozone exposure resulted in sustained pulmonary or systemic health effects, bronchoalveolar lavage fluid, serum metabolic and inflammatory end points, and kidney histopathology were evaluated in dams at GD 21. Growth parameters assessed in GD 21 offspring included fetal weight, length, and body composition. RESULTS: Measures of maternal uterine arterial flow, including resistance index and mean velocity, indicated that resistance increased between GD 15 and GD 21 in 0.8 ppm dams but decreased in controls, although absolute values were similar in both groups on GD 21. Ozone-exposed dams also had lower serum glucose and higher free fatty acid concentrations than controls on GD 21. On GD 21, both male and female offspring had lower body weight than controls, and pooled subsets of 3 male and 3 female fetuses from litters exposed to 0.8 ppm ozone had lower lean mass and fat mass than pooled control offspring. CONCLUSIONS: Findings from our experimental model suggest that the offspring of dams exposed to ozone during implantation had reduced growth compared with controls, possibly as a consequence of ozone-induced vascular dysfunction. https://doi.org/10.1289/EHP2019. PMID- 29269337 TI - Characteristics of Adults Seeking Health Care Provider Support Facilitated by Mobile Technology: Secondary Data Analysis. AB - BACKGROUND: Mobile health technology is rapidly evolving with the potential to transform health care. Self-management of health facilitated by mobile technology can maximize long-term health trajectories of adults. Little is known about the characteristics of adults seeking Web-based support from health care providers facilitated by mobile technology. OBJECTIVE: This study aimed to examine the following: (1) the characteristics of adults who seek human support from health care providers for health concerns using mobile technology rather than from family members and friends or others with similar health conditions and (2) the use of mobile health technology among adults with chronic health conditions. Findings of this study were interpreted in the context of the Efficiency Model of Support. METHODS: We first described characteristics of adults seeking Web-based support from health care providers. Using chi-square tests for categorical variables and t test for the continuous variable of age, we compared adults seeking Web-based and conventional support by demographics. The primary aim was analyzed using multivariate logistic regression to examine whether chronic health conditions and demographic factors (eg, sex, income, employment status, race, ethnicity, education, and age) were associated with seeking Web-based support from health care providers. RESULTS: The sample included adults (N=1453), the majority of whom were female 57.60% (837/1453), white 75.02% (1090/1453), and non Hispanic 89.13% (1295/1453). The age of the participants ranged from 18 to 92 years (mean 48.6, standard deviation [SD] 16.8). The majority 76.05% (1105/1453) of participants reported college or higher level of education. A disparity was found in access to health care providers via mobile technology based on socioeconomic status. Adults with annual income of US $30,000 to US $100,000 were 1.72 times more likely to use Web-based methods to contact a health care provider, and adults with an annual income above US $100,000 were 2.41 to 2.46 times more likely to access health care provider support on the Web, compared with those with an annual income below US $30,000. After adjusting for other demographic covariates and chronic conditions, age was not a significant factor in Web-based support seeking. CONCLUSIONS: In this study, the likelihood of seeking Web-based support increased when adults had any or multiple chronic health conditions. A higher level of income and education than the general population was found to be related to the use of mobile health technology among adults in this survey. Future study is needed to better understand the disparity in Web-based support seeking for health issues and the clinicians' role in promoting access to and use of mobile health technology. PMID- 29269338 TI - Blended Interventions to Change Behavior in Patients With Chronic Somatic Disorders: Systematic Review. AB - BACKGROUND: Blended behavior change interventions combine therapeutic guidance with online care. This new way of delivering health care is supposed to stimulate patients with chronic somatic disorders in taking an active role in their disease management. However, knowledge about the effectiveness of blended behavior change interventions and how they should be composed is scattered. OBJECTIVE: This comprehensive systematic review aimed to provide an overview of characteristics and effectiveness of blended behavior change interventions for patients with chronic somatic disorders. METHODS: We searched for randomized controlled trials published from 2000 to April 2017 in PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials. Risk of bias was assessed using the Cochrane Collaboration tool. Study characteristics, intervention characteristics, and outcome data were extracted. Studies were sorted based on their comparison group. A best-evidence synthesis was conducted to summarize the effectiveness. RESULTS: A total of 25 out of the 29 included studies were of high quality. Most studies (n=21; 72%) compared a blended intervention with no intervention. The majority of interventions focused on changing pain behavior (n=17; 59%), and the other interventions focused on lifestyle change (n=12; 41%). In addition, 26 studies (90%) focused on one type of behavior, whereas 3 studies (10%) focused on multiple behaviors. A total of 23 studies (79%) mentioned a theory as basis for the intervention. The therapeutic guidance in most studies (n=18; 62%) was non face-to-face by using email, phone, or videoconferencing, and in the other studies (partly), it was face-to-face (n=11; 38%). In 26 studies (90%), the online care was provided via a website, and in 3 studies (10%) via an app. In 22 studies (76%), the therapeutic guidance and online care were integrated instead of two separate aspects. A total of 26 outcome measures were included in the evidence synthesis comparing blended interventions with no intervention: for the coping strategy catastrophizing, we found strong evidence for a significant effect. In addition, 1 outcome measure was included in the evidence synthesis comparing blended interventions with face-to-face interventions, but no evidence for a significant effect was found. A total of 6 outcome measures were included in the evidence synthesis comparing blended interventions with online interventions, but no evidence for a significant effect was found. CONCLUSIONS: Blended behavior change interventions for patients with chronic somatic disorders show variety in the type of therapeutic guidance, the type of online care, and how these two delivery modes are integrated. The evidence of the effectiveness of blended interventions is inconsistent and nonsignificant for most outcome measures. Future research should focus on which type of blended intervention works for whom. PMID- 29269339 TI - Estimating the Population Impact of a New Pediatric Influenza Vaccination Program in England Using Social Media Content. AB - BACKGROUND: The rollout of a new childhood live attenuated influenza vaccine program was launched in England in 2013, which consisted of a national campaign for all 2 and 3 year olds and several pilot locations offering the vaccine to primary school-age children (4-11 years of age) during the influenza season. The 2014/2015 influenza season saw the national program extended to include additional pilot regions, some of which offered the vaccine to secondary school children (11-13 years of age) as well. OBJECTIVE: We utilized social media content to obtain a complementary assessment of the population impact of the programs that were launched in England during the 2013/2014 and 2014/2015 flu seasons. The overall community-wide impact on transmission in pilot areas was estimated for the different age groups that were targeted for vaccination. METHODS: A previously developed statistical framework was applied, which consisted of a nonlinear regression model that was trained to infer influenza like illness (ILI) rates from Twitter posts originating in pilot (school-age vaccinated) and control (unvaccinated) areas. The control areas were then used to estimate ILI rates in pilot areas, had the intervention not taken place. These predictions were compared with their corresponding Twitter-based ILI estimates. RESULTS: Results suggest a reduction in ILI rates of 14% (1-25%) and 17% (2-30%) across all ages in only the primary school-age vaccine pilot areas during the 2013/2014 and 2014/2015 influenza seasons, respectively. No significant impact was observed in areas where two age cohorts of secondary school children were vaccinated. CONCLUSIONS: These findings corroborate independent assessments from traditional surveillance data, thereby supporting the ongoing rollout of the program to primary school-age children and providing evidence of the value of social media content as an additional syndromic surveillance tool. PMID- 29269340 TI - Exploring Advance Care Planning in Taiwanese Indigenous Cancer Survivors: Proposal for a Pilot Case-Control Study. AB - BACKGROUND: Research on Taiwanese indigenous cancer survivors' end-of-life (EOL) planning is still in its infancy, despite recent government and societal efforts to promote quality EOL care. Previous national studies in Taiwan have characterized indigenous peoples as a socioeconomically disadvantaged minority group. Compared with their mainstream cohorts, these remote residents are vulnerable to multiple social welfare problems, receiving and accessing little in the way of health care in rural mountain areas. Although advance care planning (ACP) has been shown to help patients achieve better quality of dying, very little is known about indigenous intentions for such interventions. Relevant studies are scarce in Taiwan, and programs for cancer survivors have been based almost entirely on nonindigenous populations. Since there has been no research on Taiwanese indigenous people's aims for ACP, there is a need to understand the impact of survivorship on ACP readiness among those who are currently living with, through, and beyond cancer. OBJECTIVE: We aim to identify differences in ACP intent and readiness among indigenous peoples with and without cancer diagnoses. We will identify the impact of factors such as tribal cultural beliefs and quality of life along with cancer exposure on the outcome of ACP readiness differences. In particular, we will examine the effects of ACP knowledge from previous ACP participation, EOL care experiences, and personal registry status of Do-Not-Resuscitate (DNR) in the national database. A secondary objective is to describe indigenous people's intent to participate in public education related to EOL planning. METHODS: A descriptive case-control study (N=200) is proposed where controls are matched to cases' attributes of age, gender, and cancer diagnosis. This matching analysis allows assessment of cancer as an exposure while taking into account age and gender as confounding variables. We are currently in the process of training personnel and extracting clinical and administrative information from the health care system of collaborating facilities. This carefully designed study provides a unique opportunity because for the first time in Taiwan, cancer survivorship and ACP readiness for EOL planning will be examined among difficult-to-reach indigenous peoples. RESULTS: We plan to complete this study in approximately 3 years. CONCLUSIONS: In this study, we expect to survey palliative care usage in the remote indigenous group, understand factors that influence ACP readiness, and later foster culturally appropriate ACP public participation and policies in order to facilitate collaboration between cancer health care providers in various Taiwanese subcultures. PMID- 29269341 TI - The Impact of mHealth Interventions on Breast Cancer Awareness and Screening: Systematic Review Protocol. AB - BACKGROUND: Mobile health (mHealth) is the use of mobile communication technologies to promote health by supporting health care practices (eg, health data collection, delivery of health care information). mHealth technologies (such as mobile phones) can be used effectively by health care practitioners in the distribution of health information and have the potential to improve access to and quality of health care, as well as reduce the cost of health services. Current literature shows limited scientific evidence related to the benefits of mHealth interventions for breast cancer, which is the leading cause of cancer deaths in women worldwide and contributes a large proportion of all cancer deaths, especially in developing countries. Women, especially in low- and middle income countries (LMICs), are faced with low odds of surviving breast cancer. This finding is likely due to multiple factors related to health systems: low priority of women's health and cancer on national health agendas; lack of awareness that breast cancer can be effectively treated if detected early; and societal, cultural, and religious factors that are prevalent in LMICs. The proposed systematic review will examine the impact of mHealth interventions on breast cancer awareness and screening among women aged 18 years and older. OBJECTIVE: The objectives of this study are to identify and describe the various mHealth intervention strategies that are used for breast cancer, and assess the impact of mHealth strategies on breast cancer awareness and screening. METHODS: Literature from various databases such as MEDLINE, EMBASE, PsycINFO, CINAHL, and Cochrane Central Register of Controlled Trials will be examined. Trial registers, reports, and unpublished theses will also be included. All mobile technologies such as cell phones, personal digital assistants, and tablets that have short message service, multimedia message service, video, and audio capabilities will be included. mHealth is the primary intervention. The search strategy will include keywords such as "mHealth," "breast cancer," "awareness," and "screening," among other medical subject heading terms. Articles published from January 1, 1964 to December 31, 2016 will be eligible for inclusion. Two authors will independently screen and select studies, extract data, and assess the risk of bias, with discrepancies resolved by dialogue involving a third author. We will assess statistical heterogeneity by examining the types of participants, interventions, study designs, and outcomes in each study, and pool studies judged to be statistically homogeneous. In the assessment of heterogeneity, a sensitivity analysis will be considered to explore statistical heterogeneity. Statistical heterogeneity will be investigated using the Chi-square test of homogeneity on Cochrane's Q statistic and quantified using the I-squared statistic. RESULTS: The search strategy will be refined with the assistance of an information specialist from November 1, 2017 to January 31, 2018. Literature searches will take place from February 2018 to April 2018. Data extraction and capturing in Review Manager (RevMan, Version 5.3) will take place from May 1, 2018 to July 31, 2018. The final stages will include analyses and writing, which is anticipated occur between August 2018 and October 2018. CONCLUSIONS: The knowledge derived from this study will inform health care stakeholders, including researchers, policy makers, investors, health professionals, technologists, and engineers, on the impact of mHealth interventions on breast cancer screening and awareness. TRIAL REGISTRATION: Prospero registration number CRD42016050202. PMID- 29269342 TI - Automatic Classification of Users' Health Information Need Context: Logistic Regression Analysis of Mouse-Click and Eye-Tracker Data. AB - BACKGROUND: Users searching for health information on the Internet may be searching for their own health issue, searching for someone else's health issue, or browsing with no particular health issue in mind. Previous research has found that these three categories of users focus on different types of health information. However, most health information websites provide static content for all users. If the three types of user health information need contexts can be identified by the Web application, the search results or information offered to the user can be customized to increase its relevance or usefulness to the user. OBJECTIVE: The aim of this study was to investigate the possibility of identifying the three user health information contexts (searching for self, searching for others, or browsing with no particular health issue in mind) using just hyperlink clicking behavior; using eye-tracking information; and using a combination of eye-tracking, demographic, and urgency information. Predictive models are developed using multinomial logistic regression. METHODS: A total of 74 participants (39 females and 35 males) who were mainly staff and students of a university were asked to browse a health discussion forum, Healthboards.com. An eye tracker recorded their examining (eye fixation) and skimming (quick eye movement) behaviors on 2 types of screens: summary result screen displaying a list of post headers, and detailed post screen. The following three types of predictive models were developed using logistic regression analysis: model 1 used only the time spent in scanning the summary result screen and reading the detailed post screen, which can be determined from the user's mouse clicks; model 2 used the examining and skimming durations on each screen, recorded by an eye tracker; and model 3 added user demographic and urgency information to model 2. RESULTS: An analysis of variance (ANOVA) analysis found that users' browsing durations were significantly different for the three health information contexts (P<.001). The logistic regression model 3 was able to predict the user's type of health information context with a 10-fold cross validation mean accuracy of 84% (62/74), followed by model 2 at 73% (54/74) and model 1 at 71% (52/78). In addition, correlation analysis found that particular browsing durations were highly correlated with users' age, education level, and the urgency of their information need. CONCLUSIONS: A user's type of health information need context (ie, searching for self, for others, or with no health issue in mind) can be identified with reasonable accuracy using just user mouse clicks that can easily be detected by Web applications. Higher accuracy can be obtained using Google glass or future computing devices with eye tracking function. PMID- 29269343 TI - Developing Online Recruitment and Retention Methods for HIV Prevention Research Among Adolescent Males Who Are Interested in Sex with Males: Interviews with Adolescent Males. AB - BACKGROUND: Adolescent males interested in sex with males (AMSM) are an important audience for HIV prevention interventions, but they are difficult to reach due to their age and social stigma. OBJECTIVE: We aim to identify efficient methods to recruit and retain AMSM in online research. METHODS: Interviews with 14-to-18 year-old AMSM (N=16) were conducted at 2017 Pride events in Boston, MA and Providence, RI. RESULTS: Participants reported that (1) social media platforms are viable recruitment venues; (2) recruitment advertisements should describe the study using colorful/bright pictures, familiar words, and information about compensation; (3) surveys should be <20 minutes in length; (4) modest compensation (eg, email gift card, US $10 to $20) was preferred; and (5) communications that remind participants about the length and content of surveys, and compensation, should be sent between study activities to increase retention. CONCLUSIONS: Soliciting input from AMSM provides critical guidance regarding recruitment and retention procedures to increase the efficiency of HIV prevention research for this at-risk group. PMID- 29269344 TI - Understanding a Nonlinear Causal Relationship Between Rewards and Physicians' Contributions in Online Health Care Communities: Longitudinal Study. AB - BACKGROUND: The online health care community is not just a place for the public to share physician reviews or medical knowledge, but also a physician-patient communication platform. The medical resources of developing countries are relatively inadequate, and the online health care community is a potential solution to alleviate the phenomenon of long hospital queues and the lack of medical resources in rural areas. However, the success of the online health care community depends on online contributions by physicians. OBJECTIVE: The aim of this study is to examine the effect of incentive mechanisms on physician's online contribution behavior in the online health community. We addressed the following questions: (1) from which specialty area are physicians more likely to participate in online health care community activities, (2) what are the factors affecting physician online contributions, and (3) do incentive mechanisms, including psychological and material rewards, result in differences of physician online contributions? METHODS: We designed a longitudinal study involving a data sample in three waves. All data were collected from the Good Doctor website, which is the largest online health care community in China. We first used descriptive statistics to investigate the physician online contribution behavior in its entirety. Then multiple linear and quadratic regression models were applied to verify the causal relationship between rewards and physician online contribution. RESULTS: Our sample included 40,300 physicians from 3607 different hospitals, 10 different major specialty areas, and 31 different provinces or municipalities. Based on the multiple quadratic regression model, we found that the coefficients of the control variables, past physician online contributions, doctor review rating, clinic title, hospital level, and city level, were .415, .189, -.099, -.106, and -.143, respectively. For the psychological (or material) rewards, the standardized coefficient of the main effect was 0.261 (or 0.688) and the standardized coefficient of the quadratic effect was -0.015 (or -0.049). All estimates were statistically significant (P<.001). CONCLUSIONS: Physicians with more past physician online contribution, with higher review ratings, coming from lower level clinics, not coming from tertiary hospitals, and not coming from big cities were more willing to participate in online health care community activities. To promote physician online contribution, it is necessary to establish an appropriate incentive mechanism including psychological and material rewards. Finally, our findings suggest two guidelines for designing a useful incentive mechanism to facilitate physician online contribution. First, material reward is more useful than psychological reward. Second, as indicated by the concave-down-increasing causal relationship between rewards and physician online contribution, although an appropriate reward is effective in encouraging willingness on the part of physicians to contribute to the online health care community, the effect of additional rewards is limited. PMID- 29269345 TI - PEGPH20 May Improve Standard-of-Care Therapy in Pancreatic Cancer. AB - The HA-degrading drug PEGPH20 plus standard therapy extends survival in metastatic pancreatic cancer. PMID- 29269346 TI - Targeting JAG1 Sensitizes Bone Metastases to Chemotherapy. AB - Chemotherapy induces JAG1 expression in osteoblasts, promoting chemoresistance in bone metastases. PMID- 29269347 TI - mTORC2-Driven Lipid Synthesis Promotes Liver Tumorigenesis. AB - mTORC2-induced lipid metabolism promotes hepatosteatosis progression to hepatocellular carcinoma. PMID- 29269348 TI - R-2HG Targets FTO to Increase m6A Levels and Suppress Tumor Growth. AB - R-2HG, thought to be an oncometabolite in IDH-mutant tumors, has antitumor activity in leukemia and glioma. PMID- 29269349 TI - Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages. AB - RATIONALE: Myocardial infarction is a major cause of adult mortality worldwide. The origin(s) of cardiac fibroblasts that constitute the postinfarct scar remain controversial, in particular the potential contribution of bone marrow lineages to activated fibroblasts within the scar. OBJECTIVE: The aim of this study was to establish the origin(s) of infarct fibroblasts using lineage tracing and bone marrow transplants and a robust marker for cardiac fibroblasts, the Collagen1a1 green fluorescent protein reporter. METHODS AND RESULTS: Using genetic lineage tracing or bone marrow transplant, we found no evidence for collagen-producing fibroblasts derived from hematopoietic or bone marrow lineages in hearts subjected to permanent left anterior descending coronary artery ligation. In fact, fibroblasts within the infarcted area were largely of epicardial origin. Intriguingly, collagen-producing fibrocytes from hematopoietic lineages were observed attached to the epicardial surface of infarcted and sham-operated hearts in which a suture was placed around the left anterior descending coronary artery. CONCLUSIONS: In this controversial field, our study demonstrated that the vast majority of infarct fibroblasts were of epicardial origin and not derived from bone marrow lineages, endothelial-to-mesenchymal transition, or blood. We also noted the presence of collagen-producing fibrocytes on the epicardial surface that resulted at least in part from the surgical procedure. PMID- 29269350 TI - Estimates of Mortality Benefit From Ideal Cardiovascular Health Metrics: A Dose Response Meta-Analysis. AB - BACKGROUND: Several studies have shown an inverse relationship between ideal cardiovascular health (CVH) and mortality. However, there are no studies that pool these data to show the shape of the relationship and quantify the mortality benefit from ideal CVH. METHODS AND RESULTS: We conducted a systematic internet literature search of multiple databases including MEDLINE, Web of Science, Embase, CINAHL, and Scopus for longitudinal studies assessing the relationship between ideal CVH and mortality in adults, published between January 1, 2010, and May 31, 2017. We included studies that assessed the relationship between ideal CVH and mortality in populations that were initially free of cardiovascular disease. We conducted a dose-response meta-analysis generating both study specific and pooled trends from the correlated log hazard ratio estimates of mortality across categories of ideal CVH metrics. A total of 6 studies were included in the meta-analysis. All of the studies indicated a linear decrease in (cardiovascular disease and all-cause) mortality with increasing ideal CVH metrics. Overall, each unit increase in CVH metrics was associated with a pooled hazard ratio for cardiovascular disease mortality of 0.81 (95% confidence interval, 0.75-0.87), while each unit increase in ideal CVH metrics was associated with a pooled hazard ratio of 0.89 (95% confidence interval, 0.86 0.93) for all-cause mortality. CONCLUSIONS: Our meta-analysis showed a strong inverse linear dose-response relationship between ideal CVH metrics and both all cause and cardiovascular disease-related mortality. This study suggests that even modest improvements in CVH is associated with substantial mortality benefit, thus providing a strong public health message advocating for even the smallest improvements in lifestyle. PMID- 29269351 TI - Reduction of Arterial Stiffness After Kidney Transplantation: A Systematic Review and Meta-Analysis. AB - BACKGROUND: End-stage kidney disease is associated with increased arterial stiffness. Although correction of uremia by kidney transplantation (KTx) could improve arterial stiffness, results from clinical studies are unclear partly due to small sample sizes. METHOD AND RESULTS: We conducted a systematic review and meta-analysis of before-after design studies performed in adult KTx patients with available measures of arterial stiffness parameters (pulse wave velocity [PWV], central pulse pressure [PP], and augmentation index) before and at any time post KTx. Mean difference of post- and pre-KTx values of different outcomes were estimated using a random effect model with 95% confidence interval. To deal with repetition of measurement within a study, only 1 period of measurement was considered per study by analysis. Twelve studies were included in meta-analysis, where a significant decrease of overall PWV by 1.20 m/s (95% CI 0.67-1.73, I2=72%), central PWV by 1.20 m/s (95% CI 0.16-2.25, I2=83%), peripheral PWV by 1.17 m/s (95% CI 0.17-2.17, I2=79%), and brachial-ankle PWV by 1.21 m/s (95% CI 0.66-1.75, I2=0%) was observed. Central PP (reported in 4 studies) decreased by 4.75 mm Hg (95% CI 0.78-10.28, I2=50%). Augmentation index (reported in 7 studies) decreased by 10.5% (95% CI 6.9-14.1, I2=64%). A meta-regression analysis showed that the timing of assessment post-KTx was the major source of the residual variance. CONCLUSIONS: This meta-analysis suggests a reduction of the overall arterial stiffness in patients with end-stage kidney disease after KTx. PMID- 29269352 TI - Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi-Ethnic Study of Atherosclerosis). AB - BACKGROUND: APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self-identified black participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AND RESULTS: Cross sectional associations of APOL1 genotypes (high-risk=2 alleles; low-risk=0 or 1 allele) with coronary artery calcification, carotid-intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C-based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high-risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high-risk group was 82% more likely to develop incident heart failure compared with the low-risk group (95% confidence interval, 1.01-3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00-3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03 3.35) slightly attenuated this association. The APOL1 high-risk genotypes were not significantly associated with other clinical CVD outcomes. CONCLUSIONS: Among blacks without baseline CVD, the APOL1 high-risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD. PMID- 29269353 TI - Newly Identified NO-Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function. AB - BACKGROUND: Guanylyl cyclase, a heme-containing alpha1beta1 heterodimer (GC1), produces cGMP in response to Nitric oxide (NO) stimulation. The NO-GC1-cGMP pathway negatively regulates cardiomyocyte contractility and protects against cardiac hypertrophy-related remodeling. We recently reported that the beta1 subunit of GC1 is detected at the intercalated disc with connexin 43 (Cx43). Cx43 forms gap junctions (GJs) at the intercalated disc that are responsible for electrical propagation. We sought to determine whether there is a functional association between GC1 and Cx43 and its role in cardiac homeostasis. METHODS AND RESULTS: GC1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC1 and Cx43 are associated. Mice lacking the alpha subunit of GC1 (GCalpha1 knockout mice) displayed a significant decrease in GJ function (dye-spread assay) and Cx43 membrane lateralization. In a cardiac-hypertrophic model, angiotensin II treatment disrupted the GC1-Cx43 association and induced significant Cx43 membrane lateralization, which was exacerbated in GCalpha1 knockout mice. Cx43 lateralization correlated with decreased Cx43-containing GJs at the intercalated disc, predictors of electrical dysfunction. Accordingly, an ECG revealed that angiotensin II-treated GCalpha1 knockout mice had impaired ventricular electrical propagation. The phosphorylation level of Cx43 at serine 365, a protein-kinase A upregulated site involved in trafficking/assembly of GJs, was decreased in these models. CONCLUSIONS: GC1 modulates ventricular Cx43 location, hence GJ function, and partially protects from electrical dysfunction in an angiotensin II hypertrophy model. Disruption of the NO-cGMP pathway is associated with cardiac electrical disturbance and abnormal Cx43 phosphorylation. This previously unknown NO/Cx43 signaling could be a protective mechanism against stress-induced arrhythmia. PMID- 29269354 TI - Atrial Fibrillation Promotion in a Rat Model of Rheumatoid Arthritis. AB - BACKGROUND: The prevalence of atrial fibrillation (AF) is significantly higher in rheumatoid arthritis (RA) patients, but the underlying mechanisms remain poorly understood. The goal of this study was to assess the effects of RA on AF susceptibility and atrial arrhythmogenic remodeling in a rat model of RA. METHODS AND RESULTS: Collagen-induced arthritis was induced in rats by immunization with type II collagen in Freund's incomplete adjuvant. Among the rats that developed arthritis, AF susceptibility and atrial remodeling were examined 8 weeks after the primary immunization. AF inducibility and duration were substantially increased in collagen-induced arthritis rats, and AF duration was significantly and positively correlated with the serum IL-6 and TNF-alpha levels. Rats with collagen-induced arthritis showed prolonged atrial conduction time with no changes in the atrial effective refractory period. Atrial conduction delay was accompanied by significantly increased atrial fibrosis. In addition, atrial structural and autonomic remodeling, including left atrial dilation, apoptosis and autophagy of atrial myocytes, and atrial heterogeneous sympathetic hyperinnervation, was observed. Interestingly, we found that collagen-induced arthritis had no significant effects on connexins, Nav1.5, and the main ion channels' protein expressions in atria. CONCLUSIONS: We demonstrated that RA increased AF susceptibility by inducing AF-promoting atrial remodeling. This study may provide insights into mechanisms underlying RA-induced AF and validate a model that is suitable for further mechanistic and therapeutic exploration. PMID- 29269355 TI - Cardiac Conduction System in Congenitally Corrected Transposition of the Great Arteries and Its Clinical Relevance. PMID- 29269356 TI - Sensory neuronopathy associated with cholangiocarcinoma diagnosed 6 years after symptom onset. AB - A pure sensory neuronopathy (also referred to as a sensory ganglionopathy) is one of a handful of classical neurological paraneoplastic syndromes. Current guidelines recommend that in cases of sensory neuronopathy, a search for an underlying malignancy be pursued for up to 4 years. We report the case of a 52 year-old woman with a sensory neuronopathy who was eventually diagnosed with a cholangiocarcinoma 6 years after the onset of her disease. A CT fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed 18 and 24 months after disease onset failed to identify an underlying neoplasm. Immunomodulatory treatment with corticosteroids, intravenous immunoglobulins and plasma exchange were ineffective. Investigations for Sjogren's disease were negative. A third FDG-PET performed 6 years after symptom onset identified a cholangiocarcinoma, which was confirmed histologically following open resection. Since the tumour was removed, our patient's condition has not progressed, but there has been no improvement and she remains severely disabled. PMID- 29269357 TI - Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologist's perspective. AB - A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure. PMID- 29269358 TI - Stenotrophomonas maltophilia: an emerging multidrug-resistant opportunistic pathogen in the immunocompromised host. AB - Stenotrophomonas maltophilia is a multidrug-resistant opportunistic pathogen with increasing prevalence and high morbidity and mortality. In addition to its classic association with pulmonary infections, S. maltophilia can cause skin and soft tissue infections with varying clinical presentations. We describe the case of a man in his 30s with B-cell acute lymphoblastic leukaemia who presented with a solitary patch of faint but tender purpura found to have rapidly progressive S. maltophilia infection diagnosed on skin biopsy. S. maltophilia infection should be considered in the cutaneous evaluation of the immunocompromised host. PMID- 29269359 TI - A disclosed diagnosis for 24 year's unknown illness. AB - IgG4-related disease (IgG4-RD) is a newly described illness over the last several years. A 57-year-old man, who had been followed for chronic kidney disease (CKD), chronic pancreatitis and history of operated cholangitis, was admitted to our hospital for abdominal pain and worsening renal function. Serum levels of IgG and IgG4 were elevated. CT scan showed the characteristic findings of IgG4-related retroperitoneal fibrosis, pancreas and kidney disease. An endoscopic biopsy revealed the finding compatible with IgG4-RD. Steroid therapy led to the remission of his abdominal pain. Patients with CKD of unknown aetiology may have IgG4-RD. PMID- 29269360 TI - Management of atypical femoral fracture in a patient with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a generalised connective tissue disorder associated with low bone mass, bone fragility and increased susceptibility to fractures. First-line treatment to improve bone mineral density (BMD) is usually with bisphosphonates but long-term usage has been associated with uncommon complications such as atypical femoral fractures (AFF). Treatment with teriparatide in this situation has been reported with positive outcomes. However, choice of treatment after 2 years of teriparatide has not been well studied or reported. We describe a patient with OI treated with bisphosphonates for 9 years, who then suffered a spontaneous AFF, was subsequently started on teriparatide for 2 years followed by 6 monthly Denosumab. 1 year post-treatment with Denosumab, there was significant improvement in BMD, good fracture healing and no new fractures. This case highlights the potential use of denosumab following 2 years of teriparatide treatment in patients with OI with AFF. PMID- 29269361 TI - Uvular necrosis following diagnostic gastroscopy. AB - Uvular necrosis is an extremely rare complication of gastroscopy. We describe the fifth published case of uvular necrosis following an uncomplicated diagnostic gastroscopy in a young man. Presentation with severe sore throat and inability to swallow saliva occurred within 24 hours of gastroscopy and resolved with conservative treatment. PMID- 29269362 TI - Successful embolisation of an intracranial meningioma via a right-sided aortic arch. AB - Right aortic arch is an unusual arch variation. Supra-aortic neurointervention in such cases has been sparingly reported. This case highlights the unusual association of a left hemispheric convexity meningioma with a right aortic arch which was successfully navigated. Particle embolisation of the meningioma produced good results followed by complete surgical excision and gratifying overall final outcome in this challenging scenario. PMID- 29269363 TI - A surgeon's nightmare: pyoderma gangrenosum with pathergy effect mimicking necrotising fasciitis. AB - A 53-year-old woman was admitted for vulval swelling and fever. She was initially diagnosed with vulval cellulitis and given parenteral antibiotics. Within 1 week, she developed necrotic-looking skin lesions extending from her vulva to her buttock. Emergency surgical debridement with diversion colostomy was performed in view of suspected necrotising fasciitis. Shortly after the surgery, she developed necrotic-looking skin lesions at the peripheral venous cannula insertion site, central line insertion site, and around her surgical wounds and stoma. A second surgical debridement was performed and shortly afterwards, similar skin lesions appeared around her surgical wounds. Her clinical progression was suggestive of pyoderma gangrenosum with pathergy effect. Hence, she was started on topical steroid, systemic steroid and immunosuppressant. The skin lesions responded well to medical therapy. Further systemic workup for conditions associated with this disease revealed findings suspicious for myelodysplastic syndrome. PMID- 29269364 TI - Deliberate self-poisoning with long-acting anticoagulant rodenticides. AB - Long-acting anticoagulant rodenticides, also called superwarfarins, are known for their greater potency, longer half-life and delayed onset of symptoms. Cases of superwarfarin poisoning can pose a diagnostic and clinical challenge due to a wide array of presentations and prolonged severe coagulopathy requiring months of high-dose oral vitamin K therapy. The most common presentation of long-acting anticoagulant rodenticide poisoning is mucocutaneous bleeding, with other common presentations including haematuria, gingival bleeding, epistaxis and gastrointestinal bleeding. We discuss a case of deliberate self-poisoning with long-acting anticoagulant rodenticides presenting with haematuria and coagulation values above measurable limits. This case is important as it required immediate and maintenance therapy in order to prevent profound bleeding, as well as the evaluation of the patient's psychosocial factors to ensure medical compliance and to prevent refractory complications or repeated self-harm. PMID- 29269365 TI - Spinal cord abscess secondary to infected dorsal dermal sinus in an infant: uncommon presentation of a known entity. AB - Infection along the congenital dermal sinus tract is well known. However, congenital dorsal dermal sinus presenting with intramedullary abscess is quite rare. The sinus tract usually presents in the midline and acts as a portal of entry for infection that may manifest as meningitis, extradural or subdural abscess and may further involve the cord. Surgical drainage of pus and complete excision of the sinus tract is the standard treatment. Here we describe an infant with an infected congenital dorsal dermal sinus with atypical presentation as large paracentral abscess in the upper back. We further highlight the importance of recognising and treating these skin dimples even when clinically silent to avoid catastrophic complications. PMID- 29269366 TI - Subacute combined degeneration of the spinal cord in vitamin B12 and copper deficiency. PMID- 29269367 TI - Auditory agnosia caused by bilateral putamen haemorrhage. AB - A 55-year-old right-handed man with a history of hypertension suddenly fell and developed right hemiparesis. Neurological examination revealed that he was alert, but did not appropriately respond to verbal questions and commands. Detailed examination revealed that he could correctly respond to written commands. His speech was almost fluent, showing no paraphasia and normal articulation. His written sentences were legible. Pure tone audiometry showed that his auditory acuity was relatively preserved. His brainstem auditory evoked potential components from I to V were recorded bilaterally with normal latency. Cerebral CT demonstrated fresh bleeding in the left putamen and an old haemorrhage on the opposite side. He was treated by antihypertensive therapy and rehabilitation. Although there remained mild sensory deficit on his right extremities and he felt a slight noise during conversation, he had little difficulty with verbal communication when he was transferred to another hospital on day 38. PMID- 29269368 TI - Colonic perforation by an intrathecal baclofen pump catheter causing delayed Escherichia coli meningitis. AB - Intrathecal baclofen (ITB) delivery via an implanted pump is frequently used for the treatment of spasticity. This is an effective and safe neurosurgical and pharmacological intervention associated with an improvement in patient quality of life. There is, however, a risk of device-related infection. We present a patient with pump-site infection and Escherichia coli meningitis secondary to transcolonic perforation of an intrathecal baclofen pump catheter. While this is rare, we review the intraoperative precautions and best practices that should be taken to prevent and manage this unusual complication. PMID- 29269369 TI - Primary apocrine carcinoma of an unusual site. AB - Primary apocrine carcinoma is a rare malignancy most commonly occurring in apocrine dense areas like axilla. There are only about 200 cases reported to date. We report a case of primary apocrine carcinoma present at an unusual site, that is, the arm. A wide local excision of the mass was done and was diagnosed as apocrine carcinoma on histopathological examination and was confirmed by immunohistochemistry. Wide local excision is the treatment required. PMID- 29269370 TI - Endodontic management of taurodontism with a complex root canal anatomy in mandibular posterior teeth. AB - One of the biggest challenges in endodontic treatment is to comprehensively understand the variation of tooth root canal anatomy. To a large degree, the anatomy and furcation distribution of teeth, which vary from nationality and ethnic groups, will influence the clinical diagnosis, treatment plan and even prognosis. Taurodontism, as one of anatomic variation in tooth structures, is relatively hard to be seen in dental clinics. Two special cases of taurodontism with varied root canal anatomies in mandibular second premolar and first molar are reported in this paper. PMID- 29269371 TI - Mystery ring: a case of TIPS stent migration. PMID- 29269372 TI - Giant ductal pseudoaneurysm in infancy: a lesson learnt the hard way. PMID- 29269373 TI - Ultrawide field imaging with navigable magnifier for diagnosis of diffuse unilateral subacute neuroretinitis. PMID- 29269374 TI - Nasal tip schwannoma mimicking rhinophyma. PMID- 29269375 TI - Recurrent lower gastrointestinal bleeding in an 87-year-old woman. PMID- 29269376 TI - Biomarker-Based Therapy in Pancreatic Ductal Adenocarcinoma: An Emerging Reality? AB - Over the last decade, many of the major solid organ cancers have seen improvements in survival due to development of novel therapeutics and corresponding biomarkers that predict treatment efficacy or resistance. In contrast, favorable outcomes remain challenging in pancreatic ductal adenocarcinoma (PDAC), in part related to the lack of validated biomarkers for patient and treatment selection and thus optimal clinical decision-making. Increasingly, however, therapeutic development for PDAC is accompanied by bioassays to evaluate response and to study mechanism of actions with a corresponding increase in the number of trials in mid to late stage with integrated biomarkers. In addition, blood-based biomarkers that provide a measure of disease activity and allow for minimally invasive tumor analyses are emerging, including circulating tumor DNA, exosomes, and circulating tumor cells. In this article, we review potential biomarkers for currently approved therapies as well as emerging biomarkers for therapeutics under development. Clin Cancer Res; 24(10); 2241-50. (c)2017 AACR. PMID- 29269378 TI - Tumor Side as Model of Integrative Molecular Classification of Colorectal Cancer. AB - It has long since been recognized that colorectal cancer is molecularly heterogeneous and its clinical behavior differs if the primary tumor was located in the right or left side of the colon. Recent studies have shown that part of this heterogeneity is captured by the anatomic location of the tumor. Clin Cancer Res; 24(5); 989-90. (c)2017 AACRSee related article by Loree et al., p. 1062. PMID- 29269377 TI - Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice. AB - Purpose: Fibroblast activation protein (FAP) is overexpressed in cancer associated fibroblasts and is an interesting target for cancer immune therapy, with prior studies indicating a potential to affect the tumor stroma. Our aim was to extend this earlier work through the development of a novel FAP immunogen with improved capacity to break tolerance for use in combination with tumor antigen vaccines.Experimental Design: We used a synthetic consensus (SynCon) sequence approach to provide MHC class II help to support breaking of tolerance. We evaluated immune responses and antitumor activity of this novel FAP vaccine in preclinical studies, and correlated these findings to patient data.Results: This SynCon FAP DNA vaccine was capable of breaking tolerance and inducing both CD8+ and CD4+ immune responses. In genetically diverse, outbred mice, the SynCon FAP DNA vaccine was superior at breaking tolerance compared with a native mouse FAP immunogen. In several tumor models, the SynCon FAP DNA vaccine synergized with other tumor antigen-specific DNA vaccines to enhance antitumor immunity. Evaluation of the tumor microenvironment showed increased CD8+ T-cell infiltration and a decreased macrophage infiltration driven by FAP immunization. We extended this to patient data from The Cancer Genome Atlas, where we find high FAP expression correlates with high macrophage and low CD8+ T-cell infiltration.Conclusions: These results suggest that immune therapy targeting tumor antigens in combination with a microconsensus FAP vaccine provides two fisted punch-inducing responses that target both the tumor microenvironment and tumor cells directly. Clin Cancer Res; 24(5); 1190-201. (c)2018 AACR. PMID- 29269379 TI - Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction. AB - OBJECTIVE: Chronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia. METHODS: A cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER). RESULTS: In the UK, the cost per quality adjusted life-year (QALY) gained for sacubitril/valsartan (using cardiovascular mortality) was L17 100 (?20 400) versus enalapril. In Denmark, the ICER for sacubitril/valsartan was Kr 174 000 (?22 600). In Colombia, the ICER was COP$39.5 million (?11 200) per QALY gained. Deterministic sensitivity analysis showed that results were most sensitive to the extrapolation of mortality, duration of treatment effect and time horizon, but were robust to other structural changes, with most scenarios associated with ICERs below the willingness-to-pay threshold for all three country settings. Probabilistic sensitivity analysis suggested the probability that sacubitril/valsartan was cost-effective at conventional willingness-to-pay thresholds was 68%-94% in the UK, 84% in Denmark and 95% in Colombia. CONCLUSIONS: Our analysis suggests that, in all three countries, sacubitril/valsartan is likely to be cost-effective compared with an ACEI (the current standard of care) in patients with HF-REF. PMID- 29269380 TI - Resting heart rate, temporal changes in resting heart rate, and overall and cause specific mortality. AB - OBJECTIVE: Most studies investigating the association between resting heart rate (RHR) and mortality have focused on cardiovascular disease (CVD) mortality, and measured RHR at only one time point. We aimed to assess associations of RHR and changes in RHR over approximately a decade with overall and cause-specific mortality. METHODS: We used data from participants in the Melbourne Collaborative Cohort Study with RHR measures at baseline (1990-1994; n=41 386; 9846 deaths) and at follow-up (2003-2007; n=21 692; 2818 deaths). RHR measures were taken by trained staff, using Dinamap monitors. Cox models were used to estimate HR and 95% CI for the associations between RHR and mortality. Vital status and cause of death were ascertained until August 2015 and December 2013, respectively. RESULTS: After adjustment for confounders, including blood pressure and known medical conditions but not arrhythmias or atrial fibrillation, RHR was associated with a higher risk of death of similar magnitude for CVD (HR per 10 beats per minute (bpm)=1.11, 95% CI 1.07 to 1.16), cancer (HR=1.10, 95% CI 1.06 to 1.13) and other causes (HR=1.20, 95% CI 1.16 to 1.25). Higher mortality was observed for most cancer sites, including breast (HR=1.16, 95% CI 1.03 to 1.31), colorectal (HR=1.18, 95% CI 1.08 to 1.29), kidney (HR=1.27, 95% CI 1.03 to 1.57) and lung cancer (HR=1.19, 95% CI 1.10 to 1.29). Temporal increases in RHR were associated with higher mortality, particularly for individuals whose RHR increased by more than 15 bpm. CONCLUSIONS: RHR and changes in RHR over a decade are associated with mortality risk, including from causes other than CVD such as breast, colorectal or lung cancer. Monitoring of RHR may have utility in identifying individuals at higher mortality risk. PMID- 29269381 TI - Independent and combined effects of airway remodelling and allergy on airway responsiveness. AB - Airway remodelling and allergic inflammation are key features of airway hyperresponsiveness (AHR) in asthma; however, their interrelationships are unclear. The present study investigated the separate and combined effects of increased airway smooth muscle (ASM) layer thickness and allergy on AHR. We integrated a protocol of ovalbumin (OVA)-induced allergy into a non-inflammatory mouse model of ASM remodelling induced by conditional and airway-specific expression of transforming growth factor-alpha (TGF-alpha) in early growth response-1 (Egr-1)-deficient transgenic mice, which produced thickening of the ASM layer following ingestion of doxycycline. Mice were sensitised to OVA and assigned to one of four treatment groups: Allergy - normal chow diet and OVA challenge; Remodelling - doxycycline in chow and saline challenge; Allergy and Remodelling - doxycycline in chow and OVA challenge; and Control - normal chow diet and saline challenge. Airway responsiveness to methacholine (MCh) and histology were assessed. Compared with the Control group, airway responsiveness to MCh was increased in the Allergy group, independent of changes in wall structure, whereas airway responsiveness in the Remodelling group was increased independent of exposure to aeroallergen. The combined effects of allergy and remodelling on airway responsiveness were greater than either of them alone. There was a positive relationship between the thickness of the ASM layer with airway responsiveness, which was shifted upward in the presence of allergy. These findings support allergy and airway remodelling as independent causes of variable and excessive airway narrowing. PMID- 29269384 TI - Methods to drive systems biology forward. PMID- 29269382 TI - A framework for exhaustively mapping functional missense variants. AB - Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes. PMID- 29269385 TI - The Guilty Mother. PMID- 29269383 TI - From network to phenotype: the dynamic wiring of an Arabidopsis transcriptional network induced by osmotic stress. AB - Plants have established different mechanisms to cope with environmental fluctuations and accordingly fine-tune their growth and development through the regulation of complex molecular networks. It is largely unknown how the network architectures change and what the key regulators in stress responses and plant growth are. Here, we investigated a complex, highly interconnected network of 20 Arabidopsis transcription factors (TFs) at the basis of leaf growth inhibition upon mild osmotic stress. We tracked the dynamic behavior of the stress responsive TFs over time, showing the rapid induction following stress treatment, specifically in growing leaves. The connections between the TFs were uncovered using inducible overexpression lines and were validated with transient expression assays. This study resulted in the identification of a core network, composed of ERF6, ERF8, ERF9, ERF59, and ERF98, which is responsible for most transcriptional connections. The analyses highlight the biological function of this core network in environmental adaptation and its redundancy. Finally, a phenotypic analysis of loss-of-function and gain-of-function lines of the transcription factors established multiple connections between the stress-responsive network and leaf growth. PMID- 29269386 TI - Racial and Ethnic Disparities in Early Childhood Obesity. AB - OBJECTIVES: The prevalence of childhood obesity is significantly higher among racial and/or ethnic minority children in the United States. It is unclear to what extent well-established obesity risk factors in infancy and preschool explain these disparities. Our objective was to decompose racial and/or ethnic disparities in children's weight status according to contributing socioeconomic and behavioral risk factors. METHODS: We used nationally representative data from ~10 700 children in the Early Childhood Longitudinal Study Birth Cohort who were followed from age 9 months through kindergarten entry. We assessed the contribution of socioeconomic factors and maternal, infancy, and early childhood obesity risk factors to racial and/or ethnic disparities in children's BMI z scores by using Blinder-Oaxaca decomposition analyses. RESULTS: The prevalence of risk factors varied significantly by race and/or ethnicity. African American children had the highest prevalence of risk factors, whereas Asian children had the lowest prevalence. The major contributor to the BMI z score gap was the rate of infant weight gain during the first 9 months of life, which was a strong predictor of BMI z score at kindergarten entry. The rate of infant weight gain accounted for between 14.9% and 70.5% of explained disparities between white children and their racial and/or ethnic minority peers. Gaps in socioeconomic status were another important contributor that explained disparities, especially those between white and Hispanic children. Early childhood risk factors, such as fruit and vegetable consumption and television viewing, played less important roles in explaining racial and/or ethnic differences in children's BMI z scores. CONCLUSIONS: Differences in rapid infant weight gain contribute substantially to racial and/or ethnic disparities in obesity during early childhood. Interventions implemented early in life to target this risk factor could help curb widening racial and/or ethnic disparities in early childhood obesity. PMID- 29269387 TI - Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy. AB - Bleomycin has progressively been used to treat low-flow vascular malformations in children. No significant systemic side effects have been reported in large series after low doses, but some authors are still concerned about its use. We report a case of a severe acute lung toxicity after a low dose of a second bleomycin intralesional injection in a 5-year-old girl. She had no risk factors and presented a cervical low-flow venous malformation. Twenty-four hours after this second administration, she presented with fever and respiratory distress. A chest radiograph showed bilateral opacities and computerized tomography revealed extensive and diffuse lung ground-glass opacities. The patient started to receive intravenous methylprednisolone, but she experienced progressively increased dyspnea, and montelukast was added. She improved and was discharged from the hospital without oxygen support, with montelukast and prednisolone for tapering doses during months. Five months after onset, the patient is developing well, is active, and walks and talks without dyspnea. A new low-dose computed tomography shows improvement in radiologic findings. This is the second case of pulmonary toxicity observed in a child after bleomycin intralesional administration, and the first reported after the lowest dose of this drug to date (7 mg: 0.28 mg/kg; 10 U: 0.4 U/kg). A delay in the diagnosis and treatment of this complication can be fatal. Any physician who treats these patients must be alert and consider this complication in children with respiratory symptoms after bleomycin sclerotherapy. Early detection of pulmonary toxicity would allow prompt therapy and could avoid pulmonary damage. PMID- 29269388 TI - Risk Factors of Sudden Cardiac Death in the Young: Multiple-Year Community-Wide Assessment. AB - BACKGROUND: Prevention of sudden cardiac arrest (SCA) in the young remains a largely unsolved public health problem, and sports activity is an established trigger. Although the presence of standard cardiovascular risk factors in the young can link to future morbidity and mortality in adulthood, the potential contribution of these risk factors to SCA in the young has not been evaluated. METHODS: We prospectively ascertained subjects who experienced SCA between the ages of 5 and 34 years in the Portland, Oregon, metropolitan area (2002-2015, catchment population ~1 million). We assessed the circumstances, resuscitation outcomes, and clinical profile of subjects who had SCA by a detailed evaluation of emergency response records, lifetime clinical records, and autopsy examinations. We specifically evaluated the association of standard cardiovascular risk factors and SCA, and sports as a trigger for SCA in the young. RESULTS: Of 3775 SCAs in all age groups, 186 (5%) occurred in the young (mean age 25.9+/-6.8, 67% male). In SCA in the young, overall prevalence of warning signs before SCA was low (29%), and 26 (14%) were associated with sports as a trigger. The remainder (n=160) occurred in other settings categorized as nonsports. Sports-related SCAs accounted for 39% of SCAs in patients aged <=18, 13% of SCAs in patients aged 19 to 25, and 7% of SCAs in patients aged 25 to 34. Sports-related SCA cases were more likely to present with shockable rhythms, and survival from cardiac arrest was 2.5-fold higher in sports-related versus nonsports SCA (28% versus 11%; P=0.05). Overall, the most common SCA-related conditions were sudden arrhythmic death syndrome (31%), coronary artery disease (22%), and hypertrophic cardiomyopathy (14%). There was an unexpectedly high overall prevalence of established cardiovascular risk factors (obesity, diabetes mellitus, hypertension, hyperlipidemia, smoking) with >=1 risk factors in 58% of SCA cases. CONCLUSIONS: Sports was a trigger of SCA in a minority of cases, and, in most patients, SCA occurred without warning symptoms. Standard cardiovascular risk factors were found in over half of patients, suggesting the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages. PMID- 29269389 TI - Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Malignancy Risk in Adults With Congenital Heart Disease. AB - BACKGROUND: Adults with congenital heart disease (CHD) are exposed to increasing amounts of low-dose ionizing radiation (LDIR) from cardiac procedures. Cancer prevalence in this population is higher than in the general population. This study estimates the association between LDIR exposure from cardiac procedures and incident cancer in adult patients with CHD. METHODS: The study population derived from the Quebec Congenital Heart Disease Database. We measured cumulative numbers of LDIR-related cardiac procedures for each patient until 1 year before the time of cancer diagnosis or administrative censoring. To assess the association between LDIR exposure and cancer risk, we conducted a nested case-control study and matched cancer cases with controls on sex, CHD severity, birth year, and age. RESULTS: The study included 24 833 adult patients with CHD aged 18 to 64 years from 1995 to 2009. In >250 791 person-years of follow-up, 602 cancer cases were observed (median age, 55.4 years). The cumulative incidence of cancer estimated up to 64 years of age was 15.3% (95% confidence interval [CI], 14.2-16.5). Cases had more LDIR-related cardiac procedures than controls (1410 versus 921 per 1000 adult patients with CHD, P<0.0001). Cumulative LDIR exposure was independently associated with cancer (odds ratio [OR], 1.08 per procedure; 95% CI, 1.04-1.13). Similar results were obtained by using dose estimates for LDIR exposure (OR, 1.10 per 10 mSv; 95% CI, 1.05-1.15) with a possible dose-related response. The effect measure was in the same direction, and the association was persistent for exposure from >=6 procedures in all sensitivity analyses: after excluding most smoking-related cancer cases (OR, 1.10 per procedure; 95% CI, 1.05-1.16 and OR when exposure from >=6 procedures, 3.08; 95% CI, 1.77-5.37), and after applying a 3-year lag period (OR, 1.09 per procedure; 95% CI, 1.03-1.14 and OR when exposure from >=6 procedures: 2.58; 95% CI, 1.43-4.69). CONCLUSIONS: To our knowledge, this is the first large population-based study to analyze and document the association between LDIR-related cardiac procedures and incident cancer in the population of adults with CHD. Confirmations of these findings by prospective studies are needed to reinforce policy recommendations for radiation surveillance in patients with CHD where no regulation currently exists. Physicians ordering and performing cardiac imaging should ensure that exposure is as low as reasonably achievable without sacrificing quality of care. PMID- 29269390 TI - Prognostic Implications of Magnetic Resonance-Derived Quantification in Asymptomatic Patients With Organic Mitral Regurgitation: Comparison With Doppler Echocardiography-Derived Integrative Approach. AB - BACKGROUND: Magnetic resonance imaging (MRI) is an accurate method for the quantitative assessment of organic mitral regurgitation (OMR). The aim of the present study was to compare the discriminative power of MRI quantification and the recommended Doppler echocardiography (ECHO)-derived integrative approach to identify asymptomatic patients with OMR and adverse outcome. METHODS: The study population consisted of 258 asymptomatic patients (63+/-14 years, 60% men) with preserved left ventricular ejection fraction (>60%) and chronic moderate and severe OMR (flail 25%, prolapse 75%) defined by using the ECHO-derived integrative approach. All patients underwent MRI to quantify regurgitant volume (RV) of OMR by subtracting the aortic forward flow volume from the total left ventricular stroke volume. Severe OMR was defined as RV>=60 mL. RESULTS: Mean ECHO-derived RV was on average 17.1 mL larger than the MRI-derived RV (P<0.05). Concordant grading of OMR severity with both techniques was observed in 197 (76%) individuals with 62 (31%) patients having severe OMR (MRI SEV-ECHO SEV) and 135 (69%) patients having moderate OMR (MRI MOD-ECHO MOD). The remaining 61 (24%) individuals had discordant findings (MRI SEV-ECHO MOD or MRI MOD-ECHO SEV) between the 2 techniques. The majority of these differences in OMR classification were observed in patients with late systolic or multiple jets (both kappa<0.2). Patients with eccentric jets showed moderate agreement (kappa=0.53; 95% confidence interval, 0.41-0.64). In contrast, a very good agreement (kappa=0.90; 95% confidence interval, 0.82-0.98) was observed in a combination of holosystolic, central, and single jet. During a median follow-up of 5.0 years (interquartile range, 3.5-6.0 years), 38 (15%) patients died and 106 (41%) either died or developed indication for mitral valve surgery. In separate Cox regression analyses, the MRI-derived left ventricular end-systolic volume index, RV, and OMR category (severe versus moderate), and the ECHO-derived OMR category were independent predictors of all-cause mortality (all P<0.05). The MRI-derived RV showed the largest area under the curve to predict mortality (0.72) or its combination with the development of indication for mitral valve surgery (0.83). CONCLUSIONS: The findings of the present study suggest that the MRI-derived assessment of OMR can better identify patients with severe OMR and adverse outcome than ECHO-derived integrative approach warranting close follow-up and perhaps, early mitral valve surgery. PMID- 29269391 TI - FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes. AB - FoxP3+ regulatory T cells (Tregs) are a central element of immunological tolerance. FoxP3 is the key determining transcription factor of the Treg lineage, interacting with numerous cofactors and transcriptional targets to determine the many facets of Treg function. Its absence leads to devastating lymphoproliferation and autoimmunity in scurfy mutant mice and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients. To finely map transcriptionally active regions of the protein, with respect to disease-causing variation, we performed a systematic alanine-scan mutagenesis of FoxP3, assessing mutational impacts on DNA binding and transcriptional activation or repression. The mutations affected transcriptional activation and repression in a variegated manner involving multiple regions of the protein and varying between different transcriptional targets of FoxP3. There appeared to be different modalities for target genes related to classic immunosuppressive function vs. those related to atypical or tissue-Treg functions. Relevance to in vivo Treg biology was established by introducing some of the subtle Foxp3 mutations into the mouse germline by CRISPR-based genome editing. The resulting mice showed Treg populations in normal numbers and exhibited no overt autoimmune manifestations. However, Treg functional defects were revealed upon competition or by system stress, manifest as a strikingly heightened susceptibility to provoked colitis, and conversely by greater resistance to tumors. These observations suggest that some of the missense mutations that segregate in human populations, but do not induce IPEX manifestations, may have unappreciated consequences in other diseases. PMID- 29269392 TI - Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. AB - PARKIN, an E3 ligase mutated in familial Parkinson's disease, promotes mitophagy by ubiquitinating mitochondrial proteins for efficient engagement of the autophagy machinery. Specifically, PARKIN-synthesized ubiquitin chains represent targets for the PINK1 kinase generating phosphoS65-ubiquitin (pUb), which constitutes the mitophagy signal. Physiological regulation of PARKIN abundance, however, and the impact on pUb accumulation are poorly understood. Using cells designed to discover physiological regulators of PARKIN abundance, we performed a pooled genome-wide CRISPR/Cas9 knockout screen. Testing identified genes individually resulted in a list of 53 positive and negative regulators. A transcriptional repressor network including THAP11 was identified and negatively regulates endogenous PARKIN abundance. RNAseq analysis revealed the PARKIN encoding locus as a prime THAP11 target, and THAP11 CRISPR knockout in multiple cell types enhanced pUb accumulation. Thus, our work demonstrates the critical role of PARKIN abundance, identifies regulating genes, and reveals a link between transcriptional repression and mitophagy, which is also apparent in human induced pluripotent stem cell-derived neurons, a disease-relevant cell type. PMID- 29269393 TI - Structural basis for the regulation of beta-glucuronidase expression by human gut Enterobacteriaceae. AB - The gut microbiota harbor diverse beta-glucuronidase (GUS) enzymes that liberate glucuronic acid (GlcA) sugars from small-molecule conjugates and complex carbohydrates. However, only the Enterobacteriaceae family of human gut associated Proteobacteria maintain a GUS operon under the transcriptional control of a glucuronide repressor, GusR. Despite its potential importance in Escherichia, Salmonella, Klebsiella, Shigella, and Yersinia opportunistic pathogens, the structure of GusR has not been examined. Here, we explore the molecular basis for GusR-mediated regulation of GUS expression in response to small-molecule glucuronides. Presented are 2.1-A-resolution crystal structures of GusRs from Escherichia coli and Salmonella enterica in complexes with a glucuronide ligand. The GusR-specific DNA operator site in the regulatory region of the E. coli GUS operon is identified, and structure-guided GusR mutants pinpoint the residues essential for DNA binding and glucuronide recognition. Interestingly, the endobiotic estradiol-17-glucuronide and the xenobiotic indomethacin-acyl-glucuronide are found to exhibit markedly differential binding to these GusR orthologs. Using structure-guided mutations, we are able to transfer E. coli GusR's preferential DNA and glucuronide binding affinity to S. enterica GusR. Structures of putative GusR orthologs from GUS-encoding Firmicutes species also reveal functionally unique features of the Enterobacteriaceae GusRs. Finally, dominant-negative GusR variants are validated in cell-based studies. These data provide a molecular framework toward understanding the control of glucuronide utilization by opportunistic pathogens in the human gut. PMID- 29269394 TI - Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation. AB - Platelet aggregation at the site of vascular injury is essential in clotting. During this process, platelets are bridged by soluble fibrinogen that binds surface integrin receptors. One mystery in the mechanism of platelet aggregation pertains to how resting platelets ignore soluble fibrinogen, the third most abundant protein in the bloodstream, and yet avidly bind immobile fibrinogen on the surface of other platelets at the primary injury site. We speculate that platelet integrins are mechanosensors that test their ligands across the platelet platelet synapse. To investigate this model, we interrogate human platelets using approaches that include the supported lipid bilayer platform as well as DNA tension sensor technologies. Experiments suggest that platelet integrins require lateral forces to mediate platelet-platelet interactions. Mechanically labile ligands dampen platelet activation, and the onset of piconewton integrin tension coincides with calcium flux. Activated platelets display immobilized fibrinogen on their surface, thus mediating further recruitment of resting platelets. The distribution of integrin tension was shown to be spatially regulated through two myosin-signaling pathways, myosin light chain kinase and Rho-associated kinase. Finally, we discovered that the termination of integrin tension is coupled with the exposure of phosphatidylserine. Our work reveals the highest spatial and temporal resolution maps of platelet integrin mechanics and its role in platelet aggregation, suggesting that platelets are physical substrates for one another that establish mechanical feedback loops of activation. The results are reminiscent of mechanical regulation of the T-cell receptor, E-cadherin, and Notch pathways, suggesting a common feature for signaling at cell junctions. PMID- 29269397 TI - beta-Adrenergic receptor agonists attenuate pericyte loss in diabetic retinas through Akt activation. AB - Pericytes (PCs) are crucial in maintaining the quiescence of endothelial cells (ECs) and the integrity of EC tight junctions. Especially in diabetic retinopathy (DR), PC loss is one of the early pathologic changes in capillaries of diabetic retinas. Thus, preventing PC loss is beneficial for attenuating vision impairment in patients with DR. Although many studies have revealed the mechanism of PC loss in retinas, little is known about the mechanisms that increase PC survival. We focused on the effect of beta-adrenergic receptor agonists (beta-agonists) on PC loss in diabetic retinas. In this study, beta-agonists increased the cell viability of PCs by increasing PC survival and proliferation. Mechanistically, beta-agonist-induced protein kinase B activation in PCs reduced PC apoptosis in response to various stimuli. beta2-agonists more potently increased PC survival than beta1-agonists. beta2-Agonist reduced vascular leakage and PC loss in retinas of mice with streptozotocin-induced diabetes. In cocultures of PCs and ECs, beta2-agonists restored the altered permeability and ZO-1 expression in ECs induced by PC loss. We concluded that beta-agonists, especially beta2-agonists, increase PC survival, thereby preventing diabetes-induced PC loss in retinas. These results provide a potential therapeutic benefit of beta-agonists for preventing PC loss in DR.-Yun, J.-H., Jeong, H.-S., Kim, K.-J., Han, M. H., Lee, E. H., Lee, K., Cho, C.-H. beta-Adrenergic receptor agonists attenuate pericyte loss in diabetic retinas through Akt activation. PMID- 29269396 TI - Mechanism of prostaglandin E2-induced transcriptional up-regulation of Oncostatin M by CREB and Sp1. AB - Oncostatin-M (OSM) is a pleotropic cytokine belonging to the interleukin-6 family. Differential expression of OSM in response to varying stimuli and exhibiting repertoire of functions in different cells renders it challenging to study the mechanism of its expression. Prostaglandin E2 (PGE2) transcriptionally increased osm levels. In silico studies of ~1 kb upstream of osm promoter region yielded the presence of CRE (cyclic AMP response element)-like sites at the distal end (CREosm). Deletion and point mutation of CREosm clearly indicated that this region imparted an important role in PGE2-mediated transcription. Nuclear protein(s) from PGE2-treated U937 cells, bound to this region, was identified as CRE-binding protein (CREB). CREB was phosphorylated on treatment and was found to be directly associated with CREosm The presence of cofactors p300 and CREB binding protein in the complex was confirmed. A marked decrease in CREB phosphorylation, binding and transcriptional inhibition on treatment with PKA (protein kinase A) inhibitor, H89 (N-[2-[[3-(4-bromophenyl)-2 propenyl]amino]ethyl]-5-soquinolinesulfonamide), revealed the role of phosphorylated CREB in osm transcription. Additionally, other nuclear protein(s) were specifically associated with the proximal GC region (GCosm) post PGE2 treatment, later confirmed to be specificity protein 1 (Sp1). Interestingly, Sp1 bound to the proximal osm promoter was found to be associated with phospho-CREB p300 complex bound to the distal osm promoter. Knockdown of Sp1 abrogated the expression and functionality of OSM. Thus, the present study conclusively proves that these transcription factors, bound at the distal and proximal promoter elements are found to associate with each other in a DNA-dependent manner and both are responsible for the PGE2-mediated transcriptional up-regulation of Oncostatin-M. PMID- 29269395 TI - Quantitative historical analysis uncovers a single dimension of complexity that structures global variation in human social organization. AB - Do human societies from around the world exhibit similarities in the way that they are structured, and show commonalities in the ways that they have evolved? These are long-standing questions that have proven difficult to answer. To test between competing hypotheses, we constructed a massive repository of historical and archaeological information known as "Seshat: Global History Databank." We systematically coded data on 414 societies from 30 regions around the world spanning the last 10,000 years. We were able to capture information on 51 variables reflecting nine characteristics of human societies, such as social scale, economy, features of governance, and information systems. Our analyses revealed that these different characteristics show strong relationships with each other and that a single principal component captures around three-quarters of the observed variation. Furthermore, we found that different characteristics of social complexity are highly predictable across different world regions. These results suggest that key aspects of social organization are functionally related and do indeed coevolve in predictable ways. Our findings highlight the power of the sciences and humanities working together to rigorously test hypotheses about general rules that may have shaped human history. PMID- 29269398 TI - MiR-184 expression is regulated by AMPK in pancreatic islets. AB - AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In beta cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits [beta-cell-specific AMPK double-knockout (betaAMPKdKO) mice] impairs insulin secretion in vivo and beta-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic beta-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human beta cells. We identified 14 down-regulated and 9 up-regulated miRNAs in betaAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for beta-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of beta cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in beta cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets. PMID- 29269399 TI - Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke. AB - Stroke continues to be a leading cause of death and disability worldwide, yet effective treatments are lacking. Previous studies have indicated that stem-cell transplantation could be an effective treatment. However, little is known about the direct impact of transplanted cells on injured brain tissue. We wanted to help fill this knowledge gap and investigated effects of hematopoietic stem/progenitor cells (HSPCs) on the cerebral microcirculation after ischemia reperfusion injury (I/RI). Treatment of HSPCs in I/RI for up to 2 wk after cerebral I/RI led to decreased mortality rate, decreased infarct volume, improved functional outcome, reduced microglial activation, and reduced cerebral leukocyte adhesion. Confocal microscopy and fluorescence-activated cell sorting analyses showed transplanted HSPCs emigrate preferentially into ischemic cortex brain parenchyma. We isolated migrated HSPCs from the brain; using RNA sequencing to investigate the transcriptome, we found metallothionein (MT, particularly MT-I) transcripts were dramatically up-regulated. Finally, to confirm the significance of MT, we exogenously administered MT-I after cerebral I/RI and found that it produced neuroprotection in a manner similar to HSPC treatment. These findings provide novel evidence that the mechanism through which HSPCs promote repair after stroke maybe via direct action of HSPC-derived MT-I and could therefore be exploited as a useful therapeutic strategy for stroke.-Smith, H. K., Omura, S., Vital, S. A., Becker, F., Senchenkova, E. Y., Kaur, G., Tsunoda, I., Peirce, S. M., Gavins, F. N. E. Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke. PMID- 29269401 TI - Reply. PMID- 29269402 TI - Does the Volume of CSF Removed Affect the Response to a Tap in Normal Pressure Hydrocephalus? PMID- 29269400 TI - LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. AB - The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/beta-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/beta-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)- PyMT- and MMTV- Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV- Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ~90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 ( SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.-Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. PMID- 29269403 TI - Systematic Radiation Dose Reduction in Cervical Spine CT of Human Cadaveric Specimens: How Low Can We Go? AB - BACKGROUND AND PURPOSE: While the use of cervical spine CT in trauma settings has increased, the balance between image quality and dose reduction remains a concern. The purpose of our study was to compare the image quality of CT of the cervical spine of cadaveric specimens at different radiation dose levels. MATERIALS AND METHODS: The cervical spine of 4 human cadavers (mean body mass index; 30.5 +/- 5.2 kg/m2; range, 24-36 kg/m2) was examined using different reference tube current-time products (45, 75, 105, 135, 150, 165, 195, 275, 355 mAs) and a tube voltage of 120 kV(peak). Data were reconstructed with filtered back-projection and iterative reconstruction. Qualitative image noise and morphologic characteristics of bony structures were quantified on a Likert scale. Quantitative image noise was measured. Statistics included analysis of variance and the Tukey test. RESULTS: Compared with filtered back-projection, iterative reconstruction provided significantly lower qualitative (mean noise score: iterative reconstruction = 2.10/filtered back-projection = 2.18; P = .003) and quantitative (mean SD of Hounsfield units in air: iterative reconstruction = 30.2/filtered back-projection = 51.8; P < .001) image noise. Image noise increased as the radiation dose decreased. Qualitative image noise at levels C1-4 was rated as either "no noise" or as "acceptable noise." Any shoulder position was at level C5 and caused more artifacts at lower levels. When we analyzed all spinal levels, scores for morphologic characteristics revealed no significant differences between 105 and 355 mAs (P = .555), but they were worse in scans at 75 mAs (P = .025). CONCLUSIONS: Clinically acceptable image quality of cervical spine CTs for evaluation of bony structures of cadaveric specimens with different body habitus can be achieved with a reference mAs of 105 at 120 kVp with iterative reconstruction. Pull-down of shoulders during acquisition could improve image quality but may not be feasible in trauma patients with unknown injuries. PMID- 29269404 TI - MR Imaging-Based Evaluations of Olfactory Bulb Atrophy in Patients with Olfactory Dysfunction. AB - BACKGROUND AND PURPOSE: Although the olfactory bulb volume as assessed with MR imaging is known to reflect olfactory function, it is not always measured during olfactory pathway assessments in clinical settings. We aimed to evaluate the utility of visual olfactory bulb atrophy and neuropathy analyses using MR imaging in patients with olfactory dysfunction. MATERIALS AND METHODS: Thirty-four patients who presented with subjective olfactory loss between March 2016 and February 2017 were included. Patients underwent a nasal endoscopic examination, olfactory testing with the Korean Version of the Sniffin' Sticks test, and MR imaging. All patients completed the Sino-Nasal Outcome Test and Questionnaire of Olfactory Disorders. Olfactory bulb atrophy and neuropathy were evaluated on MR images by 2 head and neck radiologists. RESULTS: The etiology of olfactory loss was chronic rhinosinusitis with/without nasal polyps in 15 (44.1%) patients, respiratory viral infection in 7 (20.6%), trauma in 2 (5.9%), and idiopathic in 10 (29.4%) patients. Although 10 (29.4%) of the 34 patients were normosmic according to the Sniffin' Sticks test, their scores on the other tests were like those of patients who were hyposmic/anosmic according to the Sniffin' Sticks test. However, the detection rate of olfactory bulb atrophy was significantly higher in patients with hyposmia/anosmia than it was in patients with normosmia (P = .002). No difference in olfactory bulb neuropathy was identified among patients with normosmia and hyposmia/anosmia (P = .395). CONCLUSIONS: MR imaging evaluations of olfactory bulb atrophy can be used to objectively diagnose olfactory dysfunction in patients with subjective olfactory loss. PMID- 29269405 TI - White Matter Changes Related to Subconcussive Impact Frequency during a Single Season of High School Football. AB - BACKGROUND AND PURPOSE: The effect of exposing the developing brain of a high school football player to subconcussive impacts during a single season is unknown. The purpose of this pilot study was to use diffusion tensor imaging to assess white matter changes during a single high school football season, and to correlate these changes with impacts measured by helmet accelerometer data and neurocognitive test scores collected during the same period. MATERIALS AND METHODS: Seventeen male athletes (mean age, 16 +/- 0.73 years) underwent MR imaging before and after the season. Changes in fractional anisotropy across the white matter skeleton were assessed with Tract-Based Spatial Statistics and ROI analysis. RESULTS: The mean number of impacts over a 10-g threshold sustained was 414 +/- 291. Voxelwise analysis failed to show significant changes in fractional anisotropy across the season or a correlation with impact frequency, after correcting for multiple comparisons. ROI analysis showed significant (P < .05, corrected) decreases in fractional anisotropy in the fornix-stria terminalis and cingulum hippocampus, which were related to impact frequency. The effects were strongest in the fornix-stria terminalis, where decreases in fractional anisotropy correlated with worsening visual memory. CONCLUSIONS: Our findings suggest that subclinical neurotrauma related to participation in American football may result in white matter injury and that alterations in white matter tracts within the limbic system may be detectable after only 1 season of play at the high school level. PMID- 29269406 TI - Prenatal Factors Associated with Postnatal Brain Injury in Infants with Congenital Diaphragmatic Hernia. AB - BACKGROUND AND PURPOSE: Approximately 60% of infants with congenital diaphragmatic hernia have evidence of brain injury on postnatal MR imaging. It is unclear whether any brain injury is present before birth. In this study, we evaluated fetal MR imaging findings of brain injury and the association of congenital diaphragmatic hernia severity with postnatal brain injury. MATERIALS AND METHODS: Fetal MR imaging and postnatal brain MR imaging were retrospectively evaluated in 36 cases of congenital diaphragmatic hernia (from 2009 to 2014) by 2 pediatric neuroradiologists. Brain injury on postnatal MR imaging and brain injury and congenital diaphragmatic hernia severity on fetal MR imaging were recorded. Correlations between brain abnormalities on fetal and postnatal brain MR imaging were analyzed. Postnatal brain injury findings correlating with the severity of congenital diaphragmatic hernia were also assessed. RESULTS: On fetal MR imaging, enlarged extra-axial spaces (61%), venous sinus distention (21%), and ventriculomegaly (6%) were identified. No maturational delay, intracranial hemorrhage, or brain parenchymal injury was identified on fetal MR imaging. On postnatal MR imaging, 67% of infants had evidence of abnormality, commonly, enlarged extra-axial spaces (44%). Right-sided congenital diaphragmatic hernia was associated with a greater postnatal brain injury score (P = .05). Low observed-to-expected lung volume was associated with postnatal white matter injury (P = .005) and a greater postnatal brain injury score (P = .008). Lack of liver herniation was associated with normal postnatal brain MR imaging findings (P = .03). CONCLUSIONS: Fetal lung hypoplasia is associated with postnatal brain injury in congenital diaphragmatic hernia, suggesting that the severity of lung disease and associated treatments affect brain health as well. We found no evidence of prenatal brain parenchymal injury or maturational delay. PMID- 29269407 TI - Better Than Nothing: A Rational Approach for Minimizing the Impact of Outflow Strategy on Cerebrovascular Simulations. AB - BACKGROUND AND PURPOSE: Computational fluid dynamics simulations of neurovascular diseases are impacted by various modeling assumptions and uncertainties, including outlet boundary conditions. Many studies of intracranial aneurysms, for example, assume zero pressure at all outlets, often the default ("do-nothing") strategy, with no physiological basis. Others divide outflow according to the outlet diameters cubed, nominally based on the more physiological Murray's law but still susceptible to subjective choices about the segmented model extent. Here we demonstrate the limitations and impact of these outflow strategies, against a novel "splitting" method introduced here. MATERIALS AND METHODS: With our method, the segmented lumen is split into its constituent bifurcations, where flow divisions are estimated locally using a power law. Together these provide the global outflow rate boundary conditions. The impact of outflow strategy on flow rates was tested for 70 cases of MCA aneurysm with 0D simulations. The impact on hemodynamic indices used for rupture status assessment was tested for 10 cases with 3D simulations. RESULTS: Differences in flow rates among the various strategies were up to 70%, with a non-negligible impact on average and oscillatory wall shear stresses in some cases. Murray-law and splitting methods gave flow rates closest to physiological values reported in the literature; however, only the splitting method was insensitive to arbitrary truncation of the model extent. CONCLUSIONS: Cerebrovascular simulations can depend strongly on the outflow strategy. The default zero-pressure method should be avoided in favor of Murray-law or splitting methods, the latter being released as an open-source tool to encourage the standardization of outflow strategies. PMID- 29269408 TI - Pressure Mapping and Hemodynamic Assessment of Intracranial Dural Sinuses and Dural Arteriovenous Fistulas with 4D Flow MRI. AB - The feasibility of 4D flow MR imaging to visualize flow patterns and generate relative pressure maps in the dural venous sinus in healthy subjects (n = 60) and patients with dural arteriovenous fistulas (n = 7) was investigated. Dural venous drainage was classified based on torcular Herophili anatomy by using 4D flow MR imaging-derived angiograms and magnitude images. Subjects were scanned in a 3T clinical MR imaging system. 4D flow MR imaging enabled noninvasive characterization of dural sinus anatomy and mapping of relative pressure differences. PMID- 29269409 TI - Mechanism for Covalent Binding of MLN3126, an Oral Chemokine C-C Motif Receptor 9 Antagonist, to Serum Albumins. AB - N-{4-Chloro-2-[(1-oxidopyridin-4-yl)carbonyl]phenyl}-4-(propan-2 yloxy)benzenesulfonamide (MLN3126) is an orally available chemokine C-C motif receptor 9 selective antagonist. In nonclinical pharmacokinetic studies of MLN3126, nonextractable radioactivity was observed in plasma after oral administration of 14C-labeled MLN3126 ([14C]MLN3126) to Sprague-Dawley (SD) rats. In this study, the nonextractable radioactive component was digested with trypsin or a nonspecific protease, pronase, after chemical reduction to obtain drug peptide adducts or drug-amino acid adducts. The chemical structure of these adducts was characterized by liquid chromatography/mass spectrometry. The results demonstrated that the major part of the nonextractable radioactivity was accounted for by covalent binding via the Schiff base formed specifically between the epsilon-amino group of lysine residue 199 in rat serum albumin and the carbonyl group of MLN3126. The half-life (t1/2) of the total radioactivity in plasma during and after 21 daily multiple oral administrations of [14C]MLN3126 to SD rats was approximately 5-fold shorter than the reported t1/2 of albumin in rats. The data indicated that the covalent binding was reversible under physiologic conditions. The formation of the covalent binding was also confirmed in in vitro incubations with serum albumins from rats, humans, and dogs in the same manner, indicating that there are no qualitative interspecies differences in the formation of the Schiff base. PMID- 29269410 TI - Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor. AB - Growth factors have key roles in liver physiology and pathology, particularly by promoting cell proliferation and growth. Recently, it has been shown that in mouse hepatocytes, epidermal growth factor receptor (EGFR) plays a crucial role in the activation of the xenosensor constitutive androstane receptor (CAR) by the antiepileptic drug phenobarbital. Due to the species selectivity of CAR signaling, here we investigated epidermal growth factor (EGF) role in CAR signaling in primary human hepatocytes. Primary human hepatocytes were incubated with CITCO, a human CAR agonist, or with phenobarbital, an indirect CAR activator, in the presence or absence of EGF. CAR-dependent gene expression modulation and PXR involvement in these responses were assessed upon siRNA-based silencing of the genes that encode CAR and PXR. EGF significantly reduced CAR expression and prevented gene induction by CITCO and, to a lower extent, by phenobarbital. In the absence of EGF, phenobarbital and CITCO modulated the expression of 144 and 111 genes, respectively, in primary human hepatocytes. Among these genes, only 15 were regulated by CITCO and one by phenobarbital in a CAR-dependent manner. Conversely, in the presence of EGF, CITCO and phenobarbital modulated gene expression only in a CAR-independent and PXR-dependent manner. Overall, our findings suggest that in primary human hepatocytes, EGF suppresses specifically CAR signaling mainly through transcriptional regulation and drives the xenobiotic response toward a pregnane X receptor (PXR)-mediated mechanism. PMID- 29269411 TI - The G-quadruplex (G4) resolvase DHX36 efficiently and specifically disrupts DNA G4s via a translocation-based helicase mechanism. AB - Single-stranded DNA (ssDNA) and RNA regions that include at least four closely spaced runs of three or more consecutive guanosines strongly tend to fold into stable G-quadruplexes (G4s). G4s play key roles as DNA regulatory sites and as kinetic traps that can inhibit biological processes, but how G4s are regulated in cells remains largely unknown. Here, we developed a kinetic framework for G4 disruption by DEAH-box helicase 36 (DHX36), the dominant G4 resolvase in human cells. Using tetramolecular DNA and RNA G4s with four to six G-quartets, we found that DHX36-mediated disruption is highly efficient, with rates that depend on G4 length under saturating conditions (kcat) but not under subsaturating conditions (kcat/Km ). These results suggest that a step during G4 disruption limits the kcat value and that DHX36 binding limits kcat/Km Similar results were obtained for unimolecular DNA G4s. DHX36 activity depended on a 3' ssDNA extension and was blocked by a polyethylene glycol linker, indicating that DHX36 loads onto the extension and translocates 3'-5' toward the G4. DHX36 unwound dsDNA poorly compared with G4s of comparable intrinsic lifetime. Interestingly, we observed that DHX36 has striking 3'-extension sequence preferences that differ for G4 disruption and dsDNA unwinding, most likely arising from differences in the rate limiting step for the two activities. Our results indicate that DHX36 disrupts G4s with a conventional helicase mechanism that is tuned for great efficiency and specificity for G4s. The dependence of DHX36 on the 3'-extension sequence suggests that the extent of formation of genomic G4s may not track directly with G4 stability. PMID- 29269412 TI - The ubiquitin-proteasome system functionally links neuronal Tomosyn-1 to dendritic morphology. AB - Altering the expression of Tomosyn-1 (Tomo-1), a soluble, R-SNARE domain containing protein, significantly affects behavior in mice, Drosophila, and Caenorhabditis elegans Yet, the mechanisms that modulate Tomo-1 expression and its regulatory activity remain poorly defined. Here, we found that Tomo-1 expression levels influence postsynaptic spine density. Tomo-1 overexpression increased dendritic spine density, whereas Tomo-1 knockdown (KD) decreased spine density. These findings identified a novel action of Tomo-1 on dendritic spines, which is unique because it occurs independently of Tomo-1's C-terminal R-SNARE domain. We also demonstrated that the ubiquitin-proteasome system (UPS), which is known to influence synaptic strength, dynamically regulates Tomo-1 protein levels. Immunoprecipitated and affinity-purified Tomo-1 from cultured rat hippocampal neurons was ubiquitinated, and the levels of ubiquitinated Tomo-1 dramatically increased upon pharmacological proteasome blockade. Moreover, Tomo-1 ubiquitination appeared to be mediated through an interaction with the E3 ubiquitin ligase HRD1, as immunoprecipitation of Tomo-1 from neurons co precipitated HRD1, and this interaction increases upon proteasome inhibition. Further, in vitro reactions indicated direct, HRD1 concentration-dependent Tomo-1 ubiquitination. We also noted that the UPS regulates both Tomo-1 expression and functional output, as HRD1 KD in hippocampal neurons increased Tomo-1 protein level and dendritic spine density. Notably, the effect of HRD1 KD on spine density was mitigated by additional KD of Tomo-1, indicating a direct HRD1/Tomo-1 effector relationship. In summary, our results indicate that the UPS is likely to participate in tuning synaptic efficacy and spine dynamics by precise regulation of neuronal Tomo-1 levels. PMID- 29269413 TI - beta1,4-Galactosyltransferase V activates Notch1 signaling in glioma stem-like cells and promotes their transdifferentiation into endothelial cells. AB - Malignant glioblastoma multiforme is one of the most aggressive human cancers, with very low survival rates. Recent studies have reported that glioma stem-like cells transdifferentiate into endothelial cells, indicating a new mechanism for tumor angiogenesis and potentially providing new therapeutic options for glioblastoma treatment. Glioma malignancy is strongly associated with altered expression of N-linked oligosaccharide structures on the cell surface. We have previously reported that beta1,4-galactosyltransferase V (beta1,4GalTV), which galactosylates the GlcNAcbeta1-6Man arm of the branched N-glycans, is highly expressed in glioma and promotes glioma cell growth in vitro and in vivo However, the mechanism by which beta1,4GalTV stimulates glioma growth is unknown. Here we demonstrate that short hairpin RNA-mediated beta1,4GalTV knockdown inhibits the tumorigenesis of glioma stem-like cells and reduces their transdifferentiation into endothelial cells. We also found that beta1,4GalTV overexpression increased glioma stem-like cell transdifferentiation into endothelial cells and that this effect required beta1,4GalTV galactosylation activity. Moreover, beta1,4GalTV promoted beta1,4-galactosylation of Notch1 and increased Notch1 protein levels. Of note, ectopic expression of activated Notch1 rescued the inhibitory effect of beta1,4GalTV depletion on glioma stem-like cell transdifferentiation. In summary, our findings indicate that beta1,4GalTV stimulates transdifferentiation of glioma stem-like cells into endothelial cells by activating Notch1 signaling. These detailed insights shed important light on the mechanisms regulating glioma angiogenesis. PMID- 29269414 TI - Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes. AB - Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands, and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared with WT cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin induced IRS1 degradation after CD36 knockdown. Overexpression of WT CD36, but not a ubiquitination-defective CD36 mutant, delayed IRS1 degradation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multisubunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus. PMID- 29269415 TI - Identification of a precursor processing protease from the spider Cupiennius salei essential for venom neurotoxin maturation. AB - Spider venom neurotoxins and cytolytic peptides are expressed as elongated precursor peptides, which are post-translationally processed by proteases to yield the active mature peptides. The recognition motifs for these processing proteases, first published more than 10 years ago, include the processing quadruplet motif (PQM) and the inverted processing quadruplet motif (iPQM). However, the identification of the relevant proteases was still pending. Here we describe the purification of a neurotoxin precursor processing protease from the venom of the spider Cupiennius salei The chymotrypsin-like serine protease is a 28-kDa heterodimer with optimum activity at venom's pH of 6.0. We designed multiple synthetic peptides mimicking the predicted cleavage sites of neurotoxin precursors. Using these peptides as substrates, we confirm the biochemical activity of the protease in propeptide removal from neurotoxin precursors by cleavage C-terminal of the PQM. Furthermore, the PQM protease also cleaves the iPQM relevant for heterodimerization of a subgroup of neurotoxins. An involvement in the maturing of cytolytic peptides is very likely, due to high similarity of present protease recognition motifs. Finally, bioinformatics analysis, identifying sequences of homolog proteins from 18 spiders of 9 families, demonstrate the wide distribution and importance of the isolated enzyme for spiders. In summary, we establish the first example of a PQM protease, essential for maturing of spider venom neurotoxins. In the future, the here described protease may be established as a powerful tool for production strategies of recombinant toxic peptides, adapted to the maturing of spider venom toxins. PMID- 29269417 TI - Working time rules must be kept after Brexit, say medical leaders. PMID- 29269416 TI - Countervailing, time-dependent effects on host autophagy promotes intracellular survival of Leishmania. AB - Autophagy is essential for cell survival under stress and has also been implicated in host defense. Here, we investigated the interactions between Leishmania donovani, the main etiological agent of visceral leishmaniasis, and the autophagic machinery of human macrophages. Our results revealed that during early infection-and via activation of the Akt pathway-Leishmania actively inhibits the induction of autophagy. However, by 24 h, Leishmania switched from being an inhibitor to an overall inducer of autophagy. These findings of a dynamic, biphasic response were based on the accumulation of lipidated light chain 3 (LC3), an autophagosome marker, by Western blotting and confocal fluorescence microscopy. We also present evidence that Leishmania induces delayed host cell autophagy via a mechanism independent of reduced activity of the mechanistic target of rapamycin (mTOR). Notably, Leishmania actively inhibited mTOR-regulated autophagy even at later stages of infection, whereas there was a clear induction of autophagy via some other mechanism. In this context, we examined host inositol monophosphatase (IMPase), reduced levels of which have been implicated in mTOR-independent autophagy, and we found that IMPase activity is significantly decreased in infected cells. These findings indicate that Leishmania uses an alternative pathway to mTOR to induce autophagy in host macrophages. Finally, RNAi-mediated down-regulation of host autophagy protein 5 (ATG5) or autophagy protein 9A (ATG9A) decreased parasite loads, demonstrating that autophagy is essential for Leishmania survival. We conclude that Leishmania uses an alternative pathway to induce host autophagy while simultaneously inhibiting mTOR-regulated autophagy to fine-tune the timing and magnitude of this process and to optimize parasite survival. PMID- 29269418 TI - Biomarker-related risk for myocardial infarction and serious infections in patients with rheumatoid arthritis: a population-based study. AB - BACKGROUND: Rheumatoid arthritis (RA) disease activity and associated systemic inflammation has been associated with serious infection (SIEs), myocardial infarction (MI) and coronary heart disease (CHD) events based on a few registry studies or clinical trials. There are few data from large-scale population-based studies given feasibility challenges in conducting such investigations. METHODS: Multibiomarker disease activity (MBDA) test scores (n=77 641) were linked to Medicare for US patients with RA. Outcomes of interest were hospitalised pneumonia/sepsis (SIE), MI and a composite CHD outcome. The MBDA score ranges from 1 to 100 and was analysed as time-varying. Cox proportional hazards models evaluated the association between MBDA score and SIEs, MI and CHD events, controlling for potential confounders. A sensitivity analysis excluded C reactive protein (CRP) from the MBDA score. RESULTS: There were 17 433 and 16 796 patients eligible for the SIE and MI/CHD analyses, respectively. Mean (SD) age was 69 (11) years, 79% were women, 81% were white and 38% were disabled. Over 16 424 person years of follow-up, there were 452 SIE events, 132 MIs and 181 CHD events. Higher MBDA scores were associated with SIEs (HR=1.32, 95% CI 1.23 to 1.41 per 10 unit MBDA score change). For MI/CHD events, a threshold effect was present; higher disease activity by MBDA score was associated with increased MI (HR=1.52, 95% CI 0.92 to 2.49) and CHD rates (HR=1.54, 95% CI 1.01 to 2.34, comparing scores >=30 vs <30). Analyses of the MBDA score without CRP yielded similar results. CONCLUSION: Higher MBDA scores were associated with hospitalised infection, MI and CHD events in a large, predominantly older, US RA population. PMID- 29269419 TI - (Z)-2-(3,4-Dichlorophenyl)-3-(1H-Pyrrol-2-yl)Acrylonitrile Exhibits Selective Antitumor Activity in Breast Cancer Cell Lines via the Aryl Hydrocarbon Receptor Pathway. AB - We have previously reported the synthesis and breast cancer selectivity of (Z)-2 (3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (ANI-7) in cancer cell lines. To further evaluate the selectivity of ANI-7, we have expanded upon the initial cell line panel to now include the breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, MDA-MB-231); normal breast cells (MCF-10A); and cell lines derived from colon (HT29), ovarian (A2780), lung (H460), skin (A431), neuronal (BE2C), glial (U87, SJG2), and pancreatic (MIA) cancers. We now show that ANI-7 is up to 263-fold more potent at inhibiting the growth of breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468) than normal breast cells (MCF-10A) or cell lines derived from other tumor types. Measures of growth inhibition, cell cycle analysis, morphologic assessment, Western blotting, receptor binding, gene expression, small interfering RNA technology, reporter activity, and enzyme inhibition assays were exploited to define the mechanism of action of ANI-7. In this work, we report that ANI-7 mediates its effects via the activation of the aryl hydrocarbon receptor (AhR) pathway and the subsequent induction of CYP1 metabolizing mono-oxygenases. The metabolic conversion of ANI-7 induces DNA damage, checkpoint activation, S-phase cell cycle arrest, and cell death in sensitive breast cancer cell lines. Basal expression of AhR, the AhR nuclear translocator, and the CYP1 family members do not predict for sensitivity; however, inherent expression of the phase II-metabolizing enzyme sulfur transferase 1A1 does. For the first time, we identify (Z)-2-(3,4-dichlorophenyl) 3-(1H-pyrrol-2-yl)acrylonitrile as a new AhR ligand. PMID- 29269420 TI - Structural mechanisms of centromeric nucleosome recognition by the kinetochore protein CENP-N. AB - Accurate chromosome segregation requires the proper assembly of kinetochore proteins. A key step in this process is the recognition of the histone H3 variant CENP-A in the centromeric nucleosome by the kinetochore protein CENP-N. We report cryo-electron microscopy (cryo-EM), biophysical, biochemical, and cell biological studies of the interaction between the CENP-A nucleosome and CENP-N. We show that human CENP-N confers binding specificity through interactions with the L1 loop of CENP-A, stabilized by electrostatic interactions with the nucleosomal DNA. Mutational analyses demonstrate analogous interactions in Xenopus, which are further supported by residue-swapping experiments involving the L1 loop of CENP A. Our results are consistent with the coevolution of CENP-N and CENP-A and establish the structural basis for recognition of the CENP-A nucleosome to enable kinetochore assembly and centromeric chromatin organization. PMID- 29269421 TI - High-temperature pairing in a strongly interacting two-dimensional Fermi gas. AB - The nature of the normal phase of strongly correlated fermionic systems is an outstanding question in quantum many-body physics. We used spatially resolved radio-frequency spectroscopy to measure pairing energy of fermions across a wide range of temperatures and interaction strengths in a two-dimensional gas of ultracold fermionic atoms. We observed many-body pairing at temperatures far above the critical temperature for superfluidity. In the strongly interacting regime, the pairing energy in the normal phase considerably exceeds the intrinsic two-body binding energy of the system and shows a clear dependence on local density. This implies that pairing in this regime is driven by many-body correlations, rather than two-body physics. Our findings show that pairing correlations in strongly interacting two-dimensional fermionic systems are remarkably robust against thermal fluctuations. PMID- 29269423 TI - Coherent single-atom superradiance. AB - Superradiance is a quantum phenomenon emerging in macroscopic systems whereby correlated single atoms cooperatively emit photons. Demonstration of controlled collective atom-field interactions has resulted from the ability to directly imprint correlations with an atomic ensemble. Here we report cavity-mediated coherent single-atom superradiance: Single atoms with predefined correlation traverse a high-quality factor cavity one by one, emitting photons cooperatively with the N atoms that have already gone through the cavity (N represents the number of atoms). Enhanced collective photoemission of N-squared dependence was observed even when the intracavity atom number was less than unity. The correlation among single atoms was achieved by nanometer-precision position control and phase-aligned state manipulation of atoms by using a nanohole-array aperture. Our results demonstrate a platform for phase-controlled atom-field interactions. PMID- 29269424 TI - Correction: Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases. PMID- 29269422 TI - Dicer uses distinct modules for recognizing dsRNA termini. AB - Invertebrates rely on Dicer to cleave viral double-stranded RNA (dsRNA), and Drosophila Dicer-2 distinguishes dsRNA substrates by their termini. Blunt termini promote processive cleavage, while 3' overhanging termini are cleaved distributively. To understand this discrimination, we used cryo-electron microscopy to solve structures of Drosophila Dicer-2 alone and in complex with blunt dsRNA. Whereas the Platform-PAZ domains have been considered the only Dicer domains that bind dsRNA termini, unexpectedly, we found that the helicase domain is required for binding blunt, but not 3' overhanging, termini. We further showed that blunt dsRNA is locally unwound and threaded through the helicase domain in an adenosine triphosphate-dependent manner. Our studies reveal a previously unrecognized mechanism for optimizing antiviral defense and set the stage for the discovery of helicase-dependent functions in other Dicers. PMID- 29269427 TI - Correction for Pandharkar et al., "Studies on the Antileishmanial Mechanism of Action of the Arylimidamide DB766: Azole Interactions and Role of CYP5122A1". PMID- 29269425 TI - A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer. AB - Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs. PMID- 29269426 TI - Srf controls satellite cell fusion through the maintenance of actin architecture. AB - Satellite cells (SCs) are adult muscle stem cells that are mobilized when muscle homeostasis is perturbed. Here, we show that serum response factor (Srf) is needed for optimal SC-mediated hypertrophic growth. We identified Srf as a master regulator of SC fusion required in both fusion partners, whereas it was dispensable for SC proliferation and differentiation. We show that SC-specific Srf deletion leads to impaired actin cytoskeleton and report the existence of finger-like actin-based protrusions at fusion sites in vertebrates that were notoriously absent in fusion-defective myoblasts lacking Srf. Restoration of a polymerized actin network by overexpression of an alpha-actin isoform in Srf mutant SCs rescued their fusion with a control cell in vitro and in vivo and reestablished overload-induced muscle growth. These findings demonstrate the importance of Srf in controlling the organization of actin cytoskeleton and actin based protrusions for myoblast fusion in mammals and its requirement to achieve efficient hypertrophic myofiber growth. PMID- 29269428 TI - Pyrazinamide Is a Two-Edged Sword: Do WHO Guidelines Matter? PMID- 29269429 TI - Reply to Chang et al., "Pyrazinamide Is a Two-Edged Sword: Do WHO Guidelines Matter?" PMID- 29269430 TI - Efficacy Analysis in Healthy-Volunteer Influenza Challenge Trials: Intention To Treat. PMID- 29269431 TI - Reply to Hunsberger and Memoli, "Efficacy Analysis in Healthy-Volunteer Influenza Challenge Trials: Intention To Treat". PMID- 29269432 TI - Erratum for Madelain et al., "Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses". PMID- 29269433 TI - Erratum for Hoberman et al., "Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media". PMID- 29269434 TI - Erratum for Alsultan et al., "Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis". PMID- 29269435 TI - Erratum for del Barrio-Tofino et al., "Genomics and Susceptibility Profiles of Extensively Drug-Resistant Pseudomonas aeruginosa Isolates from Spain". PMID- 29269436 TI - Transition from children's to adults' services for young people using health or social care services (NICE Guideline NG43). PMID- 29269437 TI - Case-control study of household contacts to examine immunological protection from Bordetella pertussis transmission - study protocol. AB - BACKGROUND: There is mounting evidence that the recent resurgence of pertussis in many countries is in part related to the acellular vaccine, which has been administered in Canada since 1997. This vaccine elicits a different cell-mediated immune response than the previously used whole-cell vaccine, and its effectiveness wanes over time. The aim of this study is to understand the immunological, demographic and clinical factors that mediate protection from pertussis on exposure. METHODS: This is a household case-control study protocol. Following notification of an index case in a household, a study team will conduct a home visit to collect data and biological specimens. The study team will return to the household 8 weeks from the onset of illness in the index case. The Th1, Th2 and Th17 responses, cytokine expression, IgG subclass, blood cell counts and presence of Bordetella pertussis will be determined. We will use laboratory and statistical analyses to determine immunological differences between contacts who are infected with B. pertussis and contacts who remain healthy, and to determine which clinical and demographic covariates are associated with a reduced risk of infection. INTERPRETATION: The results of this study will be essential for understanding the immune response required for protection from infection with B. pertussis and will contribute to our understanding of the shortcomings of the current vaccine. PMID- 29269438 TI - Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. AB - OBJECTIVE: Intestinal microbiota is implicated in the pathogenesis of autoimmune type 1 diabetes in humans and in non-obese diabetic (NOD) mice, but evidence on its causality and on the role of individual microbiota members is limited. We investigated if different diabetes incidence in two NOD colonies was due to microbiota differences and aimed to identify individual microbiota members with potential significance. DESIGN: We profiled intestinal microbiota between two NOD mouse colonies showing high or low diabetes incidence by 16S ribosomal RNA gene sequencing and colonised the high-incidence colony with the microbiota of the low incidence colony. Based on unaltered incidence, we identified a few taxa which were not effectively transferred and thereafter, transferred experimentally one of these to test its potential significance. RESULTS: Although the high-incidence colony adopted most microbial taxa present in the low-incidence colony, diabetes incidence remained unaltered. Among the few taxa which were not transferred, Akkermansia muciniphila was identified. As A. muciniphila abundancy is inversely correlated to the risk of developing type 1 diabetes-related autoantibodies, we transferred A. muciniphila experimentally to the high-incidence colony. A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3gamma, outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development. CONCLUSION: Transfer of the whole microbiota may not reduce diabetes incidence despite a major change in gut microbiota, but single symbionts such as A. muciniphila with beneficial metabolic and immune signalling effects may reduce diabetes incidence when administered as a probiotic. PMID- 29269439 TI - Tailoring the colorectal cancer disease assessment to the treatment strategy. PMID- 29269440 TI - Selecting a risk assessment tool to use in practice:a 10-point guide. AB - With the increase in the number of risk assessment tools and clinical algorithms in many areas of science and medicine, this Perspective article provides an overview of research findings that can assist in informing the choice of an instrument for practical use. We take the example of violence risk assessment tools in criminal justice and forensic psychiatry, where there are more than 200 such instruments and their use is typically mandated. We outline 10 key questions that researchers, clinicians and other professionals should ask when deciding what tool to use, which are also relevant for public policy and commissioners of services. These questions are based on two elements: research underpinning the external validation, and derivation or development of a particular instrument. We also recommend some guidelines for reporting drawn from consensus guidelines for research in prognostic models. PMID- 29269441 TI - Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study. AB - BACKGROUND: Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. METHODS: We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. RESULTS: The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. CONCLUSIONS: Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. TRIAL REGISTRATION NUMBER: Results, NCT01620645. PMID- 29269442 TI - Exploring boar sperm sialylation during capacitation using boronic acid functionalized beads. AB - Sialic acid (SA), which usually occupies the terminal position of oligosaccharide chains in mammalian spermatozoa, has important functions in fertilization. Compared with other methods, such as lectin probing, boronic acid could recognize and bind SA with a higher affinity and specificity at pH 6.9. In this study, two boronic acid carriers, 3-aminophenylboronic acid-labeled fluorescent latex (CML APBA) and magnetic beads (CMM-APBA were applied to explore surface sialylation profile and sialoglycoproteins of the boar sperm. There are three binding sections of CML-APBA on the head of ejaculated sperm: acrosomal region, equatorial segment and the head posterior, which are the major regions undergoing sialylation. After capacitation in vitro, two major binding patterns of CML-APBA exists on sperm head. On some spermatozoa, sialylation exists on the equatorial segment and the posterior head, whilst on other spermatozoa, sialylation occurs on the acrosomal region and equatorial segment. Flow cytometry analysis suggested that the level of sialylation on boar sperm membrane decreases after capacitation. Furthermore, using CMM-APBA, we pulled down sialylated proteins from spermatozoa. Among them, two decapacitation factors associating on sperm surface, AWN and PSP-1, were identified. The levels of the two proteins reduced during capacitation, which might contribute to the decrease of sialylation on boar sperm surface. PMID- 29269444 TI - The fibroblast growth factor 8 family in the female reproductive tract. AB - Several growth factor families have been shown to be involved in the function of the female reproductive tract. One subfamily of the fibroblast growth factor (FGF) superfamily, namely the FGF8 subfamily (including FGF17 and FGF18), has become important as Fgf8 has been described as an oocyte-derived factor essential for glycolysis in mouse cumulus cells and aberrant expression of FGF18 has been described in ovarian and endometrial cancers. In this review, we describe the pattern of expression of these factors in normal ovaries and uteri in rodents, ruminants and humans, as well as the expression of their receptors and intracellular negative feedback regulators. Expression of these molecules in gynaecological cancers is also reviewed. The role of FGF8 and FGF18 in ovarian and uterine function is described, and potential differences between rodents and ruminants have been highlighted especially with respect to FGF18 signalling within the ovarian follicle. Finally, we identify major questions about the reproductive biology of FGFs that remain to be answered, including (1) the physiological concentrations within the ovary and uterus, (2) which cell types within the endometrial stroma and theca layer express FGFs and (3) which receptors are activated by FGF8 subfamily members in reproductive tissues. PMID- 29269446 TI - Comment on "Rapid cooling and cold storage in a silicic magma reservoir recorded in individual crystals". AB - Rubin et al (Reports, 16 June 2017, p. 1154) proposed that gradients in lithium abundance in zircons from a rhyolitic eruption in New Zealand reflected short lived residence at magmatic temperatures interleaved with long-term "cold" (<650 degrees C) storage. Important issues arise with the interpretation of these lithium gradients and consequent crystal thermal histories that raise concerns about the validity of this conclusion. PMID- 29269448 TI - Science, big and small. PMID- 29269447 TI - Response to Comment on "Rapid cooling and cold storage in a silicic magma reservoir recorded in individual crystals". AB - In a recent paper, we used Li concentration profiles and U-Th ages to constrain the thermal conditions of magma storage. Wilson and co-authors argue that the data instead reflect control of Li behavior by charge balance during partitioning and not by experimentally determined diffusion rates. Their arguments are based on (i) a coupled diffusion mechanism for Li, which has been postulated but has not been documented to occur, and (ii) poorly constrained zircon growth rates combined with the assumption of continuous zircon crystallization. PMID- 29269450 TI - Saturn's rings are solar system newcomers. PMID- 29269445 TI - Recurrent infection progressively disables host protection against intestinal inflammation. AB - Intestinal inflammation is the central pathological feature of colitis and the inflammatory bowel diseases. These syndromes arise from unidentified environmental factors. We found that recurrent nonlethal gastric infections of Gram-negative Salmonella enterica Typhimurium (ST), a major source of human food poisoning, caused inflammation of murine intestinal tissue, predominantly the colon, which persisted after pathogen clearance and irreversibly escalated in severity with repeated infections. ST progressively disabled a host mechanism of protection by inducing endogenous neuraminidase activity, which accelerated the molecular aging and clearance of intestinal alkaline phosphatase (IAP). Disease was linked to a Toll-like receptor 4 (TLR4)-dependent mechanism of IAP desialylation with accumulation of the IAP substrate and TLR4 ligand, lipopolysaccharide-phosphate. The administration of IAP or the antiviral neuraminidase inhibitor zanamivir was therapeutic by maintaining IAP abundance and function. PMID- 29269451 TI - Safety concerns derail dengue vaccination program. PMID- 29269452 TI - Deep Pacific cooled by 'little ice age' waters. PMID- 29269453 TI - Deadly virus threatens European pigs and boar. PMID- 29269454 TI - Were nomads the world's first traders? PMID- 29269455 TI - Blockade harms Qatari science. PMID- 29269456 TI - Cosmic convergence. PMID- 29269457 TI - The runners up. PMID- 29269458 TI - Breakdowns of the year. PMID- 29269459 TI - What can machine learning do? Workforce implications. PMID- 29269460 TI - A New World of plants. PMID- 29269461 TI - How seismic waves lose energy. PMID- 29269462 TI - How land plant life cycles first evolved. PMID- 29269463 TI - The rise of near-zero-index technologies. PMID- 29269464 TI - The quest for durable resistance. PMID- 29269465 TI - Supercooled water reveals its secrets. PMID- 29269466 TI - Complex regulation of plant sex by peptides. PMID- 29269467 TI - Managing quantities of antimicrobials. PMID- 29269468 TI - Response. PMID- 29269469 TI - Addendum to "Editorial Retraction of the Report 'Environmentally relevant concentrations of microplastic particles influence larval fish ecology,' by O. M. Lonnstedt and P. Eklov". PMID- 29269470 TI - Continue U.S.-Cuban science diplomacy. PMID- 29269471 TI - An illuminating cosmic collision. PMID- 29269472 TI - Maxima in the thermodynamic response and correlation functions of deeply supercooled water. AB - Femtosecond x-ray laser pulses were used to probe micrometer-sized water droplets that were cooled down to 227 kelvin in vacuum. Isothermal compressibility and correlation length were extracted from x-ray scattering at the low-momentum transfer region. The temperature dependence of these thermodynamic response and correlation functions shows maxima at 229 kelvin for water and 233 kelvin for heavy water. In addition, we observed that the liquids undergo the fastest growth of tetrahedral structures at similar temperatures. These observations point to the existence of a Widom line, defined as the locus of maximum correlation length emanating from a critical point at positive pressures in the deeply supercooled regime. The difference in the maximum value of the isothermal compressibility between the two isotopes shows the importance of nuclear quantum effects. PMID- 29269473 TI - Determination of intrinsic attenuation in the oceanic lithosphere-asthenosphere system. AB - We recorded P and S waves traveling through the oceanic lithosphere-asthenosphere system (LAS) using broadband ocean-bottom seismometers in the northwest Pacific, and we quantitatively separated the intrinsic (anelastic) and extrinsic (scattering) attenuation effects on seismic wave propagation to directly infer the thermomechanical properties of the oceanic LAS. The strong intrinsic attenuation in the asthenosphere obtained at higher frequency (~3 hertz) is comparable to that constrained at lower frequency (~100 seconds) by surface waves and suggests frequency-independent anelasticity, whereas the intrinsic attenuation in the lithosphere is frequency dependent. This difference in frequency dependence indicates that the strong and broad peak dissipation recently observed in the laboratory exists only in the asthenosphere and provides new insight into what distinguishes the asthenosphere from the lithosphere. PMID- 29269474 TI - Variation in the AvrSr35 gene determines Sr35 resistance against wheat stem rust race Ug99. AB - Puccinia graminis f. sp. tritici (Pgt) causes wheat stem rust, a devastating fungal disease. The Sr35 resistance gene confers immunity against this pathogen's most virulent races, including Ug99. We used comparative whole-genome sequencing of chemically mutagenized and natural Pgt isolates to identify a fungal gene named AvrSr35 that is required for Sr35 avirulence. The AvrSr35 gene encodes a secreted protein capable of interacting with Sr35 and triggering the immune response. We show that the origin of Pgt isolates virulent on Sr35 is associated with the nonfunctionalization of the AvrSr35 gene by the insertion of a mobile element. The discovery of AvrSr35 provides a new tool for Pgt surveillance, identification of host susceptibility targets, and characterization of the molecular determinants of immunity in wheat. PMID- 29269476 TI - Asylum applications respond to temperature fluctuations. AB - International negotiations on climate change, along with recent upsurges in migration across the Mediterranean Sea, have highlighted the need to better understand the possible effects of climate change on human migration-in particular, across national borders. Here we examine how, in the recent past (2000-2014), weather variations in 103 source countries translated into asylum applications to the European Union, which averaged 351,000 per year in our sample. We find that temperatures that deviated from the moderate optimum (~20 degrees C) increased asylum applications in a nonlinear fashion, which implies an accelerated increase under continued future warming. Holding everything else constant, asylum applications by the end of the century are predicted to increase, on average, by 28% (98,000 additional asylum applications per year) under representative concentration pathway (RCP) scenario 4.5 and by 188% (660,000 additional applications per year) under RCP 8.5 for the 21 climate models in the NASA Earth Exchange Global Daily Downscaled Projections (NEX-GDDP). PMID- 29269475 TI - Loss of AvrSr50 by somatic exchange in stem rust leads to virulence for Sr50 resistance in wheat. AB - Race-specific resistance genes protect the global wheat crop from stem rust disease caused by Puccinia graminis f. sp. tritici (Pgt) but are often overcome owing to evolution of new virulent races of the pathogen. To understand virulence evolution in Pgt, we identified the protein ligand (AvrSr50) recognized by the Sr50 resistance protein. A spontaneous mutant of Pgt virulent to Sr50 contained a 2.5 mega-base pair loss-of-heterozygosity event. A haustorial secreted protein from this region triggers Sr50-dependent defense responses in planta and interacts directly with the Sr50 protein. Virulence alleles of AvrSr50 have arisen through DNA insertion and sequence divergence, and our data provide molecular evidence that in addition to sexual recombination, somatic exchange can play a role in the emergence of new virulence traits in Pgt. PMID- 29269477 TI - An integrated assessment of the vascular plant species of the Americas. AB - The cataloging of the vascular plants of the Americas has a centuries-long history, but it is only in recent decades that an overview of the entire flora has become possible. We present an integrated assessment of all known native species of vascular plants in the Americas. Twelve regional and national checklists, prepared over the past 25 years and including two large ongoing flora projects, were merged into a single list. Our publicly searchable checklist includes 124,993 species, 6227 genera, and 355 families, which correspond to 33% of the 383,671 vascular plant species known worldwide. In the past 25 years, the rate at which new species descriptions are added has averaged 744 annually for the Americas, and we can expect the total to reach about 150,000. PMID- 29269479 TI - Attempts to ban seven words at CDC are condemned by public health advocates. PMID- 29269478 TI - My second-chance Ph.D. PMID- 29269480 TI - REBOA at Role 2 Afloat: resuscitative endovascular balloon occlusion of the aorta as a bridge to damage control surgery in the military maritime setting. AB - Role 2 Afloat provides a damage control resuscitation and surgery facility in support of maritime, littoral and aviation operations. Resuscitative endovascular balloon occlusion of the aorta (REBOA) offers a rapid, effective solution to exsanguinating haemorrhage from pelvic and non-compressible torso haemorrhage. It should be considered when the patient presents in a peri-arrest state, if surgery is likely to be delayed, or where the single operating table is occupied by another case. This paper will outline the data in support of endovascular haemorrhage control, describe the technique and explore how REBOA could be delivered using equipment currently available in the Royal Navy Role 2 Afloat equipment module. Also discussed are potential future directions in endovascular resuscitation. PMID- 29269481 TI - Daily number of patient contacts as alternative measure of workload in general practice. PMID- 29269482 TI - Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. AB - Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82-Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML. PMID- 29269483 TI - RNA G-quadruplex secondary structure promotes alternative splicing via the RNA binding protein hnRNPF. AB - It is generally thought that splicing factors regulate alternative splicing through binding to RNA consensus sequences. In addition to these linear motifs, RNA secondary structure is emerging as an important layer in splicing regulation. Here we demonstrate that RNA elements with G-quadruplex-forming capacity promote exon inclusion. Destroying G-quadruplex-forming capacity while keeping G tracts intact abrogates exon inclusion. Analysis of RNA-binding protein footprints revealed that G quadruplexes are enriched in heterogeneous nuclear ribonucleoprotein F (hnRNPF)-binding sites and near hnRNPF-regulated alternatively spliced exons in the human transcriptome. Moreover, hnRNPF regulates an epithelial-mesenchymal transition (EMT)-associated CD44 isoform switch in a G-quadruplex-dependent manner, which results in inhibition of EMT. Mining breast cancer TCGA (The Cancer Genome Atlas) data sets, we demonstrate that hnRNPF negatively correlates with an EMT gene signature and positively correlates with patient survival. These data suggest a critical role for RNA G quadruplexes in regulating alternative splicing. Modulation of G-quadruplex structural integrity may control cellular processes important for tumor progression. PMID- 29269484 TI - Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming. AB - The majority of breast cancers expresses the estrogen receptor (ER+) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include Runx2, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing Runx2 significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER+ breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through selective mRNA translational reprogramming. PMID- 29269487 TI - Epidemiology and return to play following isolated syndesmotic injuries of the ankle: a prospective cohort study of 3677 male professional footballers in the UEFA Elite Club Injury Study. AB - AIM: To determine the epidemiology of isolated syndesmotic injuries in professional football players. METHODS: Data from 15 consecutive seasons of European professional football between 2001 and 2016 contributed to the dataset of this study. Match play and training data from a total of 3677 players from 61 teams across 17 countries have been included. Team medical staff recorded player exposure and time loss injuries. Injury incidence was defined as the number of injuries per 1000 player-hours. Injury burden was defined as number of days absence per 1000 player-hours. Seasonal trends for isolated syndesmotic injury incidence, isolated syndesmotic injury proportion of ankle ligament injuries and isolated syndesmotic injury burden were analysed via linear regression. RESULTS: The isolated syndesmotic injury incidence was 0.05 injuries per 1000 hours of exposure (95% CI 0.04 to 0.06) or one injury per team every three seasons. The injury incidence during match play was 13 times higher compared with during training, 0.21 (95% CI 0.16 to 0.26) and 0.02 (95% CI 0.01 to 0.02), respectively. Out of the 1320 ankle ligament injuries registered during the 15 seasons, 94 (7%) were diagnosed as isolated syndesmotic injuries. An annual increase in injury incidence was observed (R2=0.495, b=0.003, 95% CI 0.001 to 0.004, P=0.003). However, no significant annual change of injury burden was observed (R2=0.033, b=0.032, 95% CI -0.073 to 0.138, P=0.520). Seventy-four per cent of the injuries were contact related, and the mean (+/-SD) absence following an isolated syndesmotic injury was 39 (+/-28) days. CONCLUSIONS: The incidence of isolated syndesmotic injuries in elite professional European football annually increased between 2001 and 2016. PMID- 29269485 TI - YAP repression of the WNT3 gene controls hESC differentiation along the cardiac mesoderm lineage. AB - Activin/SMAD signaling in human embryonic stem cells (hESCs) ensures NANOG expression and stem cell pluripotency. In the presence of Wnt ligand, the Activin/SMAD transcription network switches to cooperate with Wnt/beta-catenin and induce mesendodermal (ME) differentiation genes. We show here that the Hippo effector YAP binds to the WNT3 gene enhancer and prevents the gene from being induced by Activin in proliferating hESCs. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) data show that YAP impairs SMAD recruitment and the accumulation of P-TEFb-associated RNA polymerase II (RNAPII) C-terminal domain (CTD)-Ser7 phosphorylation at the WNT3 gene. CRISPR/CAS9 knockout of YAP in hESCs enables Activin to induce Wnt3 expression and stabilize beta-catenin, which then synergizes with Activin-induced SMADs to activate a subset of ME genes that is required to form cardiac mesoderm. Interestingly, exposure of YAP-/- hESCs to Activin induces cardiac mesoderm markers (BAF60c and HAND1) without activating Wnt-dependent cardiac inhibitor genes (CDX2 and MSX1). Moreover, canonical Wnt target genes are up-regulated only modestly, if at all, under these conditions. Consequently, YAP-null hESCs exposed to Activin differentiate precisely into beating cardiomyocytes without further treatment. We conclude that YAP maintains hESC pluripotency by preventing WNT3 expression in response to Activin, thereby blocking a direct route to embryonic cardiac mesoderm formation. PMID- 29269488 TI - Rest and return-to-sport recommendations following sport-related concussion (PEDro synthesis). PMID- 29269486 TI - Heat-shock protein 40 is the key farnesylation target in meristem size control, abscisic acid signaling, and drought resistance. AB - Protein farnesylation is central to molecular cell biology. In plants, protein farnesyl transferase mutants are pleiotropic and exhibit defective meristem organization, hypersensitivity to the hormone abscisic acid, and increased drought resistance. The precise functions of protein farnesylation in plants remain incompletely understood because few relevant farnesylated targets have been identified. Here, we show that defective farnesylation of a single factor heat-shock protein 40 (HSP40), encoded by the J2 and J3 genes-is sufficient to confer ABA hypersensitivity, drought resistance, late flowering, and enlarged meristems, indicating that altered function of chaperone client proteins underlies most farnesyl transferase mutant phenotypes. We also show that expression of an abiotic stress-related microRNA (miRNA) regulon controlled by the transcription factor SPL7 requires HSP40 farnesylation. Expression of a truncated SPL7 form mimicking its activated proteolysis fragment of the membrane bound SPL7 precursor partially restores accumulation of SPL7-dependent miRNAs in farnesyl transferase mutants. These results implicate the pathway directing SPL7 activation from its membrane-bound precursor as an important target of farnesylated HSP40, consistent with our demonstration that HSP40 farnesylation facilitates its membrane association. The results also suggest that altered gene regulation via select miRNAs contributes to abiotic stress-related phenotypes of farnesyl transferase mutants. PMID- 29269489 TI - Identification of Bacterial Species That Can Utilize Fructose-Asparagine. AB - Salmonella enterica serovar Typhimurium is the only organism demonstrated to utilize fructose-asparagine (F-Asn) as a source of carbon and nitrogen. In this report, we first used a bioinformatics approach to identify other microorganisms that encode homologs of the Salmonella F-Asn utilization enzymes FraB (deglycase), FraD (kinase), and FraE (asparaginase). These candidate organisms were then tested with up to four different methods to confirm their ability to utilize F-Asn. The easiest and most broadly applicable method utilized a biological toxicity assay, which is based on the observation that F-Asn is toxic to a Salmonella fraB mutant. Candidate organisms were grown in a rich medium containing F-Asn, and depletion of F-Asn from the medium was inferred by the growth of a Salmonella fraB mutant in that same medium. For select organisms, the toxicity assay was cross-validated by direct mass spectrometry-aided measurement of F-Asn in the spent-culture media and through demonstration of FraB and FraD enzyme activity in cellular extracts. For prototrophs, F-Asn utilization was additionally confirmed by growth in a minimal medium containing F-Asn as the sole carbon source. Collectively, these studies established that Clostridiumbolteae, Clostridium acetobutylicum, and Clostridium clostridioforme can utilize F-Asn, but Clostridium difficile cannot; Klebsiella oxytoca and some Klebsiella pneumoniae subspecies can utilize F-Asn; and some Citrobacter rodentium and Citrobacter freundii strains can also utilize F-Asn. Within Salmonella enterica, the host-adapted serovars Typhi and Paratyphi A have lost the ability to utilize F-Asn.IMPORTANCE Fructose-asparagine (F-Asn) is a precursor to acrylamide that is found in human foods, and it is also a nutrient source for Salmonella enterica, a foodborne pathogen. Here, we determined that among the normal intestinal microbiota, there are species of Clostridium that encode the enzymes required for F-Asn utilization. Using complementary experimental approaches, we have confirmed that three members of Clostridium, two members of Klebsiella, and two members of Citrobacter can indeed utilize F-Asn. The Clostridium spp. likely compete with Salmonella for F-Asn in the gut and contribute to competitive exclusion. FraB, one of the enzymes in the F-Asn utilization pathway, is a potential drug target because inhibition of this enzyme leads to the accumulation of a toxic metabolite that inhibits the growth of Salmonella species. This study identifies the potential off-target organisms that need to be considered when developing therapeutics directed at FraB. PMID- 29269490 TI - An Attenuated Salmonella enterica Serovar Typhimurium Strain and Galacto Oligosaccharides Accelerate Clearance of Salmonella Infections in Poultry through Modifications to the Gut Microbiome. AB - Salmonella is estimated to cause one million foodborne illnesses in the United States every year. Salmonella-contaminated poultry products are one of the major sources of salmonellosis. Given the critical role of the gut microbiota in Salmonella transmission, a manipulation of the chicken intestinal microenvironment could prevent animal colonization by the pathogen. In Salmonella, the global regulator gene fnr (fumarate nitrate reduction) regulates anaerobic metabolism and is essential for adapting to the gut environment. This study tested the hypothesis that an attenuated Fnr mutant of Salmonella enterica serovar Typhimurium (attST) or prebiotic galacto-oligosaccharides (GOS) could improve resistance to wild-type Salmonella via modifications to the structure of the chicken gut microbiome. Intestinal samples from a total of 273 animals were collected weekly for 9 weeks to evaluate the impact of attST or prebiotic supplementation on microbial species of the cecum, duodenum, jejunum, and ileum. We next analyzed changes to the gut microbiome induced by challenging the animals with a wild-type Salmonella serovar 4,[5],12:r:- (Nalr) strain and determined the clearance rate of the virulent strain in the treated and control groups. Both GOS and the attenuated Salmonella strain modified the gut microbiome but elicited alterations of different taxonomic groups. The attST produced significant increases of Alistipes and undefined Lactobacillus, while GOS increased Christensenellaceae and Lactobacillus reuteri The microbiome structural changes induced by both treatments resulted in a faster clearance after a Salmonella challenge.IMPORTANCE With an average annual incidence of 13.1 cases/100,000 individuals, salmonellosis has been deemed a nationally notifiable condition in the United States by the Centers for Disease Control and Prevention (CDC). Earlier studies demonstrated that Salmonella is transmitted by a subset of animals (supershedders). The supershedder phenotype can be induced by antibiotics, ascertaining an essential role for the gut microbiota in Salmonella transmission. Consequently, modulation of the gut microbiota and modification of the intestinal microenvironment could assist in preventing animal colonization by the pathogen. Our study demonstrated that a manipulation of the chicken gut microbiota by the administration of an attenuated Salmonella strain or prebiotic galacto-oligosaccharides (GOS) can promote resistance to Salmonella colonization via increases of beneficial microorganisms that translate into a less hospitable gut microenvironment. PMID- 29269491 TI - Enzyme Activities at Different Stages of Plant Biomass Decomposition in Three Species of Fungus-Growing Termites. AB - Fungus-growing termites rely on mutualistic fungi of the genus Termitomyces and gut microbes for plant biomass degradation. Due to a certain degree of symbiont complementarity, this tripartite symbiosis has evolved as a complex bioreactor, enabling decomposition of nearly any plant polymer, likely contributing to the success of the termites as one of the main plant decomposers in the Old World. In this study, we evaluated which plant polymers are decomposed and which enzymes are active during the decomposition process in two major genera of fungus-growing termites. We found a diversity of active enzymes at different stages of decomposition and a consistent decrease in plant components during the decomposition process. Furthermore, our findings are consistent with the hypothesis that termites transport enzymes from the older mature parts of the fungus comb through young worker guts to freshly inoculated plant substrate. However, preliminary fungal RNA sequencing (RNA-seq) analyses suggest that this likely transport is supplemented with enzymes produced in situ Our findings support that the maintenance of an external fungus comb, inoculated with an optimal mixture of plant material, fungal spores, and enzymes, is likely the key to the extraordinarily efficient plant decomposition in fungus-growing termites.IMPORTANCE Fungus-growing termites have a substantial ecological footprint in the Old World (sub)tropics due to their ability to decompose dead plant material. Through the establishment of an elaborate plant biomass inoculation strategy and through fungal and bacterial enzyme contributions, this farming symbiosis has become an efficient and versatile aerobic bioreactor for plant substrate conversion. Since little is known about what enzymes are expressed and where they are active at different stages of the decomposition process, we used enzyme assays, transcriptomics, and plant content measurements to shed light on how this decomposition of plant substrate is so effectively accomplished. PMID- 29269492 TI - Autoinducer 2-dependent Escherichia coli biofilm formation is enhanced in a dual species co-culture. AB - Biofilms in nature typically consist of multiple species, and microbial interactions are likely to have crucial impact on biofilm development, structure and functions. The best understood form of communication within bacterial communities is by means of production, release and detection of signal molecules (autoinducers), known as quorum sensing. Although autoinducers mainly promote intraspecies communication, autoinducer 2 (AI-2) is produced and detected by variety of bacteria, thus principally allowing interspecies communication. Here we show the importance of AI-2 mediated signaling in formation of mixed biofilms by Enterococcus faecalis and Escherichia coli Our results demonstrate that AI-2 produced by E. faecalis promotes collective behavior of E. coli at lower cell densities, enhancing autoaggregation of E. coli but also leading to the chemotaxis-dependent co-aggregation between the two species. Finally, we show that formation of such mixed dual-species biofilms increases stress resistance of both E. coli and E. faecalisIMPORTANCE The role of interspecies communication in development of mixed microbial communities is becoming increasingly apparent, but specific examples of such communication remain limited. A universal signal molecule autoinducer 2 (AI-2) is well known to regulate cell density-dependent phenotypes of many bacterial species, but despite its potential for interspecies communication the role of AI-2 in establishment of multispecies communities is not well understood. In this study, we explore AI-2 signaling in a dual-species community between two bacteria species that naturally co-occur in their mammalian hosts, Escherichia coli and Enterococcus faecalis We show that active production of AI-2 by E. faecalis allows E. coli to perform collective behaviors already at low cell densities. Additionally, AI-2 and chemotaxis-dependent co-aggregation with E. faecalis creates nucleation zones for rapid growth of E. coli microcolonies in the mixed biofilm and enhances stress resistance of both species. PMID- 29269493 TI - Environmental Stress-Induced Bacterial Lysis and Extracellular DNA Release Contribute to Campylobacter jejuni Biofilm Formation. AB - Campylobacter jejuni is a microaerophilic bacterium and is believed to persist in a biofilm to antagonize environmental stress. This study investigated the influence of environmental conditions on the formation of C. jejuni biofilm. We report an extracellular DNA (eDNA)-mediated mechanism of biofilm formation in response to aerobic and starvation stress. The eDNA was determined to represent a major form of constitutional material of C. jejuni biofilms and to be closely associated with bacterial lysis. Deletion mutation of the stress response genes spoT and recA enhanced the aerobic influence by stimulating lysis and increasing eDNA release. Flagella were also involved in biofilm formation but mainly contributed to attachment rather than induction of lysis. The addition of genomic DNA from either Campylobacter or Salmonella resulted in a concentration-dependent stimulation effect on biofilm formation, but the effect was not due to forming a precoating DNA layer. Enzymatic degradation of DNA by DNase I disrupted C. jejuni biofilm. In a dual-species biofilm, eDNA allocated Campylobacter and Salmonella at distinct spatial locations that protect Campylobacter from oxygen stress. Our findings demonstrated an essential role and multiple functions of eDNA in biofilm formation of C. jejuni, including facilitating initial attachment, establishing and maintaining biofilm, and allocating bacterial cells.IMPORTANCECampylobacter jejuni is a major cause of foodborne illness worldwide. In the natural environment, the growth of C. jejuni is greatly inhibited by various forms of environmental stress, such as aerobic stress and starvation stress. Biofilm formation can facilitate the distribution of C. jejuni by enabling the survival of this fragile microorganism under unfavorable conditions. However, the mechanism of C. jejuni biofilm formation in response to environmental stress has been investigated only partially. The significance of our research is in identifying extracellular DNA released by bacterial lysis as a major form of constitution material that mediates the formation of C. jejuni biofilm in response to environmental stress, which enhances our understanding of the formation mechanism of C. jejuni biofilm. This knowledge can aid the development of intervention strategies to limit the distribution of C. jejuni. PMID- 29269494 TI - Promising Prebiotic Candidate Established by Evaluation of Lactitol, Lactulose, Raffinose, and Oligofructose for Maintenance of a Lactobacillus-Dominated Vaginal Microbiota. AB - Perturbations to the vaginal microbiota can lead to dysbiosis, including bacterial vaginosis (BV), which affects a large portion of the female population. In a healthy state, the vaginal microbiota is characterized by low diversity and colonization by Lactobacillus spp., whereas in BV, these species are displaced by a highly diverse population of bacteria associated with adverse vaginal health outcomes. Since prebiotic ingestion has been a highly effective approach to invigorate lactobacilli for improved intestinal health, we hypothesized that these compounds could stimulate lactobacilli at the expense of BV organisms to maintain vaginal health. Monocultures of commensal Lactobacillus crispatus, Lactobacillus vaginalis, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus jensenii, and Lactobacillus iners, in addition to BV-associated organisms and Candida albicans, were tested for their ability to utilize a representative group of prebiotics consisting of lactitol, lactulose, raffinose, and oligofructose. The disaccharide lactulose was found to most broadly and specifically stimulate vaginal lactobacilli, including the strongly health associated species L. crispatus, and importantly, not to stimulate BV organisms or C. albicans Using freshly collected vaginal samples, we showed that exposure to lactulose promoted commensal Lactobacillus growth and dominance and resulted in healthy acidity partially through lactic acid production. This provides support for further testing of lactulose to prevent dysbiosis and potentially to reduce the need for antimicrobial agents in managing vaginal health.IMPORTANCE Bacterial vaginosis (BV) and other dysbioses of the vaginal microbiota significantly affect the quality of life of millions of women. Antimicrobial therapy is often poorly effective, causes side effects, and does not prevent recurrences. We report one of very few studies that have evaluated how prebiotics compounds that are selectively fermented by beneficial bacteria such as Lactobacillus spp.-can modulate the vaginal microbiota. We also report use of a novel in vitro polymicrobial model to study the impact of prebiotics on the vaginal microbiota. The identification of prebiotic lactulose as enhancing Lactobacillus growth but not that of BV organisms or Candida albicans has direct application for retention of homeostasis and prevention of vaginal dysbiosis and infection. PMID- 29269495 TI - Inoculation method could impact the outcome of microbiological experiments. AB - For the last 150 years, bacteria have primarily been investigated in liquid bacth cultures (LBC). Contrary to most expectations, these cultures are not a homogeneous mixture of single-celled bacteria as free-floating bacterial aggregates eventually develop in most LBC. These aggregates share characteristics with biofilms such as increased antibiotic tolerance. We have investigated how aggregates develop and what influences this development in LBC of Pseudomonas aeruginosa We focused on how the method of inoculation impacted aggregation by assessing aggregate frequency and size using confocal laser scanning microscopy. Four traditional methods of initiating an overnight bacterial culture were investigated comprising inoculation directly from frozen culture, using agar grown cells, or using cells grown in liquid. We discovered a direct link between the inoculation method and the size and frequency of biofilm aggregates in a LBC, with inoculation directly from a plate resulting in the most numerous and largest aggregates. These large aggregates had an overall impact on the cultures' subsequent tolerance towards tobramycin indicating that the inoculation method has a profound impact on antibiotic tolerance. We also observed a mechanism where pre-formed aggregates recruited single cells from the surrounding culture in a "snowball effect", building up aggregated biomass in the culture. This recruitment was found to rely heavily on the exopolysaccharide Psl. Additionally, we found that both Escherichia coli and Staphylococcus aureus also produce aggregates in LBC. Our results stress the importance of inoculation consistency throughout experiments and the substantial impact aggregate development in LBC has on the output of microbiological experiments.IMPORTANCE Liquid pure cultures are fundamental to the field of microbiological research. These cultures are normally thought of as a homogeneous mix of single cell bacteria. The present study shows how this is not always true. Bacteria may aggregate in these liquid cultures. The aggregation can be induced by the method chosen for inoculation. The presence of aggregates can significantly change the outcome of experiments by altering the phenotype of the cultures. The study found a mechanism where pre formed aggregates are able to recruit surrounding single cells in a form of snowball effect creating more and larger aggregates in the culture. Once formed, these aggregates are hard to remove. Aggregates in liquid cultures may be an immense unseen challenge for microbiologists. PMID- 29269496 TI - A Single Mechanosensitive Channel Protects Francisella tularensis subsp. holarctica from Hypoosmotic Shock and Promotes Survival in the Aquatic Environment. AB - Francisella tularensis subsp. holarctica is found in North America and much of Europe and causes the disease tularemia in humans and animals. An aquatic cycle has been described for this subspecies, which has caused waterborne outbreaks of tularemia in at least 10 countries. In this study, we sought to identify the mechanosensitive channel(s) required for the bacterium to survive the transition from mammalian hosts to freshwater, which is likely essential for the transmission of the bacterium between susceptible hosts. A single 165-amino-acid MscS-type mechanosensitive channel (FtMscS) was found to protect F. tularensis subsp. holarctica from hypoosmotic shock, despite lacking much of the cytoplasmic vestibule domain found in well-characterized MscS proteins from other organisms. The deletion of this channel did not affect virulence within the mammalian host; however, FtMscS was required to survive the transition from the host niche to freshwater. The deletion of FtMscS did not alter the sensitivity of F. tularensis subsp. holarctica to detergents, H2O2, or antibiotics, suggesting that the role of FtMscS is specific to protection from hypoosmotic shock. The deletion of FtMscS also led to a reduced average cell size without altering gross cell morphology. The mechanosensitive channel identified and characterized in this study likely contributes to the transmission of tularemia between hosts by allowing the bacterium to survive the transition from mammalian hosts to freshwater.IMPORTANCE The contamination of freshwater by Francisella tularensis subsp. holarctica has resulted in a number of outbreaks of tularemia. Invariably, the contamination originates from the carcasses or excreta of infected animals and thus involves an abrupt osmotic downshock as the bacteria enter freshwater. How F. tularensis survives this drastic change in osmolarity has not been clear, but here we report that a single mechanosensitive channel protects the bacterium from osmotic downshock. This channel is functional despite lacking much of the cytoplasmic vestibule domain that is present in better-studied organisms such as Escherichia coli; this report builds on previous studies that have suggested that parts of this domain are dispensable for downshock protection. These findings extend our understanding of the aquatic cycle and ecological persistence of F. tularensis, with further implications for mechanosensitive channel biology. PMID- 29269497 TI - Covalent Structure and Bioactivity of the Type AII Lantibiotic Salivaricin A2. AB - Lantibiotics are a class of lanthionine-containing, ribosomally synthesized, and posttranslationally modified peptides (RiPPs) produced by Gram-positive bacteria. Salivaricin A2 belongs to the type AII lantibiotics, which are generally considered to kill Gram-positive bacteria by binding to the cell wall precursor lipid II via a conserved ring A structure. Salivaricin A2 was first reported to be isolated from a probiotic strain, Streptococcus salivarius K12, but the structural and bioactivity characterizations of the antibiotic have remained limited. In this study, salivaricin A2 was purified and its covalent structure was characterized. N-terminal analogues of salivaricin A2 were generated to study the importance for bioactivity of the length and charge of the N-terminal amino acids. Analogue salivaricin A2(3-22) has no antibacterial activity and does not have an antagonistic effect on the native compound. The truncated analogue also lost its ability to bind to lipid II in a thin-layer chromatography (TLC) assay, suggesting that the N-terminal amino acids are important for binding to lipid II. The creation of N-terminal analogues of salivaricin A2 promoted a better understanding of the bioactivity of this antibiotic and further elucidated the structural importance of the N-terminal leader peptide. The antibacterial activity of salivaricin A2 is due not only to the presence of the positively charged N-terminal amino acid residues, but to the length of the N-terminal linear peptide.IMPORTANCE The amino acid composition of the N-terminal linear peptide of salivaricin A2 is crucial for function. Our study shows that the length of the amino acid residues in the linear peptide is crucial for salivaricin A2 antimicrobial activity. Very few type AII lantibiotic covalent structures have been confirmed. The characterization of the covalent structure of salivaricin A2 provides additional support for the predicted lanthionine and methyl-lanthionine ring formations present in this structural class of lantibiotics. Removal of the N-terminal Lys1 and Arg2 residues from the peptide causes a dramatic shift in the chemical shift values of amino acid residues 7 through 9, suggesting that the N-terminal amino acids contribute to a distinct structural conformer for the linear peptide region. The demonstration that the bioactivity could be partially restored with the substitution of N-terminal alanine residues supports further studies aimed at determining whether new analogues of salivaricin A2 for novel applications can be synthesized. PMID- 29269499 TI - Temporal and Regional Variability in the Skin Microbiome of Humpback Whales along the Western Antarctic Peninsula. AB - The skin is the first line of defense between an animal and its environment, and disruptions in skin-associated microorganisms can be linked to an animal's health and nutritional state. To better understand the skin microbiome of large whales, high-throughput sequencing of partial small subunit rRNA genes was used to study the skin-associated bacteria of 89 seemingly healthy humpback whales (Megaptera novaeangliae) sampled along the Western Antarctic Peninsula (WAP) during early (2010) and late (2013) austral summers. Six core groups of bacteria were present in 93% or more of all humpback skin samples. A shift was observed in the average relative abundances of these core bacteria over time, with the emergence of four additional core groups of bacteria that corresponded to a decrease in water temperature, possibly caused by season- or foraging-related changes in skin biochemistry that influenced microbial growth, or other temporal factors. The skin microbiome differed between whales sampled at several regional locations along the WAP, suggesting that environmental factors or population may also influence the whale skin microbiome. Overall, the skin microbiome of humpback whales appears to provide insight into animal- and environment-related factors and may serve as a useful indicator for animal health or ecosystem alterations.IMPORTANCE The microbiomes of wild animals are currently understudied but may provide information about animal health and/or animal-environment interactions. In the largest sampling of any marine mammal microbiome, this study demonstrates conservation in the skin microbiome of 89 seemingly healthy humpback whales sampled in the Western Antarctic Peninsula, with shifts in the bacterial community composition related to temporal and regional variability. This study is important because it suggests that the skin microbiome of humpback whales could provide insight into animal nutritional or seasonal/environment-related factors, which are becoming increasingly important to recognize due to unprecedented rates of climate change and anthropogenic impact on ocean ecosystems. PMID- 29269498 TI - Transcriptional Response to Lactic Acid Stress in the Hybrid Yeast Zygosaccharomyces parabailii. AB - Lactic acid has a wide range of applications starting from its undissociated form, and its production using cell factories requires stress-tolerant microbial hosts. The interspecies hybrid yeast Zygosaccharomyces parabailii has great potential to be exploited as a novel host for lactic acid production, due to high organic acid tolerance at low pH and a fermentative metabolism with a high growth rate. Here we used mRNA sequencing (RNA-seq) to analyze Z. parabailii's transcriptional response to lactic acid added exogenously, and we explore the biological mechanisms involved in tolerance. Z. parabailii contains two homeologous copies of most genes. Under lactic acid stress, the two genes in each homeolog pair tend to diverge in expression to a significantly greater extent than under control conditions, indicating that stress tolerance is facilitated by interactions between the two gene sets in the hybrid. Lactic acid induces downregulation of genes related to cell wall and plasma membrane functions, possibly altering the rate of diffusion of lactic acid into cells. Genes related to iron transport and redox processes were upregulated, suggesting an important role for respiratory functions and oxidative stress defense. We found differences in the expression profiles of genes putatively regulated by Haa1 and Aft1/Aft2, previously described as lactic acid responsive in Saccharomyces cerevisiae Furthermore, formate dehydrogenase (FDH) genes form a lactic acid-responsive gene family that has been specifically amplified in Z. parabailii in comparison to other closely related species. Our study provides a useful starting point for the engineering of Z. parabailii as a host for lactic acid production.IMPORTANCE Hybrid yeasts are important in biotechnology because of their tolerance to harsh industrial conditions. The molecular mechanisms of tolerance can be studied by analyzing differential gene expression under conditions of interest and relating gene expression patterns to protein functions. However, hybrid organisms present a challenge to the standard use of mRNA sequencing (RNA-seq) to study transcriptional responses to stress, because their genomes contain two similar copies of almost every gene. Here we used stringent mapping methods and a high quality genome sequence to study the transcriptional response to lactic acid stress in Zygosaccharomyces parabailii ATCC 60483, a natural interspecies hybrid yeast that contains two complete subgenomes that are approximately 7% divergent in sequence. Beyond the insights we gained into lactic acid tolerance in this study, the methods we developed will be broadly applicable to other yeast hybrid strains. PMID- 29269500 TI - Enteric Viruses in Surface Waters from Argentina: Molecular and Viable-Virus Detection. AB - Water resources contaminated with wastewater are an important source for the dissemination of enteric viruses with an impact on the health of the population. The aim of the study was to assess the viral contamination of freshwater from a dam in Argentina by using infectious enterovirus detection, viral RNA amplification, and a genetic characterization of five enteric viruses associated with diarrhea and hepatitis. Enterovirus infectivity (iEV) was evaluated by cell culture and direct immunofluorescence. The detection of the viral genome of rotavirus (RV), human astrovirus (HAstV), norovirus (NoV), hepatitis A virus (HAV), and hepatitis E virus (HEV) was performed by reverse transcriptase PCR (RT PCR). A total of 48 water samples from 4 monitoring points on the body of the dam from January to December 2012 and 66 water samples from 3 tourist beaches on the edge of the dam from October 2013 to October 2015 were collected monthly. During the first period, the overall viral frequency detection was 52.1% for group A RV, 50% for HAstV, 60.4% for NoV, 22.9% for HAV, 2.1% for HEV, and 64.6% for iEV. The overall frequency detection for the second sampling was 18.2% for RV and HAstV, 31.8% for NoV, 7.57% for HEV, and 66.7% for iEV. There was no detection of HAV during this period. The genotypes and genogroups detected through the study correlated with the most common genomic variants associated with human gastrointestinal and hepatitis illnesses. The results obtained could alert the health systems and environmental sanitation to make decisions for viral control and prevention in our environment.IMPORTANCE The study shows the impact of anthropic contamination of one of the most important tourist water resources in Argentina. This course of recreational water would be a favorable scenario for infection, as well as a reservoir for the enteric viruses, creating a risk for the population exposed to these waters. The results obtained could alert the health systems and environmental sanitation to make decisions for the control and prevention of viral diseases in this environment. PMID- 29269501 TI - Catecholamine-Modulated Novel Surface-Exposed Adhesin LIC20035 of Leptospira spp. Binds Host Extracellular Matrix Components and Is Recognized by the Host during Infection. AB - In this study, the effect of the host stress hormone catecholamine on Leptospira gene transcripts encoding outer membrane proteins was investigated. There was no impact of catecholamine supplementation on the in vitro growth pattern of Leptospira interrogans; however, 7 genes out of 41 were differentially transcribed, and the effect was reversed to the basal level in the presence of the antagonist propranolol. Comprehensive analysis of one of the differentially regulated proteins, LIC20035 (in serovar Copenhageni)/LB047 (in serovar Lai) (due to catecholamine supplementation), revealed immunogenicity and ability to adhere to host extracellular matrices. Protease accessibility assay and phase partition of integral membrane proteins of Leptospira showed LIC20035/LB047 to be an outer membrane surface-exposed protein. The recombinant LIC20035 protein can be serologically detected using human/bovine sera positive for leptospirosis. Moreover, the recombinant LIC20035 can bind to diverse host extracellular matrices, with a higher affinity toward collagen and chondroitin sulfate.IMPORTANCE Leptospirosis is a neglected tropical disease of global importance. This study aimed to identify outer membrane proteins of pathogenic Leptospira responding to host chemical signals like catecholamines, with the potential to serve as virulence factors, new serodiagnostic antigens, and vaccine candidates. This study mimicked the plausible means by which Leptospira during infection and hormonal stress intercepts host catecholamines to disseminate in host tissues. PMID- 29269502 TI - Enhancing the Adaptability of the Deep-Sea Bacterium Shewanella piezotolerans WP3 to High Pressure and Low Temperature by Experimental Evolution under H2O2 Stress. AB - Oxidative stresses commonly exist in natural environments, and microbes have developed a variety of defensive systems to counteract such events. Although increasing evidence has shown that high hydrostatic pressure (HHP) and low temperature (LT) induce antioxidant defense responses in cells, there is no direct evidence to prove the connection between antioxidant defense mechanisms and the adaptation of bacteria to HHP and LT. In this study, using the wild-type (WT) strain of a deep-sea bacterium, Shewanella piezotolerans WP3, as an ancestor, we obtained a mutant, OE100, with an enhanced antioxidant defense capacity by experimental evolution under H2O2 stress. Notably, OE100 exhibited better tolerance not only to H2O2 stress but also to HHP and LT (20 MPa and 4 degrees C, respectively). Whole-genome sequencing identified a deletion mutation in the oxyR gene, which encodes the transcription factor that controls the oxidative stress response. Comparative transcriptome analysis showed that the genes associated with oxidative stress defense, anaerobic respiration, DNA repair, and the synthesis of flagella and bacteriophage were differentially expressed in OE100 compared with the WT at 20 MPa and 4 degrees C. Genetic analysis of oxyR and ccpA2 indicated that the OxyR-regulated cytochrome c peroxidase CcpA2 significantly contributed to the adaptation of WP3 to HHP and LT. Taken together, these results confirmed the inherent relationship between antioxidant defense mechanisms and the adaptation of a benthic microorganism to HHP and LT.IMPORTANCE Oxidative stress exists in various niches, including the deep-sea ecosystem, which is an extreme environment with conditions of HHP and predominantly LT. Although previous studies have shown that HHP and LT induce antioxidant defense responses in cells, direct evidence to prove the connection between antioxidant defense mechanisms and the adaptation of bacteria to HHP and LT is lacking. In this work, using the deep-sea bacterium Shewanella piezotolerans WP3 as a model, we proved that enhancement of the adaptability of WP3 to HHP and LT can benefit from its antioxidant defense mechanism, which provided useful insight into the ecological roles of antioxidant genes in a benthic microorganism and contributed to an improved understanding of microbial adaptation strategies in deep-sea environments. PMID- 29269504 TI - Neuroinflammation as a potential therapeutic target in dementia with Lewy bodies. PMID- 29269503 TI - Metagenomics Reveals the Impact of Wastewater Treatment Plants on the Dispersal of Microorganisms and Genes in Aquatic Sediments. AB - Wastewater treatment plants (WWTPs) release treated effluent containing mobile genetic elements (MGEs), antibiotic resistance genes (ARGs), and microorganisms into the environment, yet little is known about their influence on nearby microbial communities and the retention of these factors in receiving water bodies. Our research aimed to characterize the genes and organisms from two different WWTPs that discharge into Lake Michigan, as well as from surrounding lake sediments to determine the dispersal and fate of these factors with respect to distance from the effluent outfall. Shotgun metagenomics coupled to distance decay analyses showed a higher abundance of genes identical to those in WWTP effluent genes in sediments closer to outfall sites than in sediments farther away, indicating their possible WWTP origin. We also found genes attributed to organisms, such as those belonging to Helicobacteraceae, Legionellaceae, Moraxellaceae, and Neisseriaceae, in effluent from both WWTPs and decreasing in abundance in lake sediments with increased distance from WWTPs. Moreover, our results showed that the WWTPs likely influence the ARG composition in lake sediments close to the effluent discharge. Many of these ARGs were located on MGEs in both the effluent and sediment samples, indicating a relatively broad propensity for horizontal gene transfer (HGT). Our approach allowed us to specifically link genes to organisms and their genetic context, providing insight into WWTP impacts on natural microbial communities. Overall, our results suggest a substantial influence of wastewater effluent on gene content and microbial community structure in the sediments of receiving water bodies.IMPORTANCE Wastewater treatment plants (WWTPs) release their effluent into aquatic environments. Although treated, effluent retains many genes and microorganisms that have the potential to influence the receiving water in ways that are poorly understood. Here, we tracked the genetic footprint, including genes specific to antibiotic resistance and mobile genetic elements and their associated organisms, from WWTPs to lake sediments. Our work is novel in that we used metagenomic data sets to comprehensively evaluate total gene content and the genetic and taxonomic context of specific genes in environmental samples putatively impacted by WWTP inputs. Based on two different WWTPs with different treatment processes, our findings point to an influence of WWTPs on the presence, abundance, and composition of these factors in the environment. PMID- 29269505 TI - Functional lesional neurosurgery for tremor: back to the future? AB - For nearly a century, functional neurosurgery has been applied in the treatment of tremor. While deep brain stimulation has been in the focus of academic interest in recent years, the establishment of incisionless technology, such as MRI-guided high-intensity focused ultrasound, has again stirred interest in lesional approaches.In this article, we will discuss the historical development of surgical technique and targets, as well as the technological state-of-the-art of conventional and incisionless interventions for tremor due to Parkinson's disease, essential and dystonic tremor and tremor related to multiple sclerosis (MS) and midbrain lesions. We will also summarise technique-inherent advantages of each technology and compare their lesion characteristics. From this, we identify gaps in the current literature and derive future directions for functional lesional neurosurgery, in particularly potential trial designs, alternative targets and the unsolved problem of bilateral lesional treatment. The results of a systematic review and meta-analysis of the consistency, efficacy and side effect rate of lesional treatments for tremor are presented separately alongside this article. PMID- 29269506 TI - A new splice-site mutation in SLC12A6 causing Andermann syndrome with motor neuronopathy. PMID- 29269507 TI - A witness protection program for science. PMID- 29269508 TI - TEMPERATURE-SENSITIVE MUTANTS OF ANACYSTIS NIDULANS. AB - One hundred forty-two temperature-sensitive mutants of Anacystis nidulans were isolated. None are supplementable at the non-permissive temperature, suggesting the possibility that mutations resulting in auxotrophy are lethal in this organism. PMID- 29269509 TI - Prospective, Cluster-Randomized Trial to Implement the Ottawa Model for Smoking Cessation in Diabetes Education Programs in Ontario, Canada. AB - OBJECTIVE: To test whether a practice-level intervention to promote the systematic identification, treatment, and follow-up of smokers (the Ottawa Model for Smoking Cessation [OMSC]) would improve long-term abstinence rates among smoker-patients with type 2 diabetes or prediabetes receiving care from diabetes education programs in Ontario, Canada. RESEARCH DESIGN AND METHODS: The Tobacco Intervention in Diabetes Education study was a matched-pair, cluster-randomized clinical trial. Within each pair, sites were randomly allocated to either an OMSC intervention (n = 7) or a wait-list control (WLC) condition (n = 7). Diabetes education programs in the OMSC group introduced standardized processes to identify smokers and routinely provided smoking cessation interventions and follow-up. Smokers in the OMSC group received counseling, a discount card to partially cover the cost of smoking cessation medication, and follow-up telephone calls over a 6-month period. Diabetes education programs in the WLC condition were offered the OMSC intervention after a 1-year waiting period. Smokers in the WLC group received usual care for smoking cessation from their diabetes educator. The primary end point was carbon monoxide (CO)-confirmed 7-day point prevalence abstinence from smoking at 6-month follow-up. RESULTS: A total of 313 smokers (OMSC group n = 199, WLC group n = 114) with diabetes or prediabetes were enrolled. The CO-confirmed abstinence rate at 6 months was 11.1% in the OMSC group versus 2.6% in the WLC group (odds ratio 3.73 [95% CI 1.20, 11.58]; P = 0.02). CONCLUSIONS: Implementation of the OMSC in diabetes education programs resulted in clinically and statistically significant improvements in long-term abstinence among smokers with diabetes or prediabetes. PMID- 29269510 TI - Long-term Diet Quality and Risk of Type 2 Diabetes Among Urban Chinese Adults. AB - OBJECTIVE: Little evidence exists regarding long-term diet quality and the risk of type 2 diabetes among Asian populations, who have undergone a nutrition transition and a diabetes epidemic. RESEARCH DESIGN AND METHODS: A total of 117,919 Chinese men and women, 40-74 years old, free of diabetes, cardiovascular disease, and cancer at baseline, were followed from 1996 to 2015. Diet quality was assessed by a healthy diet score (HDS) based on eight commonly consumed food groups previously suggested to be related to diabetes. Long-term diet quality and its changes were assessed by repeated surveys using food-frequency questionnaires. RESULTS: We identified 6,111 incident diabetes cases during a mean follow-up of 11.5 years. Higher HDS was associated with lower diabetes risk (hazard ratio [HR] 0.85 [95% CI 0.78-0.92] in the highest vs. lowest quintile, Pcontinuous <0.0001) after adjustment for potential confounders including BMI. Maintaining a high HDS during follow-up was associated with 26% lower risk compared with a consistently low HDS (HR 0.74 [95% CI 0.63-0.85]). The inverse association between HDS and diabetes was observed regardless of participants' age, sex, smoking and exercise habits, obesity status, and metabolic disease status but was more prominent among those who participated in leisure-time exercise (Pinteraction = 0.004). When considered jointly, a sustained high HDS plus exercise was associated with a 45% reduced risk of diabetes (HR 0.55 [95% CI 0.45-0.67]). CONCLUSIONS: A high-quality diet, especially maintained over the long term and in conjunction with leisure-time exercise, is associated with lower risk of type 2 diabetes among urban Chinese adults. PMID- 29269511 TI - Validation of Risk Equations for Complications of Type 2 Diabetes (RECODe) Using Individual Participant Data From Diverse Longitudinal Cohorts in the U.S. AB - OBJECTIVE: We sought to validate Risk Equations for Complications of Type 2 Diabetes (RECODe) among diverse populations. RESEARCH DESIGN AND METHODS: We compared risk predictions from RECODe equations and from two alternative risk models (UK Prospective Diabetes Study Outcomes Model 2 [UKPDS OM2] and American College of Cardiology/American Heart Association Pooled Cohort Equations) to observed outcomes in two studies: the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,555 adults with type 2 diabetes, median follow-up 9.1 years) and the Jackson Heart Study (JHS, n = 1,746 adults with type 2 diabetes, median follow-up 8.0 years). Outcomes included nephropathy by multiple measures (microalbuminuria, macroalbuminuria, renal failure, end-stage renal disease, and reduction in glomerular filtration rate), moderate to severe diabetic retinopathy by Airlie House classification, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, congestive heart failure, and all-cause mortality. RESULTS: RECODe equations for microvascular and cardiovascular outcomes had C-statistics for discrimination ranging from 0.71 to 0.85 in MESA and 0.64 to 0.91 in JHS for alternative outcomes. Calibration slopes in MESA ranged from 0.62 for a composite nephropathy outcome, 0.83-1.04 for individual nephropathy outcomes, 1.07 for retinopathy, 1.00-1.05 for cardiovascular outcomes, and 1.03 for all-cause mortality. Slopes in JHS ranged from 0.47 for retinopathy, 0.97-1.16 for nephropathy, 0.72-1.05 for cardiovascular outcomes, and 1.01 for all-cause mortality. The alternative models had C-statistics 0.50-0.72 and calibration slopes 0.07-0.60. CONCLUSIONS: RECODe equations improved risk estimation for diverse patients with type 2 diabetes, as compared with two commonly used alternatives. PMID- 29269512 TI - Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial beta1 Integrin. AB - OBJECTIVE: Accumulating evidence suggests a role of semaphorins in vascular homeostasis. Here, we investigate the role of Sema7A (semaphorin 7A) in atherosclerosis and its underlying mechanism. APPROACH AND RESULTS: Using genetically engineered Sema7A-/-ApoE-/- mice, we showed that deletion of Sema7A attenuates atherosclerotic plaque formation primarily in the aorta of ApoE-/- mice on a high-fat diet. A higher level of Sema7A in the atheroprone lesser curvature suggests a correlation of Sema7A with disturbed flow. This notion is supported by elevated Sema7A expression in human umbilical venous endothelial cells either subjected to oscillatory shear stress or treated with the PKA (protein kinase A)/CREB (cAMP response element-binding protein) inhibitor H89 (N [2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl hydrate). Further studies using the partial carotid artery ligation model showed that disturbed flow in the left carotid artery of Sema7A+/+ApoE-/- mice promoted the expression of endothelial Sema7A and cell adhesion molecules, leukocyte adhesion, and plaque formation, whereas such changes were attenuated in Sema7A-/-ApoE-/- mice. Further studies showed that blockage of beta1 integrin, a known Sema7A receptor, or inhibition of FAK (focal adhesion kinase), MEK1/2 (mitogen-activated protein kinase kinase 1/2), or NF-kappaB (nuclear factor-kappaB) significantly reduced the expression of cell adhesion molecules and THP-1 (human acute monocytic leukemia cell line) monocyte adhesion in Sema7A-overexpressing human umbilical venous endothelial cells. Studies using chimeric mice suggest that vascular, most likely endothelial, Sema7A plays a major role in atherogenesis. CONCLUSIONS: Our findings indicate a significant role of Sema7A in atherosclerosis by mediating endothelial dysfunction in a beta1 integrin-dependent manner. PMID- 29269514 TI - 2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis: Factor XI as a Target for New Anticoagulants. AB - The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI-deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development. PMID- 29269513 TI - PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation. AB - OBJECTIVE: BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. APPROACH AND RESULTS: Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 MUM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (MUm2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%-38.7%; P<0.001) at 2 hours and by 21.4% (9.3%-32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%-47.3%; P<0.001) at 2 hours and 23.3% (5.1%-38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. CONCLUSIONS: BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439190. PMID- 29269515 TI - Sex Differences in Hemodynamic and Microvascular Mechanisms of Myocardial Ischemia Induced by Mental Stress. AB - OBJECTIVE: To investigate sex-specific vascular mechanisms for mental stress induced myocardial ischemia (MSIMI). APPROACH AND RESULTS: Baseline data from a prospective cohort study of 678 patients with coronary artery disease underwent myocardial perfusion imaging before and during a public speaking stressor. The rate-pressure product response was calculated as the difference between the maximum value during the speech minus the minimum value during rest. Peripheral vasoconstriction by peripheral arterial tonometry was calculated as the ratio of pulse wave amplitude during the speech over the resting baseline; ratios <1 indicate a vasoconstrictive response. MSIMI was defined as percent of left ventricle that was ischemic and as a dichotomous variable. Men (but not women) with MSIMI had a higher rate-pressure product response than those without MSIMI (6500 versus 4800 mm Hg bpm), whereas women (but not men) with MSIMI had a significantly lower peripheral arterial tonometry ratio than those without MSIMI (0.5 versus 0.8). In adjusted linear regression, each 1000-U increase in rate pressure product response was associated with 0.32% (95% confidence interval, 0.22-0.42) increase in inducible ischemia among men, whereas each 0.10-U decrease in peripheral arterial tonometry ratio was associated with 0.23% (95% confidence interval, 0.11-0.35) increase in inducible myocardial ischemia among women. Results were independent of conventional stress-induced myocardial ischemia. CONCLUSIONS: Women and men have distinct cardiovascular reactivity mechanisms for MSIMI. For women, stress-induced peripheral vasoconstriction with mental stress, and not increased hemodynamic workload, is associated with MSIMI, whereas for men, it is the opposite. Future studies should examine these pathways on long term outcomes. PMID- 29269516 TI - Programmed for sex: Nutrition-reproduction relationships from an inter generational perspective. AB - Reproduction is our biological reason for being. Our physiology has been shaped via countless millennia of evolution with this one purpose in mind, so that at birth we are 'programmed for sex', although this will not kick-start functionally until puberty. Our development from an early embryo is focused on making us fit to reproduce and is intimately connected to nutrition and energy stores. Fluctuations in food supply has probably been a key evolutionary shaper of the reproductive process, and this review hypothesizes that we have developed rapid, non-genomic adaptive mechanisms to such fluctuations to better fit offspring to their perceived (nutritional) environment, thus giving them a reproductive advantage. There is abundant evidence for this notion from 'fetal programming' studies and from experimental 'inter-generational' studies involving manipulation of parental (especially paternal) diet and then examining metabolic changes in resulting offspring. It is argued that the epigenetic reprogramming of germ cells that occurs during fetal life, after fertilisation and during gametogenesis provides opportunities for sensing of the (nutritional) environment so as to affect adaptive epigenetic changes to alter offspring metabolic function. In this regard, there may be adverse effects of a modern Western diet, perhaps because it is deficient in plant-derived factors that are proven to be capable of altering the epigenome, folate being a prime example; we have evolved in tune with such factors. Therefore, parental and even grandparental diets may have consequences for health of future generations, but how important this might be and the precise epigenetic mechanisms involved are unknown. PMID- 29269519 TI - London GP clinic sees big jump in patient registrations after Babylon app launch. PMID- 29269518 TI - LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell-promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients. Cancer Res; 78(4); 909-21. (c)2017 AACR. PMID- 29269517 TI - Cell-free fetal DNA and spontaneous preterm birth. AB - Inflammation is known to play a key role in preterm and term parturition. Cell free fetal DNA (cff-DNA) is present in the maternal circulation and increases with gestational age and some pregnancy complications (e.g. preterm birth, preeclampsia). Microbial DNA and adult cell-free DNA can be pro-inflammatory through DNA-sensing mechanisms such as Toll-like receptor 9 and the Stimulator of Interferon Genes (STING) pathway. However, the pro-inflammatory properties of cff DNA, and the possible effects of this on pregnancy and parturition are unknown. Clinical studies have quantified cff-DNA levels in the maternal circulation in women who deliver preterm and women who deliver at term and show an association between preterm labor and higher cff-DNA levels in the 2nd, 3rd trimester and at onset of preterm birth symptoms. Together with potential pro-inflammatory properties of cff-DNA, this rise suggests a potential mechanistic role in the pathogenesis of spontaneous preterm birth. In this review, we discuss the evidence linking cff-DNA to adverse pregnancy outcomes, including preterm birth, obtained from preclinical and clinical studies. PMID- 29269520 TI - Emergence and evolution of TP53 mutations are key features of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide. PMID- 29269521 TI - Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients with immunodeficiencies: a single-center case series of 25 patients and a review of the literature. AB - Although it is known that B-cell lymphomas occur more frequently in immunocompromised patients, thus far such an association has not been clearly established for T-cell lymphomas. Of the 251 patients who were diagnosed with a T cell non-Hodgkin lymphoma in our center between 1999 and 2014, at least 25 were identified in immunocompromised patients. Herein, we retrospectively analyzed the clinical and pathological characteristics of these 25 cases. In addition, we searched the literature and present an overview of 605 previously published cases. The actual number of patients with B-cell chronic lymphocytic leukemia and patients on immunosuppressive drugs for inflammatory bowel disease or rheumatoid arthritis in the total cohort of 251 patients diagnosed with T-cell non-Hodgkin lymphoma was much higher than the number of patients expected to have these diseases in this cohort, based on their prevalence in the general population. This, together with the large number of additional cases found in the literature, suggest that the risk of developing T-cell non-Hodgkin lymphoma is increased in immunocompromised patients. Compared to T-cell non-Hodgkin lymphoma in the general population, these lymphomas are more often located extranodally, present at a younger age and appear to have a poor outcome. The observations made in the study herein should raise awareness of the possible development of T-cell non Hodgkin lymphoma in immunodeficient patients, and challenge the prolonged use of immunosuppressive drugs in patients who are in clinical remission of their autoimmune disease. PMID- 29269522 TI - miR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia. AB - The microRNAs miR-144 and -451 are encoded by a bicistronic gene that is strongly induced during red blood cell formation (erythropoiesis). Ablation of the miR 144/451 gene in mice causes mild anemia under baseline conditions. Here we show that miR-144/451-/- erythroblasts exhibit increased apoptosis during recovery from acute anemia. Mechanistically, miR-144/451 depletion increases the expression of the miR-451 target mRNA Cab39, which encodes a co-factor for the serine-threonine kinase LKB1. During erythropoietic stress, miR-144/451-/- erythroblasts exhibit abnormally increased Cab39 protein, which activates LKB1 and its downstream AMPK/mTOR effector pathway. Suppression of this pathway via drugs or shRNAs enhances survival of the mutant erythroblasts. Thus, miR-144/451 facilitates recovery from acute anemia by repressing Cab39/AMPK/mTOR. Our findings suggest that miR-144/451 is a key protector of erythroblasts during pathological states associated with dramatically increased erythropoietic demand, including acute blood loss and hemolytic anemia. PMID- 29269523 TI - No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy. PMID- 29269524 TI - New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis. AB - Primary familial and congenital polycythemia is characterized by erythropoietin hypersensitivity of erythroid progenitors due to germline nonsense or frameshift mutations in the erythropoietin receptor gene. All mutations so far described lead to the truncation of the C-terminal receptor sequence that contains negative regulatory domains. Their removal is presented as sufficient to cause the erythropoietin hypersensitivity phenotype. Here we provide evidence for a new mechanism whereby the presence of novel sequences generated by frameshift mutations is required for the phenotype rather than just extensive truncation resulting from nonsense mutations. We show that the erythropoietin hypersensitivity induced by a new erythropoietin receptor mutant, p.Gln434Profs*11, could not be explained by the loss of negative signaling and of the internalization domains, but rather by the appearance of a new C-terminal tail. The latter, by increasing erythropoietin receptor dimerization, stability and cell-surface localization, causes pre-activation of erythropoietin receptor and JAK2, constitutive signaling and hypersensitivity to erythropoietin. Similar results were obtained with another mutant, p.Pro438Metfs*6, which shares the same last five amino acid residues (MDTVP) with erythropoietin receptor p.Gln434Profs*11, confirming the involvement of the new peptide sequence in the erythropoietin hypersensitivity phenotype. These results suggest a new mechanism that might be common to erythropoietin receptor frameshift mutations. In summary, we show that primary familial and congenital polycythemia is more complex than expected since distinct mechanisms are involved in the erythropoietin hypersensitivity phenotype, according to the type of erythropoietin receptor mutation. PMID- 29269525 TI - Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia. AB - Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria. PMID- 29269526 TI - Hematopoietic stem cell transplantation for patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a retrospective study of 21 patients from SFGM-TC centers. PMID- 29269527 TI - Risk of progression of monoclonal gammopathy of undetermined significance into lymphoplasmacytic malignancies: determining demographic differences in the USA. PMID- 29269528 TI - ALCL: is it now a curable disease? PMID- 29269529 TI - Etoposide for HLH: the limits of efficacy. PMID- 29269530 TI - Single-cell dissection of monosomy 7 syndromes. PMID- 29269531 TI - CK2: a key regulator of thrombopoiesis. PMID- 29269532 TI - Acquired "pyro"-poikilocytosis. PMID- 29269533 TI - Konkle BA. Impacting inhibitor development in hemophilia A. Blood. 2017;130(15):1689-1690. PMID- 29269534 TI - Li H, Choesang T, Bao W, et al. Decreasing TfR1 expression reverses anemia and hepcidin suppression in beta-thalassemic mice. Blood. 2017;129(11):1514-1526. PMID- 29269535 TI - Wang X, Haylock D, Hu CS, et al. A thrombopoietin receptor antagonist is capable of depleting myelofibrosis hematopoietic stem and progenitor cells. Blood. 2016;127(26):3398-3409. PMID- 29269536 TI - Holtan SG, Weisdorf DJ. Vorinostat is victorious in GVHD prevention. Blood. 2017;130(15):1690-1691. PMID- 29269537 TI - Results of the HLH-2004 study. PMID- 29269538 TI - No chocolate for Fido. PMID- 29269539 TI - Welsh vets lead way with brachy position. PMID- 29269540 TI - Medivet to rethink breed policy after row. PMID- 29269541 TI - More cases of Alabama rot confirmed in UK. PMID- 29269542 TI - Wales aiming to be officially TB-free by 2041. PMID- 29269543 TI - Clarity on use of formaldehyde in fish. PMID- 29269544 TI - Social media giant takes action on wildlife 'selfies'. AB - Georgina Mills explains how Instagram is warning its users of the dangers of wildlife photography. PMID- 29269545 TI - Equine disease surveillance: quarterly summary. PMID- 29269546 TI - Control and disease clearance after neurological EHV-1 in the UK. PMID- 29269548 TI - Is christmas eve the busiest day in practice? PMID- 29269549 TI - Using dexmedetomidine to alleviate noise-induced fear and anxiety in dogs. PMID- 29269550 TI - The data behind veterinary workforce reccomendations. PMID- 29269551 TI - Association of Charity Vets meeting. PMID- 29269552 TI - Collaborating on One Health and veterinary public health education. PMID- 29269553 TI - John Fishwick, BVA President and Stephen May, RCVS President respond. PMID- 29269554 TI - Peppa Pig and clinical resources. PMID- 29269555 TI - Correction. PMID- 29269558 TI - Long-term outcome of thyrotoxicosis in childhood and adolescence in the west of Scotland: the case for long-term antithyroid treatment and the importance of initial counselling. AB - BACKGROUND: Thyrotoxicosis is both rarer and more severe in children than in adults, rendering management difficult and often unsatisfactory. OBJECTIVE: To ascertain outcome in a geographically defined area of Scotland between 1989 and 2014. METHOD: Retrospective case note review with follow-up questionnaire to family doctors for patients with Graves' disease and Hashimoto's thyroiditis. RESULTS: Sixty-six patients (58 females:8 males) comprising 53 with Graves' disease and 13 with Hashimoto's thyroiditis were diagnosed at median 10.4 (2.9 15.8) years and followed up for 11.8 (2.6-30.2) years. Antithyroid drug (ATD) therapy was stopped electively in 35 patients after 4.5 (1.5-8.6) years, resulting in remission in 10/13 Hashimoto's thyroiditis and 10/22 Graves' disease. Side effects occurred in 12 patients receiving carbimazole, six of whom changed to propylthiouracil; no adverse events occurred in the latter patients.Second-line therapy was given to 37 patients (34 with Graves' disease), comprising radioiodine (22) at 15.6 (9.3-24.4) years for relapse (6), poor control/adherence (14) or electively (2); and surgery (16) at 12 (6.4-21.3) years for relapse (4), poor control/adherence (5) and electively (7). Adherence problems with thyroxine replacement were reported in 10/33 patients in adulthood. CONCLUSIONS: Hashimoto's thyroiditis should be distinguished from Graves' disease at diagnosis since the prognosis for remission is better. Remission rates for Graves' disease are low (10/53 patients), time to remission variable and adherence with both ATD and thyroxine replacement often problematic. We recommend (a) the giving of long-term ATD rather than a fixed course of treatment in GD and (b) meticulous and realistic counselling of families from the time of diagnosis onwards. PMID- 29269559 TI - Point-of-care C reactive protein to identify serious infection in acutely ill children presenting to hospital: prospective cohort study. AB - OBJECTIVE: Acute infection is the most common presentation of children to hospital. A minority of these infections are serious, but early recognition and adequate management are essential. We aimed to develop improved tools to assess children attending ambulatory hospital care, integrating clinical features with point-of-care C reactive protein (CRP). DESIGN: Prospective observational diagnostic study. SETTING AND PATIENTS: 5517 acutely ill children (1 month-16 years) presenting to 106 paediatricians at six outpatient clinics and six emergency departments in Belgium. INDEX TEST: Point-of-care CRP alongside vital signs and objective symptoms measurements. MAIN OUTCOME: Hospital admission for >24 hours with a serious infection <5 days after presentation. RESULTS: An algorithm was developed consisting of clinical features and CRP. This achieved 97.1% (95% CI 94.3% to 98.7%) sensitivity and 99.6% (95% CI 99.2% to 99.8%) negative predictive value, excluding serious infections in 36.4% of children. It stratifies patients into three groups based on CRP level: high-risk group with CRP >75 mg/L (26.8% risk of infection), intermediate-risk group with CRP 20-75 mg/L and at least one of seven clinical features (8.1%), and lower risk group with CRP <20 mg/L with at least one of the 11 features (3.8%). Children in intermediate-risk or low-risk groups with normal clinical assessment have 0.6% and 0.4% risk of serious infections, respectively. CONCLUSIONS: Conducting a CRP test may first enable children to be stratified into three risk groups, guiding assessment of clinical features that could be performed by junior doctors or nurses. In one-third of acutely ill children, the algorithm could exclude serious infection. Prospective validation of the algorithm is needed. CLINICAL TRIAL REGISTRATION: NCT02024282 (post-results). PMID- 29269560 TI - Quantification of the Arrhythmogenic Effects of Spontaneous Atrial Extrasystole Using High-Resolution Epicardial Mapping. AB - BACKGROUND: Atrial extrasystoles (AES) can initiate atrial fibrillation. However, the impact of spontaneous AES on intra-atrial conduction is unknown. The aims of this study were to examine conduction disorders provoked by AES and to correlate these conduction differences with patient characteristics, mapping locations, and type of AES. METHODS AND RESULTS: High-resolution epicardial mapping (electrodes N=128 or N=192; interelectrode distance, 2 mm) of the entire atrial surface was performed in patients (N=164; 69.5% male; age 67.2+/-10.5 years) undergoing open chest cardiac surgery. AES were classified as premature, aberrant, or prematurely aberrant. Conduction delay and conduction block were quantified during sinus rhythm and AES and subsequently compared. Median incidence of conduction delay and conduction block during sinus rhythm was 1.2% (interquartile, 0%-2.3%) and 0.4% (interquartile, 0%-2.1%). In comparison, the median incidence of conduction delay and conduction block during 339 AES was respectively 2.8% (interquartile, 1.3%-4.6%) and 2.2% (interquartile, 0.3%-5.1%) and differed between the types of AES (prematurely aberrant>aberrant>premature). The degree of prematurity was not associated with a higher incidence of conduction disorders (P>0.05). In contrast, a higher degree of aberrancy was associated with a higher incidence of conduction disorders; AES emerging as epicardial breakthrough provoked most conduction disorders (P>=0.002). AES caused most conduction disorders in patients with diabetes mellitus and left atrial dilatation (P<0.05). CONCLUSIONS: Intraoperative high-resolution epicardial mapping showed that conduction disorders are mainly provoked by prematurely aberrant AES, particularly in patients with left atrial dilation and diabetes mellitus or emerging as epicardial breakthrough. PMID- 29269561 TI - Shared cancer neoantigens: Making private matters public. AB - In this issue of JEM, Chheda et al. (https://doi.org/10.1084/jem.20171046) report that a conserved hotspot mutation associated with an aggressive form of brain cancer generates an immunogenic T cell epitope restricted by a common HLA subtype, thereby creating a "public" neoantigen. PMID- 29269562 TI - Occupational exposures to leaded and unleaded gasoline engine emissions and lung cancer risk. AB - OBJECTIVES: To determine whether occupational exposure to gasoline engine emissions (GEE) increased the risk of lung cancer and more specifically whether leaded or unleaded GEE increased the risk. METHODS: Two population-based case control studies were conducted in Montreal, Canada. The first was conducted in the early 1980s and included many types of cancer including lung cancer. The second was conducted in the late 1990s and focused on lung cancer. Population controls were used in both studies. Altogether, there were 1595 cases and 1432 population controls. A comprehensive expert-based exposure assessment procedure was implemented and exposure was assessed for 294 agents, including unleaded GEE, leaded GEE and diesel engine emissions (DEE). Logistic regression analyses were conducted to estimate ORs between various metrics of GEE exposure and lung cancer, adjusting for smoking, DEE and other potential confounders. RESULTS: About half of all controls were occupationally exposed to GEE. Irrespective of the metrics of exposure (any exposure, duration of exposure and cumulative exposure) and the type of lung cancer, and the covariates included in models, none of the point estimates of the ORs between occupational exposure to leaded or unleaded GEE and lung cancer were above 1.0. Pooling two studies, the OR for any exposure to leaded GEE was 0.82 (0.68-1.00). CONCLUSIONS: Our results do not support the hypothesis that occupational exposure to GEE increases the risk of lung cancer. PMID- 29269564 TI - CJASN: What's Behind and What's Ahead. PMID- 29269565 TI - Trust Patient Insights at Both the Individual and National Level. PMID- 29269566 TI - Bortezomib sensitizes thyroid cancer to BRAF inhibitor in vitro and in vivo. AB - Although overall survival rate for patients with thyroid cancer (TC) is high, there is an alarming 10-year recurrence rate of up to 30% conferring a ~50% survival among these high-risk patients. The BRAFV600E mutation is estimated to be present in over 50% of papillary thyroid cancer (PTC) cases besides being associated with carcinogenesis and poor prognosis. We assessed the status of NF kappaB, Ki-67, cyclin D1 and BRAFV600E in TC tissues and TC cell lines using immunohistochemistry and Western blot analysis. Concurrently, we evaluated the outcomes of combined targeting of the proteasome pathway in addition to selective BRAF inhibitors in cases of PTC. In this study, BRAFV600E-bearing TC cells were treated with BRAFV600E inhibitor, Vemurafenib alone or in combination with the proteasome inhibitor, Bortezomib. The combination of both drugs showed synergistic effects as evidenced by cell growth inhibition (P < 0.05), increased G2-phase cell cycle arrest and induced apoptosis (P < 0.05). In our TC xenograft model, the combination of Vemurafenib and Bortezomib significantly reduced tumor size (P < 0.05) and expression of the markers of cell growth and proliferation, Ki-67 and cyclin D1 (P < 0.001), when compared to monotherapy. Further analysis demonstrated that treatment with Bortezomib sensitized TC cells to Vemurafenib via mitochondrial dysregulation and apoptosis of TC cells, as evidenced by the increase in the expression of p53, Noxa protein, the loss of mitochondrial membrane potential, cytochrome c release and Poly (ADP-ribose) polymerase cleavage. Our results demonstrate a strong clinical potential for the combination of the Bortezomib and the BRAF inhibitor Vemurafenib as an efficient therapeutic approach for the treatment of TC. PMID- 29269563 TI - The epidemiology of malignant mesothelioma in women: gender differences and modalities of asbestos exposure. AB - INTRODUCTION: The epidemiology of gender differences for mesothelioma incidence has been rarely discussed in national case lists. In Italy an epidemiological surveillance system (ReNaM) is working by the means of a national register. METHODS: Incident malignant mesothelioma (MM) cases in the period 1993 to 2012 were retrieved from ReNaM. Gender ratio by age class, period of diagnosis, diagnostic certainty, morphology and modalities of asbestos exposure has been analysed using exact tests for proportion. Economic activity sectors, jobs and territorial distribution of mesothelioma cases in women have been described and discussed. To perform international comparative analyses, the gender ratio of mesothelioma deaths was calculated by country from the WHO database and the correlation with the mortality rates estimated. RESULTS: In the period of study a case list of 21 463 MMs has been registered and the modalities of asbestos exposure have been investigated for 16 458 (76.7%) of them. The gender ratio (F/M) was 0.38 and 0.70 (0.14 and 0.30 for occupationally exposed subjects only) for pleural and peritoneal cases respectively. Occupational exposures for female MM cases occurred in the chemical and plastic industry, and mainly in the non asbestos textile sector. Gender ratio proved to be inversely correlated with mortality rate among countries. CONCLUSIONS: The consistent proportion of mesothelioma cases in women in Italy is mainly due to the relevant role of non occupational asbestos exposures and the historical presence of the female workforce in several industrial settings. Enhancing the awareness of mesothelioma aetiology in women could support the effectiveness of welfare system and prevention policies. PMID- 29269568 TI - New-Generation Fetal Dose Estimates for Radiopharmaceuticals. PMID- 29269567 TI - Standards for UNiversal reporting of patient Decision Aid Evaluation studies: the development of SUNDAE Checklist. AB - BACKGROUND: Patient decision aids (PDAs) are evidence-based tools designed to help patients make specific and deliberated choices among healthcare options. The International Patient Decision Aid Standards (IPDAS) Collaboration review papers and Cochrane systematic review of PDAs have found significant gaps in the reporting of evaluations of PDAs, including poor or limited reporting of PDA content, development methods and delivery. This study sought to develop and reach consensus on reporting guidelines to improve the quality of publications evaluating PDAs. METHODS: An international workgroup, consisting of members from IPDAS Collaboration, followed established methods to develop reporting guidelines for PDA evaluation studies. This paper describes the results from three completed phases: (1) planning, (2) drafting and (3) consensus, which included a modified, two-stage, online international Delphi process. The work was conducted over 2 years with bimonthly conference calls and three in-person meetings. The workgroup used input from these phases to produce a final set of recommended items in the form of a checklist. RESULTS: The SUNDAE Checklist (Standards for UNiversal reporting of patient Decision Aid Evaluations) includes 26 items recommended for studies reporting evaluations of PDAs. In the two-stage Delphi process, 117/143 (82%) experts from 14 countries completed round 1 and 96/117 (82%) completed round 2. Respondents reached a high level of consensus on the importance of the items and indicated strong willingness to use the items when reporting PDA studies. CONCLUSION: The SUNDAE Checklist will help ensure that reports of PDA evaluation studies are understandable, transparent and of high quality. A separate Explanation and Elaboration publication provides additional details to support use of the checklist. PMID- 29269569 TI - Intraindividual Comparison of 18F-PSMA-1007 and 18F-DCFPyL PET/CT in the Prospective Evaluation of Patients with Newly Diagnosed Prostate Carcinoma: A Pilot Study. AB - The introduction of 18F-labeled prostate-specific membrane antigen (PSMA) targeted PET/CT tracers, first 18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) and more recently 18F-PSMA-1007 (((3S,10S,14S)-1-(4-(((S)-4-carboxy-2-((S)-4-carboxy-2-(6-18F fluoronicotinamido)butanamido)butanamido)methyl)phenyl)-3-(naphthalen-2-ylmethyl) 1,4,12-trioxo-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid)), have demonstrated promising results for the diagnostic workup of prostate cancer. This clinical study presents an intraindividual comparison to evaluate tracer-specific characteristics of 18F-DCFPyL versus 18F-PSMA-1007. Methods: Twelve prostate cancer patients, drug-naive or before surgery, received similar activities of about 250 MBq of 18F-DCFPyL and 18F-PSMA-1007 48 h apart and were imaged 2 h after injection on the same PET/CT scanner using the same reconstruction algorithm. Normal-organ biodistribution and tumor uptake were quantified using SUVmaxResults: PSMA-positive lesions were detected in 12 of 12 prostate cancer patients. Both tracers, 18F-DCFPyL and 18F-PSMA-1007, detected the same lesions. No statistical significance could be observed when comparing the SUVmax of 18F DCFPyL and 18F-PSMA-1007 for local tumor, lymph node metastases, and bone metastases. With regard to normal organs, 18F-DCFPyL had statistically significant higher uptake in kidneys, urinary bladder, and lacrimal gland. Vice versa, significantly higher uptake of 18F-PSMA-1007 in muscle, submandibular and sublingual gland, spleen, pancreas, liver, and gallbladder was observed. Conclusion: Excellent imaging quality was achieved with both 18F-DCFPyL and 18F PSMA-1007, resulting in identical clinical findings for the evaluated routine situations. Nonurinary excretion of 18F-PSMA-1007 might present some advantage with regard to delineation of local recurrence or pelvic lymph node metastasis in selected patients; the lower hepatic background might favor 18F-DCFPyL in late stages, when rare cases of liver metastases can occur. PMID- 29269570 TI - The Future of the Past Is the Present: The Role of the UEMS/EBNM in the Current Challenge of Educating Nuclear Medicine Specialists. PMID- 29269571 TI - Staging, Restaging, and Treatment Response Assessment in Lymphomas: What We Should Know. PMID- 29269572 TI - Regarding "Is 16 Months of Specialized Nuclear Medicine Training Enough for Best Patient Care?" PMID- 29269573 TI - Pollen-Expressed Leucine-Rich Repeat Extensins Are Essential for Pollen Germination and Growth. AB - During pollen tube growth, the walls of the tube provide the mechanical strength resisting turgor pressure to protect two sperm cells. Cell wall proteins may play an important role in this process. Pollen tube cell wall proteins known as leucine-rich repeat extensins (LRXs) harbor a leucine-rich repeat domain and an extensin domain. In this study, the functions of four pollen-expressed LRXs, LRX8, LRX9, LRX10, and LRX11 (LRX8-11), were characterized in Arabidopsis (Arabidopsis thaliana). LRX8-11 displayed a consistent expression pattern in mature pollen grains and pollen tubes. In a phenotypic analysis of four single mutants, six double mutants, four triple mutants, and a quadruple mutant, the triple and quadruple mutant plants displayed markedly reduced seed set and decreased male transmission efficiency accompanied by compromised pollen germination and pollen tube growth. GFP-fused LRX8, LRX10, and LRX11 were found to be localized to pollen tube cell walls. An immunohistochemical analysis of pollen tube cell wall polysaccharides showed an increase in the amount of rhamnogalacturonan I in the subapical walls of pollen tubes of the lrx9 lrx10 lrx11 and lrx8 lrx9 lrx11 mutants and a decrease in the content of fucosylated xyloglucans in lrx8 lrx9 lrx11 compared with wild-type plants. Moreover, the callose content in the apical walls of pollen tubes increased in the lrx8 lrx9 lrx11 mutant. In conclusion, we propose that LRX8-11 function synergistically to maintain pollen tube cell wall integrity; thus, they play critical roles in pollen germination and pollen tube growth. PMID- 29269575 TI - A New Barley Stripe Mosaic Virus Allows Large Protein Overexpression for Rapid Function Analysis. AB - Understanding the genetic and molecular bases of gene function is of increasing importance to harness their potential to produce plants with novel traits. One important objective is the improvement of plant productivity to meet future demands in food crop production. Gene function is mostly characterized through overexpression or silencing in transgenic plants. This approach is a lengthy procedure, especially in cereals. Plant viral expression systems can be used for rapid expression of proteins. However, current systems have a small cargo capacity and have mostly been used for gene silencing. Here, a four-component barley stripe mosaic virus-based system with high cargo capacity was constructed for the rapid and stable expression of recombinant proteins in different plant species, allowing function analyses at different stages of development. Fluorescent marker proteins are expressed at high levels within 1 week, and a proof of efficient function analysis is shown using the aluminum malate transporter1 gene. In addition to the ability of gene cotransformation, this work demonstrates that the four-component barley stripe mosaic virus-based system allows the overexpression of cDNAs of up to 2,100 nucleotides (encoding a protein of ~78 kD), thereby providing an invaluable tool to accelerate functional genomics and proteomic research in monocot and dicot species. PMID- 29269574 TI - Plant Lipid Droplets and Their Associated Proteins: Potential for Rapid Advances. AB - Cytoplasmic lipid droplets (LDs) of neutral lipids (triacylglycerols [TAGs], sterylesters, etc.) are reserves of high-energy metabolites and other constituents for future needs. They are present in diverse cells of eukaryotes and prokaryotes. An LD has a core of neutral lipids enclosed with a monolayer of phospholipids and proteins, which play structural and/or metabolic roles. During the past 3 decades, studies of LDs in diverse organisms have blossomed after they were found to be involved in prevalent human diseases and industrial uses. LDs in plant seeds were studied before those in mammals and microbes, and the latter studies have since moved forward. Plant LDs carry a hallmark protein called oleosin, which has a long hydrophobic hairpin penetrating the TAG core and stabilizing the LD. The oleosin gene first appeared in green algae and has evolved in enhancing promoter strength, tandem repeats, and/or expression specificity, leading to the appearance of new LD organelles, such as tapetosomes in Brassicaceae. The synthesis of LDs occurs with TAG-synthesizing enzymes on the endoplasmic reticulum (ER), and nascent TAGs are sequestered in the acyl moiety region between the bilayers of phospholipids, which results in ER-LD swelling. Oleosin is synthesized on the cytosol side of the ER and extracts the LD from the ER-LD to cytosol. This extraction of LD to the cytosol is controlled solely by the innate properties of oleosin, and modified oleosin can redirect the LD to the ER lumen and then vacuoles. The breakdown of LDs requires lipase associating with core retromer and binding to peroxisomes, which then send the enzyme to LDs via tubular extensions. Two groups of LD-associated proteins, caleosin/dioxygenase/steroleosin and LD/oil body-associated proteins, participate in cellular stress defenses via enzymic activities and binding, respectively. The surface of LDs in all plant cells may be an inert refuge for these and other proteins, which exert functions on diverse cell components. Oleosin-LDs have been explored for commercial applications; successes in their uses will rely on overcoming conceptual and technical difficulties. PMID- 29269577 TI - Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children. AB - International guidelines recommend that severe asthma can only be diagnosed after contributory factors, including adherence, have been addressed. Accurate assessment of adherence is difficult in clinical practice. We hypothesised that electronic monitoring in children would identify nonadherence, thus delineating the small number with true severe asthma.Asthmatic children already prescribed inhaled corticosteroids were prospectively recruited and persistence of adherence assessed using electronic monitoring devices. Spirometry, airway inflammation and asthma control were measured at the start and end of the monitoring period.93 children (62 male; median age 12.4 years) were monitored for a median of 92 days. Median (range) monitored adherence was 74% (21-99%). We identified four groups: 1) good adherence during monitoring with improved control, 24% (likely previous poor adherence); 2) good adherence with poor control, 18% (severe therapy resistant asthma); 3) poor adherence with good control, 26% (likely overtreated); and 4) poor adherence with poor control, 32%. No clinical parameter prior to monitoring distinguished these groups.Electronic monitoring is a useful tool for identifying children in whom a step up in treatment is indicated. Different approaches are needed in those who are controlled when adherent or who are nonadherent. Electronic monitoring is essential in a paediatric severe asthma clinic. PMID- 29269578 TI - Exhaled breath to screen for malignant pleural mesothelioma: a validation study. AB - Malignant pleural mesothelioma (MPM) is predominantly caused by asbestos exposure and has a poor prognosis. Breath contains volatile organic compounds (VOCs) and can be explored as an early detection tool. Previously, we used multicapillary column/ion mobility spectrometry (MCC/IMS) to discriminate between patients with MPM and asymptomatic high-risk persons with a high rate of accuracy. Here, we aim to validate these findings in different control groups.Breath and background samples were obtained from 52 patients with MPM, 52 healthy controls without asbestos exposure (HC), 59 asymptomatic former asbestos workers (AEx), 41 patients with benign asbestos-related diseases (ARD), 70 patients with benign non asbestos-related lung diseases (BLD) and 56 patients with lung cancer (LC).After background correction, logistic lasso regression and receiver operating characteristic (ROC) analysis, the MPM group was discriminated from the HC, AEx, ARD, BLD and LC groups with 65%, 88%, 82%, 80% and 72% accuracy, respectively. Combining AEx and ARD patients resulted in 94% sensitivity and 96% negative predictive value (NPV). The most important VOCs selected were P1, P3, P7, P9, P21 and P26.We discriminated MPM patients from at-risk subjects with great accuracy. The high sensitivity and NPV allow breath analysis to be used as a screening tool for ruling out MPM. PMID- 29269576 TI - Group VII Ethylene Response Factors in Arabidopsis: Regulation and Physiological Roles. PMID- 29269579 TI - Mediastinal staging by videomediastinoscopy in clinical N1 non-small cell lung cancer: a prospective multicentre study. AB - A quarter of patients with clinical N1 (cN1) non-small cell lung cancer (NSCLC) based on positron emission tomography-computed tomography (PET-CT) imaging have occult mediastinal nodal involvement (N2 disease). In a prospective study, endosonography alone had an unsatisfactory sensitivity (38%) in detecting N2 disease. The current prospective multicentre trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) or VAM-lymphadenectomy (VAMLA).Consecutive patients with operable and resectable (suspected) NSCLC and cN1 after PET-CT imaging underwent VAM(LA). The primary study outcome was sensitivity to detect N2 disease. Secondary endpoints were the prevalence of N2 disease, negative predictive value (NPV) and accuracy of VAM(LA).Out of 105 patients with cN1 on imaging, 26% eventually developed N2 disease. Invasive mediastinal staging with VAM(LA) had a sensitivity of 73% to detect N2 disease. The NPV was 92% and accuracy 93%. Median number of assessed lymph node stations during VAM(LA) was 4 (IQR 3-5), and in 96%, at least three stations were assessed.VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1 lung cancer, and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with a one in four chance of occult-positive mediastinal nodes after negative PET CT. PMID- 29269580 TI - Correspondence regarding the article "The asbestos fibre burden in human lungs: new insights into the chrysotile debate". PMID- 29269582 TI - Respiratory irritants in e-cigarette refill liquids across nine European countries: a threat to respiratory health? PMID- 29269581 TI - Growth and nutritional status, and their association with lung function: a study from the international Primary Ciliary Dyskinesia Cohort. AB - Chronic respiratory disease can affect growth and nutrition, which can influence lung function. We investigated height, body mass index (BMI), and lung function in patients with primary ciliary dyskinesia (PCD).In this study, based on the international PCD (iPCD) Cohort, we calculated z-scores for height and BMI using World Health Organization (WHO) and national growth references, and assessed associations with age, sex, country, diagnostic certainty, age at diagnosis, organ laterality and lung function in multilevel regression models that accounted for repeated measurements.We analysed 6402 measurements from 1609 iPCD Cohort patients. Height was reduced compared to WHO (z-score -0.12, 95% CI -0.17 to 0.06) and national references (z-score -0.27, 95% CI -0.33 to -0.21) in male and female patients in all age groups, with variation between countries. Height and BMI were higher in patients diagnosed earlier in life (p=0.026 and p<0.001, respectively) and closely associated with forced expiratory volume in 1 s and forced vital capacity z-scores (p<0.001).Our study indicates that both growth and nutrition are affected adversely in PCD patients from early life and are both strongly associated with lung function. If supported by longitudinal studies, these findings suggest that early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression and lung function impairment in PCD. PMID- 29269584 TI - The effect of smoking on exacerbation risk in eosinophilic patients with COPD. PMID- 29269583 TI - Two-year follow-up after endobronchial coil treatment in emphysema: results from the REVOLENS study. PMID- 29269585 TI - The effect of smoking on exacerbation risk in eosinophilic patients with COPD. PMID- 29269586 TI - Correspondence regarding the article "The asbestos fibre burden in human lungs: new insights into the chrysotile debate". PMID- 29269587 TI - Adherence in severe asthma: time to get it right. PMID- 29269588 TI - Correspondence regarding the article "The asbestos fibre burden in human lungs: new insights into the chrysotile debate". PMID- 29269590 TI - Optimising the utility of pleural fluid adenosine deaminase for the diagnosis of adult tuberculous pleural effusion in Hong Kong. AB - INTRODUCTION: Pleural fluid adenosine deaminase level can be applied to rapidly detect tuberculous pleural effusion. We aimed to establish a local diagnostic cut off value for pleural fluid adenosine deaminase to identify patients with tuberculous pleural effusion, and optimise its utility. METHODS: We retrospectively reviewed the medical records of consecutive adults with pleural fluid adenosine deaminase level measured by the Diazyme commercial kit (Diazyme Laboratories, San Diego [CA], United States) during 1 January to 31 December 2011 in a cluster of public hospitals in Hong Kong. We considered its level alongside early (within 2 weeks) findings in pleural fluid and pleural biopsy, with and without applying Light's criteria in multiple scenarios. For each scenario, we used the receiver operating characteristic curve to identify a diagnostic cut-off value for pleural fluid adenosine deaminase, and estimated its positive and negative predictive values. RESULTS: A total of 860 medical records were reviewed. Pleural effusion was caused by congestive heart failure, chronic renal failure, or hypoalbuminaemia caused by liver or kidney diseases in 246 (28.6%) patients, malignancy in 198 (23.0%), non-tuberculous infection in 168 (19.5%), tuberculous pleural effusion in 157 (18.3%), and miscellaneous causes in 91 (10.6%). All those with tuberculous pleural effusion had a pleural fluid adenosine deaminase level of <=100 U/L. When analysis was restricted to 689 patients with pleural fluid adenosine deaminase level of <=100 U/L and early negative findings for malignancy and non-tuberculous infection in pleural fluid, the positive predictive value was significantly increased and the negative predictive value non-significantly reduced. Using this approach, neither additionally restricting analysis to exudates by Light's criteria nor adding closed pleural biopsy would further enhance predictive values. As such, the diagnostic cut-off value for pleural fluid adenosine deaminase is 26.5 U/L, with a sensitivity of 87.3%, specificity of 93.2%, positive predictive value of 79.2%, negative predictive value of 96.1%, and accuracy of 91.9%. Sex, age, and co morbidity did not significantly affect prediction of tuberculous pleural effusion using the cut-off value. CONCLUSION: We have established a diagnostic cut-off level for pleural fluid adenosine deaminase in the diagnosis of tuberculous pleural effusion by restricting analysis to a level of <=100 U/L, and considering early pleural fluid findings for malignancy and non-tuberculous infection, but not Light's criteria. PMID- 29269589 TI - Dietary antioxidants and 10-year lung function decline in adults from the ECRHS survey. AB - The relationship between lung function decline and dietary antioxidants over 10 years in adults from three European countries was investigated.In 2002, adults from three participating countries of the European Community Respiratory Health Survey (ECRHS) answered a questionnaire and underwent spirometry (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)), which were repeated 10 years later. Dietary intake was estimated at baseline with food frequency questionnaires (FFQ). Associations between annual lung function decline (mL) and diet (tertiles) were examined with multivariable analyses. Simes' procedure was applied to control for multiple testing.A total of 680 individuals (baseline mean age 43.8+/-6.6 years) were included. A per-tertile increase in apple and banana intake was associated with a 3.59 mL.year-1 (95% CI 0.40, 7.68) and 3.69 mL.year-1 (95% CI 0.25, 7.14) slower decline in FEV1 and FVC, respectively. Tomato intake was also associated with a slower decline in FVC (4.5 mL.year-1; 95% CI 1.28, 8.02). Only the association with tomato intake remained statistically significant after the Simes' procedure was performed. Subgroup analyses showed that apple, banana and tomato intake were all associated with a slower decline in FVC in ex-smokers.Intake of fruits and tomatoes might delay lung function decline in adults, particularly in ex-smokers. PMID- 29269591 TI - Universal, colorimetric microRNA detection strategy based on target-catalyzed toehold-mediated strand displacement reaction. AB - In this work, we developed a novel, label-free, and enzyme-free strategy for the colorimetric detection of microRNA (miRNA), which relies on a target-catalyzed toehold-mediated strand displacement (TMSD) reaction. The system employs a detection probe that specifically binds to the target miRNA and sequentially releases a catalyst strand (CS) intended to trigger the subsequent TMSD reaction. Thus, the presence of target miRNA releases the CS that mediates the formation of an active G-quadruplex DNAzyme which is initially caged and inactivated by a blocker strand. In addition, a fuel strand that is supplemented for the recycling of the CS promotes another TMSD reaction, consequently generating a large number of active G-quadruplex DNAzymes. As a result, a distinct colorimetric signal is produced by the ABTS oxidation promoted by the peroxidase mimicking activity of the released G-quadruplex DNAzymes. Based on this novel strategy, we successfully detected miR-141, a promising biomarker for human prostate cancer, with high selectivity. The diagnostic capability of this system was also demonstrated by reliably determining target miR-141 in human serum, showing its great potential towards real clinical applications. Importantly, the proposed approach is composed of separate target recognition and signal transduction modules. Thus, it could be extended to analyze different target miRNAs by simply redesigning the detection probe while keeping the same signal transduction module as a universal signal amplification unit, which was successfully demonstrated by analyzing another target miRNA, let-7d. PMID- 29269592 TI - Tongue coating: its characteristics and role in intra-oral halitosis and general health-a review. AB - Tongue coating (TC), a grayish-white deposit on the tongue, is the main cause of intra-oral halitosis (IOH), a socially unacceptable condition. This review covers the general features of TC, including its formation and the factors that influence it. Volatile sulfur compounds (VSCs) are the principal elements of IOH, and TC and periodontal diseases are the two main sources of VSCs. This review covers the relationship between VSCs, TC, and periodontal disease. We comprehensively discuss the methods employed to quantify TC, its microbial composition, its influence on general health and its importance in general medicine. PMID- 29269593 TI - Quasicrystals: What do we know? What do we want to know? What can we know? AB - More than 35 years and 11 000 publications after the discovery of quasicrystals by Dan Shechtman, quite a bit is known about their occurrence, formation, stability, structures and physical properties. It has also been discovered that quasiperiodic self-assembly is not restricted to intermetallics, but can take place in systems on the meso- and macroscales. However, there are some blank areas, even in the centre of the big picture. For instance, it has still not been fully clarified whether quasicrystals are just entropy-stabilized high temperature phases or whether they can be thermodynamically stable at 0 K as well. More studies are needed for developing a generally accepted model of quasicrystal growth. The state of the art of quasicrystal research is briefly reviewed and the main as-yet unanswered questions are addressed, as well as the experimental limitations to finding answers to them. The focus of this discussion is on quasicrystal structure analysis as well as on quasicrystal stability and growth mechanisms. PMID- 29269594 TI - Small-angle X-ray scattering tensor tomography: model of the three-dimensional reciprocal-space map, reconstruction algorithm and angular sampling requirements. AB - Small-angle X-ray scattering tensor tomography, which allows reconstruction of the local three-dimensional reciprocal-space map within a three-dimensional sample as introduced by Liebi et al. [Nature (2015), 527, 349-352], is described in more detail with regard to the mathematical framework and the optimization algorithm. For the case of trabecular bone samples from vertebrae it is shown that the model of the three-dimensional reciprocal-space map using spherical harmonics can adequately describe the measured data. The method enables the determination of nanostructure orientation and degree of orientation as demonstrated previously in a single momentum transfer q range. This article presents a reconstruction of the complete reciprocal-space map for the case of bone over extended ranges of q. In addition, it is shown that uniform angular sampling and advanced regularization strategies help to reduce the amount of data required. PMID- 29269595 TI - Construction of weavings in the plane. AB - This work develops, in graph-theoretic terms, a methodology for systematically constructing weavings of overlapping nets derived from 2-colorings of the plane. From a 2-coloring, two disjoint simple, connected graphs called nets are constructed. The union of these nets forms an overlapping net, and a weaving map is defined on the intersection points of the overlapping net to form a weaving. Furthermore, a procedure is given for the construction of mixed overlapping nets and for deriving weavings from them. PMID- 29269596 TI - Improving the convergence rate of a hybrid input-output phasing algorithm by varying the reflection data weight. AB - In an iterative projection algorithm proposed for ab initio phasing, the error metrics typically exhibit little improvement until a sharp decrease takes place as the iteration converges to the correct high-resolution structure. Related to that is the small convergence probability for certain structures. As a remedy, a variable weighting scheme on the diffraction data is proposed. It focuses on phasing low- and medium-resolution data first. The weighting shifts to incorporate more high-resolution reflections when the iteration proceeds. It is found that the precipitous drop in error metrics is replaced by a less dramatic drop at an earlier stage of the iteration. It seems that once a good configuration is formed at medium resolution, convergence towards the correct high-resolution structure is almost guaranteed. The original problem of phasing all diffraction data at once is reduced to a much more manageable one due to the dramatically smaller number of reflections involved. As a result, the success rate is significantly enhanced and the speed of convergence is raised. This is illustrated by applying the new algorithm to several structures, some of which are very difficult to solve without data weighting. PMID- 29269597 TI - A one-step mechanism for new twinning modes in magnesium and titanium alloys modelled by the obliquity correction of a (58 degrees , a + 2b) prototype stretch twin. AB - The ?{ 11{?overline 2}2?} and ?{ 11{?overline 2}6?} twinning modes were recently discovered by Ostapovets et al. [Philos. Mag. (2017), 97, 1088-1101] and interpreted as ?{ {10{?overline 1}2} ?}-?{ {10{?overline 1}2} ?} double twins formed by the simultaneous action of two twinning shears. Another interpretation is proposed here in which the two conjugate twinning modes result from a one-step mechanism based on a (58 degrees , a + 2b) prototype stretch twin and differ from each other only by their obliquity correction. The results are also compared with the classical theory of twinning and with the Westlake-Rosenbaum model. PMID- 29269598 TI - The limit of application of the Scherrer equation. AB - The Scherrer equation is a widely used tool to obtain crystallite size from polycrystalline samples. Its limit of applicability has been determined recently, using computer simulations, for a few structures and it was proposed that it is directly dependent on the linear absorption coefficient (MU0) and Bragg angle (thetaB). In this work, a systematic study of the Scherrer limit is presented, where it is shown that it is equal to approximately 11.9% of the extinction length. It is also shown that absorption imposes a maximum value on it and that this maximum is directly proportional to sin thetaB/MU0. PMID- 29269599 TI - Multislice imaging of integrated circuits by precession X-ray ptychography. AB - A method for nondestructively visualizing multisection nanostructures of integrated circuits by X-ray ptychography with a multislice approach is proposed. In this study, tilt-series ptychographic diffraction data sets of a two-layered circuit with a ~1.4 um gap at nine incident angles are collected in a wide Q range and then artifact-reduced phase images of each layer are successfully reconstructed at ~10 nm resolution. The present method has great potential for the three-dimensional observation of flat specimens with thickness on the order of 100 um, such as three-dimensional stacked integrated circuits based on through silicon vias, without laborious sample preparation. PMID- 29269602 TI - Information exchange using a prescribed form and involvement of occupational health nurses promotes occupational physicians to collaborate with attending physicians for supporting workers with illness in Japan. AB - The maintenance of a balance between work and disease treatment is an important issue in Japan. This study explored factors that affect collaboration between occupational physicians (OPs) and attending physicians (APs). A questionnaire was mailed to 1,102 OPs. The questionnaire assessed the demographic characteristics of OPs; their opinions and behaviors related to collaboration, including the exchange of medical information with APs; and the occupational health service system at their establishments. In total, 275 OPs completed the questionnaire (25.0% response rate). Over 80% of respondents believed OPs should collaborate with APs. After adjusting for company size, collaboration >10 times/year (with regard to both returning to work following sick leave and annual health check-ups for employees) was significantly associated with environmental factors, such as the presence of occupational health nurses (odds ratio (OR): 5.56 and 5.01, respectively, p<0.05) and the use of prescribed forms for information exchange (OR: 4.21 and 3.63, respectively, p<0.05) but not with the demographic characteristics of the OPs (p>0.05). The majority of OPs believed that collaboration with APs is important for supporting workers with illnesses. Support systems including prescribed forms of information exchange and occupational health nurses, play pivotal roles in promoting this collaboration. PMID- 29269603 TI - Association between long work hours and depressive state: a pilot study of propensity score matched Japanese white-collar workers. AB - Although long work hours have been associated with various physical health problems, studies of their association with mental health have yielded inconsistent results, due to differences in study settings, study outcome and/or unmeasured background factors. In this study, we used a propensity score method to evaluate the association between work hours and depressive state. A total of 467 Japanese white-collar workers were surveyed and divided into long and regular work hour groups according to overtime work records. Propensity score matching was performed based on 32 individual background and workplace factors, yielding 74 pairs of propensity-matched subjects. CES-D score, an indicator of depressive state, did not differ significantly among the two groups (p=0.203). However, work motivation, work control, social support and emotional stability correlated with CES-D score. These findings suggest that work control and social support factors are more associated with depressive state than control of work hours. These results also suggest that it is possible to use propensity score matching to evaluate the association between work hours and mental health in occupational study settings. Further studies, in larger populations, are required to determine the association between work hours and mental health parameters. PMID- 29269604 TI - The effects of nighttime napping on sleep, sleep inertia, and performance during simulated 16 h night work: a pilot study. AB - OBJECTIVES: This study aimed to elucidate the effects of two naps taken at night on morning waking state and performance. METHODS: The participants were 12 women. The experiment was performed in a laboratory over 2 days (16:00-09:00). In this crossover comparative study, three experimental nap conditions were used (naps from 22:30 to 00:00 and from 02:30 to 03:00 (22:30-NAP), 00:30 to 02:00 and 04:30 to 05:00 (00:30-NAP), and no naps (NO-NAP), respectively). Measurement items were a Visual Analog Scale for sleepiness and fatigue, the Psychomotor Vigilance Test (PVT), and single-digit addition calculations (10 min) every hour for 18 h from 16:00 to 09:00, excluding nap times. RESULTS: Sleep inertia and sleepiness were noted directly after napping. Less sleepiness and fatigue were noted in the nap groups between 06:00 and 09:00 in the morning than in the NO-NAP condition and PVT response times were faster. Since participants in the nap groups were able to conduct more single-digit addition calculations, the performance of these groups appeared to be superior to that of the NO-NAP condition. Furthermore, the performance of calculations was significantly better in the 00:30-NAP than in the 22:30-NAP. CONCLUSIONS: Taking two naps during a simulated night shift helps improve sleepiness and fatigue and maintain performance. Taking a nap in the early morning appears to be promising for improving the waking state. PMID- 29269605 TI - Development of a method for monitoring personal exposure to benzyl violet 4B and direct blue 15 in workplace air. AB - OBJECTIVES: The purpose of this research was to develop a method for monitoring personal exposure to benzyl violet 4B (BV) and direct blue 15 (DB) in workplace air for risk assessment. METHODS: We evaluated the utility of the proposed method by examining the following: recovery; method limit of quantification; reproducibility; and storage stability of the samples. RESULTS: An air sampling cassette containing a glass fiber filter was chosen as the sampler. BV and DB were extracted from the sampler filters with a solution of water and methanol (7:3, v/v) and then analyzed by a high-performance liquid chromatograph equipped with a photo-diode array detector. The overall recoveries from spiked samplers were 94-102% and 94-99% for BV and DB, respectively. The recovery after seven days of storage at 4 degrees C exceeded 95%. The method limits of quantification were 0.250 and 1.25 MUg/sample for BV and DB, respectively. The relative standard deviations, which represent the overall reproducibility defined as precision, were 0.6-4.1% and 0.8-2.9% for BV and DB, respectively. CONCLUSIONS: The proposed method enables 4 h personal exposure monitoring of BV and DB at concentrations of 1-2,000 MUg/m3 for BV and 5-2,000 MUg/m3 for DB, with a 240 l sampling. Thus, the proposed method is useful for estimating worker exposure to BV and DB. PMID- 29269606 TI - Challenge or hindrance: Does job stress affect presenteeism among Chinese healthcare workers? AB - BACKGROUND: We examined the effects of challenge stress and hindrance stress on general health and presenteeism among Chinese healthcare workers. METHODS: Structural equation modeling was used to evaluate data from a national hospital survey in China (n = 1392). Job stress, general health, and presenteeism were measured by the Perceived Ability to Work Scale, the 8-item Short-Form Health Survey, and the Challenge- and Hindrance-Related Self-reported Stress Scale. RESULTS: Challenge stress and hindrance stress were significantly positively correlated (beta = 0.62, SE = 0.021; p < 0.001). Challenge stress was directly negatively associated with presenteeism (beta = -0.05, SE = 0.037; p < 0.001), while hindrance stress was positively associated with presenteeism (beta = 0.25, SE = 0.040; p < 0.001). These associations with presenteeism were partially mediated by health. CONCLUSIONS: Hospital managers should provide healthcare workers with an appropriate level of challenge, but employee health is the most important consideration. Further efforts targeting job stress and health of junior healthcare workers are required. PMID- 29269607 TI - Identification and Characterization of a Novel NADPH Oxidase 1 (Nox1) Inhibitor That Suppresses Proliferation of Colon and Stomach Cancer Cells. AB - Reactive oxygen species (ROS) generated by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox)1 mediate cellular signalings involved in normal physiological processes, and aberrant control of Nox1 has been implicated in the pathogenesis of various diseases. Therefore, Nox1 could have great potential as a therapeutic target. Here, we identified a novel Nox1 inhibitor, NOS31 secreted from Stretomyces sp. and analyzed its chemical structure. Furthermore, NOS31 was found to selectively inhibit Nox1-mediated ROS generation, with only a marginal effect on other Nox isoforms (Nox2-5) and no ROS scavenging activity. This compound blocked both Nox organizer 1 (NOXO1)/Nox activator 1 (NOXA1)-dependent and phorbol 12-myristate 13-acetate-stimulated Nox1 mediated ROS production in colon cancer cells. NOS31 inhibited the proliferation of several colon carcinoma and gastric cancer cell lines that upregulate the Nox1 system, whereas it had no appreciable effect on normal cells with low levels of Nox1. The finding suggests that NOS31 is a unique, potent Nox1 inhibitor of microbial origin and raises its possibility as a therapeutic agent for inhibiting gastrointestinal cancer cell growth. PMID- 29269608 TI - Non-suckling starvation of neonatal mice promotes primordial follicle formation with activation of ovarian autophagy. AB - Around the time of oocyte meiotic arrest, germ cell nest breakdown occurs, and primordial follicle (PF) formation is initiated at the perinatal stage. Recently, autophagy was implicated in this process. Autophagy is induced by nutrient starvation. This study was conducted to understand how starvation affects PF formation and autophagy induction during neonatal life. Suckling of neonatal female mice was blocked immediately after birth for 12-36 h to induce starvation. The numbers of PFs at each stage were subsequently counted from serial sections of ovaries. The expression of autophagy-related proteins was also evaluated. The number of PFs peaked at 60 h after birth in the control group. The numbers for the starvation groups were significantly higher than those for the control groups at 12 and 36 h. LC3B was clearly present in the oocyte cytoplasm. At 36 h after birth, the starvation group showed a higher rate of LC3II/LC3-I expression as a marker for autophagy. Moreover, the expression of p62 as a selective substrate for autophagy decreased compared to the control group. The expression of caspase 9 as a marker for apoptosis tended to be lower at 36 h in the starvation groups. These results indicate that starvation promotes PF formation with a concomitant activation of autophagy in early neonatal ovaries, suggesting that autophagy induction during follicle assembly might increase the number of PFs. PMID- 29269609 TI - Identification of quantitative trait loci associated with the susceptibility of mouse spermatozoa to cryopreservation. AB - Although it is known that the susceptibility of mouse spermatozoa to freezing thawing varies greatly with genetic background, the underlying mechanisms remain to be elucidated. In this study, to map genetic regions responsible for the susceptibility of spermatozoa to freezing-thawing, we performed in vitro fertilization using spermatozoa from recombinant inbred mice derived from the C57BL/6J and DBA/2J strains, whose spermatozoa showed distinct fertilization abilities after freezing. Genome-wide interval mapping identified two suggestive quantitative trait loci (QTL) associated with fertilization on chromosomes 1 and 11. The strongest QTL on chromosome 11 included 70 genes at 59.237260-61.324742 Mb and another QTL on chromosome 1 included 43 genes at 153.969506-158.217850 Mb. These regions included at least 15 genes involved with testicular expression and possibly with capacitation or sperm motility. Specifically, the Abl2 gene on chromosome 1, which may affect subcellular actin distribution, had polymorphisms between C57BL/6J and DBA/2J that caused at least three amino acid substitutions. A correlation analysis using recombinant inbred strains revealed that the fertilization rate was strongly correlated with the capacitation rate of frozen thawed spermatozoa after preincubation. This result is consistent with the fact that C57BL/6J frozen-thawed spermatozoa recover their fertilization capacity following treatment with methyl-beta-cyclodextrin to enhance sperm capacitation. Thus, our data provide important clues to the molecular mechanisms underlying cryodamage to mouse spermatozoa. PMID- 29269610 TI - Coexistence of Anti-Glomerular Basement Membrane Glomerulonephritis and Membranous Nephropathy in a Female Patient with Preserved Renal Function. AB - Renal prognosis for anti-glomerular basement membrane (GBM) glomerulonephritis is poor. The greater the amount of anti-GBM antibody binding the antigen (type IV collagen of the glomerular basement membrane), the greater the number of crescents that develop in glomeruli, resulting in progression of renal impairment. Immunofluorescence staining reveals linear IgG depositions on glomerular capillary walls. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in middle-aged to elderly patients. Immune complex is deposited in the sub-epithelial space of the glomerulus resulting in the development of a membranous lesion. Immunofluorescence staining reveals granular IgG depositions on glomerular capillary walls. Coexisting anti-GBM glomerulonephritis and MN are rare and, here we report a case of coexisting anti GBM glomerulonephritis and MN with preserved renal function. There are some cases of coexisting anti-GBM glomerulonephritis and MN do not show severely decreased renal function. A 76-year-old Japanese woman presented with nephrotic syndrome, microscopic hematuria, and was positive for anti-GBM antibody. Kidney biopsy revealed linear and granular IgG depositions in glomerular capillary walls, crescent formations, and electron-dense deposits in the sub-epithelial space. She was diagnosed with anti-GBM glomerulonephritis and MN. Steroid and cyclosporine therapy achieved complete remission, and kidney function was preserved. In conclusion, coexisting anti-GBM glomerulonephritis and MN can have preserved renal function. IgG subclass of deposited anti-GBM antibody may be associated with the severity of anti-GBM glomerulonephritis. In addition, in the case of nephrotic syndrome with hematuria, we should consider the possibility of coexisting anti-GBM glomerulonephritis and MN. PMID- 29269612 TI - [Investigation of the Japan Society for Occupational Health general subjects which has been searched from National Diet Library ownership]. PMID- 29269611 TI - Effects of triclosan on acute toxicity, genetic toxicity and oxidative stress in goldfish (Carassius auratus). AB - Triclosan (TCS) is used as an antimicrobial agent and has been widely dispersed and detected in the aquatic environment. However, it remains uncertain whether TCS is genotoxic or not. In this study, the acute toxicity of TCS in goldfish (Carassius auratus) was studied. Then, based on the results for acute toxicity, other goldfish were exposed to various concentrations of TCS (control, DMSO control, and 1/4, 1/2, and 1/8 LC50) for 14 days, and the effects on genetic toxicity were evaluated using micronucleus (MN) and nuclear abnormalities (NA) frequencies in peripheral blood and the comet assay in the liver of the goldfish. In addition, malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), and total antioxidant capacity (T-AOC) in the liver were assayed to evaluate oxidative stress and the possible mechanism of genotoxicity. The 96 h median lethal concentration of TCS was 1111.9 ug/l. After 14 days of exposure, the MN and NA frequencies were significantly increased in peripheral blood of the TCS treated groups compared with the solvent control, and the comet tail moment and MDA in the liver in the highest dose of TCS groups were also significantly high. Meanwhile, an evident change in GSH, CAT, and T-AOC of the liver was found as the TCS exposure concentration increased. The results showed that TCS caused oxidative stress and a genotoxic response in goldfish, suggesting that it presents a potential ecotoxicological risk to aquatic ecosystems. PMID- 29269613 TI - Two-Year Outcomes and Predictors of Target Lesion Revascularization for Non-Left Main Coronary Bifurcation Lesions Following Two-Stent Strategy With 2nd Generation Drug-Eluting Stents. AB - BACKGROUND: Data on outcomes of non-left main coronary bifurcation lesions treated with the 2-stent strategy using 2nd-generation drug-eluting stents (DES) are insufficient.Methods and Results:The 2-year outcomes and predictors of target lesion revascularization (TLR) in 356 patients with 364 non-left main coronary bifurcation lesions treated with the 2-stent strategy using 2nd-generation DES were retrospectively evaluated. The primary outcome measure was defined as TLR. The median follow-up duration was 3.6 years (interquartile range, 2.7-4.9 years). A 2-year clinical follow-up was achieved in 99.2%. The 2-year cumulative incidence of TLR was 9.2%. Multiple stents implanted in either the main branch (adjusted odds ratio [OR] 3.01; 95% confidence interval [CI]: 1.37-6.62; P=0.006) or the side branch (adjusted OR 4.55; 95% CI: 1.99-10.4; P<0.001) and the culprit in the left anterior descending artery and its diagonal branch (adjusted OR 0.33; 95% CI: 0.15-0.75: P=0.008) were independent predictors of TLR within 2 years. CONCLUSIONS: The 2-year outcomes for the 2-stent strategy using 2nd-generation DES in non-left main coronary bifurcation lesions were acceptable. Coronary bifurcation location in the left anterior descending artery and its diagonal branch is protective against TLR, whereas multiple stents implanted in either the main branch or the side branch was associated with TLR. PMID- 29269614 TI - [Development of Body Phantom for Evaluation of Appropriate Administered Radioactivities and Image Quality on 99mTc-DMSA Scintigraphy in Pediatric Nuclear Medicine]. AB - PURPOSE: We conducted a field survey about pediatric nuclear medicine. As a result, it was suggested that 99mTc-DMSA scintigraphy was performed at many institutions, whereas various examinations such as image acquisition and processing are not carried out using the renal phantom. Therefore, we developed the body phantom for the evaluation of appropriate administered radioactivities and image quality with renal scintigraphy in pediatric nuclear medicine. METHODS: We created three differently sized body phantoms (1-, 5-, and 20-year-old models). These pediatric body phantoms were filled with a 99mTc solution based on the consensus guideline of pediatric radiopharmaceutical administered radioactivity in Japan. The planar image was evaluated using acquisition count, uniformity and defect contrast. SPECT images were evaluated with a recovery coefficient (RC). RESULTS: The acquisition counts for pediatric body phantoms were relatively corresponded to the clinical study. The appropriate acquisition counts and the pixel size for the planar image were approximately 140 counts per pixel and 1.23-1.35 mm at 5 min acquisition times in 1- and 5-year-old pediatric body phantom studies, respectively. Although the uniformity and the cold contrast did not depend on pixel size and body size, the cold contrast was affected by body size. The RC for SPECT images depended on the performance of SPECT systems, the resolution recovery algorithm and body phantom size. CONCLUSION: The developed pediatric body phantom could allow us to establish optimal image acquisition and more evidence on renal scintigraphy in pediatric nuclear medicine. PMID- 29269615 TI - [Influence on Head Computed Tomography Image by Difference of Beam Hardening Correction Method]. AB - It is well known that head computed tomography (CT) examination is an area affected by beam hardening because the brain parenchyma surrounded by thick bones is an object to be imaged. Therefore, it is essential to use the beam hardening correction process. However, the beam hardening correction processing varies depending on the apparatus. The purpose of this study is to verify the influence on the image by the difference of the beam hardening correction method from the CT value of the phantom and to prove the effect of the beam hardening correction method. We obtained CT value fluctuation amount, CT value correction amount, and CT value correction effect by the beam hardening from the CT value measurement result of phantom imaging. This was compared with 1st pass method, 2nd pass method, and Brain forward projected model-based iterative reconstruction solution. From the results, it was confirmed that the intensity and precision of the beam hardening correction process differ depending on the correction method. As a result, in the head CT examination, even if the same subject is imaged, there is a possibility of a difference in CT value due to the beam hardening correction method. PMID- 29269616 TI - [Factors for Degaussing of a Cochlear Implant Magnet in the MR Scanner]. AB - This study examined the conditions influencing degauss of the magnet using magnetic resonance imaging (MRI). Poly methyl methacrylate (PMMA) was used to fix the measurement magnets to the MRI bed at angles from 0 degrees to 180 degrees for the magnetic flux vector of static magnetic field. The PMMA was moved in the MRI magnetic field. Magnetic flux density was measured before and after bed movement, and the rate of degauss was calculated. The contents examined are as follows: (1) the angle of the magnetic flux vector of the measurement magnets for the magnetic flux vector of the static magnetic field, (2) the number of movements, (3) moving velocity, and (4) the movement on the spatial gradient of magnetic field. Mann-Whitney U test was used for statistical analysis of the data. In conclusion, the effect of the angle of the magnetic flux vector of the implant magnet was high under the conditions of degauss in this study. Therefore, during the MRI examination of a patient with a cochlear implant magnet, the operators identified the directions of the magnetic flux vector and static magnetic field of the implant magnet. PMID- 29269617 TI - [Estimate of the Approximation Function of Spectral Hounsfield Unit Curves in Dual Energy CT Imaging]. AB - The purpose of this study was to reveal the optimal function for regression of spectral Hounsfield Unit (HU) curves. The optimization procedure consists of the following steps: 1) obtaining dual energy CT (DECT) images of the RMI 467 phantom, 2) obtaining virtual monochromatic images from DECT images, 3) mapping each region of interest (ROI) to a phantom rod on virtual monochromatic images, 4) obtaining spectral HU curves for all rods, 5) regression of spectral HU curves using various functions, including linear, quadratic polynomial, cubic polynomial, quartic polynomial, quintic polynomial, sextic polynomial, septic polynomial, exponential, corrected exponential, bi-exponential, and logarithm, and 6) calculating the coefficients and the Akaike Information Criterion (AIC) of the functions listed above. Results indicated that the quintic polynomial function is suitable for analyzing the regression of spectral HU curves. The coefficients generated by the quartic or higher order polynomial functions were significantly higher than those generated by other functions (p<0.05). The median AIC of the quintic polynomial was the lowest among all functions. Therefore, we conclude that the quintic polynomial is the best function to use for the regression of spectral HU curves. PMID- 29269618 TI - [A Proposal for Evaluating the Positional Accuracy of Add-on Six-degrees-of freedom Radiotherapy Couch in Couch Rotation for Image-guided Radiotherapy]. AB - PURPOSE: In this study, we proposed and evaluated position correction accuracy assessment method with a phantom for IGRT system with add-on six-degrees-of freedom radiotherapy (6D) couches in couch rotation. METHODS AND MATERIALS: A phantom was used in a self-build phantom. We were scanned with computed tomography (CT) for radiotherapy planning and planned treatment isocenter to fall in line with CT center by treatment planning system. At first, we examined data of CT slice thickness for digitally reconstructed radiograph of QA phantom. Next, we measured uncertainty for IGRT system. We performed position correction accuracy for IGRT system with QA phantom and digital angle meter. RESULTS: Detection and correction errors for pitch and roll direction were within 0.3 degree in all verifications. CONCLUSIONS: We proposed a quality control method for position correction accuracy of 6D couch. The method was able to evaluate the accuracy of detection and correction of 6D couch and revealed the deviation of the origin of the couch rotation. PMID- 29269619 TI - [Evaluation of Dose Reduction of the Active Collimator in Multi Detector Row CT]. AB - The purpose of this study was to evaluate the performance of active collimator by changing acquisition parameters and obtaining dose profiles in z-axis direction. Dose profiles along z-axis were obtained using XRQA2 Gafchromic film. As a result, the active collimator reduced overranging about 55% compared to that without the active collimator. In addition, by changing the combination of X-ray beam width (32 mm, 40 mm), pitch factor (1.4, 0.6), and the X-ray tube rotation time (0.5 s/rot, 1.0 s/rot), the overranging changed from 19.4 to 34.9 mm. Although the active collimator is effective for reducing overranging, it is necessary to adjust acquisition parameters by taking the properties of the active collimator for acquisition parameters, especially setting beam width, into consideration. PMID- 29269620 TI - [Evaluation of Image Quality of Readout Segmented EPI with Readout Partial Fourier Technique]. AB - Readout segmented EPI (readout segmentation of long variable echo-trains: RESOLVE) segmented k-space in the readout direction. By using the partial Fourier method in the readout direction, the imaging time was shortened. However, the influence on image quality due to insufficient data sampling is concerned. The setting of the partial Fourier method in the readout direction in each segment was changed. Then, we examined signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and distortion ratio for changes in image quality due to differences in data sampling. As the number of sampling segments decreased, SNR and CNR showed a low value. In addition, the distortion ratio did not change. The image quality of minimum sampling segments is greatly different from full data sampling, and caution is required when using it. PMID- 29269621 TI - [Examination of Lower-extremity MRA Using Single-shot Balanced SSFP with Saturation Recovery]. AB - Currently, non-contrast angiography using the balanced steady-state free precession (b-SSFP) method, which uses a short scan time imaging method, has been reported as an alternative to lower-extremity MRA's conventional method. We investigated a new imaging method using balanced SSFP. This method uses a sequence of spectral attenuated inversion recovery (SPAIR) pulse for fat suppression, selective saturation pre-pulse for imaging range of background signal suppression, and rest slab on the downstream side of the imaging range for vein signal suppression. In the examination, we changed dummy pulse (0, 5, 10), saturation delay time (150 ms, 225 ms, 300 ms), and acquisition time (200 ms, 250 ms, 300 ms). For physical evaluation, we used the ROI method and for visual evaluation, we used the Scheffe's method. CR was the best and the visual evaluation was also good 10 for dummy pulse, a saturation delay time of 150 ms, and an acquisition time of 200 ms. Balanced SSFP with saturation recovery has the potential to shorten scanning times. Balanced SSFP with saturation recovery is useful for lower-extremity MRA. PMID- 29269623 TI - [6. DRL for Mammography]. PMID- 29269622 TI - [Clinical Application of Iterative Reconstruction at CT]. PMID- 29269624 TI - [Preface]. PMID- 29269625 TI - [2. Development of Neuroimaging Using Preclinical MRI, and the Clinical Application]. PMID- 29269626 TI - [Radiological Physics and Technology (RPT): Current Status and Its Future]. PMID- 29269628 TI - [Participation/Dispatch Reports on International Conferences in 2017]. PMID- 29269627 TI - [Cited and Non-cited Articles: From the Analysis of Articles Published in RPT and Others]. PMID- 29269629 TI - [The Lifetime Treasure Obtained from the JSRT Individual Research Mentorship Program for Two Years]. PMID- 29269630 TI - [The IMDRF and DITTA Activities for the Global Harmonization of Medical Device Regulations]. PMID- 29269631 TI - [Let's Make Your Life Enjoyable by Using English!] PMID- 29269632 TI - Spine and Spinal Cord Injury Associated with a Fracture in Elderly Patients with Ankylosing Spondylitis. AB - There are few cases of spinal cord injury with ankylosing spondylitis (AS). This study investigated the clinical results of a spinal cord injury with a fracture in elderly patients with AS. Nine patients who had sustained a spinal cord injury with vertebral fractures in ankylosed spines were included in this study. The mean age was 79.3 years; two were male and seven were female. The mechanism of injury, the level of vertebral fractures, clinical methods, the follow-up period, and treatment outcomes were investigated. The mechanism of injury of six cases was a fall and in the others was a slip. The levels of vertebral fractures were a cervical lesion (n = 5), a thoracic lesion (n = 3), and a lumbar lesion (n = 1). Six cases underwent a surgical procedure with posterior fusion and decompression, two cases were treated only with a brace, and one case was treated with a halo vest. The mean follow-up period was 4.3 years. The neurological deficit treatment outcomes were improved or no change in four cases each and one case had died. There was not much difference in treatment outcomes between a surgical treatment and a conservative treatment. Computed tomography imaging to evaluate the entire spine is required in all patients with AS with a possible spinal fracture. A surgical treatment and early rising and rehabilitation should be recommended for patients with fractures and AS to avoid further complications, not from the standpoint of improving the neurological status. PMID- 29269634 TI - The Association between Work-Related Stress and Autonomic Imbalance among Call Center Employees in Japan. AB - There is little epidemiological evidence linking subjective stress to objective etiologic indicators. To clarify an association between work-related stress and autonomic nervous function, we examined call center employees (167 males and 371 females) undergoing electrocardiography (ECG) at the time of annual health checkups. The questionnaire was composed of the Brief Job Stress Questionnaire based on the demand-control-support model and the Social Readjustment Rating Scale including detailed contents of home stress. The Bazett's corrected QT (QTc) interval, QT index, and heart rate were obtained from the ECG data. The male employees showed significantly higher scores of job demand, job control, and supervisor support than the female ones. In the male employees, QT index indicating the extent of autonomic imbalance and heart rate were associated with high score of supervisor support and low score of coworker support (P < 0.05), but no significant relationships were seen between QTc interval and either job strain (i.e., job demand and job control) or home stress. By contrast, the female employees showed no significant links between any autonomic indicators and either work-related stress or home stress. These data suggest that work-related stress affected QT index in male employees suffering specific occupational stressors such as emotional abuse from unsatisfied customers. Specifically, supports from supervisors and coworkers were paradoxically associated with QT index, implying that supervisors may have failed to effectively support such male employees. Also, autonomic nervous function in male employees appears to be more vulnerable to work-related stress than that in female ones. PMID- 29269633 TI - Usefulness of Consciousness Sedation with Dexmedetomidine and Pentazocine during Endovascular Treatment for Acute Stroke. AB - We investigated the safety and efficacy of consciousness sedation with dexmedetomidine (DEX) during the endovascular treatment of patients with acute cerebral infarction. Between April 2014 and November 2016, 38 stroke patients underwent endovascular thrombectomy (EVT) under local anesthesia and DEX consciousness sedation. The continuous intravenous administration of low-dose DEX (0.3-0.4 MUg/kg/h) was started before entering the operating room. Patients not completely immobilized received an iv bolus of pentazocine (PTZ) and/or DEX (0.5 0.6 MUg/kg/h). EVT was performed using a stent retriever and/or direct thrombo aspiration. DEX sedation was stopped as soon as the operation was finished. A stent retriever was used in 8 (21.1%), direct thrombo-aspiration in 10 (26.3%), a stent retriever plus thrombo-aspiration in 14 (36.8%), and other devices in 6 patients (15.8%). Reperfusion exceeding 50% (thrombolysis in cerebral infarction >2b) was obtained in 30 patients (78.9%). DEX sedation alone immobilized 24 patients (63.2%), 14 (36.8%) required the additional injection of DEX or PTZ when EVT devices were navigated to the lesion. The administration of DEX and PTZ elicited no significant respiratory depression or cardiac dysfunction interfering with the procedures. Consciousness sedation by DEX was effective during the endovascular treatment of acute stroke patients. Under DEX sedation and the injection of PTZ, EVT was possible without significantly changing the patients' vital signs. PMID- 29269635 TI - Lower Incidence of Cervical Intraepithelial Neoplasia among Young Women with Human Papillomavirus Vaccination in Miyagi, Japan. AB - The Japanese national immunization programme for Human Papillomavirus (HPV) started in 2010. Vaccination rates increased up to 70% in women in the 1996-1999 birth. However, the proactive recommendation for HPV vaccine was suspended in 2013, following repeated media reports of adverse events. Vaccination rates plumped to less than 1% in women born since 2002. In this study, incidence of abnormal cytology and histology was examined in terms of HPV vaccination among 5,924 women aged 20 to 24 years in the fiscal year (FY) 2014 and 2015. The total rate of vaccination was 16.9% (1,002/5,924). In case of FY 2015, the rates of vaccination were 59.26%, 49.68%, 11.97%, 9.08%, and 4.58% in those aged 20, 21, 22, 23, and 24 years old, respectively. The rates of high-grade squamous intraepithelial lesion (HSIL) or worse were 0.20% (2/1,002) in women with HPV vaccination and 1.14% (56/4,922) in those without HPV vaccination, indicating a significant reduction of 82.46% with vaccination (P < 0.0001). The rates of cervical intraepithelial neoplasia (CIN) 1+ were 0.80% (8/1,002) in women with vaccination and 2.28% (112/4,922) in those without vaccination. The reduction rate of CIN1+ was 64.91% (P = 0.0025). The rates of CIN2+ were 0.10% (1/1,002) with vaccination and 0.69% (34/4,922) without vaccination. The reduction rate of CIN2+ was 85.51% (P = 0.0261). Our data are the first to demonstrate a significant reduction of CIN2+ cases in an Asian population. Scientific discussion is needed to restart the proactive recommendation for HPV vaccine in Japan. PMID- 29269636 TI - Diagnosing Corticobasal Syndrome Based on the Presence of Visual Hallucinations and Imaging with Amyloid Positron Emission Tomography. AB - A 61-year-old woman was admitted to our hospital due to memory difficulties, visual hallucinations, and slowly progressing motor difficulties in the limbs. A clinical examination revealed bradykinesia, gait disturbance, left-side-dominant rigidity, ideomotor apraxia, dressing apraxia, left-sided spatial agnosia, impaired visuospatial ability, and executive dysfunction. Her symptoms were unresponsive to levodopa, and corticobasal syndrome (CBS) was diagnosed. One year later, amyloid positron emission tomography revealed amyloid beta accumulation in the bilateral cerebral cortices; at this point, CBS with underlying Alzheimer's disease pathology (CBS-AD) was diagnosed. Visual hallucinations may help differentiate CBS with corticobasal degeneration (CBS-CBD) from other pathologies, including CBS-AD. PMID- 29269637 TI - The First Report of a Japanese Case of Seipinopathy with a BSCL2 N88S Mutation. AB - Seipinopathy is an autosomal dominant neurodegenerative disease caused by mutations of the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene. We report the first Japanese case of seipinopathy with a heterozygous mutation of p.N88S in the BSCL2 gene. The patient showed bilateral hyperreflexia of the biceps, triceps, brachioradialis, and knee, as well as the pes cavus and distal dominant weakness and atrophy of both arms and legs, suggesting the involvement of both upper and lower motor neurons. Mutations of the BSCL2 gene have been known to cause motor neuron degeneration through endoplasmic reticulum stress. Seipinopathy should be considered in patients with symptoms mimicking amyotrophic lateral sclerosis. PMID- 29269638 TI - The Diagnosis of Spontaneous Coronary Artery Dissection by Optical Coherence Tomography. AB - Spontaneous coronary artery dissection (SCAD) is rare, but it frequently presents as acute myocardial infarction. It is frequently fatal and most cases are diagnosed at autopsy. We herein present the case of a 65-year-old woman with ST elevation and myocardial infarction due to SCAD. Optical coherence tomography (OCT) helped us to confirm the diagnosis. The information on the intravascular morphology provided by OCT imaging is much more detailed in comparison to that provided by coronary angiography (CAG) and intravascular ultrasound (IVUS). PMID- 29269639 TI - Adrenal Ewing's Sarcoma in an Elderly Man. AB - Ewing's sarcoma usually arises in the bones of children and adolescents. We herein report a 74-year-old man with Ewing's sarcoma in the adrenal gland. The diagnosis was confirmed by a genetic test, pathological studies, and several imaging studies. He already had multiple liver metastases when he was transferred to our hospital and died on the 37th day. The diagnosis was further confirmed by autopsy studies. Adrenal Ewing's sarcoma is very rare, and our patient was older than other reported cases. Ewing's sarcoma should be considered even in elderly patients with adrenal tumors. PMID- 29269640 TI - Readministration of Nivolumab after Persistent Immune-related Colitis in a Patient with Recurrent Melanoma. AB - Nivolumab shows promising efficacy against metastatic melanoma. However, immune related adverse events are of great concern. We herein report a case of persistent colitis that developed during nivolumab monotherapy and nivolumab readministration. An 82-year-old Japanese woman with recurrent melanoma developed Grade 3 colitis after 6 cycles of nivolumab. She was treated with corticosteroid for 28 days. Follow-up by computed tomography and colonoscopy after corticosteroid treatment revealed persistent pancolitis. Her symptoms ameliorated spontaneously in two months. Given the amelioration, nivolumab was restarted and resulted in the maintenance of stable disease for 21 months without recurrence of colitis. Even in cases of persistent colitis over several months, nivolumab readministration should be considered. PMID- 29269641 TI - Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome) Complicated by Perforation of the Small Intestine and Cholecystitis. AB - We report a case of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) complicated by perforation of the small intestine and necrotizing cholecystitis. A 69-year-old man with a history of bronchial asthma was admitted with mononeuritis multiplex. The laboratory findings included remarkable eosinophilia. He was treated with corticosteroids and his laboratory indices showed improvement; however, his functional deficits remained. His neuropathy gradually improved after the addition of intravenous immunoglobulin (IVIG). He was subsequently treated with oral prednisolone (40 mg/day) as maintenance therapy. Within a month after finishing IVIG, he developed perforation of the small intestine and necrotizing cholecystitis. Intestinal perforation has often been reported as a gastrointestinal complication of EGPA. In contrast, cholecystitis is a rare complication. We report this case because the manifestation of more than one complication is extremely rare. Gastrointestinal symptoms may be a complication of EGPA itself and/or immunosuppressive treatment. PMID- 29269642 TI - The Effectiveness of the Semi-quantitative Assessment of Microalbuminuria Using Routine Urine Dipstick Screening in Patients with Diabetes. AB - Objective The early diagnosis and treatment of microalbuminuria is important for preventing the progression of diabetic kidney disease in patients with diabetes. In this study, we assessed the accuracy of the semi-quantitative measurement of microalbuminuria by urine dipstick screening in patients with diabetes. Methods The semi-quantitative urinary albumin-to-creatinine ratio (QUACR) was used for microalbuminuria screening. A total of 291 diabetes patients with normoalbuminuria [urine albumin-to-creatinine ratio (UACR) <30 mg/g?Cre; n=205] or microalbuminuria (UACR 30-299 mg/g?Cre; n=86) were enrolled as study participants. Both the qualitative test of albumin (QUA) and the QUACR of early morning or spot urine samples were performed at the same time. A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic utility of the QUACR to that of the QUA in the detection of microalbuminuria. Results The sensitivity and specificity values of the QUACR were 84.9% and 76.6%, respectively. Those of the QUA were 53.5% and 84.4%, respectively. In the ROC analysis, the area under the curve values of the QUACR and QUA for the diagnosis of microalbuminuria were 0.807 (95% confidence interval: 0.752-0.863) and 0.689 (0.618-0.760), respectively. Conclusion These results suggest that the QUACR is a simple and efficient test-with high levels of sensitivity and specificity-for the detection of microalbuminuria in patients with diabetes. PMID- 29269643 TI - The First Case of Non-leukemic Sarcoma Composed of Mixed-phenotype Acute Leukemia, B/myeloid, Not Otherwise Specified. AB - Isolated sarcoma with features of mixed-phenotype acute leukemia (MPAL) is an extremely rare disease and it can be easily misdiagnosed as lymphoma or other malignancies. We herein report the case of a 61-year-old woman with non-leukemic sarcoma of the right pleura, pretracheal lymph node, and supraclavicular lymph node with features of MPAL, B/myeloid, not otherwise specified, which was first misdiagnosed as diffuse large B cell lymphoma. After performing a detailed re examination of the biopsy specimens, few scattered eosinophilic myelocytes allowed us to reach a correct diagnosis of MPAL and the patient was thereafter successfully treated by intensified chemotherapy followed by cord blood transplantation. PMID- 29269644 TI - Myasthenia Gravis Complicated with Peripheral T-cell Lymphoma, Not Otherwise Specified (PTCL-NOS), Following Thymectomy and Longstanding Tacrolimus Therapy. AB - Myasthenia gravis (MG), a neuromuscular junction autoimmune disease, sometimes complicates second malignancies; however, T-cell lymphoproliferative disorders have rarely been reported. A 55-year-old man, who received oral tacrolimus and prednisolone for MG for 16 years after thymectomy, presented with left abdominal pain, lymphadenopathy, and splenomegaly. A lymph node biopsy revealed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). This is the first report of oral tacrolimus leading to a T-cell lymphoproliferative disorder in patient without a history of transplantation. Physicians should be aware of the possibility of rare T-cell lymphoproliferative disorders, such as PTCL-NOS, occurring as complications in MG patients on immunosuppressive regimens after thymectomy. PMID- 29269645 TI - A Rare Coexistence of Pheochromocytoma and Parkinson's Disease With Diagnostic Challenges. AB - We herein report a case of pheochromocytoma occurring in the course of Parkinson's disease. The coexistence of these two disease is extremely rare, with only four cases hitherto reported across the public databases. It is also noteworthy that biochemical tests, which are critical for the diagnosis of pheochromocytoma, are severely confounded by dopaminergic medications for Parkinson's disease, highlighting the importance of image-based modalities in this setting. We further attempted to gain insight into the potential molecular mechanisms, proposing that hypoxia-inducible factor signaling could make these two diseases mutually exclusive, while excessive reactive oxygen species could enable their coexistence. PMID- 29269646 TI - Pulmonary Hypertension and Its Response to Treatment in a Patient with Kyphosis related Alveolar Hypoventilation. AB - Pulmonary hypertension (PH) with kyphoscoliosis-related alveolar hypoventilation is uncommon, so little is known about the effectiveness of treatments for this condition. A 66-year-old man with kyphosis who had been treated with nocturnal noninvasive positive-pressure ventilation developed PH with a mean pulmonary arterial pressure (PAP) of 32 mmHg and a pulmonary vascular resistance (PVR) of 5.95 Wood units. After addition of oxygen therapy and tadalafil, his condition improved. One year later, his mean PAP and PVR were 25 mmHg and 3.62 Wood units, respectively. This case shows the therapeutic potential of vasoactive medications for alveolar hypoventilation-related PH. PMID- 29269647 TI - Peptic Ulcers in Fukushima Prefecture Related to the Great East Japan Earthquake, Tsunami and Nuclear Accident. AB - Objective Due to the Great East Japan Earthquake, which occurred in March 2011, many residents of Fukushima Prefecture were affected by a radiation accident in addition to suffering loss or damage from the earthquake and the subsequent tsunami. The aim of this study was to evaluate the actual condition of patients with peptic ulcers related to the disaster. Methods Patients with peptic ulcers at six hospitals in three different regions of Fukushima Prefecture during the two months following the disaster and the corresponding period of the year before and the year after the disaster were enrolled in this study. Changes by period and region in the number of esophagogastroduodenoscopy (EGD) examinations and the number of peptic ulcer patients were evaluated as the primary endpoints. Changes in the frequencies of hemorrhagic ulcers were evaluated by period and by region as secondary endpoints. Results The numbers of EGDs and peptic ulcer cases compared to the previous year decreased in 2011 and then increased in 2012. However, the ratio of hemorrhagic ulcers to peptic ulcers was higher in 2011 (51.9%) than in 2010 (38.1%) and 2012 (31.1%), and the 2011 hemorrhagic ulcer ratio was the highest at 63.6% in the coastal area. Regarding bleeding cases during 2011, the rate at 1 month after the disaster (64.1%) was higher than the rate at 2 months after the disaster (40.5%) (p=0.033). Conclusion The number of patients with peptic ulcers did not increase immediately following the disaster in Fukushima Prefecture. However, the rate of bleeding patients increased soon after the disaster, especially in the coastal area. PMID- 29269648 TI - Lymph Node Collision Tumor Consisting of Metastatic Pulmonary Adenocarcinoma and Diffuse Large B-cell Lymphoma. AB - A 67-year-old man presented with a fever and general malaise. Computed tomography showed multiple nodules in the lungs and liver, associated with mediastinal and para-aortic lymphadenopathy. Bone marrow aspiration revealed diffuse large B-cell lymphoma (DLBCL). Renal and liver dysfunction and pancytopenia inhibited chemotherapy administration; the patient subsequently died of multiorgan failure. An autopsy revealed pulmonary adenocarcinoma with metastases to the lungs, liver, and adrenal glands; the DLBCL spread to the liver, spleen, and bone marrow. Adenocarcinoma and DLBCL collision was observed in the mediastinal and para aortic lymph nodes. This was a rare case of collision metastasis occurring in the lymph node. PMID- 29269649 TI - Dural Arterivenous Fistula at the Cavernous Sinus Diagnosed by Arterial Spin labeled Imaging. AB - We herein report a case of dural arteriovenous fistula (DAVF) at the cavernous sinus that was diagnosed by arterial spin-labeled imaging (ASL). A 67-year-old woman was referred to our hospital due to double vision and bilateral conjunctival injection. Conventional magnetic resonance imaging findings were normal. However, abnormal hyperintense signals on ASL were detected. Furthermore, the abnormality disappeared after successful endovascular embolization. Although conventional digital subtraction angiography is the standard tool for diagnosing DAVF, we speculated that ASL might be useful to this end as well. PMID- 29269650 TI - Isolated Shoulder Palsy due to Intracerebral Hemorrhage. AB - A small cortical infarction confined to the medial location of the precentral knob on the precentral gyrus may cause isolated shoulder palsy. However, there are no reports indicating intracerebral hemorrhage as a cause of isolated shoulder palsy. We herein report the case of a 48-year-old man who presented with isolated shoulder palsy as an initial symptom of subcortical hemorrhage at the precentral gyrus. Such cases may be easily misdiagnosed as shoulder or cervical spine problems. The distribution of muscle weakness is the key to an accurate diagnosis. PMID- 29269651 TI - Comparison of the Brachial-ankle Pulse Wave Velocity between Patients with Acute Coronary Syndrome and Effort Angina Pectoris. AB - Objective Coronary artery disease (CAD) is one of the clinical categories of atherosclerotic diseases. There have been reports indicating that the pathological findings of coronary artery plaque differ between acute coronary syndrome (ACS) and effort angina pectoris (EAP). The brachial-ankle pulse wave velocity (baPWV) has been reported to be a good indicator of atherosclerotic disease. However, the baPWV may not be equally effective for evaluating ACS and EAP. In this study, we compared the baPWV in patients with ACS and those with EAP. Methods Two hundred and seventy patients were enrolled in this study. All patients underwent coronary angiography, and were separated into normal (CONT), ACS and EAP groups according to the clinical and coronary angiographic findings. The baPWV was evaluated and the results were compared among the groups. Results The baPWV was significantly higher in the EAP group than in the other groups. The baPWV in the ACS group was almost the same as that of the CONT group and was significantly higher in the EAP group than in the ACS group across almost all age groups. Conclusion The present study showed that the baPWV is high in patients with EAP. In contrast, the baPWV in the ACS group was almost normal and was similar to that of the CONT group. ACS occurs due to plaque rupture induced by atherosis, which may occur independent of sclerosis in the coronary artery. EAP may occur in proportion to systemic arterial sclerosis. The baPWV is suitable for screening for EAP, but not for ACS. PMID- 29269652 TI - To Use, or Not to Use Carbapenem When Extended-spectrum beta-lactamase (ESBL) producing Bacteria Are Isolated from Sputum Cultures, That Is the Question. PMID- 29269654 TI - Metastatic Lung Adenocarcinoma Mimicking Meningioma. PMID- 29269653 TI - Expansion of NKG2C-expressing Natural Killer Cells after Umbilical Cord Blood Transplantation in a Patient with Peripheral T-cell Lymphoma with Cytotoxic Molecules. AB - A 64-year-old woman presented with generalized lymphadenopathy and systemic manifestations. The examination of a biopsy specimen revealed peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) expressing cytotoxic molecules. Umbilical cord blood transplantation was successful during a partial remission state after the administration of salvage chemotherapy. The donor-derived large granular lymphocytes started to increase as a result of cytomegalovirus reactivation. The fraction of natural killer (NK) cells expressing the NKG2C molecule accounted for one-third of the total lymphocytes for almost two years. We implicitly indicate the association between the persistence of donor-derived NKG2C+ NK cell-expansion and maintaining a complete remission in similar cases of aggressive PTCL-NOS. PMID- 29269655 TI - Chronic Brachial Plexus Neuritis That Developed into Typical Neuralgic Amyotrophy and Positively Responded to Immunotherapy. AB - Based on the hypothesis that autoimmunity plays a role in the pathogenesis of neuralgic amyotrophy (NA), immunotherapy is sometimes administered. Early intervention is recommended for a good prognosis. We herein report the case of a 55-year-old man who presented with neuralgia, weakness, and muscle atrophy in his right shoulder girdle and upper arm, which progressed for ten months following a marine sports accident. The patient was diagnosed with NA. His neurological deficits gradually improved after several courses of immunotherapy, suggesting that in addition to being effective for treating early-stage disease, immunotherapy may be effective for treating chronic cases. PMID- 29269656 TI - A Volumetric Computed Tomography Analysis of the Normal Lung in Idiopathic Pulmonary Fibrosis: The Relationship with the Survival. AB - Objective An image analysis of high-resolution computed tomography (HRCT) can provide objective quantitation of the disease status in idiopathic pulmonary fibrosis (IPF). However, to our knowledge, no reports have investigated the utility of the normal lung volume for evaluating mortality from IPF. This study aimed to evaluate the relationship between the normally attenuated lung volume on HRCT as a percentage of whole-lung volume (NL%) and IPF mortality. Methods The NL% was determined by HRCT (between -950 and -701 Hounsfield units) using a density mask technique and volumetric software. The NL%, visual assessments of the normal lung by two radiologists, pulmonary function variables, and the gender, age, and physiology (GAP) index were retrospectively evaluated for 175 patients with IPF. Uni- and multivariate Cox proportional hazards analyses and C statistics for mortality were performed. Results The univariate Cox proportional hazards analysis identified the NL% as a prognostic factor [hazard ratio, 0.949; 95% confidence interval (CI), 0.936-0.964; p<0.0001]. In the multivariate analysis, the NL% was a prognostic factor, but the radiologists' visual assessment scores of normal lung were not. The C index increased when the NL% was included in the models of the pulmonary function variables. Furthermore, the C index for a combined model of GAP stage and categorized NL% (0.758; 95% CI, 0.751 0.762) was higher than for the model with the GAP stage alone (0.689; 95% CI, 0.672-0.709). Conclusion The NL% was a prognostic factor in our study population. Quantification of the normal lung using our method may help improve the IPF staging systems. PMID- 29269657 TI - Infective Endocarditis on Caseous Calcification of the Mitral Annulus Involving Both the Anterior and Posterior Annulus: A Rare Case Report. AB - A 72-year-old man with end-stage renal disease and who was on dialysis was admitted with fever and chills. Two years previously, he had been diagnosed with caseous calcification of the mitral annulus (CCMA). Blood cultures revealed Staphylococcus aureus, and echocardiography revealed vegetation attached to the CCMA lesion, progressing to both the anterior and posterior annulus. Infective endocarditis (IE) was diagnosed and antibiotic (ampicillin) treatment was initiated. Emergent mitral valve replacement was performed after the occurrence of multiple cerebral infarctions. During surgery, we identified vegetation attached to the CCMA lesion. After surgery, the patient showed a good recovery and was discharged. This case demonstrates that IE can be complicated with CCMA. PMID- 29269658 TI - Pleurisy Caused by Mycobacterium abscessus in a Young Patient with Dermatomyositis: A Case Report and Brief Review of the Literature. AB - M. abscessus is a rapidly growing mycobacteria (RGM) and is the most common cause of pulmonary RGM infection. M. abscessus pleurisy is extremely rare. We herein report the case of a young patient with M. abscessus pleurisy without any lung lesions. A laboratory analysis of the pleural effusion revealed lymphocyte predominance and increased adenosine deaminase, similar to the findings observed in tuberculous pleurisy. The patient was initially treated for tuberculous pleurisy, which resulted in the partial improvement of the patient's symptoms and pleural effusion. M. abscessus pleurisy should be considered, especially in immunocompromised individuals, even in the absence of pulmonary involvement. PMID- 29269659 TI - Successful Treatment of Rapidly Progressive Unclassifiable Idiopathic Interstitial Pneumonia with Anti-melanoma Differentiation-associated Gene-5 Antibody by Intensive Immunosuppressive Therapy. AB - We describe a case of a woman who presented with a persistent cough, general fatigue, and a fever. Interstitial lung disease was rapidly progressive and resistant to high-dose steroid therapy. She tested positive for the presence of anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, although she had no skin manifestations of dermatomyositis. She was eventually diagnosed with unclassifiable idiopathic interstitial pneumonia and was successfully treated with intensive immunosuppressive therapy including intravenous cyclophosphamide. To our knowledge, this is the first report of anti-MDA-5 antibody in a patient with idiopathic interstitial pneumonia. PMID- 29269660 TI - Nephrotic Syndrome with Thrombocytopenia, Lymphadenopathy, Systemic Inflammation, and Splenomegaly. AB - Nephrotic syndrome can be caused by various diseases, from primary kidney diseases to systemic diseases. A kidney biopsy is useful for confirming the causes of nephrotic syndrome and in its management. We herein describe a case of nephrotic syndrome with thrombocytopenia, lymphadenopathy, systemic inflammation, splenomegaly, kidney enlargement, and progressive renal insufficiency. A kidney biopsy showed endothelial swelling with mild interstitial fibrosis and tubular atrophy. This case met the diagnostic criteria for TAFRO syndrome. Little is known about TAFRO syndrome, especially in relation to the associated kidney pathophysiology. The accumulation of a greater number of cases in which the kidney biopsy findings are investigated is needed to clarify the pathogenesis of kidney involvement in this condition. PMID- 29269661 TI - Pazopanib-induced Endothelial Injury with Podocyte Changes. AB - Pazopanib has been reported to induce proteinuria; however, no pathological findings have been reported. We herein report the case of a 31-year-old man with rhabdomyosarcoma treated with pazopanib who developed nephrotic syndrome. A renal biopsy revealed endothelial injury with podocyte changes. Based on the biopsy findings, we diagnosed the patient with nephrotic syndrome caused by pazopanib. Following the discontinuation of pazopanib, the patient's proteinuria gradually decreased without any specific treatment. We should be careful when encountering drug-induced proteinuria in patients taking pazopanib. PMID- 29269662 TI - Magnetic Resonance Imaging-guided Focused Ultrasound Thalamotomy for Parkinson's Disease. AB - Thalamotomy is effective in treating refractory tremor in Parkinson's disease (PD). We herein report a PD patient who underwent left ventral intermediate nucleus and ventro oralis posterior nucleus thalamotomy using magnetic resonance imaging-guided focused ultrasound (MRgFUS). Right-side resting tremor and rigidity were abolished immediately following the ultrasound energy delivery. In addition, left-side resting tremor and rigidity also improved. No adverse events occurred during the procedure. We observed the exacerbation of bradykinesia, which might have been caused by edema around the target. This is the first report of thalamotomy using MRgFUS for PD patient from Japan. Further investigations concerning the efficacy and safety of this procedure are necessary. PMID- 29269663 TI - Vascular Lake Phenomenon. PMID- 29269664 TI - Cardiac Magnetic Resonance Imaging of Very Late Intrapericardial Hematoma 8 Years after Coronary Artery Bypass Grafting. AB - A 55-year-old man presented with dyspnea, edema, and appetite loss. He had undergone coronary artery bypass grafting 8 years previously. He had jugular venous distention and Kussmaul's sign. Contrast-enhanced cardiac magnetic resonance imaging (CMRI) demonstrated an intrapericardial mass compressing the right ventricular (RV) cavity. T1- and T2-weighted black-blood images showed a mass with heterogeneous high signal intensity and a thick and dark rim. The mass was considered to be a chronic hematoma. After pericardiotomy with surgical removal of the hematoma, CMRI showed the marked improvement of the RV function. Late intrapericardial hematoma is rare and CMRI is useful for making a differential diagnosis. PMID- 29269665 TI - EGFR-mutant Non-small Cell Lung Cancer Accompanied by Transient Asymptomatic Pulmonary Opacities Successfully Treated with "Stop-And-Go" Osimertinib. AB - A 69-year-old man with post-operative recurrence of lung adenocarcinoma was treated with multiple chemotherapies, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. A second biopsy revealed an EGFR T790M mutation. As 10th-line chemotherapy, osimertinib was initiated. After 24 weeks, chest computed tomography (CT) revealed asymptomatic ground-glass opacities in both lobes. After four weeks of osimertinib discontinuation, imaging revealed rapid lung cancer progression. Osimertinib was resumed. After 11 weeks, CT revealed decreased lung nodules with no exacerbation of interstitial lung disease. We describe a patient who experienced transient asymptomatic pulmonary opacities during treatment with osimertinib, which was successfully managed by a "stop-and-go" approach. PMID- 29269666 TI - The Diagnosis of Gastric Mucosa-associated Lymphoid Tissue Lymphoma by Flow Cytometry and Fluorescence in situ Hybridization of Biopsy Specimens. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma and reactive inflammatory lymphoid changes are frequently difficult to distinguish based on a routine histological differential diagnosis. We were unable to diagnose gastric MALT lymphoma histologically using specimens obtained by endoscopy, although a flow cytometry (FCM) analysis demonstrated clonality of neoplastic cells by separating cells by CD45 gating. Furthermore, a fluorescence in situ hybridization (FISH) analysis showed trisomy 18. We therefore diagnosed gastric MALT lymphoma with trisomy 18. We recommend that FCM and FISH analyses of biopsy specimens be considered for diagnosing gastric MALT lymphoma if this diagnosis is suspected based on endoscopic findings. PMID- 29269667 TI - Jejunal Metastasis from Hepatocellular Carcinoma. AB - A 76-year-old man with hepatocellular carcinoma associated with alcoholic cirrhosis was hospitalized for lightheadedness and melena. He had undergone multiple surgeries and had been treated with transcatheter arterial chemoembolization and sorafenib. Neither upper nor lower gastrointestinal endoscopy detected the source of bleeding. Oral double-balloon enteroscopy revealed a mass lesion in the upper jejunum, 20 cm from the Treitz ligament on the anal side, which was identified as the source of bleeding. Subsequently, a biopsy was performed. A histopathological examination detected a hepatocellular carcinoma, and a final diagnosis of jejunal metastasis from hepatocellular carcinoma was established. PMID- 29269668 TI - Rituximab-induced Acute Thrombocytopenia in a Patient with Follicular Lymphoma: A Case Report and Review of the Literature. AB - Rituximab is a highly effective agent that is used in the treatment of B-cell lymphoma. Rituximab-induced acute thrombocytopenia is a rare side effect that has previously been reported in a small number of patients with malignant lymphoma; its mechanism is still unknown. We herein report the case of a 74-year old man who was diagnosed with follicular lymphoma and who developed severe acute thrombocytopenia the day after the administration of rituximab. Coagulation abnormality, which mimicked disseminated intravascular coagulation, also appeared. When physicians use rituximab to treat high-risk patients, the platelet count should be closely monitored to avoid possible adverse events. PMID- 29269669 TI - Autobullectomy in a Patient with COPD. PMID- 29269671 TI - Hypersegmented Neutrophils in Methotrexate Toxicity. PMID- 29269670 TI - Successful Treatment of Mitral Regurgitation after Transapical Transcatheter Aortic Valve Implantation by Percutaneous Edge-to-edge Mitral Valve Repair (MitraClip(r)) -The First Combination Therapy Performed in Japan. AB - A 75-year old man with a history of inferior myocardial infarction was admitted with symptoms of progressive heart failure 3 months after undergoing transapical transcatheter aortic valve implantation (TAVI). Echocardiography revealed severe mitral regurgitation (MR) caused by posterior leaflet tethering, without traumatic injury of the mitral valve or chordae. The patient was successfully treated by percutaneous edge-to-edge mitral valve repair (MitraClip(r)). This case highlights the role of MitraClip(r) in high-risk patients suffering from MR, and suggests that apical contractile loss or adhesion caused by apical puncture and suturing in transapical TAVI may be one of the mechanisms of worsening MR. PMID- 29269672 TI - Prominent Tendon Xanthomas and Abdominal Aortic Aneurysm Associated with Cerebrotendinous Xanthomatosis Identified Using Whole Exome Sequencing. AB - A 63-year-old man was hospitalized due to an abdominal pulsatile mass. Computed tomography revealed a saccular type abdominal aortic aneurysm, the diameter of which was 52 mm. A physical examination revealed prominent Achilles tendon thickness and plantar xanthomas. He was born in a family of consanguineous marriage, where his parents were second cousins. He had no familial history of high low-density lipoprotein cholesterol, tendon xanthomas, or premature atherosclerosis. Whole-exome sequencing assuming recessive inheritance determined his genetic diagnosis to be cerebrotendinous xanthomatosis caused by homozygous mutations (c.410G>A or p.Arg137Gln) in the cytochrome P450 subfamily 27 A1 (CYP27A1) gene. PMID- 29269673 TI - Twitching of the Pacemaker Pocket Induced by Radiofrequency Energy Delivery to the Cavotricuspid Isthmus. AB - An 82-year-old man with a permanent pacemaker (PM) implanted for sick sinus syndrome complained of palpitation due to paroxysmal atrial fibrillation and flutter. During extensive pulmonary vein isolation, the atrial lead was dislodged to the level of the tricuspid annulus. Radiofrequency energy delivery to the cavotricuspid isthmus reproducibly caused twitching of the PM pocket. The atrial lead was repositioned to the right atrial appendage, PM check revealed no functional change in the PM or lead performance. This is the first reported case of twitching of the PM pocket due to electromagnetic interference. PMID- 29269674 TI - Specific Gastric Blood Vessels in Sinistral Portal Hypertension. PMID- 29269675 TI - Giant Coronary Arterial Aneurysm of the Proximal Left Anterior Descending Artery as the Cause of Wide Splitting of the Second Heart Sound. AB - Even in modern clinical cardiology, basic auscultation skill is not obsolete and is still important because it can always provide a clue to an underlying pathophysiology. We demonstrate an unusual mechanism of pathological wide splitting of the second heart sound due to external compression of the pulmonary trunk in a patient with a giant coronary arterial aneurysm of the proximal left anterior descending artery. Echocardiography, when combined with a three dimensional anatomical analysis with cardiac computed tomography, was useful for elucidating the mechanism of the abnormal heart sounds. PMID- 29269676 TI - Pulmonary Hemorrhaging Caused by Acute Severe Mitral Regurgitation during Transcatheter Aortic Valve Implantation. AB - Transcatheter aortic valve implantation (TAVI) has been validated as a reliable therapy for aortic stenosis (AS), similar to surgical aortic valve replacement. Due to the methodological differences between the two therapeutic options, each has unique complications. We experienced a hitherto unreported complication of TAVI. An 81-year-old man underwent TAVI for severe AS. Acute mitral regurgitation (MR) occurred during valve deployment. Interference of the guidewire with the mitral subvalvular structure caused transient severe MR, leading to the development of pulmonary hemorrhaging. During TAVI, careful attention should be paid to the position of the guidewire, changes in hemodynamics and degree of MR. PMID- 29269678 TI - A Reddish Submucosal Tumor after Nephrectomy. PMID- 29269677 TI - Signet-ring Cell Carcinoma Derived from a Main Duct-type Intraductal Papillary Mucinous Neoplasm of the Pancreas: A Case Report with Long-term Follow-up. AB - We herein report the case of a 74-year-old man who underwent surgery 9 years after his initial visit and who was pathologically diagnosed with signet-ring cell carcinoma (SRCC) derived from a main-duct-type intraductal papillary mucinous neoplasm (MD-IPMN). At the first imaging examination, only a small pancreatic cyst with mild dilation of the main pancreatic duct (MPD) was detected in the pancreatic head. Eventually, MD-IPMN with mural nodules and MPD dilation (30 mm) developed in the pancreatic body, while the pancreatic head cyst remained unchanged. Total pancreatectomy was performed and the MD-IPMN was pathologically diagnosed as SRCC derived from an intestinal-type MD-IPMN. PMID- 29269679 TI - Cerebral Air Embolism Caused by Persistent Cough. PMID- 29269681 TI - The Diagnosis of Legionella pneumophila Serogroup 5 Bacteremic Pneumonia during Severe Neutropenia Using Loop-mediated Isothermal Amplification. AB - A 60-year-old man developed pneumonia after undergoing autologous peripheral blood stem cell transplantation for diffuse large-B cell lymphoma. A urinary antigen test and sputum culture were both negative for Legionella pneumophila; however, a sputum sample that was examined by loop-mediated isothermal amplification (LAMP) was positive for Legionella spp. On admission, the results of blood culturing using a BACTEC system were negative for 7 days. However, L. pneumophila serogroup 5 was detected in a blood subculture using WYOalpha medium. The patient was successfully treated with a fluoroquinolone-based regimen. LAMP is useful for the diagnosis of Legionella spp. PMID- 29269680 TI - Severe Adult-onset Still Disease with Constrictive Pericarditis and Pleuritis That Was Successfully Treated with Tocilizumab in Addition to Corticosteroids and Cyclosporin A. AB - Adult-onset Still disease (AOSD) is a systemic inflammatory disease characterized by fever, arthritis and rash. Corticosteroids represent a promising therapeutic option for AOSD; however, some resistant cases require immunosuppressants and biologic agents. We herein report the case of a 29-year-old Japanese man with severe AOSD, accompanied by constrictive pericarditis (CP) and pleuritis. Although 2 courses of steroid pulse and subsequent high-dose of prednisolone and cyclosporine A improved the patient's CP and pleuritis, his fever and inflammatory responses persisted. Tocilizumab (TCZ) was added to his treatment, which resulted in a rapid remission. This case suggests the usefulness of TCZ in the treatment of severe AOSD with CP and pleuritis. PMID- 29269682 TI - Autoimmune Hemolytic Anemia Obscured by the Obstructive Jaundice Associated with IgG4-related Sclerosing Cholangitis in a Patient with Type 1 Autoimmune Pancreatitis: A Case Report and Review of the Literature. AB - Type 1 autoimmune pancreatitis (AIP) is a pancreatic manifestation of IgG4 retated disease that is often associated with IgG4-related sclerosing cholangitis (IgG4-SC). Autoimmune hemolytic anemia (AIHA) is an immune-related disease that causes hemolytic anemia. Although type 1 AIP/IgG4-SC and AIHA have a shared etiology as a presumed autoimmune disease, they rarely overlap, and their association has not been clarified. Secondary AIHA might not be diagnosed appropriately because the obstructive jaundice observed in type 1 AIP/IgG4-SC can obscure the presence of hemolytic jaundice. We herein report a case of type 1 AIP/IgG4-SC overlapping with secondary AIHA along with a review of the literature. PMID- 29269683 TI - Emergence of Smoldering ANCA-associated Glomerulonephritis during the Clinical Course of Mixed Connective Tissue Disease and Sjogren's Syndrome. AB - A 67-year-old woman presented with hematuria and proteinuria 16 and 11 months ago, respectively. She had been followed up as mixed connective tissue disease and Sjogren's syndrome for over 19 years. Blood chemistry showed no elevated serum creatinine or C-reactive protein but did reveal myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) of 300 U/dL. A kidney biopsy showed pauci-immune focal necrotizing glomerulonephritis. She was treated with prednisolone and rituximab, resulting in normal urinalysis and decreased MPO ANCA. The complication of ANCA-associated glomerulonephritis should not be overlooked when abnormal urinalysis findings appear in the course of connective tissue disease, irrespective of the presence of rapidly progressive glomerulonephritis. PMID- 29269684 TI - The Clinical Difference in the Platelet Counts between Liver Cirrhosis with Nonalcoholic Fatty Liver Disease and Hepatitis C Virus. AB - Objective The rate of platelet count reduction appears to differ among different liver diseases. In the present study, we investigated the difference in the platelet counts of patients with nonalcoholic fatty liver disease (NAFLD) and those with chronic liver disease due to hepatitis C virus (CLD-HCV). Methods The study population included 620 patients with NAFLD and 405 patients with CLD-HCV, all of whom were diagnosed by liver biopsy. The relationships between the grade of fibrosis and the platelet count in the two diseases were compared. The optimal cut-off value for the diagnosis of liver cirrhosis (LC) was measured. The relationships between the platelet count and anti-platelet antibodies, the serum thrombopoietin level, the grade of splenomegaly and liver stiffness were also investigated in both LC groups. Results In NAFLD patients, the platelet count was significantly higher at each grade of fibrosis in comparison to CLD-HCV. The optimal cut-off value for the diagnosis of LC was 16.0*104/MUL [sensitivity, 86.7%; specificity, 87.6%; area under the curve (AUC), 0.930] in NAFLD and 12.7*104/MUL (sensitivity, 57.8%; specificity, 88.2%; AUC, 0.863) in CLD-HCV. No anti-platelet antibodies were detected in patients with either type of LC. The serum thrombopoietin levels, the distribution of splenomegaly grades, and liver stiffness did not differ between the two LC groups to a statistically significant extent. As the splenomegaly grade increased, the platelet count decreased. Conclusion The optimal cut-off values for diagnosing LC differed between the two diseases and should be determined separately. The reason for the difference in platelet reduction is still unclear, and requires further investigation. PMID- 29269685 TI - Platypnea-orthodeoxia Syndrome Induced by Multiple Vertebral Compression Fractures and an Atrial Septal Defect. AB - Platypnea-orthodeoxia syndrome (POS) is a rare condition that is characterized by dyspnea and arterial oxygen desaturation, which worsen on standing and which are relieved by recumbency. We treated an 80-year-old woman with an atrial septal defect (ASD) who demonstrated POS following thoracic and lumbar vertebral compression fractures. The surgical closure of the ASD relieved her symptoms. The etiology might have been multiple compression fractures causing kyphosis and aortic distortion producing right atrial compression and increased right-to-left flow through the ASD. POS should be considered in the differential diagnosis of patients who develop dyspnea after vertebral compression fractures. The careful assessment of the patient's history and clinical condition helps in the diagnosis of POS. PMID- 29269686 TI - Supramolecular Complex of Methyl-beta-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent. AB - Methyl-beta-cyclodextrin (M-beta-CyD) exhibits cytotoxic activity, and has the potentials as an antitumor agent. However, a tumor-selectivity of M-beta-CyD is low, leading to low antitumor activity and the adverse effects. Meanwhile, hyaluronic acid (HA) is known as a promising tumor targeting ligand, because various cancer cells overexpress CD44, a HA-binding glycoprotein. In the present study, to develop a tumor-selective delivery system for M-beta-CyD, we designed a supramolecular complex of M-beta-CyD with adamantane-grafted HA (Ad-HA/M-beta CyD) and evaluated it as a tumor-selective antitumor agent. M-beta-CyD formed a stable complex with Ad-HA (Kc>104 M-1). In addition, Ad-HA/M-beta-CyD formed slightly a negative-charged nanoparticle with ca. 140 nm of a particle size, indicating the favorable physicochemical properties for antitumor agents. Ad-HA/M beta-CyD showed the superior cytotoxic activity via CD44-mediated endosomal pathways in HCT116 cells (CD44(+)), a human colon cancer cell line. In addition, cytotoxic activity of Ad-HA/M-beta-CyD was induced by apoptosis. These results suggest that Ad-HA/M-beta-CyD has the potentials as a tumor-selective supramolecular antitumor agent. PMID- 29269687 TI - Angiotensin II, a unique vasoactive agent dissociates myosin light chain phosphorylation from contraction. AB - Angiotensin II (100 nM) induced bi-phasic increases in cytosolic Ca2+ level ([Ca2+]i) through the activation of angiotensin II type 1 receptor. Pharmacological examinations using 10 uM verapamil, 30 uM La3+, and 1 uM thapsigargin indicated that the first phase of the [Ca2+]i-increase was mediated by Ca2+ release from sarcoplasmic reticulum (SR) and Ca2+ influx independently of voltage dependent Ca2+ channel (VDC). In contrast, the second phase of [Ca2+]i increase was mediated by Ca2+ influx through VDC. Although both [Ca2+]i and myosin light chain (MLC)-phosphorylation at the first phase was apparently exceeded the threshold for contraction as estimated by high K+-induced responses, there was no appreciable contraction, indicating the dissociation between MLC phosphorylation and force during this phase. In contrast, the second phase of [Ca2+]i was associated with the increases in both MLC phosphorylation and force. These results suggest that angiotensin II is a unique agonist which dissociates MLC-phosphorylation from muscle force during the Ca2+ releases from SR. PMID- 29269688 TI - Anesthetic and cardiorespiratory effects of single-bolus intravenous alfaxalone with or without intramuscular xylazine-premedication in calves. AB - The anesthetic and cardiorespiratory effects of xylazine-alfaxalone combination were evaluated in calves. Six calves (age: 6-9 months old; weight: 114-310 kg) were anesthetized with intravenous alfaxalone 15 min after administration of intramuscular saline (0.5 ml/100 kg) or xylazine (0.1 mg/kg; 0.5 ml/100 kg of a 2% xylazine solution). Anesthesia induction was smooth and orotracheal intubation was achieved in all calves. The calves anesthetized with xylazine-alfaxalone required a smaller induction dose of alfaxalone (1.23 +/- 0.17 mg/kg, P=0.010) and accepted endotracheal intubation for a significantly longer period (16.8 +/- 7.2 min, P=0.022) than the calves anesthetized with alfaxalone alone (2.28 +/- 0.65 mg/kg 7.3 +/- 1.6 min). At 5 min after induction, tachycardia (heart rate: 166 +/- 47 beats/min of heart rate), hypertension (mean arterial blood pressure: 147 +/- 81 mmHg) and hypoxemia (partial pressure of arterial blood oxygen [PaO2]: 43 +/- 10 mmHg) were observed in the calves anesthetized with alfaxalone alone, whereas hypoxemia (PaO2: 47 +/- 7 mmHg) and mild hypercapnia (partial pressure of arterial blood carbon dioxide: 54 +/- 5 mmHg) were observed in the calves anesthetized with xylazine-alfaxalone. Premedication with xylazine provided a sparing effect on the induction dose of alfaxalone and a prolongation of anesthetic effect. Oxygen supplementation should be considered to prevent hypoxemia during anesthesia. PMID- 29269689 TI - Clinical factors related to the efficacy of tyrosine kinase inhibitor therapy in radioactive iodine refractory recurrent differentiated thyroid cancer patients. AB - New insights in thyroid cancer biology propelled the development of targeted therapies as salvage treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC), and the tyrosine kinase inhibitor (TKI) lenvatinib has recently become available as a new line of therapy for RR-DTC. The aim of this study is to investigate clinical factors related to the efficacy of TKI therapy in recurrent RR-DTC patients and identify the optimal timing for the start of TKI therapy. The subjects consisted of 29 patients with progressive RR-DTC, 9 males and 20 females, median age 66 years. A univariate analysis was conducted in relation to progression free survival (PFS) and overall survival (OS) by the Kaplan-Meier method for the following variables: age, sex, histology of the primary tumor, thyroglobulin doubling time before the start of lenvatinib therapy, site of the target lesions, presence of a tumor-mediated symptom at the start of lenvatinib therapy, and baseline tumor size of the target lesions. Median duration of lenvatinib therapy was 14.7 months and median drug intensity was 9.5 mg. At the time of the data cut-off for the analysis, 9 patients (31.0%) have died of their disease (DOD), and a PR (partial response), SD (stable disease), and PD (progressive disease) were observed in 20 patients (69%), 6 patients (20.7%), 3 patients (10.3%), respectively. Univariate analyses showed that the presence of a symptom was the only factor significantly related to poorer PFS and OS. Clinical benefit of TKI therapy will be possibly limited when the therapy starts after tumor-mediated symptoms appear. PMID- 29269690 TI - [A case of cardiogenic embolism, which occurred under appropriate warfarin use, treated with thoracoscopic left atrial appendectomy]. AB - A 74-year-old man with a past medical history of bradycardiac atrial fibrillation and an old cerebral infarction presented with dysarthria. He had been treated with warfarin and PT-INR on admission was 2.0. MRI of the head revealed an acute ischemic stroke involving the cerebellum and left occipital lobe. Because transesophageal cardiac echography showed a thrombus in the left atrial appendage, anticoagulant treatment with warfarin and heparin was initiated. The thrombus was enlarging; therefore, we changed the anticoagulant therapy to apixaban with heparin on day 11. On day 17, a hemorrhagic cerebral infarction occurred. After the hemorrhage diminished, we treated him with warfarin aiming for a PT-INR between 3 and 4. The thrombus gradually shrank and disappeared on day 110. Finally, a thoracoscopic left atrial appendectomy was performed as a secondary prevention, with no recurrence till date. PMID- 29269691 TI - [A case of myasthenia-like symptoms induced by cibenzoline overdosage]. AB - The present patient was an 87-year-old man who had been taking cibenzoline for tachyarrhythmia. Five years after initiation of administration, he was referred to our hospital for ptosis that worsened from midday, as well as weakness of the facial and limb muscles. He tested negative for anti-acetylcholine receptor antibody but positive in the edrophonium test, suggesting that he had myasthenia gravis. He was admitted to our hospital 3 years later due to worsening symptoms of ptosis and muscle weakness. He had hypoglycemia, cardiac conduction defect, and renal dysfunction. In addition, blood concentration of cibenzoline was markedly high (1,850 ng/ml). We terminated the administration of cibenzoline, after which the patient's neurologic symptoms improved. Our findings suggest that cibenzoline toxicity must be considered in differentiating myasthenia gravis when a patient also presents with renal dysfunction. PMID- 29269692 TI - [A case of mitochondrial disease with multiple mitochondrial DNA deletions suspected amyotrophic lateral sclerosis-frontotemporal dementia]. AB - A 76-year-old woman showed a dramatic lowering of her tone of voice in October 2014, followed by muscle weakness of the left arm. The previous attending physician noticed remarkable left dominant frontotemporal lobe atrophy on cranial MRI. Her dysarthria, dysphagia and the muscle weakness of her extremities worsened, and a muscle biopsy revealed mitochondrial abnormality. The mitochondrial DNA from her muscle showed multiple deletions; the previous physician therefore diagnosed the patient with mitochondrial disease. The patient resembled amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). No other cases of ALS-FTD with mitochondrial disease have been reported in Japan. We therefore consider the present case to be valuable. PMID- 29269693 TI - [A case of chronic inflammatory demyelinating polyradiculoneuropathy, showing radicular pain due to tuberous hypertrophy of the spinal roots and plexuses after 20 years interval without relapsing sensorimotor symptoms]. AB - A 40-year-old man visited our department because of chest and back pain. He had a history of diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) 20 years ago. He received immunosuppressive therapy and had no relapses after that. On Admission, MRI showed tuberous hypertrophy of the spinal roots, intercostal nerves, and brachial and lumbar plexuses. The genetic analysis showed no mutations in any of Charcot-Marie-Tooth related genes. He was finally diagnosed with CIDP and administration of high dose intravenous methylprednisolone relieved his chest and back pain within a few days. We present a rare case of CIDP in which showed marked enlarged spinal roots in long clinical course and have a relapse with radicular pain without sensorimotor symptoms. PMID- 29269694 TI - [An anti-RNP antibody-positive case of aseptic meningitis induced by non steroidal anti-inflammatory drugs in a young woman]. AB - A 19-year-old woman developed high fever, headache, and nausea after taking Loxoprofen for pharyngitis, followed by disturbed consciousness and nuchal stiffness. The patient and her mother had a history of Raynaud's phenomenon. Cerebrospinal fluid (CSF) examination indicated a diagnosis of aseptic meningitis and revealed high levels of Q albumin and IgG index. Anti-RNP antibodies were positive in serum and CSF. Her symptoms disappeared immediately after cessation of Loxoprofen and a drug lymphocyte stimulation test was negative, confirming a diagnosis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced aseptic meningitis. It should be kept in mind that an immune abnormality such as serum and CSF anti-RNP antibodies may play a role in development of NSAIDs-induced aseptic meningitis. A history of usage of NSAIDs and a thorough examination of collagen diseases are useful for identification of the origin of aseptic meningitis in a young woman. PMID- 29269695 TI - [A case of chronic progressive neuro-Behcet disease with extensive cerebral atrophy and elevated CSF IL-6 activity treated with infliximab]. AB - A 43-year-old man without a previous episode of uveitis presented with slowly progressive neurological symptoms that appeared within the past year such as dysarthria, ataxic gait, and behavioral changes. Brain MRI findings showed atrophic lesions in the brainstem and cerebellum. Because these clinical symptoms and abnormal MRI findings indicated spinocerebellar degeneration as the initial diagnosis, he was admitted to our hospital. On admission, we noticed that he had non-neurological manifestations of Behcet disease, such as stomatitis, genital ulcers, and folliculitis. HLA-B51 was positive. He also showed pleocytosis (29 cells/mm3, predominantly mononuclear cells) and elevated cerebrospinal fluid (CSF) IL-6 levels (213 pg/ml), hence he was diagnosed with chronic progressive neuro-Behcet disease (CPNBD). The therapeutic effect of a high-dose intravenous methylprednisolone pulse (1,000 mg/day for 3 days) and methotrexate (maximum dosage, 16 mg/week) was poor against both neurological symptoms and CSF findings. Intravenous infliximab therapy (5 mg/kg, 2 weeks) dramatically decreased CSF IL-6 levels (13 pg/ml) but clinical symptoms remained unchanged. MRI findings of extensive cerebral atrophy and increased CSF IL-6 levels at the pretreatment time point reflected irreversible neurological involvement in CPNBD. For cases with progressive psychiatric symptoms and cerebellar ataxia in the early stage of the disease, skin manifestations should be examined immediately, CSF IL-6 levels measured, and immunosuppressive therapy initiated before CPNBD progresses to brainstem atrophy. PMID- 29269696 TI - [Case of posterior reversible encephalopathy syndrome caused by Fisher syndrome]. AB - This report presents a case of a 71-year-old woman with Fisher syndrome who had posterior reversible encephalopathy syndrome (PRES) before the initiation of intravenous immunoglobulin (IVIg) treatment. She had symptoms of common cold 2 weeks before the onset of PRES. On the day of the onset, she began to stagger while walking. On day 2, she developed hypertension, vision impairment, and limb weakness and was admitted to the hospital. On day 3, she was provided steroid pulse therapy. On day 4, she developed convulsions and right imperfection single paralysis and was transferred to the our hospital. During the transfer, the patient was conscious. Her blood pressure was high at 198/107 mmHg. She had mild weakness in her limbs and face, light perception in both eyes, dilation of both pupils, total external ophthalmoplegia, no tendon reflexes, and limb and trunk ataxia. We diagnosed PRES because of the high signal intensities observed on T2 weighted MRI on both sides of the parietal and occipital lobes. We also diagnosed Fisher syndrome because of a positive anti-GQ1b immunoglobulin G antibody test and albuminocytologic dissociation in the cerebrospinal fluid. PRES showed prompt improvement with antihypertensive therapy, whereas Fisher syndrome slowly improved over a course of 2 months. This case is the first report of PRES without IVIg suggesting that Fisher syndrome induces hypertension and causes PRES. PMID- 29269697 TI - [Clinical, epidemiological, and etiological studies of adult aseptic meningitis: a report of 12 cases of herpes simplex meningitis, and a comparison with cases of herpes simplex encephalitis]. AB - We treated 437 cases of adult aseptic meningitis and 12 cases (including 2 recurrent patients; age, 31.8 +/- 8.9 years; 7 females) of herpes simplex meningitis from 2004 to 2016. The incidence rate of adult herpes simplex meningitis in the cases with aseptic meningitis was 2.7%. One patient was admitted during treatment of genital herpes, but no association was observed between genital herpes and herpes simplex meningitis in the other cases. The diagnoses were confirmed in all cases as the cerebrospinal fluid (CSF) was positive for herpes simplex virus (HSV)-DNA. For diagnosis confirmation, the DNA test was useful after 2-7 days following initial disease onset. Among other types of aseptic meningitis, the patients with herpes simplex meningitis showed relatively high white blood cell counts and relatively high CSF protein and high CSF cell counts. CSF cells showed mononuclear cell dominance from the initial stage of the disease. During same period, we also experienced 12 cases of herpes simplex encephalitis and 21 cases of non-hepatic acute limbic encephalitis. Notably, the patients with herpes simplex meningitis were younger and their CSF protein and cells counts were higher than those of the patients with herpes simplex encephalitis. PMID- 29269698 TI - [Stroke due to infective endocarditis diagnosed by the retrieved thrombus: a case report]. AB - A 80-years-old woman suddenly presented with aphasia, right hemiparesis, and dysesthesia. MRA showed the left middle cerebral artery occlusion. She was diagnosed as hyperacute ischemic stroke. She was treated with intravenous recombinant tissue plasminogen activator and underwent endovascular thrombectomy. On admission, she had a fever and high C reactive protein, and was treated with antibiotic therapy. The pathological diagnosis of the retrieved thrombus revealed the cluster of the gram positive cocci. The blood culture was negative and thransthoracic echocardiogram did not detect the vegetation. She was finally diagnosed as cardioembolic stroke due to infective endocarditis based on the pathological diagnosis of the retrieved thrombus. The pathological diagnosis of the retrieved thrombus was quite important to clarify the cause of ischemic stroke. PMID- 29269699 TI - Next Generation Sequencing and Genome-Wide Genotyping Identify the Genetic Causes of Intellectual Disability in Ten Consanguineous Families from Jordan. AB - Intellectual disability (ID), occurs in approximately 1 to 3% of the population and tends to be higher in low-income countries and in inbred communities. Despite the high rates of consanguineous marriages and the likely enrichment for recessive forms of ID, the genetic bases of ID in Jordan are largely unstudied. In this study, whole exome sequencing (WES) and homozygosity mapping were used to identify the genetic causes of ID in ten families from Jordan. The studied families are characterized by consanguineous marriage and having one or more progeny with ID. Likely disease-causing missense mutations were identified in eight families; four families are due to mutations in genes previously implicated with ID and the other four families are due to mutations in genes that are not previously implicated with ID. The novel genes include: BSN (Protein Basson), PTCHD2 (Protein dispatched homolog 3), DHRS3 (Short-chain dehydrogenase/reductase 3), and LGI3 (Leucine-rich repeat LGI family member 3). In addition, copy number variant (CNV) deletion and/or duplication were identified in 2 families; one family with 3.5 mega base (Mb) deletion on chromosome17 previously implicated with Smith Magenis Syndrome, and the other family with a novel combination of deletion and duplication in chromosomes 5 and 11. In this pilot study, four genes and one CNV deletion/duplication are identified for the first time in association with ID. The finding of this study further demonstrates the power of WES and homozygosity mapping for clinical diagnostics of ID in consanguineous families in small populations. PMID- 29269700 TI - Polymorphisms in ACE and ACTN3 Genes and Blood Pressure Response to Acute Exercise in Elite Male Athletes from Serbia. AB - Physiological adaptations to various types of prolonged and intensive physical activity, as seen in elite athletes from different sports, include changes in blood pressure (BP) response to acute exercise. Also, functional polymorphisms of the angiotensin I converting enzyme (ACE) and alfa-actinin-3 (ACTN3) genes are shown to be associated with BP parameters changes, both in athletes and sedentary population. In this study, an Alu insertion (I)/deletion (D) polymorphism in ACE gene, as well as nonsense mutation in the gene encoding ACTN3 have been scored in 107 elite Serbian athletes classified according to their sporting discipline to power/sprint (short distance runners/swimmers), endurance (rowers, footballers, middle-distance swimmers) or mixed sports (water polo, handball, volleyball players). Presence of nonfunctional allele in ACTN3 is associated with significantly increased maximal systolic BP (SBPmax, p = 0.04). Athletes with Alu insertion in ACE had significantly (p = 0.006) larger decline of systolic BP after 3 minutes of recovery (SBPR3), calculated as the percentage of maximal SBP response during exercise stress testing. Concomitant presence of non-functional variant in ACTN3 gene decreased this beneficiary effect of ACE mutation on SBPR3. Long term enrollment in power/sprint sports significantly increased resting diastolic BP (DBPrest: 74 mmHg) and SBPmax (197 mmHg) and improved SBPR3 (74.8%) compared to enrolment in endurance (72 mmHg; 178 mmHg; 81.1%) and mixed sports (69 mmHg; 185 mmHg; 80.0%). Lack of the effect of genotype by sport interaction on BP parameters suggests that the long-term effects of different disciplines on BP are not mediated by these two genes. PMID- 29269701 TI - Impact of Stent-to-Vessel Diameter Ratio on Restenosis in the Superficial Femoral Artery After Endovascular Therapy. AB - BACKGROUND: Although stent-to-vessel (S/V) diameter ratio has been described as a restenotic factor after superficial femoral artery (SFA) stenting, the reference vessel diameter is commonly measured distally at a healthy site. It remains unclear whether S/V ratio assessed at the lesion site would be more predictive than that assessed distally at a healthy site.Methods and Results:A total of 117 patients (mean age, 73+/-7 years; 74% male) who underwent successful nitinol stent implantation in SFA lesions (mean lesion length, 172+/-104 mm) on intravascular ultrasound (IVUS) were retrospectively analyzed. S/V ratio at the proximal and distal healthy site, and at the smallest lesion site, was evaluated on IVUS. One-year restenosis predictors were evaluated on multivariate analysis. Mean S/V diameter ratio on IVUS at proximal and distal healthy sites, and at the lesion site, was 0.98+/-0.11, 1.02+/-0.11 and 1.15+/-0.16, respectively. One-year primary patency was 77%. On multivariate analysis, lesion length (OR, 1.06 per 10 mm increment; P=0.046) and S/V ratio measured at the lesion site (OR, 1.34 per 0.1 increment; P=0.032), but not that at the distal healthy site (OR, 1.05 per 0.1 increment; P=0.705), were significantly associated with 1-year restenosis. CONCLUSIONS: S/V ratio assessed on IVUS at the lesion site, but not at the distal healthy site, was independently associated with 1-year restenosis after SFA stenting. PMID- 29269702 TI - Insufficient Warfarin Therapy Is Associated With Higher Severity of Stroke Than No Anticoagulation in Patients With Atrial Fibrillation and Acute Anterior Circulation Stroke. AB - BACKGROUND: Insufficient anticoagulant intensity on admission is common in stroke patients with atrial fibrillation (AF) on vitamin K antagonist (VKA) therapy. Nevertheless, the effects of VKA under-treatment on stroke severity or arterial occlusion are not well known. The aim of the present study was to investigate the relationship between insufficient VKA therapy and stroke severity, or the site of arterial occlusion in patients with acute ischemic stroke (AIS) and AF.Methods and Results:From March 2011 through July 2016, 446 consecutive patients with AF and AIS were recruited. Of the 446 patients, 364 (167 women; median age, 79 years; IQR, 71-86 years) with anterior-circulation stroke were assessed to investigate the effects of insufficient VKA. Of these, 281 were on no anticoagulant, 53 were undertreated with a VKA, and 30 were sufficiently treated with VKA on admission (PT-INR >=2.0 for patients <70 years and PT-INR >=1.6 for >=70 years old). On multivariate analysis, insufficient VKA was independently associated with severe stroke (i.e., initial NIHSS score >=10; OR, 2.70, P=0.022) and higher prevalence of proximal artery occlusion (OR, 1.91; P=0.039) compared with no anticoagulant therapy. CONCLUSIONS: Insufficient VKA therapy on admission was associated with higher severity of stroke and higher prevalence of proximal artery occlusion in patients with AF and acute anterior-circulation stroke compared with no anticoagulant medication. PMID- 29269703 TI - BNIP3 expression in bovine follicle and corpus luteum. AB - BNIP3 (BCL2/adenovirus E1B nineteen kilodalton interacting protein-3), a member of the BCL2 family, is activated under hypoxic conditions and induces apoptosis or mitochondrial autophagy for adapting cells to hypoxia. The physiological roles of BNIP3 in the mammalian ovary are still unclear. In order to understand the role of BNIP3 in the bovine ovary, we examined its mRNA and protein expressions of BNIP3 in follicular granulosa cells and corpus luteum (CL). BNIP3 mRNA and protein expressions in granulosa cells from large follicles (>10 mm) at the follicular stage were much higher than those in small follicles (2-8 mm). BNIP3 mRNA and protein expressions in the CL peaked at the early luteal stage. In bovine granulosa cells cultured for 6 hr under hypoxia (3% O2) and normoxia (20% O2), BNIP3 mRNA expression was higher under hypoxia. These results of the present study suggest that BNIP3 has some roles in luteal formation in the bovine ovary, and that the highly expressed BNIP3 in the granulosa cells from large follicles at the follicular stage is related to the roles of BNIP3 in the luteal formation. PMID- 29269704 TI - Intermediate-grade mammary gland adenocarcinoma in an 18-year-old female black leopard (Panthera pardus) with acute pancreatic necrosis and chronic interstitial nephropathy. AB - An 18-year-old female black leopard (Panthera pardus) showed renal failure, leukocytosis and presence of subcutaneous masses in the lower abdominal region and right shoulder; she eventually died. Histopathological observations included a mammary gland carcinoma with comedo, solid and tubulopapillary patterns in subcutaneous tissue, and highly proliferated tumor cells in systemic organs. The tumor cells were positive for cytokeratin AE1/AE3. The mammary gland tumor was diagnosed as intermediate-grade adenocarcinoma, based on a previously reported histological grading system of feline mammary carcinomas. Chronic interstitial nephritis was estimated to have been ongoing for 5 years, whilst acute necrotic pancreatitis in relation to tumor metastasis could have been the cause of death. PMID- 29269705 TI - Dietary L-serine modifies free amino acid composition of maternal milk and lowers the body weight of the offspring in mice. AB - The growth of offspring is affected not only by the protein in maternal milk but also by the free amino acids (FAAs) contained in it. L-Serine (L-Ser) is known as an important FAA for the development of the central nervous system and behavioral activity. However, it is not clear whether L-Ser is transported into the pool of FAAs contained in milk and thereby affects the growth of offspring. Using mice, the current study investigated the effects of dietary L-Ser during pregnancy and lactation on milk and plasma FAA composition, as well as on growth, behavior, and plasma FAAs of offspring. Dietary L-Ser did not significantly affect the maternal, anxiety-like, or cognitive behaviors of either the dam or the offspring. The FAA composition notably differed between plasma and milk in dams. In milk, dietary L-Ser increased free L-Ser levels, while glutamic acid, L alanine, D-alanine and taurine levels were decreased. The body weight of the offspring was lowered by dietary L-Ser. The concentrations of plasma FAAs in 13 day-old offspring (fed only milk) were not altered, but 20-day-old offspring (fed both milk and parental diet) showed higher plasma L-Ser and D-Ser concentrations as a result of the dietary L-Ser treatment. In conclusion, the present study found that dietary L-Ser transported easily from maternal plasma to milk and that dietary L-Ser treatment could change the FAA composition of milk, but that an enhanced level of L-Ser in milk did not enhance the plasma L-Ser level in the offspring. PMID- 29269706 TI - High Dietary Saturated Fat is Associated with a Low Risk of Intracerebral Hemorrhage and Ischemic Stroke in Japanese but not in Non-Japanese: A Review and Meta-Analysis of Prospective Cohort Studies. AB - AIM: The associations between dietary saturated fatty acids and the risks of stroke subtypes in cohort studies were examined by a meta-analysis of separate ethnic Japanese and non-Japanese cohorts, and causes of their difference were elucidated. METHOD: Log hazard ratio (HR) with 95% confidence interval (CI) of the highest versus the lowest saturated fat intake from cohort studies were weighed by an inverse variance method to combine HRs. RESULTS: Five studies of intracerebral hemorrhage and 11 studies/comparisons of ischemic stroke were selected. A meta-analysis of intracerebral hemorrhage excluding subarachnoid hemorrhage showed a strong inverse association in Japanese (n=3, HR=0.55, 95% CI 0.32-0.94) but not in non-Japanese (n=2, HR=0.98, 95% CI 0.62-1.53). A meta analysis of ischemic stroke showed a mild inverse association in Japanese (n=4, HR=0.82, 95% CI 0.71-0.93) but not in non-Japanese (n=7, HR= 0.93, 95% CI 0.84 1.03). The effect size of saturated fat in reducing the risk of stroke in Japanese was stronger for intracerebral hemorrhage (45% reduction) than for ischemic stroke (18% reduction). CONCLUSIONS: In Japanese but not in non Japanese, a diet high in saturated fat is associated with a low risk of intracerebral hemorrhage and ischemic stroke. This may be due to differences in the range of intake of saturated fat, genetic susceptibility, incidence of lacunar infarction, and/or confounding factors such as dietary proteins. An intervention study targeting Japanese will be required to verify the causality. PMID- 29269707 TI - A Case of Paraneoplastic Limbic Encephalitis in a Patient with Invasive Thymoma with Anti-Glutamate Receptor Antibody-Positive Cerebrospinal Fluid: A Case Report. AB - BACKGROUND: Thymoma is known to cause autoimmune neuromuscular disease. However, anti-glutamate receptor antibody limbic encephalitis (LE) with thymoma is relatively rare. CASE PRESENTATION: A 68-year-old woman was admitted with progressive memory impairment and personality change. Brain magnetic resonance imaging (MRI) revealed high intensity in the bilateral limbic areas on T2 weighted fluid-attenuation inversion recovery (FLAIR) images. Chest computed tomography revealed a mass in the anterior mediastinum. Surgical resection of the tumor, which was consistent with a type B3 thymoma, resulted in clinical improvement. After surgery, the cerebrospinal fluid (CSF) was found to be positive for anti-N-methyl-D-aspartate (NMDA) type glutamate receptor antibodies. These findings led to the diagnosis of paraneoplastic LE (PLE) associated with thymoma. CONCLUSION: When a patient presents with neurologic symptoms of unknown origin, the possibility of LE accompanied by thymoma should be considered. Rapid treatment is desirable before the symptoms become irreversible. PMID- 29269708 TI - Comparison of methods for detection of chytrid fungus (Batrachochytrium dendrobatidis) in bullfrog tadpole mouthparts. AB - We previously reported that the tadpole of bullfrog (Lithobates catesbeiana) is a useful model for the field surveillance of the Batrachochytrium dendrobatidis (Bd) distribution. In the present study, we compared Bd detection rates in swab scraped and resected mouthpart samples, using nested polymerase chain reaction (PCR). The resulting detection rates for swab-scraped and resected specimens were 67 and 65%, respectively, with no significant difference. Furthermore, we performed a histopathological examination for Bd distribution in the mouthparts; we found that Bd infection occurred in the tip and basement of the jaw sheaths and tooth rows. We recommend using swab-scraped samples for Bd detection. Moreover, careful attention should be paid to scraping the tip and basement of the jaw sheaths and the entire oral cavity to reduce the rates of false-negative results on nested PCR of the mouthparts of bullfrog tadpoles. PMID- 29269709 TI - Remifentanil decreases oral tissue blood flow while maintaining internal carotid artery blood flow during sevoflurane anesthesia in rabbits. AB - The aim of this study was to investigate the effect of remifentanil infusion on oral tissue blood flow including submandibular gland tissue blood flow (SBF) and internal carotid artery blood flow (ICBF) in rabbits during sevoflurane anesthesia. Twelve male Japan White rabbits were anesthetized with sevoflurane and remifentanil. Remifentanil was infused at 0.2 and 0.4 ug/kg/min. Measurements included circulatory variables, common and external carotid artery blood flow (CCBF, ECBF), ICBF, tongue mucosal blood flow (TMBF), masseter muscle tissue blood flow (MBF), mandibular bone marrow tissue blood flow (BBF), tongue muscle tissue blood flow (TBF) and SBF. Vascular resistances for each tissue, including the tongue mucosa, masseter muscle, mandibular bone marrow, tongue muscle and submandibular gland, were calculated by dividing the mean arterial pressure by the respective tissue blood flow. Remifentanil infusion decreased oral tissue blood flow and circulatory variables. CCBF, ECBF and ICBF did not change. The calculated vascular resistance in each oral tissue, except for the tongue mucosa, increased in an infusion-rate-dependent manner. These results showed that remifentanil infusion reduced TMBF, MBF, BBF, TBF and SBF in an infusion-rate dependent manner without affecting ICBF under sevoflurane anesthesia. PMID- 29269710 TI - A Simple Method to Differentiate Atrioventricular Node Reentrant Tachycardia from Orthodromic Reciprocating Tachycardia. AB - Discrimination between atrioventricular node reentry tachycardia (AVNRT) and orthodromic reciprocating tachycardia (ORT) during an electrophysiological study is sometimes challenging. This study aimed to investigate if the difference in the local VA (ventricle-atrium) interval during ventricular entrainment pacing and during tachycardia (DVA, defined as the shortest local VA interval of coronary sinus [CS] during entrainment minus the shortest local VA interval of CS during tachycardia) was different in patients with AVNRT and patients with ORT.Diagnoses of AVNRT or ORT through a concealed accessory pathway (AP) were made according to conventional electrophysiological criteria and ablation results. Entrainment by right ventricular (RV) pacing was performed in each patient before ablation and patients with successful entrainment were included in the study. The DVA was compared between patients with AVNRT and patients with ORT. The DVA in patients with AVNRT was significantly longer than that in patients with ORT (120 +/- 20 versus 5.7 +/- 9; P < 0.001). In each patient with AVNRT of slow-fast type, fast-slow type, and slow-slow type, the DVA was more than 48 ms. In each patient with ORT using a left free wall accessory pathway (AP), right free wall AP, and septal AP, the DVA was less than 20 ms.DVA was found to be a rapid, useful test in distinguishing patients with AVNRT from those with ORT. PMID- 29269711 TI - Effect of Switching from Cilnidipine to Azelnidipine on Cardiac Sympathetic Nerve Function in Patients with Heart Failure Preserved Ejection Fraction. AB - Cardiac sympathetic nerve activity is known to play a key role in the development and progression of heart failure (HF). Azelnidipine, an L-type calcium channel blocker (CCB), inhibits the sympathetic nerve activity of the central system. In contrast, cilnidipine, an N-type CCB, inhibits the sympathetic nerve activity of the peripheral system. CCBs are recommended as class IIa in patients with HF preserved ejection fraction (HFpEF); however, there are no comparative data on the difference in effect of cilnidipine and azelnidipine in patients with HFpEF and hypertension. We investigated the difference in effect of azelnidipine compared with cilnidipine in patients with HFpEF. Twenty-four consecutive HF patients who received angiotensin II type1a receptor blocker and beta blocker from April 2013 to January 2015 were enrolled. Cilnidipine was switched to azelnidipine during the follow-up period. Blood pressures, heart rate, blood tests, echocardiography, and 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy were measured before and after 6 months from azelnidipine administration. B-type natriuretic peptide tended to decrease after switching to azelnidipine; however, there were no significant differences between the pre state and post-state (pre-state: 118.5 pg/mL and post-state: 78.4 pg/mL, P = 0.137). Other laboratory findings, including catecholamine, also did not change significantly. In echocardiography, there were no significant differences in systolic and diastolic functions at the pre-state and post-state. As for MIBG, there were no significant changes in heart/mediastinum ratio. However, washout rate was significantly reduced (pre-state: 42.9 and post-state: 39.6, P = 0.030). Azelnidipine improved the dysfunction of cardiac sympathetic nerve activity compared with cilnidipine in patients with HFpEF. PMID- 29269712 TI - Congenital Double-Orifice Mitral Valve in Asymptomatic Patients. AB - Congenital double-orifice mitral valve (DOMV) is a rare malformation that may affect both mitral valve and apparatus, and it is usually associated with other cardiac disorders. Asymptomatic DOMV is extremely rare. We present two similar cases of asymptomatic congenital double-orifice mitral valve. Both cases presented functionally normal mitral valve apparatus with two equally sized orifices, which were formed by a central fibrosis. In addition, final confirmatory diagnosis was made using three-dimensional (3D) echocardiography in both cases. PMID- 29269713 TI - The effects of health education and promotion with regard to severe fever with thrombocytopenia syndrome (SFTS) in rural residents: A pilot study in China. AB - Severe fever with thrombocytopenia syndrome (SFTS) has spread throughout Asia, including China, South Korea, and Japan. In China, the main victims of SFTS were farmers. Measures to protect farmers were urgently needed but limited, and health education and promotion was proposed as an option. A pilot community trial was conducted to provide health education about SFTS in 2013 in Daishan County, Zhejiang Province, China, and results indicated that health education had promise. An educational campaign was conducted for three years. The incidence of SFTS decreased 0.3 per 1,000 person-years, and rural residents' awareness of SFTS increased substantially. Numerous habits or work practices that increased the likelihood of tick bites have also been changed. In the future, education could emphasize adopting healthy habits or work practices to reduce tick bites and thus reduce the incidence of SFTS, like regularly weeding around a house surrounded by shrubs, not sitting or lying on the ground when resting, and protecting one's self when doing farm work. PMID- 29269715 TI - Evaluation of Chewing Movement in Skeletal Class III Patients with Orthognathic Treatment. AB - The objective of this study was to clarify the influence of improvement in morphology on chewing movement in patients with skeletal reversed occlusion following orthognathic treatment. A total of 10 patients with skeletal class III reversed occlusion undergoing orthognathic treatment were included in the study. A number of parameters, including chewing rhythm, maximum opening and closing velocities, and opening distance during chewing of gum, were measured in a pre- (Pre) and post-treatment (Post) group. The laterality and stability of the measured items were then compared between the two groups and with those in another group of subjects with normal occlusion (Control). Laterality of chewing movement was greater in the Pre group than in the Control group, and significant differences were noted in all parameters, apart from closing Vmax and opening distance. No significant difference was noted in any parameter between the Post and Control groups. The coefficient of variation was significantly higher in the Pre group than in the Control group, apart from for opening phase. All parameters showed a significant decrease in the Post group compared with in the Pre group, yielding a stable chewing movement. Comparison of the Post and Control groups revealed no significant difference in any of the parameters, apart from in the occluding phase. These findings suggest that orthognathic treatment of skeletal class III malocclusion improves chewing movement to levels close to those in subjects with normal occlusion. PMID- 29269714 TI - Low-density lipoprotein receptor deficiency impaired mice osteoblastogenesis in vitro. AB - Postmenopausal osteoporosis affected most elderly women with co-existence of lipid and bone metabolism disorders. However, the cellular and molecular mechanisms underlying the parallel progression and cross-talk of these systems remained unclear. In the present study, low-density lipoprotein receptor knockout (LDLR-/-) mice were chosen to elucidate the effect of LDLR in regulating the differentiation of osteoblasts, which were responsible for bone formation and modulation of osteoclastogenesis. Primary osteoblasts were isolated from the calvarium of newborn LDLR-/- or wild-type mice followed by osteoblastic differentiation culture in vitro. Alkaline phosphatase activity was significantly decreased in LDLR-/- osteoblasts compared to wild-type controls, combined with calcium deposit formation delay, implying impaired osteoblastogenesis in vitro. Consistent with these findings, the expression of runt-related transcription factor 2 (Runx2) was decreased 3 days after differentiation in LDLR-/- osteoblasts compared to wild-type controls. Moreover, the expression of Osterix was decreased 7 days after differentiation in LDLR-/- osteoblasts compared to wild-type controls, later than Runx2.However, the osteoclastogenesis modulation role of osteoblasts was unaffected by the LDLR deficiency, evidenced by the same level of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) axis between LDLR-/- and wild-type control osteoblasts. Our results provide a novel insight into the role of LDLR during osteoblastic differentiation and improve understanding of cross-talk between bone and lipid metabolisms. PMID- 29269716 TI - Number of Non-vital Teeth as Indicator of Tooth Loss during 10-year Maintenance: A Retrospective Study. AB - The purpose of this study was to investigate whether number of non-vital teeth was an indicator of tooth loss during maintenance. Thirty-three general practitioners provided data on 321 patients undergoing maintenance over 10 years. The number of present teeth (PT), smoking status, level of bone loss, number of non-vital teeth, and reason for tooth loss during that period were investigated. Multiple logistic regression was performed to identify whether the number of non vital teeth was associated with tooth loss. The average number of lost teeth was 1.07+/-1.82; that of PT at baseline was 24.4+/-3.9; and that of non-vital teeth at baseline was 5.4+/-4.5. Multiple logistic regression revealed a significant association between >8 non-vital teeth and tooth loss during maintenance (odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.18-4.87). It also demonstrated relationships between >8 non-vital teeth and root fracture or caries (OR: 3.90; 95%CI: 1.68-9.03 or OR: 2.85, 95%CI: 1.14-7.10, respectively). The number of non vital teeth was associated with tooth loss during maintenance. The results suggest that patients with many non-vital teeth before commencement of maintenance are particularly at risk of tooth loss due to root fracture or caries. Therefore, the number of non-vital teeth offers a useful indicator of potential tooth loss. PMID- 29269717 TI - Comparison of Effect of Oral Premedication with Ibuprofen or Dexamethasone on Anesthetic Efficacy of Inferior Alveolar Nerve Block in Patients with Irreversible Pulpitis: A Prospective, Randomized, Controlled, Double-blind Study. AB - The purpose of this prospective, randomized, double-blind, placebo-controlled study was to determine the effect of preoperative oral administration of ibuprofen or dexamethasone on the success rate of inferior alveolar nerve block (IANB) in patients with symptomatic irreversible pulpitis. Seventy-eight patients with irreversible pulpitis were randomly divided into 3 groups (26 per group) and given one of the following at 1 hr prior to performing local anesthesia: a placebo; 400 mg ibuprofen; or 4 mg dexamethasone. Each patient recorded their pain level on a visual analog scale before taking the medication or placebo, at 15 min after completion of IANB, and during treatment if pain occurred. The success of the anesthesia was defined as no or mild pain at any stage during the endodontic procedure. The success rate of the IANB was 38.5, 73.1, and 80.8% with the placebo, ibuprofen, and dexamethasone, respectively. Both ibuprofen and dexamethasone were significantly more effective than the placebo. No significant difference was observed, however, between the two experimental medications in terms of effectiveness. The results of the present study suggest that premedication with ibuprofen or dexamethasone increases the success rate of an IANB in patients with symptomatic irreversible pulpitis in the mandibular molars. PMID- 29269718 TI - Treatment of Severe Chronic Periodontitis with Surgical and Prosthetic Intervention: A 9-year Follow-up Case Report. AB - A 60-year-old woman presented with the chief complaint of mobility of tooth #16. Gingival swelling and calculus were observed. Clinical examination revealed that 49.4% of sites had a probing depth (PD) of >=4 mm and 72% of sites bleeding on probing. Radiographic examination revealed vertical bone resorption in #35 and horizontal resorption in other regions. Periapical region radiolucency on #16 and 27 suggested a perio-endo lesion. The clinical diagnosis was severe chronic periodontitis. Initial periodontal therapy mainly comprised the following: oral hygiene instruction; quadrant scaling and root planing (SRP); extraction of #16, 27, and 31; and placement of provisional restorations. Open flap debridement was performed for teeth with a PD >=4 mm. Bone defects exceeding the root apex were found in #17, 41, 42, and 45 intraoperatively. Teeth #41, 42, and 45 were extracted. After confirming the stability of the periodontal tissue, final prostheses were placed on #14-17, 13-22, 35-37, 33-43, 44-46, and 47. Following reevaluation, the patient was placed on supportive periodontal therapy (SPT). After 6 years, the patient experienced dull pain in and pus discharge from #17. Repeated SRP yielded no improvement, so the tooth was extracted and a removable partial denture placed on #16 and 17. Nine years have passed since the start of SPT and the level of plaque control has remained adequate and periodontal condition stable. PMID- 29269719 TI - Intentional Partial Pulpotomy for Treatment of Immature Permanent Maxillary Incisor with Talon Cusp. AB - We report the successful morphological correction of a maxillary lateral incisor with a talon cusp and the preservation of vital pulp by employing an intentional partial pulpotomy. A talon cusp is a comparatively rare morphological tooth anomaly that may cause multiple clinical problems. An 11-year-old girl was referred to our department for morphological correction of a maxillary lateral incisor with a talon cusp prior to orthodontic treatment. Following a detailed CT examination of the interior morphology, the abnormal cusp was resected and an intentional partial pulpotomy performed. Five years postoperatively, the tooth showed no abnormalities. These results indicate that an intentional partial pulpotomy following a detailed CT examination is effective in correcting complicated morphological anomalies such as a talon cusp containing extended dental pulp. PMID- 29269720 TI - Case of Inverted Supernumerary Tooth in Nasal Cavity. AB - The eruption of a tooth into the nasal cavity is a rare clinical entity. We report a case of an inverted supernumerary tooth in the nasal cavity. A 2-year old boy was referred to our institution after examination at a local otorhinolaryngology department for otitis media. Radiological examination revealed a tooth-like structure in the right nasal cavity. The tooth was protruding from the floor of the nasal cavity along with granulation tissue. The diagnosis was an inverted tooth in the right nasal cavity. Forceps extraction was performed under general anesthesia. PMID- 29269721 TI - Orthodontic Treatment for Bloch-Sulzberger Syndrome in Patient with Cleft Lip and Palate. AB - We performed orthodontic treatment, fitted prostheses, and provided restorative treatment in a patient with Bloch-Sulzberger syndrome and cleft lip and palate during the early mixed dentition period. We report the case after a subsequent 6 year retention phase including the period of pubertal growth. A girl aged 8 years 4 months visited our hospital with the chief complaint of crowding of the anterior teeth and anterior crossbite. She had bilateral cleft lip, alveolus, and palate; a Class II molar relationship; winging of both the maxillary bilateral central incisors; and spacing in the mandibular anterior teeth arches. Anterior crossbite comprised 0 mm overbite and -1 mm overjet. The crown diameter was at least one standard deviation smaller than normal in both the deciduous and permanent teeth, and the crowns were slightly peg-shaped. Panoramic radiograph confirmed congenital absence of 21 permanent teeth. Cephalometric analysis revealed poor growth of the maxilla, downward growth of the mandible, and lingual inclination of the maxillary central incisors. The diagnosis was skeletal anterior crossbite with cleft lip, alveolus, and palate, accompanied by hypodontia. Orthodontic treatment comprised an edgewise appliance and an expansion arch to improve crowding and anterior crossbite. The appliance was removed 2 years after treatment initiation, followed by crown restorations of the maxillary central incisors and mandibular deciduous anterior teeth. A metal retainer was then fitted to the maxillary dentition. She was subsequently placed in a 6-year retention phase including pubertal growth, during which occlusal stability and esthetics were maintained. PMID- 29269722 TI - Preliminary Study of Temporal Change in Free Flap Volume after Tongue Reconstruction. AB - The purpose of this study was to investigate three-dimensionally temporal change in flap volume after free flap reconstructive surgery in tongue cancer patients. The results revealed an average change in flap volume of 82.3% at 1 year postoperatively. Change in tongue volume at approximately 6 months postoperatively showed a correlation with triglyceride levels. A correlation was also found between albumin levels and tongue volume at 1 year onwards postoperatively. The goal of such surgery in patients with tongue cancer is to reconstruct a functional tongue. Taking postoperative change in tongue volume into consideration is therefore of importance in minimizing postoperative dysphagia. PMID- 29269723 TI - Pre-Liver Transplant Muscle Loss Is a Risk Factor for Post-Liver Transplantation Left Ventricular Systolic Dysfunction. AB - BACKGROUND The development of left ventricular systolic dysfunction (LVSD) after liver transplant (LT) can result in increased morbidity and mortality in the immediate period following liver transplant. The aim of this study was to evaluate low muscle mass due to chronic liver disease, as a potential risk factor for LVSD after LT. MATERIAL AND METHODS A retrospective chart review was completed for all adult patients who received a liver transplant between January 2002 and January 2015 at a single academic LT center. Collected data included patient demographics, medical history, laboratory data, radiology results, and pathology. Echocardiograms were reviewed for patients identified as having LVSD diagnosed within 1 year after LT (left ventricular ejection fraction <55%). The total psoas area (TPA), a marker of low muscle mass, was determined by measuring the average cross-sectional area of the psoas muscle on MRI or CT scans before transplant at the level of L4 vertebra. RESULTS Of the 503 post-LT patients reviewed, 144 (28.6%) had pre-and post-LT echocardiograms. Of these 144 patients, 17 developed LVSD, of which 15 (88.2%) occurred within 1 year after LT. The average age at transplant of those with LVSD was 58.9+/-6 years, with a mean MELD score of 30.7+/-6. The mean TPA normalized for height for patients with LVSD was 297.68+/-86.99 mm2/m2 compared to 382.1+/-104.2 mm2/m2 for those with normal EF (p= 0.002). BMI, MELD score, and etiology of cirrhosis were not significant risk factors for post-LT LVSD in our study population. During the study period, 35.2% (n=6) of LVSD patients died within 1 year after LT. CONCLUSIONS Although LVSD is thought to be a rare complication after LT, those with muscle loss as predicted by mean TPA measurements normalized for height may be at highest risk. PMID- 29269724 TI - Lymphedema of the Transplanted Kidney and Abdominal Wall with Ipsilateral Pleural Effusion Following Kidney Biopsy in a Patient Treated with Sirolimus: A Case Report and Review of the Literature. AB - BACKGROUND Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor, which is used in immunosuppressive treatment regimens in organ transplant recipients. Although mTOR inhibitors are well tolerated, their adverse effects have been reported. Sirolimus treatment in transplant recipients has been reported to be associated with lymphedema of the skin and subcutaneous tissues, and with pleural effusion, but edema of internal organs and organomegaly have not been previously reported. A case is presented lymphedema of the transplanted kidney and abdominal wall with ipsilateral pleural effusion following kidney biopsy in a patient treated with sirolimus. CASE REPORT A 32-year-old woman with a history of end stage renal disease of unknown etiology had undergone right renal transplantation from an unrelated living donor, eight years previously. She was referred to our hospital with dyspnea, localized abdominal pain, and swelling of the transplanted kidney. The symptoms appeared following a kidney biopsy and the replacement of cyclosporin with sirolimus four months previously. On examination, she had localized swelling of the abdominal wall overlying the transplanted kidney, and a right pleural effusion. Hydronephrosis and nephrotic syndrome were excluded as causes of kidney enlargement. Following the withdrawal of sirolimus therapy her symptoms resolved within three months. CONCLUSIONS A case is described of lymphedema of the transplanted kidney and abdominal wall with ipsilateral pleural effusion following kidney biopsy attributed to her change in anti-rejection therapy to sirolimus. This case report should raise awareness of this unusual complication of sirolimus anti-rejection therapy and its possible effects on the lymphatic system. PMID- 29269725 TI - Effect of Calcipotriol on IFN-gamma-Induced Keratin 17 Expression in Immortalized Human Epidermal Keratinocyte Cells. AB - BACKGROUND Calcipotriol ointment has been demonstrated to be a very safe and effective topical drug for psoriasis. This study aims to investigate the effect of calcipotriol on IFN-gamma-induced keratin 17 (K17) expression in a human keratinocyte cell line (HaCaT), which is a widely accepted as a mimic in vitro model for psoriasis. MATERIAL AND METHODS We used Western blot, immunofluorescence staining, and luciferase reporter system assays to evaluate the expression of K17 and the possible underlying mechanisms. RESULTS Administration of IFN-gamma (125-1000 U) increased K17 expression in a dose dependent manner, and 250 U/ml IFN-gamma significantly elevated K17 expression. The experimental results showed that calcipotriol at concentrations of 10^-7 M and 10^-5 M suppressed the IFN-gamma-induced K17 expression by 58.10% and 70.68%, respectively. Through immunofluorescence staining and luciferase reporter assay, we found that Vitamin D Response Element (VDRE) affected IFN-activated site (Gamma-activated sequence, GAS) function at the transcriptional level and was involved in the inhibition of K17 expression. CONCLUSIONS Our data suggest that calcipotriol downregulates IFN-gamma-mediated K17 expression in keratinocytes in a dose-dependent manner via VDRE effect GAS function. The inhibitory effect of calcipotriol on K17 expression may be a potential mechanism and function in the treatment psoriasis. PMID- 29269726 TI - [A study of incidence and clinical characteristics of adverse drug reactions in hospitalized patients.] AB - OBJECTIVE: Adverse drug reactions (ADR) are one of the ten main causes of mortality in the world, as a cause of hospital admissions or prolongation hospitalizations days created an important health and economic impact. This study aimed to detect incidence and characterize ADRs that occurred during hospitalization and associated with admission in Internal Medicine service. METHODS: Observational and prospective study of intensive RAM monitoring patients admitted in Internal Medicine services in a third level hospital over a twelve months period in 2014. The assessment consisted of a complete and protocol collecting information about the patients and related to suspected ADRs during hospitalization. Statistical analysis was performed using SPSS v.20.0. RESULTS: The study included 253 patients and in 54 (21,34%) ADR were detected, the risk of experiencing an ADR was associated with the age (p=0.012). ADR-related hospitalizations incidence were 7,11%, and fatal ADR incidence were 1,97%. With regard to severity 81,2% were severe. Gastrointestinal disorders represented the most common ADRs followed by metabolism and nutrition disorders and vascular disorders. The drugs most frequently associated with ADRs were cardiovascular agents, antiinfective drugs and central nervous system agents. 72.2% of the patients who suffered ADR had polypharmacy. CONCLUSIONS: In our study incidence of adverse drug reactions in hospitalized patients was 21,34%, this data and ADR's related to admission to hospital or fatal ADR's are mainly suffered by pluripathology and polymedicated elderly patients with worst renal function values. In these patients a more careful prescription should be made. PMID- 29269728 TI - Solving for ambiguities in radar geophysical exploration of planetary bodies by mimicking bats echolocation. AB - Sounders are spaceborne radars which are widely employed for geophysical exploration of celestial bodies around the solar system. They provide unique information regarding the subsurface structure and composition of planets and their moons. The acquired data are often affected by unwanted artifacts, which hinder the data interpretation conducted by geophysicists. Bats possess a remarkable ability in discriminating between a prey, such as a quick-moving insect, and unwanted clutter (e.g., foliage) by effectively employing their bio sonar perfected in million years of evolution. Striking analogies occur between the characteristics of bats sonar and the one of a radar sounder. Here we propose an adaptation of the unique bat clutter discrimination capability to radar sounding by devising a novel clutter detection model. The proposed bio-inspired strategy proves its effectiveness on Mars experimental data and paves the way for a new generation of sounders which eases the data interpretation by planetary scientists. PMID- 29269727 TI - Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. AB - Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor 4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b+F4/80low hepatic infiltrating macrophages, but not CD11b+F4/80high Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4-MD2 complex, palmitate binds a monomeric TLR4-MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1beta expression in macrophages. Palmitate-induced ROS generation in human CD68lowCD14high macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease. PMID- 29269729 TI - A conserved ankyrin repeat-containing protein regulates conoid stability, motility and cell invasion in Toxoplasma gondii. AB - Apicomplexan parasites are typified by an apical complex that contains a unique microtubule-organizing center (MTOC) that organizes the cytoskeleton. In apicomplexan parasites such as Toxoplasma gondii, the apical complex includes a spiral cap of tubulin-rich fibers called the conoid. Although described ultrastructurally, the composition and functions of the conoid are largely unknown. Here, we localize 11 previously undescribed apical proteins in T. gondii and identify an essential component named conoid protein hub 1 (CPH1), which is conserved in apicomplexan parasites. CPH1 contains ankyrin repeats that are required for structural integrity of the conoid, parasite motility, and host cell invasion. Proximity labeling and protein interaction network analysis reveal that CPH1 functions as a hub linking key motor and structural proteins that contain intrinsically disordered regions and coiled coil domains. Our findings highlight the importance of essential protein hubs in controlling biological networks of MTOCs in early-branching protozoan parasites. PMID- 29269730 TI - Promoter-enhancer interactions identified from Hi-C data using probabilistic models and hierarchical topological domains. AB - Proximity-ligation methods such as Hi-C allow us to map physical DNA-DNA interactions along the genome, and reveal its organization into topologically associating domains (TADs). As the Hi-C data accumulate, computational methods were developed for identifying domain borders in multiple cell types and organisms. Here, we present PSYCHIC, a computational approach for analyzing Hi-C data and identifying promoter-enhancer interactions. We use a unified probabilistic model to segment the genome into domains, which we then merge hierarchically and fit using a local background model, allowing us to identify over-represented DNA-DNA interactions across the genome. By analyzing the published Hi-C data sets in human and mouse, we identify hundreds of thousands of putative enhancers and their target genes, and compile an extensive genome-wide catalog of gene regulation in human and mouse. As we show, our predictions are highly enriched for ChIP-seq and DNA accessibility data, evolutionary conservation, eQTLs and other DNA-DNA interaction data. PMID- 29269731 TI - Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mellitus or prediabetes. AB - Dietary treatment is important in management of type 2 diabetes or prediabetes, but uncertainty exists about the optimal diet. We randomized adults (n = 34) with glycated hemoglobin (HbA1c) > 6.0% and elevated body weight (BMI > 25) to a very low-carbohydrate ketogenic (LCK) diet (n = 16) or a moderate-carbohydrate, calorie-restricted, low-fat (MCCR) diet (n = 18). All participants were encouraged to be physically active, get sufficient sleep, and practice behavioral adherence strategies based on positive affect and mindful eating. At 12 months, participants in the LCK group had greater reductions in HbA1c levels (estimated marginal mean (EMM) at baseline = 6.6%, at 12 mos = 6.1%) than participants in MCCR group (EMM at baseline = 6.9%, at 12 mos = 6.7%), p = .007. Participants in the LCK group lost more weight (EMM at baseline = 99.9 kg, at 12 mos = 92.0 kg) than participants in the MCCR group (EMM at baseline = 97.5 kg, at 12 mos = 95.8 kg), p < .001. The LCK participants experienced larger reductions in diabetes related medication use; of participants who took sulfonylureas or dipeptidyl peptidase-4 inhibitors at baseline, 6/10 in the LCK group discontinued these medications compared with 0/6 in the MCCR group (p = .005). In a 12-month trial, adults with elevated HbA1c and body weight assigned to an LCK diet had greater reductions in HbA1c, lost more weight, and reduced more medications than those instructed to follow an MCCR diet. PMID- 29269733 TI - The physiological and neuroendocrine correlates of hunger in the Red Junglefowl (Gallus gallus). AB - The ability to regulate food intake is critical to survival. The hypothalamus is central to this regulation, integrating peripheral signals of energy availability. Although our understanding of hunger in rodents is advanced, an equivalent understanding in birds is lacking. In particular, the relationship between peripheral energy indices and hypothalamic 'hunger' peptides, agouti related protein (AgRP), pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) is poorly understood. Here, we compare AgRP, POMC and NPY RNA levels in the hypothalamus of Red Junglefowl chicks raised under ad libitum, chronic restriction and intermittent feeding regimens. Hypothalamic gene expression differed between chronically and intermittently restricted birds, confirming that different restriction regimens elicit different patterns of hunger. By assessing the relationship between hypothalamic gene expression and carcass traits, we show for the first time in birds that AgRP and POMC are responsive to fat-related measures and therefore represent long-term energy status. Chronically restricted birds, having lower indices of fat, show elevated hunger according to AgRP and POMC. NPY was elevated in intermittently fasted birds during fasting, suggesting a role as a short-term index of hunger. The different physiological and neuroendocrine responses to quantitative versus temporal feed restriction provide novel insights into the divergent roles of avian hunger neuropeptides. PMID- 29269734 TI - Inferring evolutionary responses of Anolis carolinensis introduced into the Ogasawara archipelago using whole genome sequence data. AB - Invaded species often can rapidly expand and establish in novel environments through adaptive evolution, resulting in devastating effects on native communities. However, it is unclear if genetic variation at whole-genomic levels is actually reduced in the introduced populations and which genetic changes have occurred responding to adaptation to new environments. In the 1960s, Anolis carolinensis was introduced onto one of the Ogasawara Islands, Japan, and subsequently expanded its range rapidly throughout two of the islands. Morphological comparison showed that lower hindlimb length in the introduced populations tended to be longer than those in its native Florida populations. Using re-sequenced whole genomic data, we estimated that the effective population size at the time of introduction was actually small (less than 50). We also inferred putative genomic regions subject to natural selection after this introduction event using SweeD and a method based on Tajima's D, pi and F ST . Five candidate genes that were potentially subject to selection were estimated by both methods. The results suggest that there were standing variations that could potentially contribute to adaptation to nonnative environments despite the founder population being small. PMID- 29269732 TI - Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1. AB - Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer. PMID- 29269736 TI - Identification of minimal parameters for optimal suppression of chaos in dissipative driven systems. AB - Taming chaos arising from dissipative non-autonomous nonlinear systems by applying additional harmonic excitations is a reliable and widely used procedure nowadays. But the suppressory effectiveness of generic non-harmonic periodic excitations continues to be a significant challenge both to our theoretical understanding and in practical applications. Here we show how the effectiveness of generic suppressory excitations is optimally enhanced when the impulse transmitted by them (time integral over two consecutive zeros) is judiciously controlled in a not obvious way. Specifically, the effective amplitude of the suppressory excitation is minimal when the impulse transmitted is maximum. Also, by lowering the impulse transmitted one obtains larger regularization areas in the initial phase difference-amplitude control plane, the price to be paid being the requirement of larger amplitudes. These two remarkable features, which constitute our definition of optimum control, are demonstrated experimentally by means of an analog version of a paradigmatic model, and confirmed numerically by simulations of such a damped driven system including the presence of noise. Our theoretical analysis shows that the controlling effect of varying the impulse is due to a subsequent variation of the energy transmitted by the suppressory excitation. PMID- 29269735 TI - Conditionally reprogrammed primary airway epithelial cells maintain morphology, lineage and disease specific functional characteristics. AB - Current limitations to primary cell expansion led us to test whether airway epithelial cells derived from healthy children and those with asthma and cystic fibrosis (CF), co-cultured with an irradiated fibroblast feeder cell in F-medium containing 10 uM ROCK inhibitor could maintain their lineage during expansion and whether this is influenced by underlying disease status. Here, we show that conditionally reprogrammed airway epithelial cells (CRAECs) can be established from both healthy and diseased phenotypes. CRAECs can be expanded, cryopreserved and maintain phenotypes over at least 5 passages. Population doublings of CRAEC cultures were significantly greater than standard cultures, but maintained their lineage characteristics. CRAECs from all phenotypes were also capable of fully differentiating at air-liquid interface (ALI) and maintained disease specific characteristics including; defective CFTR channel function cultures and the inability to repair wounds. Our findings indicate that CRAECs derived from children maintain lineage, phenotypic and importantly disease-specific functional characteristics over a specified passage range. PMID- 29269737 TI - Precipitation variability increases in a warmer climate. AB - Understanding changes in precipitation variability is essential for a complete explanation of the hydrologic cycle's response to warming and its impacts. While changes in mean and extreme precipitation have been studied intensively, precipitation variability has received less attention, despite its theoretical and practical importance. Here, we show that precipitation variability in most climate models increases over a majority of global land area in response to warming (66% of land has a robust increase in variability of seasonal-mean precipitation). Comparing recent decades to RCP8.5 projections for the end of the 21st century, we find that in the global, multi-model mean, precipitation variability increases 3-4% K-1 globally, 4-5% K-1 over land and 2-4% K-1 over ocean, and is remarkably robust on a range of timescales from daily to decadal. Precipitation variability increases by at least as much as mean precipitation and less than moisture and extreme precipitation for most models, regions, and timescales. We interpret this as being related to an increase in moisture which is partially mitigated by weakening circulation. We show that changes in observed daily variability in station data are consistent with increased variability. PMID- 29269738 TI - Author Correction: Zebrafish as an animal model in epilepsy studies with multichannel EEG recordings. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29269739 TI - Fast polarization mechanisms in the uniaxial tungsten-bronze relaxor strontium barium niobate SBN-81. AB - The high-frequency dielectric response of the uniaxial strontium barium niobate crystals with 81% of Sr has been studied from 1 kHz to 30 THz along the polar c axis by means of several techniques (far infrared, time domain terahertz, high frequency and low-frequency dielectric spectroscopies) in a wide temperature interval 20-600 K. Relaxor properties were observed in the complex dielectric response and four main excitations were ascertained below the phonon frequencies. These fast polarization mechanisms take place at THz, GHz and MHz ranges and show different temperature evolution. The central mode excitation in the THz range, related to anharmonic dynamics of cations, slightly softens from high temperatures and then hardens below T ~ 400 K. Below the phase transition (at T ~ 330 K) an additional microwave excitation appears near 10 GHz related to micro domain wall oscillations. The strongest relaxation appears in the GHz range and slows down on cooling according to the Arrhenius law. Finally, another relaxation, present in the MHz range at high temperatures, also slows down on cooling at least to the kHz range. These two relaxations are due to polar fluctuations and nanodomains dynamics. Altogether, the four excitations explain the dielectric permittivity maximum in the kHz range. PMID- 29269740 TI - Structural basis for high specificity of octopine binding in the plant pathogen Agrobacterium tumefaciens. AB - Agrobacterium pathogens of octopine- and nopaline-types force host plants to produce either octopine or nopaline compounds, which they use as nutrients. Two Agrobacterium ABC-transporters and their cognate periplasmic binding proteins (PBPs) OccJ and NocT import octopine and nopaline/octopine, respectively. Here, we show that both octopine transport and degradation confer a selective advantage to octopine-type A. tumefaciens when it colonizes plants. We report the X-ray structures of the unliganded PBP OccJ and its complex with octopine as well as a structural comparison with NocT and the related PBP LAO from Salmonella enterica, which binds amino acids (lysine, arginine and ornithine). We investigated the specificity of OccJ, NocT and LAO using several ligands such as amino acids, octopine, nopaline and octopine analogues. OccJ displays a high selectivity and nanomolar range affinity for octopine. Altogether, the structural and affinity data allowed to define an octopine binding signature in PBPs and to construct a OccJ mutant impaired in octopine binding, a selective octopine-binding NocT and a non-selective octopine-binding LAO by changing one single residue in these PBPs. We proposed the PBP OccJ as a major trait in the ecological specialization of octopine-type Agrobacterium pathogens when they colonize and exploit the plant host. PMID- 29269741 TI - Bacterial Nanocellulose Loaded with Bromelain: Assessment of Antimicrobial, Antioxidant and Physical-Chemical Properties. AB - Bacterial nanocellulose (BNC) has desirable properties for wound healing such as high purity, good shape retention, and high water binding capacity. Bromelain is a protease found in pineapple tissues and has been applied in several fields, it has anti-inflammatory and anticancer properties, promotes cell apoptosis, amongst others. In this work, a BNC based device for the controlled release of bromelain was developed. BNC were submersed in sterilized bromelain solution and incubated at 25 degrees C under 100 rpm for 24 h. Physical-chemical properties, protein concentration, antioxidant and antimicrobial activities were measured. Results demonstrate that BNC could improve bromelain antimicrobial activity 9 times. Those findings allow concluding that bromelain is a promising molecule to be incorporated into BNC's. The BNC's characteristics seem to represent a new promising delivery system of the loaded biomolecule, and protected from external actions. PMID- 29269743 TI - Thermoluminescence of coral skeletons: a high-sensitivity proxy of diagenetic alteration of aragonite. AB - Diagenetic alteration of aragonite coral skeletons causes changes in their chemical and isotopic compositions. Such altered coral samples are unsuitable for age dating or paleoclimate reconstructions. Recently developed microanalysis techniques have elucidated secondary aragonite precipitation and calcite overgrowth on primary aragonitic coral skeletons, but an effective screening method for bulk samples is still desirable. Although powder X-ray diffraction (XRD) analysis is widely used for this purpose, its detection limit for calcite (1-2% at best) is not sufficient to detect very small amounts of diagenetic calcite. Here, we propose that thermoluminescence (TL) spectra can be used to detect the presence of tiny amounts of secondary calcite in coral skeletons. We used a TL spectrometer with a Fourier-transform detector to detect the calcite component in TL spectra of powdered skeletons of modern and fossil corals (from 127 ka and 3.5 Ma) in which calcite was not detectable by XRD. The key element is manganese, because the TL emission efficiency and the partition coefficient of Mn are greater for calcite than for aragonite. As a result, the calcite spectral component becomes evident. Thus, the TL spectroscopic technique is a highly sensitive tool for screening fossil corals for diagenetic alteration. PMID- 29269742 TI - Prognostic and predictive role of spatially positioned tumour infiltrating lymphocytes in metastatic HER2 positive breast cancer treated with trastuzumab. AB - Disease outcomes of HER2+ breast cancers have dramatically changed after targeted therapies, such as trastuzumab, came to clinical practice but predictive factors for trastuzumab sensitivity and resistance are frequently unknown. Current work included metastatic breast cancer patients (n = 48), who were treated with trastuzumab and had pre-treatment tumour samples available. The tumours were immunostained for T-cell (CD3, CD8), natural killer (NK)-cell (CD56) and macrophage (CD68) markers and quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumour locations. High number of CD3 and CD8 positive T-cells was associated with significant survival benefit in the center of the tumour (CT) (p = 0.007, p = 0.001) but not in the invasive margin. The number of NK-cells and macrophages in the CT showed non-significant tendency towards improved survival. In subgroup analyses, high density of CD8 CT cells was associated with significant survival benefit in non-bone only disease, in TX or T1-3, and in ER+ tumours (p = 0.006, p = 0.003, p = 0.001). Moreover, high CD8 CT cell density associated significantly with long trastuzumab interruption periods in response. The results suggest important prognostic and predictive role of tumour infiltrating lymphocytes in center of the tumours in metastatic HER2+ breast cancer. PMID- 29269745 TI - Electron-blocking by the potential barrier originated from the asymmetrical local density of state in the oxide semiconductor. AB - Defect generation in oxide semiconductor thin-film transistors under high-voltage driving has not been studied in depth despite being a crucial bottleneck in the making of the integrated circuit utilized in an oxide semiconductor. Here we report on the origin of the asymmetrical transport characteristics caused by the degradation in the oxide semiconductor during integrated circuit driving. The variation of the current profiles based on test conditions is related to the generation of local defect states in the oxide material; this generation could be caused by the structural change of the material. The numerical calculations show that the flow of the electron is blocked by the "electrical pocket" formed by the electric-field distortion due to the local defect states near the edge of the electrode. PMID- 29269744 TI - Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells. AB - The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in many cellular processes, including the proliferation, survival and differentiation of lung cancer cells. Thus, PI3K is a promising therapeutic target for lung cancer treatment. In this study, we applied free and open-source protein-ligand docking software, screened 3167 FDA-approved small molecules, and identified putative PI3Kalpha inhibitors. Among them, econazole nitrate, an antifungal agent, exhibited the highest activity in decreasing cell viability in pathological types of NSCLC cell lines, including H661 (large cell lung cancer) and A549 (adenocarcinoma). Econazole decreased the protein levels of p-AKT and Bcl-2, but had no effect on the phosphorylation level of ERK. It inhibited cell growth and promote apoptosis in a dose-dependent manner. Furthermore, the combination of econazole and cisplatin exhibited additive and synergistic effects in the H661 and A549 lung cancer cell lines, respectively. Finally, we demonstrated that econazole significantly suppressed A549 tumor growth in nude mice. Our findings suggest that econazole is a new PI3K inhibitor and a potential drug that can be used in lung cancer treatment alone or in combination with cisplatin. PMID- 29269746 TI - Acute effects of sauna bathing on cardiovascular function. AB - Emerging evidence suggests beneficial effects of sauna bathing on the cardiovascular system. However, the effects of sauna bathing on parameters of cardiovascular function and blood-based biomarkers are uncertain. We aimed to investigate whether sauna bathing induces changes in arterial stiffness, blood pressure (BP), and several blood-based biomarkers. We conducted an experimental study including 102 participants (mean age (SD): 51.9 (9.2) years, 56% male) who had at least one cardiovascular risk factor. Participants were exposed to a single sauna session (duration: 30 min; temperature: 73 degrees C; humidity: 10 20%). Cardiovascular as well as blood-based parameters were collected before, immediately after, and after 30-min recovery. Mean carotid-femoral pulse wave velocity was 9.8 (2.4) m/s before sauna and decreased to 8.6 (1.6) m/s immediately after sauna (p < 0.0001). Mean systolic BP decreased after sauna exposure from 137 (16) to 130 (14) mmHg (p < 0.0001) and diastolic BP from 82 (10) to 75 (9) mmHg (p < 0.0001). Systolic BP after 30 min recovery remained lower compared to pre-sauna levels. There were significant changes in hematological variables during sauna bathing. Plasma creatinine levels increased slightly from sauna until recovery period, whereas sodium and potassium levels remained constant. This study demonstrates that sauna bathing for 30 min has beneficial effects on arterial stiffness, BP, and some blood-based biomarkers. These findings may provide new insights underlying the emerging associations between sauna bathing and reduced risk of cardiovascular outcomes. PMID- 29269747 TI - Persisting disparities between sexes in outcomes of ruptured abdominal aortic aneurysm hospitalizations. AB - We sought to describe and analyze discrepancies between sexes in the outcomes of patients hospitalized for ruptured abdominal aortic aneurysms (rAAA) by conducting a retrospective analysis of the Nationwide Inpatient Sample. The review included all adult patients (>=18 years old) hospitalized with a primary diagnosis of rAAA between January 2002 and December 2014. In-hospital mortality differences between females and males were analyzed overall and separately among those receiving endovascular AAA repair (EVAR) or open AAA repair (OAR). In hospital mortality for females declined from 61.0% in 2002 to 49.0% in 2014 (P for trend <0.001), while mortality for males declined from 48.6% in 2002 to 32.2% in 2014 (P for trend <0.001). Among those receiving EVAR, females were significantly more likely to die in the hospital than males (adjusted odds ratio [OR], 1.44; 95% CI, 1.12-1.84). In addition, the odds of mortality among those receiving OAR were higher for females than males (adjusted OR, 1.14; 95% CI: 1.00 1.31). These data provide evidence that despite overall decreasing trends in mortality for both sexes, females remain at higher risk of death compared with males regardless of surgical repair procedure. PMID- 29269748 TI - Attraction of Culex mosquitoes to aldehydes from human emanations. AB - Anecdotes related to preferential mosquito bites are very common, but to date there is no complete explanation as to why one out of two people systematically receives more mosquito bites than the other when both are equally accessible. Here we tested the hypothesis that two constituents of skin emanations, 6-methyl 5-heptan-2-one (6-MHO) and geranylacetone (GA), are natural repellents and may account for differential attraction in different ratios. We studied skin emanations from two human subjects, confirmed in behavioral assays that female southern house mosquitoes are significantly more attracted to subject A (attractant) than to subject N (non-attractant), and tested their 6-MHO/GA ratios in a dual-choice olfactometer. Although repelling at high doses, 6-MHO/GA mixtures were not active at the levels emitted by human skin. We found, however, differential attraction elicited by the aldehydes in the ratios produced by subjects A and N. When tested in a dose commensurate with the level released from human skin and in the ratio produced by subject A, the aldehyde mixture significantly attracted mosquitoes. By contrast, an aldehyde mixture at the same ratio released by subject N did not attract mosquitoes. We, therefore, hypothesized that aldehydes may play a role in the commonly observed differential attraction. PMID- 29269749 TI - Therapeutic effect of molecular hydrogen in corneal UVB-induced oxidative stress and corneal photodamage. AB - The aim of this study is to examine whether molecular hydrogen (H2) is able to reduce oxidative stress after corneal damage induced by UVB irradiation. We previously found that UVB irradiation of the cornea caused the imbalance between the antioxidant and prooxidant enzymes in the corneal epithelium, followed by the imbalance between metalloproteinases and their physiological inhibitors (imbalances in favour of prooxidants and metalloproteinases) contributing to oxidative stress and development of the intracorneal inflammation. Here we investigate the effect of H2 dissolved in PBS in the concentration 0.5 ppm wt/vol, applied on rabbit corneas during UVB irradiation and healing (UVB doses 1.01 J/cm2 once daily for four days). Some irradiated corneas remained untreated or buffer treated. In these corneas the oxidative stress appeared, followed by the excessive inflammation. Malondiladehyde and peroxynitrite expressions were present. The corneas healed with scar formation and neovascularization. In contrast, in H2 treated irradiated corneas oxidative stress was suppressed and malondiladehyde and peroxynitrite expressions were absent. The corneas healed with the restoration of transparency. The study provides the first evidence of the role of H2 in prevention of oxidative and nitrosative stress in UVB irradiated corneas, which may represent a novel prophylactic approach to corneal photodamage. PMID- 29269750 TI - Design, fabrication and characterization of Computer Generated Holograms for anti counterfeiting applications using OAM beams as light decoders. AB - In this paper, we present the design, fabrication and optical characterization of computer-generated holograms (CGH) encoding information for light beams carrying orbital angular momentum (OAM). Through the use of a numerical code, based on an iterative Fourier transform algorithm, a phase-only diffractive optical element (PO-DOE) specifically designed for OAM illumination has been computed, fabricated and tested. In order to shape the incident beam into a helicoidal phase profile and generate light carrying phase singularities, a method based on transmission through high-order spiral phase plates (SPPs) has been used. The phase pattern of the designed holographic DOEs has been fabricated using high-resolution Electron Beam Lithography (EBL) over glass substrates coated with a positive photoresist layer (polymethylmethacrylate). To the best of our knowledge, the present study is the first attempt, in a comprehensive work, to design, fabricate and characterize computer-generated holograms encoding information for structured light carrying OAM and phase singularities. These optical devices appear promising as high-security optical elements for anti-counterfeiting applications. PMID- 29269752 TI - Description of exposure profiles for seven environmental chemicals in a US population using recursive partition mixture modeling (RPMM). AB - Biomonitoring studies have shown that humans are exposed to numerous environmental chemicals. Previous work provides limited insights into the dynamic relationship between different chemicals within a population. The objective of this study is to develop an analytical method identifying exposure profiles of seven common environmental chemicals and determine how exposure profiles differ by sociodemographic groups and National Health and Nutrition Examination Survey (NHANES) 2003-2012 cycle year. We used recursive partition mixture modeling (RPMM) to define classes of the population with similar exposure profiles of lead, cadmium, 2,4-dichlorophenol, 2,5-dichlorophenol, bisphenol A (BPA), triclosan, and benzophenone-3 in individuals aged >=6 years. Additionally, quasibinomial logistic regression was used to examine the association between each class and selected demographic characteristics. Eight exposure profiles were identified. Individuals who clustered together and had the highest chemical exposures were more likely to be older, to be Non-Hispanic Black (NHB) or Other Hispanic (OH), more likely to live below the poverty line, more likely to be male, and more likely to have participated in the earlier NHANES cycle (2003 2004). The developed method described the dynamic relationship between chemicals and shows that this relationship is different for subpopulations based on their sociodemographic characteristics. PMID- 29269753 TI - Particulate matter and markers of glycemic control and insulin resistance in type 2 diabetic patients: result from Wellcome Trust Genetic study. AB - There is growing evidence that air pollution is associated with increased risk of type 2 diabetes (T2DM). However, information related to whether particulate matter (PM) contributing to worsened metabolic control in T2DM patients is inconsistent. We examined the association of PM10 exposure with glucose-function parameters in young-onset T2DM patients. We investigated the association between a year ambient concentration of PM10 at residential places, using AERMOD dispersion model, with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), 2 h post meal plasma glucose (2hPG), homeostasis model assessment of insulin resistance (HOMA-IR), beta-cell function (HOMA-beta) and disposition index (DI) in 1213 diabetic patients from the Wellcome Trust Genetic study at the Diabetes Unit, KEM Hospital Research Center, Pune, India. We used linear regression models and adjusted for a variety of individual and environmental confounding variables. Possible effect modification by age, gender, waist-to-hip ratio (WHR) and smoking status were investigated. Sensitivity analysis assessed the impact of relative humidity (RH) and temperature a day before examination and anti-diabetic and HHR medication (Hydralazine, Hydrochlorothiazide and Reserpine). We found that 1 SD increment in background concentration of PM10 at residential places (43.83 ug/m3) was significantly associated with 2.25 mmol/mol and 0.38 mmol/l increase in arithmetic means of HbA1c and 2hPG, respectively. A similar increase in PM10 was also associated with 4.89% increase in geometric mean of HOMA-IR. The associations remained significant after adjustment to RH and temperature, and WHR and smoking enhanced the size of the effect. Our study suggests that long-term exposure to PM10 is associated with higher glycaemia and insulin resistance. In context of our previous demonstration of association of SO2 and NO x and plasma C reactive protein, we suggest that air pollution could influence progression of diabetes complications. Prospective studies and interventions are required to define mechanism and confirm causality. PMID- 29269751 TI - Cerebellar-dependent associative learning is impaired in very preterm born children and young adults. AB - Preterm birth incorporates an increased risk for cerebellar developmental disorders likely contributing to motor and cognitive abnormalities. Experimental evidence of cerebellar dysfunction in preterm subjects, however, is sparse. In this study, classical eyeblink conditioning was used as a marker of cerebellar dysfunction. Standard delay conditioning was investigated in 20 adults and 32 preschool children born very preterm. Focal lesions were excluded based on structural magnetic resonance imaging. For comparison, an equal number of matched term born healthy peers were tested. Subgroups of children (12 preterm, 12 controls) were retested. Preterm subjects acquired significantly less conditioned responses (CR) compared to controls with slower learning rates. A likely explanation for these findings is that preterm birth impedes function of the cerebellum even in the absence of focal cerebellar lesions. The present findings are consistent with the assumption that prematurity results in long-term detrimental effects on the integrity of the cerebellum. It cannot be excluded, however, that extra-cerebellar pathology contributed to the present findings. PMID- 29269755 TI - Prevalence of asthma and allergic symptoms in Suzhou, China: Trends by domestic migrant status. AB - Rapid urbanization in developing countries, with significant rural-to-urban and between-urban areas migration, presents a natural epidemiological model to better understand population-level trends in asthma and allergy prevalance without confounding by genetic factors. This cross-sectional study, conducted November 2014 to January 2015 in Suzhou, China, investigated differences in asthma and allergic symptoms between domestic migrant residents and long-term residents and their children. Using multivariate logistic regression, the odds ratios for children in migrant families compared to those in long-term resident families in Suzhou for doctor-diagnosed asthma, pneumonia, rhinitis, and eczema were 0.56 (95% CI: 0.42.0.73), 0.60 (95% CI: 0.49, 0.72), 0.63 (95% CI:0.52, 0.77), and 0.73 (95% CI: 0.60, 0.89), respectively. While there was a lower prevalence of asthma and allergic symptoms for domestic migrants (children and parents) compared to the local population in Suzhou, migrant children had a higher asthma rate than their parents. This follows the trend of increasing asthma rates for children in the urban local population, suggesting an environmental component. Parental migration plays a role in both parental and children's health but further investigations are needed to determine how these results may be shaped by early life exposures, lifestyle differences, and other environmental factors. PMID- 29269754 TI - Exposure to acute air pollution and risk of bronchiolitis and otitis media for preterm and term infants. AB - Our aim is to estimate associations between acute increases in particulate matter with diameter of 2.5 um or less (PM2.5) concentrations and risk of infant bronchiolitis and otitis media among Massachusetts births born 2001 through 2008.Our case-crossover study included 20,017 infant bronchiolitis and 42,336 otitis media clinical encounter visits. PM2.5 was modeled using satellite, remote sensing, meteorological and land use data. We applied conditional logistic regression to estimate odds ratios (ORs) and confidence intervals (CIs) per 10 ug/m3 increase in PM2.5. We assessed effect modification to determine the most susceptible subgroups. Infant bronchiolitis risk was elevated for PM2.5 exposure 1 day (OR = 1.07, 95% CI = 1.03-1.11) and 4 days (OR = 1.04, 95% CI = 0.99-1.08) prior to clinical encounter, but not 7 days. Non-significant associations with otitis media varied depending on lag. Preterm infants were at substantially increased risk of bronchiolitis 1 day prior to clinical encounter (OR = 1.17, 95% CI = 1.08-1.28) and otitis media 4 and 7 days prior to clinical encounter (OR = 1.09, 95% CI = 1.02-1.16 and OR = 1.08, 95% CI = 1.02-1.15, respectively). In conclusion, preterm infants are most susceptible to infant bronchiolitis and otitis media associated with acute PM2.5 exposures. PMID- 29269756 TI - Variability and exposure classification of urinary levels of non-essential metals aluminum, antimony, barium, thallium, tungsten and uranium in healthy adult men. AB - Arsenic, cadmium and lead are well-known toxic metals, and there are substantial studies on variability of these metals in urine to optimize design of exposure assessment. For urinary levels of other nonessential metals such as aluminum (Al), antimony (Sb), barium (Ba), thallium (Tl), tungsten (W) and uranium (U), however, their within-individual and between-individual variability are unclear. Therefore, we collected 529 samples from 11 healthy adult men on 8 days during a 3-month period. We measured urinary metals and creatinine (Cr) levels, assessed the reproducibility using intraclass correlation coefficients (ICCs), and performed sensitivity and specificity analyses to assess how well 1, 2 or 3 specimens could classify exposure. Al, Sb, Ba, W and U levels measured from spot samples varied greatly over days and months (Cr-adjusted ICCs = 0.01-0.14). Serial measures of Tl levels measured from spot samples had fair-to-good reproducibility over 5 consecutive days (Cr-adjusted ICC = 0.40), but worsened when the specimens were collected months apart (Cr-adjusted ICC = 0.16). To identify men who were highly exposed (top 33%) based on their 3-month averages, tests of single spot samples and tests of first-morning voids had high specificities (0.73-0.85) but relatively low sensitivities (0.27-0.60). Collection of repeated urine specimens from each individual improved the classification. PMID- 29269758 TI - Munc13 marks the spot. PMID- 29269759 TI - Calcium control of myelin sheath growth. PMID- 29269757 TI - The diversity and disparity of the glial scar. AB - Injury or disease to the CNS results in multifaceted cellular and molecular responses. One such response, the glial scar, is a structural formation of reactive glia around an area of severe tissue damage. While traditionally viewed as a barrier to axon regeneration, beneficial functions of the glial scar have also been recently identified. In this Perspective, we discuss the divergent roles of the glial scar during CNS regeneration and explore the possibility that these disparities are due to functional heterogeneity within the cells of the glial scar-specifically, astrocytes, NG2 glia and microglia. PMID- 29269760 TI - Stay alert, don't get hurt. PMID- 29269762 TI - Promoting diversity in neuroscience. PMID- 29269761 TI - From entorhinal neural codes to navigation. PMID- 29269763 TI - Plasmacytoid dendritic cells: Division of labour. PMID- 29269764 TI - Inflammasome: Looking death in the eye. PMID- 29269765 TI - Response to Orlova et al. "Science not art: statistically sound methods for identifying subsets in multi-dimensional flow and mass cytometry data sets". PMID- 29269766 TI - Science not art: statistically sound methods for identifying subsets in multi dimensional flow and mass cytometry data sets. PMID- 29269767 TI - Innate immunity: Revealing the secrets of IL-1 secretion. PMID- 29269768 TI - One-step Conversion of Levulinic Acid to Succinic Acid Using I2/t-BuOK System: The Iodoform Reaction Revisited. AB - The iodoform reaction has long been used as a qualitative test for acetyl and/or ethanol units in organic molecules. However, its synthetic applications are quite limited. Here, we describe a tuned iodoform reaction for oxidative demethylation reaction with I2 and t-BuOK in t-BuOH, in which in situ-generated t-BuOI serves as the chemoselective iodinating agent. This system enables one-step conversion of levulinic acid to succinic acid, a major four-carbon chemical feedstock. This oxidative demethylation is also applicable to other compounds containing an acetyl group/ethanol unit, affording the corresponding carboxylic acids in a selective manner. PMID- 29269769 TI - Lipid moieties on lipoproteins of commensal and non-commensal staphylococci induce differential immune responses. AB - Lipoproteins (Lpp) of Gram-positive bacteria are major players in alerting our immune system. Here, we show that the TLR2 response induced by commensal species Staphylococcus aureus and Staphylococcus epidermidis is almost ten times lower than that induced by noncommensal Staphylococcus carnosus, and this is at least partially due to their different modifications of the Lpp lipid moieties. The N terminus of the lipid moiety is acylated with a long-chain fatty acid (C17) in S. aureus and S. epidermidis, while it is acylated with a short-chain fatty acid (C2) in S. carnosus. The long-chain N-acylated Lpp, recognized by TLR2-TLR1 receptors, silences innate and adaptive immune responses, while the short-chain N acetylated Lpp, recognized by TLR2-TLR6 receptors, boosts it. PMID- 29269770 TI - Spontaneous and specific chemical cross-linking in live cells to capture and identify protein interactions. AB - Covalently locking interacting proteins in situ is an attractive strategy for addressing the challenge of identifying weak and transient protein interactions, yet it is demanding to execute chemical reactions in live systems in a biocompatible, specific, and autonomous manner. Harnessing proximity-enabled reactivity of an unnatural amino acid incorporated in the bait toward a target residue of unknown proteins, here we genetically encode chemical cross-linkers (GECX) to cross-link interacting proteins spontaneously and selectively in live cells. Obviating an external trigger for reactivity and affording residue specificity, GECX enables the capture of low-affinity protein binding (affibody with Z protein), elusive enzyme-substrate interaction (ubiquitin-conjugating enzyme UBE2D3 with substrate PCNA), and endogenous proteins interacting with thioredoxin in E. coli cells, allowing for mass spectrometric identification of interacting proteins and crosslinking sites. This live cell chemistry-based approach should be valuable for investigating currently intangible protein interactions in vivo for better understanding of biology in physiological settings. PMID- 29269771 TI - Microbial stress mediated intercellular nanotubes in an anaerobic microbial consortium digesting cellulose. AB - The anaerobic digestion process is a multi - step reaction dependent on concerted activities such as exchange of metabolites among physiologically different microbial communities. This study investigated the impact of iron oxide nanoparticles on the anaerobic sludge microbiota. It was shown there were three distinct microbial phases following addition of the nanoparticles: microbial stress and cell death of approximately one log order of magnitude, followed by microbial rewiring, and recovery. Furthermore, it was noted that cellular stress led to the establishment of intercellular nanotubes within the microbial biomass. Intercellular nanotube - mediated communication among genetically engineered microorganisms and ad hoc assembled co - cultures have been previously reported. This study presents evidence of intercellular nanotube formation within an environmental sample - i.e., anaerobic sludge microbiota subjected to stress. Our observations suggested a mode of microbial communication in the anaerobic digestion process not previously explored and which may have implications on bioreactor design and microbial functions. PMID- 29269772 TI - Cell Cycle Model System for Advancing Cancer Biomarker Research. AB - Progress in understanding the complexity of a devastating disease such as cancer has underscored the need for developing comprehensive panels of molecular markers for early disease detection and precision medicine applications. The present study was conducted to assess whether a cohesive biological context can be assigned to protein markers derived from public data mining, and whether mass spectrometry can be utilized to screen for the co-expression of functionally related biomarkers to be recommended for further exploration in clinical context. Cell cycle arrest/release experiments of MCF7/SKBR3 breast cancer and MCF10 non tumorigenic cells were used as a surrogate to support the production of proteins relevant to aberrant cell proliferation. Information downloaded from the scientific public domain was queried with bioinformatics tools to generate an initial list of 1038 cancer-associated proteins. Mass spectrometric analysis of cell extracts identified 352 proteins that could be matched to the public list. Differential expression, enrichment, and protein-protein interaction analysis of the proteomic data revealed several functionally-related clusters of relevance to cancer. The results demonstrate that public data derived from independent experiments can be used to inform biological research and support the development of molecular assays for probing the characteristics of a disease. PMID- 29269774 TI - Tunable direct band gap photoluminescent organic semiconducting nanoparticles from lignite. AB - Fluorescent organic semiconducting dots (OSDs) with tunable particle size and surface functionality are synthesized from lignite by chemical oxidation method followed by ultra-sonication techniques and dialysis. The defects and oxygen functionalities play a vital role in the photoluminescent property of the synthesized nanoparticles along with quantum confinement effect. These nanomaterials are suitable for imaging and chemical sensing applications as there is no photobleaching and quenching even after a continuous UV exposure of 24 hours and storage of 2 years. The excellent excitation dependent luminescence of the synthesized carbon dots can be utilized for making a low-cost carbon-based sensor for Cu2+ metal ions sensing. The OSDs show good ratiometric fluorescent sensing and can be used as a reliable probe for the detection of Cu2+ ions. They exhibit excellent detection limit of copper ion in acidic solution to a very low concentration of 0.0089 nM. The fluorescent nanodots synthesized from such an abundant and cost-effective precursor exhibiting high copper ion sensitivity is being reported for the first time. PMID- 29269773 TI - Integration of miRNA and gene expression profiles suggest a role for miRNAs in the pathobiological processes of acute Trypanosoma cruzi infection. AB - Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America. Its acute phase is associated with high parasitism, myocarditis and profound myocardial gene expression changes. A chronic phase ensues where 30% develop severe heart lesions. Mouse models of T. cruzi infection have been used to study heart damage in Chagas disease. The aim of this study was to provide an interactome between miRNAs and their targetome in Chagas heart disease by integrating gene and microRNA expression profiling data from hearts of T. cruzi infected mice. Gene expression profiling revealed enrichment in biological processes and pathways associated with immune response and metabolism. Pathways, functional and upstream regulator analysis of the intersections between predicted targets of differentially expressed microRNAs and differentially expressed mRNAs revealed enrichment in biological processes and pathways such as IFNgamma, TNFalpha, NF-kB signaling signatures, CTL-mediated apoptosis, mitochondrial dysfunction, and Nrf2-modulated antioxidative responses. We also observed enrichment in other key heart disease-related processes like myocarditis, fibrosis, hypertrophy and arrhythmia. Our correlation study suggests that miRNAs may be implicated in the pathophysiological processes taking place the hearts of acutely T. cruzi-infected mice. PMID- 29269775 TI - Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression. AB - Aberrant integration of newborn hippocampal granule cells is hypothesized to contribute to the development of temporal lobe epilepsy. To test this hypothesis, we used a diphtheria toxin receptor expression system to selectively ablate these cells from the epileptic mouse brain. Epileptogenesis was initiated using the pilocarpine status epilepticus model in male and female mice. Continuous EEG monitoring was begun 2-3 months after pilocarpine treatment. Four weeks into the EEG recording period, at a time when spontaneous seizures were frequent, mice were treated with diphtheria toxin to ablate peri-insult generated newborn granule cells, which were born in the weeks just before and after pilocarpine treatment. EEG monitoring continued for another month after cell ablation. Ablation halted epilepsy progression relative to untreated epileptic mice; the latter showing a significant and dramatic 300% increase in seizure frequency. This increase was prevented in treated mice. Ablation did not, however, cause an immediate reduction in seizures, suggesting that peri-insult generated cells mediate epileptogenesis, but that seizures per se are initiated elsewhere in the circuit. These findings demonstrate that targeted ablation of newborn granule cells can produce a striking improvement in disease course, and that the treatment can be effective when applied months after disease onset. PMID- 29269776 TI - Progress towards rubella elimination after implementation of rubella immunization for over 20 years in Shandong province, China. AB - The rubella vaccine has been included in the immunization program in Shandong province of China since 1995. Here we observed the rubella vaccine coverage, epidemiology, serosurvey, and virological surveillance data, in order to identify the challenges impeding the progress towards to its elimination following the implementation of rubella immunization over a 21-year period in Shandong province. We first noted that the annual increase in vaccination coverage resulted in decreased rate of rubella incidence, which was maintained at a low level. Second, the average age of rubella patients had shifted to the 15-29-year age group, making this group the main population affected by the rubella virus (RV). Third, more than 90% of the study population were immune to rubella. However, the positive rate of rubella IgG in some cities was relatively lower indicating that an insufficient proportion of individuals had been vaccinated. Finally, the transmission of the genotype 1E RV was gradually interrupted due to the implementation of rubella vaccination. Unfortunately, the endemicity of the imported genotype 2B RV was established due to the pockets with unvaccinated people. Therefore, comprehensive vaccination coverage of the population, combined with high quality monitoring of rubella, is necessary to achieve the rubella elimination goal. PMID- 29269777 TI - Curved surface effect and manipulation of electronic states in nanosilicon. AB - It is interesting in low-dimensional nanostructures of silicon that the two quantum effects play different roles in nanosilicon emission, in which the quantum confinement (QC) effect opens band gap and makes emission shift into shorter wavelengths (blue-shift) as the size of the nanocrystals is reduced; however the breaking symmetry originating from impurities on nanosilicon produces the localized electronic states in band gap and makes emission shift into longer wavelengths (red-shift). The results of experiment and calculation demonstrated that the energy levels of nanosilicon can be manipulated through these quantum effects, where the curved surface (CS) effect of impurity atoms bonding on nanosilicon is important in breaking symmetry of nanosilicon system. Here, the CS effect plays an important role on impuritied nanosilicon in smaller scale with larger surface curvature, in which a few characteristic parameters have been found to describe the breaking symmetry of nanosilicon system, such as bonding angle and projecting length of bonds on curved surface. More interesting, the coupling ways between the QC effect and the CS effect determinate the levels position of localized states in band gap and manipulate emission wavelength, where a few new phenomena were explored. PMID- 29269778 TI - Despite limitations in content range, the SCIM-III is reproducible and a valid indicator of physical function in youths with spinal cord injury and dysfunction. AB - STUDY DESIGN: Multi-center, repeated measures OBJECTIVES: Evaluate psychometric properties of the SCIM-III in children. SETTING: Seven facilities in North America METHODS: One-hundred and twenty-seven youths, mean age of 10.8 years and chronic spinal cord injury/dysfunction completed two administrations of the Spinal Cord Independence Measure-III (SCIM-III). Mean, standard deviation, range values were calculated for SCIM-III total and subscales for the entire sample, four age groups and injury characteristics. Test-retest reliability, concurrent validity, and floor and ceiling effects were examined. RESULTS: Total SCIM-III and self-care (SC) subscale scores for the youngest age group were lower than those for the three older age groups. There were statistically significant differences in SC subscale scores between neurological level (NL) C5-T1 and T2 T12; C5-T1 and L1-S4/5; and T2-T12 and L1-S4/5 and in in-room, and indoor/outdoor mobility subscale scores between C1-C4 and T2-T12; C1-C4 and L1-S4/5; C5-T1 and T2-T12; C5-T1 and L1-S4/5; and T2-T12 and L1-S4/5. All scores between motor complete and motor incomplete differed. Test-retest reliability was good (ICC values = > 0.84) and there was moderate to strong correlation between SCIM-III and the FIM(r) Instrument (r = 0.77-0.92). Ceiling effects were present in the SC subscale for the oldest age group (24%) and for NL L1-S4/5 (35.5%) and in in-room mobility subscale for 6-12 (45.7%), 13-15 (30.43%) and 16-17 (60%) ages, paraplegia (42.4%), tetraplegia (37.1%), incomplete injuries (50%), and T2-T12 (38%) and L1-S4/5 (100%) NL. CONCLUSION: Despite limitations in content range, the SCIM-III is reproducible, and a valid indicator of physical functioning in youth with SCI/D 6 years of age and older. SPONSORSHIP: The study was funded by the Craig H. Neilsen Foundation, Spinal Cord Injury Research on the Translation Spectrum, Senior Research Award Grant #282592 (Mulcahey, PI). PMID- 29269779 TI - A longitudinal study of self-reported spasticity among individuals with chronic spinal cord injury. AB - STUDY DESIGN: A longitudinal study. OBJECTIVES: To describe the prevalence and stability of self-reported spasticity severity in adults with chronic spinal cord injury (SCI) over a 3-year timeframe and examine predictors of severity and change in spasticity severity. SETTING: The data were collected by mail at a medical university in the Southeastern United States. METHODS: A total of 1790 adults with chronic SCI responded to two self-report assessments, one between 2007 and 2009 (baseline) and another between 2011 and 2014 (follow-up). Average spasticity severity was measured on a numeric rating scale from 0 (no spasticity) to 10 (spasticity as bad as you can imagine). Frequency of prescription medication use for spasticity in the past year was also reported (never, sometimes/weekly, daily). RESULTS: About 82.5% of participants had spasticity at baseline and 86.5% at follow-up. There was a significant change in spasticity severity (0.9 +/- 2.3; p < 0.001), corresponding to a 31% increase in mean severity. Overall, the frequency of medication use did not significantly change. At baseline, 55.6% of participants reported using medications for spasticity in the past year; 54.9% reported use at follow-up. Variables significantly associated with spasticity severity included race/ethnicity, age, and spasticity medication use. CONCLUSIONS: Spasticity is highly prevalent after SCI. Though severity is mild on average, a statistically significant increase was observed over a relatively short natural timeframe. The changes observed in spasticity severity categories (mild, moderate, severe) highlight the need to monitor spasticity in individuals with chronic SCI. PMID- 29269780 TI - Transmission of heat modes across a potential barrier. AB - Controlling the transmission of electrical current using a quantum point contact constriction paved a way to a large variety of experiments in mesoscopic physics. The increasing interest in heat transfer in such systems fosters questions about possible manipulations of quantum heat modes that do not carry net charge (neutral modes). Here we study the transmission of upstream neutral modes through a quantum point contact in fractional hole-conjugate quantum Hall states. Employing two different measurement techniques, we were able to render the relative spatial distribution of these chargeless modes with their charged counterparts. In these states, which were found to harbor more than one downstream charge mode, the upstream neutral modes are found to flow with the inner charge mode-as theoretically predicted. These results unveil a universal upstream heat current structure and open the path for more complex engineering of heat flows and cooling mechanisms in quantum nano-electronic devices. PMID- 29269781 TI - ANP32A dysregulation contributes to abnormal megakaryopoiesis in acute megakaryoblastic leukemia. PMID- 29269782 TI - Immunotoxicological impact and biodistribution assessment of bismuth selenide (Bi2Se3) nanoparticles following intratracheal instillation in mice. AB - Variously synthesized and fabricated Bi2Se3 nanoparticles (NPs) have recently been explored for their theranostic properties. Herein, we investigated the long term in-vivo biodistribution of Bi2Se3 NPs and systematically screened its immune toxic potential over lungs and other secondary organs post intratracheal instillation. X-Ray CT scan and ICP MS results revealed significant particle localization and retention in lungs monitored for 1 h and 6 months time period respectively. Subsequent particle trafficking was observed in liver, the major reticuloendothelial organ followed by gradual but incomplete renal clearance. Pulmonary cytotoxicity was also found to be associated with persistent neutrophilic and ROS generation at all time points following NP exposure. The inflammatory markers along with ROS generation further promoted oxidative stress and exaggerated additional inflammatory pathways leading to cell death. The present study, therefore, raises serious concern about the hazardous effects of Bi2Se3 NPs and calls for further toxicity assessments through different administration routes and doses as well. PMID- 29269783 TI - Phased uplift of the northeastern Tibetan Plateau inferred from a pollen record from Yinchuan Basin, northwestern China. AB - The uplift of the Tibetan Plateau (TP) significantly affected both regional and global climates. Although there is evidence that the Tibetan Plateau experienced uplift during the Quaternary, the timing and amplitude are poorly constrained. However, the increased availability of long sedimentary records of vegetation change provides an opportunity to reconstruct the timing of the uplift. Here, we present a well-dated, high-resolution pollen record for the last 2.6 Ma from the Yinchuan Basin, which was incised by the Yellow River with its source in the northeastern Tibetan Plateau. Variations in the Artemisia/Chenopodiaceae (A/C) ratio of the reveal changes in moisture conditions in the Yinchuan Basin during glacial-interglacial cycles, as well as a gradual long-term aridification trend which is consistent with progressive global cooling. However, fluctuations in the percentages of Picea and Abies differ from those of the A/C ratio and we propose that they reflect changes in the vegetation and environment of high elevation areas. The Picea and Abies records reveal two phases of increased representation, at 2.1 and 1.2 Ma, which may indicate phases in the uplift of the northeastern Tibetan Plateau. Thus, they provide independent evidence for the timing of the uplift of the Tibetan Plateau during the Quaternary. PMID- 29269785 TI - Ageing: Somatic mutations accumulate in ageing and diseased neurons. PMID- 29269784 TI - Endosomal binding kinetics of Eps15 and Hrs specifically regulate the degradation of RTKs. AB - Activation of EGF-R and PDGF-R triggers autophosphorylation and the recruitment of Eps15 and Hrs. These two endosomal proteins are important for specific receptor sorting. Hrs is recruiting ubiquitinated receptors to early endosomes to further facilitate degradation through the ESCRT complex. Upon receptor activation Hrs becomes phosphorylated and is relocated to the cytosol, important for receptor degradation. In this work we have studied the endosomal binding dynamics of Eps15 and Hrs upon EGF-R and PDGF-R stimulation. By analysing the fluorescence intensity on single endosomes after ligand stimulation we measured a time-specific decrease in the endosomal fluorescence level of Eps15-GFP and Hrs YFP. Through FRAP experiments we could further register a specific change in the endosomal-membrane to cytosol binding properties of Eps15-GFP and Hrs-YFP. This specific change in membrane fractions proved to be a redistribution of the immobile fraction, which was not shown for the phosphorylation deficient mutants. We here describe a mechanism that can explain the previously observed relocation of Hrs from the endosomes to cytosol after EGF stimulation and show that Eps15 follows a similar mechanism. Moreover, this specific redistribution of the endosomal protein binding dynamics proved to be of major importance for receptor degradation. PMID- 29269786 TI - Peripheral neuropathies: Antisense therapy for Charcot-Marie-Tooth disease? PMID- 29269787 TI - YVO4:Nd3+ nanophosphors as NIR-to-NIR thermal sensors in wide temperature range. AB - We report on the potential application of NIR-to-NIR Nd3+-doped yttrium vanadate nanoparticles with both emission and excitation operating within biological windows as thermal sensors in 123-873 K temperature range. It was demonstrated that thermal sensing could be based on three temperature dependent luminescence parameters: the luminescence intensity ratio, the spectral line position and the line bandwidth. Advantages and limitations of each sensing parameter as well as thermal sensitivity and thermal uncertainty were calculated and discussed. The influence of Nd3+ doping concentration on the sensitivity of luminescent thermometers was also studied. PMID- 29269788 TI - Minimizing carry-over PCR contamination in expanded CAG/CTG repeat instability applications. AB - Expanded CAG/CTG repeats underlie the aetiology of 14 neurological and neuromuscular disorders. The size of the repeat tract determines in large part the severity of these disorders with longer tracts causing more severe phenotypes. Expanded CAG/CTG repeats are also unstable in somatic tissues, which is thought to modify disease progression. Routine molecular biology applications involving these repeats, including quantifying their instability, are plagued by low PCR yields. This leads to the need for setting up more PCRs of the same locus, thereby increasing the risk of carry-over contamination. Here we aimed to reduce this risk by pre-treating the samples with a Uracil N-Glycosylase (Ung) and using dUTP instead of dTTP in PCRs. We successfully applied this method to the PCR amplification of expanded CAG/CTG repeats, their sequencing, and their molecular cloning. In addition, we optimized the gold-standard method for measuring repeat instability, small-pool PCR (SP-PCR), such that it can be used together with Ung and dUTP-containing PCRs, without compromising data quality. We performed SP-PCR on myotonic-dystrophy-derived samples containing an expansion as large as 1000 repeats, demonstrating the applicability to clinically-relevant material. Thus, we expect the protocols herein to be applicable for molecular diagnostics of expanded repeat disorders. PMID- 29269789 TI - High-Temperature Requirement A1 (Htra1) - A Novel Regulator of Canonical Wnt Signaling. AB - Different cancer types as well as many other diseases are caused by aberrant activation of the canonical Wnt signal transduction pathway, and it is especially implicated in the development and progression of colorectal cancer (CRC). The main effector protein of the canonical Wnt signaling cascade is beta-catenin, which binds to the T- cell factor/lymphoid enhancer factor (TCF/LEF) and triggers the activation of Wnt target genes. Here, we identify the serine protease High Temperature Requirement A1 (HTRA1) as a novel component of the canonical Wnt pathway. We show that the HTRA1 protein inhibits the Wnt/beta-catenin signaling, in both paracrine and autocrine manners, and affects the expression of several Wnt target genes. Moreover, HTRA1 forms a complex with beta-catenin and reduces the proliferation rates of cells. Taken together, our findings indicate that HTRA1 functions as a novel suppressor of the canonical Wnt signaling pathway. PMID- 29269790 TI - Tailoring tobacco hairy root metabolism for the production of stilbenes. AB - Tobacco hairy root (HR) cultures, which have been widely used for the heterologous production of target compounds, have an innate capacity to bioconvert exogenous t-resveratrol (t-R) into t-piceatannol (t-Pn) and t pterostilbene (t-Pt). We established genetically engineered HR carrying the gene encoding stilbene synthase (STS) from Vitis vinifera and/or the transcription factor (TF) AtMYB12 from Arabidopsis thaliana, in order to generate a holistic response in the phenylpropanoid pathway and coordinate the up-regulation of multiple metabolic steps. Additionally, an artificial microRNA for chalcone synthase (amiRNA CHS) was utilized to arrest the normal flux through the endogenous chalcone synthase (CHS) enzyme, which would otherwise compete for precursors with the STS enzyme imported for the flux deviation. The transgenic HR were able to biosynthesize the target stilbenes, achieving a production of 40 MUg L-1 of t-R, which was partially metabolized into t-Pn and t-Pt (up to 2.2 MUg L-1 and 86.4 MUg L-1, respectively), as well as its glucoside piceid (up to 339.7 MUg L-1). Major metabolic perturbations were caused by the TF AtMYB12, affecting both primary and secondary metabolism, which confirms the complexity of biotechnological systems based on seed plant in vitro cultures for the heterologous production of high-value molecules. PMID- 29269791 TI - The effect of istradefylline for Parkinson's disease: A meta-analysis. AB - Adenosine A2A receptor antagonists are an alternative treatment strategy for Parkinson's disease. Several randomized placebo controlled studies have tested the effect of A2A receptor antagonist istradefylline, and more robust evidence has been acquired. This meta-analysis aimed to provide evidence for its efficacy and safety on patients with Parkinson's disease. After a systematic literature search, we calculated the pooled standardized mean difference and risk ratio for continuous and dichotomous variables, respectively. Further, sensitivity analyses were performed to confirm the effect estimated by meta-analyses. Publication bias was assessed by funnel plot and deviation of intercept. Six studies satisfied our inclusion criteria. Istradefylline (40 mg/day) decreased off time and improved motor symptoms of Parkinson's disease in homogeneous studies. Istradefylline at 20 mg/day decreased off time and improved motor symptoms, but heterogeneity was found in the analysis of the former among studies. There was a significant effect of istradefylline on dyskinesia in homogeneous studies. Publication bias, however, was observed in the comparison of dyskinesia. Other adverse events showed no significant difference. The present meta-analysis suggests that istradefylline at 40 mg/day could alleviate off time and motor symptoms derived from Parkinson's disease. Dyskinesia might be worsened, but publication bias prevents this from being clear. PMID- 29269792 TI - Corrigendum: Chemical formation of hybrid di-nitrogen calls fungal codenitrification into question. AB - This corrects the article DOI: 10.1038/srep39077. PMID- 29269793 TI - Low-dose donor memory T-cell infusion after TCR alpha/beta depleted unrelated and haploidentical transplantation: results of a pilot trial. AB - Recovery of immunity is delayed in recipients of T-depleted grafts. Adoptive transfer of memory T-cells may improve immune response to common pathogens. A cohort of 53 patients with malignant (n = 36) and non-malignant conditions (n = 17) received TCR alpha/beta depleted grafts from haploidentical (n = 25) or MUD (n = 28) donors. Donor lymphocytes were depleted of CD45RA-positive cells. At a median of 48 days after transplantation, patients received DLI at 25 * 103/kg CD3 cells from haploidentical or 100 * 103/kg CD3 from MUD donors. Up to 3 doses of donor lymphocytes were administered at monthly intervals, escalating to 100 * 103/kg in haploidentical transplants and 300 * 103/kg in MUD transplants. At a median follow-up of 23 months, the cumulative incidence of de novo acute GVHD after DLI is 2% (1 of 43), while the rate of reactivation of preexisting aGVHD was 50% (5 of 10). The transplant-related mortality is 6%. The overall survival rates are 80% and 88% in malignant and non-malignant conditions, respectively. Among patients with absent CMV-specific immune reactivity at baseline (n = 31) expansion of CMV-specific T-cells was demonstrated in 20 (64.5%) within 100 days. Infusions of low dose donor memory T-lymphocytes are safe and constitute a simple measure to prevent infections in the setting of alpha/beta T cell-depleted transplantation. PMID- 29269794 TI - Neuralgic amyotrophy following high-dose melphalan and autologous peripheral blood stem cell transplantation for AL amyloidosis. PMID- 29269795 TI - Impact of prior melphalan exposure on stem cell collection in light chain amyloidosis. AB - Use of melphalan in multiple myeloma was observed to have a deleterious effect on stem cell collection in older studies. There is limited data on the impact of melphalan in light chain (AL) amyloidosis, especially in the plerixafor era. We retrospectively evaluated stem cell mobilization in 610 patients with AL amyloidosis, of which 79 had prior exposure to melphalan, 167 to other chemotherapeutics, while 364 had no chemotherapy exposure. Collection of CD34+ stem cells * 106/kg was lower in the melphalan group. Median total yields in the melphalan, non-melphalan, and no chemotherapy groups were 5.5, 7.7, and 7.8, respectively; p < 0.001. Day-1 yields were 2.7, 3.5, and 4.0 (p = 0.0003), respectively, and median yields per collection were 2.0, 3.3, and 4.0 (p < 0.001), respectively. Similar results were observed in the sub-group analysis after plerixafor was integrated in our collection algorithm (2009). Patients in the melphalan group had higher failure rate of 9% vs. 2% each in the other two groups (p = 0.006). Impact of melphalan was dose-dependent, with cumulative melphalan exposure of >150 mg (median: three cycles) resulting in lower yields. Therefore, duration of melphalan exposure prior to stem cell collection should be limited, ideally, not exceeding more than two cycles of treatment. PMID- 29269796 TI - A prospective study of intravenous pentamidine for PJP prophylaxis in adult patients undergoing intensive chemotherapy or hematopoietic stem cell transplant. AB - Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is recommended for patients undergoing hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy. Trimethoprim-sulfamethoxazole and inhaled pentamidine are used frequently, but are limited, by their tolerability and therefore compliance. Intravenous (IV) pentamidine is a potential alternative agent. Here we conducted the first prospective study of the safety and efficacy of IV pentamidine for PJP prophylaxis in adult patients undergoing HSCT or intensive chemotherapy (clinicaltrials.gov NCT02669706). Fifty patients requiring PJP prophylaxis were enrolled and received monthly IV pentamidine at 4 mg/kg (maximum 300 mg) while undergoing intensive chemotherapy or HSCT. Patients were followed for the occurrence of PJP pneumonia and for adverse events. Satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. There were no grade 3/4 events. The TSQM questionnaire indicated that the majority of patients were satisfied with the administration of IV pentamidine (n = 43, 86%, p = 0.01). There were no cases of PJP during the 24 month follow-up period. Our study illustrates the safety, feasibility, and high degree of patient satisfaction when using IV pentamidine for PJP prophylaxis. PMID- 29269798 TI - Long-term survival following post-allograft relapse of T-cell acute lymphoblastic leukaemia: a novel approach using nelarabine and donor lymphocyte infusions. PMID- 29269797 TI - Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. AB - We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement. PMID- 29269799 TI - Recurrent arthritis and immune reconstitution inflammatory syndrome in hematopoietic stem cell transplantation (HSCT). PMID- 29269800 TI - Tandem autologous-haploidentical transplantation is a feasible and effective program for refractory Hodgkin lymphoma. PMID- 29269801 TI - Deconditioning, fatigue and impaired quality of life in long-term survivors after allogeneic hematopoietic stem cell transplantation. AB - Long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for treatment-related adverse events, that may worsen physical capacity and may induce fatigue and disability. The aims of this prospective study were to evaluate exercise capacity in allotransplant survivors and its relationship with fatigue and disability. Patient-reported outcomes and exercise capacity were evaluated in 71 non-relapse patients 1 year after allo HSCT, using validated questionnaires, cardiopulmonary exercise testing (CPET) with measure of peak oxygen uptake (peakVO2) and deconditioning, pulmonary function testing, echocardiography and 6-min walk test. A high proportion (75.4%) of allo-HSCT survivors showed abnormal cardiopulmonary exercise testing parameters as compared to predicted normal values, including 49.3% patients who exhibited moderate to severe impairment in exercise capacity and 37.7% patients with physical deconditioning. PeakVO2 values were not accurately predicted by 6 min walk distances (r = 0.53). Disability and fatigue were strongly associated with decreased peakVO2 values (p = 0.002 and p = 0.008, respectively). Exercise capacity was reduced in most allo-HSCT long-term survivors. Because reduced exercise capacity was associated with fatigue, disability and a decrease in quality of life, cardiopulmonary exercise testing should be performed in every patient who reports fatigue and disability. PMID- 29269802 TI - Donor derived T-cell large granular lymphocyte leukemia after cord blood transplant for pediatric T-cell lymphoblastic leukemia. PMID- 29269803 TI - Successful hematopoietic stem cell transplantation after myeloablative conditioning in three patients with dedicator of cytokinesis 8 deficiency (DOCK8) related Hyper IgE syndrome. PMID- 29269804 TI - Endocrine complications in patients with transfusion-dependent thalassaemia after haemopoietic stem cell transplantation. PMID- 29269805 TI - Reduction of DMSO concentration in cryopreservation mixture from 10% to 7.5% and 5% has no impact on engraftment after autologous peripheral blood stem cell transplantation: results of a prospective, randomized study. AB - The procedure of autologous peripheral blood stem cell transplantation (autoPBSCT) requires cryopreservation of cells in a mixture containing dimethyl sulfoxide (DMSO). DMSO is necessary to secure cell viability, however, its infusion may be toxic to stem cell recipient. The aim of this study was to prospectively evaluate the impact of DMSO concentration on engraftment after autoPBSCT.One-hundred-fifty patients were randomly assigned to one of three study arms; their leukapheresis products were cryopreserved in 10%, 7.5% or 5% DMSO. The study groups did not differ with regard to the diagnosis (mainly lymphomas and multiple myeloma), age, conditioning regimen, and the number of transplanted hematopoietic stem cells. 143 patients were treated with autoPBSCT. The frequency of adverse effects during and shortly after infusion was the lowest in 5% DMSO arm (p = 0.02 compared to 10% DMSO). 4 patients died due to infection before the engraftment. The median time to leukocyte and neutrophil recovery was 10 days in all study groups (p = 0.36 and p = 0.2). As well, the median day of platelet recovery was the same for all DMSO concentrations and equaled 15 days (p = 0.61).In view of these results, 5% DMSO mixture may be considered a new standard in cryopreservation of hematopoietic stem cells. PMID- 29269806 TI - Reduction of severe acute graft-versus-host disease using a combination of pre transplant anti-thymocyte globulin and post-transplant cyclophosphamide in matched unrelated donor transplantation. PMID- 29269808 TI - Effectiveness and tolerability of first-line autologous stem cell transplant and maintenance rituximab for mantle cell lymphoma. PMID- 29269807 TI - No association between donor telomere length and outcomes after allogeneic unrelated hematopoietic cell transplant in patients with acute leukemia. AB - Recent studies suggest improved survival in patients with severe aplastic anemia receiving hematopoietic cell transplant (HCT) from unrelated donors with longer telomeres. Here, we tested whether this effect is generalizable to patients with acute leukemia. From the Center for International Blood and Marrow Transplant Research (CIBMTR(r)) database, we identified 1097 patients who received 8/8 HLA matched unrelated HCT for acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) between 2004 and 2012 with myeloablative conditioning, and had pre HCT blood sample from the donor in CIBMTR repository. The median age at HCT for recipients was 40 years (range <=1-68), and 32 years for donors (range = 18-61). We used qPCR for relative telomere length (RTL) measurement, and Cox proportional hazard models for statistical analyses. In a discovery cohort of 300 patients, longer donor RTL (>25th percentile) was associated with reduced risks of relapse (HR = 0.62, p = 0.05) and acute graft-versus-host disease II-IV (HR = 0.68, p = 0.05), and possibly with a higher probability of neutrophil engraftment (HR = 1.3, p = 0.06). However, these results did not replicate in two validation cohorts of 297 and 488 recipients. There was one exception; a higher probability of neutrophil engraftment was observed in one validation cohort (HR = 1.24, p = 0.05). In a combined analysis of the three cohorts, no statistically significant associations (all p > 0.1) were found between donor RTL and any outcomes. PMID- 29269809 TI - Access to alternative donor hematopoietic search and transplantation for acute leukemia in different macro-regions of Italy. A GITMO/IBMDR study. AB - Hematopoietic Stem Cell Transplantation activity levels vary across European countries. No data are available on the homogeneity of access to the transplant procedure for patient with leukaemia, within any European country. We measured homogeneity of the rate of alternative donor search in patients affected by acute leukaemia resident in each Italian region and macro-region during years 2010 2013. A total of 2747 alternative donor searches were studied. Twenty-one percent of all donor searches were made through extra-regional migration. Rate of alternative donor searches varied among the country's regions and macro-regions. The rate of donor searches was 38% lower in South Italy than in North Italy, and the rate of alternative donor transplantations performed was 45% lower. A reduced rate of alternative donor search in South macro-region was observed in all age cohorts. Despite the overall allogeneic transplant rate in Italy is relatively high, there are wide regional differences in access to transplant from alternative donor. Extra-regional migration cannot completely compensate for the lower access to transplant of acute leukaemia patients living in those regions where transplant activity is low. PMID- 29269810 TI - Epithelial chimerism in lung tissue after allogeneic hematopoietic stem cell transplantation. PMID- 29269812 TI - Questions and answers in EBD Volume 18. PMID- 29269811 TI - Sleep disruption among cancer patients following autologous hematopoietic cell transplantation. AB - Despite a high prevalence of sleep disruption among hematopoietic cell transplant (HCT) recipients, relatively little research has investigated its relationships with modifiable cognitive or behavioral factors or used actigraphy to characterize sleep disruption in this population. Autologous HCT recipients who were 6-18 months post transplant completed self-report measures of cancer-related distress, fear of cancer recurrence, dysfunctional sleep cognitions, and inhibitory sleep behaviors upon enrollment. Patients then wore an actigraph for 7 days and completed a self-report measure of sleep disruption on day 7 of the study. Among the 84 participants (age M = 60, 45% female), 41% reported clinically relevant sleep disruption. Examination of actigraph data confirmed that, on average, sleep was disrupted (wake after sleep onset M = 66 min) and sleep efficiency was less than recommended (sleep efficiency M = 78%). Cancer related distress, fear of recurrence, dysfunctional sleep cognitions, and inhibitory sleep behaviors were related to self-reported sleep disruption (p values<0.05) but not objective sleep indices. Results suggest that many HCT recipients experience sleep disruption after transplant. Cancer-related distress, fear of recurrence, dysfunctional sleep cognitions, and maladaptive sleep behaviors are related to self-reported sleep disruption and should be considered targets for cognitive behavioral intervention in this population. PMID- 29269813 TI - Early treatment of class III malocclusion with facemask. AB - Data sourcesThe Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, Medline and the ClinicalTrials.gov databases.Study selectionRandomised controlled trials (RCTs) and controlled clinical trials (CCTs) of children aged 7-12 years with class III malocclusion undergoing fixed or removable orthodontic treatment for early correction were included.Data extraction and synthesisTwo reviewers independently selected studies, abstracted data and assessed risk of bias. The Cochrane risk of bias tool was used for RCTs and the Downs and Black and the Newcastle-Ottawa scales for CCTs. The primary outcome was correction of reverse overjet. Mean differences (MD) with 95% confidence intervals were calculated and a random effects meta-analysis conducted.ResultsFifteen studies (nine RCTs, six CCTs) were included. Only three of the RCTs were considered to be at low risk of bias, all six CCTs were at high risk of bias.Three RCTs (141 patients) compared protraction facemask and untreated control. The results for reverse overjet (MD = 2.5 mm; 95% CI, 1.21 3.79) and ANB angle (MD = 3.90; 95% CI, 3.54-4.25) were statistically significant favouring the facemask group. All CCTs demonstrated a statistically significant benefit in favour of the use of each appliance. However, the studies had high risk of bias.ConclusionsThere is a moderate amount of evidence to show that early treatment with a facemask results in positive improvement for both skeletal and dental effects in the short term. However, there was lack of evidence on long term benefits. There is some evidence with regard to the chincup, tandem traction bow appliance and removable mandibular retractor, but the studies had a high risk of bias. Further high-quality, long-term studies are required to evaluate the early treatment effects for Class III malocclusion patients. PMID- 29269814 TI - Topical intra-pocket anaesthetic gel reduces the risk and intensity of pain during periodontal scaling and root planing and probing. AB - Data sourcesMedline, Scopus, Web of Science, LILACS, BBO, Cochrane Library, SIGLE, ProQuest Dissertations and Theses, Periodicos Capes Theses, Current Controlled Trials, International Clinical Trials Registry Platform, the ClinicalTrials.gov, Rebec (www.rebec.gov.br), EU Clinical Trials Register (www.clinicaltrialsregister.eu), abstracts of the annual conference of the International Association for Dental Research (IADR) and its regional divisions. Reference lists of primary studies and related articles from PubMed.Study selectionRandomised controlled trials, parallel, crossover or split-mouth designs comparing intra-pocket anaesthesia with an anaesthetic gel with placebo in patients requiring periodontal probing or SRP were considered.Data extraction and synthesisTwo authors shortlisted 11 final articles based on the inclusion criteria. Data extraction was performed by three authors using customised forms after calibration. The risk of bias in the included studies was evaluated using the Cochrane collaboration tool for assessing risk of bias in randomised controlled trials.1ResultsThe authors used VAS and Heft-Parker scale to measure pain intensity and reported Hedge's g standardised difference in the means. The mean reduction in VAS and Heft-Parker scale were - 0.576 (CI = - 0.94 to - 0.22; p = 0.002) and - 1.814 (CI = - 3.38 to - 0.245; p = 0.023) respectively. This indicates a positive effect of anaesthetic gel in pain intensity reduction. For risk of pain, the authors reported the odds ratio of 0.025 (CI 0.003-0.25; p = 0.002). As far as the need for rescue anaesthesia using the same anaesthetic gel and/or injected anaesthetics, the odds ratio was 0.358 (95% CI 0.174-0.736; p = 0.005). Both these findings show the efficacy of anaesthetic gel in controlling the risk of pain during SRP and probing.ConclusionsThe risk and intensity of pain during probing and SRP as well as the need for additional rescue anaesthesia using the same anaesthetic gel and/or injected anaesthetics is reduced with the application of topical intra-pocket anaesthetic gel. PMID- 29269816 TI - Oral care with chlorhexidine seems effective for reducing the incidence of ventilator-associated pneumonia. AB - Data sourcesElectronic databases searched were Cochrane Oral Health's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline Ovid, Embassy Ovid, LILACS BIREME Virtual Health Library, CINAHL EBSCO, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wan Fang Database and VIP Database ClinicalTrials.gov and the World Health Organisation International Clinical Trials Registry Platform for ongoing trials. No restrictions on language or date of publication.Study selectionRandomised controlled trials (RCTs) were included evaluating OHC in the form of mouthwashes, swabs or toothbrushing or in combination in critically ill patients receiving mechanical ventilation.Data extraction and synthesisTwo reviewers carried out data extraction independently. Study authors were contacted for additional information. Random-effects meta-analyses were performed where data could be pooled.ResultsThirty-eight RCTs (6,016 participants) were included. Five trials (13%) were assessed at low risk of bias, 26 studies (68%) high and seven studies (18%) of unclear risk of bias. There were four main comparisons; chlorhexidine (CHX mouthrinse or gel) versus placebo/usual care, toothbrushing versus no toothbrushing, powered versus manual toothbrushing and comparisons of oral care solutions.Evidence from 18 RCTs (2451 participants, 86% adults) shows that CHX mouthrinse or gel, as part of OHC, reduces the risk of VAP compared to placebo or usual care from 25% to about 19% (RR 0.74, 95% confidence intervals (CI) 0.61 to 0.89, P = 0.002, heterogeneity I2 = 31%). Number needed to treat (NNT) = 17 (95% CI 10 to 33).There is no evidence of a difference between CHX and placebo/usual care for the outcomes of mortality (RR 1.09, 95% CI 0.96 to 1.23, P = 0.18, I2 = 0%, 15 RCTs, 2163 participants, moderate quality evidence), duration of mechanical ventilation (MD -0.09 days, 95% CI -1.73 to 1.55 days, P = 0.91, I2 = 36%, five RCTs, 800 participants, low quality evidence) or duration of intensive care unit (ICU) stay (MD 0.21 days, 95% CI -1.48 to 1.89 days, P = 0.81, I2 = 9%, six RCTs, 833 participants, moderate quality evidence). There is insufficient evidence to determine the effect of CHX on duration of systemic antibiotics, oral health indices, caregivers' preferences or cost. Only two studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.The effect of toothbrushing (+/- antiseptics) is uncertain on the outcomes of VAP (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11, I2 = 64%, five RCTs, 889 participants, very low quality evidence) and mortality (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24, I2 = 0%, five RCTs, 889 participants, low quality evidence) compared to OHC without toothbrushing (+/- antiseptics).There is insufficient evidence to determine whether toothbrushing affects duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, adverse effects, caregivers' preferences or cost.Only one trial (78 participants) compared use of a powered toothbrush with a manual toothbrush, providing insufficient evidence to determine the effect on any of the outcomes of this review.Fifteen trials compared various other oral care solutions. There is very weak evidence that povidone iodine mouthrinse is more effective than saline/placebo (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, three studies, 356 participants, high risk of bias) and that saline rinse is more effective than saline swab (RR 0.47, 95% CI 0.37 to 0.62, P <0.001, I2 = 84%, four studies, 488 participants, high risk of bias) in reducing VAP. Due to variation in comparisons and outcomes among trials, there is insufficient evidence concerning the effects of other oral care solutions.ConclusionsThe results from high quality evidence found that oral hygiene care (OHC), including chlorhexidine mouthwash or gel, reduces the risk of developing ventilator-associated pneumonia in critically ill patients from 25% to about 19%. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay.There is no evidence that OHC including both antiseptics and toothbrushing is different from OHC with antiseptics alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline/placebo, and saline rinse is more effective than saline swab in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. There is also insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects. PMID- 29269817 TI - Compliance with removable orthodontic appliances. AB - Data sourcesMedline via OVID, PubMed, Cochrane Central Register of Controlled Trials, Web of Science Core Collection, LILACS and BBO databases. Unpublished clinical trials accessed using ClinicalTrials.gov, National Research Register, ProQuest Dissertation and Thesis database.Study selectionTwo authors searched studies from inception until May 2016 without language restrictions. Quantitative and qualitative studies incorporating objective data on compliance with removable appliances, barriers to appliance wear compliance, and interventions to improve compliance were included.Data extraction and synthesisQuality of research was assessed using the Cochrane Collaboration's risk of bias tool, the risk of bias in non-randomised studies of interventions (ROBINS-I), and the mixed methods appraisal tool. Statistical heterogeneity was investigated by examining a graphic display of the estimated compliance levels in conjunction with 95% confidence intervals and quantified using the I-squared statistic. A weighted estimate of objective compliance levels for different appliances in relation to stipulated wear and self-reported levels was also calculated. Risk of publication bias was assessed using funnel plots. Meta-regression was undertaken to assess the relative effects of appliance type on compliance levels.ResultsTwenty-four studies met the inclusion criteria. Of these, 11 were included in the quantitative synthesis. The mean duration of objectively measured wear was considerably lower than stipulated wear time amongst all appliances. Headgear had the greatest discrepancy (5.81 hours, 95% confidence interval, 4.98, 6.64). Self reported wear time was consistently higher than objectively measured wear time amongst all appliances. Headgear had the greatest discrepancy (5.02 hours, 95% confidence interval, 3.64, 6.40). Two studies found an increase in compliance with headgear and Hawley retainers when patients were aware of monitoring. Five studies found younger age groups to be more compliant than older groups. Three studies also found compliance to be better in the early stages of treatment. Integration between quantitative and qualitative studies was not possible.ConclusionsCompliance with removable orthodontic appliances is suboptimal. Patients wear appliances for considerably less time than stipulated and self-reported. Compliance may be increased when patients are aware of monitoring; however, further research is required to identify effective interventions and possible barriers in order to improve removable orthodontic appliance compliance. PMID- 29269818 TI - Overdentures may have little impact on nutrient status. AB - Data sourcesData sources Medline, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL).Study selectionRandomised control trials (RCTs), cohort study or case control studies involving prosthetic treatment where the outcomes included change in intakes of macronutrients (ie proteins, fats and carbohydrates) and/or micronutrients (eg vitamins and calcium) and/or indicators for nutritional status were considered.Data extraction and synthesisTwo reviewers independently screened the studies, with one reviewer abstracting data for checking by a second reviewer. Risk of bias was assessed independently by two reviewers using the Cochrane risk of bias tool. A fixed effects model was used to estimate the weighted mean difference (WMD) and 95% CI for change in body mass index (BMI), albumin and serum vitamin B12 between overdenture and conventional denture six months after treatment.ResultsEight studies (six RCTs and two prospective cohort studies) involving a total of 901 patients were included in a narrative synthesis. Three RCTs (322 patients) contributed to a meta-analysis suggesting no significant difference in change in BMI between an overdenture and conventional denture six months after treatment WMD= -0.18 kg/m2 (95%CI; -0.52 to 0.16), and no significant difference in change in albumin or vitamin B12 between the two treatments.ConclusionsThe modifying effect of overdenture treatment on nutritional status might be limited. Further studies are needed to evaluate the effectiveness and efficacy of denture treatments. PMID- 29269819 TI - No difference in the long-term clinical performance of direct and indirect inlay/onlay composite restorations in posterior teeth. AB - Data sourcesMedline, Embase, the Cochrane Oral Health Group's Trials Register and CENTRAL. Unpublished literature was searched on ClinicalTrials.gov, the National Research Register, and Pro-Quest Dissertation Abstracts and Thesis database. Hand searching of reference lists only.Study selectionRandomised controlled trials with a minimum of three years follow-up that compared direct to indirect inlays or onlays in posterior teeth. Primary outcome was failure (the need to replace or repair).Data extraction and synthesisTwo reviewers independently and in duplicate performed the study selection and two extracted data independently using a customised data extraction form. The unit of analysis was the restored tooth. Risk of bias was assessed using the Cochrane Risk of Bias tool. Meta-analysis was conducted on two studies using the random-effects model.ResultsThree studies were included. Across these studies there were 239 participants in whom 424 restorations were placed. Two studies compared direct and indirect inlays and had follow-up of five and 11 years respectively. One study compared direct and indirect onlays with a follow-up of five years. The studies were at unclear or high risk of bias. For direct and indirect inlays, Relative Risk (RR) of failure after five years was 1.54 (95% Cl: 0.42, 5.58; p = 0.52) in one study and, in another was 0.95 (95% Cl: 0.34, 2.63; p = 0.92) over 11 years. For onlays there was also no statistically-significant difference in survival, though overall five year survival was 87% (95% CI: 81-93%).ConclusionsThere is insufficient evidence to favour the direct or indirect technique for the restoration of posterior teeth with inlays and onlays. PMID- 29269820 TI - No clear evidence on the clinical performance of different removable prosthetic options in partially edentulous patients. AB - Data sourcesMedline/PubMed, Embase, BIOSIS/Ovid, SciSearch/DIMDI, Cochrane library, FIZ Technik Web and hand searches of the journals; Clinical Oral Investigations, International Journal of Prosthodontics, Journal of Prosthetic Dentistry, Deutsche Zahnarztliche Zeitschrift, Swiss Dental Journal, Journal of Dentistry and the Journal of Dental Research.Study selectionRandomised controlled trials, prospective and retrospective studies on survival rates of removable dental prostheses in the moderately reduced dentition with at least 15 participants having an observation period of at least two years, and a dropout rate of less than 25% were considered.Data extraction and synthesisTwo reviewers abstracted data. A qualitative summary of the included studies was carried out. Studies providing data that permitted a Kaplan-Meier analysis were included in meta-analysis.ResultsThe review included 19 studies, six of which were in multiple publications. Cast-metal framework dentures showed failure rates of 33% and 50% after five years. One study with a 25-year observation period reported failure rates of 50%. Proper pretreatment and a good recall scheme improve the results. Bilateral attachment prostheses showed failure rates of 11% and 30% after five years. Unilateral attachment prostheses showed failure rates of 75% after five years. Double-crown prostheses dentures show failure rates of 0% to 21.7% after three to six years.ConclusionsWithin the limitations of this study, it seems that removable partial dentures, (RPD), given suitable pretreatment and follow-up regimes, can provide a satisfactory treatment option. Based on only one paper, they revealed acceptable results even over a very long observation period (25 years). PMID- 29269821 TI - Which adhesive strategy for non-carious cervical lesions? AB - Data sourcesMedline, Scopus, Web of Science, Latin American and Caribbean Health Sciences Literature database (LILACS), Brazilian Library in Dentistry (BBO), Cochrane Library, System for Information on Grey literature in Europe (SIGLE), ProQuest Dissertations and Theses, Periodicos Capes Theses database, Current Controlled Trials (www.controlled-trials.com), International Clinical trials registry platform (http://apps.who.int/trialsearch/), the ClinicalTrials.gov (www.clinicaltrials.gov), Rebec (www.rebec.gov.br) and EU Clinical Trials Register (https://www.clinicaltrialsregister.eu), abstracts of the annual conference of the International Association for Dental Research (IADR) and their regional divisions.Study selectionTwo reviewers selected studies; parallel or split-mouth randomised controlled trials (RCTs) comparing adhesive strategies were considered.Data extraction and synthesisData were abstracted by two reviewers and into four follow up periods, 1 year; 18 months to 2 years; 3 years and 4 to 5 years. The Cochrane risk of bias tool was used to assess study quality. Data outcomes were dichotomous and summarised using relative risks and random effects meta-analysis.ResultsTwenty-nine studies were included in the meta analysis. Bonding strategy did not influence postoperative sensitivity (risk ratio [RR] 1.04; 95% CI 0.81 to 1.34) or retention rates (RR = 1.04; 95% CI 0.81 to 1.34). The etch-and-rinse approach produced less marginal discoloration at 18 months to 2 years (RR 1.51; 95% CI 1.21 to 1.90) and at 4 to 5 years (RR 1.81; 95% CI 1.28 to 2.55) (p<0.0007).ConclusionsComposite resin restorations placed with self-etch and etch-and-rinse adhesives produce restoration with similar clinical service and POS, however using etch-and-rinse adhesives one can reduce marginal discoloration. PMID- 29269822 TI - Fixed and removable orthodontic retainers and periodontal health. AB - Data sourcesMedline, PubMed, Cochrane Central Register of Controlled Trials, LILACS and BBO databases with no language restrictions; unpublished literature was searched in Proquest Dissertations and Theses database, clinicaltrials.gov and controlled-trials.com.Study selectionRandomised and nonrandomised controlled clinical trials, prospective cohort studies, and case series (with a minimum sample size of 20 patients) in patients who underwent fixed or removable appliance orthodontic therapy with a minimum follow-up period of six months. The primary outcome was periodontal health; while failure rates, impact of orthodontic retainers on patient-reported outcomes and cost-effectiveness served as secondary outcomes.Data extraction and synthesisFull texts of relevant abstracts were retrieved and data extracted using pre-piloted data collection forms by two authors. Study quality was assessed with Cochrane Collaboration's Risk of Bias tool (RCTs) and Newcastle-Ottawa Scale (NOS) for non-randomised studies. Only RCTs at low or unclear risk of bias and non-randomised studies of moderate or high methodological quality were included in the meta-analysis (MA). If moderate to high heterogeneity was present (I2 > 50%), MA was not performed.ResultsOut of the 18 included RCTs, 11 were assessed to be of low risk of bias while five out of six prospective cohort studies were considered high quality using the NOS. The authors did not perform MA because of significant heterogeneity that existed among different studies.With regards to periodontal health, there was no significant difference in probing depth and bleeding on probing between fixed mandibular stainless steel (SS) retainers (bonded to anterior teeth or canines only), fibre reinforced composite retainers or Hawley retainers at three-year follow-up. However, there was increased plaque accumulation around fibre reinforced composite retainers compared to SS retainers. The failure rates of mandibular stainless steel fixed retainers bonded from canine to canine was 0.29 (95 % confidence interval [CI], 0.26, 0.33) over a follow-up period of six to 36 months. The failure risk for mandibular stainless steel fixed retainers bonded to canines only was 0.25 (CI, 0.16, 0.33) over a follow-up period of one to three years. A meta-regression showed that follow-up period was not a predictor of failure rate for mandibular stainless steel fixed retainers. The failure rates of removable retainers (Hawley's or vacuum formed retainers) are lower than the bonded fixed retainers. Removable Hawley's retainer was associated with increased discomfort as well as higher levels of embarrassment with speech and aesthetics. In terms of cost-effectiveness, vacuum formed retainers were found to be significantly more cost-effective than Hawley retainers or mandibular stainless steel fixed retainers bonded to canines.ConclusionsThere is a lack of high-quality evidence to endorse the use of one type of orthodontic retainer based on their effect on periodontal health, risk of failure, patient-reported outcomes and cost-effectiveness. PMID- 29269824 TI - Are there more adverse effects with lingual orthodontics? AB - Data sourcesPubMed, Embase, Cochrane Library and LILACS database, review of references cited in included articles and a manual search of leading orthodontic journals. No language restrictions were imposed in the search. Study authors were contacted when necessary.Study selectionRandomised controlled trials (RCTs) and controlled clinical trials (CCTs) in healthy patients that directly compared the adverse effects following treatment using buccal and lingual appliances. Studies involving single arch or dual arch appliances were considered. Studies on patients with systemic diseases, animal studies and in vitro studies were excluded. The primary outcomes of interest to the authors were a list of adverse effects: pain, caries, eating and speech difficulties and oral hygiene.Data extraction and synthesisTwo authors reviewed the titles and abstracts of all studies identified through the search without blinding to names of authors or publication dates. Selected articles from searches were evaluated independently by two authors against established inclusion criteria, disagreements were resolved by consensus or by consulting a third author. Two authors independently assessed the risk of bias using the Cochrane Collaboration's tool (randomised trials) and the Newcastle-Ottawa Scale for non-randomised studies. The level of agreement between the authors was assessed using the Cohen kappa statistic. A meta-analysis was performed to provide pooled effect estimate (expressed as odds ratio) as well as 95% confidence interval. The outcomes of interest were pain, caries, eating difficulties, speech difficulties and deficient oral hygiene. Heterogeneity was quantified using I2 statistic and potential causes explored. Publication bias was assessed using a funnel plot.ResultsEight articles were included; three RCTs and five CCTs. One RCT was considered to be at high risk of bias, one moderate risk and one low risk. Of the non-randomised studies, four were low risk and one was high risk of bias. Six studies involving a total of 131 patients were included in a meta-analysis. The lingual appliance was associated with significant pain in the tongue (OR=28.32, 95% CI 8.6-93.28), difficulty in maintaining oral hygiene (OR=3.49, 95%CI 1.02-11.95) and greater speech difficulty (OR = 9.39, 95% CI 3.78-23.33) compared to buccal appliances. On the other hand, patients with lingual appliances had decreased pain in the lips and cheeks. There was no difference between the two appliances with regards to caries risk.ConclusionsLimited available evidence indicates that lingual orthodontic appliances are associated with increased pain in the tongue, speech difficulties and difficulty in maintaining oral hygiene. PMID- 29269825 TI - Limited evidence shows short-term benefit of probiotics when used as an adjunct to scaling and root planing in the treatment of chronic periodontitis. AB - Data sourcesMedline, Cochrane Central Register of Controlled Trials and Science Direct databases. Hand searches of the Journal of Clinical Periodontology, Journal of Periodontology, Journal of Periodontal Research, Journal of Dental Researc h and reference searches of the included articles and related reviews.Study selectionTwo authors independently screened the literature to identify relevant randomised controlled trials (RCTs) on patients with chronic periodontitis (CP) treated with SRP and probiotic, SRP and placebo or SRP alone, with pocket probing depth (PPD) as the primary outcome. No minimum follow-up period was set for study inclusion.Data extraction and synthesisRisk of bias assessment was done independently using the Cochrane tool. Data were extracted using a predefined form. Weighted mean differences and 95% confidence intervals were calculated and meta-analysis conducted using fixed and random effects models.ResultsThree of the four included studies were included for meta-analysis. All three studies showed significant heterogeneity though they were rated as having low risk of bias. The number of patients ranged between 30 and 40 and follow-up duration ranged between 42 and 360 days amongst these studies. The reported primary outcomes were PPD and clinical attachment level (CAL); bleeding on probing, gingival index, gingival bleeding index, need for surgery and risk of disease progression were reported as secondary outcomes.Overall, the authors did not find a statistically significant reduction in PPD [-0.46mm, (-0.95, 0.02; p = 0.06)] in the probiotic group. However, when pockets were stratified as moderate and deep pockets, probiotic group showed significant reduction in PPD in moderate [0.18, (-0.28, -0.07; p = 0.01)] and deep pockets [-0.67, (-0.85, -0.49; p<0.001)]. The overall CAL gain [-0.42mm (-0.68, -0.16; p = 0.002)] and reduction in BOP [-14.66% (-24.49, -4.83; p = 0.003)] were significant in the probiotic group short-term.ConclusionsThe meta-analysis shows some beneficial effect of Lactobacillus reuteri with reduction of PPD especially in deep periodontal pockets, CAL gain was similar to other adjuncts.1, 2 However, studies with larger number of patients and longer-term follow-up are needed to confirm these findings. PMID- 29269826 TI - Communicating the Evidence. PMID- 29269827 TI - Long-lived efficient delayed fluorescence organic light-emitting diodes using n type hosts. AB - Organic light-emitting diodes have become a mainstream display technology because of their desirable features. Third-generation electroluminescent devices that emit light through a mechanism called thermally activated delayed fluorescence are currently garnering much attention. However, unsatisfactory device stability is still an unresolved issue in this field. Here we demonstrate that electron transporting n-type hosts, which typically include an acceptor moiety in their chemical structure, have the intrinsic ability to balance the charge fluxes and broaden the recombination zone in delayed fluorescence organic electroluminescent devices, while at the same time preventing the formation of high-energy excitons. The n-type hosts lengthen the lifetimes of green and blue delayed fluorescence devices by > 30 and 1000 times, respectively. Our results indicate that n-type hosts are suitable to realize stable delayed fluorescence organic electroluminescent devices. PMID- 29269828 TI - Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway. AB - Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway. PMID- 29269829 TI - Factoring economic costs into conservation planning may not improve agreement over priorities for protection. AB - Conservation organizations must redouble efforts to protect habitat given continuing biodiversity declines. Prioritization of future areas for protection is hampered by disagreements over what the ecological targets of conservation should be. Here we test the claim that such disagreements will become less important as conservation moves away from prioritizing areas for protection based only on ecological considerations and accounts for varying costs of protection using return-on-investment (ROI) methods. We combine a simulation approach with a case study of forests in the eastern United States, paying particular attention to how covariation between ecological benefits and economic costs influences agreement levels. For many conservation goals, agreement over spatial priorities improves with ROI methods. However, we also show that a reliance on ROI-based prioritization can sometimes exacerbate disagreements over priorities. As such, accounting for costs in conservation planning does not enable society to sidestep careful consideration of the ecological goals of conservation. PMID- 29269830 TI - Preliminary study of confounding factors of elastography and the application of fine-needle aspiration in thyroid nodules with indeterminate elastography. AB - To investigate confounding factors of real-time ultrasound elastography (RTE) and to evaluate the diagnostic performance of ultrasound (US)-guided FNA for thyroid nodules with indeterminate elastography compared with conventional US. This study included 244 nodules with indeterminate elastography caused by several confounding factors (large or small size, deep location, isthmic or paratracheal location, calcification, thyroiditis, conflicting results between conventional US and RTE), and corresponding prevalences of malignancy were calculated. Additionally, conventional US and US-FNA data were collected and compared. The prevalences of malignancy of confounding factors were 74.1%, 75.0%, 73.3%, 46.2%, 27.3%, and 53.2%, respectively. Sonographic features (border, margin, echogenicity, echohomogeneity, and microcalcification) were significantly different between benign and malignant thyroid nodules (p < 0.05), and most of them exhibited good sensitivity but unsatisfactory specificity and accuracy. While US-FNA exhibited better performance with a sensitivity of 96.9%, a specificity of 99.1% and an accuracy of 98.0% in the diagnosis of malignancy. Given that indeterminate RTE is inevitable with a rather high malignant risk due to several confounding factors, our study revealed that US-FNA was a valuable tool in nodules with indeterminate elastography by increasing the detection rate of thyroid malignancy. PMID- 29269831 TI - Disposable aptamer-sensor aided by magnetic nanoparticle enrichment for detection of salivary cortisol variations in obstructive sleep apnea patients. AB - We report a disposable point-of-care sensing platform specific to salivary cortisol detection. The sensor is inkjet printed on a paper substrate with a metalloporphyrin based macrocyclic catalyst ink that can electrochemically reduce cortisol, captured by aptamer functionalized magnetic nanoparticles. The sensor consists of a thin magnet disc, aligned at the back of the electrode, in order to populate the magnetic nanoparticle bound cortisol at the sensing electrode area. Proof of concept studies were performed to detect salivary cortisol levels in human subjects with high and low risks for obstructive sleep apnea (OSA). High selectivity was observed to salivary cortisol against a background of closely related steroids. PMID- 29269832 TI - Decision-making in plants under competition. AB - Plants can plastically respond to light competition in three strategies, comprising vertical growth, which promotes competitive dominance; shade tolerance, which maximises performance under shade; or lateral growth, which offers avoidance of competition. Here, we test the hypothesis that plants can 'choose' between these responses, according to their abilities to competitively overcome their neighbours. We study this hypothesis in the clonal plant Potentilla reptans using an experimental setup that simulates both the height and density of neighbours, thus presenting plants with different light-competition scenarios. Potentilla reptans ramets exhibit the highest vertical growth under simulated short-dense neighbours, highest specific leaf area (leaf area/dry mass) under tall-dense neighbours, and tend to increase total stolon length under tall sparse neighbours. These responses suggest shifts between 'confrontational' vertical growth, shade tolerance and lateral-avoidance, respectively, and provide evidence that plants adopt one of several alternative plastic responses in a way that optimally corresponds to prevailing light-competition scenarios. PMID- 29269833 TI - Elucidating the major hidden genomic components of the A, C, and AC genomes and their influence on Brassica evolution. AB - Decoding complete genome sequences is prerequisite for comprehensive genomics studies. However, the currently available reference genome sequences of Brassica rapa (A genome), B. oleracea (C) and B. napus (AC) cover 391, 540, and 850 Mbp and represent 80.6, 85.7, and 75.2% of the estimated genome size, respectively, while remained are hidden or unassembled due to highly repetitive nature of these genome components. Here, we performed the first comprehensive genome-wide analysis using low-coverage whole-genome sequences to explore the hidden genome components based on characterization of major repeat families in the B. rapa and B. oleracea genomes. Our analysis revealed 10 major repeats (MRs) including a new family comprising about 18.8, 10.8, and 11.5% of the A, C and AC genomes, respectively. Nevertheless, these 10 MRs represented less than 0.7% of each assembled reference genome. Genomic survey and molecular cytogenetic analyses validates our insilico analysis and also pointed to diversity, differential distribution, and evolutionary dynamics in the three Brassica species. Overall, our work elucidates hidden portions of three Brassica genomes, thus providing a resource for understanding the complete genome structures. Furthermore, we observed that asymmetrical accumulation of the major repeats might be a cause of diversification between the A and C genomes. PMID- 29269834 TI - Water quality assessment based on the water quality index method in Lake Poyang: The largest freshwater lake in China. AB - Twenty-four samplings were conducted every 3 months at 15 sites from January 2009 to October 2014 in Lake Poyang, and 20 parameters were analyzed and classified into three groups (toxic metals, easily treated parameters, and others). The assessment results based on water quality index (WQI) showed that the water quality in Lake Poyang was generally "moderate", according to the classification of the surface water quality standard (GB3838-2002) in China, but a deteriorating trend was observed at the interannual scale. Seasonally, the water quality was best in summer and worst in winter. Easily treated parameters generally determined the WQI value in the assessment, especially total nitrogen (TN) and total phosphorus (TP), while toxic metals and other parameters in Lake Poyang were generally at low and safe levels for drinking water. Water level (WL) has a net positive effect on water quality in Lake Poyang through dilution of environmental parameters, which in practice means TN. Consequently, local management agencies should pay more attention to nutrient concentrations during the monitoring schedule, as well as during the low-water periods which manifest a relatively bad water quality state, especially with the prevailing low WL observed recently in Lake Poyang. PMID- 29269835 TI - Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. AB - Protein:protein interactions are among the most difficult to treat molecular mechanisms of disease pathology. Cystine-dense peptides have the potential to disrupt such interactions, and are used in drug-like roles by every clade of life, but their study has been hampered by a reputation for being difficult to produce, owing to their complex disulfide connectivity. Here we describe a platform for identifying target-binding cystine-dense peptides using mammalian surface display, capable of interrogating high quality and diverse scaffold libraries with verifiable folding and stability. We demonstrate the platform's capabilities by identifying a cystine-dense peptide capable of inhibiting the YAP:TEAD interaction at the heart of the oncogenic Hippo pathway, and possessing the potency and stability necessary for consideration as a drug development candidate. This platform provides the opportunity to screen cystine-dense peptides with drug-like qualities against targets that are implicated for the treatment of diseases, but are poorly suited for conventional approaches. PMID- 29269838 TI - Micro-patterned agarose gel devices for single-cell high-throughput microscopy of E. coli cells. AB - High-throughput microscopy of bacterial cells elucidated fundamental cellular processes including cellular heterogeneity and cell division homeostasis. Polydimethylsiloxane (PDMS)-based microfluidic devices provide advantages including precise positioning of cells and throughput, however device fabrication is time-consuming and requires specialised skills. Agarose pads are a popular alternative, however cells often clump together, which hinders single cell quantitation. Here, we imprint agarose pads with micro-patterned 'capsules', to trap individual cells and 'lines', to direct cellular growth outwards in a straight line. We implement this micro-patterning into multi-pad devices called CapsuleHotel and LineHotel for high-throughput imaging. CapsuleHotel provides ~65,000 capsule structures per mm2 that isolate individual Escherichia coli cells. In contrast, LineHotel provides ~300 line structures per mm that direct growth of micro-colonies. With CapsuleHotel, a quantitative single cell dataset of ~10,000 cells across 24 samples can be acquired and analysed in under 1 hour. LineHotel allows tracking growth of > 10 micro-colonies across 24 samples simultaneously for up to 4 generations. These easy-to-use devices can be provided in kit format, and will accelerate discoveries in diverse fields ranging from microbiology to systems and synthetic biology. PMID- 29269836 TI - A gradient relationship between low birth weight and IQ: A meta-analysis. AB - Multiple studies have reported that individuals with low birth weights (LBW, <2500 g) have a lower intelligence quotient (IQ) than those with normal birth weights (NBW, >=2500 g). Based on 57 eligible individual studies including 12,137 participants, we performed a meta-analysis to estimate the association between low birth weight and individuals' IQ scores (IQs). The pooled weight mean difference (WMD) in IQs between NBW and LBW individuals was 10 (95% CI 9.26 11.68). The WMD was stable regardless of age. No publication bias was detected. The mean IQs of the extremely low birth weight (ELBW, <1000 g), very low birth weight (VLBW, 1000-1499 g), moderately low birth weight (MLBW, 1500-2499 g) and NBW individuals were 91, 94, 99 and 104, respectively. Additionally, the WMD in IQs with NBW were 14, 10 and 7 for ELBW, VLBW, and MLBW individuals, respectively. Two studies permitted estimates of the influence of social determinants of health to the discrepancy in IQs, which was 13%. Since IQ is inherited and influenced by environmental factors, parental IQs and other factors contribute to residual confounding of the results. As the conclusion was based on population studies, it may not be applicable to a single individual. PMID- 29269837 TI - QTL analysis of cocoon shell weight identifies BmRPL18 associated with silk protein synthesis in silkworm by pooling sequencing. AB - Mechanisms that regulate silk protein synthesis provide the basis for silkworm variety breeding and silk gland bioreactor optimization. Here, using the pooling sequencing-based methodology, we deciphered the genetic basis for the varied silk production in different silkworm strains. We identified 8 SNPs, with 6 on chromosome 11 and 1 each on chromosomes 22 and 23, that were linked with silk production. After conducting an association analysis between gene expression pattern, silk gland development and cocoon shell weight (CSW), BMGN011620 was found to be regulating silk production. BMGN011620 encodes the 60S ribosomal protein, L18, which is an indispensable component of the 60S ribosomal subunit; therefore we named it BmRPL18. Moreover, the clustering of linked SNPs on chromosome 11 and the analysis of differentially expressed genes reported in previous Omics studies indicated that the genes regulating silk protein synthesis may exhibit a clustering distribution in the silkworm genome. These results collectively advance our understanding of the regulation of silk production, including the role of ribosomal proteins and the clustered distribution of genes involved in silk protein synthesis. PMID- 29269839 TI - Unforeseen swimming and gliding mode of an insect gut symbiont, Burkholderia sp. RPE64, with wrapping of the flagella around its cell body. AB - A bean bug symbiont, Burkholderia sp. RPE64, selectively colonizes the gut crypts by flagella-mediated motility: however, the mechanism for this colonization remains unclear. Here, to obtain clues to this mechanism, we characterized the swimming motility of the Burkholderia symbiont under an advanced optical microscope. High-speed imaging of cells enabled the detection of turn events with up to 5-ms temporal resolution, indicating that cells showed reversal motions (theta ~ 180 degrees ) with rapid changes in speed by a factor of 3.6. Remarkably, staining of the flagellar filaments with a fluorescent dye Cy3 revealed that the flagellar filaments wrap around the cell body with a motion like that of a ribbon streamer in rhythmic gymnastics. A motility assay with total internal reflection fluorescence microscopy revealed that the left-handed flagellum wound around the cell body and propelled it forward by its clockwise rotation. We also detected periodic-fluorescent signals of flagella on the glass surface, suggesting that flagella possibly contacted the solid surface directly and produced a gliding-like motion driven by flagellar rotation. Finally, the wrapping motion was also observed in a symbiotic bacterium of the bobtail squid, Aliivibrio fischeri, suggesting that this motility mode may contribute to migration on the mucus-filled narrow passage connecting to the symbiotic organ. PMID- 29269840 TI - Leukocyte-Associated Immunoglobulin-like Receptor-1 is regulated in human myocardial infarction but its absence does not affect infarct size in mice. AB - Heart failure after myocardial infarction (MI) depends on infarct size and adverse left ventricular (LV) remodelling, both influenced by the inflammatory response. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor of ITAM-dependent cell activation, present on almost all immune cells. We investigated regulation of LAIR-1 leukocyte expression after MI in patients and hypothesized that its absence in a mouse model of MI would increase infarct size and adverse remodelling. In patients, LAIR-1 expression was increased 3 days compared to 6 weeks after MI on circulating monocytes (24.8 +/- 5.3 vs. 21.2 +/- 5.1 MFI, p = 0.008) and neutrophils (12.9 +/- 4.7 vs. 10.6 +/- 3.1 MFI, p = 0.046). In WT and LAIR-1-/- mice, infarct size after ischemia reperfusion injury was comparable (37.0 +/- 14.5 in WT vs. 39.4 +/- 12.2% of the area at risk in LAIR-1-/-, p = 0.63). Remodelling after permanent left coronary artery ligation did not differ between WT and LAIR-1-/- mice (end-diastolic volume 133.3 +/- 19.3 vs. 132.1 +/- 27.9 MUL, p = 0.91 and end-systolic volume 112.1 +/- 22.2 vs. 106.9 +/- 33.5 MUL, p = 0.68). Similarly, no differences were observed in inflammatory cell influx or fibrosis. In conclusion, LAIR-1 expression on monocytes and neutrophils is increased in the acute phase after MI in patients, but the absence of LAIR-1 in mice does not influence infarct size, inflammation, fibrosis or adverse cardiac remodelling. PMID- 29269841 TI - Burst intensification by singularity emitting radiation in multi-stream flows. AB - Burst Intensification by Singularity Emitting Radiation (BISER) is proposed. Singularities in multi-stream flows of emitting media cause constructive interference of emitted travelling waves, forming extremely localized sources of bright coherent emission. Here we for the first time demonstrate this extreme localization of BISER by direct observation of nano-scale coherent x-ray sources in a laser plasma. The energy emitted into the spectral range from 60 to 100 eV is up to ~100 nJ, corresponding to ~1010 photons. Simulations reveal that these sources emit trains of attosecond x-ray pulses. Our findings establish a new class of bright laboratory sources of electromagnetic radiation. Furthermore, being applicable to travelling waves of any nature (e.g. electromagnetic, gravitational or acoustic), BISER provides a novel framework for creating new emitters and for interpreting observations in many fields of science. PMID- 29269842 TI - Using newborn screening analytes to identify cases of neonatal sepsis. AB - Neonatal sepsis is associated with high mortality and morbidity, yet challenges with available diagnostic approaches can lead to delays in therapy. Our study assessed whether newborn screening analytes could be utilized to identify associations with neonatal sepsis. We linked a newborn screening registry with health databases to identify cases of sepsis among infants born in Ontario from 2010-2015. Correlations between sepsis and screening analytes were examined within three gestational age groups (early preterm: <34 weeks; late preterm: 34 36 weeks; term: >=37 weeks), using multivariable logistic regression models. We started with a model containing only clinical factors, then added groups of screening analytes. Among 793,128 infants, 4,794 were diagnosed with sepsis during the neonatal period. Clinical variables alone or in combination with hemoglobin values were not strongly predictive of neonatal sepsis among infants born at term or late preterm. However, model fit improved considerably after adding markers of thyroid and adrenal function, acyl-carnitines, and amino acids. Among infants born at early preterm gestation, neither clinical variables alone nor models incorporating screening analytes adequately predicted neonatal sepsis. The combination of clinical variables and newborn screening analytes may have utility in identifying term or late preterm infants at risk for neonatal sepsis. PMID- 29269843 TI - Application of Fourier transform infrared spectroscopy with chemometrics on postmortem interval estimation based on pericardial fluids. AB - Postmortem interval (PMI) evaluation remains a challenge in the forensic community due to the lack of efficient methods. Studies have focused on chemical analysis of biofluids for PMI estimation; however, no reports using spectroscopic methods in pericardial fluid (PF) are available. In this study, Fourier transform infrared (FTIR) spectroscopy with attenuated total reflectance (ATR) accessory was applied to collect comprehensive biochemical information from rabbit PF at different PMIs. The PMI-dependent spectral signature was determined by two dimensional (2D) correlation analysis. The partial least square (PLS) and nu support vector machine (nu-SVM) models were then established based on the acquired spectral dataset. Spectral variables associated with amide I, amide II, COO-, C-H bending, and C-O or C-OH vibrations arising from proteins, polypeptides, amino acids and carbohydrates, respectively, were susceptible to PMI in 2D correlation analysis. Moreover, the nu-SVM model appeared to achieve a more satisfactory prediction than the PLS model in calibration; the reliability of both models was determined in an external validation set. The study shows the possibility of application of ATR-FTIR methods in postmortem interval estimation using PF samples. PMID- 29269845 TI - Morphological stabilization and KPZ scaling by electrochemically induced co deposition of nanostructured NiW alloy films. AB - We have assessed the stabilizing role that induced co-deposition has in the growth of nanostructured NiW alloy films by electrodeposition on polished steel substrates, under pulsed galvanostatic conditions. We have compared the kinetic roughening properties of NiW films with those of Ni films deposited under the same conditions, as assessed by Atomic Force Microscopy. The surface morphologies of both systems are super-rough at short times, but differ at long times: while a cauliflower-like structure dominates for Ni, the surfaces of NiW films display a nodular morphology consistent with more stable, conformal growth, whose height fluctuations are in the Kardar-Parisi-Zhang universality class of rough two dimensional interfaces. These differences are explained by the mechanisms controlling surface growth in each case: mass transport through the electrolyte (Ni) and attachment of the incoming species to the growing interface (NiW). Thus, the long-time conformal growth regime is characteristic of electrochemical induced co-deposition under current conditions in which surface kinetics is hindered due to a complex reaction mechanism. These results agree with a theoretical model of surface growth in diffusion-limited systems, in which the key parameter is the relative importance of mass transport with respect to the kinetics of the attachment reaction. PMID- 29269844 TI - Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function. AB - Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu3 induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu3-LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu3-LTD following a single, 20 min restraint stress exposure. Finally, blocking mGlu3 activation in vivo prevented the stress-induced maladaptive changes to amydalo-cortical physiology and motivated behavior. These data demonstrate that mGlu3 mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu3 modulation as a treatment for stress-related psychiatric disorders. PMID- 29269846 TI - Modeling and prediction of copper removal from aqueous solutions by nZVI/rGO magnetic nanocomposites using ANN-GA and ANN-PSO. AB - Reduced graphene oxide-supported nanoscale zero-valent iron (nZVI/rGO) magnetic nanocomposites were prepared and then applied in the Cu(II) removal from aqueous solutions. Scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy and superconduction quantum interference device magnetometer were performed to characterize the nZVI/rGO nanocomposites. In order to reduce the number of experiments and the economic cost, response surface methodology (RSM) combined with artificial intelligence (AI) techniques, such as artificial neural network (ANN), genetic algorithm (GA) and particle swarm optimization (PSO), has been utilized as a major tool that can model and optimize the removal processes, because a tremendous advance has recently been made on AI that may result in extensive applications. Based on RSM, ANN-GA and ANN-PSO were employed to model the Cu(II) removal process and optimize the operating parameters, e.g., operating temperature, initial pH, initial concentration and contact time. The ANN-PSO model was proven to be an effective tool for modeling and optimizing the Cu(II) removal with a low absolute error and a high removal efficiency. Furthermore, the isotherm, kinetic, thermodynamic studies and the XPS analysis were performed to explore the mechanisms of Cu(II) removal process. PMID- 29269847 TI - Biodegradation of weathered polystyrene films in seawater microcosms. AB - A microcosm experiment was conducted at two phases in order to investigate the ability of indigenous consortia alone or bioaugmented to degrade weathered polystyrene (PS) films under simulated marine conditions. Viable populations were developed on PS surfaces in a time dependent way towards convergent biofilm communities, enriched with hydrocarbon and xenobiotics degradation genes. Members of Alphaproteobacteria and Gammaproteobacteria were highly enriched in the acclimated plastic associated assemblages while the abundance of plastic associated genera was significantly increased in the acclimated indigenous communities. Both tailored consortia efficiently reduced the weight of PS films. Concerning the molecular weight distribution, a decrease in the number-average molecular weight of films subjected to microbial treatment was observed. Moreover, alteration in the intensity of functional groups was noticed with Fourier transform infrared spectrophotometry (FTIR) along with signs of bio erosion on the PS surface. The results suggest that acclimated marine populations are capable of degrading weathered PS pieces. PMID- 29269848 TI - Thromboembolic and neurologic sequelae of discontinuation of an antihyperlipidemic drug during ongoing warfarin therapy. AB - Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit warfarin deactivation via the hepatic cytochrome P450 system. Therefore, antihyperlipidemic discontinuation has been hypothesized to result in underanticoagulation, as warfarin metabolism is no longer inhibited. We quantified the risk of venous thromboembolism (VTE) and ischemic stroke (IS) due to statin and fibrate discontinuation in warfarin users, in which warfarin was initially dose-titrated during ongoing antihyperlipidemic therapy. Using 1999 2011 United States Medicaid claims among 69 million beneficiaries, we conducted a set of bidirectional self-controlled case series studies-one for each antihyperlipidemic. Outcomes were hospital admissions for VTE/IS. The risk segment was a maximum of 90 days immediately following antihyperlipidemic discontinuation, the exposure of interest. Time-varying confounders were included in conditional Poisson models. We identified 629 study eligible-persons with at least one outcome. Adjusted incidence rate ratios (IRRs) for all antihyperlipidemics studied were consistent with the null, and ranged from 0.21 (0.02, 2.82) for rosuvastatin to 2.16 (0.06, 75.0) for gemfibrozil. Despite using an underlying dataset of millions of persons, we had little precision in estimating IRRs for VTE/IS among warfarin-treated persons discontinuing individual antihyperlipidemics. Further research should investigate whether discontinuation of gemfibrozil in warfarin users results in serious underanticoagulation. PMID- 29269849 TI - New Types of Experiments Reveal that a Neuron Functions as Multiple Independent Threshold Units. AB - Neurons are the computational elements that compose the brain and their fundamental principles of activity are known for decades. According to the long lasting computational scheme, each neuron sums the incoming electrical signals via its dendrites and when the membrane potential reaches a certain threshold the neuron typically generates a spike to its axon. Here we present three types of experiments, using neuronal cultures, indicating that each neuron functions as a collection of independent threshold units. The neuron is anisotropically activated following the origin of the arriving signals to the membrane, via its dendritic trees. The first type of experiments demonstrates that a single neuron's spike waveform typically varies as a function of the stimulation location. The second type reveals that spatial summation is absent for extracellular stimulations from different directions. The third type indicates that spatial summation and subtraction are not achieved when combining intra- and extra- cellular stimulations, as well as for nonlocal time interference, where the precise timings of the stimulations are irrelevant. Results call to re examine neuronal functionalities beyond the traditional framework, and the advanced computational capabilities and dynamical properties of such complex systems. PMID- 29269850 TI - Corrigendum: BCIP: A gene-centered platform for identifying potential regulatory genes in breast cancer. AB - This corrects the article DOI: 10.1038/srep45235. PMID- 29269851 TI - Corrigendum: Rapid identification of intact bacterial resistance plasmids via optical mapping of single DNA molecules. AB - This corrects the article DOI: 10.1038/srep30410. PMID- 29269852 TI - The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. AB - Platelets play a critical role in vascular inflammation through the podoplanin and collagen/fibrin receptors, C-type-lectin-like-2 (CLEC-2) and glycoprotein VI (GPVI), respectively. Both receptors regulate endothelial permeability and prevent peri-vascular bleeding in inflammation. Here we show that platelet specific deletion of CLEC-2 but not GPVI leads to enhanced systemic inflammation and accelerated organ injury in two mouse models of sepsis-intra-peritoneal lipopolysaccharide and cecal ligation and puncture. CLEC-2 deficiency is associated with reduced numbers of podoplanin-expressing macrophages despite increased cytokine and chemokine levels in the infected peritoneum. Pharmacological inhibition of the interaction between CLEC-2 and podoplanin regulates immune cell infiltration and the inflammatory reaction during sepsis, suggesting that activation of podoplanin underlies the anti-inflammatory action of platelet CLEC-2. We suggest podoplanin-CLEC-2 as a novel anti-inflammatory axis regulating immune cell recruitment and activation in sepsis. PMID- 29269853 TI - Catalytic asymmetric synthesis of a nitrogen heterocycle through stereocontrolled direct photoreaction from electronically excited state. AB - The reactivity of photoexcited molecules has been extensively studied for decades but until today direct bond-forming reactions of such excited states in a catalytic and asymmetric fashion are restricted to the synthesis of cyclobutanes via [2 + 2] photocycloadditions. Herein, we demonstrate a previously elusive visible-light-induced catalytic asymmetric [2 + 3] photocycloaddition of alkenes with vinyl azides. A wide range of complex 1-pyrrolines are obtained as single diastereoisomers and with up to >99% enantiomeric excess using a simple reaction setup and mild reaction conditions. The reaction is proposed to proceed through the photoexcitation of a complex out of chiral rhodium catalyst coordinated to alpha,beta-unsaturated N-acylpyrazole substrates. All reactive intermediates remain bound to the catalysts thereby providing a robust catalytic scheme (no exclusion of air necessary) with excellent stereocontrol. This work expands the scope of stereocontrolled bond-forming reactions of photoexcited intermediates by providing catalytic asymmetric access to a key nitrogen heterocycle in organic chemistry. PMID- 29269854 TI - Publisher Correction: Quantitative and organisational changes in mature extracellular matrix revealed through high-content imaging of total protein fluorescently stained in situ. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29269855 TI - Coupling ultracold atoms to a superconducting coplanar waveguide resonator. AB - Ensembles of trapped atoms interacting with on-chip microwave resonators are considered as promising systems for the realization of quantum memories, novel quantum gates, and interfaces between the microwave and optical regime. Here, we demonstrate coupling of magnetically trapped ultracold Rb ground-state atoms to a coherently driven superconducting coplanar resonator on an integrated atom chip. When the cavity is driven off-resonance from the atomic transition, the microwave field strength in the cavity can be measured through observation of the AC shift of the atomic hyperfine transition frequency. When driving the cavity in resonance with the atoms, we observe Rabi oscillations between hyperfine states, demonstrating coherent control of the atomic states through the cavity field. These observations enable the preparation of coherent atomic superposition states, which are required for the implementation of an atomic quantum memory. PMID- 29269856 TI - Proteomic investigation of effects of hydroxysafflor yellow A in oxidized low density lipoprotein-induced endothelial injury. AB - Oxidized low-density lipoprotein (ox-LDL)-induced vascular endothelial damage is a key event in early atherosclerosis. Safflower has been used to treat atherosclerotic heart disease in China for many years, but its molecular basis remains unclear. Hydroxysafflor yellow A (HSYA) is the main active ingredient of aqueous safflower extract. We identified the proteins involved in HSYA activity against ox-LDL-induced endothelial injury using isobaric tags for relative and absolute quantification-coupled two-dimensional liquid chromatography-tandem mass spectrometry. HSYA (1, 5, or 25 MUM) alleviated ox-LDL-induced endothelial damage in a dose-dependent manner. We quantitated approximately 2700 protein species, of which 77 were differentially expressed following HSYA treatment. Most protein changes were related to structural molecules, metabolic enzymes, and proteins involved in signal transduction. Several differentially expressed proteins were further validated by western blot analysis. We also analysed the role of the mitochondrial membranous voltage-dependent anion-selective channel protein 2 (VDAC2) in HSYA treatment using small interfering RNA. VDAC2 functioned as a downstream anti-apoptosis effector during HSYA treatment of ox-LDL-induced endothelial impairment. These results further our understanding of the mechanisms responsible for the effects of HSYA. PMID- 29269858 TI - An updated reconstruction of basaltic crust emplacement in Tyrrhenian sea, Italy. AB - Basaltic crust is present in the oceans and marginal seas. Oceanic accretion from inception to ending may be usefully recognized in small basin setting like the Tyrrhenian. Alternating episodes of strong and moderate extensional tectonics characterized the small Tyrrhenian opening. Hyperextension (drifting) of late Miocene and latemost Pliocene age was followed by Pliocene and Late Quaternary moderate extension (rifting). Early hyperextension (~7.5-6.3 Ma) acted in the submerged margin of Hercynian Sardinia. Sardinia offshore, E-directed low-angle faults were accompanied by MORB-like volcanism of non linear shape in the shallow Vavilov plain - inherited segment of alpine-age orogen. Late hyperextension (~1.9 1.7 Ma) acted along the central N-S lineament of Vavilov plain, former metamorphic core complex. At the lineament northern side, E-dipping detachment faulting exposed serpentinized peridotite. At the other side, Vavilov volcano was faulted and its east flank tilted westwards. At the same time, volcanism with affinity to transitional MORB induced opening of Marsili basin. The drift episodes were characterized by absence or scarcity of volcanic activity on the conjugated emerged margins. The rift episodes (respectively ~5-1.9 Ma, and ~1/0.8 Ma-Recent) saw growth of major north-south trending volcanoes in bathyal area as intense volcanic activity developed on the continental margins. PMID- 29269857 TI - A molecular basis for water motion detection by the mechanosensory lateral line of zebrafish. AB - Detection of water motion by the lateral line relies on mechanotransduction complexes at stereocilia tips. This sensory system is comprised of neuromasts, patches of hair cells with stereociliary bundles arranged with morphological mirror symmetry that are mechanically responsive to two opposing directions. Here, we find that transmembrane channel-like 2b (Tmc2b) is differentially required for mechanotransduction in the zebrafish lateral line. Despite similarities in neuromast hair cell morphology, three classes of these cells can be distinguished by their Tmc2b reliance. We map mechanosensitivity along the lateral line using imaging and electrophysiology to determine that a hair cell's Tmc2b dependence is governed by neuromast topological position and hair bundle orientation. Overall, water flow is detected by molecular machinery that can vary between hair cells of different neuromasts. Moreover, hair cells within the same neuromast can break morphologic symmetry of the sensory organ at the stereocilia tips. PMID- 29269859 TI - Deep sequencing of blood and gut T-cell receptor beta-chains reveals gluten induced immune signatures in celiac disease. AB - Celiac disease (CD) patients mount an abnormal immune response to gluten. T-cell receptor (TCR) repertoires directed to some immunodominant gluten peptides have previously been described, but the global immune response to in vivo gluten exposure in CD has not been systematically investigated yet. Here, we characterized signatures associated with gluten directed immune activity and identified gluten-induced T-cell clonotypes from total blood and gut TCR repertoires in an unbiased manner using immunosequencing. CD patient total TCR repertoires showed increased overlap and substantially altered TRBV-gene usage in both blood and gut samples, and increased diversity in the gut during gluten exposure. Using differential abundance analysis, we identified gluten-induced clonotypes in each patient that were composed of a large private and an important public component. Hierarchical clustering of public clonotypes associated with dietary gluten exposure identified subsets of highly similar clonotypes, the most proliferative of which showing significant enrichment for the motif ASS[LF]R[SW][TD][DT][TE][QA][YF] in PBMC repertoires. These results show that CD associated clonotypes can be identified and that common gluten associated immune response features can be characterized in vivo from total repertoires, with potential use in disease stratification and monitoring. PMID- 29269860 TI - Effects of the Qinghai-Tibet Railway on the Landscape Genetics of the Endangered Przewalski's Gazelle (Procapra przewalskii). AB - The Przewalski's gazelle (Procapra przewalskii) is one of the most endangered ungulates in the world, with fewer than 2,000 individuals surviving in nine habitat fragments on the Qinghai-Tibet Plateau and isolated by human settlements and infrastructure. In particular, the Qinghai-Tibet railway, which crosses the largest part of the gazelle's distribution, remains a major concern because of its potential to intensify landscape genetic differentiation. Here, using mtDNA sequencing and microsatellite genotyping to analyze 275 Przewalski's gazelle samples collected throughout the range, we observed low level of genetic diversity (mtDNA pi = 0.0033) and strong phylogeographic structure. Overall, the nine patches of gazelles can be further clustered into five populations, with a strong division between the eastern vs. western side of Qinghai Lake. Our study provides the first evidence of the genetic divergence between the Haergai North and Haergai South gazelle populations, corresponding to the recent construction of a wired enclosure along the Qinghai-Tibet railway less than ten years ago, an equivalent of five generations. Well-designed wildlife corridors across the railway along with long-term monitoring of the anthropogenic effects are therefore recommended to alleviate further habitat fragmentation and loss of genetic diversity in Przewalski's gazelle. PMID- 29269861 TI - Influence of body mass index on incidence and prognosis of acute myeloid leukemia and acute promyelocytic leukemia: A meta-analysis. AB - Previous studies have demonstrated an association between high body mass index (BMI) and acute myeloid leukemias (AML), particularly acute promyelocytic leukemia (APL). However, the effect of obesity and overweight on the incidence of AML is not supported by all studies, and the relationship between obesity and prognosis of AML and APL has not been established. Thus, we conducted a meta analysis to determine the role of BMI on the risk and clinical outcome of AML, including APL. Twenty-six eligible studies enrolling 12,971 AML (including 866 APL) patients were retrieved and analyzed. Overweight and obesity was associated with an increased incidence of AML (relative risk [RR], 1.23; 95% confidence interval [CI], 1.12-1.35; P < 0.001). High BMI did not significantly affect overall survival (OS) (hazard ratio [HR], 0.97; 95% CI, 0.92-1.03; P = 0.323) or disease-free survival (HR, 0.98; 95% CI, 0.88-1.10; P = 0.755) in patients with non-APL AML. By contrast, APL patients with high BMI had shorter OS (HR, 1.77; 95% CI, 1.26-2.48; P = 0.001) and a higher risk of differentiation syndrome (HR, 1.53; 95% CI, 1.03-2.27, P = 0.04). Overall, our findings suggest that patients with overweight or obesity have a higher incidence of AML, and high BMI is a predictor of adverse clinical outcomes in APL. PMID- 29269862 TI - Three-Dimensional Evaluation of Posterior Pole and Optic Nerve Head in Myopes with Glaucoma. AB - The degree of myopia is represented by a global index, such as refractive error or axial length. However, the progression of myopia mainly develops in the posterior eyeball. Therefore, it is reasonable to assume that the evaluation of myopia should be confined to the posterior segment, where most of the growth and lengthening occurs. Swept source optical coherence tomography software can reconstruct the scans to the coronal view of the posterior pole, which provides additional anterior-posterior depth (z axis in the Cartesian coordinates) that is not provided with the common fundus photograph. We deduced that the parameter of deepest point of the eyeball (DPE) as a surrogate for posterior pole configuration. Between myopes with and without normal tension glaucoma (NTG) with similar axial length, myopes with NTG had deeper and more distant location of the DPE from the optic disc. The difference of the DPE position between the myopes with and without NTG may have implications for the larger optic disc tilt and torsion characteristic of myopes with NTG. Furthermore, these data suggest that myopes with NTG go through excessive posterior scleral remodeling, which may result in vulnerable optic nerve head. PMID- 29269863 TI - Environment spectrum and coherence behaviours in a rare-earth doped crystal for quantum memory. AB - We theoretically investigate the dynamics of environment and coherence behaviours of the central ion in a quantum memory based on a rare-earth doped crystal. The interactions between the central ion and the bath spins suppress the flip-flop rate of the neighbour bath spins and yield a specific environment spectral density S(omega). Under dynamical decoupling pulses, this spectrum provides a general scaling for the coherence envelope and coherence time, which significantly extend over a range on an hour-long time scale. The characterized environment spectrum with ultra-long coherence time can be used to implement various quantum communication and information processing protocols. PMID- 29269864 TI - Prefabrication of a functional bone graft with a pedicled periosteal flap as an in vivo bioreactor. AB - The in vivo bioreactor principle, which focuses on using the body as a living bioreactor to cultivate stem cells, bioscaffolds, and growth factors and leveraging the body's self-regenerative capacity to regenerate new tissue, has been considered a potential approach for bone defect reconstruction. The histological characteristics of the periosteum allow it to possess a remarkable capacity to induce bone growth and remodeling, making it suitable as an in vivo bioreactor strategy for bone graft prefabrication. The present study was designed to prefabricate vascularized bone grafts using pedicled periosteal flaps and decellularized bone matrix (DBM) scaffolds in a rabbit model. The muscular pouches created in the femoral muscle were acted as a control. Our histological results revealed that both the periosteal flap group and muscular pouch group induced bone tissue formation on the DBM surface at both 8 and 16 weeks postoperatively. However, micro-computed tomography (microCT) scanning, biomechanical, and histomorphometric findings indicated that bone grafts from the periosteal flap group showed larger bone mass, faster bone formation rates, higher vascular density, and stronger biomechanical properties than in the muscular pouch group. We suggest that using the pedicled periosteal flap as an in vivo bioreactor is a promising approach for functional bone graft prefabrication. PMID- 29269865 TI - Functional characterization of a novel non-coding mutation "Ghent +49A > G" in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia cataract syndrome. AB - Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare disorder usually caused by heterozygous mutations in the iron-responsive element (IRE) in the 5' untranslated region (5'UTR) of the L-ferritin gene (FTL), disturbing the binding of iron regulatory proteins (IRPs) and the post-transcriptional regulation of ferritin expression. Here, the proband of a consanguineous family displayed moderate bilateral cataracts and elevated serum ferritin in the absence of iron overload. The parents and siblings showed variable degrees of mild bilateral cataracts combined with elevated levels of circulating ferritin. Sequencing of FTL identified a novel 5'UTR mutation c.-151A > G, also named "Ghent +49A > G". The zygosity of the mutation, occurring in homozygous and heterozygous state in the proband and other affected family members respectively, correlated well with severity of ophthalmological and hematological manifestations. The substitution is expected to impair the secondary structure of the upper IRE stem. Functional characterization of +49A > G by electrophoretic mobility shift assays demonstrated a reduced binding affinity for IRP1 compared to the wild-type IRE of FTL. Overall, we have expanded the repertoire of deleterious biallelic FTL IRE mutations in HHCS with this novel +49A > G mutation, the zygosity of which correlated well with the disease expression. PMID- 29269866 TI - DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty. AB - Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) commonly co occur among HIV-infected individuals. These co-occurring conditions may produce interacting epigenetic effects in white blood cells that influence immune function and health outcomes. Here, we report an epigenome-wide association analysis comparing IDU+/ HCV+ and IDU-/HCV- in 386 HIV-infected individuals as a discovery sample and in 412 individuals as a replication sample. We observe 6 significant CpGs in the promoters of 4 genes, NLRC5, TRIM69, CX3CR1, and BCL9, in the discovery sample and in meta-analysis. We identify 19 differentially methylated regions on chromosome 6 harboring MHC gene clusters. Importantly, a panel of IDU+/HCV+-associated CpGs discriminated HIV frailty based upon a validated index with an area under the curve of 79.3% for high frailty and 82.3% for low frailty. These findings suggest that IDU and HCV involve epigenetic programming and that their associated methylation signatures discriminate HIV pathophysiologic frailty. PMID- 29269867 TI - Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4. AB - Abnormalities in epigenetic modifiers are emerging as driving events in prostate cancer (PCa). The histone methyltransferase KMT2D, a frequently aberrant epigenetic modifier in various tumors, has an undefined role in PCa. Moreover, little is known regarding KMT2D's mutation in Chinese patients or its downstream signaling pathways and targets. Here, we profiled the mutational spectrum of 32 significantly PCa-associated genes by using disease-targeted sequencing, and found that KMT2D was highly mutated (63.04%, 29/46) in Chinese patients. Moreover, high KMT2D transcription was also associated with poor prognosis in an independent cohort (n = 51). In KMT2D-knockdown PC-3 and DU145 cells, cell proliferation (P < 0.01), invasion (P < 0.001), and migration (P < 0.01) were consequently suppressed. KMT2D depletion effectively suppressed tumor growth by 92.21% in vivo. Notably, integrative analyses of RNAseq and ChIPseq characterized two crucial genes downregulated by KMT2D, leukemia inhibitory factor receptor (LIFR) and Kruppel-like factor-4 (KLF4), which are regulators in PI3K/Akt and EMT, respectively. Our present study revealed that KMT2D epigenetically activates PI3K/Akt pathway and EMT by targeting LIFR and KLF4 and thus serves as a putative epigenetic-based target for treating PCa. PMID- 29269868 TI - Gain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1. AB - Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell invasive growth and metastasis, yet the mechanisms mediating these functions still largely remain elusive. We show here that overexpression of the GOF mutant p53 G245D and other GOF p53 mutants enhances the invasive cell growth of p53-deficient head and neck squamous cell carcinoma (HNSCC) UM-SCC-1 cells both in in vitro three-dimensional culture and in an in vivo orthotopic nude mouse model of HNSCC through a novel transcription-independent mechanism. We demonstrate that the expression of the oncogenic forkhead transcription factor FOXM1 is upregulated by GOF mutant p53s. Moreover, we show that overexpression of GOF mutant p53 G245D decreases the AMP-activated protein kinase (AMPK)-mediated phosphorylation of FOXO3a, a tumor suppressive forkhead transcription factor, leading to its cytoplasmic accumulation. This downregulation of FOXO3a's activity, in turn, leads to de-repression of FOXM1 expression. Importantly, we show that either overexpression of FOXO3a or downregulation of FOXM1 impairs both GOF mutant p53-mediated cell invasion in vitro and pulmonary metastases of UM-SCC 1 cells in vivo. Finally, not only do oral cancer patients with p53 mutations exhibit higher levels of FOXM1 expression than patients with wild-type p53, but also HNSCC patients with TP53 mutations and high levels of FOXM1 expression have the poorest survival outcomes. Given our prior demonstration that GOF mutant p53s inhibit AMPK, our current study, establishes and demonstrates a novel transcription-independent GOF mutant p53-AMPK-FOXO3a-FOXM1 signaling cascade that plays an important role in mediating mutant p53s' gain-of-function activities in HNSCCs. PMID- 29269869 TI - Registration and retention of dentists on the General Dental Council register between 2006 and 2016. AB - Background There is considerable uncertainty over the dental future workforce requirements in the United Kingdom. This uncertainty has not been helped by the lack of clarity on the possible impacts on workforce following the results of the referendum to leave the European Union and enactment of Article 50.Aim This paper sets out to describe the contribution to the dental workforce over the reported period of non-UK qualified dental graduates.Results For the last three years over a third of new registrants have qualified from outside of the UK with over a quarter of registrants entering through mutual recognition of their qualification. Furthermore, the findings highlight the relatively short period for which those entering the register from the European Economic Area remain on the register when compared to other entrants.Discussion Those responsible for workforce policy will need to react rapidly to these findings given the short time period remaining to negotiate the terms and conditions of Britain's exit and this must include clarification of the entitlements of the current and future dental EEA qualified graduates. PMID- 29269870 TI - Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition. AB - Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high risk DLBCL patients. PMID- 29269871 TI - CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters. AB - Gene expression mediated by the transcription factor cAMP-responsive element binding protein (CREB) is essential for a wide range of brain processes. The transcriptional coactivartor CREB-regulated transcription coactivator-1 (CRTC1) is required for efficient induction of CREB target genes during neuronal activity. However, the mechanisms regulating induction of specific CREB/CRTC1 dependent genes during neuronal activity remain largely unclear. Here, we investigated the molecular mechanisms regulating activity-dependent gene transcription upon activation of the CREB/CRTC1 signaling pathway in neurons. Depolarization and cAMP signals induce preferential transcription of activity dependent genes containing promoters with proximal CRE/TATA sequences, such as c fos, Dusp1, Nr4a1, Nr4a2 and Ptgs2, but not genes with proximal CRE/TATA-less promoters (e.g. Nr4a3, Presenilin-1 and Presenilin-2). Notably, biochemical and chromatin immunoprecipitation analyses reveal constitutive binding of CREB to target gene promoters in the absence of neuronal activity, whereas recruitment of CRTC1 to proximal CRE/TATA promoters depends on neuronal activity. Neuronal activity induces rapid CRTC1 dephosphorylation, nuclear translocation and binding to endogenous CREB. These results indicate that neuronal activity induces a preferential binding of CRTC1 to the transcriptional complex in CRE/TATA containing promoters to engage activity-dependent transcription in neurons. PMID- 29269872 TI - The monounsaturated fatty acid oleate is the major physiological toxic free fatty acid for human beta cells. AB - Free fatty acids (FFAs) can cause glucose intolerance and diabetes. Lipotoxicity to the pancreatic beta cells is considered to be a major underlying cause for this phenomenon. The aim of this study was to analyse the toxicity profile of FFAs in the human EndoC-betaH1 beta-cell line and to compare the results with isolated rat and human islets with special reference to the physiologically most prevalent FFAs palmitic acid (PA) and oleic acid (OA). Toxicity after a 2-day incubation with the different FFAs was analysed by the caspase-3 assay and confirmed by the propidium iodide and annexin V staining tests. The long-chain saturated PA (C16:0) and the monounsaturated OA (C18:1) were both toxic to human EndoC-betaH1 beta cells and pseudoislets, as well as to rat islets, and, as confirmed in a pilot experiment, also to human islets. Furthermore, OA provided no protection against the toxicity of PA. Likewise, elaidic acid (EA, the trans isomer of OA; trans-OA) was significantly toxic, in contrast to the non metabolisable analogues methylated PA (MePA) and methylated OA (MeOA). Fatty acids with a chain length < C16 were not toxic in EndoC-betaH1 beta cells. Caspase-3 was also activated by linoleic acid (LA)(C18:2) but not by gamma linolenic acid (gamma-LNA)(C18:3). Overall, only long-chain FFAs with chain lengths > C14, which generate hydrogen peroxide in the peroxisomal beta oxidation, were toxic. This conclusion is also supported by the toxicity of the branched-chain FFA pristanic acid, which is exclusively metabolised in the peroxisomal beta-oxidation. The lack of a protective effect of the monounsaturated fatty acid OA has important consequences for a beta-cell protective lipid composition of a diet. A cardioprotective diet with a high OA content does not fulfil this requirement. PMID- 29269873 TI - Disentangling the influence of climate, soil and belowground microbes on local species richness in a dryland ecosystem of Northwest China. AB - Xinjiang Uygur Autonomous Region (XUAR) covers one of the largest drylands in the world, while the relative effects of different environmental factors on plant diversity are poorly understood. We sampled 66 sites in a typical dryland of XUAR, which covers more than 450,000 km2, to evaluate the relative influences of different factors on the patterns of local plant species richness (LPSR). We found that overall and herbaceous LPSR were positively correlated with water availability, soil nutrients but negatively correlated with energy availability, while the shrub LPSR showed the opposite response. Climate, soil attributes together explained 53.2% and 59.2% of the variance in overall and herbaceous LPSR, respectively; revealing that LPSR patterns were shaped by abiotic and underground biotic factors together. Only 31.5% of the variance in the shrub LPSR was explained by soil attributes, indicating that shrub LPSR was mainly limited by non-climatic factors. There findings provide robust evidence that relative contribution of climate and soil attributes differ markedly depending on the plant functional group. Furthermore, we found the different relationship between microbes and plant diversity, indicating that the linkages between soil microbial diversity and plant diversity may vary across functional groups of microbes and plant. These findings provide robust evidence that the relative roles of climate, soil and microbes differ markedly depending on the plant functional group. Microbial richness showed a significantly pure influence on the LPSR of all groups, suggesting that microbes play a non-negligible role in regulating plant diversity in dryland ecosystems. PMID- 29269874 TI - Fabrication of pH-responsive PLGA(UCNPs/DOX) nanocapsules with upconversion luminescence for drug delivery. AB - The integration of anticancer drugs and inorganic nanocrystals in polymer nanocapsules is a widely used strategy to improve their functionality, stability and sustained release. However, the complexity in the preparation of functional nanocapsules and their reproducibility still challenge these promising drug carriers in clinical application. Here we introduce a simple one-step self assembly strategy to prepare multifunctional nanocapsules based on simultaneous poly (DL-lactic-co-glycolic acid) (PLGA) encapsulation of antitumor drug doxorubicin hydrochloride (DOX) and NaYF4:Yb,Er@NaGdF4 upconversion nanoparticles (UCNPs) for cancer cell imaging and drug delivery. The obtained PLGA(UCNPs/DOX) nanocapsules with a small size of ~150 nm possessed bright upconversion fluorescence and could act as T 1- weighted contrast agents for magnetic resonance imaging (MRI). Moreover, the PLGA(UCNPs/DOX) nanocapsules exhibited pH responsive drug releasing behavior, causing the loaded DOX easily releasing at cancer cells, and an obvious cytotoxicity via MTT assay. The endocytosis process of PLGA (UCNPs/DOX) nanocapsules is evaluated using optical microscopy and upconversion fluorescence microscopy. These results demonstrated that the developed PLGA nanocapsules could serve as multifunctional drug delivery systems for cancer imaging and therapy. PMID- 29269875 TI - Cryo-EM structure of a licensed DNA replication origin. AB - Eukaryotic origins of replication are licensed upon loading of the MCM helicase motor onto DNA. ATP hydrolysis by MCM is required for loading and the post catalytic MCM is an inactive double hexamer that encircles duplex DNA. Origin firing depends on MCM engagement of Cdc45 and GINS to form the CMG holo-helicase. CMG assembly requires several steps including MCM phosphorylation by DDK. To understand origin activation, here we have determined the cryo-EM structures of DNA-bound MCM, either unmodified or phosphorylated, and visualize a phospho dependent MCM element likely important for Cdc45 recruitment. MCM pore loops touch both the Watson and Crick strands, constraining duplex DNA in a bent configuration. By comparing our new MCM-DNA structure with the structure of CMG DNA, we suggest how the conformational transition from the loaded, post-catalytic MCM to CMG might promote DNA untwisting and melting at the onset of replication. PMID- 29269876 TI - Amino acids as modulators of the European seabass, Dicentrarchus labrax, innate immune response: an in vitro approach. AB - Teleost innate immune system is a most developed and powerful system in which fish highly rely throughout their lives. Conditions in aquaculture farms are particularly prone to disease, thus, health and welfare ensuring strategies are an urgent call to which nutrition is gradually becoming a most regarded achievement tool. This study intended to evaluate different amino acids' effect on immune-related mechanisms as well as their potential as enhancers of European seabass, Dicentrarchus labrax, leucocyte functioning. To achieve these goals, primary cultures of head-kidney leucocytes were established and kept in amino acid (glutamine, arginine, tryptophan or methionine) supplemented culture media in two doses. The effects of amino acids treatments were then evaluated after stimulation with either Vibrio anguillarum or Vibrio anguillarum lipopolysaccharides by measuring nitric oxide production, extracellular respiratory burst, ATP and arginase activities, and expression of immune-related genes. Glutamine, arginine and tryptophan showed to be particularly relevant regarding cell energy dynamics; arginine and tryptophan supplementation also resulted in down-regulation of important immune-related genes. Immune responses in cells treated with methionine were generally enhanced but further studies, particularly those of enzymes activity, are essential to complement gene expression results and to better understand this nutrient's immune role in fish. PMID- 29269877 TI - The Effect of Time, Roasting Temperature, and Grind Size on Caffeine and Chlorogenic Acid Concentrations in Cold Brew Coffee. AB - The extraction kinetics and equilibrium concentrations of caffeine and 3 chlorogenic acid (3-CGA) in cold brew coffee were investigated by brewing four coffee samples (dark roast/medium grind, dark roast/coarse grind, medium roast/medium grind, medium roast/coarse grind) using cold and hot methods. 3-CGA and caffeine were found at higher concentrations in cold brew coffee made with medium roast coffees, rather than dark roast. The grind size did not impact 3-CGA and caffeine concentrations of cold brew samples significantly, indicating that the rate determining step in extraction for these compounds did not depend on surface area. Caffeine concentrations in cold brew coarse grind samples were substantially higher than their hot brew counterparts. 3-CGA concentrations and pH were comparable between cold and hot brews. This work suggests that the difference in acidity of cold brew coffee is likely not due to 3-CGA or caffeine concentrations considering that most acids in coffee are highly soluble and extract quickly. It was determined that caffeine and 3-CGA concentrations reached equilibrium according to first order kinetics between 6 and 7 hours in all cold brew samples instead of 10 to 24 hours outlined in typical cold brew methods. PMID- 29269880 TI - Large bipolaron density at organic semiconductor/electrode interfaces. AB - Bipolaron states, in which two electrons or two holes occupy a single molecule or conjugated polymer segment, are typically considered to be negligible in organic semiconductor devices due to Coulomb repulsion between the two charges. Here we use charge modulation spectroscopy to reveal a bipolaron sheet density >1010 cm-2 at the interface between an indium tin oxide anode and the common small molecule organic semiconductor N,N'-Bis(3-methylphenyl)-N,N'-diphenylbenzidine. We find that the magnetocurrent response of hole-only devices correlates closely with changes in the bipolaron concentration, supporting the bipolaron model of unipolar organic magnetoresistance and suggesting that it may be more of an interface than a bulk phenomenon. These results are understood on the basis of a quantitative interface energy level alignment model, which indicates that bipolarons are generally expected to be significant near contacts in the Fermi level pinning regime and thus may be more prevalent in organic electronic devices than previously thought. PMID- 29269878 TI - Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells. AB - The role of glutaminolysis in providing metabolites to support tumour growth is well-established, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated. Here we show that normal mammary epithelial cells consume glutamine, but do not secrete glutamate. Indeed, low levels of extracellular glutamate are necessary to maintain epithelial homoeostasis, and provision of glutamate drives disruption of epithelial morphology and promotes key characteristics of the invasive phenotype such as lumen-filling and basement membrane disruption. By contrast, primary cultures of invasive breast cancer cells convert glutamine to glutamate which is released from the cell through the system Xc- antiporter to activate a metabotropic glutamate receptor. This contributes to the intrinsic aggressiveness of these cells by upregulating Rab27 dependent recycling of the transmembrane matrix metalloprotease, MT1-MMP to promote invasive behaviour leading to basement membrane disruption. These data indicate that acquisition of the ability to release glutamate is a key watershed in disease aggressiveness. PMID- 29269879 TI - Broadly neutralizing antiviral responses induced by a single-molecule HPV vaccine based on thermostable thioredoxin-L2 multiepitope nanoparticles. AB - Vaccines targeting the human papillomavirus (HPV) minor capsid protein L2 are emerging as chemico-physically robust and broadly protective alternatives to the current HPV (L1-VLP) vaccines. We have previously developed a trivalent L2 vaccine prototype exploiting Pyrococcus furiosus thioredoxin (PfTrx) as a thermostable scaffold for the separate presentation of three distinct HPV L2(20 38) epitopes. With the aim of achieving a highly immunogenic, yet simpler and more GMP-production affordable formulation, we report here on a novel thermostable nanoparticle vaccine relying on genetic fusion of PfTrx-L2 with the heptamerizing coiled-coil polypeptide OVX313. A prototype HPV16 monoepitope version of this nanoparticle vaccine (PfTrx-L2-OVX313; median radius: 8.6 +/- 1.0 nm) proved to be approximately 10-fold more immunogenic and with a strikingly enhanced cross-neutralization capacity compared to its monomeric counterpart. Vaccine-induced (cross-)neutralizing responses were further potentiated in a multiepitope derivative displaying eight different L2(20-38) epitopes, which elicited neutralizing antibodies against 10 different HPVs including three viral types not represented in the vaccine. Considering the prospective safety of the PfTrx scaffold and of the OVX313 heptamerization module, PfTrx-OVX313 nanoparticles lend themselves as robust L2-based immunogens with a high translational potential as a 3rd generation HPV vaccine, but also as a novel and extremely versatile peptide-antigen presentation platform. PMID- 29269881 TI - Generation of therapeutic protein variants with the human serum albumin binding capacity via site-specific fatty acid conjugation. AB - Extension of the serum half-life is an important issue in developing new therapeutic proteins and expanding applications of existing therapeutic proteins. Conjugation of fatty acid, a natural human serum albumin ligand, to a therapeutic protein/peptide was developed as a technique to extend the serum half-life in vivo by taking advantages of unusually long serum half-life of human serum albumin (HSA). However, for broad applications of fatty acid-conjugation, several issues should be addressed, including a poor solubility of fatty acid and a substantial loss in the therapeutic activity. Therefore, herein we systematically investigate the conditions and components in conjugation of fatty acid to a therapeutic protein resulting in the HSA binding capacity without compromising therapeutic activities. By examining the crystal structure and performing dye conjugation assay, two sites (W160 and D112) of urate oxidase (Uox), a model therapeutic protein, were selected as sites for fatty acid-conjugation. Combination of site-specific incorporation of a clickable p-azido-L-phenylalanine to Uox and strain-promoted azide-alkyne cycloaddition allowed the conjugation of fatty acid (palmitic acid analog) to Uox with the HSA binding capacity and retained enzyme activity. Deoxycholic acid, a strong detergent, greatly enhanced the conjugation yield likely due to the enhanced solubility of palmitic acid analog. PMID- 29269883 TI - Corrigendum: Quantum State Transmission in a Superconducting Charge Qubit-Atom Hybrid. AB - This corrects the article DOI: 10.1038/srep38356. PMID- 29269882 TI - Age-Related Eye Disease and Participation in Cognitive Activities. AB - Studies have found a benefit to living a cognitively active life in older age. Our goal was to quantify participation in cognitively stimulating activities in adults with and without age-related eye disease. We conducted a cross-sectional hospital-based study in Montreal, Canada of older adults (n = 303) having either age-related macular degeneration (AMD) (n = 96), glaucoma (n = 93), or normal vision (n = 114). To be eligible, the AMD group had to have bilateral late stage AMD with a better eye visual acuity of 20/30 or worse. The glaucoma group had to have a diagnosis of bilateral primary open-angle glaucoma with visual field mean deviation < = -4 dB in their better eye. Further inclusion criteria included age >= 65 and a Mini-Mental State Exam Blind score >= 10. Cognitive activities were measured using the Victoria Longitudinal Study Activity Questionnaire. Linear regression was used. Patients with AMD (beta = -4.2, 95% confidence interval (CI) -6.0, -2.4) and glaucoma (beta = -1.8, 95% CI -3.3, -0.3) participated in fewer cognitive activities per month compared to those with normal vision after adjusting for age, sex, education, diabetes, number of comorbidities, cognition, and cataract. People with AMD and glaucoma participated in fewer cognitive activities, which could put them at risk for future cognitive impairment. PMID- 29269884 TI - The mediating role of sleep in the fish consumption - cognitive functioning relationship: a cohort study. AB - Greater fish consumption is associated with improved cognition among children, but the mediating pathways have not been well delineated. Improved sleep could be a candidate mediator of the fish-cognition relationship. This study assesses whether 1) more frequent fish consumption is associated with less sleep disturbances and higher IQ scores in schoolchildren, 2) such relationships are not accounted for by social and economic confounds, and 3) sleep quality mediates the fish-IQ relationship. In this cohort study of 541 Chinese schoolchildren, fish consumption and sleep quality were assessed at age 9-11 years, while IQ was assessed at age 12. Frequent fish consumption was related to both fewer sleep problems and higher IQ scores. A dose-response relationship indicated higher IQ scores in children who always (4.80 points) or sometimes (3.31 points) consumed fish, compared to those who rarely ate fish (all p < 0.05). Sleep quality partially mediated the relationship between fish consumption and verbal, but not performance, IQ. Findings were robust after controlling for multiple sociodemographic covariates. To our knowledge, this is the first study to indicate that frequent fish consumption may help reduce sleep problems (better sleep quality), which may in turn benefit long-term cognitive functioning in children. PMID- 29269885 TI - Mesenchymal Stem Cell-Conditioned Medium Reduces Disease Severity and Immune Responses in Inflammatory Arthritis. AB - We evaluated the therapeutic potential of mesenchymal stem cell-conditioned medium (CM-MSC) as an alternative to cell therapy in an antigen-induced model of arthritis (AIA). Disease severity and cartilage loss were evaluated by histopathological analysis of arthritic knee joints and immunostaining of aggrecan neoepitopes. Cell proliferation was assessed for activated and naive CD4+ T cells from healthy mice following culture with CM-MSC or co-culture with MSCs. T cell polarization was analysed in CD4+ T cells isolated from spleens and lymph nodes of arthritic mice treated with CM-MSC or MSCs. CM-MSC treatment significantly reduced knee-joint swelling, histopathological signs of AIA, cartilage loss and suppressed TNFalpha induction. Proliferation of CD4+ cells from spleens of healthy mice was not affected by CM-MSC but reduced when cells were co-cultured with MSCs. In the presence of CM-MSC or MSCs, increases in IL-10 concentration were observed in culture medium. Finally, CD4+ T cells from arthritic mice treated with CM-MSC showed increases in FOXP3 and IL-4 expression and positively affected the Treg:Th17 balance in the tissue. CM-MSC treatment reduces cartilage damage and suppresses immune responses by reducing aggrecan cleavage, enhancing Treg function and adjusting the Treg:Th17 ratio. CM-MSC may provide an effective cell-free therapy for inflammatory arthritis. PMID- 29269887 TI - Towards sustainable processing of columbite group minerals: elucidating the relation between dielectric properties and physico-chemical transformations in the mineral phase. AB - Current methodologies for the extraction of tantalum and niobium pose a serious threat to human beings and the environment due to the use of hydrofluoric acid (HF). Niobium and tantalum metal powders and pentoxides are widely used for energy efficient devices and components. However, the current processing methods for niobium and tantalum metals and oxides are energy inefficient. This dichotomy between materials use for energy applications and their inefficient processing is the main motivation for exploring a new methodology for the extraction of these two oxides, investigating the microwave absorption properties of the reaction products formed during the alkali roasting of niobium-tantalum bearing minerals with sodium bicarbonate. The experimental findings from dielectric measurement at elevated temperatures demonstrate an exponential increase in the values of the dielectric properties as a result of the formation of NaNbO3-NaTaO3 solid solutions at temperatures above 700 degrees C. The investigation of the evolution of the dielectric properties during the roasting reaction is a key feature in underpinning the mechanism for designing a new microwave assisted high temperature process for the selective separation of niobium and tantalum oxides from the remainder mineral crystalline lattice. PMID- 29269886 TI - Non-invasive multimodal optical coherence and photoacoustic tomography for human skin imaging. AB - The cutaneous vasculature is involved in many diseases. Current clinical examination techniques, however, cannot resolve the human vasculature with all plexus in a non-invasive manner. By combining an optical coherence tomography system with angiography extension and an all optical photoacoustic tomography system, we can resolve in 3D the blood vessels in human skin for all plexus non invasively. With a customized imaging unit that permits access to various parts of patients' bodies, we applied our multimodality imaging system to investigate several different types of skin conditions. Quantitative vascular analysis is given for each of the dermatological conditions to show the potential diagnostic value of our system in non-invasive examination of diseases and physiological processes. Improved performance of our system over its previous generation is also demonstrated with an updated characterization. PMID- 29269888 TI - Food reformulation and nutritional quality of food consumption: an analysis based on households panel data in France. AB - BACKGROUND/OBJECTIVES: We aimed to quantify the contribution of food reformulation to changes in the nutritional quality of consumers' food purchases, and compare it with the impact of substitutions made by consumers. SUBJECTS/METHODS: Using a brand-specific data set in France, we considered the changes in the nutrient content of food products in four food sectors over a 3 year period. These data were matched with data on consumers' purchases to estimate the change in the nutritional quality of consumers' purchases. This change was divided into three components: the reformulation of food products, the launching of new products and the consumers' substitutions between products. Key nutrients were selected for each food group: breakfast cereals (sugar, fats, SFA, fiber, and sodium), biscuits and cakes (sugar, fats, SFA, and fiber), potato chips (fats, SFA, and sodium) and soft drinks (sugar). RESULTS: Product reformulation initiatives have improved existing products for most food group nutrient pairs. In particular, the contribution of food reformulation to the change in nutritional quality of food purchases was strong in potato chips (the sales-weighted mean SFA and sodium contents decreased by 31.4% to 52.1% and 6.7% to 11.1%, respectively), and breakfast cereals (the sales-weighted mean sodium content decreased by 7.3% to 9.7%). Regarding the launching of new products, the results were ambiguous. Consumers' substitutions between food items were not generally associated to an improvement in the nutritional quality of the food purchases. CONCLUSIONS: Policies aiming to promote food reformulation may have greater impact than those promoting changes in consumer behavior. PMID- 29269889 TI - Changes in body composition in children with acute graft-versus-host disease within the first 100 days after hematopoietic stem cell transplantation. AB - BACKGROUND: Acute graft-versus-host-disease (aGVHD) is one of the main complications of hematopoietic stem cell transplantation (HSCT). This study investigated the changes in body composition of pediatric patients with aGVHD during the first 100 days after HSCT. METHODS: Fifty-five children receiving HSCT were divided into two groups (aGVHD and non-aGVHD). Body mass index Z-scores (BMI z), arm muscle area index (AMAI), fat mass index (FMI), and fat-free mass index (FFMI) were measured on the day of transplantation (H0), and on the 30th (H30), 60th (H60), and 100th day (H100) after the transplantation. The correlative factors on body composition were evaluated. RESULTS: In the aGVHD group, the rates of absolute change of BMI-z at H30, H60, and H100 showed a significant increase as compared to that at H0, especially at H30 which was remarkably higher than that of the non-aGVHD group (P = 0.008). AMAI showed a continuous decrease from H0 to H100 in the aGVHD group; also FFMI was found to be lower than that of the non-aGVHD group during the first 100 days after transplantation, however, no significant differences were found between the two groups. At H60 and H100, FFMI in the aGVHD group was lower than that in the non-aGVHD group (P = 0.014, P = 0.032, respectively). Glucocorticoid treatment and the occurrence of mucositis were the key factors for changes in body composition in the aGVHD group. CONCLUSIONS: Changes in body composition are characterized by a lean reduction in body mass and increase in adipose tissues in the early stage of post transplantation in the aGVHD children. Glucocorticoid treatment and occurrence of mucositis are the two important factors that were found to affect body composition after HSCT. PMID- 29269890 TI - The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND/OBJECTIVES: Recently, the role of a low-carbohydrate diet in diabetes management has generated interest with claims being made regarding its superiority over the traditional high-carbohydrate, low-fat dietary approach. This systematic review and meta-analysis evaluated the interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes. SUBJECTS/METHODS: Randomised controlled trials were searched for which included adults with type 2 diabetes aged 18 years or more. The intervention was a low carbohydrate diet as defined by the author compared to a control group of usual care. MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, ISRCTN, ProQuest and opengrey.eu were searched. Independent experts were contacted and reference lists of selected papers were checked. Results were analysed descriptively and meta-analyses were completed to include trials that presented data at 1 year. RESULTS: Eighteen studies (n = 2204) were eligible for inclusion within the systematic review. The definition of a low-carbohydrate diet varied. At trial end, the descriptive analysis suggested that the low carbohydrate intervention arm (LCIA) may promote favourable outcomes in terms of HbA1c, triglycerides and HDL cholesterol. The LCIA demonstrated reduced requirements for diabetes medication, which may have reduced the observed benefit of dietary carbohydrate restriction on HbA1c. Seven studies provided data to be included in the meta-analyses at 1 year. The meta-analyses showed statistical significance in favour of the LCIA for HbA1c (estimated effect = -0.28%, 95% CI 0.53 to -0.02, p = 0.03; chi 2 = 13.15, df = 6, p = 0.03; I 2 = 54%), HDL cholesterol (estimated effect = 0.06 mmol/L, 95% CI 0.04-0.09, p < 0.00001; chi 2 = 6.05, df = 6, p = 0.42; I 2 = 1%), triglycerides (estimated effect = -0.24 mmol/L, 95% CI -0.35 to -0.13, p < 0.0001; chi 2 = 1.88, df = 6, p = 0.93; I 2 = 0%) and systolic blood pressure (estimated effect = -2.74 mmHg, 95% CI -5.27 to 0.20, p = 0.03; chi 2 = 10.54, df = 6, p = 0.10; I 2 = 43%). Meta-analyses for weight, total cholesterol, LDL cholesterol and diastolic blood pressure did not demonstrate a statistically significant difference between interventions. Dietary adherence was an issue in most studies. A very low-carbohydrate diet (<50 g/day) seems unrealistic in this population, however, a low-carbohydrate diet (<130 g/day) appears to be achievable. Improved clinical outcomes were observed in some studies as a result of achieving a low- or moderate-carbohydrate diet. Fifteen out of 18 studies were considered high risk of bias, with performance bias being a common issue. CONCLUSIONS: Reducing dietary carbohydrate may produce clinical improvements in the management of type 2 diabetes. Further research is needed to understand the true effect of dietary carbohydrate restriction on HbA1c independent of medication reduction and to address known issues with adherence to this dietary intervention. Clarity is needed regarding appropriate classification of a low-carbohydrate diet. PMID- 29269891 TI - Beta oscillations in major depression - signalling a new cortical circuit for central executive function. AB - This study aimed to examine alterations in electroencephalography (EEG) phase synchronization in working memory processing in depressed patients. Sixty-four channel EEG signals were recorded from 33 depressed patients and 32 healthy controls during a visual n-back task. Alterations in functional connections in the patients were investigated using event-related phase coherence in terms of the phase synchronization index (PSI). Compared with the control subjects, the depressed patients showed a lower task-dependent increase in the PSI of delta, theta, and alpha oscillations in a frontoparietal network, but a higher task dependent increase in the PSI of beta oscillations in the frontoparietal network. Additionally, depressed patients showed a lower task-dependent decrease in the PSI of delta, theta, alpha, and beta oscillations in centro-parieto-occipital sites. Insufficient phase synchronization and desynchronization during working memory processing reflects impairments in cortical inhibition, memory, and attention efficiency in major depression, while the abnormal increase in phase synchronization in beta oscillations in the frontoparietal network may indicate a new cortical circuit concerned with the repair of impaired ability in attention, memory retention, and working memory central executive processing. These findings present a compensatory mechanism for impaired cognitive function in major depression, and advance our understanding of functional aspect of beta oscillations. PMID- 29269892 TI - miRNA-36 inhibits KSHV, EBV, HSV-2 infection of cells via stifling expression of interferon induced transmembrane protein 1 (IFITM1). AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with all forms of Kaposi's sarcoma worldwide. Little is currently known about the role of microRNAs (miRNAs) in KSHV entry. We recently demonstrated that KSHV induces a plethora of host cell miRNAs during the early stages of infection. In this study, we show the ability of host cell novel miR-36 to specifically inhibit KSHV induced expression of interferon induced transmembrane protein 1 (IFITM1) to limit virus infection of cells. Transfecting cells with miR-36 mimic specifically lowered IFITM1 expression and thereby significantly dampening KSHV infection. In contrast, inhibition of miR-36 using miR-36 inhibitor had the direct opposite effect on KSHV infection of cells, allowing enhanced viral infection of cells. The effect of miR-36 on KSHV infection of cells was at a post-binding stage of virus entry. The highlight of this work was in deciphering a common theme in the ability of miR-36 to regulate infection of closely related DNA viruses: KSHV, Epstein-Barr virus (EBV), and herpes simplexvirus-2 (HSV-2). Taken together, we report for the first time the ability of host cell miRNA to regulate internalization of KSHV, EBV, and HSV-2 in hematopoietic and endothelial cells. PMID- 29269893 TI - The acceptability and feasibility of emailed parent questionnaires for medical and developmental surveillance after NICU discharge. AB - OBJECTIVES: The following are the objectives of this study: (1) Assess the feasibility and acceptability of emailing parent-reported measures of infant health and development after NICU discharge. (2) Examine whether post-discharge questionnaire data helps identify infants most likely to benefit from specialized follow-up care. STUDY DESIGN: Parents of 51 infants <32 weeks' gestation received email questionnaires at 44 weeks postmenstrual age (PMA) and 6 months corrected age (CA). Adverse infant outcomes were assessed in-person at 6 months: (1) Bayley III cognitive or motor score <85; (2) weight, length, or head circumference <10th percentile; (3) new referral for medical or developmental services. RESULTS: Questionnaire response was 48 (94%) at 44 weeks PMA and 46 (90%) at 6 months CA. 36 (70%) infants were assessed at 6 months; 72% had at least 1 adverse outcome. Poorer transition home, feeding problems, and special health care needs at 44 weeks PMA predicted adverse outcomes. Feeding problems, maternal depression, and lower infant health-related quality of life at 6 months CA correlated with adverse outcomes. CONCLUSIONS: Emailed questionnaires after NICU discharge were feasible to implement and acceptable to families. Repeated post-discharge assessments may help identify infants at heightened health and developmental risk. PMID- 29269896 TI - Oral health: Terrifying mineral. PMID- 29269898 TI - Oral surgery II: Part 6. Oral and maxillofacial trauma. AB - Oral and maxillofacial trauma can range from an avulsed tooth as a result of a simple fall, to pan-facial injuries in the context of a polytraumatised patient involved in a road traffic accident. Regardless of aetiology, similar principles apply to all oral and maxillofacial injuries, and this chapter broadly outlines the more common forms of oral and maxillofacial trauma and the options available for their management. Throughout the chapter all references and values are for adult patients unless indicated. PMID- 29269894 TI - Bacterial community structure and novel species of magnetotactic bacteria in sediments from a seamount in the Mariana volcanic arc. AB - Seamounts are undersea mountains rising abruptly from the sea floor and interacting dynamically with underwater currents. They represent unique biological habitats with various microbial community structures. Certain seamount bacteria form conspicuous extracellular iron oxide structures, including encrusted stalks, flattened bifurcating tubes, and filamentous sheaths. To extend our knowledge of seamount ecosystems, we performed an integrated study on population structure and the occurrence of magnetotactic bacteria (MTB) that synthesize intracellular iron oxide nanocrystals in sediments of a seamount in the Mariana volcanic arc. We found Proteobacteria dominant at 13 of 14 stations, but ranked second in abundance to members of the phylum Firmicutes at the deep water station located on a steep slope facing the Mariana-Yap Trench. Live MTB dwell in biogenic sediments from all 14 stations ranging in depth from 238 to 2,023 m. Some magnetotactic cocci possess the most complex flagellar apparatus yet reported; 19 flagella are arranged in a 3:4:5:4:3 array within a flagellar bundle. Phylogenetic analysis of 16S rRNA gene sequences identified 16 novel species of MTB specific to this seamount. Together the results obtained indicate that geographic properties of the seamount stations are important in shaping the bacterial community structure and the MTB composition. PMID- 29269901 TI - Fluoridated single malt to hit supermarket shelves. PMID- 29269899 TI - Claims of Russian hacking in BDA elections. PMID- 29269904 TI - Orthodontics: Orthodox or orthodent? PMID- 29269905 TI - Dental erosion: Bitterness-induced bruxism. PMID- 29269906 TI - An evaluation of defensive dentistry: w(h)ither the profession? AB - Introduction Defensive dentistry has become a popular choice for dentists in practice over the past decade, partly in response to the supposed increasing risks to patient safety, of litigation and of health and safety concerns to patients and staff.Methods Using a quantitative analysis, care plans of 96 dentists were examined from one day in April 2017 and compared against these known risks. One thousand four hundred and seventeen care plans were coded by treatment type. The risks of completing each item were coded as high or low for either clinical risk, health and safety risk and risk of litigation. Subsequently, semi structured interviews were conducted with 12 participants; five practitioners of over 25 years' experience and seven practitioners of less than five years' experience.Results All assessments and treatments, including no treatment, had recognised risks. 'Doing nothing' also carried a risk of litigation. Four themes were identified from the interviews: 'there by the grace of God, go I', 'limitations on the scope of practice', 'fear' and 'c'est la vie'.Discussion The profession is at a crossroads. The options for the future are discussed, including immediate retraining for all dental care professionals.Conclusion Within the limitations of this study, it is concluded that increasingly, no risk or only low risk treatments will be undertaken by the profession, with both experienced and less experienced practitioners limiting their scope of practice, with possible deleterious consequences on the dental health of the population. PMID- 29269908 TI - Dentists' personalities tested. PMID- 29269907 TI - Clinical examination & record-keeping: Part 3: Electronic records. AB - This article is the third and final part of a BDJ series of Practice papers on the subject of clinical examination and related record keeping. The series is taken from the Faculty of General Dental Practice UK (FGDP[UK]) 2016 Good Practice Guidelines book on this topic, edited by A. M. Hadden. This particular article covers the creation and maintenance of electronic patient records, including security and encryption guidance. It is important to note that throughout this article (and the BDJ series and associated FGDP[UK] book), the specific guidelines will be marked as follows: A: Aspirational, B: Basic, C: Conditional. Further information about this guideline notation system is provided in Part 1 of this series ( 2017; 223: 765-768). PMID- 29269912 TI - Dental care in modern art (1914-2014). AB - Background Representations of 'dentists in action' in modern art have never been systematically researched. This paper surveys and analyses these portrayals for the first time.Methods Relevant paintings, prints, sculptures, and installations were identified by means of keyword searches in search engines, OPACs and picture libraries as well as handsearch.Results Between 1914 and 2014 more than 75 works of art with dental treatment as a motif appeared across the globe. Virtually every modern style from post-impressionism to 'crossover art' are represented, including world famous artists such as Dubuffet or Dali. Syringes, Doriot's transmissions and contra-angle handpieces are worked into an iconographic code. In contrast, elements of an increasing hygiene consciousness (gloves, face masks and protective glasses) are integrated only fragmentarily. The dentist-patient relationship is predominantly portrayed professionally and realistically and the stereotype of the male dentist dominates.Discussion For almost a century it has been argued that dentists in action had largely disappeared from artistic production after 1900. The results presented here force a revision of this idea and encourage the further discovery of pictorial sources. Only in this way can the fascinating theme of 'dentistry in art' become an attractive part of dental humanities. PMID- 29269914 TI - Dental regulation: Christmas Quality Care inspection. PMID- 29269919 TI - Sugar-touting nanny arrested for child abuse. PMID- 29269916 TI - Safeguarding: Graphic Christmas cards. PMID- 29269921 TI - 'Appy Dental Christmas. PMID- 29269922 TI - Cake culture continues to plague office workers. PMID- 29269925 TI - A dentist's life: Dental celebrity on tour. PMID- 29269927 TI - Cracking down on a Christmas classic. PMID- 29269931 TI - Demographic history influences spatial patterns of genetic diversityin recently expanded coyote (Canis latrans) populations. AB - Human-mediated range expansions have increased in recent decades and represent unique opportunities to evaluate genetic outcomes of establishing peripheral populations across broad expansion fronts. Over the past century, coyotes (Canis latrans) have undergone a pervasive range expansion and now inhabit every state in the continental United States. Coyote expansion into eastern North America was facilitated by anthropogenic landscape changes and followed two broad expansion fronts. The northern expansion extended through the Great Lakes region and southern Canada, where hybridization with remnant wolf populations was common. The southern and more recent expansion front occurred approximately 40 years later and across territory where gray wolves have been historically absent and remnant red wolves were extirpated in the 1970s. We conducted a genetic survey at 10 microsatellite loci of 482 coyotes originating from 11 eastern U.S. states to address how divergent demographic histories influence geographic patterns of genetic diversity. We found that population structure corresponded to a north south divide, which is consistent with the two known expansion routes. Additionally, we observed extremely high genetic diversity, which is atypical of recently expanded populations and is likely the result of multiple complex demographic processes, in addition to hybridization with other Canis species. Finally, we considered the transition of allele frequencies across geographic space and suggest the mid-Atlantic states of North Carolina and Virginia as an emerging contact zone between these two distinct coyote expansion fronts. PMID- 29269932 TI - Estimation of contemporary effective population size and population declines using RAD sequence data. AB - Large genomic data sets generated with restriction site-associated DNA sequencing (RADseq), in combination with demographic inference methods, are improving our ability to gain insights into the population history of species. We used a simulation approach to examine the potential for RADseq data sets to accurately estimate effective population size (N e) over the course of stable and declining population trends, and we compare the ability of two methods of analysis to accurately distinguish stable from steadily declining populations over a contemporary time scale (20 generations). Using a linkage disequilibrium-based analysis, individual sampling (i.e., n >= 30) had the greatest effect on N e estimation and the detection of population size declines, with declines reliably detected across scenarios ~10 generations after they began. Coalescent-based inference required fewer sampled individuals (i.e., n = 15), and instead was most influenced by the size of the SNP data set, with 25,000-50,000 SNPs required for accurate detection of population trends and at least 20 generations after decline began. The number of samples available and targeted number of RADseq loci are important criteria when choosing between these methods. Neither method suffered any apparent bias due to the effects of allele dropout typical of RAD data. With an understanding of the limitations and biases of these approaches, researchers can make more informed decisions when designing their sampling and analyses. Overall, our results reveal that demographic inference using RADseq data can be successfully applied to infer recent population size change and may be an important tool for population monitoring and conservation biology. PMID- 29269933 TI - Nanopore DNA Sequencing and Genome Assembly on the International Space Station. AB - We evaluated the performance of the MinION DNA sequencer in-flight on the International Space Station (ISS), and benchmarked its performance off-Earth against the MinION, Illumina MiSeq, and PacBio RS II sequencing platforms in terrestrial laboratories. Samples contained equimolar mixtures of genomic DNA from lambda bacteriophage, Escherichia coli (strain K12, MG1655) and Mus musculus (female BALB/c mouse). Nine sequencing runs were performed aboard the ISS over a 6-month period, yielding a total of 276,882 reads with no apparent decrease in performance over time. From sequence data collected aboard the ISS, we constructed directed assemblies of the ~4.6 Mb E. coli genome, ~48.5 kb lambda genome, and a representative M. musculus sequence (the ~16.3 kb mitochondrial genome), at 100%, 100%, and 96.7% consensus pairwise identity, respectively; de novo assembly of the E. coli genome from raw reads yielded a single contig comprising 99.9% of the genome at 98.6% consensus pairwise identity. Simulated real-time analyses of in-flight sequence data using an automated bioinformatic pipeline and laptop-based genomic assembly demonstrated the feasibility of sequencing analysis and microbial identification aboard the ISS. These findings illustrate the potential for sequencing applications including disease diagnosis, environmental monitoring, and elucidating the molecular basis for how organisms respond to spaceflight. PMID- 29269935 TI - Corrigendum: Probing the early stages of shock-induced chondritic meteorite formation at the mesoscale. AB - This corrects the article DOI: 10.1038/srep45206. PMID- 29269934 TI - The expression of AURKA is androgen regulated in castration-resistant prostate cancer. AB - Although second generation endocrine therapies have significantly improved survival, castration-resistant prostate cancer (CRPC) cells are eventually able to escape available hormonal treatments due to reactivation of androgen receptor (AR) signaling. Identification of novel, non-classical and druggable AR-target genes may provide new approaches to treat CRPC. Our previous analyses suggested that Aurora kinase A (AURKA) is regulated by androgens in prostate cancer cells that express high levels of AR. Here, we provide further evidence that AURKA is significantly overexpressed in AR-positive CRPC samples carrying amplification of AR gene and/or expressing AR in high levels. We also demonstrate androgen-induced AR binding in the intronic region of AURKA. The expression of AURKA is increased upon androgen stimulation in LNCaP-ARhi cells that express high levels of AR. The growth of the cells was also significantly inhibited by an AURKA specific inhibitor, alisertib (MLN8237). Together, these findings suggest that the expression of AURKA is regulated by androgen in prostate cancer cells that highly express AR, emphasizing its potential as a therapeutic target in patients with CRPC. PMID- 29269936 TI - Functional characterization and discovery of modulators of SbMATE, the agronomically important aluminium tolerance transporter from Sorghum bicolor. AB - About 50% of the world's arable land is strongly acidic (pH <= 5). The low pH solubilizes root-toxic ionic aluminium (Al3+) species from clay minerals, driving the evolution of counteractive adaptations in cultivated crops. The food crop Sorghum bicolor upregulates the membrane-embedded transporter protein SbMATE in its roots. SbMATE mediates efflux of the anionic form of the organic acid, citrate, into the soil rhizosphere, chelating Al3+ ions and thereby imparting Al resistance based on excluding Al+3 from the growing root tip. Here, we use electrophysiological, radiolabeled, and fluorescence-based transport assays in two heterologous expression systems to establish a broad substrate recognition profile of SbMATE, showing the proton and/or sodium-driven transport of 14C citrate anion, as well as the organic monovalent cation, ethidium, but not its divalent analog, propidium. We further complement our transport assays by measuring substrate binding to detergent-purified SbMATE protein. Finally, we use the purified membrane protein as an antigen to discover native conformation binding and transport function-altering nanobodies using an animal-free, mRNA/cDNA display technology. Our results demonstrate the utility of using Pichia pastoris as an efficient eukaryotic host to express large quantities of functional plant transporter proteins. The nanobody discovery approach is applicable to other non-immunogenic plant proteins. PMID- 29269937 TI - A Randomized, Double-Blind, Crossover Pilot Trial of Rice Endosperm Protein Supplementation in Maintenance Hemodialysis Patients. AB - In maintenance hemodialysis (MHD) patients, low protein intake is associated with protein-energy wasting, a risk factor that affects outcome. However, increased protein intake may lead to hyperphosphatemia and hyperkalemia, which are also mortality risk factors. Here, we evaluated the safety and effects of purified rice endosperm protein (REP), which contains less phosphorus and potassium than soy and casein proteins, as a supplemental protein source for MHD patients. This randomized, double-blind, placebo-controlled, crossover pilot study of REP supplementation (5 g/day * 4 weeks) was carried out in 50 Japanese adult MHD patients (1 dropped out); the primary outcome was the change in the urea kinetic based normalized protein catabolic rate (nPCR), an indicator of protein intake in MHD patients. Intention-to-treat analyses of 24 patients in the REP-first group and 25 in the placebo-first group showed that REP supplementation increased nPCR significantly by 0.07 g/kg/day (95% confidence interval, 0.03-0.11), whereas changes in serum phosphorus and potassium concentrations were not different from the placebo. REP supplementation did not show a significant effect on other nutritional or metabolic parameters and no specific complications. In conclusion, purified REP with efficient bioavailability may be safe and useful for dietary supplementation in MHD patients. PMID- 29269940 TI - Corrigendum: Mechanisms underlying the activity-dependent regulation of locomotor network performance by the Na+ pump. AB - This corrects the article DOI: 10.1038/srep16188. PMID- 29269938 TI - The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis. AB - New Delhi metallo-beta-lactamases (NDMs), the recent additions to metallo-beta lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of beta-lactam antibiotics and rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM 1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80-2.32 A, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme intermediate/product derivatives, EI1, EI2, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Delta2 to Delta1, absence of a bridging water molecule and an exclusive beta-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the beta-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors. PMID- 29269939 TI - Influence of solubilization and AD-mutations on stability and structure of human presenilins. AB - Presenilin (PS1 or PS2) functions as the catalytic subunit of gamma-secretase, which produces the toxic amyloid beta peptides in Alzheimer's disease (AD). The dependence of folding and structural stability of PSs on the lipophilic environment and mutation were investigated by far UV CD spectroscopy. The secondary structure content and stability of PS2 depended on the lipophilic environment. PS2 undergoes a temperature-dependent structural transition from alpha-helical to beta-structure at 331 K. The restructured protein formed structures which tested positive in spectroscopic amyloid fibrils assays. The AD mutant PS1L266F, PS1L424V and PS1DeltaE9 displayed reduced stability which supports a proposed 'loss of function' mechanism of AD based on protein instability. The exon 9 coded sequence in the inhibitory loop of the zymogen was found to be required for the modulation of the thermal stability of PS1 by the lipophilic environment. PMID- 29269941 TI - Diffusion MRI measurements in challenging head and brain regions via cross-term spatiotemporally encoding. AB - Cross-term spatiotemporal encoding (xSPEN) is a recently introduced imaging approach delivering single-scan 2D NMR images with unprecedented resilience to field inhomogeneities. The method relies on performing a pre-acquisition encoding and a subsequent image read out while using the disturbing frequency inhomogeneities as part of the image formation processes, rather than as artifacts to be overwhelmed by the application of external gradients. This study introduces the use of this new single-shot MRI technique as a diffusion monitoring tool, for accessing regions that have hitherto been unapproachable by diffusion-weighted imaging (DWI) methods. In order to achieve this, xSPEN MRI's intrinsic diffusion weighting effects are formulated using a customized, spatially-localized b-matrix analysis; with this, we devise a novel diffusion weighting scheme that both exploits and overcomes xSPEN's strong intrinsic weighting effects. The ability to provide reliable and robust diffusion maps in challenging head and brain regions, including the eyes and the optic nerves, is thus demonstrated in humans at 3T. New avenues for imaging other body regions are also briefly discussed. PMID- 29269942 TI - A dynamic map for learning, communicating, navigating and improving therapeutic development. PMID- 29269943 TI - Regulatory policy for the development of targeted therapies for low-frequency molecular subtypes of disease. PMID- 29269944 TI - The evolving paradigm of cancer trials. PMID- 29269945 TI - Human Sexual Cycles are Driven by Culture and Match Collective Moods. AB - Human reproduction does not happen uniformly throughout the year and what drives human sexual cycles is a long-standing question. The literature is mixed with respect to whether biological or cultural factors best explain these cycles. The biological hypothesis proposes that human reproductive cycles are an adaptation to the seasonal (hemisphere-dependent) cycles, while the cultural hypothesis proposes that conception dates vary mostly due to cultural factors, such as holidays. However, for many countries, common records used to investigate these hypotheses are incomplete or unavailable, biasing existing analysis towards Northern Hemisphere Christian countries. Here we show that interest in sex peaks sharply online during major cultural and religious celebrations, regardless of hemisphere location. This online interest, when shifted by nine months, corresponds to documented human births, even after adjusting for numerous factors such as language and amount of free time due to holidays. We further show that mood, measured independently on Twitter, contains distinct collective emotions associated with those cultural celebrations. Our results provide converging evidence that the cyclic sexual and reproductive behavior of human populations is mostly driven by culture and that this interest in sex is associated with specific emotions, characteristic of major cultural and religious celebrations. PMID- 29269947 TI - Supporting the sharing of research. PMID- 29269946 TI - Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma. AB - CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC50 = 6 nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC50 values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases. PMID- 29269948 TI - Muscling toward therapy with ERBB3 and NGFR. PMID- 29269949 TI - PERK links the clock and protein stress in cancer. PMID- 29269950 TI - Sugar fuels T-cell memory. PMID- 29269952 TI - Evaluation of a chemical risk assessment method of South Korea for chemicals classified as carcinogenic, mutagenic or reprotoxic (CMR). AB - OBJECTIVES: Chemicals were used in various fields by the development of industry and science and technology. The Chemical Hazard Risk Management (CHARM) was developed to assess the risk of chemicals in South Korea. In this study, we were to evaluate the CHARM model developed for the effective management of workplace chemicals. MATERIAL AND METHODS: We used 59 carcinogenic, mutagenic or reprotoxic (CMR) materials, which are both the work environment measurement result and the usage information among the manufacturer data. The CHARM model determines the risk to human health using the exposure level (based on working environment measurements or a combination of the quantity used and chemical physical properties (e.g., fugacity and volatility)), hazard (using occupational exposure limit (OEL) or Risk phrases (R-phrases)/Hazard statements (H-statements) from the Material Safety Data Sheet (MSDS)). RESULTS: The risk level was lower when using the results of the work environment measurement than when applying the chemical quantity and physical properties in the exposure level evaluation method. It was evaluated as grade 4 for the CMR material in the hazard class determination. The risk assessment method by R-phrases was evaluated more conservatively than the risk assessment method by OEL. And the risk assessment method by H-statements was evaluated more conservatively than the risk assessment method by R-phrases. CONCLUSIONS: The CHARM model was gradually conservatively assessed as it proceeded in the next step without quantitative information for individual workplaces. The CHARM is expected to help identify the risk if the hazards and exposure levels of chemicals were identified in individual workplaces. For CMR substances, although CHARM is highly evaluated for hazards, the risk is assessed to be low if exposure levels are assessed low. When evaluating the risk of highly hazardous chemicals such as CMR substances, we believe the model should be adapted to be more conservative and classify these as higher risk. Int J Occup Med Environ Health 2018;31(4):491-501. PMID- 29269953 TI - Letter to the Editor (July 28, 2017) concerning the paper "Mortality for chronic degenerative diseases in Tuscany: Ecological study comparing neighboring areas with substantial difference in environmental pollution". PMID- 29269951 TI - Mechanoreciprocity in cell migration. AB - Cell migration is an adaptive process that depends on and responds to physical and molecular triggers. Moving cells sense and respond to tissue mechanics and induce transient or permanent tissue modifications, including extracellular matrix stiffening, compression and deformation, protein unfolding, proteolytic remodelling and jamming transitions. Here we discuss how the bi-directional relationship of cell-tissue interactions (mechanoreciprocity) allows cells to change position and contributes to single-cell and collective movement, structural and molecular tissue organization, and cell fate decisions. PMID- 29269954 TI - Authors' response (August 21, 2017) to the letter to the Editor concerning the paper "Mortality for chronic-degenerative diseases in Tuscany: Ecological study comparing neighboring areas with substantial difference in environmental pollution". PMID- 29269955 TI - Update Breast Cancer 2017 - Implementation of Novel Therapies. AB - In recent years, numerous new therapy options for patients with breast cancer have been developed in clinical studies, with some options already approved for routine treatment. As the speed at which innovations are introduced increases, the importance of conferences also increases, as conferences are where the data underpinning new therapies are usually presented for the first time. This review looks at publications of the ASCO (American Society of Clinical Oncology) and ESMO (European Society of Medical Oncology) conferences in 2017, summarizes them and evaluates them in the context of existing data. The focus is on new insights for neoadjuvant therapy and new treatment options in the metastatic setting, such as the use of CDK4/6 inhibitors or PARP inhibitors. The first results of treatments with checkpoint inhibitors are presented. With the patent expiry of trastuzumab, a number of study results for trastuzumab biosimilars have also been published. The digitization of patient care provides the first results on quality of life and prognosis of patients with advanced cancer. Digital communications between patients and physicians are being evaluated in several studies in Germany. As the discussion about patient-relevant endpoints for patients in the metastatic setting continues, overall survival rates from studies of big endocrine-based therapies are urgently needed. Preliminary analyses of small study cohorts offer initial insights. In the context of improving patient care, in the coming years, questions will center on which patients particularly benefit from certain therapies and which patients need particular protection from specific side effects. Questions about these predictors are raised in many scientific projects as attention increasingly focuses on this topic. PMID- 29269956 TI - Circulating Tumour Cells, Circulating Tumour DNA and Circulating MicroRNA in Metastatic Breast Carcinoma - What is the Role of Liquid Biopsy in Breast Cancer? AB - Dissemination of tumour cells and the development of solid metastases occurs via blood vessels and lymphatics. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) can be detected in venous blood in patients with early and metastatic breast cancer, and their prognostic relevance has been demonstrated on numerous occasions. Repeated testing for CTCs and ctDNA, or regular so-called "liquid biopsy", can be performed easily at any stage during the course of disease. Additional molecular analysis allows definition of tumour characteristics and heterogeneity that may be associated with treatment resistance. This in turn makes personalised, targeted treatments possible that may achieve both improved overall survival and quality of life. PMID- 29269957 TI - A Systematic Review of Mycoplasma and Ureaplasma in Urogynaecology. AB - Mycoplasma species relevant to the urogenital tract include mycoplasma hominis, mycoplasma genitalia and ureaplasma urealyticum. Their occurrence in the context of urogynaecological disease has been demonstrated in urethritis, cystitis and upper renal tract infections. Their role in hyperactive bladder and interstitial cystitis/painful bladder syndrome is controversial. All the above-mentioned microorganisms can occur as commensals or as potential pathogens. In most cases their role in any particular pathology cannot be proven, only presumed. The aim of this systematic review was to summarise current knowledge on the influence of mycoplasma and ureaplasma in urogynaecological pathology and to provide clinical guidance on diagnosis (when and how is pathogen detection indicated?) and treatment. 377 relevant articles were analysed. In summary: a urethral swab for PCR analysis of the three bacteria should be performed in the context of symptomatic sterile leukocyturia, chronic urethritis and suspected hyperactive bladder or interstitial cystitis/painful bladder syndrome. Symptomatic women should be treated strictly according to results of the antibiogram. PMID- 29269958 TI - Repetitive Maturation of Oocytes From Non-Stimulated Xenografted Ovarian Tissue From a Prepubertal Patient Indicating the Independence of Human Ovarian Tissue. AB - Introduction: Modern anti-cancer strategies have distinctly increased survival rates; nevertheless, often accompanied by sterility. Currently, the only option for preserving fertility in prepubertal females is to cryopreserve ovarian tissue and re-transplant frozen-thawed tissue to restore fertility after treatment. Our aim was to report the occurrence of repetitive antral follicle formation and oocyte maturation in a prepubescent ovarian tissue xenograft without exogenous hormone stimulation. Material and Methods: Frozen-thawed ovarian tissue from a 6 year-old patient suffering from nephroblastoma was xenotransplanted in oophorectomized severe combined immunodeficiency (SCID) mice to evaluate follicle development. Ergebnisse: Repetitive follicle development to the antral stage occurred in the same xenograft of prepubertal ovarian tissue without exogenous hormone administration; 37 days after retrieving a maturing oocyte (this first retrieval has been previously published), another, completely mature oocyte was harvested from the xenograft. Subsequent histological evaluation of the grafted tissue showed primordial follicles, nearly all stages of developing follicles, as well as large atretic ones. Many clusters with dormant primordial follicles were also present. Conclusion: Xenotransplanted prepubertal ovarian tissue has the potential for repetitive oocyte retrieval cycles without administering exogenous hormones. The results indicate that the human ovarian tissue might be able to synchronize the hypothalamus-hypophysis-axes of the mouse to the physiological human cycle; this should be investigated in future studies. PMID- 29269959 TI - How Metamorphosis Is Different in Plethodontids: Larval Life History Perspectives on Life-Cycle Evolution. AB - Plethodontid salamanders exhibit biphasic, larval form paedomorphic, and direct developing life cycles. This diversity of developmental strategies exceeds that of any other family of terrestrial vertebrate. Here we compare patterns of larval development among the three divergent lineages of biphasic plethodontids and other salamanders. We discuss how patterns of life-cycle evolution and larval ecology might have produced a wide array of larval life histories. Compared with many other salamanders, most larval plethodontids have relatively slow growth rates and sometimes exceptionally long larval periods (up to 60 mo). Recent phylogenetic analyses of life-cycle evolution indicate that ancestral plethodontids were likely direct developers. If true, then biphasic and paedomorphic lineages might have been independently derived through different developmental mechanisms. Furthermore, biphasic plethodontids largely colonized stream habitats, which tend to have lower productivity than seasonally ephemeral ponds. Consistent with this, plethodontid larvae grow very slowly, and metamorphic timing does not appear to be strongly affected by growth history. On the basis of this, we speculate that feeding schedules and stress hormones might play a comparatively reduced role in governing the timing of metamorphosis of stream-dwelling salamanders, particularly plethodontids. PMID- 29269960 TI - Social Factors Linking Stigma-Related Stress with Alcohol Use among Lesbians. AB - A conceptual model linking stigma-related stress and lesbian women's alcohol use and related problems via social factors (i.e., social constraints and social isolation), depressive symptoms, and negative reinforcement drinking motives (i.e., coping and conformity) was tested. Self-identified lesbian women (N = 1048), age 18-35 years in the United States completed an online survey of discrimination, stigma consciousness, social isolation, social constraints, depressive symptoms, drinking motives, alcohol use and related problems. The hypothesized path model showed excellent model fit. The predicted pathway of stigma-related stressors to alcohol outcomes via social factors, depressive symptoms, and coping/conformity motives was largely supported. Results highlight the importance of social factors in linking stigma-related stress to alcohol use and related problems among lesbians. Understanding the underlying social mechanisms connecting stigma to negative health outcomes may help inform intervention efforts to reduce alcohol use and related problems among lesbians and associated health disparities. PMID- 29269961 TI - Development of a new UHV/XHV pressure standard (Cold Atom Vacuum Standard). AB - The National Institute of Standards and Technology has recently begun a program to develop a primary pressure standard that is based on ultra-cold atoms, covering a pressure range of 1 * 10-6 Pa to 1 * 10-10 Pa and possibly lower. These pressures correspond to the entire ultra-high vacuum (UHV) range and extend into the extreme-high vacuum (XHV). This cold-atom vacuum standard (CAVS) is both a primary standard and absolute sensor of vacuum. The CAVS is based on the loss of cold, sensor atoms (such as the alkali-metal lithium) from a magnetic trap due to collisions with the background gas (primarily H2) in the vacuum. The pressure is determined from a thermally-averaged collision cross section, which is a fundamental atomic property, and the measured loss rate. The CAVS is primary because it will use collision cross sections determined from ab initio calculations for the Li + H2 system. Primary traceability is transferred to other systems of interest using sensitivity coefficients. PMID- 29269962 TI - Post-thaw amendment of cryopreserved sperm for use in artificial insemination of a viviparous fish, the green swordtail Xiphophorus helleri. AB - Sperm cryopreservation protocols have been developed for live-bearers such as the green swordtail Xiphophorus helleri and the platyfish Xiphophorus couchianus. Despite the high post-thaw motility (~75%) obtained in both species, the requirements of sperm storage within the female reproductive tract coupled with the process of internal fertilization place functional demands upon cryopreserved sperm samples far beyond those of oviparous species. The purpose of this study was to facilitate the artificial insemination process with cryopreserved sperm of X. helleri through evaluation of parameters related to sperm quality after thawing. Specifically, this study evaluated the effects on motility for fresh and thawed sperm samples of centrifugation (for concentration of sperm and washing for removal of cryoprotectant), ionic composition, and additions of glucose and fetal bovine serum (FBS) in extender solutions. Centrifugation at 1000 *g for 10 min at 4 degrees C was found to have no adverse effects on sperm motility of fresh samples, and for cryopreserved samples, the removal of glycerol by washing yielded higher and longer post-thaw motility (e.g., 168 h vs. 48 h for the controls). Suspension of fresh sperm samples in magnesium-free Hanks' balanced salt solution (HBSS) did not affect motility; however, HBSS prepared with the absence of potassium or calcium, and the use of unsupplemented saline (NaCl alone) as extenders significantly reduced sperm motility. The presence of glucose in HBSS yielded higher and longer motility for fresh and thawed samples, but addition of glucose at greater than 2 g/L were unnecessary. Addition of 20% FBS prior to freezing was found to increase the post-thaw motility significantly compared to control treatment with 14% glycerol alone. Also addition of 20% FBS after thawing and centrifugation was found to induce the formation of sperm bundles, which may be beneficial for internal fertilization success. In conclusion, concentration of sperm and the removal of cryoprotectant (through centrifugation), and the addition of 20% FBS in the extender is recommended for future insemination trials with cryopreserved samples. PMID- 29269963 TI - Selection and Validation of Predictive Models of Radiation Effects on Tumor Growth Based on Noninvasive Imaging Data. AB - The use of mathematical and computational models for reliable predictions of tumor growth and decline in living organisms is one of the foremost challenges in modern predictive science, as it must cope with uncertainties in observational data, model selection, model parameters, and model inadequacy, all for very complex physical and biological systems. In this paper, large classes of parametric models of tumor growth in vascular tissue are discussed including models for radiation therapy. Observational data is obtained from MRI of a murine model of glioma and observed over a period of about three weeks, with X-ray radiation administered 14.5 days into the experimental program. Parametric models of tumor proliferation and decline are presented based on the balance laws of continuum mixture theory, particularly mass balance, and from accepted biological hypotheses on tumor growth. Among these are new model classes that include characterizations of effects of radiation and simple models of mechanical deformation of tumors. The Occam Plausibility Algorithm (OPAL) is implemented to provide a Bayesian statistical calibration of the model classes, 39 models in all, as well as the determination of the most plausible models in these classes relative to the observational data, and to assess model inadequacy through statistical validation processes. Discussions of the numerical analysis of finite element approximations of the system of stochastic, nonlinear partial differential equations characterizing the model classes, as well as the sampling algorithms for Monte Carlo and Markov chain Monte Carlo (MCMC) methods employed in solving the forward stochastic problem, and in computing posterior distributions of parameters and model plausibilities are provided. The results of the analyses described suggest that the general framework developed can provide a useful approach for predicting tumor growth and the effects of radiation. PMID- 29269964 TI - Judges' Perceptions of Screening, Assessment, Prevention, and Treatment for Substance Use, Mental Health, and HIV among Juveniles on Community Supervision: Results of a National Survey. AB - Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) National Survey was funded in part to describe the current status of screening, assessment, prevention and treatment for substance use, mental health, and HIV for youth on community supervision within the US juvenile justice system. Surveys were administered to community supervision agencies and their primary behavioral healthcare providers, as well as the juvenile or family court judge with the largest caseload of youth on community supervision. This article presents the findings from the judges' survey. Survey results indicated juvenile and family court judges were open to innovations for improving the court's performance, rated their relationships with collaborators highly, and appreciated the impact of screening, assessment, prevention, and treatment on judicial practices. PMID- 29269965 TI - Truancy in the United States: Examining Temporal Trends and Correlates by Race, Age, and Gender. AB - Background: Truancy has long been regarded a common problem in urgent need of effective intervention. Knowledge about factors associated with truancy can guide the development and implementation of interventions. Method: This paper examined trends in truancy rates between 2002-2014 and correlates of truancy across racial/ethnic groups. Variables of interest included sociodemographic factors (e.g., age, gender, socio-economic background), behavioral factors (e.g., substance use, violence), and psychosocial factors (e.g., academic engagement, grades, parental control). Using data from a large sample of adolescents (n=209,393; 12-17 years) we estimated truancy prevalence rates and examined trends and correlates via regression analyses. Results: Truancy rates remained constant between 2002 (10.8%) and 2014 (11.1%). Rates were highest among older youth, females, and Hispanic youth. For all racial/ethnic groups, truancy was significantly correlated with alcohol and marijuana use, fighting, the propensity to take risks, and lower academic engagement and school grades. Other factors were differentially associated with racial/ethnic groups. This divergence in risk patterns for different racial/ethnic groups points to some heterogeneity amongst truant youth. Discussion: Despite truancy reduction efforts, truancy rates have remained stable. Efforts to prevent truancy and to intervene with truant youth may need to target risk factors more prevalent in specific racial/ethnic groups. PMID- 29269966 TI - Call for Perseverance and Resources: The Vital Teeth of Key to Success in Ayurveda Research. PMID- 29269967 TI - Antidiabetic Effects of Artemisia Species: A Systematic Review. AB - Background: Over the last century, human life style and food habits have drastically changed which lead to various chronic diseases. Diabetes mellitus is one such disease which is causing serious problems to human health. Allopathic drugs are not much effective in handling the disease and its complications. Hence focus has been turned towards the traditional system of medicine. Medicinal plants play an important role in the management of diabetes mellitus. Methods: Experimental studies conducted on species of Artemisia on diabetic animal models and human published since the year 2000 until April, 2017 were reviewed. Each article was critically appraised by two independent reviewers for their methodological quality using the JBIMAStARI tool. Result: A total of 14 studies were included in this review and the blood glucose data obtained from these critically reviewed studies clearly showed that both the aqueous and alcoholic extracts of species of Artemisia produced significant hypoglycemic effects in alloxan, Streptozotocin and high fat diet induced diabetic animals and diabetic humans with different mechanisms of action as compared to standard antidiabetic medications. Discussion and Conclusion: The antidiabetic effect of single or multiple doses of aqueous and alcoholic extracts of Artemisia species was due to the active compounds of these plants and they all are effective in lessening the blood glucose level in all of those experimental studies. Despite the presence of known antidiabetic medicines in the pharmaceutical market, therapeutic remedies from these medicinal plants have been utilized with success to treat this disorder and its complications with a relatively less side effects. PMID- 29269968 TI - A Metallurgical Study of Naga Bhasma. AB - Background: The metal Naga (Lead) is being used by Indians since ancient times. Its external and internal uses have been described in Caraka, Susruta and other Ayurvedic Samhita. According to most of the Rasa texts, Naga Bhasma and its formulations are used in many diseases such as Prameha, Jvara, Gulma, Sukrameha etc. Objectives: In the present study, Naga Bhasma was prepared by the traditional Puta method (TPM) and by the electric muffle furnace Puta method (EMFPM) and standardized using Metallographic studies. Doing so helps in the study of the microstructure of Naga Bhasma and also helps in the identification of the metal particles along with the nature of compound formed during the Marana (Bhasmikarana) process. Setting and Design: Different samples from initial raw material to final product of Naga Bhasma were collected during the pharmaceutical process (1st, 30th and 60thPuta) from both methods i.e. TPM and EMFPM. Samples from both methods were studied using metallographic examination. Materials and Methods: The processing of the Naga Bhasma (sastiputa) was done according to Ananda Kanda[9] Samples from the raw material i.e. Asodhita Naga (raw Lead) and that processed after 1st, 30th and 60th Puta from both methods i.e. traditional Puta method (using heat from burning of cow dung cakes) and electric muffle furnace Puta method were taken. They were mounted on self hardening acrylic base. After careful polishing to obtain scratch free surface of product, they were used for metallurgical study. Conclusion: This study shows that traditional Puta method may be better than electric muffle furnace Puta method because of more homogeneous distribution of Lead sulphide in the Naga Bhasma which is prepared by traditional method. PMID- 29269969 TI - Determination of Antimicrobial Potential of Five Herbs used in Ayurveda Practices against Candida albicans, Candida parapsilosis and Methicillin Resistant Staphylococcus aureus. AB - Background: Medicinal plants are an important source of novel antimicrobial agents. Ayurvedic treatment involves the use of a variety of medicinal plants that merit investigation. Aims: To investigate the antimicrobial activity of bark of Pongamia pinnata (L.) Pierre, stem of Rubia cordifolia Linn, leaves of Jasminum officinale Linn, stem of Berberis ceylanica C.K. Schneid. and fruit of Garcina zeylanica Roxb. Subjects and Methods: Aqueous and ethanolic extracts of dried bark of Pongamia pinnata (Magul karanda), dried stem of Rubia cordifolia Linn (Welmadata), tender leaves of Jasminum officinale Linn (Jasmine) and dried stem of Berberis ceylanica (Daruharidra) were prepared according to standard protocols and tested for antimicrobial activity against five clinical isolates and one standard strain each of Candida albicans (ATCC 10231), Candida parapsilosis (ATCC 22019) and six Methicillin Resistant Staphylococcus aureus (MRSA) clinical isolates using the well diffusion method. Experiments were done in triplicates using well diffusion method. The plant extracts which gave a zone of inhibition in the well diffusion assay were further tested for Minimum Inhibitory Concentrations (MIC). Results: Aqueous and ethanolic extracts of Berberis ceylanica and ethanolic extract of Rubia cordifolia had antimicrobial activity against Candida albicans and Candida parapsilosis. Aqueous and ethanolic extracts of Garcinia zeylanica, and the ethanolic extracts of Jasminum officinale, Rubia cordifolia and Pongamia pinnata had antimicrobial activity against MRSA. Conclusions: Berberis ceylanica and Rubia crodifolia had antimicrobial activity against Candida species while Garcinia zeylanica, Jasminum officinale, Rubia crodifolia and Pongamia pinnata had antimicrobial activity against MRSA. PMID- 29269970 TI - Traditional Consumption of the Fruit Pulp of Chrysophyllum albidum (Sapotaceae) in Pregnancy may be Serving as an Intermittent Preventive Therapy against Malaria Infection. AB - Background: The bark of Chrysophyllum albidum is reported to possess antimalarial property. The fruit pulp of C. albidum consumed by pregnant women of south eastern Nigeria may also possess antimalarial activity. The present preliminary study investigated the antimalarial potential of the pulp juice and seed of C. albidum. Methods: Schizonticidal activity was evaluated using the Peter's 4-day suppressive test. The prophylactic and curative antimalarial activities of the extracts were evaluated in Albino mice inoculated with Plasmodium berghei. Results: The oral acute toxic dose of the pulp extract is beyond 5000 mg/kg. The seed and pulp possess both suppressive and curative properties. The seed extract suppressed early infection by 72.97% and 97.30%, at 500 and 1000 mg/kg, respectively. The pulp juice recorded 72.97% and 81.08%, at 500 and 1000 mg/kg, respectively. At 500 mg/kg dose, the level of parasite control on Day 7 was the same (96.10%) for both seed and pulp. Conclusion: This study demonstrates the presence of antimalarial constituents in the chemically uncharacterized samples (fruit pulp and seed) of C. albidum. Its ethnomedicinal use may be valuable in pregnancy where it may possibly serve as an intermittent preventive therapy against malaria. PMID- 29269971 TI - Effect of Bhramari Pranayama Practice on Pulmonary Function in Healthy Adolescents: A Randomized Control Study. AB - Context: Pranayama, the fourth limb of ancient astanga yoga consists of breathing techniques which produce various physiological and psychological effects. Though various types of pranayama and their effects have been scientifically established, Bhramari pranayama (Bhr.P) is the one whose effects still remain understated. Aims: The present study was conducted to find the effects of Bhramari pranayama practice on pulmonary function in healthy adolescents. Study Design: Randomized control trial. Subjects and Methods: 90 healthy adolescents including 32 females and 58 males participated in the study. They were randomly divided into Bhr.P group (n = 45) and Control group (n = 45) by a simple lottery method. Pulmonary function test was done at baseline and at end of 12th week using RMS Helios spirometry. Pranayama group students were trained to do Bhr.P as 3 to 4 breaths/min for 5 min followed by 2 min rest. This was one cycle and in this way, they were instructed to do five cycles each time for 45 minutes five days in a week. Control group students were not allowed to practice any kind of exercise throughout the study period. Statistical Analysis: Student paired and unpaired T tests were used to analyse the intra group and intergroup differences using R statistical software. Results: A significant (P < 0.05) improvement in all pulmonary function parameters; FVC, FEV1, FEV1/FVC ratio, FEF 25%-75% and PEFR was seen in the Bhr.P group than the control group adolescents. Slow vital capacity (SVC) and Maximum Voluntary Volume (MVV) also showed significant improvement in the pranayama group. Conclusions: Bhramari Pranayama practice is effective in improving the pulmonary function among the adolescents which could be utilized for further clinical studies. PMID- 29269972 TI - Protective Effect of Standardized Extract of Passiflora incarnata Flower in Parkinson's and Alzheimer's Disease. AB - Background: Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Flavonoids exert their antioxidant effects by neutralizing all types of oxidizing radicals including the superoxide and hydroxyl radicals. Passiflora incarnata Linn. (Passifloraceae) is an important plant used in Ayurveda for the treatment of various disorders of the CNS and is a rich source of flavonoids. Aim: In the present study, we investigated the antioxidant, antiparkinsonian, and memory enhancing activity of flavonoid rich n-butanol extract of P. incarnata flowers (BEPIF). Materials and Methods: Antioxidant activity was assessed using DPPH and hydrogen peroxide scavenging assay. The antiparkinsonian activity was evaluated using haloperidol induced catalepsy and tacrine induced vacuous chewing movement and memory enhancing activity was assessed using elevated plus maze and object recognition test. Statistical Analysis: The results were analyzed by Analysis of Variance test followed by Dunnett's test. Results: Administration of BEPIF decreased transfer latency on day 2 and 9 significantly in elevated plus maze test and showed a significant increase in discrimination index in the object recognition test which is suggestive of its cognitive improvement action. Pretreatment with BEPIF showed a significant reduction in the haloperidol induced catalepsy and the tacrine induced jaw movements which are suggestive of its antiparkinsonian activity. In DPPH and H2O2 scavenging assay, BEPIF exhibited significant free radical scavenging activity. Conclusions: It can be concluded that the butanolic extract of P. incarnata flowers has significant antiparkinsonian and cognition enhancing activity which may be associated with its antioxidant potential. Thus, P. incarnata flowers may be employed in treatment of dementia and parkinsonism. PMID- 29269973 TI - Chemical Characterization of an Ayurvedic Herbo-Mineral Formulation - Vasantakusumakara Rasa: A Potential Tool for Quality Assurance. AB - Background: Herbo-mineral formulations of Ayurveda contain specified metals or minerals as composition, which have their beneficial effects on biological systems. These metals or minerals are transformed into non-toxic forms through meticulous procedures explained in Ayurveda. Though literature is available on quality aspects of such herbo-mineral formulations; contemporary science is raising concerns at regular intervals on such formulations. Thus, it becomes mandate to develop quality profiles of all formulations that contain metals or minerals in their composition. Considering this, it is planned to evaluate analytical profile of Vasantakusumakara Rasa. Objective: To prepare Vasantakusumakara Rasa as per Standard operating Procedures (SoP) mentioned in classical text and to characterize it chemically using modern analytical techniques. Materials and Methods: The drug (Vasantakusumakara Rasa) in three batches was prepared in GMP certified pharmacy. Physico-chemical analysis, Assay of elements and HPTLC were carried out as per API. XRD was conducted using Rigaku Ultima-IV X-ray diffractometer. Results: The analysis shown the presence of Mercury, Tin, Gold, Silver, Iron, Zinc and Calcium etc., and HPTLC revealed presence of organic constituents from plant material. The XRD indicated the presence of cinnabar (mercury sulphide from Rasa Sindhura), cassiterite (tin oxide from Vanga Bhasma), massicot (lead oxide from Naga bhasma) and Magnetite (di-iron oxide from Loha bhasma). Conclusion: The physico chemical analysis reveals that VKR prepared by following classical guidelines is very effective in converting the macro elements into therapeutically effective medicines in micro form. Well prepared herbo-mineral drugs offer many advantages over plant medicines due to their longer shelf life, lesser doses, easy storing facilities, better palatability etc. The inferences and the standards laid down in this study certainly can be utilized as baseline data of standardization and QC. PMID- 29269974 TI - Anti-anxiety and Anti-depressant Like Effects of Murraya koenigii in Experimental Models of Anxiety and Depression. AB - Background: Presence of free radical scavenging activity in Murrayakoenigii, commonly known as Curry leaves, has been shown in previous studies. Oxidative stress plays an important role in the development of various neurobehavioral disorders including anxiety and depression. Aim: The present study aimed to evaluate the effects of Murraya koenigii in animal models of depression and anxiety. Materials and Methods: The effect of incremental doses of Murraya koenigii aqueous leaf extract was evaluated on spontaneous motor activity (SMA), open arm incursions in elevated plus maze, and despair behaviour in forced swim (FST) and tail suspension (TST) tests as compared to control groups in Swiss albino mice. Results: Murraya koenigii 300 mg/kg, p.o. (MK300) and 400 mg/kg, p.o. (MK400) reduced the SMA count from 754 +/- 64.9 to 540 +/- 29 and 295 +/- 34 respectively, which was statistically significant. MK300 and MK400 reduced significantly the open arm count from 29 +/- 8.6 to 16 +/- 7 and 10 +/- 3.9, respectively. On FST, MK400 reduced the duration of immobility from 145.5 +/- 29 to 91 +/- 17.3, which was statistically significant. On TST, MK produced a dose dependent decrease in the duration of immobility; however, it was statistically significant only with MK400. Conclusion: Murraya koenigii aqueous leaf extract reduced the despair behavior in experimental animal models, suggesting an anti depressant like activity. Murraya koenigii extract also reduced spontaneous locomotor activity in a dose-dependent manner suggesting a sedative and/or anxiolytic effect though there wasn't any anxiolytic effect in the elevated plus maze test. PMID- 29269975 TI - Management of Recurrent Nasal Vestibular Furunculosis by Jalaukavacarana and Palliative Treatment. AB - Nasal vestibular furunculosis is a common bacterial skin infection among the general population mostly affecting adults and children. It is characterized by acute localized infection of hair follicle in the skin lining of the nasal vestibule caused by Staphylococcus aureus. Immunodeficiency also plays an important role in recurrent skin and soft tissue infections (SSTI) including Nasal furunculosis. Though, the lesion is small, it is extremely painful and tender. Treatment is mostly conservative which consists of warm compresses, analgesics to relieve pain, topical and systemic antibiotics directed against staphylococcus. With rapidly increasing resistance to antibacterial agents, management of these bacterial infections is becoming increasingly difficult. In Ayurveda, it can be correlated with Nasarunasikha (Nasal furunculosis). Morphologically, it appears like pidika (Furuncle) which is characterized by Ragayuktasotha (inflammation with reddening. Jalaukavacarana (Leech therapy) is one of the ancient and important parasurgical procedures described in Ayurveda for treatment of various diseases. In this case, a leech has been applied at the affected area. After leech treatment, throbbing pain was reduced in its intensity followed by gradual reduction in swelling and reddening in two days. This case suggests the utility of leech application in Nasal vestibular furunculosis. PMID- 29269976 TI - A Case Study on Successful Ayurvedic Management of a Rare Case of Reiter's Syndrome. AB - Reiter's syndrome is a clinical syndrome of arthritis, urethritis, conjunctivitis, and mucocutaneous lesions. Skin and mucosal involvement is observed in about 10% of the cases. A 34-year-old male was brought in severe condition. He had red colored foul smelling maculopapular skin lesions all over body, swollen and painful knee and shoulder joints. History revealed that he was suffering from Reiter's syndrome since 2003. He used to get admitted between the months of February and May every year due to aggravation of symptoms. Every time he was treated with systemic antibiotics, corticosteroids, immunosuppressants and non-steroidal anti-inflammatory drugs. He was successfully treated with external application and internal medication with tikta (bitter) and kasaya (astringent) drugs. He got significant relief in skin lesions as well as joint pain and his quality of life was markedly improved. This case study demonstrates that Reiter's syndrome can be well managed with Ayurvedic medicines. PMID- 29269977 TI - Autoimmune Bullous Skin Disease Managed with Ayurvedic Treatment: A Case Report. AB - Autoimmune bullous diseases are a group of rare, acquired disorders characterized by overlapping features, resistance to treatment, and potential fatality. They need quick and proper management to avoid fatal complications. Ayurveda is found to provide better relief in some autoimmune disorders. Herein, we report a 40 year-old male of autoimmune bullous skin disorder (Visphotaka) who failed to respond to allopathic medicines and was subsequently treated with Ayurvedic medicines and achieved complete remission. PMID- 29269978 TI - Knowledge and Awareness of Pharmacovigilance among Ayurveda Physicians in Himachal Pradesh. PMID- 29269979 TI - Eye-Tracking Evidence that Happy Faces Impair Verbal Message Comprehension: The Case of Health Warnings in Direct-to-Consumer Pharmaceutical Television Commercials. AB - Risk warning or disclosure information in advertising is only effective in correcting consumers' judgments if enough cognitive capacity is available to process that information. Hence, comprehension of verbal warnings in TV commercials may suffer if accompanied by positive visual elements. This research addresses this concern about cross-modality interference in the context of direct to-consumer (DTC) pharmaceutical commercials in the United States by experimentally testing whether positive facial expressions reduce consumers' understanding of the mandated health warning. A content analysis of a sample of DTC commercials reveals that positive facial expressions are more prevalent during the verbal warning act of the commercials than during the other acts. An eye-tracking experiment conducted with specially produced DTC commercials, which vary the valence of characters' facial expressions during the health warning, provides evidence that happy faces reduce objective comprehension of the warning. PMID- 29269981 TI - The incidence, risk factors and determinants of perinatal outcome of umbilical cord prolapses in Lagos, Nigeria. AB - Background: Umbilical cord prolapse is an obstetric emergency which is associated with significant perinatal mortality and morbidity as well as long-term handicap. Objectives: The objective of this study was to determine the incidence of cord prolapse, elucidate the risk factors as well as the fetal outcome at the Lagos University Teaching Hospital (LUTH). Design and Setting: A retrospective study at a tertiary care center in Lagos, Nigeria. Materials and Methods: A descriptive retrospective study of all pregnancies complicated by prolapse of the umbilical cord in LUTH from January 1, 2001 to December 31, 2010. Results: A total of 13,592 deliveries were conducted during the study period and 52 of which were complicated by cord prolapse at various cervical dilatations, thus giving an incidence of 3.8/1000 deliveries. Umbilical cord prolapses occurred commonly in women with multiple parities (51.9%), pregnancies with abnormal presentations (breech precisely) in 42.3%, abnormal lie in 30.8% with majority of the cord prolapse occurring after spontaneous membrane rupture (73.1%) while 26.9% occurred following amniotomy. Twenty-nine (55.8%) cases occurred outside the hospital setting; 69.2% of the children affected were term. The mean diagnosis delivery interval was 53.3 +/- 25.5 min, and cesarean section was the mode of delivery in 84.6%. Twenty-five percent of the children had Apgar score of >=7 at the 1st min of life increasing to 69.2% at 5 min. The perinatal mortality was however 19.2%. Conclusion: Umbilical cord prolapse is associated with a significant perinatal mortality in this study, especially in those with spontaneous rupture of membranes that occurred outside the hospital setting. PMID- 29269980 TI - Within-Subject Reliability and between-Subject Variability of Oxidative Stress Markers in Saliva of Healthy Subjects: A Longitudinal Pilot Study. AB - The present study evaluated diurnal variations and day-to-day fluctuations of salivary oxidative stress (OS) markers in healthy adult individuals. Whole unstimulated saliva was collected at 2 time intervals over 3 consecutive days. Glutathione peroxidase (GPX), superoxide dismutase (SOD), total antioxidant capacity (TAC), and uric acid (UA) were analyzed using spectrophotometric methods, while 8-hydroxydeoxyguanosine (8-OHdG) and malondialdehyde (MDA) were determined using immunoassays. No significant differences for salivary OS markers between men and women were observed. For all examined OS markers, no significant day-to-day variations were demonstrated. Significant diurnal variations were found in salivary GPX, TAC and MDA levels. For SOD, TAC, GPX, and UA, good-to moderate intraindividual coefficients of variations (CVs) were observed in more than 75% of the subjects. For MDA and 8-OHdG, intraindividual CVs > 35% were observed in 60% and 40% of the subjects, respectively. Between-subject variance was wide for all examined OS markers (CV% 30.08%-85.70%). Due to high intraindividual variability in the salivary concentrations of MDA and 8-OHdG, those markers cannot be reliably verified based on single measurements and multiple measurements over several days would provide more reliable information. Salivary SOD, TAC, GPX, and UA proved stable across three days of measurement. Trial Registration. ClinicalTrials.gov NCT03029494. Registered on 2017-01-19. PMID- 29269982 TI - Diagnostic accuracy of spot albumin creatinine ratio and its association with fetomaternal outcome in preeclampsia and eclampsia. AB - Introduction: Hypertensive disorders in pregnancy are one of the leading causes of maternal and perinatal mortality. Proteinuria is one of the common and important features of preeclampsia. To evaluate the diagnostic accuracy of albumin-creatinine ratio (ACR) in woman with preeclampsia and eclampsia and examine the association between ACR and fetomaternal outcome. Materials and Methods: Prospective study carried out over a period of 1 year in the Department of Obstetrics and Gynaecology, after informed consent and ethical clearance total ninety pregnant women from gestational age 20 to 40 weeks were enrolled, including, thirty preeclampsia, thirty antepartum eclampsia, considered as cases and thirty normotensive pregnant women as controls. Preeclampsia was defined as per National High Blood Pressure Education Program 2000 working group. All patients were asked for a spot midstream urine sample, followed by 24 h urine collection. Urinary protein was estimated by the sulfosalicylic acid method and creatinine by the Jaffe's method. The urinary ACR was determined by automated analyzer. Results: Mean value of urinary ACR of controls was significantly lower (0.103 +/- 0.037) as compared to both groups. On comparing between groups the difference was significant (<0.001), a strong correlation between urinary ACR levels and 24 h urinary proteins was observed. Conclusion: In our study, an association of raised ACR values with severity of disease as well as with adverse fetomaternal outcome was observed. PMID- 29269983 TI - Effects of atorvastatin on proteinuria of type 2 diabetic nephropathy in patients with history of gestational diabetes mellitus: A clinical study. AB - Background: Gestational diabetes is known as one of the diseases through pregnancy. In the present study, changes in proteinuria after atorvastatin administration among patients with history of gestational diabetes were studied. Materials and Methods: In this randomized clinical trial, 42 patients were included in the study. Atorvastatin was administered for 21 patients, and 21 patients were designated as control group. Lipid profile, protein, and 24 h urine creatinine (uCr) levels were determined in the beginning and 3 months after intervention. P < 0.05 was considered statistically significant. Results: Lipid profile in intervention group was enhanced; low-density lipoprotein (LDL) had decreased while triglyceride had not changed and high-density lipoprotein had been increased. There was no statistically significant change in serum Cr, serum urea, estimated glomerular filtration rate, uCr, urine volume, 24-h urine protein level, or urine protein/Cr ratio on both groups during the study; also, there was no statistically significant difference between groups. Conclusions: Although LDL level decreased after atorvastatin therapy, atorvastatin therapy had no effect on the level of proteinuria or other parameters related to kidney function. PMID- 29269984 TI - Clinical feature and management of immune thrombocytopenic purpura in a tertiary hospital in Northwest Nigeria. AB - Background: Immune thrombocytopenic purpura (ITP) is a rare bleeding disorder that may remit spontaneously. Life-threatening bleeding may require transfusion support, steroids, and other immunosuppressive therapy or splenectomy. Objective: To review the clinical presentation and laboratory features of ITP at Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria. Subjects and Methods: A retrospective analytic study of case notes and bone marrow (BM) records of patients diagnosed with ITP at Haematology Department, ABUTH, Zaria, from January 1, 2004, to December 31, 2012. Results: There were nine cases (six females, three males), aged 6-20 (mean 11.11) years. The presentations were epistaxis 8 (88.9%), purpura 4 (44.4%), gum bleeding 4 (44.4%), menorrhagia 2 (22.2%), and intracranial hemorrhage (ICH) 1 (11.1%). Only 1 (11.1%) had clinical splenomegaly. Platelet count of <20 * 109/L was found in 4 (44.4%) while 6 (66.7%) had packed cell volume of <25%. All the nine cases had BM megakaryocytic hyperplasia. Six patients had blood transfusion support while 7 (77.8%) patients received oral prednisolone therapy with time to cessation of bleeding of 12-16 (mean of 8) weeks. One case had spontaneous remission while another had anti-D due to relapse after steroid therapy; this resulted in transient rise in platelet counts. None had other immunosuppressive therapy or splenectomy. Six (66.7%) cases were lost to follow-up after achieving remission and one died of ICH. Conclusion: ITP is not common in our center though its clinical presentations are varied. However, prednisolone and blood transfusion therapy are central to the management of these patients with favorable outcome. PMID- 29269985 TI - Are semen parameters worsening? Comparing semen parameters 10 years apart. AB - Background: Semen parameters, especially sperm count and motility have been said to be diminishing over time with implications for fertility and infertility treatment. Objective: The objective of this study was to study semen parameters 10 years apart and describe any observed change. Design: A retrospective study carried out at Nordica Fertility Centre, Lagos, Nigeria. Semen parameters of 100 consecutive men who sought fertility treatment on account of infertility in 2003 and semen parameters of 100 consecutive men who also sought fertility treatment at the center in 2013 on account of infertility were analyzed and compared. A paired t-test was performed to ascertain whether sperm counts have diminished over the last decade. The World Health Organization semen values were used as standard. Main Outcome Measures: They are sperm count, motility, and mean progressive motility. Results: The mean sperm count in the 2003 group was 34.6 * 106/ml (range: 0.1-105.0 106/ml) compared with 21.8 * 106/ml (range: 0.1-80.0 * 106/ml) in the 2013 group. The mean motility was 47.9% in the 2003 group and 45.3% in the 2013 group. The mean progressive motility in the 2003 group was predominantly graded as good (50% good, 44% fair, 2% poor, 4% no motility) while in the 2013 group, the predominant grade of mean progressive motility was fair (15% good, 81% fair, 4% poor). Normal morphology was more commonly seen in the 2013 group compared to the 2003 group. Mean semen volume was 2.7 and 2.6 ml in 2003 and 2013 groups, respectively. The mean difference in sperm count (mean = 12.8, standard deviation = 31.6, n = 100) was significantly >0 providing evidence that sperm counts have diminished in the last decade. Conclusion: There was a statistically significant 37% drop in mean sperm count and mean progressive motility worsened in the last decade. These may have far-reaching effects on infertility and its treatment. PMID- 29269986 TI - Etiology, clinical characteristics, and management of pleural effusion in Ilorin, Nigeria. AB - Background: Pleural effusion (PE) is a primary manifestation or secondary complication of many disorders. This study reviews the pattern and management of PE in a Nigerian hospital. Materials and Methods: The medical records of 213 patients with clinical diagnosis of PE over a period of 3 years were reviewed. Results: PE accounted for 0.5% of the total hospital admissions. The most common cause of PE was tuberculosis (TB) (32.9%), followed by malignancy (29.1%) and pneumonia (15.0%). The male to female ratio was 1.3:1. TB was the leading cause of effusion in males, while it was malignancy in females. Pneumonia accounted for 61.9% of PE in preschool age and 66.7% in school age. Breathlessness (50.0%), cough (39.4%), and chest pain (24.9%) were the common presentations. Most (90.1%) of them were exudative effusion and with half in the right lung. Chest radiography (91.6%), pleural fluid for Ziehl-Neelsen stain (74.7%), cytology (59.2%), and tissue biopsy (57.8%) were the common diagnostic investigations. The majority (92.0%) had closed thoracostomy tube drainage, while 9.9% had chemical pleurodesis. The intra-hospital mortality was 10 (4.7%). Conclusion: TB, malignancy, and pneumonia are the leading causes of PE. A multidisciplinary approach is needed for optimal management. PMID- 29269987 TI - Secundum atrial septal defect with Eisenmenger syndrome: A scarcely reported disease in Nigeria. AB - Atrial septal defect (ASD) may be rarely associated with Eisenmenger syndrome (ES), the most advanced form of pulmonary vascular disease to complicate a congenital heart disease. In spite of availability of pediatric cardiologists and two-dimensional-echochardiography in many tertiary health care centers in Nigeria, late referral and late diagnosis of ASD still occur leading to the development of ES. We describe a case of a 19-year-old male with ASD who presented late with ES. PMID- 29269988 TI - Ileoileal intussusception caused by the metastasis of cutaneous malignant melanoma to the small bowel 6 years after its excision presenting with small bowel obstruction. PMID- 29269989 TI - THE INFLUENCE OF LEXICAL FACTORS ON VOWEL DISTINCTIVENESS: EFFECTS OF JAW POSITIONING. AB - The phonetic characteristics of words are influenced by lexical characteristics, including word frequency and phonological neighborhood density (Baese-Berke & Goldrick, 2009; Wright, 2004). In our previous research, we replicated this effect with neurologically healthy young adults (Munson & Solomon, 2004). In research with the same set of participants, we showed that speech sounded less natural when produced with bite blocks than with an unconstrained jaw (Solomon, Makashay, & Munson, 2016). The current study combined these concepts to examine whether a bite-block perturbation exaggerated or reduced the effects of lexical factors on normal speech. Ten young adults produced more challenging lexical stimuli (i.e. infrequent words with many phonological neighbors) with shorter vowels and more disperse F1/F2 spaces than less challenging words (i.e. frequent words with few phonological neighbors). This difference was exaggerated when speaking with a 10-mm bite block, though the interaction between jaw positioning and lexical competition did not achieve statistical significance. Results indicate that talkers alter vowel characteristics in response both to biomechanical and linguistic demands, and that the effect of lexical characteristics is robust to the articulatory reorganization required for successful bite-block compensation. PMID- 29269990 TI - More than a Rural Revolt: Landscapes of Despair and the 2016 Presidential Election. PMID- 29269991 TI - Phrase frequency effects in free recall: Evidence for redintegration. AB - Four experiments examined the effects of word and phrase frequency on free recall. Word frequency did not affect word recall, but when participants studied and recalled lists of compositional adjective-noun phrases (e.g. alcoholic beverages), phrase frequency had a consistently beneficial effect: both words from frequent phrases were more likely to be recalled than for infrequent phrases, providing evidence that long-term memory for phrases can aid in pattern completion, or redintegration. We explain these results and those of a previous study of phrase frequency effects in recognition memory (Jacobs et al., 2016) by assuming that the language processing system provides features that are linked to episodic contexts. Recall tasks map from these contexts to linguistic elements, and recognition maps from linguistic elements to contexts. Word and phrase frequency effects in both memory tasks emerge both within the language processing system and from multiple stored episodes, and the fact that the representations of phrases are tied to knowledge of their component words, rather than being representational islands. PMID- 29269992 TI - Assessing the functions of non-suicidal self-injury: Psychometric properties of the Inventory of Statements About Self-injury (ISAS). AB - The present study reports the psychometric properties of the Inventory of Statements About Self-injury (ISAS), a measure designed to comprehensively assess the functions of non-suicidal self-injury (NSSI). The ISAS assesses 13 functions of NSSI, as well as the frequency of 12 NSSI behaviors. The ISAS was administered to 235 young adults from a college population who had performed at least one NSSI behavior. Consistent with previous research, ISAS functions comprised two factors representing interpersonal and intrapersonal functions. In addition, the ISAS factors exhibited excellent internal consistency and expected correlations with both clinical constructs (e.g., borderline personality disorder, suicidality, depression, anxiety) and contextual variables (e.g., tendency to self-injure alone). Findings support the reliability and validity of the ISAS. The ISAS may be useful in research and treatment contexts as a comprehensive measure of NSSI functions. PMID- 29269993 TI - Alternative Lens Model Equations for Dichotomous Judgments about Dichotomous Criteria. AB - Objective: The Brunswik lens model typically represents a judge's accuracy using parameters derived from linear regression. This is not optimal if the judgment or the ecological criterion is dichotomous. Alternative approaches, modeling dichotomies using logistic regression, or linearizing judgments with confidence ratings, have not been compared with the same data. Method: Four techniques for deriving lens model equation parameters were compared: 1) linear and 2) logistic regression applied to dichotomous patient outcomes and judgments; 3) linear regression with confidence-adjusted judgments but dichotomous patient outcomes; and 4) a hybrid with a linear model of the confidence-adjusted judgments and a logistic model of the patient outcomes. Results: Judgment accuracy (ra) was slightly higher with confidence adjustment of the categorical judgments. The logistic lens model accounted for a higher proportion of ra than the linear lens model; the confident-linear and hybrid lens models were intermediate. For up to a quarter of participants, different methods identified different cues as most important. Display condition differences in achievement ra and in lens model components are similar with all lens model methods. Conclusion: Each of the three alternative lens model equation methods improves on the linear lens model equation's decomposition of the accuracy of dichotomous judgments. Confidence adjustment improves achievement although it requires additional work from the subjects. The logistic lens model equation explains the highest proportion of achievement, but with a small stimulus set it is more vulnerable to cue intercorrelations than either the linear or the confident linear lens model equation. PMID- 29269994 TI - Intracellular Eukaryotic Pathogens' Virulence Attributes and Their Interplay with Host Immune Defenses. PMID- 29269996 TI - Shape Matching and Registration by Data-driven EM. AB - In this paper, we present an efficient and robust algorithm for shape matching, registration, and detection. The task is to geometrically transform a source shape to fit a target shape. The measure of similarity is defined in terms of the amount of transformation required. The shapes are represented by sparse-point or continuous-contour representations depending on the form of the data. We formulate the problem as probabilistic inference using a generative model and the EM algorithm. But this algorithm has problems with initialization and computing the E-step. To address these problems, we define a discriminative model which makes use of shape features. This gives a hybrid algorithm which combines the generative and discriminative models. The resulting algorithm is very fast, due to the effectiveness of shape-features for solving correspondence requiring typically only four iterations. The convergence time of the algorithm is under a second. We demonstrate the effectiveness of the algorithm by testing it on standard datasets, such as MPEG7, for shape matching and by applying it to a range of matching, registration, and foreground/background segmentation problems. PMID- 29269997 TI - An Open Trial Targeting Food Cue Reactivity and Satiety Sensitivity in Overweight and Obese Binge Eaters. AB - Data suggests that individuals who binge eat are more responsive to food cues in the environment and less sensitive to satiety cues. The aim of this open trial was to evaluate the feasibility, acceptability, and initial effectiveness of a novel treatment grounded in Schachter's externality theory targeting food cue reactivity and satiety responsiveness with obese adults who binge eat. Treatment was provided in groups, and utilized appetite monitoring, cue-exposure treatment, in vivo exercises, self-monitoring, and coping skills. Twenty-eight overweight and obese adults who binge eat (82% female; mean age = 47.5 years [SD = 12.8]; BMI = 38.9 [SD = 10.3]; 79% White non-Hispanic) participated in a 4-month group based treatment program. Assessments were conducted at baseline, posttreatment, and 3-month follow-up time points. Results indicated that this treatment was well accepted and had high retention at posttreatment. Initial effectiveness showed significant decreases in BMI, and improvements in loss of control and overeating episodes, food responsiveness, and power of food. The majority of results were maintained at the 3-month follow-up time point. This open trial provides preliminary evidence for the feasibility, acceptability, and initial effectiveness of this treatment on both eating disorder symptoms and weight in obese adults who binge eat. Because these data are preliminary, further treatment development and randomized controlled studies are needed. PMID- 29269995 TI - The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer. AB - Inflammation is part of our body's response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field. PMID- 29269998 TI - Endoscopic Eradication Therapy in Barrett's Esophagus. AB - Endoscopic eradication therapy (EET), the standard of care for treatment of Barrett's esophagus with dysplasia and early neoplasia, consists of a combination of endoscopic resection and ablative modalities. Resection techniques primarily include endoscopic mucosal resection or endoscopic submucosal dissection. Resection of nodular disease is generally followed by one of multiple ablative therapies among which radiofrequency ablation has the best evidence supporting safety and efficacy. These advanced endoscopic procedures require both experience and expertise in the cognitive and procedural aspects of EET. However, very few formal programs exist that teach endoscopists the necessary skills to perform EET in a safe, standardized, and efficacious manner. Case volume at both the endoscopist and center level has been shown to impact clinical outcomes based on limited data. As a result, some recent guidelines endorse case volume as a measure of competency. Quality indicators, which can be used as benchmarks for training and as part of pay for quality initiatives, have recently been derived for EET. However, quality metrics in EET have not been widely accepted, nor are they broadly used currently. While the efficacy of EET for BE is established, there is a need for application of quality metrics to both assure adequate training in these procedures, as well as to assess treatment outcomes. A standardized EET training curriculum during endoscopic training, with competency assessment of both new clinicians and endoscopists in practice has potential to improve care in EET. PMID- 29269999 TI - Topical nepafenac for prevention of post-cataract surgery macular edema in diabetic patients: patient selection and perspectives. AB - Since its first description, the prevention of pseudophakic cystoid macular edema (PCME) continues to pose challenges for ophthalmologists. Recent evidence suggests that prophylaxis is unnecessary in patients without risk factors. Diabetes mellitus is generally considered as a risk factor for the development of PCME after cataract surgery since it causes breakdown of the blood-retinal barrier. Diabetic retinopathy (DR) increases the risk even further. Therefore, prophylactic nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered in diabetic patients, especially if they have DR. NSAIDs block the cyclooxygenase enzymes responsible for prostaglandin production and reduce the incidence of PCME after cataract surgery. Nepafenac seems superior to other NSAIDs in terms of ocular penetration allowing higher and sustained therapeutic levels in retina and choroid. Topical steroids are less effective and may cause intraocular pressure increase limiting their long-term use. Nepafenac is cost effective, when the burden of PCME prevention is compared with the burden of treatment. Prevention is much cheaper and less harmful than invasive treatments like periocular or intravitreal injections. Overall, both nepafenac 0.1% and nepafenac 0.3% are well tolerated. They should be used carefully in patients with compromised corneas such as those with severe dry eye or penetrating grafts. If otherwise healthy cataract patients have >=2 risk factors, like PCME in the other eye or posterior capsule rupture during surgery, treatment should be considered. Once-daily nepafenac 0.3% dosing may improve postoperative outcomes through increased patient compliance and may reduce treatment burden further. Every patient should be assessed in terms of risks/benefits of the treatment, in individual basis, before cataract surgery. PMID- 29270000 TI - Three-dimensional mapping of peripapillary retinal layers using a spectral domain optical coherence tomography. AB - Purpose: To map and view the effects of age, gender, and axial length on seven individual retinal layers around the optic nerve head (ONH). Methods: We scanned 242 healthy patients using the Spectralis spectral domain optical coherence tomography in an outpatient setting. The layers were observed on the Early Treatment Diabetic Retinopathy Study sectors using the standard Spectralis Family Acquisition Module 6.0.11.0. The center was the ONH, the inner circle (IC) was 1 3 mm away, and the outer circle (OC) was 3-6 mm away. The seven layers were retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE). Additionally, we calculated the mean thickness of two combined layers: inner retinal layer (IRL) and photoreceptor layer (PL). Finally, we measured the mean of the total retinal thickness (TRT). Results: The TRT was highest at the inferior end in the IC and at the nasal end in the OC. The RPE (p<0.001) and PL (p<0.001) were thicker in males; however, the IRL (p=0.015) was thicker in females. We found that the RNFL (p<0.001, r=0.139), GCL (p<0.001, r=0.116), IPL (p=0.016, r=0.059), INL (p<0.001, r=0.104), OPL (p=0.009, r=0.064), ONL (p<0.001, r=0.157), RPE (p=0.001, r=0.079), IRL (p<0.001, r=0.190), PL (p=0.030, r=0.053), and TRT (p<0.001, r=0.191) correlated negatively with age. The axial length significantly and negatively correlated at the GCL (p=0.003, r=0.093), IPL (p=0.020, r=0.072), INL (p=0.018, r=0.073), ONL (p<0.001, r=0.110), IRL (p=0.003, r=0.092), and TRT (p=0.003, r=0.094). We found poor reproducibility in the IC; however, this was excellent in the OC. Conclusion: We found significant differences in layers according to age, gender, and axial length. Additionally, reproducibility can be improved by altering the algorithm to account for the ONH parameters. PMID- 29270001 TI - High-dose atorvastatin versus moderate dose on early vascular protection after ST elevation myocardial infarction. AB - Background and aim: Clinical benefits of early high-dose statin therapy after acute coronary syndromes are widely known; however, there is poor evidence on the specific setting of ST-elevation myocardial infarction (STEMI) and dose-dependent effects of this therapy on endothelial function and inflammatory biomarkers in the most vulnerable phase after acute coronary syndromes: the postdischarge period. In our study, we compared the short-term effects of high (80 mg) vs moderate doses of atorvastatin (20 mg) in patients with STEMI undergoing primary percutaneous coronary intervention on endothelial function and vascular inflammation. The aim of our study was the evaluation of dose-dependent short term effects. Subjects and methods: We enrolled 52 patients within 48 hours of a STEMI to atorvastatin 80 mg (n=26) or 20 mg (n=26). Every patient underwent endothelial function evaluation by the reactive hyperemia-peripheral arterial tonometry (RH-PAT) index on the first day and 1 month after the STEMI. At the same time, we measured lipid profile and serum levels of high-sensitivity CRP, IL6, TNFalpha, and oxidized LDL. Results: After 1 month of therapy, we observed differences in high-sensitivity CRP levels (0.04+/-0.02 mg/dL vs 0.36+/-0.3 mg/dL, P=0.001), IL6 (1.12+/-0.93 pg/mL vs 3.13+/-2.84 pg/mL, P=0.03), and improvement in RH-PAT index (1.96+/-0.16 vs 1.72+/-0.19, P=0.002) in the group treated with high-dose vs moderate-dose atorvastatin. There was no significant difference in levels of TNFalpha or oxidized LDL with atorvastatin 20 mg, while there was a reduction in these variables in the group treated with atorvastatin 80 mg. We observed a correlation between high-sensitivity polymerase chain reaction and RH-PAT index on the 30th day after STEMI (r=0.5, P=0.001). Conclusion: Higher dose statin therapy in patients with STEMI undergoing primary percutaneous coronary intervention showed early greater vascular protective effects that moderate dose. PMID- 29270003 TI - Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers. AB - Objective: This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs. Materials and methods: This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration-time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews. Results: The geometric mean ratios and 90% CIs for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 0.8782 (0.8167-0.9444) and 0.9662 (0.9210-1.0136) for telmisartan and 1.0069 (0.9723-1.0427) and 1.0324 (0.9969-1.0690) for S amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting. Conclusion: For both telmisartan and S-amlodipine, the Cmax and AUCt 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs. PMID- 29270002 TI - Gut microbiota-derived short-chain fatty acids and kidney diseases. AB - Gut microbiota and its metabolites play pivotal roles in host physiology and pathology. Short-chain fatty acids (SCFAs), as a group of metabolites, exert positive regulatory effects on energy metabolism, hormone secretion, immune inflammation, hypertension, and cancer. The functions of SCFAs are related to their activation of transmembrane G protein-coupled receptors and their inhibition of histone acetylation. Though controversial, growing evidence suggests that SCFAs, which regulate inflammation, oxidative stress, and fibrosis, have been involved in kidney disease through the activation of the gut-kidney axis; however, the molecular relationship among gut microbiota-derived metabolites, signaling pathways, and kidney disease remains to be elucidated. This review will provide an overview of the physiology and functions of SCFAs in kidney disease. PMID- 29270004 TI - EUREKA study - the evaluation of real-life use of a biophotonic system in chronic wound management: an interim analysis. AB - Objective: Interest has grown regarding photobiomodulation (PBM) with low-level light therapy, which has been shown to positively affect the stages of the wound healing process. In a real-life context clinical setting, the objective of the EUREKA study was to investigate efficacy, safety, and quality of life associated with the use of a BioPhotonic gel (LumiHealTM) in the treatment of chronic wounds such as venous leg ulcers (VLUs), diabetic foot ulcers (DFUs), and pressure ulcers (PUs). This BioPhotonic gel represents a new, first-in-class emission spectrum of light, including fluorescence, to induce PBM and modulate healing. Design: The multicenter, prospective, interventional, uncontrolled, open-label study enrolled 100 patients in 12 wound centers in Italy. We performed an early interim analysis based on the first 33 subjects (13 VLU, 17 DFU, 3 PU) in seven centers who completed the study. Main results: Seventeen patients (52%) achieved total wound closure (full re-epithelialization for 2 weeks) during the study period. Two patients (6%) were considered "almost closed" (decrease of the wound area of more than 90% at study end) and three others (9%) were considered "ready for skin grafting". No related serious adverse events were observed, and the compliance was excellent. After the treatment, the average time to "pain-free" was 11.9 days in the VLU group. Quality of life was improved with overall increase of 26.4% of the total score (Cardiff Wound Impact Schedule, p=0.001). Conclusion: The study revealed a positive efficacy profile of the BioPhotonic gel in promoting wound healing and reactivating the healing process in different types of chronic, hard-to-heal wounds. The treatment was shown to be safe and well tolerated by the patients, and a reduction of pain perception was also detected during the treatment period. The improvement of the quality of life was accompanied by a high level of clinician satisfaction. PMID- 29270005 TI - The contribution of symptoms and comorbidities to the economic impact of COPD: an analysis of the German COSYCONET cohort. AB - Background: Although patients with COPD often have various comorbidities and symptoms, limited data are available on the contribution of these aspects to health care costs. This study analyzes the association of frequent comorbidities and common symptoms with the annual direct and indirect costs of patients with COPD. Methods: Self-reported information on 33 potential comorbidities and symptoms (dyspnea, cough, and sputum) of 2,139 participants from the baseline examination of the German COPD cohort COSYCONET was used. Direct and indirect costs were calculated based on self-reported health care utilization, work absence, and retirement. The association of comorbidities, symptoms, and COPD stage with annual direct/indirect costs was assessed by generalized linear regression models. Additional models analyzed possible interactions between COPD stage, the number of comorbidities, and dyspnea. Results: Unadjusted mean annual direct costs were ?7,263 per patient. Other than COPD stage, a high level of dyspnea showed the strongest driving effect on direct costs (+33%). Among the comorbidities, osteoporosis (+38%), psychiatric disorders (+36%), heart disease (+25%), cancer (+24%), and sleep apnea (+21%) were associated with the largest increase in direct costs (p<0.01). A sub-additive interaction between advanced COPD stage and a high number of comorbidities reduced the independent cost driving effects of these factors. For indirect costs, besides dyspnea (+34%), only psychiatric disorders (+32%) and age (+62% per 10 years) were identified as significant drivers of costs (p<0.04). In the subsequent interaction analysis, a high number of comorbidities was found to be a more crucial factor for increased indirect costs than single comorbidities. Conclusion: Detailed knowledge about comorbidities in COPD is useful not only for clinical purposes but also to identify relevant cost factors and their interactions and to establish a ranking of major cost drivers. This could help in focusing therapeutic efforts on both clinically and economically important comorbidities in COPD. PMID- 29270006 TI - Risk factors for the discontinuation of roflumilast in patients with chronic obstructive pulmonary disease. AB - Introduction: Roflumilast is a phosphodiesterase-4 inhibitor, which can decrease exacerbation in patients with chronic obstructive pulmonary disease (COPD). However, adverse effects are a major barrier to medication use, and little is known regarding the risk factors for discontinuation of roflumilast in COPD patients. Method: A search of the clinical databases identified all patients who were prescribed roflumilast between December 2012 and April 2015 in the four hospitals of The Catholic University of Korea, Korea. The study subjects were limited to patients who had taken 500 MUg of roflumilast. We studied the factors associated with drug discontinuation and drug adverse events by univariate and multivariate analyses. Results: Among 154 eligible patients, 54 (35.1%) discontinued their roflumilast prescription. Most patients were elderly, male, current or former smokers, and had moderate-to-severe airflow limitation. Low body mass index (BMI) patients were more likely to undergo drug discontinuation (1-unit decrease in BMI: odds ratio [OR] =1.165, p=0.006; BMI <23 kg/m2: OR =2.960, p=0.004). Fifty-five patients (35.7%) had adverse events. Loss of appetite, diarrhea, nausea, headache, and weight loss were the most frequent adverse events. Low-BMI patients were more likely to experience adverse events (1 unit decrease in BMI: OR =1.151, p=0.010; BMI <23 kg/m2: OR =2.644, p=0.009). Conclusions: The patient discontinuation and adverse events rates in this study were higher than in previous randomized controlled studies. Discontinuation of roflumilast in ethnic Koreans is more likely to occur in low-BMI patients. In a clinical setting, low-BMI patients can more easily discontinue roflumilast; clinicians should, therefore, provide greater care for these patients. PMID- 29270007 TI - A pre-post intervention study of pulmonary rehabilitation for adults with post tuberculosis lung disease in Uganda. AB - Setting: The study was conducted at Mulago Hospital, Kampala, Uganda. Objective: As chronic respiratory disease (CRD) is a huge, growing burden in Africa, with few available treatments, we aimed to design and evaluate a culturally appropriate pulmonary rehabilitation (PR) program in Uganda for people with post tuberculosis lung disorder (p-TBLD). Design: In a pre-post intervention study, a 6-week, twice-weekly PR program was designed for people with p-TBLD. Outcome measures included recruitment, retention, the Clinical COPD Questionnaire (CCQ), tests of exercise capacity, and biometrics. Given this was a developmental study, no formal statistical significance testing was undertaken. Results: In all, 34 participants started PR and 29 (85%) completed all data collection. The mean age of the 29 participants was 45 years, and 52% were female. The mean (95% confidence interval) CCQ score at baseline was 1.8 (1.5, 2.0), at the end of PR was 1.0 (0.8, 1.2), and at 6 weeks after the end of PR was 0.8 (0.7, 1.0). The Incremental Shuttle Walking Test (ISWT) was 299 m (268.5, 329.4) at baseline, 377 (339.6, 413.8) at the end of PR, and 374 (334.2, 413.5) at 6 weeks after the end of PR. Improvements were seen in measures of chest pain; 13/29 (45%) participants reported chest pain at baseline but only 7/29 (24%) at the end of PR, and in those with persistent pain, the mean pain scores decreased. Mild hemoptysis was reported in 4/29 (17%) participants at baseline and in 2/29 (7%) at the end of PR. Conclusion: PR for people with p-TBLD in Uganda was feasible and associated with clinically important improvements in quality of life, exercise capacity, and respiratory outcomes. PR uses local resources, requires little investment, and offers a new, sustainable therapy for p-TBLD in resource-limited settings. With the rising global burden of CRD, further studies are needed to assess the value of PR in p-TBLD and other prevalent forms of CRD. PMID- 29270008 TI - Impact of mild to moderate COPD on feasibility and prognosis in non-small cell lung cancer patients who received chemotherapy. AB - Background: Non-small cell lung cancer (NSCLC) is the predominant cause of death in patients with COPD, and the severity of COPD in NSCLC patients is classified mainly as mild to moderate. Most advanced NSCLC patients with mild to moderate COPD are treated with chemotherapy; however, the feasibility for and prognosis after chemotherapy of these patients are not well understood. The aim of this study was to elucidate the impact of mild to moderate COPD on the feasibility for and prognosis after chemotherapy in NSCLC patients. Patients and methods: A retrospective review was performed on 268 NSCLC patients who received first-line chemotherapy from 2009 to 2014 in our institution. Finally, 85 evaluable patients were included in this study. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients with mild to moderate COPD and those without COPD (non-COPD). Results: Forty-three patients were classified as COPD (27 cases mild and 16 cases moderate) and 42 patients as non-COPD. The COPD group were older and had fewer never-smokers than the non-COPD group. The objective response rate did not differ between groups (p=0.14). There was no significant difference in overall survival between COPD and non-COPD groups (15.0 and 17.0 months, log-rank test p=0.57). In the multivariate Cox's proportional hazard model, the adjusted hazard ratio (HRadj) was statistically significant for male sex (HRadj =5.382, 95% CI: 1.496 19.359; p=0.010), pathological diagnosis of adenocarcinoma (HRadj =0.460, 95% CI: 0.223-0.948; p=0.035), and epithelial growth factor receptor negative mutation (HRadj =6.040, 95% CI: 1.158-31.497; p=0.033), but not for the presence of COPD (HRadj =0.661, 95% CI: 0.330-1.325; p=0.24). Toxicity profile in COPD group was favorable, as in the non-COPD group. Conclusion: Mild to moderate COPD did not have a significant deleterious impact on toxicity and prognosis in NSCLC patients. PMID- 29270009 TI - Ex vivo distribution of gold nanoparticles in choroidal melanoma. PMID- 29270010 TI - Induction of a robust immune response against avian influenza virus following transdermal inoculation with H5-DNA vaccine formulated in modified dendrimer based delivery system in mouse model. AB - This study was aimed to evaluate the immunogenicity of recombinant plasmid deoxyribonucleic acid (DNA), pBud-H5-green fluorescent protein (GFP)-interferon regulatory factor (IRF)3 following delivery using polyamidoamine (PAMAM) dendrimer and transactivator of transcription (TAT)-conjugated PAMAM dendrimer as well as the effect of IRF3 as the genetic adjuvant. BALB/c mice were vaccinated transdermally with pBud-H5-GFP, PAMAM/pBud-H5-GFP, TAT-PAMAM/pBud-H5-GFP, and TAT PAMAM/pBud-H5-GFP-IRF3. The expression analysis of H5 gene from the blood by using quantitative real-time reverse transcriptase polymerase chain reaction confirmed the ability of PAMAM dendrimer as a carrier for gene delivery, as well as the ability of TAT peptide to enhance the delivery efficiency of PAMAM dendrimer. Mice immunized with modified PAMAM by TAT peptide showed higher hemagglutination inhibition titer, and larger CD3+/CD4+ T cells and CD3+/CD8+ T cells population, as well as the production of cytokines, namely, interferon (IFN)-gamma, interleukin (IL)-2, IL-15, IL-12, IL-6, and tumor necrosis factor alpha compared with those immunized with native PAMAM. These results suggest that the function of TAT peptide as a cell-penetrating peptide is able to enhance the gene delivery, which results in rapid distribution of H5 in the tissues of the immunized mice. Furthermore, pBud-H5-GFP co-expressing IRF3 as a genetic adjuvant demonstrated the highest hemagglutination inhibition titer besides larger CD3+/CD4+ and CD3+/CD8+ T cells population, and strong Th1-like cytokine responses among all the systems tested. In conclusion, TAT-PAMAM dendrimer-based delivery system with IRF3 as a genetic adjuvant is an attractive transdermal DNA vaccine delivery system utilized to evaluate the efficacy of the developed DNA vaccine in inducing protection during challenge with virulent H5N1 virus. PMID- 29270011 TI - Transport and release of colloidal 3-mercaptopropionic acid-coated CdSe-CdS/ZnS core-multishell quantum dots in human umbilical vein endothelial cells. AB - Colloidal semiconductor quantum dots (QDs) have been extensively researched and developed for biomedical applications, including drug delivery and biosensing assays. Hence, it is pivotal to understand their behavior in terms of intracellular transport and toxicological effects. In this study, we focused on 3 mercaptopropionic acid-coated CdSe-CdS/ZnS core-multishell quantum dots (3MPA QDs) converted from the as-grown octadecylamine-coated quantum dots (ODA-QDs) and their direct and dynamic interactions with human umbilical vein endothelial cells (HUVECs). Live cell imaging using confocal fluorescence microscopy showed that 3MPA-QDs first attached to and subsequently aggregated on HUVEC plasma membrane ~25 min after QD deposition. The aggregated QDs started being internalized at ~2 h and reached their highest internalization degree at ~24 h. They were released from HUVECs after ~48 h. During the 48 h period, the HUVECs responded normally to external stimulations, grew, proliferated and wound healed without any perceptible apoptosis. Furthermore, 1) 3MPA-QDs were internalized in newly formed LysoTracker-stained early endosomes; 2) adenosine 5'-triphosphate-induced [Ca2+]i modulation caused a transient decrease in the fluorescence of 3MPA-QDs that were attached to the plasma membrane but a transient increase in the internalized 3MPA QDs; and 3) fluorescence signal modulations of co-stained LysoTracker and QDs induced by the lysosomotropic agent Gly-Phe-beta-naphthylamide were spatially co localized and temporally synchronized. Our findings suggest that 3MPA-QDs converted from ODA-QDs are a potential nontoxic fluorescent probe for future use in clinical applications. Moreover, the photophysical strategy and techniques reported in this work are easily applicable to study of direct interactions between other nanoparticles and live cells; contributing to awareness and implementation of the safe applications of nanoparticles. PMID- 29270012 TI - pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer. AB - Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)-block-poly(l lysine) (PEG-b-PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l-lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5-6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy. PMID- 29270013 TI - Effects of asenapine on agitation and hostility in adults with acute manic or mixed episodes associated with bipolar I disorder. AB - Background: Bipolar disorder is associated with an increased risk of aggression. However, effective management of hostility and/or agitation symptoms may prevent patients from becoming violent. This analysis investigated the efficacy of the antipsychotic asenapine on hostility and agitation in patients with bipolar I disorder. Methods: Data were pooled from three randomized, double-blind, placebo controlled, Phase III trials of asenapine in adults with manic or mixed episodes of bipolar I disorder (NCT00159744, NCT00159796, and NCT00764478). Post hoc analyses assessed the changes from baseline to day 21 on the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS) hostility related item scores in asenapine- or placebo-treated patients with at least minimal or mild symptom severity and on the PANSS-excited component (PANSS-EC) total score in agitated patients. Changes were adjusted for improvements in overall mania symptoms to investigate direct effects on hostility. Results: Significantly greater changes in favor of asenapine versus placebo were observed in YMRS hostility-related item scores (irritability: least squares mean difference [95% confidence interval] =-0.5 [-0.87, -0.22], P=0.001; disruptive aggressive behavior: -0.7 [-0.99, -0.37], P<0.0001), PANSS hostility item score ( 0.2 [-0.44, -0.04]; P=0.0181), and PANSS-EC total score (-1.4 [-2.4, -0.4]; P=0.0055). Changes in the YMRS disruptive-aggressive behavior score and the sum of the hostility-related items remained significant after adjusting for improvements in other YMRS item scores. Conclusion: Asenapine significantly reduced hostility and agitation in patients with bipolar I disorder; improvement was at least partially independent of overall improvement on mania symptoms. PMID- 29270014 TI - Altered emotional prosody processing in patients with Parkinson's disease after subthalamic nucleus stimulation. AB - Background: Patients with Parkinson's disease (PD) exhibit deficits in recognizing and expressing vocal emotional prosody. The aim of this study was to explore emotional prosody processing in patients with PD shortly after subthalamic nucleus (STN) deep brain stimulation (DBS). Methods: Two groups of patients with PD (pre-DBS and post-DBS) and one healthy control (HC) group were recruited as participants. All participants (PD and HC) were assessed using the Montreal Affective Voices database 50 Voices Recognition test. All participants were asked to nonverbally express five basic emotions (happiness, anger, fear, sadness, and neutral) to test emotional prosody expression. Fifteen native Chinese speakers were recruited as raters. We recorded the accuracy rate, reaction time, confidence level, and two acoustic parameters (mean pitch and mean intensity). Results: The PD groups scored lower than the HC group in recognizing and expressing emotional prosody. STN DBS had no significant effect on the recognition of emotional prosody but had a significant effect on fear prosody expression. Pearson's correlation analysis revealed significant correlations between performance on emotional prosody recognition tests and performance on emotional prosody expression tests in both the pre-DBS PD and post-DBS PD groups. Conclusion: Shortly after STN DBS, the ability to recognize emotional prosody was not altered, but fear expression was impaired. We identified associations between abnormalities in emotional prosody recognition and expression deficits both before and after STN DBS, indicating that the processes involved in recognizing and expressing emotional prosody may share a common system. PMID- 29270015 TI - Effect of a novel nutraceutical combination on serum lipoprotein functional profile and circulating PCSK9. AB - Background: A beneficial effect on cardiovascular risk may be obtained by improving lipid-related serum lipoprotein functions such as high-density lipoproteins (HDLs) cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) and by reducing proprotein convertase subtilisin kexin type 9 (PCSK9), independently of lipoprotein concentrations. Aim: We aimed to evaluate the effect of an innovative nutraceutical (NUT) combination containing red yeast rice (monacolin K 3.3 mg), berberine 531.25 mg and leaf extract of Morus alba 200 mg (LopiGLIK(r)), on HDL-CEC, serum CLC and on circulating PCSK9 levels. Materials and methods: Twenty three dyslipidemic subjects were treated for 4 weeks with the above NUT combination. HDL-CEC was measured using specific cell-based radioisotopic assays; serum CLC and PCSK9 concentrations were measured fluorimetrically and by enzyme-linked immunosorbent assay, respectively. Results: The NUT combination significantly reduced plasma level of the total cholesterol and low-density lipoprotein cholesterol (-9.8% and -12.6%, respectively). Despite no changes in HDL-cholesterol, the NUT combination improved total HDL-CEC in 83% of the patients, by an average of 16%, as a consequence of the increase mainly of the ATP-binding cassette A1-mediated CEC (+28.5%). The NUT combination significantly reduced serum CLC (-11.4%) while it did not change PCSK9 plasma levels (312.9+/-69.4 ng/mL vs 334.8+/-103.5 mg/L, before and after treatment, respectively). Conclusion: The present NUT combination improves the serum lipoprotein functional profile providing complementary beneficial effects, without any detrimental increase of PCSK9 plasma levels. PMID- 29270017 TI - The promise of an interactive, online curriculum in improving the competence of those working in healthcare settings to address sexual assault. PMID- 29270016 TI - Extracorporeal ultrafiltration for acute heart failure: patient selection and perspectives. AB - Most patients presenting with acute heart failure (AHF) show signs and symptoms of fluid overload, which are closely associated with short-term and long-term outcomes. Ultrafiltration is an extremely appealing strategy for patients with AHF and concomitant overt fluid overload not fully responsive to diuretic therapy. However, although there are several theoretical beneficial effects associated with ultrafiltration, published reports have shown controversial findings. Differences in selection of the study population and in ultrafiltration indications and protocols, and high variability in the pharmacologic therapy used for the control group could explain some of these conflicting results. Here, we aimed to provide an overview on the current medical evidence supporting the use of ultrafiltration in AHF, with a special focus on the identification of potential candidates who may benefit the most from this therapeutic option. PMID- 29270018 TI - Potential Effectiveness of Point-of-Use Filtration to Address Risks to Drinking Water in the United States. AB - Numerous contemporary incidents demonstrate that conventional control strategies for municipal tap water have limited ability to mitigate exposures to chemicals whose sources are within distribution systems, such as lead, and chemicals that are not removed by standard treatment technologies, such as perfluorooctanoic acid (PFOA)/perfluorooctanesulfonic acid (PFOS). In these situations, point-of use (POU) controls may be effective in mitigating exposures and managing health risks of chemicals in drinking water, but their potential utility has not been extensively examined. As an initial effort to fill this information gap, we conducted a critical review and analysis of the existing literature and data on the effectiveness of POU drinking water treatment technologies for reducing chemical contaminants commonly found in tap water in the United States. We found that many types of water treatment devices available to consumers in the United States have undergone laboratory testing and often certification for removal of chemical contaminants in tap water, but in most cases their efficacy in actual use has yet to be well characterized. In addition, the few studies of POU devices while "in use" focus on traditional contaminants regulated under the Safe Drinking Water Act, but do not generally consider nontraditional contaminants of concern, such as certain novel human carcinogens, industrial chemicals, pesticides, pharmaceuticals, personal care products, and flame retardants. Nevertheless, the limited information available at present suggests that POU devices can be highly effective when used prophylactically and when deployed in response to contamination incidents. Based on these findings, we identify future areas of research for assessing the ability of POU filters to reduce health related chemical contaminants distributed through public water systems and private wells. PMID- 29270019 TI - Intracellular Lipid Droplets: From Structure to Function. AB - Lipid droplets (LDs) are unique intracellular organelles that are mainly constituted by neutral lipids (triglycerides, sterol esters). As such they serve as the main site of energy storage in the cell and they are akin to oil emulsions in water. To prevent the direct exposure of the hydrophobic neutral lipids to the aqueous environment of the cytosol, LDs are surrounded by a monolayer of phospholipids that thus behave as a natural surfactant. This interfacial structure is rather unique inside the cell, but a molecular understanding of how the LD structure modulates its functions is still lacking, mainly due to technical challenges in both experimental and computational approaches to investigate oil-in-water emulsions. Recently, we have investigated the structure of LDs using a combination of existing and newly developed computational approaches that are optimized to study oil-water interfaces.1 Our simulations provide a comprehensive molecular characterization of the unique surface properties of LDs, suggesting structure-function relationship in several LD related metabolic processes. PMID- 29270020 TI - Differential radiation response between normal astrocytes and glioma cells revealed by comparative transcriptome analysis. AB - Normal astrocytes are more resistant to radiation than glioma cells. Radiation resistant glioma cells and normal astrocytes usuallly share similar mechanisms of radioresistance. Investigation of the underlying mechanisms of differential radiation response between normal astrocytes and glioma cells is thus significant for improvement of glioma treatment. Here, we report on the differential radiation responses between normal astrocytes and glioma cells at the transcriptome level. Human astrocytes (HA) and U251 glioma cell lines were used as in vitro models. The transcriptome profiles of radiation-treated and nontreated HA and U251 cells were generated by next-generation sequencing. In total, 296 mRNAs and 224 lncRNAs in HA and 201 mRNAs and 107 lncRNAs in U251 were found to be differentially expressed after radiation treatment. Bioinformatics analyses indicated that radiation causes similar alterations in HA and U251 cells, while several key pathways involved in cancer development and radiation resistance, including P53, TGF-beta, VEGF, Hippo and serotonergic synapse pathways, were oppositely regulated by radiation treatment, suggesting their important role in this process. Furthermore, we showed the critical role of Hippo/YAP signaling in radiation resistance of glioma cells. In summary, our findings revealed novel insights about differential responses between normal astrocytes and glioma cells. Our work suggested that YAP inhibitor could not be used in combination with radiation for glioma treatment. PMID- 29270021 TI - Hopea odorata extract inhibits hepatocellular carcinoma via induction of caspase dependent apoptosis. AB - Introduction: Cancer is a disease with a global burden and is a major and increasing threat to public health. The demand for new modalities to treat and prevent cancer is high. Given the toxic side effects of standard treatments, such as chemotherapy, there is greater research interest in naturally derived compounds due to their selective toxicity to cancer cells. This study aimed to test the anticancer activity of a crude extract of Hopea odorata on hepatocellular carcinoma (HCC) HepG2 cell line. Methods: Methanol extracts of H. odorata were prepared from the bark of H. odorata plants (H. odorata extract). The in vitro cytotoxicity of H. odorata extracts on human HCC cell line HepG2 compared to normal human fibroblasts (HFs) was assessed by Alamar Blue assay. Caspase-3/7 was detected using a reagent that consists of DEVD peptide conjugated to a nucleic acid-binding dye. Apoptosis induction by the H. odorata plant extract on HepG2 was evaluated by Annexin V/7-AAD using flow cytometry. Disintegrated nuclei of plant-treated cells were observed under a fluorescent microscope using Hoechst and propidium iodide (PI) staining. In addition, using the Hoechst/PI staining technique, the ratio of dead to total cells was determined by distinguishing Hoechst and PI fluorescent signals. Results: We found that the IC50 value of H. odorata extract on HepG2 was 12.67+/-5 ug/mL and on HF was 44+/-3 ug/mL. The IC50 value of doxorubicin on HepG2 was 153.3+/-15 ng/mL and on HF was 6.3+/-0.6 ng/mL. The selectivity index (SI) of H. odorata extract for HepG2 cells was ~3.48, while the SI of doxorubicin for HepG2 cells was ~0.04. The ratio of dead to total cells increased in a dose-dependent manner for HepG2 cells when observed under a fluorescent microscope, while the ratio of dead to total cells barely changed for HF cells. The H. odorata extract inhibited HepG2 cells via the activation of caspase-3/7. At 250 ug/mL concentration of the H. odorata extract, 35% of HepG2 cells were induced into apoptosis, and the cells exhibited disintegrated nuclei under a fluorescent microscope. Conclusion: These findings demonstrate that the methanolic bark extracts of H. odorata plant induce apoptosis and selective cytotoxicity toward HepG2 but not HF. Therefore, purification of compounds from H. odorata bark extracts may be useful as anticancer agents, and thus, more studies are warranted to investigate the anticancer properties of H. odorata. PMID- 29270022 TI - Long noncoding RNA NEAT1 promotes nasopharyngeal carcinoma progression through regulation of miR-124/NF-kappaB pathway. AB - Nasopharyngeal carcinoma (NPC) is one of the most common malignancies and seriously endangers people's health. Recently, long noncoding RNA (lncRNA) NEAT1 has been determined as an oncogenic gene in a variety of cancers. However, the effect of NEAT1 in NPC and its underlying mechanism have not been well elaborated. In this study, the data showed that NEAT1 was upregulated and miR-124 was downregulated in NPC tissues and cells. Loss-of-function revealed that NEAT1 knockdown inhibited proliferation and promoted apoptosis of NPC cells while gain of-function revealed that upregulated NEAT1 showed an opposite effect. Moreover, NEAT1 was demonstrated to suppress miR-124 expression by direct interaction in NPC cells. Additionally, miR-124 reversed NEAT1-mediated pro-proliferation and anti-apoptosis effect. Furthermore, miR-124 regulated NPC cell proliferation and apoptosis via NF-kappaB signal pathway. Mouse models of NPC confirmed that NEAT1 overexpression facilitated tumor growth by modulating miR-124 in vivo. Taken together, this study indicated that upregulated NEAT1 promoted the tumorigenesis and progression of NPC through regulating miR-124/NF-kappaB signaling pathway, suggesting an attractive therapy target for NPC patients. PMID- 29270023 TI - Deletion and downregulation of MTAP contribute to the motility of esophageal squamous carcinoma cells. AB - Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, with a low 5-year overall survival rate. In previous studies, we and others have found that 9p21.3 was the most frequently deleted region in ESCC. The MTAP gene, which is located close to CDKN2A/B in 9p21.3, encodes methylthioadenosine phosphorylase. This enzyme plays an important role during the process of adenosine transfer. In the present study, we found that MTAP is deleted at the genomic level in 19.1% (64/341) of primary ESCC tumors, and decreased mRNA and protein expression were present in 31.1% (28/90) and 33.3% (6/18) of ESCCs, respectively. Further statistical analysis showed a positive correlation between deletion and decreased mRNA expression of MTAP in the ESCC tissues tested (coefficient: 0.826; P=1.17*10-23). Knockdown of MTAP expression using small interfering RNA-mediated silencing promoted the invasion and migration of ESCC cells. Also, overexpression of MATP using pcDNA3.1-MTAP plasmid decreased the cell invasion and migration. At the molecular level, MTAP knockdown downregulated E-cadherin and p-GSK3beta but upregulated Slug expression. Our results indicated that MTAP deletion results in the decreased expression in ESCCs and that it plays a role in promoting the mobility and inducing the epithelial-to-mesenchymal transition of ESCC cells via the GSK3beta/Slug/E-cadherin axis. The data suggest that MTAP might function as a tumor suppressor gene in ESCC. PMID- 29270024 TI - Overexpression of UHRF2 in intrahepatic cholangiocarcinoma and its clinical significance. AB - Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) has been implicated in tumorigenesis. However, its roles in intrahepatic cholangiocarcinoma (ICC) are still unclear. In this study, UHRF2 expression was analyzed in several kinds of cancers by referring to public Oncomine database, and the levels of UHRF2 mRNA and protein were determined in ICC cells and tissues. Then, the roles of UHRF2 in ICC were investigated by UHRF2 interference. Moreover, the relationship between UHRF2 and E-cadherin expression was examined in ICC cells and samples. Finally, the prognostic role of UHRF2 in ICC was analyzed in 139 ICC patients by Cox regression and Kaplan-Meier methods. We found UHRF2 was overexpressed in multiple human cancers, as well as in ICC, and the invasion, migration, proliferation, and antiapoptosis of ICC cells were inhibited by UHRF2 interference. Moreover, the epithelial-mesenchymal transition-related marker E-cadherin was upregulated in ICC cells which was influenced by UHRF2 expression. Clinically, UHRF2 expression was positively associated with microvascular invasion and lymphatic metastasis of ICC, and patients in the UHRF2high group had much lower overall survival and higher recurrence rates than patients in the UHRF2low group. A multivariate analysis revealed that UHRF2 overexpression was a new prognostic marker for ICC. Thus, our results indicated that high level of UHRF2 might be a novel predictor for the prognosis of ICC. PMID- 29270025 TI - Targeting of GIT1 by miR-149* in breast cancer suppresses cell proliferation and metastasis in vitro and tumor growth in vivo. AB - Breast cancer remains a major cause of cancer-related death in women worldwide. Dysregulation of microRNAs (miRNAs) is involved in the initiation and progression of breast cancer. Moreover, it was found that GIT1 was widely involved in the development of many human cancers. Herein, we aimed to investigate the expression changes of miR-149* and GIT1 and the functional effects of miR-149*/GIT1 link in breast cancer. Quantitative reverse transcription-polymerase chain reaction (qRT PCR) and Western blot (WB) were used to examine the expression levels of miR-149* and GIT1. Dual luciferase reporter assay was utilized to confirm the target interaction between miR-149* and GIT1. The biological functions, including cell proliferation, invasion, and migration, of miR-149* and GIT1 were determined by MTT assay and Transwell assays, respectively. Eventually, the tumor xenograft model in nude mice injected with stable transfected MDA-MB-231 cells was established to verify the effects of miR-149* and GIT1 on tumor growth. Our results showed that miR-149* expression was decreased, whereas GIT1 expression was increased in clinical samples of breast cancer. Based on the inverse expression trend between miR-149* and GIT1, we further demonstrated that miR-149* indeed directly targets GIT1. Subsequently, it was observed that inhibition of miR-149* significantly promoted cell proliferation, invasion, and migration, but the ability of cell proliferation, invasion, and migration was obviously declined after silencing of GIT1 in MDA-MB-231 cells transfected with miR-149* mimic and/or si-GIT1. Finally, it was also found that elevated miR-149* decelerated the tumor growth, while restored GIT1 accelerated the tumor growth in nude mice after 35 days of tumor xenograft. Collectively, these findings concluded that miR-149* might exert a tumor suppressive role in breast cancer by targeting GIT1. PMID- 29270026 TI - Detection of hepatitis C virus (HCV) among health care providers in an Egyptian university hospital: different diagnostic modalities. AB - Background: Hepatitis C virus (HCV) infection has received much attention and is placed at the core of the infection control agenda. It is considered as a major public health problem in Egypt, where the highest prevalence of HCV exists. The great risk of exposure to infection of health care providers (HCPs) has highlighted the urgent need for implementing an infection control program. Objective: The purpose of this study was to detect the prevalence of HCV infection among HCPs in Zagazig University Hospitals and to assess the performance of different diagnostic modalities. Methodology: Blood, polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and saliva tests were performed in enrolled HCPs. Results: This study compared HCV diagnosis Hepanostika HCV Ultra ELISA as a screening test and PCR as gold standard test, which resulted in 40.6% positive results by ELISA compared to 34.8% by PCR (p<0.0001), while OraQuick HCV rapid antibody compared to PCR shows that 37.7% of the participants were positive by OraQuick HCV rapid antibody test. Application of standard precautions while dealing with blood has negative significant correlation with HCV infection (rs =-0.265, p=0.03). Conclusion: HCPs at Zagazig University Hospitals are at high risk for HCV infection. Lack of compliance and awareness of prevention and control of the infection are associated cofactors. Serum HCV-Ab detection by Hepanostika HCV Ultra ELISA and OraQuick HCV rapid antibody test are sensitive and specific serologic assays for diagnosis with correspondent results to that obtained by quantitative real-time PCR. PMID- 29270028 TI - Identification of dihydrogambogic acid as a matrix metalloproteinase 1 inhibitor by high-throughput screening. PMID- 29270027 TI - Visceral-to-subcutaneous fat ratio as a predictor of the multiple metabolic risk factors for subjects with normal waist circumference in Korea. AB - Purpose: Visceral obesity has been recognized as a predictor of metabolic risk factors. However, few studies have evaluated the metabolic risks in subjects with normal waist circumference (WC). We aimed to examine if the visceral-to subcutaneous fat ratio (VSR) has diagnostic value to identify multiple metabolic risk factors in subjects with normal WC, compared with visceral fat area (VFA) and subcutaneous fat area (SFA). Methods: This is a cross-sectional study in which we have compared mean VFA, SFA, and VSR according to each metabolic risk factor. We performed a receiver operating characteristic (ROC) curve analysis for VFA, SFA, and VSR to assess their accuracy in picking out two or more non-adipose factors for metabolic syndrome. Results: For each metabolic risk factor, mean VSRs were significantly different between groups (risk-absent group vs risk present group) in men and women, except for men with low high-density lipoprotein. However, mean VFAs and SFAs showed no significant differences between groups. VSR showed superior diagnostic values in predicting at least two non-adipose metabolic risk factors in men and similar diagnostic value in women. Areas under ROC curves for VSR and VFA were 0.705 and 0.649 in men (P=0.028) and 0.798 and 0.785 in women (P=0.321). Conclusion: For men with a normal WC, VSR appeared to effectively predict the presence of multiple metabolic risk factors. Thus, VSR may serve as an indicator for identifying men who have a normal WC and multiple metabolic risk factors. PMID- 29270029 TI - Preventive effect of Oenothera rosea on N-methyl-N-nitrosourea-(NMU) induced gastric cancer in rats. AB - Background: Currently, gastric cancer (GC) is considered a public health problem worldwide. Using medicinal plants for the prevention of chronic diseases such as cancer constitutes new alternatives in traditional medicine. Oenothera rosea (OR) could be an option, but it needs to be evaluated. Aim: The main objective of this study was to evaluate the protective effect of OR extract on N-methyl-N nitrosourea (NMU)-induced GC in rats. Methods: In total, 80 male Holtzman rats were randomized into five groups. Group A received the saline solution (5mL/kg), group B received NMU 500 MUg/kg (cancer inductor) by oral administration for 16 weeks, and groups C, D, and E were treated with OR extract (100, 200, and 300 mg/kg, respectively) and NMU in order to evaluate the preventive effect on cancer induced by NMU for 16 weeks. Blood and histological samples of stomachs were collected to determine histopathological, biochemical, and hematological parameters between different experimental groups. Results: Groups C, D, and E presented less histopathological changes such as anaplastic and hyperplastic cells, compared with group B. Hematological and biochemical parameters were recorded, and superoxide dismutase, malondialdehyde, and nitric oxide levels were statistically less than those of NMU group (P<0.05, P<0.01, and P<0.01). Conclusion: Considering the histopathological signs and the antioxidant activity in vivo as well as hematological and biochemical parameters of ethanolic extract of OR, we concluded that its administration in rats has a protective effect on GC, which is induced experimentally. This species could be studied in clinical trials for patients with GC in the future. PMID- 29270030 TI - Comparison of survival outcomes between radical hysterectomy and definitive radiochemotherapy in stage IB1 and IIA1 cervical cancer. AB - Introduction: There is an ongoing debate regarding the optimal local treatment modalities for stage IB1 and IIA1 cervical cancer. The aim of this study was to determine whether radical hysterectomy or definitive radiochemotherapy is superior in stage IB1 and IIA1 cervical squamous cell carcinoma (SCC). Methods: From 1990 to 2010, a total of 3,769 patients with stage IB1 and IIA1 cervical SCC were included from the Surveillance, Epidemiology, and End Results database and were stratified according to whether they received radical hysterectomy or primary radiochemotherapy. Propensity score-matching (PSM) methods were used to balance patient baseline characteristics. Cancer-specific survival (CSS) and overall survival (OS) were compared between the two groups. Results: Of the 3,769 patients, 3,653 (96.9%) and 116 (3.1%) patients received radical hysterectomy and definitive radiochemotherapy, respectively. Radiochemotherapy was rarely used for definitive treatment prior to 2000. Before PSM, patients who were older, of black ethnicity, and with larger tumor size and stage IIA1 disease were more likely to receive definitive radiochemotherapy. A total of 116 pairs were completely matched using PSM. The local treatment modalities had no effect on CSS or OS in either unmatched or matched populations. In the matched population, the 8-year CSS rates were 82.1% and 76.5% in surgery and radiochemotherapy groups, respectively (p=0.382). The 8-year OS rates were 74.6% and 67.8% in surgery and radiochemotherapy groups, respectively (p=0.205). Conclusion: Our population based study suggests that there is no clear local treatment of choice on survival outcomes between radical hysterectomy and definitive radiochemotherapy in patients with stage IB1 and IIA1 cervical SCC. PMID- 29270031 TI - Efficacy of intravenous tramadol and low-dose ketamine in the prevention of post spinal anesthesia shivering following cesarean section: a double-blinded, randomized control trial. AB - Background: Shivering is a frequent and undesirable complication of spinal anesthesia. It is a physiologic response to increase the body core temperature in an attempt to raise metabolic heat production. However, shivering may trigger myocardial ischemia; increase intraocular and intracranial pressures, increase wound pain, delay wound healing and interfere with pulse rate, blood pressure and electrocardiogram monitoring. We aimed to compare the efficacy of intravenous (IV) ketamine with IV tramadol for the prevention of shivering in patients who underwent cesarean delivery under spinal anesthesia. Patients and methods: A prospective, randomized, double-blind study was conducted. One hundred and twenty three American Society of Anesthesiologist I and II patients, aged between 18 and 39 years, who underwent cesarean section were included in the study. Patients were randomly allocated to one of three groups: group S (n=41; control group) received saline, group K (n=41) received ketamine 0.2 mg/kg and group T (n=41) received tramadol 0.5 mg/kg. Incidence and grade of shivering and side effects between the treatment groups were recorded. Results: The incidence of shivering was significantly reduced in the ketamine and tramadol groups (41.5% and 53.7%, respectively) compared to the saline group (70.7%; p=0.028). Grade 3 shivering occurred in 16 (39%) patients in the saline group, compared to 9 (22%) in the tramadol group and 8 (19.5%) in the ketamine group (p=0.011). Only two cases in the saline group developed grade 4 shivering (p<0.01). Neonatal outcome and perioperative complications were comparable among the three groups. Conclusion: The prophylactic administration of low-dose IV ketamine or IV tramadol is effective for reducing the incidence and intensity of shivering. We recommend low dose IV ketamine or tramadol prophylaxis for parturients undergoing cesarean section under spinal anesthesia. PMID- 29270032 TI - Ocular-muscle surgery for filamentary keratitis that developed in double elevator palsy. AB - Purpose: To report a case of filamentary keratitis occurring in the cornea hidden under the eyelids by squint surgery. Methods: A 69-year-old female patient with a history of amblyopia was referred for intractable filamentary keratitis in the left eye. The strabismus angle was 35Delta hypertrophic, and ocular motility was within the normal range. Slit-lamp examination of her left eye revealed filamentary keratitis in more than one-third of the upper cornea behind the upper eyelid. Her right eye was diagnosed as supranuclear double elevator palsy. We performed strabismus surgery on her right eye, including inferior rectus muscle recession (5 mm) in combination with superior rectus muscle resection (5 mm) under local anesthesia. Following surgery, the left eye squint angle was improved. The filamentary keratitis of the left eye disappeared, and there was no recurrence over the following 5 years. Conclusion: The squint surgery of paralyzed right eye decreased the strabismus angle, subsequently resulting in the disappearance of the filamentary keratitis in the left eye via the resolution of the relative blepharoptosis. Although the squint operation performed was not for the purpose of improving binocular function, we want to conclude that it can treat the filamentary keratitis behind the eyelid. PMID- 29270033 TI - Olaratumab: a platelet-derived growth factor receptor-alpha-blocking antibody for the treatment of soft tissue sarcoma. AB - The outcome of patients with unresectable or metastatic soft tissue sarcoma (STS) remains poor with few treatment options. A number of randomized trials in the first-line setting have shown no difference in overall survival between combination anthracycline schedules and single-agent doxorubicin. A Phase Ib/randomized Phase II trial of doxorubicin with or without the platelet-derived growth factor receptor-alpha (PDGFRalpha)-blocking antibody, olaratumab, demonstrated a significant difference in median overall survival in favor of the olaratumab arm. The results of this trial led to the approval of olaratumab in combination with doxorubicin in adult anthracycline-naive unresectable STS. In this review, we discuss the potential role of PDGFRalpha signaling, early clinical data with olaratumab in sarcomas, the Phase Ib/II trial and ongoing trials with olaratumab in sarcomas. PMID- 29270034 TI - Occult atrial fibrillation in endurance athletes. PMID- 29270035 TI - Epidemiology and evolution of the diagnostic classification of factitious disorders in DSM-5. AB - A systematic search for all case reports and case series of adult patients with factitious disorders (FD) in the databases MEDLINE, Scopus, and PsycINFO was conducted. FD is a psychiatric disorder in which sufferers intentionally fabricate physical or psychological symptoms in order to assume the role of a patient, without any obvious gain. The clinical and demographic profile of patients with FD has not been sufficiently clear. Thus, the aims of this study were to outline a demographic and clinical profile of a large sample of patients with FD and to study the evolution of the position of FD in the Diagnostic and Statistical Manual of Mental Disorders. One thousand six hundred thirty-six records were obtained based on key search terms, after exclusion of duplicate records. Five hundred seventy-seven articles were identified as potentially eligible for the study, of which 314 studies were retrieved for full-text review. These studies included 514 cases. Variables extracted included age, gender, reported occupation, comorbid psychopathology, clinical presentation, and factors leading to the diagnosis of FD. In the sample, 65.4% of patients were females. Mean age at presentation was 33.5 years. A health care profession was reported most frequently (n=113). Patients were most likely to present in psychiatry, neurology, emergency, and internal medicine departments. The broad survey of sociodemographic profile of the sample has highlighted some important points for early diagnosis and early psychiatric treatment. The study showed that the patients did not meet Diagnostic and Statistical Manual of Mental Disorders-5 diagnostic criteria in 11.3% of cases. PMID- 29270036 TI - The NHS Bowel Cancer Screening Program: current perspectives on strategies for improvement. AB - Colorectal cancer (CRC) is the third most common cancer in the UK. The English National Health Service (NHS) Bowel Cancer Screening Program (BCSP) was introduced in 2006 to improve CRC mortality by earlier detection of CRC. It is now offered to patients aged 60-74 years and involves a home-based guaiac fecal occult blood test (gFOBt) biennially, and if positive, patients are offered a colonoscopy. This has been associated with a 15% reduction in mortality. In 2013, an additional arm to BCSP was introduced, Bowelscope. This offers patients aged 55 years a one-off flexible sigmoidoscopy, and if several adenomas are found, the patients are offered a completion colonoscopy. BCSP has been associated with a significant stage shift in CRC diagnosis; however, the uptake of bowel cancer screening remains lower than that for other screening programs. Further work is required to understand the reasons for nonparticipation of patients to ensure optimal uptake. A change of gFOBt kit to the fecal immunochemical tests (FIT) in the English BCSP may further increase patient participation. This, in addition to increased yield of neoplasia and cancers with the FIT kit, is likely to further improve CRC outcomes in the screened population. PMID- 29270038 TI - Takotsubo Cardiomyopathy Precipitated by Tapering of Anxiolytic Medication: A Case Report. AB - Takotsubo cardiomyopathy is a transient apical ballooning of the left ventricle typically with electrocardiographic changes and enzyme release without evidence of obstructive coronary artery disease. It typically occurs in postmenopausal women and may have a predilection for patients with anxiety disorders. The following is a case in which we believe takotsubo cardiomyopathy was induced by the tapering of antianxiety medications. We feel that health care professionals should be aware of this possibility in such a patient population especially when they have demonstrated cardiovascular symptomatology. PMID- 29270037 TI - Clinical and Echocardiographic Predictors of Arrhythmias Detected With 24-Hour Holter Electrocardiography Among Hypertensive Heart Failure Patients in Nigeria. AB - Background: Hypertensive heart failure (HHF) is the commonest form of heart failure in Nigeria. There is paucity of data in Nigeria on 24-hour Holter electrocardiography (24-HHECG) and important predictors of arrhythmias among HHF patients. Objectives: To determine the 24-HHECG characteristics among HHF patients. To determine the clinical and echocardiographic predictors of arrhythmias detected using 24-HHECG among HHF patients. Methods: A total of 100 HHF patients as well as 50 age-matched and sex-matched apparently healthy controls were prospectively recruited over a period of 1 year. They all had baseline laboratory tests, echocardiography, and 24-HHECG. Results: Hypertensive heart failure patients had significantly higher counts of premature ventricular contractions (PVCs) than the controls (P <= .001). Ventricular tachycardia (VT) was recorded in 29% of HHF patients as compared with controls who had no VT on 24 HHECG. The standard deviation of all normal to normal sinus RR intervals over 24 hours (SDNN) was abnormally reduced among HHF patients when compared with controls (P = .046). There was positive correlation between atrial fibrillation (AF) and the following parameters: PVCs (r = .229, P = .015), New York Heart Association (NYHA) (r = .196, P = .033), and VT (r = .223, P = .018). Following multiple linear regression, left ventricular ejection fraction (LVEF) (P <= .001) and serum urea (P = .037) were predictors of PVCs among HHF patients. Serum creatinine (P <= .001), elevated systolic blood pressure (SBP) (P = .005), and PVCs (P <= .001) were important predictors of VT among HHF patients. Conclusions: Renal dysfunction and reduced LVEF were important predictors of ventricular arrhythmias. High counts of PVCs and elevated SBP were predictive of the occurrence of VT among HHF patients. The NYHA class and ventricular arrhythmias have a significant positive correlation with AF. The SDNN is reduced in HHF patients. PMID- 29270039 TI - Peritoneal Dialysis and Retroperitoneal Laparoscopic Radical Nephrectomy: A Favorable Experience With a Patient Complicated by Renal Cell Carcinoma. AB - Peritoneal dialysis (PD) is an accepted modality for managing end-stage kidney disease. We herein report a 75-year-old female patient on chronic PD who was complicated by renal cell carcinoma. She was successfully treated with retroperitoneal laparoscopic radical nephrectomy followed by a prompt resumption of the procedure. Various surgeries disturbing the abdominal wall integrity often disrupt the regular PD schedule, and using minimally invasive approaches is therefore an attractive therapeutic option. Our experience emphasizes the feasibility and safety of a retroperitoneal approach-based laparoscopic technique based on several empirical examples. However, systemic studies on this topic are obviously lacking, so we strongly recommend the accumulation of more cases similar to our own. Several surgical concerns that need to be dealt with among PD patients are also discussed. PMID- 29270040 TI - The Effects of Astym Therapy(r) on a Child With Spastic Diplegic Cerebral Palsy. AB - Purpose: Limited research exists regarding use of Astym(r) therapy with neurologic conditions. The purpose of this case was to describe using Astym therapy in treating spastic diplegic cerebral palsy (CP). Case description: A 6 year-old female was treated more than 9 months (36 sessions) for decreased flexibility, muscle weakness, spasticity, and abnormal gait. Examination findings: Gait performed with articulated ankle-foot orthoses (75% of the time) or foot orthosis (25%); lack of active dorsiflexion (DF); lack of heel strike during gait; spasticity in hamstrings, gastrocnemius, hip adductors; hamstring flexibility (90/90 test position) 50 degrees right and 60 degrees left; gastrocnemius flexibility neutral bilaterally; and Peabody Developmental Motor Scales, second edition (PDMS-2) age equivalence (in months) 23 locomotion, 25 object manipulation, and 21 stationary tasks. Therapeutic interventions included Astym therapy, stretching, strengthening, neuromuscular reeducation, and gait training. Outcomes: At 6 months, flexibility improved bilaterally to 10 degrees past neutral in gastrocnemius and 0 degrees in hamstrings. The PDMS-2 age equivalence scores were 27 locomotion, 32 object manipulation, and 28 stationary tasks. At discharge, patient ambulated full-time with foot orthosis, exhibiting improved stride length bilaterally with active ankle DF to initiate heel strike. Spasticity was unchanged. Discussion: Astym therapy was effective in treating a child with spastic diplegic CP, resulting in enhanced strength, flexibility, and gait. PMID- 29270041 TI - A New Procedure for Wrapped-Negative Pressure Wound Therapy for Congestion After Arterialized Venous Flap Surgery. AB - Negative pressure wound therapy (NPWT) is a method for treating wound. However, there are no case reports using NPWT for treating congestion after arterialized venous flap. Therefore, this study reported favorable outcomes after using a single-use NPWT system for managing congestion. A 39-year-old man had his index finger caught by a press machine. The finger had a soft tissue defect at the ventral part. An arterialized venous flap taken from the right forearm was transplanted. Perfusion of the flap was favorable, but on postoperative day 5, congestion and the edema of the flap were found. Then, NPWT was initiated. The congestion and edema in the flap were improved without complications such as flap necrosis and wound infection. At 4 months postoperatively, the morphology of the finger was favorable. In this study, NPWT was speculated to force the deeper blood vessels within the flap to dilate with inducing drainage and the simultaneous reduction in excess blood flow to the cortical layer, resulting in the improvement of congestion. Negative pressure wound therapy was used for treating congestion after the transplantation of arterialized venous flap, and the wound was favorably managed. PMID- 29270043 TI - Should there be greater exposure to interventional radiology in the undergraduate curriculum? AB - Medical imaging has been one of the most revolutionary innovations in medicine. Today, as health care professionals shift their focus toward more sophisticated technology and minimally invasive procedures, interventional radiology (IR) has become a rapidly expanding specialty. Despite these advances, there is a lack of doctors specializing in this field. A growing body of evidence suggests that the low number of applicants for posts may be due to poor exposure to the specialty at medical school. In this article, we outline the importance of IR in today's health care system. Next, we evaluate the evidence that there is a lack of knowledge of IR not only among medical students in the UK but globally. We further discuss how a more effective incorporation of IR in the undergraduate curriculum can enhance medical students' interest in the field and subsequently increase the number of doctors specializing in IR. Finally, we suggest alternative strategies to gauge medical students' interest in IR, including teaching via e-learning and virtual reality. PMID- 29270042 TI - Evaluation of FreeStyle Libre Flash Glucose Monitoring System on Glycemic Control, Health-Related Quality of Life, and Fear of Hypoglycemia in Patients with Type 1 Diabetes. AB - Background/objectives: In the current era of modern technology and the development of smart devices such as the flash glucose monitoring (FGM) systems, patients can easily monitor their glucose levels more frequently without any inconvenience. In this study, we evaluate the effect of FreeStyle Libre FGM system on glycemic control, hypoglycemia, health-related quality of life (QoL), and the fear of hypoglycemia (FOH) among children and young people with type 1 diabetes (T1D). Design and methods: A prospective study was conducted at the Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia, between January 2017 and May 2017 on 47 (aged 13-19 years) registered patients with T1D who used conventional finger-pricking method for self-testing the glucose. At baseline visit, the FGM sensors were placed on each participant by a trained diabetes educator. The data collected from the sensors were computed to generate the respective ambulatory glucose profiles so as to determine the total number of scans conducted during the study period. At the baseline and at 3 months of the experiment, a trained interviewer administered the questionnaire Hypoglycemia Fear Survey-Child Version (HFS-C) and PedsQL 3.0 (QoL questionnaire) to each patient. The age, sex, weight, height, adjusted body mass index, duration of diabetes, treatment modality, and glycosylated hemoglobin A1c (HbA1c) levels of each patient were recorded. Results: As compared with the baseline, a significant improvement was noted in the behavior of FOH (P = .0001), worry (P = .0001), QoL (P = .002), HbA1c level (P = .008), and hypoglycemia (P = .023) at 3 months. Significant improvement was noted in the behavior (P = .0001), worry (P = .0001), QoL (P = .003), HbA1c level (P = .014), and hypoglycemia (P = .001) among the multiple-dose insulin injection-treated patients as compared with baseline. Significant improvement was noted in the behavior (P = .0001), worry (P = .0001), and hypoglycemia (P = .001) among the insulin pump-treated patients as compared with baseline. A positive correlation was recorded in the behavior (r = .47; P < .001), QoL (r = .70; P < .001), and the mean number of FGM scans. A negative correlation was recorded in the worry (r = -.43; P = .002), HbA1c level (r = .58; P < .001), hypoglycemia (r = -.65; P < .001), and the mean number of FGM scans. Conclusions: The frequent use of FGM scanning reduced the frequency of hypoglycemia, HbA1c level, and worry and increased the behavior and QoL. As compared with self-testing by the conventional finger-pricking method, the use of FGM increased the frequency of self-testing and thus diabetes control. PMID- 29270044 TI - Condensing embryology teaching for medical students: can it be taught in 2 hours? AB - Introduction: Embryology forms a valuable part of the medical school curriculum. However, medical students traditionally struggle with revising embryology and appreciating its relevance. Condensing the teaching content, implementing peer teaching methods, and increasing clinical focus in curricula have been suggested as methods to improve student engagement. Methods: Medical students at two universities were taught a condensed version of the embryological curriculum in 2 hours by final-year medical students. Students' confidence with the topics covered in the embryological curricula was assessed using anonymized precourse and postcourse questionnaires. Students were asked to further evaluate the quality, delivery, and content of the teaching in the postcourse questionnaire and were given the opportunity to provide written comments. All questions consisted of a statement stem and a five-point Likert scale. Results: Students scored significantly higher levels of confidence with embryology after implementation of the course. They found the talk to be effectively delivered, clear, and relevant to their examinations. Conclusion: We have demonstrated that it is possible to design and produce an embryology teaching program that covers an undergraduate embryology curriculum in a chronological systems-based manner in 2 hours with successful results. PMID- 29270045 TI - Evidence in medicine: math versus biology! PMID- 29270046 TI - No evidence of excessive cancer screening in female noncarriers from BRCA1/2 mutation-positive families. AB - Background: In families with a proven BRCA1/2 mutation, women not carrying the familial mutation should follow the cancer screening recommendations applying to women in the general population. In the present study, we evaluated the cancer screening practices of unaffected noncarriers from families with a proven BRCA mutation, and we assessed the role of family history in their screening practices. Methods: Self-report data were provided retrospectively by 220 unaffected female noncarriers for periods of up to 10 years (mean: 4.3 years) since disclosure of their BRCA1/2 genetic test result. A ratio for the annual frequency of breast and ovarian cancer screening exams (mammography, breast ultrasonography, breast magnetic resonance imaging, transvaginal or pelvic ultrasound, cancer antigen 125 testing) was calculated as number of screening exams divided by the number of years in the individual observation period. Results: The annual average for mammography exams was 0.15, 0.4, 0.56, and 0.71 in women 30-39, 40-49, 50-59, and 60-69 years of age respectively. The uptake of other breast and ovarian cancer screening exams was very low. Mammography and breast ultrasonography and magnetic resonance imaging were generally more frequent among participants with at least 1 first-degree relative affected by breast cancer. Conclusions: In most noncarriers, screening practices are consistent with the guidelines concerning women in the general population. When noncarriers adopt screening behaviours that are different from those that would be expected for average-risk women, those behaviours are influenced by their familial cancer history. Impact: Decision tools might help female noncarriers to be involved in their follow-up in accordance with their genetic status and their family history, while taking into account the benefits and disadvantages of cancer screening. PMID- 29270047 TI - Patterns of cancer centre follow-up care for survivors of breast, colorectal, gynecologic, and prostate cancer. AB - Background: Rising demand on cancer system resources, alongside mounting evidence that demonstrates the safety and acceptability of primary care-led follow-up care, has resulted in some cancer centres discharging patients back to primary care after treatment. At the same time, the ways in which routine cancer follow up care is provided across Canada continue to vary widely. The objectives of the present study were to investigate patterns of routine follow-up care at a cancer centre for breast, colorectal, gynecologic, and prostate cancer survivors; factors associated with receipt of follow-up care at a cancer centre; and changes in follow-up care at a cancer centre over time. Methods: We identified all people diagnosed in Nova Scotia with an invasive breast, colorectal, gynecologic, or prostate cancer between 1 January 2006 and 31 December 2013. We linked the resulting population-based dataset, at the patient level, to cancer centre or clinic data and to census data. We identified a nonmetastatic survivor cohort (n = 12,267) and developed decision rules to differentiate routine from non-routine visits during the follow-up care period (commencing 1 year after diagnosis). Descriptive statistics were computed to describe the patterns of routine follow up care at a cancer centre. Negative binomial regression was used to examine factors associated with visits made and changes over time. Results: Nearly half the survivors (48.4%) had at least 1 follow-up visit to the cancer centre, with variation by disease site (range: 30.2%-62.4%). Disease site and stage at diagnosis were associated with receipt of follow-up care at a cancer centre. For instance, compared with breast cancer survivors, survivors of gynecologic cancer had more visits [incidence rate ratio (irr): 1.48; 95% confidence interval (ci): 1.34 to 1.64], and survivors of colorectal cancer had fewer visits (irr: 0.45; 95% ci: 0.40 to 0.51). Year of diagnosis was associated with follow-up at a cancer centre, with each successive calendar year being associated with an 8% increase in visits made (irr: 1.08; 95% ci: 1.07 to 1.10). Conclusions: Despite evidence that follow-up care can be effectively and safely delivered in primary care, and despite intensifying demands on oncology services, many survivors continue to receive routine follow-up care at a cancer centre. PMID- 29270048 TI - Wait times for diagnosis and treatment of lung cancer: a single-centre experience. AB - Background: Multiple clinical practice guidelines recommend rapid evaluation of patients with suspected lung cancer. It is uncertain whether delays in diagnosis and management have a negative effect on outcomes. Methods: This retrospective study included 551 patients diagnosed with lung cancer through the diagnostic assessment program at the Institut universitaire de cardiologie et de pneumologie de Quebec between September 2013 and March 2015. Median wait times between initial referral, diagnosis, and first treatment were calculated and compared with recommended targets. Analyses were performed to evaluate for specific factors associated with longer wait times and for the effect of delays on the outcomes of progression-free survival (pfs), relapse-free survival (rfs) after primary surgical resection, and overall survival (os). Results: Most patients were investigated and treated within recommended targets. Of the entire cohort, 379 patients were treated at our institution. Of those 379 patients, 311 (82%) were treated within recommended targets. In comparing patients within and outside target times, the only statistically significant difference was found in the distribution of treatment modalities: patients meeting targets were more likely to be treated with surgery or chemotherapy rather than with radiation. The pfs on first treatment modality was influenced by clinical stage, but not by time to therapy [hazard ratio (hr): 1.10; p = 0.65]. The os for the entire cohort was also influenced by stage, but not by delays (hr: 1.04; p = 0.87). For the 209 patients treated by surgery with curative intent, a significant reduction in rfs was associated with male sex and TNM stage, but not with delays (hr: 1.11; p = 0.83). The os after primary surgical resection was also associated with TNM stage, but not with delays (hr: 1.82; p = 0.43). Conclusions: Recommended targets for wait times in the investigation and treatment of lung cancer can be achieved within a diagnostic assessment program. Compared with radiation treatment, treatment with surgery or chemotherapy is more likely to be completed within targets. Delays in investigation and treatment do not appear to negatively affect the clinical outcomes of os, rfs, and pfs. Prospective studies are needed to evaluate whether efficient work-up and treatment influence other important variables, such as quality of life, cost of care, and access to therapies while performance status is adequate. PMID- 29270049 TI - The views of patients with brain cancer about palliative care: a qualitative study. AB - Background: Palliative care, a specialty aimed at providing optimal care to patients with life-limiting and chronic conditions, has several benefits. Although palliative care is appropriate for neurosurgical conditions, including brain cancer, few studies have examined the views of brain cancer patients about palliative care. We aimed to explore the thoughts of brain cancer patients about palliative care, their opinions about early palliative care, and their preferred care setting. Methods: Semi-structured interviews and the qualitative research methodologies of grounded theory were used to explore perceptions of palliative care on the part of 39 brain cancer outpatients. Results: Seven overarching actions emerged: ?Patients would prefer to receive palliative care in the home.?Increased time with caregivers and family are the main appeals of home care.?Patients express dissatisfaction with brief and superficial interactions with health care providers.?Patients believe that palliative care can contribute to their emotional well-being.?Patients are open to palliative care if they believe that it will not diminish optimism.?There is a preconceived idea that palliative care is directly linked to active dying, and that supposed link generates fear in some patients.?Patients prefer to be educated about palliative care as an option early in their illness, even if they are fearful of it. Conclusions: Overall, when educated about the true meaning of palliative care, most patients express interest in accessing palliative care services. Although the level of fear concerning palliative care varies in patients, most recognize the associated benefits. PMID- 29270050 TI - Toward improved goals-of-care documentation in advanced cancer: report on the development of a quality improvement initiative. AB - Background: Documentation of advance care planning for patients with terminal cancer is known to be poor. Here, we describe a quality improvement initiative. Methods: Patients receiving palliative chemotherapy for metastatic lung, pancreatic, colorectal, and breast cancer during 2010-2015 at the Cancer Centre of Southeastern Ontario were identified from electronic pharmacy records. Clinical notes were reviewed to identify documentation of care plans in the event of acute deterioration. After establishing baseline practice, we sought to improve documentation of goals of care and referral rates to palliative care. Using quality improvement methodology, we developed a guideline, a standardized documentation system, and a process to facilitate early referral to palliative care. Results: During 2010-2015, 456 patients were included in the baseline cohort: 63% with lung cancer, 16% with colorectal cancer, 13% with pancreatic cancer, and 7% with breast cancer. Care goals in the event of an acute illness were documented by medical oncologists in 6% of cases (26 of 456). Of the 456 patients, 47% (n = 214) were seen by palliative care; care goals were documented by palliative care in 48% of the patients seen (103 of 214). With those baseline data in hand, a local practice guideline and process was developed to facilitate the identification of patients for whom advance care planning and early palliative care referral should be considered. A system was also established so that goals-of-care documentation will be supported with a written framework and broadly accessible in the electronic medical record. Conclusions: Low rates of documentation of advance care planning and referral to palliative care persist and have stimulated a local quality improvement initiative. PMID- 29270051 TI - The predictive effect of primary tumour location in the treatment of metastatic colorectal cancer: a Canadian consensus statement. AB - In recently published data, the predictive value of primary tumour location for the treatment of metastatic colorectal cancer with available biologic therapies has been explored. Recognizing the potential effect of those data on clinical practice, we convened a meeting of Canadian experts who treat metastatic colorectal cancer to develop a set of national, evidence-based treatment guidelines based on primary tumour location. This report summarizes the relevant evidence and presents the consensus recommendations of those experts. PMID- 29270052 TI - The OncoSim model: development and use for better decision-making in Canadian cancer control. AB - The Canadian Partnership Against Cancer was created in 2007 by the federal government to accelerate cancer control across Canada. Its OncoSim microsimulation model platform, which consists of a suite of specific cancer models, was conceived as a tool to augment conventional resources for population level policy- and decision-making. The Canadian Partnership Against Cancer manages the OncoSim program, with funding from Health Canada and model development by Statistics Canada. Microsimulation modelling allows for the detailed capture of population heterogeneity and health and demographic history over time. Extensive data from multiple Canadian sources were used as inputs or to validate the model. OncoSim has been validated through expert consultation; assessments of face validity, internal validity, and external validity; and model fit against observed data. The platform comprises three in-depth cancer models (lung, colorectal, cervical), with another in-depth model (breast) and a generalized model (25 cancers) being in development. Unique among models of its class, OncoSim is available online for public sector use free of charge. Users can customize input values and output display, and extensive user support is provided. OncoSim has been used to support decision-making at the national and jurisdictional levels. Although simulation studies are generally not included in hierarchies of evidence, they are integral to informing cancer control policy when clinical studies are not feasible. OncoSim can evaluate complex intervention scenarios for multiple cancers. Canadian decision-makers thus have a powerful tool to assess the costs, benefits, cost-effectiveness, and budgetary effects of cancer control interventions when faced with difficult choices for improvements in population health and resource allocation. PMID- 29270053 TI - Using family history forms in pediatric oncology to identify patients for genetic assessment. AB - Objective: We set out to identify and offer genetic testing to the 5%-10% of pediatric cancer patients who have been estimated to carry germline mutations in inherited cancer predisposition syndromes. Clinical genetic testing has become widely available, and thus in busy oncology clinics, tools are needed to identify patients who could benefit from a referral to genetics. Methods: We studied the clinical utility of administering a family history form in the pediatric oncology long-term follow-up clinic to identify patients who might have an inherited cancer predisposition syndrome. Genetic testing involved primarily Sanger sequencing in clia (Clinical Laboratory Improvement Amendments)-certified laboratories. Results: Of 57 patients who completed forms, 19 (33.3%) met criteria for referral to genetics. A significant family history of cancer was present for 4 patients, and 12 patients underwent genetic testing. Of 18 genetic tests ordered, none identified a pathogenic mutation, likely because of a small sample size and a candidate-gene approach to testing. Three families were also identified for further assessment based on a family history of breast cancer, with two of families having members eligible for BRCA1 and BRCA2 testing. Conclusions: Genetic testing in pediatric oncology patients is important to guide the management of patients who have an inherited cancer predisposition syndrome and to identify other family members at risk when mutations are identified. When no mutations are identified, that information is often reassuring to families who are worried about siblings. However, in the absence of an identified genetic cause in a patient, some uncertainty remains. PMID- 29270054 TI - Survivorship care plans for breast cancer patients: understanding the quality of the available evidence. AB - Aim: The overall goal of the present study was to contribute to consistency in the provincial approach to survivorship care planning through knowledge synthesis and exchange. Our review focused on the research concerning the physical and emotional challenges of breast cancer (bca) patients and survivors and the effects of the interventions that have been used for lessening those challenges. Methods: The psychosocial topics identified in bca survivorship care plans created by two different initiatives in our province provided the platform for our search criteria: quality of life (qol), sexual function, fatigue, and lifestyle behaviours. We conducted an umbrella review to retrieve the best possible evidence, and only reviews investigating the intended outcomes in bca survivors and having moderate-to-high methodologic quality scores were included. Results: Of 486 reports retrieved, 51 reviews met the inclusion criteria and form part of the synthesis. Our results indicate that bca patients and survivors experience numerous physical and emotional challenges and that interventions such as physical activity, psychoeducation, yoga, and mindfulness-based stress reduction are beneficial in alleviating those challenges. Conclusions: Our study findings support the existing survivorship care plans in our province with respect to the physical and emotional challenges that bca survivors often face. However, the literature concerning cancer risks specific to bca survivors is scant. Although systematic reviews are considered to be the "gold standard" in knowledge synthesis, our findings suggest that much remains to be done in the area of synthesis research to better guide practice in cancer survivorship. PMID- 29270055 TI - Feasibility of assessing patient health benefits and incurred costs resulting from early dysphagia intervention during and immediately after chemoradiotherapy for head-and-neck cancer. AB - Background: Resource limitations affect the intensity of speech-language pathology (slp) dysphagia interventions for patients with head-and-neck cancer (hnc). The objective of the present study was to assess the feasibility of a prospective clinical trial that would evaluate the effects on health and patient costs of early slp dysphagia intervention for hnc patients planned for curative concurrent chemoradiotherapy (ccrt). Methods: Patients with hnc planned for curative ccrt were consecutively recruited and received dysphagia-specific intervention before, during, and for 3 months after treatment. Swallowing function, body mass index, health-related quality of life (qol), and out-of pocket costs were measured before ccrt, at weeks 2 and 5 during ccrt, and at 1 and 3 months after ccrt. Actuarial percutaneous endoscopic gastrostomy (peg) removal rates and body mass index in the study patients and in a time-, age-, and disease-matched cohort were compared. Results: The study enrolled 21 patients (mean age: 54 years; 19 men). The study was feasible, having a 95% accrual rate, 10% attrition, and near completion of all outcomes. Compared with the control cohort, patients receiving dysphagia intervention trended toward a higher rate of peg removal at 3 months after ccrt [61% (32%-78%) vs. 53% (23%-71%), p = 0.23]. During ccrt, monthly pharmaceutical costs ranged between $239 and $348, with work loss in the range of 18-30 days for patients and 8-12 days for caregivers. Conclusions: We demonstrated the feasibility of comparing health and economic outcomes in patients receiving and not receiving early slp dysphagia intervention. These preliminary findings suggest that early slp dysphagia intervention for hnc patients might reduce peg dependency despite worsening health. Findings also highlight effects on financial security for these patients and their caregivers. PMID- 29270056 TI - An evaluation of the behaviour-change techniques used on Canadian cancer centre Web sites to support physical activity behaviour for breast cancer survivors. AB - Background: Cancer centre Web sites can be a useful tool for distributing information about the benefits of physical activity for breast cancer (bca) survivors, and they hold potential for supporting health behaviour change. However, the extent to which cancer centre Web sites use evidence-based behaviour change techniques to foster physical activity behaviour among bca survivors is currently unknown. The aim of our study was to evaluate the presentation of behaviour-change techniques on Canadian cancer centre Web sites to promote physical activity behaviour for bca survivors. Methods: All Canadian cancer centre Web sites (n = 39) were evaluated by two raters using the Coventry, Aberdeen, and London-Refined (calo-re) taxonomy of behaviour change techniques and the eEurope 2002 Quality Criteria for Health Related Websites. Descriptive statistics were calculated. Results: The most common behaviour change techniques used on Web sites were providing information about consequences in general (80%), suggesting goal-setting behaviour (56%), and planning social support or social change (46%). Overall, Canadian cancer centre Web sites presented an average of M = 6.31 behaviour change techniques (of 40 that were coded) to help bca survivors increase their physical activity behaviour. Evidence of quality factors ranged from 90% (sites that provided evidence of readability) to 0% (sites that provided an editorial policy). Conclusions: Our results provide preliminary evidence that, of 40 behaviour-change techniques that were coded, fewer than 20% were used to promote physical activity behaviour to bca survivors on cancer centre Web sites, and that the most effective techniques were inconsistently used. On cancer centre Web sites, health promotion specialists could focus on emphasizing knowledge mobilization efforts using available research into behaviour-change techniques to help bca survivors increase their physical activity. PMID- 29270057 TI - Reasons for lack of referral to medical oncology for systemic therapy in stage IV non-small-cell lung cancer: comparison of 2003-2006 with 2010-2011. AB - Introduction: Only approximately 25% of stage iv non-small-cell lung cancer (nsclc) patients receive systemic therapy. For such patients, we examined factors affecting referral to a cancer centre (cc) and to medical oncology (mo), and use of systemic therapy. Methods: Using the Glans-Look Lung Cancer database, we completed a chart review of stage iv nsclc patients diagnosed in Southern Alberta during 2003-2006 and 2010-2011, comparing median overall survival (mos), referral, and treatment in the two cohorts. Results: Of the 922 patients diagnosed in 2003-2006 and the 560 diagnosed in 2010-2011, 94% and 82% respectively were referred to a cc, with 22% and 23% receiving traditional chemotherapy (tctx). Referral to a cc or mo and use of tctx correlated with survival (p < 0.0001): The mos duration was 11.2 months in those receiving tctx and 1.0 months in those not referred to a cc. The overall mos duration was similar in the two cohorts (4.1 months vs. 3.9 months, p = 0.47). Major reasons for lack of referral to mo included poor functional status, rapid decline, and patient wish, which were similar to the reasons for forgoing tctx. In the two cohorts, 87 (9.4%) and 42 (7.5%) patients received epidermal growth factor inhibitors, with a mos duration of 16.2 months. Multivariable analysis showed that male sex [hazard ratio (hr): 1.16; p = 0.008] and pulmonary embolus (hr: 1.2; p = 0.002) correlated with worse survival. In contrast, receipt of chemotherapy (hr: 0.5; p < 0.001) and enrolment in a clinical trial (hr: 0.76; p = 0.049) correlated with better survival. Conclusions: Our experience confirms that, over time, uptake of systemic therapy, including tctx and targeted therapy, changed little despite their established efficacy. Most of the factors limiting systemic therapy uptake appear to be non-modifiable at the time of referral. Rapid diagnosis and the availability of well-tolerated drugs for all nsclc patients will likely be the most important factors in increasing systemic therapy uptake in this population. PMID- 29270058 TI - Ovarian function after chemotherapy in young breast cancer survivors. AB - Background: As cure rates for breast cancer improve, there is increasing evidence that late effects of treatment-and impaired fertility in particular-are emerging as important concerns among young breast cancer survivors. Older reports have evaluated the occurrence of amenorrhea after treatment, but few data have been reported about the incidence of biochemical evidence for impaired ovarian function in patients who do not become overtly menopausal. Methods: We conducted a cross-sectional study evaluating anti-Mullerian hormone (amh) in premenopausal chemotherapy-treated breast cancer survivors and control patients. Random serum levels of amh and other relevant clinical data were collected for 100 premenopausal chemotherapy-treated breast cancer survivors and 76 control subjects. Subgroup analyses were performed for women with regular menstrual cycles at the time of amh testing. Results: After adjustment for age, amh was significantly lower in the overall group of patients receiving chemotherapy (p = 0.002) and in the subgroup reporting normal cycles (p = 0.03). Cyclophosphamide produced a significant dose-dependent reduction in amh (p < 0.001); trastuzumab was associated with increased amh in survivors with normal cycles. Overall, serum amh in survivors was roughly equivalent to that measured in control patients 12 years older. Conclusions: Young breast cancer survivors often experience significant impairment of ovarian function despite having normal menstrual cycles after treatment. Those results have important implications for patient counselling and the timing of possible referral to a fertility specialist. PMID- 29270059 TI - Mental health services use by melanoma patients receiving adjuvant interferon: association of pre-treatment mental health care with early discontinuation. AB - Background: Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. Methods: This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd ifn. Associations between early hd-ifn discontinuation and health services use were examined. Results: Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). Conclusions: Stage iib iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered. PMID- 29270060 TI - Risk and predictors of suicide in colorectal cancer patients: a Surveillance, Epidemiology, and End Results analysis. AB - Background: The risk of suicide is higher for patients with colorectal cancer (crc) than for the general population. Given known differences in morbidity and sites of recurrence, we sought to compare the predictors of suicide for patients with colon cancer and with rectal cancer. Methods: Using the U.S. Surveillance, Epidemiology, and End Results database, adult patients with confirmed adenocarcinoma of the colon or rectum during 1973-2009 were identified. Parametric and nonparametric tests were used to assess selected variables, and Cox proportional hazards regression models were used to determine predictors of suicide. Results: The database identified 187,996 patients with rectal cancer and 443,368 with colon cancer. Compared with the rectal cancer group, the colon cancer group was older (median age: 70 years vs. 67 years; p < 0.001) and included more women (51% vs. 43%, p < 0.001). Suicide rates were similar in the colon and rectal cancer groups [611 (0.14%) vs. 337 (0.18%), p < 0.001]. On univariate analysis, rectal cancer was a predictor of suicide [hazard ratio (hr): 1.26; 95% confidence interval (ci): 1.10 to 1.43]. However, after adjusting for clinical and pathology factors, rectal cancer was not a predictor of suicide (hr: 1.05; 95% ci: 0.83 to 1.33). In the colon cancer cohort, independent predictors of suicide included older age, male sex, white race, and lack of primary resection. The aforementioned predictors, plus metastatic disease, similarly predicted suicide in the rectal cancer cohort. Conclusions: The suicide risk in crc patients is low (<0.2%), and no difference was found based on location of the primary tumour. Sex, age, race, distant spread of disease, and intact primary tumour were the main predictors of suicide among crc patients. Further studies and interventions are needed to target these high-risk groups. PMID- 29270061 TI - Strategic planning in an academic radiation medicine program. AB - Background: In this paper, we report on the process of strategic planning in the Radiation Medicine Program (rmp) at the Princess Margaret Cancer Centre. The rmp conducted a strategic planning exercise to ensure that program priorities reflect the current health care environment, enable nimble responses to the increasing burden of cancer, and guide program operations until 2020. Methods: Data collection was guided by a project charter that outlined the project goal and the roles and responsibilities of all participants. The process was managed by a multidisciplinary steering committee under the guidance of an external consultant and consisted of reviewing strategic planning documents from close collaborators and institutional partners, conducting interviews with key stakeholders, deploying a program-wide survey, facilitating an anonymous and confidential e mail feedback box, and collecting information from group deliberations. Results: The process of strategic planning took place from December 2014 to December 2015. Mission and vision statements were developed, and core values were defined. A final document, Strategic Roadmap to 2020, was established to guide programmatic pursuits during the ensuing 5 years, and an implementation plan was developed to guide the first year of operations. Conclusions: The strategic planning process provided an opportunity to mobilize staff talents and identify environmental opportunities, and helped to enable more effective use of resources in a rapidly changing health care environment. The process was valuable in allowing staff to consider and discuss the future, and in identifying strategic issues of the greatest importance to the program. Academic programs with similar mandates might find our report useful in guiding similar processes in their own organizations. PMID- 29270062 TI - Identifying barriers to accrual in radiation oncology randomized trials. AB - Background: Data about factors driving accrual to radiation oncology trials are limited. In oncology, 30%-40% of trials are considered unsuccessful, many because of poor accrual. The goal of the present study was to inform the design of future trials by evaluating the effects of institutional, clinician, and patient factors on accrual rates to a randomized radiation oncology trial. Methods: Investigators participating in sabr-comet (NCT01446744), a randomized phase ii trial open in Canada, Europe, and Australia that is evaluating the role of stereotactic ablative radiotherapy (sabr) in oligometastatic disease, were invited to complete a survey about factors affecting accrual. Institutional ethics approval was obtained. The primary endpoint was the annual accrual rate per institution. Univariable and multivariable linear regression analyses were used to identify factors predictive of annual accrual rates. Results: On univariable linear regression analysis, off-trial availability of sabr (p = 0.014) and equipoise of the referring physician (p = 0.014) were found to be predictive of annual accrual rates. The annual accrual rates were lower when centres offered sabr for oligometastases off-trial (median: 3.7 patients vs. 8.4 patients enrolled) and when referring physicians felt that, compared with having equipoise, sabr was beneficial (median: 4.8 patients vs. 8.4 patients enrolled). Multivariable analysis identified perceived level of equipoise of the referring physician to be predictive of the annual accrual rate (p = 0.023). Conclusions: The level of equipoise of referring physicians might play a key role in accrual to radiation oncology randomized controlled trials. Efforts to communicate with and educate referring physicians might therefore be beneficial for improving trial accrual rates. PMID- 29270063 TI - A systematic review and network meta-analysis of post-imatinib therapy in advanced gastrointestinal stromal tumour. AB - Background: The standard first-line systemic therapy for advanced gastrointestinal stromal tumour (gist) is imatinib. However, most gists develop imatinib resistance, highlighting the need for new agents in the imatinib refractory setting. Currently, no randomized studies have directly compared the available post-first-line treatments. Methods: In a systematic review, the medline, embase, and central databases, and American Society of Clinical Oncology abstracts to July 2014 were searched to identify randomized controlled trials that included gist patients treated with post-first-line therapies. Hazard ratios (hrs) for progression-free (pfs) and overall survival (os) were extracted. Direct pairwise meta-analyses and indirect comparisons using the Butcher method were performed. Results: Four studies were identified for the systematic review. One study showed that sunitinib in the second-line setting (vs. placebo) was associated with improved pfs, but not improved os. Three studies examined the third-line setting (imatinib resumption vs. placebo, regorafenib vs. placebo, nilotinib vs. best supportive care). In the third-line settings, the two placebo controlled and the non-placebo-controlled trials showed significant heterogeneity (I2 = 98%). Indirect comparisons of imatinib resumption and regorafenib suggested that the hr for pfs was 0.59 (95% confidence interval: 0.31 to 1.12; p = 0.10), trending in favour of regorafenib. Indirect comparisons found that toxicities were higher in the regorafenib group, with a risk difference of 27.8% for any grade toxicities and 19.5% for grades 3 and 4 toxicities. Conclusions: Because a head-to-head study of imatinib resumption compared with regorafenib is unlikely ever to be conducted, our study suggests that, in terms of pfs, regorafenib might be the preferred treatment. However, given the increased toxicity observed with regorafenib, clinicians should interpret that evidence with caution at an individual patient level. PMID- 29270064 TI - Systemic therapy for recurrent epithelial ovarian cancer: a clinical practice guideline. AB - Objective: The purpose of this guideline is to recommend systemic therapy options for women with recurrent epithelial ovarian cancer, including fallopian tube and primary peritoneal cancers. Methods: This document updates the recommendations published in the 2011 Optimal Chemotherapy for Recurrent Ovarian Cancer guideline from Cancer Care Ontario. Draft recommendations were formulated based on evidence obtained through a systematic review of phase ii and iii randomized controlled trials (rcts). The draft recommendations underwent internal review by clinical and methodology experts, and external review by clinical practitioners through a survey assessing the clinical relevance and overall quality of the guideline. Feedback from the internal and external reviews was integrated into the clinical practice guideline. Results: The primary literature search yielded thirty-six primary research papers representing thirty rcts that met the eligibility criteria. The guideline provides recommendations for patients with serous tumour histologies and with recurrent, platinum-resistant, and platinum-sensitive ovarian cancer. Conclusions: The body of evidence from trials that included olaparib and bevacizumab consistently shows a benefit in progression-free survival (pfs) without a corresponding benefit in overall survival (os). The Working Group for this guideline designated pfs, which is associated with symptom control, as a critical outcome. A finding of net benefit can therefore be concluded based on significant differences in pfs. However, that benefit is not without identified harms. Given the identified harms, patient involvement in the decision-making process must take into consideration the side effect profiles of olaparib and bevacizumab within the context of improved pfs but minimal change in os. PMID- 29270065 TI - Adult chronic myelomonocytic leukemia with trisomy 11: a case report. AB - Chronic myelomonocytic leukemia (cmml) is an indolent disease in the category of myelodysplastic and myeloproliferative neoplasms, which can often evolve into acute leukemic neoplasms. Although cytogenetic abnormalities such as trisomy 8 or absence of chromosome Y are well known, few reports about cmml with trisomy 11 have been published. Here, we report a case of cmml with trisomy 11 as the sole chromosomal abnormality, resulting in a very poor outcome. Based on a bone marrow specimen, cmml-1 with trisomy 11 was diagnosed in a 79-year-old man presenting with anemia and atypical peripheral blood cells. Because of the patient's age, he was followed without receiving anticancer treatment. Two months after his diagnosis, the patient's leucocytosis and anemia rapidly worsened, with increasing numbers of immature peripheral cells, which was strongly suggestive of leukemic transformation. Because of acute kidney injury superimposed on chronic kidney disease that led to poor performance status, cytotoxic chemotherapy was not considered feasible, and the patient was transferred to a hospice care facility. PMID- 29270066 TI - Orbital mass as first presentation of metastatic p16-positive oropharyngeal squamous cell carcinoma. AB - We describe a case in which a 67-year-old man was diagnosed with a metastatic recurrence of p16-positive oropharyngeal squamous cell carcinoma after presenting with a medial orbital mass in the region of the nasolacrimal apparatus. A review of the literature revealed that metastasis to the orbit from any malignancy is an uncommon occurrence, and no cases of p16-positive oropharyngeal squamous cell carcinoma have previously been reported. Our case highlights the importance of maintaining a high index of suspicion during surveillance visits with such patients. PMID- 29270067 TI - Feasibility of Radial Endobronchial Ultrasound-Guided Bronchoscopic Cryobiopsy without Fluoroscopy for Lung Parenchymal Lesions. AB - Background: Cryobiopsy is used to biopsy peripheral lung lesions through flexible bronchoscopy with fluoroscopic guidance. However, fluoroscopy is not available at some institutions. This study evaluated the feasibility of radial endobronchial ultrasound-guided bronchoscopic cryobiopsy without fluoroscopy. Methods: This retrospective study was conducted at Chang Gung Memorial Hospital, Linkou branch, in Taiwan. This study enrolled patients who received bronchoscopy examinations with cryotechnology between July 2014 and June 2016. The data were collected through medical chart review. Results: During the study period, 101 patients underwent bronchoscopy examinations with cryotechnology. Ninety patients with endobronchial tumors were excluded from this study. Eleven patients who underwent radial endobronchial ultrasound-guided bronchoscopic cryobiopsy for lung parenchymal lesions were enrolled into this study. The mean age was 61.1 +/- 13.8 years. Five patients were men, and the other six were women. The number of cryobiopsies ranged from 1 to 3. In the histological biopsies, the mean specimen diameter was 0.53 +/- 0.23 cm, and the mean biopsy area was 0.20 +/- 0.19 cm2. Nine of 11 patients had pathological diagnoses. No complications, including pneumothorax, respiratory failure, or major bleeding, were recorded after the procedure. Conclusions: Endobronchial ultrasound is used to ensure biopsy location, and endobronchial ultrasound-guided cryobiopsy is a feasible technique to biopsy peripheral lung lesions in selected cases at institutions without fluoroscopy equipment. This study provided some rationale for further studies examining the impact of fluoroscopy. PMID- 29270068 TI - Is There a Correlation between New Scoring Systems and Systemic Inflammation in Stable Bronchiectasis? AB - Aim: The present study aimed to investigate the relation between FACED and BSI scores, which were developed to measure the severity of bronchiectasis, and systemic inflammation in patients with stable bronchiectasis. Methods: FACED and BSI scores of 117 patients with stable bronchiectasis were calculated. The correlations between mean scores and CRP levels, leukocyte count, and neutrophil/lymphocyte ratio were investigated. Findings: Mean BSI and FACED scores were 7.2 +/- 5.2 and 2.1 +/- 1.8, respectively. The severity of bronchiectasis as determined based on BSI and FACED increased significantly with increasing levels of CRP in patients with stable bronchiectasis (p=0.001 and p=0.027, resp.). No significant changes were found in leukocyte count (p=0.72 and p=0.09, resp.) and N/L ratio (p=0.45 and p=0.71, resp.). BSI and FACED scores were significantly correlated with CRP but not with leukocyte count or N/L ratio. Conclusion: In patients with stable bronchiectasis who are evaluated based on FACED and BSI scores, CRP can be a useful biomarker as a direct indicator of the severity of systemic inflammation. PMID- 29270069 TI - A genome-wide association study for body weight in Japanese Thoroughbred racehorses clarifies candidate regions on chromosomes 3, 9, 15, and 18. AB - Body weight is an important trait to confirm growth and development in humans and animals. In Thoroughbred racehorses, it is measured in the postnatal, training, and racing periods to evaluate growth and training degrees. The body weight of mature Thoroughbred racehorses generally ranges from 400 to 600 kg, and this broad range is likely influenced by environmental and genetic factors. Therefore, a genome-wide association study (GWAS) using the Equine SNP70 BeadChip was performed to identify the genomic regions associated with body weight in Japanese Thoroughbred racehorses using 851 individuals. The average body weight of these horses was 473.9 kg (standard deviation: 28.0) at the age of 3, and GWAS identified statistically significant SNPs on chromosomes 3 (BIEC2_808466, P=2.32E 14), 9 (BIEC2_1105503, P=1.03E-7), 15 (BIEC2_322669, P=9.50E-6), and 18 (BIEC2_417274, P=1.44E-14), which were associated with body weight as a quantitative trait. The genomic regions on chromosomes 3, 9, 15, and 18 included ligand-dependent nuclear receptor compressor-like protein (LCORL), zinc finger and AT hook domain containing (ZFAT), tribbles pseudokinase 2 (TRIB2), and myostatin (MSTN), respectively, as candidate genes. LCORL and ZFAT are associated with withers height in horses, whereas MSTN affects muscle mass. Thus, the genomic regions identified in this study seem to affect the body weight of Thoroughbred racehorses. Although this information is useful for breeding and growth management of the horses, the production of genetically modified animals and gene doping (abuse/misuse of gene therapy) should be prohibited to maintain horse racing integrity. PMID- 29270070 TI - Comparison of commercial RNA extraction kits and qPCR master mixes for studying gene expression in small biopsy tissue samples from the equine gastric epithelium. AB - Gastric tissue biopsy and gene expression analysis are important tools for disease diagnosis and study of the physiology of the equine stomach. However, RNA extraction from gastric biopsy samples is a complex procedure because the samples contain low quantities of RNA and are contaminated with mucous protein and bacterial flora. The objectives of these studies were to compare the performance of RNA extraction methods and to investigate the sensitivity of commercial qPCR master mixes for gene expression analysis of gastric biopsy samples. Three commercial RNA extraction methods (TRIzolTM, GENEzolTM and MiniPrepTM) and four qPCR master mixes with SYBR(r) green (qPCRBIO, KAPA, QuantiNova, and PerfeCTa) were compared. RNA qualification and quantitation were compared. Real-time PCR was used to compare qPCR master mixes. The results revealed that TRIzol and GENEzol obtained significantly higher yield of RNA (P<0.01) but that TRIzol had the highest contamination of protein and DNA (P<0.05). Conversely, MiniPrep resulting in a significantly higher purification of RNA (P<0.05) but provided the lowest yield of RNA (P<0.01). For PCR master mixes, KAPA was significantly (P<0.05) more sensitive than other qPCR kits for all amounts of DNA template, particularly at the lowest amount of cDNA. In conclusion, GENEzol is the best method to obtain a high RNA yield and purification and it is more cost-effective than the others as well. Regarding the qPCR master mixes, KAPA SYBR qPCR Master Mix (2x) Universal is superior to the other tested master mixes for studying gene expression in equine gastric biopsies. PMID- 29270071 TI - Clinical usefulness of intravenous constant rate infusion of fentanyl and medetomidine under sevoflurane anesthesia in Thoroughbred racehorses undergoing internal fixation surgery. AB - A total of 20 racehorses with longitudinal fractures underwent internal fixation surgery under sevoflurane anesthesia combined with infusion of medetomidine (3 ug/kg/hr) alone (10 horses, group M) or medetomidine and fentanyl (7 ug/kg/hr) (10 horses, group FM). In group FM, the end-tidal sevoflurane concentration during surgery was maintained significantly lower than in group M (2.8-2.9% for group M vs. 2.2-2.6% for group FM, P<0.01). The mean arterial blood pressure was maintained over 70 mmHg using dobutamine infusion (group M, 0.36-0.54 ug/kg/min; group FM, 0.27-0.65 ug/kg/min), and the recovery qualities were clinically acceptable in both groups. In conclusion, co-administration of fentanyl and medetomidine by constant rate infusion may be a clinically useful intraoperative anesthetic adjunct for horses to reduce the requirement of sevoflurane when they undergo orthopedic surgery. PMID- 29270072 TI - Equine ocular mast cell tumor: histopathological and immunohistochemical description. AB - This report describes an ocular mast cell tumor in a 13-year-old female sport horse. Clinical examination revealed a solitary firm mass located in the ocular mucosa, protruding from behind the left lower eyelid. The lesion was surgically removed and submitted to histopathology. Microscopically, the mass was composed of sheets of well-differentiated neoplastic round cells circumscribed by delicate connective tissue. Positive Giemsa and Toluidine Blue staining confirmed the presence of cytoplasmic granules. Neoplastic cells showed strong membranous and mild diffuse cytoplasmic immunoreactivity for c-KIT and a low KI-67 proliferative index. Based on these findings, a diagnosis of ocular mast cell tumor was made. Six months after surgical removal, no evidence of ocular lesion recurrence was detected. PMID- 29270073 TI - Isolation of equine peripheral blood stem cells from a Japanese native horse. AB - The sizes of Japanese native horses have drastically decreased, and protection of these populations is important for Japanese horse culture. Social trials as well as scientific attempts are necessary for maintaining the breed. Mesenchymal stem cells (MSCs) have potential as a cell source for various cell therapies. However, there have been no reports on MSCs of Japanese native horses. We aimed to isolate and characterize MSCs from a Japanese native horse, the Noma horse. Plastic adherent and self-replicating cells were isolated from a Noma horse's peripheral blood (PB). The isolated cells had trilineage potential and a surface antigen of mesenchymal cells, so they fulfilled the minimal criteria of MSCs. Therefore, PB can be one source of MSCs for Japanese native horses. PMID- 29270074 TI - Foaling rate of mares that were rebred after pregnancy loss in Hidaka, Japan. AB - The purpose of this study was to evaluate foaling rates of mares that were rebred after the pregnancy loss in same reproductive season and to examine factors influencing them in Hidaka, Japan. The study included 82 Thoroughbred mares that had experienced pregnancy loss. The foaling rate of the mares that were rebred after pregnancy loss was 57.3%. The foaling rate decreased as the period until detection of pregnancy loss increased. Aging and lower body condition score of mares decreased the foaling rate. PMID- 29270075 TI - Factors affecting the prognosis for uterine torsion: the effect of treatment based on measurements of serum progesterone and estradiol concentrations after surgery. AB - This is a retrospective study of uterine torsion (UT) in seven mares. In two cases, serum progesterone and estradiol concentrations were also investigated. The mare and foal/fetus survival rate was 57% (4/7). Four cases presented with clockwise torsion, and two cases presented with counterclockwise torsion. The direction was undetermined in one case. The degree of torsion varied. Correction of torsion was performed by ventral midline celiotomy in all cases. In the two cases with measured hormone levels, elevated levels of P4 were decreased through medication. All mares discharged from the hospital with a live fetus were able to carry a live fetus. Early diagnosis and treatment of UT increases the possibility of helping mares and foals in cases with acute UT. PMID- 29270076 TI - Efficacy and safety of praziquantel against Schistosoma haematobium in the Ikata Likoko area of southwest Cameroon. AB - Background: Schistosomiasis remains a parasitic infection of public health importance especially in Africa south of the Sahara including Cameroon. Chemotherapy using praziquantel has been the most effective and widespread control measure used. However, there are reports of reduced efficacy of the drug. The aim of this study was to assess the efficacy and safety of praziquantel against Schistosoma haematobium among infected individuals in the Ikata-Likoko area of southwest Cameroon. Following a baseline study, S. haematobium egg load was determined using the urine filtration technique and microscopy. Participants were treated with a unique dose of praziquantel of 40 mg/Kg body weight. A control test was carried out on the 42nd day post-treatment to determine the proportion of positive participants with viable eggs (cure rate) and the egg loads. The egg loads obtained during the control and at baseline were used to calculate the egg reduction rate (ERR) used as the main indicator of praziquantel efficacy according to the WHO, 2013 protocol. Results: At baseline, the prevalence of S. haematobium was 34.3% (177/516). Out of these a total of 174 participants aged between 4 and 76 years were recruited into the study. A total of 130 participants came for follow up on day 42. Among them, 22.3% (29) were positive for eggs of S. haematobium but none of the eggs were viable giving a cure rate of 100%. The overall mean egg load per 10 mL (MEL/10 mL) of urine reduced from 31 (1-400) at baseline to 6.0 (1-35) on day 42. The overall ERR was reduced (80.3%). However, the efficacy was satisfactory (ERR >= 90%) in females, children ? 5 years, and some localities and for individuals with heavy infection intensity. Fifteen (8.6%) of the participants presented minor adverse events including abdominal disorders, headache and vomiting but did not last for more than 24 h. Conclusions: Treatment with praziquantel was efficacious and safe showing reduction in prevalence as well as mean egg load in some individuals with few adverse events recorded. The distribution of praziquantel in the area should be extended to other age groups and not just school-age children. A study with multiple drug doses and longer period of evaluation could reveal more information on praziquantel efficacy in the area. PMID- 29270077 TI - Household structure vs. composition: Understanding gendered effects on educational progress in rural South Africa. AB - BACKGROUND: Demographers have long been interested in the relationship between living arrangements and gendered outcomes for children in sub-Saharan Africa. Most extant research conflates household structure with composition and has revealed little about the pathways that link these components to gendered outcomes. OBJECTIVES: First, we offer a conceptual approach that differentiates structure from composition with a focus on gendered processes that operate in the household; and second, we demonstrate the value of this approach through an analysis of educational progress for boys and girls in rural South Africa. METHODS: We use data from the 2002 round of the Agincourt Health and Demographic Surveillance System. Our analytical sample includes 22,997 children aged 6-18 who were neither parents themselves nor lived with a partner or partner's family. We employ ordinary least squares regression models to examine the effects of structure and composition on educational progress of girls and boys. RESULTS: The results suggest that non-nuclear structures are associated with similar negative effects for both boys and girls compared to children growing up in nuclear households. However, the presence of other kin in the absence of one or both parents results in gendered effects favouring boys. CONCLUSION: The absence of any gendered effects when using a household structure typology suggests that secular changes to attitudes about gender equity trump any specific gendered processes stemming from particular configurations. On the other hand, gendered effects that appear when one or both parents are absent show that traditional gender norms and/or resource constraints continue to favour boys. CONTRIBUTION: Despite the wealth of literature on household structure and children's educational outcomes in sub-Saharan Africa, the conceptual basis of these effects has not been well articulated. We have shown the value of unpacking household structure to better understand how gender norms and gendered resource allocations impact education. PMID- 29270078 TI - Hibernoma: a rare case of adipocytic tumor in head and neck. AB - Background: Hibernoma is a rare soft tissue tumor stem from persistent fetal brown fat tissue. This benign tumor may occasionally occur in head and neck area and, in most cases, is characterized by an asymptomatic slow growth. Case presentation: We presented an uncommon case of hibernoma of the posterior cervical triangle occurring in a 30-year-old man referred to the department of otolaryngology. The patient suffered from a right, very painful, and rapidly growing mass since 3 months. MRI examination reported both an infiltrating mass and a homogenous enhancement of an underlying vascularization after the injection of intravenous contrast. According to the risk of sarcoma, a surgical procedure was made to completely excise the mass that was a hibernoma. Conclusions: Hibernoma may occur with an uncommon clinical presentation imitating malignancy. MRI plays a key role in the differential diagnosis and surgery remains the better therapeutic approach. PMID- 29270079 TI - Communication skills intervention: promoting effective communication between nurses and mechanically ventilated patients. AB - Background: Patients in the Intensive Care Unit (ICU) often experience communication difficulties - usually associated with mechanical ventilation - resulting in psychological problems such as anxiety, fear, and depression. Good communication between nurses and patients is critical for success from personalised nursing care of each patient. The purpose of this study is to describe nurses' experience of a communication skills training intervention. Methods: A convenience sample of twenty intensive care nurses participated in the study. Data was collected by means of interviews with nurses. Data from the interviews were analysed using qualitative thematic content analysis. Results: Six themes emerged: (1) acceptance of knowledge and skills developed during workshops; (2) management support; (3) appreciation of augmentative and alternative communication (AAC) devices; (4) change in attitudes; and (5) the need to share knowledge with others and (6) inclusion of communication skills workshop training as an integral part of an orientation programme for all nurses. Conclusion: The findings of this study indicated that the application of augmentative and alternative communication devices and strategies can improve nurse-patient communication in intensive care units. Therefore, the implementation of communication skills training for intensive care nurses should constantly be encouraged and, indeed, introduced as a key element of ICU care training. PMID- 29270080 TI - Video-assisted Thoracoscopic surgery (VATS) lobectomy for lung cancer does not induce a procoagulant state. AB - Background: Changes in the coagulation system in patients undergoing surgery for lung cancer have been sparsely investigated and the impact of the surgical trauma on the coagulation system is largely unknown in these patients. An increased knowledge could potentially improve the thromboprophylaxis regimes. The aim of this study was to assess the coagulation profile evoked in patients undergoing curative surgery by Video-Assisted Thoracoscopic Surgery (VATS) lobectomy for primary lung cancer. Methods: Thirty-one patients diagnosed with primary lung cancer undergoing VATS lobectomy were prospectively included. The coagulation profile was assessed preoperatively and in the first two days postoperatively using a wide range of standard coagulation tests, dynamic whole blood coagulation measured by rotational thromboelastometry (ROTEM(r)) and thrombin generation evaluated by calibrated automated thrombography. Patients did not receive thromboprophylactic treatment. Data was analyzed using repeated measures one-way ANOVA. Results: The standard coagulation parameters displayed only subtle changes after surgery and the ROTEM(r) and thrombin generation results remained largely unchanged. Conclusions: Patients undergoing VATS lobectomy are normocoagulable in the preoperative state and a VATS lobectomy does not significantly influence the coagulation. Trial registration: The trial is registered at ClinicalTrials.gov (Identifier: NCT01741506) and at EudraCTno. 2012-002409-23. Registered December 2012. PMID- 29270081 TI - Treatment outcomes and late toxicities of intensity-modulated radiation therapy for 1091 Japanese patients with localized prostate cancer. AB - Aim: This study aimed to evaluate the treatment result of intensity-modulated radiation therapy (IMRT) in a large number of Japanese patients with prostate cancer. Background: A total of 1091 patients with localized prostate cancer were recruited between March 2006 and July 2014. The patients were stratified into low (n = 205 [18.8%]), intermediate- (n = 450 [41.2%]), high- (n = 345 [31.6%]), and very high-risk (n = 91 [8.3%]) groups according to the National Comprehensive Cancer Network classification. All patients were irradiated via IMRT at a dose of 74-78 Gy with or without androgen-deprivation therapy. The mean follow-up period was 50 months (range, 2-120 months). Results: The biochemical failure-free rate (BFFR), the clinical failure-free rate, and the overall survival rate at the 5 year follow-up for all patients was 91.3%, 96.2%, and 99.1%, respectively. In univariate analysis, the prostate-specific antigen (PSA) levels (<=20 vs. >20 ng/ml) were significantly correlated with BFFR. A trend toward higher BFFR was noted in patients with a Gleason score (GS) of <=7 than in patients with GS >=8. In multivariate analysis, only PSA (<=20 vs. >20 ng/ml) was significantly correlated with BFFR. The cumulative incidence rate of gastrointestinal and genitourinary toxicity (>=grade 2) at the 5-year follow-up was 11.4% and 4.3%, respectively. Conclusions: The findings of this study indicate that IMRT is well tolerated and is associated with both good long-term tumor control and excellent outcomes in patients with localized prostate cancer. PMID- 29270082 TI - Frequency of whole breast irradiation (WBRT) after intraoperative radiotherapy (IORT) is strongly influenced by institutional protocol qualification criteria. AB - Background: Accelerated partial breast irradiation (APBI) is a promising method of adjuvant radiotherapy for select patients. Intraoperative radiotherapy (IORT) is a form of APBI, and appropriate patient selection is important. Aim: The aim of our study was to analyse the influence of our protocol on the frequency of WBRT after IORT and our protocol's correlation with the reported use of WBRT according to TARGIT guidelines. We also aimed to verify how changes in our protocol influenced the frequency of WBRT. Material and methods: Between April 20, 2010 and May 10, 2017, we identified 207 patients irradiated with IORT for APBI. Results: Ninety-one patients (44%) met the criteria for APBI only, while 116 (56%) should have been offered additional WBRT. Retrospective analysis showed that WBRT was applied statistically significantly less frequently compared with strict protocol indications: 99 patients (47.8%) received APBI only and 108 (51.2%) underwent adjuvant WBRT (p < 0.0001). Applying the TARGIT trial guidelines, 69 patients (33.4%) should have been offered WBRT (p < 0.0001), which is twice the number of patients treated with WBRT in our study. Changing the protocol to less restrictive criteria would have statistically significantly decreased the number of patients (95, 46%) offered WBRT (p < 0.0001). Conclusions: Following international guidelines, 46% of patients should receive WBRT after IORT, which is 1.5-2 times more than for the TARGIT criteria. In our analysis, a high percentage of patients (19%) did not receive WBRT after IORT despite the protocol recommendations. The chosen protocol strongly influences the frequency of adjuvant WBRT. PMID- 29270083 TI - The Socialization of Children's Memory: Linking Maternal Conversational Style to the Development of Children's Autobiographical and Deliberate Memory Skills. AB - Data from a large-scale, longitudinal research study with an ethnically and socioeconomically diverse sample were utilized to explore linkages between maternal elaborative conversational style and the development of children's autobiographical and deliberate memory. Assessments were made when the children were 3, 5, and 6 years of age, and the results reveal concurrent and longitudinal linkages between maternal conversational style in a mother-child reminiscing task and children's autobiographical memory performance. Maternal conversational style while reminiscing was also significantly related to children's strategic behaviors and recall in two deliberate memory tasks, both concurrently and longitudinally. Results from this examination replicate and extend what is known about the linkages between maternal conversational style, children's abilities to talk about previous experiences, and children's deliberate memory skills as they transition from the preschool to early elementary school years. PMID- 29270084 TI - Access to and Use of Clinical Services and Disease-Modifying Therapies by People with Progressive Multiple Sclerosis in the United Kingdom. AB - Background: According to current UK guidelines, everyone with progressive multiple sclerosis (MS) should have access to an MS specialist, but levels of access and use of clinical services is unknown. We sought to investigate access to MS specialists and use of clinical services and disease-modifying therapies (DMTs) by people with progressive MS in the United Kingdom. Methods: A UK-wide online survey was conducted via the UK MS Register. The inclusion criteria were age 18 years or older, primary or secondary progressive MS, and a member of the UK MS Register. Participants were asked about access to MS specialists, recent clinical service use, receipt of regular review, and current and previous DMT use. Participant demographic data, quality of life, and disease impact measures were from the UK MS Register. Results: In total, 1298 individuals responded: 7% were currently taking a DMT, 23% had previously taken a DMT, and 95% reported access to an MS specialist. The most used practitioners were MS doctors/nurses (50%), general practitioners (45%), and physiotherapists (40%). Seventy-four percent of participants received a regular review, although 37% received theirs less often than annually. Current DMT use was associated with better quality of life, but past DMT use was associated with poorer quality of life and higher impact of disease. Conclusions: Access to and use of MS specialists was high. However, a gap in service provision was highlighted in both receipt and frequency of regular reviews. PMID- 29270085 TI - Project Extension for Community Healthcare Outcomes (ECHO) in Multiple Sclerosis: Increasing Clinician Capacity. AB - Background: A pilot program using the Project Extension for Community Healthcare Outcomes (ECHO) model was conducted for multiple sclerosis (MS) clinicians in the Pacific Northwest. The pilot was a collaboration between the National Multiple Sclerosis Society and faculty at the University of Washington. The goal was to determine the feasibility of using this telehealth model to increase the capacity and capability of clinicians in rural areas to treat people with MS. Methods: Thirteen practice sites with 24 clinicians were recruited to participate. Videoconferencing was used to conduct weekly sessions consisting of brief didactics followed by case consultations. Results: Most participants completing the outcome survey (10 of 15) indicated that they were more confident in treating patients with MS. They were satisfied with the training, felt better able to care for their patients, and had made changes in their treatment based on the case consultations and didactic content. They valued the case studies and case-based didactics and learned from each other as well as from the team. Conclusions: The pilot MS Project ECHO warrants further investigation regarding its potential effect on access to MS care delivery for underserved populations. PMID- 29270086 TI - Triaging Patients with Multiple Sclerosis in the Emergency Department: Room for Improvement. AB - Background: Patients with multiple sclerosis (MS) present to the emergency department (ED) for various reasons. Although true relapse is rarely the underlying culprit, ED visits commonly result in new magnetic resonance imaging (MRI) and neurology admissions. We studied ED visits in patients with MS and evaluated decision making regarding diagnostic/therapeutic interventions and visit outcomes. We identified potential areas for improvement and used the data to propose a triaging algorithm for patients with MS in the ED. Methods: We reviewed the medical records from 176 ED visits for patients with MS in 2014. Results: Ninety-seven visits in 75 patients were MS related (66.6% female; mean +/- SD age, 52.6 +/- 13.8 years; mean +/- SD disease duration, 18.5 +/- 10.5 years). Thirty-three visits were for new neurologic symptoms (category 1), 29 for worsening preexisting symptoms (category 2), and 35 for MS-related complications (category 3). Eighty-nine visits (91.8%) resulted in hospital admission (42.7% to neurology). Only 39% of ordered MRIs showed radiographic activity. New relapses were determined in 27.8% of the visits and were more prevalent in category 1 compared with category 2 (P = .003); however, the two categories had similar rates of ordered MRIs and neurology admissions. Conclusions: New relapse is a rare cause of ED visits in MS. Unnecessary MRIs and neurology admissions can be avoided by developing a triaging system for patients with MS based on symptom stratification. PMID- 29270087 TI - Fatigue and Mood States in Nursing Home and Nonambulatory Home-Based Patients with Multiple Sclerosis. AB - Background: Multiple sclerosis (MS) is a chronic, progressively disabling condition of the central nervous system. We sought to evaluate and compare mood states in patients with MS with increased disability residing in nursing homes and those receiving home-based care. Methods: We conducted a cross-sectional analysis of the New York State Multiple Sclerosis Consortium to identify patients with MS using a Kurtzke Expanded Disability Status Scale (EDSS) score of 7.0 or greater. The nursing home group was compared with home-based care patients regarding self-reported levels of loneliness, pessimism, tension, panic, irritation, morbid thoughts, feelings of guilt, and fatigue using independent samples t tests and chi2 tests. Multivariate logistic regression analyses were used to investigate risk-adjusted differences in mood states. Results: Ninety four of 924 patients with EDSS scores of at least 7.0 lived in a nursing home (10.2%). Nursing home patients were less likely to use disease-modifying therapy and had higher mean EDSS scores compared with home-based patients. However, nursing home patients were less likely than home-based patients to report fatigue (odds ratio [OR] for no fatigue, 3.8; 95% CI, 2.1-7.2), feeling tense (OR for no tension, 1.7; 95% CI, 1.1-2.7), and having feelings of pessimism (OR for no pessimism, 1.8; 95% CI, 1.2-2.8). Conclusions: The nursing home patients with MS were less likely to report fatigue, pessimism, and tension than those receiving home-based care. Further studies should examine ways of facilitating a greater degree of autonomy and decision-making control in MS patients receiving home based care. PMID- 29270088 TI - Shared Decision Making and Autonomy Among US Participants with Multiple Sclerosis in the NARCOMS Registry. AB - Background: Treatment decisions in multiple sclerosis (MS) are affected by many factors and are made by the patient, doctor, or both. With new disease-modifying therapies (DMTs) emerging, the complexity surrounding treatment decisions is increasing, further emphasizing the importance of understanding decision-making preferences. Methods: North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants completed the Fall 2014 Update survey, which included the Control Preferences Scale (CPS). The CPS consists of five images showing different patient/doctor roles in treatment decision making. The images were collapsed to three categories: patient-centered, shared, and physician centered decision-making preferences. Associations between decision-making preferences and demographic and clinical factors were evaluated using multivariable logistic regression. Results: Of 7009 participants, 79.3% were women and 93.5% were white (mean [SD] age, 57.6 [10.3] years); 56.7% reported a history of relapses. Patient-centered decision making was most commonly preferred by participants (47.9%), followed by shared decision making (SDM; 42.8%). SDM preference was higher for women and those taking DMTs and increased with age and disease duration (all P < .05). Patient-centered decisions were most common for respondents not taking a DMT at the time of the survey and were preferred by those who had no DMT history compared with those who had previously taken a DMT (P < .0001). There was no difference in SDM preference by current MS disease course after adjusting for other disease-related factors. Conclusions: Responders reported most commonly considering their doctor's opinion before making a treatment decision and making decisions jointly with their doctor. DMT use, gender, and age were associated with decision-making preference. PMID- 29270089 TI - Barriers to the Accessibility and Continuity of Health-Care Services in People with Multiple Sclerosis: A Literature Review. AB - Background: Individuals with multiple sclerosis (MS) face a range of barriers to accessing and using health-care services. The aim of this review was to identify specific barriers to accessing and using health-care services based on a continuum of the health-care delivery system. Methods: Literature searches were conducted in the PubMed, PsycINFO, CINAHL, and Web of Science databases. The following terms were searched as subject headings, key words, or abstracts: health care, access, barriers, physical disability, and multiple sclerosis. The literature search produced 361 potentially relevant citations. After screening titles, abstracts, and citations, eight citations were selected for full-text review. Results: Health-care barriers were divided into three continuous phases of receiving health care. In the before-visit phase, the most commonly identified barrier was transportation. In the during-visit phase, communication quality was the major concern. In the after-visit phase, discontinued referral was the major barrier encountered. Conclusions: There are multiple interrelated barriers to accessing and using health-care services along the health-care delivery continuum for people with MS and its associated physical disabilities, ranging from complex and long-recognized barriers that will likely require extended advocacy to create policy changes to issues that can and should be addressed through relatively minor changes in health-care delivery practices, improved care coordination, and increased provider awareness, education, and responsiveness to patients' needs. PMID- 29270092 TI - Editorial. PMID- 29270090 TI - Alemtuzumab in Multiple Sclerosis: Lessons from Social Media in Enhancing Patient Care. AB - Background: Alemtuzumab is a monoclonal antibody that has been approved for the treatment of relapsing-remitting multiple sclerosis (MS). Alemtuzumab is associated with infusion reactions and potential autoimmune complications. Patient education and understanding are crucial to favorable outcomes. Our objective was to observe communication on a peer-to-peer Facebook group for content, accuracy of posts, and number of "likes" per post and to compare shared themes to current approved prescribing information and educational modules. Methods: We identified a Facebook group specific to alemtuzumab in MS. A 14-day window was observed. Posts were classified as "sharing" or "seeking information." Content analysis was used for information-seeking posts. Accuracy of replies was compared with product prescribing information. Results: We reviewed 458 posts. Members contemplating receiving or currently receiving alemtuzumab primarily used Facebook for information gathering (54.6%), followed by seeking emotional support and sharing personal experiences (45.4%). Most shared experiences (83.6%) were positive. Themes for information were predominantly consistent with standard protocols. Complications discussed included infection (15.50%), bone pain (11.80%), immune thrombocytopenia (8.07%), and fatigue (7.46%). Accuracy of replies was consistent with product information except for immune thrombocytopenia. Conclusions: Some patients with MS look to online groups for discussion, peer support, and information. Although written guidelines on the studied home page reinforce that online discussion "does not replace medical advice," inaccurate information does occur. Health-care providers' reviews of these online sites allow insight into the real-world experiences of patients receiving alemtuzumab, with potential for modification of educational approaches by health-care professionals. PMID- 29270093 TI - The effect of lubricating eye drops on optical coherence tomography imaging of the retina. AB - Introduction: The goal of this study was to examine the potential value of corneal lubrication in improving the quality of optical coherence tomography (OCT) imaging of the retina. Materials and Methods: This study is a consecutive series of 13 eyes of 11 patients in whom repeated attempts at OCT imaging failed to yield a good quality study despite the absence of significant media opacity or inadequate pupil dilation. Immediately following several poor quality scans, each eye received lubricating eye drops. The quality of images before and after the administration of drops was assessed. Results: A statistically significant improvement in OCT image quality was observed following the administration of eye drops in each case. The change in mean signal strength (SS) was from 4.35 to 6.26 (p=0.0002). The proportion of scans with erroneous edge detection decreased from 41 to 13 percent. Discussion: Lubricating drops appear to improve the quality and feasibility of OCT imaging in selected cases. PMID- 29270094 TI - A 39-year-old man with blindness following the application of raw cassava extract to the eyes. PMID- 29270095 TI - A 68-year-old man with a recurrent orbital lesion. PMID- 29270096 TI - A 48-year-old man presents with bilateral corneal deposits. PMID- 29270097 TI - Incidence of postoperative cystoid macular edema by a single surgeon. AB - Objective: To evaluate the clinical and angiographic incidence of cystoid macular edema (CME) after cataract surgery, and to determine the impact of intraoperative triamcinolone acetonide. Methods: This is a prospective, single-center trial looking at 81 eyes of 61 patients who underwent clear-cornea incision phacoemulsification with lens implantation under topical anesthesia by a single surgeon. Outcome measures included clinical and angiographic CME, the impact of operative time, medications, and systemic disease on the presence of CME. Results: Eight eyes (9.87%) demonstrated angiographic CME at the one-week and six week follow-up visits. Two eyes showed evidence of clinical CME (2.46%) on examination. Subjects with diabetes had an increased risk of angiographic CME. Conclusion: The incidence of clinically significant and angiographic CME in this study is confirmatory of previous studies in the literature. The use of intraoperative subconjunctival triamcinolone acetonide did not appear to significantly reduce the development of post-operative CME. PMID- 29270098 TI - Bloch Equations for Proton Exchange Reactions in an Aqueous Solution. AB - The extension of the Bloch equations for acid-base reactions in an aqueous solution is revisited. The acid-base reactions are second-order, and several reactions catalyzed by distinct catalysts may happen simultaneously. By constructing pseudo first-order reactions and assuming fast dissemination of protons from catalysts to solvent water, this extension converges to the well known Bloch-McConnell equations for a two-site first-order exchange. Thus, explicit relationships between the parameters appearing in the reactions and the Bloch-McConnell equations are established. The dependencies of exchange rates and chemical exchange saturation transfer effects on pH were numerically and experimentally investigated for representative examples. PMID- 29270099 TI - Erbium-Based Perfusion Contrast Agent for Small-Animal Microvessel Imaging. AB - Micro-computed tomography (micro-CT) facilitates the visualization and quantification of contrast-enhanced microvessels within intact tissue specimens, but conventional preclinical vascular contrast agents may be inadequate near dense tissue (such as bone). Typical lead-based contrast agents do not exhibit optimal X-ray absorption properties when used with X-ray tube potentials below 90 kilo-electron volts (keV). We have developed a high-atomic number lanthanide (erbium) contrast agent, with a K-edge at 57.5 keV. This approach optimizes X-ray absorption in the output spectral band of conventional microfocal spot X-ray tubes. Erbium oxide nanoparticles (nominal diameter < 50 nm) suspended in a two part silicone elastomer produce a perfusable fluid with viscosity of 19.2 mPa-s. Ultrasonic cavitation was used to reduce aggregate sizes to <70 nm. Postmortem intact mice were perfused to investigate the efficacy of contrast agent. The observed vessel contrast was >4000 Hounsfield units, and perfusion of vessels < 10 MUm in diameter was demonstrated in kidney glomeruli. The described new contrast agent facilitated the visualization and quantification of vessel density and microarchitecture, even adjacent to dense bone. Erbium's K-edge makes this contrast agent ideally suited for both single- and dual-energy micro-CT, expanding potential preclinical research applications in models of musculoskeletal, oncological, cardiovascular, and neurovascular diseases. PMID- 29270101 TI - Beyond the brotherhood: Skoal Bandits' role in the evolution of marketing moist smokeless tobacco pouches. AB - Background: Since 2006, "snus" smokeless tobacco has been sold in the U.S.. However, U.S. Smokeless Tobacco (USST) and Swedish Match developed and marketed pouched moist snuff tobacco (MST) since 1973. Methods: Analysis of previously secret tobacco documents, advertisements and trade press. Results: USST partnered with Swedish Match, forming United Scandia International to develop pouch products as part of the "Lotus Project." Pouched MST was not commonly used, either in Sweden or the U.S. prior to the Lotus Project's innovation in 1973. The project aimed to transform smokeless tobacco from being perceived as an "unsightly habit of old men" into a relevant, socially acceptable urban activity, targeting 15-35 year-old men. While USST's initial pouched product "Good Luck," never gained mainstream traction, Skoal Bandits captured significant market share after its 1983 introduction. Internal market research found that smokers generally used Skoal Bandits in smokefree environments, yet continued to smoke cigarettes in other contexts. Over time, pouch products increasingly featured increased flavor, size, nicotine strength and user imagery variation. Conclusions: Marlboro and Camel Snus advertising mirrors historical advertising for Skoal Bandits, designed to recruit new users and smokers subjected to smokefree places. Despite serious efforts, pouched MST marketing has been unable to dispel its association with traditional smokeless tobacco stereotypes as macho and rural. Public education efforts to discourage new users and dual use of MST and cigarettes should emphasize that "new" pouch products are simply repackaging "old" smokeless tobacco. PMID- 29270100 TI - Common founder effects of hereditary hemochromatosis, Wilson's disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes. AB - Background: Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p.C282Y mutation is inherited with other recessive disorders such as Wilson's disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation (KCNQ1/p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. Methods: LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Results: Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjallsjo river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1(NM_138691),c.1814T>C,(p.L605P) mutation, possibly of Finnish origin. Conclusions: Deep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson's disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN/p.S660Afs*30 and TMC1/p.L605P were identified,none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1st cousin unions and only 2 (2.0 %) was born out of wedlock. PMID- 29270102 TI - From Blood to Brain: Adult-Born Neurons in the Crayfish Brain Are the Progeny of Cells Generated by the Immune System. AB - New neurons continue to be born and integrated into the brains of adult decapod crustaceans. Evidence in crayfish indicates that the 1st-generation neural precursors that generate these adult-born neurons originate in the immune system and travel to the neurogenic niche via the circulatory system. These precursors are attracted to the niche, become integrated amongst niche cells, and undergo mitosis within a few days; both daughters of this division migrate away from the niche toward the brain clusters where they will divide again and differentiate into neurons. In the crustacean brain, the rate of neuronal production is highly sensitive to serotonin (5-hydroxytryptamine, 5-HT) levels. These effects are lineage-dependent, as serotonin's influence is limited to late 2nd-generation neural precursors and their progeny. Experiments indicate that serotonin regulates adult neurogenesis in the crustacean brain by multiple mechanisms: via direct effects of serotonin released from brain neurons into the hemolymph or by local release onto target cells, or by indirect influences via a serotonin mediated release of agents from other regions, such as hormones from the sinus gland and cytokines from hematopoietic tissues. Evidence in crayfish also indicates that serotonin mediates the attraction of neural precursors generated by the immune system to the neurogenic niche. Thus, studies in the crustacean brain have revealed multiple roles for this monoamine in adult neurogenesis, and identified several pathways by which serotonin influences the generation of new neurons. PMID- 29270104 TI - They Are What You Hear in Media Reports: The Racial Stereotypes toward Uyghurs Activated by Media. AB - Stereotypes from the major nationality toward minorities constitute a widely concerning problem in many countries. As reported by previous studies, stereotypes can be activated by media information that portrays the negative aspects of the target group. The current study focused on the neural basis of the modulation of negative media information on Han Chinese stereotypes toward Uyghurs by using event-related potentials. We employed the lexical decision task, in which participants were asked to categorize the presented word as positive or negative. Behavioral result showed that participants had a shorter reaction time to positive adjectives than to negative adjectives. The data of brain activity showed that compared with the Han condition, the Uyghurs condition elicited smaller N400 differences in the media priming group, whereas there was no significant N400 deflection difference between Han Chinese and Uyghurs in the control group. The current results suggested that the negative media information might influence their judgments toward other groups reflected in the deflection of N400 amplitude. Therefore, in order to mitigate or even eliminate stereotypes about national minorities, the effort of the media is important. PMID- 29270103 TI - Neural Interfaces for Intracortical Recording: Requirements, Fabrication Methods, and Characteristics. AB - Implantable neural interfaces for central nervous system research have been designed with wire, polymer, or micromachining technologies over the past 70 years. Research on biocompatible materials, ideal probe shapes, and insertion methods has resulted in building more and more capable neural interfaces. Although the trend is promising, the long-term reliability of such devices has not yet met the required criteria for chronic human application. The performance of neural interfaces in chronic settings often degrades due to foreign body response to the implant that is initiated by the surgical procedure, and related to the probe structure, and material properties used in fabricating the neural interface. In this review, we identify the key requirements for neural interfaces for intracortical recording, describe the three different types of probes microwire, micromachined, and polymer-based probes; their materials, fabrication methods, and discuss their characteristics and related challenges. PMID- 29270105 TI - The Significance of the Right Dorsolateral Prefrontal Cortex for Pitch Memory in Non-musicians Depends on Baseline Pitch Memory Abilities. AB - Pitch memory is a resource which is shared by music and language. Neuroimaging studies have shown that the right dorsolateral prefrontal cortex (DLPFC) is activated during pitch memory processes. The present study investigated the causal significance of this brain area for pitch memory in non-musicians by applying cathodal and sham transcranial direct current stimulation (tDCS) over the right DLPFC and examining the impact on offline pitch and visual memory span performances. On the overall sample (N = 22) no significant modulation effect of cathodal stimulation on the pitch span task was found. However, when dividing the sample by means of a median split of pre-test pitch memory abilities into a high and low performing group, a selective effect of significantly impaired pitch memory after cathodal tDCS in good performers was revealed. The visual control task was not affected by the stimulation in either group. The results support previous neuroimaging studies that the right DLPFC is involved in pitch memory processes in non-musicians and highlights the importance of baseline pitch memory abilities for the modulatory effect of tDCS. PMID- 29270106 TI - Methylglyoxal Requires AC1 and TRPA1 to Produce Pain and Spinal Neuron Activation. AB - Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated immunohistochemical phosphorylation of extracellular signal-regulated kinase (p-ERK) and multiple pain-like behaviors in wild-type rats and mice and after disruption of either TRPA1 or AC1. Methylglyoxal produced conditioned place avoidance (CPA) (a measure of affective pain), dose-dependent licking and lifting nociceptive behaviors, hyperalgesia to heat and mechanical stimulation, and p-ERK in the spinal cord dorsal horn. TRPA1 knockout or intrathecal administration of a TRPA1 antagonist (HC030031) attenuated methylglyoxal-evoked p-ERK, nociception, and hyperalgesia. AC1 knockout abolished hyperalgesia but not nociceptive behaviors. These results indicate that intraplantar administration of methylglyoxal recapitulates multiple signs of painful diabetic neuropathy found in animal models of or patients with diabetes, including the activation of spinal nociresponsive neurons and the potential involvement of a TRPA1-AC1 sensitization mechanism. We conclude that administration of MG is a valuable model for investigating both peripheral and central components of a MG-TRPA1-AC1 pathway that contribute to painful diabetic neuropathy. PMID- 29270107 TI - Abstinent Heroin Addicts Tend to Take Risks: ERP and Source Localization. AB - Abnormal decision making is a behavioral characteristic of drug addiction. Indeed, drug addicts prefer immediate rewards at the expense of future interests. Assessing the neurocognitive basis of decision-making related to drug dependence, combining event-related potential (ERP) analysis and source localization techniques, may provide new insights into understanding decision-making deficits in drug addicts and further guide withdrawal treatment. In this study, EEG was performed in 20 abstinent heroin addicts (AHAs) and 20 age-, education- and gender-matched healthy controls (HCs) while they participated in a simple two choice gambling task (99 vs. 9). Our behavioral results showed that AHAs tend to select higher-risk choices compared with HCs (i.e., more "99" choices than "9"). ERP results showed that right hemisphere preponderance of stimulus-preceding negativity was disrupted in AHAs, but not in HCs. Feedback-related negativity of difference wave was higher in AHAs than HCs, with the P300 amplitude associated with risk magnitude and valence. Using source localization that allows identification of abnormal brain activity in consequential cognitive stages, including the reward expectation and outcome evaluation stages, we found abnormalities in both behavioral and neural responses on gambling in AHAs. Taken together, our findings suggest AHAs have risk-prone tendency and dysfunction in adaptive decision making, since they continue to choose risky options even after accruing considerable negative scores, and fail to shift to a safer strategy to avoid risk. Such abnormal decision-making bias to risk and immediate reward seeking may be accompanied by abnormal reward expectation and evaluation in AHAs, which explains their high risk-seeking and impulsivity. PMID- 29270108 TI - Conformational Ensembles of alpha-Synuclein Derived Peptide with Different Osmolytes from Temperature Replica Exchange Sampling. AB - Intrinsically disordered proteins (IDP) are a class of proteins that do not have a stable three-dimensional structure and can adopt a range of conformations playing various vital functional role. Alpha-synuclein is one such IDP which can aggregate into toxic protofibrils and has been associated largely with Parkinson's disease (PD) along with other neurodegenerative diseases. Osmolytes are small organic compounds that can alter the environment around the proteins by acting as denaturants or protectants for the proteins. In the present study, we have conducted a series of replica exchange molecular dynamics simulations to explore the role of osmolytes, urea which is a denaturant and TMAO (trimethylamine N-oxide), a protecting osmolyte, in aggregation and conformations of the synuclein peptide. We observed that both the osmolytes have significantly distinct impacts on the peptide and led to transitions of the conformations of the peptide from one state to other. Our findings highlighted that urea attenuated peptide aggregation and resulted in the formation of extended peptide structures whereas TMAO led to compact and folded forms of the peptide. PMID- 29270109 TI - The Effect of Visual Experience on Perceived Haptic Verticality When Tilted in the Roll Plane. AB - The orientation of the body in space can influence perception of verticality leading sometimes to biases consistent with priors peaked at the most common head and body orientation, that is upright. In this study, we investigate haptic perception of verticality in sighted individuals and early and late blind adults when tilted counterclockwise in the roll plane. Participants were asked to perform a stimulus orientation discrimination task with their body tilted to their left ear side 90 degrees relative to gravity. Stimuli were presented by using a motorized haptic bar. In order to test whether different reference frames relative to the head influenced perception of verticality, we varied the position of the stimulus on the body longitudinal axis. Depending on the stimulus position sighted participants tended to have biases away or toward their body tilt. Visually impaired individuals instead show a different pattern of verticality estimations. A bias toward head and body tilt (i.e., Aubert effect) was observed in late blind individuals. Interestingly, no strong biases were observed in early blind individuals. Overall, these results posit visual sensory information to be fundamental in influencing the haptic readout of proprioceptive and vestibular information about body orientation relative to gravity. The acquisition of an idiotropic vector signaling the upright might take place through vision during development. Regarding early blind individuals, independent spatial navigation experience likely enhanced by echolocation behavior might have a role in such acquisition. In the case of participants with late onset blindness, early experience of vision might lead them to anchor their visually acquired priors to the haptic modality with no disambiguation between head and body references as observed in sighted individuals (Fraser et al., 2015). With our study, we aim to investigate haptic perception of gravity direction in unusual body tilts when vision is absent due to visual impairment. Insofar, our findings throw light on the influence of proprioceptive/vestibular sensory information on haptic perceived verticality in blind individuals showing how this phenomenon is affected by visual experience. PMID- 29270110 TI - Anodal Transcranial Direct Current Stimulation Increases Bilateral Directed Brain Connectivity during Motor-Imagery Based Brain-Computer Interface Control. AB - Transcranial direct current stimulation (tDCS) has been shown to affect motor and cognitive task performance and learning when applied to brain areas involved in the task. Targeted stimulation has also been found to alter connectivity within the stimulated hemisphere during rest. However, the connectivity effect of the interaction of endogenous task specific activity and targeted stimulation is unclear. This study examined the aftereffects of concurrent anodal high definition tDCS over the left sensorimotor cortex with motor network connectivity during a one-dimensional EEG based sensorimotor rhythm brain-computer interface (SMR-BCI) task. Directed connectivity following anodal tDCS illustrates altered connections bilaterally between frontal and parietal regions, and these alterations occur in a task specific manner; connections between similar cortical regions are altered differentially during left and right imagination trials. During right-hand imagination following anodal tDCS, there was an increase in outflow from the left premotor cortex (PMC) to multiple regions bilaterally in the motor network and increased inflow to the stimulated sensorimotor cortex from the ipsilateral PMC and contralateral sensorimotor cortex. During left-hand imagination following anodal tDCS, there was increased outflow from the stimulated sensorimotor cortex to regions across the motor network. Significant correlations between connectivity and the behavioral measures of total correct trials and time-to-hit (TTH) correct trials were also found, specifically that the input to the left PMC correlated with decreased right hand imagination performance and that flow from the ipsilateral posterior parietal cortex (PPC) to midline sensorimotor cortex correlated with improved performance for both right and left hand imagination. These results indicate that tDCS interacts with task specific endogenous activity to alter directed connectivity during SMR-BCI. In order to predict and maximize the targeted effect of tDCS, the interaction of stimulation with the dynamics of endogenous activity needs to be examined comprehensively and understood. PMID- 29270113 TI - Commentary: Localized vs. Systematic Neurodegeneration: A Paradigm Shift in Understanding Neurodegenerative Diseases. PMID- 29270112 TI - Scopolamine Reduces Electrophysiological Indices of Distractor Suppression: Evidence from a Contingent Capture Task. AB - Limited resources for the in-depth processing of external stimuli make it necessary to select only relevant information from our surroundings and to ignore irrelevant stimuli. Attentional mechanisms facilitate this selection via top-down modulation of stimulus representations in the brain. Previous research has indicated that acetylcholine (ACh) modulates this influence of attention on stimulus processing. However, the role of muscarinic receptors as well as the specific mechanism of cholinergic modulation remains unclear. Here we investigated the influence of ACh on feature-based, top-down control of stimulus processing via muscarinic receptors by using a contingent capture paradigm which specifically tests attentional shifts toward uninformative cue stimuli which display one of the target defining features In a double-blind, placebo controlled study we measured the impact of the muscarinic receptor antagonist scopolamine on behavioral and electrophysiological measures of contingent attentional capture. The results demonstrated all the signs of functional contingent capture, i.e., attentional shifts toward cued locations reflected in increased amplitudes of N1 and N2Pc components, under placebo conditions. However, scopolamine did not affect behavioral or electrophysiological measures of contingent capture. Instead, scopolamine reduced the amplitude of the distractor-evoked Pd component which has recently been associated with active suppression of irrelevant distractor information. The findings suggest a general cholinergic modulation of top-down control during distractor processing. PMID- 29270114 TI - Adolescent Corticosterone and TrkB Pharmaco-Manipulations Sex-Dependently Impact Instrumental Reversal Learning Later in Life. AB - Early-life trauma can increase the risk for, and severity of, several psychiatric illnesses. These include drug use disorders, and some correlations appear to be stronger in women. Understanding the long-term consequences of developmental stressor or stress hormone exposure and possible sex differences is critically important. So-called "reversal learning" tasks are commonly used in rodents to model cognitive deficits in stress- and addiction-related illnesses in humans. Here, we exposed mice to the primary stress hormone corticosterone (CORT) during early adolescence (postnatal days 31-42), then tested behavioral flexibility in adulthood using an instrumental reversal learning task. CORT-exposed female, but not male, mice developed perseverative errors. Despite resilience to subchronic CORT exposure, males developed reversal performance impairments following exposure to physical stressors. Administration of a putative tyrosine kinase receptor B (trkB) agonist, 7,8-dihydroxyflavone (7,8-DHF), during adolescence blocked CORT-induced errors in females and improved performance in males. Conversely, blockade of trkB by ANA-12 impaired performance. These data suggest that trkB-based interventions could have certain protective benefits in the context of early-life stressor exposure. We consider the implications of our findings in an extended "Discussion" section. PMID- 29270115 TI - Objects Mental Rotation under 7 Days Simulated Weightlessness Condition: An ERP Study. AB - During the spaceflight under weightlessness condition, human's brain function may be affected by the changes of physiological effects along with the distribution of blood and body fluids to the head. This variation of brain function will influence the performance of astronauts and therefore create possible harm to flight safety. This study employs 20 male subjects in a 7-day-6 degrees head down tilted (HDT) bed rest model to simulate physiological effects under weightlessness condition, and use behavioral, electrophysiological techniques to compare the changes of mental rotation ability (MR ability) before and after short-term simulated weightlessness state. Behavioral results suggested that significant linear relationship existed between the rotation angle of stimuli and the reaction time, which means mental rotation process do happen during the MR task in simulated weightlessness state. In the first 3 days, the P300 component induced by object mental rotation followed the "down-up-down" pattern. In the following 4 days it changed randomly. On HDT D2, the mean of the amplitude of the P300 was the lowest, while increased gently on HDT D3. There was no obvious changing pattern of the amplitude of P300 observed after 3 days of HDT. Simulated weightlessness doesn't change the basic process of mental rotation. The effect of simulated weightlessness is neural mechanism of self-adaptation. MR ability didn't bounce back to the original level after HDT test. PMID- 29270111 TI - Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. AB - Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments. PMID- 29270116 TI - COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function. AB - Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-O methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val158Met polymorphism (rs4680) of the COMT gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. COMT genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether COMT genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val158Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of COMT genotype and sex, consistent with a U-shaped relationship with enzyme activity. COMT genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of COMT genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with COMT among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity. PMID- 29270118 TI - Culture Modulates the Brain Response to Harmonic Violations: An EEG Study on Hierarchical Syntactic Structure in Music. AB - We investigated the role of culture in processing hierarchical syntactic structures in music. We examined whether violation of non-local dependencies manifest in event related potentials (ERP) for Western and Iranian excerpts by recording EEG while participants passively listened to sequences of modified/original excerpts. We also investigated oscillatory and synchronization properties of brain responses during processing of hierarchical structures. For the Western excerpt, subjective ratings of conclusiveness were marginally significant and the difference in the ERP components fell short of significance. However, ERP and behavioral results showed that while listening to culturally familiar music, subjects comprehended whether or not the hierarchical syntactic structure was fulfilled. Irregularities in the hierarchical structures of the Iranian excerpt elicited an early negativity in the central regions bilaterally, followed by two later negativities from 450-700 to 750-950 ms. The latter manifested throughout the scalp. Moreover, violations of hierarchical structure in the Iranian excerpt were associated with (i) an early decrease in the long range alpha phase synchronization, (ii) an early increase in the oscillatory activity in the beta band over the central areas, and (iii) a late decrease in the theta band phase synchrony between left anterior and right posterior regions. Results suggest that rhythmic structures and melodic fragments, representative of Iranian music, created a familiar context in which recognition of complex non local syntactic structures was feasible for Iranian listeners. Processing of neural responses to the Iranian excerpt indicated neural mechanisms for processing of hierarchical syntactic structures in music at different levels of cortical integration. PMID- 29270117 TI - White Matter Microstructural Changes Following Quadrato Motor Training: A Longitudinal Study. AB - Diffusion tensor imaging (DTI) is an important way to characterize white matter (WM) microstructural changes. While several cross-sectional DTI studies investigated possible links between mindfulness practices and WM, only few longitudinal investigations focused on the effects of these practices on WM architecture, behavioral change, and the relationship between them. To this aim, in the current study, we chose to conduct an unbiased tract-based spatial statistics (TBSS) analysis (n = 35 healthy participants) to identify longitudinal changes in WM diffusion parameters following 6 and 12 weeks of daily Quadrato Motor Training (QMT), a whole-body mindful movement practice aimed at improving well-being by enhancing attention, coordination, and creativity. We also investigated the possible relationship between training-induced WM changes and concomitant changes in creativity, self-efficacy, and motivation. Our results indicate that following 6 weeks of daily QMT, there was a bilateral increase of fractional anisotropy (FA) in tracts related to sensorimotor and cognitive functions, including the corticospinal tracts, anterior thalamic radiations, and uncinate fasciculi, as well as in the left inferior fronto-occipital, superior and inferior longitudinal fasciculi. Interestingly, significant FA increments were still present after 12 weeks of QMT in most of the above WM tracts, but only in the left hemisphere. FA increase was accompanied by a significant decrease of radial diffusivity (RD), supporting the leading role of myelination processes in training-related FA changes. Finally, significant correlations were found between training-induced diffusion changes and increased self-efficacy as well as creativity. Together, these findings suggest that QMT can improve WM integrity and support the existence of possible relationships between training-related WM microstructural changes and behavioral change. PMID- 29270119 TI - Functions of Learning Rate in Adaptive Reward Learning. AB - As a crucial cognitive function, learning applies prediction error (the discrepancy between the prediction from learning and the world state) to adjust predictions of the future. How much prediction error affects this adjustment also depends on the learning rate. Our understanding to the learning rate is still limited, in terms of (1) how it is modulated by other factors, and (2) the specific mechanisms of how learning rate interacts with prediction error to update learning. We applied computational modeling and functional magnetic resonance imaging to investigate these issues. We found that, when human participants performed a reward learning task, reward magnitude modulated learning rate. Modulation strength further predicted the difference in behavior following high vs. low reward across subjects. Imaging results further showed that this modulation was reflected in brain regions where the reward feedback is also encoded, such as the medial prefrontal cortex (MFC), precuneus, and posterior cingulate cortex. Furthermore, for the first time, we observed that the integration of the learning rate and the reward prediction error was represented in MFC activity. These findings extend our understanding of adaptive learning by demonstrating how it functions in a chain reaction of prediction updating. PMID- 29270120 TI - Gender Differences in Food Choice: Effects of Superior Temporal Sulcus Stimulation. AB - The easy availability of food has caused a shift from eating for survival to hedonic eating. Women, compared to men, have shown to respond differently to food cues in the environment on a behavioral and a neural level, in particular to energy rich (compared to low energy) foods. It has been demonstrated that the right posterior superior temporal sulcus (STS) is the only region exhibiting greater activation for high vs. low calorie food choices. In order to test for a possible causal role of STS in food choice, we applied high frequency transcranial random noise stimulation (tRNS) on STS assuming a different response pattern between males and females. Our participants (18 females, 17 males) performed a forced choice task between food pairs matched for individual liking but differed in calorie, during the left STS, right STS stimulation and sham condition. Male participants showed a general preference for low calorie (LC) foods compared to females. In addition, we observed in males, but not in females, an increase of high calorie (HC) food choice during right STS tRNS compared to sham condition and left STS tRNS. Finally, we found an increase of missed choices during right STS stimulation compared to sham condition and left STS stimulation. In conclusion, thanks to tRNS evidence, we both confirm the involvement and suggest a causal role of right posterior STS in feeding behavior. Moreover, we suggest that gender differences exist in STS mechanisms underlying food choice. PMID- 29270121 TI - Validation of Minimally-Invasive Sample Collection Methods for Measurement of Telomere Length. AB - Objective: The discovery of telomere length (TL) as a biomarker of cellular aging and correlate of age-related disease has generated a new field of research in the biology of healthy aging. Although the most common method of sample collection for TL is venous blood draw, less-invasive DNA collection methods are becoming more widely used. However, how TL relates across tissues derived from these sample collection methods is poorly understood. The current study is the first to characterize the associations in TL across three sample collection methods: venous whole blood, finger prick dried blood spot and saliva. Methods: TL was measured in 24 healthy young adults using three modes of sample collection for each participant: venous whole blood, finger prick dried blood spot and saliva. Relative TL was measured using quantitative polymerase chain reaction. Results: TL in finger prick dried blood spots (DBS) washighly correlated with TL in whole blood (r = 0.84, p < 0.001). Salivary TL was also correlated with whole blood TL (r = 0.56, p = 0.005), but this association was not as strong as that of dried blood spot TL (Steiger's Z = 2.12, p = 0.034). TL was longer in saliva than in whole blood or DBS (p's < 0.001). Conclusions: These findings have important implications for future study design by supporting the validity of less-invasive methods that can be implemented with vulnerable populations or in the field. Further, these findings aid in interpreting the burgeoning area of biological aging research and may shed light on our understanding of inconsistencies in the empirical literature. PMID- 29270122 TI - Differential Effects of the Factor Structure of the Wechsler Memory Scale-Revised on the Cortical Thickness and Complexity of Patients Aged Over 75 Years in a Memory Clinic Setting. AB - The Wechsler Memory Scale-Revised (WMS-R) is one of the internationally well known batteries for memory assessment in a general memory clinic setting. Several factor structures of the WMS-R for patients aged under 74 have been proposed. However, little is known about the factor structure of the WMS-R for patients aged over 75 years and its neurological significance. Thus, we conducted exploratory factor analysis to determine the factor structure of the WMS-R for patients aged over 75 years in a memory clinic setting. Regional cerebral blood flow (rCBF) was calculated from single-photon emission computed tomography data. Cortical thickness and cortical fractal dimension, as the marker of cortical complexity, were calculated from high resolution magnetic resonance imaging data. We found that the four factors appeared to be the most appropriate solution to the model, including recognition memory, paired associate memory, visual-and working memory, and attention as factors. Patients with mild cognitive impairments showed significantly higher factor scores for paired associate memory, visual-and-working memory, and attention than patients with Alzheimer's disease. Regarding the neuroimaging data, the factor scores for paired associate memory positively correlated with rCBF in the left pericallosal and hippocampal regions. Moreover, the factor score for paired associate memory showed most robust correlations with the cortical thickness in the limbic system, whereas the factor score for attention correlated with the cortical thickness in the bilateral precuneus. Furthermore, each factor score correlated with the cortical fractal dimension in the bilateral frontotemporal regions. Interestingly, the factor scores for the visual-and-working memory and attention selectively correlated with the cortical fractal dimension in the right posterior cingulate cortex and right precuneus cortex, respectively. These findings demonstrate that recognition memory, paired associate memory, visual-and-working memory, and attention can be crucial factors for interpreting the WMS-R results of elderly patients aged over 75 years in a memory clinic setting. Considering these findings, the results of WMS-R in elderly patients aged over 75 years in a memory clinic setting should be cautiously interpreted. PMID- 29270124 TI - Enhancing the Promise of Drug Repositioning through Genetics. AB - The development of new drugs has become challenging as the necessary investments in time and money have increased while drug approval rates have decreased. A potential solution to this problem is drug repositioning which aims to use existing drugs to treat conditions for which they were not originally intended. One approach that may enhance the likelihood of success is to reposition drugs against a target that has a genetic basis. The multitude of genome-wide association studies (GWASs) conducted in recent years represents a large potential pool of novel targets for drug repositioning. Although trait-associated variants identified from GWAS still need to be causally linked to a target gene, recently developed functional genomic techniques, databases, and workflows are helping to remove this bottleneck. The pre-clinical validation of repositioning against these targets also needs to be carefully performed to ensure that findings are not confounded by off-target effects or limitations of the techniques used. Nevertheless, the approaches described in this review have the potential to provide a faster, cheaper and more certain route to clinical approval. PMID- 29270123 TI - Role of Sex Hormones on Brain Mitochondrial Function, with Special Reference to Aging and Neurodegenerative Diseases. AB - The mitochondria have a fundamental role in both cellular energy supply and oxidative stress regulation and are target of the effects of sex steroids, particularly the neuroprotective ones. Aging is associated with a decline in the levels of different steroid hormones, and this decrease may underline some neural dysfunctions. Besides, modifications in mitochondrial functions associated with aging processes are also well documented. In this review, we will discuss studies that describe the modifications of brain mitochondrial function and of steroid levels associated with physiological aging and with neurodegenerative diseases. A special emphasis will be placed on describing and discussing our recent findings concerning the concomitant study of mitochondrial function (oxidative phosphorylation, oxidative stress) and brain steroid levels in both young (3 month-old) and aged (20-month-old) male and female mice. PMID- 29270125 TI - Gene Mutations as Emerging Biomarkers and Therapeutic Targets for Relapsed Acute Myeloid Leukemia. AB - It is believed that there are key differences in the genomic profile between adult and childhood acute myeloid leukemia (AML). Relapse is the significant contributor of mortality in patients with AML and remains as the leading cause of cancer death among children, posing great challenges in the treatment of AML. The knowledge about the genomic lesions in childhood AML is still premature as most genomic events defined in children were derived from adult cohorts. However, the emerging technologies of next generation sequencing have narrowed the gap of knowledge in the biology of AML by the detection of gene mutations for each sub type which have led to the improvement in terms of prognostication as well as the use of targeted therapies. In this review, we describe the recent understanding of the genomic landscape including the prevalence of mutation, prognostic impact, and targeted therapies that will provide an insight into the pathogenesis of AML relapse in both adult and childhood cases. PMID- 29270126 TI - High-Intensity Interval Training Attenuates Insulin Resistance Induced by Sleep Deprivation in Healthy Males. AB - Introduction: Sleep deprivation can impair several physiological systems and recently, new evidence has pointed to the relationship between a lack of sleep and carbohydrate metabolism, consequently resulting in insulin resistance. To minimize this effect, High-Intensity Interval Training (HIIT) is emerging as a potential strategy. Objective: The aim of this study was to investigate the effects of HIIT on insulin resistance induced by sleep deprivation. Method: Eleven healthy male volunteers were recruited, aged 18-35 years, who declared taking 7-8 h sleep per night. All volunteers were submitted to four different conditions: a single night of regular sleep (RS condition), 24 h of total sleep deprivation (SD condition), HIIT training followed by regular sleep (HIIT+RS condition), and HIIT training followed by 24 h of total sleep deprivation (HIIT+SD condition). They performed six training sessions over 2 weeks and each session consisted of 8-12 * 60 s intervals at 100% of peak power output. In each experimental condition, tests for glucose, insulin, cortisol, free fatty acids, and insulin sensitivity, measured by oral glucose tolerance test (OGTT), were performed. Results: Sleep deprivation increased glycaemia and insulin levels, as well as the area under the curve. Furthermore, an increase in free fatty acids concentrations and basal metabolism was observed. There were no differences in the concentrations of cortisol. However, HIIT before 24 h of sleep deprivation attenuated the increase of glucose, insulin, and free fatty acids. Conclusion: Twenty-four hours of sleep deprivation resulted in acute insulin resistance. However, HIIT is an effective strategy to minimize the deleterious effects promoted by this condition. PMID- 29270127 TI - miR-1338-5p Modulates Growth Hormone Secretion and Glucose Utilization by Regulating ghitm in Genetically Improved Farmed Tilapia (GIFT, Oreochromis niloticus). AB - MicroRNAs (miRNAs) are endogenous, non-coding small RNA molecules about 22 nt in length, which could regulate the expressions of target genes and participate in growth and development of organisms. Genetically improved farmed tilapia (GIFT, Oreochromis niloticus) is an important economic freshwater species in China and the growth performance is one of the main breeding indicators. Growth hormone inducible transmembrane protein (ghitm) plays an important role in growth and development of both mammals and invertebrates; however, little studies have been reported on fish. Our previous experiments indicated that miR-1338-5p expression may be negatively correlated with ghitm expression. In this study, we firstly used qRT-PCR and northern blot to verify the expression of miR-1338-5p and ghitm, and determined the binding site of miR-1338-5p in the ghitm 3'-untranslated region (UTR) by luciferase reporter assay. Secondly, juveniles GIFT injected with miR-1338-5p antagomir were used to analyze the regulatory function of the miR 1338-5p-ghitm pair in vivo. The results showed that the ghitm 3'-UTR was complementary to the 5' 2-8-nt site of miR-1338-5p. Inhibition of miR-1338-5p promoted ghitm expression in the pituitary and liver of GIFT. ghitm could interfere in the growth hormone (Gh)-growth hormone receptor (Ghr)-insulin-like growth factor (Igf) signaling pathway by competing with the ghr1 for combination with Gh, and then reduce the growth of GIFT. Moreover, the reduction of Gh in serum may regulate insulin secretion and result in the increasing sugar and fat storage in serum and liver. Our results suggest that miR-1338-5p participates in the growth and development of GIFT through the regulation of ghitm, which provides theoretical support for the study of the fish growth mechanism. PMID- 29270129 TI - P311 Deficiency Leads to Attenuated Angiogenesis in Cutaneous Wound Healing. AB - P311 was identified to markedly promote cutaneous wound healing by our group. Angiogenesis plays a key role in wound healing. In this study, we sought to define the role of P311 in skin wound angiogenesis. It was noted that P311 was expressed in endothelial cells in the dermis of murine and human skin wounds. The expression of P311 was confirmed in cultured murine dermal microvascular endothelial cells (mDMECs). Moreover, it was found that knockout of P311 could attenuate the formation of tubes and motility of mDMECs significantly in vitro. In the subcutaneous Matrigel implant model, the angiogenesis was reduced significantly in P311 knockout mice. In addition, wound healing was delayed in P311 knockout mice compared with that in the wild type. Granulation tissue formation during the defective wound healing showed thinner and blood vessel numbers in wound areas in P311 knockout mice were decreased significantly. A reduction in VEGF and TGFbeta1 was also found in P311 KO mice wounds, which implied that P311 may modulate the exprssion of VEGF and TGFbeta1 in wound healing. Together, our findings suggest that P311 plays an important role in angiogenesis in wound healing. PMID- 29270130 TI - Polymorphism rs1761667 in the CD36 Gene Is Associated to Changes in Fatty Acid Metabolism and Circulating Endocannabinoid Levels Distinctively in Normal Weight and Obese Subjects. AB - The multifunctional CD36 scavenger receptor facilitates fatty acid (FA) uptake and oxidation and it has been involved in the pathophysiology related to dysfunctional FA metabolism. The common variant in the CD36 gene, rs1761667 (A/G), whose allele A is characterized by a reduced protein expression, has been associated with taste sensitivity to and preference for fat. We therefore aimed at evaluating whether the CD36 polymorphism may influence fatty acid metabolism and endocannabinoid biosynthesis in normal weight (NW) and obese (OB) subjects. Red blood cell (RBC) fatty acid composition, and plasma endocannabinoid levels were determined. In NW subjects with AA genotype was found a marked reduction of RBC saturated fatty acids and palmitic/linoleic ratio (PA/LA), considered as de novo lipogenesis (DNL) biomarkers. Remarkably, to the reduction of DNL biomarkers corresponded an increase of omega-6 index, an indirect marker of the impact on fatty acid metabolism of dietary omega-6 fatty acids, endocannabinoid levels and a higher waist/hip ratio. The presence of the G allele was instead associated with increased endocannabinoid plasma levels and a trend for increased waist/hip ratio in obese subjects, even though exhibited decreased BMI with respect to those with AA genotype. These data indicate that the CD36 polymorphism, rs1761667, leads to a distinct metabolic pattern in NW and in OB subjects. Therefore, their determination may be crucial in developing personalized therapeutic strategies for ameliorating dyslipidemia and other metabolic disorders. PMID- 29270128 TI - Stem Cells from Dental Pulp: What Epigenetics Can Do with Your Tooth. AB - Adult stem cells have attracted scientific attention because they are able to self-renew and differentiate into several specialized cell types. In this context, human dental tissue-derived mesenchymal stem cells (hDT-MSCs) have emerged as a possible solution for repairing or regenerating damaged tissues. These cells can be isolated from primary teeth that are naturally replaced, third molars, or other dental tissues and exhibit self-renewal, a high proliferative rate and a great multilineage potential. However, the cellular and molecular mechanisms that determine lineage specification are still largely unknown. It is known that a change in cell fate requires the deletion of existing transcriptional programs, followed by the establishment of a new developmental program to give rise to a new cell lineage. Increasing evidence indicates that chromatin structure conformation can influence cell fate. In this way, reversible chemical modifications at the DNA or histone level, and combinations thereof can activate or inactivate cell-type-specific gene sequences, giving rise to an alternative cell fates. On the other hand, miRNAs are starting to emerge as a possible player in establishing particular somatic lineages. In this review, we discuss two new and promising research fields in medicine and biology, epigenetics and stem cells, by summarizing the properties of hDT-MSCs and highlighting the recent findings on epigenetic contributions to the regulation of cellular differentiation. PMID- 29270133 TI - Role of Broad-Complex (Br) and Kruppel homolog 1 (Kr-h1) in the Ovary Development of Nilaparvata lugens. AB - Ovarian development plays an important role in the life history of insects and is crucial for control of the insect population. The metamorphosis of an insect is precisely regulated by the interaction of the juvenile hormone and ecdysone. To understand the role of NlBr and NlKr-h1 in ovary development, we used RNA interference (RNAi) to down-regulate the expression of Broad-Complex (Br) and Kruppel homolog 1 (Kr-h1), two important down-stream transcription factors of juvenile hormone and ecdysone signaling. We further investigated their effects on metamorphosis and ovary development. The results showed that both NlBr and NlKr h1 are induced by ecdysone. The down-regulation of NlBr and NlKr-h1 alone or together by RNAi is more effective than the topical application of ecdysone on the number of ovarioles, suggesting the necessity of NlBr and NlKr-h1 in determining the number of ovarioles. The ovarian grade was significantly increased/decreased by the topical application of ecdysone and down-regulation of NlBr and NlKr-h1. The pre-oviposition period was also increased. When NlBr and NlKr-h1 were down-regulated together, the ovary grade was not significantly different compared to the control (dsGFP), indicating that the development of the ovary is under the control of both NlBr and NlKr-h1. The interaction between the NlBr and NlKr-h1 on the number of ovarioles and the development of the ovary indicates cross-talk between both juvenile hormone and ecdysone signaling at the transcription level in the brown planthopper. Both genes are nuclear transcription factors and may regulate signaling via down-stream genes. These results would help to both enhance the current understanding of the regulatory mechanism of the interaction between juvenile hormone and ecdysone signaling pathways during ovarian development and to design chemicals to control pests. PMID- 29270132 TI - Discovery of a Potential Plasma Protein Biomarker Panel for Acute-on-Chronic Liver Failure Induced by Hepatitis B Virus. AB - Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF), characterized by an acute deterioration of liver function in the patients with chronic hepatitis B (CHB), is lack of predicting biomarkers for prognosis. Plasma is an ideal sample for biomarker discovery due to inexpensive and minimally invasive sampling and good reproducibility. In this study, immuno-depletion of high-abundance plasma proteins followed by iTRAQ-based quantitative proteomic approach was employed to analyze plasma samples from 20 healthy control people, 20 CHB patients and 20 HBV-ACLF patients, respectively. As a result, a total of 427 proteins were identified from these samples, and 42 proteins were differentially expressed in HBV-ACLF patients as compared to both CHB patients and healthy controls. According to bioinformatics analysis results, 6 proteins related to immune response (MMR), inflammatory response (OPN, HPX), blood coagulation (ATIII) and lipid metabolism (APO-CII, GP73) were selected as biomarker candidates. Further ELISA analysis confirmed the significant up regulation of GP73, MMR, OPN and down-regulation of ATIII, HPX, APO-CII in HBV ACLF plasma samples (p < 0.01). Moreover, receiver operating characteristic (ROC) curve analysis revealed high diagnostic value of these candidates in assessing HBV-ACLF. In conclusion, present quantitative proteomic study identified 6 novel HBV-ACLF biomarker candidates and might provide fundamental information for development of HBV-ACLF biomarker. PMID- 29270131 TI - The Sensitivity of the Crayfish Reward System to Mammalian Drugs of Abuse. AB - The idea that addiction occurs when the brain is not able to differentiate whether specific reward circuits were triggered by adaptive natural rewards or falsely activated by addictive drugs exist in several models of drug addiction. The suitability of crayfish (Orconectes rusticus) for drug addiction research arises from developmental variation of growth, life span, reproduction, behavior and some quantitative traits, especially among isogenic mates reared in the same environment. This broad spectrum of traits makes it easier to analyze the effect of mammalian drugs of abuse in shaping behavioral phenotype. Moreover, the broad behavioral repertoire allows the investigation of self-reinforcing circuitries involving appetitive and exploratory motor behavior, while the step-wise alteration of the phenotype by metamorphosis allows accurate longitudinal analysis of different behavioral states. This paper reviews a series of recent experimental findings that evidence the suitability of crayfish as an invertebrate model system for the study of drug addiction. Results from these studies reveal that unconditioned exposure to mammalian drugs of abuse produces a variety of stereotyped behaviors. Moreover, if presented in the context of novelty, drugs directly stimulate exploration and appetitive motor patterns along with molecular processes for drug conditioned reward. Findings from these studies indicate the existence of drug sensitive circuitry in crayfish that facilitates exploratory behavior and appetitive motor patterns via increased incentive salience of environmental stimuli or by increasing exploratory motor patterns. This work demonstrates the potential of crayfish as a model system for research into the neural mechanisms of addiction, by contributing an evolutionary, comparative context to our understanding of natural reward as an important life sustaining process. PMID- 29270134 TI - Novel Small Molecule Inhibitors of Protein Kinase D Suppress NF-kappaB Activation and Attenuate the Severity of Rat Cerulein Pancreatitis. AB - Nuclear factor-kappa B (NF-kappaB) activation is a key early signal regulating inflammatory and cell death responses in acute pancreatitis. Our previous in vitro studies with molecular approaches on AR42J cell showed that protein kinase D (PKD/PKD1) activation was required in NF-kappaB activation induced by cholecystokinin 8 (CCK) or carbachol (CCh) in pancreatic acinar cells. Recently developed small molecule PKD inhibitors, CID755673 and CRT0066101, provide potentially important pharmacological approaches to further investigate the effect of PKD in pancreatitis therapy. The aim of this study was to explore whether CID755673 and CRT0066101 block NF-kappaB activation with in vitro and in vivo models of experimental pancreatitis and whether the small molecule PKD inhibitors have therapeutic effects when given before or after the initiation of experimental pancreatitis. Freshly prepared pancreatic acini were incubated with CID755673 or CRT006101, followed by hyperstimulation with CCK or CCh. For in vivo experimental pancreatitis, rats were treated with intraperitoneal injection of CID755673 or CRT0066101 prior to or after administering cerulein or saline. PKD activation and NF-kappaB-DNA binding activity in nuclear extracts from pancreatic acini and tissue were measured. The effects of PKD inhibitors on pancreatitis responses were evaluated. Our results showed that both CID755673 or CRT0066101 selectively and specifically inhibited PKD without effects on related protein kinase Cs. Inhibition of PKD resulted in significantly attenuation of NF-kappaB activation in both in vitro and in vivo models of experimental pancreatitis. NF kappaB inhibition by CID755673 was associated with decreased inflammatory responses and attenuated severity of the disease, which were indicated by less inflammatory cell infiltration, reduced pancreatic interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), decreased intrapancreatic trypsin activation, and alleviation in pancreatic necrosis, edema and vacuolization. Furthermore, PKD inhibitor CID755673, given after the initiation of pancreatitis in experimental rat model, significantly attenuated the severity of acute pancreatitis. Therapies for acute pancreatitis are limited. Our results indicate that small chemical PKD inhibitors have significant potential as therapeutic interventions by suppressing NF-kappaB activation. PMID- 29270135 TI - In Vivo Sarcomere Lengths Become More Non-uniform upon Activation in Intact Whole Muscle. AB - The sarcomere force-length relationship has been extensively used to predict muscle force potential. The common practice is to measure the mean sarcomere length (SL) in a relaxed muscle at a single location and at a given length, and this mean SL is assumed to represent the SLs at other locations across the muscle. However, in a previous study, we found that SLs are highly non-uniform across an intact passive muscle. Moreover, SL non-uniformity increases during activation in single myofibril experiments. Myofibrils lack some structural proteins that comprise an intact muscle, and therefore, the increased SL dispersion upon activation seen in myofibrils may not occur in intact whole muscle. The objectives of the current study were (i) to measure the distribution of SLs in an activated intact muscle; and (ii) to assess the feasibility of using the mean SL measured at a specific location of the muscle to predict muscle force. Using state-of-the-art multi-photon microscopy and a miniature tendon force transducer, in vivo sarcomeres in the mouse tibialis anterior were imaged simultaneously with muscle force during isometric tetanic contractions. We found that in vivo SL dispersion increased substantially during activation and reached average differences of ~1.0 MUm. These differences in SL are associated with theoretical force differences of 70-100% of the maximal isometric force. Furthermore, SLs measured at a single location in the passive muscle were poor predictors of active force potential. Although mean SLs in the activated muscle were better predictors of force potential, predicted forces still differed by as much as 35% from the experimentally measured maximal isometric forces. PMID- 29270137 TI - The Deeper the Love, the Deeper the Hate. AB - Love and hate are basic human affects. Previous research has focused on the classification, functions, and other aspects of these two affects. However, few studies have been conducted on the relationship between love and hate. The present study investigated whether similarity within romantic partners was associated with greater feelings of love in the absence of betrayal, and greater hate induced in the presence of betrayal by using vignettes to induce love and hate in a sample of 59 young adults. The results showed that people who shared similar values and interests with the target persons were more likely to experience stronger love. Additionally, stronger feelings of love were associated with greater hate after the relationship was broken, suggesting a link between romantic love and hate. Our study revealed a complex picture of love and hate. People have different emotional reactions toward different target persons in the context of romantic love and hate. If one loves someone deeply and sometimes hates that person, the feeling of love may still be dominant in the context of betrayal. However, if one does not love that person, hate will be a much stronger feeling than love. PMID- 29270136 TI - Methodological Flaws, Conflicts of Interest, and Scientific Fallacies: Implications for the Evaluation of Antidepressants' Efficacy and Harm. AB - Background: In current psychiatric practice, antidepressants are widely and with ever-increasing frequency prescribed to patients. However, several scientific biases obfuscate estimates of antidepressants' efficacy and harm, and these are barely recognized in treatment guidelines. The aim of this mini-review is to critically evaluate the efficacy and harm of antidepressants for acute and maintenance treatment with respect to systematic biases related to industry funding and trial methodology. Methods: Narrative review based on a comprehensive search of the literature. Results: It is shown that the pooled efficacy of antidepressants is weak and below the threshold of a minimally clinically important change once publication and reporting biases are considered. Moreover, the small mean difference in symptom reductions relative to placebo is possibly attributable to observer effects in unblinded assessors and patient expectancies. With respect to trial dropout rates, a hard outcome not subjected to observer bias, no difference was observed between antidepressants and placebo. The discontinuation trials on the efficacy of antidepressants in maintenance therapy are systematically flawed, because in these studies, spontaneous remitters are excluded, whereas half of all patients who remitted on antidepressants are abruptly switched to placebo. This can cause a severe withdrawal syndrome that is easily misdiagnosed as a relapse when assessed on subjective symptom rating scales. In accordance, the findings of naturalistic long-term studies suggest that maintenance therapy has no clear benefit, and non-drug users do not show increased recurrence rates. Moreover, a growing body of evidence from hundreds of randomized controlled trials suggests that antidepressants cause suicidality, but this risk is underestimated because data from industry-funded trials are systematically flawed. Unselected, population-wide observational studies indicate that depressive patients who use antidepressants are at an increased risk of suicide and that they have a higher rate of all-cause mortality than matched controls. Conclusion: The strong reliance on industry-funded research results in an uncritical approval of antidepressants. Due to several flaws such as publication and reporting bias, unblinding of outcome assessors, concealment and recoding of serious adverse events, the efficacy of antidepressants is systematically overestimated, and harm is systematically underestimated. Therefore, I conclude that antidepressants are largely ineffective and potentially harmful. PMID- 29270138 TI - Development of Visuospatial Attention in Typically Developing Children. AB - The aim of the present study is to investigate the development of visuospatial attention in typically developing children and to propose reference values for children for the following six visuospatial attention tests: star cancellation, Ogden figure, reading test, line bisection, proprioceptive pointing and visuo proprioceptive pointing. Data of 159 children attending primary or secondary school in the Federation Wallonie Bruxelles (Belgium) were analyzed. Results showed that the children's performance on star cancellation, Ogden figure and reading test improved until the age of 13 years, whereas their performance on proprioceptive pointing, visuo-proprioceptive pointing and line bisection was stable with increasing age. These results suggest that the execution of different types of visuospatial attention tasks are not following the same developmental trajectories. This dissociation is strengthened by the lack of correlation observed between tests assessing egocentric and allocentric visuospatial attention, except for the star cancellation test (egocentric) and the Ogden figure copy (ego- and allocentric). Reference values are proposed that may be useful to examine children with clinical disorders of visuospatial attention. PMID- 29270139 TI - Restoration and the City: The Role of Public Urban Squares. AB - Over recent decades, the study of psychological restoration has attracted a considerable amount of interest within and without the boundaries of environmental psychology, with most of the work focused on analyzing restoration in natural contexts. However, little attention has been paid to the (possible) restorative potential of urban settings, as they have usually been expected not to be restorative and to present some elements that might imply negative health outcomes in the short and long term. In this field study, our aim was to evaluate restoration in urban squares. To this end, we measured participants' attentional and affective states both before and after spending half an hour in an urban square. A sample of 46 subjects contemplated and walked through one of the two selected squares that differed in restorative potential (PRS). Analyses revealed a statistically significant increase in cognitive performance and a decrease in negative affect in both squares. They also showed that participants reported greater stress recovery rates in one of the settings. These results support the idea that cities can be potentially restorative and justify the relevance of a research area focused on the urban designs, which may offer psychological benefits to urban citizens. PMID- 29270140 TI - Sentence Repetition as a Tool for Screening Morphosyntactic Abilities of Bilectal Children with SLI. AB - The clinical significance of sentence repetition tasks (SRTs) for assessing children's language ability is well-recognized. SRT has been identified as a good clinical marker for children with (specific) language impairment as it shows high diagnostic accuracy levels. Furthermore, qualitative analysis of repetition samples can provide information to be used for intervention protocols. Despite the fact that SRT is a familiar task in assessment batteries across several languages, it has not yet been measured and validated in bilectal settings, such as Cypriot Greek, where the need for an accurate screening tool is urgent. The aims of the current study are three-fold. First, the performance of a group of (Cypriot) Greek-speaking children identified with SLI is evaluated using a SRT that elicits complex morphosyntactic structures. Second, the accuracy level of the SRT for the identification of SLI is explored. Third, a broad error analysis is carried out to examine and compare the morphosyntactic abilities of the participating children. A total of 38 children aged 5-9 years participated in this study: a clinical group of children with SLI (n = 16) and a chronological age-matched control group (n = 22). The ability of the children to repeat complex morphosyntactic structures was assessed using a SRT consisting of 24 sentences. The results showed that the SRT yielded significant differences in terms of poorer performance of children with SLI compared to typically developing peers. The diagnostic accuracy of the task was validated, since regression analysis showed that the task is sensitive and specific enough to identify children with SLI. Finally, qualitative differences between children with SLI and those with TLD regarding morphosyntactic abilities were detected. This study showed that a SRT that elicits morphosyntactically complex structures could be a potential clinical indicator for SLI in Cypriot Greek. The task has the potential to be used as a referral criterion in order to identify children whose language needs to be evaluated further. Implications for speech-language therapists and policy makers are discussed. PMID- 29270141 TI - Impact of Response Stimulus Interval on Transfer of Non-local Dependent Rules in Implicit Learning: An ERP Investigation. AB - In the literature on implicit learning, controversy exists regarding whether the knowledge obtained from implicit sequence learning consists of context-bound superficial features or context-free structural rules. To explore the nature of implicit knowledge, event related potentials (ERP) recordings of participants' performances in a non-local dependent transfer task under two response-stimulus interval (RSI) conditions (250 and 750 ms) were obtained. In the behavioral data, a transfer effect was found in the 750 ms RSI condition but not in the 250 ms RSI condition, suggesting that a long RSI is the basis for the occurrence of non local dependent transfer, as which might have provided enough reaction time for participants to process and capture the implicit rule. Moreover, P300 amplitude was found to be sensitive to the impact of RSI on the training process (i.e., the longer RSI elicited higher P300 amplitudes), while variations in both N200 (i.e., a significant increase) and P300 amplitudes (i.e., a significant decrease) were found to be related to the presence of a transfer effect. Our results supported the claim that implicit learning can involve abstract rule knowledge acquisition under an appropriate RSI condition, and that amplitude variation in early ERP components (i.e., N200 and P300) can be useful indexes of non-local dependent learning and transfer effects. PMID- 29270142 TI - Perceptual-Semantic Congruency Facilitates Semantic Discrimination of Thermal Qualities. AB - The ability to sense temperature is vital to our life. It signals the environmental condition, reflects the physiological conditions of our own body, and generates feelings of pleasantness or unpleasantness. Moreover, recent studies have demonstrated implicit associations between physical temperature and social/emotional concepts, suggesting the processing of temperature may even influence cognition. In this work, we examined the effect of physical warmth and coldness on semantic cognition. Participants performed speeded target categorization for thermal descriptors in the form of semantic words or illustrative figures representing the thermal qualities "warm" or "cold" while physical thermal stimulation was presented. We compared the average reaction time (RT) for the congruent and incongruent conditions managed by response key assignments. In the congruent condition, the response key for the symbol associated with warmth (coldness) was assigned to the hand with warm (cold) thermal stimulation, and in the incongruent condition the key assignment was reversed. Our results demonstrate that the average RT in the congruent condition was faster than in the incongruent one for both forms of thermal descriptors, suggesting that the experience of physical temperature facilitates the internal processing of the meaning of thermal quality. PMID- 29270143 TI - Processing Relative Clause Extractions in Swedish. AB - Relative clauses are considered strong islands for extraction across languages. Swedish comprises a well-known exception, allegedly allowing extraction from relative clauses (RCE), raising the possibility that island constraints may be subject to "deep variation" between languages. One alternative is that such exceptions are only illusory and represent "surface variation" attributable to independently motivated syntactic properties. Yet, to date, no surface account has proven tenable for Swedish RCEs. The present study uses eyetracking while reading to test whether the apparent acceptability of Swedish RCEs has any processing correlates at the point of filler integration compared to uncontroversial strong island violations. Experiment 1 tests RCE against licit that-clause extraction (TCE), illicit extraction from a non-restrictive relative clause (NRCE), and an intransitive control. For this, RCE was found to pattern similarly to TCE at the point of integration in early measures, but between TCE and NRCE in total durations. Experiment 2 uses RCE and extraction from a subject NP island (SRCE) to test the hypothesis that only non-islands will show effects of implausible filler-verb dependencies. RCE showed sensitivity to the plausibility manipulation across measures at the first potential point of filler integration, whereas such effects were limited to late measures for SRCE. In addition, structural facilitation was seen across measures for RCE relative to SRCE. We propose that our results are compatible with RCEs being licit weak island extractions in Swedish, and that the overall picture speaks in favor of a surface rather than a deep variation approach to the lack of island effects in Swedish RCEs. PMID- 29270144 TI - Measuring Prosocial Tendencies in Germany: Sources of Validity and Reliablity of the Revised Prosocial Tendency Measure. AB - The prosocial tendencies measure (PTM; Carlo and Randall, 2002) is a widely used measurement for prosocial tendencies in English speaking participants. This instrument distinguishes between six different types of prosocial tendencies that partly share some common basis, but also can be opposed to each other. To examine these constructs in Germany, a study with 1067 participants was conducted. The study investigated the structure of this German version of the PTM-R via exploratory factor analysis, confirmatory factor analysis, correlations with similar constructs in subsamples as well as via measurement invariance test concerning the original English version. The German translation showed a similar factor structure to the English version in exploratory factor analysis and in confirmatory factor analysis. Measurement invariance was found between the English and German language versions of the PTM and support for the proposed six factor structure (altruistic, anonymous, compliant, dire, emotional and public prosocial behavior) was also found in confirmatory factor analysis. Furthermore, the expected interrelations of these factors of prosocial behavior tendencies were obtained. Finally, correlations of the prosocial behavior tendencies with validating constructs and behaviors were found. Thus, the findings stress the importance of seeing prosocial behavior not as a single dimension construct, but as a factored construct which now can also be assessed in German speaking participants. PMID- 29270146 TI - Generalized Structured Component Analysis with Uniqueness Terms for Accommodating Measurement Error. AB - Generalized structured component analysis (GSCA) is a component-based approach to structural equation modeling (SEM), where latent variables are approximated by weighted composites of indicators. It has no formal mechanism to incorporate errors in indicators, which in turn renders components prone to the errors as well. We propose to extend GSCA to account for errors in indicators explicitly. This extension, called GSCAM, considers both common and unique parts of indicators, as postulated in common factor analysis, and estimates a weighted composite of indicators with their unique parts removed. Adding such unique parts or uniqueness terms serves to account for measurement errors in indicators in a manner similar to common factor analysis. Simulation studies are conducted to compare parameter recovery of GSCAM and existing methods. These methods are also applied to fit a substantively well-established model to real data. PMID- 29270145 TI - Decision Making under Ambiguity and Objective Risk in Higher Age - A Review on Cognitive and Emotional Contributions. AB - The ability of decision making plays a highly relevant role in our survival, but is adversely affected during the process of aging. The present review aims to provide a better understanding of age-related differences in decision making and the role of cognitive and emotional factors in this context. We reviewed the literature about age-effects on decision-making performance, focusing on decision making under ambiguous and objective risk. In decisions under ambiguous risks, as measured by the Iowa Gambling Task, decisions are based on the experiences with consequences. In this case, many articles have attributed age-related impairments in decision making to changes in emotional and somatic reward- and punishment processing. In decisions under objective risks, as measured for example by the Game of Dice Task, decisions can be based on explicit information about risks and consequences. In this case, age-related changes have been attributed mainly to a cognitive decline, particularly impaired executive functions. However, recent findings challenge these conclusions. The present review summarizes neuropsychological and neurophysiological findings of age-related differences in decision making under ambiguous and objective risk. In this context, the relevance of learning, but also of cognitive and emotional contributors - responsible for age-related differences in decision making - are additionally pointed out. PMID- 29270147 TI - Is a High Tone Pointy? Speakers of Different Languages Match Mandarin Chinese Tones to Visual Shapes Differently. AB - Studies investigating cross-modal correspondences between auditory pitch and visual shapes have shown children and adults consistently match high pitch to pointy shapes and low pitch to curvy shapes, yet no studies have investigated linguistic-uses of pitch. In the present study, we used a bouba/kiki style task to investigate the sound/shape mappings for Tones of Mandarin Chinese, for three groups of participants with different language backgrounds. We recorded the vowels [i] and [u] articulated in each of the four tones of Mandarin Chinese. In Study 1 a single auditory stimulus was presented with two images (one curvy, one spiky). In Study 2 a single image was presented with two auditory stimuli differing only in tone. Participants were asked to select the best match in an online 'Quiz.' Across both studies, we replicated the previously observed 'u curvy, i-pointy' sound/shape cross-modal correspondence in all groups. However, Tones were mapped differently by people with different language backgrounds: speakers of Mandarin Chinese classified as Chinese-dominant systematically matched Tone 1 (high, steady) to the curvy shape and Tone 4 (falling) to the pointy shape, while English speakers with no knowledge of Chinese preferred to match Tone 1 (high, steady) to the pointy shape and Tone 3 (low, dipping) to the curvy shape. These effects were observed most clearly in Study 2 where tone-pairs were contrasted explicitly. These findings are in line with the dominant patterns of linguistic pitch perception for speakers of these languages (pitch-change, and pitch height, respectively). Chinese English balanced bilinguals showed a bivalent pattern, swapping between the Chinese pitch-change pattern and the English pitch-height pattern depending on the task. These findings show for that the supposedly universal pattern of mapping linguistic sounds to shape is modulated by the sensory properties of a speaker's language system, and that people with high functioning in more than one language can dynamically shift between patterns. PMID- 29270148 TI - Tranylcypromine Causes Neurotoxicity and Represses BHC110/LSD1 in Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids Model. AB - Recent breakthroughs in human pluripotent stem cell-derived cerebral organoids provide a valuable platform for investigating the human brain after different drugs treatments and for understanding the complex genetic background to human pathology. Here, we identified tranylcypromine, which is used to treat refractory depression, caused human-induced pluripotent stem cell-derived brain organoids neurotoxicity, leading to decreased proliferation activity and apoptosis induction. Moreover, tranylcypromine treatment affects neurons and astrocytes, which impairs cell density and arrangement. Finally, staining of histone demethylation-related genes revealed that tranylcypromine suppresses the transcriptional activity of BHC110/LSD1-targeted genes and increases the expression of histone di-methylated K4. These results show that human brain organoids can be applied as an in vitro model for CNS drug screening to evaluate structural, cellular, and molecular changes in the normal brains or brains of patients with neuropsychiatric disorders after drug treatments. PMID- 29270149 TI - High Mortality among 30-Day Readmission after Stroke: Predictors and Etiologies of Readmission. AB - Background: Although some risk factors for stroke readmission have been reported, the mortality risk is unclear. We sought to evaluate etiologies and predictors of 30-day readmissions and determine the associated mortality risk. Methods: This is a retrospective case-control study evaluating 1,544 patients admitted for stroke (hemorrhagic, ischemic, or TIA) from January 2013 to December 2014. Of these, 134 patients readmitted within 30 days were identified as cases; 1,418 other patients, with no readmissions were identified as controls. Patients readmitted for hospice or elective surgery were excluded. An additional 248 patients deceased on index admission were included for only a comparison of mortality rates. Factors explored included socio-demographic characteristics, clinical comorbidities, stroke characteristics, and length of stay. Chi-square test of proportions and multivariable logistic regression were used to identify independent predictors of 30-day stroke readmissions. Mortality rates were compared for index admission and readmission and among readmission diagnoses. Results: Among the 1,544 patients in the main analysis, 67% of index stroke admissions were ischemic, 22% hemorrhagic, and 11% TIA. The 30-day readmission rate was 8.7%. The most common etiologies for readmission were infection (30%), recurrent stroke and TIA (20%), and cardiac complications (14%). Significantly higher proportion of those readmitted for recurrent strokes and TIAs presented within the first week (p = 0.039) and had a shorter index admission length of stay (p = 0.027). Risk factors for 30-day readmission included age >75 (p = 0.02), living in a facility prior to index stroke (p = 0.01), history of prior stroke (p = 0.03), diabetes (p = 0.03), chronic heart failure (p <= 0.001), atrial fibrillation (p = 0.03), index admission to non-neurology service (p < 0.01), and discharge to other than home (p < 0.01). On multivariate analysis, index admission to a non-neurology service was an independent predictor of 30-day readmission (p <= 0.01). The mortality after a within 30-day readmission after stroke was higher than index admission (36.6 vs. 13.8% p <= 0.001) (OR 3.6 95% CI 2.5-5.3). Among those readmitted, mortality was significantly higher for those admitted for a recurrent stroke (p = 0.006). Conclusion: Approximately one-third of 30-day readmissions were infection related and one-fifth returned with recurrent stroke or TIA. Index admission to non-neurology service was an independent risk factor of 30-day readmissions. The mortality rate for 30-day readmission after stroke is more than 2.5 times greater than index admissions and highest among those readmitted for recurrent stroke. Identifying high-risk patients for readmission, ensuring appropriate level of service, and early outpatient follow-up may help reduce 30-day readmission and the high associated risk of mortality. PMID- 29270150 TI - A Novel Sonification Approach to Support the Diagnosis of Alzheimer's Dementia. AB - Alzheimer's disease is the most common neurodegenerative form of dementia that steadily worsens and eventually leads to death. Its set of symptoms include loss of cognitive function and memory decline. Structural and functional imaging methods such as CT, MRI, and PET scans play an essential role in the diagnosis process, being able to identify specific areas of cerebral damages. While the accuracy of these imaging techniques increases over time, the severity assessment of dementia remains challenging and susceptible to cognitive and perceptual errors due to intra-reader variability among physicians. Doctors have not agreed upon standardized measurement of cell loss used to specifically diagnose dementia among individuals. These limitations have led researchers to look for supportive diagnosis tools to enhance the spectrum of diseases characteristics and peculiarities. Here is presented a supportive auditory tool to aid in diagnosing patients with different levels of Alzheimer's. This tool introduces an audible parameter mapped upon three different brain's lobes. The motivating force behind this supportive auditory technique arise from the fact that AD is distinguished by a decrease of the metabolic activity (hypometabolism) in the parietal and temporal lobes of the brain. The diagnosis is then performed by comparing metabolic activity of the affected lobes to the metabolic activity of other lobes that are not generally affected by AD (i.e., sensorimotor cortex). Results from the diagnosis process compared with the ground truth show that physicians were able to categorize different levels of AD using the sonification generated in this study with higher accuracy than using a standard diagnosis procedure, based on the visualization alone. PMID- 29270151 TI - Hyperacute Simultaneous Cardiocerebral Infarction: Rescuing the Brain or the Heart First? AB - Concurrent acute ischemic stroke and acute myocardial infarction is an uncommon medical emergency condition. The challenge for the physicians regarding the management of this situation is paramount since early management of one condition will inevitably delay the other. We present two illustrative cases of "hyperacute simultaneous cardiocerebral infarction" who presented with simultaneous cardiocerebral infarction and arrived at the hospital within the thrombolytic therapeutic window for acute ischemic stroke of 4.5 h. We propose an algorithm for managing the patient with hyperacute simultaneous cardiocerebral infarction based on hemodynamic status and suggest close cardiac monitoring based on the site of cerebral infarction. PMID- 29270152 TI - Importance of a Rapid and Accurate Diagnosis in Strongyloides Stercoralis and Human T-Lymphotropic Virus 1 Co-infection: A Case Report and Review of the Literature. AB - Strongyloides (S.) stercoralis and Human T-Lymphotropic Virus 1 (HTLV-1) share some endemic regions such as Japan, Jamaica, and South America and are mostly diagnosed elsewhere in immigrants from endemic areas. This co-infection has not been documented in Argentina although both pathogens are endemic in the Northwest. We present a case of S. stercoralis and HTLV-1 co-infection with an initial presentation due to gastrointestinal symptoms which presented neither eosinophilia nor the presence of larvae in stool samples in a non-endemic area for these infections. A young Peruvian woman living in Buenos Aires attended several emergency rooms and finally ended up admitted in a gastroenterology ward due to incoercible vomiting, diarrhea, abdominal pain, fever, and weight loss. Gastrointestinal symptoms started 3 months before she returned to Argentina from a trip to Peru. She presented malnutrition and abdominal distension parameters. HIV-1 and other immunodeficiencies were discarded. The serial coproparasitological test was negative. Computed tomography showed diffuse thickening of duodenal and jejunal walls. At the beginning, vasculitis was suspected and corticosteroid therapy was initiated. The patient worsened rapidly. Skin, new enteral biopsies, and a new set of coproparasitological samples revealed S. stercoralis. Then, HTLV-1 was suspected and infection was confirmed. Ivermectin and albendazole were administrated, until the stool sample remained negative for 2 weeks. Larvae were not observed in fresh stool, Ritchie method, and agar culture 1 week post-treatment. Although she required initial support with parenteral nutrition due to oral intolerance she slowly progressed favorably. It has been highly recommended to include a rapid and sensitive PCR strategy in the algorithm to confirm Strongyloides infection, which has demonstrated to improve early diagnosis in patients at-risk of disseminated strongyloidiasis. PMID- 29270153 TI - The Effect of the 2015 Earthquake on the Bacterial Community Compositions in Water in Nepal. AB - We conducted a study to examine the effect of seasonal variations and the disruptive effects of the 2015 Nepal earthquake on microbial communities associated with drinking water sources. We first characterized the microbial communities of water samples in two Nepali regions (Kathmandu and Jhapa) to understand the stability of microbial communities in water samples collected in 2014. We analyzed additional water samples from the same sources collected from May to August 2015, allowing the comparison of samples from dry-to-dry season and from dry-to-monsoon seasons. Emphasis was placed on microbes responsible for maintaining the geobiochemical characteristics of water (e.g., ammonia-oxidizing and nitrite-oxidizing bacteria and archaea and sulfate-reducing bacteria) and opportunistic pathogens often found in water (Acinetobacter). When examining samples from Jhapa, we identified that most geobiochemical microbe populations remained similar. When examining samples from Kathmandu, the abundance of microbial genera responsible for maintaining the geobiochemical characteristics of water increased immediately after the earthquake and decreased 8 months later (December 2015). In addition, microbial source tracking was used to monitor human fecal contamination and revealed deteriorated water quality in some specific sampling sites in Kathmandu post-earthquake. This study highlights a disruption of the environmental microbiome after an earthquake and the restoration of these microbial communities as a function of time and sanitation practices. PMID- 29270154 TI - Herpes Simplex Virus 1 Envelope Cholesterol Facilitates Membrane Fusion. AB - Methyl beta-cyclodextrin (MbetaCD) treatment of herpes simplex virus 1 (HSV-1) reduced envelope cholesterol levels and inhibited viral entry and infectivity in several cell types, regardless of the dependence of entry on endocytosis or low pH. Viral protein composition was similar in MbetaCD-treated and untreated virions, and ultrastructural analysis by electron microscopy revealed that cholesterol removal did not grossly affect virion structure or integrity. Removal of envelope cholesterol greatly reduced virion fusion activity as measured by fusion-from-without, suggesting that virion cholesterol is critical for the step of membrane fusion. MbetaCD-treatment of HSV-1 did not reduce viral attachment to the cells nor endocytic uptake of HSV-1 from the cell surface. The pre-fusion form of gB present in the HSV-1 envelope undergoes conformational changes in response to mildly acidic pH. These gB changes occurred independently of envelope cholesterol. Removal of cholesterol compromised virion stability as measured by recovery of infectivity following cycles of freeze-thaw. Taken together, the data suggest that HSV-1 envelope cholesterol is important for viral entry and infectivity due to a critical role in membrane fusion. PMID- 29270155 TI - A Bacterial Surface Display System Expressing Cleavable Capsid Proteins of Human Norovirus: A Novel System to Discover Candidate Receptors. AB - Human noroviruses (HuNoVs) are the dominant cause of food-borne outbreaks of acute gastroenteritis. However, fundamental researches on HuNoVs, such as identification of viral receptors have been limited by the currently immature system to culture HuNoVs and the lack of efficient small animal models. Previously, we demonstrated that the recombinant protruding domain (P domain) of HuNoVs capsid proteins were successfully anchored on the surface of Escherichia coli BL21 cells after the bacteria were transformed with a plasmid expressing HuNoVs P protein fused with bacterial transmembrane anchor protein. The cell surface-displayed P proteins could specifically recognize and bind to histo-blood group antigens (HBGAs, receptors of HuNoVs). In this study, an upgraded bacterial surface displayed system was developed as a new platform to discover candidate receptors of HuNoVs. A thrombin-susceptible "linker" sequence was added between the sequences of bacterial transmembrane anchor protein and P domain of HuNoV (GII.4) capsid protein in a plasmid that displays the functional P proteins on the surface of bacteria. In this new system, the surface-displayed HuNoV P proteins could be released by thrombin treatment. The released P proteins self assembled into small particles, which were visualized by electron microscopy. The bacteria with the surface-displayed P proteins were incubated with pig stomach mucin which contained HBGAs. The bacteria-HuNoV P proteins-HBGAs complex could be collected by low speed centrifugation. The HuNoV P proteins-HBGAs complex was then separated from the recombinant bacterial surface by thrombin treatment. The released viral receptor was confirmed by using the monoclonal antibody against type A HBGA. It demonstrated that the new system was able to capture and easily isolate receptors of HuNoVs. This new strategy provides an alternative, easier approach for isolating unknown receptors/ligands of HuNoVs from different samples including mammalian cell lines, oysters, and fresh produce. PMID- 29270156 TI - Dual Expression of the Salmonella Effector SrfJ in Mammalian Cells and Plants. AB - SrfJ is an effector of the Salmonella pathogenicity island 2-encoded type III secretion system. Salmonella enterica serovar Typhimurium expresses srfJ under two disparate sets of conditions: media with low Mg2+ and low pH, imitating intravacuolar conditions, and media with myo-inositol (MI), a carbohydrate that can be used by Salmonella as sole carbon source. We investigated the molecular basis for this dual regulation. Here, we provide evidence for the existence of two distinct promoters that control the expression of srfJ. A proximal promoter, PsrfJ, responds to intravacuolar signals and is positively regulated by SsrB and PhoP and negatively regulated by RcsB. A second distant promoter, PiolE, is negatively regulated by the MI island repressor IolR. We also explored the in vivo activity of these promoters in different hosts. Interestingly, our results indicate that the proximal promoter is specifically active inside mammalian cells whereas the distant one is expressed upon Salmonella colonization of plants. Importantly, we also found that inappropriate expression of srfJ leads to reduced proliferation inside macrophages whereas lack of srfJ expression increases survival and decreases activation of defense responses in plants. These observations suggest that SrfJ is a relevant factor in the interplay between Salmonella and hosts of different kingdoms. PMID- 29270157 TI - Screening and Detecting Salmonella in Different Food Matrices in Southern Tunisia Using a Combined Enrichment/Real-Time PCR Method: Correlation with Conventional Culture Method. AB - A combined enrichment/ newly developed invA TaqMan(r) real-time PCR (qPCR) method as a screening assay to detect Salmonella spp. in 500 naturally food matrices is evaluated. DNA template for qPCR was extracted from an overnight pre-enriched sample in buffered peptone water using lysis-guanidine isothiocyanate method. Heterologous internal amplification control (IAC) was incorporated during qPCR assays and co-amplified with the invA gene of the target pathogen. InvA qPCR exhibited 100% specificity when testing 94 Salmonella strains (inclusivity) and 32 non-Salmonella strains (exclusivity). The qPCR showed a consistent detection of two copies of the invA gene/PCR reaction, a good intra- and inter-run reproducibility with a good PCR efficiency (89.6%). QPCR was sensitive and showed Salmonella detection at 8.5 * 100 CFU mL-1 of artificially spiked poultry meat BWP solution in less than 40 cycles. When analyzing 500 different food matrices and comparing the results with the ISO 6579:2002 conventional culture method, the sensitivity and specificity were 100 and 76.6%, respectively. QPCR showed Salmonella spp. DNA in raw poultry meat 27/45 (60%), milk 31/93 (33.3%), raw red meat 5/13 (38.5%), and fish 11/46 (23.9%) samples. The prevalence of Salmonella spp. in cakes, dairy, cooked meals, charcuterie products using qPCR was 11/14 (26.8%), 5/22 (22.7%), 32/150 (21.3%), and 5/20 (25%), respectively, compared to 0% as demonstrated by culture. S. Anatum was the most common serovar found associated with red meat compared to S. kentucky isolated from fish and poultry meat. In conclusion, our study is the first to use a combined enrichment/invA qPCR method as a screening assay to detect Salmonella DNA in different types of commercialized food in Southern Tunisia. QPCR results indicate that Salmonella contamination is common in milk and in other types of food samples. PMID- 29270158 TI - Commercial Biocides Induce Transfer of Prophage Phi13 from Human Strains of Staphylococcus aureus to Livestock CC398. AB - Human strains of Staphylococcus aureus commonly carry the bacteriophage PhiSa3 that encodes immune evasion factors. Recently, this prophage has been found in livestock-associated, methicillin resistant S. aureus (MRSA) CC398 strains where it may promote human colonization. Here, we have addressed if exposure to biocidal products induces phage transfer, and find that during co-culture, Phi13 from strain 8325, belonging to PhiSa3 group, is induced and transferred from a human strain to LA-MRSA CC398 when exposed to sub-lethal concentrations of commercial biocides containing hydrogen peroxide. Integration of PhiSa3 in LA MRSA CC398 occurs at multiple positions and the integration site influences the stability of the prophage. We did not observe integration in hlb encoding beta hemolysin that contains the preferred PhiSa3 attachment site in human strains, and we demonstrate that this is due to allelic variation in CC398 strains that disrupts the phage attachment site, but not the expression of beta-hemolysin. Our results show that hydrogen peroxide present in biocidal products stimulate transfer of PhiSa3 from human to LA-MRSA CC398 strains and that in these strains prophage stability depends on the integration site. Knowledge of PhiSa3 transfer and stability between human and livestock strains may lead to new intervention measures directed at reducing human infection by LA-MRSA strains. PMID- 29270160 TI - Antibacterial and Antioxidant Activities of Novel Actinobacteria Strain Isolated from Gulf of Khambhat, Gujarat. AB - Bacterial secondary metabolites possess a wide range of biologically active compounds including antibacterial and antioxidants. In this study, a Gram positive novel marine Actinobacteria was isolated from sea sediment which showed 84% 16S rRNA gene sequence (KT588655) similarity with Streptomyces variabilis (EU841661) and designated as Streptomyces variabilis RD-5. The genus Streptomyces is considered as a promising source of bioactive secondary metabolites. The isolated novel bacterial strain was characterized by antibacterial characteristics and antioxidant activities. The BIOLOG based analysis suggested that S. variabilis RD-5 utilized a wide range of substrates compared to the reference strain. The result is further supported by statistical analysis such as AWCD (average well color development), heat-map and PCA (principal component analysis). The whole cell fatty acid profiling showed the dominance of iso/anteiso branched C15-C17 long chain fatty acids. The identified strain S. variabilis RD-5 exhibited a broad spectrum of antibacterial activities for the Gram-negative bacteria (Escherichia coli NCIM 2065, Shigella boydii NCIM, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas sp. NCIM 2200 and Salmonella enteritidis NCIM), and Gram-positive bacteria (Bacillus subtilis NCIM 2920 and Staphylococcus aureus MTCC 96). Extract of S. variabilis strain RD-5 showed 82.86 and 89% of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and metal chelating activity, respectively, at 5.0 mg/mL. While H2O2 scavenging activity was 74.5% at 0.05 mg/mL concentration. Furthermore, polyketide synthases (PKSs types I and II), an enzyme complex that produces polyketides, the encoding gene(s) detected in the strain RD-5 which may probably involve for the synthesis of antibacterial compound(s). In conclusion, a novel bacterial strain of Actinobacteria, isolated from the unexplored sea sediment of Alang, Gulf of Khambhat (Gujarat), India showed promising antibacterial activities. However, fractionation and further characterization of active compounds from S. variabilis RD-5 are needed for their optimum utilization toward antibacterial purposes. PMID- 29270159 TI - Eugenol Induces Phenotypic Alterations and Increases the Oxidative Burst in Cryptococcus. AB - Eugenol is a phenolic compound and the main constituent of the essential oil of clove India. Although there are reports of some pharmacological effects of eugenol, this study is the first that proposes to evaluate the antifungal effects of this phenol against both Cryptococcus gattii and C. neoformans cells. The effect of eugenol against yeast cells was analyzed for drug susceptibility, alterations in cell diameter, capsule properties, amounts of ergosterol, oxidative burst, and thermodynamics data. Data demonstrated that there is no interaction between eugenol and fluconazole and amphotericin B. Eugenol reduced the cell diameter and the capsule size, increased cell surface/volume, changed positively the cell surface charge of cryptococcal cells. We also verified increased levels of reactive oxygen species without activation of antioxidant enzymes, leading to increased lipid peroxidation, mitochondrial membrane depolarization and reduction of lysosomal integrity in cryptococcal cells. Additionally, the results showed that there is no significant molecular interaction between eugenol and C. neoformans. Morphological alterations, changes of cellular superficial charges and oxidative stress play an important role in antifungal activity of eugenol against C. gattii and C. neoformans that could be used as an auxiliary treatment to cutaneous cryptococcosis. PMID- 29270161 TI - Antimicrobial Potential of Carvacrol against Uropathogenic Escherichia coli via Membrane Disruption, Depolarization, and Reactive Oxygen Species Generation. AB - Bacterial resistance to antibiotics poses a serious threat to cure diseases associated with microbial infection. Among the resistant bacteria, extended spectrum beta-lactamase (ESBL)-producing bacteria are the most concerned one as they encode the enzyme beta-lactamase that confers resistance to most beta-lactam antibiotics. The present study was carried out to determine the antimicrobial potential and the principle mechanism of action of carvacrol against ESBL Escherichia coli isolated from ascitic fluid of a patient having a urinary tract infection. Carvacrol exhibited a minimum inhibitory concentration (MIC) of 450 MUg/ml at which it reduced E. coli cell counts significantly in a time-dependent manner. Carvacrol completely diminished the growth of E. coli after 2 h of incubation at its MIC. Fluorescent imaging displayed the elevated reactive oxygen species level and bacterial membrane depolarization leading to E. coli cell death in presence of carvacrol at its MIC. Furthermore, carvacrol displayed a severe detrimental effect on bacterial membrane disruption and cellular material release. In addition, a significant effect of carvacrol at sub-inhibitory concentration was observed on motility of E. coli cells and invasion of human colon HCT-116 cells in an ex vivo model. Based on the results, we conclude a potential antimicrobial role of carvacrol against ESBL E. coli. PMID- 29270162 TI - Clarification of Taxonomic Status within the Pseudomonas syringae Species Group Based on a Phylogenomic Analysis. AB - The Pseudomonas syringae phylogenetic group comprises 15 recognized bacterial species and more than 60 pathovars. The classification and identification of strains is relevant for practical reasons but also for understanding the epidemiology and ecology of this group of plant pathogenic bacteria. Genome-based taxonomic analyses have been introduced recently to clarify the taxonomy of the whole genus. A set of 139 draft and complete genome sequences of strains belonging to all species of the P. syringae group available in public databases were analyzed, together with the genomes of closely related species used as outgroups. Comparative genomics based on the genome sequences of the species type strains in the group allowed the delineation of phylogenomic species and demonstrated that a high proportion of strains included in the study are misclassified. Furthermore, representatives of at least 7 putative novel species were detected. It was also confirmed that P. ficuserectae, P. meliae, and P. savastanoi are later synonyms of P. amygdali and that "P. coronafaciens" should be revived as a nomenspecies. PMID- 29270163 TI - Role of sfk1 Gene in the Filamentous Fungus Penicillium roqueforti. AB - The sfk1 (suppressor of four kinase) gene has been mainly studied in Saccharomyces cerevisiae, where it was shown to be involved in growth and thermal stress resistance. This gene is widely conserved within the phylum Ascomycota. Despite this, to date sfk1 has not been studied in any filamentous fungus. Previously, we found that the orthologous of sfk1 was differentially expressed in a strain of Penicillium roqueforti with an altered phenotype. In this work, we have performed a functional characterization of this gene by using RNAi-silencing technology. The silencing of sfk1 in P. roqueforti resulted in decreased apical growth and the promotion of conidial germination, but interesting, it had no effect on conidiation. In addition, the attenuation of the sfk1 expression sensitized the fungus to osmotic stress, but not to thermal stress. RNA-mediated gene-silencing of sfk1 also affected cell wall integrity in the fungus. Finally, the silencing of sfk1 depleted the production of the main secondary metabolites of P. roqueforti, namely roquefortine C, andrastin A, and mycophenolic acid. To the best of our knowledge this is the first study of the sfk1 gene in filamentous fungi. PMID- 29270164 TI - Luteolin-7-O-Glucoside Present in Lettuce Extracts Inhibits Hepatitis B Surface Antigen Production and Viral Replication by Human Hepatoma Cells in Vitro. AB - Hepatitis B virus (HBV) infection is endemic in Asia and chronic hepatitis B (CHB) is a major public health issue worldwide. Current treatment strategies for CHB are not satisfactory as they induce a low rate of hepatitis B surface antigen (HBsAg) loss. Extracts were prepared from lettuce hydroponically cultivated in solutions containing glycine or nitrate as nitrogen sources. The lettuce extracts exerted potent anti-HBV effects in HepG2 cell lines in vitro, including significant HBsAg inhibition, HBV replication and transcription inhibition, without exerting cytotoxic effects. When used in combination interferon-alpha 2b (IFNalpha-2b) or lamivudine (3TC), the lettuce extracts synergistically inhibited HBsAg expression and HBV replication. By using differential metabolomics analysis, Luteolin-7-O-glucoside was identified and confirmed as a functional component of the lettuce extracts and exhibited similar anti-HBV activity as the lettuce extracts in vitro. The inhibition rate on HBsAg was up to 77.4%. Moreover, both the lettuce extracts and luteolin-7-O-glucoside functioned as organic antioxidants and, significantly attenuated HBV-induced intracellular reactive oxygen species (ROS) accumulation. Luteolin-7-O-glucoside also normalized ROS-induced mitochondrial membrane potential damage, which suggests luteolin-7-O-glucoside inhibits HBsAg and HBV replication via a mechanism involving the mitochondria. Our findings suggest luteolin-7-O-glucoside may have potential value for clinical application in CHB and may enhance HBsAg and HBV clearance when used as a combination therapy. PMID- 29270165 TI - Enhancing the Resolution of Rumen Microbial Classification from Metatranscriptomic Data Using Kraken and Mothur. AB - The advent of next generation sequencing and bioinformatics tools have greatly advanced our knowledge about the phylogenetic diversity and ecological role of microbes inhabiting the mammalian gut. However, there is a lack of information on the evaluation of these computational tools in the context of the rumen microbiome as these programs have mostly been benchmarked on real or simulated datasets generated from human studies. In this study, we compared the outcomes of two methods, Kraken (mRNA based) and a pipeline developed in-house based on Mothur (16S rRNA based), to assess the taxonomic profiles (bacteria and archaea) of rumen microbial communities using total RNA sequencing of rumen fluid collected from 12 cattle with differing feed conversion ratios (FCR). Both approaches revealed a similar phyla distribution of the most abundant taxa, with Bacteroidetes, Firmicutes, and Proteobacteria accounting for approximately 80% of total bacterial abundance. For bacterial taxa, although 69 genera were commonly detected by both methods, an additional 159 genera were exclusively identified by Kraken. Kraken detected 423 species, while Mothur was not able to assign bacterial sequences to the species level. For archaea, both methods generated similar results only for the abundance of Methanomassiliicoccaceae (previously referred as RCC), which comprised more than 65% of the total archaeal families. Taxon R4-41B was exclusively identified by Mothur in the rumen of feed efficient bulls, whereas Kraken uniquely identified Methanococcaceae in inefficient bulls. Although Kraken enhanced the microbial classification at the species level, identification of bacteria or archaea in the rumen is limited due to a lack of reference genomes for the rumen microbiome. The findings from this study suggest that the development of the combined pipelines using Mothur and Kraken is needed for a more inclusive and representative classification of microbiomes. PMID- 29270166 TI - Disseminated Tuberculosis and Chronic Mucocutaneous Candidiasis in a Patient with a Gain-of-Function Mutation in Signal Transduction and Activator of Transcription 1. AB - In humans, recessive loss-of-function mutations in STAT1 are associated with mycobacterial and viral infections, whereas gain-of-function (GOF) mutations in STAT1 are associated with a type of primary immunodeficiency related mainly, but not exclusively, to chronic mucocutaneous candidiasis (CMC). We studied and established a molecular diagnosis in a pediatric patient with mycobacterial infections, associated with CMC. The patient, daughter of a non-consanguineous mestizo Mexican family, had axillary adenitis secondary to BCG vaccination and was cured with resection of the abscess at 1-year old. At the age of 4 years, she had a supraclavicular abscess with acid-fast-staining bacilli identified in the soft tissue and bone, with clinical signs of disseminated infection and a positive Gene-X-pert test, which responded to anti-mycobacterial drugs. Laboratory tests of the IL-12/interferon gamma (IFN-gamma) circuit showed a higher production of IL-12p70 in the whole blood from the patient compared to healthy controls, when stimulated with BCG and BCG + IFN-gamma. The whole blood of the patient produced 35% less IFN-gamma compared to controls assessed by ELISA and flow cytometry, but IL-17 producing T cells from patient were almost absent in PBMC stimulated with PMA plus ionomycin. Signal transduction and activator of transcription 1 (STAT1) was hyperphosphorylated at tyrosine 701 in response to IFN-gamma and -alpha, as demonstrated by flow cytometry and Western blotting in fresh blood mononuclear cells and in Epstein-Barr virus lymphoblastoid cell lines (EBV-LCLs); phosphorylation of STAT1 in EBV-LCLs from the patient was resistant to inhibition by staurosporine but sensitive to ruxolitinib, a Jak phosphorylation inhibitor. Genomic DNA sequencing showed a de novo mutation in STAT1 in cells from the patient, absent in her parents and brother; a known T385M missense mutation in the DNA-binding domain of the transcription factor was identified, and it is a GOF mutation. Therefore, GOF mutations in STAT1 can induce susceptibility not only to fungal but also to mycobacterial infections by mechanisms to be determined. PMID- 29270168 TI - Adenosine A2A Receptor Deletion Blocks the Beneficial Effects of Lactobacillus reuteri in Regulatory T-Deficient Scurfy Mice. AB - The lack of a functional Foxp3 transcription factor and regulatory T (Treg) cells causes lethal, CD4+ T cell-driven autoimmune diseases in scurfy (SF) mice and humans. Recent studies have shown that adenosine A2A receptor activation limits inflammation and tissue damage, thereby playing an anti-inflammatory role. However, the role of the adenosine A2A receptor in the development of disease in SF mice remains unclear. Using a genetic approach, we found that adenosine A2A receptor deletion in SF mice (SF[Formula: see text]) does not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of pro-inflammatory cytokines seen in the Treg-deficiency state. As shown previously, Lactobacillus reuteri DSM 17938 treatment prolonged survival and reduced multiorgan inflammation in SF mice. In marked contrast, A2A receptor deletion completely blocked these beneficial effects of L. reuteri in SF mice. Altogether, these results suggest that although absence of the adenosine A2A receptor does not affect the development of disease in SF mice, it plays a critical role in the immunomodulation by L. reuteri in Treg-deficiency disease. The adenosine A2A receptor and its activation may have a role in treating other Treg dysfunction-mediated autoimmune diseases. PMID- 29270167 TI - Protective Microbiota: From Localized to Long-Reaching Co-Immunity. AB - Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., "disease tolerance") and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a "co-immunity," where an organism is protected by both its own immune system and components of its microbiota. PMID- 29270170 TI - Commentary: Severe Sequelae to Mold-Related Illness As Demonstrated in Two Finnish Cohorts. PMID- 29270169 TI - Circulating Plasmablasts from Chronically Human Immunodeficiency Virus-Infected Individuals Predominantly Produce Polyreactive/Autoreactive Antibodies. AB - Understanding the B-cell response during chronic human immunodeficiency virus (HIV) infection is essential for eliciting broad and potent neutralizing antibodies (Abs). In this study, we analyzed the plasmablast repertoire of chronically HIV-infected individuals in combination with antiretroviral therapy (ART). Among the obtained 72 recombinant monoclonal antibodies (mAbs), 27.8% weakly bound to HIV gp140 and were non-neutralizing. Remarkably, 56.9% were polyreactive and 55.6% were autoreactive. The prominent feature of being polyreactive/autoreactive is not limited to anti-gp140 Abs. Furthermore, these polyreactive/autoreactive Abs displayed striking cross-reactivity with DWEYS in the N-methyl-d-aspartate receptor (NMDAR), and this binding induced SH-SY5Y cell apoptosis. We also found higher frequencies of VH4-34 utilization and VH replacement in the plasmablast repertoire of chronically HIV-infected individuals, which may contribute to the generation of poly/autoreactive Abs. Taken together, these data demonstrate that circulating plasmablasts in chronically HIV-infected individuals experienced with ART predominantly produce poly/autoreactive Abs with minimal anti-HIV neutralizing capacity and potential cross-reactivity with autoantigens. This may represent another dysfunction of B cells during chronic HIV infection. PMID- 29270171 TI - Placental Histopathology and Clinical Presentation of Severe Congenital Zika Syndrome in a Human Immunodeficiency Virus-Exposed Uninfected Infant. AB - In the large Zika virus (ZIKV) epidemic that occurred in Brazil in 2015, the intrauterine fetal exposure to ZIKV was associated with a significant risk of developing microcephaly and neurological disorders in the infected infants. ZIKV associated disease has since been reported in 24 countries in the Americas. At present, definitive evidence is lacking regarding the intrauterine co-exposure to ZIKV and other viral infections and whether the coinfection impacts the risk of acquiring either infection or disease severity. Here, we provide evidence of intrauterine exposure to both ZIKV and human immunodeficiency virus (HIV) infections, causing congenital Zika syndrome in an HIV-exposed uninfected infant. Clinical, imaging and laboratory examinations of the pregnant woman and the newborn were performed. Histopathology, ZIKV/HIV-specific immunoassays, and ultrastructural evaluation of the placenta were performed. The Zika-asymptomatic, HIV-positive pregnant woman underwent ultrasounds revealing fetal cerebral ventriculomegaly, microcephaly, and brain atrophy. Her baby girl was born small for gestational age and with the neurological sequelae of congenital Zika syndrome. The evaluation of the abnormally large term placenta revealed severe damage to the maternal decidua and chorionic villi, cells positive for ZIKV specific antigens but not for HIV antigens, and intracellular membranous clusters of virus-like particles approximately 25 nm in diameter. The rapid progression and severity of the congenital Zika syndrome may be related to the uncontrolled HIV disease in the mother. The poor inflammatory response observed in the placenta may have reduced the inherent risk of mother-to-child transmission of HIV. PMID- 29270172 TI - Edwardsiella tarda Tunes Tricarboxylic Acid Cycle to Evade Complement-Mediated Killing. AB - Evasion of complement-mediated killing is a common phenotype for many different types of pathogens, but the mechanism is still poorly understood. Most of the clinic isolates of Edwardsiella tarda, an important pathogen infecting both of human and fish, are commonly found serum-resistant. To explore the potential mechanisms, we applied gas chromatography-mass spectrometry (GC-MS)-based metabolomics approaches to profile the metabolomes of E. tarda EIB202 in the presence or absence of serum stress. We found that tricarboxylic acid (TCA) cycle was greatly enhanced in the presence of serum. The quantitative real-time PCR (qRT-PCR) and enzyme activity assays validated this result. Furthermore, exogenous succinate that promotes the TCA cycle increased serum resistance, while TCA cycle inhibitors (bromopyruvate and propanedioic acid) that inhibit TCA cycle, attenuated serum resistance. Moreover, the enhanced TCA cycle increased membrane potential, thus decreased the formation of membrane attack complex at cell surface, resulting serum resistance. These evidences suggested a previously unknown membrane potential-dependent mechanism of serum resistance. Therefore, our findings reveal that pathogen mounts a metabolic trick to cope with the serum complement-mediated killing. PMID- 29270174 TI - Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis. AB - The spleen is an important site for central regulation of immune function by noradrenergic sympathetic nerves, but little is known about this major region of neuroimmune communication in humans. Experimental studies using animal models have established that sympathetic innervation of the spleen is essential for cholinergic anti-inflammatory responses evoked by vagal nerve stimulation, and clinical studies are evaluating this approach for treating inflammatory diseases. Most data on sympathetic nerves in spleen derive from rodent studies, and this work has established that remodeling of sympathetic innervation can occur during inflammation. However, little is known about the effects of sepsis on spleen innervation. Our primary goals were to (i) localize noradrenergic nerves in human spleen by immunohistochemistry for tyrosine hydroxylase (TH), a specific noradrenergic marker, (ii) determine if nerves occur in close apposition to leukocytes, and (iii) determine if splenic sympathetic innervation is altered in patients who died from end stage sepsis. Staining for vesicular acetylcholine transporter (VAChT) was done to screen for cholinergic nerves. Archived paraffin tissue blocks were used. Control samples were obtained from trauma patients or patients who died after hemorrhagic stroke. TH + nerves were associated with arteries and arterioles in all control spleens, occurring in bundles or as nerve fibers. Individual TH + nerve fibers entered the perivascular region where some appeared in close apposition to leukocytes. In marked contrast, spleens from half of the septic patients lacked TH + nerves fibers and the average abundance of TH + nerves for the septic group was only 16% of that for the control group (control: 0.272 +/- 0.060% area, n = 6; sepsis: 0.043 +/- 0.026% area, n = 8; P < 0.005). All spleens lacked cholinergic innervation. Our results provide definitive evidence for the distribution of noradrenergic nerves in normal human spleen and the first evidence for direct sympathetic innervation of leukocytes in human spleen. We also provide the first evidence for marked loss of noradrenergic nerves in patients who died from sepsis. Such nerve loss could impair neuroimmunomodulation and may not be limited to the spleen. PMID- 29270175 TI - Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus. AB - Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host-pathogen interaction studies. PMID- 29270173 TI - Interferon Lambda Genetics and Biology in Regulation of Viral Control. AB - Type III interferons, also known as interferon lambdas (IFNlambdas), are the most recent addition to the IFN family following their discovery in 2003. Initially, IFNlambda was demonstrated to induce expression of interferon-stimulated genes and exert antiviral properties in a similar manner to type I IFNs. However, while IFNlambda has been described to have largely overlapping expression and function with type I IFNs, it has become increasingly clear that type III IFNs also have distinct functions from type I IFNs. In contrast to type I IFNs, whose receptor is ubiquitously expressed, type III IFNs signal and function largely at barrier epithelial surfaces, such as the respiratory and gastrointestinal tracts, as well as the blood-brain barrier. In further support of unique functions for type III IFNs, single nucleotide polymorphisms in IFNL genes in humans are strongly associated with outcomes to viral infection. These biological linkages have also been more directly supported by studies in mice highlighting roles of IFNlambda in promoting antiviral immune responses. In this review, we discuss the current understanding of type III IFNs, and how their functions are similar to, and different from, type I IFN in various immune cell subtypes and viral infections. PMID- 29270176 TI - Goats without Prion Protein Display Enhanced Proinflammatory Pulmonary Signaling and Extracellular Matrix Remodeling upon Systemic Lipopolysaccharide Challenge. AB - A naturally occurring mutation in the PRNP gene of Norwegian dairy goats terminates synthesis of the cellular prion protein (PrPC), rendering homozygous goats (PRNPTer/Ter) devoid of the protein. Although PrPC has been extensively studied, particularly in the central nervous system, the biological role of PrPC remains incompletely understood. Here, we examined whether loss of PrPC affects the initial stage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Acute pulmonary inflammation was induced by intravenous injection of LPS (Escherichia coli O26:B6) in 16 goats (8 PRNPTer/Ter and 8 PRNP+/+). A control group of 10 goats (5 PRNPTer/Ter and 5 PRNP+/+) received sterile saline. Systemic LPS challenge induced sepsis-like clinical signs including tachypnea and respiratory distress. Microscopic examination of lungs revealed multifocal areas with alveolar hemorrhages, edema, neutrophil infiltration, and higher numbers of alveolar macrophages, with no significant differences between PRNP genotypes. A total of 432 (PRNP+/+) and 596 (PRNPTer/Ter) genes were differentially expressed compared with the saline control of the matching genotype. When assigned to gene ontology categories, biological processes involved in remodeling of the extracellular matrix (ECM), were exclusively enriched in PrPC-deficient goats. These genes included a range of collagen-encoding genes, and proteases such as matrix metalloproteinases (MMP1, MMP2, MMP14, ADAM15) and cathepsins. Several proinflammatory upstream regulators (TNF-alpha, interleukin-1beta, IFN-gamma) showed increased activation scores in goats devoid of PrPC. In conclusion, LPS challenge induced marked alterations in the lung tissue transcriptome that corresponded with histopathological and clinical findings in both genotypes. The increased activation of upstream inflammatory regulators and enrichment of ECM components could reflect increased inflammation in the absence of PrPC. Further studies are required to elucidate whether these alterations may affect the later reparative phase of ALI. PMID- 29270178 TI - Editorial: NK Cells in Human Diseases: Friends or Foes? PMID- 29270177 TI - Role of Incretin Axis in Inflammatory Bowel Disease. AB - The inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract and involve a complicated reciprocity of environmental, genetic, and immunologic factors. Despite substantial advances in the foundational understanding of the immunological pathogenesis of IBD, the detailed mechanism of the pathological progression in IBD remains unknown. In addition to Th1/Th2 cells, whose role in IBD has been previously well defined, recent evidence indicates that Th17 cells and Tregs also play a crucial role in the development of IBD. Diets which contain excess sugars, salt, and fat may also be important actors in the pathogenesis of IBD, which may be the cause of high IBD incidence in western developed and industrialized countries. Up until now, the reason for the variance in prevalence of IBD between developed and developing countries has been unknown. This is partly due to the increasing popularity of western diets in developing countries, which makes the data harder to interpret. The enterocrinins glucagon-like peptides (GLPs), including GLP-1 and GLP-2, exhibit notable benefits on lipid metabolism, atherosclerosis formation, plasma glucose levels, and maintenance of gastric mucosa integrity. In addition to the regulation of nutrient metabolism, the emerging role of GLPs and their degrading enzyme dipeptidyl peptidase-4 (DPP-4) in gastrointestinal diseases has gained increasing attention. Therefore, here we review the function of the DPP-4/GLP axis in IBD. PMID- 29270180 TI - N-Terminus-Mediated Degradation of ACS7 Is Negatively Regulated by Senescence Signaling to Allow Optimal Ethylene Production during Leaf Development in Arabidopsis. AB - Senescence is the final phase of leaf development, characterized by key processes by which resources trapped in deteriorating leaves are degraded and recycled to sustain the growth of newly formed organs. As the gaseous hormone ethylene exerts a profound effect on the progression of leaf senescence, both the optimal timing and amount of its biosynthesis are essential for controlled leaf development. The rate-limiting enzyme that controls ethylene synthesis in higher plants is ACC synthase (ACS). In this study, we evaluated the production of ethylene and revealed an up-regulation of ACS7 during leaf senescence in Arabidopsis. We further showed that the promoter activity of ACS7 was maintained at a relatively high level throughout the whole rosette development process. However, the accumulation level of ACS7 protein was extremely low in the light-grown young seedlings, and it was gradually restored as plants aging. We previously demonstrated that degradation of ACS7 is regulated by its first 14 N-terminal residues, here we compared the phenotypes of transgenic Arabidopsis overexpressing a truncated ACS7 lacking the 14 residues with transgenic plants overexpressing the full-length protein. Results showed that seedlings overexpressing the truncated ACS7 exhibited a senescence phenotype much earlier than their counterparts overexpressing the full-length gene. Fusion of the 14 residues to SSPP, a PP2C-type senescence-suppressed protein phosphatase, effectively rescued the SSPP-induced suppression of rosette growth and development but had no effect on the delayed senescence. This observation further supported that N-terminus-mediated degradation of ACS7 is negatively regulated by leaf senescence signaling. All results of this study therefore suggest that ACS7 is one of the major contributors to the synthesis of 'senescence ethylene'. And more importantly, the N-terminal 14 residue-mediated degradation of this protein is highly regulated by senescence signaling to enable plants to produce the appropriate levels of ethylene required. PMID- 29270179 TI - Aging, Obesity, and Inflammatory Age-Related Diseases. AB - The increase in the prevalence of obesity represents a worldwide phenomenon in all age groups and is pathologically and genetically correlated with several metabolic and cardiovascular diseases, representing the most frequent age-related diseases. Obesity superimposed on aging drastically increases chronic low-grade inflammation (inflammaging), which is an important link between obesity, insulin resistance, and age-associated diseases. Immune cells of both the innate and the adaptive immune systems infiltrate the adipose tissue (AT) and during obesity induce inflammatory responses associated with metabolic switches and changes in phenotypes and function of immune cell subsets. Obesity poses new health problems especially when it occurs in the context of other diseases, many of them frequently affect elderly subjects. An emerging problem is the decreased proportion of patients with obesity achieving clinical response to therapy. In this review, we will discuss the reciprocal influences of immune cell and AT inflammation in aging and age-associated diseases and the complex relationship of nutrient and energy-sensing homeostatic checkpoints, which contribute to shape the phenotype of the AT. We will specifically examine type-2 diabetes, rheumatoid arthritis, osteoarthritis, cognitive impairment, and dementia, where obesity plays a significant role, also in shaping some clinical aspects. PMID- 29270181 TI - Biostimulant Effects of Seed-Applied Sedaxane Fungicide: Morphological and Physiological Changes in Maize Seedlings. AB - Most crops are routinely protected against seed-born and soil-borne fungal pathogens through seed-applied fungicides. The recently released succinate dehydrogenase inhibitor (SDHI), sedaxane(r), is a broad-spectrum fungicide, used particularly to control Rhizoctonia spp., but also has documented growth enhancement effects on wheat. This study investigates the potential biostimulant effects of sedaxane and related physiological changes in disease-free maize seedlings (3-leaf stage) at increasing application doses (25, 75 and 150 MUg a.i. seed-1) under controlled sterilized conditions. We show sedaxane to have significant auxin-like and gibberellin-like effects, which effect marked morphological and physiological changes according to an approximate saturation dose-response model. Maximum benefits were attained at the intermediate dose, which significantly increased root length (+60%), area (+45%) and forks (+51%), and reduced root diameter as compared to untreated controls. Sedaxane enhanced leaf and root glutamine synthetase (GS) activity resulting in greater protein accumulation, particularly in the above-ground compartment, while glutamate synthase (GOGAT) activity remained almost unchanged. Sedaxane also improved leaf phenylalanine ammonia-lyase (PAL) activity, which may be responsible for the increase in shoot antioxidant activity (phenolic acids), mainly represented by p coumaric and caffeic acids. We conclude that, in addition to its protective effect, sedaxane can facilitate root establishment and intensify nitrogen and phenylpropanoid metabolism in young maize plants, and may be beneficial in overcoming biotic and abiotic stresses in early growth stages. PMID- 29270182 TI - Genome-Wide Identification of Chalcone Reductase Gene Family in Soybean: Insight into Root-Specific GmCHRs and Phytophthora sojae Resistance. AB - Soybean (Glycine max [L.] Merr) is one of the main grain legumes worldwide. Soybean farmers lose billions of dollars' worth of yield annually due to root and stem rot disease caused by the oomycete Phytophthora sojae. Many strategies have been developed to combat the disease, however, these methods have proven ineffective in the long term. A more cost effective and durable approach is to select a trait naturally found in soybean that can increase resistance. One such trait is the increased production of phytoalexin glyceollins in soybean. Glyceollins are isoflavonoids, synthesized via the legume-specific branch of general phenylpropanoid pathway. The first key enzyme exclusively involved in glyceollin synthesis is chalcone reductase (CHR) which coacts with chalcone synthase for the production of isoliquiritigenin, the precursor for glyceollin biosynthesis. Here we report the identification of 14 putative CHR genes in soybean where 11 of them are predicted to be functional. Our results show that GmCHRs display tissue-specific gene expression, and that only root-specific GmCHRs are induced upon P. sojae infection. Among 4 root-specific GmCHRs, GmCHR2A is located near a QTL that is linked to P. sojae resistance suggesting GmCHR2A as a novel locus for partial resistance that can be utilized for resistance breeding. PMID- 29270185 TI - A Novel AP2/ERF Transcription Factor CR1 Regulates the Accumulation of Vindoline and Serpentine in Catharanthus roseus. AB - As one type of the most important alkaloids in the world, terpenoid indole alkaloids (TIAs) show a wide range of pharmaceutical activities that are beneficial for clinical treatments. Catharanthus roseus produces approximately 130 identified TIAs and is considered to be a model plant to study TIA biosynthesis. In order to increase the production of high medical value metabolites whose yields are extremely low in C. roseus, genetic engineering combined with transcriptional regulation has been applied in recent years. By using bioinformatics which is based on RNA sequencing (RNA-seq) data from methyl jasmonate (MeJA)-treated C. roseus as well as phylogenetic analysis, the present work aims to screen candidate genes that may be involved in the regulation of TIA biosynthesis, resulting in a novel AP2/ERF transcription factor, CR1 (Catharanthus roseus 1). Subsequently, virus-induced gene silencing (VIGS) of CR1 was carried out to identify the involvement of CR1 in the accumulations of several TIAs and quantitative real-time PCR (qRT-PCR) was then applied to detect the expression levels of 7 genes in the related biosynthetic pathway in silenced plants. The results show that all the 7 genes were upregulated in CR1-silenced plants. Furthermore, metabolite analyses indicate that silencing CR1 could increase the accumulations of vindoline and serpentine in C. roseus. These results suggest a novel negative regulator which may be involved in the TIAs biosynthetic pathway. PMID- 29270184 TI - microRNAs and Their Targets in Apple (Malus domestica cv. "Fuji") Involved in Response to Infection of Pathogen Valsa mali. AB - miRNAs are important regulators involving in plant-pathogen interactions. However, their roles in apple tree response to Valsa canker pathogen (Valsa mali, Vm) infection were poorly understood. In this study, we constructed two miRNA libraries using the twig bark tissues of apple tree (Malus domestica Borkh. cv. "Fuji") inoculated with Vm (IVm) and PDA medium (control, BMd). Among all detected miRNAs, 23 miRNAs were specifically isolated from BMd and 39 miRNAs were specifically isolated from IVm. Meanwhile, the expression of 294 miRNAs decreased; and another 172 miRNAs showed an increased expression trend in IVm compared with that in BMd. Furthermore, two degradome sequencing libraries were also constructed to identify the target genes of these miRNAs. In total, 353 differentially expressed miRNAs between IVm and BMd were detected to be able to target 1,077 unigenes with 2,251 cleavage sites. Based on GO and KEGG analysis, these genes were found to be mainly related to transcription regulation and signal transduction. In addition, we selected 17 miRNAs and 22 corresponding target genes to screen the expression profiles when apple twigs were infected by Vm. The expression trends of most miRNAs/target genes were consist with the results of deep sequencing. Many of them may involve in the apple twig-Vm interaction by inducing/reducing their expression. What's more, miRNAs and their target genes regulate the apple twig-Vm interaction by forming many complicated regulation networks rather than one to one model. It is worth that a conserved miRNAs mdm-miR482b, which was down regulated in IVm compared with BMd, has 14 potential target genes, most of which are disease resistance related genes. This indicates that mdm-miR482b may play important roles in apple twig response to Vm. More important, the feedback regulation of sRNA pathway in apple twig is also very complex, and play critical role in the interaction between apple twig and Vm based on the results of expression analysis. In all, the results will provide insights into the crucial functions of miRNAs in the woody plant, apple tree-Vm interaction. PMID- 29270183 TI - Comparative Histological and Transcriptional Analysis of Maize Kernels Infected with Aspergillus flavus and Fusarium verticillioides. AB - Aspergillus flavus and Fusarium verticillioides infect maize kernels and contaminate them with the mycotoxins aflatoxin, and fumonisin, respectively. Genetic resistance in maize to these fungi and to mycotoxin contamination has been difficult to achieve due to lack of identified resistance genes. The objective of this study was to identify new candidate resistance genes by characterizing their temporal expression in response to infection and comparing expression of these genes with genes known to be associated with plant defense. Fungal colonization and transcriptional changes in kernels inoculated with each fungus were monitored at 4, 12, 24, 48, and 72 h post inoculation (hpi). Maize kernels responded by differential gene expression to each fungus within 4 hpi, before the fungi could be observed visually, but more genes were differentially expressed between 48 and 72 hpi, when fungal colonization was more extensive. Two way hierarchal clustering analysis grouped the temporal expression profiles of the 5,863 differentially expressed maize genes over all time points into 12 clusters. Many clusters were enriched for genes previously associated with defense responses to either A. flavus or F. verticillioides. Also within these expression clusters were genes that lacked either annotation or assignment to functional categories. This study provided a comprehensive analysis of gene expression of each A. flavus and F. verticillioides during infection of maize kernels, it identified genes expressed early and late in the infection process, and it provided a grouping of genes of unknown function with similarly expressed defense related genes that could inform selection of new genes as targets in breeding strategies. PMID- 29270186 TI - Variations of Histone Modification Patterns: Contributions of Inter-plant Variability and Technical Factors. AB - Inter-individual variability of conspecific plants is governed by differences in their genetically determined growth and development traits, environmental conditions, and adaptive responses under epigenetic control involving histone post-translational modifications. The apparent variability in histone modifications among plants might be increased by technical variation introduced in sample processing during epigenetic analyses. Thus, to detect true variations in epigenetic histone patterns associated with given factors, the basal variability among samples that is not associated with them must be estimated. To improve knowledge of relative contribution of biological and technical variation, mass spectrometry was used to examine histone modification patterns (acetylation and methylation) among Arabidopsis thaliana plants of ecotypes Columbia 0 (Col-0) and Wassilewskija (Ws) homogenized by two techniques (grinding in a cryomill or with a mortar and pestle). We found little difference in histone modification profiles between the ecotypes. However, in comparison of the biological and technical components of variability, we found consistently higher inter individual variability in histone mark levels among Ws plants than among Col-0 plants (grown from seeds collected either from single plants or sets of plants). Thus, more replicates of Ws would be needed for rigorous analysis of epigenetic marks. Regarding technical variability, the cryomill introduced detectably more heterogeneity in the data than the mortar and pestle treatment, but mass spectrometric analyses had minor apparent effects. Our study shows that it is essential to consider inter-sample variance and estimate suitable numbers of biological replicates for statistical analysis for each studied organism when investigating changes in epigenetic histone profiles. PMID- 29270188 TI - Elongated Hypocotyl 5-Homolog (HYH) Negatively Regulates Expression of the Ambient Temperature-Responsive MicroRNA Gene MIR169. AB - Arabidopsis microRNA169 (miR169) is an ambient temperature-responsive microRNA that plays an important role in stress responses and the floral transition. However, the transcription factors that regulate the expression of MIR169 have remained unknown. In this study, we show that Elongated Hypocotyl 5-Homolog (HYH) directly binds to the promoter of MIR169a and negatively regulates its expression. Absolute quantification identified MIR169a as the major locus producing miR169. GUS reporter assays revealed that the deletion of a 498-bp fragment (-1,505 to -1,007, relative to the major transcriptional start site) of MIR169a abolished its ambient temperature-responsive expression. DNA-affinity chromatography followed by liquid chromatography-mass spectrometry analysis identified transcription factor HYH as a trans-acting factor that binds to the 498-bp promoter fragment of pri-miR169a. Electrophoretic mobility shift assays and chromatin immunoprecipitation-quantitative PCR demonstrated that the HYH.2 protein, a predominant isoform of HYH, directly associated with a G-box-like motif in the 498-bp fragment of pri-miR169a. Higher enrichment of HYH.2 protein on the promoter region of MIR169a was seen at 23 degrees C, consistent with the presence of more HYH.2 protein in the cell at the temperature. Transcript levels of pri-miR169a increased in hyh mutants and decreased in transgenic plants overexpressing HYH. Consistent with the negative regulation of MIR169a by HYH, the diurnal levels of HYH mRNA and pri-miR169a showed opposite patterns. Taken together, our results suggest that HYH is a transcription factor that binds to a G-box-like motif in the MIR169a promoter and negatively regulates ambient temperature-responsive expression of MIR169a at higher temperatures in Arabidopsis. PMID- 29270187 TI - Characterization of UGT716A1 as a Multi-substrate UDP:Flavonoid Glucosyltransferase Gene in Ginkgo biloba. AB - Ginkgo biloba L., a "living fossil" and medicinal plant, is a well-known rich source of bioactive flavonoids. The molecular mechanism underlying the biosynthesis of flavonoid glucosides, the predominant flavonoids in G. biloba, remains unclear. To better understand flavonoid glucosylation in G. biloba, we generated a transcriptomic dataset of G. biloba leaf tissue by high-throughput RNA sequencing. We identified 25 putative UDP-glycosyltransferase (UGT) unigenes that are potentially involved in the flavonoid glycosylation. Among them, we successfully isolated and expressed eight UGT genes in Escherichia coli, and found that recombinant UGT716A1 protein was active toward broad range of flavonoid/phenylpropanoid substrates. In particular, we discovered the first recombinant UGT protein, UGT716A1 from G. biloba, possessing unique activity toward flavanol gallates that have been extensively documented to have significant bioactivity relating to human health. UGT716A1 expression level paralleled the flavonoid distribution pattern in G. biloba. Ectopic over expression of UGT716A1 in Arabidopsis thaliana led to increased accumulation of several flavonol glucosides. Identification and comparison of the in vitro enzymatic activity of UGT716A1 homologs revealed a UGT from the primitive land species Physcomitrella patens also showed broader substrate spectrum than those from higher plants A. thaliana, Vitis vinifera, and Medicago truncatula. The characterization of UGT716A1 from G. biloba bridges a gap in the evolutionary history of UGTs in gymnosperms. We also discuss the implication of UGT716A1 for biosynthesis, evolution, and bioengineering of diverse glucosylated flavonoids. PMID- 29270189 TI - High Temperature-Induced Expression of Rice alpha-Amylases in Developing Endosperm Produces Chalky Grains. AB - Global warming impairs grain filling in rice and reduces starch accumulation in the endosperm, leading to chalky-appearing grains, which damages their market value. We found previously that high temperature-induced expression of starch lytic alpha-amylases during ripening is crucial for grain chalkiness. Because the rice genome carries at least eight functional alpha-amylase genes, identification of the alpha-amylase(s) that contribute most strongly to the production of chalky grains could accelerate efficient breeding. To identify alpha-amylase genes responsible for the production of chalky grains, we characterized the histological expression pattern of eight alpha-amylase genes and the influences of their overexpression on grain appearance and carbohydrate components through a series of experiments with transgenic rice plants. The promoter activity of most alpha-amylase genes was elevated to various extents at high temperature. Among them, the expression of Amy1A and Amy3C was induced in the internal, especially basal to dorsal, region of developing endosperm, whereas that of Amy3D was confined near the ventral aleurone. These regions coincided with the site of occurrence of chalkiness, which was in clear contrast to conventionally known expression patterns of the enzyme in the scutellum and aleurone during seed germination. Furthermore, overexpression of alpha-amylase genes, except for Amy3E, in developing endosperm produced various degrees of chalky grains without heat exposure, whereas that of Amy3E yielded normal translucent grains, as was the case in the vector control, even though Amy3E-overexpressing grains contained enhanced alpha-amylase activities. The weight of the chalky grains was decreased due to reduced amounts of starch, and microscopic observation of the chalky part of these grains revealed that their endosperm consisted of loosely packed round starch granules that had numerous pits on their surface, confirming the hydrolysis of the starch reserve by alpha-amylases. Moreover, the chalky grains contained increased amounts of soluble sugars including maltooligosaccharides at the expense of starch. The integrated analyses proposed that expression of Amy1A, Amy3C, and Amy3D at the specific regions of the developing endosperm could generate the chalkiness. This finding provides the fundamental knowledge to narrow down the targets for the development of high temperature-tolerant premium rice. PMID- 29270190 TI - AT2G21280 Only Has a Minor Role in Chloroplast Division. AB - Chloroplast division is an important cellular process, which involves complicated coordination of multiple proteins. In mutant plants with chloroplast division defects, chloroplasts are usually found to be with enlarged size and reduced numbers. Previous studies have shown that AT2G21280, which was named as GC1 (GIANT CHLOROPLAST 1) or AtSulA, was an important chloroplast division gene, because either reduced expression or overexpression of the gene could result in an apparent chloroplast division phenotype (Maple et al., 2004; Raynaud et al., 2004). To further study the function of AT2G21280, we obtained mutants of this gene by CRISPR/Cas9-mediated gene editing and T-DNA insertion. Most of the chloroplasts in the mutants were similar to that of the wild type in size. Larger chloroplasts were rarely found in the mutants. Moreover, we obtained transgenic plants overexpressing AT2G21280, analyzed the chloroplast division phenotype, and found there were no significant differences between the wild type and various overexpressing plants. Phylogenetic analysis clearly indicated that AT2G21280 was not in the family of bacterial cell division protein SulA. Instead, BLAST analysis suggested that AT2G21280 is an NAD dependent epimerase/dehydratase family enzyme. Since the main results of the previous studies that AT2G21280 is an important chloroplast division gene cannot be confirmed by our intensive study and large chloroplasts are rarely found in the mutants, we think the previous names of AT2G21280 are inappropriate. Localization study results showed that AT2G21280 is a peripheral protein of the inner envelope of chloroplasts in the stroma side. AT2G21280 is well conserved in plants and cyanobacteria, suggesting its function is important, which can be revealed in the future study. PMID- 29270191 TI - Tissue-Specific Expression of DNA Methyltransferases Involved in Early-Life Nutritional Stress of Chicken, Gallus gallus. AB - DNA methylation was reported as a possible stress-adaptation mechanism involved in the transcriptional regulation of stress responsive genes. Limited data are available on effects of psychological stress and early-life nutritional stress on DNA methylation regulators [DNMTs: DNA (cytosine-5)-methyltransferase 1 (DNMT1), DNMT1 associated protein (DMAP1), DNMT 3 alpha (DNMT3A) and beta (DNMT3B)] in avian species. The objectives of this study were to: (1) investigate changes in expression of DNMT1, DMAP1, DNMT3A, and DNMT3B following acute (AS) or chronic immobilization stress (CS); (2) test immediate effect of early-life nutritional stress [food deprivation (FD) for 12 h (12hFD) or 36 h (36hFD) at the post hatching period] on expression of DNA methylation regulators and glucocorticoid receptor (GR), and the long-term effect of early-life nutritional stress at 6 weeks of age. Expression of DNMTs and plasma corticosterone (CORT) concentration decreased by CS compared to AS (p < 0.05), indicating differential roles of DNA methylation regulators in the stress response. Plasma CORT at 12hFD and 36hFD birds increased compared to control birds (12hF and 36hF), but there were no significant differences in plasma CORT of 12hFD and 36hFD birds at 6 weeks of age compared to 6 week controls. DNMT1, DMAP1, and DNMT3B expression in the anterior pituitary increased by 12hFD, but decreased at 36hFD compared to their controls (P < 0.05). In liver, DNMT1, DNMT3A, and DNMT3B expression decreased by 12hFD, however, no significant changes occurred at 36hFD. Expression of DMAP1, DNMT3A, and DNMT3B in anterior pituitary and DMAP1 and DNMT3A expression in liver at 6 weeks of age were higher in 36hFD stressed birds compared to controls as well as 12hFD stressed birds. Hepatic GR expression decreased by 12hFD and increased by 36hFD (p < 0.05). Expression patterns of GR in the liver of FD stress-induced birds persisted until 6 weeks of age, suggesting the possible lifelong involvement of liver GR in early-life nutritional stress response of birds. Taken together, results suggest that DNA methylation regulator genes are tissue specifically responsive to acute and chronic stress, and hepatic GR may play a critical role in regulating the early-life nutritional stress response of birds. In addition, the downregulation of DNMT1 and DMAP1 may be one of the adaptive mechanisms to chronic early-life nutritional stress via passive demethylation. PMID- 29270193 TI - Developmental Coordination Disorder in a Patient with Mental Disability and a Mild Phenotype Carrying Terminal 6q26-qter Deletion. AB - Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with variable phenotype spectrum. Although intellectual disability, facial dysmorphism, seizures and brain abnormalities are typical features of this syndrome, genotype-phenotype correlation needs to be better understood. We report the case of a 6-year-old Caucasian boy with a clinical diagnosis of intellectual disability, delayed language development and dyspraxia who carries an approximately 8 Mb de novo heterozygous microdeletion in the 6q26-q27 locus identified by karyotype and defined by high-resolution SNP-array analysis. This patient has no significant structural brain or other organ malformation, and he shows a very mild phenotype compared to similar 6q26-qter deletion. The patient phenotype also suggests that a dyspraxia susceptibility gene is located among the deleted genes. PMID- 29270192 TI - Adaptive Evolution of Energy Metabolism-Related Genes in Hypoxia-Tolerant Mammals. AB - Animals that are able to sustain life under hypoxic conditions have long captured the imagination of biologists and medical practitioners alike. Although the associated morphological modifications have been extensively described, the mechanisms underlying the evolution of hypoxia tolerance are not well understood. To provide such insights, we investigated genes in four major energy metabolism pathways, and provide evidence of distinct evolutionary paths to mammalian hypoxia-tolerance. Positive selection of genes in the oxidative phosphorylation pathway mainly occurred in terrestrial hypoxia-tolerant species; possible adaptations to chronically hypoxic environments. The strongest candidate for positive selection along cetacean lineages was the citrate cycle signaling pathway, suggestive of enhanced aerobic metabolism during and after a dive. Six genes with cetacean-specific amino acid changes are rate-limiting enzymes involved in the gluconeogenesis pathway, which would be expected to enhance the lactate removal after diving. Intriguingly, 38 parallel amino acid substitutions in 29 genes were observed between hypoxia-tolerant mammals. Of these, 76.3% were radical amino acid changes, suggesting that convergent molecular evolution drives the adaptation to hypoxic stress and similar phenotypic changes. This study provides further insights into life under low oxygen conditions and the evolutionary trajectories of hypoxia-tolerant species. PMID- 29270194 TI - Toward Model Building for Visual Aesthetic Perception. AB - Several models of visual aesthetic perception have been proposed in recent years. Such models have drawn on investigations into the neural underpinnings of visual aesthetics, utilizing neurophysiological techniques and brain imaging techniques including functional magnetic resonance imaging, magnetoencephalography, and electroencephalography. The neural mechanisms underlying the aesthetic perception of the visual arts have been explained from the perspectives of neuropsychology, brain and cognitive science, informatics, and statistics. Although corresponding models have been constructed, the majority of these models contain elements that are difficult to be simulated or quantified using simple mathematical functions. In this review, we discuss the hypotheses, conceptions, and structures of six typical models for human aesthetic appreciation in the visual domain: the neuropsychological, information processing, mirror, quartet, and two hierarchical feed-forward layered models. Additionally, the neural foundation of aesthetic perception, appreciation, or judgement for each model is summarized. The development of a unified framework for the neurobiological mechanisms underlying the aesthetic perception of visual art and the validation of this framework via mathematical simulation is an interesting challenge in neuroaesthetics research. This review aims to provide information regarding the most promising proposals for bridging the gap between visual information processing and brain activity involved in aesthetic appreciation. PMID- 29270195 TI - Ensembling Variable Selectors by Stability Selection for the Cox Model. AB - As a pivotal tool to build interpretive models, variable selection plays an increasingly important role in high-dimensional data analysis. In recent years, variable selection ensembles (VSEs) have gained much interest due to their many advantages. Stability selection (Meinshausen and Buhlmann, 2010), a VSE technique based on subsampling in combination with a base algorithm like lasso, is an effective method to control false discovery rate (FDR) and to improve selection accuracy in linear regression models. By adopting lasso as a base learner, we attempt to extend stability selection to handle variable selection problems in a Cox model. According to our experience, it is crucial to set the regularization region Lambda in lasso and the parameter lambdamin properly so that stability selection can work well. To the best of our knowledge, however, there is no literature addressing this problem in an explicit way. Therefore, we first provide a detailed procedure to specify Lambda and lambdamin. Then, some simulated and real-world data with various censoring rates are used to examine how well stability selection performs. It is also compared with several other variable selection approaches. Experimental results demonstrate that it achieves better or competitive performance in comparison with several other popular techniques. PMID- 29270196 TI - Underwater Inherent Optical Properties Estimation Using a Depth Aided Deep Neural Network. AB - Underwater inherent optical properties (IOPs) are the fundamental clues to many research fields such as marine optics, marine biology, and underwater vision. Currently, beam transmissometers and optical sensors are considered as the ideal IOPs measuring methods. But these methods are inflexible and expensive to be deployed. To overcome this problem, we aim to develop a novel measuring method using only a single underwater image with the help of deep artificial neural network. The power of artificial neural network has been proved in image processing and computer vision fields with deep learning technology. However, image-based IOPs estimation is a quite different and challenging task. Unlike the traditional applications such as image classification or localization, IOP estimation looks at the transparency of the water between the camera and the target objects to estimate multiple optical properties simultaneously. In this paper, we propose a novel Depth Aided (DA) deep neural network structure for IOPs estimation based on a single RGB image that is even noisy. The imaging depth information is considered as an aided input to help our model make better decision. PMID- 29270197 TI - A Hybrid Semi-Supervised Anomaly Detection Model for High-Dimensional Data. AB - Anomaly detection, which aims to identify observations that deviate from a nominal sample, is a challenging task for high-dimensional data. Traditional distance-based anomaly detection methods compute the neighborhood distance between each observation and suffer from the curse of dimensionality in high dimensional space; for example, the distances between any pair of samples are similar and each sample may perform like an outlier. In this paper, we propose a hybrid semi-supervised anomaly detection model for high-dimensional data that consists of two parts: a deep autoencoder (DAE) and an ensemble k-nearest neighbor graphs- (K-NNG-) based anomaly detector. Benefiting from the ability of nonlinear mapping, the DAE is first trained to learn the intrinsic features of a high-dimensional dataset to represent the high-dimensional data in a more compact subspace. Several nonparametric KNN-based anomaly detectors are then built from different subsets that are randomly sampled from the whole dataset. The final prediction is made by all the anomaly detectors. The performance of the proposed method is evaluated on several real-life datasets, and the results confirm that the proposed hybrid model improves the detection accuracy and reduces the computational complexity. PMID- 29270198 TI - Objective Endoscopic Analysis with Linked Color Imaging regarding Gastric Mucosal Atrophy: A Pilot Study. AB - Objectives: We aimed to determine whether linked color imaging (LCI), a new image enhanced endoscopy that enhances subtle differences in mucosal colors, can distinguish the border of endoscopic mucosal atrophy. Methods: This study included 30 patients with atrophic gastritis. In endoscopy, we continuously took images in the same composition with both LCI and white light imaging (WLI). In each image, the color values of atrophic and nonatrophic mucosae were quantified using the International Commission on Illumination 1976 (L*, a*, b*) color space. Color differences at the atrophic border, defined as Euclidean distances of color values between the atrophic and nonatrophic mucosae, were compared between WLI and LCI for the overall cohort and separately for patients with Helicobacter pylori infection status. Results: We found that the color difference became significantly higher with LCI than with WLI in the overall samples of 90 points in 30 patients. LCI was 14.79 +/- 6.68, and WLI was 11.06 +/- 5.44 (P < 0.00001). LCI was also more effective in both of the Helicobacter pylori-infected group (P = 0.00003) and the Helicobacter pylori-eradicated group (P = 0.00002). Conclusions: LCI allows clear endoscopic visualization of the atrophic border under various conditions of gastritis, regardless of Helicobacter pylori infection status. PMID- 29270199 TI - CD60b: Enriching Neural Stem/Progenitor Cells from Rat Development into Adulthood. AB - CD60b antigens are highly expressed during development in the rat nervous system, while in the adult their expression is restricted to a few regions, including the subventricular zone (SVZ) around the lateral ventricles-a neurogenic niche in the adult brain. For this reason, we investigated whether the expression of C60b is associated with neural stem/progenitor cells in the SVZ, from development into adulthood. We performed in vitro and in vivo analyses of CD60b expression at different stages and identified the presence of these antigens in neural stem/progenitor cells. We also observed that CD60b could be used to purify and enrich a population of neurosphere-forming cells from the developing and adult brain. We showed that CD60b antigens (mainly corresponding to ganglioside 9-O acetyl GD3, a well-known molecule expressed during central nervous system development and mainly associated with neuronal migration) are also present in less mature cells and could be used to identify and isolate neural stem/progenitor cells during development and in the adult brain. A better understanding of molecules associated with neurogenesis may contribute not only to improve the knowledge about the physiology of the mammalian central nervous system, but also to find new treatments for regenerating tissue after disease or brain injury. PMID- 29270200 TI - Plasma Rich in Growth Factors Induces Cell Proliferation, Migration, Differentiation, and Cell Survival of Adipose-Derived Stem Cells. AB - Adipose-derived stem cells (ASCs) are a promising therapeutic alternative for tissue repair in various clinical applications. However, restrictive cell survival, differential tissue integration, and undirected cell differentiation after transplantation in a hostile microenvironment are complications that require refinement. Plasma rich in growth factors (PRGF) from platelet-rich plasma favors human and canine ASC survival, proliferation, and delaying human ASC senescence and autophagocytosis in comparison with serum-containing cultures. In addition, canine and human-derived ASCs efficiently differentiate into osteocytes, adipocytes, or chondrocytes in the presence of PRGF. PRGF treatment induces phosphorylation of AKT preventing ASC death induced by lethal concentrations of hydrogen peroxide. Indeed, AKT inhibition abolished the PRGF apoptosis prevention in ASC exposed to 100 MUM of hydrogen peroxide. Here, we show that canine ASCs respond to PRGF stimulus similarly to the human cells regarding cell survival and differentiation postulating the use of dogs as a suitable translational model. Overall, PRGF would be employed as a serum substitute for mesenchymal stem cell amplification to improve cell differentiation and as a preconditioning agent to prevent oxidative cell death. PMID- 29270201 TI - The role of bone marrow mononuclear cell-conditioned medium in the proliferation and migration of human dermal fibroblasts. AB - Background: Several recent studies have demonstrated the great potential of bone marrow cells in regenerative medicine, not only for their ability to differentiate to match a damaged cell type, but also because they synthesize and release various growth factors and cytokines.We examined the effect of bone marrow cell-conditioned medium in the healing process, especially in terms of fibroblast proliferation and migration. Methods: These in vitro studies consisted of co-culture (without direct contact) of dermal fibroblasts with mononuclear bone marrow cells and the use of conditioned medium obtained from these cultures in a scratch wound model. Results: Mononuclear cells were found to increase the proliferation of fibroblasts, and the conditioned medium showed a stimulatory effect on the migration of fibroblasts. Conclusion: When considered together with the observed increase in growth factor levels in conditioned medium, it appears that these cells act through a paracrine mechanism. PMID- 29270202 TI - Knockdown of Rab21 inhibits proliferation and induces apoptosis in human glioma cells. AB - Background: Gliomas are commonly malignant tumors that arise in the human central nervous system and have a low overall five-year survival rate. Previous studies reported that several members of Rab GTPase family are involved in the development of glioma, and abnormal expression of Rab small GTPases is known to cause aberrant tumor cell behavior. In this study, we characterized the roles of Rab21 (Rab GTPase 21), a member of Rab GTPase family, in glioma cells. Methods: The study involved downregulation of Rab21 in two glioma cell lines (T98G and U87) through transfection with specific-siRNA. Experiments using the MTT assay, cell cycle analysis, apoptosis assay, real-time PCR and western blot were performed to establish the expression levels of related genes. Results: The results show that downregulation of Rab21 can significantly inhibit cell growth and remarkably induce cell apoptosis in T98G and U87 cell lines. Silencing Rab21 resulted in significantly increased expression of apoptosis-related proteins (caspase7, Bim and Bax) in glioma cells. Conclusions: We inferred that Rab21 silencing can induce apoptosis and inhibit proliferation in human glioma cells, indicating that Rab21 might act as an oncogene and serve as a novel target for glioma therapy. PMID- 29270203 TI - Development of a Cardiovascular Simulator for Studying Pulse Diagnosis Mechanisms. AB - This research was undertaken to develop a cardiovascular simulator for use in the study of pulse diagnosis. The physical (i.e., pulse wave transmission and reflection) and physiological (i.e., systolic and diastolic pressure, pulse pressure, and mean pressure) characteristics of the radial pulse wave were reproduced by our simulator. The simulator consisted of an arterial component and a pulse-generating component. Computer simulation was used to simplify the arterial component while maintaining the elastic modulus and artery size. To improve the reflected wave characteristics, a palmar arch was incorporated within the simulator. The simulated radial pulse showed good agreement with clinical data. PMID- 29270204 TI - Effect of Tai Chi Training on Dual-Tasking Performance That Involves Stepping Down among Stroke Survivors: A Pilot Study. AB - Descending stairs demands attention and neuromuscular control, especially with dual-tasking. Studies have demonstrated that stroke often degrades a survivor's ability to descend stairs. Tai Chi has been shown to improve dual-tasking performance of healthy older adults, but no such study has been conducted in stroke survivors. This study investigated the effect of Tai Chi training on dual tasking performance that involved stepping down and compared it with that of conventional exercise among stroke survivors. Subjects were randomized into Tai Chi (n = 9), conventional exercise (n = 8), and control (n = 9) groups. Those in the former two groups received 12-week training. Assessments included auditory Stroop test, stepping down test, and dual-tasking test involving both simultaneously. They were evaluated before training (time-1), after training (time-2), and one month after training (time-3). Tai Chi group showed significant improvement in the auditory Stroop test from time-1 to time-3 and the performance was significantly better than that of the conventional exercise group in time-3. No significant effect was found in the stepping down task or dual-tasking in the control group. These results suggest a beneficial effect of Tai Chi training on cognition among stroke survivors without compromising physical task performance in dual-tasking. The effect was better than the conventional exercise group. Nevertheless, further research with a larger sample is warranted. PMID- 29270205 TI - Protective Effect of Yang Mi Ryung(r) Extract on Noise-Induced Hearing Loss in Mice. AB - Noise-induced hearing loss (NIHL) results from the damage of the delicate hair cells inside the ear after excessive stimulation of noise. Unlike certain lower animals such as amphibians, fishes, and birds, in humans, hair cells cannot be regenerated once they are killed or damaged; thus, there are no therapeutic options to cure NIHL. Therefore, it is more important to protect hair cells from the noise before the damage occurs. In this study, we report the protective effect of Yang Mi Ryung extract (YMRE) against NIHL; this novel therapeutic property of YMRE has not been reported previously. Our data demonstrates that the hearing ability damaged by noise is markedly restored in mice preadministrated with YMRE before noise exposure, to the level of normal control group. Our study also provides the molecular mechanism underlying the protective effect of YMRE against NIHL by showing that YMRE significantly blocks noise-induced apoptotic cell death and reduces reactive oxygen species (ROS) production in cochleae. Moreover, quantitative polymerase chain reaction (qPCR) analysis demonstrates that YMRE has anti-inflammatory properties, suppressing the mRNA levels of TNFalpha and IL-1beta induced by noise exposure. In conclusion, YMRE could be a useful preventive intervention to prevent hearing impairment induced by the exposure to excessive noise. PMID- 29270206 TI - Multiple imputation using linked proxy outcome data resulted in important bias reduction and efficiency gains: a simulation study. AB - Background: When an outcome variable is missing not at random (MNAR: probability of missingness depends on outcome values), estimates of the effect of an exposure on this outcome are often biased. We investigated the extent of this bias and examined whether the bias can be reduced through incorporating proxy outcomes obtained through linkage to administrative data as auxiliary variables in multiple imputation (MI). Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we estimated the association between breastfeeding and IQ (continuous outcome), incorporating linked attainment data (proxies for IQ) as auxiliary variables in MI models. Simulation studies explored the impact of varying the proportion of missing data (from 20 to 80%), the correlation between the outcome and its proxy (0.1-0.9), the strength of the missing data mechanism, and having a proxy variable that was incomplete. Results: Incorporating a linked proxy for the missing outcome as an auxiliary variable reduced bias and increased efficiency in all scenarios, even when 80% of the outcome was missing. Using an incomplete proxy was similarly beneficial. High correlations (> 0.5) between the outcome and its proxy substantially reduced the missing information. Consistent with this, ALSPAC analysis showed inclusion of a proxy reduced bias and improved efficiency. Gains with additional proxies were modest. Conclusions: In longitudinal studies with loss to follow-up, incorporating proxies for this study outcome obtained via linkage to external sources of data as auxiliary variables in MI models can give practically important bias reduction and efficiency gains when the study outcome is MNAR. PMID- 29270207 TI - Nest site preference depends on the relative density of conspecifics and heterospecifics in wild birds. AB - Background: Social learning allows animals to eavesdrop on ecologically relevant knowledge of competitors in their environment. This is especially important when selecting a habitat if individuals have relatively little personal information on habitat quality. It is known that birds can use both conspecific and heterospecific information for social learning, but little is known about the relative importance of each information type. If provided with the choice between them, we expected that animals should copy the behaviour of conspecifics, as these confer the best information for that species. We tested this hypothesis in the field for Pied Flycatchers Ficedula hypoleuca arriving at their breeding grounds to select a nest box for breeding. We assigned arbitrary symbols to nest boxes of breeding pied flycatchers (conspecifics) and blue and great tits, Cyanistes caeruleus and Parus major (heterospecifics), in 2014 and 2016 in two areas with different densities of tits and flycatchers. After ca 50% of flycatchers had returned and a flycatcher symbol was assigned to their nest box, we gave the later arriving flycatchers the choice between empty nest boxes with either a conspecific (flycatcher) or a heterospecific (tit) symbol. Results: As expected, Pied Flycatchers copied the perceived nest box choice of conspecifics, but only in areas that were dominated by flycatchers. Against our initial expectation, flycatchers copied the perceived choice of heterospecifics in the area heavily dominated by tits, even though conspecific minority information was present. Conclusions: Our results confirm that the relative density of conspecifics and heterospecifics modulates the propensity to copy or reject novel behavioural traits. By contrasting conspecific and heterospecific ecology in the same study design we were able to draw more general conclusions about the role of fluctuating densities on social information use. PMID- 29270208 TI - Mothers' experiences of a telephone based breastfeeding support intervention after discharge from neonatal intensive care units: a mixed-method study. AB - Background: After discharge from a neonatal intensive care unit (NICU), many mothers of preterm infants (gestational age < 37 weeks) experience a lack of support for breastfeeding. An intervention study was designed to evaluate the effects of proactive (a daily telephone call initiated by a member of a breastfeeding support team) and/or reactive (mothers could call the breastfeeding support team) telephone based breastfeeding support for mothers after discharge from the NICU. The mothers in the intervention group had access to both proactive and reactive support; the mothers in the control group only had access to reactive support. The aim of this study was to explore the mothers' experiences of the proactive and reactive telephone support. Methods: This study was a qualitatively driven, mixed-method evaluation using three data sources: questionnaires with qualitative open-ended questions, visual analogue scales and telephone interviews. In total, 365 mothers contributed data for this study. The qualitative data were analysed with an inductive thematic network analysis, while the quantitative data were analysed with Student's t-test and the chi-square test. Results: Proactive support contributed to greater satisfaction and involvement in breastfeeding support. The mothers who received proactive support reported that they felt strengthened, supported and secure, as a result of the continuous care provided by staff who were knowledgeable and experienced (i.e., in breastfeeding and preterm infants), which resulted in the global theme 'Empowered by proactive support'. The mothers who received reactive support experienced contradictory feelings; some felt secure because they had the opportunity to call for support, whereas others found it difficult to decide when and if they should use the service, which resulted in the global theme; 'Duality of reactive support'. Conclusion: There were positive aspects of both proactive (i.e., greater satisfaction and feelings of empowerment) and reactive support (i.e., the opportunity to call for support); however, the provision of reactive support alone may be inadequate for those with the greatest need for support as they are the least likely to access it. Trial registration: NCT01806480 on 5 March 2013. PMID- 29270209 TI - Evaluation of parameters affecting switchgrass tissue culture: toward a consolidated procedure for Agrobacterium-mediated transformation of switchgrass (Panicum virgatum). AB - Background: Switchgrass (Panicum virgatum), a robust perennial C4-type grass, has been evaluated and designated as a model bioenergy crop by the U.S. DOE and USDA. Conventional breeding of switchgrass biomass is difficult because it displays self-incompatible hindrance. Therefore, direct genetic modifications of switchgrass have been considered the more effective approach to tailor switchgrass with traits of interest. Successful transformations have demonstrated increased biomass yields, reduction in the recalcitrance of cell walls and enhanced saccharification efficiency. Several tissue culture protocols have been previously described to produce transgenic switchgrass lines using different nutrient-based media, co-cultivation approaches, and antibiotic strengths for selection. Results: After evaluating the published protocols, we consolidated these approaches and optimized the process to develop a more efficient protocol for producing transgenic switchgrass. First, seed sterilization was optimized, which led to a 20% increase in yield of induced calluses. Second, we have selected a N6 macronutrient/B5 micronutrient (NB)-based medium for callus induction from mature seeds of the Alamo cultivar, and chose a Murashige and Skoog-based medium to regenerate both Type I and Type II calluses. Third, Agrobacterium-mediated transformation was adopted that resulted in 50-100% positive regenerated transformants after three rounds (2 weeks/round) of selection with antibiotic. Genomic DNA PCR, RT-PCR, Southern blot, visualization of the red fluorescent protein and histochemical beta-glucuronidase (GUS) staining were conducted to confirm the positive switchgrass transformants. The optimized methods developed here provide an improved strategy to promote the production and selection of callus and generation of transgenic switchgrass lines. Conclusion: The process for switchgrass transformation has been evaluated and consolidated to devise an improved approach for transgenic switchgrass production. With the optimization of seed sterilization, callus induction, and regeneration steps, a reliable and effective protocol is established to facilitate switchgrass engineering. PMID- 29270210 TI - Predicting Outcomes in Emergency Medical Admissions Using a Laboratory Only Nomogram. AB - Background: We describe a nomogram to explain an Acute Illness Severity model, derived from emergency room triage and admission laboratory data, to predict 30 day in-hospital survival following an emergency medical admission. Methods: For emergency medical admissions (96,305 episodes in 50,612 patients) between 2002 and 2016, the relationship between 30-day in-hospital mortality and admission laboratory data was determined using logistic regression. The previously validated Acute Illness Severity model was then transposed to a Kattan-style nomogram with a Stata user-written program. Results: The Acute Illness Severity was based on the admission Manchester triage category and biochemical laboratory score; these latter were based on the serum albumin, sodium, potassium, urea, red cell distribution width, and troponin status. The laboratory admission data was predictive with an AUROC of 0.85 (95% CI: 0.85, 0.86). The sensitivity was 94.4%, with a specificity of 62.7%. The positive predictive value was 21.2%, with a negative predictive value of 99.1%. For the Kattan-style nomogram, the regression coefficients are converted to a 100-point scale with the predictor parameters mapped to a probability axis. The nomogram would be an easy-to-use tool at the bedside and for educational purposes, illustrating the relative importance of the contribution of each predictor to the overall score. Conclusion: A nomogram to illustrate and explain the prognostic factors underlying an Acute Illness Severity Score system is described. PMID- 29270211 TI - Research on Gastroesophageal Reflux Disease Based on Dynamic Features of Ambulatory 24-Hour Esophageal pH Monitoring. AB - Ambulatory 24-hour esophageal pH monitoring has been considered as the gold standard for diagnosing gastroesophageal reflux disease (GERD), and in clinical application, static parameters are widely used, such as DeMeester score. However, a shortcoming of these static variables is their relatively high false negative rate and long recording time required. They may be falsely labeled as nonrefluxers and not appropriately treated. Therefore, it is necessary to seek more accurate and objective parameters to detect and quantify GERD. This paper first describes a new effort that investigated the feasibility of dynamic features of 24-hour pH recording. Wavelet energy, information entropy, and wavelet entropy were estimated for three groups (severe, mild-to-moderate, and normal). The results suggest that wavelet energy and entropy are physiologically meaningful since they differentiated patients with varying degrees of GERD. K means clustering algorithm was employed to obtain the sensitivity and specificity of new parameters. It is obvious that information entropy goes with the highest sensitivity of 87.3% and wavelet energy has the highest specificity of 97.1%. This would allow a more accurate definition of the best indicators to detect and quantify GERD as well as provide an alternative insight into the early diagnosis of GERD. PMID- 29270212 TI - Longitudinal course of eating disorders after transsexual treatment: a report of two cases. AB - Background: Several reports have been published on patients with gender dysphoria and eating disorders. However, there have been few reports on the longitudinal course of eating disorders after gender reassignment surgery (GRS)/gender confirmation surgery (GCS). Case presentation: We report two Japanese cases of transsexual persons with eating disorders who underwent GRS/GCS, one male-to female (MtF) and one female-to-male (FtM). Case 1 was a 35-year MtF person who had a 14-year-course of bulimia nervosa that developed after GRS. Case 2 was a 35 year FtM person with anorexia nervosa who underwent GCS 9 years before. Conclusions: We found that the treatment of our transsexual patients influenced the course of their eating disorders for a long period, which could be attributable partly to the cultural situation in Japan, an East Asian country. It is possible that many gender identity problems and identity problems in general persist even after surgery and treatment; therefore, continual clinical support should be provided for patients with gender dysphoria and eating disorders even after hormonal therapy or GRS/GCS. PMID- 29270213 TI - Somatic manifestation of distress: clinical medicine, psychological, and public health perspectives. PMID- 29270214 TI - Responding to safety concerns and chronic needs: trends over time. AB - Background: For the past 20 years, the Ontario child welfare sector has made significant legislative and policy changes. Changes to legislation and policy can impact the public and sector's response to child maltreatment and inform identified trends. Using an investigative taxonomy of urgent protection and chronic need this paper examines the shift in the nature of investigated maltreatment over time. Methods: Data from five cycles of the Ontario Incidence Studies of Reported Child Abuse and Neglect (1993, 1998, 2003, 2008 and 2013) were used. Provincial incidence rates were calculated by dividing the weighted estimates by the child population 15 years of age and under and then multiplying by 1000 in order to produce an annual incidence rate per 1000 children. Investigations were divided into urgent (severe physical harm, sexual abuse, neglect and physical abuse of children under 4) and chronic (risk only, exposure to intimate partner violence, emotional maltreatment, neglect and physical abuse of children four or over). Tests of statistical significance were calculated to assess changes in subtypes between cycles. Results: Between 1993 and 2013, the rate of child maltreatment related investigations completed in Ontario has increased from 20.48 per 1000 children to 53.27 per 1000 children. Overall there has been a decline in the incidence of urgent investigations from 9.31 per 1000 child maltreatment investigations in 1993 to 5.94 per 1000 maltreatment investigations in 2013. There has been a fourfold increase in the incidence of chronic investigations from 11.18 per 1000 child maltreatment investigations in 1993 to 47.33 per 1000 maltreatment investigations in 2013. Conclusion: The nature of child protection work using the urgent-chronic taxonomy shows a dramatic shift in the types of concerns identified without a corresponding shift in the way families are assessed for need. The provision of a forensic investigation to all families does not distinguish between urgent safety concerns and needs that may require prolonged engagement. Effective service provision requires more precision in our response to these diverse concerns. PMID- 29270215 TI - A program of family-centered care for adolescents in short-term stay groups of juvenile justice institutions. AB - Background: To provide successful treatment to detained adolescents, staff in juvenile justice institutions need to work in family-centered ways. As juvenile justice institutions struggled to involve parents in their child's treatment, we developed a program for family-centered care. Methods: The program was developed in close collaboration with staff from the two juvenile justice institutions participating in the Dutch Academic Workplace Forensic Care for Youth. To achieve an attainable program, we chose a bottom-up approach in which ideas for family centered care were detailed and discussed by workgroups consisting of group leaders, family therapists, psychologists, other staff, researchers, and a parent. Results: The family-centered care program distinguishes four categories of parental participation: (a) informing parents, (b) parents meeting their child, (c) parents meeting staff, and (d) parents taking part in the treatment program. Additionally, the family-centered care program includes the option to start family therapy during detention of the youths, to be continued after discharge from the juvenile justice institutions. Training and coaching of staff are core components of the family-centered care program. Conclusions: The combination of training and the identification of attainable ways for staff to promote parental involvement makes the family-centered care program valuable for practice. Because the program builds on suggestions from previous research and on the theoretical background of evidence-based family therapies, it has potential to improve care for detained adolescents and their parents. Further research is required to confirm if this assumption is correct. PMID- 29270217 TI - Many, more, most: four risk profiles of adolescents in residential care with major psychiatric problems. AB - Background: The development of delinquent behaviour is largely determined by the presence of (multiple) risk factors. It is essential to focus on the patterns of co-occurring risk factors in different subgroups in order to better understand disruptive behaviour. Aims and hypothesis: The aim of this study was to examine whether subgroups could be identified to obtain more insight into the patterns of co-occurring risk factors in a population of adolescents in residential care. Based on the results of prior studies, at least one subgroup with many risk factors in multiple domains and one subgroup with primarily risk factors in a single domain were expected. Methods: The structured assessment of violence risk in youth and the juvenile forensic profile were used to operationalize eleven risk factors in four domains: individual, family, peer and school. Data from 270 male adolescents admitted to a hospital for youth forensic psychiatry and orthopsychiatry in the Netherlands were available. Latent class analysis was used to identify subgroups and significant differences between the subgroups were examined in more detail. Results: Based on the fit statistics and the clinical interpretability, the four-class model was chosen. The four classes had different patterns of co-occurring risk factors, and differed in the included external variables such as psychopathology and criminal behaviour. Conclusions: Two groups were found with many risk factors in multiple domains and two groups with fewer (but still several) risk factors in single domains. This study shed light on the complexity of disruptive behaviour, providing a better insight into the patterns of co-occurring risk factors in a heterogeneous population of adolescents with major psychiatric problems admitted to residential care. PMID- 29270218 TI - The relationships between gender, psychopathic traits and self-reported delinquency: a comparison between a general population sample and a high-risk sample for juvenile delinquency. AB - Background: Studies have shown that youths with high psychopathic traits have an earlier onset of delinquent behavior, have higher levels of delinquent behavior, and show higher rates of recidivism than youths with low psychopathic traits. Furthermore, psychopathic traits have received much attention as a robust indicator for delinquent and aggressive behavior in both boys and girls. However, there is a notable lack of research on gender differences in the relationship between psychopathic traits and delinquent behavior. In addition, most of the studies on psychopathic traits and delinquent behavior were conducted in high risk samples. Therefore, the first objective of the current study was to investigate the relationship between psychopathic traits and specific forms of self-reported delinquency in a high-risk sample for juvenile delinquency as well as in a general population sample. The second objective was to examine the influence of gender on this relationship. Finally, we investigated whether the moderating effect of gender was comparable in the high-risk sample for juvenile delinquency and the general population sample. Methods: Participants were 1220 adolescents of the German-speaking part of Switzerland (N = 351 high-risk sample, N = 869 general population sample) who were between 13 and 21 years of age. The Youth Psychopathic traits Inventory (YPI) was used to assess psychopathic traits. To assess the lifetime prevalence of the adolescents' delinquent behavior, 15 items derived from a self-report delinquency instrument were used. Logistic regression analyses were used to examine the relationship between gender, psychopathic traits and self-reported delinquency across both samples. Results: Our results demonstrated that psychopathic traits are related to non-violent and violent offenses. We found no moderating effect of gender and therefore we could not detect differences in the moderating effect of gender between the samples. However, there was a moderating effect of sample for the relationship between the callous and unemotional YPI scale and non-violent offenses. In addition, the regression weights of gender and sample were, for non-violent offenses, reduced to non-significance when adding the interaction terms. Conclusions: Psychopathic traits were found to be present in a wide range of youths (i.e., high-risk as well as general population sample, young children as well as adolescents, boys as well as girls) and were related to delinquent behavior. The influence of age and YPI scales on self-reported delinquency was more robust than the influence of gender and sample. Therefore, screening for psychopathic traits among young children with psychosocial adjustment problems seems relevant for developing effective intervention strategies. PMID- 29270216 TI - A longitudinal study of socioeconomic status, family processes, and child adjustment from preschool until early elementary school: the role of social competence. AB - Objective: Using a short-term longitudinal design, this study examined the concurrent and longitudinal relationships among familial socioeconomic status (SES; i.e., family income and maternal and paternal education levels), marital conflict (i.e., constructive and destructive marital conflict), parenting practices (i.e., positive and negative parenting practices), child social competence (i.e., social skills), and child behavioral adjustment (i.e., internalizing and externalizing problems) in a comprehensive model. Methods: The sample included a total of 1604 preschoolers aged 5 years at Time 1 and first graders aged 6 years at Time 2 (51.5% male). Parents completed a self-reported questionnaire regarding their SES, marital conflict, parenting practices, and their children's behavioral adjustment. Teachers also evaluated the children's social competence. Results: The path analysis results revealed that Time 1 family income and maternal and paternal education levels were respectively related to Time 1 social skills and Time 2 internalizing and externalizing problems, both directly and indirectly, through their influence on destructive and constructive marital conflict, as well as negative and positive parenting practices. Notably, after controlling for Time 1 behavioral problems as mediating mechanisms in the link between family factors (i.e., SES, marital conflict, and parenting practices) and behavioral adjustment, Time 1 social skills significantly and inversely influenced both the internalization and externalization of problems at Time 2. Conclusions: The merit of examining SES, marital conflict, and parenting practices as multidimensional constructs is discussed in relation to an understanding of processes and pathways within families that affect child mental health functioning. The results suggest social competence, which is influenced by the multidimensional constructs of family factors, may prove protective in reducing the risk of child maladjustment, especially for children who are socioeconomically disadvantaged. PMID- 29270219 TI - Transcriptomic characterization of Caecomyces churrovis: a novel, non-rhizoid forming lignocellulolytic anaerobic fungus. AB - Anaerobic gut fungi are the primary colonizers of plant material in the rumen microbiome, but are poorly studied due to a lack of characterized isolates. While most genera of gut fungi form extensive rhizoidal networks, which likely participate in mechanical disruption of plant cell walls, fungi within the Caecomyces genus do not possess these rhizoids. Here, we describe a novel fungal isolate, Caecomyces churrovis, which forms spherical sporangia with a limited rhizoidal network yet secretes a diverse set of carbohydrate active enzymes (CAZymes) for plant cell wall hydrolysis. Despite lacking an extensive rhizoidal system, C. churrovis is capable of growth on fibrous substrates like switchgrass, reed canary grass, and corn stover, although faster growth is observed on soluble sugars. Gut fungi have been shown to use enzyme complexes (fungal cellulosomes) in which CAZymes bind to non-catalytic scaffoldins to improve biomass degradation efficiency. However, transcriptomic analysis and enzyme activity assays reveal that C. churrovis relies more on free enzymes compared to other gut fungal isolates. Only 15% of CAZyme transcripts contain non-catalytic dockerin domains in C. churrovis, compared to 30% in rhizoid-forming fungi. Furthermore, C. churrovis is enriched in GH43 enzymes that provide complementary hemicellulose degrading activities, suggesting that a wider variety of these activities are required to degrade plant biomass in the absence of an extensive fungal rhizoid network. Overall, molecular characterization of a non-rhizoid-forming anaerobic fungus fills a gap in understanding the roles of CAZyme abundance and associated degradation mechanisms during lignocellulose breakdown within the rumen microbiome. PMID- 29270220 TI - Bioflocculants' production in a biomass-degrading bacterium using untreated corn stover as carbon source and use of bioflocculants for microalgae harvest. AB - Background: Bioflocculation has been developed as a cost-effective and environment-friendly method to harvest multiple microalgae. However, the high production cost of bioflocculants makes it difficult to scale up. In the current study, low-cost bioflocculants were produced from untreated corn stover by a biomass-degrading bacterium Pseudomonas sp. GO2. Results: Pseudomonas sp. GO2 showed excellent production ability of bioflocculants through directly hydrolyzing various biomasses. The untreated corn stover was selected as carbon source for bioflocculants' production due to its highest flocculating efficiency compared to that when using other biomasses as carbon source. The effects of fermentation parameters on bioflocculants' production were optimized via response surface methodology. According to the optimal model, an ideal flocculating efficiency of 99.8% was obtained with the fermentation time of 130.46 h, initial pH of 7.46, and biomass content of 0.64%. The relative importance of carboxymethyl cellulase and xylanase accounted for 51.8% in the process of bioflocculants' production by boosted regression tree analysis, further indicating that the bioflocculants were mainly from the hydrolysates of biomass. Biochemical analysis showed that it contained 59.0% polysaccharides with uronic acid (34.2%), 32.1% protein, and 6.1% nucleic acid in the bioflocculants, which had an average molecular weight as 1.33 * 106 Da. In addition, the bioflocculants showed the highest flocculating efficiency at a concentration of 12.5 mg L-1 and were stable over broad ranges of pH and temperature. The highest flocculating efficiencies obtained for Chlorella zofingiensis and Neochloris oleoabundans were 77.9 and 88.9%, respectively. Conclusions: The results indicated that Pseudomonas sp. GO2 can directly utilize various untreated lignocellulolytic biomasses to produce low-cost bioflocculants, which showed the high efficiency to harvest two green microalgae in a low GO2 fermentation broth/algal culture ratio. PMID- 29270221 TI - Identification of alcohol stress tolerance genes of Synechocystis sp. PCC 6803 using adaptive laboratory evolution. AB - Background: Synechocystis sp. PCC 6803 is an attractive organism for the production of alcohols, such as isobutanol and ethanol. However, because stress against the produced alcohol is a major barrier for industrial applications, it is highly desirable to engineer organisms with strong alcohol tolerance. Results: Isobutanol-tolerant strains of Synechocystis sp. PCC 6803 were obtained by long term passage culture experiments using medium containing 2 g/L isobutanol. These evolved strains grew on medium containing 5 g/L isobutanol on which the parental strain could not grow. Mutation analysis of the evolved strains revealed that they acquired resistance ability due to combinatorial malfunctions of slr1044 (mcpA) and slr0369 (envD), or slr0322 (hik43) and envD. The tolerant strains demonstrated stress resistance against isobutanol as well as a wide variety of alcohols such as ethanol, n-butanol, and isopentanol. As a result of introducing an ethanol-producing pathway into the evolved strain, its productivity successfully increased to 142% of the control strain. Conclusions: Novel mutations were identified that improved the stress tolerance ability of various alcohols in Synechocystis sp. PCC 6803. PMID- 29270222 TI - Surgical retrieval of a swallowed denture in a schizophrenic patient: a case report. AB - Background: Accidental foreign body ingestion is a common phenomenon in children between 6 months to 6 years of age. In adults, foreign body ingestion is commonly observed in the geriatric population and in patients with psychiatric disorders. Over 80% of ingested foreign bodies pass uneventfully through the intestinal tract. Endoscopic retrieval is needed in about 20% while surgical intervention is indicated in less than 1%. Herein we report an extremely rare case of esophagocutaneous fistula following operative retrival of an impacted denture in the esophagus with spontaneous healing within 3 weeks. A similar case to the best of our knowledge has so far not been reported previously. Case presentation: A case of accidental ingestion of a dental prosthesis in a 35-year old schizophrenic patient is presented. The patient was referred to our department after accidentally swallowing one of his dental prosthesis. Surgical retrieval was indicated after two unsuccessful endoscopic retrieval attempts. The denture was retrieved following a longitudinal incision of the esophagus via a left cervical approach. The postoperative course was complicated by a clinically suspected esophagocutaneous fistula which was managed conservatively via nothing per os with enteral feeding via a nasogastric tube. Secretion ceased 3 weeks later and a fistula could not be found on contrast enhanced radiographic examination with gastrographin(r). Conclusion: Esophagocutaneous fistula represents a rare but serious complication following foreign body ingestion. An interdisciplinary management including an early surgical consultation should be considered in patients with foreign body impaction in the esophagus following failure of endoscopic retrieval. PMID- 29270223 TI - Predicting hepatic failure with a new diagnostic technique by preoperative liver scintigraphy and computed tomography: a pilot study in 123 patients undergoing liver resection. AB - Background: A novel index, total liver LU15, has been identified as a surrogate marker for liver function. We evaluated the ability of preoperative remnant liver LU15 values to predict postoperative hepatic failure. Methods: Preoperative risk factors for postoperative hepatic failure and remnant liver LU15 were evaluated in 123 patients undergoing liver resection for several diseases from September 1st, 2007 to December 1st, 2016. We calculated the remnant liver LU15 value from the total liver LU15 value and the functional remnant liver ratio. Risk factors for postoperative hepatic failure was determined by univariate and multivariate analysis. Results: Hepatic failure grade B/C developed postoperatively in six patients of seven patients within Makuuchi criteria / without criteria for remnant liver LU15. Operative time (p = 0.0242) and criteria for remnant liver LU15 (p = 0.0001) were prognostic factors for hepatic failure according to the univariate analysis. And criteria for remnant liver LU15 (p = 0.0009) was only prognostic factor by multivariate analysis. Conclusion: Based on the findings form this pilot study, it appears that patients with a remnant liver LU15 value of 13 or less may have a high risk of postoperative hepatic failure. PMID- 29270224 TI - Exploring unnecessary invasive procedures in the United States: a retrospective mixed-methods analysis of cases from 2008-2016. AB - Background: Unnecessary invasive procedures risk harming patients physically, emotionally, and financially. Very little is known about the factors that provide the motive, means, and opportunity (MMO) for unnecessary procedures. Methods: This project used a mixed-methods design that involved five key steps: (1) systematically searching the literature to identify cases of unnecessary procedures reported from 2008 to 2016; (2) identifying all medical board, court, and news records on relevant cases; (3) coding all relevant records using a structured codebook of case characteristics; (4) analyzing each case using a MMO framework to develop a causal theory of the case; and (5) identifying typologies of cases through a two-step cluster analysis using variables hypothesized to be causally related to unnecessary procedures. Results: Seventy-nine cases met inclusion criteria. The mean number of documents or sources examined for each case was 36.4. Unnecessary procedures were performed for at least five years in most cases (53.2%); 56.3% of the cases involved 30 or more patients, and 37.5% involved 100 or more patients. In nearly all cases the physician was male (96.2%) and working in private practice (92.4%); 57.0% of the physicians had an accomplice, 48.1% were 50 years of age or older, and 40.5% trained outside the U.S. The most common motives were financial gain (92.4%) and suspected antisocial personality (48.1%), followed by poor problem-solving or clinical skills (11.4%) and ambition (3.8%). The most common environmental factors that provided opportunity for unnecessary procedures included a lack of oversight (40.5%) or oversight failures (39.2%), a corrupt moral climate (26.6%), vulnerable patients (20.3%), and financial conflicts of interest (13.9%). Conclusions: Unnecessary procedures usually appear motivated by financial gain and occur in settings that have oversight problems. Preventive efforts should focus on early detection by peers and institutions, and decisive action by medical boards and federal prosecutors. PMID- 29270225 TI - Are Brazil's Deforesters Avoiding Detection? AB - Rates of deforestation reported by Brazil's official deforestation monitoring system have declined dramatically in the Brazilian Amazon. Much of Brazil's success in its fight against deforestation has been credited to a series of policy changes put into place between 2004 and 2008. In this research, we posit that one of these policies, the decision to use the country's official system for monitoring forest loss in the Amazon as a policing tool, has incentivized landowners to deforest in ways and places that evade Brazil's official monitoring and enforcement system. As a consequence, we a) show or b) provide several pieces of suggestive evidence that recent successes in protecting monitored forests in the Brazilian Amazon may be doing less to protect the region's forests than previously assumed. PMID- 29270226 TI - De novo paternal origin duplication of chromosome 11p15.5: report of two Chinese cases with Beckwith-Wiedemann syndrome. AB - Background: The molecular etiology of Beckwith-Wiedemann syndrome (BWS) is complex and heterogeneous. Several subtypes of epigenetic-genetic alterations including aberrant methylation patterns, segmental uniparental disomy, single gene mutations, and copy number changes have been described. An integrated molecular approach to analyze the epigenetic-genetic alterations is required for accurate diagnosis of BWS. Case presentation: We reported two Chinese cases with BWS detected by genome-wide copy number analysis and locus-specific methylation profiling. Prenatal analysis on cord blood of patient 1 showed a de novo paternal origin duplication spanning 896Kb at 11p15.5. Patient 2 was referred at 2-month old and the genetic analysis showed a de novo 228.8Kb deletion at 11p15.5 telomeric end and a de novo duplication of 2.5 Mb at 11p15.5-15.4. Both the duplications are of paternal origin with gain of methylation at the imprinting center 1 and thus belong to the subgroup of a low tumor risk. Conclusion: Results from these two cases and other reported cases from literature indicated that paternally derived duplications at 11p15.5 region cause BWS. Combined chromosome microarray analysis and methylation profiling provided reliable diagnosis for this subtype of BWS. Characterization of genetic defects in BWS patients could lead to better understanding the genetic mechanisms of this clinically and genetically heterogeneous disorder. PMID- 29270227 TI - Cluster ensemble based on Random Forests for genetic data. AB - Background: Clustering plays a crucial role in several application domains, such as bioinformatics. In bioinformatics, clustering has been extensively used as an approach for detecting interesting patterns in genetic data. One application is population structure analysis, which aims to group individuals into subpopulations based on shared genetic variations, such as single nucleotide polymorphisms. Advances in DNA sequencing technology have facilitated the obtainment of genetic datasets with exceptional sizes. Genetic data usually contain hundreds of thousands of genetic markers genotyped for thousands of individuals, making an efficient means for handling such data desirable. Results: Random Forests (RFs) has emerged as an efficient algorithm capable of handling high-dimensional data. RFs provides a proximity measure that can capture different levels of co-occurring relationships between variables. RFs has been widely considered a supervised learning method, although it can be converted into an unsupervised learning method. Therefore, RF-derived proximity measure combined with a clustering technique may be well suited for determining the underlying structure of unlabeled data. This paper proposes, RFcluE, a cluster ensemble approach for determining the underlying structure of genetic data based on RFs. The approach comprises a cluster ensemble framework to combine multiple runs of RF clustering. Experiments were conducted on high-dimensional, real genetic dataset to evaluate the proposed approach. The experiments included an examination of the impact of parameter changes, comparing RFcluE performance against other clustering methods, and an assessment of the relationship between the diversity and quality of the ensemble and its effect on RFcluE performance. Conclusions: This paper proposes, RFcluE, a cluster ensemble approach based on RF clustering to address the problem of population structure analysis and demonstrate the effectiveness of the approach. The paper also illustrates that applying a cluster ensemble approach, combining multiple RF clusterings, produces more robust and higher-quality results as a consequence of feeding the ensemble with diverse views of high-dimensional genetic data obtained through bagging and random subspace, the two key features of the RF algorithm. PMID- 29270228 TI - TSPmap, a tool making use of traveling salesperson problem solvers in the efficient and accurate construction of high-density genetic linkage maps. AB - Background: Recent advances in nucleic acid sequencing technologies have led to a dramatic increase in the number of markers available to generate genetic linkage maps. This increased marker density can be used to improve genome assemblies as well as add much needed resolution for loci controlling variation in ecologically and agriculturally important traits. However, traditional genetic map construction methods from these large marker datasets can be computationally prohibitive and highly error prone. Results: We present TSPmap, a method which implements both approximate and exact Traveling Salesperson Problem solvers to generate linkage maps. We demonstrate that for datasets with large numbers of genomic markers (e.g. 10,000) and in multiple population types generated from inbred parents, TSPmap can rapidly produce high quality linkage maps with low sensitivity to missing and erroneous genotyping data compared to two other benchmark methods, JoinMap and MSTmap. TSPmap is open source and freely available as an R package. Conclusions: With the advancement of low cost sequencing technologies, the number of markers used in the generation of genetic maps is expected to continue to rise. TSPmap will be a useful tool to handle such large datasets into the future, quickly producing high quality maps using a large number of genomic markers. PMID- 29270229 TI - Sparse generalized linear model with L0 approximation for feature selection and prediction with big omics data. AB - Background: Feature selection and prediction are the most important tasks for big data mining. The common strategies for feature selection in big data mining are L1, SCAD and MC+. However, none of the existing algorithms optimizes L0, which penalizes the number of nonzero features directly. Results: In this paper, we develop a novel sparse generalized linear model (GLM) with L0 approximation for feature selection and prediction with big omics data. The proposed approach approximate the L0 optimization directly. Even though the original L0 problem is non-convex, the problem is approximated by sequential convex optimizations with the proposed algorithm. The proposed method is easy to implement with only several lines of code. Novel adaptive ridge algorithms (L0ADRIDGE) for L0 penalized GLM with ultra high dimensional big data are developed. The proposed approach outperforms the other cutting edge regularization methods including SCAD and MC+ in simulations. When it is applied to integrated analysis of mRNA, microRNA, and methylation data from TCGA ovarian cancer, multilevel gene signatures associated with suboptimal debulking are identified simultaneously. The biological significance and potential clinical importance of those genes are further explored. Conclusions: The developed Software L0ADRIDGE in MATLAB is available at https://github.com/liuzqx/L0adridge. PMID- 29270230 TI - An automated pipeline for bouton, spine, and synapse detection of in vivo two photon images. AB - Background: In the nervous system, the neurons communicate through synapses. The size, morphology, and connectivity of these synapses are significant in determining the functional properties of the neural network. Therefore, they have always been a major focus of neuroscience research. Two-photon laser scanning microscopy allows the visualization of synaptic structures in vivo, leading to many important findings. However, the identification and quantification of structural imaging data currently rely heavily on manual annotation, a method that is both time-consuming and prone to bias. Results: We present an automated approach for the identification of synaptic structures in two-photon images. Axon boutons and dendritic spines are structurally distinct. They can be detected automatically using this image processing method. Then, synapses can be identified by integrating information from adjacent axon boutons and dendritic spines. In this study, we first detected the axonal boutons and dendritic spines respectively, and then identified synapses based on these results. Experimental results were validated manually, and the effectiveness of our proposed method was demonstrated. Conclusions: This approach will helpful for neuroscientists to automatically analyze and quantify the formation, elimination and destabilization of the axonal boutons, dendritic spines and synapses. PMID- 29270231 TI - Identifying the primary outcome for a randomised controlled trial in rheumatoid arthritis: the role of a discrete choice experiment. AB - Background: This study sought to establish the preferences of people with Rheumatoid Arthritis (RA) about the best outcome measure for a health and fitness intervention randomised controlled trial (RCT). The results of this study were used to inform the choice of the trial primary and secondary outcome measure. Methods: A discrete choice experiment (DCE) was used to assess people's preferences regarding a number of outcomes (foot and ankle pain, fatigue, mobility, ability to perform daily activities, choice of footwear) as well as different schedules and frequency of delivery for the health and fitness intervention. The outcomes were chosen based on literature review, clinician recommendation and patients' focus groups. The DCE was constructed in SAS software using the D-efficiency criteria. It compared hypothetical scenarios with varying levels of outcomes severity and intervention schedule. Preference weights were estimated using appropriate econometric models. The partial log-likelihood method was used to assess the attribute importance. Results: One hundred people with RA completed 18 choice sets. Overall, people selected foot and ankle pain as the most important outcome, with mobility being nearly as important. There was no evidence of differential preference between intervention schedules or frequency of delivery. Conclusions: Foot and ankle pain can be considered the patient choice for primary outcome of an RCT relating to a health and fitness intervention. This study demonstrated that, by using the DCE method, it is possible to incorporate patients' preferences at the design stage of a RCT. This approach ensures patient involvement at early stages of health care design. PMID- 29270232 TI - Diagnostic accuracy of resting systolic toe pressure for diagnosis of peripheral arterial disease in people with and without diabetes: a cross-sectional retrospective case-control study. AB - Background: The resting systolic toe pressure (TP) is a measure of small arterial function in the periphery. TP is used in addition to the ankle-brachial index when screening for peripheral arterial disease (PAD) of the lower limb in those with diabetes, particularly in the presence of lower limb medial arterial calcification. It may be used as an adjunct assessment of lower limb vascular function and as a predictor of wound healing. The aim of this study was to determine the diagnostic accuracy of TP for detecting PAD in people with and without diabetes. Methods: This was a retrospective case-control study. Two researchers extracted information from consecutive patient records, including TP measurements, colour Duplex ultrasound results, demographic information, and medical history. Measures of diagnostic accuracy were determined by receiver operating curve (ROC) analysis, and calculation of sensitivity, specificity, and positive and negative likelihood ratios. Results: Three hundred and nintey-four participants with suspected PAD were included. In the diabetes group (n = 176), ROC analysis of TP for detecting PAD was 0.78 (95%CI: 0.69 to 0.84). In the control group (n = 218), the ROC of TP was 0.73 (95%CI: 0.70 to 0.80). TP had highest sensitivity when anatomical distribution of disease was both proximal and distal (diabetes group: 79.49%, the control group: 82.61%). TP yielded highest sensitivity in mild disease (50-75% stenosis) in diabetes group, (81.82%) and moderate disease (>75% stenosis) in control group (80.77%). Conclusions: Our findings indicate that TPs are useful to assist in diagnosing PAD in clinical practice, however, results should be interpreted with caution due to the small probability of PAD being present with a negative test. PMID- 29270233 TI - Low distribution of genes encoding virulence factors in Shigella flexneri serotypes 1b clinical isolates from eastern Chinese populations. AB - Background: The ability of Shigella to invade, colonize, and eventually kill host cells is influenced by many virulence factors. However, there is no analysis of related genes in Jiangsu Province of China so far. Shigella flexneri was collected from 13 cities of Jiangsu Province through the provincial Centers for Disease Control (CDC) for analysis of distribution of major virulence genes (ipaH, ipaBCD, ial, virF, virB, sigA, set1A, sepA, sat, pic, set1B and sen) detected by PCR technology. Results: A total of 545 isolates received were confirmed as S. flexneri which belongs to 11 serotypes of S. flexneri, among which serotype 2a was the most predominant (n = 223, 40.9%). All isolates were positive for ipaH gene, followed by sat (94.1%), sigA (78.9%), set1B (78.0%), pic (77.6%), set1A (74.5%), virF (64.8%), sepA (63.5%), sen (56.9%), ipaBCD (50.5%), ial (47.0%) and virB (47.0%). The presence of virulence genes in different serotypes was distinct. The existence of virulence genes of serotype 1b was generally lower than other serotype-the positive rate for virulence genes was between 0.0 and 14.1% except for ipaH and sat. In addition, virulence genes also fluctuated in different regions and at different times in Jiangsu province. The result of analysis on the relationship between virulence genes of S. flexneri showed that the existence of virulence genes of Shigella could be well represented by multiplex PCR combination ipaH + ial + set1A, which had a high clinical value. Conclusions: The present study was designed to explore the prevalence of 12 S. flexneri-associated virulence genes. The data showed high diversity of virulence genes with regard to periods, regions and serotypes in Jiangsu Province of China. PMID- 29270234 TI - Colistin resistant Escherichia coli carrying mcr-1 in urban sludge samples: Dhaka, Bangladesh. AB - Of 48 bacteria belonging to the family Enterobacteriaceae tested from urban sludge samples, one Escherichia coli isolate was resistant to colistin and possessed the resistance marker gene mcr-1 found for the first time from Bangladesh. The colistin resistant E. coli was multidrug resistant showing resistance to 11 different antibiotics tested. PMID- 29270236 TI - Journal of Circulating Biomarkers looks forward after being indexed in PubMed Central. PMID- 29270235 TI - The repetitive landscape of the 5100 Mbp barley genome. AB - Background: While transposable elements (TEs) comprise the bulk of plant genomic DNA, how they contribute to genome structure and organization is still poorly understood. Especially in large genomes where TEs make the majority of genomic DNA, it is still unclear whether TEs target specific chromosomal regions or whether they simply accumulate where they are best tolerated. Results: Here, we present an analysis of the repetitive fraction of the 5100 Mb barley genome, the largest angiosperm genome to have a near-complete sequence assembly. Genes make only about 2% of the genome, while over 80% is derived from TEs. The TE fraction is composed of at least 350 different families. However, 50% of the genome is comprised of only 15 high-copy TE families, while all other TE families are present in moderate or low copy numbers. We found that the barley genome is highly compartmentalized with different types of TEs occupying different chromosomal "niches", such as distal, interstitial, or proximal regions of chromosome arms. Furthermore, gene space represents its own distinct genomic compartment that is enriched in small non-autonomous DNA transposons, suggesting that these TEs specifically target promoters and downstream regions. Furthermore, their presence in gene promoters is associated with decreased methylation levels. Conclusions: Our data show that TEs are major determinants of overall chromosome structure. We hypothesize that many of the the various chromosomal distribution patterns are the result of TE families targeting specific niches, rather than them accumulating where they have the least deleterious effects. PMID- 29270238 TI - Adjuvant-Loaded Spiky Gold Nanoparticles for Activation of Innate Immune Cells. AB - INTRODUCTION: Gold nanoparticles are versatile carriers for delivery of biomacromolecules. Here, we have developed spiky gold nanoparticles (SGNPs) that can efficiently deliver immunostimulatory agents. OBJECTIVES: Our goal was to develop a platform technology for co-delivery of multiple adjuvant molecules for synergistic stimulation and maturation of innate immune cells. METHODS: SGNPs were synthesized by a seed-mediated, surfactant-free synthesis method and incorporated with polyinosinic-polycytidylic acid (pIC) and DNA oligonucleotide containing unmethylated CpG motif (CpG) by an electrostatic layer-by-layer approach. Adjuvant-loaded SGNP nano-complexes were examined for their biophysical and biochemical properties and studied for immune activation using bone marrow derived dendritic cells (BMDCs). RESULTS: We have synthesized SGNPs with branched nano-spikes layered with pIC and/or CpG. Adjuvant-loaded SGNP nano-complexes promoted cellular uptake of the adjuvants. Importantly, we achieved spatio temporal control over co-delivery of pIC and CpG via SGNPs, which produced synergistic enhancement in cytokine release (IL-6, TNF-alpha) and upregulation of co-stimulatory markers (CD40, CD80, CD86) in BMDCs, compared with pIC, CpG, or their admixtures. CONCLUSION: SGNPs serve as a versatile delivery platform that allows flexible and on-demand cargo fabrication for strong activation of innate immune cells. PMID- 29270239 TI - Targeted bisulfite sequencing identified a panel of DNA methylation-based biomarkers for esophageal squamous cell carcinoma (ESCC). AB - Background: DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis. However, limited DNA methylation-based biomarkers have been described in esophageal squamous cell carcinoma (ESCC). Methods: A high throughput DNA methylation dataset (100 samples) of ESCC from The Cancer Genome Atlas (TCGA) project was analyzed and validated along with another independent dataset (12 samples) from the Gene Expression Omnibus (GEO) database. The methylation status of peripheral blood mononuclear cells and peripheral blood leukocytes from healthy controls was also utilized for biomarker selection. The candidate CpG sites as well as their adjacent regions were further validated in 94 pairs of ESCC tumor and adjacent normal tissues from the Chinese Han population using the targeted bisulfite sequencing method. Logistic regression and several machine learning methods were applied for evaluation of the diagnostic ability of our panel. Results: In the discovery stage, five hyper methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 * 10-4; cg19396867, P = 3.60 * 10-4; cg20655070, P = 3.60 * 10-4; cg26671652, P = 5.77 * 10-4; and cg27062795, P = 3.60 * 10-4. In the validation stage, the methylation status of both the five CpG sites and their adjacent genomic regions were tested. The diagnostic model based on the combination of these five genomic regions yielded a robust performance (sensitivity = 0.75, specificity = 0.88, AUC = 0.85). Eight statistical models along with five-fold cross-validation were further applied, in which the SVM model reached the best accuracy in both training and test dataset (accuracy = 0.82 and 0.80, respectively). In addition, subgroup analyses revealed a significant difference in diagnostic performance between the alcohol use and non alcohol use subgroups. Conclusions: Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis. PMID- 29270240 TI - Bronchial biopsy specimen as a surrogate for DNA methylation analysis in inoperable lung cancer. AB - Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results: Four thousand seven hundred and twenty-six CpGs (P < 1.0E-07) that were highly methylated in tumor tissues were identified from 42 lung cancer patients. Ten CpGs were selected for prediction of lung cancer. Genes including the 10 CpGs were classified into three categories: (i) transcription (HOXA9, SOX17, ZNF154, HOXD13); (ii) cell signaling (HBP1, SFRP1, VIPR2); and (iii) adhesion (PCDH17, ITGA5, CD34). Three logistic regression models based on the 10 CpGs classified 897 TCGA primary lung tissues with a sensitivity of 95.0~97.8% and a specificity of 97.4~98.7%. However, the classification performance of the models was very poor in bronchial washing samples: the area under the curve (AUC) was equal to 0.72~0.78. The methylation levels of the 10 CpGs in bronchial biopsy were not significantly different from those in surgically resected tumor tissues (P > 0.05, Wilcoxon rank-sum test). However, their methylation levels were significantly different between paired bronchial biopsy and washing (P < 0.05, Wilcoxon signed-rank test). Conclusions: The present study suggests that bronchial biopsy specimen may be used as a surrogate for DNA methylation analysis in patient with inoperable lung cancer. PMID- 29270237 TI - Proposed guidelines to evaluate scientific validity and evidence for genotype based dietary advice. AB - Nutrigenetic research examines the effects of inter-individual differences in genotype on responses to nutrients and other food components, in the context of health and of nutrient requirements. A practical application of nutrigenetics is the use of personal genetic information to guide recommendations for dietary choices that are more efficacious at the individual or genetic subgroup level relative to generic dietary advice. Nutrigenetics is unregulated, with no defined standards, beyond some commercially adopted codes of practice. Only a few official nutrition-related professional bodies have embraced the subject, and, consequently, there is a lack of educational resources or guidance for implementation of the outcomes of nutrigenetic research. To avoid misuse and to protect the public, personalised nutrigenetic advice and information should be based on clear evidence of validity grounded in a careful and defensible interpretation of outcomes from nutrigenetic research studies. Evidence requirements are clearly stated and assessed within the context of state-of-the art 'evidence-based nutrition'. We have developed and present here a draft framework that can be used to assess the strength of the evidence for scientific validity of nutrigenetic knowledge and whether 'actionable'. In addition, we propose that this framework be used as the basis for developing transparent and scientifically sound advice to the public based on nutrigenetic tests. We feel that although this area is still in its infancy, minimal guidelines are required. Though these guidelines are based on semi-quantitative data, they should stimulate debate on their utility. This framework will be revised biennially, as knowledge on the subject increases. PMID- 29270241 TI - Associations Between Adolescents' Perceptions of Alcohol Norms and Alcohol Behaviors: Incorporating Within-School Variability. AB - Background: Social norm interventions have been implemented in schools to address concerns of alcohol use among high school students; however, research in this area has not incorporated measures of variability that may better reflect the complexity of social influences. Purpose: To examine the association between perceived alcohol norms, the student and school-level variability of those norms, and alcohol use behaviors among high school students. Methods: A sample of 25,824 students from 58 high schools completed an online self-report survey. Hierarchical linear regression models were fit to examine the relationships between student- and school-level alcohol norm predictors, within school variability, and current alcohol use and binge drinking. Results: Individual- and school-level norms were predictive of both current alcohol use and binge drinking. Whereas measures of norm diversity at the school-level were not predictive of alcohol use behaviors, individual norm proximity was predictive of both current alcohol use and binge drinking. Discussion: The study findings were both consistent with prior research and support assertions that variability measures should be incorporated into social norms research approaches. Translation to Health Education Practice: The findings support the incorporation of student-level variability measures, which could assist in identifying students who are susceptible to peer influence. PMID- 29270242 TI - A High Rigidity and Precision Scanning Tunneling Microscope with Decoupled XY and Z Scans. AB - A new scan-head structure for the scanning tunneling microscope (STM) is proposed, featuring high scan precision and rigidity. The core structure consists of a piezoelectric tube scanner of quadrant type (for XY scans) coaxially housed in a piezoelectric tube with single inner and outer electrodes (for Z scan). They are fixed at one end (called common end). A hollow tantalum shaft is coaxially housed in the XY-scan tube and they are mutually fixed at both ends. When the XY scanner scans, its free end will bring the shaft to scan and the tip which is coaxially inserted in the shaft at the common end will scan a smaller area if the tip protrudes short enough from the common end. The decoupled XY and Z scans are desired for less image distortion and the mechanically reduced scan range has the superiority of reducing the impact of the background electronic noise on the scanner and enhancing the tip positioning precision. High quality atomic resolution images are also shown. PMID- 29270243 TI - Improving the Accessibility of Mobile OCR Apps Via Interactive Modalities. AB - Mobile optical character recognition (OCR) apps have come of age. Many blind individuals use them on a daily basis. The usability of such tools, however, is limited by the requirement that a good picture of the text to be read must be taken, something that is difficult to do without sight. Some mobile OCR apps already implement auto-shot and guidance mechanisms to facilitate this task. In this paper, we describe two experiments with blind participants, who tested these two interactive mechanisms on a customized iPhone implementation. These experiments bring to light a number of interesting aspects of accessing a printed document without sight, and enable a comparative analysis of the available interaction modalities. PMID- 29270244 TI - Lactose intolerance and gastrointestinal cow's milk allergy in infants and children - common misconceptions revisited. AB - Lactose is the main carbohydrate in human and mammalian milk. Lactose requires enzymatic hydrolysis by lactase into D-glucose and D-galactose before it can be absorbed. Term infants express sufficient lactase to digest about one liter of breast milk daily. Physiological lactose malabsorption in infancy confers beneficial prebiotic effects, including the establishment of Bifidobacterium-rich fecal microbiota. In many populations, lactase levels decline after weaning (lactase non-persistence; LNP). LNP affects about 70% of the world's population and is the physiological basis for primary lactose intolerance (LI). Persistence of lactase beyond infancy is linked to several single nucleotide polymorphisms in the lactase gene promoter region on chromosome 2. Primary LI generally does not manifest clinically before 5 years of age. LI in young children is typically caused by underlying gut conditions, such as viral gastroenteritis, giardiasis, cow's milk enteropathy, celiac disease or Crohn's disease. Therefore, LI in childhood is mostly transient and improves with resolution of the underlying pathology. There is ongoing confusion between LI and cow's milk allergy (CMA) which still leads to misdiagnosis and inappropriate dietary management. In addition, perceived LI may cause unnecessary milk restriction and adverse nutritional outcomes. The treatment of LI involves the reduction, but not complete elimination, of lactose-containing foods. By contrast, breastfed infants with suspected CMA should undergo a trial of a strict cow's milk protein-free maternal elimination diet. If the infant is not breastfed, an extensively hydrolyzed or amino acid-based formula and strict cow's milk avoidance are the standard treatment for CMA. The majority of infants with CMA can tolerate lactose, except when an enteropathy with secondary lactase deficiency is present. PMID- 29270245 TI - Preclinical Antileukemia Activity of Tramesan: A Newly Identified Bioactive Fungal Metabolite. AB - Despite improvements that occurred in the last decades in the acute myeloid leukemia (AML) treatment, clinical results are still unsatisfactory. More effective therapies are required, and innovative approaches are ongoing, including the discovery of novel antileukemia natural compounds. Several studies have described the activity of extracts from mushrooms which produce compounds that exhibited immunological and antitumor activities. The latter has been demonstrated to be promoted in vitro by mushroom polysaccharides via induction of apoptosis. However, the antileukemia activity of these compounds on primary cells is still not reported. In the present study, we examined the in vitro effects of Tramesan (TR), a bioactive compound extracted from Trametes versicolor, on leukemic cell lines and primary cells. Our results demonstrated that TR induced a marked growth inhibition of leukemic cell lines and primary cells from AML patients. The antiproliferative effects of TR were associated in primary AML cells with a significant increase of apoptosis. No significant cytotoxic effects were observed in normal peripheral blood mononuclear cells (MNC) from healthy donors. Our data demonstrated a cytotoxic activity of TR on leukemia cells prompting further translational applications. Ongoing studies are elucidating the molecular mechanisms underlying its antileukemic activity. PMID- 29270246 TI - The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers. AB - Cancer therapies are associated with increased infertility risk due to accelerated reproductive aging. Oxidative stress (OS) is a potential mechanism behind ovarian toxicity by cyclophosphamide (CPM), the most ovotoxic anticancer drug. An important sensor of OS is SIRT1, a NAD+-dependent deacetylase which regulates cellular defence and cell fate. This study investigated whether the natural carotenoid crocetin and the synthetic compound AS101 protect the ovary against CPM by modulating SIRT1 and mitochondrial markers. We found that the number of primordial follicles of female CD1 mice receiving crocetin plus CPM increased when compared with CPM alone and similar to AS101, whose protective effects are known. SIRT1 increased in CPM mouse ovaries revealing the occurrence of OS. Similarly, mitochondrial SIRT3 rose, whilst SOD2 and the mitochondrial biogenesis activator PGC1-alpha decreased, suggesting the occurrence of mitochondrial damage. Crocetin and AS101 administration prevented SIRT1 burst suggesting that preservation of redox balance can help the ovary to counteract ovarian damage by CPM. Decreased SIRT3 and increased SOD2 and PGC1-alpha in mice receiving crocetin or AS101 prior to CPM provide evidence for mitochondrial protection. Present results improve the knowledge of ovarian damage by CPM and may help to develop interventions for preserving fertility in cancer patients. PMID- 29270247 TI - Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome. AB - Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH), a critical step in the progression of nonalcoholic fatty liver disease (NAFLD) to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7), through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7-/-) and coeval wild-type (WT) mice were fed a high-fat diet (HFD) or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7 /- than WT mice, and only 1/7 Pr2x7-/- animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7-/- animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets. PMID- 29270249 TI - Draft genome sequences of three fungal-interactive Paraburkholderia terrae strains, BS007, BS110 and BS437. AB - Here, we report the draft genome sequences of three fungal-interactive 10.1601/nm.27008 strains, denoted BS110, BS007 and BS437. Phylogenetic analyses showed that the three strains belong to clade II of the genus 10.1601/nm.1619, which was recently renamed 10.1601/nm.26956. This novel genus primarily contains environmental species, encompassing non-pathogenic plant- as well as fungal interactive species. The genome of strain BS007 consists of 11,025,273 bp, whereas those of strains BS110 and BS437 have 11,178,081 and 11,303,071 bp, respectively. Analyses of the three annotated genomes revealed the presence of (1) a large suite of substrate capture systems, and (2) a suite of genetic systems required for adaptation to microenvironments in soil and the mycosphere. Thus, genes encoding traits that potentially confer fungal interactivity were found, such as type 4 pili, type 1, 2, 3, 4 and 6 secretion systems, and biofilm formation (PGA, alginate and pel) and glycerol uptake systems. Furthermore, the three genomes also revealed the presence of a highly conserved five-gene cluster that had previously been shown to be upregulated upon contact with fungal hyphae. Moreover, a considerable number of prophage-like and CRISPR spacer sequences was found, next to genetic systems responsible for secondary metabolite production. Overall, the three 10.1601/nm.27008 strains possess the genetic repertoire necessary for adaptation to diverse soil niches, including those influenced by soil fungi. PMID- 29270248 TI - Complete genome sequence analysis of Archaeoglobus fulgidus strain 7324 (DSM 8774), a hyperthermophilic archaeal sulfate reducer from a North Sea oil field. AB - Archaeoglobus fulgidus is the type species of genus Archaeoglobus Stetter 1998, a hyperthermophilic sulfate reducing group within the Archaeoglobi class of the euryarchaeota phylum. Members of this genus grow heterotrophically or chemolithoautotrophically with sulfate or thiosulfate as electron acceptors. Except for A. fulgidus strain 7324 and the candidate species "Archaeoglobus lithotrophicus", which both originate from deep oil-fields, the other members of this genus have been recovered from marine hydrothermal systems. Here we describe the features of the A. fulgidus strain 7324 genome as compared to the A. fulgidus VC16 type strain. The 2.3 Mbp genome sequence of strain 7324 shares about 93.5% sequence identity with that of strain VC16T but is about 138 Kbp longer, which is mostly due to two large 'insertions' carrying one extra cdc6 (cell-cycle control protein 6) gene, extra CRISPR elements and mobile genetic elements, a high-GC ncRNA gene (hgcC) and a large number of hypothetical gene functions. A comparison with four other Archaeoglobus spp. genomes identified 1001 core Archaeoglobus genes and more than 2900 pan-genome orthologous genes. PMID- 29270250 TI - Complete genome sequence of lytic bacteriophage RG-2014 that infects the multidrug resistant bacterium Delftia tsuruhatensis ARB-1. AB - A lytic bacteriophage RG-2014 infecting a biofilm forming multidrug resistant bacterium Delftia tsuruhatensis strain ARB-1 as its host was isolated from a full scale municipal wastewater treatment plant. Lytic phage RG-2014 was isolated for developing phage based therapeutic approaches against Delftia tsuruhatensis strain ARB-1. The strain ARB-1 belongs to the Comamonadaceae family of the Betaproteobacteria class. RG-2014 was characterized for its type, burst size, latent and eclipse time periods of 150 +/- 9 PFU/cell, 10-min, <5-min, respectively. The phage was found to be a dsDNA virus belonging to the Podoviridae family. It has an isometric icosahedrally shaped capsid with a diameter of 85 nm. The complete genome of the isolated phage was sequenced and determined to be 73.8 kbp in length with a G + C content of 59.9%. Significant similarities in gene homology and order were observed between Delftia phage RG 2014 and the E. coli phage N4 indicating that it is a member of the N4-like phage group. PMID- 29270252 TI - Lies, Damned Lies, and Surveys. PMID- 29270253 TI - Predictions and Prescriptions for Institutions Sponsoring Graduate Medical Education. PMID- 29270251 TI - Draft genome sequence of Acidithiobacillus thiooxidans CLST isolated from the acidic hypersaline Gorbea salt flat in northern Chile. AB - 10.1601/nm.2199 CLST is an extremely acidophilic gamma-proteobacteria that was isolated from the Gorbea salt flat, an acidic hypersaline environment in northern Chile. This kind of environment is considered a terrestrial analog of ancient Martian terrains and a source of new material for biotechnological applications. 10.1601/nm.2199 plays a key role in industrial bioleaching; it has the capacity of generating and maintaining acidic conditions by producing sulfuric acid and it can also remove sulfur layers from the surface of minerals, which are detrimental for their dissolution. CLST is a strain of 10.1601/nm.2199 able to tolerate moderate chloride concentrations (up to 15 g L-1 Cl-), a feature that is quite unusual in extreme acidophilic microorganisms. Basic microbiological features and genomic properties of this biotechnologically relevant strain are described in this work. The 3,974,949 bp draft genome is arranged into 40 scaffolds of 389 contigs containing 3866 protein-coding genes and 75 RNAs encoding genes. This is the first draft genome of a halotolerant 10.1601/nm.2199 strain. The release of the genome sequence of this strain improves representation of these extreme acidophilic Gram negative bacteria in public databases and strengthens the framework for further investigation of the physiological diversity and ecological function of 10.1601/nm.2199 populations. PMID- 29270254 TI - Gender Diversity in Residency Training: The Case for Affirmative Inclusion. PMID- 29270255 TI - Assessment Pearls for Competency-Based Medical Education. PMID- 29270256 TI - The 2017 ACGME Common Work Hour Standards: Promoting Physician Learning and Professional Development in a Safe, Humane Environment. PMID- 29270257 TI - Crowdsourcing in Surgical Skills Acquisition: A Developing Technology in Surgical Education. AB - Background : The application of crowdsourcing to surgical education is a recent phenomenon and adds to increasing demands on surgical residency training. The efficacy, range, and scope of this technology for surgical education remains incompletely defined. Objective : A systematic review was performed using the PubMed database of English-language literature on crowdsourced evaluation of surgical technical tasks up to April 2017. Methods : Articles were reviewed, abstracted, and analyzed, and were assessed for quality using the Medical Education Research Study Quality Instrument (MERSQI). Articles were evaluated with eligibility criteria for inclusion. Study information, performance task, subjects, evaluative standards, crowdworker compensation, time to response, and correlation between crowd and expert or standard evaluations were abstracted and analyzed. Results : Of 63 unique publications initially identified, 13 with MERSQI scores ranging from 10 to 13 (mean = 11.85) were included in the review. Overall, crowd and expert evaluations demonstrated good to excellent correlation across a wide range of tasks (Pearson's coefficient 0.59-0.95, Cronbach's alpha 0.32-0.92), with 1 exception being a study involving medical students. There was a wide range of reported interrater variability among experts. Nonexpert evaluation was consistently quicker than expert evaluation (ranging from 4.8 to 150.9 times faster), and was more cost effective. Conclusions : Crowdsourced feedback appears to be comparable to expert feedback and is cost effective and efficient. Further work is needed to increase consistency in expert evaluations, to explore sources of discrepant assessments between surgeons and crowds, and to identify optimal populations and novel applications for this technology. PMID- 29270258 TI - Attending Physician Remote Access of the Electronic Health Record and Implications for Resident Supervision: A Mixed Methods Study. AB - Background : Advances in information technology have increased remote access to the electronic health record (EHR). Concurrently, standards defining appropriate resident supervision have evolved. How often and under what circumstances inpatient attending physicians remotely access the EHR for resident supervision is unknown. Objective : We described a model of attending remote EHR use for resident supervision, and quantified the frequency and magnitude of use. Methods : Using a mixed methods approach, general medicine inpatient attendings were surveyed and interviewed about their remote EHR use. Frequency of use and supervisory actions were quantitatively examined via survey. Transcripts from semistructured interviews were analyzed using grounded theory to identify codes and themes. Results : A total of 83% (59 of 71) of attendings participated. Fifty seven (97%) reported using the EHR remotely, with 54 (92%) reporting they discovered new clinical information not relayed by residents via remote EHR use. A majority (93%, 55 of 59) reported that this resulted in management changes, and 54% (32 of 59) reported making immediate changes by contacting cross-covering teams. Six major factors around remote EHR use emerged: resident, clinical, educational, personal, technical, and administrative. Attendings described resident and clinical factors as facilitating "backstage" supervision via remote EHR use. Conclusions : In our study to assess attending remote EHR use for resident supervision, attendings reported frequent remote use with resulting supervisory actions, describing a previously uncharacterized form of "backstage" oversight supervision. Future work should explore best practices in remote EHR use to provide effective supervision and ultimately improve patient safety. PMID- 29270259 TI - Supervision Is Not Education: The Dark Side of Remote Access to the Electronic Health Record. PMID- 29270260 TI - Straight Line Scoring by Clinical Competency Committees Using Emergency Medicine Milestones. AB - Background : In 2013, milestone ratings became a reporting requirement for emergency medicine (EM) residency programs. Programs rate each resident in the fall and spring on 23 milestone subcompetencies. Objective : This study examined the incidence of straight line scoring (SLS) for EM Milestone ratings, defined as a resident being assessed the same score across the milestone subcompetencies. Methods : This descriptive analysis measured the frequencies of SLS for all Accreditation Council for Graduate Medical Education (ACGME)-accredited EM programs during the 2015-2016 academic year. Outcomes were the frequency of SLS in the fall and spring milestone assessments, changes in the number of SLS reports, and reporting trends. Chi-square analysis compared nominal variables. Results : There were 6257 residents in the fall and 6588 in the spring. Milestone scores were reported for 6173 EM residents in the fall (99% of 6257) and spring (94% of 6588). In the fall, 93% (5753 residents) did not receive SLS ratings and 420 (7%) did, with no significant difference compared with the spring (5776 [94%] versus 397 [6%]). Subgroup analysis showed higher SLS results for residents' first ratings (183 of 2136 versus 237 of 4220, P < .0001) and for their final ratings (200 of 2019 versus 197 of 4354, P < .0001). Twenty percent of programs submitted 10% or more SLS ratings, and a small percentage submitted more than 50% of ratings as SLS. Conclusions : Most programs did not submit SLS ratings. Because of the statistical improbability of SLS, any SLS ratings reduce the validity assertions of the milestone assessments. PMID- 29270261 TI - On Rating Angels: The Halo Effect and Straight Line Scoring. PMID- 29270262 TI - Nuance and Noise: Lessons Learned From Longitudinal Aggregated Assessment Data. AB - Background : Competency-based medical education requires frequent assessment to tailor learning experiences to the needs of trainees. In 2012, we implemented the McMaster Modular Assessment Program, which captures shift-based assessments of resident global performance. Objective : We described patterns (ie, trends and sources of variance) in aggregated workplace-based assessment data. Methods : Emergency medicine residents and faculty members from 3 Canadian university affiliated, urban, tertiary care teaching hospitals participated in this study. During each shift, supervising physicians rated residents' performance using a behaviorally anchored scale that hinged on endorsements for progression. We used a multilevel regression model to examine the relationship between global rating scores and time, adjusting for data clustering by resident and rater. Results : We analyzed data from 23 second-year residents between July 2012 and June 2015, which yielded 1498 unique ratings (65 +/- 18.5 per resident) from 82 raters. The model estimated an average score of 5.7 +/- 0.6 at baseline, with an increase of 0.005 +/- 0.01 for each additional assessment. There was significant variation among residents' starting score (y-intercept) and trajectory (slope). Conclusions : Our model suggests that residents begin at different points and progress at different rates. Meta-raters such as program directors and Clinical Competency Committee members should bear in mind that progression may take time and learning trajectories will be nuanced. Individuals involved in ratings should be aware of sources of noise in the system, including the raters themselves. PMID- 29270263 TI - Competency Assessment in Family Medicine Residency: Observations, Knowledge-Based Examinations, and Advancement. AB - Background : The Family Medicine (FM) Milestones are competency-based assessments of residents in key dimensions relevant to practice in the specialty. Residency programs use the milestones in semiannual reviews of resident performance from the time of entry into the program to graduation. Objective : Using a national sample, we investigated the relationship of FM competency-based assessments to resident progress and the complementarity of milestones with knowledge-based assessments in FM residencies. Methods : We used midyear and end-of-year milestone ratings for all FM residents in Accreditation Council for Graduate Medical Education-accredited programs during academic years 2014-2015 and 2015 2016. The milestones contain 22 items across 6 competencies. We created a summative index across the milestones. The American Board of Family Medicine database provided resident demographics and in-training examination (ITE) scores. We linked information to the milestone data. Results : The sample encompassed 6630 FM residents. The summative milestone index increased, on average, for each cohort (postgraduate year 1 [PGY-1] to PGY-2 and PGY-2 to PGY-3) at each assessment. The correlation between the milestone index that excluded the medical knowledge milestone and ITE scores was r = .195 (P < .001) for PGY-1 to PGY-2 cohort and r = .254 (P < .001) for PGY-2 to PGY-3 cohort. For both cohorts, ITE scores and composite milestone assessments were higher for residents who advanced than for those who did not. Conclusions : Competency-based assessment using the milestones for FM residents seems to be a viable multidimensional tool to assess the successful progression of residents. PMID- 29270264 TI - Sometimes Means Some of the Time: Residents' Overlapping Responses to Vague Quantifiers on the ACGME-I Resident Survey. AB - Background : Vague quantifiers used in the Accreditation Council for Graduate Medical Education-International (ACGME-I) resident survey are open to interpretation, raising concerns about the validity of survey scores. Residency programs may be unduly cited if survey responses are affected by differing judgments of vague quantifiers. Objective : Through investigating frequency judgment overlap, we assessed the validity of vague quantifiers by quantifying variation in residents' frequency judgment of the following response options: never, rarely, sometimes, very often, and extremely often. Methods : We conducted a cross-sectional survey of residents in 2 ACGME-I accredited institutions in Singapore. Participants assigned a frequency judgment to response options in 8 questions in the ACGME-I Resident Survey. Overlap in frequency judgment was computed using the minimum and maximum frequency judgment for each response option. This was ascertained to have occurred when the maximum frequency of the preceding category exceeded the minimum frequency of the downstream categories. The percentage of participants whose frequency judgment overlapped was computed. Results : Of 652 residents, 289 (44%) responded; after exclusions of incomplete and careless responses, 119 responses (18%) were included in the study. Frequency judgment overlap was more frequent for vague quantifiers that are adjacent, ranging from 11% to 50% for questions in faculty, evaluation, and resources domains. The percentage of frequency judgment overlap was greatest for duty hour questions, with an overlap between 21% and 47% for adjacent categories. Conclusions : Residents demonstrated wide variation in frequency judgment of vague quantifiers, especially on the duty hour questions in the ACGME-I resident survey. PMID- 29270265 TI - Teaching High-Value Care in Pediatrics: A National Survey of Current Practices and Guide for Future Curriculum Development. AB - Background : Health care expenditures in the United States are increasing at an unsustainable pace. There have been calls to incorporate education on resource stewardship into medical training, yet the perceived need for and current use of high-value care (HVC) curricula in pediatrics residency programs is unknown. Objective : We described the current national landscape of HVC curricula in pediatrics residencies, including characterization of current programs, barriers to the practice of HVC, and clarification of preferred curricula types. Methods : Using a cross-sectional study design, we conducted a national, anonymous, web based survey of pediatrics residency program directors and pediatrics chief residents in fall 2014. Results : We received responses from 85 of 199 (43%) pediatrics program directors and 74 of 199 (37%) pediatrics chief residents. Only 10% (8 of 80) of program directors and 12% (8 of 65) of chief residents reported having a formal curriculum on HVC. Respondents identified the largest barriers to HVC as a lack of cost transparency (program directors) and attending physicians having the final say in treatment decisions (chief residents). The majority of respondents (83%, 121 of 146) agreed their program needs a HVC curriculum, and 90% (131 of 145) reported they would use a curriculum if it was available. Respondents significantly preferred a case-based conference discussion format over other approaches. Conclusions : Most pediatrics residency programs responding to a survey lacked formal HVC curricula. There is a desire nationally for HVC education in pediatrics, particularly in a case-based discussion format. PMID- 29270266 TI - Google Glass Video Capture of Cardiopulmonary Resuscitation Events: A Pilot Simulation Study. AB - Background : Video recording of resuscitation from fixed camera locations has been used to assess adherence to guidelines and provide feedback on performance. However, inpatient cardiac arrests often happen in unpredictable locations and crowded rooms, making video recording of these events problematic. Objective : We sought to understand the feasibility of Google Glass (GG) as a method for recording inpatient cardiac arrests and capturing salient resuscitation factors for post-event review. Methods : This observational study involved recording simulated cardiac arrest events on inpatient medical wards. Each simulation was reviewed by 3 methods: in-room physician direct observation, stationary video camera (SVC), and GG. Nurse and physician specialists analyzed the videos for global visibility and audibility, as well as recording quality of predefined resuscitation events and behaviors. Resident code leaders were surveyed regarding attitudes toward GG use in the clinical emergency setting. Results : Of 11 simulated cardiac arrest events, 9 were successfully recorded by all observation methods (1 GG failure, 1 SVC failure). GG was judged slightly better than SVC recording for average global visualization (3.95 versus 3.15, P = .0003) and average global audibility (4.77 versus 4.42, P = .002). Of the GG videos, 19% had limitations in overall interpretability compared with 35% of SVC recordings (P = .039). All 10 survey respondents agreed that GG was easy to use; however, 2 found it distracting and 3 were uncomfortable with future use during actual resuscitations. Conclusions : GG is a feasible and acceptable method for capturing simulated resuscitation events in the inpatient setting. PMID- 29270267 TI - Nighthawk: Making Night Float Education and Patient Safety Soar. AB - Background : Some residency programs responded to duty hour restrictions by implementing night rotations. Night supervision models can vary, resulting in potential patient safety issues and educational voids for residents. Objective : We evaluated the impact of multiple evidence-based interventions on resident satisfaction with supervision, perception of the education value of night rotations, and residents' use of online educational materials. Methods : The night team was augmented with an intern to assist with admissions and a senior resident (the "nighthawk") to supervise inpatient care and deliver a night medicine curriculum. We instituted a "must-call" list, with specific clinical events requiring mandatory attending notification, and reduced conflict in the role of the night float team. We studied patient contact, online curriculum use, residents' perceptions of nighthawk involvement, exposure to educational materials, and satisfaction with supervision. Results : During the first half of academic year 2016-2017, 51% (64 of 126) of trainees were on the night medicine rotation. The nighthawk reviewed 1007 intern plans (15 per night; range, 6-36) and supervised 215 hands-on evaluations, including codes and rapid responses (3 per night; range, 0-12). The number of users of the online education materials increased by 85% (13 to 24), and instances of use increased 35% (85 to 115). The majority of residents (79%, 27 of 34) favored the new system. Conclusions : A nighthawk rotation, a must-call list, and reducing conflict in night team members' roles improved resident satisfaction with supervision and the night medicine rotation, resulting in increased communication. PMID- 29270268 TI - Development and Evaluation of a Novel Survey Tool Assessing Inpatient Consult Service Performance. AB - Background : Subspecialty consultation in inpatient medicine is increasing, and enhancing performance of consultation services may have a broad-reaching impact. Multisource feedback is an important tool in assessing competence and improving performance. A mechanism for primary team resident feedback on performance of consult services has not been described. Objective : We developed and evaluated an instrument designed to assess internal medicine (IM) subspecialty inpatient consult service performance. We hypothesized that the instrument would be feasible to administer and provide important information to fellowship directors. Methods : The instrument was administered in 2015 and 2016 at a single academic center. All IM residents were invited to evaluate 10 IM subspecialty consult services on 4 items and an overall satisfaction rating. The instrument allowed for free-text feedback to fellows. Program directors completed another survey assessing the impact of the consult service evaluation. Results : A total of 113 residents responded (47 in 2015 and 66 in 2016, for a combined response rate of 35%). Each of the 4 items measured (communication, professionalism, teaching, and pushback) correlated significantly with the overall satisfaction rating in univariate and multivariate analyses. There were no differences in ratings across postgraduate year or year of administration. There was considerable variation in ratings among the services evaluated. The 7 program directors who provided feedback found the survey useful and made programmatic changes following evaluation implementation. Conclusions : A primary team resident evaluation of inpatient medicine subspecialty consult services is feasible, provides valuable information, and is associated with changes in consult service structure and curricula. PMID- 29270269 TI - Comprehensive Assessment of Struggling Learners Referred to a Graduate Medical Education Remediation Program. AB - Background : Implementation of the Next Accreditation System has provided a standardized framework for identifying learners not meeting milestones, but there is as yet no corresponding framework for remediation. Objective : We developed a comprehensive assessment process that allows correct diagnosis of a struggling learner's deficit(s) to promote successful remediation. Methods : At the University of Pennsylvania, resident learners within the Department of Medicine who are not meeting milestones are referred to the Early Intervention Remediation Committee (EIRC). The EIRC, composed of 14 faculty members with expertise in remediation, uses a standardized process to assess learners' deficits. These faculty members categorize primary deficits as follows: medical knowledge, clinical reasoning, organization and efficiency, professionalism, and communication skills. The standardized process of assessment includes an analysis of the learner's file, direct communication with evaluators, an interview focused on learner perception of the problem, screening for underlying medical or psychosocial issues, and a review of systems for deficits in the 6 core competencies. Participants were surveyed after participating in this process. Results : Over a 2-year period, the EIRC assessed and developed remediation plans for 4% of learners (14 of a total 342). Following remediation and reassessment, the identified problems were satisfactorily resolved in all cases with no disciplinary action. While the process was time intensive, an average of 45 hours per learner, the majority of faculty and residents rated it as positive and beneficial. Conclusions : This structured assessment process identifies targeted areas for remediation and adds to the tools available to Clinical Competency Committees. PMID- 29270271 TI - Does an Objective Structured Clinical Examination Fit Your Assessment Toolbox? PMID- 29270270 TI - A Resident Initiative Improves Hepatitis C Screening Rates in Primary Care Clinics. AB - Background : Electronic reminders for clinical patient counseling have proven to be an effective response to national recommendations to increase risk factor and birth cohort hepatitis C virus (HCV) screening. It is not known whether a resident-led educational intervention alone could increase screening rates where support for electronic intervention may be limited. Objective : We determined whether a resident-designed and resident-implemented educational intervention would significantly improve HCV screening rates in primary care clinics. Methods : The baseline HCV screening rate was determined retrospectively in our resident community-based primary care clinics. We then implemented an educational intervention that included presenting during resident conference, posting signs in resident work areas, and providing educational pamphlets to patients. We collected screening rate data at 3 and 6 months postintervention. The screening rate was defined as patients screened in clinic divided by the number of patients eligible for screening. Results : The screening rate increased significantly from preintervention (6%, 64 of 1023) to 3 months (35%, 363 of 1026) and 6 months (41%, 443 of 1070) and between 3 and 6 months (P < .001). The percentage of screened patients who pursued testing increased significantly between preintervention (62%, 16 of 26) and 6 months (81%, 105 of 130), and between 3 months (67%, 95 of 141) and 6 months (P = .019). Conclusions : An educational intervention designed and implemented by residents significantly increased the screening and testing rates for HCV in community-based resident clinics. PMID- 29270272 TI - Joy and the ACGME Common Program Requirements. PMID- 29270273 TI - When a Mass Casualty Is Your Own. PMID- 29270274 TI - ICRE Top Research Papers. PMID- 29270275 TI - A Question of Goals: Is Reducing Resident Burnout Enough? PMID- 29270276 TI - Reconciling Entrustment and Competence. PMID- 29270277 TI - Ensuring Success of a Residents-as-Mentors Program: Promoting Mentor Availability. PMID- 29270278 TI - Preventing Publication Misrepresentation Among Residency and Fellowship Applicants. PMID- 29270279 TI - Immediate Application of Knowledge Gained: From Journal Article to Improved Patient Care-Important Patient Clues Trainees May Be Missing. PMID- 29270280 TI - Imperiled Mohs Surgery Match Exemptions Damage the Match and Should Be Restricted. PMID- 29270281 TI - Association of the 2003 and 2011 ACGME Resident Duty Hour Reforms With Internal Medicine Initial Certification Examination Performance. PMID- 29270282 TI - Improvement in Context: Exploring Aims, Improvement Priorities, and Environmental Considerations in a National Sample of Programs Using "Small Data". AB - Background: In 2013, the Accreditation Council for Graduate Medical Education (ACGME) transitioned into a new accreditation system to reduce burden, focus on outcomes, and promote innovation and improvement. One component is a self-study that includes aims, an environmental assessment, and setting improvement priorities. The ACGME initiated voluntary site visits following the self-study. Objective: We explored common themes in program aims and assessment of their environment. Methods: Using grounded theory, inductive and deductive qualitative methods, and truth grounding, we analyzed data from voluntary site visits of 396 core and subspecialty programs between June 2015 and September 2017, with a focus on common themes. Results: We report common themes for aims and the dimensions of the environmental assessment. Themes for strengths include a collegial, supportive learning environment; responsive leaders; and experiences that prepare residents for unsupervised practice. Improvement priorities encompass low learner engagement and "content mismatch" in didactic education, balancing education and service at a time of growing clinical volumes, and improving the utility of assessment systems. Common opportunities encompass collaborations that improve education, involving alumni and harnessing technology to enrich education, while threats include an unsustainable effort for many program leaders, clinical pressures on faculty, and loss of external sites important for education. Linked dimensions of the environmental assessment suggest benefit in a growing focus on learners, and approaches to ensure a humanistic learning environment that allows for growth, self-determination, and inclusion. Conclusions: The findings highlight actionable themes for the environmental assessment. We discuss implications for programs, institutions, and the ACGME. PMID- 29270283 TI - Sparsifying machine learning models identify stable subsets of predictive features for behavioral detection of autism. AB - Background: Autism spectrum disorder (ASD) diagnosis can be delayed due in part to the time required for administration of standard exams, such as the Autism Diagnostic Observation Schedule (ADOS). Shorter and potentially mobilized approaches would help to alleviate bottlenecks in the healthcare system. Previous work using machine learning suggested that a subset of the behaviors measured by ADOS can achieve clinically acceptable levels of accuracy. Here we expand on this initial work to build sparse models that have higher potential to generalize to the clinical population. Methods: We assembled a collection of score sheets for two ADOS modules, one for children with phrased speech (Module 2; 1319 ASD cases, 70 controls) and the other for children with verbal fluency (Module 3; 2870 ASD cases, 273 controls). We used sparsity/parsimony enforcing regularization techniques in a nested cross validation grid search to select features for 17 unique supervised learning models, encoding missing values as additional indicator features. We augmented our feature sets with gender and age to train minimal and interpretable classifiers capable of robust detection of ASD from non ASD. Results: By applying 17 unique supervised learning methods across 5 classification families tuned for sparse use of features and to be within 1 standard error of the optimal model, we find reduced sets of 10 and 5 features used in a majority of models. We tested the performance of the most interpretable of these sparse models, including Logistic Regression with L2 regularization or Linear SVM with L1 regularization. We obtained an area under the ROC curve of 0.95 for ADOS Module 3 and 0.93 for ADOS Module 2 with less than or equal to 10 features. Conclusions: The resulting models provide improved stability over previous machine learning efforts to minimize the time complexity of autism detection due to regularization and a small parameter space. These robustness techniques yield classifiers that are sparse, interpretable and that have potential to generalize to alternative modes of autism screening, diagnosis and monitoring, possibly including analysis of short home videos. PMID- 29270284 TI - A Bottom Up Approach Towards Artificial Oxygenases by Combining Iron Coordination Complexes and Peptides. AB - Supramolecular systems resulting from the combination of peptides and a chiral iron coordination complex catalyze asymmetric epoxidation with aqueous hydrogen peroxide, providing good to excellent yields and high enantioselectivities in short reaction times. The peptide is shown to play a dual role; the terminal carboxylic acid assists the iron center in the efficient H2O2 activation step, while its beta-turn structure is crucial to induce high enantioselectivity in the oxygen delivering step. The high levels of stereoselection (84-92% ee) obtained by these supramolecular catalysts in the epoxidation of 1,1'-alkyl orthosubstituted styrenes, a notoriously challenging class of substrates for asymmetric catalysis, are not attainable with any other epoxidation methodology described so far. The current work combining an iron center ligated to N and O based ligands, and a peptide scaffold that shapes the second coordination sphere may be seen as a bottom up approach towards the design of artificial oxygenases. PMID- 29270285 TI - Dynamic Volume Completion and Deformation. AB - A new class of dynamic volume completion is introduced, where image elements (e.g., occluding semi-ellipses placed at the edge of an object) can link across a gap between two or more objects, leading to the perception of illusory volumes that deform as those image elements are set into relative motion. These new demonstrations provide further evidence that volume completion is not dictated solely by contour relatability constraints, but is instead a dynamic process of 3D shape construction that also takes into account dynamic cues to object shape, even in the absence of any contour relatability whatsoever. PMID- 29270286 TI - The Inference of Friendly Communicative Atmosphere Created by Geometric Shapes. AB - Many previous studies on inference of social behaviors using geometric shapes have explored causality, animacy, intention, and desire inferred from the movements of such shapes; however, inference of communicative atmosphere in terms of friendliness/antagonism using geometric shapes has not yet been studied well. This study investigated how a friendly/antagonistic communicative atmosphere was inferred from the movement of two egg shapes. We developed animations for these shapes involving forward/backward/parallel tilts with coincidence/incoincidence of synchronous movement. Results showed significant differences in the inference of friendly/antagonistic atmosphere between coincident and incoincident synchronous movement. In addition, the inference of a friendly atmosphere was affected by the combination of forward tilt with incoincident movement, which may be interpreted as interaction between the shapes, such as responding or providing feedback. This suggests that individuals may infer a friendly/antagonistic communicative atmosphere from both coincident movement and incoincident movement interpreted as an interaction. PMID- 29270287 TI - Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells. AB - Background: The aim of this study is to determine the effect of hypoxia on axitinib and sorafenib-treated renal cell carcinoma (RCC) cells. Hypoxia is a crucial factor influencing transcription process via protein modulation, which was shown i.e. in pancreatic cancer. Until now, hypoxia has been defined as associated with poorer outcome and inducing chemotherapy resistance in solid tumors. The unique phenomenon of pseudo-hypoxia connected with vhl mutation was observed in clear-cell, but not in papillary RCC, and the treatment of this subtype of cancer is still challenging. Despite the introduction of new antiangiogenic targeted therapies (inter alia tyrosine kinase inhibitors, TKIs), patients still develop both primary and acquired resistance. Overcoming resistance to TKIs, also in papillary RCC, may be possible by finding significantly modified protein expression. To do this, hypoxic 3D in vitro models must be developed to mimic both molecular pathways typical for low oxygen tension and cell-cell dynamics in tumor-like spatial structures. Results: Clear-cell and papillary renal cell carcinoma (cc and pRCC) cell lines were used in the study to determine the impact of hypoxia on primary drug resistance phenomenon previously observed in papillary, but not in ccRCC. Resistance was confirmed in monolayer culture and in 3D models in soft agar and suspension culture. Human papillary kidney cancer stem-like cells (HKCSCs) cultured in hypoxia developed resistance to sorafenib, while when cultured in normoxia resistance to axitinib has developed. Flow cytometry revealed that hypoxia decreased proliferation rates in all investigated RCC cells. In HKCSCs, there was an increase of quiescent cells (Ki67-) and percentage of cells arrested in S phase. It also appeared that map2k1 and eif4b protein expression is altered in papillary RCC resistant to tested drugs at different oxygen tensions. Also, HKCSCs did not express vegfr-1, braf nor c-kit, TKIs target receptors, which were present in ccRCC cells sensitive to TKI treatment. Conclusions: The results confirm that low oxygen tension affects RCC cells. Hypoxia facilitates induction of sorafenib resistance in pRCC and induces map2k1 overexpression, while normoxic axitinib-resistant cells up regulated eif4b. Further studies may determine if map2k1 or eif4b proteins play a role in pRCC resistance to TKIs. It is also of interest to establish if other than vegfr-1, braf, c-kit receptors can serve as potential molecular targets for more effective anti-RCC strategies. PMID- 29270288 TI - First confirmation by PCR of Jaagsiekte sheep retrovirus in Ireland and prevalence of ovine pulmonary adenocarcinoma in adult sheep at slaughter. AB - Background: Ovine pulmonary adenocarcinoma (OPA), caused by Jaagsiekte sheep retrovirus (JSRV), is characterised by the development of invariably fatal lung tumours primarily in adult sheep. High infection rates and disease prevalence can develop during initial infection of flocks, leading to on-farm economic losses and animal welfare issues in sheep with advanced disease. The disease has been reported in Ireland and is notifiable, but the presence of JSRV has never been confirmed using molecular methods in this country. Additionally, due to the difficulties in ante-mortem diagnosis (especially of latently-infected animals, or those in the very early stages of disease), accurate information regarding national prevalence and distribution is unavailable. This study aimed to confirm the presence of JSRV in Ireland and to obtain estimates regarding prevalence and distribution by means of an abattoir survey utilising gross examination, histopathology, JSRV-specific reverse transcriptase polymerase chain reaction (RT PCR) and SU protein specific immunohistochemistry (IHC) to examine the lungs of adult sheep. Results: Lungs from 1911 adult sheep were examined macroscopically in the abattoir and 369 were removed for further testing due to the presence of gross lesions of any kind. All 369 were subject to histopathology and RT-PCR, and 46 to IHC. Thirty-one lungs (31/1911, 1.6%) were positive for JSRV by RT-PCR and/or IHC but only ten cases of OPA were confirmed (10/1911, 0.5%) Four lung tumours not associated with JSRV were also identified. JSRV-positive sheep tended to cluster within the same flocks, and JSRV-positive sheep were identified in the counties of Donegal, Kerry, Kilkenny, Offaly, Tipperary, Waterford and Wicklow. Conclusions: The presence of JSRV has been confirmed in the Republic of Ireland for the first time using molecular methods (PCR) and IHC. In addition, an estimate of OPA prevalence in sheep at slaughter and information regarding distribution of JSRV infection has been obtained. The prevalence estimate appears similar to that of the United Kingdom (UK). Results also indicate that the virus has a diverse geographical distribution throughout Ireland. These data highlights the need for further research to establish national control and monitoring strategies. PMID- 29270289 TI - Beamforming for hyperthermia treatment by training a weighted network of an ultrasonic array. AB - We propose a beamforming algorithm based on waveform diversity for hyperthermia treatment of breast cancer using an ultrasonic array. The introduced array has a structure with a network connecting the feeding nodes and the array elements, and the objective of the algorithm is to train the weight matrix of the network to minimize the difference between the generated beam pattern and the ideal one. The training procedure of the algorithm, which is inspired by the idea of machine learning, comprises three parts: forward calculation, comparison, and backward calculation. The forward calculation maps the weight matrix to the beam pattern, and in the comparison step, the generated beam pattern is modified based on the error, and finally, the backward calculation maps the modified beam pattern to a refined weight matrix which performs better than the original one. An optimal weight matrix is obtained by iterative training. The effectiveness of the algorithm is demonstrated by using numerical simulations. PMID- 29270290 TI - Can a toxin gene NAAT be used to predict toxin EIA and the severity of Clostridium difficile infection? AB - Background: Diagnosis of C. difficile infection (CDI) is controversial because of the many laboratory methods available and their lack of ability to distinguish between carriage, mild or severe disease. Here we describe whether a low C. difficile toxin B nucleic acid amplification test (NAAT) cycle threshold (CT) can predict toxin EIA, CDI severity and mortality. Methods: A three-stage algorithm was employed for CDI testing, comprising a screening test for glutamate dehydrogenase (GDH), followed by a NAAT, then a toxin enzyme immunoassay (EIA). All diarrhoeal samples positive for GDH and NAAT between 2012 and 2016 were analysed. The performance of the NAAT CT value as a classifier of toxin EIA outcome was analysed using a ROC curve; patient mortality was compared to CTs and toxin EIA via linear regression models. Results: A CT value <=26 was associated with >=72% toxin EIA positivity; applying a logistic regression model we demonstrated an association between low CT values and toxin EIA positivity. A CT value of <=26 was significantly associated (p = 0.0262) with increased one month mortality, severe cases of CDI or failure of first line treatment. The ROC curve probabilities demonstrated a CT cut off value of 26.6. Discussions: Here we demonstrate that a CT <=26 indicates more severe CDI and is associated with higher mortality. Samples with a low CT value are often toxin EIA positive, questioning the need for this additional EIA test. Conclusions: A CT <=26 could be used to assess the potential for severity of CDI and guide patient treatment. PMID- 29270291 TI - Mini-review on initiatives to interfere with the propagation and clearance of alpha-synuclein in Parkinson's disease. AB - In this mini-review, we summarize recent findings relating to the prion-like propagation of alpha-synuclein (alpha-syn) and the development of novel therapeutic strategies to target synucleinopathy in Parkinson's disease (PD). We link the Braak's staging hypothesis of PD with the recent evidence from in-vivo and in-vitro studies for the prion-like cell-to-cell propagation of alpha-syn (via exocytosis and endocytosis). The classical accumulation of aggregated alpha syn in PD may result from an increased production or a failure in the mechanisms of clearance of alpha-syn. We discuss novel agents, currently in clinical trial for PD including the ones that impact the aggregation of alpha-syn and others that interfere with alpha-syn endocytosis as a means to target the progression of the disease. PMID- 29270292 TI - Contribution of chronic conditions to functional limitations using a multinomial outcome: results for the older population in Belgium and Brazil. AB - Background: The global phenomenon of population ageing is creating new challenges in both high and middle income countries, as functional limitations are expected to increase with age. The attribution method has been proposed to identify which conditions contribute most to disability using cross-sectional data. Although the original method was based on binary outcomes, we recently proposed an extension to multinomial responses, since different disability levels are often investigated in surveys. This is the first application of the extended method to evaluate differences in the contribution of chronic conditions to functional limitations in the older population of Brazil and Belgium. Methods: Representative data from individuals aged >=65 years who participated in the 2008 or 2013 Health Interview Surveys in Belgium (N = 4521) or in the 2008 National Household Sample Survey in Brazil (N = 28,437) were analysed. Individuals were classified as without, moderate or severe functional limitations, based on three activities of daily living: eating, showering, and toileting. Six chronic conditions common to the surveys - diabetes, heart diseases, musculoskeletal conditions, depression, chronic respiratory diseases, and cancer - were included in the analysis. Separate multinomial additive hazards models by gender for each country were fitted. Results: The prevalence of moderate functional limitations was larger in men in Brazil (8.4%) compared to Belgium (6.0%) and similar in women (approximately 12.0%). Conversely, the severe prevalence in men was similar in the two countries (around 8.0%) and higher in women from Belgium (16.6%) than from Brazil (9.1%). Musculoskeletal conditions were the main contributors to the prevalence of functional limitations in men and women in Belgium but only in men and women with moderate functional limitations in Brazil. Depression and heart diseases contributed most to the severe prevalence of functional limitations in men and women in Brazil, respectively. Conclusions: Our findings provide a better understanding of differences in the prevalence of different levels of functional limitations in Brazil and Belgium. These differences can be related to differences in socioeconomic conditions, health care access and quality, disease diagnosis, stage of epidemiology transition, life expectancy, and the prevalence of lifestyle risk factors in the two countries. PMID- 29270294 TI - Being stressed outside the park-conservation of African elephants (Loxodonta africana) in Namibia. AB - The conservation of the African savanna elephant (Loxodonta africana) is of prime importance for many African countries. Interactions between elephants and humans are known to induce stress and thereby have the potential to affect elephants' fitness. In Namibia, anthropogenic disturbances are increasing due to increasing human population size and development, particularly near protected areas, such as national parks. In this study, we investigated elephant stress levels in relation to their land use, specifically their protection status, comparing elephants within Etosha National Park in Namibia with elephants residing outside the park. We noninvasively collected dung samples of 91 elephants and determined the concentration of faecal glucocorticoid metabolites (fGCM), an indicator of physiological stress. Elephants outside the park (N = 35) had significantly higher concentrations of fGCM than those inside ENP (N = 56), suggesting that, despite including community-based conservancies, unprotected areas are more stressful for elephants than protected areas, most likely due to increased interactions with humans. We also found that males had lower fGCM concentrations than females, but no significant effect of age, body size or group size was detected. Additionally, herd sizes were significantly smaller and calf recruitment was potentially lower in unprotected areas. These findings underpin the importance of protected areas such as ENP, while encouraging decision-makers to continue reducing and mitigating potential human-induced disturbances. PMID- 29270296 TI - Squamous cell carcinoma (SCC) arising in esophageal colon interposition. AB - The idea of using the colon to replace a resected esophagus has a long history. The colon has become a favored organ for esophageal reconstruction in adults with esophageal cancer when the stomach is not suitable or is unavailable. In this article, we introduce an 84-year-old woman that she had surgery 40 years ago and presented with an invasive well differentiated squamous cell carcinoma of colonic origin in reconstructed esophagus. PMID- 29270293 TI - Targeting Fibronectin for Cancer Imaging and Therapy. AB - During cancer progression, the extracellular matrix (ECM) undergoes dramatic changes, which promote cancer cell migration and invasion. In the remodeled tumor ECM, fibronectin (FN) level is upregulated to assist tumor growth, progression, and invasion. FN serves as a central organizer of ECM molecules and mediates the crosstalk between the tumor microenvironment and cancer cells. Its upregulation is correlated with angiogenesis, cancer progression, metastasis, and drug resistance. A number of FN-targeting ligands have been developed for cancer imaging and therapy. Thus far, FN-targeting imaging agents have been tested for nuclear imaging, MRI, and fluorescence imaging, for tumor detection and localization. FN-targeting therapeutics, including nuclear medicine, chemotherapy drugs, cytokines, and photothermal moieties, were also developed in cancer therapy. Because of the prevalence of FN overexpression in cancer, FN targeting imaging agents and therapeutics have the promise of broad applications in the diagnosis, treatment, and image-guided interventions of many types of cancers. This review will summarize current understanding on the role of FN in cancer, discuss the design and development of FN-targeting agents, and highlight the applications of these FN-targeting agents in cancer imaging and therapy. PMID- 29270295 TI - Population-level plasticity in foraging behavior of western gulls (Larus occidentalis). AB - Background: Plasticity in foraging behavior among individuals, or across populations may reduce competition. As a generalist carnivore, western gulls (Larus occidentalis) consume a wide range of marine and terrestrial foods. However, the foraging patterns and habitat selection (ocean or land) of western gulls is not well understood, despite their ubiquity in coastal California. Here, we used GPS loggers to compare the foraging behavior and habitat use of western gulls breeding at two island colonies in central California. Results: Gulls from offshore Southeast Farallon Island (SFI; n = 41 gulls) conducted more oceanic trips (n = 90) of shorter duration (3.8 +/- 3.3 SD hours) and distance (27.1 +/- 20.3 km) than trips to the mainland (n = 41) which were nearly 4 times longer and 2 times farther away. In contrast, gulls from coastal Ano Nuevo Island (ANI; n = 20 gulls) foraged at sites on land more frequently (n = 103) but trip durations (3.6 +/- 2.4 h) and distances (20.8 +/- 9.4 km) did not differ significantly from oceanic trips (n = 42) where trip durations were only slightly shorter (2.9 +/- 2.7 h) and equidistant (20.6 +/- 12.1 km). Gulls from both colonies visited more sites while foraging at sea but spent significantly longer (3-5 times) durations at each site visited on land. Foraging at sea was also more random compared to foraging trips over land where gulls from both colonies visited the same sites on multiple trips. The total home range of gulls from SFI (14,230 km2) was 4.5 times larger than that of gulls from ANI, consistent with greater resource competition resulting from a larger abundance of seabirds at SFI. Conclusions: Population level plasticity in foraging behavior was evident and dependent on habitat type. In addition, gulls from SFI were away foraging longer than gulls from ANI (22% vs. 7.5%, respectively), which impacts the defense of territories and attempts at nest predation by conspecifics. Our results can be used to explain lower chick productivity at SFI, and can provide insight into increased gull activity in urban areas. PMID- 29270297 TI - Breast cancer metastasis to the spleen: a case report and literature review. AB - Splenic metastasis from cancers is extremely rare. They usually occur and are detected simultaneously with metastasis to other organs. We present a case of splenic metastasis from carcinoma of the breast occurring 5 years after initial treatment. The metastatic recurrence was an oligometastic form made from the association of a unique bone metastasis to a rib and the metastasis to the spleen. Treatment of the metastatic recurrence was a second line hormonotherapy as the primitive tumor was estrogen receptors positive and gave a 2 year's long control of the disease. A clinical progression occurred then, the patient complained from pain in the left hypochondrium and was objective on [18F]-FDG PET which leaded to splenectomy. This case is being reported because of the rarity of the lesion and its originality is the first reported case with use of an in vivo demonstration of estrogen receptors expression in the spleen metastasis using PET/CT with 16alpha-[18F]-Fluoroestradiol. PMID- 29270298 TI - Spontaneous and CRISPR/Cas9-induced mutation of the osmosensor histidine kinase of the canola pathogen Leptosphaeria maculans. AB - Background: The dicarboximide fungicide iprodione has been used to combat blackleg disease of canola (Brassica napus), caused by the fungus Leptosphaeria maculans. For example, in Australia the fungicide was used in the late 1990s but is no longer registered for use against blackleg disease, and therefore the impact of iprodione on L. maculans has not been investigated. Results: Resistance to iprodione emerged spontaneously under in vitro conditions at high frequency. A basis for this resistance was mutations in the hos1 gene that encodes a predicted osmosensing histidine kinase. While loss of the homologous histidine kinase in some fungi has deleterious effects on growth and pathogenicity, the L. maculans strains with the hos1 gene mutated had reduced growth under high salt conditions, but were still capable of causing lesions on B. napus. The relative ease to isolate mutants with resistance to iprodione provided a method to develop and then optimize a CRISPR/Cas9 system for gene disruptions in L. maculans, a species that until now has been particularly difficult to manipulate by targeted gene disruptions. Conclusions: While iprodione is initially effective against L. maculans in vitro, resistance emerges easily and these strains are able to cause lesions on canola. This may explain the limited efficacy of iprodione in field conditions. Iprodione resistance, such as through mutations of genes like hos1, provides an effective direction for the optimization of gene disruption techniques. PMID- 29270299 TI - ATNT: an enhanced system for expression of polycistronic secondary metabolite gene clusters in Aspergillus niger. AB - Background: Fungi are treasure chests for yet unexplored natural products. However, exploitation of their real potential remains difficult as a significant proportion of biosynthetic gene clusters appears silent under standard laboratory conditions. Therefore, elucidation of novel products requires gene activation or heterologous expression. For heterologous gene expression, we previously developed an expression platform in Aspergillus niger that is based on the transcriptional regulator TerR and its target promoter PterA. Results: In this study, we extended this system by regulating expression of terR by the doxycycline inducible Tet-on system. Reporter genes cloned under the control of the target promoter PterA remained silent in the absence of doxycycline, but were strongly expressed when doxycycline was added. Reporter quantification revealed that the coupled system results in about five times higher expression rates compared to gene expression under direct control of the Tet-on system. As production of secondary metabolites generally requires the expression of several biosynthetic genes, the suitability of the self-cleaving viral peptide sequence P2A was tested in this optimised expression system. P2A allowed polycistronic expression of genes required for Asp-melanin formation in combination with the gene coding for the red fluorescent protein tdTomato. Gene expression and Asp melanin formation was prevented in the absence of doxycycline and strongly induced by addition of doxycycline. Fluorescence studies confirmed the correct subcellular localisation of the respective enzymes. Conclusion: This tightly regulated but strongly inducible expression system enables high level production of secondary metabolites most likely even those with toxic potential. Furthermore, this system is compatible with polycistronic gene expression and, thus, suitable for the discovery of novel natural products. PMID- 29270300 TI - Center Variation and the Effect of Center and Provider Characteristics on Clinical Outcomes in Kidney Transplantation: A Systematic Review of the Evidence. AB - Background: Kidney transplantation is the best treatment option for patients with end-stage renal disease. While patient-level factors affecting survival are established, the presence of variation in the management of transplant recipients remains unknown. Objective: The objective of this study was to examine center variation in kidney transplantation and identify center and provider characteristics that may be associated with clinical outcomes. Design: This is a systematic review. Data sources: Ovid Medline, Embase, and Cochrane library from inception to June 2016 were used. Study eligibility: Any study examining the association between center or provider characteristics and graft or patient survival, quality of life, or functional status were included. Results: We identified 6327 records and 24 studies met eligibility. Most studies used data registries. Characteristics evaluated include center volume (n = 17), provider volume (n = 2), provider experience (n = 1), center type (n = 2), and location of follow-up (n = 1). Outcomes assessed included graft survival (n = 24) and patient survival (n = 9). Significant center variation was described in 12 of 15 and 5 of 7 studies for graft and patient survival. There was a significant and positive association between center volume and graft and patient survival in 8 and 2 studies, respectively. Provider experience and volume were significantly associated with less allograft loss and provider volume with lower risk of death. There was no association between graft survival and location of follow-up or center type. Limitations: There was substantial heterogeneity in the variables assessed and methodology used to analyze associations. Conclusion: This systematic review found center variation in kidney transplantation. Future studies in the current era are necessary to better evaluate this important topic. PMID- 29270301 TI - Mental health service user experiences of targeted violence and hostility and help-seeking in the UK: a scoping review. AB - Background: The aim of this research scoping review was to assemble an evidence base for the UK on mental health service user experiences and perspectives on mental health-related targeted violence and hostility ('disability hate crime'). It also aims to address some of the gaps in the knowledge on risk management, help-seeking and prevention from the perspectives of those who experienced targeted violence and hostility because of their mental health problems or psychiatric status. Methods: Seven key mental health and social care bibliographic databases were searched for relevant UK research studies from 1990 until 2016. Grey literature was identified through online searches. A scoping review charting approach and thematic analysis methodology were used to analyse the studies. Results: In total 13 studies were finally included, over half of which used survey methods. All studies included people with experiences of mental health problems. The studies provide information on: the types of potential hate crime; indicate where incidents take place; give some insight into the victims' relationship with the perpetrators; the location of incidents as well as the psychological, social, financial and physical impacts on the victim; the types of help-seeking behaviours adopted by the victims; a range coping strategies that people with mental health problems adopted in response to experiences of targeted violence or abuse. Conclusion: This scoping review provides a UK-based overview of mental health service user concepts and experiences of mental health-related targeted violence and hostility ('disability hate crime'). It reveals some specific issues relating to mental health and disability hate crime. Further investigation into disability hate crime with a specific focus on mental health is required. This is a UK-based overview, which offers a useful comparator for researchers, practitioners and policy-makers internationally. PMID- 29270302 TI - A Comparison of Subjective and Objective Job Demands and Fit with Personal Resources as Predictors of Retirement Timing in a National U.S. Sample. AB - Population aging and attendant pressures on public budgets have spurred considerable interest in understanding factors that influence retirement timing. A range of sociodemographic and economic characteristics predict both earlier and later retirement. Less is known about the role of job characteristics on the work choices of older workers. Researchers are increasingly using the subjective ratings of job characteristics available in the Health and Retirement Study in conjunction with more objective measures of job characteristics from the Occupational Information Network (O*NET) database. Employing a theoretically informed model of job demands-personal resources fit, we constructed mismatch measures between resources and job demands (both subjectively and objectively assessed) in physical, emotional, and cognitive domains. When we matched comparable measures across the two data sources in the domains of physical, emotional, and cognitive job demands, we found that both sources of information held predictive power in relation to retirement timing. Physical and emotional but not cognitive mismatch were associated with earlier retirement. We discuss theoretical and practical implications of these findings and directions for future research. PMID- 29270304 TI - Sonogram of coccygeus muscle in dairy cows with different gestational ages. AB - Background: The change in size and weight of the female reproductive organs during gestation and birth might be affect the perineal muscles and this condition in dairy cow not been reported. This study aimed to assess the ultrasonographic image of coccygeus muscle in 11 inseminated dairy cows with different gestational ages and postpartum. Methods: Gestational age was calculated based on the record of artificial insemination and confirmed by using transrectal brightness mode ultrasonography. Perineal hair between the sacrum and ischium bones was shaved along 3-5 cm before being ultrasound. The images of perineal area were obtained by transcutaneous ultrasound using a 5.0 MHz transducer. The thickness and intensity of the coccygeus muscle were measured and analyzed by gestational status and postpartum to show the differences. Results: The results showed that the thickness of coccygeus muscle increased with the increase in gestational age. Muscle intensity only increased at young gestational age. However, it decreased with the increase in gestational age (P < 0.05). Conclusions: The ultrasound image of coccygeus muscle was affected by gestational status, thus this method may be used as one of the new methods of indirect gestational detection on dairy cows. PMID- 29270305 TI - Vitamin D toxicity of dietary origin in cats fed a natural complementary kitten food. AB - Case series summary: This case series describes two young sibling cats and an additional unrelated cat, from two separate households, that developed hypercalcaemia associated with hypervitaminosis D. Excessive vitamin D concentrations were identified in a natural complementary tinned kitten food that was fed to all three cats as part of their diet. In one of the cases, there was clinical evidence of soft tissue mineralisation. The hypercalcaemia and soft tissue mineralisation resolved following withdrawal of the affected food and medical management of the hypercalcaemia. Relevance and novel information: This case series demonstrates the importance of obtaining a thorough dietary history in patients presenting with hypercalcaemia and the measurement of vitamin D metabolites when investigating such cases. Complementary foods may have the potential to induce nutritional toxicity even when fed with complete, nutritionally balanced diets. PMID- 29270303 TI - NEC-zero recommendations from scoping review of evidence to prevent and foster timely recognition of necrotizing enterocolitis. AB - Background: Although decades have focused on unraveling its etiology, necrotizing enterocolitis (NEC) remains a chief threat to the health of premature infants. Both modifiable and non-modifiable risk factors contribute to varying rates of disease across neonatal intensive care units (NICUs). Purpose: The purpose of this paper is to present a scoping review with two new meta-analyses, clinical recommendations, and implementation strategies to prevent and foster timely recognition of NEC. Methods: Using the Translating Research into Practice (TRIP) framework, we conducted a stakeholder-engaged scoping review to classify strength of evidence and form implementation recommendations using GRADE criteria across subgroup areas: 1) promoting human milk, 2) feeding protocols and transfusion, 3) timely recognition strategies, and 4) medication stewardship. Sub-groups answered 5 key questions, reviewed 11 position statements and 71 research reports. Meta analyses with random effects were conducted on effects of standardized feeding protocols and donor human milk derived fortifiers on NEC. Results: Quality of evidence ranged from very low (timely recognition) to moderate (feeding protocols, prioritize human milk, limiting antibiotics and antacids). Prioritizing human milk, feeding protocols and avoiding antacids were strongly recommended. Weak recommendations (i.e. "probably do it") for limiting antibiotics and use of a standard timely recognition approach are presented. Meta analysis of data from infants weighing <1250 g fed donor human milk based fortifier had reduced odds of NEC compared to those fed cow's milk based fortifier (OR = 0.36, 95% CI 0.13, 1.00; p = 0.05; 4 studies, N = 1164). Use of standardized feeding protocols for infants <1500 g reduced odds of NEC by 67% (OR = 0.33, 95% CI 0.17, 0.65, p = 0.001; 9 studies; N = 4755 infants). Parents recommended that NEC information be shared early in the NICU stay, when feedings were adjusted, or feeding intolerance occurred via print and video materials to supplement verbal instruction. Discussion: Evidence for NEC prevention is of sufficient quality to implement. Implementation that addresses system-level interventions that engage the whole team, including parents, will yield the best impact to prevent NEC and foster its timely recognition. PMID- 29270307 TI - Antihypertensive treatment with telmisartan in a cat with amlodipine-induced gingival hyperplasia. AB - Case summary: Systemic arterial hypertension is commonly reported in middle-aged to-older cats. Amlodipine is recommended as the initial antihypertensive drug in cats. In this case report, gingival hyperplasia secondary to the use of amlodipine in a cat is described. Benazepril as a monotherapy was unsuccessful in reducing blood pressure in this cat. After replacement of benazepril by telmisartan, gingival hyperplasia disappeared and blood pressure was well controlled. Relevance and novel information: This case report describes the first reported case of reversible gingival hyperplasia as a result of the treatment with amlodipine. It also contains the first published data on the effect of telmisartan in a hypertensive cat. PMID- 29270306 TI - Uterus unicornis and pregnancy in two feline littermates. AB - Case series summary: A queen, tom and four 1-year-old female offspring presented for routine neuter. Two of the littermates (cats 1 and 2) were diagnosed with a uterine abnormality during surgery. The left uterine horn of both cats appeared as a thin, solid, cord-like structure, whereas the right uterine horn of both cats appeared to have intermittent bulges consistent with pregnancy. The two other littermates, queen and tom were reproductively normal. The uteruses of the affected cats were nearly identical with a gross and histopathologic diagnosis of uterus unicornis with concurrent pregnancy. Ovaries were present, bilaterally. An oviduct was present only on the single normally developed and pregnant uterine horn in both cats. At a postoperative follow-up evaluation, abdominal ultrasound was performed on the two cats with uterine abnormalities. Cat 1 was ultrasonographically within normal limits. Cat 2 was diagnosed with ipsilateral renal agenesis on the same side as the absent uterine horn. Relevance and novel information: The complexity of uterus unicornis and renal aplasia is demonstrated by this unique presentation of five related cats for ovariohysterectomy. This report raises questions regarding the genetic, environmental, hormonal or other underlying causes of this anatomic abnormality in cats that may spur additional research. This is the first publication describing uterus unicornis in gravid feline littermates, with one of the cats having ipsilateral renal agenesis. This is also the first publication to describe oviduct agenesis on the affected uterine horn in feline uterus unicornis. PMID- 29270308 TI - Multilocus genotyping of Giardia duodenalis isolates from breeding cattery cats in Japan. AB - Objectives: The present study reports the multilocus genotyping of Giardia duodenalis isolates from cats maintained in breeding catteries in Japan and discusses their potential for zoonotic transmission. Methods: A total of 41 faecal samples positive for Giardia-specific antigen were procured from cats maintained in five breeding catteries and subjected to PCR to amplify four gene loci, namely small subunit ribosomal RNA (SSU rRNA), glutamate dehydrogenase (gdh), beta-giardin (bg) and triose phosphate isomerase (tpi ). The PCR-amplified DNA fragments were sequenced to determine the G duodenalis genotypes (synonym for assemblages). Results: The most commonly occurring single assemblage was assemblage F (68.3%; n = 28/41), followed by assemblage A (12.2%; n = 5/41) and assemblage C (2.4%; n = 1/41). The mixed assemblages were identified as follows: assemblages F and A (9.8%; n = 4/41), assemblages F and C (4.9%; n = 2/41) and assemblages C and D (2.4%; n = 1/41). Additional sub-genotyping of assemblage A isolates based on three of the sequenced loci (gdh, bg and tpi ) revealed that all eight isolates were identified as sub-assemblage AI and/or AII. Conclusions and relevance: The present study is the first to report the detection of dog adapted assemblages C and D in feline isolates from Japan. In addition, zoonotic sub-assemblage AI and human-adapted sub-assemblage AII were also identified. Thus, we concluded that the risk of transmission of G duodenalis from breeding cattery cats to humans is considerable and cannot be ignored. PMID- 29270309 TI - Randomized, Placebo-controlled Crossover Study of Dalfampridine Extended-release in Transverse Myelitis. AB - Background: Dalfampridine has the potential to be effective in patients with transverse myelitis (TM) as this rare disorder shares some clinical and pathogenic similarities with multiple sclerosis. Methods: This is a randomized, double-blind, placebo-controlled crossover study of dalfampridine extended release (D-ER, Ampyra(r)). Sixteen adult study participants with monophasic TM confirmed by MRI were enrolled if their baseline timed 25-foot walking speed was between 5 and 60 seconds. Participants were randomized to receive 10 mg twice daily doses of either D-ER or placebo control for eight weeks, then crossed over to the second arm of placebo or dalfampridine for eight weeks. The primary outcome measure was the timed 25-foot walk. Results: Of 16 enrolled participants, three withdrew and 13 completed the trial. Among the 13 completers, nine individuals showed an average timed walk that was faster in the D-ER arm compared to the placebo arm, but only four participants met the stricter statistical threshold to be classified as a responder. Analyses of secondary clinical outcome measures including strength, balance assessments, spasticity, and Expanded Disability Status Scale (EDSS) score showed trends toward improvement with D-ER. Conclusions: D-ER may be beneficial in TM to improve walking speed and other neurological functions. PMID- 29270310 TI - Experimental inoculation of Treponema pedis T A4 failed to induce ear necrosis in pigs. AB - Ear necrosis is a syndrome affecting pigs shortly after weaning and is regarded as an animal welfare issue. The etiology is unknown but Treponema spp., predominantly Treponema pedis, are commonly detected in the lesions. Oral treponemes have been suggested as source of infection, transferred by biting and licking behavior. In this study, five pigs were intradermally inoculated with Treponema pedis strain T A4 with the aim of investigating if this strain would induce ear lesions. Three pigs served as controls. The inoculation was repeated after 29 days, and the study continued for 56 days. Serum samples were collected throughout the study and analyzed by ELISA for IgG antibodies towards T. pedis T A4 lysate. Skin biopsies were taken from the inoculation area at the end of the study. Gingival samples were collected and cultivated for treponemes, for comparison to the inoculation strain and to follow colonisation. The challenged pigs did not develop any clinical signs of infection and no spirochetes were detected in sections from skin biopsies. The number of Treponema-positive gingival samples increased during the study. In the challenge group, IgG towards the bacterial lysate peaked 7 days after each inoculation and decreased rapidly hereafter. In the control group a weak IgG response was observed after the second inoculation, possibly caused by the oral treponemes. PMID- 29270311 TI - Haemorrhagic bowel syndrome in fattening pigs. AB - Background: Haemorrhagic bowel syndrome (HBS) is a sporadically occurring disorder in fattening pigs, characterized by sudden death in combination with severe abdominal distension and intense red colouration of the intestine. Deep understanding of aetiology and pathogenesis of HBS are still lacking, although several risk factors are known. Case presentation: In a continuously stocked fattening farm with 1500 pigs and liquid feeding based on whey, the mortality rate increased from 1.7% to 3.5% during summer time. Sporadic sudden death of growing pigs occurred along with severe abdominal distension as the main sign in these animals. All batches arriving at the farm received in-feed medication with Tiamulin hydrogen fumarate (2 mg/kg body weight/day; according to the license for use in Switzerland) due to detection of Brachyspira hyodysenteriae in the past, although a partial sanitation had been conducted thereafter. No changes of the origins, housing and the feeding procedure were reported. A herd examination was conducted revealing a hygiene problem in the feeding system. For further diagnostics a necropsy was performed, showing a pale carcass with a bloated abdomen due to a haemorrhagic infarction of part of the small intestine caused by a mesenteric torsion. Furthermore, a feed analysis was conducted, revealing a pH value of 5 in the liquid feed, and a severe contamination with Enterobacteriaceae was detected. Based on these examinations, HBS was diagnosed. Subsequently, the farmer controlled the pH-value of the liquid feed with formic acid, improved the cleaning procedure of the liquid feeding system and stopped the in-feed medication. Following the implementation of these measures, key performance indicators improved significantly, but 4 months later the same clinical manifestation occurred again. This time huge variations in the pH-value of the liquid feed between different feeding times were recorded and were attributed to improper mixing of the formic acid in the whey tank. After implementation of a technical solution to control the pH-value, the health status improved again. Conclusion: In the present case, it is likely that the cause of the clinical manifestation of HBS was a contamination of Enterobacteriaceae in the liquid feed facilitated by a hygiene problem in the feeding system, and a chronic dysbacteriosis of the intestinal tract due to the non-justified routine use of antimicrobials. Speculatively, the prophylactic antimicrobial treatment was unnecessary and might even have exacerbated the clinical problem. PMID- 29270312 TI - Developing Substance Use Programming for Person-Oriented Recovery and Treatment (SUPPORT): protocol for a pilot randomized controlled trial. AB - Background: There is a lack of evidence-based substance use disorder treatment and services targeting returning inmates. Substance Use Programming for Person Oriented Recovery and Treatment (SUPPORT) is a community-driven, recovery oriented approach to substance abuse care which has the potential to address this service gap. SUPPORT is modeled after Indiana's Access to Recovery program, which was closed due to lack of federal support despite positive improvements in clients' recovery outcomes. SUPPORT builds on noted limitations of Indiana's Access to Recovery program. The ultimate goal of this project is to establish SUPPORT as an effective and scalable recovery-oriented system of care. A necessary step we must take before launching a large clinical trial is pilot testing the SUPPORT intervention. Methods: The pilot will take place at Public Advocates in Community Re-Entry (PACE), nonprofit serving individuals with felony convictions who are located in Marion County, Indiana (Indianapolis). The pilot will follow a basic parallel randomized design to compare clients receiving SUPPORT with clients receiving standard services. A total of 80 clients within 3 months of prison release will be recruited to participate and randomly assigned to one of the two intervention arms. Quantitative measures will be collected at multiple time points to understand SUPPORT's impact on recovery capital and outcomes. We will also collect qualitative data from SUPPORT clients to better understand their program and post-discharge experiences. Discussion: Successful completion of this pilot will prepare us to conduct a multi-site clinical trial. The ultimate goal of this future work is to develop an evidence-based and scalable approach to treating substance use disorder among persons returning to society after incarceration. Trial registration: ClinicalTrials.gov (Clinical Trials ID: NCT03132753 and Protocol Number: 1511731907). Registered 28 April 2017. PMID- 29270313 TI - Using a Community-Engaged Research (CEnR) approach to develop and pilot a photo grid method to gain insights into early child health and development in a socio economic disadvantaged community. AB - Plain English summary: This paper reports on the use of a Community-Engaged Research (CEnR) approach to develop a new research tool to involve members of the community in thinking about priorities for early child health and development in a deprived area of the UK. The CEnR approach involves researchers, professionals and members of the public working together during all stages of research and development.Researchers used a phased approach to the development of a Photo Grid tool including reviewing tools which could be used for community engagement, and testing the new tool based on feedback from workshops with local early years professionals and parents of young children.The Photo Grid tool is a flat square grid on which photo cards can be placed. Participants were asked to pace at the top of the grid the photos they considered most important for early child health and development, working down to the less important ones at the bottom. The findings showed that the resulting Photo Grid tool was a useful and successful method of engaging with the local community. The evidence for this is the high numbers of participants who completed a pilot study and who provided feedback on the method. By involving community members throughout the research process, it was possible to develop a method that would be acceptable to the local population, thus decreasing the likelihood of a lack of engagement. The success of the tool is therefore particularly encouraging as it engages "seldom heard voices," such as those with low literacy. Abstract: Background: The aim of this research was to consult with professionals and parents to develop a new research toolkit (Photo Grid), to understand community assets and priorities in relation to early child health and development in Blackpool, a socio-economic disadvantaged community. A Community-Engaged Research (CEnR) approach was used to consult with community members. This paper describes the process of using a CEnR approach in developing a Photo Grid toolkit. Methods: A phased CEnR approach was used to design, test and pilot a Photo Grid tool. Members of the Blackpool community; parents with children aged 0-4 years, health professionals, members of the early year's workforce, and community development workers were involved in the development of the research tool at various stages. They were recruited opportunistically via a venue-based time-space sampling method. In total, 213 parents and 18 professionals engaged in the research process. Results: Using a CEnR approach allowed effective engagement with the local community and professionals, evidence by high levels of engagement throughout the development process. This approach improved the acceptability and usability of the resulting Photo Grid toolkit. Community members found the method accessible, engaging, useful, and thought provoking. Conclusions: The Photo Grid toolkit was seen by community members as accessible, engaging, useful and thought provoking in an area of high social deprivation, complex problems, and low literacy. The Photo Grid is an adaptable tool which can be used in other areas of socio-economic disadvantage to engage with the community to understand a wide variety of complex topics. PMID- 29270314 TI - Retinal malperfusion in albuminuric Type 1 diabetes mellitus patients without clinical signs of diabetic retinopathy: a prospective pilot study. AB - Background: To report fluorescein angiography findings in a group of albuminuric Type 1 diabetes mellitus (T1DM) patients without diabetic retinopathy. Methods: Fifteen albuminuric T1DM patients with normal/near normal estimated glomerular filtration rate without diabetic retinopathy underwent fluorescein angiography; presence of microaneurysms, vascular permeability changes and retinal malperfusion were evaluated. Results: Fluorescein angiography revealed microaneurysms, blood-retinal barrier breakdown and retinal ischemia in 10 (67%) and 11 (73%); 8 (53%) and 9 (60%); 2 (13%) and 5 (33%) of patients at baseline and follow up, respectively. Follow up time averaged 24.6 months, minimum follow up time was 20 months. Patients who presented retinal malperfusion had higher HbA1C and lower estimated glomerular filtration rate. Conclusions: Most albuminuric T1DM patients with a normal fundus exam had angiographic signs of diabetic retinopathy, some presenting retinal malperfusion. Retinal changes may be found with more sensitive testing in these patients, especially with impaired estimated glomerular filtration rate, even if the fundus exam is normal, and fluorescein angiography should be considered. These findings point to a homogenous presentation of the diabetic microangiopathies. PMID- 29270315 TI - Recent advances in the use of ZFN-mediated gene editing for human gene therapy. AB - Targeted genome editing with programmable nucleases has revolutionized biomedical research. The ability to make site-specific modifications to the human genome, has invoked a paradigm shift in gene therapy. Using gene editing technologies, the sequence in the human genome can now be precisely engineered to achieve a therapeutic effect. Zinc finger nucleases (ZFNs) were the first programmable nucleases designed to target and cleave custom sites. This article summarizes the advances in the use of ZFN-mediated gene editing for human gene therapy and discusses the challenges associated with translating this gene editing technology into clinical use. PMID- 29270316 TI - Effect of Cap-Lenticule Diameter Difference on the Visual Outcome and Higher Order Aberrations in SMILE: 0.4 mm versus 1.0 mm. AB - Purpose: To evaluate the effect of cap-lenticule diameter difference (CLDD) on the visual outcome and higher-order aberrations (HOAs) of small-incision lenticule extraction (SMILE). Methods: A total of 132 patients who had bilateral SMILE for myopia or myopic astigmatism were included. The CLDD was 0.4 mm in 54 patients (group 1) and 1.0 mm in 78 patients (group 2). The refractive parameters, uncorrected (UDVA) and corrected distance visual acuity (CDVA), and HOAs were determined preoperatively and during six months follow-up. Results: Group 1 had better CDVA (in logMAR) compared to group 2 at day 1 (-0.07 +/- 0.07 versus 0.04 +/- 0.07, resp.; p < 0.001) and week 1 (-0.07 +/- 0.07 versus -0.04 +/- 0.07, resp.; p = 0.001). The visual acuity improved more in group 1 than in group 2. The UDVA (in logMAR) was 0.07 +/- 0.07 and 0.29 +/- 0.09 at day 1 (p < 0.001) and -0.08 +/- 0.07 and -0.06 +/- 0.06 at six months (p = 0.038) in group 1 and group 2, respectively. Group 1 was associated with significantly less induction of HOAs (0.24 +/- 0.08 MUm and 0.32 +/- 0.26 MUm, resp.; p = 0.002). Conclusions: In SMILE, 0.4 mm CLDD is associated with better visual outcome and less induction of HOAs than 1.0 mm. Narrow CLDD should be considered in SMILE to increase the visual acuity particularly in the early postoperative period. PMID- 29270317 TI - Growth Patterns in the Irish Pyridoxine Nonresponsive Homocystinuria Population and the Influence of Metabolic Control and Protein Intake. AB - A low methionine diet is the mainstay of treatment for pyridoxine nonresponsive homocystinuria (HCU). There are various guidelines for recommended protein intakes for HCU and clinical practice varies. Poor growth has been associated with low cystine levels. This retrospective review of 48 Irish pyridoxine nonresponsive HCU patients assessed weight, height, body mass index (BMI), protein intake, and metabolic control up to 18 years at nine set time points. Patients diagnosed through newborn screening (NBS) were compared to late diagnosed (LD) patients. At 18 years the LD group (n = 12, mean age at diagnosis 5.09 years) were heavier (estimated effect +4.97 Kg, P = 0.0058) and taller (estimated effect +7.97 cm P = 0.0204) than the NBS group (n = 36). There was no difference in growth rate between the groups after 10 years of age. The HCU population were heavier and taller than the general population by one standard deviation with no difference in BMI. There was no association between intermittently low cystine levels and height. Three protein intake guidelines were compared; there was no difference in adult height between those who met the lowest of the guidelines (Genetic Metabolic Dietitians International) and those with a higher protein intake. PMID- 29270318 TI - HIV among Female Sex Workers in Five Cities in Burkina Faso: A Cross-Sectional Baseline Survey to Inform HIV/AIDS Programs. AB - Background: Female sex workers (FSWs) are considered a vulnerable population for HIV infection and a priority for HIV/AIDS response programs. This study aimed to determine HIV prevalence among FSWs in five cities in Burkina Faso. Methods: FSWs aged 18 and older were recruited using respondent driven sampling (RDS) in five cities (Ouagadougou, Bobo-Dioulasso, Koudougou, Ouahigouya, and Tenkodogo) in Burkina Faso from 2013 to 2014. HIV testing was performed using the HIV testing national algorithm. We conducted bivariate and multivariate logistic regression analysis to assess correlates of HIV in all cities combined (not RDS-adjusted). Results: Among Ouagadougou, Koudougou, and Ouahigouya FSWs, RDS-adjusted HIV prevalence was 13.5% (95% Confidence Interval [CI]: 9.6-18.7), 13.3% (95% CI: 7.6 22.4), and 13.0% (95% CI: 7.6-21.3), respectively, compared to 30.1% (95% CI: 25.5-35.1) among Bobo-Dioulasso FSWs. Factors associated with HIV infection were age (adjusted odds ratio [aOR] = 7.84 95% CI: 3.78-16.20), being married or cohabitating (aOR = 2.43, 95% CI: 1.31-4.49), and history of pregnancy (aOR = 5.24, 95% CI: 1.44-18.97). Conclusion: These results highlight the need to strengthen HIV prevention among FSWs, through behavior change strategies, and improve access to sexual and reproductive health services. PMID- 29270319 TI - The Bidirectional Relationship between Tuberculosis and Diabetes. AB - The burden of tuberculosis (TB) especially in developing countries continues to remain high despite efforts to improve preventive strategies. Known traditional risk factors for TB include poverty, malnutrition, overcrowding, and HIV/AIDS; however, diabetes, which causes immunosuppression, is increasingly being recognized as an independent risk factor for tuberculosis, and the two often coexist and impact each other. Diabetes may also lead to severe disease, reactivation of dormant tuberculosis foci, and poor treatment outcomes. Tuberculosis as a disease entity on the other hand and some commonly used antituberculous medications separately may cause impaired glucose tolerance. This review seeks to highlight the impact of comorbid TB and diabetes on each other. It is our hope that this review will increase the awareness of clinicians and managers of TB and diabetes programs on the effect of the interaction between these two disease entities and how to better screen and manage patients. PMID- 29270321 TI - New Insights into the Role of the Locus Coeruleus-Noradrenergic System in Memory and Perception Dysfunction. PMID- 29270322 TI - A Case of MDMA-Associated Cerebral and Pulmonary Edema Requiring ECMO. AB - A 20-year-old female presented with confusion, generalized tonic-clonic seizures, and severe hyponatremia after ingesting 3,4-methylenedioxymethamphetamine (MDMA). Brain computed tomography (CT) demonstrated cerebral edema. Her hospital course was rapidly complicated by respiratory failure and shock requiring intubation and vasopressors. Refractory acute respiratory distress syndrome (ARDS) was diagnosed which was unresponsive to conventional and salvage therapies, requiring initiation of extracorporeal membrane oxygenation (ECMO), leading to normalization of oxygenation parameters. Hyponatremia was corrected and the encephalopathy resolved. The patient was decannulated and extubated after three days. MDMA-induced hyponatremia is hypothesized to result from enhanced serotonergic activity and arginine vasopressin (AVP) release in the brain leading to hyperthermia-induced polydipsia and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. A common but often unrecognized complication of severe hyponatremia is the Ayus-Arieff syndrome where cerebral edema causes neurogenic pulmonary edema via centrally mediated increases in catecholamine release and capillary injury. For our patient, ECMO was required for three days while the hyponatremia was corrected which led to rapid clearing of the cerebral edema and neurogenic pulmonary edema. This case illustrates that, in selecting patients with refractory ARDS from MDMA-associated cerebral and pulmonary edema, ECMO may be a temporizing and life-saving modality of treatment. PMID- 29270320 TI - Restrictive Cardiomyopathies: The Importance of Noninvasive Cardiac Imaging Modalities in Diagnosis and Treatment-A Systematic Review. AB - Restrictive cardiomyopathy (RCM) is the least common among cardiomyopathies. It can be idiopathic, familial, or secondary to systematic disorders. Marked increase in left and/or right ventricular filling pressures causes symptoms and signs of congestive heart failure. Electrocardiographic findings are nonspecific and include atrioventricular conduction and QRS complex abnormalities and supraventricular and ventricular arrhythmias. Echocardiography and cardiac magnetic resonance (CMR) play a major role in diagnosis. Echocardiography reveals normal or hypertrophied ventricles, preserved systolic function, marked biatrial enlargement, and impaired diastolic function, often with restrictive filling pattern. CMR offering a higher spatial resolution than echocardiography can provide detailed information about anatomic structures, perfusion, ventricular function, and tissue characterization. CMR with late gadolinium enhancement (LGE) and novel approaches (myocardial mapping) can direct the diagnosis to specific subtypes of RCM, depending on the pattern of scar formation. When noninvasive studies have failed, endomyocardial biopsy is required. Differentiation between RCM and constrictive pericarditis (CP), nowadays by echocardiography, is important since both present as heart failure with normal-sized ventricles and preserved ejection fraction but CP can be treated by means of anti-inflammatory and surgical treatment, while the treatment options of RCM are dictated by the underlying condition. Prognosis is generally poor despite optimal medical treatment. PMID- 29270323 TI - Hyperplastic Polyps and Gastroduodenal Pseudomelanosis. AB - Pseudomelanosis is a rare endoscopic finding of the upper gastrointestinal tract characterized by hemosiderin deposits in histiocytes of lamina propria. We report a case of 72-year-old lady on chronic oral iron supplementation diagnosed with gastric hyperplastic polyps with background pseudomelanosis of stomach and duodenum. Concomitant occurrence of gastric pseudomelanosis, duodenal pseudomelanosis, and gastric hyperplastic polyps has never been reported. Its presence in the absence of gastritis raises question if pseudomelanosis could be associated with hyperplastic polyp. With limited literature on its etiology and prognosis, these patients should be prospectively followed and reported to study the natural history of the disease. PMID- 29270324 TI - Early Onset of Tenofovir-Related Fanconi Syndrome in a Child with Acute Hepatitis B: A Case Report and Systematic Review of Literature. AB - Tenofovir disoproxil fumarate- (TDF-) related nephropathy is known to be a long term complication of this drug, more commonly observed in HIV-infected patients, but occurring also in hepatitis B. Cases of Fanconi Syndrome associated with TDF have been reported in adult patients, usually as a long-term complication of chronic hepatitis B treatment. We present here a case of a 12-year-old male developing a severe acute HBV hepatitis treated with TDF. The patient achieved an early virological and biochemical response, but with a subsequent onset of proximal renal tubular damage, consistent with Fanconi Syndrome. After withdrawing this drug and switching to Entecavir, a complete resolution of tubulopathy and, after 6 months, a complete HBsAg seroconversion occurred. To our knowledge, this is the first report of an early renal injury due to TDF-therapy in a pediatric patient treated for acute hepatitis B. PMID- 29270325 TI - Pleomorphic Adenoma Originating from Heterotopic Salivary Tissue of the Upper Neck: A Diagnostic Pitfall. AB - Pleomorphic adenoma directly arising in the neck is thought to originate from heterotopic salivary gland tissue. In this article, we present the case of a 55 year-old female patient with a histologically proven pleomorphic adenoma located at the left mandibular angle, anteriorly to the sternocleidomastoid muscle and posteroinferiorly to the submandibular gland. As the patient also had an ipsilateral thyroid nodule with coarse calcifications, clinical and radiological features suggested a possible level II metastatic lymph node. However, ultrasound guided fine needle aspiration cytology and postsurgery histopathological examination revealed a pleomorphic adenoma arising from heterotopic salivary gland tissue unrelated to a benign thyroid nodule. In this article, we provide a review of the existing literature on heterotopic salivary gland tissue and related neoplasms and discuss their imaging presentation. PMID- 29270326 TI - Q Fever Presented as a Large Retroperitoneal Pseudotumoral Mass. AB - Background: Q fever is an infection caused by Coxiella burnetii, an intracellular organism. Acute infection is most often a benign and asymptomatic process; however, some individuals may go on to develop subacute and persistent localized symptomatic Q fever. As such, the clinical and histopathologic findings of Q fever are widely variable and may be missed if clinical suspicion is not high. Case Presentation: Herein we report the first case of C. burnetii infection presenting as an isolated retroperitoneal mass. A 61-year-old male underwent axillary-bifemoral bypass surgery. His postoperative course was complicated by the discovery of a large retroperitoneal mass. Conclusion: Clinical and histopathologic findings of Coxiella burnetii infection are variable and can be deceiving. These are often nonspecific, especially in its persistent localized infectious stages. PMID- 29270327 TI - Nontraumatic Acute Elevation of Pancreatic Enzymes following Percutaneous Nephrolithotomy: A Rare Complication. AB - Herein, we report the case of a 48-year-old female who developed nontraumatic acute pancreatitis following left supracostal Percutaneous Nephrolithotomy. Three hours postoperatively, the patient developed fever with signs and symptoms consistent with hydrothorax, which was confirmed radiologically and was managed conservatively. The following days, the patient developed manifestations of Systemic Inflammatory Response Syndrome with epigastric pain, nausea, and vomiting. Blood, urine, and sputum cultures were negative. Serum amylase and lipase levels were elevated 3 and 13 times above the normal level, respectively. Imaging studies revealed no pathologic findings from pancreas. These findings were consistent with the diagnosis of acute pancreatitis. PMID- 29270328 TI - A Method for Identifying Pollution Sources of Heavy Metals and PAH for a Risk Based Management of a Mediterranean Harbour. AB - A procedure for assessing harbour pollution by heavy metals and PAH and the possible sources of contamination is proposed. The procedure is based on a ratio matching method applied to the results of principal component analysis (PCA), and it allows discrimination between point and nonpoint sources. The approach can be adopted when many sources of pollution can contribute in a very narrow coastal ecosystem, both internal and outside but close to the harbour, and was used to identify the possible point sources of contamination in a Mediterranean Harbour (Port of Vado, Savona, Italy). 235 sediment samples were collected in 81 sampling points during four monitoring campaigns and 28 chemicals were searched for within the collected samples. PCA of total samples allowed the assessment of 8 main possible point sources, while the refining ratio-matching identified 1 sampling point as a possible PAH source, 2 sampling points as Cd point sources, and 3 sampling points as C > 12 point sources. By a map analysis it was possible to assess two internal sources of pollution directly related to terminals activity. The study is the prosecution of a previous work aimed at assessing Savona-Vado Harbour pollution levels and suggested strategies to regulate the harbour activities. PMID- 29270330 TI - Activating Racial and Ethnic Minorities to Engage in Preventive Health: Patient Preferences for Health Reminders. AB - Objectives: The objective of this study was to determine racial and ethnic minority patient receptiveness to health reminders, and preferences for media channels and messengers for preventive health reminders. Methods: A pen and paper survey was administered to patients in the waiting room of a publicly funded clinic serving predominately racial and ethnic minorities. Results: Three-fourths of participants said they would like to receive health reminders. The top three preferred methods of receiving health reminders were via text message, phone call, and letter by mail. About half of participants wanted their doctor or nurse to send them the health reminder. Conclusions: Health reminders could be a tool to successfully encourage racial and ethnic minority patients to participate in their own health. If physicians or nurses use a cell phone text message, a phone call, or a letter to send these health reminders they may be particularly effective at improving patient health outcomes. PMID- 29270331 TI - Research Update: Materials design of implantable nanogenerators for biomechanical energy harvesting. AB - Implantable nanogenerators are rapidly advanced recently as a promising concept for harvesting biomechanical energy in vivo. This review article presents an overview of the most current progress of implantable piezoelectric nanogenerator (PENG) and triboelectric nanogenerator (TENG) with a focus on materials selection, engineering, and assembly. The evolution of the PENG materials is discussed from ZnO nanostructures, to high-performance ferroelectric perovskites, to flexible piezoelectric polymer mesostructures. Discussion of TENGs is focused on the materials and surface features of friction layers, encapsulation materials, and device integrations. Challenges faced by this promising technology and possible future research directions are also discussed. PMID- 29270332 TI - Alagille syndrome: Genetics and Functional Models. AB - Purpose of review: We review the genetics of the autosomal dominant, multi-system disorder, Alagille syndrome and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion. Recent findings: Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human induced pluripotent stem cells, provide new opportunities in which to study disease mechanisms and manifestations. Summary: We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille syndrome patients. PMID- 29270329 TI - Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence. AB - Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the "multi-hit" hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent "hits" are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies. PMID- 29270333 TI - Microsatellite analysis of genetic diversity and population structure of hermaphrodite ridge gourd (Luffa hermaphrodita). AB - Out of 103 microsatellite markers used for studying the genetic diversity among local landraces of Luffa species, 56 were found polymorphic, including 38 gSSR and 18 eSSR, respectively. A total of 197 amplification products were obtained. The mean number of alleles per locus was 3.52. The PIC ranged from 0.037 to 0.986, while size of amplified product ranged from 105 to 500 bp. Cucumber derived SSRs were amplified within L. acutangula (68%), L. aegyptiaca (61.16%), and L. hermaphrodita (60.2%), with an average of 63.12% cross-transferability. The Jaccard's coefficient ranged from 0.66 to 0.97, with an average of 0.81. High genetic variability was observed for node of 1st hermaphrodite flower (6.4-17), days to 1st hermaphrodite flower (38-52.1), days to 1st fruit harvest (43-65), number of fruit per cluster (1-5.9), fruit length (3.9-25 cm), fruit weight (18.4 175 g), number of fruit per plant (20-147.5), and yield per plant (2.2-4.7 kg). Two sub-populations were identified including 21 genotypes (sub-population I) and 06 genotypes (sub-population II), these two sub-populations showed 0.608-0.395% of the ancestral relationship to each other. This study provides information for future exploration, collection, and utilization of Luffa genotypes, as well as the polymorphic markers identified could be available for the study of landmarks in linkages, genomic structures, evolutionary ecology, and marker-assisted selection (MAS) in Luffa species. PMID- 29270334 TI - In vitro propagation via organogenesis and synthetic seeds of Urginea altissima (L.f.) Baker: a threatened medicinal plant. AB - Efficient in vitro propagation systems via organogenesis and synthetic seeds were developed for the first time for conservation and commercial propagation from leaf or longitudinal thin cell layer (lTCL) leaf or shoot-tip explants of Urginea altissima. Various plant growth regulators and phloroglucinol were used in semi solid and liquid Murashige and Skoog (MS) medium to establish multiplication of shoots and roots for in vitro regeneration. Of the various treatments, the highest number of shoots (17.4 per lTCL leaf explant) was obtained on liquid MS medium supplemented with 10 uM meta-Topolin (mT) and 2 uM benzyladenine followed by transferal to semi-solid MS media. The shoot tips were encapsulated with liquid MS medium plus 3% (w/v) sodium alginate and 100 mM calcium chloride. Adventitious shoot regeneration (91.0%; 12.6 shoots per synthetic seed) of synthetic seeds was achieved on semi-solid MS medium supplemented with 10 uM mT and 2 uM naphthaleneacetic acid (NAA) after 15 days of storage in darkness at 25 +/- 2 degrees C. Regenerated shoots rooted (9.8 roots per shoot; 6.5 cm long) efficiently when transferred to 5 uM indole-3-butyric acid and 2.5 uM NAA. All the plantlets were successfully acclimatized (100%) in a vermiculite:soil (1:1 v/v) mixture in the greenhouse. PMID- 29270335 TI - Field-Controlled Electrical Switch with Liquid Metal. AB - When immersed in an electrolyte, droplets of Ga-based liquid metal (LM) alloy can be manipulated in ways not possible with conventional electrocapillarity or electrowetting. This study demonstrates how LM electrochemistry can be exploited to coalesce and separate droplets under moderate voltages of ~1-10 V. This novel approach to droplet interaction can be explained with a theory that accounts for oxidation and reduction as well as fluidic instabilities. Based on simulations and experimental analysis, this study finds that droplet separation is governed by a unique limit-point instability that arises from gradients in bipolar electrochemical reactions that lead to gradients in interfacial tension. The LM coalescence and separation are used to create a field-programmable electrical switch. As with conventional relays or flip-flop latch circuits, the system can transition between bistable (separated or coalesced) states, making it useful for memory storage, logic, and shape-programmable circuitry using entirely liquids instead of solid-state materials. PMID- 29270336 TI - Through-Bond Energy Transfer Cassette with Dual-Stokes Shifts for "Double Checked" Cell Imaging. AB - Organic dyes generally suffer from small Stokes shift that usually leads to self quenching and -gaining errors during the fluorescent imaging process. Here, a through-bond energy transfer (TBET) cassette is developed with large Stokes shift to pursue precise cell imaging. The TBET is constructed by covalently conjugated tetraphenylethene (acts as donor) and rhodamine (acceptor) through an acetylene bond. The constructed TBET cassette distinctly behaves as dual-Stokes shifts, including a large pseudo-Stokes shift caused by energy transfer, from donor's absorption to acceptor's emission (up to 260 nm) and a smaller Stokes shift of acceptor molecules itself. Due to the intrinsic dual-Stokes shifts, TBET cassette exhibits specific "dual distinct absorbances, single shared emission" properties, which can be excitated under two different laser channels. By colocalization of the imaging readouts of these two channels, the precisely "double checked" fluorescent imaging is achieved in living cells. PMID- 29270338 TI - Corrosion-Protected Hybrid Nanoparticles. AB - Nanoparticles composed of functional materials hold great promise for applications due to their unique electronic, optical, magnetic, and catalytic properties. However, a number of functional materials are not only difficult to fabricate at the nanoscale, but are also chemically unstable in solution. Hence, protecting nanoparticles from corrosion is a major challenge for those applications that require stability in aqueous solutions and biological fluids. Here, this study presents a generic scheme to grow hybrid 3D nanoparticles that are completely encapsulated by a nm thick protective shell. The method consists of vacuum-based growth and protection, and combines oblique physical vapor deposition with atomic layer deposition. It provides wide flexibility in the shape and composition of the nanoparticles, and the environments against which particles are protected. The work demonstrates the approach with multifunctional nanoparticles possessing ferromagnetic, plasmonic, and chiral properties. The present scheme allows nanocolloids, which immediately corrode without protection, to remain functional, at least for a week, in acidic solutions. PMID- 29270337 TI - Electronic and Optoelectronic Applications Based on 2D Novel Anisotropic Transition Metal Dichalcogenides. AB - With the continuous exploration of 2D transition metal dichalcogenides (TMDs), novel high-performance devices based on the remarkable electronic and optoelectronic natures of 2D TMDs are increasingly emerging. As fresh blood of 2D TMD family, anisotropic MTe2 and ReX2 (M = Mo, W, and X = S, Se) have drawn increasing attention owing to their low-symmetry structures and charming properties of mechanics, electronics, and optoelectronics, which are suitable for the applications of field-effect transistors (FETs), photodetectors, thermoelectric and piezoelectric applications, especially catering to anisotropic devices. Herein, a comprehensive review is introduced, concentrating on their recent progresses and various applications in recent years. First, the crystalline structure and the origin of the strong anisotropy characterized by various techniques are discussed. Specifically, the preparation of these 2D materials is presented and various growth methods are summarized. Then, high performance applications of these anisotropic TMDs, including FETs, photodetectors, and thermoelectric and piezoelectric applications are discussed. Finally, the conclusion and outlook of these applications are proposed. PMID- 29270339 TI - Steering Photoelectrons Excited in Carbon Dots into Platinum Cluster Catalyst for Solar-Driven Hydrogen Production. AB - In composite photosynthetic systems, one most primary promise is to pursue the effect coupling among light harvesting, charge transfer, and catalytic kinetics. Herein, this study designs the reduced carbon dots (r-CDs) as both photon harvesters and photoelectron donors in combination with the platinum (Pt) clusters and fabricated the function-integrated r-CD/Pt photocatalyst through a photochemical route to control the anchoring of Pt clusters on r-CDs' surface for solar-driven hydrogen (H2) generation. In the obtained r-CD/Pt composite, the r CDs absorb solar photons and transform them into energetic electrons, which transfer to the Pt clusters with favorable charge separation for H2 evolution reaction (HER). As a result, the efficient coupling of respective natures from r CDs in photon harvesting and Pt in proton reduction is achieved through well steered photoelectron transfer in the r-CD/Pt system to cultivate a remarkable and stable photocatalytic H2 evolution activity with an average rate of 681 umol g-1 h-1. This work integrates two functional components into an effective HER photocatalyst and gains deep insights into the regulation of the function coupling in composite photosynthetic systems. PMID- 29270340 TI - Netrin-1 Promotes Inflammation Resolution to Achieve Endothelialization of Small Diameter Tissue Engineering Blood Vessels by Improving Endothelial Progenitor Cells Function In Situ. AB - The transplant of small-diameter tissue engineering blood vessels (small-diameter TEBVs) (<6 mm) in vascular replacement therapy often fails because of early onset thrombosis and long-standing chronic inflammation. The specific inflammation state involved in small-diameter TEBVs transplants remains unclear, and whether promoting inflammation resolution would be useful for small-diameter TEBVs therapy need study. The neural protuberant orientation factor 1 (Netrin-1) is found present in endothelial cells of natural blood vessels and has anti inflammatory effects. This work generates netrin-1-modified small-diameter TEBVs by using layer-by-layer self-assembly to resolve the inflammation. The results show that netrin-1 reprograms macrophages (MPhi) to assume an anti-inflammatory phenotype and promotes the infiltration and subsequent efflux of MPhi from inflamed sites over time, which improves the local microenvironment and the function of early homing endothelial progenitor cells (EPCs). Small-diameter TEBVs modified by netrin-1 achieve endothelialization after 30 d and retain patency at 14 months. These findings suggest that promoting the resolution of inflammation in time is necessary to induce endothelialization of small-diameter TEBVs and prevent early thrombosis and problems associated with chronic inflammation. Furthermore, this work finds that the MPhi-derived exosomes can target and regulate EPCs, which may serve as a useful treatment for other inflammatory diseases. PMID- 29270341 TI - Hematological Effects of Gold Nanorods on Erythrocytes: Hemolysis and Hemoglobin Conformational and Functional Changes. AB - Gold nanorods (GNRs) are a unique class of metal nanostructures that have attractive potentials in biomedical applications, and the concern on their biological safety is concomitantly increasing. Hemocompatibility is extremely important as their contact with blood circulation is unavoidable during in vivo delivery. Herein, two kinds of GNRs coated with hexadecyltrimethylammonium bromide (C-GNRs) or poly(sodium-p-styrenesulfonate) are used to test their potential toxicological effects in blood. C-GNRs with positive surface charges efficiently induce hemolysis when encountering erythrocytes. Cellular internalization of C-GNRs is found, and they subsequently bind with hemoglobin, forming bioconjugates. The interaction between hemoglobin and C-GNR (stoichiometry 32.7:1) is regulated by electrostatic forces. Chromophores like tryptophan (Trp) are found to interact with C-GNRs, causing enhancement in fluorescence intensity. The conformation of protein is partially altered, evidenced by decrease in alpha-helical, increase in beta-sheet and random coil of hemoglobin. Although C-GNRs do not essentially decrease oxygen binding capacity of hemoglobin, they hamper oxygen release from the protein. Heme, the oxygen binding unit, releases from hemoglobin upon C-GNR treatment, which could contribute to C-GNR-induced hemolysis. This study demonstrates the hematological effects of GNRs, revealing their potential risk in biomedical applications. PMID- 29270342 TI - Photogating in Low Dimensional Photodetectors. AB - Low dimensional materials including quantum dots, nanowires, 2D materials, and so forth have attracted increasing research interests for electronic and optoelectronic devices in recent years. Photogating, which is usually observed in photodetectors based on low dimensional materials and their hybrid structures, is demonstrated to play an important role. Photogating is considered as a way of conductance modulation through photoinduced gate voltage instead of simply and totally attributing it to trap states. This review first focuses on the gain of photogating and reveals the distinction from conventional photoconductive effect. The trap- and hybrid-induced photogating including their origins, formations, and characteristics are subsequently discussed. Then, the recent progress on trap- and hybrid-induced photogating in low dimensional photodetectors is elaborated. Though a high gain bandwidth product as high as 109 Hz is reported in several cases, a trade-off between gain and bandwidth has to be made for this type of photogating. The general photogating is put forward according to another three reported studies very recently. General photogating may enable simultaneous high gain and high bandwidth, paving the way to explore novel high-performance photodetectors. PMID- 29270343 TI - Simultaneous Optimization of Carrier Concentration and Alloy Scattering for Ultrahigh Performance GeTe Thermoelectrics. AB - In order to locate the optimal carrier concentrations for peaking the thermoelectric performance in p-type group IV monotellurides, existing efforts focus on aliovalent doping, either to increase (in PbTe) or to decrease (in SnTe and GeTe) the hole concentration. The limited solubility of aliovalent dopants usually introduces insufficient phonon scattering for thermoelectric performance maximization. With a decrease in the size of cation, the concentration of holes, induced by cation vacancies in intrinsic compounds, increases rapidly from ~1018 cm-3 in PbTe to ~1020 cm-3 in SnTe and then to ~1021 cm-3 in GeTe. This motivates a strategy here for reducing the carrier concentration in GeTe, by increasing the mean size of cations and vice-versa decreasing the average size of anions through isovalent substitutions for increased formation energy of cation vacancy. A combination of the simultaneously resulting strong phonon scattering due to the high solubility of isovalent impurities, an ultrahigh thermoelectric figure of merit, zT of 2.2 is achieved in GeTe-PbSe alloys. This corresponds to a 300% enhancement in average zT as compared to pristine GeTe. This work not only demonstrates GeTe as a promising thermoelectric material but also paves the way for enhancing the thermoelectric performance in similar materials. PMID- 29270344 TI - Toward Aerogel Electrodes of Superior Rate Performance in Supercapacitors through Engineered Hollow Nanoparticles of NiCo2O4. AB - A biomass-templated pathway is developed for scalable synthesis of NiCo2O4@carbon aerogel electrodes for supercapacitors, where NiCo2O4 hollow nanoparticles with an average outer diameter of 30-40 nm are conjoined by graphitic carbon forming a 3D aerogel structure. This kind of NiCo2O4 aerogel structure shows large specific surface area (167.8 m2 g-1), high specific capacitance (903.2 F g-1 at a current density of 1 A g-1), outstanding rate performance (96.2% capacity retention from 1 to 10 A g-1), and excellent cycling stability (nearly without capacitance loss after 3000 cycles at 10 A g-1). The unique structure of the 3D hollow aerogel synergistically contributes to the high performance. For instance, the 3D interconnected porous structure of the aerogel is beneficial for electrolyte ion diffusion and for shortening the electron transport pathways, and thus can improve the rate performance. The conductive carbon joint greatly enhances the specific capacity, and the hollow structure prohibits the volume changes during the charge-discharge process to significantly improve the cycling stability. This work represents a giant step toward the preparation of high-performance commercial supercapacitors. PMID- 29270346 TI - Ultrahigh Electrocatalytic Conversion of Methane at Room Temperature. AB - Due to the greenhouse effect, enormous efforts are done for carbon dioxide reduction. By contrast, more attention should be paid for the methane oxidation and conversion, which can help the effective utilization of methane without emission. However, methane conversion and utilization under ambient conditions remains a challenge. Here, this study designs a Co3O4/ZrO2 nanocomposite for the electrochemical oxidation of methane gas using a carbonate electrolyte at room temperature. Co3O4 activated the highly efficient oxidation of methane under mild electric energy with the help of carbonate as an oxidant, which is delivered by ZrO2. Based on the experimental results, acetaldehyde is the key intermediate product. Subsequent nucleophilic addition and free radical addition reactions accounted for the generation of 2-propanol and 1-propanol, respectively. Surprisingly, this work achieves a production efficiency of over 60% in the conversion of methane to produce these long-term stable products. The as-proposed regional electrochemical methane oxidation provides a new pathway for the synthesis of higher alcohols with high production efficiencies under ambient conditions. PMID- 29270345 TI - Exploitation of the Large-Area Basal Plane of MoS2 and Preparation of Bifunctional Catalysts through On-Surface Self-Assembly. AB - The development of nonprecious electrochemical catalysts for water splitting is a key step to achieve a sustainable energy supply for the future. Molybdenum disulfide (MoS2) has been extensively studied as a promising low-cost catalyst for hydrogen evolution reaction (HER), whereas HER is only catalyzed at the edge for pristine MoS2, leaving a large area of basal plane useless. Herein, on surface self-assembly is demonstrated to be an effective, facile, and damage-free method to take full advantage of the large ratio surface of MoS2 for HER by using multiscale simulations. It is found that as supplement of edge sites of MoS2, on MoS2 M(abt)2 (M = Ni, Co; abt = 2-aminobenzenethiolate) owns high HER activity, and the self-assembled M(abt)2 monolayers on MoS2 can be obtained through a simple liquid-deposition method. More importantly, on-surface self-assembly provides potential application for overall water splitting once the self assembled systems prove to be of both HER and oxygen evolution reaction activities, for example, on-MoS2 Co(abt)2. This work opens up a new and promising avenue (on-surface self-assembly) toward the full exploitation of the basal plane of MoS2 for HER and the preparation of bifunctional catalysts for overall water splitting. PMID- 29270347 TI - Full-Color Emission Polymer Carbon Dots with Quench-Resistant Solid-State Fluorescence. AB - Polymer carbon dots (PCDs) represent a new class of carbon dots (CDs) possessing sub-fluorophores and unique polymer-like structures. However, like small molecule dyes and traditional CDs, PCDs often suffer from self-quenching effect in solid state, limiting their potential applications. Moreover, it is hard to prepare PCDs that have the same chemical structure, exhibiting full-color emission under one fixed excitation wavelength by only modulating the concentration of the PCDs. Herein, self-quenching-resistant solid-state fluorescent polymer carbon dots (SSFPCDs) are prepared, which exhibit strong red SSF without any other additional solid matrices, while having a large production yield (~89%) and a considerable quantum yield of 8.50%. When dispersed in water or solid matrices in gradient concentrations, they can exhibit yellow, green, and blue fluorescence, realizing the first SSFPCDs with the same chemical structure emitting in full-color range by changing the ratio of SSFPCDs to the solid matrices. PMID- 29270348 TI - 3D Printing of Lotus Root-Like Biomimetic Materials for Cell Delivery and Tissue Regeneration. AB - Biomimetic materials have drawn more and more attention in recent years. Regeneration of large bone defects is still a major clinical challenge. In addition, vascularization plays an important role in the process of large bone regeneration and microchannel structure can induce endothelial cells to form rudimentary vasculature. In recent years, 3D printing scaffolds are major materials for large bone defect repair. However, these traditional 3D scaffolds have low porosity and nonchannel structure, which impede angiogenesis and osteogenesis. In this study, inspired by the microstructure of natural plant lotus root, biomimetic materials with lotus root-like structures are successfully prepared via a modified 3D printing strategy. Compared with traditional 3D materials, these biomimetic materials can significantly improve in vitro cell attachment and proliferation as well as promote in vivo osteogenesis, indicating potential application for cell delivery and bone regeneration. PMID- 29270349 TI - Electroionic Antagonistic Muscles Based on Nitrogen-Doped Carbons Derived from Poly(Triazine-Triptycene). AB - Electroactive soft actuators and bioinspired artificial muscles have received burgeoning interest as essential components in future electronic devices such as soft haptic-feedback systems, human-friendly wearable electronics, and active biomedical devices. However, important challenging issues including fast response time, ultralow input power, robust operation in harsh environments, high resolution controllability, and cost-effectiveness remain to be resolved for more practical applications. Here, an electroionic antagonistic artificial muscle is reported based on hierarchically porous nitrogen-doped carbon (HPNC) electrodes derived from a microporous poly(triazine-triptycene) organic framework (PtztpOF). The HPNC, which exhibits hierarchically micro- and mesoporous structures, high specific capacitance of 330 F g-1 in aqueous solution, large specific surface area of 830.46 m2 g-1, and graphitic nitrogen doping, offers high electrical conductivity of 0.073 MS m-1 and outstanding volumetric capacitance of 10.4 MF m 3. Furthermore, it is demonstrated that a novel electroionic antagonistic muscle based on HPNC electrodes successfully displays extremely reliable and large bending deformations and long-term durability under ultralow input voltages. Therefore, microporous polymer or covalent organic frameworks can be applied to provide significant improvements in electroactive artificial muscles, which can play key roles as technological advances toward bioinspired actuating devices required for next-generation soft and wearable electronics. PMID- 29270350 TI - Pursuing Polymer Dielectric Interfacial Effect in Organic Transistors for Photosensing Performance Optimization. AB - Polymer dielectrics in organic field-effect transistors (OFETs) are essential to provide the devices with overall flexibility, stretchability, and printability and simultaneously introduce charge interaction on the interface with organic semiconductors (OSCs). The interfacial effect between various polymer dielectrics and OSCs significantly and intricately influences device performance. However, understanding of this effect is limited because the interface is buried and the interfacial charge interaction is difficult to stimulate and characterize. Here, this challenge is overcome by utilizing illumination to stimulate the interfacial effect in various OFETs and to characterize the responses of the effect by measuring photoinduced changes of the OFETs performances. This systemic investigation reveals the mechanism of the intricate interfacial effect in detail, and mathematically explains how the photosensitive OFETs characteristics are determined by parameters including polar group of the polymer dielectric and the OSC side chain. By utilizing this mechanism, performance of organic electronics can be precisely controlled and optimized. OFETs with strong interfacial effect can also show a signal additivity caused by repeated light pulses, which is applicable for photostimulated synapse emulator. Therefore, this work enlightens a detailed understanding on the interface effect and provides novel strategies for optimizing OFET photosensory performances. PMID- 29270351 TI - Overcoming the Limitations of Sputtered Nickel Oxide for High-Efficiency and Large-Area Perovskite Solar Cells. AB - Perovskite solar cells (PSCs) are one of the promising photovoltaic technologies for solar electricity generation. NiO x is an inorganic p-type semiconductor widely used to address the stability issue of PSCs. Although high efficiency is obtained for the devices employing NiO x as the hole transport layer, the fabrication methods have yet to be demonstrated for industrially relevant manufacturing of large-area and high-performance devices. Here, it is shown that these requirements can be satisfied by using the magnetron sputtering, which is well established in the industry. The limitations of low fill factor and short circuit current commonly observed in sputtered NiO x -derived PSCs can be overcome through magnesium doping and low oxygen partial pressure deposition. The fabricated PSCs show a high power conversion efficiency of up to 18.5%, along with negligible hysteresis, improved ambient stability, and high reproducibility. In addition, good uniformity is also demonstrated over an area of 100 cm2. The simple and well-established approach constitutes a reliable and scale method paving the way for the commercialization of PSCs. PMID- 29270352 TI - An Aqueous Ca-Ion Battery. AB - Multivalent-ion batteries are emerging as low-cost, high energy density, and safe alternatives to Li-ion batteries but are challenged by slow cation diffusion in electrode materials due to the high polarization strength of Mg- and Al-ions. In contrast, Ca-ion has a low polarization strength similar to that of Li-ion, therefore a Ca-ion battery will share the advantages while avoiding the kinetics issues related to multivalent batteries. However, there is no battery known that utilizes the Ca-ion chemistry due to the limited success in Ca-ion storage materials. Here, a safe and low-cost aqueous Ca-ion battery based on a highly reversible polyimide anode and a high-potential open framework copper hexacyanoferrate cathode is demonstrated. The prototype cell shows a stable capacity and high efficiency at both high and low current rates, with an 88% capacity retention and an average 99% coloumbic efficiency after cycling at 10C for 1000 cycles. The Ca-ion storage mechanism for both electrodes as well as the origin of the fast kinetics have been investigated. Additional comparison with a Mg-ion cell with identical electrodes reveals clear kinetics advantages for the Ca-ion system, which is explained by the smaller ionic radii and more facile desolvation of hydrated Ca-ions. PMID- 29270353 TI - Enhanced Proton Conductivity in Y-Doped BaZrO3 via Strain Engineering. AB - The effects of stress-induced lattice distortions (strain) on the conductivity of Y-doped BaZrO3, a high-temperature proton conductor with key technological applications for sustainable electrochemical energy conversion, are studied. Highly ordered epitaxial thin films are grown in different strain states while monitoring the stress generation and evolution in situ. Enhanced proton conductivity due to lower activation energies is discovered under controlled conditions of tensile strain. In particular, a twofold increased conductivity is measured at 200 degrees C along a 0.7% tensile strained lattice. This is at variance with conclusions coming from force-field simulations or the static calculations of diffusion barriers. Here, extensive first-principles molecular dynamic simulations of proton diffusivity in the proton-trapping regime are therefore performed and found to agree with the experiments. The simulations highlight that compressive strain confines protons in planes parallel to the substrate, while tensile strain boosts diffusivity in the perpendicular direction, with the net result that the overall conductivity is enhanced. It is indeed the presence of the dopant and the proton-trapping effect that makes tensile strain favorable for proton conduction. PMID- 29270355 TI - Expression of a specific extracellular matrix signature is a favorable prognostic factor in acute myeloid leukemia. AB - Relapse of acute myeloid leukemia (AML) is still dramatically frequent, imposing the need for early markers to quantify such risk. Recent evidence point to a prominent role for extracellular matrix (ECM) in AML, but its prognostic value has not yet been investigated. Here we have investigated whether the expression of a 15-ECM gene signature could be applied to clinical AML research evaluating a retrospective cohort of 61 AML patients and 12 healthy donors. Results show that patients whose ECM signature expression is at least twice as that of healthy donors have considerably longer relapse-free survival, with further stage specific therapy outcomes. PMID- 29270354 TI - Nonlocal Response in Infrared Detector with Semiconducting Carbon Nanotubes and Graphdiyne. AB - Semiconducting single-walled carbon nanotubes (s-SWNTs) are regarded as an important candidate for infrared (IR) optical detection due to their excellent intrinsic properties. However, the strong binding energy of excitons in s-SWNTs seriously impedes the development of s-SWNTs IR photodetector. This Communication reports an IR photodetector with highly pure s-SWNTs and gamma-graphdiyne. The heterojunctions between the two materials can efficiently separate the photogenerated excitons. In comparison to device fabricated only with s-SWNTs, this IR detector shows a uniform response in the whole channel of the device. The response time is demonstrated to be below 1 ms. The optimal responsivity and detectivity approximately reach 0.4 mA W-1 and 5 * 106 cmHz1/2 W-1, respectively. PMID- 29270356 TI - Altered task-based and resting-state amygdala functional connectivity following real-time fMRI amygdala neurofeedback training in major depressive disorder. AB - Background: We have previously shown that in participants with major depressive disorder (MDD) trained to upregulate their amygdala hemodynamic response during positive autobiographical memory (AM) recall with real-time fMRI neurofeedback (rtfMRI-nf) training, depressive symptoms diminish. Here, we assessed the effect of rtfMRI-nf on amygdala functional connectivity during both positive AM recall and rest. Method: The current manuscript consists of a secondary analysis on data from our published clinical trial of neurofeedback. Patients with MDD completed two rtfMRI-nf sessions (18 received amygdala rtfMRI-nf, 16 received control parietal rtfMRI-nf). One-week prior-to and following training participants also completed a resting-state fMRI scan. A GLM-based functional connectivity analysis was applied using a seed ROI in the left amygdala. We compared amygdala functional connectivity changes while recalling positive AMs from the baseline run to the final transfer run during rtfMRI-nf training, as well during rest from the baseline to the one-week follow-up visit. Finally, we assessed the correlation between change in depression scores and change in amygdala connectivity, as well as correlations between amygdala regulation success and connectivity changes. Results: Following training, amygdala connectivity during positive AM recall increased with widespread regions in the frontal and limbic network. During rest, amygdala connectivity increased following training within the fronto-temporal-limbic network. During both task and resting-state analyses, amygdala-temporal pole connectivity decreased. We identified increased amygdala precuneus and amygdala-inferior frontal gyrus connectivity during positive memory recall and increased amygdala-precuneus and amygdala-thalamus connectivity during rest as functional connectivity changes that explained significant variance in symptom improvement. Amygdala-precuneus connectivity changes also explain a significant amount of variance in neurofeedback regulation success. Conclusions: Neurofeedback training to increase amygdala hemodynamic activity during positive AM recall increased amygdala connectivity with regions involved in self referential, salience, and reward processing. Results suggest future targets for neurofeedback interventions, particularly interventions involving the precuneus. PMID- 29270357 TI - White matter changes and gait decline in cerebral small vessel disease. AB - The relation between progression of cerebral small vessel disease (SVD) and gait decline is uncertain, and diffusion tensor imaging (DTI) studies on gait decline are lacking. We therefore investigated the longitudinal associations between (micro) structural brain changes and gait decline in SVD using DTI. 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort (RUN DMC), a prospective cohort of participants with cerebral small vessel disease aged 50-85 years. Gait (using GAITRite) and magnetic resonance imaging measures were assessed during baseline (2006-2007) and follow-up (2011 - 2012). Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline. Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline. 56.2% were male, mean age was 62.9 years (SD8.2), mean follow-up duration was 5.4 years (SD0.2) and mean gait speed decline was 0.2 m/s (SD0.2). Stride length decline was associated with white matter atrophy (beta = 0.16, p = 0.007), and increase in mean white matter radial diffusivity and mean diffusivity, and decrease in mean fractional anisotropy (respectively, beta = - 0.14, p = 0.009; beta = - 0.12, p = 0.018; beta = 0.10, p = 0.049), independent of age, sex, height, follow-up duration and baseline stride length. Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase (primarily explained by radial diffusivity increase) in multiple white matter tracts, with the strongest associations found in the corpus callosum and corona radiata, independent of traditional small vessel disease markers. White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up. These findings suggest that progression of SVD might play an important role in gait decline. PMID- 29270358 TI - Identifying neural drivers of benign childhood epilepsy with centrotemporal spikes. AB - Epilepsy is a neurological disorder characterized by abnormal electrical discharges in a group of brain cells. Benign childhood epilepsy, which affect children under the age of 12 years, has been reported to contribute to the cognitive impairment of these children, even in the absence of structural abnormalities. Functional connectivity models have been applied to provide a deeper understanding of the processes that control and regulate interictal activity of benign childhood epilepsy. These studies have shown regions of increased connectivity and activity, particularly at the epileptic zone, which is usually the central region around the sensorimotor cortex, and in the immediate regions surrounding the zone and reduced activity in distant regions, such as the frontal lobe and temporal regions. The present study was designed to identify the neural drivers involved in the initiation and propagation of epileptic activity and the causal relationships between brain regions with increased and decreased connectivity and functional activity. We used three different models to identify neural drivers and casual connectivity with dynamic causal modelling (DCM) of EEG data. All models showed that the central region, the source of the epileptic activity, is the major driver of the brain network during interictal discharges. Other regions include the temporoparietal junction and temporal pole. The central region also had influence on the frontal and contralateral hemisphere, which might explain the cognitive deficits observed in these patients. PMID- 29270360 TI - Molecular identification of Sarcocystis halieti n. sp., Sarcocystis lari and Sarcocystis truncata in the intestine of a white-tailed sea eagle (Haliaeetus albicilla) in Norway. AB - An emaciated white-tailed sea eagle (Haliaeetus albicilla) from Western Norway was found and nursed briefly before it died. The necropsy revealed that the principal cause of death was an inflammation and occlusion of the bile ducts. A secondary finding was the presence in the intestinal mucosa of numerous sporulated Sarcocystis oocysts measuring 21.8-22.8 * 16.0-17.0 MUm. The aim of this study was to identify these oocysts to species level using molecular methods. Genomic DNA was extracted from 10 mucosal scrapings containing oocysts and subjected to PCR amplification and sequencing of four DNA regions: the 18S and 28S rRNA genes, the ITS1 region and the cox1 gene. DNA of three previously known Sarcocystis spp. was identified, but only two of these, Sarcocystis halieti n. sp. and Sarcocystis lari, both employing sea birds as intermediate hosts, were considered to have used the sea eagle as a definitive host and to have formed oocysts in its intestine. The third species found, Sarcocystis truncata, employs red deer as intermediate hosts and seems to use felids as definitive hosts based on its phylogenetic position and prevalence. The sea eagle had probably recently ingested portions of one of the latter hosts (red deer or cat/lynx) containing stages (sarcocysts/oocysts) and thus DNA of S. truncata. The species S. halieti and S. lari could only be unambiguously separated from their most closely related congeners on the basis of their ITS1 sequences. This is the first report of Sarcocystis oocysts in sea eagles and the first identification to species level of Sarcocystis oocysts in any type of eagle. The sea eagle also acted as intermediate host of an unidentified Sarcocystis spp. as evidenced by the finding of six thin-walled sarcocysts in a histological section of cardiac muscle. PMID- 29270361 TI - Developing and Validating an Abbreviated Version of the Microscale Audit for Pedestrian Streetscapes (MAPS-Abbreviated). AB - Purpose: Macroscale built environment factors (e.g., street connectivity) are correlated with physical activity. Less-studied but more modifiable microscale elements (e.g., sidewalks) may also influence physical activity, but shorter audit measures of microscale elements are needed to promote wider use. This study evaluated the relation of an abbreviated 54-item streetscape audit tool with multiple measures of physical activity in four age groups. Methods: We developed a 54-item version from the original 120-item Microscale Audit of Pedestrian Streetscapes (MAPS). Audits were conducted on 0.25-0.45 mile routes from participant residences toward the nearest nonresidential destination for children (N=758), adolescents (N=897), younger adults (N=1,655), and older adults (N=367). Active transport and leisure physical activity were measured with surveys, and objective physical activity was measured with accelerometers. Items to retain from original MAPS were selected primarily by correlations with physical activity. Mixed linear regression analyses were conducted for MAPS-Abbreviated summary scores, adjusting for demographics, participant clustering, and macroscale walkability. Results: MAPS-Abbreviated and original MAPS total scores correlated r=.94 The MAPS-Abbreviated tool was related similarly to physical activity outcomes as the original MAPS. Destinations and land use, streetscape and walking path characteristics, and overall total scores were significantly related to active transport in all age groups. Street crossing characteristics were related to active transport in children and older adults. Aesthetics and social characteristics were related to leisure physical activity in children and younger adults, and cul-de-sacs were related with physical activity in youth. Total scores were related to accelerometer-measured physical activity in children and older adults. Conclusion: MAPS-Abbreviated is a validated observational measure for use in research. The length and related cost of implementation has been cited as a barrier to use of microscale instruments, so availability of this shorter validated measure could lead to more widespread use of streetscape audits in health research. PMID- 29270359 TI - Challenges and techniques for presurgical brain mapping with functional MRI. AB - Functional magnetic resonance imaging (fMRI) is increasingly used for preoperative counseling and planning, and intraoperative guidance for tumor resection in the eloquent cortex. Although there have been improvements in image resolution and artifact correction, there are still limitations of this modality. In this review, we discuss clinical fMRI's applications, limitations and potential solutions. These limitations depend on the following parameters: foundations of fMRI, physiologic effects of the disease, distinctions between clinical and research fMRI, and the design of the fMRI study. We also compare fMRI to other brain mapping modalities which should be considered as alternatives or adjuncts when appropriate, and discuss intraoperative use and validation of fMRI. These concepts direct the clinical application of fMRI in neurosurgical patients. PMID- 29270362 TI - Clinical value of drugs of abuse point of care testing in an emergency department setting. AB - Objective: Toxicology screening tests for drugs-of-abuse and therapeutic drugs in urine (TST-U) are often used to assess whether a patient's clinical condition can be explained by the use of drugs-of-abuse (DOA) and/or therapeutic drugs. TST-U have clinical value when they support clinical decision making by influencing diagnosis and patient care. We aim to quantify the influence of TST-U results on diagnosis and patient care in an emergency department. Our secondary objective is to identify specific patients for which a TST-U is most warranted or mostly unhelpful. Methods: This prospective observational study was performed at the emergency department of a middle-sized urban teaching hospital. A point of care TST-U has been used in this department for three years. When a TST-U is considered indicated by a physician, the influence of the TST-U result on diagnosis and patient care is quantified before and after the test results are available, by means of a questionnaire. Urgency and complaints upon admission have also been registered. Results: Of 100 TST-U results 37% were reported having a substantial influence on diagnosis and 25% on patient care. TST-U had a substantial influence on diagnosis in 48% of patients with decreased consciousness, 47% of patients with psychiatric symptoms and in 47% of patients with "other" complaints. In this last category patients with neurological symptoms benefited most. In patients who were already suspected to be intoxicated, only 18% of the TST-U results had substantial influence on diagnosis. Conclusions: The use of point of care TST-U in an Emergency Department helps physicians to understand the clinical condition of a patient. They influence the way a patient is treated to a lesser extent. These tests are most helpful in patients with decreased consciousness, psychiatric or neurological symptoms and mostly unhelpful in patients who, upon admission, are already known to be intoxicated. PMID- 29270363 TI - Evaluation of acute and sublethal effects of chloroquine (C18H26CIN3) on certain enzymological and histopathological biomarker responses of a freshwater fish Cyprinus carpio. AB - In this study the toxicity of antimalarial drug chloroquine (CQ) on certain enzymological (GOT, GPT and LDH) and histopathological alterations (Gill, liver and kidney) of a freshwater fish Cyprinus carpio was studied after acute (96 h) and sublethal (35 days) exposure. The median lethal concentration (96 h) of CQ was 31.62 mg/ml. During acute treatment (CQ at 31.62 mg/ml) the treated fish groups showed a significant increase in GOT and GPT activities in blood plasma; whereas LDH activity was decreased when compare to control groups. To analyse the effects of drug at the lowest concentration, the fish were exposed to 3.16 mg/ml (1/10th of 96 h LC50 value) for 96 h. In sublethal treatment (3.16 mg/ml) GOT activity increased up to 14th day and decreased during the rest of the exposure period (21, 28 and 35th day). A biphasic response in GPT activity was observed. LDH activity was found to be increased throughout the study period (35 days) compare to control groups. The alterations in enzyme activities in blood plasma were found to be significant at p < 0.05 (DMRT). Many histopathological changes in vital organs such as gill, liver and kidney of fish were observed in CQ treated group (acute and sub-lethal) compare to normal group. The alterations in the enzymological and histopathological study in the present investigation indicate that the drug CQ has toxic effects on non-target organisms. We conclude that the alterations in enzymological parameters and histopathological changes can be used as biomarker to assess the health of the aquatic organism/environment. Further data on molecular studies are needed to define the mode of action and toxicity of these emerging pollutants. PMID- 29270364 TI - MUSex, pregnancy, and age-specific differences of blood manganese levels in relation to iron status; what does it mean? AB - The objective of the present study was to evaluate sex, menopause, pregnancy, and age-specific differences of blood manganese (Mn) levels in relation to iron status, and to assess the toxicological implications of these relationships. Females of childbearing age have higher concentrations of blood Mn than males because women have lower concentrations of ferritin. Previous studies indicated significant increases in blood Mn levels throughout pregnancy, and that the geometric mean of blood Mn was significantly higher in premenopausal women than postmenopausal women. This may be due to the enhanced absorption of Mn because of upregulation of iron absorption, which is especially important during late pregnancy. Mn concentrations are highest in infancy, decreased with age up to adolescence, and did not change during adulthood. Thus, the relationship of iron with Mn may be the major factor affecting blood Mn levels according to menstrual stage, reproductive status, menopausal factors, and age. However, Mn absorbed via the gastrointestinal system seems to be less neurotoxic than inhaled or parenteral Mn, due to the tight enterohepatic homeostatic control of this essential element. Furthermore, children and pregnant women had no adverse health effects from blood levels of Mn that were associated with adverse effects in adult workers. In conclusion, the differences between a physiological and a pathological hypermanganesemia complicate interpretation of the dose-response relationship. PMID- 29270366 TI - Microinterventions produce immediate but not lasting benefits in mood and distress. AB - Untreated depression remains one of the largest public health concerns. However, barriers such as unavailability of mental health providers and high cost of services limit the number of people able to benefit from traditional treatments. Though unsupported Internet interventions have proven effective at bypassing many of these barriers given their reach and scalability, attrition from interventions has been an ongoing concern. Microinterventions, or ultra-brief online tools meant to produce a rapid improvement in mood, may offer a way to provide the benefits of unsupported Internet interventions quickly, before attrition might occur. This study examined the immediate and lasting effects of three microinterventions (Breathing Exercises, Thought Records, and a Pleasant Activities Selector) on mood and distress. Participants (N=122) were randomized into three groups, each group completing two of the three microinterventions. Participants were asked to rate their mood and level of distress before and after completing the microintervention. Depression and perceived stress were assessed at baseline and at four weekly follow-ups. Although lasting effects were not found, a significant within-group reduction in distress and improvement in mood were observed immediately following the completion of the microintervention. This study demonstrates the potential benefits of microinterventions to individuals for their immediate needs vis-a-vis mood and distress. PMID- 29270365 TI - New research highlights: Impact of chronic ingestion of white kidney beans (Phaseolus vulgaris L. var. Beldia) on small-intestinal disaccharidase activity in Wistar rats. AB - The chronic ingestion of raw or undercooked kidney beans (Phaseolus vulgaris L.) is involved in the pathogenesis of multiple organ dysfunction; the underlying mechanisms are still poorly understood. The objective of this study was to assess the gavage effects of a raw Beldia bean variety on the brush border disaccharidase activities in the jejunal mucosa of Wistar rats. Twenty young adult male rats were randomly assigned into 2 groups of 10 rats each: Control, rats were gavaged with 300 mg of a rodent pellet flour suspension (RPFS); Experimental, rats were orogastrically fed a dose of 300 mg Beldia bean flour suspension (BBFS). Prior to determining the disaccharidase activity by Dahlqvist method, the blood and stool specimens were collected on day 10. The sera and feces were screened for the presence of lectins by serologic and hemagglutination assays. The results showed that the brush border maltase and sucrase activities were significantly diminished but lactase activity did not undergo any change in BBFS-gavaged animals as compared with control. Preliminary immunobiochemical assays revealed the absence of lectins in the systemic circulation and feces of rats, but further work is required to prove this. Overall, the dietary administration of BBFS caused depression of the activity of the small intestinal enzymes maltase and sucrase. PMID- 29270367 TI - Smoke produced from plants waste material elicits growth of wheat (Triticum aestivum L.) by improving morphological, physiological and biochemical activity. AB - The experimental work presented in this study was carried out with the hypothesis that plant derived smoke enhanced the morphological, physiological and biochemical attributes of a cereal crop, wheat (Triticum aestivum L.). Furthermore, this study supported the hypothesis that plant derived smoke acts as vegetative growth promoter, inexpensive, rapid and most appropriate eco-friendly bio-fertilizer for sustainable agriculture. Plant derived smoke was generated by burning of plant material (leaf, straws etc) in a specially designed furnace, and seeds were treated with this smoke for different time duration. Four level of plant derived smoke (1 h, 2 h, 3 h and 4 h) along with control were tested on four wheat cultivars in CRD repeated pot experiment. The smoke-related treatments modified number of morphological, physiological and biochemical features of wheat. Compared with the control, aerosol smoke treatment of the seeds significantly improved root length (2.6%), shoot length (7.7%), RFW (0.04%), SFW (0.7%), SDW (0.1%) and leaf area (63.9%). All the smoke-related treatments significantly promoted RWC (17.3%), water potential (1.5%), osmotic potential (1.4%) and MSI (14.6%) whereas a pronounced increase in chlorophyll a (24.9%), chlorophyll b (21.7%) and total chlorophyll contents (15.5%) were recorded in response to aerosol-smoke treatments. Plant derived smoke exposure applied for short time i.e. 1 h & 2 h induced significant results as compared to prolonged PDS exposure (3 h and 4 h). The best results were observed in Pak-13 and Glaxy-13 wheat cultivars. These findings indicated that the plant-derived smoke treatment has a great potential to improve morphological, physiological and biochemical features of wheat crop. PMID- 29270368 TI - Tell me something I don't know. PMID- 29270369 TI - Systematic review and meta-analysis of surgical outcomes in Marfan patients undergoing aortic root surgery by composite-valve graft or valve sparing root replacement. AB - Background: A major, life-limiting feature of Marfan syndrome (MFS) is the presence of aneurysmal disease. Cardiovascular intervention has dramatically improved the life expectancy of Marfan patients. Traditionally, the management of aortic root disease has been undertaken with composite-valve graft replacing the aortic valve and proximal aorta; more recently, valve sparing procedures have been developed to avoid the need for anticoagulation. This meta-analysis assesses the important surgical outcomes of the two surgical techniques. Methods: A systematic review and meta-analysis of 23 studies reporting the outcomes of aortic root surgery in Marfan patients with data extracted for outcomes of early and late mortality, thromboembolic events, late bleeding complications and surgical reintervention rates. Results: The outcomes of 2,976 Marfan patients undergoing aortic root surgery were analysed, 1,624 patients were treated with composite valve graft (CVG) and 1,352 patients were treated with valve sparing root replacement (VSRR). When compared against CVG, VSRR was associated with reduced risk of thromboembolism (OR =0.32; 95% CI, 0.16-0.62, P=0.0008), late hemorrhagic complications (OR =0.18; 95% CI, 0.07-0.45; P=0.0003) and endocarditis (OR =0.27; 95% CI, 0.10-0.68; P=0.006). Importantly there was no significant difference in reintervention rates between VSRR and CVG (OR =0.89; 95% CI, 0.35-2.24; P=0.80). Conclusions: There is an increasing body of evidence that VSRR can be reliably performed in Marfan patients, resulting in a durable repair with no increased risk of re-operation compared to CVG, thus avoiding the need for systemic anticoagulation in selected patients. PMID- 29270370 TI - Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. AB - Many different heritable connective tissue disorders (HCTD) have been described over the past decades. These syndromes often affect the connective tissue of various organ systems, including heart, blood vessels, skin, joints, bone, eyes, and lungs. The discovery of these HCTD was followed by the identification of mutations in a wide range of genes encoding structural proteins, modifying enzymes, or components of the TGFbeta-signaling pathway. Three typical examples of HCTD are Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), and Loeys-Dietz syndrome (LDS). These syndromes show some degree of phenotypical overlap of cardiovascular, skeletal, and cutaneous features. MFS is typically characterized by cardiovascular, ocular, and skeletal manifestations and is caused by heterozygous mutations in FBN1, coding for the extracellular matrix (ECM) protein fibrillin-1. The most common cardiovascular phenotype involves aortic aneurysm and dissection at the sinuses of Valsalva. LDS is caused by mutations in TGBR1/2, SMAD2/3, or TGFB2/3, all coding for components of the TGFbeta-signaling pathway. LDS can be distinguished from MFS by the unique presence of hypertelorism, bifid uvula or cleft palate, and widespread aortic and arterial aneurysm and tortuosity. Compared to MFS, LDS cardiovascular manifestations tend to be more severe. In contrast, no association is reported between LDS and the presence of ectopia lentis, a key distinguishing feature of MFS. Overlapping features between MFS and LDS include scoliosis, pes planus, anterior chest deformity, spontaneous pneumothorax, and dural ectasia. EDS refers to a group of clinically and genetically heterogeneous connective tissue disorders and all subtypes are characterized by variable abnormalities of skin, ligaments and joints, blood vessels, and internal organs. Typical presenting features include joint hypermobility, skin hyperextensibility, and tissue fragility. Up to one quarter of the EDS patients show aortic aneurysmal disease. The latest EDS nosology distinguishes 13 subtypes. Many phenotypic features show overlap between the different subtypes, which makes the clinical diagnosis rather difficult and highlights the importance of molecular diagnostic confirmation. PMID- 29270371 TI - Etiology and pathogenesis of the Marfan syndrome: current understanding. AB - Much has changed regarding Marfan syndrome (MFS) over the past few decades. Once described solely as a heritable disorder of connective tissue, MFS is now one of a number of conditions recognized to be a disorder of abnormal signalling in the TGF-beta pathway. The cardinal features of MFS, once encompassed by the ocular, skeletal and cardiovascular systems, are now known to encompass many more organ systems, especially as people with MFS grow older. They are growing older by several decades compared to the 1970's because of profound improvements in diagnosis and management of the cardiovascular features, especially dilatation of the aortic root. This dilatation can be detected first in infancy and followed up by echocardiography. Progressive enlargement increases the risk of type A dissection and aortic regurgitation, the major causes of early mortality, in untreated patients today. Medical therapy with beta-adrenergic blockade, first shown to be effective in the 1980's, can retard this dilatation. In the past decade, angiotensin receptor blockade, which reduces aberrant signalling through one of the TGF-beta pathways, also can be effective. However, when dilatation of the root becomes such that the risk of dissection increases to an unacceptable degree, surgical therapy becomes necessary. In the mid-1970's, the composite graft, introduced by Hugh Bentall, markedly reduced mortality. In the past decade, a valve-spring aortic root replacement, advanced by Tirone David, has become widely adopted. Mid-term results are quite encouraging. Other cardiovascular involvement, such as mitral valve prolapse, type B dissection, and dilatation and dissection of aortic branches, also require close monitoring. Currently, life-expectancy in people with MFS who are diagnosed early and treated prophylactically is approaching that of the general population. PMID- 29270372 TI - Non-cardiac manifestations of Marfan syndrome. AB - Because of the widespread distribution of fibrillin 1 in the body, Marfan syndrome (MFS) affects virtually every system. The expression of this single dominantly inherited gene is variable within a family, and between families. There is some genotype-phenotype correlation which is helpful in guiding long term prognosis, and management. In general gene mutations have been reported in clusters, with those having mainly ocular manifestations occurring in exons 1 to 15 of this 65-exon gene; those causing cardiac problems often involving cysteine replacement in a calcium binding EGF-like sequence; the most severe mutations occurring in exons 25-32, causing neonatal MFS diagnosed at birth, and severe enough to cause death frequently before the age of 2. Other correlations will certainly be found in future. This condition is progressive, and the manifestations unfold according to age. For example, if the lens is going to dislocate this usually occurs by age 10; scoliosis usually presents itself between the ages of 8 and 15; height should be monitored carefully between the onset of puberty and cessation of growth approximately age 17 or 18. Holistic care should be offered by one doctor who oversees the patient's welfare. This should be a paediatrician, paediatric cardiologist, or general practitioner in the case of an affected child. Thereafter, the physician in charge of the most seriously affected system should be aware that other systems need to be managed through a referral network. PMID- 29270373 TI - Biomechanical properties of the thoracic aorta in Marfan patients. AB - Background: Marfan syndrome (MFS), a genetic disorder of the connective tissue, has been strongly linked to dilation of the thoracic aorta, among other cardiovascular complications. As a result, MFS patients frequently suffer from aortic dissection and rupture, contributing to the high rate of mortality and morbidity among MFS patients. Despite the significant effort devoted to the investigation of mechanical and structural properties of aneurysmal tissue, studies on Marfan aneurysmal biomechanics are scarce. Ex vivo mechanical characterization of MFS aneurysmal tissue can provide a better insight into tissue strength outside the physiologic loading range and serve as a basis for improved risk assessment and failure prediction. Methods: The mechanical and microstructural properties of MFS aneurysmal thoracic aorta (MFS, n=15, 39.5+/ 3.91 years), non-MFS aneurysmal thoracic aorta (TAA, n=8, 52.8+/-4.9 years), healthy human thoracic aorta (HH, n=8, 75.4+/-6.1 years), and porcine thoracic aorta (n=10) are investigated. Planar biaxial tensile testing and uniaxial failure testing were utilized to characterize the mechanical and failure properties of the tissue, respectively. Verhoeff-Van Gieson (VVG) and PicroSirius Red stains were utilized to visualize the elastin and collagen fiber architecture, respectively. Results: MFS tissue was found to have age-dependent but diameter-independent mechanical, structural, and morphological properties, also showing extensive elastin fiber degradation. Non-MFS thoracic aneurysmal aorta was thicker and stiffer than age-matched MFS tissue. Moreover, non-MFS thoracic aneurysmal mechanics resembled closely the mechanics of older healthy human tissue. Younger MFS tissue (<40 years) exhibited similar mechanical and structural properties to aged porcine tissue. Conclusions: Both age and aneurysmal presence were found to be factors associated with increased stiffness in aortic tissue, and aortic diameter was not a significant determinant of mechanical property deterioration. Additionally, the presence of MFS was found to induce stiffening of the thoracic aorta, although not to the extent of the non MFS aneurysm. PMID- 29270374 TI - Natural history of aortic root aneurysms in Marfan syndrome. AB - Background: Cardiovascular complications account for a significant proportion of the shortened lifespan of Marfan syndrome (MFS) patients, with aortic dissection being the most dreadful complication. The aortic root dilates initially in MFS patients, and given its important hemodynamic role, this can lead to aortic regurgitation and poses a substantial risk of aortic dissection. This study seeks to evaluate the natural history of aortic root aneurysms in MFS patients, with a focus on growth rates and correlation of root diameter with the risk of developing aortic complications. Methods: Seventy-eight patients confirmed to have MFS and aortic root dilatation were retrospectively reviewed, and their aortic root diameters serially analyzed. Annual growth rate estimates and yearly rates of adverse events were computed and correlated with aortic diameter. Results: The mean annual growth rate of the aortic root was estimated to be 0.26+/-0.05 cm/year (range 0.13 to 0.35 cm). Larger aneurysms grew faster, reaching up to 0.46 cm/year for aneurysms >6 cm. Mean age at onset of aortic dissection was 36+/-4 years. Annual rates of adverse events (rupture, dissection and death) were obtained using a logistic regression model at sizes 3.5, 4, 4.5, 5, 5.5 and 6 cm. A sharp increase of 23% in the probability of the risk of complications at diameters 5.5 to 6 cm was recognized. Conclusions: Aortic root aneurysms in MFS patients tend to have a faster expansion rate compared to non MFS individuals, with aortic root diameter having a significant impact on the yearly risk of developing aortic complications. PMID- 29270375 TI - Aortic dissection in patients with Marfan syndrome based on the IRAD data. AB - Between January 1996 and May 2017, the International Registry on Acute Aortic Dissections has collected information on a total of 6,424 consecutive patients with acute aortic dissection, including 258 individuals with a diagnosis of Marfan syndrome. Patients with Marfan syndrome presented at a significantly younger age compared to patients without Marfan syndrome (38.2+/-13.2 vs. 63.0+/ 14.0 years; P<0.001) and in general had fewer comorbidities, although they more frequently had a known aortic aneurysm and history of prior cardiac surgery. We noted significantly larger diameters of the aortic annulus and root in the Marfan syndrome cohort, but no larger diameters more distally. The in-hospital mortality in type A dissection was not significantly different in patients with or without Marfan syndrome, despite the differences in age and comorbidities and the lower incidence of aortic rupture in the Marfan syndrome cohort. In contrast, the in hospital mortality of Marfan syndrome patients with type B dissection appears to be lower than that of patients without Marfan syndrome. The Marfan syndrome cohort that was treated with open surgery for type B dissection seemed to do especially well, with a 0% mortality rate (n=27). Follow-up data for type A and B dissections combined show an estimated five-year survival rate of 80.1% and an estimated reintervention rate of 55.3% in patients with Marfan syndrome. Such a high rate of reinterventions highlights the need for careful surveillance and treatment for patients with Marfan syndrome surviving the acute phase of aortic dissection. PMID- 29270376 TI - Pregnancy and Marfan syndrome. AB - Pregnancy in women with Marfan syndrome (MFS) presents challenges to the clinician and the patient due to the increased incidence of maternal complications and involvement of the fetus, and deserves special consideration. The leading cause of morbidity and mortality in MFS is aortic dissection. This article presents an extensive review of available clinical information and provides recommendations for the management of patients with MFS during pregnancy. PMID- 29270377 TI - Medical management of aortic disease in Marfan syndrome. AB - Marfan syndrome (MFS) is a hereditary disorder with numerous pathophysiological effects, some specifically creating elastic dysfunction in cardiovascular organs. Aortic dilatation, dissection and rupture are major concerns in the management of MFS patients. Predilection to form aneurysms is an indication for prophylactic medical management of thoracic aortic aneurysm disease in these patients. The current guidelines describe beta-blockers as the standard of care with angiotensin receptor blockers (ARBs) emerging as an equal, if not better alternative. We elaborate current evidence for and against different medical regimens used for the medical management of MFS patients. PMID- 29270379 TI - Endovascular therapy in Marfan syndrome: PRO. AB - Marfan syndrome (MFS) is an inherited connective tissue disorder that is associated with arterial fragility and aortic pathologies. The endovascular treatment of patients with MFS is controversial. Published series suggest that while endovascular intervention can be carried out with a low rate of immediate morbidity and mortality, midterm follow up demonstrates sizeable numbers of complications. However, in certain situations-such as rupture, reintervention for patch aneurysms, and elective interventions in which the landing zone is within a previously placed graft-endovascular interventions are appropriate. We present a review of the literature and our institutional perspective on this complex topic. PMID- 29270378 TI - Re-interventions on the thoracic and thoracoabdominal aorta in patients with Marfan syndrome. AB - The advent of multi-gene panel genetic testing and the discovery of new syndromic and non-syndromic forms of connective tissue disorders have established thoracic aortic aneurysms as a genetically mediated disease. Surgical results in patients with Marfan syndrome (MFS) provide an important benchmark for this patient population. Prophylactic aortic root surgery prevents acute dissection and has contributed to the improved survival of MFS patients. In the majority of patients, re-interventions are driven by a history of dissection. Patients undergoing elective root repair have a low risk for re-interventions on the root itself. Experienced centers have results after valve-sparing procedures at 10 years comparable with those seen after a modified Bentall procedure. In patients where only the ascending aorta was replaced during the initial surgery, re intervention rates are high as the root continues to dilate. The fate of the aortic arch in MFS patients presenting with dissection is strongly correlated with the extent of the initial surgery. Not replacing the entire ascending aorta and proximal aortic arch results in a high rate of re-interventions. Nevertheless, the additional burden of replacing the entire aortic arch during emergent proximal repair is not very well defined and makes comparisons with patients undergoing elective arch replacement difficult. Interestingly, replacing the entire aortic arch during initial surgery for acute dissection does not protect from re-interventions on downstream aortic segments. MFS patients suffering from type B dissection have a high risk for re-interventions ultimately leading up to replacement of the entire thoracoabdominal aorta even if the dissection was deemed uncomplicated by conventional criteria. While current guidelines do not recommend the implantation of stent grafts in MFS patients, implantation of a frozen-elephant-trunk to create a stable proximal landing zone for future endovascular or open procedures has emerged as a means to address aortic arch and descending aortic pathologies. PMID- 29270380 TI - Endovascular surgery in Marfan syndrome: CON. AB - The frequency of endovascular stent grafting procedures to treat various conditions of the thoracic aorta has increased dramatically over the past three decades. Stent grafting has been applied on a limited basis in patients with Marfan syndrome and other connective tissue disorders, despite recommendations from current guidelines and expert consensus statements against its use in this setting. A review of publications reporting outcomes after stent grafting of the descending thoracic aorta in Marfan patients with acute or chronic aortic dissection indicates that these procedures can be accomplished with rates of early mortality, stroke and spinal cord ischemic injury that are comparable to those observed in patients who do not have Marfan syndrome. However, the rates of primary treatment failure (principally endoleak), secondary treatment failure, need for open repair and late death among the Marfan patients are substantially higher than those observed in patients without this condition. In addition, the rates of retrograde aortic dissection and development of stent-graft induced new entry (SINE), are also greater among patients with Marfan syndrome. All of these findings argue strongly against the routine use of endovascular grafts in Marfan patients with type B or residual type A dissection. Few data are available to assess the role of endografting in Marfan patients with aneurysmal disease, but the progressive aortic dilatation noted in these patients argues strongly against its use in this setting as well. At present, the available data indicate that there is no justification for elective stent grafting in Marfan patients with aortic dissection or aneurysm. The only reasonable indications for primary aortic stent grafting are in the setting of acute aortic dissection or rupture, where the intervention is considered life-saving and rarely, considering the relatively young age of these patients, where the risk of open operation is considered to be prohibitive. PMID- 29270381 TI - Aortic valve sparing root surgery for Marfan syndrome. AB - Aortic valve sparing root surgery (AVSRS) is a safe and durable alternative for patients with dilated roots or pure aortic regurgitation (AR), which avoids the risks of anticoagulation or valvular degeneration with prosthetic valves. Notwithstanding the theoretical challenges of greater tissue fragility in Marfan syndrome (MFS), AVSRS has been demonstrated to have equal outcomes in this condition as it does in those without MFS. The benefits of retaining the native aortic valve in this generally younger age group extend beyond those of avoiding the inconvenience and complications of prolonged exposure to anticoagulants and include ease of management for future aortic, cardiac and non-cardiac procedures which are the norm for these patients. The essential principles of AVSRS in MFS do not differ from those for the rest of the population. Successful repair and durable valve function depend on a sound understanding of the close interaction between the structure and function of this exquisitely designed piece of engineering. We are fortunate to have numerous tools in our surgical armamentarium to preserve these valves. It is the purpose of this paper to demystify the complex structure-function interactions of the aortic valve, thereby gaining an intuition for AVSRS. We will also elaborate on specific technical details of established techniques that we have found successful in preserving the normal function of these valves in the long term. PMID- 29270382 TI - Valve-sparing versus composite root replacement procedures in patients with Marfan syndrome. PMID- 29270383 TI - Valve-sparing aortic root replacement in patients with Marfan syndrome-the Homburg experience. PMID- 29270384 TI - Aortic valve repair in patients with Marfan syndrome-the "Brussels approach". PMID- 29270385 TI - Thoracoabdominal aortic aneurysm repair in Marfan syndrome: how we do it. PMID- 29270387 TI - Bicuspid aortic valve. PMID- 29270386 TI - Two-Stage Elephant Trunk approach for open management of distal aortic arch and descending aortic pathology in patients with Marfan syndrome. PMID- 29270388 TI - Editorial: Self-Eating on Demand: Autophagy in Cancer and Cancer Therapy. PMID- 29270389 TI - Domesticating Cancer: An Evolutionary Strategy in the War on Cancer. AB - Since cancer shares the same molecular machinery as the host, most therapeutic interventions that aim to target cancer would inadvertently also adversely affect the host. In addition, cancer continuously evolves, streamlining its host-derived genome for a new single-celled existence. In particular, short-term clinical success observed with most antineoplastic therapies directly relate to the fact that cancer is constantly evolving. However, the clonal evolution of cancer occasionally also render cancer cells uniquely susceptible to therapeutic interventions, as is exemplified by the clinical relevance of synthetic lethality. Synthetic lethality describes a situation where the simultaneous loss of function in two genes results in lethality, but where a loss of function in either single gene is tolerated. This observation suggests that the evolution of cancer, usually seen as a major clinical challenge, may also afford a key opportunity in lowering on-target toxicities accosted with chemotherapy. As an example, by subjecting cancer to specific selection regimes, cancer can in effect be placed on evolutionary trajectories leading to the development of "targetable" phenotypes such as synthetic lethal interactions. However, such a selection regime would have to overcome a range of obstacles such as on-target toxicity and the selection of an evolvable trait. Since the majority of cancer evolution manifests as a loss of function, we suggest that the induction of auxotrophic phenotypes (i.e., where an organism lose the ability to synthesize specific organic compounds required for growth and thus become dependent on it from dietary sources) may represent an attractive therapeutic option. As an example, animals can obtain vitamin C either by de novo synthesis or from their diet. However, since the maintenance of synthetic pathways is costly, such pathways are often lost if no longer necessary, resulting in the organism being auxotrophic toward the dietary compound. Similarly, increasing the maintenance cost of a redundant pathway in cancer cells is likely to select for clones that have lost such a redundant pathway. Inhibition of a pathway, while supporting the activity of a compensating pathway, may thus induce auxotrophism in cancer cells but not in genomic stable host cells. PMID- 29270390 TI - Vaginal Lactobacilli Reduce Neisseria gonorrhoeae Viability through Multiple Strategies: An in Vitro Study. AB - The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae (GC) underline the need of "antibiotic-free" strategies for the control of gonorrhea. The aim of this study was to assess the anti-gonococcal activity of 14 vaginal Lactobacillus strains, belonging to different species (L. crispatus, L. gasseri, L. vaginalis), isolated from healthy pre-menopausal women. In particular, we performed "inhibition" experiments, evaluating the ability of both lactobacilli cells and culture supernatants in reducing GC viability, at two different contact times (7 and 60 min). First, we found that the acidic environment, associated to lactobacilli metabolism, is extremely effective in counteracting GC growth, in a pH- and time-dependent manner. Indeed, a complete abolishment of GC viability by lactobacilli supernatants was observed only for pH values < 4.0, even at short contact times. On the contrary, for higher pH values, no 100%-reduction of GC growth was reached at any contact time. Experiments with organic/inorganic acid solutions confirmed the strict correlation between the pH levels and the anti-gonococcal effect. In this context, the presence of lactate seemed to be crucial for the anti-gonococcal activity, especially for pH values in the range 4.4-5.3, indicating that the presence of H+ ions is necessary but not sufficient to kill gonococci. Moreover, experiments with buffered supernatants led to exclude a direct role in the GC killing by other bioactive molecules produced by lactobacilli. Second, we noticed that lactobacilli cells are able to reduce GC viability and to co-aggregate with gonococci. In this context, we demonstrated that released-surface components with biosurfactant properties, isolated from "highly-aggregating" lactobacilli, could affect GC viability. The antimicrobial potential of biosurfactants isolated from lactobacilli against pathogens has been largely investigated, but this is the first report about a possible use of these molecules in order to counteract GC infectivity. In conclusion, we identified specific Lactobacillus strains, mainly belonging to L. crispatus species, able to counteract GC viability through multiple mechanisms. These L. crispatus strains could represent a new potential probiotic strategy for the prevention of GC infections in women. PMID- 29270391 TI - Differentially Regulated Host Proteins Associated with Chronic Rhinosinusitis Are Correlated with the Sinonasal Microbiome. AB - The chronic inflammatory nature of chronic rhinosinusitis (CRS) makes it a morbid condition for individuals with the disease and one whose pathogenesis is poorly understood. To date, proteomic approaches have been applied successfully in a handful of CRS studies. In this study we use a multifaceted approach, including proteomics (iTRAQ labeling) and microbiome (bacterial 16S rRNA gene sequencing) analyses of middle meatus swabs, as well as immune cell analysis of the underlying tissue, to investigate the host-microbe interaction in individuals with CRS (n = 10) and healthy controls (n = 9). Of the total 606 proteins identified in this study, seven were significantly (p < 0.05) more abundant and 104 were significantly lower in the CRS cohort compared with healthy controls. The majority of detected proteins (82% of proteins identified) were not significantly correlated with disease status. Elevated levels of blood and immune cell proteins in the CRS cohort, together with significantly higher numbers of B cells and macrophages in the underlying tissue, confirmed the inflammatory status of CRS individuals. Protein PRRC2C and Ras-related protein (RAB14) (two of the seven elevated proteins) showed the biggest fold difference between the healthy and CRS groups. Validation of the elevated levels of these two proteins in CRS samples was provided by immunohistochemistry. Members of the bacterial community in the two study cohorts were not associated with PRRC2C, however members of the genus Moraxella did correlate with RAB14 (p < 0.0001, rho = -0.95), which is a protein involved in the development of basement membrane. In addition, significant correlations between certain members of the CRS bacterial community and 33 lower abundant proteins in the CRS cohort were identified. Members of the genera Streptococcus, Haemophilus and Veillonella were strongly correlated with CRS and were significantly associated with a number of proteins with varying functions. The results from this study reveal a strong association between the host and microbes in the sinonasal cavity. Proteins identified as associated with CRS could be new targets for drug therapies and biomarkers for assessment of treatment efficacy. PMID- 29270392 TI - Carbohydrate restriction ameliorates nephropathy by reducing oxidative stress and upregulating HIF-1alpha levels in type-1 diabetic rats. AB - Background: Carbohydrate restricted diet regimen is widely accepted as therapeutic approach for the treatment of kidney disease associated with type-2 diabetes, obesity and hypertensive disorders. The present study tested the influence of carbohydrate-energy restricted diet (CR) on type-1 diabetes induced renal dysfunction, hypoxia and structural alterations against diabetic rat group fed control diet (ad libitium). Methods: Male wistar rats weighing between 180 and 190 g were subjected to 30% carbohydrate energy restricted diet (CR) and diabetes was induced by administration of streptozotocin (45 mg/kg., i.p). Assessment of renal function was done after 4 weeks by determining the serum levels of creatinine, BUN, proteinuria. Oxidative stress was determined by estimating the reduced glutathione, malonaldehyde levels, catalase activity and extent of renal hypoxia by estimating the HIF-1alpha levels in kidney tissue homogenates. Histological studies were conducted on kidney sections using hematoxylin and eosin, periodic acid-schiff staining. Results: Diabetic rats exhibited marked hyperglycemia and renal dysfunction developed in diabetic rats fed control diet (ad libitium) as shown by significantly elevated levels of serum creatinine, BUN and massive proteinuria after 4 weeks period. CR diet treatment in diabetic rats significantly lowered hyperglycemia, reversed the above renal functional abnormalities, reduced oxidative stress and enhanced HIF-1alpha levels. Furthermore histological examination of kidney sections from CR diet treated diabetic rat group showed absence of glomerular hypertrophy, mesangial expansion and tubular vacoulations. Conclusion: Our results demonstrated that CR diet treatment in diabetic rats attenuated renal damage by reducing oxidative stress and preventing the development of hypoxia by up-regulating HIF-1alpha levels. PMID- 29270393 TI - Iranian university students lifestyle and health status survey: study profile. AB - Background: The physical health assessment of university students in Iran is a national large scale assessment examining health behaviors among tertiary education students. Understanding risky health behaviors which are the major sources of global mortality and morbidity in adulthood is the key objective of this assessment. Methods: In academic year of 2012-2013, newly admitted students (N = 151,671) at 74 governmental eligible universities that had health center from 28 provinces were invited to participate in the health assessment program. The physical health behaviors of the students were evaluated by using questionnaire. The test-retest reliability method was applied to estimate the reliability of physical health questionnaire. After filling out the questionnaires, students were led to the examination room for the measurement of height, weight and blood pressure. Results: From the total study population, 84,298 student's ages between 18 and 29 years old, were participated in the health assessment. The mean response proportion was 63%. The mean age of students was 21.5 +/- 4.01, with 49.20% percent being <20 years old. 32.31% were between 20 and 24 years, 13.44% between 25 and 29 years, 69% of the participants were undergraduate 34.9% were master's students, and 2.9% were Ph.D. students. The mean BMI for total students was 22.5 +/- 4.0 and regarding to gender, the mean BMI for male and female were 23.0 +/- 4.1 and 22.2 +/- 3.8 respectively. Conclusion: Analysis of student's findings will generate multiple studies which report different aspects of physical health of Iranian university students who constitute a large proportion of young adult aged 18-29 years in the country. This assessment also provides opportunity to compare Iranian student's behavioral patterns with the behavioral pattern of students worldwide. PMID- 29270394 TI - Clinical Assessment and Diagnosis of Germline Predisposition to Hematopoietic Malignancies: The University of Chicago Experience. AB - With the increasing use of clinical genomics to guide cancer treatment and management, there is a rise in the identification of germline cancer predisposition syndromes and a critical need for patients with germline findings to be referred for surveillance and care. The University of Chicago Hematopoietic Malignancies Cancer Risk Team has established a unique approach to patient care for individuals with hereditary hematologic malignancies through close communication and coordination between our pediatric and adult programs. Dedicated program members, including physicians, nurses, genetic counselors, and clinical research assistants, screen individuals for cancer predisposition at initial diagnosis through survivorship, in addition to testing individuals with an established family history of a cancer predisposition syndrome. Sample procurement, such as a skin biopsy at the time of bone marrow aspirate/biopsy in individuals with a positive screen, has facilitated timely identification of clinical germline findings or has served as a pipeline for translational research. Our integrated translational research program has led to the identification of novel syndromes in collaboration with other investigators, which have been incorporated iteratively into our clinical pipeline. Individuals are referred for clinical assessment based on personal and family history, identification of variants in susceptibility genes via molecular tumor testing, and during evaluation for matched related allogeneic stem cell transplantation. Upon referral, genetic counseling incorporates education with mindfulness of the psychosocial issues surrounding germline testing at different ages. The training and role of genetic counselors continues to grow, with the discovery of new predisposition syndromes, in the age of improved molecular diagnostics and new models for service delivery, such as telemedicine. With the identification of new syndromes that may predispose individuals to hematologic malignancies, surveillance guidelines will continue to evolve and may differ between children and adults. Thus, utilizing a collaborative approach between the pediatric and adult oncology programs facilitates care within families and optimizes the diagnosis and care of individuals with cancer predisposition syndromes. PMID- 29270395 TI - Prenatal Opioid Exposure and Intermittent Hypoxemia in Preterm Infants: A Retrospective Assessment. AB - Introduction: Intermittent hypoxemia (IH) is defined as episodic drops in oxygen saturation (SpO2). Preterm infants are at increased risk for IH due to their immature respiratory control/apnea of prematurity. The clinical relevance of IH is a relatively new observation with rising evidence linking IH to neonatal morbidities and long-term impairment. Hence, assessing factors that influence IH in preterm infants is imperative. Given the epidemic of opioid misuse in the USA, there is an urgent need to understand the impact of prenatal opioid exposure on neonatal outcomes. Hence, we wanted to assess the relationship between isolated prenatal opioid exposure and IH in preterm infants. Methods: In order to accurately calculate IH, SpO2 data were prospectively collected using high resolution pulse oximeters during the first 8 weeks of life in preterm infants less than 30 weeks gestational age. Data related to prenatal opioid misuse were retrospectively collected from medical charts. Infants with tobacco or poly-drug exposure were excluded. The primary outcome measure is percent time spent with SpO2 below 80% (%time-SpO2 < 80). The secondary outcome measure is the number of severe IH events/week with SpO2 less than 80% (IH-SpO2 < 80). Results: A total of 82 infants with isolated opioid exposure (n = 14) or who were unexposed (n = 68) were included. There were no significant differences in baseline characteristics between opioid exposed and unexposed groups. There was a statistically significant increase of 0.23 (95% CI: 0.03, 0.43, p = 0.03) in mean of the square root of %time-SpO2 < 80. The number of IH-SpO2 < 80 events was higher in the opioid exposed group (mean difference = 2.95, 95% CI: -0.35, 6.25, p-value = 0.08), although statistical significance was not quite attained. Conclusion: This study shows that preterm infants prenatally exposed to opioids have increased IH measures compared to unexposed infants. Interestingly, the increased IH in the opioid exposed group persists beyond the immediate postnatal period. PMID- 29270397 TI - Commentary: Management of High-Grade Penile Curvature Associated with Hypospadias in Children. PMID- 29270396 TI - Pediatric Thrombolysis: A Practical Approach. AB - The incidence of pediatric venous thromboembolic disease is increasing in hospitalized children. While the mainstay of treatment of pediatric thrombosis is anticoagulation, reports on the use of systemic thrombolysis, endovascular thrombolysis, and mechanical thrombectomy have steadily been increasing in this population. Thrombolysis is indicated in the setting of life- or limb-threatening thrombosis. Thrombolysis can rapidly improve venous patency thereby quickly ameliorating acute signs and symptoms of thrombosis and may improve long-term outcomes such as postthrombotic syndrome. Systemic and endovascular thrombolysis can result in an increase in minor bleeding in pediatric patients, compared with anticoagulation alone, and major bleeding events are a continued concern. Also, endovascular treatment is invasive and requires technical expertise by interventional radiology or vascular surgery, and such expertise may be lacking at many pediatric centers. The goal of this mini-review is to summarize the current state of knowledge of thrombolysis/thrombectomy techniques, benefits, and challenges in pediatric thrombosis. PMID- 29270398 TI - Using the Drosophila Nephrocyte to Model Podocyte Function and Disease. AB - Glomerular disorders are a major cause of end-stage renal disease and effective therapies are often lacking. Nephrocytes are considered to be part of the Drosophila excretory system and form slit diaphragms across cellular membrane invaginations. Nehphrocytes have been shown to share functional, morphological, and molecular features with podocytes, which form the glomerular filter in vertebrates. Here, we report the progress and the evolving tool-set of this model system. Combining a functional, accessible slit diaphragm with the power of the genetic tool-kit in Drosophila, the nephrocyte has the potential to greatly advance our understanding of the glomerular filtration barrier in health and disease. PMID- 29270399 TI - Diminution of Heart Rate Variability in Bipolar Depression. AB - Autonomic nervous system (ANS) dysregulation in depression is associated with symptoms associated with the ANS. The beat-to-beat pattern of heart rate defined as heart rate variability (HRV) provides a noninvasive portal to ANS function and has been proposed to represent a means of quantifying resting vagal tone. We quantified HRV in bipolar depressed (BDD) patients as a measure of ANS dysregulation seeking to establish HRV as a potential diagnostic and prognostic biomarker for treatment outcome. Forty-seven BDD patients were enrolled. They were randomized to receive either escitalopram-celecoxib or escitalopram-placebo over 8 weeks in a double-blind study design. Thirty-five patients completed the HRV studies. Thirty-six healthy subjects served as controls. HRV was assessed at pretreatment and end of study and compared with that of controls. HRV was quantified and corrected for artifacts using an algorithm that incorporates time and frequency domains to address non-stationarity of the beat-to-beat heart rate pattern. Baseline high frequency-HRV (i.e., respiratory sinus arrhythmia) was lower in BDD patients than controls, although the difference did not reach significance. Baseline low-frequency HRV was significantly lower in BDD patients (ln4.20) than controls (ln = 5.50) (p < 0.01). Baseline heart period was significantly shorter (i.e., faster heart rate) in BDD patients than controls. No significant change in HRV parameters were detected over the course of the study with either treatment. These findings suggest that components of HRV may be diminished in BDD patients. PMID- 29270400 TI - Using Intervention Mapping to Develop Health Education Components to Increase Colorectal Cancer Screening in Puerto Rico. AB - Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related mortality in Puerto Rico (PR). Although largely preventable through screening and treatment of precancerous polyps, CRC screening rates in PR remain low while CRC incidence and mortality continue to increase. Methods: We used intervention mapping (IM), a systematic framework using theory and evidence to plan a health promotion intervention to increase colorectal cancer screening (CRCS) among Puerto Rican adults 50 years and older who are patients of Federally Qualified Health Centers (FQHCs) in PR. Results: To inform the development of a logic model of the problem during the needs assessment phase, we determined the CRC incidence and mortality rates in PR using recent data from the PR Cancer Registry, conducted a literature review to better understand behavioral and environmental factors influencing CRC among Hispanics in general and in Puerto Ricans, and collected new data. We conducted seven focus groups to identify community needs and resources, specific sub-behaviors related to CRCS (performance objectives) and the determinants of CRCS. We then developed matrices of change objectives that would guide the content, behavioral change method selection, and the practical applications that would be included in the program. We selected two overarching methods: entertainment education and behavioral journalism and developed practical applications, materials, and messages containing several other methods including modeling, persuasion, information, and tailoring. We developed and pretested a Tailored Interactive Multimedia Intervention, newsletter, an action plan, and supplemental print materials for patients. We also developed a patient mediated provider prompt to increase provider recommendation and improve patient provider communication. Conclusion: The use of IM for systematic planning produced a detailed coherent plan for the CRCS educational intervention. Guided by IM processes, steps, and tasks, we used community level information, existing literature, theory, and new data to develop health education materials that were well received by the priority population and will likely increase CRCS among FQHC patients in PR. PMID- 29270401 TI - Data Sharing: Convert Challenges into Opportunities. AB - Initiatives for sharing research data are opportunities to increase the pace of knowledge discovery and scientific progress. The reuse of research data has the potential to avoid the duplication of data sets and to bring new views from multiple analysis of the same data set. For example, the study of genomic variations associated with cancer profits from the universal collection of such data and helps in selecting the most appropriate therapy for a specific patient. However, data sharing poses challenges to the scientific community. These challenges are of ethical, cultural, legal, financial, or technical nature. This article reviews the impact that data sharing has in science and society and presents guidelines to improve the efficient sharing of research data. PMID- 29270402 TI - Physical Therapy for Neurological Conditions in Geriatric Populations. AB - With more of the world's population surviving longer, individuals often face age related neurology disorders and decline of function that can affect lifestyle and well-being. Despite neurophysiological changes affecting the brain function and structure, the aged brain, in some degree, can learn and relearn due to neuroplasticity. Recent advances in rehabilitation techniques have produced better functional outcomes in age-related neurological conditions. Physical therapy (PT) of the elderly individual focuses in particular on sensory-motor impairments, postural control coordination, and prevention of sarcopenia. Geriatric PT has a significant influence on quality of life, independent living, and life expectancy. However, in many developed and developing countries, the profession of PT is underfunded and understaffed. This article provides a brief overview on (a) age-related disease of central nervous system and (b) the principles, approaches, and doctrines of motor skill learning and point out the most common treatment models that PTs use for neurological patients. PMID- 29270403 TI - Defining and Systematic Analyses of Aggregation Indices to Evaluate Degree of Calcium Oxalate Crystal Aggregation. AB - Crystal aggregation is one of the most crucial steps in kidney stone pathogenesis. However, previous studies of crystal aggregation were rarely done and quantitative analysis of aggregation degree was handicapped by a lack of the standard measurement. We thus performed an in vitro assay to generate aggregation of calcium oxalate monohydrate (COM) crystals with various concentrations (25-800 MUg/ml) in saturated aggregation buffer. The crystal aggregates were analyzed by microscopic examination, UV-visible spectrophotometry, and GraphPad Prism6 software to define a total of 12 aggregation indices (including number of aggregates, aggregated mass index, optical density, aggregation coefficient, span, number of aggregates at plateau time-point, aggregated area index, aggregated diameter index, aggregated symmetry index, time constant, half-life, and rate constant). The data showed linear correlation between crystal concentration and almost all of these indices, except only for rate constant. Among these, number of aggregates provided the greatest regression coefficient (r = 0.997; p < 0.001), whereas the equally second rank included aggregated mass index and optical density (r = 0.993; p < 0.001 and r = -0.993; p < 0.001, respectively) and the equally forth were aggregation coefficient and span (r = 0.991; p < 0.001 for both). These five indices are thus recommended as the most appropriate indices for quantitative analysis of COM crystal aggregation in vitro. PMID- 29270404 TI - Platelet-Rich Plasma Supports Proliferation and Redifferentiation of Chondrocytes during In Vitro Expansion. AB - Articular cartilage regeneration is insufficient to restore sports injuries or defects that can occur from trauma. Treatment options for cartilage repair include autologous chondrocyte implantation (ACI) by isolation, expansion, and reimplantation of healthy donor chondrocytes. Chondrocyte expansion onto 2D substrates leads to dedifferentiation and loss of the cellular phenotype. We aimed to overcome the state of dedifferentiation by biochemical stimuli with platelet derivatives such as platelet-rich plasma (PRP) and hyperacute serum (HAS) to achieve sufficient cell numbers in combination with variable oxygen tension. Human articular chondrocytes from osteoarthritic (OA) cartilage chondrocytes were switched from 10% FCS supplementation to either 10% PRP or 10% HAS after initial passaging for further experiments under normoxic (20% O2) or hypoxic (1% O2) conditions. An XTT assay measured the effect of PRP or HAS on the cell proliferation at 3, 6, and 9 days. The chondrogenic redifferentiation potential of dedifferentiated chondrocytes was determined with reverse transcriptase quantitative real-time PCR for markers of expression for type II collagen (COL2A1), type I collagen (COL1A1), and matrix metalloproteinases MMP3, matrix metalloproteinase 13 (MMP13) at 24 and 72 h. Measured protein levels of 100% PRP or HAS by multiplex quantification revealed basic fibroblast growth factor, G-CSF, and PDGF were significantly higher in PRP than in HAS (p < 0.05) but LEPTIN levels did not differ. The quantified protein levels did not differ when isolated from same donors at a different time. Chondrocyte proliferation indicated that supplementation of 10% HAS enhanced the proliferation rate compared to 10% PRP or 10% FCS at 6 and 9 days significantly (p < 0.05). mRNA levels for expression of COL1A1 were significantly downregulated (p < 0.05) when cultured with 10% PRP than 10% HAS or 10% FCS under normoxic/hypoxic conditions. COL2A1 was significantly upregulated (p < 0.05) in PRP than 10% HAS or 10% FCS. MMP3 expression was downregulated after 72 h under all conditions. MMP13 was upregulated with 10% PRP at both 24 and 72 h but significantly downregulated under hypoxia (1% O2) for all circumstances. While HAS has its effect on chondrocyte proliferation, PRP enhances both proliferation and redifferentiation of dedifferentiated chondrocytes. PRP can replace standard usage of FCS for chondrogenic priming and expansion as implications for clinical use such as ACI procedures. PMID- 29270406 TI - Mitochondria and Lysosomes: Discovering Bonds. AB - In the last decade, the traditional view of lysosomes has been challenged by the recognition that lysosomes are not only degradative organelles, but also metabolic sensors that play a key role in the regulation of metabolism and cell growth. Similarly, mitochondria are now seen as crucial metabolic hubs dictating cell fate decisions, not just ATP-producing machines. Importantly, these functions are generally performed as a coordinate response of distinct organelles that are physically and functionally connected. While the association between mitochondria and the endoplasmic reticulum is well known, a similar interaction between mitochondria and lysosomes is now emerging. This interaction could be required to shuttle amino acids, lipids and ions such as Ca2+ between the two organelles, thereby modulating their metabolic functions. In addition, a tethering complex linking the two organelles has recently been described in yeast, although the mammalian counterpart has yet to be identified. Here, we discuss the implications of these recent findings. PMID- 29270407 TI - Innovative Approaches to Increase Access to Medicines in Developing Countries. AB - Access to essential medicines is problematic for one third of all persons worldwide. The price of many medicines (i.e., drugs, vaccines, and diagnostics) is unaffordable to the majority of the population in need, especially in least developed countries, but also increasingly in middle-income countries. Several innovative approaches, based on partnerships, intellectual property, and pricing, are used to stimulate innovation, promote healthcare delivery, and reduce global health disparities. No single approach suffices, and therefore stakeholders need to further engage in partnerships promoting knowledge and technology transfer in assuring essential medicines to be manufactured, authorized, and distributed in low- and middle-income countries (LMICs) in an effort of making them available at affordable and acceptable conditions. PMID- 29270405 TI - Therapy for Cancer: Strategy of Combining Anti-Angiogenic and Target Therapies. AB - The concept that blood supply is required and necessary for cancer growth and spreading is intuitive and was firstly formalized by Judah Folkman in 1971, when he demonstrated that cancer cells release molecules able to promote the proliferation of endothelial cells and the formation of new vessels. This seminal result has initiated one of the most fascinating story of the medicine, which is offering a window of opportunity for cancer treatment based on the use of molecules inhibiting tumor angiogenesis and in particular vascular-endothelial growth factor (VEGF), which is the master gene in vasculature formation and is the commonest target of anti-angiogenic regimens. However, the clinical results are far from the remarkable successes obtained in pre-clinical models. The reasons of this discrepancy have been partially understood and well addressed in many reviews (Bergers and Hanahan, 2008; Bottsford-Miller et al., 2012; El-Kenawi and El-Remessy, 2013; Wang et al., 2015; Jayson et al., 2016). At present anti angiogenic regimens are not used as single treatments but associated with standard chemotherapies. Based on emerging knowledge of the biology of VEGF, here we sustain the hypothesis of the efficacy of a dual approach based on targeting pro-angiogenic pathways and other druggable targets such as mutated oncogenes or the immune system. PMID- 29270408 TI - Protein Translocation into the Intermembrane Space and Matrix of Mitochondria: Mechanisms and Driving Forces. AB - Mitochondria contain two aqueous subcompartments, the matrix and the intermembrane space (IMS). The matrix is enclosed by both the inner and outer mitochondrial membranes, whilst the IMS is sandwiched between the two. Proteins of the matrix are synthesized in the cytosol as preproteins, which contain amino terminal matrix targeting sequences that mediate their translocation through translocases embedded in the outer and inner membrane. For these proteins, the translocation reaction is driven by the import motor which is part of the inner membrane translocase. The import motor employs matrix Hsp70 molecules and ATP hydrolysis to ratchet proteins into the mitochondrial matrix. Most IMS proteins lack presequences and instead utilize the IMS receptor Mia40, which facilitates their translocation across the outer membrane in a reaction that is coupled to the formation of disulfide bonds within the protein. This process requires neither ATP nor the mitochondrial membrane potential. Mia40 fulfills two roles: First, it acts as a holdase, which is crucial in the import of IMS proteins and second, it functions as a foldase, introducing disulfide bonds into newly imported proteins, which induces and stabilizes their natively folded state. For several Mia40 substrates, oxidative folding is an essential prerequisite for their assembly into oligomeric complexes. Interestingly, recent studies have shown that the two functions of Mia40 can be experimentally separated from each other by the use of specific mutants, hence providing a powerful new way to dissect the different physiological roles of Mia40. In this review we summarize the current knowledge relating to the mitochondrial matrix-targeting and the IMS targeting/Mia40 pathway. Moreover, we discuss the mechanistic properties by which the mitochondrial import motor on the one hand and Mia40 on the other, drive the translocation of their substrates into the organelle. We propose that the lateral diffusion of Mia40 in the inner membrane and the oxidation-mediated folding of incoming polypeptides supports IMS import. PMID- 29270409 TI - Defective Protein Catabolism in Atherosclerotic Vascular Inflammation. AB - Vascular inflammation in atheroprone vessels propagates throughout the arterial tree in dyslipidemic patients, thereby accelerating atherosclerotic progression. To elucidate the mechanism of vascular inflammation, most previous studies have focused on inflammation-related signals that are sent in response to vasoactive stimuli. However, it is also important to understand how normal blood vessels become defective and start degenerating. Growing evidence suggests that major protein catabolism pathways, including the ubiquitin-proteasome, autophagy, and calpain systems, are disturbed in atheroprone vessels and contribute to the pathogenesis of atherosclerosis. Indeed, dysregulation of ubiquitin-proteasome pathways results in the accumulation of defective proteins in blood vessels, leading to vascular endothelial dysfunction and apoptosis in affected cells. Impaired autophagy-lysosomal degradation affects smooth muscle cell transformation and proliferation, as well as endothelial integrity and phagocytic clearance of cellular corpses. Dysregulation of the calpain system confers proatherogenic properties to endothelial cells, smooth muscle cells, and macrophages. In this review article, we will discuss the current information available on defective protein catabolism in atheroprone vessels and its potential interrelation with inflammation-related signals. PMID- 29270410 TI - Extracorporeal Shockwave Therapy Increases Growth Factor Release from Equine Platelet-Rich Plasma In Vitro. AB - Introduction: Extracorporeal shockwave therapy (ESWT) and platelet-rich plasma (PRP) are common treatments for soft tissue injuries in horses. Shockwave triggers cell specific responses to promote healing. Growth factors released from PRP also promote healing. It has been hypothesized that greater growth factor release would amplify the healing process. The combination of ESWT and PRP could promote healing in injured tendons and ligaments in the horse. The objective of this study was to determine if application of shockwaves to PRP samples increases the concentration of transforming growth factor-beta1 (TGF-beta1) and platelet derived growth factor betabeta (PDGF-betabeta) released from the platelets in vitro. Materials and methods: PRP was produced from blood drawn from six horses. The PRP from each horse was exposed to the following treatments: (1) positive control (freeze-thaw cycle), (2) untreated negative control, or shockwaves with either (3) a "standard probe" (ESWT-S) with a 2 cm focal width and medium energy density or (4) a "power probe" (ESWT-P) with a 1 cm focal width and high energy density. After each treatment, the samples were centrifuged, and the supernatant was harvested. The supernatant was then used for growth factor quantification via commercially available ELISA kits for TGF-beta1 and PDGF-betabeta. Results: Concentrations of TGF-beta1 and PDGF-betabeta in PRP that underwent a freeze-thaw cycle were significantly increased compared with all other treatments. Both ESWT S and ESWT-P resulted in significantly increased TGF-beta1 concentrations, 46 and 33%, respectively, when compared with the negative control. Both ESWT-S and ESWT P resulted in significantly increased PDGF-betabeta concentrations, 219 and 190%, respectively, when compared with the negative control. Discussion: These data indicate that the application of ESWT to PRP increases the expression of growth factors in vitro. This suggests that the combination therapy of local PRP injection followed by ESWT may stimulate release of growth factors from platelets after they have been injected into the area of injury. Conclusion: The combination of PRP and ESWT might result in synergism of two modalities previously utilized individually for tendon and ligament injuries in horses. PMID- 29270411 TI - Estimating the Efficacy of a Commercial Phase I Inactivated Vaccine in Decreasing the Prevalence of Coxiella burnetii Infection and Shedding in Red Deer (Cervus elaphus). AB - The red deer (Cervus elaphus) is a relevant reservoir for Coxiella burnetii in Iberia. C. burnetii genotypes that infect red deer also infect humans and domestic animals. Integrated control approaches that target both domestic and wild ruminants are, therefore, required to reduce C. burnetii infection risks in Iberia, especially in wildlife-livestock-human interaction scenarios. The aim of this field experiment was to test the efficacy of an inactivated phase I vaccine [Inactivated phase I vaccine (IPIV); Coxevac(r)] when used to control C. burnetii shedding prevalence and burden in red deer as a tool to prevent transmission to livestock and humans. A semi-extensively bred red deer population in which C. burnetii is endemic was used as a model of the Iberian context. Around 75% of the reproductive hinds (>1 year old; N = 441) in the population were first vaccinated early in 2012 and were then revaccinated 3 weeks later; they were subsequently revaccinated biannually until January 2014. 75% of the yearling females left as replacement in 2012 and 2013 were vaccinated in June and revaccinated thereafter following the same protocol. 25% of the population, including the replacement females, was kept as a control group throughout the study. Changes in the humoral immune response after vaccination were estimated by analyzing sera collected at 10 different times between January 2011 and January 2015. The vaccinated and control hinds were surveyed at 2.5, 3.5, and 4.5 months after calving in 2012, 2013, and 2014 to collect vaginal swabs, milk, and feces. The presence and burden of C. burnetii DNA in swabs, milk, and feces was evaluated by means of real-time PCR. Vaccination induced high antibody prevalence and levels. The proportion of animals shedding C. burnetii in vaginal secretions and milk did not change over time in the vaccination group with respect to the control group. In contrast, there was a significant reduction in the proportion of deer shedding C. burnetii in feces in both the vaccinated and control groups. The decrease in the proportion of fecal shedders coincided with a significant reduction in the incidence of infection of non-vaccinated yearling females in the population. This finding suggests that long-term vaccination with IPIV could reduce environmental contamination with C. burnetii and control transmission, perhaps making this a promising tool with which to control C. burnetii in red deer in the future. PMID- 29270412 TI - Relationship between Feline calicivirus Load, Oral Lesions, and Outcome in Feline Chronic Gingivostomatitis (Caudal Stomatitis): Retrospective Study in 104 Cats. AB - Objective: This study was performed to assess the relationship between oral Feline calicivirus (FCV) load and severity of lesions at the time of presentation of cats suffering from feline chronic gingivostomatitis (FCGS) (part 1) and treatment outcome after dental extractions (part 2). We hypothesized that a higher FCV viral load would be positively correlated with the severity of lesions at presentation and negatively correlated with treatment outcome. In addition, the effect of dental extractions on outcome and the influence of preoperative severity of lesions on the outcome were investigated. Materials and methods: Cats with FCGS were included in the study if they had been diagnosed with caudal stomatitis, had been tested positive for FCV using a real-time reverse transcriptase-PCR test on oropharyngeal swab, and had dental extractions performed within the authors' department. General practitioners provided all previous medical treatments. Cats with recheck examinations were included in part 2 of the study. Multivariate statistical analysis was performed to assess the relationship between the different parameters. Results: One hundred four cats met the requirements for part 1 and 56 cats for part 2 of the study. Data collected from patients' record included patient history, viral testing results, extent and severity of oral lesions, extent of teeth extraction. Signalment, history, preoperative treatment, and severity of caudal and alveolar stomatitis score were not associated with FCV load (P > 0.05). Presence of lingual ulcers was significantly correlated with FCV load (P = 0.0325). Clinical cure (32.1%) or very significant improvement (19.6%) was achieved in 51.8% of cats within 38 days. Concomitantly, 60.7% of the owners considered their cat cured (41.1%) or significantly improved (19.6%). Extent of teeth extraction was not found to influence the clinical outcome (P > 0.05). Conclusion: The results of this study did not support the hypothesis that FCV oral load is correlated with the severity of oral lesions or with the outcome following dental extractions. In addition, the severity of caudal inflammation was not correlated with healing time or achievement of cure. PMID- 29270413 TI - CD133 mRNA may be a suitable prognostic marker for human breast cancer. AB - Breast cancer is the most commonly malignant cancers in women. CD133 protein is a widely used marker for isolating cancer stem cell (CSC). Its expression is associated with the prognosis of many cancers. However, whether CD133 mRNA could be used as an independent prognostic factor for breast cancer remains inconsistent in previous studies. In this study, I used the Gene Expression-Based Outcome for Breast Cancer Online algorithm (GOBO) software to analysis the prognostic roles of CD133 mRNA in the subtypes of breast cancer. I found that CD133 mRNA is associated with distant metastasis free survival (DMFS) in the patient with all tumors, ER-positive tumors, tamoxifen (TAM) tumors, LN-negative tumors, ER-positive/LN-negative tumors, ER-negative tumors, grade 2 tumors, HER2 enriched tumors, and untreated tumors. These results could provide a molecular target for the subtypes of breast cancer. In this study, I conclude that CD133 mRNA may be a suitable prognostic marker for human breast cancer. PMID- 29270414 TI - Alopecia and platelet-derived therapies. AB - Background: Platelet rich plasma (PRP) injections have emerged as a promising regenerative therapy for androgenetic alopecia (AGA). To date, injections of both autologous native and activated PRP have been administered to hair loss patients, and positive results have been observed. However, little to no work has yet to be seen wherein PRP treatments are combined with hair restoration surgeries. Furthermore, the PRP activation protocol in the hair restoration setting employs compounds with potentially deleterious side effects, namely thrombin or calcium gluconate. Therefore, the objectives of this work are to evaluate the effectiveness of platelet and platelet-derived products as augmented graft therapies in hair restoration surgeries and to compare the follicular regeneration rate of follicles transplanted in the presence of platelet lysate (PL) versus activated PRP (AA-PRP). Methods: PL was administered to the frontal scalp of three male AGA patients. Three treatment zones measuring 4 cm-2 were mapped in the midline scalp region of each patient and equal number of follicular grafts were placed in each box along with PL, AA-PRP, or normal saline. The transplanted follicular grafts of a fourth patient were placed solely with PL. Hair checks in which the surface area of hair coverage was quantified were performed at follow-up appointments ranging from 3.5 to 7 months post-surgery. In these appointments, the number of follicular units with hairs measuring 50 mm or more were counted to determine the percentage of graft hair regeneration. Growth factor (GF) concentrations [vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-beta1), PDGF-BB, IGF-1] in PL and AA-PRP were also measured for an independent subject set. Results: Follicular regeneration in transplanted grafts was found to be superior for those placed with PL rather than AA-PRP or saline at all follow-up dates. Specifically, at 3.5 months post-op, 89%+/-9%, 74%+/-7%, and 57%+/-10% of follicular units had regenerated hair in the PL, AA-PRP, and saline treatment zones, respectively. At 4 months post-op, 99%, 75%, and 71% of follicle regeneration had occurred in the PL, AA-PRP, and saline treatment areas, respectively. Impressively, when PL was injected alone, the patient experienced a 50% increase in follicular unit density and a 122% increase in hair density 7 months post-injection. When GF concentrations were measured, PL generated from a 30-min sonication of PRP was found to have significantly higher levels of VEGF, PDGF-BB, and TGF-beta1 than AA PRP. Conclusions: PRP remains a promising hair loss therapy and should be evaluated further for use not only as an independent therapeutic tool, but also as a treatment to augment surgical procedures. PL in particular affords an effective and efficacious therapeutic product given that the lysate may be obtained by mechanical rather than chemical means. Ultrasonic waves provide sufficient energy to rupture platelet cell walls, and centrifugation may be used to separate the lysate from cell fragments prior to delivery. PMID- 29270415 TI - A step forward in disease modelling for mitochondrial diseases. PMID- 29270416 TI - Stem cell extracellular vesicles and kidney injury. AB - Extracellular vesicles (EVs) appear as a new promising cell-free therapy for acute and chronic renal diseases. EVs retain characteristics of the cell of origin and those derived from stem cells may mimic their regenerative properties per se. In fact, EVs contain many active molecules such as proteins and RNA species that act on target cells through different mechanisms, stimulating proliferation and angiogenesis and reducing apoptosis and inflammation. There are several reports that demonstrate a general regenerative potential of EVs derived from mesenchymal stromal cells (MSCs) of different sources in kidney injury models. In addition, a promising new approach is the use of EVs in the graft perfusion solution for kidney conditioning before transplant. Here we summarize the application of EVs released by stem cells in preclinical models of acute and chronic renal damage, comparing animal models, use of EVs of different cell origin and of their sub-fractions, doses, route of administration and efficacy of treatment. PMID- 29270417 TI - Personalized medicine in a dish: the growing possibility of neuropsychiatric disease drug discovery tailored to patient genetic variants using stem cells. PMID- 29270418 TI - Human induced pluripotent stem cells illuminate pathways and novel treatment targets for age-related macular degeneration. PMID- 29270419 TI - Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia. AB - When injected into acutely infarcted rodent or pig hearts, naturally secreted nanovesicles known as exosomes from cardiac-derived progenitor cells (CPCs) reduce scar size and improve cardiac function. In this regard, exosomes fully mimic the benefits of injecting their parent cells. This recognition paves the way to the development of exosome-based, cell-free treatments for heart disease that could possibly supplant cell-based therapies. Mechanisms of benefit of these vesicles are incompletely understood but cytoprotection, stimulation of angiogenesis, induction of antifibrotic cardiac fibroblasts, and modulation of M1/M2 polarization of macrophages infiltrating the infarcted region can all play important roles. Accordingly, the beneficial molecules carried by CPC-secreted exosomes have been identified only in part but cytoprotective and proangiogenic microRNAs (miRNA) and proteins have been described. Besides CPC-secreted exosomes, vesicles released from other cell types including mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iSPCs) have also been associated with cardioprotection. This review aims to discuss recent advances in our understanding of the role of secreted vesicles in cardiac repair, with a focus on CPC-derived exosomes. PMID- 29270420 TI - Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of non-arteritic ischemic optic neuropathy (NAION). AB - Background: Ten patients with bilateral visual loss due to sequential non arteritic ischemic optic neuropathy (NAION) underwent autologous Bone Marrow Derived Stem Cell (BMSC) therapy within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical study utilizing autologous BMSC in the treatment of optic nerve and retinal diseases that meet inclusion criteria. Methods: The average age of the patients treated was 69.8 years. The average duration of visual loss in eyes treated was 9.8 years and ranged from 1 to 35 years. Affected eyes were treated with either retrobulbar, subtenons and intravenous BMSC or, following vitrectomy, intra-optic nerve, subtenons and intravenous BMSC. The primary outcome was visual acuity as measured by Snellen or converted to LogMAR. Results: Following therapy in SCOTS, 80% of patients experienced improvement in Snellen binocular vision (P=0.029) with 20% remaining stable; 73.6% of eyes treated gained vision (P=0.019) and 15.9% remained stable in the post-operative period. There was an average of 3.53 Snellen lines of vision improvement per eye with an average 22.74% and maximum 83.3% improvement in LogMAR acuity per eye. The average LogMAR change in treated eyes was a gain of 0.364 (P=0.0089). Improvements typically manifested no later than 6 months post procedure. Conclusions: The use of BMSC in the Stem Cell Ophthalmology Treatment Study achieved meaningful visual improvements in a significant percentage of the NAION patients reported. Improvements typically manifested no later than 6 months post-procedure. Duration of visual loss did not appear to affect the ability of the eyes to respond to treatment. Possible mechanisms by which visual improvement occurred may include BMSC paracrine secretion of proteins and hormones, transfer of mitochondria, release of messenger RNA or other compounds via exosomes or microvesicles and neuronal transdifferentiation of the stem cells. PMID- 29270421 TI - Stem cell transplant in inflammatory bowel disease: a promising modality of treatment for a complicated disease course. AB - Inflammatory bowel disease (IBD) is a complex, relapsing and remitting, disease characterized by an exaggerated immune response in a susceptible host. The symptoms and complications of the disease can be debilitating. Advances in medical treatment in the last decade changed the course of the disease in many patients. Despite the use of novel agents for controlling disease, a proportion of patients' disease courses continue to be either refractory, or become resistant, to available therapeutic options. Stem-cell therapy, with hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs), is a promising modality of treatment for severe refractory cases, mainly Crohn's disease (CD) patients. HSCs have the ability to migrate to damaged tissue, which provides them with further properties to differentiate to epithelial or immune-modulatory cells to restore normal mucosal tissue and integrity. MSCs therapy is a promising model for patients with perianal CD due to their immunosuppressive properties, ability to migrate to areas of injury, and demonstration of colonic healing, including fistulizing tracts. The results from ongoing clinical trials will provide a valuable understanding of the future of stem-cell therapy as a treatment option in refractory cases of IBD, a disease whose pathogenesis remains unknown, and is notoriously difficult to treat. PMID- 29270422 TI - Breast cancer stem cells-from origins to targeted therapy. AB - Breast cancer is marked as one of the leading causes of malignancy-related morbidities worldwide. In spite of aggressive interventions, the inevitability of relapse and metastasis severely impede survival rates. Mounting evidence highlight the insidious role of cancer stem cells (CSCs), a small but significant subpopulation of undifferentiated cells that drive tumour progression, spread and resistance to conventional therapy. The nature and significance of breast CSCs remains poorly understood, and even disputed by many researchers. This review discusses the origins, biomarkers, signalling pathways, regulatory mechanisms, and targeted therapy of breast CSCs. PMID- 29270423 TI - Household Food Insecurity in Southeastern Iran: Severity and Related Factors. AB - Background: Today, more than one billion people globally suffer from poverty and food insecurity. This study aimed to determine the severity of and factors related to household food insecurity in Zahedan, Southeastern Iran. Methods: This cross-sectional study was conducted on a total of 2,160 households between November 2014 and December 2015. Demographic and socioeconomic data were collected through interviewing the household mothers. Household food security status was assessed through the USDA 18-item questionnaire. The data were analyzed using chi-square test, one-way ANOVA, and logistic regression model. Results: Total food insecurity in the households investigated was 58.8%. There were significant associations (P < 0.001) between household food insecurity status and the socioeconomic status of the households, ethnicity, education, age, and employment status of the head of the household and the mother of the household. Discussion: The results showed that more than half of the households examined suffer from food insecurity. Interventions to improve the food security status of people should be designed and implemented to improve people's knowledge, skills, and attitudes related to healthy eating and food preparation. People's access to healthy foods and knowledge of how to select healthy foods (especially on a limited budget) should also be improved. PMID- 29270424 TI - Exposure to Workplace Bullying: The Role of Coping Strategies in Dealing with Work Stressors. AB - Studies investigating both work- and individual-related antecedents of workplace bullying are scarce. In reply, this study investigated the interaction between workload, job insecurity, role conflict, and role ambiguity (i.e., work-related antecedents), and problem- and emotion-focused coping strategies (i.e., individual-related antecedents) in association with exposure to workplace bullying. Problem-focused coping strategies were hypothesised to decrease (i.e., buffer) the associations between workload, job insecurity, role conflict, and role ambiguity and exposure to bullying, while emotion-focused coping strategies were hypothesised to increase (i.e., amplify) these associations. Results for a heterogeneous sample (N = 3,105) did not provide evidence for problem-focused coping strategies as moderators. As expected, some emotion-focused coping strategies amplified the associations between work-related antecedents and bullying: employees using "focus on and venting of emotions" or "behavioural disengagement" in dealing with job insecurity, role conflict, or role ambiguity were more likely to be exposed to bullying. Similarly, "seeking social support for emotional reasons" and "mental disengagement" amplified the associations of role ambiguity and the associations of both role conflict and role ambiguity, respectively. To prevent bullying, organisations may train employees in tempering emotion-focused coping strategies, especially when experiencing job insecurity, role conflict, or role ambiguity. PMID- 29270426 TI - Secular Changes of Adiposity in Czech Children Aged from 3 to 6 Years: Latent Obesity in Preschool Age. AB - BMI, skinfold thickness, and circumferential measures were assessed in groups of normal healthy Czech boys (n = 1764) and girls (n = 1762) 3-6 years of age in the late 1950s and 1960s (sample C), in the 1990s (sample B), and in 2014-2016 (sample A). During these decades BMI has not changed significantly, and in selected groups (boys 3, 5, and 6, girls 3 and 6 years) it was most recently found to be significantly lower (P <= 0.05). Subscapular, suprailiac, triceps, midthigh, and above patella skinfold thicknesses significantly increased in sample A as compared to sample C (P <= 0.001). Comparison of the same skinfolds measured in the nineties (sample B) and more recently (sample A) showed similar increase of subcutaneous fat (P <= 0.001). The increase of adiposity characterized by skinfolds occurring in spite of not markedly changed BMI indicates significant changes of body composition-latent (also hidden) obesity. The increase of adiposity was relatively greatest on the trunk (P <= 0.001)-which is considered a marker of the greatest health risk. The decrease of femoral circumference (P <= 0.05) along with simultaneous increase of thigh skinfold (P <= 0.01) revealed the decrease of muscle mass in the lower extremity, obviously due to the reduction of weight-transferring physical activity. PMID- 29270427 TI - Evidence-Based Public Health 2017. PMID- 29270425 TI - Current Therapeutic Options for Heart Failure in Elderly Patients. AB - Heart failure (HF) is a major and growing public health problem with high morbidity and mortality (Ponikowski et al., 2016). It affects 1-2% of the general population in developed countries, and the average age at diagnosis is 76 years. Because of a better management of acute phase and comorbidities, HF incidence is increasing in elderly patients, with a prevalence rising to 10% among people aged 65 years or older (Mozaffarian et al., 2014). Therefore, a substantial number of elderly patients need to be treated. However, because of clinical trial exclusion criteria or coexisting comorbidities, currently recommended therapies are widely based on younger population with a much lower mean age. In this review, we will focus on available pharmacological, electrical, and mechanical therapies, underlining pros, cons, and practical considerations of their use in this specific patient population. PMID- 29270428 TI - Translational Hemorrhagic Stroke: Physiology, Pharmaceutical Drugs, and Management. PMID- 29270429 TI - Analysis of Draft Genome Sequence of Pseudomonas sp. QTF5 Reveals Its Benzoic Acid Degradation Ability and Heavy Metal Tolerance. AB - Pseudomonas sp. QTF5 was isolated from the continuous permafrost near the bitumen layers in the Qiangtang basin of Qinghai-Tibetan Plateau in China (5,111 m above sea level). It is psychrotolerant and highly and widely tolerant to heavy metals and has the ability to metabolize benzoic acid and salicylic acid. To gain insight into the genetic basis for its adaptation, we performed whole genome sequencing and analyzed the resistant genes and metabolic pathways. Based on 120 published and annotated genomes representing 31 species in the genus Pseudomonas, in silico genomic DNA-DNA hybridization (<54%) and average nucleotide identity calculation (<94%) revealed that QTF5 is closest to Pseudomonas lini and should be classified into a novel species. This study provides the genetic basis to identify the genes linked to its specific mechanisms for adaptation to extreme environment and application of this microorganism in environmental conservation. PMID- 29270430 TI - HMMBinder: DNA-Binding Protein Prediction Using HMM Profile Based Features. AB - DNA-binding proteins often play important role in various processes within the cell. Over the last decade, a wide range of classification algorithms and feature extraction techniques have been used to solve this problem. In this paper, we propose a novel DNA-binding protein prediction method called HMMBinder. HMMBinder uses monogram and bigram features extracted from the HMM profiles of the protein sequences. To the best of our knowledge, this is the first application of HMM profile based features for the DNA-binding protein prediction problem. We applied Support Vector Machines (SVM) as a classification technique in HMMBinder. Our method was tested on standard benchmark datasets. We experimentally show that our method outperforms the state-of-the-art methods found in the literature. PMID- 29270431 TI - Clot Structure and Fibrinolysis in Thrombosis and Hemostasis. PMID- 29270432 TI - Episodic Frequency of Energy-Dense Food Consumption in Women with Excessive Adiposity. AB - Each episode of fatty or sugary food consumption contributes to the pathophysiological alterations found in obesity. The present study estimated episodic frequency of energy-dense food (EDF) consumption in 348 adult women with excessive adiposity. Participants reported in open questions their habitual exercise and EDF consumption per week. Body fat percentage was measured using electric impedance analysis. Variations in EDF consumption by age, fat mass, and exercise levels were examined by factorial analysis of variance. The frequency of consumption of EDF was on average 12 times per week and it did not vary significantly across subgroups. It is argued that, to reduce obesity and its comorbidities, lowering a high episodic frequency of EDF consumption could be recommended in clinical settings. PMID- 29270433 TI - ZnCl2 Incorporated into Experimental Adhesives: Selected Physicochemical Properties and Resin-Dentin Bonding Stability. AB - The aim of this study was to evaluate the degree of conversion (DC%), water sorption (WS), solubility (SO), and resin-dentin bonding stability of experimental adhesive systems containing ZnCl2. Different concentrations (wt.%) of ZnCl2 were added to a model etch-and-rinse adhesive system consisting of BISGMA, HEMA, UDMA, GDMA, water, and ethanol: Zn0 (0%-control group); Zn2 (2%); Zn3.5 (3.5%); and Zn5 (5%). Adper Single Bond 2 (SB) was used as commercial reference. The samples were light cured for 20s using a quartz-tungsten-halogen unit (650 mW/cm2). DC% (n = 5) was measured using FT-IR spectroscopy, and WS and SO (n = 5) were calculated based on ISO4049. Microtensile bond strength (MUTBS) and nanoleakage (NL) were measured after 24 h and 12 months of water storage (n = 10). Data were analyzed using ANOVA and Tukey's HSD test (5%). Zn5 presented the lowest DC% and the highest WS and SO (p < 0.05). Zn0 and Zn2 presented statistically similar DC%, WS, SO, and immediate MUTBS. All adhesives containing ZnCl2 maintained a MUTBS stability after 12 months, but only Zn2 and Zn3.5 did not suffer an increase in NL. SB presented the highest immediate MUTBS but the greatest reduction after 12 months (p < 0.05). The addition of 2 wt.% of ZnCl2 in adhesive formulations seems to be a promising way to improve the resin-dentin bonding stability. Higher concentrations than 2 wt.% could impair some physicochemical properties. PMID- 29270434 TI - High-Dose Compound Heat Map for 3D-Cultured Glioblastoma Multiforme Cells in a Micropillar and Microwell Chip Platform. AB - Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. To cure GBM patients, many target-specific chemotherapeutic agents have been developing. However, 2D monolayer cell-based toxicity and efficacy tests did not efficiently screen agents due to the pool reflection of in vivo microenvironments (cell-to-cell and cell-to-extracellular matrix interaction). In this study, we used a 3D cell-based, high-throughput screening method reflecting the microenvironments using a micropillar and microwell chip platform to draw a high-dose heat map of the cytotoxicity and efficacy of 70 compounds, with two DMSO controls. Moreover, the high-dose heat map model compared the responses of four 3D-cultured patient-derived GBM cells and astrocytes to high dosages of compounds with respect to efficacy and cytotoxicity, respectively, to discern the most efficacious drug for GBM. Among the 70 compounds tested, cediranib (a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases) exhibited the lowest cytotoxicity to astrocytes and high efficacy to GBM cells in a high-dose heat map model. PMID- 29270435 TI - Sciatic Nerve Palsy following Total Hip Replacement: Are Patients Personal Characteristics More Important than Limb Lengthening? A Systematic Review. AB - Sciatic nerve palsies are rare but potentially devastating complications, accounting for more than 90% of neurologic injuries following total hip replacement. A systematic literature screening was carried out searching papers evaluating an exclusive population of postarthroplasty sciatic nerve palsies to ascertain (1) the influence of limb lengthening itself on sciatic nerve palsy, (2) the most important risk factors, (3) the long-term prognosis, and (4) the outcomes of different treatments. Fourteen manuscripts were finally included. The wide prevalence of retrospective case series decreased the global methodological quality of the retrieved papers. A hazardous lengthening threshold cannot be surely identified. Developmental dysplasia of the hip and previous hip surgeries are the most frequently recognized risk factors. Rate of full nerve function restoration approximates two-thirds of the cases, independently of the extent of initial neural damage. Poor evidences are available about the best treatment strategy. Well-structured multicentric prospective comparative studies are needed to substantiate or contrast the finding of this review. Anyway, since the onset of palsies is probably due to a combination of individual factors, risk of nerve damage and potential for nerve recovery should be evaluated on an individual basis. PMID- 29270436 TI - An ECM-Mimicking, Mesenchymal Stem Cell-Embedded Hybrid Scaffold for Bone Regeneration. AB - While biologically feasible, bone repair is often inadequate, particularly in cases of large defects. The search for effective bone regeneration strategies has led to the emergence of bone tissue engineering (TE) techniques. When integrating electrospinning techniques, scaffolds featuring randomly oriented or aligned fibers, characteristic of the extracellular matrix (ECM), can be fabricated. In parallel, mesenchymal stem cells (MSCs), which are capable of both self-renewing and differentiating into numerous tissue types, have been suggested to be a suitable option for cell-based tissue engineering therapies. This work aimed to create a novel biocompatible hybrid scaffold composed of electrospun polymeric nanofibers combined with osteoconductive ceramics, loaded with human MSCs, to yield a tissue-like construct to promote in vivo bone formation. Characterization of the cell-embedded scaffolds demonstrated their resemblance to bone tissue extracellular matrix, on both micro- and nanoscales and MSC viability and integration within the electrospun nanofibers. Subcutaneous implantation of the cell-embedded scaffolds in the dorsal side of mice led to new bone, muscle, adipose, and connective tissue formation within 8 weeks. This hybrid scaffold may represent a step forward in the pursuit of advanced bone tissue engineering scaffolds. PMID- 29270437 TI - Description and Validation of TAVIApp: A Novel Mobile Application for Support of Physicians in the Management of Aortic Stenosis-Management of Aortic Stenosis with TAVIApp. AB - Background: Aortic stenosis (AS) is the most common heart valve disease in developed countries. The advent of transcatheter aortic valve implantation (TAVI) significantly improved patients' outcome but made clinical management more complex. The aim of the present study was to describe TAVIApp, a mobile app we developed to guide the management of AS, and test its efficacy. Methods and Results: Clinical cases comprising 42 patients with AS were blindly evaluated by (A) an interventional cardiologist, assisted by the Heart Team (EXPERT), (B) young residents in cardiology, and (C) a young resident supported by TAVIApp. There was poor concordance between Group A and Group B with low performance by young residents (k = 0.52; p < 0.001). However, concordance increased to an optimal value when young residents were supported by TAVIApp (k = 1.0; p < 0.001) for the diagnosis of severe AS and eligibility assessment. Furthermore, regarding the selection of the most appropriate prosthesis size, concordance to Group A was poor without TAVIApp support (Group B) (k = 0.78; p = 0.430), but excellent with TAVIApp (k = 1.0; p < 0.001). Conclusions: This study is the first describing and validating a new mobile application to support the management of AS. TAVIApp supports cardiologists in the evaluation of stenosis severity, eligibility for TAVI or AVR, and selection of the most appropriate prosthesis size in individual patients. PMID- 29270439 TI - Genetic Factors of Autoimmune Diseases 2017. PMID- 29270438 TI - The Landscape of Glucose-Lowering Therapy and Cardiovascular Outcomes: From Barren Land to Metropolis. AB - The choice of glucose-lowering therapy (GLT) has expanded to include 11 different classes in addition to insulin. Since the 2008 Food and Drug Administration guidance for industry and mandate of demonstrating cardiovascular (CV) safety prior to any new drug approval, there were several trials primarily conducted to establish that goal. Some had neutral effects, while there were positively beneficial outcomes with more recent studies. Hospitalization for congestive heart failure has also been a heterogeneous finding among the different classes of GLT, with drug outcomes ranging from risky to beneficial. The current review selectively focuses on the evidence for CV outcomes for each class of GLT and summarizes the existing guidelines with regard to these drugs in heart disease. Moreover, it illustrates the dynamic status in the development of evidence. Finally, the review enables healthcare providers to formulate a plan for hypoglycemic therapy which will optimize CV health, in a patient-centered manner. PMID- 29270440 TI - Epidemiology of Injuries Sustained as a Result of Intentional Player Contact in High School Football, Ice Hockey, and Lacrosse: 2005-2006 Through 2015-2016. AB - Background: Lacrosse and ice hockey are quickly growing in popularity, while football remains the most popular sport among high school student-athletes. Injuries remain a concern, given the physical nature of these contact sports. Purpose: To describe the rates and patterns of injuries sustained as a result of intentional player contact in United States high school boys' football, ice hockey, and lacrosse. Study Design: Descriptive epidemiology study. Methods: We conducted a secondary analysis of High School RIO (Reporting Information Online) data, including exposure and injury data collected from a large sample of high schools in the United States from 2005-2006 through 2015-2016. Data were analyzed to calculate rates, assess patterns, and evaluate potential risk factors for player-to-player contact injuries. Results: A total of 34,532 injuries in boys' football, ice hockey, and lacrosse occurred during 9,078,902 athlete-exposures (AEs), for a rate of 3.80 injuries per 1000 AEs in the 3 contact sports of interest. The risk of injuries was found to be greater in competition compared with practice for all 3 sports, with the largest difference in ice hockey (rate ratio, 8.28) and the smallest difference in lacrosse (rate ratio, 3.72). In all 3 contact sports, the most commonly injured body site in competition and practice caused by both tackling/checking and being tackled/checked was the head/face. However, a significantly greater proportion of concussions sustained in football were the result of tackling compared with being tackled (28.2% vs 24.1%, respectively). In addition, a significantly greater proportion of concussions were sustained in competition compared with practice for all 3 sports. Conclusion: This study is the first to collectively compare injury rates and injury patterns sustained from intentional player-to-player contact in boys' high school football, ice hockey, and lacrosse. Notably, there was a relatively high risk of injuries and concussions during football practices. PMID- 29270441 TI - Retrospective Analysis of the Accuracy of Ultrasound-Guided Magnetic Resonance Arthrogram Injections of the Hip in the Office Setting. AB - Background: Ultrasound (US)-guided intra-articular hip injections have been proposed in the literature to be accurate, reliable, and safe alternatives to fluoroscopy-guided injections. Purpose: To evaluate the accuracy of US-guided magnetic resonance (MR) arthrogram injections of the hip performed in the office setting by a single orthopaedic surgeon and elucidate the potential effects that patient age, sex, and body mass index (BMI) have on contrast placement. Study Design: Case series; Level of evidence, 4. Methods: From a review of the senior author's office database, 89 patients (101 hips) who had US-guided MR arthrogram injections performed between December 2014 and June 2016 were identified. Official radiology reports were evaluated to determine whether extra-articular contrast was noted. Patient variables, including BMI, age, and sex, were evaluated between patients who had inappropriately placed contrast and those who did not. Results: Of the 101 hip injections, there were 6 cases that demonstrated inadequate contrast placement within the joint, likely secondary to extravasation or incorrect placement; however, an MR arthrogram was adequately interpreted in all cases. There were no significant differences noted between those with appropriate versus inappropriate contrast placement when evaluating BMI (P = .57), age (P = .33), or sex (P = .67), and neither group had an adverse event. Conclusion: US-guided injections are safe and accurate alternatives to fluoroscopy-guided injections in the office setting, with 94% accuracy. Furthermore, BMI, age, and sex did not play a statistically significant role among patients with inappropriately placed contrast. PMID- 29270442 TI - Low-input Capture-C: A Chromosome Conformation Capture Assay to Analyze Chromatin Architecture in Small Numbers of Cells. AB - Chromosome conformation capture (3C) techniques are crucial to understanding tissue-specific regulation of gene expression, but current methods generally require large numbers of cells. This protocol describes two new low-input Capture C approaches that can generate high-quality 3C interaction profiles from 10,000 20,000 cells, depending on the resolution used for analysis. PMID- 29270443 TI - SNAPR: a bioinformatics pipeline for efficient and accurate RNA-seq alignment and analysis. AB - The process of converting raw RNA sequencing data to interpretable results can be circuitous and time consuming, requiring multiple steps. We present an RNA-seq mapping algorithm that streamlines this process. Our algorithm utilizes a hash table approach to leverage the availability and power of high memory machines. SNAPR, which can be run on a single library or thousands of libraries, can take compressed or uncompressed FASTQ and BAM files as inputs, and can output a sorted BAM file, individual read counts, gene fusions and identify exogenous RNA species in a single step. SNAPR also does native Phred score filtering of reads. SNAPR is also well suited for future sequencing platforms that generate longer reads. Using SNAPR, we show how we can analyze data from hundreds of TCGA samples in a matter of hours, while identifying gene fusions and viral events at the same time. With the references genome and transcriptome undergoing periodic updates, and the need for uniform parameters when integrating multiple data sets, there is great need for a streamlined process for RNA-seq analysis. We demonstrate how SNAPR does this efficiently and accurately, with the high-throughput capacity needed to do high-volume analyses. PMID- 29270444 TI - Validation of Methods to Assess the Immunoglobulin Gene Repertoire in Tissues Obtained from Mice on the International Space Station. AB - Spaceflight is known to affect immune cell populations. In particular, splenic B cell numbers decrease during spaceflight and in ground-based physiological models. Although antibody isotype changes have been assessed during and after space flight, an extensive characterization of the impact of spaceflight on antibody composition has not been conducted in mice. Next Generation Sequencing and bioinformatic tools are now available to assess antibody repertoires. We can now identify immunoglobulin gene- segment usage, junctional regions, and modifications that contribute to specificity and diversity. Due to limitations on the International Space Station, alternate sample collection and storage methods must be employed. Our group compared Illumina MiSeq sequencing data from multiple sample preparation methods in normal C57Bl/6J mice to validate that sample preparation and storage would not bias the outcome of antibody repertoire characterization. In this report, we also compared sequencing techniques and a bioinformatic workflow on the data output when we assessed the IgH and Igkappa variable gene usage. This included assessments of our bioinformatic workflow on Illumina HiSeq and MiSeq datasets and is specifically designed to reduce bias, capture the most information from Ig sequences, and produce a data set that provides other data mining options. We validated our workflow by comparing our normal mouse MiSeq data to existing murine antibody repertoire studies validating it for future antibody repertoire studies. PMID- 29270445 TI - Transgenerational paternal transmission of acquired traits: Stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes. AB - In recent years, it has become evident that pre-conceptual exposure of males to various environmental factors induces epigenetic changes in sperm, which can mediate the transmission of acquired traits in their offspring. The most thoroughly examined paternal exposures involve stress and elevated corticosterone, which have been shown to modulate offspring phenotypes in a manner that is relevant to predisposition to brain disorders, and psychiatric illness in particular. Recent seminal studies have demonstrated that key epigenetic information transmitted via the paternal germline involves small non coding (snc) RNA transcripts such as microRNAs. Following fertilisation, these sncRNAs appear to regulate development so as to modify the phenotype of the offspring. Understanding the mechanisms involved in such transgenerational effects may facilitate future screening of human sperm for 'epigenetic health' and the tailoring of therapeutic interventions according to genetic and epigenetic contributions to illness. PMID- 29270447 TI - The metagenome of Caracolus marginella gut microbiome using culture independent approaches and shotgun sequencing. AB - Studies underestimate the microbial diversity and genotypic traits in the snails' microbiome. Caracolus marginella, a land snail native to Caribbean islands, can adapt to different environments. Our research focused on the generation of a metagenomic library from C. marginella gut, to further explore the diversity and functional traits. Thirty specimens of C. marginella were collected from the four regions of Puerto Rico. High molecular weight (40 kb) metagenomic libraries were generated using a direct DNA isolation method. DNA was end-repaired and ligated into a pCCFOS1 fosmid vector; then, the cloned DNA was transduced into Escherichia coli EPI300. The master pool library contains approximately 60,200 clones and restriction enzyme digestion showed that 90% of the library contains insert. After removing the fosmid and host genome sequences, 567,015 sequences were analyzed using the MG-RAST online server. The Bacteria domain was the most abundant (82.15%), followed by viruses (16.49%), eukaryotes (0.83%) and archaea (0.31%). The Proteobacteria (51.47%) was predominant in the gut environment, followed by unidentified virus (16.28%), and Actinobacteria (8.52%). Escherichia coli, Streptomyces avermitilis, and Burkholderia sp. were the most abundant species present. Subsystem functional analysis showed that 35.00% of genes belong to transposable elements, 10.00% of genes belong to clustering-based subsystems, 4.00% of genes belong to the production of cofactors and secondary metabolites, and 2.00% resistance to antibiotics and toxic compounds. The data generated in this research is the first metagenomic examination of a snail gut in Puerto Rico, and will serve as a baseline to start understanding of C. marginella gut microbiome. PMID- 29270448 TI - Data related to the PC71BM loading and it's impact on nanostructuring for blend of PBDTTT-EFT:PC71BM bulk heterojunction solar cell. AB - The data included in this article is based on additional supporting information presented in our recent publication Komilian et al. [1]. The role of acceptor material (PC71BM) in restructuring copolymer PBDTTT-EFT from its relaxed pristine structure to interfaces suitable for exciton dissociation is discussed. The analysis of data indicates that the impact of acceptor material on nanostructuring initiates concurrent processes some of which supports and some impedes charge extractions. Therefore, this manuscript is designed to identify these processes and give and account of their impact on power conversion efficiency. PMID- 29270446 TI - Event Boundaries in Memory and Cognition. AB - Research on event cognition is rapidly developing and is revealing fundamental aspects of human cognition. In this paper, we review recent and current work that is driving this field forward. We first outline the Event Horizon Model, which broadly describes the impact of event boundaries on cognition and memory. Then, we address recent work on event segmentation, the role of event cognition in working memory and long-term memory, including event model updating, and long term retention. Throughout we also consider how event cognition varies across individuals and groups of people and consider the neural mechanisms involved. PMID- 29270449 TI - Draft genomes of Enterococcus faecium strains isolated from human feces before and after eradication therapy against Helicobacter pylori. AB - The abundance of Enterococci in the human intestinal microbiota environment is usually < 0.1% of the total bacterial fraction. The multiple resistance to antibiotics of the opportunistic Enterococcus spp. is alarming for the world medical community because of their high prevalence among clinically significant strains of microorganisms. Enterococci are able to collect different mobile genetic elements and transmit resistance to antibiotics to wide range of Gram positive and Gram-negative species of microorganisms, including the transmission of vancomycin resistance to methicillin-resistant strains of Staphylococcus aureus. The number of infections caused by antibiotics resistant strains of Enterococcus spp. is increasing. Here we present a draft genomes of Enterococcus faecium strains. These strains were isolated from human feces before and after (1 month) Helicobacter pylori eradication therapy. The samples were subject to whole genome sequencing using Illumina HiSeq. 2500 platform. The data is available at NCBI https://www.ncbi.nlm.nih.gov/bioproject/PRJNA412824. PMID- 29270450 TI - Clustering of commercial fish sauce products based on an e-panel technique. AB - Fish sauce is a brownish liquid seasoning with a characteristic flavor that is produced in Asian countries and limited areas of Europe. The types of fish and shellfish and fermentation process used in its production depend on the region from which it derives. Variations in ingredients and fermentation procedures yield end products with different smells, tastes, and colors. For this data article, we employed an electronic panel (e-panel) technique including an electronic nose (e-nose), electronic tongue (e-tongue), and electronic eye (e eye), in which smell, taste, and color are evaluated by sensors instead of the human nose, tongue, and eye to avoid subjective error. The presented data comprise clustering of 46 commercially available fish sauce products based separate e-nose, e-tongue, and e-eye test results. Sensory intensity data from the e-nose, e-tongue, and e-eye were separately classified by cluster analysis and are shown in dendrograms. The hierarchical cluster analysis indicates major three groups on e-nose and e-tongue data, and major four groups on e-eye data. PMID- 29270451 TI - Data supporting the angiotensin II activates MEL18 to deSUMOylate HSF2 for hypertension-related heart failure. AB - In association with the published article "Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy" (Huang et al., 2017) [1], this data article contains information about deSUMOylation of HSF2 on lysine 82 on angiotensin II (ANG II) -induced cardiac hypertrophy, which is mediated by MEL18. Isolated adult human whole heart tissue showed MEL18-mediated HSF2-IGF-IIR pathway is upregulated in hypertension human heart, compared to health human heart. PMID- 29270452 TI - Experimental data for the slug two-phase flow characteristics in horizontal pipeline. AB - The data presented in this article were the basis for the study reported in the research articles entitled "Statistical assessment of experimental observation on the slug body length and slug translational velocity in a horizontal pipe" (Al Kayiem et al., 2017) [1] which presents an experimental investigation of the slug velocity and slug body length for air-water tow phase flow in horizontal pipe. Here, in this article, the experimental set-up and the major instruments used for obtaining the computed data were explained in details. This data will be presented in the form of tables and videos. PMID- 29270453 TI - Dataset on information strategies for energy conservation: A field experiment in India. AB - The data presented in this article are related to the research article entitled: "Information strategies for energy conservation: a field experiment in India" (Chen et al., 2017) [1]. The availability of high-resolution electricity data offers benefits to both utilities and consumers to understand the dynamics of energy consumption for example, between billing periods or times of peak demand. However, few public datasets with high-temporal resolution have been available to researchers on electricity use, especially at the appliance-level. This article describes data collected in a residential field experiment for 19 apartments at an Indian faculty housing complex during the period from August 1, 2013 to May 12, 2014. The dataset includes detailed information about electricity consumption. It also includes information on apartment characteristics and hourly weather variation to enable further studies of energy performance. These data can be used by researchers as training datasets to evaluate electricity usage consumption. PMID- 29270454 TI - Data on fluoride concentration levels in semi-arid region of Medak, Telangana, South India. AB - According to the World Health Organization recommendation, the optimal fluoride concentration levels in drinking water have to be in the range of 0.5 and 1.5 mg/L since this permissible range is essential for normal mineralization of bones and teeth as well as for dental enamel formation in human's body Bell and budwig, 1970;Adimalla and Venkatayogi, 2017;Narsimha and Sudarshan, 2013,2016;2017[1], [2], [4], [5], [6]. If continues intake of high fluoride (>1.5) water can severely cause dental and skeletal fluorosis. The investigated area people majorly depend on groundwater for drinking purposes and fluoride concentration ranged from 0.2 to 7.4 mg/L with mean concentration of 2.7 mg/L and data was compared with WHO guidelines for drinking purposes. Overall, data reveals that the 57% of groundwater samples data was not safe for drinking purposes. Therefore, distribution of fluoride in the groundwater of Medak region in Telangana was suggested to intake drinking water, which are below level of fluoride concentration in the groundwater and take care about health implications. PMID- 29270455 TI - Data on corrosion and scaling potential of drinking water resources using stability indices in Jolfa, East Azerbaijan, Iran. AB - This cross-sectional study was conducted on the drinking water resources of the city of Jolfa (East Azerbaijan province, Iran) from samples taken from 30 wells. Calcium hardness, pH, total alkalinity, TDS, temperature and other chemical parameters were measured using standard methods. The Langelier, Rayzner, Puckhorius and aggressive indices were calculated. The results showed that the Langelier, Reynar, Puckorius, Larson-skold and aggressive indices were 1.15 (+/- 0.43), 6.92 (+/- 0.54), 6.42 (+/- 0.9), 0.85 (+/- 0.72) and 12.79 (+/- 0.47), respectively. In terms of water classification, 30% of samples fell into the NaCl category and 26.6% in the NaHCO3 category and 43.4% samples in the CaHCO3, MgHCO3 and MgCl category. The sedimentation indices indicated that the water of the wells could be considered as corrosive. PMID- 29270456 TI - Data on DNA gel sample load, gel electrophoresis, PCR and cost analysis. AB - The data presented in this article provide supporting information to the related research article "Comparison of ten different DNA extraction procedures with respect to their suitability for environmental samples" (Kuhn et al., 2017) [1]. In that article, we compared the suitability of ten selected DNA extraction methods based on DNA quality, purity, quantity and applicability to universal PCR. Here we provide the data on the specific DNA gel sample load, all unreported gel images of crude DNA and PCR results, and the complete cost analysis for all tested extraction procedures and in addition two commercial DNA extraction kits for soil and water. PMID- 29270457 TI - Drinking water pollution with respective of fluoride in the semi-arid region of Basara, Nirmal district, Telangana State, India. AB - Fluoride is an essential microelement for human health. Statistically, smaller quantities (<1.0 mg/L) in drinking water are usually considered to have a beneficial effect on the rate of occurrence of dental caries, particularly among children, but excessive continuous exposure (>1.5 mg/L) to fluoride can give rise to a number of adverse effects, including dental fluorosis, skeletal fluorosis, increased rate of bone fractures, decreased birth rates, increased rate of urolithiasis (kidney stones), impaired thyroid function, and impaired development of intelligence in children [1], [2], [3], [4], [5]. The data suggested that the north-eastern part of the Basara region having high fluoride concentration, which is unsuitable for drinking purposes. Hence, this unsuitable drinking water cause fluorosis in this Basara and surrounding villages, and especially based on the findings suggests, where the fluoride levels are in below maximum permissible limits that water ingests to the people to avoid further fluorosis. PMID- 29270458 TI - Palmoplantar keratoderma as a presenting sign of primary biliary cirrhosis. PMID- 29270459 TI - A community-based One Health education program for disease risk mitigation at the human-animal interface. AB - The interface between humans, domestic animals, and wildlife has been implicated in the emergence of infectious diseases and the persistence of endemic human and animal diseases. For individuals who reside at this interface, particularly those in low-resource settings, the development of disease risk assessment and mitigation skills must be prioritized. Using a community engagement-One Health approach, we implemented a training program aimed at advancing these skills among agro-pastoralists living adjacent to conservation areas in South Africa. The program included professional development of local facilitators who then conducted workshops with community members. Workshops used a series of experiential, inquiry-based activities to teach participants the concepts of pathogen transmission and disease risk assessment and mitigation. The program was implemented over four weeks with 10 facilitators and 78 workshop participants. We conducted a within-subjects experimental study using a mixed methods design to evaluate the program in terms of facilitator and participant One Health knowledge and practices. Quantitative data included pre/post written assessments; qualitative data included focus group discussions, semi-structured interviews, and pre/post photographs. Mean post-test scores of facilitators increased by 17% (p = 0.0078). For workshop participants, improvements in knowledge were more likely for females than males (OR = 7.315, 95% CI = 2.258-23.705, p = 0.0009) and participants with a higher versus lower education level, albeit borderline non significant (OR = 4.781, 95% CI = 0.942-24.264, p = 0.0590). Qualitative analysis revealed the implementation of risk mitigation strategies by 98% (60/61) of workshop participants during the three-month follow-up and included improved personal and domestic hygiene practices and enhanced animal housing. Although further evaluation is recommended, this program may be appropriate for consideration as a scalable approach by which to mitigate human and animal infectious disease risk in high-risk/low-resource communities. PMID- 29270461 TI - Digitally Scanned Radiographs versus Conventional Films for Determining Clarity of Periapical Lesions and Quality of Root Canal Treatment. AB - Aim: To compare digital images of conventional radiographs with the original radiographs for perceived clarity of periapical lesions and the quality of root canal treatment. Materials and Methods: One hundred and four intraoral periapical radiographs of patients with endodontically treated teeth were randomly selected. The radiographs were digitized using an MD300 USB X-ray Reader. The digital images were transferred to an HP laptop. Three evaluators compared each conventional radiograph with the matching digital image. The images were ranked for clarity and assessed for diagnostic quality; data were analyzed using the Reliability Calculation "ReCal." Results. Both the digital images and conventional films had comparable clarity and diagnostic quality. Results indicated a moderate agreement between the evaluators. Conclusions: Conventional radiographs digitized using an MD300 USB X-ray Reader have similar clarity and diagnostic quality in comparison to the original radiographs. PMID- 29270460 TI - Patient-provider communication styles in HIV treatment programs in Bamako, Mali: A mixed-methods study to define dimensions and measure patient preferences. AB - Effective patient-provider communication (PPC) promotes patient adherence and retention in long-term care. Sub-Saharan Africa faces unprecedented demand for chronic care for HIV patients on antiretroviral therapy (ART), yet adherence and retention remain challenging. In high-income countries, research describing patient preferences for different PPC styles has guided interventions to improve PPC and patient outcomes. However, research on PPC preferences in sub-Saharan Africa is limited. We sought to define PPC dimensions relevant to ART programs in Bamako, Mali through recordings of clinical interactions, in-depth interviews and focus-group discussions with 69 patients and 17 providers. Qualitative analysis revealed two PPC dimensions similar to those described in the literature on patient-centered communication (level of psychosocial regard, balance of power), and one unique dimension that emerged from the data (guiding patient behavior: easy/tough/sharp). To assess preferences toward contrasting PPC styles within dimensions, we conducted a vignette-based survey with 141 patients across five ART facilities. Significantly more participants chose the vignette demonstrating high psychosocial regard (52.2%) compared to a biomedical style (22.5%) (p<0.001). Within balance of power, a statistically similar proportion of participants chose the vignette demonstrating shared power (40.2%) compared to a provider-dominated style (35.8%). In guiding patient behavior, a similar proportion of participants preferred the vignette depicting the "easy" (38.4%) and/or "tough" style (40.6%), but significantly fewer preferred the "sharp" style (14.5%) (p<0.001). Highly educated participants chose biomedical and shared power styles more frequently, while less educated participants more frequently indicated "no preference". Working to understand, develop, and tailor PPC styles to patients in chronic care may help support patient retention and ultimately, clinical outcomes. Emphasis on developing skills in psychosocial regard and on adapting styles of power balance and behavioral guidance to individual patients is likely to yield positive results and should be considered a high priority for ART providers in Mali. PMID- 29270462 TI - Sirolimus Ointment for Facial Angiofibromas in Individuals with Tuberous Sclerosis Complex. AB - Background. Facial angiofibromas affect most patients with tuberous sclerosis complex. They tend to progress, can cause recurrent bleeding and facial disfigurement, and have significant psychological effects. We reviewed the effectiveness and safety of topical sirolimus ointment 0.1%. We also assessed the effect of treatment on quality of life. Methods. We report our experience in using sirolimus ointment in 14 patients with TSC (9 children and 5 adults). The impact of sirolimus ointment was monitored with digital photography, dermatological review using a validated Facial Angiofibroma Severity Index (FASI), and quality of life assessments using the questionnaires PedsQL for children and SF36 for adults. Results. The FASI scores were improved in 12/14 cases after six months' treatment, and improvement was more likely in children (median FASI scores of improvement after treatment were 3 points for children and 1 for adults). Proxy-reported PedsQL scores for the total psychosocial domain improved significantly in the children in the cohort with treatment. Conclusions. Sirolimus ointment 0.1% administered once a day was effective in treating facial angiofibromas. It appears to be safe and well tolerated and to have a positive impact on patients' quality of life. It appeared to be most beneficial when started in childhood. PMID- 29270463 TI - The Experience of Patients During the Clinical Management Pathway of Abdominal Aortic Aneurysms at a NHS Trust. AB - Background: The epidemiology of abdominal aortic aneurysm (AAA) is changing. Outcomes for aortic surgery have improved. However, the accepted guideline for the management of AAAs has remained unchanged over the last 2 decades. We aimed to gain insight into the patients' experience while they are managed under the traditional clinical pathway. Method: With the help of a patient focus group, we designed a survey to assess the patients' perception of the disease and their experience during different stages of the AAA clinical care pathway (surveillance, perioperative care, postoperative follow-up). An invitation to participate in the survey was sent to all patients with AAA who were receiving care at the Oxford Regional Vascular Services Unit, part of the Oxford University Hospitals NHS Trust. Results: We received 194 responses from patients with AAA. One hundred seventy-seven were male, with a median age of 75 to 79 years. Just over a third had undergone surgery already, and the remaining 63% were either in surveillance or awaiting surgery. Their experience during the AAA management pathway was mostly positive. Of the issues that were most important to them in terms of their medical care, the provision of explanation and regularity of monitoring stood out as the most common considerations. Conclusion: Patients are generally satisfied with the care they received, but there is room for improvement. They have also highlighted key areas that are most important to them in terms of their medical care. These should guide the future direction for quality improvement and research. PMID- 29270464 TI - Web-Based Parent-Training for Parents of Youth With Impairment From Anxiety. AB - Child Anxiety Tales, an online web-based cognitive-behavioral parent-training program for parents of youth with anxiety, was developed and evaluated. Parents (N = 73; 59 females; 52.1% Caucasian, 42.5% African American, 4.1% Hispanic) who reported concerns about anxiety in their child (aged 7-14 yrs; Mean=10.1 +/-1.6) were randomly assigned to (a) parent-training provided through Child Anxiety Tales (CAT), (b) parent-training provided via bibliotherapy (BIB), or (c) a waitlist control (WLC). Measures of parent knowledge, the acceptability of training, and child symptomatology were completed at pre- and post-parent training and at 3-month follow-up. Findings support the feasibility, acceptability, and beneficial effects on knowledge of Child Anxiety Tales for parents of youth with impairment from anxiety. PMID- 29270466 TI - Circadian mood variations in Twitter content. AB - Background: Circadian regulation of sleep, cognition, and metabolic state is driven by a central clock, which is in turn entrained by environmental signals. Understanding the circadian regulation of mood, which is vital for coping with day-to-day needs, requires large datasets and has classically utilised subjective reporting. Methods: In this study, we use a massive dataset of over 800 million Twitter messages collected over 4 years in the United Kingdom. We extract robust signals of the changes that happened during the course of the day in the collective expression of emotions and fatigue. We use methods of statistical analysis and Fourier analysis to identify periodic structures, extrema, change points, and compare the stability of these events across seasons and weekends. Results: We reveal strong, but different, circadian patterns for positive and negative moods. The cycles of fatigue and anger appear remarkably stable across seasons and weekend/weekday boundaries. Positive mood and sadness interact more in response to these changing conditions. Anger and, to a lower extent, fatigue show a pattern that inversely mirrors the known circadian variation of plasma cortisol concentrations. Most quantities show a strong inflexion in the morning. Conclusion: Since circadian rhythm and sleep disorders have been reported across the whole spectrum of mood disorders, we suggest that analysis of social media could provide a valuable resource to the understanding of mental disorder. PMID- 29270465 TI - The mighty fibroblast and its utility in scleroderma research. AB - Fibroblasts are the effector cells of fibrosis characteristic of systemic sclerosis (SSc, scleroderma) and other fibrosing conditions. The excess production of extracellular matrix (ECM) proteins is the hallmark of fibrosis in different organs, such as skin and lung. Experiments designed to assess the pro fibrotic capacity of factors, their signaling pathways, and potential inhibitors of their effects that are conducted in fibroblasts have paved the way for planning clinical trials in SSc. As such, fibroblasts have proven to be valuable tools in the search for effective anti-fibrotic therapies for fibrosis. Herein we highlight the characteristics of fibroblasts, their role in the etiology of fibrosis, utility in experimental assays, and contribution to drug development and clinical trials in SSc. PMID- 29270467 TI - Efficacy of Stellate Ganglion Blockade in Managing Electrical Storm: A Systematic Review. AB - BACKGROUND: The efficacy of percutaneous stellate ganglion block (SGB) for managing electrical storm (ES) is not well understood. OBJECTIVE: To characterize the efficacy of SGB as a treatment for ES. METHODS: We conducted literature searches using PubMed/Medline and Google Scholar, for mixed combinations of terms including "stellate ganglion block", *ganglion block (ade)", "sympathetic block (ade)" and "arrhythmia", "ventricular arrhythmia (VA)" or "tachycardia" (VT), "ventricular fibrillation" (VF), "electrical storm". Inclusion criteria were presentation with guideline-defined ES and treatment with SGB. Exclusion criteria: presentation with any supraventricular arrhythmia, VA without ES, or surgical sympathectomy. Studies lacking basic demographic data, arrhythmia description, and outcomes were excluded. RESULTS: Of 3,374 publications reviewed, 38 patients from 23 studies met study criteria (52 +/- 19.1 years, 11 F, 17 with ischemic cardiomyopathy). Anti-arrhythmics were used in all patients. Mean Left ventricular ejection fraction was 31 +/- 10%. ES was triggered by acute myocardial infarction in 15 patients and QT prolongation in 7 patients. The most common local anesthetic used for SGB was bupivacaine (0.25-0.5%). SGB resulted in a significant decrease in VA burden (12.4+/-8.8 vs. 1.04+/-2.12 episodes/day, p< 0.001) and number of external and ICD shocks (10.0+/-9.1 vs. 0.05+/-0.22 shocks/day, p< 0.01). Following SGB, 80.6% of patients survived to discharge. CONCLUSION: SGB is an effective acute treatment for ES. However, larger prospective randomized studies are needed to better understand the role of SGB in ES and other VAs. PMID- 29270468 TI - Deep Anterior lamellar Keratoplasty: In search of Holy Grail! PMID- 29270470 TI - Surgical treatment of Duane retraction syndrome. AB - Purpose: Surgical treatment in Duane retraction syndrome (DRS) can be very challenging even for the strabismus specialists because of a wide spectrum of diversity in clinical manifestations. The purpose of this article is to review these different surgical treatments. Methods: A comprehensive search was performed using PubMed database with the different keywords of "Duane retraction syndrome" and "surgery". Articles were selected from original English papers published since 2000. The full text of the selected articles was reviewed, and some articles were added based upon the references of the initial articles. We also provided selected case examples about some of these procedures. Results: 125 articles were found in the initial search of which 37 articles were mostly related to the topic of this review. The number finally increased to 59 articles after considering the relative references of the initial articles. Different surgical methods performed on horizontal and vertical rectus muscles (recession, resection, transposition, Y splitting, periosteal fixation and posterior fixation suture) are reviewed. Careful selection of the surgical technique is important to achieve optimal results. Conclusion: With accurate diagnosis of patients with DRS and proper surgical management, several adverse situations associated with this syndrome (amblyopia, abnormal head posture, upshoot, downshoot, and muscle underaction) can be prevented. PMID- 29270471 TI - Comparison of macular choroidal thickness in patients with pseudoexfoliation syndrome to normal control subjects with enhanced depth SD-OCT imaging. AB - Purpose: To test the hypothesis that macular choroidal thickness is lower in patients with pseudoexfoliation syndrome (PXS) as compared to healthy control subjects. Methods: In this cross-sectional, observational study, 38 non glaucomatous PXS subjects and 37 healthy volunteers were enrolled in a tertiary care Glaucoma Clinic. The macular region was scanned with the enhanced depth imaging (EDI) protocol of a spectral domain optical coherence tomography (SD-OCT) device (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany). Macular choroidal thickness and volumes were compared in nine sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) layout profile across the central 3.45 mm zone after manual segmentation of the choroidal thickness. Linear mixed modeling was used to adjust for confounding variables. Results: Six PXS eyes and 8 control eyes were excluded due to poor image quality leaving 32 PXS and 29 control eyes for final analyses. The average age and axial length of the PXS and control groups were 67.94 +/- 7.30 vs 64.86 +/- 7.04 and 22.91 +/- 0.77 vs 23.24 +/- 0.66 mm, respectively, (P = 0.10 and 0.20). There was no significant difference in retinal nerve fiber layer (RNFL) thickness between the two groups (P = 0.24). The choroidal thickness was significantly lower in the central subfield subfoveal area (P = 0.02) and in the inner superior (P = 0.03) and inner nasal quadrants (P = 0.03) in the PXS group compared to the control group, as was the choroidal volume (P = 0.02). No significant difference was found in macular choroidal thickness after adjusting for age, gender, and axial length. While there was a significant negative association between age and central subfield choroidal thickness in the control group (r = -0.48, P = 0.01), this association was not significant in the PXS group (r = -0.08, P = 0.68). Conclusions: Our findings demonstrate that the choroid does not seem to be significantly altered in PXS eyes. Choroidal thickness changes need to be explored in PXS eyes with glaucoma. PMID- 29270469 TI - Updates on corneal collagen cross-linking: Indications, techniques and clinical outcomes. AB - Purpose: To review the historical background and basic principles of collagen cross-linking, to bring together the data regarding the outcomes and complications of collagen cross-linking and finally to explore the efficacy and safety of new variations of this technique. Methods: A literature review was performed using PubMed and Scopus. The following keywords were used for literature search: cross linking, crosslinking, cross-linking, keratoconus, keratectasia. Results: In contrast to traditional treatment modalities for keratoconus (KCN), this new technique addresses the progression of the disease. Several clinical studies have been conducted to assess the efficacy of corneal collagen cross-linking (CXL) in the last decade. The results were promising as collagen cross-linking showed significant improvement in visual acuity and keratometric values. Moreover, initial results show that it is a safe procedure with few reported complications. Conclusion: CXL is an emerging treatment method in ophthalmology that offers the possibility to effectively treat progressive KCN. PMID- 29270472 TI - Efficacy of corneal cooling on postoperative pain management after photorefractive keratectomy: A contralateral eye randomized clinical trial. AB - Purpose: To compare chilled and room temperature balanced salt solution (BSS) and bandage contact lens (BCL) on post photorefractive keratectomy (PRK) pain. Methods: In a prospective, single-masked, controlled eye study, one hundred eyes of fifty patients were divided into two groups which received room temperature or chilled BSS and BCL in each eye, and compared for post-PRK pain. Three different pain evaluation systems were used to evaluate pain between the groups at 1 and 6 h and days 1, 2, 3, 5, and 7, postoperatively. Results: 15 patients were male (30%), and 35 were female (70%). The mean age was 29 +/- 5 (20-40) y/o. The mean spherical equivalent (SE) of preoperative refractive error in both groups was not statistically significantly different (-4.18 +/- 1.5 in chilled and -4.19 +/- 1.7 in room-temperature groups, respectively; P = 0.94). The mean time of epithelial healing was 6.16 +/- 1.7 (3-13) days in the chilled and 6.10 +/- 1.59 (3-12) in the room temperature group (P = 0.32). Best corrected visual acuity (BCVA) at 1 month was 0.013 +/- 0.03 (0-0.22) logarithm of the minimum angle of resolution (logMAR) in the chilled group and 0.014 +/- 0.04 (0-0.22) logMAR in the room temperature group, postoperatively (P = 0.84). No statistically significant difference was found between the two groups by any of the three pain scoring systems. No clinically important corneal haziness was found in the groups during follow-up. Conclusion: Chilled BSS and BCL do not seem to be superior to room temperature in reducing post-PRK pain. PMID- 29270473 TI - Dry eye signs and symptoms in night-time workers. AB - Purpose: To determine the effect of night-time working on dry eye signs and symptoms. Methods: A total of 50 healthy subjects completed a dry eye questionnaire and underwent clinical examinations including basic Schirmer's test and tear breakup time (TBUT) test on two consecutive days, before and after the night shift (12-hrs night-shift). Results: All dry eye symptoms were aggravated significantly after the night shift (P < 0.05). Conjunctival redness increased after the night shift (P = 0.001). TBUT reduced significantly after the night shift (8.06 vs 10.98 s) (P = 0.001). Basic Schirmer's test increased after the night-shift compared to its values before the shift (19.04 vs 17.34 mm) (P = 0.037). Conclusion: Our study showed that night-time working can cause tear film instability and exacerbation of dry eye symptoms. PMID- 29270474 TI - Optical aberrations, accommodation, and visual acuity with a bioanalogic continuous focus intraocular lens after cataract surgery. AB - Purpose: To evaluate the visual outcomes, pseudoaccommodation, and wavefront aberrometry after implantation of Wichterle IOL-Continuous Focus (WIOL-CF(r), Gelmed International, Kamenne Zehrovice, Czech Republic) by i-Trace aberrometry. Methods: In this retrospective interventional case series study, after cataract surgery with implantation of accommodative WIOL-CF(r), the patients were evaluated with i-Trace aberrometer for measurement of modulation transfer function (MTF), point spread function (PSF), total aberrations, higher order aberrations (HOAs) at far and near and pseudoaccommodation. The pre and postoperative visual acuity at near and distance were also measured. Results: Forty eyes of 20 patients (aged 40-77 years) were enrolled in this study with mean follow-up time of up 13.10 +/- 5.52 months. The mean logMAR corrected distance visual acuity (CDVA) improved from 0.20 +/- 0.14 preoperatively to 0.10 +/- 0.09 at the last follow-up after surgery (P = 0.002). The results were 60% J1, 70% J2, 85% J3, 90% J4, 95% J5 and 100% for J6. The mean pseudoaccommodation, range of accommodation volume, and average of peak accommodation were -2.52 +/- 1.56 diopters (D), 1.50 to 5.25 D and -3.25 +/- 1.25 D, respectively. The mean MTF at 5 cycles per degree at far was 0.200 +/- 0.10 and for near was 0.207 +/- 0.10. PSF at far and near was 0.0002 and 0.001, respectively. The mean root mean square (RMS) value of HOAs; total, coma spherical aberration, trefoil, and secondary astigmatism were 1.08 +/- 0.48 MUm, 0.89 +/- 0.45 MUm, -0.33 +/- 0.23 MUm, 0.25 +/- 0.17 MUm, and 0.15 +/- 0.13 MUm for far and 0.88 +/- 0.49 MUm, 0.73 +/- 0.46 MUm, -0.25 +/- 0.22 MUm, 0.19 +/- 0.16 MUm and 0.11 +/- 0.10 MUm for near, respectively. There was a decrease in HOAs at near relative to far (P < 0.05). Conclusion: WIOL-CF(r) seems to be an acceptable accommodative intraocular lens (IOL) in terms of uncorrected near and distant visual outcomes, MTF and HOA. PMID- 29270475 TI - Comparison of free conjunctival autograft versus amniotic membrane transplantation for pterygium surgery. AB - Purpose: To compare the recurrence rate and surgical outcomes of amniotic membrane transplantation (AMT) and free conjunctival autograft (CAT) for pterygium surgery. Methods: In this prospective study, 60 patients with primary pterygium were randomly assigned to two groups of CAT or AMT and were compared in terms of recurrence rate, mean healing time of corneal epithelial defects, the mean level of inflammation, and complications. Results: The mean +/- SD age of patients was 48.98 +/- 9.8 years (range, 27-71 years). 73.3% were men, and 26.7% were women. The groups did not differ with respect to demographic characteristics (P > 0.05). Patients were followed for an average of 12.6 +/- 1.3 months. The recurrence rates were 6.7% and 3.3% in the AMT and CAT groups, respectively (P > 0.05). Comparison of mean inflammation score showed higher inflammation in the AMT group in the first, third, and sixth postoperative month (P < 0.05). Mean healing times of corneal epithelial defects were 2.5 +/- 0.572 and 2.67 +/- 0.479 days in the CAT and AMT groups, respectively (P = 0.173). Conclusions: No significant complication was observed during or after both surgical methods. No statistically significant difference was seen in visual acuity changes and epithelial healing in CAT and AMT groups, but more inflammation and recurrence rate were seen in AMT group. PMID- 29270476 TI - Investigation of the effects of Islamic fasting on ocular parameters. AB - Purpose: To investigate the effects of religious fasting during the month of Ramadan on intraocular pressure (IOP), refractive error, corneal tomography and biomechanics, ocular biometry, and tear film layer properties. Methods: This prospective study was carried out one week before and in the last week of Ramadan. Ninety-four eyes of 94 healthy adult volunteers (54 males and 40 females) with a mean +/- SD age of 35.12 +/- 9.07 were enrolled in this study. Patients with any systemic disorder, ocular disease, or a history of previous surgery were excluded. Corneal tomography and biomechanics, ocular biometry, IOP, refractive error, and tear break up time (TBUT) were evaluated in non-fasting and fasting periods by the Pentacam (Oculus), Corvis ST (Oculus), IOL Master (Carl Zeiss), computerized tonometer (Topcon CT-1/CT-1P), auto kerato-refractometer (Topcon KR-1), and Keratograph 5M (Oculus), respectively. Results: There was no significant difference in the central corneal thickness (CCT) between the study groups (P = 0.123) using the Pentacam while the Corvis ST showed a significant difference in all participants (P < 0.0001). Moreover, the peak distance (distance of the two surrounding peaks of the cornea at the highest concavity) of male and female participants showed a significant difference between the fasting and non-fasting groups (P = 0.002). The anterior chamber depth (ACD) using the Pentacam decreased in the male group (P = 0.004) in the fasting period. During the fasting period, computerized tonometer showed a decrease in IOP only in males in comparison to the non-fasting group (P = 0.018) while the Corvis ST showed decreased IOP in all participants (P < 0.0001). The steep keratometry (K2) in the corneal posterior surface appeared to be different in males between the study groups (P = 0.034). We were unable to show any significant difference in other ocular parameters between fasting and non-fasting periods. Conclusion: This study showed that ACD, IOP, CCT, and peak distance were different between fasting and non-fasting groups while no difference was observed in other ocular parameters. Interpretations of these significant differences should be considered in the clinical setting. PMID- 29270477 TI - The quantitative measurements of foveal avascular zone using optical coherence tomography angiography in normal volunteers. AB - Purpose: To provide normative data of foveal avascular zone (FAZ) and thickness. Methods: In this cross-sectional study both eyes of each normal subject were scanned with optical coherence tomography angiography (OCTA) for foveal superficial and deep avascular zone (FAZ) and central foveal thickness (CFT) and parafoveal thickness (PFT). Results: Out of a total of 224 eyes of 112 volunteers with a mean age of 37.03 (12-67) years, the mean superficial FAZ area was 0.27 mm2, and deep FAZ area was 0.35 mm2 (P < 0.001), with no difference between both eyes. Females had a larger superficial (0.32 +/- 0.11 mm2 versus 0.23 +/- 0.09 mm2) and deep FAZ (0.40 +/- 0.14 mm2 versus 0.31 +/- 0.10 mm2) (P < 0.001) than males. By multivariate linear regression analysis, in normal eyes, superficial FAZ area varied significantly with the gender, CFT, and deep FAZ. Deep FAZ varied with the gender and CFT. Conclusion: The gender and CFT influence the size of normal superficial and deep FAZ of capillary network. PMID- 29270478 TI - Chronic subclinical inflammation after phakic intraocular lenses implantation: Comparison between Artisan and Artiflex models. AB - Purpose: To compare chronic subclinical inflammation induced after implantation of Artisan vs. Artiflex phakic intraocular lenses (pIOLs). Methods: This prospective, comparative, non-randomized study included consecutive patients with moderate to high myopia who underwent Artisan or Artiflex pIOL implantation with standard surgery and postoperative care. Anterior chamber flare was assessed quantitatively using laser flare photometry (LFP) at baseline, 1 week, 1 month, 3 months, 6 months, and 2 years after surgery. Results: PIOLs were implanted in 72 eyes (40 patients); Artisan pIOLs in 16 eyes (Artisan group) and Artiflex pIOLs in 56 eyes (Artiflex group). The mean preoperative anterior chamber flare was 6.5 +/- 2.3 (range, 4.2-9.5) photons per millisecond (ph/ms) and 4.2 +/- 0.9 (range, 2.5-11.7) ph/ms in Artisan and Artiflex groups, respectively (P = 0.400). In spite of early postoperative rise, the flare value returned to preoperative levels 6 months after pIOL implantation and remained stable up to 2 years. The amount of flare was not statistically different between Artisan and Artiflex groups in any postoperative follow-up (all P > 0.05). The trend in flare changes was not different between the studied groups (ANCOVA, P = 0.815). Conclusion: The inflammatory response induced by implantation of either type of Artisan and Artiflex pIOLs is short-lived without statistically significant difference between the two models. PMID- 29270479 TI - The prevalence of uncorrected refractive errors in underserved rural areas. AB - Purpose: To determine the prevalence of uncorrected refractive errors, need for spectacles, and the determinants of unmet need in underserved rural areas of Iran. Methods: In a cross-sectional study, multistage cluster sampling was done in 2 underserved rural areas of Iran. Then, all subjects underwent vision testing and ophthalmic examinations including the measurement of uncorrected visual acuity (UCVA), best corrected visual acuity, visual acuity with current spectacles, auto-refraction, retinoscopy, and subjective refraction. Need for spectacles was defined as UCVA worse than 20/40 in the better eye that could be corrected to better than 20/40 with suitable spectacles. Results: Of the 3851 selected individuals, 3314 participated in the study. Among participants, 18.94% [95% confidence intervals (CI): 13.48-24.39] needed spectacles and 11.23% (95% CI: 7.57-14.89) had an unmet need. The prevalence of need for spectacles was 46.8% and 23.8% in myopic and hyperopic participants, respectively. The prevalence of unmet need was 27% in myopic, 15.8% in hyperopic, and 25.46% in astigmatic participants. Multiple logistic regression showed that education and type of refractive errors were associated with uncorrected refractive errors; the odds of uncorrected refractive errors were highest in illiterate participants, and the odds of unmet need were 12.13, 5.1, and 4.92 times higher in myopic, hyperopic and astigmatic participants as compared with emmetropic individuals. Conclusion: The prevalence of uncorrected refractive errors was rather high in our study. Since rural areas have less access to health care facilities, special attention to the correction of refractive errors in these areas, especially with inexpensive methods like spectacles, can prevent a major proportion of visual impairment. PMID- 29270480 TI - Ultrasonographic motion analysis of lower eyelid compartments in patients with chronic thyroid associated ophthalmopathy. AB - Purpose: To present the qualitative and quantitative ultrasonographic findings of lower eyelid compartments in patients with chronic thyroid associated ophthalmopathy (TAO) compared to normal subjects. Methods: In a prospective study, dynamic and static ultrasonographic investigation, applying high resolution (15 MHz) ultrasound was performed to assess the lower eyelid, in 15 TAO patients that were in chronic phase and 10 normal subjects. The thickness and echogenisity of dermis, orbicular oculi muscle, lower eyelid retractor muscle, lower eyelid fat pads, and their qualitative relationships during vertical excursion of the globe were evaluated in static and dynamic investigation. Correlation of ultrasonic and clinical findings was evaluated. Results: The mean age of the patients was 41.82 +/- 7.4 years, and the controls were age-matched (mean age, 42.8 +/- 5.6 years). Mean proptosis of the involved eyes was 3.3 mm, and mean lower lid retraction was 2.4 mm in chronic TAO group. Pattern of fat motion was blocky in chronic TAO patients compared to normal jelly motion of the fat in normal cases. In analyzing the range of motion, the difference was significant in the motion of both superficial and deep fat pockets between the two groups (P < 0.001). Limitation of fat motion correlated both with proptosis and lower eyelid retraction (Pearson correlation coefficient = -0.77 vs -0.43, P < 0.001). Fibrotic changes of lower lid fat pads appear in the tissue around the septum on observation. Considering the ultrasound findings, a new staging method is proposed in this study that starts with the appearance of echodense points, getting worse in fine bands, progresses to thick bands and ends in cord formation in the lower lid fat pocket that determines total fibrosis. Conclusion: Development of a series of static and dynamic changes in ultrasound is related to the clinical findings in chronic phase of TAO. The limitation of motion and fibrotic changes of lower eyelid fat pads were more detectable in cases with a more severe proptosis and lower lid retraction. It is considered that ultrasound findings can be a representative of the severity of involvement in the chronic phase of the TAO. PMID- 29270481 TI - Traumatic glaucoma due to paintball injuries: A case series. AB - Purpose: To study the management and outcomes of patients with paintball injuries resulting in traumatic glaucoma. Methods: A retrospective review was performed, identifying four patients with a confirmed diagnosis of traumatic glaucoma secondary to paintball sports. Results: Four male patients with paintball gun injuries presented with a mean follow-up time of 51 months after the date of injury. The mean age was 23.5 +/- 18.6 years. Three patients presented with blunt trauma, while one patient had a ruptured globe. Presenting visual acuity (VA) was hand motions in three of the patients and no light perception in the fourth patient. All patients were diagnosed with traumatic glaucoma and treated with glaucoma medications during their follow-up. Two patients received tube shunts to control intraocular pressures (IOPs). At the time of most recent follow-up, three patients had elevated IOPs and were not on any medications. VA at the last follow up was 20/400 or worse. Conclusions: Traumatic glaucoma can be managed with surgical and medical interventions, while VA usually does not return to baseline levels prior to the injury. Prognostic predictors can be used to guide treatment and identify patients who should be closely followed. Because the presentation and onset is widely variable, follow-up and screening is crucial even years after the injury. PMID- 29270482 TI - Can acupuncture therapy help patients with retinitis-pigmentosa? AB - Purpose: To evaluate the effect of acupuncture therapy on visual function of patients with retinitis-pigmentosa (RP). Methods: In a prospective study, 23 RP subjects received ten sessions of body-acupuncture. Pre and post-treatment evaluations included best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), near visual acuity (NVA), and static 30-2 perimetry. Results: UCVA, BCVA, and NVA improvements after acupuncture therapy were statistically and clinically significant (P = 0.048, P = 0.0005, P = 0.002, respectively). The changes of mean foveal threshold (MFT) and mean deviation (MD) were statistically significant (P = 0.031, P = 0.02). There were no statistically significant difference between different age group and genders. Subjective symptoms of improvement were seen in most of cases. Conclusion: Future studies are needed to show the effect of acupuncture therapy on visual function of patients with RP. PMID- 29270483 TI - Removal of subfoveal perfluorocarbon liquid: Report of 3 cases. AB - Purpose: To report removal of retained subfoveal perfluorocarbon liquid (PFCL) after vitrectomy for retinal detachment. Methods: Three patients underwent 3-port 23-gauge vitrectomy in an attempt to remove retained subfoveal PFCL bubble secondary to retinal detachment surgery. In two patients, removal was achieved via a 23-G needle whereas the third patient with multiple small subfoveal droplets, multiple punctures were required and in that case a small 40-G needle was used.We assessed best corrected visual acuity (BCVA), fundus imaging, and spectral domain optical coherence tomography (SD-OCT) of all patients before and after surgery. Results: The subfoveal PFCL was successfully removed in all 3 eyes and although a functional improvement was documented, outer retinal atrophy and photoreceptor loss was observed in all our cases. Conclusions: SD-OCT allows early recognition of retained subfoveal PFCL. Surgical removal may lead to retinal morphologic restoration and functional improvement. While we achieved complete removal of PFCL with both 23-G and 40-G instrumentation, we believe the versatility and ease justifies the universal usage of 40-G retinotomy needles. PMID- 29270484 TI - Ocular manifestations in Edward's syndrome, a case report and literature review. AB - Purpose: To report a case with Edward's syndrome and ocular manifestations. Methods: A three-year-old female visited our clinic. The diagnosis of Edward's Syndrome was made prior to the ophthalmic visit based on a karyotype study report. Complete ophthalmic evaluations were done for the patient. Results: On the initial ophthalmic examination, bilateral ptosis, epicanthal folds, and 40 prism diopters alternate esotropia (ET) were seen. In the fundus examination, decreased red reflexes along with retinal folds, pigmentary retinopathy (patches of hyperpigmentation in the fovea and retinal periphery), and optic disc atrophy in both eyes were seen. Conclusion: Our case adds some evidence to the literature that ET may be one of the classic manifestations and anomalies in trisomy 18. PMID- 29270485 TI - Incremental and Once- to Twice-Weekly Hemodialysis: From Experience to Evidence. PMID- 29270487 TI - A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis. AB - Introduction: Steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay end-stage renal disease. Methods: Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti-transforming growth factor-beta antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria. Results: Of 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m2 and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was -18.5% (P = 0.008), +10.5% (P = 0.52), and +9.0% (P = 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252. Discussion: The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power. PMID- 29270486 TI - Novel Therapies for Acute Kidney Injury. AB - Acute kidney injury (AKI) is a common disease with a complex pathophysiology. The old paradigm of identifying renal injury based on location-prerenal, intrarenal, and postrenal-is now being supplanted with a new paradigm based on observable kidney injury patterns. The pathophysiology of AKI on a molecular and microanatomical level includes inflammation, immune dysregulation, oxidative injury, and impaired microcirculation. Treatment has traditionally been supportive, including the avoidance of nephrotoxins, judicious volume and blood pressure management, hemodynamic monitoring, and renal replacement therapy. Fluid overload and chloride-rich fluids are now implicated in the development of AKI, and resuscitation with a balanced, buffered solution at a conservative rate will mitigate risk. Novel therapies, which address specific observable kidney injury patterns include direct oxygen-free radical scavengers such as alpha-lipoic acid, curcumin, sodium-2-mercaptoethane sulphonate, propofol, and selenium. In addition, angiotensin II and adenosine receptor antagonists hope to ameliorate kidney injury via manipulation of renal hemodynamics and tubulo-glomerular feedback. Alkaline phosphatase, sphingosine 1 phosphate analogues, and dipeptidylpeptidase-4 inhibitors counteract kidney injury via manipulation of inflammatory pathways. Finally, genetic modifiers such as 5INP may mitigate AKI via transcriptive processes. PMID- 29270488 TI - Associations of Dietary Protein and Energy Intakes With Protein-Energy Wasting Syndrome in Hemodialysis Patients. AB - Introduction: The associations of dietary protein and/or energy intakes with protein or energy wasting in patients on maintenance hemodialysis are controversial. We examined these in the Hemodialysis (HEMO) Study. Methods: In 1487 participants in the HEMO Study, baseline dietary protein intake (grams per kilogram per day) and dietary energy intake (kilocalories per kilograms per day) were related to the presence of the protein-energy wasting (PEW) syndrome at month 12 (defined as the presence of at least 1 criteria in 2 of the 3 categories of low serum chemistry, low body mass, and low muscle mass) in logistic regression models. In additional separate models, protein intake estimated from equilibrated normalized protein catabolic rate (enPCR) was also related to the PEW syndrome. Results: Compared with the lowest quartile, the highest quartile of baseline dietary protein intake was paradoxically associated with increased risk of the PEW syndrome at month 12 (odds ratio [OR]: 4.11; 95% confidence interval [CI]: 2.79-6.05). This relationship was completely attenuated (OR: 1.35; 95% CI: 0.88-2.06) with adjustment for baseline body weight, which suggested mathematical coupling. Results were similar for dietary energy intake. Compared with the lowest quartile of baseline enPCR, the highest quartile was not associated with the PEW syndrome at 12 months (OR: 0.78; 95% CI: 0.54-1.12). Discussion: These data do not support the use of dietary protein intake or dietary energy intake criteria in the definition of the PEW syndrome in patients on maintenance hemodialysis. PMID- 29270489 TI - Hemodialysis Patients Treated for Hepatitis C Using a Sofosbuvir-based Regimen. AB - Introduction: There is paucity of data on sofosubvir (SOF)-based therapy in patients on maintenance hemodialysis (MHD). The objective of this report is to describe our experience using SOF-based direct antiviral agent (DAA) therapy in MHD patients in India. Methods: All patients on MHD and treated with SOF-based therapy were included in this study. Before starting treatment, viral load, genotype, liver fibroscan, and upper gastrointestinal endoscopy were performed in all patients. SOF 400 mg/d or on an alternate day, ribavirin 200 mg/d and daclatasvir 60 mg/d were used in different regimens. Hepatitis C virus RNA was assessed at day 10 and at 4 weeks, at end of therapy, and at 12 weeks after stopping therapy. Results: A total of 62 treatment-naive patients were included. Mean age was 33.3 +/- 10.2 years; 66% were men. Median number of copies were 106/dl. None had clinical evidence of cirrhosis. The most common genotype was genotype 1 in 64.5% of cases, followed by genotype 3 in 29% of cases. Thirty-nine patients were treated with SOF every other day/ribavirin, 2 patients with SOF daily/ribavirin, 6 with SOF every other day/daclatasvir, and 15 patients with SOF daily/daclatasvir. All patients were treated for 12 weeks. Fifty-nine (95.2%) patients had a sustained viral response (SVR). There was no impact of genotype on SVR. Twenty-three patients (37%) had complications while on therapy; 13 (20.3%) had dyspepsia, 4 had tuberculosis, and 3 had bacterial pneumonia. Most of the patients (n = 23; 56%) in the ribavirin group required an increase in the erythropoietin dose. No patient discontinued therapy due to complications. Discussion: SOF-based DAAs were well tolerated and efficacious in this cohort of patients on MHD. PMID- 29270490 TI - Safety and Tolerability Study of an Intravenously Administered Small Interfering Ribonucleic Acid (siRNA) Post On-Pump Cardiothoracic Surgery in Patients at Risk of Acute Kidney Injury. AB - Introduction: Patients undergoing on-pump cardiac surgery are at an increased risk of acute kidney injury. QPI-1002, a small interfering ribonucleic acid, is under clinical development for the prevention of acute kidney injury. The safety, tolerability, and pharmacokinetics of QPI-1002 was evaluated in this first-in man, Phase 1 study of a small, interfering ribonucleic acid in patients at risk of acute kidney injury after on-pump cardiac surgery. Methods: In this phase 1 randomized, placebo-controlled dose-escalation study, a single i.v. dose of QPI 1002 was administered in subjects undergoing on-pump cardiac surgery. Subjects received placebo (n = 4), or QPI-1002 in increasing doses of 0.5 mg/kg (n = 3), 1.5 mg/kg (n = 3), 5 mg/kg (n = 3), and 10 mg/kg (n = 3). Results: A total of 16 subjects were enrolled in the study. The average maximum concentration and area under the curve from the time of dosing to the last measurable concentration of QPI-1002 were generally dose proportional, indicating that exposure increased with increasing dose. The average mean residence time (mean residence time to the last measurable concentration) was 10 to 13 minutes in all 4 drug-dosing cohorts. Adverse events occurred at a similar rate in all study groups. Of the total 109 reported adverse events, the events were distributed as 26 in the placebo group and 21, 19, 24, and 19 in the QPI-1002 0.5, 1.5, 5.0, and 10.0 mg/kg groups, respectively. Eight of the 16 subjects experienced at least 1 serious adverse event: 4 (100%) in the placebo group and 4 (33.3%) in the combined QPI-1002 cohorts. Discussion: QPI-1002 was rapidly eliminated from plasma. QPI-1002 was safe and well tolerated across all dose groups. Overall, no dose-limiting toxicities or safety signals were observed in the study. Further development of QPI-1002 for prophylaxis of acute kidney injury is warranted. PMID- 29270491 TI - Effect of Thrombotic Microangiopathy on Clinical Outcomes in Indian Patients With Lupus Nephritis. AB - Introduction: In addition to glomerular lesion, renal vascular lesion is also an important prognostic marker of lupus nephritis (LN). Among patients with various vascular changes, individuals with thrombotic microangiopathy (TMA) present with severe clinical manifestations and have a high mortality. The aim of the present study was to assess the spectrum and impact of TMA on the outcomes of LN. In a prospective observational study of 2.5 years' duration, clinical and renal histopathological data regarding biopsy-proven LN were noted, and evaluation for antiphospholipid syndrome (APS) as a cause of TMA in LN was also carried out. Methods: Study subjects were followed up actively for 6 months, and various outcomes were noted. Cases were divided into 2 groups as LN with TMA and LN without TMA, and various features were compared between the 2 groups. Outcomes recorded were complete response (CR), partial response (PR), treatment failure, and death. Results: Of the 197 patients with LN, 50 patients (25.4%) were diagnosed with co-existing renal TMA. Five patients (10%) were found to have concomitant APS. As compared to patients without TMA, those with TMA had significantly higher rates of oliguria (P = 0.035), advanced renal injury, that is, serum creatinine > 3mg/dl (P = 0.002), fibrocellular and fibrous crescents (P = 0.01), and tubular atrophy (P = 0.001). Outcomes included CR in 15 patients (30%), PR in 10 (20%), failure in 19 (38%), and death in 6 (12%). Patients with LN with TMA had higher rates of treatment failure (P = 0.02) compared to the group without TMA. Discussion: The presence of TMA in patients with LN is associated with adverse clinicopathological presentation and poor outcome. PMID- 29270492 TI - Natural History and Genotype-Phenotype Correlation in Female X-Linked Alport Syndrome. AB - Introduction: X-linked Alport syndrome (XLAS) is a hereditary disease characterized by progressive nephritis, hearing loss, and ocular abnormalities. Affected male patients usually progress to end-stage renal disease in early or middle adulthood, and disease severity is strongly correlated with genotype. However, the clinical course in female patients has rarely been reported. Methods: We conducted a retrospective analysis of females with genetically proven XLAS (n = 275) and their affected female family members (n = 61) from 179 Japanese families. Patients suspected to have Alport syndrome from pathologic findings or a family history who were referred from anywhere in Japan for genetic diagnosis between 2006-2015 were included in this study. Clinical and laboratory data were collected from medical records at the time of registration for genetic analysis. Results: Proteinuria was detected in 175 genetically proven patients (72.6%), and the median age for developing proteinuria was 7.0 years. Fifty-two of 336 patients developed end-stage renal disease with a median renal survival age of 65.0 years. No obvious genotype-phenotype correlation was observed. Additionally, targeted sequencing for podocyte-related genes in patients with severe phenotypes revealed no obvious variants considered to be modifier genes except for 1 patient with a COL4A3 gene variant. Discussion: This study revealed that phenotypes in female XLAS patients may be severe, but genotype does not help to predict the disease severity. Clinicians must therefore pay careful attention to the clinical course and appropriate treatment in females with XLAS. PMID- 29270494 TI - The Association of Daily Activity Levels and Estimated Kidney Function in Men and Women With Predialysis Chronic Kidney Disease. AB - Introduction: Chronic kidney disease (CKD) is often accompanied by complications including poor physical activity level. However, only a few studies have objectively characterized physical activity levels in predialysis CKD. Our study sought to measure daily activity levels by accelerometry in individuals with CKD (stages III-V) and to determine the association between daily activity and kidney function. Methods: We determined kidney function by means of the estimated glomerular filtration rate (eGFR) using the Modification of Diet and Renal Disease (MDRD) equation. Participants wore an accelerometer for 7 consecutive days, and we measured multiple physical activity outcomes including total daily activity, sedentary, light, and moderate-vigorous activity. Average durations and intensity of activity were determined according to stage of CKD. The association between kidney function and activity level was determined by regression analysis. Results: We analyzed data from 110 individuals (60% men and 40% women) with stages III to V CKD. The mean age of our participants was 64 years, mean body mass index was 27.5 kg/m2, and mean eGFR was 23.7 +/- 1.2 ml/min/1.73 m2. Our participants were primarily sedentary (mean duration of inactivity = 1152 +/- 100 minutes per day; 79% of day). Light activity was performed 280 +/- 99 minutes per day, and individuals participated in only 6 +/- 9 minutes per day of moderate vigorous activity. The eGFR did not predict physical activity level (P > 0.05 for all). Discussion: Individuals with stages III to V CKD are sedentary, and do not meet the national recommendations of 150 minutes of moderate-vigorous activity per week. Further study is required to determine whether interventions to increase activity levels in patients with CKD are associated with improved health outcomes. PMID- 29270493 TI - Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection-A Proof-of-Concept Study. AB - Introduction: Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD. Methods: Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of >=11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN. Results: At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (-12.2 bursts/min1, 95% CI [-13.6, -10.7]) and LV mass (-27 g/m2, 95% CI [-47, -8]) were reduced. Mean ambulatory BP (systolic: -24 mm Hg, 95% CI [-42, -5] and diastolic: -13 mm Hg, 95% CI [-22, -4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: -25 mm Hg, 95% CI [-45, -5] and diastolic: -13 mm Hg, 95% CI [-24, -1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months. Discussion: Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD. PMID- 29270495 TI - The Association Between Fibroblast Growth Factor 23 and Renal Transplantation Outcome Is Modified by Follow-up Duration and Glomerular Filtration Rate Assessment Method. AB - Introduction: Fibroblast growth factor 23 (FGF23) could contribute to cardiovascular morbidity in chronic kidney disease. In studies of kidney transplant recipients, a high circulating level of FGF23 has been associated with death and graft loss independently of estimated glomerular filtration rate (GFR). Whether FGF23 is associated with adverse outcomes in the early posttransplantation period is unknown. Methods: We analyzed a cohort of 845 kidney transplant recipients in stable condition who had GFR measured in the first years after transplantation with a median follow-up of 71 months. Results: A high FGF23 concentration was associated with death or graft loss in univariate analysis, but this association was lost after adjustment for measured GFR. In contrast, FGF23 remained significantly associated with the composite outcome when estimated GFR was substituted for measured GFR. We also observed that follow-up duration modified the association between FGF23 and outcome. Although FGF23 was not associated with any endpoint in the full duration of the study, we found an independent association between FGF23 and the incidence of graft loss within the 4 years after FGF23 measurement. We did not find an association between FGF23 levels and left ventricular mass in a subgroup of 227 patients who had echocardiography performed within 3 months of FGF23 measurement. Discussion: This study demonstrates that FGF23 measured during the first year after transplantation is not an independent predictor of death and graft loss and is not associated with left ventricular hypertrophy in the posttransplantation period. It further unveils important factors modifying the association between FGF23 and outcome in this population. PMID- 29270496 TI - Lupus Nephritis in Males: Clinical Features, Course, and Prognostic Factors for End-Stage Renal Disease. AB - Introduction: Because of their rarity in men, systemic lupus erythematous and lupus nephritis (LN) are poorly understood in men. Our aim was to analyze the clinical presentation and course of histology-proven systemic lupus erythematous and LN in males and to determine the risk factors for progression to end-stage renal disease. Methods: Fifty patients from 2 historical cohorts in Spain (Hospital 12 de Octubre) and Uruguay were retrospectively analyzed and compared with a female cohort matched for age and disease characteristics. Results: The median age at the time of renal biopsy was 27 years (range, 8-79 years). The main forms of presentation were nephrotic syndrome in 26 of 50 patients (52%), and class IV LN in 34 of 50 (68%). After treatment, 21 patients (45.6%) achieved complete renal remission. During follow-up, 12 patients required renal replacement therapy, and 3 patients died of infectious causes. When patients who required renal replacement therapy were compared with those who did not require it, several parameters showed significant differences (P < 0.05) at the time of renal biopsy: estimated glomerular filtration rate < 60 ml/min, hypertension, hypoalbuminemia, and concomitant visceral involvement (neurologic, cardiovascular, and/or pulmonary). In the multivariate analysis, only estimated glomerular filtration rate < 60 ml/min persisted as a risk factor for progression to end-stage renal disease. When compared with a cohort of female patients with LN, there were no significant differences in remission or renal survival. Discussion: LN in males usually presents as nephrotic syndrome, and type IV LN is the most frequent form. An estimated glomerular filtration rate < 60 ml/min at the time of renal biopsy is associated with poor renal outcomes. There were no differences in remission or progression of LN in males when compared with a cohort of female patients with LN. PMID- 29270498 TI - Safety and Efficacy of Combination ACTHar Gel and Tacrolimus in Treatment Resistant Focal Segmental Glomerulosclerosis and Membranous Glomerulopathy. AB - Introduction: H.P. ACTHar gel is a preparation of melanocortin peptides that has been used to treat resistant forms of nephrotic syndrome. To determine whether combination therapy with ACTHar gel and tacrolimus reduces proteinuria and stabilizes renal function, we conducted a prospective, open-label trial in patients with treatment-resistant membranous glomerulopathy (MGN) and focal segmental glomerulosclerosis (FSGS). Methods: Nine patients with treatment resistant MGN and 13 with treatment-resistant FSGS received subcutaneous ACTHar gel for 6 months. Patients with no response or a partial response to ACTHar gel alone received an additional 6 months of therapy with combination ACTHar gel and oral tacrolimus. The study endpoint was the percentage of patients achieving a complete or partial remission after 6 months of combination therapy. Results: Among patients with MGN, treatment with ACTHar gel alone achieved a partial remission in 44% and no response in 56% of patients. No patient achieved a complete response with ACTHar gel therapy alone. An additional 6 months of combination therapy with ACTHar gel and tacrolimus resulted in partial and complete response rates of 25% and 75%, respectively. Among patients with FSGS, ACTHar gel therapy alone resulted in complete and partial response rate of 7.7% and 62.0%. Combination therapy increased complete response rates to 17% and partial responses to 66%. Proteinuria (urinary protein-to-creatinine ratio) was significantly reduced in both patients with MGN and those with FSGS after 6 months of ACTHar gel alone and was further reduced among the patients with MGN with the addition of tacrolimus. There were no significant changes in estimated glomerular filtration rate during the treatment phase or long-term follow-up. Discussion: Combination therapy with ACTHar gel and tacrolimus was well tolerated by patients with treatment-resistant MGN and FSGS and significantly reduced proteinuria and improved clinical response rates compared with ACTHar gel alone. PMID- 29270497 TI - Autosomal Dominant Polycystic Kidney Patients May Be Predisposed to Various Cardiomyopathies. AB - Introduction: Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Experimental evidence suggests an important role of the polycystins in cardiac development and myocardial function. To determine whether ADPKD may predispose to the development of cardiomyopathy, we have evaluated the coexistence of diagnoses of ADPKD and primary cardiomyopathy in our patients. Methods: Clinical data were retrieved from medical records for patients with a coexisting diagnosis of ADPKD and cardiomyopathies evaluated at the Mayo Clinic (1984-2015). Results: Among the 58 of 667 patients with available echocardiography data, 39 (5.8%) had idiopathic dilated cardiomyopathy (IDCM), 17 (2.5%) had hypertrophic obstructive cardiomyopathy, and 2 (0.3%) had left ventricular noncompaction. Genetic data were available for 19, 8, and 2 cases of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction, respectively. PKD1 mutations were detected in 42.1%, 62.5%, and 100% of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction cases, respectively. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (15%). In at least 1 patient from 3 IDMC families and 1 patient from a hypertrophic obstructive cardiomyopathy family, the cardiomyopathy did not segregate with ADPKD, suggesting that the PKD mutations may be predisposing factors rather than solely responsible for the development of cardiomyopathy. Discussion: Coexistence of ADPKD and cardiomyopathy in our tertiary referral center cohort appears to be higher than expected by chance. We suggest that PKD1 and PKD2 mutations may predispose to primary cardiomyopathies and that genetic interactions may account for the observed coexistence of ADPKD and cardiomyopathies. PMID- 29270499 TI - Feasibility of Incremental 2-Times Weekly Hemodialysis in Incident Patients With Residual Kidney Function. AB - Introduction: We hypothesized that at least half of incident hemodialysis (HD) patients on 3-times weekly dialysis could safely start on an incremental, 2-times weekly HD schedule if residual kidney function (RKF) had been considered. Methods: RKF is assessed in all our HD patients. This single-center, retrospective cohort study of incident adult HD patients, who survived >=6 months on a 3-times weekly HD regimen and had a timed urine collection within 3 months of starting HD, assessed each patient's theoretical ability to achieve adequate urea clearance, ultrafiltration rate, and hemodynamic stability if on 2-times weekly HD. Results: Of the 410 patients in the cohort, we found that 112 (27%) could have optimally and 107 (26%) could have been appropriately considered for 2 times weekly incremental HD. In general, diuretics were underutilized in >50% of subjects who had adequate RKF urea clearance. The optimal 2-times weekly patients had better potassium and phosphorus control. The correlation coefficient of calculated residual kidney urea clearance with 24-hour urine volume and with kinetic model residual kidney clearance was 0.68 and 0.99, respectively. Discussion: More than 50% of incident HD patients with RKF have adequate kidney urea clearance to be considered for 2-times weekly HD. When additionally ultrafiltration volume and blood pressure stability are taken into account, more than one-fourth of the total cohort could optimally start HD in an incremental fashion. PMID- 29270500 TI - Optimizing Automated Peritoneal Dialysis Using an Extended 3-Pore Model. AB - Introduction: In the current study, an extended 3-pore model (TPM) is presented and applied to the problem of optimizing automated peritoneal dialysis (APD) with regard to osmotic water transport (UF), small/middle-molecule clearance, and glucose absorption. Methods: Simulations were performed for either intermittent APD (IPD) or tidal APD (TPD). IPD was simulated for fill and drain volumes of 2 L, whereas TPD was simulated using a tidal volume of 0.5 L, 1 L, or 1.5 L with full drains and subsequent fills (2 L) occurring after every fifth dwell. A total of 25 cycles for a large number of different dialysate flow rates (DFR) were simulated using 3 different glucose concentrations (1.36%, 2.27%, and 3.86%) and 3 different peritoneal transport types: slow (peritoneal equilibrium test D/Pcrea < 0.6), fast (peritoneal equilibrium test D/Pcrea > 0.8), and average. Solute clearance and UF were simulated to occur during the entire dwell, including both fill and drain periods. Results: It is demonstrated that DFRs exceeding ~ 3 L/h are of little benefit both for UF and small-solute transport, whereas middle molecule clearance is enhanced at higher DFRs. The simulations predict that large reductions (> 20%) in glucose absorption are possible by using moderately higher DFRs than a standard 6 * 2 L prescription and by using shorter optimized "bi modal" APD regimens that alternate between a glucose-free solution and a glucose containing solution. Discussion: Reductions in glucose absorption appear to be significant with the proposed regimens for APD; however, further research is needed to assess the feasibility and safety of these regimens. PMID- 29270502 TI - Renal Involvement in Methylmalonic Aciduria. PMID- 29270503 TI - The Effect of War on Syrian Refugees With End-Stage Renal Disease. PMID- 29270501 TI - Agitated Saline Bubble-Enhanced Ultrasound for Assessing Appropriate Position of Hemodialysis Central Venous Catheter in Critically Ill Patients. PMID- 29270504 TI - United States Dialysis Facilities With a Racial Disparity in Kidney Transplant Waitlisting. PMID- 29270505 TI - A Case of Fibronectin Glomerulopathy Caused by Missense Mutations in the Fibronectin 1 Gene. PMID- 29270506 TI - A Case of a "Voiding" Hypertension. PMID- 29270507 TI - Immunotactoid Glomerulopathy of 10-Years' Duration: Insights Gained From Sequential Biopsies. PMID- 29270508 TI - Three Cases of Hemodialysis Patients Receiving High-Dose Ceftriaxone: Serum Concentrations and Its Neurotoxicity. PMID- 29270509 TI - Ischemic Stroke of Possible Embolic Etiology Associated With Nephrotic Syndrome. PMID- 29270510 TI - Iron Overload in Dialysis Patients: Rust or Bust? PMID- 29270512 TI - Chronic Kidney Disease in Panama: Results From the PREFREC Study and National Mortality Trends. AB - Introduction: The magnitude of chronic kidney disease (CKD) in Panama has yet to be described. We investigated the association between sociodemographic and cardiovascular exposures with CKD in 2 Panamanian provinces. Further, we analyzed national trends of CKD mortality from 2001 to 2014. Methods: Data were derived from Prevalencia de Factores de Riesgo de Enfermedad Cardiovascular (PREFREC [Survey on Risk Factors Associated With Cardiovascular Disease]), a cross sectional study designed to analyze the prevalence of risk factors associated with cardiovascular disease. Biomarkers of kidney function were measured in 3590 participants. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2 and/or albuminuria >=30 mg/g creatinine. Odds ratios (ORs) with 95% confidence intervals (CIs) for CKD were calculated using logistic regression. We calculated age-standardized CKD mortality rates in the country using the National Mortality Register. Annual percentage change and 95% CIs were estimated to evaluate the trends over time. Results: The prevalence of CKD was 12% (reduced eGFR: 3.3%; albuminuria; 9.9%). CKD was associated with hypertension (OR: 1.8; 95% CI: 1.2-2.7), age 60 years or older (OR: 1.9; 95% CI: 1.2-2.9), and previous myocardial infarction (OR: 2.4; 95% CI: 1.0-5.7), whereas monthly family income was inversely associated with CKD (OR: 0.4; 95% CI: 0.1-0.9) (adjusted). A sustained increase in the trend of CKD mortality was observed from 2001 to 2006, followed by a decreasing trend in subsequent years. Cocle province had the highest adjusted mortality rate. Discussion: CKD poses a significant health problem for Panama. Health inequalities and an increase of cardiometabolic risk factors warrant robust epidemiological surveillance, improved diagnosis, and treatment. Further national studies aimed to address geographical disparities are necessary. PMID- 29270511 TI - Occupational Heat Stress and Kidney Health: From Farms to Factories. AB - Millions of workers around the world are exposed to high temperatures, intense physical activity, and lax labor practices that do not allow for sufficient rehydration breaks. The extent and consequences of heat exposure in different occupational settings, countries, and cultural contexts is not well studied. We conducted an in-depth review to examine the known effects of occupational heat stress on the kidney. We also examined methods of heat-stress assessment, strategies for prevention and mitigation, and the economic consequences of occupational heat stress. Our descriptive review summarizes emerging evidence that extreme occupational heat stress combined with chronic dehydration may contribute to the development of CKD and ultimately kidney failure. Rising global temperatures, coupled with decreasing access to clean drinking water, may exacerbate the effects of heat exposure in both outdoor and indoor workers who are exposed to chronic heat stress and recurrent dehydration. These changes create an urgent need for health researchers and industry to identify work practices that contribute to heat-stress nephropathy, and to test targeted, robust prevention and mitigation strategies. Preventing occupational heat stress presents a great challenge for a concerted multidisciplinary effort from employers, health authorities, engineers, researchers, and governments. PMID- 29270513 TI - Urinary Stone Disease and Cardiovascular Disease Risk in a Rural Chinese Population. AB - Introduction: Urinary stone disease (USD) is associated with cardiovascular disease (CVD) in Western populations. However, the prevalence and relationship between USD and CVD risk have not been fully examined in the Chinese population. Methods: We performed a cross-sectional study of 10,281 participants in rural China. All subjects underwent renal ultrasound to detect USD, brachial-ankle pulsewave velocity (baPWV) measurement to estimate arterial stiffness, and ankle brachial index (ABI) examination to detect peripheral arterial disease (PAD) (defined as ABI <0.9 on at least 1 side of the body). Results: Mean age of the study population was 55.4 +/- 10.0 years; 47.1% were men. Among all participants, 5.7% (n = 582) had USD, mean baPWV was 15.6 +/- 3.2 m/s, and 4.0% had PAD. The prevalence of USD increased in parallel with mean arterial pressure, albuminuria, Framingham risk score, and baPWV. In multivariate analyses after adjustment for demographic characteristics, USD was significantly associated with an increased risk of hypertension (odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.08 1.62), albuminuria (OR: 2.17; 95% CI: 1.74-2.69), chronic kidney disease (OR: 2.11; 95% CI: 1.70-2.62), increased arterial stiffness (OR: 1.24; 95% CI: 1.01 1.52), and PAD (OR: 1.50; 95% CI: 1.04-2.16). Discussion: In rural China, USD was associated with a high prevalence of traditional CVD risk factors, increased arterial stiffness, and PAD. The presence of USD should increase physician awareness of the concomitant presence of CVD risk factors. PMID- 29270514 TI - Impact of Regular or Extended Hemodialysis and Hemodialfiltration on Plasma Oxalate Concentrations in Patients With End-Stage Renal Disease. AB - Introduction: Calcium oxalate supersaturation is regularly exceeded in the plasma of patients with end-stage renal disease (ESRD). Previous reports have indicated that hemodialfiltration (HDF) lowers elevated plasma oxalate (POx) concentrations more effectively compared with hemodialysis (HD). We reevaluate the therapeutic strategy for optimized POx reduction with advanced dialysis equipment and provide data on the effect of extended treatment time on dialytic oxalate kinetics. Methods: Fourteen patients with ESRD who underwent HDF 3 times a week for 4 to 4.5 hours (regular HDF; n = 8) or 7 to 7.5 hours (extended HDF; n = 6) were changed to HD for 2 weeks and then back to HDF for another 2 weeks. POx was measured at baseline, pre-, mid-, and postdialysis, and 2 hours after completion of the treatment session. Results: Baseline POx for all patients averaged 28.0 +/ 7.0 MUmol/l. Intradialytic POx reduction was approximately 90% and was not significantly different between groups or treatment modes [F(1) = 0.63; P = 0.44]. Mean postdialysis POx concentrations were 3.3 +/- 1.8 MUmol/l. A rebound of 2.1 +/- 1.9 MUmol/l was observed within 2 hours after dialysis. After receiving 2 weeks of the respective treatment, predialysis POx concentrations on HD did not differ significantly from those on HDF [F(1) = 0.21; P = 0.66]. Extended treatment time did not provide any added benefit [F(1) = 0.76; P = 0.40]. Discussion: In contrast to earlier observations, our data did not support a benefit of HDF over HD for POx reduction. With new technologies evolving, our results emphasized the need to carefully reevaluate and update traditional therapeutic regimens for optimized uremic toxin removal, including those used for oxalate. PMID- 29270515 TI - Right Ventricular Function, Peripheral Edema, and Acute Kidney Injury in Critical Illness. AB - Introduction: The cardiorenal syndrome generally focuses on left ventricular function, and the importance of the right ventricle as a determinant of renal function is described less frequently. In a cohort of critically ill patients with echocardiographic measurements obtained within 24 hours of admission to the intensive care unit, we examined the association of right ventricular function with acute kidney injury (AKI) and AKI-associated mortality. We also examined whether clinical measurement of volume overload modified the association between ventricular function and AKI in a subpopulation with documented admission physical examinations. Methods: Among 1879 critically ill patients with echocardiographic ventricular measurements, 43% (n = 807) had ventricular dysfunction-21% (n = 388), 9% (n = 167), and 13% (n = 252) with isolated left ventricular dysfunction, isolated right ventricular dysfunction, and biventricular dysfunction, respectively. Overall, ventricular dysfunction was associated with a 43% higher adjusted risk of AKI (95% confidence interval [CI] 1.14-1.80; P = 0.002) compared with those with normal biventricular function, whereas isolated left ventricular dysfunction, isolated right ventricular dysfunction, and biventricular dysfunction were associated with a 1.34 (95% CI 1.00-1.77, P = 0.05), 1.35 (95% CI 0.90-2.10, P = 0.14) and 1.67 (95% CI 1.23 2.31, P = 0.002) higher adjusted risk. Although an episode of AKI was associated with an approximately 2-fold greater risk of hospital mortality in those with isolated left ventricular dysfunction and biventricular dysfunction, in those with isolated right ventricular dysfunction, AKI was associated with a 7.85-fold greater risk of death (95% CI 2.89-21.3, P < 0.001). Independent of ventricular function, peripheral edema was an important determinant of AKI. Discussion: Like left ventricular function, right ventricular function is an important determinant of AKI and AKI-associated mortality. Volume overload, independently of ventricular function, is a risk factor for AKI. Whether establishment of euvolemia might mitigate AKI risk will require further study. PMID- 29270516 TI - Higher Pretransplantation Hemoglobin A1c Is Associated With Greater Risk of Posttransplant Diabetes Mellitus. AB - Introduction: Posttransplantation diabetes mellitus (PTDM) is a common complication among kidney transplant recipients and is associated with a higher risk of cardiovascular events and poorer graft and patient survival. The association of pretransplantation hemoglobin A1c (HbA1c) with PTDM remains unclear. Identifying recipients at greatest risk for PTDM may help guide monitoring and treatment strategies to prevent or delay the onset of PTDM. Methods: We analyzed data from 1499 nondiabetic primary kidney transplant recipients with available pretransplantation HbA1c values in the United States Renal Data System (USRDS) from 2005 to 2011. Recipients with pretransplantation diabetes diagnosis or HbA1c >= 6.5% were excluded. We assessed the association of pretransplantation HbA1c with PTDM using Cox proportional hazards models. Pretransplantation HbA1c level as a continuous variable was modeled using restricted cubic splines with knots at the 25th, 50th, and 75th percentiles. Based on results from this model, pretransplantation HbA1c was further modeled using a linear spline with a single knot at 5.4%. Results: A total of 395 recipients (26.4%) developed PTDM over a median follow-up of 1.8 years. Pretransplantation HbA1c was not significantly associated with risk of PTDM below 5.4%, whereas each 1% higher HbA1c above 5.4% was associated with an adjusted hazard ratio of 1.84 (95% confidence interval = 1.28, 2.66; P for change in slope = 0.04). Discussion: Higher pretransplantation HbA1c above 5.4% is independently associated with greater risk of PTDM among kidney transplant recipients. A continuous relationship between pretransplantation HbA1c and risk of PTDM suggests that increased risk starts at HbA1c levels well below current thresholds for prediabetes. PMID- 29270517 TI - Long-term Kidney Outcomes in Patients With Acquired Thrombotic Thrombocytopenic Purpura. AB - Introduction: Severe acute kidney injury (AKI) and chronic kidney disease (CKD) are considered to be uncommon in patients with acquired thrombotic thrombocytopenic purpura. However, a recent case series from a tertiary care hospital indicated that 54 (59%) of 92 patients with thrombotic thrombocytopenic purpura presented with AKI; 14 (15%) required dialysis; and 12 (22%) of the 54 patients had CKD at follow-up. Methods: In this prospective analysis of 78 patients diagnosed with their first episode of thrombotic thrombocytopenic purpura and enrolled in the Oklahoma Thrombotic Thrombocytopenic Purpura Registry from 1995 to 2015, we assessed AKI at diagnosis using Kidney Disease: Improving Global Outcomes criteria, and CKD at follow-up as defined by estimated glomerular filtration rate <60 ml/min per 1.73 m2 determined by the Chronic Kidney Disease Epidemiology Collaboration equation. Results: Forty-five (58%) patients had AKI; 8 (10%) had stage 3 AKI, and 3 (4%) required dialysis. AKI was not associated with the patients' demographic or presenting clinical features. Three of the 8 patients with stage 3 AKI died; among the 5 survivors, estimated glomerular filtration rate was 77 to 107 ml/min per 1.73 m2 (median, 92) with median follow up of 8.1 years. Among all 62 surviving patients who have had follow-up serum creatinine measurements, 4 (6%) had CKD with median follow-up of 6.4 years. AKI was not associated with the occurrence of CKD (P = 0.74). No patients have required continuing renal replacement therapy. Discussion: In this population based prospective cohort of consecutive patients with thrombotic thrombocytopenic purpura, without selection or referral bias, severe AKI and CKD are uncommon. PMID- 29270518 TI - Exercise Training in Elderly People Undergoing Hemodialysis: A Systematic Review and Meta-analysis. AB - Introduction: Previous reviews have indicated the effectiveness of exercise in people undergoing hemodialysis. However, these analyses did not take into account whether the subjects were elderly. We performed a systematic review of the effects of exercise training in elderly people undergoing hemodialysis and updated the evidence of exercise for people undergoing hemodialysis by adding recent research data. Methods: We searched 8 electronic databases up to June 2016. Inclusion criteria were as follows: randomized controlled trial, English publication, subjects aged 18 and older undergoing hemodialysis, evaluation of physical function as an outcome of exercise intervention. We defined elderly as age 60 years and older. The main outcomes were exercise tolerance (peak/maximum oxygen consumption) and walking ability (6-minute walk distance). Secondary outcomes were lower extremity muscle strength and quality of life. Results: After screening of 10,923 references, 30 comparisons were entered into the analysis. However, because we found only 1 study in which elderly subjects were treated, we could not perform a meta-analysis for these people. For the general population undergoing hemodialysis, supervised exercise training was shown to significantly increase peak/maximum oxygen consumption (standard mean difference, 0.62; 95% confidence interval 0.38-0.87; P < 0.001), 6-minute walk distance (standard mean difference, 0.58; 95% confidence interval 0.24-0.93; P < 0.001), lower extremity muscle strength (standard mean difference, 0.94; 95% confidence interval 0.67 1.21; P < 0.001), and quality of life (standard mean difference, 0.53; 95% confidence interval 0.52-0.82; P < 0.001). Discussion: Our analysis on the effectiveness of exercise training in elderly people undergoing hemodialysis as compared with nonelderly people was somewhat inconclusive. Future studies should be carried out for elderly people to identify the most favorable exercise program for this population. PMID- 29270520 TI - Serum Potassium Levels and Risk of Sudden Cardiac Death Among Patients With Chronic Kidney Disease and Significant Coronary Artery Disease. AB - Introduction: Chronic kidney disease (CKD) patients have increased risks of sudden cardiac arrest and sudden cardiac death (SCA/SCD) that are not explained by traditional risk factors. We examined associations between serum potassium and SCA/SCD in a large cohort of patients with coronary artery disease (CAD) and moderate CKD. Methods: Among 22,009 patients who underwent cardiac catheterization at our institution between 1999 and 2011, 6181 patients had an estimated glomerular filtration rate of <=60 ml/min per 1.73 m2 and were not receiving renal replacement therapy. The risk of SCA/SCD and all-cause mortality associated with potassium concentration was evaluated at the time of cardiac catheterization (baseline) and most proximate to SCA/SCD events. Covariate adjusted Cox models were used to examine relationships between baseline potassium measurements and outcomes. A propensity score-matched, case-control design was used to assess risk associations of potassium measurements obtained proximate to SCA events. Results: In the baseline potassium analysis, compared with levels in the normal range, there was no significant risk association between hyperkalemia (>5 mEq/l) or hypokalemia (<3.5 mEq/l) and SCA/SCD or all-cause death after covariate adjustment. In the proximate potassium analysis, hyperkalemia occurred more frequently than hypokalemia (16.7% vs. 3%), and was associated with a doubling in SCA/SCD risk (adjusted odd ratio: 2.37; 95% confidence interval: 1.33 4.23) whereas there was no significant relationship between hypokalemia and outcome. Discussion: Among CKD patients with significant CAD, elevated serum potassium levels >5.0 mEq/l are common and are associated with an increased short term risk of SCA/SCD. Early detection and treatment of hyperkalemia may reduce the high risk of SCD among CKD patients. PMID- 29270519 TI - Polymorphisms in Renal Ammonia Metabolism Genes Correlate With 24-Hour Urine pH. AB - Introduction: Urine pH is critical for net acid and solute excretion, but the genetic factors that contribute to its regulation are incompletely understood. Methods: We tested the association of single nucleotide polymorphisms (SNPs) from 16 genes related to ammonia (NH3) metabolism (15 biological candidates selected a priori, 1 selected from a previous genome-wide association study analysis) to that of 24-hour urine pH in 2493 individuals of European descent across 2 different cohorts using linear regression, adjusting for age, sex, and body mass index. Results: Of 2871 total SNPs in these genes, 13 SNPs in ATP6V0A4 (a4 subunit of hydrogen- adenosine triphosphatase), SLC9A3 (sodium/hydrogen exchanger, isoform 3), and RHCG (Rhesus C glycoprotein), and 12 SNPs from insulin like growth factor binding protein 7 (IGFBP7) had a meta-analysis P value <0.01 in the joint analysis plus a consistent direction of effect and at a least suggestive association (P < 0.1) in both cohorts. The maximal effect size (in pH units) for each additional minor allele of the identified SNPs was -0.13 for IGFBP7, -0.08 for ATP6V0A4, 0.06 for RHCG, and -0.06 for SLC9A3; SNP rs34447434 in IGFBP7 had the lowest meta-analysis P value (P = 7.1 * 10-8). After adjusting for net alkali absorption, urine pH remained suggestively associated with multiple SNPs in IGFBP, 1 SNP in ATP6V0A4, and a new SNP in GLS (phosphate dependent glutaminase). Discussion: Overall, these findings suggest that variants in common genes involved in ammonia metabolism may substantively contribute to basal urine pH regulation. These variations might influence the likelihood of developing disease conditions associated with altered urine pH, such as uric acid or calcium phosphate kidney stones. PMID- 29270521 TI - Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4. AB - Introduction: In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. Methods: A post hoc analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. Results: In total, 750 of 961 tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. Discussion: In this study, AAEs were common but well tolerated in ADPKD patients on tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding tolvaptan dosing and titration decisions in the future. PMID- 29270522 TI - Membranous Glomerulopathy With Light Chain-Restricted Deposits: A Clinicopathological Analysis of 28 Cases. AB - Introduction: Membranous glomerulopathy (MG) is a common cause of nephrotic syndrome that results from the formation of immune complexes along the subepithelial aspect of the glomerular basement membranes. Although it is most frequently caused by polytypic deposits, cases with light chain isotype restricted deposits are rarely seen. Methods: We conducted a retrospective analysis of 28 cases of MG that showed light chain isotype restriction. Results: The mean age at diagnosis was 62.2 years and the male-to-female ratio was 1. All patients presented with proteinuria (73.1% nephrotic range), and the mean serum creatinine was 1.5 mg/dl. Six patients had an underlying lymphoproliferative disorder (LPD), 2 had autoimmune disease, and 1 patient was positive for both hepatitis B and syphilis. Only 1 of the patients with an LPD had a detectable monoclonal Ig. Four patients (14.3%) showed focal proliferation or crescents, 3 of whom had an underlying LPD. Kappa (kappa) restriction was seen in 26 of 28 patients (85.7%). Staining for IgG subclasses was performed in 19 cases, 14 of which showed positive staining for a single subclass. PLA2R was positive in 7 of 27 cases. 30% of PLA2R-negative patients and 28.6% of those with positive staining for a single IgG subclass had an associated LPD. Discussion: The majority of MG cases with light chain isotype-restricted deposits lack a recognizable secondary etiology. However, the absence of PLA2R positivity, positive staining for a single IgG subclass, and presence of focal proliferation are worrisome histopathologic features that should prompt a thorough clinical workup to exclude the presence of an underlying LPD. PMID- 29270523 TI - Association of Arterial Stiffness and Central Pressure With Cognitive Function in Incident Hemodialysis Patients: The PACE Study. AB - Introduction: Cognitive impairment commonly occurs in hemodialysis patients, with vascular disease potentially implicated in its pathogenesis. However, the relationship of detailed vascular assessment with cognitive function in patients new to hemodialysis has not been demonstrated. Methods: In a prospective study of incident hemodialysis participants enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD (PACE) study, we determined aortic stiffness by pulse wave velocity (PWV), systemic arterial stiffness by the augmentation index (AIx) and central pulse pressure (cPP), and examined their associations with cognitive processing speed, executive function, and global cognitive impairment measured by the Trail making test A (TMTA), Trail making test B (TMTB), and the modified Mini Mental State Exam (3MS). Results: Mean baseline age was 55 +/- 13 years, 58% were male, 72% were African American, 35% had coronary artery disease, 55% had diabetes, and 10% had cognitive impairment. At baseline, higher PWV and cPP were associated with a longer TMTA, and a higher PWV was associated with a longer TMTB, but the associations were attenuated after multivariable adjustment. At 1 year, PWV was not independently associated with TMTA, TMTB, or 3MS. However, unadjusted and adjusted analyses revealed every 10% increase in AIx and 10 mm Hg increase in cPP were associated with longer TMTB (time differenceAIx: 0.14; 95% confidence interval [CI]: 0.02-0.25 log-seconds; time differencecPP: 0.11; 95% CI: 0.05-0.17 log-seconds) and global cognitive impairment (odds ratio [OR]AIx: 10.23; 95% CI: 1.77-59.00; ORcPP: 2.88; 95% CI: 1.48-5.59). Discussion: Higher AIx and cPP, which are indicative of abnormal wave reflections in distal vessels, are associated with, and might contribute to, declining cognitive function in patients starting hemodialysis. PMID- 29270524 TI - Associations Between Low Serum Testosterone and All-Cause Mortality and Infection Related Hospitalization in Male Hemodialysis Patients: A Prospective Cohort Study. AB - Introduction: Infectious diseases are the second highest cause of death in patients on dialysis. In addition, testosterone deficiency or hypogonadism is prevalent in dialysis patients. However, to our knowledge, no studies have investigated the association between testosterone levels and infectious events. We aimed to evaluate whether serum testosterone levels are associated with infection-related hospitalization in male hemodialysis patients in a prospective cohort study. Methods: We divided the study population into 3 groups based on serum testosterone levels. Associations between testosterone levels and clinical outcomes of infection-related hospitalization, all-cause mortality, and cardiovascular disease (CVD) events were analyzed using the Cox proportional hazard model. Results: Nine hundred two male patients were enrolled and followed up for a median of 24.7 months. Their mean +/- SD age was 63.4 +/- 11.8 years, and their median (interquartile range) of total testosterone was 11.7 nmol/l (7.9 14.9 nmol/l). During follow-up, 123 participants died. Infection-related hospitalization and CVD events occurred in 116 and 151 patients, respectively. Infection-related hospitalization was more frequent in the lower testosterone tertile than in the higher testosterone tertile (hazard ratio [HR]: 2.12; 95% confidence interval [CI]: 1.18-3.79; P = 0.01) in adjusted models. Moreover, all cause mortality was significantly greater in the lower testosterone tertile than in the higher testosterone tertile in adjusted analysis (HR: 2.26; 95% CI: 1.21 4.23; P = 0.01). In contrast, there were no significant differences in CVD events by testosterone level. Discussion: Low levels of testosterone may be associated with higher rates of infection-related hospitalization and all-cause mortality in male hemodialysis patients. PMID- 29270525 TI - A Cross-sectional Prospective Study of Asymptomatic Urinary Abnormalities, Blood Pressure, and Body Mass Index in Healthy School Children. AB - Introduction: Screening school children for urinary abnormalities is an inexpensive task but is not commonly undertaken in India. Although debated in western countries, its utility in early diagnosis of kidney disorders has been proved by studies from Asia. We examined the prevalence of asymptomatic urinary abnormalities (AUA), obesity, and hypertension in school children and analyzed data to identify potential risk factors among those detected with such abnormalities. Methods: Children and adolescents 8 to 18 years of age of either gender, attending 14 public schools in West Bengal, were screened prospectively from July 2013 to July 2016 for detecting asymptomatic urinary abnormalities by a spot urine test using a dipstick. Sociodemographic profile, medical examination (weight, height, and blood pressure), and questionnaire-based data were recorded. Results: A total of 11,000 children were screened. Of these, data from 9306 children were available for AUA, obesity, and hypertension. The prevalence rate was 7.44% (95% confidence interval [CI] = 6.91%-7.97%) for at least 1 AUA. Isolated hematuria was present in 5.2% (95% CI 4.75%-5.65%), whereas isolated proteinuria was present in 1.9% (95% CI = 1.62%-2.18%). The prevalence of prehypertension was 13.43% (95% CI = 12.74%-14.12%) and that of hypertension and abnormal body mass index was 4.05% (95% CI = 6.43%-7.47%) and 38.67 (95% CI = 37.68%-39.66%) respectively. Discussion: The prevalence rates of AUA were comparable with those in some Asian countries but higher than in most developed countries. Of children and adolescents 8 to 18 years of age, those 13 to 18 years had significantly more high risk factors such as AUA, hypertension, and obesity. PMID- 29270526 TI - One- and 2-Year Mortality Prediction for Patients Starting Chronic Dialysis. AB - Introduction: Mortality risk of patients with end-stage renal disease (ESRD) is highly elevated. Methods to estimate individual mortality risk are needed to provide individualized care and manage expanding ESRD populations. Many mortality prediction models exist but have shown deficiencies in model development (data comprehensiveness, validation) and in practicality. Therefore, our aim was to design 2 easy-to-apply prediction models for 1- and 2-year all-cause mortality in patients starting long-term renal replacement therapy (RRT). Methods: We used data from the Finnish Registry for Kidney Diseases with complete national coverage of RRT patients. Model training group included all incident adult patients who started long-term dialysis in Finland in 2000 to 2008 (n = 4335). The external validation cohort consisted of those who entered dialysis in 2009 to 2012 (n = 1768). Logistic regression with stepwise variable selection was used for model building. Results: We developed 2 prognostic models, both of which only included 6 to 7 variables (age at RRT start, ESRD diagnosis, albumin, phosphorus, C-reactive protein, heart failure, and peripheral vascular disease) and showed sufficient discrimination (c-statistic 0.77 and 0.74 for 1- and 2-year mortality, respectively). Due to a significantly lower mortality in the newer cohort, the models, to a degree, overestimated mortality risk. Discussion: Mortality prediction algorithms could be more widely implemented into management of ESRD patients. The presented models are practical with only a limited number of variables and fairly good performance. PMID- 29270527 TI - Rapid Biolayer Interferometry Measurements of Urinary CXCL9 to Detect Cellular Infiltrates Noninvasively After Kidney Transplantation. AB - Introduction: Measuring the chemokine CXCL9 in urine by enzyme-linked immunosorbent assay (ELISA) can diagnose acute cellular rejection (ACR) noninvasively after kidney transplantation, but the required 12- to 24-hour turnaround time is not ideal for rapid, clinical decision-making. Methods: We developed a biolayer interferometry (BLI)-based assay to rapidly measure urinary CXCL9 in <1 hour. We validated this new assay versus standard ELISA in 86 urine samples from kidney transplantation recipients with various diagnoses. We then used BLI to analyze samples from 56 kidney transplantation recipients, including 46 subjects who experienced an acute rise in serum creatinine associated with biopsy-proven ACR (n = 22), subclinical rejection (n = 15), or no infiltrates (n = 9), and 10 stable kidney transplantation recipients with surveillance biopsies. To assess its usefulness in detecting adequacy of therapy we serially measured serum creatinine and urinary CXCL9 in 6 subjects after treatment for ACR, and correlated the results with histological diagnoses on follow-up biopsies. Results: BLI accurately and reproducibly detected urinary CXCL9 in <1 hour. BLI based results showed that urinary CXCL9 was >200 pg/ml in subjects with ACR and <=100 pg/ml in subjects with stable kidney function without cellular infiltrates. In samples obtained after treatment for ACR, BLI CXCL9 measurements detected biopsy-proven intragraft infiltrates despite treatment-induced reduction in serum creatinine. Discussion: Together, our proof-of-principle results demonstrate that BLI-based urinary CXCL9 detection has potential as a point-of-care noninvasive biomarker to diagnose and guide therapy for ACR in kidney transplantation recipients. PMID- 29270530 TI - Hepatic Iron Load at Magnetic Resonance Imaging Is Normal in Most Patients Receiving Peritoneal Dialysis. PMID- 29270529 TI - Altered Protein Composition of Subcutaneous Adipose Tissue in Chronic Kidney Disease. AB - Introduction: Loss of renal function is associated with high mortality from cardiovascular disease (CVD). Patients with chronic kidney disease (CKD) have altered circulating adipokine and nonesterified fatty acid concentrations and insulin resistance, which are features of disturbed adipose tissue metabolism. Because dysfunctional adipose tissue contributes to the development of CVD, we hypothesize that adipose tissue dysfunctionality in patients with CKD could explain, at least in part, their high rates of CVD. Therefore we characterized adipose tissue from patients with CKD, in comparison to healthy controls, to search for signs of dysfunctionality. Methods: Biopsy samples of subcutaneous adipose tissue from 16 CKD patients and 11 healthy controls were analyzed for inflammation, fibrosis, and adipocyte size. Protein composition was assessed using 2-dimensional gel proteomics combined with multivariate analysis. Results: Adipose tissue of CKD patients contained significantly more CD68-positive cells, but collagen content did not differ. Adipocyte size was significantly smaller in CKD patients. Proteomic analysis of adipose tissue revealed significant differences in the expression of certain proteins between the groups. Proteins whose expression differed the most were alpha-1-microglobulin/bikunin precursor (AMBP, higher in CKD) and vimentin (lower in CKD). Vimentin is a lipid droplet associated protein, and changes in its expression may impair fatty acid storage/mobilization in adipose tissue, whereas high levels of AMBP may reflect oxidative stress. Discussion: These findings demonstrate that adipose tissue of CKD patients shows signs of inflammation and disturbed functionality, thus potentially contributing to the unfavorable metabolic profile and increased risk of CVD in these patients. PMID- 29270528 TI - Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy. AB - Introduction: IgA nephropathy is a chronic renal disease characterized by mesangial immunodeposits that contain autoantigen, which is aberrantly glycosylated IgA1 with some hinge-region O-glycans deficient in galactose. Macroscopic hematuria during an upper respiratory tract infection is common among patients with IgA nephropathy, which suggests a connection between inflammation and disease activity. Interleukin-6 (IL-6) is an inflammatory cytokine involved in IgA immune response. We previously showed that IL-6 selectively increases production of galactose-deficient IgA1 in IgA1-secreting cells from patients with IgA nephropathy. Methods: We characterized IL-6 signaling pathways involved in the overproduction of galactose-deficient IgA1. To understand molecular mechanisms, IL-6 signaling was analyzed by kinomic activity profiling and Western blotting, followed by confirmation assays using siRNA knock-down and small molecule inhibitors. Results: STAT3 was differentially activated by IL-6 in IgA1 secreting cells from patients with IgA nephropathy compared with those from healthy control subjects. Specifically, IL-6 induced enhanced and prolonged phosphorylation of STAT3 in the cells from patients with IgA nephropathy, which resulted in overproduction of galactose-deficient IgA1. This IL-6-mediated overproduction of galactose-deficient IgA1 could be blocked by small molecule inhibitors of JAK/STAT signaling. Discussion: Our results revealed that IL-6 induced aberrant activation of STAT3-mediated overproduction of galactose deficient IgA1. STAT3 signaling pathway may thus represent a new target for disease-specific therapy of IgA nephropathy. PMID- 29270531 TI - Hereditary Renal Amyloidosis Associated With a Novel Apolipoprotein A-II Variant. PMID- 29270532 TI - Proliferative Glomerulonephritis With Masked Monoclonal Deposits Responsive to Myeloma Therapy. PMID- 29270533 TI - A Case of Hyperphosphatemia and Elevated Fibroblast Growth Factor 23: A Brief Review of Hyperphosphatemia and Fibroblast Growth Factor 23 Pathway. PMID- 29270534 TI - Impact of Near Real-Time Urine Neutrophil Gelatinase-Associated Lipocalin Assessment on Clinical Practice. PMID- 29270535 TI - Successful Live Kidney Transplantation After Chikungunya Disease in the Donor. PMID- 29270536 TI - Management of Severe Hyponatremia With a Custom Continuous Renal Replacement Therapy in an Infant With Newly Diagnosed Chronic Kidney Disease. PMID- 29270537 TI - Immunomodulatory Device Therapy in a Pediatric Patient With Acute Kidney Injury and Multiorgan Dysfunction. PMID- 29270538 TI - Erratum: Afshinnia F, Rajendiran TM, Karnovsky A, et al. Lipidomic Signature of Progression of Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort. Kidney Int Rep. 2016;1:256-268. AB - [This corrects the article DOI: 10.1016/j.ekir.2016.08.007.]. PMID- 29270539 TI - Model-Based Normalization of a Fractional-Crystal Collimator for Small-Animal PET Imaging. AB - Previously, we proposed to use a coincidence collimator to achieve fractional crystal resolution in PET imaging. We have designed and fabricated a collimator prototype for a small-animal PET scanner, A-PET. To compensate for imperfections in the fabricated collimator prototype, collimator normalization, as well as scanner normalization, is required to reconstruct quantitative and artifact-free images. In this study, we develop a normalization method for the collimator prototype based on the A-PET normalization using a uniform cylinder phantom. We performed data acquisition without the collimator for scanner normalization first, and then with the collimator from eight different rotation views for collimator normalization. After a reconstruction without correction, we extracted the cylinder parameters from which we generated expected emission sinograms. Single scatter simulation was used to generate the scattered sinograms. We used the least-squares method to generate the normalization coefficient for each LOR based on measured, expected and scattered sinograms. The scanner and collimator normalization coefficients were factorized by performing two normalizations separately. The normalization methods were also verified using experimental data acquired from A-PET with and without the collimator. In summary, we developed a model-base collimator normalization that can significantly reduce variance and produce collimator normalization with adequate statistical quality within feasible scan time. PMID- 29270540 TI - "Great Expectations": Reflections on Possible Analogies between our Patients and the Characters of Charles Dickens. PMID- 29270541 TI - Expectations of Shoulder Surgery Are Not Altered by Surgeon Counseling of the Patient. AB - Purpose The primary objective of this study was to evaluate if the current mechanisms of preoperative counseling influence patients' expectations of shoulder surgery. Methods Patients were asked to complete the Hospital for Special Surgery's (HSS) Shoulder Surgery Expectations Survey. The first survey was completed before the first appointment with one of four fellowship-trained shoulder surgeons. The second survey was completed after patients consented for surgery. Our analysis also included patient demographics and surgical factors. Results A total of 41 patients completed the HSS Shoulder Surgery Expectations Survey before and after their first appointment with the surgeon during which they consented to shoulder surgery. Before seeing the surgeon, the mean HSS Shoulder Surgery Expectations score was 72.5. After seeing the surgeon and being consented for surgery, the mean HSS Shoulder Surgery Expectations score was 74.8. The mean change in HSS Shoulder Surgery Expectations score (+2.3) was not statistically significant ( p value = 0.242). We did not find any significant correlations between patients' expectations and demographics or surgical factors. Total HSS Shoulder Surgery Expectations scores and change in scores were not statistically different between the four surgeons ( p = 0.146). Conclusion Patient expectations were not substantially altered after preoperative counseling. Further investigation is necessary to investigate factors correlated with expectations, the implication of unaltered expectations on the postoperative outcome, and methods for improving the preoperative counseling process. Level of Evidence Level II, prospective cohort study. PMID- 29270542 TI - Hyaluronic Acid Intra-Articular Injections in Patients Affected by Moderate to Severe Glenohumeral Osteoarthritis: A Prospective Randomized Study. AB - Purpose The aim of this study was to evaluate the efficacy and safety of intra articular injection treatment with high molecular weight HA (Hyalubrix, 30 mg/2 mL, molecular weight > 1,500 kDa) in patients affected by moderate to severe glenohumeral osteoarthritis (OA). Methods Seventy-eight patients, affected by shoulder OA grade II-IV were randomized in two groups. Patients included in case group were treated with three intra-articular injections of HA and a specific physiotherapy program, whereas patients included in the control group received the only physical therapy. The follow-up examination was 6 months for both groups. The evaluation of functional status of treated shoulder, range of motion, and pain was performed before treatment and at the final follow-up examination by means of the Constant score. The safety evaluation of the treatment was also performed recording any adverse events. Results Statistical analysis revealed a significant difference ( p < 0.05) between the two groups in terms of pain reduction and improvement in the activities of daily living. In particular, case group subjects affected by grade III and IV OA had a significant improvement in the Constant score (18.2 +/- 5.4 and 19.2 +/- 5.9, respectively). Conclusion This study showed that the combination of intra-articular injection of hyaluronic acid (Hyalubrix, 30 mg/2 mL) with physical therapy program was more effective in comparison with the only physical therapy in reducing pain in patients affected by glenohumeral OA. Level of Evidence Level II, randomized controlled study. PMID- 29270543 TI - Shoulder Adhesive Capsulitis in Type 1 Diabetes Mellitus: A Cross-Sectional Study on 943 Cases in Sardinian People. AB - Purpose To evaluate the prevalence of adhesive capsulitis (AC) of the shoulder in patients with type 1 diabetes mellitus (T1DM) in Sardinia. Methods In this cross-sectional study, we evaluated 943 patients with T1DM attending the division of Endocrinology and Metabolism at the University Hospital in Sassari, Italy. The criteria for diagnosing AC were: pain for at least 1 month, inability to lie on the affected shoulder, and restricted active and passive shoulder joint movements in at least three planes. Age, gender, duration of DM, blood pressure, and presence of neuropathy and retinopathy were noted. Metabolic control of DM was evaluated with glycosylated hemoglobin A1c (GHbA1c) blood concentrations. Results AC was diagnosed in 331 patients (prevalence: 35.1%). Age, duration of DM, high blood pressure levels, and the presence of neuropathy and retinopathy were significantly associated with AC. No significant association was observed between gender and AC. There was no significant difference in mean levels of GHbA1c in T1DM patients with or without AC. Conclusion This study shows that AC of the shoulder is a common disorder in patients with T1DM in Sardinia. It is significantly associated with age, duration of DM, and related complications. Level of Evidence Level IV, observational cross-sectional study. PMID- 29270544 TI - Distance of the Posterior Interosseous Nerve from the Radial Head during Elbow Arthroscopy: An Anatomical Study. AB - Purpose The aims of this study were to measure the distance of the posterior interosseous nerve (PIN) from the radial head (RH) and its variations with forearm movements. Methods Five fresh frozen cadaver specimens were dissected under arthroscopy. An anterior capsulectomy extended to the entire lateral compartment was performed. The need of soft tissue dissection to isolate the nerve in the extracapsular space was recorded. The distance between the nerve and the anterior part of the RH was then measured with a graduated caliper inserted via the midlateral portal with the forearm in neutral position, full pronation, and full supination. Results The PIN was identifiable in all the specimens. In four cases, it was surrounded by a thick layer of adipose tissue, and further dissection was necessary to isolate it. Damage of the PIN during dissection occurred in one case, in which the proximal part of the nerve was accidentally cut. In three of the remaining cases, an increased distance was measured with the forearm in supination, as compared with neutral and full pronation position. Conclusion This anatomical study suggests that in most of the cases, the PIN does not lay just extracapular at the level of the radiocapitellar joint, but is surrounded by a thick layer of adipose tissue. Furthermore, its distance from the RH appears to increase with forearm supination. This position could increase the safe working space between RH and PIN. Clinical Relevance Knowledge of PIN position in relation to the anterior elbow capsule and its changes with forearm movements can help reduce the iatrogenic injuries during elbow arthroscopy. PMID- 29270545 TI - Treatment of Early Hip Osteoarthritis: Ultrasound-Guided Platelet Rich Plasma versus Hyaluronic Acid Injections in a Randomized Clinical Trial. AB - Purpose The aim of this study was to compare the clinical efficacy of ultrasound guided intra-articular injections of autologous platelet rich plasma (PRP) versus hyaluronic acid (HA) for symptomatic early osteoarthritis (OA) of the hip. Methods A prospective controlled double-blinded randomized trial on 80 patients with hip OA was conducted. The patients were divided in two groups of 40 patients each: group 1 underwent three PRP intra-articular ultrasound-guided injections, whereas group 2 underwent three HA injections. WOMAC, VAS, and Harris Hip Score were evaluated for both groups before and at 6 and 12 months after treatment. Results The two groups were comparable in age, sex, body mass index, and severity of hip OA. Both groups showed a significant improvement from baseline at 6-month and 12-month follow-ups for all the outcome measures. No major complications were observed during the treatment and at follow-ups in both the groups. Conclusion PRP did not offer significantly better results compared with HA in patients with moderate signs of OA, and thus it should not be considered as first-line treatment. Level of Evidence Level II, randomized controlled trial. PMID- 29270546 TI - Combined Intra- and Extra-Articular Technique in Revision Anterior Cruciate Ligament Reconstruction. AB - Purpose The aim of the study was to evaluate the "over the top" (OTT) nonanatomical technique for revision of anterior cruciate ligament (ACL) reconstruction. Methods Twenty-four patients with a mean age of 31.9 +/- 11.2 years underwent revision of ACL reconstruction using OTT technique. International Knee Documentation Committee (IKDC) score, Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, Tegner score, Subjective Patient Outcome for Return to Sport (SPORTS) score, Anterior Cruciate Ligament-Return to Sport After Injury (ACL-RSI) scale, and KT-1000 evaluation were recorded at a mean follow-up of 30.7 +/- 18.9 months. Results Postoperatively, the IKDC objective total score significantly improved ( p = 0.0046). The KOOS, Lysholm, and Tegner scores also improved, but the results were not statistically significant (62.4 vs. 72.6, 6.5 vs. 75.8, and 4.1 vs. 6.0, respectively). The subjective IKDC evaluation score improved from an average of 51.1 points to 63.7 points at the last follow-up ( p = 0.0027). The RTP prevalence was 81.8%, with 44.4% of the patients returning to the same preinjury level. According to the SPORTS score, 16.6% of patients played sport without limitations in activity and performance. The average ACL-RSI score was 52.1 +/- 27.0. No major complications were reported. A total of 21.5% of patients underwent surgical removal of staples. The failure prevalence was 14.3% and the cumulative survivorship, calculated using the Kaplan-Meier method, was equal to 70% at 60 months of follow-up. Conclusion The OTT technique in the revision ACL reconstruction provided improvement in objective and subjective scores, good RTP prevalence, and acceptable rate of complication and failure. One of the advantages was the possibility to avoid the femoral tunnel. Level of Evidence Level IV, therapeutic case series. PMID- 29270547 TI - Relationship between Clinical, MRI, and Arthroscopic Findings: A Guide to Correct Diagnosis of Meniscal Tears. AB - Purpose The aim of this prospective study was to compare and correlate clinical, MRI, and arthroscopic findings in cases of suspected meniscal tears. Using arthroscopic findings as the gold standard, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of clinical investigation and MRI were evaluated to determine if is possible, after a careful examination, to bypass MRI and perform directly arthroscopy in suspected cases. Methods A total of 80 patients with a history of knee trauma, preoperative RX, and MRI underwent arthroscopy over an 8-month period at our department. All patients had a clinical examination performed by an experienced knee surgeon. These examiners evaluated and recorded the results of three tests: medial and lateral joint line tenderness test, McMurray's test, and Apley's test. The injury was classified as a meniscal tear if there were at least two positive tests. Finally, using the arthroscopic findings as the gold standard, sensibility, specificity, accuracy, positive and negative predictive values of clinical examination, and MRI were evaluated and compared. Results Clinical examination performed by an experienced knee surgeon reported better sensitivity (91 vs. 85%), specificity (87 vs. 75%), accuracy (90 vs. 82%), positive predictive value (94 vs. 88%), and negative predictive value (81 vs. 71%) than MRI for medial meniscal tears. These parameters showed minimal differences for lateral meniscal tears. Conclusion Clinical examination performed by an experienced knee surgeon provided equal or better results to diagnose meniscal injuries in comparison to MRI. MRI is not necessary to confirm these lesions and should not be used as the primary diagnostic tool. Level of Evidence Level II, prospective study. PMID- 29270548 TI - Analysis of Injuries and Risk Factors in Taekwondo during the 2014 Italian University Championship. AB - Purpose This study aims to analyze the risk factors and type of injuries occurring in Taekwondo athletes participating in a national competition. Methods Out of the 127 competitors, 18 athletes got injured during a Taekwondo championship who were analyzed for the following parameters: modality of training; age, weight; belt color; and the type of injury. Results Around 89% of the injuries were due to bruising and were found mainly on the lower limbs (61%) during the elimination rounds and during the first match of the day. The higher probability of injury was in the second round (56%), and during the first match of the day (72%). Nearly all the athletes were able to complete the game in which they were injured (83%). Comparing the average age of the athletes suffering an injury (23.6 +/- 2.06 years) with their average years of training (8.4 +/- 7.05 years) it can be noted that these athletes began this discipline rather late. The more is the training age and the weekly hours of training, the more are the numbers of matches completed, even as injured. Beginners with a low-level belt suffered more injuries than the experienced subjects did. Conclusion The following risk factors for injury were found: starting to practice in late age, weekly training sessions with a few number of hours, male sex, low-level belt, elimination rounds, the first match of the day, and second round. Level of Evidence Level III, observational analytic study without a control group. PMID- 29270549 TI - Effects of Notchplasty on Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - Purpose Notchplasty is a complementary surgical procedure often performed during anterior cruciate ligament reconstruction (ACLR) with the aim to widen the intercondylar notch and to avoid graft impingement. The aim of this review was to analyze the current literature evidence concerning the effects of notchplasty on clinical outcome after primary ACLR. Methods Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed, and MEDLINE were used to search English language studies, from January 1990 to July 2015, concerning the effects of the notchplasty on ACLR, using the following keywords: "ACL" OR "anterior cruciate ligament" OR "ACL reconstruction" OR "anterior cruciate ligament reconstruction" AND "notch" OR "notchplasty" OR "intercondylar notch". Randomized and nonrandomized trials, case series, technical notes, biomechanical studies and radiological study were included. Results At the final screening 16 studies were included. Despite widely used, the usefulness of notchplasty during ACLR remains unclear. Some concerns emerged regarding potential harmful effects of notchplasty, mostly related to the knee biomechanics and postoperative blood loss. Notchplasty can be useful in the treatment of arthrofibrosis and in presence of bony spurs of the notch both in primary and revision surgery. However, the level of evidence of available literature is poor and there is a strong need for randomized controlled trials investigating the role of notchplasty on ACLR. Conclusion We suggest being aware of potential complications following notchplasty during ACLR before deciding to perform notchplasty in primary ACLR, reserving it for the surgical management of arthrofibrosis, treatment of notch osteophytosis and revision ACLR. Level of Evidence Level IV, systematic review of level II-IV studies. PMID- 29270550 TI - Tuberculosis of the Knee: A Case Report and Literature Review. AB - Tuberculosis (TB) is currently in resurgence due to immigration from endemic areas. Skeletal TB frequently mimics more common etiologies and can be difficult to diagnose. A case of TB knee arthritis in a young woman with painful and swelling knee is reported here. Arthrotomy was performed and inflamed synovial tissue was found, with multiple rice bodies in the eroded lateral femoral condyle. The patient was treated with an antituberculosis polytherapy and at 1 year follow-up, she reported relief from pain and swelling. We believe that all surgeons assessing patients from TB endemic regions have to adopt an updated approach to TB treatment. Thus, a literature review is also reported here on the current strategies used in different knee TB cases. PMID- 29270551 TI - All-Arthroscopic Treatment of Intra- and Extra-Articular Localized Villonodular Synovitis of Knee. AB - Pigmented villonodular synovitis (PVNS) is a rare, benign, proliferative neoplastic condition affecting synovial-lined anatomic spaces. PVNS is characterized by hypertrophy of a synovial membrane by villous, nodular, and villonodular proliferation, with pigmentation secondary to hemosiderin deposition. The two forms of PVNS that have been described are diffuse (DPVNS) and localized (LPVNS). The knee is the most commonly involved anatomic location, followed by hip, ankle, shoulder, and elbow. Diagnosis of PVNS is not always obvious clinically. Various imaging modalities are often necessary to exclude other conditions and narrow the diagnosis. Magnetic resonance imaging has become the modality of choice for diagnosing PVNS. We present a case of intra-articular LPVNS with an extra-articular extension through the posterior capsule that has been successfully removed in an all-arthroscopic fashion. PMID- 29270552 TI - Suture Anchors Fixation in MPFL Reconstruction using a Bioactive Synthetic Ligament. AB - Medial patellofemoral ligament (MPFL) reconstruction has a key role in patellofemoral instability surgery. Many surgical techniques have been described so far using different types of grafts (autologous, heterologous, or synthetic) and fixation techniques. The hereby described technique for MPFL reconstruction relies on the use of a biosynthetic graft (LARS Arc Sur Tille, France). Fixation is obtained by means of suture anchors on the patellar side and a resorbable interference screw on the femoral side locating the insertion point according to Schottle et al. An early passive range of motion (ROM) recovery is fundamental to reduce the risk of postoperative stiffness; a partial weight bearing with crutches is allowed until 6 weeks after the surgery. In our experience, the use of a biosynthetic graft and suture anchors provides stable fixation, minimizing donor site morbidity and reducing the risk of patellar fracture associated with transosseous tunnels. This technique represents a reliable and reproducible alternative for MPFL reconstruction, thereby minimizing the risk of possible complications. PMID- 29270553 TI - Successful Treatment of Osgood-Schlatter Disease with Autologous-Conditioned Plasma in Two Patients. AB - Osgood-Schlatter Disease (OSD) is a painful, growth-related overuse condition of the tibial tuberosity, leading to inflammation of the patellar ligament at the tibial tuberosity. It primarily affects young adolescents, athletic population, and usually, resolves with age or skeletal maturity. Therapy is usually conservative, with surgery indicated in a minority of cases. For patients with treatment-resistant or refractory OSD, an alternative is the application of autologous platelet concentrate. Here, we describe two cases in which autologous conditioned plasma therapy was used to treat OSD, and present the treatment protocol developed in our clinic. PMID- 29270554 TI - Postgraduate Training in Joint Surgery: The Role of Scientific Societies. PMID- 29270555 TI - Use and Effectiveness of the Cadaver-Lab in Orthopaedic and Traumatology Education: An Italian Survey. AB - Purpose The purpose of this study is to provide basic information on the availability and current use of cadaver laboratories in the education of orthopaedic residents and trainees and to determine the interest for the implementation of this type of training. Methods All Orthopaedic residents and trainees who attended a cadaver laboratory organized by SIGASCOT (Italian Society of the Knee, Arthroscopy, Sports Traumatology, Cartilage and Orthopaedic Technology) between 2013 and 2016 were asked to complete a survey on the availability and current use of cadaver laboratories in the education of Orthopaedic residents and trainees. The survey was sent via e-mail to 102 Orthopaedic residents and trainees. All data were analyzed and all responses are presented as counts, percentages, or means. Results Thirty-eight (37.2%) Orthopaedics and traumatology residents and trainees completed the survey and were included in this analysis. Eighteen trainees (18/38; 44.3%) attended a cadaver laboratory focused on lower limb surgery, whereas 20 (20/38; 52.7%) on upper limb surgery. Twenty participants (55.7%) perceived skills laboratory sessions as extremely beneficial to the understanding and becoming familiar with the normal surgical anatomy; moreover, 16 (45.7%) participants considered the cadaver laboratory extremely beneficial to the understanding of a specific surgical technique and very beneficial (44.4%) to become confident with arthroscopic or other specific surgical instruments. Over 60% of participants perceived cadaver laboratory to be very to extremely beneficial to increase confidence and speed in the operating room (OR), and more than a half of them considered skills laboratory sessions to be extremely beneficial to increase participation and decrease the occurrence of damages in the real surgical activity. Conclusion Orthopaedic residents and trainees found the addition of a cadaver laboratory for teaching surgical skills a significant benefit to both their overall education and surgical skills training. Level of Evidence Level IV, survey study. PMID- 29270556 TI - Do Knee Bracing and Delayed Weight Bearing Affect Mid-Term Functional Outcome after Anterior Cruciate Ligament Reconstruction? AB - Purpose The aim of this study was to assess the effect of knee bracing and timing of full weight bearing after anterior cruciate ligament reconstruction (ACLR) on functional outcomes at mid-term follow-up. Methods We performed a retrospective study on 41 patients with ACLR. Patients were divided in two groups: ACLR group, who received isolated ACL reconstruction and ACLR-OI group who received ACL reconstruction and adjunctive surgery. Information about age at surgery, bracing, full or progressive weight bearing permission after surgery were collected for the two groups. Subjective IKDC score was obtained at follow up. Statistical analysis was performed to compare the two groups for IKDC score. Subgroup analysis was performed to assess the effect of postoperative regimen (knee bracing and weight bearing) on functional outcomes. Results The mean age of patients was 30.8 +/- 10.6 years. Mean IKDC score was 87.4 +/- 13.9. The mean follow-up was 3.5 +/- 1.8 years. Twenty-two (53.7%) patients underwent ACLR only, while 19 (46.3%) also received other interventions, such as meniscal repair and/or collateral ligament suture. Analysis of overall data showed no differences between the groups for IKDC score. Patients in the ACLR group exhibited a significantly better IKDC score when no brace and full weight bearing after 4 weeks from surgery was prescribed in comparison with patients who worn a brace and had delayed full weight bearing. No differences were found with respect to the use of brace and postoperative weight bearing regimen in the ACLR-OI group. Conclusion Brace and delayed weight bearing after ACLR have a negative influence on long-term functional outcomes. Further research is required to explore possible differences in the patients operated on ACLR and other intervention with respect to the use of a brace and the timing of full weight bearing to identify optimal recovery strategies. Level of Evidence Level III, retrospective observational study. PMID- 29270557 TI - Revision Total Knee Arthroplasty with Metaphyseal Sleeves without Stem: Short Term Results. AB - Purpose The aim of this study was to evaluate the efficacy of revision total knee arthroplasty (TKA) with cementless metaphyseal sleeves without stems either in the femoral or tibial side or in both. Methods In this retrospective study, 51 patients (51 knees) operated in the period 2010 to 2015 met the above mentioned criteria and were invited to a medical examination including X-rays. Forty-six were available for the study. Mean follow-up was 37 months. Knee Society score (KSS) (objective knee score), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and range of motion (ROM) were used as outcome scores and compared with baseline values. X-rays were also examined and compared with postoperative exams to evaluate the presence of loosening, radiolucent lines, and bone ingrowth. Satisfaction of the patients was also investigated using a linear scale from 1 to 10. Results KSS improved from 39 to 77 ( p < 0.01); WOMAC score improved from 76 to 41 ( p < 0.01). Twenty four (52%) patients were satisfied, 15 (32%) were partially satisfied, and 7 (16%) were unsatisfied. ROM improved from 93 to 96 degrees (nonsignificant difference). X-rays showed no loosening of the implants, radiolucent lines in 4 patients (3 of them were asymptomatic) and bone ingrowth in 43 out of 46 patients. Conclusion In this short-term retrospective study, the use of sleeves without stem was a safe and effective procedure in revision TKA. We found a significant improvement in clinical results compared with baseline values and no signs of implant loosening. Level of Evidence Level IV, therapeutic case series. PMID- 29270558 TI - Clinical Outcomes and Return to Sports in Patients with Chronic Achilles Tendon Rupture after Minimally Invasive Reconstruction with Semitendinosus Tendon Graft Transfer. AB - Objective The purpose of the study is to evaluate the clinical results and return to sports in patients undergoing reconstruction of the Achilles tendon after minimally invasive reconstruction with semitendinosus tendon graft transfer. Methods Eight patients underwent surgical reconstruction with a minimally invasive technique and tendon graft augmentation with ipsilateral semitendinosus tendon for chronic Achilles tendon rupture (more than 30 days after the injury and a gap of >6 cm). Patients were evaluated at a minimum follow up of 24 months after the surgery through the American Orthopaedic Foot and Ankle Society (AOFAS), the Achilles Tendon Total Rupture Scores (ATRS), the Endurance test, the calf circumference of the operated limb, and the contralateral and the eventual return to sports activity performed before the trauma. Results The mean age at surgery was 50.5 years. Five men and three women underwent the surgery. The average AOFAS was 92, mean Endurance test was 28.1, and the average ATRS was 87. All patients returned to their daily activities, and six out of eight patients have returned to sports activities prior to the accident (two football players, three runners, one tennis player) at a mean of 7.0 (range: 6.7-7.2) months after the surgery. No patient reported complications or reruptures. Conclusion Our study confirms encouraging results for the treatment of Achilles tendon rupture with a minimally invasive technique with semitendinosus graft augmentation. The technique can be considered safe and allows patients to return to their sports activity. Level of Evidence Level IV, therapeutic case series. PMID- 29270559 TI - Risk Factors for Shoulder Stiffness: Current Concepts. AB - Shoulder stiffness is a condition of painful restriction of the glenohumeral range of motion. Numerous risk factors for primary and postoperative shoulder stiffness have been described. This article summarizes the known aspects of the pathophysiology of shoulder stiffness, with special attention to elements of molecular biology and genetics, which could influence the risk of developing shoulder stiffness. Furthermore, the role of hormonal and metabolic factors, medical disorders, drugs, and of other published risk factors for primary and postoperative shoulder stiffness is reviewed and discussed. Finally, aspects related to shoulder surgery and postoperative rehabilitation protocols, which could influence the development of postoperative stiffness are presented. PMID- 29270560 TI - Ceramic Total Knee Arthroplasty: Ready to Go? AB - Total knee arthroplasty (TKA) is a well-established surgical procedure in the late stages of knee osteoarthritis. Nevertheless, this procedure is associated with a percentage of unsatisfactory results and biomechanical failures, with aseptic loosening being the most common cause of revision. Beside these problems, cutaneous and systemic hypersensitivity reactions to metals have arisen as an increasing concern after joint arthroplasties, even if allergies against implant materials are still a quite rare and not well-known problem. Ceramic composites have been recently used in prosthetic components, showing minimum wear and excellent long-term results in total hip replacement, due to their high resistance to scratching and their better wettability with respect to cobalt chromium alloy. Furthermore, the biologic response to debris generated from these bearings is less aggressive. Knee joint simulator tests and clinical results demonstrate promising results of TKAs with ceramic components that should led to benefit for the patients. PMID- 29270561 TI - Postarthroscopy Osteonecrosis of the Knee: Current Concepts. AB - Knee osteonecrosis is a severe disease rapidly leading to end-stage osteoarthritis, which was classified into three categories: spontaneous, secondary, and postarthroscopy. To understand postarthroscopy osteonecrosis of the knee, all the three types of knee osteonecrosis have to be deepened. This article reviewed spontaneous and secondary osteonecroses of the knee, with special focus upon postarthroscopy osteonecrosis, which is a rare form, affecting patients operated for arthroscopic knee surgery, most commonly for meniscectomy. Due to its rarity, patients and surgeons are often unprepared for this complication. A correct diagnosis is essential for appropriate treatment, and also to determine if a preexisting osteonecrosis was present, avoiding medicolegal sequelae, although many authors agree that osteonecrosis (both spontaneous and postarthroscopy) represent unpreventable and unpredictable conditions. In spontaneous osteonecrosis, the treatment is defined according to the size and the degree of the lesion, whereas in postarthroscopy osteonecrosis, the size of the lesion has no prognostic value, and therefore, the choice of the correct treatment is based more on the timing of the diagnosis. A diagnostic and therapeutic algorithm was outlined on the basis of the actual knowledge. PMID- 29270563 TI - Talonavicular Coalition as a Cause of Foot Pain. AB - Tarsal coalitions have an incidence of 2% and are often underdiagnosed. These are considered to be one of the causes of chronic ankle and foot pain. Among all tarsal coalitions, the talonavicular type represents a rare and uncommon condition. The purpose of this article was to present the case of a 35-year-old male patient with a bilateral talonavicular coalition treated conservatively. A review of the literature was also performed to understand the management of this rare condition. PMID- 29270562 TI - Patellofemoral Arthroplasty: Current Concepts and Review of the Literature. AB - Patellofemoral osteoarthritis (PFOA) can be associated with anterior knee pain, stiffness, and functional impairment. Some authors report that PFOA affects approximately 9% of patients older than 40 years with a greater prevalence in females. Etiology of PFOA is multifactorial and is related to the presence of abnormal stresses at the PF joint due to knee- and patient-related factors. The need for a joint preserving treatment by isolated replacement of the injured compartment of the knee led to the development of PF arthroplasty (PFA). When a correct PF replacement is performed, PFA preserves physiologic tibiofemoral joint, thus allowing patients for a rapid recovery with a high satisfaction. The outcomes for PFA are quite variable with a trend toward good to excellent results, mainly owing to the improvement in surgical techniques, patient selection, and implant design. The development of the second generation of PFA improved the outcomes, which is attributed to the different trochlear designs. Recently, encouraging results have been provided by the association of PFA and unicompartmental knee arthroplasty (UKA). In many studies, the main cause of PFA failure is progression of tibiofemoral OA. The aim of this brief review of literature is to summarize the clinical features, indications and contraindications, surgical techniques, complications, and outcomes of PFA. PMID- 29270564 TI - Total Hip Arthroplasty in an Inveterate Femoral Neck Fracture in a Patient with Congenital Insensitivity to Pain with Anhidrosis. AB - Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare disorder characterized by autonomic and sensory nerves malfunction with insensitivity to both deep and superficial painful stimuli, inability to sweat and produce tears, and mild to moderate mental retardation with self-mutilating behavior. Related consequences of inveterate musculoskeletal injuries represent a major issue for these patients, since pain cannot act as a protection mechanism. For the same reason, the patients are at risk during postoperative rehabilitation, which should be taken into account when selecting an orthopaedic implant. To our knowledge, only one case of total hip arthroplasty has been reported in the literature to date. A 21-year-old Caucasian male patient affected with CIPA arrived at our attention complaining about a functional limitation of the left hip. No history of trauma was reported. The X-rays showed an inveterate femoral neck fracture with a severe necrosis and resorption of the femoral head. We decided to perform a total hip arthroplasty with a cemented stem and a cemented dual mobility cup. The postoperative course and rehabilitation were satisfactory, with excellent clinical results, measured with the Harris Hip Score at 1 year. PMID- 29270565 TI - Neglected Posterior Knee Dislocation: An Unusual Case Report. AB - Chronic dislocation of the knee is a rare condition due to a diagnostic mistake during emergency assessment. Usually, dislocation obliges the surgeon to carry out a broad assessment, with vascular and neurological examination, and a thorough assessment of joint injuries. The immediate and stable closed reduction can resolve neurovascular compression. The most serious late sequela is joint instability with impairment of ambulation and patient's autonomy. Treatment of neglected knee dislocation is surgical, that is, arthrodesis or arthroplasty, the latter representing the treatment of choice. The case described herein appears unique because of the clinical and radiographic features. Interestingly, over the years, the neurovascular bundle has inadvertently adapted to the posterior femur displacement without secondary damage. PMID- 29270566 TI - Anatomic Double-Bundle Medial Patellofemoral Ligament Reconstruction with Autologous Semitendinosus: Aperture Fixation Both at the Femur and the Patella. AB - Medial patellofemoral ligament (MPFL) represents the main restraint against lateral patellar displacement. The MPFL insertion at the patella is up to 30 mm wide and is located along the upper half of the medial patellar rim. The femoral insertion of the MPFL is approximately 10 mm distal to the apex of the adductor tubercle and 16 mm proximal to the medial epicondyle. Since most of the patients suffer from MPFL rupture just after the first patellar dislocation, MPFL reconstruction results necessarily in all cases of chronic objective patellar instability to reestablish the primary passive patellofemoral stabilizer. Over time, different techniques of MPFL reconstruction have been proposed with promising results in terms of patient satisfaction and redislocation rate. However, each of these techniques may present peculiar problems and/or complications. An anatomic double-bundle MPFL reconstruction through an aperture fixation both at the femur and at the patella is here presented. The anatomic double-bundle MPFL reconstruction could allow recreating the fan-shape and biomechanics of original MPFL, whereas aperture fixation could provide a strong and safe fixation without risk of loosening or slackening of the graft. PMID- 29270567 TI - Evaluation of the wound healing potential of Aloe vera-based extract of Nerium oleander. AB - OBJECTIVE: Nerium oleander (Apocynaceae) and Aloe vera (Liliaceae) are among the widely used herbal remedies for treating skin diseases and possess numerous activities such as antibacterial, antiviral, antifungal, and antioxidant. The aim of this study was to investigate the possible wound healing effect of Aloev era based extract of the N. oleander leaf (NAE-8(r)) based on its antioxidant, anti inflammatory, and DNA repair capacity along with histological changes and to compare them with the traditional silver sulfadiazine treatment (SSD). METHODS: Twenty-four Wistar albino rats were randomly grouped as follows: i) control, ii) burn alone (burn), iii) burn with topical NAE-8(r) (burn+NAE-8(r)) treatment, and iv) burn with topical 1% silver sulfadiazine (burn+SSD) treatment. All groups received their related topical application twice a day for 14 consecutive days. Upon completion of the experimental protocol, trunk blood and skin tissues were collected for measuring malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), %DNA in the tail (%DNAT) levels along with histological examinations. RESULTS: Thermal injury-induced alterations in MDA, GSH, MPO, TNF-alpha, IL-1beta, and %DNAT levels were significantly reversed by NAE-8(r) treatment. These ameliorative effects were also supported by histological findings. CONCLUSION: Findings of the present study suggest that NAE-8(r) is a promising remedy for treating skin burn injury. PMID- 29270568 TI - Deceased donor liver transplantation from donors with central nervous system malignancy: Experience of the Inonu University. AB - OBJECTIVE: Liver transplantation from deceased donors with a central nervous system (CNS) malignancy has some risk of tumor transmission to the recipient. Though the risk is small, this group of donors is regarded as marginal. The use of marginal grafts may be an acceptable alternative practice in order to expand the donor pool in countries where there is a shortage of donated organs. The aim of this study was to examine and present the outcomes of liver transplantations performed using donors with a CNS tumor. METHODS: Between March 2002 and July 2017, 1990 (deceased donor: n=399, 20%; living donor: n=1591, 80%) liver transplantations were performed at the center. Of the 399 deceased donors, 17 (4.2%) had a CNS tumor. The data of donors with a CNS tumor and of recipients who survived for more than 1 month (n=11) were retrospectively reviewed. Demographic data, the grade of the CNS tumor, tumor transmission to recipient data, and survival rates were analyzed. RESULTS: Only 2 (18%) grafts were provided locally, 6 (54%) were offered to the transplantation center after all of the national centers had declined them, and 3 (37%) were made available to us by the national coordination center for patients with a documented notification of urgency. High grade (grade III-IV) brain tumors were detected in 7 (64%) donors, while low grade (grade I-II) tumors were found in 2 patients. The remaining 2 donors were not pathologically graded because the diagnosis was made radiologically. The 1-, 3-, and 5-year overall and tumor-free survival of the patients was estimated at 100%, 70%, and 45%, respectively. CONCLUSION: A median survival of 40 months (range: 13-62 months) was achieved in recipients of grafts from a donor with a CNS tumor and no donor-related malignant transformation was observed. PMID- 29270569 TI - Impact of insulin resistance and obesity on intracytoplasmic sperm injection outcomes in young women with polycystic ovary syndrome. AB - OBJECTIVE: To examine effects of body mass index (BMI) and insulin resistance (IR) on the in vitro fertilization (IVF) outcomes in women with polycystic ovary syndrome (PCOS). METHODS: A total of 106 women with PCOS who underwent intracytoplasmic sperm injection were investigated. The patients were stratified into groups according to their BMI [healthy weight: BMI <25 kg/m2 (n=51), overweight: <=25-29.9 kg/m2 (n=27), and obese: >=30 kg/m2 (n=28)]. Secondly, the patients were classified based on the presence of IR (IR was considered to be present if homeostatic model assessment-IR was >2.5). The main outcome measures were reproductive and IVF outcomes with respect to BMI and IR. RESULTS: The basal hormonal evaluations, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH, estradiol, testosterone, DHEAS, AMH, and antral follicle counts, were similar between the groups of BMI and IR. The number of retrieved oocytes, MII oocytes, embryo counts, and fertilization and pregnancy rates were similar between lean and overweight/obese PCOS with and without IR. Even though pregnancy and delivery rates per started cycle and embryo transfer were higher in healthy-weight women with PCOS than in overweight/obese patients, it did not reach statistical significance. CONCLUSION: Reproductive outcomes in women with PCOS according to BMI and IR were similar. Neither BMI nor IR had an independent effect on ovarian response and IVF success in young women with PCOS. PMID- 29270570 TI - Clinical approach to pediatric neck masses: Retrospective analysis of 98 cases. AB - OBJECTIVE: Pediatric neck masses (PNMs) are a frequently encountered problem in otorhinolaryngology practice. The clinical approach to cervical masses in childhood varies from that of adults. Due to differences among clinicians in the assessment of a PNM, studies investigating this subject are significant contributions to the literature. For this reason, a review was conducted of pediatric PNM cases with an open biopsy (incisional/excisional) and a histopathological diagnosis. METHODS: The hospital records of 98 (34 girls, 64 boys) pediatric patients aged between 8.5 months and 16 years were reviewed. The history, physical examination findings, blood tests, medical treatments, imaging reports, and the pathology and/or microbiology results of the patients were recorded and evaluated. The cervical masses were categorized according to the etiology, imaging features, size, and location. RESULTS: Surgical biopsy was planned due to the suspicion of malignancy, typical clinical presentation or location, or size greater than 20 mm despite antibiotherapy for 2 to 6 weeks. Excisional biopsy (91.8%) was the first choice for histopathological sampling. Infectious masses were observed most commonly, followed by congenital and neoplastic masses, at a rate of 49%, 27.6%, and 23.4%, respectively. Hodgkin lymphoma was the most frequent type of malignancy (39.1%). Thyroglossal and branchial cysts constituted 74.1% of congenital masses. Sixty-seven percent of all masses were solid, and the lateral levels of the neck were the most affected locations (44.9%). CONCLUSION: In most cases, the diagnosis can be made with a detailed history and physical examination. In the presence of nonspecific findings, blood tests, imaging, and histopathological sampling are required. Ultrasound should be the first preference for imaging, and excisional biopsy is suggested rather than fine needle aspiration biopsy for histopathological sampling in pediatric neck masses. PMID- 29270571 TI - Investigation of the vitamin B12 deficiency with peripheral neuropathy in patients with type 2 diabetes mellitus treated using metformin. AB - OBJECTIVE: The relationship between vitamin B12 deficiency and peripheral neuropathy has been shown in a number of previous studies. Metformin is the indispensable first-line treatment for type 2 diabetes mellitus (DM) worldwide. One of the adverse effects of the use of metformin is vitamin B12 deficiency. In the present study, we investigated the relationship between vitamin B12 deficiency and peripheral neuropathy due to the use of metformin. METHODS: Patient's laboratory and electromyography (EMG) data were retrospectively reviewed. Patients with no EMG report and other necessary information were excluded from the study. RESULTS: Eighty-six patients with type 2 DM using metformin were included in the study. Of these patients, 26 were males and 60 were females. The mean age of the patients was 55.1+/-7.7 years. The mean body mass index of the patients was 29.1+/-9.01 kg/m2. The mean HbA1c level of the patients was 8.6%+/-2.1%. The mean duration of diabetes was 8.02+/-5.4 years. The incidence of vitamin B12 deficiency was 38.4%. Peripheral neuropathy was detected in 33.7% patients. There was no statistically significant difference in vitamin B12 levels between patients with peripheral neuropathy and those without peripheral neuropathy (p=0.64). CONCLUSION: Therefore, it can be concluded that the lack of vitamin B12 secondary to the use of metformin did not significantly increase the frequency of peripheral neuropathy. PMID- 29270573 TI - Evaluation of the relationship between the femoro-tibial angle and meniscal injury. AB - OBJECTIVE: The purpose of this study was to assess the relationship between the presence of meniscal injury and the femorotibial angle in the knee joint. METHODS: Patients who underwent knee magnetic resonance imaging (MRI) at our department between January 2015 and March 2015 were included in this study. Knee MR images of these patients were retrospectively re-evaluated for meniscal injury. The anatomic femorotibial angle measurements of the patients were calculated using AP knee radiograms. The relationship between femorotibial angle values and the presence of meniscal injury was analyzed. RESULTS: One hundred and fourteen knee joints of 101 patients were included. The mean age of the patients was 40.6+/-13.4 years. The number of injured medial menisci was 92 and the average femorotibial angle in these knees was 5.6+/-1.88; the number of non injured medial menisci was 22 and the average femorotibial angle value in these knees was 5.8+/-1.92 (p=0.82); The number of lateral meniscus with injury was 22 and the mean femorotibial angle value in these knees was 6.1+/-1.50; the number of lateral meniscus without injury was 92 and the average femorotibial angle value in these knees was 5.6+/-1.96 (p=0.20). CONCLUSION: In our study, there was no statistically significant correlation between femorotibial angle values and the presence of injury in medial and lateral meniscuses. We believe that frontal plane bone alignment disorder of the knee does not have a predisposition to meniscal injury. PMID- 29270572 TI - Lipid profile and plasma atherogenic index in postmenopausal osteoporosis. AB - OBJECTIVE: The goal of this study was to investigate the relationship between the lipid profile, plasma atherogenic index (PAI), and osteoporosis in postmenopausal women. METHODS: The data of age, duration of menopause, height, weight, lipid profile, bone mineral density (BMD) value, and history of oral contraceptive use of 407 postmenopausal women who had not been menstruating for at least 12 months, were between the ages 45 and 80, and presented at the obstetrics and gynecology polyclinic of Kartal Dr. Lutfi Kirdar Tr aining and Research Hospital were reviewed. The patients were divided into 2 groups according to the presence of osteoporosis, and the data compared. The level of significance was accepted as p<0.05. RESULTS: A total of 142 postmenopausal patients with osteoporosis were included in the study. The mean age was 61.7+/-6.9 years. In the control group, there were 263 postmenopausal women without osteoporosis, with a mean age of 58.3+/-4.5 years. There was no statistically significant difference with respect to triglyceride level; however, in the osteoporosis group, the level of total cholesterol and low-density lipoprotein (LDL) were lower, and the level of high density lipoprotein (HDL) was higher (p=0.762, p=0.002, p=0.01, p<0.001, respectively). CONCLUSION: A high level of HDL, and low LDL and PAI values, which are important for the prevention of cardiovascular disease, were found to be negative factors for BMD. PMID- 29270574 TI - Fear of childbirth in urban and rural regions of Turkey: Comparison of two resident populations. AB - OBJECTIVE: Childbirth is a natural physiological event experienced by many women; however, it is frequently also a source of fear in women. Rates of cesarean sections in Turkey are higher in the urban areas than in the rural areas. We hypothesized that lower fear of childbirth (FOC) rates would be observed in the city having the lowest cesarean section rates in Turkey. This study aimed to compare FOC in women in two resident populations: one in a rural area and the other in an urban area. METHODS: This study was conducted on 253 pregnant women in Istanbul, a large urban municipality, and Siirt, a city in rural Turkey. A descriptive information form and the A version of the Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) were used. RESULTS: Severe FOC levels were recorded in women in the Istanbul sample; moreover, these levels were higher than those recorded in women in the Siirt sample. In addition, women in the Istanbul sample preferred vaginal birth to cesarean section and had greater FOC, a finding which demonstrates that women prefer vaginal birth even though they have a higher FOC level and live in a city with high cesarean section rates. Where women live (rural versus urban areas) affects their perception of birth and consequently, their FOC levels. CONCLUSION: The results of this study suggest that further cross-cultural and regional research is needed for better understanding FOC and factors associated with elevated FOC levels within each cultural setting. PMID- 29270575 TI - Evaluation of rhabdomyolysis patients who opted for emergency services. AB - OBJECTIVE: Rhabdomyolysis is a clinical and biochemical syndrome caused by skeletal muscle injury. Our aim was to contribute to the existing data on rhabdomyolysis in our country by evaluating the etiologic, demographic, and clinical features of rhabdomyolysis patients who applied to a tertiary hospital emergency department. METHODS: We retrospectively evaluated the data of patients who applied to the tertiary hospital emergency department from January 2015 to January 2016. The study population comprised patients admitted to the emergency department of our hospital with creatinine kinase levels above 5000 U/L at admission. The data of all cases that were included in the study were scanned by the researchers using the hospital's computer-based data recording system. Age, sex, creatine kinase levels, complaints, etiology, whether or not acute renal failure developed, hospitalization and discharge status, and clinic of hospitalization were screened for all patients. RESULTS: The creatine kinase levels of the patients at admission ranged from 5052 to 59140 U/L [median 7882 U/L (IQR: 7840)]. The most frequent (23.5%) cause of admission was extremity pain. The most common reason (19.6%) in the etiology was exercise. Twenty-one patients (41.1%) were admitted to clinics, and 1 patient (1.9%) died. Acute renal failure was observed in 4 patients (8.8%). CONCLUSION: Rhabdomyolysis is a clinical syndrome that can be life-threatening owing to muscle destruction. Although it is suspected after a traumatic injury, it should also be considered when other potential symptoms are observed. All clinicians should be aware of its common causes, diagnosis, and treatment options. PMID- 29270576 TI - The management of acute appendicitis in liver transplant patients: How effective is the Alvarado score? AB - OBJECTIVE: The incidence of acute appendicitis after liver transplantation (LT) is extremely low, reported to be 0.09% to 0.49%, but the efficacy of the Alvarado score in this patient group has not been studied. This study was an investigation of the clinical management of patients who developed acute appendicitis after LT and the usefulness of the Alvarado score in the diagnosis. METHODS: The study was performed using the data of 7 patients treated for acute appendicitis who were among 1990 patients who underwent LT between March 2002 and July 2017. The Alvarado score of the patients was calculated and reliability was analyzed. RESULTS: In this study, the incidence of acute appendicitis in LT patients was 0.35%. All of the patients were in the adult age group; 86% were male. The mean age was 46.4+/-10.7 years and the timeframe for the development of appendicitis after transplantation was a median of 12 months (range: 4-101 months). The median Alvarado score was 7 (range: 5-9). All of the patients had an Alvarado score above 5 and 71% had a score of 7 or more. CONCLUSION: Acute appendicitis is very rare in LT patients. As with non-transplant patients, Alvarado scoring can be safely performed in LT patients. PMID- 29270577 TI - Hallucination: A rare complication of levetiracetam theraphy. AB - Levetiracetam is a new antiepileptic drug. In addition to epilepsy, it is also used for treating anxiety disorders and dystonia as well as tardive dyskinesia associated with the use of levodopa and neuroleptic drugs. Phenytoin therapy in a 10-year-old boy with convulsions was discontinued following cardiac rhythm impairment. The patient was then started on levetiracetam. However, visual and auditory hallucinations were observed on the 1st day of levetiracetam therapy. Levetiracetam was discontinued and replaced with sodium valproate, and the hallucinations resolved. The purpose of this report was to remind physicians that hallucinations are one of the rare complications of levetiracetam. PMID- 29270578 TI - A case of a large Chiari network mimicking a right atrial thrombus. AB - The Chiari network is described as a reticulated network of fibers connected to the Eustachian valve identified as the embryological remnant of the right valve of the sinus venosus. It is an incidental finding without any significant pathophysiological consequences. However, the presence of the Chiari network in the right atrium obliges the physician to differentiate from other right atrial pathologies. We present a case of a large Chiari network mimicking a right atrial thrombus with incidental finding in a 76-year-old man undergoing coronary artery bypass surgery. PMID- 29270579 TI - Early rehabilitation results in a child who developed herpes simplex encephalitis. AB - In this case, a 4-year-old girl was admitted to the emergency service with the complaints of a sudden onset of fever, shortness of breath, jerking motions of the hands and feet and a sliding mouth. Her condition deteriorated, and she was kept under observation in the intensive care unit for 6 days. The Glasgow Coma Score of the patient was 1. Lumbar puncture revealed a white blood cell count of 0 and cerebrospinal fluid was positive for herpes simplex virus 1 and 2. Antiviral therapy was administered for 14 days. One month earlier, the patient had experienced a herpes labialis infection, which suggested herpes simplex encephalitis (HSE). Cranial magnetic resonance imaging indicated significant bilateral cerebral ischemic changes, which also supported suspicion of HSE. After antiviral treatment, the patient was referred to the department of physical therapy and rehabilitation. The Functional Independence Measure for Children (WeeFIM) scale was used to evaluate the patient. A 30-session rehabilitation program based on the Bobath concept of neurodevelopmental therapy was implemented. Before the treatment, the WeeFIM score was 20 points, and at its conclusion, the score was 88 points. The patient began to walk without limitation and the choreoathetosis was almost completely corrected. The patient was discharged with medical treatment and a home-based exercise training program. PMID- 29270580 TI - Gastric cancer with adenocarcinoma and yolk sac tumor components: A rare entity. AB - Despite a sharp worldwide decline in the incidence and mortality due to gastric cancer during the second half of the 20th century, gastric cancer remains the world's second leading cause of cancer-related deaths. Variants of gastric cancer account for approximately 5% of all stomach carcinomas. Herein, we report on a rare case of combined germ cell tumor and adenocarcinoma that arose in the stomach of a 68-year-old woman with a high level of alpha-fetoprotein in the serum. Clinical and pathological findings are presented. PMID- 29270581 TI - Dural prostate metastasis presenting as a subdural hematoma. AB - The incidence of subdural hematoma is approximately 13.1/100.000 per year. Subdural hematoma due to skull and dura mater metastases is rare. In this study, a 71-year-old patient with prostate adenocarcinoma who presented with chronic subdural hematoma due to skull bone and dura mater metastasis is presented. PMID- 29270582 TI - Using terlipressin in a pediatric patient with septic shock resistant to catecholamines. AB - Sepsis and septic shock are important causes of morbidity and mortality in critically ill children. The goal of treatment is to ensure adequate mean arterial pressure to maintain organ perfusion. The growing number of instances of peripheral vascular hyporeactivity to catecholamines has necessitated the search for alternative vasopressors. A 14-year-old boy had septic shock, with a high cardiac index and low systemic vascular resistance index (SVRI) measurements according to pulse contour analysis, despite treatment with dopamine, dobutamine, adrenaline, and noradrenaline infusions. A terlipressin (TP) 10 MUg/kg intravenous bolus was administered, followed by a 1 MUg/kg/minute continuous infusion. The response to TP treatment was assessed using pulse contour analysis. The mean arterial pressure and SVRI increased, and the cardiac index and heart rate decreased within 10 minutes after bolus administration of TP. Noradrenaline infusion could be reduced to 0.7 MUg/kg/minute within 5 hours. The goal in presenting this case was to evaluate the vasoconstrictor effects of TP, a long acting vasopressin analogue, in septic shock. PMID- 29270583 TI - Structural Connectivity Guided Sparse Effective Connectivity for MCI Identification. AB - Recent advances in network modelling techniques have enabled the study of neurological disorders at a whole-brain level based on functional connectivity inferred from resting-state magnetic resonance imaging (rs-fMRI) scan possible. However, constructing a directed effective connectivity, which provides a more comprehensive characterization of functional interactions among the brain regions, is still a challenging task particularly when the ultimate goal is to identify disease associated brain functional interaction anomalies. In this paper, we propose a novel method for inferring effective connectivity from multimodal neuroimaging data for brain disease classification. Specifically, we apply a newly devised weighted sparse regression model on rs-fMRI data to determine the network structure of effective connectivity with the guidance from diffusion tensor imaging (DTI) data. We further employ a regression algorithm to estimate the effective connectivity strengths based on the previously identified network structure. We finally utilize a bagging classifier to evaluate the performance of the proposed sparse effective connectivity network through identifying mild cognitive impairment from healthy aging. PMID- 29270584 TI - Synthesis of azulene-substituted benzofurans and isocoumarins via intramolecular cyclization of 1-ethynylazulenes, and their structural and optical properties. AB - The preparation of azulene-substituted benzofurans and isocoumarins was established by two types of intramolecular cyclization reaction of 1 ethynylazulenes. 2-(1-Azulenyl)- and 2,3-bis(1-azulenyl)benzofurans were prepared by the palladium-catalyzed cross-coupling reaction of 1-iodoazulenes with 2 ethynylphenol and that of 1-ethynylazulenes with 2-iodophenol under Sonogashira Hagihara reaction conditions following the intramolecular nucleophilic addition of the oxygen nucleophile to the presumed 1-arylethynylazulenes. In contrast, 1 (phenylethynyl)azulenes bearing an o-methoxycarbonyl function on the substituted phenyl moiety exhibited intramolecular cyclization either in the presence of trifluoroacetic acid or N-iodosuccinimide (NIS) to afford azulene-substituted isocoumarins and 4-iodoisocoumarins, and the structures were clarified by single crystal X-ray analysis. The optical properties of these compounds were also investigated by UV/vis spectroscopy and theoretical calculations. PMID- 29270585 TI - Conformational switching via an intramolecular H-bond modulates the fluorescence lifetime in a novel coumarin-imidazole conjugate. AB - Achieving synthetic control over light-driven molecular dynamics is essential for designing complex molecule-based devices. Here we design a novel coumarin imidazole conjugate (1) whose excited state structural dynamics are primarily controlled by a distant intramolecular H-bonding interaction within the backbone. The coumarin conjugate is based on a 1,2,4,5-aryl substituted imidazole framework (aryl = -Ph and -PhOH) covalently connected to the coumarin moiety via a C-N bond. A carefully positioned OH group in the aryl part of the imidazole fragment resulted in achieving two dissimilar O-HN and O-HO distal intramolecular hydrogen bonding interactions. NMR studies in conjunction with density functional theory (DFT) at the B3LYP/6-311G(d,p) level of theory show the existence of two ground state conformers with a rotational barrier of 6.12 kcal mol-1. Due to the presence of conformational isomers of 1, the local excited state dynamics of the parent coumarin get biased towards a long-lived fluorescence state with diminished non-radiative decay channels. Time-resolved emission studies show an ~4-5 times increase in the excited state lifetime in 1 when compared to coumarin imidazole conjugates, 2 and 3, without the OH group. Solvent dependent studies show that solvent polarity, the H-bond donating ability and viscosity dictate the conformational distribution in the ground state and the dynamical evolution to the final emissive state. Our studies highlight the importance of rotamerism around the C1-C4 single bond, which leads to rigidification along the coumarin imidazole backbone through a combination of distal H-bonding and solvent interactions. The concept of new emission signaling pathways caused by conformational switching between two states offers a new paradigm to introduce functional allostery in macromolecular backbones. PMID- 29270586 TI - Simulations of hydrogen, carbon dioxide, and small hydrocarbon sorption in a nitrogen-rich rht-metal-organic framework. AB - Grand canonical Monte Carlo (GCMC) simulations of gas sorption were performed in Cu-TDPAH, also known as rht-MOF-9, hereafter [1], a metal-organic framework (MOF) with rht topology consisting of Cu2+ ions coordinated to 2,5,8-tris(3,5 dicarboxyphenylamino)-1,3,4,6,7,9,9b-heptaazaphenalene (TDPAH) ligands. This MOF is notable for the presence of open-metal copper sites and high nitrogen content on the linkers. [1] Exhibits one of the highest experimental H2 uptakes at 77 K/1 atm within the extant rht-MOF family (ca. 2.72 wt%) and also has strong affinity for CO2 (5.83 mmol g-1 at 298 K/1 atm). Our simulations, which include explicit many-body polarization interactions, accurately modeled macroscopic thermodynamic properties (e.g., sorption isotherms and isosteric heats of adsorption (Qst)) as well as the binding sites for H2, CO2, CH4, C2H2, C2H4, and C2H6 in the MOF. Four different binding sites were observed through analysis of the radial distribution function (g(r)) about the two chemically distinct Cu2+ ions, simulated annealing calculations, and examination of the three-dimensional histogram showing the sites of occupancy: (1) at the Cu2+ ion facing toward the center of the linker (CuL), (2) at the Cu2+ ion facing away from the center of linker (CuC), (3) nestled between three [Cu2(O2CR)4] units in the corner of the truncated tetrahedral (T-Td) cage and (4) straddling the copper nuclei parallel to the axis of the Cu-Cu bond within the T-Td cage. The low-loading (initial) binding site in the MOF is highly sensitive to the partial charges of the Cu2+ ions that were used for parametrization. It was discovered that most sorbates prefer to sorb onto or near the Cu2+ ions that exhibit the greater partial positive charge (i.e., at site 1). The simulated H2 and CO2 sorption results obtained using a polarizable potential for the respective sorbates are in good agreement with the corresponding experimental data, especially near ambient pressure. Simulations of gas sorption were also performed in [1] using nonpolarizable potentials for the individual sorbates; these include potentials from the TraPPE force field for most sorbates. PMID- 29270587 TI - Importance of protein flexibility on molecular recognition: modeling binding mechanisms of aminopyrazine inhibitors to Nek2. AB - NIMA-related kinase 2 (Nek2) plays a significant role in cell cycle regulation, and overexpression of Nek2 has been observed in several types of carcinoma, suggesting it is a potential target for cancer therapy. In this study, we attempted to gain more insight into the binding mechanisms of a series of aminopyrazine inhibitors of Nek2 through multiple molecular modeling techniques, including molecular docking, molecular dynamics (MD) simulations and free energy calculations. The simulation results showed that the induced fit docking and ensemble docking based on multiple protein structures yield better predictions than conventional rigid receptor docking, highlighting the importance of incorporating receptor flexibility into the accurate predictions of the binding poses and binding affinities of Nek2 inhibitors. Additionally, we observed that the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations did not show better performance than the docking scoring to rank the binding affinities of the studied inhibitors, suggesting that MM/GBSA is system-dependent and may not be the best choice for the Nek2 systems. Moreover, the detailed information on protein-ligand binding was characterized by the MM/GBSA free energy decomposition, and a number of derivatives with improved docking scores were designed. It is expected that our study can provide valuable information for the future rational design of novel and potent inhibitors of Nek2. PMID- 29270588 TI - [Change of intracellular Ca2+ concentration and related signaling pathway in hippocampal cells after high-intensity sound exposure]. AB - High-intensity sound often leads to the dysfunction and impairment of central nervous system (CNS), but the underlying mechanism is unclear. The present study was aimed to investigate the related mechanisms of CNS lesions in Bama miniature pig model treated with high-intensity sound. The pigs with normal hearing were divided into control and high-intensity sound (900 Hz-142 dB SPL, 15 min) groups. After the treatment, hippocampi were collected immediately. Fluo-4 was used to indicate intracellular Ca2+ concentration ([Ca2+]i) change. Real-time PCR and Western blot were used to detect mRNA and protein expressions of calcium-sensing receptor, L-Ca2+ channel alpha2/delta1 subunit, PKC and PI3K, respectively. DAPI staining was used to identify nuclear features. The result showed that high intensity sound exposure resulted in significantly swollen cell nucleus and increased [Ca2+]i in hippocampal cells. Compared with control group, high intensity sound group showed increased levels of PI3K, PKC and L-Ca2+ channel alpha2/delta1 subunit mRNA expressions, as well as up-regulated PKC and calcium sensing receptor protein expressions. These results suggest that the high intensity sound activates PKC signaling pathway and induces calcium overload, eventually leads to hippocampal injury, which would supply a novel strategy to prevent nervous system from high-intensity sound-induced injury. PMID- 29270589 TI - [Comparison of Parkinson's monkey models induced by unilateral and bilateral intracerebroventricular injections of MPP]. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases, but its pathogenesis is still unclear. Recently a new approach has been used to develop Parkinsonian monkeys with unilateral intracerebroventricular injections of 1-methyl-4-phenylpyridinium ion (MPP+). However, this new method still has some shortcomings, which limits the potential application of MPTP-induced PD monkey models. In the present study, we aimed to develop a modified protocol to induce chronic Parkinsonian non-human primate model with low-dose MPP+ by bilateral intracerebroventricular injections. The induced time of PD model, model stability, phenotypes and 99Tcm-TRODAT-1 single-photon emission computed tomography (SPECT) brain imaging of dopamine transporter were compared between unilateral and bilateral modeling groups. The results showed that PD symptoms in the bilateral modeling group were induced earlier, more serious, and lasted longer after the administration stage, compared with those of the unilateral modeling group. In the unilateral modeling group, radioactive uptake of the striatum was decreased significantly in the left side (MPP+ injected side), but unaffected in the right side. While in the bilateral modeling group, the radioactive uptake of the bilateral striatum was declined dramatically and symmetrically. These results suggest that bilateral intracerebroventricular injection of MPP+ is superior to unilateral intracerebroventricular injection in establishing chronic Parkinsonian non-human primate model and may supply a better animal model for PD research. PMID- 29270590 TI - [Antioxidant effects of celastrol against hydrogen peroxide-induced oxidative stress in the cell model of amyotrophic lateral sclerosis]. AB - To investigate the anti-oxidative effect of celastrol on H2O2-induced oxidative stress in the cell model of amyotrophic lateral sclerosis (ALS) and its molecular mechanism, NSC34 motor neuron-like cells were transfected with EGFP-G93A-SOD1 plasmid and used as in vitro ALS cell model. SOD1G93A transfected NSC34 cells were treated with different doses of H2O2 and celastrol. The survival rate of the cells was detected by CCK-8 assay, and malondialdehyde (MDA) content was detected by corresponding kit. The mRNA expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione S-transferases (GST) were detected by real-time PCR. The activation of intracellular MEK/ERK and PI3K/Akt signal pathways was detected by Western blot. The results showed that pre-incubation of celastrol (50 nmol/L) for 4 h prior to H2O2 (10 MUmol/L) co-treatment for another 24 h significantly attenuated H2O2-induced cell death and MDA level in SOD1G93A transfected NSC34 cells. Real-time PCR showed that the mRNA expressions of GCLC and GST were enhanced with pre-incubation of celastrol. Celastrol quickly induced phosphorylation of ERK1/2 and Akt within 30 min and 1 h respectively in SOD1G93A transfected NSC34 cells. Pharmacological inhibitors of MEK (PD98059, 10 MUmol/L) or Akt (MK2206, 10 MUmol/L) could reverse the phosphorylation of ERK1/2 and Akt, and abolish up-regulation of GCLC and GST induced by celastrol at mRNA levels. Taken together, we conclude that celastrol exerts a beneficial antioxidant effect in SOD1G93ANSC34 cells, which might be dependent on MEK/ERK and PI3K/Akt signaling pathway activation. PMID- 29270591 TI - Caveolin-1 is involved in DNA damage and repair signaling in X-irradiated Chang liver cells. AB - Caveolin-1 (Cav-1), as an important structural protein of caveolae, has been proven to be correlated with several signal transduction pathways. Recent studies have shown that Cav-1 may play a critical role in response to DNA damage in irradiated pancreatic cancer cells. However, it is not known whether down regulation of Cav-1 is required to enhance the damage of other kinds of human cells exposed to X-radiation. In this study, the role of Cav-1 in Chang liver cell line (CHL) exposed to X-radiation was investigated. Cav-1 knockdown cell line (CHL-CAV7) was stably established by the siRNA plasmids transfection, and Cav-1 expression was suppressed by 60%, compared with that of control group (CHL C) which was transfected with non-targeting plasmids. Cellular survival ability and the expressions of proteins related to DNA damage and repair were examined by colony formation assay and Western blot, respectively. Down-regulation of Cav-1 expression induced a significant decrease of the survival rate in CHL-CAV7 cells exposed to 8 and 10 Gy X-radiation. Compared with CHL-C cells, CHL-CAV7 cells showed increased gammaH2AX expression, as well as decreased p-ATM, DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) and p53 protein expressions when treated with X-radiation. Meanwhile, the colocalization of Mdm2 and Cav-1 was decreased in CHL-CAV7 cells compared with that in CHL-C cells. These results suggest that the down-regulation of Cav-1 may aggravate DNA damage of CHL cells through reducing the interaction of Cav-1 and Mdm2, which results in the promotion of p53 degradation. PMID- 29270592 TI - [Activating transcription factor 6-C/EBP homologous protein pathway mediates advanced glycated albumin-induced macrophage apoptosis]. AB - The purpose of this study was to investigate whether activating transcription factor 6 (ATF6), a sensor to endoplasmic reticulum stress (ERS), would mediate advanced glycated albumin (AGE-alb)-induced macrophage apoptosis and to elucidate the possible molecular mechanisms. RAW264.7 macrophages were cultured in vitro and treated with AGE-alb (2, 4 and 6 g/L), normal control albumin or tunicamycin (TM, 4 mg/L) for 24 h. ATF6 small interfering RNA (siRNA) was transfected to RAW264.7 cells by Lipofectamine 2000. Cell viability and apoptosis were determined by MTT method and Annexin V-FITC/propidium iodide apoptosis detection kit, respectively. The activities of lactate dehydrogenase (LDH) in medium and caspase-3 in cells were measured by corresponding detection kits. ATF6 nuclear translocation was detected by Western blot and immunofluorescence cytochemistry. Protein and mRNA levels of C/EBP homologous protein (CHOP, a key-signaling component of ERS-induced apoptosis) were detected by Western blot and real-time fluorescence quantitative PCR, respectively. The results showed that similar to TM, AGE-alb increased the expression of CHOP at both the protein and mRNA levels in a concentration dependent manner. ATF6, as a factor that positively regulates CHOP expression, was activated by AGE-alb in a concentration dependent manner. siRNA-mediated knockdown of ATF6 significantly inhibited AGE-alb-induced macrophage injury, as indicated by the increased cell viability and the decreased LDH release, apoptosis and caspase-3 activation. Additionally, ATF6 siRNA attenuated AGE-alb-induced CHOP upregulation at both the protein and mRNA levels. These results suggest that ATF6 and its downstream molecule CHOP are involved in AGE-alb-induced macrophage apoptosis. PMID- 29270593 TI - [Vasodilation of quercetin on rat renal artery and the relationship with L-type voltage-gated Ca2+ channels and protein kinase C]. AB - To investigate the diastolic function of quercetin on rat renal artery in vitro and its mechanism, the tension of rat renal artery was recorded by multi myograph system, and the L-type voltage-gated Ca2+ channels (LVGC) current was recorded by whole-cell patch clamp technique. Quercetin produced relaxation effect on rat renal artery pre-contracted by 60 mmol/L KCl or 1 * 10-5 mol/L phenylephrine, and the maximal diastolic percentage was (84.53 +/- 7.35)% or (76.42 +/- 4.63)%. There was no statistical difference in the maximal diastolic percentage between endothelium-intact and endothelium-denuded groups. Pre-incubation of protein kinase C (PKC) inhibitor C6303 inhibited the maximal diastolic amplitude induced by quercetin. The peak current density of LVGC in rat renal artery vascular smooth muscle cells (VSMCs) was (23.17 +/- 1.33) pA/pF. Quercetin (10 MUmol/L) inhibited the peak current to (10.46 +/- 1.35) pA/pF, and the inhibition percentage was 54.86%. C6303 (1 MUmol/L) partially reversed the inhibitory effect of quercetin, and the inhibition percentage was 62.08% (P < 0.05). These results suggest that quercetin can relax rat renal artery in vitro in a concentration dependent and endothelium-independent manner. The vasodilation of quercetin may be related to inhibition of LVGC current and activation of PKC. PMID- 29270594 TI - Frozen section with improved H&E staining for follicular morphometric analysis of mouse ovary in oestrus cycle. AB - Careful analysis of follicular morphology and numbers of different follicular maturation stages, in combination with the measurements of gonadotropic and sex hormone profiles, provide an accurate and rapid evaluation system of the ovarian function. The aim of this study is to improve the existing methods of ovarian tissue section preparation and staining methods, and to establish a fast and easy method to observe and evaluate follicular maturation stage and numbers using mouse ovary samples. Ovaries were collected at menstrual phases of proestrus, oestrus, metestrus and diestrus from C57BL/6J female mice. Then the ovaries were fixed in 4% paraformaldehyde, dehydrated with graded sucrose, embedded with OCT, frozen-sectioned at 7 MUm thick, and subjected to quick haematoxylin & eosin staining for observation. The results showed that the present method was able to distinguish secondary, preantral, antral, and preovulatory follicles. Although our method was unable to discriminate and distinguish primordial follicles and primary follicles, the results were comparable to those from more complicated techniques. We conclude that this improved and quick method can be used in combination with hormone analysis to investigate ovarian development and function in different mouse models. PMID- 29270595 TI - [Comparison of the synchronous changes of vascular tension and intracellular Ca2+ signal in third-order branches of mesenteric arteries under the different objective amplification of confocal microscope]. AB - This study was aimed to establish an optimized method to observe the synchronous changes of vascular tension and intracellular Ca2+ signal in the third-order branches of mesenteric arteries (sMA, diameter: 100-300 MUm). The vascular tension and intracellular Ca2+ signal changes in response to potassium chloride (KCl), endothelin-1 (ET-1) and Gd3+ were detected using confocal wire myograph system and confocal laser scanning microscopy imaging technique, respectively. The experimental results were analyzed to explore the optimal experimental conditions. The results showed that KCl caused contraction in sMA significantly, and the intracellular Ca2+ level of vascular smooth muscle cells (VSMCs) was also increased under 20* and 40* objective lens. Compared with those under the 40* objective lens, the Ca2+ signal change was larger and the fluorescence value was more stable under the 20* objective lens, whereas the Ca2+ signal change was not obvious under the 10* objective lens. ET-1 (1-10 nmol/L) caused concentration dependent contraction in sMA significantly, and the intracellular Ca2+ signal of VSMCs was also enhanced in a concentration dependent manner. Additionally, Gd3+ significantly reduced the contraction of sMA and the intracellular Ca2+ signal of VSMCs caused by ET-1. The results suggest that the intracellular Ca2+ signal of VSMCs changes with vascular contraction or relaxation caused by the agonists or antagonists of Ca2+ channels. We successfully recorded both changes synchronously using confocal wire myograph system and confocal laser scanning microscopy imaging technique at the same time. Based on the analysis of the experimental results, we concluded that 20* objective lens provides the best experimental condition. Compared to combination of vascular tone detection method and real time cellular fluorescence imaging technique, the present synchronous method is convenient and helpful to reduce experimental error. PMID- 29270596 TI - [Astrocytes as therapeutic targets after spinal cord injury]. AB - Spinal cord injury (SCI) is a challenging medical problem in the field of neurology, showing high incidence rate, disability rate, treatment cost and low aged trend. Despite the clinical application of drug intervention, surgical treatment and modern rehabilitation training, no ideal curative effect has been achieved. Therefore, future study is necessary to clarify detailed pathological mechanism of SCI and identify the potential target cells for therapeutic intervention. In the central nervous system (CNS), astrocytes are the most abundant and widely distributed glial cells which play multiple key roles in maintaining homeostasis of the CNS in physiological and pathological conditions. Increasing evidence indicates that astrocytes are ideal therapeutic target cells for SCI. Here, we review current knowledge of the roles of astrocytes in the pathological reaction after SCI, astroglial transplantation and astrocyte reprogramming. PMID- 29270597 TI - [Progress in the application of neural oscillations cross-frequency coupling in cognitive function research]. AB - Neural oscillations cross-frequency coupling (CFC) refers to the effect of the cross modulation between the electrophysiological oscillation rhythm in different ensembles of neurons. The CFC can reflect the mechanism of information transfer and exchange of local field potentials, electroencephalograph (EEG) and other neural electrophysiological activities at different spatial and temporal scales and plays an important role in the study of cognitive function. This paper introduces the basic phenomenon and classifications of neural oscillation CFC briefly, and reviews the typical applications in the study of the animal cognition model and human cognitive function in recent years, respectively. The main problems are also summarized and the future research is prospected in order to provide new ideas to promote the study and application of the CFC. PMID- 29270598 TI - [Progress in metabolism and function of myelin lipids]. AB - Myelin is a highly specialized membrane structure, wrapping around the axons. It is essential for the protection of axons, insulation and maintenance of the saltatory conduction of the action potential. Myelin membrane is rich in lipids, however, the lipid composition varies significantly from other biological membranes. Since myelination requires extraordinarily high level of lipid synthesis, the integrity of myelin is susceptible to numerous lipid metabolism disorders. Studies on transgenic mice targeting key molecules of various lipid biosynthesis pathways have elucidated the lipid metabolism and functions of myelin. Besides, myelinating glial cells have a remarkable capacity to take up extracellular lipids, which also contributes to myelination. Therefore, understanding the metabolism and functions of myelin lipids will help us to understand the role of lipids in myelin damage-related diseases and provide novel strategies for the treatment of demyelinating diseases. In this paper, some progresses in metabolism and functions of myelin lipids are reviewed. PMID- 29270599 TI - [A sketch of the overlap in the neural circuitry underlying psychological- and physical-pain]. AB - From the phenomenological point of view, pain can be classified into psychological-pain and physical-pain. Emerging evidence has shown that the psychological- and physical-pain recruit overlapping neural activity in regions associated with the affective component of pain, and share some common pain circuits, e.g., the dorsal anterior cingulate cortex (dACC) and the anterior insula (AI) play important roles in both psychological- and physical-pain. Therefore, understanding the way in which psychological- and physical-pain demonstrate either similarity or discrepancy may provide new insights into the relationship between the two types of experiences and potential targets for treating psychological suffering. This review summarizes research progress that has been obtained through experiments conducted in human and nonhuman animals to discuss the similarity, discrepancy and interaction between psychological- and physical-pain. The important next steps, e.g., uncovering the mechanisms underlying the overlap of psychological- and physical-pain; and whether chronic psychological-pain shapes brain plasticity as physical-pain does, are also discussed. PMID- 29270600 TI - [Neutrophils regulate the process of angiogenesis]. AB - Neutrophils are one of the most abundant leukocytes present in the human blood circulation system, which could provide continuous immune surveillance. Recent studies have shown that neutrophils are closely related to angiogenesis. Neutrophils could release various cytokines, which regulate the angiogenic process by affecting the growth and migration of endothelial cells directly or indirectly. In the present review, the regulatory effects of neutrophils on angiogenic process and mechanisms are analyzed and summarized, which would provide clues for the treatment of related diseases using neutrophils as the targets in the future. PMID- 29270601 TI - [Research progress in the modulating effect of high-density lipoprotein on neutrophil function]. AB - For a long period, studies about the modulating effect of high-density lipoprotein (HDL) on inflammatory cells mainly focus on cardiovascular diseases. In recent years, researchers have found the significant role of HDL in many other fields, such as diabetes, metabolic syndrome, chronic kidney disease, systemic inflammatory disease, autoimmune diseases and infectious diseases. Researches have shown that HDL can inhibit the function of activated neutrophil via disturbing the cytokine production, deformation, adhesion, transmigration and pathogen elimination. Clinical trials have discovered that serum HDL level is negatively correlated with neutrophil-to-lymphocyte ratio in healthy males with low HDL level. In addition, serum HDL level is closely associated with disease severity of severe acute pancreatitis. Consequently, understanding the effect and mechanism of the regulation of HDL on neutrophil function plays an important role in remedying the diseases resulted from excessively activated neutrophil. PMID- 29270602 TI - [L-VDCC autoregulation abnormality contributes to calcium overload in myocardial ischemia-reperfusion injury]. AB - Calcium overload is a vital mechanism of myocardial ischemia-reperfusion injury, which is a hot therapeutic target in cardiovascular research. It has been well recognized that the dysfunction of calcium relevant proteins, including L-type voltage- dependent calcium channel (L-VDCC), sarco/endoplasmic reticulum ATPase 2a (SERCA2a)/phospholamban (PLB), RyR2, Na+/Ca2+ exchanger, Na+/H+ exchanger, etc. contributes to calcium overload in cardiomyocytes during ischemia reperfusion injury, in which the diastolic calcium concentration is increased and the amplitude of calcium transients is decreased. There are two phases in calcium increase. The early phase is partially mediated by calcium channels, and the latter one is mainly mediated by Na+/Ca2+ exchanger. L-VDCC, a main subtype of calcium channels in myocardium, is involved in calcium overload, but the underlying molecular mechanism is not well elucidated yet. L-VDCC is regulated by intrinsic and extrinsic pathways. PKG and PKA as extrinsic regulators are not proper candidates to increase L-VDCC activity of cardiomyocyte in vitro, whereas the myocardial ischemia-reperfusion injury is highly possible to enhance L-VDCC activity by delaying calcium-dependent inactivation (CDI), advancing calcium dependent facilitation (CDF), and weakening distal carboxy terminus (DCT) inhibition. Therefore, it is rational to propose that the L-VDCC autoregulation abnormality may play an important role in calcium overload during myocardial ischemia-reperfusion injury. PMID- 29270604 TI - Suturing Technique for the Correction of the Obtuse Nasolabial Angle. PMID- 29270603 TI - A Cross-sectional Analysis of Adverse Events and Litigation for Injectable Fillers. AB - Importance: Injectable fillers are increasing in popularity as a noninvasive option to address concerns related to facial aging and volume loss. To our knowledge, there have been no large-scale analyses of adverse events and associated litigation related to filler injections. Objectives: To determine risks of injectable fillers and analyze factors raised in litigation related to injectable fillers. Design, Setting, and Participants: In this cross-sectional review, the US Food and Drug Administration's (FDA) manufacturer and user facility device experience (MAUDE) database was evaluated for complications from the use of the following fillers: Juvederm, Restylane, Belotero, Sculptra, Radiesse, Artefill, Bellafill, and Juvederm Voluma from 2014 to 2016. The Westlaw Next database was used to identify jury verdicts. Main Outcomes and Measures: Complications were organized by type of filler used, location of injection, and severity. Intra-arterial injections without sequelae and those resulting in blindness or necrosis were considered severe complications. Factors raised during the litigation process were also analyzed. Results: Of 1748 adverse events analyzed, most cases stemmed from cheek (751 [43.0%]) or lip (524 [30.0%]) injection. Commonly reported adverse events reported included swelling (755 [43.2%]) and infection (725 [41.5%]). Among FDA-reported complications, blindness was significantly associated with dorsal nasal injections (P < .001). Vascular compromise with and without sequela of dermal necrosis and blindness were significantly associated with Radiesse injections P < .001. Of the 9 malpractice cases identified, two-thirds involved allegations of inadequate informed consent, and the median award in cases resolved with payment was $262 000. Conclusions and Relevance: Although specific complication profiles vary by material and injection site, common adverse events associated with injectable fillers include swelling and infection. More serious events include vascular compromise, resulting in necrosis and blindness; these events are also raised in cases involving litigation. This analysis illustrates the importance of outlining these risks in a comprehensive preoperative informed consent process. Level of Evidence: NA. PMID- 29270605 TI - A meta-analysis of perceptual and cognitive functions involved in useful-field-of view test performance. AB - The useful-field-of-view (UFOV) test measures the amount of information someone can extract from a visual scene in one glance. Its scores show relatively strong relationships with everyday activities. The UFOV test consists of three computer tests, suggested to measure processing speed and central vision, divided attention, and selective attention. However, other functions seem to be involved as well. In order to investigate the contribution of these suggested and other perceptual and cognitive functions, we performed a meta-analysis of 116 Pearson's correlation coefficients between UFOV scores and other test scores reported in 18 peer-reviewed articles. We divided these correlations into nine domains: attention, executive functioning, general cognition, memory, spatial ability, visual closure, contrast sensitivity, visual processing speed, and visual acuity. A multivariate mixed-effects model analysis revealed that each domain correlated significantly with each of the UFOV subtest scores. These correlations were stronger for Subtests 2 and 3 than for Subtest 1. Furthermore, some domains were more strongly correlated to the UFOV than others across subtests. We did not find interaction effects between subtest and domain, indicating that none of the UFOV subtests is more selectively sensitive to a particular domain than the others. Thus, none of the three UFOV subtests seem to measure one clear construct. Instead, a range of visual and cognitive functions is involved. Perhaps this is the reason for the UFOV's high ecological validity, as it involves many functions at once, making it harder to compensate if one of them fails. PMID- 29270606 TI - Erythematous Velvety Plaque of the Scrotum and Penis. PMID- 29270607 TI - Suturing Technique for the Correction of the Obtuse Nasolabial Angle-Reply. PMID- 29270608 TI - Association of Preoperative and Postoperative Serum Carcinoembryonic Antigen and Colon Cancer Outcome. AB - Importance: Guidelines recommend measuring preoperative carcinoembryonic antigen (CEA) in patients with colon cancer. Although persistently elevated CEA after surgery has been associated with increased risk for metastatic disease, prognostic significance of elevated preoperative CEA that normalized after resection is unknown. Objective: To investigate whether patients with elevated preoperative CEA that normalizes after colon cancer resection have a higher risk of recurrence than patients with normal preoperative CEA. Design, Setting, and Participants: This retrospective cohort analysis was conducted at a comprehensive cancer center. Consecutive patients with colon cancer who underwent curative resection for stage I to III colon adenocarcinoma at the center from January 2007 to December 2014 were identified. Exposures: Patients were grouped into 3 cohorts: normal preoperative CEA, elevated preoperative but normalized postoperative CEA, and elevated preoperative and postoperative CEA. Main Outcomes and Measures: Three-year recurrence-free survival (RFS) and hazard function curves over time were analyzed. Results: A total of 1027 patients (461 [50.4%] male; median [IQR] age, 64 [53-75] years) were identified. Patients with normal preoperative CEA had 7.4% higher 3-year RFS (n = 715 [89.7%]) than the combined cohorts with elevated preoperative CEA (n = 312 [82.3%]) (P = .01) but had RFS similar to that of patients with normalized postoperative CEA (n = 142 [87.9%]) (P = .86). Patients with elevated postoperative CEA had 14.9% lower RFS (n = 57 [74.5%]) than the combined cohorts with normal postoperative CEA (n = 857 [89.4%]) (P = .001). The hazard function of recurrence for elevated postoperative CEA peaked earlier than for the other cohorts. Multivariate analyses confirmed that elevated postoperative CEA (hazard ratio [HR], 2.0; 95% CI, 1.1-3.5), but not normalized postoperative CEA (HR, 0.77; 95% CI, 0.45-1.30), was independently associated with shorter RFS. Conclusions and Relevance: Elevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Routine measurement of postoperative, rather than preoperative, CEA is warranted. Patients with elevated postoperative CEA are at increased risk for recurrence, especially within the first 12 months after surgery. PMID- 29270611 TI - Funding Innovation in a Learning Health Care System. PMID- 29270612 TI - Indirect vs Direct Voice Therapy for Children With Vocal Nodules: A Randomized Clinical Trial. AB - Importance: Benign vocal fold nodules affect 12% to 22% of the pediatric population, and 95% of otolaryngologists recommend voice therapy as treatment. However, no randomized clinical trials that we are aware of have shown its benefits. Objective: To determine the impact of voice therapy in children with vocal fold nodules according to pretherapy and posttherapy scores on the Pediatric Voice-Related Quality of Life (PVRQOL) survey; secondary objectives included changes in phonatory parameters. Design, Setting, and Participants: For this multicenter randomized clinical trial, 114 children ages 6 to 10 years with vocal fold nodules, PVRQOL scores less than 87.5, and dysphonia for longer than 12 weeks were recruited from outpatient voice and speech clinics. This age range was identified because these patients have not experienced pubertal changes of the larynx, tolerate stroboscopy, and cooperate with voice therapy. Participants were blinded to treatment arm. Interventions: Participants received either indirect or direct therapy for 8 to 12 weeks. Indirect therapy focused on education and discussion of voice principles, while direct treatment used the stimulus, response, antecedent paradigm. Main Outcomes and Measures: The primary outcome measure was PVRQOL score change before and after treatment. Secondary phonatory measures were also compared. Results: Overall, 114 children were recruited for study (mean [SD] age, 8 [1.4] years; 83 males [73%]); with 57 randomized to receive either indirect or direct therapy. Both direct and indirect therapy approaches showed significant differences in PVRQOL scores pretherapy to posttherapy. The mean increase in PVRQOL score for direct therapy was 19.2, and 14.7 for indirect therapy (difference, 4.5; 95.3% CI, -10.8 to 19.8). Of 44 participants in the direct therapy group, 27 (61%) achieved a clinically meaningful PVRQOL improvement, compared with 26 of 49 (53%) for indirect therapy (difference, 8%; 95% CI, -12 to 28). Post hoc stratification showed robust effects in the direct therapy group for older children (Cohen d = 0.50) and the latter two-thirds of participants (Cohen d = 0.46). Vocal fold nodules reduced in size in 31% (22 of 70) and completely resolved in 11% (8 of 70) of participants who consented to a second set of images after going through the recruitment process. Conclusions and Relevance: Both direct and indirect voice therapy improved voice-related quality of life in children with vocal fold nodules, although there was no significant difference between approaches. Future studies may focus upon which voice therapy approaches are effective in treating age defined populations. Trial Registration: clinicaltrials.gov Identifier: NCT01255735. PMID- 29270614 TI - Hypercoagulability and Severe Obstructive Sleep Apnea-Reply. PMID- 29270613 TI - Association of Sudden Sensorineural Hearing Loss With Risk of Cardiocerebrovascular Disease: A Study Using Data From the Korea National Health Insurance Service. AB - Importance: The interruption of vascular supply to the cochlea has been proposed as a major etiological factor for sudden sensorineural hearing loss (SSNHL), and several risk factors for cardiocerebrovascular disease (CCVD) are associated with SSNHL, including heavy smoking, alcohol consumption, and thromboembolic events. However, the link between SSNHL and CCVD has not been fully evaluated. Objective: To investigate the association between SSNHL and CCVD. Design, Setting, and Participants: A retrospective propensity score-matched cohort study was conducted using a nationwide representative sample from the National Sample Cohort 2002 through 2013 data from the Korea National Health Insurance Service. The SSNHL group (n = 154) included certain patients who were diagnosed with SSNHL between January 2003 and December 2005. The comparison group was selected (4 patients for every 1 patient with SSNHL; n = 616) using propensity score matching, according to sociodemographic factors and the year of enrollment. Each patient was monitored until 2013. Main Outcomes and Measures: Survival analysis, the log-rank test, and Cox proportional hazards regression models were used to calculate the incidence, survival rate, and hazard ratio of CCVD for each group. Results: Among the 770 patients, 385 (50.0%) were female and 370 (48.1%) were aged between 45 and 64 years. Of the total study population, 66 patients developed CCVD, such as stroke and acute myocardial infarction, during the 11-year follow-up period: 18 patients in the SSNHL group (incidence, 13.5 cases per 1000 person-years) and 48 from the comparison group (incidence, 7.5 cases per 1000 person-years). After adjustment for other factors, the hazard ratio of CCVD during the 11-year follow up period was 2.18 times (95% CI, 1.20-3.96) greater for patients with SSNHL. An increased risk of stroke was associated with SSNHL (HR, 2.02; 95% CI, 1.16-3.51); however, there was no relation between SSNHL and risk of myocardial infarction (HR, 1.18; 95% CI, 0.25-5.50). Conclusions and Relevance: This observational study using nationwide data suggests that SSNHL is associated with an increased incidence of CCVD, specifically stroke. Therefore, patient surveillance for signs of CCVD should be considered for patients who receive a diagnosis of SSNHL. PMID- 29270617 TI - Errors Table 2. PMID- 29270616 TI - Our Shared Humanity-Music as a Means of Facilitating Conversations on End-of-Life Care. PMID- 29270618 TI - Human-Machine Collaboration-A New Form of Paternalism? PMID- 29270615 TI - Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis. AB - Importance: Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non-small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics. Objective: To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics. Data Sources: This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017. Study Selection: Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients' clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017. Data Extraction and Synthesis: Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method. Results: In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P < .001). They prolonged overall survival in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P < .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P = .54; interaction, P = .005), and they prolonged overall survival in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24). The relative treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (<65 years [HR, 0.71] vs >=65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), or sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82). Conclusion and Relevance: Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second line therapy in NSCLC. The finding of no overall survival benefit for patients with EGFR mutant tumors suggests that checkpoint inhibitors should be considered only after other effective therapies have been exhausted. The findings of this meta-analysis could also assist in the design and interpretation of future trials and in economic analyses. PMID- 29270619 TI - A Case of Progressive Dimming Vision. PMID- 29270621 TI - Generalized Radiopacities of the Craniofacial Skeleton. PMID- 29270620 TI - Traumatic Tympanic Membrane Perforations Diagnosed in Emergency Departments. AB - Importance: Tympanic membrane perforations (TMPs) are frequent events leading to evaluation in the primary care and otolaryngology offices or the emergency department (ED). Despite specific warning labels on packaging of cotton-tipped applicators regarding the risk of injury to the ear canal with personal use, these products are commonly used to remove ear cerumen. Objective: To analyze the mechanism of injury for traumatic TMPs among patients presenting to the ED. Design, Setting, and Participants: Cross-sectional analysis of cases from 100 emergency departments in the United States. The National Electronic Injury Surveillance System was searched on April 3, 2015, for ear-related injuries with analysis information regarding patient age, patient sex, time and date of injury, specific injury diagnoses, and specific injury mechanisms that occurred across 5 years, from January 1, 2010, through December 31, 2014. Main Outcomes and Measures: Diagnoses of traumatic TMP documented in the ED visit record as well as patient demographics, diagnoses, and other aspects of the injury, including mechanism of injury. Results: There were 949 case entries in the database for traumatic TMP, which extrapolates to 4852 ED visits nationally. Of 949 patients evaluated, 568 (59.8%) were men and 381 (40.2%) were women resulting in a male to female ratio of 1.49:1. Most injuries occurred in patients 18 years or younger (602 of 949 [63.4%]) with children younger than 6 years most at risk (331 of 949 [34.9%]). Ear canal instrumentation including foreign bodies was noted in 581 of 949 cases (61.2%), with cotton-tipped applicators noted in 261 (44.9%) of these cases. While foreign body instrumentation represented the leading cause of traumatic TMP in patients aged 0 to 5 years (284 of 331 cases [85.8%]), 6 to 12 years (108 of 158 [68.4%]), 19 to 36 years (85 of 223 [38.1%]), 37 to 54 years (48 of 91 [52.7%]), and 55 years or older (22 of 33 [66.7%]), water trauma was the leading cause of TMP in patients aged 13 to 18 years (43 of 113 cases [38.1%]). Conclusions and Relevance: Traumatic TMP represents a common reason for evaluation in the ED. Despite common warnings regarding risk of injury to the tympanic membrane with use of a cotton-tipped applicator, it is still a major cause of traumatic TMPs. Other injury mechanisms also play an important role in the teenage and young adult populations. PMID- 29270622 TI - Immediate Effects of External Vibration vs Placebo on Vocal Function Therapy in Singers: A Randomized Clinical Trial. AB - Importance: External vibration therapy (EVT) has been widely used in chronic pain conditions, musculoskeletal rehabilitation, and athletic training. Vibration therapy has been suggested to enhance vocal performance and has been popularized in social media. However, there is no evidence to support its effect on vocal function. Objective: To evaluate the immediate effects of EVT in trained singers using acoustic and self-assessment parameters. Design, Setting, and Participants: Prospective, randomized, placebo-controlled interventional study at St Michael's Hospital Voice Clinic, affiliated with the University of Toronto. Data collection and analysis were performed by investigators who were blinded to the group assignment of the participants. Study participants were randomized to EVT or a placebo (control) group. The study dates were September 2015 to December 2016. Interventions: Participants attended the voice laboratory at St Michael's Hospital, where a standardized data collection protocol was performed, including acoustic parameters, voice range profile, and soft voice tasks, followed by subjective rating of vocal effort or discomfort. The EVT group underwent EVT to 5 neck sites bilaterally. The placebo group underwent the same protocol with a modified device. After the intervention, the participants repeated the standardized data collection. Main Outcomes and Measures: The primary outcome in this study was acoustic analysis (jitter, shimmer, and pitch range) compared before and after treatment. In addition, secondary outcomes included perceived effort or discomfort evaluated by participants after 4 voice tasks proposed to investigate more subtle voice properties. Within and between groups, data sets were statistically analyzed for potential treatment effect. Results: Among 27 participants (age range, 18-50 years; all female), 14 were randomized to the intervention group and 13 to the placebo group. Comparison of the treatment effect on the vowel token acoustic parameters evaluated showed that, after EVT, participants had a more cohesive change with a restricted 95% CI compared with placebo. The mean change in fundamental frequency after intervention was 5.00 Hz in both groups but the 95% CI was much wider after placebo (-30.30 to 19.20) than after EVT (-18.10 to 7.50). After EVT, the effect size was notable in the vowel (0.83) and SVT3 (0.79) task. Conclusions and Relevance: In this study, EVT demonstrated a more predictable change in acoustic metrics compared with the placebo treatment. Effort ratings for 6 voice tasks evaluated in this study were not found to be different after EVT compared with the placebo treatment. Trial Registration: clinicaltrials.gov Identifier: NCT02083341. PMID- 29270623 TI - Hypercoagulability and Severe Obstructive Sleep Apnea. PMID- 29270625 TI - Carcinoembryonic Antigen-Still More to Learn From the Real World. PMID- 29270624 TI - Association of Gastroesophageal Reflux With Malignancy of the Upper Aerodigestive Tract in Elderly Patients. AB - Importance: Chronic inflammatory states have been linked to the development of malignancy. Gastroesophageal reflux disease (GERD) is a known risk factor for esophageal adenocarcinoma as the end result of chronic inflammatory changes. Objective: To investigate the association of GERD with the risk of malignancy in the upper aerodigestive tract (UADT). Design, Setting, and Participants: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to conduct a case-control study of individuals in the United States who had been added from January 2003 through December 2011 and were 66 years or older. The study included patients diagnosed with malignancy of the larynx, hypopharynx, oropharynx, tonsil, nasopharynx, and paranasal sinuses. GERD was examined as an exposure. Controls were matched from a 5% random sample of Medicare beneficiaries without cancer. Multivariable unconditional logistic regression was performed. Main Outcomes and Measures: Incidence of invasive malignancies of the UADT. Results: A total of 13 805 patients (median [range] age, 74 [66-99] years; 3418 women [24.76%] and 10 387 men [75.24%]) with malignancy of the UADT were compared with 13 805 patients without disease and were matched for sex, age group, and year of diagnosis. GERD was associated with a greater odds of developing malignancy of the larynx (adjusted odds ratio [aOR], 2.86; 95% CI, 2.65-3.09), hypopharynx (aOR, 2.54; 95% CI 1.97-3.29), oropharynx (aOR, 2.47; 95% CI, 1.90 3.23), tonsil (aOR, 2.14; 95% CI, 1.82-2.53), nasopharynx (aOR, 2.04; 95% CI, 1.56-2.66), and paranasal sinuses (aOR, 1.40; 95% CI, 1.15-1.70). Conclusions and Relevance: GERD is associated with the presence of malignancy of the UADT in the US elderly population. This epidemiological association requires further examination to determine causality and diagnostic utility. PMID- 29270626 TI - Addition to Funding/Support. PMID- 29270627 TI - Payments, Conflict of Interest, and Trustworthy Otolaryngology Clinical Practice Guidelines. PMID- 29270628 TI - Prevalence of Laryngeal Cleft in Pediatric Patients With Esophageal Atresia. AB - Importance: Esophageal atresia (EA), with or without tracheoesophageal fistula (TEF), and laryngeal cleft are rare congenital anomalies that often occur together. Previous reports have established a link between EA/TEF and laryngeal cleft, but there have been no large case series to further characterize this relationship. Objectives: To assess the prevalence of laryngeal cleft among patients with EA/TEF, identify associations between types of laryngeal cleft and EA/TEF, and identify factors associated with the timing of diagnosis for both conditions. Design, Setting, and Participants: Retrospective analysis of 270 patients. The Esophageal Atresia database was used to identify patients seen at the Esophageal and Airway Treatment (EAT) Center at Boston Children's Hospital, Boston, Massachusetts, a tertiary referral hospital, from August 1, 2009, to August 1, 2016. Patients were included if they were younger than 18 years at the time they were diagnosed with EA, TEF, or both and had undergone a procedure or examination by a surgeon from the EAT Center. Patients with acquired airway or esophageal problems were excluded. Main Outcomes and Measures: Data regarding patient demographics, primary diagnoses, dates of diagnosis, comorbidities, and airway/esophageal surgical interventions were collected and analyzed. Association between type of EA/TEF and laryngeal cleft type was evaluated. Secondary outcomes were age at diagnosis between patients who resided in Massachusetts and those who resided outside the state. Results: Of 270 patients diagnosed with EA/TEF during the 7-year period, 138 (51.1%) were male, and the median age at diagnosis of EA/TEF was 1.0 years (IQR, 0.4-2.0) and at diagnosis of laryngeal cleft was 1.1 years (interquartile range [IQR], 0.6-2.8). Laryngeal cleft was diagnosed in 53 of the 270 patients (19.6%) (95% CI, 14.9%-24.4%). No apparent difference was found in the distribution of types of laryngeal cleft by type of EA/TEF. Among patients with EA/TEF type A or B, 9 patients (56%) had a type I cleft, 6 (38%) had a type II cleft, and 1 (6%) had a type III cleft. Among those with EA/TEF type C or D, 20 (57%) had a type I cleft, 11 (31%) had a type II cleft, and 3 (9%) had a type III cleft. Out-of-state patients were more likely to be diagnosed with EA/TEF at an older age than in-state patients (mean difference, 1.5 years; 95% CI, 0-2.9 years). Conclusions and Relevance: Pediatric patients with EA/TEF have a much greater prevalence of laryngeal cleft than the general population. Multidisciplinary esophageal and airway programs serve as an ideal clinical setting for management of EA/TEF. PMID- 29270629 TI - Clinicopathologic Features of Tuberculous Serpiginous-like Choroiditis. PMID- 29270630 TI - Adult-Onset Giant Cervical Mass. PMID- 29270631 TI - Financial Conflicts of Interest Among Oncology Clinical Pathway Vendors. PMID- 29270632 TI - Association of Dietary Fatty Acid Intake With Glaucoma in the United States. AB - Importance: Identifying whether an association exists between daily dietary polyunsaturated fatty acid (PUFA) consumption and the prevalence of glaucoma in the United States may provide modifiable dietary risk factors for the development of glaucoma. Objective: To analyze the association between glaucoma and daily dietary intake of PUFAs, including omega-3 fatty acids, in the US population. Design, Setting, and Participants: Data from 3865 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2008 database who were 40 years or older, had participated in the vision health and dietary intake questionnaires, and had available results from laboratory tests and eye examinations that included frequency-doubling technology visual field loss detection tests and optic disc photographs were included. Data collection was performed by NHANES from 2005 to 2006. Data for the present study were downloaded from their database May 1 to 30, 2017. Data analyses were performed from June 1 to October 1, 2017. Exposures: Daily dietary intake of PUFAs, including omega-3 fatty acids. Main Outcomes and Measures: Prevalence of glaucoma in the United States as defined using the Rotterdam criteria, which included a combination of optic cupping or asymmetry and visual field defect results. Results: Of the 83 643 392 weighted survey participants included in this cross-sectional study, 43 660 327 (52.2%) were women and 3 076 410 (3.7%) met our criteria for having glaucoma. Compared with participants without glaucoma, those with glaucoma were older (mean [SE] age, 61.4 [0.8] vs 53.7 [0.4] years; P < .001). Increased levels of daily dietary intake of eicosapentaenoic acid (odds ratio [OR], 0.06; 95% CI, 0.00-0.73) and docosahexaenoic acid (OR, 0.06; 95% CI, 0.01-0.87) were associated with significantly lower odds of having glaucoma. However, participants with daily total dietary PUFA intake levels in the second (OR, 2.84; 95% CI, 1.39 5.79) and third (OR, 2.97; 95% CI, 1.08-8.15) quartiles showed significantly increased odds of meeting our criteria for a diagnosis of glaucoma. Conclusions and Relevance: Increased daily dietary consumption levels of eicosapentaenoic acid and docosahexaenoic acid were associated with lower likelihood of glaucomatous optic neuropathy. However, consumption levels of total PUFAs in the higher quartiles were associated with a higher risk of glaucoma, which may have resulted from the relative intakes of omega-6 and omega-3 fatty acids and other confounding comorbidities. This study also hypothesizes that increasing the proportion of dietary omega-3 consumption levels while controlling overall daily PUFA intake may be protective against glaucoma. However, longitudinal studies or randomized clinical trials are needed to assess these hypotheses. PMID- 29270634 TI - Nasopharyngeal Swelling in a Patient With Cystic Fibrosis Following Endoscopic Sinus Surgery. PMID- 29270633 TI - Evaluation of Industry Relationships Among Authors of Otolaryngology Clinical Practice Guidelines. AB - Importance: Financial relationships between physicians and industry have influence on patient care. Therefore, organizations producing clinical practice guidelines (CPGs) must have policies limiting financial conflicts during guideline development. Objectives: To evaluate payments received by physician authors of otolaryngology CPGs, compare disclosure statements for accuracy, and investigate the extent to which the American Academy of Otolaryngology-Head and Neck Surgery complied with standards for guideline development from the Institute of Medicine (IOM). Design, Setting, and Participants: This cross-sectional analysis retrieved CPGs from the American Academy of Otolaryngology-Head and Neck Surgery Foundation that were published or revised from January 1, 2013, through December 31, 2015, by 49 authors. Data were retrieved from December 1 through 31, 2016. Industry payments received by authors were extracted using the Centers for Medicare & Medicaid Services Open Payments database. The values and types of these payments were then evaluated and used to determine whether self-reported disclosure statements were accurate and whether guidelines adhered to applicable IOM standards. Main Outcomes and Measures: The monetary amounts and types of payments received by physicians who author otolaryngology guidelines and the accuracy of disclosure statements. Results: Of the 49 physicians in this sample, 39 (80%) received an industry payment. Twenty-one authors (43%) accepted more than $1000; 12 (24%), more than $10 000; 7 (14%), more than $50 000; and 2 (4%), more than $100 000. Mean (SD) financial payments amounted to $18 431 ($53 459) per physician. Total reimbursement for all authors was $995 282. Disclosure statements disagreed with the Open Payments database for 3 authors, amounting to approximately $20 000 among them. Of the 3 IOM standards assessed, only 1 was consistently enforced. Conclusions and Relevance: Some CPG authors failed to fully disclose all financial conflicts of interest, and most guideline development panels and chairpersons had conflicts. In addition, adherence to IOM standards for guideline development was lacking. This study is relevant to CPG panels authoring recommendations, physicians implementing CPGs to guide patient care, and the organizations establishing policies for guideline development. PMID- 29270635 TI - Human-Machine Collaboration-A New Form of Paternalism?-Reply. PMID- 29270636 TI - Cataract Surgery Outcomes in Eyes With Primary Epiretinal Membrane. AB - Importance: Primary epiretinal membrane (ERM) is a common retinal disorder with a prevalence of 4% to 18.5%. Although ERM and cataracts commonly occur together, to our knowledge, no studies have investigated the outcome of cataract surgery alone in this setting. Objective: To analyze the visual outcome and cystoid macular edema risk with cataract surgery in eyes with primary ERM. Design, Setting, and Participants: In this retrospective clinical database study, data were collected from July 2003 to March 2015 from 8 locations in the United Kingdom. Cataract surgery data of 217 557 eyes were extracted from the electronic medical record of the UK National Health Service. After exclusion of 57 561 eyes with combined surgery, prior vitrectomy, copathology, and complications, 812 eyes with primary ERM and 159 184 reference eyes were analyzed. Main Outcomes and Measures: We report on visual acuity (VA), the incidence of cystoid macular edema, and the need for ERM surgery. Results: The mean (SD) age of patients in the ERM group was 73.7 (9.23) years, and 395 of 812 were men (46.8%). The mean (SD) age of patients in the reference group was 74.4 (12.19) years, and 65 265 of 159 184 were men (41%). Epiretinal membrane eyes assessed at 4 to 12 weeks postoperatively gained 0.27 (0.32) logMAR (approximately 3 Snellen lines), with 200 of 448 (44.6%) improving by 0.30 logMAR or more (>=3 Snellen lines) and 32 of 448 (7.1%) worsening by 0.30 logMAR or more. Reference eyes gained a mean (SD) of 0.44 (0.26) logMAR (approximately 4 Snellen lines), with 48 583 of 77 408 (62.8%) improving by 0.30 logMAR or more and 2125 of 77 408 (2.7%) worsening by 0.30 logMAR or more. Although all eyes with preoperative VA of 20/40 or less improved, only reference eyes with preoperative VA of more than 20/40 showed improvement. Cystoid macular edema developed in 57 of 663 ERM eyes (8.6%) (95% CI, 6.69-10.98) and 1731 of 125 435 reference eyes (1.38%) (95% CI, 1.32-1.45) (P < .001). Epiretinal membrane surgery was performed in 43 of 663 (6.5%) ERM eyes. Conclusions and Relevance: On average, VA improved 0.27 logMAR (approximately 3 Snellen lines) in eyes with ERM. Eyes with ERM and VA of 20/40 or less showed more benefit after cataract surgery than those with better preoperative vision. However, compared with eyes without ERM, higher rates of cystoid macular edema and a lower postoperative VA gain were noted. PMID- 29270637 TI - Talker Differences in Clear and Conversational Speech: Perceived Sentence Clarity for Young Adults With Normal Hearing and Older Adults With Hearing Loss. AB - Purpose: The purpose of this study is to examine talker differences for subjectively rated speech clarity in clear versus conversational speech, to determine whether ratings differ for young adults with normal hearing (YNH listeners) and older adults with hearing impairment (OHI listeners), and to explore effects of certain talker characteristics (e.g., gender) on perceived clarity. Relationships among clarity ratings and other speech perceptual and acoustic measures were also explored. Method: Twenty-one YNH and 15 OHI listeners rated clear and conversational sentences produced by 41 talkers on a scale of 1 (lowest possible clarity) to 7 (highest possible clarity). Results: While clarity ratings varied significantly among talkers, listeners rated clear speech significantly clearer than conversational speech for all but 1 talker. OHI and YNH listeners gave similar ratings for conversational speech, but ratings for clear speech were significantly higher for OHI listeners. Talker gender effects differed for YNH and OHI listeners. Ratings of clear speech varied among subgroups of talkers with different amounts of experience talking to people with hearing loss. Conclusions: Perceived clarity varies widely among talkers, but nearly all produce clear speech that sounds significantly clearer than their conversational speech. Few differences were seen between OHI and YNH listeners except the effect of talker gender. PMID- 29270638 TI - Delusional Infestation: Perspectives from Scottish Dermatologists and a 10-year Case Series from a Single Centre. AB - Perceptions of the clinical management of delusional infestation (DI) were compared with clinical outcomes in this 10-year case series from a single centre in Dundee, UK. An online questionnaire (survey-monkey, a TM brand of online survey available for free for basic use) was sent to Scottish Dermatologists to gauge their opinions and confidence in the management of DI. Also, a retrospective review of medical case notes of patients seen by dermatologists in one institution was undertaken and clinical outcomes were reported by patients' general practitioners (GP). The survey showed that 61% of responding dermatologists encountered 1-5 cases of DI per year. Twenty-four percent respondees were 'confident' in managing patients with DI, 54% were 'somewhat confident'. Forty-seven patients (62% female, 70% single) were seen over the 10 years; 43% brought a self-collected specimen to clinic, 68% of patients had a psychiatric comorbidity, 23% of patients had primary DI and 11/47 (23%) were seen by a psychiatrist. Clinical outcomes as rated by patients' GPs were reasonable or good in 2/3 patients. A poor outcome was seen in 12 patients and associated with chronic pain in 50% (p < 0.01) and psychiatric comorbidity in 100% (p < 0.01). We conclude that good outcomes can be achieved in some patients with DI without psychiatric input and without psychoactive treatment. PMID- 29270639 TI - [Provision of aids to visually impaired people at the workplace]. AB - The provision of aids for occupational use with partially sighted and blind people is not a measure for the necessary care but for an optimal work performance to secure the long-term occupational participation. This objective requires a significantly expanded consultation, which includes the occupational requirements at the specific workplace. The costs are not usually borne by the statutory health insurance but by another social insurance agency depending on the individual case. In this article several aids are presented in an occupational context, as well as the procedure for provision. PMID- 29270640 TI - [Differential diagnoses of dry eye syndrome and blepharitis]. AB - Dry eye syndrome and blepharitis are diseases that affect many patients from different age groups. There is not only a great variability in the manifestation between patients but they also show a mixture of associated symptoms. Thus, very different ocular and systemic diseases have to be included in the differential diagnosis of a primary dry eye disorder. This article provides a structured overview of these differential diagnoses and their characteristic appearance as well as the pitfalls and therapeutic options. PMID- 29270641 TI - Characterizing the subjective, observer-rated, and physiological effects of hydromorphone relative to heroin in a human laboratory study. AB - BACKGROUND: This study compared the effects of the several doses of the opioid agonists heroin and hydromorphone across two routes of administration in humans. The goal was to guide development of human laboratory studies of opioid effects and inform subsequent injection pharmacotherapy trials of hydromorphone-assisted treatment. METHODS: A within-subject (N = 16), double-blind, double-dummy, placebo-controlled, evaluation of acute doses of heroin and hydromorphone was completed at four dose levels (placebo, low, medium, high) across two routes of administration (intravenous, subcutaneous) in non-physically dependent, opioid experienced individuals. Subject and observer ratings, as well as physiological outcomes, were assessed. RESULTS: Within each route of administration, heroin and hydromorphone produced effects that were qualitatively similar on most variables across the doses examined. All effects were dose-dependent. The drugs produced different effects on VAS ratings of "Feels Like Heroin," a Heroin Identification Test, observer agonist ratings, and oxygen saturation levels. Drug-dependent differences emerged at the highest doses in all cases. Few significant main effects of Route were identified and their pattern was not uniform. Relative potency calculations across all subject, observer, and physiological outcomes that met analysis criteria revealed similar profiles and resulted in mean heroin:hydromorphone potencies of 3.35:1 and 2.88:1 for the intravenous and subcutaneous routes, respectively, and intravenous:subcutaneous potencies of 0.47:1 and 0.49:1 for heroin and hydromorphone, respectively. CONCLUSIONS: Hydromorphone produced similar subjective and physiological effects as heroin, but was more potent than heroin. The current findings support the use of hydromorphone as a model for heroin in human laboratory and clinical treatment studies, and help identify appropriate hydromorphone dose conversion ratios to produce effects qualitatively similar to heroin. PMID- 29270642 TI - The associations between radiographic hand osteoarthritis definitions and hand pain: data from the osteoarthritis initiative. AB - The goal of our study was to evaluate the associations between various definitions of radiographic hand osteoarthritis (OA) and self-reported hand pain. We conducted a cross-sectional study with 3604 participants from the Osteoarthritis Initiative (OAI). Posteroanterior radiographs of the dominant hand were read using a modified Kellgren-Lawrence (KL) scale. For our primary analysis, hand OA at person level was defined as two or more finger joints with KL grade 2 or higher. In addition, for the purpose of exploratory analyses, we explored more conservative definitions of hand OA as well as different sum scores and digit- and row-based scores. The majority of definitions of radiographic hand OA were statistically significantly associated with self-reported hand pain. In our main analysis, persons with two or more finger joints with KL grade > 2 were approximately two times more likely to self-report hand pain than persons without radiographic hand OA. Increasing KL grades and increasing number of joints affected lead to stronger associations. Almost all definitions of hand OA were related to pain. Individuals with more severely affected joints or with higher number of affected joints are more likely to report hand pain than their peers. Specifically, individuals with hand joints with KL 3 or 4 have the greatest likelihood of hand pain. PMID- 29270643 TI - Hemispherical photoacoustic imaging of myocardial infarction: in vivo detection and monitoring. AB - OBJECTIVES: This study aimed to demonstrate the capacity for noninvasive localisation and characterisation of myocardial infarction (MI) in vivo using a hemispherical photoacoustic imaging (PAI) system. MI remains a leading cause of morbidity and mortality worldwide. To enable optimal treatment of patients, timely and accurate diagnosis and longitudinal monitoring is critical. METHODS: Ischaemia was induced in Balb/c mice by ligation of the left anterior descending artery. The hemispherical PAI system, equipped with 128 ultrasonic transducers spirally distributed on the surface, along with parallel data acquisition, was applied for imaging of the mouse heart. RESULTS: Our study showed that hemispherical PAI can delineate thoracic vessels and the morphology of the entire heart. Longitudinal PAI images revealed gradual expansion of the infarcted area along with necrosis and fibrosis, which were quantitatively validated by triphenyltetrazolium chloride staining. After MI modelling, the photoacoustic (PA) signal intensity decreased by 399.1 +/- 56.3 (p < 0.001), a ~2.5-fold reduction compared to that of healthy cardiac tissue. The calculated size of the enlarged heart, 10.4 +/- 6.0 mm2 (p < 0.001), represents an increase of ~18% versus that of a healthy heart. CONCLUSIONS: PAI enables MI diagnosis and injury localisation with its capabilities for both deep organ imaging and lesion region differentiation. KEY POINTS: * Photoacoustic imaging (PAI), combining optical absorption and ultrasonic resolution, can delineate cardiac anatomy. * PAI can diagnose myocardial infarction lesions with 10 mm imaging depth in vivo. * Quantified results are in excellent agreement with enzyme and histological examinations. * PAI can serve as a complementary modality to SPECT and ultrasound imaging. * This study will encourage further PAI development for clinical use. PMID- 29270645 TI - Applying Incremental Sampling Methodology to Soils Containing Heterogeneously Distributed Metallic Residues to Improve Risk Analysis. AB - This study compares conventional grab sampling to incremental sampling methodology (ISM) to characterize metal contamination at a military small-arms range. Grab sample results had large variances, positively skewed non-normal distributions, extreme outliers, and poor agreement between duplicate samples even when samples were co-located within tens of centimeters of each other. The extreme outliers strongly influenced the grab sample means for the primary contaminants lead (Pb) and antinomy (Sb). In contrast, median and mean metal concentrations were similar for the ISM samples. ISM significantly reduced measurement uncertainty of estimates of the mean, increasing data quality (e.g., for environmental risk assessments) with fewer samples (e.g., decreasing total project costs). Based on Monte Carlo resampling simulations, grab sampling resulted in highly variable means and upper confidence limits of the mean relative to ISM. PMID- 29270644 TI - Preoperative multiparametric MRI of the prostate for the prediction of lymph node metastases in prostate cancer patients treated with extended pelvic lymph node dissection. AB - OBJECTIVES: To assess the role of preoperative multiparametric MRI (mpMRI) of the prostate in the prediction of nodal metastases in patients treated with radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND). METHODS: We retrospectively analyzed 101 patients who underwent both preoperative mpMRI of the prostate and RP with ePLND at our institution. For each patient, complete preoperative clinical data and tumour characteristics at mpMRI were recorded. Final histopathologic stage was considered the standard of reference. Univariate and multivariate logistic regression analyses were performed. RESULTS: Nodal metastases were found in 23/101 (22.8%) patients. At univariate analyses, all clinical and radiological parameters were significantly associated to nodal invasion (all p<0.03); tumour volume at MRI (mrV), tumour ADC and tumour T-stage at MRI (mrT) were the most accurate predictors (AUC = 0.93, 0.86 and 0.84, respectively). A multivariate model including PSA levels, primary Gleason grade, mrT and mrV showed high predictive accuracy (AUC = 0.956). Observed prevalence of nodal metastases was very low among tumours with mrT2 stage and mrV<1cc (1.8%). CONCLUSION: Preoperative mpMRI of the prostate can predict nodal metastases in prostate cancer patients, potentially allowing a better selection of candidates to ePLND. KEY POINTS: * Multiparametric-MRI of the prostate can predict nodal metastases in prostate cancer * Tumour volume and stage at MRI are the most accurate predictors * Prevalence of nodal metastases is low for T2-stage and <1cc tumours * Preoperative mpMRI may allow a better selection of candidates to lymphadenectomy. PMID- 29270647 TI - Is the Factor-of-2 Rule Broadly Applicable for Evaluating the Prediction Accuracy of Metal-Toxicity Models? AB - In aquatic toxicology, a toxicity-prediction model is generally deemed acceptable if its predicted median lethal concentrations (LC50 values) or median effect concentrations (EC50 values) are within a factor of 2 of their paired, observed LC50 or EC50 values. However, that rule of thumb is based on results from only two studies: multiple LC50 values for the fathead minnow (Pimephales promelas) exposed to Cu in one type of exposure water, and multiple EC50 values for Daphnia magna exposed to Zn in another type of exposure water. We tested whether the factor-of-2 rule of thumb also is supported in a different dataset in which D. magna were exposed separately to Cd, Cu, Ni, or Zn. Overall, the factor-of-2 rule of thumb appeared to be a good guide to evaluating the acceptability of a toxicity model's underprediction or overprediction of observed LC50 or EC50 values in these acute toxicity tests. PMID- 29270646 TI - Endocrine Activities of Pesticides During Ozonation of Waters. AB - Two yeast-based bioassays were used to assess the endocrine activity potential of transformation products formed during the ozonation of water containing a variety of pesticides (propiconazole, atrazine, 2,4-dichlorophenoxyacetic acid [2,4-D], tebuconazole, climbazole, myclobutanil, irgarol, terbutryn, dicamba, mecoprop and diuron). Ozone experiments were conducted first in reverse osmosis water to isolate the effects of the pesticides and then in synthetic wastewater and wastewater effluent to investigate whether the results translated to more complex matrices. The findings demonstrate the recalcitrant nature of most pesticides during ozonation, with removals below 50%, except for irgarol, terbutryn and climbazole with removals up to 70%. This study is the first one to investigate the removal of the fungicides myclobutanil and tebuconazole by ozonation and is one of the first studies to investigate the androgenic activity of ozonation transformation products of contaminants of emerging concern. These findings also demonstrated that during ozonation the initial anti-androgenic activity was removed while the estrogenic activity remained undetected and the androgenic activity increased to levels up to 60% of the anti-androgenic activity of the DHT control. These results indicate that bioactivity should be considered in the evaluation of treatment performance and risks assessment associated to wastewater discharges. PMID- 29270648 TI - Automated volumetric modulated arc therapy planning for whole pelvic prostate radiotherapy. AB - BACKGROUND: For several tumor entities, automated treatment planning has improved plan quality and planning efficiency, and may enable adaptive treatment approaches. Whole-pelvic prostate radiotherapy (WPRT) involves large concave target volumes, which present a challenge for volumetric arc therapy (VMAT) optimization. This study evaluates automated VMAT planning for WPRT-VMAT and compares the results with manual expert planning. METHODS: A system for fully automated multi-criterial plan generation was configured for each step of sequential-boost WPRT-VMAT, with final "autoVMAT" plans being automatically calculated by the Monaco treatment planning system (TPS; Elekta AB, Stockholm, Sweden). Configuration was based on manually generated VMAT plans (manualVMAT) of 5 test patients, the planning protocol, and discussions with the treating physician on wishes for plan improvements. AutoVMAT plans were then generated for another 30 evaluation patients and compared to manualVMAT plans. For all 35 patients, manualVMAT plans were optimized by expert planners using the Monaco TPS. RESULTS: AutoVMAT plans exhibited strongly improved organ sparing and higher conformity compared to manualVMAT. On average, mean doses (Dmean) of bladder and rectum were reduced by 10.7 and 4.5 Gy, respectively, by autoVMAT. Prostate target coverage (V95%) was slightly higher (+0.6%) with manualVMAT. In a blinded scoring session, the radiation oncologist preferred autoVMAT plans to manualVMAT plans for 27/30 patients. All treatment plans were considered clinically acceptable. The workload per patient was reduced by > 70 min. CONCLUSION: Automated VMAT planning for complex WPRT dose distributions is feasible and creates treatment plans that are generally dosimetrically superior to manually optimized plans. PMID- 29270649 TI - Emergency-to-Elective Surgery Ratio: A Global Indicator of Access to Surgical Care. AB - BACKGROUND: Surgical care is essential to health systems but remains a challenge for low- and middle-income countries (LMICs). Current metrics to assess access and delivery of surgical care focus on the structural components of surgery and are not readily applicable to all settings. This study assesses a new metric for surgical care access and delivery, the ratio of emergent surgery to elective surgery (Ee ratio), which represents the number of emergency surgeries performed for every 100 elective surgeries. METHODS: A systematic search of PubMed and Medline was conducted for studies describing surgical volume and acuity published between 2006 and 2016. The relationship between Ee ratio and three national indicators (gross domestic product, per capital healthcare spending, and physician density) was analyzed using weighted Pearson correlation coefficients (r w) and linear regression models. RESULTS: A total of 29 studies with 33 datasets were included for analyses. The median Ee ratio was 14.6 (IQR 5.5-62.6), with a range from 1.6 to 557.4. For countries in sub-Saharan Africa the median value was 62.6 (IQR 17.8-111.0), compared to 9.4 (IQR 3.4-13.4) for the United States and 5.5 (IQR 4.4-10.1) for European countries. In multivariable linear regression, the per capita healthcare spending was inversely associated with the Ee ratio, with a 63-point decrease in the Ee ratio for each 1 point increase in the log of the per capita healthcare spending (regression coefficient beta = 63.2; 95% CI -119.6 to -6.9; P = 0.036). CONCLUSIONS: The Ee ratio appears to be a simple and valid indicator of access to available surgical care. Global health efforts may focus on investment in low-resource settings to improve access to available surgical care. PMID- 29270650 TI - Fascio-Adipo-Cutaneous Lateral Advancement Flap for Treatment of Pilonidal Sinus: A Modification of the Karydakis Operation-Cohort Study. AB - BACKGROUND: Pilonidal sinus is a common chronic disease affecting young adults. Many surgical procedures have been developed for its treatment, but an optimal one has still not been achieved. This study presents a modification to the Karydakis operation. METHODS: A total of 265 patients with chronic pilonidal sinus between May 2008 and May 2015 were included in this study and submitted to fascio-adipo-cutaneous lateral advancement flap as 1-day case surgery. Any Septic complication was treated firstly. Follow-up examinations were conducted during the first three postoperative months at the outpatient clinic at regular intervals and thereafter by phone calls or direct examination to check for recurrences. RESULTS: Males constituted 93.6% with a mean age of 21.6 +/- 7.7 year. The median disease duration was 15 months. Twenty-eight patients had recurrent disease. The mean operative time was 41.4 +/- 12.7 min. The mean time out of work was 11.6 +/- 4.6 days. Complications occurred in 19 patients (7.1%) in the form of seroma in six patients (2.2%), superficial wound infection occurred in nine patients (3.3%), cuticular wound disruption occurred in four patients (1.5%). All patients completed 3-months follow-up, but 48 patients were lost at variable intervals with the remaining 217 patients completed follow-up throughout the period of the study with a median follow-up of 43 months. No reported recurrence and 96.7% of the patients were satisfied about their wound. CONCLUSION: This modification is simple with low complication rate, no recurrence, and excellent patient satisfaction. PMID- 29270651 TI - Image-Guided Proper Liver Segmentectomy. AB - BACKGROUND: The new cross-sectional radiological tools, 3D computed tomography and magnetic resonance, allow a precise study of the liver anatomy. Thanks to these imaging techniques, a new space inside the liver parenchyma, the "hepatic core," was recently recognized, where the hila of liver segments are present. METHODS: On the basis of anatomical and radiological observations, we identified a new virtual plane of dissection, named "hepato-portal," which is useful in liver segmentectomy, if integrated with the classical planes of dissection. RESULTS: Simulated surgical procedures can be intra-operatively transferred by ultrasounds. In this way, we performed ten "proper" liver segmentectomies through preliminary sections of the hilar vessels and a precise dissection of the boundaries of each segment. CONCLUSIONS: Our experience underlines the value of integrating anatomy and radiology in the simulated liver surgery. PMID- 29270652 TI - Blunt Cerebrovascular Artery Injury and Stroke in Severely Injured Patients: An International Multicenter Analysis. AB - INTRODUCTION: Blunt cerebrovascular injury (BCVI) is considered to be a rare entity in patients with high-energy trauma and is a potentially preventable cause of secondary brain damage. If it occurs, it may be fatal or associated with poor outcomes related to devastating complications. We hypothesized that analyses of epidemiology and concomitant injuries may predict the development of BCVI and associated complications. METHODS: The TraumaRegister DGU(r) (TR-DGU), a prospectively maintained database, was used for retrospective data analysis (01/2009-12/2015). INCLUSION CRITERIA: adult trauma patients (>=16 years) with severe injuries (ISS >= 16 points) with and without BCVI. Subgroups: carotid artery injury (CAI) and vertebral artery injury (VAI). The degree of vascular injury was classified according to the Abbreviated Injury Scale values. Demographic, injury, therapy and outcome characteristic data (length of stay, stroke, multiple organ failure and mortality) were collected and analyzed for each patient with SPSS statistics (Version 23, IBM Inc., Armonk, NY). RESULTS: Out of 76,480 individuals, a total of 786 patients with BCVI (1%) were identified. The 435 CAI patients included 263 dissections, 78 pseudoaneurysms and 94 bilateral injuries. The 383 VAI patients presented with 198 dissections, 43 pseudoaneurysms, 122 thrombotic occlusions and 20 bilateral injuries. The risk for stroke was excessive in BCVI patients versus controls (11.5 vs. 1.1%, p < 0.001) and increased with vascular injury severity, up to 24.1% in CAI patients and 30.0% in VAI patients. We confirmed that cervical spine injuries were a major BCVI predictor (OR 6.46, p < 0.001, 95% CI 5.34-7.81); furthermore, high-energy mechanisms (OR 1.79), facial fractures (OR 1.56) and general injury severity (OR 1.05) were identified as independent predictors. Basilar skull fractures (BSF) were found with comparable frequency (p = 0.63) in both groups, and the predictive value was found to be insignificant (OR 1.1, p = 0.36, 95% CI 0.89 1.37). Age >= 60 years was associated with a decreased risk for BCVI (OR 0.54, p < 0.001, 95% CI 0.45-0.65); however, in BCVI patients over 60 years of age, mortality was excessive (OR 4.33, p < 0.001, 95% CI 2.40-7.80). Even after adjusting for head injuries, BCVI-associated stroke remained a significant risk factor for mortality (OR 2.52, p < 0.001, 95% CI 1.13-5.62). CONCLUSION: Our data validated cervical spine injuries as a major predictor, but the predictive value of BSF must be scrutinized. Patient age appears to play a contradictory role in BCVI risk and BCVI-associated mortality. Predicting which patients will develop BCVI remains an ongoing challenge, especially since many patients do not present with concomitant injuries of the head or spine and therefore might not be captured by standard screening criteria. PMID- 29270653 TI - Novel Approach to Treat Uncomplicated Sigmoid Volvulus Combining Minimally Invasive Surgery with Enhanced Recovery, in a Rural Hospital in Zambia. AB - AIM: In sub-Saharan Africa, sigmoid volvulus is a frequent cause of bowel obstruction. The aim of this study was to evaluate the results of acute sigmoid resection and anastomosis via a mini-laparotomy in patients with uncomplicated sigmoid volvulus, following the principles of "Enhanced Recovery After Surgery (ERAS)", in a low-resource setting. MATERIALS AND METHODS: Patients with uncomplicated sigmoid volvulus were operated acutely, via a mini-laparotomy, according to the principles of ERAS. Intraoperative complications, duration of operation, morbidity, mortality and length of hospital stay were evaluated, retrospectively. RESULTS: From 1 March 2012 to 1 September 2017, 31 consecutive patients were treated with acute sigmoid resection and anastomosis, via a mini laparotomy. There were 29 men and 2 women, median age 57 (range 17-92) years. Patients were operated after a median period of 4 (range 1.5-18) hours. The median duration of the operative procedure was 50 (range 30-105) minutes. Two patients died (6.3%). One patient died during an uncomplicated operation. The cause of death is unknown. One patient with a newly diagnosed HIV infection had an anastomotic dehiscence. After Hartmann's procedure, he died on the 17th post operative day as a result of a HIV-related double-sided pneumonia, without signs of abdominal sepsis. One patient had an urinary retention and 1 patient haematuria after bladder catheter insertion. CONCLUSION: Acute sigmoid resection and primary anastomosis via a mini-laparotomy for uncomplicated sigmoid volvulus, without preoperative endoscopic decompression is a safe procedure with a low morbidity and mortality. PMID- 29270654 TI - Associations Between the Prognostic Nutritional Index and Morbidity/Mortality During Intestinal Resection in Patients with Ulcerative Colitis. AB - BACKGROUND: Onodera's prognostic nutritional index (O-PNI) is a well-known predictor of the prognosis of several surgeries. The aim of this study was to evaluate the association between O-PNI and surgical outcome during surgery for ulcerative colitis (UC). METHODS: This was a single-institution retrospective cohort study conducted in the Department of Inflammatory Bowel Disease at Hyogo College of Medicine, Japan. The preoperative predictive factors associated with mortality, morbidity, and pouch-related complications (PRCs) were examined separately from surgical procedure. RESULTS: A total of 1151 patients with UC who underwent surgery between January 2000 and December 2015 were included. Total colectomy (TC) alone, ileal pouch-anal anastomosis (IPAA) with ileostomy, and IPAA without ileostomy were performed in 254 patients, 736 patients, and 161 patients, respectively. Mortality and morbidity were found in nine (0.8%) and 320 (27.8%) patients, respectively. The median O-PNI score was 22.6 in patients with mortality and 35.6 in patients without mortality among TC alone (p < 0.01). The significant predictive factors for mortality among TC alone were older age [p = 0.03, odds ratio (OR) 6.8], higher C-reactive protein (p = 0.02, OR 14.5), and O PNI < 24.9 (p = 0.04, OR 5.6). Among IPAA with ileostomy, an American Society of Anesthesiologists score >=3 (p = 0.01, OR 2.3), prednisolone (PSL) dosage just before surgery >=14 mg/day (p = 0.04, OR 1.8), and O-PNI < 35.5 (p < 0.01, OR 2.1) were predictors of PRCs. O-PNI did not predict PRCs among IPAA without ileostomy. CONCLUSION: Lower O-PNI may predict the prognosis in patients with UC. O-PNI may be a useful indicator for decision-making regarding surgical timing and procedure. PMID- 29270655 TI - Transvaginal Hybrid NOTES Cholecystectomy: A Single-Centre Long-Term Experience on Sexual Function. AB - INTRODUCTION: Transvaginal hybrid NOTES cholecystectomy is an alternative approach to the traditional laparoscopic technique. Despite increasing data regarding clinical outcomes following transvaginal hybrid NOTES cholecystectomy, there is still a lack of long-term results, particularly with regard to sexual function. Therefore, the aim of this study was to evaluate long-term outcome of a series of transvaginal hybrid cholecystectomy. PATIENTS AND METHODS: Female patients with symptomatic cholecystolithiasis who underwent transvaginal hybrid NOTES cholecystectomy were retrospectively analysed regarding clinical and surgical outcome parameters. Furthermore, all patients received a 17-question survey postoperative with questions about sexual intercourse, the domains satisfaction and pain of the German Female Sexual Function Index. RESULTS: Overall, 47 of 80 patients were included in the study with a completed survey responses (return rate 58.6%), with a mean age of 48 years, mean body mass index of 29 and mean operative time of 47 min. The median follow-up was 40 months. There were no intra- or postoperative complications and no conversion to a laparoscopic or open approach. No significant differences were found for postoperative sexual function (painful intercourse, inability to achieve orgasm), although sexual intercourse was less frequent postoperatively (p = 0.022). Forty four patients (93.7%) were satisfied with the aesthetic and the overall postoperative result, and 40 patients (85.1%) would recommend the applied surgical technique to friends and family. CONCLUSION: The findings show that transvaginal hybrid NOTES cholecystectomy is a safe procedure for female patients, particularly with regard to sexual function. PMID- 29270656 TI - Prognostic Significance of the Preoperative Ratio of C-Reactive Protein to Albumin and Neutrophil-Lymphocyte Ratio in Gastric Cancer Patients. AB - BACKGROUND: The ratio of C-reactive protein to albumin (CRP/Alb) is a biochemical marker of systemic inflammatory response and has been associated with poor survival in cancer. This study retrospectively investigated the relationship between the CRP/Alb ratio and prognosis in gastric cancer patients. METHODS: This study enrolled 453 patients with a histopathological diagnosis of gastric adenocarcinoma who underwent curative surgery. RESULTS: A statistically significant weak correlation was observed between CRP/Alb ratio and neutrophil/lymphocyte ratio (NLR) (r = 0.19; P < 0.0001). There were statistically significant correlations between high CRP/Alb ratio and age (P = 0.0004), tumor size (P = 0.02), depth of invasion (P = 0.012), and lymph node metastasis (P = 0.022). A high NLR was significantly correlated with age (P = 0.0027), tumor size (P = 0.0006), depth of invasion (P < 0.0001), lymphatic involvement (P = 0.0031), venous involvement (P = 0.0022), and stage of disease (P = 0.0024). Based on results by receiver operating characteristic analysis, patients were divided as follows: CRP/Alb ratio >= 0.0232 (CARHigh), CRP/Alb ratio < 0.0232 (CARLow), NLR >= 2.43 (NLRHigh), and NLR < 2.43 (NLRLow). Five year survival rates of patients with both CARHigh and NLRHigh, either CARHigh or NLRHigh, and both CARLow and NLRLow were 59.6, 75.8, and 87.5%, respectively, with statistically significant differences (P < 0.0001). Multivariate analysis revealed that the combination of CRP/Alb ratio and NLR was an independent prognostic indicator. CONCLUSIONS: The combination of CRP/Alb ratio and NLR may be useful in predicting prognosis in gastric cancer patients. PMID- 29270657 TI - Splenic Infarction as a Delayed Febrile Complication Following Radical Gastrectomy for Gastric Cancer Patients: Computed Tomography-Based Analysis. AB - BACKGROUND: The aim of this study was to evaluate the incidence and clinical characteristics of splenic infarction (SI) in gastric cancer patients who have undergone gastrectomy. METHODS: For this study, the medical records of 1084 patients were reviewed and 877 patients were ultimately enrolled. The times of symptom onset, diagnosis of SI, and complete resolution on CT were calculated from the day of the operation. Based on the wedge shape of the SI in all cases, the total volume of the SI was measured based on that of a corn kernel. RESULTS: Thirty-six patients (4.10%) were diagnosed with SI after gastrectomy; four of these patients (0.45%) developed complications associated with the SI. Total gastrectomy and extended lymph node dissection were risk factors for development of SI. Patients with complications exhibited inflammatory signs between 7 and 10 days after surgery. The mean volume of the SI was 4025.69 mm3. The mean time to complete resolution on the CT scan was 327 days postoperatively. In 30 cases, small branched arteries from the splenic artery that could have caused the SI were retrospectively detected on the preoperative CT scans. CONCLUSION: Although the incidence of the SI was low, large volume of the SI is associated with complication development. Measuring the infarction volume via a CT scan may be useful to decide on the treatment strategy. Preoperative 3-D reconstruction of the splenic artery tributaries may help reduce the risk of inadvertent SI. PMID- 29270658 TI - Determination of soyasaponins in Fagioli di Sarconi beans (Phaseolus vulgaris L.) by LC-ESI-FTICR-MS and evaluation of their hypoglycemic activity. AB - Soyasaponins are oleanene-type triterpenoid saponins, naturally occurring in many edible plants that have attracted a great deal of attention for their role in preventing chronic diseases. The aim of this study was to establish the distribution and the content of soyasaponins in 21 ecotypes of Fagioli di Sarconi beans (Phaseolus vulgaris, Leguminosae). High-performance reversed-phase liquid chromatography (RPLC) with positive electrospray ionization (ESI(+)) and Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) in conjunction with infrared multiphoton dissociation (IRMPD) was applied for the unambiguous identification of soyasaponins Ba (m/z 959.5213, [C48H79O19]+), Bb (m/z 943.5273, [C48H79O18]+), Bd (m/z 957.5122, [C48H77O19]+), and Be (m/z 941.5166, [C48H77O18]+), which are the only commercially available reference standards. In addition, the several diagnostic product ions generated by IRMPD in the ICR-MS cell allowed us the putative identification of soyasaponins Bb' (m/z 797.4680, [C42H69O14]+), alphag (m/z 1085.5544, [C54H85O22]+), betag (m/z 1069.5600, [C54H85O21]+), and gammag (m/z 923.5009, [C48H75O17]+), establishing thus their membership in the soyasaponin group. Quantitative and semiquantitative analysis of identified soyasaponins were also performed by RPLC-ESI(+) FTICR-MS; the total concentration levels were found ranging from 83.6 +/- 9.3 to 767 +/- 37 mg/kg. In vitro hypoglycemic outcomes of four soyasaponin standards were evaluated; significant inhibitory activities were obtained with IC50 values ranging from 1.5 +/- 0.1 to 2.3 +/- 0.2 MUg/mL and 12.0 +/- 1.1 to 29.4 +/- 1.4 MUg/mL for alpha glucosidase and alpha-amylase, respectively. This study represents the first detailed investigation on the antidiabetic activity of bioactive constituents found in Fagioli di Sarconi beans. Graphical abstract The first detailed RPLC ESI(+) FTICR-MS investigation of the qualitative and semiquantitative profile of soyasaponins, occurring in 21 ecotypes of Fagioli di Sarconi beans (P. vulgaris L.). PMID- 29270659 TI - Bioleaching of two different genetic types of chalcopyrite and their comparative mineralogical assessment. AB - The bioleaching of two different genetic types of chalcopyrite by the moderate thermophile Sulfobacillus thermosulfidooxidans was investigated by leaching behaviors elucidation and their comparative mineralogical assessment. The leaching experiment showed that the skarn-type chalcopyrite (STC) revealed a much faster leaching rate with 33.34% copper extracted finally, while only 23.53% copper was bioleached for the porphyry-type chalcopyrite (PTC). The mineralogical properties were analyzed by XRD, SEM, XPS, and Fermi energy calculation. XRD indicated that the unit cell volume of STC was a little larger than that of PTC. SEM indicated that the surface of STC had more steps and ridges. XPS spectra showed that Cu(I) was the dominant species of copper on the surfaces of the two chalcopyrite samples, and STC had much more copper with lower Cu 2p3/2 binding energy. Additionally, the Fermi energy of STC was much higher than that of PTC. These mineralogical differences were in good agreement with the bioleaching behaviors of chalcopyrite. This study will provide some new information for evaluating the oxidation kinetics of chalcopyrite. PMID- 29270660 TI - Successfully navigating the early years of a faculty position. PMID- 29270661 TI - Aglaophenia octodonta (Cnidaria, Hydrozoa) and the Associated Microbial Community: a Cooperative Alliance? AB - Recently, genetic approaches have revealed a surprising bacterial world as well as a growing knowledge of the enormous distribution of animal-bacterial interactions. In the present study, the diversity of the microorganisms associated to the hydroid Aglaophenia octodonta was studied with epifluorescence, optical, and scanning electron microscopy. Small subunit ribosomal RNA gene sequencing with "universal" and taxon-specific primers allowed the assignment of the microalgae to Symbiodinium and the peritrich ciliates to Pseudovorticella, while the luminous vibrios were identified as Vibrio jasicida of the Harvey clade. To understand the possible relationships among Vibrio jasicida, Symbiodinium, A. octodonta, and Pseudovorticella, specific treatments were conducted in microcosm experiments, with the antibiotic ampicillin and other substances that interfere with bacterial and hydroid metabolism. Treatment of A. octodonta with ampicillin resulted in a decrease of bacterial luminescence followed by Pseudovorticella detachment and Symbiodinium expulsion and suggesting that these microorganisms form a "consortium" with beneficial metabolic interdependence. This hypothesis was reinforced by the evidence that low concentrations of hydrogen peroxide, which stimulate the bacterial oxidative metabolism and luminescence by releasing oxygen, were able to counteract the detrimental effect of ampicillin on the stability of the studied A. octodonta association. A model is proposed in which microalgae that release oxygen during photosynthesis are useful to luminous bacteria for their metabolism and for establishing/maintaining symbiosis leading to a close alliance and mutual benefit of the system A. octodonta-Vibrio jasicida-Pseudovorticella sp.-Symbiodinium sp. PMID- 29270662 TI - Food Storage by the Savanna Termite Cornitermes cumulans (Syntermitinae): a Strategy to Improve Hemicellulose Digestibility? AB - It has been suggested that food storage inside the nest may offer termites with a nutritional provision during low resource availability. Additionally, feces employed as construction material provide an excellent environment for colonization by microorganisms and, together with the storage of plant material inside the nest, could thus provide some advantage to the termites in terms of lignocellulose decomposition. Here, we conducted for the first time a comprehensive study of the microbial communities associated to a termite exhibiting food storage behavior using Illumina sequencing of the 16S and (ITS2) regions of rRNA genes, together with enzymatic assays and data collected in the field. Cornitermes cumulans (Syntermitinae) stored grass litter in nodules made from feces and saliva located in the nest core. The amount of nodules increased with nest size and isolation, and interestingly, the soluble fraction of extracts from nodules showed a higher activity against hemicellulosic substrates compared to termite guts. Actinobacteria and Sordariales dominated microbial communities of food nodules and nest walls, whereas Spirochetes and Pleosporales dominated gut samples of C. cumulans. Within Syntermitinae, however, gut bacterial assemblages were dissimilar. On the other hand, there is a remarkable convergence of the bacterial community structure of Termitidae nests. Our results suggest that the role of nodules could be related to food storage; however, the higher xylanolytic activity in the nodules and their associated microbiota could also provide C. cumulans with an external source of predigested polysaccharides, which might be advantageous in comparison with litter-feeding termites that do not display food storage behavior. PMID- 29270663 TI - [Lichen nitidus and lichen striatus]. AB - Lichen nitidus is a rare, chronic dermatosis which occurs more often in children than in adults. It presents with tiny, monomorphous, lichenoid, mostly asymptomatic papules in regional or disseminated distribution which show a pathognomonic histological pattern. The pathogenesis is unclear; however, immunologic phenomena and genetic factors are under discussion. In rare cases, an association with other dermatoses and systemic diseases has been described. Moreover, medical treatments have been incriminated as triggers. Considering the self-limited course in mostly young patients, treatment must be thoroughly weighed. Possible therapeutic options include topical corticosteroids and calcineurin inhibitors as well as oral antihistamines, corticosteroids and narrow band ultraviolet B phototherapy. Lichen striatus is an acquired, usually asymptomatic dermatosis occurring mostly in preschool children. The characteristic feature is the arrangement of small, flat, light red- to skin colored papules along the lines of Blaschko. Therefore, a postzygotic mutation of epidermal progenitor cells induced to express new surface antigens by trigger factors as infections, vaccinations or trauma with consecutive immune reaction is assumed. Nail involvement of the affected limb can rarely occur. Lichen striatus usually heals without scarring within several months, so that therapies with severe side effects are obsolete. Mild topical corticosteroids or calcineurin inhibitors may be used, especially if patients exceptionally suffer from pruritus. A postinflammatory hypopigmentation can persist for months to years. PMID- 29270664 TI - Molecular diversity of Photorhabdus and Xenorhabdus bacteria, symbionts of Heterorhabditis and Steinernema nematodes retrieved from soil in Benin. AB - The diversity of 43 bacterial strains isolated from Beninese entomopathogenic nematodes was investigated molecularly by analyzing the 16S rRNA, recA, and gyrB genes. Based on 16S rRNA sequence analysis, 15 bacterial strains were identified as Xenorhabdus sp., 27 strains as Photorhabdus sp., and one as Serratia sp. The Xenorhabdus strains were isolated from Steinernema nematodes and identified as Xenorhabdus indica based on 16S rRNA gene and concatenated recA and gyrB sequence analysis. However, analysis of 16S rRNA and concatenated recA and gyrB gene sequences of the Photorhabdus strains, all isolated from Heterorhabditis nematodes, resulted in two separate sub-clusters (A) and (B) within the Photorhabdus luminescens group, distinct from the existing subspecies. They share low sequence similarities with nearest phylogenetic neighbors Photorhabdus luminescens subsp. luminescens HbT, Photorhabdus luminescens subsp. caribbeanensis HG29T, and Photorhabdus luminescens subsp. noenieputensis AM7T. PMID- 29270665 TI - [Intramedullary injection with tethered cord : Case report of a rare complication during spinal anesthesia]. AB - Although very rare, severe neurological complications can occur when undergoing spinal anesthesia. This report describes and analyses a case of spinal injury due to an undiagnosed tethered cord (TC) during spinal anesthesia for a cesarean section of a 31-year-old woman expecting twins. As a consequence of spinal dysraphism during embryogenesis, an atypically low conus level can occur and increase the risk of injury during neuraxial anesthesia, especially in the absence of symptoms. Injuries can be caused by mechanical trauma from direct needle injury, hematoma or neurotoxicity from local anesthetics. Special attention should therefore be paid to frequent symptoms, such as a hairy nevus on the back, deformities of the feet or bladder and bowels, voiding and micturition dysfunction in order to reduce the risk of complications. PMID- 29270666 TI - [Acute perioperative right heart insufficiency : Diagnostics and treatment]. AB - Acute right heart failure is often overlooked as a cause of cardiopulmonary insufficiency. The various pathologies underlying right heart failure at the level of afterload, preload and contractility, make rapid, targeted diagnostics necessary. In addition to clinical symptoms and laboratory chemical parameters, echocardiography in particular is relevant for making a diagnosis. Symptomatic treatment of the endangered patient is essential. The focus is on a reduction of right ventricular pressure and afterload, a correction of systemic hypotension and positive inotropic support of the right ventricle. Mechanical organ replacement and support procedures are increasingly being used in the case of persistent right heart failure and expand the possibilities for treatment. Decisive for the prognosis is a causal treatment adapted to the underlying triggering disease. PMID- 29270667 TI - [Reimbursement of intensive care services in the German DRG system : Current problems and possible solutions]. AB - The reimbursement of intensive care and nursing services in the German health system is based on the diagnosis-related groups (G-DRG) system. Due to the lack of a central hospital planning, the G-DRG system has become the most important influence on the development of the German health system. Compared to other countries, intensive care in Germany is characterized by a high number of intensive care beds, a low nurse-to-patient ratio, no official definition of the level of care, and a minimal available data set from intensive care units (ICUs). Under the given circumstances, a shortage of qualified intensive care nurses and physicians is currently the largest threat for intensive care in Germany. To address these deficiencies, we suggest the following measures: (1) Integration of ICUs into the levels of care which are currently developed for emergency centers at hospitals. (2) Mandatory collection of structured data sets from all ICUs including quality criteria. (3) A reform of intensive care and nursing reimbursement under consideration of adequate staffing in the individual ICU. (4) Actions to improve ICU staffing and qualification. PMID- 29270668 TI - Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy. AB - Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor infiltrating lymphocytes to the tumor site, where they participate in immune scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD 1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy. PMID- 29270670 TI - The function of BTG3 in colorectal cancer cells and its possible signaling pathway. AB - PURPOSE: B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior. METHODS: BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression. RESULTS: BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data. CONCLUSIONS: BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior. PMID- 29270672 TI - Monitoring saltwater intrusion in Rupert Bay, Quebec, Canada, after the partial diversion of a major tributary. AB - As part of a large hydroelectric project in northern Quebec (Canada), a portion of the flow of the Rupert River was diverted toward the existing La Grande hydroelectric complex. As a result of the partial diversion, the discharge of the Rupert River at its mouth is reduced by an average of 50% annually. This corresponds to an 18% decrease in the total freshwater inflow into the bay and, thus, to a shift of the upstream limit of the saltwater intrusion in Rupert Bay. Changes in saltwater intrusion had been predicted numerically as part of the project's environmental impact assessment (EIA). In the project's conditions of authorization, monitoring the hydraulic conditions and the extent of saltwater intrusion in the Rupert Bay was required by government authorities. The objective of this paper is to present the results of this environmental monitoring and, more specifically, to validate the modifications predicted in the EIA in terms of both saltwater intrusion limit and hydraulic conditions in the Rupert Bay. Results obtained during 2 years of monitoring are within the predicted trends and order of magnitude of changes anticipated in the EIA. The results, thus, confirm that the shift of the upstream limit of the saltwater front along the channels of the bay was conservatively predicted by numerical modeling. PMID- 29270673 TI - The role of head and hand movements for infants' predictions of others' actions. AB - In everyday life, both the head and the hand movements of another person reveal the other's action target. However, studies on the development of action prediction have primarily included displays in which only hand and no head movements were visible. Given that infants acquire in their first year both the ability to follow other's gaze and the ability to predict other's reaching actions, the question is whether they rely mostly on the hand or the head when predicting other's manual actions. The current study aimed to provide an answer to this question using a screen-based eye tracking setup. Thirteen-month-old infants observed a model transporting plastic rings from one side of the screen to the other side and place them on a pole. In randomized trials the model's head was either visible or occluded. The dependent variable was gaze-arrival time, which indicated whether participants predicted the model's action targets. Gaze arrival times were not found to be different when the head was visible or rendered invisible. Furthermore, target looks that occurred after looks at the hand were found to be predictive, whereas target looks that occurred after looks at the head were reactive. In sum, the study shows that 13-month-olds are capable of predicting an individual's action target based on the observed hand movements but not the head movements. The data suggest that earlier findings on infants' action prediction in screen-based tasks in which often only the hands were visible may well generalize to real-life settings in which infants have visual access to the actor's head. PMID- 29270671 TI - Gating mechanism of Kv11.1 (hERG) K+ channels without covalent connection between voltage sensor and pore domains. AB - Kv11.1 (hERG, KCNH2) is a voltage-gated potassium channel crucial in setting the cardiac rhythm and the electrical behaviour of several non-cardiac cell types. Voltage-dependent gating of Kv11.1 can be reconstructed from non-covalently linked voltage sensing and pore modules (split channels), challenging classical views of voltage-dependent channel activation based on a S4-S5 linker acting as a rigid mechanical lever to open the gate. Progressive displacement of the split position from the end to the beginning of the S4-S5 linker induces an increasing negative shift in activation voltage dependence, a reduced z g value and a more negative DeltaG 0 for current activation, an almost complete abolition of the activation time course sigmoid shape and a slowing of the voltage-dependent deactivation. Channels disconnected at the S4-S5 linker near the S4 helix show a destabilization of the closed state(s). Furthermore, the isochronal ion current mode shift magnitude is clearly reduced in the different splits. Interestingly, the progressive modifications of voltage dependence activation gating by changing the split position are accompanied by a shift in the voltage-dependent availability to a methanethiosulfonate reagent of a Cys introduced at the upper S4 helix. Our data demonstrate for the first time that alterations in the covalent connection between the voltage sensor and the pore domains impact on the structural reorganizations of the voltage sensor domain. Also, they support the hypothesis that the S4-S5 linker integrates signals coming from other cytoplasmic domains that constitute either an important component or a crucial regulator of the gating machinery in Kv11.1 and other KCNH channels. PMID- 29270674 TI - Differences in chunking behavior between young and older adults diminish with extended practice. AB - Previous research found reduced motor chunking behavior in older adults compared to young adults. However, it remains unclear whether older adults are unable to use a chunking strategy or whether they are just slower in developing them. Our goal was to investigate the effect of extended practice on the development of chunking behavior in healthy older adults. A group of young and a group of healthy older adults between 74 and 85 years of age visited the lab on 2 days. A sequence of 3 and a sequence of 6 elements were both practiced 432 times in a discrete sequence production task. We found that age differences in chunking behavior, as measured by the difference between initiation and execution of the sequence, diminish with extended practice. Furthermore, in older, but not in young adults, slow responses that are often interpreted as the first response of a next motor chunk were associated with a finger that was also slow during performance of the random sequences. This finding calls for more attention to biomechanical factors in future theory about aging and sequence learning. PMID- 29270675 TI - The effect of altered lignin composition on mechanical properties of CINNAMYL ALCOHOL DEHYDROGENASE (CAD) deficient poplars. AB - MAIN CONCLUSION: CAD-deficient poplars enabled studying the influence of altered lignin composition on mechanical properties. Severe alterations in lignin composition did not influence the mechanical properties. Wood represents a hierarchical fiber-composite material with excellent mechanical properties. Despite its wide use and versatility, its mechanical behavior has not been entirely understood. It has especially been challenging to unravel the mechanical function of the cell wall matrix. Lignin engineering has been a useful tool to increase the knowledge on the mechanical function of lignin as it allows for modifications of lignin content and composition and the subsequent studying of the mechanical properties of these transgenics. Hereby, in most cases, both lignin composition and content are altered and the specific influence of lignin composition has hardly been revealed. Here, we have performed a comprehensive micromechanical, structural, and spectroscopic analysis on xylem strips of transgenic poplar plants, which are downregulated for cinnamyl alcohol dehydrogenase (CAD) by a hairpin-RNA-mediated silencing approach. All parameters were evaluated on the same samples. Raman microscopy revealed that the lignin of the hpCAD poplars was significantly enriched in aldehydes and reduced in the (relative) amount of G-units. FTIR spectra indicated pronounced changes in lignin composition, whereas lignin content was not significantly changed between WT and the hpCAD poplars. Microfibril angles were in the range of 18 degrees -24 degrees and were not significantly different between WT and transgenics. No significant changes were observed in mechanical properties, such as tensile stiffness, ultimate stress, and yield stress. The specific findings on hpCAD poplar allowed studying the specific influence of lignin composition on mechanics. It can be concluded that the changes in lignin composition in hpCAD poplars did not affect the micromechanical tensile properties. PMID- 29270676 TI - Correction to: Minimally invasive posterior cervical foraminotomy for treatment of radiculopathy : An effective, time-tested, and cost-efficient motion preservation technique. AB - Correction to: Oper Orthop Traumatol 2017 https://doi.org/10.1007/s00064-017-0516 6 In this article the following acknowledgement was missing:Acknowledgement: With the kind assistance of Deutsche Arthrose-Hilfe e. .... PMID- 29270677 TI - Pericardiac slipknot. PMID- 29270678 TI - Inspiratory preload obliteration may injure lungs via cyclical "on-off" vascular flow. PMID- 29270679 TI - Acute ischemia of the thumb caused by radial artery cannulation. PMID- 29270680 TI - Saharan dust particles in snow samples of Alps and Apennines during an exceptional event of transboundary air pollution. AB - Southern European countries are often affected in summer by transboundary air pollution from Saharan dust. However, very few studies deal with Saharan dust pollution at high altitudes in winter. In Italy, the exceptional event occurred on February 19, 2014, colored in red the entire mountain range (Alps and Apennines) and allowed to characterize the particulate matter deposited on snow from a morphological and chemical point of view. Snow samples were collected after this event in four areas in the Alps and one in the Apennines. The particulate matter of the melted snow samples was analyzed by scanning electron microscopy with energy dispersive X-ray spectrometry (SEM-EDS) and by inductively coupled plasma mass spectrometry (ICP-MS). These analyses confirmed the presence of Saharan dust particle components in all areas with similar percentages, supported also by the positive correlations between Mg-Ca, Al-Ca, Al-Mg, and Al-K in all samples. PMID- 29270681 TI - Impact of early access to multidisciplinary care on treatment outcomes in patients with skull base chordoma. AB - OBJECTIVE: To determine if early access to multidisciplinary surgical care affects outcomes in patients with skull base chordoma. METHOD: A retrospective chart review of prospectively collected data was performed on 51 patients treated from 1993 to 2014. The cohort was divided into those presenting (1) for initial management (ID, n = 21) or (2) with persistent/progressive disease after prior biopsy/surgery (PD, n = 30) outside of a multidisciplinary setting. The impact of initial surgical management in a multidisciplinary center on progression-free survival (PFS) was assessed with Kaplan-Meier and log-rank analyses. RESULTS: Mean follow-up, median PFS, median overall survival (OS), and 10-year OS for the entire cohort was 70 months, 47 months, 159 months, and 19%, respectively. Initial management in a multidisciplinary center resulted in a significant improvement in PFS versus initial surgery with or without radiotherapy (XRT) outside of this setting (64 vs 25 months, p = 0.035). Initial surgical resection outside of a multidisciplinary setting increased the risk of recurrence/progression on univariate (HR, 2.276; p = 0.022) and multivariate analysis (HR, 2.831; p = 0.006), respectively. CONCLUSIONS: The results from this study emphasize the impact that coordinated multidisciplinary surgical care has on patient outcomes for chordomas of the clivus. Biopsy followed by attempted radical resection at a dedicated center does not affect PFS and, therefore, represents a reasonable first step in management for patients presenting outside of multidisciplinary setting. PMID- 29270683 TI - Revision adenoidectomy in children: residual vs regrowth? PMID- 29270682 TI - Comparison of two surgical suture techniques in uvulopalatopharyngoplasty and expansion sphincter pharyngoplasty. AB - BACKGROUND: Uvulopalatopharyngoplasty (UPPP) and expansion sphincter pharyngoplasty (ESP) are two standard surgical procedures for treatment of snoring and sleep apnea. In a prospective clinical trial, we compared a standard simple interrupted suture technique for closure of the tonsillar pillars with a running locked suture. METHODS: Each suture technique was randomly assigned either to the left or the right tonsillar pillars in 28 patients. During the first week, patients were daily checked for suture dehiscence and again on days 10 and 21, the end of followup. Time to perform the sutures was measured intraoperative and surgical complications were recorded. RESULTS: During followup, suture dehiscence was observed in 15/28 interrupted and 16/28 running sutures (p > 0.5). If a dehiscence occurred during the observation period, the median day of dehiscence was 10 (1 and 3 quartile: 5.75 and 17) days for the interrupted suture and 10 (5-11) days for the running locked suture technique (p > 0.05). The mean (+/- SD) surgical time for the interrupted suture was 5.2 +/- 1.9 and 3.5 +/- 1.8 min for the running locked suture (p < 0.001). Postoperative bleedings occurred in 4/28 running sutures and 2/28 interrupted sutures. CONCLUSION: The running locked suture technique is an equally safe and time saving way of wound closure in UPPP and ESP. PMID- 29270684 TI - Effects of coal spoil amendment on heavy metal accumulation and physiological aspects of ryegrass (Lolium perenne L.) growing in copper mine tailings. AB - Copper mine tailings pose many threats to the surrounding environment and human health, and thus, their remediation is fundamental. Coal spoil is the waste by product of coal mining and characterized by low levels of metals, high content of organic matter, and many essential microelements. This study was designed to evaluate the role of coal spoil on heavy uptake and physiological responses of Lolium perenne L. grown in copper mine tailings amended with coal spoil at rates of 0, 0.5, 1, 5, 10, and 20%. The results showed that applying coal spoil to copper mine tailings decreased the diethylenetriaminepentaacetic acid (DTPA) extractable Cd, Cu, Pb, and Zn contents in tailings and reduced those metal contents in both roots and shoots of the plant. However, application of coal spoil increased the DTPA-extractable Cr concentration in tailings and also increased Cr uptake and accumulation by Lolium perenne L. The statistical analysis of physiological parameters indicated that chlorophyll and carotenoid increased at the lower amendments of coal spoil followed by a decrease compared to their respective controls. Protein content was enhanced at all the coal spoil amendments. When treated with coal spoil, the activities of superoxide dismutases (SOD), peroxidase (POD), and catalase (CAT) responded differently. CAT activity was inhibited, but POD activity was increased with increasing amendment ratio of coal spoil. SOD activity increased up to 1% coal spoil followed by a decrease. Overall, the addition of coal spoil decreased the oxidative stress in Lolium perenne L., reflected by the reduction in malondialdehyde (MDA) contents in the plant. It is concluded that coal spoil has the potential to stabilize most metals studied in copper mine tailings and ameliorate the harmful effects in Lolium perenne L. through changing the physiological attributes of the plant grown in copper mine tailings. PMID- 29270687 TI - Correction to: Efficacy and safety of rotigotine in elderly patients with Parkinson's disease in comparison with the non-elderly: a post hoc analysis of randomized, double-blind, placebo-controlled trials. AB - Unfortunately, the online published article has errors in Table 1 and Table 2. The corrected tables are given in the following page. PMID- 29270686 TI - Long-term follow-up more than 10 years after HSCT: a monocentric experience. AB - BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) is used in aggressive relapsing and progressive multiple sclerosis (MS). The multicentre studies and case series reported have relatively short follow-up. AIM: To evaluate long-term effect and safety of HSCT in MS. MATERIALS AND METHODS: Patients referred to the MS centre of Cagliari and undergoing HSCT were included. Variations in relapses and EDSS before and after HSCT were evaluated by Wilcoxon test. A descriptive analysis was made for other clinical data. RESULTS: Nine patients (female 6, males 3; 5 relapsing-remitting, 2 secondary progressive, 1 primary progressive, and 1 progressive relapsing) performed HSCT (1999-2006). The median follow-up was 11 years (11-18). Eight patients underwent aHSCT, seven using a low intensity conditioning regimen, and one an intermediate intensity. The primary progressive underwent allogeneic HSCT, due to onco hematological disease. The relapses number decreased in the 2 years following the procedure compared to the two preceding years (p = 0.041). New relapses or disease progressions were observed after a range of 7 (low intensity regimen)-118 (intermediate intensity) months. At last follow-up, the EDSS was stable in two patients, improved in two, and worse in five (maximum 2 EDSS in one patient). Six patients showed new lesions, and seven gadolinium-enhancing on brain MRI after a mean of 23.3 and 19.8 months, respectively. Two serious adverse events were reported: melanoma, and progressive multifocal leukoencephalopathy. CONCLUSIONS AND DISCUSSION: Our results confirm in a long follow-up the efficacy of HSCT in reducing relapses and disability progression. The risk/benefit profile is better for intermediate intensity regimens. PMID- 29270685 TI - INTEREST IN CD2, a global patient-centred study of long-term cervical dystonia treatment with botulinum toxin. AB - BACKGROUND: Longitudinal cohort studies provide important information about the clinical effectiveness of an intervention in the routine clinical setting, and are an opportunity to understand how a population presents for treatment and is managed. METHODS: INTEREST IN CD2 (NCT01753349) is a prospective, international, 3-year, longitudinal, observational study following the course of adult idiopathic cervical dystonia (CD) treated with botulinum neurotoxin type A (BoNT A). The primary objective is to document long-term patient satisfaction with BoNT A treatment. Here we report baseline data. RESULTS: This analysis includes 1036 subjects (67.4% of subjects were female; mean age was 54.7 years old; mean TWSTRS Total score was 31.7). BoNT-A injections were usually given in line with BoNT-A prescribing information. The most commonly injected muscles were splenius capitis (87.3%), sternocleidomastoid (82.6%), trapezius (64.3%), levator scapulae (40.9%) and semispinalis capitis (26.9%); 35.5% of subjects were injected using a guidance technique. Most subjects (87.8%) had been previously treated with BoNT-A (median interval between last pre-study injection and study baseline was 4 months); of these 84.8% reported satisfaction with BoNT-A treatment at peak effect during their previous treatment cycle and 51.5% remained satisfied at the end of the treatment. Analyses by geographical region revealed heterogeneity in the clinical characteristics and BoNT-A injection practice of CD subjects presenting for routine treatment. CONCLUSIONS: These baseline analyses provide sizeable data regarding the epidemiology and clinical presentation of CD, and demonstrate an international heterogeneity of clinical practice. Future longitudinal analyses of the full 3-year study will explore how these factors impact treatment satisfaction. PMID- 29270688 TI - Incidence and risk factors for surgical site infection following open reduction and internal fixation of adult tibial plateau fractures. AB - PURPOSE: The aim of this study was to identify independent risk factors for surgical site infection (SSI) and quantify the incidence of SSI in tibial plateau fractures after open reduction and internal fixation (ORIF). METHODS: This retrospective study was performed at a level 1 trauma centre from January 2015 to June 2016. Data of adult patients with tibial plateau fractures treated by ORIF were extracted from the electronic medical records. A total of 370 patients were collected. We reviewed the patients' demographics, characteristics of fracture, treatment-related variables, and indexes of laboratory examination. Multivariate logistic analysis models were performed respectively to determine independent predictors of SSI. RESULTS: Twenty-one patients developed SSI in this study. The overall incidence of SSI after ORIF of tibial fracture was 5.7%, with six (1.6%) for deep infection and 15 (4.1%) for superficial SSI. Independent predictors of SSI identified by multivariate analysis were open fracture (odds ratio=4.53; 95% CI=1.64-15.26; p=0.000), intra-operative duration (odds ratio=2.72; 95% CI=1.17 6.29; p=0.020), and smoking (odds ratio=4.79; 95% CI=1.46-15.73; p=0.010). CONCLUSIONS: The SSI incidence was high (5.7%) after surgical tibial plateau fractures by ORIF and open fracture, operative time, and smoking were identified as independent related risk factors. Therefore, we recommend that a smoking cessation program is introduced immediately at the time of admission to hospital. More reasonable management strategies on open injury should be utilized to reduce the SSI rate. PMID- 29270689 TI - Discussion: Abdominal Contouring Outcomes in Class III Obesity: Analysis of the ACS-NSQIP Database. PMID- 29270690 TI - Commentary on 'Using Four-Layers Sculpted Rib Cartilage Framework to Increase Transverse Height of the Reconstructive Ear in One Operative Stage for Microtia Patients'. PMID- 29270691 TI - Comment on: Complications and Treatment Strategy After Breast Augmentation by Polyacrylamide Hydrogel Injection-Summary of 10 Years' Clinical Experience. PMID- 29270692 TI - Public Interest in Breast Augmentation: Analysis and Implications of Google Trends Data. AB - INTRODUCTION: Breast augmentation is the most common aesthetic surgery performed in the United States (US) annually. Analysis of Google Trends (GT) data may give plastic surgeons useful information regarding worldwide, national, and regional interest for breast augmentation and other commonly performed aesthetic surgeries. METHODS: Data were collected using GT for breast augmentation and associated search terms from January 2004 to May 2017. Case volume was obtained from the American Society of Plastic Surgeons (ASPS) annual reports for the calendar year 2005-2016. RESULTS: Trend analysis showed that total search term volume for breast augmentation and breast implants gradually decreased worldwide and in the US over the study period while the search term boob job slowly increased. Univariate linear regression demonstrated a statistically significant positive correlation between average annual Google search volume of "breast augmentation" and the annual volume of breast augmentations performed in the US according to ASPS data (R 2 = 0.44, p = 0.018). There was no significant correlation between national volume of breast augmentations performed and search volume using the terms "breast implants" or "boob job" over time (p = 0.84 and p = 0.07, respectively). In addition, there appears to be country specific variation in interest based on time of year and peaks in interest following specific policies. CONCLUSIONS: To our knowledge, this is the first and only analysis of GT data in the plastic surgery literature to date. To that end, this study highlights this large and potentially powerful data set for plastic surgeons both in the US and around the world. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29270693 TI - Expander/Implant Removal After Breast Reconstruction: Analysis of Risk Factors and Timeline. AB - INTRODUCTION: Removal of tissue expanders (TE) or implants is a dire consequence of breast reconstruction, and has the potential to halt the reconstructive efforts. Our goals were to characterize a cohort of patients with TE/implant removal, to perform a time-based analysis, and to review the bacteriology associated with explanted devices. MATERIALS AND METHODS: Review of a prospectively maintained database was performed to identify patients who underwent TE/implant removal. Patient characteristics, surgical technique, adjuvant therapies, indications, complications, culture results were obtained. Data were analyzed according to timing of explantation. RESULTS: A total of 55 TE and implants were removed in 43 patients. Reasons for explantation were infection (58%), patient request (22%), and wound-related complications (20%). The majority of explantations occurred after 30 days (62%), and after Stage I (81%). Median days to explantation was 62. Patients of older age (p = 0.01) and higher BMI (p = 0.02) were more likely to undergo explantation after Stage I. The most commonly cultured organisms were S. epidermidis (10.9%), S. aureus (10.9%) and P. aeruginosa (10.9%). Antibiotic resistance was commonly encountered for ampicillin, cefazolin, penicillin, and erythromycin. CONCLUSION: Infection is the most common reason for explantation after prosthetic breast reconstruction. Patients should be carefully monitored for a prolonged period of time after Stage I, as the majority of explantations occur in this stage but beyond 30 days. For oral treatment, fluoroquinolones and trimethoprim-sulfamethoxazole and for IV treatment a combination of vancomycin or daptomycin with piperacillin-tazobactam or imipenems/carbapenems appear to be appropriate choices according to our culture results. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29270694 TI - Commentary for Modified Island Technique for Prominent Ears. PMID- 29270695 TI - Panniculectomy Outcomes in Patients with End-Stage Renal Disease in Preparation for Renal Transplant. AB - PURPOSE: End-stage renal disease (ESRD) is associated with increased cardiovascular risk factors, electrolyte imbalances, and iron deficiency anemia. These factors may increase the risk of adverse outcomes in patients undergoing panniculectomy. There is a paucity of data regarding outcomes in patients with ESRD undergoing panniculectomy. The purpose of this study is to investigate whether ESRD is associated with increased rate of complications following a panniculectomy. METHOD: The Nationwide Inpatient Sample database (2006-2011) was used to identify patients who underwent a panniculectomy. Among this cohort, patients diagnosed with end-stage renal disease were identified. Patients excluded from the study were emergency admissions, pregnant women, patients less than 18 years old, and patients with concurrent nephrectomy or kidney transplants. Demographic factors, comorbidities, and postoperative complications were evaluated. Chi-squared and risk-adjusted multivariate logistic regression analyses were performed to determine whether end-stage renal disease was associated with increased rate of postoperative complications. RESULTS: A total of 34,779 panniculectomies were performed during the study period. Of these, 613 (1.8%) were diagnosed with ESRD. Patients with ESRD were older (mean age 58.9 vs. 49.3, p < 0.01) and more likely to have Medicare (63.5 vs. 18.4%, p < 0.01). They had higher rates of comorbidities, including diabetes, hypertension, congestive heart failure, chronic lung disease, chronic anemia, liver disease, peripheral artery disease, obesity, and coagulopathies (p < 0.01). The procedure was more likely to occur at a large, teaching hospital (p < 0.01). Postoperatively, patients with ESRD had a higher rate of death (3.3 vs. 0.2%, p < 0.01), wound complications (10.6 vs. 6.2%, p < 0.01), venous thromboembolism (4.9 vs. 0.8%, p < 0.01), blood transfusions (25.3% vs. 7.0%, p < 0.01), non-renal major medical complications (40.0% vs. 8.4%), and longer hospital stay (9.2 vs. 3.8 days, p < 0.01). Multivariate logistic regression analysis controlling for age, race, sex, hospital location/teaching hospital, payer, and all comorbidities demonstrated that ESRD was independently associated with increased venous thromboembolisms (OR 2.38, 95% CI 1.48-3.83) and non-renal major medical complications (OR 1.51, 95% CI 1.19-1.91). ESRD was not independently associated with increased rate of wound complications or transfusions. CONCLUSION: Patients with ESRD are at increased risk of VTE and non-renal major medical complications following panniculectomy. Moreover, patients with ESRD have longer hospital stays and higher rates of mortality. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29270696 TI - Surgical Management of the Giant Pannus: Indications, Strategies, and Outcomes. AB - The obesity pandemic continues to produce an inexorable increase in the number of patients requiring surgical treatment of obesity and obesity-related complications. Along with this growing number of patients, there is a concomitant increase in the complexity of management. One particular example is the treatment of patients with an exceptionally large and morbid pannus. In this report, we detail the management of seven patients suffering from a giant pannus. Medical and surgical variables were assessed. A quality of life questionnaire was administered pre- and postoperatively. All seven patients suffered some obesity related medical morbidity and six of seven (86%) had local complications of the giant pannus. Each patient underwent giant panniculectomy [resection weight > 13. 6 kg (30 lb)]. The mean resection weight was 20.0 kg. Four of seven (57%) patients experienced postoperative complications, with two (29%) requiring re operation and blood transfusion. Six patients were available for long-term follow up; 100% of participants indicated an increased quality of life while five (83%) reported additional postoperative weight loss, increase in exercise frequency and walking ability, and improved ability to work. Our results indicate that giant panniculectomy is a challenging and risky procedure, but careful patient selection and intraoperative scrutiny can ameliorate these risks and afford patients a dramatically improved quality of life. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29270699 TI - Comments on "Risk of mortality of node-negative, ER/PR/HER2 breast cancer subtypes in T1, T2, and T3 tumors" by Parise CA and Caggiano V, Breast Cancer Res Treat, 2017. AB - We would like to express our opinion regarding a Parise and Caggiano paper recently published in your journal. We certainly believe this is a great contribution, since it found that node-negative HER2 (+) breast cancer patients have better survival contrary to the common knowledge. This finding could reflect the consequences of targeted therapies that are changing the natural history of the disease. However, we think that such an interesting analysis could also have been done with stage III and IV patients, since this group of people could benefit greatly from these findings. In fact, new guidelines now recommend the use of HER2-specific therapy for stage IV patients with positive markers, even for life if they do not show signs of progression. Additionally, we would like to discuss the value of adding the Ki-67 marker to the classification proposed by the authors, because several papers consider it an important prognostic factor. PMID- 29270698 TI - Goshajinkigan for reducing chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. AB - BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is common and presents with persistent and challenging symptoms for which there is no effective means of prevention. This systematic review assessed the efficacy and safety of Goshajinkigan in the prevention of CIPN. METHODS: A comprehensive literature search was conducted using Scopus, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and ICHUSHI. Randomised controlled trials comparing Goshajinkigan with an alternative strategy for preventing CIPN were selected. RESULTS: Of five studies included in the review, Goshajinkigan did not reduce the risk of CIPN when the common terminology criteria for adverse events was used [risk ratio (RR) 0.94, 95% confidence interval (CI) 0.57-1.57 for grade >=2 CIPN and RR 1.08, 95% CI 0.59-2.00 for grade >=3 CIPN]. When the neurotoxicity criteria of Debiopharm was used, Goshajinkigan tended to decrease the risk of CIPN, but not significantly (RR 0.74, 95% CI 0.33-1.64 for grade >=2 CIPN and RR 0.65, 95% CI 0.28-1.52 for grade >=3 CIPN). CONCLUSIONS: Goshajinkigan tended to prevent persistence but not severity of CIPN. Higher quality trials using multiple measures are needed in the future to clarify the preventive effect of Goshajinkigan and to assess the various aspects of CIPN. PMID- 29270700 TI - Diagnostic and therapeutic applications of miRNA-based strategies to cancer immunotherapy. AB - Cancer immunotherapy has shown impressive clinical results in the last decade, improving both solid and hematologic cancer patients' overall survival. Nevertheless, most of the molecular aspects underlying the response to this approach are still under investigation. miRNAs in particular have been described as regulators of a plethora of different immunologic processes and thus have the potential to be key in the future developments of immunotherapy. In this review, we summarize and discuss the emerging role of miRNAs in the diagnosis and therapeutics of the four principal cancer immunotherapy approaches: immune checkpoint blockade, adoptive cell therapy, cancer vaccines, and cytokine therapy. In particular, this review is focused on potential roles for miRNAs to be adjuvants in soluble factor- and cell-based therapies, with the aim of helping to increase specificity and decrease toxicity, and on the potential for rationally identified miRNA-based diagnostic approaches to aid in precision clinical immunooncology. PMID- 29270697 TI - Abstracts from the 13th WINFOCUS World Congress on Ultrasound in Emergency & Critical Care. PMID- 29270701 TI - Density functional theory studies on the generation of trimethylenemethanes from the ring opening of dialkoxymethylenecyclopropanes and methylenecyclopropanethioacetals and follow-up reactions. AB - This work reports a detailed DFT study on the generation of trimethylenemethanes (TMMs) from the ring opening of dialkoxymethylenecyclopropane (DMCP), methylenecyclopropanethioacetal (MCPT), and substituted derivatives of DMCP and MCPT, as well as follow-up reactions of the TMMs. The singlet DMCP and MCPT were found to be 51.32 and 53.77 kcal mol-1 more stable than the triplet DMCP and MCPT respectively, corresponding to triplet:singlet population ratios of 1:1038 and 1:1040, respectively, at 25 degrees C using Boltzmann distribution, implying that the proportion of the triplet species is negligible at 25 degrees C. The ring-opening reactions occur through singlet transition states with barriers of 40.68 and 42.27 kcal mol-1 for DMCP and MCPT, respectively, and yield TMMs that are very unstable compared to the precursors, with the triplet TMM being far more stable than the singlet. Whereas the singlet TMMs readily undergo cycloaddition reactions with olefins to form five-membered carbocyclic rings, the triplet species do not. The selectivity of the reactions of the DMCP TMMs is very sensitive to temperature; at 25 degrees C, cycloaddition with olefins and ring closure to form ketenes have very comparable barriers while temperatures above 150 degrees C favor the exclusive formation of a ketene followed by dimerization. In MCPT, ring closure to form ketenes is the favored reaction at all temperatures studied. Pathways for the generation of trimethylenemethanes from their precursors and follow-up reactions. PMID- 29270702 TI - The Michel Benoist and Robert Mulholland yearly European Spine Journal Review : A survey of the "medical" articles in the European Spine Journal, 2017. PMID- 29270703 TI - Remarkable efficacy of temozolomide for relapsed spinal myxopapillary ependymoma with multiple recurrence and cerebrospinal dissemination: a case report and literature review. AB - PURPOSE: Myxopapillary ependymomas are intradural tumors which grow from the terminal filum of the spinal cord. Although they are classified as WHO grade I, they sometimes cause cerebrospinal fluid dissemination or local recurrence. In this report, we describe a case in that temozolomide (TMZ) showed remarkable efficacy on a recurrent spinal myxopapillary ependymoma. CASE REPORT: A 26-year old female underwent resection of an intradural myxopapillary ependymoma at L5 initially. Although an en bloc total resection, including the capsule, could be achieved, she needed two additional tumor resection surgeries with postoperative radiotherapy at L4 and at L3 (2 and 6 years after the initial surgery, respectively). Moreover, 4 years after the initial surgery, a disseminated metastatic tumor occurred at T11/12 and local radiotherapy was not effective. After the third surgery, an aggressive adjuvant therapy was necessary because there was a high risk of another recurrence. Therefore, TMZ was administered for 1 year. After 6 months of TMZ treatment, remarkably, the disseminated metastatic tumor at T11/12 had disappeared completely. Presently, 6 years after finishing the TMZ treatment, the follow-up MRI has shown no recurrence in the brain and whole spine. CONCLUSIONS: TMZ is usually used in the treatment of glioblastoma and, recently, it has been reported to be effective for the lower grade spinal gliomas including spinal intramedullary ependymomas. However, for myxopapillary ependymomas, there has been no report that TMZ is effective. According to our results, TMZ could be one of the possible candidates for adjuvant therapy in multiple recurrent myxopapillary ependymomas. PMID- 29270704 TI - Alterations in the activity of certain enzymes in the gills of a carp Labeo rohita exposed to an azo dye, Eriochrome black T: a biochemical investigation. AB - In Labeo rohita exposed to sub-lethal concentrations of an azo dye, Eriochrome black T for 4 days, gills show considerable alterations in the activity of certain metabolic enzymes-alkaline phosphatase, acid phosphatase, carboxylesterase, lactate dehydrogenase, and succinate dehydrogenase; and antioxidant enzymes-catalase and peroxidase. The activities of alkaline phosphatase, acid phosphatase, carboxylesterase, succinate dehydrogenase, catalase, and peroxidase decline significantly. This has been associated with impaired metabolic function of the gills due to azo dye toxicity. The activity of lactate dehydrogenase, in contrast, shows a gradual increase, reflecting a shift from aerobic to anaerobic metabolism. In the fish kept for recovery for 8 days, after exposing the fish to the dye for 4 days, activity of succinate dehydrogenase, alkaline phosphatase, and lactate dehydrogenase gradually become similar to control. Nevertheless, activity of acid phosphatase, catalase, peroxidase, and carboxylesterase, although recover gradually, remained significantly low as compared to that of control. This study signifies that the dye is highly toxic to Labeo rohita and suggests that the activity of metabolic and antioxidant enzymes can be used as biomarker for fish toxicity. PMID- 29270705 TI - Temporal Trends in Population Level Impacts of Risk Factors for Sexually Transmitted Infections Among Men Who Have Sex with Men, Heterosexual Men, and Women: Disparities by Sexual Identity (1998-2013). AB - Sexually transmitted infections (STIs) remain a significant public health problem worldwide. We aimed to describe the temporal trends and relative contributions of established risk factors to STIs among sexual health center attendees. This retrospective study included more than 90,000 individuals who attended a sexual health center in Sydney, Australia, during the period 1998-2013. Multivariable logistic regression models were used to identify the correlates of STI diagnoses for three groups: men who have sex with men (MSM), heterosexual men, and women separately. Trends in population attributable risk percentages (PAR%) were estimated to assess the relative contributions of the risk factors on STI diagnosis. STI diagnosis rates among sexual health clinic attendees increased by 75% from 16 to 28% among MSM and more than doubled among heterosexual men and women (7-15 and 5-12%, respectively). Inconsistent condom use, three or more sex partners, sex overseas, past STI diagnosis, and contact with an STI case collectively contributed 61, 74 and 55% of the STI diagnoses among MSM, heterosexual men and women, respectively. Increase in STI diagnosis associated with temporal trends in combined risk factors including condomless sex, multiple sex partners, past STI diagnosis, and contact with an STI case. Although the majority of the factors considered in this study have been significantly associated with STI positivity in all three groups, their overall population level contributions to the epidemic have changed substantially. Our results indicated significant disparities between the MSM and heterosexual men and women as well as sex-specific differences in terms of sexual behaviors. PMID- 29270706 TI - Exciting Times: New Advances Towards Understanding the Regulation and Roles of Kainate Receptors. AB - Kainate receptors (KARs) are glutamate-gated ion channels that play fundamental roles in regulating neuronal excitability and network function in the brain. After being cloned in the 1990s, important progress has been made in understanding the mechanisms controlling the molecular and cellular properties of KARs, and the nature and extent of their regulation of wider neuronal activity. However, there have been significant recent advances towards understanding KAR trafficking through the secretory pathway, their precise synaptic positioning, and their roles in synaptic plasticity and disease. Here we provide an overview highlighting these new findings about the mechanisms controlling KARs and how KARs, in turn, regulate other proteins and pathways to influence synaptic function. PMID- 29270707 TI - Low-level laser therapy for the treatment of androgenic alopecia: a review. AB - There are many new low-level laser technologies that have been released commercially that claim to support hair regrowth. In this paper, we will examine the clinical trials to determine whether the body of evidence supports the use of low-level laser therapy (LLLT) to treat androgenic alopecia (AGA). A literature search was conducted through Pubmed, Embase, and Clinicaltrials.gov for clinical trials using LLLT to treat AGA. Thirteen clinical trials were assessed. Review articles were not included. Ten of 11 trials demonstrated significant improvement of androgenic alopecia in comparison to baseline or controls when treated with LLLT. In the remaining study, improvement in hair counts and hair diameter was recorded, but did not reach statistical significance. Two trials did not include statistical analysis, but showed marked improvement by hair count or by photographic evidence. Two trials showed efficacy for LLLT in combination with topical minoxidil. One trial showed efficacy when accompanying finasteride treatment. LLLT appears to be a safe, alternative treatment for patients with androgenic alopecia. Clinical trials have indicated efficacy for androgenic alopecia in both men and women. It may be used independently or as an adjuvant of minoxidil or finasteride. More research needs to be undertaken to determine the optimal power and wavelength to use in LLLT as well as LLLT's mechanism of action. PMID- 29270708 TI - Potential role of S100A8 in skin rejuvenation with the 1064-nm Q-switched Nd:YAG laser. AB - The 1064-nm Q-switched Nd:YAG laser is demonstrated to be effective for non ablative skin rejuvenation, but the molecular mechanism by which dermis responses to laser-induced damage and initiates skin remodeling is still unclear. HaCaT cells and 3T3 skin fibroblasts were irradiated with the 1064-nm Q-switched Nd:YAG laser at the different doses. Then, cells were collected and lysed for PCR and Western blot analysis. Cell viability was detected by Cell Counting Kit-8 (CCK-8) before and after laser irradiation. The expressions of S100A8, advanced glycosylation end product-specific receptor (RAGE) and inflammatory cytokines in two cell lines were markedly upregulated after laser treatments. The PCR, Western blot, and ELISA analysis showed the significant increase of type I and III procollagen in the 3T3 cells treated with the 1064-nm laser. Interestingly, si S100A8 effectively inhibited the expression of cytokines and collagen, while S100A8 treatments significantly increased them. P-p38 and p-p65 levels were also elevated after the 1064-nm laser irradiation, which is positively related with S100A8. Cell viability and reactive oxygen species (ROS) levels were not changed, while the content of superoxidase dismutase (SOD) in two cells was increased after laser irradiation. Our results demonstrated that the overexpression of S100A8 induced by the 1064-nm laser irradiation triggered inflammatory reactions in skin cells. The inflammatory microenvironment and improvement of skin antioxidant capacity contribute to new collagen synthesis in the skin cells. Thus, S100A8 was required for laser-induced new collagen synthesis in skin cells. p38/MAPK and NF-kappaB signal pathways were involved in S100A8-mediated inflammatory reactions in response to laser irradiation. PMID- 29270709 TI - The Role of Distance and Quality on Facility Selection for Maternal and Child Health Services in Urban Kenya. AB - Universal access to health care requires service availability and accessibility for those most in need of maternal and child health services. Women often bypass facilities closest to home due to poor quality. Few studies have directly linked individuals to facilities where they sought maternal and child health services and examined the role of distance and quality on this facility choice. Using endline data from a longitudinal survey from a sample of women in five cities in Kenya, we examine the role of distance and quality on facility selection for women using delivery, facility-based contraceptives, and child health services. A survey of public and private facilities offering reproductive health services was also conducted. Distances were measured between household cluster location and both the nearest facility and facility where women sought care. A quality index score representing facility infrastructure, staff, and supply characteristics was assigned to each facility. We use descriptive statistics to compare distance and quality between the nearest available facility and visited facility among women who bypassed the nearest facility. Facility distance and quality comparisons were also stratified by poverty status. Logistic regression models were used to measure associations between the quality and distance to the nearest facility and bypassing for each outcome. The majority of women bypassed the nearest facility regardless of service sought. Women bypassing for delivery traveled the furthest and had the fewest facility options near their residential cluster. Poor women bypassing for delivery traveled 4.5 km further than non-poor women. Among women who bypassed, two thirds seeking delivery and approximately 46% seeking facility based contraception or child health services bypassed to a public hospital. Both poor and non-poor women bypassed to higher quality facilities. Our findings suggest that women in five cities in Kenya prefer public hospitals and are willing to travel further to obtain services at public hospitals, possibly related to free service availability. Over time, it will be important to examine service quality and availability in public sector facilities with reduced or eliminated user fees, and whether it lends itself to a continuum of care where women can visit one facility for multiple services reducing travel burden. PMID- 29270710 TI - Serum ischemia modified albumin is a possible new marker of oxidative stress in phenylketonuria. AB - The role of oxidative stress in the pathogenesis of phenylketonuria (PKU) associated disorders has been implicated. Ischemia modified albumin (IMA) is a modified form of serum albumin, which is produced under the conditions of oxidative stress. The aim of this study was to measure the serum level of IMA in the PKU patients and to investigate its ability in predicting the status of oxidative stress in these patients. Fifty treated-PKU patients and fifty age- and sex-matched healthy subjects were included in the study. The blood samples were obtained and the serum level of phenylalanine (Phe) was measured using reverse phase HPLC method. The levels of IMA, malondialdehyde (MDA), gamma-glutamyl transferase (GGT) activity, and uric acid (UA) were determined using colorimetric methods. The levels of serum Phe, IMA, and MDA were significantly higher (p < 0.001) and the level of UA (p < 0.05) was lower in the PKU patients compared to control group. Serum IMA level was positively correlated with MDA (r = 0.585, p < 0.001) and UA (r = 0.6, p < 0.001). An inverse relationship was observed between the serum level of IMA and Phe (r = - 0.410, p < 0. 01). Results of the present study suggest that serum IMA level could be used as a novel marker for the evaluation of oxidative stress in the PKU patients. PMID- 29270712 TI - Volumetric assessment of sphenoid sinuses through segmentation on CT scan. AB - PURPOSE: Computed tomography represents the gold standard for the assessment of morphological characteristics of sphenoid sinuses, whose anatomy has acquired a novel interest because of the recent introduction of transsphenoidal surgery and robot-assisted procedures. One of the most relevant parameters for planning surgical intervention is the volume of sphenoid sinuses, and with time few population studies have been published. However, at present, no data are available concerning the relation between volume and anatomical variants of sphenoid sinuses. METHODS: We retrospectively evaluated head CT-scans of 100 patients (age range 25-99 years; mean age males 45.0; mean age females 50.5 years) to calculate the volume of sphenoid sinuses through automatic segmentation. Possible statistically significant differences according to sex and variants of pneumatization, and type of sinus were assessed, respectively, through Student's t test and one-way ANOVA test (p < 0.05). RESULTS: Average volume of sphenoid sinuses in males was 10.005 +/- 5.101 cm3, in females 7.920 +/ 3.176 cm3. Differences according to sex were statistically significant (p < 0.05). Patients with pneumatization of pterygoid processes, dorsum sellae and anterior clinoid processes had a significantly higher volume than unaffected subjects. Moreover, differences of volume according to the type of sphenoid sinus were statistically significant (p < 0.05). CONCLUSIONS: Results show that volume of sphenoid sinuses strongly depend upon the type of sinus and possible pneumatization variants. Moreover, the important of ethnic variability is confirmed. PMID- 29270714 TI - Overexpression and RNA interference of TwDXR regulate the accumulation of terpenoid active ingredients in Tripterygium wilfordii. AB - OBJECTIVE: To examine the putative regulatory role of TwDXR in terpenoid biosynthesis and terpenoid biosynthetic pathway-related gene expression, through overexpression and RNA interference with TwDXR. RESULTS: We obtained 1410 and 454 bp TwDXR-specific fragments to construct overexpression and RNAi vectors. qRT-PCR was used to detect the expression of TwDXR and terpenoid biosynthesis pathway related genes. The overexpression of TwDXR led to a 285% upregulation and the TwDXR RNAi led to a reduction to 26% of the control (empty vector-transformed cells) levels. However, pathway-related genes displayed different trends. When TwDXR was overexpressed, TwDXS expression decreased by 31% but increased to 198% when TwDXR expression was inhibited. The accumulation of terpenoids was also assayed. In the overexpression group, differences were not significant whereas the contents of triptolide and celastrol in the TwDXR RNAi samples were diminished by 27.3 and 24.0%, respectively. CONCLUSION: The feedback regulation of gene transcription and the accumulation of terpenoids in terpenoid biosynthesis in Tripterygium wilfordii were verified by TwDXR overexpression and RNAi experiments. PMID- 29270715 TI - p70S6K activation promotes the transdifferentiation of fibroblasts to myofibroblasts in pterygium tissue growth on the cornea. AB - OBJECTIVE: To investigate the role of p70S6K in the transdifferentiation of fibroblasts to myofibroblasts in pterygium tissue growth on the cornea. RESULTS: Quantitative real-time PCR and immunohistochemistry showed that p70S6K expression was higher in pterygium tissues than in normal conjunctival tissues. Higher p70S6K RNA expression levels were correlated with higher pterygium grades. Additionally, western blot analysis revealed that phosphorylated (activated) p70S6K (p-p70S6K) expression was significantly correlated with alpha-smooth muscle actin (alpha-SMA, a hallmark of transdifferentiation) expression in cultured human pterygium fibroblasts (HPFs). Furthermore, p70S6K knockdown and the specific mTOR inhibitor rapamycin decreased the expression levels of p-p70S6K and alpha-SMA in cultured fibroblasts from grade T3 pterygium. CONCLUSIONS: p70S6K activation promotes the transdifferentiation of pterygium fibroblasts to myofibroblasts. Thus, targeting p70S6K may be a useful strategy in the management of pterygium. PMID- 29270716 TI - Pre-administration of rats with Helicobacter pylori gamma-glutamyl-transpeptidase alleviates osteoarthritis. AB - OBJECTIVE: To determine the efficacy of Helicobacter pylori gamma-glutamyl transpeptidase (GGT) in osteoarthritis (OA) therapy. RESULTS: Oral administration of rats with rGGT alleviated joint pain in the acute phase of iodoacetate (IA) induced OA. The CXCL1/IL-6 in blood and in articular tissue as well as circulating granulocytes in the recipients of GGT, were reduced. This might be associated with the expansion of regulatory T cells in the inguinal lymph nodes and increased articular IL-10. CONCLUSION: We provide preclinical evidence that H. pylori GGT may represent a promising candidate for OA therapy. PMID- 29270717 TI - [Mosquito-transmitted infections]. AB - Mosquito-transmitted diseases represent one of the greatest health risks when traveling to tropical and sub-tropical countries. Only Japanese encephalitis and yellow fever can be avoided by inoculation, and only malaria can be prevented by chemoprophylaxis. Exposure prophylaxis is the only protection against all other mosquito-born diseases. These infections need to be carefully considered in the differential diagnosis of returning travelers, taking current epidemiology into account. This review discusses common infectious diseases and the options for their diagnosis and therapy. PMID- 29270719 TI - Correction to: Estimating effect size when there is clustering in one treatment group. AB - Equation (26) is formatted incorrectly in the pdf version. It should appear as follows. PMID- 29270718 TI - IRES-based co-expression of influenza virus conserved genes can promote synergistic antiviral effects both in vitro and in vivo. AB - Vaccination is the most effective method for the prevention of influenza virus infection. Currently used influenza vaccines that target the highly polymorphic viral surface antigens can provide protection when well matched with circulating virus strains. Antigenic drift or cyclically occurring pandemics may hamper the efficacy of these vaccines, which are chosen prior to each flu season. Therefore, a universal vaccine, designed to induce broadly cross-protective immunity against the highly conserved internal antigens M1 and nucleoprotein could provide durable protection against various influenza virus subtypes, and it could also reduce the impact of pandemic influenza, which occurs less frequently. Here, we describe a new influenza vaccine candidate in which two highly conserved antigens, nucleoprotein (NP) and matrix (M1), are simultaneously expressed from a bicistronic vector termed pIRESM1/NP. Mice were immunized intradermally four times with the pIRESM1/NP construct. The protection efficacy of the gene-based vaccine was assessed by IFN-gamma and Granzyme B ELISpot assays, follow-up observation of weight loss, and survival rates of the mice groups against lethal challenges with influenza A virus subtypes H1N1 and H5N1. The group that received pIRESM1/NP showed full protection against disease following lethal challenge with H1N1 and H5N1. This group also generated significantly higher host immune cellular responses than the other groups. These results demonstrate that a DNA vaccine strategy based on co-expression of the M1 and NP proteins could provide an effective way to control influenza virus infection. PMID- 29270720 TI - Pain and chronic pain epidemiology : Implications for clinical and public health fields. PMID- 29270721 TI - Detrusor underactivity in pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The association between pelvic organ prolapse (POP) and detrusor underactivity (DU) is not well defined. The primary outcome of this study was to evaluate the prevalence of DU in a cohort of patients with POP and its association with symptoms, anatomy. and urodynamic findings. The secondary outcome was to evaluate the evolution of lower urinary tract symptoms after POP repair between DU and non-DU patients. METHODS: Consecutive patients who underwent preoperative urodynamic tests were retrospectively analyzed. Detrusor underactivity was evaluated by the Bladder Contractility Index (BCI = pDetQmax + Qmax * 5) proposed by Abrams. A BCI < 100 was considered indicative of an underactive bladder. Patients with underactive bladder were considered group A, whereas the remaining patients were classified as group B. RESULTS: A total of 518 patients were studied. According to BCI, detrusor underactivity was identified in 212 (40.9%) patients (group A). Group A showed higher rates of voiding symptoms (59.4% vs 36.3%, p < 0.0001) and positive (>100 ml) postvoid residual (29.7% vs 9.8%, p < 0.0001). Conversely, they displayed lower rates of urge incontinence (15.1% vs 23.2%, p = 0.02) and detrusor overactivity (15.6% vs 23.9%, p = 0.02). Preoperative Pelvic Organ Prolapse Quantification (POP-Q) demonstrated greater Aa (+1.1 +/- 1.5 vs +0.9 +/- 1.5, p = 0.03) and Ba (+1.4 +/- 1.7 vs +1.2 +/- 1.7, p = 0.04) points values in patients in group A. After POP surgery, postoperative voiding symptoms were similar in the two groups (16% vs 15.7%, p = 0.91). CONCLUSIONS: Our study showed a 40.9% prevalence of DU in POP patients. DU was associated with the presence of voiding symptoms and positive PVR. Moreover, cystocele showed to be more severe in DU group. After surgical repair of POP, voiding symptoms of DU patients became equal to non-DU ones, suggesting that obstruction removal might recover DU in these patients. PMID- 29270722 TI - Functional pelvic floor anatomy in Nepali women attending a general gynaecology clinic. AB - INTRODUCTION AND HYPOTHESIS: Limited existing evidence suggests that there is a high prevalence of female pelvic organ prolapse (POP) amongst Nepali women. However, to date, no comprehensive assessment of pelvic floor functional anatomy has been undertaken in this population. Our study aimed to determine functional pelvic floor anatomy in Nepali women attending a general gynaecology clinic. METHODS: One hundred and twenty-nine consecutive women attending the clinic were offered an interview, clinical examination [International Continence Society Pelvic Organ Prolapse Quantification system (ICS/POP-Q)] and 4D translabial ultrasound (TLUS). Most presented with general gynaecological complaints. Five were excluded due to previous pelvic surgery, leaving 124. RESULTS: A POP-Q exam was possible in 123 women, of whom 29 (24%) were diagnosed with a significant cystocele, 50 (41%) significant uterine prolapse and seven (6%) significant posterior compartment prolapse. Evaluation of 4D TLUS data sets was possible in 120 women, of whom 25 (21%) had a significant cystocele, 45 (38%) significant uterine prolapse and ten (8%) significant descent of the rectal ampulla. In 13 cases, there was a rectocele with a mean depth of 14 (10-28) mm. Of 114 women in whom uterine position could be determined, 68 (60%) had a retroverted uterus associated with significant uterine prolapse (P 0.038). CONCLUSIONS: POP is common in Nepali women attending a general gynaecology clinic, with a high prevalence of uterine prolapse (40%). Uterine retroversion was seen in 60% and was associated with uterine prolapse. Patterns of POP in Nepal seem to be different from patterns observed in Western populations. PMID- 29270724 TI - [Urethral reconstruction in patients with failed hypospadia repair]. AB - BACKGROUND: The tasks involved in reconstructing the urethra after failed hypospadias repair range from correction of a trivial meatal stenosis to reconstruction of the entire anterior urethra. OBJECTIVES: To describe pathological findings in the urethra after failed hypospadias repair and the respective surgical methods used for their correction. MATERIALS AND METHODS: The various pathological findings after unsuccessful hypospadias surgery are classified according to their location and complexity. RESULTS: The general rules of reconstruction that should be applied in each particular situation are described. CONCLUSIONS: Successful reconstruction of the urethra in patients with failed hypospadias surgery requires experience and good knowledge of the anatomy of the normal and hypospadic urethra and penis. Mastery of plastic surgical techniques and profound knowledge of the various surgical methods of hypospadias surgery are essential. PMID- 29270723 TI - Are school factors and urbanization supportive for being physically active and engaging in less screen-based activities? AB - OBJECTIVES: The aim was to assess the association between physical activity and screen-based activities in adolescents and selected school factors and urbanization and whether these associations were modified by degree of urbanization. METHODS: We obtained data regarding the fifth-ninth grade students from 130 schools in 2014 via the Health Behaviour in School-aged Children cross sectional study in Slovakia (n = 9743, mean age = 13.5, 50.3% boys). We explored the associations using multilevel logistic regression. RESULTS: We found significant associations between physical activity and the accessibility of an area for skating/tennis court [odds ratio (OR) = 1.20 and 95% confidence interval (CI) 1.01-1.42], and between physical activity and active breaks (OR = 0.83 and 95% CI 0.69-0.99). The rates of screen-based activities were higher in small towns (OR = 1.63, 95% CI 1.29-2.06), towns (OR = 1.30, 95% CI 1.08-1.57), and cities (OR = 1.40, 95% CI 1.04-1.87) than in villages. CONCLUSIONS: School environment and degree of urbanization are associated with adolescents' physical activity and screen-based activities. This holds positively for access to an area for skating/tennis court and negatively for active breaks regarding physical activity and for living in villages regarding less use of screens. PMID- 29270725 TI - Selecting living donors for uterus transplantation: lessons learned from two transplantations resulting in menstrual functionality and another attempt, aborted after organ retrieval. AB - PURPOSE: To contribute to establishing donor selection criteria based on our experience with two successful living-donor human uterus transplantations (UTx) and an aborted attempt. METHODS: This interventional study included three patients with uterine agenesis, aged 23, 34, and 23 years, scheduled for UTx, and their uterus-donating mothers, aged 46, 61, and 46 years, respectively. Interventions included preoperative investigations, donor surgery, back-table preparation, and recipient surgery. Preoperative imaging, surgical data, histopathology, menstrual pattern, and uterine blood flow were the main outcome measures. RESULTS: In the first case (46-year-old mother/23-year-old daughter), donor/recipient surgery took 12.12/5.95 h. Regular spontaneous menstruations started 6-week post-transplantation, continuing at 24-28-day intervals throughout the 6-month observation period. Repeated follow-up cervical biopsies showed no signs of rejection. In the second case (61-year-old donor), surgery lasted 13.10 h; attempts to flush the retrieved uterus failed due to extreme resistance of the left uterine artery (UA) and inability to perfuse the right UA. Transplantation was aborted to avoid graft vessel thrombosis or insufficient blood flow during potential pregnancy. Histopathology revealed intimal fibrosis and initial sclerosis (right UA), extensive intimal fibrosis (parametric arterial segments), and subtotal arterial stenosis (myometrial vascular network). In the third case (46-year-old mother/23-year-old daughter), donor/recipient surgery took 9.05/4.52 h. Menstruations started 6-week post-transplantation. Repeated cervical biopsies showed no signs of rejection during the initial 12-week follow-up period. CONCLUSIONS: Meticulous preoperative evaluation of potential living uterus donors is essential. This may include selective contrast-enhanced UA angiograms and limitation of donor age, at least in donors with risk factors for atherosclerosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03048396. PMID- 29270726 TI - Therapy-free interval has prognostic value in patients with recurrent cervical cancer treated with chemotherapy following definitive concurrent chemoradiotherapy: methodological issues. PMID- 29270728 TI - Leptin and soluble leptin receptor in association with gestational diabetes: a prospective case-control study. AB - PURPOSE: To assess the association of serum leptin and its receptor (SLeptinR) with the risk of gestational diabetes mellitus (GDM) and to evaluate the longitudinal circulation of these peptides in pregnancy. METHODS: This study consisted of 53 subjects diagnosed with GDM and 43 normal glucose tolerance (NGT) pregnant women. Serum leptin and SLeptinR were measured at 24-28 weeks, prior and after delivery, and post-puerperium. RESULTS: Lower levels of leptin and SLeptinR were observed in GDM compared to NGT. Leptin [OR 0.97 (95% CI 0.94-1.0)] and SLeptinR [OR 0.86 (95% CI 0.79-0.93]) were inversely associated with GDM. Participants in the lowest tertile for leptin and SLeptinR had a 2.8-fold (95% CI 1.0-7.6) and a 5.7-fold (95% CI 1.9-17.3) higher risk of developing GDM compared with the highest tertile, respectively. These relationships were attenuated after adjustment for covariates. In both the groups, peak leptin was observed at 24-28 weeks, decreasing continuously during pregnancy (p > 0.05) and after delivery (p < 0.017). SLeptinR level increased (p < 0.001) during pregnancy and decreased (p < 0.005) after delivery in GDM, however, levels remained the same in NGT. In GDM, leptin and SLeptinR was positively and inversely correlated with BMI and HOMA-IR at 24-28 weeks and post-puerperium, respectively. The cord levels of both leptin and SLeptinR were lower than maternal levels. There were no significant differences in serum cord leptin and SLeptinR levels between the groups. CONCLUSION: Leptin and SLeptinR are independently and inversely associated with GDM. Lower levels of these peptides may play an important role in the pathophysiology of GDM and pre-diabetic state in post-puerperium. PMID- 29270727 TI - Does she have adnexal torsion? Prediction of adnexal torsion in reproductive age women. AB - PURPOSE: The aim of this study was to investigate the association of clinical, laboratory and ultrasound findings with the surgical diagnosis of adnexal torsion in a retrospective cohort of women operated for suspected torsion. METHODS: The study included 199 reproductive age women > 16-year-old who underwent urgent laparoscopy for suspected adnexal torsion between January 2008 and December 2014. The association of various parameters with adnexal torsion was analyzed with a multivariate logistic regression analysis and described as odds ratios (OR) +/- 95% confidence intervals (CI). RESULTS: Adnexal torsion was surgically diagnosed in 111/199 (55.8%) cases. On the multivariate logistic regression analysis, complaints of nausea/vomiting (OR 4.5, 95% CI 1.8-11.1), peritoneal irritation signs (OR 100.9, 95% CI 4.2-2421.9), elevated white blood cell count > 11,000 cells/mL (OR 3.7, 95% CI 1.3-10.8), presence of free pelvic fluid on ultrasound (OR 34.4, 95% CI 6.7-177.9), ultrasound findings suggestive of ovarian edema (OR 4.2, 95% CI 1.5-11.6), ultrasound findings suggestive of benign cystic teratoma (OR 7.8. 95% CI 1.2-49.4) and location of the ultrasound pathology on the right side (OR 4.7. 95% CI 1.9-11.9) were positively associated with adnexal torsion, while ultrasound findings suggestive of hemorrhagic corpus luteum cyst (OR 0.04, 95% CI 0.008-0.2) were negatively associated with adnexal torsion. By combining these eight parameters, the ROC curve was calculated, yielding an area under the curve of 0.93, 95% CI 0.90-0.97 (p < 0.0001). CONCLUSION: Routine clinical, laboratory and grayscale ultrasound findings may be incorporated into the emergency room workup of women with suspected adnexal torsion. Laparoscopy should be considered in all patients with suspected adnexal torsion. PMID- 29270729 TI - Screening and treatment for short cervical length in pregnancy: a physician survey in the United States. AB - PURPOSE: To evaluate how physicians in the United States (US) screen for, define, and treat a short cervix to prevent preterm birth. METHODS: This was a cross sectional, web-based survey of 500 physicians treating pregnant patients with a short cervix in the US. Respondents' geographic region was monitored to ensure balance across the nine US Census divisions. RESULTS: Respondents were predominantly obstetrician/gynecologists (86%, 429/500; mean age 49 years). Physicians reported that a median of 90% of their pregnant patients undergo cervical length screening; 81% (407/500) use transvaginal ultrasound. Physicians consult multiple evidence sources to inform their patient care, most commonly clinical guidelines (83%; 413/500) and published research (70%; 349/500). Most physicians (98%; 490/500) reported treating pregnant patients with a short cervix; 95% (474/500) use synthetic and/or natural progestogen, alone or in combination with other treatment modalities. If reimbursement was not a concern, 47% of physicians (230/500) would choose vaginal progesterone as their preferred treatment to prevent preterm birth in all patients with a short cervix, and 45% (218/500) would choose a synthetic progestogen. CONCLUSION: US guidelines recommend transvaginal ultrasound for cervical length screening; 81% of physicians in this study reported using this method. Most physicians surveyed use progestogens to treat a short cervix, with approximately half choosing a synthetic progestin (45%) and half choosing natural progesterone (47%) as their preferred treatment, despite national guidelines recommending only vaginal natural progesterone for this indication. Additional physician education is required to implement current and best practices. PMID- 29270730 TI - Effects of selective calcium-permeable AMPA receptor blockade by IEM 1460 on psychotomimetic-induced hyperactivity in the mouse. AB - Diminished glutamate neurotransmission via the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of D-serine by overstimulation of the calcium-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug or antibody-associated psychoses and schizophrenia, because D-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- [(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide), on the hyperactivity following an injection of a schizophrenomimetic NMDAR antagonist, phencyclidine, in the mouse. The subcutaneous IEM 1460 application produced a dose-dependent inhibition of the increased movement counts after the subcutaneous injection of phencyclidine. This inhibiting influence was also seen on the hyperactivity elicited by another NMDAR antagonist, dizocilpine. Moreover, the IEM 1460 administration attenuated the ability of a schizophrenomimetic dopamine agonist, methamphetamine, to increase spontaneous movements. These findings indicate that dysregulation of the CP-AMPAR could, at least in part, be implicated in the glutamate pathology of schizophrenia and/or related psychotic symptoms and be a potential target for the development of their novel treatment. PMID- 29270731 TI - Author Correction: Domestic horses (Equus caballus) prefer to approach humans displaying a submissive body posture rather than a dominant body posture. AB - In the original publication, data availability text was incorrectly published. The correct text should read as below. PMID- 29270732 TI - Genetic engineering modification and fermentation optimization for extracellular production of recombinant proteins using Escherichia coli. AB - As a common expression host, Escherichia coli has received more and more attention due to the recently developed secretory expression system, which offers advantages like reduced downstream bioprocesses and improved product quality. These advantages, coupled with high-density fermentation technology, make it a preferred system for large-scale production of many proteins utilized in industry and agriculture at a reduced process cost. To improve the secretion efficiency of target proteins, various strategies, including signal peptide optimization, periplasmic leakage, and chaperones co-expression have been developed. In addition, the optimization of the fermentation conditions such as temperature, inducer, and medium were also taken into account for the extracellular production in the high-density fermentation to reduce the cost of production. Here, these strategies ranging from genetic engineering to fermentation optimization were summarized for the future guidance of extracellular production of recombinant proteins using E. coli. PMID- 29270734 TI - Novel actinomycin group compound from newly isolated Streptomyces sp. RAB12: isolation, characterization, and evaluation of antimicrobial potential. AB - Streptomyces sp. RAB12 having potential to produce novel actinomycin group compounds was isolated from soil samples collected from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, garden premises using International Streptomycetes Project (ISP) protocols. The 16S rRNA sequence of the strain RAB12 exhibited identity with Streptomyces sp. 13647M and the sequence was deposited in NCBI under the accession number KY 203650 while the strain RAB12 was deposited in The Microbial Type Culture Collection and Gene Bank (MTCC) with accession number MTCC 12747. Cell-free extract of this novel strain revealed two bioactive principles viz., RSP 01 and RSP 02. HR-MS analysis indicated a molecular mass of 1269.61 and 1270.63 m/z g/mol for RSP 01 and RSP 02, respectively. Proton 1H, 13C NMR, 2D NMR and mass spectroscopy analysis revealed a similar fingerprint to that actinomycin D except for a peak at deltaH3.59 J (1H NMR) and delta 208.88 (13C NMR) for RSP 01 compound suggesting the presence of keto carbonyl at 5-oxo position on the proline moiety which is absent in actinomycin D. Purified RSP 02 depicted a similarity with RSP 01 except a peak in the 1H proton NMR at deltaH 3.81 J. HR-ESI mass spectra confirmed the molecular formulae for RSP 01 and RSP 02 as C62H84N12O17 and C62H86N12O17, respectively. Antimicrobial activity profile revealed higher antimicrobial activity against bacterial strains (Pseudomonas aeruginosa, Micrococcus luteus, Staphylococcus aureus, Salmonella typhi, and Bacillus subtilis) and Candida albicans compared to standard actinomycin D. MIC and MBC for RSP 01 were observed to be 0.0039 and 0.0078 (MUg/ml) against C. albicans, while for actinomycin D, it was found to be 0.031 and 0.62 (MUg/ml), respectively indicating a tenfold higher potency. Thus, these RSP 01 and RSP 02 compounds from Streptomyces sp. RAB12 may be promising candidates for industrial and clinical applications. PMID- 29270733 TI - Knockout of the SREBP system increases production of the polyketide FR901512 in filamentous fungal sp. No. 14919 and lovastatin in Aspergillus terreus ATCC20542. AB - In the production of useful microbial secondary metabolites, the breeding of strains is generally performed by random mutagenesis. However, because random mutagenesis introduces many mutations into genomic DNA, the causative mutations leading to increased productivity are mostly unknown. Therefore, although gene targeting is more efficient for breeding than random mutagenesis, it is difficult to apply. In this study, a wild-type strain and randomly mutagenized strains of fungal sp. No. 14919, a filamentous fungus producing the HMG-CoA reductase inhibitor polyketide FR901512, were subjected to point mutation analysis based on whole genome sequencing. Among the mutated genes found, mutation of the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) had a positive effect on increasing FR901512 productivity. By complementing the SCAP gene in the SCAP-mutated strain, productivity was decreased to the level of the SCAP-intact strain. Conversely, when either the SCAP or SREBP gene was deleted, the productivity was significantly increased. By genomic transcriptional analysis, the expression levels of three enzymes in the ergosterol biosynthesis pathway were shown to be decreased by SCAP mutation. These findings led to the hypothesis that raw materials of polyketides, such as acetyl-CoA and malonyl-CoA, became more available for FR901512 biosynthesis due to depression in sterol biosynthesis caused by knockout of the SREBP system. This mechanism was confirmed in Aspergillus terreus producing the polyketide lovastatin, which is structurally similar to FR901512. Thus, knockout of the SREBP system should be considered significant for increasing the productivities of polyketides, such as HMG-CoA reductase inhibitors, by filamentous fungi. PMID- 29270735 TI - Practice of community pharmacists related to multivitamin supplements: a simulated patient study in Iran. AB - Background Multivitamin supplements are a subset of dietary supplements sold in pharmacies as over-the-counter medicines. Community pharmacists are regarded as responsible professionals and relied on for their safe practice and efficacy. Objective The aim of this study was to evaluate the counselling practices of community pharmacists relating to typical use, interactions, contraindications, and side effects of multivitamin supplements using simulated patients. Setting Ninety-seven community pharmacies in Kerman, Iran. Method Two male students acted as simulated patients who role-played a scenario in the community pharmacies in two steps. In step 1, they spontaneously mentioned they were a student and did not eat properly through lack of time and requested a multivitamin supplement. In Step 2, if the pharmacists did not request a drug history, they would explain that they had severe acne and had been taking oral isotretinoin for a month. The counselling practice of the pharmacists was audio recorded. Main outcome measure The number of pharmacists who provided information about multivitamin use and identified isotretinoin-vitamin A interaction. Results Thirteen pharmacists in charge were absent at the time of the purchases. None of the pharmacists provided information about contraindications and side effects of multivitamin products. Twenty pharmacists provided instruction for multivitamin use, and two pharmacists took a drug history. In Step 1, only two pharmacists identified isotretinoin vitamin A interaction, but in Step 2, this number increased to 15. Conclusion The counselling practice of pharmacists should be improved to promote effective and safe use of multivitamin supplements. PMID- 29270736 TI - Progress in the research on venous thromboembolism. AB - Venous thromboembolism (VTE) is a common disease with high risk for death and recurrence and can severely impair patients' quality of life. Despite decades of study on this troublesome disease, there are still many unsolved problems in terms of pathogenesis, diagnosis and treatment. Hundreds of articles with various study methods and controversial research results are published every year. Thus it is crucial to keep track of reliable recent studies and articles on VTE in order to better understand it and to handle intricate related clinical events more reasonably. We reviewed high-qualified articles and guidelines from recent years and summarized VTE-related progresses in this review. PMID- 29270737 TI - Long non-coding RNA ANRIL in gene regulation and its duality in atherosclerosis. AB - The antisense transcript long non-coding RNA (lncRNA) (antisense non-coding RNA in the INK4 locus, ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF). In the context of gene regulation, ANRIL is responsible for directly recruiting polycomb group (PcG) proteins, including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2), to modify the epigenetic chromatin state and subsequently inhibit gene expression in cis-regulation. On the other hand, previous reports have indicated that ANRIL is capable of binding to a specific site or sequence, including the Alu element, E2F transcription factor 1 (E2F1), and CCCTC-binding factor (CTCF), to achieve trans-regulation functions. In addition to its function in cell proliferation, adhesion and apoptosis, ANRIL is very closely associated with atherosclerosis- related diseases. The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis. Linear transcripts have been shown to be a risk factor for atherosclerosis, whereas circular transcripts are protective against atherosclerosis. Furthermore, ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation, which is considered to be one of the causes of atherosclerosis. Collectively, ANRIL plays an important role in the formation of atherosclerosis, and the artificial modification of ANRIL transcripts should be considered following the development of this disease. PMID- 29270738 TI - Long-term Helicobacter pylori infection does not induce tauopathy and memory impairment in SD rats. AB - Helicobacter pylori (H.pylori) infection is a recognized risk factor of dementia, while its role and mechanism in Alzheimer disease (AD) remained unclarified. Our previous study has identified that injection of soluble H.pylori filtrate could induce AD-like pathologic changes and cognitive impairment in SD rats. In the present study, we further explored the effect of long-term stomach colonization of H.pylori bacteria on the brains of SD rats. The results showed that H.pylori bacteria gavage induced an efficient colonization of H.pylori in the stomach after four weeks. However, there was no significant change of tau phosphorylation at Thr205 (pT205), Thr231 (pT231), Ser396 (pS396) and Ser404 (pS404) sites in the hippocampus and cerebral cortex. The H.pylori-infected rats also showed no cognitive impairment. These observations may result from inefficient release of bacterial pathogenic factors or the overall lack of host inflammatory responses. We conclude that SD rat with long-term H.pylori colonization in the stomach is not a suitable animal model for exploring the effects of H.pylori infection on brain function in human beings; administration of bacterial filtrates may better reveal the systemic pathologic changes induced by bacterial infection in animals which show a negative host response to bacterial colonization. PMID- 29270739 TI - Inhibition of HBV replication by delivering the dual-gene expression vector pHsa miR16-siRNA in HepG2.2.15 cells. AB - This study aimed to construct the dual-gene expression vector pHsa-miR16-siRNA which can express human miR-16 and HBV X siRNA, and examine its regulatory effect on HBV gene expression in the HepG2.2.15 cell line. The expression vectors siR 1583 and pHsa-miR16-siRNA were designed and constructed. HepG2.2.15 cells were transfected with the empty vector, siR-1583, pmiR-16 and pHsa-miR16-siRNA, respectively. ELISA was performed to measure the expression of HBsAg and HBeAg in the culture supernatant 48 and72 h post transfection. Fluorescence quantitative PCR was used to measure the HBV mRNA degradation efficiency and HBV DNA copy number. The results showed that the expression of HBV genes was significantly inhibited in HepG2.2.15 cells transfected with siR-1583, pmiR-16 and pHsa-miR16 siRNA, respectively, when compared with that in cells transfected with the empty vectors, with the inhibitory effect of pHsa-miR16-siRNA being the most significant. ELISA showed that the inhibitory rates of HBsAg and HBeAg in pHsa miR16-siRNA transfected cells were correspondingly 87.3% and 85.0% at 48 h, and 88.6% and 86.5% at 72 h post transfection (P<0.01 vs. control group). RT-PCR showed that the level of HBV mRNA decreased by 80.2% (t=-99.22, P<0.01), the genomic HBV DNA by 92.8% (t=-73.06, P<0.01), and the supernatant of HBV DNA copy number by 89.8% (t=-47.13, P<0.01) in pHsa-miR16-siRNA transfected group. It was suggested that the dual-gene expression vector pHsa-miR16-siRNA can inhibit the replication of HBV more efficiently than a single-gene expression vector. PMID- 29270741 TI - Application of seasonal auto-regressive integrated moving average model in forecasting the incidence of hand-foot-mouth disease in Wuhan, China. AB - Outbreaks of hand-foot-mouth disease (HFMD) have occurred many times and caused serious health burden in China since 2008. Application of modern information technology to prediction and early response can be helpful for efficient HFMD prevention and control. A seasonal auto-regressive integrated moving average (ARIMA) model for time series analysis was designed in this study. Eighty-four month (from January 2009 to December 2015) retrospective data obtained from the Chinese Information System for Disease Prevention and Control were subjected to ARIMA modeling. The coefficient of determination (R 2), normalized Bayesian Information Criterion (BIC) and Q-test P value were used to evaluate the goodness of-fit of constructed models. Subsequently, the best-fitted ARIMA model was applied to predict the expected incidence of HFMD from January 2016 to December 2016. The best-fitted seasonal ARIMA model was identified as (1,0,1)(0,1,1)12, with the largest coefficient of determination (R 2=0.743) and lowest normalized BIC (BIC=3.645) value. The residuals of the model also showed non-significant autocorrelations (P Box-Ljung (Q)=0.299). The predictions by the optimum ARIMA model adequately captured the pattern in the data and exhibited two peaks of activity over the forecast interval, including a major peak during April to June, and again a light peak for September to November. The ARIMA model proposed in this study can forecast HFMD incidence trend effectively, which could provide useful support for future HFMD prevention and control in the study area. Besides, further observations should be added continually into the modeling data set, and parameters of the models should be adjusted accordingly. PMID- 29270740 TI - 'Outbreak Gold Standard' selection to provide optimized threshold for infectious diseases early-alert based on China Infectious Disease Automated-alert and Response System. AB - The China Infectious Disease Automated-alert and Response System (CIDARS) was successfully implemented and became operational nationwide in 2008. The CIDARS plays an important role in and has been integrated into the routine outbreak monitoring efforts of the Center for Disease Control (CDC) at all levels in China. In the CIDARS, thresholds are determined using the "Mean+2SD" in the early stage which have limitations. This study compared the performance of optimized thresholds defined using the "Mean +2SD" method to the performance of 5 novel algorithms to select optimal "Outbreak Gold Standard (OGS)" and corresponding thresholds for outbreak detection. Data for infectious disease were organized by calendar week and year. The "Mean+2SD", C1, C2, moving average (MA), seasonal model (SM), and cumulative sum (CUSUM) algorithms were applied. Outbreak signals for the predicted value (Px) were calculated using a percentile-based moving window. When the outbreak signals generated by an algorithm were in line with a Px generated outbreak signal for each week, this Px was then defined as the optimized threshold for that algorithm. In this study, six infectious diseases were selected and classified into TYPE A (chickenpox and mumps), TYPE B (influenza and rubella) and TYPE C [hand foot and mouth disease (HFMD) and scarlet fever]. Optimized thresholds for chickenpox (P55), mumps (P50), influenza (P40, P55, and P75), rubella (P45 and P75), HFMD (P65 and P70), and scarlet fever (P75 and P80) were identified. The C1, C2, CUSUM, SM, and MA algorithms were appropriate for TYPE A. All 6 algorithms were appropriate for TYPE B. C1 and CUSUM algorithms were appropriate for TYPE C. It is critical to incorporate more flexible algorithms as OGS into the CIDRAS and to identify the proper OGS and corresponding recommended optimized threshold by different infectious disease types. PMID- 29270742 TI - Video-assisted thoracoscopic surgery for the treatment of mediastinal lymph node tuberculous abscesses. AB - The mediastinal lymph node tuberculous abscesses (MLNTAs) are secondary to mediastinal tuberculous lymphadenitis. Surgical excision is often required when cold abscesses form. This study was aimed to examine video-assisted thoracoscopic surgery (VATS) for the treatment of MLNTA. Clinical data of 16 MLNTA patients who were treated in our hospital between December 1, 2013 and December 1, 2015 were retrospectively analyzed. All of the patients underwent the radical debridement and drainage of abscesses, and intrathoracic lesions were removed by VATS. They were also administered the intensified anti-tuberculosis treatment (ATT), and engaged in normal physical activity and follow-up for 3 to 6 months. The results showed that VATS was successfully attempted in all of the 16 MLNTA patients and they all had good recovery. Two patients developed complications after surgery, with one patient developing recurrent laryngeal nerve injury, and the other reporting poor wound healing. It was concluded that VATS is easy to perform, and safe, and has high rates of success and relatively few side-effects when used to treat MLNTA. PMID- 29270744 TI - Risk factors for acute kidney injury after orthotopic liver transplantation: A single-center data analysis. AB - Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality. The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT. A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital, China, were retrospectively analyzed. Their demographic characteristics and perioperative parameters were collected, and AKI was diagnosed using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) staging criteria. It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index, urine volume, operation duration (especially > 480 min), and the postoperative use of vasopressors. It was concluded that relative low urine output, long operation duration, and the postoperative use of vasopressors are risk factors for AKI following OLT. PMID- 29270743 TI - A modified surgical approach of hepatopancreatoduodenectomy for advanced gallbladder cancer: Report of two cases and literature review. AB - Gallbladder cancer (GBC) is the most common cancer of the biliary tract, constituting 80%-95% of malignant biliary tract tumors. Surgical resection is currently regarded as the sole curative treatment for GBC. Hepatopancreatoduodenectomy (HPD) has been adopted to remove the advanced gallbladder tumor together with the infiltrated parts within the liver, lower biliary tract and the peripancreatic region of GBC patients. However, patients who underwent HPD were reported to have a distinctly higher postoperative morbidity (71.4%, ranging from 30.8% to 100%) and mortality (13.2%, ranging from 2.4% to 46.9%) than those given pancreatoduodenectomy (PD) alone. We present two patients with advanced GBC who underwent a modified surgical approach of HPD: PD with microwave ablation (MWA) of adjacent liver tissues and the technique of intraductal cooling of major bile ducts. No serious complications like bile leakage, pancreatic fistula, hemorrhage and organ dysfunction, etc. occurred in the two patients. They had a rapid recovery with postoperative hospital stay being 14 days. Application of this approach effectively eliminated tumor infiltrated adjacent tissues, and maximally reduced the postoperative morbidity and mortality. This modified surgical method is secure and efficacious for the treatment of locally advanced GBC. PMID- 29270745 TI - Efficacy of EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients harboring different types of EGFR mutations: A retrospective analysis. AB - With the development of molecular pathology, many types of epidermal growth factor receptor (EGFR) mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations (co-occurrence of two or more different mutations), has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate (DCR) was 93.7% with two patients (0.2%) achieving complete response (CR), the median progression free survival (PFS) was 13.0 months (95% confidence interval [CI], 11.6-14.4 months), and the median overall survival (OS) was 55.0 months (95% CI, 26.3-83.7 months). Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858R mutation (P<0.001). Patients with classic mutations (del-19 and/or L858R mutations) demonstrated longer PFS (P<0.001) and OS (P=0.017) than those with uncommon mutations (single rare and/or complex mutations). Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS (hazard ratio [HR]=0.308, 95% CI, 0.191-0.494, P<0.001) and OS (HR=0.221, 95% CI, 0.101 0.480, P<0.001). The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations (especially for the patients with single rare mutations) are needed to determine a better precision treatment. PMID- 29270746 TI - Look into hepatic progenitor cell associated trait: Histological heterogeneity of hepatitis B-related combined hepatocellular-cholangiocarcinoma. AB - Combined hepatocellular-cholangiocarcinoma (CHC) is a mixed tumor containing elements of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Its remarkable histological heterogeneity has been linked to putative hepatic progenitor cell (HPC) origin. However, detailed histological or phenotypic description is rarely documented. In the present study, we reassessed 68 cases previously diagnosed as hepatitis B-related CHCs by immunohistochemistry and double-fluorescence immunostaining, focusing on HPC associated phenotypic observation of intermediate area of the tumor. It was found that tumor cells showed remarkable heterogeneity in intermediate area. Tumor cells with intermediate morphology between hepatocytes and cholangiocytes were oval-shaped and small with scant cytoplasm and hyperchromatic nuclei, arranging in solid nests mostly. By Keratin 7 (K7) staining, it appeared that the nests of tumor cells represented a maturation process from the undifferentiated small cells to mature hepatocytes through the "transitional" cells. Then, these small cells were further confirmed with intermediate phenotype as HPC by exploring immature hepatocellular marker and HPC/biliary markers co-localization. In conclusion, the HPC associated trait in CHC can be interpreted by HPC origin or gain of "stemness" by dedifferentiation. It is still too soon to give a final word that it is innate or acquired signature of HPC associated trait in CHC. PMID- 29270747 TI - Knockdown of GRHL3 inhibits activities and induces cell cycle arrest and apoptosis of human colorectal cancer cells. AB - The Grainyhead-like 3 (GRHL3) is involved in epidermal barrier formation, neural tube closure and wound repair. Previous studies have suggested that GRHL3 has been linked to many different types of cancers. However, to date, its effects on human colorectal cancer (CRC) has not been clarified yet. Our microarray analysis has indicated predominant GRHL3 expression in CRC. The purpose of this study was to investigate the expression and significance of GRHL3 in CRC tumorigenesis using CRC tissues and paired paracancerous tissues, as well as using distinct CRC cell lines (HT29 and DLD1). We observed increased GRHL3 expression at both mRNA and protein levels in CRC tissues and CRC cell lines using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Moreover, silencing GRHL3 with siRNA could suppress CRC cell proliferation, viability and migration in vitro. We also found that knockdown of GRHL3 could promote cell cycle arrest at G0/G1 phase in HT29 cells and DLD1 cells, and induce cell apoptosis in HT29 cells. Together, our study revealed the down-regulation of GRHL3 in vitro could inhibit CRC cell activity and trigger cell cycle arrest at G0/G1 phase and apoptosis. PMID- 29270748 TI - Overexpression of CircRNA BCRC4 regulates cell apoptosis and MicroRNA-101/EZH2 signaling in bladder cancer. AB - Emerging evidence has indicated that circular RNAs (circRNAs) play pivotal roles in the regulation of cellular processes and are found to be aberrantly expressed in a variety of tumors. However, the clinical role of circRNAs in bladder cancer (BC) and the molecular mechanisms have yet to be fully understood. In this study, the clinical specimens were obtained and the expression level of a circRNA BCRC4 was detected by real-time PCR in both BC tissues and cell line. The circular RNA over-expression plasmid was constructed and transfected into BC cells and related cell line. The cell cycles and apoptosis were observed using inverted microscope and flow cytometry. Western blotting was used to compare the relative protein expression of groups with different treatments. It was found that circRNA BCRC4 expression was lower in BC tissues than in adjacent normal tissues. Furthermore, consequences of forced-expression of BCRC4 promoted apoptosis and inhibited viability of T24T and UMUC3 cells, and up-regulated BCRC4-increased miR-101 level, which suppressed EZH2 expression in both RNA and protein levels. In addition, gambogic acid (GA) is a promising natural anticancer compound for BC therapy, and GA treatment increased the BCRC4 expression in T24T and UMUC3 cells in a dose-dependent manner. Altogether, our findings suggest that BCRC4 functions as a tumor suppressor in BC, and mediates anticancer function, at least in part, by up-regulating the expression of miR-101. Targeting this newly identified circRNA may help us develop a novel strategy for treating human BC. PMID- 29270749 TI - MMP26: A potential biomarker for prostate cancer. AB - The application of prostate-specific antigen (PSA) in the screening and diagnosis of prostate cancer (PCa) has improved the clinical management of PCa patients. However, the PSA assay has been faced with criticism due to its potential association with over-diagnosis and subsequent overtreatment of indolent patients. Matrix metalloproteinase-26 (MMP26) is a member of matrix metalloproteinases (MMPs) and has been reported to be highly expressed in many cancers. This investigation evaluated the potential of serum MMP26 as a biomarker for PCa. The level of serum MMP26 was measured by enzyme-linked immunosorbent assay (ELISA) in 160 subjects including PCa group (n=80), benign prostatic hyperplasia (BPH) group (n=40) and control group (n=40). Furthermore, we evaluated the expression of MMP26 in tissues by immunohistochemistry. The results showed the serum MMP26 levels were significantly higher in PCa group than in BPH group and control group. Similarly, the MMP26 protein was positive in PCa tissues and negative in BPH tissues and control tissues. In conclusion, these results suggested MMP26 could be used as a potential serum biomarker in the diagnosis of PCa. PMID- 29270750 TI - RNAi-mediated human Nestin silence inhibits proliferation and migration of malignant melanoma cells by G1/S arrest via Akt-GSK3beta-Rb pathway. AB - Human Nestin (hNestin) has been found to express in melanoma, and its expression is positively correlated with the advanced stage of melanoma. However, the precise role of hNestin in the development of melanoma has not been fully understood. The present study aimed to explore the role of hNestin in the proliferation and invasion of melanoma cells. The lentivirus vector carrying a short hairpin RNAs (shRNAs) targeting hNestin (hNestin-shRNA-LV) was stably infected into human melanoma cells UACC903, which expressed high levels of hNestin. The effects of hNestin knockdown on the proliferation, apoptosis, migration of melanoma cells and the related signaling pathways were investigated by immunofluorence, Western blotting and reverse transcription polymerase chain reaction (RT-PCR), respectively. The results showed that hNestin was expressed in most melanoma specimens and the melanoma cells studied. Knockdown of hNestin expression significantly inhibited the proliferation of melanoma cells, blocked the formation of cell colony, arrested cell cycle at G1/S stage and suppressed the activation of Akt and GSK3beta. hNestin-silent cells also showed a sheet-like appearance with tight cell-cell adhesion, decreased membrane expression of N cadherin and beta-catenin, and attenuated migration. Furthermore, hNestin silence resulted in the inhibition of tumor growth in vivo. Our study indicates that hNestin knockdown suppresses the proliferation of melanoma cells, which might be through affecting Akt-GSK3beta-Rb pathway-mediated G1/S arrest, and hNestin silence inhibits the migration by selectively modulating the expression of cell adhesion molecules in the process of epithelial-mesenchymal transition. PMID- 29270751 TI - Cardiac myeloperoxidase activity is elevated in hypertensive pregnant rats. AB - Myeloperoxidase (MPO) is released from activated neutrophils. The inflammation in preeclampsia was found to be associated with endothelial dysfunction. We hypothesized that cardiac and circulating MPO levels are elevated in hypertensive pregnancy. Systolic and diastolic blood pressure and heart rate were measured on pregnancy days 14, 16, 18 and 20 in normal pregnant and hypertensive pregnant rats. Left and right ventricle weights, the number of viable fetuses, litter size, fetal and placenta weights were recorded on gestational day 21. Circulating and cardiac MPO activities, soluble fms-like tyrosine kinase-1 (sFlt-1) and vascular endothelial growth factor (VEGF) and nitric oxide (NO) were detected. The results showed increases in cardiac (left, but not right ventricle) and circulating MPO activities, and concomitantly lower number of viable fetuses, litter size, and fetal and placenta weights, and decreases in NO in hypertensive pregnant rats. Also, the increases in circulating sFlt-1 and VEGF were found in hypertensive pregnant group. In conclusion, maternal and fetal detrimental changes along with increases in circulating sFlt-1 and VEGF in hypertensive pregnancy may be associated with increases in cardiac and circulating MPO activities, confirming the causative role of inflammatory response in preeclampsia. PMID- 29270752 TI - Expression of E2A in mid-secretory endometrium of women suffering from recurrent miscarriage. AB - E2A is involved in promoting forkhead box P3 (FOXP3) and retinoid-related orphan receptor gamma t (RORgammat) gene transcription, which are pivotal transcription factors of T regulatory cells and Th17 cells, respectively. Little is known about the involvement of E2A in pregnancy process. This study aimed to investigate the expression of E2A, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and Foxp3 in luteal phase endometrium of women suffering recurrent miscarriage (RM) (n=21) and control group (n=11) by immunohistochemistry, with the Vectra(r) automated quantitative pathology imaging system for analysis. The percentage of E2A+ cells and CTLA-4+ cells was significantly higher in the endometrium of women with RM than in the controls. There was positive correlation between E2A and CTLA 4 (r=0.523, P=0.002), E2A and FOXP3 (r=0.380, P=0.032), and FOXP3 and CTLA-4 (r=0.625, P=0.000) in the mid-secretory phase of endometrium for all subjects. It was concluded that the abnormal expression of endometrial E2A existed in mid secretory endometrium of women with RM, and there was a positive correlation between E2A and FOXP3, and E2A and CTLA-4, suggesting the possible regulation role of E2A involved in regulating endometrium receptivity. PMID- 29270753 TI - Acetyl-L-carnitine: An effective antioxidant against cryo-damage on human spermatozoa with asthenospermia. AB - A variety of natural and artificial cryoprotectant extenders have been explored to enhance sperm recovery following cryopreservation-thawing process. The current investigation is aimed at evaluating the effect of acetyl-L-carnitine on human spermatozoa and reactive species oxygen (ROS) level after freezing-thawing process. The spermatozoa were collected from 35 male patients diagnosed as having asthenospermia. The cryopreservation of human spermatozoa treated with acetyl-L carnitine at different concentrations (group B: 2.5 mmol/L, group C: 7.5 mmol/L, group D: 15 mmol/L) was compared with control (group A: no acetyl-L-carnitine given). For the frozen-thawed spermatozoa, the viability, motility and DNA integrity were measured by comet assay, acrosome integrity by FITC-PNA staining and ROS level was determined in each group. The results showed that there were no significant differences in motility and viability between group A and group B, while the motility and viability of spermatozoa in group C and group D were significantly increased as compared with those in group A. As compared with group A, the values for DNA integrity parameters including comet rate (CR), tail DNA percentage (TD), tail length (TL) and Oliver tail moment (OTM) were significantly reduced in group C and group D. Group C and group D also displayed a higher proportion of intact acrosome than group A. No significant difference in ROS level was found between group A and group B, while with the increase in acetyl-L carnitine concentration, the ROS level in groups C and D was significantly reduced as compared with that in group A. In conclusion, acetyl-L-carnitine at a concentration of 7.5 mmol/L is an effective antioxidant against cryo-damage on post-thawed human spermatozoa. PMID- 29270754 TI - Reproductive outcomes in women with prior cesarean section undergoing in vitro fertilization: A retrospective case-control study. AB - The impact of prior cesarean section (CS) on the pregnancy and neonatal outcomes of in vitro fertilization and embryo transfer (IVF-ET) was investigated. A retrospective analysis was performed on 144 patients with prior CS between January 2013 and December 2015. The pregnancy, delivery, and neonatal outcomes of patients who had previous CS delivery and received IVF-ET were analyzed. The control group comprised 166 patients who had only previous vaginal delivery (VD) and received IVF-ET during the same period. The results showed that the basal follicle stimulating hormone level, estradiol level on human chorionic gonadotropin (hCG) day, gonadotrophin dosage, duration of stimulation, retrieved oocytes, fertilization rate, high-quality embryo rate, multiple birth rate, abortion rate and ectopic pregnancy rate had no significant difference between the two groups (P>0.05). The pregnancy rate (40.28% vs. 54.22%) and implantation rate (24.01% vs. 34.67%) were significantly lower (P<0.05), and the ratio of embryo difficulty transfer (9/144 vs. 0/166) was significantly higher in CS group than in VD group. The risk of pernicious placenta previa and postpartum hemorrhage in twin deliveries was significantly increased in CS group as compared with that in VD group (P<0.05), and gestational age and neonatal birth weight were significantly reduced in twin deliveries as compared with singleton deliveries in both groups (P<0.05). It was suggested that the existence of CS scar may impact embryo implantation and clinical pregnancy outcome, and increase the difficulty of ET. We should limit the number of transfer embryos to avoid multiple pregnancies and strengthen gestational supervision in patients with cesarean scar. PMID- 29270755 TI - Congenital vaginal atresia: A report of 39 cases in a regional Obstetrics and Gynecology Hospital. AB - To investigate the clinical course and management of congenital vaginal atresia. This retro-spective analysis included patients with congenital vaginal atresia treated from March 2004 to August 2014 at the Obstetrics and Gynecology Hospital of Fudan University. Thirty-nine patients were included in this study. Their average age was 16.87+/-2.2 years when they came to our hospital. Totally, 51% of the patients had isolated congenital vaginal atresia with a normal cervix, whereas the others had either cervical atresia or imperforate hymen. The primary presenting signs and symptoms included primary amenorrhea (71.8%), periodic abdominalgia (41.0%), abdominal pain (36.0%), dyspareunia (10.3%), menstrual disorders (5.1%), and pelvic mass (5.1%). Ultrasound and magnetic resonance imaging (MRI) were effective inspection methods for the screening of urogenital tract-associated anomalies. Vagi-noplasty mainly included simple vagina reconstruction with insertion of a mold (n=22) and split-thickness skin grafting (n=4). In 64% of surgical patients, normal menstrual bleeding was achieved. Four of the patients subsequently became pregnant and delivered at term. Primary amenorrhea, periodic abdominalgia and abdominal pain are the main reasons for the post pubertal patients to visit doctors. Surgical methods can successfully provide these patients an opportunity for subsequent conservative management, can result in normal menstrual bleeding, resolve cyclic pelvic pain, and provide some po-tential for fertility. PMID- 29270756 TI - Transposition of branches of radial nerve innervating supinator to posterior interosseous nerve for functional reconstruction of finger and thumb extension in 4 patients with middle and lower trunk root avulsion injuries of brachial plexus. AB - This study aimed to investigate the reconstruction of the thumb and finger extension function in patients with middle and lower trunk root avulsion injuries of the brachial plexus. From April 2010 to January 2015, we enrolled in this study 4 patients diagnosed with middle and lower trunk root avulsion injuries of the brachial plexus via imaging tests, electrophysiological examinations, and clinical confirmation. Muscular branches of the radial nerve, which innervate the supinator in the forearm, were transposed to the posterior interosseous nerve to reconstruct the thumb and finger extension function. Electrophysiological findings and muscle strength of the extensor pollicis longus and extensor digitorum communis, as well as the distance between the thumb tip and index finger tip, were monitored. All patients were followed up for 24 to 30 months, with an average of 27.5 months. Motor unit potentials (MUP) of the extensor digitorum communis appeared at an average of 3.8 months, while MUP of the extensor pollicis longus appeared at an average of 7 months. Compound muscle action potential (CMAP) appeared at an average of 9 months in the extensor digitorum communis, and 12 months in the extensor pollicis longus. Furthermore, the muscle strength of the extensor pollicis longus and extensor digitorum communis both reached grade III at 21 months. Lastly, the average distance between the thumb tip and index finger tip was 8.8 cm at 21 months. In conclusion, for patients with middle and lower trunk injuries of the brachial plexus, transposition of the muscular branches of the radial nerve innervating the supinator to the posterior interosseous nerve for the reconstruction of thumb and finger extension function is practicable and feasible. PMID- 29270757 TI - Three dimensional orbital magnetic resonance T2-mapping in the evaluation of patients with Graves' ophthalmopathy. AB - The clinical application of orbital magnetic resonance (MR) T2-mapping imaging in detecting the disease activity of Graves' ophthalmopathy (GO), and the predictive values of therapy response to intravenous glucocorticoid (ivGC) were investigated. Approved by the local institutional review board (IRB), 106 consecutive patients with GO were included in this prospective study. All subjects were divided into two groups according to the patients' clinical activity score (CAS): the CAS positive group (CAS >=3) or the CAS negative group (CAS <3). T2 relaxation time of extraocular muscles (T2RT; ms) and the areas of four extra-ocular muscles (AEOMs; mm2) were measured by 3D T2-mapping MR sequence before and after methylprednisolone treatment, so as the CAS and some ophthalmic examinations including visual acuity, intra-ocular pressure, eyeball movement, diplopia and proptosis. In addition, 24 healthy volunteers were recruited as the control group. The mean T2RT and AEOMs in CAS positive group were higher than those in CAS negative group. Both CAS positive and negative groups had significantly higher mean T2RT and AEOMs than the control group (P<0.01). There was a positive correlation between T2RT and AEOMs values in GO patients, both of them had a positive correlation with CAS and the ophthalmic examinations. It was concluded that to evaluate the activity of GO, CAS was mostly related to inflammation symptoms of ocular surface, more than that, T2RT and AEOMs were also related to abnormal findings of the ophthalmic examinations including high ocular pressure, impaired eyeball movement, diplopia and proptosis. T2RT and AEOMs can reflex the inflammation state of ocular muscles better. CAS combined with 3D T2 mapping MR imaging could improve the sensitivity of detection of active GO so as the prediction and evaluation of the response to methylprednisolone treatment. PMID- 29270758 TI - Safety and efficacy of etanercept monotherapy for moderate-to-severe plaque psoriasis: A prospective 12-week follow-up study. AB - Etanercept has been shown to be effective for the treatment of moderate-to-severe plaque psoriasis. Since most clinical trials examined etanercept in combination with other drugs, the efficacy and safety of etanercept monotherapy for moderate to-severe plaque psoriasis have not been well established. This prospective study enrolled 61 Chinese patients with moderate-to-severe plaque psoriasis to explore the efficacy and safety of etanercept monotherapy. These patients were treated with etanercept at a subcutaneous dose of 25 mg, twice a week, for 12 weeks. All the 61 patients completed the treatment and showed significant improvement in psoriasis area and severity index (PASI) scores. At 4, 8, and 12 weeks after treatment, the response rates (PASI75) were 0%, 21.31%, and 40.98%, respectively. It was concluded that etanercept monotherapy is efficacious and safe for patients with moderate- to-severe plaque psoriasis. PMID- 29270759 TI - Prognosis of 591 fetuses with ultrasonic soft markers during mid-term pregnancy. AB - The present study aimed to examine the value of ultrasonic soft markers in prenatal screening by analyzing the clinical outcome of fetuses with ultrasonic soft markers during the second trimester of pregnancy. A retrospective analysis was performed to evaluate the outcome of 591 fetuses with ultrasonic soft markers from January 2015 to August 2016 in Zhongnan Hospital of Wuhan University, China. It was found that 591 fetuses showed ultrasonic soft markers in 4927 cases with the occurrence rate being 12.0%. Among them, 564 fetuses (95.4%) were delivered and the remaining 27 cases (4.6%) were aborted. Five hundred and sixty-seven cases had single ultrasonic soft marker, including echogenic intracardiac focus (n=343), mild renal pelvis dilatation (n=116), short long bones (n=72), single umbilical artery (n=31), mild lateral ventriculomegaly (n=21), choroid plexus cysts (n=19), and echogenic bowel (n=13), with the disappearing rates in pregnancy being 97.1% (333/343), 77.6% (90/116), 0% (0/72), 0% (0/31), 57.1% (12/21), 89.5% (17/19) and 61.5% (8/13) respectively. The rate of pregnancy termination due to single ultrasonic soft marker was 3.4% (19/567), and that was 33.3% (8/24) due to two ultrasonic soft markers with the difference being statistically significant (P<0.05). The reasons of pregnancy termination included malformations (polycystic kidney, cleft lip and palate, congenital heart diseases, pcromphalus, hypospadias, hydrocephalus), chromosome abnormality, and stillbirth. It was concluded that single ultrasonic soft marker is usually transient manifestation in pregnancy. Without the other structural defects, single ultrasonic soft marker usually disappears spontaneously with favorable prognosis in a low-risk population. It is suggested that ultrasonic soft markers should be appropriately interpreted to avoid unnecessary invasive examination. PMID- 29270760 TI - Incidence of atrial fibrillation after off-pump versus on-pump coronary artery bypass grafting: A meta-analysis of randomized clinical trials and propensity score matching trials. AB - The association between atrial fibrillation (AF) after coronary artery bypass grafting (CABG) and the surgical techniques selected has been extensively reported. However, no consistent results were obtained. In the present study, a meta-analysis was conducted by searching the electronic databases PubMed, Embase, Web of Science, and Cochrane to identify the association of post-CABG AF with on pump (conventional CABG, cCABG) or off-pump CABG (OPCABG). Outcomes from randomized clinical trials (RCTs) and propensity score matching (PSM) trials were pooled by using the fixed-effect or the random-effect modeling method, and verified by the quality-effect modeling method. There were 35 studies with 36 independent reports that met the inclusion criteria and were eventually included in our meta-analysis. The total odds ratio (OR) of the incidence of post-CABG AF between OPCABG and cCABG was 0.80 (95% CI 0.71-0.91). The 25 randomized clinical trials (RCTs) had an OR of 0.69 (95% CI 0.56-0.86), while the OR of the 11 PSM trials was 0.88 (95% CI 0.77-1.00). Twenty-six studies involving the patients at a mean age no more than 65 years showed an OR of 0.76 (95% CI 0.64-0.90), whereas 10 studies with patients greater than 65 years old showed an OR of 0.90 (95% CI 0.78-1.05). The results of this meta-analysis suggest that OPCAB surgery may reduce the incidence of post-CABG AF when compared to cCABG and that younger patients may benefit more from OPCAB and have a lower incidence of post-CABG AF. PMID- 29270761 TI - Correlation between Survivin expression and laryngeal carcinoma: A meta-analysis. AB - In order to provide evidence for evidence-based medicine in the treatment and prognosis of laryngeal cancer in China, the meta-analysis electronically retrieved the case-control studies published in China about the Survivin expression and its association with clinical pathological features in the tissues of laryngeal carcinoma. The results showed that a total of 25 case-control studies were finally included with 1333 cases of laryngeal cancer and 528 cases of controls. The difference in the expression of Survivin between the two groups was statistically significant [OR=18.34, 95% CI (11.82, 28.47), P<0.00001]. The difference in the expression of Survivin between laryngeal carcinoma patients with lymph node metastasis or not was statistically significant [OR=0.25, 95% CI (0.17, 0.37), P<0.00001]. The expression of Survivin in clinical I-II stage group was significantly lower than in the clinical stage III-IV group [OR=0.24, 95% CI (0.18, 0.32), P<0.00001]. The expression of Survivin in patients with low/medium differentiation was significantly lower than that in those with high differentiation [OR=0.33, 95% CI (0.26, 0.43), P<0.00001]. The difference in the expression of Survivin among different T stages of laryngeal carcinoma was statistically significant [OR=0.35, 95% CI (0.21, 0.58), P<0.00001]. In conclusion, Survivin may play an important role in the occurrence and development of laryngeal carcinoma, and its high expression is related to the poor prognosis of patients with laryngeal cancer. PMID- 29270763 TI - New name for Journal of Huazhong University of Science and Technology [Medical Sciences]: Current Medical Science. PMID- 29270762 TI - Hepatic resection combined with radiofrequency ablation versus hepatic resection alone for multifocal hepatocellular carcinomas: A meta-analysis. AB - This meta-analysis aimed to comprehensively assess the efficacy and safety of hepatic resection combined with radiofrequency ablation versus hepatic resection (HR) alone for the treatment of multifocal hepatocellular carcinomas (HCC). A literature search was conducted from the database including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and China Biology Medicine (CBM) disc. The primary outcomes included the 1-, 3-, 5-year overall survival (OS) and disease-free survival (DFS) rate. The secondary outcomes contained the intraoperative parameters and postoperative adverse events (AEs). These parameters were all analyzed by RevMan 5.3 software. After carefully screening relevant studies, four retrospective studies of high quality involving 466 patients (197 in the combined group and 269 in the HR group) were included in this study. The pooled results showed that the 1-, 3-, 5-year OS rate in the combined group were comparable with those in the HR group (OR=0.77, 0.96, 0.88; P=0.33, 0.88, 0.70, respectively). Similarly, there was no significant difference in 1-, 3-, 5-year DFS rate between the combined group and the HR alone group (OR=0.57, 0.83, 0.72; P=0.17, 0.37, 0.32, respectively). And the intraoperative parameters and postoperative AEs were also comparable between the above two cohorts. However, two included studies reported that tumor often recurred in the ablation site in the combined group. The present meta-analysis indicated that the HR combined with RFA could reach a long-term survival outcome similar to curative HR for multifocal HCC patients. And this therapy may be a promising alternative for these patients with marginal liver function or complicated tumor distribution. Furthermore, high quality randomized controlled trials (RCTs) are imperative to verify this conclusion. PMID- 29270764 TI - Erratum to: Chinese medicine formula "Shenqi San" extract inhibits proliferation of human lung adenocarcinoma A549 cells via inducing apoptosis. AB - The original version of this article unfortunately contained a mistake. The presentation of the affiliation number was incorrect. The corrected one is given below.Zhong-zhu AI () 1?. PMID- 29270765 TI - Vitamin D and renal outcome: the fourth outcome of CKD-MBD? Oshima Award Address 2015. AB - Bone fracture, cardiovascular events, and mortality are three outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD), and the umbrella concept originally described for dialysis patients. The reported association of serum phosphorus or fibroblast growth factor 23 (FGF23) levels with renal outcome suggests that the fourth relevant outcome of CKD-MBD in predialysis patients is renal outcome. We found that proteinuria of 2+ or greater with a dipstick test was associated with low vitamin D status due to urinary loss of 25-hydroxyvitamin D (25D). Moreover, active vitamin D or its analogues decrease proteinuria. Given our finding that maxacalcitol does not repress renin, the reduction of proteinuria by this agent is likely due to direct upregulation of the nephrin and podocin in podocytes. Moreover, this agent downregulates the mesenchymal marker desmin in podocytes and blocks transforming growth factor-beta autoinduction, leading to attenuation of renal fibrosis in a unilateral ureteral obstructive (UUO) model. These facts are reminiscent of the suppression of epithelial mesenchymal transition (EMT) by vitamin D. EMT blockage may explain our finding that vitamin D prescription in renal transplant recipients is associated with a lower incidence of cancer. We also reported that low vitamin D status and high FGF23 levels predict a worse renal outcome. However, administration of massive doses of 25D exacerbates renal fibrosis in UUO kidneys in 1alpha-hydroxylase knockout mice. Moreover, FGF23 inhibits 1alpha-hydroxylase in proximal tubules and monocytes. Taken together, local 1,25(OH)2D in the kidney tissue but not 25D seems to protect the kidney. PMID- 29270766 TI - Characterisation of Cronobacter strains isolated from hospitalised adult patients. AB - Bacteria belonging to the genus Cronobacter are opportunistic pathogens known for causing rare but serious infections in neonates, including meningitis, necrotising enterocolitis and sepsis. Cronobacter infections occur also in adult populations, however, they generally have milder manifestations and their prevalence is uncertain. In this study, the presence of Cronobacter strains from adult patients in the University Hospital in Bratislava was investigated and overall 18 confirmed isolates from 321 patients (5.3%) were recovered. No Cronobacter positive sample was detected in 215 sputum samples from outpatients. The highest occurrence of Cronobacter strains was observed from stroke patients and this may be associated with an abnormal swallowing ability. The isolated strains belonged to the species Cronobacter sakazakii and Cronobacter malonaticus. In silico genotyping (MLST, CRISPR-cas array profiling) of whole genome sequences assigned the strains to three different MLST clones. The majority (12/18) of the isolated strains were sequence type ST513 or single locus variants ST514 and ST515, thereby being members of C. sakazakii pathovar clonal complex CC4. However, according to core genome MLST analysis the ST513-ST515 strains created a unique cluster substantially different from other CC4 strains. The isolated strains were susceptible to 18 tested antibiotics. All strains possess a genomic island encoding for increased thermal tolerance. As Cronobacter strains are frequently present in dried foods of plant origin, spread of a specific clone within a hospital may be caused by food transmission and may be facilitated by its tolerance to environmental stresses such as desiccation and temperature. PMID- 29270767 TI - Mixed cropping regimes promote the soil fungal community under zero tillage. AB - Fungi of yield soils represent a significant portion of the microbial biomass and reflect sensitivity to changes in the ecosystem. Our hypothesis was that crops included in cropping regimes under the zero tillage system modify the structure of the soil fungi community. Conventional and molecular techniques provide complementary information for the analysis of diversity of fungal species and successful information to accept our hypothesis. The composition of the fungal community varied according to different crops included in the cropping regimes. However, we detected other factors as sources of variation among them, season and sampling depth. The mixed cropping regimes including perennial pastures and one crop per year promote fungal diversity and species with potential benefit to soil and crop. The winter season and 0-5 cm depth gave the largest evenness and fungal diversity. Trichoderma aureoviride and Rhizopus stolonifer could be used for monitoring changes in soil under zero tillage. PMID- 29270768 TI - Performance of two immunochromatographic tests for diagnosis of visceral leishmaniasis in patients coinfected with HIV. AB - Because of visceral leishmaniasis (VL) urbanization and spreading of the human immunodeficiency virus (HIV) infection to rural areas, coinfection has become more common. Here, we compared the accuracy of Kalazar Detect(r) (KD), an rK39 based immunochromatographic (IC) test, and OrangeLife(r) (OL), an rK39 + rK28 IC test, for diagnosing VL in patients coinfected with HIV in an endemic area in Brazil. Seventy-six VL patients and 40 patients with other diseases, of which 31 and 21 patients, respectively, were infected with HIV, were examined. The sensitivity of OL and KD tests was 88.89 and 95.45%, respectively, in patients without HIV. The sensitivity dropped to 67.74 and 61.29%, respectively, in coinfected patients. The decrease in sensitivity was not related to a decrease in the production of Leishmania-specific IgG. Because of the low sensitivity of rk39 test in HIV-infected patients, we suggest that patients with negative rK39 results should undergo further investigation with additional serological tests that are not based only on the rK39 antigen and examination of bone marrow aspirates. PMID- 29270770 TI - Adverse Drug Reaction Reports Received Through the Mobile App, VigiBIP(r): A Comparison with Classical Methods of Reporting. AB - INTRODUCTION: The use of mobile apps is increasing in medicine. In pharmacovigilance, mobile apps may help to increase adverse drug reaction reporting and improve the communication of safety issues. The Toulouse University Pharmacovigilance Center has developed VigiBIP(r), a free smartphone app available on Android and Apple stores, for reporting adverse drug reactions and requesting drug safety information. OBJECTIVE: The present study was performed to compare the main characteristics of spontaneous adverse drug reaction reports received through VigiBIP(r) with classical methods of reporting (phone, e-mail, fax, letter, website) during 25 months (2015-17). METHODS: Using the Chi squared test, we compared the type of reporter, adverse drug reaction seriousness, drugs involved and reported ADRs using VigiBIP(r) and classical methods of reporting RESULTS: A total of 4102 reports were received by the Toulouse University Pharmacovigilance Center, including 4.7% through VigiBip(r). Patients' reports were significantly more frequent with VigiBip(r) (6.7%) than with classical methods (3.4%) [p = 0.01]. Reported adverse drug reactions and involved drugs differed according to the method of reporting used. CONCLUSION: Our study shows that a mobile app is an additional tool used in pharmacovigilance. Types of reporters and adverse drug reactions in VigiBIP were different to those seen in classical methods of reporting. PMID- 29270769 TI - Exposure to a cyanobacterial toxin increases larval amphibian susceptibility to parasitism. AB - Anthropogenic activities are promoting the proliferation of aquatic primary producers in freshwater habitats, including cyanobacteria. Among various problems stemming from eutrophication, cyanobacterial blooms can be toxic due to the production of secondary compounds, including microcystins such as microcystin-LR (MC-LR); however, it is unknown whether cyanotoxins can affect the susceptibility of aquatic vertebrates such as fish and larval amphibians to parasites or pathogens even though infectious diseases can significantly affect natural populations. Here, we examined how exposure to environmentally relevant concentrations of MC-LRs affected the resistance of larval amphibians (northern leopard frog, Rana pipiens) to infection by a helminth parasite (the trematode Echinostoma sp.), and whether this was manifested by reductions in host anti parasite behavior. Exposure to a relatively high (82 MUg L-1) concentration of MC LR caused over 70% mortality, and tadpoles that survived exposure to the low MC LR (11 MUg L-1) treatment had significantly higher infection intensities than those in the control; however, anti-parasite behavior was not affected by treatment. Our results indicate that MC-LR can have both direct and indirect negative effects on larval amphibians by increasing their mortality and susceptibility to parasitism, which may have implications for other aquatic vertebrates in eutrophic habitats dominated by cyanobacteria as well. PMID- 29270771 TI - Quantification of myocardial blood flow with 11C-hydroxyephedrine dynamic PET: comparison with 15O-H2O PET. AB - BACKGROUND: 11C-hydroxyephedrine (HED) PET has been used to evaluate the myocardial sympathetic nervous system (SNS). Here we sought to establish a simultaneous approach for quantifying both myocardial blood flow (MBF) and the SNS from a single HED PET scan. METHODS: Ten controls and 13 patients with suspected cardiac disease were enrolled. The inflow rate of 11C-HED (K1) was obtained using a one-tissue-compartment model. We compared this rate with the MBF derived from 15O-H2O PET. In the controls, the relationship between K 1 from 11C HED PET and the MBF from 15O-H2O PET was linked by the Renkin-Crone model. RESULTS: The relationship between K 1 from 11C-HED PET and the MBF from 15O-H2O PET from the controls' data was approximated as follows: K 1 = (1 - 0.891 * exp(- 0.146/MBF)) * MBF. In the validation set, the correlation coefficient demonstrated a significantly high relationship for both the whole left ventricle (r = 0.95, P < 0.001) and three coronary territories (left anterior descending artery: r = 0.96, left circumflex artery: r = 0.81, right coronary artery: r = 0.86; P < 0.001, respectively). CONCLUSION: 11C-HED can simultaneously estimate MBF and sympathetic nervous function without requiring an additional MBF scan for assessing mismatch areas between MBF and SNS. PMID- 29270772 TI - Assessing 'No Evidence of Disease Activity' Status in Patients with Relapsing Remitting Multiple Sclerosis Receiving Fingolimod in Routine Clinical Practice: A Retrospective Analysis of the Multiple Sclerosis Clinical and Magnetic Resonance Imaging Outcomes in the USA (MS-MRIUS) Study. AB - BACKGROUND: 'No evidence of disease activity' (NEDA), a composite measure of clinical and magnetic resonance imaging outcomes, provides a comprehensive assessment of disease activity, but is not extensively reported in clinical practice. NEDA-3 is defined as patients with no new/enlarged T2 or gadolinium enhancing lesions, no relapses, and no disability progression (according to Expanded Disability Status Scale scores). NEDA-4 comprises the components of NEDA 3 and a fourth criterion of <= 0.4% annualized brain volume loss. OBJECTIVE: The objective of this study was to assess NEDA status among patients with relapsing remitting multiple sclerosis receiving fingolimod in clinical practice. METHODS: Clinical and magnetic resonance imaging data were retrospectively collected from 590 patients who initiated fingolimod at 33 multiple sclerosis centers in the USA. Patients were required to have a magnetic resonance imaging scan in the 6 months before or 1 month after fingolimod initiation (index period) and in the 9 24 months after fingolimod initiation (post-index period). Magnetic resonance imaging data were systematically quantified at a centralized reading facility. The proportions of patients with NEDA-3 or NEDA-4 status during fingolimod treatment were assessed. RESULTS: During the follow-up period (median: 16 months), data to assess NEDA-3 and NEDA-4 were available for 586 and 325 patients, respectively. In the post-index period, 58.7% of patients achieved NEDA 3 status (no relapses, 85.2%; no new/enlarged T2/gadolinium-enhancing lesions, 76.3%; no disability progression, 87.9%) and 37.2% achieved NEDA-4 status (no relapses, 86.5%; no new/enlarged T2/gadolinium-enhancing lesions, 78.8%; no disability progression, 91.1%; brain volume loss <= 0.4, 58.2%). CONCLUSION: Among patients receiving fingolimod, over half achieved NEDA-3 status and over one-third achieved NEDA-4 status. PMID- 29270775 TI - ROCK1-PredictedmicroRNAs Dysregulation Contributes to Tumor Progression in Ewing Sarcoma. AB - Over the last decade, the rho-associated kinases and several metastasis associated microRNAs have emerged as important contributors of tumor invasion. However, despite prominence, our understanding of their involvement in the metastatic potential of Ewing Sarcoma (EWS) is incomplete. The expression profiles of ROCK1 or ROCK2 and miR-124-3p, miR-138-5p, miR-139-5p, miR-335-5p and miR-584-5p (all of which were previously predicted or validated to regulate these kinases) were evaluated through qRT-PCR and associated with clinical parameters. In vitro assays to evaluate colony formation and invasion/migration capacieties were performed on SK-ES-1 cells transfected with pre-miR mimics. ROCK1 expression was significantly reduced in EWS tissues, though there was no association with pathological parameters. miR-124-3p, miR-139-5p and miR-335-3p were also found significantly downregulated and positively correlated with ROCK1. Stratification indicated an association between lower levels of miR-139-5p and miR-584-5p with disease progression (p < 0.05), while reduced expression of the former and miR 124-3p were associated with reduced survival. In vitro miR-139-5p overexpression yielded inconsistent results: while mir-139-5p restoration significantly reduced invasion, the clonogenic capacity of cells was increased. Our study demonstrated that down-regulation of miR-124-3p, miR-139-5p and miR-584-5p are associated with disease progression in EWS and may serve as a risk assessment biomarkers though, as seen for mir-139-5p, their specific role remain to be elucidated for considering tailoring treatment options. PMID- 29270774 TI - Conservation of sequence motifs suggests that the nonclassical MHC class I lineages CD1/PROCR and UT were established before the emergence of tetrapod species. AB - Humans have a number of nonclassical major histocompatibility complex (MHC) class I molecules that are quite divergent from the classical ones, and that may have separated from the classical lineage in pre-mammalian times. To estimate when in evolution the respective nonclassical lineages separated from the classical lineage, we first identified "phylogenetic marker motifs" within the evolution of classical MHC class I; the selected motifs are rather specific for and rather stably inherited within clades of species. Distribution of these motifs in nonclassical MHC class I molecules indicates that the lineage including the nonclassical MHC class I molecules CD1 and PROCR separated from the classical lineage before the emergence of tetrapod species, and that the human nonclassical MHC class I molecules FCGRT, MIC/ULBP/RAET, HFE, MR1, and ZAG show similarity with classical MHC class I at the avian/reptilian level. An MR1-like alpha1 exon sequence was identified in turtle. Our system furthermore indicates that the lineage UT, hitherto only found in non-eutherian mammals, predates tetrapod existence, and we identified UT genes in reptiles. If only accepting wide distribution of a lineage among extant species as true evidence for ancientness, the oldest identified nonclassical MHC class I lineage remains the fish-specific lineage Z, which was corroborated in the present study by finding both Z and classical-type MHC class I sequences in a primitive fish, the bichir. In short, we gained important new insights into the evolution of classical MHC class I motifs and the probable time of origin of nonclassical MHC class I lineages. PMID- 29270777 TI - Association Between Polymorphisms in the Promoter Region of microRNA-34b/c and the Chemoradiotherapy Efficacy for Locally Advanced Esophageal Squamous Cell Carcinoma in Chinese Han Population. AB - The study aims to explore the association between polymorphisms in the promoter region of microRNA-34b/c (miR-34b/c) and the chemoradiotherapy efficacy for locally advanced esophageal squamous cell carcinoma (ESCC) in Chinese Han population. A total of 175 locally advanced ESCC cases and 186 healthy individuals were enrolled as the case and control groups. Denaturing high performance liquid chromatography (DHPLC) was applied to determine the genotypes of subjects. Subjects in the case group were classified into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). CR + PR were defined as the sensitive group, and SD + PD were defined as the resistance group. All patients were followed up for 3 ~ 36 months. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of rs4938723 in the promoter region of miR-34b/c in the chemoradiotherapy efficacy for patients with locally advanced ESCC. The distribution of genotype and allele of rs4938723 in the promoter region of miR-34b/c was significantly different between the case and control group (both P < 0.05), and CC genotype and C allele could decrease the risk of ESCC (CC genotype: OR = 0.57, 95%CI = 0.32 ~ 0.99, P = 0.045; C allele: OR = 0.72, 95%CI = 0.54 ~ 0.97, P = 0.032). MiR-34b/c rs4938723 was associated with ESCC TNM staging, differentiation degree, and lymph node metastasis (LNM) for ES CC patients (all P < 0.05). The chemoradiotherapy efficacy of patients with CC genotype was better than that of patients with (TT + TC) genotypes (P < 0.05). ROC curve results showed that the area under curve (AUC), sensitivity and specificity were 0.777, 85.1% and 71.3%, respectively. The average median progression free survival (PFS) of patients with (TT + TC) genotypes was significantly shorter than those patients with CC genotype (P < 0.05). Our study provides evidence that miR-34b/c rs4938723 is closely related with the chemoradiotherapy efficacy for locally advanced ESCC. PMID- 29270776 TI - Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors and Non-Small Cell Lung Cancer (NSCLC) - Advances in Molecular Diagnostic Techniques to Facilitate Targeted Therapy. AB - A subset of patients with non-small cell lung cancer (NSCLC) respond well to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), due to the presence of sensitising mutations in the gene encoding EGFR. Mutations associated with resistance to first generation EGFR TKIs have also been identified, which lead to therapeutic failure and the requirement for new drugs. Three generations of EGFR TKIs have been developed and either have been, or are being, evaluated as first and/or second line therapeutic agents. In this review, we consider the advances in molecular diagnostic techniques that are used, or are in development, to facilitate the targeted EGFR TKI therapy of patients with NSCLC. A literature search was conducted in May 2017 using PubMed, and spanning the period September 2005 (EU approval date of erlotinib) to May 2017. Search terms used were: EGFR TKI, NSCLC, clinical trial, erlotinib, gefitinib, afatinib, EGFR mutations, Exon 19 deletion, and Leu858Arg. The use of molecular data, in conjunction with other clinical and diagnostic information, will assist physicians to make the best therapeutic choice for each patient with advanced NSCLC. Personalized medicine and a rapidly developing therapy landscape will enable these patients to achieve optimal responses to EGFR TKIs. PMID- 29270778 TI - BCL-2 and PAX2 Expressions in EIN which Had Been Previously Diagnosed as Non Atypical Hyperplasia. AB - The relationship between PAX2 and another anti-apoptotic gene, BCL-2, has been shown in a limited number of studies. The aims of this study are to investigate the value of PAX2 and BCL-2 expressions in lesions which have been defined as nonatypical hyperplasia in terms of detecting EIN and to evaluate the relations of these proteins in EIN. For this purpose, 108 cases of non-atypical endometrial hyperplasia diagnosed from 2006 to 2011 were re-evaluated. Immunohistochemical studies with PAX2 and BCL-2 were performed in 20 cases with EIN and 34 cases with benign hyperplasia. The mean BCL-2 immunohistochemistry scores of benign hyperplasia and EIN cases were 4.06 +/- 1.04 and 4.63 +/- 2.03, respectively. The mean BCL-2 score of EIN cases was significantly higher than benign hyperplasia (p = 0.021). The mean PAX2 scores of benign hyperplasia and EIN cases were 4.32 +/- 1.07 and 2.19 +/- 2.34, respectively. The mean PAX2 scores of EIN cases were significantly lower than benign hyperplasia (p = 0.001). BCL-2 expression was increased compared to normal endometrium in 66.7% of EIN cases, and PAX2 expression was decreased in 73.3%. Consistent with this, in 60% of cases, BCL-2 expression was increased compared to normal endometrium, while PAX2 expression was decreased. BCL-2 and PAX2 protein expression changes occur in early phases of endometrial tumorigenesis. These changes are often seen as a simultaneous increase in BCL-2 expression and decrease in PAX2 expression. PMID- 29270773 TI - Neurodevelopmental consequences of pediatric cancer and its treatment: applying an early adversity framework to understanding cognitive, behavioral, and emotional outcomes. AB - Today, children are surviving pediatric cancer at unprecedented rates, making it one of modern medicine's true success stories. However, we are increasingly becoming aware of several deleterious effects of cancer and the subsequent "cure" that extend beyond physical sequelae. Indeed, survivors of childhood cancer commonly report cognitive, emotional, and psychological difficulties, including attentional difficulties, anxiety, and posttraumatic stress symptoms (PTSS). Cognitive late- and long-term effects have been largely attributed to neurotoxic effects of cancer treatments (e.g., chemotherapy, cranial irradiation, surgery) on brain development. The role of childhood adversity in pediatric cancer - namely, the presence of a life-threatening disease and endurance of invasive medical procedures - has been largely ignored in the existing neuroscientific literature, despite compelling research by our group and others showing that exposure to more commonly studied adverse childhood experiences (i.e., domestic and community violence, physical, sexual, and emotional abuse) strongly imprints on neural development. While these adverse childhood experiences are different in many ways from the experience of childhood cancer (e.g., context, nature, source), they do share a common element of exposure to threat (i.e., threat to life or physical integrity). Therefore, we argue that the double hit of early threat and cancer treatments likely alters neural development, and ultimately, cognitive, behavioral, and emotional outcomes. In this paper, we (1) review the existing neuroimaging research on child, adolescent, and adult survivors of childhood cancer, (2) summarize gaps in our current understanding, (3) propose a novel neurobiological framework that characterizes childhood cancer as a type of childhood adversity, particularly a form of early threat, focusing on development of the hippocampus and the salience and emotion network (SEN), and (4) outline future directions for research. PMID- 29270779 TI - Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic. AB - INTRODUCTION: Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009. METHODS: This is the first integrated descriptive analysis of post marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials. RESULTS: The first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses. CONCLUSION: More than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population. FUNDING: Grunenthal GmbH. PMID- 29270781 TI - Long-Term Effectiveness of Liraglutide for Treatment of Type 2 Diabetes in a Real Life Setting: A 24-Month, Multicenter, Non-interventional, Retrospective Study. AB - INTRODUCTION: The aim of the study was to evaluate whether the reduction in glycated hemoglobin (HbA1c) observed in clinical trials with liraglutide in type 2 diabetes (T2D) could be attained in routine clinical practice. METHODS: ReaL was a multicenter, non-interventional, observational, retrospective, longitudinal study on the effectiveness of liraglutide, a human glucagon-like peptide-1 analog, in individuals with T2D treated in daily practice in Italy. Between 26 March and 16 November 2015, data were taken from clinical records of patients aged >= 18 years with treatment follow-up data of up to 24 months and who received their first prescription of liraglutide in 2011. RESULTS: A total of 1723 patients were included in the analysis. At baseline, mean age was 58.9 years, duration of diabetes was 9.6 years, and HbA1c was 8.3%. At 12 months, 36.1% of patients were prescribed the maximum 1.8 mg dose; 43.5% [95% confidence interval (CI): 40.9; 46.2] of patients attained the primary outcome of a reduction in HbA1c of >= 1% point at 12 months. At 24 months, 40.9% (95% CI 38.1; 43.7) of patients had attained the HbA1c target of <= 7%. Additionally, body weight significantly decreased by 3.4 kg (95% CI - 3.6; - 3.1, p < 0.0001). CONCLUSION: In this observational study conducted in routine clinical practice for up to 2 years, treatment with liraglutide improved HbA1c and reduced body weight in a similar fashion to that observed under randomized clinical trial conditions. The data support the use of liraglutide as an effective treatment for T2D in clinical practice. FUNDING: Novo Nordisk S.p.A. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02255266. PMID- 29270780 TI - Development of a Framework Based on Reflective MCDA to Support Patient-Clinician Shared Decision-Making: The Case of the Management of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NET) in the United States. AB - INTRODUCTION: Well- or moderately differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are often slow-growing, and some patients with unresectable, asymptomatic, non-functioning tumors may face the choice between watchful waiting (WW), or somatostatin analogues (SSA) to delay progression. We developed a comprehensive multi-criteria decision analysis (MCDA) framework to help patients and physicians clarify their values and preferences, consider each decision criterion, and support communication and shared decision-making. METHODS: The framework was adapted from a generic MCDA framework (EVIDEM) with patient and clinician input. During a workshop, patients and clinicians expressed their individual values and preferences (criteria weights) and, on the basis of two scenarios (treatment vs WW; SSA-1 [lanreotide] vs SSA-2 [octreotide]) with evidence from a literature review, expressed how consideration of each criterion would impact their decision in favor of either option (score), and shared their knowledge and insights verbally and in writing. RESULTS: The framework included benefit-risk criteria and modulating factors, such as disease severity, quality of evidence, costs, and constraints. Overall and progression-free survival being most important, criteria weights ranged widely, highlighting variations in individual values and the need to share them. Scoring and considering each criterion prompted a rich exchange of perspectives and uncovered individual assumptions and interpretations. At the group level, type of benefit, disease severity, effectiveness, and quality of evidence favored treatment; cost aspects favored WW (scenario 1). For scenario 2, most criteria did not favor either option. CONCLUSIONS: Patients and clinicians consider many aspects in decision making. The MCDA framework provided a common interpretive frame to structure this complexity, support individual reflection, and share perspectives. FUNDING: Ipsen Pharma. PMID- 29270782 TI - A case of pancreatic neuroendocrine tumor with multiple cystic components of various sizes. AB - The patient was a 51-year-old woman who, while undergoing a thorough health checkup, was found to have a tumor (measuring 60 mm in diameter) in the tail of the pancreas by abdominal ultrasonography. Contrast-enhanced computed tomography revealed delayed contrast enhancement; the tumor also contained numerous low absorption areas showing poor contrast enhancement. On magnetic resonance imaging, the tumor was visualized as having high signal intensity areas inside the tumor on T2-weighted images. Positron emission tomography revealed an abnormal accumulation in the area corresponding to the tumor. Endoscopic ultrasonography (EUS) revealed a relatively hyperechoic solid area, with a number of echo-free areas of various sizes that assumed a honeycomb appearance. EUS guided fine needle aspiration was carried out targeting the solid area within the tumor, which led to a diagnosis of pancreatic neuroendocrine tumor (PNET). Histopathological examination of the resected specimen revealed that the tumor was composed of numerous cysts of various sizes and solid components. The cysts contained no evidence of necrosis or bleeding. Immunohistochemically, the cystic as well as solid components were CD56 (+), synaptophysin (+) and chromogranin A (+) with MIB1 labeling index of 5%. On the basis of these findings, the final diagnosis was PNET (G2). PMID- 29270783 TI - Statin use is not associated with improved 30-day survival in patients undergoing surgery for colorectal cancer. AB - PURPOSE: Besides the lipid-lowering properties, statins are thought to have anti inflammatory effects and it has been shown that statins directly attenuate the inflammatory stress response after surgical trauma. The aim of the study was to examine the association between preoperative statin use and 30-day mortality as well as postoperative complications after curative-intended surgery for colorectal cancer. METHODS: The study was a Danish nationwide register-based observational study. A total of 29,352 patients undergoing surgery for colorectal cancer between January 1, 2003, and December 31, 2012, were included in the study. At the time of surgery, 5961 were registered as statin users. The outcomes were 30-day mortality and risk of postoperative complications. RESULTS: The adjusted hazard ratio of 30-day mortality was 0.91 (95 CI 0.80-1.04, P = 0.16) among statin users compared with the non-statin group. There was no difference between the two groups regarding the risk of infectious complications (sepsis, anastomotic leakage, pneumonia) (odds ratio 0.95, 95% CI 0.86-1.05, P = 0.31). For other postoperative complications (cardiovascular events, stroke, renal failure, respiratory insufficiency, and thromboembolic events), there was no significant difference between the two groups (odds ratio 0.89, 95% CI 0.78-1.01, P = 0.06). CONCLUSION: The study did not show an improved 30-day survival after surgery for colorectal cancer in patients treated with statins in the year preceding surgery. No overall association with the risk of postoperative complications was shown. PMID- 29270784 TI - Anal canal squamous cell cancer: are surgical alternatives to chemoradiation just as effective? AB - PURPOSE: The purpose of this paper is to study long-term oncologic outcomes after different treatment strategies for anal canal cancer (SCAC). METHODS: Patients with SCAC (2004-2013) were identified from Surveillance, Epidemiology, and End Results (SEER) database. Patients undergoing radiation (RT) were compared to those undergoing local excision (LE), abdominoperineal resection (APR), and abdominoperineal resection after radiation (RT + APR). Overall survival (OS) and cancer-specific survival (CSS) data were evaluated using Kaplan-Meier and Cox regression. RESULTS: Two thousand seven hundred and seventy-two (83.8%) patients underwent RT, 382 (11.6%) LE, 77 (2.3%) APR, 76 (2.3%) RT + APR. Median age for the four groups was 60, 57, 64, and 56 years and 32, 49.7, 53.2, and 39.5% were male, respectively, while median tumor size was 4.4, 2.6, 5.3, and 5.5 cm, respectively. Five-year OS of RT, LE, APR, and RT + APR groups was 63.7, 79.6, 25.8, and 41.8% while CSS was 79.6, 92.5, 75.6, and 58.8%, respectively, (p < 0.001). Adjusted hazard ratios for OS for LE, APR, and RT + APR with RT as reference were 1.007 (0.702-1.444), 2.311 (1.367-3.906), and 2.072 (1.016-4.228), respectively. CONCLUSION: These data suggest that APR does not provide better outcomes in treatment of SCAC. Chemoradiation remains the gold standard treatment for majority of patients. Local excision is associated with favorable outcomes in some circumstances. PMID- 29270785 TI - Impact of transanal drainage tube on anastomotic leakage after laparoscopic low anterior resection. AB - BACKGROUND: Although a few reports have suggested transanal drainage tube (TDT) can reduce the pressure in the anastomotic portion, it remains unclear whether TDT can prevent anastomotic leakage (AL). In addition, little is known about the relationship between AL and daily fecal volume through TDT. This study investigated the role of TDT for the prevention of AL following laparoscopic low anterior resection (LAR). METHODS: This is a retrospective analysis of a prospectively maintained database of 201 rectal cancer patients who underwent laparoscopic LAR. The relationship between AL and daily fecal volume through TDT was examined. RESULTS: AL occurred in 25 patients. Based on the TDT grouping, AL occurred in 10.7% (19/178) of the TDT group, whereas it occurred in 26.1% (6/23) of the non-TDT group (P = 0.046). In the 178 patients with TDT placement, the daily fecal volumes on postoperative days (PODs) 2-5 were significantly higher compared with those on POD 1 (P < 0.05). The daily fecal volume was observed to be gradually increasing until POD 3 or 4 (median, 25 or 23 ml/day, respectively) and then significantly decreasing on POD 5 (10 ml/day) (P < 0.05). The AL rate of the patients whose daily fecal volume exceeded 100 ml/day in two or more days was significantly higher than that of those in 0 or 1 day (26.9 vs. 7.9%; P < 0.01). CONCLUSIONS: TDT could be efficient to prevent AL following laparoscopic LAR. Postoperative fecal volume may be a reliable predictor of AL. PMID- 29270786 TI - Refugees in Europe: national overviews from key countries with a special focus on child and adolescent mental health. AB - Many European countries are becoming multicultural at a previously unseen rate. The number of immigrants including refugees has considerably increased since 2008, and especially after the beginning of the war in Syria. In 2015, 88,300 unaccompanied minors sought asylum in the Member States of the European Union (EU) and most came from Syria, Afghanistan, Iran, Iraq, Somalia and Eritrea. As a reaction to increased immigration, governments in many countries including Germany, Sweden and Norway implemented more restrictive immigration policy. A requirement for all countries, however, is the protection and welfare provision for all arriving children, regardless of their nationality, ensured by international and national legal frameworks. This paper provides an overview of the post 2015 immigration crisis in key European countries with a special focus on current demographics, refugee children, mental health studies, policies and practical support available for refugees. PMID- 29270787 TI - Interpretation criteria for FDG PET/CT in multiple myeloma (IMPeTUs): final results. IMPeTUs (Italian myeloma criteria for PET USe). AB - : ?: FDG PET/CT (18F-fluoro-deoxy-glucose positron emission tomography/computed tomography) is a useful tool to image multiple myeloma (MM). However, simple and reproducible reporting criteria are still lacking and there is the need for harmonization. Recently, a group of Italian nuclear medicine experts defined new visual descriptive criteria (Italian Myeloma criteria for Pet Use: IMPeTUs) to standardize FDG PET/CT evaluation in MM patients. The aim of this study was to assess IMPeTUs reproducibility on a large prospective cohort of MM patients. MATERIALS AND METHODS: Patients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN(r) and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff's alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease). RESULTS: Eighty-six patients (211 FDG PET/CT scans) were included in this analysis. Median patient age was 58 years (range, 35-66 years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff's alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4. CONCLUSIONS: IMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway. PMID- 29270788 TI - F18-choline PET/CT guided surgery in primary hyperparathyroidism when ultrasound and MIBI SPECT/CT are negative or inconclusive: the APACH1 study. AB - PURPOSE: To evaluate the sensitivity of F18-choline (FCH) PET/CT for parathyroid adenoma detection prior to surgery in patients with primary hyperparathyroidism and negative or inconclusive cervical ultrasound and Tc99m-sestaMIBI SPECT/CT. METHODS: We conducted a prospective bicentric study (NCT02432599). All patients underwent FCH PET/CT. The result was scored positive, inconclusive or negative. The number of uptakes and their sites were recorded. The FCH PET/CT result guided the surgical procedure (minimally invasive parathyroidectomy, bilateral cervical exploration, or other in case of multiple or ectopic foci). FCH PET/CT results were compared to the surgical and pathological findings and the follow-up. RESULTS: Twenty-five patients were included. Mean calcium and PTH levels prior to surgery were 2.76 +/- 0.17 mmol/l and 94.8 +/- 37.4 ng/l. Nineteen (76%) FCH PET/CTs were scored positive, 3 (12%) inconclusive and 3 (12%) negative, showing 21 cases of uniglandular disease, including 1 ectopic localization and 1 case of multiglandular (3 foci) disease. Mean lesion size was 13.1 +/- 8.6 mm. Twenty four patients underwent surgery. FCH PET/CT guided surgery in 22 (88%) patients, allowing for 17 minimally invasive parathyroidectomies, 1 bilateral cervical exploration for multifocality and 4 other surgical procedures. Two patients with negative FCH-PET/CT underwent bilateral cervical exploration. When dichotomizing the FCH PET/CT results, thereby classifying the inconclusive FCH PET/CT results as positive, the per lesion and per patient sensitivities were 91.3% (95%CI: 72.0 98.9) and 90.5% (95%CI: 69.6-98.8) and the corresponding positive predictive values were 87.5% (95%CI: 67.6-97.3) and 86.4% (95%CI: 65.1-97.1), respectively. Twenty-one (88%) patients were considered cured after surgery. Their mean calcium level after surgery was 2.36 +/- 0.17 mmol/l. CONCLUSIONS: Preoperative FCH PET/CT has a high sensitivity and positive predictive value for parathyroid adenoma detection in patients with primary hyperparathyroidism and negative or inconclusive conventional imaging results. Bilateral cervical exploration could be avoided in the majority (75%) of patients. PMID- 29270789 TI - Improving AIDS Care After Trauma (ImpACT): Pilot Outcomes of a Coping intervention Among HIV-Infected Women with Sexual Trauma in South Africa. AB - : Improving AIDS Care after Trauma (ImpACT), a coping intervention for HIV infected women with sexual abuse histories, was evaluated for feasibility and potential efficacy in a public clinic in Cape Town, South Africa. Sixty-four participants were enrolled prior to starting antiretroviral therapy (ART). After completing baseline assessments, participants were randomly assigned to standard of care (SoC: three adherence counseling sessions) or ImpACT (SoC plus four individual and three group sessions). Participants completed assessments at 3 months (after individual sessions) and 6 months post-baseline. In exploratory analysis of primary outcomes, ImpACT participants, compared to SoC, reported greater reductions in avoidance and arousal symptoms of PTSD and greater increases in ART adherence motivation at 3 months. Clinically significant decreases in overall PTSD symptoms were also demonstrated at 3 months. These effects continued as trends at the 6-month assessment, in addition to increases in social/spiritual coping. In analysis of secondary outcomes, high levels of non adherence to ART and poor care engagement were evident at 6 months, with no differences between study arms. A trauma-focused, culturally-adapted individual intervention delivered by a non-specialist in the HIV care setting is feasible and acceptable. Preliminary findings suggest ImpACT has potential to reduce PTSD symptoms and increase ART adherence motivation, but a more intensive intervention may be needed to improve and maintain care engagement among this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02223390. PMID- 29270790 TI - Budget Impact Analysis of Brivaracetam Adjunctive Therapy for Partial-Onset Epileptic Seizures in Valencia Community, Spain. AB - BACKGROUND AND OBJECTIVE: More than 30% of patients with epilepsy have inadequate control of seizures with drug therapy. The goal of this study is to determine the budget impact (BI) of the introduction of brivaracetam to the portfolio of approved drugs in Spain as adjunctive therapy for the treatment of partial-onset epilepsy in patients over 16 years old with a 5-year time horizon in the Valencia Community, a Spanish region with a population of 5 million. METHODS: The BI model compares the pharmaceutical expenditure on antiepileptics in two scenarios: with and without brivaracetam. It assumes that the introduction and increased use of brivaracetam will lead to a proportional decrease in consumption of coexisting adjunctive antiepileptics and calculates the evolution of the consumption of brivaracetam over 5 years (2016-2020). The model was designed from the perspective of the Spanish National Health System. Data on the candidate population, consumption of antiepileptics, market share and pharmaceutical expenditure were obtained from real-world data. Finally, a sensitivity analysis was carried out on the set of variables involved in the evolution of costs using a Monte-Carlo simulation. RESULTS: The model estimates that the target population eligible for adjunctive antiepileptics will hold at around 2352 between 2016 and 2020. Annual expenditure on antiepileptics is approximately ?3.6 million. The number of patients eligible for treatment with brivaracetam would increase from 42 to 179 and annual savings of 0.09-0.37% would be created, representing ?41,873 over 5 years (0.23% of the total budget). The sensitivity analysis corroborates that the probability of achieving savings with brivaracetam is around 84%. CONCLUSIONS: Brivaracetam is a therapeutic alternative that allows savings for the health system in patients with non-controlled epilepsy in monotherapy, having a fixed, predictable annual cost (independent of dose) from the first day of treatment as the lack of need for titration means the patient is within a range of therapeutic doses from the first dose. PMID- 29270791 TI - Research progress in human infection with avian influenza H7N9 virus. AB - Since the identification of the novel reassortant avian influenza A (H7N9) virus in China in 2013, until Jun 30, 2017, the virus has caused five epidemic waves leading to a total of 1,552 human infections, with a fatality rate of about 40%. In the spring of 2017, highly pathogenic avian influenza (HPAI) H7N9 virus emerged and has caused 25 human infections. The HPAI H7N9 virus has some biological differences from the LPAI one, such as its multiple basic amino acid residues on HA leading to its independence on trypsin for replication. The pathogenicity of the HPAI H7N9 virus to experimental animals or humans is still unclear. A(H7N9) vaccine development for pandemic preparedness is ongoing, including the reassortment (H7N9/PR8) reverse genetic based vaccine, the virus like particle (VLP) vaccine, the intranasal live attenuated influenza vaccine (LAIV), the non-adjuvant Vero cell culture-derived inactivated whole-virus vaccine, the MDCK culture-derived vaccine, the H7 DNA vaccine and the recombinant replicative H7N9 virus (H7N9-53TM) vaccine. Five neuramidinase resistant sites of A(H7N9) virus isolated from patients have been reported. Some alternative drugs have been studied, such as DAS181 (Fludase), ribavirin, troglitazone and minocycline. Persistent surveillance and enhanced global control are essential to fight against human infections with A(H7N9) virus. PMID- 29270792 TI - Functional brain network mapping with dual regression. PMID- 29270793 TI - Pathogen genomic surveillance elucidates the origins, transmission and evolution of emerging viral agents in China. AB - In the past twenty years, numerous novel zoonotic viral agents with pandemic potential have emerged in China, such as the severe acute respiratory syndrome (SARS) coronavirus and, more recently, the avian-origin influenza A/H7N9 virus, which have caused outbreaks among humans with high morbidity and mortality. In addition, several emerging and re-emerging viral pathogens have also been imported into China from travelers, e.g. the Middle East respiratory syndrome (MERS) coronavirus and Zika virus (ZIKV). Herein, we review these emerging viral pathogens in China and focus on how surveillance by pathogen genomics has been employed to discover and annotate novel pathogenic agents, identify natural reservoirs, monitor the transmission events and delineate their evolution and adaption to the human host. We also highlight the application of genomic sequencing in the recent Ebola epidemics in Western Africa. In summary, genomic sequencing has become a standard research tool in the field of emerging infectious diseases which has been proven invaluable in containing these viral infections and reducing burden of disease in humans and animals. Genomic surveillance of pathogenic agents will serve as a key epidemiological and research tool in the modern era of precision infectious diseases and in the future studies of virosphere. PMID- 29270794 TI - Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis. AB - Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine (DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium (DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine, the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota. PMID- 29270795 TI - Spondylocostal Dysostosis (Jarcho Levin Syndrome). PMID- 29270796 TI - Developing and Testing Fidelity of Manikins for Training in Cardio-Pulmonary Resuscitation: Need of the Hour! PMID- 29270797 TI - Immunomodulatory constituents from Ascomycetous fungi. AB - Our screening project, namely, search for new immunomodulatory constituents from Ascomycetous fungi, was guided by the effects on mitogen-induced proliferations of mouse spleen lymphocytes. On the project, the defatted crude extracts from Gelasinospora multiforis, G. heterospora, G. longispora, G. kobi, Diplogelasinospora grovesii, Emericella aurantio-brunnea, Eupenicillium crustaceum, etc., submitted to the solvent partition followed by fractionation with repeated chromatography monitored by immunomodulatory activity to afford many active constituents, of which molecular structures including absolute configurations and immunomodulatory activities were elucidated. All of these immunomodulatory constituents isolated on the project were practically not immunostimulants but immunosuppressants. PMID- 29270798 TI - Hybrid value foraging: How the value of targets shapes human foraging behavior. AB - In hybrid foraging, observers search visual displays for multiple instances of multiple target types. In previous hybrid foraging experiments, although there were multiple types of target, all instances of all targets had the same value. Under such conditions, behavior was well described by the marginal value theorem (MVT). Foragers left the current "patch" for the next patch when the instantaneous rate of collection dropped below their average rate of collection. An observer's specific target selections were shaped by previous target selections. Observers were biased toward picking another instance of the same target. In the present work, observers forage for instances of four target types whose value and prevalence can vary. If value is kept constant and prevalence manipulated, participants consistently show a preference for the most common targets. Patch-leaving behavior follows MVT. When value is manipulated, observers favor more valuable targets, though individual foraging strategies become more diverse, with some observers favoring the most valuable target types very strongly, sometimes moving to the next patch without collecting any of the less valuable targets. PMID- 29270799 TI - Endorectal ultrasound in the identification of rectal tumors for transanal endoscopic surgery: factors influencing its accuracy. AB - Endorectal ultrasound (ERUS) is considered the technique of choice for selecting patients for transanal endoscopic surgery (TEM). The aim of this study was to evaluate the accuracy of ERUS in patients with rectal tumors who later underwent TEM, and to analyze the factors that influence this accuracy. Observational study including prospective data collection of patients with rectal tumors undergoing TEM with curative intent between June 2004 and May 2016. Preoperative staging by EUS (uT) was correlated with the pathology results after TEM (pT). The accuracy of the EUS was evaluated and a series of variables (tumor morphology, height, lesion size, quadrant, definitive pathology, the surgeon assessing the ERUS, and waiting time from the date of the ERUS until surgery) were analyzed as possible predictors of diagnostic accuracy. Six hundred and fifty-one patients underwent TEM, of whom 495 met the inclusion criteria. The overall accuracy of EUS was 78%, sensitivity 83.78%, specificity 20%, PPV 91.3%, and NPV 11%. Forty patients (8.08%) were understaged and 50 (10.9%) were overstaged. In the multivariate analysis, the surgeon's experience emerged as the most important predictor of accuracy (p < 0.001; OR 2.75, 95% CI 1.681-4.512). The EUS was less accurate with larger lesions (p = 0.004; OR 0.219, 95% CI 0.137-0.349) and when the definitive diagnosis was adenocarcinoma (p < 0.001; OR 0.84, 95% CI 0.746-0.946). ERUS accuracy rates are variable and there is a possibility of understaging and overstaging that must be taken into consideration. This accuracy is dependent on the operator's experience as well on lesion size; in addition, it is lower for lesions shown to be cancers in the final pathology report. PMID- 29270800 TI - Prospective cohort study on mesh shrinkage measured with MRI after laparoscopic ventral hernia repair with an intraperitoneal iron oxide-loaded PVDF mesh. AB - BACKGROUND: Current data on shrinkage of intraperitoneal meshes come mainly from animal studies. High-quality human data in prospective studies are scarce. METHODS: We used the ability to visualize intraperitoneal PVDF meshes enhanced with iron particles (DynaMesh IPOM visible) with magnetic resonance imaging (MRI) to determine the amount of shrinkage between 1 and 13 months postoperatively. All measurements of the width, length, and surface area of the mesh were performed with a standardized methodology independently by four radiologists blinded for the timing of the MRI. RESULTS: Of the 15 patients undergoing laparoscopic ventral hernia repair, 13 patients received an MRI both at 1 and at 13 months. Evaluation of inter-rater reliability between the radiologists showed intra-class correlations of 0.95 (95% CI 0.92-0.98) for the width, 0.96 (95% CI 0.93-0.98) for the length, and 0.99 (90% CI 0.99-1.00) for the surface area of the mesh. The change between measurement at implantation and 1-month MRI was - 0.7 cm (P = 0.023; - 3.6%) for the width and - 1.9 cm (P = 0.001; - 7.2%) for the length. The change between 1 and 13 months was - 0.06 cm (P = 0.74; shrinkage = 0.3%) for the width, - 0.12 cm (P = 0.56; shrinkage = 0.5%) for the length, and - 4.0 cm2 (P = 0.20; shrinkage = 1.0%) for the surface area of the mesh. CONCLUSION: There is excellent inter-rater reliability between radiologists when measuring width, length, and surface area of visible intraperitoneal PVDF mesh with MRI. There is no significant shrinkage between 1 and 13 months of intraperitoneal PVDF mesh after laparoscopic ventral hernia repair. PMID- 29270801 TI - Diagnostic accuracy of contrast-enhanced ultrasound in assessing the therapeutic response to radio frequency ablation for liver tumors: systematic review and meta analysis. AB - BACKGROUND: To review the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) used to detect residual or recurrent liver tumors after radiofrequency ablation (RFA). This technique uses contrast-enhanced computer tomography or/and contrast-enhanced magnetic resonance imaging as the gold standard of investigation. METHODS: MEDLINE, EMBASE, and COCHRANE were systematically searched for all potentially eligible studies comparing CEUS with the reference standard that follows RFA. Risk of bias and applicability concerns were addressed by adopting the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled point estimates for sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios (DOR) with 95% CI were computed before plotting the sROC (summary receiver operating characteristic) curve. Meta regression and subgroup analysis were used to identify the source of the heterogeneity that was detected. Publication bias was evaluated using Deeks' funnel plot asymmetry test. RESULTS: Ten eligible studies on 1162 lesions that occurred between 2001 and 2016 were included in the final analysis. The quality of the included studies assessed by the QUADAS-2 tool was considered reasonable. The pooled sensitivity and specificity of CEUS in detecting residual or recurrent liver tumors had the following values: 0.90 (95% CI 0.85-0.94) and 1.00 (95% CI 0.99-1.00), respectively. Overall DOR was 420.10 (95% CI 142.30-1240.20). The sources of heterogeneity could not be precisely identified by meta-regression or subgroup analysis. No evidence of publication bias was found. CONCLUSION: This study confirmed that CEUS exhibits high sensitivity and specificity in assessing therapeutic responses to RFA for liver tumors. PMID- 29270802 TI - Laparoscopic liver hanging maneuver through the retrohepatic tunnel on the right side of the inferior vena cava combined with a simple vascular occlusion technique for laparoscopic right hemihepatectomy. AB - BACKGROUND: Laparoscopic hepatectomy has been performed in many hospitals, with the development of the laparoscopic operation technique. However, performing complex laparoscopic hepatectomy, such as right hemihepatectomy, is still a challenge. The aim of this study was to describe the application of a simple vascular occlusion technique and new liver hanging maneuver (LHM) in complex laparoscopic hepatectomy, which are both advocated by Chen Xiaoping for open hepatectomy. METHODS: The clinical data of 29 consecutive patients who underwent laparoscopic right hemihepatectomy (LRH) from October 2014 to October 2016 were retrospectively analyzed. During operation, the vascular occlusion technique without hilus dissection and LHM through the retrohepatic avascular tunnel on the right side of the inferior vena cava were used. RESULT: All 29 operations were successfully performed laparoscopically, while adopting Chen's methods. The study consisted of 23 patients with hepatocellular carcinoma, four patients with intrahepatic cholangiocarcinoma, and two patients with hepatic metastasis of colonic carcinoma. The tumor size was 12.4 +/- 1.9 cm. The operation time of LRH was 190.3 +/- 49.9 min. The intraoperative blood loss of LRH was 281.7 +/- 117.8 mL; five patients required blood transfusion, and the amount of blood transfusion was 300.0 +/- 89.4 mL. No case was converted to open surgery, and no death occurred. All resulted in R0 resections. The median free margin was 20.1 +/- 10.8 mm. The time of postoperative oral diet intake was 2.10 +/- 0.96 days. The complication rate was 17.2%. The average hospital stay after operation was 10.0 +/- 2.9 days. CONCLUSION: Complex hepatectomy is a bloodless procedure that can be performed under a laparoscope safely using Chen's methods of vascular occlusion technique and LHM. PMID- 29270803 TI - Early outcomes of an enhanced recovery protocol for open repair of ventral hernia. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are evidence-based quality improvement pathways reported to be associated with improved patient outcomes. The purpose of this study was to compare short-term outcomes for open ventral hernia repair (VHR) before and after implementation of an ERAS protocol. METHODS: After obtaining IRB approval, surgical databases were searched for VHR cases for two years prior and eleven months after protocol implementation for retrospective review. Groups were compared on perioperative characteristics and clinical outcomes using chi-square, Fisher's exact, or Mann-Whitney U test, as appropriate. RESULTS: One hundred and seventy-one patients underwent VHR (46 patients with ERAS protocol in place and 125 historic controls). Age, gender, ASA Class, comorbidities, and smoking status were similar between the two groups. Body mass index was lower among ERAS patients (p = .038). ERAS patients had earlier return of bowel function (median 3 vs. 4 days) (p = .003) and decreased incidence of superficial surgical site infection (SSI) (7 vs. 25%) (p = .008) than controls. CONCLUSION: An ERAS protocol for VHR demonstrated improved patient outcomes. A system-wide culture focused on enhanced recovery is needed to ensure improved patient outcomes. PMID- 29270805 TI - Combination of etoposide and fisetin results in anti-cancer efficiency against osteosarcoma cell models. AB - Osteosarcoma chemotherapy is often limited by chemoresistance, resulting in poor prognosis. Combined chemotherapy could, therefore, be used to prevent resistance to chemotherapeutics. Here, the effects of fisetin on osteosarcoma cells were investigated, as well as cytostatic potential in combination with the anti-cancer drug etoposide. For this, different osteosarcoma cell lines were treated with fisetin, with etoposide and with respective combinations. Fisetin was associated with decrease in colony formation in Saos-2 and in U2OS cells but not in MG-63 cells. Notwithstanding, upon evaluation of cellular growth by crystal violet assay, MG-63 and Saos-2 cells showed decreased cell proliferation at 40 and 20 uM fisetin, respectively. Depending on the relative concentrations, fisetin:etoposide combinations showed negative-to-positive interactions on the inhibition of cell proliferation. In addition, fisetin treatment up to 50 uM for 48 h resulted in G2-phase cell cycle arrest. Regardless of the combination, fisetin:etoposide increased % cells in G2-phase and decreased % cells in G1 phase. In addition, mixtures with more positive combined effects induced increased % cells in S-phase. Compared to etoposide treatment, these combinations resulted in decreased levels of cyclins B1 and E1, pointing to the role of these regulators in fisetin-induced cell cycle arrest. In conclusion, these results show that the combination of fisetin with etoposide has higher anti-proliferative effects in osteosarcoma associated with cell cycle arrest, allowing the use of lower doses of the chemotherapeutic agent, which has important implications for osteosarcoma treatment. PMID- 29270806 TI - Mesenchyme-derived factors enhance preneoplastic growth by non-genotoxic carcinogens in rat liver. AB - Many frequently prescribed drugs are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action and health risks for humans remain to be elucidated. Here, we investigated the impact of two model NGC, the anti-epileptic drug phenobarbital (PB) and the contraceptive cyproterone acetate (CPA), on intrahepatic epithelial-mesenchymal crosstalk and on growth of first stages of hepatocarcinogenesis. Unaltered hepatocytes (HC) and preneoplastic HC (HCPREN) were isolated from rat liver for primary culture. DNA replication of HC and HCPREN was increased by in vitro treatment with 10 uM CPA, but not 1 mM PB. Next, mesenchymal cells (MC) obtained from liver of rats treated with either PB (50 mg/kg bw/day) or CPA (100 mg/kg bw/day), were cultured. Supernatants from both types of MC raised DNA synthesis of HC and HCPREN. This indicates that PB induces replication of HC and HCPREN only indirectly, via growth factors secreted by MC. CPA, however, acts on HC and HCPREN directly as well as indirectly via mesenchymal factors. Transcriptomics and bio-informatics revealed that PB and CPA induce extensive changes in the expression profile of MC affecting many growth factors and pathways. MC from PB-treated rats produced and secreted enhanced levels of HBEGF and GDF15, factors found to suppress apoptosis and/or induce DNA synthesis in cultured HC and HCPREN. MC from CPA-treated animals showed enhanced expression and secretion of HGF, which strongly raised DNA replication of HC and HCPREN. In conclusion, our findings reveal profound effects of two prototypical NGC on the hepatic mesenchyme. The resulting release of factors, which suppress apoptosis and/or enhance cell replication preferentially in cancer prestages, appears to be crucial for tumor promotion by NGC in the liver. PMID- 29270807 TI - A methodology for the assessment of inhalation exposure to aluminium from antiperspirant sprays. AB - Inhalative exposure can occur accidentally when using cosmetic spray products. Usually, a tiered approach is applied for exposure assessment, starting with rather conservative, simplistic calculation models that may be improved with measured data and more refined modelling. Here we report on an advanced methodology to mimic in-use conditions for antiperspirant spray products to provide a more accurate estimate of the amount of aluminium possibly inhaled and taken up systemically, thus contributing to the overall body burden. Four typical products were sprayed onto a skin surrogate in defined rooms. For aluminium, size related aerosol release fractions, i.e. inhalable, thoracic and respirable, were determined by a mass balance method taking droplet maturation into account. These data were included into a simple two-box exposure model, allowing calculation of the inhaled aluminium dose over 12 min. Systemic exposure doses were calculated for exposure of the deep lung and the upper respiratory tract using the Multiple Path Particle Deposition Model (MPPD) model. The total systemically available dose of aluminium was in all cases found to be less than 0.5 ug per application. With this study it could be demonstrated that refinement of the input data of the two-box exposure model with measured data of released airborne aluminium is a valuable approach to analyse the contribution of antiperspirant spray inhalation to total aluminium exposure as part of the overall risk assessment. We suggest the methodology which can also be applied to other exposure modelling approaches for spray products, and further is adapted to other similar use scenarios. PMID- 29270809 TI - Strangulation of the small intestine caused by an intra-mesosigmoid hernia: a case report. AB - Sigmoid mesocolon hernia is an uncommon type of internal hernia with only a few cases reported to date. This disease entity can progress rapidly to cause vascular disturbance, necrosis, and perforation of the bowel wall; therefore, early diagnosis and surgical treatment are essential. We describe the case of an intra-mesosigmoid hernia in a 60-year-old man without history of previous abdominal surgery who presented with sudden acute abdominal pain and vomiting. Based on computed tomography, which showed ascites and small bowel obstruction, we diagnosed him as having strangulation of the small intestine caused by a sigmoid mesocolic hernia and performed emergency surgery. Laparotomy revealed small intestinal strangulation, extensive engorgement, and discoloration of bowel loops. Approximately 100 cm of the small intestine extending from the ligament of Treitz had undergone strangulation and herniated into the defect of sigmoid mesocolon, leading to a diagnosis of an intra-mesosigmoid hernia. Because the incarcerated portion of the small intestine was viable, we did not perform intestinal resection and reconstruction but closed the defect in the sigmoid mesocolon. His postoperative course was uneventful. PMID- 29270808 TI - Challenge in particle delivery to cells in a microfluidic device. AB - Micro and nanotechnology can potentially revolutionize drug delivery systems. Novel microfluidic systems have been employed for the cell culture applications and drug delivery by micro and nanocarriers. Cells in the microchannels are under static and dynamic flow perfusion of culture media that provides nutrition and removes waste from the cells. This exerts hydrostatic and hydrodynamic forces on the cells. These forces can considerably affect the functions of the living cells. In this paper, we simulated the flow of air, culture medium, and the particle transport and deposition in the microchannels under different angles of connection inlet. It was found that the shear stress induced by the medium culture flow is not so high to damage the cells and that it is roughly uniform in the cell culture section (CCS). However, the local shear stresses in the other parts of the microchip differ by changing the angles of the connection inlet. The results showed that the particle deposition was a function of the particle size, the properties of the fluid, and the flow rate. At a lower air flow rate, both small and large particles deposited in the entrance region and none of them reached the CCS. Once the airflow rate increased, the drag of the flow could overcome the diffusion of the small particles and deliver them to the CCS so that more than 88% of the 100 nm and 98% of the 200 nm particles deposited in the CCS. However, larger particles with average diameters in micrometers could not reach the CCS by the airflow even at high flow rate. In contrast, our findings indicated that both small and large particles could be delivered to the CCS by liquid flow. Our experimental data confirm that microparticles (with diameters of 5 and 20 MUm) suspended in a liquid can reach the CCS at a well-adjusted flow rate. Consequently, a liquid carrier is suggested to transport large particles through microchannels. As a powerful tool, these numerical simulations provide a nearly complete understanding of the flow field and particle patterns in microchips which can significantly lower the trial and error in the experiment tests and accordingly save researchers considerable cost and time for drug delivery to the cell in the microchip by micro/nanocarriers. PMID- 29270810 TI - Improvement Science Meets Improvement Scholarship: Reframing Research for Better Healthcare. AB - In this editorial essay I explore the possibilities of 'improvement scholarship' in order to set the scene for the theme of, and the other papers in, this issue. I contrast a narrow conception of quality improvement (QI) research with a much broader and more inclusive conception, arguing that we should greatly extend the existing dialogue between 'problem-solving' and 'critical' currents in improvement research. I have in mind the potential for building a much larger conversation between those people in 'improvement science' who are expressly concerned with tackling the problems facing healthcare and the wider group of colleagues who are engaged in health-related scholarship but who do not see themselves as particularly interested in quality improvement, indeed who may be critical of the language or concerns of QI. As one contribution to that conversation I suggest that that the increasing emphasis on theory and rigour in improvement research should include more focus on normative theory and rigour. The remaining papers in the issue are introduced including the various ways in which they handle the 'implicit normativity' of QI research and practice, and the linked theme of combining relatively 'tidy' and potentially 'unruly' forms of knowledge. PMID- 29270811 TI - Indocyanine green angiography findings of cystoid macular edema secondary to paclitaxel therapy. AB - PURPOSE: To report 2 cases of paclitaxel-related maculopathy manifesting as cystoid macular edema (CME) with late petaloid hyperfluorescence on indocyanine green angiography (IA). CASES: A 74-year-old man (patient 1) undergoing paclitaxel chemotherapy for gastric and metastatic liver cancer and a 69-year-old man (patient 2) receiving paclitaxel for hypopharyngeal cancer presented with anorthopia in both eyes. Spectral domain-optical coherence tomography (SD-OCT) revealed macular edema in both eyes of each patient. Fluorescein angiography showed weak petaloid pooling around the fovea in the late phase. IA revealed CME with petaloid hyperfluorescence that matched the region of macular edema detected by SD-OCT. The CME was attenuated in the right eye but not in the left eye of patient 1 at 2 weeks after discontinuation of paclitaxel treatment, whereas it was no longer apparent in either eye at 3 months. The CME was no longer detected in either eye of patient 2 at 3 months after discontinuation of paclitaxel. CONCLUSION: These cases suggest that paclitaxel-induced CME may result from intraretinal accumulation of intracellular fluid and minimal impairment of the blood retinal barrier. PMID- 29270812 TI - Comparison of longitudinal changes in circumpapillary retinal nerve fiber layer and ganglion cell complex thickness after acute primary angle closure: a 12-month prospective study. AB - PURPOSE: To compare longitudinal changes in circumpapillary retinal nerve fiber layer (cpRNFL) and ganglion cell complex (GCC) thicknesses and factors that are related to changes in cpRNFL and GCC thicknesses after acute primary angle closure (APAC). STUDY DESIGN: A prospective consecutive case series. METHODS: This study was a prospective, consecutive case series study including 64 eyes of 64 subjects with APAC. cpRNFL and GCC thicknesses were measured by RTVue-100 OCT. To measure cpRNFL and GCC thicknesses, the "three-dimensional (3D) optic disc scan and ONH scan" and "GCC" scan mode were used. Differences in cpRNFL and GCC thicknesses between the affected eye and fellow eye were compared, and logistic regression analysis was performed to investigate the factors associated with longitudinal changes in cpRNFL and GCC thicknesses. RESULTS: The average, superior and inferior cpRNFL, and GCC thicknesses were thicker in the affected eye than in the fellow eye within 1 week after remission and gradually decreased up to 12 months after remission. Compared with the cpRNFL and GCC thicknesses at 1 week after remission, the cpRNFL and GCC thicknesses at 1 month, 3 months, 6 months, and 12 months after remission were significantly thinner. Logistic regression analysis revealed that a longer duration from the onset of symptoms to adjustment of treatment (cpRNFL: odds ratio = 0.865, p = 0.003) (GCC: odds ratio = 0.824, p = 0.001) was associated with abnormal cpRNFL and GCC thicknesses. CONCLUSION: A week after APAC both cpRNFL and GCC thicknesses were thicker in the affected eye than in the fellow eye and further decreased up to 12 months post APAC. A longer duration from the onset of symptoms to adjustment of treatment was associated with cpRNFL and GCC loss after APAC. PMID- 29270813 TI - Semi-automated software to measure luminal and stromal areas of choroid in optical coherence tomographic images. AB - PURPOSE: To determine the capabilities of "EyeGround" software in measuring the choroidal cross sectional areas in optical coherence tomographic (OCT) images. STUDY DESIGN: Cross sectional, prospective study. METHODS: The cross-sectional area of the subfoveal choroid within a 1500 um diameter circle centered on the fovea was measured both with and without using the EyeGround software in the OCT images. The differences between the evaluation times and the results of the measurements were compared. The inter-rater, intra-rater, inter-method agreements were determined. RESULTS: Fifty-one eyes of 51 healthy subjects were studied: 24 men and 27 women with an average age of 35.0 +/- 8.8 years. The time for analyzing a single image was significantly shorter with the software at 3.2+/-1.1 min than without the software at 12.1+/-5.1 min (P <0.001). The inter-method correlation efficient for the measurements of the whole choroid was high [0.989, 95% CI (0.981-0.994)]. With the software, the inter-rater correlation efficient was significantly high [0.997, 95% CI (0.995-0.999)], and the intra-rater correlation efficient was also significantly high [0.999, 95% CI (0.999-1.0)]. CONCLUSION: The EyeGround software can measure the choroidal area in the OCT cross sectional images with good reproducibility and in a significantly shorter times. It can be a valuable tool for analyzing the choroid. PMID- 29270804 TI - 11th German Conference on Chemoinformatics (GCC 2015) : Fulda, Germany. 8-10 November 2015. PMID- 29270814 TI - Baseline data from a multicenter, 5-year, prospective cohort study of Japanese age-related macular degeneration: an AMD2000 report. AB - PURPOSE: To report research participants' baseline characteristics in the AMD2000 study, a prospective, multicenter, 5-year, observational cohort study of Japanese age-related macular degeneration (AMD). The characteristics were determined using multimodal imaging. METHODS: Patients with AMD were recruited at 18 clinical sites in Japan between April 2006 and March 2009. Each patient underwent a complete ophthalmic examination, including measurement of best-corrected visual acuity (Landolt chart), indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens, optical coherence tomography imaging, fundus photography, and fluorescein and indocyanine green angiography. RESULTS: Four hundred sixty participants (326 men [70.9%]) were included in the study. At enrollment, 131 eyes (28.5%) had hard drusen and 125 eyes (27.2%) had soft drusen in the macular area. A total of 455 eyes (98.9%) were diagnosed as having wet AMD, and 5 eyes (1.1%), as having dry AMD. Of the 455 eyes with wet AMD, 209 eyes (45.4%) had typical AMD, 228 eyes (49.6%) had polypoidal choroidal vasculopathy (PCV), and 18 eyes (3.9%) had retinal angiomatous proliferation. The size of choroidal neovascularization (CNV) was significantly smaller with indocyanine green angiography than with fluorescein angiography (P < 0.001). Poor baseline visual acuity was associated with cystoid macular edema, older age, scar, extrafoveal macular edema, subfoveal CNV, large branching vascular network, and hard exudates. CONCLUSION: Japanese patients with AMD are predominantly male, lack drusen, and have a high rate of PCV. PMID- 29270817 TI - The crystal structure of Z-DNA with untypically coordinated Ca2+ ions. AB - DNA oligomer duplexes with alternating cytosines and guanines in their sequence tend to form helices of the Z-DNA type, where the sugar and phosphate backbone forms a left-handed helix in a zigzag fashion with a repeat of two successive Watson-Crick pairs of nucleotides. Z-DNA duplexes often crystallize in complexes with diverse metal ions interacting with polar DNA atoms in various ways. This work describes the high-resolution crystal structure of a Z-DNA d(CGCGCG)2 duplex in complex with Ca2+ ions, unusually coordinated as an approximate pentagonal bipyramid by two neighboring guanines through their O6 and N7 atoms and a water molecule in the equatorial plane and a phosphate oxygen atom and another water molecule in the apical positions. PMID- 29270816 TI - Arctic berry extracts target the gut-liver axis to alleviate metabolic endotoxaemia, insulin resistance and hepatic steatosis in diet-induced obese mice. AB - AIMS/HYPOTHESIS: There is growing evidence that fruit polyphenols exert beneficial effects on the metabolic syndrome, but the underlying mechanisms remain poorly understood. In the present study, we aimed to analyse the effects of polyphenolic extracts from five types of Arctic berries in a model of diet induced obesity. METHODS: Male C57BL/6 J mice were fed a high-fat/high-sucrose (HFHS) diet and orally treated with extracts of bog blueberry (BBE), cloudberry (CLE), crowberry (CRE), alpine bearberry (ABE), lingonberry (LGE) or vehicle (HFHS) for 8 weeks. An additional group of standard-chow-fed, vehicle-treated mice was included as a reference control for diet-induced obesity. OGTTs and insulin tolerance tests were conducted, and both plasma insulin and C-peptide were assessed throughout the OGTT. Quantitative PCR, western blot analysis and ELISAs were used to assess enterohepatic immunometabolic features. Faecal DNA was extracted and 16S rRNA gene-based analysis was used to profile the gut microbiota. RESULTS: Treatment with CLE, ABE and LGE, but not with BBE or CRE, prevented both fasting hyperinsulinaemia (mean +/- SEM [pmol/l]: chow 67.2 +/- 12.3, HFHS 153.9 +/- 19.3, BBE 114.4 +/- 14.3, CLE 82.5 +/- 13.0, CRE 152.3 +/- 24.4, ABE 90.6 +/- 18.0, LGE 95.4 +/- 10.5) and postprandial hyperinsulinaemia (mean +/- SEM AUC [pmol/l * min]: chow 14.3 +/- 1.4, HFHS 31.4 +/- 3.1, BBE 27.2 +/- 4.0, CLE 17.7 +/- 2.2, CRE 32.6 +/- 6.3, ABE 22.7 +/- 18.0, LGE 23.9 +/- 2.5). None of the berry extracts affected C-peptide levels or body weight gain. Levels of hepatic serine phosphorylated Akt were 1.6-, 1.5- and 1.2-fold higher with CLE, ABE and LGE treatment, respectively, and hepatic carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-1 tyrosine phosphorylation was 0.6-, 0.7- and 0.9-fold increased in these mice vs vehicle-treated, HFHS-fed mice. These changes were associated with reduced liver triacylglycerol deposition, lower circulating endotoxins, alleviated hepatic and intestinal inflammation, and major gut microbial alterations (e.g. bloom of Akkermansia muciniphila, Turicibacter and Oscillibacter) in CLE-, ABE- and LGE-treated mice. CONCLUSIONS/INTERPRETATION: Our findings reveal novel mechanisms by which polyphenolic extracts from ABE, LGE and especially CLE target the gut-liver axis to protect diet-induced obese mice against metabolic endotoxaemia, insulin resistance and hepatic steatosis, which importantly improves hepatic insulin clearance. These results support the potential benefits of these Arctic berries and their integration into health programmes to help attenuate obesity-related chronic inflammation and metabolic disorders. DATA AVAILABILITY: All raw sequences have been deposited in the public European Nucleotide Archive server under accession number PRJEB19783 ( https://www.ebi.ac.uk/ena/data/view/PRJEB19783 ). PMID- 29270815 TI - A postmortem stereological study of the amygdala in Williams syndrome. AB - Perturbations to the amygdala have been observed in neurological disorders characterized by abnormalities in social behavior, such as autism and schizophrenia. Here, we quantitatively examined the amygdala in the postmortem human brains of male and female individuals diagnosed with Williams Syndrome (WS), a neurodevelopmental disorder caused by a well-defined deletion of ~ 26 genes, and accompanied by a consistent behavioral profile that includes profound hypersociability. Using unbiased stereological sampling, we estimated nucleus volume, number of neurons, neuron density, and neuron soma area in four major amygdaloid nuclei- the lateral nucleus, basal nucleus, accessory basal nucleus, and central nucleus- in a sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. Boundaries of the four nuclei examined were drawn on Nissl-stained coronal sections as four separate regions of interest for data collection. We found that the lateral nucleus contains significantly more neurons in WS compared to TD. WS and TD do not demonstrate significant differences in neuron number in the basal, accessory basal, or central nuclei, and there are no significant differences between WS and TD in nuclei volume, neuron density, and neuron soma area in any of the four nuclei. A similarly designed study reported a decrease in lateral nucleus neuron number in autism, mirroring the opposing extremes of the two disorders in the social domain. These results suggest that the number of neurons in the lateral nucleus may contribute to pathological disturbances in amygdala function and sociobehavioral phenotype. PMID- 29270818 TI - The influence of anti-hyperglycemic drug therapy on cardiovascular and heart failure outcomes in patients with type 2 diabetes mellitus. AB - Patients with type 2 diabetes mellitus (DM) are at a substantially increased risk of heart failure (HF) and HF mortality. Despite the lack of evidence that tight glycemic control reduces the incidence of cardiovascular (CV) events, a growing body of evidence suggests that the choice of glucose-lowering agents may influence outcomes including HF. Thiazolidinediones are associated with a significant risk of HF. For metformin, sulphonylureas and insulin, little data is available to indicate the impact on HF. The glucagon-like peptide-1 (GLP-1) agonists, liraglutide and semaglutide, have been shown to reduce major CV events, but did not affect rates of hospitalization for HF. Clinical trials have demonstrated diverse effects of Dipeptidyl peptidase-4 (DPP-4) inhibitors on HF; saxagliptin showed an increased risk of HF admissions, alogliptin was associated with higher rates of new HF admissions, while sitagliptin had a neutral effect. The sodium-glucose cotransporter 2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have been recently shown to reduce the incidence of HF and cardiovascular mortality in patients with and without a history of HF. This review will summarize key findings of the impact of glucose-lowering agents on CV safety and HF-associated outcomes, present available data on the underlying mechanisms for the benefits of the SGLT2 inhibitors on HF, and discuss strategies to improve outcomes in patients with DM and high CV risk. PMID- 29270819 TI - Pediatric Eosinophilic Esophagitis Endotypes: Are We Closer to Predicting Treatment Response? AB - Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven gastrointestinal disease that is characterized by esophageal eosinophilia. Currently, there are no Food and Drug Administration (FDA)-approved treatments for EoE, but the two most commonly prescribed therapies include topical corticosteroids and food elimination diets. Clinical trials have revealed a significant proportion of cases that are resistant to topical corticosteroids, and although we define EoE as a food antigen-driven disease, not all patients with EoE respond to elimination diets or even elemental diets. The varied response to treatments highlights the heterogeneity of EoE and the need for new treatment strategies. Despite the clinical differences in treatment response, predicting the outcome remains difficult since factors including age, histologic severity at diagnosis, atopic history, and anthropometrics are not predictive of treatment response. In our practice at an academic pediatric referral center, we observe distinct clinical EoE phenotypes, including cases with atopy, connective tissue disorders, or responsiveness to a proton pump inhibitor. Similar to the work in progress with asthma, stratification of patients with EoE by clinical phenotypes and/or molecular endotypes will likely assist with therapy selection and prediction of natural history. Molecular analysis with gene expression panels also shows promise in helping us classify patients based on molecular endotypes. In additional to the clinical and molecular classifications, more accurate histologic diagnostic criteria for EoE may help us tease out small differences between patient cohorts. Despite the leaps in knowledge over the past decade regarding EoE pathogenesis, it remains a challenge to predict the response to treatment. Future studies focused on molecular, genetic, and immunologic analyses of larger patient cohorts are needed to assist in identifying EoE phenotypes and endotypes as we attempt to improve patient outcomes in pediatric EoE. PMID- 29270821 TI - Safety in the operating room during orthopedic trauma surgery-incidence of adverse events related to technical equipment and logistics. AB - BACKGROUND: Safety in the operating room is widely debated. Adverse events during surgery are potentially dangerous for the patient and staff. The incidence of adverse events during orthopedic trauma surgery is unknown. Therefore, we performed a study to quantify the incidence of these adverse events. Primary objective was to determine the incidence of adverse events related to technical equipment and logistics. The secondary objective was to evaluate the consequences of these adverse events. METHODS: We completed a cross-sectional observational study to assess the incidence, consequences and preventability of adverse events related to technical equipment and logistics during orthopedic trauma surgery. During a 10 week period, all orthopedic trauma operations were evaluated by an observer. Six types of procedures were differentiated: osteosynthesis; arthroscopy; removal of hardware; joint replacement; bone grafting and other. Adverse events were divided in six categories: staff dependent factors; patient dependent factors; anaesthesia; imaging equipment; operation room equipment and instruments and implants. Adverse events were defined as any factor affecting the surgical procedure in a negative way. RESULTS: Hundred-fifty operative procedures were included. In 54% of the procedures, at least one adverse event occurred. In total, 147 adverse events occurred, with a range of 1-5 per procedure. Most adverse events occurred during joint replacement procedures. Thirty-seven percent of the incidents concerned defect, incorrect connected or absent instruments. In 36% of the procedures adverse events resulted in a prolonged operation time with a median prolongation of 10.0 min. CONCLUSION: In more than half of orthopedic trauma surgical procedures adverse events related to technical equipment and logistics occurred, most of them could easily be prevented. These adverse events could endanger the safety of the patient and staff and should therefore be reduced. LEVEL OF EVIDENCE: 4. PMID- 29270820 TI - Stem Cell Transplantation and Physical Exercise in Parkinson's Disease, a Literature Review of Human and Animal Studies. AB - The absence of effective and satisfactory treatments that contribute to repairing the dopaminergic damage caused by Parkinson's Disease (PD) and the limited recovery capacity of the nervous system are troubling issues and the focus of many research and clinical domains. Recent advances in the treatment of PD through stem cell (SC) therapy have recognized their promising restorative and neuroprotective effects that are implicated in the potentiation of endogenous mechanisms of repair and contribute to functional locomotor improvement. Physical exercise (PE) has been considered an adjuvant intervention that by itself induces beneficial effects in patients and animal models with Parkinsonism. In this sense, the combination of both therapies could provide synergic or superior effects for motor recovery, in contrast with their individual use. This review aims to provide an update on recent progress and the potential effectiveness of SC transplantation and PE for the treatment of locomotor deficits in PD. It has reviewed the neuropathological pathways involved in the classical motor symptoms of this condition and the mechanisms of action described in experimental studies that are associated with locomotor enhancement through exercise, cellular transplantation, and their union in some neurodegenerative conditions. PMID- 29270822 TI - Deep postoperative spine infection treated by negative pressure therapy in patients with progressive spinal deformities. AB - BACKGROUND: The aim of the study is to review the outcome of using the VAC system in children and adolescents who have developed postoperative spinal infection after posterior instrumented spinal fusion, and to evaluate whether this technique is also feasible in patients treated with posterior instrumented fusion with polyester sublaminar bands. METHODS: A total of 11 out of 118 consecutive children and adolescents (5 males) with deep postoperative spinal infection were identified; infections were categorised as early (acute), delayed (subacute) or late (chronic) according to time of onset. Irrespective of the etiology and the onset, all the deep infections were managed with the reported technique. All the patients had regular clinical and radiological follow-up. RESULTS: Eight out of 11 patients developed an early (72.7%), 2 a delayed (18.2%) and 1 a late deep postoperative infection (9.1%); 7 out of 11 (63.6%) showed severe mental compromise. No statistically significant differences were observed for mean number of VAC dressing changes (p = 0.81) and mean length of hospitalisation comparing patients with early infection versus patients with delayed or late infections (p = 0.32). Mean number of VAC dressing changes (p = 0.02) and mean number of hospitalisation days (p = 0.05) were higher in patients with underlying neurological disorders than in those without, while mean length of hospitalisation was longer in neuromuscular patients. CONCLUSIONS: The application of the VAC system, as an adjunct to surgical debridement and adequate antibiotic therapy, is a reliable method for the treatment of postoperative infection in children and adolescents undergoing spinal instrumentation and fusion. It can reduce the need for further complex soft-tissue procedure, removal of hardware with consequent loss of correction, and pseudoarthrosis. Finally, the use of VAC therapy is not contraindicated in patients treated with hybrid constructs with sublaminar bands. LEVEL OF EVIDENCE: III. PMID- 29270823 TI - Phalaenopsis flowering locus VE regulates floral organ maturation. AB - KEY MESSAGE: PaFVE is low ambient temperature-inducible and acts as a systemic regulator in the early stage of floral development in Phalaenopsis. Phalaenopsis aphrodite: subsp. formosana, a native orchid species of Taiwan, is an economically important ornamental crop that requires low ambient temperature for floral transition. Currently, limited genetic information about such orchid species hampers genetic manipulation for specific or improved floral traits, and the control of flowering time independent of temperature regulation. In this study, the sequence of the full-length of Phalaenopsis flowering locus VE (PaFVE) gene was determined. Spatial and temporal expression studies showed that mRNA transcripts of PaFVE were inducible by low ambient temperature, and high levels of expression occurred after spiking initiation and remained high throughout the early stage of floral development. Further investigation revealed that floral organ development was impeded in PaFVE-silenced P. aphrodite, but flowering time and floral organogenesis were not compromised. Analysis of the downstream flowering genes suggested that the delay in floral maturation is associated with a corresponding decrease in the expression of downstream flowering genes, PaSOC1, PaSOC1L and PaAGL24. The ectopic expression of PaFVE in Arabidopsis resulted in an accelerated flowering time, accompanied by an increase in the expression of AtSOC1, thus revealing the functional role of PaFVE as a floral regulator. Overall, our results demonstrate that PaFVE has evolutionarily diverged and conserved functions, and serves as a regulator of floral organ maturation in Phalaenopsis and a regulator of flowering time in Arabidopsis. PMID- 29270824 TI - Correction to: Comparison of the effect of activated or non-activated PRP in various concentrations on osteoblast and fibroblast cell line proliferation. AB - In the original publication of this article, the affiliation of the corresponding author has been published incorrectly. Now the correct affiliation has been provided in this erratum. PMID- 29270825 TI - Provided information and parents' comprehension at the time of admission of their child in pediatric intensive care unit. AB - : This study evaluated the first interaction (FI) between parents and health care providers at the time of admission of a child in pediatric intensive care unit (PICU), and explored the extent to which parents understood the medical information. This prospective study took place in three French university affiliated PICUs. Forty-two parents of 30 children were interviewed. The physician and nurse who took care of the child completed a questionnaire. We evaluated parents' comprehension (excellent, fair, or poor) by comparing parents' and physicians' responses to six items: diagnosis, affected organ, reason for hospitalization, prognosis, treatments, and further investigations. Parent physician FI occurred within 24 h of child's admission. Two thirds of the parents were dissatisfied to wait before receiving information. Most of the parents had an excellent comprehension of the affected organ (n = 25/28, 89.3%) and prognosis (n = 26/30, 86.7%). Two thirds of the parents understood the reason for hospitalization (n = 18/28, 64.3%) and diagnosis (n = 19/30, 63.3%). Less than half the parents understood child's treatments (n = 10/30, 33.3%) and further investigations (n = 8/21, 38.1%). When a nurse delivered information on treatment, parental comprehension improved (p = 0.053). CONCLUSION: Parents complained of their wait time before receiving information. Most of them had an excellent comprehension. An improved communication between nurses and physicians is mandatory, and the active participation of nurses to give information to the parents should be encouraged. What is known: * In pediatric intensive care unit, health care providers deliver information to parents on their child's condition, which fosters the trust between them to build a partnership. * Various guidelines exist to help health care providers communicate with parents in PICU, but never mention the specific time of admission. What is new: * Even though parents could wait before entering the unit, they all received information on their child's condition within 24 hours after admission. * Parents understood the information well, and nurses improved the parental comprehension of the treatments by reformulating. PMID- 29270826 TI - Paediatric departments need to improve residents' training in adolescent medicine and health: a position paper of the European Academy of Paediatrics. AB - : In many European countries, paediatric junior staff has no formal training in adolescent medicine and is ill-equipped to deal with issues and health problems such as substance use, unprotected sex, eating disorders and transition to adult care. This position paper of the European Academy of Paediatrics proposes a set of competency-based training goals and objectives as well as pedagogic approaches that are expected to improve the capacity of paediatricians to meet the needs of this important segment of the paediatric population. The content has been developed from available publications and training programmes and mostly covers the generic aspects of adolescent healthcare, such as how to communicate effectively, how to review and address lifestyles, how to perform a respectful and relevant physical examination, how to address common problems of adolescents and how to support adolescents in coping with a chronic condition. CONCLUSION: The European Academy of Paediatrics urges national bodies, paediatric associations and paediatric teaching departments to adopt these training objectives and put them into practice, so that paediatricians will be better prepared in the future to meet the challenge of delivering appropriate and effective healthcare to adolescents. PMID- 29270827 TI - Chemotherapy-induced nausea and vomiting (CINV) in patients with advanced lung cancer during the first-line treatment: assessment by physicians, nurses, and patients from an Italian multicenter survey. AB - PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) still represents a common side-effect of chemotherapy, and often, its perception differs between patients and healthcare professionals. The aim of this study was to evaluate the agreement on the perception of CINV and other items among clinicians, patients, and nurses. METHODS: This observational prospective study was part of an evaluation program promoted by the Women Against Lung Cancer in Europe (WALCE) Onlus. From August 2015 to February 2016, a survey was administered in 11 oncologic institutions to 188 stage IV lung cancer patients and to their oncologists and nurses during first-line chemotherapy. Our survey investigated 11 aspects: anxiety, mood, weakness, appetite, nausea, vomiting, pain, drowsiness, breath, general condition, and trust in treatments. These items were assessed through Numerical Rating Scale at four consecutive evaluations: at T0 (immediately prior to the first cycle), at T1 (immediately prior to the second cycle), at T2 (immediately prior to the third cycle), and at T3 (immediately prior to the fourth cycle). Clinician versus patient (CvP), nurse versus patient (NvP), and clinician versus nurse (CvN) agreements were estimated applying Weighted Cohen's kappa. A multivariate logistic model and generalized equation estimates were applied to evaluate factors possibly influencing CINV development. RESULTS: The incidence of patients reporting CINV varied from 40% at T0 to 71% at T3. Both CvP and NvP agreement on the investigated items were mainly moderate, slightly increasing over time, and becoming substantial for some items, in particular for NvP. Pre-chemotherapy anxiety in its mild, moderate, and severe manifestations, as well as mild, moderate, and severe anxiety experienced after chemotherapy start, exposed patients to a higher risk of anticipatory and acute/delayed CINV, respectively. CONCLUSIONS: Despite clinical staff awareness of patients' status and perceptions, CINV still represents a clinical problem. This study confirms that particular attention should be paid to anxiety due to its key role in CINV development. PMID- 29270829 TI - Evaluation of the effects of a clinically implemented exercise program on physical fitness, fatigue, and depression in cancer survivors. AB - PURPOSE: Despite national recommendations, exercise programs are still not clinically implemented as standard of care for cancer survivors. This investigation examined the effects of a clinically implemented and personalized exercise program on physical fitness, fatigue, and depression in a diverse population of cancer survivors. The association of various participant characteristics on program performance was also examined. METHODS: Data were collected from 170 cancer survivors who had participated in a clinical exercise program. Any cancer type was included and survivors were either undergoing medical treatment or had completed treatment (< 6 months prior to program initiation). Baseline and post program measures of estimated VO2peak, grip strength, fatigue, and depression were compared in survivors who completed the program follow-up. Multiple regressions were performed to investigate the association of age, gender, body mass index (BMI), and medical treatment status on baseline and change scores in outcome measures, as well as program adherence. RESULTS: All measures improved in participants who completed the program (p < 0.01). Age, gender, and BMI were associated with baseline measures of estimated VO2peak and grip strength (p < 0.01), and age was inversely associated with baseline fatigue (p = 0.02). Only BMI was inversely associated with change in estimated VO2peak (p < 0.01). No participant characteristics or baseline measures were predictive of program adherence (p > 0.05). CONCLUSION: This investigation provides evidence that a personalized, clinical exercise program can be effective at improving physical fitness, fatigue, and depression in a diverse population of cancer survivors. PMID- 29270828 TI - The effects of multi-disciplinary psycho-social care on socio-economic problems in cancer patients: a cluster-randomized trial. AB - PURPOSE: We examined whether multi-disciplinary stepped psycho-social care decreases financial problems and improves return-to-work in cancer patients. METHODS: In a university hospital, wards were randomly allocated to either stepped or standard care. Stepped care comprised screening for financial problems, consultation between doctor and patient, and the provision of social service. Outcomes were financial problems at the time of discharge and return-to work in patients < 65 years old half a year after baseline. The analysis employed mixed-effect multivariate regression modeling. RESULTS: Thirteen wards were randomized and 1012 patients participated (n = 570 in stepped care and n = 442 in standard care). Those who reported financial problems at baseline were less likely to have financial problems at discharge when they had received stepped care (odds ratio (OR) 0.2, 95% confidence interval (CI) 0.1, 0.7; p = 0.01). There was no evidence for an effect of stepped care on financial problems in patients without such problems at baseline (OR 1.1, CI 0.5, 2.6; p = 0.82). There were 399 patients < 65 years old who were not retired at baseline. In this group, there was no evidence for an effect of stepped care on being employed half a year after baseline (OR 0.7, CI 0.3, 2.0; p = 0.52). TRIAL REGISTRATION: NCT01859429 CONCLUSIONS: Financial problems can be avoided more effectively with multi disciplinary stepped psycho-social care than with standard care in patients who have such problems. PMID- 29270830 TI - Medical doctors and the foundation of the International Red Cross. PMID- 29270831 TI - Trying to prolong life no matter what, or to dignify it till the end: the dilemma of modern medicine: reply. PMID- 29270832 TI - Oxidative stress management during non-invasive ventilation in acute respiratory failure. PMID- 29270833 TI - N-Benzoyl dithieno[3,2-b:2',3'-d]pyrrole-based hyperbranched polymers by direct arylation polymerization. AB - BACKGROUND: Although poly(N-acyl dithieno[3,2-b:2',3'-d]pyrrole)s have attracted great attention as a new class of conducting polymers with highly stabilized energy levels, hyperbranched polymers based on this monomer type have not yet been studied. Thus, this work aims at the synthesis of novel hyperbranched polymers containing N-benzoyl dithieno[3,23,2-b:2',3'-d]pyrrole acceptor unit and 3-hexylthiophene donor moiety via the direct arylation polymerization method. Their structures, molecular weights and thermal properties were characterized via 1H NMR and FTIR spectroscopies, GPC, TGA, DSC and XRD measurements, and the optical properties were investigated by UV-vis and fluorescence spectroscopies. RESULTS: Hyperbranched conjugated polymers containing N-benzoyl dithieno[3,23,2 b:2',3'-d]pyrrole acceptor unit and 3-hexylthiophene donor moiety, linked with either triphenylamine or triphenylbenzene as branching unit, were obtained via direct arylation polymerization of the N-benzoyl dithieno[3,23,2-b:2',3' d]pyrrole, 2,5-dibromo 3-hexylthiophene and tris(4-bromophenyl)amine (or 1,3,5 tris(4-bromophenyl)benzene) monomers. Organic solvent-soluble polymers with number-average molecular weights of around 18,000 g mol-1 were obtained in 80-92% yields. The DSC and XRD results suggested that the branching structure hindered the stacking of polymer chains, leading to crystalline domains with less ordered packing in comparison with the linear analogous polymers. The results revealed that the hyperbranched polymer with triphenylbenzene as the branching unit exhibited a strong red-shift of the maximum absorption wavelength, attributed to a higher polymer stacking order as a result of the planar structure of triphenylbenzene. CONCLUSION: Both hyperbranched polymers with triphenylamine/triphenylbenzene as branching moieties exhibited high structural order in thin films, which can be promising for organic solar cell applications. The UV-vis absorption of the hyperbranched polymer containing triphenylbenzene as branching unit was red-shifted as compared with the triphenylamine-containing polymer, as a result of a higher chain packing degree. PMID- 29270834 TI - Value-Based Pricing: L'Enfant Terrible? PMID- 29270836 TI - Novel ultrasound-guided inter-semispinal plane block: a comparative pilot study in healthy volunteers. AB - We previously reported that a novel multifidus cervicis plane (MCP) block could anesthetize the dorsal rami of the cervical spinal nerves. While MCP sonoanatomy is easily detectable in most patients, it is sometimes difficult to recognize the MCP injection plane, especially in elderly patients. Thus, we proposed the inter semispinal plane (ISP) block as an alternative for the MCP block. The aim of this study was to evaluate the utility of the ISP block by evaluating the area and duration of anesthesia, compared with that of the MCP block in eight healthy volunteers. Each participant underwent unilateral ultrasound-guided MCP block and ISP block. For each block, 20 ml of ropivacaine 0.2% was injected, and the area of anesthesia was determined using the pinprick test. The anesthetic area ranged from C4 to T2 (3/8; 37.5%), T3 (2/8; 25%), or T4 (3/8; 37.5%) in the MCP block, and from C4 to T1 (1/8; 12.5%), T2 (3/8; 37.5%), T3 (2/8; 25%), or T4 (1/8; 12.5%) in the ISP block. The mean (standard deviation) duration of sensory loss following MCP and ISP blocks was 329 (77) min and 349 (70) min, respectively. Thus, the ISP block may be a reliable alternative to the MCP block. PMID- 29270835 TI - Australian Utility Weights for the EORTC QLU-C10D, a Multi-Attribute Utility Instrument Derived from the Cancer-Specific Quality of Life Questionnaire, EORTC QLQ-C30. AB - BACKGROUND: The EORTC QLU-C10D is a new multi-attribute utility instrument derived from the widely used cancer-specific quality-of-life (QOL) questionnaire, EORTC QLQ-C30. The QLU-C10D contains ten dimensions (Physical, Role, Social and Emotional Functioning; Pain, Fatigue, Sleep, Appetite, Nausea, Bowel Problems), each with four levels. To be used in cost-utility analysis, country-specific valuation sets are required. OBJECTIVE: The aim of this study was to provide Australian utility weights for the QLU-C10D. METHODS: An Australian online panel was quota-sampled to ensure population representativeness by sex and age (>= 18 years). Participants completed a discrete choice experiment (DCE) consisting of 16 choice-pairs. Each pair comprised two QLU-C10D health states plus life expectancy. Data were analysed using conditional logistic regression, parameterised to fit the quality-adjusted life-year framework. Utility weights were calculated as the ratio of each QOL dimension-level coefficient to the coefficient on life expectancy. RESULTS: A total of 1979 panel members opted in, 1904 (96%) completed at least one choice-pair, and 1846 (93%) completed all 16 choice-pairs. Dimension weights were generally monotonic: poorer levels within each dimension were generally associated with greater utility decrements. The dimensions that impacted most on choice were, in order, Physical Functioning, Pain, Role Functioning and Emotional Functioning. Oncology-relevant dimensions with moderate impact were Nausea and Bowel Problems. Fatigue, Trouble Sleeping and Appetite had relatively small impact. The value of the worst health state was -0.096, somewhat worse than death. CONCLUSIONS: This study provides the first country-specific value set for the QLU-C10D, which can facilitate cost-utility analyses when applied to data collected with the EORTC QLQ-C30, prospectively and retrospectively. PMID- 29270838 TI - Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. AB - Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, alpha-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process. PMID- 29270839 TI - Revisited larval morphology of Thanatophilus rugosus (Coleoptera: Silphidae). AB - Determination of insect species and their instars, occurring on human remains, is important information that allows us to use insects for estimation of postmortem interval and detect possible manipulation with the body. However, larvae of many common species can be identified only by molecular methods, which is not always possible. The instar determination is even more challenging, and qualitative characters that would allow a more precise identification are mostly unknown. Thanatophilus rugosus (Linnaeus, 1758) is a common necrophagous beetle in the whole Palaearctic region from Europe to Japan. The species is often encountered on corpses of large vertebrates including humans, and its potential to become a useful bioindicator for forensic entomology is therefore high. Adults can be easily distinguished from other species; however, larvae were never thoroughly described to allow species and instar identification. The aim of this study was to provide reliable morphological characters that would allow species and instar identification of T. rugosus larvae. The material for morphological study was obtained from rearing under controlled conditions (20 degrees C and 12:12 h of light/dark period), and specimens that were not studied morphologically were allowed to complete their development. Quantitative and qualitative morphological characters for instar and species identification are described and illustrated. Additionally, we report observations of biology and developmental length for all stages of the species. PMID- 29270840 TI - Personal-Level and Group-Level Discrimination and Mental Health: the Role of Skin Color. AB - OBJECTIVE: This study investigates the association between personal-level and group-level discrimination and common mental disorders (CMDs) among Afro Brazilian women, aiming to explore the role of skin color on this association. METHODS: This is a cross-sectional study involving 1130 women who were participating in the Social Change, Asthma and Allergy in Latin America (SCAALA) study, whose children were recruited from 24 geographical micro-regions representative of the population without sanitation. Measures of discrimination were defined by: experiences (personal-level) and concern about discrimination (group-level) using the Experiences of Discrimination Scale. Skin color was registered by self-declaration, being classified as white, brown, and black. The association between "self-reported" discrimination and CMDs was evaluated using Poisson regression analysis. RESULTS: Prevalence of CMDs was high (38.3%), especially in the group exposed to discriminatory experiences and black women. Experiences and concern about discrimination were positive and significantly associated with mental health, before and after adjustment for potential confounders. The effect of discrimination on CMDs was lower among black women, suggesting the development of other strategies to confront racism. CONCLUSION: This study emphasizes the use of both personal- and group-level discrimination measures, as well as skin color, for the evaluation of mental disorders in public health research. Further studies of health consequences of discrimination will require investigation of protective factors for mental disorders in the population suffering discrimination and racism. PMID- 29270841 TI - Trends in Racial/Ethnic Disparities Among Patients Living with HIV in Texas, 1996 to 2013. AB - National studies show that Blacks with HIV have higher mortality rates compared to Whites. This study aimed to identify trends in Black racial disparities among Texas residents living with HIV. Using HIV surveillance data from the Texas Department of State Health Services, a cohort of HIV-diagnosed patients (N = 70,996) were identified and grouped according to year of diagnosis, 1996-1997 (T1), 1998-2006 (T2), 2007-2010 (T3), and 2011-2013 (T4). Survival analysis was used to examine racial differences in death rate (analysis 1) and clinical progression to AIDS (analysis 2) for each subcohort, using Blacks as the reference group. In analysis 1, Whites (hazard ratio, HR = 0.80, 95% confidence interval, CI = 0.74-0.87, p < 0.001; HR = 0.82, 95% CI = 0.78-0.87, p < 0.001; respectively) and Hispanics (HR = 0.72, 95% CI = 0.66-0.79, p < 0.001; HR = 0.77, 95% CI = 0.74-0.81, p < 0.001, respectively) had lower death rates in T1 and T2. This remained significant after adjusting for covariates. In T3, death rate was higher for Hispanics after adjustment (HR = 1.13, 95% CI = 1.00-1.28, p < 0.05). In T4, death rate was higher for Whites (HR = 1.66, 95% CI = 1.30-2.13, p < 0.001) and Hispanics (HR = 1.66, 95% CI = 1.34-2.06, p < 0.001). These relationships became non-significant after adjusting for covariates. In analysis 2, the rate of clinical progression to AIDS was higher for Hispanics in all subcohorts. The significance remained after adjusting for covariates. The rate of clinical progression to AIDS was lower for Whites after adjustments in T2 and T3. Additional studies are needed to understand factors that may explain this unexpected finding of improved survival for Blacks over time. Such studies may inform decision-making in HIV care to reduce Black HIV disparities. PMID- 29270843 TI - Disentangling Race and Socioeconomic Status in HealthDisparities Research: an Examination of Black and White Clergy. AB - AIM: Sophisticated adjustments for socioeconomic status (SES) in health disparities research may help illuminate the independent role of race in health differences between Blacks and Whites. In this study of people who share the same occupation (United Methodist Church clergy) and state of residence (North Carolina), we employed naturalistic and statistical matching to estimate the association between race-above and beyond present SES and other potential confounds-and health disparities. METHODS: We compared the health of 1414 White and 93 Black clergy. Then, we used propensity scores to match Black and White participants on key socioeconomic, demographic, occupational, and physical activity characteristics and re-examined differences in health. RESULTS: Prior to propensity score matching, Black clergy reported worse physical health than their White counterparts. They had greater body mass index, higher prevalence of diabetes and hypertension, and lower physical health functioning. White clergy reported less favorable mental health. They had higher severity of depression and anxiety symptoms as well as lower quality of life and mental health functioning. Propensity score analysis revealed that matching on SES and other key variables accounted for most, but not all, of the observed racial differences. Racial disparities in hypertension, depression severity, and mental health functioning persisted despite adjustments. CONCLUSIONS: Race contributed to health disparities in some outcomes in our study population, above and beyond our measures of participants' present SES and key demographic, occupational, and physical activity variables. This study provides evidence supporting the position that race contributes to health disparities through pathways other than SES. PMID- 29270842 TI - Donor and Recipient Ethnicity Impacts Renal Graft Adverse Outcomes. AB - Renal transplant outcomes have been shown to be impacted by ethnicity. Prior studies have evaluated the disparate transplant outcomes of Black recipients and recipients of Black donors. However, it has remained unclear whether other donor ethnicities independent of medical comorbidities can influence transplant outcomes. Utilizing the Scientific Registry of Transplant Recipients (SRTR) (with greater than 100,000 patients), we evaluated the effect of each ethnicity, Black, American Indian, Hispanic, Native Hawaiian or other Pacific Islander, and Asian as compared to White recipients on adverse kidney transplant outcomes, assessing for delayed graft function, positive urine protein, acute rejection, and graft failure. Additionally, we assessed the interplay of donor ethnicity on recipient transplant outcomes, which has not previously been comprehensively examined. Logistic regression analysis that took into consideration gender, age, comorbidities, graft type, donor ethnicity, body mass index (BMI), HLA mismatch, ever been on hemodialysis, and time on dialysis indicates that Black recipients have worse outcomes compared to Whites in all outcomes assessed. A logistic regression analysis showed that recipient ethnicity was an independent risk factor for adverse outcomes. Notably, we found that donor ethnicity also independently affects graft outcomes. Hispanic donors lead to better outcomes in Whites and Blacks, while Asian donors have the best outcomes amongst Asian recipients. Recipients of Black donors fared the worst of all ethnicity donors. These data suggest the potential importance of risk stratification for the donor allograft and developing risk calculators that include both donor and recipient ethnicity may be useful, which the current Kidney Donor Profile Index (KDPI) does not currently take into account as they give black donors a different weight, but the same score is assigned to Whites, Asians, and Hispanics. PMID- 29270844 TI - Monoclonal B lymphocytosis and minimal change disease: a new monoclonal B-cell disorder of renal significance? AB - Chronic lymphocytic leukemia (CLL) may induce renal complications, which are becoming increasingly common, but in this context the occurrence of minimal change disease (MCD) remains rare. Monoclonal B lymphocytosis (MBL) is a precursor state of CLL and is currently under recognized. Since MBL is seen as a benign disorder that rarely evolves into CLL, screening for MBL is not standardized and does not require any treatment. When reviewing renal disease associated with MBL, there is very scant data in the literature and to date there is no case describing the association between MBL and MCD. Here, we describe the case of a 71-year old woman admitted for nephrotic syndrome (NS). We diagnosed a MBL. Kidney biopsy revealed MCD. Treatment with corticosteroids was introduced but no improvement was observed. Chemotherapy with rituximab and chlorambucil was thus started, leading to complete remission of both MBL and MCD. To our knowledge, this is the first description of the association of MBL and MCD. This case suggests that screening for MBL may have unexpected diagnostic and therapeutic implications in patients presenting with seemingly idiopathic NS. PMID- 29270845 TI - Anatomical variations of the left anonymous trunk are associated with central venous catheter dysfunction. AB - BACKGROUND: Internal jugular vein cannulation has become increasingly widespread. Compared to the left internal jugular vein (LIJV), the right internal jugular vein (RIJV) is the preferred choice for the placement of central venous catheter (CVC) for hemodialysis, mostly due to the major technical difficulties and higher rate of complications of the LIJV approach. We aimed to investigate whether variability in the direction of the LIJV/brachiocephalic vein (BV) axis on the frontal plane could be a decisive factor in determining CVC dysfunctions. METHODS: Retrospective cohort study. From our Register, a total of 1489 consecutive patients (age 69 +/- 9 years, males 60%) in whom a CVC for hemodialysis was placed from January 2012 to June 2014 were selected. RESULTS: LIJV cannulation, compared with RIJV, was associated with a higher rate of catheter dysfunction during an observational period of 2 weeks after catheter placement (16 vs.12%; p = 0.005). This complication was strongly correlated with the amplitude of the angle between the LIJV and the ipsilateral BV axis on the frontal plane; an angle <= 110 degrees was associated with a higher rate of catheter dysfunction (78 vs.16%; p < 0.001). CONCLUSIONS: The anatomical clarification presented in our study provides useful data that could explain the dysfunction rate of CVC inserted in the LIJV. Clinicians who insert high-flow catheters (such as hemodialysis catheters) should be aware of LIJV/BV axis variability and of the possible risks of CVC dysfunction when the angle between the LIJV and ipsilateral BV is <= 110 degrees . PMID- 29270846 TI - Lupus podocytopathy: a distinct entity of lupus nephritis. AB - Systemic lupus erythematosus (SLE) patients clinically presenting with nephrotic syndrome demonstrating minimal change disease (MCD), mesangial proliferation (MsP) or focal segmental glomerulosclerosis (FSGS), while on electronic microscopy, diffuse podocyte foot process effacement in absence of sub-epithelial or sub-endothelial deposition is the only morphological feature and now diagnosed as lupus podocytopathy. Lupus podocytopathy with glomerular morphology of MCD or MsP usually presents with typical nephrotic syndrome and sensitive to glucocorticoid treatment, but the relapse rate could reach up to 90% on maintenance treatment with glucocorticoid alone. Glucocorticoid plus other immunosuppressive agents could significantly decrease the relapse rate. Lupus podocytopathy with FSGS presents with a higher rate of acute kidney injury and less sensitivity to glucocorticoid treatment. The long-term outcomes of lupus podocytopathy are optimistic, but pathological transition could occur after renal relapses. The unique clinical and morphological features of lupus podocytopathy indicate that this special SLE-associated glomerulopathy should be included in the upcoming revised pathological classification of lupus nephritis. PMID- 29270847 TI - Cytotoxicity Test Based on Human Cells Labeled with Fluorescent Proteins: Fluorimetry, Photography, and Scanning for High-Throughput Assay. AB - PURPOSE: High- and medium-throughput assays are now routine methods for drug screening and toxicology investigations on mammalian cells. However, a simple and cost-effective analysis of cytotoxicity that can be carried out with commonly used laboratory equipment is still required. PROCEDURES: The developed cytotoxicity assays are based on human cell lines stably expressing eGFP, tdTomato, mCherry, or Katushka2S fluorescent proteins. Red fluorescent proteins exhibit a higher signal-to-noise ratio, due to less interference by medium autofluorescence, in comparison to green fluorescent protein. Measurements have been performed on a fluorescence scanner, a plate fluorimeter, and a camera photodocumentation system. RESULTS: For a 96-well plate assay, the sensitivity per well and the measurement duration were 250 cells and 15 min for the scanner, 500 cells and 2 min for the plate fluorimeter, and 1000 cells and less than 1 min for the camera detection. These sensitivities are similar to commonly used MTT (tetrazolium dye) assays. The used scanner and the camera had not been previously applied for cytotoxicity evaluation. An image processing scheme for the high resolution scanner is proposed that significantly diminishes the number of control wells, even for a library containing fluorescent substances. The suggested cytotoxicity assay has been verified by measurements of the cytotoxicity of several well-known cytotoxic drugs and further applied to test a set of novel bacteriotoxic compounds in a medium-throughput format. CONCLUSION: The fluorescent signal of living cells is detected without disturbing them and adding any reagents, thus allowing to investigate time-dependent cytotoxicity effects on the same sample of cells. A fast, simple and cost-effective assay is suggested for cytotoxicity evaluation based on mammalian cells expressing fluorescent proteins and commonly used laboratory equipment. PMID- 29270848 TI - Role of CT Density in PET/CT-Based Assessment of Lymphoma. AB - PURPOSE: In patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL), primary staging, as well as intermediate and late response assessment, is often performed by integrated 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/X-ray computed tomography (PET/CT). The purpose of this analysis was to evaluate if findings in patients with histopathologically proven HL or NHL might correlate with semi-automated density measurements of target lesions (TLs) in the CT component of the integrated PET/CT examination. PROCEDURES: After approval by the institutional review board, 176 lymph nodes (LN) in 90 PET/CT examinations of 90 patients were retrospectively analyzed (HL, 108 TLs out of 55 patients; NHL, 68 TLs out of 35 patients). PET/CT was performed for reasons of primary staging, response evaluation as interim PET, or as final examination after therapy, according to the clinical schedule. Analyses of TLs were performed on the basis of tracer uptake (SUV) 60 min after tracer injection and volumetric CT histogram analysis in non-contrast-enhanced CT. RESULTS: All patients were diagnosed with HL or NHL in a pretreatment biopsy. Prior to therapy induction, staging of all patients was performed using contrast-enhanced CT of the neck to the pelvis, or by [18F]FDG PET/CT. Of the 176 TLs, 119 were classified as malignant, and 57 were benign. Malignant TLs had significantly higher CT density values compared to benign (p < 0.01). CONCLUSION: Density measurements of TLs in patients with HL and NHL correlate with the dignity of TLs and might therefore serve as a complementary surrogate parameter for the differentiation between malignant and benign TLs. A possible density threshold in clinical routine might be a 20-Hounsfield units (HU) cutoff value to rule out benignancy in TLs that are above the 20-HU threshold. PMID- 29270849 TI - The Effect of Predictive Testing in Adult-Onset Neurodegenerative Diseases on Social and Personal Life. AB - Follow-up studies on predictive testing for hereditary neurodegenerative diseases mainly focussed on psychological outcomes. We investigated whether the social and personal life of mutation carriers differ negatively from non-carriers and untested at-risk individuals. Asymptomatic individuals (>= 35 years) who received a genetic test result for Huntington's disease, frontotemporal dementia or Alzheimer's disease more than 2 years before the onset of the study and untested subjects at 50% risk were invited to complete a questionnaire and an additional questionnaire with extra or adjusted items. Of the 283 selected individuals, 115 returned a positive informed consent (response rate 39.6%). Of these, 17 carriers, 30 non-carriers and 27 untested persons (n = 74) fulfilled the criteria and completed both questionnaires. We found no significant differences in employment, financial situation and lifestyle or anxiety and depression between carriers and non-carriers or untested individuals at risk. Carriers were more often single and childless, though these differences were not significant. The findings of this study suggest that the result of predictive testing on adult onset neurodegenerative diseases does not have a large negative effect on social and personal life, although these observations should be interpreted with caution because of the small number of participants and low response rate. PMID- 29270850 TI - Benthic phototrophic community from Kiran soda lake, south-eastern Siberia. AB - Phototrophic bacterial mats from Kiran soda lake (south-eastern Siberia) were studied using integrated approach including analysis of the ion composition of water, pigments composition, bacterial diversity and the vertical distribution of phototrophic microorganisms in the mats. Bacterial diversity was investigated using microscopic examination, 16S rRNA gene Illumina sequencing and culturing methods. The mats were formed as a result of decomposition of sedimented planktonic microorganisms, among which cyanobacteria of the genus Arthrospira predominated. Cyanobacteria were the largest part of phototrophs in the mats, but anoxygenic phototrophs were significant fraction. The prevailing species of the anoxygenic phototrophic bacteria are typical for soda lakes. The mats harbored aerobic anoxygenic phototrophic bacteria, purple sulfur and non-sulfur bacteria, as well as new filamentous phototrophic Chloroflexi. New strains of Thiocapsa sp. Kir-1, Ectothiorhodospira sp. Kir-2 and Kir-4, Thiorhodospira sp. Kir-3 and novel phototrophic Chloroflexi bacterium Kir15-3F were isolated and identified. PMID- 29270851 TI - Genome sequencing and heterologous expression of antiporters reveal alkaline response mechanisms of Halomonas alkalicola. AB - Halomonas alkalicola CICC 11012s is an alkaliphilic and halotolerant bacterium isolated from a soap-making tank (pH > 10) from a household-product plant. This strain can propagate at pH 12.5, which is fatal to most bacteria. Genomic analysis revealed that the genome size was 3,511,738 bp and contained 3295 protein-coding genes, including a complete cell wall and plasma membrane lipid biosynthesis pathway. Furthermore, four putative Na+/H+ and K+/H+ antiporter genes, or gene clusters, designated as HaNhaD, HaNhaP, HaMrp and HaPha, were identified within the genome. Heterologous expression of these genes in antiporter-deficient Escherichia coli indicated that HaNhaD, an Na+/H+ antiporter, played a dominant role in Na+ tolerance and pH homeostasis in acidic, neutral and alkaline environments. In addition, HaMrp exhibited Na+ tolerance; however, it functioned mainly in alkaline conditions. Both HaNhaP and HaPha were identified as K+/H+ antiporters that played an important role in high alkalinity and salinity. In summary, genome analysis and heterologous expression experiments demonstrated that a complete set of adaptive strategies have been developed by the double extremophilic strain CICC 11012s in response to alkalinity and salinity. Specifically, four antiporters exhibiting different physiological roles for different situations worked together to support the strain in harsh surroundings. PMID- 29270852 TI - [Unsuccessful pain treatment over 6 years of a thoracic radiculopathy caused by an unrecognized Tarlov cyst]. AB - This article presents a case of unsuccessful pharmaceutical and invasive pain treatment for 6 years without any adequate diagnostics in a female suffering from unilateral thoracic radiculopathy (Th8, right) leading to severe disability and unemployment. The origin was an undetected Tarlov cyst. After resection of the cyst the pain and other complaints disappeared (follow up: 8 months) without need for further pain medication. This case underlines the necessity of adequate diagnostics ahead of long-term pain treatment. Thoracic Tarlov cysts are very uncommon but should be included in the differential diagnosis because curative treatment may be possible. PMID- 29270853 TI - [Types of pain coping in chronic pain patients]. AB - BACKGROUND: The characterization of subtypes of chronic pain patients based on their pain coping profiles may contribute to a better understanding of the pain syndrome, to more specific indications of established treatment options as well as to further development of therapeutic interventions. OBJECTIVE: The aim of this study was to examine whether different subgroups of chronic pain patients emerge when using the German pain coping questionnaire (FESV) to identify homogeneous subgroups of pain coping patterns. Furthermore, the aim was to examine whether these pain coping subgroups differ in terms of sociodemographic characteristics, as well as pain and treatment-related aspects. MATERIAL AND METHODS: A total of 166 inpatients with a chronic pain disorder according to ICD 10 F45.41 were examined as part of the routine assessment within an interdisciplinary pain treatment program. Cognitive and behavioral pain coping and pain-related psychological impairment were measured with the FESV as components of pain coping. Using cluster analyses, homogeneous patient subgroups were generated on the basis of pain coping data. The resulting subgroups were subsequently compared regarding sociodemographic characteristics, pain-related impairment, global psychological distress, depression, anxiety, perceived stress, utilization of social support and motivation for psychotherapy. RESULTS AND CONCLUSION: The results revealed three distinct subgroups regarding pain coping patterns: (1) high impairment and high coping, (2) low impairment and high coping and (3) high impairment and low coping. The subgroups differed significantly in almost all characteristics, except for pain duration and pain intensity. The categorization into the abovementioned pain coping subtypes may assist clinicians in tailoring pain treatment to the needs and characteristics of the individual patients. PMID- 29270854 TI - Hydrogen-bonding behavior of various conformations of the HNO3...(CH3OH)2 ternary system. AB - Nine minima were found on the intermolecular potential energy surface for the ternary system HNO3(CH3OH)2 at the MP2/aug-cc-pVDZ level of theory. The cooperative effect, which is a measure of the hydrogen-bonding strength, was probed in these nine conformations of HNO3...(CH3OH)2. The results are discussed here in terms of structures, energetics, infrared vibrational frequencies, and topological parameters. The cooperative effect was observed to be an important contributor to the total interaction energies of the cyclic conformers of HNO3...(CH3OH)2, meaning that it cannot be neglected in simulations in which the pair-additive potential is applied. Graphical abstract The H-bonding behavior of various conformations of the HNO3(CH3OH)2 trimer was investigated. PMID- 29270855 TI - A prospective pilot study of Dilapan-S compared with Propess for induction of labour at 41+ weeks in nulliparous pregnancy. AB - BACKGROUND: The incidence of labour induction has risen worldwide over the past decade, and this may contribute to the rising caesarean delivery rate. The mechanisms for induction of labour are generally divided into two categories: mechanical and pharmacological. AIMS: The objective of this study was to determine if mechanical induction with Dilapan-S is an acceptable, safe method of induction of labour in post-dates uncomplicated nulliparous pregnancy. METHODS: This was a single-centre prospective observational pilot study trial. Fifty-two low-risk nulliparous women with an unfavourable cervix, scheduled for induction of labour for post-dates >= 41 weeks gestation, were offered induction of labour with Dilapan-S or Propess from May 2016 until November 2016. The primary outcomes measured were compliance to study protocol and maternal (infection, hyperstimulation) and neonatal outcomes (Apgar score at birth). The secondary outcome measures included change in Bishop's score and caesarean delivery rate. RESULTS: Compliance to study protocol was 25/26 (96%); it was possible to insert Dilapan-S in all but one woman. There were no differences in maternal and neonatal primary outcomes between the groups. There were no cases in either arm of hyperstimulation with either induction method. No difference between the groups was noted in the caesarean delivery rate nor in the mean change in Bishop's score. CONCLUSIONS: Dilapan-S is an acceptable, safe form of induction of labour in post-dates uncomplicated nulliparous pregnancy. No cases of hyperstimulation were found, and therefore, Dilapan-S may be a suitable option for outpatient induction of labour in low-risk post-dates nulliparas. PMID- 29270856 TI - Lumped parameter model for hemodynamic simulation of congenital heart diseases. AB - The recent development of computer technology has made it possible to simulate the hemodynamics of congenital heart diseases on a desktop computer. However, multi-scale modeling of the cardiovascular system based on computed tomographic and magnetic resonance images still requires long simulation times. The lumped parameter model is potentially beneficial for real-time bedside simulation of congenital heart diseases. In this review, we introduce the basics of the lumped parameter model (time-varying elastance chamber model combined with modified Windkessel vasculature model) and illustrate its usage in hemodynamic simulation of congenital heart diseases using examples such as hypoplastic left heart syndrome and Fontan circulation. We also discuss the advantages of the lumped parameter model and the problems for clinical use. PMID- 29270857 TI - Prior exposure to aspirin in acute coronary syndrome patients: a cardiovascular risk marker or a predictor of adverse outcome? A contemporary data of a national registry. AB - Despite the known protective cardiovascular effect of aspirin, former studies identified its prior exposure to an acute coronary syndrome (ACS) as an independent risk factor for adverse events. However, those studies did not reflect contemporary approaches. In the current study, we determine whether patients exposed to aspirin before an ACS have a worse cardiovascular risk profile and if it predicts higher risk of recurrent cardiovascular events or mortality. A cohort of patients enrolled in a national registry of ACS was analyzed according to prior exposure to aspirin. A propensity score standardized patients according to baseline comorbidities. Multivariable COX regression analysis was performed in unmatched and matched populations for a primary endpoint (composite of all-cause mortality and/or cardiovascular rehospitalization) and two secondary endpoints (all-cause mortality and cardiovascular rehospitalization, separately) at 1-year follow-up. Among 5533 ACS patients, 1763 were previously exposed to aspirin. They were older and had more comorbidities; contemporary approaches, both coronary angiography and percutaneous coronary angioplasty were less likely to be performed. Before matching the population, prior exposure to aspirin was an independent predictor of primary composite endpoint (p = 0.002) and cardiovascular rehospitalization as the secondary endpoint (p = 0.001). There were no statistically significant differences between both groups in the multivariable model for the primary or secondary endpoints after matching. Previous exposure to aspirin identified ACS patients with worse baseline characteristics, establishing its role as a cardiovascular risk marker. However, our data do not support including aspirin pretreatment in risk stratification scores as an adverse prognostic variable. PMID- 29270858 TI - Homozygous protein C deficiency presenting as neonatal purpura fulminans: management with fresh frozen plasma, low molecular weight heparin and protein C concentrate. AB - Purpura fulminans in neonates is a rapidly progressive thrombotic disorder manifesting as hemorrhagic skin infarction and disseminated intravascular coagulation. Being inherited in an autosomal dominant manner, it is a medical emergency. Clinical presentations of patients may vary depending on the genetic mutations. Retinal and intracranial hemorrhages are the worst clinical scenarios with persistent morbidity. During acute phase, fresh frozen plasma, protein C concentrates and anticoagulant therapy should be administered rapidly. Here we report a patient with homozygous protein C deficiency. PMID- 29270859 TI - Sinonasal Leiomyosarcoma: Clinicopathological Analysis of Nine Cases with Emphasis on Common Association with Other Malignancies and Late Distant Metastasis. AB - Sinonasal tract (SNT) leiomyosarcoma (LMS) is exceedingly rare with < 100 cases reported. Their relationship to retinoblastoma and other malignancies, along with previous irradiation has not been clarified. Routine and consultation cases were reviewed for histologically and immunohistochemically proven SNT LMS. The tumors were tested with antibodies against alpha-smooth muscle actin, desmin, h caldesmon, HMB45, S100 protein, Rb1, MDM2, CDK4 and EBV (EBER-ISH). Nine tumors affecting 5 males and 4 females aged 26 to 77 years (median: 48 years) were identified in the maxillary sinus (n = 4), nasal cavity (n = 3) and combined SNT (n = 2). Three patients had previous irradiation (2 for retinoblastoma, 1 for fibrous dysplasia) and 1 patient had chemotherapy and stem cell transplantation for Hodgkin lymphoma. One patient had prostatic adenocarcinoma (prior) and rectal adenocarcinoma (post) to the LMS. All patients with follow-up developed either local recurrences and/or metastases, principally to lung (time to metastasis: 16 156 months, mean 62 months). Histologically, 6 tumors were conventional high grade LMS, two had glycogen-rich clear cell (PEComa-like) morphology and one was spindle cell low-grade. The latter showed grade 2 in the recurrence and grade 3 in the lung metastases. Two cases showed dedifferentiation to anaplastic pleomorphic (inflammatory MFH-like) phenotype. Immunohistochemistry revealed diffuse expression of at least 2 smooth muscle markers in 8 and only actin in one case/s. All other markers were negative. RB1 loss was observed in 6/8 cases tested. Sinonasal tract leiomyosarcomas are rare aggressive sarcomas that frequently develop in a background of previous cancer therapy (4/9), most frequently irradiation. Their varied morphology underlines the wide differential diagnostic considerations. Long-term survival may be achieved with aggressive multimodal therapy. PMID- 29270860 TI - Predictors of colonization with Staphylococcus species among patients scheduled for cardiac and orthopedic interventions at tertiary care hospitals in north eastern Germany-a prevalence screening study. AB - As methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection in humans are a global challenge. In Mecklenburg and Western Pomerania (Germany) 1,517 patients who underwent surgical interventions were systematically screened for MRSA and MSSA colonization on the day of hospital admission and discharge. Demographic data, risk factors and colonization status of the (i) nose, (ii) throat, (iii) groin, and (iv) thorax or site of surgical intervention were determined. Of the 1,433 patients who were included for further evaluation, 331 (23.1%) were colonized with MSSA, while only 17 (1.2%) were MRSA carriers on the day of hospital admission. A combination of nose, throat and groin swabs returned a detection rate of 98.3% for MSSA/MRSA. Trauma patients had lower prevalence of MRSA/MSSA (OR 0.524, 95% CI: 0.37-0.75; p < 0.001) than patients with intended orthopedic interventions. Males showed significantly higher nasal S. aureus carrier rates than females (odds ratio (OR) = 1.478; 95% CI: 1.14-1.92; p = 0.003). Nasal S. aureus colonization was less frequent among male smokers as compared to non-smokers (chi2 = 16.801; phi = 0.154; p < 0.001). Age, gender and smoking had a significant influence on S. aureus colonization. Combining at least three different swabbing sites should be considered for standard screening procedure to determine S. aureus colonization at patients scheduled for cardiac or orthopedic interventions at tertiary care hospitals. PMID- 29270861 TI - Evaluation of the use of sonication of retrieved implants for the diagnosis of prosthetic joint infection in a routine setting. AB - In order to evaluate the usefulness of sonication of retrieved implants for the diagnosis of prosthetic joint infection (PJI) in a large group of patients in a routine setting, we designed a 3-year retrospective study. Patients were classified into two groups: those meeting the clinical criteria of PJI and those that did not (control group). Two hundred patients and 276 samples were included. The types of infection were early (n = 44), delayed (n = 53), positive intraoperative cultures (n = 13) and late-acute (n = 8). The culture sensitivities of sonicate fluid, periprosthetic tissue, synovial fluid and combination of periprosthetic tissue and/or synovial fluid were 69.5, 52.8, 54.8 and 60.2%, respectively. The specificities were 97.6, 90.3, 93.0 and 89.9%, respectively. Sonicate fluid culture of implants was more sensitive than peri implant tissue, synovial fluid and combination of periprosthetic tissue and/or synovial fluid for all infection types, though it was especially useful in delayed infection: 91.3% vs. 60.0% (p = 0.0015), 63.2% (p = 0.0005) and 66.7% (p = 0.0001), respectively. When sonicate fluid culture of implants was performed in addition to conventional cultures, the sensitivity increased significantly in total (from 60.2 to 77.1%) and delayed PJI (from 45.1 to 71.7%). On the other hand, for early PJI, sonicate fluid culture of prosthesis was not superior to conventional diagnostic methods. PMID- 29270862 TI - Capsular genotype and lipooligosaccharide locus class distribution in Campylobacter jejuni from young children with diarrhea and asymptomatic carriers in Bangladesh. AB - Campylobacter jejuni-related diarrheal diseases is one of the major health issues among young children (0-59 months old) in low-income countries. Monitoring of the capsular (capsule polysaccharide, CPS) types of virulent C. jejuni strains in regions where the disease is endemic is of great importance for the development of a customized capsule-based multivalent vaccine. Therefore, we aimed to determine the prevalence of CPS genotypes among C. jejuni strains isolated from young children with enteritis (n = 152) and asymptomatic carriers matched by age, sex, and residence defined as the control group (n = 215) in Bangladesh. CPS genotyping was performed using a newly established multiplex polymerase chain reaction (PCR) method and lipooligosaccharide (LOS) locus classes (A-E) were characterized using PCR as well. We identified 24 different CPS genotypes among the 367 isolates. Four prevalent capsular types, HS5/31 complex (n = 27, 18%), HS3 (n = 26, 17%), HS4A (n = 10, 7%), and HS8/17 (n = 10, 7%) covered almost 50% of the strains from enteritis patients and 43% of the isolates from controls. In combination, the CPS genotype and LOS class was not discriminative between cases and controls. Dominant capsular types previously identified in C. jejuni strains isolated from patients with Guillain-Barre syndrome in Bangladesh were rarely detected in strains isolated from the young children. A similar distribution was evident among enteritis- and control-related strains when comparison was done between CPS types and LOS classes. This is the first systematic study presenting the distribution of CPS genotypes of C. jejuni strains isolated in Bangladesh from children with diarrhea and controls, with capsular genotypes HS5/31 complex, HS3, HS4A, and HS8/17 being prevalent in both. In conclusion, systematic studies are required to develop a multivalent capsule-based vaccine for children in low income countries. PMID- 29270863 TI - Pluripotent Stem Cell-Derived Human Tissue: Platforms to Evaluate Drug Metabolism and Safety. AB - Despite the improvements in drug screening, high levels of drug attrition persist. Although high-throughput screening platforms permit the testing of compound libraries, poor compound efficacy or unexpected organ toxicity are major causes of attrition. Part of the reason for drug failure resides in the models employed, most of which are not representative of normal organ biology. This same problem affects all the major organs during drug development. Hepatotoxicity and cardiotoxicity are two interesting examples of organ disease and can present in the late stages of drug development, resulting in major cost and increased risk to the patient. Currently, cell-based systems used within industry rely on immortalized or primary cell lines from donated tissue. These models possess significant advantages and disadvantages, but in general display limited relevance to the organ of interest. Recently, stem cell technology has shown promise in drug development and has been proposed as an alternative to current industrial systems. These offerings will provide the field with exciting new models to study human organ biology at scale and in detail. We believe that the recent advances in production of stem cell-derived hepatocytes and cardiomyocytes combined with cutting-edge engineering technologies make them an attractive alternative to current screening models for drug discovery. This will lead to fast failing of poor drugs earlier in the process, delivering safer and more efficacious medicines for the patient. PMID- 29270864 TI - The Effectiveness of Dance Interventions on Physical Health Outcomes Compared to Other Forms of Physical Activity: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Physical inactivity is one of the key global health challenges as it is associated with adverse effects related to ageing, weight control, physical function, longevity, and quality of life. Dancing is a form of physical activity associated with health benefits across the lifespan, even at amateur levels of participation. However, it is unclear whether dance interventions are equally as effective as other forms of physical activity. OBJECTIVE: The aim was to systematically review the literature on the effectiveness of structured dance interventions, in comparison to structured exercise programmes, on physical health outcome measures. METHODS: Seven databases were searched from earliest records to 4 August 2017. Studies investigating dance interventions lasting > 4 weeks that included physical health outcomes and had a structured exercise comparison group were included in the study. Screening and data extraction were performed by two reviewers, with all disagreements resolved by the primary author. Where appropriate, meta-analysis was performed or an effect size estimate generated. RESULTS: Of 11,434 studies identified, 28 (total sample size 1276 participants) met the inclusion criteria. A variety of dance genres and structured exercise interventions were compared. Meta-analyses showed dance interventions significantly improved body composition, blood biomarkers, and musculoskeletal function. The effect of either intervention on cardiovascular function and self-perceived mobility was equivalent. CONCLUSION: Undertaking structured dance of any genre is equally and occasionally more effective than other types of structured exercise for improving a range of health outcome measures. Health practitioners can recommend structured dance as a safe and effective exercise alternative. PMID- 29270866 TI - Where do Peer Providers Fit into Newly Integrated Mental Health and Primary Care Teams? A Mixed Method Study. AB - Little is known about the involvement of peer providers in integrated behavioral health teams. This study asks where peer providers fit within integrated care teams in Los Angeles County. Social network analysis combined with qualitative fieldwork was used to understand the network positions of peer providers in 14 integrated pilot programs. Four programs' peer providers were highly central, while 3 programs' were on the network's periphery. Positional variation appeared to be related to the peers' mental health status. Targeted efforts are needed to support the implementation of peer providers on integrated teams at the program and system levels. PMID- 29270865 TI - Endurance Performance is Influenced by Perceptions of Pain and Temperature: Theory, Applications and Safety Considerations. AB - Models of endurance performance now recognise input from the brain, including an athlete's ability to cope with various non-pleasurable perceptions during exercise, such as pain and temperature. Exercise training can reduce perceptions of both pain and temperature over time, partly explaining why athletes generally have a higher pain tolerance, despite a similar pain threshold, compared with active controls. Several strategies with varying efficacy may ameliorate the perceptions of pain (e.g. acetaminophen, transcranial direct current stimulation and transcutaneous electrical stimulation) and temperature (e.g. menthol beverages, topical menthol products and other cooling strategies, especially those targeting the head) during exercise to improve athletic performance. This review describes both the theory and practical applications of these interventions in the endurance sport setting, as well as the potentially harmful health consequences of their use. PMID- 29270868 TI - The Beauty in Perfect Imperfection. AB - Modern technologies sanction a new plasticity of physical form. However, the increasing global popularity of aesthetic procedures (re)produces normative beauty ideals in terms of perfection and symmetry. These conditions limit the semblance of freedom by people to control their own bodies. Cultural emancipation may come from principles in Eastern philosophy. These reveal beauty in authenticity, including imperfection. Wabi-sabi acclaims beauty in common irregularity, while kintsugi celebrates beauty in visible signs of repair, like scars. These principles resist pressure to medicalize dissatisfaction with healthy bodies and invite multi-sited interventions to educate taste and aesthetic choices. PMID- 29270867 TI - Single- versus double-row repair for full-thickness rotator cuff tears using suture anchors. A systematic review and meta-analysis of basic biomechanical studies. AB - PURPOSE: The purpose of this study was to perform a systematic review and meta analysis comparing single- and double-row biomechanical studies to evaluate load to failure, mode of failure and gap formation. MATERIALS AND METHODS: A systematic review of MEDLINE, Embase, Scopus and Google Scholar was performed from 1990 through 2016. The inclusion criteria were: documentation of ultimate load to failure, failure modes and documentation of elongation or gap formation. Studies were excluded if the study protocol did not use human specimens. Publication bias was assessed by funnel plot and Egger's test. The risk of bias was established using the Cochrane Collaboration's risk of bias tool. Heterogeneity was assessed using chi 2 and I 2 statistic. RESULTS: Eight studies were included. The funnel plot was asymmetric suggesting publication bias, which was confirmed by Egger's test (p = 0.04). The pooled estimate for load to failure demonstrated significant differences (SMD 1.228, 95% CI: 0.55-5.226, p = 0.006, I 2 = 60.47%), favouring double-row repair. There were no differences for failure modes. The pooled estimate for elongation/gap formation demonstrated significant differences (SMD 0.783, 95% CI: 0.169-1.398, p = 0.012, I 2 = 58.8%), favouring double-row repair. CONCLUSION: The results of this systematic review and meta analysis suggest that double-row repair is able to tolerate a significantly greater load to failure. Gap formation was also significantly lower in the double row repair group, but both of these findings should be interpreted with caution because of the inherent interstudy heterogeneity. LEVEL OF EVIDENCE: Systematic review and meta-analysis. PMID- 29270870 TI - FGFR1 gene amplification in squamous cell carcinomas of the lung: a potential favorable prognostic marker for women and for patients with advanced cancer. AB - In squamous cell carcinoma (SCC) of the lung, mutations within the genes of fibroblast growth factor receptors (FGFR) such as K660N/K660E in FGFR2 and R248C/S249C in FGFR3 and FGFR1 gene amplification have been described, but their prognostic relevance still remains unclear. In order to detect the mutation frequencies and to define their prognostic value for associated clinicopathologic features and survival of patients, resected DeltaNp63/p40-positive SCC of the lung (n = 101) were screened for FGFR1 gene amplification by fluorescence in situ hybridization performed on formalin-fixed paraffin embedded tissues and for the presumed driver mutations in genes of FGFR2 and FGFR3 by PCR and Sanger sequencing. Twenty-two of 101 SCCs (22%) were positive for amplification based on a FGFR1/centromere (chromosome 8) ratio > 2.0 or higher. In advanced tumor stages (III-IV), the overall survival of patients carrying FGFR1 gene amplification was significantly higher (p = 0.006). Among women, FGFR1 gene amplification was significantly associated with longer overall survival (p = 0.023). The presence of FGFR1 gene amplification was associated with patient age (65 versus 69 years, p = 0.046), but not with gender, tumor stage, histologic subtype, tumor grade, or DeltaNp63/p40 immunoreactivity. The S249C mutation in the FGFR3 gene was identified in one out of 101 SCCs (1%); the K600N, K660E, or R248C mutations were not identified. These results suggest that FGFR1 gene amplification is a frequent alteration in SCC of the lung and appears not to be a negative but rather a favorable prognostic marker for women and particularly for patients with advanced SCC of the lung (stage III-IV). PMID- 29270872 TI - Additional new insights into Biometeorology. PMID- 29270871 TI - Exogenous growth factors do not affect the development of individually cultured murine embryos. AB - PURPOSE: The objective of this study was to evaluate the effects of multiple growth factors on the development of individually cultured murine embryos. METHODS: Embryos produced by in vitro fertilization using in vitro (IVM) or in vivo (IVO) matured oocytes from three strains of mice (CF1, Swiss Webster, B6D2F1) were cultured individually (10 MUl) in the absence (control) or presence of growth factors (paf, epidermal growth factor [EGF], insulin-like growth factor 1 [IGF-1], and granulocyte-macrophage colony-stimulating factor [GM-CSF]). Blastocyst formation, hatching, and blastocyst cell numbers (trophectoderm, inner cell mass, and total) were evaluated on days 4 and 5 of culture. Post-hatching development of CF1 IVO embryos was also evaluated in vitro and in vivo. RESULTS: The presence of growth factors did not improve the proportion of embryos forming blastocysts or initiating hatching for any of the types of embryos tested. The only significant (P < 0.05) effect of growth factors was a decrease in the proportion of embryos that formed blastocysts by day 5 in CF1 IVM embryos. The presence of growth factors also did not affect blastocyst cell numbers. For CF1 IVO embryos, the presence of growth factors during culture did not affect the proportion of embryos that attached to fibronectin-coated dishes, the size of the resulting outgrowths, or in vivo development following transfer. CONCLUSION: Combinations of paf, EGF, GM-CSF, and IGF-1 did not improve development of murine embryos cultured individually in a sequential medium containing a defined protein source. PMID- 29270873 TI - Characterization of a xylanolytic bacterial strain C10 isolated from the rumen of a red deer (Cervus elaphus) closely related of the recently described species Actinomyces succiniciruminis, A. glycerinitolerans, and A. ruminicola. AB - Gram-stain-positive, catalase and oxidase-negative and short rod-shaped bacterium C10 with occasional branching was isolated under strictly anaerobic conditions from the rumen fluid of a red deer (Cervus elaphus) in the course of study attempting to uncover new xylanolytic and cellulolytic rumen bacteria inhabiting the digestive tract of wild ruminants in the Czech Republic. The anaerobic M10 medium containing bovine rumen fluid and carboxymethylcellulose as a defined source of organic carbon was used in the process of bacterial isolation. The 16S rRNA gene similarity revealed recently characterized new species Actinomyces succiniciruminis Am4T (GenBank accession number of the gene retrieved from the complete genome: LK995506) and Actinomyces glycerinitolerans G10T (GenBank accession number from the complete genome: NZFQTT01000017) as the closest relatives (99.7 and 99.6% gene pairwise identity, respectively), followed by the Actinomyces ruminicola DSM 27982T (97.2%, in all compared fragment of 41468 pb). Due to the taxonomic affinity of the examined strain to both species A. succiniciruminis and A. glycerinitolerans, its taxonomic status towards these species was evaluated using variable regions of rpsA (length of 519 bp) and rplB (597 bp) gene sequences amplified based on specific primers designed so as to be applicable in differentiation, classification, and phylogeny of Actinomyces species/strains. Comparative analyses using rpsA and rplB showed 98.5 and 97.9% similarities of C10 to A. succiniciruminis, respectively, and 97.5 and 97.6% similarities to A. glycerinitolerans, respectively. Thus, gene identities revealed that the evaluated isolate C10 (=DSM 100236 = LMG 28777) is a little more related to the species A. succiniciruminis isolated from the rumen of a Holstein-Friesian cow than A. glycerinitolerans. Phylogenetic analyses confirmed affinity of strain C10 to both recently characterized species. Unfortunately, they did not allow the bacterial strain to be classified into a particular species. Phenotypic characterization suggested similar conclusions. This brief contribution is aimed at classification and detailed phenotypic characterization of bacterial strain C10 isolated from the rumen of a wild red deer exhibiting, from the point of view of Actinomyces species, noteworthy cellulolytic and xylanolytic activities. PMID- 29270874 TI - Frustule morphogenesis of raphid pennate diatom Encyonema ventricosum (Agardh) Grunow. AB - Diatoms stand out among other microalgae due to the high diversity of species specific silica frustules whose components (valves and girdle bands) are formed within the cell in special organelles called silica deposition vesicles (SDVs). Research on cell structure and morphogenesis of frustule elements in diatoms of different taxonomic groups has been carried out since the 1950s but is still relevant today. Here, cytological features and valve morphogenesis in the freshwater raphid pennate diatom Encyonema ventricosum (Agardh) Grunow have been studied using light and transmission electron microscopy of cleaned frustules and ultrathin sections of cells, and scanning electron and atomic force microscopy of the frustule surface. Data have been obtained on chloroplast structure: the pyrenoid is spherical, penetrated by a lamella (a stack of two thylakoids); the girdle lamella consists of several short lamellae. The basic stages of frustule morphogenesis characteristic of raphid pennate diatoms have been traced, with the presence of cytoskeletal elements near SDVs being observed throughout this process. Degradation of the plasmalemma and silicalemma is shown to take place when the newly formed valve is released into the space between sister cells. The role of vesicular transport and exocytosis in the gliding of pennate diatoms is discussed. PMID- 29270876 TI - Identification of ARL4C as a Peritoneal Dissemination-Associated Gene and Its Clinical Significance in Gastric Cancer. AB - BACKGROUND: In gastric cancer (GC), peritoneal dissemination (PD) occurs frequently and is incurable. In this study, we aimed to identify PD-associated genes in GC. METHODS: We identified a PD-associated gene using three GC datasets: highly disseminated peritoneal GC cell lines, the Singapore dataset and The Cancer Genome Atlas (TCGA) dataset. We assessed the clinicopathological significance of the gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and performed immunohistochemical analysis for the gene in our patient cohort. We also performed survival analyses of the gene in our patient cohort, the Singapore dataset and the GSE62254 datasets. Moreover, gene set enrichment analysis (GSEA) was performed using the Singapore and TCGA datasets. Finally, in vitro experiments such as invasion/migration assays, immunofluorescence staining of actin filaments, epidermal growth factor (EGF) treatment analysis, and gene expression analysis were conducted using three gene-knockdown GC cell lines (AGS, 58As9, MKN45). RESULTS: ADP-ribosylation factor-like 4c (ARL4C) was identified as a PD-associated gene, and immunohistochemical analysis showed that ARL4C was overexpressed in GC cells. High ARL4C expression was associated with the depth of invasion (p < 0.01) and PD (p < 0.05) and was a poor prognostic factor (p < 0.05) in our patient cohort, the Singapore dataset and the GSE62254 dataset. ARL4C expression positively correlated with the epithelial-mesenchymal transition (EMT) gene set in GSEA. Moreover, ARL4C knockdown reduced invasion/migration capacity, SLUG expression, and the formation of lamellipodia or filopodia in AGS and 58As9 cells. Finally, EGF treatment increased ARL4C expression in MKN45 cells. CONCLUSIONS: ARL4C was associated with PD and was a poor prognostic factor in GC, possibly through promoting invasive capacity by activation of both EMT and motility. PMID- 29270875 TI - Physiological and transcriptomic analyses of a yellow-green mutant with high photosynthetic efficiency in wheat (Triticum aestivum L.). AB - Optimizing the antenna size by reducing the chlorophyll (Chl) content is an effective strategy to improve solar energy conversion efficiencies in dense crop monocultures. To elucidate the physiological and molecular mechanisms that regulate Chl biosynthesis and understand the effects of lower Chl content on the photosynthetic process, a light-intensity-dependent yellow-green wheat mutant (Jimai5265yg) was characterized to determine its morphological, histological, physiological, and transcriptional differences with wild type. In addition to lower Chl content with a higher Chl a/b ratio, Jimai5265yg has spherical chloroplasts with few plastoglobule. It is counterintuitive that the photochemical quantum yield of both photosystem I and photosystem II and the following CO2 assimilation rate significantly increased, but the value of nonphotochemical quenching decreased, indicating a reduction of the photoprotective capacity of this yellow-green mutant. Analysis of intermediate pools and the expression of genes in the Chl synthesis pathway indicated that Mg protoporphyrin IX (Mg-Proto IX) synthesis was partially blocked due to the imbalanced expression of Mg-chelatase subunits. Interestingly, the expression of photosynthesis-associated nuclear genes (PhANGs) was upregulated, resembling gun mutants which have defects in the Mg-Proto IX-mediated plastid-to-nucleus signaling pathway. A genetic analysis indicated that the yellow-green phenotype was controlled by two nuclear recessive genes located on chromosomes 4AL and 4BL. Jimai5265yg is a novel chlorina mutant which could be used for understanding photosynthesis improvement mechanisms. PMID- 29270877 TI - Clinical Surveillance After Macroscopically Complete Surgery for Low-Grade Appendiceal Mucinous Neoplasms (LAMN) with or Without Limited Peritoneal Spread: Long-Term Results in a Prospective Series. AB - BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is the most common primary lesion of pseudomyxoma peritonei, a disease whose standard treatment is cytoreduction and hyperthermic intraperitoneal chemotherapy. The optimal management of LAMN is not well defined. This study prospectively assessed a clinical surveillance strategy for LAMN with or without limited peritoneal spread. METHODS: During 2003-2017, the study prospectively enrolled 41 patients treated by macroscopically complete surgery for LAMN with or without limited peritoneal spread (pelvis and right lower quadrant). Follow-up assessment included thoracic-abdomino-pelvic computed tomography scan and serum tumor markers scheduled after surgery, then every 6 months for 5 years, and yearly thereafter. All specimens were reviewed by a dedicated pathologist. RESULTS: Appendectomy and five right colectomies were performed for 36 patients. Nine patients also underwent macroscopically complete cytoreduction of mucinous peritoneal disease, and four patients had hysterectomy plus bilateral salphingo oophorectomy. Appendiceal rupture was evaluable in 38 of the 41 patients, being present in 21 patients (51.2%). Mucin, cells, or both outside the appendix were observed in 24 patients (58.5%). The median follow-up period was 58 months (range 9.3-162 months). The 5-year recurrence-free survival rate was 95.1%. Only two patients experienced peritoneal recurrences (4.9%), respectively 18 and 22 months after appendectomy. Their primary lesions were LAMNs with and without appendix wall rupture or extra-appendiceal mucin, respectively. No death occurred. CONCLUSION: These findings strongly suggest that radically resected LAMN, even with limited peritoneal spread, carries a low recurrence risk. Furthermore, appendix wall perforation and the presence of mucin, cells, or both outside the appendix were not associated with a higher risk of metachronous peritoneal dissemination. In this setting, clinical and radiologic surveillance is a viable choice. PMID- 29270878 TI - Reply to "Questions About In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy". PMID- 29270879 TI - Outcomes and Predictive Factors of Isolated Limb Infusion for Patients with In transit Melanoma in China. AB - PURPOSE: This study was designed to evaluate the efficacy of isolated limb infusion (ILI) treatment in Chinese patients with in-transit melanoma and to identify factors predictive of the outcome. METHODS: A total of 150 patients with in-transit melanoma who received a single ILI between 2007 and 2016 were identified from a prospectively collected database. RESULTS: All patients had AJCC Stages IIIb, IIIc, and IV disease. Acral lentiginous melanoma (ALM) accounted for 79% of patients, and 59% had a high burden of disease (BOD). The complete response (CR) and partial response (PR) rates were 6 and 35%, respectively. Forty-five percent of patients experienced grade III-IV limb toxicities, but no grade V toxicity was observed. Patients with a low BOD, high limb temperature, high peak creatine phosphokinase (CK) level, and grade III-IV limb toxicity achieved higher response rates. Stage IV disease and high BOD were associated with worse infield progression-free survival (PFS) and overall survival (OS), whereas patients with CR or PR to ILI had better infield PFS and OS. Multivariate analyses showed that disease stage, BOD, and a CR were independent predictors of infield PFS, whereas disease stage and a response to ILI were independent predictors of OS. CONCLUSIONS: ILI is well-tolerated but the response rate in Chinese patients was lower than that reported in US and Australian studies. The prevalence of the ALM histological type, advanced disease stages, and a high BOD may be the main reasons for this. A response to ILI, BOD, and disease stage are prognostic factors for survival. PMID- 29270880 TI - Proximity and grooming patterns reveal opposite-sex bonding in Rwenzori Angolan colobus monkeys (Colobus angolensis ruwenzorii). AB - Close proximity and social grooming are important bonding mechanisms in primates. These behaviors show the social structure of a species and many studies have found positive correlations between the degree of kinship and grooming and proximity. We used 1 year of data collected via instantaneous scan sampling on a large "supertroop" of Colobus angolensis ruwenzorii at Lake Nabugabo, Uganda, to examine partner preferences for grooming and nearest neighbors in each age-sex class. Little is known about this species, so we based our hypotheses on congeners. Of the five species of black-and-white colobus, data on sex-biased dispersal patterns are available for three (C. guereza, C. vellerosus, and C. polykomos), all of which show male-biased dispersal with occasional female dispersal. We thus predicted that female C. a. ruwenzorii would be more strongly bonded than males, showing greater proximity and grooming. We did not expect bonding between the sexes since congeners do not show this pattern. We found that among adult dyads, males and females were more likely to be found in loose proximity, and to groom, than would be expected given group composition. Conversely, both males and females had relatively weak same-sex relationships. Between the sexes, adult males had higher proximity and grooming indices with adult females without infants than with females with infants. These observations indicate that this subspecies is cross-bonded and that both sexes may disperse. Furthermore, our findings suggest that the social organization and social structure of C. a. ruwenzorii differ greatly from other black-and-white colobus species. PMID- 29270881 TI - The rewarding effects of number and surface area of food in rats. AB - Visual cues have an important role in food preference for both rats and humans. Here, we aim to isolate the effects of numerosity, density, and surface area on food preference and running speed in rats, by using a forced-choice maze paradigm. In Experiment 1, rats preferred and ran faster for a group of multiple smaller pellets rather than a single large pellet, corroborating previous research (Capaldi, Miller, & Alptekin Journal of Experimental Psychology: Animal Behavior Processes, 15(1), 75-80, 1989). Further experiments tested the prevailing hypothesis that multiple food pieces are more reinforcing because they occupy a larger surface area. Experiment 2 controlled for numerosity by utilizing a continuous food: mashed potatoes flattened to cover a larger surface area or rounded into a ball. The rats preferred and ran faster for the flattened potatoes, suggesting surface area plays a role in quantity estimations. Finally, in Experiment 3, rats displayed no preference or difference in running speed between a group of scattered and clustered pellets when number of pellets were kept constant. Taken together, these results suggest that density has an important role in food perception-that is, the rewarding effect of higher numerosity or larger surface area is removed when the food does not fill out the entire space. Alternative explanations and implications for human diet are discussed. PMID- 29270883 TI - Cell-free one-pot conversion of (+)-valencene to (+)-nootkatone by a unique dye decolorizing peroxidase combined with a laccase from Funalia trogii. AB - A combined system of a unique dye-decolorizing peroxidase (Ftr-DyP) and a laccase obtained from the basidiomycete Funalia trogii converted the precursor (+) valencene completely to the high-value grapefruit flavour constituent (+) nootkatone, reaching a concentration maximum of 1100 mg/L. In the presence of 1 mM Mn2+ and 2.5 mM p-coumaric acid, (+)-nootkatone was the predominating volatile product, and only traces of substrate and the nootkatols were detectable after 24 h. Hence, the two-enzyme-system reproduced the oxidizing activity observed before for the crude culture supernatant. The newly discovered Ftr-DyP was purified, sequenced and further characterized as a thermostable, non-glycosylated protein with a pH-optimum in the acidic range and a calculated mass of 52.3 kDa. Besides the typical activity of DyPs towards anthraquinone dyes, Ftr-DyP also oxidized Mn2+ and showed activity in the absence of hydrogen peroxide. Neither the DyP from Mycetinis scorodonius nor the manganese peroxidase from Nematoloma frowardii were able to replace Ftr-DyP in this reaction. A hypothetical reaction mechanism is presented. PMID- 29270882 TI - Anterior cutaneous nerve entrapment syndrome (ACNES). AB - The abdominal wall is frequently overlooked as a potential source of chronic abdominal pain. In anterior cutaneous nerve entrapment syndrome (ACNES), irritated intercostal nerves cause severe abdominal pain. Current textbooks fail to acknowledge ACNES. Aim of the present review is to provide detailed information on patient history, physical examination, and a three-step treatment protocol including abdominal wall injections and a localized removal of terminal branches of intercostal nerves. PMID- 29270884 TI - Necrosis is a consistent factor to recurrence of meningiomas: should it be a stand-alone grading criterion for grade II meningioma? AB - The purpose of this study was to evaluate spontaneous necrosis as a possible isolated factor for progression and recurrence in grade I meningiomas classified according to the current World Health Organization (WHO) classification. Meningiomas are the most frequently reported primary intracranial tumours, accounting for more than 35%. The 2016 WHO classification of central nervous system tumors stratifies meningiomas in grades I (benign), II (atypical), and III (malignant), according to histopathological aspects and the risk of progression or recurrence. Among 110 patients with intracranial meningiomas, 70 were WHO grade I meningiomas with no findings of atypia (G1WON), 15 were WHO grade I with necrosis (G1WN), 21 were WHO grade II (G2), and 4 were WHO grade III (G3). The mean follow-up was 5.9 +/- 0.2 years. High performance scale (KPS >= 80) was different (p < 0.001) between WHO grade I meningiomas without (81.4%) and with (60%) necrosis. The 5-year mortality rate was 1.4, 6.7 and 5.9% for G1WON, G1WN and G2, respectively, with significant difference (p = 0.011) related to the presence of necrosis. The risk of recurrence was 3.7 times higher in G1WN than in G1WON (p = 0.017), and 4.2 times in G2 (p = 0.010). Progression-free survival (PFS) was clearly higher in patients with G1WON compared to G1WN and G2 (p = 0.002 and p < 0.001, respectively). There was no significant difference in PFS between G1WN and G2 (p = 0.692). Retreatment was also superior in meningioma with necrosis. Our findings provide clear statistical data to consider that patients with benign meningiomas and histologic findings of spontaneous necrosis are at increased risk of progression and recurrence compared to those with benign lesion without atypical features. Statistical analysis curves also suggest that these lesions behave more similarly to those currently classified as WHO grade II meningioma. PMID- 29270885 TI - The Potency of Induced Pluripotent Stem Cells in Cartilage Regeneration and Osteoarthritis Treatment. AB - Osteoarthritis (OA) is the most common chronic disabling condition effecting the elderly, significantly impacting an individual patient's quality of life. Current treatment options for OA are focused on pain management and slowing degradation of cartilage. Some modern surgical techniques aimed at encouraging regeneration at defect sites have met with limited long-term success. Mesenchymal stem cells (MSCs) have been viewed recently as a potential tool in OA repair due to their chondrogenic capacity. Several studies have shown success with regards to reducing patient's OA-related pain and discomfort but have been less successful in inducing chondrocyte regeneration. The heterogeneity of MSCs and their limited proliferation capacity also raises issues when developing an off-the-shelf treatment for OA. Induced pluripotent stem cell (iPSC) technology, which allows for the easy production of cells capable of prolonged self-renewal and producing any somatic cell type, may overcome those limitations. Patient derived iPSCs can also be used to gain new insight into heredity-related OA. Efforts to generate chondrocytes from iPSCs through embryoid bodies or mesenchymal intermediate stages have struggled to produce with optimal functional characteristics. However, iPSCs potential to produce cells for future OA therapies has been supported by iPSC-derived teratomas, which have shown an ability to produce functional, stable articular cartilage. Other iPSCs-chondrogenic protocols are also improving by incorporating tissue engineering techniques to better mimic developmental conditions. PMID- 29270886 TI - Comparison of the Adult ADHD Self Report Scale Screener for DSM-IV and DSM-5 in a Dually Diagnosed Correctional Population. AB - The diagnosis of Attention Deficit Hyperactivity Disorder in adults with Substance Use Disorders is complicated. A specific screening tool, such as the World Health Organization Adult ADHD Self Report Scale Screener can be the first step in identifying the condition. Recently, the screener has been revised because the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition, made some changes to the criteria for Attention Deficit Hyperactivity Disorder. This study compared the screeners based upon the Fourth and Fifth edition of the Manual. One hundred and forty patients, including seventy with Attention Deficit Hyperactivity Disorder, completed both screeners, independent from a clinical diagnostic interview. The sensitivity, specificity, and predictive values were calculated based on four different scoring methods: a categorical score of three or four positive answers, and a dimensional score of twelve or fourteen. Both screening instruments appeared to perform equally without significant differences between them, no matter which scoring system was used. However, the only satisfactory result was obtained using the dimensional scoring with a cutoff of 12, providing a sensitivity and negative predictive value above 80%. This is a lower cut off than recommended in community and clinic samples. It is possible that the cut off of the screener may need to be adjusted depending on the circumstances within which it is used. PMID- 29270887 TI - Episodic future thinking reduces delay discounting and cigarette demand: an investigation of the good-subject effect. AB - Episodic future thinking (EFT), an intervention involving mental simulation of future events, has been shown to reduce both delay discounting and cigarette self administration. In the present study, we extended these findings by showing that EFT in a web-based sample of smokers reduces delay discounting and intensity of demand for cigarettes (ad libitum consumption) in a hypothetical purchase task. No effect was observed on elasticity of demand (sensitivity to price) or cigarette craving. We also explored whether demand characteristics (specifically, the "good-subject" effect) might be responsible for observed effects. EFT participants were significantly better able than control participants to discern the experimental hypothesis. However, EFT participants were not better than controls at identifying whether they had been assigned to the experimental group and, likewise, showed no differences in attitudes about the experiment and experimenter. Importantly, effects of EFT on delay discounting and demand remained significant even when controlling for measures of demand characteristics, indicating that EFT's effects are independent of participants' perceptions about the experiment. PMID- 29270888 TI - Pathways linking racial/ethnic discrimination and sleep among U.S.-born and foreign-born Latinxs. AB - This study examined the association between racial/ethnic discrimination and sleep through psychological distress and body mass index (BMI), and determined whether the aforementioned associations vary between U.S. and foreign-born Latinxs. Participants were 1332 Latinx adults enrolled in the Texas City Stress and Health Study. Multistage sampling methods were used to select participants. A model linking racial/ethnic discrimination with sleep disturbances through direct and indirect (i.e., psychological distress and BMI) paths demonstrated good fit. Greater racial/ethnic discrimination was associated with greater psychological distress and higher BMI. Psychological distress and BMI were also significant predictors of sleep disturbances. The indirect path from racial/ethnic discrimination to sleep disturbances via psychological distress was significant. A model with parameters constrained to be equal between U.S.-born and foreign born Latinxs suggested associations were comparable between these groups. Our study demonstrated the relevance of racial/ethnic discrimination to sleep disturbances, particularly its association via psychological distress among Latinxs. PMID- 29270889 TI - The carpal tunnel syndrome in children. AB - INTRODUCTION: Carpal tunnel syndrome (CTS) in children represents a complex challenge for the hand surgeon because of its rarity, poor patient cooperation, frequently associated malformation syndromes and mental retard, atypical symptoms and nuanced and poor sensitivity of instrumental tests. The most frequently associated causes with the CTS in children are rare congenital malformations and diseases, requiring an overall assessment of the young patient and a high degree of suspicion for the potentially associated canalicular syndrome. On the other hand, the associated syndromes may be the main ally for a diagnosis that starts from the knowledge of the literature and the surgeon's suspicion by observing the child wailing. Early diagnosis and decompression treatment is mandatory. MATERIALS AND METHODS: The authors report a case series of 26 children and analyze the etiology and diagnostic algorithms. Patient assessment was based on complete clinical examination and medical history collection of these young patients with the involvement of the family and educators. RESULTS: In all 26 patients treated, along an average period of 23 months (minimum 12, maximum 30), no signs of recurrence or persistence of median nerve disturbances were recorded. CONCLUSIONS: In conclusion, we believe that anamnesis, a careful physical examination and analysis of instrumental examinations, should be accompanied by a thorough knowledge of rare diseases in the context of congenital malformations. The carpal tunnel syndrome, while well known and treated by each orthopedic surgeon, reveals a mysterious aspect in the context of the "fabulous" world of childhood illnesses, even more difficult than rare congenital diseases. PMID- 29270890 TI - Degradation of the stress-responsive enzyme formate dehydrogenase by the RING type E3 ligase Keep on Going and the ubiquitin 26S proteasome system. AB - KEY MESSAGE: KEG is involved in mediating the proteasome-dependent degradation of FDH, a stress-responsive enzyme. The UPS may function to suppress FDH mediated stress responses under favorable growth conditions. Formate dehydrogenase (FDH) has been studied in bacteria and yeasts for the purpose of industrial application of NADH co-factor regeneration. In plants, FDH is regarded as a universal stress protein involved in responses to various abiotic and biotic stresses. Here we show that FDH abundance is regulated by the ubiquitin proteasome system (UPS). FDH is ubiquitinated in planta and degraded by the 26S proteasome. Interaction assays identified FDH as a potential substrate for the RING-type ubiquitin ligase Keep on Going (KEG). KEG is capable of attaching ubiquitin to FDH in in vitro assays and the turnover of FDH was increased when co-expressed with a functional KEG in planta, suggesting that KEG contributes to FDH degradation. Consistent with a role in regulating FDH abundance, transgenic plants overexpressing KEG were more sensitive to the inhibitory effects of formate. In addition, FDH is a phosphoprotein and dephosphorylation was found to increase the stability of FDH in degradation assays. Based on results from this and previous studies, we propose a model where KEG mediates the ubiquitination and subsequent degradation of phosphorylated FDH and, in response to unfavourable growth conditions, reduction in FDH phosphorylation levels may prohibit turnover allowing the stabilized FDH to facilitate stress responses. PMID- 29270893 TI - Correction to: Is emotion recognition the only problem in ADHD? Effects of pharmacotherapy on face and emotion recognition in children with ADHD. AB - The author would like to correct the error in the publication of the original article. The corrected details are given below for your reading. PMID- 29270892 TI - Multi-Table Differential Correlation Analysis of Neuroanatomical and Cognitive Interactions in Turner Syndrome. AB - Girls and women with Turner syndrome (TS) have a completely or partially missing X chromosome. Extensive studies on the impact of TS on neuroanatomy and cognition have been conducted. The integration of neuroanatomical and cognitive information into one consistent analysis through multi-table methods is difficult and most standard tests are underpowered. We propose a new two-sample testing procedure that compares associations between two tables in two groups. The procedure combines multi-table methods with permutation tests. In particular, we construct cluster size test statistics that incorporate spatial dependencies. We apply our new procedure to a newly collected dataset comprising of structural brain scans and cognitive test scores from girls with TS and healthy control participants (age and sex matched). We measure neuroanatomy with Tensor-Based Morphometry (TBM) and cognitive function with Wechsler IQ and NEuroPSYchological tests (NEPSY II). We compare our multi-table testing procedure to a single-table analysis. Our new procedure reports differential correlations between two voxel clusters and a wide range of cognitive tests whereas the single-table analysis reports no differences. Our findings are consistent with the hypothesis that girls with TS have a different brain-cognition association structure than healthy controls. PMID- 29270891 TI - De novo transcriptome analyses reveals putative pathway genes involved in biosynthesis and regulation of camptothecin in Nothapodytes nimmoniana (Graham) Mabb. AB - KEY MESSAGE: Comprehensive transcriptome analysis of leaf and root tissues of Nothapodytes nimmoniana unravels several putative pathway genes, transcription factors and CYPs related to camptothecin (CPT) biosynthesis. Additionally, post transcriptional suppression by artificial microRNA (aMIR) of NnCYP76B6 (geraniol 10-hydroxylase) suggests its role in CPT biosynthesis. Tissue-specific LC-MS/MS analysis revealed the presence of secologanin as the central intermediate of MIA pathway in N. nimmoniana. Nothapodytes nimmoniana is a rich source of potent anticancer drug camptothecin (CPT) whose biosynthetic pathway is unresolved due to the lack of genomic and transcriptomic information. Present investigation entails deep transcriptome analysis of N. nimmoniana which led to identification of putative pathway genes and regulatory components involved in CPT biosynthesis. Using Illumina HiSeq 2500 sequencing platform a total of 31,172,889 (6.23 Gb) and 31,218,626 (6.24 Gb) raw reads were generated from leaf and root wood, respectively. These were assembled de novo into 138,183 unique contigs. Additionally, 16 cytochrome P450 transcripts related to secondary metabolism were also identified. Further, transcriptome data pool presented 1683 putative transcription factors of which transcripts corresponding to WRKY TFs were the most abundant (14.14%). A total of 2741 transcripts were differentially expressed out of which 478 contigs showed downregulation in root wood and 2263 contigs were up-regulated. Further, comparative analyses of 17 genes involved in CPT biosynthetic pathway were validated by qRT-PCR. On basis of intermediates, two distinct seco-iridoid pathways are involved in the biosynthesis of monoterpene indole alkaloids either through multiple isomers of strictosidinic acid or strictosidine. Tissue-specific LC-MS/MS analysis revealed the presence of secologanin as the central intermediate of MIA pathway in N. nimmoniana. Geraniol 10 hydroxylase (NnCYP76B6) an important enzyme in CPT biosynthesis which specifically shunts geraniol into the secologanin pathway was also cloned from the trancriptome resource. In planta transient expression of NnCYP76B6 showed a significant enhancement in mRNA transcript levels coincident with enhanced CPT accumulation. Further, artificial microRNA (aMIR) mediated downregulation of NnCYP76B6 resulted in reduction of mRNA transcript levels as well as CPT content in comparison to control. These empirical results suggest a plausible regulatory role for NnCYP76B6 in CPT biosynthesis and also establish a valuable repository for deciphering various structural, rate limiting and regulatory genes of CPT biosynthetic pathway. PMID- 29270894 TI - In-column immobilization of Cs-saturated crystalline silicotitanates using phenolic resins. AB - The in situ immobilization of granulated Cs-saturated crystalline silicotitanates (Cs-CST) in fixed-bed columns has been investigated using commercially available phenol formaldehyde (PF) resin as a binding agent. Two types of PF resin were investigated as part of this study both being prepared from resol polymer having a formaldehyde:phenol ratio of 3:1. However, one of the resol polymers had water as the primary solvent and the other ethanol. Both resol polymers were observed to completely infiltrate the space between the Cs-CST beads and also the pores within the beads themselves. PF resin monoliths prepared after curing the water based resol at 180 degrees C were considerably less porous than the ethanol based counterparts cured under the same conditions. The enhanced macroporosity of the resin prepared from the ethanol-based resol was presumably the result from enhanced gas bubble generation. Little or no micro- or mesoporosity was measured using nitrogen porosimetry. For both resins cured at 180 degrees C, intimate contacts with the Cs-CST beads were observed that were not modified even after complete immersion in water over long time frames. Little or no migration of Cs from Cs-CST to the resin binder was observed. The compressive strength of the Cs CST-PF resin monoliths was measured and benchmarked against cement monoliths and was found to be two to three times higher than cement in the case of the water based resin. Leaching of the monoliths was conducted in demineralized water at 90 degrees C. Normalized Cs mass losses of the order of 1.0 g/m2 were measured after 30 days for the ethanol-based resin monoliths. For the less porous water based monoliths, the normalized mass loss was one order of magnitude lower. The leaching of monoliths irradiated with a 2-MGy dose of gamma radiation showed no difference in Cs mass loss suggesting that the ability to retain Cs of either the CST or PF resin was not affected. PF resins are capable of acting as a mechanically robust, radiation-resistant, and impermeable active secondary barrier reducing the likelihood of Cs entry into the biosphere. PMID- 29270896 TI - Treatment of artificial wastewater containing two azo textile dyes by vertical flow constructed wetlands. AB - The release of untreated dye textile wastewater into receiving streams is unacceptable not only for aesthetic reasons and its negative impacts on aquatic life but also because numerous dyes are toxic and carcinogenic to humans. Strategies, as of now, used for treating textile wastewaters have technical and economical restrictions. The greater part of the physico-chemical methods, which are used to treat this kind of wastewater, are costly, produce large amounts of sludge and are wasteful concerning some soluble dyes. In contrast, biological treatments such as constructed wetlands are cheaper than the traditional methods, environmental friendly and do not produce large amounts of sludge. Synthetic wastewater containing Acid Blue 113 (AB113) and Basic Red 46 (BR46) has been added to laboratory-scale vertical-flow construction wetland systems, which have been planted with Phragmites australis (Cav.) Trin. ex Steud. (common reed). The concentrations 7 and 208 mg/l were applied for each dye at the hydraulic contact times of 48 and 96 h. Concerning the low concentrations of BR46 and AB113, the unplanted wetlands are associated with significant (rho < 0.05) reduction performances, if compared with planted wetlands concerning the removal of dyes. For the high concentrations of AB113, BR46 and a mixture of both of them, wetlands with long contact times were significantly (rho < 0.05) better than wetlands that had short contact times in terms of dye, colour and chemical oxygen demand reductions. Regarding nitrate nitrogen (NO3-N), the reduction percentage rates of AB113, BR46 and a mixture dye of both of them were between 85 and 100%. For low and high inflow dye concentrations, best removals were generally recorded for spring and summer, respectively. PMID- 29270895 TI - Numerical simulation of pollutant transport in soils surrounding subway infrastructure. AB - With continued urbanization, public transport infrastructure, e.g., subways, is expected to be built in historically industrial areas. To minimize the transfer of volatile organic compounds and metalloids like arsenic from industrial areas into subway environments and reduce their impact on public health, the transport of pollutants in soil was simulated in this study. During numerical simulations of a contaminated site, the pollutant (arsenic) was transported from layers of higher to lower concentration, and concentration changes were particularly evident in the early simulation stages. The pollutant was transported in soil along the direction of groundwater flow and spread from the center to the periphery of the contaminated zone without inputs from pollution sources. After approximately 400 days, the concentration of all layers became uniform, with slow decreases occurring over time. The pollutant supply rate had a major influence on the pollutant diffusion distance. When other conditions were kept constant, higher supply rates resulted in longer diffusion distances. The simulation results show that a diaphragm wall of a certain depth can effectively control the diffusion of pollutants in soil. These results can be used to improve environmental assessments and remediation efforts and inform engineering decisions during the construction of urban infrastructure at sites affected by historical pollution. PMID- 29270897 TI - Influence of photolabile pharmaceuticals on the photodegradation and toxicity of fluoxetine and fluvoxamine. AB - Pharmaceuticals in the aquatic environment may be decomposed by abiotic and biotic factors. Photodegradation is the most investigated abiotic process, as it occurs in the natural environment and may be applied in wastewater treatment technology. Although pharmaceuticals are detected in effluents and surface water in a mixture, the photodegradation process is mainly evaluated with single compounds. The photodegradation of fluoxetine (FLU) and fluvoxamine (FLX) in the presence of diclofenac (DCF) and triclosan (TCS) was investigated with HPLC and bioassay. FLU did not degrade under UV-Vis irradiation in SunTest CPS+ either with or without the tested additives, although small amounts of desmethyl fluoxetine and 4-(trifluoromethyl)phenol were formed. In contrast, during irradiation, FLX isomerized to cis-FLX. This process was enhanced by DCF and TCS, but to a lesser degree than by humic acids. Thus, the presence and composition of the matrix should be considered in the environmental risk assessment of pharmaceuticals. As the toxicity of the tested solutions depended only on the concentration of the tested drugs, it was suggested that the biological activity of the photodegradation products was lower than that of the parent compounds. PMID- 29270899 TI - Environmental assessment in health care organizations. AB - The aim of this research is to design a multi-criteria model for environmental assessment of health care organizations. This is a model which guarantees the objectivity of the results obtained, is easy to apply, and incorporates a series of criteria, and their corresponding descriptors, relevant to the internal environmental auditing processes of the hospital. Furthermore, judgments were given by three experts from the areas of health, the environment, and multi criteria decision techniques. From the values assigned, geometric means were calculated, giving weightings for the criteria of the model. This innovative model is intended for application within a continuous improvement process. A practical case from a Spanish hospital is included at the end. Information contained in the sustainability report provided the data needed to apply the model. The example contains all the criteria previously defined in the model. The results obtained show that the best-satisfied criteria are those related to energy consumption, generation of hazardous waste, legal matters, environmental sensitivity of staff, patients and others, and the environmental management of suppliers. On the other hand, those areas returning poor results are control of atmospheric emissions, increase in consumption of renewable energies, and the logistics of waste produced. It is recommended that steps be taken to correct these deficiencies, thus leading to an acceptable increase in the sustainability of the hospital. PMID- 29270898 TI - Characterization and 2D structural model of corn straw and poplar leaf biochars. AB - The integrated experimental methods were used to analyze the physicochemical properties and structural characteristics and to build the 2D structural model of two kinds of biochars. Corn straw and poplar leaf biochars were gained by pyrolysing the raw materials slowly in a furnace at 300, 500, and 700 degrees C under oxygen-deficient conditions. Scanning electron microscope was applied to observe the surface morphology of the biochars. High temperatures destroyed the pore structures of the biochars, forming a particle mixture of varying sizes. The ash content, yield, pH, and surface area were also observed to describe the biochars' properties. The yield decreases as the pyrolysis temperature increases. The biochars are neutral to alkaline. The biggest surface area is 251.11 m2/g for 700 degrees C corn straw biochar. Elemental analysis, infrared microspectroscopy, solid-state C-13 NMR spectroscopy, and pyrolysis gas chromatography-mass spectrometry (Py-GC-MS) were also used to study the structural characteristics and build the 2D structural models of biochars. The C content in the corn straw and poplar leaf biochars increases with the increase of the pyrolysis temperature. A higher pyrolysis temperature makes the aryl carbon increase, and C=O, OH, and aliphatic hydrocarbon content decrease in the IR spectra. Solid-state C-13 NMR spectra show that a higher pyrolysis temperature makes the alkyl carbon and alkoxy carbon decrease and the aryl carbon increase. The results of IR microspectra and solid-state C-13 NMR spectra reveal that some noticeable differences exist in these two kinds of biochars and in the same type of biochar but under different pyrolysis temperatures. The conceptual elemental compositions of 500 degrees C corn straw and poplar leaf biochars are C61H33NO13 and C59H41N3O12, respectively. Significant differences exist in the SEM images, physicochemical properties, and structural characteristics of corn straw and poplar leaf biochars. PMID- 29270900 TI - Facing to real sustainability-conservation agriculturalpractices around the world. PMID- 29270901 TI - POLSOIL: research on soil pollution in China. PMID- 29270902 TI - Periodontitis, tooth loss and cognitive functions among older adults. AB - OBJECTIVE: This study aims to evaluate the potential association between periodontitis, the number of teeth and cognitive functions in a cohort of older adults in Sweden. MATERIAL AND METHODS: In total, 775 individuals from 60 to 99 years of age were selected for the study. A clinical and radiographic examination was performed. The number of teeth and prevalence of periodontal pockets and bone loss was calculated and categorised. Cognitive functions were assessed using the Mini-Mental State Examination (MMSE) and clock test. The education level was obtained from a questionnaire. Data were analysed using chi-square tests and multivariate logistic regression. RESULTS: Age and gender were associated with the prevalence of bone loss. Age and education were associated with lower number of teeth. Gender was also associated with the presence of pockets. The multivariate logistic regression analysis demonstrated a statistically significant association between prevalence of bone loss, the number of teeth and the outcome on MMSE test. This association remained even after adjustment for age, education and gender. Tooth loss was also associated with lower outcome on clock test. Presence of periodontal pockets >= 5 mm was not associated with cognitive test outcome. CONCLUSIONS: A history of periodontitis and tooth loss may be of importance for cognitive functions among older adults. CLINICAL RELEVANCE: Diseases with and inflammatory profile may have an impact on cognitive decline. PMID- 29270903 TI - Acute exhaustive rowing exercise reduces skin microvascular dilator function in young adult rowing athletes. AB - PURPOSE: The effect of acute exhaustive exercise session on skin microvascular reactivity was assessed in professional rowers and sedentary subjects. A potential involvement of altered hemodynamic parameters and/or oxidative stress level in the regulation of skin microvascular blood flow by acute exercise were determined. METHODS: Anthropometric, biochemical, and hemodynamic parameters were measured in 18 young healthy sedentary men and 20 professional rowers who underwent a single acute exercise session. Post-occlusive reactive hyperemia (PORH), endothelium-dependent acetylcholine (ACh), and endothelium-independent sodium nitroprusside (SNP) microvascular responses were assessed by laser Doppler flowmetry in skin microcirculation before and after acute exercise. Serum lipid peroxidation products and plasma antioxidant capacity were measured using spectrophotometry. RESULTS: At baseline, rowers had significantly lower diastolic blood pressure (DBP) and heart rate (HR), and higher stroke volume (SV), PORH, and endothelium-dependent vasodilation than sedentary. Acute exercise caused a significant increase in systolic blood pressure, DBP, HR, and SV and a decrease in total peripheral resistance in both groups. Acute exercise induced a significant impairment in PORH and ACh-induced response in rowers, but not in sedentary, whereas the SNP-induced vasodilation was not affected by acute exercise in any group. Antioxidant capacity significantly increased only in sedentary after acute exercise. CONCLUSION: Single acute exercise session impaired microvascular reactivity and endothelial function in rowers but not in sedentary, possibly due to (1) more rowing grades and higher exercise intensity achieved by rowers; (2) a higher increase in arterial pressure in rowers than in sedentary men; and (3) a lower antioxidant capacity in rowers. PMID- 29270904 TI - Cardiac magnetic resonance T1 and extracellular volume mapping with motion correction and co-registration based on fast elastic image registration. AB - OBJECTIVE: Our aim was to investigate the technical feasibility of a novel motion compensation method for cardiac magntic resonance (MR) T1 and extracellular volume fraction (ECV) mapping. MATERIALS AND METHODS: Native and post-contrast T1 maps were obtained using modified look-locker inversion recovery (MOLLI) pulse sequences with acquisition scheme defined in seconds. A nonrigid, nonparametric, fast elastic registration method was applied to generate motion-corrected T1 maps and subsequently ECV maps. Qualitative rating was performed based on T1 fitting error maps and overlay images. Local deformation vector fields were produced for quantitative assessment. Intra- and inter-observer reproducibility were compared with and without motion compensation. RESULTS: Eighty-two T1 and 39 ECV maps were obtained in 21 patients with diverse myocardial diseases. Approximately 60% demonstrated clear quality improvement after motion correction for T1 mapping, particularly for the poor-rating cases (23% before vs 2% after). Approximately 67% showed further improvement with co-registration in ECV mapping. Although T1 and ECV values were not clinically significantly different before and after motion compensation, there was improved intra- and inter-observer reproducibility after motion compensation. CONCLUSIONS: Automated motion correction and co registration improved the qualitative assessment and reproducibility of cardiac MR T1 and ECV measurements, allowing for more reliable ECV mapping. PMID- 29270906 TI - Possible options to slow down the advancement rate of Tarbela delta. AB - The pivot point of delta in Tarbela dam has reached at about 10.6 km from the dam face which may result in blocking of tunnels. Tarbela delta was modeled from 1979 to 2060 using hec-6 model. Initially, the model was calibrated for year 1999 and validated for years 2000, 2001, 2002, and 2006 by involving the data of sediment concentration, reservoir cross sections (73 range lines), elevation-area capacity curves, and inflows and outflows from the reservoir. Then, the model was used to generate future scenarios, i.e., run-1, run-2, and run-3 with pool levels; 428, 442, and 457 m, respectively, till 2060. Results of run-1 and run-2 showed advancement to choke the tunnels by 2010 and 2030, respectively. Finally, in run 3, the advancement was further delayed showing that tunnels 1 and 2 will be choked by year 2050 and pivot point will reach at 6.4 km from the dam face. PMID- 29270907 TI - Evaluation of days of total collection and use of internal markers in nutritional trials with small ruminants. AB - Two experiments were conducted to evaluate the number of days required for total fecal collection and the viability of using the indigestible dry matter (iDM), indigestible neutral detergent fiber (iNDF), and indigestible acid detergent fiber (iADF) internal markers to determine the fecal excretion of dry matter (FEDM) and digestibility in nutritional trials with small ruminants. Eight sheep in the first experiment and eight goats in the second experiment were distributed into two 4 * 4 Latin square designs. There were no significant differences between days of total fecal collection for FEDM; digestibility of dry matter (DM), organic matter (OM), crude protein (CP), ether extract (EE), neutral detergent fiber corrected for ash and protein (NDFap), and non-fibrous carbohydrates corrected for ash and protein (NFCap); and total digestible nutrients (TDN) in both species. The results suggest that only 1 day of total collection is sufficient to obtain the FEDM and the digestibility of the nutritional components in sheep and goats. The markers are efficient in determining fecal production and digestibility in these animal species. PMID- 29270908 TI - Stapleless Laparoscopic Sleeve Gastrectomy: Reasoning and Technical Insights. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) with staple line reinforcement (SLR) is a popular and safe treatment option for morbid obesity. We have developed, devised, and described our own method of stapleless laparoscopic sleeve gastrectomy, which in our limited study appeared safe, efficacious, and potentially cost-effective. METHODS: We analyzed the outcome of our modified LSG in a case series of three middle-aged women (median age 42 years old). Our main modification was sutured closure of the stomach rather than the commonly utilized technique of stapled closure. Our primary measure of success was the occurrence of post-operative leak. Secondary measures were (a) length of operation, (b) duration of inpatient stay, and (c) percentage of weight loss at 6 and 12 months post operation. RESULTS: Median operative time = 132 min (120-195 min), and median inpatient stays were 2 days. No post-operative leaks were recorded. The median excess weight loss at 6 months was 39% of initial weight loss and 57.7% at 12 months. CONCLUSIONS: Stapleless LSG has the potential to be an affordable alternative to the traditional LSG. High-powered studies and a formal cost analysis are required. PMID- 29270909 TI - Sequential testing with different tissue transglutaminase antibodies, a new approach for diagnosis of celiac disease. AB - BACKGROUND: The diagnosis of celiac disease (CeD) in clinical practice relies on serological testing for IgA antibodies to human tissue transglutaminase (anti tTG) which diagnose CeD autoimmunity. We compared three kits for their performance in diagnosis of the disease and evaluated the point prevalence of CeD autoimmunity in a South Indian urban population. METHODS: In the first part of the study, sera from 90 patients with documented CeD and 92 healthy controls were tested for anti-tTG using three different kits. One thousand nine hundred and seventeen healthy adults residing in urban areas of Vellore and Kancheepuram districts were tested for CeD autoimmunity using a sequential two-test strategy. RESULTS: The sensitivity, specificity, false positivity, false negativity, positive predictive value, and negative predictive value for the three assays respectively were as follows: 95.5%, 82.6%, 17.3%, 4.4%, 84.3%, and 95% for the Aeskulisa New Generation Assay; 85.5%, 100%, 0%, 14.4%, 100%, and 87.6% for Quanta Lite; and 71.1%, 100%, 0%, 28.8%, 100%, and 71% for Celiac Microlisa. The ROC curves showed good discrimination for all three ELISAs with an AUC of 0.947, 0.950, and 0.886 for the Aeskulisa, Quanta Lite, and Celiac Microlisa, respectively. Of 1917 (males 908, females 1009) healthy adults, 113 (5.89%) were seropositive for IgA anti-htTG in the Aeskulisa test. Two of the latter tested positive in the Quanta Lite assay and/or the Celiac Microlisa assay. The CeD autoimmunity prevalence in this urban population was 1.0 per thousand (95% confidence interval 0.3 to 3.7 per thousand). CONCLUSION: Sequential testing for anti-tTG using first a highly sensitive assay followed by a very specific assay is a new strategy for screening for CeD in clinical practice. PMID- 29270910 TI - Cell cycle in egg cell and its progression during zygotic development in rice. AB - KEY MESSAGE: Rice egg is arrested at G1 phase probably by OsKRP2. After fusion with sperm, karyogamy, OsWEE1-mediated parental DNA integrity in zygote nucleus, zygote progresses cell cycle to produce two-celled embryo. In angiosperms, female and male gametes exist in gametophytes after the complementation of meiosis and the progression of nuclear/cell division of the haploid cell. Within the embryo sac, the egg cell is specially differentiated for fertilization and subsequent embryogenesis, and cellular programs for embryonic development, such as restarting the cell cycle and de novo gene expression, are halted. There is only limited knowledge about how the cell cycle in egg cells restarts toward zygotic division, although the conversion of the cell cycle from a quiescent and arrested state to an active state is the most evident transition of cell status from egg cell to zygote. This is partly due to the difficulty in direct access and analysis of egg cells, zygotes and early embryos, which are deeply embedded in ovaries. In this study, precise relative DNA amounts in the nuclei of egg cells, developing zygotes and cells of early embryos were measured, and the cell cycle of a rice egg cell was estimated as the G1 phase with a 1C DNA level. In addition, increases in DNA content in zygote nuclei via karyogamy and DNA replication were also detectable according to progression of the cell cycle. In addition, expression profiles for cell cycle-related genes in egg cells and zygotes were also addressed, and it was suggested that OsKRP2 and OsWEE1 function in the inhibition of cell cycle progression in egg cells and in checkpoint of parental DNA integrity in zygote nucleus, respectively. PMID- 29270912 TI - Surface ultrastructural (SEM) characteristics of oropharyngeal cavity of house sparrow (Passer domesticus). AB - The focus of the present study is to provide a full morphological description of the oropharyngeal cavity of the house sparrow. The head of six birds was prepared for gross examination and by stereo and electron microscopy. The bifid lingual apex has multiple long, rostrally directed needle-like processes. The lateral border of the apex carries rostromedially directed needle-like processes. The dorsal lingual surface of the apex and body carries numerous caudomedially directed filiform papillae and many orifices of lingual salivary glands. The lingual body is divided into two parts: rostral and caudal. The caudal part is divided into two laterally elevated regions by a median groove, while the rostral part is bounded laterally by a rostrodorsally directed papillary row, which on SEM is formed from two rows. On SEM, the lingual root has many orifices of posterior salivary glands. The pharyngeal papillary row is located at the caudal border of the laryngeal mound, but this single papillary row is formed from two rows at SEM magnification. The laryngeal cleft continues caudally as a laryngeal fissure bounded by two longitudinal rows of caudally directed papillae; at high SEM magnification, this fissure is divided into two halves by a median ridge which carries caudally directed papillae on its posterior part. The choanal cleft proceeds rostrally by the median tubercle. There are a small number of orifices of palatine salivary glands. The morphological characters of the oropharyngeal cavity of the sparrow confirm its adaptation to surrounding environmental conditions and available food particles. PMID- 29270911 TI - A network-based meta-analysis for characterizing the genetic landscape of human aging. AB - Great amounts of omics data are generated in aging research, but their diverse and partly complementary nature requires integrative analysis approaches for investigating aging processes and connections to age-related diseases. To establish a broader picture of the genetic and epigenetic landscape of human aging we performed a large-scale meta-analysis of 6600 human genes by combining 35 datasets that cover aging hallmarks, longevity, changes in DNA methylation and gene expression, and different age-related diseases. To identify biological relationships between aging-associated genes we incorporated them into a protein interaction network and characterized their network neighborhoods. In particular, we computed a comprehensive landscape of more than 1000 human aging clusters, network regions where genes are highly connected and where gene products commonly participate in similar processes. In addition to clusters that capture known aging processes such as nutrient-sensing and mTOR signaling, we present a number of clusters with a putative functional role in linking different aging processes as promising candidates for follow-up studies. To enable their detailed exploration, all datasets and aging clusters are made freely available via an interactive website ( https://gemex.eurac.edu/bioinf/age/ ). PMID- 29270913 TI - Fulvestrant: A Review in Advanced Breast Cancer Not Previously Treated with Endocrine Therapy. AB - Fulvestrant (Faslodex(r)), a selective estrogen receptor (ER) degrader, is now indicated for the treatment of ER+ or hormone-receptor positive (HR+)/HER2- advanced breast cancer in postmenopausal women previously untreated with endocrine therapy. In the phase 3 FALCON trial conducted in this setting, intramuscular fulvestrant 500 mg/month (plus an additional dose at 2 weeks) was significantly more effective in prolonging progression-free survival (PFS) than oral anastrozole 1 mg/day (particularly in patients with non-visceral disease), with this benefit seemingly driven by fulvestrant recipients responding significantly longer to treatment. Other efficacy measures, including objective response rate, did not significantly or markedly differ between the two regimens and median overall survival was not yet calculable. Fulvestrant was generally well tolerated in this trial, displaying an overall tolerability profile consistent with its known tolerability in other breast cancer settings. Thus, monotherapy with intramuscular fulvestrant is a generally well tolerated and more effective treatment option than standard-of-care anastrozole for ER+ or HR+/HER2- advanced breast cancer in postmenopausal women not previously treated with endocrine therapy. PMID- 29270914 TI - A randomized comparison between interscalene and combined infraclavicular suprascapular blocks for arthroscopic shoulder surgery. AB - BACKGROUND: This randomized trial aimed to evaluate combined infraclavicular suprascapular blocks (ICB-SSBs) as a diaphragm-sparing alternative to interscalene blocks (ISBs) for arthroscopic shoulder surgery. We hypothesized that ICB-SSB would provide equivalent postoperative analgesia to ISB 30 min after surgery without the risk of hemidiaphragmatic paralysis. METHODS: Following research ethics board approval and written informed consent, participants in the ISB group received an ultrasound-guided ISB with 20 mL of levobupivacaine 0.25% and epinephrine 5 ug.mL-1. In the ICB-SSB group, ultrasound-guided ICB (20 mL) and SSB (10 mL) were carried out using the same local anesthetic. Thirty minutes after the block was performed, a blinded investigator assessed the presence of hemidiaphragmatic paralysis. Subsequently, all patients underwent general anesthesia. Postoperatively, a blinded investigator recorded pain scores at rest at 0.5, 1, 2, 3, 6, 12 and 24 hr. Consumption of intra- and postoperative narcotics was also tabulated. RESULTS: Compared to its ICB-SSB counterpart, the ISB group displayed non-equivalent (i.e., lower) postoperative pain scores at 30 min (difference of the medians, -4; 99% confidence interval [CI], -6 to -3), required less cumulative morphine iv at 24 hr (difference of the means, -6.1 mg; 95% CI, -10.5 to -1.6), and resulted in a higher incidence of hemidiaphragmatic paralysis (18/20 vs 0/20 patients, respectively; P < 0.001). Although postoperative pain scores at one, two, and three hours appeared lower in the ISB group, the upper bounds of the 99% CIs did not exceed the equivalence margin. CONCLUSION: Compared with ICB-SSB, ISB provided non-equivalent (i.e., lower) postoperative pain scores 30 min after arthroscopic shoulder surgery. Thereafter, postoperative analgesia was comparable between the two groups. Further trials are required to compare ISB with ICB-SSB using a proximal (i.e., costoclavicular) technique for ICB. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT02993939. Registered 12 December 2016. PMID- 29270915 TI - Review of the enhanced recovery pathway for children: perioperative anesthetic considerations. AB - PURPOSE: Enhanced recovery after surgery (ERAS) pathways have been used for two decades to improve perioperative recovery in adults. Nevertheless, little is known about their effectiveness in children. The purpose of this review was to consider pediatric ERAS pathways, review the literature concerned with their potential benefit, and compare them with adult ERAS pathways. SOURCE: A PubMed literature search was performed for articles that included the terms enhanced recovery and/or fast track in the pediatric perioperative period. Pediatric patients included those from the neonatal period through teenagers and/or youths. PRINCIPAL FINDINGS: The literature search revealed a paucity of articles about pediatric ERAS. This lack of academic investigation is likely due in part to the delayed acceptance of ERAS in the pediatric surgical arena. Several pediatric studies examined individual components of adult-based ERAS pathways, but the overall study of a comprehensive multidisciplinary ERAS protocol in pediatric patients is lacking. CONCLUSION: Although adult ERAS pathways have been successful at reducing patient morbidity, the translation, creation, and utility of instituting pediatric ERAS pathways have yet to be realized. PMID- 29270917 TI - Correction to: Sexual Minority Stress, Coping, and Physical Health Indicators. AB - The original version of this article unfortunately contains a mistake. In page 229, first paragraph, line 5, the value 0.353 should read as 0.347. In page 230, first paragraph, line 10, the value 0.121 should read as - 0.121. PMID- 29270905 TI - The Oxygen Paradox, the French Paradox, and age-related diseases. AB - A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and pate) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428 1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance, "healthspan," "lifespan," and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as "Adaptive Homeostasis" (Davies Mol Asp Med 49:1-7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573-2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself. PMID- 29270916 TI - MRI radiomics analysis of molecular alterations in low-grade gliomas. AB - PURPOSE: Low-grade gliomas (LGG) are classified into three distinct groups based on their IDH1 mutation and 1p/19q codeletion status, each of which is associated with a different clinical expression. The genomic sub-classification of LGG requires tumor sampling via neurosurgical procedures. The aim of this study was to evaluate the radiomics approach for noninvasive classification of patients with LGG and IDH mutation, based on their 1p/19q codeletion status, by testing different classifiers and assessing the contribution of the different MR contrasts. METHODS: Preoperative MRI scans of 47 patients diagnosed with LGG with IDH1-mutated tumors and a genetic analysis for 1p/19q deletion status were included in this study. A total of 152 features, including size, location and texture, were extracted from fluid-attenuated inversion recovery images, [Formula: see text]-weighted images (WI) and post-contrast [Formula: see text]. Classification was performed using 17 machine learning classifiers. Results were evaluated by a fivefold cross-validation analysis. RESULTS: Radiomic analysis differentiated tumors with 1p/19q intact ([Formula: see text]; astrocytomas) from those with 1p/19q codeleted ([Formula: see text]; oligodendrogliomas). Best classification was obtained using the Ensemble Bagged Trees classifier, with sensitivity [Formula: see text] 92%, specificity [Formula: see text] 83% and accuracy [Formula: see text] 87%, and with area under the curve [Formula: see text] 0.87. Tumors with 1p/19q intact were larger than those with 1p/19q codeleted ([Formula: see text] vs. [Formula: see text] cc, respectively; [Formula: see text]) and predominantly located to the left insula ([Formula: see text]). CONCLUSION: The proposed method yielded good discrimination between LGG with and without 1p/19q codeletion. Results from this study demonstrate the great potential of this method to aid decision-making in the clinical management of patients with LGG. PMID- 29270918 TI - Metabolomic Estimation of the Diagnosis and Onset Time of Permanent and Transient Cerebral Ischemia. AB - Determining the time of stroke onset in order to apply recanalization therapies within the accepted therapeutic window and the correct diagnosis of transient ischemic attack (TIA) are two common clinical problems in acute cerebral ischemia management. Therefore, biomarkers helping in this conundrum could be very helpful. We developed mouse models of distal middle cerebral artery occlusion mimicking TIA and ischemic stroke (IS), respectively. Plasma samples were analyzed by metabolomics at 6, 12, 24, and 48 h post onset in order to find TIA- and time-related stroke biomarkers. The results were validated in a second experimental cohort. Plasma metabolomic profiles identified time after stroke events with a very high accuracy. Specific metabolites pointing to a recent event (< 6 h) were identified. A multivariate (partial least square discriminant analyses [PLS-DA]) model was also able to separate samples from TIA, IS, and sham events with high accuracy and to obtain specific metabolites for each time point. The combination of mice models of focal ischemia with plasma metabolomics allows the discovery of candidate biomarkers for the diagnosis and estimation of onset time of stroke and TIA diagnosis. PMID- 29270920 TI - Erratum to: Bisulfite Sequencing Using Small DNA Amounts. PMID- 29270921 TI - [Visual diagnosis perineal groove]. PMID- 29270919 TI - Trichloroethylene and Parkinson's Disease: Risk Assessment. AB - This study was conducted to investigate the mechanism of action and extent of selective dopaminergic neurodegeneration caused by exposure to trichloroethylene (TCE) leading to the endogenous formation of the neurotoxin 1-trichloromethyl 1,2,3,4-tetrahydro-beta-carboline (TaClo) in rodents. Beginning at 3 months of age, male C57BL/6 mice received oral TCE dissolved in vehicle for 8 months. Dopaminergic neuronal loss was assessed by nigral tyrosine hydroxylase (TH) immunoreactivity. Selective dopaminergic neurodegeneration was determined based on histological analysis of non-dopaminergic neurons in the brain. Behavioral assays were evaluated using open field activity and rotarod tests. Mitochondrial complex I activity, oxidative stress markers, and microglial activation were also examined in the substantia nigra. The level of TaClo was detected using HPLC electrospray ionization tandem mass spectrometry. Dopaminergic neurotoxicity of TaClo was determined in midbrain organotypic cultures from rat pups. Following 8 months of TCE treatment, there was a progressive and selective loss of 50% of the dopaminergic neurons in mouse substantia nigra (SN) and about 50% loss of dopamine and 72% loss of 3,4-dihydroxyphenylacetic acid in the striatum, respectively. In addition, motor deficits, mitochondrial impairment, oxidative stress, and inflammation were measured. TaClo content was quantified in the brain after TCE treatment. In organotypic cultures, TaClo rather than TCE induced dopaminergic neuronal loss, similar to MPP+. TCE exposure may stimulate the endogenous formation of TaClo, which is responsible for dopaminergic neurodegeneration. However, even prolonged administration of TCE was insufficient for producing a greater than 50% loss of nigral dopamine neurons, indicating that additional co-morbid factors would be needed for mimicking the profound loss of dopamine neurons seen in Parkinson's disease. PMID- 29270922 TI - Giant symptomatic rectal lipoma resected by endoscopic submucosal dissection. PMID- 29270923 TI - Expression and Significance of MMPs in Synovial Fluid, Serum and PBMC Culture Supernatant Stimulated by LPS in Osteoarthritis Patients With or Without Diabetes. AB - OBJECTIVE: Patients with Type 2 Diabetes mellitus (T2DM) are prone to osteoarthritis (OA). Matrix metalloproteinases (MMPs), an essential modulator in cartilage matrix homeostasis, increase in T2DM and OA. We aimed to ascertain the expression difference of MMPs and function in mononuclear cells after stimulating by lipopolysaccharide (LPS) in OA patients with or without diabetes. METHODS: 30 knee OA patients without T2DM (OA group), 20 knee OA patients with T2DM (DM-OA group) and 5 healthy volunteers recruited as control were enrolled from January 2016 to January 2017. The expression levels of MMPs in both serum and synovial fluid were initially detected in three groups by enzyme-linked immunosorbent assay (ELISA). After stimulation of peripheral blood mononuclear cell (PBMC) with LPS, the release of MMPs were determined and evaluated. RESULTS: The expression of MMP-1, -7, -8, -9, -10 and -12 in synovial fluid in DM-OA group were significantly higher than in OA group and healthy control. The expression of MMP 1 and -7 in serum were highest in DM-OA group. LPS significantly promotes the production of MMP-1, -8, -9 and -10 in PBMC of each group after 4 h stimulation. It is worth to note that the LPS-stimulated MMP-8 and -9 elevations were more prominent in DM-OA group compared with their counterparts. CONCLUSION: High levels of MMP-1, -7, -8, -9, -10, and -12 in the synovial fluid might be one of important reasons that diabetes patients are more frequently suffered from OA. Inflammation-induced malfunction of mononuclear cells would stimulate MMP-8 and 9 secretion to various extents. PMID- 29270924 TI - Serum 1,5-Anhydroglucitol Concentrations Remain Valid as a Glycemic Control Marker In Diabetes with Earlier Chronic Kidney Disease Stages. AB - PURPOSE: To investigate the reliability of 1,5-anhydroglucitol (1,5-AG) in diabetes with mild or moderate renal dysfunction. METHODS: 668 patients diagnosed with diabetes as DM group and 336 healthy controls as non-DM group were enrolled in this study. DM group was divided into four groups according to estimated glomerular filtration rate (eGFR). Serum concentrations of 1,5-AG, fructosamine (FMN) and glycated hemoglobin (HbA1c) were assayed via the enzymatic method, the nitro reduction four nitrogen thiazole blue test,high performance liquid chromatography respectively. RESULTS: In diabetic Patients with eGFR>=30 mL/min, significant negative association still existed between logarithmic transformed 1,5-AG values (ln1,5-AG) and HbA1c (all P<0.001) as well as fasting plasma glucose (FPG) (all P<0.05). Besides, eGFR was not one of the determinants of 1,5 AG levels in both DM group (standard beta=-0.049, P=0.383 ) and healthy controls (r=-0.095, P=0.084 ). Stepwise multiple linear regression showed that serum uric acid (UA) is one of the influencing factors of 1,5-AG (standard beta=0.119, P=0.015) and among the three glycemic markers, only HbA1c was found to be correlated with the homeostasis model assessment for b-cell function (HOMA-beta) (standard beta=0.097, P=0.012). CONCLUSIONS: 1,5-AG values remain reliable as a glycemic control marker In diabetes with mild or moderate dysfunction. Serum UA was significantly and positively correlated with 1,5-AG levels. HbA1c may be a good biomarker for insulin resistance compared with 1,5-AG and FMN. PMID- 29270925 TI - Sagittal Abdominal Diameter does not Predict Metabolic Traits Better than Waist Circumference-Related Measures of Abdominal Obesity in Obese Subjects. AB - BACKGROUND: Recently, we showed that in subjects with a body mass index (BMI) >35 kg/m2 waist circumference (WC) is associated with metabolic traits but associations were weaker in men than in women. AIMS: To confirm our previous observation that anthropometric measures of abdominal obesity are closer linked to metabolic traits in obese women than obese men. To test whether sagittal abdominal diameter (SAD) provides a better prediction of metabolic traits in obese subjects than WC related measures. METHODS: SAD and WC along with metabolic traits were assessed in 204 women and 69 men (BMI 30.1-64.0 kg/m2). RESULTS: In women, abdominal obesity measures were associated with glycated hemoglobin levels (HbA1c), fasting serum glucose, insulin, triglycerides (TG), total cholesterol (Chol), high-density lipoprotein (HDL), and uric acid levels as well as Chol/HDL ratio and homeostatic model assessment of insulin resistance (HOMA-IR) independently of age and BMI. SAD predicted serum insulin and Chol better than WC, whereas WC was superior to SAD in predicting HbA1c, glucose, HOMA-IR, TG, HDL, Chol/HDL, and uric acid. Of note, the combination of SAD and WC provided a better prediction of insulin, HOMA-IR, TG, and uric acid than each of these anthropometric alone. In men, only fasting glucose, Chol, and uric acid levels were associated with abdominal obesity markers. CONCLUSION: Data show various associations between anthropometric measures of abdominal obesity and metabolic traits in obese women but overall much less in obese men. Most metabolic traits are better predicted by WC than by SAD. PMID- 29270926 TI - Surgical Therapy for Idiopathic Pigmented Intravitreal Cyst. PMID- 29270927 TI - [Isolated Unilateral Strabismus Sursoadductorius (Congenital Trochlear Palsy) with and without Hypotrophia of the Superior Oblique Muscle-Orthoptic Differences in Adulthood]. AB - PURPOSE: The clinical feature of unilateral decompensating strabismus sursoadductorius (dSSA; often called congenital superior oblique palsy, CSOP) is not an etiologically uniform entity. Hypotrophy of the superior oblique muscle (HMOS) is a frequent and immediate cause of dSSA/CSOP. In this study, clinical characteristics of dSSA/CSOP with and without HMOS are compared. PATIENTS AND METHODS: Twenty-five consecutive patients (age 14 - 69 years; median 43 years) were included in this study, 14 with 3T MRI-proven HMOS (group 1) and 11 without HMOS (group 2). HMOS was defined as a reduction of the medio-lateral (ML) as well as based on ML and cranio-caudal (CC) diameter calculated area = (ML . CC/4) . pi of the affected superior oblique muscle (SOM) < 80% in comparison to the contralateral SOM (measured on the single coronal image on which the muscle has its greatest extent). The two groups were compared in terms of head tilt, cyclo- and vertical deviation and the Bielschowsky head tilt test. Patients were classified according the Knapp's classification. RESULTS: Both the incidence of head tilt with 14/14 vs. 5/11 (chi2 = 0.003) and its degree: 11.1 +/- 4.5 degrees vs. 3.2 +/- 4.1 degrees (p < 0.001) was higher in group 1 than in group 2, as well as the Bielschowsky head tilt test: 9.3 +/- 4.3 degrees vs. 3.8 +/- 4.9 degrees (p = 0.008). The average amount of hypertropia was larger in group 1 than in group 2 during adduction: 16.7 +/- 5.3 degrees vs. 9.3 +/- 3.4 degrees (p < 0.001) as well as during adduction and downgaze of the affected eye: 14.6 +/ 7.1 vs. 7.2 +/- 3.7 degrees (p = 0.03). In the sagittal plane, the increase of vertical deviation was larger in group 1 than in group 2: 2.8 +/- 7.8 vs. - 2.4 +/- 4.2 (p = 0.04); the excyclodeviation was larger in group 1 in all three planes (sagittal plane, adduction and abduction) in comparison to group 2: 1.3 +/ 4.1 vs. - 2.9 +/- 2.8 (p = 0.006), 2.4 +/- 5.2 vs. - 2.2 +/- 2.9 (p = 0.01), 0.5 +/- 3.8 vs. - 2.7 +/- 3.9 (p = 0.05). Knapp's class II was found in 6 of 15 patients in group 1 and only in this patient group (chi2 = 0.03). CONCLUSIONS: In both groups, the vertical deviation showed a great dispersion. In patients without HMOS (group 2), vertical deviation in adduction did not exceed 15 degrees . Patients with HMOS (group 1) do not show the typical features of a later acquired trochlear palsy due to an early developed compensating innervation. A vertical deviation in adduction of more than 15 degrees , increasing excyclodeviation towards downgaze in all three planes (sagittal plane, adduction and abduction) and Knapp's class II are relatively reliable predictors of a hypoplasia of the SOM. An internationally uniform term for this group of patients, such as superior oblique weakness or superior oblique hypotrophy, would be desirable. PMID- 29270928 TI - Comparison of Optic Disc Parameters in Hyperopic and Emmetropic Eyes of Healthy Children with HRT and OCT. AB - PURPOSE: To investigate, through Heidelberg retina tomography II (HRT II) and RTVue-100 optical coherence tomography (OCT), normal parameters of the optic nerve head (ONH) in highly hyperopic children, and compare these with a group of children with low hyperopia and emmetropia, as fundus examination of highly hyperopic children often shows crowding of the optic disc, which may be difficult to distinguish from mild optic disc swelling. PATIENTS AND METHODS: ONH of the higher hyperopic eye was examined with HRT II and the peripapillary nerve fiber layer (RNFL) with RTVue-100, in 6 to 15-year-old full-term children with normal visual acuity and spherical equivalent >= + 3.0 D (hyperopic group) and < + 3.0 to - 1.0 D (emmetropic group). RESULTS: Thirty highly hyperopic children and 33 emmetropic controls had a mean spherical equivalent of + 5.1 +/- 1.5 D and a mean age of 8.4 +/- 2.8 years, and + 1.0 +/- 1.2 D and 9.6 +/- 2.6 years, respectively. There was no significant difference in OCT-assessed RNFL thickness between the two groups. Compared to the emmetropic group, following HRT parameters were significantly smaller in the hyperopic group: Disc area (1.41 vs. 1.68 mm2, p = 0.023), cup area (0.19 vs. 0.37 mm2, p = 0.0001), cup volume (0.03 vs. 0.08 mm3, p = 0.02), cup/disc area (0.13 vs. 0.20, p = 0.006), linear cup/disc (0.33 vs. 0.42, p = 0.004), and mean cup depth (0.13 vs. 0.17 mm, p = 0.019). CONCLUSION: In children, ONH of highly hyperopic eyes are smaller than those of emmetropic eyes. RNFL thickness and neural rim volume are similar to emmetropic eyes. They can therefore appear more crowded. PMID- 29270929 TI - [Atropine for the Prevention of Progression in Myopia - Data, Side Effects, Practical Guidelines]. AB - The prevalence of myopia has increased worldwide in recent decades. In East Asia's metropolises >= 80% of young adults are affected. This dramatic increase is mainly caused by changes in lifestyle and behaviour. Atropine has been used for more than 100 years to arrest myopia progression. It has become an evidence based treatment regimen in the last decade, although the exact mechanism of the effect of treatment is still unknown. Atropine eye drops can slow myopia progression by an average of - 0.54 dioptres (D)/year in Asian children and - 0.35 D/year in Caucasian children. However, a non-response rate of about 10% has been found. Treatment should be established in schoolchildren only (age >= 6 years) with myopia <= - 2 D (spherical equivalent, cycoplegic refraction) and with documented myopic progression of - 0.5 D in the preceding year. 0.01% eyedrops should be instilled into the lower fornix at bedtime. Atropine 0.01% therapy is well tolerated. Atropine is usually administered for 2 years since efficacy is somewhat better in the second year. During treatment, a 6-month follow-up with cycoplegic refraction and axial length measurement is recommended. After the 2-year period, atropine withdrawal is justified if progression is less than - 0.25 D/year in the second year. Even after atropine has been stopped, follow-up examinations are needed to detect any rebound. Atropine-therapy is resumed if progression is again higher than - 0.5 D/year. Topical atropine is used off-label. PMID- 29270930 TI - [Conservative treatment options for female incontinence]. AB - In this narrative review, we give an overview of contemporary conservative treatment concepts for urinary incontinence in female patients. Hereby, we focus on pure stress urinary incontinence, urge incontinence and mixed urinary incontinence. We emphasise the value of rationally used diagnostic methods to be able to distinguish between these subentities. Regarding conservative treatment options, we focus on life-style changes, pelvic floor muscle training and drug treatment, and we discuss the results of recent studies. In addition, we provide current expert opinions and recommendations to facilitate the integration of these findings into the daily clinical routine. PMID- 29270931 TI - Steven K. Feske, MD. PMID- 29270932 TI - Women's Issues in Neurology. PMID- 29270933 TI - Migraine in Women. AB - Migraine is one of the most common neurological disorders, affecting women disproportionally at a rate of 3:1. Prior to puberty, boys and girls are equally affected, but the female preponderance emerges after puberty. Migraine pathophysiology is not fully understood, and although the hormonal effect of estrogen is significant, other factors are at play. This article will focus on the hormonal influence on migraine in women. Here we review our most recent understanding of migraine and menstrual migraine, including epidemiology, pathophysiology, and treatment strategies for this challenging disorder, as well as migraine during pregnancy, postpartum period, breastfeeding, perimenopause, and menopause. We also review the risks and benefits of exogenous hormone use in this population and discuss stroke risk in women with migraine aura. By understanding these aspects of migraine in women, we hope to arm practitioners with the knowledge and tools to help guide treatment of this debilitating disorder in this large population. PMID- 29270934 TI - Delivery of a Personalized Treatment Approach to Women with Epilepsy. AB - Personalized treatment for women with epilepsy is essential, and requires thorough weighing of the risks and benefits of the initial diagnostic and therapeutic options chosen, with readjustments of the antiepileptic regimen throughout the patient's life.Approximately one-third of women with epilepsy have a catamenial pattern, and the most common pattern is an increase in seizure frequency in the perimenstrual phase. These women are also more likely to experience a decrease in seizure frequency during pregnancy and menopause. A good treatment option for catamenial epilepsy is still lacking.For contraception, an intrauterine device is currently the preferred choice. Prior to conception, it is advisable to review the known impact of different antiepileptic drugs on the developing fetus and to optimize the patient's treatment regimen. Pregnancy registries and observational studies have provided key data and continue to refine our understanding of the risks to the structural and cognitive development of the fetus of specific antiepileptic drugs, including polytherapies and newer medications. Different studies consistently report that valproic acid has notably high relative risks for congenital malformations, lower IQ, and features of autism. During pregnancy, there is growing evidence that therapeutic dose monitoring is beneficial for seizure control. Counseling about seizure safety and minimizing provoking factors during the peripartum period is important for the patient with epilepsy.Clinical studies continue to investigate the complex relationship between cycling sex steroid hormones, epilepsy, and antiepileptic medications, with hopes to better explain drug clearance changes during pregnancy, changes in seizure frequency, and neuroendocrine abnormalities. Thorough understanding of these key factors and a continuous review of literature for updated data on different treatment options will enable optimal treatment recommendations that will improve the health of women with epilepsy and their children. PMID- 29270935 TI - Psychogenic Nonepileptic Seizures in Women. AB - Psychogenic nonepileptic seizures (PNES) are the most common type of functional neurological symptom disorders and are frequently diagnosed in tertiary care epilepsy monitoring units. These are associated with significant decline in social functioning and quality of life. The majority of patients with PNES are women, outnumbering men by a ratio of 3:1. Female sex preponderance occurs after puberty and usually before the age of 55 years. Many of the psychiatric risk factors in PNES (depression, anxiety, history of traumatic experiences, other somatic symptom disorders) are more common in women and may partially account for the difference in sex prevalence. Neurobiological and neurohumoral mechanisms may also play a role, but our understanding is limited at this point. In this review, we present information on epidemiology and risk factors, neurobiological and psychological mechanisms, clinical approach to diagnosis, evidence-based treatment, and long-term outcomes. We highlight findings related to differences between women and men in PNES. Most of these data are not decisive and require further corroboration. While the disorder may be more frequently suspected in women, all patients with suspected PNES deserve an objective and thorough investigation of their symptoms. Early and accurate identification of this disorder should be a priority, especially as evidence-based treatments, which may lead to improved outcomes, are increasingly available. PMID- 29270936 TI - Reproductive Issues in MS. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, predominantly affecting women of childbearing age. Therefore, issues of conception, pregnancy, and delivery are of significant importance to patients and treating physicians. We discuss immunologic and clinical effects of pregnancy on the course of MS including both immunosuppression on a local level and a heightened state of immunocompetence on a global level. Clinical outcomes of the Pregnancy in Multiple Sclerosis trials are reported. We analyze and update the available data on safety and efficacy of immunomodulating MS treatments and symptomatic treatments for pregnant and lactating women, and address specific issues of MS management at the time of pregnancy. We review the data related to estrogen-based MS therapies currently or previously in trials. Pregnancy does not appear to be associated with adverse outcomes in MS patients. Some evidence suggests possible beneficial effects, although clear prospective data of sufficient length and quality are limited. Long-term relapse rates or disability progression do not seem to be affected by pregnancy in MS patients. The use of immunosuppressive or immunomodulatory agents in pregnancy is not routinely advisable but could be considered under special circumstances. PMID- 29270937 TI - Neuromuscular Disorders in Pregnancy. AB - Neuromuscular disorders may present and progress differently in women than in men. During pregnancy, medication adjustment, hormonal effects, and other alterations in physiology may influence the manifestation of a variety of neuromuscular disorders. The expression of existing conditions may change; previously asymptomatic conditions may be unmasked, or entirely new conditions may develop. Additionally, neuromuscular disorders and their treatments may have implications for the fetus. Such factors must be carefully considered when counseling and treating pregnant women and those considering pregnancy. This article reviews considerations specific to women and issues surrounding pregnancy in disorders of the neuromuscular junction, focal neuropathies, and acquired and inherited disorders of the nerve and muscle. PMID- 29270938 TI - Movement Disorders in Women. AB - Movement disorders such as Parkinson's disease (PD), restless legs syndrome (RLS), chorea, essential tremor, and Tourette syndrome, occur in men and women of all ages. Yet, considerable sex differences in epidemiology, clinical features, and treatment exist in these disorders. In this review, we highlight key differences in the evaluation and management of women with movement disorders, addressing sex-specific complications of treatment and unique challenges surrounding the management of movement disorders during pregnancy. We review the complex relationship between estrogen and movement disorders, including the putative neuroprotective effects of estrogen in PD and the modulatory effects on RLS and chorea associated with autoimmune disease. Further understanding of sex specific and hormonal effects on clinical features will be important to optimize the management of women with movement disorders in the future. PMID- 29270939 TI - Sleep Disorders in Pregnancy. AB - Sleep and pregnancy are dynamic processes with unique and evolving physiological substrates. Given the "restorative hypothesis" of sleep as an anabolic process essential for cellular and tissue regeneration, the largely unexplored role of sleep in gestational physiology and pregnancy outcomes promises to be a fascinating topic. Emerging literature suggests that objectively measured or self reported short sleep duration may be a risk for adverse pregnancy outcomes, including gestational diabetes mellitus (GDM), gestational hypertension, and cesarean delivery. In this review, we discuss obstructive sleep apnea (OSA) and restless legs syndrome (RLS), two sleep disorders prevalent in pregnancy. OSA is especially likely in high-risk pregnancy where it is associated with comorbid cardiovascular and metabolic disturbances. We review new data strongly suggesting that OSA is an independent risk factor for GDM and gestational hypertension. It remains to be seen if sleep disruption, whether or not in the context of gestational RLS and gestational OSA, is a modifiable factor for adverse pregnancy outcomes. Clinicians are encouraged to query sleep symptoms in pregnant women and to have a low threshold to pursue investigations for OSA, including the subjective symptoms of snoring, witnessed apneas, and daytime sleepiness, and also medical comorbidities, such as chronic hypertension. PMID- 29270940 TI - Stroke in Pregnancy. AB - Pregnancy and the postpartum period confer an increased risk of stroke. The risk appears to be increased for all strokes during the puerperium and for hemorrhagic strokes during pregnancy. During pregnancy, physiologic systems are under increased stress to accommodate the growing fetus, which results in substantial hemodynamic, cardiovascular, hematologic, immunologic, and structural connective tissue changes that account for much of this increased risk. In addition, preeclampsia-eclampsia has major effects on the vascular system, and this disorder, unique to pregnancy, is another major contributor to this risk. The common independent vascular risk factors for stroke, such as hypertension, diabetes, hyperlipidemia, and smoking, may also be present to contribute to the risks conferred by pregnancy. Though uncommon, stroke during pregnancy and in the postpartum period causes substantial morbidity and mortality in affected women, and it poses a significant risk to the fetus. This review will discuss the epidemiology of pregnancy-associated stroke, specific risk factors and mechanisms, clinical presentation and management, and future directions. PMID- 29270941 TI - Cerebrovascular Hemodynamics in Women. AB - Sex and gender, as biological and social factors, significantly influence health outcomes. Among the biological factors, sex differences in vascular physiology may be one specific mechanism contributing to the observed differences in clinical presentation, response to treatment, and clinical outcomes in several vascular disorders. This review focuses on the cerebrovascular bed and summarizes the existing literature on sex differences in cerebrovascular hemodynamics to highlight the knowledge deficit that exists in this domain. The available evidence is used to generate mechanistically plausible and testable hypotheses to underscore the unmet need in understanding sex-specific mechanisms as targets for more effective therapeutic and preventive strategies. PMID- 29270942 TI - Neurosurgical Issues in Pregnancy. AB - Although rare, intracranial hemorrhage due to rupture of cerebral vascular malformations or intracranial aneurysms during pregnancy is a potentially devastating and life-threatening disorder, posing a diagnostic and therapeutic challenge to a multidisciplinary team of neurosurgeons, neurologists, obstetricians, and anesthesiologists. Despite the significant risk of morbidity and mortality affecting both the mother and the unborn child, knowledge of the natural history, epidemiology, and appropriate management of cerebral vascular malformations and intracranial aneurysms in pregnant women is limited. Although emergent neurosurgical concerns usually outweigh obstetric considerations, and treatment of these disorders is generally similar in pregnant and nonpregnant women, any necessary and feasible modifications to protect the unborn child should be made. This article reviews the management of ruptured intracranial aneurysms and cerebral vascular malformations, including arteriovenous malformations, cavernous malformations, and moyamoya disease, in women during pregnancy, partus, and puerperium. PMID- 29270943 TI - Sex Matters in Neuroinfectious Diseases. AB - Although sex and gender have a major impact on the susceptibility and immunologic response to infectious diseases, these factors are often neglected. Identifying the mechanisms underlying sex-based differences in infectious diseases will facilitate the rational design and implementation of preventive and therapeutic strategies that reduce risk and improve outcomes for women and men. In this article, we discuss two examples in neuroinfectious diseases of how sex matters: (1) the heightened risk of cerebrovascular disease in women living with HIV infection and (2) the implications of Zika virus infection on sexual and reproductive health and vaccine development for women. PMID- 29270944 TI - The Neurology of Immune-Mediated Disorders in Women. AB - Many neuroinflammatory disorders have a predilection for women; even if there is no female predominance, neuroinflammatory conditions in women pose a management challenge for several reasons. Disease activity of these conditions may change during pregnancy and commonly increases in the postpartum period. Uncontrolled disease activity may affect pregnancy outcomes. Moreover, immunomodulating agents that are used to suppress the disease activity may have a negative impact on fertility, pregnancy, and fetal outcomes, and on infants who are breastfed. Adverse effects of immunosuppressants extend beyond the reproductive issues and may include bone loss, increased risk of cancers, and infectious complications. The successful management of women with these disorders requires that not only practitioners understand and recognize the adverse effects of immunosuppressants, but also seek to prevent adverse outcomes through counseling about contraceptive choices, safety monitoring, risk surveillance, and other strategies. PMID- 29270945 TI - Neuroimaging in Pregnant Women. AB - Choosing the most appropriate diagnostic neuroimaging study for a pregnant woman involves assessing the pretest likelihood of serious treatable neurologic disease, the diagnostic utility of various available computed tomography (CT) and magnetic resonance (MR) modalities, and the risks of each. Of these three elements-pretest differential diagnosis, utility of MRI and CT, and risks of MR and CT-the risk component is perhaps the least well understood by most physicians. We provide a basic review of the intrinsic risks of MRI and CT, particularly radiation biology and radiation safety, as well as the risks pertaining to the use of contrast agents, to reduce provider confusion and anxiety and improve quality, safety, and efficiency of neuroimaging diagnosis in pregnant patients. We believe that a better understanding of the associated very low risks with mother and fetus will reassure the reader that CT remains the most appropriate tool for initial rapid diagnosis of acute neurological conditions in pregnancy and that in urgent situations CT should not be withheld or delayed due to exaggerated concern about radiation. Noncontrast MRI, while not without risk, is generally considered safe in pregnancy, as no evidence of fetal adverse effects has been demonstrated to date. Iodinated CT contrast agents are likely safer than gadolinium-based MRI contrast agents because of gadolinium accumulation in the amniotic fluid and fetal tissue, although no harmful effects of tissue gadolinium accumulation are known. In most but not all pregnant patients presenting with a new or worsening neurological abnormality, the risks intrinsic to the disease will outweigh the risks of imaging. In an individual patient, the pretest probability of serious treatable disease and acuity of presentation will usually suggest an optimal imaging strategy and choice of test. This optimal strategy will also depend on the immediate availability and level of sophistication of the scanners, software, technologists, and radiologists. As such, the standard of care for imaging in pregnancy requires direct consultation between the referring clinician and radiologist to determine the most appropriate strategy and brief documentation of the resulting consensus risk-benefit assessment. PMID- 29270946 TI - Ethical Issues in the Neurology of Pregnancy. AB - Decision making for pregnant women and fetuses who suffer brain injuries is emotionally difficult and conceptually challenging. Occasionally, both the pregnant woman and the fetus have suffered an injury that confers a poor neurological prognosis, and decisions about one of them will have implications for the other-making the process of decision making even more problematic. In this article, decision-making standards and principles are reviewed for both pregnant women and fetuses, using a real case from the author's institution. Practical suggestions are made regarding deliberative processes and consultative models that can help with these difficult cases. PMID- 29270947 TI - Effects of Neonatal Thoracoscopic Surgery on Tissue Oxygenation: A Pilot Study on (Neuro-) Monitoring and Outcomes. AB - INTRODUCTION: Multiple reports have questioned the feasibility of neonatal thoracoscopic repair of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA). The aim of this study is to examine the effects of CO2 pneumothorax on cerebral and renal rSO2 and to assess the potential predictive value of these data on neurodevelopmental outcome after neonatal thoracoscopic surgery for CDH or EA. METHODS: A prospective observational pilot study. Cerebral and renal regional tissue oxyhemoglobine saturation (rSO2) rSO2 were assessed using near infrared spectroscopy (NIRS) during thoracoscopic surgery in neonates with CDH and with EA, in addition to routine anesthesia monitoring. Cerebral and renal rSO2, linked to repeated arterial blood gas analyses, heart rate, blood pressure, and to structured longitudinal neurodevelopmental follow-up. RESULTS: Baseline estimated marginal means of cerebral rSO2 values (CDH: 82%, EA: 91%) did not change significantly during pneumothorax (CDH: 81%, EA 79% [n.s. versus baseline]) despite severe acidosis (lowest pH, CDH: 6.99, EA: 7.1). Neurodevelopmental outcomes at 24 months were normal in all 7 patients who were available for evaluation. CONCLUSION: Neonatal thoracoscopic repair of CDH and EA using CO2-pneumothorax leads to severe acidosis. Cerebral rSO2 remained within clinical acceptable limits during intraoperative periods of acidosis. Neurodevelopmental outcome was favorable within the first 24 months. The potential of NIRS to further improve perioperative care and long-term outcome in this specific patient group deserves further investigation. PMID- 29270948 TI - Topical Mitomycin C Application in Pediatric Patients with Recurrent Esophageal Strictures-Report on Unfavorable Results. AB - OBJECTIVE: Recurrent esophageal strictures (ESs) following esophageal atresia repair or caustic ingestion represent a common clinical problem. Recently, Mitomycin C was reported to improve the outcome of patients by reducing the number of endoscopic dilatations. However, other groups failed to exhibit a beneficial effect. We report on our experience with topic Mitomycin C application following endoscopic dilatation for recurrent ES. METHODS: Retrospective chart review of patients with ES treated at the Hannover Medical School (Location A) and the University of Leipzig (Location B) between 2009 and 2015. A Mitomycin C soaked cotton swab was endoscopically placed at the area of stricture in all subjects. Successful treatment was defined as resolution of stricture after Mitomycin C therapy with not more than three dilatations thereafter. Our results were compared with published outcomes of alternative studies that involved 10 or more patients. RESULTS: A total of 11 children received Mitomycin C concurrently with endoscopic dilatations. Seven children (64%) had gross type C esophageal atresia, two patients (18%) gross type A esophageal atresia, and two children (18%) caustic injury.After a median follow-up of 34 months (range, 14-75 months) and a median number of 3 +/- 2.5 dilatations with Mitomycin C application per patient (range, 1-9), 6 of 11 patients (55%) achieved a resolution of their strictures. Five patients (45%) did not respond to Mitomycin C therapy, of which two needed esophageal redo-surgery. CONCLUSION: We failed to confirm the high success rates of Mitomycin C treatment for recurrent ESs. Given the fact that there is limited data to prove the beneficial effect of Mitomycin C treatment, pediatric surgeons should carefully consider whether the advantages of this therapy outweigh the necessity of life-long endoscopic follow-ups. Further randomized controlled studies are recommended. PMID- 29270949 TI - Clinical Perspectives of Lithium's Neuroprotective Effect. AB - Evidence for a neuroprotective effect of lithium has accumulated over the last 2 decades, and this phenomenon has been regarded as an important mechanism of lithium action in mood disorders. It has been reflected by an increase in cerebral gray matter volume in lithium-treated subjects and by the favorable influence of lithium on cognitive functions. A neuroprotective effect of lithium also makes this ion a possible candidate for use as a therapeutic drug in neurology, especially in neurodegenerative disorders. In this paper, neurochemical mechanisms of neuroprotective action of lithium will be characterized. A possible association between the effect of lithium on brain structures reflected in neuroimaging studies, as well as on cognitive functions, and its neuroprotective action, will be considered. Data from experimental, epidemiological, and clinical studies have also pointed to an antidementia effect of lithium, bringing about some promise of using lithium in the treatment of mild cognitive impairment and Alzheimer's disease. The results of attempts of employing lithium in other neurodegenerative disorders will also be discussed. PMID- 29270951 TI - Day of Week and Surgery Location Effects on Stay Length and Cost for Total Joint Arthroplasty: Academic versus Orthopaedic-Specific Hospital. AB - Demand for total hip (THA) and knee arthroplasties (TKA) is expected to rise sharply by 2030. Increasing demand in conjunction with financial pressure requires the use of cost-effective total joint arthroplasty (TJA) strategies. This study examined the effects that day of week and surgery location [academic (AH) versus orthopaedic-specific (OsH) hospital] have on length of stay (LOS) and cost for primary TJA patients in one multihospital university-based medical center. An Institutional Review Board-approved database of adult patients undergoing primary THA or TKA from June 2013 to December 2014 was constructed. Surgery location, day of procedure, age, American Society of Anesthesiologists (ASA) classification, LOS, and cost were recorded for each patient. Data were compared for significant differences using analysis of variance, t-Test or rank sum and for strength of correlations using Pearson's or Spearman's tests. A total of 1,291 patients met inclusion criteria. OsH showed significantly lower cost and shorter LOS than AH. Wednesday surgeries had significantly higher cost and longer LOS than all other days. Friday surgeries had significantly lower cost and shorter LOS than other days. ASA 3 and 4 were associated with the highest cost and longest LOS. LOS had a moderately strong direct correlation to cost. ASA did not have a strong correlation with LOS or cost. Data separated for THA and TKA showed similar results. At our institution, OsH provides more consistent and lower LOS and cost across all ASA classes. Wednesday and Thursday surgeries have increased LOS and cost than other days, which may be due to weekend discharge difficulties (average LOS is 3.0 days). PMID- 29270950 TI - Patients with Revision Modern Megaprostheses of the Distal Femur Have Improved Disease-Specific and Health-Related Outcomes Compared to Those with Primary Replacements. AB - We asked whether there would be any difference between primary and revision modern cemented fixed hinge megaprosthesis of the distal femur in function and activity-related outcomes following treatment of a bone tumor. An identical custom-made fixed hinge cemented megaprosthesis with a hydroxyapatite collar was used in all cases. The main outcomes were joint-specific function, disease specific activity, and health-related quality of life. Implant survival was also evaluated. Patients in the revision group performed slightly better than patients in the primary group on disease-specific (Toronto Extremity Salvage Score, p = 0.033; Musculoskeletal Tumor Society, p = 0.072) and health-related outcomes (Short Form 36 [SF-36] physical component, p = 0.085; SF-36 mental component, p = 0.069) but not on joint-specific outcomes (Knee Society Score, p = 0.94). The cumulative probabilities of revision for any reason were 14.5% (7-25%) at 5 years with no statistically significant difference between primary and revision procedures (p = 0.77). In conclusion, patients undergoing a revision have similar joint-specific functional outcome but improved disease-specific and health related outcomes. Implant survival are similar between groups. PMID- 29270952 TI - [Pulmonary Immune Mechanisms in Tuberculosis]. AB - Tuberculosis is transmitted by inhalation of Mycobacterium tuberculosis containing aerosols; 75 % of all patients show pulmonary manifestation. Immune responses after exposure that lead to clinical symptoms occur mainly in the respiratory tract and are only poorly understood. In most cases, cells of the innate immune system are believed to control the growth of or eradicate inhaled mycobacteria. However, this cannot be verified in vivo using standard methods. Subsequently, CD4+ and CD8+ T cell-driven adaptive immune responses are induced that attempt to control bacterial growth. The humoral defence appears to be less important. This article gives an overview of the current understanding of pulmonary immune mechanisms during exposure, latent infection, active disease and therapy of tuberculosis. PMID- 29270953 TI - [Updated Recommendation for Treatment of Metastatic Non-Small Cell Lung Cancer]. AB - Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decisionmaking. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC. PMID- 29270954 TI - Usability and Suitability of the Omics-Integrating Analysis Platform tranSMART for Translational Research and Education. AB - BACKGROUND: Platforms like tranSMART assist researchers in analyzing clinical and corresponding omics data. Usability is an important, yet often overlooked, factor affecting the adoption and meaningful use. Analyses on the specific needs of translational researchers and considerations about the application of such platforms for education are rare. OBJECTIVES: The aim of this study was to test whether tranSMART can be used in education and how well medical students and professional researchers can handle it; to identify which kind of translational researchers-in terms of skills, experienced limitations, and available data-can take advantage of tranSMART; and to evaluate the usability and to generate recommendations for improvements. METHODS: An online-based test has been done by medical students (N = 109) and researchers (N = 26). The test comprised 13 tasks in the context of four typical research scenarios based on experimental and clinical data. A web questionnaire was provided to identify both the needs and the conditions of research as well as to evaluate the system's usability based on the "System Usability Scale" (SUS). RESULTS: Students and researchers were able to handle tranSMART well and coped with most scenarios: cohort identification, data exploration, hypothesis generation, and hypothesis validation were answered with a rate of correctness between 82 and 100%. Of the total, 72.2% of the teaching researchers considered tranSMART suitable for their lessons and 84.6% of the researchers considered the platform useful for their daily work; 65.4% of the researchers named the nonavailability of a platform like tranSMART as a restriction on their research. The usability was rated "acceptable" with a SUS of 70.8. CONCLUSION: tranSMART is potentially suitable for education purposes and fits most of the needs of translational researchers. Improvements are needed on the presentation of analysis results and on the guidance of users through the analysis, especially to ensure the compliance of the analysis with the requirements of statistical testing. PMID- 29270956 TI - A study of the blood flow restriction pressure of a tourniquet system to facilitate development of a system that can prevent musculoskeletal complications. AB - BACKGROUND: After an emergency or disaster, subsequent trauma can cause severe bleeding and this can often prove fatal, so promptly stopping that bleeding is crucial to preventing avoidable trauma deaths. A tourniquet is often used to restrict blood flow to an extremity. In operation and hospital, the tourniquet systems currently in use are pneumatically actuated by an air compressor, so they must have a steady power supply. These devices have several drawbacks: they vibrate and are noisy since they are pneumatically actuated and they are far from portable since they are large and heavy. INTRODUCTION: Presumably, the drawbacks of pneumatic tourniquets could be overcome by developing a small, lightweight, vibration-free, quiet, and battery-powered tourniquet system. The current study built a small, vibration-free electrohydrodynamic (EHD) pump and then used that pump to restrict blood flow to the leg of rats in an experiment. This study explored the optimal conditions for effective restriction of blood flow by assessing biochemical and musculoskeletal complications following the restriction of blood flow, and this study also examined whether or not an EHD pump could be used to actuate a tourniquet system. METHODS: A tourniquet cuff (width 12 mm * length 150 mm, material: polyolefin) was placed on the thigh of Wistar rats and pressure was applied for 2 hours by a device that uses EHD phenomena to generate pressure (an EHD pump). Animals were divided into four groups based on how much compressive pressure was applied with a tourniquet: 40 kPa (300 mm Hg, n = 13), 30 kPa (225 mm Hg, n = 12), 20 kPa (150 mm Hg, n = 15), or 0 kPa (controls, n = 25). Tissue oxygen saturation (regional oxygen saturation, denoted here as rSO2) was measured to assess the restriction of blood flow. To assess behavior once blood flow resumed, animal activity was monitored for third day and the amount of movement was counted with digital counters. Body weight was measured before and after the behavioral experiment, and changes in body weight were determined. Blood was sampled after a behavioral experiment and biochemically assessed and creatine kinase (CK) levels were measured. RESULTS: Tissue oxygen saturation decreased significantly in each group. When a tourniquet was applied at a pressure of 30 kPa or more, tissue oxygen saturation decreased significantly. The amount of movement (the count) over third day decreased more when a tourniquet was applied at a higher pressure. The control group resumed the same amount of movement per day second after blood flow resumed. Animals to which a tourniquet was applied at a pressure of 20 or 30 kPa resumed the same amount of movement third day after blood flow resumed. In contrast, animals to which a tourniquet was applied at a pressure of 40 kPa did not resume the same amount of movement third day after blood flow resumed. After the behavioral experiment, animals to which a tourniquet was applied at a pressure of 40 kPa had a significantly lower body weight in comparison to the control group. After the behavioral experiment, animals to which a tourniquet was applied at a pressure of 40 kPa had significantly elevated CK levels in comparison to the control group. DISCUSSION AND CONCLUSION: A relationship between blood flow restriction pressure and tissue oxygen saturation was noted. rSO2 measurement can be used to assess the restriction of blood flow during surgery. On the basis of the decrease in rSO2, blood flow was effectively restricted at a pressure of 30 kPa or more. When, however, blood flow was restricted at a pressure of 40 kPa, weight loss and decreased movement were noted and CK levels increased after the behavioral experiment. Thus, complications had presumably developed due to damage to muscle tissue. These findings indicate that blood flow was effectively restricted in this experiment and they also indicate the existence of an optimal blood flow restriction pressure that does not cause musculoskeletal complications. The pressure in question was around 30 kPa. The tourniquet system that was developed here is actuated with an EHD pump that is still in the trial stages. That said, its pressure can readily be controlled and this pump could be used in a tourniquet system since it is quiet, vibration-free, and small. The pressure of this pump can be finely adjusted to prevent musculoskeletal complications. PMID- 29270957 TI - Presence of undertriage and overtriage in simple triage and rapid treatment. AB - OBJECTIVE: We evaluated the use of the Simple Triage and Rapid Treatment (START) method by Emergency Medical Services (EMS) and hypothesized that EMS can categorize patients using the START algorithm accurately. DESIGN: Retrospective Chart Review. SETTING: Inner-city Tertiary-Care Institutional Emergency Department (ED). PARTICIPANTS: Patients >= 18 years transported by EMS with a START color of Red, Yellow, or Green during the state triage tag exercise, October 9-15, 2011. INTERVENTIONS: EMS assigned each patient a START triage tag. Chart review of the electronic EMS run sheets was performed by investigators to determine a START color. MAIN OUTCOME MEASURES: START triage colors were re categorized as Red = 1, Yellow = 2, and Green = 3. The difference between the investigators' color and EMS color were coded as: 0 for agreement in triage, -1 for undertriage by one category, -2 for undertriage by two categories, 1 for overtriage by one category, 2 for overtriage by two categories. RESULTS: Of 224 participants, START triage colors were: Red = 7.1 percent, Yellow = 19.2 percent, Green = 73.7 percent. The mean difference in triage categories was 0.228 (95% CI: 0.114-0.311, p<.001). 71.0 percent of patients were triaged to the same category, 5.8 percent undertriaged by one category, 0 percent undertriaged by two categories, 17.9 percent overtriaged by one category, and 5.4 percent overtriaged by two categories. CONCLUSION: EMS was more likely to overtriage using START. All patients who were overtriaged by two categories were ambulatory at the scene, which implies other findings not in START may affect triage. PMID- 29270958 TI - Planning for a medical surge incident: Is rehabilitation the missing link? AB - This mixed methods study explored surge planning for patients who will need rehabilitative care after a mass casualty incident. Planning for a patient surge incident typically considers only prehospital and hospital care. However, in many cases, disaster patients need rehabilitation for which planning is often overlooked. The purpose of this study was to explore this hidden dimension of patient rehabilitation for surge planning and preparedness and ask: 1. To what extent can an analysis of standard patient acuity assessment tools [Simple Triage and Rapid Treatment and Injury Severity Score] be used to project future demand for admission to rehabilitative care? 2. What improvements to medical disaster planning are needed to address patient surge related to rehabilitation? This study found that standard patient benchmarks can be used to project demand for rehabilitation following a mass casualty incident, and argues that a reconceptualization of surge planning to include rehabilitation would improve medical disaster planning. PMID- 29270955 TI - Clinical Informatics Researcher's Desiderata for the Data Content of the Next Generation Electronic Health Record. AB - OBJECTIVE: Clinical informatics researchers depend on the availability of high quality data from the electronic health record (EHR) to design and implement new methods and systems for clinical practice and research. However, these data are frequently unavailable or present in a format that requires substantial revision. This article reports the results of a review of informatics literature published from 2010 to 2016 that addresses these issues by identifying categories of data content that might be included or revised in the EHR. MATERIALS AND METHODS: We used an iterative review process on 1,215 biomedical informatics research articles. We placed them into generic categories, reviewed and refined the categories, and then assigned additional articles, for a total of three iterations. RESULTS: Our process identified eight categories of data content issues: Adverse Events, Clinician Cognitive Processes, Data Standards Creation and Data Communication, Genomics, Medication List Data Capture, Patient Preferences, Patient-reported Data, and Phenotyping. DISCUSSION: These categories summarize discussions in biomedical informatics literature that concern data content issues restricting clinical informatics research. These barriers to research result from data that are either absent from the EHR or are inadequate (e.g., in narrative text form) for the downstream applications of the data. In light of these categories, we discuss changes to EHR data storage that should be considered in the redesign of EHRs, to promote continued innovation in clinical informatics. CONCLUSION: Based on published literature of clinical informaticians' reuse of EHR data, we characterize eight types of data content that, if included in the next generation of EHRs, would find immediate application in advanced informatics tools and techniques. PMID- 29270959 TI - Invoking the "expectant" triage category: Can we make the paradigm shift? AB - Medical triage is the process of determining the priority of patients' treatments based on the severity of their condition. Triage provides the healthcare provider the ability to identify the most urgent cases first, with the goal of maximizing each individual patient's outcome. When resources are challenged, such as in a disaster, the healthcare provider's goal becomes to maximize overall population survival. In this context, the triage process must identify patients who require resources urgently, as well as those who have the best chance of survival. The revised triage process must include an "expectant management" category, to identify patients for whom further resuscitation is delayed, as they have a poor chance of survival and require significant resources. The paradigm shift that is required in these circumstances can be challenging for pediatric healthcare providers. Many may find themselves unable to change the decision-making process that would favor overall survival and best outcome for the most members of a population, while potentially not addressing the most sick or injured because they have low chances of survival. We hypothesized that participating in a multiprofessional ethics-based educational session regarding making difficult triage decisions may improve participants' perceived ability to use the "expectant" triage category in a disaster setting. Participants took part in an ethics-based educational session and completed a pre- and postsurvey. Results demonstrated a significant change in the participants' self-perceived comfort level using the disaster triage tools and improved their confidence to use the expectant triage category in a disaster setting. PMID- 29270960 TI - Verification of the airway securing capacity of a life jacket in a flood disaster. AB - OBJECTIVE: To verify the life jacket's airway-securing capacity to keep the nose and mouth out of the water in a flood disaster. DESIGN: Physical experiment. SETTING: University of Miyazaki. MATERIALS AND METHODS: We experimented with an open channel in which we created a wave and running water. In the channel, we observed a dummy attached to a balloon as a buoyant body. We used 170-, 220-, and 320-ml balloons. Experiment 1, we reproduced a tsunami. We created three sizes of wave. Experiment 2, we reproduced running water. When we installed an obstacle at the channel bottom, the current that submerged the dummy occurred downstream of the obstacle. We measured the submergence time of the dummy. RESULTS: For the medium-sized wave, the submergence time decreased as the balloon volume increased. For the largest wave, the submergence time was the shortest for a balloon of 220 ml, not 320 ml. Experiment 2, the submergence time decreased as the balloon volume increased. However, a dummy attached to a 320-ml balloon remained downstream of the obstacle. CONCLUSIONS: The biggest drawback is that the parameters of this study are not based on real-world experience. Therefore, if an evacuee with a life jacket is submerged in a flood disaster, we cannot easily decide whether the buoyancy is appropriate because in some situations, buoyancy adversely affected airway security. If we could decide buoyancy based on specific disaster conditions, the airway-securing capacity of a life jacket would improve. PMID- 29270961 TI - The pulmonary consequences of sandstorms in Saudi Arabia: A comprehensive review and update. AB - Sandstorms represent a major natural hazard in the Arabian Peninsula. Their pulmonary consequences can be life-threatening, especially to those with a history of allergies, asthma, and chronic obstructive pulmonary diseases. Novel presentations of respiratory diseases caused by sandstorms can now be traced to specific chemical and organic components of sandstorms. We present an update of the pathophysiology of pulmonary conditions based on the results of clinical and epidemiologic research as well as from greater knowledge of the complex chemical composition of sandstorms. This has led to more precise therapeutic approaches to severe respiratory illnesses and a greater understanding of risk factors for morbidity and mortality due to Arabian sandstorms. PMID- 29270962 TI - A hospital mass casualty exercise using city buses and a tent as a hybrid system for patient decontamination. AB - OBJECTIVE: A hospital mass casualty simulation exercise testing feasibility of two city buses and a tent as a hybrid system for patient decontamination. DESIGN: Observational study of a single mass casualty simulation exercise involving patient decontamination SETTING: Held on May 26, 2016 at the Montreal General Hospital, a Level 1 Trauma center without a garage. PATIENTS, PARTICIPANTS: Twenty-one medical staff including nurses, doctors, and patient attendants, and 30 volunteer-simulated patients. INTERVENTIONS: The foregrounds of the hospital were cordoned off to create a single-entry point for the simulated patients that were identified as contaminated (C) by staff wearing personal protective equipment. Non-contaminated patients were directed to a separate hospital entrance. C patients were triaged in Bus 1 to determine priority for decontamination. Bus 2 served as a holding area for stable patients awaiting decontamination. Patients were decontaminated in appropriate tent sections (non ambulatory, ambulatory male or female) and then directed to the emergency department. RESULTS: Direct observation and participant feedback suggested that buses may provide adequate shelter for C patients. However, buses had limited capacity for non-ambulatory patients, who were not easily transported inside. Furthermore, areas of improvement were identified in communication, staffing, equipment, and coordination of operations. CONCLUSIONS: The use of city buses as triage and waiting zones prior to decontamination appears feasible for centers without a garage and facing unpredictable weather conditions. Further simulations are required for fine-tuning and testing real-time unfolding of tasks, ideally during an unannounced exercise. PMID- 29270963 TI - Achieving the Sustainable Development Goal 3: challenges in HIV testing in the Eastern Mediterranean Region. PMID- 29270964 TI - Drug utilization in primary healthcare centres in the Gaza Strip. AB - This study was carried out to analyse drug-prescribing practices in primary healthcare centres (PHCs) in the Gaza Strip. We retrospectively evaluated 2569 prescriptions from 22 PHCs during January-December 2014. Systematic random sampling was applied. Analysis followed the World Health Organization recommended core prescribing indicators. The mean number of drugs prescribed per encounter was 2 (standard deviation 0.9); the percentage of drugs prescribed by generic name was 10.1%; and 67.5% of prescriptions contained an antibiotic followed by analgesics (39.4%). Major omission errors were found in 89.5% of all prescriptions. For all drugs prescribed, drug duration, strength, frequency, dose and dosage form were not mentioned in 79.3%, 65.4%, 30.6%, 23.3% and 12.5% of prescriptions, respectively. Nonofficial abbreviations were used to write 87.4% of prescriptions. There is a clear need to develop standards for drug prescribing, standard treatment guidelines for drug use, along with continuing medical education programmes, and the implementation of monitoring systems to ensure that they are adhered to. PMID- 29270965 TI - Effect of pre-pregnancy maternal body mass index on pregnancy outcomes in nulliparous women in the Islamic Republic of Iran. AB - This study was conducted to evaluate the effect of pre-pregnancy BMI on pregnancy outcomes. BMI was calculated measured in 360 nulliparous women. According to BMI, pregnant women were placed into three groups: group I (lean group BMI <= 19.8), group II (normal weight group BMI = 19.9-24.9), and group III (obese group BMI >= 25). Data were analyzed using SPSS 16. The mean duration of the first and the second stage of labour were significantly different between three groups (P < 0.001). Cesarean section ratio in group I was lower than group II (OR = 0.15; P = 0.013). Instrumental delivery in group III was more than group II (OR=4.6; P = 0.002). Risk of nonreactive non-stress test (NST) was significantly different between groups II and III (OR = 5.7; P = 0.009). Induction ratio in group I was lower than group II (OR=0.43; P = 0.002). Deviation of BMI from the normal level is associated with adverse outcomes of pregnancy and delivery. PMID- 29270966 TI - Factors associated with folic acid knowledge and intake among pregnant women in Sudan. AB - Preconceptual folic acid use is known to have a protective effect against neural tube defects (NTDs). This study assessed knowledge and determinants of awareness on folic acid use among pregnant women at Omdurman Maternity Hospital, Sudan during 2014. The standardized, anonymous questionnaire was used to collect data. Almost 80% of respondents had heard of folic acid. College-educated women (92.2%) knew more about folic acid and used it more often in the pre-conceptual period (8.3%). Doctors were the commonest source of information on folic acid (62%). Fewer subjects (8.9%) knew that it prevented birth defects, and 33.8% of subjects knew that green leafy vegetables are a source of folic acid. Of all subjects, only 3.2% use it preconceptually. Supplementation of folic acid preconceptually needs to be addressed in order to reduce the rate of NTDs found in Sudan. PMID- 29270967 TI - Developing a socioeconomic index for health research in Iraq. AB - Although socioeconomic status is one of the essential factors in much health research, it is one of the most difficult constructs to measure. The aim of this study was to develop a relatively accurate, easy-to-calculate method to estimate socioeconomic status (SES) for health research in Iraq as well as similar profile countries in the developing world. After reviewing various methods of calculating SES, a new method is proposed based on the 3 main variables: education, occupation and wealth/income. Additional refinement was done based on experience and job status. Content validity was calculated through experts' opinions and reliability through test/retest. Based on experts' opinions, it was found that the calculated content validity ratio for the SES index was relatively high and the correlation coefficient reliability for the six variables (education, occupation, income, wealth, experience and job status) was very high. Thus, the suggested method is reasonably valid, reliable as well as easy to calculate. PMID- 29270968 TI - Toxic metals in maternal blood, cord blood and meconium of newborn infants in Pakistan. AB - Toxic metals and deficiency/excess of trace elements can have adverse effects on health. The aim of this study was to quantify toxic metals lead, cadmium and trace elements zinc, copper, aluminium (Al) and Iron (Fe) levels in pregnant women, cord blood and meconium of new-born infants from industrial zones of Karachi, Pakistan. Analytical research was performed from 2011-2012 in low socio economic pregnant mothers and newborn infants from 20 towns near Sindh Industrial Trading Estates, Federal B industrial area and Korangi industrial areas, Karachi, where environmental pollution was anticipated. Blood samples of pregnant women (n = 416), cord blood (n = 309) and meconium (n = 309) were analyzed quantitatively for metals and trace elements. Results indicated that mothers residing in steel towns were found to have the highest levels of lead. Meconium contained high levels of toxic heavy metals and trace elements compared to cord blood and maternal blood. Maternal blood toxic metals were present in high quantities. Therefore, safety measures should be taken when industrial waste is disposed of in order to prevent population contamination. PMID- 29270969 TI - Pregnancy outcome variables and associated factors in different nationalities living in Kuwait. AB - This study aimed to investigate differences in pregnancy outcome among various nationalities residing in Kuwait. Cross-sectional data were collected from 369 mother-infant dyads at delivery on mother height (MH), mother haemoglobin (mHb), child haemoglobin (cHb), mid-upper arm circumference (MUAC), gestational age (GA), placental weight (PW), birth weight (BW), crown-heal length (CHL), and head circumference (HC). Significant differences among various nationalities were observed in mHb, HC, CHL, PW and MH. Kuwaiti and Indian women had lower PW and their babies had lower HC and CHL. Prevalence of anaemia (Hb <11.0 g/dL) ranged from 7.1% (Lebanese) to 30.0% (Kuwaiti) with the overall prevalence of 19.5%. Prevalence of low birth weight was 3.5%. Multiple linear regression analysis revealed PW as a significant predictor of BW, CHL and HC. Significant differences among various nationalities were observed in mHb, HC, CHL, PW and MH.The significance of these differences and their contributing factors needs further research. PMID- 29270970 TI - Near-miss cases admitted to a maternal intensive care unit, Alexandria, Egypt. AB - Survival of severe pregnancy complication is known as maternal near-miss; however, studies on maternal near-miss are few in the Eastern Mediterranean Region. To identify the predisposing factors and diagnoses of near-miss cases, patients admitted to the maternal intensive care unit of El-Shatby University Hospital in Alexandria, Egypt, were assessed. A prospective survey was conducted where 448 cases that fulfill the WHO criteria of near-miss and admitted to El Shatby maternal intensive care unit during 2014 were interviewed, their records were reviewed and were followed up to assess their outcome. Low maternal education and inadequate antenatal care were significantly associated with maternal mortality. Severe pre-eclampsia and post-partum hemorrhage were the most common causes of admission (40.2% and 23.8% respectively). Mortality index was 8.5%. Sepsis and multiple organ dysfunction were significant predictors of maternal mortality. PMID- 29270971 TI - First study in Qatar to reveal high Legionella counts in cooling towers. AB - Legionella spp. is transmitted from water to humans by aerosol-generating devices, including cooling towers (CTs). There have not been published reports about Legionella in these systems in Qatar. Ten CTs in Qatar University were sampled on a monthly basis. Bacteria were recovered from 90 water samples by filtration and concentration. Legionella DNA copy number (CN) was assessed by quantitative RT-PCR. Legionella DNA was detected in 100% of the samples. The bacterial counts ranged from 0.006 to 199.56 CFU/mL, and critical counts were found in 51 (56.7 %) samples. Moreover, 7 (7.8%) samples showed a count of more than 100 CFU/mL. The highest counts were found in the months of May and June. These results suggest that this organism is found in high number in tested CTs, presenting a potential health risk to the local population. PMID- 29270972 TI - Sodium chloride composition of commercial white bread in Morocco. AB - This study aimed to evaluate the amount of salt provided by the consumption of bread in daily food intake and compare it to recommended salt intake. Chloride ion concentrations were measured using Mohr's Method to indirectly quantify added salt in bread samples from 80 professional bakeries in Casablanca, Morocco. Results showed that the average amount of added salt during the preparation of white bread is 17.42 +/- 1.28 g / kg, which is the equivalent of a daily intake of 8 to 9 g of salt through bread alone, and exceeds all recommendations. The high salt content of white bread might be a contributing factor to the high sodium intake in Morocco, especially considering that bread is a staple food in the country. Any policies or initiatives to reduce sodium consumption should target bread as a strategic vehicle to reduce salt intake. PMID- 29270974 TI - WHO events addressing public health priorities. PMID- 29270973 TI - Assessment of World Health Organization Collaborating Centres in the Eastern Mediterranean Region. AB - Following in-house training, there was a need for assessing perceived performance of World Health Organization (WHO) collaborating centres in the Eastern Mediterranean Region, with special relevance to WHO's programme of work. Thus, a questionnaire was shared with responsible officers covering: selection process, frequency of communication, monitoring mechanisms, key delivered activities, and identified gaps during implementation. These included: tendency to implement regular activities, weak technical capacity and communication, and discrepancies between planned activities and actual implementation. Recommendations for centres included: establishing communication plan/modalities, selecting activities of global/regional nature, and mobilizing resources for work plan implementation. Recommendations for responsible officers included: carefully explaining updated WHO rules and regulations; ensuring that specific terms of reference are set as per WHO's global/regional mandates; setting up regular communication mechanisms; agreeing on regular monitoring and coordination modalities; and ensuring that redesignation planning takes place during the 4th year of prior designation period. PMID- 29270975 TI - Intracranial 4D flow magnetic resonance imaging reveals altered haemodynamics in sickle cell disease. AB - Stroke risk in children with sickle cell disease (SCD) is currently assessed with routine transcranial Doppler ultrasound (TCD) measurements of blood velocity in the Circle of Willis (CoW). However, there is currently no biomarker with proven prognostic value in adult patients. Four-dimensional (4D) flow magnetic resonance imaging (MRI) may improve risk profiling based on intracranial haemodynamics. We conducted neurovascular 4D flow MRI and blood sampling in 69 SCD patients [median age 15 years (interquartile range, IQR: 12-50)] and 14 healthy controls [median age 21 years (IQR: 18-43)]. We measured velocity, flow, lumen area and endothelial shear stress (ESS) in the CoW. SCD patients had lower haematocrit and viscosity, and higher velocity, flow and lumen area, with lower ESS compared to healthy controls. We observed significant age-related decline in haemodynamic 4D flow parameters; velocity (Spearman's rho = -0.36 to -0.61), flow (rho = -0.26 to -0.52) and ESS (rho = -0.14 to -0.54) in SCD patients. Further analysis in only adults showed that velocity values were similar in SCD patients compared to healthy controls, but that the additional 4D flow parameters, flow and lumen area, were higher, and ESS lower, in the SCD group. Our data suggest that 4D flow MRI may identify adult patients with an increased stroke risk more accurately than current TCD-based velocity. PMID- 29270976 TI - Are early-life antecedents of suicide mortality associated with psychiatric disorders and suicidal ideation in midlife? AB - OBJECTIVE: To establish whether previously identified early-life antecedents of suicide mortality (i.e. low birthweight, younger maternal age, higher birth order, externalizing problems and adversities) are associated with proximal psychiatric disorders and suicidal ideation, which are themselves associated with an increased risk of suicide. METHODS: Participants were from the 1958 British birth-cohort (N = 8905) with information on prenatal/childhood experiences and the Clinical Interview Schedule-Revised at age 45 years. Outcomes were as follows: any internalizing disorder (anxiety disorder/depressive episode), depressive episode, alcohol use disorder and suicidal ideation. RESULTS: After adjustment, higher birth order (Ptrend = 0.043), younger maternal age (Ptrend = 0.017) and increased number of childhood adversities (Ptrend = 0.026) were associated with an increased risk of internalizing disorders. For example, the OR (95% CI) in fourth- or later-born children was 1.48 (1.06-2.07) and for young maternal age (<19 years) was 1.31 (0.89-1.91). Effect sizes were similar in magnitude for depressive episode and suicidal ideation, although associations did not reach conventional significance levels. No associations were found for low birthweight and externalizing problems (in males) and investigated outcomes. CONCLUSION: Associations for younger maternal age, higher birth order and adversities with adult internalizing disorders suggest that psychiatric disorders may be on the pathway linking some early-life factors and suicide. PMID- 29270977 TI - A novel IFIH1 mutation in the pincer domain underlies the clinical features of both Aicardi-Goutieres and Singleton-Merten syndromes in a single patient. PMID- 29270978 TI - General single-index survival regression models for incident and prevalent covariate data and prevalent data without follow-up. AB - This article mainly focuses on analyzing covariate data from incident and prevalent cohort studies and a prevalent sample with only baseline covariates of interest and truncation times. Our major task in both research streams is to identify the effects of covariates on a failure time through very general single index survival regression models without observing survival outcomes. With a strict increase of the survival function in the linear predictor, the ratio of incident and prevalent covariate densities is shown to be a non-degenerate and monotonic function of the linear predictor under covariate-independent truncation. Without such a structural assumption, the conditional density of a truncation time in a prevalent cohort is ensured to be a non-degenerate function of the linear predictor. In light of these features, some innovative approaches, which are based on the maximum rank correlation estimation or the pseudo least integrated squares estimation, are developed to estimate the coefficients of covariates up to a scale factor. Existing theoretical results are further used to establish the n -consistency and asymptotic normality of the proposed estimators. Moreover, extensive simulations are conducted to assess and compare the finite-sample performance of various estimators. To illustrate the methodological ideas, we also analyze data from the Worcester Heart Attack Study and the National Comorbidity Survey Replication. PMID- 29270979 TI - Australian veterinarians - global challenges. AB - This paper discusses the wide range of roles that Government veterinarians play both in Australia and globally. The paper was presented as a plenary session at the National Australian Veterinary Association Annual Conference. PMID- 29270980 TI - Eltrombopag, low-dose rituximab, and dexamethasone combination as frontline treatment of newly diagnosed immune thrombocytopaenia. PMID- 29270981 TI - Acculturation, depression and oral health of immigrants in the USA. AB - OBJECTIVES: The objectives were to describe the oral health status of immigrants in the USA, describe the association between acculturation and oral health by accounting for the effects of depression and to explore the effects of interaction between acculturation and depression on the oral health of immigrants. METHODS: Data were from the 2011-2012 National Health and Nutrition Examination Survey (NHANES). Oral health status was assessed by both self-rated oral health and clinically diagnosed periodontitis, each coded as a binary outcome. Acculturation was operationalised as length of stay in the USA and speaking English at home. Depression was assessed using the Patient Health Questionnaire-9. Multiple logistic regression models were used to examine the association of acculturation and depression status with oral health. RESULTS: In 2011-2012, 36.6% immigrants reported poor oral health and 53.0% were diagnosed with periodontitis. A length of stay in the USA of 30+ years (adjusted odds ratio [AOR] = 0.43, 95% confidence interval [95% CI]: 0.21-0.89) reduced the odds of having periodontitis in comparison with a length of stay in the USA of fewer than 5 years. Speaking English at home (AOR = 0.64, 95% CI: 0.43-0.96) reduced the odds of having periodontitis compared with speaking other languages. Depression was negatively associated with self-reported good oral health (AOR = 0.43, 95% CI: 0.20-0.92) and positively associated with clinically diagnosed periodontitis (AOR = 1.89, 95% CI: 1.18-3.04). The effects of acculturation did not differ according to depression status. CONCLUSION: A longer stay in the USA and speaking English at home were associated with less periodontitis among the immigrants. PMID- 29270982 TI - A comparison of minimal residual disease detection in autografts among ASO-qPCR, droplet digital PCR, and next-generation sequencing in patients with multiple myeloma who underwent autologous stem cell transplantation. PMID- 29270983 TI - Recent advances in understanding the pathogenesis and management of reticular dysgenesis. AB - Reticular Dysgenesis is a rare immunodeficiency which is clinically characterized by the combination of Severe Combined Immunodeficiency (SCID) with agranulocytosis and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 (AK2) were identified to cause this phenotype. In this review, we will demonstrate important clinical differences between reticular dysgenesis and other SCID entities and summarize recent concepts in the understanding of the pathophysiology of the disease and the management strategies for this difficult condition. PMID- 29270984 TI - G protein-coupled receptor gpr34l mutation affects thrombocyte function in zebrafish. AB - Haemostasis is a defence mechanism that has evolved to protect organisms from losing their circulating fluid. We have previously introduced zebrafish as a model to study the genetics of haemostasis to identify novel genes that play a role in haemostasis. Here, we identify a zebrafish mutant that showed prolonged time to occlusion (TTO) in the laser injury venous thrombosis assay. By linkage analysis and fine mapping, we found a mutation in the orphan G protein-coupled receptor 34 like gene (gpr34l) causing a change of Val to Glu in the third external loop of Gpr34l. We have shown that injection of zebrafish gpr34l RNA rescues the prolonged TTO defect. The thrombocytes from the mutant showed elevated levels of cAMP that supports the defective thrombocyte function. We also have demonstrated that knockdown of this gene by intravenous Vivo-Morpholino injections yielded a phenotype similar to the gpr34l mutation. These results suggest that the lack of functional Gpr34l leads to increased cAMP levels that result in defective thrombocyte aggregation. PMID- 29270985 TI - Inverse correlation of Vdelta2+ T-cell recovery with EBV reactivation after haematopoietic stem cell transplantation. AB - Epstein-Barr virus (EBV) reactivation remains a life-threatening complication in recipients of a haploidentical haematopoietic stem cell transplantation (haploHSCT). Reconstitution of adaptive T lymphocytes is generally compromised at the early stages following transplant, suggesting an important role of other effector cells in preventing EBV infection. Our previous studies demonstrated that recovery of CD4- CD8- T cells negatively correlated with EBV reactivation after haploHSCT. In this prospective study on 132 adult patients with haematopoietic malignancy, recovery of T-cell subpopulations was characterized post-haploHSCT. We showed that the median counts of peripheral Vdelta2 cells were continuously lower in recipients with EBV reactivation compared with controls at 30, 60 and 90 days after haploHSCT (P values: 0.006, <0.001 and 0.019, respectively). Landmark study further indicated that the cumulative incidence of EBV reactivation was significantly decreased in recipients with higher day-30 Vdelta2 counts. Activation of Vdelta2 cells upon EBV reactivation was accompanied by an induction of cell apoptosis. Cytotoxic effect of Vdelta2 cells on EBV infected cells was confirmed by in vitro experiments. Together, our findings uncovered a significant correlation of recovered Vdelta2 with EBV reactivation following haploHSCT. These results will help to better understand the intrinsic anti-virus immunity and develop gammadelta T-based therapy strategies after haematopoietic transplantation. PMID- 29270986 TI - Bone microarchitecture and bone mineral density in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) patients are at increased risk of reduced bone mineral density (BMD) and fractures. The aetiology of bone loss in MS is unclear. Trabecular bone score (TBS) is a novel analytical tool that provides a measurement of the bone microarchitecture. Decreased TBS predicts increased fracture risk independently of BMD. To date, no studies have investigated TBS in MS patients. OBJECTIVES: To assess bone quality in MS patients by TBS and to evaluate potential risk factors that may affect BMD and TBS in patients with MS. METHODS: Two hundred sixty MS patients were included. TBS was calculated using TBS iNsight software (MediMaps(r) ). Multivariable regression analyses were performed with information on smoking, alcohol, glucocorticoid (GC) treatment, sun exposure, physical activity, vitamin D and BMI. RESULTS: Trabecular bone score was not significantly different from an age-matched reference population. Low TBS was associated with high age (P = .014) and smoking (P = .03). Smoking and physical inactivity were associated with low BMD in spine (P = .034, P = .032). GC treatment was not associated with TBS. CONCLUSION: We could not find altered TBS values among MS patients, suggesting that BMD alone, and not the bone microarchitecture, is affected in MS. However, larger studies are needed to verify these findings and to establish the role of TBS in MS. As in the background population, physical activity and non-smoking habits are associated with better bone health in MS. PMID- 29270987 TI - Exploring the perceived usefulness of practical food groups in day treatment for individuals with eating disorders. AB - BACKGROUND/AIM: Recovery from eating disorders is a challenging process. Emerging literature suggests that occupational therapists may provide a useful contribution in delivering purposeful eating-related interventions as a potential treatment to support sustained cognitive and behavioural changes for individuals with eating disorders. This study aimed to evaluate participants' perceptions of the contribution of occupational therapy practical food groups (food based outings and cooking groups) in supporting their functional recovery. METHODS: Individuals attended practical food groups as part of standard treatment at an outpatient eating disorders day program. Ninety-nine participants completed questionnaires at discharge and up to three follow-up points (6, 12 and 24 months). Questions related to practical food groups were analysed, exploring participants' experiences and perceived usefulness of groups using rating-scale and open-ended questions. Open-ended responses were analysed using thematic analysis. Descriptive statistics were calculated for responses to rating-scale questions. RESULTS: At discharge, participants rated the importance and usefulness of practical food groups as high (4.73 and 4.43 on 5-point scales, respectively), but tended to rate their enjoyment of the groups lower (3.50 on a 5-point scale). Some skill transfer was typically reported by participants at discharge (3.92 on a 5-point scale). One core theme, 'success through participation', emerged from qualitative comments. Six subthemes were also identified: helpful components of practical food groups; perceived benefit of exposure; impact of applying cognitive and behavioural skills; challenges affecting participation; facilitating adaptation; and influence of eating disorders on challenging feared foods. CONCLUSION: This study highlights that participation in practical food groups was perceived as useful in assisting individuals to improve eating behaviours and, in some circumstances, transfer these skills into their lives outside of day program. Results suggest that occupational therapists may have an important contribution in delivering these interventions to support recovery and facilitate application of adaptive coping strategies. PMID- 29270988 TI - The association of weight change in young adulthood and smoking status with risk of prostate cancer recurrence. AB - The decades before prostate cancer diagnosis represent an etiologically relevant time period for prostate cancer carcinogenesis. However, the association of weight gain in young adulthood with subsequent biochemical recurrence among men with prostate cancer is not well studied, particularly among smokers. We conducted a prospective cohort study of 1,082 men with prostate cancer and treated with either radical prostatectomy or radiation between 2003 and 2010. The association of weight at age 20, weight at age 50 and weight change from age 20 to age 50 with biochemical recurrence was assessed using Cox Proportional Hazards with adjustment for confounders. Stratum-specific hazard ratio (HR) estimates by smoking status were evaluated. In the overall cohort, weight at age 20 (HR per 30 kg: 1.56, 95% confidence interval (CI): 1.02, 2.38, p-trend: 0.039), weight at age 50 (HR per 30 kg: 1.80, 95% CI: 1.32, 2.47, p-trend: <0.001) and weight change from age 20 to age 50 (HR per 30 kg: 1.84, 95% CI: 1.24, 2.74, p-trend: 0.003) were associated with biochemical recurrence. In stratified analyses, weight change from age 20 to age 50 was significantly associated with biochemical recurrence only in former smokers (HR per 30 kg: 3.87, 95% CI: 1.88, 8.00, p trend: <0.001) and ever smokers (HR per 30 kg: 2.38, 95% CI: 1.27, 4.45, p-trend: 0.007). No significant association was observed between weight gain in young adulthood and biochemical recurrence in never smokers. Our study adds further evidence that weight gain during early adult years conveys long-term risk for adverse cancer outcomes. PMID- 29270989 TI - Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis. AB - OBJECTIVE: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years). METHODS: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or >=50% seizure reduction. RESULTS: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies. SIGNIFICANCE: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria. PMID- 29270991 TI - Using the cognitive interviewing process to improve survey design by allied health: A qualitative study. AB - BACKGROUND/AIM: Allied health professionals frequently use surveys to collect data for clinical practice and service improvement projects. Careful development and piloting of purpose-designed surveys is important to ensure intended measuring (that respondents correctly interpret survey items when responding). Cognitive interviewing is a specific technique that can improve the design of self-administered surveys. The aim of this study was to describe the use of the cognitive interviewing process to improve survey design, which involved a purpose designed, online survey evaluating staff use of functional electrical stimulation. METHODS: A qualitative study involving one round of cognitive interviewing with three occupational therapists and three physiotherapists. RESULTS: The cognitive interviewing process identified 11 issues with the draft survey, which could potentially influence the validity and quality of responses. The raised issues included difficulties with: processing the question to be able to respond, determining a response to the question, retrieving relevant information from memory and comprehending the written question. Twelve survey amendments were made following the cognitive interviewing process, comprising four additions, seven revisions and one correction. CONCLUSIONS: The cognitive interviewing process applied during the development of a purpose-designed survey enabled the identification of potential problems and informed revisions to the survey prior to its use. PMID- 29270990 TI - Using the fast fourier transform in binding free energy calculations. AB - According to implicit ligand theory, the standard binding free energy is an exponential average of the binding potential of mean force (BPMF), an exponential average of the interaction energy between the unbound ligand ensemble and a rigid receptor. Here, we use the fast Fourier transform (FFT) to efficiently evaluate BPMFs by calculating interaction energies when rigid ligand configurations from the unbound ensemble are discretely translated across rigid receptor conformations. Results for standard binding free energies between T4 lysozyme and 141 small organic molecules are in good agreement with previous alchemical calculations based on (1) a flexible complex ( R~0.9 for 24 systems) and (2) flexible ligand with multiple rigid receptor configurations ( R~0.8 for 141 systems). While the FFT is routinely used for molecular docking, to our knowledge this is the first time that the algorithm has been used for rigorous binding free energy calculations. (c) 2017 Wiley Periodicals, Inc. PMID- 29270992 TI - How I manage patients with inherited haemophilia A and B and factor inhibitors. AB - Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. 'Bypassing agents' may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at 'good' or 'bad risk' for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities. PMID- 29270993 TI - Use of hormone replacement therapy improves the prognosis in patients with colorectal cancer: A population-based study in Sweden. AB - The association between hormone therapy (estrogen, with or without progesterone) and colorectal cancer (CRC) has received considerable scientific interest but previous research has generated inconsistent results. We aimed to examine whether post-diagnostic use of hormone therapy might protect against CRC mortality and all-cause mortality. Women diagnosed with CRC between January 2007 and December 2012 were identified from the Swedish Cancer Registry and linked to the Swedish Prescribed Drug Register to retrieve hormone therapy users after CRC diagnosis. A total of 1,109 patients were diagnosed with CRC and used hormone therapy post-CRC diagnosis. Time-dependent Cox regression with 1-year lag was used to calculate the hazard ratio (HR) of CRC mortality and all-cause mortality associated with post-diagnostic use of hormone therapy. Use of hormone therapy after CRC diagnosis was associated with a 26% risk reduction in CRC mortality (HR = 0.67, 95%CI 0.56-0.79) and a 30% risk reduction in all-cause mortality (HR = 0.68, 95%CI 0.59-0.77). The risk reduction was even stronger if women also used hormone therapy before the diagnosis of CRC and for women with higher cumulative doses of hormone therapy. The risk reduction was largely consistent irrespective of CRC severity. Our data suggests that use of hormone therapy after CRC diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality. PMID- 29270994 TI - Rational ideation and empiric validation of an innovative digital dermographic tester. AB - BACKGROUND: Dermographism is a condition characterized by a weal response to a combination of pressure and traction on skin surface, and its diagnosis is based on medical history, clinical criteria and provocation test. The Dermographic Tester(r) , a pen-sized tool containing a spring-loaded blunt tip, is the most widely used instrument for the provocation test, and it exerts increasing pressures on the skin surface according to an arbitrary units (AU) scale. Analysing the mechanism of function and trying to convert the AUs to SI units (g/mm2 ), we found that this instrument had some defects and limits that would compromise a true and repeatable quantification of the weal response threshold. Consequently, we decided to develop a new instrument, the Digital Dermographic Tester (DDT), which is engineered with an inside force sensor to implement features lacking in the current tools, in the hope of enhancing the precision of the provocation test. AIM: To validate the effectiveness and accuracy of the DDT. METHODS: We tested the DDT on 213 participants purposely sampled to obtain three groups, each with a different pattern of reaction to mechanical stimuli. Based on anamnestic, diagnostic and symptomatic criteria, patients were divided into dermographic urticaria (DU), spontaneous urticaria (SU) and healthy control (HC) groups. The DDT was used to apply 12 levels of pressure to the skin surface, and a frequency distribution of positive reactions was displayed for each group. RESULTS: A force of 36-40 g/mm2 appropriately differentiated physiological from pathological conditions with high sensitivity and specificity. CONCLUSIONS: The DDT was found to be capable of differentiating patients with DU patients from those with SU and from HCs, and was able to precisely identify the weal elicitation threshold. PMID- 29270995 TI - HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease. AB - BACKGROUND: Azathioprine (AZA)-induced pancreatitis is an unpredictable and dose independent adverse event affecting 2%-7% of patients with inflammatory bowel disease (IBD) patients treated with AZA. There are no tools in clinical practice to identify at-risk individuals; however, a genome wide association study (GWAS) identified a strong association between the Class II HLA gene region polymorphism (rs2647087) and thiopurine-induced pancreatitis. AIM: To independently confirm the findings of the GWAS in an IBD cohort, to evaluate its utility in clinical practice and to offer a novel AZA treatment algorithm for IBD based on pharmacogenomic principles. METHODS: A retrospective cohort study evaluated 373 AZA-exposed IBD patients from a tertiary care academic centre in London, Canada. Due to the limited number of patients taking mercaptopurine (MP), such patients were not included this cohort. All subjects underwent screening for the single nucleotide polymorphism (SNP) rs2647087 mapped to the HLA-DQA1*02:01-HLA DRB1*07:01 haplotype and were sub-divided based on the presence (n = 13) or absence (n = 360) of an AZA-induced pancreatitis diagnosis. The risk of AZA induced pancreatitis was assessed based on rs2647087 genotype. RESULTS: The risk of pancreatitis during AZA-therapy was highly predictable and genotype dependent: 0.53% for wild type (A/A), 4.25% (OR = 4.19, 95% CI 1.02-36.45, P = 0.044) for heterozygous (A/C), and 14.63% (OR = 15.83, 95% CI 3.80-145.26, P = 0.0001) for homozygous variant (C/C) patients. CONCLUSIONS: The class II HLA region (at rs2647087) is an important marker of AZA-induced pancreatitis risk. We propose a simple and clinically implementable algorithm based on rs2647087 and TPMT genotypes for AZA selection and dosing for patients with IBD. PMID- 29270996 TI - Actions of p-synephrine on hepatic enzyme activities linked to carbohydrate metabolism and ATP levels in vivo and in the perfused rat liver. AB - p-Synephrine is one of the main active components of the fruit of Citrus aurantium (bitter orange). Extracts of the bitter orange and other preparations containing p-synephrine have been used worldwide to promote weight loss and for sports performance. The purpose of the study was to measure the action of p synephrine on hepatic enzyme activities linked to carbohydrate and energy metabolism and the levels of adenine mononucleotides. Enzymes and adenine mononucleotides were measured in the isolated perfused rat liver and in vivo after oral administration of the drug (50 and 300 mg/kg) by using standard techniques. p-Synephrine increased the activity of glycogen phosphorylase in vivo and in the perfused liver. It decreased, however, the activities of pyruvate kinase and pyruvate dehydrogenase also in vivo and in the perfused liver. p Synephrine increased the hepatic pools of adenosine diphosphate and adenosine triphosphate. Stimulation of glycogen phosphorylase is consistent with the reported increased glycogenolysis in the perfused liver and increased glycemia in rats. The decrease in the pyruvate dehydrogenase activity indicates that p synephrine is potentially capable of inhibiting the transformation of carbohydrates into lipids. The capability of increasing the adenosine triphosphate-adenosine diphosphate pool indicates a beneficial effect of p synephrine on the cellular energetics. PMID- 29270997 TI - The anatomy of free fibula osteoseptocutaneous flap in neophalloplasty in transgender surgery. AB - The Free Fibula Osteoseptocutaneous flap is a reliable option when used in neophalloplastic procedures. It possesses intrinsic rigidity that is sufficient for penetrative intercourse, and satisfactory sensation. We review the pros and cons of this procedure, as well the anatomy and surgical steps involved. Surgical text descriptions were enhanced by the creation of new anatomic illustrations. Anatomy of the donor and recipient sites, as well as the surgical technique leading to creation of the neophallus are demonstrated in detail with new relevant illustrations. The free fibula osteoseptocutaneous flap provides the neophallus with many desirable characteristics. Its thick subcutaneous and fascial layer, along with the thicker fibula (compared to the radius), allows for a neophallus of greater diameter. Skin marking, flap lifting, and transfer to the perineum with all relevant neurovascular anastomosis; fibular artery is anastomosed with the femoral artery, while the fibular veins are anastomosed to branches of the saphenous vein, as well as neurorrhaphy of the dorsal nerves of the clitoris and the LSCN are demonstrated. The osteomatized fibula is fixed to the periosteum of the pubic symphysis as shown. Anatomical traits of the Free Fibula Osteoseptocutaneous flap allow intercourse without prosthesis. The donor site scar in this procedure can be covered by a long sock, and donor site morbidity is acceptable. Clin. Anat. 31:169-174, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29270998 TI - Revealing life-history traits by contrasting genetic estimations with predictions of effective population size. AB - Effective population size, a central concept in conservation biology, is now routinely estimated from genetic surveys and can also be theoretically predicted from demographic, life-history, and mating-system data. By evaluating the consistency of theoretical predictions with empirically estimated effective size, insights can be gained regarding life-history characteristics and the relative impact of different life-history traits on genetic drift. These insights can be used to design and inform management strategies aimed at increasing effective population size. We demonstrated this approach by addressing the conservation of a reintroduced population of Asiatic wild ass (Equus hemionus). We estimated the variance effective size (Nev ) from genetic data (N ev =24.3) and formulated predictions for the impacts on Nev of demography, polygyny, female variance in lifetime reproductive success (RS), and heritability of female RS. By contrasting the genetic estimation with theoretical predictions, we found that polygyny was the strongest factor affecting genetic drift because only when accounting for polygyny were predictions consistent with the genetically measured Nev . The comparison of effective-size estimation and predictions indicated that 10.6% of the males mated per generation when heritability of female RS was unaccounted for (polygyny responsible for 81% decrease in Nev ) and 19.5% mated when female RS was accounted for (polygyny responsible for 67% decrease in Nev ). Heritability of female RS also affected Nev ; hf2=0.91 (heritability responsible for 41% decrease in Nev ). The low effective size is of concern, and we suggest that management actions focus on factors identified as strongly affecting Nev, namely, increasing the availability of artificial water sources to increase number of dominant males contributing to the gene pool. This approach, evaluating life history hypotheses in light of their impact on effective population size, and contrasting predictions with genetic measurements, is a general, applicable strategy that can be used to inform conservation practice. PMID- 29270999 TI - Therapeutic plasma exchange for thrombotic thrombocytopenic purpura with refractory thrombocytopenia. AB - Thrombotic thrombocytopenic purpura (TTP) is an acute, life-threatening illness with disseminated platelet-rich thromboses of small vessels that variably presents with the classic clinical "pentad" of microangiopathic hemolytic anemia, thrombocytopenia, fever, altered mental status, and acute kidney injury. Most cases are caused by an acquired autoantibody to ADAMTS13, a metalloproteinase that cleaves large von Willebrand Factor (vWF) multimers. The mainstay of treatment is daily therapeutic plasma exchange (TPE), sometimes with adjunctive pharmacologic immunosuppression. TPE is generally continued until the platelet count is greater than 150 * 103 /uL and the lactate dehydrogenase is near normal for 2-3 consecutive days. Unfortunately, there is no clear guidance for when thrombocytopenia is refractory for a prolonged period of time. The following case describes such a scenario in which consecutive ADAMTS13 activity and inhibitor levels were used to guide the decision to stop treatment with TPE in a patient who failed to recover their platelet count. PMID- 29271001 TI - Development and Qualification of a Drug-Disease Modeling Platform to Characterize Clinically Relevant Endpoints in Type 2 Diabetes Trials. AB - Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by persistently elevated blood glucose concentration (hyperglycemia). We developed a mechanistic drug-disease modeling platform based on data from more than 4,000 T2DM subjects in seven phase II/III clinical trials. The model integrates longitudinal changes in clinically relevant biomarkers of glycemic control with information on baseline disease state, demographics, disease progression, and different therapeutic interventions, either when given alone or as add-on combination therapy. The model was able to simultaneously characterize changes in fasting plasma glucose, fasting serum insulin, and glycated hemoglobin A1c following administration of sulfonylurea, metformin, and thiazolidinedione as well as disease progression in clinical trials ranging from 16-104 weeks of treatment. The mechanistic components of this generalized mechanism-based platform, based on knowledge of pharmacology, insulin-glucose homeostatic feedback, and diabetes pathophysiology, allows its application to be further expanded to other antidiabetic drug classes and combination therapies. PMID- 29271000 TI - Case report of Schopf-Schulz-Passarge syndrome resulting from a missense mutation, p.Arg104Cys, in WNT10A. AB - Schopf-Schulz-Passarge syndrome (SSPS) is a rare ectodermal dysplasia characterized by cysts of the eyelids, hypodontia, hypotrichosis, palmoplantar keratosis and onychodystrophy, and it is not common in Asia according to the published work. This autosomal recessive disorder was believed to result from mutations in the WNT10A gene. We report a 54-year-old Taiwanese man with SSPS resulted from a homozygous mutation (p.Arg104Cys) in WNT10A. This mutation has not been reported in odonto-onycho-dermal dysplasia but was demonstrated to link with dental abnormalities. This report implies the significance of WNT10A gene mutation in ectodermal dysplasia and highlights the clinical features of SSPS. PMID- 29271002 TI - Neutrophilic urticarial dermatosis: a novel association with poststreptococcal rheumatic disease. AB - Neutrophilic urticarial dermatosis (NUD), a particular clinical and histological entity, can provide a strong pointer to underlying systemic disease, most frequently rheumatological diseases. We report the first case of NUD in association with a post-streptococcal rheumatic disease, with symptoms including recurrent sore throat, raised antistreptolysin O titre, persistent transient urticaria, polyarthralgia, rheumatic mitral valve disease and Jaccoud arthropathy. Histologically, NUD is characterized by an intense superficial and deep neutrophilic interstitial and perivascular infiltrate, without significant oedema or blood vessel damage. These neutrophils may have a tendency to concentrate along the basement membrane and extend into the epidermis, hair follicles, sebaceous glands and sweat glands (a feature termed 'neutrophilic epitheliotropism'). Clinicians should remain cognizant of NUD, and in particular its frequent association with an underlying inflammatory disorder. PMID- 29271003 TI - Evaluation of a P,N-ligated iridium(I) catalyst in hydrogen isotope exchange reactions of aryl and heteroaryl compounds. AB - We have developed a novel and efficient iridium-catalyzed hydrogen isotope exchange reaction method with secondary and tertiary sulfonamides at ambient temperatures. Furthermore N-oxides and phosphonamides have been successfully applied in hydrogen isotope exchange reactions with moderate to excellent deuterium introduction. PMID- 29271004 TI - Oseltamivir and indomethacin reduce the oxidative stress in brain and stomach of infected rats. AB - The aim of this study was to determine the effect of oseltamivir and indomethacin on lipid peroxidation (LP), GABA levels, and ATPase activity in brain and stomach of normal and infected rats (IR), as novel inflammation model. Female Sprague Dawley rats grouped five each, either in the absence or presence of a live culture of Salmonella typhimurium (S. typh), were treated as follows: group 1 (control), PBS buffer; group 2, oseltamivir (100 mg/kg); group 3, indomethacin (67 MUg/rat); group 4, oseltamivir (100 mg/kg) + indomethacin (67 MUg/rat). All drugs were given intraperitoneally for 5 days. IR received the same treatments and the brain and stomach of the rats were removed in order to measure levels of GABA, LP, and total ATPase, using validated methods. Levels of GABA increased in stomach and cortex of IR with oseltamivir, but decreased in striatum and cerebellum/medulla oblongata of IR with indomethacin. LP decreased in the three brain regions of IR with oseltamivir. ATPase increased in stomach of IR and non IR with oseltamivir and in striatum and cerebellum/medulla oblongata of IR with indomethacin. Results suggest that the effect of free radicals produced in an infection and inflammatory condition caused by S. typh could be less toxic by a combination of oseltamivir and indomethacin. PMID- 29271005 TI - Stoichiometry-Controlled Inversion of Supramolecular Chirality in Nanostructures Co-assembled with Bipyridines. AB - To control supramolecular chirality of the co-assembled nanostructures, one of the remaining issues is how stoichiometry of the different molecules involved in co-assembly influence chiral transformation. Through co-assembly of achiral 1,4 bis(pyrid-4-yl)benzene and chiral phenylalanine-glycine derivative hydrogelators, stoichiometry is found to be an effective tool for controlling supramolecular chirality inversion processes. This inversion is mainly mediated by a delicate balance between intermolecular hydrogen bonding interactions and pi-pi stacking of the two components, which may subtly change the stacking of the molecules, in turn, the self-assembled nanostructures. This study exemplifies a simplistic way to invert the handedness of chiral nanostructures and provide fundamental understanding of the inherent principles of supramolecular chirality. PMID- 29271006 TI - Long noncoding RNA LINC00978 promotes cancer growth and acts as a diagnostic biomarker in gastric cancer. AB - OBJECTIVES: Long noncoding RNAs (lncRNAs) play important roles in cancer development and progression. The deregulated expression of LINC00978 has been reported in human cancers. However, the expression pattern and biological roles of LINC00978 in gastric cancer (GC) remain unclear. In this study, we investigated the potential roles and clinical value of LINC00978 in gastric cancer. MATERIALS AND METHODS: QRT-PCR was performed to investigate the expression of LINC00978 in gastric cancer cell lines, tissues and serum samples. Cell counting, colony formation, transwell migration and matrigel invasion assays were performed to determine the effects of shRNA-mediated knockdown of LINC00978 on gastric cancer cell functions. In vivo tumour growth assay was also conducted. Flow cytometry, immunohistochemistry, western blot and qRT-PCR were used for potential mechanism study. RESULTS: LINC00978 expression level was elevated in GC tumour tissues, serum samples and cell lines. The expression level of LINC00978 was significantly correlated with tumour size (P = 0.02), lymphatic metastasis (P = 0.009) and TNM stage (P = 0.009). LINC00978 knockdown inhibited the proliferation of GC cells by suppressing cell cycle progression and inducing apoptosis. LINC00978 knockdown also inhibited the migration and invasion of GC cells. In addition, LINC00978 knockdown inhibited the activation of TGF-beta/SMAD signalling pathway and the process of epithelial-mesenchymal transition (EMT) in GC cells. Moreover, the in vivo tumorigenicity of LINC00978 knockdown GC cells in mice was significantly decreased. CONCLUSIONS: LINC00978 promotes gastric cancer progression and may serve as a potential biomarker for GC. PMID- 29271007 TI - The inhibitory effects of capillarisin on cell proliferation and invasion of prostate carcinoma cells. AB - OBJECTIVES: Capillarisin (Cap), an active component of Artemisia capillaris root extracts, is characterized by its anti-inflammatory, anti-oxidant and anti-cancer properties. Nevertheless, the functions of Cap in prostate cancer have not been fully explored. We evaluated the potential actions of Cap on the cell proliferation, migration and invasion of prostate carcinoma cells. MATERIALS AND METHODS: Cell proliferation and cell cycle distribution were measured by water soluble tetrazolium-1 and flow cytometry assays. The expression of cyclins, p21, p27, survivin, matrix metallopeptidase (MMP2 and MMP9) were assessed by immunoblotting assays. Effects of Cap on invasion and migration were determined by wound closure and matrigel transmigration assays. The constitutive and interlukin-6 (IL-6)-inducible STAT3 activation of prostate carcinoma cells were determined by immunoblotting and reporter assays. RESULTS: Capillarisin inhibited androgen-independent DU145 and androgen-dependent LNCaP cell growth through the induction of cell cycle arrest at the G0/G1 phase by upregulating p21 and p27 while downregulating expression of cyclin D1, cyclin A and cyclin B. Cap decreased protein expression of survivin, MMP-2, and MMP-9 and therefore blocked the migration and invasion of DU145 cells. Cap suppressed constitutive and IL-6 inducible STAT3 activation in DU145 and LNCaP cells. CONCLUSIONS: Our data indicate that Cap blocked cell growth by modulation of p21, p27 and cyclins. The inhibitory effects of Cap on survivin, MMP-2, MMP-9 and STAT3 activation may account for the suppression of invasion in prostate carcinoma cells. Our data suggest that Cap might be a therapeutic agent in treating advanced prostate cancer with constitutive STAT3 or IL-6-inducible STAT3 activation. PMID- 29271008 TI - Autonomous Motility of Polymer Films. AB - Adaptive soft materials exhibit a diverse set of behaviors including reconfiguration, actuation, and locomotion. These responses however, are typically optimized in isolation. Here, the interrelation between these behaviors is established through a state space framework, using Nylon 6 thin films in a humidity gradient as an experimental testbed. It is determined that the dynamic behaviors are a result of not only a response to but also an interaction with the applied stimulus, which can be tuned via control of the environment and film characteristics, including size, permeability, and coefficient of hygroscopic expansion to target a desired behavior such as multimodal locomotion. Using these insights, it is demonstrated that films simultaneously harvest energy and information from the environment to autonomously move down a stimulus gradient. Improved understanding of the coupling between an adaptive material and its environment aids the development of materials that integrate closed loop autonomous sensing, actuation, and locomotion. PMID- 29271009 TI - Automatic mining of symptom severity from psychiatric evaluation notes. AB - OBJECTIVES: As electronic mental health records become more widely available, several approaches have been suggested to automatically extract information from free-text narrative aiming to support epidemiological research and clinical decision-making. In this paper, we explore extraction of explicit mentions of symptom severity from initial psychiatric evaluation records. We use the data provided by the 2016 CEGS N-GRID NLP shared task Track 2, which contains 541 records manually annotated for symptom severity according to the Research Domain Criteria. METHODS: We designed and implemented 3 automatic methods: a knowledge driven approach relying on local lexicalized rules based on common syntactic patterns in text suggesting positive valence symptoms; a machine learning method using a neural network; and a hybrid approach combining the first 2 methods with a neural network. RESULTS: The results on an unseen evaluation set of 216 psychiatric evaluation records showed a performance of 80.1% for the rule-based method, 73.3% for the machine-learning approach, and 72.0% for the hybrid one. CONCLUSIONS: Although more work is needed to improve the accuracy, the results are encouraging and indicate that automated text mining methods can be used to classify mental health symptom severity from free text psychiatric notes to support epidemiological and clinical research. PMID- 29271010 TI - Impact of a novel biomarker, T-LAK cell-originating protein kinase (TOPK) expression on outcome in malignant glioma. AB - This study aimed to evaluate the biological features of T-lymphokine-activated killer cell-originating protein kinase (TOPK) in vitro and to assess clinical impact of TOPK on the outcome in patients with malignant glioma. TOPK protein level and TOPK mRNA and protein levels in six glioma cell lines were examined using Western blot and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Immunohistochemistry was performed to examine their subcellular localization of TOPK. Using surgical specimens from 57 patients with gliomas, TOPK and Ki-67 expressions were examined by immunohistochemistry. Their co localization was also examined with double immunofluorescence immunohistochemistry. Impacts of TOPK/Ki-67 expression on the overall survival (OS) and progression-free survival (PFS) in 32 patients with glioblastoma multiforme (GBM) were examined, using Kaplan-Meier and Cox proportion hazard models. Immunohistochemistry revealed that approximately 20-30% of glioma cells were positive for TOPK in vitro. TOPK mRNA was identified in all glioma cell lines on RT-PCR. The value of TOPK/GAPDH was 0.27 +/- 0.11. TOPK and Ki-67 expressions were significantly higher in GBM patients than in non-GBM patients. A majority of TOPK-positive cells were also positive for Ki-67 and vice versa. Multivariate analysis revealed that a low TOPK expression (<= 12.7%) was an independent predictor of longer OS (P = 0.0372), and that gross total removal and a low TOPK expression (<= 12.7%) were independent predictors of longer PFS (P = 0.0470 and P = 0.0189, respectively). The findings strongly suggest biological and clinical importance of TOPK expression in gliomas, indicating a novel therapeutic potential of TOPK inhibitors to treat malignant gliomas. PMID- 29271011 TI - Insights into the metabolic functioning of a multipartner ciliate symbiosis from oxygen-depleted sediments. AB - Symbioses between anaerobic or microaerophilic protists and prokaryotes are common in anoxic and oxygen-depleted habitats ranging from marine sediments to gastrointestinal tracts. Nevertheless, little is known about the mechanisms of metabolic interaction between partners. In these putatively syntrophic associations, consumption of fermentative end products (e.g., hydrogen) by the prokaryotic symbionts is thought to facilitate protistan anaerobic metabolism. Here, we employed metagenomic and metatranscriptomic sequencing of a microaerophilic or anaerobic karyorelictid ciliate and its prokaryotic symbionts from oxygen-depleted Santa Barbara Basin (CA, USA) sediments to assess metabolic coupling within this consortium. This sequencing confirmed the predominance of deltaproteobacterial symbionts from the Families Desulfobacteraceae and Desulfobulbaceae and suggested active symbiont reduction of host-provided sulphate, transfer of small organic molecules from host to symbionts and hydrogen cycling among the symbionts. In addition, patterns of gene expression indicated active cell division by the symbionts, their growth via autotrophic processes and nitrogen exchange with the ciliate host. Altogether, this research underscores the importance of symbiont metabolism to host fermentative metabolism and, thus, likely its success in anoxic and low-oxygen habitats, but also suggests ciliate associated prokaryotes play a role in important biogeochemical processes. PMID- 29271012 TI - Nuclear magnetic resonance-based determination of dioxygen binding sites in protein cavities. AB - The location and ligand accessibility of internal cavities in cysteine-free wild type T4 lysozyme was investigated using O2 gas-pressure NMR spectroscopy and molecular dynamics (MD) simulation. Upon increasing the concentration of dissolved O2 in solvent to 8.9 mM, O2 -induced paramagnetic relaxation enhancements (PREs) to the backbone amide and side chain methyl protons were observed, specifically around two cavities in the C-terminal domain. To determine the number of O2 binding sites and their atomic coordinates from the 1/r6 distance dependence of the PREs, we established an analytical procedure using Akaike's Information Criterion, in combination with a grid-search. Two O2 accessible sites were identified in internal cavities: One site was consistent with the xenon-binding site in the protein in crystal, and the other site was established to be a novel ligand-binding site. MD simulations performed at 10 and 100 mM O2 revealed dioxygen ingress and egress as well as rotational and translational motions of O2 in the cavities. It is therefore suggested that conformational fluctuations within the ground-state ensemble transiently develop channels for O2 association with the internal protein cavities. PMID- 29271013 TI - Do needle and syringe programs reduce risky behaviours among people who inject drugs in Kermanshah City, Iran? A coarsened exact matching approach. AB - INTRODUCTION AND AIMS: In this study, we used a 'coarsened exact matching' method to evaluate the relationship between two levels of needle and syringe program (NSP) utilisation and HIV-related risk behaviours among people who inject drugs (PWID). DESIGN AND METHODS: Using snowball sampling, we recruited 500 PWID (all male) in Kermanshah City, Iran between September and December 2014 in a cross sectional survey. We categorised participants into two groups, including high (i.e. receiving 60% or more of their syringes from an NSP) and low (i.e. receiving less than 60% of their syringes from NSP) NSP users. Then, we applied coarsened exact matching to match the two groups based on confounding covariates (age, place of residence, income, receiving methadone maintenance treatment) and made statistically equivalent comparison groups to estimate the effect of the NSP on injection risk behaviours. RESULTS: Participants with low NSP use were more likely to report borrowing syringes in past 2 months (odds ratio [OR] 1.71; 95% confidence interval [CI] 1.30, 1.86; P < 0.04), in comparison with participants with high NSP use. Regarding recent syringe lending, low NSP use was also significantly and positively associated with this outcome (OR 3.34; 95% CI 1.70, 5.20; P < 0.02). Reusing one's own syringe was reported more frequently in low NSP use group (OR 1.40; 95% CI 1.22, 3.97; P < 0.03). DISCUSSION AND CONCLUSIONS: NSPs are a promising approach to reduce injection-related risk behaviours among PWID in Kermanshah, Iran. Expanded coverage of high-quality NSPs is recommended. PMID- 29271014 TI - Prevalence of Publicly Available Expanded Access Policies. AB - The Food and Drug Administration's expanded access program allows patients with serious or immediately life-threatening conditions to seek access to experimental drugs and treatments from their manufacturers. The 21st Century Cures Act of 2016 sought to increase the transparency of manufacturers' approaches to expanded access by requiring public listing of five key pieces of information about their expanded access programs: 1) relevant contact information, 2) procedures for making requests, 3) general criteria used to evaluate requests, 4) length of time anticipated to acknowledge receipt of requests, and 5) a reference to pertinent information on ClinicalTrials.gov. Manufacturers were given 60 days from the Act's enactment, or until February 11, 2017, to post this information. We reviewed a sample of pharmaceutical manufacturers' expanded access policies to determine what information is readily available to patients online, including assessing whether the information described in the Act is available. PMID- 29271015 TI - The effect of daytime napping and full-night sleep on the consolidation of declarative and procedural information. AB - Many studies investigating sleep and memory consolidation have evaluated full night sleep rather than alternative sleep periods such as daytime naps. This multi-centre study followed up on, and was compared with, an earlier full-night study (Schabus et al., 2004) investigating the relevance of daytime naps for the consolidation of declarative and procedural memory. Seventy-six participants were randomly assigned to a nap or wake group, and performed a declarative word-pair association or procedural mirror-tracing task. Performance changes from before to after a 90-min retention interval filled with sleep or quiet wakefulness were evaluated between groups. Associations between performance changes, sleep architecture, spindles, and slow oscillations were investigated. For the declarative task we observed a trend towards stronger forgetting across a wake period compared with a nap period, and a trend towards memory increase over the full-night. For the procedural task, accuracy was significantly decreased following daytime wakefulness, showed a trend to increase with a daytime nap, and significantly increased across full-night sleep. For the nap protocol, neither sleep stages, spindles, nor slow oscillations predicted performance changes. A direct comparison of day and nighttime sleep revealed that daytime naps are characterized by significantly lower spindle density, but higher spindle activity and amplitude compared with full-night sleep. In summary, data indicate that daytime naps protect procedural memories from deterioration, whereas full-night sleep improves performance. Given behavioural and physiological differences between day and nighttime sleep, future studies should try to characterize potential differential effects of full-night and daytime sleep with regard to sleep-dependent memory consolidation. PMID- 29271016 TI - Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play. AB - The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion. PMID- 29271017 TI - A prediction model-based algorithm for computer-assisted database screening of adverse drug reactions in the Netherlands. AB - PURPOSE: The statistical screening of pharmacovigilance databases containing spontaneously reported adverse drug reactions (ADRs) is mainly based on disproportionality analysis. The aim of this study was to improve the efficiency of full database screening using a prediction model-based approach. METHODS: A logistic regression-based prediction model containing 5 candidate predictors was developed and internally validated using the Summary of Product Characteristics as the gold standard for the outcome. All drug-ADR associations, with the exception of those related to vaccines, with a minimum of 3 reports formed the training data for the model. Performance was based on the area under the receiver operating characteristic curve (AUC). Results were compared with the current method of database screening based on the number of previously analyzed associations. RESULTS: A total of 25 026 unique drug-ADR associations formed the training data for the model. The final model contained all 5 candidate predictors (number of reports, disproportionality, reports from healthcare professionals, reports from marketing authorization holders, Naranjo score). The AUC for the full model was 0.740 (95% CI; 0.734-0.747). The internal validity was good based on the calibration curve and bootstrapping analysis (AUC after bootstrapping = 0.739). Compared with the old method, the AUC increased from 0.649 to 0.740, and the proportion of potential signals increased by approximately 50% (from 12.3% to 19.4%). CONCLUSIONS: A prediction model-based approach can be a useful tool to create priority-based listings for signal detection in databases consisting of spontaneous ADRs. PMID- 29271018 TI - Sellar and suprasellar granular cell tumor of the neurohypophysis: A rare case report and review of the literature. AB - Granular cell tumors of the neurohypophysis are rare tumors with a WHO grade of I. Symptomatic tumors are even more rare. In this case, we present a 50-year-old patient with a sellar and suprasellar granular cell tumor of the neurohypophysis, who reported headaches, blurred vision and unsteady gait. CT imaging showed a sellar and suprasellar mass approximately 2.9 cm in diameter with clear boundaries. Histologically, the tumor lacked any obvious atypia and contained densely arranged polygonal tumor cells with abundant granular eosinophilic cytoplasm. Staining for Alpha-1 AntiChymotrypsin (AACT), TTF-1 and PAS was diffusely positive, and S-100 staining was focally positive in the tumor cells. CD34, CK, EMA, GFAP and HMB45 staining were negative. The Ki-67 index was < 1%. According to these findings, the tumor was diagnosed as a symptomatic granular cell tumor of the neurohypophysis. We suggest that identifying the location of the tumor with imaging is helpful for understanding the granular cell tumor of the neurohypophysis. Prompt diagnosis and treatment are critical for patients. PMID- 29271019 TI - Seed dispersal as an ecosystem service: frugivore loss leads to decline of a socially valued plant, Capsicum frutescens. AB - Species interactions, both mutualistic and antagonistic, are widely recognized as providing important ecosystem services. Fruit-eating animals influence plant recruitment by increasing germination during gut passage and moving seeds away from conspecifics. However, relative to studies focused on the importance of frugivores for plant population maintenance, few studies target frugivores as ecosystem service providers, and frugivores are underappreciated as ecosystem service providers relative to other mutualists such as pollinators. Here, we use an accidental experiment to elucidate the role of seed dispersal by frugivores for maintaining a culturally and economically important plant, the donne' sali chili (Capsicum frutescens) in the Mariana Islands. One of the islands (Guam) has lost nearly all of its native forest birds due to an invasive snake (Boiga irregularis), whereas nearby islands have relatively intact bird populations. We hypothesized that frugivore loss would influence chili recruitment and abundance, which could have economic and cultural impacts. By using video cameras, we confirmed that birds were the primary seed dispersers. We used captive bird feeding trials to obtain gut-passed seeds to use in a seedling emergence experiment. The experiment showed that gut-passed seeds emerged sooner and at a higher proportion than seeds from whole fruits. Consistent with our findings that birds benefit chilies, we observed lower chili abundance on Guam than on islands with birds. In a survey questionnaire of island residents, the majority of residents reported an association between the wild chili and local cultural values and traditions. In addition, we identified a thriving market for chili products, suggesting benefits of wild chilies to people in the Marianas both as consumers and producers. Our study therefore documents seed dispersal as both a cultural and a supporting ecosystem service. We provide a comprehensive case study on how seed-dispersed plants decline in the absence of their disperser, and how to apply mixed-methods in ecosystem service assessments. Furthermore, we suggest that scientists and resource managers may utilize fruit-frugivore mutualisms concerning socially valuable plants to gather support for frugivore and forest conservation efforts. PMID- 29271020 TI - Pathways towards different long-term outcomes after naturalistic psychotherapy. AB - This study suggests some potential pathways leading towards maintained gains or further growth versus deterioration after naturalistic psychotherapy with experienced clinicians. This is explored in a way that transcends specific theoretical orientations. Sixteen therapies, all showing reliable improvement on Outcome Questionnaire 45.2 (OQ-45) at treatment termination but varying in later post-therapy development, were included in this study. Building on previous content and correlational analyses, individual cases were explored qualitatively in search for developmental patterns of potential relevance for long-term outcome. Patterns re-emerging across several cases were described in light of the OQ-45 trajectories of clients providing them. Six pathways, associated with different long-term outcomes, emerged. Four of these, "Reflective route towards regulation of affects," "Gaining autonomy through a secure holding relationship," "Opening up as a new relational/emotional experience," and "Lasting acceptance of "reality"," re-emerged in clients showing maintained/growing treatment effects. Two pathways, entitled "Residual problems grow and overshadow progress" and "Core problems remain beneath superficial change," seemed linked to deterioration after termination of therapy. We suggest the former pathways as some possible routes towards enduring good outcome, and the latter as some patterns to avoid when trying to secure therapy gains will not be only temporary. PMID- 29271021 TI - Marginal Fit of Metal-Ceramic Copings: Effect of Luting Cements and Tooth Preparation Design. AB - PURPOSE: To evaluate the effect of the triad finish line design, axial wall convergence angle, and luting cement on the marginal fit of metal copings used in metal-ceramic crowns. MATERIALS AND METHODS: Schematic dies and their respective copings were cast in NiCr alloy. The dies exhibited the following finish line/convergence angle combinations: sloping shoulder/6 degrees , sloping shoulder/20 degrees , shoulder/6 degrees , shoulder/20 degrees . Marginal fit was evaluated under a stereomicroscope, before and after cementation. Copings were air-abraded with 50 MUm Al2 O3 particles and cemented with Cimento de Zinco, RelyX U100, or Panavia F cements (n = 10/group). Data were square-root transformed and analyzed by 3-way factorial random effect model and Tukey's post hoc test (alpha = 0.05). RESULTS: Statistical analysis showed significance for the interactions finish line and convergence angle (p < 0.05), convergence angle and time (p < 0.001), and luting cement and time (p < 0.001). Sloping shoulder/20 degrees provided the highest marginal discrepancy when compared to the other finish line/convergence angle combinations, which were statistically similar among each other. For both convergence angles and for all luting cements, the marginal discrepancy was significantly higher after cementation. Before and after cementation, 6 degrees provided better marginal fit than 20 degrees . After cementation, Panavia F provided higher marginal discrepancy than Cimento de Zinco. CONCLUSION: Lower convergence angle combined with shoulder and a low consistency luting cement is preferable to cement metal copings. PMID- 29271022 TI - Randomized control trial comparing effectiveness of weekly versus daily antenatal oral iron supplementation in preventing anemia during pregnancy. AB - AIM: This study was conducted to determine whether weekly antenatal oral iron and folate supplementation is an effective alternative to a daily regimen in non anemic pregnant women to prevent anemia and iron deficiency during the third trimester. METHODS: From December 2014 to April 2015, non-anemic pregnant women (n = 292) who presented to the Academic Obstetric Unit, Teaching Hospital Mahamodera Galle, Sri Lanka, at 14-22 weeks gestation and who had been treated with mebendazole 100 mg twice daily for three days were randomly allocated to receive 120 mg elemental iron, 3 mg folic acid and 100 mg vitamin C weekly (n = 149) or 60 mg elemental iron, 1 mg folic acid and 100 mg vitamin C daily (n = 143). Side effects were assessed at four weekly intervals and hemoglobin concentration (Hb), hematocrit and serum ferritin (SF) were measured at 32-36 weeks gestation. RESULTS: Only 106 participants in each group completed the study. There were no significant differences between the groups in mean duration of supplementation; presupplementation and post-supplementation mean Hb, hematocrit or SF levels; risk of developing anemia, ID or high Hb levels by an intension to treat analysis; and in those who completed the trial. Significantly greater side effects occurred in the daily compared to the weekly supplementation group. CONCLUSION: In non-anemic pregnant women, a weekly regimen is an effective alternative to a daily regimen for antenatal oral iron and folate supplementation for preventing anemia and iron deficiency during the third trimester. PMID- 29271023 TI - Polycystin-2 Plays an Essential Role in Glucose Starvation-Induced Autophagy in Human Embryonic Stem Cell-Derived Cardiomyocytes. AB - Autophagy is a process essential for cell survival under stress condition. The patients with autosomal dominant polycystic kidney disease, which is caused by polycystin-1 or polycystin-2 (PKD2) mutation, display cardiovascular abnormalities and dysregulation in autophagy. However, it is unclear whether PKD2 plays a role in autophagy. In the present study, we explored the functional role of PKD2 in autophagy and apoptosis in human embryonic stem cell-derived cardiomyocytes. HES2 hESC line-derived cardiomyocytes (HES2-CMs) were transduced with adenoviral-based PKD2-shRNAs (Ad-PKD2-shRNAs), and then cultured with normal or glucose-free medium for 3 hours. Autophagy was upregulated in HES2-CMs under glucose starvation, as indicated by increased microtubule-associated protein 1 light chain 3-II level in immunoblots and increased autophagosome and autolysosome formation. Knockdown of PKD2 reduced the autophagic flux and increased apoptosis under glucose starvation. In Ca2+ measurement, Ad-PKD2-shRNAs reduced caffeine-induced cytosolic Ca2+ rise. Co-immunoprecipitation and in situ proximity ligation assay demonstrated an increased physical interaction of PKD2 with ryanodine receptor 2 (RyR2) under glucose starvation condition. Furthermore, Ad-PKD2-shRNAs substantially attenuated the starvation-induced activation of AMP activated protein kinase (AMPK) and inactivation of mammalian target of rapamycin (mTOR). The present study for the first time demonstrates that PKD2 functions to promote autophagy under glucose starvation, thereby protects cardiomyocytes from apoptotic cell death. The mechanism may involve PKD2 interaction with RyR2 to alter Ca2+ release from sarcoplasmic reticulum, consequently modulating the activity of AMPK and mTOR, resulting in alteration of autophagy and apoptosis. Stem Cells 2018;36:501-513. PMID- 29271024 TI - Importance of oesophageal ultrasound in mediastinal staging of lung cancer. PMID- 29271025 TI - Chlamydia trachomatis, Ureaplasma urealyticum and Neisseria gonorrhoeae among Chinese women with urinary tract infections in Shanghai: A community-based cross sectional study. AB - AIM: This study explored chlamydia trachomatis (CT), ureaplasma urealyticum (UU) and/or neisseria gonorrhoeae (NG) in 5893 women with urinary tract infections (UTIs) in Shanghai. METHODS: From January 2009 to December 2014, 5893 women with UTIs in Shanghai were selected to undergo CT, UU and NG detection. Baseline characteristics including age, education level, occupation, reproductive history, sexual behavior and contraceptive method were obtained for epidemiological analysis. RESULTS: The total CT, UU and/or NG infection rate in the urine samples of 5893 patients was 50.69% (2987/5893), while the infection rate in vaginal secretion samples was 56.22% (3313/5893). The two detection methods were consistent. Patients aged 21-30, service personnel and unemployed persons had the highest rates of CT, UU and/or NG infection, while patients with higher education levels exhibited lower rates. As the number of previous pregnancies, natural births, abortions, sexual partners and the frequency of sexual intercourse increased, the rates of CT, UU and/or NG infection were elevated. Sexual intercourse during the menstruation period, a lack of cleaning before sexual intercourse and the use of intrauterine devices could all lead to an increased rate of CT, UU and/or NG infection. CONCLUSIONS: These data revealed that the rate of CT, UU and/or NG infection may be associated with age, education level, occupation, reproductive history, sexual behavior and type of contraceptive method in female patients with UTI in Shanghai. PMID- 29271026 TI - Vonoprazan- vs proton-pump inhibitor-based first-line 7-day triple therapy for clarithromycin-susceptible Helicobacter pylori: A multicenter, prospective, randomized trial. AB - BACKGROUND: The eradication rate of vonoprazan-based first-line triple therapy (combined with clarithromycin and amoxicillin) (V-AC) was reported to be 97.6% in patients with clarithromycin (CAM)-susceptible Helicobacter pylori in a phase III study, whereas our real-world, prospective, multicenter cohort study yielded an eradication rate <90%. OBJECTIVE: To validate the eradication rate of V-AC using CAM-susceptible testing in a multicenter, prospective, randomized trial. METHODS: We included 147 treatment-naive H. pylori-positive patients [41 with CAM resistant infections and 106 with CAM-susceptible infections]. The CAM susceptible group patients were randomized to either the V-AC group (vonoprazan 20 mg bid, amoxicillin 750 mg bid, and clarithromycin 200 or 400 mg bid) or PPI AC group (lansoprazole 30 mg, rabeprazole 10 mg, or esomeprazole 20 mg bid; amoxicillin 750 mg bid; and clarithromycin 200 or 400 mg bid). All CAM-resistant H. pylori were eradicated by V-AC, as measured by the urea breath test around 8 weeks after eradication. Safety was evaluated by patient questionnaires. RESULTS: The intention-to-treat and per-protocol eradication rates of V-AC in the CAM susceptible H. pylori-infected patients were 87.3% (95% confidence interval 75.5% 94.7%) and 88.9% (77.4%-95.8%). The respective eradication rates of PPI-AC were 76.5% (62.5%-87.2%) and 86.7% (73.2%-94.9%). No significant difference was observed between the V-AC and PPI-AC regimes in terms of the intention-to-treat (P = .21) or per-protocol (P = .77) analyses. The questionnaire scores did not differ significantly between the groups. Both the intention-to-treat and per protocol eradication rates of V-AC in the CAM-resistant patients were 82.9% (67.9%-92.8%). CONCLUSION: The eradication rate of V-AC treatment in the CAM susceptible H. pylori-infected patients was <90%, as was that by PPI-AC, thus V AC is not ideal regimen in CAM-susceptible H. pylori. However, the 82.9% eradication rate of V-AC in the CAM-resistant infections may indicate the potential of V-AC with modified dose, dosing interval, and treatment duration. (UMIN000016337). PMID- 29271027 TI - Introduction to this double issue: Jail diversion and collaboration across the justice continuum. PMID- 29271028 TI - Response to letter to the editor PD-17-0390, a comment on "Comparing methods for fetal fraction determination and quality control of NIPT samples". PMID- 29271029 TI - A comment on "Comparing methods for fetal fraction determination and quality control of NIPT samples". PMID- 29271030 TI - Prelisting predictions of early postoperative survival in infant heart transplantation using classification and regression tree analysis. AB - Infants listed for heart transplantation experience high waitlist and early post transplant mortality, and thus, optimal allocation of scarce donor organs is required. Unfortunately, the creation and validation of multivariable regression models to identify risk factors and generate individual-level predictions are challenging. We sought to explore the use of data mining methods to generate a prediction model. CART analysis was used to create a model which, at the time of listing, would predict which infants listed for heart transplantation would survive at least 3 months post-transplantation. A total of 48 infants were included; 13 died while waiting, and six died within 3 months of heart transplant. CART analysis identified RRT, blood urea nitrogen, and hematocrit as terminal nodes with alanine transaminase as an intermediate node predicting death. No patients listed on RRT (n = 10) survived and only three of 12 (25%) patients listed on ECLS survived >3 months post-transplant. CART analysis overall accuracy was 83%, with sensitivity of 95% and specificity 76%. This study shows that CART analysis can be used to generate accurate prediction models in small patient populations. Model validation will be necessary before incorporation into decision-making algorithms used to determine transplant candidacy. PMID- 29271031 TI - Time to acknowledge the mixed effects of cannabis on health: a summary and critical review of the NASEM 2017 report on the health effects of cannabis and cannabinoids. PMID- 29271032 TI - Ultrasonographic diagnosis of severe placental invasion. AB - AIM: Placental invasion is a life-threatening obstetric complication. The aim of this study was to identify the optimal ultrasonographic (US) criteria for placenta increta/percreta in order to improve diagnostic accuracy. METHODS: In a retrospective diagnostic study, all 116 patients at Peking University Third Hospital who had been diagnosed with placental invasion from October 2006 to October 2013 were included. Depending on their clinical and/or histopathological diagnosis, the study was divided into two groups: the Placenta Accreta Group (63 cases) and the Placenta Increta/Percreta Group (53 cases). The US images were analyzed for differences between placenta accreta and placenta increta/percreta. RESULTS: The sonographic criteria found to have predictive value for placenta increta/percreta using a regression model were: deficiency of retroplacental sonolucent zone and/or segmental retroplacental myometrial thinning less than 1 mm, multiple vascular lacunae presenting a 'moth hole' appearance, and placenta previa. Using a cut-off point of 0.589, the sensitivity and specificity were 81.1% and 77.8%, respectively. The area under the receiver-operator curve was 0.848 (P < 0.001). CONCLUSION: US diagnosis not only allows the detection of placental invasion, but also facilitates preliminary classification. The three aforementioned criteria facilitate the identification of placenta increta/percreta for precise and comprehensive clinical decision-making. PMID- 29271033 TI - Patient participation in pro re nata medication in psychiatric inpatient settings: An integrative review. AB - Pro re nata (PRN) medication is widely used and studied in psychiatric care, but our knowledge about patient participation in its administration is fragmented. The aim of this integrative review was to describe and synthesize previous knowledge of patient participation in PRN in psychiatric inpatient settings. We conducted both electronic and manual searches, using the CINAHL, Scopus, PsycINFO, and PubMed databases, and eight scientific journals. Searches were limited to the English language, to the years 2006-2016, and to selected papers using inclusion, exclusion, and quality criteria. We identified 16 relevant papers, and these showed that patient participation included patient-related starting points, including the patients' willingness to participate and their knowledge of the medication. The patients' participation in PRN practices was demonstrated by the opportunity to request PRN and to refuse any PRN that was offered. Patient participation was shown to be linked to certain situations where PRN was recommended. The role that the professionals played in patient participation included interacting with patients, providing counselling and alternatives for PRN. Our results also revealed that coercion was used administering PRN. The existing literature exposed challenges that need to be addressed if patient participation in the use of PRN medication is to be effectively achieved in psychiatric inpatient settings. Equal partnerships between patients, nurses, and physicians are an essential part of this process, and further research into PRN medication is urgently needed, particularly studies that focus on patients' experiences. PMID- 29271034 TI - Double-balloon versus single-balloon catheter for cervical ripening and labor induction: A systematic review and meta-analysis. AB - We searched Embase, PubMed and the Cochrane Library for randomized or quasi randomized controlled trials to compare the use of single-balloon to double balloon catheters. The risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI) was calculated using fixed-effects or random-effects models. Four studies involving a total of 793 pregnant women were included. There were no significant differences in the rate of cesarean (RR 1.09, 95% CI 0.86, 1.38; P = 0.48), or vaginal deliveries within 24 h (RR 0.94, 95% CI 0.82, 1.09; P = 0.42), the mean time to delivery (MD 0.39, 95% CI -0.90, 1.68 h; P = 0.55) or Bishop score improvement (MD 0.62, 95%CI -0.18, 1.42; P = 0.13) between the groups. Women who received the double-balloon catheter had a similar risk of maternal intrapartum fever and post-partum hemorrhage. Pain during ripening was only reported in one trial and was significantly higher with the double balloon, whereas pain during device insertion was measured in two trials: one reported no difference while the other reported significantly increased pain with the double balloon. The double-balloon and single-balloon (Foley) catheters had similar effectiveness and safety. The Foley catheter is significantly cheaper, widely available and accessible, has a longer history of use and remains the logical choice over the double-balloon catheter for cervical ripening. PMID- 29271035 TI - Embracing the next generation of plant scientists. PMID- 29271036 TI - Corrigendum. PMID- 29271037 TI - Corrigendum. PMID- 29271038 TI - Rugged fitness landscapes and Darwinian demons in trait-based ecology. PMID- 29271039 TI - Novel DNAJ-related proteins in Arabidopsis thaliana. AB - Classical DNAJ proteins are co-chaperones that together with HSP70s control protein homeostasis. All three classical types of DNAJ proteins (DNAJA, DNAJB and DNAJC types) possess the J-domain for interaction with HSP70. DNAJA proteins contain, in addition, both the zinc-finger motif and the C-terminal domain which are involved in substrate binding, while DNAJB retains only the latter and DNAJC comprises only the J-domain. There is increasing evidence that some of the activities of DNAJ proteins do not require the J-domain, highlighting the functional significance of the other two domains. Indeed, the so-called DNAJ-like proteins with a degenerate J-domain have been previously coined as DNAJD proteins, and also proteins containing only a DNAJ-like zinc-finger motif appear to be involved in protein homeostasis. Therefore, we propose to extend the classification of DNAJ-related proteins into three different groups. The DNAJD type comprises proteins with a J-like domain only, and has 15 members in Arabidopsis thaliana, whereas proteins of the DNAJE (33 Arabidopsis members) and DNAJF (three Arabidopsis members) types contain a DNAJA-like zinc-finger domain and DNAJA/B-like C-terminal domain, respectively. Here, we provide an overview of the entire repertoire of these proteins in A. thaliana with respect to their physiological function and possible evolutionary origin. PMID- 29271040 TI - The push and pull of plant specialized metabolism underlies a long-standing, colorful mystery. PMID- 29271041 TI - Comparison of the CIELab and CIEDE 2000 Color Difference Formulas on Gingival Color Space. AB - PURPOSE: To evaluate the CIELAB and CIEDE2000 formulas to determine which better reflects the difference in color perception, and whether there are gender differences in color perception. MATERIALS AND METHODS: Fifty-six participants grouped 21 different-colored disks made of pink porcelain (color range: from 36.8 to 63.9 for L* , from 16.4 to 35.2 for a* , from 6.2 to 21.6 for b* ), in which the only requirement was that each group be comprised of disks with chromatically indistinguishable colors. Each participant was free to choose the number and composition of the groups. Using the results obtained, a dissimilarity matrix was generated, and nonmetric multidimensional scaling (MDS) was applied to obtain the coordinates of the disks within a Euclidean space. RESULTS: The linear correlation coefficient between the interpoint distances of the MDS configuration (MDS_total sample) and the color differences with the CIELAB formula (DeltaE*ab ) was 0.719 (p < 0.001), whereas with the CIEDE2000 formula (DeltaE00), it was 0.726 (p < 0.001). For the configuration obtained in the women's group (MDS_w), the correlations between the interpoint distances and the CIELab color difference was 0.720 (p < 0.001), and the CIEDE2000 color differences was 0.730 (p < 0.001). For the configuration obtained in the men's group (MDS_m), the perceived color differences, calculated with both formulas, were less sensitive, 0.670 for CIELab formula and 0.677 for CIEDE2000 formula. CONCLUSIONS: Considering the limitations of this study, the data analyzed indicated that the CIEDE2000 formula reflected the color differences perceived by the human eye similar to the CIELAB formula (DeltaE*ab ). Also, women were confirmed to be more sensitive than men to differences in color. PMID- 29271042 TI - A simple and reliable method reducing sulfate to sulfide for multiple sulfur isotope analysis. AB - RATIONALE: Precise analysis of four sulfur isotopes of sulfate in geological and environmental samples provides the means to extract unique information in wide geological contexts. Reduction of sulfate to sulfide is the first step to access such information. The conventional reduction method suffers from a cumbersome distillation system, long reaction time and large volume of the reducing solution. We present a new and simple method enabling the process of multiple samples at one time with a much reduced volume of reducing solution. METHODS: One mL of reducing solution made of HI and NaH2 PO2 was added to a septum glass tube with dry sulfate. The tube was heated at 124 degrees C and the produced H2 S was purged with inert gas (He or N2 ) through gas-washing tubes and then collected by NaOH solution. The collected H2 S was converted into Ag2 S by adding AgNO3 solution and the co-precipitated Ag2 O was removed by adding a few drops of concentrated HNO3 . RESULTS: Within 2-3 h, a 100% yield was observed for samples with 0.2-2.5 MUmol Na2 SO4 . The reduction rate was much slower for BaSO4 and a complete reduction was not observed. International sulfur reference materials, NBS-127, SO-5 and SO-6, were processed with this method, and the measured against accepted delta34 S values yielded a linear regression line which had a slope of 0.99 +/- 0.01 and a R2 value of 0.998. CONCLUSIONS: The new methodology is easy to handle and allows us to process multiple samples at a time. It has also demonstrated good reproducibility in terms of H2 S yield and for further isotope analysis. It is thus a good alternative to the conventional manual method, especially when processing samples with limited amount of sulfate available. PMID- 29271043 TI - Prognostic significance of clinical presentation, induction and rescue treatment in 42 cases of canine centroblastic diffuse large B-cell multicentric lymphoma in the United Kingdom. AB - Canine lymphoma is a heterogeneous group of diseases and many previous studies have evaluated the response of a mixed population of lymphoma cases to one specific treatment protocol. The aim of this retrospective study was to describe the outcome and prognostic factors in 42 cases of multicentric centroblastic diffuse large B-cell lymphoma treated with either a COP-type (35%) or CHOP-type (64%) induction chemotherapy. The objective response rate to induction therapy was 94%; entire dogs had a greater rate of complete vs partial remissions than neutered dogs (P = .017). Median progression-free survival for the first remission (PFS1) was 182 days; absence of anaemia at diagnosis (P = .002) and pretreatment neutrophil:lymphocyte ratio (NLR) below 9.44 (P = .015) were independently predictive of longer PFS1. Fifty-eight percent of dogs received rescue protocols with an objective response rate of 81%; 31% of dogs received further rescue protocols (up to a total of 5) and the median number of protocols administered were 2. Median overall survival (OS) was 322 days, the 1-year survival rate was 38% and the 2-year survival rate was 9%. Lymphocyte:monocyte ratio above 1.43 (P = .031), NLR below 11.44 (P = .009), the combination of induction and rescue therapy (P = .030) and the total number of doxorubicin doses used (P = .002) were independently predictive of longer OS. Use of a COP-type protocol induction compared with CHOP did not undermine OS providing doxorubicin was used as rescue therapy. PMID- 29271044 TI - Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors. AB - The circadian clock, which regulates cellular physiology, such as energy metabolism, resides in each cell level throughout the body. Recently, it has been elucidated that the cellular circadian clock is closely linked with cellular differentiation. Moreover, the misregulation of cellular differentiation in mouse embryonic stem cells (ESCs) induced abnormally differentiated cells with impaired circadian clock oscillation, concomitant with the post-transcriptional suppression of CLOCK proteins. Here, we show that the circadian molecular oscillation is disrupted in dysdifferentiation-mediated mouse kidney tumors induced by partial in vivo reprogramming, resembling Wilms tumors. The expression of CLOCK protein was dramatically reduced in the tumor cells despite the Clock mRNA expression. We also showed that a similar loss of CLOCK was observed in human Wilms tumors, suggesting that the circadian molecular clockwork may be disrupted in dysdifferentiation-mediated embryonal tumors such as Wilms tumors, similar to the in vivo reprogramming-induced mouse kidney tumors. These results support our previous reports and may provide a novel viewpoint for understanding the pathophysiological nature of cancers through the correlation between cellular differentiation and circadian clock. PMID- 29271046 TI - Technical Standardization of Laparoscopic Left Hemicolectomy - Video Vignette. AB - Large multicentre trials have shown good safety profiles and low complication rates for laparoscopic management of left-sided colon cancer [1-3]. However, there are a wide range of options and variations in technique, which extend the learning curve of trainee surgeons. Here we provide a video to demonstrate a standardized operative technique simplified into 'one plane, two points and three lines' when applied to laparoscopic left hemicolectomy. This article is protected by copyright. All rights reserved. PMID- 29271045 TI - Quantitative assessment of cerebral venous blood T2 in mouse at 11.7T: Implementation, optimization, and age effect. AB - PURPOSE: To develop a non-contrast-agent MRI technique to quantify cerebral venous T2 in mice. METHODS: We implemented and optimized a T2 -relaxation-under spin-tagging (TRUST) sequence on an 11.7 Tesla animal imaging system. A flow sensitive-alternating-inversion-recovery (FAIR) module was used to generate control and label images, pair-wise subtraction of which yielded blood signals. Then, a T2 -preparation module was applied to produce T2 -weighted images, from which blood T2 was quantified. We conducted a series of technical studies to optimize the imaging slice position, inversion slab thickness, post-labeling delay (PLD), and repetition time. We also performed three physiological studies to examine the venous T2 dependence on hyperoxia (N = 4), anesthesia (N = 3), and brain aging (N = 5). RESULTS: Our technical studies suggested that, for efficient data acquisition with minimal bias in estimated T2 , a preferred TRUST protocol was to place the imaging slice at the confluence of sagittal sinuses with an inversion-slab thickness of 2.5-mm, a PLD of 1000 ms and a repetition time of 3.5 s. Venous T2 values under normoxia and hyperoxia (inhaling pure oxygen) were 26.9 +/- 1.7 and 32.3 +/- 2.2 ms, respectively. Moreover, standard isoflurane anesthesia resulted in a higher venous T2 compared with dexmedetomidine anesthesia (N = 3; P = 0.01) which is more commonly used in animal functional MRI studies to preserve brain function. Venous T2 exhibited a decrease with age (N = 5; P < 0.001). CONCLUSION: We have developed and optimized a noninvasive method to quantify cerebral venous blood T2 in mouse at 11.7 T. This method may prove useful in studies of brain physiology and pathophysiology in animal models. Magn Reson Med 80:521-528, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29271047 TI - Solubilization of Hydrophobic Catalysts Using Nanoparticle Hosts. AB - A modular strategy for the solubilization and protection of hydrophobic transition metal catalysts using the hydrophobic pockets of water soluble gold nanoparticles is reported. Besides preserving original catalyst activity, this encapsulation strategy provides a protective environment for the hydrophobic catalyst and brings reusability. This system provides a versatile platform for the encapsulation of different hydrophobic transition metal catalysts, allowing a wide range of catalysis in water while uniting the advantages of homogeneous and heterogeneous catalysis in the same system. PMID- 29271048 TI - Synthesis of Difluoromethylthioesters from Aldehydes. AB - Difluoromethylthioester compounds are yet another important kind of organofluorine compound and are reported here for the first time. They can be efficiently synthesized from various aldehydes. The synthetic method features mild reaction conditions, good tolerance of functional groups, broad substrate scope, and importantly, no metal is involved in the reaction. The approach has the potential to become an important tool for the late-stage functionalization of advanced synthetic intermediates, and should have many applications in medicinal chemistry. PMID- 29271049 TI - Decline in opioid prescribing after federal rescheduling of hydrocodone products. AB - PURPOSE: To examine differences in opioid prescribing by patient characteristics and variation in hydrocodone combination product (HCP) prescribing attributed to states, before and after the 2014 Drug Enforcement Administration's reclassification of HCP from schedule III to the more restrictive schedule II. METHODS: We used 2013 to 2015 data for 9 202 958 patients aged 18 to 64 from a large nationally representative commercial health insurance program to assess the temporal trends in the monthly rate of opioid prescribing. RESULTS: HCP prescribing decreased by 26% from June 2013 to June 2015; the rate of prescriptions for any opioid decreased by 11%. Prescribing of non-hydrocodone schedule III opioids increased slightly while prescribing of non-hydrocodone schedule II opioids and tramadol was stable. Absolute decreases in HCP prescribing rates were larger in patients being treated for cancer (-2.26% vs 0.7% for non-cancer patients, P < 0.0001) and in those with high comorbidities ( 2.13% vs -0.55% for those with no comorbidity, P < 0.0001). Differences in the absolute and relative changes in HCP prescribing rates among states were large; for example, a relative decrease of 46.7% in Texas and a 12.7% increase in South Dakota. The variation in HCP prescribing attributable to the state of residence increased from 6.6% in 2013 to 8.7% in 2015. CONCLUSIONS: The 2014 federal policy was associated with a decrease in rates of HCP and total opioid prescribing. The large decrease in the rates of HCP prescribing for patients with actively treated cancer may represent an unintended consequence. PMID- 29271051 TI - Parvalbumin neurons as a hub in autism spectrum disorders. PMID- 29271050 TI - The pomegranate (Punica granatum L.) genome provides insights into fruit quality and ovule developmental biology. AB - Pomegranate (Punica granatum L.) has an ancient cultivation history and has become an emerging profitable fruit crop due to its attractive features such as the bright red appearance and the high abundance of medicinally valuable ellagitannin-based compounds in its peel and aril. However, the limited genomic resources have restricted further elucidation of genetics and evolution of these interesting traits. Here, we report a 274-Mb high-quality draft pomegranate genome sequence, which covers approximately 81.5% of the estimated 336-Mb genome, consists of 2177 scaffolds with an N50 size of 1.7 Mb and contains 30 903 genes. Phylogenomic analysis supported that pomegranate belongs to the Lythraceae family rather than the monogeneric Punicaceae family, and comparative analyses showed that pomegranate and Eucalyptus grandis share the paleotetraploidy event. Integrated genomic and transcriptomic analyses provided insights into the molecular mechanisms underlying the biosynthesis of ellagitannin-based compounds, the colour formation in both peels and arils during pomegranate fruit development, and the unique ovule development processes that are characteristic of pomegranate. This genome sequence provides an important resource to expand our understanding of some unique biological processes and to facilitate both comparative biology studies and crop breeding. PMID- 29271052 TI - Usefulness of hemostatic sealants for minimizing ovarian damage during laparoscopic cystectomy for endometriosis. AB - AIM: We aimed to evaluate the impact of topical hemostatic sealants and bipolar coagulation during laparoscopic ovarian endometriotic cyst resection on ovarian reserve by comparing the rates of decrease in anti-Mullerian hormone (AMH). METHODS: A randomized prospective data collection was made on women aged 19-45 years who planned to have laparoscopic ovarian cystectomy at one of two institutions (n = 80), Kangbuk Samsung Hospital, Seoul, Korea or National Health Insurance Service Ilsan Hospital, Goyang, Korea, from January 2014 to April 2016. Patients were randomly divided into two groups treated with either a topical hemostatic sealant or bipolar coagulation for hemostasis. The hemostatic group was randomized to the FloSeal or TachoSil subgroups. Preoperative and 3-month postoperative AMH levels were checked and the rates of decrease of AMH were compared. All patients enrolled were treated with dienogest (Visanne) for 6-12 months. None were lost to follow-up at postoperative 3 months, but about one third of the patients had been lost to follow-up by 6-12 months. RESULTS: AMH was significantly decreased in both groups 3 months postoperatively; however, the rate of decrease in the bipolar coagulation group was greater than that in the hemostatic sealant group, 41.9% (interquartile range [IQR], 22.29-65.24) versus 18.1% (IQR, 10.94-29.90), P = 0.007. Between the two hemostatic subgroups, there was no significant difference in AMH decrease rate, 14.95% (IQR, 11.34-21.21) versus 18.1% (IQR 9.76-40.70), P = 0.204. CONCLUSION: Hemostatic sealants may be an alternative to bipolar coagulation for preservation of ovarian reserve after laparoscopic ovarian cystectomy for endometriosis. PMID- 29271054 TI - Use of the hCONSORT criteria as a reporting standard for herbal interventions for common dermatoses: a systematic review. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) is increasing in Western countries, including in the area of dermatology. However, Western healthcare providers have not integrated CAM into regular practice owing to a lack of reliable data supporting its use. To encourage high-quality research related to the use of CAM and specifically herbal interventions, the CONsolidated Standards Of Reporting Trials (CONSORT) extension criteria on reporting herbal interventions (hCONSORT) were published in 2006. OBJECTIVES: To evaluate the adherence of randomized controlled trials (RCTs) investigating herbal interventions for acne, atopic dermatitis (AD) and psoriasis to the hCONSORT criteria. METHODS: A comprehensive search of the PubMed, Embase and Cochrane Library databases was conducted. RCTs published between 2009 and 2014 assessing therapeutic outcomes of plant-based interventions for acne, AD or psoriasis were included. Investigators determined the number of unique hCONSORT criteria satisfied per report. anova was used to examine differences in scores by disease entity. RESULTS: The vast majority of reviewed studies reported < 50% of information recommended in the hCONSORT criteria. Limitations include the small number of dermatological conditions examined, exclusion of reports based on language and lack of assessment of overall adherence to CONSORT criteria. CONCLUSIONS: Our data indicate lack of adherence to hCONSORT extension criteria. Adherence to hCONSORT guidelines should be encouraged in order to provide high quality reporting of research on herbal interventions in dermatology. Doing so may ease the integration of CAM into conventional medical practice and provide actionable data to providers. PMID- 29271055 TI - Sequential application of mineralized electroconductive scaffold and electrical stimulation for efficient osteogenesis. AB - Osteogenic differentiation is enhanced by many inductive factors including biochemical agents, biomechanical stresses, and electrical stimulation. Regularly studies have focused on one factor at a time, while synergies can promote more effective and functional osteogenesis. Herein, for the first time, functional synergism between application of electrical stimulation and HA nanoparticles was evaluated in osteogenic differentiation. Prepared electrospun biocompatible conductive scaffold by amalgamating chitosan, aniline-pentamer, and hydroxyapatite incorporation was seeded by human bone-marrow-derived mesenchymal stem cells. The cells seeded on the scaffolds with and without hydroxyapatite were exposed to electrical stimulation and subsequently, osteogenic molecular markers and related signaling pathways were investigated. In general, all investigated osteogenic markers (osteocalcin, alkaline phosphatase, osteonectin, and Runx2) were upregulated transcriptionally in the cells seeded on the chitosan embedded scaffolds. Separate utilization of electrical stimulation or hydroxyapatite-enhanced osteogenesis, while the cells exposed to both stimulators simultaneously, expressed higher levels of some of osteogenic genes significantly. Considering the functions and the positions of the markers in osteogenic signaling pathways, it can be concluded that HA might cooperate in the allocation of stem cells to osteoprogenitors in the early phase of osteogenesis while electrical stimulation helps committed cells with maturation and acquiring functional phenotypes. Altogether investigation of the synergism between different stimulators and exploiting the interactions in an optimized manner could lead to more efficient osteogenesis protocol for effective bone regeneration and tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1200-1210, 2018. PMID- 29271053 TI - Networks of myelin covariance. AB - Networks of anatomical covariance have been widely used to study connectivity patterns in both normal and pathological brains based on the concurrent changes of morphometric measures (i.e., cortical thickness) between brain structures across subjects (Evans, ). However, the existence of networks of microstructural changes within brain tissue has been largely unexplored so far. In this article, we studied in vivo the concurrent myelination processes among brain anatomical structures that gathered together emerge to form nonrandom networks. We name these "networks of myelin covariance" (Myelin-Nets). The Myelin-Nets were built from quantitative Magnetization Transfer data-an in-vivo magnetic resonance imaging (MRI) marker of myelin content. The synchronicity of the variations in myelin content between anatomical regions was measured by computing the Pearson's correlation coefficient. We were especially interested in elucidating the effect of age on the topological organization of the Myelin-Nets. We therefore selected two age groups: Young-Age (20-31 years old) and Old-Age (60-71 years old) and a pool of participants from 48 to 87 years old for a Myelin-Nets aging trajectory study. We found that the topological organization of the Myelin-Nets is strongly shaped by aging processes. The global myelin correlation strength, between homologous regions and locally in different brain lobes, showed a significant dependence on age. Interestingly, we also showed that the aging process modulates the resilience of the Myelin-Nets to damage of principal network structures. In summary, this work sheds light on the organizational principles driving myelination and myelin degeneration in brain gray matter and how such patterns are modulated by aging. PMID- 29271056 TI - Under-utilisation of high-dose-rate brachytherapy boost in men with intermediate high risk prostate cancer treated with external beam radiotherapy. AB - INTRODUCTION: The aim of this study was to evaluate the use of high-dose-rate brachytherapy (HDR-BT) boost with definitive external beam radiotherapy (EBRT) in prostate cancer (CaP) management. METHODS: The study population comprised men with intermediate-high risk CaP captured in the population-based Prostate Cancer Outcome Registry Victoria (PCOR-Vic), treated with EBRT from January 2010 to December 2015. The primary outcome is the proportion of men who received HDR-BT boost. Multivariate logistic regressions were used to evaluate the effect of patient-, tumour- and treatment-factors on the likelihood of HDR-BT use. Medicare Benefit Schedule (MBS) data was accessed to evaluate the Australia-wide pattern of HDR-BT use. RESULTS: One thousand eight hundred and six patients were included in this study - 886 (49%) intermediate-risk, and 920 (51%) high-risk CaP patients. Overall, only 124 (7%) patients had EBRT + HDR-BT - 47 (5%) intermediate-risk and 77 (8%) high-risk CaP patients (P = 0.01). There is higher proportion of patients who had HDR-BT in public institutions (7% public vs. 3% private, P = 0.005) and in metropolitan centres (9% metropolitan vs. 2% regional, P < 0.001). In multivariate analyses, older patients were less likely to have HDR BT (OR = 0.92; 95% CI = 0.89-0.94, P < 0.001), while patients with high-risk CaP (OR = 1.8; 95% CI = 1.3-2.7; P = 0.002) treated in metropolitan centres (OR = 5.0; 95% CI = 2.6-9.8; P < 0.001) and public institutions (OR = 3.8; 95% CI = 1.5 9.4; P = 0.005) were more likely to have EBRT + HDR-BT. There was significant decline in numbers of HDR-BT performed throughout Australia, from 313 cases in 2010 to 125 cases in 2015. CONCLUSION: High-dose-rate brachytherapy is under utilised with EBRT in this contemporary population-based cohort of Victorian men with CaP. The decline in HDR-BT use was also observed nationally. PMID- 29271057 TI - Pre-treatment neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are prognostic of progression in early stage classical Hodgkin lymphoma. AB - To determine whether pre-treatment neutrophil/lymphocyte (NLR) or platelet/lymphocyte ratios (PLR) are predictive for progression in early-stage classical Hodgkin lymphoma (cHL), we derived NLR and PLR values for 338 stage I/II cHL patients and appropriate cut-off point values to define progression. Two year freedom from progression (FFP) for patients with NLR >=6.4 was 82.2% vs. 95.7% with NLR <6.4 (P < 0.001). Similarly, 2-year FFP was 84.3% for patients with PLR >=266.2 vs. 96.1% with PLR <266.2 (P = 0.003). On univariate analysis, both NLR and PLR were significantly associated with worse FFP (P = 0.001). On multivariate analysis, PLR remained a significant, independent prognostic factor (P < 0.001). PMID- 29271059 TI - What is the role for a licensing examination in the UK? PMID- 29271058 TI - A finite element analysis of the optimal bending angles in a running loop for mesial translation of a mandibular molar using indirect skeletal anchorage. AB - OBJECTIVES: To estimate the optimal bending angles in the running loop for mesial translation of a mandibular second molar using indirect skeletal anchorage and to clarify the mechanics of tipping and rotating the molar. METHODS: A three dimensional finite element model was developed for predicting tooth movement, and a mechanical model based on the beam theory was constructed for clarifying the force systems. RESULTS: When using a running loop without bends, the molar tipped mesially 14.4 degrees and lingually 0.6 degrees , rotated counterclockwise 4.1 degrees , and the incisors retracted 0.02 mm and intruded 0.05 mm. These angles were about the same as those estimated by the beam theory. When the amount of tip back and toe-in angles was 11.0 degrees , mesial translation of the molar was achieved, and incisors retracted 0.10 mm and intruded 0.30 mm. CONCLUSIONS: Mesial translation of a mandibular second molar without any significant movement of anterior teeth was achieved during protraction by controlling the tip back and toe-in angles and enhancing anterior anchorage with the combined use of a running loop and indirect skeletal anchorage. PMID- 29271060 TI - Effects of a simulated emergency airway management education program on the self efficacy and clinical performance of intensive care unit nurses. AB - AIM: To examine the effects of a simulated emergency airway management education program on the self-efficacy and clinical performance among nurses in intensive care units. METHODS: A one-group, pre- and post-test design was used. Thirty-five nurses who were working in adult intensive care units participated in this study. The simulation education program included lectures, skill demonstration, skill training, team-based practice, and debriefing. Self-efficacy and clinical performance questionnaires were completed before the program and 1 week after its completion. The data were analyzed by using descriptive statistics and the paired t-test to compare the mean differences between the pre-test and post-test. The scores before and after education were compared. RESULTS: After education, there was a significant improvement in the nurses' self-efficacy and clinical performance in emergency airway management situations. CONCLUSION: Simulation education effectively improved the self-efficacy and clinical performance of the nurses who were working in intensive care units. Based on the program for clinical nurses within a hospital, it will provide information that might advance clinical nursing education. PMID- 29271061 TI - Effects of loading on chondrocyte hypoxia, HIF-1alpha and VEGF in the mandibular condylar cartilage of young rats. AB - OBJECTIVES: To investigate hypoxia-inducible factor 1-alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression under altered loading, and to explore the relationship between loading and hypoxia in the mandibular condylar cartilage of young rats. SETTING AND SAMPLE POPULATION: Eighty Sprague Dawley rats. MATERIAL AND METHODS: The reduced loading group was fed soft food, and their incisors were cut to avoid occlusal contact. The increased loading group was fed hard food and had forced jaw-opening. Ten rats from each group (n = 10) were sacrificed at 12, 24, 48, and 96 hours after initiation of the experiment. Pimonidazole hydrochloride (Hypoxyprobe-1, HP-1) was used as a hypoxia marker to confirm the hypoxic state. Hypoxic chondrocytes as indicated by HP-1, HIF-1alpha and VEGF protein expressions were recognized by immunohistochemical detection. HIF-1alpha and VEGF mRNA expressions were detected by semi-quantitative RT-PCR. RESULTS: Hypoxyprobe-1 was confined in the upper layers of cartilage, and was most strongly expressed in the weight-bearing area of TMJ at 12 and 96 hours. Staining of HIF-1alpha and VEGF was most strongly expressed in the chondrocytes of the fibrous and proliferative layer at all time points. Furthermore, expressions were also displayed in the hypertrophic and calcified layers at 48 and 96 hours. The expressions of HIF-1alpha and VEGF mRNA were higher in the increased loading group than in the reduced loading group at 48 and 96 hours (P < . 05). CONCLUSION: Mechanical loading seems to directly induce weight-bearing area hypoxia followed by new vessel formation, which indicates that these factors are related and important for the development of cartilage. PMID- 29271063 TI - Unique regulation of Na-glutamine cotransporter SN2/SNAT5 in rabbit intestinal crypt cells during chronic enteritis. AB - : The only Na-nutrient cotransporter described in mammalian small intestinal crypt cells is SN2/SNAT5, which facilitates glutamine uptake. In a rabbit model of chronic intestinal inflammation, SN2 stimulation is secondary to an increase in affinity of the cotransporter for glutamine. However, the immune regulation of SN2 in the crypt cells during chronic intestinal inflammation is unknown. We sought to determine the mechanism of regulation of Na-nutrient cotransporter SN2 by arachidonic acid metabolites in crypt cells. The small intestines of New Zealand white male rabbits were inflamed via inoculation with Eimeria magna oocytes. After 2-week incubation, control and inflamed rabbits were subjected to intramuscular injections of arachidonyl trifluoromethyl ketone (ATK), piroxicam and MK886 for 48 hrs. After injections, the rabbits were euthanized and crypt cells from small intestines were harvested and used. RESULTS: Treatment of rabbits with ATK prevented the release of AA and reversed stimulation of SN2. Inhibition of cyclooxygenase (COX) with piroxicam did not affect stimulation of SN2. However, inhibition of lipoxygenase (LOX) with MK886, thus reducing leukotriene formation during chronic enteritis, reversed the stimulation of SN2. Kinetic studies showed that the mechanism of restoration of SN2 by ATK or MK886 was secondary to the restoration of the affinity of the cotransporter for glutamine. For all treatment conditions, Western blot analysis revealed no change in SN2 protein levels. COX inhibition proved ineffective at reversing the stimulation of SN2. Thus, this study provides evidence that SN2 stimulation in crypt cells is mediated by the leukotriene pathway during chronic intestinal inflammation. PMID- 29271064 TI - Monitoring and surveillance for multiple micronutrient supplements in pregnancy. AB - The World Health Organization (WHO) recommends iron-folic acid (IFA) supplementation during pregnancy to improve maternal and infant health outcomes. Multiple micronutrient (MMN) supplementation in pregnancy has been implemented in select countries and emerging evidence suggests that MMN supplementation in pregnancy may provide additional benefits compared to IFA alone. In 2015, WHO, the United Nations Children's Fund (UNICEF), and the Micronutrient Initiative held a "Technical Consultation on MMN supplements in pregnancy: implementation considerations for successful incorporation into existing programmemes," which included a call for indicators needed for monitoring, evaluation, and surveillance of MMN supplementation programmes. Currently, global surveillance and monitoring data show that overall IFA supplementation programmes suffer from low coverage and intake adherence, despite inclusion in national policies. Common barriers that limit the effectiveness of IFA-which also apply to MMN programmes include weak supply chains, low access to antenatal care services, low-quality behaviour change interventions to support and motivate women, and weak or non existent monitoring systems used for programme improvement. The causes of these barriers in a given country need careful review to resolve them. As countries heighten their focus on supplementation during pregnancy, or if they decide to initiate or transition into MMN supplementation, a priority is to identify key monitoring indicators to address these issues and support effective programmes. National and global monitoring and surveillance data on IFA supplementation during pregnancy are primarily derived from cross-sectional surveys and, on a more routine basis, through health and logistics management information systems. Indicators for IFA supplementation exist; however, the new indicators for MMN supplementation need to be incorporated. We reviewed practice-based evidence, guided by the WHO/Centers for Disease Control and Prevention logic model for vitamin and mineral interventions in public health programmes, and used existing manuals, published literature, country reports, and the opinion of experts, to identify monitoring, evaluation, and surveillance indicators for MMN supplementation programmes. We also considered cross-cutting indicators that could be used across programme settings, as well as those specific to common delivery models, such as antenatal care services. We then described mechanisms for collecting these data, including integration within existing government monitoring systems, as well as other existing or proposed systems. Monitoring data needs at all stages of the programme lifecycle were considered, as well as the feasibility and cost of data collection. We also propose revisions to global , national-, and subnational-surveillance indicators based on these reviews. PMID- 29271062 TI - Contribution of buried distal amino acid residues in horse liver alcohol dehydrogenase to structure and catalysis. AB - The dynamics of enzyme catalysis range from the slow time scale (~ms) for substrate binding and conformational changes to the fast time (~ps) scale for reorganization of substrates in the chemical step. The contribution of global dynamics to catalysis by alcohol dehydrogenase was tested by substituting five different, conserved amino acid residues that are distal from the active site and located in the hinge region for the conformational change or in hydrophobic clusters. X-ray crystallography shows that the structures for the G173A, V197I, I220 (V, L, or F), V222I, and F322L enzymes complexed with NAD+ and an analogue of benzyl alcohol are almost identical, except for small perturbations at the sites of substitution. The enzymes have very similar kinetic constants for the oxidation of benzyl alcohol and reduction of benzaldehyde as compared to the wild type enzyme, and the rates of conformational changes are not altered. Less conservative substitutions of these amino acid residues, such as G173(V, E, K, or R), V197(G, S, or T), I220(G, S, T, or N), and V222(G, S, or T) produced unstable or poorly expressed proteins, indicating that the residues are critical for global stability. The enzyme scaffold accommodates conservative substitutions of distal residues, and there is no evidence that fast, global dynamics significantly affect the rate constants for hydride transfers. In contrast, other studies show that proximal residues significantly participate in catalysis. PMID- 29271066 TI - From manageable to losing control: a grounded theory study of psychosis risk syndrome. AB - AIM: The purpose of this study is to develop a theoretical explanation of the prodromal schizophrenia process, or so-called psychosis risk syndrome, by describing patients' own experiences with symptoms, thoughts and feelings. METHODS: A total of 40 interviews were conducted in Taiwan. A Grounded Theory method was selected because of its demonstrated effectiveness in generating theory around dynamic and complex processes on which little is known, all of which is the case with psychosis risk syndrome. Constant comparison analysis, memo writing, member checking, and theoretical sampling were adopted. RESULTS: A core theoretical framework was developed in which the process of the psychosis risk syndrome is described as proceeding from manageable to uncontrollable. Four stages emerged from the analysis: (1) something is wrong, (2) boiling up, (3) breaking point, and (4) losing control. CONCLUSIONS: The framework resulting from this Grounded Theory research is innovative in presenting patterns and clinical staging that marks the progression from premorbid stage to full-blown psychosis. In addition to specifying the detailed process through in-depth interviews, this research makes two fundamental contributions by: (1) adding evidence to current science and (2) taking patients' experience into consideration to improve the validity of screening tools and design appropriate intervention programs for people with early warning signs of developing schizophrenia. PMID- 29271065 TI - Atypical teratoid/rhabdoid tumor with retained INI1 (SMARCB1) expression and loss of BRG1 (SMARCA4). AB - Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive malignancy of the central nervous system (CNS) usually diagnosed in infancy or childhood, most often characterized by loss of expression of the SMARCB1 gene product integrase interactor 1 (INI1) protein. We report a case of AT/RT in a 3 month old boy with retained expression of INI1 by immunohistochemistry. Additional testing demonstrated loss of expression of the SMARCA4 gene product Brahma-related gene 1 (BRG1) protein by immunohistochemistry, confirmed by next generation sequencing showing a nonsense mutation in SMARCA4. This case illustrates that positivity for INI1 does not rule out a diagnosis of AT/RT, and additional testing, including BRG1/SMARCA4 analysis, is warranted in cases where clinical suspicion is high. PMID- 29271067 TI - Sex- and age-dependent effects of celiac disease on growth and weight gain in children with type 1 diabetes: Analysis of the type 1 diabetes Exchange Clinic Registry. AB - BACKGROUND: Celiac disease (CD) is common in patients with type 1 diabetes (T1D) and effects of CD on growth in children with T1D remain unclear. METHODS: We analyzed heights, weights, and body mass index (BMI) in 215 matched pediatric CD/control pairs in the T1D Exchange Clinic Registry. CD was defined by a clinic reported diagnosis and positive celiac serology (n = 80) and/or positive small bowel biopsy (n = 135). Cases and controls were matched by age (mean: 14 years), diabetes duration (median: 7 years), sex (57% female), and clinic site. There were 5569 height/weight measurements. RESULTS: Gluten was restricted for varying periods of time in 61% of females and 51% of males with CD. Females with CD were shorter than female controls at all ages (P = 0.01). Weight z-scores were initially lower in preschool females with CD but similar to controls by middle childhood. Males with CD were initially shorter but adult heights were similar. Height in both sexes and weight in males were lower in CD participants diagnosed at younger age. Growth in T1D children with biopsy-proven CD, 76% of them were gluten-restricted, was comparable to that of T1D controls. CONCLUSION: Concurrent CD impairs linear growth in T1D females at all stages of development and in young T1D males. Young females with CD have lower weights, but both sexes have similar weights by middle childhood. Children younger at CD onset remain shorter throughout childhood; males younger at CD onset have persistently lower weights. Long-term gluten restriction may restore weight gain and linear growth in children with CD and T1D. PMID- 29271068 TI - High fat diet blunts the effects of leptin on ventilation and on carotid body activity. AB - KEY POINTS: Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models. ABSTRACT: Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation. PMID- 29271069 TI - Paranoia and maladaptive behaviours in homelessness: The mediating role of emotion regulation. AB - OBJECTIVES: Current research has implicated a role for cognitive and emotional processes in the pathways to becoming homeless. Evidence implicates three risk factors, which are often associated with an increased incidence of homelessness: paranoid thinking, emotion regulation, and engaging in maladaptive behaviours. Maladaptive behaviours include deliberate self-harm, substance misuse, and high risk sexual practices. Currently, no studies have investigated the specific psychological mechanisms, such as difficulty regulating emotions, which underpin the association between paranoia and maladaptive behaviours. DESIGN: A mediational design was employed in a group of homeless individuals. METHOD: Participants (N = 40), who were homeless at the time of the study, completed a single-session assessment of paranoia, emotion regulation, and maladaptive behaviours. RESULTS: Mediation analyses indicated that individuals scoring high on paranoia were more likely to engage in maladaptive behaviours, particularly substance misuse and aggression, when they had difficulty regulating their emotions. These results demonstrate a novel finding relating to the effect of emotion regulation in maintaining psychopathology and behaviours in vulnerable individuals, which may in turn sustain periods of homelessness. CONCLUSIONS: Emotion regulation may therefore be one particular psychological mechanism through which severe mental illness affects engagement in self-destructive behaviours in homelessness. These findings have valuable clinical implications for targeted therapeutic interventions, in this often difficult to treat homeless population. PRACTITIONER POINTS: Psychosis is over-represented in the homeless population; the cycle of homelessness may be attenuated by addressing psychotic symptomology. Homeless individuals engage in drug abuse, self-harm, aggression, and high-risk sexual practices due to an inability to regulate distressing emotions effectively. Therapeutic interventions, such as MBT and DBT, which target emotion regulation difficulties, may be useful in reducing maladaptive behaviours and preventing homelessness, by providing emotion regulation strategies to cope when homeless persons become distressed. PMID- 29271071 TI - A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy. AB - BACKGROUND: Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy. METHODS: Genetic testing in the proband was performed using custom clinical exome and targeted next-generation sequencing. This was followed by segregation analysis of the variant in the parents by Sanger sequencing and evaluation of the splice variant by RNA sequencing. RESULTS: Clinical exome sequencing identified a novel homozygous intronic splice variant in the EMC1 gene (chr1:19564510C>T, c.1212 + 1G>A, NM_015047.2). Neither population databases (ExAC and 1000 genomes) nor our internal database (n = 1,500) had reported this rare variant, predicted to affect the splicing. RNA sequencing data from the proband confirmed aberrant splicing with intron 11 retention, thereby introducing a stop codon in the resultant mRNA. This nonsense mutation is predicted to result in the premature termination of protein synthesis leading to loss of function of the EMC1 protein. CONCLUSION: We report, for the first time the role of aberrant EMC1RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease-associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations. PMID- 29271070 TI - Visual Motion Prediction and Verbal False Memory Performance in Autistic Children. AB - : Recent theoretical accounts propose that atypical predictive processing can explain the diverse cognitive and behavioral features associated with autism, and that difficulties in making predictions may be related to reduced contextual processing. In this pre-registered study, 30 autistic children aged 6-14 years and 30 typically developing children matched in age and non-verbal IQ completed visual extrapolation and false memory tasks to assess predictive abilities and contextual processing, respectively. In the visual extrapolation tasks, children were asked to predict when an occluded car would reach the end of a road and when an occluded set of lights would fill up a grid. Autistic children made predictions that were just as precise as those made by typically developing children, across a range of occlusion durations. In the false memory task, autistic and typically developing children did not differ significantly in their discrimination between items presented in a list and semantically related, non presented items, although the data were insensitive, suggesting the need for larger samples. Our findings help to refine theoretical accounts by challenging the notion that autism is caused by pervasively disordered prediction abilities. Further studies will be required to assess the relationship between predictive processing and context use in autism, and to establish the conditions under which predictive processing may be impaired. Autism Res 2018, 11: 509-518. (c) 2017 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: It has been suggested that autistic individuals have difficulties making predictions and perceiving the overall gist of things. Yet, here we found that autistic children made similar predictions about hidden objects as non-autistic children. In a memory task, autistic children were slightly less confused about whether they had heard a word before, when words were closely related in meaning. We conclude that autistic children do not show difficulties with this type of prediction. PMID- 29271072 TI - Three-year follow-up after psychotherapy for young people with bipolar disorder. AB - OBJECTIVES: (1) To examine the differences between interpersonal and social rhythm therapy (IPSRT) and specialist supportive care (SSC) in the longer term impacts of IPSRT and SSC on cumulative depression and mania symptoms over a further 78-week follow-up period post treatment. (2) To calculate the survival time before recurrence of a new mood episode over the 3-year period. METHODS: One hundred young people with bipolar disorder aged between 15 and 36 years who had been randomized to treatment with either IPSRT or SSC for 78 weeks were followed up for a subsequent 78 weeks. The Longitudinal Interval Follow-up Evaluation was completed at 26-week intervals. A Mann-Whitney U test was used to determine if there were significant differences between therapy types and a Kaplan-Meier survival analysis was used to determine time to recurrence. Cox regression was used to assess the association between time to relapse and therapy type. RESULTS: There were no significant differences between therapies at each of the data points for either depression or mania scores. The mean change in depression and mania in both groups was significantly different for all three follow-up data points. The actuarial cumulative recurrence rates were 53% for IPSRT and 49% for SSC. There was no significant difference between the groups in time to recurrence. CONCLUSIONS: While there were no significant differences between the two therapies, there was an overall reduction in symptoms in both therapies. There may be sustained benefits in providing intensive psychotherapies in conjunction with pharmacotherapy for young people with bipolar disorder. PMID- 29271073 TI - Oxygen anion (O- ) and hydroxide anion (HO- ) reactivity with a series of old and new refrigerants. AB - The reactivity of a series of commonly used halogenated compounds (trihalomethanes, chlorofluorocarbon, hydrochlorofluorocarbon, fluorocarbons, and hydrofluoroolefin) with hydroxide and oxygen anion is studied in a compact Fourier transform ion cyclotron resonance. O- is formed by dissociative electron attachment to N2 O and HO- by a further ion-molecule reaction with ammonia. Kinetic experiments are performed by increasing duration of introduction of the studied molecule at a constant pressure. Hydroxide anion reactions mainly proceed by proton transfer for all the acidic compounds. However, nucleophilic substitution is observed for chlorinated and brominated compounds. For fluorinated compounds, a specific elimination of a neutral fluorinated alkene is observed in our results in parallel with the proton transfer reaction. Oxygen anion reacts rapidly and extensively with all compounds. Main reaction channels result from nucleophilic substitution, proton transfer, and formal H2+ transfer. We highlight the importance of transfer processes (atom or ion) in the intermediate ion-neutral complex, explaining part of the observed reactivity and formed ions. In this paper, we present the first reactivity study of anions with HFO 1234yf. Finally, the potential of O- and HO- as chemical ionization reagents for trace analysis is discussed. PMID- 29271074 TI - Improving rates of overweight, obesity and extreme obesity in New Zealand 4-year old children in 2010-2016. AB - BACKGROUND: Prevalence of childhood obesity is high in developed countries, and there is a growing concern regarding increasing socio-economic disparities. OBJECTIVES: To assess trends in the prevalence of overweight, obesity and extreme obesity among New Zealand 4-year olds, and whether these differ by socio-economic and ethnic groupings. METHODS: A national screening programme, the B4 School Check, collected height and weight data for 75-92% of New Zealand 4-year-old children (n = 317 298) between July 2010 and June 2016. Children at, or above, the 85th, 95th and 99.7th percentile for age and sex adjusted body mass index (according to World Health Organization standards) were classified as overweight, obese and extremely obese, respectively. Prevalence rates across 6 years (2010/11 to 2015/16) were examined by sex, across quintiles of socio-economic deprivation, and by ethnicity. RESULTS: The prevalence of overweight, obesity and extreme obesity decreased by 2.2 [95% CI, 1.8-2.5], 2.0 [1.8-2.2] and 0.6 [0.4-0.6] percentage points, respectively, between 2010/2011 and 2015/2016. The downward trends in overweight, obesity and extreme obesity in the population persisted after adjustment for sex, ethnicity, deprivation and urban/rural residence. Downward trends were also observed across sex, ethnicity and deprivation groups. CONCLUSIONS: The prevalence of obesity appears to be declining in 4-year-old children in New Zealand across all socio-economic and ethnic groups. PMID- 29271075 TI - Transporter-Mediated Alterations in Patients With NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate. AB - The expression of hepatic transporters, including organic anion transporting polypeptides (OATPs) and multidrug resistance-associated proteins (MRPs), is altered in nonalcoholic steatohepatitis (NASH); however, functional data in humans are lacking. In this study, 99m Tc-mebrofenin (MEB) was used to evaluate OATP1B1/1B3 and MRP2 function in NASH patients. Healthy subjects (n = 14) and NASH patients (n = 7) were administered MEB (~2.5 mCi). A population pharmacokinetic model was developed to describe systemic and hepatic MEB disposition. Study subjects were genotyped for SLCO1B1 variants. NASH increased systemic and hepatic exposure (median +/- 2 SE, healthy vs. NASH) to MEB (AUC0 300,blood : 1,780 +/- 242 vs. 2,440 +/- 775 MUCi*min/L, P = 0.006; AUC0-180,liver : 277 +/- 36.9 vs. 433 +/- 40.3 kcounts*min/sec, P < 0.0001) due to decreased biliary clearance (0.035 +/- 0.008 vs. 0.017 +/- 0.002 L/min, P = 0.0005) and decreased Vcentral (11.1 +/- 0.57 vs. 6.32 +/- 1.02 L, P < 0.0001). MEB hepatic CLuptake was reduced in NASH and also in healthy subjects with SLCO1B1 *15/*15 and *1A/*15 genotypes. The pharmacokinetics of drugs that are OATP1B1/1B3 and MRP2 substrates may be substantially altered in NASH. PMID- 29271076 TI - The association of low muscle mass with soluble receptor for advanced glycation end products (sRAGE): The Korean Sarcopenic Obesity Study (KSOS). AB - BACKGROUND: Advanced glycation end products (AGEs) are accumulated with aging in various tissues of humans. The soluble receptor for AGEs (sRAGE) exerts a protective role against the development of aging-related chronic disorders by neutralizing the action of AGEs. We investigated the implication of sRAGE on low muscle mass in Asian men and women. METHODS: This cross-sectional study included a 390-participant, nondiabetic subcohort recruited within the framework of the Korean Sarcopenic Obesity Study, an ongoing prospective cohort study. Low muscle mass was defined based on the distribution of appendicular skeletal muscle mass divided by body mass index, as proposed by the Foundation for the National Institutes Sarcopenia Project. RESULTS: Serum sRAGE levels were significantly lower in participants with low muscle mass than in participants without low muscle mass (0.76 [0.60-1.00] ng/mL vs 0.87 [0.67-1.15] ng/mL, P = .005). In age- and sex-adjusted correlation analyses, appendicular skeletal muscle mass divided by body mass index was associated with sRAGE (r = 0.109, P = .037). Furthermore, decreased circulating levels of sRAGE are independently associated with low muscle mass (odds ratio = 0.254, P = .002) after adjusting for confounding factors, including insulin resistance and inflammatory markers. CONCLUSIONS: The present study shows that a low circulating level of sRAGE may be an independent risk factor for the presence of low muscle mass. PMID- 29271077 TI - Macromolecular Coating Enables Tunable Selectivity in a Porous PDMS Matrix. AB - Whether for laboratory use or clinical practice, many fields in Life Sciences require selective filtering. However, most existing filter systems lack the ability to easily tune their filtration behavior. Two key elements for efficient filtering are a high surface-to-volume ratio and the presence of suitable chemical groups which establish selectivity. In this study, an artificial PDMS based capillary system with highly tunable selectivity properties is presented. The high surface-to-volume ratio of this filter system is generated by first embedding sugar fibers into a synthetic polymer matrix and then dissolving these fibers from the cured polymer. To functionalize this filter, the inner surface of the capillaries is coated with purified or synthetic macromolecules. Depending on the type of macromolecule used for filter functionalization, selective sieving is observed based on steric hindrance, electrostatic binding, electrostatic repulsion, or specific binding interactions. Furthermore, it is demonstrated that enzymes can be immobilized in the capillary system which allows for performing multiple cycles of enzymatic reactions with the same batch of enzymes and without the need to separate the enzymes from their reaction products. In addition to lab scale filtration and enzyme immobilization applications demonstrated here, the functionalized porous PDMS matrix may also be used to test binding interactions between different molecules. PMID- 29271078 TI - Immediate post-insertion tip migration of peripherally inserted central catheters dependent on arm position and depth of inspiration. AB - INTRODUCTION: The purpose of this study is to assess the degree of PICC tip migration with breathing and arm movement to determine whether accurate positioning is feasible or futile. METHODS: A prospective cohort of 218 consecutive patients undergoing PICC insertion at our institution between January and August 2015 was selected, of which 129 met inclusion criteria. The position of insertion was used as control with the arm at 90 degrees during inspiration, followed by three study images: expiration with arm unchanged, inspiration with arm fully adducted and inspiration with arm fully abducted. Mean and standard deviations (SD) of change in PICC position were determined. ANOVA, Pearson correlation coefficients and Chi-square tests were used to assess the effects of vessel choice, PICC calibre and angle of arm abduction. Complications were recorded. RESULTS: Movement was predominantly caudal with a mean of 10.4 mm (SD 16.5) with similar degrees of movement in the expiration (12.3 mm) and adduction (12.9 mm) views (P = 0.709). Arm abduction resulted in a mean caudal movement of 6.5 mm. (SD 18.6); however, the degree of abduction had no predictable effect on PICC movement. Thirty-two per cent of cases demonstrated movement into the right atrium. Neither vessel choice nor type of PICC was shown to have a significant effect on PICC movement. CONCLUSION: There is large amplitude of PICC tip position change with depth of inspiration and arm position resulting in frequent right atrial position. Despite this there were no associated complications in our cohort which compliments emerging international opinion regarding intra-atrial PICC tip position. PMID- 29271079 TI - Oral health behaviours of parents and young children in a practice-based caries prevention trial in Northern Ireland. AB - OBJECTIVES: The NICPIP trial evaluated the costs and effects of a caries prevention intervention delivered to 2- to 3-year-old children attending dental practices in Northern Ireland. This supplementary study explored the oral health behaviours of children and their parents to help understand the reasons for the trial's findings. METHODS: A mixed methods study that included a questionnaire completed by all parents (n = 1058) at the time they brought their child for the NICPIP final clinical assessment. The questionnaire collected data on frequency of toothbrushing and sugar consumption. Questionnaire data were analysed by trial group and caries status. Parents of trial participants (n = 42) were invited to take part in telephone interviews. Parents were purposively sampled according to trial group and whether or not their child developed caries. The interviews explored how and why oral health behaviours happened. Interview data were audio recorded, transcribed verbatim and analysed thematically. RESULTS: The questionnaire data indicated that toothbrushing and between-meal sugar snacking were common in the majority of children. The children of parents who automatically reminded their child to brush their teeth were more likely to remain caries-free (Odds Ratio 1.24; 95% CI 1.08, 1.41; P = .002). Frequency of sweet drink consumption was associated with the child developing caries (Odds Ratio 0.88; 95% CI 0.79, 0.98; P = .021). The interview data showed that parents had positive attitudes towards brushing both in terms of perceived importance and expected outcomes. Attitudes towards sugar snacking were more complex, with parents reporting difficulties in controlling this behaviour. Sugar was described as being something that was "ever present" in children's lives. CONCLUSIONS: Toothbrushing was widely adopted from a young age, but between-meal sugar consumption was highly prevalent. The results suggest that effective family-level and population-level interventions are needed to reduce sugar consumption if substantial improvements in caries prevention are to be achieved. PMID- 29271080 TI - The effect of the interdialytic interval on cognitive function in patients on haemodialysis. AB - BACKGROUND: Cognitive deficits are common among individuals on haemodialysis (HD). The degree of dysfunction may shift over the course of the interdialytic interval. OBJECTIVES: To use ecological momentary assessment (EMA) to examine the relationship between the length of the interdialytic interval and reports of cognitive dysfunction. DESIGN: A quantitative study whereby each patient's cognitive functioning was measured during both short and long interdialytic intervals. PARTICIPANTS: Adults maintained on HD (Female n = 15, Male n = 11; MAge = 42.7 +/- 15.8 years) were drawn from a standalone HD unit within a large university medical centre. MEASUREMENTS: Tests of baseline neurocognitive functioning were undertaken (Mini-Mental Status Examination, Digit Span, California Verbal Learning Test, Benton Visual Retention Test, Trail-Making Test) and smartphone-based electronic diary reports of cognitive impairment were made around six times each day for one week. RESULTS: Cognitive function and aptitude in this sample, although low, did not reflect clinically-significant impairment, with a mean Mini-Mental Status Exam score of 25.7 +/- 3.0. Diary reports of cognitive impairment were also minimal, with an overall mean rating of .22 out of 5. Contrary to expectations, cognitive impairment was significantly greater on the one-day interdialytic days than on Day 2 of the two-day interdialytic interval (beta = .094, p = .017). CONCLUSIONS: Although cognitive impairment appears to be mild in stable, young patients with end stage renal disease, volumetric disruptions caused by HD may exacerbate such dysfunction. PMID- 29271081 TI - Incidence and risk factors of postoperative pneumonia following cancer surgery in adult patients with selected solid cancer: results of "Cancer POP" study. AB - The aim of this study was to investigate the incidence and risk factors of postoperative pneumonia (POP) within 1 year after cancer surgery in patients with the five most common cancers (gastric, colorectal, lung, breast cancer, and hepatocellular carcinoma [HCC]) in South Korea. This was a multicenter and retrospective cohort study performed at five nationwide cancer centers. The number of cancer patients in each center was allocated by the proportion of cancer surgery. Adult patients were randomly selected according to the allocated number, among those who underwent cancer surgery from January to December 2014 within 6 months after diagnosis of cancer. One-year cumulative incidence of POP was estimated using Kaplan-Meier analysis. An univariable Cox's proportional hazard regression analysis was performed to identify risk factors for POP development. As a multivariable analysis, confounders were adjusted using multiple Cox's PH regression model. Among the total 2000 patients, the numbers of patients with gastric cancer, colorectal cancer, lung cancer, breast cancer, and HCC were 497 (25%), 525 (26%), 277 (14%), 552 (28%), and 149 (7%), respectively. Overall, the 1-year cumulative incidence of POP was 2.0% (95% CI, 1.4-2.6). The 1 year cumulative incidences in each cancer were as follows: lung 8.0%, gastric 1.8%, colorectal 1.0%, HCC 0.7%, and breast 0.4%. In multivariable analysis, older age, higher Charlson comorbidity index (CCI) score, ulcer disease, history of pneumonia, and smoking were related with POP development. In conclusions, the 1-year cumulative incidence of POP in the five most common cancers was 2%. Older age, higher CCI scores, smoker, ulcer disease, and previous pneumonia history increased the risk of POP development in cancer patients. PMID- 29271082 TI - Quantifying River-Groundwater Interactions of New Zealand's Gravel-Bed Rivers: The Wairau Plain. AB - New Zealand's gravel-bed rivers have deposited coarse, highly conductive gravel aquifers that are predominantly fed by river water. Managing their groundwater resources is challenging because the recharge mechanisms in these rivers are poorly understood and recharge rates are difficult to predict, particularly under a more variable future climate. To understand the river-groundwater exchange processes in gravel-bed rivers, we investigate the Wairau Plain Aquifer using a three-dimensional groundwater flow model which was calibrated using targeted field observations, "soft" information from experts of the local water authority, parameter regularization techniques, and the model-independent parameter estimation software PEST. The uncertainty of simulated river-aquifer exchange flows, groundwater heads, spring flows, and mean transit times were evaluated using Null-space Monte-Carlo methods. Our analysis suggests that the river is hydraulically perched (losing) above the regional water table in its upper reaches and is gaining downstream where marine sediments overlay unconfined gravels. River recharge rates are on average 7.3 m3 /s, but are highly dynamic in time and variable in space. Although the river discharge regularly hits 1000 m3 /s, the net exchange flow rarely exceeds 12 m3 /s and seems to be limited by the physical constraints of unit-gradient flux under disconnected rivers. An important finding for the management of the aquifer is that changes in aquifer storage are mainly affected by the frequency and duration of low-flow periods in the river. We hypothesize that the new insights into the river-groundwater exchange mechanisms of the presented case study are transferable to other rivers with similar characteristics. PMID- 29271083 TI - Yet more evidence that myelin protons can be directly imaged with UTE sequences on a clinical 3T scanner: Bicomponent T2* analysis of native and deuterated ovine brain specimens. AB - PURPOSE: UTE sequences with a minimal nominal TE of 8 us have shown promise for direct imaging of myelin protons (T2 , < 1 ms). However, there is still debate about the efficiency of 2D slice-selective UTE sequences in exciting myelin protons because the half excitation pulses used in these sequences have a relatively long duration (e.g., 0.3-0.6 ms). Here, we compared UTE and inversion recovery (IR) UTE sequences used with either hard or half excitation pulses (durations 32 us or 472 us, respectively) for imaging myelin in native and deuterated ovine brain at 3T. METHODS: Freshly frozen ovine brains were dissected into ~2 mm-thick pure white matter and ~3 to 8 mm-thick cerebral hemisphere specimens, which were imaged before and/or after different immersion time in deuterium oxide. RESULTS: Bicomponent T2* analysis of UTE signals obtained with hard excitation pulses detected an ultrashort T2 component (STC) fraction (fS ) of 0% to 10% in native specimens, and up to ~86% in heavily deuterated specimens. fS values were significantly affected by the TIs used in IR-UTE sequences with either hard or half excitation pulses in native specimens but not in heavily deuterated specimens. The STC T2* was in the range of 150 to 400 us in all UTE and IR-UTE measurements obtained with either hard or half excitation pulses. CONCLUSION: Our results further support myelin protons as the major source of the ultrashort T2* signals seen on IR-UTE images and demonstrate the potential of IR UTE sequences with half excitation pulses for directly imaging myelin using clinical scanners. Magn Reson Med 80:538-547, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29271084 TI - Vitamin D deficiency and supplementation in patients with aggressive B-cell lymphomas treated with immunochemotherapy. AB - Vitamin D deficiency has been reported to be a negative prognostic factor in elderly patients with aggressive B-cell lymphomas. In vitro data suggest that vitamin D supplementation may enhance rituximab-mediated cytotoxicity. We prospectively assessed 25-hydroxyvitamin D [25(OH)D] levels at diagnosis in a cohort of 155 patients with aggressive B-cell lymphomas of whom 128 had diffuse large B-cell lymphoma (DLBCL) not otherwise specified. 25(OH)D levels were deficient (<20 ng/mL) in 105 (67%), insufficient (20-29 ng/mL) in 32 (21%), and normal (>=30 ng/mL) in 18 (12%) patients with a seasonal variation. Patient characteristics associated with lower 25(OH)D levels were poor performance status, overweight, B-symptoms, elevated LDH, lower albumin and hemoglobin levels. As a result of a change in practice pattern, 116 patients received vitamin D3 (cholecalciferol) supplementation that included a loading phase with daily replacement and subsequent maintenance phase with a weekly dose of 25,000 IU until end of treatment. This resulted in a significant increase in 25(OH)D levels, with normalization in 56% of patients. We analyzed the impact of 25(OH)D levels on event-free survival in patients treated with Rituximab-CHOP. 25(OH)D levels below 20 ng/mL at diagnosis and IPI were independently associated with inferior EFS. Moreover, patients with normalized 25(OH)D levels following supplementation showed better EFS than patients with persistently deficient/insufficient 25(OH)D levels. Our study provides the first evidence that achievement of normal 25(OH)D levels after vitamin D3 supplementation is associated with improved outcome in patients with DLBCL and deficient/insufficient 25(OH)D levels when receiving rituximab-based treatment. PMID- 29271085 TI - Tempol augments the blunted cutaneous microvascular thermal reactivity in healthy young African Americans. AB - NEW FINDINGS: What is the central question of this study? The purpose was to determine whether there is a difference between African Americans and Caucasians in cutaneous microvascular function and whether this difference is attributable to elevated oxidative stress. What is the main finding and its importance? The main finding is that African Americans have an attenuated cutaneous vasodilatation during local heating relative to Caucasians that is restored with local infusion of the superoxide dismutase mimetic, tempol. This suggests that superoxide mediates microvascular dysfunction and might contribute to the greater prevalence of cardiovascular disease in this population. ABSTRACT: African Americans (AA) have elevated risk for cardiovascular disease relative to other populations. We hypothesized that the cutaneous hyperaemic response to local heating is reduced in young AA relative to Caucasian Americans (CA) and that this is attributable to elevated oxidative stress. As such, ascorbic acid (a global antioxidant) and tempol (a superoxide dismutase mimetic) would improve this response in AA. Microdialysis fibres received lactated Ringer solution (control), 10 mm ascorbic acid or 10 MUm 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) at a rate of 2.0 MUl min-1 . Cutaneous vascular conductance (CVC) was calculated as the red blood cell flux divided by mean arterial pressure. Data were presented as a percentage of maximal CVC (%CVCmax ) induced by 44 degrees C heating plus sodium nitroprusside. Twenty-four (12 AA, 12 CA) young (23 +/- 4 years old) subjects participated. During 39 degrees C heating, the %CVCmax was lower in AA at the control (CA, 65 +/- 20% versus AA, 47 +/- 15%; P < 0.05) and ascorbic acid sites (CA, 73 +/- 14% versus AA: 49 +/- 17%; P < 0.01). At the tempol site, there were no differences between groups. This was followed by infusion of 10 mm l-NAME at all sites to assess the contribution of nitric oxide to vasodilatation during local heating. The contribution of nitric oxide was lower in AA relative to CA at 39 degrees C; however, this was restored with tempol. These data suggest that: (i) cutaneous vasodilatation in response to local heating is blunted in AA relative to CA; and (ii) elevated superoxide generation attenuates nitric oxide-mediated cutaneous vasodilatation in AA. PMID- 29271086 TI - Doctors with Asperger's: the impact of a diagnosis. AB - BACKGROUND: Asperger syndrome (AS) is part of a spectrum of disorders encompassing difficulties with social interaction that may result in specific educational needs for doctors in training. There is currently limited research on the impact of AS on working as a doctor. METHODS: This is a qualitative study using semi-structured interviews to explore the perceptions of trainees diagnosed with AS following input from a professional support service, and the perspectives of the staff involved in their professional development. FINDINGS: Receiving a diagnosis of AS was viewed as a double-edged sword, allowing the development of insight into lifelong difficulties, but also creating the potential for prejudice. Understanding AS traits provided an explanation for challenges in the workplace and therefore opportunities to find solutions. Understanding AS traits provided an explanation for challenges in the workplace DISCUSSION: This study explores the benefits and disadvantages of defining and labelling a specific professional support need for a group of trainees. It also reveals the need for improved awareness of AS amongst all clinical educators. PMID- 29271088 TI - The impact of aid on health outcomes in Uganda. AB - The health sector has attracted significant foreign aid; however, evidence on the effectiveness of this support is mixed. This paper combines household panel data with geographically referenced subnational foreign aid data to investigate the contribution of health aid to health outcomes in Uganda. Using a difference-in differences approach, we find that aid had a strong effect on reducing the productivity burden of disease indicated by days of productivity lost due to illness but was less effective in reducing disease prevalence. Consequently, health aid appeared to primarily quicken recovery times rather than prevent disease. In addition, we find that health aid was most beneficial to individuals who lived closest to aid projects. Apart from the impact of aid, we find that aid tended to not be targeted to localities with the worse socioeconomic conditions. Overall, the results highlight the importance of allocating aid close to subnational areas with greater need to enhance aid effectiveness. PMID- 29271089 TI - Endothelin-1-induced expression of alpha-smooth muscle actin in human myometrial fibroblasts. AB - AIM: We aimed to investigate the potential role of endothelin-1 (ET-1) in the regulation of the expression of alpha-smooth muscle actin (alpha-SMA) in human myometrial fibroblasts. METHODS: Primary myometrial fibroblasts were obtained from myometrium and were identified by immunocytochemical staining. Then, 1 * 107 cells were treated with ET-1 at a concentration of 0.1, 1.0, 10.0, or 100.0 nM for 24 h. To investigate the time course effects of ET-1 on the growth of fibroblasts, 1 * 107 cells were treated with 10.0 nM ET-1 for 6, 12, 24, and 48 h. Real-time quantitative PCR (qPCR) and Western blot analysis were used to determine the expression of alpha-SMA mRNA and protein, respectively. RESULTS: Human myometrial fibroblasts were identified by immunohistochemistry. Compared with the control group, the expression levels of alpha-SMA mRNA and protein were identified in cells treated with ET-1 at a concentration of 0.1, 1.0, 10.0, or 100.0 nM for 24 h (P < 0.05). ET-1 treatment affected the expression of alpha-SMA mRNA and protein in a dose-dependent manner (P < 0.05). The induction of alpha SMA mRNA and protein expression increased from 6 to 48 h. CONCLUSION: The results show that ET-1 induces the expression of alpha-SMA in human myometrium in vitro. PMID- 29271091 TI - Corrigendum. PMID- 29271090 TI - Peptide (Lys-Leu) and amino acids (Lys and Leu) supplementations improve physiological activity and fermentation performance of brewer's yeast during very high-gravity (VHG) wort fermentation. AB - Lys and Leu were generally considered as the key amino acids for brewer's yeast during beer brewing. In the present study, peptide Lys-Leu and a free amino acid (FAA) mixture of Lys and Leu (Lys + Leu) were supplemented in 24 degrees P wort to examine their effects on physiological activity and fermentation performance of brewer's yeast during very high-gravity (VHG) wort fermentation. Results showed that although both peptide Lys-Leu and their FAA mixture supplementations could increase the growth and viability, intracellular trehalose and glycerol content, wort fermentability, and ethanol content for brewer's yeast during VHG wort fermentation, and peptide was better than their FAA mixture at promoting growth and fermentation for brewer's yeast when the same dose was kept. Moreover, peptide Lys-Leu supplementation significantly increased the assimilation of Asp, but decreased the assimilation of Gly, Ala, Val, (Cys)2, Ile, Leu, Tyr, Phe, Lys, Arg, and Pro. However, the FAA mixture supplementation only promoted the assimilation of Lys and Leu, while reduced the absorption of total amino acids to a greater extent. Thus, the peptide Lys-Leu was more effective than their FAA mixture on the improvement of physiological activity, fermentation performance, and nitrogen metabolism of brewer's yeast during VHG wort fermentation. PMID- 29271092 TI - Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications. AB - BACKGROUND: Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well. METHODS: We performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database. RESULTS: We did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database. CONCLUSION: The yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large-scale genomic databases used to identify variants that contribute to disease risk. PMID- 29271093 TI - Multilevel convergence of interoceptive impairments in hypertension: New evidence of disrupted body-brain interactions. AB - Interoception, the sensing of visceral body signals, involves an interplay between neural and autonomic mechanisms. Clinical studies into this domain have focused on patients with neurological and psychiatric disorders, showing that damage to relevant brain mechanisms can variously alter interoceptive functions. However, the association between peripheral cardiac-system alterations and neurocognitive markers of interoception remains poorly understood. To bridge this gap, we examined multidimensional neural markers of interoception in patients with early stage of hypertensive disease (HTD) and healthy controls. Strategically, we recruited only HTD patients without cognitive impairment (as shown by neuropsychological tests), brain atrophy (as assessed with voxel-based morphometry), or white matter abnormalities (as evidenced by diffusion tensor imaging analysis). Interoceptive domains were assessed through (a) a behavioral heartbeat detection task; (b) measures of the heart-evoked potential (HEP), an electrophysiological cortical signature of attention to cardiac signals; and (c) neuroimaging recordings (MRI and fMRI) to evaluate anatomical and functional connectivity properties of key interoceptive regions (namely, the insula and the anterior cingulate cortex). Relative to controls, patients exhibited poorer interoceptive performance and reduced HEP modulations, alongside an abnormal association between interoceptive performance and both the volume and functional connectivity of the above regions. Such results suggest that peripheral cardiac system impairments can be associated with abnormal behavioral and neurocognitive signatures of interoception. More generally, our findings indicate that interoceptive processes entail bidirectional influences between the cardiovascular and the central nervous systems. PMID- 29271094 TI - Increased proportions of B cells with spontaneous production of interleukin-10 in HIV-infected individuals are normalized during combination antiretroviral therapy: a longitudinal study. AB - Interleukin-10 (IL-10)-producing B cells (B10 cells) may inhibit HIV-specific T cells and are elevated in untreated HIV infection. We aimed to determine the effect of combination antiretroviral treatment (cART) on the proportion of B10 cells. Furthermore, we compared B10-cell proportions in HIV-infected progressors and viremic controllers. This was a prospective study including HIV-infected progressors, viremic controllers and healthy controls. Progressors initiating cART were followed for 6 months. Purified B cells were stimulated with CpG, alone or in combination with HIV gp120, and the proportion of B10 cells was measured by flow cytometry. Without stimulation, the B10-cell proportion was higher in progressors than in healthy controls, while viremic controllers and healthy controls had comparable proportions. Moreover, the proportion of CD24hi CD38hi transitional B cells was higher in progressors than in healthy controls. After initiation of cART, the proportion of B10 cells and transitional B cells decreased. In conclusion, progressors had elevated B10-cell proportions, while viremic controllers displayed normal proportions. After initiation of cART, the B10-cell proportion decreased. This could limit B10-cell-mediated suppression of specific CD8+ T-cell responses. PMID- 29271095 TI - Peak season plant activity shift towards spring is reflected by increasing carbon uptake by extratropical ecosystems. AB - Climate change is lengthening the growing season of the Northern Hemisphere extratropical terrestrial ecosystems, but little is known regarding the timing and dynamics of the peak season of plant activity. Here, we use 34-year satellite normalized difference vegetation index (NDVI) observations and atmospheric CO2 concentration and delta13 C isotope measurements at Point Barrow (Alaska, USA, 71 degrees N) to study the dynamics of the peak of season (POS) of plant activity. Averaged across extratropical (>23 degrees N) non-evergreen-dominated pixels, NDVI data show that the POS has advanced by 1.2 +/- 0.6 days per decade in response to the spring-ward shifts of the start (1.0 +/- 0.8 days per decade) and end (1.5 +/- 1.0 days per decade) of peak activity, and the earlier onset of the start of growing season (1.4 +/- 0.8 days per decade), while POS maximum NDVI value increased by 7.8 +/- 1.8% for 1982-2015. Similarly, the peak day of carbon uptake, based on calculations from atmospheric CO2 concentration and delta13 C data, is advancing by 2.5 +/- 2.6 and 4.3 +/- 2.9 days per decade, respectively. POS maximum NDVI value shows strong negative relationships (p < .01) with the earlier onset of the start of growing season and POS days. Given that the maximum solar irradiance and day length occur before the average POS day, the earlier occurrence of peak plant activity results in increased plant productivity. Both the advancing POS day and increasing POS vegetation greenness are consistent with the shifting peak productivity towards spring and the increasing annual maximum values of gross and net ecosystem productivity simulated by coupled Earth system models. Our results further indicate that the decline in autumn NDVI is contributing the most to the overall browning of the northern high latitudes (>50 degrees N) since 2011. The spring-ward shift of peak season plant activity is expected to disrupt the synchrony of biotic interaction and exert strong biophysical feedbacks on climate by modifying the surface albedo and energy budget. PMID- 29271096 TI - Factors influencing accuracy of cortical thickness in the diagnosis of Alzheimer's disease. AB - There is great value to use of structural neuroimaging in the assessment of Alzheimer's disease (AD). However, to date, predictive value of structural imaging tend to range between 80% and 90% in accuracy and it is unclear why this is the case given that structural imaging should parallel the pathologic processes of AD. There is a possibility that clinical misdiagnosis relative to the gold standard pathologic diagnosis and/or additional brain pathologies are confounding factors contributing to reduced structural imaging classification accuracy. We examined potential factors contributing to misclassification of individuals with clinically diagnosed AD purely from cortical thickness measures. Correctly classified and incorrectly classified groups were compared across a range of demographic, biological, and neuropsychological data including cerebrospinal fluid biomarkers, amyloid imaging, white matter hyperintensity (WMH) volume, cognitive, and genetic factors. Individual subject analyses suggested that at least a portion of the control individuals misclassified as AD from structural imaging additionally harbor substantial AD biomarker pathology and risk, yet are relatively resistant to cognitive symptoms, likely due to "cognitive reserve," and therefore clinically unimpaired. In contrast, certain clinical control individuals misclassified as AD from cortical thickness had increased WMH volume relative to other controls in the sample, suggesting that vascular conditions may contribute to classification accuracy from cortical thickness measures. These results provide examples of factors that contribute to the accuracy of structural imaging in predicting a clinical diagnosis of AD, and provide important information about considerations for future work aimed at optimizing structural based diagnostic classifiers for AD. PMID- 29271098 TI - A guide to the contained use of plant virus infectious clones. AB - Plant virus infectious clones are important tools with wide-ranging applications in different areas of biology and medicine. Their uses in plant pathology include the study of plant-virus interactions, and screening of germplasm as part of prebreeding programmes for virus resistance. They can also be modified to induce transient plant gene silencing (Virus Induced Gene Silencing - VIGS) and as expression vectors for plant or exogenous proteins, with applications in both plant pathology and more generally for the study of plant gene function. Plant viruses are also increasingly being investigated as expression vectors for in planta production of pharmaceutical products, known as molecular farming. However, plant virus infectious clones may pose a risk to the environment due to their ability to reconstitute fully functional, transmissible viruses. These risks arise from both their inherent pathogenicity and the effect of any introduced genetic modifications. Effective containment measures are therefore required. There has been no single comprehensive review of the biosafety considerations for the contained use of genetically modified plant viruses, despite their increasing importance across many biological fields. This review therefore explores the biosafety considerations for working with genetically modified plant viruses in contained environments, with focus on plant growth facilities. It includes regulatory frameworks, risk assessment, assignment of biosafety levels, facility features and working practices. The review is based on international guidance together with information provided by plant virus researchers. PMID- 29271097 TI - Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition? AB - BACKGROUND: Nutrition screening on admission to hospital is mandated in many countries, but to date, there is no consensus on which tool is optimal in the oncology setting. Wasting conditions such as cancer cachexia (CC) and sarcopenia are common in cancer patients and negatively impact on outcomes; however, they are often masked by excessive adiposity. This study aimed to inform the application of screening in cancer populations by investigating whether commonly used nutritional screening tools are adequately capturing nutritionally vulnerable patients, including those with abnormal body composition phenotypes (CC, sarcopenia, and myosteatosis). METHODS: A prospective study of ambulatory oncology outpatients presenting for chemotherapy was performed. A detailed survey incorporating clinical, nutritional, biochemical, and quality of life data was administered. Participants were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST), and the Nutritional Risk Index (NRI). Computed tomography (CT) assessment of body composition was performed to diagnose CC, sarcopenia, and myosteatosis according to consensus criteria. RESULTS: A total of 725 patients (60% male, median age 64 years) with solid tumours participated (45% metastatic disease). The majority were overweight/obese (57%). However, 67% were losing weight, and CT analysis revealed CC in 42%, sarcopenia in 41%, and myosteatosis in 46%. Among patients with CT-identified CC, the MUST, MST, and NRI tools categorized 27%, 35%, and 7% of them as 'low nutritional risk', respectively. The percentage of patients with CT-identified sarcopenia and myosteatosis that were categorised as 'low nutritional risk' by MUST, MST and NRI were 55%, 61%, and 14% and 52%, 50%, and 11%, respectively. Among these tools, the NRI was most sensitive, with scores <97.5 detecting 85.8%, 88.6%, and 92.9% of sarcopenia, myosteatosis, and CC cases, respectively. Using multivariate Cox proportional hazards models, NRI score < 97.5 predicted greater mortality risk (hazard ratio 1.8, confidence interval: 1.2-2.8, P = 0.007). CONCLUSIONS: High numbers of nutritionally vulnerable patients, with demonstrated abnormal body composition phenotypes on CT analysis, were misclassified by MUST and MST. Caution should be exercised when categorizing the nutritional risk of oncology patients using these tools. NRI detected the majority of abnormal body composition phenotypes and independently predicted survival. Of the tools examined, the NRI yielded the most valuable information from screening and demonstrated usefulness as an initial nutritional risk grading system in ambulatory oncology patients. PMID- 29271099 TI - Overcoming the species hybridization barrier by ploidy manipulation in the genus Oryza. AB - In most eudicot and monocot species, interspecific and interploidy crosses generally display abnormalities in the endosperm that are the major cause of a post-zygotic hybridization barrier. In some eudicot species, however, this type of hybridization barrier can be overcome by the manipulation of ploidy levels of one parental species, suggesting that the molecular mechanisms underlying the species hybridization barrier can be circumvented by genome dosage. We previously demonstrated that endosperm barriers in interspecific and interploidy crosses in the genus Oryza involve overlapping but different mechanisms. This result contrasts with those in the genus Arabidopsis, which shows similar outcomes in both interploidy and interspecific crosses. Therefore, we postulated that an exploration of pathways for overcoming the species hybridization barrier in Oryza endosperm, by manipulating the ploidy levels in one parental species, might provide novel insights into molecular mechanisms. We showed that fertile hybrid seeds could be produced by an interspecific cross of female tetraploid Oryza sativa and male diploid Oryza longistaminata. Although the rate of nuclear divisions did not return to normal levels in the hybrid endosperm, the timing of cellularization, nucellus degeneration and the accumulation of storage products were close to normal levels. In addition, the expression patterns of the imprinted gene MADS87 and YUCCA11 were changed when the species barrier was overcome. These results suggest that the regulatory machinery for developmental transitions and imprinted gene expression are likely to play a central role in overcoming species hybridization barriers by genome dosage in the genus Oryza. PMID- 29271100 TI - Managing opioid overdose in pregnancy with take-home naloxone. AB - Programs have recently been established in Australia and internationally to allow wider access to naloxone to people at risk of opioid overdose yet there are no guidelines relating to the administration of naloxone to pregnant women, particularly regarding dose requirements and resuscitative measures peculiar to pregnancy. This paper provides practical guidelines to health workers in relation to any complications that may arise during opioid overdose response (including the administration of naloxone) for pregnant women and the follow up required ensuring best possible outcomes for mother and baby. PMID- 29271101 TI - Selectivity in the Aerobic Dearomatization of Phenols: Total Synthesis of Dehydronornuciferine by Chemo- and Regioselective Oxidation. AB - We describe a selective aerobic oxidation of meta-biaryl phenols that enables rapid access to functionalized phenanthrenes. Aerobic oxidations attract interest due to their efficiency, but remain underutilized in complex molecule settings due to challenges of selectivity. We discuss these issues in the context of Cu catalysis, and highlight the advantages of confining oxygen activation and substrate oxidation to the catalyst's inner-coordination sphere. This gives rise to predictable selectivity that we use for a concise synthesis of the aporphine dehydronornuciferine. PMID- 29271102 TI - High-performance liquid chromatography study of gatifloxacin and sparfloxacin using erythrosine as post-column resonance Rayleigh scattering reagent and mechanism study. AB - Herein, a highly selective high-performance liquid chromatography (HPLC) coupled with resonance Rayleigh scattering (RRS) method was developed to detect gatifloxacin (GFLX) and sparfloxacin (SPLX). GFLX and SPLX were first separated by HPLC, then, in pH 4.4 Britton-Robinson (BR) buffer medium, protonic quaternary ammonia cation of GFLX and SPLX reacted with erythrosine (ERY) to form 1:1 ion association complexes, which resulted in a significant enhancement of RRS signal. The experimental conditions of HPLC and post-column RRS have been investigated, including detection wavelength, flow rate, pH, reacting tube length and reaction temperature. Reaction mechanism were studied in detail by calculating the distribution fraction. The maximum RRS signals for GFLX and SPLX were recorded at lambdaex = lambdaem = 330 nm. The detection limits were 3.8 ng ml-1 for GFLX and 17.5 ng ml-1 for SPLX at a signal-to-noise ratio of 3. The developed method was successfully applied to the determination of GFLX and SPLX in water samples. Recoveries from spiked water samples were 97.56-98.85%. PMID- 29271104 TI - Erratum. PMID- 29271103 TI - Pharmacokinetics and pharmacodynamics of canagliflozin in pediatric patients with type 2 diabetes. AB - OBJECTIVE: Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG ). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric T2D patients. METHODS: Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2 , underwent PK and PD assessments after receiving a single daily dose of canagliflozin 100 mg (n = 8) or 300 mg (n = 9) for 14 days. Data are presented as mean (SD). RESULTS: There were dose-dependent increases in the PK of canagliflozin 100 and 300 mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with canagliflozin 100 mg and to 69.1 (9.6) mg/dL with canagliflozin 300 mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with canagliflozin 100 mg and from 0.1 (0.04) g to 68.6 (26.5) g with canagliflozin 300 mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. CONCLUSIONS: In pediatric T2D patients, canagliflozin 100 and 300 mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder. PMID- 29271105 TI - New insights into diet breadth of polyphagous and oligophagous aphids on two Arabidopsis ecotypes. AB - We investigated whether plant ecotype might affect aphid performance and behavior. The probing behaviors of the polyphagous aphid Myzus persicae and the oligophagous aphid Brevicoryne brassicae on two ecotypes of Arabidopsis thaliana, WS and Col-0 were recorded using the direct current electrical penetration graph method (DC-EPG). Myzus persicae displayed a significant preference for the WS ecotype but was not greatly disturbed on Col-0, while B. brassicae discriminated between the two A. thaliana ecotypes, feeding less on WS than on Col-0. A Principal Component Analysis of aphid probing behavior data recorded on Col-0 and WS ecotypes showed that the one of M. persicae was positively correlated with the phloem ingestion phases while the one of B. brassicae was more related to nonfeeding phase. The survival of the aphid species was followed during early larval stages on the two ecotypes and a significantly higher mortality was observed of B. brassicae neonates compared to M. persicae, both reared on WS. Moreover, transcriptomic analysis of noninfested plant leaves from both ecotypes was monitored and underlined constitutive differences between Col-0 and WS gene expression that might explain the different aphid behaviors. Among a unigene set comprising 39 042 sequences for A. thaliana, 6% were differently expressed affecting, for example, the secondary metabolites and cell wall pathways: two third upregulated in WS and one third upregulated in Col-0. Thus, the "ecotype" variable should be taken into account when setting up a plant-insect experimental research. PMID- 29271106 TI - Efficacy and tolerability of treatment with mirabegron compared with solifenacin in the management of overactive bladder syndrome: A retrospective analysis. AB - AIM: The aim of this study was to compare the efficacy and tolerability of solifenacin and mirabegron in patients with overactive bladder (OAB) syndrome. METHODS: We carried out a retrospective analysis in 342 women affected by OAB syndrome; 168 were treated with solifenacin 5 mg/daily and 174 with mirabegron 50 mg/daily. A clinical evaluation, 3-day voiding diary, and urodynamic testing was performed. Patients completed the Overactive Bladder Questionnaire - Short Form, the King's Health Questionnaire, and the Patient Global Impression of Improvement questionnaire. The adverse effects were evaluated. The two groups were compared at baseline and at 12 weeks. RESULTS: After 12 weeks, a significant reduction in the mean number/24 h of voids and urgent micturition episodes/24 h was observed in both groups. Detrusor overactivity decreased from 58.3% to 13.1% in the solifenacin group and from 58% to 11% in the mirabegron group. Twenty (12%) and 18 (10.7%) patients taking solifenacin reported constipation and dry mouth, respectively, versus four (2.3%) and five (2.9%) patients taking mirabegron, respectively, but there was no difference between the groups in the change in vital signs. The Overactive Bladder Questionnaire - Short Form and King's Health Questionnaire scores did not demonstrate significant differences and the abandonment rates in the solifenacin and mirabegron groups were 25.5% and 20%, respectively. CONCLUSION: Solifenacin and mirabegron showed the same efficacy in the treatment of OAB but solifenacin had more adverse effects. PMID- 29271107 TI - Optimizing the identification of risk-relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families. AB - The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence-based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger-sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2-negative families to be subjected to the BROCA-Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss-of heterozygosity and further molecular studies. We identified loss-of-function mutations in 6 out 20 high-risk families, 5 of which occurred on BRCA1, CHEK2 and ATM and are esteemed to be risk-relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre-organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk-relevant alleles impacting on the clinical management of their carriers. PMID- 29271109 TI - Violence in mental health settings: A systematic review. AB - The introduction of smoke-free policies is increasingly common in mental health settings, to improve health. However, a barrier to implementing smoke-free polices is staff concern that violence will increase. We conducted a systematic review comparing the rates of violence before and after the introduction of smoke free policies in mental health settings. Two authors searched major electronic databases. We included studies reporting the prevalence of violence (verbal and/or physical or combined) before and after the introduction of a smoke-free policy in a mental health, forensic, or addiction setting. We included 11 studies in the review. A narrative synthesis was used to describe the key results of each study. Six studies measured physical violence specifically; four reported a decrease or no change and two reported a short-term increase. Five of these six studies also measured verbal violence; two found an increase, with one of the studies reporting that this increase was temporary. Three reported a decrease in verbal violence. A further five studies evaluated the rate of combined verbal and physical violence; four reported a decrease or no change and the other an increase. We conclude that the introduction of smoke-free policies generally does not lead to an increase in violence. There is a need for more robust studies to support this finding. However, the conclusions from this review may be a step in reducing staff concerns. PMID- 29271108 TI - Validation of screening questionnaires for evaluation of knee osteoarthritis prevalence in the general population of Singapore. AB - BACKGROUND: The prevalence of symptomatic knee osteoarthritis (KOA) in Singapore is unknown. We aimed to: (i) validate questionnaires to screen for symptomatic KOA; and (ii) estimate the prevalence of symptomatic KOA in Singapore using the validated algorithms. METHODS: Subjects aged >=50 years were evaluated for symptomatic KOA based on American College of Rheumatology clinical and radiographic criteria in a rheumatology clinic, and completed three sets of adapted screening questionnaires. The better performing screening questionnaire with adequate sensitivity and specificity was adminitered to a nationally representative sample of survey subjects (n = 3364) to estimate the weighted prevalence of symptomatic KOA in Singapore. RESULTS: Out of 146 subjects evaluated in the clinic, 45 had symptomatic KOA. A screening algorithm which consisted of three KOA symptoms or one symptom plus physician-diagnosed KOA produced high specificity (0.95, 95% confidence intervals [CI]: 0.88-0.98) but low sensivity (0.44, 95% CI: 0.30-0.60). Replacing the term 'KOA' with 'physician diagnosed ageing-related knee problem' improved the sensivity (0.62, 95% CI: 0.47 0.76) without significantly compromising the specificity (0.87, 95% CI: 0.79 0.93). The prevalence of symptomatic KOA weighted to the Singapore population distribution were 4.7% and 11%, using the most conservative and more liberal algorithms, respectively. There was a sharp rise in prevalence after age of 40. The weighted prevalence of KOA was higher in women and among Indian and Malay than Chinese. CONCLUSION: Our study adapted and validated questionnaires to the local context to screen for symptomatic KOA. We estimated the prevalence of symptomatic KOA in Singapore utilizing the better-performing algorithms. PMID- 29271111 TI - The lifetime costs of overweight and obesity in childhood and adolescence: a systematic review. AB - BACKGROUND: Research into lifetime costs of obesity in childhood is growing. This review synthesizes that knowledge. METHODOLOGY: A computerized search of the international literature since 2000 was conducted. Mean total lifetime healthcare and productivity costs were estimated and inflated to 2014 Irish euros. RESULTS: This resulted in 13 published articles. The methodology used in these studies varied widely, and only one study estimated both healthcare and productivity costs. Cognizant of this heterogeneity, the mean total lifetime cost of a child or adolescent with obesity was ?149,206 (range, ?129,410 to ?178,933) for a boy and ?148,196 (range, ?136,576 to ?173,842) for a girl. This was divided into an average of ?16,229 (range, ?6,580 to ?35,810) in healthcare costs and ?132,977 (range, ?122,830 to ?143,123) in productivity losses for boys and ?19,636 (range, ?8,016 to ?45,283) and ?128,560, respectively, for girls. Income penalty accounted for the greater part of productivity costs, amounting to ?97,118 (range, ?86,971 to ?107,264) per male adolescent with obesity and ?126,108 per female adolescent. CONCLUSIONS: Healthcare costs and income penalty appear greater in girls while costs because of workdays lost seem greater in boys. There is proportionality between body mass index and costs. Productivity costs are greater than healthcare costs. PMID- 29271110 TI - Hallucination- and speech-specific hypercoupling in frontotemporal auditory and language networks in schizophrenia using combined task-based fMRI data: An fBIRN study. AB - Hypercoupling of activity in speech-perception-specific brain networks has been proposed to play a role in the generation of auditory-verbal hallucinations (AVHs) in schizophrenia; however, it is unclear whether this hypercoupling extends to nonverbal auditory perception. We investigated this by comparing schizophrenia patients with and without AVHs, and healthy controls, on task-based functional magnetic resonance imaging (fMRI) data combining verbal speech perception (SP), inner verbal thought generation (VTG), and nonverbal auditory oddball detection (AO). Data from two previously published fMRI studies were simultaneously analyzed using group constrained principal component analysis for fMRI (group fMRI-CPCA), which allowed for comparison of task-related functional brain networks across groups and tasks while holding the brain networks under study constant, leading to determination of the degree to which networks are common to verbal and nonverbal perception conditions, and which show coordinated hyperactivity in hallucinations. Three functional brain networks emerged: (a) auditory-motor, (b) language processing, and (c) default-mode (DMN) networks. Combining the AO and sentence tasks allowed the auditory-motor and language networks to separately emerge, whereas they were aggregated when individual tasks were analyzed. AVH patients showed greater coordinated activity (deactivity for DMN regions) than non-AVH patients during SP in all networks, but this did not extend to VTG or AO. This suggests that the hypercoupling in AVH patients in speech-perception-related brain networks is specific to perceived speech, and does not extend to perceived nonspeech or inner verbal thought generation. PMID- 29271112 TI - Smoking, alcohol, and diet in relation to risk of pancreatic cancer in China: a prospective study of 0.5 million people. AB - In China, the incidence of pancreatic cancer (PC) has increased in recent decades. However, little is known about the relevance to PC risk of lifestyle and behavioral factors such as smoking, alcohol drinking, and diet. The China Kadoorie Biobank prospective study recruited 512,891 adults (210,222 men, 302,669 women) aged 30-79 (mean 52) years from 10 diverse areas during 2004-08. During ~9 years of follow-up, 688 incident cases of PC were recorded among those who had no prior history of cancer at baseline. Cox regression yielded adjusted hazard ratios (HR) for PC associated with smoking, alcohol and selected dietary factors. Overall, 74% of men were ever-regular smokers and 33% of men drank at least weekly, compared with only 3% and 2% of women, respectively. Among men, current regular smoking was associated with an adjusted HR of 1.25 (95% CI 1.08-1.44) for PC, with greater excess risk in urban than rural areas (1.46 [1.19-1.79] vs 1.04 [0.86-1.26]). Heavy, but not light to moderate, alcohol drinking (i.e. >=420 g/week) was associated with significant excess risk (1.69 [1.21-2.37]), again more extreme in urban than rural areas (1.93 [1.29-2.87] vs 1.35 [0.74-2.48]). Overall, regular consumption of certain foodstuffs was associated with PC risk, with adjusted daily vs never/rare consumption HRs of 0.66 (0.56-0.79) for fresh fruit and 1.16 (1.01-1.33) for red meat. In China, smoking and heavy alcohol drinking were independent risk factors for PC in men. Lower fresh fruit and higher red meat consumption were also associated with higher risk of PC. PMID- 29271113 TI - Trends and clinicopathological predictors of axillary evaluation in ductal carcinoma in situ patients treated with breast-conserving therapy. AB - The aim of this study was to investigate the trends of axillary lymph node evaluation in ductal carcinoma in situ (DCIS) patients treated with breast conserving therapy (BCT) and to identify the clinicopathological predictors of axillary evaluation. DCIS patients treated with BCT in 2006-2015 at our institute were retrospectively included in the analysis. Patients were categorized into three groups: sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), and non-evaluation. Univariate and multivariate logistic regression analyses were performed to identify factors that predicted axillary evaluation. A total of 315 patients were identified, among whom 135 underwent SLNB, and 15 underwent ALND. The proportion of patients who underwent axillary evaluation increased from 33.0% in 2006-2010 to 53.8% in 2011-2015 (P < 0.001), however, no patients had lymph node metastasis based on final pathology. In multivariate analysis, high-grade tumor favored axillary evaluation (OR = 4.376, 95% CI:1.410 13.586, P = 0.011); while excision biopsy favored no axillary evaluation compared with other biopsy methods (OR = 0.418, 95% CI: 0.192-0.909, P = 0.028). Subgroup analysis of patients treated in 2011-2015 revealed that high-grade tumor (OR = 5.898, 95% CI: 1.626-21.390, P = 0.007) and palpable breast lump (OR = 2.497, 95% CI: 1.037-6.011, P = 0.041) were independent predictors of axillary lymph node evaluation. Despite the significant decrease in ALND and a concerning overuse of SLNB, we identified no axillary lymph node metastasis, which justified omitting axillary evaluation in these patients. High-grade tumor, palpable lump, and biopsy method were independent predictors of axillary evaluations. Excision biopsy of suspicious DCIS lesions may potentially preclude the invasive component of the disease and help to avoid axillary surgery. PMID- 29271114 TI - Viral kinetics analysis and virological characterization of treatment failures in patients with chronic hepatitis C treated with sofosbuvir and an NS5A inhibitor. AB - BACKGROUND: The combination of sofosbuvir (SOF) plus an NS5A inhibitor for 12 weeks is highly efficacious in patients with chronic hepatitis C. As the costs of generic production of sofosbuvir and NS5A inhibitor are rapidly decreasing, the combination of these DAAs will be the standard treatment in most low- to middle income countries in the future. AIM: To identify key predictors of response that can be used to tailor treatment decisions. METHODS: A cohort of 216 consecutive patients infected with HCV genotype 1 (1a: n = 57; 1b: n = 77), 2 (n = 4), 3 (n = 33) or 4 (n = 44) were treated with sofosbuvir (SOF) + daclatasvir (n = 176) or SOF + ledipasvir (n = 40) for 12 weeks. The viral kinetics was analysed using the biphasic model and the cure boundary was used to predict time to clear HCV. RESULTS: The overall SVR rate was high (94.4%; n = 204), regardless of the time to viral suppression or low-level viraemia at the end of treatment. The model based predicted HCV RNA levels at the end of treatment could not differentiate patients who did from those who did not achieve SVR. The presence of NS5A resistance-associated substitutions [position 28 (OR = 70.3, P<.001) and/or 31 (OR = 61.6, P = .002)] at baseline was predictive of virological failure in cirrhotic patients but was not associated with on-treatment viral kinetics. CONCLUSION: This real-world study confirms the excellent results of clinical trials with therapies based on a combination of SOF plus an NS5A inhibitor. It suggests that a personalized approach including baseline NS5A inhibitor resistance testing may inform treatment decisions in cirrhotic patients. PMID- 29271115 TI - Barriers and enablers for iron folic acid (IFA) supplementation in pregnant women. AB - In order to inform large scale supplementation programme design, we review and summarize the barriers and enablers for improved coverage and utilization of iron and folic acid (IFA) supplements by pregnant women in 7 countries in Africa and Asia. Mixed methods were used to analyse IFA supplementation programmes in Afghanistan, Bangladesh, Indonesia, Ethiopia, Kenya, Nigeria, and Senegal based on formative research conducted in 2012-2013. Qualitative data from focus-group discussions and interviews with women and service providers were used for content analysis to elicit common themes on barriers and enablers at internal, external, and relational levels. Anaemia symptoms in pregnancy are well known among women and health care providers in all countries, yet many women do not feel personally at risk. Broad awareness and increased coverage of facility-based antenatal care (ANC) make it an efficient delivery channel for IFA; however, first trimester access to IFA is hindered by beliefs about when to first attend ANC and preferences for disclosing pregnancy status. Variable access and poor quality ANC services, including insufficient IFA supplies and inadequate counselling to encourage consumption, are barriers to both coverage and adherence. Community based delivery of IFA and referral to ANC provides earlier and more frequent access and opportunities for follow-up. Improving ANC access and quality is needed to facilitate IFA supplementation during pregnancy. Community-based delivery and counselling can address problems of timely and continuous access to supplements. Renewed investment in training for service providers and effective behaviour change designs are urgently needed to achieve the desired impact. PMID- 29271116 TI - A Non-Competitive Inhibitor of VCP/p97 and VPS4 Reveals Conserved Allosteric Circuits in Type I and II AAA ATPases. AB - AAA ATPases have pivotal functions in diverse cellular processes essential for survival and proliferation. Revealing strategies for chemical inhibition of this class of enzymes is therefore of great interest for the development of novel chemotherapies or chemical tools. Here, we characterize the compound MSC1094308 as a reversible, allosteric inhibitor of the type II AAA ATPase human ubiquitin directed unfoldase (VCP)/p97 and the type I AAA ATPase VPS4B. Subsequent proteomic, genetic and biochemical studies indicate that MSC1094308 binds to a previously characterized drugable hotspot of p97, thereby inhibiting the D2 ATPase activity. Our results furthermore indicate that a similar allosteric site exists in VPS4B, suggesting conserved allosteric circuits and drugable sites in both type I and II AAA ATPases. Our results may thus guide future chemical tool and drug discovery efforts for the biomedically relevant AAA ATPases. PMID- 29271117 TI - Dynamics of HCV epidemiology in Aydin province of Turkey and the associated factors. AB - This paper gives an update on the local distributions of HCV genotypes in Aydin province of Turkey, provides a comparison with the previous records, and discusses the potential causal reasons shaping the evolving genotype profiles. Patient files from 2011 to 2016 were retrospectively analyzed, and newly detected cases were documented. Out of 286 patients, male and female ratios were determined to remain nearly the same (~50%). Genotype 1 was still the most common (90.2%), followed by genotype 3 (5.9%), genotype 2 (2.1%), and genotype 4 (1.4%) in frequency. There were international patients (4.50%). One patient had genotyped 2+3 together. Genotypes 4 and 2+3 were detected for the first time, and the patients with genotype 4 were interestingly all male and also domestic individuals. However, these patients traveled or lived abroad in the past due to occupational reasons, thereby likely acquired the infection while abroad. HCV surveillance system is currently inadequate and some infected patients may go undetected in the province. Remapping the regional distribution of HCV genotypes from time-to-time is required for identifying the local dynamics and causes leading to it. This process enhances the clinical preparation and readiness for the better management of the disease. PMID- 29271119 TI - Multiple-micronutrient supplementation: Evidence from large-scale prenatal programmes on coverage, compliance and impact. AB - Micronutrient deficiencies during pregnancy pose important challenges for public health, given the potential adverse outcomes not only during pregnancy but across the life-course. Provision of iron-folic acid (IFA) supplements is the strategy most commonly practiced and recommended globally. How to successfully implement IFA and multiple micronutrient supplementation interventions among pregnant women and to achieve sustainable/permanent solutions to prenatal micronutrient deficiencies remain unresolved issues in many countries. This paper aims to analyse available experiences of prenatal IFA and multiple micronutrient interventions to distil learning for their effective planning and large-scale implementation. Relevant articles and programme-documentation were comprehensively identified from electronic databases, websites of major-agencies and through hand-searching of relevant documents. Retrieved documents were screened and potentially relevant reports were critically examined by the authors with the aim of identifying a set of case studies reflecting regional variation, a mix of implementation successes and failures, and a mix of programmes and large scale experimental studies. Information on implementation, coverage, compliance, and impact was extracted from reports of large-scale interventions in Central America, Southeast Asia, South Asia, and Sub-Saharan Africa. The WHO/CDC Logic Model for Micronutrient Interventions in Public Health was used as an organizing framework for analysing and presenting the evidence. Our findings suggest that to successfully implement supplementation interventions and achieve sustainable permanent solutions efforts must focus on factors and processes related to quality, cost-effectiveness, coverage, utilization, demand, outcomes, impacts, and sustainability of programmes including strategic analysis, management, collaborations to pilot a project, and careful monitoring, midcourse corrections, supervision and logistical-support to gradually scaling it up. PMID- 29271118 TI - Prominin-1/CD133: Lipid Raft Association, Detergent Resistance, and Immunodetection. AB - The cell surface antigen prominin-1 (alias CD133) has gained enormous interest in the past 2 decades and given rise to debates as to its utility as a biological stem and cancer stem cell marker. Important and yet often overlooked knowledge that is pertinent to its physiological function has been generated in other systems given its more general expression beyond primitive cells. This article briefly discusses the importance of particular biochemical features of CD133 with relation to its association with membrane microdomains (lipid rafts) and proper immunodetection. It also draws attention toward the adequate use of detergents and caveats that may apply to the interpretation of the results generated. Stem Cells Translational Medicine 2018;7:155-160. PMID- 29271120 TI - Contribution of neuraminidase 3 to the differentiation of induced regulatory T cells. AB - Neuraminidase family enzymes that hydrolyze the terminal sialic acid linkage in biomolecules are involved in various immune responses. We previously showed that Th1 and Th2 cells differentially express several neuraminidases. Herein, the expression of neuraminidases in induced regulatory T (iTreg) cells was investigated in comparison with that in other T-cell subsets. Contrary to the tendency toward higher neuraminidase 1 mRNA expression in in vitro-differentiated Th2 cells, compared to Th1, Th17 and iTreg cells, we observed significantly higher expression of neuraminidase 3 (Neu3) in iTreg cells. Furthermore, the expression of Neu3 in FoxP3+ CD62L- spleen cells was higher than that in FoxP3+ CD62L+ and FoxP3- cells. Lentiviral expression of Neu3 in naive CD4+ T cells during the stimulation culture led to upregulation of FoxP3 expression. On the basis of these findings, we conclude that Neu3 contributes to the differentiation of iTreg cells by upregulation of FoxP3. PMID- 29271121 TI - microRNA regulation in an ancient obligate endosymbiosis. AB - Although many insects are associated with obligate bacterial endosymbionts, the mechanisms by which these host/endosymbiont associations are regulated remain mysterious. While microRNAs (miRNAs) have been recently identified as regulators of host/microbe interactions, including host/pathogen and host/facultative endosymbiont interactions, the role miRNAs may play in mediating host/obligate endosymbiont interactions is virtually unknown. Here, we identified conserved miRNAs that potentially mediate symbiotic interactions between aphids and their obligate endosymbiont, Buchnera aphidicola. Using small RNA sequence data from Myzus persicae and Acyrthosiphon pisum, we annotated 93 M. persicae and 89 A. pisum miRNAs, among which 69 were shared. We found 14 miRNAs that were either highly expressed in aphid bacteriome, the Buchnera-housing tissue, or differentially expressed in bacteriome vs. gut, a non-Buchnera-housing tissue. Strikingly, 10 of these 14 miRNAs have been implicated previously in other host/microbe interaction studies. Investigating the interaction networks of these miRNAs using a custom computational pipeline, we identified 103 miRNA::mRNA interactions shared between M. persicae and A. pisum. Functional annotation of the shared mRNA targets revealed only two over-represented cluster of orthologous group categories: amino acid transport and metabolism, and signal transduction mechanisms. Our work supports a role for miRNAs in mediating host/symbiont interactions between aphids and their obligate endosymbiont Buchnera. In addition, our results highlight the probable importance of signal transduction mechanisms to host/endosymbiont coevolution. PMID- 29271122 TI - Circulating levels of miR-122 and nonalcoholic fatty liver disease in pre pubertal obese children. AB - OBJECTIVES: The liver-specific miR-122 was proposed as biomarker for NAFLD in adults. Here, we investigated the relationship between miR-122 levels, parameters of liver metabolism and NAFLD in pre-pubertal obese children. METHODS: Parameters of liver metabolism (ALT, AST and GGT) of three European cohorts were included (German cohort [n = 71; age: 11.53 +/- 1.29 years; BMI z-score: 2.96 +/- 0.64], Italian cohort [n = 45; age: 9.60 +/- 2.11 years; BMI z-score: 3.57 +/- 1.16], Slovenian cohort [n = 31; age: 7.53 +/- 1.47 years; BMI z-score: 3.66 +/- 0.88]). MiR-122 levels and CK18 concentrations were measured in fasting blood samples. In the German and Italian cohort, the diagnosis of NAFLD and grading of NAFLD was assessed by ultrasound. RESULTS: NAFLD was diagnosed in n = 50 patients of the German cohort (29.6%) and in n = 29 patients (72.5%) of the Italian cohort. In all three cohorts, miR-122 was positively correlated with ALT and AST as well as with CK18 concentrations. MiR-122 levels were higher in children with NAFLD compared with healthy controls. CONCLUSIONS: MiR-122 levels in pre-pubertal obese children could be a potential biomarker for paediatric NAFLD. PMID- 29271123 TI - Disturbances of dental development distinguish patients with oligodontia ectodermal dysplasia from isolated oligodontia. AB - OBJECTIVE: To investigate phenotypic differences in dental development between isolated oligodontia and oligodontia-ectodermal dysplasia (ED). SETTING AND SAMPLE POPULATION: A total of 129 patients diagnosed with isolated oligodontia and 22 patients with oligodontia as part of ED were eligible. METHODS: The phenotype of dental development was assessed for the frequency of missing a certain tooth, dental age, development of each tooth present, abnormal size and abnormal shape of teeth. The data were analysed building linear, ordinal and logistic regression models. RESULTS: Compared to patients with isolated oligodontia, patients with oligodontia-ED missed more frequently central incisors and second molars in both jaws, and lateral incisors in the mandible (P < .05). Oligodontia-ED was associated with delayed development of the permanent dentition (beta = -0.10; 95% CI: -0.17, -0.03). Specifically, the maxillary teeth: right central incisor, right lateral incisor, right second premolar and left second premolar were delayed approximately from 2 to 4 developmental stages. In addition, the left mandibular second premolar was 3 developmental stages delayed. Abnormal shape of teeth was 7 times more evident in patients with oligodontia-ED compared to patients with isolated oligodontia (OR = 6.54; 95% CI: 2.34, 18.28). The abnormal size of teeth was not a distinctive characteristic for oligodontia ED. CONCLUSIONS: Oligodontia-ED distinguishes from isolated oligodontia by more disturbances in dental development. The abnormal shape of incisors and canines in a patient with oligodontia can raise suspicions for accompanying ectodermal abnormalities. PMID- 29271124 TI - The importance of oesophageal ultrasound in mediastinal staging of lung cancer - Reply. PMID- 29271126 TI - Persistent polyclonal B-cell lymphocytosis: two nuclei and sometimes more. PMID- 29271125 TI - Microglial modulation of neuronal activity in the healthy brain. AB - Investigations on the role of microglia in the brain have traditionally been focused on their contributions to disease states. However, recent observations have now convincingly shown that microglia in the healthy brain are not passive bystanders, but instead play a critical role in both central nervous system development and homeostasis of synaptic circuits in the adult. Here, we review the various mechanisms by which microglia impact neuronal communication in the healthy adult brain, both by sensing nearby synaptic responses and by actively modulating neuronal function. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 593-603, 2018. PMID- 29271127 TI - Real-time elastosonography of lipomatous vs. malignant subcutaneous neoplasms in dogs: Preliminary results. AB - Real-time elastography is a recently introduced ultrasound technique allowing the investigation of elastic properties of tissues. A diagnostic accuracy study was conducted to test the performance of this technique in the assessment of subcutaneous lesions in dogs. Fifty-two dogs were prospectively included in the preliminary study (34 malignant and 18 benign lesions). B-mode ultrasound was performed assessing the shape, margins, heterogeneity, and echotexture of the lesions. On elastosonography, assessment of the percentage of softness/hardness was recorded. A qualitative assessment was performed according to the Tsukuba elasticity score with a 1-5 score, representing the increased percentage of high stiffness areas. Results were compared with cytology/histopathology of the lesions. Receiver Operating Curves of the overall diagnostic sensitivity and specificity were obtained. Fisher's exact test and Pearsons's Chi-squared test estimated the relationship between the B-mode appearance of the lesions and final diagnosis. A hardness cutoff of 50.25% was identified between lesions, with malignant neoplasms having higher percentages. A 100% specificity and 89% sensitivity for correctly detecting the nature of the lesion on elastosonography was established. Qualitative assessment of the Tsukuba elasticity score established 1.5 as the cutoff between elastograms of lipomatous and malignant lesions, with 100% sensitivity and 61% specificity in differentiating them. Real time elastosonography is a novel, noninvasive, and accurate technique for differentiating malignant from benign lipomatous lesions in dogs. This method could be considered as a complementary tool with additional diagnostic value for routine invasive procedures, such as fine needle aspirates. PMID- 29271128 TI - Optimization and comparison of CD4-targeting lipid-polymer hybrid nanoparticles using different binding ligands. AB - Monoclonal antibodies and peptides are conjugated to the surface of nanocarriers (NCs) for targeting purposes in numerous applications. However, targeting efficacy may vary with their specificity, affinity, or avidity when linked to NCs. The physicochemical properties of NCs may also affect targeting. We compared the targeting efficacy of the CD4 binding peptide BP4 and an anti-CD4 monoclonal antibody (CD4 mAb) and its fragments, when conjugated to lipid-coated poly(lactic co-glycolic) acid nanoparticles (LCNPs). Negatively charged LCNPs with cholesteryl butyrate in the lipid layer (cbLCNPs) dramatically reduced nonspecific binding, leading to higher targeting specificity, compared to neutral or positively charged LCNPs with DOTAP (dtLCNP). cbLCNPs surface conjugated with a CD4 antibody (CD4-cbLCNPs) or its fragments (fCD4-cbLCNPs), but not BP4, showed high binding in vitro to the human T cell line 174xCEM, and preferential binding to CD3+ CD14-CD8- cells from pigtail macaque peripheral blood mononuclear cells. CD4-cbLCNPs showed 10-fold higher binding specificity for CD4+ than CD8+ T cells, while fCD4-cbLCNPs demonstrated the highest binding level overall, but only three fold higher binding specificity. This study demonstrates the importance of zeta potential on NC targeting and indicates that CD4 mAb and its fragments are the best candidates for delivery of therapeutic agents to CD4+ T cells. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1177-1188, 2018. PMID- 29271130 TI - [Image of the month. Dermatitis Artefacta.] PMID- 29271129 TI - Shorter preschool, leukocyte telomere length is associated with obesity at age 9 in Latino children. AB - The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages. PMID- 29271131 TI - [Endocarditis of mitral and aortic prosthetic heart valves caused by Aggregatibacter aphrophilus]. AB - We present the case of an acute endocarditis of mitral and aortic prosthetic heart valves caused by Aggregatibacter aphrophilus (Haemophilus aphrophilus paraphrophilus). This third report in the literature emphasizes the diagnostic work-up and the role of positron emission tomography combined with computed tomography in this setting. The specificities of endocarditis due to the HACEK group (Haemophilus spp., Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens and Kingella spp.) and the specific microbiological data and therapeutic options pertinent to this germ are discussed. PMID- 29271132 TI - [Post-obstructive diuresis : diagnosis and management]. AB - The syndrome of "post-obstructive diuresis" corresponds to a massive polyuria and natriuresis occurring after the drainage of an obstructive acute kidney injury. Such a complication needs to be readily detected and managed because of the significant risk for haemodynamic disorders. On the basis of a clinical observation, we describe the pathophysiology of post-obstructive diuresis, as well as its diagnostic and therapeutic management. PMID- 29271133 TI - [Incidence and treatment of complications observed after endoscopic mucosal resection of superficial digestive tumours in a regional general hospital]. AB - Superficial digestive tumours resection by endoscopic mucosal resection and sub mucosal dissection causes very few complications according to the results obtained in expert centers. This work reports the rate of complications observed in a regional hospital, also comparing the results of their therapeutic management. The first 100 patients treated by endoscopic mucosal resection and sub-mucosal dissection, conducted by conventional techniques, were studied. The usual complications (stenosis, bleeding, perforation) were identified and details of their treatment reported. The overall complication rate was 16 %. Symptomatic stenoses are observed in 4 % of patients. Secondary bleeding occurs in 5 % of cases. Endoscopic management of these complications is effective in all cases, when it is attempted. Perforations complicate 7 % of the procedures. Two patients were assigned to surgery, successfully, the other 5 patients were treated by endoscopic sutures without damage. The complication rates observed in our department are comparable with results reported by the reference western centers. Their endoscopic management is usually successful and rescue surgery is unfrequent. PMID- 29271134 TI - [What is the value of low-energie lasers in the treatment of androgenetic alopecia ?] AB - Male and female androgenetic alopecia is a common, chronic, psychologically stressful disorder affecting more than 50 % of the individuals by 50 years of age. Despite the current topical (minoxidil) or oral (the inhibitors of 5-? reductase finasteride or dutasteride) treatments, there is a need for more effective management options. The current clinical evidence, the possible mechanisms of action and the rare adverse events of the low level laser therapy in the treatment of androgenetic alopecia are presented. PMID- 29271135 TI - [Hypophosphatasia]. AB - Hypophosphatasia (HPP) is a rare genetic disorder characterized by the diminution of the enzymatic activity of the alkaline phosphatase (ALP). The disease mainly involves multiple defects of the mineralization of the skeleton including bone fragilities. It will be expressed to varying degrees of severity and will allow to characterize different forms of HPP. Unfortunately, the prevalence of this pathology remains probably underestimated and its diagnosis must be multidisciplinary by taking into account the biochemical assays, the clinical history as well as the radiological imaging. So, in the approach of this diagnosis, a retrospective screening was carried out by the clinical chemistry department of the CHU of Liege. The aim of this study is to potentially identify the affected patients on the basis of their biochemical assays and their anamnesis in order to propose a genetic screening. Unfortunately, no case could be formally identified, which testifies the difficulty to establish a diagnosis of the slight forms encountered mainly in the adults. PMID- 29271136 TI - [Tiredness of life in older adults]. AB - Tiredness of life in older adults can lead to a request for the wish to die. This article provides a practical approach for physicians of this problem on the basis of a flow chart. The main causes of tiredness of life should be identified and evaluated for their reversibility and treatment options. The first group are the physical factors which, besides organ pathology, should also take frailty into account as a possible cause. A second important group are the psychological risk factors such as psychiatric disorders, loneliness, dignity, subjective well being, coping and spiritual power. These factors also determine the complaint and needs of the patient. Here is a multidisciplinary assessment and approach desirable. This multidisciplinary approach also applies to the socioeconomic risk factors. In addition, the caregiver should examine if the weariness of life indeed gives rise to the suffering of the older person and to what extent this is hopeless and unbearable suffering. Hopelessness is a professional judgment about the remaining treatment and care perspective and is often objectified; unbearable is a matter of the patient and therefore always subjective and personal. The current legislation on euthanasia, the reversibility of the underlying causes and the unbearable suffering will determine whether the request of the patient with tiredness of life can be considered. Some questions will not fit within the proposed framework. For those a multidisciplinary advice of an ethics committee may be desirable. PMID- 29271137 TI - [Complementarity between randomised controlled trials and observational registries : the example of cardiovascular prevention with SGLT2 inhibitors]. AB - Evidence-based medicine (EBM) is mainly supported by the results of randomised controlled trials (RCTs). If the latter offer guarantees of reliability, especially by minimizing the influence of confounding factors and potential biases, they also have limitations. Observational databases resulting from real life registries, if possible build in a prospective manner, may offer some solutions, but are also exposed to limitations. This article compares the advantages and disadvantages of the two sources of information, which ideally should be complementary. For the purpose of illustration, we shall compare the recent results of RCTs and of observational databases from multinational registries that investigated the effects of sodium-glucose cotransporter type 2 inhibitors (gliflozins) on cardiovascular outcomes in patients with type 2 diabetes. PMID- 29271138 TI - [Study and opinion on toxicity of aristolochic acid]. AB - On October 18th, 2017, a research article named "Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia" was published on Science Translational Medicine. This article pointed out that herbs containing aristolochic acids could cause liver cancer by inducing the specific "aristolochic acids mutational signature". The public was also suggested to avoid the intake of herbs containing aristolochic acids. Since 2000, CFDA has gradually abolished the medicinal standards for herbs containing aristolochic acids such as caulis aristolochiae manshuriensis, aristolochia heterophylla and radix aristolochiae. Related drugs have been strengthened supervision since then. Chinese Pharmacopoeia has also removed the records of a series of related herbs. State Administration of Traditional Chinese Medicine held a conference on the "toxicity" of aristolochic acids as soon as the article was published. After a discussion of the studies on the toxicity of aristolochic acids, experts attending the meeting discovered several problems, including the unclearness of exposure history, tumor-producing dose and latent period, the absence of some key factors such as hepatitis B, the small sample size, miscellaneous factors, incomplete evidence chains, the missing of analyses between data with huge differences, the insufficiency of fundamental research arguments, etc. In order to understand the toxicity of aristolochic acids and the carcinogenic risks, as well as guide clinical safe medication, the experts suggested that:1Complete the systematical evaluation of aristolochic acids carcinogenicity as soon as possible. Scientifically elucidate the relationship between aristolochic acids and the genesis of liver cancer. 2Establish medication risk warnings of aristolochic acids and strengthen the supervision. 3Make an in-depth study of the toxicity of traditional Chinese medicine. Find out the adverse effects of all traditional Chinese medicine step by step. PMID- 29271139 TI - [Development and application of component-based Chinese medicine theory]. AB - Traditional Chinese medicine (TCM) prescription is the main therapies for disease prevention and treatment in Chinese medicine. Following the guidance of the theory of TCM and developing drug by composing prescriptions of TCM materials and pieces, it is a traditional application mode of TCM, and still widely used in clinic. TCM prescription has theoretical advantages and rich clinical application experience in dealing with multi-factor complex diseases, but scientific research is relatively weak. The lack of scientific cognition of the effective substances and mechanism of Chinese medicine leads to insufficient understanding of the efficacy regularity, which affects the stability of effect and hinders the improvement of quality of Chinese medicinal products. Component-based Chinese medicine (CCM) is an innovation based on inheritance, which breaks through the tradition of experience-based prescription and realize the transformation of compatibility from herbal pieces to components. CCM is an important achievement during the research process of modernization of Chinese medicine. Under the support of three national "973" projects, in order to reveal the scientific connotation of the prescription compatibility theory and develop innovative Chinese drugs, we have launched theoretical innovation and technological innovation around the "two relatively clear", and opened up the research field of CCM. CCM is an innovation based on inheritance, breaking through the tradition of experience based prescription, and realizing the transformation from compatibility of herbal pieces to component compatibility, which is an important achievement of the modernization of traditional Chinese medicine. In the past more than 10 years, with the deepening of research and the expansion of application, the theory and methods of CCM and efficacy-oriented compatibility have been continuously improved. The value of CCM is not only in developing new drug, more important is to build a communication bridge between traditional Chinese medicine and modern science and construct the system of key technologies which meet the need of innovation and development of TCM. This paper focused on the research progress, related concepts and technology development of CCM, as well as its application prospect in the theory research of Chinese medicine, development of innovative Chinese drugs, secondary development of Chinese patent medicine and upgrading of pharmaceutical technology. PMID- 29271140 TI - [Safety evaluation and risk control measures of Psoralea corylifolia]. AB - Through a systematic and comprehensive study of domestic and foreign literatures and information, this study aims to trace the herbal origin and the toxicity recorded in ancient and current documents, analyze the safety case reports of Psoralea corylifolia and experimental studies on toxicity in recent years, and make a preliminary summary about the clinical characteristics and potential risk factors of cases related to the safety of P. corylifolia and its preparations. The study involved 84 patients in the safety case reports of P. corylifolia. The adverse events were mainly liver damage (55.95%) and light toxic contact dermatitis (38.10%), sugguesting that P. corylifolia may lead to liver damage and photo toxicity. However, reproductive toxicity and renal damage were only reported in animal studies, but not in clinical reports. Because of its complicated ingredients, the toxic components and mechanisms of P. corylifolia have not been clear at present. Therefore, the authors proposed to strictly apply P. corylifolia in clinic, use it rationally and combine it with other medications. Besides, efforts shall be made to strength the guidance for doctors, the safety monitoring of P. corylifolia and relevant preparations, and actively carry out safety-related basic and clinical studies, so as to give a better guidance to safe medication, full exert the efficacy and avoid the medication risk. PMID- 29271141 TI - [Systematic evaluation for safety of traditional Chinese medicine Areca catechu and its preparations]. AB - The authors systemically evaluated and analyzed the safety of Areca catechu from domestic and foreign literatures about the herbal origin, toxicity recorded in ancient/current documents, safety case reports of clinical A. catechu, experimental studies on toxicity in recent years, and differences of safety risk between edible and medicinal A. catechu. Subsequently, they proposed a preliminary summary about the clinical characteristics and potential risk factors of safety related cases of A. catechu and its preparations. According to the authors, although clinical adverse events of A. catechu were fewer and controllable, clinicians shall stillstrictly standardize its application, and rationally combine it with other herbs, while strengthening fundamental and clinical studies related to safety, so as to give better guidance to safety application of A. catechu in clinic. PMID- 29271142 TI - [Safety evaluation and risk control measures of Cassiae Semen]. AB - In this study, the authors reviewed domestic and foreign literatures, conducted the textual research on origin and development of Cassia Semen, studied records in ancient books and ancient and modern literatures, clinical adverse reactions and relevant experimental studies in recent years, and summarized the clinical features and influencing factors related to the safety of Cassiae Semen. According to the findings,Cassia Semen's safety risks are mainly liver and kidney system damages, with the main clinical features of fatigue, anorexia, disgusting of oil, yellow urine and gray stool; digestive system injury, with the main clinical features of diarrhea, abdominal distension, nausea and loose stool; reproductive system damage, with the main clinical features of vaginal bleeding. Allergic reactions and clinical adverse events, with the main clinical features for numb mouth, itching skin, nausea and vomiting, diarrhea, wheezing and lip cyanosis were also reported. The toxicological studies on toxic components of Cassiae Semen obtusifolia were carried out through acute toxicity test, subacute toxicity test, subchronic toxicity test and chronic toxicity test. Risk factors might include patients, compatibility and physicians. Physicians should strictly abide by the medication requirements in the Pharmacopoeia, pay attention to rational compatibility, appropriate dosage,correct usage and appropriate processing, control the dosage below 15 g to avoid excessive intake, strictly control the course of treatment to avoid accumulated poisoning caused by long term administration. At the same time, clinicians should pay attention to the latest research progress, update the knowledge structure, quickly find the latest and useful materials from clinical practice, scientific research and drug information and other literatures, make evaluation and judgment for the materials, establish a traditional Chinese medicine intelligence information library, and strengthen the control over adverse effects with a pre-warning consciousness. The authors suggested standardizing clinical medication of Cassiae Semen, and avoiding misuse or excessive use; clinicians should prescribe it in strict accordance with there commended usage and dosage in the Pharmacopoeia, and focus on the safety signal accumulation in clinic, while strengthening studies for toxic substance basis and toxicity mechanism, in order to give full play to Cassiae Semen's clinical efficacy and reduce its adverse reactions. PMID- 29271143 TI - [Comprehensive evaluation and risk control measures of Xanthii Fructus]. AB - By retrieving domestic and foreign literatures, the authors provided a systematic review for effects of Xanthii Fructus, toxicity recorded in ancient/current literatures and relevant toxicological experience, and summarized clinical characteristics of clinical cases related to Xanthii Fructus and influencing factors. In addition to liver and kidney injuries as the major side effects of Xanthii Fructus, neurotoxicity and cardio-toxicity of Xanthii Fructus were also common clinical adverse events. However, there have been a few animal experimental studies so far. Oral administration and external application with Xanthii Fructus have often caused skin reactions, even such severe cases as exfoliative dermatitis. The authors suggested standardizing the clinical medication, avoiding to use untreated prescriptions and unprocessed herbs, ensuring the effective and safety use of Xanthii Fructus in strict accordance with the recommended dosage and usage in pharmacopeia, paying attention to the accumulation of safety signals, strengthening studies on toxic substance, toxicity mechanism, and synergy and attenuation effects. PMID- 29271144 TI - [Safety evaluation of Sophora tonkinensis and risk control]. AB - The aim is to systemically review and evaluate the safety of Sophora tonkinensis from the literature on the herbal origin, toxicity record in modern literature and toxicological studies and publications in recent years. By systematic review and analysis, the results showed that its toxicity mainly involved the nervous system, the digestive system and the respiratory system, and respiratory failure may be the direct cause of death. The main symptoms included headache, dizziness, vomiting, nausea, abdominal pain, limbs weakness, palpitation, and chest distress; as well as pale complexion, limbs trembling, convulsions, chills, high heart rate, fall of blood pressure, shock, and respiratory failure to death in severe cases. High dose and long term medication may cause serious brain damage, especially in adolescents and children. The authors have proposed to use rationally under guidance of physician and strictly according to the dosage recommended by pharmacopoeia. The patients shall not be credulous about the folk prescriptions and test recipes to use it for,prevention of colds and treatment of sore throat at will. In addition, the researches on the conventional treatment methods for S. tonkinensis poisoning, the toxic substance basis, and toxicity mechanism shall be strengthened in further studies. These efforts will play important role in exerting the drug effect and avoiding side effect. PMID- 29271145 TI - [Comprehensive regulation effect of traditional Chinese medicine on proliferation and differentiation of neural stem cells]. AB - Since the discovery of neural stem cells(NSCs) in embryonic and adult mammalian central nervous systems, new approaches for proliferation and differentiation of NSCs have been put forward. One of the approaches to promote the clinical application of NSCs is to search effective methods to regulate the proliferation and differentiation. This problem is urgently to be solved in the medical field. Previous studies have shown that traditional Chinese medicine could promote the proliferation and differentiation of NSCs by regulating the relevant signaling pathway in vivo and in vitro. Domestic and foreign literatures for regulating the proliferation and differentiation of neural stem cells in recent 10 years and the reports for their target and signaling pathways were analyzed in this paper. Traditional Chinese medicine could regulate the proliferation and differentiation of NSCs through signaling pathways of Notch, PI3K/Akt, Wnt/beta-catenin and GFs. However, studies about NSCs and traditional Chinese medicine should be further deepened; the mechanism of multiple targets and the comprehensive regulation function of traditional Chinese medicine should be clarified. PMID- 29271146 TI - [Structure-activity relationship of plant polysaccharides]. AB - Plant polysaccharides have a variety of biological activities and have become the focus of many fields such as the areas of medicine and food for the features of safety, high efficiency and low toxicity. The chemical structure of plant polysaccharides is the foundation for the biological activity. Polysaccharides with different chemical structures have great differences in biological activity. The exploration of the structure-activity relationship of plant polysaccharides has guiding significance for the development of new drugs and the health care products of saccharides. Many biological activities of plant polysaccharides such as anti-hepatic injury, antineoplastic, antiviral, hypoglycemia, anticoagulation, anti-oxidation and immunoregulation have been discovered. Therefore, this paper focuses on the bioactivity as the main line, and summarizes the studies on structure-activity relationship and mechanism of plant polysaccharides at home and abroad in recent years. The key point is the structure-activity relationship between plant polysaccharides and the anti-hepatic injury, antineoplastic, antiviral, hypoglycemia, and anticoagulation activities, providing reference for intensive study and exploration of structure-activity relationship of plant polysaccharides as well as development and application of polysaccharides products. PMID- 29271147 TI - [Research progress on identification and quality control of Cervi Cornu Pantotrichum]. AB - Cervi Cornu Pantotrichum, as a traditional Chinese medicine, has great potential for development. However, the identification and quality control system is not perfect, leading to the market chaos and chronic slow growth in deep processing of Cervi Cornu Pantotrichum. This paper gives an overview of present situation in identification and quality control system of the Cervi Cornu Pantotrichum, and analyzes present problems. Based on these results, the feasibility study scheme in identification and quality control system for Cervi Cornu Pantotrichum would be then put forward, providing ideas to establish its comprehensive evaluation system. PMID- 29271148 TI - [Grade classification of Scutellariae Radix slices based on determination of section color and lustre]. AB - By determination the section color and lustre indexes as well as the content of baicalin in 30 batches of Scutellariae Radix slices, calculate the correlation of these two, screen the color and lustre indexes which could represent their intrinsic quality, and establish a new grade classification method based on the results. The results showed that samples met the conditions of ?L>=-37, ?b>=45 simultaneously were picked grade and the content of baicalin was of >=200 mg*g-1 definitely; Samples inconsistent with any one of above conditions were general grade. This research indicated that indexes of ?L and ?b could characterize both the color and luster of slice and intrinsic quality, so that could be used as the indexes to classify the grades of Scutellariae Radix slices accurately, easily and objectively. The research results would provide new ideas and references for grade classification of traditional Chinese medicine slices. PMID- 29271149 TI - [Preparation and in vivo study of liposomes mediated by glycyrrhetinic acid derivative ligand 18-GA-Gly]. AB - Based on the research of active liver targeting liposomes mediated by glycyrrhetinic acid ligand at home and abroad, this paper focuses on the liver targeting effect of liposomes mediated with 18-GA-Gly, a kind of glycyrrhetinic acid ligand. salvianolic acid B(Sal B)-tanshinone IIA (TSN)liposomes mediated by 18-GA-Gly as well as the liposomes with unmodified ligands were prepared by film dispersion-high pressure homogenization method, and then the particle size, potential, encapsulation efficiency and ligand binding rate were detected. Plasma samples of the heart, liver, spleen, lung and kidney tissues were taken at different time points after tail vein injections. The contents of Sal B and TSN in each sample were determined with UPLC methods and the liver targeting effect of 18-GA-Gly ligands was evaluated. The results showed that the particle size, potential, encapsulation efficiency and ligand binding rate met the basic requirements; in vivo targeting investigation results showed no difference between GLY-TS-Lip group and TS-Lip group. The liposomes mediated by glycyrrhetinic acid derivative ligand 18-GA-Gly can increase the peak concentration of Sal B and TSN in liver, but showed no significant liver targeting effect. PMID- 29271150 TI - [Study on biopharmaceutics classification system for Chinese materia medica of extract of Huanglian]. AB - One of the advantages of biopharmaceutics classification system of Chinese materia medica (CMMBCS) is expanding the classification research level from single ingredient to multi-components of Chinese herb, and from multi-components research to holistic research of the Chinese materia medica. In present paper, the alkaloids of extract of huanglian were chosen as the main research object to explore their change rules in solubility and intestinal permeability of single component and multi-components, and to determine the biopharmaceutical classification of extract of Huanglian from holistic level. The typical shake flask method and HPLC were used to detect the solubility of single ingredient of alkaloids from extract of huanglian. The quantitative research of alkaloids in intestinal absorption was measured in single-pass intestinal perfusion experiment while permeability coefficient of extract of huanglian was calculated by self defined weight coefficient method. PMID- 29271151 TI - [Bile-resistant Gram-negative bacteria effect of different kinds of root decoction pieces]. AB - To investigate the microbial contamination in Chinese herbal decoction pieces with different functional types by studying the total aerobic microbial count (TAMC), and total yeast and mould count (TYMC) in 40 samples of 8 types of root decoction pieces; further evaluate the contamination load of bile-resistant Gram negative bacteria, and identify the Gram-negative bacteria by using biochemical identification system for Gram-negative bacteria. Our results showed that the TAMC value was more than 1 000 CFU*g-1 in 85% (34/40) samples, and was more than 100 CFU*g-1 in 30% (12/40) samples; the contamination of bile-resistant Gram negative bacteria was detected in 45% (18/40) of the samples. The bile-resistant Gram-negative bacteria load of seven batches of samples was N>1 000 MPN*g-1. Sixteen bacterium strains including Serratia plymouthensis, Cedecea neteri, Escherichia vulneris, Klebsiella oxytoca, Enterobacter amnigenus, E. cloacae, E. sakazakii, Proteus penneri and E. gergoviae were obtained and identified. E. cloacae was the predominant bacterium that was isolated from Salviae Miltiorrhizae Radix et Rhizoma, while E. amnigenus, Yersinia pseudotuberculosis was the typical bacterium of Ophiopogonis Radix and Codonopsis Radix, respectively. All these suggested that the contamination of bile-resistant Gram negative bacteria was severe for the root decoction pieces in Wuhan city. Microbial species have certain selection specificity for medicinal ingredients, so the type and limit of control bacteria for detection should be formulated according to the pollution type and quantity of bile-resistant Gram-negative bacteria. PMID- 29271152 TI - [Chemical constituents of liquid culture of symbiotic Chaetomium globosum ML-4 of oyster and their in vitro antitumor activity]. AB - Isolation and purification of chemical constituents of liquid culture of symbiotic Chaetomium globosum ML-4 of oyster was performed through silica gel column chromatography, gel filtration over Sephadex LH-20, preparative TLC and HPLC. Five compounds were obtained and their structures were determined as chaetoglobosin V(1), chaetoglobosin Vb(2), tyrosol(3), 5-methyluracil(4)and uracil(5), respectively, based on HR-MS and NMR data and comparison with literatures. In vitro cytotoxicity of compounds against human hepatocellular carcinoma cell line SMMC-7721 were measured byMTT method, and results showed that compound 1 could obviously inhibit the proliferation of SMMC-7721 cells with an IC50 value of 60.5 mg*L-1, while the IC50 value of positive control cisplatin was 19.96 mg*L-1. Further studies discovered that compound 1 could lead to G2 phase arrest in SMMC-7721 cells and induce SMMC-7721 cells apoptosis. The ratio of Bcl 2/Bax in SMMC-7721 cells was decreased. The expression of protein Caspases-3,-8, 9 was improved and the expression and phosphorylation level of Akt were reduced. Aforementioned results revealed that in vitro antitumor activity of compound 1 against SMMC-7721 cells were related to G2 phase cell cycle arrest and induced apoptosis. The induced-apoptosis was involved in both the mitochondrial pathway and the death receptor pathway and connected with activity decline of PI3K/Akt signaling pathway. PMID- 29271153 TI - [Chemical constituents from hypoglycemic active part of Plantaginis Semen]. AB - The chemical constituents of Plantaginis Semen with hypoglycemic effect was investigated in this paper. The previous results of the in vivo hypoglycemic effect showed that 60% ethanol extract of Plantaginis Semen decreased the levels of FBG and improved the glucose tolerance in high fat diet(HFD)-induced diabetic C57BL/6 mice. Then, in the present study, the above potential bioactive extract was separated and purified by silica gel, ODS, Sephadex LH-20 column chromatography, medium pressure liquid chromatography(MPLC)and preparative HPLC. The structures of isolated compounds were identified by physicochemical properties and spectral analyses. Eight compounds were obtained and identified as 4, 4a, 5, 7a-tetrahydro-7-(hydroxymethyl)cyclopenta[c]pyran-3(1H)-one(1), iridolactone(2), pedicularislacton(3), rehmaglutin C(4), geniposidic acid(5), p hydroxylphenylglycerol(6), 1, 2-benzenediol-4-(2-hydroxyethyl)(7), and 3-buten-2 one-4-[3-(beta-D-glucopyranosyloxy)-4-hydroxyphenyl](8). Among them, compounds 1 5 were iridoids, and 6-8 were phenolic acids. Compound 1 was a new natural product, and compounds 2-4, 6 and 8 were isolated from the Plantaginaceae family for the first time. PMID- 29271154 TI - [Chemical constituents from stems of Ilex asprella]. AB - Phytochemical investigation on the stems of Ilex asprella by using various chromatographic techniques led to the isolation of 13 compounds. By spectroscopic analyses and comparisons the spectral data with those in literatures, these compounds were identified as salicifoneoliganol(1), rel-(7R,8S)-3,3',5-trimethoxy 4',7-epoxy-8,5'-neolignan-4,9,9'-triol 9-beta-D-glucopyranoside(2),(+) cycloolivil(3),(+)-syringaresinol-4'-O-beta-D-monoglucoside(4), liriodendrin(5), caffeic acid (6), 3,4-dihydroxy-5-methoxybenzaldehyde(7), benzene-1,2,4-triol(8), 3,4,5-trimethoxyphenyl-1-O-beta-D-apiofuranosyl(1"->6')-glucopyranoside(9), aeculetin(10), cryptochlorogenic acid ethyl ester(11), chlorogenic acid ethyl ester(12), and rel-5-(3S,8S-dihydroxy-1R,5S-dimethyl-7-oxa-6-oxobicyclo [3,2,1]oct-8-yl)-3-methyl-2Z,4E-pentadienoic acid(13). Among them, compounds 7, 8, 11, and 13 were isolated from genus Ilex for the first time, and 1-3, 9, 10, and 12 were isolated from this speciesfor the first time. The anti-inflammatory assay results of these compounds showed that compounds 1 and 9 showed moderate inhibitory effect against NO production in RAW 267. 4 cells with IC50 values of 35.7 and 50.6 MUmol*L-1, in vitro respectively, whereas compound 10 showed weak inhibition(IC50 value 98.7 MUmol*L-1). PMID- 29271155 TI - [Chemical constituents from Pteris dispar and their anti-tumor activity in vitro]. AB - The dried whole plant of Pteris dispar were milled and extracted with 95% EtOH. The resulting dried extract was isolated by kinds of chromatographic column, including polyamide, Sephadex LH-20, preparative HPLC. As a result, ten diterpenes were isolated from the plant. By analyzing of ESI-MS and NMR spectroscopic data, the structures were established as geopyxin B(1), geopyxin E(2), ent-11alpha-hydroxy-18-acetoxykaur-16-ene(3), ent-14beta-hydroxy-18 acetoxykaur-16-ene(4), neolaxiflorin L(5), ent-3beta,19-dihydroxy-kaur-16-ene(6), ent-3beta-hydroxy-kaur-16-ene(7), 7beta,17-dihydroxy-16alpha-ent-kauran-19-oic acid 19-O-beta-D-glucopyranoside ester(8), crotonkinin C(9)and crotonkinin C(10). Compounds 1-10 were obtained from P. dispar for the first time. Compounds 1 and 2 showed moderate activities against Bel-7402 with IC50 values of 7.50 and 10.60 MUmol*L-1, and against HepG2 with IC50 values of 6.68,11.80 MUmol*L-1, respectively. PMID- 29271156 TI - [Study on differences of Ainsliaea fragrans from different sources based on UFLC Q-TOF-MS/MS and PCA analysis]. AB - A rapid and accurate method of UFLC-Q-TOF-MS/MS combined with multivariate statistical analysis was established for the identification of Ainsliaea fragrans from different origins in this study. The A. fragrans from different producing areas of Jiangxi, Yunnan, Henan and Jiangsu were determined by UFLC-Q-TOF-MS/MS in the negative ion mode. And the data of the study were analyzed by the Markerview and other software for the PCA and OPLS-DA cluster analysis as well as t test. The results of the principal component analysis(PCA)showed that the main components from different origins were well distinguished. And the results of multivariate statistical showed the differences and similarities between different producing areas. Besides, 40 different compounds were identified in the negative ion mode. This method for identifying A. fragrans from different producing areas has the advantages of rapid accuracy and simplicity, which laid the foundation for the evaluation of the quality of the A. fragrans. PMID- 29271157 TI - [Comparison of chemical quality characteristics between radial striations and non radial striations in tuberous root of Rehmannia glutinosa]. AB - An HPLC method was established to determine the contents of catalpol, acteoside, rehmaionoside A, rehmaionoside D, leonuride in three part of Rehmanni glutinosa in Beijing No.1 variety R. glutinosa during the growth period, This method, in combination with its HPLC fingerprint was used to evaluate its overall quality characteristics.The results showed that:1 the content of main components of R. glutinosa varied in different growth stages ;2 there was a great difference of the content of main components between theradial striations and the non-radial striations; 3 the two sections almost have the same content distribution of catalpol, acteoside and rehmaionoside D; 4the content of rehmaionoside A in non radial striations was higher than that in radial striations,while the content of leonuride in radial striations was higher than that in non-radial striations.; 5the HPLC fingerprint of radial striations, non-radial striations and whole root tuber were basically identical, except for the big difference in the content of chemical components. The result of clustering displayed that the radial striations, non-radial striations, and whole root were divided into two groups. In conclusion, there was a significant difference in the quality characteristics of radial striations and non-radial striations of R. glutinosa. This research provides a reference for quality evaluation and geoherbalism of R. glutinosa. PMID- 29271158 TI - [Effects of Fritillariae Cirrhosae Bulbus on MMP-2,MMP-9 and TIMP-1 in murine asthma model]. AB - To investigate the effects of Fritillariae Cirrhosae Bulbus on airway remodeling and matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9(MMP-9), tissue inhibitor-1 of metalloproteinase(TIMP-1) of a murine asthma model, and explore its mechanism in treatment of asthma. BALB/C murines were randomly divided into the normal group, model group, high dose group, low dose group, and positive control group. Except for the normal group, all the other groups received ovalbumin(OVA) to establish murine asthma model. After successful modeling, the murines in high dose group and low dose group were orally administered with Fritillariae Cirrhosae Bulbus powder at the dose of 18.0 mg*kg-1 and 9.0 mg*kg-1, respectively; the murines in positive control group were injected intraperitoneally with dexamethasone at the dose of 0.5 mg*kg-1; while the murines in normal group and the model group were orally administered with the same volume of normal saline. All the drugs were given to murines per day for 28 d. The variations of airway responsiveness, variations of the total cell count and leukocyte differential count in bronchoalveolar lavage fluid(BALF), and the variations of thicknesses of bronchial wall and airway smooth muscle of each group were observed. The levels of MMP-2, MMP-9 and TIMP-1 were measured by ELISA; and the expression levels of MMP-2, MMP-9 and TIMP-1 mRNA were detected by RT-PCR. The results showed that as compared with the normal group, the airway responsiveness, the count of total cells, neutrophils, macrophage, lymphocytes, eosinophils in BALF, and the thicknesses of bronchial wall and airway smooth muscle were increased significantly in the model group(P<0.01); as compared with the model group, the above indicators were decreased significantly in the high dose group, low dose group and positive control group (P<0.05 or P<0.01). As compared with the normal group, the levels and expressions of MMP-2, MMP-9 and TIMP-1 mRNA were increased significantly in the model group(P<0.01); while as compared with the model group, these levels were decreased significantly in the high dose group, low dose group and positive control group(P<0.01). In conclusion, Fritillariae Cirrhosae Bulbus can improve airway remodeling in a murine asthma model, and its mechanisms may be related to down-regulating MMP-2, MMP-9 and TIMP-1 levels. PMID- 29271159 TI - [Effects of Astragali Radix combined with Angelicae Sinensis Radix on the proliferation of hematopoietic stem cells senescence model in mice]. AB - The aim is to study the effect and its mechanism of Astragalus Radix combined with Angelicae Sinensis Radix on the proliferation of hematopoietic stem cells(HSCs) in senescence model. After drug-containing plasma of rats was prepared via intragastric administration, HSCs of mice were cultured in vitro, and then they were divided into blank control group, model group, blank plasma group, Astragalus Radix + Angelicae Sinensis Radix 1?1 group and 10?1 group, Angelicae Sinensis Radix plasma group, and Astragalus Radix plasma group. HSCs senescence model was induced by using tert-butyl hydrogen peroxide(t-BHP), and intervened by drug-containing plasma. Cells senescence rate was tested by SA-beta galactosidase staining method; cell cycle distribution was determined by flow cytometry; Cyclin D1, P21, and P53 mRNA were measured with RT-PCR, and Cyclin D1 protein expression was measured by Western blot. Results showed that after being induced by t-BHP, senescence rate of HSCs was increased; cell proliferation ability was decreased; count of G0/G1 phase cells was increased; count of G2/M+S phase cells was reduced; Cyclin D1 expression was down-regulated while P53, P21 expression was up-regulated, which were reversed by Astragalus Radix + Angelicae Sinensis Radix 1?1 and 10?1, single Angelicae Sinensis Radix, and single Astragalus Radix plasma. Furthermore, the above effects were most obvious in Astragalus Radix+Angelicae Sinensis Radix 1?1 group. These results suggested that t-BHP can promote HSCs senescence and reduce cell proliferation ability. Angelicae Sinensis Radix, Astragalus Radix and their combinations can inhibit HSCs senescence, promote HSCs proliferation as well as cell cycle conversion; moreover, the effects of 1?1 Astragalus Radix+Angelicae Sinensis Radix were strongest. The mechanisms may be related to up-regulating the expression of cell cycle positive regulator, down-regulating the expression of cell cycle negative regulator, thus promoting the cells to enter the proliferation phase from the stationary phase. PMID- 29271160 TI - [Effect of Zuotai and HgS on gene expression of drug-metabolizing enzymes in livers of mice]. AB - Zuotai and cinnabar(96%HgS) are contained in many traditional medicines. To examine their potential effects on drug metabolism genes, mice were orally given Zuotai or HgS at doses of 10, 30, 100, 300 mg*kg-1 for 7 days. HgCl2(33.6 mg*kg 1) was gavaged for control. Twenty-four hour later after the last administration, livers were collected, and expressions of genes related to metabolic enzymes and transporters were examined. Zuotai and HgS had no effects on major phase-1, phase 2 and transporter genes; HgCl2 increased the expressions of CYP2B10, CYP4A10, OATP1A4, UGT1A1, UGT2A3, SULT1A1, SULT2A1, MRP1, MRP3 and MRP4; expression of OATP1A1 was decreased by HgCl2, but not by Zuotai and HgS. Therefore, Zuotai and HgS have different adverse effects on drug-metabolizing genes from HgCl2. PMID- 29271161 TI - [Effect of chloroform extracts from Longdan Xiegan decoction in inhibiting hydrolytic enzyme activity of Candida albicans isolated from VVC patients]. AB - To investigate the inhibitory effect and mechanism of chloroform extracts from Longdan Xiegan decoction(CELX) against hydrolytic enzymes activity of Candida albicans isolated from vulvovaginal candidiasis(VVC) patients. Secreted aspartyl proteinase(Sap), phospholipase(PL) and lipase(Lip) positive strains were identified from 15 strains of C. albicans with milk culture medium, egg yolk culture medium and tween-80 medium, respectively. Then, the activities of Sap, PL, and Lip were detected in the above media. qRT-PCR was used to detect the changes in gene expressions of aspartic protease(SAP1-7,10), phospholipase B(PLB1 2) and lipase(LIP3-6). Secreted aspartyl proteinase and phospholipase of 15 VVC clinical strains were positive, and lipase of 11 strains were positive. Compared with the blank control group, the drug CELX-containing medium(milk medium, egg yolk culture medium, tween-80 medium) experiment showed that the sedimentation of colonies decreased gradually in each culture medium with the increase of CELX dose. When the concentration of CELX was 256 mg*L-1, the colony almost disappeared, which indicated the enzyme activity was significantly weakened. The results of qRT-PCR showed that SAP1, SAP2, SAP3, SAP4, SAP7, SAP9 and SAP10 were down-regulated by 62%, 55%, 62%, 84%, 61%, 51%, 68%, respectively, except for SAP5 and SAP6; and PLB1, LIP3, LIP4, LIP6 were down-regulated by 67%, 51%, 54%, 55%, respectively. The findings suggested that CELX may inhibit the activities of Sap, PL, and Lip, which are important virulence factors of C. albicans. PMID- 29271162 TI - [Macrophage activation by low molecular weight saccharides from Cistanche deserticola]. AB - To investigate the immune activation effect and mechanism of low molecular weight saccharides from Cistanche deserticola(LMSC) on mouse peritoneal macrophages, RAW264.7 cells. The RAW264.7 cells were divided into the normal control group, LPS positive control group, and LMSC treatment groups. The RAW264.7 cells were treated with various concentrations of LMSC from 3.91 to 62.5 g*L -1. The neutral red assay was employed to detect the phagocytic activity of macrophages. NO release was detected by using NO kit, and macrophage activation associated protein expression levels (TNF-alpha, IL-6, IKKbeta, p-IKKbeta, IkappaBalpha, p IkappaBalpha, NF-kappaB, and p-NF-kappaB) were detected by Western blot. Results showed that LMSC had an activation effect on macrophages; it can significantly increase the release of NO in RAW264.7 cells and promote the expression of cytokines TNF-alpha and IL-6. Moreover, LMSC significantly increased the phosphorylation of IKKbeta, IkappaBalpha, and NF-kappaB p65. Furthermore, mannitol's one of the main constituents in LMSC significantly enhanced the phagocytic activity of macrophages. These results showed that LMSC could activate macrophages by up-regulating the NF-kappaB signaling pathway, and mannitol may be one of the main active components in LMSC. PMID- 29271163 TI - [Study on Material Basis and Mechanism of Erzhi Wan prevent Alzheimer's disease by network pharmacology]. AB - The present study is to explore the material basis and mechanism of Erzhi Wan the prevented Alzheimer's disease by using network pharmacology. The key target of Alzheimer's disease was docked with the Erzhi Wan compounds, and the drugs-target combined with target-signal pathway network model was established by Cytoscape 3.2.1 software. Thirty compounds have a strong interaction with key target of Alzheimer's disease and three key pathways related with Wnt, MAPK and PI3K-Akt mTOR. There are 5 ingredients such as quercetin,geraniol,beta sitosterol,nerol,eriodictyol that could be verified from literature.This result initially revealed the material basis for Erzhi Wan for Alzheimer's disease and the mechanism in terms of three signaling pathways. The network pharmacology method found that the active ingredients of Erzhi Wan for Alzheimer's disease may be quercetin,geraniol,beta-sitosterol,nerol,and eriodictyol, and the mechanism may be related to three signal pathways including Wnt, MAPK, and PI3K-Akt-mTOR. PMID- 29271164 TI - [Pharmacokinetics of Mori Folium flavones and alkaloids in normal and diabetic rats]. AB - To study the pharmacokinetic effect of Mori Folium flavones and alkaloids in normal and diabetic rats. An UPLC-TQ-MS method was developed for the simultaneous determination of rutin, isoquercitrin, astragalin, kaempferol, quercetin, chlorogenic acid, cryptochlorogenic acid, neochlorogenic acid, DNJ and fagomine in plasma of rats. The diabetic rat model was induced through intravenous injection with alloxan and high-fat diet. Samples of plasma of rats were obtained at different time points, after the rats were administrated with Mori Folium flavones and alkaloids. After the deproteinization with acetonitrile, the concentrations of Mori Foliam constituents in rats at different time points were detected by UPLC-TQ-MS method, and pharmacokinetic parameters were calculated by DAS 2.0 software. The results showed that quercetin and kaempferol reached peak at 0.333 h, indicating that Mori Folium flavonoid constituents were absorbed and distributed quickly. At about 4 h after administration, both of them reached the peak concentrations for the second time, suggesting that they stayed in intestine for a long time. DNJ and fagomine in gastrointestinal tract can be quickly absorbed into blood, and the concentration in plasma reached peak after 0.667 h, suggesting that both of them could be rapidly distributed in the systemic circulation of rats. Cryptochlorogenic acid, neochlorogenic acid, quercetin, kaempferol and rutin were found to have a higher Cmax and AUC0-t in normal rats than those in diabetic rats. The t1/2values of cryptochlorogenic acid and neochlorogenic acid were shorter in diabetic rats, while quercetin, kaempferol and rutin had a longer t1/2value in diabetic rats. Chlorogenic acid, astragalin, isoquercitrin, fagomine had a higher Cmax in diabetic rats, and the t1/2values of astragalin and fagomine were longer, which suggested differences in absorption of active ingredients under normal and diabetic conditions. PMID- 29271165 TI - [Effect of Panax notoginseng preparations on platelet function]. AB - To systematically evaluate the effect of Panax notoginseng preparations (PNPs) on platelet function six literature databases including PubMed, EMbase, the Cochrane Library, CNKI, WanFang, and SinoMed were searched to collect RCTs of PNPs. RCTs reporting the outcomes of platelet function could be included. Biases were evaluated by Cochrane handbook. Two reviewers screened literature, extracted data and assessed the risk of bias of included studies independently. Inconsistency were solved by discussion.Meta-analysis was conducted by RevMan 5.3 software.A total of 36 RCTs were involved with the outcome including MPAR, PLT, TXB2 and safety. The results of systematic review showed that compared with placebo [SMD=1.84,95%CI(1.33,2.35),P<0.000 01] and non-antiplatelet agents [SMD=0.74,95%CI(0.19,1.28),P=0.008] PNPs can reduce the MPAR level; PNPs combined with non-antiplatelet agents can reduce MPAR [SMD=2.34,95%CI(1.14,3.54),P=0.000 1] and TXB2(SMD=1.25,95%CI(0.75,1.76),P<0.000 01]; PNPs combined with anti platelet agents have better effect on MPAR [SMD=0.93,95%CI(0.58,1.29),P<0.000 01] and TXB2 [SMD=1.16,95%CI(0.74,1.58),P<0.000 01]. In terms of hemorrhagic adverse reactions, PNPs combined with anti-platelet agents haven't increase adverse events. Current evidences suggested that PNPs can reduce MPAR level and TXB2. PNPs combined with anti-platelet or non-antiplatelet agents can improve efficacy. However, due to the huge clinical heterogeneity and poor methodological quality, the evidence is not strng enough. Rigorous designed clinical trials are warranted. PMID- 29271166 TI - [Rapidly identify chemical constituents of Schisandra propinqua by UPLC-Q Tof/MSE]. AB - This study was to identify the chemical constituents of Schisandra propinqua, one herbal medicine of Yi nationality in China by using ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF/MSE). Acetonitrile- water containing 0.1% formic acid was used as the mobile phase for gradient elution. Data were collected under ESI negative mode and ESI positive mode, and then screened and verified by the software of UNIFI and Masslynx4.1. Based on the accurate mass, fragment ions, neutral losses, mass error, retention time, reference substance, isotope information, the intensity of fragments, as well as the previous reports, the known compounds were validated and identified. The chemical structures of the unknown components were identified according to exact molecular weight, MS fragment, chromatographic retention behavior, and characteristic fragments of known congener compounds. A total of 68 chemical components were identified from S. propinqua, including 3 flavonoids, 10 flavanols, 34 lignans compounds (including 20 dibenzocyclooctene lignans), 4 triterpenoids, 17 organic acid and other compounds. 37 compounds of them were found in S. propinqua for the first time, and one potential compound needed to be identified. PMID- 29271167 TI - [Ideas and methods on efficient screening of traditional medicines for anti osteoporosis activity based on M-Act/Tox integrated evaluation using zebrafish]. AB - The increasingly apparent liver injury problems of bone strengthening Chinese medicines have brought challenges for clinical application, and it is necessary to consider both effectiveness and safety in screening anti-osteoporosis Chinese medicines. Metabolic transformation is closely related to drug efficacy and toxicity, so it is significant to comprehensively consider metabolism action/toxicity(M-Act/Tox) for screening anti-osteoporosis Chinese medicines. The current evaluation models and the number of compounds(including metabolites) severely restrict efficient screening in vivo. By referring to previous relevant research and domestic and abroad literature, zebrafish M-Act/Tox integrative method was put forward for efficiently screening anti-osteoporosis herb medicines, which has organically integrated zebrafish metabolism model, osteoporosis model and toxicity evaluation method. This method can break through the bottleneck and blind spots that trace compositions can't achieve efficient and integrated in vivo evaluation, and realize both efficient and comprehensive screening on anti-osteoporosis traditional medicines based on in vivo process taking both safety and effectiveness into account, which is significant to accelerate discovery of effective and safe innovative traditional Chinese medicines for osteoporosis. PMID- 29271168 TI - [Strategies to prevent bacteriophage infection in industrial fermentation]. AB - During the development of bacteria-based biotechnology, bacteriophage infection is one of the constant threats and troublesome problems in industrial fermentation. The core of puzzled bacteriophage infection is a complex arm race of coevolution between bacteriophages and their hosts where bacteriophage has evolved lots of escaped ways against bacterial resistance mechanisms. The strategies of rationally designing factories and rotation of starter strains could reduce the risk of bacteriophage infection, but often fail to avoid. Genetic engineering to increase bacterial resistance is one of the strategies to prevent bacteriophage infection and more knowledge about bacteriophage and its host is needed. Recently, there are some new findings on bacterial resistance mechanisms which provide new solutions for bacteriophage infection. For example, it is possible for a rational design of resistant strains to use CRISPR-Cas based technologies just based on the sequences of bacteriophages. Moreover, it is also possible to avoid the escape of bacteriophage by iteratively building up resistance levels to generate robust industrial starter cultures. Quorum-sensing signal molecules have recently been proved to be involved in the interactions between bacteria and bacteriophages, which provides a possible way to solve bacteriophage infection from a population level. Finally, the rapid development of bacteriophage genome editing and synthetic biology will bring some new cues for preventing bacteriophage infection in industrial fermentation. PMID- 29271169 TI - [Improvement of pyruvate production by Escherichia coli via pathway engineering and Tn5 transposon mediated mutagenesis]. AB - To develop a high-yield pyruvate strain, we first engineered a pyruvate-producing Escherichia coli KLPP from wild-type E. coli MG1655 by blocking the pathways for byproduct formation via gene knockout. Then, we built a library of mutant containing 7 197 monoclones by using the pUT Mini-Tn5 transposon vector for random mutagenesis with E. coli KLPP. We developed a high-throughput method for pyruvate detection based on dinitrophenylhydrazine reaction using 96-well microplate reader. After two-round screening we successfully obtained six mutants with increased pyruvate titer using this method, the titer of pyruvate was increased by 38%, 31%, 19%, 28%, 44% and 14%, respectively. The position of transposon insertion was determined by whole genome re-sequencing, and the gene locus possibly influencing pyruvate production was analyzed, which laid the foundation for subsequent strain improvement by metabolic engineering. PMID- 29271170 TI - [Deletion of a dynamic surface loop improves thermostability of (R)-selective amine transaminase from Aspergillus terreus]. AB - Chiral amines are important building blocks for the synthesis of pharmaceutical products and fine chemicals. Highly stereoselective synthesis of chiral amines compounds through asymmetric amination has attracted more and more attention. omega-transaminases (omega-TAs) are a promising class of natural biocatalysts which provide an efficient and environment-friendly access to production of chiral amines with stringent enantioselectivity and excellent catalytic efficiency. Compared with (S)-omega-TA, the research focused on (R)-omega-TA was relatively less. However, increasing demand for chiral (R)-amines as pharmaceutical intermediates has rendered industrial applications of (R)-omega-TA more attractive. Improving the thermostability of (R)-omega-TA with potential biotechnological application will facilitate the preparation of chiral amines. In this study, the dynamic surface loop with higher B-factor from Aspergillus terreus (R)-omega-TA was predicted by two computer softwares (PyMOL and YASARA). Then mutant enzymes were obtained by deleting amino acid residues of a dynamic surface loop using site-directed mutagenesis. The results showed that the best two mutants R131del and P132-E133del improved thermostability by 2.6 C and 0.9 C in T5010 (41.1 C and 39.4 C, respectively), and 2.2-fold and 1.5-fold in half life (t1/2) at 40 C (15.0 min and 10.0 min, respectively), compared to that of wild type. Furtherly, the thermostability mechanism of the mutant enzymes was investigated by molecular dynamics (MD) simulation and intermolecular interaction analysis. R131del in the loop region has lower root mean square fluctuation (RMSF) than the wild type at 400 K for 10 ns, and mutant enzyme P132-E133del increases four hydrogen bonds in the loop region. In this study, we obtain two stability-increased mutants of (R)-omega-TA from A. terreus by deleting its dynamic surface loop and also provide methodological guidance for the use of rational design to enhance the thermal stability of other enzymes. PMID- 29271171 TI - [From waste to treasure: turning activated sludge into bioplastic poly-3 hydroxybutyrate]. AB - Large quantity of activated sludge is generated from wastewater treatment but without yet an appropriate deposition. High temperature can lyse the activate sludge so that nitrogen and phosphorus containing nutrients are released. Halomonas CJN was found to grow on the heat lysed activated sludge and glucose for production of bioplastic poly-3-hydroxybutyrate (PHB) in the absence of yeast extract, nitrogen and phosphorus sources as well as trace elements. This reduces the PHB production cost significantly. Furthermore, acetic acid formed from anaerobic fermentation of heat lysed activated sludge can be used to replace glucose for cell growth but not much for PHB production. After construction of an additional PHB synthesis pathway in Halomonas CJN, we can produce PHB entirely from heat lysed activated sludge, reducing production cost of PHB roughly from Y 30 000 Yuan/ton to Y 20 000 Yuan/ton, thus turning waste activated sludge to valuable raw material resource. PMID- 29271172 TI - [Identification and characterization of a taxol-producing endophytic fungus from Taxus media]. AB - To enrich the resource pool of endophytic fungi from plants which produce taxol, a taxol-producing endophytic fungus TMS-26 was isolated from the stem of Taxus Media. The result of high performance liquid chromatography (HPLC) showed that TMS-26 extract exhibited similar chromatographic peaks and retention time (4.545 min) with authentic taxol. Then mass spectrometry (MS) analysis further confirmed that TMS-26 extracts contained the same mass peaks with authentic taxol ((M+Na)+=876). These indicated that the isolated endophytic fungus TMS-26 can produce taxol. According to the morphological characteristics, the molecular analysis of 18S rDNA and internal transcribed spacer nuclear rDNA gene sequence, the fungus was identified as Aspergillus fumigatus TMS-26. PMID- 29271173 TI - [Cloning and expression of Bmintegrin beta1 in silkworm Bombyx mori]. AB - Integrins are transmembrane glycoproteins, closely related to many physiological and pathological processes. In order to explore its role in silkworm, by PCR and Rapid-amplification of cDNA ends (RACE) technology, the full-length cDNA of Bmintegrin beta1 in silkworm was acquired. The domain was predicted by domain prediction website. Phylogenetic tree was constructed to analyze its evolutionary relationship. By prokaryotic expression system, protein purification method and immunizing mouse, the antibody against Bmintegrin beta1 recombinant protein was obtained. The spatial-temporal expression profile of Bmintegrin beta1 was investigated by semi quantitative PCR and Western blotting. Then we identified all 3 different spliceosomes, and they shared a common open reading frame of 2 502 bp, encoding 833 amino acids. Bmintegrin beta1 contained all the classic domains of the integrin family, such as Integrin-B-tail, transmembrane domain etc. Phylogenetic analysis indicated that Bmintegrin beta1 was close to the homologous proteins from Heliothis assulta and Danaus plexippus. In order to understand the function of Bmintegrin beta1 further, we generated the antibody. In addition, Western blotting demonstrated that the antibody recognized the Bmintegrin beta1 recombinant protein. Then, semi quantitative PCR and Western blotting results showed that Bmintegrin beta1 was widely expressed in most of tissues, among of them, it's exhibited the highest expression level in hemacyte. Overall, this study provides a foundation for the study of silkworm integrin family. PMID- 29271174 TI - [Expression and characterization of a keratinase encoding gene gm2886 in Streptomyces pactum ACT12 strain]. AB - By bioinformatics analysis, a putative keratinase gene gm2886 (Accession number: KY368946) was discovered in the genome of a feather-degrading strain, Streptomyces albidoflavus Fea-10. gm2886 was ligated into integrative Escherichia coli-Streptomyces shuttle vector pSET152 under the promoter PermE and added with C-terminal His-tag. The expression vector was transformed into Streptomyces pactum ACT12 by conjugal transfer and the recombinant protein GM2886-His6 was detected in fermentation broth. GM2886-His6 was purified and characterized. Its size was nearly 36 kDa. GM2886-His6 showed proteolytic activity towards a variety of substrates and could even degrade insoluble substrates, such as azure keratin and chicken feathers. The optimal pH and temperature of GM2886-His6 for proteolysis of casein was pH 10.0 and 50 C, respectively. The enzyme activity was inhibited by PMSF, but not EDTA, indicating that GM2886-His6 was a serine proteinase. Our results laid the foundation for the research of the molecular biological mechanism on feather-degrading and for the further utilization of Fea 10. PMID- 29271175 TI - [Expression, purification and immunoreactivity characterization of extracellular antigenic domains of NMDAR1 protein]. AB - This study aimed to construct prokaryotic recombinant plasmids for expression of the extracellular domains of NMDAR1 protein, purify and characterize the immunoreactivity of the recombinant proteins. Based on the mRNA sequence of human NMDAR1 gene, we predicted the structure of the antigenic domains in the extracellular part of the protein using the "phyre2" software. Primers were designed to amplify the nucleic acid fragments encoding the NMDAR1 extracellular antigenic domains by RT-PCR. The amplified gene fragments were cloned into pCold SUMO vector to construct the recombinant plasmids which were transformed into Escherichia coli DH5alpha. The positive colonies harboring the recombinant plasmids were picked and verified by PCR and DNA sequencing. Then, the recombinant plasmids were transformed into E. coli BL21(DE3) strain and induced by IPTG for protein expression. The recombinant proteins were purified by Ni-NTA affinity chromatography. The target proteins were further purified by removing the 6 His-SUMO tag using enzyme excision followed by gel filtration chromatography using AKTA purifier. The purity of the recombinant proteins were evaluated by SDS-PAGE and the immunoreactivity were characterized by Western blotting. Three DNA fragments encoding the extracellular domains of NMDAR1 protein, including NR1-M1 (encoding 19-393 aa), NR1-S1 (encoding 394-544 aa) and NR1-S2 (encoding 663-800 aa), were amplified by RT-PCR. The NR1-S1 and NR1-S2 were linked with G (arginine) and T (threonine) amino acid as a combined fragment. The NR1-M1 and NR1-S1-GT-S2 fragments were cloned into pCold-SUMO vector and two recombinant plasmids, pCold-SUMO-M1 and pCold-SUMO-S1-GT-S2, were generated and expressed in E. coli. SDS-PAGE analysis showed that the recombinant plasmids expressed soluble NR1-M1 and NR1-S1-GT-S2 proteins in bacterial. After affinity chromatography and gel filtration chromatography, we obtained high purity target proteins. Western blotting assay showed that the recombinant proteins NR1-M1 and NR1-S1-GT-S2 can bind specially with their corresponding antibodies, suggesting the recombinant proteins retained antigenic reactivity. We constructed a prokaryotic expression system for expressing the NMDAR1 protein extracellular parts that had immunoreactivity successfully, and the purified proteins can be used for studying NMDAR1 function and testing the autoantibodies. PMID- 29271176 TI - [Expression, purification and characterization of 3-Deoxy-D-manno-octulosonate 8 phosphate synthase from Phyllostachys edulis]. AB - 3-Deoxy-D-manno-octulosonate 8-phosphate synthase (KDO8PS) is the key enzyme to synthesize eight-carbon sugar in plant and gram-negative bacterial cell wall. To analyze the polymerization and characterization in plant KDO8PS, the candidate gene was cloned from fresh Phyllostachys edulis seedling by RT-PCR. The open reading frame of PeKDO8PS is 876 bp deduced into 291 amino acid residues. The target protein was overexpressed in Escherichia coli induced by IPTG and then lager amount of fusion protein was purified through two-step methods with affinity chromatography and size-exclusion chromatography (SEC). SEC analysis shows that PeKDO8PS protein existed mainly in the form of dime in solution. Glutaraldehyde cross-linking experiments confirmed that the enzyme could form dimers. Further we identified that KDO8PS at high concentration two dimers could form tetramer in aqueous solution by analytical ultracentrifuge (AUC) analysis. The pH of the catalytic reaction was between 4.0 and 9.0, the optimum pH value was 8, the thermal stability range was between 25 and 65 C, and the optimum temperature was about 55 C. The enzyme activity was inhibited by some metal ions at lower concentrations, especially in the presence of Fe3+metal ion and activated by metal protease inhibitor EDTA at low concentration. PMID- 29271177 TI - [Construction of prototrophic glutathione-high-producing yeast strain mediated by CRISPR/Cas9]. AB - Glutathione (GSH), a non-protein thiol product with various biological activities, has been widely used in pharmaceutical and food industries. Recently, genetic engineering becomes an important strategy for obtaining GSH-high producing strains. However, auxotrophic selection markers used may result in reduced cell growth or GSH production. In the present study, clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9-associated-system (CRISPR Cas), in which gRNA expression constructs and homologous DNA fragments of target genes were co-transformed into Saccharomyces cerevisiae cells, was used for the construction of the prototrophic strain derived from the engineered auxotrophic strain W303-1b/FGP. As a result, the prototrophic strain W303-1b/FGPPT showed a significantly shorter culture cycle compared with the auxotrophic strain. Furthermore, chemically defined medium could be used to culture strain W303 1b/FGPPT that might have great interests in industrial fermentation. PMID- 29271178 TI - [Comparison of three methods for preparation of bacterial ghosts from avian pathogenic Escherichia coli]. AB - Bacterial ghosts are bacterial cell envelopes devoid of cytoplasmic contents while maintaining their cellular morphology, which can be used as a new vaccine and delivery vector. In this study, a clinical isolate of avian pathogenic Escherichia coli (APEC) strain DE17 was used to prepare bacterial ghost through three different ways. The results showed that the cleavage efficiency of DE17 bacterial ghost was 99.9% with the lysis plasmid containing the PhiX174 lysis gene E. Scanning electron microscopy showed that transmembrane tunnels were formed in the middle or both ends of the cell envelope of DE17. Furthermore, the DE17 bacterial ghost was prepared with one of cell penetrating peptides (CPPs) named MAP (KLALKLALKALKAALKLA), which will completely inactivate DE17 (OD600=0.1) by 10 MUmol/L MAP. The cell envelope showed a gully-like structure and obvious transmembrane tunnels were not found through the SEM. However, the DE17 could not be lysed by importing the lysis plasmid (pBV220-MAP), which was used to express MAP. The present study will benefit for research on bacterial ghost preparation methods and provide a reference for biosafety of bacterial ghost vaccines. PMID- 29271179 TI - [Construction and high-density fermentation of alkaline pectate lyase high-yield yeast]. AB - Pectate lyase is widely applied in ramie degumming and fabric bioscouring in the textile industry. Compared to conventional processes that involve high alkaline and high temperature treatment, enzyme based treatments have significant advantages in fibers protectiveness, improved efficiency of refining, reduced energy consumption and pollution. Hence, it would be highly desirable to construct high-yield alkaline pectate lyase engineered strains and reduce the pectate lyase production cost. In the previous study, pectate lyase gene pel from Bacillus subtilis168 was expressed in Pichia pastoris GS115 after codon usage optimization based on the vector pHBM905A. To improve the expression level, the vector pHBM905BDM with optimized promoter and signal peptide was used to express the optimized gene pels in GS115. The transformant had increased activity from 68 U/mL to 100 U/mL with the improvement in the transcription level by 27% measured by qPCR. The transformants were further screened on pectin plates, where higher halo forming strains were picked for shake-flask fermentation and strain GS115 pHBM905BDM-pels4 showed the highest activity of 536 U/mL. Then plasmid pPIC9K pels was constructed and electroporated into the GS115-pHBM905BDM-pels4 cells. Subsequently, high-copy transformant was screened by using the medium containing antibiotics G418, strain GS115-pHBM905BDMpPIC9K- pels1 was identified with increased activity of 770 U/mL and the copy number of pels was 7 confirmed by qPCR. Finally, the activity of pectate lyase produced by GS115-pHBM905BDM-pPIC9K pels1reached to 2 271 U/mL in a 5-L fermentor. The activity of pectate lyase in our study reached the highest level of expression in P. pastoris, showing good application potential in the textile industry. PMID- 29271180 TI - [Whole-cell biotransformation for simultaneous synthesis of L-2-aminobutyric acid and D-gluconic acid in recombinant Escherichia coli]. AB - A whole-cell catalyst using Escherichia coli BL21(DE3) as a host, expressing L- threonine dehydratase from Escherichia coli, and co-expressing leucine dehydrogenase from Bacillus cereus and glucose dehydrogenase from Bacillus subtilis for cofactor regeneration, was constructed and used for one-pot production of L-2-aminobutyric acid (L-ABA) and D- gluconic acid from L-threonine and D-glucose. We used shake-flask culture to study the whole-cell catalytic condition including temperature, pH, proper permeabilization of cells and optimal wet cells amount. Moreover, the whole-cell catalyst was cultured in 5-L fermentor by fed-batch fermentation, and 164 g/L L-threonine and 248 g/L D-glucose were converted to 141.6 g/L L-ABA and 269.4 g/L D-gluconic acid. The whole-cell catalyst is promising to fulfill industrial requirements for L-ABA and D-gluconic acid. PMID- 29271181 TI - Should we be aware of autonomic nervous system control before performing head down laparoscopy? PMID- 29271182 TI - Outcomes of Endoscopic Submucosal Dissection for Early Gastric Cancer with Undifferentiated-Type Histology: A Clinical Simulation Using a Non-Selected Surgical Cohort. AB - Background/Aims: Outcomes of endoscopic submucosal dissection (ESD) for undifferentiated-type early gastric cancer (EGC) need to be further evaluated. We aimed to simulate the outcomes of ESD for undifferentiated-type EGC from a surgical database. Methods: Among 802 patients who underwent gastrectomy with endoscopic biopsy for poorly differentiated adenocarcinoma (PD-type) or signet ring cell carcinoma (SRC-type), ESD candidates meeting the expanded indication (n=280) were selected by reviewing the endoscopic images. According to the surgical pathologic results, the outcomes of the ESD simulation were evaluated. Results: Among the candidates, 104 (37.1%) were PD-type and 176 (62.9%) were SRC type. The curative resection (CR) rate was 42.1%. Among the patients with CR, three patients (2.5%) showed lymph node metastasis (LNM). Three EGCs with CR and LNM were mucosal cancers >=1.0 cm in size. The CR rate was higher in the SRC-type than in the PD-type (48.3% vs 31.7%, respectively, p=0.007). In the SRC-type, the CR rate was increased, with a smaller size criterion for the ESD indication, but was similar between the 1.0 cm and 0.6 cm criteria (63.3% and 63.6%, respectively), whereas the CR rate was below 50% in all of the different tumor size criteria (2.0 to 0.6 cm) in the PD-type. Conclusions: In undifferentiated type EGC, ESD should be considered in selected patients with tumor sizes <1 cm and SRC histology. PMID- 29271183 TI - Subclassification and Detection of New Markers for the Discrimination of Primary Liver Tumors by Gene Expression Analysis Using Oligonucleotide Arrays. AB - Background/Aims: The failure to correctly differentiate between intrahepatic cholangiocarcinoma (CC) and hepatocellular carcinoma (HCC) is a significant clinical problem, particularly in terms of the different treatment goals for both cancers. In this study a specific gene expression profile to discriminate these two subgroups of liver cancer was established and potential diagnostic markers for clinical use were analyzed. Methods: To evaluate the gene expression profiles of HCC and intrahepatic CC, Oligonucleotide arrays (AffymetrixU133A) were used. Overexpressed genes were checked for their potential use as new markers for discrimination and their expression values were validated by reverse transcription polymerase chain reaction and immunohistochemistry analyses. Results: 695 genes/expressed sequence tags (ESTs) in HCC (245 up-/450 down regulated) and 552 genes/ESTs in CC (221 up-/331 down-regulated) were significantly dysregulated (p<0.05, fold change >2, >=70%). Using a supervised learning method, and one-way analysis of variance a specific 270-gene expression profile that enabled rapid, reproducible differentiation between both tumors and nonmalignant liver tissues was established. A panel of 12 genes (e.g., HSP90beta, ERG1, GPC3, TKT, ACLY, and NME1 for HCC; SPT2, T4S3, CNX43, TTD1, HBD01 for CC) were detected and partly described for the first time as potential discrimination markers. Conclusions: A specific gene expression profile for discrimination of primary liver cancer was identified and potential marker genes with feasible clinical impact were described. PMID- 29271184 TI - Genetic Polymorphisms of PNPLA3 and SAMM50 Are Associated with Nonalcoholic Fatty Liver Disease in a Korean Population. AB - Background/Aims: The development of nonalcoholic fatty liver disease (NAFLD) is associated with multiple genetic and environmental factors. Methods: We performed a genome-wide association study to identify the genetic factors related to NAFLD in a Korean population-based sample of 1,593 subjects with NAFLD and 2,816 controls. We replicated the data in another sample that included 744 NAFLD patients and 1,137 controls. We investigated single-nucleotide polymorphisms (SNPs) that were related to NAFLD. Results: After adjusting for age, sex and body mass index, rs738409, rs12483959 and rs2281135, located in the PNPLA3 gene, were validated in our population (p<8.56*10-8) in the same linkage disequilibrium block. Additionally, rs2143571, rs3761472, and rs2073080 in the SAMM50 gene showed significant associations with NAFLD (p<8.56*10-8). Furthermore, these six SNPs showed significant associations with the severity of fatty liver (all p<2.0*10-10 in the discovery set and p<2.0*10-6 in the validation set) and NAFLD, with elevated levels of alanine aminotransferase (all p<2.0*10-10 in the discovery set and p<2.0*10-6 in the validation set). Conclusions: We demonstrated that the PNPLA3 and SAMM50 genes are significantly associated with the presence and severity of NAFLD in a Korean population. These findings confirm the important roles of genetic factors in the pathogenesis of NAFLD. PMID- 29271186 TI - Forming Intermediate Phase on the Surface of PbI2 Precursor Films by Short-Time DMSO Treatment for High-Efficiency Planar Perovskite Solar Cells via Vapor Assisted Solution Process. AB - Morphology regulation is vital to obtain high-performance perovskite films. Vapor assisted deposition provides a simple approach to prepare perovskite films with controlled vapor-solid reaction. However, dense PbI2 precursor films with large crystal grains make it difficult for organic molecules to diffuse and interact with inner PbI2 frame. Here, a surface modification process is developed to optimize the surface layer morphology of PbI2 precursor films and lower the resistance of the induced period in crystallization. The vapor optimization time is shortened to several seconds, and the intermediate phase forms on the surface layer of PbI2 films. We achieve porous PbI2 surface with smaller grains through dimethyl sulfoxide vapor treatment, which promotes the migration and reaction rate between CH3NH3I vapor and PbI2 layer. The PbI2 precursor films undergo dramatic morphological evolution due to the formed intermediate phase on PbI2 surface layer. Taking advantage of the proposed surface modification process, we achieve high-quality uniform perovskite films with larger crystal grains and without residual PbI2. The repeatable perovskite solar cells (PSCs) with modified films exhibit power conversion efficiency of up to 18.43% for planar structure. Moreover, the devices show less hysteresis because of improved quality and reduced defect states of the films. Our work expands the application of morphology control through forming intermediate phase and demonstrates an effective way to enhance the performance of the PSCs. PMID- 29271187 TI - Dispiro and Propellane: Novel Molecular Platforms for Highly Efficient Organic Light-Emitting Diodes. AB - The incorporation of spatially oriented aromatic motifs in rigid molecular platforms is of great interest for the design of organic electronic materials. These structures can create unusual packing patterns and charge transport properties in the solid state which are not possible for simple planar structures. Herein, we showed that the novel dispiro and propellane motifs were successfully used as robust molecular platforms for the construction of host materials (TPA, Cz, SF, and SO). The propellane derivative with three functional groups arranged in the staggered conformation was studied for the first time as the host for organic light-emitting diodes (OLEDs). The green and red phosphorescent OLEDs hosted by these dispiro and propellane derivatives exhibited excellent electroluminescence performance. Particularly, the red OLED hosted by the propellane-type SF achieved maximum efficiencies of 47.3 cd A-1, 40.2 lm W-1, and 26.6% and 97.6 cd A-1, 77.8 lm W-1, and 27.0% for the green OLED without any light out-coupling enhancement. These results suggest that the dispiro and propellane molecular platforms have great potential in the construction of OLED materials. PMID- 29271185 TI - Direct Detection of Drug-Resistant Hepatitis B Virus in Serum Using a Dendron Modified Microarray. AB - Background/Aims: Direct sequencing is the gold standard for the detection of drug resistance mutations in hepatitis B virus (HBV); however, this procedure is time consuming, labor-intensive, and difficult to adapt to high-throughput screening. In this study, we aimed to develop a dendron-modified DNA microarray for the detection of genotypic resistance mutations and evaluate its efficiency. Methods: The specificity, sensitivity, and selectivity of dendron-modified slides for the detection of representative drug-resistance mutations were evaluated and compared to those of conventional slides. The diagnostic accuracy was validated using sera obtained from 13 patients who developed viral breakthrough during lamivudine, adefovir, or entecavir therapy and compared with the accuracy of restriction fragment mass polymorphism and direct sequencing data. Results: The dendron modified slides significantly outperformed the conventional microarray slides and were able to detect HBV DNA at a very low level (1 copy/uL). Notably, HBV mutants could be detected in the chronic hepatitis B patient sera without virus purification. The validation of our data revealed that this technique is fully compatible with sequencing data of drug-resistant HBV. Conclusions: We developed a novel diagnostic technique for the simultaneous detection of several drug resistance mutations using a dendron-modified DNA microarray. This technique can be directly applied to sera from chronic hepatitis B patients who show resistance to several nucleos(t)ide analogues. PMID- 29271188 TI - Enhanced Solar Light Absorption and Photoelectrochemical Conversion Using TiN Nanoparticle-Incorporated C3N4-C Dot Sheets. AB - In this work, a promising strategy to increase the broadband solar light absorption was developed by synthesizing a composite of metal-free carbon nitride carbon dots (C3N4-C dots) and plasmonic titanium nitride (TiN) nanoparticles (NPs) to improve the photoelectrochemical water-splitting performance under simulated solar radiation. Hot-electron injection from plasmonic TiN NPs to C3N4 played a role in photocatalysis, whereas C dots acted as catalysts for the decomposition of H2O2 to O2. The use of C dots also eliminated the need for a sacrificial reagent and prevented catalytic poisoning. By incorporating the TiN NPs and C dots, a sixfold improvement in the catalytic performance of C3N4 was observed. The proposed approach of combining TiN NPs and C dots with C3N4 proved effective in overcoming low optical absorption and charge recombination losses and also widens the spectral window, leading to improved photocatalytic activity. PMID- 29271189 TI - Detection of Sulfide Using Mercapto Tetrazine-Protected Fluorescent Gold Nanodots: Preparation of Paper-Based Testing Kit for On-Site Monitoring. AB - This work demonstrates the development of a highly sensitive method to detect and quantify sulfide ions (S2-) in water samples. First, we synthesized 6-mercapto-s triazolo(4,3-b)-s-tetrazine (MTT) by the reaction between formaldehyde and 4 amino-3-hydrazino-5-mercapto-1,2,4-triazole at room temperature. The synthetic MTT was used as a capping ligand for the synthesis of gold nanodots (AuNDs) via a one-pot green method at room temperature with only a 10 min reaction time. Transmission electron microscopy images exhibited that the MTT-AuNDs have an average particle size of 1.9 nm and an emission maximum at 672 nm upon excitation at 360 nm. The synthesized highly red emissive MTT-AuNDs are used as specific fluorescent probes for the detection of S2-. The fluorescence of MTT-AuNDs was significantly and dose-dependently quenched by the addition of S2-. The observed fluorescence quenching was ascribed to the formation of an Au2S complex, which was determined by Raman and mass spectroscopy. A good linearity was achieved for the increasing concentration of S2- from 870 nM to 16 MUM, and the detection limit was found to be 2 nM (S/N = 3). The S2- detection system that is described in this study was validated and agreed well with the standard methylene blue method. Furthermore, the present sensor was examined for its use in quantifying S2- in real water samples obtained from lakes and rivers. In addition, the specificity was checked against the most likely ion interferences in real water. Moreover, a cost-effective and viable paper-based S2- sensor was fabricated for environmental monitoring based on the use of MTT-AuNDs. The developed system would be an environmentally friendly and easy-to-use detection device for S2- in water. PMID- 29271190 TI - Aggregation-Induced Emission Probe for Specific Turn-On Quantification of Soluble Transferrin Receptor: An Important Disease Marker for Iron Deficiency Anemia and Kidney Diseases. AB - Transferrin receptor (TfR) is overexpressed on the surface of many cancer cells due to its vital roles in iron circulation and cellular respiration. Soluble transferrin receptor (sTfR), a truncated extracellular form of TfR in serum, is an important marker of iron deficiency anemia (IDA) and bone marrow failure in cancer patients. More recently, sTfR level in urine has been related to a specific kidney disease of Henoch-Schonlein purpura nephritis (HSPN). Despite the universal significance of sTfR, there is still a lack of a simple and sensitive method for the quantification of sTfR. Furthermore, it is desirable to have a probe that can detect both TfR and sTfR for further comparison study. In this work, we developed a water-soluble AIE-peptide conjugate with aggregation-induced emission (AIE) characteristics. Taking advantage of the negligible emission from molecularly dissolved tetraphenylethene (TPE), probe TPE-2T7 was used for the light-up detection of sTfR. The probe itself is nonemissive in aqueous solution, but it turns on its fluorescence upon interaction with sTfR to yield a detection limit of 0.27 MUg/mL, which is much lower than the sTfR level in IDA patients. Furthermore, a proof-of-concept experiment validates the potential of the probe for diagnosis of HSPN by urine test. PMID- 29271192 TI - Controlled Synthesis of a Three-Segment Heterostructure for High-Performance Overall Water Splitting. AB - Developing earth-abundant, highly active, and robust electrocatalysts capable of both oxygen and hydrogen evolution reactions is crucial for the commercial success of renewable energy technologies. Here we demonstrate a facile and universal strategy for fabricating transition metal (TM) sulfides by controlling the atomic ratio of TM precursors for water splitting in basic media. Density functional theory calculations reveal that the incorporation of Fe/Co can significantly improve the catalytic performance. The optimal material exhibits extremely small overpotentials of 208 mV for oxygen evolution and 68 mV for hydrogen evolution at 10 mA cm-2 with robust long-term stability. The optimized material was used as bifunctional electrodes for overall water splitting, which delivers 10 mA cm-2 at a very low cell voltage of 1.44 V with robust stability over 80 h at 100 mA cm-2 without degradation, much better than the combination of Pt and RuO2 as benchmark catalysts. The excellent water-splitting performance sheds light on the promising potential of such sulfides as high activity and robust stable electrodes. PMID- 29271193 TI - In Situ Synthesized Silver Nanoclusters for Tracking the Role of Telomerase Activity in the Differentiation of Mesenchymal Stem Cells to Neural Stem Cells. AB - Human mesenchymal stem cells (hMSCs) have potential use in cell replacement therapy for central nervous system disorders. However, the factors that impacted the differentiation process are unclear at the present stage because the powerful analytical method is the bottleneck. Herein, a novel strategy was developed for self-imaging and biosensing of telomerase activity in stem cells, using in situ biosynthesized silver nanoclusters (AgNCs) full of C bases. The present AgNCs possess synthetic convenience, long-time stability, and cytocompatibility. The weak fluorescence of these AgNCs is quickly turned on when approaching telomerase because of the strong interaction between C bases on AgNCs and G bases in telomerase, resulting in telomerase-dependent fluorescent signals. The developed method demonstrated high sensitivity and selectivity and broad dynamic linear range with a low detection limit. Using this powerful tool, it was first discovered that telomerase activity plays important roles in the proliferation of hMSCs and neural stem cells (NSCs) as well as during the differentiation processes from hMSCs to NSCs. PMID- 29271191 TI - Histidine-Lysine Axial Ligand Switching in a Hemoglobin: A Role for Heme Propionates. AB - The hemoglobin of Synechococcus sp. PCC 7002, GlbN, is a monomeric group I truncated protein (TrHb1) that coordinates the heme iron with two histidine ligands at neutral pH. One of these is the distal histidine (His46), a residue that can be displaced by dioxygen and other small molecules. Here, we show with mutagenesis, electronic absorption spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy that at high pH and exclusively in the ferrous state, Lys42 competes with His46 for the iron coordination site. When b heme is originally present, the population of the lysine-bound species remains too small for detailed characterization; however, the population can be increased significantly by using dimethyl-esterified heme. Electronic absorption and NMR spectroscopies showed that the reversible ligand switching process occurs with an apparent pKa of 9.3 and a Lys-ligated population of ~60% at the basic pH limit in the modified holoprotein. The switching rate, which is slow on the chemical shift time scale, was estimated to be 20-30 s-1 by NMR exchange spectroscopy. Lys42-His46 competition and attendant conformational rearrangement appeared to be related to weakened bis-histidine ligation and enhanced backbone dynamics in the ferrous protein. The pH- and redox-dependent ligand exchange process observed in GlbN illustrates the structural plasticity allowed by the TrHb1 fold and demonstrates the importance of electrostatic interactions at the heme periphery for achieving axial ligand selection. An analogy is drawn to the alkaline transition of cytochrome c, in which Lys-Met competition is detected at alkaline pH, but, in contrast to GlbN, in the ferric state only. PMID- 29271196 TI - Anthropogenic Perchlorate Increases since 1980 in the Canadian High Arctic. AB - An ice core of 15.5 m retrieved from Agassiz Ice Cap (Nunavut, Canada) in April 2009 was analyzed for perchlorate to obtain a temporal trend in the recent decades and to better understand the factors affecting High Arctic deposition. The continuous record dated from 1936 to 2007, covers the periods prior to and during the major atmospheric releases of organic chlorine species that affected the stratospheric ozone levels. Concentrations and yearly fluxes of perchlorate and chloride showed a significant correlation for the 1940-1959 period, suggesting a predominant tropospheric formation by lightning. While concentration of chloride remained unchanged from 1940s until 2009, elevated levels of perchlorate were observed after 1979. A lack of significant increases in either sulfate or chloride between 1980 and 2001 suggests that the effect of volcanic activities on the perchlorate at the study site during this period could be insignificant. Therefore, the elevated perchlorate in the ice could most likely be attributed to anthropogenic activities that influenced perchlorate sources and formation mechanisms after 1979. Our results show that anthropogenic contribution could be responsible for 66% of perchlorate found in the ice. Although with some differences in trends and amounts, deposition rate found in this study is similar to those observed at Devon Island (Nunavut, Canada), Eclipse Icefield (Yukon, Canada) and Summit Station (Greenland). Methyl chloroform, a chlorinated solvent largely used after 1976, peaked in the atmosphere in 1990 and has a much shorter atmospheric life than chlorofluorocarbons (CFCs). This study proposes methyl chloroform (CH3CCl3) as the significant anthropogenic source of perchlorate in the Canadian High Arctic between 1980 and 2000, with HCFC-141b (Cl2FC-CH3), a relatively short-lived CFC probably responsible for a slower decrease in perchlorate deposition after the late 1990s. The presence of aerosols in the stratosphere appears to suppress perchlorate production after 1974. As both methyl chloroform and HCFC-141b had no new significant emissions after 2003, deposition of perchlorate in High Arctic is expected to remain at pre-1980 levels. PMID- 29271195 TI - Palladium-Catalyzed Difluoromethylation of Aryl Chlorides and Triflates and Its Applications in the Preparation of Difluoromethylated Derivatives of Drug/Agrochemical Molecules. AB - A palladium-catalyzed difluoromethylation of a series of aryl chlorides and triflates under mild conditions was described. A variety of common functional groups were tolerated. In addition, by using this protocol, several drug molecules containing an aryl chloride unit were successfully difluoromethylated, thus enabling medicinal chemists to rapidly access novel drug derivatives with potentially improved properties via late-stage functionalization. PMID- 29271194 TI - Scalable Regioselective and Stereoselective Synthesis of Functionalized (E)-4 Iodobut-3-en-1-ols: Gram-Scale Total Synthesis of Fungal Decanolides and Derivatives. AB - A reliable protocol to synthesize both racemic and chiral (E)-4-iodobut-3-en-1 ols from aldehydes or epoxides, respectively, containing various aromatic and aliphatic substitutions has been established. The utility of these compounds was then demonstrated by providing access to known fungal decanolides as well as novel aromatic macrocycles. The protocol provided a gram-scale route to (-) aspinolide A and (-)-5-epi-aspinolide A utilizing a catalytic Nozaki-Hiyama-Kishi reaction to close the macrolide in the final step in 65-84% yields. PMID- 29271197 TI - Photoelectron Transfer at ZnTPyP Self-Assembly/TiO2 Interfaces for Enhanced Two Photon Photodynamic Therapy. AB - Two-photon (TP) absorption nanomaterials are highly desirable for deep-tissue clinical diagnostics and orthotopic disease treatment. Here, a well-designed core/shell nanostructure was successfully synthesized with a ZnTPyP self-assembly nanocrystal (ZSN) inner core coated by a homogeneous TiO2 layer outside (ZSN-TO). The ZSN is a good photosemiconductor, showing both one-photon (OP) and TP absorption properties for red fluorescence emission and electron-hole pair generation; TiO2 with good biocompatibility acts as the electron acceptor, which can transfer photoelectron from ZSN to TiO2 for highly effective electron-hole separation, favoring the production of long-life superoxide anion (O2*-) by electrons and oxygen and strong oxidizing hydroxyl radical (*OH) by holes and surrounding H2O. Once pretreated with ZSN-TO, the simultaneous OP-405 nm or TP 800 nm laser stimulation and fluorescent imaging of reactive oxygen species (ROS) showed dynamical and continuous generation of ROS in HeLa cells, with cytotoxicity significantly increasing via the type-1-like photodynamic therapy process. The results demonstrated that the combination of organic ZSN with inorganic TiO2 has great applications as an excellent photosensitizer for deep tissue fluorescent imaging and noninvasive disease treatment via TP photodynamic therapy. PMID- 29271198 TI - Phase Engineering of Perovskite Materials for High-Efficiency Solar Cells: Rapid Conversion of CH3NH3PbI3 to Phase-Pure CH3NH3PbCl3 via Hydrochloric Acid Vapor Annealing Post-Treatment. AB - Organometal halide CH3NH3PbI3 (MAPbI3) has been commonly used as the light absorber layer of perovskite solar cells (PSCs), and, especially, another halide element chlorine (Cl) has been often incorporated to assist the crystallization of perovskite film. However, in most cases, a predominant MAPbI3 phase with trace of Cl- is obtained ultimately and the role of Cl involvement remains unclear. Herein, we develop a low-cost and facile method, named hydrochloric acid vapor annealing (HAVA) post-treatment, and realize a rapid conversion of MAPbI3 to phase-pure MAPbCl3, demonstrating a new concept of phase engineering of perovskite materials toward efficiency enhancement of PSCs for the first time. The average grain size of perovskite film after HAVA post-treatment increases remarkably through an Ostwald ripening process, leading to a denser and smoother perovskite film with reduced trap states and enhanced crystallinity. More importantly, the generation of MAPbCl3 secondary phase via phase engineering is beneficial for improving the carrier mobility with a more balanced carrier transport rate and enlarging the band gap of perovskite film along with optimized energy level alignment. As a result, under the optimized HAVA post-treatment time (2 min), we achieved a significant enhancement of the power conversion efficiency (PCE) of the MAPbI3-based planar heterojunction-PSC device from 14.02 to 17.40% (the highest PCE reaches 18.45%) with greatly suppressed hysteresis of the current-voltage response. PMID- 29271199 TI - Novel PVP/HTA Hybrids for Multifunctional Rewritable Paper. AB - Owing to its benefits to reducing paper production and consumption, ink-free rewritable paper has attracted great attention and it is desirable to develop rewritable paper based on its low-cost, robust, and environmentally benign color switching systems. Herein, we report the fabrication of a rewritable paper based on novel poly(vinylpyrrolidone)/hexatungstic acid (HTA) hybrids with fast dual mode color switching. As-prepared rewritable paper shows fast and reversible colorless-blue or blue-colorless color switching upon photo- or hydroprinting, owing to the fast redox transformations of the unique HTA clusters. More interestingly, the rewritable paper can be used as a template for noble-metal reduction and the noble metal can be deposited on the reduced area of the paper to form well-ordered patterns in high resolution. This rewritable paper can be produced in large scale, and the composition can be facilely tuned with various polyoxometalates or polymers. It may not only be an attractive alternative to current paper prints but also be potentially used for noble-metal reduction to prepare photolithographic circuits and optoelectronic devices. PMID- 29271200 TI - 23-Electron Octahedral Molybdenum Cluster Complex [{Mo6I8}Cl6]. AB - Photoactive transition metal compounds that are prone to reversible redox reactions are important for myriad applications, including catalysis, optoelectronics, and sensing. This article describes chemical and electrochemical methods to prepare cluster complex (Bu4N)[{Mo6I8}Cl6], a rare example of a 23 e- cluster complex within the family of octahedral clusters of Mo, W, and Re. The low temperature and room temperature crystal structures; electronic structure; and the magnetic, optical, and electrochemical properties of this complex are described. PMID- 29271201 TI - Multiscale Computational Design of Functionalized Photocathodes for H2 Generation. AB - We present an integrated computational approach combining first-principles density functional theory (DFT) calculations with wxAMPS, a solid-state drift/diffusion device modeling software, to design functionalized photocathodes for high-efficiency H2 generation. As a case study, we have analyzed the performance of p-type Si(111) photocathodes functionalized with a set of 20 mixed aryl/methyl monolayers, which have a known synthetic route for attachment to Si(111). DFT is used to screen for high-performing monolayers by calculating the surface dipole induced by the functionalization. The trend in the calculated surface dipoles was validated using previously published experimental measurements. We find that the molecular dipole moment is a descriptor of the surface dipole. wxAMPS is used to predict the open-circuit voltage (efficiency) of the photocathode by calculating the photocurrent versus voltage behavior using the DFT surface dipole calculations as inputs to the simulation. We find that Voc saturates beyond a surface dipole of ~0.3 eV, suggesting an upper limit for achievable device performance. This computational approach provides a possibility for the rational design of functionalized photocathodes for enhanced H2 generation by combining the angstrom-scale results obtained using DFT with the micron-to-nanometer scale capabilities of wxAMPS. PMID- 29271202 TI - Unimolecular Reaction Pathways of a gamma-Ketohydroperoxide from Combined Application of Automated Reaction Discovery Methods. AB - Ketohydroperoxides are important in liquid-phase autoxidation and in gas-phase partial oxidation and pre-ignition chemistry, but because of their low concentration, instability, and various analytical chemistry limitations, it has been challenging to experimentally determine their reactivity, and only a few pathways are known. In the present work, 75 elementary-step unimolecular reactions of the simplest gamma-ketohydroperoxide, 3-hydroperoxypropanal, were discovered by a combination of density functional theory with several automated transition-state search algorithms: the Berny algorithm coupled with the freezing string method, single- and double-ended growing string methods, the heuristic KinBot algorithm, and the single-component artificial force induced reaction method (SC-AFIR). The present joint approach significantly outperforms previous manual and automated transition-state searches - 68 of the reactions of gamma ketohydroperoxide discovered here were previously unknown and completely unexpected. All of the methods found the lowest-energy transition state, which corresponds to the first step of the Korcek mechanism, but each algorithm except for SC-AFIR detected several reactions not found by any of the other methods. We show that the low-barrier chemical reactions involve promising new chemistry that may be relevant in atmospheric and combustion systems. Our study highlights the complexity of chemical space exploration and the advantage of combined application of several approaches. Overall, the present work demonstrates both the power and the weaknesses of existing fully automated approaches for reaction discovery which suggest possible directions for further method development and assessment in order to enable reliable discovery of all important reactions of any specified reactant(s). PMID- 29271203 TI - Oxidative Difluoromethylation of Tetrahydroisoquinolines Using TMSCF2SPh: Synthesis of Fluorinated Pyrrolo[2,1-a]isoquinolines and Benzo[a]quinolizidines. AB - An efficient C1-difluoromethylation of tetrahydroisoquinolenes was achieved using TMSCF2SPh as a difluoromethylating agent and 2,2,6,6-tetramethylpiperidine-1 oxoammonium tetrafluoroborate (TEMPO+BF4-) as an oxidant. The process provides an access to a variety of C1-difluoro(phenylsulfanyl)methylated tetrahydroisoquinoline adducts in good yields. These adducts were employed as key precursors for preparing fluorinated pyrrolo[2,1-a]isoquinoline and benzo[a]quinolizidines. PMID- 29271204 TI - Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S Adenosylmethionine Decarboxylase. AB - New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization. PMID- 29271205 TI - Grain Boundary Modification via F4TCNQ To Reduce Defects of Perovskite Solar Cells with Excellent Device Performance. AB - Solar cells based on hybrid organic-inorganic metal halide perovskites are being developed to achieve high efficiency and stability. However, inevitably, there are defects in perovskite films, leading to poor device performance. Here, we employ an additive-engineering strategy to modify the grain boundary (GB) defects and crystal lattice defects by introducing a strong electron acceptor of 2,3,5,6 tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) into perovskite functional layer. Importantly, it has been found that F4TCNQ is filled in GBs and there is a significant reduction of metallic lead defects and iodide vacancies in the perovskite crystal lattice. The bulk heterojunction perovskite-F4TCNQ film exhibits superior electronic quality with improved charge separation and transfer, enhanced and balanced charge mobility, as well as suppressed recombination. As a result, the F4TCNQ doped perovskite device shows excellent device performance, especially the reproducible high fill factor (up to 80%) and negligible hysteresis effect. PMID- 29271206 TI - Design Growth of MAPbI3 Single Crystal with (220) Facets Exposed and Its Superior Optoelectronic Properties. AB - MAPbI3 is deemed as the most prominent member in hybrid perovskites family because of its extremely optoelectronic properties. However, some issues and puzzles are still in expectation of their answers, such as stabilities, hysteresis, ferroelectricity, and so on. To bridge the distinctions between MAPbI3 single crystal and thin films, large-size single crystals are demanded. On the contrary, crystal structure anisotropy-dependent optoelectronic properties is an inevitable topic. A series of large-size MAPbI3 single crystals with (220) facets exposed were successfully grown, using high concentration solutions and large-size seed crystals to match growth rates of (100) and (220) facets. The optoelectronic properties of photocurrents, responsivity, EQE, and detectivity clearly showed significant anisotropy of optoelectronic properties in MAPbI3 single crystal. According to ion migration theory, the anisotropy of optoelectronic properties was interpreted. We hope this result will be helpful to guide oriented growth MAPbI3 thin films. PMID- 29271207 TI - Lattice Mismatch in Crystalline Nanoparticle Thin Films. AB - For atomic thin films, lattice mismatch during heteroepitaxy leads to an accumulation of strain energy, generally causing the films to irreversibly deform and generate defects. In contrast, more elastically malleable building blocks should be better able to accommodate this mismatch and the resulting strain. Herein, that hypothesis is tested by utilizing DNA-modified nanoparticles as "soft," programmable atom equivalents to grow a heteroepitaxial colloidal thin film. Calculations of interaction potentials, small-angle X-ray scattering data, and electron microscopy images show that the oligomer corona surrounding a particle core can deform and rearrange to store elastic strain up to +/-7.7% lattice mismatch, substantially exceeding the +/-1% mismatch tolerated by atomic thin films. Importantly, these DNA-coated particles dissipate strain both elastically through a gradual and coherent relaxation/broadening of the mismatched lattice parameter and plastically (irreversibly) through the formation of dislocations or vacancies. These data also suggest that the DNA cannot be extended as readily as compressed, and thus the thin films exhibit distinctly different relaxation behavior in the positive and negative lattice mismatch regimes. These observations provide a more general understanding of how utilizing rigid building blocks coated with soft compressible polymeric materials can be used to control nano- and microstructure. PMID- 29271208 TI - Room-Temperature Skyrmions in an Antiferromagnet-Based Heterostructure. AB - Magnetic skyrmions as swirling spin textures with a nontrivial topology have potential applications as magnetic memory and storage devices. Since the initial discovery of skyrmions in non-centrosymmetric B20 materials, the recent effort has focused on exploring room-temperature skyrmions in heavy metal and ferromagnetic heterostructures, a material platform compatible with existing spintronic manufacturing technology. Here, we report the surprising observation that a room-temperature skyrmion phase can be stabilized in an entirely different class of systems based on antiferromagnetic (AFM) metal and ferromagnetic (FM) metal IrMn/CoFeB heterostructures. There are a number of distinct advantages of exploring skyrmions in such heterostructures including zero-field stabilization, tunable antiferromagnetic order, and sizable spin-orbit torque (SOT) for energy efficient current manipulation. Through direct spatial imaging of individual skyrmions, quantitative evaluation of the interfacial Dzyaloshinskii-Moriya interaction, and demonstration of current-driven skyrmion motion, our findings firmly establish the AFM/FM heterostructures as a promising material platform for exploring skyrmion physics and device applications. PMID- 29271209 TI - Rediscovering the MP15 Family (M = Li, Na, and K) as an Anisotropic Layered Semiconducting Material. AB - The binary alkaline metal phosphides family MP15 (M = Li, Na, K) exhibiting a layered structure nature and in-plane anisotropy is discussed through first principles. Their thickness-dependent bandstructures are reported for the first time. Furthermore, the transport studies demonstrate that single-layer MP15 exhibits a large anisotropic ratio for carrier mobility (both electron and hole) (~101-102 magnitude) between two special crystal directions, which is the record high value among the reported two-dimensional anisotropic materials. Additionally, the chemical stability under ambient conditions and the binding energy which relates to experimental exfoliation are also investigated. The high anisotropy of the layered semiconducting MP15 family could open up considerable promise for anisotropic optics, electronics, optoelectronics devices, and energy storage applications. PMID- 29271210 TI - [Catheter-related Bloodstream Infections: Do We Know All of It?] AB - BACKGROUND: Catheter-related bloodstream infections (CRBSI) represent a life threatening complication. They are associated with high morbidity, mortality and healthcare costs. Cancer patients are at particular risk due to the nature of the disease and the therapy-associated immunodeficiency. Although the incidence of catheter-related infections decreased in the past decade, the mortality rate remains high at 12-25%. The incidence of CRBSI differs among patients. While the incidence in ICU patients across the Europe was reported to be 0.5-4.1 episodes per 1.000 catheter-days, the incidence in cancer patients was 1.1-7.5 episodes per 1.000 catheter-days. One of the factors negatively influencing the incidence is the lack of uniformity in CRBSI definitions, etiology and risk factors for surveillance purposes. PURPOSE: This preview not only presents the definitions of catheter-related infections and etiology and risk factors for developing CRBSI, it also it also summarizes epidemiologic data, diagnostic techniques, and the prevention and treatment strategies for CRBSI according to knowledge acquired over the last 10 years. Following the implementation of the prevention strategies guidelines for CRBSI published in 2011 by Center for Disease Control and Prevention and Healthcare Infection Control Practices Advisory Committee, the incidence of CRBSI has decreased by more than 50%. As central venous catheters are a common part of cancer treatment, every oncologist should be aware of the risk of catheter-related infections. The prevention and treatment guidelines with surveillance of CRBSI should be the gold standard in the care of cancer patients as well. CONCLUSION: Adherence to evidence-based guidelines for prevention of catheter-related infections and surveillance of CRBSI are the basic steps required to reduce the rate of CRBSI. Implementation of these strategies in hospital healthcare policy, particularly in written form, and control of adherence and reporting of the incidence rate to higher authorities are strongly recommended. When these interventions were successfully implemented, they reduced the incidence rate under 1 episode of CRBSI per 1.000 catheter-days in Western countries. Each healthcare facility using central venous catheters should be advised to implement these strategies, particular when treating cancer patients.Key words: central venous catheter - catheter-related infections - cancer - epidemiology - etiology - guidelines - prevention and control - therapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 8. 4. 2017Accepted: 4. 6. 2017. PMID- 29271211 TI - [Molecular Pathogenesis of Testicular Germ Cell Tumors]. AB - BACKGROUND: Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men and their incidence has been increasing over the past decades. Several factors may combine and play a role in the TGCT etiology, including environmental factors and genetic predispositions at multiple genomic loci that affect both testicular germ cells and stromal cells, and their interactions within the testicular microenvironment. The pathogenesis of TGCT starts prenatally with primordial germ cell arrest, and further proceeds postnatally, giving rise to in situ germ cell neoplasia and, finally, to invasive TGCT with the characteristic 12p chromosome amplification. Apart from the genes localized here, further molecular mechanisms have been linked to TGCT pathogenesis, such as the activation of the KIT/KITL signaling pathway, and aberrations in genes involved in DNA reparation, regulation of cellular differentiation, proliferation, and survival. Despite the relatively good prognosis and known etiopathogenesis of these tumors, neither targeted therapy nor molecular prognostic/predictive factors have yet been implemented in the management of TGCT, because there is not enough information about the molecular pathways or molecules involved in TGCT development that could be used for patient stratification and treatment. Current high-throughput technologies, such as next generation sequencing at the exome or transcriptome level could provide this missing information on genetic predispositions and other factors influencing the clinical course of the disease and treatment response in TGCT. AIM: In this review, we summarize the main molecular characteristics of TGCT and the probable mechanisms participating in tumor initiation and progression.Key words: testicular germ cell tumors - signaling pathways - molecular aberrations - predictive factors - prognostic factors The work was supported by the Czech Ministry of Education, Youth and Sports NPU I nr.LO 1604. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 20. 3. 2017Accepted: 23. 7. 2017. PMID- 29271212 TI - [Preoperative Axillary Lymph Node Marking in Patients with Breast Cancer]. AB - BACKGROUND: Axillary dissection (AD) is an integral part of the surgical staging of breast cancer. This operation can be source of major long term complications, e. g., lymphedema. Reducing the radicality of these operations has been the subject of many clinical trials, especially those addressing the metastatic infiltration of axillary lymph nodes uncovered either by clinical staging or by sentinel lymph node (SLN) biopsy (when the clinical staging was negative). Exact clinical (mainly ultrasonographic) staging and marking of the lymph nodes detected by staging plays a key role in deciding the optimum clinical regimen. PURPOSE: Three possibilities were tested in clinical trials: The possibility of replacing the AD by radiotherapy in the case of tumorous infiltration of SLN, when clinical staging was negative; the possibility of omitting AD (in patients with positive clinical axillary staging) and replacing it with SLN biopsy after neoadjuvant chemotherapy; and the possibility of marking lymph nodes in axilla that were suspected of infiltration at the time of clinical staging. RESULTS: The studies showed clear evidence that avoiding AD was safe in oncology patients who showed infiltration of axillary SLN and negative clinical staging. Despite the high false negativity of using SLN biopsies in patients with a positive clinical staging after neoadjuvant chemotherapy, this false negativity could be reduced by using lymph node marking. By implementing these methods, it should be possible to define exactly the group of patients in whom complete pathological remission occurs after neoadjuvant chemotherapy.Key words: breast neoplasms - axilla - lymph nodes The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 17. 4. 2017Accepted: 2. 7. 2017. PMID- 29271213 TI - [Milk Thistle (Silybum Marianum) as a Supportive Phytotherapeutic Agent in Oncology]. AB - BACKGROUND: Milk thistle (Silybum marianum) has been traditionally used in medicine, particularly in the treatment of liver diseases. Today, it is used for the same purpose in evidence-based medicine (EBM). Its main active ingredient is a complex of flavonolignans, known as silymarin. Silymarin is used as a hepatoprotective agent, but its potential therapeutic use in oncology patients has drawn attention only recently. PURPOSE: The aim of this review is to provide comprehensive information on the potential therapeutic effects of milk thistle in oncology patients and potential indications for its use as a supportive therapy either as an anticarcinogenic agent or as an agent that attenuates the side effects of oncological treatments. Evidence of its effects and its safety, and possible interactions with other cancer treatments are emphasized. Available findings are supported mainly by in vitro studies and the results of animal research, but the number of clinical trials in oncology patients is increasing. Based on the results of these studies, milk thistle or silymarin could be beneficial in oncology patients, especially for the treatment of the side effects of anticancer chemotherapeutics. Evidence from clinical studies shows that it has mainly beneficial effects in hepatotoxicity and radiotherapy-induced skin and mucosa damage at dosages of 160-600 mg daily.Key words: phytotherapy - drug-herb interactions - cancer - adverse effects - milk thistle - Silybum marianum This publication was written at Masaryk University as part of the project "Experimental and translational pharmacological research and development", number MUNI/A/1063/2016 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2017. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 4. 6. 2017Accepted: 18. 9. 2017. PMID- 29271214 TI - [The Role of Palliative Radiotherapy in Bleeding from Locally Advanced Gastrointestinal Tumors]. AB - BACKGROUND: Patients with locally advanced gastrointestinal tumors present with typical symptoms including pain, obstructive problems with passage disorders and bleeding. The last of them negatively affects their quality of life and is potentially lethal. Palliative radiotherapy is used in hemostatic indication to control bleeding from locally advanced or recurrent inoperable gastrointestinal tumors for many years. PURPOSE: This review summarizes information and available literature about mechanisms, efficiency and toxicity of palliative radiotherapy used in hemostatic indication, separately for each part of the digestive system. Although most of the published studies are retrospective, all of them show fast, effective and technically safe control of bleeding with minimal risk of toxicity and show an improvement of quality of life. Hypofractionated radiotherapy, with a smaller number of high doses, seems to be the appropriate palliative fractionation schedule. The higher daily dose is associated with faster initiation of hemostatic effect, while few radiotherapy treatment sessions are comfortable for patients; both of them meet the basic principles of state-of-the art palliative care. In addition to external beam radiotherapy, high dose rate brachytherapy represents another possibility in this indication, especially for locally advanced inoperable anal and rectal cancer. Brachytherapy is simple, practical and most importantly a one-time procedure with high local effect without significant toxicity. CONCLUSION: Radiotherapy is an important treatment possibility for palliative care of bleeding from locally advanced inoperable gastrointestinal cancers. Future prospective studies employing modern radiotherapeutic techniques and procedures are needed to provide consistent and clear evidence in order to weigh risks against benefits of palliative hemostatic radiotherapy in current daily clinical practice.Key words: locally advanced gastrointestinal tumors - bleeding - palliative radiotherapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 8. 5. 2017Accepted: 23. 7. 2017. PMID- 29271215 TI - [The Impact of Corticotherapy on the Diagnostic Yield of Stereotactic Biopsy in Patients with Brain Lymphoma]. AB - : Backround: Because of the dismal prognosis of untreated brain lymphoma early histological verification using stereobiopsy is decisive for patient with this disease. The study analysed the diagnostic yield of stereobiopsy in brain lymphoma patients with respect to prebiopsy corticosteroid administration. PATIENTS AND METHODS: Patients with brain lymphomas were identified in a group of 162 stereotactic biopsies (108 frame-based and 54 frameless) of patients harboring suspected brain tumor. Non conclusive biopsies were reevaluated to exclude the possibility of missed lymphoma. RESULTS: Total 9 patients (8.3%) and 4 patients (7.4%) had lymphomas in the frame-based and frameless stereobiopsy groups, resp. In 10 patients, corticosteroid treatment of perifocal brain oedema was conducted continually up until biopsy (including one patient with corticotherapy for pulmonary disease). Lesion regression was observed in 6 of these patients. Transient lesion remission was observed during corticotherapy in one patient with lesion recurrence after steroid discontinuation. In 2 patients, corticosteroids were not administered before biopsy. The results of stereobiopsy were inconclusive in 8 patients (4.9%). Before biopsy, the possibility of brain lymphoma was considered in 3 patients, but the final diagnoses were autoimmune vasculitis, histological changes after embolic events from the thrombosed pulmonary veins in pulmonary malformation and local inflammation. CONCLUSION: Although the extent of brain lymphoma decreased after corticosteroid administration, corticotherapy does not exclude valid diagnostic biopsy.Key words: brain lymphoma - stereotaxic techniques - frameless stereotaxy - stereotactic biopsy - corticosreroids Part of the message was presented on XLI. Brno Oncological Days within the Glio Meeting and published in the form of a short abstract. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 27. 5. 2017Accepted: 2. 7. 2017. PMID- 29271216 TI - [The Inclusion of a Gemcitabine + Nab-paclitaxel Regimen as a 2nd Line Treatment for Advanced Pancreatic Cancer - First Experience]. AB - INTRODUCTION: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The outcomes at all stages of the disease are the worst among patients with solid tumors. PATIENTS AND METHODS: Analyses were conducted on 19 patients treated with gamcitabine + nab-paclitaxel for locally advanced or metastatic pancreatic cancer as a second line treatment between October, 2014, and December, 2016, at Department of Oncology of First Faculty of Medicine and General University Hospital in Prague. Patients were treated with gemcitabine (1,000 mg/sqm) + nab-paclitaxel (125 mg/sqm) at days 1, 8 and 15 of each 28-day cycle. Antitumor efficacy (disease control rate (DCR), time to progression (TTP), and overall survival (OS)) and adverse events were monitored. RESULTS: Disease control according to RECIST criteria was achieved in nine cases (56.3%, two partial regressions were observed). The median TTP was 5.5 months and median OS was 10.1 months. CONCLUSION: In patients with advanced or metastatic pancreatic cancer with good performance statuses (0-1) gemcitabine + nab-paclitaxel as a second line treatment led to a prolongation in time to progression and higher overall survival with good quality of life.Key words: pancreatic cancer - gemcitabine - nab-paclitaxel - efficiency - toxicity This project was supported by grant PROGRES-Q-25/LF1, The League Against Cancer a AZV CR 15-28188A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 11. 7. 2017Accepted: 20. 9. 2017. PMID- 29271217 TI - [Cognitive Deficits in Cancer Patients with Haematological Malignancies]. AB - BACKGROUND: Cognitive deficits are one of the most common adverse effects of chemotherapy (CHT). Previous reports suggest that this is due to the so-called chemo brain syndrome, the symptoms of which manifest mainly as impairments in executive functions, speed of information processing, memory, attention, and motor speed. However, empirical evidence for these manifestations is currently ambiguous. METHODS: The research group consisted of 26 cancer patients with haematological malignancies who had undergone chemotherapy treatment. Cognitive performance was measured by two screening cognitive tests, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Test (MoCA). RESULTS: MMSE detected cognitive deficits in 34.6% of patients whereas MoCA identified mild or moderate cognitive impairment in up to 80.7% of patients. The highest error rates were found in tasks focused on memory, attention, spatial orientation, executive functions, and abstraction. Cognitive deficit progressed with age, but not with duration of therapy. CONCLUSION: Deficits in cognitive functions occur in a considerable number of patients after CHT, although the diagnosis depends on the sensitivity of the detection method. Screening scales usually provide the first indication of impaired cognitive functioning and may indicate the need for further neuropsychological examination. Early diagnosis of reduced cognitive functions is a prerequisite for effective psychological intervention to help patients cope with the undesirable effects of chemotherapy treatment more quickly.Key words: chemotherapy - cognitive dysfunction - chemo brain - cognitive screening - neuropsychological tests - psychology The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 4. 7. 2017Accepted: 24. 8. 2017. PMID- 29271218 TI - The Role of Adjuvant Radiotherapy in the Treatment of Papillary Tumors of the Pineal Region: Some General Considerations and a Case Report. AB - BACKGROUND: Papillary tumor of the pineal region (PTPR) is a recently defined tumor entity. Its clinical course is characterized by frequent local recurrence, and patients may experience the burden of symptoms due to the anatomical location of the growing mass. Guidelines for treatment protocols, and the role of radiotherapy are still being investigated. CASE: We report the case of a 27-year old woman who was referred to our department after she was diagnosed with PTPR and had undergone multiple surgical interventions. We delivered adjuvant conformal radiotherapy on the gross residual tumor to a total dose of 59.4 Gy (33 * 1.8 Gy). DISCUSSION: After a follow-up period of 41 months, we obtained a complete response to the treatment, according to the Response evaluation criteria in solid tumors criteria (RECIST). Radiation treatment was well tolerated, and the patient did not develop acute and late side effects. The neurological symptoms, which were documented at the diagnosis and after the surgical procedure, have not been recorded at last follow-up. CONCLUSIONS: Formal consensus for managing patients with a diagnosis of PTPR are nonexistent. Despite surgery, this tumor has a tendency to recur. Radiotherapy could have a role in the adjuvant setting and needs to be investigated in a multicenter setting with a long follow-up.Key words: radiotherapy - neurosurgery - magnetic resonance - pineal region - brain tumor. PMID- 29271219 TI - Biliary cannulation effectiveness and pancreatitis risk using two early precut techniques. AB - INTRODUCTION: Precut techniques allow for successful biliary cannulation rates approaching 100% but there may be an associated increase in the risk of complications. Recently, early needle-knife precut has been shown to be a safe procedure and is now used as a pancreatitis prevention resource for difficult cannulation cases. The goal of the present study was to assess cannulation and pancreatitis rates using two early precut techniques. PATIENTS AND METHODS: This was a retrospective study of endoscopic retrograde cholangio-pancreatography (ERCP) procedures performed from 2013 to 2016. The efficacy and safety of simple cannulation, needle-knife precut and transpancreatic precut were assessed. RESULTS: Simple cannulation was achieved in 369 (73.4%) of 503 evaluable ERCP procedures. Needle-knife precut was successful in 51 (96.2%) of 53 attempts and transpancreatic precut was successful in 75 (96.2%) of 78 attempts. The overall cannulation rate was 98.4%. There were eleven (2.4%) pancreatitis events, six (1.8%) with simple cannulation (two severe, one fatal), five (6.3%) with transpancreatic precut (two severe) and zero events with the needle-knife precut procedure. Among the patients undergoing the precut procedure, seven experienced perforations (two severe) and there were seven bleeding events. The overall complication rate was 14.4%. CONCLUSIONS: The complementary use of either precut technique provides a satisfactory biliary cannulation rate. However, the rates of pancreatitis and other severe complications are higher for transpancreatic versus needle-knife precut, therefore the indications for both techniques should be modified. PMID- 29271220 TI - EUS-guided ethanol ablation therapy for gastric stromal tumors. AB - EUS-guided fine-needle ethanol injection (FNI) therapy of some types of cystic and solid tumors has been documented. However, reported cases to date of gastrointestinal-stromal tumors (GIST) treated with this technique are scarce. Ethanol ablation is an alternative treatment with a low rate of adverse events in selected cases. PMID- 29271221 TI - Effectiveness of direct-acting antiviral therapy in patients with a HCV/HIV coinfection. A multicenter cohort study. AB - INTRODUCTION: The effectiveness of direct-acting antiviral (DAA) agents has been demonstrated in clinical trials both in patients with mono and coinfections. The goal of the study was to analyze the effectiveness and toxicity of this therapy in real-life patients with a HIV/HCV coinfection and to identify variables that are associated with an unfavorable outcome. METHODS: This was a multicenter ambispective study in a cohort of coinfected patients. Data were collected from eight centers in Castilla-La Mancha from 2014 to 2016. An intent-to-treat analysis was performed and any loss to follow-up, treatment withdrawal or toxicity was considered as a failure. RESULTS: A total of 229 patients were included with a median age of 49.6 years and the majority were male (83%). Fewer than 10% had a detectable HIV-related viral load (VL). The most prevalent HCV genotype was 1 (65.1%). Fifty percent had cirrhotic liver disease and 65% had over 800,000 copies/ml of HCV VL. The global sustained viral response (SVR) was reached by 91.7% of cases. The most commonly used DAA regimen was sofosbuvir/ledipasvir. Ribavirin was included in 52% of regimens, 65.9% of cases completed 12-week regimens and 30% completed 24-week schemes. There were 19 therapy failures. No differences were observed between the various DAA strategies used. No independent predictor was found for SVR. CONCLUSIONS: HCV treatment in coinfected patients is highly successful in terms of SVR rate in the real-life setting and toxicity is exceptional. We identified no specific predictors of an unfavorable outcome. PMID- 29271222 TI - IgG4-related sclerosing mesenteritis, a rare condition that causes abdominal pain. AB - The identification of IgG4-related disease as a distinct immune-mediated condition encompassing disorders that were traditionally seen as idiopathic has been a revolution in the diagnostic and therapeutic algorithm in several medical fields. This condition usually involves multiple organs (isolated organ involvement is uncommon except in the pancreas) with characteristic histopathological findings. We report a case that was assessed due to abdominal pain and subsequently diagnosed with IgG4-related sclerosing mesenteritis. A comprehensive work-up of the case ruled out other conditions and a diagnosis of IgG4-related sclerosing mesenteritis was made according to radiographic and histopathological criteria. PMID- 29271223 TI - The association between a positive lactulose methane breath test and rectocele in constipated patients. AB - OBJECTIVES: Rectocele with constipation might be related to methane (CH4) producing intestinal bacteria. We investigated the breath CH4 levels and the clinical characteristics of colorectal motility in constipated patients with rectocele. METHODS: A database of consecutive female outpatients was reviewed for the evaluation of constipation according to the Rome III criteria. The patients underwent the lactulose CH4 breath test (LMBT), colon marker study, anorectal manometry, defecography and bowel symptom questionnaire. The profiles of the lactulose breath test (LBT) in 33 patients with rectocele (with size >= 2 cm) and 26 patients with functional constipation (FC) were compared with the breath test results of 30 healthy control subjects. RESULTS: The mean size of rectocele was 3.52 +/- 1.06 cm. The rate of a positive LMBT (LMBT+) was significantly higher in patients with rectocele (33.3%) than in those with FC (23.1%) or healthy controls (6.7%) (p = 0.04). Breath CH4 concentration was positively correlated with rectosigmoid colon transit time in rectocele patients (gamma = 0.481, p < 0.01). A maximum high pressure zone pressure > 155 mmHg was a significant independent factor of LMBT+ in rectocele patients (OR = 8.93, 95% CI = 1.14-71.4, p = 0.04). CONCLUSIONS: LMBT+ might be expected in constipated patients with rectocele. Moreover, increased rectosigmoid colonic transit or high anorectal pressure might be associated with CH4 breath levels. Breath CH4 could be an important therapeutic target for managing constipated patients with rectocele. PMID- 29271224 TI - Intestinal pneumatosis and pneumoperitoneum in an oncological scenario: a change of attitude. AB - Pneumoperitoneum and cystic intestinal pneumatosis associated to chemotherapy treatment are rare entities, with non-well stablished etiology and controversial management. We report two cases of oncological patients presenting with this complication as incidental finding in CT scan. Their course was favourable under conservative non-surgical approach associated with interruption of chemoterapy treatment. PMID- 29271225 TI - From the intestinal flora to the microbiome. AB - In this article, the history of the microbiota is reviewed and the related concepts of the microbiota, microbiome, metagenome, pathobiont, dysbiosis, holobiont, phylotype and enterotype are defined. The most precise and current knowledge about the microbiota is presented and the metabolic, nutritional and immunomodulatory functions are reviewed. Some gastrointestinal diseases whose pathogenesis is associated with the intestinal microbiota, including inflammatory bowel disease, irritable bowel syndrome and celiac disease, among others, are briefly discussed. Finally, some prominent and promising data with regard to the fecal microbiota transplantation in certain digestive illness are discussed. PMID- 29271226 TI - Ectopic pancreas: a very unusual intestinal mass. AB - The ectopic pancreas is a rare entity, characterized by the presence of pancreatic islets in different locations of the gastrointestinal tract. Its clinical manifestations are nonspecific and it is often diagnosed incidentally in imaging tests or intraoperatively. Its management is controversial, since its malignancy is infrequent; however, its resection is recommended in the case of a casual intraoperative finding to establish the definitive histological diagnosis. Therefore, the ectopic pancreas should be included in the differential diagnosis of intestinal masses. PMID- 29271227 TI - Serum thymosin beta4 as a noninvasive biomarker in patients with nonalcoholic steatohepatitis. AB - OBJECTIVE: The aim of the study was to determine whether serum thymosin beta4 (Tbeta4) can be a useful noninvasive biomarker to differentiate between nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver (NAFL). METHODS: The study included 24 NAFL patients and 21 NASH patients. The levels of Tbeta4, 8 hydroxydeoxyguanosine acid (8-OhdG), liver function parameters, blood lipid, and glucose were detected in the venous blood of all patients. The NAFLD histological activity score (NAS) was examined in biopsy specimens from all patients. Statistical analysis was performed in order to find differences between the two abovementioned groups. In addition, receiver operator characteristic (ROC) analyses for alanine aminotransferase (ALT) and Tbeta4 levels were performed in NAFL and NASH patients and the cut-off value was determined. Associations between the variables were tested using correlation coefficient calculations. Statistical significance was set at a p value of < 0.05. RESULTS: Serum Tbeta4 content was 5.12 +/- 1.87 mg/l in the NAFL group and 2.98 +/- 1.35 mg/l in the NASH group (p < 0.001). Serum Tbeta4 content and NAS, histological features of hepatic steatosis, lobular inflammation and ballooning, ALT, glucose and 8-OhdG levels were negatively correlated (p < 0.05 for all) in the NASH group. The correlation coefficient values were -0.530, -0.562, -0.574, -0.438, -0.446, -0.426 and 0.563, respectively. On the basis of ROC analysis, the best predictive Tbeta4 cut off value for detecting NASH was 3.94 mg/l (85.7% sensitivity and 79.2% specificity, which were higher than those of ALT). CONCLUSION: Serum Tbeta4 level can be used as a biomarker for the diagnosis of NASH and was negatively correlated with the oxidation state of the liver. PMID- 29271228 TI - Clinico-pathological and oncological differences between right and left-sided colon cancer (stages I-III): analysis of 950 cases. AB - PURPOSE: The objective of the study was to analyze the clinico-pathological differences and the oncologic outcomes between right and left-sided colon cancer. PATIENTS AND METHODS: The patients cohort was identified from a prospective register of colon cancer, 950 patients underwent surgery (stages I, II and III), of which 431 had right-sided colon cancer and 519 had left-sided colon cancer. RESULTS: More laparoscopic resections were performed (101 vs 191; p < 0.001) and operating times were longer (146 min vs 165 min; p < 0.001) in the left-sided colon group. Patients with right-sided colon cancer more frequently received transfusions (18.8% vs 11.3%; p < 0.001) and experienced a greater number of complications (28.5% vs 20.9%, p = 0.004), although severity and operative mortality were similar in both groups (1.2% vs 0.2%). Mucinous adenocarcinomas and undifferentiated tumors were more frequent in the right-sided group (12% vs 6.5%; p < 0.001). Early stage was predominant in the left-sided colon tumors (28.2% vs 34.5%, p = 0.02). There were no differences in disease-free survival (DFS) in stages I and II after a median follow-up of 103 months. However, a greater survival at five and ten years in left-sided, stage III tumors was observed, with a trend towards statistical significance (p = 0.06). No differences were found with regard to the patterns of recurrence. CONCLUSIONS: Right-sided colon cancer exhibits phenotypical differences with regard to left sided colon cancer. In stage III disease, left-sided colon cancer has a greater survival with a trend towards statistical significance. Overall, tumor location is a variable that should be taken into consideration in clinical studies of colon cancer. PMID- 29271229 TI - Imaging of osteoarthritis-recent research developments and future perspective. AB - In osteoarthritis research, imaging plays an important role in clinical trials and epidemiological observational studies. In this narrative review article, we will describe recent developments in imaging of osteoarthritis in the research arena, mainly focusing on literature evidence published within the past 3 years (2014-2017). We will primarily focus on MRI including advanced imaging techniques that are not currently commonly used in routine clinical practice, although radiography, ultrasound and nuclear medicine (radiotracer) imaging will also be discussed. Research efforts to uncover the disease process of OA as well as to discover a disease modifying OA drug continue. MRI continues to play a large role in these endeavors, while compositional MRI techniques will increasingly become important due to their ability to assess "premorphologic" biochemical changes of articular cartilage and other tissues in and around joints. Radiography remain the primary imaging modality for defining inclusion/exclusion criteria as well as an outcome measure in OA clinical trials, despite known limitations for visualization of OA features. Compositional MRI techniques show promise for predicting structural and clinical outcomes in OA research. Ultrasound can be a useful adjunct to radiography and MRI particularly for evaluation of hand OA. Newer imaging techniques such as hybrid PET/MRI may have a potential but require further research and validation. PMID- 29271230 TI - 18F-DOPA uptake parameters in glioma: effects of patients' characteristics and prior treatment history. AB - OBJECTIVE: In amino acid positron emission tomography brain tumour imaging, tumour-to-background uptake parameters are often used for treatment monitoring. We studied the effects of patients' characteristics and anticancer treatments on 18F-fluoro-l-phenylalanine uptake of normal brain and tumour lesions, with particular emphasis on temozolomide (TMZ) chemotherapy. METHODS: 155 studies from 120 patients with glioma were analysed. Average uptake of normal background (standardized uptake value, SUVbckgr) and basal ganglia (SUVbg), as well as tumour-to-brain ratios (TBR) were compared between positron emission tomography/CT studies acquired before (Group A, n = 48), after (Group B, n = 50) or during (Group C, n = 57) TMZ treatment, using analysis of variance. RESULTS: Overall, mean SUVbckgr and mean SUVbg were 1.06 +/- 0.26 and 2.12 +/- 0.47, respectively. Female had significantly higher SUVbckgr (p = 0.002) and SUVbg (p = 0.012) than male patients. Age showed a positive correlation with SUVbg (p = 0.001). In the overall cohort, there were significant effects of TMZ on SUVbckgr (p = 0.0237) and TBR (p = 0.0138). In particular, SUVbckgr was lower in Group C than in Group B (1.00 +/- 0.25 vs 1.14 +/- 0.31, p = 0.0173). Significant variations of SUVbckr could be observed in female only. TBR was significantly higher in Group C than in Group B (2.37 +/- 0.54 vs 2.06 +/- 0.38, p = 0.010). Variations of SUVbg between groups slightly missed significance (p = 0.0504). CONCLUSION: Temozolomide chemotherapy and patients' characteristics, including gender and age, affect physiological [18F]-fluoro-l-phenylalanine uptake and, consequently, the calculation of TBRs. Advances in knowledge: For the first time, the effects of past or concurrent temozolomide chemotherapy on brain physiological amino acid uptake have been investigated. Such effects are relevant and should be taken into account when evaluating tumour-to-background ratios. PMID- 29271232 TI - An Innovative Laboratory Procedure to Expand Chondrocytes with Reduced Dedifferentiation. AB - Objective In vitro expansion of chondrocytes is required for cartilage tissue engineering and clinical cell-based cartilage repair practices. However, the dedifferentiation of chondrocytes during in vitro expansion continues to be a challenge. This study focuses on identifying a cell culture surface to support chondrocyte expansion with reduced dedifferentiation. Design A less adhesive culture surface, non-tissue culture treated surface (NTC), was tested for its suitability for culturing chondrocytes. The cell expansion and the expression of chondrocyte markers were monitored for at least 2 passages on NTC in comparison with conventional tissue culture treated polystyrene surface (TCP). The ability of expanded chondrocytes to form cartilage tissues was evaluated using pellet culturing and subcutaneous implantation in nude mice. Results NTC supported bovine chondrocyte proliferation to a clinically relevant expansion requirement within 2 passages. Chondrocyte phenotypes were better maintained when cultured on NTC than on TCP. In vitro pellet culture studies showed that chondrocytes expanded on NTC expressed a higher level of chondrocyte extracellular matrix. Furthermore, the cells expanded on NTC or TCP were implanted subcutaneously as pellets in nude mice for 6 weeks. The recovered pellets showed cartilage-like tissue formation from cells expanded on NTC but not from the cells expanded on TCP. Conclusions This study presents an innovative and easy culturing procedure to expand chondrocytes with reduced dedifferentiation. This procedure has potential to be developed to expand chondrocytes in vitro for basic research, tissue engineering, and possibly for clinical applications. PMID- 29271231 TI - Overuse of CT and MRI in paediatric emergency departments. AB - The aim of this review is to survey CT and MRI overuse in the paediatric emergency department (ED) population. CT is one of the most important modalities employed in the ED. Not surprisingly, its high accuracy, rapid acquisition and availability have resulted in overuse. An obvious limitation of CT is ionizing radiation; in addition there are economic implications to overuse. Studies from the last two decades have shown increase in paediatric ED CT utilization in the first decade, reaching a plateau forming around 2008, followed by a decrease in the last decade. This decrease occurred in conjunction with campaigns raising awareness to the risks of radiation exposure. Although a trend of decrease in overuse have been observed, great variability has been shown across different facilities, as well as among physicians, with more pronounced overuse in non teaching and non-children dedicated EDs. The leading types of paediatric ED CTs are head and abdominal scans. Decision rules, such as PECARN for head injury and the Alvarado score for abdominal pain, as well as using alternative imaging modalities, have been shown to reduce CT overuse in these two categories. MRI has the obvious benefit of avoiding radiation exposure, but the disadvantages of higher costs, less availability and less tolerability in younger children. Although anecdotally paediatric ED MRI usage has increased in recent years, only scarce reports have been published. In our opinion, there is need to conduct up to-date studies covering paediatric CT and MRI overuse trends, usage variability and adherence to clinical protocols. PMID- 29271233 TI - 99mTc-sestamibi SPECT/CT for the characterization of renal masses: a pictorial guide. AB - In parallel to the increased utilization of cross-sectional imaging, the incidence of small renal masses has steadily risen in recent years. At the present time, anatomical imaging techniques are limited in their ability to differentiate benign from malignant renal masses. Moreover, renal mass biopsy has a high non-diagnostic rate, poor negative-predictive ability, and carries potential risks as well as substantial costs. As a result, benign renal masses are often unnecessarily resected for the false presumption of cancer. 99mTc sestamibi single photon emission computed tomography/computed tomography (SPECT/CT) is a molecular imaging test that allows for the differentiation of benign renal oncocytomas and hybrid oncocytomic/chromophobe tumours apart from malignant renal cell carcinomas on the basis of differences in mitochondrial content as well as multidrug resistant pump expression. Herein, we review the principles of 99mTc-sestamibi SPECT/CT administration and image interpretation for the purpose of renal mass characterization. PMID- 29271234 TI - Enhanced pre-operative axillary staging using intradermal microbubbles and contrast-enhanced ultrasound to detect biopsy sentinel lymph nodes in breast cancer: does molecular subtype matter? PMID- 29271235 TI - Prediction of histological grade of hepatocellular carcinoma using quantitative diffusion-weighted MRI: a retrospective multivendor study. AB - OBJECTIVE: To evaluate the usefulness of quantitative diffusion-weighted (DW) imaging acquired by multivendor magnetic resonance units for predicting grade of hepatocellular carcinoma (HCC). METHODS: 83 patients with 100 histologically diagnosed HCCs who underwent pre-operative liver DW imaging with b = 0 and1000 s mm-2 or b = 0 and800 s mm-2 at any of six institutions were included. Two radiologists independently measured the apparent diffusion coefficient (ADC) of the lesion as well as non-ADC parameters, such as the relative contrast ratio and the contrast-to-noise ratio (CNR) between the lesion and the liver parenchyma on high b-value DW images. The diagnostic performance of the DW parameters in discriminating poorly-differentiated HCCs was compared using receiver operating characteristic (ROC) analysis. RESULTS: The areas under the receiver operating characteristic curves for the CNR (86.4% [95% confidence interval (CI) (77.2 95.6] and 83.9% [95% CI 71.2-96.6] for b = 1000 and 800 s mm-2, respectively] and the relative contrast ratio (85.3% [95% CI 75.5-94.8] and 83.5% [95% CI 70.5 96.4]) tended to be superior to the ADC [71.1% [95% CI (56.9-85.2)] and 75.7% [95% CI (55.1-96.2)]; p < 0.05 for CNR vs ADC for b = 1000 s mm-2, but not significant for other parameters) for discrimination of poorly-differentiated HCCs. CONCLUSION: All DW parameters could discriminate HCC grade. Non-ADC parameters might be more useful than the ADC for predicting poorly-differentiated HCCs. Advances in knowledge: The utility of quantitative DW parameters for predicting HCC grade was demonstrated by using multivendor MR units. PMID- 29271236 TI - Effects of contrast administration on cardiac MRI volumetric, flow and pulse wave velocity quantification using manual and software-based analysis. AB - OBJECTIVE: The aim of the current study was to determine the effects of gadolinium contrast agent on right (RV) and left ventricular (LV) volumetric, aortic flow and pulse wave velocity (PWV) quantification using manual, semi automatic and fully automatic analysis techniques. METHODS: 61 participants free from known cardiovascular disease were recruited. Cardiac MR was performed on a 3 T scanner. A balanced steady-state free precession stack was acquired of the ventricles with phase contrast imaging of the aorta performed pre- and post administration of 10 ml 0.5 mmol ml-1 gadoterate meglumine. The images were analysed manually, and using a semi-automated and a fully automated technique. RESULTS: 54 completed the study. Gadolinium-based contrast administration significantly increase the signal-to-noise ratio (pre: 830 +/- 398 vs post: 1028 +/- 540, p = 0.003) with no significant change in contrast-to-noise ratio (pre: 583 +/- 302 vs post: 559 +/- 346, p = 0.54). On LV analysis, post-contrast analysis yielded significantly higher end systolic volume (54 +/- 20 vs 57 +/- 18 ml, p = 0.04), and lower ejection fraction (59 +/- 9 vs 57 +/- 8%, p = 0.023). On RV analysis, gadolinium contrast resulted in no significant differences. Similar results were seen using the semi-automated and fully-automated techniques but with a larger magnitude of difference. Conversely, using both manual and software analysis aortic flow and PWV quantification proved robust to the effects of contrast agent producing only small non-significant differences. CONCLUSION: Gadolinium contrast administration significantly alters LV endocardial contour detection with this effect amplified when using semi-automated analysis techniques. In comparison, RV and PWV analysis is robust to these effects. Advances in knowledge: Contrast administration alters LV quantification but not flow analysis. However, these differences are small. PMID- 29271238 TI - Diamond Stress View Radiograph for Thumb Metacarpophalangeal Hyperextension. AB - BACKGROUND: Successful surgical management of thumb carpometacarpal (CMC) arthritis requires treatment of coexisting metacarpophalangeal (MCP) hyperextension deformity when present. The surgeon's decision to offer thumb CMC arthritis patients the option of no additional treatment, MCP capsulodesis, or MCP arthrodesis relies on the severity of the MCP deformity measured in clinic. The authors present a novel patient-performed radiographic stress view to measure MCP hyperextension. METHODS: Fifty-seven thumbs in 30 consecutive patients offered thumb CMC arthroplasty were enrolled. Clinic goniometer measurements, patient-performed stress view radiographs, and intraoperative manual stress views of each MCP joint were documented for study. Paired samples t test was used to compare the differences between the preoperative measurements and intraoperative measurements of the right and left thumb groups. RESULTS: The clinic goniometer measurements were significantly different ( P = .0001) than the MCP stress view obtained while the patient was under anesthesia. The difference in the new patient-derived x-ray stress view was not statistically significant compared with the stress view under anesthesia in the left ( P = .91) or right ( P = .53) groups. CONCLUSIONS: This new patient-performed stress view of the MCP joint allows accurate, objective measurement of hyperextension to aide in the decision making and patient education for the need of additional MCP joint surgery when addressing thumb CMC arthritis. PMID- 29271237 TI - A high 18F-FDOPA uptake is associated with a slow growth rate in diffuse Grade II III gliomas. AB - OBJECTIVE: In diffuse Grade II-III gliomas, a high 3,4-dihydroxy-6-(18F)-fluoro-L phenylalanine (18F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUVmax)/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18F-FDOPA uptake in diffuse Grade II-III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year. METHODS: 20 patients (42 +/- 10 years, 10 female) with newly-diagnosed diffuse Grade II-III gliomas (17 with IDH mutation) were retrospectively included. All had a 18F-FDOPA PET, quantified with SUVmax ratio, along with a serial MRI enabling VDE determination. RESULTS: SUVmax ratio was above 1.8 in 5 patients (25%) all of whom had a VDE <4 mm/year (100%) and IDH mutation (100%). Moreover, a SUVmax ratio above 1.8 was associated with higher rates of VDE <4 mm/year in the overall population (45 vs 0%, p = 0.04) and also in the subgroup of patients with IDH mutation (45 vs 0%, p = 0.10). CONCLUSION: This pilot study shows that in diffuse Grade II-III gliomas, a high 18F-FDOPA uptake would be predictive of low tumour growth, with a different prognostic significance than IDH mutation. Advances in knowledge: 18F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse Grade II-III gliomas. PMID- 29271241 TI - What Are Staff Perceptions About Their Current Use of Emergency Departments for Long-Term Care Residents at End of Life? AB - The goal of this study was to examine current rates of resident deaths, Emergency Department (ED) use within the last year of life, and hospital deaths for long term care (LTC) residents. Using a mixed-methods approach, we compared these rates across four LTC homes in Ontario, Canada, and explored potential explanations of variations across homes to stimulate staff reflections and improve performance based on a quality improvement approach. Chart audits revealed that 59% of residents across sites visited EDs during the last month of life and 26% of resident deaths occurred in hospital. Staff expressed surprise at the amount of hospital use during end of life (EOL). Reflections suggested that clinical expertise, comfort with EOL communication, clinical resources (i.e., equipment), and family availability for EOL decision making could all affect nondesirable hospital transfers at EOL. Staff appeared motivated to address these areas of practice following this reflective process. PMID- 29271240 TI - Innovations in image-guided preoperative breast lesion localization. AB - Screening mammography increases detection of non-palpable breast lesions requiring image-guided localization prior to surgery. Accurate preoperative localization is crucial for successful surgical outcomes. Wire-guided localization is currently the most widely used localization method for non palpable breast lesions; however, this technique has multiple disadvantages including patient discomfort, possible wire transection and migration, suboptimal surgical incision placement due to wire location and limited scheduling flexibility decreasing operating room efficiency. As a result, promising new techniques including radioactive seed localization, non-radioactive radar localization and magnetic seed localization have been developed as alternatives. In this article, we provide an overview of these techniques and discuss their advantages, drawbacks and currently available outcome data. PMID- 29271239 TI - Hyperpolarized gas MRI in pulmonology. AB - Lung diseases have a high prevalence amongst the world population and their early diagnosis has been pointed out to be key for successful treatment. However, there is still a lack of non-invasive examination methods with sensitivity to early, local deterioration of lung function. Proton-based lung MRI is particularly challenging due to short T2* times and low proton density within the lung tissue. Hyperpolarized gas MRI is aan emerging technology providing a richness of methodologies which overcome the aforementioned problems. Unlike proton-based MRI, lung MRI of hyperpolarized gases may rely on imaging of spins in the lung's gas spaces or inside the lung tissue and thereby add substantial value and diagnostic potential to lung MRI. This review article gives an introduction to the MR physics of hyperpolarized media and presents the current state of hyperpolarized gas MRI of 3Headvasd and 129Xe in pulmonology. Key applications, ranging from static and dynamic ventilation imaging as well as oxygen-pressure mapping to 129Xe dissolved-phase imaging and spectroscopy are presented. Hyperpolarized gas MRI is compared to alternative examination methods based on MRI and future directions of hyperpolarized gas MRI are discussed. PMID- 29271243 TI - Exploring halide anion affinities to native cyclodextrins by mass spectrometry and molecular modelling. AB - The binding affinities of cyclodextrins complexation with chlorine (Cl-), bromine (Br-) and iodine (I-), were measured by mass spectrometric titrimetry, and the fitting of the binding constants was based on the concentration measurement of the cyclodextrin equilibrium. The binding constants (lg Ka) for alpha-, beta- or gamma-cyclodextrin with Cl- were 3.99, 4.03 and 4.11, respectively. The gas-phase binding affinity of halide anions for native cyclodextrins was probed by collision-induced dissociation. In collision-induced dissociation, the centre-of mass frame energy results revealed that in the gas phase, for the same type of cyclodextrin, the stability of the complexes decreased in order: Cl > Br > I, and for the same halide anion, the binding stability of the complex with alpha-, beta or gamma-cyclodextrin decreased in the order: gamma-cyclodextrin >beta cyclodextrin > alpha-cyclodextrin. The density functional theory calculations showed that halide anion binding on the primary face had a lower energy than the secondary face and hydrogen bonding was the main driving force for complex formation. The higher stability of the gamma-cyclodextrin complex with the Cl anion can be attributed to the higher charge density of the Cl anion and better flexibility of gamma-cyclodextrin. PMID- 29271242 TI - The role of personal and household members' substance use in health-related quality of life in women living with HIV/AIDS. AB - Advances in HIV treatments have led to a greater focus on health-related quality of life (HRQOL) among people living with HIV/AIDS. The current study examined factors associated with HRQOL among 378 women in HIV care. HRQOL was measured using a modified version of the 12-Item Short Form Health Survey; scores were derived for the mental and physical composite summaries (MCS and PCS). We measured personal alcohol use and drug use. Household members' substance use were assessed by asking participants about the alcohol/drug status of persons with whom they live. Multivariate generalized linear models were used to estimate the linear association between MCS and PCS scores and personal and household members' alcohol and drug use. We found lower MCS scores were significantly associated with personal alcohol use and living with someone with alcohol or/and drug problems. Lower PCS scores were not significantly associated with personal alcohol use or living with someone with alcohol or/and drug problems. Findings suggest that universal screening and targeted interventions for alcohol use by the patient or household members may offer potential strategies for improving mental health quality of life among women living with HIV/AIDS. PMID- 29271244 TI - Comparative digestibility of energy and ileal amino acids in yeast extract and spray-dried porcine plasma fed to pigs. AB - Two experiments were conducted to evaluate the digestible (DE) and metabolisable energy (ME), apparent (AID) and standardised ileal digestibility (SID) of amino acids (AA) in yeast extract (YE) and spray-dried porcine plasma (SDPP). In Experiment 1, 18 barrows (25.1 +/- 1.2 kg body weight [BW]) were randomly allotted to three treatments with six replicates per treatment. The DE and ME of YE was 20.64 and 19.31 MJ/kg, respectively, which were not significantly different with the DE and ME of SDPP (18.74 and 18.05 MJ/kg, respectively). In Experiment 2, six barrows (20.6 +/- 2.6 kg BW) fitted with ileal T-cannulas were fed three diets in a repeated 3-period Latin square design. For Met and Glu, the AID tended to be, while the SID was significantly higher (p < 0.05), in YE than in SDPP. The AID of Cys tended to be lower in YE (p = 0.07), while the SID of Phe tended to be higher in YE than in SDPP (p = 0.06). Accordingly, YE could be a potential substitute for SDPP as a superior protein ingredient in diets for pigs in terms of the available energy and AA digestibility. PMID- 29271245 TI - Effect on oxidative stress, hepatic chemical metabolizing parameters, and genotoxic damage of mad honey intake in rats. AB - A total of 66 male Wistar rats were used and six groups (control: 10 animals and experimental: 12 animals) were formed. While a separate control group was established for each study period, mad honey application to the animals in the experimental group was carried out with a single dose (12.5 g kg-1 body weight (b.w.); acute stage), at a dose of 7.5 g kg-1 b.w. for 21 days (subacute stage), and at a dose of 5 g kg-1 b.w. for 60 days (chronic stage). Tissue and blood oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), 4 hydroxynonenal (HNE), superoxide dismutase, catalase, glutathione (GSH) peroxidase, and glucose-6-phosphate dehydrogenase), hepatic chemical metabolizing parameters in the liver (cytochrome P450 2E1, nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase, nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase (CYTC), GSH S-transferase (GST), and GSH), and micronucleus and comet test in some samples were examined. Findings from the study showed that single and repeated doses given over the period increased MDA, NO, and HNE levels while decreasing/increasing tissue and blood antioxidant enzyme activities. From hepatic chemical metabolizing parameters, GST activity increased in the subacute and chronic stages and CYTC activity increased in the acute period, whereas GSH level decreased in the subacute stage. Changes in tail and head intensities were found in most of the comet results. Mad honey caused oxidative stresses for each exposure period and made some significant changes on the comet test in certain periods for some samples obtained. In other words, according to the available research results obtained, careless consumption of mad honey for different medical purposes is not appropriate. PMID- 29271246 TI - Evaluation of a faecal dysbiosis test for irritable bowel syndrome in subjects with and without obesity. AB - Biomarkers for irritable bowel syndrome (IBS) are demanded. An altered faecal microbiome has been reported in subjects with IBS and could be a valuable biomarker. This study evaluated the diagnostic properties of a new test for faecal dysbiosis, designed to distinguish IBS from healthy volunteers and compared the prevalence rates of dysbiosis related to IBS and morbid obesity. Subjects with and without morbid obesity and IBS were included. The faecal microbiota was assessed with GA-mapTM Dysbiosis Test (Genetic Analysis AS, Oslo, Norway). The test result was given as dysbiosis (yes/no). Comparisons were made between four groups: subjects with IBS and morbid obesity (IBS+/MO+); subjects without IBS and with morbid obesity (IBS-/MO+); subjects with IBS and without morbid obesity (IBS+/MO-); and healthy volunteers (IBS-/MO-).The prevalence rates of dysbiosis in the groups IBS+/MO+, IBS-/MO+, IBS+/MO- and IBS-/MO- were 18/28 (64%), 45/71 (63%), 31/63 (49%) and 38/91 (42%). Dysbiosis was more prevalent in subjects with morbid obesity, both in those with and without IBS, than in healthy volunteers (p values .04 and .006). Used as a diagnostic test for IBS in subjects without morbid obesity, the positive and negative likelihood ratios (LR) were 1.18 (0.83-1.67) and 0.87 (0.65-1.18), respectively, and in subjects with morbid obesity the LR were 1.01 (95% CI: 0.73-1.41) and 0.98 (0.54-1.75) respectively. The dysbiosis test was unsuitable as a diagnostic test for IBS. Dysbiosis was statistically significantly associated with morbid obesity, but not with IBS. PMID- 29271247 TI - "That little doorway where I could suddenly start shouting out": Barriers and enablers to the disclosure of distressing voices. AB - Hearing distressing voices is a key feature of psychosis. The time between voice onset and disclosure may be crucial as voices can grow in complexity. This study aimed to investigate barriers and enablers to early voice disclosure. In total, 20 voice hearers were interviewed, and Thematic Analysis was used to identify themes. Beliefs about the effect of disclosure on self and others acted as a barrier and enabler to voices being discussed. Voice hearing awareness should be increased among young people, the public, and care services. To support earlier disclosure, measures should be taken to increase skill among those likely to be the recipients of disclosure. PMID- 29271248 TI - Assessing amyotrophic lateral sclerosis prevalence in Norway from 2009 to 2015 from compulsory nationwide health registers. AB - OBJECTIVE: In Norway, diagnoses from specialist health care visits, drug prescriptions, and causes of deaths are registered in compulsory health registers. We aimed to determine amyotrophic lateral sclerosis (ALS) prevalence from 2009 to 2015 by combining these registers. METHODS: We validated the Norwegian Patient Registry (NPR) through hospital files, and linked it with the Norwegian Cause of Death Registry and the Norwegian Prescription Database. Poisson regression models were fitted for estimating gender ratios, time trends and possible interactions. Similar models were used for mortality data subtracted from the dataset. RESULTS: Eleven percent of patients with at least one ALS related entry in NPR did not have ALS. ALS prevalence could nevertheless be reliably estimated through ascertaining cases identified in two separate registers, or with at least two entries in NPR with first entry within four years prior to prevalence date. ALS prevalence remained stable, and was 7.6/100,000 (95% CI 6.9-8.4) at 31st December 2015. Mean male:female ratio was higher for prevalence (1.8; 95% CI 1.6-2.0) than for mortality (1.5; 95% CI 1.2-1.8) (p = 0.04). There were also significant regional differences in prevalence (p < 0.01) but not in mortality. CONCLUSIONS: Norwegian compulsory health registers provide reliable tools for ALS surveillance, and suggest gender and regional differences in survival after diagnosis. PMID- 29271249 TI - Effect of phosphodiesterase inhibitors on renal functions and oxidant/antioxidant parameters in streptozocin-induced diabetic rats. AB - The goal of this study was to investigate the effect of different phosphodiesterase inhibitors (PDEIs), on renal oxidant/antioxidant balance in diabetic rats. Our study was conducted on 125 rats, diabetes was induced in 100 rats by a single administration of streptozocin (STZ). Diabetic rats were divided into four equal groups. The first group was assigned as diabetic control, the remaining three groups were treated with pentoxifylline, sildenafil and milrinone via drinking water for 15 successive days, another group of 25 normal rats was assigned as non-diabetic control. Significant increase in plasma levels of glucose, urea, creatinine, malondialdehyde (MDA), and nitric oxide (NO) with a concomitant decrease in the levels of insulin, reduced glutathione (GSH), glutathione peroxidase (Gpx), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC) were observed in diabetic rats. These alterations were reverted back to near normal level after treatment with PDEIs. Our data seem to suggest a potential role of PDEIs in maintaining health in diabetes by reducing the progression of diabetic nephropathy. PMID- 29271250 TI - Barriers and Facilitators to Implementing the Uruguayan Dietary Guidelines in Everyday Life: A Citizen Perspective. AB - An in-depth understanding of the citizen's perception and behavior is needed for the development of targeted public policies and interventions that can successfully encourage people to shift their dietary patterns and contribute to the prevention of non-communicable diseases. The present work aimed to identify barriers and facilitators for the adoption of the new Uruguayan dietary guidelines from a citizen perspective. Twelve semistructured focus groups were conducted with a total of 91 people (81% female, age 18-64 years) from 3 Uruguayan cities. Findings identified several multifaceted barriers, including lack of value given to food, meals and cooking, taste preferences for unhealthy foods, the unsupportive social context in terms of household preferences, customs and social norms, and lack of control of the situation through insufficient food capabilities, time scarcity, and an adverse food market environment. The potential facilitators discussed in the focus groups were mainly related to policies and regulations to discourage consumption of unhealthful products and the provision of more education and information. In addition, respondents acknowledged the need for own actions in terms of seeking greater cooking skills and enjoyment, incorporating changes in their daily routines and promoting a more supportive social environment. Results suggest that supportive actions are needed to support citizen's adoption of the new Uruguayan dietary guidelines. PMID- 29271251 TI - Informed decision-making with and for people with dementia: Developing and pilot testing an education program for legal representatives (PRODECIDE). AB - Background People living with dementia are often appointed a legal representative, to support and protect their ethical and legal rights to informed healthcare decisions. However, legal representatives usually have no qualifications in healthcare. Objective The aim of this study was to explore decision-making processes with participation of legal representatives and, resulting from this, to develop and pilot test an education program for legal representatives in Germany. Methods We conducted interviews with legal representatives and senior citizens about decision-making processes in healthcare, with special focus on percutaneous endoscopic gastrostomy, physical restraints, and prescription of antipsychotics for people with dementia. We generated a curriculum based on systematic literature searches and the results of these interviews. We tested the education program for comprehensibility, feasibility, usability, and acceptance. Results Personal interviews with voluntary ( n = 12) and professional ( n = 12) representatives, and senior citizens ( n = 14) were conducted. Preferences, attitudes, and wishes regarding percutaneous endoscopic gastrostomy, physical restraints, and antipsychotics, and the process of decision-making, were heterogeneous. A structural approach is lacking. The education program proxy-decison-making (PRODECIDE) comprises four modules: (A) decision-making processes and methods; (B-D) evidence-based knowledge about percutaneous endoscopic gastrostomy, physical restraints, and antipsychotics. We conducted eight trainings with 47 legal representatives. PRODECIDE was well accepted. Comprehensibility of contents and materials was rated high. The program seems feasible for implementation. Conclusion PRODECIDE seems suitable to improve the decision-making processes of legal representatives in Germany. Implementation will be appropriate if efficacy is proven; a randomized controlled trial is currently underway. PMID- 29271252 TI - Use of antipsychotics and benzodiazepines for dementia: Time for action? What will be required before global de-prescribing? AB - Comparing how nations including the UK, USA, Canada, Australia and others have made attempts aimed at improving the care and treatment of dementia patients can provide useful insights into methods that prove successful. The UK-based 2009 Banerjee Report provided international leadership in addressing treatment and practices for dementia patients with an aim to reduce prescribing of antipsychotic drugs. A historical account of the different government policies and developments with the similar aims of de-prescribing are examined. Using Australia as one example, different national strategies are discussed in the context of those that have been tried and failed. In addition, policies that have successfully reduced the controversial current practices of overprescribing antipsychotics or related psychotropic drugs for dementia patients are presented. The evidence overwhelmingly indicates such treatments only exacerbate the disease or precipitate death - giving justification to the recent call for use of chemical restraints such as antipsychotics to be included under 'Elder Abuse' when considering law reform necessary to regulate compliance . PMID- 29271253 TI - Effects of oral exposure to sodium sulphite-treated deoxynivalenol (DON) contaminated maize on performance and plasma concentrations of toxins and metabolites in piglets. AB - The objective of the present study was to demonstrate the efficiency of the decontamination process applied to deoxynivalenol (DON)-contaminated maize by sodium sulphite (Na2SO3) treatment in vivo. Additionally, in vitro characterisation of the toxicity of the DON sulphonates (DONS 1, 2 and 3 denote structurally different forms), the resulting DON metabolites, on peripheral blood mononuclear cells (PBMC) should substantiate the inactivation of DON. In a piglet experiment, both DON-contaminated maize and -uncontaminated control maize either untreated (DON-, CON-) or Na2SO3-treated (DON+, CON+) were mixed into feed and fed for 42 d starting from weaning. The results showed that feed intake and daily weight gain of animals fed DON- were significantly lower compared to animals fed CON- and CON+, whereas group DON+ reached the control level or even exceeded it. The feed-to-gain ratio was unaffected (p = 0.45). Furthermore, DON concentrations in plasma markedly reflected the diets' DON concentrations. These were < 0.1, < 0.1, 5.4 and 0.8 mg/kg feed for CON-, CON+, DON- and DON+, and amounted to 0.3, 0.4, 33.0 and 9.3 ng/ml in plasma, respectively. Whereas DONS 2 and 3 were detected in the DON+ diet, only DONS 2 was recovered in plasma. Regarding the toxicity of DONS, no or much lower toxicity was found compared to DON. DONS 1 and Na2SO3 did not affect the viability of PBMC. At 32.71MUM DONS2 the viability was reduced by 50% and thus this compound was less toxic than DON by a factor of 73. Consequently, wet preservation of maize with Na2SO3 was an effective tool to avoid the adverse effects of DON on performance of piglets. PMID- 29271254 TI - Concurrent intradural meningioma and schwannoma at the same lumbar level in a patient without neurofibromatosis: a case report. AB - Spinal schwannomas coexisting with meningiomas in patient without neurofibromatosis are extremely rare lesions. Here we present a case of 59-year old patient with concurrent spinal meningioma and schwannoma at L1-L2 spinal level. This is the first case of the concurrent intradural tumours at the same lumbar level. PMID- 29271255 TI - Antiviral activity of aconite alkaloids from Aconitum carmichaelii Debx. AB - Four diterpenoid alkaloids, namely, (a) hypaconitine, (b) songorine, (c) mesaconitine and (d) aconitine, were isolated from the ethanol root extract of Aconitum carmichaelii Debx. The antiviral activities of these alkaloids against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) were evaluated. Antiviral activity test in vivo showed that compounds a and c, which were C19 diterpenoid alkaloids, showed inactivation efficacy values of 82.4 and 85.6% against TMV at 500 MUg/mL, respectively. By contrast, compound c presented inactivation activity of 52.1% against CMV at 500 MUg/mL, which was almost equal to that of the commercial Ningnanmycin (87.1% inactivation activity against TMV and 53.8% inactivation activity against CMV). C19-Diterpenoid alkaloids displayed moderate to high antiviral activity against TMV and CMV at 500 MUg/mL, dosage plays an important role in antiviral activities. This paper is the first report on the evolution of aconite diterpenoid alkaloids for antiviral activity against CMV. PMID- 29271256 TI - Measuring Intent to Aid of Lay Responders: Survey Development and Validation. AB - BACKGROUND: Increasing lay responder cardiopulmonary resuscitation and automated external defibrillator use during sudden cardiac arrest depends on an individual's choice. Investigators designed and piloted an instrument to measure the affective domain of helping behaviors by applying the theory of planned behavior (TPB) to better understand lay responders' intent to use lifesaving skills. METHOD: Questionnaire items were compiled into 10 behavioral domains informed by the TPB constructs followed by refinement via piloting and expert review. Two samples from an American Red Cross-trained lay-responder population ( N = 4,979) provided data for an exploratory (EFA, n = 235) and confirmatory (CFA, n = 198) factor analyses. EFA derived interitem relationships into factors and affective subscales. CFA yielded statistical validation of factors and subscales. RESULTS: The EFA identified four factors, aligned with the TPB constructs of attitudes, norms, confidence, and intention to act to explain 57% of interitem variance. The internal consistency of factor-derived subscales ranged between 0.71 and 0.91. Reduction of instrument items went from 47 to 32 (32%). The CFA yielded good model fit with the switching of the legal ramification item from the social norm to intention construct. CONCLUSION: The Intent to Aid (I2A) survey derived from this investigation aligned with the constructs of the TPB yielding four subscales. The I2A allows health education researchers to differentiate modalities and content impact on learner intention to act in a first aid (FA) emergency. I2A compliments cognitive and psychomotor measurements of learning outcomes. The experimental instrument aims to allow curricula developers and program evaluators a means of assessing the affective domain of human learning regarding intention-to-act in an FA emergency. In combination of with assessment of functional knowledge and essential skills, this instrument may provide curricula developers and health educators an avenue to better describe intention to act in an FA emergency. PMID- 29271257 TI - A two-dimensional numerical study of peristaltic contractions in obstructed ureter flows. AB - The flow of urine from the kidneys to the bladder is accomplished via peristaltic contractions in the ureters. The peristalsis of urine through the ureter can sometimes be accompanied, more specifically, obstructed to a certain degree, by entities such as kidney stones. In this paper, 2D axisymmetric computational fluid dynamics simulations are carried out using the commercial code ANSYS FLUENT[Formula: see text], to model the peristaltic movement of the ureter with and without stone. The peristaltic movement was assumed to be a sinusoidal wave on the boundary of the ureter with a specific physiological velocity. While the first part of the study considers flow in the ureter with prescribed peristaltic contractions in absence of any obstruction, the second part compares the effect of varying obstructions (0, 5, 15, and 35%) in terms of spherical stones of different sizes. Pressure contours, velocity vectors, and profiles of pressure gradient magnitudes and wall shear stresses are presented along one bolus of the ureter, during contraction and expansion of the ureteral wall, in order to understand backflow, trapping and reflux phenomena, as well as monitor the health of the ureteral wall in the presence of any obstruction. The 35% ureteral obstruction case resulted in a significant backflow at the inlet in comparison to the other cases, and also a wall shear stress that was up to 20x larger than the case without any obstruction. PMID- 29271258 TI - Real-world effectiveness, adherence and persistence among patients with type 2 diabetes mellitus initiating dulaglutide treatment. AB - OBJECTIVES: To assess glycemic effectiveness, adherence and persistence within 6 months of treatment initiation with dulaglutide, a once weekly GLP-1 receptor agonist, in a US real-world setting. METHODS: This retrospective claims analysis included adults (>=18 years) with T2DM from the HealthCore Integrated Research Database, who had HbA1c laboratory results around initiation and within 6 months after initiation. Glycemic control was assessed by change in HbA1c from pre initiation to post-initiation. Patients were considered adherent if their proportion of days covered (PDC) was >=0.80; persistence was measured as days of continuous therapy from initiation to 6 months after initiation with no gaps >45 days between fills. RESULTS: Of the 308 analyzed patients, the majority (n = 188; 61%) were adherent to dulaglutide (mean PDC 0.76; SD 0.26), with 115 patients (37%) discontinuing treatment. Mean persistence was 152 days/5 months. Mean HbA1c decreased from 8.49% (SD 1.70, median 8.20%) at baseline to 7.59% (SD 1.51, median 7.30%) at follow-up, corresponding to a mean HbA1c change of -0.90% (95% confidence interval [CI] -1.08 to -0.73; p < .01; median -0.70%). Patients who were adherent to or persistent with dulaglutide experienced larger reductions ( 1.14% and -1.12% respectively), as did those without prior GLP-1 RA use (-1.03%). The proportion of patients with HbA1c <7% increased from 18% to 40%. CONCLUSIONS: Dulaglutide was associated with a significant decrease in HbA1c levels 6 months after treatment initiation. Patients who adhered to or persisted with dulaglutide therapy, or were naive to GLP-1 RA use, experienced greater decreases in HbA1c levels. PMID- 29271259 TI - Ipilimumab for the treatment of metastatic prostate cancer. AB - INTRODUCTION: Immunotherapy with checkpoint inhibitors is beginning to be recognized as a valid weapon for the treatment of metastatic prostate cancer (PCa) when chemotherapy fails. Ipilimumab (ipi) is a fully humanized monoclonal antibody that blocks the activity of CTLA4. It also has a molecular weight of 148 kDa and is water-soluble at physiological pH. Ipi was first approved by the FDA for the treatment of malignant melanoma and is currently being studied in metastatic castration-resistant prostate cancer, with promising early results. Areas covered: The aim of this review is to collate the most significant preclinical and clinical studies available that look at ipi to propose new strategies for the future. Expert opinion: Additional studies are required to reduce toxicity and increase the activity of ipi in PCa. A possible strategy is to combine ipi with standard anti-cancer therapeutics such as vaccines, PDL1 inhibitors, antiandrogen drugs, and chemotherapy agents. Several initial results have suggested that combination strategies are useful to increase the activity in mCRPC, even if the toxicity of the treatment can increase. The activity of combined treatments is still not predictable, but considering the ongoing studies, we believe that they have good potential that will lead to the discovery of an optimal therapeutic strategy. PMID- 29271261 TI - Docking studies for melatonin receptors. AB - INTRODUCTION: Melatonin is a neurohormone that controls many relevant physiological processes beyond the control of circadian rhythms. Melatonin's actions are carried out by two main types of melatonin receptors; MT1 and MT2. These receptors are important, and not just because of the biological actions of its natural agonist; but also, because melatonin analogues can improve or antagonize their biological effect. Area covered: The following article describes the importance of melatonin as a biologically relevant molecule. It also defines the receptors for this substance, as well as the second messengers coupled to these receptors. Lastly, the article describes the amino acid residues involved in the docking process in both MT1 and MT2 melatonin receptors. Expert opinion: The biological actions of melatonin and their interpretations are becoming more relevant and therefore require the development of new pharmacological tools. Understanding the second messenger mechanisms involved in melatonin actions, as well as the characteristics of the docking of this molecule to MT1 and MT2 melatonin receptors, will permit the development of more selective agonists and antagonists which will help us to better understand this molecule as well to develop new therapeutic compounds. PMID- 29271262 TI - Pharmacological interventions for stress ulcer prophylaxis in critically ill patients: a mixed treatment comparison network meta-analysis and a recursive cumulative meta-analysis. AB - BACKGROUND: Proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RA), sucralfate and antacids are the commonly administered agents for stress ulcer prophylaxis (SUP) in critically ill patients. The authors of this paper have conducted a network meta-analysis to compare the efficacy of these agents in SUP. METHODS: Electronic databases were searched for randomized controlled trials, cohort studies and conference abstracts for studies comparing a SUP agent in critically ill patients to another active SUP agent or placebo. Overt, occult and clinically significant upper gastro-intestinal (UGI) bleeding, all-cause mortality, pneumonia, gastric colonization and ICU length of stay were considered as the outcome measures. A random effects model was used to generate pooled estimates. RESULTS: A total of 53 studies (4258 participants) were included. The pooled estimates were in favor of PPI and sucralfate for the overt UGI bleeding. PPI and H2RA bolus were associated with increased risk of gastric colonization and pneumonia. CONCLUSIONS: SUP in critically ill patients was not associated with any benefit with regard to clinically significant bleeding episodes. However, PPI and sucralfate significantly reduces overt UGI bleeding. On the contrary, PPI and H2RA bolus are associated with an increased risk of gastric colonization and pneumonia. PMID- 29271263 TI - Foodomics for human health: current status and perspectives. AB - INTRODUCTION: In the post-genomic era, the opportunity to combine and integrate cutting-edge analytical platforms and data processing systems allowed the birth of foodomics, 'a discipline that studies the Food and Nutrition domains through the application of advanced omics technologies to improve consumer's well-being, health, and confidence'. Since then, this discipline has rapidly evolved and researchers are now facing the daunting tasks to meet consumers' needs in terms of food traceability, sustainability, quality, safety and integrity. Most importantly, today it is imperative to provide solid evidence of the mechanisms through which food can promote human health and well-being. Areas covered: In this review, the complex relationships connecting food, nutrition and human health will be discussed, with emphasis on the relapses for the development of functional foods and nutraceuticals, personalized nutrition approaches, and the study of the interplay among gut microbiota, diet and health/diseases. Expert commentary: Evidence has been provided supporting the role of various omic platforms in studying the health-promoting effects of food and customized dietary interventions. However, although associated to major analytical challenges, only the proper integration of multi-omics studies and the implementation of bioinformatics tools and databases will help translate findings from clinical practice into effective personalized treatment strategies. PMID- 29271264 TI - Inhibition studies of Brucella suis beta-carbonic anhydrases with a series of 4 substituted pyridine-3-sulphonamides. AB - The two beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Brucella suis, BsuCA1 and BsuCA2, were investigated for their inhibition profile with a series of pyridine-3-sulphonamide derivatives incorporating 4-hetaryl moieties. BsuCA1 was effectively inhibited by these sulphonamides with inhibition constants ranging between 34 and 624 nM. BsuCA2 was less sensitive to these inhibitors, with KIs in the range of 62 nM - > 10 uM. The nature of the 4 substituent present on the pyridine ring was the main factor influencing the inhibitory profile against both isoforms, with 4-halogenophenylpiperazin-1-yl and 3,4,5-trisubstituted-pyrazol-1-yl derivatives showing the most effective inhibition. Some of these sulphonamides were most effective bacterial CA than human (h) CA I and II inhibitors, making them selective for the prokaryotic enzymes. Investigation of bacterial CA inhibitors may be relevant for finding antibiotics with a new mechanism of action compared to the clinically used agents for which substantial drug resistance emerged. PMID- 29271260 TI - Protein biomarkers for subtyping breast cancer and implications for future research. AB - INTRODUCTION: Breast cancer subtypes are currently defined by a combination of morphologic, genomic, and proteomic characteristics. These subtypes provide a molecular portrait of the tumor that aids diagnosis, prognosis, and treatment escalation/de-escalation options. Gene expression signatures describing intrinsic breast cancer subtypes for predicting risk of recurrence have been rapidly adopted in the clinic. Despite the use of subtype classifications, many patients develop drug resistance, breast cancer recurrence, or therapy failure. Areas covered: This review provides a summary of immunohistochemistry, reverse phase protein array, mass spectrometry, and integrative studies that are revealing differences in biological functions within and between breast cancer subtypes. We conclude with a discussion of rigor and reproducibility for proteomic-based biomarker discovery. Expert commentary: Innovations in proteomics, including implementation of assay guidelines and standards, are facilitating refinement of breast cancer subtypes. Proteomic and phosphoproteomic information distinguish biologically functional subtypes, are predictive of recurrence, and indicate likelihood of drug resistance. Actionable, activated signal transduction pathways can now be quantified and characterized. Proteomic biomarker validation in large, well-designed studies should become a public health priority to capitalize on the wealth of information gleaned from the proteome. PMID- 29271265 TI - Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease. AB - Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification. PMID- 29271266 TI - Human vaginal pH and microbiota: an update. AB - A woman's vaginal pH has many implications on her health and it can be a useful tool in disease diagnosis and prevention. For that reason, the further examination of the relationship between the human vaginal pH and microbiota is imperative. In the past several decades, much has been learned about the physiological mechanisms modulating the vaginal pH, and exogenous/genetic factors that may influence it. A unified, coherent understanding of these concepts is presented to comprehend their interrelationships and their cumulative effect on a woman's health. In this review, we explore research on vaginal pH and microbiota throughout a woman's life, vaginal intermediate cell anaerobic metabolism and net proton secretion by the vaginal epithelial, and the way these factors interact to acidify the vaginal pH. This review provides foundational information about what a microbiota is and its relationship with human physiology and vaginal pH. We then evaluate the influence of physiological mechanisms, demographic factors, and propose ideas for the mechanisms behind their action on the vaginal pH. PMID- 29271267 TI - LDL cholesterol levels after switch from atorvastatin to rosuvastatin. AB - OBJECTIVE: Initial statin therapy may not always adequately reduce elevated low density lipoprotein cholesterol (LDL-C) levels. Although alternative therapies are available, switching to another statin may be beneficial, especially for those at highest risk of cardiovascular disease and events. This study examined changes in LDL-C levels following a switch from 40/80 mg of atorvastatin (ATV) to 20/40 mg of rosuvastatin (RSV). METHODS: This retrospective cohort study used data from the MarketScan administrative claims databases linked to laboratory values. Patients with or at risk for atherosclerotic cardiovascular disease (ASCVD) who switched from ATV 40/80 mg to RSV 20/40 mg and had LDL-C values measured within 90 days before and 30-180 days after the switch were included. The change in LDL-C was quantified for each patient and summarized across all patients and within each switch pattern (e.g. ATV40 to RSV20). RESULTS: There was a significant mean (SD) decrease in LDL-C of 21% (30%) across the whole sample (N = 136) after switching from ATV to RSV. The greatest decrease occurred in patients who switched from ATV40 to RSV40 (N = 20; -29% [19%]; p < .001). Similar changes were observed overall and within each switch pattern when the analysis was limited to patients who were persistent on RSV in the post-switch period (N = 112; -24% [24%]; p < .001). CONCLUSIONS: Switching from ATV to RSV was associated with a significant decrease in LDL-C among high-risk patients. Switching between these two high-intensity statins may offer a viable alternative to other treatment modifications aimed at lowering LDL-C in this population. PMID- 29271268 TI - Triple fixed inhaled therapy in frequent chronic obstructive pulmonary disease exacerbators: potential advantages for various degrees of airways obstruction. AB - INTRODUCTION: Inhaled therapies are the therapeutic mainstay in stable chronic obstructive pulmonary disease (COPD). They are represented by long-acting bronchodilators (anticholinergics or beta2-agonists) and by inhaled corticosteroids, currently available as a monotherapy or as combination therapies in one inhaler. Combinations of anticholinergics and beta2 agonists or beta2 agonists and inhaled corticosteroids are widely used per the prescription guidelines. The advantage of them are related with higher adherence and better acceptability by the patients as compared to both components dosed with individual inhalers. Bronchodilator combinations have also been demonstrated to exhibit a superior efficacy due to their synergistic mechanism of action when compared to either monotherapy. Triple therapies with anticholinergic-beta2 agonist-inhaled corticosteroid have been under investigation over the last few years and recently one such product became available in the EU for the treatment of stable COPD. Areas covered: The the FULFIL trial (Lung FUnction and quality of LiFe assessment in COPD with closed trIpLe therapy) investigated the efficacy and safety of fluticasone/vilanterol/umeclidinium once daily therapy in COPD patients. Expert opinion: The results discussed in this paper support the use of this combination in advanced COPD but also in earlier stages in patients with frequent exacerbation. However further and more long-term assessments are required. PMID- 29271269 TI - Prior disclosure and emotional expression: Interactive effects on post-traumatic stress disorder symptoms. AB - : Background Previous research has revealed mixed findings with regard to the effects of disclosure on trauma recovery. More recently, studies on psychological trauma have found associations among religion, meaning, and health. This study investigated prior disclosure as a moderator for the association between religious emotional expression and adaptive trauma processing, as measured by post-traumatic stress disorder (PTSD) symptoms. Methods Using Pennebaker's written emotional expression paradigm, 105 participants were assigned to either a conventional trauma-writing condition or religious trauma-writing condition. PTSD symptoms were assessed at baseline and again at one-month post writing. Results A two-way interaction was found between prior disclosure and writing condition on PTSD symptoms at follow-up. For the religious trauma-writing condition only, there was a significant difference between low versus high disclosure participants in PTSD symptoms at follow-up, such that low prior disclosure participants registered fewer PTSD symptoms than high prior disclosure participants, while prior disclosure did not have such effect in the conventional trauma-writing condition. LIMITATIONS: This two-way interaction may be further qualified by other important psychosocial variables, such as differences in personality, coping style, social support, or use of prayer as a form of disclosure, which were not assessed in this study. Conclusion Religious emotional expression may encourage adaptive trauma processing, especially for individuals with low prior disclosure. These findings encourage further investigation of the conditions under which disclosure and religion may be a beneficial factor in trauma adaptation and treatment. PMID- 29271270 TI - Nomophobia: an emerging issue in medical institutions? AB - BACKGROUND: Nomophobia is No Mobile Phone Phobia - the fear of being without a mobile device or beyond mobile phone contact. The time and money wastage by medical students is a negative aspect of mobile phone dependence. This time can be utilized for academic and recreational activities. AIM: To assess the prevalence of Nomophobia in the students in 1st year MBBS. METHODS: Study area: A medical college in Pune city. STUDY PERIOD: December 2015 to February 2016. A cross-sectional study was carried out on all the students of 1st year MBBS. A predesigned and pretested questionnaire was used to collect data. Data were analyzed statistically by simple proportions using SPSS v20. RESULTS: A total of 145 students were monitored according to inclusion and exclusion criteria. Amongst all the participants, 45.5% were males (66/145) and 54.5% were females (79/145). Mild Nomophobia was found in 17.9% students whereas 60% had moderate and 22.1% had severe Nomophobia. Amongst the males, 56.06% and 24.24% had moderate and severe Nomophobia, respectively while in females, moderate and severe Nomophobia was found to be 63.25% and 20.25%, respectively. CONCLUSION: Nomophobia is found to be prevalent in students of 1st year MBBS. PMID- 29271271 TI - Cost-effectiveness of grass pollen subcutaneous immunotherapy (SCIT) compared to sublingual immunotherapy (SLIT) and symptomatic treatment in Austria, Spain, and Switzerland. AB - BACKGROUND: While specific immunotherapy (SIT) has been proven to be cost effective for the treatment of allergic rhinitis compared to symptomatic treatment, there is a lack of European studies in which sublingual (SLIT) and subcutaneous (SCIT) immunotherapy were compared. The present analysis is focused on the cost-effectiveness of SCIT compared to SLIT and symptomatic treatment of grass pollen allergy in Austria, Spain, and Switzerland. It will address specific properties of the underlying healthcare systems. METHODS: The investigation is based on a previously published health economic model calculation. This was designed as a Markov model with pre-defined health stages and a duration of 9 years covering specific preparations for SCIT (Allergovit) and SLIT (Oralair). The effectiveness was assessed as symptom-score based quality-adjusted life years (QALYs). Additionally, total cost has been determined as well as the cost effectiveness of SCIT. The robustness of model results was proved in further sensitivity analyses. RESULTS: With regard to the effectiveness of both SCIT and SLIT, preparations were dominant compared to pharmacological symptomatic therapy. Both strategies were associated with additional cost, but, combined with the results on effectiveness, both have to be regarded as cost-effective. A direct comparison of the SCIT (Allergovit) and SLIT (Oralair) showed lower total costs of SCIT vs SLIT for Austria, Spain, and Switzerland (?1,368 vs ?2,012, ?2,229 vs ?2,547, and ?1,901 vs ?2,220) and superior effectiveness (SCIT =8.02 QALYs; SLIT =7.98 QALYs; and symptomatic therapy =7.90 QALYs). CONCLUSION: In patients with allergic rhinitis, SIT offers cost-effective treatment options compared to symptomatic treatment. When comparing SCIT (Allergovit) and SLIT (Oralair), SCIT was dominant in terms of QALYs as well as costs, in particular due to a slightly higher patient compliance and lower drug costs. PMID- 29271272 TI - Identification of the potential targets for keloid and hypertrophic scar prevention. AB - PURPOSE: We aimed to explore the molecular mechanism of pathologic skin scar and novel target for scar prevention. MATERIALS AND METHODS: Microarray data derived from keloid and hypertrophic scar were downloaded from ArrayExpress database. The common differentially expressed genes (DEGs) in keloid and hypertrophic scar samples were investigated by function and pathway analysis. The protein-protein interaction (PPI) network was constructed and the modules were screened. RESULTS: There were a total of 485 DEGs related with skin scar, including 247 up-regulated genes and 238 down-regulated genes. The up-regulated genes were closely related with Rho protein signal transduction, cytoskeleton organization, and Ras protein signal transduction related biological process. The down-regulated genes were enriched in sterol metabolic process, fatty acid metabolic process, and steroid metabolic process. PPI network was constructed with 680 protein pairs and modules 1 and 2 were screened out. Fos proto-oncogene (FOS) and early growth response 1 (EGR1) were significant transcriptional factors in the two modules. CONCLUSIONS: FOS and EGR1 may be potential targets for skin scar prevention. PMID- 29271274 TI - Ovarian response to controlled ovarian stimulation in women with different polycystic ovary syndrome phenotypes. AB - Controlled ovarian stimulation (COH) in PCOS is a challenge for fertility expert both ovarian hyperstimulation syndrome (OHSS) and oocytes immaturity are the two major complication. Ovarian response to COH vary widely among POCS patients and while some patients are more likely to show resistance to COH, other experienced an exaggerated response. The aim of our study is to investigate a possible correlation between PCOS phenotypes and the variety of ovarian response to COH and ART outcomes in patients with different PCOS phenotypes. We retrospectively analyzed a total of 71 cycles performed in 44 PCOS infertile patients attending ART at Centre of Infertility and Assisted Reproduction of Pisa University between January 2013 and January 2016. Patientsundergoing IVF with GnRH-antagonist protocol and 150-225 UI/days of recombinant FSH; triggering was carried out using 250 mg of recombinant hCG or a GnRH analogous on the basis of the risk to OHSS. We observed that Phenotype B had a tendency to have a greater doses of gonadotropins used respect to all phenotypes. Phenotype A group showed a greater serum estrogen levels compared to all phenotypes groups, a greater number of follicles of diameter between 8-12 mm found by ultrasound on the day of triggering and a greater mean number of freeze embryo. Additionally serum AMH and antral follicles count (AFC) follow the same trend in the different phenotypes ad they were significantly higher in phenotype A and in phenotype D. In conclusion this study shows that the features of PCOS phenotypes reflect the variety of ovarian response to COH as well as the risks to develop OHSS. Serum AMH and AFC are related to the degree of ovulatory dysfunction making these 'added values' in identifying the different PCOS phenotypes. Phenotype A seems to be the phenotype with the higher risk to develop OHSS and the use of GnRH as a trigger seems to improve oocyte quality. To classify PCOS phenotype at diagnosis might help clinicians to identify patients at greater risk of OHSS, customize therapy and subsequently plan the trigger agent. PMID- 29271273 TI - Mindfulness as a protective factor against depressive symptoms in people with fibromyalgia. AB - BACKGROUND: Depressive symptoms complicate pain management for people with FM, with adverse consequences such as a greater need for pain medications and limited pain coping strategies. Determining risks and protective factors associated with depressive symptoms in persons with FM could inform the development and implementation of mental health interventions. AIMS: To formulate and test a behavioral activation model of depression with mindfulness as a protective factor for people with FM. METHODS: We conducted an online cross-sectional survey with 117 adults with FM from community and clinic networks. Path analysis was used to assess the relationships of pain intensity, perceived stress, activity interference, pain catastrophizing and mindfulness with depressive symptoms. RESULTS: Mindfulness has a negative direct association with depressive symptoms and a negative indirect association with depressive symptoms through perceived stress, activity interference and pain catastrophizing. Perceived stress, activity interference and pain catastrophizing had direct associations with depressive symptoms. Finally, perceived stress, activity interference and pain catastrophizing had indirect associations with depressive symptoms through pain intensity. CONCLUSIONS: Mindfulness seems to play an important role as a protective factor against the negative effects of stress and depression among people with FM and should be included in mental health interventions for chronic pain. PMID- 29271275 TI - Usefulness of psychoeducational intervention in chronic insomnia: an actigraphic study. AB - BACKGROUND: Chronic Insomnia is a severe and disabling condition characterized by difficulty in initiating or maintaining sleep, waking up too early, despite adequate opportunity and circumstances for sleep. Maladaptive thoughts and dysfunctional beliefs about sleep are considered crucial factors in developing and perpetuating this disorder. AIMS: The aim of the study was to explore the usefulness, in patients with chronic insomnia, of a one-session psychoeducational intervention on sleep-related maladaptive thoughts and beliefs, and on sleep perception. METHODS: Thirty-eight patients with chronic insomnia were enrolled in the study and randomly assigned to receive psychoeducational intervention (PI+) or to act as controls (PI-). Patients wore an actigraph and compiled a sleep diary for 14 d. After the first 7 d, only PI+ patients received one session of psychoeducational intervention. RESULTS: A significant reduction of sleep related preoccupations, a reduction of dysfunctional beliefs about sleep, and an improvement of subjective perception of sleep were observed in the PI+ group, but not in the PI- group. No significant modification was observed for objective total sleep time. CONCLUSIONS: Our results suggest that one-session psychoeducational intervention is associated with a decrease of sleep-related maladaptive thoughts and beliefs, and with an improvement on subjective sleep perception. PMID- 29271276 TI - Delivery of cognitive-behaviour therapy for psychosis: a service user preference trial. AB - BACKGROUND: Clinical guidelines recommend cognitive behaviour therapy (CBT) for people with psychosis, however, implementation is poor and not everyone wishes to engage with therapy. Understanding service user (SU) preferences for receiving such treatments is a priority for services. AIMS: To explore SU preferences and outcomes of different methods of delivering CBT for psychosis. METHOD: SUs experiencing psychosis could choose between treatment as usual (TAU); TAU plus telephone-delivered CBT with self-help, CBT recovery manual (TS); high support CBT (HS - TAU plus TS plus group sessions) or randomisation. Participants received their option of choice and were followed-up on several outcomes over 9 and 15 months. RESULTS: Of 89 people recruited, three chose to be randomised and 86 expressed a treatment preference (32 chose TAU, 34 chose TS, 23 chose HS). There were few differences between those who chose therapy compared to those who chose TAU. Those who had more positive impacts from their symptoms were significantly more likely to choose TAU. CONCLUSIONS: Most people had strong preferences about treatment delivery and a substantial number did not wish to receive additional therapy. These findings have to be considered when planning and allocating resources for people with psychosis. PMID- 29271277 TI - Mental health service user participation in Chinese culture: a model of independence or interdependence? AB - BACKGROUND: Current models of user participation in mental health services were developed within Western culture and thus may not be applicable to Chinese communities. AIMS: To present a new model of user participation, which emerged from research within a Chinese community, for understanding the processes of and factors influencing user participation in a non-Western culture. METHOD: Multiple qualitative methods, including focus groups, individual in-depth interviews, and photovoice, were applied within the framework of constructivist grounded theory and collaborative research. RESULTS: Diverging from conceptualizations of user participation with emphasis on civil rights and the individual as a central agent, participants in the study highlighted the interpersonal dynamics between service users and different players affecting the participation intensity and outcomes. They valued a reciprocal relationship with their caregivers in making treatment decisions, cooperated with staff to observe power hierarchies and social harmony, identified the importance of peer support in enabling service engagement and delivery, and emphasized professional facilitation in advancing involvement at the policy level. CONCLUSIONS: User participation in Chinese culture embeds dynamic interdependence. The proposed model adds this new dimension to the existing frameworks and calls for attention to the complex local ecology and cultural consistency in realizing user participation. PMID- 29271278 TI - The effect of vitamin D supplementation on insulin resistance, visceral fat and adiponectin in vitamin D deficient women with polycystic ovary syndrome: a randomized placebo-controlled trial. AB - INTRODUCTION: Low plasma 25-hydroxy-vitamin D (25OHD) is associated with polycystic ovary syndrome (PCOS). Vitamin D deficiency may contribute to the development of insulin resistance, visceral fat and low level of adiponectin which are common feature in PCOS women. This study aimed to evaluate the effect of vitamin D supplementation on insulin resistance, visceral fat, and adiponectin in hypovitaminosis D women with polycystic ovary syndrome. METHODS: In this randomized, placebo-controlled clinical trial, 44 PCOS women aged 20-38 years with plasma 25OHD <20 ng/mL were randomized in the intervention or placebo groups and followed for 8 weeks. Participants received 50,000 IU of oral vitamin D3 once weekly in the intervention group or placebo. The visceral adipose tissue, Insulin resistance (HOMA-IR), HOMA-B, QUICKI, and circulating adiponectin were compared before and after the intervention within groups using paired tests and the mean changes were analyzed between two groups by independent t-test. RESULTS: Of 44 eligible participates, 36 patients (81.8%) completed the study. After 8 week intervention, vitamin D supplementation compared to the placebo group significantly decreased fasting plasma glucose (FPG) (7.67 +/- 7.66 versus 1.71 +/- 7.50 mg/dL, p = .001) and significantly increased homeostasis model of assessment-estimated B cell function (HOMA-B) (129.76 +/- 121.02 versus 48.32 +/- 128.35, p = .014), Adiponectin (5.17 +/- 8.09 versus -5.29 +/- 8.64 mg/dL, p = .001), and serum vitamin D level (28.24 +/- 6.47 versus 3.55 +/- 4.25 ng/mL, p = .001). CONCLUSION: Vitamin D supplementation in vitamin D deficient women with PCOS, improved the FPG, HOMA-B, Adiponectin, and serum vitamin D level. PMID- 29271279 TI - Cost-effectiveness analysis of bariatric surgery for morbid obesity in Belgium. AB - AIMS: This study presents the cost-effectiveness analysis of bariatric surgery in Belgium from a third-party payer perspective for a lifetime and 10-year horizon. MATERIALS AND METHODS: A decision analytic model incorporating Markov process was developed to compare the cost-effectiveness of gastric bypass, sleeve gastrectomy, and adjustable gastric banding against conventional medical management (CMM). In the model, patients could undergo surgery, or experience post-surgery complications, type 2 diabetes, cardiovascular diseases, or die. Transition probabilities, costs, and utilities were derived from the literature. The impact of different surgical methods on body mass index (BMI) level in the base-case analysis was informed by the Scandinavian Obesity Surgery Registry and the Swedish Obese Subject (SOS) study. Healthcare resource use and costs were obtained from Belgian sources. A base-case analysis was performed for the population, the characteristics of which were obtained from surgery candidates in Belgium. RESULTS: In the base-case analysis over a 10-year time horizon, the increment in quality-adjusted life-years (QALYs) gained from bariatric surgery vs CMM was 1.4 per patient, whereas the incremental cost was ?3,788, leading to an incremental cost-effectiveness ratio (ICER) of ?2,809 per QALY. Over a lifetime, bariatric surgery produced savings of ?9,332, an additional 1.1 life years and 5.0 QALYs. Bariatric surgery was cost-effective at 10 years post-surgery and dominant over conventional management over a lifetime horizon. LIMITATIONS: The model did not include the whole scope of obesity-related complications, and also did not account for variation in surgery outcomes for different populations of diabetic patients. Also, the data about management of patients after surgery was based on assumptions and the opinion of a clinical expert. CONCLUSIONS: It was demonstrated that a current mix of bariatric surgery methods was cost-effective at 10 years post-surgery and cost-saving over the lifetime of the Belgian patient cohort considered in this analysis. PMID- 29271280 TI - Validity of the Male Depression Risk Scale in a representative Canadian sample: sensitivity and specificity in identifying men with recent suicide attempt. AB - BACKGROUND: Clinical practice and literature has supported the existence of a phenotypic sub-type of depression in men. While a number of self-report rating scales have been developed in order to empirically test the male depression construct, psychometric validation of these scales is limited. AIM: To confirm the psychometric properties of the multidimensional Male Depression Risk Scale (MDRS-22) and to develop clinical cut-off scores for the MDRS-22. METHOD: Data were obtained from an online sample of 1000 Canadian men (median age (M) = 49.63, standard deviation (SD) = 14.60). Confirmatory factor analysis (CFA) was used to replicate the established six-factor model of the MDRS-22. RESULTS: Psychometric values of the MDRS subscales were comparable to the widely used Patient Health Questionnaire-9. CFA model fit indices indicated adequate model fit for the six factor MDRS-22 model. ROC curve analysis indicated the MDRS-22 was effective for identifying those with a recent (previous four-weeks) suicide attempt (area under curve (AUC) values = 0.837). The MDRS-22 cut-off identified proportionally more (84.62%) cases of recent suicide attempt relative to the PHQ-9 moderate range (53.85%). CONCLUSION: The MDRS-22 is the first male-sensitive depression scale to be psychometrically validated using CFA techniques in independent and cross nation samples. Additional studies should identify differential item functioning and evaluate cross-cultural effects. PMID- 29271281 TI - An evaluation of flipped e-learning experiences. AB - AIM: The "flipped" classroom is an educational strategy gaining popularity for its growing evidence base that suggests it may successfully improve learning outcomes. Also known as reverse instruction, this approach has been typically implemented and studied in in-person post-secondary settings. The utilization of a flipped approach in the healthcare education literature has been examined in a wide range of contexts, but little has been written regarding continuing professional development (CPD). Therefore, with success in other contexts there is potential for the flipped classroom approach to enhance student satisfaction, learner engagement, and learning outcomes in the context of online education for CPD. METHODS: In this paper, we describe the structure and format of such a course using a qualitative case study framework. RESULTS: This study contributes to a more comprehensive understanding of effective ways of overcoming distributed learning challenges in online CPD using a flipped approach. PMID- 29271282 TI - Implementation of a Psychosocial Intervention Program for Working Caregivers. AB - The overall aim of this pilot study was to examine the feasibility and acceptability of a multicomponent, psychosocial intervention specifically designed to meet the unique needs of caregivers who are balancing caregiving duties with work responsibilities. Seventy-one family caregivers employed at a private, nonprofit institution in South Florida were randomized to either the Caregiver Workstation condition ( n = 35) or a control condition ( n = 36). Sixty two caregivers completed the 5-month follow-up. Our results indicate that an intervention tailored to the time demands of a working caregiver is feasible, acceptable to caregivers, and has the potential to have positive long-term effects. Currently, there are limited data available regarding the benefits of employer programs for caregivers or the type of programs caregivers find most useful. This pilot study is the first step in developing a working caregiver intervention program that can be implemented on a broad-scale basis. PMID- 29271283 TI - Charged residues on the side of the nucleosome contribute to normal Spt16-gene interactions in budding yeast. AB - Previous work in Saccharomyces cerevisiae identified three residues located in close proximity to each other on the side of the nucleosome whose integrity is required for proper association of the Spt16 component of the FACT complex across transcribed genes. In an effort to gain further insights into the parameters that control Spt16 interactions with genes in vivo, we tested the effects of additional histone mutants on Spt16 occupancy across two constitutively transcribed genes. These studies revealed that mutations in several charged residues in the vicinity of the three residues originally identified as important for Spt16-gene interactions also significantly perturb normal association of Spt16 across genes. Based on these and our previous findings, we propose that the charge landscape across the region encompassed by these residues, which we refer to as the Influences Spt16-Gene Interactions or ISGI region, is an important contributor to proper Spt16-gene interactions in vivo. PMID- 29271284 TI - Amygdala reactivity to fearful faces correlates positively with impulsive aggression. AB - Facial expressions robustly activate the amygdala, a brain structure playing a critical role in aggression. Whereas previous studies suggest that amygdala reactivity is related to various measures of impulsive aggression, we here estimate a composite measure of impulsive aggression and evaluate whether it is associated with amygdala reactivity to angry and fearful faces. We estimated amygdala reactivity with functional magnetic resonance imaging in 47 men with varying degree of aggressive traits (19 incarcerated violent offenders and 28 healthy controls). We modeled a composite "impulsive aggression" trait construct (LVagg) using a linear structural equation model, with a single latent variable capturing the shared correlation between five self-report measures of trait aggression, anger and impulsivity. We tested for associations between amygdala reactivity and the LVagg, adjusting for age and group. The LVagg was significantly positively associated with amygdala reactivity to fearful (p = 0.001), but not angry faces (p = 0.9). We found no group difference in amygdala reactivity to fearful or angry faces. The findings suggest that that amygdala reactivity to fearful faces is represented by a composite index of impulsive aggression and provide evidence that impulsive aggression is associated with amygdala reactivity in response to submissive cues, i.e., fearful faces. PMID- 29271285 TI - FA and cRGD dual modified lipid-polymer nanoparticles encapsulating polyaniline and cisplatin for highly effective chemo-photothermal combination therapy. AB - A combination of chemotherapy and photothermal therapy as a promising strategy has exhibited noticeable therapeutic effect on cancer therapy. To ensure the exertion of synergistic effect on a tumor region, a multifunctional vehicle for selectively delivering therapeutic agent into tumor cells is highly desirable. Thus, folate-poly (ethylene glycol)-distearoylphosphatidylcholine (FA-PEG-DSPE), cRGD [cyclic (Arg-Gly-Asp-D-Phe-Lys)]-PEG-DSPE and lecithin were employed to develop dual modified nanoparticles (FA/cRGD-PNPs) encapsulating polyaniline and cisplatin by a film-ultrasonic dispersion method. The FA/cRGD-PNPs showed a uniform size of 102.7 nm, remarkable stability and monodispersity, and highly localized temperature respond. Compared to chemo or photothermal treatment alone, the combined treatment on cells in vitro significantly suppressed the survival rate of MDA-MB-231 cells (1.87%) and MGC-803 cells (2.37%) treated for 48 h. The results further indicated the induced cell apoptosis rate of MDA-MB-231 cells reached to 92.6% with treatment for 24 h. Hence, our research highlights the great potential in drug delivery and the combination of chemotherapy and photothermal therapy. PMID- 29271286 TI - Influences on Care for Others: Attachment Security, Personal Suffering, and Similarity Between Helper and Care Recipient. AB - Research indicates that dispositional attachment security fosters empathy, and that short-term increases in security ("security priming") increase empathy and willingness to help others. In two experiments, we examined effects of recalling one's own vulnerability ( feeling hurt by a relationship partner) and security priming on empathy for a recipient in need. In Study 1, the recipient was a middle-aged homeless woman (low similarity to participants); in Study 2, the recipient was a college-aged woman whose boyfriend had been unfaithful (high similarity to participants). In both studies, hurt feelings influenced participants' empathy, but the nature of the influence varied as a function of target-participant similarity. In Study 1, hurt feelings decreased empathy and increased caregiving avoidance. In Study 2, hurt feelings not only increased empathy but also aroused caregiving anxiety. Furthermore, security priming weakened defensive barriers against helping: In Study 1, it reduced caregiving avoidance, and in Study 2, it reduced caregiving anxiety. PMID- 29271287 TI - Elucidating the Dark Side of Envy: Distinctive Links of Benign and Malicious Envy With Dark Personalities. AB - Researchers have recently drawn a contrast between two forms of envy: benign and malicious envy. In three studies (total N = 3,123), we challenge the assumption that malicious envy is destructive, whereas benign envy is entirely constructive. Instead, both forms have links with the Dark Triad of personality. Benign envy is associated with Machiavellian behaviors, whereas malicious envy is associated with both Machiavellian and psychopathic behaviors. In Study 1, this pattern emerged from meta-analyzed trait correlations. In Study 2, a manipulation affecting the envy forms mediated an effect on antisocial behavioral intentions. Study 3 replicated these patterns by linking envy to specific antisocial behaviors and their impact on status in the workplace. Together, our correlational and experimental results suggest that the two forms of envy can both be malevolent. Instead of evaluating envy's morality, we propose to focus on its functional value. PMID- 29271288 TI - Repeated social defeat induces transient glial activation and brain hypometabolism: A positron emission tomography imaging study. AB - Psychosocial stress is a risk factor for the development of depression. Recent evidence suggests that glial activation could contribute to the development of depressive-like behaviour. This study aimed to evaluate in vivo whether repeated social defeat (RSD) induces short- and long-term inflammatory and metabolic alterations in the brain through positron emission tomography (PET). Male Wistar rats ( n = 40) were exposed to RSD by dominant Long-Evans rats on five consecutive days. Behavioural and biochemical alterations were assessed at baseline, day 5/6 and day 24/25 after the RSD protocol. Glial activation (11C PK11195 PET) and changes in brain metabolism (18F-FDG PET) were evaluated on day 6, 11 and 25 (short-term), and at 3 and 6 months (long-term). Defeated rats showed transient depressive- and anxiety-like behaviour, increased corticosterone and brain IL-1beta levels, as well as glial activation and brain hypometabolism in the first month after RSD. During the third- and six-month follow-up, no between-group differences in any investigated parameter were found. Therefore, non-invasive PET imaging demonstrated that RSD induces transient glial activation and reduces brain glucose metabolism in rats. These imaging findings were associated with stress-induced behavioural changes and support the hypothesis that neuroinflammation could be a contributing factor in the development of depression. PMID- 29271289 TI - Insertion mechanics of bioinspired needles into soft tissues. AB - INTRODUCTION: Most studies to date confirm that any increase in the needle insertion force increases the damage to the tissue. When it comes to brain tissue, even minor damage can cause a long-lasting traumatic brain injury. Thus there is a great demand for innovative minimally invasive needles among the medical community. In our previous studies a novel bioinspired needle design with specially designed barbs was used to perform insertion tests into Polyvinyl chloride (PVC) tissue-mimicking gels, in which it decreased the insertion force by as much as 25%. MATERIAL AND METHODS: In this work, bioinspired needles were designed using a CAD software, and were then manufactured using a 3 D printer. The insertion tests into bovine brain and liver were then performed to further investigate the performance of our bioinspired needles in real tissues. RESULTS: Our results show that there was a 10-25% decrease in the insertion force for insertions into bovine brain, and a 35-45% reduction in the insertion force for insertions into bovine liver using the proposed bioinspired needles. CONCLUSION: The reduction in the insertion force is due to the decrease in the friction force of the bioinspired needle with the bovine tissues, and its results are consistent with our previous results. PMID- 29271290 TI - Excessive game playing is associated with musculoskeletal pain among youth athletes: a cross-sectional study in Miyagi prefecture. AB - Youth athletes are known to be at high risk of musculoskeletal (MSK) injuries. Children in developed countries are increasingly adopting a sedentary lifestyle. Although some risk factors related to sports activities have been reported, the effect of lifestyle (i.e. screen time behaviour) on MSK pain in youth athletes is not well known. This study aimed to examine the association of game playing and TV viewing with MSK pain among youth athletes. A self-administered questionnaire was mailed to youth athletes belonging to the Miyagi Amateur Sports Association. The final study population included 6,143 youth athletes (male, 71.1%; age range, 6-15 years). Multiple logistic regression analysis was used to examine the association of game playing and TV viewing behaviour with MSK pain. The point prevalence of MSK pain was 25.5%. The longest category of game playing time (>=3 h) was significantly associated with MSK pain as compared with the shortest category (<1 h) (odds ratio, 1.39; 95% confidence interval, 1.12-1.73, p = 0.003). There was no significant association between TV viewing time and MSK pain. These results suggest that game playing time might be an associated factor for MSK pain among youth athletes. PMID- 29271291 TI - Evaluation of exercise-induced modulation of glial activation and dopaminergic damage in a rat model of Parkinson's disease using [11C]PBR28 and [18F]FDOPA PET. AB - Evidence suggests that exercise can modulate neuroinflammation and neuronal damage. We evaluated if such effects of exercise can be detected with positron emission tomography (PET) in a rat model of Parkinson's disease (PD). Rats were unilaterally injected in the striatum with 6-hydroxydopamine (PD rats) or saline (controls) and either remained sedentary (SED) or were forced to exercise three times per week for 40 min (EX). Motor and cognitive functions were evaluated by the open field, novel object recognition, and cylinder tests. At baseline, day 10 and 30, glial activation and dopamine synthesis were assessed by [11C]PBR28 and [18F]FDOPA PET, respectively. PET data were confirmed by immunohistochemical analysis of microglial (Iba-1) / astrocyte (GFAP) activation and tyrosine hydroxylase (TH). [11C]PBR28 PET showed increased glial activation in striatum and hippocampus of PD rats at day 10, which had resolved at day 30. Exercise completely suppressed glial activation. Imaging results correlated well with post mortem Iba-1 staining, but not with GFAP staining. [18F]FDOPA PET, TH staining and behavioral tests indicate that 6-OHDA caused damage to dopaminergic neurons, which was partially prevented by exercise. These results show that exercise can modulate toxin-induced glial activation and neuronal damage, which can be monitored noninvasively by PET. PMID- 29271293 TI - Are We "Motorically" Wired to Others? High-Level Motor Computations and Their Role in Autism. AB - High-level motor computations reflect abstract components far apart from the mere motor performance. Neural correlates of these computations have been explored both in nonhuman and human primates, supporting the idea that our brain recruits complex nodes for motor representations. Of note, these computations have exciting implications for social cognition, and they also entail important challenges in the context of autism. Here, we focus on these challenges benefiting from recent studies addressing motor interference, motor resonance, and high-level motor planning. In addition, we suggest new ideas about how one maps and shares the (motor) space with others. Taken together, these issues inspire intriguing and fascinating questions about the social tendency of our high-level motor computations, and this tendency may indicate that we are "motorically" wired to others. Thus, after furnishing preliminary insights on putative neural nodes involved in these computations, we focus on how the hypothesized social nature of high-level motor computations may be anomalous or limited in autism, and why this represents a critical challenge for the future. PMID- 29271294 TI - Infectious spondylodiscitis: 5-year analysis of a tertiary hospital in Portugal. PMID- 29271295 TI - Im/mobilities and dis/connectivities in medical globalisation: How global is Global Health? AB - The interdisciplinary, politically contested field of Global Health has often been described as a consequence of, and response to, an intensification of the mobilities of, and connectivities between, people, pathogens, ideas, and infrastructure across national borders and large distances. However, such global mobilities and connectivities are not as omnidirectional and unpatterned as the rhetoric of many Global Health actors suggests. Instead, we argue that they are suffused by a plethora of institutional, national, and global political agendas, and substantially shaped by transnational and postcolonial power relations. Furthermore, the configurations that are typically subsumed under the category of Global Health represent only a minor part of the range of im/mobilities and dis/connectivities that are essential for understanding transformations of epidemiological patterns, health care infrastructures, and the responses to health-related challenges in a globalising world. In order to broaden such a limiting analytical perspective, we propose to expand the analytical focus in studying Global Health phenomena by paying close attention to the myriad ways in which particular im/mobilities and dis/connectivities constitute medicine and well-being in global and transnational settings. Pursuing a conceptual shift from studies of 'Global Health' to studying 'medical globalization' may carve out new analytical ground for such an endeavour. PMID- 29271292 TI - Chronic limb-threatening ischemia could benefit from growth hormone therapy for wound healing and limb salvage. AB - Revascularization for chronic limb-threatening ischemia (CLTI) is necessary to alleviate symptoms and wound healing. When it fails or is not possible, there are few alternatives to avoid limb amputation in these patients. Although experimental studies with stem cells and growth factors have shown promise, clinical trials have demonstrated inconsistent results because CLTI patients generally need arteriogenesis rather than angiogenesis. Moreover, in addition to the perfusion of the limb, there is the need to improve the neuropathic response for wound healing, especially in diabetic patients. Growth hormone (GH) is a pleiotropic hormone capable of boosting the aforementioned processes and adds special benefits for the redox balance. This hormone has the potential to mitigate symptoms in ischemic patients with no other options and improves the cardiovascular complications associated with the disease. Here, we discuss the pros and cons of using GH in such patients, focus on its effects on peripheral arteries, and analyze the possible benefits of treating CLTI with this hormone. PMID- 29271296 TI - Understanding men's networks and perceptions of leadership to promote HIV testing and treatment in Agincourt, South Africa. AB - Understanding informal leadership in high HIV prevalence settings is important for the success of popular opinion leader (POL) and other HIV testing and treatment promotion strategies which aim to leverage the influence of these leaders. We conducted a study in Mpumalanga province, South Africa, in which we aimed to: (1) describe men's personal networks and key social relationships; and (2) describe the types of individuals men identify as leaders. We administered a structured questionnaire with 45 men (15 HIV-positive and 30 HIV-negative) in which men enumerated and described characteristics of individuals they share personal matters with, and people they considered as leaders. We further conducted in-depth interviews with 25 of these men to better understand men's conceptualisation of leadership in their community. Family members were prominent in men's personal networks and among the leaders they nominated. Men living with HIV were much more likely to know others living with HIV, and described friendships on the basis of the shared experience of HIV treatment. Future POL interventions aiming to promote HIV testing and care among men in rural South Africa should consider the importance of family in community leadership, and seek to leverage the influence of connections between men living with HIV. PMID- 29271297 TI - From dynamic chromatin architecture to DNA damage repair and back. AB - Maintaining the integrity of the genome in the face of DNA damage is crucial to ensure the survival of the cell and normal development. DNA lesions and repair occur in the context of the chromatin fiber, whose 3D organization and movements in the restricted volume of the nucleus are under intense scrutiny. Here, we highlight work from our and other labs that addresses how the dynamic organization of the chromatin fiber affects the repair of damaged DNA and how, conversely, DNA damage and repair affect the structure and dynamics of chromatin in the budding yeast nucleus. PMID- 29271298 TI - Antenatal HIV Testing in Sub-Saharan Africa During the Implementation of the Millennium Development Goals: A Systematic Review Using the PEN-3 Cultural Model. AB - This study systematically explored the barriers and facilitators to routine antenatal HIV testing from the perspective of pregnant women in sub-Saharan Africa during the implementation period of the Millennium Development Goals. Articles published between 2000 and 2015 were selected after reviewing the title, abstract, and references. Twenty-seven studies published in 11 African countries were eligible for the current study and reviewed. The most common barriers identified include communication with male partners, patient convenience and accessibility, health system and health-care provider issues, fear of disclosure, HIV-related stigma, the burden of other responsibilities at home, and the perception of antenatal care as a "woman's job." Routine testing among pregnant women is crucial for the eradication of infant and child HIV infections. Further understanding the interplay of social and cultural factors, particularly the role of women in intimate relationships and the influence of men on antenatal care seeking behaviors, is necessary to continue the work of the Millennium Development Goals. PMID- 29271300 TI - Isolate Specificity and Polygenic Inheritance of Resistance in Barley to Diverse Heterologous Puccinia striiformis Isolates. AB - Barley is a host to Puccinia striiformis f. sp. hordei, and is an intermediate or near nonhost to the formae speciales adapted to wheat (P. striiformis f. sp. tritici) and to barley grass (P. striiformis f. sp. pseudo-hordei). The genetic basis of resistance to these forms of P. striiformis is not well understood. Accordingly, a recombinant inbred line (RIL) population was developed using a P. striiformis-susceptible accession (Biosaline-19) and the immune cultivar Pompadour. We investigated the genetic basis of resistance to four diverse P. striiformis isolates (P. striiformis f. sp. pseudo-hordei, and P. striiformis f. sp. tritici pathotypes 104 E137 A-, 134 E16 A+, and 64 E0 A-). and determined that the immunity in Pompadour at the seedling stage to the different P. striiformis isolates was due to quantitative trait loci (QTL) on chromosomes 1H, 3H, 5H, and 7H with both overlapping and distinct specificities. Further histological analysis confirmed the presence of isolate specificity. The RILs were also assessed in the field for resistance to P. striiformis f. sp. pseudo hordei, P. striiformis f. sp. hordei, and the leaf rust pathogen (P. hordei) to identify pleiotropic QTL loci effective at the adult plant stage and determine whether the leaf rust resistance in Pompadour (Rph20) was also effective to P. striiformis. RILs that were seedling susceptible to P. striiformis f. sp. pseudo hordei were resistant in the field, implicating the involvement of adult plant resistance (APR). Additional QTLs were identified on chromosome 7H at the same genetic position as Rph23 (APR to leaf rust), suggesting either pleiotropic resistance or the presence of a stripe rust resistance gene closely linked to or allelic with Rph23. Unlike many pleiotropic APR genes identified and isolated in wheat, our data suggest that the Rph20 locus does not confer resistance to the P. striiformis isolates used in this study (P. striiformis f. sp. hordei [chi2 (independence) = 2.47 P > 0.12] and P. striiformis f. sp. pseudo-hordei [chi2 (independence) = 0.42 P > 0.60]). PMID- 29271301 TI - A Bayesian framework for performance assessment and comparison of imaging biomarker quantification methods. AB - Quantitative biomarkers derived from medical images are being used increasingly to help diagnose disease, guide treatment, and predict clinical outcomes. Measurement of quantitative imaging biomarkers is subject to bias and variability from multiple sources, including the scanner technologies that produce images, the approaches for identifying regions of interest in images, and the algorithms that calculate biomarkers from regions. Moreover, these sources may differ within and between the quantification methods employed by institutions, thus making it difficult to develop and implement multi-institutional standards. We present a Bayesian framework for assessing bias and variability in imaging biomarkers derived from different quantification methods, comparing agreement to a reference standard, studying prognostic performance, and estimating sample size for future clinical studies. The statistical methods are illustrated with data obtained from a positron emission tomography challenge conducted by members of the NCI's Quantitative Imaging Network program, in which tumor volumes were measured manually and with seven different semi-automated segmentation algorithms. Estimates and comparisons of bias and variability in the resulting measurements are provided along with an R software package for the technical performance analysis and an online web application for sample size and power analysis. PMID- 29271299 TI - Contrast-Enhanced Near-Infrared Optical Imaging Detects Exacerbation and Amelioration of Murine Muscular Dystrophy. AB - Assessment of muscle pathology is a key outcome measure to measure the success of clinical trials studying muscular dystrophies; however, few robust minimally invasive measures exist. Indocyanine green (ICG)-enhanced near-infrared (NIR) optical imaging offers an objective, minimally invasive, and longitudinal modality that can quantify pathology within muscle by imaging uptake of ICG into the damaged muscles. Dystrophic mice lacking dystrophin (mdx) or gamma sarcoglycan (Sgcg-/-) were compared to control mice by NIR optical imaging and magnetic resonance imaging (MRI). We determined that optical imaging could be used to differentiate control and dystrophic mice, visualize eccentric muscle induced by downhill treadmill running, and restore the membrane integrity in Sgcg /- mice following adeno-associated virus (AAV) delivery of recombinant human SGCG (desAAV8hSGCG). We conclude that NIR optical imaging is comparable to MRI and can be used to detect muscle damage in dystrophic muscle as compared to unaffected controls, monitor worsening of muscle pathology in muscular dystrophy, and assess regression of pathology following therapeutic intervention in muscular dystrophies. PMID- 29271302 TI - PEG-coumarin nanoaggregates as pi-pi stacking derived small molecule lipophile containing self-assemblies for anti-tumour drug delivery. AB - Polymeric self-assemblies formed by non-covalent interactions such as hydrophobic interactions, hydrogen bonding, pi-pi stacking, host-guest and electrostatic interactions have been utilised widely and exhibit controlled release of encapsulated drug. Beside carrier-carrier interactions, small molecule amphiphiles exhibiting carrier-drug interactions have recently been an area of interest for cancer drug delivery, as most of the hydrophobic anti-tumour drugs are aromatic and exhibit pi-pi conjugated structure. In the present study PEG coumarin (PC) conjugates forming self-assembled nanoaggregates were synthesised with PEG (polyethylene glycol) as hydrophilic block and coumarin as small molecule lipophilic segment. Curcumin (CUR) as model conjugated aromatic drug was loaded in to the nanoaggregates via dual hydrophobic and pi-pi stacking interactions. The interactions between the conjugates and CUR, drug release profile and in vitro anti-tumour efficacy were investigated in detail. CUR-loaded nanoaggregate self-assembly was driven by pi-pi interactions and a maximum loading level of about 18 wt.% (~60 % encapsulation efficiency) was achieved. The average hydrodynamic diameter (Dav) was in the range of 120-160 nm and a spherical morphology was observed by transmission electron microscopy (TEM). A sustained release of CUR was observed for 90 h. Cytotoxicity evaluation of CUR loaded nanoaggregates on pancreatic cancer cell lines indicated higher efficacy, IC50 ~11 and ~15 MUM as compared to free CUR, IC50 ~14 and ~20 MUM on human pancreatic carcinoma (MIA PaCa-2) and human pancreatic duct epithelioid carcinoma (PANC-1) cell lines respectively. PC conjugates provided a new strategy of fabricating nanoparticles for drug delivery and may form the basis for the development of advanced biomaterials in near future. PMID- 29271303 TI - Assessing alliance ruptures and resolutions: Reliability and validity of the Collaborative Interactions Scale-revised version. AB - OBJECTIVE: This study presents the revised version of the Collaborative Interactions Scale (CIS) [Colli, A., & Lingiardi, V. (2009). The Collaborative Interactions Scale: A new transcript-based method for the assessment of therapeutic alliance ruptures and resolutions in psychotherapy. Psychotherapy Research, 19(6), 718-734.], an observer-rated measure for the assessment of therapeutic-alliance ruptures and resolutions. Intensive use of the previous scale resulted in three criticisms: (i) excessive time required to perform evaluations, (ii) the low occurrence of some items, and (iii) the scale's low capacity to capture some patient-therapist interactions in fine detail. In this study, we aimed to describe the scale revision process and evaluate interrater reliability and scale validity by comparing sessions of patients with and without personality disorders (PDs). METHOD: Three raters conducted a blind evaluation of a sample of 60 sessions (180 segments; 3607 narrative units) with 30 patients (15 had a PD diagnosis and 15 had a DSM-5 clinical syndrome diagnosis without a PD). RESULTS: Interrater reliability results ranged from acceptable to excellent and were comparable to those of the former version. Patients with PDs showed a greater number of alliance ruptures and a smaller number of collaborative processes than patients without PDs. Moreover, therapists presented more negative interventions with the PD sample than with the non-PD sample. CONCLUSIONS: The results indicate that the revised CIS is a reliable rating system that is useful for both empirical research and clinical assessments. Clinical or methodological significance of this article: The CIS-R is a reliable rating system that is suitable for both empirical research and clinical assessment. It is useful for recognizing rupture and resolution processes, both in clinical everyday practice and in psychotherapists' training. Application of the CIS-R promotes clinical reflection on the therapeutic action used to manage ruptures in a session. PMID- 29271304 TI - Fetal brain sparing in a mouse model of chronic maternal hypoxia. AB - Hypoxic stress is a common occurrence during human pregnancy, yet little is known about its effects on the fetal brain. This study examined the fetal hemodynamic responses to chronic hypoxia in an experimental mouse model of chronic maternal hypoxia (11% O2 from E14.5 to E17.5). Using high-frequency Doppler ultrasound, we found fetal cerebral and ductus venosus blood flow were both elevated by 69% and pulmonary blood flow was decreased by 62% in the fetuses exposed to chronic hypoxia compared to controls. This demonstrates that brain sparing persists during chronic fetal hypoxia and is mediated by "streaming," where highly oxygenated blood preferentially flows through the ductus venosus towards the cerebral circulation, bypassing the liver and the lungs. Consistent with these changes in blood flow, the fetal brain volume measured by MRI is preserved, while the liver and lung volumes decreased compared to controls. However, hypoxia exposed fetuses were rendered vulnerable to an acute hypoxic challenge (8% O2 for 3 min), demonstrating global blood flow decreases consistent with imminent fetal demise rather than elevated cerebral blood flow. Despite this vulnerability, there were no differences in adult brain morphology in the mice exposed to chronic maternal hypoxia compared to controls. PMID- 29271305 TI - ?Como puede la Promocion de la Salud abordar los Determinantes Ecologicos de la Salud? PMID- 29271306 TI - Comment la promotion de la sante peut-elle aborder les determinants ecologiques de la sante ? PMID- 29271307 TI - How can health promotion address the ecological determinants of health? PMID- 29271309 TI - Resumes. PMID- 29271310 TI - Resumenes. PMID- 29271311 TI - President's Annual State of the Academy Report. PMID- 29271312 TI - Fatal Purpureocillium lilacinum pneumonia in a green tree python. AB - A 10-y-old female green tree python ( Morelia viridis) died of fungal pneumonia caused by Purpureocillium lilacinum, which was confirmed histologically and by PCR and subsequent DNA sequencing. The same fungal species was cultivated from a swab taken from the terrarium in which the snake was housed. Clinical and environmental P. lilacinum isolates were indistinguishable by the typing method applied, strongly suggesting clonal relatedness of both isolates. Because no other underlying predisposing respiratory infection could be detected by virus specific PCR or histopathology, P. lilacinum was considered a primary pulmonary pathogen in this tree python. PMID- 29271313 TI - von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina. AB - von Willebrand disease (vWD) is the most common inherited coagulopathy in dogs, particularly in Doberman Pinschers. We developed a pyrosequencing-based assay to estimate the frequency of the c.7437G>A mutation associated with vWD type 1 in the Doberman Pinscher population of Buenos Aires, Argentina. We found a 0.41 frequency for the mutated allele, which varied significantly within families (family 1 = 0.43, family 2 = 0.58, unrelated animals = 0.35). The use of a popular founder male carrier of mutant allele A increased vWD incidence within a family and in the general population. The mode of inheritance was confirmed as autosomal dominant with incomplete penetrance. No differences were found between sexes and coat colors. Pyrosequencing was a good complement to clinical and coagulation tests for vWD type 1 diagnosis and a useful alternative for detecting the c.7437G>A mutation. PMID- 29271314 TI - [City hall holds the key to weight control]. AB - Doctors can play a major role in reducing obesity in the community, but that requires an unconventional approach. Treatment of individual patients with diet or drugs is largely ineffective. In contrast, comprehensive community interventions such as one pioneered by EPODE in France have successfully reduced the prevalence of corpulence in children. Such a community approach requires simultaneously engagement by town governments, retailers, associations, restaurants, caterers, media, schools and kindergartens to cooperate in improving diets, reducing caloric intake and increasing activity. Physicians are by far the most highly trusted source of information when it comes to health matters. Therefore, a few words from a doctor at the right time and in the right place, e.g. at a city council meeting, could tip the scales. Individual doctors cannot cure patients' obesity by themselves in their offices, but a few hours per year spent on persuading key stakeholders might help to turn the tide on obesity in the community. PMID- 29271315 TI - [The last specialist secretary of state in the Netherlands: Els Borst-Eilers]. AB - The announcement of the appointment of Hugo de Jonge as the Netherlands Secretary of State for Health means that there is little chance of having a 'specialist' in this post in the near future. Els Borst-Eilers is generally considered to have been the last specialist Secretary of State for Health in the Netherlands. Whether or not she can rightly be considered to be a specialist, this was certainly the image that she cultivated and also used for political ends, for instance, to depoliticise sensitive issues. In this article, we highlight a particularly good example: the medical experiment involving providing approximately 700 long-term addicts with heroin under medical supervision, which Borst implemented with the consent of the Netherlands parliament in 1998. PMID- 29271316 TI - [Nocdurna: old medication is looking for a new ailment]. AB - Desmopressin has been launched in a new jacket: Nocdurna. Desmopressin has so far been used mainly for treatment of bedwetting in children and adolescents. The indication for desmopressin has now been expanded to 'nocturia as a consequence of idiopathic night-time polyuria in adults'. We strongly doubt the added value of this medication for this indication. PMID- 29271317 TI - [The physician and prevention: by all means deliberate extensively, but do make a decision]. AB - The role of prevention in medical care has recently been described and discussed in various strategy reports by Dutch medical professional organisations. However, there are still doubts concerning the effectiveness and feasibility of practising preventive medicine. Both inconclusive evidence on its effectiveness, including on long-term outcomes of preventive medicine interventions, and studies showing positive results have been published. In general, more intensive approaches towards lifestyle change are more effective. Regarding disease-related prevention intervention, various authors stress that this is undoubtedly a task reserved for physicians. Their degree of responsibility and input is less clear when it comes to indicated and selective prevention. Nonetheless, for these latter types of prevention there seems to be a role reserved for the physician, given the increase in lifestyle-related chronic diseases and the prevalence of social class related health inequity. Here, the author argues that physicians are ideally positioned as advisor and motivator, especially towards more vulnerable patients. Aftercare can be organised in partnership with other providers. To take an active role in prevention still needs 'guts', and physicians are challenged to take a position in this. PMID- 29271318 TI - [Obesity in the clinic room: diagnostics first, followed by effective treatment]. AB - In clinical practice, relatively little attention is directed towards identifying underlying causes and contributing factors to weight gain in patients with obesity. However, recognising these "hidden fattening factors" is important as it can lead to more effective treatment strategies. In particular if underlying causes can be solved first, this could help to realise sustainable weight reduction. Besides the well-known lifestyle-related aspects, obesity may be caused or maintained by medication use, endocrine or hypothalamic disorders, monogenetic or syndromic diseases, and mental factors, which may require specific (medical) treatment. For lifestyle-related obesity, a combined lifestyle intervention (CLI) is a first step to combat obesity. This treatment comprises intensive guidance regarding healthy nutrition, physical activity, and behavioural psychology. In case of morbid obesity and insufficient effects of CLI after one year, weight-reducing medication or a bariatric intervention can be considered. This systematic strategy for diagnostics and treatment of obesity is illustrated by two clinical cases. PMID- 29271319 TI - [Societal aspects of the risk of cardiovascular disease]. AB - A 57-year-old man of Turkish descent is treated for coronary artery disease. In addition to drug treatment and percutaneous revascularization, modification of lifestyle-related risk factors is indicated. His risk profile includes smoking, hypertension and inadequate physical activity. Adherence to medication is suboptimal and his wife is a smoker too. Limited health literacy and acculturation, and resource limitations impede adequate lifestyle changes. Guidance of this patient is challenging; it is not straightforward to influence the societal components of his issues from a medical office. Evidence-based lifestyle interventions are scarce, and their validation - if validated at all - was performed in populations that are not representative of the patient in question. However, physicians can contribute to achieving societal change by participating in national programs aimed at improving infrastructure, improving health literacy, development of ethnicity-specific interventions, availability of healthy food, discouragement of smoking, and creating an infrastructure that promotes physical activity in daily life. PMID- 29271320 TI - [Obesity: lack of moral fibre of doctors, patients or politicians?] AB - Obesity is the most important avoidable cause of death. It is associated with many chronic illnesses, such as diabetes, hypertension, sleep apnoea and several cancers. Although bariatric surgery is effective in treating obesity and associated health problems, it is not the solution of this health issue. What should doctors do to prevent obesity in our society? Politics and the government play a leading role in any necessary behavioural change in society. Other countries have taken effective measures, such as better information on food and food products, sugar and fat taxes and stimulating walking or cycling instead of driving. PMID- 29271321 TI - [An activity-friendly environment: that's also the doctor's business]. AB - Achieving and maintaining sufficient levels of physical activity is important for the health of the Dutch population. However, the vast majority of the Dutch population - including children - does not comply with the current physical activity guideline. This is the case despite excellent infrastructure which allows safe movement and facilitates walking or cycling to school or work. Perhaps the layout of our living environment is unattractive for movement. It may possibly be unchallenging for young people or too much concrete for adults. In this article we discuss the role of the physical environment on physical activity and ultimately our health. Ways in which the environment could influence the levels of physical activity of the population are also considered. PMID- 29271322 TI - [Collaboration on health in the neighbourhood: role for GPs? Experiences from the 'Prevention in the neighbourhood' project]. AB - There are two reasons why general practitioners (GPs) should collaborate with others in their neighbourhood: social problems that translate into physical symptoms and addressing healthy lifestyles and prevention. PMID- 29271323 TI - [The limits of general practice]. AB - New epidemics are evolving in modern day society. Obesity, addiction to smoking and a general lack of exercise are threatening the health of the population seen by the general practitioner. It is time for action! But can we solve these problems in general practice, during consulting hours? Or have we reached the limits to what we can achieve as general practitioners in reducing addiction to smoking and stimulating weight loss? Of course, we can still help to coach individuals who consult us with one of these problems, but although healthcare in Dutch general practice is of a high standard much more is needed to solve these new epidemics and the problems that threaten the health of the population. Other stakeholders - such as political parties, municipal health services and the government - should also have to bear the responsibility. PMID- 29271324 TI - [Mackenbachs ladder]. AB - At the seventh NTvG Congress, held on 5 November 2016, Professor Johan Mackenbach, Chair of the Department of Public Health at the Erasmus University in Rotterdam, the Netherlands, quoted Rudolf Virchow, when he said that 'politics is just medicine on a large scale'. According to Virchow, medical doctors are particularly well qualified to lead society on account of their knowledge of the causes of disease. Mackenbach introduced the idea of a 'ladder of political activism', a ladder with four levels at which healthcare professionals could be politically engaged and could exert their influence on political decision making. In this contribution, the author describes her experience as a member of the Dutch parliament, standing on what Mackenbach calls the highest rung of this ladder, and indicates why she thinks it is important that healthcare professionals take an active part in the public debate and try to influence political decision making. The knowledge they have gained in the consulting room is indispensable in this setting. PMID- 29271325 TI - [Medical social responsibility in an era of personalized medicine]. AB - How much social responsibility do physicians have? Historically, care for collective health and well-being has been part and parcel of the responsibility of the medical profession. The changes in the urban environment to which physicians contributed at the end of the 19th century bear witness to this. During the 20th century, however, the medical search for extra health gain has focused increasingly on the individual. This has reached a provisional zenith in personalized medicine. This article argues that physician are letting patients, society and themselves down by paying so much attention to the individual and so little to social factors that cause disease or promote health. The exceptional position that physicians occupy in identifying and tackling pathological processes advocates an increase in societal and political engagement. PMID- 29271326 TI - Description of Metagonimus pusillus sp. nov. (Trematoda: Heterophyidae): phylogenetic relationships within the genus. AB - As a result of experimental studies conducted in the Russian southern Far East, adult worms from the genus Metagonimus were obtained. A comparative analysis of the morphometry of these worms with other Metagonimus representatives showed that they are most similar to M. katsuradai Izumi, 1935 and M. otsurui Shimazu & Urabe, 2002 found in Japan, due to the ratio of suckers and the positions of the testicle, uterus and vitellaria. However, Russian worms differ from species in Japan by other metric characters: they differ from M. otsurui by the maximum size of most organs and from M. katsuradai by body width, pharynx length, and maximum size of testes and ovary. At the same time, they are identical to a trematode from the Russian southern Far East, which was previously identified as M. katsuradai. The validity of this species was also confirmed by genetic data. According to the 28S gene and the internal transcribed spacer 2 (ITS2) region of rDNA, as well as the cytochrome c oxidase I (cox1) gene of mtDNA, the Metagonimus specimens found in Russia differ from published genetic data for other members of this genus. However, both morphological similarity and molecular data showed that M. pusillus sp. nov., M. katsuradai and M. otsurui are most likely cryptic species. Furthermore, additional data based on a mitochondrial marker were provided for M. suifunensis Shumenko, Tatonova & Besprozvannykh, 2017 from Russia. PMID- 29271327 TI - An outbreak of Escherichia coli O157:H7 infections following a dairy education school field trip in Washington state, 2015. AB - On 27 April 2015, Washington health authorities identified Escherichia coli O157:H7 infections associated with dairy education school field trips held in a barn 20-24 April. Investigation objectives were to determine the magnitude of the outbreak, identify the source of infection, prevent secondary illness transmission and develop recommendations to prevent future outbreaks. Case finding, hypothesis generating interviews, environmental site visits and a case control study were conducted. Parents and children were interviewed regarding event activities. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Environmental testing was conducted in the barn; isolates were compared to patient isolates using pulsed-field gel electrophoresis (PFGE). Sixty people were ill, 11 (18%) were hospitalised and six (10%) developed haemolytic uremic syndrome. Ill people ranged in age from <1 year to 47 years (median: 7), and 20 (33%) were female. Twenty-seven case-patients and 88 controls were enrolled in the case-control study. Among first-grade students, handwashing (i.e. soap and water, or hand sanitiser) before lunch was protective (adjusted OR 0.13; 95% CI 0.02-0.88, P = 0.04). Barn samples yielded E. coli O157:H7 with PFGE patterns indistinguishable from patient isolates. This investigation provided epidemiological, laboratory and environmental evidence for a large outbreak of E. coli O157:H7 infections from exposure to a contaminated barn. The investigation highlights the often overlooked risk of infection through exposure to animal environments as well as the importance of handwashing for disease prevention. Increased education and encouragement of infection prevention measures, such as handwashing, can prevent illness. PMID- 29271328 TI - Influence of IL28B and MxA gene polymorphisms on HCV clearance in Han Chinese population. AB - The high rate of chronic hepatitis C (CHC) was one of the key issues of global public health concern. Interferon (IFN)-lambda relevant genes were in the antiviral treatment pathway, not only influenced hepatitis C virus (HCV) spontaneous clearance, but also affected the IFN-mediated viral clearance. The aim of this study was to identify the association of interleukin 28B (IL28B), myxovirus resistance A (MxA) gene polymorphisms with HCV spontaneous clearance and therapeutic response in Chinese CHC patients. IL28B and MxA gene genotypes were detected among 231 CHC carriers, 428 subjects with HCV spontaneous clearance and 662 CHC patients with pegylated IFN-alpha and ribavirin (pegIFN-alpha/RBV) treatment. Patients with MxA rs2071430 TT genotype were more likely to develop HCV infection chronicity (additive model: odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.48, P = 0.042). IL28B rs1298075 variant genotypes (additive model: OR 0.58, 95% CI 0.34-0.98, P = 0.040) and MxA rs17000900 variant genotypes (additive model: OR 0.54, 95% CI 0.30-0.99, P = 0.048) were less likely to achieve a sustained virological response. The life table indicated that patients with IL28B rs1298075 AG genotype were slower to achieve a viral load 106 copies/ml (all P < 0.05). This study illustrated that the carriage of IL28B rs12980275 AA had a positive effect on treatment response to pegIFN-alpha/RBV among Chinese CHC patients. PMID- 29271329 TI - Relationships between milk mid-IR predicted gastro-enteric methane production and the technical and financial performance of commercial dairy herds. AB - Considering economic and environmental issues is important in ensuring the sustainability of dairy farms. The objective of this study was to investigate univariate relationships between lactating dairy cow gastro-enteric methane (CH4) production predicted from milk mid-IR (MIR) spectra and technico-economic variables by the use of large scale and on-farm data. A total of 525 697 individual CH4 predictions from milk MIR spectra (MIR-CH4 (g/day)) of milk samples collected on 206 farms during the Walloon milk recording scheme were used to create a MIR-CH4 prediction for each herd and year (HYMIR-CH4). These predictions were merged with dairy herd accounting data. This allowed a simultaneous study of HYMIR-CH4 and 42 technical and economic variables for 1024 herd and year records from 2007 to 2014. Pearson correlation coefficients (r) were used to assess significant relationships (P<0.05). Low HYMIR-CH4 was significantly associated with, amongst others, lower fat and protein corrected milk (FPCM) yield (r=0.18), lower milk fat and protein content (r=0.38 and 0.33, respectively), lower quantity of milk produced from forages (r=0.12) and suboptimal reproduction and health performance (e.g. longer calving interval (r= 0.21) and higher culling rate (r=-0.15)). Concerning economic results, low HYMIR CH4 was significantly associated with lower gross margin per cow (r=0.19) and per litre FPCM (r=0.09). To conclude, this study suggested that low lactating dairy cow gastro-enteric CH4 production tended to be associated with more extensive or suboptimal management practices, which could lead to lower profitability. The observed low correlations suggest complex interactions between variables due to the use of on-farm data with large variability in technical and management practices. PMID- 29271330 TI - Leucine alters immunoglobulin a secretion and inflammatory cytokine expression induced by lipopolysaccharide via the nuclear factor-kappaB pathway in intestine of chicken embryos. AB - The mammalian target of rapamycin (mTOR) has been shown to be involved in lipopolysaccharide (LPS)-induced immune responses in many mammal cells. Here, we suggest that the mTOR pathway is involved in the intestinal inflammatory responses evoked by LPS treatment in chicken embryos. The intestinal tissue from Specific pathogen free chick embryos was cultured in the presence of LPS for 2 h. Secretory immunoglobulin A (sIgA) concentrations, messenger RNA (mRNA) expression of cytokines, and protein levels of nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinase (MAPK), mTOR and p70 ribosomal S6 kinase (p70S6K) were determined. The results showed that LPS treatment increased sIgA concentrations in a dose-dependent manner. The mRNA levels of interleukine (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha and Toll-like receptor (TLR) 4 were upregulated by LPS treatment (P<0.05). Lipopolysaccharide increased the phosphorylation of Jun N terminal kinase (JNK), p38 MAPK and NF-kappaB (P<0.05) while decreasing the phosphorylation level of mTOR (P<0.05). Supplementation of leucine at doses of 10, 20 and 40 mM dose-dependently decreased sIgA production. Leucine supplementation at 40 mM restored the phosphorylation level of mTOR and p70S6K while suppressing the phosphorylation levels of NF-kappaB (P<0.05) and partially down-regulating the phosphorylation of p38 MAPK and JNK. The transcription of IL 6 was significantly decreased by leucine supplementation. These results suggested that leucine could alleviate LPS-induced inflammatory responses by down regulating NF-kappaB signaling pathway and evoking mTOR/p70S6K signaling pathway, which may involve in the regulation of the intestinal immune system in chicken embryos. PMID- 29271332 TI - The hefty fetal phenotype hypothesis revisited: high birth weight, type 2 diabetes and gestational diabetes in a Saskatchewan cohort of First Nations and non-First Nations women. AB - Although low birth weight (LBW) increases the risk for type 2 diabetes (T2DM), the relationship between high birth weight (HBW) and T2DM is less definitive and largely confined to North American Indigenous populations. We re-examined the relationship between LBW (4000 g) and both T2DM and gestational diabetes (GDM) among First Nations and non-First Nations women in Saskatchewan. We analyzed new data for female subjects from a 2001 case-control study that led to our hefty fetal phenotype hypothesis. Using survival analysis techniques and a validated algorithm for identifying diabetes in health care administrative data, we followed a 1950-1984 birth cohort of 2003 women until March 31, 2013. Cox regression analysis determined the time to occurrence of first episode of GDM and diagnosis of T2DM by birth weight and ethnicity. First Nations women with HBW demonstrated a greater risk for developing both T2DM [hazard ratios (HR) 1.568; 95% confidence interval (CI) 1.188, 2.069] and GDM (HR 1.468; 95% CI 1.016, 2.121) than those with normal birth weight (NBW). Non-First Nations women with LBW had a greater risk of developing GDM than those with NBW (HR 1.585; 95% CI 1.001, 2.512). HBW is a risk factor for GDM and T2DM among First Nations women. This is likely due to exposure of these women to their own mothers' diabetic pregnancies or gestational impaired glucose tolerance. This inter-generational amplification of T2DM risk mediated through prenatal exposures appears to play a substantial role in the epidemic of T2DM among First Nations peoples. PMID- 29271331 TI - Assessing the impact of public education on a preventable zoonotic disease: rabies. AB - Effective methods to increase awareness of preventable infectious diseases are key components of successful control programmes. Rabies is an example of a disease with significant impact, where public awareness is variable. A recent awareness campaign in a rabies endemic region of Azerbaijan provided a unique opportunity to assess the efficacy of such campaigns. A cluster cross-sectional survey concerning rabies was undertaken following the awareness campaign in 600 households in 38 randomly selected towns, in districts covered by the campaign and matched control regions. This survey demonstrated that the relatively simple awareness campaign was effective at improving knowledge of rabies symptoms and vaccination schedules. Crucially, those in the awareness campaign group were also 1.4 times more likely to report that they had vaccinated their pets, an essential component of human rabies prevention. In addition, low knowledge of appropriate post-exposure treatment and animal sources of rabies provide information useful for future public awareness campaigns in the region and other similar areas. PMID- 29271333 TI - Diagnostic accuracy of enzyme-linked immunosorbent assay (ELISA) and immunoblot (IB) for the detection of antibodies against Neospora caninum in milk from dairy cows. AB - The aim of the study was to estimate the sensitivity and specificity of enzyme linked immunosorbent assay (ELISA) and immunoblot (IB) for detecting antibodies of Neospora caninum in dairy cows, in the absence of a gold standard. The study complies with STRADAS-paratuberculosis guidelines for reporting the accuracy of the test. We tried to apply Bayesian models that do not require conditional independence of the tests under evaluation, but as convergence problems appeared, we used Bayesian methodology, that does not assume conditional dependence of the tests. Informative prior probability distributions were constructed, based on scientific inputs regarding sensitivity and specificity of the IB test and the prevalence of disease in the studied populations. IB sensitivity and specificity were estimated to be 98.8% and 91.3%, respectively, while the respective estimates for ELISA were 60% and 96.7%. A sensitivity analysis, where modified prior probability distributions concerning IB diagnostic accuracy applied, showed a limited effect in posterior assessments. We concluded that ELISA can be used to screen the bulk milk and secondly, IB can be used whenever needed. PMID- 29271334 TI - Pig identification and meat traceability by multiallelic amplification fragments with multiple single nucleotide polymorphisms. AB - Compared with conventional identification methods, DNA-based genetic approaches such as single nucleotide polymorphisms (SNPs) and satellites are much more reliable for pig identification and meat traceability. In this study, multiallelic amplification fragments with multiple SNPs, incorporating the advantages of both SNPs and microsatellites, were explored for the first time for pig identification and meat traceability. Primer pairs for multiallelic fragments and their optimal SNPs were successfully selected and used for identification of individuals from Suzhong and Duroc populations. Meanwhile, the combined panel of the above mentioned primer pairs together with their optimal SNPs for Suzhong and/or Duroc pigs were validated for identification of the hybrids (Suzhong*Duroc). Therefore, we have successfully selected multiallelic amplification fragments with multiple SNPs to identify pigs and their meat samples from Suzhong, Duroc or their hybrids. Our study demonstrates that our method is more powerful for pig identification or meat traceability than SNPs or microsatellites. PMID- 29271335 TI - To what extent is a breed-specific database necessary to differentiate meat from pasture-fed and stall-fed lambs using visible spectroscopy? AB - Carotenoid pigments signature in the fat using visible reflectance spectroscopy has shown high potential for distinguishing pasture-fed (P) from stall concentrate-fed (S) lamb carcasses. However, a recent study demonstrated a between-breed variability in the digestive and metabolic fate of carotenoids pigments. The present study was therefore designed to investigate the extent to which this between-breed variability may affect the reliability of diet authentication using visible spectroscopy of the fat. We used 1054 male lambs from three breeds (Romane (ROM), Ile-de-France (OIF) and Limousine (LIM)). The breed-feed breakdown was 148 P and 258 S ROM, 102 P and 92 S OIF and 168 P and 286 S LIM lambs. The reflectance spectrum of perirenal fat was measured at 24 h postmortem at wavelengths between 400 and 700 nm. We quantified light absorption in the 450 to 510 nm area by calculating a traceability index (AVMI 450 to 510) considered as an indicator of the carotenoid concentration in the fat (method 1) and we performed a multivariate analysis over the full set of reflectance data between 400 and 700 nm (method 2). The reliability of method 1 proved very variable across breeds, with a percentage of correctly classified lambs reaching 95.3%, 90.5% and 79.4% in ROM, LIM and OIF lambs, respectively. Despite these between-breeds differences, the threshold of the linear discriminant analysis performed on AVMI 450 to 510 was fairly similar between breeds; when all the data for the three breeds were pooled, the threshold cut-off value was 224 units and the method correctly classified 90.2% of the 1054 lambs. Using the full range of reflectance data (method 2) enabled to significantly increase the proportion of correctly classified lambs for both OIF and LIM breeds, but not for ROM breed. It enabled to correctly classify 96.1%, 94.5% and 94.8% of the ROM, LIM and OIF lambs. The reliability of the discrimination was not significantly different when pooling all lambs for the three breeds than when using a breed-specific database (93.9% and 95.2%, respectively). PMID- 29271336 TI - Estimating survival rates in MERS-CoV patients 14 and 45 days after experiencing symptoms and determining the differences in survival rates by demographic data, disease characteristics and regions: a worldwide study. AB - Although Middle East respiratory syndrome coronavirus (MERS-CoV) has a recorded 5 years of circulation in 27 countries worldwide, there is no international study to assess whether there is variation in mortality by region. Neither has there been a comprehensive study detailing how the disease characteristics of MERS-CoV influence mortality in patients presenting symptoms. This study aimed to assess how region, patient and disease characteristics influence 14- and 45-day mortality in MERS patients. The author utilised publically available data on MERS CoV. The study included 883 MERS patients reported between 5 January 2015 and 10 March 2017. Data on patient and disease characteristics were collected. The mean age at MERS-CoV diagnosis was 54.3 years: 69.1% were male, and 86.7% of the cases were reported from Saudi Arabia. About 40% of MERS patients studied were over the age of 60. The study estimated 14- and 45-day survival rates after initial onset of symptoms: 83.67% and 65.9%, respectively. Saudi Arabian MERS patients exhibited 4.1 and 5.0 times higher 14-day (adjusted hazard risk (aHR) = 4.1; 95% confidence interval (CI) 1.012-16.921) and 45-day (aHR = 5.0; 95% CI 1.856 13.581) mortality risk compared with MERS patients in the Republic of Korea or other countries. Similarly, Middle Eastern MERS patients showed 5.3 and 4.1 times higher 14-day (aHR = 5.3; 95% CI 1.070-25.902) and 45-day (aHR = 4.1; 95% CI 1.288-113.076) mortality risk compared with MERS patients in the Republic of Korea or other countries. The results demonstrated a link between mortality and geography, disease and patient factors such as regions, symptoms, source of infections, underlying medical conditions, modes of transmission, non-healthcare workers and those of older age. Educational programmes, access to healthcare and early diagnosis could be implemented as modifiable factors to reduce the higher mortality rates in MERS patients. PMID- 29271337 TI - An evaluation of potential dustbathing substrates for commercial broiler chickens. AB - Provision of an appropriate dustbathing substrate may allow broiler chickens to satisfy a natural motivation and give them an opportunity to exercise. The main aim of this study was to evaluate the extent to which different substrates promote dustbathing behaviour in broilers. The trial was replicated over three production cycles in one commercial broiler house, with ~22 000 Ross broilers housed per cycle. The birds were provided with access to five experimental substrates from day 10 of the 6-week production cycle. The substrates included the following: (1) peat (P), (2) oat hulls (OH), (3) straw pellets (SP), (4) clean wood shavings (WS), and (5) litter control (C). The substrates were provided in 15 steel rings (1.1 m in diameter, three rings per substrate) dispersed throughout the house. The level of occupancy of the rings, behaviours performed in each substrate, and the effect of ring position (central or edge of house) were assessed in weeks 3, 4, 5 and 6 using scan sampling from video footage. Where substrates successfully promoted dustbathing, the length and components of the bouts (including number of vertical wing shakes and ground pecks) were also assessed. Results showed that birds used P significantly more than the remaining substrates for dustbathing (P0.05). The use of OH is likely to be more environmentally sustainable than that of P, and our results suggest that this substrate is relatively successful in promoting dustbathing. However, a preference was still observed for P and further work should investigate whether other suitable substrates could better reflect its qualities. PMID- 29271338 TI - History and Current Use of Antimicrobial Drugs in Veterinary Medicine. AB - This chapter briefly reviews the history and current use of antimicrobials in animals, with a focus on food animals in the more economically developed countries. It identifies some of the differences between human medical and food animal use, particularly in growth promotional and "subtherapeutic" use of medically-important antibiotics in animals. The public health impact of the extensive use of antibiotics in food animals for these purposes, differences internationally in such usage, and the major changes in current practices now underway in agricultural use are summarized. The emerging framing of the dimensions of antimicrobial resistance within a "One Health" framework is focusing global efforts to address the antimicrobial resistance crisis in a collaborative manner. The rapidly evolving development and application of practices of antimicrobial stewardship in animal is a critical part of the huge global effort to address antimicrobial resistance. The outcome is still uncertain. PMID- 29271339 TI - Virtual chromoendoscopy for the real-time assessment of colorectal polyps in vivo: a systematic review and economic evaluation. AB - BACKGROUND: Current clinical practice is to remove a colorectal polyp detected during colonoscopy and determine whether it is an adenoma or hyperplastic by histopathology. Identifying adenomas is important because they may eventually become cancerous if untreated, whereas hyperplastic polyps do not usually develop into cancer, and a surveillance interval is set based on the number and size of adenomas found. Virtual chromoendoscopy (VCE) (an electronic endoscopic imaging technique) could be used by the endoscopist under strictly controlled conditions for real-time optical diagnosis of diminutive (<= 5 mm) colorectal polyps to replace histopathological diagnosis. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of the VCE technologies narrow-band imaging (NBI), flexible spectral imaging colour enhancement (FICE) and i-scan for the characterisation and management of diminutive (<= 5 mm) colorectal polyps using high-definition (HD) systems without magnification. DESIGN: Systematic review and economic analysis. PARTICIPANTS: People undergoing colonoscopy for screening or surveillance or to investigate symptoms suggestive of colorectal cancer. INTERVENTIONS: NBI, FICE and i-scan. MAIN OUTCOME MEASURES: Diagnostic accuracy, recommended surveillance intervals, health-related quality of life (HRQoL), adverse effects, incidence of colorectal cancer, mortality and cost-effectiveness of VCE compared with histopathology. DATA SOURCES: Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and Database of Abstracts of Reviews of Effects were searched for published English-language studies from inception to June 2016. Bibliographies of related papers, systematic reviews and company information were screened and experts were contacted to identify additional evidence. REVIEW METHODS: Systematic reviews of test accuracy and economic evaluations were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were conducted, where possible, to inform the independent economic model. A cost utility decision-analytic model was developed to estimate the cost-effectiveness of VCE compared with histopathology. The model used a decision tree for patients undergoing endoscopy, combined with estimates of long-term outcomes (e.g. incidence of colorectal cancer and subsequent morbidity and mortality) derived from University of Sheffield School of Health and Related Research's bowel cancer screening model. The model took a NHS perspective, with costs and benefits discounted at 3.5% over a lifetime horizon. There were limitations in the data on the distribution of adenomas across risk categories and recurrence rates post polypectomy. RESULTS: Thirty test accuracy studies were included: 24 for NBI, five for i-scan and three for FICE (two studies assessed two interventions). Polyp assessments made with high confidence were associated with higher sensitivity and endoscopists experienced in VCE achieved better results than those without experience. Two economic evaluations were included. NBI, i-scan and FICE are cost-saving strategies compared with histopathology and the number of quality-adjusted life-years gained was similar for histopathology and VCE. The correct surveillance interval would be given to 95% of patients with NBI, 94% of patients with FICE and 97% of patients with i-scan. LIMITATIONS: Limited evidence was available for i-scan and FICE and there was heterogeneity among the NBI studies. There is a lack of data on longer-term health outcomes of patients undergoing VCE for assessment of diminutive colorectal polyps. CONCLUSIONS: VCE technologies, using HD systems without magnification, could potentially be used for the real-time assessment of diminutive colorectal polyps, if endoscopists have adequate experience and training. FUTURE WORK: Future research priorities include head-to-head randomised controlled trials of all three VCE technologies; more research on the diagnostic accuracy of FICE and i-scan (when used without magnification); further studies evaluating the impact of endoscopist experience and training on outcomes; studies measuring adverse effects, HRQoL and anxiety; and longitudinal data on colorectal cancer incidence, HRQoL and mortality. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016037767. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29271340 TI - Retinal Injury Following Laser Pointer Exposure. AB - BACKGROUND: Recent years have seen a marked increase in laser-pointerrelated injuries, which sometimes involve severe retinal damage and irreversible visual impairment. These injuries are often caused by untested or incorrectly classified devices that are freely available over the Internet. METHODS: We reviewed pertinent publications retrieved by a systematic search in the PubMed and Web of Science databases and present our own series of clinical cases. RESULTS: We identified 48 publications describing a total of 111 patients in whom both acute and permanent damage due to laser pointers was documented. The spectrum of damage ranged from focal photoreceptor defects to macular foramina and retinal hemorrhages associated with loss of visual acuity and central scotoma. On initial presentation, the best corrected visual acuity (BCVA) was less than 20/40 (Snellen equivalent) in 55% of the affected eyes and 20/20 or better in 9% of the affected eyes. Treatment options after laserpointer- induced ocular trauma are limited. Macular foramina and extensive hemorrhages can be treated surgically. In our series of 7 cases, we documented impaired visual acuity, central visual field defects, circumscribed and sometimes complex changes of retinal reflectivity, and intraretinal fluid. Over time, visual acuity tended to improve, and scotoma subjectively decreased in size. CONCLUSION: Laser pointers can cause persistent retinal damage and visual impairment. In view of the practically unimpeded access to laser pointers (even high-performance ones) over the Internet, society at large now needs to be more aware of the danger posed by these devices, particularly to children and adolescents. PMID- 29271342 TI - Changing Infection Patterns. PMID- 29271341 TI - Community-Acquired Pneumonia in Adults. AB - BACKGROUND: The clinical spectrum of community-acquired pneumonia ranges from infections that can be treated on an outpatient basis, with 1% mortality, to those that present as medical emergencies, with a mortality above 40%. METHODS: This article is based on pertinent publications and current guidelines retrieved by a selective search of the literature. RESULTS: The radiological demonstration of an infiltrate is required for the differentiation of pneumonia from acute bronchitis regardless of whether the patient is seen in the outpatient setting or in the emergency room. For risk prediction, it is recommended that the CRB-65 criteria, unstable comorbidities, and oxygenation should be taken into account. Amoxicillin is the drug of choice for mild pneumonia; it should be given in combination with clavulanic acid if there are any comorbid illnesses. The main clinical concerns in the emergency room are the identification of acute organ dysfunction and the management of sepsis. Intravenous beta-lactam antibiotics should be given initially, in combination with a macrolide if acute organ dysfunction is present. The treatment should be continued for 5-7 days. Cardiovascular complications worsen the patient's prognosis and should be meticulously watched for. Structured followup care includes the follow-up of comorbid conditions and the initiation of recommended preventive measures such as antipneumococcal and anti-influenza vaccination, the avoidance of drugs that increase the risk, smoking cessation, and treatment of dysphagia, if present. CONCLUSION: Major considerations include appropriate risk stratification and the implementation of a management strategy adapted to the degree of severity of the disease, along with the establishment of structured follow-up care and secondary prevention, especially for patients with comorbidities. PMID- 29271343 TI - The Prevalence of Nosocomial Infection and Antibiotic Use in German Hospitals. AB - BACKGROUND: In 2011 and again in 2016, the European Centre for Disease Prevention and Control (ECDC) asked all European countries to carry out nationwide studies on the prevalence of nosocomial infection (NI) and antibiotic use (AU). Data on NI and AU constitute an essential basis for the development of measures to prevent infection and lessen antibiotic resistance. METHODS: The German prevalence study of 2016 was carried out according to the ECDC protocol. Alongside a sample of 49 acute-care hospitals requested by the ECDC that was representative in terms of size (number of beds), further hospitals were invited to participate as well. Analyses were made of the overall group (218 hospitals, 64 412 patients), the representative group (49 hospitals), and the core group (46 hospitals). The core group consisted of the hospitals that had participated in the study of 2011. RESULTS: The prevalence of patients with NI was 4.6% in the overall group in 2016; it had been 5.1% in 2011 (p <0.01). In the representative group, the prevalence was 3.6% (compared to 5.1% in 2011, p <0.01). In the core group, the prevalence of NI was the same in 2016 as it had been in 2011. The prevalence of patients with ABU in the overall group remained the same, but a fall was seen in the representative group (21.5% versus 23.3%; p <0.01) and a rise in the core group (27.3% versus 26.2%; p = 0.02). The staff-patient ratio among the infection prevention and control professionals improved in all three groups. CONCLUSION: A decrease in NI and AU prevalence was seen in the representative group, while mixed results were seen in the other analyzed groups. Further efforts to reduce NI and ABA are clearly necessary. PMID- 29271344 TI - Condyloma in the Nose. PMID- 29271345 TI - Surveillance of Antibiotic Use and Resistance in Intensive Care Units (SARI). AB - BACKGROUND: The project entitled Surveillance of Antibiotic Use and Resistance in Intensive Care Units (SARI) was initiated in Germany in 2000. In this article, we describe developments in antibiotic use and resistance rates in the participating intensive care units over the years 2001-2015. METHODS: The intensive care units supplied monthly figures on patient days, antibiotic use (in defined daily doses, DDD), and resistance data for 13 pathogens. The density of antibiotic use per 1000 patient days was calculated on the basis of antibiotic use, DDD, and patient days, and the resistance density per 1000 patient days was calculated from the number of resistant pathogens. RESULTS: In the years 2001-2015, data on 2 920 068 patient days were collected in 77 intensive care units. The average overall antibiotic use rose by 19% over this period, with a marked increase in the density of carbapenem use (from 76 to 250 DDD per 1000 patient days, +230%) and piperacillin-tazobactam use (from 42 to 146 DDD per 1000 patient days, +247%). The proportion of Escherichia coli and Klebsiella pneumoniae isolates that were resistant to third-generation cephalosporins increased markedly initially, then remained stable over the remainder of the observation period. The proportion of methicillin-resistant Staphylococcus aureus was stable over the entire period. The rates of vancomycin resistance among Enterococcus faecium isolates and imipenem resistance among gram-negative pathogens increased from 2.3% to 13.3% and from 0.1% to 0.3%, respectively. CONCLUSION: The resistance density of gram negative multiresistant pathogens in the participating intensive care units increased markedly. The rise in imipenem-resistant pathogens arouses particular concern. The increased use of broad-spectrum/reserve antibiotics may well have contributed to this development. Efforts to use antibiotics rationally, e.g., with the support of multidisciplinary "antibiotic stewardship" teams, are therefore vitally important. As participation in SARI is voluntary, these surveillance data cannot be considered representative of Germany as a whole. PMID- 29271347 TI - Invasive Mycosis in an Immunosuppressed Patient. PMID- 29271346 TI - Uncomplicated Bacterial Communityacquired Urinary Tract Infection in Adults. AB - BACKGROUND: Uncomplicated bacterial community-acquired urinary tract infection is among the more common infections in outpatient practice. The resistance level of pathogens has risen markedly. This S3 guideline contains recommendations based on current evidence for the rational use of anti - microbial agents and for the prevention of inappropriate use of certain classes of antibiotics and thus of the resulting drug resistance. The prevention of recurrent urinary tract infection is considered in this guideline for the first time. METHODS: The guideline was updated under the aegis of the German Urological Society (Deutsche Gesellschaft fur Urologie). A systematic literature search (period: 2008-2015) concerning the diagnosis, treatment, and prevention of uncomplicated urinary tract infections was carried out in the Cochrane Library, MEDLINE, and Embase databases. Randomized, controlled trials and systemic reviews were included. Relevant guidelines were identified in a guideline synopsis. RESULTS: Symptom-oriented diagnostic evaluation is highly valued. For the treatment of cystitis, fosfomycin trometamol, nitrofurantoin, nitroxolin, pivmecillinam and trimethoprim are all equally recommended. Fluorquinolones and cephalosporins are not recommended. Uncomplicated pyelonephritis with a mild to moderate clinical course ought to be treated with oral cefpodoxime, ceftibuten, ciprofloxacin, or levofloxacin. For acute, uncomplicated cystitis, with mild to moderate symptoms, symptomatic treatment alone may be considered instead of antibiotics after discussion of the options with the patient. Mainly non-antibiotic measures are recommended for prophylaxis against recurrent urinary tract infection. CONCLUSION: Physicians who treat uncomplicated urinary tract infections should familiarize themselves with the newly revised guideline's recommendations on the selection and dosage of antibiotic treatment so that they can responsibly evaluate and plan antibiotic treatment for their affected patients. PMID- 29271348 TI - Yellow Nail Syndrome. PMID- 29271349 TI - Effect on growth and osteoblast mineralization of hydroxyapatite-zirconia (HA ZrO2) obtained by a new low temperature system. AB - Ceramics and bioceramics, as hydroxyapatite and zirconium, are used in bone tissue engineering. Hydroxyapatite has chemical properties similar to the bone while zirconium offers suitable mechanical properties. The aim of this article is to evaluate the ability to support cellular growth and osteoblastic mineralization of hydroxyapatite-zirconium obtained by a new system based on different low temperatures, as 873 degrees K (HZ600), 923 degrees K (HZ650) and 973 degrees K (HZ700). Hydroxyapatite-zirconia obtained by this new system was examined in terms of thermogravimetric features and X-ray diffractograms. Furthermore, the ability for supporting osteoblast growth and mineralization were analyzed. By x-ray diffraction analysis, we clearly demonstrated that no high temperature processing was required. Moreover, it is possible to form tetragonal zirconium at 650 degrees C. Proliferation assay showed that osteoblast growth was not influenced by any of the composite evaluated. Regarding osteogenic marker Col1, a 2 fold increase in expression was observed for HZ650 compared to HZ600 and HZ700. Interestingly, osteoblasts grown on HZ650 showed globular accretions covered with collagen bundles and calcium-rich extracellular matrix whereas HZ600 and HZ700 showed no phosphate or calcium deposits. This study demonstrated that at 650 degrees C is possible to generate stable tetragonal-zirconium and the resulting HZ650 composite is able to promote a suitable osteoblast mineralization process. PMID- 29271350 TI - Automatic T1 bladder tumor detection by using wavelet analysis in cystoscopy images. AB - Correct classification of cystoscopy images depends on the interpreter's experience. Bladder cancer is a common lesion that can only be confirmed by biopsying the tissue, therefore, the automatic identification of tumors plays a significant role in early stage diagnosis and its accuracy. To our best knowledge, the use of white light cystoscopy images for bladder tumor diagnosis has not been reported so far. In this paper, a texture analysis based approach is proposed for bladder tumor diagnosis presuming that tumors change in tissue texture. As is well accepted by the scientific community, texture information is more present in the medium to high frequency range which can be selected by using a discrete wavelet transform (DWT). Tumor enhancement can be improved by using automatic segmentation, since a mixing with normal tissue is avoided under ideal conditions. The segmentation module proposed in this paper takes advantage of the wavelet decomposition tree to discard poor texture information in such a way that both steps of the proposed algorithm segmentation and classification share the same focus on texture. Multilayer perceptron and a support vector machine with a stratified ten-fold cross-validation procedure were used for classification purposes by using the hue-saturation-value (HSV), red-green-blue, and CIELab color spaces. Performances of 91% in sensitivity and 92.9% in specificity were obtained regarding HSV color by using both preprocessing and classification steps based on the DWT. The proposed method can achieve good performance on identifying bladder tumor frames. These promising results open the path towards a deeper study regarding the applicability of this algorithm in computer aided diagnosis. PMID- 29271351 TI - Validity and reliability of smartphone orientation measurement to quantify dynamic balance function. AB - OBJECTIVE: Postural control is frequently compromised after sub-concussive and concussive head trauma, and balance testing is an integral part of neuromotor assessment and management. The main objective of this paper is to develop a novel smartphone-based neuromotor assessment protocol for screening of dynamic balance decrements stemming from head trauma. APPROACH: Experiments 1 and 2 compared Android smartphone orientation detection algorithms to a biomechanics laboratory motion capture system using a pendulum (i.e. non-biological movement) and a human stepping task (i.e. biological movement). Experiment 3 examined the test-retest reliability of a stepping-in-place protocol in three different sensory conditions (eyes open, no-vision, head shake) using temporal and spatial variability metrics extracted from thigh orientation signal in a sample of healthy young adults. MAIN RESULTS: Smartphone sensors provided valid measurements of movement timing and amplitude variables. However, sensor firmware version and Android OS version significantly affected quality of measurement. High test-retest reliability was shown for the temporal and spatial variables of interest during the stepping-in place task. SIGNIFICANCE: Collectively, these experiments show that our smartphone application is a valid and reliable way to measure leg movement characteristics (mean stride time and its variability (CV), Peak Thigh SD, Thigh ROM, and Peak Return Velocity) during dynamic balance activity, which could provide an objective way to assess neuromotor function after head trauma and in other populations with balance dysfunction. PMID- 29271352 TI - Noninvasive mapping reveals recurrent and suddenly changing patterns in atrial fibrillation-a magnetocardiographic study. AB - OBJECTIVE: To study noninvasive magnetocardiographic (MCG) mapping of ongoing atrial fibrillation (AF) and, for the possible mapping patterns observed, to develop simplified but meaningful descriptors or parameters, providing a possible basis for future research and clinical use of the mappings. APPROACH: MCG mapping with simultaneous ECG was recorded during arrhythmia in patients representing a range of typical, clinically classical atrial arrhythmias. The recordings were assessed using MCG map animations, and a method to compute magnetic field map orientation (MFO) and its time course was created to facilitate presentation of the findings. All the data were segmented into four categories of ECG waveform regularity. MAIN RESULTS: In visual observation of the MCG animations, an abundance of clear spatial and temporal patterns with regularity were found, often perceived as rotations of the map. This rotation and its sudden reversals of direction were distinctly present in the time course of the MFO. The shortest segments with consistent rotation lasted for some hundreds of milliseconds, i.e. a couple of cycles, but segments lasting for tens of seconds were observed as well. In the ECG, all four categories of regularity were present. The rotation of the MFO was observed in all patients under study and regardless of the ECG categories. Further, a change in ECG category during a measurement was frequently, but not always, found to be simultaneous with a change in the rotation pattern of the MFO. Utilization of spatial information of MCG mapping could enable detection of both regularities and instantaneous phenomena during AF. SIGNIFICANCE: Cardiac mapping may offer a useful noninvasive means to study the mechanisms of AF, including superior temporal resolution. PMID- 29271353 TI - Evidence for nodal superconductivity in a layered compound Ta4Pd3Te16. AB - We report an investigation of the London penetration depth Deltalambda(T) on single crystals of the layered superconductor Ta4Pd3Te16, where the crystal structure has quasi-one-dimensional characteristics. A linear temperature dependence of Deltalambda(T) is observed for T<< Tc, in contrast to the exponential behavior of fully gapped superconductors. This indicates the existence of line nodes in the superconducting energy gap. A detailed analysis shows that the normalized superfluid density rhos(T), which is converted from Deltalambda(T), can be well described by a multigap scenario, with nodes in one of the superconducting gaps, providing clear evidence for nodal superconductivity in Ta4Pd3Te16. PMID- 29271354 TI - Stillinger-Weber potential for elastic and fracture properties in graphene and carbon nanotubes. AB - This paper presents a new framework for determining the Stillinger-Weber (SW) potential parameters for modeling fracture in graphene and carbon nanotubes. In addition to fitting the equilibrium material properties, the approach allows fitting the potential to the forcing behavior as well as the mechanical strength of the solid, without requiring ad hoc modification of the nearest-neighbor interactions for avoiding artificial stiffening of the lattice at larger deformation. Consistent with the first-principles results, the potential shows the Young's modulus of graphene to be isotropic under symmetry-preserving and symmetry-breaking deformation conditions. It also shows the Young's modulus of carbon nanotubes to be diameter-dependent under symmetry-breaking loading conditions. The potential addresses the key deficiency of existing empirical potentials in reproducing experimentally observed glass-like brittle fracture in graphene and carbon nanotubes. In simulating the entire deformation process leading to fracture, the SW-potential costs several factors less computational time compared to the state-of-the-art interatomic potentials that enables exploration of the fracture processes in large atomistic systems which are inaccessible otherwise. PMID- 29271355 TI - White reflection from cuttlefish skin leucophores. AB - The highly diverse and changeable body patterns of cephalopods require the production of whiteness of varying degrees of brightness for their large repertoire of communication and camouflage behaviors. Leucophores are structural reflectors that produce whiteness in cephalopods; they are dermal aggregates of numerous leucocytes containing spherical leucosomes ranging in diameter from 200 2000 nm. In Sepia officinalis leucophores, leucocytes always occur in various combinations with iridocytes, cells containing plates that function as Bragg stacks to reflect light of particular wavelengths. Both spheres and plates contain the high-refractive-index protein reflectin. Four leucophore skin patterning components were investigated morphologically and with spectrometry. In descending order of brightness they are: white fin spots, White zebra bands, White square, and White head bar. Different densities, thicknesses and proportions of leucocytes and iridocytes were correlated with the relative brightness measurements of the skin. That is, White fin spots and White zebra bands had leucocytes of the highest density, the greatest number of reflective cell layers, and the highest proportion of leucocytes to iridocytes. In contrast, the White square and White head bar had the lowest density of reflective cells, fewer cell layers and the lowest ratios of leucocytes to iridocytes. Leucophores are white in white light, yet reflect whatever colors are in the available light field: e.g. red in red light, green in green light, etc. Leucophores are physiologically passive, thus their ultrastructure alone is capable of diffusing all ambient wavelengths in all directions, regardless of the angle of incident light. However, the specific optical contributions of spherical leucosomes versus the associated plate-like iridosomes in producing whiteness versus brightness are yet to be determined. This study reveals complex morphological arrangements that produce white structural coloration for different brightnesses of skin by differentially combining spheres and plates. PMID- 29271356 TI - Aptamer-conjugated DNA nano-ring as the carrier of drug molecules. AB - Due to its predictable self-assembly and structural stability, structural DNA nanotechnology is considered one of the main interdisciplinary subjects encompassing conventional nanotechnology and biotechnology. Here we have fabricated the mucin aptamer (MUC1)-conjugated DNA nano-ring intercalated with doxorubicin (DNRA-DOX) as potential therapeutics for breast cancer. DNRA-DOX exhibited significantly higher cytotoxicity to the MCF-7 breast cancer cells than the controls, including DOX alone and the aptamer deficient DNA nano-ring (DNR) with doxorubicin. Interactions between DOX and DNRA were studied using spectrophotometric measurements. Dose-dependent cytotoxicity was performed to prove that both DNR and DNRA were non-toxic to the cells. The drug release profile showed a controlled release of DOX at normal physiological pH 7.4, with approximately 61% released, but when exposed to lysosomal of pH 5.5, the corresponding 95% was released within 48 h. Owing to the presence of the aptamer, DNRA-DOX was effectively taken up by the cancer cells, as confirmed by confocal microscopy, implying that it has potential for use in targeted drug delivery. PMID- 29271357 TI - Spin dynamics of FeGa3-x Ge x studied by electron spin resonance. AB - The intermetallic semiconductor FeGa3 acquires itinerant ferromagnetism upon electron doping by a partial replacement of Ga with Ge. We studied the electron spin resonance (ESR) of high-quality single crystals of FeGa3-x Ge x for x from 0 up to 0.162 where ferromagnetic order is observed. For x = 0 we observed a well defined ESR signal, indicating the presence of pre-formed magnetic moments in the semiconducting phase. Upon Ge doping the occurrence of itinerant magnetism clearly affects the ESR properties below ~40 K, whereas at higher temperatures an ESR signal as seen in FeGa3 prevails independent on the Ge content. The present results show that the ESR of FeGa3-x Ge x is an appropriate and direct tool to investigate the evolution of 3d-based itinerant magnetism. PMID- 29271358 TI - A Monte Carlo simulation study for the gamma-ray/neutron dual-particle imager using rotational modulation collimator (RMC). AB - The aim of this work is to develop a gamma-ray/neutron dual-particle imager, based on rotational modulation collimators (RMCs) and pulse shape discrimination (PSD)-capable scintillators, for possible applications for radioactivity monitoring as well as nuclear security and safeguards. A Monte Carlo simulation study was performed to design an RMC system for the dual-particle imaging, and modulation patterns were obtained for gamma-ray and neutron sources in various configurations. We applied an image reconstruction algorithm utilizing the maximum-likelihood expectation-maximization method based on the analytical modeling of source-detector configurations, to the Monte Carlo simulation results. Both gamma-ray and neutron source distributions were reconstructed and evaluated in terms of signal-to-noise ratio, showing the viability of developing an RMC-based gamma-ray/neutron dual-particle imager using PSD-capable scintillators. PMID- 29271359 TI - A realistic pelvic phantom for electrical impedance measurement. AB - OBJECTIVE: To design and fabricate an anatomically and conductively accurate phantom for electrical impedance studies of non-invasive bladder volume monitoring. APPROACH: A modular pelvic phantom was designed and fabricated, consisting of a mechanically and conductively stable boundary wall, a background medium, and bladder phantoms. The wall and bladders are made of conductive polyurethane. The background material is an ultrasound gel-based mixture, with conductivity matched to a weighted average of the pelvic cavity organs, bone, muscle and fat. The phantom boundary is developed using a computer tomography model of a male human pelvis. The bladder phantoms were designed to correlate with human bladder dimensions. Electrical impedance measurements of the phantom were recorded, and images produced using six different bladder phantoms and a realistic finite element model. MAIN RESULTS: Five different bladder volumes were successfully imaged using an empty bladder as a reference. The average conductivity index from the reconstructed images showed a strong positive correlation with the bladder phantom volumes. SIGNIFICANCE: A conductively and anatomically accurate pelvic phantom was developed for non-invasive bladder volume monitoring using electrical impedance measurements. Several bladders were designed to correlate with actual human bladder volumes, allowing for accurate volume estimation. The conductivity of the phantom is accurate over 50-250 kHz. This phantom can allow changeable electrode location, contact and size; multi layer electrodes configurations; increased complexity by addition of other organ or bone phantoms; and electrode movement and deformation. Overall, the pelvic phantom enables greater scope for experimentation and system refinement as a precursor to in-man clinical studies. PMID- 29271360 TI - Negative thermal expansion in the superconducting precursor phase SmFeAsO. AB - The fluorine-doped rare-earth iron oxypnictide series SmFeAsO1 xFx (0 <= x <= 0.10) was investigated with high resolution powder x-ray scattering. In agreement with previous studies, the parent compound SmFeAsO exhibits a tetragonal-to-orthorhombic structural distortion at TS= 130 K which is rapidly suppressed by x ~ 0.10 deep within the superconducting dome. The change in unit cell symmetry is followed by a previously unreported magnetoelastic distortion at 120 K. The temperature dependence of the thermal expansion coefficient alphaV reveals a rich phase diagram for SmFeAsO: (i) a global minimum at 125 K corresponds to the opening of a spin-density wave instability as measured by pump-probe femtosecond spectroscopy whilst (ii) a global maximum at 110 K corresponds to magnetic ordering of the Sm and Fe sublattices as measured by magnetic x-ray scattering. At much lower temperatures than TN, SmFeAsO exhibits a significant negative thermal expansion on the order of -20 ppm.K-1 in contrast to the behavior of other rare-earth oxypnictides such as PrFeAsO and the actinide oxypnictide NpFeAsO where the onset of alpha < 0 only appears in the vicinity of magnetic ordering. Correlating this feature with the temperature and doping dependence of the resistivity and the unit cell parameters, we interpret this result as being due to the condensation of itinerant electrons caused by the opening of a SDW gap, consistent with transport measurements. PMID- 29271361 TI - Adaptive spectral tracking for coherence estimation: the z-tracker. AB - OBJECTIVE: A major challenge in non-stationary signal analysis is reliable estimation of correlation. Neurophysiological recordings can be many minutes in duration with data that exhibits correlation which changes over different time scales. Local smoothing can be used to estimate time-dependency, however, an effective framework needs to adjust levels of smoothing in response to changes in correlation. APPROACH: Here we present a novel data-adaptive algorithm, the z tracker, for estimating local correlation in segmented data. The algorithm constructs single segment coherence estimates using multi-taper windows. These are subject to adaptive Kalman filtering/smoothing in the z-domain to construct a local coherence estimate for each segment. The error residual for each segment determines the levels of process noise, allowing the filter to adapt rapidly to sudden changes in correlation while applying greater smoothing to data where the correlation is consistent across segments. The method is compared to wavelet coherence, calculated using orthogonal Morse wavelets. MAIN RESULTS: The performance of the z-tracker is quantified against Morse wavelet coherence using a mean square deviation (MSD) metric. The z-tracker has significantly lower MSD than the wavelet estimate for time-varying coherence over long time scales (~10 20 s), whereas the wavelet has lower MSD for coherence varying over short time scales (~1-2 s). The z-tracker also has a lower MSD for slowly varying coherence with occasional step changes. The method is applied to detect changes in coherence in paired LFP recordings from rat prefrontal cortex and amygdala in response to a pharmacological challenge. SIGNIFICANCE: The z-tracker provides an effective and efficient method to estimate time varying correlation in multivariate data, leading to better characterisation of neurophysiology signals where correlation is subject to slow modulation over time. A number of suggestions are included for future refinements. PMID- 29271362 TI - A thermoresponsive nanorattle containing two different catalysts for controllable one-pot tandem catalysis. AB - In the present work, a thermoresponsive nanorattle with a Ag nanoparticle (NP) core (one catalyst in the nanorattle), and a poly(N-isopropylacrylamide) shell was developed. An imidazole group was grafted on the polymer shell by copolymerization as the other catalyst. Owing to the catalytic activities of the imidazole group and Ag NP with regards to hydrolysis and reduction, respectively, this nanorattle exhibited tandem-reaction catalytic abilities. In addition, because of the shrinkage of the poly(N-isopropylacrylamide) shell at high temperatures, the tandem reaction could be controlled to stop at the first reaction step. That is to say, only the hydrolysis reaction was catalyzed by the imidazole group being grafted on the surface of the shell. The reduction step in the tandem reaction catalyzed by the Ag particle, however, was switched off by the shrinkage of the poly(N-isopropylacrylamide) shell. This protocol opens up an opportunity to develop controllable catalysts for complicated chemical processes. PMID- 29271363 TI - Underscreening in ionic liquids: a first principles analysis. AB - An attempt is made to understand the underscreening effect, observed in concentrated electrolyte solutions or melts, on the basis of simple, admittedly crude models involving charged (for the ions) and neutral (for the solvent molecules) hard spheres. The thermodynamic and structural properties of these 'primitive' and 'semi-primitive' models are calculated within mean spherical approximation, which provides the basic input required to determine the partial density response functions. The screening length [Formula: see text], which is unambiguously defined in terms of the wave-number-dependent response functions, exhibits a cross-over from a low density, Debye-like regime, to a regime where [Formula: see text] increases with density beyond a critical density at which the Debye length [Formula: see text] becomes comparable to the ion diameter. In this high density regime the ratio [Formula: see text] increases according to a power law, in qualitative agreement with experimental measurements, albeit at a much slower rate. PMID- 29271364 TI - Static structure of active Brownian hard disks. AB - We explore the changes in static structure of a two-dimensional system of active Brownian particles (ABP) with hard-disk interactions, using event-driven Brownian dynamics simulations. In particular, the effect of the self-propulsion velocity and the rotational diffusivity on the orientationally-averaged fluid structure factor is discussed. Typically activity increases structural ordering and generates a structure factor peak at zero wave vector which is a precursor of motility-induced phase separation. Our results provide reference data to test future statistical theories for the fluid structure of active Brownian systems. This manuscript was submitted for the special issue of the Journal of Physics: Condensed Matter associated with the Liquid Matter Conference 2017. PMID- 29271365 TI - Flory-type theories of polymer chains under different external stimuli. AB - In this Review, we present a critical analysis of various applications of the Flory-type theories to a theoretical description of the conformational behavior of single polymer chains in dilute polymer solutions under a few external stimuli. Different theoretical models of flexible polymer chains in the supercritical fluid are discussed and analysed. Different points of view on the conformational behavior of the polymer chain near the liquid-gas transition critical point of the solvent are presented. A theoretical description of the co solvent-induced coil-globule transitions within the implicit-solvent-explicit-co solvent models is discussed. Several explicit-solvent-explicit-co-solvent theoretical models of the coil-to-globule-to-coil transition of the polymer chain in a mixture of good solvents (co-nonsolvency) are analysed and compared with each other. Finally, a new theoretical model of the conformational behavior of the dielectric polymer chain under the external constant electric field in the dilute polymer solution with an explicit account for the many-body dipole correlations is discussed. The polymer chain collapse induced by many-body dipole correlations of monomers in the context of statistical thermodynamics of dielectric polymers is analysed. PMID- 29271366 TI - Verruciform xanthoma of the thumb. PMID- 29271367 TI - Angioma like carcinoma telangiectoides: An unusual presentation of breast carcinoma metastasis. PMID- 29271368 TI - Letter in response to "Effectiveness and safety of levocetirizine 10 mg versus a combination of levocetirizine 5 mg and montelukast 10 mg in chronic urticaria resistant to levocetirizine 5 mg: A double-blind, randomized, controlled trial" by Sarkar et al. PMID- 29271369 TI - Author's reply. PMID- 29271370 TI - Acral porokeratosis associated with anonychia. PMID- 29271371 TI - Herpetic perforation of prepuce. PMID- 29271372 TI - Antihypertensives in dermatology Part I - Uses of antihypertensives in dermatology. AB - Hypertension is a global health problem. Antihypertensives are the mainstay of treatment for hypertension. Some of them were accidentally found to be useful in alopecias and infantile hemangiomas and have now become standard treatment for these conditions as well. Antihypertensives are also being studied for other dermatological indications, where they have shown promising efficacy. This review focuses on the dermatological indications for antihypertensives, discussing the drugs that have been tried, as well as their efficacy, dosage, duration of therapy, and adverse effects. PMID- 29271373 TI - Comparison of Long-term Outcomes in Patients with Premature Triple-vessel Coronary Disease Undergoing Three Different Treatment Strategies: A Prospective Cohort Study. AB - BACKGROUND: Patients with premature triple-vessel disease (PTVD) have a higher risk of recurrent coronary events and repeat revascularization; however, the long term outcome of coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and medical therapy (MT) alone for PTVD patients is controversial. The aim of this study is to evaluate the long-term outcome of PTVD patients among these three treatment strategies, to find out the most appropriate treatment methods for these patients. METHODS: One thousand seven hundred and ninety-two patients with PTVD (age: men <=50 years and women <=60 years) were enrolled between 2004 and 2011. The primary end point was all-cause death. The secondary end points were cardiac death, myocardial infarction, stroke, or repeat revascularization. RESULTS: PCI, CABG, and MT alone were performed in 933 (52.1%), 459 (25.6%), and 400 (22.3%) patients. Both PCI and CABG were associated with lower all-cause death (4.6% vs. 4.1% vs. 15.5%, respectively, P < 0.01) and cardiac death (2.8% vs. 2.0% vs. 9.8%, respectively, P < 0.01) versus MT alone. The rate of repeat revascularization in the CABG group was significantly lower than those in the PCI and MT groups. After adjusting for baseline factors, PCI and CABG were still associated with similar lower risk of all-cause death and cardiac death versus MT alone (all-cause death: hazard ratio [HR]: 0.35, 95% confidence interval [CI]: 0.23-0.53, P < 0.01 and HR: 0.35, 95% CI: 0.18-0.70, P = 0.003, respectively, and cardiac death: HR: 0.32, 95% CI: 0.19-0.54, P < 0.01 and HR: 0.36, 95% CI: 0.14-0.93, P = 0.03, respectively). CONCLUSIONS: PCI and CABG provided equal long-term benefits for all-cause death and cardiac death for PTVD patients. Patients undergoing MT alone had the worst long-term clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov; Identifier: NCT02634086. https://www.clinicaltrials.gov/ct2/show/record/NCT02634086?term=NCT02634086&rank= . PMID- 29271374 TI - Relationship between Neutrophil-to-Lymphocyte Ratio and Pulse Wave Velocity in Young Patients with Systemic Lupus Erythematosus. AB - BACKGROUND: The incidence of atherosclerosis-related myocardial infarction can be as much as 50-fold greater in young patients with systemic lupus erythematosus (SLE) than in age-matched controls. There are several explanations for this phenomenon, all of which result in a chronic state of low-grade inflammation. Recently, the neutrophil-to-lymphocyte ratio (NLR) has been proposed as a useful biomarker of inflammation. Pulse wave velocity (PWV) is a reliable indicator of vascular damage and atherosclerosis. There is a paucity of data concerning the relationship between NLR and atherosclerosis as measured by PWV in patients with SLE. This study aimed to verify whether there is a positive correlation between NLR and PWV and to explore factors that influence PWV in young SLE patients. METHODS: A total of 90 female patients with SLE were enrolled in this cross sectional investigation. Traditional and nontraditional cardiovascular risk factors were assessed on the same day that brachial-ankle PWV (baPWV) was examined. The patients were divided into three groups according to their mean baPWV values: patients whose mean baPWV value was lower than the first tertile were placed in Group 1; patients whose mean baPWV value was between the first tertile and the second tertile were placed in Group 2; and patients whose mean baPWV value was higher than the second tertile were placed in Group 3. SPSS 20.0 was used to perform all statistical analyses in this study. Both univariate linear regression and multivariate regression models were utilized to analyze the association between NLR and arterial stiffness. RESULTS: Systolic blood pressure, diastolic blood pressure (DBP), and triglycerides were all significantly different among Groups 1, 2, and 3 (111.90 +/- 12.85 mmHg vs. 114.60 +/- 12.88 mmHg vs. 129.43 +/- 16.21 mmHg, P < 0.001; 68.77 +/- 8.63 mmHg vs. 71.87 +/- 9.77 mmHg vs. 82.57 +/- 14.89 mmHg, P < 0.001; and 1.44 [0.91-2.47] mmol/L vs. 0.98 [0.78-1.26] mmol/L vs. 2.20 [0.94-3.66] mmol/L, P = 0.030; respectively), as were creatinine (57.50 [52.00-69.00] MUmol/L vs. 55.50 [49.00-64.00] MUmol/L vs. 64.00 [56.00-86.00] MUmol/L, P = 0.045) and blood urea nitrogen (4.27 [3.79-6.22] mmol/L vs. 4.16 [3.47-4.84] mmol/L vs. 5.88 [4.04-8.19] mmol/L, P = 0.011). NLRs were significantly different among Groups 1, 2, and 3 (2.16 [1.56-3.42] vs. 3.12 [1.91-4.19] vs. 5.29 [2.63-7.25], P = 0.001). NLR, together with DBP and the SLE disease activity index, independently predicts PWV. CONCLUSIONS: This study demonstrated that there was a positive correlation between NLR and PWV. Moreover, we found that disease activity and DBP were also positively correlated with PWV. PMID- 29271375 TI - Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma. AB - BACKGROUND: The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) negatively regulates phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor development and chemosensitivity of lung adenocarcinoma (ADC). METHODS: We retrospectively investigated the expression and significance of NEDD4-1, PTEN, and p-Akt proteins in 135 paired ADC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthermore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3- (4,5 dimethylthiazol-2-yl) -5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)- 2H tetrazolium method. The ability of migration and invasion of A549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase (PI3K)/Akt activity, and its downstream target proteins. RESULTS: NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression of NEDD4-1 in ADC (78.5%, 106/135) was significantly much higher than that in adjacent normal lung tissue (13.3%, 29/135, P < 0.01), and it was associated with lymph node metastasis, tumor-node metastasis (TNM) stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC (60.7% vs. 100.0% in noncancerous specimens, P = 0.007), and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues (71.1% 96/135) was much higher than that in adjacent lung epithelial cells (6.7%, 9/135, P < 0.01). Kaplan-Meier and multivariate analysis demonstrated that expressions of NEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins. CONCLUSIONS: NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the PI3K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC. PMID- 29271376 TI - Path Analysis on Medical Expenditures of 855 Patients with Chronic Kidney Disease in a Hospital in Beijing. AB - BACKGROUND: Investigate into the medical expenditures of chronic kidney disease (CKD) patients through path analysis method of three consecutive years within a Grade-A tertiary hospital in Beijing to conduct the main influencing factors in diagnosis-related groups (DRGs) grouping of the diagnosis, and reassess the present grouping process to provide information and reference on cost control for hospitals and medical management departments. METHODS: Eight hundred and fifty five inpatient cases whose first diagnosis were defined as CKD in the year 2014 2016 within the hospital were selected as the sample of the study, multiple linear regression and path analysis method were adopted in DRGs grouping process to investigate the main influencing factors of total medical expenditures and DRGs grouping process. RESULTS: The maximum proportion of the medical costs within CKD patients was the costs on treatment, with the highest of 35.3% on the year 2014, the second was the costs on drug, which accounted for <30% during consecutive years, and the third was the costs on examination, which accounted for about 20% on average. The main influencing factors of medical expenditures included the type of dialysis, length of hospitalization, the admission of Intensive Care Unit (ICU), and so on. The coefficients toward the effect for total costs were 0.416, 0.376, and 0.094, respectively. CONCLUSIONS: It is suggested that the type of dialysis and the admission of ICU were the major influencing factors of inpatient medical expenditures on CKD patients, and should be taken into consideration into the reassessment of DRGs grouping process to realize the localization and generalization of prospective payment system based on DRGs within the regional area and promote the implementation of medical cost control measures to reduce the economic burdens among patients and the society. PMID- 29271377 TI - Diagnosis and Differential Diagnosis of Desmoplastic Fibroblastoma by Clinical, Radiological, and Histopathological Analyses. AB - BACKGROUND: Desmoplastic fibroblastoma (collagenous fibroma) is an uncommon benign soft-tissue tumor, rarely involving bone. It shares some overlapping features with other infiltrate tumors, such as desmoid-type fibromatosis, neurofibroma, and low-grade fibromyxoid sarcoma. The misdiagnosis may cause unnecessary surgical overtreatment, especially for those involving bone. In order to deepen the understanding of the diagnosis and differential diagnosis of desmoplastic fibroblastoma, we planned to analyze the clinical, radiological, and histopathological features and the outcome of desmoplastic fibroblastoma on the basis of case analysis and literature review. METHODS: Sixteen cases were retrieved from the surgical pathology records from May 2011 to April 2016 in the Department of Pathology in Beijing Jishuitan Hospital. Formalin-fixed, paraffin embedded specimens of 16 cases of desmoplastic fibroblastoma were collected. Hematoxylin and eosin stain and immunohistochemistry were used to observe the histological features of desmoplastic fibroblastoma of soft tissue and bone. The images for diagnosis obtained from the ultrasonic examination, X-ray, magnetic resonance imaging, and computed tomography were used to observe the radiological features. Related literatures were retrieved from the PubMed and CNKI databases. RESULTS: Sixteen cases of desmoplastic fibroblastoma of soft tissue were located in the hand (n = 7), foot (n = 4), upper arm (n = 1), shoulder (n = 1), forearm (n = 2), and one case occurred in the proximal femur. Age ranged from 32 to 82 years (median age: 58 years). There were six females and ten males. Histologically, the lesions of soft tissue appeared as well-circumscribed masses with abundant collagenous matrix and low vascularity. Tumor cells were stellate- or spindle-shaped and uniformly distributed within the extracellular matrix. In five cases, the desmoplastic fibroblastoma were found to have infiltrated into the skeletal muscle tissue. In one case of desmoplastic fibroblastoma of bone, radiographs revealed osteolytically well-defined lesion. Immunohistochemistry stain showed that vimentin and smooth muscle actin were positive in all cases of desmoplastic fibroblastoma. CONCLUSIONS: Desmoplastic fibroblastoma (collagenous fibroma) has prominent clinical, histopathological, and radiological features. Before the differential diagnosis from other tumors is obtained by thorough analysis and comparison of the similar and different characteristics, the appropriate surgical management and accurate prognosis evaluation could not be delivered to the patient. PMID- 29271378 TI - Analysis of the Characteristics of Pregnancy and Delivery before and after Implementation of the Two-child Policy. AB - BACKGROUND: After the two-child policy is fully implemented, new challenges regarding pregnancy management and the treatment of pregnancy complications will arise. The aim of this study was to analyze the characteristics of pregnancy and delivery before and after the implementation of the two-child policy to make suggestions on the quality assurance of the new era of obstetrics. METHODS: In total, 5895 cases of pregnant women who delivered from April 2016 to March 2017 in Peking University Third Hospital served as the study group and 5103 cases of pregnant women who delivered from January to December 2015 served as the control group. The characteristics of pregnancy and delivery were retrospectively analyzed. RESULTS: In the study group, the percentage of pregnant women who were older (over 40 years) (3.6% vs. 2.2%), were multipara (30.3% vs. 17.0%), received irregular prenatal care (1.5% vs. 0.9%), were transferred for treatment from a subordinate hospital (4.4% vs. 2.8%), and were not residents of Beijing (3.8% vs. 2.2%), were significantly increased compared with the control group (P < 0.05). In the study group, the rate of a hypertensive disorder complicating pregnancy (6.4% vs. 5.0%), gestational diabetes mellitus (25.3% vs. 23.1%), dangerous placenta previa (3.0% vs. 2.3%), placental implantation (2.4% vs. 1.8%), and severe postpartum hemorrhage (2.8% vs. 1.9%) was significantly increased compared with the control group (P < 0.05). In the study group, the cesarean section rate during primipara was significantly reduced compared with the control group (42.0% vs. 44.2%). However, the rate during multipara was significantly increased compared with the control group (P < 0.05). Indications for cesarean section in the study group as well as the percentages of scared uterus and placenta previa were significantly increased compared with the control group (P < 0.05). CONCLUSIONS: According to the current situation, better methods are needed to strengthen pregnancy and delivery management, reduce the rate of cesarean section, and ensure a positive outcome for mothers and babies. PMID- 29271380 TI - Prevalence and Associated Factors of Eating Disorders in Weight Management Centers in Tanta, Egypt. AB - BACKGROUND: Eating disorders (EDs) are serious illnesses associated with medical complications and have been increased, especially among societies with an excessive concern about weight, shape, or appearance. This study aimed to investigate the prevalence of EDs among the individuals attending weight management centers and its associated factors. METHODS: A cross-sectional study was carried out among individuals attending four weight management centers in Tanta, Gharbia Governorate, Egypt during the period from July to December 2016. Precoded interview questionnaires were used to identify the following data: sociodemographic characteristics and medical history of depression or psychological disorders and the Eating Attitude Test (EAT-40) was used to assess the attitudes, behavior, and traits associated with the EDs. RESULTS: A total of 400 participants (112 males and 288 females) were included in the study. According to EAT-40 questionnaires, the prevalence of positive and negative EDs was 65.0% (n = 260) and 35.0% (n = 140), respectively. EDs were more likely reported by females, married singles, rural residents, those with higher education, and nonworking or part-time working patients, those who were overweight or obese, and who were suffering from depression or any psychological problems. Logistic regression analysis revealed that the independent predictors of EDs were age (adjusted odds ratio [OR]: 1.06), nonworking (adjusted OR: 2.32) or part-time working (adjusted OR: 2.18), increased body weight (adjusted OR: 2.66 for overweight and adjusted OR: 1.24 for obese), and having a history of depression or any psychological problem (adjusted OR: 2.76). Factor analysis of EAT-40 revealed four factors (eating behavior, diet-related lifestyle, weight concern, and food preoccupation) that were responsible for 33.2% of the total variance. CONCLUSIONS: EDs are prevalent among individuals attending the weight management centers in a northern city in Egypt. Specific management strategies are warranted to address this commonly prevalent disease. PMID- 29271379 TI - Plasmacytoid Dendritic Cell Function and Cytokine Network Profiles in Patients with Acute or Chronic Hepatitis B Virus Infection. AB - BACKGROUND: Plasmacytoid dendritic cells (pDCs) and cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to explore the frequency and function of pDC and serum cytokine network profiles in patients with acute or chronic HBV infection. METHODS: The healthy individuals (HI group), hepatitis B envelope antigen (HBeAg)-positive chronic HBV patients in immune tolerance (IT) phase (IT group), HBeAg-positive chronic HBV patients (CHB group), and acute HBV patients (AHB group) were enrolled in this study. The frequency of cluster of differentiation antigen 86 (CD86) + pDC and the counts of CD86 molecular expressed on surface of pDC were tested by flow cytometer. The quantitative determinations of cytokines, including Fms-like tyrosine kinase 3 ligand (Flt-3L), interferon (IFN)-alpha2, IFN-gamma, interleukin (IL)-17A, IL-6, IL-10, transforming growth factor (TGF)-beta1 and TGF beta2, were performed using Luminex multiplex technology. RESULTS: In this study, there were 13 patients in HI group, 30 in IT group, 50 in CHB group, and 32 in AHB group. Compared with HI group, HBV infected group (including all patients in IT, CHB and AHB groups) had significantly higher counts of CD86 molecular expressed on the surface of pDC (4596.5 +/- 896.5 vs. 7097.7 +/- 3124.6; P < 0.001). The counts of CD86 molecular expressed on the surface of pDC in CHB group (7739.2 +/- 4125.4) was significantly higher than that of IT group (6393.4 +/- 1653.6, P = 0.043). Compared with IT group, the profile of cytokines of Flt-3L, IFN-gamma, and IL-17A was decreased, IFN-alpha2 was significantly increased (P = 0.012) in CHB group. The contents of IL-10, TGF-beta1, and TGF-beta2 in AHB group were significantly increased compared with IT and CHB groups (all P < 0.05). CONCLUSIONS: This study demonstrated that the function of pDC was unaffected in HBV infection. The enhanced function of pDC and IFN-alpha2 might involve triggering the immune response from IT to hepatitis active phase in HBV infection. Acute patients mainly presented as down-regulation of the immune response by enhanced IL-10 and TGF-beta. PMID- 29271381 TI - Risk Factors for Carbapenem-resistant Klebsiella pneumoniae Infection and Mortality of Klebsiella pneumoniae Infection. AB - BACKGROUND: Klebsiella pneumoniae (KP) is a pathogen commonly causing nosocomial infection. Carbapenem-resistant KP (CRKP) is more resistant to multiple antimicrobial drugs than carbapenem-susceptible KP (CSKP) isolates. The aim of the present study was to identify the risk factors for CRKP infection and the predictors of mortality among KP-infected adult patients. METHODS: Patients with CRKP and CSKP infection were categorized as the case group and control group, respectively, and we conducted a 1:1 ratio case-control study on these groups. The CRKP isolates collected were tested for antimicrobial susceptibility and presence of KP carbapenemase (KPC) gene. Clinical data were collected to identify risk factors for CRKP infection and mortality of KP infection. Risk factors were analyzed under univariable and multivariable logistic regression model. RESULTS: The independent risk factors for CRKP infection were admission to Intensive Care Unit (odds ratio [OR]: 15.486, 95% confidence interval [CI]: 3.175-75.541, P < 0.001); use of beta-lactams and beta-lactamase inhibitor combination (OR: 4.765, 95% CI: 1.508-15.055, P = 0.008); use of cephalosporins (OR: 8.033, 95% CI: 1.623 39.763, P = 0.011); fluoroquinolones (OR: 6.090, 95% CI: 1.343-27.613, P = 0.019); and indwelling of urethral catheter (OR: 6.164, 95% CI: 1.847-20.578, P = 0.003). However, older age (OR: 1.079, 95% CI: 1.005-1.158, P = 0.036), Charlson comorbidity index (OR: 4.690, 95% CI: 2.094-10.504, P = 0.000), and aminoglycoside use (OR: 670.252, 95% CI: 6.577-68,307.730, P = 0.006) were identified as independent risk factors for patient deaths with KP infection. The mortality of CRKP group was higher than that of the CSKP group. KPC gene did not play a role in the CRKP group. CRKP mortality was high. CONCLUSION: Implementation of infection control measures and protection of the immunefunction are crucial. PMID- 29271382 TI - Diffusion-weighted 7.0T Magnetic Resonance Imaging in Assessment of Intervertebral Disc Degeneration in Rats. AB - BACKGROUND: Intervertebral disc degeneration (IDD) is a major cause of disc protrusion, likely to be associated with decrease of water content. This research aimed to evaluate IDD by diffusion-weighted imaging (DWI) with a 7.0 Tesla (T) magnetic resonance imaging (MRI) machine. METHODS: A total of 24 healthy Sprague Dawley rats were randomly selected and divided into four groups (A, B, C, and D), each consisting of 3 male and 3 female rats (28, 42, 56, and 70 days old, respectively). All the rats were imaged with a 7.0T MRI, producing T2WI, T1WI, and functional DWI sequences. Data were collected and apparent diffusion coefficient (ADC) charts were constructed. Nucleus pulposus and annulus fibrosus regions were identified, several regions of interest were chosen, and their ADC values were obtained. After imaging, rats were sacrificed and their intervertebral discs (L1-L6) were dissected, yielding a total of 144 discs. Protein was extracted for the purpose of Western blotting. Comparison among multiple samples used one-way analysis of variance and least significant difference methods. RESULTS: 7.0T MRI revealed evident decrease in signal intensity within intervertebral discs of Sprague-Dawley rats with age. Intervertebral disc ADC values significantly decreased from Group A (0.00154 +/- 0.00008) to Group D (0.00107 +/- 0.00007; P < 0.01); nucleus pulposus ADC values significantly decreased from Group A (0.00164 +/- 0.00005) to Group D (0.00140 +/ 0.00007; P < 0.01) and annulus fibrosus ADC values significantly decreased from Group A (0.00129 +/- 0.00014) to Group D (0.00082 +/- 0.00012; P < 0.01). Meanwhile, it also revealed evident decrease from high spinal level to low spinal level: nucleus pulposus ADC values in Group A significantly decreased from L1/L2 (0.00163 +/- 0.00006) to L6/S1 (0.00139 +/- 0.00004; P < 0.01). While annulus fibrosus ADC values did not differ significantly between levels in Group A (P > 0.05). Western blotting showed that aggrecan content of intervertebral discs decreased from Group A (1.88 +/- 0.16) to Group D (0.17 +/- 0.04) with age (P < 0.01); Type II collagen content of intervertebral discs decreased from Group A (2.22 +/- 0.04) to Group D (0.20 +/- 0.01) with age (P < 0.01). No significant differences in aggrecan and Type II collagen content of L1-L6 intervertebral discs in Group A were noted (P > 0.05). Mean ADC values of different intervertebral regions were positively correlated with aggrecan and Type II collagen content (aggrecan: r = 0.631, P < 0.01; Type II collagen: r = 0.680, P < 0.01). CONCLUSION: 7.0T MRI-DWI could be applied to effectively diagnose and research early IDD in tiny variations. PMID- 29271383 TI - Magnetic Resonance Imaging and Biomechanical Analysis of Adipose-derived Stromal Vascular Fraction Applied on Rotator Cuff Repair in Rabbits. AB - BACKGROUND: Adipose-derived stromal vascular fraction (ADSVF) can be applied to repair tendon and ligament tears. ADSVF treatment has a better therapeutic potential than adipose stem cells alone in promoting the healing of connective tissue injury in rabbit models. Magnetic resonance imaging (MRI) and biomechanical testing were used in this study to evaluate the efficiency of SVF in the healing of tendon-bone interface of a rotator cuff injury after reattachment. METHODS: A total of 36 rabbits were studied between March and June 2016, 18 rabbits received the SVF-fibrin glue (SVF-FG) treatment and the other 18 formed the control group. ADSVF was isolated from each rabbit. A bilateral amputation of the supraspinatus tendon and parallel reconstruction was also performed on all the 36 rabbits. Then, a mixture of SVF and FG was injected into the tendon-bone interface of the SVF-FG group, whereas the control group only received FG. The animals were randomly sacrificed at 4, 8, and 12 weeks after surgery (n = 6 per group), respectively. The shoulders were prepared for MRI scanning and analysis of biomechanical properties. Analyses of variance were performed using SPSS 13.0. RESULTS: MRI scanning showed that the signal-to-noise quotient of the SVF-FG group was not significantly higher than that of the control group at either 4 (20.1 +/- 3.6 vs. 18.2 +/- 3.4, F = 1.570, P = 0.232) or 8 weeks (20.7 +/- 3.3 vs. 18.0 +/- 3.0, F = 2.162, P = 0.117) posttreatment, and only became significant after 12 weeks (27.5 +/- 4.6 vs. 22.1 +/- 1.9, F = 4.968, P = 0.009). Biomechanical properties such as the maximum load, maximum strength, and the stiffness for the SVF-FG group were significantly greater than that for the control group at 8 weeks' posttreatment (maximum load: 166.89 +/- 11.62 N vs. 99.40 +/- 5.70 N, P < 0.001; maximum strength: 8.22 +/- 1.90 N/mm vs. 5.82 +/-0.68 N/mm, P < 0.010; and the stiffness: 34.85+/- 3.00 Pa vs. 24.57+/- 5.72 Pa, P < 0.010). CONCLUSION: Local application of ADSVF might lead to better tendon-bone healing in rabbit models. PMID- 29271384 TI - Protective Effects of Leukemia Inhibitory Factor on Retinal Vasculature and Cells in Streptozotocin-induced Diabetic Mice. AB - BACKGROUND: Leukemia inhibitory factor (LIF) has been reported to possess various pharmacological effects, including displaying vascular and neuroprotective properties, during retinal disease. The aim of this study was to investigate the vascular and structural changes in the retina of diabetic mice and to explore whether LIF prevents experimental diabetes-induced retinal injury in the early stages. METHODS: Diabetes was induced in C57Bl/6J mice with streptozotocin (STZ) injections. Successful diabetic animal models were randomly separated into two groups: the diabetic group (n = 15) and the LIF-treated group (n = 15). Normal C57BL/6 mice served as the normal control group (n = 14). Recombinant human LIF was intravitreally injected 8 weeks after the diabetic model was successfully established. Retinas were collected and evaluated using histological and immunohistochemical techniques, and flat-mounted retinas and Western blotting were performed at 18 weeks after the induction of diabetes and 2 days after the intravitreal injection of LIF. The analysis of variance test were used. RESULTS: Histological analysis showed that there were fewer retinal ganglion cells (RGCs) and the inner nuclear layer (INL) became thinner in the diabetic model group (RGC 21.8 +/- 4.0 and INL 120.2 +/- 4.6 MUm) compared with the normal control group (RGC 29.0 +/- 6.7, t = -3.02, P = 0.007; INL 150.7 +/- 10.6 MUm, t = -8.88, P < 0.001, respectively). After LIF treatment, the number of RGCs (26.9 +/- 5.3) was significantly increased (t = 3.39, P = 0.030) and the INL (134.5 +/- 14.2 MUm) was thicker compared to the diabetic group (t = 2.75, P = 0.013). In the anti-Brn 3a-labeled retinas, the number of RGCs in the LIF-treated group (3926.0 +/- 143.9) was obviously increased compared to the diabetic group (3507.7 +/- 286.1, t = 2.38, P = 0.030), while no significance was found between the LIF-treated group and the control group (4188.3 +/- 114.7, t = -2.47, P = 0.069). Flat mounted retinas demonstrated that a disorganized, dense distribution of the vessel was prominent in the diabetic model group. Vessel distribution in the LIF treated mouse group was typical and the thickness was uniform. The levels of phosphosignal transducer and activator of transcription 3 activation were obviously higher in the LIF-injected retinas than those in the diabetic control group (t = 3.85, P = 0.019) and the normal control (t = -3.20, P = 0.019). CONCLUSION: The present study provides evidence that LIF treatment protects the integrity of the vasculature and prevents retinal injury in the early stages of diabetic retinopathy in STZ-induced diabetic models. PMID- 29271385 TI - Anti-apoptosis Effect of Decoy Receptor 3 in Cholangiocarcinoma Cell Line TFK-1. AB - BACKGROUND: Decoy receptor 3 (DcR3) is a protein with anti-apoptotic effect that belongs to the tumor necrosis factor receptor superfamily. DcR3 is highly expressed in a variety of malignant tumors including cholangiocarcinoma and its expression was found to be related to the clinical stage, the invasion, and the metastasis of the tumor. This in vitro study aimed to investigate the effect of downregulated expression of DcR3 on cell viability, cell apoptosis, and cell cycle in cholangiocarcinoma cell line TFK-1. METHODS: Three different cell lines were cultured: human cholangiocarcinoma TFK-1, human biliary epithelial carcinoma HuCCT-1, and human cholangiocarcinoma RBE. The cholangiocarcinoma cell line with the highest expression of DcR3 was selected for further investigation. The expression of DcR3 was silenced/knocked down by transfection with DcR3-siRNA in the selected cell line. Various biological phenotype parameters such as cell viability, apoptosis, and cell cycle were observed. RESULTS: The mRNA and protein levels of DcR3 were measured in the three cell lines, and TFK-1 was selected. After the treatment with DcR3-siRNA for 48 h, DcR3 mRNA and protein expression in the treatment group were 38.45% (P < 0.01) and 48.03% (P < 0.05) of that of the control, respectively. It was found that the cell viability decreased to 61.87% of the control group (P < 0.01) after the downregulation of DcR3 in cholangiocarcinoma cell line TFK-1 by transfection with DcR3-siRNA, while the percentage of apoptotic cells was 2.98 times as compared with the control group (P < 0.05). Compared with the control group the ratio of G0/G1increased, and the ratio of G2/M decreased in the treatment group. However, the differences were not statistically significant. CONCLUSIONS: The effect of DcR3 on the growth and apoptosis of cholangiocarcinoma has been demonstrated. DcR3 is not only a predictive marker for malignant tumor but it is also likely to be a potential target for cancer gene therapy. Further studies should focus on exploring the binding ligand of DcR3, the signaling pathway involved, and the molecular mechanism for the regulation of DcR3 expression in cholangiocarcinoma. PMID- 29271387 TI - Skin Microbiome: An Actor in the Pathogenesis of Psoriasis. PMID- 29271386 TI - Development of Bariatric and Metabolic Endoscopy. AB - OBJECTIVE: With the evolution of society and changes in human lifestyle, obesity is becoming increasingly prevalent worldwide, and obesity-related comorbidities such as diabetes, hyperlipidemia, hypertension, and coronary heart disease are more common. As a result, new devices and methods for bariatric and metabolic endoscopy are being developed for clinical use, offering new options for patients. This review discussed the progress in bariatric and metabolic endoscopy. DATA SOURCES: This review was based on data in articles published in the PubMed database up to September 2017, with the following keywords: "obesity", "endoscopy", "weight loss", and "metabolism". STUDY SELECTION: Original articles about various endoscopic methods of weight loss and other reviews of bariatric and metabolic endoscopy were included and analyzed. RESULTS: The technology of bariatric and metabolic endoscopy has advanced rapidly in recent years. The intragastric balloon (IGB), with its comparatively long period of development, is the most mature and widely used instrument. Multiple new endoscopic devices have been created in recent years, with different targets to achieve weight loss. Despite the proliferation of new devices, the lack of clinical data results in a shortage of clinical experience and instruction in the use of this new equipment. CONCLUSIONS: Bariatric and metabolic endoscopy would help obese people lose weight or prepare for bariatric surgery and hopefully alleviate some of the complications of bariatric procedures. Adequate studies and data are still needed for the new endoscopic devices. PMID- 29271388 TI - Anxiety and Depression among Families of Deceased Donors in China. PMID- 29271389 TI - Intrauterine Cardiac Intervention for Fetal Pulmonary Valve Obstruction Lesion. PMID- 29271390 TI - Is Warfarin Indicated in Behcet's Syndrome Associated with Thrombosis? Reflections on Treatment and Death of a Patient. PMID- 29271391 TI - Mucoepidermoid Carcinomas Presented as Lobar Pneumonia. PMID- 29271392 TI - Acute Epiglottitis in a Diabetic Adult Patient. PMID- 29271393 TI - Long-term Survival Associated with Crizotinib in a Lung Cancer Patient with a Pulmonary Artery Embolism. PMID- 29271394 TI - A Case of Primary Vitreous Retinal Lymphoma. PMID- 29271395 TI - Eosinophilic Pustular Folliculitis Associated with Cutaneous Angiosarcoma. PMID- 29271396 TI - Spontaneous Absorption of a Lumbar Epidural Hematoma after Interlaminar Epidural Steroid Injection in a Patient with Spinal Stenosis: Close Observation as a Treatment Strategy. PMID- 29271397 TI - The transcription factor ZEB1 promotes an aggressive phenotype in prostate cancer cell lines. AB - It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial-mesenchymal transition program. This process is associated with tumoral cells acquiring invasive and malignant properties and has the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) as one of its main activators. However, the role of ZEB1 in promoting malignancy in prostate cancer (PCa) is still unclear. Here, we report that ZEB1 expression correlates with Gleason score in PCa samples and that expression of ZEB1 regulates epithelial-mesenchymal transition and malignant characteristics in PCa cell lines. The results showed that ZEB1 expression is higher in samples of higher malignancy and that overexpression of ZEB1 was able to induce epithelial mesenchymal transition by upregulating the mesenchymal marker Vimentin and downregulating the epithelial marker E-Cadherin. On the contrary, ZEB1 silencing repressed Vimentin expression and upregulated E-Cadherin. ZEB1 expression conferred enhanced motility and invasiveness and a higher colony formation capacity to 22Rv1 cells whereas DU145 cells with ZEB1 silencing showed a decrease in those same properties. The results showed that ZEB1 could be a key promoter of tumoral progression toward advanced stages of PCa. PMID- 29271398 TI - Abnormal synapses, recombination, and impaired double-strand break repair in a man with nonobstructive azoospermia. PMID- 29271399 TI - Intermittent, low-dose, antiandrogen monotherapy as an alternative therapeutic option for patients with positive surgical margins after radical prostatectomy. AB - The aim of the present study was to determine whether oncologic outcomes and adverse events associated with active on/off intermittent antiandrogen monotherapy (daily bicalutamide, 50 mg per day) are comparable with those of standard external beam radiation therapy (EBRT) or combined androgen blockade (CAB) therapy in prostate cancers with positive surgical margins after radical prostatectomy. Two hundred twenty-three patients with positive surgical margins post-radical prostatectomy who underwent active surveillance (AS, n = 32), EBRT without hormone therapy (n = 55), intermittent antiandrogen monotherapy without EBRT (IAAM, n = 50), or CAB without EBRT (n = 86), between 2007 and 2014, were reviewed retrospectively. Pathologic outcomes, biochemical recurrence rates, radiological disease progression, and adverse events were collected from medical records. Biochemical recurrence rates, biochemical recurrence-free survival rates, and radiological recurrence were not different between the groups (P = 0.225, 0.896, and 0.284, respectively). Adverse event rates and severities were lower for IAAM compared with EBRT or CAB (both P < 0.05), but were comparable to those for AS (P = 0.591 and 0.990, respectively). Grade >=3 adverse events were not reported in the IAAM or AS groups. Erectile dysfunction and loss of libido rates were lower in the IAAM group compared with the EBRT and CAB groups (P = 0.032). Gastrointestinal complications were more frequently reported in the EBRT group (P = 0.008). Active on/off IAAM treatment might be an appropriate treatment option for patients with positive surgical margins after radical prostatectomy. Furthermore, regarding oncologic outcomes, IAAM was comparable to standard EBRT but had a milder adverse event profile. PMID- 29271401 TI - Corrigendum: Superstatistical model of bacterial DNA architecture. AB - This corrects the article DOI: 10.1038/srep43034. PMID- 29271400 TI - Phosphoglycerate mutase 1 knockdown inhibits prostate cancer cell growth, migration, and invasion. AB - Phosphoglycerate mutase 1 (PGAM1) is upregulated in many cancer types and involved in cell proliferation, migration, invasion, and apoptosis. However, the relationship between PGAM1 and prostate cancer is poorly understood. The present study investigated the changes in PGAM1 expression in prostate cancer tissues compared with normal prostate tissues and examined the cellular function of PGAM1 and its relationship with clinicopathological variables. Immunohistochemistry and Western blotting revealed that PGAM1 expression was upregulated in prostate cancer tissues and cell lines. PGAM1 expression was associated with Gleason score (P = 0.01) and T-stage (P = 0.009). Knockdown of PGAM1 by siRNA in PC-3 and 22Rv1 prostate cancer cell lines inhibited cell proliferation, migration, and invasion and enhanced cancer cell apoptosis. In a nude mouse xenograft model, PGAM1 knockdown markedly suppressed tumor growth. Deletion of PGAM1 resulted in decreased expression of Bcl-2, enhanced expression of Bax, caspases-3 and inhibition of MMP-2 and MMP-9 expression. Our results indicate that PGAM1 may play an important role in prostate cancer progression and aggressiveness, and that it might be a valuable marker of poor prognosis and a potential therapeutic target for prostate cancer. PMID- 29271402 TI - Corrigendum: Development and validation of a prognostic model for predicting 30 day mortality risk in medical patients in emergency department (ED). AB - This corrects the article DOI: 10.1038/srep46474. PMID- 29271403 TI - Corrigendum: Scavenger receptor collectin placenta 1 is a novel receptor involved in the uptake of myelin by phagocytes. AB - This corrects the article DOI: 10.1038/srep44794. PMID- 29271404 TI - Corrigendum: Vidatox 30 CH has tumor activating effect in hepatocellular carcinoma. AB - This corrects the article DOI: 10.1038/srep44685. PMID- 29271405 TI - Corrigendum: Drosophila Dullard functions as a Mad phosphatase to terminate BMP signaling. AB - This corrects the article DOI: 10.1038/srep32269. PMID- 29271406 TI - Corrigendum: Feasibility of placenta-derived mesenchymal stem cells as a tool for studying pregnancy-related disorders. AB - This corrects the article DOI: 10.1038/srep46220. PMID- 29271407 TI - Corrigendum: CRISPR/Cas9-mediated efficient and heritable targeted mutagenesis in tomato plants in the first and later generations. AB - This corrects the article DOI: 10.1038/srep24765. PMID- 29271408 TI - Corrigendum: The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells. AB - This corrects the article DOI: 10.1038/srep42845. PMID- 29271409 TI - Erratum: Variation of outdoor illumination as a function of solar elevation and light pollution. AB - This corrects the article DOI: 10.1038/srep26756. PMID- 29271410 TI - Corrigendum: SUV39H1 Reduction Is Implicated in Abnormal Inflammation in COPD. AB - This corrects the article DOI: 10.1038/srep46667. PMID- 29271411 TI - Corrigendum: Kinetic ways of tailoring phases in high entropy alloys. AB - This corrects the article DOI: 10.1038/srep34628. PMID- 29271412 TI - Corrigendum: Soil warming enhances the hidden shift of elemental stoichiometry by elevated CO2 in wheat. AB - This corrects the article DOI: 10.1038/srep23313. PMID- 29271413 TI - Concordance study of PD-L1 expression in primary and metastatic bladder carcinomas: comparison of four commonly used antibodies and RNA expression. AB - Therapy with anti-PD-L1 immune check-point inhibitors is approved for several cancers, including advanced urothelial carcinomas. PD-L1 prevalence estimates vary widely in bladder cancer, and lack of correlation between expression and clinical outcomes and immunotherapy response may be attributed to methodological differences of the immunohistochemical reagents and procedures. We characterized PD-L1 expression in 235 urothelial carcinomas including 79 matched pairs of primary and metastatic cancers using a panel of four PD-L1 immunoassays in comparison with RNAscope assay using PD-L1-specific probe (CD274). The antibody panel included three FDA-approved clones (22C3 for pembrolizumab, 28.8 for nivolumab, SP142 for atezolizumab), and a commonly used clone E1L3N. Manual scoring of tissue microarrays was performed in each of 235 tumors (624 tissue cores) and compared to an automated image analysis. Expression of PD-L1 in tumor cells by >=1 marker was detected in 41/142 (28.9%) primary tumors, 13/77 (16.9%) lymph nodes, and 2/16 (12.5%) distant metastases. In positive cases, high PD-L1 expression (>50% cells) was detected in 34.1% primary and 46.7% metastases. Concordant PD-L1 expression status was present in 71/79 (89.9%) cases of matched primary and metastatic urothelial carcinomas. PD-L1 sensitivity ranked from highest to lowest as follows: RNAscope, clone 28.8, 22C3, E1L3N, and SP142. Pairwise concordance correlation coefficients between the four antibodies in 624 tissue cores ranged from 0.76 to 0.9 for tumor cells and from 0.30 to 0.85 for immune cells. RNA and protein expression levels showed moderate to high agreement (0.72-0.87). Intra-tumor expression heterogeneity was low for both protein and RNA assays (interclass correlation coefficients: 0.86-0.94). Manual scores were highly concordant with automated Aperio scores (0.94-0.97). A significant subset of 56/235 (23.8%) urothelial carcinomas stained positive for PD-L1 with high concordance between all four antibodies and RNA ISH assay. Despite some heterogeneity in staining, the overall results are highly concordant suggesting diagnostic equivalence of tested assays. PMID- 29271414 TI - Clinicopathologic and outcome study of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. AB - It is believed that sessile serrated adenomas/polyps lead to the development of microsatellite unstable cancer via a dysplasia-carcinoma sequence. Little is known regarding the morphologic and biologic features, and outcome of sessile serrated adenomas/polyps with dysplasia, or of its specific dysplasia subtypes (intestinal versus serrated). The aims of this study were to analyze and compare the clinical, pathologic, and outcome characteristics of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. The study included 86 patients with sessile serrated adenomas/polyps with dysplasia (50 serrated dysplasia, 22 intestinal dysplasia, 14 mixed serrated and intestinal dysplasia). The clinical and pathologic features, and the prevalence rate of prior, concurrent, and future neoplastic lesions, were compared between sessile serrated adenomas/polyps with intestinal versus serrated dysplasia and with matched control patients with >=1 conventional adenoma. The mean age of the patients, polyp size, and prevalence of adenocarcinoma within the polyps were significantly higher in sessile serrated adenomas/polyps with high versus low-grade dysplasia. Sessile serrated adenomas/polyps with intestinal dysplasia showed a significantly higher rate of adenocarcinoma (23%) compared with those with serrated dysplasia (6%, P=0.05), and the high-grade lesions occurred at a significantly younger age in the former compared with the latter (65 versus 76 years, P=0.05). Compared with patients with conventional adenomas, patients with sessile serrated adenomas/polyps with dysplasia showed a significantly higher rate of invasive carcinoma within the polyps (12 versus 0%, P=0.01) and a significantly lower association with prior or future conventional adenomas. Sessile serrated adenomas/polyps with dysplasia should be considered high-risk neoplastic precursor lesions, particularly those with intestinal dysplasia. Cancer may develop from sessile serrated adenomas/polyps with either type of dysplasia. PMID- 29271417 TI - What is rheology? AB - The topic of the 2017 Cambridge Ophthalmology Symposium was 'Go with the flow: rheology, fluid flow and the eye'. This paper is based on the opening presentation that was aimed to introduce key concepts within the topic of rheology to ophthalmologists and other scientists unfamiliar with the field. Examples are drawn from applications related to the eye. PMID- 29271416 TI - Cryo-EM structure of human ATR-ATRIP complex. AB - ATR (ataxia telangiectasia-mutated and Rad3-related) protein kinase and ATRIP (ATR-interacting protein) form a complex and play a critical role in response to replication stress and DNA damage. Here, we determined the cryo-electron microscopy (EM) structure of the human ATR-ATRIP complex at 4.7 A resolution and built an atomic model of the C-terminal catalytic core of ATR (residues 1 521-2 644) at 3.9 A resolution. The complex adopts a hollow "heart" shape, consisting of two ATR monomers in distinct conformations. The EM map for ATRIP reveals 14 HEAT repeats in an extended "S" shape. The conformational flexibility of ATR allows ATRIP to properly lock the N-termini of the two ATR monomers to favor ATR ATRIP complex formation and functional diversity. The isolated "head-head" and "tail-tail" each adopts a pseudo 2-fold symmetry. The catalytic pockets face outward and substrate access is not restricted by inhibitory elements. Our studies provide a structural basis for understanding the assembly of the ATR ATRIP complex and a framework for characterizing ATR-mediated DNA repair pathways. PMID- 29271415 TI - Clinical relevance and concordance of HER2 status in local and central testing-an analysis of 1581 HER2-positive breast carcinomas over 12 years. AB - Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P<0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates. PMID- 29271418 TI - Matrix regeneration agents improve wound healing in non-stressed human corneal epithelial cells. AB - PurposeMatrix regenerating agents (RGTAs) emerged as promising in vivo wound healing agents. These agents could prove beneficial for the treatment of dry eye disease-associated corneal micro-erosions; therefore, we aimed to evaluate the wound healing efficacy of regenerative agents (RGTAs or serum) in an in vitro model of hyperosmolarity (HO) stressed and non-stressed human corneal epithelial cells.Patients and methodsThe migration and proliferation induced by the regenerative agents was evaluated using an in vitro scratch wound assay and brome deoxy-uridine incorporation. The inflammatory profile and effects of osmoregulators were also investigated. The two-tailed paired t-test calculated the statistical significance, with P-value<0.05 considered significant.ResultsThe most efficient inducer of re-epithelization was 2% serum, followed closely by 2% RGTA with an average improvement in cell migration of 1.8- and 1.4-fold, respectively, when compared with the non-treated control. Hyperosmolar stress significantly reduced the restorative effects of both serum and RGTAs; these effects were, however, neutralized by the osmoregulator betaine.ConclusionThese findings suggest that RGTAs could provide efficient treatment for dry-eye associated corneal micro-lesions if ocular surface HO is neutralized. PMID- 29271419 TI - Surgical outcomes of three different surgical techniques for treatment of convergence insufficiency intermittent exotropia. AB - PurposeTo determine the outcomes of three different techniques of strabismus surgery in patients with convergence insufficiency intermittent exotropia (CI X(T)).Patients and methodsSixty-seven patients with CI-X(T) with near-distance disparity (NDD) >=10 prism diopter (PD) were included in this 1-year follow-up prospective study and were randomly divided into three groups: slanted bilateral LR recession (S-BLR) group in which 22 patients underwent bilateral slanting recession of the lateral rectus (LR) muscle, the I-RR group with 23 patients who underwent improved unilateral medial rectus (MR) resection and LR recession with the amounts of resection and recession biased to near and distance deviation, respectively, and the A-BLR group with 22 patients who underwent bilateral augmented LR recession based on the near deviation. A successful outcome at distant and near was defined as exodeviation between 10 PD of exophoria/tropia and 5 PD of esophoria/tropia. Cumulative probabilities of success, preoperative and postoperative distant, near deviations, and NDD among groups were analyzed and compared.ResultsThe success rate of distant exodeviation, near exodeviation, and NDD in the three groups after 1 year was statistically insignificant (P=0.054, 0.233, and 0.142, respectively). At the 1 year follow-up, vertical pattern strabismus (V and A patterns) was a feature of the S-BLR group, whereas the rate of postoperative overcorrection and undercorrection was significant in the A-BLR and I-RR groups, respectively.ConclusionThe success rate of correction of distant exodeviation, near exodeviation, and NDD was statistically indifferent among the three groups. However, each procedure has its specific postoperative concerns, which should be considered before implementing in patients with CI X(T). PMID- 29271420 TI - Gun trauma and ophthalmic outcomes. AB - PurposeThis retrospective cohort study assesses the visual outcomes of patients who survive gunshot wounds to the head.MethodsThe Elmhurst City Hospital Trauma Registry and Mount Sinai Data Warehouse were queried for gun trauma resulting in ocular injury over a 16-year period. Thirty-one patients over 16 years of age were found who suffered a gunshot wound to the head and resultant ocular trauma: orbital fracture, ruptured globe, foreign body, or optic nerve injury. Gun types included all firearms and air guns. Nine patients were excluded due to incorrect coding or unavailable charts. Statistical analysis was performed using a simple bivariate analysis (chi2).ResultsOf the 915 victims of gun trauma to the head, 27 (3.0%) sustained ocular injuries. Of the 22 patients whose records were accessible, 18 survived. Eight of the 18 surviving patients (44%) suffered long term visual damage, defined as permanent loss of vision in at least one eye to the level of counting fingers or worse. Neither location of injury (P=0.243), nor type of gun used (P=0.296), nor cause of gun trauma (P=0.348) predicted visual loss outcome. The Glasgow Coma Scale eye response score on arrival to the hospital also did not predict visual loss outcome (P=0.793).ConclusionThere has been a dearth of research into gun trauma and even less research on the visual outcomes following gun trauma. Our study finds that survivors of gun trauma to the head suffer long-term visual damage 44% of the time after injury. PMID- 29271422 TI - Skillful prediction of northern climate provided by the ocean. AB - This corrects the article DOI: 10.1038/ncomms15875. PMID- 29271421 TI - Peripapillary retina nerve fiber layer thickness and macular ganglion cell layer thickness in patients with obstructive sleep apnea syndrome. AB - PurposeTo investigate the association of the severity of obstructive sleep apnea syndrome (OSAS) with peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GC-IPL).Materials and methodsIn this cross sectional study, 145 patients with OSAS and 40 healthy subjects were enrolled. OSAS patients were further divided into mild (n=50), moderate (n=36), and severe (n=59) OSAS groups according to their apnea-hypopnea index (AHI) values. Spectral domain optical coherence tomography was used to measure the peripapillary RNFL and GC-IPL thicknesses.ResultsThere was no statistical difference between the RNFL thickness in OSAS and control groups (P>0.05). Both average GC-IPL and minimum GC-IPL thicknesses were significantly lower in severe OSAS group than in healthy controls (P<0.05 for both). There was a significant negative correlation between AHI and both average GC-IPL (r=-0.232, P=0.005) and minimum GC-IPL (r= 0.233, P=0.005) thicknesses.ConclusionsOur study results suggest that although RNFL thickness did not differ significantly between OSAS and control groups, ganglion cell layer thickness in OSAS patients is much lower than in healthy population. Ganglion cell thickness showed a significant correlation with the severity of OSAS. PMID- 29271423 TI - Cavity enhanced liquid-phase stopped-flow kinetics. AB - The first application of liquid-phase broadband cavity enhanced spectroscopy (BBCEAS) to the measurement of stopped-flow kinetics is reported. The stopped flow technique is widely used for the study of the kinetics of fast liquid-phase reactions down to millisecond timescales. UV-visible absorption spectroscopy is commonly used as the detection method. Increased sensitivity can potentially allow reactions which are too fast to be measured, to be studied by slowing down the reaction rate through the use of lower concentration of reactants. A simple low cost BBCEAS experimental setup was coupled to a commercial stopped-flow instrument. Comparative standard absorption measurements were also made using a UV-visible double-beam spectrometer as the detector. Measurements were made on the reaction of potassium ferricyanide with sodium ascorbate under pseudo-first order conditions at pH 8 and pH 9.2 A cavity enhancement factor (CEF) of 78 at 434 nm was obtained whilst the minimum detectable change in the absorption coefficient alphamin(t), was 1.35 * 10-5 cm-1 Hz-1/2. The kinetic data at pH 9.2 was too fast to be measured using conventional spectroscopy, whilst the BBCEAS measurements allowed 30 fold lower concentration of reactants to be used which slowed down the reaction rate enough to allow the rate constant to be determined. The BBCEAS results showed a 58 fold improvement in sensitivity over the conventional measurements and also compared favourably with the relatively few previous liquid-phase cavity enhanced kinetic studies which have been performed using significantly more complex and expensive experimental setups. PMID- 29271424 TI - Water soluble two-photon fluorescent organic probes for long-term imaging of lysosomes in live cells and tumor spheroids. AB - The morphological alteration of lysosomes is a powerful indicator of various pathological disorders. In this regard, we have designed and synthesized a new water soluble fluorescent Schiff-base ligand (L-lyso) containing two hydroxyl groups. L-lyso exhibits excellent two-photon properties with tracking of lysosomes in live cells as well as in 3D tumor spheroids. Furthermore, it can label lysosomes for more than 3 days. Thus, L-lyso has an edge over the commercially available expensive LysoTracker probes and also over other reported probes in terms of its long-term imaging, water solubility and facile synthesis. PMID- 29271425 TI - Emerging biosensor platforms for the assessment of water-borne pathogens. AB - Pathogens are key contaminants in water that are responsible for the generation of various water-borne diseases, and include viruses, fungi, bacteria, and protozoan parasites. The pathogenic effects of these species in water depend on their shape, size, composition, and structure. The resulting water-borne diseases are a serious threat to the environment, including to humans and animals, and are directly responsible for environmental deterioration and pollution. The potential presence of these pathogens requires sensitive, powerful, efficient, and ideally real-time monitoring methods for their reproducible quantification. Conventional methods for pathogen detection mainly rely on time-consuming enrichment steps followed by biochemical identification strategies, which require assay times ranging from 24 h to up to a week. However, in recent years, significant efforts have been made towards the development of biosensing technologies enabling rapid and close-to-real-time detection of water-borne pathogens. This review summarizes recent developments in biosensors and sensing systems based on a variety of transducer technologies for water-quality monitoring, with specific focus on rapid pathogen detection. PMID- 29271426 TI - Combined quantum mechanical and molecular mechanical method for metal-organic frameworks: proton topologies of NU-1000. AB - Metal-organic frameworks (MOFs) are materials with applications in catalysis, gas separations, and storage. Quantum mechanical (QM) calculations can provide valuable guidance to understand and predict their properties. In order to make the calculations faster, rather than modeling these materials as periodic (infinite) systems, it is useful to construct finite models (called cluster models) and use subsystem methods such as fragment methods or combined quantum mechanical and molecular mechanical (QM/MM) methods. Here we employ a QM/MM methodology to study one particular MOF that has been of widespread interest because of its wide pores and good solvent and thermal stability, namely NU-1000, which contains hexanuclear zirconium nodes and 1,3,6,8-tetrakis(p-benzoic acid)pyrene (TBAPy4-) linkers. A modified version of the Bristow-Tiana-Walsh transferable force field has been developed to allow QM/MM calculations on NU 1000; we call the new parametrization the NU1T force field. We consider isomeric structures corresponding to various proton topologies of the [Zr6(MU3-O)8O8H16]8+ node of NU-1000, and we compute their relative energies using a QM/MM scheme designed for the present kind of problem. We compared the results to full quantum mechanical (QM) energy calculations and found that the QM/MM models can reproduce the full QM relative energetics (which span a range of 334 kJ mol-1) with a mean unsigned deviation (MUD) of only 2 kJ mol-1. Furthermore, we found that the structures optimized by QM/MM are nearly identical to their full QM optimized counterparts. PMID- 29271427 TI - An imine-gallium Lewis pair stabilized oxophosphinidene via an unexpected phosphirene rearrangement. AB - The reaction of a DAC-derived phosphirene 1 with AlCl3 reveals the formation of a simple donor acceptor adduct 2 of the DAC carbonyl fragments with AlCl3. In contrast, GaCl3 induces an unexpected rearrangement leading to the formation of an imine/GaCl3 stabilized 1,2-azaphosphole-based oxophosphinidene 3. This latter compound represents the first example of the R-P[double bond, length as m-dash]O fragment stabilized by a main group donor-acceptor interaction. PMID- 29271428 TI - Development of a novel secondary phosphine oxide-ruthenium(ii) catalyst and its application for carbonyl reduction. AB - A secondary phosphine oxide-phosphine mixed tridentate ligand and its ruthenium complex have been developed. This complex shows excellent catalytic activity for carbonyl reduction, especially for the reduction of alpha,beta-unsaturated aldehydes. The turnover number and selectivity can reach up to 36 500 and 99%, respectively. Control experiments and DFT calculations supported an outer-sphere mechanism during the hydrogenation reaction. PMID- 29271429 TI - From biological enzyme to single atomic Fe-N-C electrocatalyst for efficient oxygen reduction. AB - Inspired by metabolic processes in biological systems, animal blood as a biowaste rich in biological enzymes with molecular Fe-N centers was successfully explored to produce an efficient electrocatalyst with single atomic Fe-N-C active sites for oxygen reduction reaction. PMID- 29271430 TI - Energy level diagram of HC(NH2)2PbI3 single crystal evaluated by electrical and optical analyses. AB - Recently, organic-inorganic halide perovskites have received attention for applications in solar cells. Measurements of high-quality single crystals reveal lower defect densities and longer carrier lifetimes than those of conventional thin films, which result in improved electrical and optical properties. However, single crystal surfaces are sensitive to exposure to ambient conditions, and degrade under long-term storage in air. The surface also shows differences from the bulk in terms of its optical and electronic characteristics. For a heterojunction device, the interface at the single crystal is important. Understanding the difference between the surface and bulk properties offers insights into device design. Here, we prepared non-sliced and sliced formamidinium lead iodide (FAPbI3; FA+ = HC(NH2)2+) single crystals with a bandgap of 1.4 eV, which matches well with the requirements for solar cell photoabsorption layers. We evaluate the energy level diagrams of the surface and bulk regions, respectively. Our data indicate that the valence band maximum of the surface region is at a higher energy level than that of the bulk region. We also discuss hypotheses for the well-known and unexplained phenomena (multiple bandgaps and bandgap narrowing) seen in the absorption and photoluminescence spectra of single crystals. We conclude that these effects are likely caused by a combination of the degraded surface, Rashba-splitting in bulk, and self absorption by the single crystal itself. PMID- 29271431 TI - Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2016, 18, 23006. AB - In a recent article, Phys. Chem. Chem. Phys., 2016, 18, 23006, MD simulations have been used to clarify why indole is much more soluble in methanol than in water. Structural data indicate that water and methanol make very similar interactions with the indole molecule and do not provide clues to rationalize the origin of the solubility difference. In the present comment, I have shown that the relevant quantity is the magnitude of the reversible work of cavity creation. The latter magnitude proves to be markedly larger in water than in methanol, clarifying why most non-ionic solutes, with the exception of molecules able to form multiple H-bonds, such as urea, are more soluble in methanol. PMID- 29271432 TI - Chiral sulfoxides: advances in asymmetric synthesis and problems with the accurate determination of the stereochemical outcome. AB - Chiral sulfoxides are in extremely high demand in nearly every sector of the chemical industry concerned with the design and development of new synthetic reagents, drugs, and functional materials. The primary objective of this review is to update readers on the latest developments from the past five years (2011 2016) in the preparation of optically active sulfoxides. Methodologies covered include catalytic asymmetric sulfoxidation using either chemical, enzymatic, or hybrid biocatalytic means; kinetic resolution involving oxidation to sulfones, reduction to sulfides, modification of side chains, and imidation to sulfoximines; as well as various other methods including nucleophilic displacement at the sulfur atom for the desymmetrization of achiral sulfoxides, enantioselective recognition and separation based on either metal-organic frameworks (MOF's) or host-guest chemistry, and the Horner-Wadsworth-Emmons reaction. A second goal of this work concerns a critical discussion of the problem of the accurate determination of the stereochemical outcome of a reaction due to the self-disproportionation of enantiomers (SDE) phenomenon, particularly as it relates to chiral sulfoxides. The SDE is a little-appreciated phenomenon that can readily and spontaneously occur for scalemic samples when subjected to practically any physicochemical process. It has now been unequivocally demonstrated that ignorance in the SDE phenomenon inevitably leads to erroneous interpretation of the stereochemical outcome of catalytic enantioselective reactions, in particular, for the synthesis of chiral sulfoxides. It is hoped that this two-pronged approach to covering the chemistry of chiral sulfoxides will be appealing, engaging, and motivating for current research-active authors to respond to in their future publications in this exciting area of current research. PMID- 29271433 TI - Ambipolar charge transport in a bis-diketopyrrolopyrrole small molecule semiconductor with tunable energetic disorder. AB - Energetic disorder and activation energy are important parameters that influence the charge carrier mobility in organic semiconductors. Herein, we investigate temperature-dependent ambipolar charge transport alongside its thermal activation energy in organic field-effect transistors (OFETs) based on a diketopyrrolopyrrole (DPP) based small molecule BTDPP2. The determined energetic disorder in BTDPP2 is analogous to those of highly crystalline molecules, such as pentacene, while lower than those of widely used fullerene derivatives (PCBM) or semi-crystalline polymers, such as P3HT. We demonstrate that the energetic disorder and activation energy in BTDPP2 are both impacted by the crystallinity, which is tuned by thermal annealing; moreover, to a certain extent, these two parameters can reduce with increasing the structural order. Moreover, the energetic disorder tends to decrease when BTDPP2 is subjected to thermal annealing. Through comparing the electron transport in BTDPP2 based OFETs and vertical diodes, in which the electron densities differentiate substantially, the different activation energies are roughly described in terms of achievable carrier densities in these two devices. To the best of our knowledge, this aspect has not been addressed on the electron transport in molecular semi-conductive materials. Our results shine light on fundamental understandings of charge transport properties in solution processed small molecules holding promise for opto-electronic applications. PMID- 29271434 TI - Engineering highly sensitive whole-cell mercury biosensors based on positive feedback loops from quorum-sensing systems. AB - Mercury contamination represents a global threat. A simple, sensitive, and rapid means of detecting trace mercury is urgently needed. Herein, we have developed a series of mercury biosensors by combining quorum sensing-based positive feedback systems with a mercury-specific operon, merR. Our results have demonstrated that the sensitivity and fluorescence intensity of the engineered E. coli cells were greatly improved thanks to the positive feedback system. In addition, by fitting the fluorescence signals to the classic Hill equation, we discovered that the responses of the engineered E. coli cells were close to ultrasensitive curves. Our work highlights quorum-sensing systems as a powerful tool in biosensor designs. PMID- 29271436 TI - Functional metal complexes from CuAAC "click" bidentate and tridentate pyridyl 1,2,3-triazole ligands. AB - Ligands containing the bidentate 2-pyridyl-1,2,3-triazole and tridentate 2,6 pyridyl-bis(1,2,3-triazole) moieties have emerged as alternatives to 2,2' bypridine and 2,2':6',2''-terpyridine and other nitrogen-containing bi- and tri dentate chelators. Because these "click" ligands are readily functionalised they are attractive options for the development of functional coordination complexes. This Frontiers Article discusses key recent reports on functional CuAAC "click" complexes in the areas of biological agency, photophysics, and catalysis. PMID- 29271435 TI - Home food preparation techniques impacted the availability of natural antioxidants and bioactivities in kale and broccoli. AB - This study evaluated the effects of grinding and chopping with/without microwaving on the health-beneficial components, and antioxidant, anti inflammation and anti-proliferation capacities of commercial kale and broccoli samples. The availability of indole-3-carbinol (I3C) was evaluated using high performance liquid chromatography. The total phenolic contents, the scavenging activities against DPPH, oxygen, hydroxyl and ABTS cation radicals, and cell based antioxidant activities were determined for the antioxidant capacities. The results indicated that chopping released the least nutraceutical components and antioxidant compounds. Microwaving had no effect on the I3C release from kale, but resulted in an elevated (more than 2-fold) release of I3C from broccoli. In addition, the choice of a blender affected the availability of the anti proliferative compounds from the vegetables, while it had no effect on the availability of their anti-inflammatory compounds. In summary, different food preparation methods could strongly impact the availability of bioactive factors in the selected vegetables. These findings suggest that choosing an appropriate food processing method for each vegetable might be critical to obtain desirable health-beneficial effects. PMID- 29271437 TI - The role of surface ligands in determining the electronic properties of quantum dot solids and their impact on photovoltaic figure of merits. AB - Surface chemistry plays a crucial role in determining the electronic properties of quantum dot solids and may well be the key to mitigate loss processes involved in quantum dot solar cells. Surface ligands help to maintain the shape and size of the individual dots in solid films, to preserve the clean energy band gap of the individual particles and to control charge carrier conduction across solid films, in turn regulating their performance in photovoltaic applications. In this report, we show that the changes in size, shape and functional groups of small chain organic ligands enable us to modulate mobility, dielectric constant and carrier doping density of lead sulfide quantum dot solids. Furthermore, we correlate these results with performance, stability and recombination processes in the respective photovoltaic devices. Our results highlight the critical role of surface chemistry in the electronic properties of quantum dots. The role of the size, functionality and the surface coverage of the ligands in determining charge transport properties and the stability of quantum dot solids have been discussed. Our findings, when applied in designing new ligands with higher mobility and improved passivation of quantum dot solids, can have important implications for the development of high-performance quantum dot solar cells. PMID- 29271438 TI - Thermo-responsive PNIPAm nanopillars displaying amplified responsiveness through the incorporation of nanoparticles. AB - The possibility of combining more than one stimulus-responsive property into a single material holds interesting potential for the creation of adaptive devices to be used in diverse fields such as drug delivery, nanomedicine and tissue engineering. This paper describes a novel material based on thermo-responsive PNIPAm nanopillars with amplified surface properties through the incorporation of Fe3O4 nanoparticles. The incorporation of magnetic nanoparticles into the nanopillars, prepared via surface-initiated atom-transfer radical polymerization in anodized aluminum oxide templates, sharply increased their stiffness and hydrophobicity when increasing the temperature above the volume phase transition temperature. Furthermore, their magnetic response turned out to be proportional to the amount of the incorporated nanoparticles. The possibility of sharply increasing the stiffness with a temperature variation close to the human body temperature paves the way to the application of these substrates as "smart" scaffolds for cell culture. Additionally, the presence of superparamagnetic nanoparticles in the nanopillars offers the possibility of using these nanostructured systems for magnetic hyperthermia. PMID- 29271439 TI - Coordination-driven fast self-assembly of a charge-transfer hydrogel with reversible photochromism. AB - Utilizing metal-ligand binding as the driving force, a unique photochromic hydrogel cross-linked by metal ions and pi-acidic naphthalene bisimide dyes was obtained by simply mixing a two-phase solution. The mechanism of the coordination driven self-assembly is elucidated by the morphological, XRD, FT-IR, ESR, UV-Vis and TGA studies and the controlled experiments. PMID- 29271440 TI - Fate and exposure modeling in regulatory chemical evaluation: new directions from retrospection. AB - The development and application of fate and exposure modeling has undergone fundamental changes over the last 20 years. This has, in part, been driven by different needs within the regulatory community to address chemicals of concern using different approaches. Here we present a retrospective look at fate and exposure model application over the last two decades keeping an international regulatory perspective and using the Government of Canada's Chemicals Management Plan to illustrate concepts. We discuss the important role fate and exposure modeling has played to help address key data gaps when evaluating the risk of chemicals for both human health and ecological reasons. Yet limitations for more widespread model application within a regulatory context remain. Consequently, we identify specific data gaps and regulatory needs with an eye towards new directions for 21st century chemical evaluation. We suggest that one factor limiting greater model application is the need for increased awareness and agreement of what chemical exposure assessment encompasses within the risk assessment paradigm. This is of particular importance today because of the increased availability of computational and high-throughput data and methods for chemical assessment allowing evaluators to potentially examine exposure from site of release to site of toxic action, thus linking exposure with toxicology. We further suggest there is a need for discussion at a global level to promote the awareness of new tools and approaches available for fate and exposure modeling and suggest that this could be organized using the aggregate exposure pathways concept. PMID- 29271441 TI - Graphene oxide is degraded by neutrophils and the degradation products are non genotoxic. AB - Neutrophils were previously shown to digest oxidized carbon nanotubes through a myeloperoxidase (MPO)-dependent mechanism, and graphene oxide (GO) was found to undergo degradation when incubated with purified MPO, but there are no studies to date showing degradation of GO by neutrophils. Here we produced endotoxin-free GO by a modified Hummers' method and asked whether primary human neutrophils stimulated to produce neutrophil extracellular traps or activated to undergo degranulation are capable of digesting GO. Biodegradation was assessed using a range of techniques including Raman spectroscopy, transmission electron microscopy, atomic force microscopy, and mass spectrometry. GO sheets of differing lateral dimensions were effectively degraded by neutrophils. As the degradation products could have toxicological implications, we also evaluated the impact of degraded GO on the bronchial epithelial cell line BEAS-2B. MPO-degraded GO was found to be non-cytotoxic and did not elicit any DNA damage. Taken together, these studies have shown that neutrophils can digest GO and that the biodegraded GO is non-toxic for human lung cells. PMID- 29271442 TI - Immunomodulating protein aggregates in soy and whey hydrolysates and their resistance to digestion in an in vitro infant gastrointestinal model: new insights in the mechanism of immunomodulatory hydrolysates. AB - Hydrolysates, which are used in hypoallergenic infant formulas, have been found to possess immune modulating effects. For an optimal utilization of hydrolysates, the working mechanisms and responsible proteins underlying the effects should be elucidated. In this study, the immunomodulating activity of whey and soy hydrolysates was studied by quantifying TLR activation and assessing cytokine production in hydrolysate stimulated dendritic cells. The responsible protein fraction was identified and characterized by gel electrophoresis. The immune effects under gastrointestinal conditions were studied by digesting the hydrolysates in an in vitro infant digestion model, after which the digests were analyzed. In both soy and whey hydrolysates, TLR activation and cytokine production in dendritic cells were induced by a fraction containing protein aggregates larger than 1000 kDa, which were formed by electrostatic interactions and disulfide bonds. Only soy aggregates remained intact during duodenal digestion, and maintained the TLR activating capacity. Soy and whey protein aggregates larger than 1000 kDa possess immunomodulatory properties, but only soy aggregates remain under intestinal digestion conditions. This knowledge is important for a better understanding of the effects of hydrolysates. PMID- 29271443 TI - A study on the redox, spectroscopic, and photophysical characteristics of a series of octahedral hexamolybdenum(ii) clusters: [{Mo6X8}Y6]2- (X, Y = Cl, Br, or I). AB - We report a systematic study on the redox, spectroscopic, and photophysical properties of a series of [{Mo6X8}Y6]2- (X, Y = Cl, Br, or I. 1-9). All of the [{Mo6X8}Y6]2- clusters show intense and long-lived phosphorescence in both CH3CN and crystalline phases at 298 K. We found that the emission quantum yields (Phiem) of 1-9 increase in the sequences X = Cl < Br < I and Y = I < Br < Cl for given Y and X, respectively. The emission lifetimes (tauem) of the clusters also increase in the sequence Y = I < Br < Cl for given {Mo6X8}4+-core clusters. The present data demonstrate that arbitrary combinations of X and Y in [{Mo6X8}Y6]2- could tune tauem and Phiem in the ranges of 85-300 MUs and 0.09-0.47, respectively. Both capping (X) and terminal ligand (Y) effects on the photophysical properties of the clusters are discussed on the basis of the energy gap (i.e., emission energy) dependence of the nonradiative decay rate constant. PMID- 29271444 TI - Anti-diabetic activity of a polyphenol-rich extract from Phellinus igniarius in KK-Ay mice with spontaneous type 2 diabetes mellitus. AB - The present study investigated the anti-diabetic activity and potential mechanisms of the polyphenol rich extract from Phellinus igniarius (PI-PRE) in vitro and in vivo. Four main phenolic compounds of PI-PRE were purified and identified as 7,8-dihydroxycoumarin, 3,4-dihydroxybenzalacetone, 7,3'-dihydroxy 5'-methoxyisoflavone and inoscavin C by the off-line semipreparative liquid chromatography-nuclear magnetic resonance protocol. In vitro, PI-PRE stimulated GLUT4 translocation by 2.34-fold and increased glucose uptake by 1.73-fold in L6 cells. However, the selective AMP-activated protein kinase (AMPK) inhibitor, compound C, completely reversed the PI-PRE-induced GLUT4 translocation. In vivo, KK-Ay mice treated with PI-PRE for four weeks had lower fasting blood glucose levels, as well as other blood-lipid indexes, compared with the vehicle control group. Mechanistic studies showed that the expressions of p-AMPKalpha and GLUT4 were significantly increased by treatment with PI-PRE in L6 cells. In KK-Ay mice, the expression of p-AMPKalpha was enhanced in the liver and skeletal muscle, and the expression of GLUT4 was increased in skeletal muscle. These findings suggest that PI-PRE possesses potential anti-diabetic effects including improving glucose tolerance, reducing hyperglycemia, and normalizing insulin levels. These effects are partly due to the activation of GLUT4 translocation via the modulation of the AMPK pathway. PMID- 29271445 TI - Photocatalytic function of the B12 complex with the cyclometalated iridium(iii) complex as a photosensitizer under visible light irradiation. AB - A visible light induced three-component catalytic system with the cobalamin derivative (B12) as a catalyst, the cyclometalated iridium(iii) complex (Irdfppy, Irppy, Irpbt and [Ir{dF(CF3)ppy}2(dtbpy)]PF6) as a photosensitizer and triethanolamine as an electron source under N2 was developed. This catalytic system showed a much higher catalytic efficiency than the previous catalytic system using [Ru(ii)(bpy)3]Cl2 as the photosensitizer for the dechlorination reaction of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT). Noteworthy is the fact that the remarkable high turnover number (over ten thousand) based on B12, which ranks at the top among the reported studies, was obtained when Irdfppy was used as a photosensitizer. This photocatalytic system was also successfully applied to the B12 enzyme-mimic reaction, i.e., the 1,2-migration of the phenyl group of 2-bromomethyl-2-phenylmalonate. The plausible reaction mechanism was proposed, which involved two quenching pathways, an oxidative quenching pathway and a reductive quenching pathway, to be responsible for the initial electron transfer of the excited-state photosensitizers during the DDT dechlorination reaction. Transient photoluminescence experiments revealed that the oxidative quenching of the photosensitizer dominated over the reductive quenching pathway. PMID- 29271446 TI - Controlled growth of vertically aligned ultrathin In2S3 nanosheet arrays for photoelectrochemical water splitting. AB - This paper reports a facile solvothermal method for the in situ growth of vertically aligned In2S3 nanosheet arrays (NSAs) on fluorine-doped tin oxide substrates. The as-synthesized two-dimensional graphene-like In2S3 nanosheets show an ultrathin thickness down to 3.7 nm consisting of the duodenary interplanar spacing of the (222) plane and a tunable bandgap varying from 2.32 to 2.58 eV. The film thickness and nanosheet density of the In2S3 NSAs can be adjusted by varying the reaction time and precursor concentration. The In2S3 NSAs with a higher film thickness exhibit relatively higher photocurrent due to their stronger light absorption as well as larger surface area for sufficient charge separation and redox reaction. The photoelectrochemical performance of the In2S3 photoanodes can be greatly enhanced by constructing an effective heterojunction with ZnO to promote the photocarrier separation. The In2S3/ZnO NSAs have demonstrated an optimal photocurrent density of 349.1 MUA cm-2 at 1.2 V vs. RHE and a maximum incident photon to current efficiency of 10.26% at 380 nm, which are 13.5 and 38 times higher than those of the pristine In2S3 counterparts, respectively. PMID- 29271447 TI - Production, optimisation and characterisation of angiotensin converting enzyme inhibitory peptides from sea cucumber (Stichopus japonicus) gonad. AB - In this study, production of bioactive peptides with angiotensin converting enzyme (ACE) inhibitory activity from sea cucumber (Stichopus japonicus) gonad using commercial protamex was optimised by response surface methodology (RSM). As a result, the optimal condition to achieve the highest ACE inhibitory activity in sea cucumber gonad hydrolysate (SCGH) was hydrolysis for 1.95 h and E/S of 0.75%. For further characterisation, three individual peptides (EIYR, LF and NAPHMR) were purified and identified. The peptide NAPHMR showed the highest ACE inhibitory activity with IC50 of 260.22 +/- 3.71 MUM. NAPHMR was stable against simulated gastrointestinal digestion and revealed no significant cytotoxicity toward Caco-2 cells. Molecular docking study suggested that Arg, His and Asn residues in NAPHMR interact with the S2 pocket or Zn2+ binding motifs of ACE via hydrogen or pi-bonds, potentially contributing to ACE inhibitory effect. Sea cucumber gonad is thus a potential resource to produce ACE inhibitory peptides for preparation of functional foods. PMID- 29271448 TI - Characterization of di-4-ANEPPS with nano-black lipid membranes. AB - We report a platform based on lateral nano-black lipid membranes (nano-BLMs), where electrical measurements and fluorescence microscopy setup are combined, for the calibration of di-4-ANEPPS, a common voltage sensitive dye (VSD). The advantage of this setup is (1) its flexibility in the choice of lipids and applied voltages, (2) its high stability that enables a high voltage (500 mV) application and long-time measurements and (3) its fluorescence microscopy readout, which can be directly correlated with other fluorescence microscopy experiments using VSDs (e.g. membrane potential measurements in living cells). Using this setup, we observed that the calibration curve of di-4-ANEPPS is strongly dependent on the net electric charge of the lipids. The developed setup can be used to calibrate VSDs in different lipid environments in order to better understand their fundamental voltage-sensing mechanism in the future. PMID- 29271449 TI - Multiscale simulations of ligand adsorption and exchange on gold nanoparticles. AB - We have developed a multiscale model that combines first-principles methods with atomistic and mesoscopic simulations to explore the molecular structures and packing density of the ligands present on the gold nanoparticle (AuNP) surface, as well as the adsorption/exchange reaction kinetics of cetyltrimethylammonium bromide (CTAB)/PEG-SH ligands on different facets of gold, namely, Au(111), Au(100), and Au(110). Our model predicts that on clean gold surfaces, CTAB adsorption is diffusion limited. Specifically, CTAB has the preferentially higher adsorption rate and coverage density on Au(100) and Au(110) surfaces, forming a more compact layer with respect to that on the Au(111) surface, which could result in greater growth of gold nanoparticles along the (111) direction. As opposed to CTAB adsorption, the exchange reaction between PEG-SH with CTAB shows no selectivity to different crystal faces, and the reaction process follows Langmuir diffusion kinetics. Kinetic analysis reveals that, in water, the exchange reaction is zeroth order with respect to the concentration of an incoming PEG-SH, indicative of a dissociative exchange mechanism. The observed rate constant decreases exponentially with the PEG-SH chain length, consistent with a diffusion process for the free PEG-SH in water. In particular, we show that the exchange efficiency increases as the chain rigidness and size of the incoming ligand and/or steric bulk of the initial protecting ligand shell are decreased. Our objectives are to provide a model to assess the kinetics and thermodynamics of the adsorption/exchange reaction process, and we expect that these findings will have important implications for routine surface characterization of AuNPs. PMID- 29271450 TI - Functional reduced graphene oxide-based membranes with selective ion transport channels for zwitterionic ions separation based on the pH gradient. AB - In this work, we report a method for the fabrication of a functional free standing graphene membrane (FFGM) with high mechanical strength, enlarged interlayer spacing and ion channels for zwitterionic ions separation. To obtain the FFGM, the anionic dye Eosin Y (EY) was introduced into a graphene oxide (GO) and hydroquinone (HQ) mixture to prepare functional graphene-based membranes on Cu foil using simply a drop-casting method. In comparison with a GO membrane, the molar flux and the mechanical strength of the FFGM were dramatically increased. The FFGM was then equipped on custom-built glass reservoirs for zwitterionic amino acids (AAs) separation based on the inner pH gradient, which was formed by controlling H+ and OH- (in the feed and receiver solution) migration in rGO/GO sheets via an external electric field. With the help of the inner pH gradient and external electric field, AAs could change their charge behaviors. The ionized AAs transport through the FFGM and finally separation was realized. PMID- 29271451 TI - Modeling individual and pairs of adsorbed polymer-grafted nanoparticles: structure and entanglements. AB - We analyze the canopy structure and entanglement network of isolated polymer grafted nanoparticles (PGNs) adsorbed on a surface. As expected, increasing the monomer-surface adsorption strength causes the polymer chains to spread out to increase contact with the surface, leading to a canopy shape that is in qualitative agreement with recent experimental results. We compare height profiles and other structural features of four PGN systems to show the separate and combined effects of increasing chain length and graft density. At moderate graft density and low surface attraction strength, nearby PGN canopies interpenetrate substantially and their combined shape is similar to that of a single PGN canopy. At high graft density or surface interaction, the interparticle spacing increases significantly. We use a geometrical primitive path analysis to calculate average entanglement properties including canopy canopy entanglements between pairs of PGNs. The longer chain systems are well entangled at both graft densities considered, and we find that as the monomer surface interaction strength is increased (and the interparticle distance increases), entanglements between the two PGNs are reduced. We find that the number of inter-PGN entanglements per chain is slightly larger at the lower graft density, likely because steric constraints at high graft density tend to reduce interparticle entanglements. PMID- 29271452 TI - One-step coelectrodeposition-assisted layer-by-layer assembly of gold nanoparticles and reduced graphene oxide and its self-healing three-dimensional nanohybrid for an ultrasensitive DNA sensor. AB - A layer-by-layer (LBL) assembly was employed for preparing multilayer thin films with a controlled architecture and composition. In this study, we report the one step coelectrodeposition-assisted LBL assembly of both gold nanoparticles (AuNPs) and reduced graphene oxide (rGO) on the surface of a glassy carbon electrode (GCE) for the ultrasensitive electrochemical impedance sensing of DNA hybridization. A self-healable nanohybrid thin film with a three-dimensional (3D) alternate-layered nanoarchitecture was obtained by the one-step simultaneous electro-reduction of both graphene oxide and gold chloride in a high acidic medium of H2SO4 using cyclic voltammetry and was confirmed by different characterization techniques. The DNA bioelectrode was prepared by immobilizing the capture DNA onto the surface of the as-obtained self-healable AuNP/rGO/AuNP/GCE with a 3D LBL nanoarchitecture via gold-thiol interactions, which then served as an impedance sensing platform for the label-free ultrasensitive electrochemical detection of DNA hybridization over a wide range from 1.0 * 10-9 to 1.0 * 10-13 g ml-1, a low limit of detection of 3.9 * 10-14 g ml-1 (S/N = 3), ultrahigh sensitivity, and excellent selectivity. This study presents a promising electrochemical sensing platform for the label-free ultrasensitive detection of DNA hybridization with potential application in cancer diagnostics and the preparation of a self-healable nanohybrid thin film with a 3D alternate-layered nanoarchitecture via a one-step coelectrodeposition assisted LBL assembly. PMID- 29271454 TI - Selective delivery of adapalene to the human hair follicle under finite dose conditions using polymeric micelle nanocarriers. AB - Drug delivery systems that target the pilosebaceous unit (PSU) selectively could improve the clinical management of diseases that originate in the hair follicle. The aims of this study were (i) to prepare polymeric micelles using d-alpha tocopheryl polyethylene glycol succinate diblock copolymer that incorporated adapalene (ADA), a retinoid indicated for Acne vulgaris, and (ii) to investigate the feasibility of delivering ADA preferentially to the PSU under finite dose conditions - thereby better approximating actual conditions of use by patients. Incorporation of ADA into spherical micelles (dn <20 nm) increased aqueous solubility by ~50 000-fold (from <4 ng mL-1 to 0.2 mg mL-1). Optimized micelle solution and gel formulations (0.02% ADA) were stable after storage for 4 weeks at 4 degrees C. Finite dose experiments using full-thickness porcine and human skin revealed that ADA delivery efficiency from micelle solution and gel formulations was equivalent and was >2- and 10-fold higher than that from Differin(r) gel and Differin(r) cream (products containing ADA at 0.1% (w/w)). Follicular delivery studies in human skin, using a punch biopsy technique to extract the intact PSU, demonstrated that the micelle solution and gel formulations did indeed enable preferential delivery of ADA to the PSU (4.5- and 3.3-fold higher, respectively, than that to PSU-free skin biopsies). Confocal laser scanning microscopy provided visual corroboration that ADA was uniformly distributed in the hair follicles. In conclusion, the results confirmed that polymeric micelle nanocarriers enabled selective, targeted drug delivery to the PSU under finite dose conditions and so might improve therapy of follicular diseases and decrease off-site side-effects. PMID- 29271453 TI - Metal ion assisted interface re-engineering of a ferritin nanocage for enhanced biofunctions and cancer therapy. AB - The bottom-up self-assembly of protein subunits into supramolecular nanoarchitectures is ubiquitously exploited to recapitulate and expand the features of natural proteins to advance nanoscience in medicine. Various chemical and biological re-engineering approaches are available to render diverse functions in the given proteins. They are, unfortunately, capable of compromising protein integrity and stability after extensive modifications. In this study, we introduce a new protein re-engineering method, metal ion assisted interface re engineering (MAIR), to serve as a robust and universal strategy to extend the functions of self-assembly proteins by boosting structural features to advance their diverse biomedical applications. In particular, the MAIR strategy was applied to a widely used natural protein, ferritin, as a model protein to coordinate with copper ions in its mutagenic artificial metal binding domain. Structure directed rational protein mutagenesis was carried out at the C2 interface amino acid residues of the ferritin subunit for metal ion coordination site optimization. Copper binding at the artificial binding pocket was highly specific over the other divalent ions present in physiological fluids, and the structurally embedded copper ion in turn strengthened the overall protein integrity and stability. In the presence of isotopic copper-64, the interface re engineered ferritin worked as a chelator-free molecular nanoprobe with an extraordinarily high specific activity to allow PET imaging of tumors in live animals. We also found that the re-engineered ferritin coordinating with copper ions demonstrates high drug loading capacity of a widely used anti-cancer agent, doxorubicin (DOX), to achieve significant drug retention at the tumor site and enhance tumor regression for improved anti-cancer effects. The MAIR approach, thus, exploited the copper ion to facilitate efficient one-step labeling of mutant ferritin derivatives for simultaneous molecular imaging and drug delivery. The reported interface re-engineering strategy provides an unparalleled opportunity to expand protein biofunctions to serve as a new theranostic agent in cancer research. PMID- 29271455 TI - Governing the DNA-binding mode of styryl dyes by the length of their alkyl substituents - from intercalation to major groove binding. AB - A series of monomeric and homodimeric 4-alkoxystyryl(pyridinium) dyes was synthesized and their DNA-binding properties were investigated. We found that the length of the alkyl substituent has a crucial influence on the binding mode of the dyes, although the structure of the DNA-binding unit is the same for all compounds. Remarkably, mono- and bis-styryl derivatives comprising an oxodecyl chain represent the rare examples of small molecules that bind to the major groove of DNA. We have also demonstrated that the dyes, except the monostyryl dye with a bromopropyl substituent, form chiral aggregates in the presence of double stranded DNA. PMID- 29271456 TI - Plastic deformation and twinning mechanisms in magnesian calcites: a non equilibrium computer simulation study. AB - Deformation twinning provides a mechanism for energy dissipation in crystalline structures, with important implications on the mechanical response of carbonate biogenic materials. Carbonate crystals can incorporate magnesium, e.g. in the sea, modifying their elastic response significantly. We present a full atom computational investigation of the dependence of the twinning response of calcite with magnesium content, covering compositions compatible with three main structures, calcite, dolomite and magnesite. We find, in agreement with experiments that the incorporation of magnesium disfavors twinning as a dissipation mechanism in ordered structures (dolomite, magnesite), however the response is strongly dependent on the arrangement of the magnesium ions in the crystal structure. We show that structures with a high content of magnesium (>33%) in a disordered arrangement, lead to plastic response before twinning or fracturing. We demonstrate that the position of the magnesium ions plays a key role in the determination of the crystal deformation mode. This observation is correlated with the formation of percolation clusters of magnesium in magnesian calcites. PMID- 29271457 TI - Form factor for distorted semi-flexible polymer chains. AB - The statistical presence of kinks which form defects in semi-flexible polymer chains leads to a polydispersity in the effective persistence length. The form factor of a distorted semi-flexible polymer results as an average over this persistence polydispersity. It turns out that the scattering behavior of an ensemble of distorted semi-flexible polymer chains is quite well approximated by a form factor of an undistorted chain with a Rg-equivalent persistence length. An apparent length polydispersity is observed for short distorted chains. The Rg equivalent persistence length is significantly smaller than the innate persistence length multiplied by the fraction of regular monomers. The results are compared to related work on DNA from the literature. PMID- 29271458 TI - In6S7 nanoparticle-embedded and sulfur and nitrogen co-doped microporous carbons derived from In(tdc)2 metal-organic framework. AB - Indium sulfide nanoparticle (NP)-embedded microporous carbons co-doped with S- and N-dopants are easily prepared by a direct carbonization of the as-prepared In(iii)-based metal-organic framework (In-MOF), [Et2NH2][In(tdc)2].DEF, containing ditopic S-containing 2,5-thiophenedicarboxylate (tdc2-) bridging linkers as a potential source of S-dopant. The charge on the anionic framework of [In(tdc)2]- is balanced by Et2NH2+, which is also a potential N-dopant. Simultaneous embedding of In-based NPs, S-, and N-co-doping is achieved in a simple single step carbonization of In-MOF. Three porous carbon materials (PCMs), PCM-700, PCM-800, and PCM-900, are obtained from the carbonization of In-MOF at 700, 800, and 900 degrees C, respectively. The gas sorption analysis indicates them as good CO2 sorbents. The photocatalytic degradation of methyl orange by PCMs under visible light irradiation is also effectively operable owing to the photocatalytically active semiconducting indium sulfide NP with a small bandgap. The main component of indium sulfide NPs is revealed as In6S7 based on the powder X-ray diffraction pattern. Small amounts of metallic In and In2S3 are also observed. The specific capacitances of PCMs are also estimated from the galvanostatic charge/discharge curves. PCM-900 exhibits the highest gravimetric specific capacitance of 99.0 F g-1 at a current density of 0.05 A g-1. PMID- 29271459 TI - Laminated bilayer MoS2 with weak interlayer coupling. AB - Laminated bilayer MoS2 structures are prepared with MoS2 nanoparticles trapped between two individual MoS2 layers which can prevent the formation of a true stacking structure held together by van der Waals interaction. The laminated bilayer MoS2 clearly indicates a weak interlayer coupling with reduced van der Waals interaction between adjacent layers. As the interlayer coupling is insufficient to modify the band structure of MoS2, the laminated bilayer MoS2 can retain the direct bandgap structure of an isolated monolayer. Furthermore, by controlling the size of the MoS2 nanoparticles trapped in between, the interlayer distance and interlayer coupling of bilayer MoS2 structures can be engineered in a wide range, resulting in different bandgap behaviors. This finding is extremely important as it provides an effective approach to fabricate bandgap engineered bilayer MoS2 structures, which is a crucial step forward to making multi-layer MoS2-based p-n junctions and homo/hetero-structures, and thus advanced electronic devices, especially optoelectronic devices. This approach is applied to not only bilayer MoS2 structures, but also other layer structured two-dimensional materials. PMID- 29271460 TI - An intramolecular tryptophan-condensation approach for peptide stapling. AB - Stapled peptides are gaining tremendous interest as next-generation therapeutic agents to target protein-protein interactions. Herein, we report an intramolecular peptide stapling method which links two tryptophan residues at the C2 position of the indole moieties via acid-mediated condensation with an aldehyde. PMID- 29271461 TI - Visible-light-driven two-way photoisomerization of 1-(1-pyrenyl)-2-(2 quinolyl)ethylene in neutral and protonated forms. AB - Diarylethylenes with large pi-systems often lose their photochemical activity (the size effect). 1-(1-Pyrenyl)-2-(2-quinolyl)ethylene (1P2QE), despite having a large conjugated pi-system of 28 electrons, undergoes two-way reversible trans cis photoisomerization both in the neutral and protonated forms with quantum yields as high as 0.13-0.83. For the neutral 1P2QE, experimental data and quantum chemical calculations indicate a diabatic (nonadiabatic) reaction mechanism. Due to high photoisomerization quantum yields and the long-wavelength absorption band at 340-460 nm and 390-560 nm for the neutral and protonated compounds, respectively, 1P2QE can be used as a molecular photoswitch that is sensitive to visible light. PMID- 29271462 TI - Elastostatic reversibility in thermally formed bulk metallic glasses: nanobeam diffraction fluctuation electron microscopy. AB - The unparalleled shaping ability of bulk metallic glasses can revolutionize commercial products having multi-length scale features with a processing time of several minutes. Despite the widespread shaping ability of these polymer-like multicomponent alloys, thermoplastic forming (TPF) can severely degrade the intrinsic properties, particularly when complex stress states are activated. The present work emphasizes the importance of elastostatic loading (ESL) which not only fully reverses deteriorated room temperature plasticity originating under TPF or post-cryostatic conditions, but also activates a rejuvenation mechanism by rendering an extended resistance against strain softening. Furthermore, the reduction in the supercooled liquid region and crystallization enthalpy measured by differential scanning calorimetry are found to be temporary, and can be fully reversed to the initial condition. HRTEM imaging of the samples are performed with an imaging spherical aberration corrector. Individual nanobeam diffraction patterns obtained by the fluctuation electron microscopy (FEM) measurements are acquired using a scanning transmission electron microscope with a probe size of 1.2 nm from a 10 * 10 raster, yielding 100 diffraction patterns. The normalized variance of a series of nanodiffraction patterns of the post-elastostatically loaded sample reveals a height decrease in the first broad peak of normalized intensity variance V(k) suggesting modifications in the medium-range structural order which in turn dramatically restores the mechanical and thermal properties. Overall, the combination of TPF and post-ESL treatment in advanced glassy metals can open a new avenue for ultra-high mechanical and thermal performance micro- and nanomechanical devices for biosensors, MOSFETs and robotics. PMID- 29271463 TI - Ratiometric photoluminescence sensing based on Ti3C2 MXene quantum dots as an intracellular pH sensor. AB - Intracellular pH sensing is of importance and can be used as an indicator for monitoring the evolution of various diseases and the health of cells. Here, we developed a new class of surface-functionalized MXene quantum dots (QDs), Ti3C2, by the sonication cutting and hydrothermal approach and further explored their intracellular pH sensing. The functionalized Ti3C2 QDs exhibit bright excitation dependent blue photoluminescence (PL) originating from the size effect and surface defects. Meanwhile, Ti3C2 QDs demonstrate a high PL response induced by the deprotonation of the surface defects. Furthermore, combining the highly pH sensitive Ti3C2 QDs with the pH insensitive [Ru(dpp)3]Cl2, we developed a ratiometric pH sensor to quantitatively monitor the intracellular pH values. These novel MXene quantum dots can serve as a promising platform for developing practical fluorescent nanosensors. PMID- 29271464 TI - Iodine(iii)-mediated intramolecular sulfeno- and selenofunctionalization of beta,gamma-unsaturated tosyl hydrazones and oximes. AB - A cascade radical cyclization/sulfenylation or selenylation of beta,gamma unsaturated hydrazones and oximes was realized under mild conditions with phenyliodine(iii) diacetate (PIDA) as the sole oxidant, leading to the construction of diversely functionalized heteroatom-containing pyrazoline and isoxazoline derivatives. This metal-free radical process is suggested to encompass a sequential C-N/O and C-S/Se bond fomation. PMID- 29271465 TI - Mechanisms of the oxygen reduction reaction on B- and/or N-doped carbon nanomaterials with curvature and edge effects. AB - Despite recent increased research interest in hetero-atom (B and/or N) doping effects on the oxygen reduction reaction (ORR) performance of carbon nanomaterials, microscopic understanding of active catalytic sites and effects of B and/or N doping has not been conclusively reached. Here, through comparative first-principles simulations between BN codoping and isolated B or N doping in both graphene nanoribbons (GNRs) and carbon nanotubes (CNTs), we not only identify active sites in these doped carbon nanomaterials, but elucidate the underlying mechanism of ORR processes. While the distortion of C-C bonds in CNTs leads to strong binding of O2, spin density distribution along the edges plays a key role in enhancing the adsorption strength of O2 on GNRs. The effective adsorption of O2 facilitates the following elementary reduction reactions. Based on thermodynamic analyses, O2 adsorption as well as the electron and proton transfer to O atom are identified as key rate-determining steps. For CNTs, a good linear scaling is found between the adsorption energies of key intermediate products and that of atomic O, and thus the latter serves as a good descriptor for ORR activities. Further, N-doped high-quality CNTs are shown to exhibit best performance. For GNRs, due to edge effects, the linear relationship is broken, which promotes the catalytic activities in the BN codoping case. These findings resolve the long-standing controversy on the synergetic effects of B and N codoping, which deepens our understanding of the reaction mechanism. This work might further facilitate the optimization of the doping strategies for high efficiency carbon-based ORR catalysts. PMID- 29271466 TI - Particles with similar LET values generate DNA breaks of different complexity and reparability: a high-resolution microscopy analysis of gammaH2AX/53BP1 foci. AB - Biological effects of high-LET (linear energy transfer) radiation have received increasing attention, particularly in the context of more efficient radiotherapy and space exploration. Efficient cell killing by high-LET radiation depends on the physical ability of accelerated particles to generate complex DNA damage, which is largely mediated by LET. However, the characteristics of DNA damage and repair upon exposure to different particles with similar LET parameters remain unexplored. We employed high-resolution confocal microscopy to examine phosphorylated histone H2AX (gammaH2AX)/p53-binding protein 1 (53BP1) focus streaks at the microscale level, focusing on the complexity, spatiotemporal behaviour and repair of DNA double-strand breaks generated by boron and neon ions accelerated at similar LET values (~135 keV MUm-1) and low energies (8 and 47 MeV per n, respectively). Cells were irradiated using sharp-angle geometry and were spatially (3D) fixed to maximize the resolution of these analyses. Both high-LET radiation types generated highly complex gammaH2AX/53BP1 focus clusters with a larger size, increased irregularity and slower elimination than low-LET gamma rays. Surprisingly, neon ions produced even more complex gammaH2AX/53BP1 focus clusters than boron ions, consistent with DSB repair kinetics. Although the exposure of cells to gamma-rays and boron ions eliminated a vast majority of foci (94% and 74%, respectively) within 24 h, 45% of the foci persisted in cells irradiated with neon. Our calculations suggest that the complexity of DSB damage critically depends on (increases with) the particle track core diameter. Thus, different particles with similar LET and energy may generate different types of DNA damage, which should be considered in future research. PMID- 29271467 TI - Electronic versus steric effects of pyridinophane ligands on Pd(iii) complexes. AB - Several new PdII and PdIII complexes supported by electronically and sterically tuned tetradentate pyridinophane ligands MeN4OMe, MeN4, and tBuN4 were isolated and fully characterized (MeN4OMe: N,N'-dimethyl-2,11-diaza[3,3](2,6)-para methoxypyridinophane; MeN4: N,N'-dimethyl-2,11-diaza[3,3](2,6)pyridinophane; tBuN4: N,N'-di-tert-butyl-2,11-diaza[3,3](2,6)pyridinophane). Cyclic voltammetry studies, UV-vis and EPR spectroscopy, and X-ray crystallography were employed to reveal that the steric properties of the N-substituents of the RN4 ligands have a pronounced effect on the electronic properties of the corresponding PdIII complexes, while the electronic tuning of the ligand pyridyl groups has a surprisingly minimal effect. An explanation for these observations was provided by DFT and TD-DFT calculations which suggest that the electronic properties of the PdIII complexes are mainly dictated by their frontier molecular orbitals that have major atomic contributions from the Pd center (mainly the Pd dz2 atomic orbital) and the axial N atom donors. PMID- 29271468 TI - A nanowire array with two types of bromoplumbate chains and high anisotropic conductance. AB - Crystalline nanowire arrays would create great opportunity for novel electrical application. Herein, we report a metal halide-based crystalline nanowire array, which was the first example constructed from two types of bromoplumbate anion chains. The single crystal shows high anisotropic conductivity with semiconducting transport along the c axis and an insulating feature perpendicular to the c direction. PMID- 29271469 TI - Nematic line defects in microfluidic channels: wedge, twist and zigzag disclinations. AB - We report an experimental study of structural transformations of disclination lines in nematic liquid crystals in microfluidic channels. The anchoring conditions of the channel walls enforce the generation of a disclination line of the wedge type in the absence of flow. The wedge disclination is transformed to a twist disclination by the flow of the nematic liquid crystal in the channel. The application of an electric field perpendicular to the channel axis induces a second transformation to a zigzag shape. The threshold field strength for the second transformation increases with increasing flow velocity. The experimental results are compared to predictions based on model director fields of the different disclination structures. PMID- 29271470 TI - Responding to the World Health Organization Gobal Disability Action Plan in Ukraine: Developing a National Disability, Health and Rehabilitation Plan. AB - In order to support the development of a National Disability, Health and Rehabilitation Plan (NDHRP) for Ukraine, a technical consultation was carried out by a Rehabilitation Advisory Team (RAT) of the International Society of Physical and Rehabilitation Medicine (ISPRM) in 2015. The consultation was based on assessment of the situation of persons with disabilities and the rehabilitation system in Ukraine. Recommendations for activities and projects to improve rehabilitation services within the healthcare system were developed and proposed. In order to reach consensus on the recommendations, dialogues were held with different stakeholders, including the Ministry of Public Health. The recommendations included: coordination of disability and rehabilitation policies within the Ministry of Public Health and among other involved ministries; translation and adaptation of international definitions of functioning, disability, and assessment tools into Ukrainian; data collection on the epidemiology of disability and the need for rehabilitation; implementation of health-related rehabilitation services; and implementation of international definitions and curricula of rehabilitation professions. The mission was regarded as successful and one year later a few changes had been adopted by the Ukrainian government. Further action based on this research is necessary. It will be important to track the changes and evaluate the results after an appropriate period of time. PMID- 29271471 TI - Progesterone concentrations and dosage with frozen embryo transfers - What's best? AB - BACKGROUND: There is a lack of consensus on the optimal dose and form of progesterone supplementation during frozen-thawed embryo transfer with hormone replacement therapy. AIMS: We aim to identify the serum progesterone concentration on day 16 most likely to result in positive pregnancy outcomes. MATERIALS AND METHODS: We undertook a retrospective study of 4582 women who underwent frozen embryo transfer with hormone replacement therapy, or natural frozen embryo transfer, over 14 years at a multi-site private in vitro fertilisation clinic. Embryos were 3-5 days of age at time of transfer. We extracted data on serum progesterone concentrations and outcomes, as well as dose and form of progesterone supplementation, from patient and pharmacy records. RESULTS: Increased live birth rates for frozen embryo transfer with hormone replacement therapy were seen with day 16 serum progesterone concentrations >50 nmol/L (26.4% vs 11.3% for <50 nmol/L; adjusted odds ratio (OR) 3.14 (95% CI 2.21 4.48)). Similarly, a decreased pregnancy loss rate was seen in this group (14.3% vs 32.6% for <=50 nmol/L; adjusted OR 0.26 (95% CI 0.12-0.58)). There was a positive correlation between live births and the number of progesterone doses per day (r = 0.119, P = 0.026) and day 16 progesterone concentrations (r = 0.128, P = 0.011). CONCLUSION: Improved pregnancy outcomes are seen with day 16 serum progesterone concentrations >50 nmol/L. There is a statistically significant correlation between live births, number of progesterone doses per day and day 16 serum progesterone concentrations in this study. PMID- 29271472 TI - The diversification of inequality. AB - We examine intersectionality on the basis of increasingly complex interactions between gender and ethnic groups, which we argue derive from the growing diversity of these groups. While we critique the concept of superdiversity, we suggest that increased diversity leads to a 'diversification of inequality'. This is characterised by an increasing incidence of inequality through the growth in migration and of the size and variety of ethnic minorities, and by a weakening of specific inequalities. We demonstrate this using the Labour Force Survey and conclude that there is a clear diversification of inequality but also that ethnicity is a more potent source of inequality than gender. Diversity also increases the reach of inequality through producing and increasing the number of intersections. PMID- 29271473 TI - Pelvic floor muscle training for prevention and treatment of urinary and faecal incontinence in antenatal and postnatal women. AB - BACKGROUND: About one-third of women have urinary incontinence and up to one tenth have faecal incontinence after childbirth. Pelvic floor muscle training (PFMT) is commonly recommended during pregnancy and after birth for both prevention and treatment of incontinence.This is an update of a review previously published in 2012. OBJECTIVES: To determine the effectiveness of pelvic floor muscle training (PFMT) in the prevention or treatment of urinary and faecal incontinence in pregnant or postnatal women. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register (16 February 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised trials in pregnant or postnatal women. One arm of the trial included PFMT. Another arm was no PFMT, usual antenatal or postnatal care, another control condition, or an alternative PFMT intervention. DATA COLLECTION AND ANALYSIS: Review authors independently assessed trials for inclusion and risk of bias. We extracted data and checked them for accuracy. Populations included: women who were continent (PFMT for prevention), women who were incontinent (PFMT for treatment) at randomisation and a mixed population of women who were one or the other (PFMT for prevention or treatment). We assessed quality of evidence using the GRADE approach. MAIN RESULTS: The review included 38 trials (17 of which were new for this update) involving 9892 women from 20 countries. Overall, trials were small to moderate sized, and the PFMT programmes and control conditions varied considerably and were often poorly described. Many trials were at moderate to high risk of bias. Other than two reports of pelvic floor pain, trials reported no harmful effects of PFMT.Prevention of urinary incontinence: compared with usual care, continent pregnant women performing antenatal PFMT may have had a lower risk of reporting urinary incontinence in late pregnancy (62% less; risk ratio (RR) for incontinence 0.38, 95% confidence interval (CI) 0.20 to 0.72; 6 trials, 624 women; low-quality evidence). Similarly, antenatal PFMT decreased the risk of urinary incontinence in the mid-postnatal period (more than three to six months' postpartum) (29% less; RR 0.71, 95% CI 0.54 to 0.95; 5 trials, 673 women; moderate-quality evidence). There was insufficient information available for the late (more than six to 12 months') postnatal period to determine effects at this time point.Treatment of urinary incontinence: it is uncertain whether antenatal PFMT in incontinent women decreases incontinence in late pregnancy compared to usual care (RR 0.70, 95% CI 0.44 to 1.13; 3 trials, 345 women; very low-quality evidence). This uncertainty extends into the mid- (RR 0.94, 95% CI 0.70 to 1.24; 1 trial, 187 women; very low-quality evidence) and late (RR 0.50, 95% CI 0.13 to 1.93; 2 trials, 869 women; very low-quality evidence) postnatal periods. In postnatal women with persistent urinary incontinence, it was unclear whether PFMT reduced urinary incontinence at more than six to 12 months' postpartum (RR 0.55, 95% CI 0.29 to 1.07; 3 trials; 696 women; very low-quality evidence).Mixed prevention and treatment approach to urinary incontinence: antenatal PFMT in women with or without urinary incontinence (mixed population) may decrease urinary incontinence risk in late pregnancy (26% less; RR 0.74, 95% CI 0.61 to 0.90; 9 trials, 3164 women; low-quality evidence) and the mid-postnatal period (RR 0.73, 95% CI 0.55 to 0.97; 5 trials, 1921 women; very low-quality evidence). It is uncertain if antenatal PFMT reduces urinary incontinence risk late postpartum (RR 0.85, 95% CI 0.63 to 1.14; 2 trials, 244 women; low-quality evidence). For PFMT begun after delivery, there was considerable uncertainty about the effect on urinary incontinence risk in the late postnatal period (RR 0.88, 95% CI 0.71 to 1.09; 3 trials, 826 women; very low-quality evidence).Faecal incontinence: six trials reported faecal incontinence outcomes. In postnatal women with persistent faecal incontinence, it was uncertain whether PFMT reduced incontinence in the late postnatal period compared to usual care (RR 0.68, 95% CI 0.24 to 1.94; 2 trials; 620 women; very low-quality evidence). In women with or without faecal incontinence (mixed population), antenatal PFMT led to little or no difference in the prevalence of faecal incontinence in late pregnancy (RR 0.61, 95% CI 0.30 to 1.25; 2 trials, 867 women; moderate-quality evidence). For postnatal PFMT in a mixed population, there was considerable uncertainty about the effect on faecal incontinence in the late postnatal period (RR 0.73, 95% CI 0.13 to 4.21; 1 trial, 107 women, very low-quality evidence).There was little evidence about effects on urinary or faecal incontinence beyond 12 months' postpartum. There were few incontinence-specific quality of life data and little consensus on how to measure it. We found no data on health economics outcomes. AUTHORS' CONCLUSIONS: Targeting continent antenatal women early in pregnancy and offering a structured PFMT programme may prevent the onset of urinary incontinence in late pregnancy and postpartum. However, the cost-effectiveness of this is unknown. Population approaches (recruiting antenatal women regardless of continence status) may have a smaller effect on urinary incontinence, although the reasons for this are unclear. It is uncertain whether a population-based approach for delivering postnatal PFMT is effective in reducing urinary incontinence. Uncertainty surrounds the effects of PFMT as a treatment for urinary incontinence in antenatal and postnatal women, which contrasts with the more established effectiveness in mid-life women.It is possible that the effects of PFMT might be greater with targeted rather than mixed prevention and treatment approaches and in certain groups of women. Hypothetically, for instance, women with a high body mass index are at risk factor for urinary incontinence. Such uncertainties require further testing and data on duration of effect are also needed. The physiological and behavioural aspects of exercise programmes must be described for both PFMT and control groups and how much PFMT women in both groups do, to increase understanding of what works and for whom.Few data exist on faecal incontinence or costs and it is important that both are included in any future trials. It is essential that future trials use valid measures of incontinence specific quality of life for both urinary and faecal incontinence. PMID- 29271474 TI - A new association between CDK5RAP2 microcephaly and congenital cataracts. AB - INTRODUCTION: Primary microcephaly type 3 is a genetically heterogeneous condition caused by a homozygous or compound heterozygous mutation in CDK5 regulatory subunit associated protein 2 (CDK5RAP2) and characterized by reduced head circumference (<5th percentile) with additional phenotypes varying from pigmentary abnormalities to sensorineural hearing loss. Until now, congenital cataracts have not been reported in patients with primary microcephaly type 3. CLINICAL REPORT: We report multiple affected family members from a consanguineous Saudi family with microcephaly and congenital cataracts. We utilized a next generation sequencing-based microcephaly gene panel that revealed a CDK5RAP2 variant (c.4055A>G; p.Glu1352Gly) as the most plausible candidate for the likely etiology in this family. Then we performed family segregation analysis using Sanger sequencing, autozygosity mapping, and whole exome sequencing, all of which revealed no other possible disease-causing variants. CONCLUSION: Here we report on a new clinical manifestation of CDK5RAP2 and expand the phenotype of primary microcephaly type 3. PMID- 29271475 TI - Role of Nrf2 in preventing oxidative stress induced chloride current alteration in human lung cells. AB - The lung tissue is one of the main targets of oxidative stress due to external sources and respiratory activity. In our previous work, we have demonstrated in that O3 exposure alters the Cl- current-voltage relationship, with the appearance of a large outward rectifier component mainly sustained by outward rectifier chloride channels (ORCCs) in human lung epithelial cells (A549 line). In the present study, we have performed patch clamp experiments, in order to identify which one of the O3 byproducts (4hydroxynonenal (HNE) and/or H2 O2 ) was responsible for chloride current change. While 4HNE exposition (up to 25 MUM for 30' before electrophysiological analysis) did not reproduce O3 effect, H2 O2 produced by glucose oxidase 10 mU for 24 hr before electrophysiological analysis mimicked O3 response. This result was confirmed treating the cell with catalase (CAT) before O3 exposure (1,000 U/ml for 2 hr): CAT was able to rescue Cl- current alteration. Since CAT is regulated by Nrf2 transcription factor, we pre treated the cells with the Nrf2 activators, resveratrol and tBHQ. Immunochemical and immunocytochemical results showed Nrf2 activation with both substances that lead to prevent OS effect on Cl- current. These data bring new insights into the mechanisms involved in OS-induced lung tissue damage, pointing out the role of H2 O2 in chloride current alteration and the ability of Nfr2 activation in preventing this effect. PMID- 29271476 TI - Haplotype-based association of two SNPs in miR-323b with unexplained recurrent spontaneous abortion in a Chinese Han population. AB - Single nucleotide polymorphisms (SNPs) in miRNAs are associated with the risk to development of certain human diseases and affect the regulatory capacity of miRNAs. However, the relationship between miRNAs polymorphisms and recurrent pregnancy loss (RPL) is still largely unknown. Our study found that one SNP rs56103835 T>C in miR-323b coding region was associated with the increase risk of human unexplained RPL (URPL), but no differences were found in another SNP rs75330474 C>T. However, in two-locus haplotype analysis, T-C haplotype was associated with an increased risk of URPL. The level of mature miR-323b was obviously up-regulated in cells transfected with T-C haplotype. T-C haplotype inhibited HTR-8/SVneo cells proliferation and migration and promoted cells apoptosis. Further experiments identified that paired-box 8 (Pax8) was a functionally relevant target of miR-323b, and its expression was reversely regulated by miR-323b. Besides, the expressions of Pax8 in villous chorionic tissues from URPL patients were lower than controls, contrary to the high expression of miR-323. More importantly, dual-luciferase assay indicated T-C haplotype, increasing miR-323b expression, could down-regulated Pax8 expression. Collectively, our data suggest that T-C haplotype in pre-miR-323b may aggravate the risk of developing URPL and influence the level of mature miR-323b and its target gene Pax8. PMID- 29271477 TI - Immunomodulatory activity of glycodelin: implications in allograft rejection. AB - Glycodelin is an immunomodulator, indispensable for the maintenance of pregnancy in humans. The glycoprotein induces apoptosis in activated CD4+ T cells, monocytes and natural killer (NK) cells, and suppresses the activity of cytotoxic T cells, macrophages and dendritic cells. This study explores the immunosuppressive property of glycodelin for its possible use in preventing graft rejection. Because glycodelin is found only in certain primates, the hypothesis was investigated in an allograft nude mouse model. It is demonstrated that treatment of alloactivated mononuclear cells with glycodelin thwarts graft rejection. Glycodelin decreases the number of activated CD4+ and CD8+ cells and down-regulates the expression of key proteins known to be involved in graft demise such as granzyme-B, eomesodermin (EOMES), interleukin (IL)-2 and proinflammatory cytokines [tumour necrosis factor (TNF)-alpha and IL-6], resulting in a weakened cell-mediated immune response. Immunosuppressive drugs for treating allograft rejection are associated with severe side effects. Glycodelin, a natural immunomodulator in humans, would be an ideal alternative candidate. PMID- 29271478 TI - Differential serum cytokine profile in patients with systemic lupus erythematosus and posterior reversible encephalopathy syndrome. AB - Systemic lupus erythematosus (SLE) patients are susceptible to the development of posterior reversible encephalopathy syndrome (PRES). The main theory concerning the physiopathology of PRES suggests that there is brain-blood barrier damage, which is associated with endothelial dysfunction, and characterized by vasogenic oedema. However, current evidence regarding its physiopathogenic mechanisms is quite scant. The aim of this study was to analyse the expression of different serum cytokines, as well as vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L), in patients with PRES/systemic lupus erythematosus (SLE) and to compare them with levels in SLE patients without PRES and in healthy controls. We performed a transversal study in a tertiary care centre in Mexico City. We included 32 subjects (healthy controls, n = 6; remission SLE, n = 6; active SLE, n = 6 and PRES/SLE patients, n = 14). PRES was defined as reversible neurological manifestations (seizures, visual abnormalities, acute confusional state), associated with compatible changes by magnetic resonance imaging (MRI). Serum samples were obtained during the first 36 h after the PRES episode and were analysed by cytometric bead array, Luminex multiplex assay or enzyme-linked immunosorbent assay (ELISA). Interleukin (IL)-6 and IL-10 levels were significantly higher in PRES/SLE patients (P = 0.013 and 0.025, respectively) when compared to the other groups. Furthermore, IL-6 and IL-10 levels displayed a positive correlation (r = 0.686, P = 0.007). There were no differences among groups regarding other cytokines, sCD40L or VEGF levels. A differential serum cytokine profile was found in PRES/SLE patients, with increased IL-6 and IL-10 levels. Our findings, which are similar to those described in other neurological manifestations of SLE, support the fact that PRES should be considered among the SLE-associated neuropsychiatric syndromes. PMID- 29271480 TI - Stem cells in lung repair and regeneration: Current applications and future promise. AB - Lung diseases are major cause of morbidity and mortality worldwide. The progress in regenerative medicine and stem cell research in the lung are currently a fast growing research topic that can provide solutions to these major health problems. Under normal conditions, the rate of cellular proliferation is relatively low in the lung in vivo, compared to other major organ systems. Lung injury leads to the activation of stem/progenitor cell populations that re-enter the cell cycle. Yet, little is known about stem cells in the lung, despite common thoughts that these cells could play a critical role in the repair of lung injuries. Nor do we fully understand the cellular and architectural complexity of the respiratory tract, and the diverse stem/progenitor cells that are involved in the lung repair and regeneration. In this review, we discuss the conceptual framework of lung stem/progenitor cell biology, and describe lung diseases, in which stem cell manipulations may be physiologically significant. In addition, we highlight the challenges of lung stem cell-based therapy. PMID- 29271479 TI - Th17, synchronically increased with Tregs and Bregs , promoted by tumour cells via cell-contact in primary hepatic carcinoma. AB - Documented reports about T helper type 17 (Th17) cells have revealed that Th17 plays a critical role in inflammation and autoimmunity diseases. However, the role of Th17 in cancer remains contradictory. The interplay between Th17 and tumour cells in the tumour microenvironment of primary hepatic carcinoma (PHC) needs to be explored further and the relationship between Th17, regulatory T cells (Tregs ) and regulatory B cells (Bregs ) has not been defined completely. In this study, numerous experiments were undertaken to elucidate the interaction of Th17 and Treg /Breg cells involved in PHC. Our work demonstrated that an increased Th17 was detected in the peripheral circulation and in tumour tissues in PHC patients. In addition, increases in peripheral blood Th17 corresponded with tumour-node-metastasis (TNM) stage progression. Also, further studies indicated that Th17 cells were promoted by tumour cells in the PHC tumour microenvironment through both contact-dependent and -independent mechanisms, but cell-contact played the major important role in promoting the production and proliferation of Th17. When isolated CD4+ CD25+ CD127low Tregs and CD4+ CD25- CD127+ non-Tregs were cultured with autologous tumour cells, it implied that the phenotype of Th17 and Tregs was modified by tumour cells in the tumour microenvironment. As well as this, Th17 cells were also found to correlate positively with CD4+ forkhead box protein 3+ Tregs and CD19+ CD5+ CD1dhi Bregs in PHC. Notably, Th17 increased synchronically with Tregs and Bregs in PHC. These findings may provide new clues to reveal the mechanisms of immune escape in PHC. PMID- 29271481 TI - Systemic pharmacological treatments for chronic plaque psoriasis: a network meta analysis. AB - BACKGROUND: Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head to head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the efficacy and safety of conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: We searched the following databases to December 2016: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registers and the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports. We checked the reference lists of included and excluded studies for further references to relevant RCTs. We searched the trial results databases of a number of pharmaceutical companies and handsearched the conference proceedings of a number of dermatology meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic and biological treatments in adults (over 18 years of age) with moderate to severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate to severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. DATA COLLECTION AND ANALYSIS: Three groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the Psoriasis Area and Severity Index score (PASI) 90) and acceptability (the inverse of serious adverse effects). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes, according to GRADE; we evaluated evidence as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. MAIN RESULTS: We included 109 studies in our review (39,882 randomised participants, 68% men, all recruited from a hospital). The overall average age was 44 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo controlled (67%), 23% were head-to-head studies, and 10% were multi-armed studies with both an active comparator and placebo. We have assessed all treatments listed in the objectives (19 in total). In all, 86 trials were multicentric trials (two to 231 centres). All of the trials included in this review were limited to the induction phase (assessment at less than 24 weeks after randomisation); in fact, all trials included in the network meta-analysis were measured between 12 and 16 weeks after randomisation. We assessed the majority of studies (48/109) as being at high risk of bias; 38 were assessed as at an unclear risk, and 23, low risk.Network meta-analysis at class level showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90.In terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents.At drug level, in terms of reaching PASI 90, all of the anti-IL17 agents and guselkumab (an anti-IL23 drug) were significantly more effective than the anti-TNF alpha agents infliximab, adalimumab, and etanercept, but not certolizumab. Ustekinumab was superior to etanercept. No clear difference was shown between infliximab, adalimumab, and etanercept. Only one trial assessed the efficacy of infliximab in this network; thus, these results have to be interpreted with caution. Tofacitinib was significantly superior to methotrexate, and no clear difference was shown between any of the other small molecules versus conventional treatments.Network meta-analysis also showed that ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab outperformed other drugs when compared to placebo in terms of reaching PASI 90: the most effective drug was ixekizumab (risk ratio (RR) 32.45, 95% confidence interval (CI) 23.61 to 44.60; Surface Under the Cumulative Ranking (SUCRA) = 94.3; high certainty evidence), followed by secukinumab (RR 26.55, 95% CI 20.32 to 34.69; SUCRA = 86.5; high-certainty evidence), brodalumab (RR 25.45, 95% CI 18.74 to 34.57; SUCRA = 84.3; moderate-certainty evidence), guselkumab (RR 21.03, 95% CI 14.56 to 30.38; SUCRA = 77; moderate-certainty evidence), certolizumab (RR 24.58, 95% CI 3.46 to 174.73; SUCRA = 75.7; moderate-certainty evidence), and ustekinumab (RR 19.91, 95% CI 15.11 to 26.23; SUCRA = 72.6; high-certainty evidence).We found no significant difference between all of the interventions and the placebo regarding the risk of serious adverse effects (SAEs): the relative ranking strongly suggested that methotrexate was associated with the best safety profile regarding all of the SAEs (RR 0.23, 95% CI 0.05 to 0.99; SUCRA = 90.7; moderate-certainty evidence), followed by ciclosporin (RR 0.23, 95% CI 0.01 to 5.10; SUCRA = 78.2; very low-certainty evidence), certolizumab (RR 0.49, 95% CI 0.10 to 2.36; SUCRA = 70.9; moderate-certainty evidence), infliximab (RR 0.56, 95% CI 0.10 to 3.00; SUCRA = 64.4; very low-certainty evidence), alefacept (RR 0.72, 95% CI 0.34 to 1.55; SUCRA = 62.6; low-certainty evidence), and fumaric acid esters (RR 0.77, 95% CI 0.30 to 1.99; SUCRA = 57.7; very low-certainty evidence). Major adverse cardiac events, serious infections, or malignancies were reported in both the placebo and intervention groups. Nevertheless, the SAEs analyses were based on a very low number of events with low to very low certainty for just over half of the treatment estimates in total, moderate for the others. Thus, the results have to be considered with caution.Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability.Regarding the other efficacy outcomes, PASI 75 and Physician Global Assessment (PGA) 0/1, the results were very similar to the results for PASI 90.Information on quality of life was often poorly reported and was absent for a third of the interventions. AUTHORS' CONCLUSIONS: Our review shows that compared to placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis on the basis of moderate- to high certainty evidence. At class level, the biologic treatments anti-IL17, anti IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents, too. This NMA evidence is limited to induction therapy (outcomes were measured between 12 to 16 weeks after randomisation) and is not sufficiently relevant for a chronic disease. Moreover, low numbers of studies were found for some of the interventions, and the young age (mean age of 44 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice.Another major concern is that short-term trials provide scanty and sometimes poorly reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. Indeed, we found no significant difference in the assessed interventions and placebo in terms of SAEs. Methotrexate appeared to have the best safety profile, but as the evidence was of very low to moderate quality, we cannot be sure of the ranking. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies as well.In terms of future research, randomised trials comparing directly active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naive patients, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents. PMID- 29271482 TI - Electrical stimulation with non-implanted devices for stress urinary incontinence in women. AB - BACKGROUND: Several treatment options are available for stress urinary incontinence (SUI), including pelvic floor muscle training (PFMT), drug therapy and surgery. Problems exist such as adherence to PFMT regimens, side effects linked to drug therapy and the risks associated with surgery. We have evaluated an alternative treatment, electrical stimulation (ES) with non-implanted devices, which aims to improve pelvic floor muscle function to reduce involuntary urine loss. OBJECTIVES: To assess the effects of electrical stimulation with non implanted devices, alone or in combination with other treatment, for managing stress urinary incontinence or stress-predominant mixed urinary incontinence in women. Among the outcomes examined were costs and cost-effectiveness. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearches of journals and conference proceedings (searched 27 February 2017). We also searched the reference lists of relevant articles and undertook separate searches to identify studies examining economic data. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of ES with non-implanted devices compared with any other treatment for SUI in women. Eligible trials included adult women with SUI or stress-predominant mixed urinary incontinence (MUI). We excluded studies of women with urgency-predominant MUI, urgency urinary incontinence only, or incontinence associated with a neurologic condition. We would have included economic evaluations had they been conducted alongside eligible trials. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data from eligible trials and assessed risk of bias, using the Cochrane 'Risk of bias' tool. We would have performed economic evaluations using the approach recommended by Cochrane Economic Methods. MAIN RESULTS: We identified 56 eligible trials (3781 randomised participants). Eighteen trials did not report the primary outcomes of subjective cure, improvement of SUI or incontinence-specific quality of life (QoL). The risk of bias was generally unclear, as most trials provided little detail when reporting their methods. We assessed 25% of the included trials as being at high risk of bias for a variety of reasons, including industry funding and baseline differences between groups. We did not identify any economic evaluations.For subjective cure of SUI, we found moderate-quality evidence that ES is probably better than no active treatment (risk ratio (RR) 2.31, 95% CI 1.06 to 5.02). We found a similar result for cure or improvement of SUI (RR 1.73, 95% CI 1.41 to 2.11), but the quality of evidence was lower. We are very uncertain if there is a difference between ES and sham treatment in terms of subjective cure because of the very low quality of evidence (RR 2.21, 95% CI 0.38 to 12.73). For subjective cure or improvement, ES may be better than sham treatment (RR 2.03, 95% CI 1.02 to 4.07). The effect estimate was 660/1000 women cured/improved with ES compared to 382/1000 with no active treatment (95% CI 538 to 805 women); and for sham treatment, 402/1000 women cured/improved with ES compared to 198/1000 with sham treatment (95% CI 202 to 805 women).Low-quality evidence suggests that there may be no difference in cure or improvement for ES versus PFMT (RR 0.85, 95% CI 0.70 to 1.03), PFMT plus ES versus PFMT alone (RR 1.10, 95% CI 0.95 to 1.28) or ES versus vaginal cones (RR 1.09, 95% CI 0.97 to 1.21).Electrical stimulation probably improves incontinence-specific QoL compared to no treatment (moderate quality evidence) but there may be little or no difference between electrical stimulation and PFMT (low quality evidence). It is uncertain whether adding electrical stimulation to PFMT makes any difference in terms of quality of life, compared with PFMT alone (very low quality evidence). There may be little or no difference between electrical stimulation and vaginal cones in improving incontinence-specific QoL (low quality evidence). The impact of electrical stimulation on subjective cure/improvement and incontinence-specific QoL, compared with vaginal cones, PFMT plus vaginal cones, or drugs therapy, is uncertain (very low quality evidence).In terms of subjective cure/improvement and incontinence-specific QoL, the available evidence comparing ES versus drug therapy or PFMT plus vaginal cones was very low quality and inconclusive. Similarly, comparisons of different types of ES to each other and of ES plus surgery to surgery are also inconclusive in terms of subjective cure/improvement and incontinence-specific QoL (very low-quality evidence).Adverse effects were rare: in total nine of the women treated with ES in the trials reported an adverse effect. We identified insufficient evidence to compare the risk of adverse effects in women treated with ES compared to any other treatment. We were unable to identify any economic data. AUTHORS' CONCLUSIONS: The current evidence base indicated that electrical stimulation is probably more effective than no active or sham treatment, but it is not possible to say whether ES is similar to PFMT or other active treatments in effectiveness or not. Overall, the quality of the evidence was too low to provide reliable results. Without sufficiently powered trials measuring clinically important outcomes, such as subjective assessment of urinary incontinence, we cannot draw robust conclusions about the overall effectiveness or cost-effectiveness of electrical stimulation for stress urinary incontinence in women. PMID- 29271483 TI - Reflecting on Participatory, Action-Oriented Research Methods in Community Psychology: Progress, Problems, and Paths Forward. AB - This paper provides a critical reflection on participatory action research (PAR) methods as they pertain to community psychology. Following a brief review of the fundamental aspects of PAR, key developments in the field are examined. These developments include the redefinition of the research enterprise among groups such as Indigenous and consumer/survivor communities, challenges that attend the "project" framing of PAR, academic and practice context challenges, and important domains in which PAR methods need to become more engaged (e.g., social media and disenfranchised youth). Three illustrative case studies of programs of work in the areas of youth homelessness, consumer/survivor engagement, and Indigenous research are provided to illustrate these contemporary challenges and opportunities in the field. The authors make the argument that without an effort to reconsider and redefine PAR, moving away from the stereotypical PAR "project" frame, these methods will continue to be poorly represented and underutilized in community psychology. PMID- 29271484 TI - Sonographic appearance of an eccrine spiradenoma: A case report. AB - Eccrine spiradenoma is a rare, benign, adnexal skin tumor of the sweat gland, which may manifest in any part of the body. It is typically located in the dermal or the subcutaneous fat layer. Eccrine spiradenomas rarely progress to malignant transformation and only a few cases of malignant transformation have been reported. Due to its rarity, there have been few reports about the sonographic appearances of eccrine spiradenoma. We report the sonographic findings in one case of eccrine spiradenoma, located in the subcutaneous fat and the deep dermal layers of the upper arm in a middle-aged woman. PMID- 29271485 TI - Prophylactic insertion of large bore peripheral intravenous catheters in maternity patients for postpartum haemorrhage: A cohort study. AB - BACKGROUND: Insertion of a 16 or 18 gauge peripheral intravenous catheter is a potentially painful intervention but one frequently experienced by pregnant women when admitted to hospital. Although the rationale for this practice is 'in case of an emergency bleed', evidence for using large-bore catheters in this population is absent. AIMS: (i) To identify the proportion of 18 gauge or larger peripheral catheters inserted into maternity patients; and (ii) to investigate the proportion of women who require blood products during their perinatal period. MATERIALS AND METHODS: Data from a sub-set of maternity patients who were included in a study of risk factors for peripheral intravenous access failure were analysed using descriptive statistics. RESULTS: One hundred and fourteen catheters were inserted in 95 women. Of the 95 first-inserted catheters, 84 (88.4%) were 16 or 18 gauge and 69 (82.1%) of these were placed in the hand or wrist. Four women (4%) received blood products, all were for non-urgent transfusions. CONCLUSION: Postpartum haemorrhage requiring a blood transfusion remains a relatively rare event. Comprehensive risk assessment should be undertaken before inserting large-bore catheters in perinatal women. Small veins in the hand and wrist should not be used for large bore catheters. PMID- 29271487 TI - All for one - O2 -sensitive K+ channels that mediate carotid body activation. PMID- 29271486 TI - No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients. AB - Belatacept is a second-generation cytotoxic T lymphocyte antigen (CTLA)-4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co-stimulation via CD28 by binding to its ligands B7.1 and B7.2. Experimental evidence suggests a potential additional mechanism for CTLA-4 Ig compounds through binding to B7 molecules expressed on antigen-presenting cells (APCs) and up-regulation of indoleamine 2,3-dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down-regulates T cell immunity. So far it remains unknown whether belatacept up-regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi-centre, investigator initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103-045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post-transplant in liver transplant patients randomized to receive either belatacept or tacrolimus-based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus-treated patients in per-protocol and in intent to-treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus-treated patients. PMID- 29271488 TI - Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing. AB - Fibrosis can develop in nearly any tissue leading to a wide range of chronic fibrotic diseases. However, current treatment options are limited. In this study, we utilized an established aged mouse model of bleomycin-induced lung fibrosis (BLM) to test our hypothesis that fibrosis may develop simultaneously in multiple organs by evaluating skin fibrosis and wound healing. Fibrosis was induced in lung in aged (18-22-month-old) C57BL/6 male mice by intratracheal BLM administration. Allogeneic adipose-derived mesenchymal stromal cells (ASCs) or saline were injected intravenously 24 hr after BLM administration. Full thickness 8-mm punch wounds were performed 7 days later to study potential systemic anti fibrotic and wound healing effects of intravenously delivered ASCs. Mice developed lung and skin fibrosis as well as delayed wound closure. Moreover, we observed similar changes in the expression of known pro-fibrotic factors in both lung and skin wound tissue, including miR-199 and protein expression of its corresponding target, caveolin-1, as well as phosphorylation of protein kinase B. Importantly, ASC-treated mice exhibited attenuation of BLM-induced lung and skin fibrosis and accelerated wound healing, suggesting that ASCs may prime injured tissues and prevent end-organ fibrosis. PMID- 29271489 TI - Differential mechanisms of adenosine- and ATPgammaS-induced microvascular endothelial barrier strengthening. AB - Maintenance of the endothelial cell (EC) barrier is critical to vascular homeostasis and a loss of barrier integrity results in increased vascular permeability. While the mechanisms that govern increased EC permeability have been under intense investigation over the past several decades, the processes regulating the preservation/restoration of the EC barrier remain poorly understood. Herein we show that the extracellular purines, adenosine (Ado) and ATPgammaS can strengthen the barrier function of human lung microvascular EC (HLMVEC). This ability involves protein kinase A (PKA) activation and decreases in myosin light chain 20 (MLC20) phosphorylation secondary to the involvement of MLC phosphatase (MLCP). In contrast to adenosine, ATPgammaS-induced PKA activation is accompanied by a modest, but significant decrease in cAMP levels supporting the existence of an unconventional cAMP-independent pathway of PKA activation. Furthermore, ATPgammaS-induced EC barrier strengthening does not involve the Rap guanine nucleotide exchange factor 3 (EPAC1) which is directly activated by cAMP, but is instead dependent upon protein kinase A-anchor protein 2 (AKAP2) expression. We also found that AKAP2 can directly interact with the myosin phosphatase-targeting protein MYPT1 and that depletion of AKAP2 abolished ATPgammaS-induced increases in transendothelial electrical resistance (TER). Adenosine-induced strengthening of the HLMVEC barrier required the coordinated activation of PKA and EPAC1 in a cAMP-dependent manner. In summary, ATPgammaS induced enhancement of the EC barrier is EPAC1-independent and is instead mediated by activation of PKA which is then guided by AKAP2, in a cAMP independent mechanism, to activate MLCP which dephosphorylates MLC20 resulting in reduced EC contraction and preservation. This article is protected by copyright. All rights reserved. PMID- 29271490 TI - The "Cross-court draf IIb" procedure for advanced nasal septum or frontal sinus pathology and nasal septum pathology. PMID- 29271491 TI - B,N-Codoped graphene as catalyst for the oxygen reduction reaction: Insights from periodic and cluster DFT calculations. AB - A comprehensive theoretical study of the oxygen reduction reaction (ORR) over B,N codoped graphene has been carried out in the framework of DFT using two different approaches based on periodic or cluster models. The comparison and integration of the information provided by the two approaches allow achieving a more complete description of the studied phenomena, combining the advantages of both models. On one hand, the analysis of the structure, stability, and electronic properties of this catalyst permits to identify and characterize the active sites and provides insights into the origin of its high catalytic activity that should be found in the synergistic coupling of the opposite effects of the two B and N heteroatoms used as dopants. On the other hand, the study of the reaction mechanisms evidences that the process is thermodynamically favorable due to the overall high exothermicity, and that the 4e- transfer is the favorite ORR pathway, being the OH hydrogenation the rate-determining step. Overall, all the reported results clearly underline the superior catalytic activity of B,N-codoped graphene toward this reaction. (c) 2017 Wiley Periodicals, Inc. PMID- 29271492 TI - Early-life exposure to Tris(1,3-dichloroisopropyl) phosphate induces dose dependent suppression of sexual behavior in male rats. AB - Exposure to endocrine-disrupting chemicals may adversely affect animals, particularly during development. Tris(1,3-dichloroisopropyl) phosphate (TDCIPP) is an organophosphate with anti-androgen function in vitro that is present in indoor dust at relatively high concentrations. In male rats, androgens are necessary for the development of reproductive organs, as well as the endocrine and central nervous systems. However, we currently do not know the exact effects of TDCIPP exposure through suckling on subsequent reproductive behavior in males. Here, we show that TDCIPP exposure (25-250 mg kg-1 via oral administration over 28 consecutive days post-birth) suppressed male sexual behavior and reduced testes size. These changes were dose-dependent and appeared first in adults rather than in juveniles. These results demonstrate that TDCIPP exposure led to normal body growth and appearance in juveniles, but disrupted the endocrine system and physiology in adults. Therefore, assays should be performed using adult animals to ensure accuracy, and to confirm the influence of chemical substances given during early mammalian life. PMID- 29271493 TI - Unilateral improvement of nail psoriasis with denervation injury. PMID- 29271494 TI - Placental pathologic lesions with a significant recurrence risk - what not to miss! AB - Here, we review three important placental pathologies with significant clinical implications and recurrence risks. They are, in order of most to least frequently seen, villitis of unknown etiology, chronic histiocytic intervillositis, and massive perivillous fibrin deposition (also known as maternal floor infarction). These entities occur in both preterm and term gestations and are observed more frequently with maternal and obstetric disorders including prior pregnancy loss, hypertension/preeclampsia, and autoimmune disease. They are associated with, and probably the cause of, significant perinatal morbidity and mortality including intrauterine growth restriction, fetal and neonatal demise, and fetal/neonatal neurocompromise (seizures and cerebral palsy). All three entities have high recurrence risks, with recurrence rates ranging from 34 to 100%. The histologic features of villitis of unknown etiology, chronic histiocytic intervillositis, and massive perivillous fibrin deposition are described herein. We discuss the clinical associations and suggest the subsequent clinical and pathological evaluation. Hypotheses as to the biology of these lesions are reviewed. PMID- 29271495 TI - A novel method to measure mitral valve area in patients with rheumatic mitral stenosis using three-dimensional transesophageal echocardiography: Feasibility and validation. AB - AIMS: Neither two- nor three-dimensional (3D) planimetry of the mitral valve (MV) orifice takes the mitral commissures into account. Thus, if the commissures are not completely fused, the MV orifice will not be planar, and MV area (MVA) will be underestimated. The study aimed to validate a novel method for measurement of the MVA using a software that traces the MV orifice including the commissures. METHODS AND RESULTS: The study included 30 patients undergoing percutaneous balloon mitral valvuloplasty for severe rheumatic mitral stenosis. All performed 3D transesophageal echocardiography (TEE) immediately before the procedure. MVA was measured using the mitral valve navigation (MVN) software of the Philips Q Lab 10.2 in a diastolic frame with maximum diastolic opening of the MV. Regular 3D planimetry of the MV orifice was also performed. Before balloon dilation, the MVA was calculated invasively using the Gorlin's formula. No significant difference was detected between MVN-derived MVA and Gorlin-derived MVA (0.98 cm2 vs. 1.0 cm2 , P = .33). A statistically significant difference was detected between Planimetry-derived MVA and Gorlin-derived MVA (0.8 cm2 vs. 1.0 cm2 , P < .001). There were significant linear correlations between MVN-derived MVA and Gorlin-derived MVA (r = .84, P < .001). Using Bland-Altman analysis, Gorlin derived MVA showed better and relatively narrower limits of agreement with MVN derived MVA than planimetry-derived MVA. CONCLUSION: Measurement of the MVA using the MVN method is feasible and is more correlated to the invasively measured MVA than the 3D planimetry method. This is the most accurate method of measuring the MVA that takes MV commissures into account. PMID- 29271496 TI - Dermoscopic features of pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum (PXE) is a disease characterized by aberrant mineralization of soft tissue and fragmentation of elastic fibres. It is often difficult to distinguish PXE clinically from pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-like PDE). However, we have identified that the dermoscopic findings in PXE include coalescing and reticulated yellow-white clods on a light purple-red background, whereas the dermoscopic findings in PXE-like PDE lack such a coloured background. To our knowledge, this is the first detailed description of dermoscopic differences between PXE and PXE-like PDE. PMID- 29271497 TI - Scalable Green Synthesis and Full-Scale Test of the Metal-Organic Framework CAU 10-H for Use in Adsorption-Driven Chillers. AB - The demand for cooling devices has increased during the last years and this trend will continue. Adsorption-driven chillers (ADCs) using water as the working fluid and low temperature waste energy for regeneration are an environmentally friendly alternative to currently employed cooling devices and can concurrently help to dramatically decrease energy consumption. Due to the ideal water sorption behavior and proven lifetime stability of [Al(OH)(m-BDC)] ? x H2 O (m-BDC2- = 1,3 benzenedicarboxylate), also denoted CAU-10-H, a green very robust synthesis process under reflux, with high yields up to 95% is developed and scaled up to 12 kg-scale. Shaping of the adsorbent is demonstrated, which is important for an application. Thus monoliths and coatings of CAU-10-H are produced using a water based binder. The composites are thoroughly characterized toward their mechanical stability and water sorption behavior. Finally a full-scale heat exchanger is coated and tested under ADC working conditions. Fast adsorption dynamic leads to a high power output and a good power density. A low regeneration temperature of only 70 degrees C is demonstrated, allowing the use of low temperature sources like waste heat and solar thermal collectors. PMID- 29271498 TI - Categorization Working Memory Span Task: Validation study of two Brazilian alternate versions. AB - BACKGROUND: The Categorization Working Memory Span Task (CWMS task) is a complex working memory (WM) span test that has been used previously to assess age and individual differences in WM as well as the relationship between WM and complex aspects of cognition such as listening comprehension. Two alternate versions of the task have been developed to be used as outcome variables in WM training protocol, which mirrors the task involved in the CWMS task. OBJECTIVES: (1) To translate and adapt the CWMS task for Brazilian Portuguese; (2) to test the equivalence of its 2 alternate versions; (3) to examine temporal stability; (4) to examine the influence of age and schooling on CWMS task; (5) to establish its relationship with other tests of WM. METHODS: Eighty-one older adults completed version A, and 86 completed version B of the CWMS task. After 6 months, a subsample (n = 85) completed the same version of the task. RESULTS: Versions A and B of the task generated comparable scores. Both versions had adequate temporal stability, which was higher for the CWMS total recall, which is the classical variable in this task to represent WM performance, when compared to the other variables generated by the test. The CWMS task variables were moderately correlated with schooling and other cognitive tests (Mini Mental State Examination, Letter-Number Sequencing, Spatial Span Backward, Digit Span Forward). CONCLUSIONS: The 2 versions of the CWMS task were equivalent and stable temporally. The task was influenced by schooling and global cognition. PMID- 29271499 TI - Mucinous adenocarcinoma in association with hidradenitis suppurativa: a new example of isoscartopic response. PMID- 29271500 TI - Fabrication of Au25 (SG)18 -ZIF-8 Nanocomposites: A Facile Strategy to Position Au25 (SG)18 Nanoclusters Inside and Outside ZIF-8. AB - Multifunctional composite materials are currently highly desired for sustainable energy applications. A general strategy to integrate atomically precise Au25 (SG)18 with ZIF-8 (Zn(MeIm)2 , MeIm = 2-methylimidazole), is developed via the typical Zn-carboxylate type of linkage. Au25 (SG)18 are uniformly encapsulated into a ZIF-8 framework (Au25 (SG)18 @ZIF-8) by coordination-assisted self assembly. In contrast, Au25 (SG)18 integrated by simple impregnation is oriented along the outer surface of ZIF-8 (Au25 (SG)18 /ZIF-8). The porous structure and thermal stability of these nanocomposites are characterized by N2 adsorption desorption isothermal analysis and thermal gravimetric analysis. The distribution of Au25 (SG)18 in the two nanocomposites is confirmed by electron microscopy, and the accessibility of Au25 (SG)18 is evaluated by the 4-nitrophenol reduction reaction. The as-prepared nanocomposites retain the high porosity and thermal stability of the ZIF-8 matrix, while also exhibiting the desired catalytic and optical properties derived from the integrated Au25 (SG)18 nanoclusters (NCs). Au25 (SG)18 @ZIF-8 with isolated Au25 sites is a promising heterogenous catalyst with size selectivity imparted by the ZIF-8 matrix. The structural distinction between Au25 (SG)18 @ZIF-8 and Au25 (SG)18 /ZIF-8 determines their different emission features, and provides a new strategy to adjust the optical behavior of Au25 (SG)18 for applications in bioimaging and biotherapy. PMID- 29271501 TI - Embedding MnO@Mn3 O4 Nanoparticles in an N-Doped-Carbon Framework Derived from Mn Organic Clusters for Efficient Lithium Storage. AB - The first synthesis of MnO@Mn3 O4 nanoparticles embedded in an N-doped porous carbon framework (MnO@Mn3 O4 /NPCF) through pyrolysis of mixed-valent Mn8 clusters is reported. The unique features of MnO@Mn3 O4 /NPCF are derived from the distinct interfacial structure of the Mn8 clusters, implying a new methodological strategy for hybrids. The characteristics of MnO@Mn3 O4 are determined by conducting high angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) and electron energy loss spectroscopy (EELS) valence-state analyses. Due to the combined advantages of MnO@Mn3 O4 , the uniform distribution, and the NPCF, MnO@Mn3 O4 /NPCF displays unprecedented lithium-storage performance (1500 mA h g-1 at 0.2 A g-1 over 270 cycles). Quantitative analysis reveals that capacitance and diffusion mechanisms account for Li+ storage, wherein the former dominates. First-principles calculations highlight the strong affiliation of MnO@Mn3 O4 and the NPCF, which favor structural stability. Meanwhile, defects of the NPCF decrease the diffusion energy barrier, thus enhancing the Li+ pseudocapacitive process, reversible capacity, and long cycling performance. This work presents a new methodology to construct composites for energy storage and conversion. PMID- 29271502 TI - High Edge Selectivity of In Situ Electrochemical Pt Deposition on Edge-Rich Layered WS2 Nanosheets. AB - Recent studies show that the Pt electrode can be slowly dissolved into the acidic media and regenerate on the working electrode along with the long-time hydrogen evolution reaction (HER) test. However, to date, the relationship between the Pt deposition and the intrinsic properties of the working electrode remains elusive. Herein, for the first time, the edge selectivity of in situ electrochemical Pt deposition on layered 2H-WS2 nanosheets, whose edge surface with rich dangling bonds is chemically active to regulate their properties, especially the interfacial reaction occurring between the electrode surface and the adjacent thin layer of the solution, is theoretically elucidated and experimentally verified by controlling the cathode polarization test using Pt wire as the counter electrode in H2 SO4 solution. It is revealed that the layered WS2 nanosheets with rich exposed edges show much stronger interaction with Pt atoms because the terminated S22- or S2- ligands on the edge exhibit much lower binding energy for Pt atoms compared with the apical S2- ligands on the terrace surface. The in situ electrochemical Pt-deposited WS2 nanosheets with rich exposed edges can act as a highly active hybrid electrocatalyst to accelerate HER kinetics and exhibit commercial Pt-like HER performance, especially in the alkaline media. PMID- 29271503 TI - What Happens Without Nickel? Cyclization Reactions of Ethylene with Ethanedithial and Related Molecules. AB - We present a computational study of the mechanism of the formation of 6-member heterocycles through the binding of ethylene to oxaldehyde, ethanedithial, and 2 thioxoacetaldehyde. This process is related to the olefin separation technology by metal dithiolenes and dioxolenes, being the formation of those heterocycles the main decomposition route. We also present a benchmark of 26 density functionals (spanning hybrid, double-hybrid, range-separated, semilocal, and local functionals) related to CCSD(T)/CBS reference values. Both the cyclization reaction and the isomerization of the cyclic product are included in the benchmark. The best functional among those tested for these reactions is omegaB97XD, and the effect of the basis set is also investigated for it. (c) 2017 Wiley Periodicals, Inc. PMID- 29271505 TI - Synthesis of In-Plane Artificial Lattices of Monolayer Multijunctions. AB - Recently, monolayers of van der Waals materials, including transition metal dichalcogenides (TMDs), are considered ideal building blocks for constructing 2D artificial lattices and heterostructures. Heterostructures with multijunctions of more than two monolayer TMDs are intriguing for exploring new physics and materials properties. Obtaining in-plane heterojunctions of monolayer TMDs with atomically sharp interfaces is very significant for fundamental research and applications. Currently, multistep synthesis for more than two monolayer TMDs remains a challenge because decomposition or compositional alloying is thermodynamically favored at the high growth temperature. Here, a multistep chemical vapor deposition (CVD) synthesis of the in-plane multijunctions of monolayer TMDs is presented. A low growth temperature synthesis is developed to avoid compositional fluctuations of as-grown TMDs, defects formations, and interfacial alloying for high heterointerface quality and thermal stability of monolayer TMDs. With optimized parameters, atomically sharp interfaces are successfully achieved in the synthesis of in-plane artificial lattices of the WS2 /WSe2 /MoS2 at reduced growth temperatures. Growth behaviors as well as the heterointerface quality are carefully studied in varying growth parameters. Highly oriented strain patterns are found in the second harmonic generation imaging of the TMD multijunctions, suggesting that the in-plane heteroepitaxial growth may induce distortion for unique material symmetry. PMID- 29271504 TI - Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease. AB - BACKGROUND: Validated diagnostic tools that are accurate, cost effective and acceptable to patients are required for disease stratification and monitoring in NAFLD. AIMS: To investigate the performance and cost of multiparametric MRI alongside existing biomarkers in the assessment of NAFLD. METHODS: Adult patients undergoing standard of care liver biopsy for NAFLD were prospectively recruited at two UK liver centres and underwent multiparametric MRI, blood sampling and transient elastography withing 2 weeks of liver biopsy. Non-invasive markers were compared to histology as the gold standard. RESULTS: Data were obtained in 50 patients and 6 healthy volunteers. Corrected T1 (cT1) correlated with NAFLD activity score (rho = 0.514, P < .001). cT1, enhanced liver fibrosis (ELF) test and liver stiffness differentiated patients with simple steatosis and NASH with AUROC (95% CI) of 0.69 (0.50-0.88), 0.87 (0.77-0.79) and 0.82 (0.70-0.94) respectively and healthy volunteers from patients with AUROC (95% CI) of 0.93 (0.86-1.00), 0.81 (0.69-0.92) and 0.89 (0.77-1.00) respectively. For the risk stratification of NAFLD, multiparametric MRI could save L150,218 per 1000 patients compared to biopsy. Multiparametric MRI did not discriminate between individual histological fibrosis stages in this population (P = .068). CONCLUSIONS: Multiparametric MRI accurately identified patients with steatosis, stratifies those with NASH or simple steatosis and reliably excludes clinically significant liver disease with superior negative predictive value (83.3%) to liver stiffness (42.9%) and ELF (57.1%). For the risk stratification of NAFLD, multiparametric MRI was cost effective and, combined with transient elastography, had the lowest cost per correct diagnosis. PMID- 29271506 TI - Single-Carbon-Nanotube Manipulations and Devices Based on Macroscale Anthracene Flakes. AB - Because of the outstanding mechanical and electrical properties of carbon nanotubes (CNTs), a CNT-based torsion pendulum is demonstrated to show great potential in nano-electromechanical systems. It is also expected to achieve various manipulations for further characterization and increase device sensitivity using ultrlong CNTs and macroscale moving parts. However, the reported top-down method limits the CNT performance and device size by introducing inevitable contamination and destruction, which greatly hinders the development of single-molecule devices. Here, a bottom-up method is introduced to fabricate heterostructures of anthracene flakes (AFs) and suspended CNTs, providing a nondamaging CNT mechanical measurement before further applications, especially for the twisting behavior, and providing a controllable and clean transfer method to fabricate CNT-based electrical devices under ambient conditions. Based on the unique geometry of CNT/AF heterostructures, various complex manipulations of single-CNT devices are conducted to investigate CNT mechanical properties and prompt novel applications of similar structures in nanotechnology. The AF-decorated CNTs show high Young's modulus (~1 TPa) and tensile strength (~100 GPa), and can be considered as the finest and strongest torsional springs. CNT-based torsion balance enables to measure fN-level forces and the torsional spring constant is two orders of magnitude lower than previously reported values. PMID- 29271507 TI - Photoactuated Pens for Molecular Printing. AB - The photoactuation of pen arrays made of polydimethylsiloxane carbon nanotube composites is explored, and the first demonstration of photoactuated pens for molecular printing is reported. Photoactuation of these composites is characterized using atomic force microscopy and found to produce microscale motion in response to modest illumination, with an actuation efficiency as high as 200 nm mW-1 on the sub-1 s time scale. Arrays of composite pens are synthesized and it is found that local illumination is capable of moving selected pens by more than 3 um out of the plane, bringing them into contact to perform controllable and high quality printing while completely shutting off the nonilluminated counterparts. In light of the scalability limitations of nanolithography, this work presents an important step and paves the way for arbitrary control of individual pens in massive arrays. As an example of a scalable soft actuator, this approach can also aid progress in other fields such as soft robotics and microfluidics. PMID- 29271508 TI - Multiscale Phase Separations for Hierarchically Ordered Macro/Mesostructured Metal Oxides. AB - Porous architectures play an important role in various applications of inorganic materials. Several attempts to develop mesoporous materials with controlled macrostructures have been reported, but they usually require complicated multiple step procedures, which limits their versatility and suitability for mass production. Here, a simple approach for controlling the macrostructures of mesoporous materials, without templates for the macropores, is reported. The controlled solvent evaporation induces both macrophase separation via spinodal decomposition and mesophase separation via block copolymer self-assembly, leading to the formation of hierarchically porous metal oxides with periodic macro/mesostructures. In addition, using this method, macrostructures of mesoporous metal oxides are controlled into spheres and mesoporous powders containing isolated macropores. Nanocomputed tomography, focused ion beam milling, and electron microscopy confirm well-defined macrostructures containing mesopores. Among the various porous structures, hierarchically macro/mesoporous metal oxide is employed as an anode material in lithium-ion batteries. The present approach could provide a broad and easily accessible platform for the manufacturing of mesoporous inorganic materials with different macrostructures. PMID- 29271509 TI - Foldable Electrode Architectures Based on Silver-Nanowire-Wound or Carbon Nanotube-Webbed Micrometer-Scale Fibers of Polyethylene Terephthalate Mats for Flexible Lithium-Ion Batteries. AB - A crumply and highly flexible lithium-ion battery is realized by using microfiber mat electrodes in which the microfibers are wound or webbed with conductive nanowires. This electrode architecture guarantees extraordinary mechanical durability without any increase in resistance after folding 1000 times. Its areal energy density is easily controllable by the number of folded stacks of a piece of the electrode mat. Deformable lithium-ion batteries of lithium iron phosphate as cathode and lithium titanium oxide as anode at high areal capacity (3.2 mAh cm 2 ) are successfully operated without structural failure and performance loss, even after repeated crumpling and folding during charging and discharging. PMID- 29271510 TI - Polymer Encapsulants Incorporating Light-Guiding Architectures to Increase Optical Energy Conversion in Solar Cells. AB - The fabrication of a new type of solar cell encapsulation architecture comprising a periodic array of step-index waveguides is reported. The materials are fabricated through patterning with light in a photoreactive binary blend of crosslinking acrylate and urethane, wherein phase separation induces the spontaneous, directed formation of broadband, cylindrical waveguides. This microstructured material efficiently collects and transmits optical energy over a wide range of entry angles. Silicon solar cells comprising this encapsulation architecture show greater total external quantum efficiencies and enhanced wide angle light capture and conversion. This is a rapid, straightforward, and scalable approach to process light-collecting structures, whereby significant increases in cell performance may be achieved. PMID- 29271511 TI - Gold(II) Trihalide Complexes from Organogold(III) Precursors. AB - The mononuclear gold(II) halide complexes [AuCl3 ]- and [AuBr3 ]- are formed in the gas phase by collision-induced homolytic splitting of the only Au-C bond in the monoalkylgold(III) precursors [CF3 AuX3 ]- . The geometries of the whole series of [AuX3 ]- complexes (X=F, Cl, Br, I) have been calculated by DFT methods. It has also been found that the neutral AuX2 molecules behave as unsaturated species, showing significant affinity for an additional X- ligand. Moreover, in the open-shell [AuX3 ]- anions, homolytic splitting of one of the Au X bonds and formation of the lower-valent [AuX2 ]- anions is favored over non reducing halide dissociation. They should therefore be prone to disproportionation. PMID- 29271512 TI - sRNA41 affects ribosome binding sites within polycistronic mRNAs in Methanosarcina mazei Go1. AB - Several noncoding RNAs potentially involved in nitrogen (N)-regulation have been detected in Methanosarcina mazei, however, targets have been identified only for one of them. Here, we report on the function of sRNA41 , highly expressed under N sufficiency. Comprising 120 nucleotides, sRNA41 shows high sequence and structural conservation within draft genomes of numerous Methanosarcina species. In silico target prediction revealed several potential targets, including genes of two homologous operons encoding for acetyl-CoA-decarbonylase/synthase complexes (ACDS) representing highly probable target candidates. A highly conserved single stranded region of sRNA41 was predicted to mask six independent ribosome binding sites of these two polycistronic mRNAs and was verified in vitro by microscale thermophoresis. Proteome analysis of the respective sRNA41 deletion mutant showed increased protein expression of both ACDS complexes in the absence of sRNA41 , whereas no effect on transcript levels was detected, arguing for sRNA41 -mediated post-transcriptional fine-tuning of ACDS expression. We hypothesize that the physiological advantage of downregulating sRNA41 under N limiting conditions is the resulting increase of ACDS protein levels. This provides sufficient amounts of amino acids for nitrogenase synthesis as well as reducing equivalents and energy for N2 -fixation, thus linking the carbon and N metabolism. PMID- 29271513 TI - Chk1 activation attenuates sensitivity of lapatinib in HER2-positive gastric cancer. AB - The ATM and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) pathway plays a pivotal role in DNA damage sensor and modulating homologous recombination. Recently, emerging evidence demonstrated that Chk1 phosphorylation was associated with chemotherapy and radiotherapy resistance. In this study, we explored the effect of ATR/Chk1 pathway on regulating lapatinib sensitivity in human epidermal growth factor receptor-2 (HER2)-positive gastric cancer cell lines. We selected two HER2 positive gastric cancer cell lines, and NCI-N87 cells exhibited higher sensitivity than MKN7 cells. Application of lapatinib inhibited phosphorylated HER2 and EGFR and the formation of epidermal growth factor receptor (EGFR)/HER2 complex in both cells. In NCI-N87 cells, lapatinib induced G1 arrest and reduced Chk1 phosphorylation through inhibiting the expression of DNA topoisomerase 2 binding protein 1 (TopBP1). While in MKN7 cells, no significant cell cycle transition was found and phosphorylated Chk1 was mildly upregulated. Inhibition of Chk1 phosphorylation enhanced the lapatinib sensitivity of MKN7 cells, which was shown by potentiated anti-proliferative effect, G1 arrest, downregulation of phosphorylated AKT and ERK along with aggravated DNA damage. In addition, increased Chk1 phosphorylation in NCI-N87 cells attenuated lapatinib-induced anti proliferative effect and G1 arrest, and abrogated reduced phosphorylated AKT and ERK. Taken together, our study provides a novel mechanism for regulating lapatinib sensitivity in HER2 positive gastric cancer cells, suggesting a new strategy in clinical treatment. PMID- 29271514 TI - Induction of the Spx regulon by cell wall stress reveals novel regulatory mechanisms in Bacillus subtilis. AB - The transcription factor Spx is the master regulator of the disulfide stress response in Bacillus subtilis. Intriguingly, the activation of Spx by diamide relies entirely on posttranslational regulatory events in spite of the complex transcriptional control of the spx gene. Here, we show that cell wall stress, but not membrane stress, also results in induction of the Spx regulon. Remarkably, two major differences were found regarding the mechanism of induction of Spx under cell wall stress in comparison to disulfide stress. First, transcriptional induction of the spx gene from a sigmaM -dependent promoter is required for accumulation of Spx in response to cell wall stress. Second, activation of the Spx regulon during cell wall stress is not accompanied by oxidation of the Spx disulfide switch. Finally, we demonstrate that cells lacking Spx have increased sensitivity toward antibiotics inhibiting both early and late steps in peptidoglycan synthesis, suggesting that the Spx regulon plays an important adaptive role in the cell wall stress response. This study expands the functional role of the Spx regulon and reveals novel regulatory mechanisms that result in induction of Spx in B. subtilis. PMID- 29271515 TI - Light-Responsive Biodegradable Nanorattles for Cancer Theranostics. AB - Cancer nanotheranostics, integrating both diagnostic and therapeutic functions into nanoscale agents, are advanced solutions for cancer management. Herein, a light-responsive biodegradable nanorattle-based perfluoropentane-(PFP)-filled mesoporous-silica-film-coated gold nanorod (GNR@SiO2 -PFP) is strategically designed and prepared for enhanced ultrasound (US)/photoacoustic (PA) dual modality imaging guided photothermal therapy of melanoma. The as-prepared nanorattles are composed of a thin mesoporous silica film as the shell, which endows the nanoplatform with flexible morphology and excellent biodegradability, as well as large cavity for PFP filling. Upon 808 nm laser irradiation, the loaded PFP will undergo a liquid-gas phase transition due to the heat generation from GNRs, thus generating nanobubbles followed by the coalescence into microbubbles. The conversion of nanobubbles to microbubbles can improve the intratumoral permeation and retention in nonmicrovascular tissue, as well as enhance the tumor-targeted US imaging signals. This nanotheranostic platform exhibits excellent biocompatibility and biodegradability, distinct gas bubbling phenomenon, good US/PA imaging contrast, and remarkable photothermal efficiency. The results demonstrate that the GNR@SiO2 -PFP nanorattles hold great potential for cancer nanotheranostics. PMID- 29271516 TI - Imperceptible Epidermal-Iontronic Interface for Wearable Sensing. AB - Recent development of epidermal electronics provides an enabling means to continuous monitoring of physiological signals and close tracking of physical activities without affecting quality of life. Such devices require high sensitivity for low-magnitude signal detection, noise reduction for motion artifacts, imperceptible wearability with long-term comfortableness, and low-cost production for scalable manufacturing. However, the existing epidermal pressure sensing devices, usually involving complex multilayer structures, have not fully addressed the aforementioned challenges. Here, the first epidermal-iontronic interface (EII) is successfully introduced incorporating both single-sided iontronic devices and the skin itself as the pressure sensing architectures, allowing an ultrathin, flexible, and imperceptible packaging with conformal epidermal contact. Notably, utilizing skin as part of the EII sensor, high pressure sensitivity and high signal-to-noise ratios are achieved, along with ultralow motion artifacts for both internal (body) and external (environmental) mechanical stimuli. Monitoring of various vital signals, such as blood pressure waveforms, respiration waveforms, muscle activities and artificial tactile sensation, is successfully demonstrated, implicating a broad applicability of the EII devices for emerging wearable applications. PMID- 29271517 TI - High-Mobility Self-Assembling Truxenone-Based n-Type Organic Semiconductors. AB - The synthesis, self-assembly, and semiconducting properties of a series of disk like truxenone derivatives, functionalized with three peripheral long alkyl chains, either directly attached or distanced by linking phenyl or ethynyl groups, are reported. The strategy of distancing the alkyl chains from the central aromatic cores induces in these discotics well-ordered columnar assemblies and has a favorable effect on their charge-carrier mobility. Electron mobility values above 1 cm2 V-1 S-1 were determined for a truxenone functionalized with three peripheral decynyl chains by means of the space charge limited current technique. DFT calculations help to rationalize the high mobility values found for these new truxenone-based systems, indicating efficient intermolecular electronic couplings (fostered by a favorable stacking configuration) and moderate intramolecular reorganization energies for electrons in the origin of such high mobilities. PMID- 29271518 TI - An Unfused-Core-Based Nonfullerene Acceptor Enables High-Efficiency Organic Solar Cells with Excellent Morphological Stability at High Temperatures. AB - Most nonfullerene acceptors developed so far for high-performance organic solar cells (OSCs) are designed in planar molecular geometry containing a fused-ring core. In this work, a new nonfullerene acceptor of DF-PCIC is synthesized with an unfused-ring core containing two cyclopentadithiophene (CPDT) moieties and one 2,5-difluorobenzene (DFB) group. A nearly planar geometry is realized through the F...H noncovalent interaction between CPDT and DFB for DF-PCIC. After proper optimizations, the OSCs with DF-PCIC as the acceptor and the polymer PBDB-T as the donor yield the best power conversion efficiency (PCE) of 10.14% with a high fill factor of 0.72. To the best of our knowledge, this efficiency is among the highest values for the OSCs with nonfullerene acceptors owning unfused-ring cores. Furthermore, no obvious morphological changes are observed for the thermally treated PBDB-T:DF-PCIC blended films, and the relevant devices can keep ~70% of the original PCEs upon thermal treatment at 180 degrees C for 12 h. This tolerance of such a high temperature for so long time is rarely reported for fullerene-free OSCs, which might be due to the unique unfused-ring core of DF PCIC. Therefore, the work provides new idea for the design of new nonfullerene acceptors applicable in commercial OSCs in the future. PMID- 29271519 TI - Is aspirin necessary in the acute phase of Kawasaki disease? AB - AIM: To explore whether aspirin is necessary for treatment in the acute phase of Kawasaki disease (KD). METHODS: Nine hundred ten patients who fulfilled the criteria of KD and maintained follow-up for 2 years were included in this retrospective study. All patients initially received a single dose of intravenous immunoglobulin (IVIG, 2 g/kg) in the acute phase. Patients were classified into three groups according to the doses of aspirin. Group 1 included 152 cases treated with IVIG only in the acute phase. Group 2 included 672 cases treated with IVIG plus 3-5 mg/kg/day aspirin as the low-dose group, and group 3 included 86 cases treated with IVIG plus 30-50 mg/kg/day aspirin as the moderate-dose group. Changes in inflammatory indices and platelet count after treatment were compared by one-way analysis of variance or analysis of covariance to analyse the clinical effect of aspirin in acute KD. The relationship between aspirin use and coronary artery lesion complications was analysed by logistic regression. RESULTS: There was no significant difference among the three groups in terms of the anti-inflammation effect revealed by C-reactive protein level, white blood cell count, percentage of neutrophils in white blood cells, decreasing platelet count or prevention of the formation of coronary artery lesion. CONCLUSIONS: The role of aspirin in the treatment of the acute phase of KD should be questioned as a definite benefit has not been shown in our study. Further prospective studies incorporating large multicentre samples of patients are needed to confirm this finding. PMID- 29271520 TI - Is there an association between PAWP/WBP2NL sequence, expression, and distribution in sperm cells and fertilization failures in ICSI cycles? AB - Successful fertilization in mammals depends on the sperm's ability to initiate intracellular Ca2+ oscillations in the egg, a phenomenon that is elicited by Sperm-oocyte activating factors (SOAFs), whose quantitative and/or qualitative defect might result in fertilization failure. One such proposed factor is Post acrosomal WW domain-binding protein (PAWP/WBP2NL), although its ability to activate human oocytes has been questioned and its implication in human fertilization failure remains unknown. Here, we sought to determine if PAWP/WBP2NL expression and distribution in sperm cells associate with low/complete fertilization failure in males participating in intracytoplasmic sperm injection (ICSI) cycles. This prospective study was conducted on eight couples referred for elective ICSI with either the woman's own (n = 4) or a donor eggs (n = 4). Eight sperm donor samples used in ICSI, which resulted in normal fertilization rates, were used as the control group. For each male patient and donor sperm, PAWP/WBP2NL sequence, protein expression, and cellular distribution were analyzed by PCR amplification-sequencing, Western blot, and immunofluorescence, respectively. PAWP/WBP2NL was present in all samples, and no significant differences were detected between patients with fertilization failure and donors in sequence variants or mean protein expression, or in the proportion of PAWP/WBP2NL-positive sperm. In conclusion, no clear association between PAWP/WBP2NL protein expression in sperm and fertilization outcome in ICSI were observed from this cohort. PMID- 29271521 TI - Rational Design of Statically and Dynamically Stable Lithium-Sulfur Batteries with High Sulfur Loading and Low Electrolyte/Sulfur Ratio. AB - The primary challenge with lithium-sulfur battery research is the design of sulfur cathodes that exhibit high electrochemical efficiency and stability while keeping the sulfur content and loading high and the electrolyte/sulfur ratio low. With a systematic investigation, a novel graphene/cotton-carbon cathode is presented here that enables sulfur loading and content as high as 46 mg cm-2 and 70 wt% with an electrolyte/sulfur ratio of as low as only 5. The graphene/cotton carbon cathodes deliver peak capacities of 926 and 765 mA h g-1 , respectively, at C/10 and C/5 rates, which translate into high areal, gravimetric, and volumetric capacities of, respectively, 43 and 35 mA h cm-2 , 648 and 536 mA h g 1 , and 1067 and 881 mA h cm-3 with a stable cyclability. They also exhibit superior cell-storage capability with 95% capacity-retention, a low self discharge constant of just 0.0012 per day, and stable poststorage cyclability after storing over a long period of six months. This work demonstrates a viable approach to develop lithium-sulfur batteries with practical energy densities exceeding that of lithium-ion batteries. PMID- 29271522 TI - Conjugative transposition of the vancomycin resistance carrying Tn1549: enzymatic requirements and target site preferences. AB - Rapid spread of resistance to vancomycin has generated difficult to treat bacterial pathogens worldwide. Though vancomycin resistance is often conferred by the conjugative transposon Tn1549, it is yet unclear whether Tn1549 moves actively between bacteria. Here we demonstrate, through development of an in vivo assay system, that a mini-Tn1549 can transpose in E. coli away from its natural Gram-positive host. We find the transposon-encoded INT enzyme and its catalytic tyrosine Y380 to be essential for transposition. A second Tn1549 protein, XIS is important for efficient and accurate transposition. We further show that DNA flanking the left transposon end is critical for excision, with changes to nucleotides 7 and 9 impairing movement. These mutations could be partially compensated for by changing the final nucleotide of the right transposon end, implying concerted excision of the two ends. With changes in these essential DNA sequences, or without XIS, a large amount of flanking DNA transposes with Tn1549. This rescues mobility and allows the transposon to capture and transfer flanking genomic DNA. We further identify the transposon integration target sites as TTTT N6-AAAA. Overall, our results provide molecular insights into conjugative transposition and the adaptability of Tn1549 for efficient antibiotic resistance transfer. PMID- 29271523 TI - Angiotensin-converting enzyme-inhibitor therapy in adolescents with type 1 diabetes in a regional cohort: Auckland, New Zealand from 2006 to 2016. AB - AIM: To review indications and use of angiotensin-converting enzyme-inhibitor (ACEI) therapy for the treatment of persistent microalbuminuria (MA) and/or hypertension (HTN) in adolescents with type 1 diabetes mellitus (T1DM). METHODS: Retrospective chart review of adolescent patients with T1DM seen within the paediatric diabetes service in Auckland, New Zealand, from 2006 to 2016. MA, HTN, patient demographic characteristics and ACEI prescribing and monitoring indices were examined. RESULTS: Five hundred adolescents with T1DM were included. There were 26 patients (5%) with MA and/or HTN. MA alone was present in 16, HTN alone in 3 and both HTN and MA in 7. The 5-year MA/HTN-free rate was 98%, and the 10 year MA/HTN-free rate was 93%. Longer disease duration and earlier diagnosis were predictors of MA/HTN. There was no significant difference in standard clinical indices between study patients and others. ACEI was prescribed for 17 of 26 patients for either HTN or MA. Within 6 weeks of ACEI commencement, less than half of the subjects had repeat serum creatinine and MA screens and no record of repeat blood pressure measurement. Despite this, all patients had 3-monthly reviews within outpatient clinics where adjustments of ACEI doses were made. CONCLUSION: In our regional adolescent population with T1DM, there were low rates of both MA and/or HTN. In those who required treatment with ACEI, clinical monitoring post-commencement of therapy was inconsistent. Local consensus guidelines for the management of persistent MA in children and adolescents with diabetes mellitus were developed in response to this study. PMID- 29271524 TI - Perovskite Quantum Dots with Near Unity Solution and Neat-Film Photoluminescent Quantum Yield by Novel Spray Synthesis. AB - In this study, a novel perovskite quantum dot (QD) spray-synthesis method is developed by combining traditional perovskite QD synthesis with the technique of spray pyrolysis. By utilizing this new technique, the synthesis of cubic-shaped perovskite QDs with a homogeneous size of 14 nm is demonstrated, which shows an unprecedented stable absolute photoluminescence quantum yield ~100% in the solution and even in the solid-state neat film. The highly emissive thin films are integrated with light emission devices (LEDs) and organic light emission displays (OLEDs). The color conversion type QD-LED (ccQD-LED) hybrid devices exhibit an extremely saturated green emission, excellent external quantum efficiency of 28.1%, power efficiency of 121 lm W-1 , and extraordinary forward direction luminescence of 8 500 000 cd m-2 . The conceptual ccQD-OLED hybrid display also successfully demonstrates high-definition still images and moving pictures with a 119% National Television System Committee 1931 color gamut and 123% Digital Cinema Initiatives-P3 color gamut. These very-stable, ultra-bright perovskite QDs have the properties necessary for a variety of useful applications in optoelectronics. PMID- 29271525 TI - Mitoimmunity-when mitochondria dictates macrophage function. AB - In the past decade, several reports have appointed the importance of mitochondria in the immune response. Our understanding of mitochondria evolved from a simple supplier of energy into a platform necessary for immunorregulation. Proinflammatory responses are associated with enhanced glycolytic activity and breakdown of the TCA cycle. Mitochondrial reactive species of oxygen (mROS) are key regulators of classically activated macrophages, with substantial impact in the anti-microbicidal activity and pro-inflammatory cytokine secretion of macrophages. The inflammasome activation in macrophages is dependent on mROS production and mitochondrial regulation and mitochondrial dynamics and functionality direct impact inflammatory responses. Alternative activated macrophage metabolism relies on fatty acid oxidation, and the mechanism responsible for this phenotype is not fully elucidated. Thus, cellular metabolism and mitochondria function is a key immunoregulatory feature of macrophage biology. In this review, we will provide insights into recently reported evidences of mitochondria-related metabolic nodes, which are important for macrophage physiology. PMID- 29271526 TI - Comparison of Marginal and Internal Adaptation of Heat-Pressed and CAD/CAM Porcelain Laminate Veneers and a 2-Year Follow-Up. AB - PURPOSE: To compare marginal and internal adaptations of porcelain laminate veneers fabricated with heat-pressed and CAD/CAM techniques, and to evaluate the clinical performances 2 years after cementation. MATERIALS AND METHODS: Thirty heat-pressed and 31 CAD/CAM porcelain laminate veneers were fabricated for 12 patients. Silicone replicas of each veneer were obtained. Replicas were sectioned into 4 parts to measure adaptations of the veneers. A stereomicroscope was used to measure from 3 locations of replicas for marginal, and 9 locations for internal adaptations at 40x magnification. Clinical evaluations were done at baseline and 6, 12, 18, and 24 months after cementation according to the modified United States Public Health Service (USPHS) criteria. Independent samples t-test compared the adaptation values between heat-pressed and CAD/CAM groups. Paired t test was used to evaluate marginal and internal adaptations of each group. Differences between the modified USPHS criteria ratings of heat-pressed and CAD/CAM groups were determined by the Mann-Whitney U test. Kaplan-Meier analysis was used to analyze the survival ratings of the veneers (p < 0.05). RESULTS: The mean marginal adaptation values of heat-pressed and CAD/CAM veneers were 295 and 314.98 MUm, respectively, and there was no statistically significant difference (p = 0.541). Internal adaptation values of groups were not statistically different either (201.82 MUm for heat pressed; 195.47 MUm for CAD/CAM p = 0.734). When marginal and internal adaptation values were compared within groups, there were significant differences both for heat-pressed (p < 0.001) and CAD/CAM (p < 0.001). All veneers were rated 100% satisfactory during the 2-year period. CONCLUSION: Within the limitations of this study, fabrication method, whether CAD/CAM or heat-pressed, had no effect on the marginal and internal adaptation of porcelain laminate veneers. The results showed that both fabrication techniques performed well after 2 years of clinical performance. PMID- 29271528 TI - A soluble inorganic pyrophosphatase from the cattle tick Rhipicephalus microplus capable of hydrolysing polyphosphates. AB - Polyphosphates have been found in all cell types examined to date and play diverse roles depending on the cell type. In eukaryotic organisms, polyphosphates have been investigated mainly in mammalian cells, and only a few studies have addressed arthropods. Pyrophosphatases have been shown to regulate polyphosphate metabolism. However, these studies were restricted to trypanosomatids. Here we focus on the tick Rhipicephalus microplus, a haematophagous ectoparasite that is highly harmful to cattle. We produced a recombinant R. microplus pyrophosphatase (rRmPPase) with the aim of investigating its kinetic parameters using polyphosphates as substrate. Molecular docking assays of RmPPase with polyphosphates were also carried out. The kinetic and Hill coefficient parameters indicated that rRmPPase has a greater affinity, higher catalytic efficiency and increased cooperativity for sodium phosphate glass type 15 (polyP15 ) than for sodium tripolyphosphate (polyP3 ). Through molecular docking, we found that polyP3 binds close to the Mg2+ atoms in the catalytic region of the protein, participating in their coordination network, whereas polyP15 interactions involve negatively charged phosphate groups and basic amino acid residues, such as Lys56, Arg58 and Lys193; polyP15 has a more favourable theoretical binding affinity than polyP3 , thus supporting the kinetic data. This study shows, for the first time in arthropods, a pyrophosphatase with polyphosphatase activity, suggesting its participation in polyphosphate metabolism. PMID- 29271529 TI - Differentiation of female Oct4-GFP embryonic stem cells into germ lineage cells. AB - Due to high infertility ratio nowadays, it is essential to explore efficient ways of enhancing mammalian reproductivity, in particular female reproductivity. Using female Oct4-GFP embryonic stem cells, we mimic the in vivo development procedure to induce ES cells into epiblast cell-like cells (EpiLCs) and then primordial germ cell-like cells (PGCLCs). GFP positive PGCLCs that showed typical PGC markers and epigenetic modification were efficiently obtained. Further transplantation of the GFP positive PGCLC and native ovary cell mixture into ovary of infertile mice revealed that both MVH and GFP positive cells could be developed in ovary, but no later developmental stage germ cells were observed. This study suggested that Oct4-GFP ES cells may be only suitable for tracing early germ cell development. PMID- 29271530 TI - Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders. AB - DNA is constantly being damaged, either by endogenous or exogenous genotoxins. In that regard, DNA repair activities are essential for maintaining genomic stability and to life itself. Mutations in genes encoding DNA repair proteins cause severe human syndromes, but DNA repair defects have also been linked to several other diseases, notably to cancer and normal aging. Recently, new evidence has emerged indicating that some DNA repair diseases display mitochondrial and metabolic dysfunction through mechanisms that are yet being uncovered. These results suggest that mitochondria play an import role in the DNA damage response pathways and that damage accumulation may lead to mitochondrial dysfunction via metabolic imbalance and mitophagy impairment. Here we review the recent findings linking mitochondrial impairment and cell death to DNA damage accumulation in the context of DNA repair defects. In addition, the general involvement of DNA damage in cellular dysfunction suggests that these phenomena may be also involved in other human pathologies in which mitochondrial dysfunction and metabolic disruption play causative roles. PMID- 29271527 TI - Chorioamnionitis, IL-17A, and fetal origins of neurologic disease. AB - The Centers for Disease Control and Prevention estimate that 1 in 323 infants have cerebral palsy. Highly correlated to intrauterine infection and inflammation, the incidence of cerebral palsy has remained constant over the last few decades despite significant advances in neonatal intensive care including improved ventilator techniques, surfactant therapy, maternal steroid administration, and use of intrapartum empiric antimicrobials. Recent advances in our understanding of immune responses to infection and inflammation have identified the cytokine IL-17A as a crucial component of early proinflammatory mediators that cause brain injury associated with neurologic impairment. Remarkably, maternal inflammatory responses to in utero inflammation and infection can also lead to potentially debilitating neurologic conditions in the offspring, which often become clinically apparent during childhood and/or early adulthood. This review details the role of IL-17A in fetal and maternal proinflammatory responses that lead to fetal brain injury and neurologic sequelae, including cerebral palsy. Recent findings regarding the role of maternal inflammatory responses in the development of childhood and adult neurologic conditions, such as autism, schizophrenia, and multiple sclerosis, will also be highlighted. PMID- 29271531 TI - Comorbidities in persons with haemophilia aged 60 years or more compared with age matched people from the general population. PMID- 29271532 TI - Capsosiphon fulvescens extracts improve obesity-associated metabolic disorders and hepatic steatosis in high-fat diet-induced obese mice. AB - Herbal dietary supplements have attracted more and more attention owing to their relative effectiveness in obesity -related metabolic disorders and diseases. This study investigated the therapeutic effects and underlying mechanisms of Capsosiphon fulvescens (CF) extracts on obesity, their associated metabolic disorders and hepatic steatosis in high-fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed with normal, HFD/Vehicle and HFD/CF (orally 300 mg/kg/day for CF). After 12 weeks, CF blocked HFD-induced body weight, food intake, liver weight, hepatic triglyceride (TG), fat mass (weight of abdominal subcutaneous fat and epididymal adipose tissue) and biochemical parameters (total cohlesterol, glucose, TG, creatinine, high-density lipoproteins cholesterol and low-density lipoprotein cholesterol) of serum. CF also had improved serum levels of adiponectin, leptin and insulin-like growth factor-1 in HFD/CF mice. Moreover, CF ameliorated the hepatic steatosis-reducing size of white adipose tissue. These results indicate that CF have anti-obesity effects and are effective for reducing metabolic risk and hepatic steatosis. PMID- 29271533 TI - Eltrombopag with i.v. immunoglobulin for safe splenectomy in refractory immune thrombocytopenia. PMID- 29271534 TI - Vascular risk factors and depression in Parkinson's disease. AB - BACKGROUND AND PURPOSE: The aim of this study was to address the vascular depression hypothesis in Parkinson's disease (PD) from a large cohort of Chinese population. METHODS: A cross-sectional analysis of 1784 Chinese patients with PD was conducted. Patients were divided into absence of depression (score <= 20) and presence of depression (score > 20) based on assessment of the Hamilton Depression Rating Scale. Other clinical assessments included the Unified PD Rating Scale (UPDRS), the Hamilton Anxiety Rating Scale, the frontal assessment battery (FAB) and the Montreal Cognitive Assessment (MoCA). RESULTS: Patients with depression showed a higher proportion of women, longer disease duration, higher UPDRS part III score, higher levodopa equivalent daily dose use, higher occurrences of motor fluctuation and dyskinesia, lower FAB score and lower MoCA score than those without depression (P < 0.05). The proportions of drinking and overweight/obesity in the depression group were significantly lower than those in the non-depression group (P < 0.05). A forward binary logistic regression model indicated that depression in PD was associated with female sex [odds ratio (OR) 1.376, P = 0.025], higher UPDRS part III score (OR 1.042, P < 0.001), lower FAB score (OR 0.937, P = 0.015), anxiety (OR 18.156, P < 0.001) and overweight/obesity (OR 0.700, P = 0.019), whereas no associations were found with hypertension, diabetes, smoking, drinking, hyperlipidaemia and heart disease. CONCLUSIONS: Our study failed to verify the vascular depression hypothesis in PD. On the contrary, it was demonstrated that overweight/obesity is negatively associated with the presence of depression in PD. PMID- 29271535 TI - The effect of visual feedback of body parts on pain perception: A systematic review of clinical and experimental studies. AB - : The aim of this systematic review was to evaluate the effect of visual feedback techniques on pain perception by analysing the effect of normal-sized, magnified or minified visual feedback of body parts on clinical and experimentally-induced pain. Databases searched: Medline, Embase, PsychInfo, PEDro, CINAHL, CENTRAL and OpenSIGLE. Studies investigating pain patients and pain-free participants exposed to experimentally-induced pain were analysed separately. Risk of bias was assessed and data were meta-analysed. Thirty four studies were included. A meta analysis of clinical data favoured mirror visual feedback (six trials; mean difference = -13.06 mm; 95% CI = -23.97, -2.16). Subgroup analysis favoured mirror visual feedback when used as a course of treatment (three trials; mean difference = -12.76 mm; 95% CI = -24.11, -1.40) and when used for complex regional pain syndrome for complex regional pain syndrome (three trials; standard mean difference = -1.44; 95% CI = -1.88, -0.99). There is insufficient evidence to determine differences between normal-sized view and a size-distorted view of the limb. Mirror visual feedback was not superior to object view or direct view of the hand for reducing experimental pain in pain-free participants. There were inconsistencies in study findings comparing normal-sized reflection of a body part and a reflection of an object, or a magnified or minified reflection. There is tentative evidence that mirror visual feedback can alleviate pain when delivered as a course of treatment, and for patients with complex regional pain syndrome. It was not possible to determine whether normal-sized, magnified or minified visual feedback of body parts affects pain perception because of contradictory findings in primary studies. SIGNIFICANCE: It was not possible to determine whether normal-sized, magnified or minified visual feedback of body parts affected pain perception in clinical or experimental settings because of contradictory findings in primary studies. This emphasizes the need for higher quality studies. PMID- 29271536 TI - Site- and Enantioselective C-H Oxygenation Catalyzed by a Chiral Manganese Porphyrin Complex with a Remote Binding Site. AB - A chiral manganese porphyrin complex with a two-point hydrogen-bonding site was prepared and probed in catalytic C-H oxygenation reactions of 3,4 dihydroquinolones. The desired oxygenation occurred with perfect site selectivity at the C4 methylene group and with high enantioselectivity in favor of the respective 4S-configured secondary alcohols (12 examples, 29-97 % conversion, 19 68 % yield, 87-99 % ee). Mechanistic studies support the hypothesis that the reaction proceeds through a rate- and selectivity-determining attack of the reactive manganese oxo complex at the hydrogen-bound substrate and an oxygen transfer by a rebound mechanism. PMID- 29271537 TI - Co-morbidities in Chinese children with attention deficit/hyperactivity disorder and reading disabilities. AB - The co-morbidity of attention deficit/hyperactivity disorder (ADHD) and reading disorder (RD) is more frequent than expected. This investigation assessed the potential uniqueness of the co-morbidity of ADHD and RD and extended existing findings to the Chinese language. A parallel group design with a post hoc analysis of group differences was employed to compare 4 groups of children (30 with ADHD, 33 with RD, 28 with ADHD + RD, and 30 typically developing) regarding their reading comprehension, attention, reading-related abilities, and cognitive abilities. The findings indicated that children with RD and/or ADHD symptom(s) exhibited diverse cognitive profiles, and the distinguishing factor contributed to different inhibitions. Additionally, Chinese-speaking children with the co morbid symptoms of RD and ADHD demonstrated greater deficits in auditory working memory and rapid naming than did the pure-deficit groups. Furthermore, although problems with phonological awareness were similar between the 2 groups, the deficiency of orthographic knowledge was more severe in children with RD than in the co-morbid group. The ADHD + RD group's cognitive and reading-related abilities displayed a relatively complicated pattern that should be considered in the diagnosis of either RD or ADHD and their remediation design. PMID- 29271538 TI - Noninvasive phase mapping of persistent atrial fibrillation in humans: Comparison with invasive catheter mapping. AB - BACKGROUND: A novel noninvasive epicardial and endocardial electrophysiology system (NEEES) to identify electrical rotors and focal activity in patients with atrial fibrillation (AF) was recently introduced. Comparison of NEEES data with results from invasive mapping is lacking. METHODS: Six male patients (59 +/- 11 years) with persistent AF underwent cardiac mapping with the NEEES, which included the creation of isopotential and phase maps. Then patients underwent catheter mapping using a PentaRay NAV catheter and the CARTO 3 system. Signals acquired by the catheter were analyzed by customized software that applied the same phase mapping algorithm as for the NEEES data. RESULTS: In all patients, noninvasive phase mapping revealed short-lived electrical rotors occurring 1.8 +/ 0.3 times per second and demonstrating 1-4 (mean 1.2 +/- 0.6) rotation cycles. Most of these rotors (72.7%) aggregated in 2-3 anatomical clusters. In two patients, focal excitation from pulmonary veins was observed. Invasive catheter mapping in the dominant rotor aggregation sites and in the three control sites demonstrated the presence of electrical rotors with properties similar to noninvasively detected rotors. Spearman's correlation coefficient between rotor occurrence rate by noninvasive and invasive mapping was 0.97 (p < .0001). Mean rotors' cycle length at dominant aggregation sites, scores of their full rotations, and the proportion of rotors with clockwise rotation were not significantly different between the mapping modalities. CONCLUSION: In patients with persistent AF, phase processing of unipolar electrograms recorded by catheter mapping could reproduce electrical rotors as characterized by NEEES based phase mapping. PMID- 29271539 TI - The delta opioid peptide D-Alanine 2, Leucine 5 Enkephaline (DADLE)-induces neuroprotection through cross-talk between the UPR and pro-survival MAPK-NGF-Bcl2 signaling pathways via modulation of several micro-RNAs in SH-SY5Y cells subjected to ER stress. AB - Parkinson's disease (PD) is the second most progressive neurodegenerative disease characterized by the loss of dopaminergic neurons and accumulation of misfolded proteins in endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR). In the present study, we aimed to determine the potential survival effect of the delta opioid neuro-peptide D-Alanine 2, Leucine 5 Enkephaline (DADLE), and its mechanism in dopaminergic SH-SY5Y cells which were subjected to ER stress. In this cellular model of PD, enhanced cell survivability was observed on DADLE treatment (but not with MU and kappa opioid agonists) along with concomitant down regulation of the UPR stress sensors and protein aggregates. The study found increased phosphorylation of MEK-1, which leads to activation of MAP kinase as well as enhanced expression of the pro-survival gene nerve growth factor and anti-apoptotic marker Bcl2. DADLE treatment could also significantly inhibit expression of the pro-apoptotic marker BIM. Next-generation sequence analysis revealed 93 micro (mi) RNAs to be differentially regulated following DADLE treatment in cells subjected to ER stress. Pathway prediction and previously published reports revealed that out of these 93 miRNAs, 34 can play a role in promoting cell survival. Specific modulation of two such miRNAs, namely miR-30c-2-3p and miR-200c, could partially reverse the positive survival effect induced by DADLE. Apart from the known miRNAs, various novel miRNAs were also observed following DADLE treatment which could also play a role in enhancing the survival of SH-SY5Y cells under ER stress. PMID- 29271540 TI - Characterization of CD127- CD25++ Treg from human colostrum. AB - PROBLEM: Breastfeeding's influence on the tolerance to environmental antigens is essential for short- and long-term homeostasis for children. Colostrum is rich in leucocytes, but it is unknown whether regulatory T cells (Treg) account for part of this cell population. METHOD OF STUDY: Frequencies of CD127- CD25++ Treg and levels of immunoregulatory-associated cell markers were determined in colostrum and were compared with autologous blood cells. In addition, we evaluated whether the birth conditions can affect these features. RESULTS: Higher frequencies of CD127 - CD25++ Treg cells expressing Foxp3 and CD45RO were observed in the colostrum. The cells' CD25, CD152, CD279, and TGF-beta expression levels were greater than those in autologous blood cells. In addition, the CD279 and TGF-beta expressions of colostrum CD127- CD25++ Treg cells were influenced by gestational age and delivery mode. CONCLUSION: The higher proportion of these cells with a function-associated phenotype may reflect certain tolerogenic effects of breastmilk on newborns and infants, contributing to immune system homeostasis. PMID- 29271541 TI - Pain begets pain. When marathon runners are not in pain anymore, they underestimate their memory of marathon pain--A mediation analysis. AB - BACKGROUND: A previous study has shown that memory of pain induced by running a marathon might be underestimated. However, little is known about the factors that might influence such a memory distortion during pain recall. The aim of the study was to investigate the memory of pain induced by running a marathon and the factors that might influence it: (1) present pain during recall and (2) recall delay. METHODS: A total of 127 marathon runners participated in the study, which comprised of two phases. After completion of the marathon, participants were asked to rate the intensity and the unpleasantness of their pain. Either a week or a month later, they were asked again to rate the intensity and the unpleasantness of the remembered and present pain experience. RESULTS: Participants underestimated remembered pain intensity and pain unpleasantness only if they did not experience pain during recall (p < 0.05). We observed a trend for underestimation after a week (p = 0.09) and significant effect after a month (p < 0.05) of recall delay. Furthermore, present pain intensity during recall significantly mediated the memory of pain intensity induced by running the marathon, but only after a month. Similarly, present pain unpleasantness during recall significantly mediated the memory of pain unpleasantness, but only after a month. CONCLUSIONS: It is concluded that memory of pain induced by running the marathon is underestimated after a month of recall delay and mediated by present pain during recall. SIGNIFICANCE: This study explores factors acting during recall, influencing memory of naturally occurring pain induced by physical effort. The empirical findings provide the first robust evidence for a causal relationship between memory of pain and present pain during recall. PMID- 29271542 TI - Beyond cardiomyocyte loss: Role of Notch in cardiac aging. AB - The knowledge of the cellular events occurring in the aging heart has dramatically expanded in the last decade and is expected to further grow in years to come. It is now clear that impaired function and loss of cardiomyocytes are major features of cardiac aging, but other events are likewise important. In particular, accumulating experimental evidence highlights the importance of fibroblast and cardiac progenitor cell (CPC) dysfunction. The Notch pathway regulates cardiomyocyte, fibroblast, and CPC activity and, thus, may be critically involved in heart disease associated with advanced age, especially heart failure. In a translational perspective, thorough investigation of the Notch system in the aging myocardium may lead to the identification of molecular targets for novel therapies for age-related cardiac disease. PMID- 29271543 TI - Sex-related inequalities in management of patients with acute coronary syndrome results from the EURHOBOP study. AB - BACKGROUND: Real-world data from different levels of hospital specialisation would help to understand if differences in management between women and men with acute coronary syndrome (ACS) are still a priority target. We aimed to identify sex inequalities in management of patients with different types of ACS. METHODS: We analysed 1757 patients with a non-ST-elevation ACS (NSTEACS) and 1184 with ST elevation myocardial infarction (STEMI) or left bundle branch block (non classifiable (NC) ACS (STEMI/NC ACS group), consecutively discharged from ten Portuguese hospitals with different specialisation levels, between 2008 and 2010. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) for the association between sex and the performance of coronary angiography, reperfusion and revascularisation. RESULTS: Among STEMI/NC ACS, men had higher probability of performing coronary angiography than women (adjusted OR = 1.64, 95% CI: 1.11 2.44), while among NSTEACS patients there was no significant difference by sex (adjusted OR = 1.26, 95% CI: 0.99-1.62). In patients who underwent coronary angiography, there was no difference in proportion of women and men submitted to revascularisation, regardless of the ACS type. Although men with STEMI/NC ACS were more likely to undergo reperfusion (crude OR = 2.17, 95% CI: 1.68-2.81), the effect became not significant after multivariable adjustment (adjusted OR = 1.33, 95% CI: 0.96-1.84). CONCLUSION: Women diagnosed with STEMI/NC, but not NSTEACS, had lower probability when compared with men to be submitted to coronary angiography. There was no difference in performance of reperfusion and revascularisation by sex. PMID- 29271544 TI - Visualizing nuclear-localized RNA using transient expression system in plants. AB - By modifying the existing cytosolic RNA visualization tool pioneered by Schonberger, Hammes, and Dresselhaus (2012), we developed a method to visualize nuclear-localized RNA. Our method uses (i) an RNA component that consists of an RNA of interest that is fused to a bacteriophage-derived MS2 sequence; and (ii) GFP fused to MS2 coat protein (MSCP), which binds specifically to MS2 as is also the case in the method for cytosolic RNA visualization. The nuclear localization sequence (NLS) at the C-terminal of MSCP-GFP tethers the probe to the nucleus. To reduce background signals in the nucleus, we replaced the NLS with a nuclear export sequence (NES) that anchors the MSCP-GFP probe in the cytosol. Our nuclear RNA visualization method differs from previous methods in two aspects: (i) We used an NES to reduce nuclear background signal so that the MSCP-GFP probe localizes in the cytosol by default; (ii) We added mCherry as a visual marker in the RNA component to increase its efficient usage in a transient system. PMID- 29271545 TI - Preanalytical issues that may cause misdiagnosis in haemophilia and von Willebrand disease. AB - von Willebrand disease (VWD) and haemophilia represent common inherited or acquired bleeding disorders, but many laboratories and clinicians continue to struggle with their diagnosis or exclusion. Difficulties in achieving a correct diagnosis or exclusion of VWD or haemophilia might be due to analytical issues. Sometimes assays may generate a wrong result (ie an analytical error) or may have limitations in their dynamic range of measurement and/or their level of low analytical sensitivity. Less well recognized is the influence of preanalytical issues on the diagnosis of VWD or haemophilia. Therefore, this narrative review aims to provide an overview of some important preanalytical aspects that may affect the diagnosis of VWD or haemophilia, as well as a range of solutions that may help in mitigating or abrogating their influence. The review includes discussion of the more commonly noted preanalytical issues, such as haemolysis/icterus/lipaemia, and sample collection, processing and transport. However, we also extensively discuss other less well-recognized preanalytical issues, including clinical requests, anticoagulants and anticoagulant therapy, and laboratory test choices to name a few. PMID- 29271546 TI - Are ungulates in forests concerns or key species for conservation and biodiversity? Reply to Boulanger et al. (DOI: 10.1111/gcb.13899). AB - Increasing species richness of light demanding species in forests may not be a conservation concern if we accept a macroecological and evolutionary baseline for biodiversity. Most of the current biodiversity in Europe has evolved in the Pleistocene or earlier, and in ecosystems markedly influenced by dynamic natural processes, including grazing. Many threatened species are associated with high light forest environments such as forest glades and edges, as these have strongly declined at least partially due to the decline of large herbivores in European forests. Hence, moderate grazing in forests should be an ecological baseline and conservation target rather than a concern. PMID- 29271547 TI - Cis variants identified in F508del complex alleles modulate CFTR channel rescue by small molecules. AB - Molecules correcting the trafficking (correctors) and gating defects (potentiators) of the cystic fibrosis causing mutation c.1521_1523delCTT (p.Phe508del) begin to be a useful treatment for CF patients bearing p.Phe508del. This mutation has been identified in different genetic contexts, alone or in combination with variants in cis. Until now, 21 exonic variants in cis of p.Phe508del have been identified, albeit at a low frequency. The aim of this study was to evaluate their impact on the efficacy of CFTR-directed corrector/potentiator therapy (Orkambi). The analysis by minigene showed that two out of 15 cis variants tested increased exon skipping (c.609C > T and c.2770G > A). Four cis variants were studied functionally in the absence of p.Phe508del, one of which was found to be deleterious for protein maturation c.1399C > T (p.Leu467Phe). In the presence of p.Phe508del, this variant was the only to prevent the response to Orkambi treatment. This study showed that some patients carrying p.Phe508del complex alleles are predicted to poorly respond to corrector/potentiator treatments. Our results underline the importance to validate treatment efficacy in the context of complex alleles. PMID- 29271548 TI - Polycystic ovarian syndrome: Assessment of approaches to diagnosis and cardiometabolic monitoring in UK primary care. AB - INTRODUCTION: Polycystic ovarian syndrome (PCOS) is one of the commonest endocrine disorders affecting women of reproductive age. We examined the specific tests that are done in primary care to lead to the diagnosis of PCOS, and to support the diagnosis once made. METHODS: One thousand seven hundred and ninety seven women were identified from a pooled GP practice database. The search included all patients defined with PCOS or related terms. Records included demographic information, medical history (diagnoses), blood test results and whether a pelvic ultrasound scan had been performed. RESULTS: The most common age of PCOS diagnosis was 20-29 years; 67.7% of the women had at least one concomitant Read-coded diagnosis. Most pelvic ultrasound scans were performed in the month immediately prior to diagnosis. In the 12 months prior to the diagnosis of PCOS being made, 30.5% of women underwent a measurement of their serum total testosterone level while 29.6% had their serum SHBG measured. For serum oestradiol, the corresponding statistics were 28.4%, LH 45.3% and for FSH 45.5% checked before diagnosis. Fasting blood glucose, random glucose and HbA1c were checked in 10.2%, 18.8% and 4.2%, of women before diagnosis, respectively, but in only 7.9%, 6.0% and 3.4% of women in the 24 months after diagnosis. There was a tendency for endocrine testing (oestradiol, LH, FSH, testosterone, SHBG) to peak in the weeks before diagnosis. For plasma glucose, testing was performed more evenly over time as for serum cholesterol. Of all women diagnosed with PCOS, 32.8% were prescribed metformin, 3.7% antihypertensives, 2.2% statins and 63.5% an oestrogen-containing contraceptive pill or HRT. CONCLUSION: The underlying pathophysiology of PCOS is still not fully understood. As a result, treatment is often focused on individual symptoms, not the syndrome itself. Robust laboratory led protocols would provide the necessary information to enable an appropriate diagnostic evaluation/cardometabolic monitoring. PMID- 29271549 TI - Comparison of the predictive accuracy of four different ECG algorithms in identification of true ablation site for the idiopathic right ventricular outflow tract tachycardias. AB - BACKGROUND: We aimed to investigate the accuracy of four algorithms in prediction of right ventricular outflow tract (RVOT) tachycardias in patients who successfully underwent radiofrequency catheter ablation. METHODS: Four algorithms; two with easy-applicability and having a memorable design (Dixit and Joshi), and two with more complex and detailed design (Ito and Zhang) were compared according to the predictive accuracy. RESULTS: Among 99 patients (mean age 36.5 +/- 8.5 years, 39.4% male), there were 51 (51.5%) septal-located and 48 (48.5%) free-wall located RVOT tachycardia. Comparison of the predictive accuracy of the algorithms showed that Zhang (91.9%) was the best algorithm for prediction of either septal or free-wall located tachycardia. The second best algorithm was the Ito (77.7%) compared to Dixit (75.8%) and Joshi (70.7%). CONCLUSION: In patients with RVOT tachycardia, algorithms with a detailed design may predict the arrhythmia location better than the easy-applicable algorithms. PMID- 29271550 TI - Efficient Synthesis of Arylated Furans by a Sequential Rh-Catalyzed Arylation and Cycloisomerization of Cyclopropenes. AB - A novel and efficient strategy for the synthesis of arylated furans was successfully developed by a RhIII -catalyzed coupling of N-phenoxyacetamides and cyclopropenyl esters. Mechanistic investigation reveals that the arylated furans are formed via arylation of the cyclopropenyl esters followed by cycloisomerization. PMID- 29271551 TI - Central sleep apnoea in heart failure with reduced ejection fraction, adaptive servo-ventilation, and left ventricular ejection fraction: the (still) missing link. PMID- 29271552 TI - Larissa Heart Failure Risk Score: a proposed simple score for risk stratification in chronic heart failure. PMID- 29271553 TI - Quantification of physical activity in adult patients with haemophilic arthropathy in prophylaxis treatment using a fitness tracker. PMID- 29271554 TI - Regulation of osteogenesis of human amniotic mesenchymal stem cells by sodium butyrate. AB - Human amniotic membrane-derived mesenchymal stem cells (hAMSCs) draw great interests for regenerative medicine due to convenient availability and low immunogenicity. However, suboptimal culture conditions limit their application. In recent years, small molecules have proven powerful in regulating stem cell fates and can be applied to stimulate their function. In the present study, the impacts of sodium butyrate (NaBu), a histone deacetylase inhibitor (HDACi), on hAMSCs were investigated. It was shown that NaBu at a low concentration inhibited cell proliferation by arresting cell cycle at G0/G1 rather than inducing apoptosis. When NaBu was supplemented at a concentration of <1.0 mM for 3 days during osteogenic induction, significantly more mineralized nodules were generated and the expression of osteogenesis-related genes (ALP, Runx2, Opn, and Ocn) and proteins (Col1a1, OPN, OCN, Runx2, and TAZ) were both significantly enhanced. However, a higher concentration (1.0 mM) and longer exposure time (14 days) of NaBu showed no such effects, which may be partially attributed to both the increased expression of histone deacetylase 8 (HDAC8) and reduced level of H3K9-Ace, thus leading to the transcriptional inhibition during osteogenesis. Further, it was indicated that ERK might be involved in the stimulatory effects of NaBu. These findings may be helpful to develop an efficient culture process for hAMSCs towards bone regeneration. PMID- 29271555 TI - Early intervention for infants and toddlers: Applications for pediatric oncology. AB - Young children (<3 years) with cancer are at risk for delays in development due to their disease and its required treatments and restrictions. In the United States, Part C of the Individuals with Disabilities Education Act describes a system of early intervention (EI) services for young children with delays or the potential for delays in development. Children with cancer may be eligible for EI but are rarely referred. Our objectives are to describe the critical impact of early childhood development on long-term outcomes, review current considerations for EI, and advocate for the referral to EI for young children with cancer. PMID- 29271556 TI - Dietary protein level affects nutrient digestibility and ileal microbiota structure in growing pigs. AB - This study aimed to determine whether dietary protein content influences pig health as indicated by ileal microbiota structure and coefficients of total tract apparent digestibility (CTTAD) of nutrients. Seventy-two gilts, with an initial body weight of 29.9 +/- 1.5 kg, were used in this 42-day feeding study. Pigs were randomly allotted to one of three dietary treatments of corn-soybean meal contained 14, 16 or 18% crude protein (CP). As dietary CP content decreased, the CTTAD of most essential amino acids (AAs), except for arginine and histidine, increased linearly, while those of most nonessential AAs decreased linearly. The concentration of total short-chain fatty acids (SCFA) was higher in pigs fed the diet with 14% CP content than others. Ileal microbiota structure was changed by dietary treatments. In particular, at the phylum level, the relative abundance of Tenericutes in ileal digesta decreased as the dietary protein content reduced, while that of cyanobacteria increased. At the genus level, the relative abundance of Weeksella, Phaseolus acutifolius, Slackia, Sulfurimonas and Aerococcus showed significant differences among the three dietary treatments. In conclusion, ileal microbiota structure was changed by dietary protein content. Moderate reduction of protein intake can benefit gut health by enhancing the gut microbial fermentation and SCFA formation. PMID- 29271557 TI - Carbohydrate-Responsive Surface Adhesion Based on the Dynamic Covalent Chemistry of Phenylboronic Acid- and Catechol-Containing Polymer Brushes. AB - A glue, based on dynamic covalent chemistry, with a strong adhesion (2.38 kg cm-2 ), water resistance and carbohydrate responsive reversibility is presented. Using surface initiated atom transfer radical polymerization (SI-ATRP), glass and silicon surfaces were coated with copolymers functionalized with phenylboronic acids and catechols. In combination with microcontact printing (MUCP) these polymer brushes give access to a carbohydrate responsive "supramolecular Velcro". PMID- 29271558 TI - An initial health economic evaluation of pharmacogenomic testing in patients treated for childhood cancer with anthracyclines. AB - BACKGROUND: Anthracyclines are a class of highly effective chemotherapeutic drugs commonly used to treat cancer patients. Anthracyclines, however, are associated with the development of serious adverse reactions, including anthracycline induced cardiotoxicity (ACT). It is not possible, within current practice, to accurately individualize treatment to minimize risk. PROCEDURE: Recently, genetic variants have been associated with the risk of ACT in children. Building on these findings and the related genetic test, a predictive model was developed which classifies pediatric patients by their risk of developing ACT. We assessed the value of this ACT-predictive risk classification in addressing ACT. RESULTS: With current care, the estimated average lifetime cost of ACT is $8,667 per anthracycline-treated patient and approximately 7% of patients are expected to die from ACT. The projected impact of the information from the new predictive model is a 17% reduction in the risk of mortality from ACT and savings of about 6%: lives saved and lower costs. CONCLUSION: The newly identified genetic variants associated with the risk of ACT provide information that allows a more reliable prediction of the risk of ACT for a given patient and can be obtained at a very moderate cost, which is expected to lead to meaningful progress in reducing harm and costs associated with ACT. PMID- 29271559 TI - Application of a Dynamic Map for Learning, Communicating, Navigating, and Improving Therapeutic Development. AB - Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness. The 4DM is freely available for utilization, modification, and further development by stakeholders across the translational ecosystem. PMID- 29271560 TI - Calculating individualized glycaemic targets using an algorithm based on expert worldwide diabetologists: Implications in real-life clinical practice. AB - BACKGROUND: The aim of this study was to assess the clinical implications of calculating an individualized HbA1c target using a recently published algorithm in a real-life clinical setting. METHODS: General practitioners (GPs) from the Spanish Society of Family Medicine Diabetes Expert Group were invited to participate in the study. Each GP selected a random sample of patients with diabetes from his or her practice and submitted their demographic and clinical data for analysis. Individualized glycaemic targets were calculated according to the algorithm. Predictors of good glycaemic control were studied. The rate of patients attaining their individualized glycaemic target or the uniform target of HbA1c < 7.0% was calculated. RESULTS: Forty GPs included 408 patients in the study. Of the 8 parameters included in the algorithm, "comorbidities," "risk of hypoglycaemia from treatment," and "diabetes duration" had the greatest impact on determining the individualized glycaemic target. Number of glucose-lowering agents and adherence were independently associated with glycaemic control. Overall, 60.5% of patients had good glycaemic control per individualized target, and 56.1% were well controlled per the uniform target of HbA1c < 7.0% (P = .20). However, 12.8% (23 of 246) of the patients with HbA1c >= 7.0% were adequately controlled per individualized target, and 2.6% (6 of 162) of the patients with HbA1c < 7.0% were uncontrolled since their individualized target was lower. CONCLUSIONS: In a real-life clinical setting, applying individualized targets did not change the overall rate of patients with good glycaemic control yet led to reclassification of 7.1% (29 of 408) of the patients. More studies are needed to validate these results in different populations. PMID- 29271561 TI - Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis. AB - Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy. PMID- 29271562 TI - HCV treatment initiation in persons with chronic kidney disease in the directly acting antiviral agents era: Results from ERCHIVES. AB - BACKGROUND: Newer direct acting antiviral agents against HCV (DAAs) are safe and efficacious in persons with chronic kidney disease (CKD). Whether approval of newer DAAs has resulted in more persons with CKD initiating HCV treatment remains unknown. METHODS: We identified HCV+ persons in ERCHIVES between October 1999 and July 2016. We excluded HIV+ and HBsAg+ and those with missing baseline HCV RNA and baseline eGFR data. We identified persons initiated on any approved DAA regimen through July 2016, by CKD stage. Logistic regression analyses were used to determine factors associated with treatment initiation. RESULTS: Among 83 706 evaluable persons, 21.1% initiated treatment. Rates differed significantly by CKD stage: 22.1% for eGFR>90 mL/min/1.73 m2 and CKD stage-2; 14.9% for CKD stage 3; and 8.0% for CKD stage-4/5. Those with CKD stage-3 were 33% less likely and those with CKD stage-4/5 were 60% less likely to initiate treatment with a DAA compared with those with baseline eGFR>90 mL/min/1.73 m2 . Treatment initiation was less likely in HCV genotype 2 (OR 0.59; 95%CI 0.53,0.66) or 3 (OR 0.53; 95%CI 0.47,0.61) and those with diabetes (OR 0.87, 95% CI 0.81,0.94), cardiovascular disease (OR 0.77, 95% CI 0.70,0.84), alcohol abuse or dependence (OR 0.74, 95% CI 0.70,0.79) or cirrhosis (OR 0.86, 95% CI 0.80,0.92) at baseline. CONCLUSIONS: Persons with more advanced CKD are less likely to receive treatment for HCV despite recent data on safety and efficacy. Strategies are needed to improve treatment rates in the HCV/CKD population. PMID- 29271563 TI - Is metformin poised for a second career as an antimicrobial? AB - Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo. PMID- 29271564 TI - Video Assisted Peri-anal Abscess Treatment (VPAT+) - Video Vignette. AB - We submit a video vignette describing how to perform a video-assistant peri-anal abscess drainage plus insertion of a draining seton. We have been using this technique within the NHS for two years successfully to manage acute perianal abscesses. This article is protected by copyright. All rights reserved. PMID- 29271565 TI - Health-related fitness in very long-term survivors of childhood cancer: A cross sectional study. AB - BACKGROUND: Impairment of health-related physical fitness (HRPF) in survivors of acute lymphoblastic leukemia has been shown. However, evidence of impairment in survivors of other pediatric malignancies and possible risk factors is limited. PARTICIPANTS AND METHODS: HRPF of 17 survivors of pediatric acute myeloid leukemia (AML), 26 survivors of neuroblastoma (NBL), 28 survivors of Wilms tumor (WT) (median age 28.8 [18.8-62.6] years) after a median follow-up time of 24.5 (6.5-43.6) years, and 74 healthy controls (median age 26.9 [17.9-61.7] years). Risk factors were investigated. Testing included submaximal cardiovascular endurance (6-Minute Walk Test (6 MWT), flexibility, and muscle strength. RESULTS: Results are expressed as mean (standard error). Survivors scored significantly lower than controls on the 6 MWT (588 +/- 6.1 m vs. controls 611 +/- 6.0 m; P = 0.008), on side flexion of the trunk (20.1 +/- 0.4 cm vs. controls 22.4 +/-0.4 cm; P < 0.001), and on vertical jump (39.7 +/- 0.8 cm vs. controls 43.8 +/- 0.8 cm; P < 0.001). Survivors of AML had lower scores on the 6 MWT (563 +/- 12.4 m) than survivors of NBL (585 +/- 9.9 m) and survivors of WT (606 +/- 9.6 m), P = 0.046. Being a survivor, higher body mass index (BMI) and no participation in sports were independently associated with lower scores on the 6 MWT. CONCLUSION: Survivors of NBL, WT, and especially AML have impaired HRPF. Higher BMI and physical inactivity at adult age appeared prominent risk factors for impaired HRPF in these survivors. PMID- 29271566 TI - Renin inhibition in heart failure and diabetes: the real story. PMID- 29271567 TI - Elsahy-Waters syndrome is caused by biallelic mutations in CDH11. AB - Elsahy-Waters syndrome (EWS), also known as branchial-skeletal-genital syndrome, is a distinct dysmorphology syndrome characterized by facial asymmetry, broad forehead, marked hypertelorism with proptosis, short and broad nose, midface hypoplasia, intellectual disability, and hypospadias. We have recently published a homozygous potential loss of function variant in CDH11 in a boy with a striking resemblance to EWS. More recently, another homozygous truncating variant in CDH11 was reported in two siblings with suspected EWS. Here, we describe in detail the clinical phenotype of the original CDH11-related patient with EWS as well as a previously unreported EWS-affected girl who was also found to have a novel homozygous truncating variant in CDH11, which confirms that EWS is caused by biallelic CDH11 loss of function mutations. Clinical features in the four CDH11 mutation-positive individuals confirm the established core phenotype of EWS. Additionally, we identify upper eyelid coloboma as a new, though infrequent clinical feature. The pathomechanism underlying EWS remains unclear, although the limited phenotypic data on the Cdh11-/- mouse suggest that this is a potentially helpful model to explore the craniofacial and brain development in EWS-affected individuals. PMID- 29271568 TI - Prader-Willi syndrome and early-onset morbid obesity NIH rare disease consortium: A review of natural history study. AB - We describe the National Institutes of Health rare disease consortium for Prader Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis, growth and development, awareness, and natural history. PWS results from errors in genomic imprinting leading to loss of paternally expressed genes due to 15q11-q13 deletion, maternal disomy 15 or imprinting defects. The 8 year study was conducted at four national sites on individuals with genetically confirmed PWS and early-onset morbid obesity (EMO) with data accumulated to gain a better understanding of the natural history, cause and treatment of PWS. Enrollment of 355 subjects with PWS and 36 subjects with EMO began in September 2006 with study completion in July 2014. Clinical, genetic, cognitive, behavior, and natural history data were systematically collected along with PWS genetic subtypes, pregnancy and birth history, mortality, obesity, and cognitive status with study details as important endpoints in both subject groups. Of the 355 individuals with PWS, 217 (61%) had the 15q11-q13 deletion, 127 (36%) had maternal disomy 15, and 11 (3%) had imprinting defects. Six deaths were reported in our PWS cohort with 598 cumulative years of study exposure and one death in the EMO group with 42 years of exposure. To our knowledge, this description of a longitudinal study in PWS represents the largest and most comprehensive cohort useful for investigators in planning comparable studies in other rare disorders. Ongoing studies utilizing this database should have a direct impact on care and services, diagnosis, treatment, genotype-phenotype correlations, and clinical outcomes in PWS. PMID- 29271569 TI - Expanding the phenotype associated with biallelic WDR60 mutations: Siblings with retinal degeneration and polydactyly lacking other features of short rib thoracic dystrophies. AB - Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra- and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N-terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co-segregated with the disease in the family. Our finding broadens the spectrum of WDR60-related phenotypes and shows the utility of broad multigene panels during the genetic work-up of patients with ciliopathies. PMID- 29271570 TI - Evolving concepts in dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) represents a particular aetiology of systolic heart failure that frequently has a genetic background and usually affects young patients with few co-morbidities. The prognosis of DCM has improved substantially during the last decades due to more accurate aetiological characterization, the red-flag integrated approach to the disease, early diagnosis through systematic familial screening, and the concept of DCM as a dynamic disease requiring constant optimization of medical and non-pharmacological evidence-based treatments. However, some important issues in clinical management remain unresolved, including the role of cardiac magnetic resonance for diagnosis and risk categorization and the interaction between genotype and clinical phenotype, and arrhythmic risk stratification. This review offers a comprehensive survey of these and other emerging issues in the clinical management of DCM, providing where possible practical recommendations. PMID- 29271571 TI - Hydrolysis Batteries: Generating Electrical Energy during Hydrogen Absorption. AB - The hydrolysis reaction of aluminum can be decoupled into a battery by pairing an Al foil with a Pd-capped yttrium dihydride (YH2 -Pd) electrode. This hydrolysis battery generates a voltage around 0.45 V and leads to hydrogen absorption into the YH2 layer. This represents a new hydrogen absorption mechanism featuring electrical energy generation during hydrogen absorption. The hydrolysis battery converts 8-15 % of the thermal energy of the hydrolysis reaction into usable electrical energy, leading to much higher energy efficiency compared to that of direct hydrolysis. PMID- 29271572 TI - Severe rhizomelic shortening in a child with a complex duplication/deletion rearrangement of chromosome X. AB - Mesomelic and rhizo-mesomelic dysplasias are a group of disorders characterized by abnormal shortening of the limbs. One of the most common causes of mesomelic shortening is the loss of the transcription factor SHOX. In this clinical report, we present a patient who in addition to mesomelic shortening has severe rhizomelic shortening and developmental delay. Karyotyping revealed a recombinant X chromosome in which the region distal to Xp22.33 (where SHOX is found) was replaced with material from Xq28. Included in the region distal to Xq28 is the gene MECP2 and this patient presents with features of MECP2 duplication syndrome. We find that this patient has skeletal features not typical with the loss of SHOX that are likely explained by the rearrangement of the X chromosome. Further delineation of this rearrangement may allow for the identification of additional genetic mechanisms critical for the development of the limbs. PMID- 29271573 TI - A framework for linking population model development with ecological risk assessment objectives. AB - The value of models that link organism-level impacts to the responses of a population in ecological risk assessments (ERAs) has been demonstrated extensively over the past few decades. There is little debate about the utility of these models to translate multiple organism-level endpoints into a holistic interpretation of effect to the population; however, there continues to be a struggle for actual application of these models as a common practice in ERA. Although general frameworks for developing models for ERA have been proposed, there is limited guidance on when models should be used, in what form, and how to interpret model output to inform the risk manager's decision. We propose a framework for developing and applying population models in regulatory decision making that focuses on trade-offs of generality, realism, and precision for both ERAs and models. We approach the framework development from the perspective of regulators aimed at defining the needs of specific models commensurate with the assessment objective. We explore why models are not widely used by comparing their requirements and limitations with the needs of regulators. Using a series of case studies under specific regulatory frameworks, we classify ERA objectives by trade-offs of generality, realism, and precision and demonstrate how the output of population models developed with these same trade-offs informs the ERA objective. We examine attributes for both assessments and models that aid in the discussion of these trade-offs. The proposed framework will assist risk assessors and managers to identify models of appropriate complexity and to understand the utility and limitations of a model's output and associated uncertainty in the context of their assessment goals. Integr Environ Assess Manag 2018;14:369-380. Published 2017. This article is a US Government work and is in the public domain in the USA. PMID- 29271574 TI - Aldosterone and Insulin Resistance: Vicious Combination in Patients on Maintenance Hemodialysis. AB - Recently, we demonstrated that plasma aldosterone contributed to insulin resistance in chronic kidney disease. The aim of this study is the clinical impact of this relationship in hemodialysis patients. In a cross section study using a total of 128 hemodialysis patients, multiple regression analysis revealed that plasma aldosterone levels were independently associated with HOMA-IR, insulin resistance index. This association was found to be more stringent in diabetic patients than in non-diabetic patients. Aldosterone levels were associated with cardiac hypertrophy and carotid artery stenosis. HOMA-IR was associated with cardiac hypertrophy. The patients whose aldosterone and HOMA-IR were above the top tertile of each parameter in this cohort showed more severe cardiac hypertrophy and lower contractile function as compared with the patients whose aldosterone levels and HOMA-IR are below the lowest tertile of each parameter. In conclusion, in hemodialysis patients, aldosterone levels and insulin resistance are closely interrelated and the constellation of the two is related to severe cardiovascular tissue damages. PMID- 29271575 TI - Nine-month results of the BIOHELIX-I clinical trial study: Evaluation of the PRO Kinetic Energy cobalt chromium bare-metal stent system. AB - OBJECTIVES: To evaluate the safety and efficacy of the PRO-Kinetic Energy (PKE) Cobalt Chromium Coronary Stent System (BIOTRONIK AG, Switzerland). BACKGROUND: Percutaneous coronary intervention is a mainstay treatment for symptomatic coronary artery disease (CAD). While drug-eluting stents constitute a majority of implants, bare-metal stents (BMS) remain important for a subset of patients. Newer generation BMS offer advantages due to stent design improvements. METHODS: The BIOHELIX-I study was a prospective, multicenter, non-randomized, single arm clinical trial designed to evaluate the safety and efficacy of the PKE bare metal stent. Thirty-three study centers (US, Columbia, Europe) enrolled 329 patients for treatment of one target lesion (<=31 mm). Eligible patients received a PKE stent(s), at least one month of dual antiplatelet therapy and were followed for 36-months. The primary endpoint was the 9-month rate of target vessel failure (TVF) compared with a prespecified performance goal of 18.7% derived from prior BMS trials. RESULTS: The mean patient age was 69 years, 28.6% with diabetes. The mean lesion length was 13.7 +/- 6.0 mm. The 9-month TVF rate was 9.06% and met the primary endpoint (P < 0.001). The TVF component rates were 0.95% cardiac death, 1.58% myocardial infarction, and 7.26% ischemia-driven target vessel revascularization (TVR). The ischemia-driven target lesion revascularization rate at 9-months was 6.62%. CONCLUSIONS: The 9-month TVF rate of the PKE stent was comparable to other BMS and is a viable option for treating CAD. The low observed rate of ischemia-driven TVR supports the safety and efficacy of the novel BMS design. PMID- 29271577 TI - Coarse fibrillatory waves in atrial fibrillation predict success of electrical cardioversion. AB - BACKGROUND: To determine whether the presence of "coarse" fibrillatory waves (Fw) seen on surface ECGs of patients with persistent atrial fibrillation (AF) predict maintenance of sinus rhythm (SR) at 6 weeks after electrical cardioversion (ECV). METHODS: Preprocedure ECGs from 94 consecutive patients with persistent AF scheduled to undergo ECV at a single centre were classified as having coarse Fw (>=0.1 mV) or fine Fw (<0.1 mV) in leads II or V1 . The primary outcome was ECG rhythm at 6-week clinical follow-up. Demographic and echocardiographic data were also collected. RESULTS: Thirty-two patient ECGs (34%) had coarse Fw on baseline ECG in either or both leads II or V1 with no significant differences in baseline demographics compared to those patients with fine Fw. At 6 weeks post-ECV, in the coarse Fw group 72% of patients maintained SR vs. 42% in the fine Fw group (chi2 , p = .006) with the odds ratio (OR) of maintaining SR at 6 weeks in the presence of coarse Fw being 3.5 (95% CI: 1.4-8.9, p = .007). Across the overall study population, there were no other significant univariate predictors of SR at 6 weeks post-ECV. CONCLUSION: Classifying persistent AF using the maximal Fw amplitude on a surface ECG is a simple and reproducible method of predicting medium-term success of ECV, independent of traditional risk factors. PMID- 29271578 TI - Cell-specific resetting of mouse islet cellular clocks by glucagon, glucagon-like peptide 1 and somatostatin. AB - AIM: Molecular clocks, operative in pancreatic islet cells, represent an intrinsic mechanism regulating intracellular metabolism and hormone secretion. Glucagon, somatostatin and glucagon-like peptide 1 (GLP-1) are essential coordinators of islet physiology. Here, we assess the synchronizing capacity of glucagon, somatostatin and GLP-1 on pancreatic alpha- and beta-cell circadian clocks. METHODS: Triple transgenic mice, expressing a circadian PER2::luciferase (luc) reporter combined with alpha- and beta-cell-specific fluorescent reporters, were employed. Isolated pancreatic islets and fluorescence-activated cell sorting separated alpha- and beta-cells were synchronized with glucagon, somatostatin analogue or GLP-1 mimetics, with subsequent real-time PER2::luc bioluminescence recording. Gene expression of Gcgr, Sstr2, Sstr3 and Glp1r in islet cells was assessed by RNA sequencing and RT-qPCR. RESULTS: Glucagon and GLP-1 mimetics (liraglutide and exenatide) induced high-amplitude rhythmic expression of the PER2::luc reporter in beta-cells, but not in alpha-cells, while the somatostatin analogue octreotide generated a significant phase shift between alpha- and beta cells. Enrichment of Gcgr and Glp1r transcripts was detected in beta-cells compared to their alpha-cell counterparts. The synchronizing effect of glucagon was dose-dependent and mediated by the adenylate cyclase signalling cascade, as it was diminished by adenylate cyclase inhibitor. CONCLUSION: We conclude that proglucagon-derived peptides and somatostatin exhibit receptor-mediated cell specific synchronizing effects for mouse alpha- and beta-cell oscillators. Differential islet cell clock modulation by glucagon and somatostatin may represent a physiological mechanism underlying paracrine regulation of rhythmic glucagon and insulin secretion. The reported here strong synchronizing properties of GLP-1 mimetics, widely used for treatment of type 2 diabetes, are of high clinical relevance. PMID- 29271576 TI - Effects of Omega-3 Fatty Acids on Markers of Inflammation in Patients With Chronic Kidney Disease: A Controversial Issue. AB - Chronic kidney disease (CKD) is a global problem which contributes to a significant morbidity and mortality in China. Concomitant inflammatory state further boosts the mortality due to cardiovascular events in patients with CKD undergoing dialysis. There is a general notion that Omega-3 fatty acids including docosahexaenoic acids (DHA) and eicosapentaenoic (EPA) have certain health benefits perhaps via the regulation of inflammation. However, the anti inflammatory effect of omega-3 fatty acids in patients with CKD is controversial. We analyzed the data of oral supplementation of omega-3 fatty acids in CKD patients by searching literature on database from inception to August 2016. The analysis included randomized controlled trials (RCTs) derived from multiple databases, and the effect of omega-3 fatty acids supplementation versus the control cohorts were compared. All of the data analysis was calculated by RevMan 5.2. A total of 12 RCTs involving 487 patients were included in the meta analysis. Among them 254 patients received omega-3 fatty acids and 233 patients served as controls who received placebo. The meta-analysis revealed no statistical significance in serum levels of C-reactive protein (CRP) (SMD, -0.20; 95% CI, -0.44 to 0.05; P = 0.11), IL-6 (SMD, 0.00; 95% CI, -0.33 to 0.33; P = 0.99) and TNF-alpha (SMD, 0.14; 95% CI, -0.17 to 0.44; P = 0.38) between the omega-3 fatty acids supplementation group and control. This suggested that there is insufficient evidence to conclude the benefit of omega-3 fatty acids oral supplementation in reducing serum levels of CRP, IL-6 and TNF-alpha in patients with CKD. PMID- 29271580 TI - Biomaterials for Skin Substitutes. AB - Patients with extensive burns rely on the use of tissue engineered skin due to a lack of sufficient donor tissue, but it is a challenge to identify reliable and economical scaffold materials and donor cell sources for the generation of a functional skin substitute. The current review attempts to evaluate the performance of the wide range of biomaterials available for generating skin substitutes, including both natural biopolymers and synthetic polymers, in terms of tissue response and potential for use in the operating room. Natural biopolymers display an improved cell response, while synthetic polymers provide better control over chemical composition and mechanical properties. It is suggested that not one material meets all the requirements for a skin substitute. Rather, a composite scaffold fabricated from both natural and synthetic biomaterials may allow for the generation of skin substitutes that meet all clinical requirements including a tailored wound size and type, the degree of burn, the patient age, and the available preparation technique. This review aims to be a valuable directory for researchers in the field to find the optimal material or combination of materials based on their specific application. PMID- 29271579 TI - Global environmental change effects on plant community composition trajectories depend upon management legacies. AB - The contemporary state of functional traits and species richness in plant communities depends on legacy effects of past disturbances. Whether temporal responses of community properties to current environmental changes are altered by such legacies is, however, unknown. We expect global environmental changes to interact with land-use legacies given different community trajectories initiated by prior management, and subsequent responses to altered resources and conditions. We tested this expectation for species richness and functional traits using 1814 survey-resurvey plot pairs of understorey communities from 40 European temperate forest datasets, syntheses of management transitions since the year 1800, and a trait database. We also examined how plant community indicators of resources and conditions changed in response to management legacies and environmental change. Community trajectories were clearly influenced by interactions between management legacies from over 200 years ago and environmental change. Importantly, higher rates of nitrogen deposition led to increased species richness and plant height in forests managed less intensively in 1800 (i.e., high forests), and to decreases in forests with a more intensive historical management in 1800 (i.e., coppiced forests). There was evidence that these declines in community variables in formerly coppiced forests were ameliorated by increased rates of temperature change between surveys. Responses were generally apparent regardless of sites' contemporary management classifications, although sometimes the management transition itself, rather than historic or contemporary management types, better explained understorey responses. Main effects of environmental change were rare, although higher rates of precipitation change increased plant height, accompanied by increases in fertility indicator values. Analysis of indicator values suggested the importance of directly characterising resources and conditions to better understand legacy and environmental change effects. Accounting for legacies of past disturbance can reconcile contradictory literature results and appears crucial to anticipating future responses to global environmental change. PMID- 29271582 TI - Telemedicine in neurology: where are we going? PMID- 29271581 TI - Cervical artery dissection in two monozygotic twin-pairs. PMID- 29271584 TI - Seizure freedom after intracranial electrode implantation in pharmacoresistant epilepsy. PMID- 29271585 TI - Catastrophic primary angiitis of the central nervous system. PMID- 29271586 TI - Comments on: 'Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - a randomized controlled trial'. PMID- 29271587 TI - The association of intracranial aneurysms and meningiomas: a hospital-based case control study. PMID- 29271589 TI - December 2017 at a glance: left ventricular ejection fraction, exercise capacity, peripartum cardiomyopathy. PMID- 29271588 TI - Pathological diagnosis of pulmonary large cell neuroendocrine carcinoma by endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a relatively rare subtype of lung malignancy. According to revised 2015 World Health Organization (WHO) criteria for the pathological diagnosis of LCNEC, neuroendocrine markers must be examined by immunohistochemistry. In this study, we reevaluated endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples of patients previously diagnosed with LCNEC using the revised WHO criteria. METHODS: Clinical tissue samples that had been obtained by EBUS TBNA between January 2004 and December 2011, and that had been pathologically diagnosed as LCNEC according to the previous criteria, were reevaluated according to the revised WHO criteria. RESULTS: The records of 471 lung cancer patients with mediastinal or hilar lymph node metastasis diagnosed by EBUS-TBNA were analyzed. Thirteen patients were diagnosed with LCNEC; one of which was diagnosed based on cytology alone because the histological material was insufficient for a histological examination. Among the 12 cases in which a histological examination was performed, nine were diagnosed with possible LCNEC based on neuroendocrine marker positivity, while three were diagnosed with suspected LCNEC because they did not meet the immunostaining criteria. The patient who was cytologically diagnosed was found to have non-small cell carcinoma with neuroendocrine morphology. CONCLUSION: LCNEC could be pathologically diagnosed based on 2015 WHO criteria using EBUS-TBNA samples. PMID- 29271591 TI - Co-morbidities in heart failure beginning to sprout-and no end in sight? PMID- 29271592 TI - A Versatile Method to Prepare Protein Nanoclusters for Drug Delivery. AB - Nanocarriers based on natural biomaterials such as peptides and proteins have shown great advantages in the field of nanomedicine. However, the complicated preparation process and possible denaturation of proteins may limit their further applications. Herein, a novel method is developed to prepare protein nanocluster drug delivery system based on the self-aggregated property of proteins under the isoelectric point condition. The crosslinked protein nanoclusters, prepared by adding modified natural crosslinking agent polysaccharide, exhibit excellent stability and autofluorescent property in physiological conditions. Hemoglobin, a model protein, is chosen for preparation of drug-loaded nanoclusters. The as prepared nanoclusters demonstrate a pH-responsive drug release behavior and can successfully deliver drugs into cancer cells. Moreover, this approach can be extended to various proteins, exemplifying the universal applicability of our new preparation method for protein-based nanoparticles. PMID- 29271593 TI - The Role of Hydrophobicity in the Cellular Uptake of Negatively Charged Macromolecules. AB - It is generally accepted that positively charged molecules are the gold standard to by-pass the negatively charged cell membrane. Here, it is shown that cellular uptake is also possible for polymers with negatively charged side chains and hydrophobic backbones. Specifically, poly[5-methoxy-2-(3-sulfopropoxy)-1,4 phenylenevinylene], a conjugated polyelectrolyte with sulfonate, as water-soluble functional groups, is shown to accumulate in the intracellular region. When the polymer hydrophobic backbone is dissolved using polyvinylpyrrolidone, an amphiphilic macromolecule, the cellular uptake is dramatically reduced. The report sheds light on the fine balance between negatively charged side groups and the hydrophobicity of polymers to either enhance or reduce cellular uptake. As a result, these findings will have important ramifications on the future design of targeted cellular delivery nanocarriers for imaging and therapeutic applications. PMID- 29271595 TI - Understanding glaucoma pathogenesis. PMID- 29271596 TI - Continuing Professional Development. PMID- 29271598 TI - Discovery of Maori and Polynesian phototransduction pathway founder mutation: what is the gene and what does it mean? PMID- 29271599 TI - Attending a conference: Students' experience. PMID- 29271601 TI - Revisiting the roots of nursing philosophy and critical theory: Past, present and future. PMID- 29271600 TI - Ivan Illich's Medical Nemesis and the 'age of the show': On the Expropriation of Death. AB - What Ivan Illich regarded in his Medical Nemesis as the 'expropriation of health' takes place on the surfaces and in the spaces of the screens all around us, including our cell phones but also the patient monitors and (increasingly) the iPads that intervene between nurse and patient. To explore what Illich called the 'age of the show', this essay uses film examples, like Creed and the controversial documentary Vaxxed, and the television series Nurse Jackie. Rocky's cancer in his last film (submitting to chemo to 'fight' cancer) highlights what Illich along with Petr Skrabanek called the 'expropriation of death'. In contrast to what Illich denotes as 'Umsonstigkeit' - grace or gift, given undeservedly, i.e., gratuitously - medical science tends to be tempted by what Illich terms scientistic 'black magic', taking over (expropriating) the life and the death of the patient in increasingly technological ways, a point underscored in the concluding section on the commercial prospects of xenotransplants using factory farm or mass-produced human-pig mosaics or chimeras. PMID- 29271602 TI - Pediatric oncology clinical trial participation where the geography is vast: Development of a clinical research system for tertiary and satellite centers in Ontario, Canada. AB - Opportunities for participation in clinical trials are a core component of the care of children with cancer. In Ontario, many pediatric patients live long distances from their cancer center. This paper describes the work that was done in order to allow patients participating in Children's Oncology Group trials to receive care, including research protocol related care, jointly between the tertiary pediatric cancer center and the closer-to-home satellite center. The system is a pragmatic risk-based model, supporting excellence in care while ensuring good conduct of the research in compliance with applicable regulations and guidelines, including ethics oversight. PMID- 29271603 TI - Genome-wide association mapping in Arabidopsis identifies novel genes underlying quantitative disease resistance to Alternaria brassicae. AB - Quantitative disease resistance (QDR) is the predominant form of resistance against necrotrophic pathogens. The genes and mechanisms underlying QDR are not well known. In the current study, the Arabidopsis-Alternaria brassicae pathosystem was used to uncover the genetic architecture underlying resistance to A. brassicae in a set of geographically diverse Arabidopsis accessions. Arabidopsis accessions revealed a rich variation in the host responses to the pathogen, varying from complete resistance to high susceptibility. Genome-wide association (GWA) mapping revealed multiple regions to be associated with disease resistance. A subset of genes prioritized on the basis of gene annotations and evidence of transcriptional regulation in other biotic stresses was analysed using a reverse genetics approach employing T-DNA insertion mutants. The mutants of three genes, namely At1g06990 (GDSL-motif lipase), At3g25180 (CYP82G1) and At5g37500 (GORK), displayed an enhanced susceptibility relative to the wild-type. These genes are involved in the development of morphological phenotypes (stomatal aperture) and secondary metabolite synthesis, thus defining some of the diverse facets of quantitative resistance against A. brassicae. PMID- 29271604 TI - The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor. AB - Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots. PMID- 29271605 TI - One-step Preparation of Monodisperse Multifunctional Macroporous Particles through a Spontaneous Physical Process. AB - Macroporous particles that combine the property features of spherical structures and porous materials are expected to find use over micro- and macroscopic length scales from miniaturized systems such as cell imaging, drug and gene delivery to industrial applications. However, the capacity for de novo design of such materials is still limited. Here, a spontaneous process to fabricate monodisperse multifunctional macroporous particles (MMMPs) by high internal phase emulsion templating is reported. An interesting physical phenomenon involving self emulsification and synergistic effects between nanoparticles and amphiphilic diblock copolymers is observed in this process. These MMMPs, featured with tailor made pore structures, pH responsiveness, and magnetic response, could be used as stimuli-responsive carriers for multiple functional molecules with a high loading and releasing efficiency. This new understanding regarding the underlying phenomena that control self-emulsification behavior and synergistic action in emulsion systems provides a unique outlook and a novel approach to the design of potentially multifunctional porous materials for controllable release and delivery processes. PMID- 29271607 TI - Mid- to long-term results of total ankle replacement in patients with haemophilic arthropathy: A 10-year follow-up. AB - INTRODUCTION: Haemophilic ankle arthropathy is caused by recurrent spontaneous joint haemorrhaging and leads to pain, deformity and loss of function. In the presence of advanced articular deterioration, therapeutic options are confined to either arthroplasty or arthrodesis, the latter still being referred to as the procedure of choice. However, total ankle replacement (TAR) has recently gained acceptance as an alternative. AIM: To investigate the mid- to long-term results of TAR in haemophilic ankle arthropathy. MATERIALS AND METHODS: Seventeen TARs in 14 male patients (mean age: 43 years [range, 27.4-57.6]), implanted between 1998 and 2012, were retrospectively analysed. Implant survival was estimated using Kaplan-Meier analysis. Haemophilic/viral status, complications and revision surgeries were recorded. Follow-up assessment of 12 TARs was performed 9.6 years (range, 3.3-17.8) postoperatively, including clinical examination, pain and satisfaction scales, the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score, and the SF-36. Radiographic evaluation of pre- and follow-up radiographs was conducted. RESULTS: Estimated implant survival was 94% at 5, 85% at 10 and 70% at 15 years, respectively. Three cases required revision surgery. At follow-up, 9.6 years (range, 3.3-17.8) postoperatively, the level of satisfaction was 76% (range, 50-100) and of pain 2/10 (range, 0-6) on the VAS. Range of motion had increased significantly (P = .037). The SF-36 summary scores were comparable to those of a matched standard population. The AOFAS hindfoot score averaged 81 points (range, 73-90). All radiographs revealed component loosening or periprosthetic radiolucency. CONCLUSION: Total ankle replacement in the presence of advanced haemophilic arthropathy is a viable treatment option with favourable mid-/long-term results, maintaining mobility of the ankle joint. PMID- 29271608 TI - A muscle-specific MuRF1-E2 network requires stabilization of MuRF1-E2 complexes by telethonin, a newly identified substrate. AB - BACKGROUND: Muscle wasting is observed in the course of many diseases and also during physiological conditions (disuse, ageing). Skeletal muscle mass is largely controlled by the ubiquitin-proteasome system and thus by the ubiquitinating enzymes (E2s and E3s) that target substrates for subsequent degradation. MuRF1 is the only E3 ubiquitin ligase known to target contractile proteins (alpha-actin, myosins) during catabolic situations. However, MuRF1 depends on E2 ubiquitin conjugating enzymes for ubiquitin chain formation on the substrates. MuRF1-E2 couples are therefore putative targets for preventing muscle wasting. METHODS: We focused on 14 E2 enzymes that are either expressed in skeletal muscle or up regulated during atrophying conditions. In this work, we demonstrated that only highly sensitive and complementary interactomic approaches (surface plasmon resonance, yeast three-hybrid, and split green fluorescent protein) allowed the identification of MuRF1 E2 partners. RESULTS: Five E2 enzymes physically interacted with MuRF1, namely, E2E1, E2G1, E2J1, E2J2, and E2L3. Moreover, we demonstrated that MuRF1-E2E1 and MuRF1-E2J1 interactions are facilitated by telethonin, a newly identified MuRF1 substrate. We next showed that the five identified E2s functionally interacted with MuRF1 since, in contrast to the non interacting E2D2, their co-expression in HEK293T cells with MuRF1 led to increased telethonin degradation. Finally, we showed that telethonin governed the affinity between MuRF1 and E2E1 or E2J1. CONCLUSIONS: We report here the first MuRF1-E2s network, which may prove valuable for deciphering the precise mechanisms involved in the atrophying muscle programme and for proposing new therapeutical approaches. PMID- 29271606 TI - Abacavir usage patterns and hypersensitivity reactions in the EuroSIDA cohort. AB - OBJECTIVES: Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC. METHODS: We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation. RESULTS: Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. CONCLUSIONS: ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population. PMID- 29271609 TI - Reducing cryptic relatedness in genomic data sets via a central node exclusion algorithm. AB - Cryptic relatedness is a confounding factor in genetic diversity and genetic association studies. Development of strategies to reduce cryptic relatedness in a sample is a crucial step for downstream genetic analyses. This study uses a node selection algorithm, based on network degrees of centrality, to evaluate its applicability and impact on evaluation of genetic diversity and population stratification. 1,036 Guzera (Bos indicus) females were genotyped using Illumina Bovine SNP50 v2 BeadChip. Four strategies were compared. The first and second strategies consist on a iterative exclusion of most related individuals based on PLINK kinship coefficient (phiij) and VanRaden's phiij, respectively. The third and fourth strategies were based on a node selection algorithm. The fourth strategy, Network G matrix, preserved the larger number of individuals with a better diversity and representation from the initial sample. Determining the most probable number of populations was directly affected by the kinship metric. Network G matrix was the better strategy for reducing relatedness due to producing a larger sample, with more distant individuals, a more similar distribution when compared with the full data set in the MDS plots and keeping a better representation of the population structure. Resampling strategies using VanRaden's phiij as a relationship metric was better to infer the relationships among individuals. Moreover, the resampling strategies directly impact the genomic inflation values in genomewide association studies. The use of the node selection algorithm also implies better selection of the most central individuals to be removed, providing a more representative sample. PMID- 29271611 TI - Improving Biomaterials Imaging for Nanotechnology: Rapid Methods for Protein Localization at Ultrastructural Level. AB - The preparation of biological samples for electron microscopy is material- and time-consuming because it is often based on long protocols that also may produce artifacts. Protein labeling for transmission electron microscopy (TEM) is such an example, taking several days. However, for protein-based nanotechnology, high resolution imaging techniques are unique and crucial tools for studying the spatial distribution of these molecules, either alone or as components of biomaterials. In this paper, we tested two new short methods of immunolocalization for TEM, and compared them with a standard protocol in qualitative and quantitative approaches by using four protein-based nanoparticles. We reported a significant increase of labeling per area of nanoparticle in both new methodologies (H = 19.811; p < 0.001) with all the model antigens tested: GFP (H = 22.115; p < 0.001), MMP-2 (H = 19.579; p < 0.001), MMP 9 (H = 7.567; p < 0.023), and IFN-gamma (H = 62.110; p < 0.001). We also found that the most suitable protocol for labeling depends on the nanoparticle's tendency to aggregate. Moreover, the shorter methods reduce artifacts, time (by 30%), residues, and reagents hindering, losing, or altering antigens, and obtaining a significant increase of protein localization (of about 200%). Overall, this study makes a step forward in the development of optimized protocols for the nanoscale localization of peptides and proteins within new biomaterials. PMID- 29271612 TI - The search for new approaches to treating type 1 plasminogen deficiency. PMID- 29271613 TI - Active Surveillance of Papillary Thyroid Microcarcinoma: A Mini-Review from Korea. AB - In Korea, the incidence of thyroid cancer increased explosively in the early 2000s, and reached a plateau in the early 2010s. Most cases of newly diagnosed thyroid cancer are small indolent microcarcinoma and could be good candidates for active surveillance (AS) instead of immediate surgery. Many considerations must be taken into account for establishing selection criteria for candidates for AS of papillary thyroid microcarcinoma (PTMC), including the characteristics of the tumor, the patient, and the medical team. If possible, AS of PTMC should be a part of a prospective clinical trial to ensure long-term safety and to identify clinical and/or molecular markers of the progression of PTMC. In this review, we discuss lessons regarding surgical interventions for PTMC, and then describe the concept, application, caveats, unanswered questions, and future perspectives of AS of PTMC. For appropriately selected patients with PTMC, AS can be a good alternative to immediate surgery. PMID- 29271614 TI - Recent Advances in Core Needle Biopsy for Thyroid Nodules. AB - Core needle biopsy (CNB) was introduced as an alternative diagnostic tool to fine needle aspiration (FNA), and is increasingly being used in the preoperative assessment of thyroid nodules. CNB provides a definitive diagnosis in most cases, but it sometimes may be inconclusive. CNB has the advantage of enabling a histologic examination in relation to the surrounding thyroid tissue, immunohistochemistry, and molecular testing that can provide a more accurate assessment than FNA in selected cases. Nevertheless, CNB should be performed only by experienced experts in thyroid interventions to prevent complications because CNB needles are larger in caliber than FNA needles. As recent evidence has accumulated, and with improvements in the technique and devices for thyroid CNB, the Korean Society of Thyroid Radiology released its 2016 thyroid CNB guidelines and the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group published a consensus statement on the pathology reporting system for thyroid CNB in 2015. This review presents the current consensus and recommendations regarding thyroid CNB, focusing on indications, complications, and pathologic classification and reporting. PMID- 29271610 TI - Concise Review: Translating Regenerative Biology into Clinically Relevant Therapies: Are We on the Right Path? AB - Despite approaches in regenerative medicine using stem cells, bio-engineered scaffolds, and targeted drug delivery to enhance human tissue repair, clinicians remain unable to regenerate large-scale, multi-tissue defects in situ. The study of regenerative biology using mammalian models of complex tissue regeneration offers an opportunity to discover key factors that stimulate a regenerative rather than fibrotic response to injury. For example, although primates and rodents can regenerate their distal digit tips, they heal more proximal amputations with scar tissue. Rabbits and African spiny mice re-grow tissue to fill large musculoskeletal defects through their ear pinna, while other mammals fail to regenerate identical defects and instead heal ear holes through fibrotic repair. This Review explores the utility of these comparative healing models using the spiny mouse ear pinna and the mouse digit tip to consider how mechanistic insight into reparative regeneration might serve to advance regenerative medicine. Specifically, we consider how inflammation and immunity, extracellular matrix composition, and controlled cell proliferation intersect to establish a pro-regenerative microenvironment in response to injuries. Understanding how some mammals naturally regenerate complex tissue can provide a blueprint for how we might manipulate the injury microenvironment to enhance regenerative abilities in humans. Stem Cells Translational Medicine 2018;7:220 231. PMID- 29271615 TI - Alternative Polyadenylation in Human Diseases. AB - Varying length of messenger RNA (mRNA) 3'-untranslated region is generated by alternating the usage of polyadenylation sites during pre-mRNA processing. It is prevalent through all eukaryotes and has emerged as a key mechanism for controlling gene expression. Alternative polyadenylation (APA) plays an important role for cell growth, proliferation, and differentiation. In this review, we discuss the functions of APA related with various physiological conditions including cellular metabolism, mRNA processing, and protein diversity in a variety of disease models. We also discuss the molecular mechanisms underlying APA regulation, such as variations in the concentration of mRNA processing factors and RNA-binding proteins, as well as global transcriptome changes under cellular signaling pathway. PMID- 29271616 TI - Decreasing Lean Body Mass with Age: Challenges and Opportunities for Novel Therapies. PMID- 29271617 TI - Effects of Single Vitamin D3 Injection (200,000 Units) on Serum Fibroblast Growth Factor 23 and Sclerostin Levels in Subjects with Vitamin D Deficiency. AB - BACKGROUND: Vitamin D deficiency remains common in all age groups and affects skeletal and non-skeletal health. Fibroblast growth factor 23 is a bone-derived hormone that regulates phosphate and 1,25-dihydroxyvitamin D homeostasis as a counter regulatory factor. 1,25-Dihydroxyvitamin D stimulates fibroblast growth factor 23 synthesis in bone, while fibroblast growth factor 23 suppresses 1,25 dihydroxyvitamin D production in the kidney. The aim of this study was to evaluate the effects of vitamin D3 intramuscular injection therapy on serum fibroblast growth factor 23 concentrations, and several other parameters associated with bone metabolism such as sclerostin, dickkopf-1, and parathyroid hormone. METHODS: A total of 34 subjects with vitamin D deficiency (defined by serum 25-hydroxyvitamin D levels below 20 ng/mL) were randomly assigned to either the vitamin D injection group (200,000 units) or placebo treatment group. Serum calcium, phosphate, urine calcium/creatinine, serum 25-hydroxyvitamin D, fibroblast growth factor 23, sclerostin, parathyroid hormone, and dickkopf-1 levels were serially measured after treatment. RESULTS: Comparing the vitamin D injection group with the placebo group, no significant changes were observed in serum fibroblast growth factor 23, parathyroid hormone, or dickkopf-1 levels. Serum sclerostin concentrations transiently increased at week 4 in the vitamin D group. However, these elevated levels declined later and there were no statistically significant differences as compared with baseline levels. CONCLUSION: Serum fibroblast factor 23, sclerostin, parathyroid hormone, and dickkopf-1 levels were not affected significantly by single intramuscular injection of vitamin D3. PMID- 29271618 TI - Detection of Polyethylene Glycol Thyrotropin (TSH) Precipitable Percentage (Macro TSH) in Patients with a History of Thyroid Cancer. AB - BACKGROUND: Owing to its large molecular size, polyethylene glycol (PEG) precipitable thyrotropin (TSH) can accumulate in the circulation, elevating TSH levels. PEG-precipitable TSH can be used to detect macro-TSH (mTSH) in serum. Our aim was to evaluate the prevalence of mTSH in patients who had undergone thyroidectomy for thyroid cancer. METHODS: Seventy-three thyroid cancer patients and 24 control subjects on levothyroxine (LT4) TSH-suppressive or replacement therapy were evaluated. Screening for mTSH was performed by adding PEG to serum in order to precipitate gamma-globulin. A percentage of PEG-precipitable TSH >=80% was considered suggestive of mTSH. RESULTS: No correlation between free-T4 (fT4) and TSH levels was found. PEG-precipitable TSH was 39.3%+/-1.9% in thyroid cancer patients and 44.1%+/-3.9% in controls. Macro-TSH was deemed to be present in one thyroid cancer patient and in two control subjects. Only in the thyroid cancer group was PEG-precipitable TSH found to be negatively correlated with fT4 concentration. No correlation was found between PEG-precipitable TSH and other clinical conditions in any patients. CONCLUSION: The presence of mTSH seems to be a rare phenomenon in thyroid cancer. In some patients with low PEG-precipitable TSH, a reduction in LT4 dosage could be suggested. LT4 dosage adjusted to body weight is the main factor in maintaining TSH in a semi-suppressed or normal range. Evaluation of mTSH could be necessary in patients in whom a balance is required between adequate TSH suppression and the avoidance of unnecessary exogenous hyperthyroxinemia. PMID- 29271619 TI - Characteristics of Korean Patients with Primary Adrenal Insufficiency: A Registry Based Nationwide Survey in Korea. AB - BACKGROUND: Primary adrenal insufficiency (PAI) is a rare, potentially life threatening condition. There are few Korean studies on PAI, and most have had small sample sizes. We aimed to examine the etiology, clinical characteristics, treatment, and mortality of PAI in Korean patients. METHODS: A nationwide, multicenter, registry-based survey was conducted to identify adults diagnosed with or treated for PAI at 30 secondary or tertiary care institutions in Korea between 2000 and 2014. RESULTS: A total of 269 patients with PAI were identified. The prevalence of PAI was 4.17 per million. The estimated incidence was 0.45 per million per year. The mean age at diagnosis was 49.0 years, and PAI was more prevalent in men. Adrenal tuberculosis was the most common cause of PAI in patients diagnosed before 2000; for those diagnosed thereafter, adrenal metastasis and tuberculosis were comparable leading causes. The etiology of PAI was not identified in 34.9% of cases. Of the patients receiving glucocorticoid replacement therapy, prednisolone was more frequently administered than hydrocortisone (69.4% vs. 26.5%, respectively), and only 27.1% of all patients received fludrocortisone. We observed an increased prevalence of metabolic disease and osteoporosis during the follow-up period (median, 60.2 months). The observed overall mortality and disease-specific mortality rates were 11.9% and 3.1%, respectively. CONCLUSION: The prevalence of PAI is significantly lower in Koreans than in reports from Western countries. The high frequency undetermined etiology in patients with PAI suggests the need to reveal accurate etiology of PAI in Korea. PMID- 29271620 TI - Rebound Feeding in the Wake of Short-Term Suspension of Food Intake Differs in the Presence of Estrous Cycle Peak versus Nadir Levels of Estradiol. AB - BACKGROUND: Short-term interruption of feeding is ordinary in modern life but negatively impacts appetite control and body weight. Estradiol (E) imposes long term inhibitory tonus on food consumption; however, E influence on energy repletion secondary to food deprivation (FD) is unclear. This study investigated the hypothesis that E signal strength regulates hyperphagic responses to FD of varying duration. METHODS: Ovariectomized female rats were implanted with E containing silastic capsules (30 [E-30] or 300 MUg [E-300]/mL) to replicate plasma concentrations at cycle nadir versus peak levels. RESULTS: Data show that food intake was increased equally in E-30 and E-300 rats after 12 hours of food deprivation (FD-12); yet, FD of 18 hours (FD-18) amplified refeeding by E-300 versus E-30. Caudal fourth ventricular administration of the 5'-monophosphate activated protein kinase (AMPK) inhibitor compound C (Cc) did not modify FD induced hyperphagia in E-30 (regardless of FD interval) or E-300 animals exposed to FD-12, but diminished refeeding after FD-18 in E-300 rats. Cc-reversible hyperglycemia occurred in refed FD-18 groups. Serum insulin was resistant to FD 12 plus refeeding, but was elevated by AMPK-dependent mechanisms in refed E-300 FD-18 rats; equivalent Cc-insensitive decrements in circulating leptin occurred in all FD groups. CONCLUSION: Current results show that estrous cycle peak, but not baseline, E levels engage hindbrain AMPK signaling to intensify hyperphagia in response to prolongation of FD. Observations of hindbrain AMPK-dependent hyperglycemia, alongside elevated insulin secretion, in refed rats exposed to FD 18 implicate this sensor in insulin resistance mechanisms of glucose partitioning in response to this metabolic imbalance. PMID- 29271621 TI - Response: Utility of the Visceral Adiposity Index and Hypertriglyceridemic Waist Phenotype for Predicting Incident Hypertension (Endocrinol Metab 2017;32:221-9, Mohsen Janghorbani et al.). PMID- 29271622 TI - Erratum: Correction of Figure. The Implication of Coronary Artery Calcium Testing for Cardiovascular Disease Prevention and Diabetes. AB - This corrects the article on p. 47 in vol. 32, PMID: 28345316. PMID- 29271623 TI - Editorial. PMID- 29271624 TI - EARLY CAREER NURSES AND MIDWIVES NEED JOBS. AB - One of the many important roles the ANMF undertakes, as the national professional and industrial organisation for nurses and midwives in Australia, is monitoring and promoting employment opportunities for early career nurses and midwives (previously referred to as graduates). PMID- 29271625 TI - THE CHANGING FACE OF NURSING UNIFORMS. AB - Nursing uniforms have transformed dramatically over the past century on the back of emerging trends, demand for practicality and comfort, and strict workplace policy. PMID- 29271626 TI - WHAT IS THE CRIMINAL REGISTRATION STANDARD? AB - Under the Health Practitioner Regulation National Law Act (2009) in each Australian jurisdiction registered health practitioners, and in some instances students are required to provide their National Board with certain information when applying for registration. PMID- 29271627 TI - ON THE FRONT LINE. THE REWARDS OF LIFE AS A MILITARY NURSE. AB - The brave men and women of Australia's military put their lives on the line to defend the country at home and abroad. Behind the scenes, military nurses work alongside troops to provide support across the gamut of healthcare. At any given time, military nurses could be working in field hospitals, supporting training exercises across Australia, or deployed overseas in war zones. Filled with adventure and unique challenges, Robert Fedele explores the highs and lows of life as a military nurse. PMID- 29271628 TI - Development of Stabilized Peptide-Based PROTACs against Estrogen Receptor alpha. AB - Peptide modulators targeting protein-protein interactions (PPIs) exhibit greater potential than small-molecule drugs in several important aspects including facile modification and relative large contact surface area. Stabilized peptides constructed by variable chemistry methods exhibit improved peptide stability and cell permeability compared to that of the linears. Herein, we designed a stabilized peptide-based proteolysis-targeting chimera (PROTAC) targeting estrogen receptor alpha (ERalpha) by tethering an N-terminal aspartic acid cross linked stabilized peptide ERalpha modulator (TD-PERM) with a pentapeptide that binds the Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. The resulting heterobifunctional peptide (TD-PROTAC) selectively recruits ERalpha to the VHL E3 ligase complex, leading to the degradation of ERalpha in a proteasome-dependent manner. Compared with the control peptides, TD-PROTAC shows significantly enhanced activities in reducing the transcription of the ERalpha-downstream genes and inhibiting the proliferation of ERalpha-positive breast cancer cells. In addition, in vivo experiments indicate that TD-PROTAC leads to tumor regression in the MCF-7 mouse xenograft model. This work is a successful attempt to construct PROTACs based on cell-permeable stabilized peptides, which significantly broadens the chemical space of PROTACs and stabilized peptides. PMID- 29271629 TI - Highly Efficient Phosphorescent Furo[3,2-c]pyridine Based Iridium Complexes with Tunable Emission Colors over the Whole Visible Range. AB - A series of highly efficient phosphorescent Ir complexes with tunable emission colors over the whole visible range have been designed and synthesized based on furo[3,2-c]pyridine ligand. By mainly varying the molecular structures of the C chelated blocks, the emission maxima of these complexes can be obviously tailored from 477 to 641 nm while keeping the considerable photoluminescence quantum yields (PLQYs) (0.55-0.78 at wavelength of 475-560 nm and 0.10-0.34 at wavelength of 590-640 nm). Correspondingly, the phosphorescent organic light-emitting diodes (OLEDs) achieve high-performance greenish-blue, green, greenish-yellow, orange, red, and deep-red electrophosphorescence, revealing state-of-art external quantum efficiences (EQEs) of 20.0% (46.6 cd/A), 31.8% (89.0 cd/A), 19.9% (71.9 cd/A), 16.6% (38.9 cd/A), 12.0% (16.7 cd/A), and 8.5% (7.3 cd/A) as well as Commision Internationale de L'Eclairage (CIE) coordinates of (0.25, 0.48), (0.30, 0.58), (0.43, 0.54), (0.62, 0.37), (0.66, 0.32), and (0.70, 0.29), respectively. The results clearly demonstrate the great potential of furo[3,2-c]pyridine based phosphors used for full-color OLED displays. PMID- 29271630 TI - Tunable Polarity Behavior and High-Performance Photosensitive Characteristics in Schottky-Barrier Field-Effect Transistors Based on Multilayer WS2. AB - Schottky-barrier field-effect transistors (SBFETs) based on multilayer WS2 with Au as drain/source contacts are fabricated in this paper. Interestingly, the novel polarity behavior of the WS2 SBFETs can be modulated by drain bias, ranging from p-type to ambipolar and finally to n-type conductivity, due to the transition of band structures and Schottky-barrier heights under different drain and gate biases. The electron mobility and the on/off ratio of electron current can reach as high as 23.4 cm2/(V s) and 8.5 * 107, respectively. Moreover, the WS2 SBFET possesses high-performance photosensitive characteristics with response time of 40 ms, photoresponsivity of 12.4 A/W, external quantum efficiency of 2420%, and photodetectivity as high as 9.28 * 1011 cm Hz1/2/W. In conclusion, the excellent performance of the WS2 SBFETs may pave the way for next-generation electronic and photoelectronic devices. PMID- 29271631 TI - Spray-Drying-Induced Assembly of Skeleton-Structured SnO2/Graphene Composite Spheres as Superior Anode Materials for High-Performance Lithium-Ion Batteries. AB - Three-dimensional skeleton-structured assemblies of graphene sheets decorated with SnO2 nanocrystals are fabricated via a facile and large-scalable spray drying-induced assembly process with commercial graphene oxide and SnO2 sol as precursors. The influences of different parameters on the morphology, composition, structure, and electrochemical performances of the skeleton structured SnO2/graphene composite spheres are studied by XRD, TGA, SEM, TEM, Raman spectroscopy, and N2 adsorption-desorption techniques. Electrochemical properties of the composite spheres as the anode electrode for lithium-ion batteries are evaluated. After 120 cycles under a current density of 100 mA g-1, the skeleton-structured SnO2/graphene spheres still display a specific discharge capacity of 1140 mAh g-1. It is roughly 9.5 times larger than that of bare SnO2 clusters. It could still retain a stable specific capacity of 775 mAh g-1 after 50 cycles under a high current density of 2000 mA g-1, exhibiting extraordinary rate ability. The superconductivity of the graphene skeleton provides the pathway for electron transportation. The large pore volume deduced from the skeleton structure of the SnO2/graphene composite spheres increases the penetration of electrolyte and the diffusion of lithium ions and also significantly enhances the structural integrity by acting as a mechanical buffer. PMID- 29271632 TI - Amorphous P2S5/C Composite as High-Performance Anode Materials for Sodium-Ion Batteries. AB - We show a general method for achieving high-performance sodium storage materials via transforming crystalline P2S5 to amorphous P2S5 adhered to carbon matrix. The amorphous P2S5/C composite shows unique structural characteristics differing from the crystalline, which is identified by X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscope (TEM) and so on. The amorphous P2S5/C composite exhibits a safe average potential of 0.82 V, a reversible capacity of 400 mA h g-1, a remarkable capacity retention of 89.4% over 4000 cycles as well as good rate capability. Our findings open up opportunities to design of advanced anodes for room-temperature sodium-ion batteries. PMID- 29271633 TI - Novel CO2 Fluorescence Turn-On Quantification Based on a Dynamic AIE-Active Metal Organic Framework. AB - Traditional CO2 sensing technologies suffer from the disadvantages of being bulky and cross-sensitive to interferences such as CO and H2O, these issues could be properly tackled by innovating a novel fluorescence-based sensing technology. Metal-organic frameworks (MOFs), which have been widely explored as versatile fluorescence sensors, are still at a standstill for aggregation-induced emission (AIE), and no example of MOFs showing a dynamic AIE activity has been reported yet. Herein, we report a novel MOF, which successfully converts the aggregation caused quenching of the autologous ligand molecule to be AIE-active upon framework construction and exhibits bright fluorescence in a highly viscous environment, resulting in the first example of MOFs exhibiting a real dynamic AIE activity. Furthermore, a linear CO2 fluorescence quantification for mixed gases in the concentration range of 2.5-100% was thus well-established. These results herald the understanding and advent of a new generation in all solid-state fluorescence fields. PMID- 29271634 TI - Dominating Role of Aligned MoS2/Ni3S2 Nanoarrays Supported on Three-Dimensional Ni Foam with Hydrophilic Interface for Highly Enhanced Hydrogen Evolution Reaction. AB - When using water splitting to achieve sustainable hydrogen production, low-cost, stable, and naturally abundant electrocatalysts are required to replace Pt-based ones for the hydrogen evolution reaction (HER). Herein, for the first time, a novel nanostructure with one-dimensional (1D) MoS2/Ni3S2 nanoarrays directly grow on a three-dimensional (3D) Ni foam is developed for this purpose, showing excellent catalytic activity and stability. The as-prepared 3D MoS2/Ni3S2/Ni composite has an onset overpotential as low as 13 mV in 1 M KOH, which is comparable to Pt-based electrocatalyst for HER. According to the classical theory, the Tafel slope of the new composite is relatively low, as it goes through a combined Volmer-Heyrovsky mechanism during hydrogen evolution. All the results attribute the excellent electrocatalytic activity of the nanostructure to the electrical coupling among Ni, Ni3S2, and MoS2, the super hydrophilic interface, the synergistic catalytic effects produced by the MoS2/Ni3S2 nanoarrays, and abundant exposed active edge sites. These unique and previously undeveloped characteristics of the 3D MoS2/Ni3S2/Ni composite make it a very promising earth-abundant electrocatalyst for HER. PMID- 29271635 TI - Versatile T1-Based Chemical Analysis Platform Using Fe3+/Fe2+ Interconversion. AB - We report a versatile analytical platform for assaying multiple analytes relying on changes in longitudinal relaxation time (T1) as a result of Fe3+/Fe2+ interconversion. The T1 of water protons in Fe3+ aqueous solution differs significantly from that of Fe2+, allowing for the development of a generally applicable T1-based assay since many redox reactions enable the interconversion between Fe2+ and Fe3+ that can result in the change of T1. Compared with conventional magnetic biosensors, this T1-based assay is free of magnetic nanoparticles (MNPs), and the stability of T1-based assay is better than conventional magnetic sensors that suffer from nonspecific adsorption and aggregation of MNPs. This T1-based assay simultaneously enables "one-step mixing" assays (such as saliva sugar) and "multiple-washing" immunoassays with good stability and sensitivity, offering a promising platform for convenient, stable, and versatile biomedical analysis. PMID- 29271636 TI - Adjuvant Photothermal Therapy Inhibits Local Recurrences after Breast-Conserving Surgery with Little Skin Damage. AB - Adjuvant treatments following breast-conserving surgery (BCS) are essential to reduce the risk of local recurrences in patients with breast cancer. However, current adjuvant treatments are based on ionizing radiation, which brings radiation-induced damage and amplifies the risk of death. Here we explore the feasibility of using non-ionizing light to induce photothermal therapy as an adjuvant treatment to BCS. In an orthotopic breast cancer mice model, we demonstrate that adjuvant photothermal therapy (aPTT) decreases the incidence of local recurrences after BCS with no expense of cosmetic outcome. In comparison with conventional photothermal therapy, the technique used in aPTT provides more uniformly distributed light energy and less risk of skin burns and local recurrences. Overall, this work represents a departure from the traditional concept of using PTT as an alternative to surgery and reveals the potential of using PTT as an alternative to adjuvant radiation therapy, which is valuable especially for patients susceptible to radiation damage. PMID- 29271637 TI - Automated Online Solid-Phase Derivatization for Sensitive Quantification of Endogenous S-Nitrosoglutathione and Rapid Capture of Other Low-Molecular-Mass S Nitrosothiols. AB - S-Nitrosothiols (RSNOs) constitute a circulating endogenous reservoir of nitric oxide and have important biological activities. In this study, an online coupling of solid-phase derivatization (SPD) with liquid chromatography-mass spectrometry (LC-MS) was developed and applied in the analysis of low-molecular-mass RSNOs. A derivatizing-reagent-modified polymer monolithic column was prepared and adapted for online SPD-LC-MS. Analytes from the LC autosampler flowed through the monolithic column for derivatization and then directly into the LC-MS for analysis. This integration of the online derivatization, LC separation, and MS detection facilitated system automation, allowing rapid, laborsaving, and sensitive detection of RSNOs. S-Nitrosoglutathione (GSNO) was quantified using this automated online method with good linearity (R2 = 0.9994); the limit of detection was 0.015 nM. The online SPD-LC-MS method has been used to determine GSNO levels in mouse samples, 138 +/- 13.2 nM of endogenous GSNO was detected in mouse plasma. Besides, the GSNO concentrations in liver (64.8 +/- 11.3 pmol/mg protein), kidney (47.2 +/- 6.1 pmol/mg protein), heart (8.9 +/- 1.8 pmol/mg protein), muscle (1.9 +/- 0.3 pmol/mg protein), hippocampus (5.3 +/- 0.9 pmol/mg protein), striatum (6.7 +/- 0.6 pmol/mg protein), cerebellum (31.4 +/- 6.5 pmol/mg protein), and cortex (47.9 +/- 4.6 pmol/mg protein) were also successfully quantified. When the derivatization was performed within 8 min, followed by LC-MS detection, samples could be rapidly analyzed compared with the offline manual method. Other low-molecular-mass RSNOs, such as S-nitrosocysteine and S-nitrosocysteinylglycine, were captured by rapid precursor-ion scanning, showing that the proposed method is a potentially powerful tool for capture, identification, and quantification of RSNOs in biological samples. PMID- 29271638 TI - Low Li+ Insertion Barrier Carbon for High Energy Efficient Lithium-Ion Capacitor. AB - Lithium-ion capacitor (LIC) is an attractive energy-storage device (ESD) that promises high energy density at moderate power density. However, the key challenge in its design is the low energy efficient negative electrode, which barred the realization of such research system in fulfilling the current ESD technological inadequacy due to its poor overall energy efficiency. Large voltage hysteresis is the main issue behind high energy density alloying/conversion-type materials, which reduces the electrode energy efficiency. Insertion-type material though averted in most research due to the low capacity remains to be highly favorable in commercial application due to its lower voltage hysteresis. To further reduce voltage hysteresis and increase capacity, amorphous carbon with wider interlayer spacing has been demonstrated in the simulation result to significantly reduce Li+ insertion barrier. Hence, by employing such amorphous carbon, together with disordered carbon positive electrode, a high energy efficient LIC with round-trip energy efficiency of 84.3% with a maximum energy density of 133 Wh kg-1 at low power density of 210 W kg-1 can be achieved. PMID- 29271639 TI - Size-Dependent Inertial Focusing Position Shift and Particle Separations in Triangular Microchannels. AB - A recent study of inertial microfluidics within nonrectangular cross-section channels showed that the inertial focusing positions changes with cross-sectional shapes; therefore, the cross-sectional shape can be a useful control parameter for microfluidic particle manipulations. Here, we conducted detail investigation on unique focusing position shift phenomena, which occurs strongly in channels with the cross-sectional shape of the isosceles right triangle. The top focusing positions shift along the channel walls to the direction away from the apex with increasing Reynolds number and decreasing particle size. A larger particle with its center further away from the side walls experiences shear gradient lift toward the apex, which leads to an opposite result with changes of Reynolds and particle size. The focusing position shift and the subsequent stabilization of corner focusing lead to changes in the number of focusing positions, which enables a novel method for microparticle separations with high efficiency (>95%) and resolution (<2 MUm). The separation method based on equilibrium focusing; therefore, the operation is simple and no complex separation optimization is needed. Moreover, the separation threshold can be easily modulated with flow rate adjustment. Rare cell separation from blood cell was successfully demonstrated with spiked MCF-7 cells in blood by achieving the yield of ~95% and the throughput of ~106 cells/min. PMID- 29271640 TI - Selenite Uptake by Ca-Al LDH: A Description of Intercalated Anion Coordination Geometries. AB - Layered double hydroxides (LDHs) are anion exchangers with a strong potential to scavenge anionic contaminants in aquatic environments. Here, the uptake of selenite (SeO32-) by Ca-Al LDHs was investigated as a function of Se concentration. Thermodynamic modeling of batch sorption isotherms shows that the formation of SeO32--intercalated AFm (hydrated calcium aluminate monosubstituent) phase, AFm-SeO3, is the dominant mechanism controlling the retention of Se at medium loadings. AFm-Cl2 shows much stronger affinity and larger distribution ratio (Rd ~ 17800 L kg-1) toward SeO32- than AFm-SO4 (Rd ~ 705 L kg-1). At stoichiometric SeO32- loading for anion exchange, the newly formed AFm-SeO3 phase results in two basal spacing, i.e., 9.93 +/- 0.06 A and ~11.03 +/- 0.03 A. Extended X-ray absorption fine structure (EXAFS) spectra indicate that the intercalated SeO32- forms inner-sphere complexes with the Ca-Al-O layers. In situ X-ray diffraction (XRD) shows that basal spacing of Ca-Al LDHs have a remarkable linear relationship with the size of hydrated intercalated anions (i.e., Cl-, SO42-, MoO42-, and SeO32-). Contrary to AFm-SeO3 with inner-sphere SeO32- complexes in the interlayer, the phase with hydrogen-bonded inner-sphere complexed SeO32- is kinetically favored but thermodynamically unstable. This work offers new insights about the determination of intercalated anion coordination geometries via XRD analyses. PMID- 29271641 TI - Improvement of the Correlative AFM and ToF-SIMS Approach Using an Empirical Sputter Model for 3D Chemical Characterization. AB - Technological progress has spurred the development of increasingly sophisticated analytical devices. The full characterization of structures in terms of sample volume and composition is now highly complex. Here, a highly improved solution for 3D characterization of samples, based on an advanced method for 3D data correction, is proposed. Traditionally, secondary ion mass spectrometry (SIMS) provides the chemical distribution of sample surfaces. Combining successive sputtering with 2D surface projections enables a 3D volume rendering to be generated. However, surface topography can distort the volume rendering by necessitating the projection of a nonflat surface onto a planar image. Moreover, the sputtering is highly dependent on the probed material. Local variation of composition affects the sputter yield and the beam-induced roughness, which in turn alters the 3D render. To circumvent these drawbacks, the correlation of atomic force microscopy (AFM) with SIMS has been proposed in previous studies as a solution for the 3D chemical characterization. To extend the applicability of this approach, we have developed a methodology using AFM-time-of-flight (ToF) SIMS combined with an empirical sputter model, "dynamic-model-based volume correction", to universally correct 3D structures. First, the simulation of 3D structures highlighted the great advantages of this new approach compared with classical methods. Then, we explored the applicability of this new correction to two types of samples, a patterned metallic multilayer and a diblock copolymer film presenting surface asperities. In both cases, the dynamic-model-based volume correction produced an accurate 3D reconstruction of the sample volume and composition. The combination of AFM-SIMS with the dynamic-model-based volume correction improves the understanding of the surface characteristics. Beyond the useful 3D chemical information provided by dynamic-model-based volume correction, the approach permits us to enhance the correlation of chemical information from spectroscopic techniques with the physical properties obtained by AFM. PMID- 29271642 TI - RNA Thermometers for the PURExpress System. AB - Cell-free synthetic biology approaches enable engineering of biomolecular systems exhibiting complex, cell-like behaviors in the absence of living entities. Often essential to these systems are user-controllable mechanisms to regulate gene expression. Here we describe synthetic RNA thermometers that enable temperature dependent translation in the PURExpress in vitro protein synthesis system. Previously described cellular thermometers lie wholly in the 5' untranslated region and do not retain their intended function in PURExpress. By contrast, we designed hairpins between the Shine-Dalgarno sequence and complementary sequences within the gene of interest. The resulting thermometers enable high-yield, cell free protein expression in an inducible temperature range compatible with in vitro translation systems (30-37 degrees C). Moreover, expression efficiency and switching behavior are tunable via small variations to the coding sequence. Our approach and resulting thermometers provide new tools for exploiting temperature as a rapid, external trigger for in vitro gene regulation. PMID- 29271643 TI - Fast Orthogonal Separation by Superposition of Time of Flight and Field Asymmetric Ion Mobility Spectrometry. AB - Ion mobility spectrometry is a powerful and low-cost technique for the identification of chemical warfare agents, toxic chemicals, or explosives in air. Drift tube ion mobility spectrometers (DT-IMS) separate ions by the absolute value of their low field ion mobility, while field asymmetric ion mobility spectrometers (FAIMS) separate them by the change of their ion mobility at high fields. However, using one of these devices alone, some common and harmless substances show the same response as the hazardous target substances. In order to increase the selectivity, orthogonal data are required. Thus, in this work, we present for the first time an ambient pressure ion mobility spectrometer which is able to separate ions both by their differential and low field mobility, providing additional information for selectivity enhancement. This novel field asymmetric time of flight ion mobility spectrometer (FAT-IMS) allows high repetition rates and reaches limits of detection in the low ppb range common for DT-IMS. The device consists of a compact 44 mm drift tube with a tritium ionization source and a resolving power of 70. An increased separation of four substances with similar low field ion mobility is shown: phosgene (K0 = 2.33 cm2/(V s)), 1,1,2-trichlorethane (K0 = 2.31 cm2/(V s)), chlorine (K0 = 2.24 cm2/(V s)), and nitrogen dioxide (K0 = 2.25 cm2/(V s)). Furthermore, the behavior and limits of detection for acetonitrile, dimethyl methylphosphonate, diisopropyl methyl phosphonate in positive polarity and carbon dioxide, sulfur dioxide, hydrochloric acid, cyanogen chloride, and hydrogen cyanide in negative polarity are investigated. PMID- 29271644 TI - Complexity in pH-Dependent Ribozyme Kinetics: Dark pKa Shifts and Wavy Rate-pH Profiles. AB - Charged bases occur in RNA enzymes, or ribozymes, where they play key roles in catalysis. Cationic bases donate protons and perform electrostatic catalysis, while anionic bases accept protons. We previously published simulations of rate pH profiles for ribozymes in terms of species plots for the general acid and general base that have been useful for understanding how ribozymes respond to pH. In that study, we did not consider interaction between the general acid and general base or interaction with other species on the RNA. Since that report, diverse small ribozyme classes have been discovered, many of which have charged nucleobases or metal ions in the active site that can either directly interact and participate in catalysis or indirectly interact as "influencers". Herein, we simulate experimental rate-pH profiles in terms of species plots in which reverse protonated charged nucleobases interact. These analyses uncover two surprising features of pH-dependent enzyme kinetics. (1) Cooperativity between the general acid and general base enhances population of the functional forms of a ribozyme and manifests itself as hidden or "dark" pKa shifts, real pKa shifts that accelerate the reaction but are not readily observed by standard experimental approaches, and (2) influencers favorably shift the pKas of proton-transferring nucleobases and manifest themselves as "wavy" rate-pH profiles. We identify parallels with the protein enzyme literature, including reverse protonation and wavelike behavior, while pointing out that RNA is more prone to reverse protonation. The complexities uncovered, which arise from simple pairwise interactions, should aid deconvolution of complex rate-pH profiles for RNA and protein enzymes and suggest veiled catalytic devices for promoting catalysis that can be tested by experiment and calculation. PMID- 29271645 TI - Asperorydines A-M: Prenylated Tryptophan-Derived Alkaloids with Neurotrophic Effects from Aspergillus oryzae. AB - As part of our program to discover new bioactive agents from fungi, 13 new alkaloids accompanying 13 known related alkaloids were isolated from a wild strain of Aspergillus oryzae L1020. Compounds 1 and 2 have unprecedented 6/6/5/7/5 and 6/6/6/5/5 chemical skeletons, representing new members of quinoline alkaloids. Compound 3 is a new macrolactam with an unusual 6/5/6/8 ring system. Compounds 4-13 are new alpha-cyclopiazonic acid-related alkaloids. The absolute configurations of 1-4, 8, and 9 were assigned by electronic circular dichroism calculations. Compounds 2, 5, 6, 11, 14, 22, and 26 exhibit pronounced neurite outgrowth-promoting effects on PC12 cells in the range of 25-100 MUM. PMID- 29271646 TI - C-S Bond Cleavage, Redox Reactions, and Dioxygen Activation by Nonheme Dicobalt(II) Complexes. AB - Synthesis and reactivity of a series of thiolate/thiocarboxylate bridged dicobalt(II) complexes were investigated in comparison with their carboxylate bridged analogues bearing free thiol/hydroxyl groups. Upon one-electron oxidation, complexes [Co2(N-Et-HPTB)(MU-SR1)](BF4)2 (R1 = Ph, 1a; Et, 1b; Py, 1c) and [Co2(N-Et-HPTB)(MU-SCOR2)](BF4)2 (R2 = Ph, 2a; Me, 2b) yielded [Co2(N-Et HPTB)(DMF)2](BF4)3 (6) (DMF = dimethylformamide) along with the corresponding disulfides (where N-Et-HPTB is the anion of N,N,N',N'-tetrakis[2-(1 ethylbenzimidazolyl)]-2-hydroxy-1,3-diaminopropane). Unlike the inertness of carboxylate bridged complexes [Co2(N-Et-HPTB)(MU-O2C-R3-SH)](BF4)2 (R3 = Ph, 3a; CH2CH2, 3b) and [Co2(N-Et-HPTB)(MU-O2CR4)](BF4)2 (R4 = Ph, 4a; Me, 4b; CH2CH2CH2OH, 5) toward O2, the bridging ethanethiolate in 1b was oxidized to yield a sulfinate bridged complex, [Co2(N-Et-HPTB)(MU-O2SEt)](BF4)2 (10). Detailed investigation of the synthetic aspects of 1a-1c led to the discovery of a C-S bond cleavage reaction and yielded the dicobalt(II) complexes [Co2(N-Et HPTB)(SH)(H2O)](BF4)2 (8a), [Co2(N-CH2Py-HPTB)(SH)(H2O)](BF4)2 (8b) (where N CH2Py-HPTB is the anion of N,N,N',N'-tetrakis[2-(1-picolylbenzimidazolyl)]-2 hydroxy-1,3-diaminopropane)), and [Co2(N-Et-HPTB)(MU-S)](BF4) (9). Both 8a and 8b feature nonheme dinuclear Co(II) units containing a terminal hydrosulfide. The present study thus reports comparative redox reactions for a rare class of 16 dicobalt(II) complexes and introduces a selective synthetic strategy for the synthesis of unprecedented dicobalt(II) complexes featuring only one terminal hydrosulfide. PMID- 29271647 TI - Predicting the Open-Shell Character of Polycyclic Hydrocarbons in Terms of Clar Sextets. AB - Rather unexpected spin-symmetry breakings of mean-field single determinants occur in singlet ground states of many families of alternating conjugated hydrocarbons which accept a full on-bond electron pairing. These symmetry breakings may be seen as an indication of the existence of unpaired electrons. Although qualitative, the concept of disjoint electronic sextets proposed by Clar (hereafter called CS) is at least a heuristic tool for predicting various features of fused polybenzenic hydrocarbons. The present work shows that identifying the preferred CS distribution enables one to rationalize the existence of one or several spin-symmetry breakings, i.e., the existence and the number of unpaired electrons in alternant fused polycyclic hydrocarbons via a simple recipe for the prediction of these features. This recipe is based on comparison between various distributions of CS on the molecular frame, subject to a restriction concerning the fragments of the graph that do not belong to the CS. This rule is successfully confronted to UDFT calculations and to a recently proposed criterion predicting the possible occurrence of spin-symmetry breaking from the topological Huckel Hamiltonian. The confrontation runs on series of rhombuses, periacenes, anthenes, and other graphene flakes or nanoribbons. The CS distribution definitely offers a qualitative guide to look at the possible occurrence of (multiple) symmetry breakings in polycyclic architectures which are commonly seen as closed-shell singlets. PMID- 29271649 TI - Kinetically Controlled Stepwise Self-Assembly of AuI-Metallopeptides in Water. AB - The combination of attractive supramolecular interactions of a hydrophobic AuI metallopeptide with the shielding effect of flexible oligoethylene glycol chains provides access to a stepwise self-assembly of a AuI-metalloamphiphile in water. Kinetic control of the supramolecular polymer morphology is achieved using a temperature-dependent assembly protocol, which yields low dispersity supramolecular polymers (metastable state I) or helical bundled nanorods (state II). PMID- 29271651 TI - Strategies toward the Enhanced Permeability and Retention Effect by Increasing the Molecular Weight of Arene Ruthenium Metallaassemblies. AB - The enhanced permeability and retention (EPR) effect is an attractive avenue to target tumors: The size of the drug is the key to accumulating predominantly in tumors. Therefore, to increase the molecular weight of arene ruthenium metallaassemblies, several strategies can be adopted, and we present here our first step in the design of larger and heavier discrete arene ruthenium metallaassemblies to reach an EPR-size dimension. PMID- 29271648 TI - Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer's Disease. AB - Bivalent compounds anchoring in different manners to the membrane were designed and biologically characterized to understand the contribution of the anchor moiety to their biological activity as neuroprotectants for Alzheimer's disease. Our results established that the anchor moiety is essential, and we identified a preference for diosgenin, as evidenced by 17MD. Studies in primary neurons and mouse brain mitochondria also identified 17MD as exhibiting activity on neuritic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondria. Significantly, our studies demonstrated that the integrated bivalent structure is essential to the observed biological activities. Further studies employing bivalent compounds as probes in a model membrane also revealed the influence of the anchor moiety on how they interact with the membrane. Collectively, our results suggest diosgenin to be an optimal anchor moiety, providing bivalent compounds with promising pharmacology that have potential applications for Alzheimer's disease. PMID- 29271650 TI - Nickel-Catalyzed Stereoselective Arylboration of Unactivated Alkenes. AB - A Ni-catalyzed method for arylboration is disclosed. The method allows for highly stereoselective arylboration of unactivated alkenes. The reactions utilize a simple Ni-catalyst and work with a broad range of alkenes and aryl bromides. The products represent useful intermediates for chemical synthesis due to the versatility of the C-B bond. Preliminary mechanistic details of the method are also disclosed. PMID- 29271652 TI - Statistical Mechanics-Based Theoretical Investigation of Solvation Effects on Glucose Anomer Preferences. AB - The importance of solvation effects on the stability of glucose anomers has been studied by the combination of quantum mechanics and statistical mechanics, namely, the reference interaction site model self-consistent field spatial electron density distribution. The preferences of alpha- and beta-glucose in H2O are well reproduced with the obtained ratio of 35:65 for alpha- and beta-glucose, respectively. Indirect interactions and bulk effects, described by the Onsager model, are relatively small compared to the direct solute-solvent interactions, especially in [DMIM]Cl and dimethyl sulfoxide. From the decomposition of solvation free energy and solvation structures, it can be seen that the interactions with the solvent molecules greatly contribute to the anomer preferences. PMID- 29271653 TI - Inhibitors of HIV-1 Attachment: The Discovery and Development of Temsavir and its Prodrug Fostemsavir. AB - Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3 glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials. PMID- 29271654 TI - Distribution of Spiked Drugs between Milk Fat, Skim Milk, Whey, Curd, and Milk Protein Fractions: Expansion of Partitioning Models. AB - The distributions of eight drugs (acetaminophen, acetylsalicylic acid/salicylic acid, ciprofloxacin, clarithromycin, flunixin, phenylbutazone, praziquantel, and thiamphenicol) were determined in milk products (skim milk, milk fat, curd, whey, and whey protein) and used to expand a previous model (from 7 drugs to 15 drugs) for predicting drug distribution. Phenylbutazone and praziquantel were found to distribute with the lipid and curd phases (>=50%). Flunixin distribution was lower but similar in direction (12% in milk fat, 39% in curd). Acetaminophen, ciprofloxacin, and praziquantel preferentially associated with casein proteins, whereas thiamphenicol and clarithromycin associated preferentially to whey proteins. Regression analyses for log [milk fat]/[skim milk] and log [curd]/[whey] had r2 values of 0.63 and 0.67, respectively, with p of <0.001 for 15 drugs (7 previously tested and 8 currently tested). The robustness of the distribution model was enhanced by doubling the number of drugs originally tested. PMID- 29271655 TI - Addition to "Essentially Trap-Free CsPbBr3 Colloidal Nanocrystals by Postsynthetic Thiocyanate Surface Treatment". PMID- 29271656 TI - Bifunctional Thiourea-Ammonium Salt Catalysts Derived from Cinchona Alkaloids: Cooperative Phase-Transfer Catalysts in the Enantioselective Aza-Henry Reaction of Ketimines. AB - An efficient enantioselective aza-Henry reaction of aryl alpha-ketoester-derived ketimines has been realized by using bifunctional thiourea-ammonium salt phase transfer catalysts, which were derived from quinine. A variety of aryl alpha ketoester-derived N-Ts ketimines were investigated, and the corresponding products were obtained in high to excellent yields (up to 99%) with good to high enantioselectivities (up to >99% ee). PMID- 29271657 TI - In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-beta-lactamase Inhibitors. AB - Zinc ion-dependent beta-lactamases (MBLs) catalyze the hydrolysis of almost all beta-lactam antibiotics and resist the action of clinically available beta lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine beta-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops. PMID- 29271658 TI - Topologically Diverse Shapes Accessible by Modular Design of Arylopeptoid Macrocycles. AB - N-Substituted aromatic cyclooligoamides composed of different combinations of ortho-, meta-, and/or para-arylopeptoid residues carrying methoxyethyl side chains have been efficiently synthesized by macrocyclization of the corresponding linear oligomers. The study of the architectures of these macrocycles in solution and solid state has revealed that tetracyclic arylopeptoids adopt sequence dependent shapes with different backbone amide conformations and side-chain orientations. Remarkably, despite the absence of intramolecular H-bonding ability, some of these arylopeptoid macrocycles show well-defined architectures in solution. PMID- 29271659 TI - Small molecule purine and pseudopurine derivatives: synthesis, cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549. AB - Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3 triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3 triazole derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3 triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation and induction of apoptosis mediated by p38 MAP kinase and NF-kappaB, respectively. Further optimisation of this compound as to reduce its toxicity in normal cells may lead to the development of novel agent effective against lung cancer. PMID- 29271660 TI - Pegylated interferon alpha 2a for the treatment of hepatitis C virus infection. AB - INTRODUCTION: Treatments for hepatitis C virus (HCV) infection have advanced rapidly in the last decade. Pegylated interferon alpha 2a (PEG-IFN alpha 2a) alone, in combination with ribavirin and with or without direct acting antivirals (DAAs) is modestly effective in the treatment of chronic HCV infection. Areas covered: The review describes the chemistry, pharmacokinetic and pharmacodynamic properties, clinical efficacy, safety and drug-drug interaction profiles of PEG IFN alpha 2a. Expert opinion: Despite the availability of DAAs and its formidable toxicity profile, PEG-IFN alpha 2a retains a role for the treatment of acute HCV and chronic HCV infection in resource limited settings and for end-stage renal disease patients and others who cannot access DAAs or are DAA-ineligible. Knowledge of pharmacogenetic profiles which favor successful treatment outcomes with IFN-based therapies may allow for selection of best candidates for the regimen. PMID- 29271661 TI - Implementation of smart technology to improve medication adherence in patients with cardiovascular disease: is it effective? AB - INTRODUCTION: Medication adherence is of key importance in the treatment of cardiovascular disease. Studies consistently show that a substantial proportion of patients is non-adherent. Areas covered: For this review, telemedicine solutions that can potentially improve medication adherence in patients with cardiovascular disease were reviewed. A total of 475 PubMed papers were reviewed, of which 74 were assessed. Expert commentary: Papers showed that evidence regarding telemedicine solutions is mostly conflictive. Simple SMS reminders might work for patients who do not take their medication because of forgetfulness. Educational interventions and coaching interventions, primarily delivered by telephone or via a web-based platform can be effective tools to enhance medication adherence. Finally, it should be noted that current developments in software engineering may dramatically change the way non adherence is addressed in the nearby future. PMID- 29271662 TI - The Complexity of Patients' Health Communication Social Networks: A Broadening of Physician Communication. AB - : Phenomenon: Patients have access to a wide variety of sources of information about their health in their day-to-day contexts. This can sometimes result in discordance between a physician's perception of a patient's health issue and a patient's perception of their health issue. Even after the physician has negotiated an understanding and treatment plan with a patient, subsequent interactions outside the physician-patient encounter may modify the patient's understanding of their health issue. A patient's reinterpretation of his or her health issue can then result in nonadherence of the treatment plan or even alternative treatment plans that the physician perceives as being unsatisfactory. Current models of physician-patient communication do not prepare physicians to manage this phenomenon. APPROACH: Using an ethnographic and a social network analysis research design, participants' patterns of social interaction around health information were investigated over a yearlong period (2012-2013) in a small rural community in Western Canada. Data included (a) individual interviews, (b) focus group interviews, and (c) field notes. Data were analyzed in a three stage process: (a) item analysis, (b) pattern analysis, and (c) structural analysis. FINDINGS: The findings highlight how physicians are only one nodal point in patients' broad, multilayered networks of communication. Interactions around health topics were not isolated events but rather occurred in various patterns of social interactions that were longitudinal and iterative. Meaning making around health topics was constructed, shared, elaborated, reconstructed, and interpreted in participants' social networks, as information was distributed through a complex temporal system of interpersonal ties. Insights: Issues concerning physician communication have been a long-standing conversation in the field of medical education. Many competency frameworks have attempted to encompass this core competency in their elaboration of the physician communicator. However, most representations and discussions in the field tend to depict physician communicators as experts who translate their knowledge to patients in a simplified way, in a single moment in time. This study suggests that educational initiatives in physician-patient communication would benefit from contextualizing physicians as part of patients' resource-rich, temporally extended, iterative process of meaning making. This alternative framing has the potential to support physicians' continuing engagement with patients as a meaningful and responsive node in patients' meaning-making networks. PMID- 29271663 TI - Open source modular ptosis crutch for the treatment of myasthenia gravis. AB - INTRODUCTION: Pharmacologic treatment of Myasthenia Gravis presents challenges due to poor tolerability in some patients. Conventional ptosis crutches have limitations such as interference with blinking which causes ocular surface drying, and frequent irritation of the eyes. To address this problem, a modular and adjustable ptosis crutch for elevating the upper eyelid in Myasthenia Gravis patients has been proposed as a non-surgical and low-cost solution. Areas covered: This paper reviews the literature on the challenges in the treatment of Myasthenia Gravis globally and focuses on a modular and adjustable ptosis crutch that has been developed by the Medical Device Laboratory at the University of Cape Town. Expert commentary: The new medical device has potential as a simple, effective and unobtrusive solution to elevate the drooping upper eyelid(s) above the visual axis without the need for medication and surgery. Access to the technology is provided through an open source platform which makes it available globally. Open access provides opportunities for further open innovation to address the current limitations of the device, ultimately for the benefit not only of people suffering from Myasthenia Gravis but also of those with ptosis from other aetiologies. PMID- 29271664 TI - The Impact of Entrepreneurial Competencies on Household Food Security Among Smallholder Farmers in KwaZulu Natal, South Africa. AB - This paper investigates the impact of entrepreneurial competencies on food security among rural farming households in KwaZulu-Natal, South Africa (SA). A total of 513 rural households were randomly selected, and the descriptive results indicated that 51% of these households were food insecure, and they were somewhat negative about their entrepreneurial competencies. The estimated results indicated that entrepreneurship had a positive impact on food security. The study findings suggest that stimulating entrepreneurship through developing entrepreneurial competencies among the farming households is important for improved food security among rural households in SA. PMID- 29271665 TI - Compatibility of booster seats and vehicles in the U.S. market. AB - OBJECTIVE: The objective of this study was to analyze booster and rear vehicle seat dimensions to identify the most frequent compatibility problems. METHODS: Measurements were collected from 40 high-back and backless boosters and 95 left rear and center rear row seating positions in 50 modern vehicles. Dimensions were compared for 3,800 booster/vehicle seat combinations. For validation and estimation of tolerance and correction factors, 72 booster installations were physically completed and compared with measurement-based compatibility predictions. Dimensions were also compared to the International Organization for Standardization (ISO) volumetric envelopes of forward-facing child restraints and boosters. RESULTS: Seat belt buckles in outboard positions accommodated the width of boosters better than center positions (success rates of 85.4 and 34.7%, respectively). Adequate head restraint clearance occurred in 71.9 to 77.2% of combinations, depending on the booster's head support setting. Booster recline angles aligned properly with vehicle seat cushion angles in 71.5% of combinations. In cases of poor angle alignment, booster angles were more obtuse than the vehicle seat angles 97.7% of the time. Head restraint interference exacerbated angle alignment issues. Data indicate success rates above 90% for boosters being fully supported by the length of the seat cushion and for adequate height clearance with the vehicle roofline. Comparison to ISO envelopes indicates that most boosters on the U.S. market are taller and angled more obtusely than ISO target envelopes. CONCLUSIONS: This study quantifies some of the common interferences between boosters and vehicles that may complicate booster usage. Data are useful for design and to prioritize specific problem areas. PMID- 29271666 TI - Identifying modifiable factors associated with health optimism in older adults. AB - OBJECTIVE: Despite the documented importance of health optimism for enhancing health outcomes, very little work has been done to examine who experiences health optimism and under what conditions. The present study sought to identify modifiable factors associated with health optimism that could constitute the focus of future intervention efforts designed to promote health optimism among older people. DESIGN: Participants were 453 (44% males) community-based Western Australians aged 60+ years (M = 70.39 years, SD = 6.06). Participants completed questionnaires to assess sociodemographic characteristics and provided information relating to physical and psychological health status. RESULTS: Almost a quarter of participants (24%; n = 108) were classified as health optimists. Results from a multivariate regression analysis found quality of life, psychological well-being, and age to be directly and positively associated with health optimism. A subsequent path analytic model found depression (negatively) and self-efficacy (positively) to be indirectly associated with health optimism via both psychological well-being and quality of life. CONCLUSION: These findings extend the limited evidence on health optimism in older adults by identifying various modifiable factors that may constitute potential areas of focus for future interventions designed to enhance health outcomes via the fostering of health optimism. PMID- 29271668 TI - Acoustic environments that support equally accessible oral higher education as a human right. AB - PURPOSE: People have the right to freedom of opinion and expression, as defined in Article 19 of the Universal Declaration of Human Rights. Higher education plays a major role in helping students to develop and express their own opinions and, therefore, should be equally accessible to all. This article focuses on how students judge the accessibility to oral instruction in higher education listening contexts. METHOD: We collected data from 191 students in higher education by means of a questionnaire, addressing understanding speech in different types of classrooms and various educational settings. RESULT: In lecture halls, understanding speech was judged to be significantly worse than in smaller classrooms. Two important negative factors were identified: background noise in classrooms and lecture halls and the non-use of a microphone. CONCLUSIONS: In lecture halls students achieve good or excellent speech perception only when lecturers are using a microphone. Nevertheless, this is not a standard practice. To achieve genuine inclusion in tertiary education programs, it is essential to remove acoustic barriers to understanding speech as much as possible. This study is a first step to identify communication facilitators to oral higher education instruction, for students with hearing loss or communication impairment. PMID- 29271667 TI - SOX7 Suppresses Wnt Signaling by Disrupting beta-Catenin/BCL9 Interaction. AB - The Wnt signaling is involved in angiogenesis and tumor development. beta-catenin is the core component of the Wnt pathway, which mediates oncogenic transcription and regulated by a series of proteins. Sex-determining region Y-box 7 (SOX7) is a member of high-mobility-group transcription factor family, which inhibits oncogenic Wnt signaling in lots of tumor cells with unknown mechanism. By coimmunoprecipitation (co-IP) and super Topflash reporter assay, SOX7 can bind beta-catenin and inhibit beta-catenin/T cell factor (TCF)-mediated transcription. Meanwhile, B cell lymphoma 9 (BCL9) drives Wnt signaling path through direct binding-mediated beta-catenin. Finally, we found that SOX7 inhibits oncogenic beta-catenin-mediated transcription by disrupting the beta-catenin/BCL9 interaction. Mechanistically, SOX7 compete with BCL9 to bind beta-catenin. Our results show SOX7 inhibited Wnt signaling as suppressor and could be an important target for anticancer therapy. PMID- 29271669 TI - Comprehension of wh-questions in Turkish-German bilinguals with aphasia: A dual case study. AB - The aim of our study was to examine the extent to which linguistic approaches to sentence comprehension deficits in aphasia can account for differential impairment patterns in the comprehension of wh-questions in bilingual persons with aphasia (PWA). We investigated the comprehension of subject and object wh questions in both Turkish, a wh-in-situ language, and German, a wh-fronting language, in two bilingual PWA using a sentence-to-picture matching task. Both PWA showed differential impairment patterns in their two languages. SK, an early bilingual PWA, had particular difficulty comprehending subject which-questions in Turkish but performed normal across all conditions in German. CT, a late bilingual PWA, performed more poorly for object which-questions in German than in all other conditions, whilst in Turkish his accuracy was at chance level across all conditions. We conclude that the observed patterns of selective cross linguistic impairments cannot solely be attributed either to difficulty with wh movement or to problems with the integration of discourse-level information. Instead our results suggest that differences between our PWA's individual bilingualism profiles (e.g. onset of bilingualism, premorbid language dominance) considerably affected the nature and extent of their impairments. PMID- 29271670 TI - Implementation and Organization of a Perioperative Lactation Program: A Descriptive Study. AB - INTRODUCTION: As breastfeeding rates rise, perioperative care of lactating women is an increasingly important issue. There is a lack of reports describing the implementation of perioperative lactation programs. Beginning in 2014, Memorial Sloan Kettering Cancer Center developed a perioperative lactation program to address the comprehensive care of lactating patients. The aim of this study was to determine the incidence of lactation in our perioperative population, as well as to describe preliminary data and experiences during the implementation of our program. MATERIALS AND METHODS: This retrospective descriptive study included lactating patients who underwent procedures requiring anesthesia care at our institution from August 2014 to February 2017. This period coincided with implementation of the lactation program, which focused on patient identification, education, and support, as well as staff education and collaboration. Patient volume and characteristics, procedure types, and intraoperative non-narcotic analgesic use were analyzed. RESULTS: Over the 30-month study period, we identified 80 lactating perioperative patients, with ~2-3 patients presenting monthly. The median (range) age of the child was 5 (0.6-24) months. Most of our lactating patients were American Society of Anesthesiologists class I-II patients (81%), who underwent general anesthesia (89%), and received at least one non narcotic analgesic intraoperatively (89%). CONCLUSION: Our study showed that we cared for lactating patients undergoing a wide range of procedures on a regular basis. The results from this study are intended to inform the next phase of our research, which will focus on determining how this work impacts outcomes such as postoperative lactation complications, breastfeeding resumption, and overall patient satisfaction. PMID- 29271671 TI - Impact of heart-specific disruption of the circadian clock on systemic glucose metabolism in mice. AB - The daily rhythm of glucose metabolism is governed by the circadian clock, which consists of cell-autonomous clock machineries residing in nearly every tissue in the body. Disruption of these clock machineries either environmentally or genetically induces the dysregulation of glucose metabolism. Although the roles of clock machineries in the regulation of glucose metabolism have been uncovered in major metabolic tissues, such as the pancreas, liver, and skeletal muscle, it remains unknown whether clock function in non-major metabolic tissues also affects systemic glucose metabolism. Here, we tested the hypothesis that disruption of the clock machinery in the heart might also affect systemic glucose metabolism, because heart function is known to be associated with glucose tolerance. We examined glucose and insulin tolerance as well as heart phenotypes in mice with heart-specific deletion of Bmal1, a core clock gene. Bmal1 deletion in the heart not only decreased heart function but also led to systemic insulin resistance. Moreover, hyperglycemia was induced with age. Furthermore, heart specific Bmal1-deficient mice exhibited decreased insulin-induced phosphorylation of Akt in the liver, thus indicating that Bmal1 deletion in the heart causes hepatic insulin resistance. Our findings revealed an unexpected effect of the function of clock machinery in a non-major metabolic tissue, the heart, on systemic glucose metabolism in mammals. PMID- 29271673 TI - The association of recovery orientation and stigmatizing beliefs. AB - BACKGROUND: Although mental health advocates and providers have promoted both recovery-oriented care and the de-stigmatization of mental illness, no studies have examined the interrelation of these two specific constructs. AIMS: This study aimed to evaluate this association, with the hypothesis that stronger perception of programmatic recovery orientation would be associated with less stigmatizing beliefs towards mental illness. METHOD: Veterans (N = 122) and mental health clinicians (N = 98) at a large Veterans Affairs Medical Center completed an assessment of recovery orientation and a measure of beliefs about mental illness. RESULTS: Stronger endorsement of programmatic recovery orientation was associated with less stigmatizing attitudes in both groups. Each of the five factors on the recovery measure was significantly and negatively associated with each of the four factors on the stigma measure. CONCLUSIONS: Perspectives of recovery orientation and stigma are significantly, but negatively, associated. Future research should investigate the direction of causality behind these observed relationships, as this will provide the opportunity to identify potential interventions to increase recovery-oriented mental health care and reduce stigmatization. PMID- 29271672 TI - NS5B polymerase inhibitors in phase II clinical trials for HCV infection. AB - INTRODUCTION: Hepatitis C virus (HCV) infection might be the first chronic viral disease to be eradicated without the introduction of a prophylactic vaccine. This is essentially due to therapeutic revolution encapsulated by the advent of direct acting antivirals (DAA) agents, whose efficacy, safety and tolerability (all oral regimens) have made the previous standard of care (interferon plus ribavirin) a vestige of the past. The new regimens achieve very high response rates and have an excellent tolerability profile. Notwithstanding, the first wave of DAAs has brought over problems regarding costs and failures which warrant research and development of further antiviral molecules. Areas covered: This review outlines the main clinical data concerning novel NS5B polymerase inhibitors currently in pipeline, focusing on the ones that have completed a phase 2 trial. Expert opinion: NS5B is one the main viral target for anti-HCV therapy. The large majority of the approved regimens so far include a NS5B inhibitor. Although not frequently, failure related to mutations can occur. The potential place in therapy in the mid-term of new NS5B inhibitors may be, in the first instance, the role of backbone in salvage combinations with DAAs of other classes. PMID- 29271674 TI - How to use neoadjuvant medical treatment to maximize surgery in melanoma. AB - INTRODUCTION: The aim of this work is to discuss the role of neoadjuvant therapy in melanoma patients, namely the potential to improve control and surgical resectability of locoregional disease. Moreover, potential survival benefits for high-risk stage III and IV melanoma patients will be addressed. Areas covered: In this review, the different available neoadjuvant treatments including chemotherapy, bio-chemotherapy, targeted therapy, immunotherapy and local therapy will be presented and discussed. The PubMed published articles were identified and searched using the following terms located in the publication title: neoadjuvant therapy and melanoma. Studies investigating targeted therapy, immunotherapy and local melanoma treatments were included. Clinicaltrial.gov was also used as a source for recruiting or ongoing but not recruiting neoadjuvant clinical trials, for which no published results are available. Expert commentary: Targeted therapy and immunotherapy in a neoadjuvant setting are still under investigation and not yet approved, however several neoadjuvant trials are ongoing. Shortly, results from these trials will answer the question whether neoadjuvant treatment translates into survival benefit and improves local disease control in stage III and IV melanoma patients. Immunotherapy and targeted therapy will play as relevant a role as in the metastatic setting, whereas chemotherapy will be used seldom. PMID- 29271675 TI - The long-term impact of undergraduate interprofessional education on graduate interprofessional practice: A scoping review. AB - Several recent high-quality systematic reviews have identified the importance of measuring outcomes in evaluating the effectiveness of interprofessional education (IPE) in healthcare, but also the process- and context-dependent nature of these outcomes. This paper presents a scoping review, the objectives of which were to evaluate the evidence for the long-term impact of undergraduate IPE on graduate interprofessional practice (IPP) and to identify areas for further research in the specific context of practice-based IPE. An initial search identified 596 potentially relevant titles published between 2008 and 2016. Screening for inclusion of documented IPE with IPP evaluation reduced this to 130. Abstract reading excluded 99 studies that were not longitudinal. Full reading of the remaining 31 articles identified 23 original studies which were analysed descriptively and tabulated. The main findings were synthesised around three themes: undergraduate evidence for a long-term impact of IPE on IPP; graduate evidence for a long-term impact of IPE on IPP; and barriers to an impact of IPE on graduate IPP. Drawing on these findings, research areas likely to produce further evidence for the impact of practice-based IPE on graduate IPP are discussed, along with some suitable methodologies. PMID- 29271677 TI - Erratum. PMID- 29271676 TI - Kinematics and pushrim kinetics in adolescents propelling high-strength lightweight and ultra-lightweight manual wheelchairs. AB - PURPOSE: The purpose of this study is to describe and compare pushrim forces, propulsive work cost, and upper body kinematics in adolescents propelling (1) a standard high strength lightweight wheelchair, and (2) an ultra-lightweight wheelchair with adjustable main axle positioning, on a level tiled floor ("Tile"), ascending a ramp ("Ramp"), and across a foam mat ("Mat"). METHODS: A within-subjects repeated measures study design was used. Eight adolescent manual wheelchair users propelled the standard and ultra-lightweight wheelchairs across the three conditions. Average pushrim tangential force, propulsive power and work per unit distance travelled, as well as upper body kinematic angles, were analyzed. RESULTS: Average pushrim tangential force (1.80 +/- 0.7 N, p = .042) and propulsive work per unit distance travelled (8.3 +/- 1.7 J.m- 1, p = .002) were higher for the standard lightweight wheelchair, whereas average speed was lower (0.12 +/- 0.03 m/s, p = .006). Maximum shoulder (9.2 +/- 2.0 degrees , p = .003) and elbow flexion (8.0 +/- 2.2 degrees , p = .009) were higher for the ultra-lightweight wheelchair. Compared with Tile, propulsion on Mat and Ramp was associated with higher average tangential force, work per unit distance, power, and maximum flexion of the neck and trunk, whereas shoulder extension and average speed were lower for Mat and Ramp. CONCLUSIONS: Compared with the standard lightweight wheelchair, ultra-lightweight wheelchair propulsion was associated with lower pushrim forces, lower energy costs, higher self-selected speeds, and increased shoulder and elbow flexion. These variables have been linked to injury risk and mobility efficiency, and the results provided evidence that differences in weight and configuration options are both contributors. Findings can inform decision-making in the prescription of manual wheelchairs for pre-adult populations. Implications for Rehabilitation A significant proportion of manual wheelchair users are children and adolescents, and due to the early onset of use they may be especially predisposed to the development of chronic overuse injuries. The study reports differences in energy costs, pushrim forces, and upper body kinematics measured when adolescents propelled standard and ultra lightweight wheelchairs across three trial conditions. In the ultra-lightweight wheelchair, reduced energy cost is linked to more efficient mobility, and lower forces may be linked to lower risk of chronic injury. Significant differences in elbow and shoulder kinematics are also reported, and the findings support the importance of both weight and setup options in the selection of manual wheelchairs. PMID- 29271682 TI - Does Experience Matter? Paramedic Cardiac Resuscitation Experience Effect on Out of-Hospital Cardiac Arrest Outcomes. AB - OBJECTIVE: Outcomes of Out-of-Hospital Cardiac Arrest (OHCA) are influenced by many factors. We postulate that paramedics who have participated in a greater number of OHCA resuscitations will have improved patient outcomes when compared to paramedics who participated in fewer resuscitations. METHODS: We conducted a retrospective analysis of prospectively collected data abstracted from the cardiac arrest database of a large urban EMS system. All OHCA cases where resuscitation was attempted during the year 2014 were reviewed. Our outcome of interest was the rate of sustained Return of Spontaneous Circulation (ROSC), which is defined as ROSC for five continuous minutes or greater. The rate of sustained ROSC was calculated from cases when paramedics served in the role of the lead medic. These rates were then analyzed using the Chi-Square test. RESULTS: A total of 1,145 cases of OHCA met criteria for inclusion in this study, of which 343 paramedics participated in at least one cardiac arrest in 2014. The median number of resuscitations was 10 with a range from 1 to 26 resuscitations. The paramedics were dichotomized into two groups; those who participated in <10 OHCAs (120/343), labeled "less experienced," and those who participated in >=10 OHCAs (223/343), labeled "more experienced." Paramedics in the less experienced group had a sustained ROSC rate of 22.2% for resuscitations in which they were the lead medic, while those in the more experienced group had a rate of 28.9% (p value = 0.047), RR 1.30 (95% CI 1.001, 1.692). CONCLUSIONS: This study demonstrated that more experienced paramedics had a statistically significant increase in achieving sustained ROSC when they were functioning in a lead role compared to less experienced paramedics. We found no other clinically significant patient outcomes related to the provider's experience. PMID- 29271683 TI - Outcome of facial rejuvenation with polydioxanone thread for Asians. AB - BACKGROUND: Techniques in rejuvenating the aging face have evolved, involving various types of threads. Facial rejuvenation with absorbable polydioxanone is popular in aesthetic clinics in Korea. AIM: The purpose of this study was to describe our polydioxanone thread method and to evaluate the outcomes of facial rejuvenation. PATIENTS/METHODS: A retrospective chart review was performed over a 12-month period. Thirty-five Asian patients were included. All participants underwent thread-lifting using polydioxanone. On each side, five 360 degrees spiral cog threads were used in the procedure. The results were evaluated using photography and patient satisfaction. RESULTS: Thirty-three patients (94.3%) were satisfied with the outcomes. Objective outcomes using photography were categorized as very much improved (68.6%), much improved (25.7%), and improved (5.7%). Subjective outcomes using patients' satisfaction were categorized as excellent, very good, good, fair, and poor. The incidence of complications was low, and the complications resolved spontaneously without any surgical interventions. Asymmetry, however, was noted. CONCLUSIONS: Using our technique, we could achieve the desired facial rejuvenation. Our method demonstrated an excellent success rate in patients with moderate degree laxity. We believe that facial rejuvenation with polydioxanone thread for Asians is a safe and effective treatment method. PMID- 29271684 TI - Identification of the Dominant Microbial Species of Spoiled Crisp Grass Carp ( Ctenopharyngodon idellus C. et V.) and Grass Carp ( Ctenopharyngodon idellus) Fillets during Cold Storage by Culture-Independent 16S rDNA Sequence Analysis. AB - A new freshwater cultivation species, crisp grass carp (CGC; Ctenopharyngodon idellus C. et V.) has a special texture and is popular with consumers; thus, we should pay close attention to its storage conditions and bacterial degradation. CGC and grass carp (GC; Ctenopharyngodon idellus) were commercialized as fillets and subsequently stored at 4 and 8 degrees C. Microbial growth parameters (total viable counts, psychrotrophic bacteria, and Pseudomonas spp.), physicochemical data (pH and total volatile base nitrogen), and sensory analysis were monitored during the storage period. Dominant microorganisms were identified using a 16S rDNA clone library and restriction fragment length polymorphism (RFLP) analysis after the fillets had spoiled completely. The results showed that Pseudomonas spp. lagged behind the psychrotrophic population and the total viable counts initially and increased more rapidly after storage for 2 days. Total volatile base nitrogen contents were found to increase with storage time in both species, coinciding with ongoing microbial change. The pH results obtained for both species during storage showed an overall increase at the end of storage. Sensory evaluation showed a shelf life of 3 and 6 days for both species at 8 and 4 degrees C, respectively. RFLP analysis of the 16S rDNA clone library revealed that there were seven and five distinct RFLP pattern groups in the microflora of the spoiled CGC and GC fillets, respectively. Through RFLP patterns and 16S rDNA sequencing from the clones, it was determined that CGC fillets stored at 4 degrees C were dominated by Pseudomonas spp. at the point of sensory rejection, whereas GC fillets were dominated by populations affiliated with Pseudomonas sp., Acinetobacter sp., and Aeromonas sp. PMID- 29271685 TI - High Phenotypic Variability among Representative Strains of Common Salmonella enterica Serovars with Possible Implications for Food Safety. AB - Salmonella is an important foodborne pathogen, whose ability to resist stress and survive can vary among strains. This variability is normally not taken into account when predictions are made about survival in foods with negative consequences. Therefore, we examined the contribution of variable phenotypic properties to survival under stress in 10 Salmonella serovars. One strain (Typhimurium 10) was intentionally RpoS-negative; however, another strain (Heidelberg) showed an rpoS mutation, rendering it inactive. We assessed an array of characteristics (motility, biofilm formation, bile resistance, acid resistance, and colony morphology) that show major variability among strains associated with a 10- to 19-fold difference between the highest and the lowest strain for most characteristics. The RpoS status of isolates did not affect variability in the characteristics, with the exception of resistance to NaCl, acetic acid, lactic acid, and the combination of acetic acid and salt, where the variability between the highest and the lowest strain was reduced to 3.1-fold, 1.7-fold, 2-fold, and 1.7-fold, respectively, showing that variability was significant among RpoS-positive strains. Furthermore, we also found a good correlation between acid resistance and lysine decarboxylase activity, showing its importance for acid resistance, and demonstrated a possible role of RpoS in the lysine decarboxylase activity in Salmonella. PMID- 29271686 TI - Bacteriostatic Effect of Quercetin as an Antibiotic Alternative In Vivo and Its Antibacterial Mechanism In Vitro. AB - Quercetin, a ubiquitous flavonoid, is known to have antibacterial effects. The purpose of this study was to investigate the effect of quercetin on cecal microbiota of Arbor Acre (AA) broiler chickens in vivo and the bacteriostatic effect and antibacterial mechanism of quercetin in vitro. In vivo, 480 AA broilers (1 day old) were randomly allotted to four treatments (negative control and 0.2, 0.4, or 0.6 g of quercetin per kg of diet) for 42 days. Cecal microbial population and distribution were measured at the end of the experiment. The cecal microflora in these broilers included Proteobacteria, Fimicutes, Bacteroidetes, and Deferribacteres. Compared with the negative control, quercetin significantly decreased the copies of Pseudomonas aeruginosa ( P < 0.05), Salmonella enterica serotype Typhimurium ( P < 0.01), Staphylococcus aureus ( P < 0.01), and Escherichia coli ( P < 0.01) but significantly increased the copies of Lactobacillus ( P < 0.01), Bifidobacterium ( P < 0.01), and total bacteria ( P < 0.01). In vitro, we investigated the bacteriostatic effect of quercetin on four kinds of bacteria ( E. coli, P. aeruginosa, S. enterica Typhimurium, and S. aureus) and the antibacterial mechanism of quercetin in E. coli and S. aureus. The bacteriostatic effect of quercetin was stronger on gram-positive bacteria than on gram-negative bacteria. Quercetin damaged the cell walls and membranes of E. coli (at 50 * MIC) and S. aureus (at 10 * MIC). Compared with the control, the activity of the extracellular alkaline phosphatase and beta-galactosidase and concentrations of soluble protein in E. coli and S. aureus were significantly increased (all P < 0.01), and the activity of ATP in S. aureus was significantly increased ( P < 0.01); however, no significant change in ATP activity in E. coli was observed ( P > 0.05). These results suggest that quercetin has potential as an alternative antibiotic feed additive in animal production. PMID- 29271687 TI - Acidification of Model Cheese Brines To Control Listeria monocytogenes. AB - Cheese brines are often used for prolonged periods, with adjustments made only to pH and salt content. Pathogens, including Salmonella enterica Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes, have been shown to survive long periods in model and commercial brines under common brining conditions. The objective of this study was to determine the survival of L. monocytogenes in model cheese brines, with and without whey added at 2%, when acidified to a pH of 2 using food-grade acids. Survival in untreated brines over a 6-month period was also assessed. Cultures of L. monocytogenes were propagated to induce salt and acid tolerance prior to inoculation at ~6 log CFU/mL into model brines (pH 5.2, 20% NaCl). Following a week-long adaption period at 12 degrees C, inoculated brines were acidified to pH 2.0 within 15 min using either hydrochloric, acetic, citric, or lactic acid, held at that pH for up to 24 h, and neutralized prior to enumeration and enrichment. Overall, each acid treatment was capable of achieving >=5-log reductions in L. monocytogenes counts within 135 min at pH 2. Hydrochloric acid required the lowest volume to achieve treatment pH and was the most effective treatment in the absence of whey. However, it was the least effective in the presence of whey. Acetic acid produced rapid inactivation in both brines but required impractical volumes of acid to reach the treatment pH. Citric acid was similarly effective in both brines but was the second least effective in terms of time to achieve a >=5-log reduction. Although only slight and insignificant differences were observed, lactic acid appears to be the more practical and promising approach for the inactivation of L. monocytogenes in cheese brines by producing the most rapid inactivation in the presence and absence of whey. Acidification as a preventive control for L. monocytogenes could increase adoption of brine treatments by small-scale cheese producers, thereby reducing food safety risks. PMID- 29271688 TI - Addressing Career-Related Needs in Adolescent and Young Adult Cancer Survivors: University Career Service Professionals' Experience and Resources. AB - Many adolescent and young adult (AYA) survivors are transitioning not only from patient to survivor but also transitioning to the workforce. AYA survivors report many career-related concerns. Career service professionals are well positioned to provide targeted resources. A survey of 40 career service professionals at colleges and universities in the United States revealed that although they have had experience working with AYA survivors, most do not feel adequately trained or aware of survivors' unique needs. However, they are highly receptive to specific resources for AYA survivors. Maximizing connections between career service professionals and AYA survivors may help address survivors' career-related concerns. PMID- 29271689 TI - Timing of Laparoscopic Cholecystectomy After Mild Biliary Pancreatitis: A Systematic Review and Meta-Analysis. AB - AIM: To compare the safety of cholecystectomy in early laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC). METHODS: We systematically searched PubMed, EMBASE, and Cochrane Library for studies that were published from January 1992 to March 2017. We included studies on patients with mild biliary pancreatitis and that reported the timing of cholecystectomy and the number of complications, readmissions, and conversion to open cholecystectomy. Moreover, we assessed the quality and bias risks of the included studies. RESULTS: After screening 4651 studies, we included 3 randomized clinical trials and 10 retrospective studies. The included studies described 2291 patients, of whom 1141 (49.8%) underwent ELC and 1150 (50.2%) underwent DLC. The reported rate of complications for ELC (6.8%) was lower than that for DLC (13.45%). The reported rate of readmission for ELC was lower than that for DLC. The length of hospital stay was longer with DLC than with ELC. ELC and DLC did not have significantly different rates of conversion to open cholecystectomy and duration of surgery. CONCLUSION: This meta-analysis provides evidence that ELC is better than DLC in many aspects for acute mild pancreatitis patients undergoing laparoscopic cholecystectomy. ELC associated with few complications and readmissions, as well as a short length of hospital stay. PMID- 29271690 TI - Surgical Outcome Analysis of Pneumovesicoscopic Ureteral Reimplantation and Endoscopic Dextranomer/Hyaluronic Acid Injection for Primary Vesicoureteral Reflux in Children: A Multicenter 12-Year Review. AB - OBJECTIVE: Vesicoureteral reflux (VUR) is a common condition associated with childhood urinary tract infection (UTI), which may lead to chronic renal failure and hypertension. Different antireflux approaches were advocated with differences in morbidity and success. The aim of this study is to review and analyze the surgical outcomes of pneumovesicoscopic ureteral reimplantation and endoscopic injection of dextranomer/hyaluronic acid (Dx/HA) in three tertiary centers. MATERIALS AND METHODS: The medical records of 215 patients (159 boys and 56 girls) for a total of 323 ureters underwent surgical interventions for primary VUR from February 2002 to August 2014 were reviewed. Data on baseline demographics, preoperative symptoms, radiological imaging studies, and postoperative outcomes were analyzed. VUR resolution was defined as when no VUR was detected by micturating cystourethrogram at 3 months or later after the intervention. Independent t-test, Mann-Whitney U test, Fisher's Exact test, and Chi-Square test were used for different parameters. All results with P value <=.05 were regarded as statistically significant. RESULTS: The mean age at operation was 3.33 and 4.63 for reimplantation and Dx/HA injection respectively. A total of 234 ureters underwent Dx/HA injection and 92 ureters underwent pneumovesicoscopic ureteral reimplantation with mean preoperative VUR grading of 3.1 and 4.2 respectively (P = .0001). The overall VUR downgrading and resolution rates were both significantly higher in reimplantation than Dx/HA injection (97.8% versus 78.6% P = .0001 and 84.3% versus 65% P = .0011). Further subgroup analyses across the different VUR gradings showed higher downgrading and resolution rates in reimplantation group than Dx/HA injection for grade 4 (100% versus 81% P = .0147 and 82.4% versus 63% P = .0411) and grade 5 VUR (97.3% versus 50% P = .0022 and 81.6% versus 40% P = .0256). Dx/HA injection was associated with shorter operation time (41.5 minutes versus 147.5 minutes, P < .001), less postoperative analgesic usage (P = .049), and shorter hospital stay (1.06 days versus 4.44 days P < .0001). No major complications were identified in both groups. The mean follow-up time was significantly longer in reimplantation group than Dx/HA group (57.25 months versus 37.85 months, P = .002). There was no significant difference in the rate of subsequent UTI development during follow-up (P = .8). CONCLUSIONS: Both Dx/HA injection and pneumovesicoscopic ureteral reimplantation are safe and effective treatments for VUR. Reimplantation is associated with significantly higher VUR downgrading and resolution rates than Dx/HA injection especially in the higher grade VUR while Dx/HA injection has significantly shorter operation time, lower postoperative analgesic usage, and shorter hospital stay. Dx/HA injection can be considered as the first line surgical treatment especially for lower grade VUR. Pneumovesicoscopic ureteral reimplantation can be used for higher grade reflux or those who failed Dx/HA treatments. PMID- 29271691 TI - Third cranial nerve palsy and Chikungunya virus infection. PMID- 29271692 TI - Systematic Mapping of Relationship-Level Protective Factors and Sexual Health Outcomes Among Sexual Minority Youth: The Role of Peers, Parents, Partners, and Providers. AB - Sexual minority youth (SMY) experience elevated rates of adverse sexual health outcomes. Although risk factors driving these outcomes are well studied, less attention has been paid to protective factors that potentially promote health and/or reduce negative effects of risk. Many factors within interpersonal relationships have been identified as protective for the sexual health of adolescents generally. We sought to systematically map the current evidence base of relationship-level protective factors specifically for the sexual health of SMY through a systematic mapping of peer-reviewed observational research. Articles examining at least one association between a relationship-level protective factor and a sexual health outcome in a sample or subsample of SMY were eligible for inclusion. A total of 36 articles reporting findings from 27 data sources met inclusion criteria. Included articles examined characteristics of relationships with peers, parents, romantic/sexual partners, and medical providers. Peer norms about safer sex and behaviorally specific communication with regular romantic/sexual partners were repeatedly protective in cross sectional analyses, suggesting that these factors may be promising intervention targets. Generally, we found some limits to this literature: few types of relationship-level factors were tested, most articles focused on young sexual minority men, and the bulk of the data was cross-sectional. Future work should expand the types of relationship-level factors investigated, strengthen the measurement of relationship-level factors, include young sexual minority women in samples, and use longitudinal designs. Doing so will move the field toward development of empirically sound interventions for SMY that promote protective factors and improve sexual health. PMID- 29271694 TI - Beneficial Effects of Kimchi, a Korean Fermented Vegetable Food, on Pathophysiological Factors Related to Atherosclerosis. AB - Atherosclerosis is a progressive disease that is characterized by accumulation of lipids and fibrous elements in large arteries. Its etiology is involved with pathophysiological factors such as lipoprotein oxidation, inflammation, and dyslipidemia. Kimchi is a Korean fermented vegetable side dish made with vegetables and kimchi condiments. To date, numerous in vitro, in vivo, and human studies have cited the health benefits of kimchi. 3-(4'-Hydroxyl-3',5' dimethoxyphenyl)propionic acid is one of the active compounds of kimchi, and its antioxidant and anti-atherosclerosclerotic effects have been reported. This review presents the laboratory and clinical evidence of the anti-atherosclerotic effects of kimchi based on its lipid-lowering, antioxidant, and anti-inflammatory activities. PMID- 29271693 TI - Integrated flow-through purification for therapeutic monoclonal antibodies processing. AB - An integrated all flow-through technology platform for the purification of therapeutic monoclonal antibodies (mAb), consisting of activated carbon and flow through cation and anion exchange chromatography steps, can replace a conventional chromatography platform. This new platform was observed to have excellent impurity clearance at high mAb loadings with overall mAb yield exceeding 80%. Robust removal of DNA and host cell protein was demonstrated by activated carbon and a new flow-through cation exchange resin exhibited excellent clearance of mAb aggregate with high monomer recoveries. A ten-fold improvement of mAb loading was achieved compared to a traditional cation exchange resin designed for bind and elute mode. High throughput 96-well plate screening was used for process optimization, focusing on mAb loading and solution conditions. Optimum operating windows for integrated flow-through purification are proposed based on performance characteristics. The combination of an all flow-through polishing process presents significant opportunities for improvements in facility utilization and process economics. PMID- 29271695 TI - Erratum. PMID- 29271696 TI - Synergy effects of Polyinosinic-polycytidylic acid, CpG oligodeoxynucleotide, and cationic peptides to adjuvant HPV E7 epitope vaccine through preventive and therapeutic immunization in a TC-1 grafted mouse model. AB - Cross-talk by pattern recognition receptors may facilitate the maturation of dendritic cells and fine tune the immune response. Thus, the inclusion of ligands agonistic to multiple receptors in a vaccine formula may be an effective strategy to elicit robust antitumor cellular immunity. We tested the adjuvant effects and possible synergy of CpG (CpG oligodeoxynucleotide), Poly I:C (polyinosinic polycytidylic acid) and the cationic peptide Cramp (cathelicidin-related antimicrobial peptide) formulated in a DOTAP (1,2-dioleoyl-3-trimethylammonium propane) liposomal HPV E7 epitope vaccine on a TC-1 grafted mouse model. The vaccine formulations were administered both preventively and therapeutically. Based on our results, both CpG and Poly I:C-adjuvanted vaccines abolished tumor development in a preventive trial and significantly suppressed tumor growth in a therapeutic trial. Increased interferon (IFN)-gamma expression and potent memory T cells in splenocytes as well as elevated CD8+IFN-gamma+ cells in both spleen and tumor tissue indicated an elevated E744-62-specific cellular immune response. Although synergistic effects were detected between CpG and Poly I:C, their adjuvant effects were not enhanced further when combined with Cramp. Because the enhancement of tumor antigen-specific cellular immune responses is vital for the clearance of infected and cancerous cells, our results contribute a potential adjuvant combination for cancer vaccines. PMID- 29271697 TI - Loading and firing the brown adipocyte. AB - Brown adipose tissue (BAT) is specialized to both store and expend chemical energy making it an ideal therapeutic target for various metabolic diseases. Fatty acids derived from lipid droplets within brown adipocytes acting on mitochondrial uncoupling protein 1 (UCP1) were long thought to be essential for non-shivering thermogenesis. Here, the roles of white adipose tissue and the liver in the provision of fuel to BAT as part of a coordinated response to temperature and dietary challenges are described. UCP1-independent modes of brown adipocyte heat production are also highlighted. A model that accommodates the findings obtained so far is further presented in which according to the conditions imposed on brown adipocytes, the relative contributions of circulating lipids and glucose for their normal function varies. Gaining deeper insight into the molecular processes which poise brown adipocytes to protect against whole body thermal and energy imbalance represents a promising future area of metabolic research. PMID- 29271698 TI - Macrolide-Resistance Selection in Tibetan Pigs with a High Load of Mycoplasma hyopneumoniae. AB - Currently, tylosin tartrate is the first-line treatment for Mycoplasma hyopneumoniae infections in China. However, the efficacy of tylosin tartrate and resistance to this treatment in M. hyopneumoniae infections of Tibetan pigs are unknown. In this study, we examined the prevalence of M. hyopneumoniae infection in Tibetan pigs at three intensive farms in Tibet, China. In addition, we investigated the efficacy of tylosin tartrate treatment for porcine enzootic pneumonia by monitoring M. hyopneumoniae DNA eradication dynamics and macrolide resistance (MR). Eighty-two of 450 (18.2%) Tibetan pigs tested positive for only M. hyopneumoniae, and most of these animals (85.1%) had symptoms and signs of pneumonia. The elimination of M. hyopneumoniae DNA was substantially faster in Tibetan pigs with a lower pretreatment M. hyopneumoniae load, and the total eradication rate was 97.4% (75/77). Two Tibetan pigs tested positive for M. hyopneumoniae that contained macrolide resistance-determining mutations in the 23S rRNA gene. Our results indicate that the pretreatment M. hyopneumoniae load may be an effective predictor of macrolide treatment efficacy (and possibly that of other antimicrobial agents) and MR. Moreover, our results suggest that danofloxacin mesylate can be used as an alternative drug for the treatment of macrolide-resistant M. hyopneumoniae infection acquired during intensive farming. PMID- 29271700 TI - Association between gaseous air pollution and hospital admissions for hypertension in Taipei, Taiwan. AB - Air pollution exposure has been reported to influence blood pressure. However, only a few epidemiological studies demonstrated association between ambient air pollution exposure and acute hypertensive events. The aim of this study was to examine the association between gaseous air pollutants exposure and hospital admissions for hypertension in Taipei, Taiwan. Data on hospital admissions for hypertension and ambient air pollution in Taipei were obtained for the 2009-2013 period. An odds ratio (OR) for number of hospital admissions for hypertension associated with each interquartile range increase in each gaseous air pollutant was calculated using a case-crossover approach, after controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single pollutant model, significant correlation was observed between number of hospital admissions for hypertension and ozone (O3) levels both on warm (>23 degrees C) and cool (<23 degrees C) days, with OR of 1.2 (95% confidence interval [CI] = 1.03-1.4) and 1.2 (95% CI = 1.02-1.42), respectively. No significant associations were found between levels of other gaseous pollutants and risk of hospital admissions for hypertension. In the two-pollutant model, O3 levels remained significant after inclusion of particulate matter 10 MUm or less in diameter (PM10), sulfur dioxide (SO2), or carbon monoxide (CO) on warm days. On cool days, O3 levels remained significant after inclusion of air pollutants other than SO2. These findings indicated that O3 exposure may trigger a rise in blood pressure to a level that results in higher number of hospital admissions. PMID- 29271701 TI - Red Ginseng Oil Inhibits TPA-Induced Transformation of Skin Epidermal JB6 Cells. AB - Red ginseng oil (RGO) has been shown to possess anti-inflammatory and hepatoprotective activity. In this study, we evaluated the inhibitory effect of RGO on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated neoplastic transformation of JB6 P+ cells. RGO pretreatment abolished the transformation of JB6 P+ cells challenged by TPA. RGO suppressed the transactivation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) transcription factors as well as protein levels of cyclooxygenase-2, cyclin D1, cyclin E, and Bcl-2 in the TPA-treated cells. Additionally, TPA-induced phosphorylations of extracellular signal-regulated kinases, 90 kDa ribosomal S6 kinase 2, c-Jun N-terminal kinases, and glycogen synthase kinase 3beta were downregulated in the presence of RGO. Furthermore, RGO induced the nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidant enzyme heme oxygenase-1 (HO-1) expression, and effectively blocked the overproduction of TPA-induced reactive oxygen species. These results suggest that RGO exerts a potent chemopreventive activity in skin cell model. PMID- 29271702 TI - Identification and Evaluation of Medical Translator Mobile Applications Using an Adapted APPLICATIONS Scoring System. AB - IMPORTANCE: With an increasing number of patients requiring translator services, many providers are turning to mobile applications (apps) for assistance. However, there have been no published reviews of medical translator apps. OBJECTIVE: To identify and evaluate medical translator mobile apps using an adapted APPLICATIONS scoring system. DESIGN: A list of apps was identified from the Apple iTunes and Google Play stores, using the search term, "medical translator." Apps not found on two different searches, not in an English-based platform, not used for translation, or not functional after purchase, were excluded. The remaining apps were evaluated using an adapted APPLICATIONS scoring system, which included both objective and subjective criteria. App comprehensiveness was a weighted score defined by the number of non-English languages included in each app relative to the proportion of non-English speakers in the United States. SETTING: The Apple iTunes and Google Play stores. PARTICIPANTS: Medical translator apps identified using the search term "medical translator." Main Outcomes and Measures: Compilation of medical translator apps for provider usage. RESULTS: A total of 524 apps were initially found. After applying the exclusion criteria, 20 (8.2%) apps from the Google Play store and 26 (9.2%) apps from the Apple iTunes store remained for evaluation. The highest scoring apps, Canopy Medical Translator, Universal Doctor Speaker, and Vocre Translate, scored 13.5 out of 18.7 possible points. CONCLUSIONS AND RELEVANCE: A large proportion of apps initially found did not function as medical translator apps. Using the APPLICATIONS scoring system, we have identified and evaluated medical translator apps for providers who care for non-English speaking patients. PMID- 29271699 TI - Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics. AB - Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided. PMID- 29271703 TI - Frequent Hub-Spoke Contact Is Associated with Improved Spoke Hospital Performance: Results from the Massachusetts General Hospital Telestroke Network. AB - BACKGROUND: For acute ischemic stroke patients, shorter time to thrombolytic (tissue plasminogen activator [tPA]) is associated with improved outcomes. INTRODUCTION: Telestroke increases tPA use at spoke hospitals, yet its effect on door-to-needle (DTN) times for tPA administration is unknown. We hypothesize that spoke hospitals with more frequent contact to a hub hospital will have shorter DTN times than those with less frequent contact. MATERIALS AND METHODS: We identified 375 patients treated with tPA by conventional or telestroke methods in an academic hub-and-spoke telestroke network for whom date and time data were available. Strength of the spoke-hub connection was the primary predictor variable, defined as the number of all telestroke consults (tPA and non-tPA) done at each spoke hospital during the year of the patient's presentation. Patient level regression analyses examined the relationship between DTN time and spoke hub connection during the year of the patient's presentation, controlling for temporal trends and clustering within hospitals. RESULTS: Sixteen spoke hospitals contributed data on 375 tPA-treated patients from 2006-2015. Hospitals treated a median of 13.5 patients with tPA per year; median hospital-level DTN was 78.8 min (interquartile range [IQR] 71.3-85). Median number of telestroke consults per year was 34 (range 3-137). Among all 375 patients, median DTN was 76 min (IQR 60 97). Strength of spoke-hub connection was significantly associated with faster DTN time for patients (1.3 min gain per 10 additional consults, p = 0.048). CONCLUSIONS: More frequent contact between a telestroke spoke and its hub was associated with faster tPA delivery for patients, even after accounting for secular trends in DTN improvements. PMID- 29271705 TI - Telehealth Alerts and Nurse Response. AB - BACKGROUND: Health monitoring within a telehealth program is a strategy to efficiently care for older adults with heart failure (HF). Limited description is identified in the literature for the extent participant submissions trigger an alert or monitoring nurses transfer telehealth alert-range data to the medical record. INTRODUCTION: The aim was to describe the initial 90 days of participant submissions measuring within alert range and nurse response to alerts with documentation to the medical record. MATERIALS AND METHODS: Review of telehealth and medical records of 187 older veterans with HF participating at one Veterans Administration Care Coordination Home Telehealth program led to reporting the proportion of participant telehealth submissions measuring within alert range and nurse response to alert-range data. RESULTS: Less than 2.5% of self-rated health status and nearly one-quarter of physiologic submissions measured within alert range. Timely nurse response averaged 28.7% and increased when submissions for vital signs, weight, or medication alerted for consecutive days. Neither alert nor nurse response data were significantly associated with characteristic measures. DISCUSSION: Clinical relevance of alert-range telehealth data is uncertain partly due to frequent alerts triggered by physiologic submissions, few health status changes noted by the participant or the monitoring nurse, and the nonsignificant association between the proportion of alerts or nurse response, respectively, with demographic or clinical baseline measures. CONCLUSIONS: Future studies are needed to identify telehealth program measures that decrease alerting data not associated with clinical worsening and increase recognition-of-change in HF health status by the participant and monitoring nurse. PMID- 29271704 TI - Incidental finding of an absent left common carotid artery. AB - We describe a case of a young woman evaluated for Raynaud's phenomenon in whom an extremely rare variation, the absence of the left common carotid artery, was incidentally detected as an isolated finding. The detection of vascular anomalies may be important for future endovascular or surgical interventions. PMID- 29271706 TI - Belo Horizonte Telehealth: Incorporation of Teleconsultations in a Health Primary Care System. AB - INTRODUCTION: The Belo Horizonte Telehealth program, a pioneer in telemedicine within the Brazilian National Health System (Sistema Unico de Sauude in Portuguese), was implemented by the Belo Horizonte City Health Department (SMSA BH) in 2004. The purpose of the present study is to analyze opinions on the obstacles, difficulties, and suggestions on the use of teleconsultations. METHODS: Semi-structured interviews were conducted among primary healthcare professionals and health managers. Content analysis for the latter was carried out using NVIVO(r) software to categorize responses. Simple descriptive quantitative aspects were analyzed to verify the use of the system over the years by the primary care unit (PCU) professionals. RESULTS: The difficulties encountered were related to the use of the system, inadequate response to teleconsultation requests, infrastructure problems, lack of practicality for the use of the program, difficulty in incorporating the program into the organizational culture, and lack of managerial support. Changes in management organization over the years have interfered with the use of the teleconsultation system. The most requested specialties were neurology, cardiology, endocrinology, and angiology. DISCUSSION: The main suggestions for increasing the number of teleconsultations requests included dissemination of information and prioritization by the management; improvement of the infrastructure; organization of the time and the agenda of the PCU professional; training the professionals for its use; and preconditioning the referrals to secondary level care to a previous teleconsultation. CONCLUSION: Teleconsultations need to be incorporated in the daily routine of PCUs by both managers and health professionals to assure its usage and improve the quality of care. PMID- 29271708 TI - Letter to the Editor. Brain herniation with surrounding CSF into the skull. PMID- 29271707 TI - Epidermoid cysts of the cavernous sinus: clinical features, surgical outcomes, and literature review. AB - OBJECTIVE: Epidermoid cysts of the cavernous sinus (CS) are rare, and no large case series of these lesions has been reported. In this study, the authors retrospectively reviewed the outcomes of the surgical management of CS epidermoid cysts undertaken at their center and performed a review of any such cysts reported in the literature over the past 40 years. METHODS: Clinical data were obtained on 31 patients with CS epidermoid cysts that had been surgically treated at the authors' hospital between 2001 and 2016. The patients' medical records, imaging data, and follow-up outcomes were retrospectively analyzed. The related literature from the past 40 years (18 articles, 20 patients) was also evaluated. RESULTS: The most common chief complaints were facial numbness or hypesthesia (64.5%), absent corneal reflex (45.2%), and abducens or oculomotor nerve deficit (35.5%). On MRI, 51.6% of the epidermoid cysts showed low T1 signals and equal or high T2 signals. In the other lesions, the radiological findings varied considerably given differences in the composition of the cysts. Surgery was performed via the extradural approach (58.1%), intradural approach (32.3%), or a combined approach (9.7%). After the operation, symptoms remained similar or improved in 90.3% of patients and new oculomotor paralysis developed after the operation in 9.7% of patients. Seven patients (22.6%) developed meningitis postoperatively (5 aseptic and 2 septic), and all of them recovered. All patients achieved good recovery before discharge (Karnofsky Performance Status score >= 70). Over an average follow-up of 4.6 +/- 3.0 years in 25 patients (80.6%), no recurrence or reoperation occurred, regardless of whether total or subtotal resection of the capsule had been achieved. CONCLUSIONS: Both the extradural and intradural approaches can enable satisfactory lesion resection. A favorable prognosis and symptomatic improvement can be expected after both total and subtotal capsule resections. Total capsule resection is encouraged to minimize the possibility of recurrence provided that the resection can be safely performed. PMID- 29271709 TI - Outcomes following cerebrospinal fluid shunting in high-grade glioma patients. AB - OBJECTIVE: The clinical course of high-grade central nervous system gliomas is occasionally complicated by hydrocephalus. The risks of shunt placement and clinical outcome following CSF diversion in this population are not well defined. METHODS: The authors retrospectively reviewed the outcomes of patients with pathologically confirmed WHO grade III or IV gliomas with shunt-treated hydrocephalus at their institution. Outcomes of patients in this cohort were compared with those of patients who underwent shunt treatment for normal pressure hydrocephalus (NPH). Hospital-reported outcomes in a national database for malignant primary brain tumor patients undergoing a ventricular shunt procedure were also reviewed. RESULTS: Forty-one patients undergoing CSF shunting between 2001 and 2016 at the authors' institution were identified. Noncommunicating and communicating hydrocephalus occurred at similar rates (51.2% vs 48.8%). Symptomatic improvement after shunting was observed in 75.0% of patients. A major complication occurred in 17.1% of cases, with 2 patients suffering an intracranial hemorrhage. Prior administration of bevacizumab was significantly associated with the incidence of hemorrhage (p = 0.026). Three patients (7.3%) died during admission, and 8 (19.5%) died within 30 days of shunt placement. The presence of ependymal or leptomeningeal enhancement was more common in patients who died within 30 days (75.0% vs 11.1%, p = 0.001). Six patients (18.1%) required readmission to the hospital within 30 days of discharge. Revision surgery was necessary in 7 patients (17.1%). The median time from shunt placement to death was 150.5 days. In comparison with patients with NPH, shunt-treated high grade glioma patients had increased in-hospital (7.3% vs 0.5%, p = 0.008) and 30 day (19.5% vs 0.8%, p < 0.001) mortality but no difference in the incidence of revision surgery (17.1% vs 17.5%, p = 0.947). Similarly, in the national Vizient Clinical Database Resource Manager, shunt-treated patients with malignant primary brain tumors had an increased length of stay (6.9 vs 3.5 days, p < 0.001), direct cost of admission ($15,755.80 vs $9871.50, p < 0.001), and 30-day readmission rates (20.6% vs 2.4%, p < 0.001) compared with patients without brain tumors who received a shunt for NPH. CONCLUSIONS: Shunting can be an effective treatment for the symptoms of hydrocephalus in patients with high-grade gliomas. However, the authors' results suggest that this procedure carries a significant risk of complications in this patient population. PMID- 29271710 TI - Microsurgical anatomy of the central core of the brain. AB - OBJECTIVE The purpose of this study was to describe in detail the cortical and subcortical anatomy of the central core of the brain, defining its limits, with particular attention to the topography and relationships of the thalamus, basal ganglia, and related white matter pathways and vessels. METHODS The authors studied 19 cerebral hemispheres. The vascular systems of all of the specimens were injected with colored silicone, and the specimens were then frozen for at least 1 month to facilitate identification of individual fiber tracts. The dissections were performed in a stepwise manner, locating each gray matter nucleus and white matter pathway at different depths inside the central core. The course of fiber pathways was also noted in relation to the insular limiting sulci. RESULTS The insular surface is the most superficial aspect of the central core and is divided by a central sulcus into an anterior portion, usually containing 3 short gyri, and a posterior portion, with 2 long gyri. It is bounded by the anterior limiting sulcus, the superior limiting sulcus, and the inferior limiting sulcus. The extreme capsule is directly underneath the insular surface and is composed of short association fibers that extend toward all the opercula. The claustrum lies deep to the extreme capsule, and the external capsule is found medial to it. Three fiber pathways contribute to form both the extreme and external capsules, and they lie in a sequential anteroposterior disposition: the uncinate fascicle, the inferior fronto-occipital fascicle, and claustrocortical fibers. The putamen and the globus pallidus are between the external capsule, laterally, and the internal capsule, medially. The internal capsule is present medial to almost all insular limiting sulci and most of the insular surface, but not to their most anteroinferior portions. This anteroinferior portion of the central core has a more complex anatomy and is distinguished in this paper as the "anterior perforated substance region." The caudate nucleus and thalamus lie medial to the internal capsule, as the most medial structures of the central core. While the anterior half of the central core is related to the head of the caudate nucleus, the posterior half is related to the thalamus, and hence to each associated portion of the internal capsule between these structures and the insular surface. The central core stands on top of the brainstem. The brainstem and central core are connected by several white matter pathways and are not separated from each other by any natural division. The authors propose a subdivision of the central core into quadrants and describe each in detail. The functional importance of each structure is highlighted, and surgical approaches are suggested for each quadrant of the central core. CONCLUSIONS As a general rule, the internal capsule and its vascularization should be seen as a parasagittal barrier with great functional importance. This is of particular importance in choosing surgical approaches within this region. PMID- 29271711 TI - Iatrogenic seeding of skull base chordoma following endoscopic endonasal surgery. AB - OBJECTIVE: Iatrogenic tumor seeding after open surgery for chordoma has been well described in the literature. The incidence and particularities related to endoscopic endonasal surgery (EES) have not been defined. METHODS: The authors retrospectively reviewed their experience with EES for clival chordoma, focusing on cases with iatrogenic seeding. The clinical, radiographic, pathological, and molecular characterization data were reviewed. RESULTS: Among 173 EESs performed for clival chordomas at the authors' institution between April 2003 and May 2016, 2 cases complicated by iatrogenic seeding (incidence 1.15%) were identified. The first case was a 10-year-old boy, who presented 21 months after an EES for a multiply recurrent clival chordoma with a recurrence along the left inferior turbinate, distinct from a right petrous apex recurrence. Both appeared as a T2 hypertintense, T1-isointense, and heterogeneously enhancing lesion on MRI. Resection of the inferior turbinate recurrence and debulking of the petrous recurrence were both performed via a purely endoscopic endonasal approach. Unfortunately, the child died 2 years later due progression of disease at the primary site, but with no sign of progression at the seeded site. The second patient was a 79-year-old man with an MRI-incompatible pacemaker who presented 19 months after EES for his clival chordoma with a mass involving the floor of the left nasal cavity that was causing an oro-antral fistula. On CT imaging, this appeared as a homogeneously contrast-enhancing mass eroding the hard palate inferiorly, the nasal septum superiorly, and the nasal process of the maxilla, with extension into the subcutaneous tissue. This was also treated endoscopically (combined transnasal-transoral approach) with resection of the mass, and repair of the fistula by using a palatal and left lateral wall rotational flap. Adjuvant hypofractionated stereotactic CyberKnife radiotherapy was administered using 35 Gy in 5 fractions. No recurrence was appreciated endoscopically or on imaging at the patient's last follow-up, 12 months after this last procedure. In both cases, pathological investigation of the original tumors revealed a fairly aggressive biology with 1p36 deletions, and high Ki-67 levels (10%-15%, and > 20%, respectively). The procedures were performed by a team of right-handed surgeons (otolaryngology and neurosurgery), using a 4-handed technique (in which the endoscope and suction are typically passed through the right nostril, and other instruments are passed through the left nostril without visualization). CONCLUSIONS: Although uncommon, iatrogenic seeding occurs during EES for clival chordomas, probably because of decreased visualization during tumor removal combined with mucosal trauma and exposure of subepithelial elements (either inadvertently or because of mucosal flaps). In addition, tumors with more aggressive biology (1p36 deletions, elevated Ki-67, or both) are probably at a higher risk and require increased vigilance on surveillance imaging and endoscopy. Further prospective studies are warranted to evaluate the authors' proposed strategies for decreasing the incidence of iatrogenic seeding after EES for chordomas. PMID- 29271712 TI - Sir Sydney Sunderland and the Sunderland Society. AB - In this historical vignette the relevant aspects of the life of the exceptional neuroscientist Sir Sydney Sunderland and of the foundation and development of the Sunderland Society are presented. The relationship of Sir Sydney with the Society is also emphasized. PMID- 29271713 TI - Disconnection of the pathological connectome for multifocal epilepsy surgery. AB - OBJECTIVE Recent neuroimaging studies suggest that intractable epilepsy involves pathological functional networks as well as strong epileptogenic foci. Combining cortico-cortical evoked potential (CCEP) recording and tractography is a useful strategy for mapping functional connectivity in normal and pathological networks. In this study, the authors sought to demonstrate the efficacy of preoperative combined CCEP recording, high gamma activity (HGA) mapping, and tractography for surgical planning, and of intraoperative CCEP measures for confirmation of selective pathological network disconnection. METHODS The authors treated 4 cases of intractable epilepsy. Diffusion tensor imaging-based tractography data were acquired before the first surgery for subdural grid implantation. HGA and CCEP investigations were done after the first surgery, before the second surgery was performed to resect epileptogenic foci, with continuous CCEP monitoring during resection. RESULTS All 4 patients in this report had measurable pathological CCEPs. The mean negative peak-1 latency of normal CCEPs related to language functions was 22.2 +/- 3.5 msec, whereas pathological CCEP latencies varied between 18.1 and 22.4 msec. Pathological CCEPs diminished after complete disconnection in all cases. At last follow-up, all of the patients were in long term postoperative seizure-free status, although 1 patient still suffered from visual aura every other month. CONCLUSIONS Combined CCEP measurement, HGA mapping, and tractography greatly facilitated targeted disconnection of pathological networks in this study. Although CCEP recording requires technical expertise, it allows for assessment of pathological network involvement in intractable epilepsy and may improve seizure outcome. PMID- 29271714 TI - A propensity score analysis of the impact of surgical intervention on unexpected 30-day readmission following admission for subdural hematoma. AB - OBJECTIVE: Subdural hematoma (SDH) is a common disease that is increasingly being managed nonoperatively. The all-cause readmission rate for SDH has not previously been described. This study seeks to describe the incidence of unexpected 30-day readmission in a cohort of patients admitted to an academic neurosurgical center. Additionally, the relationship between operative management, clinical outcome, and unexpected readmission is explored. METHODS: This is an observational study of 200 consecutive adult patients with SDH admitted to the neurosurgical ICU of an academic medical center. Demographic information, clinical characteristics, and treatment strategies were compared between readmitted and nonreadmitted patients. Multivariable logistic regression, weighted by the inverse probability of receiving surgery using propensity scores, was used to evaluate the association between operative management and unexpected readmission. RESULTS: Of 200 total patients, 18 (9%) died during hospitalization and were not included in the analysis. Overall, 48 patients (26%) were unexpectedly readmitted within 30 days. Sixteen patients (33.3%) underwent SDH evacuation during their readmission. Factors significantly associated with unexpected readmission were nonoperative management (72.9% vs 54.5%, p = 0.03) and female sex (50.0% vs 32.1%, p = 0.03). In logistic regression analysis weighted by the inverse probability of treatment and including likely confounders, surgical management was not associated with likelihood of a good outcome at hospital discharge, but was associated with significantly reduced odds of unexpected readmission (OR 0.19, 95% CI 0.08-0.49). CONCLUSIONS: Over 25% of SDH patients admitted to an academic neurosurgical ICU were unexpectedly readmitted within 30 days. Nonoperative management does not affect outcome at hospital discharge but is significantly associated with readmission, even when accounting for the probability of treatment by propensity score weighted logistic regression. Additional research is needed to validate these results and to further characterize the impact of nonoperative management on long-term costs and clinical outcomes. PMID- 29271715 TI - Microsurgical resection of brain arteriovenous malformations in the elderly: outcomes analysis and risk stratification. AB - OBJECTIVE Few outcomes studies have been published on microsurgical resection of arteriovenous malformations (AVMs) in elderly patients, and most are limited by a small sample size and the heterogeneous application of treatment modalities. This study aimed to determine whether functional outcomes at last follow-up (LFU) in patients 60 years or older differed when stratified by age. METHODS Patients 60 years or older (n = 104) who had undergone microsurgical AVM resection (total, n = 72; 60-65 years, n = 35; and > 65 years, n = 37) or observation (n = 32) were identified from a prospective database. Age, sex, Spetzler-Martin (SM) grade, supplemented SM grade, clinical presentation, AVM location, AVM-associated aneurysms, and functional outcome measured using the modified Rankin Scale (mRS score 0-2 [favorable] vs mRS score > 2 [unfavorable]) at LFU were analyzed. RESULTS AVM patients undergoing microsurgical resection were younger, had lower AVM grades, and were more likely to present with rupture. Overall outcome in the surgical group was favorable in 71% of the patients and was statistically significantly better in patients 60-65 years old (p = 0.039). In patients older than 65 years, outcome was dependent on SM grade and level of preexisting functional dependence. Patients with supplemented SM grades of greater than 6 points had favorable outcomes that were age dependent (p = 0.029). This difference was not observed in patients with lower supplemented SM grades or in those with low or high preoperative SM grades (SM grade <= 2 and grade >= 4, respectively). CONCLUSIONS This study demonstrates that favorable outcomes can be achieved with microsurgical resection of AVMs in elderly patients, with careful patient selection. Outcomes in more elderly patients (> 65 years of age) are more dependent on preoperative SM and supplemented SM grading than those in younger cohorts. PMID- 29271717 TI - Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: comparing results of the VerifyNow P2Y12 assay to thromboelastography with platelet mapping. AB - OBJECTIVE Inhibition of platelet aggregation is vital to preventing thromboembolic complications related to stent placement in endovascular neurosurgery, but excessive inhibition potentiates hemorrhagic complications. Recent evidence suggests an ideal inhibition range of 70-150 P2Y12 response units (PRU) as measured on the VerifyNow assay, which relies on photometric measurements of platelet aggregation. Thromboelastography (TEG) with platelet mapping (PM) is an alternative assay that directly measures clot formation and mechanical strength. This study compares the results of PRU to TEG-PM. METHODS Patients with simultaneous or near-simultaneous PRU and TEG-PM results who underwent cervical carotid artery stenting, intracranial stent-assisted aneurysm coiling, or flow diversion at the authors' institution between August 2015 and November 2016 were identified. PRU results were compared with the TEG maximal amplitude (MA) attributable to adenosine diphosphate (ADP) activity (MA-ADP) as measured by TEG-PM. Platelet inhibition was considered therapeutic for MA-ADP values < 50 mm or PRU < 194. The Pearson correlation coefficient was calculated, and the sensitivity and specificity of PRU were calculated assuming that the results of TEG-PM reflected the true degree of platelet inhibition. RESULTS Twenty-three patients were identified with a total of 37 matched sets of TEG-PM and PRU. Three of these pairs were excluded due to anemia outside of the PRU manufacturer's recommended range. The Pearson correlation coefficient for these values was 0.50 (p = 0.0026). The prevalence of clopidogrel nonresponders determined by TEG-PM (9%) matched reported rates (5%-12%); PRU demonstrated much higher prevalence (39%). For detecting a therapeutic level of platelet inhibition, PRU demonstrated a sensitivity of 0.59, specificity of 0.50, positive predictive value of 0.95, and negative predictive value of 0.07. Ideal inhibition was concordant in only 25% of observations in which at least one of the results was ideal. CONCLUSIONS Agreement between TEG-PM and PRU regarding the degree of platelet inhibition is poor. PRU likely overestimates clopidogrel resistance, as 93% of patients with PRU > 194 demonstrate a therapeutic level of platelet inhibition on TEG. PMID- 29271716 TI - Dynamics of postoperative serum cortisol after transsphenoidal surgery for Cushing's disease: implications for immediate reoperation and remission. AB - OBJECTIVE Successful transsphenoidal surgery for adrenocorticotropin hormone (ACTH)-producing pituitary tumors is associated with subnormal postoperative serum cortisol levels, which may guide decisions regarding immediate reoperation. However, little is known about the detailed temporal course of changes in serum cortisol in the immediate postoperative period, and the relationship of postoperative cortisol dynamics to remission and late recurrence. METHODS A single-center retrospective cohort analysis was performed for all patients undergoing pituitary surgery from 2007 through 2015. Standardized diagnostic and treatment algorithms were applied to all patients with potential Cushing's disease (CD), including microsurgical transsphenoidal adenomectomy (TSA) by a single surgeon. All patients had serum cortisol levels drawn at 6-hour intervals for 72 hours after surgery, and were offered reoperation within 3 days for normal or supranormal postoperative cortisol levels. Primary outcomes were 6-month remission and late recurrence; secondary outcomes were persistent postoperative hypocortisolism and surgical morbidity. Discriminatory levels of postoperative serum cortisol for predicting remission were calculated at various intervals after surgery using receiver operating characteristic (ROC) curves. RESULTS Among 89 patients diagnosed with CD, 81 underwent initial TSA for a potentially curable lesion; 23 patients (25.8%) underwent an immediate second TSA. For the entire cohort, 6-month remission was achieved in 77.8% and late recurrences occurred in 9.5%, at a mean of 43.5 months. Compared with patients with a single surgery, those with an immediate second TSA had similar rates of remission (78.3% vs 77.6%) and late recurrence (5.6% vs 11.1%). The rate of hypocortisolism for patients with 2 surgeries (12/23, 52.2%) was significantly greater than that for patients with single surgeries (13/58, 22.4%; p < 0.001). There was no difference in the incidence of CSF leaks between the first and second operations. Remission was achieved in 58 (92.1%) of 64 patients who completed the 2-surgery protocol. The temporal course of postoperative serum cortisol levels among patients varied considerably, with subnormal nadir levels < 2 MUg/dl occurring between 12 hours and 66 hours. Patients achieving remission had significantly lower mean serum cortisol levels at every time point after surgery (p < 0.01). By ROC curve analysis, nadir cortisol levels < 2.1 MUg/dl were predictive of 6-month remission for the entire cohort over 3 days (positive predictive value [PPV] = 94%); discriminating cortisol levels for predicting remission on postoperative day (POD) 2 were < 5.4 MUg/dl (PPV = 97%), although patients with remission after postoperative cortisol levels of 2-5 MUg/dl had a significantly higher rate of late recurrence. CONCLUSIONS There is substantial variation in the temporal course of serum cortisol levels over the first 72 hours after TSA for CD, with nadir levels predictive for remission occurring as late as POD 3. Although a cortisol level of 2.1 MUg/dl at any point was an accurate predictor of 6-month remission, levels less than 5.4 MUg/dl on POD 2 were reasonably accurate. These data may enable decisions regarding the efficacy of an immediate second surgical procedure performed during the same hospitalization; immediate reoperation is associated with excellent remission rates and low recurrence rates in patients otherwise unlikely to achieve remission, but carries a higher risk of permanent hypocortisolism. PMID- 29271718 TI - Revascularization of the anterior cerebral artery by Y-shaped superficial temporal artery interposition graft for the treatment of a de novo aneurysm arising at the site of A3-A3 bypass: technical case report. AB - The most frequently used option to reconstruct the anterior cerebral artery (ACA) is an ACA-ACA side-to-side anastomosis. The long-term outcome and complications of this technique are unclear. The authors report a case of a de novo aneurysm arising at the site of A3-A3 anastomosis. A 53-year-old woman underwent A3-A3 side-to-side anastomosis for the treatment of a ruptured right A2 dissecting aneurysm. At 44 months after surgery, a de novo aneurysm developed at the site of anastomosis. The aneurysm developed in the front wall of the anastomosis site, and projected to the anterosuperior direction. A computational fluid dynamics (CFD) study showed the localized region with high wall shear stress coincident with the pulsation in the front wall of the anastomosis site, where the aneurysm developed. A Y-shaped superficial temporal artery (STA) interposition graft was used successfully to reconstruct both ACAs, and then the aneurysm was trapped. To the authors' knowledge, this is the first case of a de novo aneurysm that developed at the site of an ACA-ACA side-to-side anastomosis. A CFD study showed that hemodynamic stress might be an underlying cause of the aneurysm formation. A Y-shaped STA interposition graft is a useful option to treat this aneurysm. Long term follow-up is necessary to detect this rare complication after ACA-ACA anastomosis. PMID- 29271719 TI - Letter to the Editor. Function outcome related to aggressive surgery for meningioma? PMID- 29271720 TI - Relapses in three patients with Takayasu arteritis under tocilizumab treatment detected by contrast enhanced ultrasound. AB - Takayasu arteritis (TA) is a rare large vessel vasculitis, affecting the aorta and its major branches, typically in young women. In this case report, we present three cases of young women of Caucasian descent who experienced relapses while under treatment with the monoclonal humanized antibody to the interleukin 6 receptor, tocilizumab. Active vasculitic lesions of the supraaortic (common carotid and axillary) arteries were detected and characterized via high resolution contrast enhanced ultrasound. Based on these cases, we discuss the potential role of contrast enhanced ultrasound in the diagnosis and follow-up of TA as well as the current data on the efficacy of tocilizumab in the treatment of TA. PMID- 29271722 TI - Telemedicine in Pediatric Gastroenterology: An Overview of Utility. AB - BACKGROUND: The availability of pediatric subspecialty services is a problem evident throughout the United States. Access to pediatric gastroenterology services, especially in rural areas, can be scarce. Telemedicine has been proposed as a tool capable of decreasing healthcare costs while extending medical care. OBJECTIVE: The purpose of this article is to review available literature regarding the utility of telemedicine as it applies to pediatric gastroenterology, specifically its role in eliminating healthcare disparities. METHODS: Research articles were identified through a PubMed search with key words focusing on telemedicine initiatives in pediatric gastroenterology, pediatric subspecialty, rural pediatric care, and adult gastroenterology. Studies were categorized based on the following areas of application: financial, time management, communication/community, and patient health and satisfaction. RESULTS: We reached the conclusion that evidence-supported trends in available literature provide a framework for pediatric gastroenterology telemedicine initiatives that can provide resource-sparing, community-enriching, and physician improving services that ultimately serve to better patient health. PMID- 29271721 TI - SlWRKY45, nematode-responsive tomato WRKY gene, enhances susceptibility to the root knot nematode; M. javanica infection. AB - The fluctuation of tomato's WRKY defense regulators during infection by the root knot nematode Meloidogyne javanica was analyzed: and the spatial and temporal expression of SlWRKY45 was studied in depth with regard to its response to nematode infection, phytohormones, and wounding. Expression of WRKY45 increased substantially within 5 d upon infection and continued through feeding-site development and gall maturation. Histological analysis of nematode feeding sites indicated that WRKY45 was highly expressed within the feeding cells and associated vascular parenchyma cells. Responses of SlWRKY45 promoters to several phytohormones showed that WRKY45 was highly induced by specific phytohormones, including cytokinin, auxin, and the defense-signaling molecule salicylic acid (SA), but not by the jasmonates. Overexpressing tomato lines were generated, and infection tests showed that, significantly, roots over-expressing SlWRKY45 contained substantially increased number of females, indicating that WRKY45 overexpression supported faster nematode development. qRT-PCR tests have shown roots overexpressing WRKY45 suppressed the jasmonic acid and salicylic acid marker genes, proteinase inhibitor (PI), and pathogenesis related protein (PR1), respectively, and also the cytokinin response factors CRF1 and CRF6. Overall, this study indicated SlWRKY45 to be a potential transcription factor whose manipulation by the invading nematode might be critical for coordination of hormone signals supporting favorable condition for nematode development in root tissue. PMID- 29271723 TI - Repair of giant postlaminectomy pseudomeningocele with fast-resorbing polymer mesh: technical report of 2 cases. AB - Pseudomeningocele is a rare but well-known complication of lumbar spine surgery, which arises in 0.068%-0.1% of individuals in large series of patients undergoing laminectomy and in up to 2% of patients with postlaminectomy symptoms. In symptomatic pseudomeningoceles, surgical reexploration and repair of the dural defect are typically necessary. Whereas the goals of pseudomeningocele repair, which are extirpation of the pseudomeningocele cavity and elimination of extradural dead space, can typically be achieved by primary closure performed using nonabsorbable sutures, giant pseudomeningoceles (> 8 cm) can require more elaborate repair in which fibrin glues, dural substitute, myofascial flaps, or all of the above are used. The authors present 2 cases of postsurgical symptomatic giant pseudomeningoceles that were repaired using a fast-resorbing polymer mesh-supported reconstruction technique, which is described here for the first time. PMID- 29271724 TI - Evaluation of predictive factors of vertebral compression fracture after conventional palliative radiotherapy for spinal metastasis from colorectal cancer. AB - OBJECTIVE Delayed consequences of spinal radiotherapy (RT), including vertebral compression fracture (VCF), are critical complications. However, the predisposing factors that contribute to VCF after conventional RT are unclear. The aim of this study was to assess the incidence of VCF and to determine the predictors of VCF following conventional spinal RT specific to colorectal cancer (CRC). METHODS The authors retrospectively reviewed 237 spinal segments (147 metastatic and 90 nonmetastatic) in 53 patients with CRC who underwent RT with a median total dose of 30 Gy in 10 fractions between January 2007 and December 2014. The primary end point was the development of a VCF following RT, either de novo VCF or the progression of a baseline VCF. VCFs were assessed using the spinal instability neoplastic score (SINS) criteria. RESULTS Among all 237 spinal segments, 22 VCFs (9.3%) were observed following RT, including 13 de novo and 9 progressive fractures, and the median time to VCF was 4 months. All VCFs developed in metastatic spines. Among 147 metastatic spinal segments, 22 fractures were observed, with a 12-month cumulative incidence of VCF of 14.8%. Results of multivariable analysis indicated sex (p = 0.023) and SINS class II/III (p < 0.001) as risk factors related to development of a VCF in metastatic spinal segments. Among the SINS criteria, a lytic tumor and the presence of a baseline VCF were identified as predictors of VCF in metastatic spinal segments. CONCLUSIONS In osteolytic or mixed lesions that were predominant in spinal metastases of CRC, the incidence of VCF was not negligible, even in patients treated with conventional spinal RT. This was especially evident in patients with spinal metastases with a SINS score >= 7. Presence of a baseline VCF after spinal RT is a predictor of VCF development and should be observed carefully. PMID- 29271725 TI - Letter to the Editor. Optimal entry point for C-1 lateral mass screw placement. PMID- 29271726 TI - Bundled payment reimbursement for anterior and posterior approaches for cervical spondylotic myelopathy: an analysis of private payer and Medicare databases. AB - OBJECTIVE Cervical spondylotic myelopathy (CSM) is a progressive spinal condition that often requires surgery. Studies have shown the clinical equivalency of anterior versus posterior approaches for CSM surgery. The purpose of this study was to determine the amount and type of resources used for anterior and posterior surgical treatment of CSM by using large national databases of clinical and financial information from patients. METHODS This study consists of 2 large cohorts of patients who underwent either an anterior or posterior approach for treatment of CSM. These patients were selected from the Medicare 5% National Sample Administrative Database (SAF5) and the Humana orthopedic database (HORTHO), which is a database of patients with private payer health insurance. The outcome measures were the cost of a 90-day episode of care, as well as a breakdown of the cost components for each surgical procedure between 2005 and 2014. RESULTS A total of 16,444 patients were included in this analysis. In HORTHO, there were 10,332 and 1556 patients treated with an anterior or posterior approach for CSM, respectively. In SAF5, there were 3851 and 705 patients who were treated by an anterior or posterior approach for CSM, respectively. The mean +/- SD reimbursements for anterior and posterior approaches in the HORTHO database were $20,863 +/- $2014 and $23,813 +/- $4258, respectively (p = 0.048). The mean +/- SD reimbursements for anterior and posterior approaches in the SAF5 database were $18,219 +/- $1053 and $25,598 +/- $1686, respectively (p < 0.0001). There were also significantly higher reimbursements for a rehabilitation/skilled nursing facility and hospital/inpatient care for patients who underwent a posterior approach in both the private payer and Medicare databases. In all cohorts in this study, the hospital-related reimbursement was more than double the surgeon-related reimbursement. CONCLUSIONS This study provides resource utilization information for a 90-day episode of care for both anterior and posterior approaches for CSM surgery. There is a statistically significant higher resource utilization for patients undergoing the posterior approach for CSM, which is consistent with the literature. Understanding the reimbursement patterns for anterior versus posterior approaches for CSM will help providers design a bundled payment for patients requiring surgery for CSM, and this study suggests that a subset of patients who require the posterior approach for treatment also require greater resources. The data also suggest that hospital-related reimbursement is the major driver of payments. PMID- 29271727 TI - Stabilization of a thoracolumbar flexion-distraction injury utilizing a temporary interspinous process construct: technical note. AB - Many techniques for fixation in the thoracolumbar spine have been described. Occasionally, particularly during operative management of unstable ligamentous or bony injuries, temporizing fixation may be required. The authors report the case of a patient with a ligamentous thoracolumbar flexion-distraction injury who underwent reduction, posterior instrumentation and fusion, and temporary fixation of the destabilized segment utilizing a novel interspinous process screw/rod construct. This construct was stable after placement and allowed for traditional instrumentation to be placed without causing secondary injury to the spinal cord. To the authors' knowledge, this technique has not previously been described. PMID- 29271728 TI - Percentage change in hemoglobin level and morbidity in spine surgery patients. AB - OBJECTIVE The aim of this study was to characterize the association between percentage change in hemoglobin (DeltaHb)-i.e., the difference between preoperative Hb and in-hospital nadir Hb concentration-and perioperative adverse events among spine surgery patients. METHODS Patients who underwent spine surgery at the authors' institution between December 4, 2008, and June 26, 2015, were eligible for this retrospective study. Patients who underwent the following procedures were included: atlantoaxial fusion, subaxial anterior cervical fusion, subaxial posterior cervical fusion, anterior lumbar fusion, posterior lumbar fusion, lateral lumbar fusion, excision of intervertebral disc, and excision of spinal cord lesion. Data on intraoperative transfusion were obtained from an automated, prospectively collected, anesthesia data management system. Data on postoperative hospital transfusions were obtained through an Internet-based intelligence portal. Percentage DeltaHb was defined as: ([preoperative Hb - nadir Hb]/preoperative Hb) * 100. Clinical outcomes included in-hospital morbidity and length of stay associated with percentage DeltaHb. RESULTS A total of 3949 patients who underwent spine surgery were identified. Of these, 1204 patients (30.5%) received at least 1 unit of packed red blood cells. The median nadir Hb level was 10.6 g/dl (interquartile range 8.7-12.4 g/dl), yielding a mean percentage DeltaHb of 23.6% (SD 15.4%). Perioperative complications occurred in 234 patients (5.9%) and were more common in patients with a larger percentage DeltaHb (p = 0.017). Hospital-related infection, which occurred in 60 patients (1.5%), was also more common in patients with greater percentage DeltaHb (p = 0.001). CONCLUSIONS Percentage DeltaHb is independently associated with a higher risk of developing any perioperative complication and hospital-related infection. The authors' results suggest that percentage DeltaHb may be a useful measure for identifying patients at risk for adverse perioperative events. PMID- 29271729 TI - Surgical treatment of thalamic tumors in children. AB - OBJECTIVE In the past, the outcome of surgical treatment for thalamic tumor was poor. These lesions were often considered inoperable. However, contemporary microsurgical techniques, together with improvements in neuroimaging that enable accurate presurgical planning, allow resection to be accomplished in a safer way. METHODS The medical records, imaging studies, and operative and pathology reports obtained for pediatric patients who were treated for thalamic tumors at the authors' department were reviewed. Neuronavigation and intraoperative monitoring of motor and somatosensory evoked potentials were used. Preoperative tractography, which helped to identify internal capsule fibers, was very important in selecting the surgical strategy. Postoperatively, an MRI study performed within 24 hours was used to assess the extent of tumor resection as partial (<= 90%), subtotal (> 90%), or gross total (no residual tumor). RESULTS Since 2002, 27 children with thalamic tumors have been treated at the authors' department. There were 9 patients with unilateral thalamic tumors, 16 with thalamopeduncular tumors, and 2 with a bilateral tumor. These last 2 patients underwent endoscopic biopsy and implantation of a ventriculoperitoneal shunt. Thirty-nine tumor debulking procedures were performed in the remaining 25 patients. Different surgical approaches were chosen according to tumor location and displacement of the posterior limb of the internal capsule (as studied on axial T2-weighted MRI) and corticospinal tract (as studied on diffusion tensor imaging with tractography, after it became available). In 12 cases, multiple procedures were performed; in 7 cases, these were done as part of a planned multistage resection. In the remaining 5 cases, the second procedure was necessary because of late recurrence or regrowth of residual tumor. At the end of the surgical phase, of 25 patients, 15 (60%) achieved a gross-total resection, 4 (16%) achieved a subtotal resection, and 6 (24%) achieved a partial resection. Eighteen patients harbored low-grade tumors in our series. In this group, the mean follow-up was 45 months (range 4-132 months). At the end of follow-up, 1 patient was dead, 12 patients were alive with no evidence of disease, 4 patients were alive with stable disease, and 1 was lost to follow-up. All patients were independent in their daily lives. The outcome of high-grade tumors in 9 patients was very poor: 2 patients died immediately after surgery, 6 died of progressive disease, and 1 was alive with residual disease at the time of this report. CONCLUSIONS This institutional review seems to offer further evidence in favor of attempts at radical resection in pediatric patients harboring unilateral thalamic or thalamopeduncular tumors. In low-grade gliomas, radical resection in a single or staged procedure can be curative without complementary treatment. Recurrences or residual regrowth can be safely managed surgically. In high-grade tumors, the role of and opportunity for radical or partial resection remains a matter of debate. PMID- 29271730 TI - Piezosurgery-, neuroendoscopy-, and neuronavigation-assisted intracranial approach for removal of a recurrent petrous apex cholesteatoma: technical note. AB - Current approaches for resection of petrous bone cholesteatomas (PBCs), such as canal wall up (closed) and canal wall down (open) mastoidectomies, in the pediatric population present recurrence rates ranging between 17% and 70% with a high rate of postoperative complications involving hearing loss and facial nerve weakness. This technical note illustrates an alternative intracranial approach that was used in combination with the techniques of piezoelectric surgery, neuroendoscopy, and neuronavigation for safe and effective removal in a difficult pediatric case of recurrent PBC. The third recurrence of a PBC in a 14-year-old girl was diagnosed by CT and MRI. A retrosigmoid approach gave access to the petrous apex, allowing for the safe and complete removal of the lesion and decompression of the facial nerve and internal carotid artery. The intraoperative implementation of piezoelectric surgery, neuronavigation, neuroendoscopy, and neuromonitoring ensured better intraoperative visualization, safer bone removal, and preservation of nerve function, facilitating a macroscopically total resection of the pathology without additional neurological damage of the adjacent tissues. Cholesteatoma extension could be clearly verified by intraoperative neuronavigation. Neuroendoscopy and piezoelectric surgery provided good support in the safe bone removal in close vicinity to neurovascular structures and in full vision inside the cholesteatoma cavity beyond the line of sight of the microscope. Hearing and facial nerve function could be preserved. The presented intracranial retrosigmoid approach combined with multiple intraoperative assisting techniques proved to be effective for the safe and complete removal of recurrent PBC, providing excellent intraoperative visualization and the possibility of preserving cranial nerve function. PMID- 29271731 TI - Presentation and outcomes in surgically and conservatively managed pediatric Rathke cleft cysts. AB - OBJECTIVE Rathke cleft cysts (RCCs) are sellar lesions that are commonly encountered in adults but infrequently diagnosed in the pediatric population. As a result, the optimal management of pediatric RCCs remains a subject of controversy. Only 2 prior surgical series have been published on pediatric RCCs and no study has compared the presentation and outcomes of surgically versus conservatively managed cases. The authors therefore performed a comparative analysis of pediatric cases of RCC in which patients were treated with surgery or managed in a conservative manner. METHODS All cases involving pediatric patients diagnosed with an RCC at the University of Virginia between 2000 and 2016 were included in this study. Patient medical records, operative notes, and neuroimaging findings were reviewed. Patients who developed visual field deficits, radiographic evidence of chiasmal compression, or medically refractory headaches were considered candidates for surgical intervention. All patients who were selected for surgery underwent an endoscopic endonasal approach with cyst fenestration. RESULTS A total of 24 pediatric patients were diagnosed with an RCC over a 16-year period. Seven patients ultimately underwent transsphenoidal cyst fenestration, and 17 were managed conservatively. The patients' age at diagnosis, cyst size, and pituitary function at the time of RCC diagnosis were similar in the conservatively and surgically managed cohorts. At diagnosis, 19 of 24 patients endorsed headaches that led to neuroimaging. All patients in the surgical cohort endorsed severe headaches at diagnosis compared with 71% in the conservative group. For the 7 patients treated with surgery, complete cyst evacuation was achieved in 86% of cases. Transient postoperative endocrinopathy occurred in 4 (57%) of 7 surgically treated individuals and resolved in all cases. In the conservative cohort, 1 patient developed a delayed pituitary related endocrinopathy. Headache resolution occurred in 5 (71%) of the 7 patients who underwent surgery and 7 (58%) of the 12 who were treated without surgery. Cyst recurrence was documented in 1 individual in the surgical cohort who underwent a subtotal cyst fenestration that ultimately required re-intervention. In the conservative cohort, spontaneous cyst shrinkage occurred in 35% of patients with a median time to regression of 23.5 months. CONCLUSIONS Pediatric RCCs are benign sellar lesions that often present with headaches. While cyst fenestration mitigates headaches in most patients, the majority of conservatively managed pediatric patients with RCCs will have spontaneous headache resolution. Furthermore, spontaneous RCC regression occurs in a substantial number of individuals. Thus, in the absence of optic compression, visual field deficit, or diagnostic uncertainty, many pediatric cases of RCC can be managed conservatively. PMID- 29271732 TI - Air gun orbitocranial penetrating injury: emergency endovascular treatment and surgical bypass following pellet migration to middle cerebral artery: case report. AB - The authors describe a 14-year-old boy presenting with an orbitocranial penetrating injury (OPI) from a metallic air gun pellet to the left eye who developed hemiparesis and speech difficulty due to migration of the pellet to the left middle cerebral artery. They highlight the potential complications associated with both OPIs and intravascular foreign body migration and occlusion by describing the patient's presentation, results of imaging evaluation, and the combined endovascular treatment and extracranial-intracranial bypass, which resulted in rapid restoration of blood flow and full neurological recovery with intact vision. Based on this case and a review of the literature on intracranial foreign body migration with resultant vascular occlusion, the authors recommend that complex OPIs be treated at centers that offer both neuroendovascular and neurovascular surgical capabilities on an urgent basis to manage both the primary injury and potential secondary vascular compromise. PMID- 29271733 TI - Developing a pediatric neurosurgical training model. AB - OBJECTIVE One of the greatest challenges of pediatric neurosurgery training is balancing the training needs of the trainee against patient safety and parental expectation. The traditional "see one, do one, teach one" approach to training is no longer acceptable in pediatric neurosurgery. The authors have developed the baby Modeled Anatomical Replica for Training Young Neurosurgeons (babyMARTYN). The development of this new training model is described, its feasibility as a training tool is tested, and a new approach of integrating simulation into day-to day training is suggested. METHODS In part 1 (development), a prototype skull was developed using novel model-making methods. In part 2 (validation), 18 trainee neurosurgeons (at various stages in training) performed the following 4 different procedures: 1) evacuation of a posterior fossa hematoma; 2) pterional craniotomy; 3) tapping of the fontanelle to obtain a CSF specimen; and 4) external ventricular drain insertion. Completion of the procedural stages (scored using a curriculum-based checklist) was used to test the feasibility of babyMARTYN as a training tool. Likert scale-based questionnaires were used to assess the model for face and content validity. Training benefit was assessed using pre- and posttraining ratings on the Physician Performance Diagnostic Inventory Scale (PPDIS). To determine the significance of improvement in median PPDIS score, the Wilcoxon matched-pairs signed-rank test was performed. RESULTS In part 1 (development), the model was successfully developed with good fidelity. In part 2 (validation), the validation data demonstrated feasibility, face, and content validity. The PPDIS score significantly increased for all groups after babyMARTYN training, thereby indicating a potential future role for babyMARTYN in the training of pediatric neurosurgeons. CONCLUSIONS This recent collaborative neurosurgical development by the Royal College of Surgeons of England is designed to supplement current neurosurgical training. High-fidelity, portable, operation specific models enable preoperative planning and have the potential to be used in an operating room environment prior to novel operations. A "see one, simulate one, do one" approach for pediatric neurosurgical training using babyMARTYN is suggested. PMID- 29271734 TI - Pharmacological properties of oral antibiotics for the treatment of uncomplicated urinary tract infections. AB - The therapeutic management of uncomplicated bacterial urinary tract infections (UTIs) is based on short-term courses of oral antibiotics. The preferred drugs are nitrofurantoin trimethoprim-sulfamethoxazole, fosfomycin trometamol, fluoroquinolones and beta-lactam agents. The choice of agent for treating uncomplicated UTIs should be based on the pharmacokinetic characteristics of the molecule so that clinical benefit is optimized and the risk of antibacterial resistance is minimized. This article discusses the general pharmacokinetic pharmacodynamic (PK/PD) aspects of antimicrobial chemotherapy, the PK/PD characteristics of oral antimicrobial agents for the treatment of uncomplicated UTIs and the pharmacological and therapeutic strategies for limiting or preventing bacterial resistance. PMID- 29271735 TI - Clinical evaluation of guidelines and therapeutic approaches in multi drug resistant urinary tract infections. AB - Antibiotic resistance represents a real health emergency worldwide, mostly due to the lack of new antibiotics active against multidrug-resistant Enterobacteriaceae. Considering the global epidemiological situation in several infections, including urinary tract infections (UTIs), some antibiotics, such as fluoroquinolones and trimethoprim/sulphamethoxazole, can no longer be used for empiric treatment due to high resistance rates. However, some old antibiotics maintain high microbiological activity against UTI pathogens: according to many recent guidelines, fosfomycin trometamol, nitrofurantoin and pivmecillinam are recommended for the first-line treatment of uncomplicated UTIs. This article provides an overview of the therapeutic management of UTIs, especially uncomplicated and recurrent cystitis, as well as complicated UTIs such as catheter-related UTIs, and UTIs in males, post-menopausal women and diabetic patients, based on the main international guidelines. PMID- 29271736 TI - Multi-drug-resistant Gram-negative bacteria causing urinary tract infections: a review. AB - Urinary tract infections (UTIs) are among the most frequent infectious diseases affecting humans, and represent an important public health problem with a substantial economic burden. Due to the high empiric use of antibiotics for the treatment of UTI, antibacterial resistance of Enterobacteriaceae, specifically the main uropathogens Escherichia coli and Klebsiella pneumoniae, has significantly increased worldwide. In this article the worldwide epidemiology of resistant Gram-negative bacteria causing UTIs, with a special focus on extended spectrum beta lactamase (ESBL) positive pathogens, as well as new threats such as multi-drug-resistant (MDR) clones (e.g. E. coli 131 (ST131) and K. pneumoniae ST258), are reviewed. The increased prevalence of MDR Enterobacteriaceae, limiting available treatment options for infections caused by these organisms, and the lack of new antibiotics provide good rationale for using older antibiotics, such as fosfomycin, that have been shown to retain some activity against MDR bacteria. PMID- 29271739 TI - New Resources for Sexual and Reproductive Health and Rights Research in Humanitarian Settings. PMID- 29271737 TI - Actual role of older oral antibiotics in the treatment of resistant Urinary Tract Infections (UTIs). PMID- 29271740 TI - Care with dignity in humanitarian crises: ensuring sexual and reproductive health and rights of displaced populations. PMID- 29271741 TI - Interventions for hyperhidrosis in secondary care: a systematic review and value of-information analysis. AB - BACKGROUND: Hyperhidrosis is uncontrollable excessive sweating that occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. The management of hyperhidrosis is uncertain and variable. OBJECTIVE: To establish the expected value of undertaking additional research to determine the most effective interventions for the management of refractory primary hyperhidrosis in secondary care. METHODS: A systematic review and economic model, including a value-of-information (VOI) analysis. Treatments to be prescribed by dermatologists and minor surgical treatments for hyperhidrosis of the hands, feet and axillae were reviewed; as endoscopic thoracic sympathectomy (ETS) is incontestably an end-of-line treatment, it was not reviewed further. Fifteen databases (e.g. CENTRAL, PubMed and PsycINFO), conference proceedings and trial registers were searched from inception to July 2016. Systematic review methods were followed. Pairwise meta-analyses were conducted for comparisons between botulinum toxin (BTX) injections and placebo for axillary hyperhidrosis, but otherwise, owing to evidence limitations, data were synthesised narratively. A decision-analytic model assessed the cost effectiveness and VOI of five treatments (iontophoresis, medication, BTX, curettage, ETS) in 64 different sequences for axillary hyperhidrosis only. RESULTS AND CONCLUSIONS: Fifty studies were included in the effectiveness review: 32 randomised controlled trials (RCTs), 17 non-RCTs and one large prospective case series. Most studies were small, rated as having a high risk of bias and poorly reported. The interventions assessed in the review were iontophoresis, BTX, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland (e.g. laser, microwave). There is moderate-quality evidence of a large statistically significant effect of BTX on axillary hyperhidrosis symptoms, compared with placebo. There was weak but consistent evidence for iontophoresis for palmar hyperhidrosis. Evidence for other interventions was of low or very low quality. For axillary hyperhidrosis cost effectiveness results indicated that iontophoresis, BTX, medication, curettage and ETS was the most cost-effective sequence (probability 0.8), with an incremental cost-effectiveness ratio of L9304 per quality-adjusted life-year. Uncertainty associated with study bias was not reflected in the economic results. Patients and clinicians attending an end-of-project workshop were satisfied with the sequence of treatments for axillary hyperhidrosis identified as being cost effective. All patient advisors considered that the Hyperhidrosis Quality of Life Index was superior to other tools commonly used in hyperhidrosis research for assessing quality of life. LIMITATIONS: The evidence for the clinical effectiveness and safety of second-line treatments for primary hyperhidrosis is limited. This meant that there was insufficient evidence to draw conclusions for most interventions assessed and the cost-effectiveness analysis was restricted to hyperhidrosis of the axilla. FUTURE WORK: Based on anecdotal evidence and inference from evidence for the axillae, participants agreed that a trial of BTX (with anaesthesia) compared with iontophoresis for palmar hyperhidrosis would be most useful. The VOI analysis indicates that further research into the effectiveness of existing medications might be worthwhile, but it is unclear that such trials are of clinical importance. Research that established a robust estimate of the annual incidence of axillary hyperhidrosis in the UK population would reduce the uncertainty in future VOI analyses. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027803. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29271743 TI - PhotonDiag2017 workshop: introductory overview. AB - This issue of the Journal of Synchrotron Radiation is a special issue including papers from the PhotonDiag2017 workshop. Here, a brief introduction is given. PMID- 29271742 TI - Paxillin facilitates timely neurite initiation on soft-substrate environments by interacting with the endocytic machinery. AB - Neurite initiation is the first step in neuronal development and occurs spontaneously in soft tissue environments. Although the mechanisms regulating the morphology of migratory cells on rigid substrates in cell culture are widely known, how soft environments modulate neurite initiation remains elusive. Using hydrogel cultures, pharmacologic inhibition, and genetic approaches, we reveal that paxillin-linked endocytosis and adhesion are components of a bistable switch controlling neurite initiation in a substrate modulus-dependent manner. On soft substrates, most paxillin binds to endocytic factors and facilitates vesicle invagination, elevating neuritogenic Rac1 activity and expression of genes encoding the endocytic machinery. By contrast, on rigid substrates, cells develop extensive adhesions, increase RhoA activity and sequester paxillin from the endocytic machinery, thereby delaying neurite initiation. Our results highlight paxillin as a core molecule in substrate modulus-controlled morphogenesis and define a mechanism whereby neuronal cells respond to environments exhibiting varying mechanical properties. PMID- 29271744 TI - Non-invasive online wavelength measurements at FLASH2 and present benchmark. AB - At FLASH2, the free-electron laser radiation wavelength is routinely measured by an online spectrometer based on photoionization of gas targets. Photoelectrons are detected with time-of-flight spectrometers and the wavelength is determined by means of well known binding energies of the target species. The wavelength measurement is non-invasive and transparent with respect to running user experiments due to the low gas pressure applied. Sophisticated controls for setting the OPIS operation parameters have been created and integrated into the distributed object-oriented control system at FLASH2. Raw and processed data can be stored on request in the FLASH data acquisition system for later correlation with data from user experiments or re-analysis. In this paper, the commissioning of the instrument at FLASH2 and the challenges of space charge effects on wavelength determination are reported. Furthermore, strategies for fast data reduction and online data processing are presented. PMID- 29271745 TI - A compact and versatile tender X-ray single-shot spectrometer for online XFEL diagnostics. AB - One of the remaining challenges for accurate photon diagnostics at X-ray free electron lasers (FELs) is the shot-to-shot, non-destructive, high-resolution characterization of the FEL pulse spectrum at photon energies between 2 keV and 4 keV, the so-called tender X-ray range. Here, a spectrometer setup is reported, based on the von Hamos geometry and using elastic scattering as a fingerprint of the FEL-generated spectrum. It is capable of pulse-to-pulse measurement of the spectrum with an energy resolution (DeltaE/E) of 10-4, within a bandwidth of 2%. The Tender X-ray Single-Shot Spectrometer (TXS) will grant to experimental scientists the freedom to measure the spectrum in a single-shot measurement, keeping the transmitted beam undisturbed. It will enable single-shot reconstructions for easier and faster data analysis. PMID- 29271746 TI - Performance of a hard X-ray split-and-delay optical system with a wavefront division. AB - The performance of a hard X-ray split-and-delay optical (SDO) system with a wavefront division scheme was investigated at the hard X-ray free-electron laser facility SACLA. For the wavefront division, beam splitters made of edge-polished perfect Si(220) crystals were employed. We characterized the beam properties of the SDO system, and investigated its capabilities for beam manipulation and diagnostics. First, it was confirmed that shot-to-shot non-invasive diagnostics of pulse energies for both branches in the SDO system was feasible. Second, nearly ideal and identical focal profiles for both branches were obtained with a spot size of ~1.5 um in full width at half-maximum. Third, a spatial overlap of the two focused beams with a sub-um accuracy was achieved by fine tuning of the SDO system. Finally, a reliable tunability of the delay time between two pulses was confirmed. The time interval was measured with an X-ray streak camera by changing the path length of the variable-delay branch. Errors from the fitted line were evaluated to be as small as +/-0.4 ps over a time range of 60 ps. PMID- 29271747 TI - FLASH free-electron laser single-shot temporal diagnostic: terahertz-field-driven streaking. AB - The commissioning of a terahertz-field-driven streak camera installed at the free electron laser (FEL) FLASH at DESY in Hamburg, being able to deliver photon pulse duration as well as arrival time information with ~10 fs resolution for each single XUV FEL pulse, is reported. Pulse durations between 300 fs and <15 fs have been measured for different FLASH FEL settings. A comparison between the XUV pulse arrival time and the FEL electron bunch arrival time measured at the FLASH linac section exhibits a correlation width of 20 fs r.m.s., thus demonstrating the excellent operation stability of FLASH. In addition, the terahertz-streaking setup was operated simultaneously to an alternative method to determine the FEL pulse duration based on spectral analysis. FLASH pulse duration derived from simple spectral analysis is in good agreement with that from terahertz-streaking measurement. PMID- 29271748 TI - Characterization of ultrafast free-electron laser pulses using extreme ultraviolet transient gratings. AB - The characterization of the time structure of ultrafast photon pulses in the extreme-ultraviolet (EUV) and soft X-ray spectral ranges is of high relevance for a number of scientific applications and photon diagnostics. Such measurements can be performed following different strategies and often require large setups and rather high pulse energies. Here, high-quality measurements carried out by exploiting the transient grating process, i.e. a third-order non-linear process sensitive to the time-overlap between two crossed EUV pulses, is reported. From such measurements it is possible to obtain information on both the second-order intensity autocorrelation function and on the coherence length of the pulses. It was found that the pulse energy density needed to carry out such measurements on solid state samples can be as low as a few mJ cm-2. Furthermore, the possibility to control the arrival time of the crossed pulses independently might permit the development of a number of coherent spectroscopies in the EUV and soft X-ray regime, such as, for example, photon echo and two-dimensional spectroscopy. PMID- 29271749 TI - THz pulse doubler at FLASH: double pulses for pump-probe experiments at X-ray FELs. AB - FLASH, the X-ray free-electron laser in Hamburg, Germany, employs a narrowband high-field accelerator THz source for unique THz pump X-ray probe experiments. However, the large difference in optical paths of the THz and X-ray beamlines prevents utilization of the machine's full potential (e.g. extreme pulse energies in the soft X-ray range). To solve this issue, lasing of double electron bunches, separated by 28 periods of the driving radiofrequency (at 1.3 GHz), timed for the temporal overlap of THz and X-ray pulses at the experimental station has been employed. In order to optimize conditions for a typical THz pump X-ray probe experiment, X-ray lasing of the first bunch to one-sixth of that of the second has been suppressed. Finally, synchronization of THz radiation pulses was measured to be ~20 fs (r.m.s.), and a solution for monitoring the arrival time for achieving higher temporal resolution is presented. PMID- 29271750 TI - Timing methodologies and studies at the FERMI free-electron laser. AB - Time-resolved investigations have begun a new era of chemistry and physics, enabling the monitoring in real time of the dynamics of chemical reactions and matter. Induced transient optical absorption is a basic ultrafast electronic effect, originated by a partial depletion of the valence band, that can be triggered by exposing insulators and semiconductors to sub-picosecond extreme ultraviolet pulses. Besides its scientific and fundamental implications, this process is very important as it is routinely applied in free-electron laser (FEL) facilities to achieve the temporal superposition between FEL and optical laser pulses with tens of femtoseconds accuracy. Here, a set of methodologies developed at the FERMI facility based on ultrafast effects in condensed materials and employed to effectively determine the FEL/laser cross correlation are presented. PMID- 29271751 TI - Grating configurations to compress free-electron laser pulses. AB - The optical layout of soft X-ray grating compressors designed to provide both positive and negative group-delay dispersion (GDD) is discussed. They are tailored for chirped-pulse-amplification experiments with seeded free-electron laser sources. Designs with plane or concave gratings are discussed, depending on the sign of the GDD to be introduced. PMID- 29271752 TI - Electron and photon diagnostics for plasma acceleration-based FELs. AB - It is now well established that laser plasma acceleration (LPA) is an innovative and good candidate in the beam acceleration field. Relativistic beams are indeed produced up to several GeV but their quality remains to be demonstrated in the highly demanding case of free-electron lasers (FELs). Several experiments have already shown the feasibility of synchrotron radiation delivery based on LPA but free-electron lasing has still to be achieved. Since the quality of the LPA beam inside the undulator is the critical issue, any LPA-based FEL experiment requires a refined characterization of the beam properties along the transport line and of the photon beam at the undulator exit. This characterization relies on diagnostics which must be adapted to the LPA specificities. Here, the electron and photon diagnostics already used on LPAs and required for LPA-based FELs are reviewed, and the critical points are illustrated using recent experiments performed around the world. PMID- 29271753 TI - Single-shot arrival timing diagnostics for a soft X-ray free-electron laser beamline at SACLA. AB - Arrival timing diagnostics performed at a soft X-ray free-electron laser (FEL) beamline of SACLA are described. Intense soft X-ray FEL pulses with one dimensional focusing efficiently induce transient changes of optical reflectivity on the surface of GaAs. The arrival timing between soft X-ray FEL and optical laser pulses was successfully measured as a spatial position of the reflectivity change. The temporal resolution evaluated from the imaging system reaches ~10 fs. This method requires only a small portion of the incident pulse energy, which enables the simultaneous operation of the arrival timing diagnostics and experiments by introducing a wavefront-splitting scheme. PMID- 29271754 TI - Laser power meters as an X-ray power diagnostic for LCLS-II. AB - For the LCLS-II X-ray instruments, laser power meters are being developed as compact X-ray power diagnostics to operate at soft and tender X-ray photon energies. These diagnostics can be installed at various locations along an X-ray free-electron laser (FEL) beamline in order to monitor the transmission of X-ray optics along the beam path. In addition, the power meters will be used to determine the absolute X-ray power at the endstations. Here, thermopile power meters, which measure average power, and have been chosen primarily for their compatibility with the high repetition rates at LCLS-II, are evaluated. A number of characteristics in the soft X-ray range are presented including linearity, calibrations conducted with a photodiode and a gas monitor detector as well as ultra-high-vacuum compatibility tests using residual gas analysis. The application of these power meters for LCLS-II and other X-ray FEL sources is discussed. PMID- 29271756 TI - Damage thresholds for blaze diffraction gratings and grazing incidence optics at an X-ray free-electron laser. AB - The Linac Coherent Light Source is upgrading its machine to high repetition rate and to extended ranges. Novel coatings, with limited surface oxidation, which are able to work at the carbon edge, are required. In addition, high-resolution soft X-ray monochromators become necessary. One of the big challenges is to design the mirror geometry and the grating profile to have high reflectivity (or efficiency) and at the same time survive the high peak energy of the free-electron laser pulses. For these reasons the experimental damage threshold, at 900 eV, of two platinum-coated gratings with different blazed angles has been investigated. The gratings were tested at 1 degrees grazing incidence. To validate a model for which the damage threshold on the blaze grating can be estimated by calculating the damage threshold of a mirror with an angle of incidence identical to the angle of incidence on the grating plus the blaze angle, tests on Pt-coated substrates have also been performed. The results confirmed the prediction. Uncoated silicon, platinum and SiB3 (both deposited on a silicon substrate) were also investigated. In general, the measured damage threshold at grazing incidence is higher than that calculated under the assumption that there is no energy transport from the volume where the photons are absorbed. However, it was found that, for the case of the SiB3 coating, the grazing incidence condition did not increase the damage threshold, indicating that the energy transport away from the extinction volume is negligible. PMID- 29271755 TI - Experimental study of EUV mirror radiation damage resistance under long-term free electron laser exposures below the single-shot damage threshold. AB - The durability of grazing- and normal-incidence optical coatings has been experimentally assessed under free-electron laser irradiation at various numbers of pulses up to 16 million shots and various fluence levels below 10% of the single-shot damage threshold. The experiment was performed at FLASH, the Free electron LASer in Hamburg, using 13.5 nm extreme UV (EUV) radiation with 100 fs pulse duration. Polycrystalline ruthenium and amorphous carbon 50 nm thin films on silicon substrates were tested at total external reflection angles of 20 degrees and 10 degrees grazing incidence, respectively. Mo/Si periodical multilayer structures were tested in the Bragg reflection condition at 16 degrees off-normal angle of incidence. The exposed areas were analysed post-mortem using differential contrast visible light microscopy, EUV reflectivity mapping and scanning X-ray photoelectron spectroscopy. The analysis revealed that Ru and Mo/Si coatings exposed to the highest dose and fluence level show a few per cent drop in their EUV reflectivity, which is explained by EUV-induced oxidation of the surface. PMID- 29271757 TI - Gratings for synchrotron and FEL beamlines: a project for the manufacture of ultra-precise gratings at Helmholtz Zentrum Berlin. AB - Blazed gratings are of dedicated interest for the monochromatization of synchrotron radiation when a high photon flux is required, such as, for example, in resonant inelastic X-ray scattering experiments or when the use of laminar gratings is excluded due to too high flux densities and expected damage, for example at free-electron laser beamlines. Their availability became a bottleneck since the decommissioning of the grating manufacture facility at Carl Zeiss in Oberkochen. To resolve this situation a new technological laboratory was established at the Helmholtz Zentrum Berlin, including instrumentation from Carl Zeiss. Besides the upgraded ZEISS equipment, an advanced grating production line has been developed, including a new ultra-precise ruling machine, ion etching technology as well as laser interference lithography. While the old ZEISS ruling machine GTM-6 allows ruling for a grating length up to 170 mm, the new GTM-24 will have the capacity for 600 mm (24 inch) gratings with groove densities between 50 lines mm-1 and 1200 lines mm-1. A new ion etching machine with a scanning radiofrequency excited ion beam (HF) source allows gratings to be etched into substrates of up to 500 mm length. For a final at-wavelength characterization, a new reflectometer at a new Optics beamline at the BESSY-II storage ring is under operation. This paper reports on the status of the grating fabrication, the measured quality of fabricated items by ex situ and in situ metrology, and future development goals. PMID- 29271758 TI - Efficient high-order suppression system for a metrology beamline. AB - High-quality metrology with synchrotron radiation requires in particular a very high spectral purity of the incident beam. This is usually achieved by a set of transmission filters with suitable absorption edges to suppress high-order radiation of the monochromator. The at-wavelength metrology station at a BESSY-II bending-magnet collimated plane-grating monochromator (c-PGM) beamline has recently commissioned a high-order suppression system (HiOS) based on four reflections from mirrors which can be inserted into the beam path. Two pairs of mirrors are aligned parallel so as not to disturb the original beam path and are rotated clockwise and counter-clockwise. Three sets of coatings are available for the different energy ranges and the incidence angle is freely tunable to find the optimum figure of merit for maximum suppression at maximum transmission for each photon energy required. Measured performance results of the HiOS for the EUV and XUV range are compared with simulations, and applications are discussed. PMID- 29271759 TI - Nanofocusing with aberration-corrected rotationally parabolic refractive X-ray lenses. AB - Wavefront errors of rotationally parabolic refractive X-ray lenses made of beryllium (Be CRLs) have been recovered for various lens sets and X-ray beam configurations. Due to manufacturing via an embossing process, aberrations of individual lenses within the investigated ensemble are very similar. By deriving a mean single-lens deformation for the ensemble, aberrations of any arbitrary lens stack can be predicted from the ensemble with ?bar{?sigma} = 0.034lambda. Using these findings the expected focusing performance of current Be CRLs are modeled for relevant X-ray energies and bandwidths and it is shown that a correction of aberrations can be realised without prior lens characterization but simply based on the derived lens deformation. The performance of aberration corrected Be CRLs is discussed and the applicability of aberration-correction demonstrated over wide X-ray energy ranges. PMID- 29271760 TI - Coatings for FEL optics: preparation and characterization of B4C and Pt. AB - Large X-ray mirrors are required for beam transport at both present-day and future free-electron lasers (FELs) and synchrotron sources worldwide. The demand for large mirrors with lengths up to 1 m single layers consisting of light or heavy elements has increased during the last few decades. Accordingly, surface finishing technology is now able to produce large substrate lengths with micro roughness on the sub-nanometer scale. At the Helmholtz-Zentrum Geesthacht (HZG), a 4.5 m-long sputtering facility enables us to deposit a desired single-layer material some tens of nanometers thick. For the European XFEL project, the shape error should be less than 2 nm over the whole 1 m X-ray mirror length to ensure the safe and efficient delivery of X-ray beams to the scientific instruments. The challenge is to achieve thin-film deposition on silicon substrates, benders and gratings without any change in mirror shape. Thin films of boron carbide and platinum with a thickness in the range 30-100 nm were manufactured using the HZG sputtering facility. This setup is able to cover areas of up to 1500 mm * 120 mm in one step using rectangular sputtering sources. The coatings produced were characterized using various thin-film methods. It was possible to improve the coating process to achieve a very high uniformity of the layer thickness. The movement of the substrate in front of the sputtering source has been optimized. A variation in B4C layer thickness below 1 nm (peak-to-valley) was achieved at a mean thickness of 51.8 nm over a deposition length of 1.5 m. In the case of Pt, reflectometry and micro-roughness measurements were performed. The uniformity in layer thickness was about 1 nm (peak-to-valley). The micro-roughness of the Pt layers showed no significant change in the coated state for layer thicknesses of 32 nm and 102 nm compared with the uncoated substrate state. The experimental results achieved will be discussed with regard to current restrictions and future developments. PMID- 29271761 TI - X-ray beam-shaping via deformable mirrors: surface profile and point spread function computation for Gaussian beams using physical optics. AB - X-ray mirrors with high focusing performances are commonly used in different sectors of science, such as X-ray astronomy, medical imaging and synchrotron/free electron laser beamlines. While deformations of the mirror profile may cause degradation of the focus sharpness, a deliberate deformation of the mirror can be made to endow the focus with a desired size and distribution, via piezo actuators. The resulting profile can be characterized with suitable metrology tools and correlated with the expected optical quality via a wavefront propagation code or, sometimes, predicted using geometric optics. In the latter case and for the special class of profile deformations with monotonically increasing derivative, i.e. concave upwards, the point spread function (PSF) can even be predicted analytically. Moreover, under these assumptions, the relation can also be reversed: from the desired PSF the required profile deformation can be computed analytically, avoiding the use of trial-and-error search codes. However, the computation has been so far limited to geometric optics, which entailed some limitations: for example, mirror diffraction effects and the size of the coherent X-ray source were not considered. In this paper, the beam-shaping formalism in the framework of physical optics is reviewed, in the limit of small light wavelengths and in the case of Gaussian intensity wavefronts. Some examples of shaped profiles are also shown, aiming at turning a Gaussian intensity distribution into a top-hat one, and checks of the shaping performances computing the at-wavelength PSF by means of the WISE code are made. PMID- 29271762 TI - Double-grating monochromatic beamline with ultrafast response for FLASH2 at DESY. AB - The preliminary design of a monochromatic beamline for FLASH2 at DESY is presented. The monochromator is tunable in the 50-1000 eV energy range with resolving power higher than 1000 and temporal response below 50 fs over the whole energy range. A time-delay-compensated configuration using the variable-line spacing monochromator design with two gratings is adopted: the first grating disperses the radiation on its output plane, where the intermediate slit performs the spectral selection; the second grating compensates for the pulse-front tilt and for the spectral dispersion due to diffraction from the first grating. PMID- 29271763 TI - Diffraction gratings metrology and ray-tracing results for an XUV Raman spectrometer at FLASH. AB - The extreme-ultraviolet double-stage imaging Raman spectrometer is a permanent experimental endstation at the plane-grating monochromator beamline branch PG1 at FLASH at DESY in Hamburg, Germany. This unique instrument covers the photon energy range from 20 to 200 eV with high energy resolution of about 2 to 20 meV (design values) featuring an efficient elastic line suppression as well as effective stray light rejection. Such a design enables studies of low-energy excitations like, for example, phonons in solids close to the vicinity of the elastic line. The Raman spectrometer effectively operates with four reflective off-axial parabolic mirrors and two plane-grating units. The optics quality and their precise alignment are crucial to guarantee best performance of the instrument. Here, results on a comprehensive investigation of the quality of the spectrometer diffraction gratings are presented. The gratings have been characterized by ex situ metrology at the BESSY-II Optics Laboratory, employing slope measuring deflectometry and interferometry as well as atomic force microscopy studies. The efficiency of these key optical elements has been measured at the at-wavelength metrology laboratory using the reflectometer at the BESSY-II Optics beamline. Also, the metrology results are discussed with respect to the expected resolving power of the instrument by including them in ray tracing studies of the instrument. PMID- 29271764 TI - Direct experimental observation of the gas density depression effect using a two bunch X-ray FEL beam. AB - The experimental observation of the depression effect in gas devices designed for X-ray free-electron lasers (FELs) is reported. The measurements were carried out at the Linac Coherent Light Source using a two-bunch FEL beam at 6.5 keV with 122.5 ns separation passing through an argon gas cell. The relative intensities of the two pulses of the two-bunch beam were measured, after and before the gas cell, from X-ray scattering off thin targets by using fast diodes with sufficient temporal resolution. At a cell pressure of 140 hPa, it was found that the after to-before ratio of the intensities of the second pulse was about 17% +/- 6% higher than that of the first pulse, revealing lower effective attenuation of the gas cell due to heating by the first pulse and subsequent gas density reduction in the beam path. This measurement is important in guiding the design and/or mitigating the adverse effects in gas devices for high-repetition-rate FELs such as the LCLS-II and the European XFEL or other future high-repetition-rate upgrades to existing FEL facilities. PMID- 29271765 TI - In situ electrochemical synchrotron radiation for Li-ion batteries. AB - Observing the electronic structure, compositional change and morphological evolution of the surface and interface of a battery during operation provides essential information for developing new electrode materials for Li-ion batteries (LIBs); this is because such observations demonstrate the fundamental reactions occurring inside the electrode materials. Moreover, obtaining detailed data on chemical phase changes and distributions by analyzing an operating LIB is the most effective method for exploring the intercalation/de-intercalation process, kinetics and the relationship between phase change or phase distribution and battery performance, as well as for further optimizing the material synthesis routes for advanced battery materials. However, most conventional in situ electrochemical techniques (other than by using synchrotron radiation) cannot clearly or precisely demonstrate structural change, electron valence change and chemical mapping information. In situ electrochemical-synchrotron radiation techniques such as X-ray absorption spectroscopy, X-ray diffraction spectroscopy and transmission X-ray microscopy can deliver accurate information regarding LIBs. This paper reviews studies regarding various applications of in situ electrochemical-synchrotron radiation such as crystallographic transformation, oxidation-state changes, characterization of the solid electrolyte interphase and Li-dendrite growth mechanism during the intercalation/de-intercalation process. The paper also presents the findings of previous review articles and the future direction of these methods. PMID- 29271766 TI - Transient thermal stress wave and vibrational analyses of a thin diamond crystal for X-ray free-electron lasers under high-repetition-rate operation. AB - High-brightness X-ray free-electron lasers (FELs) are perceived as fourth generation light sources providing unprecedented capabilities for frontier scientific researches in many fields. Thin crystals are important to generate coherent seeds in the self-seeding configuration, provide precise spectral measurements, and split X-ray FEL pulses, etc. In all of these applications a high-intensity X-ray FEL pulse impinges on the thin crystal and deposits a certain amount of heat load, potentially impairing the performance. In the present paper, transient thermal stress wave and vibrational analyses as well as transient thermal analysis are carried out to address the thermomechanical issues for thin diamond crystals, especially under high-repetition-rate operation of an X-ray FEL. The material properties at elevated temperatures are considered. It is shown that, for a typical FEL pulse depositing tens of microjoules energy over a spot of tens of micrometers in radius, the stress wave emission is completed on the tens of nanoseconds scale. The amount of kinetic energy converted from a FEL pulse can reach up to ~10 nJ depending on the layer thickness. Natural frequencies of a diamond plate are also computed. The potential vibrational amplitude is estimated as a function of frequency. Due to the decreasing heat conductivity with increasing temperature, a runaway temperature rise is predicted for high repetition rates where the temperature rises abruptly after ratcheting up to a point of trivial heat damping rate relative to heat deposition rate. PMID- 29271767 TI - Pulse-resolved intensity measurements at a hard X-ray FEL using semi-transparent diamond detectors. AB - Solid-state ionization chambers are presented based on thin diamond crystals that allow pulse-resolved intensity measurements at a hard X-ray free-electron laser (FEL), up to the 4.5 MHz repetition rate that will become available at the European XFEL. Due to the small X-ray absorption of diamond the thin detectors are semi-transparent which eases their use as non-invasive monitoring devices in the beam. FELs are characterized by strong pulse-to-pulse intensity fluctuations due to the self-amplified spontaneous emission (SASE) process and in many experiments it is mandatory to monitor the intensity of each individual pulse. Two diamond detectors with different electrode materials, beryllium and graphite, were tested as intensity monitors at the XCS endstation of the Linac Coherent Light Source (LCLS) using the pink SASE beam at 9 keV. The performance is compared with LCLS standard monitors that detect X-rays backscattered from thin SiN foils placed in the beam. The graphite detector can also be used as a beam position monitor although with rather coarse resolution. PMID- 29271768 TI - An IAEA multi-technique X-ray spectrometry endstation at Elettra Sincrotrone Trieste: benchmarking results and interdisciplinary applications. AB - The International Atomic Energy Agency (IAEA) jointly with the Elettra Sincrotrone Trieste (EST) operates a multipurpose X-ray spectrometry endstation at the X-ray Fluorescence beamline (10.1L). The facility has been available to external users since the beginning of 2015 through the peer-review process of EST. Using this collaboration framework, the IAEA supports and promotes synchrotron-radiation-based research and training activities for various research groups from the IAEA Member States, especially those who have limited previous experience and resources to access a synchrotron radiation facility. This paper aims to provide a broad overview about various analytical capabilities, intrinsic features and performance figures of the IAEA X-ray spectrometry endstation through the measured results. The IAEA-EST endstation works with monochromatic X rays in the energy range 3.7-14 keV for the Elettra storage ring operating at 2.0 or 2.4 GeV electron energy. It offers a combination of different advanced analytical probes, e.g. X-ray reflectivity, X-ray absorption fine-structure measurements, grazing-incidence X-ray fluorescence measurements, using different excitation and detection geometries, and thereby supports a comprehensive characterization for different kinds of nanostructured and bulk materials. PMID- 29271769 TI - Fast X-ray reflectivity measurements using an X-ray pixel area detector at the DiffAbs beamline, Synchrotron SOLEIL. AB - This paper describes a method for rapid measurements of the specular X-ray reflectivity signal using an area detector and a monochromatic, well collimated X ray beam (divergence below 0.01 degrees ), combined with a continuous data acquisition mode during the angular movements of the sample and detector. In addition to the total integrated (and background-corrected) reflectivity signal, this approach yields a three-dimensional mapping of the reciprocal space in the vicinity of its origin. Grazing-incidence small-angle scattering signals are recorded simultaneously. Measurements up to high momentum transfer values (close to 0.1 nm-1, also depending on the X-ray beam energy) can be performed in total time ranges as short as 10 s. The measurement time can be reduced by up to 100 times as compared with the classical method using monochromatic X-ray beams, a point detector and rocking scans (integrated reflectivity signal). PMID- 29271770 TI - Lead apatites: structural variations among Pb5(BO4)3Cl with B = P (pyromorphite), As (mimetite) and V (vanadinite). AB - The crystal structure of four Pb apatite samples, Pb5(BO4)3Cl, was refined with synchrotron high-resolution powder X-ray diffraction data, Rietveld refinements, space group P63/m and Z = 2. For this isotypic series, B = P5+ is pyromorphite, B = As5+ is mimetite and B = V5+ is vanadinite. The ionic radius for As5+ (0.355 A) is similar to that of V5+ (0.335 A), and this is twice as large as that for P5+ (0.170 A). However, the c unit-cell parameter for mimetite is surprisingly different from that of vanadinite, although their unit-cell volumes, V, are almost equal to each other. No explanation was available for this peculiar c-axis value for mimetite. Structural parameters such as average [4], [9] and [8] distances increase linearly with V (the coordination numbers for the cations are given in square brackets). Mimetite has a short Pb2-O1 distance, so the O1 oxygen atom interacts with the 6s2 lone-pair electrons of the Pb2+ cation that causes the Cl-Cl distance (= c/2) to increase to the largest value in the series because of repulsion, which causes the c-axis to increase anomalously. Although Pb apatite minerals occur naturally in ore deposits, they are also formed as scaly deposits in lead water pipes that give rise to lead in tap water, as was found recently in Flint, Michigan, USA. It is important to identify Pb-containing phases in water-pipe deposits. PMID- 29271771 TI - X-ray natural circular dichroism in langasite crystal. AB - Optical activity in the X-ray range stems from the electric-dipole-electric quadrupole interference terms mixing multipoles of opposite parity, and can be observed exclusively in systems with broken inversion symmetry. The gyration tensor formalism is used to describe the X-ray optical activity in langasite La3Ga5SiO14 crystal with the P321 space group. An experimental study of the X-ray natural circular dichroism (XNCD) near the Ga K-edge in La3Ga5SiO14 single crystal was performed at ESRF beamline ID12, both along and perpendicular to the crystal optical axis. The combination of the quantum mechanical calculations and high-quality experimental results has allowed us to separate the contributions into X-ray absorption and XNCD spectra of Ga atoms occupying three distinct Wyckoff positions. PMID- 29271772 TI - Effect of reflection and refraction on NEXAFS spectra measured in TEY mode. AB - The evolution of near-edge X-ray absorption fine structure in the vicinity of the K-absorption edge of oxygen for HfO2 over a wide range of incidence angles is analyzed by simultaneous implementation of the total-electron-yield (TEY) method and X-ray reflection spectroscopy. It is established that the effect of refraction on the TEY spectrum is greater than that of reflection and extends into the angular region up to angles 2thetac. Within angles that are less than the critical angle, both the reflection and refraction strongly distort the shape of the TEY spectrum. Limitations of the technique for the calculation of optical constants from the reflection spectra using the Kramers-Kronig relation in the limited energy region in the vicinity of thresholds are discussed in detail. PMID- 29271773 TI - X-ray Fourier transform holography by amplitude-division-type Fresnel zone plate interferometer. AB - A two-block X-ray Fresnel zone plate system forms two-beams - a plane wave and a spherical wave - which interfere at the focal distance of the virtual source of the spherical wave. An object placed in the path of the plane wave forms an object wave and the spherical wave is the reference wave. The recorded intensity distribution is the Fourier transform hologram of the object. Analytical and numerical calculations show the possibilities of this scheme to record the hologram and reconstruct the object image. Examples of recording holograms of a one-dimensional cosine-like grating and a two-dimensional grid object as well as reconstruction of the images are considered. PMID- 29271774 TI - Fast projection/backprojection and incremental methods applied to synchrotron light tomographic reconstruction. AB - Iterative methods for tomographic image reconstruction have the computational cost of each iteration dominated by the computation of the (back)projection operator, which take roughly O(N3) floating point operations (flops) for N * N pixels images. Furthermore, classical iterative algorithms may take too many iterations in order to achieve acceptable images, thereby making the use of these techniques unpractical for high-resolution images. Techniques have been developed in the literature in order to reduce the computational cost of the (back)projection operator to O(N2logN) flops. Also, incremental algorithms have been devised that reduce by an order of magnitude the number of iterations required to achieve acceptable images. The present paper introduces an incremental algorithm with a cost of O(N2logN) flops per iteration and applies it to the reconstruction of very large tomographic images obtained from synchrotron light illuminated data. PMID- 29271775 TI - Digital fast pulse shape and height analysis on cadmium-zinc-telluride arrays for high-flux energy-resolved X-ray imaging. AB - Cadmium-zinc-telluride (CZT) arrays with photon-counting and energy-resolving capabilities are widely proposed for next-generation X-ray imaging systems. This work presents the performance of a 2 mm-thick CZT pixel detector, with pixel pitches of 500 and 250 um, dc coupled to a fast and low-noise ASIC (PIXIE ASIC), characterized only by the preamplifier stage. A custom 16-channel digital readout electronics was used, able to digitize and process continuously the signals from each output ASIC channel. The digital system performs on-line fast pulse shape and height analysis, with a low dead-time and reasonable energy resolution at both low and high fluxes. The spectroscopic response of the system to photon energies below (109Cd source) and above (241Am source) the K-shell absorption energy of the CZT material was investigated, with particular attention to the mitigation of charge sharing and pile-up. The detector allows high bias voltage operation (>5000 V cm-1) and good energy resolution at moderate cooling (3.5% and 5% FWHM at 59.5 keV for the 500 and 250 um arrays, respectively) by using fast pulse shaping with a low dead-time (300 ns). Charge-sharing investigations were performed using a fine time coincidence analysis (TCA), with very short coincidence time windows up to 10 ns. For the 500 um pitch array (250 um pitch array), sharing percentages of 36% (52%) and 60% (82%) at 22.1 and 59.5 keV, respectively, were measured. The potential of the pulse shape analysis technique for charge-sharing detection for corner/border pixels and at high rate conditions (250 kcps pixel-1), where the TCA fails, is also shown. Measurements demonstrated that significant amounts of charge are lost for interactions occurring in the volume of the inter-pixel gap. This charge loss must be accounted for in the correction of shared events. These activities are within the framework of an international collaboration on the development of energy-resolved photon-counting systems for high-flux energy-resolved X-ray imaging (1-140 keV). PMID- 29271776 TI - Separation of superimposed images with subpixel shift. AB - The problem of the separation of superimposed images is considered in the particular case of a steady background and a foreground that is composed of different patterns separated in space, each with a compact support. Each pattern of the foreground may move in time independently. A single pair of these superimposed images is assumed to be available, and the displacement amplitude is typically smaller than the pixel size. Further, assuming that the background is smoothly varying in space, an original algorithm is proposed. To illustrate the performance of the method, a real test case of X-ray tomographic radiographs with moving patterns due to dust particles or surface scratches of optical elements along the beam is considered. Finally an automatic and simple treatment is proposed to erase the effects of such features. PMID- 29271777 TI - A soft X-ray free-electron laser beamline at SACLA: the light source, photon beamline and experimental station. AB - The design and performance of a soft X-ray free-electron laser (FEL) beamline of the SPring-8 Compact free-electron LAser (SACLA) are described. The SPring-8 Compact SASE Source test accelerator, a prototype machine of SACLA, was relocated to the SACLA undulator hall for dedicated use for the soft X-ray FEL beamline. Since the accelerator is operated independently of the SACLA main linac that drives the two hard X-ray beamlines, it is possible to produce both soft and hard X-ray FEL simultaneously. The FEL pulse energy reached 110 uJ at a wavelength of 12.4 nm (i.e. photon energy of 100 eV) with an electron beam energy of 780 MeV. PMID- 29271778 TI - Focusing X-ray free-electron laser pulses using Kirkpatrick-Baez mirrors at the NCI hutch of the PAL-XFEL. AB - The Pohang Accelerator Laboratory X-ray Free-Electron Laser (PAL-XFEL) is a recently commissioned X-ray free-electron laser (XFEL) facility that provides intense ultrashort X-ray pulses based on the self-amplified spontaneous emission process. The nano-crystallography and coherent imaging (NCI) hutch with forward scattering geometry is located at the hard X-ray beamline of the PAL-XFEL and provides opportunities to perform serial femtosecond crystallography and coherent X-ray diffraction imaging. To produce intense high-density XFEL pulses at the interaction positions between the X-rays and various samples, a microfocusing Kirkpatrick-Baez (KB) mirror system that includes an ultra-precision manipulator has been developed. In this paper, the design of a KB mirror system that focuses the hard XFEL beam onto a fixed sample point of the NCI hutch, which is positioned along the hard XFEL beamline, is described. The focusing system produces a two-dimensional focusing beam at approximately 2 um scale across the 2 11 keV photon energy range. XFEL pulses of 9.7 keV energy were successfully focused onto an area of size 1.94 um * 2.08 um FWHM. PMID- 29271780 TI - Open Wounds and Healed Scars: A Qualitative Study of Elderly Women's Experiences With Breast Cancer. AB - BACKGROUND: Breast cancer is more prevalent among women 60 years or older than among women younger than 60 years. However, we know much more about the breast cancer experiences of younger women than of older women. Such knowledge is important, for example, to guide treatment decisions or to provide psychosocial care. OBJECTIVE: The aim of this study was to gain insight into the experiences of women with breast cancer 70 years or older. METHODS: Semistructured interviews were conducted with 21 older patients with breast cancer in the Netherlands. We used open coding and affinity diagramming to evoke the themes reflecting the experiences of these women. RESULTS: Four themes emerged from the data: living through and coping with breast cancer, information exchange and informed choice, support experiences, and impact on daily life. Getting breast cancer took some women by surprise. However, older women with breast cancer coped fairly well and were satisfied with the support they received, especially from oncology nurses. Disturbing treatment adverse effects and changes in appearance, comorbid diseases, lack of clear information, and/or an unsupportive environment complicated their living with breast cancer. CONCLUSIONS: Even though many older women with breast cancer handle their disease rather well, some women do encounter difficulties. Lack of support, comorbid diseases, and treatment adverse effects warrant extra attention. IMPLICATIONS FOR PRACTICE: Nurses' close attention to women at risk and early intervention could help relieve individual suffering, while taking these womens' strengths into account can enhance self management.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work, provided it is properly cited. The work cannot be changed in any way or used commercially. PMID- 29271779 TI - DA+ data acquisition and analysis software at the Swiss Light Source macromolecular crystallography beamlines. AB - Data acquisition software is an essential component of modern macromolecular crystallography (MX) beamlines, enabling efficient use of beam time at synchrotron facilities. Developed at the Paul Scherrer Institute, the DA+ data acquisition software is implemented at all three Swiss Light Source (SLS) MX beamlines. DA+ consists of distributed services and components written in Python and Java, which communicate via messaging and streaming technologies. The major components of DA+ are the user interface, acquisition engine, online processing and database. Immediate data quality feedback is achieved with distributed automatic data analysis routines. The software architecture enables exploration of the full potential of the latest instrumentation at the SLS MX beamlines, such as the SmarGon goniometer and the EIGER X 16M detector, and development of new data collection methods. PMID- 29271781 TI - Screening Tool to Determine Risk of Having Muscle Dysmorphia Symptoms in Men Who Engage in Weight Training at a Gym. AB - OBJECTIVE: Although 2 screening tests exist for having a high risk of muscle dysmorphia (MD) symptoms, they both require a long time to apply. Accordingly, we proposed the construction, validation, and implementation of such a test in a mobile application using easy-to-measure factors associated with MD. DESIGN: Cross-sectional observational study. SETTING: Gyms in Alicante (Spain) during 2013 to 2014. PARTICIPANTS: One hundred forty-one men who engaged in weight training. ASSESSMENT OF RISK FACTORS: The variables are as follows: age, educational level, income, buys own food, physical activity per week, daily meals, importance of nutrition, special nutrition, guilt about dietary nonadherence, supplements, and body mass index (BMI). A points system was constructed through a binary logistic regression model to predict a high risk of MD symptoms by testing all possible combinations of secondary variables (5035). The system was validated using bootstrapping and implemented in a mobile application. MAIN OUTCOME MEASURES: High risk of having MD symptoms (Muscle Appearance Satisfaction Scale). RESULTS: Of the 141 participants, 45 had a high risk of MD symptoms [31.9%, 95% confidence interval (CI), 24.2%-39.6%]. The logistic regression model combination providing the largest area under the receiver operating characteristic curve (0.76) included the following: age [odds ratio (OR) = 0.90; 95% CI, 0.84-0.97, P = 0.007], guilt about dietary nonadherence (OR = 2.46; 95% CI, 1.06-5.73, P = 0.037), energy supplements (OR = 3.60; 95% CI, 1.54-8.44, P = 0.003), and BMI (OR = 1.33, 95% CI, 1.12-1.57, P < 0.001). The points system was validated through 1000 bootstrap samples. CONCLUSIONS: A quick, easy-to-use, 4-factor test that could serve as a screening tool for a high risk of MD symptoms has been constructed, validated, and implemented in a mobile application. PMID- 29271783 TI - Electrochemotherapy with anti-PD-1 treatment induced durable complete response in heavily pretreated metastatic melanoma patient. AB - Metastatic melanoma (MM) is one of the most lethal types of cancer. Although novel immunotherapeutics have been developed recently, still, these drugs fail to save the lives of a third of MM patients. Electrochemotherapy (ECT) is a local treatment of cancer based on a combination of electroporesis and low-dose chemotherapy. In this case report, we present the treatment history of a MM patient treated successfully with ECT and immunotherapy combination as a fifth line treatment. Our patient was a 39 year-old woman who was diagnosed with nodulary melanoma stage II. Due to a local recurrence, she was given interferon alpha treatment. After 6 months, her disease relapsed in the axillary lymph nodes, and temozolamide treatment 150 mg/m2 was initiated. After six cycles on temozolamide, she progressed both in the axillary site and in the lungs. Her BRAF mutation analysis revealed V600E positivity. Hence, BRAF inhibitor-vemurafenib 2'4 tablets per day was initiated. Within 3 months, she responded dramatically both in the axillary site and in the lungs. At the ninth month of treatment, she progressed again, at which time ipilimumab 3 mg/kg was started as a fourth line treatment. However, shortly after, she progressed again and developed a solitary brain metastasis. She was operated and had whole brain radiotherapy. At that point, nivolumab, an antiprogrammed cell death ligand-1 blocker, was the only remaining option. She showed a biphenotypical response to nivolumab; a mass on the anterior axilla was progressing while the other lymph nodes had regressed. Owing to the accessibility of the subcutaneous lesion with external electrodes, ECT was performed using IGEA Cliniprator device through a hexagonal electrode on the progressive mass, while on nivolumab treatment. A complete response was achieved, with no evidence of disease at 4 years since her local recurrence. Eradication of symptomatic, refractory lesions using ECT meets an important clinical need. Whenever a disseminated disease presents with cutaneous/subcutaneous lesions, high efficacy of ECT should be deployed to augment tumor immunogenicity and complement systemic immunotherapies. PMID- 29271782 TI - Efficacy of daclatasvir-based quadruple therapy in nonresponder patients infected by hepatitis C virus genotype 4: the ANRS HC32 QUATTRO study. AB - BACKGROUND: A few direct antiviral agents have been studied in difficult-to-treat patients infected by hepatitis C virus (HCV) genotype 4 (GT4). The efficacy of daclatasvir (DCV), asunaprevir (ASV), pegylated interferon and ribavirin (Peg IFN/RBV) association was investigated in these patients. PATIENTS AND METHODS: This open-label, single-arm, phase 2 study was conducted in HCV GT4 patients who were null or partial responders to Peg-IFN/RBV. Patients received 24 weeks of DCV (60 mg, once daily), ASV (100 mg, twice daily) and Peg-IFN/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 [sustained virologic response (SVR)12]. RESULTS: Sixty patients were included; 45 (75%) were previous null responders and 27 (45%) had cirrhosis. The most frequent subtypes were GT4a (48%) and GT4d (27%) with 25% of the patients being infected with other subtypes such as 4c, 4r, 4f, 4k, 4j and 4q. The global SVR12 was 95% (90% confidence interval: 90.4-99.6) and 96.3% (90% confidence interval: 87.5-99.5) in cirrhotic patients. All patients achieving SVR12 also achieved SVR24. Previous Peg-IFN/RBV response, IL28b genotype, cirrhosis status or GT4 subtypes did not influence SVR12 rates. Serious adverse events occurred in 13% of the patients, four being cirrhotic and four noncirrhotic. Three (5%) patients stopped HCV therapy prematurely: one because of virologic breakthrough and two because of serious adverse events. Grade 3/4 laboratory abnormalities included leukopenia (33%), neutropenia (27%), thrombocytopenia (4%) and transaminases increase (2%). CONCLUSION: Association of DCV plus ASV and peg-IFN/RBV for 24 weeks demonstrated a high rate of SVR12 in HCV GT4-infected prior nonresponders, independently of the cirrhotic status or the GT4 subtype. The safety profile was acceptable, even in cirrhotic patients. PMID- 29271784 TI - Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy. AB - Tumor-specific CD8 T cells often fail to elicit effective antitumor immune responses due to an inability to expand into a substantial effector population and persist long-term in vivo. Using an adoptive transfer model of cancer immunotherapy, we demonstrate that constitutive eomesodermin (Eomes) expression in tumor-specific CD8 T cells improves tumor rejection and survival. The increase in tumor rejection was associated with an increased number and persistence of CD8 T cells in lymphoid tissues during acute tumor rejection, tumor regrowth, and in mice that remained tumor-free. Constitutive Eomes expression increased expression of CD25, and this was associated with enhanced interleukin-2 responsiveness and tumor-specific CD8 T-cell proliferation. Moreover, constitutive Eomes expression improved cell survival. Taken together, our data suggest that constitutive Eomes expression enhances CD8 T-cell proliferation and survival, in part through the enhancement of interleukin-2 responsiveness through CD25 induction. PMID- 29271785 TI - Osteointegration of Tissue-Level Implants With Very Low Insertion Torque in Soft Bone: A Clinical Study on SLA Surface Treatment. AB - INTRODUCTION: Evidence shows lower percentage of osteointegration when implants are placed without sufficient primary stability. The present work tested the hypothesis that implants unstable at insertion could achieve osteointegration with proper implant surface treatment. MATERIALS AND METHODS: Eleven Straumann tissue-level implants with sandblasted, large-grit, acid-etched (SLA) surface treatment were placed in soft bone unfavorable to primary stability, as indicated by insertion torque lower than 10 N/cm and slight mobility on the application of a lateral load of 250 g. After 4 to 6 months of healing, a reverse torque of 35 Ncm was applied to assess osteointegration. RESULTS: All implants appeared to be clinically osseointegrated and were successfully restored and loaded with fixed partial dentures or single crowns. After 28.5 months, all implants remained functional. CONCLUSIONS: Within the limitations of the low number of implants analyzed, it can be concluded that tissue-level implants with sand-blasted and acid-etched surface treatment can achieve osteointegration, even in the absence of primary stability. PMID- 29271786 TI - Contemporary Digital Restorative and Minimal-Invasive Preservative Surgical Techniques in the Esthetic Zone: A Case Report. AB - When immediately temporizing an implant, relining and cementation of the provisional can be a challenging, time-consuming, and contaminating procedure. Excess resin and cement need to be carefully removed from the fresh wound. This can be overcome by digitally backward planning the treatment with subsequent production of a surgical guide to be used by both the technician and the dentist. In this report, a patient with a fractured and hopeless central incisor and an apical radiolucency at his compromised (root-canal treated, post and core build up) contralateral counterpart was treated using guided implant installation, immediate placement of a prefabricated screw-retained provisional, and apicoectomy. Dehiscence of the buccal plate after tooth extraction resulting in the need for hard- and soft-tissue grafting and delayed surgery did not affect the clinical outcome. PMID- 29271787 TI - Factors Influencing the Overall Satisfaction in Patients With Severe Brain Injury With Physiotherapy Services During Inpatient Rehabilitation. AB - OBJECTIVE: To determine what influences the satisfaction of rehabilitation inpatients and their relatives with physiotherapy after severe traumatic brain injury. DESIGN: A prospective purpose-designed survey of consecutive eligible patients discharged from a metropolitan brain injury unit. PARTICIPANTS: A total of 65 patients with severe traumatic brain injury and 32 relatives. RESULTS: The vast majority of patients (99%) and relatives (97%) reported being "satisfied" or "highly satisfied" with the service. Patients' overall satisfaction was influenced by the extent of actual and perceived improvement, satisfaction with certain aspects of service delivery, and quality of interaction with physiotherapy staff. Satisfaction with the amount of therapy was the key determinant for patients' overall satisfaction, whereas relatives' overall satisfaction was influenced primarily by how well they felt they were listened to by physiotherapy staff. CONCLUSION: The high satisfaction of the patients and relatives suggests that our brain injury unit provides physiotherapy that meets their expectations. Promoting recovery, providing high-quality care, and ensuring good interaction are ways to maintain high satisfaction of patients and relatives with the service. In addition, staff may have to pay particular attention to patients' satisfaction with the amount of therapy and ensure that relatives' needs are listened to. PMID- 29271788 TI - Physical, Cognitive, and Psychosocial Characteristics Associated With Mortality in Chronic TBI Survivors: A National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems Study. AB - OBJECTIVE: To compare a group of individuals who died more than 1 year posttraumatic brain injury (TBI) with a matched group of survivors and to identify physical function, cognitive function, and/or psychosocial function variables associated with mortality. DESIGN: Secondary analysis of data from a multicenter longitudinal cohort study. SETTING: Acute inpatient rehabilitation facilities and community follow-up. PARTICIPANTS: Individuals 16 years and older with a primary diagnosis of TBI. MAIN OUTCOME MEASURES: Functional Independence Measure (FIM), Disability Rating Scale, Participation Assessment with Recombined Tools Objective, Extended Glasgow Outcome Scale, Satisfaction With Life Scale. RESULTS: Individuals who died were distinguishable from their surviving counterparts. They demonstrated significantly poorer global functioning on all physical, cognitive, and psychosocial functioning variables at their most recent study follow-up visit prior to death. FIM Motor demonstrated the largest difference between survival groups, suggesting that independence in mobility may be particularly indicative of likelihood of longer-term survival. CONCLUSIONS: These findings may inform continued research to elucidate functional characteristics of individuals postchronic TBI prior to their death and to identify opportunities for prevention of accelerated death and interventions to improve health, longevity, and quality of life. PMID- 29271789 TI - Expression of PD-L1 on Immune Cells Shows Better Prognosis in Laryngeal, Oropharygeal, and Hypopharyngeal Cancer. AB - Despite great enthusiasm towards immunotherapy, reliable biomarkers are still lacking. The importance of subsets based on human papillomavirus (HPV) status is supported by a growing body of evidence. However, role of other possible subgroups such as anatomic localization of primary tumor remains controversial. Our objective was to investigate immune cell infiltrate and checkpoint inhibitor proteins in above-mentioned head and neck cancer subsets. Archival tumor samples of 106 laryngeal, oropharyngeal, and hypopharyngeal cancer patients were stained with PD-L1, PD-L2, PD-1, and CTLA-4 antibodies. Proportion of tumor-infiltrating lymphocytes was assessed as well. In HPV-negative tumors, PD-L1 immune cell positivity was associated with better disease-specific survival. PD-L1 expression on immune cells correlated with improved disease-specific survival in laryngeal tumors. Furthermore, PD-L1 immune cell positivity correlated with CTLA-4 expression on immune cells and it was accompanied by high tumor-infiltrating lymphocyte rate. PD-L1 expression on tumor cells and PD-1 status showed strong correlation in all patients and in oropharyngeal and laryngeal localization, but not in hypopharynx. HPV-negative oropharyngeal cancers showed negative PD-L1 status on tumor cells. CTLA-4 positivity was observed in 49.5% and 20.6% on immune cells and on tumor cells, respectively. We concluded that PD-L1 expression on immune cells indicates better prognosis in laryngeal squamous cell carcinoma and in HPV-negative head and neck squamous cell carcinoma. We have not found any essential differences between anatomic subgroups. A possibly distinct role of hypopharyngeal localization regarding immune activity requires further clarification. PMID- 29271790 TI - PD-L1 Immunohistochemistry Highlights Bone Marrow Involvement by Classic Hodgkin Lymphoma in Staging Biopsies: Implications for Diagnosis and Tumor Microenvironment Alterations. AB - Programmed cell death ligand 1 (PD-L1) is cell surface glycoprotein that regulates the cellular immune response and serves as a targetable immune checkpoint molecule. Previous studies have demonstrated consistent expression of PD-L1 by Reed-Sternberg (RS) cells, as well as nonmalignant tumor-infiltrating macrophages in classic Hodgkin lymphoma (CHL). Bone marrow involvement by CHL is uncommon, being present in 5% to 10% of cases, but indicates Ann Arbor stage IV disease. Given the mixed inflammatory infiltrate that characterizes CHL, detection of RS cells in small bone marrow biopsies may be difficult. We sought to investigate the diagnostic utility of PD-L1 expression in staging bone marrow biopsies from patients with newly diagnosed CHL. Forty-four staging bone marrow biopsies from patients with newly diagnosed CHL were examined for PD-L1 expression by immunohistochemistry. Eight bone marrow biopsies were positive for involvement by CHL (8/44, 18%) and all were positive for PD-L1 (8/8, 100%), including a case that was originally nondiagnostic. Membranous PD-L1 expression was restricted to RS cells and the adjacent nontumor inflammatory cells admixed within areas of fibrosis. Uninvolved bone marrow biopsies and normal-appearing marrow in cases positive for CHL were negative for PD-L1. In comparison, bone marrow biopsies with myelofibrosis caused by myeloproliferative or myelodysplastic disorders were negative for significant PD-L1 staining. PD-L1 expression in RS cells and surrounding inflammatory cells is a sensitive marker for bone marrow involvement by CHL. In cases where RS cells are infrequent, PD-L1 staining in regions of fibrosis may serve as a useful diagnostic clue to involvement by CHL. PMID- 29271791 TI - A Comprehensive Evaluation of Special AT-rich Sequence-binding Protein 2 (SATB2) Immunohistochemical Staining in Mucinous Tumors From Gastrointestinal and Nongastrointestinal Sites. AB - Special AT-rich sequence-binding protein 2 (SATB2) is an accurate marker for conventional colorectal carcinoma (CRC), although its sensitivity and specificity in mucinous tumors from the colon and other sites remains unknown. The objective of this study is to evaluate the accuracy of SATB2 expression detected by immunohistochemical assay, as a marker of primary CRC in mucinous adenocarcinomas. SATB2 immunohistochemical stains were performed on whole sections from 63 conventional CRCs (controls), 47 mucinous CRCs (mCRC), and 182 noncolorectal mucinous tumors. SATB2 intensity was scored as 1 to 3 based on the estrogen receptor/progesterone receptor grading system, and the percent positive cells was scored in broad categories as follows: 0 (negative)<=5%, 1=5% to 49%, 2>=50%. An optimal sensitivity/specificity pairing (83% and 95%, respectively) was achieved in the mCRCs when the additive intensity and percent score was >=3 (ie, intensity score+percent score=total score). Defining this total score (histologic score/"H score") as a "positive" result, the sensitivity of SATB2 for conventional CRC was 98% (62/63) versus 83% (39/47) for mCRCs (P=0.02); whereas 5% (9/182) of all noncolorectal mucinous tumors were considered positive. SATB2 especially demonstrated reduced specificity when applied to mucinous gastroesophageal and breast carcinomas, which showed significant expression in 27% and 9% of cases, respectively. In summary, SATB2 is a less sensitive marker of colorectal origin in mCRC compared with conventional CRC and shows significantly reduced specificity in mucinous gastroesophageal and breast primaries. PMID- 29271792 TI - Hematoxylin and Eosin Counterstaining Protocol for Immunohistochemistry Interpretation and Diagnosis. AB - Hematoxylin and eosin (H&E) staining is a well-established technique in histopathology. However, immunohistochemistry (IHC) interpretation is done exclusively with hematoxylin counterstaining. Our goal was to investigate the potential of H&E as counterstaining (H&E-IHC) to allow for visualization of a marker while confirming the diagnosis on the same slide. The quality of immunostaining and the fast-technical performance were the main criteria to select the final protocol. We stained multiple diagnostic tissues with class I IHC tests with different subcellular localization markers (anti-CK7, CK20, synaptophysin, CD20, HMB45, and Ki-67) and with double-staining on prostate tissues with anti-high molecular weight keratins/p63 (DAB detection) and p504s (alkaline phosphatase detection). To validate the efficacy of the counterstaining, we stained tissue microarrays from the Canadian Immunohistochemistry Quality Control (cIQc) with class II IHC tests (ER, PR, HER2, and p53 markers). Interobserver and intraobserver concordance was assessed by kappa statistics. Excellent agreement of H&E-IHC interpretation was observed in comparison with standard IHC from our laboratory (kappa, 0.87 to 1.00), and with the cIQc reference values (kappa, 0.81 to 1.00). Interobserver and intraobserver agreement was excellent (kappa, 0.89 to 1.00 and 0.87 to 1.00, respectively). We therefore show for the first time the potential of using H&E counterstaining for IHC interpretation. We recommend the H&E-IHC protocol to enhance diagnostic precision for the clinical workflow and research studies. PMID- 29271793 TI - Immunohematology Mesenchymal Stromal Cell-based Therapy: From Research to Clinic. AB - Mesenchymal stromal cells (MSC) are nonhematopoietic cells that can be isolated from several adult and fetal tissues. MSC present specific features as the capacity to support hematopoiesis and to regulate immune response. Thus, the use of MSC as a cell therapeutic product in the field of immune-hematology is of great importance. In this review, we focused on human MSC and discussed their immune-hematologic properties and their translation toward therapeutic clinical applications. Thus, these features hold great promise for cell-based therapy and are of important relevance for the field. PMID- 29271794 TI - BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry. AB - The B-Raf proto-oncogene (BRAF) encodes a cytoplasmic serine/threonine kinase with a key role in regulating the mitogen-activated protein kinase signal transduction pathway. An activating missense mutation in codon 600 of exon 15 (V600E) of BRAF gene has been identified in multiple neoplasms including melanoma, colorectal carcinoma, papillary thyroid carcinoma, hairy cell leukemia, and Langerhans cell histiocytosis. Patients with BRAF V600E-mutated melanoma respond to FDA-approved BRAF inhibitors. In addition, subsets of other BRAF V600E mutated tumors may also benefit from BRAF inhibitor therapy. Currently, clinical laboratories typically use molecular-based methods for mutation analysis. However, recently a BRAF V600E mutation-specific antibody has become available as a cost-effective alternative method to DNA-based molecular testing. We analyzed multiple tumor types including melanoma, colorectal carcinoma, papillary thyroid cancer, hairy cell leukemia, and Langerhans cell histiocytosis using both DNA based sequencing and the BRAF V600E mutation-specific antibody. Our results show a high degree of concordance between the 2 methods. However, the high concordance seems to be limited only to the V600E mutation since variant V600 mutations are missed by V600E mutation-specific immunohistochemistry. PMID- 29271795 TI - Effect of Rehabilitation on Sleep Quality After Ablation for Atrial Fibrillation: Data From a Randomized Trial. AB - BACKGROUND: Low sleep quality is common in patients with atrial fibrillation (AF). Positive effects of cardiac rehabilitation on patients treated for AF with ablation have been found, but whether cardiac rehabilitation affects sleep quality is unknown. The objectives of this study were to investigate (1) differences in sleep quality between cardiac rehabilitation and usual care groups and (2) whether other factors could affect sleep quality. METHODS: From the randomized CopenHeartRFA trial, 210 patients treated for AF with ablation were included. A rehabilitation program consisting of physical exercise and psychoeducational consultations was tested. Sleep quality was measured with the Pittsburg Sleep Quality Index (PSQI) questionnaire before intervention and at the end of intervention. Anxiety, depression, and European Heart Rhythm Association scores were assessed. RESULTS: No difference between groups in sleep quality was found (PSQI global mean [SD] score, 6.60 [3.61] points for the cardiac rehabilitation group [n = 83] and 6.08 [3.60] points for the usual care group [n = 90]; P = .34), although improvements in sleep quality were noted in both groups. Sleep latency, duration, and efficiency were significant by type of AF at 1 month. Anxiety, depression, and higher European Heart Rhythm Association scores at 4 months were associated with a higher PSQI global mean score at the end of intervention. CONCLUSION: The rehabilitation program showed no effect on sleep quality. A large proportion of patients reported poor sleep quality, and patients reporting anxiety, depression, or AF symptoms described worse sleep quality compared with patients who did not experience anxiety, depression, or AF symptoms. More research in the field is warranted. PMID- 29271796 TI - Mindfulness and Chronic Headache/Migraine: Mechanisms Explored Through the Fear Avoidance Model of Chronic Pain. AB - OBJECTIVES: To replicate a study by Schutze and colleagues on a headache sample, rather than a heterogenous chronic pain sample, investigating whether level of mindfulness predicts key components in the Fear-Avoidance Model of chronic pain (pain intensity, negative affect, pain catastrophizing, pain-related fear, pain hypervigilance, and functional disability); to investigate the relationships between level of mindfulness and headache/migraine pain intensity, frequency, and duration. MATERIALS AND METHODS: Participants were 217 individuals who self reported chronic headache/migraine (51 male, 166 female), aged between 18 and 65 years. Participants completed an online survey measuring demographics, mindfulness, the key components of the Fear-Avoidance Model, and headache pain intensity, duration, and frequency. RESULTS: Mindfulness had significant negative correlations (P<0.05) with all variables except headache pain intensity and headache frequency. Mindfulness significantly predicted negative affect, pain catastrophizing, fear of pain, pain hypervigilance, and headache duration (P<0.05). Mindfulness remained a significant predictor of negative affect and pain hypervigilance after controlling for other key components and background characteristics (P<0.05). Mindfulness did not moderate the relationship between pain intensity and pain catastrophizing (P=0.204). DISCUSSION: Findings suggest that mindfulness may be integrated into the Fear-Avoidance Model of chronic pain for individuals with chronic headache/migraine. Directions for future research are discussed. PMID- 29271797 TI - Brain Metabolite Changes in the Anterior Cingulate Cortex of Chronic Low Back Pain Patients and Correlations Between Metabolites and Psychological State. AB - OBJECTIVES: In chronic low back pain (CLBP) patients, study of altered brain metabolites in the anterior cingulate cortex (ACC) using magnetic resonance spectroscopy (MRS) could reveal the detailed pathology of CLBP and depression. The aim was to detect the central difference between CLBP and controls by means of measuring the metabolites in the ACC, and to analyze the correlations between depression and metabolites in ACC. MATERIALS AND METHODS: MRS was performed in CLBP (n=60) and control participants (n=56) to evaluate the effects of CLBP on metabolites in the ACC and to analyze the correlations between metabolites and questionnaire scores in a cross-sectional study. RESULTS: Adjusting for age and sex, a negative effect of CLBP on the N-acetylaspartate (NAA) level (estimated regression slope coefficient [B]=-0.685, P<0.001) and positive effects on the glutamate +glutamine (Glx)/creatine (B=0.136, P=0.016) and Glx/myoinositol (B=0.140, P<0.048) ratios in the ACC were found. The correlation analysis demonstrated that there was a significant moderate correlation between some questionnaire scores of emotional disorders and metabolites in the ACC of CLBP participants (absolute r>0.4, P<0.05). DISCUSSION: Lower NAA levels and higher Glx/creatine and Glx/myoinositol ratios in the ACC of CLBP participants compared with controls were revealed. The result suggests the hypothesis that excessive Glx leads to neuronal dysfunction and/or death, which was reflected as a low NAA level in the ACC of individuals with CLBP. Measurement of these metabolites using MRS potentially helps evaluate CLBP patients' condition and psychological status objectively. PMID- 29271798 TI - Does Self-compassion Benefit Couples Coping With Vulvodynia? Associations With Psychological, Sexual, and Relationship Adjustment. AB - OBJECTIVES: Vulvodynia, a chronic vulvovaginal pain condition, has deleterious consequences for the psychological, relational, and sexual well-being of affected women and their partners. Protective factors, which can reduce these negative effects, are increasingly studied in the field of chronic pain. One of these, self-compassion, entails qualities such as kindness toward oneself, and has been associated with better adjustment in individuals with chronic pain. Because many women with vulvodynia have a negative image of themselves in the context of sexuality, self-compassion may be especially relevant for this population. This study aimed to investigate self-compassion among couples coping with vulvodynia and its associations with psychological, sexual, and relationship adjustment, as well as pain during sexual intercourse. MATERIALS AND METHODS: Data were gathered from 48 women diagnosed with provoked vestibulodynia-a subtype of vulvodynia-and their partners, using self-report questionnaires pertaining to anxiety, depression, sexual distress, relationship satisfaction, and pain intensity during sexual intercourse. RESULTS: For both women and their partners, higher levels of self-compassion were associated with their own lower anxiety and depression. When partners reported higher levels of self-compassion, they were more satisfied with their relationship, and both partners and women reported lower sexual distress. No significant association was found for pain during intercourse. DISCUSSION: Findings suggest that self-compassion is a promising protective factor in the experience of vulvodynia and associated distress. Interventions aimed at increasing self-compassion could enhance the efficacy of psychological treatments for these women and their partners. Further studies are needed to better understand the correlates of self-compassion among this population. PMID- 29271799 TI - Do We Measure What Patients Feel?: An Analysis of Correspondence Between Somatosensory Modalities Upon Quantitative Sensory Testing and Self-reported Pain Experience. AB - OBJECTIVES: Hyperalgesia and allodynia are typical signs of neuropathic pain. Quantitative sensory testing (QST) is a validated tool to clinically assess these phenomena. However, whether QST reveals findings that are reported by the patients is unclear. The aim of this study was therefore to investigate the association between self-reported symptoms assessed with the painDETECT questionnaire (PDQ) with results of validated QST. MATERIALS AND METHODS: PDQ and QST data of 96 patients with chronic neuropathic pain were analyzed. Questions upon presence of painful light touch, painful cold or heat, light pressure triggering pain, and numbness upon PDQ were compared with findings of dynamic mechanical allodynia, increased sensitivity to heat, cold, or pressure pain as well as loss of detection upon QST, respectively. RESULTS: Self-reported pain symptoms upon PDQ showed only a small to moderate concordance with corresponding signs assessed upon QST, whereat the highest, but still only moderate association between self-reported symptoms and measured signs could be obtained for self reported presence of painful light touch and dynamic mechanical allodynia upon QST. However, the positive and negative likelihood ratio to predict QST values with PDQ scores did not reach convincing values. DISCUSSION: Results demonstrate that self-reported PDQ symptoms cannot predict abnormal QST values. The poor predictive power of the PDQ may depend on several factors based on possibility of comparison between PDQ and QST and also on methodical issues. Both, symptoms (questionnaires) and signs address complementary aspects of the pain experience and should be considered for diagnosis and treatment of neuropathic pain. PMID- 29271800 TI - Pediatric Adverse Event Rates Associated With Inexperience in Teaching Hospitals: A Multilevel Analysis. AB - High adverse event rates are a signal of potentially low-quality care that imposes burdens on patients, families, and hospitals. In this article, we examine the relationship between the distinct characteristics of teaching hospitals with adverse event rates among pediatric patients, controlling for patient complexity and severity using 2009-2011 Nationwide Inpatient Sample data from the Agency for Healthcare Research and Quality. We hypothesize that adverse event rates increase with the availability of more complex services and technologies (transplantation and pediatric open-heart surgery); increase as experience of providers decreases (July effect); and increase with residents per bed, a measure of both average provider inexperience and congestion. Using multilevel analysis, we find empirical evidence in support of our three hypotheses. We find that in environments where more learning occurs, more mistakes are made. Identifying high performing hospitals with large residency programs and complex service lines that have made progress in patient safety and then studying how they have done so should become a priority. These findings should then be adapted within other hospitals through publicly funded mechanisms to improve the quality of care for all children. PMID- 29271801 TI - Simulation of the Emergency Department Care Process for Pediatric Traumatic Brain Injury. AB - The treatment of patients in the emergency department (ED) with severe pediatric traumatic brain injury (TBI) is challenging, and treatment process strategies that facilitate good outcomes are not well documented. The overall objective of this study was to identify factors that can affect the care process associated with pediatric TBI. This objective was achieved using a discrete-event simulation model of patients with TBI as they progress through the ED treatment process of a Level I trauma center. This model was used to identify areas where the ED length of stay can be reduced. The number of patients arriving at any given time was also varied in the simulation model to observe the impact to bed allocation policies and changes in staff and equipment. The findings showed that implementing changes in the ED (i.e., availability of two computerized tomography scanners, formation of resuscitation teams that included eight staff personnel, and modifying the bed allocation policy) could result in a 17% reduction in the mean ED length of stay. The study outcomes would be of interest to those (e.g., health administrators, health managers, and physicians) who can make decisions related to the treatment process in an ED. PMID- 29271802 TI - Trendelenburg position in the ED: many critically ill patients in the emergency department do not tolerate the Trendelenburg position. AB - OBJECTIVES: Critically ill patients in emergency departments (ED) frequently require catheterization of the internal jugular vein. For jugular insertion, the Trendelenburg position (TP) is recommended. However, many patients in the ED do not tolerate lying in the supine or even the head-down position, or TP is contraindicated for other reasons. The aim of our trial was to investigate to which extent TP is either not tolerated or contraindicated in the target population of patients admitted to the ED. PATIENTS AND METHODS: This was a clinical observational trial, carried out in an ED of a Tertiary Healthcare Hospital, including critically ill patients. From October 2015 to January 2016, we enrolled 117 nonintubated patients over 18 years admitted to the ED of Jena University Hospital, a Tertiary Healthcare Facility. Patients were positioned in TP (15 degrees head-down) for a maximum of 10 min. If the position had to be abandoned for any reason, time to abandonment and reason for ending the position were recorded. 38.5% of all enrolled patients could not be positioned in TP because of contraindications (17.9%) or intolerance of the positioning (20.5%). RESULTS AND CONCLUSION: For central venous catheterization, TP remains the gold standard. Our trial shows the limitations of this positioning for critically ill patients. Almost 40% of the patients could not be tilted 15 degrees head-down. Therefore, guideline recommendations should be reconsidered and alternatives should be sought. PMID- 29271803 TI - Transcriptional Changes in Dorsal Spinal Cord Persist after Surgical Incision Despite Preemptive Analgesia with Peripheral Resiniferatoxin. AB - BACKGROUND: Peripheral nociceptors expressing the ion channel transient receptor potential cation channel, subfamily V, member 1, play an important role in mediating postoperative pain. Signaling from these nociceptors in the peri- and postoperative period can lead to plastic changes in the spinal cord and, when controlled, can yield analgesia. The transcriptomic changes in the dorsal spinal cord after surgery, and potential coupling to transient receptor potential cation channel, subfamily V, member 1-positive nociceptor signaling, remain poorly studied. METHODS: Resiniferatoxin was injected subcutaneously into rat hind paw several minutes before surgical incision to inactivate transient receptor potential cation channel, subfamily V, member 1-positive nerve terminals. The effects of resiniferatoxin on postincisional measures of pain were assessed through postoperative day 10 (n = 51). Transcriptomic changes in the dorsal spinal cord, with and without peripheral transient receptor potential cation channel, subfamily V, member 1-positive nerve terminal inactivation, were assessed by RNA sequencing (n = 22). RESULTS: Peripherally administered resiniferatoxin increased thermal withdrawal latency by at least twofold through postoperative day 4, increased mechanical withdrawal threshold by at least sevenfold through postoperative day 2, and decreased guarding score by 90% relative to vehicle control (P < 0.05). Surgical incision induced 70 genes in the dorsal horn, and these changes were specific to the ipsilateral dorsal horn. Gene induction with surgical incision persisted despite robust analgesia from resiniferatoxin pretreatment. Many of the genes induced were related to microglial activation, such as Cd11b and Iba1. CONCLUSIONS: A single subcutaneous injection of resiniferatoxin before incision attenuated both evoked and nonevoked measures of postoperative pain. Surgical incision induced transcriptomic changes in the dorsal horn that persisted despite analgesia with resiniferatoxin, suggesting that postsurgical pain signals can be blocked without preventing transcription changes in the dorsal horn. PMID- 29271804 TI - Exposure of Developing Brain to General Anesthesia: What Is the Animal Evidence? AB - Recently, the U.S. Food and Drug Administration issued an official warning to all practicing physicians regarding potentially detrimental behavioral and cognitive sequelae of an early exposure to general anesthesia during in utero and in early postnatal life. The U.S. Food and Drug Administration concern is focused on children younger than three years of age who are exposed to clinically used general anesthetics and sedatives for three hours or longer. Although human evidence is limited and controversial, a large body of scientific evidence gathered from several mammalian species demonstrates that there is a potential foundation for concern. Considering this new development in public awareness, this review focuses on nonhuman primates because their brain development is the closest to humans in terms of not only timing and duration, but in terms of complexity as well. The review compares those primate findings to previously published work done with rodents. PMID- 29271805 TI - Shared Cared for Stable Glaucoma Patients: Economic Benefits and Patient-centered Outcomes of a Feasibility Trial. AB - PURPOSE: The purpose of this article is to assess the quality of care and economic benefits of a shared care model managing patients with stable glaucoma in a primary eye care (PEC) clinic compared with a tertiary specialist outpatient clinic (SOC) in Singapore. PATIENTS AND METHODS: A randomized equivalence feasibility trial was preformed comparing the PEC with SOC models. Participants recruited from the SOC had no visual field progression or change in management for at least 3 years, were on a maximum of a single glaucoma medication, had no previous tube-shunt implant and were at least 3-year posttrabeculectomy surgery.Primary outcomes were clinical assessment and management, economic benefits, and patient satisfaction. Differences were analyzed using equivalence testing and generalized odds ratios. RESULTS: The trial included 233 patients, consisting of 42.1% glaucoma disc suspects (PEC: 47.4%; SOC: 36.8%), 27.5% primary angle closure suspects (PEC: 25.0%; SOC: 29.9%), 13.7% with ocular hypertension (PEC: 13.8%; SOC: 13.7%), 3.9% with primary angle closure glaucoma (PEC: 4.3%; SOC: 3.4%), and 3.0% with primary open angle glaucoma (PEC: 1.7%; SOC: 4.3%). Glaucoma clinical care for patients at PEC was as good as SOC [rate difference, 6.83%; 95% confidence interval (CI), 2.84-11.12) and management (rate difference, 7.69%; 95% CI, 3.21-12.17). In 23 cases (9.9%), 5.2% at PEC and 14.5% at SOC, there was disconcordance with the gold standard of senior consultant. Patient satisfaction at the PEC was equally high when compared with SOC (generalized odds ratio, 1.43; CI, 0.50-2.00). Direct costs per patient visit were 43% lower at PEC compared with SOC. CONCLUSION: Managing stable glaucoma patients at a primary care setting is a cost saving, safe, and effective shared care while enhancing professional collaboration between hospital and community settings. PMID- 29271806 TI - Prospective Evaluation of Standalone XEN Gel Implant and Combined Phacoemulsification-XEN Gel Implant Surgery: 1-Year Results. AB - PURPOSE: To evaluate the safety and efficacy of XEN gel implant (Allergan Inc., Irvine) as a standalone versus combined XEN-Phacoemulsification surgery (XEN+cataract) in glaucoma patients. METHODS: Prospective, interventional study. One-hundred forty-nine eyes (113 patients) with open-angle glaucoma and uncontrolled intraocular pressure (IOP) despite medical treatment were enrolled at a tertiary glaucoma center and followed up for a minimum of 1 year. Approximately two-thirds of patients underwent combined XEN+cataract surgery, while the remainder had XEN alone surgery. Primary outcome was a 20% or more decrease in IOP from medicated baseline at 1 year. Mean IOP, mean number of medications at last follow-up, and incidence of adverse effects were analyzed. RESULTS: Of 149 enrolled eyes, data of 87 (58%) were available at 1 year. A total of 109 (73.2%) eyes underwent XEN+cataract surgery and 40 (26.8%) XEN alone surgery. Mean medicated IOP was 20.0+/-7.1 at baseline and 13.9+/-4.3 mm Hg at 1 year (P<0.01), a 31% IOP reduction. Mean medications dropped from 1.9+/-1.3 preoperatively to 0.5+/-0.8 at 1 year (P<0.001). In total, 62.1% of patients achieved a >=20% IOP reduction; this proportion was higher in the XEN alone group. 57.7% of eyes achieved complete success (without any antiglaucoma medications) and 71.1% qualified success (with or without medications) when IOP<16 mm Hg was considered as the definition of success. In all, 37% of patients required needling intervention. Adverse effects included bleb revision in 5 eyes, choroidal detachment in 2 eyes, and second glaucoma surgery in 9 eyes. CONCLUSIONS: The XEN gel implant as a standalone procedure or combined with cataract surgery demonstrated safe and sustained IOP reduction after 1 year. PMID- 29271807 TI - Is Ophthalmology Residency Training in India Geared to Tackle the Glaucoma Challenge? PMID- 29271808 TI - Ultrasound Biomicroscopic Diagnosis of Angle-closure Mechanisms in Vietnamese Subjects With Unilateral Angle-closure Glaucoma. AB - OBJECTIVE: To identify the mechanisms of angle closure in the fellow eyes of Vietnamese subjects with unilateral primary angle-closure glaucoma (PACG) using ultrasound biomicroscopy (UBM) before and after prophylactic laser peripheral iridotomy (LPI). DESIGN: This is a prospective observational study. PARTICIPANTS: Patients diagnosed with PACG in one eye and primary angle-closure suspect (PACS) in the other eye were included in this study, conducted from January 2014 to October 2014 at Vietnam National Institute of Ophthalmology. MATERIALS AND METHODS: A total of 112 PACS fellow eyes of 112 patients presenting with unilateral PACG were evaluated. All subjects underwent standard ophthalmic clinical examination and UBM imaging a week before and after LPI. On the basis of UBM images, the angle-closure mechanism was defined according to the classification of Svend Vedel Kessing and John Thygesen as pupillary block (PB), plateau iris (PI), and mixed pattern. RESULTS: The proportion of PACS subjects who showed PB was 86.6%, while 13.4% showed a PI configuration before LPI. After LPI the pre-LPI PB group was reclassified, with 55.4% showing pure PB, and 31.3% showing mixed mechanisms (PB and PI). The proportion of patients with PI remained unchanged (13.4%) even after LPI. After the LPI, the angle opening significantly increased in the PB subgroup (14.01+/-2.43 degrees, P<0.01) and reclassified mixed group (6.34+/-1.71 degrees, P<0.01) but remained almost unchanged in the PI group (1.81+/-0.98 degrees, P>0.05). CONCLUSION: On the basis of the UBM criteria, PI was found in 13.4% of PACS fellow eyes of Vietnamese subjects with PACG. The clinical and UBM features of patients showing PI before LPI remained almost unchanged after the procedure. The proportion of patients showing PB pre LPI reduced from 86.6% to 55.4% showing the important role of mixed mechanisms in PACG. PMID- 29271809 TI - The Quantitative Measurements of Vascular Density and Flow Area of Optic Nerve Head Using Optical Coherence Tomography Angiography. PMID- 29271810 TI - Choroidal Microvasculature Dropout is Not Associated With Myopia, But is Associated With Glaucoma. AB - PURPOSE: To investigate the frequency of choroidal microvasculature dropout (CMvD) in healthy myopic eyes in comparison with that of myopic open-angle glaucoma (OAG) eyes and determine whether myopia is independently associated with CMvD. PATIENTS AND METHODS: Choroidal layer microvasculature images were obtained using optical coherence tomography angiography in 89 myopic OAG patients and 89 age-matched and refractive error-matched healthy myopic eyes. CMvD was defined as a complete loss of the microvasculature network on the choroidal layer vessel density (VD) map. The frequency of CMvD was compared between myopic OAG and healthy myopic eyes. Hemispheric comparisons of various parameters were performed between CMvD-affected and CMvD-unaffected hemiretina. The association of myopia with the presence and angular circumference of CMvD was evaluated using logistic and linear regression analyses. RESULTS: CMvD was identified in 40 eyes (47.6%) with myopic OAG, whereas no CMvD was found in healthy myopic eyes. Mean hemispheric visual field sensitivity (294.9+/-321.1 vs. 610.5+/-387.5, P=0.006), retinal nerve fiber layer thickness (68.9+/-11.5 vs. 82.5+/-20.6 MUm, P=0.001), and circumpapillary VD (50.5%+/-7.3% vs. 53.9%+/-8.8%, P=0.048) were significantly worse in the CMvD-affected hemiretina than in the CMvD-unaffected hemiretina. The presence and angular circumference of CMvD was significantly associated with parameters (visual field mean deviation, retinal nerve fiber layer thickness, and circumpapillary VD; P<0.05) representing glaucoma severity rather than parameters (refractive error and axial length; P>0.05) representing myopic change. CONCLUSIONS: CMvD was observed only in glaucomatous eyes and associated with severity of glaucomatous damage in myopic OAG subjects. The angular circumference of CMvD was significantly related to glaucoma severity. PMID- 29271811 TI - Surgically Induced Scleral Necrosis in a Patient With Rheumatoid Arthritis After AGV Implantation. AB - INTRODUCTION: Surgically induced scleral necrosis (SINS) is a rare entity that has till date not been reported in a patient of glaucoma undergoing Ahmed glaucoma valve (AGV) implantation. METHODS: We present a case of primary open angle glaucoma who underwent AGV implantation followed by development of scleral necrosis, involving both the scleral patch graft and host sclera. After failure of surgical and medical management, AGV had to be explanted. The patient was diagnosed with rheumatoid arthritis and had to be treated with steroids and azathioprine for the same. RESULTS: SINS is a potentially disastrous complication of ocular surgery that can occur in patients with systemic diseases like rheumatoid arthritis and requires aggressive management to salvage the eye. CONCLUSION: SINS can occur with AGV implantation. Treatment may require aggressive medical and surgical intervention. It is imperative to evaluate patients for systemic illness before planning an AGV implant. PMID- 29271812 TI - Visually Significant Cystoid Macula Edema After Glaucoma Drainage Implant Surgery. AB - PURPOSE: This study examines the incidence of visually significant cystoid macular edema (CME) after glaucoma drainage implant (GDI) surgery and analyses risk factors associated with developing CME and prognosis with treatment. MATERIALS AND METHODS: In total, 185 eyes from 185 glaucoma patients (mean age, 72.46+/-13.94 y) who underwent GDI surgery at a tertiary eye institute were recruited. Patients were classified based on the presence (CME) or absence (No CME) of CME. Pre-GDI and post-GDI best-corrected visual acuity, number of intraocular pressure (IOP)-lowering medications, IOP, standard automated perimetry and post-GDI complications, were recorded and compared between the 2 groups. Optical coherence tomography (OCT) was used to quantify retinal thickness and monitor CME. RESULTS: In total, 41 (22.2%) eyes developed visually significant CME after GDI surgery. Patients with CME had a higher incidence of pre-GDI nonsteroidal anti-inflammatory drug (P<0.01) use and higher number of prior glaucoma surgeries (P<0.01). CME patients had a higher (P<0.01) incidence of iritis, epiretinal membrane, and hypotony. CME eyes responded well to steroids, with resolving macular edema (458.4+/-151.9 vs. 322.0+/-92.0 um, P<0.01) and improving visual acuity (0.73+/-0.48 vs. 0.56+/-0.56 logarithm of minimum angle of resolution, P<0.01). Both CME and non-CME groups had equivalent lowering of IOP and post-GDI glaucoma medications; with no significant elevation in IOP in the steroid-treated CME group. CONCLUSIONS: Post-GDI surgery visually significant CME rates are potentially higher in a real hospital scenario compared with controlled clinical trials. With diligent treatment, CME resolves effectively restoring visual acuity and central macular thickness. PMID- 29271813 TI - Effect of Individualized Combined Exercise Versus Group-Based Maintenance Exercise in Patients With Heart Disease and Reduced Exercise Capacity: THE DOPPELHERZ TRIAL. AB - PURPOSE: To compare individualized endurance + resistance exercises (ICE) with a traditional cardiac maintenance program (CMP) on exercise performance in patients with cardiac disease and low exercise capacity. METHODS: Patients eligible for cardiac rehabilitation with peak exercise capacity <6 metabolic equivalents (METs) were randomly allocated to once-weekly ICE or CMP for 6 mo. ICE used 60 min of individualized moderate endurance and strength exercises. CMP used 60 min of group calisthenics plus relaxation and flexibility exercises. Maximal and submaximal endurance and strength exercise performance were assessed at baseline and 6 mo. RESULTS: Seventy patients (70 +/- 9 y; 38% female) were included in the intention-to-treat analyses. Large and significant improvements in both submaximal endurance and maximal strength were observed in the ICE group compared with the CMP group. Submaximal exercise duration (+111 +/- 112 sec vs +14 +/- 120 sec, P < .01), workload (+16 +/- 16 W vs +2 +/- 17 W, P < .01), and muscular strength (+7 +/- 8 kg vs 0 +/- 7 kg and +16 +/- 14 kg vs 0.2 +/- 12 kg for upper- and lower-body strength, P < .01) all favored ICE over CMP. No significant between-group differences were observed in peak exercise performance (+0.05 +/- 0.17 W/kg vs +0.04 +/- 0.17 W/kg, P = .83) or peak oxygen uptake (-0.1 +/- 3.1 mL/kg/min vs +0.6 +/- 3.2 mL/kg/min, P = .38). CONCLUSIONS: Patients with cardiac disease and low exercise capacity improved submaximal exercise performance and muscular strength with once-weekly ICE but not with CMP. Neither ICE nor CMP led to an improvement in peak exercise endurance performance. The implementation of ICE in this population would be feasible and may result in greater benefit for performing activities of daily living. PMID- 29271815 TI - Adequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients. AB - BACKGROUND: This study investigates the adequacy of initial everolimus (EVR) dose, with and without calcineurin inhibitors (CNI), in kidney transplant recipients. METHODS: This retrospective cohort analysis involved data from 305 kidney transplant recipients participating in 3 randomized trials receiving reduced dose cyclosporin A (CsA) combined with EVR 0.75 mg BID (CSA/EVR0.75, N = 32) or 1.5 mg BID (CSA/EVR1.5, N = 31), reduced dose tacrolimus (TAC) combined with EVR 1.5 mg BID (TAC0.05/EVR1.5, N = 83), standard dose TAC combined with EVR 1.5 mg BID (TAC0.1/EVR1.5, N = 93), and EVR 1.5 mg BID (EVR1.5, N = 66) with TAC introduction after day 5. The adequacy of the initial EVR dose, based on EVR whole blood trough between 3 and 8 ng/mL, was compared using first EVR blood concentrations obtained at day 3 after transplantation. RESULTS: Recipient age, proportion of patients with diabetes mellitus, and proportion of grafts from living donors were different among the groups. Dose-corrected EVR concentrations were higher in patients receiving CsA than in those receiving TAC or no calcineurin inhibitors (6.7 +/- 5.9 versus 5.4 +/- 2.2 versus 2.4 +/- 0.8 versus 2.5 +/- 0.9 versus 2.2 +/- 0.7, P = 0.000). No differences were observed comparing dose adjusted EVR concentrations combined with TAC or alone (P = 0.073). The proportion of patients with EVR concentration below <3 ng/mL was lower when EVR was combined with CsA (25 versus 3 versus 43 versus 33 versus 50%, P = 0.000). Later introduction of TAC did not influence EVR concentrations. There were no differences in mean CsA concentrations comparing patients receiving EVR 0.75 or 1.5 mg BID (240 +/- 143 versus 213 +/- 105 ng/mL). On the other hand, mean TAC concentrations were higher according to the initial TAC dose regimen (6.4 +/- 3.9 versus 9.8 +/- 5.9 ng/mL). CONCLUSIONS: In de novo kidney transplant recipients, the choice of the initial dose of EVR should consider the type of calcineurin inhibitor to reach target EVR concentration within the first week in a higher proportion of patients, maximizing the efficacy/toxicity profile. PMID- 29271818 TI - Association of Magnet Status and Nurse Staffing With Improvements in Patient Experience With Hospital Care, 2008-2015. AB - BACKGROUND: Little is known about the longitudinal association of hospital Magnet status (an indicator of nursing excellence) and nurse-staffing level with inpatient care experience. OBJECTIVES: To examine temporal trends in hospital performance on patient experience measured using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey and the association of these trends with Magnet status and nurse-staffing level. RESEARCH DESIGN: Longitudinal study of hospital-level data from the HCAHPS survey, the American Hospital Association Annual Survey, and the American Nurses Credentialing Center. Growth curve models were used for the analysis of longitudinal associations. SUBJECTS: A total of 26,752 hospital-year observations from 3614 US hospitals that collected at least 3 years of HCAHPS data from patients discharged between 2008 and 2015. MEASURES: Dependent variables were 7 HCAHPS measures. Independent variables included linear and quadratic time terms, hospital Magnet status, and nurse staffing level. RESULTS: There were significant improvements (P<0.001) in all 7 HCAHPS measures, but the trends were nonlinear; the improvement rates have decreased over time. Magnet hospitals and hospitals with more favorable nurse staffing consistently performed better on HCAHPS but did not improve faster than other hospitals during the study period. In subgroup analyses, HCAHPS scores did not improve for hospitals after they received Magnet recognition during the period from 2009 to 2015. CONCLUSIONS: The hospital organizational attributes that lead to Magnet recognition or better nurse staffing may be associated with higher performance on HCAHPS. Magnet status and favorable nurse staffing may be markers of hospital commitment to better patient-centered care. PMID- 29271817 TI - Students' Midprogram Content Area Performance as a Predictor of End-of-Program NCLEX Readiness. AB - Many programs have implemented end-of-program predictive testing to identify students at risk of NCLEX-RN failure. Unfortunately, for many students, end-of program testing comes too late. Regression and relative importance analysis were used to explore relationships between 9 content area assessments and an end-of program assessment shown to be predictive of NCLEX-RN success. Results indicate that scores on assessments for content areas such as medical surgical nursing and care of children are predictive of end-of-program test scores, suggesting that instructors should provide remediation at the first sign of lagging performance. PMID- 29271816 TI - Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates. AB - BACKGROUND: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. METHODS: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. RESULTS: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used. CONCLUSIONS: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates. PMID- 29271819 TI - Insurance Type and Access to Health Care Providers and Appointments Under the Affordable Care Act. AB - BACKGROUND: Millions of adults have gained insurance through the Affordable Care Act (ACA). However, disparities in access to care persist. OBJECTIVE: This study examined differences in access to primary and specialty care among patients insured by private individual market insurance plans (both on-exchange and off exchange) and Medicaid compared with those with employer-sponsored insurance. RESEARCH DESIGN: Using data from the 2014 and 2015 California Health Interview Survey, logistic regression analyses were used to calculate the odds of being unable to access primary care providers, access specialty care providers and receive a needed doctor's appointment in a timely manner, with insurance type serving as the independent variable. Interaction terms examined if the expiration of the ACA's optional Medicaid primary care fee increase in 2014 modified any of these associations. RESULTS: Findings showed poorer access to providers among those insured through Medicaid and the individual market (whether purchased through the state's health insurance exchange or off-exchange) relative to employer-based insurance. Poor access to primary care providers was seen among private coverage purchased via exchanges, relative to private coverage purchased on the individual market. In addition, findings showed that reduction of Medicaid fees coincided with reduced ability to see primary care providers. However, a similar trend was seen among those with employer-based coverage, which suggests that this change may not be attributable to reductions in Medicaid fees. CONCLUSION: Despite ACA-related gains in insurance coverage, those with on exchange and off-exchange individual private insurance plans and Medicaid encounter more barriers to care than those with employer-based insurance. PMID- 29271820 TI - Defining Multiple Chronic Conditions for Quality Measurement. AB - BACKGROUND/OBJECTIVE: Patients with multiple chronic conditions (MCCs) are a critical but undefined group for quality measurement. We present a generally applicable systematic approach to defining an MCC cohort of Medicare fee-for service beneficiaries that we developed for a national quality measure, risk standardized rates of unplanned admissions for Accountable Care Organizations. RESEARCH DESIGN: To define the MCC cohort we: (1) identified potential chronic conditions; (2) set criteria for cohort conditions based on MCC framework and measure concept; (3) applied the criteria informed by empirical analysis, experts, and the public; (4) described "broader" and "narrower" cohorts; and (5) selected final cohort with stakeholder input. SUBJECTS: Subjects were patients with chronic conditions. Participants included 21.8 million Medicare fee-for service beneficiaries in 2012 aged 65 years and above with >=1 of 27 Medicare Chronic Condition Warehouse condition(s). RESULTS: In total, 10 chronic conditions were identified based on our criteria; 8 of these 10 were associated with notably increased admission risk when co-occurring. A broader cohort (2+ of the 8 conditions) included 4.9 million beneficiaries (23% of total cohort) with an admission rate of 70 per 100 person-years. It captured 53% of total admissions. The narrower cohort (3+ conditions) had 2.2 million beneficiaries (10%) with 100 admissions per 100 person-years and captured 32% of admissions. Most stakeholders viewed the broader cohort as best aligned with the measure concept. CONCLUSIONS: By systematically narrowing chronic conditions to those most relevant to the outcome and incorporating stakeholder input, we defined an MCC admission measure cohort supported by stakeholders. This approach can be used as a model for other MCC outcome measures. PMID- 29271821 TI - Local Health Departments' Promotion of Mental Health Care and Reductions in 30 Day All-Cause Readmission Rates in Maryland. AB - BACKGROUND: Individuals affected with mental health conditions, including mood disorders and substance abuse, are at an increased risk of hospital readmission. OBJECTIVES: The objective of this study is to examine whether local health departments' (LHDs) active roles of promoting mental health are associated with reductions in 30-day all-cause readmission rates, a common quality metric. METHODS: Using datasets linked from multiple sources, including 2012-2013 State Inpatient Databases for the State of Maryland, the National Association of County and City Health Officials Profiles Survey, the Area Health Resource File, and US Census data, we employed multivariate logistic models to examine whether LHDs' active provision of mental health preventive care, mental health services, and health promotion were associated with the likelihood of having any 30-day all cause readmission. RESULTS: Multivariate logistic regressions showed that LHDs' provision of mental health preventive care, mental health services, and health promotion were negatively associated with the likelihoods of having any 30-day readmission for adults 18-64 years old (odds ratios=0.71-0.82, P<0.001), and adults 65 and above (odds ratios=0.61-0.63, P<0.001, preventive care and services, respectively). These estimated associations were more prominent among individuals with mental illness and/or substance use disorders, African Americans, Medicare, and Medicaid enrollees. CONCLUSIONS: Our results suggest that LHDs in Maryland that engage in mental health prevention, promotion, and coordination activities are associated with benefits for residents and for the health care system at large. Additional research is needed to evaluate LHD activities in other states to determine if these results are generalizable. PMID- 29271822 TI - The Association of Patient-centered Medical Home Designation With Quality of Care of HRSA-funded Health Centers: A Longitudinal Analysis of 2012-2015. AB - OBJECTIVES: (1) To evaluate the relationship between Patient-centered Medical Home (PCMH) recognition and quality of clinical care among health centers, and (2) to determine whether the duration of recognition is positively associated with cumulative quality improvement over time. METHODS: Data came from the 2012 to 2015 Uniform Data System, health centers' PCMH recognition status, and the Area Resource File. Health center was the unit of observation. The outcome variables included 11 measures of clinical quality. We pooled all years of data and modeled longitudinal data with generalized estimating equations to examine the degree of improvement in health care quality in health centers with and without PCMH recognition over the years 2012-2015. RESULTS: Health centers with PCMH recognition generally performed better on clinical quality measures than health centers that did not have PCMH recognition for all years studied. After accounting for health center and county-level potential confounders, health centers with longer periods of PCMH recognition were more likely to have improved their clinical quality on 9 of 11 measures, than health centers with fewer years of PCMH recognition. CONCLUSIONS: Health centers' length of time with PCMH recognition was positively associated with additive quality improvement. Adoption of the PCMH model of care may serve as a strategy to enhance quality of primary care services. PMID- 29271823 TI - Collecting Sexual Orientation and Gender Identity Information: Filling the Gaps in Sexual and Gender Minority Health. PMID- 29271824 TI - Major Barbara Stimson: A Historical Perspective on the American Board of Surgery Through the Accomplishments of the First Woman to Achieve Board Certification. AB - : Dr. Barbara Bartlett Stimson, AB, MD, MedScD, FACS (1898-1986) was a pioneering orthopedic surgeon from a prominent American family who, in 1940, became the first woman certified by the American Board of Surgery (ABS, certificate number 860). It would be another 7 years and approximately 2500 candidates before the next female surgeon would be certified. A member of the third class to admit women to Columbia Medical School and the second female surgical resident to complete training at Columbia-Presbyterian Medical Center, Dr. Stimson was a confident and exceptionally accomplished trailblazer for women in surgery. In this biographical sketch based upon documents from the ABS, and the archives of Vassar College and the College of Physicians and Surgeons at Columbia Presbyterian Medical Center, Dr. Stimson's motivations, attitudes, and unique accomplishments emerge as testimony to the exceptional career of this driven, self-possessed woman. Stimson was undaunted by the sex-based conventions of her time, and achieved a notable career as a surgeon in the profession she loved; first honing her skills at a busy urban fracture service in New York, then serving with distinction in the Royal Army Medical Corps during World War II, and finally returning to the states to become a respected leader in her field. Her life story and unprecedented ABS certification affirm her conviction that proven skill and ability can be used as a means of overcoming unfounded biases, and helped pave the way for future generations of board certified female surgeons in the United States. PMID- 29271825 TI - Assessing and Treating Posttraumatic Stress Disorder: An Update. PMID- 29271826 TI - Evoked Death-Related Thoughts in the Aftermath of Terror Attack: The Associations Between Mortality Salience Effect and Adjustment Disorder. AB - ICD-11 has provided a revised definition for adjustment disorder (AjD). The current study examined whether mortality salience effect, a possible consequence of a terror attack, may serve as a significant predictor associated with each of the AjD subscales. Using an online survey, 379 adult participants were recruited and filled out self-reported questionnaires dealing with adjustment disorder symptoms as well as mortality salience effect. Findings revealed that mortality salience effect was a significant predictor of all AjD subscales. The importance of mortality salience effect for AjD is discussed in light of terror management theory. PMID- 29271827 TI - The Influence of Trauma Type and Timing on PTSD Symptoms. AB - Although it is well known that different trauma histories can uniquely affect subsequent trauma-related symptoms, this is the first study to evaluate individual posttraumatic stress symptoms (PTSSs) in relation to trauma type and timing. This cross-sectional study surveyed a consecutive sample of mental health outpatients (n = 602), using regression to estimate associations between DSM-5 PTSSs and demographics, several trauma types, and age at first trauma in those with trauma (n = 367). Combat and sexual trauma were associated with worse total PTSS severity. Combat was significantly associated with arousal and intrusions (especially physical symptoms), sexual trauma with conscious avoidance and negative cognitions/mood (especially amnesia, an unconscious avoidance symptom), and physical assault with blame. Interpersonal traumas were the most common first traumas experienced, but age at first trauma was not significantly associated with PTSS severity. We discuss potential explanations and implications of these findings. PMID- 29271828 TI - Missing Syndromes. PMID- 29271829 TI - Reduction of Injection-Related Risk Behaviors After Emergency Implementation of a Syringe Services Program During an HIV Outbreak. AB - OBJECTIVE: To describe injection-related HIV risk behaviors preimplementation and postimplementation of an emergency syringe services program (SSP) in Scott County, Indiana, after an HIV outbreak among persons who inject drugs (PWID). DESIGN: Mixed methods retrospective pre-post intervention analysis. METHODS: We analyzed routine SSP program data collected at first and most recent visit among clients with >=2 visits, >=7 days apart from April 4 to August 30, 2015, to quantify changes in injection-related risk behaviors. We also analyzed qualitative data collected from 56 PWID recruited in Scott County to understand factors contributing to these behaviors. RESULTS: SSP clients included in our analysis (n = 148, 62% of all SSP clients) reported significant (P < 0.001) reductions over a median 10 weeks (range 1-23) in syringe sharing to inject (18% 2%) and divide drugs (19%-4%), sharing other injection equipment (eg, cookers) (24%-5%), and number of uses of the same syringe [2 (interquartile range: 1-4) to 1 (interquartile range: 1-1)]. Qualitative study participants described access to sterile syringes and safer injection education through the SSP, as explanatory factors for these reductions. Injection frequency findings were mixed, but overall suggested no change. The number of syringes returned by SSP clients increased from 0 at first visit to median 57. All qualitative study participants reported using sharps containers provided by the SSP. CONCLUSIONS: Analyses of an SSP program and in-depth qualitative interview data showed rapid reduction of injection-related HIV risk behaviors among PWID post-SSP implementation. Sterile syringe access as part of comprehensive HIV prevention is an important tool to control and prevent HIV outbreaks. PMID- 29271830 TI - Clinic-Based Evaluation of a Point-of-Care Creatinine Assay to Screen for Renal Impairment Among HIV-Positive Patients Receiving Tenofovir Disoproxil Fumarate. PMID- 29271831 TI - Verbal Learning and Memory After Cochlear Implantation in Postlingually Deaf Adults: Some New Findings with the CVLT-II. AB - OBJECTIVES: Despite the importance of verbal learning and memory in speech and language processing, this domain of cognitive functioning has been virtually ignored in clinical studies of hearing loss and cochlear implants in both adults and children. In this article, we report the results of two studies that used a newly developed visually based version of the California Verbal Learning Test Second Edition (CVLT-II), a well-known normed neuropsychological measure of verbal learning and memory. DESIGN: The first study established the validity and feasibility of a computer-controlled visual version of the CVLT-II, which eliminates the effects of audibility of spoken stimuli, in groups of young normal hearing and older normal-hearing (ONH) adults. A second study was then carried out using the visual CVLT-II format with a group of older postlingually deaf experienced cochlear implant (ECI) users (N = 25) and a group of ONH controls (N = 25) who were matched to ECI users for age, socioeconomic status, and nonverbal IQ. In addition to the visual CVLT-II, subjects provided data on demographics, hearing history, nonverbal IQ, reading fluency, vocabulary, and short-term memory span for visually presented digits. ECI participants were also tested for speech recognition in quiet. RESULTS: The ECI and ONH groups did not differ on most measures of verbal learning and memory obtained with the visual CVLT-II, but deficits were identified in ECI participants that were related to recency recall, the buildup of proactive interference, and retrieval-induced forgetting. Within the ECI group, nonverbal fluid IQ, reading fluency, and resistance to the buildup of proactive interference from the CVLT-II consistently predicted better speech recognition outcomes. CONCLUSIONS: Results from this study suggest that several underlying foundational neurocognitive abilities are related to core speech perception outcomes after implantation in older adults. Implications of these findings for explaining individual differences and variability and predicting speech recognition outcomes after implantation are discussed. PMID- 29271832 TI - Implementation of a Workflow Initiative for Integrating Transitional Care Management Codes in a Geriatric Primary Care Practice. AB - We implemented a transitional care management service led by a nurse care manager. An interdisciplinary team developed a workflow using a Plan-Do-Study-Act cycle for contacting patients. Of the 146 (97.9%) eligible patients, 143 (97.9%) had a phone call within 48 hours. There were 84 of 120 (70.0%) and 117 of 120 (97.5%) attendance rates of those attending visits within 7 and 14 days. A care manager-led workflow was successfully and easily implemented within a primary care practice. PMID- 29271833 TI - Evaluating the Effectiveness of a Fall Risk Screening Tool Implemented in an Electronic Medical Record System. AB - We investigated the effect of using a fall risk screening tool in an electronic medical record system by using data for 25 039 patients in 24 general wards of a single institution. The probability of the occurrence of falls decreased after the tool was implemented, but using the tool did not reduce the actual occurrence of falls. This indicates that we must improve not only the assessment of the risk of falls but also the interventions to prevent falls. PMID- 29271834 TI - Spatiotemporal expression patterns of chondroitin sulfate proteoglycan mRNAs in the developing rat brain. AB - Chondroitin sulfate proteoglycans (CSPGs) are pluripotent components of the extracellular matrix in the brain. Although previous studies have examined the developmental change in certain CSPGs in the whole brain, no known systematic studies have been carried out on the temporal or spatial expression of CSPGs. Here, we used quantitative real-time PCR to examine the CSPG mRNAs expression in the postnatal developing rat brain starting from postnatal day 5-42, mainly focusing on the parietal cortex, hippocampus, and corpus callosum. Results were further verified by immunohistochemistry. Our results showed that aggrecan, brevican, phosphacan, and NG2 generally showed upregulation across developmental stages in all three regions. Neurocan showed a rapid increase until postnatal day 10 in all three regions. Versican, however, showed a sharp decrease until postnatal day 10. Cross-region analysis showed higher expression of most CSPG members in the corpus callosum during later stages of development. Further immunohistochemistry staining confirmed our results by showing prominent CSPGs protein expression in the corpus callosum. In summary, our study reported specific temporal-expression and spatial-expression patterns of the CSPGs species. These results are consistent with the known roles of these members in neurodevelopment. The current study provided clues for the development of CSPGs as potential treatment targets in neurodevelopmental disorders. PMID- 29271835 TI - Acute Effect of Aerobic and Strength Exercise on Heart Rate Variability and Baroreflex Sensitivity in Men with Autonomic Dysfunction. AB - The extent to which post-exercise cardiac autonomic control depends on exercise modality remains unclear, particularly among individuals with autonomic dysfunction (CAdysf). This study compared heart rate variability (HRV) and baroreflex sensitivity (BRS) responses to acute aerobic (AE) and strength exercise (SE) in men with CAdysf. Twenty men were assigned into control (n=10: 33.8+/-3.0 yr; 23.7+/-1.5 kg/m) and CAdysf (n=10: 36.2+/-9.8 yr; 28.4+/-2.6 kg/m) groups. CAdysf underwent AE, SE, and a non-exercise control day (CTL) in a randomized, counter-balanced order. HRV and BRS were assessed in a supine position during 25-min of recovery after AE, SE, and CTL. Both HRV indices [P < 0.05; Effect size (Cohen's d): > 1.4] and BRS at rest were significantly lower in CAdysf than controls [P < 0.01; Effect size (Cohen's d): >= 1.36]. In CAdysf, post-exercise increases in heart rate, sympathetic activity (low-frequency band, LF), and sympathovagal balance (LF:HF ratio), as well as decreases in R-R interval, parasympathetic activity (high-frequency band, HF), and BRS were observed in AE [P < 0.05; Effect size (Cohen's d): >= 1.31] and SE [P < 0.05; Effect size (Cohen's d): >= 0.79] vs. CTL, but changes were larger after AE than SE [P < 0.05; Effect size (Cohen's d): >= 0.73]. In conclusion, both AE and SE elicited post-exercise changes in HRV and BRS among CAdysf men, primarily reflected by lowered vagal modulation, increased sympathovagal balance, and a delayed BRS recovery pattern. However, those changes seem to be more likely to occur after AE than SE. PMID- 29271836 TI - The Economic Burden of Bladder Cancer Due to Occupational Exposure. AB - OBJECTIVE: To estimate the economic burden of bladder cancer due to occupational exposures. METHODS: Using a societal perspective, we estimate the lifetime costs of newly diagnosed cases of bladder cancer in Canada that is associated with occupational exposure for the calendar year 2011. The three major categories we consider are direct, indirect, and quality of life costs. RESULTS: There were 199 newly identified cases of bladder cancer. The estimated total cost of bladder cancer for new cases in 2011 was $131 million and an average per-case cost of $658,055 CAD (2011 dollars). Of the total costs, direct costs accounted for 6%, indirect costs 29%, and health-related quality of life costs 65%. CONCLUSIONS: The per-case economic burden of bladder cancer due to occupational exposure is substantial which suggests the importance and value of exposure reduction. PMID- 29271837 TI - Hydration Status, Kidney Function, and Kidney Injury in Florida Agricultural Workers. AB - OBJECTIVE: Recent findings suggest that laboring in hot occupational environments is related to kidney damage in agricultural workers. We examined hydration status and kidney function in 192 Florida agricultural workers. METHODS: Blood and urine samples were collected over 555 workdays during the summers of 2015 and 2016. Urine-specific gravity (USG), serum creatinine, and other kidney function markers were examined pre- and post-shift on each workday. Multivariable mixed modeling was used to examine the association of risk factors with hydration status and acute kidney injury (AKI). RESULTS: Approximately 53% of workers were dehydrated (USG >=1.020) pre-shift and 81% post-shift; 33% of participants had AKI on at least one workday. The odds of AKI increased 47% for each 5-degree ( degrees F) increase in heat index. CONCLUSION: A strikingly high prevalence of dehydration and AKI exists in Florida agricultural workers. PMID- 29271838 TI - Tuberculosis Prevalence Among US Crop-Workers, 2000 to 2012: Trends and Contributing Factors. AB - OBJECTIVE: We intend to study tuberculosis (TB) in one of the poorest communities in the US, hired agriculture workers, for most recent years (2000 to 2012) including the last recession period. METHODS: Time-chart, simple mean differences, and logistic regressions were used to describe TB-prevalence and risk factors among US crop-workers. Data were drawn from the National Agricultural Workers Survey (NAWS). RESULTS: A high TB-prevalence was found among crop-workers with a dramatically increasing trend in recent years. Hispanic ethnicity, having farmworker family members, the presence of health insurance, and good spoken English were associated with an increased TB-prevalence. CONCLUSION: We found risk factors related to ethnicity and poor access to health care, a strong association between agriculture activity and TB, and an increase of TB-cases due to the 2008 downturn in this underserved population. We urge the health authorities to control this epidemic. PMID- 29271839 TI - The Impact of Work Absences on Health Services Utilization and Costs Among Employed Individuals With Depression. AB - OBJECTIVE: The aim of this study was to evaluate whether work absences are associated with increased health services utilization, total health care costs, and depression-related costs among employed individuals, aged 18 to 64 years with depression. METHODS: This was a retrospective observational study using pooled data from the 2011 to 2014 Medical Expenditure Panel Survey (MEPS). Employed individuals with depression were identified using ICD-9 codes and Clinical Classification code. Logistic regression, Poisson regression, and generalized linear models were used for analysis. RESULTS: Individuals with depression who reported work absences had greater odds of having a hospitalization event [odds ratio (OR): 7.111; 95% confidence interval (95% CI): 3.121 to 16.203], higher number of other health care visits (beta = 0.188, P = 0.041), and had higher total health care costs (beta = 0.550, P <= 0.001) than individuals with no work absences. CONCLUSION: Among employed individuals with depression, self-reported work absence is associated with significantly higher health care utilization and total health care costs. PMID- 29271840 TI - A Structured Health Intervention for Truckers (SHIFT): A Process Evaluation of a Pilot Health Intervention in a Transport Company. AB - OBJECTIVES: To undertake a process-evaluation of a structured health intervention for truckers (SHIFT) implemented in a sample of UK lorry drivers. METHODS: A combination of "debrief interviews," focus groups and one-to-one interviews, in addition to observations and reflections of the two lead researchers were used to collect data on the acceptability of SHIFT from a group of 16 lorry drivers and four transport managers. RESULTS: The SHIFT program was considered relevant and acceptable to lorry drivers. It provided them with health information tailored to their specific health needs, long-lasting tools and techniques, which helped to raise their awareness of key health issues and helped to stimulate lifestyle changes during their daily routine. CONCLUSION: This process-evaluation suggests that the SHIFT program should now be evaluated on a larger scale and tested through fully randomized controlled trials. PMID- 29271841 TI - Business Travel and Behavioral and Mental Health. AB - OBJECTIVE: Assess associations between business travel and behavioral and mental health. METHODS: Cross-sectional analyses of de-identified electronic medical record data from EHE International, Inc. a provider of corporate wellness programs. RESULTS: Higher levels of business travel were associated with poorer outcomes. Compared with traveling 1 to 6 nights/mo for work, those who traveled 21+ nights were more likely to: smoke (prevalence ratio [PR] = 3.74, 95% confidence interval [CI] 2.56, 5.46), report trouble sleeping (PR = 1.37, 95% CI 1.09, 1.71), be sedentary (PR = 1.95, 95% CI 1.56, 2.43), and score above clinical thresholds for alcohol dependence (CAGE score >1: PR = 2.04, 95% CI 1.26, 3.29), and mild or worse anxiety (Generalized Anxiety Scale [GAD-7] score >4: PR = 1.69, 95% CI 1.29, 2.21), and depression symptoms (Patient Health Questionnaire [PHQ-9] score >4: PR = 2.27, 95% CI 1.70, 3.03). CONCLUSIONS: Employers should provide programs to help employees manage stress and maintain health while traveling for work. PMID- 29271842 TI - Isolated Traumatic Subarachnoid Hemorrhage: An Evaluation of Critical Care Unit Admission Practices and Outcomes From a North American Perspective. AB - OBJECTIVES: Traumatic subarachnoid hemorrhage is a common radiographic finding associated with traumatic brain injury. The objective of this investigation is to evaluate the association between hospital-level ICU admission practices and clinically important outcomes for patients with isolated traumatic subarachnoid hemorrhage and mild clinical traumatic brain injury. DESIGN: Multicenter observational cohort. SETTING: Trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program spanning January 2012 to March 2014. PATIENTS: A total of 14,146 subjects, 16 years old and older, admitted to 215 trauma centers with isolated traumatic subarachnoid hemorrhage and Glasgow Coma Scale score 13 or greater. Patients with concurrent intracranial injuries, severe injury to other body regions, or tests positive for alcohol or illicit substances were excluded. INTERVENTION: ICU admission. MEASUREMENTS AND MAIN RESULTS: The primary outcome was need for neurosurgical intervention, defined as insertion of an intracranial monitor/drain or craniectomy/craniotomy. Secondary outcomes describing the clinical course included hospital discharge disposition, in-hospital mortality, and length of stay. Admission to ICU was common within the cohort (44.6%), yet the need for neurosurgical intervention was rare (0.24%). Variability was high between centers and remained so after adjusting for differences in case-mix and hospital-level characteristics (median odds ratio, 4.1). No significant differences in neurosurgical interventions, mortality, or discharge disposition to home under self-care were observed between groups of the highest and lowest ICU admitting hospitals. However, those in highest admitting group "stayed" in hospital 1.13 (95% CI, 1.07-1.20; p < 0.001) times that of the lowest admitting group. CONCLUSIONS: Critical care admission for mild traumatic brain injury patients with isolated traumatic subarachnoid hemorrhage is frequent and highly variable despite low probability of requiring neurosurgical intervention. Reevaluation of hospital-level practices may represent an opportunity for resource optimization when managing patients with mild clinical traumatic brain injury and associated isolated traumatic subarachnoid hemorrhage. PMID- 29271843 TI - Early Identification of Acute Respiratory Distress Syndrome in the Absence of Positive Pressure Ventilation: Implications for Revision of the Berlin Criteria for Acute Respiratory Distress Syndrome. AB - OBJECTIVES: To assess whether patients breathing spontaneously under standard oxygen could be recognized early as acute respiratory distress syndrome patients according to the current Berlin definition. DESIGN: A post hoc analysis from two prospective studies. SETTING: Twenty-three French ICUs. PATIENTS: All patients admitted for acute hypoxemic respiratory failure and treated with noninvasive ventilation were analyzed. Patients with cardiogenic pulmonary edema, acute exacerbation of chronic obstructive pulmonary disease, or hypercapnia were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The PaO2/FIO2 ratio was estimated at admission under standard oxygen and then under noninvasive ventilation 1 hour after initiation and within the first 24 hours. Among the 219 patients treated with noninvasive ventilation for acute hypoxemic respiratory failure, 180 (82%) had bilateral infiltrates including 161 patients with PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen. Among them, 127 were treated with positive end-expiratory pressure of at least 5 cm H2O, and 120 (94%) fulfilled criteria for acute respiratory distress syndrome within the first 24 hours. The mortality rate of patients with bilateral infiltrates and PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen was 29%, a rate very close to that of intubated patients with acute respiratory distress syndrome in the Berlin definition. CONCLUSIONS: Almost all patients with pulmonary bilateral infiltrates and a PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen fulfilled the acute respiratory distress syndrome criteria under noninvasive ventilation within the first 24 hours. Their mortality rate was similar to that reported in the Berlin definition of acute respiratory distress syndrome. Therefore, spontaneous breathing patients with the acute respiratory distress syndrome criteria could be identified early without positive pressure ventilation. PMID- 29271844 TI - Efficacy and Safety of Procalcitonin Guidance in Patients With Suspected or Confirmed Sepsis: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Sepsis is a leading cause of mortality in noncoronary ICUs. Although immediate start of antibiotics reduces sepsis-related mortality, antibiotics are often administered for too long, leading to suboptimal treatment and, importantly, contributes to antimicrobial resistance. Prior literature suggests that procalcitonin correlates with infection and thus may help to guide the decision on when to stop antibiotic treatment. This study was conducted as part of a regulatory submission to the U.S. Food and Drug Administration and aimed to summarize the evidence of procalcitonin guidance on efficacy and safety outcomes in adult patients with sepsis. DATA SOURCES: PubMed and the Cochrane Database of Systematic Reviews. STUDY SELECTION: English-language randomized controlled trials evaluating procalcitonin use among adult patients with suspected or confirmed sepsis published between January 2004 and May 2016. DATA EXTRACTION: Inverse-variance weighting fixed and random effects meta-analyses were performed on the following efficacy and safety endpoints: antibiotic duration, all-cause mortality, and length of ICU stay. Two reviewers independently extracted data elements from identified studies and measured risk of bias with the Cochrane Risk of Bias Tool. DATA SYNTHESIS: From a total of 369 potentially eligible articles, 10 randomized controlled trials containing 3,489 patients were used for analysis. Procalcitonin-guided patients had shorter antibiotics duration compared with controls (7.35 vs. 8.85 d; weighted mean difference, -1.49 d; 95% CI, -2.27 to 0.71; p < 0.001). Procalcitonin use had no adverse impact on mortality (risk ratio, 0.90; 95% CI, 0.79-1.03; p = 0.114) and length of ICU stay (11.09 d vs. 11.91 d; weighted mean difference, -0.84 d; 95% CI, -2.52 to 0.84; p = 0.329). CONCLUSIONS: In adult patients with suspected or confirmed sepsis, procalcitonin guidance reduces antibiotics duration with no observed adverse effects on patient outcomes. PMID- 29271845 TI - Role of Chronic Stress and Exercise on Microvascular Function in Metabolic Syndrome. AB - PURPOSE: The present study examined the effect of unpredictable chronic mild stress (UCMS) on peripheral microvessel function in healthy and metabolic syndrome (MetS) rodents and whether exercise training could prevent the vascular dysfunction associated with UCMS. METHODS: Lean and obese (model of MetS) Zucker rats (LZR and OZR) were exposed to 8 wk of UCMS, exercise (Ex), UCMS + Ex, or control conditions. At the end of the intervention, gracilis arterioles (GA) were isolated and hung in a pressurized myobath to assess endothelium-dependent (EDD) and endothelium-independent (EID) dilation. Levels of nitric oxide (NO) and reactive oxygen species (ROS) were measured through 4-amino-5-methylamino-2',7' difluorofluorescein diacetate and dihydroethidium staining, respectively. RESULTS: Compared with LZR controls, EDD and EID were lower (P = 0.0001) in LZR UCMS. The OZR-Ex group had a higher EDD (P = 0.0001) and EID (P = 0.003) compared with OZR controls, whereas only a difference in EDD (P = 0.01) was noted between the LZR-control and LZR-Ex groups. Importantly, EDD and EID were higher in the LZR (P = 0.0001; P = 0.02) and OZR (P = 0.0001; P = 0.02) UCMS + Ex groups compared with UCMS alone. Lower NO bioavailability and higher ROS were noted in the LZR-UCMS group (P = 0.0001), but not OZR-UCMS, compared with controls. The Ex and UCMS-Ex groups had higher NO bioavailability (P = 0.0001) compared with the control and UCMS groups, but ROS levels remained high. CONCLUSIONS: The comorbidity between UCMS and MetS does not exacerbate the effects of one another on GA EDD responses, but does lead to the development of other vasculopathy adaptations, which can be partially explained by alterations in NO and ROS production. Importantly, exercise training alleviates most of the negative effects of UCMS on GA function. PMID- 29271846 TI - Lower-Limb Dominance, Performance, and Fiber Type in Resistance-trained Men. AB - INTRODUCTION: Large imbalances between limbs are common and potentially dangerous, yet few studies have simultaneously examined performance and physiological asymmetries. The current study examined the associations between lower-limb dominance, drop-jumping kinematics, maximal strength, and myosin heavy chain (MHC) fiber type in the vastus lateralis. METHODS: Thirteen resistance trained men (age, 24.3 +/- 2.7 yr; height, 181.4 +/- 6.6 cm; mass, 87.7 +/- 11.3 kg) identified their dominant (DOM) and nondominant (ND) limb, performed drop jumps (30 cm) and maximal knee extensions (1-repetition maximum, or 1RM), and provided biopsies from both vastus lateralis muscles for single-fiber (109 +/- 36 per limb per person) MHC fiber-type identification (FT%). RESULTS: All participants selected "right" as the "preferred kicking limb" (DOM). DOM displayed a trend for a greater eccentric knee angular velocity (EKV; P = 0.083) and a significantly greater concentric knee angular velocity (CKVl P = 0.002) during drop jump. DOM also tended to be stronger than ND (64.3 +/- 11.3 vs 61.0 +/- 8.8 kg, P = 0.063). Slow-twitch (MHC I) fibers were more prevalent in DOM (P < 0.025), whereas ND contained more fast-twitch (MHC IIa; P < 0.025). No correlations existed between categories (jumping, 1RM, and FT%). Asymmetries of >5% were present in 6 of 12 participants for EKV, 2 of 12 for CKV, 6 of 13 for 1RM, 12 of 13 for MHC I, and 11 of 13 for MHC IIa. However, only a single participant expressed asymmetries of >5% in all dependent variables (EKV, CKV, 1RM, MHC I, and MHC IIa). CONCLUSIONS: Several statistically and clinically relevant asymmetries were identified. The FT% differences between lower limbs were large and common. The findings also seem to conclude that DOM was stronger, moved faster, and contained more MHC I. However, only 23% of participants actually displayed that result. This highlights the need to analyze and report both group and individual data, particularly when interpreting findings across multiple related, but not necessarily causal, measurements. PMID- 29271847 TI - Estimating Energy Expenditure with ActiGraph GT9X Inertial Measurement Unit. AB - PURPOSE: The purpose of this study was to explore whether gyroscope and magnetometer data from the ActiGraph GT9X improved accelerometer-based predictions of energy expenditure (EE). METHODS: Thirty participants (mean +/- SD: age, 23.0 +/- 2.3 yr; body mass index, 25.2 +/- 3.9 kg.m) volunteered to complete the study. Participants wore five GT9X monitors (right hip, both wrists, and both ankles) while performing 10 activities ranging from rest to running. A Cosmed K4b was worn during the trial, as a criterion measure of EE (30-s averages) expressed in METs. Triaxial accelerometer data (80 Hz) were converted to milli-G using Euclidean norm minus one (ENMO; 1-s epochs). Gyroscope data (100 Hz) were expressed as a vector magnitude (GVM) in degrees per second (1-s epochs) and magnetometer data (100 Hz) were expressed as direction changes per 5 s. Minutes 4-6 of each activity were used for analysis. Three two-regression algorithms were developed for each wear location: 1) ENMO, 2) ENMO and GVM, and 3) ENMO, GVM, and direction changes. Leave-one-participant-out cross-validation was used to evaluate the root mean square error (RMSE) and mean absolute percent error (MAPE) of each algorithm. RESULTS: Adding gyroscope to accelerometer-only algorithms resulted in RMSE reductions between 0.0 METs (right wrist) and 0.17 METs (right ankle), and MAPE reductions between 0.1% (right wrist) and 6.0% (hip). When direction changes were added, RMSE changed by <=0.03 METs and MAPE by <=0.21%. CONCLUSIONS: The combined use of gyroscope and accelerometer at the hip and ankles improved individual-level prediction of EE compared with accelerometer only. For the wrists, adding gyroscope produced negligible changes. The magnetometer did not meaningfully improve estimates for any algorithms. PMID- 29271848 TI - Exercise Increases Glucose Transporter-4 Levels on Peripheral Blood Mononuclear Cells. AB - PURPOSE: Glucose transporter 4 (GLUT4) plays a key role in the pathophysiology of type 2 diabetes. Glucose transporter 4 is upregulated in response to exercise, enhancing cellular glucose transport in skeletal muscle tissue. This mechanism appears to remain intact in individuals with insulin resistance. Details of the mechanism are poorly understood and are challenging to study due to the invasive nature of muscle biopsy. Peripheral blood mononuclear cells (PBMC) have documented insulin-sensitive GLUT4 activity and may serve as a proxy tissue for studying skeletal muscle GLUT4. The purpose of this study was to investigate whether GLUT4 in PBMC is affected by conditioning. METHODS: We recruited 16 student athletes from the cross-country running and skiing teams and fifteen sedentary students matched for age and sex from the University of Alaska Fairbanks. Peripheral blood mononuclear cells were collected with mononuclear cell separation tubes. The GLUT4 concentrations were measured using a commercially available enzyme linked immunosorbent assay. Additionally, correlations between PBMC GLUT4 and common indicators of insulin resistance were examined. RESULTS: Results indicate significantly higher PBMC GLUT4 levels in conditioned athletes than in their sedentary counterparts, similar to what has been documented in myocytes. Females were observed to have higher PBMC GLUT4 levels than males. Correlations were not detected between PBMC GLUT4 and hemoglobin A1c, glucose, insulin, homeostatic model assessment of insulin resistance, body mass index, or body fat. CONCLUSIONS: This study provides evidence to support exploration of PBMC as a proxy tissue for studying GLUT4 response to exercise or other noninsulin factors. PMID- 29271849 TI - Temporal Patterns of Cervical Cancer Screening Among Danish Women 55 Years and Older Diagnosed With Cervical Cancer. AB - OBJECTIVE: The aim of the study was to describe the screening history in postmenopausal women diagnosed with cervical cancer during 1990-2013 by age and screening period. MATERIALS AND METHODS: This hospital-based cohort study included women 55 years and older diagnosed with cervical cancer at Aarhus University Hospital, Denmark, during 1990-2013. Information on their previous history of cervical cancer screening was obtained from the Danish Pathology Databank. RESULTS: Overall, 47.0% (95% CI = 42.6-51.4) had no record of screening before their cervical cancer diagnosis. This proportion declined over calendar time from 69.8% (95% CI = 61.4-77.3) in 1990-1994 to 20.0% (95% CI = 12.7-29.2) in 2010-2013 and increased by age from 22.5% (95% CI = 14.6-32.0) in women aged 55 to 59 years to 63.2% (95% CI = 49.3-75.6) in women 80 years and older. Cases living in the organized screening era (i.e., birth cohorts 1943-1960) were more likely to have a record of screening than women in the preorganized screening era (i.e., birth cohorts 1901-1942) (p < .001). Of all cases, 17.7% (n = 91) had a record of screening within 5 years of diagnosis and the proportion was highest in the most recent periods and in women aged 55 to 64 years. Of cases with a record of screening within 5 years, 84.6% (95% CI = 14.5-21.2) had a normal cytology result, whereas only 8.8% (95% CI = 2.9-14.7) had high-grade squamous intraepithelial lesion or worse. CONCLUSIONS: Cervical cancer in older women may partly be attributed to a lack of screening or due to a failure in screening. However, older women were in general less screened because screening was unavailable. PMID- 29271850 TI - A Cross-Sectional Review of Cervical Cancer Messages on Twitter During Cervical Cancer Awareness Month. AB - OBJECTIVES: The objectives of this study were to quantify personal stories about cervical cancer and to determine the proportion and sentiment (positive vs negative) of messages ("tweets") that discussed cervical cancer prevention strategies on Twitter. METHODS: This study was a cross-sectional Twitter review of English-language top tweets about cervical cancer during the Cervical Cancer Awareness month, January 2016. Theme categories were identified, and tweets were independently coded by 2 reviewers; discrepancies in coding were resolved by a third reviewer. Descriptive statistical analyses were performed. RESULTS: During January 2016, approximately 348 top tweets about cervical cancer were identified. Professional health organizations produced 20.7% of tweets, and individuals identifying themselves as health-care professionals contributed an additional 4%. In addition to the tweet, 45.1% attached a photo or video; 54.6% included links to a larger article. Only 11.2% of tweets included personal stories from cervical cancer patients. Among the top tweets, 70.3% were focused on prevention through screening and/or HPV vaccination, with 97.4% recommending such practices. A substantial proportion of the Twitter traffic (24.7%) referenced the #SmearForSmear campaign by the patient-advocate organization Jo's Cervical Cancer Trust, based in the United Kingdom. CONCLUSIONS: Analysis of top tweets during the cervical cancer awareness month showed that, although personal stories about cervical cancer were rare, cervical cancer prevention was a popular topic during the cervical cancer awareness month. This was largely driven by a picture-based twitter campaign from a single advocacy organization. PMID- 29271851 TI - Utility of Human Papillomavirus Genotyping in the Management of Low-Grade Squamous Intraepithelial Lesions. AB - OBJECTIVE: The aim of the study was to determine the usefulness of human papillomavirus (HPV) partial genotyping test in the triage of newly diagnosed low grade squamous intraepithelial lesions (LSILs). MATERIALS AND METHODS: We analyzed 143 patients with LSIL diagnosed de novo. Lesions were classified as positive for HPV 16 or HPV 18, positive for HPV but not HPV 16 or HPV 18 (HPVno16no18) or no HPV detected (HPVneg). Patients were followed for a period of 2 years or until the lesion progressed. We calculated absolute and relative risks for progression and regression according to the HPV result. RESULTS: The mean (SD) age was 33.8 (11.1) years. A total of 19.6% were positive for HPV 16, 4.9% for HPV 18, and 63.6% for HPVno16no18. The absolute risk of HPV 16 for progression to cervical intraepithelial neoplasia grade 2 or more (CIN 2+) was 32.1%, 14.3% for HPV 18, and 5.8% for HPVno16no18. None of the HPVneg cases evolved to CIN 2+. The presence of HPV 16 conferred a 7.4 (95% CI = 2.7-20.3) times greater risk of developing CIN 2+ than its absence. The absolute risks for HPV 16, HPV 18, HPVno16no18, and HPVneg for regression were 53.6%, 57.1%, 75.4%, and 87.5%, respectively. Relative risks for regression were 0.7 (95% CI = 0.5 0.9) for HPV 16 and 1.3 (95% CI = 1.1-1.5) for HPVneg. CONCLUSIONS: The HPV 16 LSILs are more likely to progress to CIN 2+, so tight control and immediate colposcopy are crucial, whereas when HPV 16 is not present, follow-up could be less strict. Low-grade squamous intraepithelial lesions in which high-risk HPV is not detected do not progress to CIN 2+, so its control should be different from other LSIL, and conservative management could be an acceptable strategy. PMID- 29271852 TI - High-Risk Human Papillomavirus Detection in Urine Samples From a Referral Population With Cervical Biopsy-Proven High-Grade Lesions. AB - : The aim of the study was to evaluate the performance of the HPV-HR test to detect high-risk human papillomavirus (HPV) in urine samples in comparison with a commercial molecular HPV test. MATERIALS AND METHODS: This is a prospective study, in which 350 patients diagnosed previously with cervical intraepithelial neoplasia (CIN) grade 2 or higher were enrolled. Urine and cervical specimens were collected. Urine was tested with the HPV-HR test and cervical specimens were tested with the Cobas. RESULTS: Of the 336 evaluable patients, there were 271 cases of CIN 2+, of which 202 were CIN 3+ and the remaining 65 patients were less than CIN 2. Positivity was 77.1% (95% confidence interval [CI] = 72.5-81.5) for the urine samples and 83.6% (95% CI = 79.6-87.6) for the cervical samples. Agreement between cervical and urine samples for HPV detection was 79.8% (kappa = 0.363; 95% CI = 0.243-0.484). Sensitivity for CIN 2+ was 83.4% (95% CI = 78.4 87.6) for urine and 90.8% (95% CI = 86.7-92.9) for cervical samples. The sensitivity for CIN 3+ was 85.6% (95% CI = 80.0-90.2) for urine and 92.6% (95% CI = 88.0-95.8) for cervical samples. Specificity for worse than CIN 2 was 50.8% (95% CI = 33.7-59.0) and 46.2% (95% CI = 33.7-59.0) for urine and cervical samples, respectively. CONCLUSIONS: Although these results demonstrated slightly higher detection rates for HR-HPV and clinical sensitivity in cervical samples than in urine, when compared with histological diagnoses, urine sampling is a viable alternative to access women who do not participate in routine screening programs. PMID- 29271853 TI - Depth of Cervical Intraepithelial Neoplasia Grade 3 in Peruvian Women: Implications for Therapeutic Depth of Necrosis. AB - OBJECTIVE: To determine the involvement of cervical intraepithelial neoplasia grade 3 (CIN3) in a population of women in a lower-resource setting. METHODS: One hundred twelve consecutive cone excision specimens with histological diagnosis of CIN3 were retrieved from the National Institute of Neoplastic Diseases in Lima Peru. Two pathologists independently evaluated each specimen microscopically and confirmed 107 cases that could be measured by optical micrometry. Depth and breadth of the lesions were measured microscopically. RESULTS: The mean maximal depth of cervical involvement by CIN3 was 2 +/- 0.13 mm; depth was less than 3.5 mm in 89.7% of cases and less than 5 mm in 93.5%. Mean breadth of CIN3 was 7.3 +/ 4.4 mm; breadth was less than 15.9 mm in 95% of cases and less than 20.5 mm in 99.7%. The correlation coefficient between breadth and depth of CIN3 was 0.61. No significant correlation was found between age and depth. CONCLUSIONS: Depth of CIN3 involvement in a developing country is significantly deeper than that reported in the United States. Treatment selection for women with CIN3 and risk of treatment failure may vary between developing and developed countries because of the difference in the depth of lesions. Countries with underscreened populations need to consider the increased disease severity in devising treatment strategies. PMID- 29271854 TI - Risk Factors of Inadequate Colposcopy After Large Loop Excision of the Transformation Zone: A Prospective Cohort Study. AB - OBJECTIVE: The aim of the study was to identify the risk factors of post-large loop excision of the transformation zone (LLETZ) inadequate colposcopy. MATERIALS AND METHODS: From December 2013 to July 2014, a total of 157 patients who had a LLETZ performed for the treatment of high-grade intraepithelial lesion with fully visible cervical squamocolumnar junction were included. All procedures were performed using semicircular loops. The use of colposcopy made during each procedure was systematically documented. Dimensions and volume of LLETZ specimens were measured at the time of procedure, before formaldehyde fixation. All participants were invited for a follow-up colposcopy 3 to 6 months after LLETZ. Primary end point was the diagnosis of post-LLETZ inadequate colposcopy, defined by a not fully visible cervical squamocolumnar junction and/or cervical stenosis. RESULTS: Colposcopies were performed in a mean (SD) delay of 136 (88) days and were inadequate in 22 (14%) cases. Factors found to significantly increase the probability of post-LLETZ inadequate colposcopy were a history of previous excisional cervical therapy [adjusted odds ratio (aOR) = 4.29, 95% CI = 1.12 16.37, p = .033] and the thickness of the specimen (aOR = 3.12, 95% CI = 1.02 9.60, p = .047). The use of colposcopy for the guidance of LLETZ was statistically associated with a decrease in the risk of post-LLETZ inadequate colposcopy (aOR = 0.19, 95% CI = 0.04-0.80, p = .024) as the achievement of negative endocervical margins (aOR = 0.26, 95% CI = 0.08-0.86, p = .027). CONCLUSIONS: Although the risk of post-LLETZ inadequate colposcopy is increased in patients with history of excisional therapy and with the thickness of the excised specimen, it could be reduced with the use of colposcopic guidance and the achievement of negative endocervical margins. PMID- 29271855 TI - Lidocaine Spray Versus Paracervical Block During Loop Electrosurgical Excision Procedure: A Randomized Trial. AB - OBJECTIVE: The aim of the study was to compare the effectiveness of pain control between lidocaine spray (LS) and paracervical block (PB) with lidocaine during the loop electrosurgical excision procedure (LEEP). MATERIALS AND METHODS: A single-blinded randomized controlled trial was conducted on 132 women who underwent LEEP of the cervix. The participants were randomly allocated to either a PB group or a LS group. The PB group participants were anesthetized by PB using 10 mL of 2% lidocaine with 1:100,000 of epinephrine. The LS group participants were locally anesthetized with four puffs (40 mg) of 10% LS, which was applied thoroughly to the cervix. Pain scores, using 10-cm visual analog scales, were obtained and compared for participants in both groups during anesthesia, during excision and 30 minutes after excision. RESULTS: A total of 132 LEEPs were performed with 66 in LS group and 66 in PB group. The mean (SD) pain scores during excision were 5.2 (2.4) in the LS group and 4.2 (3.3) in the PB group (mean difference = 1.1, 95% CI = 0.8 to 2.1, p = .033), which was within the nonclinically significant margin of this study. The baseline pain score after speculum examination was not significantly different in both groups. There was no adverse effect in the LS group compared with eight cases in the PB group (tinnitus, numbness, palpitation or tachycardia, and hypertension). CONCLUSIONS: The local 40 mg of 10% LS can be used to substitute for PB for pain control during LEEP of the cervix. It also resulted in fewer adverse effects. PMID- 29271856 TI - Impact of Trainee Involvement in Cervical Excision Procedures: Does Trainee Involvement Impact Quality? AB - OBJECTIVE: Cervical excision procedures are essential to the care of cervical dysplasia and malignancy. We sought to determine whether learner involvement in cervical excision procedures affects the quality of excision specimen. MATERIALS AND METHODS: A retrospective cohort study of cervical cancer patients diagnosed from July 1, 2000, to July 1, 2015, was performed. We included patients who had (1) a cervical excision procedure, either loop electrosurgical excision procedure or cold knife cone, and (2) pathologic information available. Primary outcome was the margin status of the specimen; secondary outcome was the size of the excision specimen including both width and depth. The exposure of interest was trainee participation, defined as resident physicians under the supervision of either a gynecologist or gynecologic oncologist. Descriptive statistics and general linear models were used for analysis. RESULTS: Ninety-four patients were identified. Overall, 58% (n = 54) of procedures were performed with trainee involvement. There was no difference in age, body mass index, or specimen width between trainee-performed and nontrainee-performed excisions. There was no significant difference in the status of margins with or without a trainee [44/57 (77%) and 29/37 (78%), respectively, p = .89]. There was a statistically significant difference in median specimen depth between trainee-performed and nontrainee performed cases (15.4 mm vs 12 mm, p < .02). When adjusting for age, body mass index, excision type, indication, presence of trainee, and type of supervising physician, only the indication and type of excision were associated with greater depth of excision, (p < .01). CONCLUSIONS: Trainee involvement in cervical excision procedures does not alter the quality of excision specimen. PMID- 29271857 TI - Effects of Maintenance on Quality of Performance of Cryotherapy Devices for Treatment of Precancerous Cervical Lesions. AB - OBJECTIVE: The aim of the study was to evaluate the impact of maintenance on performance of cryosurgical equipment used in El Salvador primary health clinics. MATERIALS AND METHODS: Nine gynecological cryotherapy devices used in El Salvador were bench tested against a new machine of the same make and model. The devices were run for five successive double-freeze cycles. The El Salvador machines then received maintenance by a specialized engineer and another double-freeze cycle was performed. Temperature at the device probe tip was recorded throughout each cycle and ballistic gelatin was used as the tissue analogue to measure freeze ball dimensions achieved by the devices. Outcome measures were mean lowest sustained temperatures and freeze ball mean weight, depth, and diameter. Paired and unpaired t tests were used to compare results premaintenance versus postmaintenance and postmaintenance versus the reference, respectively. RESULTS: Premaintenance versus postmaintenance freeze ball dimensions were significantly different (mean differences in weight = 2.31 g, p = .01; depth = 2.29 mm, p = .03; diameter = 3.51 mm, p = .02). However, postmaintenance dimensions were not significantly different than those of the reference (weight = 7.44 g vs. 8.39 g, p = .07; depth = 10.71 vs. 11.24 mm, p = .1; diameter = 31.38 mm vs. 32.05 mm, p = .3). Postmaintenance, minimum, and lowest-sustained temperatures were within the recommended clinical range. CONCLUSIONS: Specialized maintenance was necessary for heavily used cryotherapy devices to perform adequately, highlighting the challenges of gas-based cryotherapy in low- and middle-income countries. PMID- 29271859 TI - Photodynamic Therapy for Vulvar Lichen Sclerosus-A Systematic Review. AB - OBJECTIVE: Lichen sclerosus (LS) is a disease affecting mostly genital and perianal areas. Photodynamic therapy (PDT) has gained interest during the past years. The present study accumulates current evidence on the efficacy of PDT in the management of vulvar LS. METHODS: We used Medline (1966-2017), Scopus (2004 2017), ClinicalTrials.gov (2008-2017) and Cochrane Central Register of Controlled Trials CENTRAL (1999-2017) databases in our primary search along with the reference lists of electronically retrieved full-text papers. RESULTS: Eleven studies were finally included in our systematic review, which recruited 337 women. The existing evidence supports that PDT results in significant relief of symptoms related to LS, hence remains confusing in evaluating the progress in the clinical appearance of the lesion. No major adverse effects were reported during therapy and during the posttreatment period. Pathologic findings seem to be conflicting, as current data do not unanimously support a beneficial histological effect. CONCLUSIONS: According to the findings of our study, PDT seems to be promising in the treatment of patients with vulvar LS. Nonetheless, current knowledge is extremely limited, and further observational studies with large patient series are needed in the field to elucidate the efficacy of PDT. PMID- 29271858 TI - Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia. AB - OBJECTIVES: Localized provoked vulvodynia (LPV) afflicts approximately 8% of women in the United States and represents a huge financial, physical, and psychological burden. Women with LPV experience intense pain localized to the vulvar vestibule (area immediately surrounding vaginal opening). We have identified mechanisms involved in the development of LPV whereby vulvar fibroblasts respond to proinflammatory stimuli to perpetuate an inflammatory response that causes pain. However, these mechanisms are not fully elucidated. Therefore, we explored the role of toll-like receptors (TLRs), a class of innate immune receptors that rapidly respond to microbial assaults. MATERIALS AND METHODS: To determine whether TLRs are expressed by vulvar fibroblasts and whether these contribute to proinflammatory mediator production and pain in LPV, we examined TLR expression and innate immune responses in fibroblasts derived from painful vestibular regions compared with nonpainful external vulvar regions. RESULTS: Human vulvar fibroblasts express functional TLRs that trigger production of inflammatory mediators associated with chronic pain. We focused on the TLR-7 imiquimod proinflammatory interaction, because imiquimod, a ligand of TLR-7, may exacerbate pain in women during treatment of human papillomavirus-associated disease. CONCLUSIONS: Human vulvar fibroblasts express a broad spectrum of TLRs (a new finding). A significantly higher TLR-mediated proinflammatory response was observed in LPV case vestibular fibroblasts, and with respect to the imiquimod TLR 7 interaction, development of chronic vestibular pain and inflammation may be a possible sequelae of treatment of vulvar human papillomavirus-associated disease. Suppressing enhanced TLR-associated innate immune responses to a spectrum of pathogen-associated molecular patterns may represent a new/effective therapeutic approach for vulvodynia. PMID- 29271860 TI - Interpretation of Nondiagnostic Vulvar Biopsies. AB - OBJECTIVE: The aim of the study was to assess clinical and histopathologic characteristics of symptomatic women who underwent a nondiagnostic biopsy of the inner vulva. MATERIALS AND METHODS: Consecutive nondiagnostic biopsies from medial labia minora, posterior fourchette, and vestibule obtained from symptomatic women between 2011 and 2015 were reviewed for this retrospective histopathologic case series. Histopathologic assessment included site, basal layer appearance, lymphocytic infiltrate, and presence of fibrosis or sclerosis. Examination findings, treatment, initial impression, and final clinical diagnosis were recorded. Descriptive statistics were performed; clinical and histopathologic characteristics were compared with Fisher exact test. RESULTS: There were 85 cases; mean age was 53 years. Most women presented with painful erythema and underwent biopsy to confirm (30, 35%) or exclude (43, 51%) lichen planus. After clinical follow-up and histopathologic review, most cases had persistent diagnostic discordance. Final clinical diagnoses were available in 70 women: lichen planus in 27 (38%), vulvodynia in 15 (21%), and the other 28 (40%) had LS (8), plasma cell vulvitis (5), psoriasis (4), dermatitis (4), candidosis (3), estrogen deficiency (3), and aphthosis (1). Histopathologic review highlighted the difficulty in distinguishing mucosa-associated lymphoid tissue from an inflammatory infiltrate in 23 (27%) of cases. Compared with other sites, biopsies from the mucocutaneous junction were more likely to be associated with a positive culture for Candida albicans. CONCLUSIONS: Nondiagnostic biopsies from the inner vulva should prompt thoughtful multidisciplinary review, but more research is required to resolve the problem of clinicopathologic discordance through better understanding of vulvar histology and pathophysiology. PMID- 29271861 TI - Painless Vulvar Masses as Initial Manifestation of Marginal Zone Lymphoma. PMID- 29271862 TI - Lung Metastasis From Fibrosarcomatous Dermatofibrosarcoma Protuberans of the Vulva: A Rare Case Report. PMID- 29271863 TI - Article Summaries for January 2018 Psychosomatic Medicine, Volume 80, Issue 1. PMID- 29271864 TI - Accelerated DNA Methylation Age: Associations With Posttraumatic Stress Disorder and Mortality. AB - OBJECTIVE: Recently developed indices of cellular age based on DNA methylation (DNAm) data, referred to as DNAm age, are being used to study factors that influence the rate of aging and the health correlates of these metrics of the epigenetic clock. This study evaluated associations between trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and accelerated versus decelerated DNAm age among military veterans. We also examined whether accelerated DNAm age predicted mortality over the course of a 6.5-year medical record review period. METHODS: Three hundred thirty-nine genotype-confirmed white, non-Hispanic, middle aged, trauma-exposed veterans underwent psychiatric assessment and genome-wide DNAm analysis. DNAm age was calculated using a previously validated algorithm. Medical records were available for a subset of 241 veterans and were reviewed approximately 6.5 years after DNA collection and PTSD assessment. RESULTS: PTSD hyperarousal symptoms were associated with accelerated DNAm age (beta = 0.20, p = .009) but trauma exposure and total PTSD severity were not. Accelerated DNAm age was also associated with 13% increased risk for all-cause mortality (hazard ratio = 1.13, 95% confidence interval = 1.01-1.26) during the medical record review period. CONCLUSIONS: Findings of this study replicate the association between PTSD and accelerated DNAm age and suggest that this effect may be specific to the hyperarousal symptom cluster. Results point to the potential utility of DNAm age algorithms for identifying individuals who are aging at an accelerated rate and for determining the factors that influence this process. PMID- 29271865 TI - Psychosomatic Medicine Reviewers in 2017. PMID- 29271867 TI - IgG Degrading Enzyme of Streptococcus Pyogenes: An Exciting New Development in Desensitization Therapy. PMID- 29271868 TI - The Cutting Edge of HLA Diagnostics. PMID- 29271869 TI - The Importance of Using Serially Measured Tacrolimus Clearance Values, Especially During the Early Posttransplantation Period. PMID- 29271870 TI - Association of postoperative organ space infection after intraoperative irrigation in appendicitis. AB - BACKGROUND: The benefit of intraoperative irrigation on postoperative abscess rates compared to suction alone is unclear. The American Association for the Surgery of Trauma grading system provides distinct disease severity stratification to determine if prior analyses were biased by anatomic severity. We hypothesized that for increasing appendicitis severity, patients receiving (high, >=2 L) intraoperative irrigation would have increased postoperative organ space infection (OSI) rate compared to (low, <2 L) irrigation. METHODS: Single institution review of adults (>18 years) undergoing appendectomy for appendicitis during 2010-2016. Demographics, operative details, irrigation volumes, duration of stay, and complications (Clavien-Dindo classification) were collected. American Association for the Surgery of Trauma grades were assigned by two independent reviewers based on operative findings. Summary, univariate, and area under the receiver operating curve analyses were performed. RESULTS: Patients (n = 1187) were identified with a mean (SD) age of 41.6 (18.4) years (45% female). Operative approach included laparoscopy (n = 1122 [94.5%]), McBurney incision (n = 10 [0.8%]), midline laparotomy (n = 16 [1.3 %]), and laparoscopy converted to laparotomy (n = 39 [3.4%)]. The mean (SD) volume of intraoperative irrigation was 410 (1200) mL. Complication rate was 26.1%. Median volume of intraoperative irrigation in patients who developed postoperative OSI was 3 [0-4] compared to 0 [0-0] in those without infection (p < 0.0001). Area under the receiver operating curve analysis determined that 2 or more liters of irrigation was associated with postoperative OSI (c statistic: 0.83, 95% confidence interval, 0.76-0.89; p < 0.001). CONCLUSION: Irrigation is used for increasingly severe appendicitis with wide variation. Irrigation volumes of 2 L or greater are associated with postoperative OSI. Improving standardization of irrigation volume (<2 L) may prevent morbidity associated with this high-volume disease. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 29271871 TI - Validation of a new American Association for the Surgery of Trauma (AAST) anatomic severity grading system for acute cholecystitis. AB - BACKGROUND: The American Association for the Surgery of Trauma (AAST) established anatomic grading to facilitate risk stratification and risk-adjusted outcomes in emergency general surgery. Cholecystitis severity was graded based on clinical, imaging, operative, and pathologic criteria. We aimed to validate the AAST anatomic grading system for acute cholecystitis. METHODS: This is a retrospective cohort study including consecutive patients admitted with acute cholecystitis at an urban, tertiary medical center between 2013 and 2016. Grade 1 is acute cholecystitis, Grade 2 is gangrenous or emphysematous cholecystitis, Grade 3 is localized perforation, and Grades 4 and 5 have regional and systemic peritonitis, respectively. Concordance between the AAST grade and outcome including mortality, length of stay (LOS), ICU use, readmission, and complications were assessed using logistic regression. RESULTS: A total of 315 patients were included. There was very good inter-rater (two independent raters) reliability for anatomic grading, kappa = 1.00, p < 0.005. The majority of patients were Grade 1 or Grade 2 (94%). Incidence of complications, LOS, ICU use, and any adverse event increased with increasing anatomic grade. When compared to Grade 1 disease, patients with Grade 2 were more likely to undergo cholecystectomy (OR 4.07 [1.93-8.56]). Grade 3 patients were at higher risk of adverse events (OR 3.83 [1.34-10.94]), longer LOS (OR 1.73 [1.03-2.92]), and ICU use (OR 8.07 [2.43-26.80]). CONCLUSIONS: AAST severity scores were independently associated with clinical outcomes in patients with acute cholecystitis. Despite low-grade disease, complications were common, and therefore a refinement of the scoring system may be necessary for more granular prediction. LEVEL OF EVIDENCE: Epidemiologic/prognostic, level III. PMID- 29271872 TI - Methanol Generates Numerous Artifacts during Sample Extraction and Storage of Extracts in Metabolomics Research. AB - Many metabolomics studies use mixtures of (acidified) methanol and water for sample extraction. In the present study, we investigated if the extraction with methanol can result in artifacts. To this end, wheat leaves were extracted with mixtures of native and deuterium-labeled methanol and water, with or without 0.1% formic acid. Subsequently, the extracts were analyzed immediately or after storage at 10 degrees C, -20 degrees C or -80 degrees C with an HPLC-HESI QExactive HF-Orbitrap instrument. Our results showed that 88 (8%) of the >1100 detected compounds were derived from the reaction with methanol and either formed during sample extraction or short-term storage. Artifacts were found for various substance classes such as flavonoids, carotenoids, tetrapyrrols, fatty acids and other carboxylic acids that are typically investigated in metabolomics studies. 58 of 88 artifacts were common between the two tested extraction variants. Remarkably, 34 of 73 (acidified extraction solvent) and 33 of 73 (non-acidified extraction solvent) artifacts were formed de novo as none of these meth(ox)ylated metabolites were found after extraction of native leaf samples with CD3OH/H2O. Moreover, sample extracts stored at 10 degrees C for several days, as can typically be the case during longer measurement sequences, led to an increase in both the number and abundance of methylated artifacts. In contrast, frozen sample extracts were relatively stable during a storage period of one week. Our study shows that caution has to be exercised if methanol is used as the extraction solvent as the detected metabolites might be artifacts rather than natural constituents of the biological system. In addition, we recommend storing sample extracts in deep freezers immediately after extraction until measurement. PMID- 29271873 TI - Bicycle Facilities That Address Safety, Crime, and Economic Development: Perceptions from Morelia, Mexico. AB - Mexico is a developing nation and, in the city of Morelia, the concept of the bicyclist as a road user appeared only recently in the Municipal Traffic Regulations. Perhaps the right bicycle infrastructure could address safety, crime, and economic development. To identify the best infrastructure, six groups in Morelia ranked and commented on pictures of bicycle environments that exist in bicycle-friendly nations. Perceptions about bike paths, but only those with impossible-to-be-driven-over solid barriers, were associated with safety from crashes, lowering crime, and contributing to economic development. Shared use paths were associated with lowering the probability of car/bike crashes but lacked the potential to deter crime and foster the local economy. Joint bus and bike lanes were associated with lower safety because of the unwillingness by Mexican bus drivers to be courteous to bicyclists. Gender differences about crash risk biking in the road with the cars (6 best/0 worst scenario) were statistically significant (1.4 for male versus 0.69 for female; p < 0.001). For crashes, crime, and economic development, perceptions about bicycle infrastructure were different in this developing nation perhaps because policy, institutional context, and policing (ticketing for unlawful parking) are not the same as in a developed nation. Countries such as Mexico should consider building cycle tracks with solid barriers to address safety, crime, and economic development. PMID- 29271874 TI - The Major Chromophore Arising from Glucose Degradation and Oxidative Stress Occurrence during Lens Proteins Glycation Induced by Glucose. AB - Glucose autoxidation has been proposed as a key reaction associated with deleterious effects induced by hyperglycemia in the eye lens. Little is known about chromophores generated during glucose autoxidation. In this study, we analyzed the effect of oxidative and dicarbonyl stress in the generation of a major chromophore arising from glucose degradation (GDC) and its association with oxidative damage in lens proteins. Glucose (5 mM) was incubated with H2O2 (0.5-5 mM), Cu2+ (5-50 MUM), glyoxal (0.5-5 mM) or methylglyoxal (0.5-5 mM) at pH 7.4, 5% O2, 37 degrees C, from 0 to 30 days. GDC concentration increased with incubation time, as well as when incubated in the presence of H2O2 and/or Cu2+, which were effective even at the lowest concentrations. Dicarbonylic compounds did not increase the levels of GDC during incubations. 1H, 13C and FT-IR spectra from the purified fraction containing the chromophore (detected by UV/vis spectroscopy) showed oxidation products of glucose, including gluconic acid. Lens proteins solutions (10 mg/mL) incubated with glucose (30 mM) presented increased levels of carboxymethyl-lysine and hydrogen peroxide that were associated with GDC increase. Our results suggest a possible use of GDC as a marker of autoxidative reactions occurring during lens proteins glycation induced by glucose. PMID- 29271875 TI - A New Label-Free Technique for Analysing Evaporation Induced Self-Assembly of Viral Nanoparticles Based on Enhanced Dark-Field Optical Imaging. AB - Nanoparticle self-assembly is a complex phenomenon, the control of which is complicated by the lack of appropriate tools and techniques for monitoring the phenomenon with adequate resolution in real-time. In this work, a label-free technique based on dark-field microscopy was developed to investigate the self assembly of nanoparticles. A bio-nanoparticle with complex shape (T4 bacteriophage) that self-assembles on glass substrates upon drying was developed. The fluid flow regime during the drying process, as well as the final self assembled structures, were studied using dark-field microscopy, while phage diffusion was analysed by tracking of the phage nanoparticles in the bulk solutions. The concentrations of T4 phage nanoparticles and salt ions were identified as the main parameters influencing the fluid flow, particle motion and, consequently, the resulting self-assembled structure. This work demonstrates the utility of enhanced dark-field microscopy as a label-free technique for the observation of drying-induced self-assembly of bacteriophage T4. This technique provides the ability to track the nano-sized particles in different matrices and serves as a strong tool for monitoring self-assembled structures and bottom-up assembly of nano-sized building blocks in real-time. PMID- 29271876 TI - GE11 Peptide as an Active Targeting Agent in Antitumor Therapy: A Minireview. AB - A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting agent to the polymer portion of a colloidal drug delivery system loaded with an antitumor drug. The goal of this minireview is to report and discuss some recent results in epidermal growth factor receptor targeting by the GE11 peptide combined with colloidal drug delivery systems as smart carriers for antitumor drugs. The minireview chapters will focus on explaining and discussing: (i) Epidermal growth factor receptor (EGFR) structures and functions; (ii) GE11 structure and biologic activity; (iii) examples of GE11 conjugation and GE11-conjugated drug delivery systems. The rationale is to contribute in gathering information on the topic of active targeting to tumors. A case study is introduced, involving research on tumor cell targeting by the GE11 peptide combined with polymer nanoparticles. PMID- 29271877 TI - Effects of Dietary Protein on Thyroid Axis Activity. AB - Thyroid hormones (TH) are essential for the normal development and function of every vertebrate. The hypothalamic-pituitary-thyroid (HPT) axis is regulated to maintain euthyroid status. One of the most influential environmental factors that determines HPT axis activity is nutrition. Both food availability and substrate diversity affect thyroid hormone economy. The present paper aims to summarize literature data concerning the influence of the amount and the type of protein on thyroid axis activity. This review sheds light on the contribution of a low protein diet or insufficient intake of essential amino acids to TH abnormalities. We believe that the knowledge of these dependencies could improve the results of nutritional interventions in thyroid axis disorders and enhance the efficiency of animal breeding. PMID- 29271878 TI - Facilitating a More Efficient Commercial Review Process for Pediatric Drugs and Biologics. AB - Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the influx of new drug and biologic candidates. As a result, it has become standard for months or even years of waiting for commercial approval by the U.S. Food and Drug Administration. These regulatory delays have generated a system that stifles growth and innovation due to the exorbitant costs associated with awaiting approval from the nation's sole regulatory agency. The recent re-emergence of diseases that impact pediatric demographics represents one particularly acute reason for developing a regulatory system that facilitates a more efficient commercial review process. Herein, we present a range of initiatives that could represent early steps toward alleviating the delays in approving life-saving therapeutics. PMID- 29271880 TI - Time Series Analysis for Spatial Node Selection in Environment Monitoring Sensor Networks. AB - Wireless sensor networks are widely used in environmental monitoring. The number of sensor nodes to be deployed will vary depending on the desired spatio-temporal resolution. Selecting an optimal number, position and sampling rate for an array of sensor nodes in environmental monitoring is a challenging question. Most of the current solutions are either theoretical or simulation-based where the problems are tackled using random field theory, computational geometry or computer simulations, limiting their specificity to a given sensor deployment. Using an empirical dataset from a mine rehabilitation monitoring sensor network, this work proposes a data-driven approach where co-integrated time series analysis is used to select the number of sensors from a short-term deployment of a larger set of potential node positions. Analyses conducted on temperature time series show 75% of sensors are co-integrated. Using only 25% of the original nodes can generate a complete dataset within a 0.5 degrees C average error bound. Our data-driven approach to sensor position selection is applicable for spatiotemporal monitoring of spatially correlated environmental parameters to minimize deployment cost without compromising data resolution. PMID- 29271879 TI - Assessing the Effectiveness of a Far-Red Fluorescent Reporter for Tracking Stem Cells In Vivo. AB - Far-red fluorescent reporter genes can be used for tracking cells non-invasively in vivo using fluorescence imaging. Here, we investigate the effectiveness of the far-red fluorescent protein, E2-Crimson (E2C), for tracking mouse embryonic cells (mESCs) in vivo following subcutaneous administration into mice. Using a knock-in strategy, we introduced E2C into the Rosa26 locus of an E14-Bra-GFP mESC line, and after confirming that the E2C had no obvious effect on the phenotype of the mESCs, we injected them into mice and imaged them over nine days. The results showed that fluorescence intensity was weak, and cells could only be detected when injected at high densities. Furthermore, intensity peaked on day 4 and then started to decrease, despite the fact that tumour volume continued to increase beyond day 4. Histopathological analysis showed that although E2C fluorescence could barely be detected in vivo at day 9, analysis of frozen sections indicated that all mESCs within the tumours continued to express E2C. We hypothesise that the decrease in fluorescence intensity in vivo was probably due to the fact that the mESC tumours became more vascular with time, thus leading to increased absorbance of E2C fluorescence by haemoglobin. We conclude that the E2C reporter has limited use for tracking cells in vivo, at least when introduced as a single copy into the Rosa26 locus. PMID- 29271881 TI - Personal, Psychosocial and Environmental Factors Related to Sick Building Syndrome in Official Employees of Taiwan. AB - Sick building syndrome (SBS) is a combination of symptoms that can be attributed to exposure to specific building conditions. The present study recruited 389 participants aged 20-65 years from 87 offices of 16 institutions to examine if personal factors, work-related psychosocial stress, and work environments, were associated with five groups of SBS symptoms, including symptoms for eyes, upper respiratory tract, lower respiratory tract, skin, and non-specific systems. Indoor environmental conditions were monitored. Data were analyzed using multivariate logistic regression (MLR) analyses and were reported as adjusted Odds Ratios (aOR). SBS symptoms for eyes were associated with older age, sensitivity to tobacco, and low indoor air flow. Upper respiratory symptoms were related to smoking, low social support, longer work days, and dry air. High indoor air flow was associated with reduced upper respiratory symptoms (aOR = 0.29; 95% confidence interval (CI) = 0.13-0.67). Lower respiratory symptoms were associated with high work pressure, longer work hours, chemical exposure, migraine, and exposure to new interior painting. Recent interior painting exposure was associated with a high estimated relative risk of low respiratory symptoms (aOR = 20.6; 95% CI = 2.96-143). Smoking, longer work days, low indoor air flow, indoor dryness, and volatile organics exposure, were associated with other non-specified symptoms including headache, tiredness, difficulty concentrating, anger, and dizziness. In conclusion, there are various SBS symptoms associated with different personal characteristics, psychosocial, and environmental factors. Psychosocial factors had stronger relationships with lower respiratory symptoms than with other types of SBS symptoms. Good ventilation could reduce risk factors and may relieve SBS symptoms. PMID- 29271882 TI - Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII. AB - Selective inhibition of tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) isoforms IX and XII is a crucial prerequisite to develop successful anticancer therapeutics. Herein, we confirmed the efficacy of the 3-nitrobenzoic acid substructure in the design of potent and selective carboxylic acid derivatives as CAs inhibitors. Compound 10 emerged as the most potent inhibitor of the tumor associated hCA IX and XII (Ki = 16 and 82.1 nM, respectively) with a significant selectivity with respect to the wide spread hCA II. Other 3-nitrobenzoic acid derivatives showed a peculiar CA inhibition profile with a notable potency towards hCA IX. PMID- 29271883 TI - Contribution of Dietary Supplements to Nutritional Adequacy by Socioeconomic Subgroups in Adults of the United States. AB - Many Americans have inadequate intakes of several nutrients, and the Dietary Guidelines for Americans 2015-2020 identified vitamins A, C, D, and E, in addition to calcium, magnesium, iron, potassium, choline, and fiber as "underconsumed nutrients". Based on nationally representative data on 10,698 adults from National Health and Nutrition Examination Surveys (NHANES), 2009 2012, assessments were made of socioeconomic differences, based on the Poverty Income Ratio (PIR), in terms of the association of dietary supplement use on nutrient intake and nutrient inadequacies. Compared to food alone, the use of any dietary supplement plus food was associated with significantly (p < 0.01) higher intakes of 15-16 of 19 nutrients examined in all socioeconomic groups; and significantly reduced rates of inadequacy for 10/17 nutrients in the subgroup PIR > 1.85 (not poor), but only 4-5/17 nutrients (calcium and vitamins A, C, D, E) for the poor and nearly poor subgroups (PIR < 1.35 and PIR 1.35 to <=1.85, respectively). An increased prevalence of intakes above the Tolerable Upper Intake Level (UL) was seen for 3-9/13 nutrients, but all were less than 5% in the PIR subgroups. In conclusion, dietary supplement use was associated with an increased micronutrient intake, decreased inadequacies, and a slight increase in the prevalence of intakes above the UL, with greater benefits seen in the PIR > 1.85 subgroup. PMID- 29271885 TI - Organic Thin Film Transistors Incorporating Solution Processable Thieno[3,2 b]thiophene Thienoacenes. AB - Bottom-gate bottom-contact organic thin film transistors (OTFTs) were prepared with four novel star-shaped conjugated molecules containing a fused thieno[3,2 b]thiophene moiety incorporated either in the core and/or at the periphery of the molecular framework. The molecules were soluble in CS2, allowing for solution processing techniques to be employed. OTFTs with different channel geometries were characterized in both air and vacuum in order to compare environmental effects on performance. Blending the small molecules with poly(styrene), an insulating polymer, facilitated the formation of an even semiconducting film, resulting in an order of magnitude increase in device mobility. The highest field effect mobilities were in air and on the order of 10-3 cm2/Vs for three of the four molecules, with a maximum mobility of 9.2 * 10-3 cm2/Vs achieved for the most conjugated small molecule. This study explores the relationship between processing conditions and OTFT devices performance for four different molecules within this new family of materials, resulting in a deeper insight into their potential as solution-processable semiconductors. PMID- 29271884 TI - Computational Studies of Snake Venom Toxins. AB - Most snake venom toxins are proteins, and participate to envenomation through a diverse array of bioactivities, such as bleeding, inflammation, and pain, cytotoxic, cardiotoxic or neurotoxic effects. The venom of a single snake species contains hundreds of toxins, and the venoms of the 725 species of venomous snakes represent a large pool of potentially bioactive proteins. Despite considerable discovery efforts, most of the snake venom toxins are still uncharacterized. Modern bioinformatics tools have been recently developed to mine snake venoms, helping focus experimental research on the most potentially interesting toxins. Some computational techniques predict toxin molecular targets, and the binding mode to these targets. This review gives an overview of current knowledge on the ~2200 sequences, and more than 400 three-dimensional structures of snake toxins deposited in public repositories, as well as of molecular modeling studies of the interaction between these toxins and their molecular targets. We also describe how modern bioinformatics have been used to study the snake venom protein phospholipase A2, the small basic myotoxin Crotamine, and the three-finger peptide Mambalgin. PMID- 29271886 TI - A Combination of Coffee Compounds Shows Insulin-Sensitizing and Hepatoprotective Effects in a Rat Model of Diet-Induced Metabolic Syndrome. AB - Since coffee may help to prevent the development of metabolic syndrome (MetS), we aimed to evaluate the short- and long-term effects of a coffee-based supplement on different features of diet-induced MetS. In this study, 24 Sprague Dawley rats were divided into control or nutraceuticals groups to receive a high-fat/high fructose diet with or without a mixture of caffeic acid (30 mg/day), trigonelline (20 mg/day), and cafestol (1 mg/day) for 12 weeks. An additional 11 rats were assigned to an acute crossover study. In the chronic experiment, nutraceuticals did not alter body weight or glycemic control, but improved fed hyperinsulinemia (mean difference = 30.80 mU/L, p = 0.044) and homeostatic model assessment insulin resistance (HOMA-IR) (mean difference = 15.29, p = 0.033), and plasma adiponectin levels (mean difference = -0.99 ug/mL, p = 0.048). The impact of nutraceuticals on post-prandial glycemia tended to be more pronounced after acute administration than at the end of the chronic study. Circulating (mean difference = 4.75 U/L, p = 0.014) and intrahepatocellular alanine transaminase activity was assessed by hyperpolarized-13C nuclear magnetic resonance NMR spectroscopy and found to be reduced by coffee nutraceuticals at endpoint. There was also a tendency towards lower liver triglyceride content and histological steatosis score in the intervention group. In conclusion, a mixture of coffee nutraceuticals improved insulin sensitivity and exhibited hepatoprotective effects in a rat model of MetS. Higher dosages with or without caffeine deserve to be studied in the future. PMID- 29271887 TI - Physiological and Pathological Roles of CaMKII-PP1 Signaling in the Brain. AB - Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII), a multifunctional serine (Ser)/threonine (Thr) protein kinase, regulates diverse activities related to Ca2+-mediated neuronal plasticity in the brain, including synaptic activity and gene expression. Among its regulators, protein phosphatase-1 (PP1), a Ser/Thr phosphatase, appears to be critical in controlling CaMKII-dependent neuronal signaling. In postsynaptic densities (PSDs), CaMKII is required for hippocampal long-term potentiation (LTP), a cellular process correlated with learning and memory. In response to Ca2+ elevation during hippocampal LTP induction, CaMKIIalpha, an isoform that translocates from the cytosol to PSDs, is activated through autophosphorylation at Thr286, generating autonomous kinase activity and a prolonged Ca2+/CaM-bound state. Moreover, PP1 inhibition enhances Thr286 autophosphorylation of CaMKIIalpha during LTP induction. By contrast, CaMKII nuclear import is regulated by Ser332 phosphorylation state. CaMKIIdelta3, a nuclear isoform, is dephosphorylated at Ser332 by PP1, promoting its nuclear translocation, where it regulates transcription. In this review, we summarize physio-pathological roles of CaMKII/PP1 signaling in neurons. CaMKII and PP1 crosstalk and regulation of gene expression is important for neuronal plasticity as well as survival and/or differentiation. PMID- 29271888 TI - Quantified, Interactive Simulation of AMCW ToF Camera Including Multipath Effects. AB - In the last decade, Time-of-Flight (ToF) range cameras have gained increasing popularity in robotics, automotive industry, and home entertainment. Despite technological developments, ToF cameras still suffer from error sources such as multipath interference or motion artifacts. Thus, simulation of ToF cameras, including these artifacts, is important to improve camera and algorithm development. This paper presents a physically-based, interactive simulation technique for amplitude modulated continuous wave (AMCW) ToF cameras, which, among other error sources, includes single bounce indirect multipath interference based on an enhanced image-space approach. The simulation accounts for physical units down to the charge level accumulated in sensor pixels. Furthermore, we present the first quantified comparison for ToF camera simulators. We present bidirectional reference distribution function (BRDF) measurements for selected, purchasable materials in the near-infrared (NIR) range, craft real and synthetic scenes out of these materials and quantitatively compare the range sensor data. PMID- 29271889 TI - Modulatory Effects of Breed, Feeding Status, and Diet on Adipogenic, Lipogenic, and Lipolytic Gene Expression in Growing Iberian and Duroc Pigs. AB - Meat quality depends on tissue composition which is in turn influenced by different factors, such as diet, genotype, age, or sex. We evaluated the effects of breed, 24 h fasting, and dietary energy source (HO: oleic acid versus CH: carbohydrates) on the expression of candidate genes involved in adipogenesis, lipogenesis, and lipolysis in the adipose tissue from Iberian and Duroc growing pigs. The Iberian pigs showed greater feed intake, backfat thickness, and saturated fatty acids (SFA) content in the subcutaneous fat, whereas the Duroc pigs had greater ham weight and polyunsaturated fatty acids (PUFA) content. In both breeds, the diet induced changes in the fatty acid (FA) composition of subcutaneous fat samples. The HO group had higher monounsaturated fatty acids (MUFA) and oleic acid, and lower SFA than the CH group. Regarding gene expression, breed and feeding status (fasting versus postprandial) had significant effects on gene expression, with quantitative interactions between them, while diet showed negligible effects. In general, adipogenic and lipogenic genes were upregulated in the Iberian pigs and in postprandial samples. In contrast, the expression of lipolytic genes showed complex interaction effects. Our results agree with the phenotypic differences between the Iberian and Duroc breeds and with the inhibition of lipogenesis by fasting. Quantitative interactions between breed and feeding status effects were observed, which indicates a different response to fasting of the two breeds, with the obese Iberian breed showing a more stable expression of lipogenic genes. These results highlight the complexity of lipid metabolism regulation, especially in relation to lipolysis processes. PMID- 29271890 TI - Individual and Combined Effects of Fumonisin B1, Deoxynivalenol and Zearalenone on the Hepatic and Renal Membrane Lipid Integrity of Rats. AB - (1) Background and (2) Methods: A 14-day in vivo, multitoxic (pure mycotoxins) rat experiment was conducted with zearalenone (ZEA; 15 MUg/animal/day), deoxynivalenol (DON; 30 MUg/animal/day) and fumonisin B1 (FB1; 150 MUg/animal/day), as individual mycotoxins, binary (FD, FZ and DZ) and ternary combinations (FDZ), via gavage in 1 mL water boluses. (3) Results: Body weight was unaffected, while liver (ZEA? vs. DON) and kidney weight (ZEA? vs. FDZ) increased. Hepatocellular membrane lipid fatty acids (FAs) referred to ceramide synthesis disturbance (C20:0, C22:0), and decreased unsaturation (C22:5 n3 and unsat. index), mainly induced by DON and to a lesser extent by ZEA. The DON-FB1 interaction was additive on C20:0 in liver lipids. In renal phospholipids, ZEA had the strongest effect on the FA profile, affecting the saturated (C18:0) and many n6 FAs; ZEA was in an antagonistic relationship with FB1 (C18:0) or DON (C18:2 n6, C20:1 n9). Hepatic oxidative stress was the most expressed in FD (reduced glutathione and glutathione peroxidase), while the nephrotoxic effect was further supported by lipid peroxidation (malondialdehyde) in the DON treatment. (4) Conclusions: In vivo study results refer to multiple mycotoxin interactions on membrane FAs, antioxidants and lipid peroxidation compounds, needing further testing. PMID- 29271891 TI - Arrest of Root Carious Lesions via Sodium Fluoride, Chlorhexidine and Silver Diamine Fluoride In Vitro. AB - OBJECTIVE: To compare the root carious lesion arrest of chlorhexidine (CHX) and silver diamine fluoride (SDF) varnishes and/or sodium fluoride rinses (NaF) in vitro. BACKGROUND: Effective and easily applicable interventions for treating root carious lesions are needed, as these lesions are highly prevalent amongst elderly individuals. METHODS: In 100 bovine dentin samples, artificial root carious lesions were induced using acetic acid and a continuous-culture Lactobacillus rhamnosus biofilm model. One quarter of each induced lesion was excavated and baseline dentinal bacterial counts assessed as Colony-Forming-Units (CFU) per mg. Samples were allocated to one of four treatments (n = 25/group): (1) untreated control; (2) 38% SDF or (3) 35% CHX varnish, each applied once, plus 500 ppm daily NaF rinse in the subsequent lesion progression phase; and (4) daily NaF rinses only. Samples were re-transferred to the biofilm model and submitted to a cariogenic challenge. After six days, another quarter of each lesion was used to assess bacterial counts and the remaining sample was used to assess integrated mineral loss (DeltaZ) using microradiography. RESULTS: DeltaZ did not differ significantly between control (median (25th/75th percentiles): 9082 (7859/9782) vol % * um), NaF (6704 (4507/9574) and SDF 7206 (5389/8082)) (p < 0.05/Kruskal-Wallis test). CHX significantly reduced DeltaZ (3385 (2447/4496)) compared with all other groups (p < 0.05). Bacterial numbers did not differ significantly between control (1451 (875/2644) CFU/ug) and NaF (750 (260/1401)) (p > 0.05). SDF reduced bacterial counts (360 (136/1166)) significantly compared with control (p < 0.05). CHX reduced bacterial counts (190 (73/517)) significantly compared with NaF and control (p < 0.05). CONCLUSION: CHX varnish plus regular NaF rinses arrested root carious lesions most successfully. PMID- 29271892 TI - Adsorption Property and Mechanism of Oxytetracycline onto Willow Residues. AB - To elucidate the adsorption property and the mechanism of plant residues to reduce oxytetracycline (OTC), the adsorption of OTC onto raw willow roots (WR-R), stems (WS-R), leaves (WL-R), and adsorption onto desugared willow roots (WR-D), stems (WS-D), and leaves (WL-D) were investigated. The structural characterization was analyzed by scanning electron microscopy, Fourier-transform infrared spectra, and an elemental analyzer. OTC adsorption onto the different tissues of willow residues was compared and correlated with their structures. The adsorption kinetics of OTC onto willow residues was found to follow the pseudo first-order model. The isothermal adsorption process of OTC onto the different tissues of willow residues followed the Langmuir and Freundlich model and the process was also a spontaneous endothermic reaction, which was mainly physical adsorption. After the willow residues were desugared, the polarity decreased and the aromaticity increased, which explained why the adsorption amounts of the desugared willow residues were higher than those of the unmodified residues. These observations suggest that the raw and modified willow residues have great potential as adsorbents to remove organic pollutants. PMID- 29271893 TI - Design and Development of a Wearable Device for Heat Stroke Detection. AB - Heat stroke can be potentially damaging for people while exercising in hot environments. To prevent this dangerous situation, we designed a wearable heat stroke-detection device (WHDD) with early notification ability. First, we used several physical sensors, such as galvanic skin response (GSR), heart beat, and body temperature, to acquire medical data from exercising people. In addition, we designed risk evaluation functional components that were based on fuzzy theory to detect the features of heat stroke for users. If a dangerous situation is detected, then the device will activate the alert function to remind the user to respond adequately to avoid heat stroke. PMID- 29271894 TI - Fast and Sensitive Ellipsometry-Based Biosensing. AB - In this work, a biosensing method based on in situ, fast, and sensitive measurements of ellipsometric parameters (Psi, ?) is proposed. Bare silicon wafer substrate is functionalized and used to bind biomolecules in the solution. Coupled with a 45 degrees dual-drive symmetric photoelastic modulator-based ellipsometry, the parameters Psi and ? of biolayer arising due to biomolecular interactions are determined directly, and the refractive index (RI) of the solution and the effective thickness and surface mass density of the biolayer for various interaction time can be further monitored simultaneously. To illustrate the performance of the biosensing method, immunosensing for immunoglobulin G (IgG) was taken as a case study. The experiment results show that the biosensor response of the limit of detection for IgG is 15 ng/mL, and the data collection time is in milliseconds. Moreover, the method demonstrates a good specificity. Such technique is a promising candidate in developing a novel sensor which can realize fast and sensitive, label-free, easy operation, and cost-effective biosensing. PMID- 29271895 TI - An Event-Triggered Machine Learning Approach for Accelerometer-Based Fall Detection. AB - The fixed-size non-overlapping sliding window (FNSW) and fixed-size overlapping sliding window (FOSW) approaches are the most commonly used data-segmentation techniques in machine learning-based fall detection using accelerometer sensors. However, these techniques do not segment by fall stages (pre-impact, impact, and post-impact) and thus useful information is lost, which may reduce the detection rate of the classifier. Aligning the segment with the fall stage is difficult, as the segment size varies. We propose an event-triggered machine learning (EvenT ML) approach that aligns each fall stage so that the characteristic features of the fall stages are more easily recognized. To evaluate our approach, two publicly accessible datasets were used. Classification and regression tree (CART), k-nearest neighbor (k-NN), logistic regression (LR), and the support vector machine (SVM) were used to train the classifiers. EvenT-ML gives classifier F-scores of 98% for a chest-worn sensor and 92% for a waist-worn sensor, and significantly reduces the computational cost compared with the FNSW- and FOSW-based approaches, with reductions of up to 8-fold and 78-fold, respectively. EvenT-ML achieves a significantly better F-score than existing fall detection approaches. These results indicate that aligning feature segments with fall stages significantly increases the detection rate and reduces the computational cost. PMID- 29271896 TI - Substituent Effects in Multivalent Halogen Bonding Complexes: A Combined Theoretical and Crystallographic Study. AB - In this manuscript, we combined ab initio calculations (RI-MP2/def2-TZVPD level of theory) and a search in the CSD (Cambridge Structural Database) to analyze the influence of aromatic substitution in charge-assisted multivalent halogen bonding complexes. We used a series of benzene substituted iodine derivatives C6H4(IF4)Y (Y = H, NH2, OCH3, F, CN, and CF3) as Lewis acids and used Cl- as electron rich interacting atoms. We have represented the Hammett's plot and observed a good regression coefficient (interaction energies vs. Hammett's sigma parameter). Additionally, we demonstrated the direct correlation between the Hammett's sigma parameter and the value of molecular electrostatic potential measured at the I atom on the extension of the C-I bond. Furthermore, we have carried out AIM (atoms in molecules) and NBO (natural bonding orbital) analyses to further describe and characterize the interactions described herein. Finally, we have carried out a search in the CSD (Cambridge Structural Database) and found several X-ray structures where these interactions are present, thus giving reliability to the results derived from the calculations. PMID- 29271897 TI - Carbon Dioxide Mediates the Response to Temperature and Water Activity Levels in Aspergillus flavus during Infection of Maize Kernels. AB - Aspergillus flavus is a saprophytic fungus that may colonize several important crops, including cotton, maize, peanuts and tree nuts. Concomitant with A. flavus colonization is its potential to secrete mycotoxins, of which the most prominent is aflatoxin. Temperature, water activity (aw) and carbon dioxide (CO2) are three environmental factors shown to influence the fungus-plant interaction, which are predicted to undergo significant changes in the next century. In this study, we used RNA sequencing to better understand the transcriptomic response of the fungus to aw, temperature, and elevated CO2 levels. We demonstrate that aflatoxin (AFB1) production on maize grain was altered by water availability, temperature and CO2. RNA-Sequencing data indicated that several genes, and in particular those involved in the biosynthesis of secondary metabolites, exhibit different responses to water availability or temperature stress depending on the atmospheric CO2 content. Other gene categories affected by CO2 levels alone (350 ppm vs. 1000 ppm at 30 degrees C/0.99 aw), included amino acid metabolism and folate biosynthesis. Finally, we identified two gene networks significantly influenced by changes in CO2 levels that contain several genes related to cellular replication and transcription. These results demonstrate that changes in atmospheric CO2 under climate change scenarios greatly influences the response of A. flavus to water and temperature when colonizing maize grain. PMID- 29271899 TI - Efficacy of Natural Polymer Derivatives on Soil Physical Properties and Erosion on an Experimental Loess Hillslope. AB - Raindrops disperse large soil aggregates into smaller particles, which can clog soil pores, cause soil crusting, reduce rainfall infiltration and increase soil loss. It was found that natural polymer derivatives were effective in improving soil physical properties and decreasing soil erosion on an experimental loess hillslope. This study investigated the effect of new natural polymer derivatives (Jag S and Jag C162) on soil properties, rainfall infiltration and sediment yield at four rates of sprayed polymers (0, 1, 3 and 5 g/m2), three rainfall intensities (1, 1.5 and 2 mm/min) and a slope gradient of 15 degrees with a silt loam soil through simulated rain. The results showed that both Jag S and Jag C162 significantly increased the shear strength and improved the aggregates composition of the soil surface. The water-stable soil aggregates >0.25 mm increased from 9% to 50% with increasing rates of Jag S and Jag C162. Jag S and Jag C162 also effectively increased rainfall infiltration and final infiltration rate, and reduced erosion compared to controls without natural polymer derivatives added. However, higher rates of Jag S produced lower infiltration rates. Although both Jag S and Jag C162 effectively influenced soil physical properties and erosion, the effect of Jag C162 was more significant than that of Jag S. PMID- 29271898 TI - Cellular and Molecular Aspects of the beta-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy. AB - The implication of the cyanotoxin beta-N-methylamino-l-alanine (BMAA) in long lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS) and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes. PMID- 29271900 TI - Research on Characteristics, Antioxidant and Antitumor Activities of Dihydroquercetin and Its Complexes. AB - Dihydroquercetin is a kind of dihydroflavonol compounds with antioxidant, antitumor, antivirus and radioresistance activities. This study attempted to produce the dihydroquercetin complexes with lecithin and beta-cyclodextrin, and research their characteristics and bioactivities via ultraviolet spectrum (UV), infrared spectroscopy (IR), scanning electron microscope (SEM), differential scanning calorimetry (DSC), X-ray diffraction spectrum (XRD), and MTT assay. Results showed that the complexes with lecithin and beta-cyclodextrin could improve the solubility and dissolution rate, and remove the characteristic endothermic peak of dihydroquercetin. IR spectra proved their interaction, and results of SEM and XRD showed the amorphous characteristics of the dihydroquercetin compounds. These results indicated that dihydroquercetin was combined by lecithin or beta-cyclodextrin with better physical and chemical properties, which would effectively improve the application value in the food and drug industries. PMID- 29271901 TI - Docosahexaenoic Acid in Combination with Dietary Energy Restriction for Reducing the Risk of Obesity Related Breast Cancer. AB - There is strong evidence that obesity poses a significant risk factor for postmenopausal breast cancer. There are multiple mechanisms by which obesity can predispose to breast cancer, prominent among which is the creation of a pro inflammatory milieu systemically in the visceral and subcutaneous tissue, as well as locally in the breast. Although dietary intervention studies have shown in general a favorable effect on biomarkers of breast cancer risk, it is still unclear whether losing excess weight will lower the risk. In this manuscript, we will review the evidence that omega-3 fatty acids, and among them docosahexaenoic acid (DHA) in particular, may reduce the risk of obesity related breast cancer primarily because of their pleotropic effects which target many of the systemic and local oncogenic pathways activated by excess weight. We will also review the evidence indicating that intentional weight loss (IWL) induced by dietary energy restriction (DER) will augment the tumor protective effect of DHA because of its complementary mechanisms of action and its ability to reverse the obesity-induced alterations in fatty acid metabolism predisposing to carcinogenesis. We believe that the combination of DER and DHA is a promising safe and effective intervention for reducing obesity-related breast cancer risk which needs to be validated in appropriately designed prospective, randomized clinical trials. PMID- 29271902 TI - Comparative Proteomic Analysis of the Effect of Periplocoside P from Periploca sepium on Brush Border Membrane Vesicles in Midgut Epithelium of Mythimna separata Larvae. AB - Periplocoside P (PSP), a novel compound isolated from Periploca sepium Bunge, possesses insecticidal activity against some lepidopterans, such as Mythimna separata. In M. separata, the brush border membrane vesicles of the midgut epithelium are the initial site of action of periplocosides. We conducted two dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight/time of flight mass spectrometry analysis to analyze differentially expressed proteins (DEPs) from periplocoside P (PSP)-treated M. separata. We successfully isolated seven up-regulated and three down-regulated DEPs that have been previously identified, as well as a novel DEP. The DEPs are implicated in protein degradation, transporter, folding, and synthesis, and in juvenile hormone biosynthesis. DEPs involved in the oxidative phosphorylation energy metabolism pathway are enriched. Through real-time polymerase chain reaction assay, we confirmed that vma1 expression is significantly up-regulated expression levels in PSP-treated M. separata larvae. Enzymology validation further indicated that PSP can significantly inhibit V-type ATPase activity in a concentration-dependent manner. Given these results, we speculate that in M. separata, the V-type ATPase A subunit in the midgut epithelium is the putative target binding site of periplocosides. This finding provides preliminary evidence for the mode of action of periplocosides. PMID- 29271904 TI - Feeding Intolerance in Children with Severe Impairment of the Central Nervous System: Strategies for Treatment and Prevention. AB - Children with severe impairment of the central nervous system (CNS) experience gastrointestinal (GI) symptoms at a high rate and severity, including retching, vomiting, GI tract pain, and feeding intolerance. Commonly recognized sources of symptoms include constipation and gastroesophageal reflux disease. There is growing awareness of sources due to the impaired nervous system, including visceral hyperalgesia due to sensitization of sensory neurons in the enteric nervous system and central neuropathic pain due to alterations in the thalamus. Challenging the management of these symptoms is the lack of tests to confirm alterations in the nervous system as a cause of symptom generation, requiring empirical trials directed at such sources. It is also common to have multiple reasons for the observed symptoms, further challenging management. Recurrent emesis and GI tract pain can often be improved, though in some not completely eliminated. In some, this can progress to intractable feeding intolerance. This comprehensive review provides an evidence-based approach to care, a framework for recurrent symptoms, and language strategies when symptoms remain intractable to available interventions. This summary is intended to balance optimal management with a sensitive palliative care approach to persistent GI symptoms in children with severe impairment of the CNS. PMID- 29271903 TI - Multifaceted Defense against Listeria monocytogenes in the Gastro-Intestinal Lumen. AB - Listeria monocytogenes is a foodborne pathogen that can cause febrile gastroenteritis in healthy subjects and systemic infections in immunocompromised individuals. Despite the high prevalence of L. monocytogenes in the environment and frequent contamination of uncooked meat and poultry products, infections with this pathogen are relatively uncommon, suggesting that protective defenses in the general population are effective. In the mammalian gastrointestinal tract, a variety of defense mechanisms prevent L. monocytogenes growth, epithelial penetration and systemic dissemination. Among these defenses, colonization resistance mediated by the gut microbiota is crucial in protection against a range of intestinal pathogens, including L. monocytogenes. Here we review defined mechanisms of defense against L. monocytogenes in the lumen of the gastro intestinal tract, with particular emphasis on protection conferred by the autochthonous microbiota. We suggest that selected probiotic species derived from the microbiota may be developed for eventual clinical use to enhance resistance against L. monocytogenes infections. PMID- 29271905 TI - Early Identification of Herbicide Stress in Soybean (Glycine max (L.) Merr.) Using Chlorophyll Fluorescence Imaging Technology. AB - Herbicides may damage soybean in conventional production systems. Chlorophyll fluorescence imaging technology has been applied to identify herbicide stress in weed species a few days after application. In this study, greenhouse experiments followed by field experiments at five sites were conducted to investigate if the chlorophyll fluorescence imaging is capable of identifying herbicide stress in soybean shortly after application. Measurements were carried out from emergence until the three-to-four-leaf stage of the soybean plants. Results showed that maximal photosystem II (PS II) quantum yield and shoot dry biomass was significantly reduced in soybean by herbicides compared to the untreated control plants. The stress of PS II inhibiting herbicides occurred on the cotyledons of soybean and plants recovered after one week. The stress induced by DOXP synthase , microtubule assembly-, or cell division-inhibitors was measured from the two leaf stage until four-leaf stage of soybean. We could demonstrate that the chlorophyll fluorescence imaging technology is capable for detecting herbicide stress in soybean. The system can be applied under both greenhouse and field conditions. This helps farmers to select weed control strategies with less phytotoxicity in soybean and avoid yield losses due to herbicide stress. PMID- 29271906 TI - Demand for Long-Term Care Insurance in China. AB - The aim of this study was to estimate willingness to pay (WTP) for long-term care insurance (LTCI) and to explore the determinants of demand for LTCI in China. We collected data from a household survey conducted in Qinghai and Zhejiang on a sample of 1842 households. We relied on contingent valuation methods to elicit the demand for LTCI and random effects logistic regression to analyze the factors associated with the demand for LTCI. Complementarily, we used document analysis to compare the LTCI designed in this study and the current LTCI policies in the pilot cities. More than 90% of the respondents expressed their willingness to buy LTCI. The median WTP for LTCI was estimated at 370.14 RMB/year, accounting for 2.29% of average annual per capita disposable income. Price, age, education status, and income were significantly associated with demand for LTCI. Most pilot cities were found to mainly rely on Urban Employees Basic Medical Insurance funds as the financing source for LTCI. Considering that financing is one of the greatest challenges in the development of China's LTCI, we suggest that policy makers consider individual contribution as an important and possible option as a source of financing for LTCI. PMID- 29271907 TI - Transitioning from Forensic Genetics to Forensic Genomics. AB - Due to its support of law enforcement, forensics is a conservative field; nevertheless, driven by scientific and technological progress, forensic genetics is slowly transitioning into forensic genomics. With this Special Issue of Genes we acknowledge and appreciate this rather recent development by not only introducing the field of forensics to the wider community of geneticists, but we do so by emphasizing on different topics of forensic relevance where genomic, transcriptomic, and epigenomic principles, methods, and datasets of humans and beyond are beginning to be used to answer forensic questions. PMID- 29271908 TI - Characterization of Polyphenolic Content in the Aquatic Plants Ruppia cirrhosa and Ruppia maritima -A Source of Nutritional Natural Products. AB - Herein, the polyphenolic content in extracts of Ruppia cirrhosa (Petagna) Grande and Ruppia maritima L.was fully characterized for the first time. High amounts of the main compound chicoric acid (CA) (<=30.2 +/- 4.3 mg/g) were found in both Ruppia species. In addition, eight flavonoids, namely the 3-O-glucopyranosides and 3-O-galactopyranosides, as well as malonylated 3-O-glycosides of quercetin and isorhamnetin, were isolated and identified. The antioxidant activity of Ruppia cirrhosa extracts and isolated compounds was investigated spectrophotometrically by a 1,1-diphenyl-2-picrylhydrazyl (DPPH.) radical scavenging assay. IC50 values were 31.8-175.7 MUg/mL for Ruppia cirrhosa extracts and 12.1-88.4 MUg/mL for isolated flavonoids. Both individual and total phenolic and flavonoid content were quantified in crude extracts using analytical HPLC. The relative high amount of total flavonoids ranged from 5.9 to 14.7 mg/g in both species, with concentrations of individual flavonoids ranging from 0.4 to 2.9 mg/g dry weight. The content of chicoric acid was twofold more in Ruppia maritima than in Ruppia cirrhosa. Seasonal variation of the quantitative content in Ruppia cirrhosa was examined. Total flavonoid content ranged from 8.4 mg/g in October to 14.7 mg/g in August, whereas the highest concentration of chicoric acid was observed in March (29.2 mg/g). PMID- 29271909 TI - Comparison of Random Forest, k-Nearest Neighbor, and Support Vector Machine Classifiers for Land Cover Classification Using Sentinel-2 Imagery. AB - In previous classification studies, three non-parametric classifiers, Random Forest (RF), k-Nearest Neighbor (kNN), and Support Vector Machine (SVM), were reported as the foremost classifiers at producing high accuracies. However, only a few studies have compared the performances of these classifiers with different training sample sizes for the same remote sensing images, particularly the Sentinel-2 Multispectral Imager (MSI). In this study, we examined and compared the performances of the RF, kNN, and SVM classifiers for land use/cover classification using Sentinel-2 image data. An area of 30 * 30 km2 within the Red River Delta of Vietnam with six land use/cover types was classified using 14 different training sample sizes, including balanced and imbalanced, from 50 to over 1250 pixels/class. All classification results showed a high overall accuracy (OA) ranging from 90% to 95%. Among the three classifiers and 14 sub-datasets, SVM produced the highest OA with the least sensitivity to the training sample sizes, followed consecutively by RF and kNN. In relation to the sample size, all three classifiers showed a similar and high OA (over 93.85%) when the training sample size was large enough, i.e., greater than 750 pixels/class or representing an area of approximately 0.25% of the total study area. The high accuracy was achieved with both imbalanced and balanced datasets. PMID- 29271911 TI - Resveratrol-Induced Changes in MicroRNA Expression in Primary Human Fibroblasts Harboring Carnitine-Palmitoyl Transferase-2 Gene Mutation, Leading to Fatty Acid Oxidation Deficiency. AB - Carnitine palmitoyltransferase-2 (CPT2) is a mitochondrial enzyme involved in long-chain fatty acid entry into mitochondria for their beta-oxidation and energy production. Two phenotypes are associated with the extremely reduced CPT2 activity in genetically deficient patients: neonatal lethality or, in milder forms, myopathy. Resveratrol (RSV) is a phytophenol produced by grape plant in response to biotic or abiotic stresses that displays anti-oxidant properties, in particular through AP-1, NFkappaB, STAT-3, and COX pathways. Some beneficiary effects of RSV are due to its modulation of microRNA (miRNA) expression. RSV can enhance residual CPT2 activities in human fibroblasts derived from CPT2-deficient patients and restores normal fatty acid oxidation rates likely through stimulation of mitochondrial biogenesis. Here, we report changes in miRNA expression linked to CPT2-deficiency, and we identify miRNAs whose expression changed following RSV treatment of control or CPT2-deficient fibroblasts isolated from patients. Our findings suggest that RSV consumption might exert beneficiary effects in patients with CPT2-deficiency. PMID- 29271912 TI - Characterization of Early Age Curing and Shrinkage of Metakaolin-Based Inorganic Binders with Different Rheological Behavior by Fiber Bragg Grating Sensors. AB - This paper reports results related to early age temperature and shrinkage measurements by means fiber Bragg gratings (FBGs), which were embedded in geopolymer matrices. The sensors were properly packaged in order to discriminate between different shrinkage behavior and temperature development. Geopolymer systems based on metakaolin were investigated, which dealt with different commercial aluminosilicate precursors and siliceous filler contents. The proposed measuring system will allow us to control, in a very accurate way, the early age phases of the binding systems made by metakaolin geopolymer. A series of experiments were conducted on different compositions; moreover, rheological issues related to the proposed experimental method were also assessed. PMID- 29271910 TI - Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling. AB - Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing stresses including oxidative and inflammatory stresses. Nrf2 is a master regulator of cellular stress responses, induces the expression of antioxidant and detoxification enzymes, and protects against oxidative stress-induced cell damage. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which was originally found to increase insulin synthesis and secretion. It is now widely accepted that GLP-1 has multiple functions beyond glucose control in various tissues and organs including brain, kidney, and heart. GLP-1 and GLP-1 receptor agonists are known to be effective in many chronic diseases, including diabetes, via antioxidative mechanisms. In this review, we summarize the current knowledge regarding the role of GLP-1 in the protection against oxidative damage and the activation of the Nrf2 signaling pathway. PMID- 29271913 TI - WARCProcessor: An Integrative Tool for Building and Management of Web Spam Corpora. AB - In this work we present the design and implementation of WARCProcessor, a novel multiplatform integrative tool aimed to build scientific datasets to facilitate experimentation in web spam research. The developed application allows the user to specify multiple criteria that change the way in which new corpora are generated whilst reducing the number of repetitive and error prone tasks related with existing corpus maintenance. For this goal, WARCProcessor supports up to six commonly used data sources for web spam research, being able to store output corpus in standard WARC format together with complementary metadata files. Additionally, the application facilitates the automatic and concurrent download of web sites from Internet, giving the possibility of configuring the deep of the links to be followed as well as the behaviour when redirected URLs appear. WARCProcessor supports both an interactive GUI interface and a command line utility for being executed in background. PMID- 29271914 TI - Hepatitis C Virus: Viral Quasispecies and Genotypes. AB - Hepatitis C virus (HCV) mainly replicates in the cytoplasm, where it easily establishes persistent infection, resulting in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Due to its high rate of mutation, HCV forms viral quasispecies, categorized based on the highly variable regions in the envelope protein and nonstructural 5A protein. HCV possesses seven major genotypes, among which genotype 1 is the most prevalent globally. The distribution of HCV genotypes varies based on geography, and each genotype has a different sensitivity to interferon treatment. Recently-developed direct-acting antivirals (DAAs), which target viral proteases or polymerases, mediate drastically better antiviral effects than previous therapeutics. Although treatment with DAAs has led to the development of drug-resistant HCV mutants, the most recently approved DAAs show improved pan-genomic activity, with a higher barrier to viral resistance. PMID- 29271915 TI - Transcriptomics Analysis on Excellent Meat Quality Traits of Skeletal Muscles of the Chinese Indigenous Min Pig Compared with the Large White Breed. AB - The Min pig (Sus scrofa) is a well-known indigenous breed in China. One of its main advantages over European breeds is its high meat quality. Additionally, different cuts of pig also show some different traits of meat quality. To explore the underlying mechanism responsible for the differences of meat quality between different breeds or cuts, the longissimus dorsi muscle (LM) and the biceps femoris muscle (BF) from Min and Large White pigs were investigated using transcriptome analysis. The gene expression profiling identified 1371 differentially expressed genes (DEGs) between LM muscles from Min and Large White pigs, and 114 DEGs between LM and BF muscles from the same Min pigs. Gene Ontology (GO) enrichment of biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the gene products were mainly involved in the IRS1/Akt/FoxO1 signaling pathway, adenosine 5'-monophosphate-activated protein kinase (AMPK) cascade effects, lipid metabolism and amino acid metabolism pathway. Such pathways contributed to fatty acid metabolism, intramuscular fat deposition, and skeletal muscle growth in Min pig. These results give an insight into the mechanisms underlying the formation of skeletal muscle and provide candidate genes for improving meat quality. It will contribute to improving meat quality of pigs through molecular breeding. PMID- 29271917 TI - Accurate Analysis of Target Characteristic in Bistatic SAR Images: A Dihedral Corner Reflectors Case. AB - The dihedral corner reflectors are the basic geometric structure of many targets and are the main contributions of radar cross section (RCS) in the synthetic aperture radar (SAR) images. In stealth technologies, the elaborate design of the dihedral corners with different opening angles is a useful approach to reduce the high RCS generated by multiple reflections. As bistatic synthetic aperture sensors have flexible geometric configurations and are sensitive to the dihedral corners with different opening angles, they specially fit for the stealth target detections. In this paper, the scattering characteristic of dihedral corner reflectors is accurately analyzed in bistatic synthetic aperture images. The variation of RCS with the changing opening angle is formulated and the method to design a proper bistatic radar for maximizing the detection capability is provided. Both the results of the theoretical analysis and the experiments show the bistatic SAR could detect the dihedral corners, under a certain bistatic angle which is related to the geometry of target structures. PMID- 29271916 TI - Bio-Functional Design, Application and Trends in Metallic Biomaterials. AB - Introduction of metals as biomaterials has been known for a long time. In the early development, sufficient strength and suitable mechanical properties were the main considerations for metal implants. With the development of new generations of biomaterials, the concepts of bioactive and biodegradable materials were proposed. Biological function design is very import for metal implants in biomedical applications. Three crucial design criteria are summarized for developing metal implants: (1) mechanical properties that mimic the host tissues; (2) sufficient bioactivities to form bio-bonding between implants and surrounding tissues; and (3) a degradation rate that matches tissue regeneration and biodegradability. This article reviews the development of metal implants and their applications in biomedical engineering. Development trends and future perspectives of metallic biomaterials are also discussed. PMID- 29271918 TI - Impact of Daily Grazing Time on Dairy Cow Welfare-Results of the Welfare Quality(r) Protocol. AB - Grazing provides livestock better opportunities to act out their species-specific behavior compared to restrictive stable conditions. The aim of the present study was to examine the effects of daily grazing time on welfare of dairy cows in organic and conventional farms based on the Welfare Quality(r) assessment protocol for dairy cattle (WQ(r)). Therefore, we applied the WQ(r) on 32 dairy farms (classified in 3 groups: Group 0, minor/zero grazing, n = 14; Group 1, medium grazing, n = 10; Group 2, high grazing, n = 8). We assessed the status of animal welfare once in winter and once in summer. For statistical analyses we used mixed models for repeated measures, with group, season, and their interaction as fixed factors. At the WQ(r) criteria level, five out of nine examined criteria improved in farms with grazing between winter and summer. In contrast, the welfare situation in minor/zero grazing farms remained largely unchanged. At the level of WQ(r) measures, only the individual parameters "% of cows with hairless patches" and "% of lame cows" were affected positively by high grazing. Grazing offers a potential to enhance welfare of dairy cows during the summer season, while beneficial effects are not guaranteed when management does not satisfy the animals' needs. PMID- 29271919 TI - Removal of Hexavalent Chromium in Portland Cement Using Ground Granulated Blast Furnace Slag Powder. AB - Using ground granulated blast-furnace slag (GGBS) under different alkaline conditions, we studied the mechanisms and extents of Cr(VI) reduction and sorption and compared them to reactions with Portland cement (PC). We also investigated the effects of mixing PC/GGBS ratios on Cr(VI) dissolution after carbonating the substrates. We observed a complete sorption and reduction of Cr(VI) to Cr(III) in a GGBS-in-Ca(OH)2 solution (pH > ~12.5) after 10 h, whereas in distilled water (pH = ~11.5) GGBS exhibited only marginal sorption and reduction (20%). Cr reactions with dissolved ions in supernatants derived from GGBS indicated that the anions dissolved from GGBS act as a reducing agent for Cr(VI) in a Ca(OH)2 solution. Soft X-ray absorption microscopy identified a partial reduction of Cr(VI) to Cr(III) on the GGBS surface. The carbonation of pure PC paste substantially increased the amount of dissolved Cr(VI) in a solution phase whereas a 5 wt % replacement of PC with GGBS significantly reduced the amount of dissolved Cr(VI). We concluded that in the mixed paste during the early curing stage GGBS reduced a significant fraction of Cr(VI) to Cr(III) and that the Cr(III) adsorbed in the GGBS-PC mixture's hydration products does not readily dissolve, even under carbonation conditions. PMID- 29271921 TI - Chiral Symmetry Breaking in Magnetoelectrochemical Etching with Chloride Additives. AB - Magnetoelectrolysis (electrolysis under magnetic fields) produces chiral surfaces on metal thin films, which can recognize the enantiomers of amino acids. Here, the chiral surface formation on copper films is reported in magnetoelectrochemical etching (MEE) at 5T with chloride additives. In the absence of additives, the surface chirality signs of MEE films depended on the magnetic field polarity. On the contrary, the MEE films prepared with the additives exhibited only d-activity in both magnetic field polarities. This result implies that the specific adsorption of chloride additives induces the chiral symmetry breaking for the magnetic field polarity. PMID- 29271920 TI - Arginylglycylaspartic Acid-Surface-Functionalized Doxorubicin-Loaded Lipid-Core Nanocapsules as a Strategy to Target Alpha(V) Beta(3) Integrin Expressed on Tumor Cells. AB - Doxorubicin (Dox) clinical use is limited by dose-related cardiomyopathy, becoming more prevalent with increasing cumulative doses. Previously, we developed Dox-loaded lipid-core nanocapsules (Dox-LNC) and, in this study, we hypothesized that self-assembling and interfacial reactions could be used to obtain arginylglycylaspartic acid (RGD)-surface-functionalized-Dox-LNC, which could target tumoral cells overexpressing alphavbeta3 integrin. Human breast adenocarcinoma cell line (MCF-7) and human glioblastoma astrocytoma (U87MG) expressing different levels of alphavbeta3 integrin were studied. RGD functionalized Dox-LNC were prepared with Dox at 100 and 500 mg.mL-1 (RGD-MCMN (Dox100) and RGD-MCMN (Dox500)). Blank formulation (RGD-MCMN) had z-average diameter of 162 +/- 6 nm, polydispersity index of 0.11 +/- 0.04, zeta potential of +13.2 +/- 1.9 mV and (6.2 +/- 1.1) * 1011 particles mL-1, while RGD-MCMN (Dox100) and RGD-MCMN (Dox500) showed respectively 146 +/- 20 and 215 +/- 25 nm, 0.10 +/- 0.01 and 0.09 +/- 0.03, +13.8 +/- 2.3 and +16.4 +/- 1.5 mV and (6.9 +/- 0.6) * 1011 and (6.1 +/- 1.0) * 1011 particles mL-1. RGD complexation was 7.73 * 104 molecules per nanocapsule and Dox loading were 1.51 * 104 and 7.64 * 104 molecules per nanocapsule, respectively. RGD-functionalized nanocapsules had an improved uptake capacity by U87MG cells. Pareto chart showed that the cell viability was mainly affected by the Dox concentration and the period of treatment in both MCF-7 and U87MG. The influence of RGD-functionalization on cell viability was a determinant factor exclusively to U87MG. PMID- 29271922 TI - Descriptor Selection via Log-Sum Regularization for the Biological Activities of Chemical Structure. AB - The quantitative structure-activity relationship (QSAR) model searches for a reliable relationship between the chemical structure and biological activities in the field of drug design and discovery. (1) Background: In the study of QSAR, the chemical structures of compounds are encoded by a substantial number of descriptors. Some redundant, noisy and irrelevant descriptors result in a side effect for the QSAR model. Meanwhile, too many descriptors can result in overfitting or low correlation between chemical structure and biological bioactivity. (2) Methods: We use novel log-sum regularization to select quite a few descriptors that are relevant to biological activities. In addition, a coordinate descent algorithm, which uses novel univariate log-sum thresholding for updating the estimated coefficients, has been developed for the QSAR model. (3) Results: Experimental results on artificial and four QSAR datasets demonstrate that our proposed log-sum method has good performance among state-of the-art methods. (4) Conclusions: Our proposed multiple linear regression with log-sum penalty is an effective technique for both descriptor selection and prediction of biological activity. PMID- 29271923 TI - The ODC 3'-Untranslated Region and 5'-Untranslated Region Contain cis-Regulatory Elements: Implications for Carcinogenesis. AB - It has been hypothesized that both the 3'-untranslated region (3'UTR) and the 5' untranslated region (5'UTR) of the ornithine decarboxylase (ODC) mRNA influence the expression of the ODC protein. Here, we use luciferase expression constructs to examine the influence of both UTRs in keratinocyte derived cell lines. The ODC 5'UTR or 3'UTR was cloned into the pGL3 control vector upstream or downstream of the luciferase reporter gene, respectively, and luciferase activity was measured in both non-tumorigenic and tumorigenic mouse keratinocyte cell lines. Further analysis of the influence of the 3'UTR on luciferase activity was accomplished through site-directed mutagenesis and distal deletion analysis within this region. Insertion of either the 5'UTR or 3'UTR into a luciferase vector resulted in a decrease in luciferase activity when compared to the control vector. Deletion analysis of the 3'UTR revealed a region between bases 1969 and 2141 that was inhibitory, and mutating residues within that region increased luciferase activity. These data suggest that both the 5'UTR and 3'UTR of ODC contain cis acting regulatory elements that control intracellular ODC protein levels. PMID- 29271924 TI - Enhancing Pediatric Palliative Care for Latino Children and Their Families: A Review of the Literature and Recommendations for Research and Practice in the United States. AB - As the demand for pediatric palliative care (PC) increases, data suggest that Latino children are less likely to receive services than non-Latino children. Evidence on how to best provide PC to Latino children is sparse. We conducted a narrative review of literature related to PC for Latino children and their families in the United States. In the United States, Latinos face multiple barriers that affect their receipt of PC, including poverty, lack of access to health insurance, language barriers, discrimination, and cultural differences. Pediatric PC research and clinical initiatives that target the needs of Latino families are sparse, underfunded, but essential. Education of providers on Latino cultural values is necessary. Additionally, advocacy efforts with a focus on equitable care and policy reform are essential to improving the health of this vulnerable population. PMID- 29271925 TI - Autologous Adipose-Derived Stem Cells Reduce Burn-Induced Neuropathic Pain in a Rat Model. AB - BACKGROUND: Burn scar pain is considered as neuropathic pain. The anti inflammation and anti-neuroinflammation effects of adipose-derived stem cells (ASCs) were observed in several studies. We designed a study using a murine model involving the transplantation of autologous ASCs in rats subjected to burn injuries. The aim was to detect the anti-neuroinflammation effect of ASC transplantation and clarify the relationships between ASCs, scar pain, apoptosis and autophagy. METHODS: We randomized 24 rats into 4 groups as followings: Group A and B, received saline injections and autologous transplantation of ASCs 4 weeks after sham burn, respectively; Group C and D, received saline injections and autologous transplantation 4 weeks after burn injuries. A designed behavior test was applied for pain evaluation. Skin tissues and dorsal horn of lumbar spinal cords were removed for biochemical analysis. RESULTS: ASC transplantation significantly restored the mechanical threshold reduced by burn injury. It also attenuated local inflammation and central neuroinflammation and ameliorated apoptosis and autophagy in the spinal cord after the burn injury. CONCLUSION: In a rat model, autologous ASC subcutaneous transplantation in post-burn scars elicited anti-neuroinflammation effects locally and in the spinal cord that might be related to the relief of post-burn neuropathic pain and attenuated cell apoptosis. Thus, ASC transplantation post-burn scars shows the potential promising clinical benefits. PMID- 29271926 TI - Automating the Timed Up and Go Test Using a Depth Camera. AB - Fall prevention is a human, economic and social issue. The Timed Up and Go (TUG) test is widely used to identify individuals with a high fall risk. However, this test has been criticized because its "diagnostic" is too dependent on the conditions in which it is performed and on the healthcare professionals running it. We used the Microsoft Kinect ambient sensor to automate this test in order to reduce the subjectivity of outcome measures and to provide additional information about patient performance. Each phase of the TUG test was automatically identified from the depth images of the Kinect. Our algorithms accurately measured and assessed the elements usually measured by healthcare professionals. Specifically, average TUG test durations provided by our system differed by only 0.001 s from those measured by clinicians. In addition, our system automatically extracted several additional parameters that allowed us to accurately discriminate low and high fall risk individuals. These additional parameters notably related to the gait and turn pattern, the sitting position and the duration of each phase. Coupling our algorithms to the Kinect ambient sensor can therefore reliably be used to automate the TUG test and perform a more objective, robust and detailed assessment of fall risk. PMID- 29271927 TI - A Novel Magnetic Actuation Scheme to Disaggregate Nanoparticles and Enhance Passage across the Blood-Brain Barrier. AB - The blood-brain barrier (BBB) hinders drug delivery to the brain. Despite various efforts to develop preprogramed actuation schemes for magnetic drug delivery, the unmodeled aggregation phenomenon limits drug delivery performance. This paper proposes a novel scheme with an aggregation model for a feed-forward magnetic actuation design. A simulation platform for aggregated particle delivery is developed and an actuation scheme is proposed to deliver aggregated magnetic nanoparticles (MNPs) using a discontinuous asymmetrical magnetic actuation. The experimental results with a Y-shaped channel indicated the success of the proposed scheme in steering and disaggregation. The delivery performance of the developed scheme was examined using a realistic, three-dimensional (3D) vessel simulation. Furthermore, the proposed scheme enhanced the transport and uptake of MNPs across the BBB in mice. The scheme presented here facilitates the passage of particles across the BBB to the brain using an electromagnetic actuation scheme. PMID- 29271929 TI - The Use of Tricyclo-DNA Oligomers for the Treatment of Genetic Disorders. AB - Antisense Oligonucleotides (ASOs) represent very attractive therapeutic compounds for the treatment of numerous diseases. The antisense field has remarkably progressed over the last few years with the approval of the first antisense drugs and with promising developments of more potent and nuclease resistant chemistries. Despite these recent clinical successes and advances in chemistry and design, effective delivery of ASOs to their target tissues remains a major issue. This review will describe the latest advances obtained with the tricyclo DNA (tcDNA) chemistry which displays unique pharmacological properties and unprecedented uptake in many tissues after systemic administration. We will examine the variety of therapeutic approaches using both fully modified tcDNA ASOs and gapmers, including splice switching applications, correction of aberrant splicing, steric blocking strategies and targeted gene knock-down mediated by RNase H recruitment. We will then discuss the merits and potential liabilities of the tcDNA chemistry in the context of ASO drug development. PMID- 29271930 TI - Epigallocatechin Gallate-Modified Graphite Paste Electrode for Simultaneous Detection of Redox-Active Biomolecules. AB - In this study, simultaneous electrochemical detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) was performed using a modified graphite paste electrode (MGPE) with epigallocatechin gallate (EGCG) and green tea (GT) powder. It was shown that the anodic peak current increased in comparison with that of the graphite paste electrode (GPE) in the cyclic voltammograms. The optimal pH for simultaneous determination of a quaternary mixture of AA-DA-UA was determined to be pH 2. The anodic peak potentials for a mixture containing AA-DA-UA were well separated from each other. The catalytic peak currents obtained at the surface of the MGPE/EGCG were linearly dependent on the AA, DA, and UA concentrations up to 23, 14, and 14 uM, respectively. The detection limits for AA, DA, and UA were 190, 90, and 70 nM, respectively. The analytical performance of this sensor has been evaluated for simultaneous detection of AA, DA, and UA in real samples. Finally, a modified electrode was prepared using GT and used for simultaneous determination of AA, DA, and UA. Based on the results, MPGE/GT showed two oxidation peaks at 0.43 and 0.6 V for DA and UA, respectively, without any oxidation peak for AA. The calibration curves at the surface of MGPE/GT were linear up to 14 uM with a detection limit of 0.18 and 0.33 uM for DA and UA, respectively. MGPEs provide a promising platform for the future development of sensors for multiplexed electrochemical detection of clinically important analytes. PMID- 29271928 TI - Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview. AB - The epithelial mesenchymal transition (EMT) plays a central role in both normal physiological events (e.g., embryonic development) and abnormal pathological events (e.g., tumor formation and metastasis). The processes that occur in embryonic development are often reactivated under pathological conditions such as oncogenesis. Therefore, defining the regulatory networks (both gene and protein levels) involved in the EMT during embryonic development will be fundamental in understanding the regulatory networks involved in tumor development, as well as metastasis. There are many molecules, factors, mediators and signaling pathways that are involved in the EMT process. Although the EMT is a very old topic with numerous publications, recent new technologies and discoveries give this research area some new perspective and direction. It is now clear that these important processes are controlled by a network of transcriptional and translational regulators in addition to post-transcriptional and post-translational modifications that amplify the initial signals. In this review article, we will discuss some key concepts, historical findings, as well as some recent progresses in the EMT research field. PMID- 29271931 TI - Transcriptome Analysis of Tomato Leaf Spot Pathogen Fusarium proliferatum: De novo Assembly, Expression Profiling, and Identification of Candidate Effectors. AB - Leaf spot disease caused by the fungus Fusarium proliferatum (Matsushima) Nirenberg is a destructive disease of tomato plants in China. Typical symptoms of infected tomato plants are softened and wilted stems and leaves, leading to the eventual death of the entire plant. In this study, we resorted to transcriptional profile analysis to gain insight into the repertoire of effectors involved in F. proliferatum-tomato interactions. A total of 61,544,598 clean reads were de novo assembled to provide a F. proliferatum reference transcriptome. From these, 75,044 unigenes were obtained, with 19.46% of the unigenes being assigned to 276 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, with 22.3% having a homology with genes from F. fujikuroi. A total of 18,075 differentially expressed genes (DEGs) were identified, 720 of which were found to code for secreted proteins. Of these, 184 were identified as candidate effectors, while 79.89% had an upregulated expression. Moreover, 17 genes that were differentially expressed in RNA-seq studies were randomly selected for validation by quantitative real time polymerase chain reaction (qRT-PCR). The study demonstrates that transcriptome analysis could be an effective method for identifying the repertoire of candidate effectors and may provide an invaluable resource for future functional analyses of F. proliferatum pathogenicity in F. proliferatum and tomato plant-host interactions. PMID- 29271932 TI - 3D Powder Printed Bioglass and beta-Tricalcium Phosphate Bone Scaffolds. AB - The use of both bioglass (BG) and beta tricalcium phosphate (beta-TCP) for bone replacement applications has been studied extensively due to the materials' high biocompatibility and ability to resorb when implanted in the body. 3D printing has been explored as a fast and versatile technique for the fabrication of porous bone scaffolds. This project investigates the effects of using different combinations of a composite BG and beta-TCP powder for 3D printing of porous bone scaffolds. Porous 3D powder printed bone scaffolds of BG, beta-TCP, 50/50 BG/beta TCP and 70/30 BG/beta-TCP compositions were subject to a variety of characterization and biocompatibility tests. The porosity characteristics, surface roughness, mechanical strength, viability for cell proliferation, material cytotoxicity and in vitro bioactivity were assessed. The results show that the scaffolds can support osteoblast-like MG-63 cells growth both on the surface of and within the scaffold material and do not show alarming cytotoxicity; the porosity and surface characteristics of the scaffolds are appropriate. Of the two tested composite materials, the 70/30 BG/beta-TCP scaffold proved to be superior in terms of biocompatibility and mechanical strength. The mechanical strength of the scaffolds makes them unsuitable for load bearing applications. However, they can be useful for other applications such as bone fillers. PMID- 29271933 TI - The Components of Bone and What They Can Teach Us about Regeneration. AB - The problem of bone regeneration has engaged both physicians and scientists since the beginning of medicine. Not only can bone heal itself following most injuries, but when it does, the regenerated tissue is often indistinguishable from healthy bone. Problems arise, however, when bone does not heal properly, or when new tissue is needed, such as when two vertebrae are required to fuse to stabilize adjacent spine segments. Despite centuries of research, such procedures still require improved therapeutic methods to be devised. Autologous bone harvesting and grafting is currently still the accepted benchmark, despite drawbacks for clinicians and patients that include limited amounts, donor site morbidity, and variable quality. The necessity for an alternative to this "gold standard" has given rise to a bone-graft and substitute industry, with its central conundrum: what is the best way to regenerate bone? In this review, we dissect bone anatomy to summarize our current understanding of its constituents. We then look at how various components have been employed to improve bone regeneration. Evolving strategies for bone regeneration are then considered. PMID- 29271934 TI - Biochemical Properties and Neuroprotective Effects of Compounds in Various Species of Berries. AB - Several species of berries, such as blueberries (Vaccinium angustifolium) and lingonberries (Vaccinium vitis-idaea L.), have attracted much scientific attention in recent years, especially due to their reported antioxidant and anti inflammatory properties. Berries, as with other types of plants, have developed metabolic mechanisms to survive various environmental stresses, some of which involve reactive oxygen species. In addition, the fruits and leaves of berries have high amounts of polyphenols, such as flavonoids, which act as potent antioxidants. These compounds could potentially be beneficial for brain aging and neurodegenerative disorders. There are now several studies documenting the beneficial effects of various berries in cell models of neurotoxicity as well as in vivo models of neurodegenerative disease. In the current review, we discuss the metabolic strategies that plants and animals have developed in order to combat reactive oxygen species. We then discuss issues of bioavailability of various compounds in mammals and provide a synopsis of studies demonstrating the neuroprotective ability of berries and polyphenols. We also summarize findings from our own research group. For example, we have detected various polyphenols in samples of blueberries and lingonberries and have found that the leaves have a much higher antioxidant capacity than the fruits. Extracts from these species have also demonstrated neuroprotective effects in cellular models of toxicity and inflammation, which are being further pursued in animal models. PMID- 29271935 TI - Analysis of Chemical Variations between Crude and Salt-Processed Anemarrhenae rhizoma Using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry Methods. AB - The present study was designed to systematically investigate the chemical profile differences between crude Anemarrhenae rhizoma (CAR) and salt-processed Anemarrhenae rhizoma (SAR). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), coupled with multivariate statistical analysis was used for the discrimination of chemical profiles and the identification of the differentiation of the chemical constitutions of CAR and SAR. In addition, seven main constituents of CAR and SAR were simultaneously determined by ultra-high-performance liquid chromatography quadrupole mass spectrometry (UHPLC-MS) for analyzing the content variations. A total of 24 components were found to be the main contributors to the significant difference between CAR and SAR. The structures of the marker compounds were identified based on their chromatographic behaviors, intact precursor ions, and characteristic MS fragmentation patterns. The potential structural transformation mechanism of furostanol saponins during salt processing was explored. The results may provide a scientific foundation for deeply elucidating the processing mechanism of Anemarrhenae rhizoma. PMID- 29271937 TI - Integration of High-Resolution Laser Displacement Sensors and 3D Printing for Structural Health Monitoring. AB - This paper presents a novel experimental design for complex structural health monitoring (SHM) studies achieved by integrating 3D printing technologies, high resolution laser displacement sensors, and multiscale entropy SHM theory. A seven story structure with a variety of composite bracing systems was constructed using a dual-material 3D printer. A wireless Bluetooth vibration speaker was used to excite the ground floor of the structure, and high-resolution laser displacement sensors (1-MUm resolution) were used to monitor the displacement history on different floors. Our results showed that the multiscale entropy SHM method could detect damage on the 3D-printed structures. The results of this study demonstrate that integrating 3D printing technologies and high-resolution laser displacement sensors enables the design of cheap, fast processing, complex, small-scale civil structures for future SHM studies. The novel experimental design proposed in this study provides a suitable platform for investigating the validity and sensitivity of SHM in different composite structures and damage conditions for real life applications in the future. PMID- 29271936 TI - Label-Free Biosensor Detection of Endocrine Disrupting Compounds Using Engineered Estrogen Receptors. AB - Endocrine Disrupting Compounds (EDCs) are chemical substances shown to interfere with endogenous hormones affecting the endocrine, immune and nervous systems of mammals. EDCs are the causative agents of diseases including reproductive disorders and cancers. This highlights the urgency to develop fast and sensitive methods to detect EDCs, which are detrimental even at very low concentrations. In this work, we propose a label-free surface plasmon resonance (SPR) biosensor method to detect specific EDCs (17 beta-estradiol (E2), ethinyl-estradiol, 4 nonylphenol, tamoxifen) through their binding to estrogen receptor alpha (ERalpha). We show that the use of rationally designed ERalpha (as bio recognition element) in combination with conformation-sensitive peptides (as amplification agent, resulting in increased responses) enables the detection of low parts per billion (ppb) levels of E2. As a proof of concept, this bioassay was used to detect E2 in (spiked) real water samples from fish farms, rivers and the sea at low ppb levels after concentration by solid phase extraction. In addition, the present SPR assay that combines a conformation-sensitive peptide with an array of ERalpha mutants is very promising for the assessment of the risk of potential estrogenic activity for chemical substances. PMID- 29271938 TI - Chaperones and the Proteasome System: Regulating the Construction and Demolition of Striated Muscle. AB - Protein folding factors (chaperones) are required for many diverse cellular functions. In striated muscle, chaperones are required for contractile protein function, as well as the larger scale assembly of the basic unit of muscle, the sarcomere. The sarcomere is complex and composed of hundreds of proteins and the number of proteins and processes recognized to be regulated by chaperones has increased dramatically over the past decade. Research in the past ten years has begun to discover and characterize the chaperones involved in the assembly of the sarcomere at a rapid rate. Because of the dynamic nature of muscle, wear and tear damage is inevitable. Several systems, including chaperones and the ubiquitin proteasome system (UPS), have evolved to regulate protein turnover. Much of our knowledge of muscle development focuses on the formation of the sarcomere but recent work has begun to elucidate the requirement and role of chaperones and the UPS in sarcomere maintenance and disease. This review will cover the roles of chaperones in sarcomere assembly, the importance of chaperone homeostasis and the cooperation of chaperones and the UPS in sarcomere integrity and disease. PMID- 29271941 TI - Potential of Sub-GHz Wireless for Future IoT Wearables and Design of Compact 915 MHz Antenna. AB - Internet of Things (IoT) technology is rapidly emerging in medical applications as it offers the possibility of lower-cost personalized healthcare monitoring. At the present time, the 2.45 GHz band is in widespread use for these applications but in this paper, the authors investigate the potential of the 915 MHz ISM band in implementing future, wearable IoT devices. The target sensor is a wrist-worn wireless heart rate and arterial oxygen saturation (SpO2) monitor with the goal of providing efficient wireless functionality and long battery lifetime using a commercial Sub-GHz low-power radio transceiver. A detailed analysis of current consumption for various wireless protocols is also presented and analyzed. A novel 915 MHz antenna design of compact size is reported that has good resilience to detuning by the human body. The antenna also incorporates a matching network to meet the challenging bandwidth requirements and is fabricated using standard, low-cost FR-4 material. Full-Wave EM simulations are presented for the antenna placed in both free-space and on-body cases. A prototype antenna is demonstrated and has dimensions of 44 mm * 28 mm * 1.6 mm. The measured results at 915 MHz show a 10 dB return loss bandwidth of 55 MHz, a peak realized gain of - 2.37 dBi in free-space and - 6.1 dBi on-body. The paper concludes by highlighting the potential benefits of 915 MHz operation for future IoT devices. PMID- 29271939 TI - Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims Proposed Under European Community Regulation 1924/2006 in the Framework of Maintenance of Skin Function. AB - Evidence suggests a protective role for several nutrients and foods in the maintenance of skin function. Nevertheless, all the requests for authorization to use health claims under Article 13(5) in the framework of maintenance of skin function presented to the European Food Safety Authority (EFSA) have received a negative opinion. Reasons for such failures are mainly due to an insufficient substantiation of the claimed effects, including the choice of inappropriate outcome variables (OVs) and methods of measurement (MMs). The present paper reports the results of an investigation aimed at collecting, collating and critically analyzing the information with relation to claimed effects (CEs), OVs and MMs related to skin health compliance with Regulation 1924/2006. CEs, OVs and MMs were collected from both the EFSA Guidance document and from the authorization requests of health claims under Article 13(5). The critical analysis of OVs and MMs was based on a literature review, and was aimed at defining their appropriateness (alone or in combination with others) in the context of a specific CE. The results highlight the importance of an adequate choice of OVs and MMs for an effective substantiation of the claims. PMID- 29271942 TI - The Antioxidant and Safety Properties of Spent Coffee Ground Extracts Impacted by the Combined Hot Pressurized Liquid Extraction-Resin Purification Process. AB - Hot pressurized liquid extraction has been used to obtain polyphenols; however, its operating conditions can generate hydroxymethylfurfural, a potential human carcinogen. The addition of ethanol can reduce process temperatures and retain extraction efficiencies, but the ethanol may reduce the recovery of polyphenols in the subsequent purification stage, affecting the antioxidant properties of the extracts. This study evaluates a combined hot pressurized liquid extraction-resin purification process to obtain polyphenol extracts from spent ground coffee reduced in hydroxymethylfurfural. A multifactorial design was developed to determine the combined effect of the extraction (ethanol content: 0-16% and temperature: 60-90 degrees C) and purification (ethanol: 60-80%) conditions on some chemical properties of the extracts. The highest recovery of polyphenols (~8 mg GAE/g dry coffee solids) and reduction of hydroxymethylfurfural (95%) were obtained at 90 degrees C and 16% of ethanol during extraction and 80% of ethanol during purification. These operating conditions retained the antioxidant capacity of the crude extract between 60% and 88% depending on the determination method and recovered 90, 98, and 100% of 4-feruloylquinic acid, epicatechin, and 5 feruloylquinic acid, respectively after purification. The combined process allows differential polyphenols' recovery and enhances the safety of the extracts. Our computational chemistry results ruled out that the overall selectivity of the integrated process was correlated with the size of the polyphenols. PMID- 29271944 TI - Extraction of the Anisotropic Plasticity of Metal Materials by Using Inverse Analysis and Dual Indentation Tests. AB - In this paper, a novel inverse computation approach is proposed to extract the anisotropic plasticity parameters of metal materials by using inverse analysis and dual indentation tests. Based on dimensional analysis and extensive finite element (FE) simulations, four independent dimensionless functions are derived to correlate the anisotropic plasticity parameters with material responses in dual indentation tests. Besides, an inverse calculation algorithm is suggested, to estimate the unknown anisotropic parameters of the indented specimens using the information collected from indentation. The proposed numerical approach is applied on a series of engineering materials. Results show that the inverse analysis is ill-posed when only the load-displacement (P-h) curves in dual indentation tests were used. This problem can be effectively alleviated by introducing the pile-up effect as the additional information. The new method is proved to be very effective and reliable. PMID- 29271943 TI - Differential Preference of Burkholderia and Mesorhizobium to pH and Soil Types in the Core Cape Subregion, South Africa. AB - Over 760 legume species occur in the ecologically-heterogeneous Core Cape Subregion (CCR) of South Africa. This study tested whether the main symbionts of CCR legumes (Burkholderia and Mesorhizobium) are phylogenetically structured by altitude, pH and soil types. Rhizobial strains were isolated from field nodules of diverse CCR legumes and sequenced for 16S ribosomic RNA (rRNA), recombinase A (recA) and N-acyltransferase (nodA). Phylogenetic analyses were performed using Bayesian and maximum likelihood techniques. Phylogenetic signals were determined using the D statistic for soil types and Pagel's lambda for altitude and pH. Phylogenetic relationships between symbionts of the narrowly-distributed Indigofera superba and those of some widespread CCR legumes were also determined. Results showed that Burkholderia is restricted to acidic soils, while Mesorhizobium occurs in both acidic and alkaline soils. Both genera showed significant phylogenetic clustering for pH and most soil types, but not for altitude. Therefore, pH and soil types influence the distribution of Burkholderia and Mesorhizobium in the CCR. All strains of Indigofera superba were identified as Burkholderia, and they were nested within various clades containing strains from outside its distribution range. It is, therefore, hypothesized that I. superba does not exhibit rhizobial specificity at the intragenic level. Implications for CCR legume distributions are discussed. PMID- 29271940 TI - Antiangiogenic Effect of Flavonoids and Chalcones: An Update. AB - Chalcones are precursors of flavonoid biosynthesis in plants. Both flavonoids and chalcones are intensively investigated because of a large spectrum of their biological activities. Among others, anticancer and antiangiogenic effects account for the research interest of these substances. Because of an essential role in cancer growth and metastasis, angiogenesis is considered to be a promising target for cancer treatment. Currently used antiangiogenic agents are either synthetic compounds or monoclonal antibodies. However, there are some limitations of their use including toxicity and high price, making the search for new antiangiogenic compounds very attractive. Nowadays it is well known that several natural compounds may modulate basic steps in angiogenesis. A lot of studies, also from our lab, showed that phytochemicals, including polyphenols, are potent modulators of angiogenesis. This review paper is focused on the antiangiogenic effect of flavonoids and chalcones and discusses possible underlying cellular and molecular mechanisms. PMID- 29271945 TI - Comparative Transcriptome Analysis Reveals Hormone Signaling Genes Involved in the Launch of Culm-Shape Differentiation in Dendrocalamus sinicus. AB - Dendrocalamus sinicus is a sympodial bamboo species endemic to Yunnan Province, China, and is the strongest bamboo species in the world. However, there is substantial variation in the basal culm shape, i.e., straight culm (SC) and bent culm (BC), among different D. sinicus as a result of genetic and growth factors. This study performed a comparative transcriptomic analysis of bamboo shoots of two variants at the early, mid-, and late shoot-development stages to examine the molecular basis of this variation. In total, 98,479 unigenes were annotated, of which 13,495 were differentially expressed in pairwise comparisons of the six libraries. More differentially expressed genes (DEGs) were involved in SC than in BC culm development. The DEGs between BC and SC were assigned to 108 metabolic pathways. The 1064 DEGs in early development might mainly control the launch of culm-shape differentiation. Sixty genes encoding components of hormone signaling pathways were differentially expressed between BC5 and SC5, indicating complex hormonal regulation of culm differentiation. The AUX/IAA, ARF, PP2C, SnRK2, and ABF genes involved in auxin and abscisic acid signaling played key roles. These results help us to understand the molecular mechanism of culm variation and other aspects of culm development in D. sinicus. PMID- 29271946 TI - Design and Synthesis of Malonamide Derivatives as Antibiotics against Methicillin Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a serious threat to humans. Most existing antimicrobial drugs, including the beta-lactam and quinoxiline classes, are not effective against MRSA. In this study, we synthesized 24 derivatives of malonamide, a new class of antibacterial agents and potentiators of classic antimicrobials. A derivative that increases bacterial killing and biofilm eradication with low cell toxicity was created. PMID- 29271947 TI - Measurement of Scenic Spots Sustainable Capacity Based on PCA-Entropy TOPSIS: A Case Study from 30 Provinces, China. AB - In connection with the sustainable development of scenic spots, this paper, with consideration of resource conditions, economic benefits, auxiliary industry scale and ecological environment, establishes a comprehensive measurement model of the sustainable capacity of scenic spots; optimizes the index system by principal components analysis to extract principal components; assigns the weight of principal components by entropy method; analyzes the sustainable capacity of scenic spots in each province of China comprehensively in combination with TOPSIS method and finally puts forward suggestions aid decision-making. According to the study, this method provides an effective reference for the study of the sustainable development of scenic spots and is very significant for considering the sustainable development of scenic spots and auxiliary industries to establish specific and scientific countermeasures for improvement. PMID- 29271949 TI - Evaluation of Behavior Change Communication Campaigns to Promote Modern Cookstove Purchase and Use in Lower Middle Income Countries. AB - Nearly three billion people worldwide burn solid fuels and kerosene in open fires and inefficient stoves to cook, light, and heat their homes. Cleaner-burning stoves reduce emissions and can have positive health, climate, and women's empowerment benefits. This article reports on the protocol and baseline data from the evaluation of four behavior change communication (BCC) campaigns carried out in lower to middle income countries aimed at promoting the sale and use of cleaner-burning stoves. Interventions implemented in Bangladesh, Kenya, and Nigeria are using a range of BCC methods including mass media, digital media, outdoor advertising, and inter-personal communication. The mixed methods evaluation comprises three large-scale surveys: one pre-BCC and two follow-ups, along with smaller scale assessments of stove uptake and patterns of use. Baseline results revealed varying levels of awareness of previous promotions and positive attitudes and beliefs about modern (i.e., relatively clean-burning) cookstoves. Differences in cookstove preferences and behaviors by gender, socio demographics, media use, and country/region were observed that may affect outcomes. Across all three countries, cost (lack of funds) a key perceived barrier to buying a cleaner-burning stove. Future multivariate analyses will examine potential dose-response effects of BCC on cookstove uptake and patterns of use. BCC campaigns have the potential to promote modern cookstoves at scale. More research on campaign effectiveness is needed, and on how to optimize messages and channels. This evaluation builds on a limited evidence base in the field. PMID- 29271948 TI - Comparative Transcriptome Analysis of Genes Involved in Anthocyanin Biosynthesis in Red and Green Walnut (Juglans regia L.). AB - Fruit color is an important economic trait. The color of red walnut cultivars is mainly attributed to anthocyanins. The aim of this study was to explore the differences in the molecular mechanism of leaf and peel color change between red and green walnut. A reference transcriptome of walnut was sequenced and annotated to identify genes related to fruit color at the ripening stage. More than 290 million high-quality reads were assembled into 39,411 genes using a combined assembly strategy. Using Illumina digital gene expression profiling, we identified 4568 differentially expressed genes (DEGs) between red and green walnut leaf and 3038 DEGs between red and green walnut peel at the ripening stage. We also identified some transcription factor families (MYB, bHLH, and WD40) involved in the control of anthocyanin biosynthesis. The trends in the expression levels of several genes encoding anthocyanin biosynthetic enzymes and transcription factors in the leaf and peel of red and green walnut were verified by quantitative real-time PCR. Together, our results identified the genes involved in anthocyanin accumulation in red walnut. These data provide a valuable resource for understanding the coloration of red walnut. PMID- 29271950 TI - Synthesis, Crystal Structure, and Supramolecular Understanding of 1,3,5-Tris(1 phenyl-1H-pyrazol-5-yl)benzenes. AB - Understanding the supramolecular environment of crystal structures is necessary to facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular structures of pyrazoles. This class of molecules with different substituents may assist in understanding how small structural changes affect the supramolecular environment. The obtained compounds did not present the formation of planar stacking interactions between benzenes in solid or liquid states. This supposition was indicated by single crystal diffraction, Density Functional Theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations, and concentration-dependent liquid-state 1H nuclear magnetic resonance (NMR). NMR showed that chemical shifts of benzene and pyrazole hydrogens confirm that planar stacking interactions are not formed in solution. The crystalline structures presented different molecular conformations. The molecular structures of 5 and 9b are in a twisted conformation, while compound 7 showed a conformation analogous to a calyx form. PMID- 29271952 TI - A Modular Plug-And-Play Sensor System for Urban Air Pollution Monitoring: Design, Implementation and Evaluation. AB - Urban air pollution has caused public concern globally because it seriously affects human life. Modern monitoring systems providing pollution information with high spatio-temporal resolution have been developed to identify personal exposures. However, these systems' hardware specifications and configurations are usually fixed according to the applications. They can be inconvenient to maintain, and difficult to reconfigure and expand with respect to sensing capabilities. This paper aims at tackling these issues by adopting the proposed Modular Sensor System (MSS) architecture and Universal Sensor Interface (USI), and modular design in a sensor node. A compact MSS sensor node is implemented and evaluated. It has expandable sensor modules with plug-and-play feature and supports multiple Wireless Sensor Networks (WSNs). Evaluation results show that MSS sensor nodes can easily fit in different scenarios, adapt to reconfigurations dynamically, and detect low concentration air pollution with high energy efficiency and good data accuracy. We anticipate that the efforts on system maintenance, adaptation, and evolution can be significantly reduced when deploying the system in the field. PMID- 29271951 TI - Neural Stem Cells and Its Derivatives as a New Material for Melanin Inhibition. AB - The pigment molecule, melanin, is produced from melanosomes of melanocytes through melanogenesis, which is a complex process involving a combination of chemical and enzymatically catalyzed reactions. The synthesis of melanin is primarily influenced by tyrosinase (TYR), which has attracted interest as a target molecule for the regulation of pigmentation or depigmentation in skin. Thus, direct inhibitors of TYR activity have been sought from various natural and synthetic materials. However, due to issues with these inhibitors, such as weak or permanent ability for depigmentation, allergy, irritant dermatitis and rapid oxidation, in vitro and in vivo, the development of new materials that inhibit melanin production is essential. A conditioned medium (CM) derived from stem cells contains many cell-secreted factors, such as cytokines, chemokines, growth factors and extracellular vesicles including exosomes. In addition, the secreted factors could negatively regulate melanin production through stimulation of a microenvironment of skin tissue in a paracrine manner, which allows the neural stem cell CM to be explored as a new material for skin depigmentation. In this review, we will summarize the current knowledge regulating depigmentation, and discuss the potential of neural stem cells and their derivatives, as a new material for skin depigmentation. PMID- 29271953 TI - [Antibody-Based Drugs and Other Recombinant Proteins for Diagnostics and Therapy of Viral Infections, Autoimmune Diseases and Cancer]. PMID- 29271954 TI - [Engineering Antibodies as Drugs: Principles and Practice]. AB - Over the last forty years, recombinant antibodies have been transformed from an unproven experimental approach to a therapeutic modality with multiple success stories in the treatment of cancer, inflammation, infections and cardiometabolic diseases. Owing to their high affinity and selectivity for the target antigen, their multimodal tunable mode of action, their modular nature and long half-life, antibodies now hold prominent positions in the pipelines of major biopharmaceutical companies. In this brief report, I aim to highlight the themes that have shaped the therapeutic antibody engineering as it exists today and to offer a personal perspective on its future developments. Distinct antibody engineering history, developments and trends in Russian Federation will not be discussed since they are detailed elsewhere in this journal issue. PMID- 29271955 TI - [Next-Generation Techniques for Discovering Human Monoclonal Antibodies]. AB - Monoclonal antibodies have found wide applications in the treatment of cancer, as well as of autoimmune, infectious, and other diseases. Several dozen new antibodies are currently undergoing different stages of clinical trials, and some of them will soon be added to the list of immunotherapeutic drugs. Most of these antibodies have been generated using hybridoma technology or a phage display. In recent years, new methods of obtaining human monoclonal antibodies have been actively developing. These methods rely on sequencing immunoglobulin genes from B lymphocytes, as well as on the creation of antibody-secreting stable B-cell lines. The term next-generation antibody-discovery platforms has already been established in the literature to refer to these approaches. Our review focuses on describing the results obtained by these methods. PMID- 29271956 TI - [Targeted Bifunctional Proteins and Hybrid Nanoconstructs for Cancer Diagnostics and Therapies]. AB - In this review, the authors' works published within the past 5 years devoted to the development of bifunctional hybrid nanostructures based on the targeting polypeptides and nanoparticles of various origin (quantum dots, nanogold, nanodiamonds, upconversion nanoparticles, magnetic and polymer nanoparticles) as modules that ensure visualization and various damaging effects on cancer cells are surveyed and the prospects of their application in theranostics and precision medicine have been contemplated. PMID- 29271957 TI - [In vitro Antiviral Activity of Recombinant Antibodies of IgG and IgA Isotypes to Hemagglutinin of the Influenza A Virus]. AB - Seasonal and highly infectious strains of the influenza A and influenza B viruses cause millions of cases of severe complications in elderly people, children, and patients with immune diseases each year. Immunoglobulin A (IgA), which is an active component of humoral immunity, can prevent the spread of the virus in the upper respiratory tract. The preparation and study of the properties of recombinant virus-specific IgA could be an important approach to finding new means of preventing and treating influenza. Based on CHO DG44 cells, we developed stable monoclonal cell lines that produce monomeric and dimeric antibodies FI6 IgA1 and FI6-IgA2m1 to hemagglutinin (HA) of the influenza A virus. When studying the productivity, growth, and stability of the obtained clones, we found that the dimeric form of antibodies of IgA1 isotype is superior to other forms. The dimeric form of IgA antibodies plays a key role in mucosal immunity. Recognizing the prospects of using dimeric IgA as prophylactic and therapeutic mucosal drugs for viral infections, we studied their virus-neutralizing and antiviral activities on MDCK cell culture and compared them with the antibodies of the IgG1 isotype. This study presents the data on antiviral and virus-neutralizing activities of the FI6-IgA1 dimers to seasonal and highly infectious strains of influenza A virus. PMID- 29271958 TI - [Analysis of the Specificity of IgA Antibodies Produced in the Mouse Small Intestine]. AB - Intestinal microbiota controls multiple aspects of body homeostasis. The microbiota composition changes easily in response to internal or external factors, which may result in dysbiosis and associated inflammatory reactions. Thus, maintaining the microbiota composition by the host immune system is crucial, and one of the main mechanisms for microbiota control is production of immunoglobulin A (IgA) at mucosal surfaces. The molecular mechanisms regulating the interactions between the immune system and microbiota remain obscure. A panel of hybridoma cell lines was constructed to produce monoclonal IgA antibodies specific to various commensal bacteria present in intestinal microbiota. The panel can be used to further understand the mechanisms whereby the adaptive immune system controls the microbiota composition. PMID- 29271959 TI - [Requirements for the Induction of Broadly Neutralizing Antibodies against HIV-1 by Vaccination]. AB - A study of the induction of broadly neutralizing antibodies (bNAbs) in HIV infected patients and vaccinated subjects revealed the main criteria for the formation of bNAbs (the duration of exposure to a viral antigen, the effect of the diversity of HIV variants, and the removal of barriers associated with the Env-dependent defense mechanisms of HIV-1). Modified trimers of the HIV-1 envelope protein (Env) exposed on virus-like particles (VLP) have unique properties: they (i) modulate the exposure of binding sites (bs) of the CD4 receptor and co-receptor; (ii) create steric restrictions for contact with bNAbs; (iii) increase the Env presentation density, thus enhancing the immune response; (iv) form stable trimers that do not induce off-target immune responses; and (v) allow additional modifications to their structure and construction of a platform with immunostimulating molecules. Immunization using a heterologous subtype-cross prime-boost regime with modified trimeric Env is capable of inducing somatic hypermutation levels necessary for the formation of bNAbs. PMID- 29271960 TI - [Peculiarities of the Mechanism of Interactions of Catalytic Antibodies with Organophosphorus Substrates]. AB - Catalytic antibodies are a promising model for creating highly specific biocatalysts with predetermined activity. However, in order to realize the directed change or improve their properties, it is necessary to understand the basics of catalysis and the specificity of interactions with substrates. In the present work, a structural and functional study of the Fab fragment of antibody A5 and a comparative analysis of its properties with antibody A17 have been carried out. These antibodies were previously selected for their ability to interact with organophosphorus compounds via covalent catalysis. It has been established that antibody A5 has exceptional specificity for phosphonate X with bimolecular reaction rate constants of 510 +/- 20 and 390 +/- 20 min^(-1)M^(-1) for kappa and lambda variants, respectively. 3D-Modeling of antibody A5 structure made it possible to establish that the reaction residue L-Y33 is located on the surface of the active site, in contrast to the A17 antibody, in which the reaction residue L-Y37 is located at the bottom of a deep hydrophobic pocket. To investigate a detailed mechanism of the reaction, A5 antibody mutants with replacements L-R51W and H-F100W were created, which made it possible to perform stopped-flow kinetics. Tryptophan mutants were obtained as Fab fragments in the expression system of the methylotrophic yeast species Pichia pastoris. It has been established that the effectiveness of their interaction with phosphonate X is comparable to the wild-type antibody. Using the data of the stopped-flow kinetics method, significant conformational changes were established in the phosphonate modification process. The reaction was found to proceed using the induced-fit mechanism; the kinetic parameters of the elementary stages of the process have been calculated. The results present the prospects for the further improvement of antibody-based biocatalysts. PMID- 29271961 TI - [Exceptional Diversity of Catalytic Antibodies with Varying Activity in the Blood of Autoimmune and Viral Disease Patients]. AB - Antibodies (ABs) that target autoantigens were more abundant in the blood of humans and animals suffering from certain autoimmune and viral diseases than in the blood of healthy donors. The emergence of ABs with diverse types of catalytic activity is among the earliest manifestations of certain autoimmune diseases. The putative mechanisms that underlie the accumulation of autoantibodies and abzymes in different autoimmune diseases are addressed in the present review. The extraordinary diversity of abzymes with various types of catalytic activity is discussed. PMID- 29271962 TI - [A Method for the Parallel and Sequential Generation of Single-Domain Antibodies for the Proteomic Analysis of Human Blood Plasma]. AB - A new efficient method for the parallel and sequential stepwise generation of single-domain antibodies to various high-abundance human-plasma proteins has been described. Single-domain antibodies have a number of features that favorably distinguish them from classical antibodies. In particular, they are able to recognize unusual unique conformational epitopes of native target proteins, small in size, and relatively easily produced and modified; have enhanced stability; and rapidly renature after denaturation. As a consequence, the immunosorbents that utilize these antibodies can be reused without any significant loss of activity. The principal novelty and universality of the described method is that it enables the sequential generation of antibodies to a number of high-abundance and yet unknown antigens of a complex protein mixture without the need for purified antigens. The effectiveness of the method is demonstrated by the example of generation of single-domain antibodies to a number of high-abundance proteins of the human blood plasma. The produced antibodies are promising biotechnological tools that can be used to develop prototypes for new diagnostic and therapeutic agents, as well as appropriate immunoaffinity-based methods for removal, enrichment, analysis, and/or targeting of specified proteins and their complexes from (in) the human blood. As we show, the generated single-domain antibodies can be efficiently used in designing new immunosorbents. As a rule, commercially available analogous immunosorbents that utilize classical antibodies remove many major proteins from the blood plasma immediately, while immunosorbents for many individual proteins are difficult to find and rather expensive. Single-domain antibodies generated by our method are unique new materials that allow for the development of more efficient and delicate approaches to pretreatment of plasma and the analysis of various blood plasma biomarkers. PMID- 29271963 TI - [Bifunctional Toxin DARP-LoPE Based on the HER2-Specific Innovative Module of a Non-Immunoglobulin Scaffold as a Promising Agent for Theranostics]. AB - We have generated and characterized HER2-specific targeted toxin based on the low immunogenic variant of Pseudomonas exotoxin A (LoPE), in which most of the human immunodominant B-cell epitopes have been inactivated. Nonimmunoglobulin DARPin based HER2-specific protein was used as a targeting module for toxin delivery to the cellular target. Using confocal microscopy, it has been found that both domains in this hybrid toxin retained their functionality, i.e., the specific interaction with HER2 receptor, as well as the internalization and effective transport to ER typical of the wild-type Pseudomonas exotoxin A. The HER2 dependent cytotoxic effect correlated with receptor expression level at the cell surface, as shown in vitro using cell lines with different levels of HER2 expression. Due to the very high selective cytotoxicity against HER2-positive human tumor cells, as well as expected low immunogenicity, we believe that this new targeted toxin may be promising for future in vivo studies as a therapeutic agent for HER2-positive tumors. PMID- 29271964 TI - [T Lymphocytes with Modified Specificity in the Therapy of Malignant Diseases]. AB - Immunotherapy is one of the most rapidly progressing and promising fields in antitumor therapy. It is based on the idea of using immune cells of patient or healthy donors for elimination of malignant cells. T lymphocytes play a key role in cell-mediated immunity including the response to tumors. Recently developed approaches of altering antigen specificity of T cells consist of their genetic modification (introduction of additional T cell receptor or chimeric antigen receptor), as well as the use of bispecific molecules that crosslink target and effector cells. These approaches are used to retarget T lymphocytes with arbitrary specificity against tumor antigens in the context of antitumor immunotherapy. The high potential of T cell immunotherapy was demonstrated in a number of clinical trials. In the future, it is possible to develop approaches to the therapy of a wide spectrum of tumors. The selection of the optimal antigen is the main challenge in successful T cell immunotherapy, as it largely determines the effectiveness of the treatment, as well as the risk of side effects. In this review we discuss potential methods of modification of T cell specificity and targets for immunotherapy. PMID- 29271965 TI - [Recombinant Monoclonal Antibodies, from Tumor Targeting to Cancer Immunotherapy: A Critical Overview]. AB - In view of the explosion of the present clinical use of monoclonal antibodies (mAbs), not only in the treatment of cancer, but also of autoimmune diseases, I was asked to review the development of mAbs in tumor diagnosis and therapy, with some illustrations of our own contribution in the field. The initial use of radiolabeled mAbs for tumor targeting and radioimmunotherapy led to the extensive clinical application of unlabeled, "humanized" mAbs for cancer therapy, which I describe with a critical perspective. The introduction of recombinant bispecific antibodies, capable of bridging T lymphocytes with tumor cells and inducing killing of the cancer cells, was found to be mostly active in the treatment of hematological malignancies. Most interestingly, the use of mAbs not directed to the tumor cells, but to inhibitory receptors expressed by cytotoxic T lymphocytes, which trigger them to kill the cancer cells, represents a new form of active cancer immunotherapy. My motivation in writing this review was related to my long-term interactions with several Russian scientists, mentioned at the end of this article. PMID- 29271966 TI - [Antibody Engineering: From the Idea to Its Implementation]. AB - The late 1970s brought opportunities to create proteins with new properties and, in particular, various derivatives of mouse monoclonal antibodies (mAbs) owing to the discoveries in molecular and cell biology and the development of bioengineering. Studies of mouse/human "chimeric" antibodies, miniantibodies to be synthesized in bacterial cells, full-size single-chain antibodies, complexes of miniantibodies with intramolecular chaperones, and other approaches made it possible to create a multitude of multifunctional biopreparations with predefined properties. The review describes, with the example of one research team, how studies in the field began and what the basis for their progress was. PMID- 29271967 TI - [Conformational Fingerprinting Using Monoclonal Antibodies
(on the Example of Angiotensin I-Converting Enzyme-ACE)]. AB - During the past 30 years my laboratory has generated 40+ monoclonal antibodies (mAbs) directed to structural and conformational epitopes on human ACE as well as ACE from rats, mice and other species. These mAbs were successfully used for detection and quantification of ACE by ELISA, Western blotting, flow cytometry and immunohistochemistry. In all these applications mainly single mAbs were used. We hypothesized that we can obtain a completely new kind of information about ACE structure and function if we use the whole set of mAbs directed to different epitopes on the ACE molecule. When we finished epitope mapping of all mAbs to ACE (and especially, those recognizing conformational epitopes), we realized that we had obtained a new tool to study ACE. First, we demonstrated that binding of some mAbs is very sensitive to local conformational changes on the ACE surface-due to local denaturation, inactivation, ACE inhibitor or mAbs binding or due to diseases. Second, we were able to detect, localize and characterize several human ACE mutations. And, finally, we established a new concept - conformational fingerprinting of ACE using mAbs that in turn allowed us to obtain evidence for tissue specificity of ACE, which has promising scientific and diagnostic perspectives. The initial goal for the generation of mAbs to ACE 30 years ago was obtaining mAbs to organ-specific endothelial cells, which could be used for organ-specific drug delivery. Our systematic work on characterization of mAbs to numerous epitopes on ACE during these years has lead not only to the generation of the most effective mAbs for specific drug/gene delivery into the lung capillaries, but also to the establishment of the concept of conformational fingerprinting of ACE, which in turn gives a theoretical base for the generation of mAbs, specific for ACE from different organs. We believe that this concept could be applicable for any glycoprotein against which there is a set of mAbs to different epitopes. PMID- 29271969 TI - miR-194-5p/BCLAF1 deregulation in AML tumorigenesis. AB - This corrects the article DOI: 10.1038/leu.2017.64. PMID- 29271968 TI - [Humanization of Murine Monoclonal anti-hTNF Antibody: The F10 Story]. AB - Tumor necrosis factor (TNF) is a proinflammatory cytokine implicated in pathogenesis of multiple autoimmune and inflammatory diseases. Anti-TNF therapy has revolutionized the therapeutic paradigms of autoimmune diseases and became one of the most successful examples of the clinical use of monoclonal antibodies. Currently, anti-TNF therapy is used by millions of patients worldwide. At the moment, fully human anti-TNF antibody Adalimumab is the best-selling anti cytokine drug in the world. Here, we present a story about a highly potent anti TNF monoclonal antibody initially characterized more than 20 years ago and further developed into chimeric and humanized versions. We present comparative analysis of this antibody with Infliximab and Adalimumab. PMID- 29271970 TI - Non-Alcoholic Fatty Liver Disease and HIV/AIDS: A New Way of Modulation of Cardiovascular Risk. AB - With the advent and subsequent success of antiretroviral therapy, HIV infection has largely become a chronic condition and is increasingly seen alongside metabolic disorders such as dyslipidemia and insulin resistance. Furthermore, the administration of antiretroviral therapy itself is associated with an increase in the incidence of metabolic risk factors, namely insulin resistance, lipoatrophy, dyslipidemia, and abnormalities of fat distribution, in HIV patients. Thus, further challenges in the management of HIV patients include the management of diabetes and the metabolic syndrome, non-alcoholic fatty liver disease. Importantly, HIV and non-alcoholic fatty liver disease are both associated with increased risk of cardiovascular disease. Overall, the management of non alcoholic fatty liver disease and cardiovascular risks associated with HIV is complex and requires specialist management. Further research is needed to address the best strategies in the management of cardiovascular disease in patients with HIV. This narrative review aims to discuss non-alcoholic fatty liver disease and HIV infection, HIV and cardiovascular disease, as well as how fatty liver modulates cardiovascular disease in HIV patients. PMID- 29271971 TI - Treatment as Prevention: Should Hepatitis C Learn the Lessons from HIV? AB - Long-term experience in the treatment of HIV-infected individuals has shown indirect benefits of early initiation of antiretroviral therapy, particularly in preventing HIV transmission. With the advent of direct-acting antivirals for the treatment of hepatitis C, the strategy of treatment-as-prevention has become feasible. However, economic, clinical, ethical, and public health issues arise from the concept of using therapeutic interventions only as prevention strategies. PMID- 29271972 TI - Hot News: HIV Epidemics - Current Burden and Future Prospects. AB - The latest estimate from the WHO is of nearly 37 million people living with HIV worldwide by the end of 2016. Roughly 20 million are receiving antiretroviral therapy. Despite this progress in diagnosis and treatment, nearly 2 million new HIV infections continue to occur annually. Whereas men having sex with men (MSM) represent the major risk population for incident cases in North America and the European Union, infection of heterosexual women is the major group in Sub-Saharan Africa. Injection drug use is a leading mechanism of HIV acquisition in Asia, including Russia and the former Soviet republics. Given that HIV cannot be eradicated from infected persons, antiretroviral therapy prescribed as early as possible and forever has become the paradigm to both avoid clinical progression and prevent further transmissions. No protective vaccines are on the horizon, at least within a 5-year view. New genetic strategies (i.e., using CRISPR) that pursue elimination or lethal dysfunction of the HIV provirus hidden in human cell reservoirs have renewed the interest for HIV cure. Ultimately, they represent the most serious hope for controlling and eliminating the HIV pandemics. In the mean time, the benefit of antiretrovirals is being extended using oral drugs at demand in uninfected persons at risk as pre-exposure prophylaxis (PrEP). However, accompanying declines in condom use and increases in sexually transmitted infections are a major concern promoting PrEP. Alerts on rising syphilis and gonorrhea, and outbreaks of acute hepatitis C and now hepatitis A reflect the lack of adequate education, especially among MSM. Altogether, the updated figures from WHO and UNAIDS on the current status of the HIV epidemics suggest that a plateau may have been reached. Thereby, major efforts will be further required to envision a HIV/AIDS-free world. Major gaps still exist in access to antiretroviral therapy, diagnosis of people unaware of their infection, education on risk behaviors and interventions for preventing new HIV infections. PMID- 29271973 TI - Correction to: Understanding Plain English Summaries: A Comparison of two Approaches to Improve the Quality of Plain English Summaries in Research. AB - [This corrects the article DOI: 10.1186/s40900-017-0064-0.]. PMID- 29271974 TI - Fluticasone propionate and increased risk of pneumonia in COPD: is it PAFR dependent? PMID- 29271975 TI - Erratum to "Prevalence of Asthma and Chronic Obstructive Pulmonary Disease in Aboriginal and Non-Aboriginal Populations: A Systematic Review and Meta-Analysis of Epidemiological Studies". AB - [This corrects the article DOI: 10.1155/2012/825107.]. PMID- 29271976 TI - Gaps within the Biomedical Literature: Initial Characterization and Assessment of Strategies for Discovery. AB - Within well-established fields of biomedical science, we identify "gaps", topical areas of investigation that might be expected to occur but are missing. We define a field by carrying out a topical PubMed query, and analyze Medical Subject Headings by which the set of retrieved articles are indexed. Medical Subject headings (MeSH terms) which occur in >1% of the articles are examined pairwise to see how often they are predicted to co-occur within individual articles (assuming that they are independent of each other). A pair of MeSH terms that are predicted to co-occur in at least 10 articles, yet are not observed to co-occur in any article, are "gaps" and were studied further in a corpus of 10 disease-related article sets and 10 related to biological processes. Overall, articles that filled gaps were cited more heavily than non-gap-filling articles and were 61% more likely to be published in multidisciplinary high-impact journals. Nine different features of these "gaps" were characterized and tested to learn which, if any, correlate with the appearance of one or more articles containing both MeSH terms within the next five years. Several different types of gaps were identified, each having distinct combinations of predictive features: a) those arising as a byproduct of MeSH indexing rules; b) those having little biological meaning; c) those representing "low hanging fruit" for immediate exploitation; and d) those representing gaps across disciplines or sub-disciplines that do not talk to each other or work together. We have built a free, open tool called "Mine the Gap!" that identifies and characterizes the "gaps" for any PubMed query, which can be accessed via the Anne O'Tate value-added PubMed search interface (http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/AnneOTate.cgi). PMID- 29271978 TI - Filming disorganized attachment. PMID- 29271977 TI - Sodium Is Not Essential for High Bioactivity of Glasses. AB - This study aims to demonstrate that excellent bioactivity of glass can be achieved without the presence of an alkali metal component in glass composition. In vitro bioactivity of two sodium-free glasses based on the quaternary system SiO2-P2O5-CaO-CaF2 with 0 and 4.5 mol% CaF2 content was investigated and compared with the sodium containing glasses with equivalent amount of CaF2. The formation of apatite after immersion in Tris buffer was followed by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), 31P and 19F solid state MAS-NMR. The dissolution study was completed by ion release measurements in Tris buffer. The results show that sodium free bioactive glasses formed apatite at 3 hours of immersion in Tris buffer, which is as fast as the corresponding sodium containing composition. This signifies that sodium is not an essential component in bioactive glasses and it is possible to make equally degradable bioactive glasses with or without sodium. The results presented here also emphasize the central role of the glass compositions design which is based on understanding of structural role of components and/or predicting the network connectivity of glasses. PMID- 29271979 TI - Struggling to be Fit: Identity, Integrity, and the Law. AB - This interdisciplinary co-authored Analysis piece introduces identity and integrity, which are argued to sit at the core of the person. It analyses approaches taken to these concepts by legal regimes, particularly in the context of individuals using artificial limbs or digital avatars. The piece concludes that law engages with identity and integrity to a limited and incomplete extent; and that law is thus inadequate in its engagement with the person, and its meaning making in this respect. This piece draws on two interdisciplinary funded projects, funded by the Wellcome Trust and the Arts and Humanities Research Council. PMID- 29271980 TI - In response to The role of smartphones in encouraging physical activity in adults. PMID- 29271981 TI - Sensory impairments and wrist fractures: A case-control study. AB - OBJECTIVES: To investigate vestibular function, foot sensation, postural control and functional abilities, and to evaluate whether these variables are associated with fall-related wrist fracture. METHODS: A case-control study was conducted with 98 subjects, age range 50-75 years, who had sustained a fall-related wrist fracture. Forty-eight sex-, age- and physical activity-matched individuals, with no previous history of wrist fracture, served as controls. Measurements included: head-shake test (HST), tuning fork, biothesiometer, Semmes-Weinstein monofilaments (MF), Sensory Organization Test (SOT), Five-Times-Sit-to-Stand Test (FTSTS), 10-m walk test (10MWT), Activities-specific Balance Confidence (ABC), and the Dizziness Handicap Inventory (DHI) scales. Logistic regression models were used to determine associations of variables with a fall-related wrist fracture. RESULTS: Vestibular asymmetry was apparent in 82% of wrist fracture subjects and 63% of controls (p = 0.012). Plantar pressure sensation (p <0.001), SOT composite scores (p< 0.001), 10MWT (p <0.001), FTSTS (p <0.001), ABC (p <0.001) and DHI (p <0.005) were significantly poorer among cases than controls. A positive HST (odds ratio (OR) 5.424; p = 0.008) and monofilament sensation (OR 3.886; p = 0.014) showed the strongest associations with having a fall-related wrist fracture. CONCLUSION: Asymmetrical vestibular function and reduced plantar pressure sensation are associated with fall-related wrist fractures among the ageing population. These factors are potential targets for future interventions. PMID- 29271982 TI - Overexpression of TAFI promotes epithelial mesenchymal transition in endometriosis. AB - OBJECTIVE: Endometriosis is a disease that occurs in women. Thrombin-activated fibrinolytic inhibitor (TAFI) is mainly secreted by stem cells and acts as a regulatory role in the body. Epithelial leaf transition plays a leading role in cell growth and invasion. Our study focuses on the mechanism of TAFI in patients with endometriosis. PATIENTS AND METHODS: The expression of TAFI was determined by immunohistochemistry. Reverse transcriptase-polymerase chain reaction (RT-PCR) served to detect the expression of TAFI and the effect of TAFI on overall survival (OS) and progression-free survival (PFS) levels. The changes of primary cytology in patients with endometriosis were observed under a microscope. The cell source was further determined by immunofluorescence labeling of vimentin and cytokeratin, and the expression of TAFI was detected by Western-blot. 3-4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell invasion assay were utilized to detect the viability and aggressiveness of cells after epithelial mesenchymal transition (EMT). RESULTS: TAFI was overexpressed in endometriosis tissues and no expression of TAFI was found in normal tissues, which is consistent with RT-PCR results. TAFI overexpressed endometriosis patients had low levels of overall OS and PFS. There were statistically significant differences. Cell morphology shows that endometriosis primary cells are mainly composed of epithelial cells and fibroblasts. Immunofluorescence assay showed that vimentin and cytokeratin were expressed in cells, and the expression of TAFI was detected by Western-blot. Compared with normal tissues, TAFI was considerably higher in patients with endometriosis. The results of Western-blot and RT-PCR showed that the expression of TAFI was significantly increased in patients with endometriosis and the cell proliferation and cell invasion were significantly accelerated. CONCLUSIONS: Our results show that TAFI is highly expressed in endometriosis and causes EMT, which accelerated the cell proliferation and cell invasion. Snail is an inhibitor of E-cadherin, which may participate in metastasis and invasion of endometriosis by mediating EMT. So, we suspect that Snail controls the occurrence of the EMT and then affects the cell metastasis and invasion, which requires further verification. PMID- 29271983 TI - The function of miR-218 and miR-618 in postmenopausal osteoporosis. AB - OBJECTIVE: Postmenopausal osteoporosis (POMP) is a serious disorder with significant physical, psychosocial, and financial consequences, which greatly reduce the postmenopausal women's life quality. The related issues of postmenopausal osteoporosis are increasingly concerned by society. Past researches have shown that miRNAs play an important role in the occurrence and development of postmenopausal osteoporosis. However, the role of miR-218 and miR 618 in the osteoporosis regulation is still unclear. MATERIALS AND METHODS: First of all, we investigated the alteration of miR-218 and miR-618 during osteoclastogenesis of RAW264.7 cells. Next, we transfected RAW264.7 cells with miR-218 or miR-618 mimics and inhibitors to explore the influences of miR-218 and miR-618 on osteoclast differentiation. Then, we conducted bioinformatics analysis and luciferase reporter assay to identify and test the target gene of miR-218 and miR-618. RESULTS: MiR-218 and miR-618 were down-regulated when RAW264.7 cells differentiated into osteoclasts. In addition, overexpression of miR-218 or miR 618 attenuated RAW264.7 cells differentiated into osteoclasts in vitro, whereas inhibition of miR-218 or miR-618 promoted this progress. This was demonstrated by increased expression of osteoclast-specific genes and TRAP staining. TLR-4 was confirmed to be the direct target of miR-218 and miR-618 by bioinformatics and luciferase reporter assay. CONCLUSIONS: These results suggested that miR-218 and miR-618 play an important role in osteoclastogenesis via TLR-4/MyD88/NF-kappaB signaling pathway. Thus, targeting miR-218 and miR-618 promise a therapeutic potential in the treatment of osteoporosis. PMID- 29271984 TI - The interplay of transcriptional and post-transcriptional regulation of migration of mesenchymal stem cells during early stages of bone fracture healing. AB - Bone fractures are a medical condition where the continuity of the bone is broken due to a fall or accident. The fracture may also be the result of medical conditions such as osteoporosis, cancers of bone or osteogenesis imperfect. During the bone fracture healing process, the mesenchymal stem cells (undifferentiated connective tissue cells) are recruited from local and systemic sources. The modulation of mesenchymal cell migration to the fractured site is the desired goal. Still, there are many processes that are still required to be studied and analyzed. We aimed to consolidate and review the available information on this topic. PMID- 29271985 TI - Autophagy attenuates the oxidative stress-induced apoptosis of Mc3T3-E1 osteoblasts. AB - OBJECTIVE: The oxidative stress-induced osteoblast apoptosis plays an important role in the pathological process of osteoporosis, but the roles of autophagy in oxidative stress and apoptosis of osteoblasts remain unclear. This study aimed to observe the role of autophagy in oxidative stress injury of osteoblasts and the relationship between autophagy and apoptosis. MATERIALS AND METHODS: Mc3T3-E1 cells were stimulated with different concentrations (0.1, 0.5, and 1 mM) of hydrogen peroxide. The cell viability was detected via cell counting kit 8 (CCK8) at different time points (0, 2, 6, 8, and 12 h), the apoptosis was detected via Western blotting and flow cytometry, and the autophagy was detected via macrophage-derived chemokine (MDC) and transmission electron microscope. The changes in expression of autophagy-associated protein, Beclin1, and LC3II/I ratio, were detected via Western blotting. Moreover, the intracellular reactive oxygen species (ROS) level and extracellular superoxide dismutase (SOD) level were observed using the autophagy regulators, rapamycin (Rap) and 3-methyladenine (3-MA), so as to clarify the interaction between autophagy and cellular oxidation. RESULTS: Hydrogen peroxide-induced apoptosis and autophagy of osteoblasts were in dose- and time-dependent manners; the hydrogen peroxide inhibitors could inhibit the autophagy level, and autophagy inhibitor (3-MA) could significantly enhance the hydrogen peroxide-induced ROS level and apoptosis rate in cells. Besides, Western blotting confirmed that the cleaved caspase-3 and cleaved poly adenosine diphosphate ribose polymerase (PARP) proteins were increased. The autophagy inducer (Rap) partially inhibited the hydrogen peroxide induced oxidative stress and apoptosis. CONCLUSIONS: Autophagy inhibits the oxidative stress-mediated apoptosis of osteoblasts, which is a potential target for the osteoporosis treatment. PMID- 29271986 TI - Mid term results of radial metaphyseal core decompression on Kienbock's disease. AB - OBJECTIVE: Kienbock's disease is a commonly seen posttraumatic avascular necrosis characterized by avascular necrosis of the lunate bone of the wrist which involves the dominant hand. In our study, we aimed to present midterm outcomes of 12 cases treated with radial metaphyseal core decompression. PATIENTS AND METHODS: In our clinic, 12 patients who applied to our outpatient clinic with intractable pain despite at least six weeks of conservative treatment were previously diagnosed and evaluated as Kienbock's disease between the years 2006 and 2014. Patients at early stage received radial metaphyseal core decompression. RESULTS: The patients were evaluated as postoperative grip strength, flexion extension gap, ulnar-radial deviation gap, VAS, Quick DASH and MAYO wrist scoring and patient satisfaction. CONCLUSIONS: We determined that interventions performed for Kienbock's disease cannot halt radiological progression. We are of the opinion that radial metaphyseal core decompression, aiming at increasing blood perfusion, improve early diagnosis and treatment of Kienbock's disease, increasing the patient satisfaction. PMID- 29271987 TI - Exosomes secreted by mice adipose-derived stem cells after low-level laser irradiation treatment reduce apoptosis of osteocyte induced by hypoxia. AB - OBJECTIVE: Kienbock's disease is a commonly seen posttraumatic avascular necrosis characterized by avascular necrosis of the lunate bone of the wrist which involves the dominant hand. In our study, we aimed to present midterm outcomes of 12 cases treated with radial metaphyseal core decompression. PATIENTS AND METHODS: In our clinic, 12 patients who applied to our outpatient clinic with intractable pain despite at least six weeks of conservative treatment were previously diagnosed and evaluated as Kienbock's disease between the years 2006 and 2014. Patients at early stage received radial metaphyseal core decompression. RESULTS: The patients were evaluated as postoperative grip strength, flexion extension gap, ulnar-radial deviation gap, VAS, Quick DASH and MAYO wrist scoring and patient satisfaction. CONCLUSIONS: We determined that interventions performed for Kienbock's disease cannot halt radiological progression. We are of the opinion that radial metaphyseal core decompression, aiming at increasing blood perfusion, improve early diagnosis and treatment of Kienbock's disease, increasing the patient satisfaction. PMID- 29271988 TI - Effects of pheophorbide a-mediated photodynamic therapy on proliferation and metastasis of human prostate cancer cells. AB - OBJECTIVE: To observe the effects of pheophorbide a-mediated photodynamic therapy (Pa-PDT) on the in vitro proliferation, apoptosis, invasion and metastasis of human prostate cancer PC-3 cells and to investigate its possible mechanism. MATERIALS AND METHODS: Pa-PDT in gradient concentrations (0 MUM, 0.25 MUM, 0.5 MUM, 1 MUM, 2 MUM, and 4 MUM) were used to act on PC-3 cells; the cell proliferation in each group was detected via methyl thiazolyl tetrazolium (MTT) assay and clone formation assay, and the cell apoptosis was detected via Hochst33258 staining and Annexin V/propidium iodide (PI) double labeling. Moreover, the effects of Pa-PDT on invasion and proliferation of PC-3 cells were observed via wound healing assay and transwell chamber assay. Finally, the expressions of apoptosis-related proteins, epithelial-mesenchymal transition (EMT)-related proteins and matrix metalloproteinases (MMPs) in each group were detected after treatment by Western blotting. RESULTS: MTT and clone formation assays showed that Pa-PDT could inhibit the proliferation of PC-3 cells in a dose dependent manner. The results of apoptosis assay revealed that Pa-PDT could significantly promote the apoptosis of PC-3 cells, obviously up-regulate the expressions of pro-apoptotic proteins, such as B-cell lymphoma-2-associated X protein (BAX), Caspase-3 and poly adenosine diphosphate-ribose polymerase (PARP), and inhibit the expression of Bcl-2. Besides, the wound healing assay and Transwell chamber assay showed that Pa-PDT could inhibit the invasion and metastasis capacities of PC-3 cells, whose relevant mechanisms were related to the fact that Pa-PDT inhibited the EMT process and down-regulated the expressions of MMPs in PC-3 cells. CONCLUSIONS: Pa-PDT can inhibit the proliferation and promote the apoptosis of PC-3 cells. Moreover, it can also inhibit the invasion and metastasis capacities of PC-3 cells via inhibiting the EMT process and down regulating the expressions of MMPs. PMID- 29271989 TI - MicroRNA-143 regulates the proliferation and apoptosis of cervical cancer cells by targeting HIF-1alpha. AB - OBJECTIVE: To investigate the effects of miR-143 on proliferation and apoptosis of cervical cancer HeLa cells and its target hypoxia-inducible factor-1alpha (HIF 1alpha). PATIENTS AND METHODS: The expression levels of miR-143 in 30 cases of normal cervical tissues, 30 cases of cervical intraepithelial neoplasia tissues, and 30 cases of cervical cancer tissues, were detected via Real-time quantitative polymerase chain reaction (qPCR). Cervical cancer HeLa cells were transfected with miR-143 mimics, and the transfection effect was detected via Real-time qPCR. In the experiment, HeLa cells were divided into three groups: non-transfection group, miR-143 control group and miR-143 transfection group. The cell proliferation in each group was detected via 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay, and the cell apoptosis in each group was detected by flow cytometry. Moreover, the messenger RNA (mRNA) and protein expression levels of HIF-1alpha in each group, were detected by qPCR and Western blotting, and the relationship between miR-143 and HIF-1alpha was verified by dual-luciferase reporter gene assay. RESULTS: The level of miR-143 in miR-143 transfection group was higher than those in non-transfection group and miR-143 control group; the differences were statistically significant (p<0.05). The proliferation rate was decreased, but the apoptosis rate was increased in miR-143 transfection group compared with those in the other two groups; the differences were statistically significant (p<0.05). The transient overexpression of miR-143 could decrease the mRNA and protein levels of HIF-1alpha in HeLa cells (p<0.01). Dual-luciferase reporter gene assay proved that HIF-1alpha was a direct target of miR-143. CONCLUSIONS: MiR-143 can regulate the proliferation and apoptosis of cervical cancer HeLa cells, and HIF-1alpha is a direct target of miR-143. PMID- 29271990 TI - MiR-638 inhibits cervical cancer metastasis through Wnt/beta-catenin signaling pathway and correlates with prognosis of cervical cancer patients. AB - OBJECTIVE: MiR-638 has been demonstrated to be correlated with several tumor progressions. However, the exact role of miRNA-638 in cervical cancer (CC) has not been investigated. The aim of present study was to explore the prognostic value of miR-638 in patients with CC and analyze molecular mechanisms of miR-638 in CC progression. PATIENTS AND METHODS: Real-time quantitative RT-PCR was performed to measure miR-638 expression level in 196 paired of CC and matched normal tissues, CC cell lines. The correlation of miR-638 with clinicopathological features and prognosis was analyzed. Furthermore, the effects of miR-638 on tumorigenicity of CC cells were evaluated by functional assays. Finally, Western blot was used to evaluate the activation of Wnt/beta-catenin signaling pathway. RESULTS: We found that miR-638 expression was downregulated in CC tissues and cell lines compared with the adjacent normal tissues and normal cell lines. In addition, low expressions of miR-638 were significantly associated with advanced FIGO stage (p =0.007), lymph node metastasis (p = 0.018) and vascular invasion (p = 0.002). Moreover, the results of Kaplan-Meier method showed that CC patients with lower miR-638 expression had significantly poorer overall survival (p = 0.0023) and progression-free survival (p = 0.0005). In a multivariate Cox model, we found that miR-638 expression was an independent prognostic factor for both overall survival and progression-free survival in patients with CC (both p = 0.001). In vitro assay showed that miR-638 overexpression suppressed cell migration and invasion of HeLa cells. The results of Western blot indicated that over-expression of miR-638 inhibited the activation of Wnt/beta-catenin signaling pathway. CONCLUSIONS: Our findings firstly showed that miR-638 might serve as a tumor suppressor. In the future, miR 638 might be regarded as a therapeutic target and a potential prognostic factor in human CC. PMID- 29271991 TI - Sensitization of TRAIL-resistant cervical cancer cells through combination of TRAIL and fucoxanthin treatments. AB - OBJECTIVE: Cervical cancer, the second most common cause of cancer death in women worldwide, is a malignant neoplasm arising from cells originating in the cervix uteri. Currently, surgery combined with chemo- and radiotherapy is the major therapeutic approach for women with early-stage cervical cancer. However, recurrent cervical cancers from acquired chemo-resistance remain a major cause of therapeutic failure. MATERIALS AND METHODS: In this study, we assessed the effects of the combination of TRAIL with fucoxanthin, which has been reported to suppress the cervical cancer cells growth on the cervical cancer treatments. HeLa cells, SiHa cells, and CaSki cells were used as in vitro model. Mice xenograft was used as in vivo model. TRAIL-resistant cells were generated from CaSki cell line. The activity of PI3K/Akt pathway was detected by Western blot. Cell viability was measured by MTT assay. RESULTS: We observed TRAIL-resistant cervical cancer cells were more sensitive to fucoxanthin treatments. By establishing a TRAIL-resistant cell line from CaSki, we found the TRAIL-resistant cells showed upregulated PI3K/Akt pathway. Moreover, CaSki TRAIL-resistant cells were more sensitive to the combination of TRAIL with either Akt inhibitor or fucoxanthin than treatment with TRAIL or fucoxanthin alone. Our in vitro and in vivo xenograft experiments demonstrate that the combination of TRAIL with fucoxanthin showed synergistically inhibitory effects on cervical cancer cells. CONCLUSIONS: The findings of this study suggest that the combined use of fucoxanthin and TRAIL might be a useful strategy against TRAIL-resistant cervical cancer. PMID- 29271992 TI - MiR-133b regulates the expression of CTGF in epithelial-mesenchymal transition of ovarian cancer. AB - OBJECTIVE: To explore the role of miR-133b in ovarian cancer and to preliminarily elucidate the mechanism of miR-133b in epithelial-mesenchymal transition (EMT) of ovarian cancer. PATIENTS AND METHODS: MiR-133b was detected in ovarian cancer specimens, and the relationship of miR-133b with each pathological index and clinical index of ovarian cancer was analyzed. The action targets of miR-133b in ovarian cancer were analyzed systematically and studied deeply via the target validation and cell function validation. Finally, the possible reasons of ovarian cancer metastasis were analyzed through the molecular regulation mechanism in EMT of ovarian cancer. RESULTS: The miR-133b level in ovarian cancer was significantly lower than in normal ovarian tissues and benign ovarian tumors (p<0.05). The level of miR-133b in ovarian cancer was related to differentiated degree and lymphatic metastasis. Dual-luciferase assay indicated that connective tissue growth factor (CTGF) was the target gene regulated by miR-133b. Reverse transcriptase-polymerase chain reaction (RT-PCR) as well as Western blot results proved that the expression level of E-cadherin representing the epithelial cell phenotype was increased, while the expression level of vimentin representing the mesenchymal cell phenotype was decreased. Transwell assay confirmed that the migration and invasion abilities of ovarian cancer cells declined after transfection with miR-133b plasmid. After co-transfection with miR-133b and CTGF overexpression plasmids, RT-PCR and Western blotting proved that the expression level of E-cadherin representing the epithelial cell phenotype was decreased, while the expression level of vimentin representing the mesenchymal cell phenotype was increased; transwell assay confirmed that the cell migration and invasion abilities were increased after co-transfection. CONCLUSIONS: The results of this study showed that miR-133b may serve as a new molecular marker of EMT of ovarian cancer, and act as a molecular marker of differentiated degree and lymphatic metastasis of ovarian cancer. PMID- 29271993 TI - AIB1 regulates the ovarian cancer cell cycle through TUG1. AB - OBJECTIVE: To explore the mechanism of amplified in breast cancer 1 (AIB1) to promote ovarian cancer progress. MATERIALS AND METHODS: Cor correlation analysis was performed to obtain the top 100 lncRNAs that were positively correlated with AIB1. The relationship of taurine upregulated gene 1 (TUG1) and clinicopathological characteristics. Moreover, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were performed to predict the biological process where TUG1 may be involved in. At last, Cell Counting Kit-8 (CCK-8), colon formation and flow cytometry were conducted to explore the biological process that TUG1 may influence. Meanwhile, Western blot was performed to explore the mechanism of TUG1. RESULTS: In this study, it was found that P73 antisense RNA 1T (TP73-AS1), LINC00654 and TUG1 had the tumor-promoting effect in the top 100 lncRNAs that were positively correlated with AIB1. The expression level of TUG1 was significantly decreased after intervention of AIB1. Then, the clinical data were analyzed and the results showed that TUG1 was related to the tumor residue, tumor staging, tumor grade and lymph node metastasis. Moreover, the bioinformatics analysis revealed that TUG1 was mainly involved in the regulation of cell cycle. After intervention in TUG1, it was found that the cell proliferation capacity was significantly decreased, and the cell cycle was arrested in G1 phase. Finally, Western blot revealed that the expressions of G1 phase-related proteins were significantly changed. This study indicated that AIB1 regulates the cycle of ovarian cancer cells through TUG1. CONCLUSIONS: This study proved that AIB1 can regulate the cell cycle through regulating TUG1. PMID- 29271994 TI - Overexpression of lncRNA MNX1-AS1 is associated with poor clinical outcome in epithelial ovarian cancer. AB - OBJECTIVE: Long non-coding RNAs MNX1-AS1(MNX1-AS1) has been proved to be associated with ovarian cancer proliferation and invasion. However, the clinical significance of MNX1-AS1 in epithelial ovarian cancer (EOC) patients remains unknown. The aim of this study was to investigate the prognostic value of the MNX1-AS1 expression in EOC. PATIENTS AND METHODS: We first measured MNX1-AS1 expression level in 177 paired of EOC and matched normal tissues by Real-time quantitative RT-PCR. The relevance of MNX1-AS1 expression to the clinicopathological factors was assessed. Overall survival (OS) and relapse-free survival (RFS) were analyzed by log-rank test, and survival curves were plotted according to Kaplan-Meier. Univariate and multivariate analyses were performed to analyze the prognostic significance of MNX1-AS1 expression. RESULTS: We found that the levels of MNX1-AS1 were higher in EOC tissue than in matched normal tissues (p<0.01). In addition, MNX1-AS1 expression level was significantly positively correlated with FIGO stage (p=0.005), grade (p=0.040) and distant metastasis (p=0.000). Kaplan-Meier survival curves demonstrated that patients with high-MNX1-AS1 expression showed poorer progression-free survival and overall survival than those with low-MNX1-AS1 expression (p<0.0001 and 0.0003, respectively). Then, Cox regression analysis revealed that FIGO stage, distant metastasis, and MNX1-AS1 expression were independent prognostic factors of both overall survival and progression-free survival for patients with EOC. CONCLUSIONS: Our findings indicated, for the first time, that MNX1-AS1 expression may be a useful marker for predicting the outcome in patients with EOC. PMID- 29271995 TI - Mir-138-5p acts as a tumor suppressor by targeting pyruvate dehydrogenase kinase 1 in human retinoblastoma. AB - OBJECTIVE: MicroRNAs have caught more attention for their role in tumor progression. Retinoblastoma (RB) is one of these ordinary malignant tumors. This study aims to identify whether mir-138-5p can regulate the development of RB, and find out its potential mechanism. MATERIALS AND METHODS: Mir-138-5p expression in RB cells was monitored by RT-qPCR. Besides, the role of mir-138-5p in RB development was explored through function experiments in vitro. The potential mechanism was further explored by RT-qPCR, luciferase assay, and Western blot assay. RESULTS: In our investigation, mir-138-5p was lower-expressed in RB cells than that in retinal pigment epithelial cells. Moreover, overexpression of mir 138-5p repressed cell viability, migration and invasion, and induced apoptosis of RB cells, while downregulated mir-138-5p increased cell viability, migration and invasion, and reduced apoptosis of RB cells. Furthermore, pyruvate dehydrogenase kinase 1 (PDK1) could be downregulated via overexpression of mir-138-5p, while PDK1 was upregulated via knockdown of mir-138-5p. CONCLUSIONS: Our results suggested that mir-138-5p could repress the development of RB via suppressing PDK1, which may offer a new vision for interpreting the mechanism of RB tumorigenesis. PMID- 29271996 TI - MiR-616 promotes proliferation and inhibits apoptosis in glioma cells by suppressing expression of SOX7 via the Wnt signaling pathway. AB - OBJECTIVE: Accumulating evidence has indicated that miR-616 exerts tumor promoter roles in several types of cancer. However, the expression pattern and roles of miR-616 in glioma progression remain unknown. This study aimed to reveal the role of miR-616 in glioma cell proliferation and its potential mechanisms. PATIENTS AND METHODS: Real-time polymerase chain reaction was used to assay the expression of miR-616 in glioma tissue samples and glioma cell lines. MTT proliferation assay and flow cytometry analysis were performed to test the apoptosis and proliferation of glioma cell after down-regulation of miR-616. The target of miR 616 was predicted by TargetScan and confirmed by luciferase reporter assay. Changes in Wnt signaling markers expression were assessed using Western blotting. RESULTS: We found that the expression of miR-616 was increased in glioma tissues and cell lines. MTT and low cytometry analysis indicated that down-regulation of miR-616 significantly inhibited proliferation and promoted apoptosis in glioma cells. Moreover, SOX7 was confirmed to be a direct target of miR-616 in glioma cells using luciferase assay and Western blotting. Finally, it was found that down-regulation of miR-616 or upregulation of SOX7 could suppress the activity of Wnt/beta-catenin signaling in glioma cells. CONCLUSIONS: Our findings indicated that miR-616 acted as a tumor promoter in glioma, and its oncogenic roles were involved in the regulation of SOX7 and Wnt/beta-catenin signaling. Moreover, knockdown of miR-616 may provide a potential therapeutic strategy for glioma. PMID- 29271997 TI - MiR-181a promotes growth of thyroid cancer cells by targeting tumor suppressor RB1. AB - OBJECTIVE: MicroRNAs (miRs) are critical regulators in cancer development and progression. The current study aimed to investigate the expression and potential function of miR-181a in thyroid cancer. PATIENTS AND METHODS: A total of 15 paired thyroid cancer tissues and adjacent normal tissues were subjected to Real time Polymerase Chain Reaction (PCR) to evaluate miR-181a expression. 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, enzyme linked immunosorbent assay (ELISA) or flow cytometry was employed to assess the growth activity, apoptosis and cell cycle, respectively, upon modulation of the miR-181a expression in TPC-1 cells. Western blot was used to assess protein expression. The interaction between miR-181a and RB1 was tested by luciferase activity assay. RESULTS: The expression of miR-181a was significantly upregulated in thyroid cancer tissues compared with the adjacent tissues. Inhibition of miR 181a attenuated cell growth, which could be abrogated by miR-181a co transfection. MiR-181a overexpression reduced apoptosis and promoted cell cycle progression; inhibition of miR-181a exerted opposite effects on both cell cycle and apoptosis. MiR-181a directly suppressed RB1 expression. RB1 expression in tumor tissues was downregulated and negatively correlated with miR-181a expression. CONCLUSIONS: miR-181a plays an oncogenic role in thyroid cancer; by targeting RB1, it promotes cell cycle progression and inhibits apoptosis. PMID- 29271998 TI - The identification of multifocal breast cancer-associated long non-coding RNAs. AB - OBJECTIVE: To identify long non-coding RNAs (lncRNAs), which may be associated with multifocal and multicentric breast cancer (MMBC) by analyzing the differential expression of non-coding RNA in MMBC and unifocal breast cancers (UBC). PATIENTS AND METHODS: 156 cases of invasive MMBC patients (136 patients with 2 focuses and 20 patients with 3 focuses) and 130 cases of UBC were collected from January 2005 to December 2015 in Yantai Yuhuangding Hospital. The differentially expressed lncRNAs in MMBC and UBC were screened by gene chip. RT PCR was used to verify the differentially expressed lncRNAs. RESULTS: Significantly different expression was found in 1080 lncRNAs between MMBC and UBC (FC > 4, p < 0.05), among which, 458 were upregulated and 622 were down regulated. In homologous lncRNAs, the expression levels of four lncRNAs including C19orf33, C3orf52, C15orf48 and C4orf19 in MMBC tissue were significantly different than those in UBC tissues. RT-PCR verified that the expression of C19orf33, C3orf52 and C15orf48 in MMBC tissue was significantly up-regulated and the expression of C4orf19 was significantly down-regulated, which was consistent with that of gene chip. CONCLUSIONS: C19orf33, C3orf52, C15orf48 and C4orf19 may have important functions in MMBC, and may be used as markers for MMBC. PMID- 29271999 TI - Expression of lncRNA TCONS_00027978 in hepatocellular carcinoma and its influence on prognosis and survival. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) have been reported to have crucial roles in the regulation of various tumors. Recently, lncRNA TCONS_00027978 (TCONS_00027978) was found to be downregulated in hepatocellular carcinoma (HCC). This study aims at analyzing the value of TCONS_00027978 in valuing the prognosis of HCC patients. PATIENTS AND METHODS: The expression of TCONS_00027978 was detected using qRT-PCR in 241 hepatocellular specimens and matched adjacent normal tissues. The association between TCONS_00027978 expression levels and clinicopathological factors was examined. Survival and Cox proportional-hazards regression analyses were performed to explore the association between TCONS_00027978 expression levels and prognosis in HCC patients. RESULTS: We found that the TCONS_00027978 expression level was significantly decreased in HCC tissues compared with matched normal tissues (p < 0.01). TCONS_00027978 was positively associated with TNM stage (p = 0.002), lymph node metastasis (p = 0.001) and histologic grade (p = 0.002) in HCC patients. In addition, Kaplan Meier analysis indicated that low levels of TCONS_00027978 expression were associated with poorer overall survival (p = 0.002) and disease-free survival (p =0.001). Subsequently, multivariate analyses indicated that low TCONS_00027978 expression was an independent poor prognostic factor for HCC patients. CONCLUSIONS: Our study is the first to demonstrate the TCONS_00027978 expression as an independent prognostic factor in HCC. PMID- 29272000 TI - High expression of LncRNA CASC15 is a risk factor for gastric cancer prognosis and promote the proliferation of gastric cancer. AB - OBJECTIVE: To investigate the expression of long non-coding RNA CASC15 in gastric cancer tissue and its effect on the proliferation of gastric cancer cell line MKN28. MATERIALS AND METHODS: We found that expression of lncRNA CASC15 in gastric cancer tissue was higher than normal gastric epithelium through the TCGA and Gene Expression Omnibus (GEO) database. Then, we detect the RNA level of CASC15 from clinical samples of 42 normal gastric epithelial tissues and 60 gastric cancer tissues. In order to explore the function of CASC15 in gastric cancer, we perform gain-function and loss-function assay in gastric cancer cell lines. RESULTS: We found that expression of lncRNA CASC15 in gastric cancer tissue was higher than normal gastric epithelium through the TCGA database and the related microarray data set was searched from Gene Expression Omnibus (GEO) database. Then, we extracted total RNA from clinical samples of 42 normal gastric epithelial tissues and 60 gastric cancer tissues. The results of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were consistent with those of TCGA analysis. Clinical data analysis showed that the expression of LncRNA CASC15 was correlated with the total survival, tumor size and TMN staging in clinical patients. Clinical data analysis showed that the expression level of CASC15 was correlated with tumor size and TNM stage in clinical patients. Compared with the negative control group, the proliferation and cell cloning ability of MKN28 cells overexpressing LncRNA CASC15 significantly increased (p<0.001), indicating that overexpression of LncRNA CASC15 promoted the proliferation of MKN28 cells. CONCLUSIONS: The expression of LncRNA CASC15 was significantly higher in gastric cancer tissues and its expression was negatively correlated with the overall survival of clinical patients. It was positively correlated with the tumor size and TMN stage. LncRNA CASC15 could promote the proliferation of gastric cancer cells and was expected to become the molecular marker for prediction and prognosis of gastric cancer, as well as a potential therapeutic target. PMID- 29272001 TI - Investigation on the regulatory effect of PGE2 on ESCC cells through the trans activation of EGFR by EP2 and the relevant mechanism. AB - OBJECTIVE: To determine whether the combination of prostaglandin E2 (PGE2) and EP2, the subtype receptor of PGE2, could trans-activate the epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: In this experiment, we selected epithelial cells from normal esophageal mucosa as the negative control group, and the ESCC EC109 and TE-1 cell strain as the observation group. Real-time PCR and Western-blotting were used to detect the expression of EP2, EGFR and phosphorylated EGFR (p-EGFR). The pre-treatment of ESCC cell strains was carried out using Butaprost (special agonist of PGE2 and EP2) and RNAi of EP2, and we observed the expression of EP2, EGFR, and p-EGFR. WST-8 (CCK-8) was applied for the detection of the cell proliferation rate. The transwell invasion experiment was conducted for the detection of the invasion capability of cells. The expression of MMP-9 (matrix metalloproteinase-9), VEGF (vascular endothelial growth factor), pro-inflammatory factors (IL-6 and TNF-alpha) in the cell supernatant were detected using ELISA. RESULTS: The high mRNA and protein expression of EP2, EGFR, and p-EGFR were found in the EC109 and TE-1 cell strains in the observation group, which were higher than those in the control group (p < 0.05). After the intervention of PGE2, EP2 expression was decreased and the p EGFR expression was increased (p < 0.05). There was no variation found in the expression of EGFR (p > 0.05). After cells were intervened using Butaprost, the expressions of EP2 and p-EGFR were increased (p < 0.05), and there were no changes identified in the expression of EGFR (p > 0.05). After the intervention of RNAi, the expression of EP2 and p-EGFR was decreased (p < .05), and no changes were identified in the expression of EGFR (p > 0.05). After the intervention of PGE2 and Butaprost, great increases were seen in the cell proliferation rate, invasion capability, and the expression of MMP-9, VEGF, IL-6, and TNF-alpha in EC109 and TE-1 cell strains (p < 0.05), however, the intervention of RNAi could reduce above indexes (p < 0.05). CONCLUSIONS: Through cell experiments, we verified that the combination of prostaglandin E2 (PGE2) and EP2, the subtype receptor of PGE2, could trans-activate the epidermal growth factor receptor (EGFR) to regulate the proliferation and invasion capability of esophageal squamous cell carcinoma (ESCC) cells, and secrete and express multiple cytokines, thus discovering the pathological mechanism of inflammation to carcinoma transition in the occurrence of ESCC, and providing the experimental evidence for the search of new target in the treatment of ESCC. ESCC cells can highly express the receptor subtype EP2 of PGE2 that can transactivate the EGFR, through which PGE2 is involved in the transition mechanism from inflammation to cancer. PMID- 29272002 TI - Inhibitory effects of int-2 gene on the invasion and metastasis of oral cancer cells. AB - OBJECTIVE: The purpose of this study was to investigate the effects of int-2 transfection on the invasiveness and metastasis of oral cancer BcaCD885 cells, and to determine the relevant mechanisms of action. MATERIALS AND METHODS: High purity int-2 eukaryotic expression plasmids were prepared and transfected using a modified cationic liposome-mediated transfection protocol. Nucleoside diphosphate kinase A (NDPKA) expression before and after transfection was examined, as well as changes in cell invasiveness and metastasis capabilities. RESULTS: Int-2 was confirmed to be stably expressed post-transfection into oral cancer cells. Expression of int-2 in BcaCD885 cells was significantly different before and after transfection. The proportion of invasive cells were 70.3%+/-8.2% and 46.5%+/-5.7%, and the proportion of chemotaxis cells were 78.5%+/-7.9% and 49.6%+/-7.5%, in the in the control and experimental groups respectively. The adhesion capability of cells in the experimental group was also significantly reduced. CONCLUSIONS: Upregulation of int-2 expression can significantly inhibit the invasion and metastasis of BcaCD885 cells. PMID- 29272003 TI - Overexpression of HOTTIP promotes proliferation and drug resistance of lung adenocarcinoma by regulating AKT signaling pathway. AB - OBJECTIVE: Lung adenocarcinoma is an important pathological type of lung cancer. Drug resistance is the main reason for failure of lung adenocarcinoma therapy. The purpose of this study is to explore the role of HOTTIP in the progression of lung adenocarcinoma and in drug resistance. PATIENTS AND METHODS: Differentially expressed lncRNAs in normal lung tissues and lung adenocarcinoma tissues were analyzed in The Cancer Genome Atlas (TCGA) database, followed by analysis of differential lncRNAs in treated sensitive and insensitive groups. HOTTIP was found to be highly expressed in lung adenocarcinoma tissues and in drug-resistant tissues. Next, the expression of HOTTIP in clinical samples and its relation to clinical data were analyzed. Then, we examined the effect of HOTTIP in lung adenocarcinoma by detecting changes in cell proliferation and drug resistance after overexpression and interference with HOTTIP. RESULTS: By analyzing the normal and lung adenocarcinoma tissues from TCGA database and the treatment of sensitive and insensitive samples, we found that HOTTIP was overexpressed in lung adenocarcinoma and significantly increased in the treatment-insensitive group. Similar results were obtained in clinical samples. In order to explore the role of HOTTIP in lung adenocarcinoma, the proliferation ability of A549 and the drug resistance of A549/PA were significantly reduced after interfering with HOTTIP. Overexpression of HOTTIP, proliferation ability of A549 and drug resistance of A549/PA was significantly enhanced. CONCLUSIONS: HOTTIP can promote the progression of lung adenocarcinoma, and the formation of lung adenocarcinoma resistance regulated by the protein kinase B (AKT) signaling pathway. PMID- 29272004 TI - Decreased expression of long non-coding RNA LINC00261 is a prognostic marker for patients with non-small cell lung cancer: a preliminary study. AB - OBJECTIVE: The previous study found that long non-coding RNA LINC00261 (LINC00261) was significantly down-regulated in non-small cell lung cancer (NSCLC). However, the function of LINC00261 in the progression of NSCLC has not been reported. The present work aimed to explore the prognostic value of LINC00261 in patients with NSCLC. PATIENTS AND METHODS: The expression of LINC00261 was determined in NSCLC tissues and matched normal lung tissues by quantitative Real-time PCR (qRT-PCR). Furthermore, we evaluated the relationship of LINC00261 and clinicopathological features with survival of patients with NSCLC. Finally, univariate and multivariate Cox regression analyses were used to explore whether LINC00261 was an independent predictor of survival. RESULTS: We found that the LINC00261 expression level in NSCLC tissues was suppressed compared with that in adjacent normal lung tissues (p < 0.01). Low expression of LINC00261 was found to significantly correlate with TNM stage (p = 0.005), lymph node status (p = 0.020), and distant metastasis (p = 0.004). Then, Kaplan-Meier analysis demonstrated that low LINC00261 expression level was associated with poorer overall survival (p = 0.0013). Furthermore, multivariate analysis showed that low expression of LINC00261 was an independent adverse prognostic factor of NSCLC (p = 0.004). CONCLUSIONS: We firstly provided evidence that LINC00261 expression was associated with poor prognosis of NSCLC patients and may serve as an independent prognostic indicator. PMID- 29272005 TI - Clinical impact of serum miR-661 in diagnosis and prognosis of non-small cell lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate whether serum miR-661 could serve as a biomarker for the diagnosis and prognosis of non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The expression of serum miR-661 was detected in 150 cases of NSCLC and 114 cases of normal healthy controls by Real time PCR. Receiver-operating characteristic (ROC) curve analysis was applied to analyze diagnostic value of serum miR-661. The relationship between serum miR-661 expression and clinicopathological characteristics was investigated. Overall survival was analyzed using Kaplan-Meier method. Moreover, Cox proportional hazards regression analyses were performed to determine the prognostic value of serum miR-661 in NSCLC patients. RESULTS: We found that the expression of serum miR-661 was significantly upregulated in NSCLC compared with healthy controls (p < 0.01). The expression level of serum miR-661 was positively correlated with histological grade (p = 0.011), lymph node metastasis (p = 0.003), distant metastasis (p = 0.021) and clinical stage (p = 0.005). Then, ROC curve analysis showed that serum miR-661 has considerable diagnostic accuracy, with an area under the ROC curve (AUC) of 0.726 (p = 0.001). Moreover, NSCLC patients with serum miR-661 higher expression have shown significantly poorer overall survival than those with lower serum miR-661 expression (p = 0.004). Furthermore, multivariate analyses showed that serum miR-661 expression levels were an independent prognostic factor for survival in NSCLC patients. CONCLUSIONS: Overall, these findings indicate that serum miR-661 may be a potential biomarker for the diagnosis and prognosis of NSCLC. PMID- 29272006 TI - Expression of C1q/TNF-related protein-3 (CTRP3) in serum of patients with gestational diabetes mellitus and its relationship with insulin resistance. AB - OBJECTIVE: In this study, the changes of insulin resistance (IR) and pancreatic beta-cell function in GDM patients were observed, changes of CTRP3 level in fasting serum and relationships with plasma glucose (PG) and pancreatic beta-cell function were explored at the same time, and the correlation between serum CTRP3 and body mass index (BMI) was preliminarily discussed, providing a new way to identify the pathogenesis of GDM. PATIENTS AND METHODS: Data of women from 24 to 28 weeks of pregnancy were collected. 100 women were selected to form gestational diabetes mellitus (GDM) group and another 100 women were chosen to constitute normal glucose tolerance (NGT) group according to the results of oral glucose tolerance test (OGTT). They were divided into GDM overweight/obesity (GDM + OW) group, GDM non-overweight/obesity (GDM + NW) group, simple overweight (OW) group and normal body weight (NW) group, according to whether the progestational body mass index (BMI) was higher than 24 kg/m2 before pregnancy. General information of all subjects, for example, age, last menstrual period, parity, diet, weight and height, were collected, and blood samples were taken from all subjects for use in detections of total cholesterol (TC), triglyceride (TG), very low-density lipoprotein (VLDL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and serum C1q/tumor necrosis factor-related protein-3 (CTRP3). RESULTS: The levels of FPG, 1 h PG, 2 h PG, fasting CP (FCP), fasting insulin (FINS), homeostasis model assessment of IR (HOMA-IR), TG and VLDL C in the GDM group, were significantly higher than those in the NGT group. TC and LDL-C in the GDM group were greater than those in the NGT group. Compared with that in the NGT group, homeostasis model assessment of beta (HOMA-beta) index was lower in the GDM group. From the NGT group to the GDM group, FPG, 1 h PG, 2 h PG, FINS and FCP had rising tendencies, and the differences were of statistical significance. Pearson correlation analysis indicated that HOMA-IR was positively correlated with pre-pregnancy BMI, FPG, 2 h PG, FINS, 1 h INS, 2 h INS, FCP, 1 h CP and 2 h CP in the GDM group, HOMA-beta was negatively related to FPG. In the NGT group, there was a positive correlation between HOMA-IR and pre-pregnancy BMI. The level of CTRP3 in fasting serum of the GDM group was distinctly lower than that of the NGT group. Pearson correlation analysis revealed that in the GDM group, fasting serum CTRP3 had positive correlations with HOMA-beta and HDL-C, but negatively associated with pre-pregnancy BMI, FPG, 1 h PG, 2 h PG, FCP, HOMA IR, TG and VLDL-C. In the NGT group, the fasting serum CTRP3 was negatively correlated with pre-pregnancy BMI. Multiple linear stepwise regression analysis showed FPG was an independent influencing factor for fasting serum CTRP3. CONCLUSIONS: With the increase of FPG, the progression of GDM IR patients is increased, and pancreatic beta-cell function progressively declines. The decrease of CTRP3 level in fasting serum in GDM patients plays a metabolic role in the pathogenesis of GDM. PMID- 29272007 TI - Effects of extended in-patient treatment training on outcome of post-stroke dysphagia. AB - OBJECTIVE: To investigate the effects of extended in-patient training on swallowing function of patients with post-stroke dysphagia. PATIENTS AND METHODS: 40 patients with post-stroke dysphagia treated between January 2013-December 2015 were randomly divided into the treatment group and the control group. During the hospitalization, patients in both groups underwent routine examinations, graded swallowing training, radio frequency electrotherapy, acupuncture, dietary guidance, body position and compensation training, etc. In addition, patients in the treatment group received training with ice stimulation. The swallowing functions and prevalence rate of adverse events of the two groups during the first three months after discharge from the hospital were compared. Twenty healthy people coming for a regular checkup during the same period were also included in this study. ELISA was used to compare the peripheral blood S100beta levels of the patients with post-stroke dysphagia and the healthy population. RESULTS: After 3-month follow-up, statistical analysis showed that 70.00% patients in the treatment group regained normal (excellent/very good) swallowing function, which was much higher than the normal rate of people in the control group (25%). The difference was statistically significant (chi2 = 8.12, p<0.05). Patients in the treatment had a lower prevalence rate of adverse events (e.g. aspiration, choking, aspiration pneumonia) (5.00%) lower than the control group (25.00%), and the difference was statistically significant (chi2 = 4.02, p<0.05). ELISA assay indicated that the peripheral blood S100beta levels in patients with dysphagia were significantly higher than the healthy population (p<0.05). But compared with the control group, patients in the treatment group patients had lower S100beta level after the treatment, and the difference was statistically significant (p<0.05). CONCLUSIONS: The extended ward training could significantly improve the swallowing function of patients with post-stroke dysphagia, restore their swallowing function, and reduce adverse events of swallowing. The operations were simple, safe and practical. The training is worthy of promotion. PMID- 29272008 TI - Apolipoprotein E 4 triggers multiple pathway-mediated Ca2+ overload, causes CaMK II phosphorylation abnormity and aggravates oxidative stress caused cerebral cortical neuron damage. AB - OBJECTIVE: Apolipoprotein E (APOE) gene polymorphism is correlated closely with resistance to brain damage. This study aims to investigate the effects of APOE4 on oxidative stress damaged cerebral cortical neuron. MATERIALS AND METHODS: Primary cerebral cortical neurons were isolated from APOE gene knock-out mice (APOE-/- mice). Oxidative stress damaged APOE-/- mouse cerebral cortical neuron model was established. Three experimental designs (experiment 1, 2, 3) were conducted by employing several methods. Lactate dehydrogenase (LDH) and superoxide dismutase (SOD) analysis were employed for neurotoxicity assessment. Flow cytometry and transferase-mediated deoxyuridine-triphosphate-biotin nick end labeling (TUNEL) were used to examine neuron apoptosis. Immunohistochemistry and Nissl staining were used to identify neuron morphology. Western blot was used to detect phosphorylated CaMK II (p-CaMK II) and cleaved caspase 3 expression. Ca2+ levels in neurons were also examined by detecting fluorescence intensity. RESULTS: APOE4 treatment (Vehicle + APOE4) significantly aggravates oxidative stress damaged cerebral cortical neuron by increasing LDH levels and decreasing SOD activities, induces neuron apoptosis compared to Vehicle group (p < 0.05). APOE4 treatment significantly enhanced Ca2+ levels compared to Sham group (p < 0.05), MK801 treatment (Vehicle + APOE4 + MK801) significantly decreased Ca2+ levels compared to the Vehicle+APOE4 group at 12 h and 24 h (p < 0.05). APOE4 triggers CaMK II phosphorylation, caspase 3 activation and neurons apoptosis. Both of MK801 and KN93 inhibit CaMK II phosphorylation, decreases caspase 3 activation, and suppresses neurons apoptosis CONCLUSIONS: APOE triggers Ca2+ overload through NMDAR and CaMK II signaling pathway, both of which cause Ca2+ concentration increasing, CaMK II phosphorylation abnormity, and finally aggravate oxidative stress damaged neurons apoptosis. PMID- 29272009 TI - The bone marrow mononuclear cells reduce the oxidative stress of cerebral infarction through PI3K/AKT/NRF2 signaling pathway. AB - OBJECTIVE: To evaluate the mechanism of bone marrow mononuclear cells (BMMNCs) in reducing the oxidative stress after cerebral infarction through PI3K/AKT/NRF2 signaling pathway. MATERIALS AND METHODS: 96 healthy SD rats, which were 6-8-week old, weighting about 250-280 g, were selected for the study. The middle cerebral artery occlusion model (MCAO) was established in SD rats using the suture method. The rats were randomly divided into sham operation group, model group, BMMNCs group and PI3K inhibitor group. 24 rats in each group were selected. 200 MUl phosphate-buffered saline (PBS) solution was injected into the caudal vein of the rats in the model group, 200 MUl PBS solution containing 5*106 BMMNCs that obtained by gradient centrifugation was injected into the rats in the BMMNCs group, meanwhile, in the PI3K inhibitor group, LY294002 (10 mmol/L/kg) was injected into the lateral ventricle of the brain. After the 3d, 7d and 14d, the modified neurological severity scores (mNSS) were used to evaluate the neurological function. The volume of cerebral infarction was assessed by TTC staining, the VEGF, BDNF, TNF-alpha, IL-1beta, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were detected by ELISA. RESULTS: The mNSS and the volume of cerebral infarction of the model group were significantly higher than those of the sham operation group (p<0.05), while the mNSS and the volume of cerebral infarction of the BMMNCs group were lower than those of the model group, higher than those of the sham operation group (p<0.05). The VEGF, BDNF, TNF-alpha, IL-1beta, MDA, SOD and GSH-Px levels of the model group were significantly higher than those of the sham operation group (p<0.05). CONCLUSIONS: BMMNCs can reduce the oxidative stress, apoptosis, and inflammatory reaction through PI3K/AKT/NRF2 signaling pathway, thus promoting the secretion of nerve and vascular cytokines, improving the neurological function and reducing the infarct scope. PMID- 29272010 TI - Ischemic preconditioning protects brain from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis through PERK pathway. AB - OBJECTIVE: The purpose of this study was to explore the effects of cerebral ischemic preconditioning which can decrease brain ischemia/reperfusion (I/R) injury by inhibiting endoplasmic reticulum (ER) stress-induced apoptosis. MATERIALS AND METHODS: The focal cerebral ischemia rat was selected as the experimental model. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in ischemic penumbra were assessed after cerebral reperfusion. We assessed terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells and measured the expressions of phosphorylation PERK (p-PERK), glucose-regulated protein 78 (GRP78), activating transcription factor-4 (ATF4) and caspase-12 in ischemic penumbra after cerebral reperfusion. RESULTS: We showed that the infarct sizes can be reduced due to the preconditioning under the influence of brain ischemia after reperfusion. The effect of preconditioning on the expression of ER stress proteins suggested the expressions of the 4 proteins p-PERK, ATF4, caspase-12 and GRP78 in the penumbra cortex by immunohistochemistry and Western blot increased after cerebral ischemia. Significant reduction of the number of TUNEL-positive cells was in the penumbra cortex of the preconditioning group. CONCLUSIONS: We found that cerebral ischemic preconditioning can protect the brain from I/R injury by inhibiting ER stress-induced apoptosis; the pathway of PERK is involved. PMID- 29272011 TI - The non-motor symptoms of Parkinson's disease of different motor types in early stage. AB - OBJECTIVE: We aimed to compare the different non-motor symptoms of different motor phenotype Parkinson's disease (PD) at an early stage. PATIENTS AND METHODS: From January 2013 to November 2016, 120 cases of PD patients who were hospitalized in Neurology Department of the First Hospital of Huai'an in Jiangsu Province and 120 cases of healthy controls with matched age and gender, were included into the research. PD patients were administered with Non-Motor symptom questionnaire (NMSQuest), the Unified Parkinson's Disease Rating Scale III (UPDRS III), the Mini-Mental State Examination score (MMSE), the Hoehn-Yahr classification, the MoCA, and GDS-15. The relationship between NMS burden and PD subtypes, age, gender and disease severity were examined using linear regression models. The prevalence of each NMS among different PD motor subtypes was analyzed using x2 test. RESULTS: Compared with the healthy controls, PD patients had a higher number of NMS. The prevalence of NMS in postural instability gait difficulty (PIGD) group is higher than that in tremor dominant (TD) group. There is no significant correlation between age, gender, MMSE scores, MoCA scores and the number of NMS. PD patients with higher UPDRS-III scores and a longer course of disease had a higher prevalence of NMS. CONCLUSIONS: NMS is also common in PD patients at an early stage. The PIGD group who have more axial injuries and more severe motor symptoms, have a higher risk of NMS burden than PD patients in TD group. PMID- 29272012 TI - Prevalence of severe irritable bowel syndrome among Italian adults. A meta analysis. AB - OBJECTIVE: To provide a summary estimate of the prevalence of irritable bowel syndrome (IBS) and IBS with severe symptomatology, stratified by gender and subtype, among Italian adults. MATERIALS AND METHODS: We searched MedLine and Scopus databases to identify surveys on IBS prevalence among Italian samples, and/or severe IBS prevalence among Caucasian populations, up to June 2017. Random effect proportion meta-analyses were used to obtain summary estimates of IBS prevalence. Raw numbers of adults with IBS or severe IBS were computed multiplying pooled prevalence estimates by the current Italian adult population. For both IBS and severe IBS, several estimates were provided according to different scenarios, using the pooled estimates from meta-analyses, their highest and lowest 95% confidence intervals (CI), and the lowest prevalence among all individual studies. RESULTS: The pooled prevalence of IBS among Italian adults, resulting from a meta-analysis of 5 studies including 40,654 subjects, was 7.7% (95% CI: 6.0%-9.7%). The lowest published estimate was 5.4%. The overall number of Italian adults with IBS may thus range between a minimum of 2,736,700 (1,797,800 females; 65.7%) and 4,915,800. From a meta-analysis of 17 studies including 16,873 subjects, the pooled proportion of severe IBS was 23.5% (95% CI: 18.7%-28.7%), with a lowest published estimate of 8.4%. The overall number of Italian adults with severe IBS may thus range between 229,900 (86,600 with constipation-predominant subtype; 70,600 diarrhea-predominant; 72,600 mixed/alternating) and 1,410,800. In a standard, still conservative scenario, based upon the lowest 95% CIs from meta-analyses, the Italians with severe IBS would be 511,800. CONCLUSIONS: Using an extremely conservative, lowest plausible estimate, no less than 230,000 Italian adults are suffering from severe IBS, requiring appropriate treatment and recognition by healthcare providers. A standardized instrument to measure IBS severity is urgently required to support diagnostic and therapeutic processes, and improve the precision of epidemiological estimates. PMID- 29272013 TI - Dual PPARalpha/gamma ligand TZD18 improves myocardial metabolic remodeling after myocardial infarction in rats. AB - OBJECTIVE: To investigate the changes in myocardial energy metabolism and the effect of peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist TZD18 on myocardial energy metabolism in rats with heart failure after myocardial infarction. MATERIALS AND METHODS: The myocardial infarction model was established by ligating the left anterior descending coronary artery. The rats were randomly divided into the myocardial infarction group (MI group), the TZD18 intervention group (TZD18 group), and the shame surgery group (sham group). 8 weeks later, the blood flow parameters were measured by carotid arterial cannulas, and ventricular remodeling indexes were calculated. Hearts were extracted from rats after the execution. The expressions of PPARalpha/gamma mRNA and alpha/beta-MHC mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). The mitochondrial oxidative respiration activity was measured by a bio-tissue oxygen consumption meter, the content of adenosine in mitochondria was measured by high-performance liquid chromatography, and tritium-labeled adenosine diphosphate incorporation assay was used to detect the transport activity of adenosine nucleotide translocases (ANT). RESULTS: The expression of PPARalpha/gamma mRNA and the ratio of alpha/beta-MHC mRNA in the MI group were significantly decreased, the content of high energy phosphates, respiration activity, ANT transport activity in mitochondria were significantly decreased, the hemodynamic indexes were disturbed and left ventricular weight/body weight ratio (LVW/BW) significantly became higher. TZD18 intervention could increase the expression level of PPARalpha/gamma mRNA and up regulate the ratio of alpha/beta-MHC mRNA, thus improving mitochondrial respiratory activity and ANT transport activity in rats with heart failure after myocardial infarction, increasing the content of high energy phosphates in mitochondria and improving the remodeling indexes in the ventricle. CONCLUSIONS: TZD18 increases both the expression of enzymes related to myocardial energy metabolism and the content of high-energy phosphates in mitochondria. Also, it improves the respiratory activity and ANT transport activity by activating PPARalpha/gamma genes, thus improving the generation and delivery of myocardial energy and protecting the myocardial cells. PMID- 29272014 TI - Relationship between the change in pacing threshold and the myocardial injury. AB - OBJECTIVE: To investigate the effects of general conditions and past medical history of patients on the short-term pacing threshold after the implantation of active electrodes of a cardiac pacemaker, and to understand whether the application of active electrodes will cause muscle injury and the severity of the injury. PATIENTS AND METHODS: A total of 156 patients who were treated with a cardiac pacemaker and implanted with single or double active electrodes in Cardiovascular Department of Central Hospital of Jiangjin District were enrolled, including 96 patients treated with a single active electrode and 60 patients treated with double active electrodes. Their clinical data were collected. During operation, the short-term atrial and ventricular pacing thresholds were monitored and recorded after the implantation of the active fixed electrode lead. RESULTS: Multivariate Logistic regression analysis showed that female sex, age, smoking, drinking, coronary heart disease, diabetes mellitus and hyperlipidemia had effects on pacing thresholds in a short-term to some extent after the implantation of active fixed electrode lead of cardiac pacemaker. The levels of myocardial enzymes, myoglobin (MYO), creatine kinase (CK), creatine kinase-MB (CK MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTNI), in patients were gradually increased after the implantation of active fixed electrode lead and reached the peak at 24 h, which were higher than those before operation (p < 0.05). The levels were decreased at 72 h with statistically significant differences. CONCLUSIONS: Female sex, age, smoking, drinking, coronary heart disease, diabetes mellitus and hyperlipidemia are independent influencing factors of pacing thresholds in a short term after the implantation of active fixed electrode lead of cardiac pacemaker. The implantation of active electrodes can raise the myocardial enzyme indexes compared with those before operation, but will fall to the preoperative levels or normal, near normal levels at 72 h after operation. The implantation of active electrodes is safe and feasible for myocardial tissues. PMID- 29272015 TI - The mechanism of miR-23a in regulating myocardial cell apoptosis through targeting FoxO3. AB - OBJECTIVE: Myocardial cell apoptosis represents important pathologic basis of ischemia-reperfusion injury (I/R). MiR-23a is related to myocardial hypertrophy and cardiac remodeling by regulating myocardial cell growth and apoptosis. This study intended to observe the regulating effect of miR-23a in myocardial cell and related target, and investigate its clinical significance to I/R injury. MATERIALS AND METHODS: The rats were divided into sham group and myocardial I/R group. Myocardial cell cycle and miR-23a expression were tested. H2O2 was applied to treat H9c2 rat myocardial cell to simulate oxidative stress during I/R. The cells were divided into blank group, NC group, miR-23a mimic group, H2O2 group, and miR-23a + H2O2 group. ROS content and cell apoptosis were detected by flow cytometry. MiR-23a, FoxO3a, and BIM gene expression were determined by qRT-PCR. FoxO3a and BIM protein levels were measured by Western blot. RESULTS: Compared with sham group, myocardial apoptosis increased, while miR-23a expression was significantly downregulated in I/R group. H2O2 treatment markedly increased ROS levels in H9c2 cells and elevated apoptosis. The overexpression of mMiR-23a effectively reduced cell apoptosis induced by H2O2 treatment. H2O2 treatment significantly decreased miR-23a expression, while markedly elevated the levels of FoxO3a and BIM. The overexpression of miR-23a apparently impeded the induction of FoxO3a and BIM by H2O2. CONCLUSIONS: The downregulation of miR-23a plays a negative role in oxidative stress and cell apoptosis induced by I/R. The overexpression of miR-23a is of significance to alleviate cell apoptosis through inhibiting FoxO3a and downstream target BIM expression. PMID- 29272016 TI - Correlation analysis of ankle-brachial index and brachial-ankle pulse wave velocity with cardiac structures and functions in patients with essential hypertension. AB - OBJECTIVE: To investigate the correlation of ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) with cardiac structures and functions changes in patients with essential hypertension (EH). PATIENTS AND METHODS: A total of 202 patients with hypertension meeting the inclusion criteria were recruited in our hospital from June 2016 to August 2017. They were divided into 4 groups: the low ABI value group, the normal ABI value group, the increased baPWV value group and the normal baPWV group. Clinical data were collected, including medical histories and received physical examinations, blood pressure measurement, biochemical tests and other examinations through the automatic atherosclerosis tester (VP-l00) and echocardiography. RESULTS: Interventricular septal thickness (IVST) of the low ABI value group was significantly larger than that of the normal ABI value group (p<0.05). Compared with those of the normal ABI value group, left ventricular ejection fraction (LVEF) and the ratio of peak velocity flow in the E wave to peak velocity flow in the A wave (E/A) of the low ABI value group were significantly decreased (p<0.05). Left atrium diameter (LAD) and IVST of the increased baPWV group were significantly greater than those of the normal baPWV group (p<0.05), and left ventricular ejection fraction (LVEF) of the former was smaller than that of the latter (p<0.05). Correlation analyses showed that ABI was negatively correlated with IVST (r=-0.713, p<0.05) but positively correlated with LVEF and E/A (r=0.685 and 0.572, respectively, p<0.05); baPWV was positively related to LAD and LVST (r=0.413 and 0.527, respectively, p<0.05) but negatively related to LVEF (r=-0.546, p<0.05). CONCLUSIONS: ABI and baPWV are significantly associated with changes in cardiac structures and functions in patients with EH, which provide a basis for early intervention in clinical. PMID- 29272017 TI - Selective cyclooxygenase-2 inhibitor NS-398 attenuates myocardial fibrosis in mice after myocardial infarction via Snail signaling pathway. AB - OBJECTIVE: The role of NS-398 in Snail pathway of myocardial cells in mice after myocardial infarction and its effect on myocardial fibrosis were investigated in this study. MATERIALS AND METHODS: C57BL/6 mice were selected to establish mouse models of myocardial infarction with permanent ligation of anterior descending branch and sham-operation models without ligation. After successful establishment of models, 30 mice were randomly divided into sham-operation group, myocardial infarction group and drug intervention group. The drug intervention group was treated with intraperitoneal injection of NS-398 (5 mg/kg) at 1 week after modeling for 3 weeks. The survival status of mice after operation was monitored, the cardiac function was detected via echocardiography, the collagen levels in heart tissue pathological sections were detected via Masson staining and Sirius red staining. Moreover, the expressions of Snail and type I collagen levels were detected via immunohistochemistry, and the Snail protein expression level and the activity and expression level of E-cadherin protein were detected via Western blotting. RESULTS: At 4 weeks after establishment of myocardial infarction model, the fibrosis reaction was obvious, and the cardiac function was decreased, accompanied with Snail activation. The administration of NS-398 for 3 weeks inhibited the Snail activity expression and significantly improved the fibrosis degree after infarction. However, it did not improve the cardiac function. Inhibiting Snail improved the fibrosis reaction after infarction, in which Snail/E-cadherin signaling pathway was involved. CONCLUSIONS: NS-398 improves the myocardial fibrosis in mice after myocardial infarction through inhibiting the Snail signaling pathway. PMID- 29272018 TI - Carvedilol alleviates the biliary cirrhosis through inhibiting the endoplasmic reticulum stress. AB - OBJECTIVE: To investigate the effects of carvedilol on inflammation, apoptosis, and hepatic fibrosis caused by biliary cirrhosis and its mechanisms in mice. MATERIALS AND METHODS: 60 male C57/BL6 mice were randomly divided into sham operation group (Sham group, n=20), biliary cirrhosis group (BDL group, n=20) and carvedilol group (CAR group, n=20). The CAR group was treated with gavage using 12.5 mg/kg carvedilol, once a day for 14 consecutive days, while the Sham group and BDL group were treated with gavage using the equivalent normal saline. After that, the mice in Sham group received the laparotomy under chloral hydrate anesthesia, followed by direct abdominal closure. The mice in BDL group and CAR group received the common bile duct ligation after anesthesia for modeling. After modeling, the survival rate of mice in each group was detected, and the blood and liver tissues were taken for detection. The morphological changes in liver tissues and apoptosis in mice in each group were detected and compared. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), superoxide dismutase (SOD), malondialdehyde (MDA), hydroxyproline, and alpha-smooth muscle actin (alpha-SMA) were also detected. The mRNA expression levels of pro-inflammatory factors, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), transforming growth factor beta-1 (TGF-beta1), alpha-SMA and collagen-1 were detected via reverse transcription polymerase chain reaction (RT-PCR). The protein expression levels of CHOP (CCAAT enhancer-binding protein homologous protein), activating transcription factor 4 (ATF4), ATF6, inositol-requiring enzyme 1 (IRE1), phosphorylated Jun N-terminal kinase (pJNK), alpha-SMA, and collagen-1, were detected via Western-blotting. RESULTS: Our study showed that carvedilol could significantly alleviate the biliary cirrhosis in mice, and improve the survival rate of mice. The ALT, AST and TBIL levels, severity of cirrhosis, and number of apoptotic cells in CAR group were significantly lower than those in BDL group. The levels of alpha-SMA and hydroxyproline in CAR group were also significantly lower than those in BDL group. The activity of SOD in CAR group was significantly higher than that in BDL group; the above differences were statistically significant (p<0.05). In addition, it was also found that carvedilol could down-regulate the mRNA expression levels of iNOS, COX-2 and TGF-beta1, down-regulate the mRNA and protein expression levels of alpha-SMA and collagen-1, and negatively regulate the ATF4-CHOP, ATF6-CHOP and IRE1-pJNK signaling pathways. CONCLUSIONS: Carvedilol has a significant effect on alleviating the biliary cirrhosis in mice, and its relevant mechanism may be that carvedilol inhibits the endoplasmic reticulum stress through the negative regulation of ATF4-CHOP, ATF6-CHOP and IRE1 pJNK signaling pathways, which needs to be confirmed by further in vitro experiments. PMID- 29272019 TI - Effect of beta-arrestin on damage of human umbilical vein endothelial cell induced by angiotensin II. AB - OBJECTIVE: beta-arrestin (ARRB2) is a member of arrestin family and a negative regulatory protein of G-coupling receptor, which is closely associated with the pathogenesis of several autoimmune diseases. This study aimed to investigate the mechanism of the effect of ARRB2 on the damage of human umbilical vein endothelial cells (HUVECs), which is induced by angiotensin II (Ang II). MATERIALS AND METHODS: ARRB2 at different concentration was used to interfere with the damage of HUVECs induced by Ang II or RNA interference technology to interfere with the expression of HUVECs followed by addition of Ang II to culture for 24 hours. Nitrate reduction method was used to measure the content of nitric oxide (NO) and radioimmunoassay was used to measure endothelin-1; Western blot assay was used to detect the expression of B-cell lymphoma-2 (Bcl-2), and flow cytometry was used to detect the intracellular level of reactive oxygen (ROS) and apoptosis of HUVECs. RESULTS: Our study found that ARRB2 could significantly reduce the generation and release of ROS, endothelin-1 (ET-1), lactic dehydrogenase (LDH) of HUVECs induced by Ang II and promote the generation of NO, superoxide dismutase (SOD) and scavenging in a dose-dependent manner. On the contrary, when expression of ARRB2 was disturbed by siRNA, increased generation and release of ROS, ET-1, and LDH were observed with reduced generation of NO, SOD and scavenging. In addition, ARRB2 could reverse the apoptosis of HUVECs induced by Ang II and was related to upregulate the expression of Bax. CONCLUSIONS: ARRB2 could protect the damage of HUVECs induced by Ang II and the mechanism was associated with upregulation of the expression of apoptosis and anti-apoptosis protein of Bcl-2. PMID- 29272020 TI - Effects of new probiotic mouthwash in patients with diabetes mellitus and cardiovascular diseases. AB - OBJECTIVE: To evaluate the impact of a new formulation of probiotic mouthwash (PM), using Biocult strong(r) dissolved in neutral mouthwash. PATIENTS AND METHODS: Forty-two patients with cardiovascular disease (CVD) or type 1 and type 2 diabetes were enrolled. Plaque Control Record (PCR) and Bleeding on Probing (BOP) were assessed at baseline and after two weeks of PM or positive control treatment in intervention group (IG) and control group (CG). Food intake was estimated by 3-day diet record. RESULTS: BOP was significantly reduced in all treatments and samples, except for IG in CVD sample (p=0.15). PCR decreased significantly in all treatments and samples (p<0.01). No significance was obtained for BOP and IP in the time x group interaction. Food intake was not significantly different between IG and CG in all samples. Nutrients such as fats and simple carbohydrates were correlated with BOP in patients who received positive control, rather than PM, indicating a lack of food influence on BOP and PCR in IG. CONCLUSIONS: PM treatment was effective in relation to the reduction of PCR and BOP. Probiotics represent a good, but additional, tool for prophylaxis, because they cannot completely substitute the classic oral hygiene methods. Moreover, one week of treatment was not sufficient to draw firm conclusions about the efficacy of the treatment itself. PMID- 29272021 TI - Anti-proliferative effect of digoxin on breast cancer cells via inducing apoptosis. AB - OBJECTIVE: Digoxin is a kind of plant-derived cardiac glycoside that is mainly used to treat heart diseases, especially in congestive heart failure or arrhythmia. However, its potentiality presented in anti-tumor remains unexplored. The purpose of this study was designed to investigate the beneficial pharmacological activity of digoxin on breast cancer cell line (MDA-MB-231, MM231). MATERIALS AND METHODS: The methyl thiazolyl tetrazolium (MTT) assay was utilized to detect the proliferation of the breast cancer MM231. The apoptotic cell numbers were determined by the flow cytometry analysis. The expressions of Bcl-2 (B-cell lymphoma-2) and Bax (Bcl2-associated X protein) were detected by Western blot analysis. RESULTS: Digoxin dose-dependently blocked the cell growth of the breast cancer MM231 through MTT assay, whereas the apoptotic numbers were significantly elevated as reflected in acridine orange staining and flow cytometry analysis. In addition, findings from Western blotting method indicated that digoxin intervention showed reduced Bcl-2 expression and elevated Bax level in MM231 cells, characterized by increased Bax/Bcl-2 ratio. CONCLUSIONS: Digoxin plays a potential anti-tumor role in breast cancer in vitro, possibly by inducing mitochondria-dependent apoptosis. PMID- 29272022 TI - Effects of gangliosides on expressions of caspase-3 and NGF in rats with acute spinal cord injury. AB - OBJECTIVE: To investigate the effects of ganglioside [monostalotetra hexosylganglioside (GM1)] on the expressions of caspase-3 and nerve growth factor (NGF) in rats with acute spinal cord injury (SCI). MATERIALS AND METHODS: Male Sprague- Dawley (SD) rats were selected and randomly divided into Sham group, SCI group and GM1 administration group. The rats in Sham group, SCI group and GM1 group were subjected to behavioral examinations of Basso Beattie Bresnahan (BBB) and oblique-plate test at 1, 7 and 14 d after operation. The content of methylene dioxyamphetamine (MDA) and the activity of superoxide dismutase (SOD) of every rat in each group were measured by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence staining assay was used to detect the expression levels of caspase-3 and NGF of rats in each group. The messenger ribonucleic acid (mRNA) and protein expressions of caspase-3 and NGF of rats in Sham group, SCI group and GM1 group were detected using reverse transcriptase-polymerase chain reaction (RT PCR) and Western blotting assay. RESULTS: The BBB scores and the results of oblique-plate test in Sham group, SCI group and GM1 group at 1, 7 and 14 d showed that the BBB scores and the results of oblique-plate test of rats in each group were significantly decreased at 1 d after SCI, and had different degrees of recovery at 7 and 14 d after injury. The results of ELISA detection revealed that SCI group had increased content of MDA and clearly decreased activity of SOD in comparison with Sham group; at the same time, MDA content in GM1 group was overtly lower than that in SCI group, while SOD activity was enhanced evidently in GM1 group compared with that in SCI group. According to immunofluorescence assay, significantly increased expression of caspase-3 and distinctly decreased expression of NGF were found in SCI group. However, this phenomenon was significantly reversed by GM1. RT-PCR and Western blotting assay severally proved that the mRNA and protein expressions of caspase-3 were raised in SCI group and decreased clearly after the administration of GM1; while the mRNA and protein expressions of NGF was significantly reduced in SCI group and overtly elevated after the administration of GM1. ANOVA showed that there were statistically significant differences in expressions of caspase-3 and NGF among Sham group, SCI group and GM1 group (p<0.05). CONCLUSIONS: GM1 has an evident effect on the expressions of caspase-3 and NGF in rats with acute SCI, and is able to down regulate the expression of caspase-3 and up-regulate the expression of NGF, so as to achieve its therapeutic effect on SCI. PMID- 29272023 TI - Absorption, metabolism and protective role of fruits and vegetables polyphenols against gastric cancer. AB - Growing evidence links free radicals to the aging processes, degenerative diseases and cancer, underlying the important role played by some antioxidants, as polyphenols, present in fruits and vegetables, which seem able to counteract the toxic effects induced by oxidative stress. The gastrointestinal tract is continuously exposed to oxidant and antioxidant substances and, in particular in this district, the food rich in antioxidants could exert a protective effect against the risk of cancer. Polyphenols have a direct protective effect on the gastrointestinal tract, detoxifying the Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), preserving antioxidant proteins and complexing metals. Although polyphenols are a class of antioxidant largely represented in vegetables and fruits, we are still uncertain whether the beneficial effects of a diet rich in plant products, are mainly due to these compounds. Our knowledge does not allow to be sure about which antioxidants are capable of having therapeutic effects, through which mechanism, the exact therapeutic dose or how long they have to be taken to have a significant protective effect. In this review we take into account the most common antioxidants, usually found in the diet and the processes regulating their absorption, metabolism and excretion, in order to elucidate the mechanism that could be responsible for the protection against cancer. PMID- 29272024 TI - Effect of NF-kappaB signaling pathway mediated by miR-711 on the apoptosis of H9c2 cardiomyocytes in myocardial ischemia reperfusion. AB - OBJECTIVE: The aim of this study was to explore the change of the expression of miR-711 in myocardial ischemia-reperfusion (I/R) injury and the possible mechanism. MATERIALS AND METHODS: The cardiomyocyte model of I/R injury was constructed. Real-time quantitative fluorescence polymerase chain reaction (qRT PCR) and Western blotting were used to detect the expression of miR-711 as well as the mRNA and protein levels of NF-kappaB (p65). Flow cytometry, CCK-8 kit, and enzyme-linked immunosorbent assay (ELISA) were used to detect the apoptosis, cell viability, and the content of LDH and MDA, respectively. RESULTS: Compared to control cells, the expression levels of miR-711, the mRNA, and protein levels of NF-kappaB were higher in H9c2 cardiomyocytes of I/R, the apoptosis rate of H9c2 cardiomyocytes of I/R was higher, the levels of LDH and MDA were higher in the supernatant of cell culture, and the cell viability was lower. In comparison to the cells of I/R, the apoptosis rate of H9c2 cardiomyocytes of I/R plus miR-711 inhibitors was lower, the levels of LDH and MDA were lower in the supernatant of cell culture, and the cell viability was higher. In comparison to control cells, the expression level of Bcl-2 was lower, and the expression levels of Bax and Caspase-3 were higher in the cells of I/R. In comparison to the cells of I/R, the expression level of Bcl-2 was lower, and the expression levels of Bax and Caspase 3 were higher in the cells of I/R plus miR-711 inhibitors. CONCLUSIONS: Overexpression of miR-711 could promote the expression of NF-kappaB (p65) in the cardiomyocytes of I/R and accelerate the transportation of NF-kappaB (p65) into the nucleus, thus promoting the apoptosis of cardiomyocytes. PMID- 29272025 TI - Hepatitis C-related hepatocellular carcinoma: diagnostic and therapeutic management in HIV-patients. AB - The efficacy of the current HIV therapy has led to increased survival and prolongation of the average life expectancy of people living with HIV (PLWH), as well as the emergence of comorbidities and non-AIDS related cancer. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Current evidence suggests that HCC is an important cause of morbidity and mortality in HIV infected patients. In fact, HCC prevalence rate is indeed higher with respect to the general population average. In this paper, we review the diagnostic and therapeutic management of Hepatitis C-related hepatocellular carcinoma in HCV-HIV co-infected patients. Several therapeutic options are available depending on several factors as HCC stage, liver functions, comorbidities and they have been divided into three groups: potentially curative, proven effective but not curative, and unproven or ineffective therapy. In HIV infected patients, surgical options are preferred compared to non-surgical therapies. Further studies, especially multicenter ones, are needed in order to define the most appropriate, evidence-based therapeutic approach to PLWH suffering from HCC. It also appears necessary to develop appropriate care guidelines for PLWH. PMID- 29272026 TI - Kaposi's sarcoma in HIV-infected patients in the era of new antiretrovirals. AB - Kaposi's Sarcoma (KS) is a multicentric angioproliferative cancer of endothelial cells (ECs) caused by Human Herpesvirus 8 (HHV8) characterized by clinical heterogeneity depending on the host immune conditions. Despite its incidence has dramatically decreased in developed countries after the introduction of Highly Active Antiretroviral Therapy (HAART), KS remains the most frequent tumor in HIV infected patients worldwide. Clinical presentation varies from an indolent slowly progressive behavior, generally limited to the skin, to an aggressive and rapidly progressing disease. In more than 50% of cases, the skin lesions are often associated with a more or less important visceral involvement, particularly to the oral cavity and the gastrointestinal tract that are involved in 35% and 40% of cases respectively. A large number of treatments can be used both as local and as systemic therapy. Particularly, HAART represents the first treatment in patients with moderate lesions limited to skin, and it can be sufficient to reduce significantly the size of lesions and, often, the complete disappear in 35% of cases after 3-9 months of treatment. In case of a rapidly progressive disease with extensive cutaneous and/or visceral involvement systemic drugs are used such as the liposomal anthracyclines pegylated liposomal doxorubicin (PLD) and daunorubicin citrate liposome (DNX), the combined treatment adriamycin bleomycin-vincristine (ABV) and bleomycin-vincristine (BV), Paclitaxel and Interferon-alfa. In patients with limited skin localization, the local treatment can play an important role. Local medical therapy is based on the use of alitretinoin, antineoplastic drugs vincristine, vinblastine and bleomycin and Sodium Tetradecyl Sulfate (STS). In addition to medical therapy, physical treatment, such as cryotherapy and radiotherapy, are also commonly used. PMID- 29272027 TI - Obsessive, compulsive, and conscientious? The relationship between OCPD and personality traits. AB - OBJECTIVE: Obsessive-compulsive personality disorder (OCPD) is defined as being overly controlling, rigid, orderly, and perfectionistic. At a definitional level, OCPD would appear to be highly related to the trait of Conscientiousness. The current study attempts to disentangle this relationship by examining the relationship at a facet level using multiple forms of OCPD assessment and using multiple reports of OCPD and personality. In addition, the relationship between OCPD and each Big Five trait was examined. METHOD: The study relied on a sample of 1,630 adults who completed self-reports of personality and OCPD. Informants and interviewers also completed reports on the targets. Bifactor models were constructed in order to disentangle variance attributable to each facet and its general factors. RESULTS: Across four sets of analyses, individuals who scored higher on OCPD tended to be more orderly and achievement striving, and more set in their ways, but less generally conscientious. OCPD was also related to select facets under each Big Five trait. Notably, findings indicated that OCPD has a strong interpersonal component and that OCPD tendencies may interfere with one's relationships with others. CONCLUSIONS: Findings suggest that OCPD's relationship with personality can be more precisely explained through its relationships with specific tendencies rather than general, higher-order traits. PMID- 29272028 TI - Intracoronary Thrombus Formation Following Carbon Monoxide Poisoning. AB - Thromboembolic events in the context of carbon monoxide (CO) exposure have been well described in the literature. Six cases of clinically significant coronary thrombosis following CO exposure were previously reported. However, factors affecting the development of coronary thrombus in CO exposure are poorly understood, and the significance of this finding in a forensic context is not clear. This article discusses a case of coronary thrombosis found at autopsy following a death in which CO poisoning was suspected. A 67-year-old man was found dead in his garage with four vehicles with their ignition in the "on" position and their tanks empty. At autopsy, severe coronary atherosclerosis and an acute nonocclusive coronary thrombus were found. Given the dissimilarities among cases and the presence of CO exposure, it was suggested that the coronary artery thrombosis is likely due to the inherent prothrombotic mechanism of CO, the only common denominator in all the cases. PMID- 29272029 TI - Telephone Follow-Up for Older Adults Discharged to Home from the Emergency Department: A Pragmatic Randomized Controlled Trial. AB - BACKGROUND/OBJECTIVES: Telephone calls after discharge from the emergency department (ED) are increasingly used to reduce 30-day rates of return or readmission, but their effectiveness is not established. The objective was to determine whether a scripted telephone intervention by registered nurses from a hospital-based call center would decrease 30-day rates of return to the ED or hospital or of death. DESIGN: Randomized, controlled trial from 2013 to 2016. SETTING: Large, academic medical center in the southeast United States. PARTICIPANTS: Individuals aged 65 and older discharged from the ED were enrolled and randomized into intervention and control groups (N = 2,000). INTERVENTION: Intervention included a telephone call from a nurse using a scripted questionnaire to identify obstacles to elements of successful care transitions: medication acquisition, postdischarge instructions, and obtaining physician follow-up. Control subjects received a satisfaction survey only. MEASUREMENTS: Primary outcome was return to the ED, hospitalization, or death within 30 days of discharge from the ED. RESULTS: Rate of return to the ED or hospital or death within 30 days was 15.5% (95% confidence interval (CI) = 13.2-17.8%) in the intervention group and 15.2% (95% CI = 12.9-17.5%) in the control group (P = .86). Death was uncommon (intervention group, 0; control group, 5 (0.51%), 95% CI = 0.06-0.96%); 12.2% of intervention subjects (95% CI = 10.1-14.3%) and 12.5% of control subjects (95% CI = 10.4-14.6%) returned to the ED, and 9% of intervention subjects (95% CI = 7.2-10.8%) and 7.4% of control subjects (95% CI = 5.8-9.0%) were hospitalized within 30 days. CONCLUSION: A scripted telephone call from a trained nurse to an older adult after discharge from the ED did not reduce ED or hospital return rates or death within 30 days. Clinicaltrials.gov identifier: NCT01893931z. PMID- 29272030 TI - An incidental finding of an asymptomatic intraneural glomus tumor: A case report and review of the literature. AB - Glomus tumors are rare, soft-tissue neoplasms arising from the thermoregulatory neuromyoarterial glomus bodies. They are commonly observed in the extremities and typically present with symptoms of cold hypersensitivity, pain and localized tenderness. Intraneural glomus tumors (INGTs) are even rarer. Here we review the literature on INGT and present an unusual case of an asymptomatic INGT, found incidentally within the excision specimen of a spiradenocarcinoma that arose near the natal cleft. Interestingly, this had not been identified on magnetic resonance imaging (MRI) used to investigate the spiradenocarcinoma. Although glomus tumors are usually considered benign, malignant transformation has been reported, highlighting the need for reporting pathologists and treating clinicians to be aware of this entity. PMID- 29272031 TI - Association between UDP-glucuronosyltransferase 2B7 tagSNPs and breast cancer risk in Chinese females. AB - This retrospective study was performed to evaluate the association between the UGT2B7 tagSNPs (rs12233719, rs4356975, rs7435335 and rs7441774) and breast cancer in Chinese females. Blood samples were collected from 672 patients with breast cancer and 670 healthy controls for DNA extraction. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to analyze UGT2B7 polymorphisms. Dual-luciferase reporter assays were further performed to investigate the regulatory function of UGT2B7 tagSNPs. The frequency of rs7441774 G allele in the breast cancer cases was statistically significantly higher than in the controls (0.412 vs 0.358, P = .006; odds ratio [OR] = 1.27, 95% CI = 1.08-1.48). After adjusting for conventional risk factors, individuals with the GG genotype had a higher breast cancer risk than those with the AA genotype (adjusted OR = 1.63, 95% CI = 1.18-2.26; P = .008). The GCGG haplotype of UGT2B7 was also associated with breast cancer (OR = 1.22, 95% CI = 1.04-1.45; P = .027). Meanwhile, the rs7441774 G allele could significantly decrease the transcriptional activity of the UGT2B7 gene. This study indicates that UGT2B7 polymorphisms may play a crucial role in the occurrence and development of breast cancer in the Han Chinese population. PMID- 29272032 TI - Improving Emergency Department Discharge Care with Telephone Follow-Up. Does It Connect? PMID- 29272033 TI - Hepatocellular carcinoma due to a baffle obstruction after the mustard operation: A case report. PMID- 29272034 TI - Intention-to-treat survival benefit in liver transplantation: Comments on Lai et al. PMID- 29272035 TI - Composite ganglioside autoantibodies and immune treatment response in MMN and MADSAM. AB - INTRODUCTION: Multifocal motor neuropathy (MMN) is a motor only, asymmetric onset neuropathy that is relatively treatment-refractory compared with classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. METHODS: We reviewed 35 patients seropositive for GM1 (monosialo-asialo [immunoglobulin M, IgM; immunoglobulin G, IgG]) and/or GD1b (disialo [IgG, IgM]) autoantibodies having MMN, classic CIDP, or MADSAM. Immune-treatment responsiveness and clinical course was compared with antibody negative disease controls. RESULTS: Seventy-nine percent of seropositives with an initial diagnosis of MMN were immunotherapy responsive compared with 46% of seronegatives (P = 0.045). Eight ganglioside antibody positive MMN patients of 19 (42%) developed sensory findings consistent with MADSAM compared with 3 of 41 (7%) seronegative MMN patients (P = 0.003). MMN and MADSAM patients with ganglioside antibody positivity had more sustained treatment responses (P = 0.03). DISCUSSION: Patients initially diagnosed with MMN seropositive for diverse GM1 autoantibodies appear more likely to have sustained treatment response and evolution to MADSAM. Muscle Nerve 57: 1000-1005, 2018. PMID- 29272036 TI - Adaptive immune response to Clostridium difficile infection: A perspective for prevention and therapy. AB - Clostridium difficile infection (CDI) is one of the most important nosocomial illnesses and a major cause of morbidity and mortality. While initial treatment of CDI is usually successful, unprovoked relapses remain an important and frustrating problem. This review examines the literature describing the natural immune response to CDI, and to what extent it can explain the propensity for relapses. In particular, we discuss studies on antibody and, to a lesser extent, B cell and T cell responses in CDI. Despite years of study, there remains incomplete understanding of the natural antibody response to the major pathogenic toxins, TcdA and TcdB, and other bacterial antigens, in CDI. Recent literature suggests that a specific subset of neutralizing antibodies that target the putative carbohydrate-binding domains of TcdB and possibly TcdA have the greatest protective ability. This is further supported by recent successful clinical trials of a humanized monoclonal antibody to the major toxin TcdB. A better understanding of how and why the most protective adaptive immune response develops may lead to improved vaccine and therapeutic targets for recurrent CDI. PMID- 29272037 TI - Liver-specific deficiency of unc-51 like kinase 1 and 2 protects mice from acetaminophen-induced liver injury. AB - : unc-51-like autophagy activating kinase 1 and 2 (Ulk1/2) regulate autophagy initiation under various stress conditions. However, the physiological functions of these Ser/Thr kinases are not well characterized. Here, we show that mice with liver-specific double knockout (LDKO) of Ulk1 and Ulk2 (Ulk1/2 LDKO) are viable, but exhibit overt hepatomegaly phenotype. Surprisingly, Ulk1/2 LDKO mice display normal autophagic activity in hepatocytes upon overnight fasting, but are strongly resistant to acetaminophen (APAP)-induced liver injury. Further studies revealed that Ulk1/2 are also dispensable for APAP-induced autophagy process, but are essential for the maximum activation of c-Jun N-terminal kinase (JNK) signaling both in vivo and in isolated primary hepatocytes during APAP treatment. Mechanistically, APAP-induced inhibition of mechanistic target of rapamycin complex 1 releases Ulk1 from an inactive state. Activated Ulk1 then directly phosphorylates and increases the kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4/7), the upstream kinases and activator of JNK, and mediates APAP-induced liver injury. Ulk1-dependent phosphorylation of MKK7 was further confirmed by a context-dependent phosphorylation antibody. Moreover, activation of JNK and APAP-induced cell death was markedly attenuated in Mkk4/7 double knockdown hepatocytes reconstituted with an Ulk1-unphosphorylatable mutant of MKK7 compared to those in cells rescued with wild-type MKK7. CONCLUSION: Together, these findings reveal an important role of Ulk1/2 for APAP-induced JNK activation and liver injury, and understanding of this regulatory mechanism may offer us new strategies for prevention and treatment of human APAP hepatotoxicity. (Hepatology 2018;67:2397-2413). PMID- 29272038 TI - Quality of care and patient-reported outcomes in carpal tunnel syndrome: A prospective observational study. AB - INTRODUCTION: Higher quality care for carpal tunnel syndrome (CTS) may be associated with better outcomes. METHODS: This prospective observational study recruited adults diagnosed with CTS from 30 occupational health centers, evaluated physicians' adherence to recommended care processes, and assessed results of the Boston Carpal Tunnel Questionnaire (BCTQ) and Short Form Health Survey version 2 (SF-12v2) at recruitment and at 18 months. RESULTS: Among 343 individuals, receiving better care (80th vs. 20th percentile for adherence) was associated with greater improvements in BCTQ Symptom Severity scores (-0.18, 95% confidence interval [CI] -0.32 to -0.05), BCTQ Functional Status scores (-0.21, 95% CI -0.34 to -0.08), and SF12-v2 Physical Component scores (1.75, 95% CI 0.33 3.16). Symptoms improved more when physicians assessed and managed activity, patients underwent necessary surgery, and employers adjusted job tasks. DISCUSSION: Efforts should be made to ensure that patients with CTS receive essential care processes including necessary surgery and activity assessment and management. Muscle Nerve 57: 896-904, 2018. PMID- 29272039 TI - Calcium channel autoimmunity: Cerebellar ataxia and lambert-eaton syndrome coexisting. AB - INTRODUCTION: Neuronal calcium channel antibodies are a biomarker of Lambert Eaton syndrome (LES) and cerebellar ataxia. We have encountered several patients with LES and cerebellar ataxia coexisting, and we sought to further define this association. METHODS: We reviewed records of patients at our institution with a diagnosis of "Lambert-Eaton syndrome" and "cerebellar ataxia." RESULTS: Seventeen patients were identified with LES and ataxia. Presenting symptoms were weakness (8), concurrent weakness and ataxia (4), ataxia (4), and other (1). Nine patients had small-cell lung carcinoma, 3 of whom had survival greater than 100 months. Immunotherapy responses were best among patients without cancer. Nine of 17 (53%) patients were alive at last follow-up (median survival 62 months; range, 8-240). DISCUSSION: Calcium channel autoimmunity should be considered in patients with coexisting cerebellar ataxia and myasthenic weakness. Affected patients may survive small-cell carcinoma or have immunotherapy-responsive neurological symptoms. Muscle Nerve, 2018. PMID- 29272040 TI - Pain in SCN4A Mutated P.A1156T muscle sodium channelopathy-a postal survey. AB - INTRODUCTION: The p.A1156T mutation alters the function of the voltage-gated sodium channel Nav1.4 on the muscle sarcolemma, causing a channelopathy without overt myotonia or periodic paralysis but with myalgic pain. METHODS: A postal survey was conducted to assess the prevalence and characteristics of pain and related symptoms in individuals with the p.A1156T mutation. A specific questionnaire, intensity and interference subscales of the Brief Pain Inventory, pain drawing, Widespread Pain Index, quality of life (RAND-36), and the Beck Depression Inventory were completed. RESULTS: Twenty of 24 patients replied. Current pain was reported by 16 respondents; the other 4 had experienced pain previously. Most commonly, pain was widespread and exercise-induced. The severity and the impact of pain on daily life were considerable, although varied. DISCUSSION: This sodium channelopathy is another entity in the growing number of diseases causing widespread myalgic pain that resembles the pain seen in fibromyalgia syndrome. Muscle Nerve 57: 1014-1017, 2018. PMID- 29272041 TI - Gut-liver axis alterations in alcoholic liver disease: Are bile acids the answer? PMID- 29272042 TI - The level of physical training modulates cytokine levels through P2X7 receptor in healthy subjects. AB - INTRODUCTION: The P2X7 receptor-NLRP3 inflammasome complex (P2X7R-Infl) regulates inflammatory and immune responses. Physical exercise modulates heat-shock proteins (Hsps), influencing cytokine levels and oxidative stress; Hsp72 triggers P2X7R-Infl-dependent responses. SUBJECTS AND METHODS: We studied the effect of a single bout of maximal exercise on lymphomonocyte expression of P2X7R, NLRP3, caspase-1, NF-kB and Hsp72 and circulating levels of IL-1beta, IL-18 and MCP-1, all modulated by P2X7R-Infl, in healthy sedentary (SED), trained (ATH), endurance (END) male individuals. RESULTS: Baseline P2X7R, NLRP3 and Caspase-1 expression progressively increased from SED to ATH and END; NF-kbeta showed the same trend. Hsp72 did not differ among groups. Acute exercise strongly reduced P2X7R in all participants, irrespective of their degree of physical training. Inflammasome responses differed across groups: in SED, NLRP3 and Caspase-1 increased; in ATH, NLRP3 reduced and caspase-1 did not vary; in END, NLRP3 and Caspase-1 declined. Baseline IL-1beta, higher in END, was unmodified after exercise; IL-18 decreased; MCP-1 doubled in SED, did not vary in ATH, declined in END. In the whole study population, significant direct relationships emerged between P2X7R expression and IL-1beta, IL-18, MCP-1 levels, all P < .001; also Caspase-1 related with these markers. A multivariate analysis showed age, BMI and P2X7R as determinants of postexercise IL-1beta levels. CONCLUSION: Endurance show higher P2X7R-Infl expression and function vs SED and ATH; however, maximal exercise determines prevailing pro-inflammatory vs anti-inflammatory responses in untrained and trained participants, respectively, highlighting a likely cause-effect relationship between degree of physical activity and P2X7R-Infl-mediated responses. PMID- 29272043 TI - Patient-reported outcomes in cirrhosis: A scoping review of the literature. AB - : Patients with cirrhosis seek improvement in their symptoms, functioning, quality of life, and satisfaction with the care they receive. However, these patient-reported outcomes (PROs) are not routinely measured for clinical care, research, or quality improvement. The members of the American Association for the Study of Liver Diseases Practice Metrics Committee, charged with developing quality indicators for clinical practice, performed a scoping review of PROs in cirrhosis. The aim is to synthesize a comprehensive set of PROs for inclusion into a standard patient-centered outcome set. We searched Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and the Cochrane Trial Library since inception, with final searches run between April 20 and June 1, 2017. Studies were included if they reported the construction and/or validation of a PRO instrument for patients with cirrhosis or if they assessed the clinical (case-mix) variables determining responses to established PRO scales. Eleven studies were selected that yielded 259 items specific to patients with cirrhosis. After removing duplicates, 152 unique items were isolated. These items were consolidated into seven domains: physical symptoms, physical function, mental health, general function, cognition, social life, and satisfaction with care. The seven domains included 52 subdomains (e.g., physical domain, abdominal pain subdomain). Twelve variables were identified that independently modified established PRO scales. These included clinical factors (severity of liver disease and its complications, medication burden, and comorbidities), specific PROs (cramps, pruritis), and surrogate outcome measures (falls, hospitalization). CONCLUSION: This scoping review identified and categorized a large existing set of PRO concepts that matter to patients with cirrhosis; these outcomes may now be translated into usable measures both for the assessment of the quality of cirrhosis care in clinical practice and to perform research from the patient's perspective. (Hepatology 2018;67:2375-2383). PMID- 29272044 TI - Dihydrotestosterone enhances growth and infectivity of Leishmania Mexicana. AB - A strong sex-associated susceptibility towards Leishmania has been reported in males, yet little is known on the effect of hormones in Leishmania physiopathogenicity. Due to the enhanced susceptibility of males to Leishmania mexicana infections, we were interested in analysing the effect exerted by the main androgen produced in males (DHT) on L. mexicana promastigotes. Thus, the aim of this study was to assess the regulation exerted by dihydrotestosterone (DHT) on L. mexicana replication, infectivity, survival and development of tissue lesions. Experiments included growth curves of L. mexicana promastigotes incubated with different doses of DHT, their infection rate, intracellular survival and lesion development in BALB/c mice. Our data show that DHT significantly enhances parasite replication, infection rate and survival in bone marrow-derived macrophages (BMMF). Promastigotes in the presence of DHT produced significantly larger lesions in BALB/c earlobes. These results suggest that DHT probably plays a critical role during L. mexicana infections, and the higher susceptibility of males possibly relates to benefits gained by the parasite from host-derived hormones. Our data shed new light on the physiopathology of Leishmania infections and are the first attempt to understand the direct interaction between Leishmania and androgens, particularly DHT. Understanding this trans-regulation process employed by parasites to exploit host molecules sheds new light on L. mexicana physiopathogenesis and opens a possible field for studies on drug development. PMID- 29272046 TI - Dual ablation of beta- and gamma-catenin: Critical regulators of junctions and their functions. PMID- 29272047 TI - Identical COL71A1 heterozygous mutations resulting in different dystrophic epidermolysis bullosa phenotypes. AB - Dystrophic epidermolysis bullosa is a rare blistering condition caused by mutations in the COL7A1 gene. Different clinical variants have been described, with dominant and recessive inheritance, but no consistent findings have been elucidated to establish a genotype-phenotype correlation. We present three unrelated patients with two identical pathogenic compound heterozygous mutations in the COL7A1 gene that developed different clinical forms of dystrophic epidermolysis bullosa-epidermolysis bullosa pruriginosa and mild recessive non Hallopeau-Siemens-raising the possibility of other genetic or environmental modifying factors responsible for the phenotype of the disease. PMID- 29272048 TI - Shape-Persistent [4+4] Imine Cages with a Truncated Tetrahedral Geometry. AB - The synthesis of shape-persistent organic cage compounds is often based on the usage of multiple dynamic covalent bond formation (such as imines) of readily available precursors. By careful choice of the precursors geometry, the geometry and size of the resulting cage can be accurately designed and indeed a number of different geometries and sizes have been realized to date. Despite of this fact, little is known about the precursors conformational rigidity and steric preorganization of reacting functional groups on the outcome of the reaction. Herein, the influence of conformational rigidity in the precursors on the formation of a [4+4] imine cage with truncated tetrahedral geometry is discussed. PMID- 29272050 TI - Exploratory and confirmatory studies have different targets and both are needed in clinical research. PMID- 29272049 TI - Candida glabrata prosthetic joint infection, successfully treated with anidulafungin: A case report and review of the literature. AB - Non-albicans Candida prosthetic joint infection (PJI) is extremely rare. A case of a Candida glabrata knee PJI is a 68-year-old splenectomised female smoker, suffering from chronic obstructive pulmonary disease (COPD) and alcoholism is reported. The patient presented with a peri-prosthetic fracture, 15 years after total knee replacement surgery. Cultures of the intraoperative peri-prosthetic tissue and materials yielded C. glabrata, as well as a methicillin-resistant S. epidermitis. The patient was treated with anidulafungin and vancomycin. The knee prosthetic joint was removed and cement-spacer with vancomycin and gentamycin was placed. Additionally, an external fixation was performed. A second stage revision surgery was planned, after completion of the antimicrobial and antifungal treatment. The patient is followed up for 4 months without signs, symptoms or findings of infection. PJI Candida infections require a high clinical suspicion index. It is of utmost importance to report these cases, since there is no consensus yet of the proper antifungal treatment. Furthermore, a literature review regarding treatment of those cases is provided. First-line treatment with an echinocandin seems most proper, due to their fungicidal properties, their effectiveness against biofilm, as well as their minimal toxicity, making them ideal for long-term use. Further experience is needed, for better understanding the disease's pathogenesis and optimal treatment. PMID- 29272051 TI - The case for normothermic machine perfusion in liver transplantation. AB - In recent years, there has been growing interest in normothermic machine perfusion (NMP) as a preservation method in liver transplantation. In most countries, because of a donor organ shortage, an unacceptable number of patients die while awaiting transplantation. In an attempt to increase the number of donor organs available, transplant teams are implanting a greater number of high-risk livers, including those from donation after circulatory death, older donors, and donors with steatosis. NMP maintains the liver ex vivo on a circuit by providing oxygen and nutrition at 37 degrees C. This permits extended preservation times, the ability to perform liver viability assessment, and the potential for liver directed therapeutic interventions during preservation. It is hoped that this technology may facilitate the enhanced preservation of marginal livers with improved posttransplant outcomes by reducing ischemia/reperfusion injury. Clinical trials have demonstrated its short-term superiority over cold storage in terms of early biochemical liver function, and it is anticipated that it may result in increased organ utilization, helping to reduce the number of wait-list deaths. However, further studies are required to demonstrate longer-term efficacy and the impact on biliary complications as well as further knowledge to exploit and maximize the potential of this exciting new technology. Liver Transplantation 24 269-275 2018 AASLD. PMID- 29272052 TI - Carbon dioxide embolism during transoral robotic thyroidectomy: A case report. AB - BACKGROUND: Carbon dioxide (CO2 ) embolism is a serious, although rare, complication of remote access thyroidectomy using CO2 insufflation. Recently, we encountered a case of CO2 embolism during transoral thyroidectomy, and present it here with a review of the literature. METHODS AND RESULTS: A 59-year-old female patient with papillary thyroid carcinoma underwent transoral robotic thyroidectomy with CO2 insufflation. During skin flap elevation, the anterior jugular vein was lacerated. Simultaneously, an electrocardiogram (ECG) showed bradycardia with premature atrial complexes, followed by asystole. After 2 cycles of cardiopulmonary resuscitation with an injection of 1-mg epinephrine, spontaneous circulation returned, and sinus tachycardia with ST segment elevation was noted in ECGs. The patient's vital signs returned to normal within 30 minutes, and normal sinus rhythm was observed. She was discharged on postoperative day 7, without neurologic and cardiac deficit. CONCLUSION: The possibility of CO2 embolism during transoral thyroidectomy with CO2 insufflation should not be overlooked. PMID- 29272053 TI - Pharmacological management of delusional infestation. PMID- 29272054 TI - Proinflammatory cytokines as serum biomarker in oral carcinoma-A prospective multi-biomarker approach. AB - BACKGROUND: Inflammation and cell-mediated immunity have a key role in different stages of carcinogenesis. The aim of this prospective study was to assess serum levels of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-alpha), and MHC class I polypeptide-related sequence B (MICB) in patients with oral premalignant lesion (OPL), oral squamous cell carcinoma (OSCC), and healthy controls in a multi-biomarker approach as a potential diagnostic and prognostic tool for OSCC. MATERIAL AND METHODS: A total of 205 patients (81 with OSCC, 75 with OPL, and 49 healthy controls) were included in this prospective study. Cytokine concentrations were measured by commercial enzyme linked immunoassay and chemiluminescence immunoassay. RESULTS: IL-6, IL-8, and sIL-2R were significantly elevated in OSCC patients compared to healthy controls and to OPL patients. Higher T-Grade (>T2) and positive lymph node involvement resulted in significantly higher IL-6 values (P < .001 and P = .037). IL-6 serum values >=5 pg/mL (n = 45) and sIL-2R serum values >=623 U/mL (n = 19) indicated a significant lower survival rate compared to OSCC patients with low IL-6 (n = 36) and sIL-2R values (n = 62, P = .023 and P = .026). ROC and classification tree analyses identified the combination of IL-6 and IL-8 as diagnostic markers with good diagnostic accuracy. CONCLUSION: In conclusion, IL-6, IL-8, and sIL-2R are strongly associated with OSCC oncogenesis and IL-6 and sIL-2R seem to be promising and potent biomarkers for evaluating patients' prognosis. PMID- 29272055 TI - Vitamin D: a possible intervention for preventing gestational diabetes? PMID- 29272056 TI - Prognostic value of tumor volume in patients with head and neck squamous cell carcinoma treated with primary surgery. AB - BACKGROUND: Tumor volume in head and neck squamous cell carcinoma (HNSCC) was mainly measured in nonsurgically treated patients. We analyzed the influence of tumor volume on complete response (CR), overall survival (OS), and clear surgical margins also in primarily surgically treated patients. METHODS: In contrast enhanced CTs, the tumor volumes of patients with incident HNSCC were measured. RESULTS: The tumor volumes of 259 patients were measured, of which 125 patients (48%) underwent primary surgery and 102 patients (84%) had clear margins. The tumor volume was not an independent factor for CR at the primary tumor site. Risk of death increased by 1.4% per mL of tumor volume (95% confidence interval [CI] 0.8%-2.0%; P < .001). The OS was better in patients treated with primary surgery, if the tumor volume was <=12 mL (P < .001). Risk of involved margins increased by 4.5% per mL of tumor volume (95% CI 0.9%-8.3%; P = .003). The predicted probability of clear margins was >=80% in tumor volumes <= 16 mL. CONCLUSION: The tumor volume had an impact on CR, OS, and clear margins. The tumor volume may also aid in selecting HNSCC treatment. PMID- 29272057 TI - Clinical usefulness of prognostic biomarkers in optic neuritis. AB - BACKGROUND AND PURPOSE: Different biological and radiological biomarkers predict clinical conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS). The aim was to explore their role in predicting the outcome of patients with optic neuritis (ON), a CIS considered to have a benign prognosis. METHODS: Sixty-eight consecutive ON patients were followed prospectively. Magnetic resonance imaging (MRI) and cerebrospinal fluid studies including oligoclonal immunoglobulin G (IgG) bands (OCGBs), lipid-specific oligoclonal IgM bands (LS-OCMBs) and neurofilament light chain quantification were performed at disease onset. Conversion to clinically definite MS (CDMS) was monitored. RESULTS: The mean time of follow-up of our series was 46.4 months. Twenty-five patients (36.7%) developed CDMS during follow-up. Neurofilament light chain levels did not predict clinical conversion. By contrast, an abnormal MRI increased the risk of CDMS [hazard ratio (HR) 12.5, P = 0.013]. The clearest association was found in patients with more than three T2 lesions. OCGBs also predicted the onset of CDMS (HR 21.3, P = 0.003) and LS-OCMBs were associated with a shorter time to CDMS (HR = 116.6, P < 0.001). CONCLUSIONS: Magnetic resonance imaging and OCGBs predicted conversion to CDMS after an ON episode. In addition, LS-OCMBs identified the ON patients more likely to develop MS early. These results, applicable to the everyday clinical setting, may be of interest for therapeutic decisions. PMID- 29272059 TI - Mechanofluorochromic Carbon Nanodots: Controllable Pressure-Triggered Blue- and Red-Shifted Photoluminescence. AB - Mechanofluorochromic materials, which change their photoluminescence (PL) colors in responding to mechanical stimuli, can be used as mechanosensors, security papers, and photoelectronic devices. However, traditional mechanofluorochromic materials can only be adjusted to a monotone direction upon the external stimuli. Controllable pressure-triggered blue- and red-shifted PL is reported for C-dots. The origin of mechanofluorochromism (MFC) in C-dots is interpreted based on structure-property relationships. The carbonyl group and the pi-conjugated system play key roles in the PL change of C-dots under high pressure. As the pressure increases, the enhanced pi-pi stacking of the pi-conjugated system causes the red shift of PL, while the conversion of carbonyl groups eventually induces a blue shift. Together with their low toxicity, good hydrophilicity, and small size, the tunable MFC property would boost various potential applications of C-dots. PMID- 29272058 TI - Sialic acid-dependent interaction of group B streptococci with influenza virus infected cells reveals a novel adherence and invasion mechanism. AB - Group B streptococci (GBS) contain a capsular polysaccharide with side chains terminating in alpha2,3-linked sialic acids. Because of this linkage type, the sialic acids of GBS are recognised by lectins of immune cells. This interaction results in a dampening of the host immune response and thus promotes immune evasion. As several influenza A viruses (IAV) use alpha2,3-linked sialic acid as a receptor determinant for binding to host cells, we analysed whether GBS and influenza viruses can interact with each other and how this interaction affects viral replication and bacterial adherence to and invasion of host cells. A co sedimentation assay revealed that viruses with a preference for alpha2,3-linked sialic acids bind to GBS in a sialic acid-dependent manner. There is, however, a large variation in the efficiency of binding among avian influenza viruses of different subtypes as shown by a hemagglutination-inhibition assay. A delay in the growth curve of IAV indicated that GBS has an inhibitory effect on virus replication. On the other hand, both the adherence and invasion efficiency of GBS were enhanced when the cells were pre-infected by IAV with appropriate receptor specificity. Our results suggest that GBS infection may result in a more severe disease when patients are co-infected by influenza viruses. This co-infection mechanism may have relevance also to other human diseases, as there are more bacterial pathogens with alpha2,3-linked sialic acids and human viruses binding to this linkage type. PMID- 29272060 TI - Immunity against hepatitis E virus infection: Implications for therapy and vaccine development. AB - Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide and an emerging cause of chronic infection in immunocompromised patients. As with viral infections in general, immune responses are critical to determine the outcome of HEV infection. Accumulating studies in cell culture, animal models and patients have improved our understanding of HEV immunopathogenesis and informed the development of new antiviral therapies and effective vaccines. In this review, we discuss the recent progress on innate and adaptive immunity in HEV infection, and the implications for the devolopment of effective vaccines and immune-based therapies. PMID- 29272061 TI - Rare presentation of heterotopic ossification along a fibula free flap pedicle in a high-volume microvascular reconstruction practice. AB - BACKGROUND: Heterotopic ossification along free flap pedicles has been reported. Reports suggest that subperiosteal dissection of the pedicle from the bone during the harvest of the fibula free flap may predispose the pedicle to heterotopic ossification. METHODS: A 56-year-old man with history of a T2N1M0 squamous cell cancer of the left tonsil who was treated with chemoradiation developed osteoradionecrosis of the mandible requiring fibula free flap reconstruction. The patient presented with a firm submandibular mass 1 year after reconstruction. RESULTS: Imaging revealed bone along the mandible projecting to the floor of the mouth. Surgery revealed heterotopic bone along the submandibular triangle and vascular pedicle. The bone was removed and the periosteum fulgurated to prevent further proliferation. CONCLUSION: Our practice includes a high-volume head and neck extirpative and reconstruction practice. To the best of our knowledge, this represents the first documented case of heterotopic ossification along a free flap pedicle despite routine subperiosteal elevation to free the peroneal artery from the proximal fibula. PMID- 29272062 TI - Long-term effects on glycaemic control and beta-cell preservation of early intensive treatment in patients with newly diagnosed type 2 diabetes: A multicentre randomized trial. AB - AIM: To determine the effects of early intensive glycaemic control with intensive insulin treatment (IIT) or initial combined oral antidiabetic drug (COAD) therapy on long-term glycaemic control and the preservation of beta-cell function in people with type 2 diabetes mellitus (T2DM). METHODS: Newly diagnosed drug-naive patients with T2DM from 8 outpatient diabetes centres were randomized to receive either IIT (n = 50; glargine/glulisine) or COAD (n = 47; glimepiride/metformin) as intensive treatment until the termination criteria to ensure euglycaemia were met. After intensive treatment, the patients completed a follow-up period with either lifestyle modification (LSM) alone or rescue therapy to maintain target glycated haemoglobin levels of <7% (53 mmol/mol) up to week 104. The primary outcomes were analysed after excluding participants who were anti-glutamic acid decarboxylase autoantibody-positive. RESULTS: Both intensive treatment methods were effective for short-term glycaemic control, but improvements in the disposition index (DI) were significantly greater in the IIT group than in the COAD group (P = .021). During the follow-up period after intensive treatment, the two groups significantly differed in rescue method regarding the maintenance of comparable levels of glycaemic control (P = .010) and more participants who received IIT exhibited well-controlled glycaemia with LSM alone. Additionally, the IIT group maintained a higher DI than the COAD group during the follow-up period. Cox regression analysis showed that the IIT method was associated with a 52.5% lower risk of failing to maintain drug-free glycaemic remission compared with the COAD method (P = .015). CONCLUSIONS: The findings indicate that outpatient clinic-based IIT to ensure euglycaemia in newly diagnosed patients with T2DM might be an effective initial therapeutic option for improvements in beta-cell function and glycaemic control over the long term, without serious adverse events. PMID- 29272063 TI - Non-severe hypoglycaemia is associated with weight gain in patients with type 1 diabetes: Results from the Diabetes Control and Complication Trial. AB - It is unclear whether the frequent non-severe episodes of hypoglycaemia observed during intensive glucose control in individuals with type 1 diabetes (T1D) are associated with subsequent weight gain. We analysed the association between non severe hypoglycaemia and weight gain in 1441 Diabetes Control and Complication Trial (DCCT) participants. Non-severe hypoglycaemia was assessed by hypo-score (ie, number of blood glucose values <70 mg/dL divided by the total number of measurements during the DCCT quarterly visits). Significant associations were observed between the hypo-score and annual and total weight gain. The annual weight gain by hypo-score tertiles was 0.8 +/- 1.2 (T1), 1.3 +/- 1.5 (T2) and 1.4 +/- 1.3 kg/y (T3), P < .001 for T2 and T3 vs T1, and for T3 vs T2. The odds ratio for a weight gain of 1.8 kg/y was 2.14 (95% CI, 1.56-2.93) for T2, and 2.53 (95%CI, 1.85-3.45) for T3 vs T1. These differences in weight gain and in risk of weight gain remained significant after adjustment for sex, age, duration of diabetes, HbA1c at baseline and treatment arms. In conclusion, our analysis shows a significant association between non-severe hypoglycaemia and weight gain in individuals with T1D from the DCCT. PMID- 29272065 TI - High-performance liquid chromatographic enantioseparation of N-aryl thioureidoalkylphosphonates and thiourylenedi(alkylphosphonates) on polysaccharide-based chiral stationary phases. AB - The first successful enantioseparation of representative O,O-diphenyl-N arylthioureidoalkylphosphonates, (+/-)-Ptc-ValP (OPh)2 & (+/-)-Ptc-LeuP (OPh)2 and thiourylenedi(isobutyl phosphonate), Tcm[ValP (OPh)2 ]2 on analytical and semipreparative scale was achieved by high-performance liquid chromatography using polysaccharide-based chiral stationary phases (CPs). Atc-AAP (OPh)2 was obtained using modified tricomponent condensations of the corresponding aldehydes, N-arylthiourea and triphenyl phosphite whereas Tcm[ValP (OPh)2 ]2 by the condensations of aldehydes, thiourea, and triphenyl phosphite. The prepared, racemic (+/-)-Atc-AAP (OPh)2 [(+/-)-Ptc-ValP (OPh)2 , (+/-)-Ptc-LeuP (OPh)2 , (+/ )-Ptc-PglyP (OPh)2 and (+/-)-Ntc-PglyP (OPh)2 ] and racemic (+/-)-Tcm[AAP (OPh)2 ]2 [(+/-)-Tcm[NvaP (OPh)2 ]2 & (+/-)-Tcm[ValP (OPh)2 ]2 ] were adequately characterized and used for chromatographic separations on high-performance liquid chromatography-chiral stationary phases. The best results were obtained for (+/-) Ptc-ValP (OPh)2 , (+/-)-Ptc-LeuP (OPh)2 and (+/-)-Tcm[ValP (OPh)2 ]2 . PMID- 29272064 TI - Real-world evidence concerning clinical and economic outcomes of switching to insulin glargine 300 units/mL vs other basal insulins in patients with type 2 diabetes using basal insulin. AB - This retrospective cohort study compared real-world clinical and healthcare resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, March 1, 2015 to May 31, 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1819 in each). Hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced the risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of associated costs. PMID- 29272066 TI - The Hypotriglyceridemic Effect of Sciadonic Acid is Mediated by the Inhibition of Delta9-Desaturase Expression and Activity. AB - SCOPE: Sciadonic acid (Scia; 20:3Delta5,11,14) is a distinctive fatty acid (FA) with a polymethylene-interrupted double bond at C5. It is specifically found in seeds from gymnosperms such as pine nuts. Published papers describe a decrease in liver and plasma triacylglycerols in rats fed with this nutriment. The present study seeks to identify the action mechanism of Scia on triacylglycerol synthesis. In this way, its nutritional effect on FA metabolism involving the Stearoyl-CoA Desaturase 1 (SCD1) is investigated. METHODS AND RESULTS: Scia is discerned in trace amount in various tissues of rats and in human serum. It is produced by Delta5-desaturation of 20:2n-6 in human transfected SH-SY5Y cell lines and also in rat hepatocytes. When Scia is incubated with cultured hepatocytes as a nutrient, the cellular FA profile is modified. In particular, the proportion of the monoenes (18:1n-9, 18:1n-7, 16:1n-7) are all decreased, correlating to the reduction of triacylglycerol amounts. This effect is mediated by the inhibition of SCD1 expression. Furthermore, Scia, as well as 20:3n-6 and 20:3n-9 but not 20:3n-3, strongly inhibit the SCD1 activity measured on liver microsomes. CONCLUSION: Overall, this study shows that Scia, despite its unusual structure, contributes to the FA metabolism and reduced triacylglycerol release by inhibiting SCD1 activity. PMID- 29272067 TI - What is "essential" about essential tremor? A diagnostic placeholder. PMID- 29272068 TI - Camelina Sativa Oil, but not Fatty Fish or Lean Fish, Improves Serum Lipid Profile in Subjects with Impaired Glucose Metabolism-A Randomized Controlled Trial. AB - SCOPE: The aim of the study is to examine whether lean fish (LF), fatty fish (FF), and camelina sativa oil (CSO), a plant-based source of alpha-linolenic acid (ALA), differ in their metabolic effects in subjects with impaired glucose metabolism. METHODS AND RESULTS: Altogether 79 volunteers with impaired fasting glucose, BMI 25-36 kg m-2 , age 43-72 years, participated in a 12-week randomized controlled trial with four parallel groups, that is, the FF (four fish meals/week), LF (four fish meals/week), CSO (10 g d-1 ALA), and control (limited intakes of fish and sources of ALA) groups. The proportions of eicosapentaenoic acid and DHA increase in plasma lipids in the FF group, and the proportion of ALA increase in the CSO group (p < 0.0001 for all). In the CSO group, total and LDL cholesterol (C) concentrations decrease compared with the FF and LF groups; LDL C/HDL-C and ApoB/ApoA-I ratios decrease compared with the LF group. There are no significant changes in glucose metabolism or markers of low-grade inflammation. CONCLUSIONS: A diet enriched in CSO improves serum lipid profile as compared with a diet enriched in FF or LF in subjects with impaired fasting glucose, with no differences in glucose metabolism or concentrations of inflammatory markers. PMID- 29272069 TI - Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: A nationwide case series of 35 patients in The Netherlands. AB - BACKGROUND: Salivary duct carcinoma, an aggressive subtype of salivary gland cancer, is mostly androgen receptor-positive. Only limited data are available on androgen deprivation therapy (ADT). METHODS: Patients with advanced androgen receptor-positive salivary duct carcinoma treated with first-line ADT were retrospectively evaluated for clinical benefit (ie, partial response [PR] and stable disease, progression-free survival [PFS] and overall survival [OS]). The OS was compared with patients with advanced salivary duct carcinoma who received best supportive care. RESULTS: Thirty-four of 35 patients who were ADT-treated were evaluable: 6 patients had a PR (18%) and 11 had stable disease (32%) leading to a clinical benefit ratio of 50%. The median PFS for the ADT-treated patients was 4 months and the median duration of clinical benefit was 11 months. The median OS was 17 months versus 5 months in 43 patients receiving best supportive care (P = .02). CONCLUSION: We recommend ADT in advanced androgen receptor positive salivary duct carcinoma given its response and clinical benefit. (c) 2017 Wiley Periodicals, Inc. Head Neck, 2017. PMID- 29272070 TI - Absence of BRAFV600E mutation in odontogenic keratocysts. AB - BACKGROUND: Mutations in the patched 1 (PTCH1) gene are the main genetic alteration reported in sporadic and nevoid basal cell carcinoma-associated odontogenic keratocyst (OKC). Oncogenic mutations, including BRAFV600E, previously considered exclusive of malignant neoplasms have been reported in odontogenic tumors. Recently, a high frequency of BRAFV600E mutation has been reported in OKC. Because of the considerable recurrence rate of OKC, the identification of druggable genetic mutations can be relevant in the management of extensive lesions. METHODS: A set of 28 OKCs was included in this work. Initially, 10 sporadic and eight OKC samples from four NBCCS patients (a pair of lesions from each syndromic patient) were submitted to targeted next-generation sequencing (NGS) of 2800 different mutations in 50 oncogenes and tumor suppressor genes, including BRAF. Ten extra sporadic OKC samples were included to assess BRAFV600E mutation using TaqMan allele-specific qPCR. RESULTS: The following missense mutations occurred in one case each: ATM p.Ser333Phe, SMO p.Gly416Glu, PIK3CA p.Ser326Phe, FBXW7 p.Ser438Phe, JAK2 p.Ser605Phe, PTEN p.Arg173His, ATM p.Cys353Arg, PTEN p.Ser294Arg, MET p.His1112Tyr. None of the 18 samples showed the BRAFV600E (or any other V600) mutation in the NGS. BRAFV600E mutation was detected by qPCR in one of the 10 OKC. Collectively, our results show BRAFV600E mutation in 1 of 28 OKC cases. CONCLUSION: On the basis of our results, OKCs do not present recurrent hotspot mutations in these 50 genes commonly mutated in cancer. In addition, BRAFV600E does not play a central role in OKC pathogenesis. PMID- 29272071 TI - The challenge of urinary tract infections in renal transplant recipients. AB - Urinary tract infections (UTI) are an important cause of morbidity and mortality in renal transplant patients. These infections are quite common, and the goal of care is to identify and reduce risk factors while providing effective prophylaxis and treatment. Better understanding of long-term outcomes from these infections has led to the distinctions among UTI, recurrent UTI, and asymptomatic bacteriuria (ASB), and that each requires a different therapeutic approach. Specifically, new research has supported the perspective that asymptomatic bacteriuria should not be treated. Symptomatic UTI, on the other hand, requires intervention and remains an ongoing challenge for infectious disease clinicians. Many bacteria species are responsible for UTI in renal transplant patients, and in recent years there has been a global rise in infection caused by bacteria with newly acquired antibacterial resistance genes. Many renal transplant patients who experience UTI will also have multiple recurring episodes, which likely has a distinct pathophysiological mechanism leading to chronic colonization of the urinary tract. In these cases, long-term management includes bacterial suppression, which aims to reduce rather than eliminate bacteria to levels below the threshold for symptomatic infection. This review will address the current understanding of UTI epidemiology, pathogenesis, and risk factors in the renal transplant community, and also focus on current prevention and treatment strategies for patients who face an environment of increasingly antibiotic resistant bacteria. PMID- 29272072 TI - The effect on glycaemic control of low-volume high-intensity interval training versus endurance training in individuals with type 2 diabetes. AB - AIM: To evaluate whether high-intensity interval training (HIIT) with a lower time commitment can be as effective as endurance training (END) on glycaemic control, physical fitness and body composition in individuals with type 2 diabetes. MATERIALS AND METHODS: A total of 29 individuals with type 2 diabetes were allocated to control (CON; no training), END or HIIT groups. Training groups received 3 training sessions per week consisting of either 40 minutes of cycling at 50% of peak workload (END) or 10 1-minute intervals at 95% of peak workload interspersed with 1 minute of active recovery (HIIT). Glycaemic control (HbA1c, oral glucose tolerance test, 3-hour mixed meal tolerance test with double tracer technique and continuous glucose monitoring [CGM]), lipolysis, VO2 peak and body composition were evaluated before and after 11 weeks of intervention. RESULTS: Exercise training increased VO2 peak more in the HIIT group (20% +/- 20%) compared with the END group (8% +/- 9%) despite lower total energy expenditure and time usage during the training sessions. HIIT decreased whole body and android fat mass compared with the CON group. In addition, visceral fat mass, HbA1c, fasting glucose, postprandial glucose, glycaemic variability and HOMA-IR decreased after HIIT. The reduced postprandial glucose in the HIIT group was driven primarily by a lower rate of exogenous glucose appearance. In the CON group, postprandial lipolysis was augmented over the 11-week control period. CONCLUSIONS: Despite a ~45% lower training volume, HIIT resulted in similar or even better improvements in physical fitness, body composition and glycemic control compared to END. HIIT therefore appears to be an important time-efficient treatment for individuals with type 2 diabetes. PMID- 29272073 TI - Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Implications for liver transplantation. AB - Nonalcoholic fatty liver disease (NAFLD), a common cause of chronic liver disease (CLD), has a global prevalence of 25%. Its progressive form, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplantation (LT) in the United States. As a result, specialty societies, including the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver, have developed guidance on the epidemiology, diagnosis, and treatment of NAFLD and NASH. Therefore, the transplant team must be well versed in the state of current knowledge about NAFLD and transplant specific issues for this increasingly important indication for LT. Liver Transplantation 24 166-170 2018 AASLD. PMID- 29272074 TI - Prevalence of vitiligo in Brazil-A population survey. PMID- 29272075 TI - Dibenzothienopyrrolo[3,2-b]pyrrole: The Missing Member of the Thienoacene Family. AB - Dibenzothienopyrrolo[3,2-b]pyrrole and the corresponding bis(S,S-dioxide) were synthesized by using a concise synthetic strategy. Despite the presence of six fused aromatic rings, pi-expanded pyrrolo[3,2-b]pyrroles of this type absorb and emit at relatively short wavelengths, which reflects inefficient pi conjugation due to the angular arrangement of the aromatic rings. They exhibit interesting and complex electrochemical behavior, which highlights their potential in organic electronics. Both heteroacenes undergo two-stage oxidation while retaining the independence of each 1-phenyl-1H-[1]benzothieno[3,2-b]pyrrole, which was proved by in situ electron spin resonance measurements. Interestingly, electrochemically generated dicationdiradicals are not only distributed over the pyrrolo[3,2 b]pyrrole scaffold, but also over the phenyl substituents located on nitrogen atoms. PMID- 29272076 TI - GIMDA: Graphlet interaction-based MiRNA-disease association prediction. AB - MicroRNAs (miRNAs) have been confirmed to be closely related to various human complex diseases by many experimental studies. It is necessary and valuable to develop powerful and effective computational models to predict potential associations between miRNAs and diseases. In this work, we presented a prediction model of Graphlet Interaction for MiRNA-Disease Association prediction (GIMDA) by integrating the disease semantic similarity, miRNA functional similarity, Gaussian interaction profile kernel similarity and the experimentally confirmed miRNA-disease associations. The related score of a miRNA to a disease was calculated by measuring the graphlet interactions between two miRNAs or two diseases. The novelty of GIMDA lies in that we used graphlet interaction to analyse the complex relationships between two nodes in a graph. The AUCs of GIMDA in global and local leave-one-out cross-validation (LOOCV) turned out to be 0.9006 and 0.8455, respectively. The average result of five-fold cross-validation reached to 0.8927 +/- 0.0012. In case study for colon neoplasms, kidney neoplasms and prostate neoplasms based on the database of HMDD V2.0, 45, 45, 41 of the top 50 potential miRNAs predicted by GIMDA were validated by dbDEMC and miR2Disease. Additionally, in the case study of new diseases without any known associated miRNAs and the case study of predicting potential miRNA-disease associations using HMDD V1.0, there were also high percentages of top 50 miRNAs verified by the experimental literatures. PMID- 29272078 TI - A statement by the Japan-Korea expert pathologists for future clinicopathological and molecular analyses toward consensus building of intraductal papillary neoplasm of the bile duct through several opinions at the present stage. AB - Intraductal papillary neoplasm of bile duct (IPNB) was described as a preinvasive neoplastic lesion of the biliary tract in the 2010 World Health Organization (WHO) classification. Although a number of studies have since been conducted on IPNBs, controversy remains, particularly regarding the standardization of its definition. Meetings by Japanese and Korean expert pathologists were held twice to resolve the pathological diagnostic aspects of IPNB. Through round-table discussions and histological reviews, we reached the common understanding that IPNBs diagnosed according to the criteria of WHO 2010 are characterized by intraductal predominant papillary or villous biliary neoplasms covering delicate fibrovascular stalks and are classified into two types pathologically. One type (type 1 IPNB) is histologically similar to intraductal papillary mucinous neoplasms of pancreas, and typically develops in the intrahepatic bile ducts, while the other (type 2 IPNB) has a more complex histological architecture with irregular papillary branching or with foci of solid-tubular components and typically involves the extrahepatic bile ducts. This report states the diagnostic pathologic features of IPNB proposed by WHO 2010. Since currently, the concept of IPNB is still confusing, the proposed diagnostic pathologic features stated here will be of use for future clinicopathological and molecular analyses toward consensus building of IPNB. PMID- 29272077 TI - Noninvasive assessment of liver steatosis in deceased donors: A pilot study. PMID- 29272079 TI - Development of lacrimal gland spheroids for lacrimal gland tissue regeneration. AB - Severe dry eye syndrome resulting from lacrimal gland (LG) dysfunction can cause blindness, yet treatments remain palliative. In vitro reconstruction of LG tissue could provide a curative treatment. We aimed to combine epithelial cells with endothelial cells and mesenchymal stem cells (MSCs) to form a 3D functional unit. Epithelial cells and MSCs were isolated from porcine LG; endothelial cells were isolated from human foreskin. MSCs were characterised (flow cytometry and differentiation potential assays). All 3 cell types were combined on Matrigel and spheroid formation observed. Spheroids were characterised [immunohistochemistry (IHC) and transmission electron microscopy] and function assessed (beta hexosaminidase assay). Spheroids were transferred to decellularised jejunum (SIS Muc) in dynamic cultures for 1 week before further characterisation. MSCs did not express CD31 but expressed CD44 and CD105 and differentiated towards osteogenic and adipogenic lineages. Spheroids formed on Matrigel within 18 hr, contracting to ~10% of the well area (p < .005). IHC revealed presence of all 3 cells within spheroids. Transmission electron microscopy revealed cell-cell contacts and polarisation at the apical surface. In static cultures, function was increased in spheroids cf. monolayer controls (p < .05) but over 72 hr, spheroid function (p < .05), viability (p < .05), and proliferation decreased, whilst apoptosis increased. On SIS-Muc under dynamic culture, however, spheroids continued to proliferate to repopulate SIS-Muc. IHC revealed LG epithelial cells coexpressing pan-cytokeratin and lysozyme, as well as endothelial cells and MSCs and cells remained capable of responding to carbachol (p < .05). These spheroids could form the basis of a regenerative medicine treatment approach for dry eye syndrome. In vivo studies are required to evaluate this further. PMID- 29272080 TI - Nanomechanics of actin filament: A molecular dynamics simulation. AB - Actin is known as the most abundant essentially protein in eukaryotic cells. Actin plays a crucial role in many cellular processes involving mechanical forces such as cell motility, adhesion, muscle contraction, and intracellular transport. However, little is known about the mechanical properties of this protein when subjected to mechanical forces in cellular processes. In this article, a series of large-scale molecular dynamics simulations are carried out to elucidate nanomechanical behavior such as elastic and viscoelastic properties of a single actin filament. Here, we used two individual methods namely, all-atoms and coarse grained molecular dynamics, to evaluate elastic properties of a single actin filament. In the other word, based on Brownian motions of the filament and using the principle of the equipartition theorem, in aqueous solution, tensile stiffness, torsional rigidity, and bending rigidity of the single actin filament are studied. The results revealed that increasing the sampling window time leads to convergence of obtained mechanical properties to the experimental values. Moreover, in order to investigate viscoelastic properties of a single actin filament, constant force steered molecular dynamics method is used to apply different external tensile loads and perform five individual creep tests on the molecule. The strain-time response of the filament for each creep test is obtained. Based on the Kelvin-Voigt model, the results reveal that a single actin filament shows a nonlinear viscoelastic behavior, with a Young's modulus of 2.85 GPa, a viscosity of 4.06 GPa.ns, and a relaxation time in the range of 1.42 ns which were measured here for the first time at the single filament level. The findings of this article suggest that molecular dynamics simulations could also be a useful tool for investigating the mechanical behavior of bio-nanomaterials. PMID- 29272081 TI - Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association. AB - The glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials and systematic reviews. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA. PMID- 29272082 TI - Simple Screening Using Ultrasonography for Prediction of Gestational Diabetes Mellitus. PMID- 29272084 TI - Letter: Features of Long-Standing Korean Type 2 Diabetes Mellitus Patients with Diabetic Retinopathy: A Study Based on Standardized Clinical Data (Diabetes Metab J 2017;41:393-404). PMID- 29272083 TI - Association of Self-Care Behaviors and Quality of Life among Patients with Type 2 Diabetes Mellitus: Chaldoran County, Iran. AB - BACKGROUND: Self-care of diabetes is an essential part for controlling the disease and improvement of quality of life in type 2 diabetes mellitus (T2DM) patients. This study aimed to analyze the associated factors of quality of life in patients with T2DM in order to design effective interventions. METHODS: This cross-sectional study was conducted on 120 T2DM patients referred to health centers of Chaldoran, West Azerbaijan Province, Iran. The quality of life's questionnaires from World Health Organization and the self-care behaviors' questionnaires were used for data collection. RESULTS: The mean age of patients was 46.30% and 53.30% of them were male. Among demographic variables, gender (P=0.002), age groups (P=0.007), and household monthly income (P=0.009) were significantly associated with total quality of life. Also, self-care nutrition (odds ratio [OR], 1.47; P=0.001), self-management of blood glucose control (OR, 1.29; P=0.002), and self-medication behavior (OR, 1.18; P=0.030) were identified as factors significantly associated with quality of life. CONCLUSION: Self-care behaviors were significantly associated with quality of life; among them, the greatest influence was observed in self-care nutrition behavior. According to the findings of this study, appropriate interventions on self-care behaviors about nutrition can improve the quality of life for T2DM patients. PMID- 29272085 TI - Response: Features of Long-Standing Korean Type 2 Diabetes Mellitus Patients with Diabetic Retinopathy: A Study Based on Standardized Clinical Data (Diabetes Metab J 2017;41:393-404). PMID- 29272086 TI - Acquisition of a Digital Intraoral Scanning Device: An Examination of Practice Volume Changes and the Economic Impact via an Interrupted Time Series Analysis. AB - OBJECTIVES: To evaluate the impact of digital scanning in general dental practices and orthodontic practices to determine the percentage of lift, i.e., the percent increase in gross receipts, of Invisalign(r) treatment starts following the introduction of an iTero(r) intraoral scanner. METHODS: An interrupted time series analysis was conducted on 48 months (24 pre- and 24 post scanner introduction) of Invisalign receipt data from 1,871 general practitioner (GP) and orthodontic practices located worldwide. Analyses also explored the presence of a longer shift in the trend of monthly Invisalign receipts after scanner introduction (i.e., pre-post slope change), and projected the impact of the introduction of the scanner within a specific subset of practices (n = 319) that represented North American GPs with low initial practice volumes (i.e., 5 or fewer receipts in the 12 months prior to acquiring the scanner). RESULTS: For the entire sample, introduction of the iTero intraoral scanner at month 25 showed a significant and abrupt increase in receipts for Invisalign therapy (b = 0.49; p < 0.001). When compared to the counterfactual regression line prediction without the scanner, in month 25 Invisalign practice receipts increased from the predicted value of 2.38 to 2.88, an increase of 20.71%. When the analysis was conducted using only low-volume GP practices in North America, the introduction of the scanner at month 25 also led to a significant and abrupt increase in practice receipts (b = 0.28; p < 0.001), and this increase was still evident 24 months after scanner introduction. CONCLUSIONS: The results show that acquiring an iTero intraoral scanner as a precursor to Invisalign therapy is associated with a significant increase in Invisalign practice receipts. When projected across the first 12 months, this increase amounts to an additional 5.92 receipts for the entire sample (i.e., 1,871 GP and orthodontic practices worldwide) and an additional 3.41 receipts for the subset of 319 low-volume, North American GPs. PMID- 29272087 TI - ANMF'S AGED CARE STAFFING AND SKILL MIX PROJECT. AB - The Australian Nursing and Midwifery Federation (ANMF) recently published the National Aged Care Staffing and Skills Mix Project Report 2016 -- Meeting residents' care needs: A study of the requirement for nursing and personal care staff, it commissioned. Conducted over the past two years the results have been integral to building the foundation of the ANMF's national aged care campaign. PMID- 29272088 TI - WORKPLACE BULLYING. AB - The ANMF's CPE website has had a major makeover including the inclusion of new topics for you to utilize towards your CPD requirements for registration in May. All existing topics have been audited and updated so you can be sure you are getting the latest information. PMID- 29272089 TI - IMMERSIVE MENTAL HEALTH SIMULATION HELPS STUDENTS WITH CHALLENGING CONVERSATIONS. AB - Simulation within nursing education is becoming a popular means of facilitating competency, where there is a tendency for this to focus on the acquisition and development of clinical and technical skills. PMID- 29272090 TI - UNITING CULTURAL PRACTICES AND SAFE SLEEP ENVIRONMENTS FOR VULNERABLE INDIGENOUS AUSTRALIAN INFANTS. AB - Sudden unexpected death in infancy (SUDI) is four times higher for Aboriginal and Torres Strait Islander babies compared to non-indigenous babies (Commission for Children and Young People and Child Guardian 2014). Co-sleeping is a culturally valued practice used by many indigenous families however is associated with an increased risk of infant death in hazardous circumstances (Venneman et al. 2012; Blair et al. 2014). PMID- 29272091 TI - ARE CLOSING THE GAP TARGETS BEING MET? AB - Long term strategies to improve the health and wellbeing of communities need to remain the central focus of government despite any changes in political power and political priorities. PMID- 29272092 TI - INDIGENOUS NURSING WORKFORCE, TO ACHIEVE EQUALITY IN HEALTHCARE SERVICES. AB - Inequities and poor health outcomes of Aboriginal people in Western Australia are well documented. Indigenous Australians continue to experience poorer health and higher death rates than non-indigenous Australians (AHW 2008). PMID- 29272093 TI - COLLABORATION AND CULTURAL SAFETY: SAFE SLEEP SPACE ALTERNATIVES WITH ABORIGINAL FAMILIES. AB - Despite a marked reduction in Aboriginal and Torres Strait Islander infant deaths from 1998 to 2012 (AIHW 2015) Aboriginal and Torres Strait Islander infants remain over-represented in sudden and unexpected infant death rates. PMID- 29272094 TI - Titanate Fibroin Nanocomposites: A Novel Approach for the Removal of Heavy-Metal Ions from water. AB - In this study, we report the fabrication of nanocomposites made of titanate nanosheets immobilized in a solid matrix of regenerated silk fibroin as novel heavy-metal-ion removal systems. The capacity of these nanocomposite films to remove lead, mercury, and copper cations from water was investigated, and as shown by the elemental quantitative analysis performed, their removal capacity is 73 mmol/g for all of the ions tested. We demonstrate that the nanocomposites can efficiently retain the adsorbed ions, with no release of titanate nanosheets occurring even after several exposure cycles to ionic solutions, eliminating the risk of release of potentially hazardous nanosubstances to the environment. We also prove that the introduction of sodium ions in the nanocomposite formulation makes the materials highly selective toward the lead ions. The developed biopolymer nanocomposites can be potentially used for the efficient removal of heavy-metal-ion pollutants from water and, thanks to their physical and optical characteristics, offer the possibility to be used in sensor applications. PMID- 29272095 TI - Hyaluronic Acid-Shelled Disulfide-Cross-Linked Nanopolymersomes for Ultrahigh Efficiency Reactive Encapsulation and CD44-Targeted Delivery of Mertansine Toxin. AB - It was and remains a big challenge for cancer nanomedicines to achieve high and stable drug loading with fast drug release in the target cells. Here, we report on novel hyaluronic acid-shelled disulfide-cross-linked biodegradable polymersomes (HA-XPS) self-assembled from hyaluronic acid-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) diblock copolymer for ultrahigh efficiency reactive encapsulation and CD44-targeted delivery of mertansine (DM1) toxin, a highly potent warhead for clinically used antibody-drug conjugates. Remarkably, HA-XPS showed quantitative encapsulation of DM1 even with a high drug loading content of 16.7 wt %. DM1-loaded HA-XPS (HA-XPS-DM1) presented a small size of ~80 nm, low drug leakage under physiological conditions, and fast glutathione-triggered drug release. MTT assays revealed that HA-XPS was noncytotoxic while HA-XPS-DM1 was highly potent to MDA-MB-231 cells with an IC50 comparable to that of free DM1. The in vitro and in vivo inhibition experiments indicated that HA-XPS could actively target MDA-MB-231 cells. Notably, HA-XPS-DM1 while causing little adverse effect could effectively inhibit tumor growth and significantly prolong survival time in MDA-MB-231 human breast tumor-bearing mice. HA-XPS-DM1 provides a novel and unique treatment for CD44-positive cancers. PMID- 29272096 TI - Surface Grafting of Ru(II) Diazonium-Based Sensitizers on Metal Oxides Enhances Alkaline Stability for Solar Energy Conversion. AB - The electrografting of [Ru(ttt)(tpy-C6H4-N2+)]3+, where "ttt" is 4,4',4"-tri-tert butyl-2,2':6',2"-terpyridine, was investigated on several wide band gap metal oxide surfaces (TiO2, SnO2, ZrO2, ZnO, In2O3:Sn) and compared to structurally analogous sensitizers that differed only by the anchoring group, i.e., -PO3H2 and -COOH. An optimized procedure for diazonium electrografting to semiconductor metal oxides is presented that allowed surface coverages that ranged between 4.7 * 10-8 and 10.6 * 10-8 mol cm-2 depending on the nature of the metal oxide. FTIR analysis showed the disappearance of the diazonium stretch at 2266 cm-1 after electrografting. XPS analysis revealed a characteristic peak of Ru 3d at 285 eV as well as a peak at 531.6 eV that was attributed to O 1s in Ti-O-C bonds. Photocurrents were measured to assess electron injection efficiency of these modified surfaces. The electrografted sensitizers exhibited excellent stability across a range of pHs spanning from 1 to 14, where classical binding groups such as carboxylic and phosphonic derivatives were hydrolyzed. PMID- 29272097 TI - Rational-Differential Design of Highly Specific Glycomimetic Ligands: Targeting DC-SIGN and Excluding Langerin Recognition. AB - At the surface of dendritic cells, C-type lectin receptors (CLRs) allow the recognition of carbohydrate-based PAMPS or DAMPS (pathogen- or danger-associated molecular patterns, respectively) and promote immune response regulation. However, some CLRs are hijacked by viral and bacterial pathogens. Thus, the design of ligands able to target specifically one CLR, to either modulate an immune response or to inhibit a given infection mechanism, has great potential value in therapeutic design. A case study is the selective blocking of DC-SIGN, involved notably in HIV trans-infection of T lymphocytes, without interfering with langerin-mediated HIV clearance. This is a challenging task due to their overlapping carbohydrate specificity. Toward the rational design of DC-SIGN selective ligands, we performed a comparative affinity study between DC-SIGN and langerin with natural ligands. We found that GlcNAc is recognized by both CLRs; however, selective sulfation are shown to increase the selectivity in favor of langerin. With the combination of site-directed mutagenesis and X-ray structural analysis of the langerin/GlcNS6S complex, we highlighted that 6-sulfation of the carbohydrate ligand induced langerin specificity. Additionally, the K313 residue from langerin was identified as a critical feature of its binding site. Using a rational and a differential approach in the study of CLR binding sites, we designed, synthesized, and characterized a new glycomimetic, which is highly specific for DC-SIGN vs langerin. STD NMR, SPR, and ITC characterizations show that compound 7 conserved the overall binding mode of the natural disaccharide while possessing an improved affinity and a strict specificity for DC-SIGN. PMID- 29272098 TI - Stable and Reversible Lithium Storage with High Pseudocapacitance in GaN Nanowires. AB - In this work, gallium nitride (GaN) nanowires (NWs) were synthesized by chemical vapor deposition (CVD) process. The hybrid electrode showed the capacity up to 486 mAh g-1 after 400 cycles at 0.1 A g-1. Even at 10 A g-1, the reversible capacity can stabilize at 75 mAh g-1 (after 1000 cycles). Pseudocapacitive capacity was defined by kinetics analysis. The dynamics analysis and electrochemical reaction mechanism of GaN with Li+ was also analyzed by ex situ XRD, HRTEM, and XPS results. These results not only cast new light on pseudocapacitance enhanced high-rate energy storage devices by self-assembled nanoengineering but also extend the application range of traditional binary III/V semiconductors. PMID- 29272099 TI - Electrospun Hydrophilic Janus Nanocomposites for the Rapid Onset of Therapeutic Action of Helicid. AB - The oral delivery of active ingredients for the fast onset of therapeutic effects is a well-known method in patients. In this study, a new kind of hydrophilic Janus structural nanocomposite was designed for the rapid dissolution and transmembrane permeation of helicid, an herbal medicine with poor water solubility. A side-by-side electrospinning process characterized by an eccentric spinneret was developed to fabricate the Janus nanocomposites. The morphology, inner structure, incorporated components and their physical states, hydrophilicity, and functional performances of the Janus nanocomposites were investigated. The experimental results demonstrated that an unspinnable fluid (polyvinylpyrrolidone K10-sodium dodecyl sulfate) could be simultaneously treated with an electrospinnable fluid (polyvinylpyrrolidone K90-helicid) to create Janus structural nanocomposites. The prepared Janus nanofibers exhibited linear morphology and notable side-by-side inner structure with all the incorporated components present in an amorphous state. Both the control of monolithic nanocomposites and the Janus composites can provide more than 10-fold the transmembrane rates of crude helicid particles. Compared with monolithic nanocomposites, the Janus nanocomposites exhibited improved hydrophilicity and can further promote the dissolution and transmembrane permeation of helicid for a potentially faster onset of therapeutic actions. The generation mechanisms and functional performance of Janus nanocomposites were suggested. The preparation protocols reported here can provide a useful approach for designing and developing new functional nanocomposites in the form of Janus structures. Meanwhile, the medicated hydrophilic Janus nanocomposites represent a newly developed kind of nano drug delivery system for the fast onset of therapeutic action of orally administered water-insoluble drugs. PMID- 29272100 TI - Rapid Analysis of Unsaturated Fatty Acids on Paper-Based Analytical Devices via Online Epoxidation and Ambient Mass Spectrometry. AB - In this work, we demonstrate a novel design that allows rapid online identification and quantitation of unsaturated fatty acid C?C location isomers via epoxidation and ambient mass spectrometry (MS). Unsaturated fatty acid solution was loaded on a paper strip placed between a low-temperature plasma probe and the inlet of a mass spectrometer. Reactive oxygen species in the plasma promoted epoxidation at the C?C, and the product was simultaneously ionized. Upon collision-induced dissociation (CID), the epoxidation product was fragmented to release diagnostic ions specific to the C?C location. The whole analytical workflow can be completed within 5 s and is particularly promising for point-of care (POC) clinical diagnosis, considering its fast, high-throughput nature, and coupling with paper-based analytical devices. PMID- 29272101 TI - Printed Thin Magnetic Films Based on Diblock Copolymer and Magnetic Nanoparticles. AB - Printing techniques have been well established for large-scale production and have developed to be effective in controlling the morphology and thickness of the film. In this work, printing is employed to fabricate magnetic thin films composed of polystyrene coated maghemite nanoparticles (gamma-Fe2O3 NPs) and polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) diblock copolymer. By applying an external magnetic field during the print coating step, oriented structures with a high content of nanoscale magnetic particles are created. The morphology of the magnetic films and the arrangement of NPs within the polymer matrix are characterized with real and reciprocal space techniques. Due to the applied magnetic field, the magnetic NPs self-assemble into microscale sized wires with controlled widths and separation distances, endowing hybrid films with a characteristic magnetic anisotropy. At the nanoscale level, due to the PS coating, the NPs disperse as single particles at low NP concentrations. The NPs self-assemble into nanosized clusters inside the PS domains when the NP concentration increases. Due to a high loading of uniformly dispersed magnetic NPs across the whole printed film, a strong sensitivity to an external magnetic field is achieved. The enhanced superparamagnetic property of the printed films renders them promising candidate materials for future magnetic sensor applications. PMID- 29272102 TI - Lithium-Sulfur Capacitors. AB - Although many existing hybrid energy storage systems demonstrate promising electrochemical performances, imbalances between the energies and kinetics of the two electrodes must be resolved to allow their widespread commercialization. As such, the development of a new class of energy storage systems is a particular challenge, since future systems will require a single device to provide both a high gravimetric energy and a high power density. In this context, we herein report the design of novel lithium-sulfur capacitors. The resulting asymmetric systems exhibited energy densities of 23.9-236.4 Wh kg-1 and power densities of 72.2-4097.3 W kg-1, which are the highest reported values for an asymmetric system to date. This approach involved the use of a prelithiated anode and a hybrid cathode material exhibiting anion adsorption-desorption in addition to the electrochemical reduction and oxidation of sulfur at almost identical rates. This novel strategy yielded both high energy and power densities, and therefore establishes a new benchmark for hybrid systems. PMID- 29272103 TI - Improved Precursor Characterization for Data-Dependent Mass Spectrometry. AB - Modern ion trap mass spectrometers are capable of collecting up to 60 tandem MS (MS/MS) scans per second, in theory providing acquisition speeds that can sample every eluting peptide precursor presented to the MS system. In practice, however, the precursor sampling capacity enabled by these ultrafast acquisition rates is often underutilized due to a host of reasons (e.g., long injection times and wide analyzer mass ranges). One often overlooked reason for this underutilization is that the instrument exhausts all the peptide features it identifies as suitable for MS/MS fragmentation. Highly abundant features can prevent annotation of lower abundance precursor ions that occupy similar mass-to-charge (m/z) space, which ultimately inhibits the acquisition of an MS/MS event. Here, we present an advanced peak determination (APD) algorithm that uses an iterative approach to annotate densely populated m/z regions to increase the number of peptides sampled during data-dependent LC-MS/MS analyses. The APD algorithm enables nearly full utilization of the sampling capacity of a quadrupole-Orbitrap-linear ion trap MS system, which yields up to a 40% increase in unique peptide identifications from whole cell HeLa lysates (approximately 53 000 in a 90 min LC-MS/MS analysis). The APD algorithm maintains improved peptide and protein identifications across several modes of proteomic data acquisition, including varying gradient lengths, different degrees of prefractionation, peptides derived from multiple proteases, and phosphoproteomic analyses. Additionally, the use of APD increases the number of peptides characterized per protein, providing improved protein quantification. In all, the APD algorithm increases the number of detectable peptide features, which maximizes utilization of the high MS/MS capacities and significantly improves sampling depth and identifications in proteomic experiments. PMID- 29272105 TI - Pseudocapacitive Coating for Effective Capacitive Deionization. AB - Capacitive deionization (CDI) features a low-cost and energy-efficient desalination approach based on electrosorption of saline ions. To enhance the salt electrosorption capacity of CDI electrodes, we coat ion-selective pseudocapacitive layers (MnO2 and Ag) onto porous carbon electrodes (activated carbon cloth) with only minimal use of a conductive additive and a polymer binder (<1 wt % in total). Optimized pseudocapacitive electrodes result in excellent single-electrode specific capacitance (>300 F/g) and great cell stability (70% retention after 500 cycles). A CDI cell out of these pseudocapacitive electrodes yields as high charge efficiency as 83% and a remarkable salt adsorption capacity up to 17.8 mg/g. Our finding of outstanding CDI performance of the pseudocapacitive electrodes with no use of costly ion-exchange membranes highlights the significant role of a pseudocapacitive layer in the electrosorption process. PMID- 29272104 TI - Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich's Ataxia. AB - Friedreich's ataxia (FA) is an autosomal recessive disease caused by an intronic GAA triplet expansion in the FXN gene, leading to reduced expression of the mitochondrial protein frataxin. FA is estimated to affect 1 in 50 000 with a mean age of death in the fourth decade of life. There are no approved treatments for FA, although experimental approaches, which involve up-regulation or replacement of frataxin protein, are being tested. Frataxin is undetectable in serum or plasma, and whole blood cannot be used because it is present in long-lived erythrocytes. Therefore, an assay was developed for analyzing frataxin in platelets, which have a half-life of 10 days. The assay is based on stable isotope dilution immunopurification two-dimensional nano-ultra high performance liquid chromatography/parallel reaction monitoring/mass spectrometry. The lower limit of quantification was 0.078 pg frataxin/MUg protein, and the assay had 100% sensitivity and specificity for discriminating between controls and FA cases. The mean levels of control and FA platelet frataxin were 9.4 +/- 2.6 and 2.4 +/- 0.6 pg/MUg protein, respectively. The assay should make it possible to rigorously monitor the effects of therapeutic interventions on frataxin expression in this devastating disease. PMID- 29272106 TI - Electronic and Steric Tuning of a Prototypical Piano Stool Complex: Rh(III) Catalysis for C-H Functionalization. AB - The history of transition metal catalysis is heavily steeped in ligand design, clearly demonstrating the importance of this approach. The intimate relationship between metal and ligand can profoundly affect the outcome of a reaction, often impacting selectivity, physical properties, and the lifetime of a catalyst. Importantly, this metal-ligand relationship can provide near limitless opportunities for reaction discovery. Over the past several years, transition metal-catalyzed C-H bond functionalization reactions have been established as a critical foundation in organic chemistry that provides new bond forming strategies. Among the d-block elements, palladium is arguably one of the most popular metals to accomplish such transformations. One possible explanation for this achievement could be the broad set of phosphine and amine based ligands available in the chemist's toolbox compatible with palladium. In parallel, other metals have been investigated for C-H bond functionalization. Among them, pentamethylcyclopentadienyl (Cp*) Rh(III) complexes have emerged as a powerful mode of catalysis for such transformations providing a broad spectrum of reactivity. This approach possesses the advantage of often very low catalyst loading, and reactions are typically performed under mild conditions allowing broad functional group tolerance. Cp*Rh(III) is considered as a privileged catalyst and a plethora of reactions involving a C-H bond cleavage event have been developed. The search for alternative cyclopentadienyl based ligands has been eclipsed by the tremendous effort devoted to exploring the considerable scope of reactions catalyzed by Cp*Rh(III) complexes, despite the potential of this strategy for enabling reactivity. Thus, ligand modification efforts in Rh(III) catalysis have been an exception and research directed toward new rhodium catalysts has been sparse. Recently, chiral cyclopentadienyl ligands have appeared allowing enantioselective Rh(III)-catalyzed C-H functionalization reactions to be performed. Alongside chiral ligands, an equally important collection of achiral cyclopentadienyl-derived ligands have also emerged. The design of this new set of ligands for rhodium has already translated to significant success in solving inherent problems of reactivity and selectivity encountered throughout the development of new Rh(III)-catalyzed transformations. This Account describes the evolution of cyclopentadienyl ligand skeletons in Rh(III)-catalysis since the introduction of pentamethylcyclopentadienyl ligands to the present. Specific emphasis is placed on reactivity and synthetic applications achieved with the new ligands with the introduction of achiral mono , di-, or pentasubstituted cyclopentadienyl ligands exhibiting a stunning effect on reactivity and selectivity. Furthermore, an underlying question when dealing with ligand modification strategies is to explain the reason one ligand outperforms another. Conjecture and speculation abound, but extensive characterization of their steric and electronic properties has been carried out and information about electronic and steric properties of the ligands all contribute to our understanding and give crucial pieces to solve the puzzle. PMID- 29272108 TI - HU-331 and Oxidized Cannabidiol Act as Inhibitors of Human Topoisomerase IIalpha and beta. AB - Topoisomerase II is a critical enzyme in replication, transcription, and the regulation of chromatin topology. Several anticancer agents target topoisomerases in order to disrupt cell growth. Cannabidiol is a major non-euphoriant, pharmacologically active component of cannabis. Previously, we examined the cannabidiol derivative HU-331 in order to characterize the mechanism of the compound against topoisomerase IIalpha. In this current work, we explore whether cannabidiol (CBD) impacts topoisomerase II activity, and we additionally examine the activity of these compounds against topoisomerase IIbeta. CBD does not appear to strongly inhibit DNA relaxation and is not a poison of topoisomerase II DNA cleavage. However, oxidation of CBD allows this compound to inhibit DNA relaxation by topoisomerase IIalpha and beta without poisoning DNA cleavage. Additionally, we found that oxidized CBD, similar to HU-331, inhibits ATP hydrolysis and can result in inactivation of topoisomerase IIalpha and beta. We also determined that oxidized CBD and HU-331 are both able to stabilize the N terminal clamp of topoisomerase II. Taken together, we conclude that while CBD does not have significant activity against topoisomerase II, both oxidized CBD and HU-331 are active against both isoforms of topoisomerase II. We hypothesize that oxidized CBD and HU-331 act against the enzyme through interaction with the N-terminal ATPase domain. According to the model we propose, topoisomerase II inactivation may result from a decrease in the ability of the enzyme to bind to DNA when the compound is bound to the N-terminus. PMID- 29272107 TI - Structural Evidence of a Major Conformational Change Triggered by Substrate Binding in DapE Enzymes: Impact on the Catalytic Mechanism. AB - The X-ray crystal structure of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase from Haemophilus influenzae (HiDapE) bound by the products of hydrolysis, succinic acid and l,l-DAP, was determined at 1.95 A. Surprisingly, the structure bound to the products revealed that HiDapE undergoes a significant conformational change in which the catalytic domain rotates ~50 degrees and shifts ~10.1 A (as measured at the position of the Zn atoms) relative to the dimerization domain. This heretofore unobserved closed conformation revealed significant movements within the catalytic domain compared to that of wild-type HiDapE, which results in effectively closing off access to the dinuclear Zn(II) active site with the succinate carboxylate moiety bridging the dinculear Zn(II) cluster in a MU-1,3 fashion forming a bis(MU-carboxylato)dizinc(II) core with a Zn-Zn distance of 3.8 A. Surprisingly, His194.B, which is located on the dimerization domain of the opposing chain ~10.1 A from the dinuclear Zn(II) active site, forms a hydrogen bond (2.9 A) with the oxygen atom of succinic acid bound to Zn2, forming an oxyanion hole. As the closed structure forms upon substrate binding, the movement of His194.B by more than ~10 A is critical, based on site-directed mutagenesis data, for activation of the scissile carbonyl carbon of the substrate for nucleophilic attack by a hydroxide nucleophile. Employing the HiDapE product-bound structure as the starting point, a reverse engineering approach called product-based transition-state modeling provided structural models for each major catalytic step. These data provide insight into the catalytic reaction mechanism and also the future design of new, potent inhibitors of DapE enzymes. PMID- 29272109 TI - Unraveling the Mechanisms of Visible Light Photocatalytic NO Purification on Earth-Abundant Insulator-Based Core-Shell Heterojunctions. AB - Earth-abundant insulators are seldom exploited as photocatalysts. In this work, we constructed a novel family of insulator-based heterojunctions and demonstrated their promising applications in photocatalytic NO purification, even under visible light irradiation. The heterojunction formed between the insulator SrCO3 and the photosensitizer BiOI, via a special SrCO3-BiOI core-shell structure, exhibits an enhanced visible light absorbance between 400-600 nm, and an unprecedentedly high photocatalytic NO removal performance. Further density functional theory (DFT) calculations and X-ray photoelectron spectroscopy (XPS) analysis revealed that the covalent interaction between the O 2p orbital of the insulator (SrCO3, n-type) and the Bi 6p orbital of photosensitizer (BiOI, p-type) can provide an electron transfer channel between SrCO3 and BiOI, allowing the transfer of the photoexcited electrons from the photosensitizer to the conduction band of insulator (confirmed by charge difference distribution analysis and time resolved fluorescence spectroscopy). The *O2- and *OH radicals are the main reactive species in photocatalytic NO oxidation. A reaction pathway study based on both in situ FT-IR and molecular-level simulation of NO adsorption and transformation indicates that this heterojunction can efficiently transform NO to harmless nitrate products via the NO -> NO+ and NO2+ -> nitrate or nitrite routes. This work provides numerous opportunities to explore earth-abundant insulators as visible-light-driven photocatalysts, and also offers a new mechanistic understanding of the role of gas-phase photocatalysis in controlling air pollution. PMID- 29272110 TI - Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection. AB - Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compounds. The binding constants (Kd) determined by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities determined by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors. PMID- 29272111 TI - Simulation of Surface Resonant X-ray Diffraction. AB - We present an ab initio numerical tool to simulate surface resonant X-ray diffraction experiments. The crystal truncation rods and the spectra around a given X-ray absorption edge are calculated at any position of the reciprocal space. Density functional theory is used to determine the resonant scattering factor of an atom within its local environment and to calculate the diffraction peak intensities for surfaces covered with a thin film or with one or several adsorbed layers. Besides the sample geometry, the collected data also depend on several parameters, such as beam polarization and incidence and exit angles. In order to account for these factors, a numerical diffractometer mimicking the experimental operation modes has been created. Finally two case studies are presented in order to compare our simulations with experimental spectra: (i) a magnetite thin film deposited on a silver substrate and (ii) an electrochemical interface consisting of bromine atoms adsorbed on copper. PMID- 29272112 TI - The Structure and Composition Statistics of 6A Binary and Ternary Crystalline Materials. AB - The fundamental principles underlying the arrangement of elements into solid compounds with an enormous variety of crystal structures are still largely unknown. This study presents a general overview of the structure types appearing in an important subset of the solid compounds, i.e., binary and ternary compounds of the 6A column oxides, sulfides and selenides. It contains an analysis of these compounds, including the prevalence of various structure types, their symmetry properties, compositions, stoichiometries and unit cell sizes. It is found that these compound families include preferred stoichiometries and structure types that may reflect both their specific chemistry and research bias in the available empirical data. Identification of nonoverlapping gaps and missing stoichiometries in these structure populations may be used as guidance in the search for new materials. PMID- 29272113 TI - A New, General Strategy for Fabricating Highly Concentrated and Viscoplastic Suspensions Based on a Structural Approach To Modulate Interparticle Interaction. AB - We report a general strategy to fabricate highly concentrated, viscoplastic and stable suspensions by designing the particle surface structure to control the interparticle attractive forces. Unlike conventional methods, where the choice of solvent is critical in balancing interparticle interactions, suspensions showing excellent stability and viscoplastic properties were made using various solvents. We demonstrated this approach using highly sparse agglomerates of carbon nanotubes (CNTs) as the particles. Our results revealed that the essential feature of the CNT agglomerate to fabricate these suspensions was high porosity with a spacing size much smaller than the overall size, which was only possible using long single-walled carbon nanotubes (SWNTs). In this way, the agglomerate surface was characterized by fine network of CNT bundles. These suspensions exhibited solid-like behavior at rest (characterized by a high yield stress of c.a. 100 Pa) and a liquid-like behavior when subjected to a stress (characterized by a significant drop of an apparent viscosity to 1 Pa.s at a shear rate of 1000 s-1). Furthermore, in contrast to conventionally fabricated suspensions, these "CNT pastes" exhibited exceptional stability at rest, under flow, and at extremely high concentrations during the drying process, with only a weakly observable dependence on solvent type. As a result, highly uniform micrometer thick SWNT films were successfully fabricated by dried blade-coated films of these pastes. Finally, we developed a simple, semiempirical model and clarified the importance of the CNT agglomerate microstructure (the ratio of spacing size/particle size and porosity) on tailoring the cohesive forces between particles to fabricate stable viscoplastic suspensions. PMID- 29272114 TI - Endosomal Escape and Delivery of CRISPR/Cas9 Genome Editing Machinery Enabled by Nanoscale Zeolitic Imidazolate Framework. AB - CRISPR/Cas9 is a combined protein (Cas9) and an engineered single guide RNA (sgRNA) genome editing platform that offers revolutionary solutions to genetic diseases. It has, however, a double delivery problem owning to the large protein size and the highly charged RNA component. In this work, we report the first example of CRISPR/Cas9 encapsulated by nanoscale zeolitic imidazole frameworks (ZIFs) with a loading efficiency of 17% and enhanced endosomal escape promoted by the protonated imidazole moieties. The gene editing potential of CRISPR/Cas9 encapsulated by ZIF-8 (CC-ZIFs) is further verified by knocking down the gene expression of green fluorescent protein by 37% over 4 days. The nanoscale CC-ZIFs are biocompatible and easily scaled-up offering excellent loading capacity and controlled codelivery of intact Cas9 protein and sgRNA. PMID- 29272115 TI - Memory of Chirality Concept in Asymmetric Intermolecular Michael Addition of alpha-Amino Ester Enolates to Enones and Nitroalkenes. AB - A highly stereoselective asymmetric intermolecular conjugate addition of alpha amino ester derivatives to cyclic enones via the memory of chirality (MOC) concept in high yields with excellent diastereo- and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability and the generality of the strategy was demonstrated by its further exploration to acyclic alpha,beta unsaturated ketone and aromatic nitroalkenes, resulting in the formation of delta keto-alpha-amino ester derivative and gamma-nitro-alpha-amino ester derivatives, respectively, with excellent ee and dr. PMID- 29272117 TI - Crystal Engineering in Supramolecular Polyoxometalate Hybrids through pH Controlled in Situ Ligand Hydrolysis. AB - A family of five different three-dimensional polyoxometalate (POM) based supramolecular hybrids were synthesized by a hydrothermal route under different pH using a hydrolyzable naphthalene diimide ligand. The mechanism of crystallographic phase variation of the POM-amino pyridine hybrids under different pH was studied through controlled experiments where the final hydrolyzed products were analyzed through NMR and single crystal X-ray diffraction. Different pH conditions led to variation in the extent of protonation and hydrolyzation of the ligand, yielding different phases. All of these were identified, and the structures of the supramolecular hybrids were characterized extensively. Mechanistic study proved that only the reaction conditions are responsible for the hydrolysis of the ligand and the in situ generated POM species do not have any role in it. Magnetic measurements confirmed the hexavalent oxidation states of the transition metal center (Mo) in the POM. Optical band gap measurements revealed that these hybrids are semiconducting in nature. Two of the compounds were studied for hydrogen peroxide mediated selective oxidation catalysis of small organic molecules and found to exhibit very good activity with high percentage of selectivity for the desired products of industrial importance. PMID- 29272118 TI - Mechanism and cis/trans Selectivity of Vinylogous Nazarov-type [6pi] Photocyclizations ?. AB - Vinylogous Nazarov-type cyclizations yield seven-membered rings from butadienyl vinyl ketones via a photochemical [6pi] photocyclization followed by subsequent isomerization steps. The mechanism of this recently developed method was investigated using unrestricted DFT, SF-TDDFT, and CASSCF/NEVPT2 calculations, suggesting three different pathways that lead either to pure trans, pure cis, or mixed cis/trans configured products. Singlet biradicals or zwitterions occur as intermediates. The computational results are supported by deuterium-labeling experiments. PMID- 29272116 TI - Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. AB - Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1 ) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Delta2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron path, leaving it kinetically stable to the vast majority of organic cellular metabolites. PMID- 29272119 TI - Mechanistic Studies on the Michael Addition of Amines and Hydrazines To Nitrostyrenes: Nitroalkane Elimination via a Retro-aza-Henry-Type Process. AB - In this article we report on the mechanistic studies of the Michael addition of amines and hydrazines to nitrostyrenes. Under the present conditions, the corresponding N-alkyl/aryl substituted benzyl imines and N-methyl/phenyl substituted benzyl hydrazones were observed via a retro-aza-Henry-type process. By combining organic synthesis and characterization experiments with computational chemistry calculations, we reveal that this reaction proceeds via a protic solvent-mediated mechanism. Experiments in deuterated methanol CD3OD reveal the synthesis and isolation of the corresponding deuterated intermediated Michael adduct, results that support the proposed slovent-mediated pathway. From the synthetic point of view, the reaction occurs under mild, noncatalytic conditions and can be used as a useful platform to yield the biologically important N-methyl pyrazoles in a one-pot manner, simple starting with the corresponding nitrostyrenes and the methylhydrazine. PMID- 29272120 TI - Reversible Coordination of H2 by a Distannyne. AB - The terphenyl tin(II) hydride [AriPr4Sn(MU-H)]2 (1) (AriPr4 = C6H3-2,6(C6H3-2,6 iPr2)2) was shown to form an equilibrium with the distannyne AriPr4SnSnAriPr4 (2) and H2 in toluene at 80 degrees C. The equilibrium constant and Gibbs free energy for the dissociation of H2 are 2.23 * 10-4 +/- 4.9% and 5.89 kcal/mol +/- 0.68%, respectively, by 1H NMR spectroscopy and 2.33 * 10-4 +/- 6.2% and 5.86 kcal/mol +/- 0.73%, respectively, by UV-vis spectroscopy, indicating that the hydride 1 is strongly favored. Further heating of 2 at ca. 100 degrees C afforded the known pentagonal-bipyramidal Sn7 cluster Sn5(SnAriPr4)2 (3). Mechanistic studies show that 3 is formed from distannyne 2, which is generated from 1. The order of the reaction for the conversion of 2 into 3 was found to be zero, and the rate constant is 1.77 * 10-5 M s-1 at 100 degrees C. Hydride 1 was further characterized by cyclic voltammetry, and its pKa was found to be 18.8(2) via titration with 1,8-diazabicyclo[5.4.0]undec-7-ene. The bond dissociation free energy was estimated to be 51.1 kcal/mol +/- 3.4% on the basis of its pKa and reduction potential. Studies with deuterium indicate ready exchange of D2 with the hydrides in 1. PMID- 29272121 TI - Nucleic Bases Alkylation with Acrylonitrile and Cyanoethylene Oxide: A Computational Study. AB - Acrylonitrile (AN) is widely used in the manufacture of resins, plastics, and polymers, where workers are exposed to it during its production, transportation, and application. After intake a portion of AN is converted to cyanoethylene oxide (CEO) by cytochrome P450 2E1. Both AN and CEO represent possible chemical carcinogens leading to DNA damage mainly in the form of the major 7-(2 oxoethyl)deoxyguanosine adduct. A kinetic model for its formation was devised and a corresponding second-order rate constant obtained from the experimental data on the reaction with CEO. A series of ab initio, density functional theory, and semiempirical calculations of activation free energies was then performed on the alkylation of nucleic bases with both CEO and AN. The combination of Hartree-Fock level of theory with the flexible 6-311++G(d,p) basis set and Langevin dipoles implicit solvation model gave the best agreement with the experimental activation barrier. It also predicted relative reactivities of all four nucleobases that are in agreement with the experimentally reported adduct yields. Moreover, this combination predicted higher reactivity of CEO than AN with all four nucleobases corroborating the experimental hypothesis that SN2 substitution of CEO rather than direct Michael addition of AN is responsible for the genotoxic properties of AN. In a broader context this paper points to the applicability of quantum chemical methods to the studies of carcinogenesis. PMID- 29272122 TI - Excitation Number: Characterizing Multiply Excited States. AB - How many electrons are excited in an electronic transition? In this Letter, we introduce the excitation number eta to answer this question when the initial and final states are each modeled by a single-determinant wave function. We show that calculated eta values lie close to positive integers, leading to unambiguous assignments of the number of excited electrons. This contrasts with previous definitions of excitation quantities which can lead to mis-assignments. We consider several examples where eta provides improved excited-state characterizations. PMID- 29272123 TI - Pseudocryptand Hosts for Paraquats and Diquats. AB - H-bonding interaction of acidic moieties (CH2OH, COOH) at the 5- and 5'-positions of bis(1,3-phenylene)-32-crown-10 (1) with di- or tritopic anions leads to enhanced formation of inclusion complexes with N,N'-dialkyl-4,4'-bipyridinium salts ("paraquats", 2); the enforced folding of the crown ethers into pseudocryptands thus leads to pseudo-pseudorotaxanes. Strikingly, in the presence of the most effective anion (trifluoroacetate, TFA), the apparent bimolecular association constants for crown-paraquat complexation increase by more than an order of magnitude and approach those for covalent cryptands derived from the crown ether. Even though they may form pseudocryptands, the picolinate, nicotinate, and isonicotinate diesters 6 of cis-(4,4')-bis(hydroxymethyl)dibenzo 30-crown-10 do not exhibit enhanced binding of either diquat or paraquat relative to the starting diol in contrast to the picolinate ester of isomeric 5,5' bis(hydroxymethyl)bis(m-phenylene)-32-crown-10, which displayed a higher binding constant than the starting diol. The results for the analogous reverse esters 7 derived from cis-(4,4')-dicarboxydibenzo-30-crown-10 and pyridylmethanols reveal weaker complexes with diquat than the normal esters 6; however, surprisingly, two reverse esters 7 complex paraquat more strongly than isomers 6. PMID- 29272125 TI - Food Intake Biomarkers for Increasing the Efficiency of Dietary Pattern Assessment through the Use of Metabolomics: Unforeseen Research Requirements for Addressing Current Gaps. PMID- 29272126 TI - Anti-inflammatory Grayanane Diterpenoids from the Leaves of Rhododendron molle. AB - Thirteen new grayanane diterpenoids (1-13), a new dimeric grayanane diterpenoid, bimollfoliagein A (14), and 15 known analogues (15-29) were isolated from the leaves of Rhododendron molle. The structures of the new compounds (1-14) were determined by extensive spectroscopic data interpretation. The absolute configurations of 1-3, 7, 8, 16, 18, and 24 were defined by single-crystal X-ray diffraction analysis. Mollfoliagein A (1) represents the first example of a 2,3:11,16-diepoxy grayanane diterpenoid, featuring a cis/trans/cis/cis/trans fused 3/5/7/6/5/5 hexacyclic ring system with a 7,13 dioxahexacyclo[10.3.3.01,11.04,9.06,8.014,17]octadecane scaffold. Diterpenoids 1 29 were evaluated for their anti-inflammatory activities in vitro, and 15, 16, 18, 19, 23-26, 28, and 29 exhibited significant inhibitory activities against nitric oxide production in lipopolysaccharide-induced RAW264.7 mouse macrophages with IC50 values ranging from 2.8 to 35.4 MUM. A preliminary structure-activity relationship for the anti-inflammatory activity of diterpenoids 1-29 is discussed. PMID- 29272124 TI - 2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Reductive Couplings with Ketones. AB - We introduce a new strategy for synthesis of chiral amines: couplings of alpha aminoalkyl nucleophiles generated by enantioselective migratory insertion of 2 azadienes to a Cu-H. In this report, we demonstrate its application in catalytic reductive coupling of 2-azadienes and ketones to furnish 1,2-amino tertiary alcohols with vicinal stereogenic centers. PMID- 29272127 TI - Coupled Electrocyclization/Prototropic Shift in the Biosynthesis of Crotinsulidane Diterpenoids. AB - The energetic viability of proposed mechanisms for the formation of the five membered ring in crotinsulidane diterpenes is assessed using density functional theory calculations. A protonation-assisted coupled four-electron electrocyclization/prototropic shift mechanism is predicted to have a low (biologically relevant) barrier. PMID- 29272128 TI - Quantum Chemical Study of the Interligand Electron Transfer in Ru Polypyridyl Complexes. AB - Quantum chemical calculations have been performed to study the photocycle of [Ru(bpy)3]2+, a complex that is extensively used as an electron donor in photocatalytic reactions. After the initial spin-allowed excitation from the nonmagnetic ground state to a singlet state of metal-to-ligand charge transfer character, the system undergoes a rapid intersystem crossing to a triplet state of equal character. The calculations indicate a lifetime of 10 fs, in good agreement with experimental estimates. Important factors for this extremely fast intersystem crossing are the large spin-orbit coupling and the large vibrational overlap of the states involved. Both MLCT states are delocalized over the three bipyridine ligands, but the delocalized electron can easily increase its degree of localization. The hopping parameters have been calculated and found to be large for the localization on two ligands and subsequently on one. The combination of localization and geometry relaxation creates a rather long-lived trapped triplet MLCT state with a calculated lifetime of 9 MUs. The addition of methyl groups on the bipyridine ligands decreases the ligand field and consequently lowers the metal-centered triplet states. This could eventually lead to opening of a fast deactivation channel of the 3MLCT states to the initial nonmagnetic states via the triplet ligand field states as occurs in the corresponding Fe(II) complex. PMID- 29272129 TI - Glutamate Induced Thermal Equilibrium Intermediate and Counteracting Effect on Chemical Denaturation of Proteins. AB - When organisms are subjected to stress conditions, one of their adaptive responses is accumulation of small organic molecules called osmolytes. These osmolytes affect the structure and stability of the biological macromolecules including proteins. The present study examines the effect of a negatively charged amino acid osmolyte, glutamate (Glu), on two model proteins, ribonuclease A (RNase A) and alpha-lactalbumin (alpha-LA), which have positive and negative surface charges at pH 7, respectively. These proteins follow two-state unfolding transitions during both heat and chemical induced denaturation processes. The addition of Glu stabilizes the proteins against temperature and induces an early equilibrium intermediate during unfolding. The stability is found to be enthalpy driven, and the free energy of stabilization is more for alpha-LA compared to RNase A. The decrease in the partial molar volume and compressibility of both of the proteins in the presence of Glu suggests that the proteins attain a more compact state through surface hydration which could provide a more stable conformation. This is also supported by molecule dynamic simulation studies which demonstrate that the water density around the proteins is increased upon the addition of Glu. Further, the intermediates could be completely destabilized by lower concentrations (~0.5 M) of guanidinium chloride and salt. However, urea subverts the Glu-induced intermediate formed by alpha-LA, whereas it only slightly destabilizes in the case of RNase A which has a positive surface charge and could possess charge-charge interactions with Glu. This suggests that, apart from hydration, columbic interactions might also contribute to the stability of the intermediate. Gdm-induced denaturation of RNase A and alpha-LA in the absence and the presence of Glu at different temperatures was carried out. These results also show the Glu-induced stabilization of both of the proteins; however, all of the unfolding transitions followed two-state transitions during chemical denaturation. The extent of stability exerted by Glu is higher for RNase A at higher temperature, whereas it provides more stability for alpha-LA at lower temperature. Thus, the experiments indicate that Glu induces a thermal equilibrium intermediate and increases the thermodynamic stability of proteins irrespective of their surface charges. The extent of stability varies between the proteins in a temperature-dependent manner. PMID- 29272130 TI - Palladium-Catalyzed C-H Bond Acetoxylation via Electrochemical Oxidation. AB - Here we describe the development of a method for the Pd-catalyzed electrochemical acetoxylation of C-H bonds. The oxidation step of the catalytic cycle is probed through cyclic voltammetry and bulk electrolysis studies of a preformed palladacycle of 8-methylquinoline. A catalytic system for C-H acetoxylation is then developed and optimized with respect to the cell configuration, rate of oxidation, and chemistry at the counter electrode. This transformation is then applied to substrates containing various directing groups and to the acetoxylation of both C(sp2)-H and C(sp3)-H bonds. PMID- 29272131 TI - Aluminum Nanorods. AB - Al nanocrystals can be synthesized by high-temperature decomposition of triisobutyl aluminum, creating a mixture of nanoparticle geometries with a significant fraction (~15%) being single-crystalline Al nanorods. The Al nanorods are elongated along their ?110? direction, and generally exhibit hexagonal cross sections consisting of two adjacent {111} facets separated by {100} facets on opposite sides. Dark-field scattering spectroscopy of individual Al nanorods reveals that rods of varying aspect ratios all possess transverse quadrupolar and octupolar modes in the visible (2-3 eV) and ultraviolet (3-5 eV) regimes. Theoretical modeling indicates that the longitudinal resonances of these nanorods span the near- and mid-infrared regions of the spectrum. This work introduces a new class of anisotropic metal nanocrystals composed of single-crystalline Al, opening the door to highly modifiable plasmonic nanorods from Earth-abundant metals. PMID- 29272132 TI - Development of an Amine-Catalyzed Regioselective Synthesis of Pyrroles. AB - A regioselective synthesis of pyrroles has been devised through the cycloaddition of 1,3-oxazolium-5-olates and enamines. Product regiochemistry is controlled by the enamine substitution pattern. Moreover, an amine-catalyzed variant of this reaction allows aldehydes to be used directly as substrates for pyrrole synthesis. PMID- 29272133 TI - Vitamin B12 Catalyzed Atom Transfer Radical Addition. AB - Vitamin B12, a natural Co-complex, catalyzes atom transfer radical addition (ATRA) of organic halides to olefins. The established conditions were found to be very selective, with atom transfer radical polymerization (ATRP) occurring only in the case of acrylates. PMID- 29272134 TI - Trapping Lithium into Hollow Silica Microspheres with a Carbon Nanotube Core for Dendrite-Free Lithium Metal Anodes. AB - Li metal anodes, which have attracted much attention for their high specific capacity and low redox potential, face a great challenge in realizing their practical application. The fatal issue of dendrite formation gives rise to internal short circuit and safety hazards and needs to be addressed. Here we propose a rational strategy of trapping Li within microcages to confine the deposition morphology and suppress dendrite growth. Microcages with a carbon nanotube core and porous silica sheath were prepared and proved to be effective for controlling the electrodeposition behavior. In addition, the insulative coating layer prevents concentrated electron flow and decreases the possibility of "hot spots" formation. Because of the Li trapper and uniform electron distribution, the electrode with delicate structure exhibits a dendrite-free morphology after plating 2 mA h cm-2 of Li. As the dendrite growth is suppressed, the as-obtained electrode maintains a high plating/stripping efficiency of 99% over 200 cycles. This work delivers new insights into the design of rational Li metal anodes and hastens the practical application of Li metal batteries. PMID- 29272135 TI - Gold Nanoparticles as Absolute Nanothermometers. AB - Nanothermometry is a challenging field that can open the door to intriguing questions ranging from biology and medicine to material sciences. Gold nanorods are excellent candidates to act as nanoprobes because they are reasonably bright emitters upon excitation with a monochromatic source. Gold nanoparticles are commonly used in photothermal therapy as efficient transducers of electromagnetic radiation into heat. In this work we use the spectrum of the anti-Stokes emission from gold nanorods irradiated in resonance to measure the absolute temperature of the nanoparticles and their surrounding medium without the need for a previous calibration. We show a 4 K accuracy in the determination of the temperature of the medium with spectral measurements of 180 s integration time. This procedure can be easily implemented in any microscope capable of acquiring emission spectra, and it is not limited to any specific shape of nanoparticles. PMID- 29272137 TI - Asymmetric Total Syntheses of (-)-Jerantinines A, C, and E, (-)-16 Methoxytabersonine, (-)-Vindoline, and (+)-Vinblastine. AB - A concise and stereocontrolled strategy for the syntheses of oxygenated Aspidosperma and Vinca alkaloids, via a stereoselective intermolecular inverse electron-demand [4 + 2] cycloaddition, a challenging alpha,beta-unsaturated ketone indolization rearrangement with excellent regio- and stereoselectivity, and an efficient Pd/C-catalyzed one-pot cascade reaction. The strategy has been demonstrated by the efficient asymmetric syntheses of antitumor drug (+) vinblastine and five other oxygenated Aspidosperma alkaloids. PMID- 29272136 TI - Roles of Mo Surface Dopants in Enhancing the ORR Performance of Octahedral PtNi Nanoparticles. AB - Doping with a transition metal was recently shown to greatly boost the activity and durability of PtNi/C octahedral nanoparticles (NPs) for the oxygen reduction reaction (ORR), but its specific roles remain unclear. By combining electrochemistry, ex situ and in situ spectroscopic techniques, density functional theory calculations, and a newly developed kinetic Monte Carlo model, we showed that Mo atoms are preferentially located on the vertex and edge sites of Mo-PtNi/C in the form of oxides, which are stable within the wide potential window of the electrochemical cycle. These surface Mo oxides stabilize adjacent Pt sites, hereby stabilizing the octahedral shape enriched with (111) facets, and lead to increased concentration of Ni in subsurface layers where they are protected against acid dissolution. Consequently, the favorable Pt3Ni(111) structure for the ORR is stabilized on the surface of PtNi/C NPs in acid against voltage cycling. Significantly, the unusual potential-dependent oxygen coverage trend on Mo-doped PtNi/C NPs as revealed by the surface-sensitive DeltaMU analysis suggests that the Mo dopants may also improve the ORR kinetics by modifying the coordination environments of Pt atoms on the surface. Our studies point out a possible way to stabilize the favorable shape and composition established on conceptual catalytic models in practical nanoscale catalysts. PMID- 29272138 TI - Janus Composite Nanorod from a Molecular Bottlebrush Containing a Block Copolymer. AB - The asymmetric ABC-type Janus polymer composite nanorods are synthesized by the in situ preferential growth of functional materials against the molecular bottlebrush containing a triblock copolymer of poly(ethylene oxide)-b-poly(2 methacryloyloxyethyl pentynoate-g-poly(acrylic acid))-b-polystyrene. PEO and PS single chains are terminated onto the opposite ends of the composite nanorods. The two polymer chains are responsible for amphiphilic performance, while the composite nanorod is responsible for the functionality. The Janus nanorods can stand vertically at an emulsion interface, making the interfaces easily functionalized and manipulated. Protection of the PAA molecular bottlebrush via electrostatic interaction is important to obtaining individual nanorods at high solid contents. A huge family of Janus composite nanorods is expected by changing the compositions of the two polymer chains and the nanorod. PMID- 29272139 TI - Generation of All-Carbon Quaternary Stereocenters at the C-3 Carbon of Lactams via [3,3]-Sigmatropic Rearrangement and Revision of Absolute Configuration: Total Synthesis of (-)-Physostigmine. AB - A diastereoselective (up to >99%) route to all carbon quaternary stereocenters at the C-3 position of cyclic lactams has been developed via Johnson-Claisen rearrangement of gamma-hydroxy-alpha,beta-unsaturated lactams. It has been observed that olefin geometry plays an important role in the development of the absolute stereochemistry of the product. Dependence of product configuration on the olefin geometry is explained by postulating probable transition states. The success of this method has been shown for multigram-scale synthesis of these substituted lactams from commercially available cheap starting materials. The synthetic usefulness of this method is also demonstrated by carrying out the total synthesis of (-)-physostigmine. PMID- 29272140 TI - Hybrid Photon-Plasmon Coupling and Ultrafast Control of Nanoantennas on a Silicon Photonic Chip. AB - Hybrid integration of nanoplasmonic devices with silicon photonic circuits holds promise for a range of applications in on-chip sensing, field-enhanced and nonlinear spectroscopy, and integrated nanophotonic switches. Here, we demonstrate a new regime of photon-plasmon coupling by combining a silicon photonic resonator with plasmonic nanoantennas. Using principles from coherent perfect absorption, we make use of standing-wave light fields to maximize the photon-plasmon interaction strength. Precise placement of the broadband antennas with respect to the narrowband photonic racetrack modes results in controlled hybridization of only a subset of these modes. By combining antennas into groups of radiating dipoles with opposite phase, far-field scattering is effectively suppressed. We achieve ultrafast tuning of photon-plasmon hybridization including reconfigurable routing of the standing-wave input between two output ports. Hybrid photonic-plasmonic resonators provide conceptually new approaches for on chip integrated nanophotonic devices. PMID- 29272141 TI - Corrigendum. AB - Yamaguchi KT, Cheung EC, Markolf KL, et al. Effects of anterior closing wedge tibial osteotomy on anterior cruciate ligament force and knee kinematics [published online November 3, 2017]. Am J Sports Med. (Original DOI: 10.1177/03635 46517736767.) This article was originally published on AJSM PreView with the sixth author, Christopher J. Lama, omitted. The article has now been corrected to accurately reflect Christopher Lama's authorship. PMID- 29272143 TI - Biological Insight from Super-Resolution Microscopy: What We Can Learn from Localization-Based Images. AB - Super-resolution optical imaging based on the switching and localization of individual fluorescent molecules [photoactivated localization microscopy (PALM), stochastic optical reconstruction microscopy (STORM), etc.] has evolved remarkably over the last decade. Originally driven by pushing technological limits, it has become a tool of biological discovery. The initial demand for impressive pictures showing well-studied biological structures has been replaced by a need for quantitative, reliable data providing dependable evidence for specific unresolved biological hypotheses. In this review, we highlight applications that showcase this development, identify the features that led to their success, and discuss remaining challenges and difficulties. In this context, we consider the complex topic of defining resolution for this imaging modality and address some of the more common analytical methods used with this data. PMID- 29272144 TI - Prevalence of Os Trigonum on CT Imaging. AB - BACKGROUND: The os trigonum is known as one of the main causes of posterior ankle impingement. In the literature, a wide variation of occurrence has been reported. METHODS: All foot and/or ankle computed tomography (CT) scans made between January 2012 and December 2013 were reviewed. CT images were assessed, blinded for patient characteristics, for the presence of an os trigonum, size of the os trigonum, and type of os trigonum. In addition, the shape of the lateral tubercle of the posterior talar process was assessed. RESULTS: A total of 628 patients (1256 ankles) were included. In 32.5% of the patients of the cohort, an os trigonum was present. In 14.3% of these patients, it was present bilaterally. In a subgroup of patients without posterior ankle impingement the prevalence was 30.3%. Of the nonaffected ankles, an os trigonum was present in 23.7%. Patients with posterior ankle impingement were more likely to have an os trigonum (adjusted odds ratio [OR], 1.86). Afro-Caribbean/Surinamese/Central African origin was associated with a lower rate of occurrence of os trigonum (adjusted OR 0.43). In the ankles without an os trigonum, an enlarged lateral tubercle of the posterior talar process was found in 34.9% and 36.5% of the ankles. CONCLUSION: This study showed that os trigonum is a common accessory bone. With a prevalence of 30.3% in a population of patients with CT imaging of both ankles and 23.7% of the nonaffected ankles, the os trigonum is more common than previously reported. Patients with posterior ankle impingement complaints had a higher prevalence of an os trigonum. In one-third of the patients without an os trigonum, there was an enlarged lateral tubercle of the posterior talar process. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29272145 TI - Finding Statistically Significant Repeats in Nucleic Acids and Proteins. AB - DNA repeats have great importance for biological research and a large number of tools for determining repeats have been developed. Herein we define a method for extracting a statistically significant subset of a determined set of repeats. Our aim was to identify a subset of repeats in the input sequences that are not expected to occur with a number of their appearances in a random sequence of the same length. It is expected that results obtained in such manner would reduce the quantity of processed material and could thereby represent a more important biological signal. With DNA, RNA, and protein sequences serving as input material, we also examined the possibility of statistical filtering of repeats in sequences over an arbitrary alphabet. A new method for selecting statistically significant repeats from a set of determined repeats has been defined. The proposed method was tested on a large number of randomly generated sequences. The application of the method on biological sequences revealed that for some viruses, shorter repeats are more statistically significant than longer ones because of their frequent appearance, whereas for bacteria, the majority of identified repeats are statistically significant. PMID- 29272147 TI - College Students' Intent to Intervene when a Peer is Engaging in Nonmedical Use of Prescription Stimulants: An Application of the Theory of Planned Behavior. AB - BACKGROUND: This study examined college students' communication surrounding nonmedical use of prescription stimulants (NPS). OBJECTIVE: Using a hypothetical scenario, the researchers employed the Theory of Planned Behavior (TPB) to investigate the relationship of students' attitudes, perceived subjective norms, and perceived behavioral control with their intent to intervene on behalf of a friend who is engaging in NPS. METHODS: College students (N = 163) at a small, Southwestern university in the United States completed anonymous web- based surveys, reporting on their attitudes, subjective norms, perceived behavioral control, and behavioral intention in the Spring of 2015. Self-reports of perceived knowledge of prescription stimulants were also collected as a control variable. RESULTS: Results of structural equation modeling support the utility of TPB in this context; participants' attitudes and subjective norms were significant predictors of behavioral intent. Perceived behavioral control was not a significant predictor. Conclusions and Importance: Based on these findings, several recommendations are offered for both researchers and practitioners who might consider a bystander intervention to address the growing NPS epidemic on college campuses. PMID- 29272149 TI - A Novel Real-Time Genome Comparison Method Using Discrete Wavelet Transform. AB - Real-time genome comparison is important for identifying unknown species and clustering organisms. We propose a novel method that can represent genome sequences of different lengths as a 12-dimensional numerical vector in real time for this purpose. Given a genome sequence, a binary indicator sequence of each nucleotide base location is computed, and then discrete wavelet transform is applied to these four binary indicator sequences to attain the respective power spectra. Afterward, moments of the power spectra are calculated. Consequently, the 12-dimensional numerical vectors are constructed from the first three order moments. Our experimental results on various data sets show that the proposed method is efficient and effective to cluster genes and genomes. It runs significantly faster than other alignment-free and alignment-based methods. PMID- 29272148 TI - Proposal of a Risk-Stratification Platform to Address Distinct Clinical Features of Pediatric Kaposi Sarcoma in Lilongwe, Malawi. PMID- 29272150 TI - Management of Hypertension. AB - In brief Current recommendations for brief managing mild to very severe high blood pressure need to be adapted for the special concerns of physically active patients. First-line treatment involves dietary changes, smoking cessation, and aerobic exercise. The next step is to add drug therapy, and diuretics and beta blockers are the initial drugs of choice because of their proven long-term efficacy. Diuretics may, however, produce hypokalemia or dehydration, and beta- blockers may cause hyperkalemia, reduce exercise capacity, or increase perceived exertion. Other antihypertensive agents may be preferable in specific situations. PMID- 29272153 TI - Nutrition on the Run. PMID- 29272151 TI - A Guide to Blister Management. AB - In brief Friction blisters are a common annoyance for virtually all active patients at every level-from weekend warriors to professional athletes. Whereas small friction blisters are usually self-limited and amenable to conservative treatment, larger ones generally respond better when they are first aseptically drained. Proper care of the blister site will ward off infection, a possible complication of both spontaneous rupture and therapeutic draining. Properly fitted shoes, socks, and athletic equipment, together with the judicious use of lubricants, can help prevent the formation of friction blisters. PMID- 29272154 TI - Persistent Foot and Ankle Pain in Young Athletes. AB - In brief When young athletes experience brief Persistent foot or ankle pain, the differential diagnosis includes overuse syndromes, exacerbated chronic or congenital conditions, and poor healing of earlier acute injuries. Often, prompt diagnosis and treatment of an acute injury might have prevented a chronic condition. Conditions discussed in this article include distal fibular epiphyseal fracture, lateral ligament sprain, tibiofibular ligament sprain, peroneal tendon dislocation, Achilles tendinitis, Se- ver's disease, talar dome osteochondral fracture, and tarsal coalition. PMID- 29272155 TI - Partial Achilles Tendon Rupture Following Corticosteroid Injection. AB - In brief Corticosteroid injections are sometimes used to treat Achilles tendinitis after conservative measures such as anti-inflammatory medications, rest, ice massage, and immobilization have failed. Some research suggests that corticosteroid injections can lead to tendon rupture, though other investigations have not shown a correlation. A case report detailing partial Achilles tendon rupture after corticosteroid injection renews concern about the risks of this treatment. PMID- 29272157 TI - First, Do No Harm. PMID- 29272156 TI - Myositis Ossificans. AB - In brief Myositis ossificans can be a troublesome complication of a muscle contusion, with significant downtime for an athletic patient, but the long-term prognosis is excellent Early diagnosis is important not only for administering expedient treatment, but also for advising the patient against activities that could compound the injury Typical findings include local swelling, tenderness, erythema, and regional warmth. X-rays will usually be negative until 2 to 4 weeks postinjury. Differentiation from osteogenic sarcoma can usually be made by history; location, and radiographic appearance. Early treatment includes rest, ice, compression, and anti-inflammatory drugs; once inflammation subsides, stretching and strengthening can begin. PMID- 29272158 TI - CME Self Test. PMID- 29272159 TI - Don't Let Altitude Sickness Bring You Down. PMID- 29272160 TI - Achilles Tendon Resting Angle Relates to Tendon Length and Function. AB - BACKGROUND: Following Achilles tendon rupture, tendon elongation leads to long term deficits in calf function. A surrogate measure of Achilles tendon length, Achilles tendon resting angle (ATRA), has been described but has not been validated against length measured using ultrasound. Therefore, the purpose of this study was to validate the ATRA against ultrasound. Secondarily, this study aimed to identify the relationship of other factors (tendon mechanical properties, heel-rise test performance) to the ATRA. METHODS: Individuals following unilateral Achilles tendon rupture were included. ATRA was measured in knee flexed and extended positions. Tendon elongation was measured using extended field of view ultrasound imaging. Continuous shear wave elastography quantified tendon mechanical properties. The relationship between variables was tested using Spearman's rho. Subgroup analysis was used to compare subjects with less then or greater than 1 year following rupture. A total of 42 participants (with a mean of 18.2 months following rupture [SD = 35.9]) were included. RESULTS: Tendon elongation related with relative ATRA with knee flexed (rho = .491, P = .001) and knee extended (rho = 0.501, P = .001) positions. In individuals greater than 1 year following rupture, relative ATRA with the knee flexed related to shear modulus (rho = .800, P = .01) and total work on the heel-rise test (rho = -.782, P = .008) relative to the uninjured side. CONCLUSION: Relative ATRA in both knee flexed and knee extended positions has a moderate relationship to tendon elongation within the first year following rupture. After 1 year, the relative ATRA with knee flexed may be a better indicator of tendon elongation and also related to tendon mechanical properties and heel-rise test performance. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 29272161 TI - Whole-Brain Radiotherapy for Brain Metastases: Evolution or Revolution? AB - An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases. PMID- 29272163 TI - Circulating Tumor Cell Eradication as an Intermediate Efficacy End Point for Metastatic Castration-Resistant Prostate Cancer: Is There Enough Evidence? PMID- 29272164 TI - Commentary: Increasing the Connectivity Between Implementation Science and Public Health: Advancing Methodology, Evidence Integration, and Sustainability. AB - Gaps remain between the outcomes of biomedical research and their application within clinical and community settings. The field of implementation science, also referred to as dissemination and implementation research, is intended to improve the adoption, uptake, and sustainability of evidence-based health interventions. The articles in this volume's symposium on implementation science and public health identify important directions in the effort to maximize the impact of research on public and population health. Leading researchers present reviews of the use of quasi-experimental designs in implementation science, the movement toward enhancing evidence-based public health, and intervention sustainability. Each article presents lessons learned from prior research and recommendations for the next generation of studies. Collectively, the symposium offers a road map for future implementation science that seeks to optimize public health. PMID- 29272162 TI - Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate Specific Antigen Across Five Randomized Phase III Clinical Trials. AB - Purpose Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1- ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (>= 5 CTCs at baseline, <= 4 at 13 weeks-the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c index. Results Of the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy-five percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. Conclusion The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion. PMID- 29272165 TI - Treatment and Prevention of Opioid Use Disorder: Challenges and Opportunities. AB - Treatment for opioid use disorder in the United States evolved in response to changing federal policy and advances in science. Inpatient care began in 1935 with the US Public Health Service Hospitals in Lexington, Kentucky, and Fort Worth, Texas. Outpatient clinics emerged in the 1960s to provide aftercare. Research advances led to opioid agonist and opioid antagonist therapies. When patients complete opioid withdrawal, return to use is often rapid and frequently deadly. US and international authorities recommend opioid agonist therapy (i.e., methadone or buprenorphine). Opioid antagonist therapy (i.e., extended-release naltrexone) may also inhibit return to use. Prevention efforts emphasize public and prescriber education, use of prescription drug monitoring programs, and safe medication disposal options. Overdose education and naloxone distribution promote access to rescue medication and reduce opioid overdose fatalities. Opioid use disorder prevention and treatment must embrace evidence-based care and integrate with physical and mental health care. PMID- 29272167 TI - Problems and Prospects: Public Health Regulation of Dietary Supplements. AB - Dietary supplements are a global business worth more than US$100 billion annually. These supplements are taken by up to 50% of adults and perhaps one third of children in economically advanced economies. Definitions of dietary supplements differ from country to country, and regulation is generally lax and often seems to be directed more toward promoting commerce than protecting public health. Supplements may directly cause toxic reactions or may interact with other supplements or pharmaceuticals. Some supplements are found to have been contaminated with heavy metals, and others do not contain the expected quantities of active ingredients. In general, supplements are not needed except in cases of established deficiencies, and excess of some nutrients can increase cancer rates. There are important public health reasons for taking some supplements, including folate and iodine in pregnancy. This review discusses the public health concerns associated with dietary supplements and suggests directions for further regulation. PMID- 29272166 TI - Data Resources for Conducting Health Services and Policy Research. AB - Rich federal data resources provide essential data inputs for monitoring the health and health care of the US population and are essential for conducting health services policy research. The six household surveys we document in this article cover a broad array of health topics, including health insurance coverage (American Community Survey, Current Population Survey), health conditions and behaviors (National Health Interview Survey, Behavioral Risk Factor Surveillance System), health care utilization and spending (Medical Expenditure Panel Survey), and longitudinal data on public program participation (SIPP). New federal activities are linking federal surveys with administrative data to reduce duplication and response burden. In the private sector, vendors are aggregating data from medical records and claims to enhance our understanding of treatment, quality, and outcomes of medical care. Federal agencies must continue to innovate to meet the continuous challenges of scarce resources, pressures for more granular data, and new multimode data collection methodologies. PMID- 29272169 TI - Erratum. PMID- 29272168 TI - Scientific Editors' Report. PMID- 29272170 TI - 'Not Becoming Mother': A Phenomenological Exploration of the Therapeutic Relationship with Transgender Clients. AB - LGBTI clients present specific challenges for the mental health profession with key issues for transgender people identified as including isolation, fear, stigma, and family rejection, all of which contribute to the transgender community's high levels of depression, anxiety, substance misuse, self-harm, and suicide. This qualitative research paper explores the experiences of Irish psychotherapists working with transgender clients to explore specifically the nature of the therapeutic relationship. Using an interpretive phenomenological approach, it examines the subjective experience of three participant psychotherapists and endeavours to make sense of the phenomenology that emerged from semi-structured interviews. The phenomenological analysis of the data collected resulted in three salient themes emerging: (i) Therapeutic identification, (ii) Maternal countertransference, and (iii) Confusion. It is hoped that these findings which relate to the therapeutic relationship will be of utmost importance to others working within the mental health profession where recovery is dependent on the strength of this relationship. PMID- 29272172 TI - Is Cannabis Use Associated with Various Indices of Motivation among Adolescents? AB - Decreased motivation is often noted as a consequence of cannabis use (CU). Previous work has yielded mixed findings, relied mostly on adult samples, and varied to the extent that it accounted for potential confounds. This study examines associations between CU and several motivation indices among adolescents. We hypothesized that regular cannabis users would report lower motivation than light users, and that greater lifetime and past 30-day CU amounts would be associated with decreased motivation. Participants were 79 adolescents, ages 14-18, classified as recent regular cannabis users (n = 36) or light users (n = 43). Frequency and amount of substance use were assessed across participants' lifetime and during the past 30 days. Motivation was measured through the Apathy Evaluation Scale and Motivation and Engagement Scale. To examine associations between CU and our motivation indices, we conducted a series of two-step hierarchical multiple regressions. Variables found to correlate with any motivation measure were entered on step 1 (e.g., mental health, other substance use) and the relevant CU variable was entered on step 2. After controlling for confounds, no significant differences were observed between regular and light users on any motivation index, p > .01. Similarly, no associations between motivation and lifetime or past 30-day CU amount were observed, p > .01. Our findings do not support a link between reduced motivation and CU among adolescents after controlling for relevant confounds. Future studies will examine the levels of CU which influence motivation in adolescents, and the conditions under which this link becomes manifest. PMID- 29272173 TI - Pearls. PMID- 29272176 TI - Energy Bars. PMID- 29272174 TI - Forum. PMID- 29272175 TI - CME Self Test. PMID- 29272177 TI - How to Warm Up and Cool Down Your Workout. PMID- 29272179 TI - Treadmill Testing in a Patient With Chest Pain. PMID- 29272178 TI - Editor's NotesWhat is Sports Medicine? PMID- 29272181 TI - Primary Amenorrhea and Persistent Stress Fracture. AB - In brief A 16-year-old cross-country runner and Nordic skier presented for a preparticipation examination with primary amenorrhea and a 3-month history of right fourth metatarsal stress fracture. The history and physical exam narrowed the cause to a hypothalamic disorder; inadequate nutrition might have played a role. The stress fracture resolved after 2 months of oral contraceptive use. The case illustrates the multifactorial nature of amenorrhea and the need for an individualized approach to diagnosis and treatment. PMID- 29272180 TI - Using Exercise to Ward Off Depression. AB - In brief For treatment of depression many physicians use exercise as an important adjunct to psychotherapy and antidepressant therapy. Low-intensity exercise and exercise that elicits an increase in [Formula: see text]o2max are equally effective in lessening depressive symptoms. Evidence has shown that exercise is as effective as psychotherapy and antidepressant therapy in treating mild-to moderate depression, and even more effective when used in conjunction with the conventional therapies. When recommending exercise to their depressed patients, physicians should be aware of the pharmacology of various antidepressants to avoid unwanted interactions. Staying alert to the risks of overtraining and exercise addiction is also important. PMID- 29272182 TI - Sternoclavicular Injuries. AB - In brief The sternoclavicular (SC) joint can incur significant injuries. These injuries are often subtle, and, without a high index of suspicion, hard to diagnose. However, specific diagnostic methods can help clarify the extent of injury, and relatively straightforward treatment protocols can help resolve all but the most severe injuries. Two areas of concern are physeal injuries and posterior dislocations. In children and young adults, injuries of the SC joint must be considered physeal fractures until proven otherwise. Disastrous complications of posterior SC dislocations have been reported, but detecting vascular compromise or other serious sequelae will help minimize their occurrence. PMID- 29272184 TI - Recovering From Shoulder Pain. PMID- 29272185 TI - Emergency Management of Poisonous Snakebites. AB - In brief Though 42 snake species in the United States can inflict a poisonous bite, management is the same for 99% of bites because 99% of bites are inflicted by pit vipers. First aid instructions stressing rapid transit to a hospital apply to all bites. Surgical intervention has no place in acute snakebite treatment. Antivenin therapy is appropriate except in cases of mild pit viper envenomation. Pit viper antivenin is the right choice for any pit viper envenomation, and the patient history will guide the choice of coral snake antivenin. For any antivenin administration, care must be taken to prevent allergic reactions. Basic supportive care involves pain control, correcting metabolic and hematologic complications, keeping the patient comfortable, and preventing serum sickness. PMID- 29272186 TI - Role of Proteins on Formation, Drainage, and Stability of Liquid Food Foams. AB - Foam is a high-volume fraction dispersion of gas into a liquid or a solid. It is important to understand the effect of formulation on shelf life and texture of food foams. The objective of this review is to elucidate mechanisms of formation and stability of foams and relate them to the formulations. Emulsifiers are important in foam formation, whereas proteins are generally preferred to provide long-term stability. Syneresis in foams is a precursor to their collapse in many instances. Intermolecular forces, conformation, and flexibility of proteins play an important role in foam stabilization. An adsorbed protein layer at air/water interfaces imparts interfacial rheology that is necessary to improve the shelf life of foam products. Wettability and spreading of food particles at the interface can stabilize or destabilize foams, depending on their properties. More studies are needed to fully understand the complex interplay of various mechanisms of destabilization in a real-food formulation. PMID- 29272187 TI - Updates on the Cronobacter Genus. AB - There has been considerable concern related to Cronobacter spp. in foods, especially due to their highlighted association with neonatal infections through the ingestion of reconstituted powdered infant formula (PIF). This concern resulted in improved microbiological criteria recommendations by the Codex Alimentarius Commission and revised WHO advice on the preparation of infant feeds. In recent years, the diversity of the genus has been well described, and various detection and typing methods have been developed. This review considers our current knowledge of the genus and how DNA-sequence-based methods have contributed considerably to research into improved detection methods and more reliable identification procedures, genotyping schemes, and genomic analysis. The broader occurrence of Cronobacter in food ingredients, finished products, and food manufacturing environments is covered. This review also highlights the significance of clonal lineages in microbial source tracking and the use of CRISPR-cas array profiling. PMID- 29272188 TI - Building a Healthy Body After Cancer: Young Adult Lymphoma Survivors' Perspectives on Exercise After Cancer Treatment. AB - PURPOSE: Our goals were to evaluate young adult lymphoma survivors' perceptions regarding benefits of exercise after cancer treatment, to identify barriers to exercise, and to understand the types of exercise interventions that may be useful in this patient population. METHODS: Young adult lymphoma survivors were invited to participate in a survey and focus group. Questions focused on elucidating barriers to exercise as well as potential opportunities for supporting patients in adequate exercise. Focus groups were audiorecorded and transcribed, and data were coded inductively for themes and applied findings. RESULTS: Eight survivors participated. Findings were categorized into five main themes: barriers to exercise, facilitators of exercise, personal responsibility for being active, interconnectedness of exercise with a healthy lifestyle, and recommendations. CONCLUSIONS: Fatigue and frustration with postcancer physical limitations are major barriers to exercise for young adult survivors, whereas support from others, data tracking, and survivor-specific resources are facilitators. Interventions that incorporate fitness tracking technology, are individually tailored, and/or create a community with other young adult survivors may be successful in this population. PMID- 29272189 TI - Introduction of Guest Editor Edward McCann, PhD, RN, RPN. PMID- 29272190 TI - Building barriers. AB - Formation of tissue barriers starts in early development where it is critical for normal cell fate selection, differentiation and organogenesis. Barrier maintenance is critical to the ongoing function of organs during adulthood and aging. Dysfunctional tissue barrier formation and function at any stage of the organismal life cycle underlies many disease states. PMID- 29272191 TI - Enhancing quality of life for patients living with brain tumours. PMID- 29272192 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 29272193 TI - Under pressure? PMID- 29272194 TI - 'It is what it is': mothers' experiences of providing bladder and bowel care to their daughters living with life-limiting conditions. AB - BACKGROUND: Informal carers (carers) support palliative patients to live at home. Most palliative patients require bladder and bowel care (B&BC) at some point, but there is limited evidence about carers providing B&BC and how best to support them. AIM: To explore carers' experiences of providing B&BC to life-limited young adults. METHODS: Interpretative phenomenological analysis of five interviews with purposively selected carers. RESULTS: One overarching theme, 'It is what it is', and three superordinate themes ('Whatever my daughter needs', 'Mum knows best', and 'Coping with caring') emerged. While B&BC could be challenging at times, it was not a major concern. Instead it engendered closeness and opportunities for carers to provide better care than they felt professionals could. CONCLUSIONS: This study informs how professionals should understand the support carers offer. Professionals should ensure that carer/patient dyads who wish to manage B&BC are supported to do so, and that their support needs are regularly assessed. PMID- 29272195 TI - Improving the quality of nursing documentation in a palliative care setting: a quality improvement initiative. AB - AIM: This paper reports on a quality-improvement project to develop nursing documentation that reflects holistic care within a specialist palliative centre. BACKGROUND: The World Health Organization definition of palliative care includes impeccable assessment and management of pain and other symptoms. However, existing nursing documentation focuses mainly on the management of physical symptoms, with other aspects of nursing less frequently documented. METHODS: Supported by a project team and expert panel, cycles of review, action and reflection were used to develop a new palliative nursing documentation. The project was divided into three phases: audits of existing nursing documentation, development of a new palliative nursing care document and audit tool, and pilot implementation and audit of the new nursing documentation. RESULTS: The new palliative nursing care document demonstrated a higher level of compliance in relation to nursing assessments and a more concise, accurate and comprehensive approach to documenting holistic nursing care and recording of patients' perspective. CONCLUSIONS: This project has enabled the consistent documentation of holistic nursing care and patients' perspectives; however, continuous education is necessary in order to sustain positive results and ensure that documentation does not become a 'tick box' exercise. Organisational support is required in order to improve documentation systems. PMID- 29272196 TI - Politics and palliative care: Equatorial Guinea. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 29272197 TI - What do patients with cancer and their families value most at the end of life? A critical analysis of advance care planning. AB - BACKGROUND: Advance care planning (ACP) is defined in a variety of ways, although it is widely understood as a process undertaken by patients, when they have capacity, to define and communicate their treatment preferences for future care. Few studies have explored the meaning and importance patients place on their ability to participate in directing their medical care. AIM: This study aimed to explore how cancer patients and their family members value autonomy at the end of life (EoL) and understand how this may impact on the way they develop and act on EoL decisions and planning. METHODS: Data were collected through in-depth semi structured interviews with patients and family members of people with cancer. Participants were recruited from metropolitan cancer centres in Sydney, Australia. Interviews were analysed using thematic analysis. FINDINGS: Findings from 11 participant interviews (five patients with cancer and six family members) were organised into four themes: 'the threat of death and cancer'; 'patients seek trust and safety at the end of life'; 'doctors are human and the healthcare system has limitations'; and 'the role of ACP'. Participants experienced cancer and death as a 'threat', to self and others and as something 'uncontrollable'. ACP was seen to have the potential to enhance EoL care by contributing to decreasing uncertainty, enhancing comfort, helping to achieve 'the small things', and in helping the family 'know what to do'. However, participants were, in general, distrustful of documentation and cognisant of uncertainty around medical outcomes and the legal limitations of their capacity to influence care. CONCLUSIONS: These findings suggest that models of ACP which are constructed around patients' 'rights' to determine what happens to their bodies may do little to enhance the quality of EoL care, as patients value veracity, trust and comfort at the EoL more than autonomy. Quality EoL care should focus on paying increased attention to the relational and social aspects of care. PMID- 29272198 TI - Teaching end-of-life care to baccalaureate nursing students: lessons learned. AB - End-of-life (EoL) care is increasingly provided by nurses outside of traditional hospice environments, yet many general nurses have limited education in EoL care. This article describes the development and evolution of an EOL care course in a baccalaureate nursing program, and the resources and strategies the faculty used to facilitate student engagement and learning. The original EoL course was then eliminated and replaced by the inclusion of EOL care education within existing courses. Faculty drew on the experience gained and lessons learned over several years to identify essential content from the course and include it in the new curriculum, to be integrated into existing courses and levels. PMID- 29272199 TI - A holistic view from birth to the end of life: end-of-life doulas and new developments in end-of-life care in the West. AB - The relatively newly-developed profession of birth doulas, who accompany perinatal women and their families during the birth process, has been in existence since the 1990s. End-of-life (EoL) doulas are another emerging profession in developed Western countries. Doulas provide non-medical support for both childbearing women and people at the EoL, as well as their families. Although birth and death would appear to be opposites, they share common characteristics and challenges, such as tending to be treated in medicalised care settings, and that they both concern vulnerable parties. Doulas, with a holistic view encompassing birth and death, may be able to contribute to the improvement of the healthcare system in modern societies. PMID- 29272200 TI - Pilot Feasibility Study of an Oncology Financial Navigation Program. AB - BACKGROUND: Few studies have reported on interventions to alleviate financial toxicity in patients with cancer. We developed a financial navigation program in collaboration with our partners, Consumer Education and Training Services (CENTS) and Patient Advocate Foundation (PAF), to improve patient knowledge about treatment costs, provide financial counseling, and to help manage out-of-pocket expenses. We conducted a pilot study to assess the feasibility and impact of this program. METHODS: Patients with cancer received a financial education course followed by monthly contact with a CENTS financial counselor and a PAF case manager for 6 months. We measured program adherence, self-reported financial burden and anxiety, program satisfaction, and type of assistance provided. RESULTS: Thirty-four patients (median age, 60.5 years) were consented (85% white and 50% commercially insured). Debt, income declines, and loans were reported by 55%, 55%, and 30% of patients, respectively. CENTS counselors assisted most often with budgeting, retirement planning, and medical bill questions. PAF case managers assisted with applications for appropriate insurance coverage, cost of living issues (eg, housing, transportation), and disability applications. High financial burden and anxiety about costs (4 or 5 on a Likert scale) were reported at baseline by 37% and 47% of patients, respectively. Anxiety about costs decreased over time in 33% of patients, whereas self-reported financial burden did not substantially change. CONCLUSION: Implementing an oncology financial navigation program is feasible, provides concrete assistance in navigating the cost of care, and mitigates anxiety about costs in a subset of patients. Future work will focus on measuring the program's impact on financial and clinical outcomes. PMID- 29272201 TI - Alternative Outpatient Chemotherapy Scheduling Method to Improve Patient Service Quality and Nurse Satisfaction. AB - INTRODUCTION: Optimal scheduling and calendar management in an outpatient chemotherapy unit is a complex process that is driven by a need to focus on safety while accommodating a high degree of variability. Primary constraints are infusion times, staffing resources, chair availability, and unit hours. METHODS: We undertook a process to analyze our existing management models across multiple practice settings in our health care system, then developed a model to optimize safety and efficiency. The model was tested in one of the community chemotherapy units. We assessed staffing violations as measured by nurse-to-patient ratios throughout the workday and at key points during treatment. Staffing violations were tracked before and after the implementation of the new model. RESULTS: The new model reduced staffing violations by nearly 50% and required fewer chairs to treat the same number of patients for the selected clinic day. Actual implementation results indicated that the new model leveled the distribution of patients across the workday with an 18% reduction in maximum chair utilization and a 27% reduction in staffing violations. Subsequently, a positive impact on peak pharmacy workload reduced delays by as much as 35 minutes. Nursing staff satisfaction with the new model was positive. CONCLUSION: We conclude that the proposed optimization approach with regard to nursing resource assignment and workload balance throughout a day effectively improves patient service quality and staff satisfaction. PMID- 29272202 TI - Development and Feasibility of Bundled Payments for the Multidisciplinary Treatment of Head and Neck Cancer: A Pilot Program. AB - PURPOSE: Despite growing interest in bundled payments to reduce the costs of care, this payment method remains largely untested in cancer. This 3-year pilot tested the feasibility of a 1-year bundled payment for the multidisciplinary treatment of head and neck cancers. METHODS: Four prospective treatment-based bundles were developed for patients with selected head and neck cancers. These risk-adjusted bundles covered 1 year of care that began with primary cancer treatment. Manual processes were developed for patient identification, enrollment, billing, and payment. Patients were prospectively identified and enrolled, and bundled payments were made at treatment start. Operational metrics tracked incremental effort for pilot processes and average payment cycle time compared with fee-for-service (FFS) payments. RESULTS: This pilot confirmed the feasibility of a 1-year prospective bundled payment for head and neck cancers. Between November 2014 and October 2016, 88 patients were enrolled successfully with prospective bundled payments. Through September 2017, 94% of patients completed the pilot with 6% still enrolled. Manual pilot processes required more effort than anticipated; claims processing was the most time-consuming activity. The production of a bundle bill took an additional 15 minutes versus FFS billing. The average payment cycle time was 37 days (range, 15 to 141 days) compared with a 15-day average under FFS. CONCLUSION: Prospective bundled payments were successfully implemented in this pilot. Additional pilots should study this payment method in higher-volume cancers. Robust systems are needed to automate patient identification, enrollment, billing, and payment along with policies that reduce administrative burden and allow for the introduction of novel cancer therapies. PMID- 29272203 TI - Sports participation, physical activity, and health in the European regions. AB - In a context of stagnation of the level of health-enhancing physical activity in Europe, this study examines the geographical stratification of sports participation and physical activity (PA) at the regional level in 28 European countries. While previous research has focused on the national approach, this study considers the regional level across 208 European regions. Individual survey data from the Eurobarometer 80.2 is combined with a regional-level approach to the 208 regions to quantify sports participation and PA at the regional level. The results show important differences and a geographical stratification of sports participation and PA among the European regions, albeit following different patterns. In particular, a north-south gap is identified in terms of PA rates and an east-west gap is detected in terms of sports participation levels. Applying the cluster technique, a taxonomy of four different European regions is developed considering both types of indicators. Finally, the existence of sports spatial spillovers among regions is verified, obtaining a positive autocorrelation among neighbouring regions for being involved in PA and sporting activities. The results may have significant implications in terms of policy measures to improve health through PA and sports participation at the regional level in Europe. PMID- 29272204 TI - Pharmacokinetics and Pharmacodynamics of Antimicrobials in Critically Ill Patients. AB - Critically ill patients with severe infections often have altered pharmacokinetic and pharmacodynamic variables that lead to challenging treatment decisions. These altered variables can often lead to inadequate dosing and poor treatment outcomes. The pharmacokinetic parameters include absorption, distribution, metabolism, and excretion. Pharmacodynamics is the relationship between drug serum concentrations and pharmacologic and toxicologic properties of the medication. In addition to these altered parameters, these critically ill patients frequently are receiving organ support in the forms of continuous renal replacement therapy or extra-corporeal membrane oxygenation. Altered pharmacodynamics can lead to decreased end-organ perfusion, which can ultimately lead to treatment failure or exposure-related toxicity. The most common antimicrobials utilized in the intensive care unit are classified by the pharmacodynamic principles of time-dependent, concentration-dependent, and concentration dependent with time-dependence. Thus, the aim of this review is to outline pharmacokinetic and pharmacodynamic changes of critically ill patients with severe infections and provide strategies for optimal antibiotic agent dosing in these patients. PMID- 29272205 TI - Protein Supplement Usage Among Male University Students: Comparisons Between Current and Previous Users. AB - OBJECTIVE: Interest in specialized dietary supplements is leading market growth, and protein supplements are popular for increasing muscle mass among young males. Therefore, this study investigated the attitudes toward and satisfaction with protein supplements to identify detailed consumer behaviors related to the consumption of protein supplements. METHOD: The study sample includes male university students in their 20s in South Korea. In total, 223 responses were entered for analysis. Questions related to attitudes, satisfaction, and future behavioral intentions were asked using 5-point Likert scales. The responses were divided into two groups, current and previous users, to identify significant differences in terms of attitudes, satisfaction, and future behavioral intentions. A descriptive analysis, analysis of variance (ANOVA), and multiple regression were run. RESULTS: The majority of respondents prefer the powdered form of supplements in bulk with a price range between 30,000 won and 60,000 won. Online shopping was preferred, while word of mouth and friends/family were considered credible information sources. The most common side effects experienced were problems with digestion and hives, although more than 78% did not experience side effects. In comparison between current and previous users in terms of attitudes and satisfaction, the following areas showed significances. Regarding attitudes, the importance of brand, preference for products from overseas, the search for nutritional facts, and reading carefully all product information were significant, while regarding satisfaction, price, effectiveness, and ease of consumption were significant. All significances showed that current users had more positive attitudes and greater satisfaction. Overall, consumers' satisfaction regarding ease of consumption influenced future behavioral intentions. CONCLUSIONS: The market for protein supplements has been growing, so measuring consumers' attitudes and satisfaction would help attract potential consumers. In addition, analyzing previous users' opinions on products could guide product development and encourage customers to return for repurchase. PMID- 29272206 TI - Effect of Incorporating Stevia and Moringa in Cookies on Postprandial Glycemia, Appetite, Palatability, and Gastrointestinal Well-Being. AB - BACKGROUND: Medicinal plants including stevia and moringa constitute an important source of health-beneficial bioactive components, and hence their intake may beneficially modulate biomarkers of chronic diseases. OBJECTIVE: The objective of the present study was to investigate the effect of incorporating stevia and moringa leaf powder in cookies on postprandial glycemia, appetite, palatability, and gastrointestinal well-being in humans. METHOD: In a randomized crossover design, 20 healthy subjects consumed 3 isocaloric test foods (each providing 50 g available carbohydrates) of control cookies (CC) made from 100% wheat flour, cookies containing stevia leaf powder (SC, 3% w/w), and cookies containing moringa leaf powder (MC, 5% w/w) as breakfast. Blood glucose and subjective appetite were measured at fasting and at 15, 30, 45, 60, 90, and 120 min after the consumption of the cookies. Palatability and gastrointestinal well-being were measured using standard questionnaires. RESULTS: Compared to CC, MC resulted in a significant decrease in postprandial blood glucose concentration at 30 and 45 min (p = 0.002 and p = 0.003, respectively) and showed a tendency (p = 0.077) for lower blood glucose incremental area under the curve (iAUC). Subjects were significantly less hungry after SC and MC intake (p = 0.035 and p = 0.041, respectively) compared to CC. All the cookies were liked by the subjects without any reported gastrointestinal discomfort. CONCLUSION: The results showed that compared to CC, MC improved postprandial glycemia and reduced hunger, while SC reduced hunger only. Future studies are now warranted to explore the mechanisms responsible for these observed effects. PMID- 29272207 TI - Exposure to respirable silica among clay brick workers in Kathmandu valley, Nepal. AB - Previous studies report high respirable silica exposures among clay brick workers globally; however, there are little data on exposures among workers in fixed chimney Bull's trench kilns, the predominant kiln type in Kathmandu valley, Nepal. We investigated respirable silica exposures among workers (N = 46) in five similar exposure groups (SEGs). Mean exposures were highest for red brick loading/carrying (331 MUg/m3), followed by green brick stacking (223 MUg/m3), fireman (102 MUg/m3), coal crushing/carrying (92 MUg/m3), and green brick molding (71 MUg/m3). The average free silica content (13.8%) in the respirable dust fraction was similar to levels reported for clay brick workers employed in other types of kilns. Dust control measures and respiratory protection are recommended, with priority given to workers assigned to red brick loading and stacking and green brick stacking and carrying. PMID- 29272208 TI - How Message Fatigue toward Health Messages Leads to Ineffective Persuasive Outcomes: Examining the Mediating Roles of Reactance and Inattention. AB - Message fatigue refers to a state of being exhausted and tired of prolonged exposure to similarly-themed messages (e.g., anti-obesity messages; So, Kim, & Cohen, 2017). This study tests a mediational model that accounts for how one's preexisting fatigue toward anti-obesity messages may contribute to two different types of resistance-reactance and disengagement-toward an incoming anti-obesity message, which, in turn, reduce intention to adopt weight-management behaviors advocated in the message. The proposed model was tested in an experimental study (N = 312) involving a sample of overweight or obese adults in the United States. In the meditational model, reactance significantly mediated the negative effects of message fatigue on intention to adopt only one of four weight-management behaviors promoted in the message. However, inattention, which was an operationalization of disengagement, significantly mediated the negative effects of message fatigue on behavioral intention to adopt all four weight-management behaviors. This study urges future research on message fatigue and resistance to persuasion to consider disengagement with a message as a significant barrier to effective health communication and to devise ways to increase engagement with messages communicating "overtaught" health issues. PMID- 29272209 TI - Self-Reported Fear Predicts Functional Performance and Second ACL Injury After ACL Reconstruction and Return to Sport: A Pilot Study. AB - BACKGROUND: Outcomes after anterior cruciate ligament reconstruction (ACLR) are highly variable. Previous studies have failed to report the relationship between fear, objective measures of function, and reinjury rates. The purpose of this study was to determine whether fear was related to functional performance measures and risk of second ACL injury after ACLR and return to sport (RTS). HYPOTHESIS: Fear will be associated with performance on functional testing and second ACL injury rate. STUDY DESIGN: Prospective cohort study. LEVEL OF EVIDENCE: Level 2. METHODS: A total of 40 patients cleared to RTS after ACLR completed the Tampa Scale of Kinesiophobia (TSK-11), hop testing, and quadriceps strength testing, bilaterally. Patients were tracked for 12 months after RTS to identify the incidence of second ACL injury. Chi-square analyses determined whether patients with high fear (TSK-11, >=17) were more likely to have lower levels of activity, greater asymmetry on functional testing, and higher reinjury rates. RESULTS: Patients with greater fear on the TSK-11 (>=17) at RTS were 4 times (odds ratio [OR], 3.73; 95% CI, 0.98-14.23) more likely to report lower levels of activity, 7 times (OR, 7.1; 95% CI, 1.5-33.0) more likely to have a hop limb symmetry lower than 95%, and 6 times (OR, 6.0; 95% CI, 1.3-27.8) more likely to have quadriceps strength symmetry lower than 90%. Patients who went on to suffer an ipsilateral second ACL injury had a greater TSK-11 score at the time of RTS (mean, 19.8 +/- 4.0) than those who did not suffer a second ACL injury (mean, 16.4 +/- 3.6) ( P = 0.03). Patients with a TSK-11 score of 19 or greater at the time of RTS were 13 times (relative risk, 13.0; 95% CI, 2.1-81.0) more likely to suffer a second ACL tear within 24 months after RTS. CONCLUSION: Patients with greater self-reported fear were less active, presented with lower single-leg hop performance and isometric quadriceps strength, and had an increased risk of suffering a second ACL injury in the 24 months after RTS. CLINICAL RELEVANCE: Self-reported fear of movement/reinjury after ACLR at the time of RTS may be an important measure to incorporate into discharge criteria prior to release to return to pivoting and cutting sports after ACLR. PMID- 29272210 TI - Sleep Disturbance, Activities of Daily Living, and Depressive Symptoms among Older Adults. AB - OBJECTIVE: Research suggests sleep disturbance plays a role in depression and risk for suicidal behavior (i.e., ideation, attempts, death by suicide). How sleep disturbance affects suicide risk is unclear and one's ability to perform activities of daily living (ADLs) may help explain this relation. This study examined associations between sleep problems, ADLs, and either depressive symptoms or suicide risk among older adults. We hypothesized that ADLs would mediate relations between sleep problems and depressive symptoms and suicide risk. METHOD: Participants (N = 134; age >=65) were recruited through Amazon's Mechanical Turk. Participants completed questionnaires that assessed insomnia symptoms, nightmares, ADLs, depressive symptoms, and suicidal behaviors. RESULTS: Nightmares were associated with depressive symptoms and suicide risk but not independently associated with ADLs. Insomnia symptoms were associated with depressive symptoms, suicide risk, and ADLs. ADLs mediated the relation between insomnia symptoms and depressive symptoms. The insomnia symptom-suicidal behavior relation and the nightmare-suicidal behavior relation were significantly mediated by a pathway containing ADLs and depressive symptoms. DISCUSSION: ADLs help explain how insomnia symptoms and nightmares confer suicide risk among older adults, either independently or in association with depressive symptoms. CLINICAL IMPLICATIONS: Practitioners should attend to ADL performance when treating older adults with insomnia and depression. PMID- 29272211 TI - Impact of Cranberry Juice Enriched with Omega-3 Fatty Acids Adjunct with Nonsurgical Periodontal Treatment on Metabolic Control and Periodontal Status in Type 2 Patients with Diabetes with Periodontal Disease. AB - OBJECTIVES: Cranberries, high in polyphenols, have been associated with a favorable glycemic response in patients with type 2 diabetes and also are beneficial for oral health. Because type 2 diabetes mellitus and periodontal disease have a physiological relationship, this study aimed to evaluate the hypothesis that cranberry juice enriched with omega-3 will improve glycemic and lipid profiles and periodontal status in patients with diabetes with periodontal disease. MATERIALS AND METHODS: In this randomized clinical trial, 41 patients with diabetes (age 35-67 years) with periodontal disease were recruited and randomly assigned to 4 groups: control (C; n = 12), receiving omega-3 (I1; n = 10, 1 g/ twice daily), cranberry juice (I2; n = 9, 200 ml, twice daily), and cranberry juice enriched with omega-3 (I3; n = 10, 200 ml, containing 1 g omega 3) twice daily for 8 weeks. Nonsurgical periodontal therapy was provided for all patients during the study. Fasting blood glucose and glycated hemoglobin, lipid profile, probing depth, anthropometric indices, and 3-day 24-hour dietary recalls were measured pre- and postintervention. RESULTS: Glycated hemoglobin was decreased significantly in I1 and I3 groups. Serum high-density lipoprotein cholesterol (HDL-C) levels increased significantly in the I3 group compared to baseline and compared to I1 and I2 groups. Probing depth was significantly reduced in all groups postintervention. CONCLUSION: Consumption of cranberry juice enriched with omega-3 can be beneficial as adjuvant therapy with nonsurgical periodontal therapy in decreasing glycated hemoglobin, increasing HDL C, and improving periodontal status in patients with diabetes with periodontal disease. PMID- 29272212 TI - Ablative Chemoembolization for Hepatocellular Carcinoma: A Prospective Phase I Case-Control Comparison with Conventional Chemoembolization. AB - Purpose To evaluate the feasibility, safety, and treatment effectiveness of ablative chemoembolization (ACE) in the treatment of hepatocellular carcinoma (HCC) and compare with a similar patient cohort who underwent conventional transarterial chemoembolization (cTACE). Materials and Methods This was a prospective phase I nonrandomized study conducted between March 2013 and October 2016 in accordance to the Declaration of Helsinki and Declaration Good Clinical Practice with written informed consent. There were 36 men and eight women (median age, 64 years [interquartile range, 58-74] and 74.5 years [interquartile range, 70-80], respectively). The primary end points were treatment safety and tumor response. The secondary end points were time to progression, progression-free survival, conversion to partial hepatectomy, and viable HCC within the tumor specimen. The end points of the study group (n = 22) were compared with those of a case-matched control group (n = 22) of patients who underwent conventional cTACE during the same period by using a Pearson chi2 test. Results Treatment with ACE was successfully completed in all patients without adverse effects. The complete response (CR) rates by patient or by tumor were both 100%. The median time to progression and median progression-free survival were significantly longer in the study group than in the control group (both were 28 months vs 10 months, respectively; P < .001). The number of patient conversions to hepatectomy was seven for ACE and three for cTACE. In the tumor specimens, viable tumor was found in two of eight specimens that underwent ACE and three of three that underwent cTACE. Conclusion ACE is a feasible, safe, and well-tolerated treatment for patients with HCC; it is highly effective and may be more effective than cTACE in achieving CR. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29272213 TI - Breast Cancer Characteristics Associated with 2D Digital Mammography versus Digital Breast Tomosynthesis for Screening-detected and Interval Cancers. AB - Purpose To determine whether the rates and tumor characteristics of screening detected and interval cancers differ for two-dimensional digital mammography (DM) versus digital breast tomosynthesis (DBT) mammography. Materials and Methods Consecutive screening mammograms from January 2009 to February 2011 (DM group, before DBT integration) and from January 2013 to February 2015 (DBT group, after complete DBT integration) were reviewed. Cancers were considered screening detected if diagnosed within 365 days of a positive screening examination and interval if diagnosed within 365 days of a negative screening examination. Z tests were used to compare cancers on DM versus DBT examinations. Results A total of 948 breast cancers were diagnosed after 78 385 DM and 76 896 DBT examinations. Although the overall rate of screening-detected cancers was similar with DM and DBT (5.0 vs 5.0 per 1000 examinations, P = .98), a higher proportion of screening detected cancers were invasive rather than in situ with DBT (74.2% [287 of 387] vs 66.0% [260 of 394], P = .01). There were no significant differences in tumor characteristics, including size at pathologic examination, grade, hormone receptor status, and nodal status, between the screening-detected invasive cancers on DM versus DBT (P = .09-.99). The rate of interval cancers was similar with DM and DBT (1.1 vs 1.1 per 1000 examinations, P = .84). Compared with symptomatic interval cancers, magnetic resonance imaging-detected interval cancers were more likely to be minimal cancers. Conclusion The overall rates of screening-detected and interval cancers are similar with DM and DBT, but a higher proportion of screening-detected cancers are invasive rather than in situ with DBT. (c) RSNA, 2017. PMID- 29272214 TI - Role of Cerebellar Dentate Functional Connectivity in Balance Deficits in Patients with Multiple Sclerosis. AB - Purpose To prospectively investigate, by using resting-state functional magnetic resonance (MR) imaging, cerebellar dentate nuclei (DNs) functional connectivity abnormalities in multiple sclerosis (MS) to explore their impact on balance impairment in patients with MS, considering the role of DNs and their projections in maintaining balance, posture, and muscle tone, Materials and Methods All subjects provided written informed consent, and the protocol was approved by the university institutional review board. Twenty-five patients with relapsing remitting MS and 20 healthy control subjects underwent a 3-T resting-state functional MR imaging and static posturography. The seed-based method was applied to identify the cerebellar DNs resting-state network; first-level and high-level analyses were performed by using software tools. Results Compared with control subjects, patients had worse postural stability and altered patterns of cerebellar DNs connectivity network, with decreased connectivity in caudate nuclei and thalami and increased connectivity in the cerebellum, pons, left amygdala, and orbitofrontal cortices (cluster level, family-wise error corrected, P < .05, z threshold > 2.3). In patients, the decreased connectivity in the left caudate nucleus was related with worse balance performance (cluster level, family wise error corrected P < .05, z threshold > 1.96) regardless of age, lesion burden, and global clinical disability. Conclusion These results reveal abnormalities of corticocerebellar circuit connectivity in patients with MS as compared with control subjects and suggest that the decreased connectivity between the DN and the left caudate nucleus could play a role in balance impairment in MS. (c) RSNA, 2017. PMID- 29272215 TI - Utility of Dual-Energy CT-based Monochromatic Imaging in the Assessment of Myocardial Delayed Enhancement in Patients with Cardiomyopathy. AB - Purpose To investigate the diagnostic utility of dual-energy computed tomography (CT)-based monochromatic imaging for myocardial delayed enhancement (MDE) assessment in patients with cardiomyopathy. Materials and Methods The institutional review board approved this prospective study, and informed consent was obtained from all participants who were enrolled in the study. Forty patients (27 men and 13 women; mean age, 56 years +/- 15 [standard deviation]; age range, 22-81 years) with cardiomyopathy underwent cardiac magnetic resonance (MR) imaging and dual-energy CT. Conventional (120-kV) and monochromatic (60-, 70-, and 80-keV) images were reconstructed from the dual-energy CT acquisition. Subjective quality score, contrast-to-noise ratio (CNR), and beam-hardening artifacts were compared pairwise with the Friedman test at post hoc analysis. With cardiac MR imaging as the reference standard, diagnostic performance of dual energy CT in MDE detection and its predictive ability for pattern classification were compared pairwise by using logistic regression analysis with the generalized estimating equation in a per-segment analysis. The Bland-Altman method was used to find agreement between cardiac MR imaging and CT in MDE quantification. Results Among the monochromatic images, 70-keV CT images resulted in higher subjective quality (mean score, 3.38 +/- 0.54 vs 3.15 +/- 0.43; P = .0067), higher CNR (mean, 4.26 +/- 1.38 vs 3.93 +/- 1.33; P = .0047), and a lower value for beam-hardening artifacts (mean, 3.47 +/- 1.56 vs 4.15 +/- 1.67; P < .0001) when compared with conventional CT. When compared with conventional CT, 70-keV CT showed improved diagnostic performance for MDE detection (sensitivity, 94.6% vs 90.4% [P = .0032]; specificity, 96.0% vs 94.0% [P = .0031]; and accuracy, 95.6% vs 92.7% [P < .0001]) and improved predictive ability for pattern classification (subendocardial, 91.5% vs 84.3% [P = .0111]; epicardial, 94.3% vs 73.5% [P = .0001]; transmural, 93.0% vs 77.7% [P = .0018]; mesocardial, 85.4% vs 69.2% [P = .0047]; and patchy. 84.4% vs 78.4% [P = .1514]). For MDE quantification, 70-keV CT showed a small bias 0.1534% (95% limits of agreement: -4.7013, 5.0080). Conclusion Dual-energy CT-based 70-keV monochromatic images improve MDE assessment in patients with cardiomyopathy via improved image quality and CNR and reduced beam-hardening artifacts when compared with conventional CT images. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29272216 TI - Recurrent Wernicke's encephalopathy in pregnancy: A case report. AB - INTRODUCTION: Wernicke's encephalopathy (WE) is an acute neurologic syndrome resulting from a deficiency in thiamine, also known as Vitamin B1. Thiamine stores can be depleted rapidly in patients with severe hyperemesis. Treatment with thiamine typically results in complete resolution of the neurological abnormalities. CASE REPORT: A 15-year-old G2P0010 at 13.2 weeks gestation presented with altered mental status and transaminitis. She had a medical termination in her previous pregnancy following an admission for a similar clinical scenario. She was initially thought to have a postoperative surgical complication due to recent cholecystectomy, but further evaluation revealed thiamine depletion. Magnetic resonance imaging confirmed the diagnosis of WE. Repletion of thiamine and folic acid resulted in rapid clinical improvement. CONCLUSION: WE should be considered in the differential diagnosis of pregnant patients with hyperemesis and altered mental status. A prior history of WE increases the risk of recurrence during pregnancy. Severe hyperemesis during pregnancy increases the risk of thiamine deficiency and WE. Early thiamine supplementation may reduce the risk of WE in patients with a prior clinical history or in patients with severe hyperemesis gravidarum. PMID- 29272217 TI - Influence of various operating conditions on wastewater treatment in an AS biofilm reactor and post-treatment using TiO2-based solar/UV photocatalysis. AB - In the present study, the effect of carbon to nitrogen (C/N) ratio, suspended biomass concentration (X), hydraulic retention time (HRT) and dissolved oxygen (DO) on chemical oxygen demand (COD) and nutrient removal from wastewater was investigated in a lab-scale activated sludge (AS)-biofilm reactor. Furthermore, in order to improve the quality of the treated wastewater, photocatalysis by TiO2 was investigated as a post-treatment technology, using solar and UV irradiations. The AS-biofilm reactor provided a substantial removal efficiency in terms of COD, ammonia nitrogen [Formula: see text], total nitrogen (TN) and total phosphorous when the system was maintained at C/N ratio 6.66, X in the range 2-2.5 g/L, HRT 10 h, DO in the range of 3.5-4.5 mg/L and organic loading rate (OLR) of 0.96 kg COD/m3 d during Run 1. Similarly, when the reactor was maintained at C/N ratio 10, X in the range of 3-3.5 g/L, HRT 8 h, DO in the range of 3.5-4.5 mg/L and OLR of 1.8 kg COD/m3 d during Run 2. The microstructure of suspended and attached biomass comprised a dense bacterial structure of cocci and bacillus microorganisms. The UV photocatalysis was found to be better than solar photocatalysis during the comparative analysis. The maximum removal efficiencies of COD, most probable number and phosphorous at optimum conditions in the case of UV and solar irradiations were 72%, 95%, 52% and 71%, 99%, 50%, respectively. PMID- 29272218 TI - How to Increase Fruit and Vegetable Consumption: A Multistakeholder Approach for Improved Health Outcomes-A Report from the Alliance for Food & Health. AB - Nutrition is the fundamental bridge between food and health. Inadequate fruit and vegetable (FV) consumption has been linked to an increase in global noncommunicable diseases, which places a greater burden on health systems (1) . Despite much emphasis from the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO) on the benefits of increased FV consumption, neither results nor an understanding of the complexity of food security and the actions of a diverse array of stakeholders needed to achieve outcomes have been attained. To address this challenge, the Alliance for Food & Health (AFH) uses a multistakeholder approach to engage cross-sector solutions. This paper, the first in a series, addresses the global challenge of FV consumption by examining and synthesizing current practices and outcomes and providing actionable recommendations for government, private-sector, and civil society stakeholders. To effectively reduce the global noncommunicable disease (NCD) burden, it is critical that stakeholders work in concordance with the WHO/FAO Second International Conference on Nutrition commitments ( Table 1 ), United Nations (UN) Decade of Action on Nutrition Action Areas ( Table 2 ), and the UN Sustainable Development Goals (SDGs) applicable to this issue ( Table 3 ). AFH's top line recommendations ( Table 4 ) align with multiple UN SDGs (2) . All recommendations connect with the following three SDGs: #2: "Zero Hunger," #3: "Good Health and Well-Being," and #17: "Partnerships for the Goals." This indicates AFH's integration of the food, agriculture, and global health communities in efforts to combat NCDs. A variety of recommendations align with #9: "Industry, Innovation, and Infrastructure," #11: "Sustainable Cities and Communities," and #12: "Responsible Consumption and Production." PMID- 29272219 TI - Gender differences in the relationship between walking activity and sleep disturbance among community-dwelling older adult with diabetes in Taiwan. AB - This study explored the gender differences in the relationship between walking activity and sleep disturbances. A cross-sectional study of 201 community dwelling older adults with diabetes was conducted in southern Taiwan. Using the Taiwanese version of the International Physical Activity Questionnaire, self administered short version (IPAQ-SS), information on physical activity and sleep disturbance conditions was collected. Among older female adults with diabetes, 54.2% reported sleep disturbance significantly higher than males (38.1%). Logistic regression analysis suggested that for women, in addition to the active group, older adults in the low-active, high-walking group exhibited a significantly lower rate of sleep disturbance than did those who walked less. PMID- 29272220 TI - In search of the good old life: Ontological breakdown and responsive hope at the margins of life. AB - What might the good life amount to at the margins of life? Taking our point of departure in Jonathan Lear's notions of ontological breakdown and radical hope as well as the phenomenology of lived time, we explore hope within the institutional aging process in Denmark. Drawing on two ethnographic cases, Vagn and Thea, we propose a phenomenological and responsive hope emerging within complex temporalities. This is a relational hope to be included among the living, to be a human being among others. Importantly, it is neither optimistic nor naive but rather hope practiced in the face of devastating life circumstances. PMID- 29272221 TI - Open Cardiac Surgery without Blood and Blood Products Transplantation. AB - BACKGROUND: Blood transfusions are the most common type of tissue and organ transplantation. Perioperative and postoperative transfusions may cause morbidity and mortality and transfusion should based on only hematocrit values but also on hemodynamic and clinical parameters of the patient, which cannot be ignored. METHODS: A prospective study was conducted between January 2015 and October 2016 with adult patients undergoing elective open heart surgery. In these patients, a protocol was established, and patients were divided into two groups as transfusion (-) and transfusion (+). In the first 24 hours in the intensive care unit, patients' drainage, 24-hours urine output, awakening and extubation times, and lactate and bilirubin levels in arterial blood gases were recorded. Thirty day mortality and morbidity, and hemodynamic and clinical data were compared between these two groups. RESULTS: We have performed a total of 138 cases; no blood and blood products were transfused in 71% (n = 98), and in 29.0% (n = 40) blood and blood products were transfused. Thirty-day mortality and morbidity (arrhythmia, infectious and pulmonary morbidity, myocardial infarction, cerebrovascular accident, renal dysfunction, sternal revision) were compared between these two groups and no statistically significant difference was observed. Patients' awakening, extubation time, cardiopulmonary bypass period, cross-clamp time, and days in intensive care unit and hospital were compared, and there was no statistically significant difference between the two groups. Conclusion: In this study, we conclude that open heart surgery without blood transfusion may be accomplished with decent peri/postoperative management. The patients who did not receive any blood or blood products were not compromised clinically or hemodynamically. No extra morbidity and mortality were seen in the non-transfusion group. Transfusion decision was based on clinical and hemodynamic parameters such as persistent hypotension or tachycardia, hyperlactatemia, low urine output, and anemic symptoms. PMID- 29272222 TI - Cardiac Rehabilitation Increases the Reliability of the 6-Minute Walk Test in Patients After Coronary Artery Bypass Graft Surgery. AB - BACKGROUND: Few data are available on the capacity for functional exercise after cardiac rehabilitation in patients who have undergone coronary artery bypass graft (CABG) surgery. The aim of this study was to determine the clinical and biochemical factors that affect the 6-minute walk test (6MWT) results in patients who have undergone CABG. METHODS: Data were prospectively collected from 56 patients consecutively admitted at our hospital between January 2013 and May 2015 for a 3-month cardiac rehabilitation program. Data were analysed retrospectively up to 90 days after cardiac surgery. In addition to clinical and biochemical parameters, the functional capacity of patients was evaluated by an exercise 6 minute walking test and echocardiography. Functional capacity was evaluated at baseline and after three months of cardiac rehabilitation. Results: Before cardiac rehabilitation, the 6MWT values were negatively correlated with Body Mass Index (BMI) and abdominal and buttock diameters (r = -0.375, -0.386, and -0.370, respectively; P < .05), and were positively correlated with metabolic equivalent (MET) values (r = 0.493, P < .05). After cardiac rehabilitation, the 6MWT values were negatively correlated with body mass index (BMI) and abdominal and buttock diameters (r = -0.382, -0.274, and -0.405, respectively; P < .05) and were positively correlated with MET and VO2 max values (r = 0.456 and 0.573, respectively; P < 0.05). Before cardiac rehabilitation, VO2 max and FEV1/FEVC values were found as factors that significantly increased 6MWT values (P < .05). After cardiac rehabilitation, VO2 max values were found as factors that significantly increased 6MWT values (P < .05). CONCLUSION: Overall, in current clinical settings, cardiac rehabilitation increases the reliability of the 6MWT. Improvement in pulmonary function after cardiac rehabilitation reduces the impact of pulmonary function on 6MWT values. The functional capacity of patients may be more reliably determined by 6MWT after cardiac rehabilitation. PMID- 29272223 TI - Acute Kidney Infarction Due to Left Ventricular Thrombus Embolization In Patient with Isolated Left Ventricular Noncompaction: A Case Report. AB - Noncompaction of the ventricular myocardium (NVM) is a rare congenital cardiomyopathy that is characterized by multiple prominent trabeculations and deep intertrabecular recesses, and occurs due to arrest of normal embryogenesis of the endocardium and myocardium. It is also referred to as isolated left ventricular noncompaction (LVNC), because lesions are mainly in the left ventricle. The main clinical manifestations are heart failure, arrhythmia, systemic embolism, and sudden death. Systemic embolism is related to the occurrence of atrial arrhythmias or thrombus formation in the left ventricle. Most resulting thromboembolisms are cerebral or in the arteries of the lower limbs, and renal artery embolisms are rare. There are reports of a few previous cases of renal infarction with diagnoses of NVM on echocardiography, but a thrombus from the left ventricle has never been identified as the cause of a renal artery embolism. This paper reports a 53-year-old male who was admitted to our hospital for LVNC and renal infarction. He had a history of atrial fibrillation 3 years previously. We diagnosed LVNC with a thrombus in the left ventricle using echocardiography. The patient was discharged after renal replacement therapy and treatment with an anticoagulant. During the 2 years of follow-up, his condition remained stable. PMID- 29272224 TI - Rapid Bioprosthetic Mitral Valve Failure after Temporary Left Ventricular Assist Device Support. AB - The technique of mechanical circulatory support or the site of cannulation may affect transvalvular flow. We describe early failure of a mitral bioprosthesis in a patient with temporary left ventricular assist device support, likely from thrombosis. Salvage with transcatheter mitral valve replacement was attempted. Temporary mechanical circulatory support strategies that maximize flow across a new bioprosthesis should be sought to avoid early valvular thrombosis. PMID- 29272225 TI - Identify Unsuitable Patients with Left Main Coronary Artery Disease in Intermediate SYNTAX Scores Treated by Percutaneous Coronary Intervention. AB - BACKGROUND: With the follow-up extending to 5 years, the outcomes of SYNTAX (Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) trial were comparable between coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) in left-main (LM) patients with intermediate SYNTAX scores of 23-32. A subdivision depending on SYNTAX score will help to identify unsuitable LM patients with intermediate SYNTAX scores to receive PCI treatment. METHODS: Between January 2011 and June 2013, 104 patients with LM Coronary Artery Disease (CAD) undergoing PCI were selected retrospectively. We compared clinical outcomes in patients with SYNTAX score <27 and >=27. The follow-up time was 25.23 +/- 7.92 months. Kaplan-Meier survival analyses and Cox proportional hazards models were used to compare various outcomes between two groups. RESULTS: Higher rates of repeated revascularization (18.2% versus 4.2%, P = .027) and major adverse cerebro-cardiovascular events (MACCE) (24.2% versus 7.0%, P = .014) were shown in patients with SYNTAX score >= 27. After multivariate adjustment, a significant higher risk of repeated revascularization (hazard ratio: 6.25, 95% confidence interval: 1.48 to 26.37, P = .013) and MACCE (hazard ratio: 4.49, 95% confidence interval: 1.41 to 14.35, P = .011) were also found in patients with SYNTAX score >= 27. CONCLUSIONS: Based on the higher rate of repeated revascularization and MACCE, patients with LM CAD and intermediate SYNTAX scores will need a subdivision to identity the one not benefit from PCI. CABG is still the standard treatment method for patients of LM CAD with a SYNTAX score of >= 27. PMID- 29272226 TI - A Case of Anterolateral Papillary Muscle Rupture Caused by Isolated First Diagonal Branch Occlusion. AB - A 74-year-old man hospitalized due to acute myocardial infarction (AMI) of the first diagonal branch developed cardiogenic shock. Ultrasonography showed anterolateral papillary muscle rupture (PMR) which caused anterior mitral leaflet prolapse and severe mitral valve regurgitation, and he successfully underwent mitral valve replacement. Anterolateral PMR causing anterior mitral leaflet prolapse due to obstruction of the first diagonal branch is rare and should be considered in such an AMI case. PMID- 29272228 TI - A Shift to the Left: Teaching the Craft of Cardiac Surgery. AB - I was in Chicago in 1987 when Dr. Shumway delivered his American Association for Thoracic Surgery (AATS) presidential address, and, like most in the audience, I knew he was correct. Having had the privilege of getting to do a lot of thoracic and cardiovascular surgery in my surgical training, I was preparing myself to make my own move to the left side of the operating table. In fact, I had already resolved that I would make my own "shift to the left" very soon after that meeting in 1987, hoping to become, like Dr. Shumway, the best first assistant I could be. Over thirty years later, I have never looked, nor moved back. However, making this move to the left side of the table - to teach surgical residents how to operate - is challenging for many surgeons in academic environments. In considering the challenges, we must remember that those of us who have agreed to teach our proteges have an obligation both to them, and to their future patients, to help them become safe, capable cardiothoracic surgeons. PMID- 29272227 TI - A Rare Complication of Patent Ductus Arteriosus Ligation: Inadvertent Ligation of the Left Pulmonary Artery. AB - BACKGROUND: The inadvertent ligation of the left pulmonary artery (LPA) is a rarely seen surgical complication that has been presented in the literature in a limited number of cases after patent ductus arteriosus (PDA) ligation surgery. Case Report: A PDA closure operation was performed on our patient, a 28-week-old preterm. In the postoperative follow-up, we identified on echocardiography taken on the same postoperative day that the ductus space was still present. On CT angiography, we determined that not only was the ductus space still continuing, but, in addition, ligation of the LPA had been performed inadvertently. An LPA reconstruction operation was performed on the patient 46 days after the first operation. However, owing to severe tissue damage in LPA, LPA reperfusion did not occur in the postoperative period. Conclusion: Although inadvertent ligation of the left pulmonary artery during PDA ligation surgery is rarely seen in patients who have undergone closure surgery, this complication should be kept in mind in the postoperative follow-up period. Patient findings such as physical examination, lung angiography and postoperative echocardiography should be assessed with this in mind. PMID- 29272229 TI - Extracorporeal Membrane Oxygenation (ECMO): An Option for Cardiac Reccovery from Advanced Cardiogenic Shock. AB - Mechanical circulatory support can prevent multi-organ failure and death in patients with advanced cardiogenic shock. Here we describe our experience using extracorporeal membrane oxygenation (ECMO) for treatment of advanced cardiogenic shock which has been used by our team for daily routine care in more than 200 patients during the last five years at the Penn State Medical Center.Venoarterial (VA) ECMO has been used as a viable therapeutic option for advanced cardiogenic shock as a bridge to recovery (BTR) or bridge to next decision (BTD). Our group performed a retrospective review of data from 155 patients from our single center cohort treated with VA ECMO for advanced cardiogenic shock. After successful ECMO treatment, the one year survival rate of patients with ischemic heart disease was 73.7 %, and the one year survival for patients with non-ischemic heart disease was 75%. PMID- 29272230 TI - CSR Cuts Bring Unintended Consequences, Prompt State Responses. AB - Eliminating the cost-sharing payments (CSRs) to insurers to hold down out-of pocket costs for low-income people who purchase individual health plans may wind up actually increasing overall federal spending by driving up premium subsidies to cover higher price plans. PMID- 29272231 TI - Drug Prices: Why So High and Why So #&*! Complicated. AB - For all the Strum und Drang, experts foresee neither a hurry-up nor a halt for 2018, just a fairly steady continued rise at roughly last year's higher-than inflation pace. The Drug Price Forecast, for example (based on hospital and nonacute settings, but not retail pharmacy), reports that that means a tidy year over-year increase of 7.61%. PMID- 29272232 TI - PBMs: Will the Amazon Cometh? AB - PBM consultant Linda Cahn says that if Amazon gets into the PBM business it could insist that drugmakers simultaneously submit the net discount price for each of their drugs for the subsequent six months. Amazon could then publicize every drug's actual price, by drug and by therapeutic category. PMID- 29272233 TI - Disasters: In the Wake of the 2017 Annus Horribilis, Preparedness Rules To Get Tougher. AB - Federal and state officials have moved this year to impose some preparedness requirements on providers that will have an effect in 2018 and years beyond. For instance, CMS' finalized emergency preparedness rules for health care providers that serve Medicare and Medicaid patients went into effect last month. PMID- 29272234 TI - Value-Based Care: 5 Not-So-Easy Pieces. AB - Here they are: Value-based care can't be done one slice at a time, new value based models will take aim at variations in care, the patient may gain a stronger voice, the tail cold wag the dog, and value-based care will create haves and have nots. Some predictability from the federal government would be welcome. PMID- 29272235 TI - ACA Repeal: Headed for a Whimper Not a Bang? AB - A year ago you probably couldn't find a Las Vegas bookmaker willing to give odds that the ACA would still be the law of the land in 2018. Turns out that repealing Obamacare and crafting a replacement acceptable to various factions of the GOP is not so easy. PMID- 29272236 TI - ACA Repeal, Part 2: Star Turn for State Regulators as Insurance Markets Will Continue To Be a Partisan Battleground. AB - Whether in a red or blue state, the state commissioner jobs do require decent working relationships with insurance companies, particularly in precarious times as insurers threaten to leave some areas with no ACA coverage because of poor market conditions or dithering in Washington, D.C. PMID- 29272237 TI - Opioids, Part 1: Health Insurers Pushed To Take Steps To Curb the Epidemic. AB - Blame for the epidemic has focused on drugmakers, drug wholesalers, and physicians who prescribed opioids too liberally. This fall, fingers pointed at health insurers. Investigative reporting showed that coverage policies that restricted access to less addictive medications might have helped fueled the epidemic. PMID- 29272238 TI - Opioids, Part 2: Novel Therapies Could Help Wean Americans Off Opioids. AB - Opioids remain the go-to products because they target the mu opioid receptor, which has been shown to be the most effective pathway to reduce pain. The holy grail for drug developers is an agent that stifles pain without producing the euphoria and addiction of opioids. PMID- 29272239 TI - Medicaid: Work Requirements and Expansion in the Offing. AB - CMS chief Seema Verma wants to reshape the entitlement program that covers about 62 million people. Verma endorses "community engagement" - work or community service - as a condition for "able-bodied" people to get Medicaid coverage and accused the Obama administration of the "soft bigotry of low expectations" for opposing such a requirement. PMID- 29272240 TI - Hospital Consolidation: FTC May be a Stick in the Spokes of Hospital Mergers. AB - For instance, in the case of Sanford Health's acquisition of Mid Dakota Clinic in North Dakota, the agency challenged the deal, claiming that the merged entity would control 75% or more of primary care and other health services in the Bismarck-Mandan metropolitan area. PMID- 29272241 TI - Better for Patients, or Better for Business-Do We Really Have To Choose? AB - A trend that is likely to continue in 2018 is the rise of consumerism and expansion of the consumer-driven marketplace. But investing in this is pricey and in an era of shrinking margins is "better for patients" always "better for business?" The Advisory Board's Zachary Hafner answers with a resounding "yes!" PMID- 29272242 TI - The Self-driving Patient: How Health Care Will Catch Up. AB - Some providers will resent less obedient patients, but others will enthusiastically support more individually appropriate solutions and take risks with their patients. It's likely that the early adopters (most likely the more affluent and educated) will soon become a noticeable minority in some physicians' offices. PMID- 29272243 TI - Copayments Not Counting Toward the Deductible Could Have Unintended Consequences. AB - Starting this year, many PBMs rolled out a new type of cost-share program that will not count copay assistance dollars toward a patient's deductible and out-of pocket maximum. This might put some patients in a bind. Patients face big, unaffordable drug bills when the assistance maximum is reached, but before they have met their deductibles. Adherence to the specialty drug could fall off sharply if patients hit the copay program limit and cannot afford therapy. PMID- 29272244 TI - A Conversation With Stephen W. Schondelmeyer. Drug and Health Care Spending: A Bubble That Will Burst Unless We Do Something. AB - This professor of pharmaceutical economics in the University of Minnesota College of Pharmacy says that the rising level of health care spending is unsustainable. He argues that drug price increases should be reviewed and PBMs should be regulated. "We need [a] bona fide rate regulation review body that can meaningfully evaluate the information presented by drug companies." PMID- 29272245 TI - Complex Ventral Hernias: A Review of Past to Present. AB - With the incidence of ventral hernias increasing, surgeons are faced with greater complexity in dealing with these conditions. Proper knowledge of the history and the advancements made in managing complex ventral hernias will enhance surgical results. This review article highlights the literature regarding complex ventral hernias, including a shift from a focus that stressed surgical technique toward a multimodal approach, which involves optimization and identification of suboptimal characteristics. PMID- 29272246 TI - Management of Uveitis in Spondyloarthropathy: Current Trends. AB - Spondyloarthritis is a chronic inflammatory disease predominantly affecting joints of the axial skeleton. However, as many as 50% of patients with this disease may have extra-articular manifestations, which include uveitis; psoriasis; inflammatory bowel disease such as Crohn disease or ulcerative colitis; cardiovascular manifestations in the form of conduction abnormalities, atherosclerosis, or valvular heart disease; pulmonary involvement; and rarely renal involvement. Uveitis occurs in 25% to 40% of patients with spondyloarthritis. Management of uveitis is crucial to prevent morbidity caused by vision loss and secondary complications. Treatment ranges from local therapies to systemic drugs and varies depending on the severity and response to treatment. Categories of medical treatment include nonsteroidal anti-inflammatory agents, corticosteroids, and steroid-sparing agents. Biologic therapies such as antitumor necrosis factor agents act early in the disease process and have revolutionized the field of rheumatology, including management of uveitis. This review will focus on the management of ophthalmic manifestations in spondyloarthropathies. PMID- 29272247 TI - Image Diagnosis: Liver Ears-Spiders on the Back of the Ears. PMID- 29272248 TI - Impact of Asynchronous Training on Radiology Learning Curve among Emergency Medicine Residents and Clerkship Students. AB - CONTEXT: Web-based learning (WBL) modules are effectively used to improve medical education curriculum; however, they have not been evaluated to improve head computed tomography (CT) scan interpretation in an emergency medicine (EM) setting. OBJECTIVE: To evaluate the effectiveness of a WBL module to aid identification of cranial structures on CT and to improve ability to distinguish between normal and abnormal findings. DESIGN: Prospective, before-and-after trial in the Emergency Department of an academic center. Baseline head CT knowledge was assessed via a standardized test containing ten head CT scans, including normal scans and those showing hemorrhagic stroke, trauma, and infection (abscess). All trainees then participated in a WBL intervention. Three weeks later, they were given the same ten CT scans to evaluate in a standardized posttest. MAIN OUTCOME MEASURES: Improvement in test scores. RESULTS: A total of 131 EM clerkship students and 32 EM residents were enrolled. Pretest scores correlated with stage of training, with students and first-year residents demonstrating the lowest scores. Overall, there was a significant improvement in percentage of correctly classified CT images after the training intervention from a mean pretest score of 32% +/- 12% to posttest score of 67% +/- 13% (mean improvement = 35% +/- 13%, p < 0.001). Among subsets by training level, all subgroups except first-year residents demonstrated a statistically significant increase in scores after the training. CONCLUSION: Incorporating asynchronous WBL modules into EM clerkship and residency curriculum provides early radiographic exposure in their clinical training and can enhance diagnostic head CT scan interpretation. PMID- 29272249 TI - Determination of zones at risk for fasciolosis in the department of Haute-Vienne, central France: a retrospective study on natural infections detected in 108,481 Galba truncatula for 37 years. AB - A retrospective study on the natural infection of Galba truncatula by Fasciola hepatica was carried out in the French department of Haute-Vienne to determine whether there are areas at risk for fasciolosis. Adult snails included in this analysis came from samples collected from pastures on 259 farms and from 121 wild watercress beds between 1970 and 2006. Fasciola hepatica infection rates were examined in relation to altitude and climatic data (mean annual rainfall, mean annual temperature) of each municipality. In a total of 108,481 snails collected in 151 municipalities, the overall prevalence of infection was 3.8% but varied according to the municipalities from which samples were taken (from 1% to 7.4%). The prevalence of F. hepatica infection in snails significantly decreased when the mean altitude of municipalities or their mean annual rainfall increased. However, this prevalence significantly increased with increasing mean annual temperatures. Studying the prevalence of infection in these snails makes it possible to delineate zones at risk for fasciolosis on the acid soils of Haute Vienne. The risk of infection for livestock would be greater in areas of Haute Vienne below 400 m above sea level and would gradually decrease when the altitude of the land increases. PMID- 29272250 TI - Changes of the peripheral blood mononuclear cells membrane fluidity from type 1 Gaucher disease patients: an electron paramagnetic resonance study. AB - Gaucher disease (GD) is a lysosomal storage disorder, caused by an impaired function of beta-glucocerebrosidase, which results in accumulation of glucocerebroside in cells, and altered membrane ordering. Using electron paramagnetic resonance spin labeling, a statistically significant difference in the order parameter between the peripheral blood mononuclear cell membranes of GD patients and healthy controls was observed. Moreover, the results show that the introduction of the enzyme replacement therapy leads to the restoration of the physiological membrane fluidity. Accordingly, this simple method could serve as a preliminary test for GD diagnosis and therapy efficiency. PMID- 29272251 TI - Metformin-induced anticancer activities: recent insights. AB - Metformin is a widely used antidiabetic drug, and there is evidence among diabetic patients that metformin is a chemopreventive agent against multiple cancers. There is also evidence in human studies that metformin is a cancer chemotherapeutic agent, and several clinical trials that use metformin alone or in combination with other drugs are ongoing. In vivo and in vitro cancer cell culture studies demonstrate that metformin induces both AMPK-dependent and AMPK independent genes/pathways that result in inhibition of cancer cell growth and migration and induction of apoptosis. The effects of metformin in cancer cells resemble the patterns observed after treatment with drugs that downregulate specificity protein 1 (Sp1), Sp3 and Sp4 or by knockdown of Sp1, Sp3 and Sp4 by RNA interference. Studies in pancreatic cancer cells clearly demonstrate that metformin decreases expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes, demonstrating that one of the underlying mechanisms of action of metformin as an anticancer agent involves targeting of Sp transcription factors. These observations are consistent with metformin-mediated effects on genes/pathways in many other tumor types. PMID- 29272252 TI - Connecting the clinical IT infrastructure to a service-oriented architecture of medical devices. AB - The new medical device communication protocol known as IEEE 11073 SDC is well suited for the integration of (surgical) point-of-care devices, so are the established Health Level Seven (HL7) V2 and Digital Imaging and Communications in Medicine (DICOM) standards for the communication of systems in the clinical IT infrastructure (CITI). An integrated operating room (OR) and other integrated clinical environments, however, need interoperability between both domains to fully unfold their potential for improving the quality of care as well as clinical workflows. This work thus presents concepts for the propagation of clinical and administrative data to medical devices, physiologic measurements and device parameters to clinical IT systems, as well as image and multimedia content in both directions. Prototypical implementations of the derived components have proven to integrate well with systems of networked medical devices and with the CITI, effectively connecting these heterogeneous domains. Our qualitative evaluation indicates that the interoperability concepts are suitable to be integrated into clinical workflows and are expected to benefit patients and clinicians alike. The upcoming HL7 Fast Healthcare Interoperability Resources (FHIR) communication standard will likely change the domain of clinical IT significantly. A straightforward mapping to its resource model thus ensures the tenability of these concepts despite a foreseeable change in demand and requirements. PMID- 29272253 TI - Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters in pregnancies with impaired utero-placental perfusion in mid gestation - a secondary analysis of the PETN-pilot trial. AB - AIM: In pregnancies complicated by impaired utero-placental perfusion, pentaeritrithyltetranitrate (PETN) has been shown to reduce the risk of severe fetal growth restriction (FGR) and perinatal death by 39%. The effect is most likely related to the vasodilatative influence of PETN. To assess its impact on utero-placental and fetal perfusion, we analyzed the Doppler parameters measured during the PETN pilot-trial. METHODS: One hundred and eleven pregnancies presenting impaired utero-placental resistance at mid-gestation were included in the trial. Fifty-four women received PETN, while 57 received a placebo. Doppler velocimetry measurements were monitored biweekly. Statistical analysis was performed using a mixed linear model. RESULTS: Within the first week of treatment, the mean pulsatility index (PI) of the uterine artery (UtA) dropped more prominently in the PETN group [-0.20, 95% confidence interval (CI): -0.34 to -0.05, P=0.007). The adjusted relative risk (RR) for abnormal cerebro-placental ratio (CPR) was significantly reduced by PETN [RR 0.412 (95% CI: 0.181-0.941)]. Kaplan-Meier analysis demonstrates the postponement of absent end-diastolic flow (AED), absent or reverse end-diastolic flow (ARED), brain sparing and abnormal cerebroplacental ratio (CPR) in the PETN group. CONCLUSION: The demonstrated effect of PETN on utero-placental and feto-placental perfusion strengthens the evidence for a positive impact in pregnancies complicated by impaired placental perfusion and might explain the effect on neonatal outcome, as shown in the PETN pilot trial. PMID- 29272254 TI - Electronic and thermoelectric properties of atomically thin C3Si3/C and C3Ge3/C superlattices. AB - The nanostructuring of graphene into superlattices offers the possibility of tuning both the electronic and thermal properties of graphene. Using classical and quantum mechanical calculations, we have investigated the electronic and thermoelectric properties of the atomically thin superlattice of C3Si3/C (C3Ge3/C) formed by the incorporation of Si (Ge) atoms into graphene. The bandgap and phonon thermal conductivity of C3Si3/C (C3Ge3/C) are 0.54 (0.51) eV and 15.48 (12.64) W m-1 K-1, respectively, while the carrier mobility of C3Si3/C (C3Ge3/C) is 1.285 * 105 (1.311 * 105) cm2 V-1 s-1 at 300 K. The thermoelectric figure of merit for C3Si3/C (C3Ge3/C) can be optimized via the tuning of carrier concentration to obtain the prominent ZT value of 1.95 (2.72). PMID- 29272256 TI - Treatments for secondary hyperparathyroidism in hemodialysis. PMID- 29272255 TI - Utility of IL-2 Complexes in Promoting the Survival of Murine Orthotopic Forelimb Vascularized Composite Allografts. AB - BACKGROUND: Vascularized composite allografts (VCA) are novel, life-enhancing forms of transplantation (Tx). However, host immune responses to the various VCA components, especially those involving skin, are complex and make selection of appropriate therapy challenging. Although the interplay between Foxp3+ T regulatory (Treg) cells and CD4 and CD8 effector T cells is of central importance in determining the acceptance or rejection of solid organ allografts, there is little information available concerning the contribution of Treg cells to VCA survival. In addition, the effects of therapeutic expansion in vivo of host Treg cell populations on VCA survival are unknown. METHODS: We established a fully major histocompatibility complex-disparate (BALB/c- > C57BL/6) murine orthotopic forelimb Tx model to explore the benefits of pre- and post-Tx IL-2/anti-IL-2 monoclonal antibody complex (IL-2C) administration to expand the host Treg cell population and thereby attempt to promote Treg cell-dependent VCA survival. RESULTS: Both strategies expanded the Treg cell population in vivo and prolonged VCA survival (P < 0.001), but IL-2C administration pre-Tx led to significantly longer survival compared with IL-2C administration post-Tx (P < 0.01). In addition, compared with post-Tx therapy, pre-Tx therapy resulted in an increased ratio of Treg cells to CD8+ T cells (P < 0.001), reduced proliferation of CD4 and CD8 effector T cells, and reduced production of IFN-gamma. Optimal effects were seen when combined with rapamycin therapy, whereas the combination of IL-2C therapy plus calcineurin inhibitor was counterproductive. CONCLUSIONS: Our studies involving different IL-2C-mediated Treg cell expansion strategies demonstrate that pre-Tx IL-2C therapy may be a useful component for developing strategies to promote VCA survival. PMID- 29272257 TI - Comparison of different oral anticoagulant regimens in patients with atrial fibrillation: is the risk of left atrial appendage thrombus formation truly comparable between regimens? PMID- 29272258 TI - PD-1+ T cells contribute differently to the pathogenesis of rheumatoid arthritis and psoriatic arthritis. PMID- 29272259 TI - Fatal course of perivalvular extension of infective endocarditis in a patient after aortic valve replacement treated with immunosuppressive drugs. PMID- 29272260 TI - Gestational gigantomastia in systemic lupus erythematosus. PMID- 29272261 TI - Pitfalls in the management of bilateral adrenal enlargement. PMID- 29272262 TI - Efficacy and safety of apixaban in real-life patients at high bleeding risk. PMID- 29272264 TI - Are cannabinoids effective for HIV wasting syndrome? AB - INTRODUCTION: Wasting syndrome is a common problem in HIV. It leads to substantive morbidity and mortality. The use of cannabinoids has been suggested as a treatment for weight, but it is not clear whether they are really safe and effective. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified eight systematic reviews including ten studies overall, of which six were randomized trials. We concluded it is not clear whether cannabinoids increase appetite or weight in HIV wasting syndrome because the certainty of the evidence is very low, and they probably lead to frequent adverse effects. PMID- 29272263 TI - Baicalin Suppresses Hypoxia-Reoxygenation-Induced Arterial Endothelial Cell Apoptosis via Suppressing PKCdelta/p53 Signaling. AB - BACKGROUND This study was aimed to investigate the protective role of baicalin on vascular endothelium exposed to ischemia reperfusion injury and the involved molecular mechanisms. MATERIAL AND METHODS Cultured human arterial endothelial cells (HAECs) were exposed to hypoxia/deoxygenation (H/R). Cells were also treated with baicalin at serially diluted concentrations. Cells were also treated with PKC activator PEP005 or specific siRNA against protein kinase Cdelta (PKCdelta). MTT assay was used to evaluate the cell viabilities. Flow cytometry was used to detect cell apoptosis. The protein phosphorylation and expression levels were determined by Western blotting. RESULTS PKCdelta-siRNA transfection increased cell viabilities and reduced cell apoptosis in HAECs exposed to H/R. Baicalin treatment preserved cell viabilities and reduced apoptosis of H/R exposed HAECs in a concentration- dependent manner. Baicalin treatment reduced phosphorylation levels of PKCdelta and p53, as well as the expression levels of active caspase3 and bax in HAECs exposed to H/R. The treatment of PKC activator PEP005 impaired the protective effects of baicalin in increasing cell viabilities and reducing apoptosis in HAECs exposed to H/R. CONCLUSIONS Baicalin exerts vascular a protective effect on HAECs exposed to H/R by reducing cell apoptosis. The PKCdelta/p53 apoptotic signaling pathway was the pharmacological target of baicalin. PMID- 29272265 TI - Do doctors have a moral duty to work in the public health sector? Ethical considerations regarding the social obligations of medicine. AB - This article discusses whether physicians have social obligations and whether these obligations imply a moral duty to work in the public sector. The article focuses on the context of the Chilean health system, which has an unequal distribution of physicians to the detriment of the public sector, thus making the issue a particularly pressing one. After addressing arguments from different ethical theories and some empirical evidence, the article concludes that the physician has some social obligations in relation to a fair distribution of health resources, and that professional excellence should incorporate cultivating virtues related to social justice. In addition, it is argued that the moral duty to work in the public sector can be placed in the context of prima facie obligations which admit exceptions and allow the possibility of conflict with other professional obligations. PMID- 29272266 TI - Is secukinumab effective for psoriatic arthritis with insufficient response to initial treatment? AB - INTRODUCTION: Psoriatic arthritis is an inflammatory arthritis without a clear etiology. Biological therapy has become key for its treatment, especially in more severe cases. There are several alternatives for biological treatment, including secukinumab. However, it is not clear how effective and safe it is, which is particularly relevant considering its high cost. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified eight systematic reviews including three randomized trials overall. We concluded secukinumab in psoriatic arthritis leads to an improvement of disease activity and symptoms, and it is probably not associated to severe adverse events. PMID- 29272267 TI - Forced expression of IL-7R promotes CD8 T cell cytotoxicity to self antigen. AB - Cross-presentation of apoptotic cell associated antigens by immature dendritic cells prevents the activation of self reactive CD8 T cells. Tolerized self reactive CD8 T cells down-regulate IL-7R expression on their surface. Whether over-expression of IL-7R can reverse their fate and function has not been examined. In this paper, we showed forced expression of IL-7R in OT-I T cells by a transgene enhanced CD8 T cell mediated diabetes in the RIP-mOVA model. Although IL-7R Tg (transgenic) did not completely reverse the deletion of OT-I T cells, it provided a significant survival advantage over w.t OT-I T cells. Furthermore, IL7R Tg OT-I T cells isolated from diabetic pancreata displayed increased production of IFN-gamma, higher expression of T-bet, and increased externalization of CD107a. We also found that immature DCs containing apoptotic cells expressed high levels of PDL-1 on their surface. Although IL-7R Tg did not change PD1 expression on activated OT-I cells in vivo, the transgene enabled a significantly lower number of OT-I T cells to induce diabetes in the absence of PDL-1. Our results demonstrated that forced expression of IL-7R not only improved the functionality of tolerized CD8 T cells, it also acted in synergy with PDL-1 deficiency to further promote CD8 T cell cytotoxicity to self antigens. PMID- 29272268 TI - Retention in care among HIV-infected pregnant and breastfeeding women on lifelong antiretroviral therapy in Uganda: A retrospective cohort study. AB - BACKGROUND: In 2013, Uganda updated its prevention of maternal-to-child transmission of HIV program to Option B+, which requires that all HIV-infected pregnant and breastfeeding women be started on lifelong antiretroviral therapy (ART) regardless of CD4 count. We describe retention in care and factors associated with loss to follow-up (LTFU) among women initiated on Option B+ as part of an evaluation of the effectiveness of the national program. METHODS: We conducted a retrospective cohort analysis of data abstracted from records of 2,169 women enrolled on Option B+ between January and March 2013 from a representative sample of 145 health facilities in all 24 districts of the Central region of Uganda. We defined retention as "being alive and receiving ART at the last clinic visit". We used Kaplan-Meier analysis to estimate retention in care and compared differences between women retained in care and those LTFU using the chi-squared test for dichotomized or categorical variables. RESULTS: The median follow-up time was 20.2 months (IQR 4.2-22.5). The proportion of women retained in HIV care at 6, 12 and 18 months post-ART initiation was 74.2%, 66.7% and 62.0%, respectively. Retention at 18 months varied significantly by level of health facility and ranged from 70.0% among those seen at hospitals to 56.6% among those seen at lower level health facilities. LTFU was higher among women aged less than 25 years, 59.3% compared to those aged 25 years and above, 40.7% (p = 0.02); among those attending care at lower level facilities, 44.0% compared to those attending care at hospitals, 34.1% (p = 0.01), and among those who were not tested for CD4 cell count at ART initiation, 69.4% compared to those who were tested, 30.9% (p = 0.002). CONCLUSION: Retention of women who were initiated on Option B+ during the early phases of roll-out was only moderate, and could undermine the effectiveness of the program. Identifying reasons why women drop out and designing targeted interventions for improved retention should be a priority. PMID- 29272269 TI - Monitoring bottlenose dolphin leukocyte cytokine mRNA responsiveness by qPCR. AB - Both veterinarians caring for dolphins in managed populations and researchers monitoring wild populations use blood-based diagnostics to monitor bottlenose dolphin (Tursiops truncatus) health. Quantitative PCR (qPCR) can be used to assess cytokine transcription patterns of peripheral blood mononuclear cells (PBMC). This can supplement currently available blood tests with information on immune status. Full realization of this potential requires establishment of normal ranges of cytokine gene transcription levels in bottlenose dolphins. We surveyed four dolphins over the span of seven months by serial bleeds. PBMC were stimulated with phytohaemagglutinin (1, 5, and 10 MUg/mL) and concanavalin A (1 MUg/mL) for 48 H in vitro. RNA from these cultures was probed by qPCR using Tursiops truncatus-specific primers (IL-1alpha, IL-1beta, IL-1RA, IL-2, IL-4, IL 6, IL-8, IL-10, IL-12p40, IL-13, IL-18, IFN-gamma and TNF-alpha). Two blood samples from an additional bottlenose dolphin diagnosed with acute pulmonary disease add further perspective to the data. We observed that mitogen choice made a significant difference in the magnitude of gene transcription observed. On the other hand, most cytokines tested exhibited limited intra-animal variation. However, IL-6 and IL-12p40 differed between older and younger dolphins. Furthermore, the magnitude of mitogenic response clusters the tested cytokines into three groups. The data provide a reference for the selection of target cytokine mRNAs and their expected range of mitogen-stimulated cytokine gene transcription for future studies. PMID- 29272271 TI - Correction: Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005285.]. PMID- 29272272 TI - The cost and utilisation patterns of a pilot sign language interpreter service for primary health care services in South Africa. AB - BACKGROUND: The World Health Organisation estimates disabling hearing loss to be around 5.3%, while a study of hearing impairment and auditory pathology in Limpopo, South Africa found a prevalence of nearly 9%. Although Sign Language Interpreters (SLIs) improve the communication challenges in health care, they are unaffordable for many signing Deaf people and people with disabling hearing loss. On the other hand, there are no legal provisions in place to ensure the provision of SLIs in the health sector in most countries including South Africa. To advocate for funding of such initiatives, reliable cost estimates are essential and such data is scarce. To bridge this gap, this study estimated the costs of providing such a service within a South African District health service based on estimates obtained from a pilot-project that initiated the first South African Sign Language Interpreter (SASLI) service in health-care. METHODS: The ingredients method was used to calculate the unit cost per SASLI-assisted visit from a provider perspective. The unit costs per SASLI-assisted visit were then used in estimating the costs of scaling up this service to the District Health Services. The average annual SASLI utilisation rate per person was calculated on Stata v.12 using the projects' registry from 2008-2013. Sensitivity analyses were carried out to determine the effect of changing the discount rate and personnel costs. RESULTS: Average Sign Language Interpreter services' utilisation rates increased from 1.66 to 3.58 per person per year, with a median of 2 visits, from 2008-2013. The cost per visit was US$189.38 in 2013 whilst the estimated costs of scaling up this service ranged from US$14.2million to US$76.5million in the Cape Metropole District. These cost estimates represented 2.3%-12.2% of the budget for the Western Cape District Health Services for 2013. CONCLUSIONS: In the presence of Sign Language Interpreters, Deaf Sign language users utilise health care service to a similar extent as the hearing population. However, this service requires significant capital investment by government to enable access to healthcare for the Deaf. PMID- 29272270 TI - Parallel evolution of the POQR prolyl oligo peptidase gene conferring plant quantitative disease resistance. AB - Plant pathogens with a broad host range are able to infect plant lineages that diverged over 100 million years ago. They exert similar and recurring constraints on the evolution of unrelated plant populations. Plants generally respond with quantitative disease resistance (QDR), a form of immunity relying on complex genetic determinants. In most cases, the molecular determinants of QDR and how they evolve is unknown. Here we identify in Arabidopsis thaliana a gene mediating QDR against Sclerotinia sclerotiorum, agent of the white mold disease, and provide evidence of its convergent evolution in multiple plant species. Using genome wide association mapping in A. thaliana, we associated the gene encoding the POQR prolyl-oligopeptidase with QDR against S. sclerotiorum. Loss of this gene compromised QDR against S. sclerotiorum but not against a bacterial pathogen. Natural diversity analysis associated POQR sequence with QDR. Remarkably, the same amino acid changes occurred after independent duplications of POQR in ancestors of multiple plant species, including A. thaliana and tomato. Genome-scale expression analyses revealed that parallel divergence in gene expression upon S. sclerotiorum infection is a frequent pattern in genes, such as POQR, that duplicated both in A. thaliana and tomato. Our study identifies a previously uncharacterized gene mediating QDR against S. sclerotiorum. It shows that some QDR determinants are conserved in distantly related plants and have emerged through the repeated use of similar genetic polymorphisms at different evolutionary time scales. PMID- 29272273 TI - Higher-than-expected prevalence of non-tuberculous mycobacteria in HIV setting in Botswana: Implications for diagnostic algorithms using Xpert MTB/RIF assay. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) can cause pulmonary infection and disease especially among people living with HIV (PLHIV). PLHIV with NTM disease may clinically present with one of the four symptoms consistent with tuberculosis (TB). We describe the prevalence of NTM and Mycobacterium tuberculosis complex (MTBC) isolated among PLHIV who presented for HIV care and treatment. METHODS: All PLHIV patients presenting for HIV care and treatment services at 22 clinical sites in Botswana were offered screening for TB and were recruited. Patients who had >=1 TB symptom were asked to submit sputa for Xpert MTB/RIF and culture. Culture growth was identified as NTM and MTBC using the SD-Bioline TB Ag MPT64 Kit and Ziehl Neelsen microscopy. NTM and MTBC isolates underwent species identification by the Hain GenoType CM and AS line probe assays. RESULTS: Among 16, 259 PLHIV enrolled 3068 screened positive for at least one TB symptom. Of these, 1940 submitted >=1 sputum specimen, 427 (22%) patients had >=1 positive culture result identified phenotypically for mycobacterial growth. Of these 247 and 180 patients were identified as having isolates were NTM and MTBC, respectively. Of the 247 patients identified with isolates containing NTM; 19 were later excluded as not having NTM based on additional genotypic testing. Among the remaining 408 patients 228 (56%, 95% confidence interval, 46-66%) with NTM. M. intracellulare was the most common isolated (47.8%). Other NTMs commonly associated with pulmonary disease included M. malmoense (3.9%), M. avium (2.2%), M. abscessus (0.9%) and M. kansasii (0.4%). After excluding NTM isolates that were non-speciated and M. gordonae 154 (67.5%) of the NTM isolates were potential pathogens. CONCLUSIONS: In the setting of HIV care and treatment, over-half (56%) of a positive sputum culture among PLHIV with TB symptoms was NTM. Though we were not able to distinguish in our study NTM disease and colonization, the study suggests culture and species identification for PLHIV presenting with TB symptoms remains important to facilitate NTM diagnosis and hasten time to appropriate treatment. PMID- 29272274 TI - Determinants of magnesium sulphate use in women hospitalized at <29 weeks with severe or non-severe pre-eclampsia. AB - OBJECTIVE: Magnesium sulphate is recommended by international guidelines to prevent eclampsia among women with pre-eclampsia, especially when it is severe, but fewer than 70% of such women receive magnesium sulphate. We aimed to identify variables that prompt Canadian physicians to administer magnesium sulphate to women with pre-eclampsia. METHODS: Data were used from the Canadian Perinatal Network (2005-11) of women hospitalized at <29 weeks' who were thought to be at high risk of delivery due to pre-eclampsia (using broad Canadian definition). Unadjusted analyses of relative risks were estimated directly and population attributable risk percent (PAR%) calculated to identify variables associated with magnesium sulphate use. A multivariable model was created and a generalized estimating equation was used to estimate the adjusted RR that explained magnesium sulphate use in pre-eclampsia. The adjusted PAR% was estimated by bootstrapping. RESULTS: Of 631 women with pre-eclampsia, 174 (30.1%) had severe pre-eclampsia, of whom 131 (75.3%) received magnesium sulphate. 457 (69.9%) women had non-severe pre-eclamspia, of whom 291 (63.7%) received magnesium sulphate. Use of magnesium sulphate among women with pre-eclampsia could be attributed to the following clinical factors (PAR%): delivery for 'adverse conditions' (48.7%), severe hypertension (21.9%), receipt of antenatal corticosteroids (20.0%), maternal transport prior to delivery (9.9%), heavy proteinuria (7.8%), and interventionist care (3.4%). CONCLUSIONS: Clinicians are more likely to administer magnesium sulphate for eclampsia prophylaxis in the presence of more severe maternal clinical features, in addition to concomitant antenatal corticosteroid administration, and shorter admission to delivery periods related to transport from another institution or plans for interventionist care. PMID- 29272275 TI - Soundwatch: Eighteen years of monitoring whale watch vessel activities in the Salish Sea. AB - The Soundwatch Boater Education Program is a vessel monitoring and public education outreach program. Soundwatch has been run by The Whale Museum (TWM) during the whale watch season (May through September) in the Haro Strait Region of the Central Salish Sea since 1993. Data collection has been in a consistent manner since 1998 and is presented here. The program compiles data on vessel types and vessel interactions with marine mammals with a focus on the Southern Resident killer whale (SRKW), Orcinas orca, which was listed as endangered under the U.S. Endangered Species Act (ESA) in 2005. The primary goal of the Soundwatch program is to reduce vessel disturbance to SRKWs and other marine wildlife through the education of boaters on regional, local and federal guidelines and regulations and the systematic monitoring of vessel activities around cetaceans. Since 1998, the number of active commercial whale watching vessels has increased over time; ranging from a low of 63 in 1999, to a high of 96 in 2015. In addition, the number of vessel incidents or violation of regulations and guidelines has also increased; ranging from a low of 398 in 1998 to a high of 2621 in 2012. Soundwatch collected data on 23 incident types, some remaining the same over the 18-year data set and some changing over time. The most common incidents over the 18 years were "Within 880 m of Lime Kiln" and "Crossing the path of whales". The numbers of people kayaking near whales also significantly increased since 2004 with the incident "kayaks spread out" with a significantly increasing trend making it difficult for whales to avoid vessels. These results suggest a need for further outreach for effective education and enforcement of whale watching guidelines and regulations in the Central Salish Sea. PMID- 29272276 TI - The performance of stroke survivors in turning-while-walking while carrying out a concurrent cognitive task compared with controls. AB - BACKGROUND: Turning-while-walking is one of the commonest causes of falls in stroke survivors. It involves cognitive processing and may be challenging when performed concurrently with a cognitive task. Previous studies of dual-tasking involving turning-while-walking in stroke survivors show that the performance of physical tasks is compromised. However, the design of those studies did not address the response of stroke survivors under dual-tasking condition without specifying the task-preference and its effect on the performance of the cognitive task. OBJECTIVE: First, to compare the performance of single-tasking and dual tasking in stroke survivors. Second, to compare the performance of stroke survivors with non-stroke controls. METHODS: Fifty-nine stroke survivors and 45 controls were assessed with an auditory Stroop test, a turning-while-walking test, and a combination of the two single tasks. The outcome of the cognitive task was measured by the reaction time and accuracy of the task. The physical task was evaluated by measuring the turning duration, number of steps to turn, and time to complete the turning-while-walking test. RESULTS: Stroke survivors showed a significantly reduced accuracy in the auditory Stroop test when dual tasking, but there was no change in the reaction time. Their performance in the turning-while-walking task was similar under both single-tasking and dual-tasking condition. Additionally, stroke survivors demonstrated a significantly longer reaction time and lower accuracy than the controls both when single-tasking and dual-tasking. They took longer to turn, with more steps, and needed more time to complete the turning-while-walking task in both tasking conditions. CONCLUSIONS: The results show that stroke survivors with high mobility function performed the auditory Stroop test less accurately while preserving simultaneous turning-while walking performance. They also demonstrated poorer performance in both single tasking and dual-tasking as compared with controls. PMID- 29272277 TI - Hygroscopic dilators vs balloon catheter ripening of the cervix for induction of labor in nulliparous women at term: Retrospective study. AB - OBJECTIVE: To compare the efficacy and safety of hygroscopic dilators and balloon catheters for ripening of the cervix in induction of labor. STUDY DESIGN: This retrospective, observational study used data from the Successive Pregnancy Birth Registry System of the Japan Society of Obstetrics and Gynecology from 2012 to 2014. Nulliparous women in whom labor was induced by mechanical methods of cervical ripening at term were enrolled. The eligible women were divided into dilator, balloon <40 mL, balloon ?40 mL, and overlapping groups. RESULTS: The groups included 4645, 4100, 6615, and 1992 women, respectively. In the overlapping group, which included the women in whom delivery was most difficult, the vaginal delivery rate was lower and the intrauterine infection and neonatal mortality rates were higher than those in the dilator group. No difference in the vaginal delivery rate was observed among the dilator, balloon <40 mL, and balloon ?40 mL groups (74.6%, 72.3%, and 73.8%, respectively; p>0.05). The vaginal instrumental delivery rate was higher in the two-balloon groups than in the dilator group. The volume of intrapartum hemorrhage was lowest in the dilator group. No significant difference in the frequencies of uterine rupture and intrauterine infection were observed among the dilator and two-balloon groups. With regard to neonatal outcomes, the frequency of a low Apgar score was statistically significantly lower in the dilator group than in the two-balloon groups. Moreover, the frequency of neonatal death tended to be lower in the dilator group than in the two-balloon groups. CONCLUSION: With regard to cervical ripening for labor induction in nulliparous women at term, the vaginal delivery rate on using a dilator and on using a balloon seems to be equivalent. Concerning maternal complications and neonatal outcomes, cervical ripening with hygroscopic dilators in labor induction might be safer. PMID- 29272278 TI - Comparison of pre-filter and post-filter ionised calcium monitoring in continuous veno-venous hemodiafiltration (CVVHD-F) with citrate anti-coagulation. AB - BACKGROUND: It is widespread practice during citrate anticoagulated renal replacement therapy to monitor circuit ionised calcium (iCa2+) to evaluate the effectiveness of anticoagulation. Whether the optimal site to sample the blood path is before or after the haemofilter is a common question. METHODS: Using a prospectively collected observational dataset from intensive care patients receiving pre-dilution continuous veno-venous haemodiafiltration (CVVHD-F) with integrated citrate anticoagulation we compared paired samples of pre and post filter iCa2+ where the target range was 0.3-0.5 mmol.L-1 as well as concurrently collected arterial iCa2+. Two nested mixed methods linear models were fitted to the data describing post vs pre filter iCa2+, and the relationship of pre, post and arterial samples. SETTING: An 11 bed general intensive care unit. PARTICIPANTS: 450 grouped samples from 152 time periods in seven patients on CRRT with citrate anticoagulation. RESULTS: The relationship of post to pre-filter iCa2+ was not 1:1 with post = 0.082 + 0.751 x pre-filter iCa2+ (95% CI intercept: 0.015-0.152, slope 0.558-0.942). Variation was greatest between patients rather than between circuits within the same patient or citrate dose. Compared to arterial iCa2+ there was no significant difference between pre and post-filter sampling sites (F-value 0.047, p = 0.827). CONCLUSION: These results demonstrate that there is minimal difference between pre and post filter samples for iCa2+ monitoring of circuit anticoagulation in citrate patients relative to the arterial iCa2+ in CVVHD-F however compared to pre-filter sampling, post filter sampling has a flatter response and greater variation. PMID- 29272279 TI - Flue-cured tobacco confirmed as a reservoir host plant for Tomato yellow leaf curl virus by agro-inoculation and Bemisia tabaci MED-mediated transmission. AB - Tomato yellow leaf curl virus (TYLCV) causes great losses in tomato production. In addition to tomato, TYLCV infects many crops or weeds as alternative hosts. These alternative hosts may serve as reservoirs for TYLCV survival and spread. Here, we tested the capability of cultivated, flue-cured tobacco to act as a reservoir host plant for TYLCV. TYLCV DNA was detected in nine flue-cured tobacco cultivars inoculated with an infectious TYLCV clone, although no visible symptoms developed on TYLCV-infected tobacco plants. The percentage of whiteflies with viral DNA increased with an increasing acquisition access period (AAP) and reached 100% after a 12 h AAP on infected tobacco plants. Using infected tobacco plants as virus resources, TYLCV was capable of being transmitted to tobacco and tomato plants by whiteflies, and typical symptoms of TYLCV infection were observed on infected tomato plants but not on infected tobacco plants. Our results suggest that flue-cured tobacco can serve as a reservoir host plant for TYLCV and may play an important role in the spread of TYLCV epidemics in China. PMID- 29272280 TI - DEV induce autophagy via the endoplasmic reticulum stress related unfolded protein response. AB - Duck enteritis virus (DEV) can infect ducks, geese, and many other poultry species and leads to acute, septic and highly fatal infectious disease. Autophagy is an evolutionarily ancient pathway that plays an important role in many viral infections. We previously reported that DEV infection induces autophagy for its own benefit, but how this occurs remains unclear. In this study, endoplasmic reticulum (ER) stress was triggered by DEV infection, as demonstrated by the increased expression of the ER stress marker glucose-regulated protein 78 (GRP78) and the dilated morphology of the ER. Pathways associated with the unfolded protein response (UPR), including the PKR-like ER protein kinase (PERK) and inositol-requiring enzyme 1 (IRE1) pathways, but not the activating transcription factor 6 (ATF6) pathway, were activated in DEV-infected duck embryo fibroblast (DEF) cells. In addition, the knockdown of both PERK and IRE1 by small interfering RNAs (siRNAs) reduced the level of LC3-II and viral yields, which suggested that the PERK-eukaryotic initiation factor 2alpha (eIF2alpha) and IRE1 x-box protein1 (XBP1) pathways may contribute to DEV-induced autophagy. Collectively, these data offer new insight into the mechanisms of DEV -induced autophagy through activation of the ER stress-related UPR pathway. PMID- 29272281 TI - Cost-effectiveness of laparoscopic versus open distal pancreatectomy for pancreatic cancer. AB - BACKGROUND: A recent Cochrane review compared laparoscopic versus open distal pancreatectomy for people with for cancers of the body and tail of the pancreas and found that laparoscopic distal pancreatectomy may reduce the length of hospital stay. We compared the cost-effectiveness of laparoscopic distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer. METHOD: Model based cost-utility analysis estimating mean costs and quality-adjusted life years (QALYs) per patient from the perspective of the UK National Health Service. A decision tree model was constructed using probabilities, outcomes and cost data from published sources. A time horizon of 5 years was used. One-way and probabilistic sensitivity analyses were undertaken. RESULTS: The probabilistic sensitivity analysis showed that the incremental net monetary benefit was positive (L3,708.58 (95% confidence intervals (CI) -L9,473.62 to L16,115.69) but the 95% CI includes zero, indicating that there is significant uncertainty about the cost-effectiveness of laparoscopic distal pancreatectomy versus open distal pancreatectomy. The probability laparoscopic distal pancreatectomy was cost effective compared to open distal pancreatectomy for pancreatic cancer was between 70% and 80% at the willingness-to-pay thresholds generally used in England (L20,000 to L30,000 per QALY gained). Results were sensitive to the survival proportions and the operating time. CONCLUSIONS: There is considerable uncertainty about whether laparoscopic distal pancreatectomy is cost-effective compared to open distal pancreatectomy for pancreatic cancer in the NHS setting. PMID- 29272282 TI - Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD - A longitudinal study. AB - BACKGROUND: Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. PATIENTS AND METHODS: This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. RESULTS: Overall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64-0.82, p<0.001) and between PC and AT (r = 0.62 0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation. CONCLUSION: The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD. PMID- 29272283 TI - Scene content is predominantly conveyed by high spatial frequencies in scene selective visual cortex. AB - In complex real-world scenes, image content is conveyed by a large collection of intertwined visual features. The visual system disentangles these features in order to extract information about image content. Here, we investigate the role of one integral component: the content of spatial frequencies in an image. Specifically, we measure the amount of image content carried by low versus high spatial frequencies for the representation of real-world scenes in scene selective regions of human visual cortex. To this end, we attempted to decode scene categories from the brain activity patterns of participants viewing scene images that contained the full spatial frequency spectrum, only low spatial frequencies, or only high spatial frequencies, all carefully controlled for contrast and luminance. Contrary to the findings from numerous behavioral studies and computational models that have highlighted how low spatial frequencies preferentially encode image content, decoding of scene categories from the scene selective brain regions, including the parahippocampal place area (PPA), was significantly more accurate for high than low spatial frequency images. In fact, decoding accuracy was just as high for high spatial frequency images as for images containing the full spatial frequency spectrum in scene-selective areas PPA, RSC, OPA and object selective area LOC. We also found an interesting dissociation between the posterior and anterior subdivisions of PPA: categories were decodable from both high and low spatial frequency scenes in posterior PPA but only from high spatial frequency scenes in anterior PPA; and spatial frequency was explicitly decodable from posterior but not anterior PPA. Our results are consistent with recent findings that line drawings, which consist almost entirely of high spatial frequencies, elicit a neural representation of scene categories that is equivalent to that of full-spectrum color photographs. Collectively, these findings demonstrate the importance of high spatial frequencies for conveying the content of complex real-world scenes. PMID- 29272284 TI - Quantification of huntingtin protein species in Huntington's disease patient leukocytes using optimised electrochemiluminescence immunoassays. AB - BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Optimizing peripheral quantification of huntingtin throughout the course of HD is valuable not only to illuminate the natural history and pathogenesis of disease, but also to detect peripheral effects of drugs in clinical trial. RATIONALE: We previously demonstrated that mutant HTT (mHTT) was significantly elevated in purified HD patient leukocytes compared with controls and that these levels track disease progression. Our present study investigates whether the same result can be achieved with a simpler and more scalable collection technique that is more suitable for clinical trials. METHODS: We collected whole blood at 133 patient visits in two sample sets and generated peripheral blood mononuclear cells (PBMCs). Levels of mHTT, as well as N-, and C-terminal and mid-region huntingtin were measured in the PBMCs using ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence immunoassay platforms, and we evaluated the relationship between different HTT species, disease stage, and brain atrophy on magnetic resonance imaging. CONCLUSIONS: The assays were sensitive and accurate. We confirm our previous findings that mHTT increases with advancing disease stage in patient PBMCs, this time using a simple collection protocol and scalable assay. PMID- 29272285 TI - Mean field analysis of algorithms for scale-free networks in molecular biology. AB - The sampling of scale-free networks in Molecular Biology is usually achieved by growing networks from a seed using recursive algorithms with elementary moves which include the addition and deletion of nodes and bonds. These algorithms include the Barabasi-Albert algorithm. Later algorithms, such as the Duplication Divergence algorithm, the Sole algorithm and the iSite algorithm, were inspired by biological processes underlying the evolution of protein networks, and the networks they produce differ essentially from networks grown by the Barabasi Albert algorithm. In this paper the mean field analysis of these algorithms is reconsidered, and extended to variant and modified implementations of the algorithms. The degree sequences of scale-free networks decay according to a powerlaw distribution, namely P(k) ~ k-gamma, where gamma is a scaling exponent. We derive mean field expressions for gamma, and test these by numerical simulations. Generally, good agreement is obtained. We also found that some algorithms do not produce scale-free networks (for example some variant Barabasi Albert and Sole networks). PMID- 29272286 TI - Research on the development efficiency of regional high-end talent in China: A complex network approach. AB - In this paper, based on the panel data of 31 provinces and cities in China from 1991 to 2016, the regional development efficiency matrix of high-end talent is obtained by DEA method, and the matrix is converted into a continuous change of complex networks through the construction of sliding window. Using a series of continuous changes in the complex network topology statistics, the characteristics of regional high-end talent development efficiency system are analyzed. And the results show that the average development efficiency of high end talent in the western region is at a low level. After 2005, the national regional high-end talent development efficiency network has both short-range relevance and long-range relevance in the evolution process. The central region plays an important intermediary role in the national regional high-end talent development system. And the western region has high clustering characteristics. With the implementation of the high-end talent policies with regional characteristics by different provinces and cities, the relevance of high-end talent development efficiency in various provinces and cities presents a weakening trend, and the geographical characteristics of high-end talent are more and more obvious. PMID- 29272288 TI - The dynamics of pico-sized and bloom-forming cyanobacteria in large water bodies in the Mekong River Basin. AB - In the face of plans for increased construction of dams and reservoirs in the Mekong River Basin, it is critically important to better understand the primary producer community of phytoplankton, especially the warm-water cyanobacteria. This is because these algae can serve as the primary source of carbon for higher trophic levels, including fishes, but can also form harmful blooms, threatening local fisheries and environmental and human health. We monitored the dynamics of three cyanobacteria-Synechococcus spp., Microcystis aeruginosa, and Dolichospermum spp.-for two years in nine large lakes and reservoirs in the Mekong River Basin. The densities of these algae were largely system-specific such that their abundance was uniquely determined within individual water bodies. However, after accounting for the system-specific effect, we found that cell densities of Synechococcus spp., M. aeruginosa, and Dolichospermum spp. varied in response to changes in photosynthetically active radiation (PAR), total nitrogen, and water level, respectively. Because both PAR and water level tend to fluctuate concordantly over a wide geographic area, Synechococcus spp., and to a lesser extent Dolichospermum spp., varied synchronously among the water bodies. Sustaining the production of pico-sized primary producers while preventing harmful algal blooms will be a key management goal for the proposed reservoirs in the Mekong Basin. PMID- 29272287 TI - Influence of cardiovascular condition on retinal and retinal nerve fiber layer measurements. AB - OBJECTIVE: To assess changes in the retinal nerve fiber layer (RNFL) and macula in subjects with cardiovascular risk factors or subclinical ischemia. DESIGN: Prospective and observational study. METHODS: A total of 152 healthy men underwent cardiovascular examination, including quantification of subclinical atheroma plaques by artery ultrasound scans, blood analysis, and a complete ophthalmic evaluation, including spectral-domain optical coherence tomography. The variables registered in cardiovascular examination were quantification of classic major risk factors, subclinical atheroma plaques by artery ultrasound scans, and analytical records. The ophthalmic evaluation registered RNFL and macular thickness. RESULTS: Mean subject age was 51.27+/-3.71 years. The 40 subjects without classic cardiovascular risk factors did not show differences in RNFL and macular thicknesses compared with the 112 subjects with at least one risk factor (except in sector 9 that showed higher thicknesses in subjects with >=1 risk factor). Comparison between the group of subjects with and without atheroma plaques revealed no differences in RNFL and macular thicknesses. The sub analysis of subjects with subclinical atheroma plaques in the common carotid artery revealed a significant reduction in central macular thickness in the left eye compared with the right eye (p = 0.016), RNFL in the superior quadrant (p = 0.007), and the 11 o'clock sector (p = 0.020). Comparison between smokers and nonsmokers revealed that smokers had significant thinning of the central macular thickness (p = 0.034), the nasal RNFL quadrant (p = 0.006), and the 3 and 5 o'clock sectors (p = 0.016 and 0.009). CONCLUSIONS: Classic cardiovascular risk factors do not cause RNFL or macular thickness reduction, but tobacco smoking habit reduces nasal RNFL thickness. Subclinical atherosclerosis in the common carotid artery associates a reduction in central macular and nasal RNFL quadrant thicknesses in the left eye compared with the right eye. PMID- 29272289 TI - Robotic exoskeleton assessment of transient ischemic attack. AB - We used a robotic exoskeleton to quantify specific patterns of abnormal upper limb motor behaviour in people who have had transient ischemic attack (TIA). A cohort of people with TIA was recruited within two weeks of symptom onset. All individuals completed a robotic-based assessment of 8 behavioural tasks related to upper limb motor and proprioceptive function, as well as cognitive function. Robotic task performance was compared to a large cohort of controls without neurological impairments corrected for the influence of age. Impairment in people with TIA was defined as performance below the 5th percentile of controls. Participants with TIA were also assessed with the National Institutes of Health Stroke Scale (NIHSS) score, Chedoke-McMaster Stroke Assessment (CMSA) of the arm, the Behavioural Inattention Test (BIT), the Purdue pegboard test (PPB), and the Montreal Cognitive Assessment (MoCA). Age-related white matter change (ARWMC), prior infarction and cella-media index (CMI) were assessed from baseline CT scan that was performed within 24 hours of TIA. Acute infarction was assessed from diffusion-weighted imaging in a subset of people with TIA. Twenty-two people with TIA were assessed. Robotic assessment showed impaired upper limb motor function in 7/22 people with TIA patients and upper limb sensory impairment in 4/22 individuals. Cognitive tasks involving robotic assessment of the upper limb were completed in 13 participants, of whom 8 (61.5%) showed significant impairment. Abnormal performance in the CMSA arm inventory was present in 12/22 (54.5%) participants. ARWMC was 11.8 +/- 6.4 and CMI was 5.4 +/- 1.5. DWI was positive in 0 participants. Quantitative robotic assessment showed that people who have had a TIA display a spectrum of upper limb motor and sensory performance deficits as well as cognitive function deficits despite resolution of symptoms and no evidence of tissue infarction. PMID- 29272290 TI - "It was pain. That's it. It was pain." Lack of oral health care among otherwise healthy young adults living with HIV in South Africa: A qualitative study. AB - INTRODUCTION: The purpose of this study is to understand engagement with and availability of dental services among people living with HIV in a low-income community of South Africa. METHODS: In depth qualitative interviewing was used to collect data, which was analyzed using an inductive content analytical approach. The study was conducted in Gugulethu, a township community located outside of Cape Town, South Africa. Local public sector health services provided free of charge are the main source of primary health and dental care for this population. Participants included South African adults (age 18-35) recently diagnosed with HIV who had a CD4 count >350 cells/mm3. RESULTS: Many participants had little to no experience with dental care, did not know which health care providers are appropriate to address oral health concerns, were not aware of available dental services, utilized home remedies to treat oral health problems, harbored many misperceptions of dental care, avoided dental services due to fear, and experienced poverty as a barrier to dental services. CONCLUSIONS: Our findings suggest that integration of oral healthcare into medical care may increase patient knowledge about oral health and access to care. Leveraging the relatively robust HIV infrastructure to address oral disease may also be an effective approach to reaching these participants and those living in resource poor communities generally. PMID- 29272291 TI - Norm, gender, and bribe-giving: Insights from a behavioral game. AB - Previous research has suggested that bribery is more normative in some countries than in others. To understand the underlying process, this paper examines the effects of social norm and gender on bribe-giving behavior. We argue that social norms provide information for strategic planning and impression management, and thus would impact participants' bribe amount. Besides, males are more agentic and focus more on impression management than females. We predicted that males would defy the norm in order to win when the amount of their bribe was kept private, but would conform to the norm when it was made public. To test this hypothesis, we conducted two studies using a competitive game. In each game, we asked three participants to compete in five rounds of creative tasks, and the winner was determined by a referee's subjective judgment of the participants' performance on the tasks. Participants were allowed to give bribes to the referee. Bribe-giving norms were manipulated in two domains: norm level (high vs. low) and norm context (private vs. public), in order to investigate the influence of informational and affiliational needs. Studies 1 and 2 consistently showed that individuals conformed to the norm level of bribe-giving while maintaining a relative advantage for economic benefit. Study 2 found that males gave larger bribes in the private context than in the public, whereas females gave smaller bribes in both contexts. We used a latent growth curve model (LGCM) to depict the development of bribe-giving behaviors during five rounds of competition. The results showed that gender, creative performance, and norm level all influence the trajectory of bribe-giving behavior. PMID- 29272292 TI - Knowledge, skills and attitudes of hospital pharmacists in the use of information technology and electronic tools to support clinical practice: A Brazilian survey. AB - : This study aimed to identify the knowledge, skills and attitudes of Brazilian hospital pharmacists in the use of information technology and electronic tools to support clinical practice. METHODS: A questionnaire was sent by email to clinical pharmacists working public and private hospitals in Brazil. The instrument was validated using the method of Polit and Beck to determine the content validity index. Data (n = 348) were analyzed using descriptive statistics, Pearson's Chi square test and Gamma correlation tests. RESULTS: Pharmacists had 1-4 electronic devices for personal use, mainly smartphones (84.8%; n = 295) and laptops (81.6%; n = 284). At work, pharmacists had access to a computer (89.4%; n = 311), mostly connected to the internet (83.9%; n = 292). They felt competent (very capable/capable) searching for a web page/web site on a specific subject (100%; n = 348), downloading files (99.7%; n = 347), using spreadsheets (90.2%; n = 314), searching using MeSH terms in PubMed (97.4%; n = 339) and general searching for articles in bibliographic databases (such as Medline/PubMed: 93.4%; n = 325). Pharmacists did not feel competent in using statistical analysis software (somewhat capable/incapable: 78.4%; n = 273). Most pharmacists reported that they had not received formal education to perform most of these actions except searching using MeSH terms. Access to bibliographic databases was available in Brazilian hospitals, however, most pharmacists (78.7%; n = 274) reported daily use of a non-specific search engine such as Google. This result may reflect the lack of formal knowledge and training in the use of bibliographic databases and difficulty with the English language. The need to expand knowledge about information search tools was recognized by most pharmacists in clinical practice in Brazil, especially those with less time dedicated exclusively to clinical activity (Chi-square, p = 0.006). CONCLUSION: These results will assist in defining minimal competencies for the training of pharmacists in the field of information technology to support clinical practice. Knowledge and skill gaps are evident in the use of bibliographic databases, spreadsheets and statistical tools. PMID- 29272293 TI - Perceived cervical cancer risk among women treated for high-grade cervical intraepithelial neoplasia: The importance of specific knowledge. AB - OBJECTIVE: Women with high-grade cervical intraepithelial neoplasia (CIN) are at increased risk for developing cervical cancer. We examine how women with high grade CIN perceive their own risk, and about pertinent knowledge concerning human high-risk papillomavirus (HPV), CIN and cervical cancer. METHODS: All patients who underwent first-time treatment of high-grade CIN (grade 2+) were followed-up at 6-months at the Karolinska University Hospital, Stockholm, Sweden and were invited to participate in the present study. This included completion of a questionnaire examining sociodemographic characteristics, self-perceived risk of cervical cancer without regular gynecologic follow-up, and 14 queries about HPV, CIN and cervical cancer knowledge, inter alia. RESULTS: The participation rate was 96.6%, with 479 women enrolled in this study. Over 75% were age 40 or younger, over half had completed university education. Most were married or co living with their partner and were gainfully employed. On a scale scored from 10 (highest self-perceived risk of cervical cancer without regular gynecologic follow-up) to 1 (lowest self-perceived risk), 64% rated their risk >= 7; almost 30% viewed their risk <= 6 and 7.5% did not rate their risk. A Specific Knowledge Scale with six of the queries explained 58.3% of the total variance. Nearly 30% of the women answered four or fewer of the six queries correctly. The Specific Knowledge Scale predicted self-perceived cervical cancer risk (Odds ratio = 11.3, 95% Confidence Interval 5.6 - 22.6) after adjusting for age, income and education. Most of the women with low self-perceived cervical cancer risk did not rate their HPV-related knowledge as good. However, 32 predominantly university educated women, with low self-perceived cervical cancer risk, considered their HPV-related knowledge good. CONCLUSION: It is vital to effectively convey accurate information about these patients' cervical cancer risk, needed preventive and follow-up measures, together with the relevant specific knowledge, for these women at increased risk for developing cervical cancer. Tailored programming to address these knowledge gaps is needed. PMID- 29272294 TI - Sparse coding reveals greater functional connectivity in female brains during naturalistic emotional experience. AB - Functional neuroimaging is widely used to examine changes in brain function associated with age, gender or neuropsychiatric conditions. FMRI (functional magnetic resonance imaging) studies employ either laboratory-designed tasks that engage the brain with abstracted and repeated stimuli, or resting state paradigms with little behavioral constraint. Recently, novel neuroimaging paradigms using naturalistic stimuli are gaining increasing attraction, as they offer an ecologically-valid condition to approximate brain function in real life. Wider application of naturalistic paradigms in exploring individual differences in brain function, however, awaits further advances in statistical methods for modeling dynamic and complex dataset. Here, we developed a novel data-driven strategy that employs group sparse representation to assess gender differences in brain responses during naturalistic emotional experience. Comparing to independent component analysis (ICA), sparse coding algorithm considers the intrinsic sparsity of neural coding and thus could be more suitable in modeling dynamic whole-brain fMRI signals. An online dictionary learning and sparse coding algorithm was applied to the aggregated fMRI signals from both groups, which was subsequently factorized into a common time series signal dictionary matrix and the associated weight coefficient matrix. Our results demonstrate that group sparse representation can effectively identify gender differences in functional brain network during natural viewing, with improved sensitivity and reliability over ICA-based method. Group sparse representation hence offers a superior data driven strategy for examining brain function during naturalistic conditions, with great potential for clinical application in neuropsychiatric disorders. PMID- 29272295 TI - Time to change focus? Transitioning from higher neonatal to higher stillbirth mortality in Sao Paulo State, Brazil. AB - BACKGROUND: Differential trends in mortality suggest that stillbirths may dominate neonatal mortality in the medium to long run. Brazil has made major efforts to improve data collection on health indicators at granular geographic levels, and provides an ideal environment to test this hypothesis. Our goals were to examine levels and trends in stillbirths and neonatal deaths and the extent to which the mortality burden caused by stillbirths dominates neonatal mortality at the municipality- and state-level. METHODS: We used data from the Brazilian Ministry of Health's repository on births, fetal, and neonatal deaths (2010-2014) to calculate stillbirth and neonatal mortality rates for Sao Paulo state's 645 municipalities. RESULTS: At the state level, 7.9 per 1000 pregnancies ended in stillbirth (fetal death >22 weeks gestation or fetal weight >500g), but this varied from 0.0 to 28.4 per 1000 across municipalities. 7.9 per 1000 live births also died within the first 28 days. 42% of municipalities had a higher stillbirth rate than neonatal mortality rate, and in 61% of areas with low neonatal mortality (<8.0 per 1000), stillbirth rates exceeded neonatal mortality rates. CONCLUSIONS: This analysis suggests large variability and inequality in mortality outcomes at the sub-national level. The results also imply that stillbirth mortality may exceed neonatal mortality in Brazil and similar settings in the next few decades, which suggests a need for a shift in policy. This work further underscores the importance of continued research into causes and prevention of stillbirth. PMID- 29272296 TI - Assessing robustness of hazard ratio estimates to outcome misclassification in longitudinal panel studies with application to Alzheimer's disease. AB - Analyses of imperfectly assessed time to event outcomes give rise to biased hazard ratio estimates. This bias is a common challenge for studies of Alzheimer's Disease (AD) because AD neuropathology can only be identified through brain autopsy and is therefore not available for most study participants. Clinical AD diagnosis, although more widely available, has imperfect sensitivity and specificity relative to AD neuropathology. In this study we present a sensitivity analysis approach using a bias-adjusted discrete proportional hazards model to quantify robustness of results to misclassification of a time to event outcome and apply this method to data from a longitudinal panel study of AD. Using data on 1,955 participants from the Adult Changes in Thought study we analyzed the association between average glucose level and AD neuropathology and conducted sensitivity analyses to explore how estimated hazard ratios varied according to AD classification accuracy. Unadjusted hazard ratios were closer to the null than estimates obtained under most scenarios for misclassification investigated. Confidence interval estimates from the unadjusted model were substantially underestimated compared to adjusted estimates. This study demonstrates the importance of exploring outcome misclassification in time to event analyses and provides an approach that can be undertaken without requiring validation data. PMID- 29272298 TI - Root growth and spatial distribution characteristics for seedlings raised in substrate and transplanted cotton. AB - In this study, transplanting cotton seedlings grown in artificial substrate is considered due to recent increased interest in cotton planting labor saving approaches. The nursery methods used for growing cotton seedlings affect root growth. However, the underlying functional responses of root growth to variations in cotton seedling transplanting methods are poorly understood. We assessed the responses of cotton (Gossypium hirsutum L.) roots to different planting methods by conducting cotton field experiments in 2012 and 2013. A one-factor random block design was used with three replications and three different cotton planting patterns (substrate seedling transplanted cotton (SSTC), soil-cube seedling transplanted cotton (ScSTC) and directly sown cotton (DSC). The distributions and variances of the root area density (RAD) and root length density (RLD) at different cotton growing stages and several yield components were determined. Overall, the following results were observed: 1) The RAD and RLD were greatest near the plants (a horizontal distance of 0 cm) but were lower at W20 and W40 cm in the absence of film mulching than at E20 and E40 cm with film mulching. 2) The roots were confined to shallow depths (20-40 cm), and the root depths of SSTC and DSC were greater than the root depths of ScSTC. 3) Strong root growth was observed in the SSTC at the cotton flowering and boll setting stages. In addition, early onset root growth occurred in the ScSTC, and vigorous root growth occurred throughout all cotton growth stages in DSC. 4) The SSTC plants had more lateral roots with higher root biomass (RB) than the ScSTC, which resulted in higher cotton yields. However, the early onset root growth in the ScSTC resulted in greater pre-frost seed cotton (PFSC) yields. These results can be used to infer how cotton roots are distributed in soils and capture nutrients. PMID- 29272297 TI - Temporal fractal analysis of the rs-BOLD signal identifies brain abnormalities in autism spectrum disorder. AB - BACKGROUND: Brain connectivity in autism spectrum disorders (ASD) has proven difficult to characterize due to the heterogeneous nature of the spectrum. Connectivity in the brain occurs in a complex, multilevel and multi-temporal manner, driving the fluctuations observed in local oxygen demand. These fluctuations can be characterized as fractals, as they auto-correlate at different time scales. In this study, we propose a model-free complexity analysis based on the fractal dimension of the rs-BOLD signal, acquired with magnetic resonance imaging. The fractal dimension can be interpreted as measure of signal complexity and connectivity. Previous studies have suggested that reduction in signal complexity can be associated with disease. Therefore, we hypothesized that a detectable difference in rs-BOLD signal complexity could be observed between ASD patients and Controls. METHODS AND FINDINGS: Anatomical and functional data from fifty-five subjects with ASD (12.7 +/- 2.4 y/o) and 55 age-matched (14.1 +/- 3.1 y/o) healthy controls were accessed through the NITRC database and the ABIDE project. Subjects were scanned using a 3T GE Signa MRI and a 32-channel RF-coil. Axial FSPGR-3D images were used to prescribe rs-BOLD (TE/TR = 30/2000ms) where 300 time points were acquired. Motion correction was performed on the functional data and anatomical and functional images were aligned and spatially warped to the N27 standard brain atlas. Fractal analysis, performed on a grey matter mask, was done by estimating the Hurst exponent in the frequency domain using a power spectral density approach and refining the estimation in the time domain with de trended fluctuation analysis and signal summation conversion methods. Voxel-wise fractal dimension (FD) was calculated for every subject in the control group and in the ASD group to create ROI-based Z-scores for the ASD patients. Voxel-wise validation of FD normality across controls was confirmed, and non-Gaussian voxels were eliminated from subsequent analysis. To maintain a 95% confidence level, only regions where Z-score values were at least 2 standard deviations away from the mean (i.e. where |Z| > 2.0) were included in the analysis. We found that the main regions, where signal complexity significantly decreased among ASD patients, were the amygdala (p = 0.001), the vermis (p = 0.02), the basal ganglia (p = 0.01) and the hippocampus (p = 0.02). No regions reported significant increase in signal complexity in this study. Our findings were correlated with ADIR and ADOS assessment tools, reporting the highest correlation with the ADOS metrics. CONCLUSIONS: Brain connectivity is best modeled as a complex system. Therefore, a measure of complexity as the fractal dimension of fluctuations in brain oxygen demand and utilization could provide important information about connectivity issues in ASD. Moreover, this technique can be used in the characterization of a single subject, with respect to controls, without the need for group analysis. Our novel approach provides an ideal avenue for personalized diagnostics, thus providing unique patient specific assessment that could help in individualizing treatments. PMID- 29272299 TI - Correction: Health assessment of future PM2.5 exposures from indoor, outdoor, and secondhand tobacco smoke concentrations under alternative policy pathways in Ulaanbaatar, Mongolia. AB - [This corrects the article DOI: 10.1371/journal.pone.0186834.]. PMID- 29272300 TI - Factors affecting availability for detection: An example using radio-collared Northern Bobwhite (Colinus virginianus). AB - Avian monitoring strategies are usually linked to bird singing or calling behavior. Individual availability for detection can change as a result of conspecific factors affecting bird behavior, though the magnitude of these effects is difficult to quantify. We evaluated behavioral and temporal factors affecting Northern Bobwhite (Colinus virginianus) breeding season individual availability for detection during three common survey times (3 min, 5 min, 10 min). We conducted 10-minute surveys associated with radio-collared male Northern Bobwhites on Peabody Wildlife Management Area, Kentucky, from 2010-2011. We homed to within 50 m of radio-collared males and recorded number of distinct Northern Bobwhite whistles (singing rate) per 1-minute interval, number of other males calling during the survey, minutes-since-sunrise, and day-of-season. We also recorded the number of minutes during a 10-minute survey that radio-collared male Northern Bobwhites called. We used logistic regression to estimate availability of radio-collared individuals for 3-minute, 5-minute, and 10-minute surveys. We also modeled number of minutes during 10-minute surveys that radio-collared Northern Bobwhites called, and we modeled singing rate. Individual availability for detection of radio-collared individuals during a 10-minute survey increased by 100% when at least 1 other Northern Bobwhite called during a survey (6.5% to 13.1%) and by 626% when 6 other Northern Bobwhites were calling (6.5% to 47.6%). Individual availability was 30% greater for 10-minute surveys than 5-minute surveys or 55% greater for 10-minute surveys than 3-minute surveys. Northern Bobwhite called most (2.8 +/- 0.66 minutes/10-min survey) and at a greater rate (11.8 +/- 1.3 calls/10-min period) when at least 5 other Northern Bobwhites called. Practitioners risk biasing population estimates low if individual availability is unaccounted for because species with low populations will not be stimulated by other calling males, are less likely to call, call less frequently, and call fewer times per minute, reducing their individual availability and likelihood to be counted on a survey even when they are present. PMID- 29272301 TI - Handwriting training in Parkinson's disease: A trade-off between size, speed and fluency. AB - BACKGROUND: In previous work, we found that intensive amplitude training successfully improved micrographia in Parkinson's disease (PD). Handwriting abnormalities in PD also express themselves in stroke duration and writing fluency. It is currently unknown whether training changes these dysgraphic features. OBJECTIVE: To determine the differential effects of amplitude training on various hallmarks of handwriting abnormalities in PD. METHODS: We randomized 38 right-handed subjects in early to mid-stage of PD into an experimental group (n = 18), receiving training focused at improving writing size during 30 minutes/day, five days/week for six weeks, and a placebo group (n = 20), receiving stretch and relaxation exercises at equal intensity. Writing skills were assessed using a touch-sensitive tablet pre- and post-training, and after a six-week retention period. Tests encompassed a transfer task, evaluating trained and untrained sequences, and an automatization task, comparing single- and dual task handwriting. Outcome parameters were stroke duration (s), writing velocity (cm/s) and normalized jerk (i.e. fluency). RESULTS: In contrast to the reported positive effects of training on writing size, the current results showed increases in stroke duration and normalized jerk after amplitude training, which were absent in the placebo group. These increases remained after the six-week retention period. In contrast, velocity remained unchanged throughout the study. CONCLUSION: While intensive amplitude training is beneficial to improve writing size in PD, it comes at a cost as fluency and stroke duration deteriorated after training. The findings imply that PD patients can redistribute movement priorities after training within a compromised motor system. PMID- 29272302 TI - A wild 'albino' bilberry (Vaccinium myrtillus L.) from Slovenia shows three bottlenecks in the anthocyanin pathway and significant differences in the expression of several regulatory genes compared to the common blue berry type. AB - Relative expressions of structural genes and a number of transcription factors of the anthocyanin pathway relevant in Vaccinium species, and related key enzyme activities were compared with the composition and content of metabolites in skins of ripe fruits of wild albino and blue bilberry (Vaccinium myrtillus) found in Slovenia. Compared to the common blue type, the albino variant had a 151-fold lower total anthocyanin and a 7-fold lower total phenolic content in their berry skin, which correlated with lower gene expression of flavonoid 3-O glycosyltransferase (FGT; 33-fold), flavanone 3-hydroxylase (FHT; 18-fold), anthocyanidin synthase (ANS; 11-fold), chalcone synthase (CHS, 7.6-fold) and MYBPA1 transcription factor (22-fold). The expression of chalcone isomerase (CHI), dihydroflavonol 4-reductase (DFR), leucoanthocyanidin reductase (LAR), anthocyanidin reductase (ANR) and MYBC2 transcription factor was reduced only by a factor of 1.5-2 in the albino berry skins, while MYBR3 and flavonoid 3',5' hydroxylase (F3'5'H) were increased to a similar extent. Expression of the SQUAMOSA class transcription factor TDR4, in contrast, was independent of the color type and does therefore not seem to be correlated with anthocyanin formation in this variant. At the level of enzymes, significantly lower FHT and DFR activities, but not of phenylalanine ammonia-lyase (PAL) and CHS/CHI, were observed in the fruit skins of albino bilberries. A strong increase in relative hydroxycinnamic acid derivative concentrations indicates the presence of an additional bottleneck in the general phenylpropanoid pathway at a so far unknown step between PAL and CHS. PMID- 29272303 TI - Aerobic capacity over 16 years in patients with rheumatoid arthritis: Relationship to disease activity and risk factors for cardiovascular disease. AB - The aim of this study was to analyse the change in aerobic capacity from disease onset of rheumatoid arthritis (RA) over 16.2 years, and its associations with disease activity and cardiovascular risk factors. Twenty-five patients (20 f/5 m), diagnosed with RA 1995-2002 were tested at disease onset and after mean 16.2 years. Parameters measured were: sub-maximal ergometer test for aerobic capacity, functional ability, self-efficacy, ESR, CRP and DAS28. At follow-up, cardiovascular risk factors were assessed as blood lipids, glucose concentrations, waist circumference, body mass index (BMI), body composition, pulse wave analysis and carotid intima-media thickness. Aerobic capacity [median (IQR)] was 32.3 (27.9-42.1) ml O2/kg x min at disease onset, and 33.2 (28.4-38.9) at follow-up (p>0.05). Baseline aerobic capacity was associated with follow-up values of: BMI (rs = -.401, p = .047), waist circumference (rs = -.498, p = .011), peripheral pulse pressure (rs = -.415, p = .039) self-efficacy (rs = .420, p = .037) and aerobic capacity (rs = .557, p = .004). In multiple regression models adjusted for baseline aerobic capacity, disease activity at baseline and over time predicted aerobic capacity at follow-up (AUC DAS28, 0-24 months; beta = -.14, p = .004). At follow-up, aerobic capacity was inversely associated with blood glucose levels (rs = -.508, p = .016), BMI (rs = -.434, p = .030), body fat% (rs = -.419, p = .037), aortic pulse pressure (rs = -.405, p = .044), resting heart rate (rs = -.424, p = .034) and self-efficacy (rs = .464, p = .020) at follow-up. We conclude that the aerobic capacity was maintained over 16 years. High baseline aerobic capacity associated with favourable measures of cardiovascular risk factors at follow-up. Higher disease activity in early stages of RA predicted lower aerobic capacity after 16.2 years. PMID- 29272304 TI - Running wheel exercise reduces alpha-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease. AB - Exercise has been recommended to improve motor function in Parkinson patients, but its value in altering progression of disease is unknown. In this study, we examined the neuroprotective effects of running wheel exercise in mice. In adult wild-type mice, one week of running wheel activity led to significantly increased DJ-1 protein concentrations in muscle and plasma. In DJ-1 knockout mice, running wheel performance was much slower and Rotarod performance was reduced, suggesting that DJ-1 protein is required for normal motor activity. To see if exercise can prevent abnormal protein deposition and behavioral decline in transgenic animals expressing a mutant human form of alpha-synuclein in all neurons, we set up running wheels in the cages of pre-symptomatic animals at 12 months old. Activity was monitored for a 3-month period. After 3 months, motor and cognitive performance on the Rotarod and Morris Water Maze were significantly better in running animals compared to control transgenic animals with locked running wheels. Biochemical analysis revealed that running mice had significantly higher DJ-1, Hsp70 and BDNF concentrations and had significantly less alpha-synuclein aggregation in brain compared to control mice. By contrast, plasma concentrations of alpha-synuclein were significantly higher in exercising mice compared to control mice. Our results suggest that exercise may slow the progression of Parkinson's disease by preventing abnormal protein aggregation in brain. PMID- 29272305 TI - A multiplex real-time PCR for the detection and differentiation of Campylobacter phages. AB - Campylobacter jejuni and C. coli are important food-borne pathogens that are widespread in animal husbandry. To combat Campylobacter along the food chain, the application of lytic phages has been shown to be a promising tool. Campylobacter phages are currently classified into three groups, of which group II and group III phages are the most common. Members of each group are closely related, whereas the two groups share only little DNA similarity. Moreover, while group III phages are specific for C. jejuni, group II phages additionally infect C. coli. Phage cocktails intended to be used for applications should be composed of various phages that differ in their host range and growth kinetics. The isolation of phages is generally performed by plaque assays. This approach has the limitation that phages are merely identified by their lytic activity on certain indicator strains and that relatively high numbers of phages must be present in a tested sample. Therefore, a more sensitive molecular detection system would be beneficial, which allows a pre-screening of samples and the quick detection and discrimination of group II and group III phages. New phages can then be isolated by use of indicator strains that may be different from those typically applied. On the basis of available Campylobacter phage genome sequences, we developed a multiplex PCR system for group II and group III phages selecting the tail tube gene and the gene for the base plate wedge, respectively, as target. Phages of both groups could be identified with primers deduced from the putative tail fiber gene. Efficient release of phage DNA from capsids was achieved by an extended heat treatment or digestion of phage particles with proteinase K/SDS yielding a detection limit of 1 pfu/ml. Individual detection of group II phages, group III phages and of both groups was studied with artificially contaminated chicken skin. To recover phages that had strongly adhered to the skin, stomaching was the most efficient technique. The developed PCR protocol was employed to detect Campylobacter phages in food and environmental samples. In 50 out of 110 samples group II and/or group III phages were identified. PMID- 29272306 TI - Impact of residential displacement on healthcare access and mental health among original residents of gentrifying neighborhoods in New York City. AB - OBJECTIVES: As gentrification continues in New York City as well as other urban areas, residents of lower socioeconomic status maybe at higher risk for residential displacement. Yet, there have been few quantitative assessments of the health impacts of displacement. The objective of this paper is to assess the association between displacement and healthcare access and mental health among the original residents of gentrifying neighborhoods in New York City. METHODS: We used 2 data sources: 1) 2005-2014 American Community Surveys to identify gentrifying neighborhoods in New York City, and 2) 2006-2014 Statewide Planning and Research Cooperative System. Our cohort included 12,882 residents of gentrifying neighborhoods in 2006 who had records of emergency department visits or hospitalization at least once every 2 years in 2006-2014. Rates of emergency department visits and hospitalizations post-baseline were compared between residents who were displaced and those who remained. RESULTS: During 2006-2014, 23% were displaced. Compared with those who remained, displaced residents were more likely to make emergency department visits and experience hospitalizations, mainly due to mental health (Rate Ratio = 1.8, 95% confidence interval = 1.5, 2.2), after controlling for baseline demographics, health status, healthcare utilization, residential movement, and the neighborhood of residence in 2006. CONCLUSIONS: These findings suggest negative impacts of displacement on healthcare access and mental health, particularly among adults living in urban areas and with a history of frequent emergency department visits or hospitalizations. PMID- 29272307 TI - Parent-progeny imputation from pooled samples for cost-efficient genotyping in plant breeding. AB - The increased usage of whole-genome selection (WGS) and other molecular evaluation methods in plant breeding relies on the ability to genotype a very large number of untested individuals in each breeding cycle. Many plant breeding programs evaluate large biparental populations of homozygous individuals derived from homozygous parent inbred lines. This structure lends itself to parent progeny imputation, which transfers the genotype scores of the parents to progeny individuals that are genotyped for a much smaller number of loci. Here we introduce a parent-progeny imputation method that infers individual genotypes from non-barcoded pooled samples of DNA of multiple individuals using a Hidden Markov Model (HMM). We demonstrate the method for pools of simulated maize double haploids (DH) from biparental populations, genotyped using a genotyping by sequencing (GBS) approach for 3,000 loci at 0.125x to 4x coverage. We observed high concordance between true and imputed marker scores and the HMM produced well calibrated genotype probabilities that correctly reflected the uncertainty of the imputed scores. Genomic estimated breeding values (GEBV) calculated from the imputed scores closely matched GEBV calculated from the true marker scores. The within-population correlation between these sets of GEBV approached 0.95 at 1x and 4x coverage when pooling two or four individuals, respectively. Our approach can reduce the genotyping cost per individual by a factor up to the number of pooled individuals in GBS applications without the need for extra sequencing coverage, thereby enabling cost-effective large scale genotyping for applications such as WGS in plant breeding. PMID- 29272309 TI - Independent relationship between serum ferritin levels and dyslipidemia in Chinese adults: A population study. AB - OBJECTIVE: Several studies have indicated that elevated levels of circulating ferritin are associated with disturbances in energy metabolism. But none of this gave a clearly pathologic mechanism. We aimed to explore the independent relationship between serum ferritin levels and dyslipidemia. METHODS: We performed multivariable logistic regression analyses to estimate the odds ratios (ORs) for dyslipidemia, lipid parameters, the homeostasis model assessment of insulin resistance (HOMA-IR) and the risk of diabetes, according to sex-specific quartiles of serum ferritin by using the data of China Health and Nutrition Survey (2009 CHNS). We used three models to estimate the strength of the correlation. The basic model (Model 1) is without adjustment and the Model 2 and Model 3 are adjusted for demographic, anthropometric, and lifestyle confounding factors. RESULTS: In both genders, the ORs for high TG level, TC level and LDL-C level increased progressively and for HDL-C decreased across the ferritin quartiles (P<0.001 for trend). After adjustment for confounding factors in different logistic regression models, the results remained unchanged. The ORs for the risk of diabetes and high HOMA-IR level in the highest quartile group of serum ferritin levels were significantly increased in Model 1, but after adjustment for lipid parameters, the ORs for the risk of diabetes was decreased from 1.91 (95% CI: 1.37-2.67; P<0.001 for trend) to 1.48 (95% CI: 1.03-2.12; P = 0.036 for trend) in men, and from 5.40 (95% CI: 3.38-8.63; P<0.001 for trend) to 1.43 (95% CI: 0.83-2.43; P = 0.498 for trend) in women, and the ORs for IR was decreased from 1.86 (95% CI: 1.57-2.20; P<0.001 for trend) to 1.25 (95% CI: 1.05 1.50; P = 0.114 for trend) in men, and from 1.93 (95% CI: 1.63-2.28; P<0.001 for trend) to 1.24 (95% CI: 1.01-1.51; P = 0.012 for trend) in women. CONCLUSION: Our results provide evidence that serum ferritin levels are significantly associated with lipid parameters, independent of glucose metabolism disorders and components of metabolic syndrome (MetS). Thus, serum ferritin plays a key role in energy metabolism disorders and may affect glucose metabolism through lipid metabolism. PMID- 29272308 TI - Restoration of type 1 iodothyronine deiodinase expression in renal cancer cells downregulates oncoproteins and affects key metabolic pathways as well as anti oxidative system. AB - Type 1 iodothyronine deiodinase (DIO1) contributes to deiodination of 3,5,3',5' tetraiodo-L-thyronine (thyroxine, T4) yielding of 3,5,3'-triiodothyronine (T3), a powerful regulator of cell differentiation, proliferation, and metabolism. Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells. However, the global effects of DIO1 expression in various tissues affected by cancer remain unknown. Here, the effects of stable DIO1 re expression were analyzed on the proteome of renal cancer cells, followed by quantitative real-time PCR validation in two renal cancer-derived cell lines. DIO1-induced changes in intracellular concentrations of thyroid hormones were quantified by L-MS/MS and correlations between expression of DIO1 and potential target genes were determined in tissue samples from renal cancer patients. Stable re-expression of DIO1, resulted in 26 downregulated proteins while 59 proteins were overexpressed in renal cancer cells. The 'downregulated' group consisted mainly of oncoproteins (e.g. STAT3, ANPEP, TGFBI, TGM2) that promote proliferation, migration and invasion. Furthermore, DIO1 re-expression enhanced concentrations of two subunits of thyroid hormone transporter (SLC7A5, SLC3A2), enzymes of key pathways of cellular energy metabolism (e.g. TKT, NAMPT, IDH2), sex steroid metabolism and anti-oxidative response (AKR1C2, AKR1B10). DIO1 expression resulted in elevated intracellular concentration of T4. Expression of DIO1-affected genes strongly correlated with DIO1 transcript levels in tissue samples from renal cancer patients as well as with their poor survival. This first study addressing effects of deiodinase re-expression on proteome of cancer cells demonstrates that induced DIO1 re-expression in renal cancer robustly downregulates oncoproteins, affects key metabolic pathways, and triggers proteins involved in anti-oxidative protection. This data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines. PMID- 29272310 TI - Long-chain n-3 and n-6 polyunsaturated fatty acids and risk of atrial fibrillation: Results from a Danish cohort study. AB - BACKGROUND: Studies of the relation between polyunsaturated fatty acids and risk of atrial fibrillation have been inconclusive. The risk of atrial fibrillation may depend on the interaction between n-3 and n-6 polyunsaturated fatty acids as both types of fatty acids are involved in the regulation of systemic inflammation. OBJECTIVE: We investigated the association between dietary intake of long chain polyunsaturated fatty acids (individually and in combination) and the risk of atrial fibrillation with focus on potential interaction between the two types of polyunsaturated fatty acids. DESIGN: The risk of atrial fibrillation in the Diet, Cancer and Health Cohort was analyzed using the pseudo-observation method to explore cumulative risks on an additive scale providing risk differences. Dietary intake of long chain polyunsaturated fatty acids was assessed by food frequency questionnaires. The main analyses were adjusted for the dietary intake of n-3 alpha-linolenic acid and n-6 linoleic acid to account for endogenous synthesis of long chain polyunsaturated fatty acids. Interaction was assessed as deviation from additivity of absolute association measures (risk differences). RESULTS: Cumulative risks in 15-year age periods were estimated in three strata of the cohort (N = 54,737). No associations between intake of n-3 or n-6 long chain polyunsaturated fatty acids and atrial fibrillation were found, neither when analyzed separately as primary exposures nor when interaction between n-3 and n-6 long chain polyunsaturated fatty acids was explored. CONCLUSION: This study suggests no association between intake of long chain polyunsaturated fatty acids and risk of atrial fibrillation. PMID- 29272311 TI - Genomic alterations during p53-dependent apoptosis induced by gamma-irradiation of Molt-4 leukemia cells. AB - Molt-4 leukemia cells undergo p53-dependent apoptosis accompanied by accumulation of de novo ceramide after 14 hours of gamma-irradiation. In order to identify the potential mediators involved in ceramide accumulation and the cell death response, differentially expressed genes were identified by Affymetrix Microarray Analysis. Molt-4-LXSN cells, expressing wild type p53, and p53-deficient Molt-4 E6 cells were irradiated and harvested at 3 and 8 hours post-irradiation. Human genome U133 plus 2.0 array containing >47,000 transcripts was used for gene expression profiling. From over 10,000 probes, 281 and 12 probes were differentially expressed in Molt-4-LXSN and Molt-4-E6 cells, respectively. Data analysis revealed 63 (upregulated) and 20 (downregulated) genes (>2 fold) in Molt 4-LXSN at 3 hours and 140 (upregulated) and 21 (downregulated) at 8 hours post irradiation. In Molt-4-E6 cells, 5 (upregulated) genes each were found at 3 hours and 8 hours, respectively. In Molt-4-LXSN cells, a significant fraction of the genes with altered expression at 3 hours were found to be involved in apoptosis signaling pathway (BCL2L11), p53 pathway (PMAIP1, CDKN1A and FAS) and oxidative stress response (FDXR, CROT and JUN). Similarly, at 8 hours the genes with altered expression were involved in the apoptosis signaling pathway (BAX, BIK and JUN), p53 pathway (BAX, CDKN1A and FAS), oxidative stress response (FDXR and CROT) and p53 pathway feedback loops 2 (MDM2 and CDKN1A). A global molecular and biological interaction map analysis showed an association of these altered genes with apoptosis, senescence, DNA damage, oxidative stress, cell cycle arrest and caspase activation. In a targeted study, activation of apoptosis correlated with changes in gene expression of some of the above genes and revealed sequential activation of both intrinsic and extrinsic apoptotic pathways that precede ceramide accumulation and subsequent execution of apoptosis. One or more of these altered genes may be involved in p53-dependent ceramide accumulation. PMID- 29272312 TI - Patients' perceptions of service quality in China: An investigation using the SERVQUAL model. AB - BACKGROUND AND AIM: The doctor-patient relationship has been a major focus of society. Hospitals' efforts to improve the quality of their medical services have been to reduce the probability of doctor-patient conflicts. In this study, we aimed to determine the gap between expectations and perceptions of service quality according to patients to provide reference data for creating strategies to improve health care quality. METHODS: Twenty-seven hospitals in 15 provinces (municipalities directly beneath the central government) were selected for our survey; we sent out 1,589 questionnaires, of which 1,520 were collected (response rate 95.65%) and 1,303 were valid (85.72% effective recovery rate). Paired t tests were used to analyze whether there were significant differences between patients' expectations and perceived service quality. A binary logistic regression analysis was used to determine whether there were significant differences in the gap between expectation and perception of service quality according to patients' demographic characteristics. RESULTS: There was a significant difference between the expected and perceived service quality (p < 0.05) according to patients both before and after receiving medical services. Furthermore, the service quality gap of each service dimension was negative. Specifically, the gaps in service quality were as follows: economy, responsiveness, empathy, assurance, reliability, and tangibles. Overall, we can conclude that patients' perceptions of service quality are lower than their expectations. CONCLUSIONS: According to the study results, the quality of health care services as perceived by patients was lower than expected. Hospitals should make adjustments according to the actual situation and should strive to constantly improve the quality of medical services for patients. PMID- 29272313 TI - Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma. AB - Asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness, mucus overproduction and airway remodeling. Notably, we have recently demonstrated that insulin-like growth factor 1 receptor (IGF1R) deficiency in mice attenuates airway hyperresponsiveness and mucus secretion after chronic house dust mite (HDM) exposure. On this basis, inbred C57BL/6 and Igf1r-deficient mice were given HDM extract to study the acute inflammatory profile and implication of Igf1r in acute asthma pathobiology. Additionally, Igf1r-deficiency was therapeutically induced in mice to evaluate the resolution of HDM-induced inflammation. Acute HDM exposure in inbred C57BL/6 mice led to a progressive increase in inflammation, airway remodeling and associated molecular indicators. Preventively-induced Igf1r-deficiency showed reduced neutrophil and eosinophil numbers in BALF and bone marrow, a significant reduction of airway remodeling and decreased levels of related markers. In addition, therapeutic targeting of Igf1r promoted the resolution of HDM-induced-inflammation. Our results demonstrate for the first time that Igf1r is important in acute asthma pathobiology and resolution of HDM-induced inflammation. Thus, IGF1R is suggested to be a promising candidate for future therapeutic approaches for the treatment and prevention of asthma. PMID- 29272314 TI - The integration of weighted gene association networks based on information entropy. AB - Constructing genome scale weighted gene association networks (WGAN) from multiple data sources is one of research hot spots in systems biology. In this paper, we employ information entropy to describe the uncertain degree of gene-gene links and propose a strategy for data integration of weighted networks. We use this method to integrate four existing human weighted gene association networks and construct a much larger WGAN, which includes richer biology information while still keeps high functional relevance between linked gene pairs. The new WGAN shows satisfactory performance in disease gene prediction, which suggests the reliability of our integration strategy. Compared with existing integration methods, our method takes the advantage of the inherent characteristics of the component networks and pays less attention to the biology background of the data. It can make full use of existing biological networks with low computational effort. PMID- 29272315 TI - Randomized clinical trials in dentistry: Risks of bias, risks of random errors, reporting quality, and methodologic quality over the years 1955-2013. AB - OBJECTIVES: To examine the risks of bias, risks of random errors, reporting quality, and methodological quality of randomized clinical trials of oral health interventions and the development of these aspects over time. METHODS: We included 540 randomized clinical trials from 64 selected systematic reviews. We extracted, in duplicate, details from each of the selected randomized clinical trials with respect to publication and trial characteristics, reporting and methodologic characteristics, and Cochrane risk of bias domains. We analyzed data using logistic regression and Chi-square statistics. RESULTS: Sequence generation was assessed to be inadequate (at unclear or high risk of bias) in 68% (n = 367) of the trials, while allocation concealment was inadequate in the majority of trials (n = 464; 85.9%). Blinding of participants and blinding of the outcome assessment were judged to be inadequate in 28.5% (n = 154) and 40.5% (n = 219) of the trials, respectively. A sample size calculation before the initiation of the study was not performed/reported in 79.1% (n = 427) of the trials, while the sample size was assessed as adequate in only 17.6% (n = 95) of the trials. Two thirds of the trials were not described as double blinded (n = 358; 66.3%), while the method of blinding was appropriate in 53% (n = 286) of the trials. We identified a significant decrease over time (1955-2013) in the proportion of trials assessed as having inadequately addressed methodological quality items (P < 0.05) in 30 out of the 40 quality criteria, or as being inadequate (at high or unclear risk of bias) in five domains of the Cochrane risk of bias tool: sequence generation, allocation concealment, incomplete outcome data, other sources of bias, and overall risk of bias. CONCLUSIONS: The risks of bias, risks of random errors, reporting quality, and methodological quality of randomized clinical trials of oral health interventions have improved over time; however, further efforts that contribute to the development of more stringent methodology and detailed reporting of trials are still needed. PMID- 29272317 TI - Instantaneous sediment transport model for asymmetric oscillatory sheet flow. AB - On the basis of advanced concentration and velocity profiles above a mobile seabed, an instantaneous analytical model is derived for sediment transport in asymmetric oscillatory flow. The applied concentration profile is obtained from the classical exponential law based on mass conservation, and asymmetric velocity profile is developed following the turbulent boundary layer theory and the asymmetric wave theory. The proposed model includes two parts: the basic part that consists of erosion depth and free stream velocity, and can be simplified to the total Shields parameter power 3/2 in accordance with the classical empirical models, and the extra vital part that consists of phase-lead, boundary layer thickness and erosion depth. The effects of suspended sediment, phase-lag and asymmetric boundary layer development are considered particularly in the model. The observed instantaneous transport rate proportional to different velocity exponents due to phase-lag is unified and summarised by the proposed model. Both instantaneous and half period empirical formulas are compared with the developed model, using extensive data on a wide range of flow and sediment conditions. The synchronous variation in instantaneous transport rate with free stream velocity and its decrement caused by increased sediment size are predicted correctly. Net transport rates, especially offshore transport rates with large phase-lag under velocity skewed flows, which existing instantaneous type formulas failed to predict, are predicted correctly in both direction and magnitude by the proposed model. Net sediment transport rates are affected not only by suspended sediment and phase-lag, but also by the boundary layer difference between onshore and offshore. PMID- 29272316 TI - Vitamin D receptor expression is essential during retinal vascular development and attenuation of neovascularization by 1, 25(OH)2D3. AB - Vitamin D provides a significant benefit to human health, and its deficiency has been linked to a variety of diseases including cancer. Vitamin D exhibits anticancer effects perhaps through inhibition of angiogenesis. We previously showed that the active form of vitamin D (1, 25(OH)2D3; calcitriol) is a potent inhibitor of angiogenesis in mouse model of oxygen-induced ischemic retinopathy (OIR). Many of vitamin D's actions are mediated through vitamin D receptor (VDR). However, the role VDR expression plays in vascular development and inhibition of neovascularization by 1, 25(OH)2D3 remains unknown. Here using wild type (Vdr +/+) and Vdr-deficient (Vdr -/-) mice, we determined the impact of Vdr expression on postnatal development of retinal vasculature and retinal neovascularization during OIR. We observed no significant effect on postnatal retinal vascular development in Vdr -/- mice up to postnatal day 21 (P21) compared with Vdr +/+ mice. However, we observed an increase in density of pericytes (PC) and a decrease in density of endothelial cells (EC) in P42 Vdr -/- mice compared with Vdr +/+ mice, resulting in a significant decrease in the EC/PC ratio. Although we observed no significant impact on vessel obliteration and retinal neovascularization in Vdr -/- mice compared with Vdr +/+ mice during OIR, the VDR expression was essential for inhibition of retinal neovascularization by 1, 25(OH)2D3. In addition, the adverse impact of 1, 25(OH)2D3 treatment on the mouse bodyweight was also dependent on VDR expression. Thus, VDR expression plays a significant role during retinal vascular development, especially during maturation of retinal vasculature by promoting PC quiescence and EC survival, and inhibition of ischemia-mediated retinal neovascularization by 1, 25(OH)2D3. PMID- 29272318 TI - Separation of 103Ru from a proton irradiated thorium matrix: A potential source of Auger therapy radionuclide 103mRh. AB - Ruthenium-103 is the parent isotope of 103mRh (t1/2 56.1 min), an isotope of interest for Auger electron therapy. During the proton irradiation of thorium targets, large amounts of 103Ru are generated through proton induced fission. The development of a two part chemical separation process to isolate 103Ru in high yield and purity from a proton irradiated thorium matrix on an analytical scale is described herein. The first part employed an anion exchange column to remove cationic actinide/lanthanide impurities along with the majority of the transition metal fission products. Secondly, an extraction chromatographic column utilizing diglycolamide functional groups was used to decontaminate 103Ru from the remaining impurities. This method resulted in a final radiochemical yield of 83 +/- 5% of 103Ru with a purity of 99.9%. Additionally, measured nuclear reaction cross sections for the formation of 103Ru and 106Ru via the 232Th(p,f)103,106Ru reactions are reported within. PMID- 29272321 TI - The "Stressful" Life of Cell Adhesion Molecules: On the Mechanosensitivity of Integrin Adhesome. AB - Cells have evolved into complex sensory machines that communicate with their microenvironment via mechanochemical signaling. Extracellular mechanical cues trigger complex biochemical pathways in the cell, which regulate various cellular processes. Integrin-mediated focal adhesions (FAs) are large multiprotein complexes, also known as the integrin adhesome, that link the extracellular matrix (ECM) to the actin cytoskeleton, and are part of powerful intracellular machinery orchestrating mechanotransduction pathways. As forces are transmitted across FAs, individual proteins undergo structural and functional changes that involve a conversion of chemical to mechanical energy. The local composition of early adhesions likely defines the regional stress levels and determines the type of newly recruited proteins, which in turn modify the local stress distribution. Various approaches have been used for detecting and exploring molecular mechanisms through which FAs are spatiotemporally regulated, however, many aspects are yet to be understood. Current knowledge on the molecular mechanisms of mechanosensitivity in adhesion proteins is discussed herein along with important questions yet to be addressed, are discussed. PMID- 29272320 TI - A systems-based assessment of the PrePex device adverse events active surveillance system in Zimbabwe. AB - BACKGROUND: Voluntary Medical Male Circumcision (VMMC) is an effective method for HIV prevention and the World Health Organization (WHO) has recommended its expansion in 14 African countries with a high prevalence of HIV and low prevalence of male circumcision. The WHO has recently pre-qualified the PrePex device, a non-surgical male circumcision device, which reduces procedure time, can increase acceptability of VMMC, and can expand the set of potential provider cadres. The PrePex device was introduced in Zimbabwe as a way to scale-up VMMC services in the country. With the rapid scale-up of the PrePex device, as well as other similar devices, a strong surveillance system to detect adverse events (AE) is needed to monitor the safety profile of these devices. We performed a systems based evaluation of the PrePex device AE active surveillance system in Zimbabwe. METHODS: The evaluation was based on the Centers for Disease Control and Prevention's Updated Guidelines for Evaluating Public Health Surveillance Systems. We adapted these guidelines to fit our local context. The evaluation incorporated the review of the standard operating procedures and surveillance system documents. Additionally, structured, in-person interviews were performed with key stakeholders who were users of the surveillance system at various levels. These key stakeholders were from the Ministry of Health, implementing partners, and health facilities in Harare. RESULTS: Clients were requested to return to the facility for follow-up on days 7, 14 and 49 after placement of the device. In the event of a severe AE, a standard report was generated by the health facility and relayed to the Ministry of Health Child and Care and donor agencies through predefined channels within 24 hours of diagnosis. Clinic staff reported difficulties with the amount of documentation required to follow up with clients and to report AEs. The surveillance system's acceptability among users interviewed was high, and users were motivated to identify all possible AEs related to this device. The surveillance system was purely paper-based and both duplicate and discrepant reporting forms between sites were identified. CONCLUSION: The PrePex AE active surveillance system was well accepted among participants in the health system. However, the amount of documentation which was required to follow-up with patients was a major barrier within the system, and might lead to decreased timeliness and quality of reporting. A passive surveillance system supported by electronic reporting would improve acceptance of the program. PMID- 29272319 TI - Rottlerin as a therapeutic approach in psoriasis: Evidence from in vitro and in vivo studies. AB - Rottlerin is a natural polyphenolic compound that was initially indicated as a PKCdelta inhibitor. However, it was recently revealed that it may target a number of molecules and have biological effects on various cell types and is considered as a possible agent for tumor and cell proliferative diseases. Psoriasis is a chronic inflammatory cutaneous disorder with undefined etiology and is characterized by abnormal cellular proliferation, angiogenesis, and inflammation. Therefore, this paper investigates the regulatory effects of rottlerin on normal human epidermal keratinocytes (NHEKs) and imiquimod (IMQ)-induced psoriasiform (IPI) lesions. In vitro results showed that rottlerin inhibited cell proliferation in NHEKs through growth arrest and NFkappaB inhibition. It may also induce apoptosis in an autophagy-dependent pathway. We found that rottlerin inhibited human microvascular endothelial cells tube formation on matrigel. Rottlerin also decreased the cell senescence of keratinocytes and intracellular ROS generation, which indicated its antioxidant effect. We also showed that rottlerin affects the expression of keratinocyte proliferation biomarkers. In 12 O-tetradecanoylphorbol13-acetate (TPA)-induced keratinocytes, rottlerin significantly inhibited the expression of the induced pro-inflammatory cytokines in keratinocytes. An animal experiment provided the corresponding evidence based on this evidence in vitro, by using IPI model, we found that rottlerin could relieve the psoriasiform of BALB/c mice by inhibiting keratinocyte proliferation, inflammatory cell infiltration, and vascular proliferation. In conclusion, our results suggest that rottlerin may prove useful in the development of therapeutic agents against psoriasis. However, the deep mechanism still requires further study. PMID- 29272322 TI - FLNa negatively regulated proliferation and metastasis in lung adenocarcinoma A549 cells via suppression of EGFR. AB - Filamin A (FLNa) is a ubiquitously expressed cytoplasmic protein, which composes of an N-terminal actin binding domain (ABD) followed by 24 Ig-like repeats. FLNa functions as a cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and serves as a signaling intermediate. Recent studies have identified FLNa as a scaffold protein that interacts with over 90 proteins and plays vital roles in cellular signaling transduction. Mutations or defects in human FLNa gene have been shown to cause numerous developmental defects. Moreover, aberrant expression of FLNa has been observed in many cancers, such as parathyroid tumor, cervical cancer, and breast cancer. However, its role in lung adenocarcinoma has seldom been discussed. In the present study, our in vitro and in vivo studies demonstrated that silencing FLNa expression in lung cancer cell line A549 cells promoted proliferation, migration, and invasiveness of A549 cells by enhancing the activation of epidermal growth factor receptor and ERK signaling pathway. These results shed light on novel functions of FLNa in lung cancer and uncovered novel mechanisms, these results provided possible targets for the prediction and treatment for lung adenocarcinoma. PMID- 29272323 TI - Scaffolding and working together: a qualitative exploration of strategies for everyday life with dementia. AB - Background: living with dementia has been described as a process of continual change and adjustment, with people with dementia and their families adopting informal strategies to help manage everyday life. As dementia progresses, families increasingly rely on help from the wider community and formal support. Methods: this article reports on a secondary analysis of qualitative data from focus groups and individual interviews with people with dementia and their carers in the North of England. In total, 65 people with dementia and 82 carers took part in the research: 26 in interviews and 121 in focus groups. Focus group and interview audio recordings were transcribed verbatim. A qualitative, inductive, thematic approach was taken for data analysis. Findings: the article applies the metaphor of scaffolding to deepen understanding of the strategies used by families. Processes of scaffolding were evident across the data where families, communities, professionals and services worked together to support everyday life for people with dementia. Within this broad theme of scaffolding were three sub themes characterising the experiences of families living with dementia: doing things together; evolving strategies; and fragility and fear of the future. Conclusions: families with dementia are resourceful but do need increasing support (scaffolding) to continue to live as well as possible as dementia progresses. More integrated, proactive work is required from services that recognises existing scaffolds and provides appropriate support before informal strategies become unsustainable; thus enabling people with dementia to live well for longer. PMID- 29272324 TI - Bioinformatics for precision oncology. AB - Molecular profiling of tumor biopsies plays an increasingly important role not only in cancer research, but also in the clinical management of cancer patients. Multi-omics approaches hold the promise of improving diagnostics, prognostics and personalized treatment. To deliver on this promise of precision oncology, appropriate bioinformatics methods for managing, integrating and analyzing large and complex data are necessary. Here, we discuss the specific requirements of bioinformatics methods and software that arise in the setting of clinical oncology, owing to a stricter regulatory environment and the need for rapid, highly reproducible and robust procedures. We describe the workflow of a molecular tumor board and the specific bioinformatics support that it requires, from the primary analysis of raw molecular profiling data to the automatic generation of a clinical report and its delivery to decision-making clinical oncologists. Such workflows have to various degrees been implemented in many clinical trials, as well as in molecular tumor boards at specialized cancer centers and university hospitals worldwide. We review these and more recent efforts to include other high-dimensional multi-omics patient profiles into the tumor board, as well as the state of clinical decision support software to translate molecular findings into treatment recommendations. PMID- 29272325 TI - GRAM-CNN: a deep learning approach with local context for named entity recognition in biomedical text. AB - Motivation: Best performing named entity recognition (NER) methods for biomedical literature are based on hand-crafted features or task-specific rules, which are costly to produce and difficult to generalize to other corpora. End-to-end neural networks achieve state-of-the-art performance without hand-crafted features and task-specific knowledge in non-biomedical NER tasks. However, in the biomedical domain, using the same architecture does not yield competitive performance compared with conventional machine learning models. Results: We propose a novel end-to-end deep learning approach for biomedical NER tasks that leverages the local contexts based on n-gram character and word embeddings via Convolutional Neural Network (CNN). We call this approach GRAM-CNN. To automatically label a word, this method uses the local information around a word. Therefore, the GRAM CNN method does not require any specific knowledge or feature engineering and can be theoretically applied to a wide range of existing NER problems. The GRAM-CNN approach was evaluated on three well-known biomedical datasets containing different BioNER entities. It obtained an F1-score of 87.26% on the Biocreative II dataset, 87.26% on the NCBI dataset and 72.57% on the JNLPBA dataset. Those results put GRAM-CNN in the lead of the biological NER methods. To the best of our knowledge, we are the first to apply CNN based structures to BioNER problems. Availability and implementation: The GRAM-CNN source code, datasets and pre trained model are available online at: https://github.com/valdersoul/GRAM-CNN. Contact: andyli@ece.ufl.edu or aconesa@ufl.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29272326 TI - On the Identification of Culturable Microorganisms for the Assessment of Biodiversity in Bioaerosols. AB - The Annals of Work Exposures and Health recently published two interesting studies combining the use of culture and molecular methods. The method involves the cultivation of bioaerosol samples on agar media and the pick-up of grown colonies 16S rRNA gene amplification, subsequent cloning, sequencing, and identification of bacterial isolates through the assignment against known gene databases. The aim of the present paper is to discuss the contribution of the proposed method in regards with the already proposed approaches used for identification of cultured bacteria. It details the new proposed method and discusses its contribution to the existing culture-based identification methods. Such methods include macroscopic and microscopic observations, miniature biochemical tests (API(r) trips, VITEK 2(r) etc.), chemical methods such as the Fatty Acid Methyl Ester (FAME) and the Matrix-assisted laser desorption/ionization time off light (MALDI-TOF) analysis as well polymerase chain reaction (PCR) followed by sequencing. The proposed method supplements the panel of existing biodiversity ones for cultivated bacteria, especially useful for infectious microorganisms, as well as culture-independent ones. As both culture-based and culture-independent methods could therefore be used for the characterization of the occupational environmental microbiome, further applications in other occupational environments as well as additional comparisons with both culture-based and culture-independent methods would complete its characterization. PMID- 29272327 TI - Developing a 'personalome' for precision medicine: emerging methods that compute interpretable effect sizes from single-subject transcriptomes. AB - : The development of computational methods capable of analyzing -omics data at the individual level is critical for the success of precision medicine. Although unprecedented opportunities now exist to gather data on an individual's -omics profile ('personalome'), interpreting and extracting meaningful information from single-subject -omics remain underdeveloped, particularly for quantitative non sequence measurements, including complete transcriptome or proteome expression and metabolite abundance. Conventional bioinformatics approaches have largely been designed for making population-level inferences about 'average' disease processes; thus, they may not adequately capture and describe individual variability. Novel approaches intended to exploit a variety of -omics data are required for identifying individualized signals for meaningful interpretation. In this review-intended for biomedical researchers, computational biologists and bioinformaticians-we survey emerging computational and translational informatics methods capable of constructing a single subject's 'personalome' for predicting clinical outcomes or therapeutic responses, with an emphasis on methods that provide interpretable readouts. KEY POINTS: (i) the single-subject analytics of the transcriptome shows the greatest development to date and, (ii) the methods were all validated in simulations, cross-validations or independent retrospective data sets. This survey uncovers a growing field that offers numerous opportunities for the development of novel validation methods and opens the door for future studies focusing on the interpretation of comprehensive 'personalomes' through the integration of multiple -omics, providing valuable insights into individual patient outcomes and treatments. PMID- 29272328 TI - Kidney Appreciates Stable Blood Pressure. PMID- 29272329 TI - Scroll Reconstruction: Fine Tuning of the Interface Between Middle and Lower Thirds in Rhinoplasty. AB - Background: The junction between upper and lower lateral cartilages, known as "the scroll area," is an important determinant of the spatial relationship between the middle and lower nasal thirds. Objectives: We offer a graduated and reproducible surgical technique of scroll area management, that takes into consideration anatomic, functional and aesthetic relationships. Methods: This study was a retrospective review of the recorded intraoperative information to investigate the frequency of the use of scroll reconstruction techniques and perioperative parameters that relate to unintended component alterations in the scroll area. 364 consecutive primary open approach rhinoplasty cases performed by the first author (O.B.) between July 2011 and September 2015 were included in the study. Results: Of the 364 cases who underwent primary open approach rhinoplasty, 329 received some form of scroll reconstruction. Scroll reconstruction was performed in all deviated cases, and 88% of straight noses. The most common technique for scroll reconstruction was overlapping repair (88.3%). As expected, both alar rim and alar crease asymmetries were very frequent in the deviated nose group, 89.4% and 75% respectively. Alar rim and alar crease asymmetries were frequent enough in the straight nose group to deserve special attention, 14.2% and 10.4% respectively. Conclusions: With careful attention to anatomic details of the scroll area, nasal tip refinements can be performed with predictable safety and accuracy. Our approach is a graduated, reproducible, and individualized way of scroll area management that aims to create the ideal cartilage configuration while preventing unintended component alterations. PMID- 29272330 TI - Anthracycline cardiotoxicity: the importance of horizontally integrating pre clinical and clinical research. PMID- 29272331 TI - The use of purified rat Leydig cells complements the H295R screen to detect chemical-induced alterations in testosterone production. AB - Exposure to endocrine disrupting chemicals has been associated with compromised testosterone production leading to abnormal male reproductive development and altered spermatogenesis. In vitro high-throughput screening (HTS) assays are needed to evaluate risk to testosterone production, yet the main steroidogenesis assay currently utilized is a human adrenocortical carcinoma cell line, H295R, which does not synthesize gonadal steroids at the same level as the gonads, thus limiting assay sensitivity. Here, we propose a complementary assay using a highly purified rat Leydig cell assay to evaluate the potential for chemical-induced alterations in testosterone production by the testis. We evaluated a subset of chemicals that failed to decrease testosterone production in the HTS H295R assay. The chemicals examined fit into one of two categories based on changes in substrates upstream of testosterone in the adrenal steroidogenic pathway (17alpha hydroxyprogesterone and 11-deoxycorticosterone) that we predicted should have elicited a decrease in testosterone production. We found that 85% of 20 test chemicals examined inhibited Leydig cell testosterone production in our assay. Importantly, we adopted a 96-well format to increase throughput and efficiency of the Leydig cell assay. We identified a selection criterion based on the AC50 values for 17alpha-hydroxyprogesterone and 11-deoxycorticosterone generated from the HTS H295R assay that will help prioritize chemicals for further testing in the Leydig cell screen. We hypothesize that the greater dynamic range of testosterone production and sensitivity of the Leydig cell assay permits the detection of small, yet significant, chemical-induced changes not detected by the HTS H295R assay. PMID- 29272332 TI - Comparing the Impact of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease. PMID- 29272334 TI - Reply to Theilacker et al. PMID- 29272335 TI - Multi-omics integration-a comparison of unsupervised clustering methodologies. AB - With the recent developments in the field of multi-omics integration, the interest in factors such as data preprocessing, choice of the integration method and the number of different omics considered had increased. In this work, the impact of these factors is explored when solving the problem of sample classification, by comparing the performances of five unsupervised algorithms: Multiple Canonical Correlation Analysis, Multiple Co-Inertia Analysis, Multiple Factor Analysis, Joint and Individual Variation Explained and Similarity Network Fusion. These methods were applied to three real data sets taken from literature and several ad hoc simulated scenarios to discuss classification performance in different conditions of noise and signal strength across the data types. The impact of experimental design, feature selection and parameter training has been also evaluated to unravel important conditions that can affect the accuracy of the result. PMID- 29272333 TI - Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept. AB - Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-beta oligomer-induced expression of Kv1.3 and Kir2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed Kv1.3 and Kir2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-beta oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule Kv1.3 blocker PAP-1 as a tool, we showed that pro inflammatory and neurotoxic microglial responses induced by amyloid-beta oligomer required Kv1.3 activity in vitro and in hippocampal slices. Since we further observed that Kv1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological Kv1.3 inhibition could mitigate the pathology induced by amyloid beta aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-beta uptake by microglia. Collectively, these results provide proof-of-concept data to advance Kv1.3 blockers to Alzheimer's disease clinical trials. PMID- 29272336 TI - The importance of early immunotherapy in patients with faciobrachial dystonic seizures. AB - Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduced disability at 24 months. Furthermore, of 80 patients with faciobrachial dystonic seizures as their initial feature, 56% developed cognitive impairment after 90 days of active faciobrachial dystonic seizures. Whereas only one patient developed cognitive impairment after cessation of faciobrachial dystonic seizures (P < 0.0001). All patients had IgG4 LGI1 antibodies, but those with cognitive impairment had higher proportions of complement-fixing IgG1 antibodies (P = 0.03). Both subclasses caused LGI1-ADAM22 complex internalization, a potential non-inflammatory epileptogenic mechanism. In summary, faciobrachial dystonic seizures show striking time-sensitive responses to immunotherapy, and their cessation can prevent the development of cognitive impairment.awx323media15681705685001. PMID- 29272337 TI - Urine Testing During Hospitalization: We Need to Keep Digging. PMID- 29272338 TI - Identification of sex differences in zebrafish (Danio rerio) brains during early sexual differentiation and masculinization using 17alpha-methyltestoterone. AB - Sexual behavior in teleost fish is highly plastic. It can be attributed to the relatively few sex differences found in adult brain transcriptomes. Environmental and hormonal factors can influence sex-specific behavior. Androgen treatment stimulates behavioral masculinization. Sex dimorphic gene expression in developing teleost brains and the molecular basis for androgen-induced behavioral masculinization are poorly understood. In this study, juvenile zebrafish (Danio rerio) were treated with 100 ng/L of 17 alpha-methyltestosterone (MT) during sexual development from 20 days post fertilization to 40 days and 60 days post fertilization. We compared brain gene expression patterns in MT-treated zebrafish with control males and females using RNA-Seq to shed light on the dynamic changes in brain gene expression during sexual development and how androgens affect brain gene expression leading to behavior masculinization. We found modest differences in gene expression between juvenile male and female zebrafish brains. Brain aromatase (cyp19a1b), prostaglandin 3a synthase (ptges3a), and prostaglandin reductase 1 (ptgr1) were among the genes with sexually dimorphic expression patterns. MT treatment significantly altered gene expression relative to both male and female brains. Fewer differences were found among MT-treated brains and male brains compared to female brains, particularly at 60 dpf. MT treatment upregulated the expression of hydroxysteroid 11-beta dehydrogenase 2 (hsd11b2), deiodinase, iodothyronine, type II (dio2), and gonadotrophin releasing hormones (GnRH) 2 and 3 (gnrh2 and gnrh3) suggesting local synthesis of 11 ketotestosterone, triiodothyronine, and GnRHs in zebrafish brains which are influenced by androgens. Androgen, estrogen, prostaglandin, thyroid hormone, and GnRH signaling pathways likely interact to modulate teleost sexual behavior. PMID- 29272339 TI - Personal Cancer Genome Reporter: variant interpretation report for precision oncology. AB - Summary: Individual tumor genomes pose a major challenge for clinical interpretation due to their unique sets of acquired mutations. There is a general scarcity of tools that can (i) systematically interrogate cancer genomes in the context of diagnostic, prognostic, and therapeutic biomarkers, (ii) prioritize and highlight the most important findings and (iii) present the results in a format accessible to clinical experts. We have developed a stand-alone, open source software package for somatic variant annotation that integrates a comprehensive set of knowledge resources related to tumor biology and therapeutic biomarkers, both at the gene and variant level. Our application generates a tiered report that will aid the interpretation of individual cancer genomes in a clinical setting. Availability and implementation: The software is implemented in Python/R, and is freely available through Docker technology. Documentation, example reports, and installation instructions are accessible via the project GitHub page: https://github.com/sigven/pcgr. Contact: sigven@ifi.uio.no. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29272340 TI - Erratum to: "Sex Differences in Risk for Alzheimer's Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study". PMID- 29272341 TI - Evaluating the Risk Factors for Hospital-Onset Clostridium difficile Infections in a Large Healthcare System. AB - In this multicenter retrospective cohort study of over 1 million patients at 150 US hospitals, proton pump inhibitors increased the odds of a patient having hospital-onset Clostridium difficile infection as did third and fourth generation cephalosporins, carbapenems, and piperacillin/tazobactam. These findings support appropriate prescribing of acid-suppression therapy and high-risk antibiotics. PMID- 29272342 TI - In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines. AB - Ghrelin gene generates several variants that regulate multiple pathophysiological functions, including tumor-related processes. In1-ghrelin is a splicing variant that was previously shown to be overexpressed in breast cancer (BCa), where it correlated with proliferation markers; however, its possible association with clinical outcome of BCa patients and underlying mechanisms are still unknown. To address this issue, expression levels and clinical associations of In1-ghrelin were analyzed in a cohort of 117 BCa samples. Additionally, a battery of cellular and molecular assays was implemented using two BCa cell lines (MCF-7 and MDA-MB 231), wherein the role of In1-ghrelin on proliferation, migration, dedifferentiation and signaling pathways was explored. The results generated revealed that high expression of In1-ghrelin in BCa samples was associated with lymph node metastasis and reduced disease-free survival. Indeed, In1-ghrelin overexpression stimulated proliferation and migration in MCF-7 and MDA-MB-231 cells. Similar results were found by treating MDA-MB-231 and MCF-7 with In1 ghrelin-derived peptides. Conversely, In1-ghrelin silencing decreased proliferation and migration capacities of MDA-MB-231. Furthermore, In1-ghrelin (but not ghrelin) overexpression increased the capacity to form mammospheres in both cell lines. These effects could be associated with activation of MAPK-ERK, Jag1/Notch, Wnt/beta-catenin and/or TGF-beta1 pathways. Altogether, our data indicate that In1-ghrelin could play relevant functional roles in the regulation of BCa development and progression and may provide insights to identify novel biomarkers and new therapeutic approaches for this pathology. PMID- 29272344 TI - Reply to Reisler et al. PMID- 29272343 TI - Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study. AB - Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 +/- 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 +/- 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease. PMID- 29272345 TI - Effects of active immunization with newly modified GnRH peptides on spermatogenesis and production performance of Holstein bulls. AB - Immunocastration via vaccination against gonadotropin-releasing hormone (GnRH) is an effective alternative to surgical castration in livestock. In this study, male mice were immunized with eight GnRH peptide derivatives. Two, which exhibited highly significant effects in mice, and one which exhibited the least significant effects were selected for active immunization of 13-month-old bulls. The effects of these GnRH vaccines on sexual development and meat quality in bulls were evaluated by examining testis length, serum hormone and GnRH antibody concentrations, observation of sexual behavior and testicular tissue sections, and evaluation of meat quality indexes. The results indicated that anti-GnRH titers increased rapidly (P < 0.05) and serum follicle stimulating hormone, luteinizing hormone, and testosterone concentrations decreased sharply after booster immunization (P < 0.05), while testis volumes were lower (P < 0.01), testicular growth was arrested and spermatogenesis inhibited in group C GnRH treated versus control bull groups. Meat quality was not significantly different in immunocastrates relative to bulls in the control group. Our collective results provide a scientific basis to further clarify the mechanisms underlying GnRH mediated regulation of livestock reproduction, and contribute to the development of an efficient, safe, and reversible immune castration vaccine. PMID- 29272347 TI - Impact of Fecal Microbiota Transplantation for Decolonization of Multidrug Resistant Organisms May Vary According to Donor Microbiota. PMID- 29272346 TI - Effectiveness of Protease Inhibitor/Nucleos(t)ide Reverse Transcriptase Inhibitor Based Second-line Antiretroviral Therapy for the Treatment of Human Immunodeficiency Virus Type 1 Infection in Sub-Saharan Africa: A Systematic Review and Meta-analysis. AB - Background: In sub-Saharan Africa, 25.5 million people are living with human immunodeficiency virus (HIV), representing 70% of the global total. The need for second-line antiretroviral therapy (ART) is projected to increase in the next decade in keeping with the expansion of treatment provision. Outcome data are required to inform policy. Methods: We performed a systematic review and meta analysis of studies reporting the virological outcomes of protease inhibitor (PI) based second-line ART in sub-Saharan Africa. The primary outcome was virological suppression (HIV-1 RNA <400 copies/mL) after 48 and 96 weeks of treatment. The secondary outcome was the proportion of patients with PI resistance. Pooled aggregate data were analyzed using a DerSimonian-Laird random effects model. Results: By intention-to-treat analysis, virological suppression occurred in 69.3% (95% confidence interval [CI], 58.2%-79.3%) of patients at week 48 (4558 participants, 14 studies), and in 61.5% (95% CI, 47.2%-74.9%) at week 96 (2145 participants, 8 studies). Preexisting resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) increased the likelihood of virological suppression. Major protease resistance mutations occurred in a median of 17% (interquartile range, 0-25%) of the virological failure population and increased with duration of second-line ART. Conclusions: One-third of patients receiving PI based second-line ART with continued NRTI use in sub-Saharan Africa did not achieve virological suppression, although among viremic patients, protease resistance was infrequent. Significant challenges remain in implementation of viral load monitoring. Optimizing definitions and strategies for management of second-line ART failure is a research priority. Prospero Registration: CRD42016048985. PMID- 29272348 TI - TCGA-assembler 2: software pipeline for retrieval and processing of TCGA/CPTAC data. AB - Motivation: The Cancer Genome Atlas (TCGA) program has produced huge amounts of cancer genomics data providing unprecedented opportunities for research. In 2014, we developed TCGA-Assembler, a software pipeline for retrieval and processing of public TCGA data. In 2016, TCGA data were transferred from the TCGA data portal to the Genomic Data Commons (GDCs), which is supported by a different set of data storage and retrieval mechanisms. In addition, new proteomics data of TCGA samples have been generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) program, which were not available for downloading through TCGA-Assembler. It is desirable to acquire and integrate data from both GDC and CPTAC. Results: We develop TCGA-assembler 2 (TA2) to automatically download and integrate data from GDC and CPTAC. We make substantial improvement on the functionality of TA2 to enhance user experience and software performance. TA2 together with its previous version have helped more than 2000 researchers from 64 countries to access and utilize TCGA and CPTAC data in their research. Availability of TA2 will continue to allow existing and new users to conduct reproducible research based on TCGA and CPTAC data. Availability and implementation: http://www.compgenome.org/TCGA-Assembler/ or https://github.com/compgenome365/TCGA-Assembler-2. Contact: zhuyitan@gmail.com or koaeraser@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29272349 TI - Hepatitis C in Patients With Minimal or No Hepatic Fibrosis: The Impact of Treatment and Sustained Virologic Response on Patient-Reported Outcomes. AB - Background: While the necessity of treatment of hepatitis C virus (HCV)-infected patients with advanced liver disease is widely accepted, the benefit of treating patients without significant liver disease is less well established. Our aim was to assess the effect of treating HCV in patients with no or minimal fibrosis (Metavir stage F0-F1) on patient-reported outcomes (PROs). Methods: HCV-infected patients with F0-F1 from 16 clinical trials were included. PROs were collected before, during, and after treatment. Results: A total of 1548 HCV-infected patients with F0-F1 were included (mean age 46 years, 43% male, 81% treatment naive). Patients were treated with interferon (IFN) + sofosbuvir (SOF) + ribavirin (RBV) (n = 91) or SOF + RBV with or without ledipasvir (n = 479) or IFN and RBV-free regimens with SOF + ledipasvir or SOF + velpatasvir or SOF + velpatasvir + voxilaprevir (n = 978). By the end of treatment, patients receiving IFN-containing regimens experienced significant decreases in most PRO domains ( 4.5 to -28.7 on a 0-100 scale), while subjects treated with IFN-free RBV containing regimens had a modest impairment (-2.3 to -8.9) (P <= .01). In contrast, treatment with regimens without IFN and RBV led to PRO improvements (+1.2 to +10.9). Regardless of the regimen, sustained virologic responses (SVRs) at 12 and 24 weeks were universally associated with PRO improvements (+2.1 to +14.7, P < .0001. Conclusions: HCV-infected subjects with no or minimal fibrosis treated with IFN- and RBV-free regimens experienced on-treatment and post-SVR PRO improvements. PMID- 29272350 TI - Gestational restricted- and over-feeding promote maternal and offspring inflammatory responses that are distinct and dependent on diet in sheep. AB - Inflammation may be a mechanism of maternal programming because it has the capacity to alter the maternal environment and can persist postnatally in offspring tissues. This study evaluated the effects of restricted- and over feeding on maternal and offspring inflammatory gene expression using reverse transcription (RT)-PCR arrays. Pregnant ewes were fed 60% (Restricted), 100% (Control), or 140% (Over) of National Research Council requirements beginning on day 30.2 +/- 0.2 of gestation. Maternal (n = 8-9 ewes per diet) circulating nonesterified fatty acid (NEFA) and expression of 84 inflammatory genes were evaluated at five stages during gestation. Offspring (n = 6 per diet per age) inflammatory gene expression was evaluated in the circulation and liver at day 135 of gestation and birth. Throughout gestation, circulating NEFA increased in Restricted mothers but not Over. Expression of different proinflammatory mediators increased in Over and Restricted mothers, but was diet-dependent. Maternal diet altered offspring systemic and hepatic expression of genes involved in chemotaxis at late gestation and cytokine production at birth, but the offspring response was distinct from the maternal. In the perinatal offspring, maternal nutrient restriction increased hepatic chemokine (CC motif) ligand 16 and tumor necrosis factor expression. Alternately, maternal overnutrition increased offspring systemic expression of factors induced by hypoxia, whereas expression of factors regulating hepatocyte proliferation and differentiation were altered in the liver. Maternal nutrient restriction and overnutrition may differentially predispose offspring to liver dysfunction through an altered hepatic inflammatory microenvironment that contributes to immune and metabolic disturbances postnatally. PMID- 29272351 TI - Nuclear Androgen Receptor Regulates Testes Organization and Oocyte Maturation in Zebrafish. AB - Androgens act through the nuclear androgen receptor (AR) to regulate gonad differentiation and development. In mice, AR is necessary for spermatogenesis, testis development, and formation of external genitalia in males and oocyte maturation in females. However, the extent to which these phenotypes are conserved in nonmammalian vertebrates is not well understood. Here, we generate zebrafish with a mutation in the ar gene (aruab105/105) and examine the role of AR in sexual determination and gonad development. We found that zebrafish AR regulates male sexual determination, because the majority of aruab105/105 mutant embryos developed ovaries and displayed female secondary sexual characteristics. The small percentage of mutants that developed testes displayed female secondary sexual characteristics, exhibited structurally disorganized testes, and were unable to release or produce normal levels of sperm, demonstrating that AR is necessary for zebrafish testis development and fertility. In females, we found that AR regulates oocyte maturation and fecundity. The aruab105/105 mutant females developed ovaries filled primarily with immature stage I oocytes and few mature stage III oocytes. Two genes whose expression is enriched in wild-type ovaries compared with testes (cyp19a1a, foxl2a) were upregulated in ar mutant testes, and two genes enriched in testes (amh, dmrt1) were upregulated in ar mutant ovaries. These findings demonstrate that AR regulates sexual determination, testis development, and oocyte maturation and suggest that AR regulates sexually dimorphic gene expression. The ar mutant we developed will be useful for modeling human endocrine function in zebrafish. PMID- 29272352 TI - Missing value imputation for LC-MS metabolomics data by incorporating metabolic network and adduct ion relations. AB - Motivation: Metabolomics data generated from liquid chromatography-mass spectrometry platforms often contain missing values. Existing imputation methods do not consider underlying feature relations and the metabolic network information. As a result, the imputation results may not be optimal. Results: We proposed an imputation algorithm that incorporates the existing metabolic network, adduct ion relations even for unknown compounds, as well as linear and nonlinear associations between feature intensities to build a feature-level network. The algorithm uses support vector regression for missing value imputation based on features in the neighborhood on the network. We compared our proposed method with methods being widely used. As judged by the normalized root mean squared error in real data-based simulations, our proposed methods can achieve better accuracy. Availability and implementation: The R package is available at http://web1.sph.emory.edu/users/tyu8/MINMA. Contact: jiankang@umich.edu or tianwei.yu@emory.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29272353 TI - New Promising Combo Therapy in Inflammatory Bowel Diseases Refractory to Anti-TNF Agents: Cyclosporine Plus Vedolizumab. PMID- 29272355 TI - Three-Dimensional Imaging and Breast Measurements: How Predictable Are We? AB - Background: Outcomes in aesthetic breast surgery are dependent on preoperative breast measurements. The accuracy of 3-dimensional (3D) imaging in measuring critical landmarks in augmentation mammaplasty surgery has not been described. Objectives: We aimed to determine the predictability of 3D imaging compared to direct measurements. Methods: Two raters measured the breasts of 28 women using four anthropometric (direct) measurements: sternal notch to nipple distance (Sn N), nipple to midline (N-M), nipple to inframammary-fold distance under maximal stretch (N-IMF), and base width (BW). Measurements (indirect) were also obtained using 3D imaging. Statistical analysis was completed with Bland-Altman plots. Results: Each rater collected 56 data points for each of the four measurements. This resulted in 224 data points per rater. The Sn-N measurement had a 0.05 cm (SD, 0.65) difference in the mean values obtained between direct and indirect measurements. N-M had a mean difference of 0.20 cm (SD, 0.62). The mean difference for BW was 1.26 cm (SD, 0.69 cm), and N-IMF showed a mean difference of 1.22 cm (SD, 0.74 cm). Three-dimensional imaging overestimated Sn-N, N-M, and BW, while it underestimated N-IMF. Conclusions: Three-dimensional imaging has good utility and is most accurate for Sn-N and N-M measurements, which require frontal imaging of a standing patient. BW and N-IMF are less accurate due to obscured landmarks on frontal imaging. The medial and lateral aspects of the breast may be obscured when measuring BW on 3D imaging, which may explain this difference. N-IMF is a dynamic measurement, and as a result, 3D imaging has limited ability to measure this distance accurately. Level of Evidence 3: PMID- 29272354 TI - Impact of the Reclassification of "Noninvasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma" to "Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features" on the Bethesda System for Reporting Thyroid Cytopathology: A Large Academic Institution's Experience. AB - Objectives: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (NEFVPTC) was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Excluding "carcinoma" from the new terminology shifted NIFTP out of the malignant category and altered Bethesda System for Reporting Thyroid Cytopathology (BSRTC) rates of malignancy (ROMs) on thyroid fine-needle aspiration (FNA). Because of potential effects on management guidelines, we examined our ROM data. Methods: In total, 750 thyroid FNAs with surgical resections from January 2013 to June 2016 were reviewed (including 87 NIFTPs). ROM was recorded for each BSRTC category: classifying NEFVPTC/NIFTP as "malignant" and reclassifying NEFVPTC/NIFTP as "nonmalignant." Results: ROM changes were as follows: nondiagnostic (ND), no change; benign, 5.5% to 2.5%; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 42.3% to 22.3%; follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 48.7% to 17.9%; suspicious for malignancy (SFM), 93.6% to 61.7%; and positive for malignancy, 100% to 97%. Conclusions: Decreased ROM was seen in most BSRTC categories, most significantly in AUS/FLUS, FN/SFN, and SFM categories. PMID- 29272356 TI - GRP94 Is an Essential Regulator of Pancreatic beta-Cell Development, Mass, and Function in Male Mice. AB - Deficiencies in pancreatic beta-cell mass contribute to both type 1 and type 2 diabetes. We investigated the role of the glucose-regulated protein (GRP) 94, an endoplasmic reticulum protein abundantly expressed in the pancreatic acini and islets, in beta-cell development, survival, and function. We used a conditional knockout (KO) mouse in which the GRP94 gene, Hsp90b1, was specifically deleted in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. These Hsp90b1 flox/flox;Pdx1Cre KO mice exhibited pancreatic hypoplasia at embryonic day (E) 16.5 to E18.5 and had significantly reduced beta-cell mass at 4 weeks after birth. Further mechanistic studies showed that deletion of GRP94 reduced beta cell proliferation with increased cell apoptosis in both Pdx1+ endocrine progenitor cells and differentiated beta cells. Although Hsp90b1 flox/flox;Pdx1Cre KO mice remained euglycemic at 8 weeks of age, they exhibited impaired glucose tolerance. In aggregate, these findings indicate that GRP94 is an essential regulator of pancreatic beta-cell development, mass, and function. PMID- 29272358 TI - The use of antidepressants in oncology: a review and practical tips for oncologists. AB - Background: The use of psychotropic drugs, namely those with an antidepressant profile (ADs), is a mandatory part of an integrated treatment of psychiatric disorders among cancer patients. We aimed to synthetize the most relevant data emerging from published studies to provide tips about the use of ADs in oncology. Design: A search was made of the major databases over the last 30 years (Embase/Medline, PsycLIT, PsycINFO, the Cochrane Library), including narrative reviews, systematic reviews and meta-analyses summarizing the results from observational studies and randomized clinical trials assessing effectiveness, safety profile, interactions, contraindications and use of ADs in oncology with regard to both psychiatric (depressive spectrum, stress-related, anxiety disorders) and cancer-related symptoms (e.g. pain, hot flashes and fatigue). Results: The weight of evidence supports the efficacy of ADs for more severe major depression in individuals with cancer and as an adjuvant treatment in cancer-related symptoms, although the methodological limitations of reported randomized controlled trials do not permit definite conclusions. Data also indicate that there should be caution in the use of ADs in cancer patients in terms of their safety profile and potential clinically significant interactions with other prescribed medications. Practical recommendations that have been made for the use of ADs in cancer patients, in the context of a multimodal approach to depression treatment, have been summarized here. Conclusions: ADs are a relatively safe and effective treatment for more severe major depression in cancer patients. However, more research is urgently needed regarding the efficacy of ADs in different cancer types and cancer settings, their interactions with anticancer agents and their additive benefit when integrated with psychosocial interventions. PMID- 29272357 TI - Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. AB - Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Deltawhite matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury. PMID- 29272359 TI - BioSeq-Analysis: a platform for DNA, RNA and protein sequence analysis based on machine learning approaches. AB - With the avalanche of biological sequences generated in the post-genomic age, one of the most challenging problems is how to computationally analyze their structures and functions. Machine learning techniques are playing key roles in this field. Typically, predictors based on machine learning techniques contain three main steps: feature extraction, predictor construction and performance evaluation. Although several Web servers and stand-alone tools have been developed to facilitate the biological sequence analysis, they only focus on individual step. In this regard, in this study a powerful Web server called BioSeq-Analysis (http://bioinformatics.hitsz.edu.cn/BioSeq-Analysis/) has been proposed to automatically complete the three main steps for constructing a predictor. The user only needs to upload the benchmark data set. BioSeq-Analysis can generate the optimized predictor based on the benchmark data set, and the performance measures can be reported as well. Furthermore, to maximize user's convenience, its stand-alone program was also released, which can be downloaded from http://bioinformatics.hitsz.edu.cn/BioSeq-Analysis/download/, and can be directly run on Windows, Linux and UNIX. Applied to three sequence analysis tasks, experimental results showed that the predictors generated by BioSeq Analysis even outperformed some state-of-the-art methods. It is anticipated that BioSeq-Analysis will become a useful tool for biological sequence analysis. PMID- 29272361 TI - Cancer and Alcohol Consumption in People Aged 50 Years or More in Europe. AB - Aims: To estimate the prevalence of hazardous drinking in individuals aged 50 and older who had or had had cancer in 17 European countries and Israel and to analyze the factors associated with their consumption. Methods: Cross-sectional study based on data from 2011 to 2013 SHARE surveys. A total of 69,509 individuals aged 50 or more from 17 European countries and Israel participated in the study. Prevalence of hazardous drinking in people with cancer was estimated (adapting the SHARE questionnaire to the AUDIT-C). To ascertain whether type of cancer or time since diagnosis were associated with hazardous drinking, Poisson regression models with robust variance were estimated, obtaining prevalence ratios (PR). Results: Overall, 5.4% of participants reported having been diagnosed with cancer. Prevalence of hazardous drinking in people with cancer was 18% in women and 23% in men. After adjusting for various socioeconomic and health variables, no significant differences were observed between hazardous drinking and type of cancer [PR = 0.99 (95% confidence interval (95% CI) = 0.83-1.17) in people with alcohol-related cancers compared to non-alcohol related cancers] and time since diagnosis [PR = 1.01 (95% CI = 0.82-1.25) in people with a cancer diagnosed >5 years ago compared to those diagnosed <=5 years ago]. Significant differences were found between hazardous drinking and smoking status and self perceived health. Conclusion: In total, 20% of people diagnosed with cancer were hazardous drinkers, despite the known relationship between alcohol use and a worse prognosis of the disease and an increased likelihood of recurrence. Short Summary: Overall, 20% of people diagnosed with cancer were hazardous drinkers. There were no significant differences in the prevalence of hazardous drinking depending on the type of cancer (alcohol-related versus non-alcohol related cancers). Highest prevalence of hazardous drinking in people with cancer is found in smokers and people with good self-perceived health. PMID- 29272362 TI - Deployment of Transchromosomal Bovine for Personalized Antimicrobial Therapy. AB - For decades, intravenous immunoglobulin (IVIg) has provided safe and effective therapy for immunodeficient patients. This proof-of-principle study describes a novel approach to generate personalized IVIg for chronic, antibiotic-resistant infection in real time. PMID- 29272360 TI - alpha7-Nicotinic Acetylcholine Receptor Agonist Ameliorates Nicotine Plus High Fat Diet-Induced Hepatic Steatosis in Male Mice by Inhibiting Oxidative Stress and Stimulating AMPK Signaling. AB - alpha7-Nicotinic acetylcholine receptor (alpha7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether PNU-282987 (PNU), a specific alpha7nAChR agonist, is effective in preventing nicotine plus HFD induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily intraperitoneal injections of 0.75 mg/kg body weight (BW) of nicotine, PNU (0.26 mg/kg BW), PNU plus nicotine, or saline for 10 weeks. PNU treatment was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis, and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress and activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) together with inhibition of its downstream target sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl coenzyme A-carboxylase (ACC). We conclude that the alpha7nAChR agonist PNU protects against nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. alpha7nAChR agonists may be an effective therapeutic strategy for ameliorating fatty liver disease, especially in obese smokers. PMID- 29272363 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy: an electrocardiogram based review. AB - Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD/C) is a pathologic condition where the right ventricle is partially or totally replaced by fatty and fibrous tissue. The electrocardiogram (ECG) has a central role for diagnosis since it comprises two major and two minor criteria in the diagnostic criteria published by the Task 1 Force, although it is not 100% necessary to make a final diagnosis, because around 10% of patients with ARVD/C present with a normal ECG. In this article, we review the 12-lead electrocardiographic findings of patients with ARVD/C. ECG criteria observed during depolarization [prolonged terminal activation duration, epsilon wave, partial right bundle branch block (RBBB) and advanced RBBB of peripheral origin with characteristic ECG patterns] and repolarization abnormalities, (negative T waves) are reviewed in detail. More common ventricular arrhythmias and risk of sudden death, and how to use the surface ECG to stratify the risk, are part of our final comments. PMID- 29272364 TI - Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. AB - Background: We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron emission tomography adapted dose-escalation of second-line BV was utilized. Patients and methods: Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. Results: Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. Conclusions: Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717). PMID- 29272366 TI - Timing of myocardial shortening determines left ventricular regional myocardial work and regional remodelling in hearts with conduction delays. AB - Aims: The interaction between asynchronous regional myocardial activation and left ventricular (LV) wall remodelling has not been well established. We investigated the relationship between time of onset of longitudinal shortening (Tonset), regional myocardial work, and segmental LV wall thickness (SWT) in patients treated with cardiac resynchronization therapy (CRT). Methods and results: We analysed 26 patients with sinus rhythm, non-ischaemic cardiomyopathy (63 +/- 9 years, 69% male, QRS duration 174 +/- 18 ms) and positive response to CRT (15% reduction in end-systolic volume). Longitudinal strain was obtained by 2D speckle-tracking echocardiography before and after [14.5 (7-29) months] CRT. Tonset and SWT were measured in 18 segments per LV. Segmental myocardial work was calculated from non-invasive segmental stress-strain loop area. Before CRT, Tonset was the shortest in septal and anteroseptal and the longest in lateral and posterior walls (P < 0.001) and not different after CRT (P = 0.733). Before CRT, septal and anteroseptal walls were significantly thinner than lateral and posterior. After CRT, reverse remodelling increased thickness in septal and anteroseptal and thinned lateral and posterior segments (P < 0.001). Before CRT, non-uniformity in work distribution with reduced work in septal and anteroseptal and increased work in lateral and posterior walls (P < 0.001) was observed. After CRT, distribution of myocardial work was uniform (P = 0.215). Conclusion: Dys synchronous myocardial shortening is related to thinning of early and thickening of late activated segments in heart failure with conduction delay. Correction of dys-synchrony leads to regression of inhomogeneity towards more evenly distributed wall thickness. Regional differences in myocardial work load that are homogenized by successful CRT are considered as the underlying pathophysiological mechanism. PMID- 29272365 TI - Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother Infant Pairs Enrolled in a Large Perinatal Study. AB - Background: The presence of antiretroviral drug-associated resistance mutations (DRMs) may be particularly problematic in human immunodeficiency virus (HIV) infected pregnant women as it can lead to mother-to-child transmission (MTCT) of resistant HIV strains. This study evaluated the prevalence and the effect of antiretroviral DRMs in previously untreated mother-infant pairs. Methods: A case control design of 1:4 (1 transmitter to 4 nontransmitters) was utilized to evaluate DRMs as a predictor of HIV MTCT in specimens obtained from mother-infant pairs. ViroSeq HIV-1 genotyping was performed on mother-infant specimens to assess for clinically relevant DRMs. Results: One hundred forty infants acquired HIV infection; of these, 123 mother-infant pairs (88%) had specimens successfully amplified using ViroSeq and assessed for drug resistance genotyping. Additionally, 483 of 560 (86%) women who did not transmit HIV to infants also had samples evaluated for DRMs. Sixty-three of 606 (10%) women had clinically relevant DRMs; 12 (2%) had DRMs against >1 drug class. Among 123 HIV-infected infants, 13 (11%) had clinically relevant DRMs, with 3 (2%) harboring DRMs against >1 drug class. In univariate and multivariate analyses, DRMs in mothers were not associated with increased HIV MTCT (adjusted odds ratio, 0.8 [95% confidence interval, .4-1.5]). Presence of DRMs in transmitting mothers was strongly associated with DRM presence in their infants (P < .001). Conclusions: Preexisting DRMs were common in untreated HIV-infected pregnant women, but did not increase the risk of HIV MTCT. However, if women with DRMs are not virologically suppressed, they may transmit resistant mutations, thus complicating infant management. PMID- 29272367 TI - 2017 expert consensus statement on catheter and surgical ablation of atrial fibrillation: letter to the Editor. PMID- 29272368 TI - Increased Cervical Human Immunodeficiency Virus (HIV) RNA Shedding Among HIV Infected Women Randomized to Loop Electrosurgical Excision Procedure Compared to Cryotherapy for Cervical Intraepithelial Neoplasia 2/3. AB - Background: Treatment of human immunodeficiency virus (HIV)-infected women to prevent cervical cancer may stimulate HIV RNA cervical shedding and risk HIV transmission. Methods: From 2011 to 2014, 400 HIV-infected women diagnosed with cervical intraepithelial neoplasia 2/3 in Kenya were randomized to loop electrosurgical excision procedure (LEEP) or cryotherapy. Cervical samples were collected at baseline and 3 weekly intervals. Samples were tested for HIV RNA using the Gen-Probe Aptima HIV assay with a minimum detection level of 60 copies/swab and analyzed using generalized estimating equations. Results: Women who received LEEP had significantly higher cervical HIV RNA levels than those who received cryotherapy at weeks 2 (adjusted incident rate ratio [aIRR], 1.07; P = .038) and 3 (aIRR, 1.08; P = .046). Within LEEP, significantly higher cervical shedding was found at weeks 2 (2.03 log10 copies/swab; P < .001) and 3 (2.04 log10 copies/swab; P < .001) compared to baseline (1.80 log10 copies/swab). Cervical HIV RNA was significantly higher following LEEP for up to 3 weeks among women on antiretroviral treatment (ART) (0.18 log10 copies/swab increase; P = .003) and in ART-naive women (1.13 log10 copies/swab increase; P < .001) compared to baseline. Within cryotherapy, cervical shedding increased in ART-naive women (0.72 log10 copies/swab increase; P = 0.004) but did not increase in women on ART. Conclusions: Women randomized to LEEP had a larger increase in post procedural cervical HIV shedding than cryotherapy. Benefits of cervical cancer prevention outweigh the risk of HIV sexual transmission; our findings underscore the importance of risk-reduction counseling. Clinical Trials Registration: NCT01298596. PMID- 29272371 TI - Risk factors for postoperative complications and long-term survival in lung cancer patients older than 80 years. AB - OBJECTIVES: The number of octogenarian lung cancer patients undergoing radical surgery has been increasing recently. However, knowledge regarding the risk factors for postoperative complications and reliable predictive factors for long term survival is limited. This study aimed to investigate the risk factors of postoperative complications, and reliable prognostic factors, in lung cancer patients older than 80 years. METHODS: Lung cancer patients aged 80 years or older who underwent radical surgery were retrospectively studied; a multi institutional analysis was conducted from January 1998 to December 2015. Preoperative and postoperative clinical data, including age, gender, smoking history, body mass index, respiratory function, Charlson Comorbidity Index, Glasgow Prognostic Score, surgical procedure, cancer histology, clinical and pathological stage, surgical result and survival time, were collected. RESULTS: A total of 337 patients, comprising 216 (64.1%) men and 121 (35.9%) women were enrolled. The median age was 82 (range 80-92) years. Of the 337 patients, 205 (60.8%) had preoperative comorbidities. Postoperative complications were observed in 119 (35.3%) patients; postoperative mortalities occurred in 6 (1.8%) patients. Univariate and multivariate analyses showed that male gender (P = 0.01) and operation time (P = 0.047) were associated with postoperative complications; in contrast, pathological Stage III (P < 0.001), male gender (P = 0.01), Charlson Comorbidity Index >=2 (P = 0.03) and Glasgow Prognostic Score = 1/2 (P = 0.04) were independent prognostic factors for overall survival. CONCLUSIONS: The risk factors for postoperative complications (male gender and operation time) and the predictive factors affecting long-term survival (male gender, Charlson Comorbidity Index, Glasgow Prognostic Score and P-stage) should be taken into account for the effective management of patients older than 80 years with lung cancer, undergoing surgery. PMID- 29272372 TI - MIB-1 index is unlikely to predict relapse-free survival in patients who underwent R0-esophagectomy for esophageal squamous cell carcinoma. AB - MIB-1 is a cell proliferation marker and has previously been investigated as a diagnostic or prognostic indicator of malignancy. Previous studies have investigated MIB-1 index and clinicopathological factors in relation to prognosis of patients with esophageal cancer, with conflicting results. The aim of this study is to assess the prognostic significance of MIB-1 index in patients with thoracic esophageal squamous cell carcinoma. A total of 78 patients who underwent R0-esophagectomy for thoracic esophageal squamous cell carcinoma were enrolled in this study. Preoperatively, 29 patients underwent chemotherapy, six underwent chemoradiotherapy, and the remaining did not undergo any preoperative therapy. The MIB-1 labeling index was reported by counting 500 tumor cells in the hot spots of nuclear labeling. Correlations between MIB-1 index, clinicopathological factors, and relapse-free survival (RFS) were investigated. The mean MIB-1 index was 39.3 +/- 21.0 (range: 0-91.3). There was no significant correlation between clinicopathological factors and MIB-1 index in the study patients, irrespective of whether they underwent preoperative therapy. Univariate analysis revealed no significant association between MIB-1 index and RFS. However, depth of tumor invasion, lymph node metastasis and stage, all showed a significant correlation to RFS. Multivariate analysis of RFS revealed that stage was the only significant factor. Conversely, MIB-1 index was not significantly related to RFS (p = 0.41). In conclusion, MIB-1 index is unlikely to be a significant prognostic indicator for esophageal cancer. PMID- 29272373 TI - Transthyretin amyloidosis in a septuagenarian masquerading as hypertrophic cardiomyopathy: the importance of multimodality imaging. PMID- 29272370 TI - A Novel Hantavirus of the European Mole, Bruges Virus, Is Involved in Frequent Nova Virus Coinfections. AB - Hantaviruses are zoonotic viruses with a complex evolutionary history of virus host coevolution and cross-species transmission. Although hantaviruses have a broad reservoir host range, virus-host relationships were previously thought to be strict, with a single virus species infecting a single host species. Here, we describe Bruges virus, a novel hantavirus harbored by the European mole (Talpa europaea), which is the well-known host of Nova virus. Phylogenetic analyses of all three genomic segments showed tree topology inconsistencies, suggesting that Bruges virus has emerged from cross-species transmission and ancient reassortment events. A high number of coinfections with Bruges and Nova viruses was detected, but no evidence was found for reassortment between these two hantaviruses. These findings highlight the complexity of hantavirus evolution and the importance of further investigation of hantavirus-reservoir relationships. PMID- 29272374 TI - Giant intramuscular cavernous haemangioma of the chest wall. PMID- 29272375 TI - De-novo Inflammatory Bowel Disease After Bariatric Surgery: A Large Case Series. AB - Background: Case reports of inflammatory bowel diseases [IBD] have been reported in patients with a history of bariatric surgery. Our aim was to characterize patients who were diagnosed with IBD after having undergone bariatric surgery. Methods: Electronic medical records were reviewed at two institutions to identify patients who developed de-novo Crohn's disease or ulcerative colitis [UC] after bariatric surgery. Data on demographics, type of bariatric surgical procedure, IBD subtype, phenotype and medication usage were obtained. The incidence rate of de-novo IBD after bariatric surgery [per 100000 person-years] and standardized incidence ratio [SIR] were estimated from a prospective bariatric surgery database. Results: A total of 44 patients with de-novo IBD after bariatric surgery were identified [31 Crohn's disease, 12 UC, one IBD unclassified]. Most patients were female [88.6%], with median age at IBD onset of 44 years [IQR, 37 52] and median time to IBD diagnosis after bariatric surgery of 7 years [IQR, 3 10]. Sixty-eight per cent underwent Roux-en-Y gastric bypass. In the prospective database, the incidence of IBD in patients who underwent bariatric surgery was 26.7 per 100000 person-years [4.5 for UC and 22.3 for Crohn's disease]. The age adjusted SIR ranged from 3.56 in the 40-49 year age group to 4.73 in the 30-39 year age group. Conclusion: We described a case series of patients developing de novo IBD after bariatric surgery. There appears to be a numerically higher incidence of Crohn's disease in this population. Confirmation of causality is required in larger patient cohorts. PMID- 29272369 TI - Human Immunodeficiency Virus Type 1 Group O Infection in France: Clinical Features and Immunovirological Response to Antiretrovirals. AB - Background: To obtain reliable clinical data of human immunodeficiency virus type 1 group O (HIV-1/O) infection, and immunovirological responses to combination antiretroviral therapy (cART), in a large series of 101 patients. Methods: Piecewise linear models were used to estimate CD4 count before and after cART initiation. Kaplan-Meier survival curves were used to estimate time to reach clinical stage C before antiretroviral therapy (ART) and to analyze time to achieve a plasma viral load (pVL) <40 copies/mL following cART initiation. Immunovirological response was assessed at the most recent visit in patients on active follow-up. Results: Data showed a 16.6% cumulative probability of reaching stage C within 5 years following diagnosis, and a mean CD4 decrease of -30.5 cells/MUL/year. cART initiation in ART-naive patients led to a mean CD4 gain of 147 cells/MUL after 12 months, and to a median pVL of <40 copies/mL after 3.8 months for 89.3%. Initiation with a nonrecommended nonnucleoside reverse transcriptase inhibitor-based vs a ritonavir-boosted protease inhibitor-based regimen resulted in a much smaller gain of around 100 CD4 cells/MUL after 1 year. Patients on follow-up since 2007 had a median CD4 count of 498 cells/MUL, and 87% had a pVL <40 copies/mL at the most recent follow-up visit. Conclusions: This work provides unique data on HIV-1/O infection, in favor of a milder natural evolution than HIV-1 group M (HIV-1/M) and of a highly efficient current management, based on HIV-1/M guidelines, despite genetic divergence. Studies of comparable HIV-1/M and HIV-1/O populations are needed to confirm these results. PMID- 29272376 TI - Early and late results of surgical treatment for isolated active native mitral valve infective endocarditis. AB - OBJECTIVES: Native mitral valve infective endocarditis (IE) is a complicated disease with high mortality and morbidity rates. Mitral valve repair (MVRep) is feasible when limited valve destruction is present. However, recurrent valve dysfunction and reintervention are common. METHODS: Between January 2000 and March 2016, 83 patients underwent surgery for isolated active native mitral valve IE. We applied an early surgery, MVRep-oriented approach with progressive utilization of patch techniques to secure a durable repair; MVRep was attempted in 67% of patients. Fifty-one (61%) patients underwent MVRep (including full-ring annuloplasty in 94%) and 32 (39%) patients underwent mitral valve replacement. RESULTS: Early mortality was 13%. No cases of early recurrent IE occurred. Predischarge echocardiography demonstrated good MVRep function in all, except 1 patient with residual (Grade 2+) regurgitation. The mean duration of follow-up was 3.7 years (interquartile range 1.5-8.4). For hospital survivors, 8-year overall survival rates were 92.4% (95% confidence interval 84.0-100%) and 74.2% (95% confidence interval 53.8-94.6%) for the MVRep and mitral valve replacement groups, respectively. Propensity score-adjusted Cox regression analysis revealed no significant difference in survival between the 2 groups (hazard ratio 0.359, 95% confidence interval 0.107-1.200; P = 0.096). Four reinterventions occurred, 2 in each group. Echocardiographic follow-up demonstrated excellent MVRep durability; no cases of mitral regurgitation and 1 case of mitral valve stenosis were seen. CONCLUSIONS: Native mitral valve IE is linked to high mortality and morbidity rates. A durable MVRep is feasible in most patients and provides excellent mid-term durability. Mitral valve replacement is a reasonable alternative when a durable repair is not likely. PMID- 29272377 TI - Traumatic leaflet injury: comparison of porcine leaflet self-expandable and bovine leaflet balloon-expandable prostheses. AB - OBJECTIVES: The main goal of this study was to compare the occurrence of post deployment leaflet injury between prostheses made of porcine and bovine pericardium. METHODS: Two types of prostheses, self-expandable prostheses with porcine pericardial leaflet on one side and balloon-expandable prostheses with bovine pericardial leaflet on the other side, were used. In each group, crimped prostheses were compared with control non-crimped prostheses. Following a 15-min period of crimping, prostheses were deployed, and their leaflets were removed and subjected to analyses. The analyses included determination of global and local hydraulic conductance of the leaflets, leaflet plasma insudation and microscopic analysis. The results were expressed as percentage (standard error of the mean) or median (interquartile range). RESULTS: A significant increase in the global hydraulic conductance was only observed in the crimped balloon-expandable prostheses: 20.1 (15.5-41.2) ml/h/m2/mmHg vs 12.3 (9.0-15.6) ml/h/m2/mmHg (P = 0.021). Similarly, areas of marked staining (a marker of local hydraulic conductance) were only seen in the bovine pericardium balloon-expandable prostheses. The incidence of leaflet plasmatic insudation was increased in the crimped prostheses compared with the control prostheses. The microscopic study revealed a higher occurrence of traumatic lesions in the crimped prostheses in comparison with the control prostheses: 33.3 +/- 21.1% vs 5.5 +/- 5.5% (P = 0.039) and 44.4 +/- 20.5% vs 5.5 +/- 5.5% (P = 0.017) in the bovine and the porcine leaflets, respectively. CONCLUSIONS: Post-deployment leaflet injury occurred in both types of prostheses. However, alteration of the global and local hydraulic conductance was important in the bovine pericardium balloon-expandable prostheses. PMID- 29272379 TI - Annual adverse event profiles after clopidogrel, prasugrel, and ticagrelor in the Food and Drug Administration Adverse Event Reporting System. PMID- 29272380 TI - Vibrioferrin production by the food spoilage bacterium Pseudomonas fragi. AB - Pseudomonas fragi is a meat and milk spoilage bacterium with high iron requirements; however, mechanisms of iron acquisition remain largely unknown. The aim of this work was to investigate siderophore production as an iron acquisition system for P. fragi. A vibrioferrin siderophore gene cluster was identified in 13 P. fragi, and experiments were conducted with a representative strain of this group (F1801). Chromeazurol S assays showed that P. fragi F1801 produced siderophores under iron starvation at optimum growth and refrigeration temperature. Conversely, supplementation of low iron media with 50 MUM FeCl3 repressed transcription of the vibrioferrin genes and siderophore production. Disruption of the siderophore receptor (pvuA) caused polar effects on downstream vibrioferrin genes, resulting in impaired siderophore production of the DeltapvuA mutant. Growth of this mutant was compared to growth of a control strain (Deltalip) with wild-type vibrioferrin genes in low iron media supplemented with iron chelators 2,2?-bipyridyl or apo-transferrin. While 25 MUM 2,2?-bipyridyl caused impaired growth of DeltapvuA, growth of the mutant was completely inhibited by 2.5 MUM apo-transferrin, but could be restored by FeCl3 addition. In summary, this work identifies a vibrioferrin-mediated iron acquisition system of P. fragi, which is required for growth of this bacterium under iron starvation. PMID- 29272378 TI - Brucella abortus lysed cells using GI24 induce robust immune response and provide effective protection in Beagles. AB - The aim of the present study is to estimate the protective efficacy of Brucella abortus lysed cells by GI24 against brucellosis in Beagles. Group A was subcutaneously (sc) immunized with sterile phosphate-buffered saline, and group B was sc immunized with approximately 3 * 109 of the lysed cells. Brucella-LPS specific serum IgG titers and IL-4, TNF-alpha and IFN-gamma concentrations were investigated by enzyme linked immunosorbent assay. All dogs were intraconjunctivally challenged with B. abortus strain 544 at 6 weeks post-prime immunization. The serum IgG titers were considerably higher in group B than in group A. The levels of IL-4, TNF-alpha and IFN-gamma in group B than in group A were significantly higher. Following challenge, no challenge strain was observed from all tissues of three dogs of group B. However, challenge strain was detected from spleen, uterus (except one Beagle) and inguinal and retropharyngeal lymph nodes of all group A Beagles. The results of this study demonstrated that sc immunization with the lysed cells induced robust antibody and cell-mediated immune responses in Beagles. The lysed cells also conferred protection against infection with B. abortus. These results suggest that sc immunization with B. abortus lysed cells by GI24 is a good vaccine candidate against brucellosis in dogs. PMID- 29272381 TI - Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial. AB - OBJECTIVES: Organ protective management during aortic arch surgery comprises deep hypothermic (18 degrees C) circulatory arrest (DHCA), or moderate hypothermia (28 degrees C/ 'tepid') with regional cerebral perfusion (TRCP). The aim of this experimental study was to evaluate the effect of distinct organ protective management on hemodynamic performance and myocardial integrity. METHODS: Ten male piglets were randomized to group DHCA (n = 5) or TRCP (n = 5) group and operated on cardiopulmonary bypass (CPB) with 60 min of aortic cross-clamping. Blood gas analysis was performed throughout the experiment. Haemodynamic assessment was performed using a thermodilution technique before and after CPB. Myocardial biopsies were taken 2 h after CPB and evaluated using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling assay and western blot analysis. RESULTS: At reperfusion, levels of central venous saturation were significantly higher (P = 0.016) and levels of lactate significantly lower (P = 0.029) in the DHCA group. After CPB, thermodilution measurements revealed higher stroke volume and lower peripheral resistance in the TRCP group (P = 0.012 and 0.037). At the end of the experiment, no significant differences regarding laboratory and haemodynamic parameters were evident. All specimens showed enrichment of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling-positive cells exclusively at the left ventricular subendocardium with no difference between groups and equal concentrations of cyclo-oxygenase-2. CONCLUSIONS: TRCP is associated with decreased peripheral resistance and higher stroke volume immediately after CPB. However, this beneficial effect is contrasted by signs of lower body hypoperfusion, which is expressed by lower central venous saturations and higher lactate levels. Distinct strategies of organ protection did not seem to affect apoptotic/necrotic and inflammatory changes in the left ventricular myocardium. PMID- 29272382 TI - Multimodality imaging in rare congenital heart disease: unilaterally absent proximal pulmonary artery in a newborn. PMID- 29272383 TI - Material, behavioural, cultural and psychosocial factors in the explanation of socioeconomic inequalities in oral health. AB - Background: This study aimed to assess the contribution of material, behavioural, cultural and psychosocial factors in the explanation of socioeconomic inequalities (education and income) in oral health of Dutch adults. Methods: Cross-sectional data from participants (25-75 years of age) of the fifth wave of the GLOBE cohort were used (n = 2812). Questionnaires were used to obtain data on material factors (e.g. financial difficulties), behavioural factors (e.g. smoking), cultural factors (e.g. cultural activities) and psychosocial factors (e.g. psychological distress). Oral health outcomes were self-reported number of teeth and self-rated oral health (SROH). Mediation analysis, using multivariable negative binomial regression and logistic regression, was performed. Results: Education level and income showed a graded positive relationship with both oral health outcomes. Adding material, behavioural, cultural and psychosocial factors substantially reduced the rate ratio for the number of teeth of the lowest education group from 0.79 (95% confidence interval (CI): 0.75-0.83) to 0.92 (95% CI: 0.87-0.97) and of the lowest income group from 0.80 (95% CI: 0.73-0.88) to 1.04 (95% CI: 0.96-1.14). Inclusion of all factors also substantially reduced the odds ratio for poor SROH of the lowest education group from 1.61 (95% CI: 1.28 2.03) to 1.12 (95% CI: 0.85-1.48) and of the lowest income groups from 3.18 (95% CI: 2.13-4.74) to 1.48 (95% CI: 0.90-2.45). Conclusion: In general, behavioural factors contributed most to the explanation of socioeconomic inequalities in adult oral health, followed by material factors. The contribution of cultural and psychosocial factors was relatively moderate. PMID- 29272384 TI - Distinct effects of the nephridial symbionts Verminephrobacter and Candidatus Nephrothrix on reproduction and maturation of its earthworm host Eisenia andrei. AB - Verminephrobacter, the most common specific symbionts in the nephridia (excretory organs) of lumbricid earthworms, have been shown to improve reproduction of the garden earthworm Aporrectodea tuberculata under nutrient limitation. It is unknown how general this beneficial trait is in the Verminephrobacter-earthworm symbiosis, whether other nephridial symbionts also affect host fitness and what the mechanism of the fitness increase is. Here we report beneficial effects of Verminephrobacter and Candidatus Nephrothrix on life history traits of the compost worm Eisenia andrei, which in addition to these two symbionts also hosts Agromyces-like bacteria in its mixed nephridial community: while growth was identical between control, Verminephrobacter-free and aposymbiotic worms, control worms produced significantly more cocoons and offspring than both Verminephrobacter-free and aposymbiotic worms, confirming the reproductive benefit of Verminephrobacter in a second host with different ecology and feeding behavior. Furthermore, worms with Verminephrobacter and Ca. Nephrothrix, or with only Ca. Nephrothrix present, reached sexual maturity significantly earlier than aposymbiotic worms; this is the first evidence for a beneficial role of Ca. Nephrothrix in earthworms. Riboflavin content in cocoons and whole earthworms was unaffected by the presence or absence of nephridial symbionts, suggesting that nutritional supplementation with this vitamin does not play a major role in this symbiosis. PMID- 29272386 TI - C-Terminal sequence is involved in the incorporation of Bgl2p glucanosyltransglycosylase in the cell wall of Saccharomyces cerevisiae. AB - A cell wall (CW) provides a protective barrier for a yeast cell and is a firm structure that nevertheless dynamically changes during cell's growth. Bgl2p is a non-covalently anchored glucanosyltransglycosylase in the CW of the yeast Saccharomyces cerevisiae. The mode of its anchorage is poorly understood, while its association with CW components is tight and resistant to 1-h treatment with 1% SDS at 37 degrees C. In order to demarcate the potential structural block responsible for incorporation of Bgl2p into the CW, bioinformatics analysis of its sequence was performed, and a conservative structural region was identified in the C-terminal region of Bgl2p, which was absent in its homologues in S. cerevisiae, the Scw4p and Scw10p. Deletion of this region disrupted the incorporation of Bgl2p into the CW and led to release of this protein through the CW into the culture medium. Two left-handed polyproline-II helices were identified in the C-terminal region of the structure model of a wild-type Bgl2p. These helices potentially formed binding sites, which were absent in the truncated protein. Using immune fluorescence microscopy, we demonstrated that C truncated Bgl2p was exported into culture medium and lost its ability to form fibrils described earlier. It was also shown that the C-terminal truncation of Bgl2p led to a more severe decrease of cell survivability in extreme conditions than BGL2 deletion. PMID- 29272385 TI - Surveillance for and Discovery of Borrelia Species in US Patients Suspected of Tickborne Illness. AB - Background: Tick-transmitted Borrelia fall into 2 heterogeneous bacterial complexes comprised of multiple species, the relapsing fever (RF) group and the Borrelia burgdorferi sensu lato group, which are the causative agents of Lyme borreliosis (LB), the most common tickborne disease in the Northern Hemisphere. Geographic expansion of LB in the United States and discovery of emerging Borrelia pathogens underscores the importance of surveillance for disease-causing Borrelia. Methods: De-identified clinical specimens, submitted by providers throughout the United States, for patients suspected of LB, anaplasmosis, ehrlichiosis, or babesiosis were screened using a Borrelia genus-level TaqMan polymerase chain reaction (PCR). Borrelia species and sequence types (STs) were characterized by multilocus sequence typing (MLST) utilizing next-generation sequencing. Results: Among 7292 specimens tested, 5 Borrelia species were identified: 2 causing LB, B. burgdorferi (n = 25) and B. mayonii (n = 9), and 3 RF borreliae, B. hermsii (n = 1), B. miyamotoi (n = 8), and Candidatus B. johnsonii (n = 1), a species previously detected only in the bat tick, Carios kelleyi. ST diversity was greatest for B. burgdorferi-positive specimens, with new STs identified primarily among synovial fluids. Conclusions: These results demonstrate that broad PCR screening followed by MLST is a powerful surveillance tool for uncovering the spectrum of disease-causing Borrelia species, understanding their geographic distribution, and investigating the correlation between B. burgdorferi STs and joint involvement. Detection of Candidatus B. johnsonii in a patient with suspected tickborne disease suggests this species may be a previously undetected cause of illness in humans exposed to bat ticks. PMID- 29272388 TI - Waterpipe tobacco smoking prevalence among young people in Great Britain, 2013 2016. AB - Background: One percent of adults in Great Britain use waterpipe tobacco at least monthly, however national epidemiological evidence among young people is absent. This study aims to assess waterpipe tobacco prevalence and correlates among young people in Great Britain. Methods: Data were analyzed from online surveys conducted annually from 2013 to 2016 with weighted national samples of 11 to 18 year olds in Great Britain (annual n = 1936-2059). Primary outcome measures were at least monthly waterpipe tobacco use and lifetime waterpipe tobacco use. Binary logistic regression models tested the association between these outcomes and age, sex, country of residence and other tobacco consumption. Results: Between 2013 and 2016, 1.7% (95% CI 1.5-2.1%) used waterpipe tobacco at least monthly and 9.9% (95% CI 9.2-10.7%) used waterpipe in their lifetime. There were no changes in prevalence over time. At least monthly use was associated with older age groups [16-18 years vs. 11-15 years, adjusted odds ratio (AOR) 2.63, 95% CI 1.55-4.46], male sex (AOR 1.82, 95% CI 1.23-2.71) and other tobacco consumption (e.g. lifetime cigarette use AOR 10.30, 95% CI 5.22-20.29). Lifetime use had similar correlates, but was not associated with male sex (AOR 0.97, 95% CI 0.80-1.17). Conclusions: One in 10 young people in Great Britain have tried waterpipe tobacco, though more frequent use appears low. We found no evidence of increasing or decreasing prevalence of waterpipe use between 2013 and 2016. Being male, older and a concurrent user of other tobacco products were correlated with waterpipe tobacco use. PMID- 29272389 TI - IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines. PMID- 29272390 TI - Cereblon suppresses the formation of pathogenic protein aggregates in a p62 dependent manner. AB - Formation of protein aggregates is the hallmark of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and frontotemporal dementia. Many ubiquitin-associated proteins are recruited to protein aggregates, such as sequestosome 1/p62 (p62), parkin, and cereblon (CRBN). However, the roles of these proteins in the regulation of the formation of protein aggregates are not well understood. Here, using cell and animal models, we discover that CRBN directly interacts with p62 and inhibits the formation of protein aggregates induced by mutant huntingtin (Htt-polyQ) and TAR DNA-binding protein 43 (TDP43C) in a p62-dependent manner. Furthermore, we find the suppression of the formation of protein aggregates by CRBN is caused by the decrease of the binding affinity of p62 to ubiquitinated proteins but not by the change of p62 protein level. Our study reveals a novel role of CRBN and the underlying molecular mechanism in the regulation of misfolded proteins in neurodegenerative diseases, which may provide new insights for finding pharmacological targets for these diseases. PMID- 29272387 TI - Contribution of Maternal Antiretroviral Therapy and Breastfeeding to 24-Month Survival in Human Immunodeficiency Virus-Exposed Uninfected Children: An Individual Pooled Analysis of African and Asian Studies. AB - Background: Human immunodeficiency virus (HIV)-infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified. Methods: Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package "frailtypack" were used to estimate the relative contribution of risk factors to overall mortality. Results: Cumulative incidence of death was 5.5% (95% confidence interval, 5.1-5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months. Conclusions: Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates. PMID- 29272391 TI - Mortality and timing of surgery in the left-sided infective endocarditis: an Italian multicentre study. AB - OBJECTIVES: Observational studies on early surgery in infective endocarditis have conflicting results. This study aims to compare the treatment strategies for early surgery (within 2 weeks of diagnosis) and late surgery/medical therapy in terms of survival among patients with the left-sided infective endocarditis. METHODS: This study included patients with the left-sided infective endocarditis registered between 2006 and 2010 in the Italian Registry of Infective Endocarditis (RIEI). A Cox proportional hazards model was used to estimate the effect of these treatment strategies on overall survival and included sociodemographic and clinical characteristics associated with treatment, risk factors for mortality and early surgery as a time-dependent covariate to avoid indication and immortal time biases. RESULTS: Among the 502 patients included, 184 (36.7%) underwent early surgery. Of the remaining 318 patients, 138 underwent late surgery. The early surgery group had fewer patients with comorbidities and with enterococcus as the causative microorganism, but this group had more complicated cardiac conditions. No difference in mortality risk was estimated between the treatment groups including early surgery as time-dependent variables (adjusted hazard ratio = 0.95, 95% confidence interval 0.55-1.63), while a distorted and overestimated beneficial effect of surgery was estimated considering surgery as a non-time-dependent variable (adjusted hazard ratio 0.41, 95% confidence interval 0.25-0.70). CONCLUSIONS: Our study did not confirm a better overall survival in patients undergoing early surgery. However, even with the use of statistical techniques to control biases, we could not draw definitive conclusions that early surgery is not beneficial. Our results need to be assessed by randomized trials before any changes in clinical practice can be recommended. PMID- 29272393 TI - Reply to Puig-Asensio et al. PMID- 29272392 TI - Pegylated Interferon-alpha-Induced Natural Killer Cell Activation Is Associated With Human Immunodeficiency Virus-1 DNA Decline in Antiretroviral Therapy-Treated HIV-1/Hepatitis C Virus-Coinfected Patients. AB - Background: Interferon alpha (IFN-alpha) can potently reduce human immunodeficiency virus type 1 (HIV-1) replication in tissue culture and animal models, but may also modulate residual viral reservoirs that persist despite suppressive antiretroviral combination therapy. However, mechanisms leading to viral reservoir reduction during IFN-alpha treatment are unclear. Methods: We analyzed HIV-1 gag DNA levels in CD4 T cells by digital droplet polymerase chain reaction and CD8 T-cell and natural killer (NK) cell phenotypes by flow cytometry in a cohort of antiretroviral therapy-treated HIV-1/hepatitis C virus-coinfected patients (n = 67) undergoing treatment for hepatitis C infection with pegylated IFN-alpha and ribavirin for an average of 11 months. Results: We observed that IFN-alpha treatment induced a significant decrease in CD4 T-cell counts (P < .0001), in CD4 T-cell-associated HIV-1 DNA copies (P = .002) and in HIV-1 DNA copies per microliter of blood (P < .0001) in our study patients. Notably, HIV-1 DNA levels were unrelated to HIV-1-specific CD8 T-cell responses. In contrast, proportions of total NK cells, CD56brightCD16- NK cells, and CD56brightCD16+ NK cells were significantly correlated with reduced levels of CD4 T-cell-associated HIV-1 DNA during IFN-alpha treatment, especially when coexpressing the activation markers NKG2D and NKp30. Conclusions: These data suggest that the reduction of viral reservoir cells during treatment with IFN-alpha is primarily attributable to antiviral activities of NK cells. PMID- 29272394 TI - Patterns of Genome-Wide Nucleotide Diversity in the Gynodioecious Plant Thymus vulgaris Are Compatible with Recent Sweeps of Cytoplasmic Genes. AB - Gynodioecy is a sexual dimorphism where females coexist with hermaphrodite individuals. In most cases, this dimorphism involves the interaction of cytoplasmic male sterility (CMS) genes and nuclear restorer genes. Two scenarios can account for how these interactions maintain gynodioecy. Either CMS genes recurrently enter populations at low frequency via mutation or migration and go to fixation unimpeded (successive sweeps), or CMS genes maintain polymorphism over evolutionary time through interactions with a nuclear restorer allele (balanced polymorphism). To distinguish between these scenarios, we used transcriptome sequencing in gynodioecious Thymus vulgaris and surveyed genome wide diversity in 18 naturally occurring individuals sampled from populations at a local geographic scale. We contrast the amount and patterns of nucleotide diversity in the nuclear and cytoplasmic genome, and find ample diversity at the nuclear level (pi = 0.019 at synonymous sites) but reduced genetic diversity and an excess of rare polymorphisms in the cytoplasmic genome relative to the nuclear genome. Our finding is incompatible with the maintenance of gynodioecy via scenarios invoking long-term balancing selection, and instead suggests the recent fixation of CMS lineages in the populations studied. PMID- 29272397 TI - Reply to Davido et al. PMID- 29272395 TI - Higher TSH Levels Within the Normal Range Are Associated With Unexplained Infertility. AB - Context: Unexplained infertility (UI), defined as the inability to conceive after 12 months of unprotected intercourse with no diagnosed cause, affects 10% to 30% of infertile couples. An improved understanding of the mechanisms underlying UI could lead to less invasive and less costly treatment strategies. Abnormalities in thyroid function and hyperprolactinemia are well-known causes of infertility, but whether thyrotropin (TSH) and prolactin levels within the normal range are associated with UI is unknown. Objective: To compare TSH and prolactin levels in women with UI and women with a normal fertility evaluation except for an azoospermic or severely oligospermic male partner. Design, Setting, and Participants: Cross-sectional study including women evaluated at a large academic health system between 1 January 2000 and 31 December 2012 with normal TSH (levels within the normal range of the assay and <=5 mIU/L) and normal prolactin levels (<=20 ng/mL) and either UI (n = 187) or no other cause of infertility other than an azoospermic or severely oligospermic partner (n = 52). Main Outcome Measures: TSH and prolactin. Results: Women with UI had significantly higher TSH levels than controls [UI: TSH 1.95 mIU/L, interquartile range: (1.54, 2.61); severe male factor: TSH 1.66 mIU/L, interquartile range: (1.25, 2.17); P = 0.003]. This finding remained significant after we controlled for age, body mass index, and smoking status. Nearly twice as many women with UI (26.9%) had a TSH >=2.5 mIU/L compared with controls (13.5%; P < 0.05). Prolactin levels did not differ between the groups. Conclusions: Women with UI have higher TSH levels compared with a control population. More studies are necessary to determine whether treatment of high-normal TSH levels decreases time to conception in couples with UI. PMID- 29272396 TI - How to assess and prepare health systems in low- and middle-income countries for integration of services-a systematic review. AB - Despite growing support for integration of frontline services, a lack of information about the pre-conditions necessary to integrate such services hampers the ability of policy makers and implementers to assess how feasible or worthwhile integration may be, especially in low- and middle-income countries (LMICs). We adopted a modified systematic review with aspects of realist review, including quantitative and qualitative studies that incorporated assessment of health system preparedness for and capacity to implement integrated services. We searched Medline via Ovid, Web of Science and the Cochrane library using terms adapted from Dudley and Garner's systematic review on integration in LMICs. From an initial list of 10 550 articles, 206 were selected for full-text review by two reviewers who independently reviewed articles and inductively extracted and synthesized themes related to health system preparedness. We identified five 'context' related categories and four health system 'capability' themes. The contextual enabling and constraining factors for frontline service integration were: (1) the organizational framework of frontline services, (2) health care worker preparedness, (3) community and client preparedness, (4) upstream logistics and (5) policy and governance issues. The intersecting health system capabilities identified were the need for: (1) sufficiently functional frontline health services, (2) sufficiently trained and motivated health care workers, (3) availability of technical tools and equipment suitable to facilitate integrated frontline services and (4) appropriately devolved authority and decision-making processes to enable frontline managers and staff to adapt integration to local circumstances. Moving beyond claims that integration is defined differently by different programs and thus unsuitable for comparison, this review demonstrates that synthesis is possible. It presents a common set of contextual factors and health system capabilities necessary for successful service integration which may be considered indicators of preparedness and could form the basis for an 'integration preparedness tool'. PMID- 29272398 TI - A prediction score for significant coronary artery disease in Chinese patients >=50 years old referred for rheumatic valvular heart disease surgery. AB - OBJECTIVES: Our goal was to establish a prediction score and protocol for the preoperative prediction of significant coronary artery disease (CAD) in patients with rheumatic valvular heart disease. METHODS: Using multivariate logistic regression analysis, we validated the model based on 490 patients without a history of myocardial infarction and who underwent preoperative screening coronary angiography. Significant CAD was defined as >=50% narrowing of the diameter of the lumen of the left main coronary artery or >=70% narrowing of the diameter of the lumen of the left anterior descending coronary artery, left circumflex artery or right coronary artery. RESULTS: Significant CAD was present in 9.8% of patients. Age, smoking, diabetes mellitus, diastolic blood pressure, low-density lipoprotein cholesterol and ischaemia evident on an electrocardiogram were independently associated with significant CAD and were entered into the multivariate model. According to the logistic regression predictive risk score, preoperative coronary angiography is recommended in (i) postmenopausal women between 50 and 59 years of age with >=9.1% logistic regression predictive risk score; (ii) postmenopausal women who are >=60 years old with a logistic regression predictive risk score >=6.6% and (iii) men >=50 years old whose logistic regression predictive risk score was >=2.8%. Based on this predictive model, 246 (50.2%) preoperative coronary angiograms could be safely avoided. The negative predictive value of the model was 98.8% (246 of 249). CONCLUSIONS: This model was accurate for the preoperative prediction of significant CAD in patients with rheumatic valvular heart disease. This model must be validated in larger cohorts and various populations. PMID- 29272399 TI - eHistology image and annotation data from the Kaufman Atlas of Mouse Development. AB - "The Atlas of Mouse Development" by Kaufman is a classic paper atlas that is the de facto standard for the definition of mouse embryo anatomy in the context of standard histological images. We have redigitized the original haematoxylin and eosin-stained tissue sections used for the book at high resolution and transferred the hand-drawn annotations to digital form. We have augmented the annotations with standard ontological assignments (EMAPA anatomy) and made the data freely available via an online viewer (eHistology) and from the University of Edinburgh DataShare archive. The dataset captures and preserves the definitive anatomical knowledge of the original atlas, provides a core image set for deeper community annotation and teaching, and delivers a unique high-quality set of high resolution histological images through mammalian development for manual and automated analysis. PMID- 29272400 TI - Clinical Laboratory Values in Human Ebola Virus Disease Support the Relevance of the Intramuscular Ebola-Kikwit Rhesus Model. PMID- 29272401 TI - Durability and Long-term Clinical Outcomes of Fecal Microbiota Transplant Treatment in Patients With Recurrent Clostridium difficile Infection. AB - Background: Fecal microbiota transplant (FMT) appears safe and effective for treatment of recurrent Clostridium difficile infection (RCDI). However, durability, long-term clinical outcomes, and patient satisfaction after FMT are not well described. Methods: Eligible patients who received FMT for RCDI at Emory Hospital between 1 July 2012 and 31 December 2016 were contacted via telephone for a follow-up survey. Of 190 eligible patients, 137 (72%) completed the survey. Results: Median time from last FMT to follow-up was 22 months. Overall, 82% (113/137) of patients at follow-up had no recurrence of C. difficile infection (CDI) post-FMT (non-RCDI group) and 18% (24/137) of patients had CDI post-FMT (RCDI group). Antibiotic exposure for non-CDI infections after FMT was more common in the RCDI group compared to the non-RCDI group (75% vs 38%, P = .0009). Overall, 11% of patients reported improvement or resolution of diagnoses not related to CDI post-FMT, and 33% reported development of a new medical condition or symptom post-FMT. Ninety-five percent of patients (122/128) indicated that they would undergo FMT again, and 70% of these 122 reported that they would prefer FMT to antibiotics as initial treatment if they were to have a CDI recurrence. Conclusions: In this follow-up survey of outcomes after FMT at a median of 22 months follow-up, 82% of patients had durable cure of CDI. Patients with recurrence had more post-FMT antibiotic exposure, underscoring the need for thoughtful antibiotic use and a potential role for prophylactic microbiome enrichment to reduce recurrence. PMID- 29272402 TI - Antimicrobial susceptibilities of clinical Legionella longbeachae isolates. PMID- 29272403 TI - Long-term survival after complete resection of non-small-cell lung cancer in patients with interstitial lung disease. AB - OBJECTIVES: Patients with lung cancer and interstitial lung disease (ILD), usual interstitial pneumonia in particular, are known to have a poor outcome. The aim of this study was to evaluate the prognostic impact of ILD in patients with non small-cell lung cancer. METHODS: A total of 2054 consecutive patients underwent complete resection of Stage IA-IIIA non-small-cell lung cancer in our institution between January 2002 and March 2013. The presence of ILD was diagnosed and categorized based on high-resolution computed tomography images. Multivariate analysis was performed to identify the prognostic factors. RESULTS: There were 106 (5%) patients with ILD. There were significantly more patients who developed severe complications (P < 0.01) in the ILD group, with 4 (4%) patients developing acute exacerbation. Although the difference in postoperative mortality rate was marginal between the groups (P = 0.07), the 5-year overall survival and cancer specific survival rates of the ILD patients were significantly worse than those of the non-ILD group (overall survival: 40.4% vs 72.0%, P < 0.01; cancer-specific survival 55.4% vs 78.6%, P < 0.01). The results of multivariate analysis showed that coexistence of ILD (hazard ratio 1.45; P = 0.01) was an independent, unfavourable prognostic factor. CONCLUSIONS: The presence of ILD led to a much poorer survival after complete resection of non-small-cell lung cancer. PMID- 29272404 TI - Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa. AB - Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is associated with different groups of genes, including those encoding proteins involved in centriole and cilium biogenesis. Exome sequencing revealed a homozygous nonsense mutation [c.304_305delGA (p. D102*)] in POC5, encoding the Proteome Of Centriole 5 protein, in a patient with RP, short stature, microcephaly and recurrent glomerulonephritis. The POC5 gene is ubiquitously expressed, and immunohistochemistry revealed a distinct POC5 localization at the photoreceptor connecting cilium. Morpholino-oligonucleotide induced knockdown of poc5 translation in zebrafish resulted in decreased length of photoreceptor outer segments and a decreased visual motor response, a measurement of retinal function. These phenotypes could be rescued by wild-type human POC5 mRNA. These findings demonstrate that Poc5 is important for normal retinal development and function. Altogether, this study presents POC5 as a novel gene involved autosomal recessively inherited RP, and strengthens the hypothesis that mutations in centriolar proteins are important cause of retinal dystrophies. PMID- 29272405 TI - Selective vulnerability in neuronal populations in nmd/SMARD1 mice. AB - Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease causing distal limb muscle atrophy that progresses proximally and is accompanied by diaphragmatic paralysis. Neuromuscular junction (NMJ) alterations have been reported in muscles of SMARD1 model mice, known as nmd mice, with varying degrees of severity, suggesting that different muscles are specifically and selectively resistant or susceptible to denervation. To evaluate the extent of NMJ pathology in a broad range of muscles, a panel of axial and appendicular muscles were isolated and immunostained from nmd mice. These analyses revealed that selective distal appendage muscles were highly vulnerable to denervation. Susceptibility to pathology was not limited to NMJ alterations, but included defects in myelination within those neurons innervating susceptible muscles. Interestingly, end plate fragmentation was present within all muscles independent of the extent of NMJ alterations, suggesting that end plate fragmentation is an early hallmark of SMARD1 pathogenesis. Expressing the full length IGHMBP2 cDNA using an adeno-associated virus (AAV9) significantly decreased all aspects of muscle and nerve disease pathology. These results shed new light onto the pathogenesis of SMARD1 by identifying specific motor units that are resistant and susceptible to neurodegeneration in an important model of SMARD1. PMID- 29272406 TI - The Effects of an Ultra-low-Volume Application of Etofenprox for Mosquito Management on Megachile rotundata (Hymenoptera: Megachilidae) Larvae and Adults in an Agricultural Setting. AB - The alfalfa leafcutting bee, Megachile rotundata F. (Hymenoptera: Megachilidae), is one of the most intensively managed solitary bees and greatly contributes to alfalfa production in both the United States and Canada. Although production of certain commodities, especially alfalfa seed, has become increasingly dependent on this species' pollination proficiency, little information is known about how M. rotundata is affected by insecticide exposure. To better understand the risk posed to M. rotundata by the increasing use of insecticides to manage mosquitoes, we conducted field experiments that directly exposed M. rotundata nests, adults, and larvae to a pyrethroid insecticide via a ground-based ultra-low-volume (ULV) aerosol generator. We directly targeted nest shelters with Zenivex(r) E20 (etofenprox) at a half-maximum rate of 0.0032 kg/ha at dusk and then observed larval mortality, adult mortality, and the total number of completed nests for both the treated and control groups. There was no significant difference in the proportion of dead (P = 0.99) and alive (P = 0.23) larvae when the control group was compared with the treated group. We also did not observe a significant difference in the number of emerged adults reared from the treated shelters (P = 0.22 and 0.50 for females and males, respectively), and the number of completed cells after exposure to the insecticides continued to increase throughout the summer, indicating that provisioning adults were not affected by the insecticide treatment. The results from this study suggest that the amount of insecticide reaching nest shelters may not be sufficient to cause significant mortality. PMID- 29272407 TI - Comparative Genomics of Bacteriophage of the Genus Seuratvirus. AB - Despite being more abundant and having smaller genomes than their bacterial host, relatively few bacteriophages have had their genomes sequenced. Here, we isolated 14 bacteriophages from cattle slurry and performed de novo genome sequencing, assembly, and annotation. The commonly used marker genes polB and terL showed these bacteriophages to be closely related to members of the genus Seuratvirus. We performed a core-gene analysis using the 14 new and four closely related genomes. A total of 58 core genes were identified, the majority of which has no known function. These genes were used to construct a core-gene phylogeny, the results of which confirmed the new isolates to be part of the genus Seuratvirus and expanded the number of species within this genus to four. All bacteriophages within the genus contained the genes queCDE encoding enzymes involved in queuosine biosynthesis. We suggest these genes are carried as a mechanism to modify DNA in order to protect these bacteriophages against host endonucleases. PMID- 29272408 TI - Patient preferences toward an interactive e-consent application for research using electronic health records. AB - Objective: The purpose of this study was to assess patient perceptions of using an interactive electronic consent (e-consent) application when deciding whether or not to grant broad consent for research use of their identifiable electronic health record (EHR) information. Materials and Methods: For this qualitative study, we conducted a series of 42 think-aloud interviews with 32 adults. Interview transcripts were coded and analyzed using a modified grounded theory approach. Results: We identified themes related to patient preferences, reservations, and mixed attitudes toward consenting electronically; low- and high information-seeking behavior; and an emphasis on reassuring information, such as data protections and prohibitions against sharing data with pharmaceutical companies. Participants expressed interest in the types of information contained in their EHRs, safeguards protecting EHR data, and specifics on studies that might use their EHR data. Discussion: This study supports the potential value of interactive e-consent applications that allow patients to customize their consent experience. This study also highlights that some people have concerns about e consent platforms and desire more detailed information about administrative processes and safeguards that protect EHR data used in research. Conclusion: This study contributes new insights on how e-consent applications could be designed to ensure that patients' information needs are met when seeking consent for research use of health record information. Also, this study offers a potential electronic approach to meeting the new Common Rule requirement that consent documents contain a "concise and focused" presentation of key information followed by more details. PMID- 29272409 TI - A role for CENP-A/Cse4 phosphorylation on serine 33 in deposition at the centromere. AB - Centromeres are the sites of assembly of the kinetochore, which connect the chromatids to the microtubules for sister chromatid segregation during cell division. Centromeres are characterized by the presence of the histone H3 variant CENP-A (termed Cse4 in Saccharomyces cerevisiae). Here, we investigated the function of serine 33 phosphorylation of Cse4 (Cse4-S33ph) in S. cerevisiae, which lies within the essential N-terminal domain (END) of the extended Cse4 N terminus. Significantly, we identified histone H4-K5, 8, 12R to cause a temperature-sensitive growth defect with mutations in Cse4-S33 and sensitivity to nocodazole and hydroxyurea. Furthermore, the absence of Cse4-S33ph reduced the levels of Cse4 at centromeric sequences, suggesting that Cse4 deposition is defective in the absence of S33 phosphorylation. We furthermore identified synthetic genetic interactions with histone H2A-E57A and H2A-L66A, which both cause a reduced interaction with the histone chaperone FACT and reduced H2A/H2B levels in chromatin, again supporting the notion that a combined defect of H2A/H2B and Cse4 deposition causes centromeric defects. Altogether, our data highlight the importance of correct histone deposition in building a functional centromeric nucleosome and suggests a role for Cse4-S33ph in this process. PMID- 29272411 TI - Combining Cue-Lure and Methyl Eugenol in Traps Significantly Decreases Catches of Most Bactrocera, Zeugodacus and Dacus Species (Diptera: Tephritidae: Dacinae) in Australia and Papua New Guinea. AB - Male fruit fly attractants, cue-lure (CL) and methyl eugenol (ME), are important in the monitoring and control of pest fruit fly species. Species respond to CL or ME but not both, and there are conflicting reports on whether combining CL (or its hydroxy analogue raspberry ketone) and ME decreases their attractiveness to different species. Fruit fly monitoring programs expend significant effort using separate CL and ME traps and avoiding lure cross-contamination, and combining the two lures in one trap would create substantial savings. To determine if combining lures has an inhibitory effect on trap catch, CL and ME wicks placed in the same Steiner trap were field tested in comparison to CL alone and ME alone in Australia and Papua New Guinea (PNG). In Australia, 24 out of 27 species trapped were significantly more attracted to CL or ME alone than the combination ME/CL lure, including the pests Bactrocera bryoniae (Tryon), B. frauenfeldi (Schiner), B. kraussi (Hardy), B. neohumeralis (Hardy), B. tryoni (Froggatt) (CL responsive), and B. musae (Tryon) (ME-responsive). In PNG, 13 out of 16 species trapped were significantly more attracted to CL or ME alone than the ME/CL combination, including the pests B. bryoniae, B. frauenfeldi, B. neohumeralis, B. trivialis (Drew), Zeugodacus cucurbitae (Coquillett) (CL-responsive) and B. dorsalis (Hendel), B. musae, and B. umbrosa (Fabricius) (ME-responsive). This study shows that combining CL and ME in the one trap in equal parts significantly reduces catches of most species of Dacini fruit flies in Australia and PNG. PMID- 29272410 TI - Genetic Competence Drives Genome Diversity in Bacillus subtilis. AB - Prokaryote genomes are the result of a dynamic flux of genes, with increases achieved via horizontal gene transfer and reductions occurring through gene loss. The ecological and selective forces that drive this genomic flexibility vary across species. Bacillus subtilis is a naturally competent bacterium that occupies various environments, including plant-associated, soil, and marine niches, and the gut of both invertebrates and vertebrates. Here, we quantify the genomic diversity of B. subtilis and infer the genome dynamics that explain the high genetic and phenotypic diversity observed. Phylogenomic and comparative genomic analyses of 42 B. subtilis genomes uncover a remarkable genome diversity that translates into a core genome of 1,659 genes and an asymptotic pangenome growth rate of 57 new genes per new genome added. This diversity is due to a large proportion of low-frequency genes that are acquired from closely related species. We find no gene-loss bias among wild isolates, which explains why the cloud genome, 43% of the species pangenome, represents only a small proportion of each genome. We show that B. subtilis can acquire xenologous copies of core genes that propagate laterally among strains within a niche. While not excluding the contributions of other mechanisms, our results strongly suggest a process of gene acquisition that is largely driven by competence, where the long-term maintenance of acquired genes depends on local and global fitness effects. This competence driven genomic diversity provides B. subtilis with its generalist character, enabling it to occupy a wide range of ecological niches and cycle through them. PMID- 29272413 TI - Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. PMID- 29272412 TI - Antagonism of Neurotensin Receptors in the Ventral Tegmental Area Decreases Methamphetamine Self-Administration and Methamphetamine Seeking in Mice. AB - Background: Neurotensin is a peptide that modulates central dopamine neurotransmission and dopamine-related behaviors. Methamphetamine self administration increases neurotensin levels in the ventral tegmental area, but the consequences for self-administration behavior have not been described. Here we test the hypothesis that antagonizing neurotensin receptors in the ventral tegmental area attenuates the acquisition of methamphetamine self-administration and methamphetamine intake. Methods: We implanted mice with an indwelling catheter in the right jugular vein and bilateral cannulae directed at the ventral tegmental area. Mice were then trained to nose-poke for i.v. infusions of methamphetamine (0.1 mg/kg/infusion) on a fixed ratio 3 schedule. Results: Mice receiving microinfusions of the neurotensin NTS1/NTS2 receptor antagonist SR142948A in the ventral tegmental area (10 ng/side) prior to the first 5 days of methamphetamine self-administration required more sessions to reach acquisition criteria. Methamphetamine intake was decreased in SR142948A-treated mice both during training and later during maintenance of self-administration. Drug seeking during extinction, cue-induced reinstatement, and progressive ratio schedules was also reduced in the SR142948A group. The effects of SR142948A were not related to changes in basal locomotor activity or methamphetamine psychomotor properties. In both SR142948A- and saline-treated mice, a strong positive correlation between methamphetamine intake and enhanced locomotor activity was observed. Conclusion: Our results suggest that neurotensin input in the ventral tegmental area during initial methamphetamine exposure contributes to the acquisition of methamphetamine self-administration and modulates later intake and methamphetamine-seeking behavior in mice. Furthermore, our results highlight the role of endogenous neurotensin in the ventral tegmental area in the reinforcing efficacy of methamphetamine, independent of its psychomotor effects. PMID- 29272414 TI - Cross-resistance Patterns to Insecticides of Several Chemical Classes Among Listronotus maculicollis (Coleoptera: Curculionidae) Populations With Different Levels of Resistance to Pyrethroids. AB - The annual bluegrass weevil (ABW), Listronotus maculicollis Kirby (Coleoptera: Curculionidae), is the most damaging golf course insect pest in eastern North America. Heavy reliance on synthetic insecticides against this pest has led to widespread problems in controlling ABW with pyrethroid resistance already reported from populations in southern New England. This study evaluated the degree and scope of ABW resistance, determined existing cross-resistance patterns, and confirmed laboratory findings under greenhouse conditions. The susceptibility of 10 ABW populations to insecticides of different chemical classes was assessed in topical, feeding, and greenhouse assays. The level of susceptibility to pyrethroids varied significantly among populations (LD50s ranging 2.4-819.1 ng per insect for bifenthrin and 1.1-362.7 ng for lambda cyhalothrin in the topical assay). Three populations were relatively susceptible to pyrethroids, and seven populations had moderate to high resistance levels (RR50 for bifenthrin ranging 30.5-343.1). The toxicity of chlorpyrifos (RR50s ranging 3.3-15.3), spinosad (RR50s 2.4-7.7), clothianidin (RR50s 4.2-9.7), and indoxacarb (RR50s 2.8-9.7) was decreased for the pyrethroid-resistant populations. Toxicity data for bifenthrin and chlorpyrifos obtained under more realistic greenhouse conditions confirmed laboratory observations, indicating that the topical assay is an accurate method of detection and measurement of resistance level. The current study expanded the previously known geographic range of ABW pyrethroid resistance to include the New York metropolitan area, New Jersey, and eastern Pennsylvania and provided clear evidence of cross-resistance not only within the pyrethroid class but also to several other chemical classes. PMID- 29272415 TI - Selectins in cancer immunity. AB - Selectins are vascular adhesion molecules that mediate physiological responses such as inflammation, immunity and hemostasis. During cancer progression, selectins promote various steps enabling the interactions between tumor cells and the blood constituents, including platelets, endothelial cells and leukocytes. Selectins are carbohydrate-binding molecules that bind to sialylated, fucosylated glycan structures. The increased selectin ligand expression on tumor cells correlates with enhanced metastasis and poor prognosis for cancer patients. While, many studies focused on the role of selectin as a mediator of tumor cell adhesion and extravasation during metastasis, there is evidence for selectins to activate signaling cascade that regulates immune responses within a tumor microenvironment. L-Selectin binding induces activation of leukocytes, which can be further modulated by selectin-mediated interactions with platelets and endothelial cells. Selectin ligand on leukocytes, PSGL-1, triggers intracellular signaling in leukocytes that are induced through platelet's P-selectin or endothelial E-selectin binding. In this review, I summarize the evidence for selectin-induced immune modulation in cancer progression that represents a possible target for controlling tumor immunity. PMID- 29272416 TI - Residue Age and Attack Pressure Influence Efficacy of Insecticide Treatments Against Ambrosia Beetles (Coleoptera: Curculionidae). AB - Management of ambrosia beetles in ornamental nurseries relies, in part, on insecticide treatments to prevent beetles from boring into trees. However, data on residual efficacy of commonly used pyrethroid insecticides is needed to gauge the duration that trees are protected during spring when peak beetle pressure occurs. Residual efficacy of bifenthrin and permethrin trunk sprays was examined in field trials which used trees injected with 10% ethanol to ensure host attack pressure. Permethrin consistently reduced attacks by Xylosandrus germanus (Blandford; Coleoptera: Curculionidae) and other ambrosia beetles for at least 4 wk, while efficacy of bifenthrin was inconsistent and lasted only about 10 d. Since previous studies demonstrated attacks are positively correlated with host ethanol emissions, we injected trees with 2.5, 5, and 10% ethanol to determine if residual efficacy was affected by attack pressure. Preventive treatments with bifenthrin reduced ambrosia beetle attacks at all concentrations of injected ethanol compared to non-sprayed controls. There was no interaction between attack pressure and insecticide treatment with respect to total attacks or attacks by X. germanus. However, increasing attack pressure did increase the probability of attacks on insecticide treated trees by X. germanus and other Scolytinae. Results from our current study will improve the ability of growers to make decisions on frequency of protective sprays, but residual efficacy of insecticide treatments may decline as attack pressure increases. Cultural practices should therefore maximize host vigor and minimize attack pressure associated with stress-induced ethanol emissions. PMID- 29272417 TI - Ambulance dispatch versus general practitioner home visit for highly urgent out of-hours primary care. AB - Background: Patients with life-threatening conditions who contact out-of-hours primary care either receive a home visit from a GP of a GP cooperative (GPC) or are handed over to the ambulance service. Objective: The objective of this study was to determine whether highly urgent visits, after a call to the GPC, are delivered by the most appropriate healthcare provider: GPC or ambulance service. Methods: We performed a cross-sectional study using patient record data from a GPC and ambulance service in an urban district in The Netherlands. During a 21 month period, all calls triaged as life-threatening (U1) to the GPCs were included. The decision to send an ambulance or not was made by the triage nurse following a protocolized triage process. Retrospectively, the most appropriate care was judged by the patient's own GP, using a questionnaire. Results: Patient and care characteristics from 1081 patients were gathered: 401 GPC visits, 570 ambulance responses and 110 with both ambulance and GPC deployment. In 598 of 1081 (55.3%) cases, questionnaires were returned by the patients' own GP. About 40% of all visits could have been carried out with a lower urgency in retrospect, and almost half of all visits should have received a different type of care or different provider. In case of ambulance response, 60.7% concerned chest pain. Conclusion: Research should be done on the process of triage and allocation of care to optimize labelling complaints with the appropriate urgency and to deploy the appropriate healthcare provider, especially for patients with chest pain. PMID- 29272418 TI - Do non-terminally ill adults want to discuss the end of life with their family physician? An explorative mixed-method study on patients' preferences and family physicians' views in Belgium. AB - Background: Research about advance care planning (ACP) has often targeted those with serious illness and limited prognosis, thereby not addressing the preferences of healthy adults or adults with a stable condition. Aims: (i) To describe to what extent patients aged 50 and older who are relatively stable or in good health are thinking about the end of life (EOL) and willing to discuss this with their family physician (FP) and (ii) to explore whether patients and FPs indicate the same topics as triggers for ACP discussions in family practice. Methods: A cross-sectional study was conducted in a diverse sample of 289 patients aged >=50 years in family practice in Flanders, Belgium. Subsequently, semi-structured interviews were conducted with patients (n = 5) and FPs (n = 5) to explore their preferences and views on ACP in family practice. Results: The majority (69.8%) of patients had thought about the EOL and would appreciate it if their FP would initiate a conversation about this (75.9%). The qualitative interviews revealed that when thinking about the EOL, a number of themes captured the thoughts of people according to both patients and FPs: (i) becoming care dependent, (ii) physical and mental deterioration, (iii) dying alone and (iv) having paperwork in order. However, on the basis of patients' ideas and FPs' experiences in practice, a difference was noticed between them when it comes to identifying the themes as triggers for initiating ACP discussions. Conclusion: Although patients are willing to discuss the EOL with their FPs, patients and FPs identified different themes as triggers to initiate discussions about the EOL. The variation in triggers could lead to missed opportunities to engage in ACP in a timely manner. PMID- 29272419 TI - Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy. AB - Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics(r). Target total and unbound trough concentrations were >=20 and >=1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing. PMID- 29272420 TI - Prevalence of Shiga-toxigenic Escherichia coli in House Flies (Diptera: Muscidae) in an Urban Environment. AB - House flies (Musca domestica L. [Diptera: Muscidae]) can act as a mechanical vector for food-borne pathogens including Shiga toxin-producing Escherichia coli (Migula; Enterobacteriales: Enterobacteriaceae) (STEC) in and around cattle feedlots. The present study assessed the prevalence of STEC in house flies from a restaurant area of a town in northeastern Kansas. Two hundred twenty-four house flies were collected over 10 wk, surface sterilized, individually homogenized, and cultured by a multifaceted approach of direct plating on selective media and an enrichment broth, followed by the immunomagnetic separation. Bacterial isolates were screened for eight serogroups of E. coli: O103, O104, O26, O111, O45, O145, O121, and O157 using multiplex polymerase chain reaction (PCR). Furthermore, O-serogroup-positive isolates were tested for virulence genes stx1, stx2, eae, and ehxA by PCR. The majority (91.5%) of flies carried enteric bacteria, and the mean value of enteric concentration on the modified Posse agar was 6.7 +/- 1.1 * 106 colony forming units per fly. Thirty-nine of the 224 flies (17.4%) were positive for one or more E. coli serogroup of interest; with the majority O103 (10.7%), followed by O26 (3.1%), O121 (1.3%), O45 (1.3%), and O104 (0.9%). However, none of the serogroup-positive isolates carried any of the virulence genes tested. Results of our study show that house flies in the urban environment do not carry STEC. Nevertheless, detection of E. coli O-serogroups with the potential to acquire virulence traits indicates that house flies in an urban environment represent a public health risk. PMID- 29272421 TI - Habitat-Specific Occupancy and a Metapopulation Model of Triatoma sordida (Hemiptera: Reduviidae), a Secondary Vector of Chagas Disease, in Northeastern Argentina. AB - Triatoma sordida Stal (Hemiptera: Reduviidae), a secondary vector of Trypanosoma cruzi Chagas (Kinetoplastida: Trypanosomatidae), occasionally colonizes human sleeping quarters in Paraguay, Bolivia, and Brazil, whereas only sylvatic and peridomestic populations are found in Argentina. We carried out a cross-sectional survey of house infestation in a well-defined rural area of northeastern Argentina to identify the key habitats of T. sordida; describe its spatial distribution in an apparently undisturbed setting under no recent insecticide treatment and use metapopulation theory to investigate these spatially structured populations. Timed-manual searches in 2,177 georeferenced sites from 368 houses yielded T. sordida in 78 sites (house infestation prevalence, 19.9%). Most triatomines occurred in chicken nests, chicken coops, and trees where chickens roosted (prime habitats). Goat or sheep corrals and pig corrals had a lower fraction of occupied sites (occupancies) and abundance. Both occupancy and catch increased with increasing refuge availability according to multimodel inference with model averaging. The majority of suitable habitats were unoccupied despite their proximity to occupied sites. The site-specific occurrence of T. sordida and Triatoma infestans Klug (Hemiptera: Reduviidae) was positively and homogeneously associated over ecotopes, showing no evidence of interspecific interference. An incidence function metapopulation model (including intersite distances and vector carrying capacity) predicted a fivefold greater occupancy relative to the observed pattern, suggesting the latter represented a transient state. T. sordida failed to colonize human sleeping quarters, thrived in peridomestic habitats occupied by chickens, and had a limited occupancy likely related to a poor colonizing ability and the relative instability of its prime habitats. PMID- 29272423 TI - Transcriptional and environmental control of bacterial denitrification and N2O emissions. AB - In oxygen-limited environments, denitrifying bacteria can switch from oxygen dependent respiration to nitrate (NO3-) respiration in which the NO3- is sequentially reduced via nitrite (NO2-), nitric oxide (NO) and nitrous oxide (N2O) to dinitrogen (N2). However, atmospheric N2O continues to rise, a significant proportion of which is microbial in origin. This implies that the enzyme responsible for N2O reduction, nitrous oxide reductase (NosZ), does not always carry out the final step of denitrification either efficiently or in synchrony with the rest of the pathway. Despite a solid understanding of the biochemistry underpinning denitrification, there is a relatively poor understanding of how environmental signals and respective transcriptional regulators control expression of the denitrification apparatus. This minireview describes the current picture for transcriptional regulation of denitrification in the model bacterium, Paracoccus denitrificans, highlighting differences in other denitrifying bacteria where appropriate, as well as gaps in our understanding. Alongside this, the emerging role of small regulatory RNAs in regulation of denitrification is discussed. We conclude by speculating how this information, aside from providing a better understanding of the denitrification process, can be translated into development of novel greenhouse gas mitigation strategies. PMID- 29272422 TI - Genomic Signature of Adaptive Divergence despite Strong Nonadaptive Forces on Edaphic Islands: A Case Study of Primulina juliae. AB - Both genetic drift and divergent selection are expected to be strong evolutionary forces driving population differentiation on edaphic habitat islands. However, the relative contribution of genetic drift and divergent selection to population divergence has rarely been tested simultaneously. In this study, restriction-site associated DNA-based population genomic analyses were applied to assess the relative importance of drift and divergent selection on population divergence of Primulina juliae, an edaphic specialist from southern China. All populations were found with low standing genetic variation, small effective population size (NE), and signatures of bottlenecks. Populations with the lowest genetic variation were most genetically differentiated from other populations and the extent of genetic drift increased with geographic distance from other populations. Together with evidence of isolation by distance, these results support neutral drift as a critical evolutionary driver. Nonetheless, redundancy analysis revealed that genomic variation is significantly associated with both edaphic habitats and climatic factors independently of spatial effects. Moreover, more genomic variation was explained by environmental factors than by geographic variables, suggesting that local adaptation might have played an important role in driving population divergence. Finally, outlier tests and environment association analyses identified 31 single-nucleotide polymorphisms as candidates for adaptive divergence. Among these candidates, 26 single-nucleotide polymorphisms occur in/near genes that potentially play a role in adaptation to edaphic specialization. This study has important implications that improve our understanding of the joint roles of genetic drift and adaptation in generating population divergence and diversity of edaphic specialists. PMID- 29272424 TI - In Vivo Production of Agrotis ipsilon Nucleopolyhedrovirus for Quantity and Quality. AB - The black cutworm, Agrotis ipsilon (Hufnagel) (Lepidoptera: Noctuidae), is a pest causing damage to a variety of plants including turf and row crops. A recently discovered baculovirus has the potential to be developed as a microbial-based biological pesticide to provide targeted control of this insect pest. In an effort to develop this baculovirus as a biological pesticide, experiments were conducted to determine parameters necessary to maximize in vivo production using cutworm larvae. Treatment combinations including three larval diets, larval age at infection (6- to 10-d old), and dosage of virus exposure (1 * 105 to 1 * 108 occlusion bodies [OBs]/ml) were evaluated. Production quantity and quality were measured as number of OBs produced and insecticidal activity of the virus, respectively. Generally speaking, insect diets that maximized larval growth resulted in a greater quantity of virus OBs. Less virus was produced when younger (small) larvae were exposed to higher dosages of virus resulting in rapid mortality and when older (large) larvae were exposed to low dosages of virus resulting in low levels of infection. Virus quality was measured as insecticidal activity (low LC50 representing high activity) and was highest for larger larvae exposed to minimal virus concentrations needed to initiate infections. When considering both quantity and quality measurements, maximum production was achieved for 8- to 9-d-old larvae fed a general purpose lepidoptera diet. These results will support the development of this baculovirus as an additional tool for the integrated control of the black cutworm. PMID- 29272425 TI - National Trade can Drive Range Expansion of Bark- and Wood-Boring Beetles. AB - Several native species of bark- and wood-boring beetles (Coleoptera) have expanded their range within their native biogeographic regions in the last years, but the role of human activity in driving this phenomenon has been underinvestigated. Here we analyze 3 yr of trapping records of native bark- and wood-boring beetles (Cerambycidae and Scolytinae) collected at 12 Italian ports and their surrounding forests to help elucidate the human role in the movement of native species within their native biogeographic region. We trapped several species that occurred either inside or outside their native distributional range within Italy. Species richness and abundance of those species found in the ports located within their native range were most strongly associated with the amount of forest cover in the surrounding landscape, suggesting that they could have arrived in the ports from the nearby forests. The abundance of the species found outside their native range was instead most strongly linked to the amount of national imports arriving at the port where trapping occurred, suggesting that they were likely introduced to the ports from other parts of Italy. This study demonstrates that national sea transportation can favor species range expansion within a country, and confirms that the forests that surround ports can serve as a source of species that can be potentially moved with exports. PMID- 29272426 TI - Bivariate Pheromone-based Monitoring of Spruce Budworm Larvae (Lepidoptera: Tortricidae). AB - A bivariate approach to pheromone-based monitoring is developed for the spruce budworm, Choristoneura fumiferana (Clem.) (Lepidoptera: Tortricidae). The approach uses captures of males at pheromone traps for generation t (?t) as a transitive term between densities of overwintering larvae in consecutive generations (L2t, L2t+1), based on a large data set including >2,000 observations in the province of Quebec (QC) between the interval 1992 and 2010. Although estimates of L2t and ?t are autocorrelated to some extent, multi-year assessments of larval densities combined with pheromone trapping are justified by the complementarity (statistical significance) of both L2t and ?t in predicting L2t+1 for 15 of 18 pairs of 2-yr intervals. Bivariate pheromone-based thresholds (number of males corresponding to specific transitions in larval densities between L2t and L2t+1) are reported for each year. As expected, thresholds for stable populations (L2t = L2t+1) were lower than for populations with positive growth rate (L2t < L2t+1). The thresholds derived in this study have limited heuristic value; however, because they vary greatly from year to year. PMID- 29272427 TI - Postharvest Irradiation Treatment for Quarantine Control of the Invasive Lobesia botrana (Lepidoptera: Tortricidae). AB - Irradiation is a postharvest treatment option for exported berries and berry-like fruits to prevent movement of the quarantine pest European grape vine moth, Lobesia botrana (Denis & Schiffermuller) (Lepidoptera: Tortricidae). The effects of irradiation on egg, larval, and pupal development in L. botrana were examined. Eggs, neonates, third and fifth instars, and early- and late-stage pupae were irradiated at target doses of 50, 100, 150, or 200 Gy or left untreated as controls in replicated factorial experiments, and survival to the adult stage was recorded. Tolerance to radiation generally increased with increasing age and developmental stage. A dose of 150 Gy prevented adult emergence in eggs and larvae. Pupae were more radiotolerant than larvae, and late-stage pupae were more tolerant than early-stage pupae. In large-scale validation tests, 150 Gy applied to fifth instars in diet prevented adult emergence, but some survival occurred in fifth instars irradiated in table grapes; however, 250 Gy prevented fifth instar survival in grapes. For most commodities, the fifth instar is the most radiotolerant life stage likely to occur with the commodity; a minimum radiation dose of 250 Gy will prevent adult emergence from this stage. For traded commodities such as table grapes that may contain L. botrana pupae, 325 Gy applied to mature female pupae sterilized emerging adults and may provide quarantine security. Radiotolerance in L. botrana is comparable to other tortricids, and the data reported here support a generic dose of 250 Gy for eggs and larvae of this group. PMID- 29272428 TI - Knockdown of the Chromatin Remodeling Gene Brahma by RNA Interference Reduces Reproductive Fitness and Lifespan in Common Bed Bug (Hemiptera: Cimicidae). AB - The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae) is a nuisance household pest causing significant medical and economic impacts. RNA interference (RNAi) of genes that are involved in vital physiological processes can serve as potential RNAi targets for insect control. Brahma is an ATPase subunit of a chromatin-remodeling complex involved in transcription of several genes for cellular processes, most importantly the homeotic genes. In this study, we used a microinjection technique to deliver double stranded RNA into female bed bugs. Delivery of 0.05 and 0.5 ug/insect of brahma dsRNA directly into hemocele resulted substantial reduction in oviposition. Eggs laid by bed bugs receiving both doses of brahma dsRNA exhibited significantly lower hatching percentage as compared to controls. In addition, brahma RNAi in female bed bugs caused significant mortality. Our results disclosed the potential of brahma RNAi to suppress bed bug population through injection of specific dsRNA, suggesting a critical function of this gene in bed bugs' reproduction and survival. Based on our data, brahma can be a promising RNAi target for suppression of bed bug population. PMID- 29272429 TI - Susceptibility of Brazilian Populations of Helicoverpa armigera and Helicoverpa zea (Lepidoptera: Noctuidae) to Vip3Aa20. AB - Transgenic maize expressing the insecticidal protein Vip3Aa20 is increasingly being adopted in Brazil. In this study, we determined the baseline susceptibility of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) and Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae) to Vip3Aa20, as part of an Insect Resistance Management (IRM) program. Diet-overlay bioassays were conducted with neonates exposed to Vip3Aa20 for 7 d. The baseline susceptibility data were obtained for seven field populations of H. armigera and six of H. zea collected from major soybean-, cotton-, and maize-producing areas in Brazil. To validate the diagnostic concentration, 11 field populations of H. zea were tested from 2014 to 2015. The LC50 for H. armigera populations ranged from 2.97 to 8.41 ug Vip3Aa20/cm2 (threefold variation), and for H. zea populations from 0.04 to 0.21 ug Vip3Aa20/cm2 (fivefold variation). The EC50 for H. armigera ranged from 0.099 to 0.455 ug Vip3Aa20/cm2 (fivefold variation), and for H. zea from 0.004 to 0.020 ug Vip3Aa20/cm2 (fivefold variation). H. armigera was more tolerant to Vip3Aa20 protein than was H. zea (~40- to 75-fold, based on LC50). Based on the LC99 value, the concentration of 6.4 ug Vip3Aa20/cm2 was defined as a diagnostic concentration for susceptibility monitoring in H. zea, and >44 ug Vip3Aa20/cm2 for H. armigera. Our baseline susceptibility data for Vip3Aa20 in H. armigera and H. zea populations will be useful in IRM programs in Brazil. PMID- 29272430 TI - Enhanced Response of Halyomorpha halys (Hemiptera: Pentatomidae) to Its Aggregation Pheromone with Ethyl Decatrienoate. AB - The invasive stink bug species, Halyomorpha halys (Stal) (Hemiptera; Pentatomidae), severely damages multiple agricultural commodities, resulting in the disruption of established IPM programs. Several semiochemicals have been identified to attract H. halys to traps and monitor their presence, abundance, and seasonal activity. In particular, the two-component aggregation pheromone of H. halys, (3S,6S,7R,10S)-10,11-epoxy-1-bisabolen-3-ol and (3R,6S,7R,10S)-10,11 epoxy-1-bisabolen-3-ol (PHER), in combination with the pheromone synergist, methyl (2E,4E,6Z)-decatrienoate (MDT), were found to be attractive. Here, we report that an analogous trienoate, ethyl (2E,4E,6Z)-decatrienoate (EDT), enhances H. halys captures when combined with PHER. In trials conducted in Eastern and Western regions of the United States, we observed that when traps were baited with the H. halys PHER + EDT, captures were significantly greater than when traps were baited with PHER alone. Traps baited with EDT alone were not attractive. Thus, the addition of EDT to lures for attracting H. halys to traps may further improve monitoring efficiency and management strategies for this invasive species. PMID- 29272431 TI - A Multimethod, Case-Controlled Study of Sleep-Wake Disturbances in Adolescents With Spina Bifida. AB - Objective: This study aimed to compare sleep-wake disturbances in adolescents with spina bifida (SB) to typically developing (TD) peers. Exploratory analyses examined sex as moderator of disrupted sleep. Methods: Adolescents with SB (ages 12-18 years; N = 37) and a demographically matched sample of TD adolescents (N = 37) completed validated sleep questionnaires and underwent 10 days of actigraphy monitoring. Results: Adolescents with SB evidenced worse sleep quality, shorter sleep duration, greater sleep maintenance difficulties, and higher levels of fatigue compared with their TD peers. Exploratory analyses revealed females with SB were particularly vulnerable to developing sleep disturbances. Conclusions: Adolescents with SB are at risk for nighttime sleep disturbances and daytime fatigue. Additional research will need to identify mechanisms and adverse consequences of poor sleep to develop interventions addressing sleep deficiency. Sex-specific disparities in sleep patterns in pediatric SB is a novel finding that requires assessment of etiological underpinnings to clarify clinical implications. PMID- 29272433 TI - New Insight into the Management of the Tomato Leaf Miner, Tuta absoluta (Lepidoptera: Gelechiidae) with Entomopathogenic Nematodes. AB - The tomato leaf miner, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), is a serious threat to tomato production in the world. Due to serious issues with insecticide resistance, there is a dire need for alternative control methods. Entomopathogenic nematodes (EPN) have potential for the biological control of T. absoluta. In the laboratory, we examined the effect of temperature, soil type, and exposure time on the efficacy of the EPN species Steinernema carpocapsae (Nematoda: Steinernematidae) and Heterorhabditis bacteriophora (Nematoda: Heterorhabditidae) against last-instar T. absoluta larvae. Both species caused high mortality in loamy sand (89%) and coco peat (93%) but not in sandy loam (17%). H. bacteriophora caused 92-96% mortality at 19, 25, and 31 degrees C; S. carpocapsae caused 89-91% mortality at 25 and 31 degrees C but only 76% at 19 degrees C. Both species caused similar mortality levels after 65-min exposure; thereafter, mortality increased only with S. carpocapsae reaching high levels even at a low concentration. Both species infected larvae within leaf galleries. When applied to whole large tomato plants in the greenhouse, both species provided similar control levels (48-51%) at high pest densities. Both species could be incorporated as an effective alternative to synthetic insecticides into T. absoluta management programs in greenhouse tomato production. PMID- 29272432 TI - Inhibition of antigen presentation during AAV gene therapy using virus peptides. AB - The clinical trial using adeno-associated virus (AAV) vector delivery of mini dystrophin in patients with Duchenne Muscular Dystrophy (DMD) demonstrated a cytotoxic lymphocyte (CTL) response targeting the transgene product. These mini dystrophin-specific T-cells have the potential to clear all transduced muscle, presenting the general gene therapy concern of overcoming the CTL response to foreign proteins that provide therapeutic benefit. In this study, we exploited a natural immunosuppression strategy employed by some viruses that results in CTL evasion only in transduced cells. After transfection of the plasmids encoding viral peptides and ovalbumin, which includes the immune-domain epitope SIINFEKL, several viral small peptides (ICP47 and US6) inhibited the SIINFEKL peptide presentation. A single AAV vector genome that consisted of either transgene AAT fused with SIINFEKL epitope and, separately, ICP47 expressed from different promoters or a single fusion protein with ICP47 linked by a furin cleavage peptide (AATOVA-ICP47) decreased antigen presentation. Compared with AAV/AATOVA in which decreased AAT expression was observed at late time points, persistent transgene expression was obtained after systemic administration of AAV/AATOVA ICP47 vectors in mice. We extended this strategy to DMD gene therapy. After administration of AAV vector encoding human mini-dystrophin fusion protein with ICP47 into mdx mice, a lower mini-dystrophin-specific CTL response was induced. Importantly, the ICP47 fusion to mini-dystrophin inhibited CTLs mediated cytotoxicity. Although demonstrated herein using AAT and mini-dystrophin transgenes in an AAV context, the collective results have implications for all gene therapy applications resulting in foreign peptides by immune suppression in only genetically modified cells. PMID- 29272434 TI - Pollen Foraging Differences Among Three Managed Pollinators in the Highbush Blueberry (Vaccinium corymbosum) Agroecosystem. AB - Highbush blueberry, Vaccinium corymbosum (Gray), production in British Columbia is dependent upon insect pollination for fruit yield with particular cultivars demonstrating low yields due to poor pollination. New managed species of pollinators are being developed to provide farmers with managed pollinator options beyond Apis mellifera (Linnaeus). Pollinators in highbush blueberry agricultural systems encounter a variety of nontarget floral resources that may affect the pollination received by the crop. Our study analyzed the differences in pollen foraging of honey bees and two species of managed bumblebees across nine farm sites. Corbicular pollen loads from pollen foraging workers were removed and identified to the lowest taxonomic level possible. Of the three managed pollinators, the corbicular pollen loads of Bombus huntii (Greene) contained the most blueberry pollen (52.1%), three times as much as the two other managed bee species. Fifteen morphotypes of pollen were identified from all foraging workers with Rosaceae being the most frequently gathered overall pollen type (n = 74). The noncrop pollen identified in our samples derived from plant species not common as weedy species in the agroecosystem suggesting that floral resource diversity outside of the farm boundaries is important to pollinators. The three managed species in our blueberry fields utilized floral resources differentially underscoring the importance of pollinator species' characteristics and large-scale floral resource landscape in developing new managed pollinators and pollination strategies. PMID- 29272435 TI - Vaccine to fibroblast growth factor 23 peptides increases eggshell strength. AB - Strategies that would increase eggshell quality could be of considerable value to egg producers. This research demonstrated the effective use of fibroblast growth factor 23 (FGF-23) peptide vaccines to increase eggshell quality of Single Comb White Leghorn laying hens (from 69 to 72 wk of age). Hens, fed a standard diet (containing 900 IU/kg vitamin D3), were intramuscularly injected (and boosted) with either a control vaccine (n = 14 hens) or one of 2 FGF-23 peptide vaccines (peptides NP1, GMNPPPYS; and NP7, YTSTERNSFH; n = 15 hens for each peptide). During peak antibody titer, eggs were collected for shell and internal quality analysis, hens were artificially inseminated, and the hatchability of fertilized eggs was determined. Laying hens vaccinated with either FGF-23 peptide NP1 or NP7 had increased (P < 0.05) plasma phosphate level (mmol/L; NP1 = 1.74, NP7 = 1.76, control = 1.47), egg specific gravity (NP1 = 1.083, NP7 = 1.083, control = 1.079), and eggshell strength (g of force; NP1 = 4002, NP7 = 4157, control = 3102) when compared to control vaccinated hens. FGF-23 peptide NP1 vaccinated hens also had increased eggshell thickness (mm, P < 0.001), shell weight (g, P = 0.032), and shell index (% of whole egg, P = 0.023) when compared to control vaccinated hens. FGF-23 peptide NP7 vaccinated hens tended to have decreased eggshell weight (P = 0.064) when compared to control vaccinated hens. Hatchability of fertilized eggs was not affected in incubations 1 and 3, but tended to be decreased (P = 0.097) by FGF-23 peptide NP1 vaccination in incubation 2. In conclusion, vaccines to FGF-23 peptides increased eggshell quality of laying hens with minimal adverse effects on egg internal quality. The effect of FGF-23 peptide vaccination on hatchability remains to be clarified. PMID- 29272436 TI - Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa. AB - Objectives: Broad-spectrum antimicrobial resistance in Pseudomonas aeruginosa (PSA) isolates is a growing concern as our therapeutic options have become significantly limited. Although ceftolozane/tazobactam (C/T) has been shown to be highly active against MDR PSA pathogens, combination regimens are often employed in real-world settings. To assist the clinical decision-making process regarding the selection of combination antibiotics and dosages for this pathogen, we performed time-kill studies assessing clinical free peak and trough C/T concentrations alone and in combination with eight anti-pseudomonal agents against four clinical MDR PSA isolates. Methods: Time-kill analyses were performed over 24 h in duplicate using C/T concentrations reflective of the free peak concentrations of a 3 g dose every 8 h (q8h; 120/25.2 mg/L) and the peak and trough of a 1.5 g q8h dose (60/12.6 and 7.5/1.6 mg/L) in humans. The activity of C/T 120, 60 and 7.5 mg/L alone and C/T 7.5 mg/L in combination with free peak and trough concentrations of clinical doses for cefepime, ciprofloxacin, colistin, aztreonam, meropenem, piperacillin/tazobactam, fosfomycin and amikacin was tested for all isolates. Results: C/T 3 and 1.5 g q8h peak concentrations demonstrated killing against the MDR PSA. Colistin and fosfomycin were synergistic with C/T as dual therapy and triple therapy regimens. Conclusions: As a result of escalating resistance, PSA is an increasingly challenging pathogen in the clinical setting. Our findings aid in the identification of novel treatment options using achievable drug exposures for the treatment of MDR PSA. PMID- 29272438 TI - The effect of luminous intensity on the attraction of phlebotomine sand flies to light traps. AB - To improve the efficiency of light traps in collecting phlebotomine sand flies, the potential effects of luminous intensity on the attraction of these insects to traps were evaluated. Sand flies were collected with Hooper Pugedo (HP) light traps fitted with 5-mm light-emitting diodes (LED) bulbs: green (520 nm wavelength-10,000, 15,000 and 20,000 millicandela (mcd) and blue (470 nm-4,000, 12,000 and 15,000 mcd). A total of 3,264 sand flies comprising 13 species were collected. The collected species were Lutzomyia longipalpis (Lutz & Neiva) (Diptera: Psychodidae) (52.48%), Evandromyia evandroi (Costa Lima & Antunes, 1939) (Diptera: Psychodidae) (32.90%) and Micropygomyia goiana (Martins, Falcao, & Silva) (Diptera: Psychodidae) (9.76%). An increase in luminous intensity of the LEDs increased the size of the sand fly catch. The lower luminous intensity of green (10,000 mcd) attracted an average of 13.7 +/- 2.8 sand flies/trap per night and the other luminous intensities accounted for a mean of 24.1 +/- 4.0 (15,000 mcd) and 28.2 +/- 5.0 (20,000 mcd) sand flies/trap per night. Regarding the blue wavelength, the lower luminous intensity (4,000 mcd) attracted an average of 27.4 +/- 4.1 sand flies/trap per night, followed by 12,000 mcd (37.6 +/- 8.7) and 15,000 mcd (40.5 +/- 7.3). Based on our data, the luminous intensity of light traps should be considered when developing light traps for monitoring or controlling phlebotomine sand flies. PMID- 29272437 TI - Apis cerana Is Less Sensitive to Most Neonicotinoids, Despite of Their Smaller Body Mass. AB - Multiple stressors and interaction between them may be responsible for the decline of global pollinators. Among them, exposure to neonicotinoids has been getting more attention and has been considered as a main stressor. The Western honey bee (Apis mellifera L.) (Hymenoptera: Apidae) and Chinese indigenous honey bee (Apis cerana F.) (Hymenoptera: Apidae) are two managed honey bee species in China. These two species are widely used in beekeeping, and many wild A. cerana is widely spread in forests and contributes to the ecosystem. It is predicated that A. cerana is more sensitive to insecticides than A. mellifera due to their smaller mass. Here, we found that although the body mass of A. cerana is significantly lower than A. mellifera, the sensitivity of the two species to neonicotinoids are not associated with their body mass but depended on the chemical structure of neonicotinoids. To dinotefuran, the two species showed the similar sensitivity. To acetamiprid, A. mellifera was less sensitive than A. cerana. However, to imidacloprid and thiamethoxam, A. mellifera was more sensitive than A. cerana. These results suggested that the sensitivity of honey bees to neonicotinoids is closely associated with the structure of pesticides, but not with body mass of bees. It is also indicated that the hazards of pesticides to the different pollinators could not be inferred from one species to another. PMID- 29272439 TI - Characterization of OXA-48-like carbapenemase producers in Canada, 2011-14. AB - Objectives: Since the first identification of the OXA-48 carbapenemase in 2001, Enterobacteriaceae harbouring OXA-48-like enzymes have been reported globally. Here, we applied WGS to characterize the molecular epidemiology of these bacterial isolates. Methods: Enterobacteriaceae non-susceptible to carbapenems isolated from patients between 2011 and 2014 were voluntarily submitted to the Canadian National Microbiology Laboratory where they were screened for carbapenemase genes. WGS was conducted on OXA-48-like producers using the Illumina MiSeq platform. WGS data were used for single nucleotide variant (SNV) analysis, MLST analysis, detection of resistance genes and partial plasmid characterization. Susceptibilities were determined using Vitek2 and Etest. Patient data provided from sites were reviewed. Results: Sixty-seven non duplicated cases were identified among Escherichia coli (n = 21) and Klebsiella pneumoniae (n = 46). Recent international travel was observed in 40.4% of cases. OXA-181 (52.2%) and OXA-48 (31.3%) were the most common variants, one E. coli OXA 48 producer was found to harbour the acquired colistin resistance gene mcr-1. The dominant STs were ST38 and ST410 in E. coli and ST14 in K. pneumoniae. Three common plasmid types were observed among isolates: IncL/M associated with OXA-48 producers, and ColKP3 and IncX3 associated with OXA-181/232 producers. Conclusions: Enterobacteriaceae with OXA-48-like carbapenemases are emerging in Canada. This study highlights the complexity of OXA-48-types identified in Canada owing to travel and the successful clones and plasmids harbouring the OXA-48-like enzyme. PMID- 29272440 TI - A survey of localized sequence rearrangements in human DNA. AB - Genomes mutate and evolve in ways simple (substitution or deletion of bases) and complex (e.g. chromosome shattering). We do not fully understand what types of complex mutation occur, and we cannot routinely characterize arbitrarily-complex mutations in a high-throughput, genome-wide manner. Long-read DNA sequencing methods (e.g. PacBio, nanopore) are promising for this task, because one read may encompass a whole complex mutation. We describe an analysis pipeline to characterize arbitrarily-complex 'local' mutations, i.e. intrachromosomal mutations encompassed by one DNA read. We apply it to nanopore and PacBio reads from one human cell line (NA12878), and survey sequence rearrangements, both real and artifactual. Almost all the real rearrangements belong to recurring patterns or motifs: the most common is tandem multiplication (e.g. heptuplication), but there are also complex patterns such as localized shattering, which resembles DNA damage by radiation. Gene conversions are identified, including one between hemoglobin gamma genes. This study demonstrates a way to find intricate rearrangements with any number of duplications, deletions, and repositionings. It demonstrates a probability-based method to resolve ambiguous rearrangements involving highly similar sequences, as occurs in gene conversion. We present a catalog of local rearrangements in one human cell line, and show which rearrangement patterns occur. PMID- 29272441 TI - Validation of the Symptom Screening in Pediatrics Tool in Children Receiving Cancer Treatments. AB - Background: The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Methods: In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations. Results: Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed. Conclusions: SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery. PMID- 29272442 TI - ExoCET: exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes. PMID- 29272443 TI - Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz. AB - Background: A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV) infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Methods: Eighty three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. Results: PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), <1% of women achieved defined protective PQ coverage. Weekly (960 mg PQ) or low-dose daily (320 or 160 mg PQ) regimens achieved protective PQ coverage for 34% and >96% of women, respectively. All regimens were safe, with <=2% of women predicted to have >=30 msec QTc increase. Conclusions: For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. Clinical Trials Registration: NCT02282293. PMID- 29272445 TI - Evaluation of Intraosseous Fluid as an Alternative Biological Specimen in Postmortem Toxicology. AB - The postmortem redistribution phenomenon is an important factor in the interpretation of blood drug concentrations as a cause or factor in death. Intraosseous fluid (IOF) may serve as an alternative matrix for drug testing. Intraosseous fluid was collected from the left and right tibias and humerus of 29 decedents using the Arrow EZ-IO Intraosseous Vascular Access System. Standard autopsy specimens including blood were also collected at the same time during autopsy. Blood and IOF specimens were screened by immunoassay for opioids, fentanyl analogs, oxycodone, methadone, cocaine, methamphetamine, amphetamines, phencyclidine, tricyclic antidepressants, benzodiazepines and cannabinoids, using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Correlation between cardiac/central blood ELISA and IOF ELISA results was mostly 100% for drug targets. Further blood confirmation analysis was performed by gas chromatography mass spectrometry also showed comparable correlation to IOF screen results. There was no significant difference between the IOF sites or sides of the body. This novel study supports the use of IOF as an alternative postmortem specimen for toxicological investigations as a potentially less-compromised tissue in decomposed or traumatized bodies. Preliminary data is provided for the screening of common drugs of abuse in IOF that may show to be subject to alternative rates of postmortem redistribution than to that of other biological specimens in future studies that quantitate IOF drug concentrations. PMID- 29272444 TI - Effects of fumonisin B1 and mycotoxin binders on growth performance, tibia characteristics, gut physiology, and stress indicators in broiler chickens raised in different stocking densities. AB - The present study was carried out to investigate the effects of stocking density, fumonisin B1 (FB), and mycotoxin binder (TB) on growth performance, bone quality, physiological stress indicators, and gut health in broiler chickens. Day-old Ross 308 male broiler chicks (n = 1,440/experiment) were randomly allocated to 72 floor pens in a 3 * 2 * 2 factorial arrangement, using 3 stocking densities (12.5 birds/m2 [HSD], 10 birds/m2 [MSD], or 7.5 birds/m2 [LSD]), 2 levels of purified FB (0 or 10 ppm), and 2 levels of TB (0 or 0.2%). Each treatment had 6 replicates (n = 6/treatment) and experiments lasted 34 days. All data were analyzed using 3 way ANOVA with stocking density level, FB, and TB as main factors. Body weight gain and feed intake were lower (P < 0.05) in broilers kept at HSD and MSD compared to LSD-housed counterparts. Birds fed an FB-contaminated diet exhibited a higher feed-to-gain ratio compared with those fed an FB-free diet (P < 0.05). None of the treatments affected intestinal morphology or ileal secretory immunoglobulin A levels. Stocking density affected tibia breaking strength (P < 0.05), which was lower in chickens housed at HSD compared with LSD-housed chickens. The heterophil/lymphocyte ratio (H/L ratio) was elevated (P < 0.05) in HSD and MSD groups compared with the LSD group. Serum nitric oxide (NO) levels were elevated (P < 0.05) in chickens fed the FB-contaminated diet compared with the control diet-fed counterparts. Significant interaction (P < 0.05) between FB and TB on serum NO levels was noted. In summary, increasing stocking density lowered growth performance and bone quality, but increased the H/L ratio. Dietary TB did not affect FB-induced increases in the feed-to-gain ratio. No interaction was observed between stocking density and FB for the measured variables. PMID- 29272446 TI - Predicting Short-Term Uptake of Electronic Cigarettes: Effects of Nicotine, Subjective Effects, and Simulated Demand. AB - Introduction: E-cigarettes have potential to support tobacco cessation or reduction, but how nicotine content affects smokers' subjective perceptions and use of e-cigarettes, rather than tobacco, is unclear. Method: Thirty-five adult daily smokers who had not previously tried e-cigarettes were recruited from two cities in New Zealand in 2016-2017. Smokers were given four e-cigarette cartridges (0, 6, 12, and 18 mg nicotine) in a randomized, blinded order over four 2-week periods. Daily cigarette smoking and e-cigarette use was monitored using ecological momentary analysis and participants completed the modified Cigarette Evaluation Questionnaire after each 2-week period. Results: Mean cigarettes per day decreased by 37% (9.69 to 6.09) when e-cigarettes were available relative to baseline (p = .008). Nicotine-containing cartridges (>0 mg) were associated with greater use (p = .023) and craving reduction (p = .026) than 0 mg. Alleviation of withdrawal symptoms (p = .048) and taste and enjoyment factors (p = .039) predicted e-cigarette use. Conclusion: Availability of e cigarettes reduced cigarette smoking behavior regardless of nicotine content, and e-cigarette use was greater with nicotine-containing cartridges. First-time users' e-cigarette use can be predicted using subjective ratings and more research is required to clarify the effect of nicotine content on subjective perceptions and use. Implications: For low-moderate dependence smokers, availability of e-cigarettes may reduce cigarette smoking behavior regardless of nicotine content, but the availability of nicotine-containing cartridges may promote greater e-cigarette use. First response to trialing e-cigarettes is an important factor in determining subsequent experimental and possibly longer-term use. PMID- 29272447 TI - TF2Network: predicting transcription factor regulators and gene regulatory networks in Arabidopsis using publicly available binding site information. AB - A gene regulatory network (GRN) is a collection of regulatory interactions between transcription factors (TFs) and their target genes. GRNs control different biological processes and have been instrumental to understand the organization and complexity of gene regulation. Although various experimental methods have been used to map GRNs in Arabidopsis thaliana, their limited throughput combined with the large number of TFs makes that for many genes our knowledge about regulating TFs is incomplete. We introduce TF2Network, a tool that exploits the vast amount of TF binding site information and enables the delineation of GRNs by detecting potential regulators for a set of co-expressed or functionally related genes. Validation using two experimental benchmarks reveals that TF2Network predicts the correct regulator in 75-92% of the test sets. Furthermore, our tool is robust to noise in the input gene sets, has a low false discovery rate, and shows a better performance to recover correct regulators compared to other plant tools. TF2Network is accessible through a web interface where GRNs are interactively visualized and annotated with various types of experimental functional information. TF2Network was used to perform systematic functional and regulatory gene annotations, identifying new TFs involved in circadian rhythm and stress response. PMID- 29272448 TI - Loop-Mediated Isothermal Amplification on Crude DNA as a Point-of-Care Test for the Diagnosis of Mycoplasma-Related Vaginitis During Early Pregnancy. AB - Background: Mycoplasma-related vaginitis gradually has been growing as a threat in adults-genitourinary infection contributes to funisitis, spontaneous abortion, and low birth weight. Until now, use of loop-mediated isothermal amplification (LAMP) to detect Ureaplasma urealyticum (UU), Mycoplasma hominis (MH), or Mycoplasma genitalium (MG) has been reported by some researchers. However, previous studies focused on purified DNA as the template for LAMP assay, which is usually extracted via commercial kit. Methods: We developed a LAMP assay for rapid detection of UU, MH, and MG genital mycoplasmas using a simple boiling method for DNA extraction, in a cohort of pregnant women with mycoplasma-related vaginitis. We monitored amplicons with the naked eye using SYBR Green I. Results: The cohort in our study showed a prevalence of 22.6% in pregnant women, as detected by UU-LAMP assay. Compared to the polymerase chain reaction (PCR) test with purified DNA, the sensitivity of the UU-LAMP in clinical specimens with crude DNA was 87.5% (95% confidence interval [CI], 64.6%->99.9). For crude DNA specimens, UU-LAMP was more sensitive and reliable than PCR, with a higher agreement rate (96.8%) and Youden index value (0.88). Conclusions: As a point-of care test, LAMP is a useful, specific, and efficient way to detect genital mycoplasmas in resource-limited settings, especially for crude DNA. PMID- 29272449 TI - Age- and Sex-Specific Differences as Predictors of Surgical Remission Among Patients With Acromegaly. AB - Context: Sex and age are factors conferring resistance to medical treatment in patients with acromegaly. However, their impact on outcomes of transsphenoidal selective adenomectomy (TSA) has not been evaluated. Objective: To analyze age- and sex-related differences concerning surgical outcomes of growth hormone (GH) secreting pituitary adenomas. Design: Retrospective. Setting: Single-center tertiary hospital. Participants: Patients with acromegaly (n = 463) who underwent TSA between January 2000 and July 2014. Intervention: TSA. Main Outcome Measurements: Tumor characteristics and surgical outcomes. Results: Sex differences existed in the baseline insulinlike growth factor-1 levels and the mean tumor size. Overall, surgical remission rates were 89.7% and 76.5% in male and female patients, respectively (P < 0.001). Total tumor tissue resection was performed in 92.6% and 85.8% of male and female participants, respectively (P = 0.021). Premenopausal women had a higher proportion of pituitary adenoma with cavernous sinus invasion than did men aged <50 years (35.3% vs 21.7%, P = 0.007). In immediate postoperative, 75-g oral glucose tolerance tests, fewer premenopausal women reached <1 ng/dL nadir GH levels than did men aged <50 years (59.9% vs 87.7%, P < 0.001). Surgical results were similar in both sexes among older patients (>=50 years). However, premenopausal women had significantly lower long-term remission rates than did men aged <50 years (69.3% vs 88.0%, P < 0.001). Conclusion: Premenopausal women with acromegaly tend to have larger tumors, more aggressive tumor types, and lower remission rates than do men. However, further studies on the clinical implications are needed. PMID- 29272450 TI - Ciliary protein trafficking mediated by IFT and BBSome complexes with the aid of kinesin-2 and dynein-2 motors. AB - Cilia and flagella of eukaryotic cells are evolutionarily conserved organelles with a microtubule-based axoneme as a scaffold. To fulfil their functions in cellular motility, sensory reception and developmental signalling, cilia contain unique proteins, such as receptors and ion channels. The assembly and maintenance of cilia depend on protein trafficking mediated by intraflagellar transport (IFT) particles as well as on selective entry and exit of proteins across the transition zone, which is located at the ciliary base. Bidirectional movement of IFT particles, which are composed of IFT-A and IFT-B complexes, is powered by kinesin-2 and dynein-2 motors. The BBSome associates with IFT particles and probably mediates the ciliary trafficking of membrane proteins. Abnormal ciliary assembly and functions due to defects in IFT particle components lead to a wide spectrum of disorders, which are collectively called the ciliopathies. We here review the IFT machinery by associating the architecture of the IFT complexes and their motor and cargo proteins with their functions. PMID- 29272452 TI - Antibiotic consumption in Shandong Province, China: an analysis of provincial pharmaceutical centralized bidding procurement data at public healthcare institutions, 2012-16. AB - Objectives: To explore the trends of antibiotic consumption in public healthcare institutions through analysing the provincial centralized bidding procurement (CBP) data in Shandong, China. Methods: The Shandong CBP system has been established since 2011, covering public healthcare institutions of 500 secondary and tertiary hospitals, 600 urban primary healthcare centres (PHCs) and 1600 rural PHCs. We collected all the antibiotic procurement records from the CBP system between 2012 and 2016. Antibiotic consumption data were calculated using Anatomical Therapeutic Chemical (ATC)/DDD methodology and normalized using DDD per 1000 inhabitants per day (DID). Results: Overall antibiotic consumption increased from 12.859 DID in 2012 to 15.802 DID in 2014, then decreased to 13.802 DID in 2016. The top three antibiotics consumed in 2016 were penicillins (4.251 DID), quinolones (2.957 DID) and macrolides (2.057 DID). PHCs consumed 80% of the total antibiotics, of which rural PHCs accounted for 88%. Antibiotic consumption peaked in 2014 for rural PHCs and in 2015 for hospitals, and declined thereafter. In urban PHCs, the consumption steadily increased from 2012 to 2016. Conclusions: Zero mark-up drug policies and national policies to improve rational use of antibiotic were associated with the reduction of antibiotic consumption in public healthcare institutions in Shandong Province. Regulations for antibiotic use in PHCs should be strengthened. PMID- 29272453 TI - Isolation in small populations of Wayampi Amerindians promotes endemicity and homogenisation of their faecal virome, but its distribution is not entirely random. AB - The isolated community of the Wayampi Amerindians has been extensively studied for the presence of beta lactamase-producing enterobacteria and their gut microbiota. However, no information about their virome was available. This study tries to establish potential associations between the virome and diverse epidemiological data, through the metagenomic study of the faecal prophages and DNA viruses from 31 samples collected in 2010. Taxonomic assignments, composition, abundance and diversity analyses were obtained to characterise the virome and were compared between groups according to several demographic, environmental and medical data. Prophages outnumbered viruses. Composition and abundance of virome indicated relatively low variability. Diversity within samples showed no significant differences, regardless of the group comparison. Significant differences were observed in the beta diversity among samples according to hospitalisation and gender, but not by extended spectrum beta lactamase carriage, antibiotic intake or possession of pets, although some viruses differed in some cases (e.g. immunodeficiency-associated stool virus associated with antibiotic intake). The faecal virome of adult Wayampi is more homogeneous than that from western populations. Not a single factor analysed can explain alone the observed distribution of the virome, but differences by gender (fewer variability in females than males) may reflect differences in life habits and work. PMID- 29272454 TI - eComment. The importance of intra-procedural end-points for the long-term success of hybrid ablation. PMID- 29272455 TI - eComment. Platelet-rich plasma and cardiac tissue regeneration. PMID- 29272456 TI - eComment. The body floss wire technique - establishing a stable platform for right carotid artery stenting in hostile aortic arches. PMID- 29272451 TI - Nonsense-mediated mRNA decay: a 'nonsense' pathway makes sense in stem cell biology. AB - Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional regulatory mechanism of gene expression in eukaryotes. Originally, NMD was identified as an RNA surveillance machinery in degrading 'aberrant' mRNA species with premature termination codons. Recent studies indicate that NMD regulates the stability of natural gene transcripts that play significant roles in cell functions. Although components and action modes of the NMD machinery in degrading its RNA targets have been extensively studied with biochemical and structural approaches, the biological roles of NMD remain to be defined. Stem cells are rare cell populations, which play essential roles in tissue homeostasis and hold great promises in regenerative medicine. Stem cells self-renew to maintain the cellular identity and differentiate into somatic lineages with specialized functions to sustain tissue integrity. Transcriptional regulations and epigenetic modulations have been extensively implicated in stem cell biology. However, post transcriptional regulatory mechanisms, such as NMD, in stem cell regulation are largely unknown. In this paper, we summarize the recent findings on biological roles of NMD factors in embryonic and tissue-specific stem cells. Furthermore, we discuss the possible mechanisms of NMD in regulating stem cell fates. PMID- 29272457 TI - Maternal subjective well-being and preventive health care system in Japan and Finland. AB - Background: Maternal well-being is an important issue not only for mothers but also for their offspring and whole families. This study aims to clarify differences in subjective well-being for mothers with infants and associated factors by comparing Japanese and Finnish mothers. Methods: In Finland, 101 mothers with infants who received health check-ups at child's age 4 months participated in the study. In Japan, 505 mothers with infants who should receive health check-ups at child's age 4 months and, whose age, age of the infant and number of children matched with the Finnish mothers were selected. The factors associated with maternal subjective well-being were explored by the linear regression analysis. All Finnish mothers had individual infant health check-ups by nurses in Child Health Clinics nearly monthly. The same nurse was responsible for following up the family throughout the years. All Japanese participants received group health check-up once at child's age 3 to 4 months, and a nurse did not cover same child and their mother. Results: Finnish mothers showed significantly better subjective well-being compared with Japanese mothers. Whereas 85% of Finnish mothers responded that they had obtained childcare information from public health nurses, significantly fewer Japanese mothers indicated the same response (8%). Linear regression analyses disclosed that mothers' subjective well-being was associated with country, mothers' stress and age. Conclusion: Finnish mothers had better subjective well-being than Japanese mothers. Our results may indicate that the Finnish health care system supports mothers better than the Japanese health care system does. PMID- 29272458 TI - Comparative Effectiveness of Antipsychotic Drugs for Rehospitalization in Schizophrenia-A Nationwide Study With 20-Year Follow-up. AB - Very little is known about the comparative long-term effectiveness of novel antipsychotics in relapse prevention, especially in first-episode schizophrenia. Nationwide data from Finnish health care registers were gathered prospectively for all persons with periods of inpatient care due to schizophrenia in Finland during 1972-2014. Altogether 62250 persons were included in the prevalent cohort, and 8719 in the incident (first-episode schizophrenia) cohort. The follow-up for antipsychotic use started at 1996 for the prevalent cohort, and at the first discharge from inpatient care for the incident cases. Within-individual Cox regression models for risk of psychiatric and all-cause hospitalization were constructed to compare risk during antipsychotic use and no use using individual as his/her own control to eliminate selection bias. With follow-up time up to 20 years (median = 14.1, interquartile range = 6.9-20.0), 59% of the prevalent cohort were readmitted to psychiatric inpatient care. Olanzapine long-acting injection (LAI; adjusted hazard ratio = 0.46, 95% confidence interval = 0.36 0.61), clozapine (0.51, 0.49-0.53), and paliperidone LAI (0.51, 0.40-0.66) were associated with the lowest risk of psychiatric rehospitalization in the prevalent cohort. Among first-episode patients, the lowest risks were observed for flupentixol LAI (0.24, 0.12-0.49), olanzapine LAI (0.26, 0.16-0.44), and perphenazine LAI (0.39, 0.31-0.50). Clozapine and LAIs were associated with the lowest risk of all-cause hospitalization in both cohorts. Clozapine and LAIs are the most effective treatments in preventing psychiatric and all-cause hospitalization among chronic and first-episode patients with schizophrenia. PMID- 29272459 TI - How does the presence of excreta affect the behavior of laying hens on scratch pads? AB - Enriched cages for laying hens provide scratch pads for foraging on the wire mesh floors. Apart from foraging on scratch pads, hens also defecate on these pads, causing them to become soiled with excreta. This study was conducted to determine the relative preference of laying hens for foraging on clean (C) scratch pads or scratch pads soiled with excreta (E), and to study the behaviors performed by hens on such pads. A total of 288 laying hens was housed in 16 enriched cages (18 hens/cage), each divided into 2 compartments. On a daily basis, half of the scratch pads (one in each compartment) were removed and cleaned, while the other half were cleaned and then covered with 550 g (0.35 g/cm2) of conspecific excreta. The C and E scratch pads were then put back into the cages in a systematic order to avoid side bias. Feed was delivered automatically onto the scratch pads as a litter substrate. The frequency of visits and the total time spent performing different behaviors on C and E pads were video-recorded [the time of video recording was relative to litter (feed) delivery on the scratch pads] for a total of 10 min/d, 3 times/wk, over a period of 4 weeks. Overall, the allocation of the time budget for different behaviors was found to be-in order of greatest to least amount of time-resting, locomotor behaviors (walking and running), foraging, and dust bathing. Laying hens showed a relative preference for E scratch pads by visiting them more frequently (P = 0.001), and spent more time (P = 0.035) foraging on them, whereas they rested for more time (P < 0.001) on C scratch pads. The relative preference for E scratch pads during foraging signifies the innate importance of foraging substrates in enriched cages for laying hens. Similarly, the longer use of C scratch pads for resting indicates the need for an ideal and clean resting surface in enriched cages. PMID- 29272460 TI - C3-glomerulopathy and MGUS: the skin beyond the kidney. PMID- 29272461 TI - Transferrin Family Genes in the Brown Planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) in Response to Three Insecticides. AB - Transferrins are involved in iron metabolism, immunity, xenobiotics tolerance, and development in eukaryotic organisms including insects. However, little is known about the relationship between transferrins and insecticide toxicology and resistance. Three transferrin family genes, NlTsf1, NlTsf2, and NlTsf3, of the brown planthopper, Nilaparvata lugens (Stal) (Hemiptera: Delphacidae)a major insect pest of rice field in Asia, had been identified and characterized in this study. Quantitative polymerase chain reaction results demonstrated that NlTsf1 was significantly higher than the other two genes in different tissues. All of them were expressed at higher levels in abdomen and head than in antenna, leg, stylet, and thorax. Compared with the control, the expression of three N. lugens transferrin family genes decreased dramatically 24 h after treatment with buprofezin, pymetrozine and imidacloprid. PMID- 29272462 TI - The roles of auxin during interactions between bacterial plant pathogens and their hosts. AB - Plant pathogens have evolved several strategies to manipulate the biology of their hosts to facilitate colonization, growth to high levels in plant tissue, and production of disease. One of the less well known of these strategies is the synthesis of plant hormones and hormone analogs, and there is growing evidence that modulation of host hormone signaling is important during pathogenesis. Several plant pathogens produce the auxin indole-3-acetic acid (IAA) and/or virulence factors that modulate host auxin signaling. Auxin is well known for being involved in many aspects of plant growth and development, but recent findings have revealed that elevated IAA levels or enhanced auxin signaling can also promote disease development in some plant-pathogen interactions. In addition to stimulating plant cell growth during infection by gall-forming bacteria, auxin and auxin signaling can antagonize plant defense responses. Auxin can also act as a microbial signaling molecule to impact the biology of some pathogens directly. In this review, we summarize recent progress towards elucidating the roles that auxin production, modification of host auxin signaling, and direct effects of auxin on pathogens play during pathogenesis, with emphasis on the impacts of auxin on interactions with bacterial pathogens. PMID- 29272463 TI - Molecular Evidence for Transstadial Transmission of Ehrlichia canis by Rhipicephalus sanguineus sensu lato Under Field Conditions. AB - This study investigated possible transstadial transmission of Ehrlichia canis by Rhipicephalus sanguineus sensu lato collected from shelter dogs and the shelter grounds in Diyarbakir Province of south-eastern Turkey. Totally 225 engorged nymphs were collected from eight infected dogs with E. canis and incubated at 28 degrees C for moulting. Unfed ticks from the shelter grounds comprising 1,800 larvae, 3,100 nymphs, and 85 adults were sorted according to sampling origin, life stage, and sex into 116 pools and screened by 16S rRNA PCR. Nine out of 26 pools of unfed adult ticks were positive for E. canis, with overall infection rate maximum likelihood estimation (MLE) of 4.83 (CI 2.39-8.87). E. canis was detected in three of 12 male pools (MLE 3.22, CI 0.86-8.83) and six of 14 female pools (MLE 6.16, CI 2.59-12.90). No adult pools collected from the shelter grounds were positive. Among 62 unfed nymph pools collected from the shelter, six were infected with E. canis (MLE 0.20, CI 0.08-0.42). No E. canis DNA was detected in any of the larva pools. Our results revealed molecular evidence for transstadial transmission of E. canis by R. sanguineus s.l. both from larva to nymph and from nymph to adult. We found no evidence of transovarial transmission. PMID- 29272464 TI - Brain Age in Early Stages of Bipolar Disorders or Schizophrenia. AB - Background: The greater presence of neurodevelopmental antecedants may differentiate schizophrenia from bipolar disorders (BD). Machine learning/pattern recognition allows us to estimate the biological age of the brain from structural magnetic resonance imaging scans (MRI). The discrepancy between brain and chronological age could contribute to early detection and differentiation of BD and schizophrenia. Methods: We estimated brain age in 2 studies focusing on early stages of schizophrenia or BD. In the first study, we recruited 43 participants with first episode of schizophrenia-spectrum disorders (FES) and 43 controls. In the second study, we included 96 offspring of bipolar parents (48 unaffected, 48 affected) and 60 controls. We used relevance vector regression trained on an independent sample of 504 controls to estimate the brain age of study participants from structural MRI. We calculated the brain-age gap estimate (BrainAGE) score by subtracting the chronological age from the brain age. Results: Participants with FES had higher BrainAGE scores than controls (F(1, 83) = 8.79, corrected P = .008, Cohen's d = 0.64). Their brain age was on average 2.64 +/- 4.15 years greater than their chronological age (matched t(42) = 4.36, P < .001). In contrast, participants at risk or in the early stages of BD showed comparable BrainAGE scores to controls (F(2,149) = 1.04, corrected P = .70, eta2 = 0.01) and comparable brain and chronological age. Conclusions: Early stages of schizophrenia, but not early stages of BD, were associated with advanced BrainAGE scores. Participants with FES showed neurostructural alterations, which made their brains appear 2.64 years older than their chronological age. BrainAGE scores could aid in early differential diagnosis between BD and schizophrenia. PMID- 29272465 TI - WRKY71 Acts Antagonistically Against Salt-Delayed Flowering in Arabidopsis thaliana. AB - Soil salinity affects various aspects of plant growth and development including flowering. Usually, plants show a delayed flowering phenotype under high salinity conditions, whereas some plants will risk their life to continue to grow, thereby escaping serious salt stress to achieve reproductive success. However, the molecular mechanisms of the escape strategies are not clear yet. In this work, we report that the transcription factor WRKY71 helps escape salt stress in Arabidopsis. The expression of the WRKY71 wild-type (WT) allele was salinity inducible. Compared with Col-0, high salt stress caused only a marginal delay in the flowering time of the activation-tagged mutant WRKY71-1D. However, flowering in the RNA interference (RNAi)-based multiple WRKY knock-out mutant (w71w8 + 28RNAi) was dramatically later than in the WT under high salinity conditions. Meanwhile, expression of FLOWERING LOCUS T (FT) and LEAFY (LFY) was greater in WRKY71-1D than in the WT, and lower in w71w8 + 28RNAi under salinity-stressed conditions. The suggestion is that WRKY71 activity hastens flowering, thereby providing a means for the plant to complete its life cycle in the presence of salt stress. PMID- 29272466 TI - Utilizing original XPCTM in feed to reduce stress susceptibility of broilers. AB - Reduction of stress is an important factor in improving poultry welfare, especially during periods of heat stress. A study was conducted to evaluate the effects of feeding the functional metabolites of Diamond V Original XPCTM to broilers reared under ambient or heat stress temperatures. Dietary treatments included: control feed (CON) and Original XPC fed continuously at 1.25 kg/MT (XPC). Half the birds in each dietary treatment were subjected to either no heat stress (24 degrees C constant) or heat stress (35 degrees C:24 degrees C for 18:6 h daily) from 28 to 42 d. At the end of the heat stress period, blood was collected from 40 birds/treatment. Blood was analyzed for plasma corticosterone (CORT), plasma HSP70 (HSP70), and heterophil/lymphocyte ratios (H/L). At 42 d, bilateral metatarsal traits were also measured in 40 birds/treatment to assess physical asymmetry. Birds fed XPC had significantly lower CORT levels than CON (P < 0.001; 5,129 +/- 617 vs. 8,433 +/- 730, respectively). Physical asymmetry scores were also significantly higher in CON compared to XPC fed broilers (P < 0.001; 1.50 +/- 0.13 vs. 0.54 +/- 0.05, respectively). H/L ratios were significantly greater in CON than for XPC birds (P = 0.01; 0.81 +/- 0.05 mm vs. 0.62 +/- 0.05 mm, respectively). No differences were observed between CON and XPC fed broilers in HSP70. However, heat stress did increase (P < 0.0001) HSP70 compared to no heat stress birds (5.65 +/- 0.12 vs. 4.78 +/- 0.11 pg/mL, for heat stress and no heat stress, respectively). Feeding XPC to broiler chickens improved animal welfare via reduced stress indicators while under heat stress or no heat stress conditions. These results indicate that feeding XPC may improve poultry welfare by reducing heat stress susceptibility. PMID- 29272467 TI - Hippocampal Subregions Across the Psychosis Spectrum. AB - Introduction: Converging evidence suggests that hippocampal subregions subserve different functions, and are differentially affected by psychosis illness progression. Despite this fact, studies have not often studied subregions cross sectionally across the psychosis spectrum. Furthermore, little is known about associations between subregion volumes and hippocampus-mediated cognition. Methods: A total of 222 participants (61 ultra high risk [UHR], 91 schizophrenia [SCZ], and 70 healthy volunteers) underwent a 3T MRI scan, as well as structured clinical interviews and a cognitive battery. Hippocampal subfield analysis was conducted with Freesurfer. We compared subregion volumes across groups, controlling for age, gender, and intracranial volume. We also examined associations in the UHR and SCZ groups between hippocampal subregion volumes and verbal learning, visual learning, and working memory. Results: We found a dose dependent relationship such that the SCZ group showed significantly greater subfield volume reductions than the UHR group, which in turn showed significantly greater subfield volume reductions than the healthy volunteer group. We also found associations between subregion volume and cognitive performance in the visual memory, verbal memory, and working memory domains. Discussion: Our study examined hippocampal subregion volumes cross-sectionally in a large sample across the psychosis spectrum, as well as links with hippocampus-mediated cognitive function. Our findings suggest that hippocampal abnormalities emerge before first psychosis episode onset, and may be etiologically informative. PMID- 29272468 TI - Multiple Proteinopathies in Familial ALS Cases With Optineurin Mutations. AB - Optineurin (OPTN) is a causative gene in familial amyotrophic lateral sclerosis (ALS) with transactivation response element DNA-binding protein of 43 kDa (TDP 43) protein pathology. Here, we report multiple proteinopathies in familial ALS cases with OPTN mutations. We examined the TDP-43, tau, and alpha-synuclein pathology of ALS cases with OPTN mutations including 2 previously reported cases (Cases 1 and 2) and 1 newly autopsied case (Case 3) that was clinically diagnosed as ALS and Parkinson disease with a heterozygous E478G OPTN mutation. Pathologic examination of Case 3 showed motor neuron degeneration and depigmentation of the substantia nigra. Neurofibrillary tangles (NFTs) were seen in the hippocampus, pontine tegmentum, and spinal cord. Accumulation of multiple proteins including phosphorylated TDP-43-positive neuronal cytoplasmic inclusions, phosphorylated tau (AT8)-positive NFTs, and alpha-synuclein-positive Lewy bodies were observed in the substantia nigra. The other 2 cases had a similar distribution of tau pathology, but lacked synuclein pathology. Consecutive sections of Case 3 revealed pTDP-43, AT8, and alpha-synuclein-positive inclusions in the same neuron and double immunofluorescence staining showed aggregation of different proteins (tau and alpha-synuclein, or tau and TDP-43) in the same neuron. Our results support the notion that OPTN mutations may lead to multiple proteins aggregation and neuronal degeneration. PMID- 29272469 TI - Looking at genetic structure and selection signatures of the Mexican chicken population using single nucleotide polymorphism markers. AB - Genetic variation enables both adaptive evolutionary changes and artificial selection. Genetic makeup of populations is the result of a long-term process of selection and adaptation to specific environments and ecosystems. The aim of this study was to characterize the genetic variability of Mexico's chicken population to reveal any underlying population structure. A total of 213 chickens were sampled in different rural production units located in 25 states of Mexico. Genotypes were obtained using the Affymetrix Axiom(r) 600 K Chicken Genotyping Array. The Identity by Descent (IBD) and the principal components analysis (PCA) were performed by SVS software on pruned single nucleotide polymorphisms (SNPs).ADMIXTURE analyses identified 3 ancestors and the proportion of the genetic contribution of each of them has been determined in each individual. The results of the Neighbor-Joining (NJ) analysis resulted consistent with those obtained by the PCA. All methods utilized in this study did not allow a classification of Mexican chicken in distinct clusters or groups. A total of 3,059 run of homozygosity (ROH) were identified and, being mainly short in length (<4 Mb), these regions are indicative of a low inbreeding level in the population. Finally, findings from the ROH analysis indicated the presence of natural selective pressure in the population of Mexican chicken.The study indicates that the Mexican chicken clearly appear to be a unique creole chicken population that was not subjected to a specific artificial selection. Results provide a genetic knowledge that can be used as a basis for the genetic management of a unique and very large creole population, especially in the view of using it in production of hybrids to increase the productivity and economic revenue of family farming agriculture, which is widely present in Mexico. PMID- 29272470 TI - Genetic correlates of clarithromycin susceptibility among isolates of the Mycobacterium abscessus group and the potential clinical applicability of a PCR based analysis of erm(41). AB - Objectives: To define the genetic basis of clarithromycin resistance among isolates of the Mycobacterium abscessus group (MAG). Methods: We analysed 133 isolates identified as MAG. Species identification was confirmed by sequencing the rpoB gene. Clarithromycin susceptibility testing was performed according to CLSI recommendations, with an extended 14 day incubation. Known resistance genotypes of erm(41) and rrl were identified by sequencing; the presence of deletions in erm(41) was detected by PCR. Results: The 133 MAG isolates included 82 M. abscessus, 27 Mycobacterium massiliense and 24 Mycobacterium bolletii. After the 3 day incubation, only five isolates demonstrated clarithromycin resistance (R); after 14 days of extended incubation, an additional 92 exhibited inducible resistance (IR), with the remaining being susceptible (S). The distribution of susceptibility phenotypes varied among the species. Among M. abscessus isolates, 11% were S, 84% IR and 5% R; among M. bolletii isolates, 96% were IR and 4% R; and among M. massiliense isolates 100% were S. Sequencing of rrl identified only a single isolate with the A2058G mutation. Deletions in erm(41) were present in 30 susceptible isolates; among the remaining 103 isolates, 97 were R or IR (sensitivity, 83%; specificity, 100%; positive predictive value, 100%; negative predictive value, 94%). Among the six susceptible isolates without deletions, all carried the erm(41) T28C point mutation. Conclusions: A significant proportion of MAG isolates demonstrate inducible resistance to clarithromycin that is only detectable with an extended 14 day incubation. Further, the majority of clarithromycin-susceptible MAG isolates have characteristic deletions in erm(41) that can rapidly and reliably be detected by a simple PCR. PMID- 29272471 TI - Commentary: The Dilemma of Papilledema in Chiari I Malformation. PMID- 29272472 TI - HIV Infection and Circulating Levels of Prosurfactant Protein B and Surfactant Protein D. AB - Prosurfactant protein B (pro-SFTPB) and surfactant protein D (SFTPD) are markers of lung inflammation and damage. We estimated geometric mean pro-SFTPB and SFTPD levels in 500 human immunodeficiency virus (HIV)-infected and 300 HIV-uninfected injection drug users, adjusting for smoking and other covariates. Pro-SFTPB levels were significantly higher among people with HIV (PWH) (adjusted geometric mean, 21.4 vs 18.1 ng/mL; P = .03), and were higher with lower CD4 counts (P trend = .001), higher HIV RNA (P trend = .05), and without highly active antiretroviral therapy (P = .03). These associations were not observed for SFTPD. Serum levels of pro-SFTPB are elevated among PWH and are associated with immunosuppression and uncontrolled viremia. PMID- 29272473 TI - Senp2 regulates adipose lipid storage by de-SUMOylation of Setdb1. AB - One major function of adipocytes is to store excess energy in the form of triglycerides. Insufficient adipose lipid storage is associated with many pathological conditions including hyperlipidemia, insulin resistance, and type 2 diabetes. In this study, we observed the overexpression of SUMO-specific protease 2 (Senp2) in adipose tissues during obesity. Adipocyte Senp2 deficiency resulted in less adipose lipid storage accompanied by an ectopic fat accumulation and insulin resistance under high-fat diet feeding. We further found that SET domain bifurcated 1 (Setdb1) was a SUMOylated protein and that SUMOylation promoted Setdb1 occupancy on the promoter locus of Pparg and Cebpa genes to suppress their expressions by H3K9me3. Senp2 could suppress Setdb1 function by de-SUMOylation. In adipocyte Senp2-deficiency mice, accumulation of the SUMOylated Setdb1 suppressed the expression of Pparg and Cebpa genes as well as lipid metabolism related target genes, which would decrease the ability of lipid storage in adipocytes. These results revealed the crucial role of Senp2-Setdb1 axis in controlling adipose lipid storage. PMID- 29272474 TI - Predicting Hospitalization and Outpatient Corticosteroid Use in Inflammatory Bowel Disease Patients Using Machine Learning. AB - Background: Inflammatory bowel disease (IBD) is a chronic disease characterized by unpredictable episodes of flares and periods of remission. Tools that accurately predict disease course would substantially aid therapeutic decision making. This study aims to construct a model that accurately predicts the combined end point of outpatient corticosteroid use and hospitalizations as a surrogate for IBD flare. Methods: Predictors evaluated included age, sex, race, use of corticosteroid-sparing immunosuppressive medications (immunomodulators and/or anti-TNF), longitudinal laboratory data, and number of previous IBD related hospitalizations and outpatient corticosteroid prescriptions. We constructed models using logistic regression and machine learning methods (random forest [RF]) to predict the combined end point of hospitalization and/or corticosteroid use for IBD within 6 months. Results: We identified 20,368 Veterans Health Administration patients with the first (index) IBD diagnosis between 2002 and 2009. Area under the receiver operating characteristic curve (AuROC) for the baseline logistic regression model was 0.68 (95% confidence interval [CI], 0.67-0.68). AuROC for the RF longitudinal model was 0.85 (95% CI, 0.84-0.85). AuROC for the RF longitudinal model using previous hospitalization or steroid use was 0.87 (95% CI, 0.87-0.88). The 5 leading independent risk factors for future hospitalization or steroid use were age, mean serum albumin, immunosuppressive medication use, and mean and highest platelet counts. Previous hospitalization and corticosteroid use were highly predictive when included in specified models. Conclusions: A novel machine learning model substantially improved our ability to predict IBD-related hospitalization and outpatient steroid use. This model could be used at point of care to distinguish patients at high and low risk for disease flare, allowing individualized therapeutic management. PMID- 29272475 TI - A beta-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects. AB - Background: Administration of beta-glucan has shown immune-enhancing effects. Our aim was to investigate whether beta-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohn's disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of beta-glucan uptake and effects on MCs in vitro. Methods: Segments of FAE and VE from 8 CD patients and 9 controls were mounted in Ussing chambers. Effects of the MC-degranulator compound 48/80 (C48/80) and yeast-derived beta-1,3/1,6 glucan on hyperpermeability were investigated. Translocation of beta-glucan and colocalization with immune cells were studied by immunofluorescence. Caco-2-cl1- and FAE-cultures were used to investigate beta-glucan-uptake using endocytosis inhibitors and HMC-1.1 to study effects on MCs. Results: beta-glucan significantly attenuated MC-induced paracellular hyperpermeability in CD and controls. Transcellular hyperpermeability was only significantly attenuated in VE. Baseline paracellular permeability was higher in FAE than VE in both groups, P<0.05, and exhibited a more pronounced effect by C48/80 and beta-glucan P<0.05. No difference was observed between CD and controls. In vitro studies showed increased passage, P<0.05, of beta-glucan through FAE-culture compared to Caco-2-cl1. Passage was mildly attenuated by the inhibitor methyl-beta-cyclodextrin. HMC-1.1 experiments showed a trend to decreasing MC-degranulation and levels of TNF-alpha but not IL 6 by beta-glucan. Immunofluorescence revealed more beta-glucan-uptake and higher percentage of macrophages and dendritic cells close to beta-glucan in VE of CD compared to controls. Conclusions: We demonstrated beneficial effects of beta glucan on intestinal barrier function and increased beta-glucan-passage through FAE model. Our results provide important and novel knowledge on possible applications of beta-glucan in health disorders and diseases characterized by intestinal barrier dysfunction. PMID- 29272476 TI - Suicidal Behavior Among Hospitalized Adults With Inflammatory Bowel Disease: A United States Nationwide Analysis. AB - Background: Suicidal behavior in inflammatory bowel disease (IBD) has been minimally explored. We aimed to determine United States (US) nationally representative prevalence estimates of suicidal ideation (SI) and suicide/self inflicted injury (S/SII) among hospitalized adults with IBD and to examine trends in suicidal behavior over time. Methods: A retrospective cross-sectional study using National (Nationwide) Inpatient Sample data (2006-2011) identified adults with Crohn's disease (CD) or ulcerative colitis (UC), SI or S/SII, and multiple comorbid risk factors for suicidal behavior. Results: We identified 331,777 (estimated 1.64 million) IBD-related hospitalizations (64% CD, 36% UC) and 39,787,239 (estimated 196.08 million) hospitalizations among the general US population. Among IBD-related hospitalizations, 2502 discharges were associated with SI (prevalence 0.76%) and 1104 with S/SII (prevalence 0.33%). Both were significantly greater in CD versus UC (P < 0.001). Relative to the general US population, IBD patients were significantly less likely to demonstrate suicidal behavior: (SI:0.33% versus 0.59%, P < 0.001) (S/SII:0.75% versus 1.04%, P < 0.001). Multivariable logistic regression revealed that IBD was associated with decreased odds of SI (adjusted odds ratio [aOR] 0.62, 95%CI 0.60-0.65) and S/SII (aOR 0.43, 95%CI 0.40-0.45) relative to the general population, and suicidal behavior was lower in IBD compared to disease-related controls with rheumatoid arthritis and systemic lupus erythematosus. Similar increasing trends in suicidal behavior were observed in IBD and non-IBD populations (2006-2011). Conclusion: In this large US database, SI or S/SII occurred in over 1% of the IBD population and was increased in CD versus UC. PMID- 29272477 TI - Dietary Patterns in women with Inflammatory Bowel Disease and Risk of Adverse Pregnancy Outcomes: Results from The Norwegian Mother and Child Cohort Study (MoBa). AB - Background: The aim of the study was to examine dietary patterns and risk of adverse pregnancy outcomes among mothers with inflammatory bowel disease (IBD) in the Norwegian Mother and Child Cohort Study (MoBa). Method: MoBa enrolled participants from all over Norway between 1999 and 2008, and the study comprised 83,988 mothers, of whom there were 183 mothers with Crohn's disease (CD) and 240 with ulcerative colitis (UC). An additional questionnaire was submitted to mothers with IBD in 2013. We extracted three exploratory dietary patterns: a "Prudent," a "Western," and a "Traditional" pattern. We explored the relationship between dietary patterns and IBD and dietary patterns and adverse pregnancy outcomes: small for gestational age (SGA) and preterm delivery (PTD). Results: IBD mothers had a significantly lower adherence to the Traditional dietary pattern [mean score -0.10 (95% CI: - 0.2 - - 0.01)] than non-IBD mothers. In IBD mothers, middle and high adherence to the Traditional dietary pattern was associated with lower risk of SGA [OR tertile 2 vs. tertile 1: 0.44 (95% CI: 0.20 - 0.97) and OR tertile 3 vs. tertile 1: 0.23 (95% CI: 0.08-0.61)] than in IBD and non-IBD mothers with low adherence. In the IBD-subset analyses, similar results were demonstrated for UC mothers [OR tertile 2 vs. tertile 1: 0.21 (95% CI: 0.05 0.80) and OR tertile 3 vs. tertile 1: 0.16 (95% CI: 0.04 - 0.60)]. Conclusion: In IBD mothers, higher adherence to a Traditional dietary pattern, characterized by high consumption of lean fish, fish products, potatoes, rice porridge, cooked vegetables, and gravy, was associated with lower risk of SGA. PMID- 29272479 TI - Surrogate Fecal Biomarkers in Inflammatory Bowel Disease: Rivals or Complementary Tools of Fecal Calprotectin? AB - Background: Current noninvasive methods for assessing intestinal inflammation in inflammatory bowel disease (IBD) remain unsatisfactory. Along with C-reactive protein and erythrocyte sedimentation rate, fecal calprotectin (FC) is the standard test for assessing IBD activity, even though its specificity and accuracy are not optimal and it lacks a validated cutoff. Over the past few decades, several fecal markers released from intestinal inflammatory cells have been investigated in IBD; they are the subject of this systematic review. Methods: A systematic electronic search of the English literature up to April 2017 was performed using Medline and the Cochrane Library. Only papers written in English that analyzed fecal biomarkers in IBD were included. In vitro studies, animal studies, studies on blood/serum samples, and studies analyzing FC or fecal lactoferrin alone were excluded. Results: Out of 1023 citations, 125 eligible studies were identified. Data were grouped according to each fecal marker including S100A12, high-mobility group box 1, neopterin, polymorphonuclear neutrophil elastase, fecal hemoglobin, alpha1-antitrypsin, human neutrophil peptides, neutrophil gelatinase-associated lipocalin, chitinase 3-like-1, matrix metalloproteinase 9, lysozyme, M2-pyruvate kinase, myeloperoxidase, fecal eosinophil proteins, human beta-defensin-2, and beta-glucuronidase. Some of these markers showed a high sensitivity and specificity and correlated with disease activity, response to therapy, and mucosal healing. Furthermore, they showed a potential utility in the prediction of clinical relapse. Conclusions: Several fecal biomarkers have the potential to become useful tools complementing FC in IBD diagnosis and monitoring. However, wide variability in their accuracy in assessment of intestinal inflammation suggests the need for further studies. PMID- 29272478 TI - Plasma microRNA Profile Differentiates Crohn's Colitis From Ulcerative Colitis. AB - Background: Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. Methods: Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. Results: Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). Conclusions: We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions. PMID- 29272480 TI - Development and Validation of a Confocal Laser Endomicroscopy-Based Score for In Vivo Assessment of Mucosal Healing in Ulcerative Colitis Patients. AB - Background: Endoscopic monitoring is fundamental for evaluating the therapeutic response in IBD, but a validated endomicroscopic mucosal healing (MH) score is not available to date. However, confocal laser endomicroscopy (CLE) might define MH more precisely than conventional endoscopy. The major aim was to establish and validate an MH score for ulcerative colitis (UC), based on CLE. Methods: In an initial pilot study (n = 10), various CLE changes were analyzed for identification of reproducible criteria for establishing a CLE score. Four reproducible CLE criteria were implemented in a following validation study. Subsequently, active UC patients (n = 23, Mayo score >=6) were prospectively included and underwent colonoscopy with CLE before and after 3 anti-TNF applications. Patients were clinically followed over a period of 3 years. The endomicroscopic MH score (eMHs; range, 0-4) was compared with histopathology and endoscopy scores from the same colonic location. Results: The eMHs showed high sensitivity, specificity, and accuracy values (100% with 95% confidence interval [CI] of 15.81%-100%; 93.75% with 95% CI of 69.77%-99.84%, and 94.44%, respectively). The eMHs showed a good correlation with the histological Gupta score (rs = 0.82, P < 0.0001) and the endoscopic Mayo subscore (rs = 0.81%, P < 0.0001). Sixty percent of therapy responders presented an eMHs <1, which translated into long-lasting clinical remission and reduced hospitalization, steroid, and surgery need. Conclusions: CLE can accurately assess MH based on the newly developed and statistically validated eMHs in UC, and it is superior in predicting the long-lasting clinical outcome based on both descriptive and functional barrier imaging (NCT01417728). PMID- 29272481 TI - Challenges in Using Real-world Clinical Practice Records for Validation of Clinical Trial Data in Inflammatory Bowel Disease: Lessons Learned. AB - Electronic medical records (EMRs) have gained widespread use in clinical practice and by default serve as a large patient database with potential for use in clinical research. Although there remains significant interest in leveraging EMRs for research purposes, extraction of data has proven to be complex and with insufficient accuracy. We describe the limitations of an EMR in our attempt to conduct a seemingly simple study aimed at validating variables identified in the PRECiSE 3, a 7-year open label safety and efficacy study of certolizumab pegol in Crohn's disease that identified clinical factors that predicted both short- and long-term efficacy. A multicenter, retrospective cohort study from 8 academic and large community practices was performed, and data were collected from each respective EMR. Significant challenges with reliable capture of key data elements were encountered, and overall a screen fail rate of 91.8% across all sites was seen. We describe these challenges and potential future directions to work together to advance accuracy and implementation of the use of EMRs in inflammatory bowel disease. PMID- 29272483 TI - Factors Associated With Length of Stay in Veterans With Inflammatory Bowel Disease Hospitalized for an Acute Flare. AB - Background: Reducing hospital costs and risk of complications by shortening length of stay has become paramount. The aim of our study was to identify predictors and potentially modifiable factors that influence length of stay among veterans with inflammatory bowel disease admitted for an acute flare. Methods: Retrospective review of patients admitted to the Dallas VA with an acute flare of their inflammatory bowel disease between 2000 and 2015. Patients with a length of stay of <=4 days were compared with those whose length of stay >4 days. Results: A total of 180 admissions involving 113 patients (59 with ulcerative colitis and 54 with Crohn's disease) were identified meeting inclusion criteria. The mean length of stay was 5.3 +/- 6.8 days, and the median length of stay was 3.0 days. On multiple logistic regression analysis, initiation of a biologic, having undergone 2 or more imaging modalities, and treatment with intravenous steroids were significant predictors of longer lengths of stay, even after controlling for age and comorbid diseases. Conclusions: We identified several predictors for longer hospital length of stay, most related to disease severity but several of which may be modifiable to reduce hospital stays, including most importantly consideration of earlier prebiologic testing. Future studies are needed to evaluate the impact of interventions targeting modifiable predictors of length of stay on health care utilization and patient outcomes. PMID- 29272482 TI - Indeterminate QuantiFERON-TB Gold Increases Likelihood of Inflammatory Bowel Disease Treatment Delay and Hospitalization. AB - Background: QuantiFERON-TB Gold (QFTG) is a blood test used to diagnose latent tuberculosis infection (LTBI) prior to TNF-alpha inhibitor (anti-TNF) initiation. We sought to determine factors associated with indeterminate QFTG results in inflammatory bowel disease (IBD) patients and whether indeterminate results are associated with IBD-related morbidity. Methods: This nested case-control study included IBD patients who underwent QFTG testing. Cases were patients with indeterminate QFTG and controls were those with negative QFTG. The association of demographic and clinical data with indeterminate QFTG result was assessed using logistic regression. We examined the clinical impact of indeterminate QFTG results on risk of hospitalization and delay in anti-TNF initiation using inverse probability-of-treatment weighting (IPTW) regression. Results: We identified 411 patients with QFTG testing (320 negative, 80 indeterminate, and 11 positive results). No patient with an indeterminate result subsequently had LTBI. Systemic corticosteroid use (OR, 4.4; 95% CI, 2.0-9.6) and hospitalization at the time of QFTG (OR, 3.8; 95% CI, 1.9-7.7) were associated with indeterminate QFTG, while immunomodulator use was nearly statistically significant (OR, 3.1; 95% CI, 0.9 9.8) and anti-TNF use was not (OR, 0.9; 95% CI, 0.2-4.6). After IPTW adjustment, indeterminate QFTG was associated with a 23.1% (95% CI, 8.2%-37.9%) greater probability of delay in anti-TNF initiation beyond 30 days and an 11.9% (95% CI, 0.6%-23.1%) greater probability of hospitalization within 60 days. Conclusions: Systemic corticosteroid use and hospitalization were associated with an indeterminate QFTG result. Indeterminate QFTG results were associated with delayed anti-TNF initiation and subsequent hospitalization. PMID- 29272484 TI - IBD Serology and Disease Outcomes in African Americans With Crohn's Disease. AB - Backgrounds: Recent studies have identified the role of serologic markers in characterizing disease phenotype, location, complications, and severity among Northern Europeans (NE) with Crohn's disease (CD). However, very little is known about the role of serology in CD among African Americans (AA). Our study explored the relationship between serology and disease phenotype in AA with CD, while controlling for genetic ancestry. Methods: AAs with CD were enrolled as participants through multicenter collaborative efforts. Serological levels of IgA anti-Saccharomyces cervisiae antibody (ASCA), IgG ASCA, E. coli outermembrane porin C, anti-CBir1, and ANCA were measured using enzyme-linked immunosorbent assays. Genotyping was performed using Illumina immunochip technology; an admixture rate was calculated for each subject. Multiple imputation by chained equations was performed to account for data missing at random. Logistic regression was used to calculate adjusted odds ratio (OR) for associations between serological markers and both complicated disease and disease requiring surgery. Results: A total of 358 patients were included in the analysis. The majority of our patients had inflammatory, noncomplicated disease (58.4%), perianal disease (55.7%), and documented colonic inflammation (86.8%). On multivariable analysis, both IgG ASCA and OmpC were associated with complicated disease (OR, 2.67; 95% CI, 1.67-4.28; OR, 2.23; 95% CI, 1.41-3.53, respectively) and disease requiring surgery (OR, 2.51; 95% CI, 1.49-4.22; OR, 3.57; 95% CI, 2.12-6.00). NE admixture to the African genome did not have any associations or interactions in relation to clinical outcome. Conclusions: Our study comprises the largest cohort of AAs with CD. The utility of serological markers for the prognosis of CD in NE applies equally to AA populations. PMID- 29272485 TI - Validation of Neutrophil CD64 Blood Biomarkers to Detect Mucosal Inflammation in Pediatric Crohn's Disease. AB - Background: In a pilot study, neutrophil CD64 surface expression was significantly elevated in newly diagnosed, pediatric-onset Crohn's disease. We aimed to test the CD64 biomarkers (neutrophil CD64 surface expression and soluble CD64) as determinates for mucosal inflammation in a larger pediatric Crohn's cohort with the hypotheses that the CD64 biomarkers would reliably detect intestinal inflammation and correlate with endoscopic severity scores. Methods: We enrolled patients referred for colonoscopy for either suspected inflammatory bowel disease or with established Crohn's. Neutrophil CD64 index was determined by flow cytometry using a commercial kit (Leuko64, Trillium) and soluble CD64 by ELISA (LifeSpan). Results: A total of 209 patients (72 controls, 76 new inflammatory bowel disease patients, and 61 established Crohn's) were enrolled. Both neutrophil CD64 index and soluble CD64 were significantly elevated in new Crohn's compared with controls. The area under the curve (AUC) for neutrophil CD64 index >=1 was 0.85 (95% confidence interval, 0.77-0.92), 75% sensitive and 89% specific for new Crohn's. Comparatively, soluble CD64 >=39 ng/mL was 92% sensitive and 85% specific (AUC, 0.93) for new Crohn's. Neutrophil CD64 index, soluble CD64, and fecal calprotectin discriminated endoscopic inactive from moderate and severe activity while soluble CD64 differentiated endoscopic mild from moderate and severe activity. Neutrophil CD64 index (r = 0.46, P < 0.001) and fecal calprotectin (r = 0.55, P < 0.001) correlated well with the Simple Endoscopic Score-Crohn's disease. Spearman correlation between the CD64 index and calprotectin was 0.39 (P < 0.001). Conclusions: In a large Crohn's disease cohort, we found that neutrophil CD64 index and soluble CD64 were significantly elevated during active gastrointestinal inflammation. PMID- 29272486 TI - A Survey Study of Gastroenterologists' Attitudes and Barriers Toward Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease. AB - Background: Therapeutic drug monitoring (TDM) may improve the efficacy and cost effectiveness of anti-TNF therapy. A standardized approach of utilizing TDM has not been established. The objective of this study was to determine gastroenterologists' attitudes and barriers toward TDM of anti-TNF therapy in clinical practice. Methods: An 18-question survey was distributed to members of the American College of Gastroenterology and Crohn's and Colitis Foundation via email. We collected physician characteristics, practice demographics, and data regarding TDM use and perceived barriers to TDM. Factors associated with the use of TDM were determined by logistic regression analysis. Results: A total of 403 gastroenterologists from 42 US states (76.4% male) met inclusion criteria: 90.1% use TDM, mostly reactively for secondary loss of response (87.1%) and primary nonresponse (66%); 36.6% use TDM proactively. The greatest barriers to TDM implementation were uncertainty about insurance coverage (77.9%), high out-of pocket patient costs (76.4%), and time lag from serum sample to result (38.5%). Factors independently associated with the use of TDM and proactive TDM were practice in an academic setting (P = 0.019), and more IBD patients seen per month (P = 0.015), and Crohn's and Colitis Foundation membership (P < 0.001), and more IBD patients on anti-TNF therapy per month (P = 0.006), respectively. If all barriers were removed, an additional one-third of physicians would apply proactive TDM. Conclusions: Lack of insurance coverage, high out-of-pocket costs, and the time lag from test to result limit use of TDM in the United States. Validation of low-cost assays, point of care testing, and studies that standardize the use of TDM are needed to make TDM more commonplace. PMID- 29272487 TI - Separation of Dual Oxidase 2 and Lactoperoxidase Expression in Intestinal Crypts and Species Differences May Limit Hydrogen Peroxide Scavenging During Mucosal Healing in Mice and Humans. AB - Background: DUOX2 and DUOXA2 form the predominant H2O2-producing system in human colorectal mucosa. Inflammation, hypoxia, and 5-aminosalicylic acid increase H2O2 production, supporting innate defense and mucosal healing. Thiocyanate reacts with H2O2 in the presence of lactoperoxidase (LPO) to form hypothiocyanate (OSCN ), which acts as a biocide and H2O2 scavenging system to reduce damage during inflammation. We aimed to discover the organization of Duox2, Duoxa2, and Lpo expression in colonic crypts of Lieberkuhn (intestinal glands) of mice and how distributions respond to dextran sodium sulfate (DSS)-induced colitis and subsequent mucosal regeneration. Methods: We studied tissue from DSS-exposed mice and human biopsies using in situ hybridization, reverse transcription quantitative polymerase chain reaction, and cDNA microarray analysis. Results: Duox2 mRNA expression was mostly in the upper crypt quintile while Duoxa2 was more apically focused. Most Lpo mRNA was in the basal quintile, where stem cells reside. Duox2 and Duoxa2 mRNA were increased during the induction and resolution of DSS colitis, while Lpo expression did not increase during the acute phase. Patterns of Lpo expression differed from Duox2 in normal, inflamed, and regenerative mouse crypts (P < 0.001). We found no evidence of LPO expression in the human gut. Conclusions: The spatial and temporal separation of H2O2-consuming and -producing enzymes enables a thiocyanate- H2O2 "scavenging" system in murine intestinal crypts to protect the stem/proliferative zones from DNA damage, while still supporting higher H2O2 concentrations apically to aid mucosal healing. The absence of LPO expression in the human gut suggests an alternative mechanism or less protection from DNA damage during H2O2-driven mucosal healing. PMID- 29272488 TI - Thiopurine Treatment in Ulcerative Colitis: A Critical Review of the Evidence for Current Clinical Practice. AB - Background: Due to toxicity problems and controversial evidence, thiopurine use in ulcerative colitis (UC) has faced a lot of criticism. We present a critical review of the literature on efficacy of thiopurines in UC. Methods: Studies evaluating therapeutic efficacy of thiopurine remission induction and/or maintenance treatment in UC were identified using the Cochrane Library, MEDLINE, and EMBASE. Results: Out of 5 randomized trials on thiopurine induction treatment, 3 demonstrated a significant effect of thiopurine treatment vs mesalamine or placebo in steroid-dependent UC patients: (1) lower endoscopic activity scores, (2) higher clinical remission rates, and (3) more patients who discontinued steroids. Two found no significant difference in clinical and endoscopic remission of azathioprine compared with sulfasalazine or placebo in patients with active UC. Out of 7 randomized trials on thiopurine maintenance treatment, 4 demonstrated significant higher clinical and endoscopic remission rates in thiopurine-treated patients compared with placebo or mesalamine. Three found no significant difference in clinical and endoscopic remission of thiopurine maintenance treatment compared with sulfasalazine or placebo. Conclusions: All studies that investigated thiopurine treatment in UC had shortcomings, such as lack of sufficient power, no use of blinding, allowed concomitant treatment with steroids, and no endoscopy to confirm active disease at study entry or to evaluate therapeutic efficacy. Hence, current clinical practice of thiopurine treatment in UC is based on minimal and controversial evidence. This underscores the need for clinical studies with sufficient power and objective end points in order to determine efficacy of thiopurines in UC. PMID- 29272489 TI - The Informational Needs and Preferences of Patients Considering Surgery for Ulcerative Colitis: Results of a Qualitative Study. AB - Background: Patients considering surgery for ulcerative colitis (UC) face a difficult decision as surgery may or may not improve quality of life. National Institute for Health and Care Excellence guidelines for UC emphasize the importance of providing quality preoperative information to patients but note no quality studies for the desired content of this information. Our aim was to explore patient information preferences prior to undergoing surgery for ulcerative colitis. Methods: Semistructured interviews with patients who underwent an operation and patients who considered but declined an operation were conducted. Interviews explored informational preferences, with emphasis on preoperative information given, preoperative information desired but not received, and retrospective informational desires. Interviews were transcribed and coded using an inductive thematic analysis using NVivo software. Data saturation was assessed after 12 interviews, with interviews continuing until saturation was achieved. Ethical approval was gained prior to interviews commencing (16/NW/0639). Results: A total of 16 interviews were conducted before data saturation was achieved (male n = 7, female n = 9). Eight patients declined surgery, and 8 opted for subtotal colectomy with permanent end ileostomy (n = 5) or ileoanal pouch (n = 3). A total of 4 themes and 14 subthemes were identified. Three dominant subthemes of informational shortcomings emerged: "long-term effects of surgery," "practicalities of daily living," and "long-term support." Peer support was desired by patients but was infrequently supported by health care professionals. Conclusions: Current preoperative information does not address patient informational needs. Surgical consultations should be adapted to suit patient preferences. Clinical practice may need to be altered to ensure that patients are better supported following surgery. PMID- 29272490 TI - Capsule Endoscopy, Magnetic Resonance Enterography, and Small Bowel Ultrasound for Evaluation of Postoperative Recurrence in Crohn's Disease: Systematic Review and Meta-Analysis. AB - Background: Anastomotic recurrence is frequent in patients with Crohn's disease (CD) following ileocecal resection. The degree of endoscopic recurrence, quantified by the Rutgeerts score (RS), is correlated with the risk of clinical and surgical recurrence. Noninvasive modalities such as capsule endoscopy (CE), magnetic resonance enterography (MRE), and intestinal ultrasound (US) may yield similar information without the need for ileocolonoscopy (IC). The aim of our meta-analysis was to evaluate the accuracy of those modalities for detection of endoscopic recurrence in postoperative CD patients. Methods: We performed a systematic literature search for studies comparing the accuracy of CE, MRE, and US with IC for detection of postoperative recurrence in CD. We calculated pooled diagnostic sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) for each comparison. Results: A total of 135 studies were retrieved; 14 studies were eligible for analysis. For CE, the pooled sensitivity was 100% (95% CI, 91%-100%), specificity was 69% (95% CI, 52%-83%), DOR was 30.8 (95% CI, 6.9-138), and AUC was 0.94. MRE had pooled sensitivity of 97% (95% CI, 89%-100%), specificity of 84% (95% CI, 62%-96%), DOR of 129.5 (95% CI, 16.4 1024.7), and AUC of 0.98. US had pooled sensitivity of 89% (95% CI, 85%-92%), specificity of 86% (95% CI, 78%-93%), DOR of 42.3 (95% CI, 18.6-96.0), and AUC 0.93. Conclusions: CE, MRE, and US provide accurate assessment of postoperative endoscopic recurrence in CD. These modalities should gain wider use for detection of postoperative recurrence; the prognostic value of those diagnostic findings merits evaluation in further prospective studies. PMID- 29272491 TI - Long-Term Outcomes After Primary Bowel Resection in Pediatric-Onset Crohn's Disease. AB - Background: There is limited evidence on the long-term outcome of intestinal resection in pediatric-onset Crohn's disease (POCD) with no established predictors of adverse outcomes. We aimed to investigate clinical outcomes and predictors for adverse outcome following intestinal resection in POCD. Methods: The medical records of patients with POCD who underwent at least 1 intestinal resection between 1990 and 2014 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, second intestinal resection, and response to nonprophylactic biologic therapy. Results: Overall, 121 patients were included. Median follow-up was 6 years (range 1-23.6). One hundred and seven (88%) patients experienced at least 1 postsurgical exacerbation, 52 (43%) were hospitalized, and 17 (14%) underwent second intestinal resection. Of 91 patients who underwent surgery after the year 2000, 37 (41%) were treated with antitumor necrosis factor alpha (anti-TNFalpha) (nonprophylactic) following intestinal resection. Time to hospitalization and to second intestinal resection were shorter among patients with extraintestinal manifestations (EIMs) (HR 2.7, P = 0.006 and HR = 3.1, P = 0.03, respectively). Time to initiation of biologic treatment was shorter in patients with granulomas (HR 2.1, P = 0.038), whereas being naive to anti-TNFalpha treatment before surgery was a protective factor for biologic treatment following surgery (HR 0.3, P = 0.005). Undergoing intestinal resection beyond the year 2000 was associated with shorter time to first flare (HR 1.9, P = 0.019) and hospitalization (HR 2.6, P = 0.028). Conclusion: Long-term risk for flares, hospitalization, or biologic treatment is significant in POCD following bowel resection. EIMs increase the risk for hospitalization and second intestinal resection. PMID- 29272492 TI - Genetic and Pharmacological Dissection of the Role of Spleen Tyrosine Kinase (Syk) in Intestinal Inflammation and Immune Dysfunction in Inflammatory Bowel Diseases. AB - Background: The DNAX adaptor protein 12 (DAP12) is a transmembrane adaptor molecule that signals through the activation of Syk (Spleen Tyrosine Kinase) in myeloid cells. The purpose of this study is to investigate the role of DAP12 and Syk pathways in inflammatory bowel diseases (IBDs). Methods: DAP12 deficient and DAP12 transgenic, overexpressing an increased amount of DAP12, mice and Syk deficient mice in the C57/BL6 background were used for these studies. Colitis was induced by administering mice with dextran sulfate sodium (DSS), in drinking water, or 2,4,6-trinitrobenzene sulfonic acid (TNBS), by intrarectal enema. Results: Abundant expression of DAP12 and Syk was detected in colon samples obtained from Crohn's disease patients with expression restricted to immune cells infiltrating the colonic wall. In rodents development of DSS colitis as measured by assessing severity of wasting diseases, global colitis score,and macroscopic and histology scores was robustly attenuated in DAP12-/- and Syk-/- mice. In contrast, DAP12 overexpression resulted in a striking exacerbation of colon damage caused by DSS. Induction of colon expression of proinflammatory cytokines and chemokines in response to DSS administration was attenuated in DAP12-/- and Syk-/- mice, whereas opposite results were observed in DAP12 transgenic mice. Treating wild-type mice with a DAP-12 inhibitor or a Syk inhibitor caused a robust attenuation of colitis induced by DSS and TNBS. Conclusions: DAP12 and Syk are essential mediators in inflammation-driven immune dysfunction in murine colitides. Because DAP12 and Syk expression is upregulated in patients with active disease, present findings suggest a beneficial role for DAP12 and Syk inhibitors in IBD. PMID- 29272493 TI - Targeting Mucosal Endothelin-A-Receptor Expression by Fluorescence Endoscopy is Feasible to Detect and Characterize Colitis-Associated Cancer in Mice. AB - Background: To facilitate onsite decision-making during endoscopy, both accurate detection and in vivo characterization of preneoplasia are prerequisites. However, no endoscopy technique is available that meets both demands satisfactorily. We evaluated endothelin-receptor A (ETAR)-guided fluorescence endoscopy (FE) in vivo and fluorescence reflectance imaging (FRI) ex vivo for detection and characterization of early dysplastic colitis-associated colonic lesions. Methods: Colorectal cancerogenesis was investigated in the inflammatory driven AOM-DSS model and spontaneous adenoma development in ApcMin mice. A Cy5.5 labeled nonpeptidic ETAR-specific imaging probe was injected intravenously to assess tumor development in vivo by white light endoscopy (WLE) and FE. Ex vivo tumors were evaluated by FRI, histological examination, and western blot analysis. In addition, tissue samples from patients with colitis-associated malignant and nonmalignant mucosal alterations were analyzed. Specificity experiments were performed using an unspecific Cy3.5-glycine tracer. Results: Overall, 62 adenomas were observed. FE was able to detect and quantify ETAR expression targeting the ETAR-specific photoprobe. A significantly higher fluorescent contrast was detected in colonic adenomas compared to adjacent nonmalignant mucosa by FE (64.3 +/- 7.9 vs. 56.6. +/- 7.0; P < 0.001). These results were confirmed by FRI examination, immunochemistry, and western blot analysis. Additionally, ETAR expression in samples from human patients with colitis-associated cancer was highly elevated compared to nonmalignant alterations. Specificity experiments indicated a high binding-specificity of the applied ETAR photoprobe (1.4 +/- 0.3 vs. 2.5 +/- 0.7; P < 0.001). Conclusions: We introduced ETAR guided FE in mice for successful in vivo detection and characterization of colorectal neoplasia on a molecular level. PMID- 29272494 TI - Prebiotic Supplementation Following Ileocecal Resection in a Murine Model is Associated With a Loss of Microbial Diversity and Increased Inflammation. AB - Background: Individuals with Crohn's disease frequently require ileocecal resection (ICR), and inflammation often recurs in the neoterminal ileum following surgery. Fructooligosaccharide (FOS) is a fermentable prebiotic that stimulates the growth of bifidobacteria and may promote anti-inflammatory activity. The aim of this study was to determine if supplementation of a postICR diet with FOS in a mouse model would be effective in stimulating the growth of bifidobacteria and reducing systemic and local inflammation. Methods: ICR was performed in IL10-/- mice (129S1/SvlmJ) with colitis. Following surgery, nonICR control and ICR mice were fed a chow diet +/- 10% FOS for 28 days. Serum, colon, and terminal ileum (TI) were analyzed for cytokine expression by MesoScale discovery platform. DNA extracted from stool was analyzed using 16s rRNA sequencing and qPCR. Expression of occludin and ZO1 was assessed using qPCR. Short-chain fatty acid (SCFA) concentrations were assessed using gas chromatography. Results: ICR led to increased systemic inflammation (P < 0.05) and a significant decline in fecal microbial diversity (P < 0.05). Mice on the FOS diet had a greater reduction in microbial diversity and also had worsened inflammation as evidenced by increased serum IL-6 (P < 0.05) and colonic IFNgamma and TNFalpha (P < 0.05). Expression of occludin and ZO1 were significantly reduced in FOS-supplemented mice. There was a correlation between loss of diversity and the bifidogenic effectiveness of FOS (r = -0.61, P < 0.05). Conclusions: FOS-supplementation of a postICR diet resulted in a decrease in fecal bacterial diversity, reduction in barrier function, and increased gut inflammation. PMID- 29272495 TI - Clinoptilolite in Dextran Sulphate Sodium-Induced Murine Colitis: Efficacy and Safety of a Microparticulate Preparation. AB - Background: Clinoptilolite is an aluminium silicate of natural origin; the microporous structure and the net negative charge of its crystal lattice allows for adsorption of ions, toxins, inflammatory mediators, and some microorganisms. We generated 2 preparations of purified clinoptilolite, which differed by about 10-fold in particle size, ie, a standard powder (GHC1) and a microparticulate fraction (GHC2) with a size of 3.6 um and 0.39 um (d50) respectively. These were examined for their ability to accelerate the recovery of mice from DSS (dextran sulphate sodium)-induced intestinal inflammation. Methods: Efficacy of clinoptilolite preparations was investigated by administering DSS-treated mice twice daily with 30 mg GHC2 or GHC1 for 5 consecutive days, followed by 5 days of recovery without DSS. To explore the safety of the microparticulate preparation (GHC2), mice were subjected to 4 cycles of DSS-exposure. We specifically verified that clinoptilolite microparticles were not systemically bioavailable by examining the gut tissue and the liver for the accumulation of microparticles by transmission electron microscopy. Results: Treatment of mice with GHC2 was superior to GHC1 and as effective as the reference compound 5-aminosalicylic acid in ameliorating the damage induced by the exposure to DSS. In addition, no clinoptilolite particle was observed in the intestinal epithelial layer, gut associated lymph follicles, or in the liver. Conclusion: Our observations confirm that a microparticulate preparation of clinoptilolite is safe and effective in a murine model of inflammatory bowel disease and supports the hypothesis that the adsorptive capacity of clinoptilolite is of potential therapeutic relevance. PMID- 29272496 TI - Changes, Changes, Changes. PMID- 29272497 TI - Resistance to Lysinibacillus sphaericus and Other Commonly Used Pesticides in Culex pipiens (Diptera: Culicidae) from Chico, California. AB - Bacillus sphaericus Neide, recently renamed as Lysinibacillus sphaericus Meyer and Neide, is a spore-forming bacterium that possesses various levels of larvicidal activity, depending on the strains, against some mosquito species. Products based on most active strains such as 2362, 2297, 1593, C3-41 that bear binary toxins, as well as mosquitocidal toxins at various levels, have been developed to combat mosquito larvae worldwide. Resistance in wild Culex mosquito populations has been reported since 1994 from France, Brazil, India, China, Thailand, and Tunisia. Laboratory studies to evaluate resistance development risk have been conducted by many groups of scientists worldwide. Products based on L. sphaericus strain 2362 were registered in the United States in 1990s, and their use for mosquito control has been increased considerably since invasion of West Nile virus. This report documents the first occurrence of high-level resistance to L. sphaericus in a natural population of Culex pipiens L. in Chico, CA, where resistance ratio was 537.0 at LC50 and 9,048.5 at LC90 when compared with susceptible laboratory colony of the same species. Susceptibility profile to other groups of pesticides with different modes of action was also determined. Various levels of resistance or tolerance were noticed to abamectin, pyriproxyfen, permethrin, and indoxacarb. Resistance management and susceptibility monitoring strategies are discussed and recommended. PMID- 29272498 TI - Current status and future prospects for disease modification in osteoarthritis. AB - OA is a chronic, progressive and disabling joint disease, leading to a poor quality of life and an enormous social and economic burden. Current therapies for OA patients remain limited, which creates an area of huge unmet medical need. For some time, researchers have been looking for approaches that can inhibit the structural progression of OA. A variety of potential disease-modifying OA drugs have been developed, targeting cartilage, inflammatory pathways or subchondral bone. In addition, non-pharmacological therapies, including joint distraction and weight loss, draw increasing attention, with some showing disease-modifying potential. Thus we performed a comprehensive review to discuss the current status of disease-modifying therapies in OA and appraise the potentials of emerging novel agents. PMID- 29272499 TI - An Experimental Evaluation of Cross-Vane Panel Traps for the Collection of Sylvatic Triatomines (Hemiptera: Reduviidae). AB - Due to the limited understanding of the sylvatic cycle of Chagas disease transmission, an efficient method to attract and capture sylvatic triatomines (Hemiptera: Reduviidae) is essential to monitor human exposure risk. Current collection methods for sylvatic species, though effective, are labor- and time intensive. This study evaluated whether modified cross-vane panel traps (commonly used in forest entomology) can be used to attract and capture flying life-stages of sylvatic triatomines and whether a commercially available lure is effective in attracting sylvatic triatomines in the field. We evaluated four trap treatments in both the wet and dry seasons in central Panama: a cross-vane panel trap fitted with an ultraviolet (UV) light, a cross-vane panel trap fitted with a commercially available human-volatile lure, a cross-vane panel trap fitted with both a UV light and a human-volatile lure, and a white sheet fitted with a UV light (a standard collection method) as a control. A total of 45 adult Rhodnius pallescens Barber were captured across 10 nights of trapping representing 112 trap-nights. There was a significant overall effect of trap type on collection success; sheet traps collected more triatomines than lure traps, and there were no differences between the sheet trap and the UV trap, nor between the sheet trap and the UV + lure trap. The lure-only trap did not capture any triatomines in this study. These results indicate that cross-vane panel traps with a UV light are as effective as a sheet trap but offer the advantage of requiring less time and effort to maintain and monitor. PMID- 29272500 TI - Does fluid collection impact radiotherapy outcomes after wide excision of lower extremity soft tissue sarcoma? AB - Background: Fluid collection (FC) of lymph or blood may accumulate at the site of excision after surgery for soft tissue sarcoma, with reported incidence rates from 10% to 36%. The purpose of this study is to analyze the impact of FC on local recurrence (LR) and wound complication rates after adjuvant postoperative radiotherapy (PORT) in lower extremity soft tissue sarcoma (LE-STS). Methods: Eighty-eight patients diagnosed with LE-STS were curatively treated with wide excision and PORT. FC developed in 51.1% of patients. Full FC volumes were included in the irradiation field throughout the full course of PORT for 36 patients (80.0%). A median of 61.2 and 63 Gy was prescribed for patients with and without FC, respectively. Results: After a median follow-up of 4.3 years, patients with and without FC had 5-year local control rates of 77.7% and 90.8% (P = 0.105). Eight patients with FC had LR, of which six patients had recurrent tumors at or within 4 cm of the FC wall and three of these patients had out-of field LR. Wound complication occurred after RT in 3 (6.7%) of 45 patients with FC and 1 (2.3%) of 43 patients without FC. Conclusions: FC presents a potential risk for increased LR, particularly near the FC wall. Based on reasonable wound complication rates, we suggest the need and feasibility of fully including FC volumes in the irradiation field. PMID- 29272501 TI - Retinal Layer Abnormalities as Biomarkers of Schizophrenia. AB - Objective: Schizophrenia is associated with several brain deficits, as well as visual processing deficits, but clinically useful biomarkers are elusive. We hypothesized that retinal layer changes, noninvasively visualized using spectral domain optical coherence tomography (SD-OCT), may represent a possible "window" to these abnormalities. Methods: A Leica EnvisuTM SD-OCT device was used to obtain high-resolution central foveal B-scans in both eyes of 35 patients with schizophrenia and 50 demographically matched controls. Manual retinal layer segmentation was performed to acquire individual and combined layer thickness measurements in 3 macular regions. Contrast sensitivity was measured at 3 spatial frequencies in a subgroup of each cohort. Differences were compared using adjusted linear models and significantly different layer measures in patients underwent Spearman Rank correlations with contrast sensitivity, quantified symptoms severity, disease duration, and antipsychotic medication dose. Results: Total retinal and photoreceptor complex thickness was reduced in all regions in patients (P < .0001). Segmentation revealed consistent thinning of the outer nuclear layer (P < .001) and inner segment layer (P < .05), as well as a pattern of parafoveal ganglion cell changes. Low spatial frequency contrast sensitivity was reduced in patients (P = .002) and correlated with temporal parafoveal ganglion cell complex thinning (R = .48, P = .01). Negative symptom severity was inversely correlated with foveal photoreceptor complex thickness (R = -.54, P = .001) and outer nuclear layer thickness (R = -.47, P = .005). Conclusions: Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease. PMID- 29272502 TI - Staphylococcus aureus SaeR/S-Regulated Factors Decrease Monocyte-Derived Tumor Necrosis Factor-alpha to Reduce Neutrophil Bactericidal Activity. AB - Background: The ability of Staphylococcus aureus to evade killing by human neutrophils significantly contributes to disease progression. In this study, we characterize an influential role for the S. aureus SaeR/S 2-component gene regulatory system in suppressing monocyte production of tumor necrosis factor alpha (TNF-alpha) to subsequently influence human neutrophil priming. Methods: Using flow cytometry and TNF-alpha specific enzyme-linked immunosorbent assays we identify the primary cellular source of TNF-alpha in human blood and in purified peripheral blood mononuclear cells (PBMCs) during interaction with USA300 and an isogenic saeR/S deletion mutant (USA300?saeR/S). Assays with conditioned media from USA300 and USA300?saeR/S exposed PBMCs were used to investigate priming on neutrophil bactericidal activity. Results: TNF-alpha production from monocytes was significantly reduced following challenge with USA300 compared to USA300?saeR/S. We observed that priming of neutrophils using conditioned medium from peripheral blood mononuclear cells stimulated with USA300?saeR/S significantly increased neutrophil bactericidal activity against USA300 relative to unprimed neutrophils and neutrophils primed with USA300 conditioned medium. The increased neutrophil bactericidal activity was associated with enhanced reactive oxygen species production that was significantly influenced by elevated TNF-alpha concentrations. Conclusions: Our findings identify an immune evasion strategy used by S. aureus to impede neutrophil priming and subsequent bactericidal activity. PMID- 29272503 TI - The impact of health sector evolution plan on hospitalization and cesarean section rates in Iran: an interrupted time series analysis. AB - Objective: To investigate the effect of the health sector evolution plan (HSEP) on hospitalization and cesarean section (C-section) rates in Kermanshah province in the western region of Iran. Design: Interrupted time series analysis. Setting: Hospital care system in Kermanshah province. Study Participants: Fifteen hospitals affiliated to Ministry of Health and Medical Education (MoHME) in Kermanshah province. Intervention(s): Health sector evolution plan. Main Outcome Measures: Hospitalization rate and C-section rate. Results: We observed a statistically significant increase in the hospitalization rate (12.9 hospitalizations per 10 000 population, P < 0.001) in the first month after the implementation of the HSEP. Compared with the monthly trend in hospitalization rate before the intervention, we found a significant increase of 0.70 hospitalizations per 10 000 population (P < 0.001) in monthly trend in hospitalization rate after the HSEP. Although the proportion of C-section from total deliveries decreased by 11% (P = 0.044) in the first month after the implementation of the HSEP, the proportion of C-section from total deliveries increased at the rate of 0.0017% (P = 0.001) per month during post-intervention period. Conclusion: We found an increase in the hospitalization rate after the intervention of HSEP. Although the C-section rate in the first month after the HSEP decreased, we observed an increasing trend in C-section rate over the study period; this implies that the HSEP did not promote vaginal delivery in Iran, which is outlined as one of the objectives of the intervention. PMID- 29272504 TI - TAD-free analysis of architectural proteins and insulators. AB - The three-dimensional (3D) organization of the genome is intimately related to numerous key biological functions including gene expression and DNA replication regulations. The mechanisms by which molecular drivers functionally organize the 3D genome, such as topologically associating domains (TADs), remain to be explored. Current approaches consist in assessing the enrichments or influences of proteins at TAD borders. Here, we propose a TAD-free model to directly estimate the blocking effects of architectural proteins, insulators and DNA motifs on long-range contacts, making the model intuitive and biologically meaningful. In addition, the model allows analyzing the whole Hi-C information content (2D information) instead of only focusing on TAD borders (1D information). The model outperforms multiple logistic regression at TAD borders in terms of parameter estimation accuracy and is validated by enhancer-blocking assays. In Drosophila, the results support the insulating role of simple sequence repeats and suggest that the blocking effects depend on the number of repeats. Motif analysis uncovered the roles of the transcriptional factors pannier and tramtrack in blocking long-range contacts. In human, the results suggest that the blocking effects of the well-known architectural proteins CTCF, cohesin and ZNF143 depend on the distance between loci, where each protein may participate at different scales of the 3D chromatin organization. PMID- 29272505 TI - Effect of fluorescent vs. poultry-specific light-emitting diode lights on production performance and egg quality of W-36 laying hens. AB - More energy-efficient, durable, affordable, and dimmable light-emitting diode (LED) lights are finding applications in poultry production. However, data are lacking on controlled comparative studies concerning the impact of such lights during the pullet rearing and subsequent laying phase. This study evaluated two types of poultry-specific LED light (PS-LED) vs. fluorescent light (FL) with regards to their effects on hen laying performance. A total of 432 Hy-Line W-36 laying hens were tested in two batches using four environmental chambers (nine cages per chamber and 6 birds per cage) from 17 to 41 weeks of age (WOA). Dim-to red PS-LED and warm-white FL were used in the laying phase. The hens had been reared under a dim-to-blue PS-LED or a warm-white FL from 1 to 16 WOA. The measured performance variables included 1) timing of sexual maturity, 2) egg production performance, 3) egg quality, and 4) egg yolk cholesterol. Results showed that the two types of light used during the laying phase had comparable performance responses for all response parameters (P > 0.05) with a few exceptions. Specifically, eggs laid from hens in the PS-LED treatment had lower shell thickness (P = 0.01) and strength (P = 0.03) than those in the FL treatment at 41 WOA. The two types of light used during the rearing phase did not influence the 17 to 41 WOA laying performance, except that hens reared under the PS-LED laid eggs with lower shell thickness (P = 0.02) at 32 WOA as compared to hens reared under the FL. This study demonstrates that the emerging poultry-specific LED lights yield comparable production performance and egg quality of W-36 laying hens to the traditional fluorescent lights. PMID- 29272506 TI - Home haemodialysis in Ireland. AB - Background: Home haemodialysis (HHD) has the potential to impact positively on patient outcomes and health resource management. There has been rejuvenated international interest in HHD in recent years. Aim: We aimed to review the activity and outcomes of the Irish HHD Programme since inception (2009-16). Design: Retrospective review. Methods: Patient data were collected using the national electronic Renal Patient database (eMEDRenal version 3.2.1) and individual centre records. All data were recorded in a coded fashion on a Microsoft Excel Spread-sheet and analysed with Stata SE software. Results: One hundred and one patients completed training and commenced HHD; a further fourty five patients were assessed for HHD suitability but did not ultimately dialyse at home. Twenty patients switched to nocturnal HHD when this resource became available. The switch from conventional in-centre dialysis to HHD led to an increase in the mean weekly hours on haemodialysis (HD) and a reduction in medication burden for the majority of patients. The overall rate of arteriovenous fistula (AVF) as primary vascular access was 62%. Most HHD complications were related to access function or access-related infection. Over the 7-years, 29 HHD patients were transplanted and 9 patients died. No deaths resulted directly from a HHD complication or technical issue. Conclusions: Patient and technique survival rates compared favourably to published international reports. However, we identified several aspects that require attention. A small number of patients were receiving inadequate dialysis and require targeted education. Ongoing efforts to increase AVF and self-needling rates in HD units must continue. Psychosocial support is critical during the transition between dialysis modalities. PMID- 29272507 TI - Education and non-pharmacological approaches for gout. AB - The objectives of this review are as follows: to highlight the gaps in patient and physician knowledge of gout and how this might impede optimal disease management; to provide recommended core knowledge points that should be conveyed to people with gout; and to review non-pharmacological interventions that can be used in gout management. MeSH terms were used to identify eligible studies examining patients' and health-care professionals' knowledge about gout and its management. A narrative review of non-pharmacological management of gout is provided. Many health-care professionals have significant gaps in their knowledge about gout that have the potential to impede optimal management. Likewise, people with gout and the general population lack knowledge about causes, consequences and treatment of this condition. Full explanation about gout, including the potential benefits of urate-lowering treatment (ULT), motivates people with gout to want to start such treatment, and there is evidence, albeit limited, that educational interventions can improve uptake and adherence to ULT. Additionally, several non-pharmacological approaches, such as rest and topical ice application for acute attacks, avoidance of risk factors that can trigger acute attacks, and dietary interventions that may reduce gout attack frequency (e.g. cherry or cherry juice extract, skimmed milk powder or omega-3 fatty acid intake) or lower serum uric acid (e.g. vitamin C), can be used as adjuncts to ULT. There is a pressing need to educate health-care professionals, people with gout and society at large to remove the negative stereotypes associated with gout, which serve as barriers to optimal gout management, and to perceive gout as a significant medical condition. Moreover, there is a paucity of high-quality trial evidence on whether certain simple individual dietary and lifestyle factors can reduce the risk of recurrent gout attacks, and further studies are required in this field. PMID- 29272508 TI - How to prevent allopurinol hypersensitivity reactions? AB - Allopurinol hypersensitivity syndrome (AHS) is a severe and sometimes life threatening adverse drug reaction. Although AHS is rare, the number of patients with gout requiring allopurinol is high, and there are sufficient overall cases of AHS to warrant consideration of preventive measures. Most cases occur within 8 9 weeks of commencing allopurinol, and good patient education at initiation may lead to rapid drug cessation at onset of symptoms. Pretreatment testing for HLA B*5801 and avoidance of allopurinol when positive reduces the risk of AHS and is cost-effective in some ethnic groups. A low starting allopurinol dose may reduce AHS risk, but the relationship between maintenance dose and AHS is more controversial. Chronic kidney disease increases AHS risk, but slowly increasing the allopurinol dose in chronic kidney disease has not been associated with AHS. Alternative newer treatments are available for patients at risk of AHS, but similar adverse reactions can also occur with these. PMID- 29272509 TI - Treatment of gout: where are we now? PMID- 29272510 TI - Cardiac and renal protective effects of urate-lowering therapy. AB - Patients with gout often have co-morbidities such as cardiovascular disease, renal failure and metabolic syndrome components. Some studies, but not all, have suggested that hyperuricaemia and gout are associated with increased risk of myocardial infarction, renal failure and death primarily because of increased risk of cardiovascular events. Therefore, knowledge of the effects of urate lowering therapy (ULT) on co-morbidities, in particular cardiovascular events and chronic kidney disease, is crucial. Randomized controlled trials (RCTs) have suggested that allopurinol, a xanthine oxidase inhibitor, could improve exercise capacity in patients with chronic stable angina and could decrease blood pressure in adolescents. In contrast, a well-designed RCT found no effect of allopurinol in patients with heart failure. The impact of ULT in patients with chronic kidney disease is unclear. Some RCTs found that allopurinol could slow the decline in kidney function, whereas a recent controlled trial found no benefit of febuxostat. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT on co-morbidities. PMID- 29272511 TI - Novel uricosurics. AB - Objective: According to recent guidelines, the mainstay of urate-lowering therapies remains xanthine oxidase inhibition. However, some patients with gout show failure to achieve the predefined target of 5-6 mg/dl with xanthine oxidase inhibitors alone, so alternative drugs are needed. The aim of this study was to review studies of novel drugs targeting uric acid transporter 1 (URAT1) and/or other urate transporters for the management of gout. Methods: MeSH terms were used to identify phase 2/3 trials assessing the efficacy of novel uricosurics. A narrative review of novel drugs targeting URAT1 and/or other urate transporters for the management of gout is provided. Results: Lesinurad is a recently approved uricosuric that inhibits URAT1 and the organic ion transporter organic anion transporter 4 (OAT4). Phase 3 trials showed that lesinurad, combined with allopurinol or febuxostat, is a potent urate-lowering therapeutic with an acceptable safety profile. Arhalofenate, another emerging uricosuric, also interacts with URAT1 and organic anion transporter 4. Phase 2 trials suggested that it can both lower serum UA levels and reduce the risk of flares. Conclusions: New drugs inhibiting URAT1 should cover the unmet need for patients with failure to respond or with contraindications to xanthine oxidase inhibitors. PMID- 29272512 TI - Treat to target in gout. AB - The treat-to-target (T2T) approach has been successfully implemented in a number of diseases. T2T has been proposed for rheumatic diseases such as RA, spondyloarthritis, lupus, and recently for gout. The level of evidence for such approaches differs from one condition to the other (moderate to high for hyperlipidaemia, for example). Practice is based on the best available evidence at any time, and in absence of good evidence for T2T in gout, some suggest a conservative only-treat-symptoms approach. Evidence suggests that not treating gout to target in the long term is overall associated with worsening outcomes, such as flares, tophi and structural damage, which is associated to loss of quality of life and mortality. Different targets have been proposed for hyperuricaemia in gout; lower than 6 mg/dl (0.36 mmol/l) for all patients, at least <5 mg/dl (0.30 mmol/l) for patients with severe-polyarticular or tophaceous gout. PMID- 29272513 TI - Imaging tools to measure treatment response in gout. AB - Imaging tests are in clinical use for diagnosis, assessment of disease severity and as a marker of treatment response in people with gout. Various imaging tests have differing properties for assessing the three key disease domains in gout: urate deposition (including tophus burden), joint inflammation and structural joint damage. Dual-energy CT allows measurement of urate deposition and bone damage, and ultrasonography allows assessment of all three domains. Scoring systems have been described that allow radiological quantification of disease severity and these scoring systems may play a role in assessing the response to treatment in gout. This article reviews the properties of imaging tests, describes the available scoring systems for quantification of disease severity and discusses the challenges and controversies regarding the use of imaging tools to measure treatment response in gout. PMID- 29272514 TI - The role of IL-1 in gout: from bench to bedside. AB - The translation of our knowledge of the biology of MSU crystal-induced IL-1 secretion gives rise to new targets and therapeutic strategies in the treatment of acute gout. The NACHT, LRR and PYD domains-containing protein 3 inflammasome is key to this, and is the subject of intense research. Novel pathways that modulate inflammasome activation, reactive oxygen species generation and extracellular processing of IL-1 have been described and show promise in in vitro and animal studies. Meanwhile, blocking IL-1 by various IL-1 inhibitors has shown the validity of this concept. Patients with acute gout treated with these inhibitors showed positive clinical and biological responses. More work needs to be performed to assess the risk/benefit profile of anti-IL-1 therapies as well as to identify those who will benefit the most from this novel approach to the treatment of gout. PMID- 29272516 TI - Genomic signatures of 60 years of bidirectional selection for 8-week body weight in chickens. AB - Sixty years, constituting 60 generations, have passed since the founding of the Virginia body weight lines, an experimental population of White Plymouth Rock chickens. Using a stringent breeding scheme for divergent 8-week body weight, the lines, which originated from a common founder population, have responded to bidirectional selection with an approximate 15-fold difference in the selected trait. They provide a model system to study the genetics of complex traits in general and the influences of artificial selection on quantitative genetic architectures in particular. As we reflect on the 60th anniversary of the initiation of the Virginia body weight lines, there is opportunity to discuss the findings obtained using different analytical and experimental genetic and genomic strategies and integrate them with a recent pooled genome resequencing dataset. Hundreds of regions across the genome show differentiation between the 2 lines, reinforcing previous findings that response to selection relied on standing variation across many genes and giving insights into the haplotype complexity underlying regions associated with body weight. PMID- 29272517 TI - Deriving common comorbidity indices from the MedDRA classification and exploring their performance on key outcomes in patients with rheumatoid arthritis. AB - Objective: To develop algorithms for calculating the Rheumatic Diseases Comorbidity Index (RDCI), Charlson-Deyo Index (CDI) and Functional Comorbidity Index (FCI) from the Medical Dictionary for Regulatory Activities (MedDRA), and to assess how these MedDRA-derived indices predict clinical outcomes, utility and health resource utilization (HRU). Methods: Two independent researchers linked the preferred terms of the MedDRA classification into the conditions included in the RDCI, the CDI and the FCI. Next, using data from the Norwegian Register-DMARD study (a register of patients with inflammatory joint diseases treated with DMARDs), the explanatory value of these indices was studied in models adjusted for age, gender and DAS28. Model fit statistics were compared in generalized estimating equation (prediction of outcome over time) models using as outcomes: modified HAQ, HAQ, physical and mental component summary of SF-36, SF6D and non RA related HRU. Results: Among 4126 patients with RA [72% female, mean (s.d.) age 56 (14) years], median (interquartile range) of RDCI at baseline was 0.0 (1.0) [range 0-6], CDI 0.0 (0.0) [0-7] and FCI 0.0 (1.0) [0-6]. All the comorbidity indices were associated with each outcome, and differences in their performance were moderate. The RDCI and FCI performed better on clinical outcomes: modified HAQ and HAQ, hospitalization, physical and mental component summary, and SF6D. Any non-RA related HRU was best predicted by RDCI followed by CDI. Conclusion: An algorithm is now available to compute three commonly used comorbidity indices from MedDRA classification. Indices performed comparably well in predicting a variety of outcomes, with the CDI performing slightly worse when predicting outcomes reflecting functioning and health. PMID- 29272515 TI - Update on colchicine, 2017. AB - Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF. However, colchicine has a wide range of anti-inflammatory activities, and studies indicate that it may be beneficial in a variety of other conditions. This paper reviews the evidence for the well-established use of colchicine in gout, as well as several other rheumatic diseases. In addition, we highlight the potential benefit of colchicine in cardiac disease, including coronary artery disease in patients both with and without gout. PMID- 29272519 TI - Ecology and Economics of Using Native Managed Bees for Almond Pollination. AB - Native managed bees can improve crop pollination, but a general framework for evaluating the associated economic costs and benefits has not been developed. We conducted a cost-benefit analysis to assess how managing blue orchard bees (Osmia lignaria Say [Hymenoptera: Megachildae]) alongside honey bees (Apis mellifera Linnaeus [Hymenoptera: Apidae]) can affect profits for almond growers in California. Specifically, we studied how adjusting three strategies can influence profits: (1) number of released O. lignaria bees, (2) density of artificial nest boxes, and (3) number of nest cavities (tubes) per box. We developed an ecological model for the effects of pollinator activity on almond yields, validated the model with published data, and then estimated changes in profits for different management strategies. Our model shows that almond yields increase with O. lignaria foraging density, even where honey bees are already in use. Our cost-benefit analysis shows that profit ranged from -US$1,800 to US$2,800/acre given different combinations of the three strategies. Adding nest boxes had the greatest effect; we predict an increase in profit between low and high nest box density strategies (2.5 and 10 boxes/acre). In fact, the number of released bees and the availability of nest tubes had relatively small effects in the high nest box density strategies. This suggests that growers could improve profits by simply adding more nest boxes with moderate number of tubes in each. Our approach can support grower decisions regarding integrated crop pollination and highlight the importance of a comprehensive ecological economic framework for assessing these decisions. PMID- 29272518 TI - Triggering nucleic acid nanostructure assembly by conditional kissing interactions. AB - Nucleic acids are biomolecules of amazing versatility. Beyond their function for information storage they can be used for building nano-objects. We took advantage of loop-loop or kissing interactions between hairpin building blocks displaying complementary loops for driving the assembly of nucleic acid nano-architectures. It is of interest to make the interaction between elementary units dependent on an external trigger, thus allowing the control of the scaffold formation. To this end we exploited the binding properties of structure-switching aptamers (aptaswitch). Aptaswitches are stem-loop structured oligonucleotides that engage a kissing complex with an RNA hairpin in response to ligand-induced aptaswitch folding. We demonstrated the potential of this approach by conditionally assembling oligonucleotide nanorods in response to the addition of adenosine. PMID- 29272520 TI - Metabolomic analysis of white and yellow seminal plasma in turkeys (Meleagris gallopavo). AB - Numerous studies have indicated that yellow semen syndrome (YSS) of turkey is associated with the production of low semen quality, resulting in reduced fertility and hatchability. It is unknown at present if the etiology of YSS also could be linked to low-molecular weight metabolites. The aim of this study was to examine the metabolome of white and yellow seminal plasma of turkeys. Two different metabolomics approaches, shotgun (direct infusion) and liquid chromatography-mass spectrometry (LC-MS), were employed to identify metabolites differentially abundant in yellow seminal plasma. Significant changes in the levels of 1549 and 2093 metabolites were detected in yellow vs. white seminal plasma using shotgun and LC-MS, respectively. Of these, 354 metabolites (189 increased and 165 decreased) after shotgun and 936 metabolites (363 increased and 573 decreased) after LC-MS were putatively identified using the Human Metabolome Database. Significantly differentiated metabolites were subjected to Ingenuity Pathway Analysis. Lipid metabolism, molecular transport, and nucleic acid metabolism were the top pathways that differentiated white and yellow seminal plasma. These data strongly suggest that disturbance of carbohydrate and lipid metabolism is characteristic for YSS. The abnormal metabolism of lipids may contribute to the numerous lipid vacuoles previously observed in the reproductive tracts of YSS males. An increased level of riboflavin in YSS may be responsible for yellow turkey semen pigmentation. A disturbance in thyroid hormone metabolism visible at protein and metabolic levels may be involved in YSS in turkey. The low quality of YSS may be linked with the presence of drug residues in the reproductive tract. PMID- 29272521 TI - Clinical High Risk Controversies and Challenge for the Experts. PMID- 29272522 TI - EZH2-, CHD4-, and IDH-linked epigenetic perturbation and its association with survival in glioma patients. AB - Glioma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase (IDH) mutations in up to 80% lower grade gliomas (LGG) and in 76% secondary glioblastomas (GBM). IDH mutations are also seen in 10%-20% of acute myeloid leukemia (AML). In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells (pre-LSCs) stage, whereas mutations in genes propagating oncogenic signal are late events in leukemia. IDH mutations are also early events in glioma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in glioma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD4 as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK4, FIP1L1, or FUBP1 collaborate with IDH mutations to negatively affect patients' survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4 at genetic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and glioma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premalignant stem cells to glioma. PMID- 29272523 TI - CYSTM, a Novel Non-Secreted Cysteine-Rich Peptide Family, Involved in Environmental Stresses in Arabidopsis thaliana. AB - The cysteine-rich transmembrane module (CYSTM) is comprised of a small molecular protein family that is found in a diversity of tail-anchored membrane proteins across eukaryotes. This protein family belongs to novel uncharacteristic non secreted cysteine-rich peptides (NCRPs) according to their conserved domain and small molecular weight, and genome-wide analysis of this family has not yet been undertaken in plants. In this study, 13 CYSTM genes were identified and located on five chromosomes with diverse densities in Arabidopsis thaliana. The CYSTM proteins could be classified into four subgroups based on domain similarity and phylogenetic topology. Encouragingly, the CYSTM members were expressed in at least one of the tested tissues and dramatically responded to various abiotic stresses, indicating that they played vital roles in diverse developmental processes, especially in stress responses. CYSTM peptides displayed a complex subcellular localization, and most were detected at the plasma membrane and cytoplasm. Of particular interest, CYSTM members could dimerize with themselves or others through the C-terminal domain, and we built a protein-protein interaction map between CYSTM members in Arabidopsis for the first time. In addition, an analysis of CYSTM3 overexpression lines revealed negative regulation for this gene in salt stress responses. We demonstrate that the CYSTM family, as a novel and ubiquitous non-secreted cysteine-rich peptide family, plays a vital role in resistance to abiotic stress. Collectively, our comprehensive analysis of CYSTM members will facilitate future functional studies of the small peptides. PMID- 29272524 TI - Leaf Chemical Compositions of Different Eggplant Varieties Affect Performance of Bemisia tabaci (Hemiptera: Aleyrodidae) Nymphs and Adults. AB - The sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) MEAM1 is a serious pest of many crops worldwide, and its control mostly depends on insecticides. One of the most preferred host plants of B. tabaci is eggplant, Solanum melongena, although preferences among different cultivars of the whiteflies vary. We hypothesized that certain nutritional and defensive chemicals of plant leaves, such as nitrogen, glucose, fructose, sucrose, amino acids, total phenolic components, and moisture content may affect whitefly's feeding and ovipositional preference, fecundity and longevity, nymph development, and survival among different eggplant varieties. To seek the most susceptible eggplant variety for use as an attractive trap crop for whitefly adults, we determined the variation of leaf chemical compositions among six eggplant varieties (H149, JSZ, JGL, TLB, DYZ, and QXN) and evaluated the effects of their leaf chemicals to the performance of nymphs and adults of B. tabaci. In choice feeding and oviposition tests, the varieties 'H149' and 'JSZ' had the most eggs. The whiteflies had significantly higher fecundity, longevity, lowest nymph development period, and higher survivals on JSZ than on other varieties. The least preferred TLB variety possessed the lowest adults and eggs, the lowest fecundity and longevity, and nymph development period. JGL, DYZ, and QXN were considered as a moderately preferred variety. Leaf chemistry revealed that highly susceptible variety possessed higher concentration of nitrogen, glucose, amino acids, and lower moisture content. The resistant variety possessed higher amount of total phenolic component. Both nutritional and defensive chemicals combined associated with nymph and adult performance of whitefly. PMID- 29272525 TI - Elevated Pentraxin-3 Concentrations in Patients With Leprosy: Potential Biomarker of Erythema Nodosum Leprosum. AB - Background: Leprosy, the leading infectious cause of disability worldwide, remains a major public health challenge in the most severely affected countries despite the sharp decline in new cases in recent years. The search for biomarkers is essential to achieve a better understanding of the molecular and cellular mechanisms underlying the disease. Methods: Pentraxin-3 (PTX3) analyses of sera from 87 leprosy patients with or without reactions were conducted via enzyme linked immunosorbent assay. In situ identification of PTX3 in skin lesion was confirmed by quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunofluorescence assays. Results: We found that PTX3 serum levels were higher in multibacillary patients when evaluated before the onset of acute erythema nodosum leprosum (ENL) and persistently elevated during reaction. Thalidomide treatment reduced PTX3 in the serum 7 days after starting treatment. In situ analyses have also demonstrated enhancement of PTX3 in ENL lesions and showed that treatment with thalidomide reduced its expression and the prominent neutrophilic infiltrate, a hallmark of the disease. Conclusions: In summary, our study provides in vivo evidence that PTX3 is enhanced during ENL but not in reversal reaction and provides a new molecular target in ENL pathogenesis. PMID- 29272526 TI - Evidence for Congenital Zika Virus Infection From Neutralizing Antibody Titers in Maternal Sera, Northeastern Brazil. AB - Reliable diagnosis of congenital Zika virus (ZIKV) infection is challenging. Here, we assessed ZIKV-specific neutralizing antibodies in 28 mothers of children with microcephaly (cases) and 122 controls from northeastern Brazil using plaque reduction neutralization tests. ZIKV-specific antibody titers were significantly higher in cases than in controls (t test, P < .0001). We identified a putative case of congenital Zika syndrome retrospectively by unusually high ZIKV-specific antibody titers. High ZIKV-specific antibody titers in cases were unrelated to prior dengue virus infection. Our data suggest a strong immunological stimulus from prolonged placental or transplacental ZIKV shedding and potential utility of maternal antibody titers to corroborate congenital ZIKV infection. PMID- 29272527 TI - Divergence of affinities, serotypes and virulence factor between CTX-M Escherichia coli and non-CTX-M producers. AB - This study was undertaken to discern the differences of the multi-locus sequence typing (MLST), O serogroups, and virulence factors among 34 CTX-M-1 Escherichia coli, 49 CTX-M-9 strains and 23 non-CTX-M isolates from chickens in Henan province, China. The MLST scheme yielded 34 sequence types, in which ST155 and ST359 were frequent (17% and 15%, respectively) and associated with zoonotic disease. The irp-2 (20% versus 2%, P = 0.0001), traT (85.3% versus 56.5%, P = 0.019), and sfaS (70.6% versus 0, P = 0.021) were significantly more prevalent in CTX-M-1 E. coli than in non-CTX-M producers. Also, CTX-M-9 isolates carried more irp-2 (17% versus 2%, P = 0.023), iroN (71.4% versus 39.1%, P = 0.019), and iss (79.6% versus 39.1%, P = 0.002) genes. In conclusion, although the 106 isolates encompassed a great genetic diversity, the CTX-M isolates harbored more virulence factor genes than non-CTX-M producers. PMID- 29272528 TI - Application of Paracoccus marcusii as a potential feed additive for laying hens. AB - Carotenoids have been used for many years as an added pigment to enhance egg yolk color. One such carotenoid, astaxanthin, has a strong antioxidant activity and is produced by several microorganisms, including the bacterium Paracoccus marcusii, which has shown promise to be used as a feed additive. Therefore, this study investigated the use of P. marcusii as a possible source of pigmentation in layer hen feed to enhance egg yolk color. Paracoccus marcusii was fed to hens in a sucrose solution (10% m/v). The hens were fed daily and all eggs were collected for analysis. Dilutions of egg contents were plated onto selective media to detect the presence of known food pathogens (E. coli, Listeria, and Salmonella). In the feeding trial, there was no negative effect on hen body weight, egg production, or overall egg quality. There was a significant increase (P < 0.05) in yolk color as well as an increase in whole egg and yolk weight. There were also no known food pathogens detected in any of the egg samples. This study has shown promising results in using this bacterium as an effective feed additive for laying hens. PMID- 29272529 TI - Induced molt using cassava meal. 2. Effects on eggshell quality, ultrastructure, and pore density in late-phase laying hens. AB - This experiment was conducted to investigate the effect of a non-fasting induced molt using cassava meal on the eggshell quality, ultrastructure, and porosity in late-phase (74 wk old) H&N Brown laying hens. Hens were randomly assigned to 3 treatments of 90 birds each: 1) Controls with no induced molt (CONT); 2) molted by full feeding with cassava meal for 3 wk (FP3); and 3) molted by full feeding with cassava meal for 4 wk (FP4). Following the treatments, groups 2 and 3 were fed a pullet developer diet for 3 weeks. During the molt period, the birds were exposed to an 8L:16D photoperiod and had access to drinking water at all times. Thereafter, all hens were fed a layer diet (17% CP) and exposed to a 16L:8D photoperiod until the end of the study. Compared to the CONT treatment, significant reductions (P < 0.05) in shell weight, thickness, and breaking strength were identified on the sixth d of feeding the molt diet. Significant (P < 0.05) improvements in these parameters were observed for the FP3 and FP4 treatments during the post-molt period, with the greater degree in the FP4 treatment. In addition, scanning electron microscopy revealed a smaller size of mammillary knobs accompanied by a higher density of mammillae in eggs taken from the molted treatments. Evidence of type B mammillae was detected in an egg produced by the CONT hens, whereas confluent and cuffing mammillae were observed in an egg taken from the FP4 birds. Reduced pore densities were found in the molted treatments in some periods of the post-molt production as compared to the CONT treatment. It was concluded that feeding the cassava molt diet for 4 wk could be an effective non-fasting molt method for improving eggshell quality, ultrastructure, and porosity in post-molt laying hens. PMID- 29272530 TI - Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction. AB - STUDY QUESTION: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)? SUMMARY ANSWER: Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro. WHAT IS KNOWN ALREADY: FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth. STUDY DESIGN, SIZE, DURATION: The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group). Fpr2 expression was also determined in placental tissues obtained from a murine model of FGR (n = 4). The functional role of FPR2 in primary trophoblasts and endothelial cells in vitro was assessed in diverse assays in a time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placentae from third-trimester pregnancies complicated by idiopathic FGR (n = 25) and those from gestation matched pregnancies with appropriately grown infants as controls (n = 25) were collected at gestation 27-40 weeks. Placental tissues were also collected from a spontaneous CBA/CaH * DBA/2 J murine model of FGR. Placental FPR2/Fpr2 mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence FPR2 expression in primary trophoblasts and in human umbilical vein endothelial cells (HUVEC), and the quantitation of cytokines, chemokines and apoptosis was performed following a cDNA array analyses. Functional effects of trophoblast differentiation were measured using HCGB/beta-hCG and syncytin-2 expression as well as markers of apoptosis, tumour protein 53 (TP53), caspase 8, B cell lymphoma 2 (BCL2) and BCL associated X (BAX). Endothelial function was assessed by proliferation, network formation and permeability assays. MAIN RESULTS AND THE ROLE OF CHANCE: Placental FPR2/Fpr2 expression was significantly decreased in FGR placentae (n = 25, P < 0.05) as well as in murine FGR placentae compared to controls (n = 4, P < 0.05). FPR2 siRNA (siFPR2) in term trophoblasts significantly increased differentiation markers, HCGB and syncytin-2; cytokines, interleukin (IL)-6, CXCL8; and apoptotic markers, TP53, caspase 8 and BAX, but significantly reduced the expression of the chemokines CXCL12 and its receptors CXCR4 and CXCR7; CXCL16 and its receptor, CXCR6; and cytokine, IL-10, compared with control siRNA (siCONT). Treatment of HUVECs with siFPR2 significantly reduced proliferation and endothelial tube formation, but significantly increased permeability of HUVECs. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Reduced expression of placental FPR2/Fpr2 was observed in the third trimester at delivery after development of FGR, suggesting that FPR2 is associated with FGR pregnancies. However, there is a possibility that the decreased placental FPR2 observed in FGR may be a consequence rather than a cause of FGR, although our in vitro functional analyses using primary trophoblasts and endothelial cells suggest that FPR2 may have a direct or indirect regulatory role on trophoblast differentiation and endothelial function in FGR. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study linking placental FPR2 expression with changes in the trophoblast and endothelial functions that may explain the placental insufficiency observed in FGR. STUDY FUNDING/COMPETING INTERESTS: P.M. and P.R.E. received funding from the Australian Institute of Musculoskeletal Science, Western Health, St. Albans, Victoria 3021, Australia. M.L. is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; Grant no. 1047025). Monash Health is supported by the Victorian Government's Operational Infrastructure Support Programme. The authors declare that there is no conflict of interest in publishing this work. PMID- 29272531 TI - LEAF LATERAL SYMMETRY1, a Member of the WUSCHEL-RELATED HOMEOBOX3 Gene Family, Regulates Lateral Organ Development Differentially from Other Paralogs, NARROW LEAF2 and NARROW LEAF3 in Rice. AB - In several eudicot species, one copy of each member of the WUSCHEL-RELATED HOMEOBOX (WOX) gene family, WOX1 and WOX3, is redundantly or differentially involved in lateral leaf outgrowth, whereas only the WOX3 gene regulating the lateral domain of leaf development has been reported in grass. In this study, we show that a WOX3 gene, LEAF LATERAL SYMMETRY1 (LSY1), regulates lateral leaf development in a different manner ftom that of other duplicated paralogs of WOX3, NARROW LEAF2 (NAL2)/NAL3, in rice. A loss-of-function mutant of LSY1 exhibited an asymmetrical defect from early leaf development, which is different from a symmetric defect in a double loss-of-function mutant of NAL2/3, whereas the expression of both genes was observed in a similar domain in the margins of leaf primordia. Unlike NAL2/3, overexpression of LSY1 produced malformed leaves whose margins were curled adaxially. Expression domains and the level of adaxial/abaxial marker genes were affected in the LSY1-overexpressing plants, indicating that LSY1 is involved in regulation of adaxial-abaxial patterning at the margins of the leaf primordia. Additive phenotypes in some leaf traits of lsy1 nal2/3 triple mutants and the unchanged level of NAL2/3 expression in the lsy1 background suggested that LSY1 regulates lateral leaf development independently of NAL2/3. Our results indicated that all of the rice WOX3 genes are involved in leaf lateral outgrowth, but the functions of LSY1 and NAL2/3 have diverged. We propose that the function of WOX3 and the regulatory mode of leaf development in rice are comparable with those of WOX1/WOX3 in eudicot species. PMID- 29272532 TI - Human Immunodeficiency Virus-Infected Women Have High Numbers of CD103-CD8+ T Cells Residing Close to the Basal Membrane of the Ectocervical Epithelium. AB - Background: Genital mucosa is the main portal of entry for various incoming pathogens, including human immunodeficiency virus (HIV), hence it is an important site for host immune defenses. Tissue-resident memory T (TRM) cells defend tissue barriers against infections and are characterized by expression of CD103 and CD69. In this study, we describe the composition of CD8+ TRM cells in the ectocervix of healthy and HIV-infected women. Methods: Study samples were collected from healthy Swedish and Kenyan HIV-infected and uninfected women. Customized computerized image-based in situ analysis was developed to assess the ectocervical biopsies. Genital mucosa and blood samples were assessed by flow cytometry. Results: Although the ectocervical epithelium of healthy women was populated with bona fide CD8+ TRM cells (CD103+CD69+), women infected with HIV displayed a high frequency of CD103-CD8+ cells residing close to their epithelial basal membrane. Accumulation of CD103-CD8+ cells was associated with chemokine expression in the ectocervix and HIV viral load. CD103+CD8+ and CD103-CD8+ T cells expressed cytotoxic effector molecules in the ectocervical epithelium of healthy and HIV-infected women. In addition, women infected with HIV had decreased frequencies of circulating CD103+CD8+ T cells. Conclusions: Our data provide insight into the distribution of CD8+ TRM cells in human genital mucosa, a critically important location for immune defense against pathogens, including HIV. PMID- 29272533 TI - Wildflowers abundant in the garden of systemic sclerosis research, while hopeful exotics will one day bloom. PMID- 29272534 TI - Leukoerythroblastosis in a Young Child with Severe Malaria and Superimposed Gram Negative Infection. AB - Background: Leukoerythroblastosis, a non-specific and often short-lasting response of the bone marrow to different diseases such as malignancies or infections, is characterized by the presence in the peripheral blood of immature red and white cells. Methods: We present a case of leukoerythoblastosis occurring in a 24 months old Mozambican girl, in the context of a severe malaria episode and an associated urinary tract infection. Peripheral blood smear was used for diagnosis of malaria and leukoerythroblastosis. Enterobacter cloacae isolation and antibiotic susceptibility testing were performed by conventional microbiology. Results: Peripheral blood smear was positive for Plasmodium falciparum and showed a leukoerythroblastosis with red cell anisopoikilocytosis and left shifted neutrophils. Urine culture confirmed the presence of a multi resistant E. cloacae. Treatment of underlying conditions resolved the leukoerythroblastic reaction. Conclusions: Leukoerythroblastosis may be related to different infectious diseases and may also appear in the context of severe malaria. Bacterial superinfection needs to be investigated. PMID- 29272535 TI - Forgetting emotional material in working memory. AB - Proactive interference (PI) is the tendency for information learned earlier to interfere with more recently learned information. In the present study, we induced PI by presenting items from the same category over several trials. This results in a build-up of PI and reduces the discriminability of the items in each subsequent trial. We introduced emotional (e.g. disgust) and neutral (e.g. furniture) categories and examined how increasing levels of PI affected performance for both stimulus types. Participants were scanned using functional magnetic resonance imaging (fMRI) performing a 5-item probe recognition task. We modeled responses and corresponding response times with a hierarchical diffusion model. Results showed that PI effects on latent processes (i.e. reduced drift rate) were similar for both stimulus types, but the effect of PI on drift rate was less pronounced PI for emotional compared to neutral stimuli. The decline in the drift rate was accompanied by an increase in neural activation in parahippocampal regions and this relationship was more strongly observed for neutral stimuli compared to emotional stimuli. PMID- 29272537 TI - Improved Maximum Parsimony Models for Phylogenetic Networks. AB - Phylogenetic networks are well suited to represent evolutionary histories comprising reticulate evolution. Several methods aiming at reconstructing explicit phylogenetic networks have been developed in the last two decades. In this article, we propose a new definition of maximum parsimony for phylogenetic networks that permits to model biological scenarios that cannot be modeled by the definitions currently present in the literature (namely, the "hardwired" and "softwired" parsimony). Building on this new definition, we provide several algorithmic results that lay the foundations for new parsimony-based methods for phylogenetic network reconstruction. PMID- 29272536 TI - Complex Relationships between Chromatin Accessibility, Sequence Divergence, and Gene Expression in Arabidopsis thaliana. AB - Variation in regulatory DNA is thought to drive phenotypic variation, evolution, and disease. Prior studies of regulatory DNA and transcription factors across animal species highlighted a fundamental conundrum: Transcription factor binding domains and cognate binding sites are conserved, while regulatory DNA sequences are not. It remains unclear how conserved transcription factors and dynamic regulatory sites produce conserved expression patterns across species. Here, we explore regulatory DNA variation and its functional consequences within Arabidopsis thaliana, using chromatin accessibility to delineate regulatory DNA genome-wide. Unlike in previous cross-species comparisons, the positional homology of regulatory DNA is maintained among A. thaliana ecotypes and less nucleotide divergence has occurred. Of the ~50,000 regulatory sites in A. thaliana, we found that 15% varied in accessibility among ecotypes. Some of these accessibility differences were associated with extensive, previously unannotated sequence variation, encompassing many deletions and ancient hypervariable alleles. Unexpectedly, for the majority of such regulatory sites, nearby gene expression was unaffected. Nevertheless, regulatory sites with high levels of sequence variation and differential chromatin accessibility were the most likely to be associated with differential gene expression. Finally, and most surprising, we found that the vast majority of differentially accessible sites show no underlying sequence variation. We argue that these surprising results highlight the necessity to consider higher-order regulatory context in evaluating regulatory variation and predicting its phenotypic consequences. PMID- 29272538 TI - Evaluation of the performance of Hy-Line Brown laying hens fed soybean or soybean free diets using cage or free-range rearing systems. AB - This study evaluated egg production and quality variables of caged and free-range Hy-Line Brown laying hens fed soybean meal (SBM) and soybean-meal-free (SBMF) diets. Hens were randomly assigned to the same 2 dietary treatments within 3 location blocks. SBM and SBMF diets with equivalent calculated nutrient content were prepared based on Hy-Line Brown rearing guidelines. The SBMF diets utilized cottonseed meal, corn distillers dried grains with solubles, corn gluten meal, and wheat middlings in place of dehulled soybean meal. The experiment was conducted between August 2015 and January of 2016 within the TAMU Poultry Research Center and data analyzed over 6 consecutive 28-day periods. Data were analyzed as a split-plot with rearing systems designated whole plots and diets designated as subplots. Hens reared in the free-range rearing system peaked a couple of wk later than those hens within the more conventional indoor caged system, and cumulative production data were considerably more variable for hens raised in the free-range environment. Cumulative egg production, feed per dozen eggs and feed conversion ratio (g feed/g egg) were 92 +/- 1.23 and 86 +/- 1.84%, 1.45 +/- 0.02 and 1.89 +/- 0.05 kg, and 2.14 +/- 0.04 and 2.77 +/- 0.08 (P < 0.05), respectively, for the caged vs. free-range rearing systems. Cumulative egg weight, feed per dozen eggs, and feed conversion ratio were 59.9 +/- 0.59 and 56.5 +/- 0.60 g, 1.57 +/- 0.04 and 1.77 +/- 0.05 kg, and 2.24 +/- 0.06 and 2.67 +/- 0.08 kg (P < 0.05) for SBM and SBMF diets, respectively. Diet did not affect cumulative egg production (P > 0.05). With respect to egg quality, there were no differences in cumulative albumen height, Haugh unit, or breaking strength, but there was a significant rearing system by diet interaction for shell thickness, with the free-range hens averaging 40.77 +/- 0.19 and 39.86 +/- 0.31 MUm (P < 0.05), respectively, for the hens fed SBM vs. SBMF diets. In conclusion, the results suggested free-range production is more variable than traditional closed house cage systems based on standard errors, and SBMF diets containing cottonseed meal can be used in both caged and free-range production systems without affecting egg production, although one might see lower egg weights. PMID- 29272539 TI - A nucleobase-centered coarse-grained representation for structure prediction of RNA motifs. AB - We introduce the SPlit-and-conQueR (SPQR) model, a coarse-grained (CG) representation of RNA designed for structure prediction and refinement. In our approach, the representation of a nucleotide consists of a point particle for the phosphate group and an anisotropic particle for the nucleoside. The interactions are, in principle, knowledge-based potentials inspired by the $?mathcal {E}$SCORE function, a base-centered scoring function. However, a special treatment is given to base-pairing interactions and certain geometrical conformations which are lost in a raw knowledge-based model. This results in a representation able to describe planar canonical and non-canonical base pairs and base-phosphate interactions and to distinguish sugar puckers and glycosidic torsion conformations. The model is applied to the folding of several structures, including duplexes with internal loops of non-canonical base pairs, tetraloops, junctions and a pseudoknot. For the majority of these systems, experimental structures are correctly predicted at the level of individual contacts. We also propose a method for efficiently reintroducing atomistic detail from the CG representation. PMID- 29272540 TI - Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI. AB - Inhibition of the bile salt export pump (BSEP) by a drug has been implicated as a risk factor for a drug's potential to cause drug-induced liver injury (DILI) and is thought to be an important mechanism leading to DILI. For a wide variety of drugs a correlation has been observed between the potency of in vitro BSEP inhibition and its propensity to cause DILI in humans. These findings were interpreted to suggest that BSEP inhibition could be an important mechanism to help explain how some drugs initiate DILI. Because the Biopharmaceutics Drug Disposition Classification System (BDDCS) can be useful in characterizing and predicting some important transporter effects in terms of drug-drug interactions, we evaluated the information provided by BDDCS in order to understand the inhibition propensity of BSEP. Here we analyze the relationship between a compound's ability to inhibit BSEP function and cause liver injury in humans using a compilation of published DILI datasets that have screened for BSEP inhibitors, other hepatic transporters and other mechanism-based toxicity key events. Our results demonstrate that there is little support for in vitro BSEP inhibition being universally DILI predictive. Rather we show that most potent BSEP inhibitors are BDDCS class 2 drugs, which we have demonstrated previously is the BDDCS class most likely to be DILI related. Since BDDCS class is not related to any proposed DILI mechanistic hypotheses, we maintain that if measures of BSEP inhibition alone or together with inhibition of other transporters cannot be differentiated from class 2 assignment, there is no support for in vitro BSEP inhibition being DILI predictive. PMID- 29272542 TI - Mutation of the OsSAC1 Gene, which Encodes an Endoplasmic Reticulum Protein with an Unknown Function, Causes Sugar Accumulation in Rice Leaves. AB - Sugars are the most abundant organic compounds produced by plants, and can be used to build carbon skeletons and generate energy. The sugar accumulation 1 (OsSAC1) gene encodes a protein with an unknown function that exhibits four N terminal transmembrane regions and two conserved domains of unknown function, DUF4220 and DUF594. OsSAC1 was found to be poorly and specifically expressed at the bottoms of young leaves and in the developing leaf sheaths. Subcellular location results showed that OsSAC1 was co-localized with ER:mCherry and targeted the endoplasmic reticulum (ER). OsSAC1 has been found to affect sugar partitioning in rice (Oryza sativa). I2/KI starch staining, ultrastructure observations and starch content measurements indicated that more and larger starch granules accumulated in ossac1 source leaves than in wild-type (WT) source leaves. Additionally, higher sucrose and glucose concentrations accumulated in the ossac1 source leaves than in WT source leaves, whereas lower sucrose and glucose concentrations were observed in the ossac1 young leaves and developing leaf sheaths than in those of the WT. Much greater expression of OsAGPL1 and OsAGPS1 (responsible for starch synthesis) and significantly less expression of OscFBP1, OscFBP2, OsSPS1 and OsSPS11 (responsible for sucrose synthesis) and OsSWEET11, OsSWEET14 and OsSUT1 (responsible for sucrose loading) occurred in ossac1 source leaves than in WT source leaves. A greater amount of the rice plasmodesmatal negative regulator OsGSD1 was detected in ossac1 young leaves and developing leaf sheaths than in those of the WT. These results suggest that ER targeted OsSAC1 may indirectly regulate sugar partitioning in carbon-demanding young leaves and developing leaf sheaths. PMID- 29272541 TI - Tumour necrosis factor inhibitor survival and predictors of response in axial spondyloarthritis-findings from a United Kingdom cohort. AB - Objectives: To analyse long-term survival and efficacy of TNFi, reasons for switching or discontinuing, baseline predictors of response and remission in axial spondyloarthritis (axSpA) patients in a UK cohort. Methods: All patients with a physician-verified diagnosis of axSpA attending two specialist centres who fulfilled the eligibility criteria for TNFi were included. Routinely recorded patient data were reviewed retrospectively. Initial TNFi was recorded as the index drug. Results: Six hundred and fifty-one patients (94% AS) were included; adalimumab (n = 332), etanercept (n = 205), infliximab (n = 51), golimumab (n = 40) and certolizumab pegol (n = 23) were index TNFi. The mean (s.d.) duration from symptom onset to time of diagnosis was 8.6 (8.7) years and mean (s.d.) duration from diagnosis to TNFi initiation was 12.6 (11.5) years. A total of 224 (34.4%) stopped index TNFi, and 105/224 switched to a second TNFi. Median drug survival for index and second TNFi were 10.2 years (95% CI: 8.8, 11.6 years) and 5.5 years (95% CI: 2.7, 8.3 years), respectively (P < 0.05). Survival rates were not influenced by choice of TNFi. HLA-B27 predicted BASDAI50 and/or two or more point reduction within 6 months and long-term drug survival (P < 0.05). Low disease activity was predicted by non-smoking and low baseline BASDAI (P < 0.05). Conclusion: We have observed good TNFi survival rates in axSpA patients treated in a real-life setting. This is best for first TNFi and not influenced by drug choice. PMID- 29272543 TI - Mapping Convergent and Divergent Cortical Thinning Patterns in Patients With Deficit and Nondeficit Schizophrenia. AB - Deficit schizophrenia (DS) is a homogeneous subtype of schizophrenia characterized by primary and enduring negative symptoms. However, the underlying neuroanatomical substrate of DS remains poorly understood. Here, we collected high-resolution structural magnetic resonance images of 115 participants, including 33 DS patients, 41 nondeficit schizophrenia (NDS) patients, and 41 healthy controls (HCs), and calculated the cortical thickness and surface area for statistical comparisons among the 3 groups. Relative to the control group, both the DS and NDS groups exhibited convergent cortical thinning in the bilateral inferior frontal gyri and the left superior temporal gyrus. The cortical thinning in the right inferior frontal cortex in the patient group was significantly positively correlated with declines of cognitive flexibility and visuospatial memory. Importantly, compared to the NDS group, the DS group exhibited a more widespread cortical thinning pattern, with the most significant differences in the left temporo-parietal junction area. For the surface area measurement, no significant group differences were observed. Collectively, these results highlight the convergent and divergent cortical thinning patterns between patients with DS and NDS, which provide critical insights into the neuroanatomical substrate of DS and improve our understanding of the biological mechanism that contributes to the negative symptoms and cognitive impairments in DS. PMID- 29272544 TI - Apremilast for the treatment of active psoriatic arthritis: a single-centre real life experience. PMID- 29272545 TI - Clinical Profile of Scrub Typhus Meningoencephalitis among South Indian Children. AB - Re-emerging scrub typhus is gaining recognition as an important cause of paediatric meningoencephalitis in tropics. We studied the clinical profile of scrub typhus meningoencephalitis (STME) in children <12 years. Of 270 serology confirmed cases of scrub typhus, 14 (5%) had features consistent with STME and 9 (64%) of these children were between 5 and 12 years of age; 12 (85%) children presented to the hospital during the second week of illness. Fever, headache and altered sensorium were observed in all children, while meningeal signs, papilledema and seizures were observed in 8 (57%), 7 (50%) and 6 (43%) children, respectively. The mean CSF protein level, glucose level, cell count and percentage of lymphocytes were 75 mg/dl, 46 mg/dl, 41 cells and 86%, respectively. STME should be considered in febrile children from endemic area with neurological features, such as headache or altered sensorium. Lumbar puncture is mandatory to confirm STME and rule out close differential diagnosis, such as pyogenic and tubercular meningitis. PMID- 29272547 TI - Detecting Environment-Dependent Diversification From Phylogenies: A Simulation Study and Some Empirical Illustrations. AB - Understanding the relative influence of various abiotic and biotic variables on diversification dynamics is a major goal of macroevolutionary studies. Recently, phylogenetic approaches have been developed that make it possible to estimate the role of various environmental variables on diversification using time-calibrated species trees, paleoenvironmental data, and maximum-likelihood techniques. These approaches have been effectively employed to estimate how speciation and extinction rates vary with key abiotic variables, such as temperature and sea level, and we can anticipate that they will be increasingly used in the future. Here we compile a series of biotic and abiotic paleodatasets that can be used as explanatory variables in these models and use simulations to assess the statistical properties of the approach when applied to these paleodatasets. We demonstrate that environment-dependent models perform well in recovering environment-dependent speciation and extinction parameters, as well as in correctly identifying the simulated environmental model when speciation is environment-dependent. We explore how the strength of the environment-dependency, tree size, missing taxa, and characteristics of the paleoenvironmental curves influence the performance of the models. Finally, using these models, we infer environment-dependent diversification in two empirical phylogenies: temperature dependence in Cetacea and $?delta^{13}C$-dependence in Ruminantia. We illustrate how to evaluate the relative importance of abiotic and biotic variables in these two clades and interpret these results in light of macroevolutionary hypotheses. Given the important role paleoenvironments are presumed to have played in species evolution, our statistical assessment of how environment-dependent models behave is crucial for their utility in macroevolutionary analysis. PMID- 29272546 TI - Sleep deprivation affects fear memory consolidation: bi-stable amygdala connectivity with insula and ventromedial prefrontal cortex. AB - Sleep plays an important role for successful fear memory consolidation. Growing evidence suggests that sleep disturbances might contribute to the development and the maintenance of posttraumatic stress disorder (PTSD), a disorders characterized by dysregulations in fear learning mechanisms, as well as exaggerated arousal and salience processing. Against this background, the present study examined the effects of sleep deprivation (SD) on the acquisition of fear and the subsequent neural consolidation. To this end, the present study assessed fear acquisition and associated changes in fMRI-based amygdala-functional connectivity following 24 h of SD. Relative to non-sleep deprived controls, SD subjects demonstrated increased fear ratings and skin conductance responses (SCR) during fear acquisition. During fear consolidation SD inhibited increased amygdala-ventromendial prefrontal cortex (vmPFC) connectivity and concomitantly increased changes in amygdala-insula connectivity. Importantly, whereas in controls fear indices during acquisition were negatively associated with amygdala vmPFC connectivity during consolidation, fear indices were positively associated with amygdala-insula coupling following SD. Together the findings suggest that SD may interfere with vmPFC control of the amygdala and increase bottom-up arousal signaling in the amygdala-insula pathway during fear consolidation, which might mediate the negative impact of sleep disturbances on PSTD symptomatology. PMID- 29272549 TI - Serum metabolomics of laryngeal cancer based on liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - The discovery of new laryngeal cancer-related metabolite biomarkers could help to facilitate early diagnosis. A serum metabolomics study from laryngeal cancer patients and healthy individuals was conducted using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Univariate and multivariate statistics were used to discriminate laryngeal cancer patients and healthy individuals. 1-Palmitoyl-sn-glycero-3-phosphocholine (LysoPC 16:0), 1-o hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) and 1,2-dipalmitoyl-sn glycero-3-phosphocholine were found to be significantly different between the laryngeal cancer group and the healthy group. They are mainly involved in phospholipids catabolism, linoleic acid metabolism, alpha-linoleic acid metabolism and arachidonic acid metabolism. The area under the curve of the biomarker combined by two metabolites (LysoPC 16:0 and PAF) was 0.935, the sensitivity was 0.962 and the specificity was 0.825. LysoPC 16:0 and PAF may show diagnostic potential for laryngeal carcinoma. PMID- 29272548 TI - Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model. AB - Prolonged seizure activity or status epilepticus (SE) is one of the most critical manifestations of organophosphate exposure. Previous studies in our laboratory have demonstrated that oxidative stress is a critical mediator of SE-induced neuronal injury. The goal of this study was to determine if diisopropylflurorphoshate (DFP) exposure in rats resulted in oxidative stress and whether scavenging reactive oxygen species attenuated DFP-induced neurotoxicity. DFP treatment increased indices of oxidative stress in a time- and region- dependent manner. Neuronal loss measured by Fluoro-Jade B staining was significantly increased in the hippocampus, piriform cortex and amygdala following DFP. Similarly, levels of the proinflammatory cytokines, particularly TNF-alpha, IL-6, and KC/GRO were significantly increased in the piriform cortex and in the hippocampus following DFP treatment. The catalytic antioxidant AEOL10150, when treatment was initiated 5 min after DFP-induced SE, significantly attenuated indices of oxidative stress, neuroinflammation and neuronal damage. This study suggests that catalytic antioxidant treatment may be useful as a novel therapy to attenuate secondary neuronal injury following organophosphate exposure. PMID- 29272551 TI - Impact of Local Groundwater Flow Model Errors on Transport and a Practical Solution for the Issue. AB - A groundwater flow model is typically used to provide the flow field for conducting groundwater solute transport simulations. The advection term of the mass conserved formulation for groundwater transport assumes that the flow field is perfectly balanced and that all water flowing into a numerical grid cell is exactly balanced by outflows after accounting for sources/sinks or internal storage. However, in many complicated regional or site-scale models, there may be localized flow balance errors that may be difficult to eliminate through tighter flow convergence tolerances due to simulation time constraints or numerical limits on convergence tolerances. Thus, if water is erroneously gained or lost within a grid cell during the flow computation, the solutes within it will also be numerically affected in the associated transport simulation. Transport solutions neglect this error in groundwater flow as the transport equations that are solved assume no error in flow. This flow imbalance error can however have consequences on the transport solution ranging from unnoticeable errors in the resulting concentrations to spurious oscillations that can grow in time and hinder further solution. An approach has been suggested here, to explicitly handle these flow imbalances during mass conserved advective transport computations and report them in the corresponding transport mass balance output, as corrections that are needed to handle errors originating in the flow solution. Example problems are provided to explain the concepts and demonstrate the impacts. PMID- 29272550 TI - Different contributions of chemokine N-terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3. AB - BACKGROUND AND PURPOSE: Chemokines and their receptors form an intricate interaction and signalling network that plays critical roles in various physiological and pathological cellular processes. The high promiscuity and apparent redundancy of this network makes probing individual chemokine/receptor interactions and functional effects, as well as targeting individual receptor axes for therapeutic applications, challenging. Despite poor sequence identity, the N-terminal regions of chemokines, which play a key role in their activity and selectivity, contain several conserved features. Thus far little is known regarding the molecular basis of their interactions with typical and atypical chemokine receptors or the conservation of their contributions across chemokine receptor pairs. EXPERIMENTAL APPROACH: We used a broad panel of chemokine variants and modified peptides derived from the N-terminal region of chemokines CXCL12, CXCL11 and vCCL2, to compare the contributions of various features to binding and activation of their shared receptors, the two typical, canonical G protein-signalling receptors, CXCR4 and CXCR3, as well as the atypical scavenger receptor CXCR7/ACKR3, which shows exclusively arrestin-dependent activity. KEY RESULTS: We provide molecular insights into the plasticity of the ligand-binding pockets of these receptors, their chemokine binding modes and their activation mechanisms. Although the chemokine N-terminal region is a critical determinant, neither the most proximal residues nor the N-loop are essential for binding and activation of ACKR3, as distinct from binding and activation of CXCR4 and CXCR3. CONCLUSION AND IMPLICATIONS: These results suggest a different interaction mechanism between this atypical receptor and its ligands and illustrate its strong propensity to activation. PMID- 29272552 TI - Echocardiographic parameters predicting acute hemodynamically significant mitral regurgitation during transfemoral transcatheter aortic valve replacement. AB - BACKGROUND: Alteration in mitral valve morphology resulting from retrograde stiff wire entanglement sometimes causes hemodynamically significant acute mitral regurgitation (MR) during transfemoral transcatheter aortic valve replacement (TAVR). Little is known about the echocardiographic parameters related to hemodynamically significant acute MR. METHODS AND RESULTS: This study population consisted of 64 consecutive patients who underwent transfemoral TAVR. We defined hemodynamically significant acute MR as changes in the severity of MR with persistent hypotension (systolic blood pressure < 80-90 mm Hg or mean arterial pressure 30 mm Hg lower than baseline). Hemodynamically significant acute MR occurred in 5 cases (7.8%). Smaller left ventricular end-systolic diameter (LVDs), larger ratios of the coiled section of stiff wire tip to LVDs (wire width/LVDs), and higher Wilkins score were significantly associated with hemodynamically significant acute MR (P < .05), whereas the parameters of functional MR (annular area, anterior-posterior diameter, tenting area, and coaptation length) were not. Moreover, when patients were divided into 4 groups according to wire-width/LVDs and Wilkins score, the group with the larger wire width/LVDs and higher Wilkins score improved prediction rates (P < .05). CONCLUSIONS: Small left ventricle or wire oversizing and calcific mitral apparatus were predictive of hemodynamically significant acute MR. These findings are important for risk stratification, and careful monitoring using intraoperative transesophageal echocardiography may improve the safety in this population. PMID- 29272553 TI - Association of postprocedural aortic regurgitation with mitral regurgitation worsened after transcatheter aortic valve replacement. AB - BACKGROUND: There is a paucity of investigation which demonstrates a predictor of mitral regurgitation (MR) worsened after aortic valve replacement (TAVR). AIM: The aim of this study was to identify the predictor of worsened MR after transcatheter TAVR. METHODS: We retrospectively studied a total of 209 patients with mild or less MR at baseline who underwent TAVR for the treatment of severe aortic stenosis with the balloon-expandable device. We found the presence of MR worsened after TAVR in 6% (12 patients) of all patients. Moderate or more postprocedural aortic regurgitation (AR) (odds ratio, 8.104; 95% confidence interval, 1.78-36.87; P = .007) was identified as a predictor of MR worsening after TAVR. In-hospital outcomes indicated that patients within whom MR worsened suffered congestive heart failure more than those with unchanged or improved MR after TAVR (P < .05). CONCLUSION: Significant postprocedural AR was associated with MR worsened from mild or less to moderate or more after TAVR. Worsened MR might affect in-hospital congestive heart failure. PMID- 29272554 TI - Shone's syndrome: Insights from three-dimensional echocardiography. AB - Shone's syndrome is a rare congenital anomaly defined as the presence of at least two of the following heart obstructions: a mitral supravalvular ring, a "parachute" mitral valve stenosis, subaortic stenosis, and aortic coarctation. A 58-year-old man presented with a mitral ring and a "parachute" mitral valve on two-dimensional transthoracic echocardiography, raising suspicion of Shone's syndrome. Three-dimensional transesophageal echocardiography revealed a subannular mitral ring inserted directly on the mitral leaflets, thus acting as a "valvar ring." This distinction can have therapeutic implications as a "valvar" mitral ring could require valve repair or replacement, instead of simple resection. PMID- 29272555 TI - Left ventricular outflow tract shape after aortic valve replacement with St. Jude Trifecta prosthesis. AB - BACKGROUND: Aortic prosthesis area (EOA) is computed by continuity equation from left ventricular (LV) stroke volume (SV) derived from LV outflow tract diameter (LVOTD ) or, when unmeasurable, from LV volumes (SVV ). There is evidence to suggest LVOT ellipticity and recommend 3D LVOT area (LVOTCSA ) adoption in aortic stenosis. We sought to evaluate if the same concept applies to supra-annular aortic prosthesis comparing SV and EOA derived from LVOTD (EOAD ) and from LVOTCSA (EOACSA ). EOA computed from SVV (EAOV ) accuracy was evaluated in this setting. Patient-prosthesis mismatch (PPM) was compared among different EOA computations. METHODS: A consecutive series of 202 patients (aged 81 +/- 4 years, 43% males) underwent St.Jude Trifecta aortic valve replacement (AVR) and were followed up with echocardiography at one-year (335 +/- 31 days). All measurements followed the EACVI or ASE guidelines, 3D X-plane modality was used to compute SVv and measure LVOTCSA ; SV was calculated from LVOTD (SVD ) and LVOTCSA (SVCSA ). PPM was indexed EOA <0.65 cm2/m2. RESULTS: LVOT showed a significant ellipticity index (1.17 +/- .27), independent of prosthesis size. EOAD (1.70 +/- 0.55 cm2) was less than EOACSA (1.95 +/- 0.62 cm2) (P < .0001). SVV was significantly lower than SVD and SVCSA . Bland-Altman analysis showed a significant correlation between SVV and SVD or SVCSA although with large bias and imprecision. The correlations improved reducing bias and imprecision when LVOT time-velocity integral was <20 cm. PPM incidence was higher in EOAV (15.6%) compared to EOAD (P = .04) or EOACSA (P < .001). CONCLUSIONS: In supra-annular AVR, LVOT retains its elliptical shape and LVOTCSA yielded larger prosthesis EOA with lower PPM incidence. PPM may be overestimated by EOAV . PMID- 29272557 TI - A Golden Access to Acenopentalenes. AB - By employing gold catalysis, starting from dialkynylated acenes a series of novel un-symmetrical aceno-annulated dibenzopentalenes has been prepared. The achieved yields range from 62-68 %. The fused systems contain naphthalene, anthracene, tetracene, and pentacene units. All new compounds are soluble and stable under standard conditions. The optical properties of the systems are dominated by the dibenzopentalene core for the smaller representatives, while for the anthracene pentacene-based aceno-benzopentalenes the optical properties of the acene group dominates. Preliminary morphology tests on thin films showed a reverse trend between crystal size and molecule size. PMID- 29272556 TI - Characterization of adherence and persistence profile in a real-life population of patients treated with adalimumab. AB - AIMS: Published data on long-term adherence and persistence with adalimumab (Humira(r) ) in clinical practice are scarce and often limited to selected patient populations. This study assessed adherence with adalimumab across different indications and identified correlates and outcomes of poor adherence. METHODS: We analysed data originating from the electronic database of Maccabi Healthcare Services (MHS) that includes 2.1 million enrolees. We randomly selected patients with at least one dispense of adalimumab since it was included in the local health basket in Israel in 2008 until the end of 2013. Patients with the following indications (n = 1339) were included: Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriatic arthritis (PSA), ankylosing spondylitis (AS) and psoriasis. Adherence with therapy was assessed by the medication possession ratio (MPR) during the follow-up period. RESULTS: Good adherence (MPR >= 80%) was observed among 80% of study patients and was associated with lower risk for >=1 hospitalization per year of follow-up (adjusted-OR = 1.94, 95% CI:1.15-3.28). Patients with AS and CD persisted on adalimumab therapy the most, reaching median use of 27.0 and 26.7 months, respectively. Half (52.4%) of the patients discontinued treatment during a mean (SD) follow-up of 3.07 (1.71) years. High socioeconomic status was associated with lower risk for discontinuation (adjusted-HR = 0.74; 0.60-0.91). UC and concomitant prednisolone use were associated with increased risk for treatment discontinuation (HR = 1.31; 1.00-1.72, and HR = 1.40; 1.17-1.68, respectively). CONCLUSION: Our results indicate encouraging persistence and adherence with adalimumab of patients with inflammatory conditions. PMID- 29272558 TI - Accuracy and Repeatability of Trajectory Rod Measurement Using Laser Scanners. AB - Three-dimensional (3D) technologies contribute greatly to bullet trajectory analysis and shooting reconstruction. There are few papers which address the errors associated with utilizing laser scanning for bullet trajectory documentation. This study examined the accuracy and precision of laser scanning for documenting trajectory rods in drywall for angles between 25 degrees and 90 degrees . The inherent error range of 0.02 degrees -2.10 degrees was noted while the overall error for laser scanning ranged between 0.04 degrees and 1.98 degrees . The inter- and intraobserver errors for trajectory rod placement and virtual trajectory marking showed that the range of variation for rod placement was between 0.1 degrees -1 degrees in drywall and 0.05 degrees -0.5 degrees in plywood. Virtual trajectory marking accuracy tests showed that 75% of data values were below 0.91 degrees and 0.61 degrees on azimuth and vertical angles, respectively. In conclusion, many contributing factors affect bullet trajectory analysis, and the use of 3D technologies can aid in reduction of errors associated with documentation. PMID- 29272559 TI - Accuracy and Reliability of Total Body Mass Estimation Techniques from Stature and Bi-iliac Breadth in Non-Hispanic U.S. Whites from the Bass Donated Skeletal Collection. AB - This paper tests the fidelity of a recent method that used the NHANES III dataset as a proxy to estimate total body mass from stature and bi-iliac breadth in U.S. White males and females. The bi-iliac breadths of 230 males and 152 females identified as non-Hispanic U.S. White from the Bass Donated Skeletal Collection were measured, and along with stature from predonor paperwork, total body mass estimates were calculated and then compared to body masses recorded on predonor paperwork. Male and female samples were subdivided by body mass index (BMI [kg/m2 ]) categories established by the World Health Organization. Our results suggest that total body mass estimates can be accurately assessed provided that the individual is within 18.50 <= BMI <= 29.99 for White males and 18.50 <= BMI <= 24.99 for White females. Recommendations on how to report total body mass estimates are also presented. PMID- 29272561 TI - Variability of left ventricular volume and ejection fraction measurements using contrast echocardiography: The influence of the left ventricular length measurements in a large cohort of patients during monitoring cardiotoxic effects of chemotherapy. AB - OBJECTIVE: To investigate the influence of length difference in left ventricular (LV) long axis between the apical four-chamber and two-chamber views on measurements of LV volumes and ejection fraction (EF). METHODS: Seven hundred consecutive cancer patients underwent contrast echocardiography from July 2010 to May 2014. All patients received the echocardiographic contrast agent Definity. Recordings of apical views were analyzed by a sonographer and then by a cardiologist. The end-diastolic and end-systolic LV volumes (EDV and ESV), and LV lengths as well as EF, were measured using the biplane Simpson's method. Inter observer variability was assessed using relative mean error (RME) and Bland Altman analysis. RESULTS: Six hundred ninety-two patients had contrast echocardiograms with complete endocardial definition. The LV length difference of the long axis measured by the cardiologist was <=1 mm in 284 studies (41%), 2 mm in 146 studies (21%), 3 mm in 103 studies (15%), and >=4 mm in 159 studies (23%). The limits of agreement (LOA) and RME increase with the increasing length difference. Compared to the groups with length difference <4 mm, the RME of the measurements of indexed EDV, indexed ESV, and EF was significantly greater in the group with length difference >=4 mm (P < .05). CONCLUSION: These results highlight the need for reviewing the LV long axis length measurements in order to provide reproducible LV volumes and EF measurements and may be used as benchmarks for quality control. A length difference of <=3 mm can be achieved in most of our patients and is associated with an excellent inter-observer agreement. PMID- 29272560 TI - Evaluation of beta-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure. AB - beta-Amino acids have a backbone that is expanded by one carbon atom relative to alpha-amino acids, and beta residues have been investigated as subunits in protein-like molecules that adopt discrete and predictable conformations. Two classes of beta residue have been widely explored in the context of generating alpha-helix-like conformations: beta3 -amino acids, which are homologous to alpha amino acids and bear a side chain on the backbone carbon adjacent to nitrogen, and residues constrained by a five-membered ring, such the one derived from trans 2-aminocyclopentanecarboxylic acid (ACPC). Substitution of alpha residues with their beta3 homologues within an alpha-helix-forming sequence generally causes a decrease in conformational stability. Use of a ring-constrained beta residue, however, can offset the destabilizing effect of alpha->beta substitution. Here we extend the study of alpha->beta substitutions, involving both beta3 and ACPC residues, to short loops within a small tertiary motif. We start from previously reported variants of the Pin1 WW domain that contain a two-, three-, or four residue beta-hairpin loop, and we evaluate alpha->beta replacements at each loop position for each variant. By referral to the phi,psi angles of the native structure, one can choose a stereochemically appropriate ACPC residue. Use of such logically chosen ACPC residues enhances conformational stability in several cases. Crystal structures of three beta-containing Pin1 WW domain variants show that a native-like tertiary structure is maintained in each case. PMID- 29272562 TI - Gram-Scale Synthesis and Highly Regioselective Bromination of 1,1,9,9 Tetramethyl[9](2,11)teropyrenophane. AB - An improved synthetic pathway to the nanobelt-like 1,1,9,9 tetramethyl[9](2,11)teropyrenophane has been developed, and enables the synthesis of gram quantities of material. Key innovations are the development of a sequential chlorination/Friedel-Crafts alkylation reaction, a sequential iodination/Wurtz coupling reaction, and a room-temperature teropyrene-forming reaction. The teropyrenophane was found to form a very stable radical cation and undergo a completely regioselective fourfold bromination reaction. PMID- 29272563 TI - A comparison between Philips and Tomtec for left ventricular deformation and volume measurements in neonatal intensive care patients. AB - BACKGROUND: Two-dimensional speckle tracking echocardiography is an emerging technique for analyzing cardiac function in newborns. Strain is a highly reliable and reproducible parameter, and reference values have been established for term and preterm newborns. Its implementation into clinical practice has been slow, partly due to lack of inter-vendor consistency. Our aim was to compare recent versions of Philips and Tomtec speckle tracking software for deformation and semiautomated volume and area measurements in neonatal intensive care patients. METHODS AND RESULTS: Longitudinal and circumferential deformation and cavity dimensions (volume, area) were determined off line from apical and short-axis images in 50 consecutive newborns with a median birthweight of 760 g (range 460 3200 g). Absolute mean endocardial global longitudinal strain measurements were similar between vendors, but with wide limits of agreement (Philips -18.9 [2.1]%, Tomtec -18.6 [2.5]%, bias -0.3 [1.7]%, and limits of agreement -3.6%-3.1%). Longitudinal strain rate and circumferential measurements showed poor correlation. All volume and area measurements correlated well between the vendors, but with significant bias. CONCLUSION: Global longitudinal strain measurements compared well between vendors but wide limits of agreement, suggesting that longitudinal measurements are preferred using similar hardware and software. PMID- 29272564 TI - Mechanisms of Action and Clinical Development of Elotuzumab. PMID- 29272565 TI - A compartment-quasi-3D multiscale approach for drug absorption, transport, and retention in the human lungs. AB - Most current models used for modeling the pulmonary drug absorption, transport, and retention are 0D compartmental models where the airways are generally split into the airways and alveolar sections. Such block models deliver low fidelity solutions and the spatial lung drug concentrations cannot be obtained. Other approaches use high fidelity CFD models with limited capabilities due to their exorbitant computational cost. Recently, we presented a novel, fast-running and robust quasi-3D (Q3D) model for modeling the pulmonary airflow. This Q3D method preserved the 3D lung geometry, delivered extremely accurate solutions, and was 25 000 times faster in comparison to the CFD methods. In this paper, we present a Q3D-compartment multiscale combination to model the pulmonary drug absorption, transport, and retention. The initial deposition is obtained from CFD simulations. The lung absorption compartment model of Yu and Rosania is adapted to this multiscale format. The lung is modeled in the Q3D format till the eighth airway generation. The remainder of the lung along with the systemic circulation and elimination processes was modeled using compartments. The Q3D model is further adapted, by allowing for various heterogeneous annular lung layers. This allows us to model the drug transport across the layers and along the lung. Using this multiscale model, the spatiotemporal drug concentrations in the different lung layers and the temporal concentration in the plasma are obtained. The concentration profile in the plasma was found to be better aligned with the experimental findings in comparison with compartmental model for the standard test cases. Thus, this multiscale model can be used to optimize the target specific drug delivery and increase the localized bioavailability, thereby facilitating applications from the bench to bedside for various patient/lung disease variations. PMID- 29272566 TI - High ferritin levels are not only but mostly because of liver specific injury. PMID- 29272567 TI - Telomere, telomerase and liver disease. PMID- 29272568 TI - Response to Portal vein thrombosis after hepatitis C eradication with direct acting antiviral therapy. PMID- 29272569 TI - Intestinal failure-associated liver disease: Risks and regression. PMID- 29272570 TI - Response to Intermediate stage treatment: Is TACE enough? PMID- 29272571 TI - Guns and Suicide: Are They Related? AB - Shooting oneself with a firearm is the leading method of suicide, accounting for over half of all such deaths. About two-thirds of the annual 33,000 gun-related fatalities in the United States are suicide-nearly 60 every day. Although most suicidal impulses are intense, they usually last for a short time, which makes prompt intervention imperative. Approximately 90% of those who attempt suicide and survive do not later die by suicide. However, attempts with a gun are usually fatal. A clear connection between firearms in the home and an increased risk of suicide exists. People who have access to these weapons are more likely to commit suicide than those who live in a home without a gun; thus, limiting access to guns decreases the opportunity for self-harm. Physicians should recommend that firearm access be removed from individuals with depression, suicidal ideations, drug abuse, impulsivity, or a mental or neurologic illness. PMID- 29272572 TI - Managing Manic Delirium in Bipolar Disorder With Features of Mania, Catatonia, and Neuroleptic Malignant Syndrome. PMID- 29272573 TI - Multifunctional Bi@PPy-PEG Core-Shell Nanohybrids for Dual-Modal Imaging and Photothermal Therapy. AB - High-performance theranostic nanoagents, which integrate multimodal imaging and photothermal therapy for clinical anticancer treatment, are highly desired. Herein, we report the synthesis and bioapplication of a multifunctional theranostic nanoagent based on polyethylene glycol (PEG)-modified polypyrrole (PPy)-coated bismuth (Bi) nanohybrids (referred to as Bi@PPy-PEG NHs) for X-ray computed tomography/photoacoustic (CT/PA) dual-modal imaging and photothermal therapy (PTT). The obtained Bi@PPy-PEG NHs have a distinct core-shell structure with the metallic Bi nanoparticle as the inner core and the PPy-PEG layer as the shell. The Bi@PPy-PEG NHs show excellent physiological stability and compatibility, without noticeable cytotoxicity. Importantly, the NHs exhibit strong NIR absorbance and remarkable photothermal conversion capability and conversion stability, with the photothermal conversion efficiency as high as ~46.3%. Thanks to the strong PTT effect, highly effective photothermal ablation on cancer cells has been achieved both in vitro and in vivo. Furthermore, a high contrast in vitro and in vivo CT/PA dual-modal imaging has been realized, showing great potential to provide comprehensive diagnosis information for antitumor treatment. In particular, the CT enhancement efficiency of the NHs is of ~14.4 HU mM-1, which is ~3.7-fold that of clinically used iohexol. Therefore, our work highlights the potential of using such core-shell Bi@PPy-PEG NHs as a versatile theranostic nanoplatform for cancer imaging and therapy. PMID- 29272574 TI - Unprecedented Reaction Mode of Phosphorus in Phosphinidene Rare-Earth Complexes: A Joint Experimental-Theoretical Study. AB - Reactions of trinuclear rare-earth metal complexes bearing functionalized phosphinidene ligand [L3Ln3(MU2-Me)2(MU3-Me)(MU3-eta1:eta2:eta2-PC6H4-o)] (L = [PhC(NC6H4iPr2-2,6)2]-, Ln = Y (1a), Lu (1b)) with phenylacetylene, CO2, diisopropyl carbodiimide, isocyanide, or PhSSPh lead to the formation of a series of phosphorus-containing products. The reaction of 1 with CS2 yields two novel P methyl-phosphindole-2,3-dithiolate dianion complexes, revealing an unusual tandem desulfurization/coupling/cyclization reaction mode of CS2. A possible reaction pathway was determined by density functional theory calculations. This emphasizes the key role of the reduction power of the formal P2- part of the phosphinidene in the C-S bond cleavage. PMID- 29272575 TI - Achieving Superprotonic Conduction in Metal-Organic Frameworks through Iterative Design Advances. AB - Two complementary design strategies, isomorphous ligand replacement and heterocycle doping, have been applied to iteratively enhance the proton conductivity of a metal-organic framework, beta-PCMOF2. The resulting materials, PCMOF21/2(Pz) and PCMOF21/2(Tz) (Pz = 1H-pyrazole, Tz = 1H-1,2,4-triazole), have their proton conduction raised almost 2 orders of magnitude compared to beta PCMOF2. The bulk conductivities of these materials are over 10-1 S cm-1 at 85 degrees C and 90% relative humidity (RH), while maintaining the parent MOF structure. A solid state synthetic route for doping 1-D channels is also presented. PMID- 29272576 TI - Kinetic Monte Carlo Study of Li Intercalation in LiFePO4. AB - Even as a commercial cathode material, LiFePO4 remains of tremendous research interest for understanding Li intercalation dynamics. The partially lithiated material spontaneously separates into Li-poor and Li-rich phases at equilibrium. Phase segregation is a surprising property of LiFePO4 given its high measured rate capability. Previous theoretical studies, aiming to describe Li intercalation in LiFePO4, include both atomic-scale density functional theory (DFT) calculations of static Li distributions and entire-particle-scale phase field models, based upon empirical parameters, studying the dynamics of the phase separation. Little effort has been made to bridge the gap between these two scales. In this work, DFT calculations are used to fit a cluster expansion for the basis of kinetic Monte Carlo calculations, which enables long time scale simulations with accurate atomic interactions. This atomistic model shows how the phases evolve in LixFePO4 without parameters from experiments. Our simulations reveal that an ordered Li0.5FePO4 phase with alternating Li-rich and Li-poor planes along the ac direction forms between the LiFePO4 and FePO4 phases, which is consistent with recent X-ray diffraction experiments showing peaks associated with an intermediate-Li phase. The calculations also help to explain a recent puzzling experiment showing that LiFePO4 particles with high aspect ratios that are narrower along the [100] direction, perpendicular to the [010] Li diffusion channels, actually have better rate capabilities. Our calculations show that lateral surfaces parallel to the Li diffusion channels, as well as other preexisting sites that bind Li weakly, are important for phase nucleation and rapid cycling performance. PMID- 29272577 TI - Copper Loading of Preformed Nanoparticles for PET-Imaging Applications. AB - Nanoparticles (NP) are promising contrast agents for positron emission tomography (PET) radionuclide imaging that can increase signal intensity by localizing clusters of PET radionuclides together. However, methods to load NPs with PET radionuclides suffer from harsh loading conditions or poor loading efficacies or result in NP surface modifications that alter targeting in vivo. We present the formation of water-dispersible, polyethylene glycol coated NPs that encapsulate phthalocyanines into NP cores at greater than 50 wt % loading, using the self assembly technique Flash NanoPrecipitation. Particles from 70 to 160 nm are produced. Phthalocyanine NPs rapidly and spontaneously chelate metals under mild conditions and can act as sinks for PET radionuclides such as 64-Cu to produce PET-active NPs. NPs chelate copper(II) with characteristic rates of 1845 M-1 h-1 at pH 6 and 37 degrees C, which produced >90% radionuclide chelation within 1 h. NP physical properties, such as core composition, core fluidity, and size, can be tuned to modulate chelation kinetics. These NPs retain 64Cu even in the presence of the strong chelator ethylene diamine tetraacetic acid. The development of these constructs for rapid and facile radionuclide labeling expands the applications of NP-based PET imaging. PMID- 29272578 TI - Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa. AB - The opportunistic Gram-negative bacterium Pseudomonas aeruginosa is a leading pathogen for infections of immuno-compromised patients and those suffering from cystic fibrosis. Its ability to switch from planktonic life to aggregates, forming the so-called biofilms, is a front-line mechanism of antimicrobial resistance. The bacterial carbohydrate-binding protein LecB is an integral component and necessary for biofilm formation. Here, we report a new class of drug-like low molecular weight inhibitors of the lectin LecB with nanomolar affinities and excellent receptor binding kinetics and thermodynamics. This class of glycomimetic inhibitors efficiently blocked biofilm formation of P. aeruginosa in vitro while the natural monovalent carbohydrate ligands failed. Furthermore, excellent selectivity and pharmacokinetic properties were achieved. Notably, two compounds showed good oral bioavailability, and high compound concentrations in plasma and urine were achieved in vivo. PMID- 29272579 TI - Adsorbate-Induced Modification of the Confining Barriers in a Quantum Box Array. AB - Quantum devices depend on addressable elements, which can be modified separately and in their mutual interaction. Self-assembly at surfaces, for example, formation of a porous (metal-) organic network, provides an ideal way to manufacture arrays of identical quantum boxes, arising in this case from the confinement of the electronic (Shockley) surface state within the pores. We show that the electronic quantum box state as well as the interbox coupling can be modified locally to a varying extent by a selective choice of adsorbates, here C60, interacting with the barrier. In view of the wealth of differently acting adsorbates, this approach allows for engineering quantum states in on-surface network architectures. PMID- 29272580 TI - Surfactant-Enhanced Photoisomerization and Photomechanical Response in Molecular Crystal Nanowires. AB - Dimethyl-2(3-anthracen-9-yl)allylidene)malonate (DMAAM) is a divinylanthracene derivative that photoisomerizes between its (E) and (Z) conformations. Crystalline nanowires composed of this molecule undergo a rapid coiling motion when exposed to visible light. In this paper, a variety of experimental techniques are used to investigate the mechanism of this transformation, including powder X-ray diffraction, polarized light microscopy, 1H NMR, and absorption spectroscopy. The results show that the presence of a surfactant like cetyltrimethylammonium bromide (CTAB) accelerates the photochemical reaction rate by at least a factor of 10 within the nanowire and is required to observe the photoinduced coiling. The accelerated reaction facilitates the transition to an amorphous phase composed of reactant and photoproduct, which leads to the rapid, large-scale shape changes that the nanowires undergo. Disruption of the highly packed crystal structure by photoisomerization also enhances the dissolution rate by a factor of about 30. The fact that the nanowires have a nominal diameter of 200 nm suggests that the presence of surface species can influence the reaction dynamics deep inside the crystal. These results show that the reaction dynamics and photomechanical motions of nanoscale molecular crystals can be extremely sensitive to surface species. PMID- 29272581 TI - Nucleation of Molecular Crystals Driven by Relative Information Entropy. AB - Simulating nucleation of molecular crystals is extremely challenging for all but the simplest cases. The challenge lies in formulating effective order parameters that are capable of driving the transition process. In recent years, order parameters based on molecular pair-functions have been successfully used in combination with enhanced sampling techniques to simulate nucleation of simple molecular crystals. However, despite the success of these approaches, we demonstrate that they can fail when applied to more complex cases. In fact, we show that order parameters based on molecular pair-functions, while successful at nucleating benzene, fail for paracetamol. Hence, we introduce a novel approach to formulate order parameters. In our approach, we construct reduced dimensional distributions of relevant quantities on the fly and then quantify the difference between these distributions and selected reference distributions. By computing the distribution of different quantities and by choosing different reference distributions, it is possible to systematically construct an effective set of order parameters. We then show that our new order parameters are capable of driving the nucleation of ordered states and, in particular, the form I crystal of paracetamol. PMID- 29272582 TI - Capillary Isoelectric Focusing-Mass Spectrometry Method for the Separation and Online Characterization of Intact Monoclonal Antibody Charge Variants. AB - We report a new online capillary isoelectric focusing-mass spectrometry (CIEF-MS) method for monoclonal antibody (mAb) charge variant analysis using an electrokinetically pumped sheath-flow nanospray ion source and a time-of-flight MS with pressure-assisted chemical mobilization. To develop a successful, reliable CIEF-MS method for mAb, we have selected and optimized many critical, interrelating reagents and parameters that include (1) MS-friendly anolyte and catholyte; (2) a glycerol enhanced sample mixture that reduced non-CIEF electrophoretic mobility and band broadening; (3) ampholyte selected for balancing resolution and MS sensitivity; (4) sheath liquid composition optimized for efficient focusing, mobilization, and electrospray ionization; (5) judiciously selected CIEF running parameters including injection amount, field strength, and applied pressure. The fundamental premise of CIEF was well maintained as verified by the linear correlation (R2 = 0.99) between pI values and migration time using a mixture of pI markers. In addition, the charge variant profiles of trastuzumab, bevacizumab, infliximab, and cetuximab, obtained using this CIEF-MS method, were corroborated by imaged CIEF-UV (iCIEF-UV) analyses. The relative standard deviations (RSD) of absolute migration time of pI markers were all less than 5% (n = 4). Triplicate analyses of bevacizumab showed RSD less than 1% for relative migration time to an internal standard and RSD of 7% for absolute MS peak area. Moreover, the antibody charge variants were characterized using the online intact MS data. To the best of our knowledge, this is the first time that direct online MS detection and characterization were achieved for mAb charge variants resolved by CIEF as indicated by a well-established linear pH gradient and correlated CIEF-UV charge variant profiles. PMID- 29272583 TI - A Transient Vinylphosphinidene via a Phosphirene-Phosphinidene Rearrangement. AB - A room-temperature-stable crystalline 2H-phosphirene (1) was prepared by treatment of an electrophilic diamidocarbene with tert-butylphosphaalkyne. Compound 1 is shown to react as a vinylphosphinidene generated via phosphirene phosphinidene rearrangement. Thermolysis is shown to affect C-N bond scission while reactions with C6Cl4O2 or (tht)AuCl afford formal oxidation of the phosphindene center and the phosphinidene-insertion into an aromatic C-C bond of a mesityl group, respectively. The latter reaction is the first example of a phosphorus analog of the Buchner ring expansion reaction. PMID- 29272585 TI - Influence of Poly(styrene- co-maleic acid) Copolymer Structure on the Properties and Self-Assembly of SMALP Nanodiscs. AB - Polymer stabilized nanodiscs are self-assembled structures composed of a polymer belt that wraps around a segment of lipid bilayer, and as such are capable of encapsulating membrane proteins directly from the cell membrane. To date, most studies on these nanodiscs have used poly(styrene- co-maleic acid) (SMA) with the term SMA-lipid particles (SMALPs) coined to describe them. In this study, we have determined the physical and thermodynamic properties of such nanodiscs made with two different SMA copolymers. These include a widely used and commercially available statistical poly(styrene- co-maleic acid) copolymer (coSMA) and a reversible addition-fragmentation chain transfer synthesized copolymer with narrow molecular weight distribution and alternating styrene and maleic acid groups with a polystyrene tail, (altSMA). We define phase diagrams for each polymer, and show that, regardless of polymer topological structure, self assembly is driven by the free energy change associated with the polymers. We also show that nanodisc size is polymer dependent, but can be modified by varying polymer concentration. The thermal stability of each nanodisc type is similar, and both can effectively solubilize proteins from the E. coli membrane. These data show the potential for the development of different SMA polymers with controllable properties to produce nanodiscs that can be optimized for specific applications and will enable more optimized and widespread use of the SMA-based nanodiscs in membrane protein research. PMID- 29272584 TI - Endohedral Metallofullerene as Molecular High Spin Qubit: Diverse Rabi Cycles in Gd2@C79N. AB - An anisotropic high-spin qubit with long coherence time could scale the quantum system up. It has been proposed that Grover's algorithm can be implemented in such systems. Dimetallic aza[80]fullerenes M2@C79N (M = Y or Gd) possess an unpaired electron located between two metal ions, offering an opportunity to manipulate spin(s) protected in the cage for quantum information processing. Herein, we report the crystallographic determination of Gd2@C79N for the first time. This molecular magnet with a collective high-spin ground state (S = 15/2) generated by strong magnetic coupling (JGd-Rad = 350 +/- 20 cm-1) has been unambiguously validated by magnetic susceptibility experiments. Gd2@C79N has quantum coherence and diverse Rabi cycles, allowing arbitrary superposition state manipulation between each adjacent level. The phase memory time reaches 5 MUs at 5 K by dynamic decoupling. This molecule fulfills the requirements of Grover's searching algorithm proposed by Leuenberger and Loss. PMID- 29272586 TI - Calculation of Diffusion Coefficients through Coarse-Grained Simulations Using the Automated-Fragmentation-Parametrization Method and the Recovery of Wilke Chang Statistical Correlation. AB - : We introduce a model for the calculation of diffusion coefficients using dissipative particle dynamics coarse-grained molecular simulations. We validate the model on experimental diffusion data of small organics and drug-like molecules in water. The new model relies on our automated-fragmentation parametrization protocol for cutting molecules into fragments, which are calibrated using the COSMO-RS thermodynamic model ( J. Chem. Inf. MODEL: 2016 , 56 ( 12 ), 2361 - 2377 , DOI: 10.1021/acs.jcim.6b00003 ). By simulations over the entire CULGI database of more than 11000 molecules, we recover the decades-old empirical Wilke-Chang correlation between diffusion coefficient and molar volume. We believe this is the first demonstration of the correlation by simulation or theory. From a comparison of simulated and experimental diffusion coefficients, we find that one full time unit of coarse-grained simulation equals 64 +/- 13 ps real time. PMID- 29272587 TI - Measuring and Manipulating the Adhesion of Graphene. AB - We present a technique to precisely measure the surface energies between two dimensional materials and substrates that is simple to implement and allows exploration of spatial and chemical control of adhesion at the nanoscale. As an example, we characterize the delamination of single-layer graphene from monolayers of pyrene tethered to glass in water and maximize the work of separation between these surfaces by varying the density of pyrene groups in the monolayer. Control of this energy scale enables high-fidelity graphene-transfer protocols that can resist failure under sonication. Additionally, we find that the work required for graphene peeling and readhesion exhibits a dramatic rate independent hysteresis, differing by a factor of 100. This work establishes a rational means to control the adhesion of 2D materials and enables a systematic approach to engineer stimuli-responsive adhesives and mechanical technologies at the nanoscale. PMID- 29272588 TI - Formation of Concentric Silica Nanogrooves Guided by the Curved Surface of Silica Particles. AB - The flexible control of nanopatterns by a bottom-up process at the nanometer scale is essential for nanofabrication with a finer pitch. We have previously reported that for the fabrication of linear nanopatterns with sub-5 nm periodicity on Si substrates the outermost surfaces of assembled micelles facing the substrates can be replicated with soluble silicate species generated from the Si substrates under basic conditions. In this study, concentrically arranged nanogrooves with a sub-5 nm periodicity were prepared on Si substrates by replicating the outermost surfaces of bent micelles guided by silica particles. The Si substrates, where silica particles and surfactants films were deposited, were exposed to an NH3-water vapor mixture. During the vapor treatment, cylindrical micelles became arranged in concentric patterns centered on the silica particles, and their outermost surfaces facing the substrates were replicated by soluble silicate species on the Si substrates. The thinness of the surfactant film on the substrate is crucial for the formation of concentric silica nanogrooves because the out-of-plane orientations of the micelles are suppressed at the interface. Surprisingly, the domains of the concentric silica nanogrooves spread to much larger areas than the maximum cross-sectional areas of the particles, and the size of the domains increased linearly with the radii of the particles. The extension of concentric nanogrooves is discussed on the basis of the orientational elastic energies of the micelles around one silica particle. This study of the formation of bent nanogrooves guided by the outlines of readily deposited nanoscale objects provides a new nanostructure-guiding process. PMID- 29272589 TI - Mitigation of Azathioprine-induced Testicular Atrophy by Taurine; An Impact on Inflammation, Oxidative Perturbations and Apoptosis. PMID- 29272590 TI - Amphetamine Derivatives and the Risk of Pulmonary Arterial Hypertension: A Missing Chapter of the Story? PMID- 29272592 TI - Breaking a Fall Can Get Complicated. PMID- 29272591 TI - Reply to Frachon: Amphetamine Derivatives and the Risk of Pulmonary Arterial Hypertension: A Missing Chapter of the Story? PMID- 29272594 TI - QuikQuiz. PMID- 29272593 TI - Growing Older and (Eating) Smarter. PMID- 29272597 TI - Scanning Sports. PMID- 29272595 TI - Pearls. PMID- 29272599 TI - Recovering From Ankle Sprains. PMID- 29272600 TI - Frustrated by Chronic Fatigue? AB - In brief When active patients relate brief chronic fatigue, three basic questions must be answered: Is there an underlying medical or psychiatric disorder? Could the fatigue be from overtraining or a sleep disturbance? Does the patient have chronic fatigue syndrome or the far more common idiopathic chronic fatigue? Answers may come from sensitive history-taking and targeted physical and laboratory exams. And the patient must play an active role in treatment, which includes reassurance, stress relief, and regular exercise. PMID- 29272598 TI - Forum. PMID- 29272601 TI - Elbow Dislocations. AB - In brief Clinically, diagnosing elbow dis-brief location is not difficult, although a supracondylar fracture of the humerus can mimic an elbow dislocation in a young patient. Fractures are common with elbow dislocations; neurovascular injury is uncommon but potentially disastrous if unrecognized. A careful neurovascular examination, therefore, is imperative both before and after reduction. Most dislocations can be treated nonoperatively with emphasis on early motion during rehabilitation. PMID- 29272603 TI - Paragliding Injuries. AB - In brief This review of 12 paragliding accidents in the Aspen, Colorado, area over a nearly 2-year period identifies causative factors and common mechanisms of injury and assesses the nature and severity of the injuries. Pilot error in judgment was the most frequent cause of accident. Lower-extremity and spinal compression fractures are common during forceful landings. Free-fall accidents, however, typically cause more serious pelvic, chest, and abdominal trauma. PMID- 29272602 TI - A Routine Stress Test? PMID- 29272605 TI - Getting Off the Couch-and Staying Off. PMID- 29272604 TI - When to Eat. AB - For some active patients, when they eat can seem just as important as what they eat. Whether to boost a workout, or to aid in weight loss, eating at specific times can make a difference. PMID- 29272606 TI - Postprandial walking reduces glucose levels in women with gestational diabetes mellitus. AB - The purpose of this study was to investigate blood glucose changes, as measured by a continuous glucose monitoring system, that occur in women with gestational diabetes mellitus (GDM) following an acute bout of moderate-intensity walking after consuming a high-carbohydrate/low-fat meal. This study found that moderate intensity walking induced greater postprandial glucose control compared with sedentary activity and it appears that moderate-intensity activity may be used to reduce postprandial glucose levels in women with GDM. PMID- 29272608 TI - Detecting and Treating Common Foot and Ankle Fractures. AB - In brief Some of the most common and potentially serious ankle and hindfoot fractures seen in a primary care sports medicine practice are fractures of the tibial plafond, malleolus, calcaneus, and talus (including osteochondral lesions). Making a careful physical exam to detect for sites of tenderness and ordering the appropriate diagnostic images-usually plain films-are important in pinpointing the diagnosis, but some injuries, like Maisonneuve fractures, can be difficult to detect. Certain injuries, like many fractures of the lateral process of the talus, can be managed conservatively with casting, but severe or displaced fractures usually require surgery. Rehabilitation typically focuses on rest and proper strengthening and stretching exercises. PMID- 29272609 TI - Contraindications to Athletic Participation. AB - In brief Physicians perform a delicate balancing act when they weigh a patient's medical condition against the safety of sports participation. This article, the second of a two-part series on contraindications to activity, examines the sensory, spinal, gastrointestinal, systemic, hematologic, and dermatologie conditions that warrant activity disqualification and provides guidelines about when it's safe to participate. Also discussed are activity considerations for patients who have lost a paired organ. PMID- 29272607 TI - Aggressive Acne Treatment. AB - In brief Too often acne treatment focuses on diminishing lesions without considering what an active patient really wants: completely clear skin. In addition to benzoyl peroxide cleansing and topical acne medication, a three-tier approach of oral agents often achieves clear skin regardless of the severity of acne. Tetracycline is the first line of treatment, followed by minocycline if the first drug is not effective. If these two antibiotics fail to clear the acne, isotretinoin can be highly effective-but patients need to know that the drug produces birth defects in almost all women who take the drug while pregnant. PMID- 29272610 TI - A Swollen, Painful Elbow. PMID- 29272612 TI - Pearls. PMID- 29272614 TI - In High Spirits? PMID- 29272613 TI - Cross-Training. PMID- 29272617 TI - Cme Self Test. PMID- 29272616 TI - Congratulations to the Unsung Olympic Heroes. PMID- 29272618 TI - Are You Practicing Cost-Effective Medicine? PMID- 29272620 TI - Top Contenders. PMID- 29272619 TI - Sex After a Heart Attack. AB - Many patients are afraid to resume sexual activity after a heart attack. Physicians can reassure them that the physical demands of sexual activity are no greater than those of many everyday activities. Although some prescribed drugs may affect sexual response, the major negative effect on sex drive and function among these patients is often psychological rather than physical. PMID- 29272621 TI - Safe Stretches for Your Inner Thighs. PMID- 29272622 TI - When the Dog Bites. AB - In brief The physician treating an active brief Patient's dog bite injury faces some controversial treatment decisions: Should the wound be sutured? Is tetanus or rabies immunization indicated? Are prophylactic antibiotics appropriate? PMID- 29272623 TI - Helping Incontinent Patients Resume Activity. AB - In brief Urinary incontinence requires prompt attention when it impairs a patient's activity level. Sometimes the patient's activities are a contributing factor. Helping patients participate with confidence is the goal of treatment. Mild stress or urge incontinence can often be treated empirically or conservatively. Methods include bladder training, pelvic muscle exercises, and medication. The next level includes a more extensive workup or, perhaps, surgery. PMID- 29272624 TI - Scanning Sports. PMID- 29272626 TI - QuikQuiz. PMID- 29272625 TI - Forum. PMID- 29272628 TI - Inadequate Recovery From Vigorous Exercise. AB - In brief Exercise-related fatigue is not brief confined to elite athletes. Frequent exercisers often experience chronic fatigue, overuse injuries, recurrent infections, and decreased motivation or performance- symptoms traditionally described as "overtraining syndrome." For this large population of active people who often do not perceive their exercise as training, patient education with emphasis on rest and recovery is essential to successful management. PMID- 29272629 TI - Pearls. PMID- 29272630 TI - Diagnosing Meniscus Injuries. AB - In brief Meniscus injuries, common brief amon9 active patients, can often JMJ be diagnosed through a careful office examination. If findings include a typical history and joint-line tenderness, more expensive imaging procedures can be avoided. Although conservative treatment can be effective if the injury is not extensive, surgery is frequently necessary. PMID- 29272633 TI - Walking Off Healthcare Costs. PMID- 29272632 TI - Syndrome X. AB - Glucose intolerance, hypertriglyceridemia, hypertension, and non-insulin dependent diabetes mellitus are part of a cluster of disorders referred to as syndrome X. Exercise helps control and mitigate the effects of several of these related diseases, making it one of the most effective treatment methods. It can also play a role in prevention. PMID- 29272631 TI - Effect of P2 receptor blockade on cutaneous vasodilation during rest and exercise in the heat in young men. AB - We assessed the role of purinergic P2 receptors in the regulation of cutaneous vasodilation in young adults at rest and during intermittent moderate-intensity exercise in the heat (35 degrees C). P2 receptor blockade augmented resting cutaneous vasodilation but had no influence during and following exercise. This increase was partly diminished by nitric oxide synthase inhibition. These results suggest a functional role of P2 receptors in the regulation of cutaneous vascular tone during ambient heat exposure at rest. PMID- 29272634 TI - Exercise Adviser. PMID- 29272635 TI - Assessing Core Temperature in Collapsed Athletes. AB - In brief When an athlete collapses, it's important to have an accurate assessment of core body temperature as soon as possible to ensure proper treatment. Aural canal temperature is easy to measure with the infrared temperature scanner, but it is unreliable for collapsed athletes. Rectal temperature is not always convenient to measure, but it remains the clinical standard for on-field assessment. PMID- 29272637 TI - Quikquiz. PMID- 29272638 TI - Supplement Savvy. PMID- 29272636 TI - Managing Inflammatory Ear Conditions. AB - In brief Otitis externa, which often afflicts swimmers, and otitis media, which can afflict almost anyone, are common inflammatory ear conditions. Ear drops containing acidifying and drying agents, often combined with topical antibiotics and topical steroids, are the appropriate treatment for otitis externa. Without the antibiotic and steroid additions, they can also be used prophylactically. Systemic antibiotic treatment is appropriate for otitis media, but not for otitis externa. PMID- 29272640 TI - Forum. PMID- 29272641 TI - Injuries in Female Gymnasts. AB - In brief We surveyed 100 young female gymnasts about injuries that occurred over a 40-month period. Though the injury rates were similar to those found in other studies of injuries among competitive female gymnasts, we observed several notable findings regarding injury patterns. Based on our results, we suggest several prevention methods that may reduce injury, such as modifying mat design and prescribing strengthening and stretching exercises. PMID- 29272642 TI - Pearls. PMID- 29272643 TI - Wrist Injuries. AB - In brief Wrist pain in an active patient is a physician's cue to look for specific clues in the history, physical exam, and diagnostic tests. Without prompt diagnosis and accurate treatment, the chronic pain can impair sports participation and performance. And in certain instances, a misdiagnosed condition, such as a carpal dislocation or distal radial physeal fracture, can lead to deformity or disability from lack of adequate treatment. PMID- 29272644 TI - Steps to Healthy Feet for Active People With Diabetes. PMID- 29272645 TI - Foot Care for Active Patients Who Have Diabetes. AB - In brief Staying active is important for people who have diabetes. Because of potential complications of the disease, however, some cautions and adjustments need to be considered, especially regarding the feet. For example, neuropathy that decreases pain perception may lead to an unnoticed foot injury, or peripheral vascular disease may cause pain that hinders activity. Patient education about self-foot care, including visual inspection, hygiene, and proper footwear, is central to management. The presence of diabetes may affect injury treatment: For example, casting may be appropriate for sprained ankle in a patient who has neuropathy. PMID- 29272646 TI - Assessing Acute Hip Injury. AB - In brief A serious sports-related hip injury is rare, but potential consequences can be devastating. The athlete with hip pain may have a variety of clinical symptoms such as groin discomfort, knee pain, swelling, and ecchymosis. A six step evaluation involving a brief history, visual inspection, palpation, neurovascular assessment, range of motion, and lab and radiographic data will assist in expedient diagnosis and treatment. Injuries can be graded as type 1, 2, or 3, with triage decisions based on injury type and varying from observation and rehabilitation to referral to a specialist. PMID- 29272647 TI - Second Impact Syndrome. AB - In brief The known risk of second impact syndrome (SIS) in football has elevated the importance of postconcussion and precompetition exams of injured football players. Six case reports demonstrate that the same mechanism of injury-minor head trauma in a player who still has symptoms from a previous concussion-can cause second impact syndrome in any contact sport. It is important to monitor postconcussion symptoms, which include headache, light-headedness, and impaired consciousness. Return-to-play guidelines for football and boxing provide a basis for making safe activity recommendations for other sports. PMID- 29272648 TI - CME Self Test. PMID- 29272649 TI - Safer Alternatives to Outdated Exercises. PMID- 29272651 TI - Partnering for Prevention. PMID- 29272652 TI - Rule changes in women's tennis target medical issues. PMID- 29272650 TI - Management Options for Plantar Fasciitis. AB - In brief Plantar fasciitis, a common over use injury is characterized by heel pain that is usually more severe when the patient first arises. Frequent precipitating factors include adverse foot mechanics, training errors, and degenerative changes. Management of plantar fasciitis is a three-part process that involves treating the inflammatory lesion, correcting precipitating factors, and instituting a graduated rehabilitation program. Use of the tension night splint has shown promising results. PMID- 29272653 TI - Pearls. PMID- 29272655 TI - A Hill of Beans. PMID- 29272656 TI - Minority Patients: Clinical Strategies to Promote Exercise. AB - By building on the strengths of minority communities, new health programs are offering physicians practical strategies for promoting healthy life-style choices for minority patients. PMID- 29272657 TI - Fun, Healthy Life-Style Choices for Your Family. PMID- 29272660 TI - forum. PMID- 29272661 TI - Injury to the Scapholunate Ligaments. AB - In brief Sprains of the ligament complex between the scaphoid and lunate bones may be more difficult to diagnose than other wrist injuries. However, patients will have characteristic localized pain and, in severe ruptures, diagnostic radiographic abnormalities. Minor scapholunate sprains usually heal with no sequelae, but severe sprains may lead to localized arthritis if the ligament complex is not repaired surgically. PMID- 29272662 TI - Traumatic Hip Dislocation. AB - In brief Traumatic posterior hip dislocation is a rare but potentially disabling injury that is most often associated with severe trauma. Prompt recognition and early reduction are essential to a good outcome. An x-ray rules out fracture of the femoral head or acetabulum and should be routinely performed before reduction of the dislocation under anesthesia. PMID- 29272663 TI - Multiple Rib Stress Fractures. AB - In brief Stress fracture of the ribs, an uncommon overuse injury, may mimic recalcitrant intercostal or back muscle strain. This report describes a 36-year old man who sustained multiple rib stress fractures after he took up golf. Fatigue of the serratus anterior muscle appeared to be the mechanism for his injury. Relative rest followed by strengthening exercises helped the patient return to pain-free activity. PMID- 29272664 TI - The Soggy Casts of Summer. PMID- 29272665 TI - Broken Nails to Blistered Heels. AB - In brief Toenail injuries, blisters, calluses, corns and plantar warts frequently cause disability among active people at all levels of training or competition. Simple office procedures, such as making a toenail protection shell or treating a blister, can minimize the patient's time away from his or her sport. Giving athletes tips on proper footwear can often help prevent these painful conditions. PMID- 29272666 TI - A More Comfortable Cast? AB - In brief This prospective study of 140 consecutive patients who needed cast immobilization tested the comfort, practicality, and possible cutaneous side effects of a waterproof cast liner that allows swimming, bathing, and hydrotherapy without special drying procedures. Minor cutaneous complications were observed in 4.3% of patients; none required medical care. Odor, itching, and difficulties with drying after wetting were minimal. Physician and patient satisfaction levels with the cast were high. PMID- 29272667 TI - pearls. PMID- 29272668 TI - Expanding Sports Medicine's Role in Primary Care. AB - Sports medicine is becoming a larger part of primary care as more people become active in sports and exercise. In addition to treating and rehabilitating patients, primary care physicians can play an important role in helping to prevent injuries while promoting fitness. PMID- 29272669 TI - scanning sports. PMID- 29272671 TI - QuikQuiz. PMID- 29272670 TI - Eating Disorders in Athletes. AB - Whether it is to better their sports performance or to look sleeker in their uniforms, many athletes face particular pressures to lose weight. Despite the public's growing awareness of eating disorders, athletes continue to struggle with them- often at risk to their health. The challenge for primary care physicians is not only to learn the warning signs of these disorders, but also to convince athletes to get medical treatment to overcome them. PMID- 29272673 TI - Scanning sports. PMID- 29272672 TI - nutrition and fitness. PMID- 29272674 TI - How to Recognize 'Athlete's Heart'. AB - In brief Chronic endurance exercise inbrief duces various cardiac adapta- JHHHM tions, including an enlarged left ventricular cavity and an appropriate increase in wall thickness (eccentric hypertrophy), greater ability to increase stroke volume during exercise, and bradycardia at rest. Strength athletes have thicker left ventricular walls with no increase in cavity size (concentric hypertrophy). In the past, chest x-rays and ECG have suggested some of these changes, however, echocardiograms have clearly established the syndrome of the athlete's heart. In addition, these adaptations seldom exceed the range of normal variation seen in the general population. Understanding these alterations helps distinguish healthy adaptations to exercise from signs of disease. PMID- 29272675 TI - Head Injuries in Soccer. AB - In brief Two soccer goalies, a 20-year-old woman and a 28-year-old man, sustained head injuries as they fielded shots on goal. One was kicked, the other kneed by another player. The female goalie suffered a mild concussion. The male goalie lost consciousness and was transported to a hospital where he scored a 7 of 15 on the Glasgow Coma Scale. Three months after the injury, he still suffered from decreased concentration and hearing loss and had not returned to work. PMID- 29272676 TI - Use and Misuse of the Tennis Elbow Strap. AB - In brief The tennis elbow strap, also known as a counterforce brace, offers one method of decreasing stress on a painful elbow. However, the strap is effective only in patients diagnosed with tennis elbow. Use of the brace for other causes of elbow pain, such as growth plate problems in children and adolescents or medial elbow instability in adults, can actually exacerbate those conditions. PMID- 29272677 TI - Undersea Emergencies. PMID- 29272678 TI - Forum. PMID- 29272679 TI - Jumper's Knee. PMID- 29272680 TI - Pearls. PMID- 29272681 TI - Heart Disease: Not for Men Only. AB - Though heart disease is the No. 1 killer of American women, many women and physicians historically have regarded it as a minor threat. That unintentional neglect is rapidly disappearing, however, as the medical community addresses the problem with new intensity, helping women to recognize and reduce their risk factors for heart disease. PMID- 29272684 TI - Vegetarian Vitality. PMID- 29272683 TI - Endurance Training. AB - To improve endurance athletes' performance, exercise physiologists and coaches often recommend over-distance training. Frequently, though, athletes misinterpret this recommendation and increase their risk of injury and staleness by training excessively. PMID- 29272685 TI - When to Use MRI. AB - MRI is an exceptional technology that has clearly proved its value for many types of athletic injuries. But the equally exceptional cost of MRI requires that physicians conduct complete physical exams and histories before ordering MRI. PMID- 29272686 TI - QuikQuiz. PMID- 29272687 TI - Can Residents Be Team Physicians? AB - Our experience shows that residents can be team physicians during their training years if they undertake independent study and have appropriate training, supervision, and a good working relationship with the staff of a local high school. PMID- 29272688 TI - We're Peer Reviewed-by and for Physicians. PMID- 29272689 TI - Effectively Treating Acne Vulgaris. AB - In brief Acne vulgaris is common in active People and, therefore, is frequently diagnosed and treated in everyday medical practice. Systemic and topical medications, combined with elimination of aggravating physical factors and introduction of a gentle skin-care regimen, will produce gratifying results for both patient and practitioner. PMID- 29272690 TI - The differential profiles of long non-coding RNAs between rheumatoid arthritis and gouty arthritis. AB - OBJECTIVE: This study was designed to determine the differential profiles of long non-coding RNAs (lncRNAs) between rheumatoid arthritis (RA) and gouty arthritis (GA), which may lead to the discovery of specific biomarkers for RA diagnosis and treatment in the future. METHODS: The profiles of lncRNAs were determined by Agilent microarray. Bioinformatics analyses, including Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, of the large dataset obtained from microarray experiments were performed. RESULTS: A total of 765 lncRNAs and 2,808 mRNAs were significantly and differentially expressed in RA samples as compared to GA samples. Moreover, of 2,808 differentially expressed mRNAs, 178 upregulated mRNAs and 21 downregulated mRNAs were identified to be strongly correlated with lncRNAs examined in this study. Bioinformatics analyses revealed the tumor-like phenotype of synovial cells in RA and the involvement of immune system process in GA. In addition, this study demonstrated the significantly different molecular origins of two Chinese Medicine syndrome patterns of RA patients -- blood stasis and non-blood stasis. CONCLUSIONS: Our study showed for the first time the differentially expressed lncRNA profiles in synovial tissues between RA and GA and between two clinical phenotypes of RA patients differentiated by Chinese Medicine. This study helps achieving personalized medicine in RA. Larger-scale studies are required to validate the data presented. PMID- 29272691 TI - Nasal steroids as a possible treatment for Alzheimer's disease. AB - Quite a number of experimental treatments, which are based on conventionally accepted understandings of Alzheimer's disease, have not yielded expected results. Therefore, conventionally accepted understanding of the mechanisms of the disease may be inadequate or even wrong. The characteristic amyloid plaques and tau tangles in the brain may be a result, not a cause. Alzheimer's disease is more likely the product of neuroinflammation and deranged brain wound healing. If so, a hypothesized treatment, intranasal glucocorticoids, might be effective. Long-term use of intranasal glucocorticoids (especially older generation steroids) for Alzheimer's treatment would potentially raise intraocular pressure, but newer intranasal steroids (fluticasone, triamcinolone, or budesonide) have a minimal effect on intraocular pressure because of their low bioavailability. PMID- 29272692 TI - Recent endeavors in MECP2 gene transfer for gene therapy of Rett syndrome. AB - Rett Syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder caused by inactivating mutations in the transcription regulator methyl CpG-binding protein 2 (MeCP2). Multiple studies have independently explored the therapeutic potential of adeno-associated viral (AAV) vector-mediated MECP2 gene transfer in mouse models of RTT. Historically, the primary risk anticipated for viral vector mediated MECP2 gene transfer in vivo has been toxicity caused by supraphysiological expression of exogenous MeCP2. Despite the anticipated risk, early studies examining AAV/MECP2 in vivo have, as a whole, supported a generally optimistic assessment of MECP2 gene therapy. More recently, toxicity assessments have identified dose-dependent side effects of AAV9/MECP2 delivered directly to the cerebrospinal fluid (CSF). Ultimately, accurate monitoring and reporting of these side effects will help ensure the development of safe AAV/MECP2 treatment paradigms as researchers explore strategies to improve widespread but properly regulated MECP2 gene transfer in the central nervous system (CNS). Importantly, despite some variability in apparent safety and efficacy, all MECP2 gene therapy studies have been united by a single feat: published treatment paradigms have extended the survival of RTT mice, regardless of injection route, treatment age, or viral genome design. With the possibility of a translatable gene therapy treatment for RTT emerging, a comprehensive overview of the preclinical MECP2 gene therapy studies published thus far is warranted. This review highlights the main findings of these publications and discusses future directions. PMID- 29272693 TI - Comprehensive antibody profiles as personalized indicators of health and disease. AB - Comprehensive, robust, and inexpensive clinical tools are needed to monitor human health and disease. In this review, we propose how a standardized, high performance antibody testing platform directed against a broad panel of antigenic targets could fulfill an important niche in personalized medicine. The panel is envisioned to encompass a defined set of diverse protein antigens known to be associated with cancer, autoimmune diseases, and infectious diseases, including proteins derived from bacterial pathogens and the human virome. Early detection of immunoreactivity to various antigens and autoantigens, before symptoms develop, might inform about evolving autoimmunity, cancer progression, or other health problems and provide unique opportunities for early, more effective clinical intervention. Furthermore, antibody detection for known pathogenic infectious agents, as well as cataloging host responses to seemingly non pathogenic microbes, could offer treatment options and/or potentially represent novel, early biomarkers for different diseases and immune status. The overarching goal would be to exploit changes in an individual's comprehensive antibody profile longitudinally as a personalized indicator for disease prediction, diagnosis, and monitoring. PMID- 29272694 TI - Post-Condylectomy Histopathologic Findings in Patients With a Positive 99mTc Methylene Diphosphonate Single-Photon Emission Computed Tomographic Diagnosis for Condylar Hyperplasia. AB - PURPOSE: To describe and correlate with age the histopathologic findings observed in a group of specimens obtained from patients who underwent high condylectomy. MATERIALS AND METHODS: In this cross-sectional study, 27 condylar specimens from patients with facial asymmetry, suspected condylar hyperplasia (CH), and a positive diagnosis by single photon emission computed tomography (SPECT) were evaluated. Histopathologic variables measured in the mandibular condyles were thickness of fibrous, proliferative, and hyperplasic cartilage layers and total tissue thickness. RESULTS: The thickness of the fibrous layer (P = .014) and proliferative layer (P = .005) and total thickness (P = .007) were significantly greater in the patients studied compared with the literature reference values, and 66.6% of cases presented cartilage islands in the calcified region. Seventeen patients no older than 22 years (85%) showed this finding, whereas only 1 patient at least 23 years old did. Therefore, the presence of cartilage islands was significantly related to age (P = .001). CONCLUSIONS: Altogether, the histopathologic findings are consistent with the positive SPECT diagnosis of CH. Histopathologic evaluation showed an increased thickness in the soft tissue layer of the affected mandibular condyle, which was particularly marked for the proliferative layer. Cartilage islands were found mostly in patients no older than 22 years. Therefore, it is not a reliable pathognomic sign for CH because it could be related to normal condylar growth. PMID- 29272695 TI - Modified Decompression of the Infraorbital Canal to Treat Trigeminal Neuralgia Affecting the Maxillary Branch. AB - PURPOSE: To modify the method of treating trigeminal neuralgia (TN) affecting the maxillary branch and to provide clinical evidence of an etiologic hypothesis of narrowing bone canal compression. MATERIALS AND METHODS: Forty patients who met the inclusion and exclusion criteria were included, and those with bony compression of the affected infraorbital canal (IOC) were selected by preoperative computer measurement. Modified decompression of the IOC was performed through the maxillary sinus with the assistance of a piezoelectric device and an endoscope. The results of the operation were evaluated. RESULTS: Fourteen patients (35.00%) had bony compression of the affected IOC. During a mean follow-up period of 29.4 months, 11 patients (78.57%) had complete pain relief (excellent); 1 (7.14%) had moderate relief with carbamazepine administration. The success rate was 85.71% (12 of 14). The postoperative numbness rate was 35.71% (5 of 14). CONCLUSION: Narrowing of the IOC might be a reason some patients with TN have no intracranial neurovascular compression and have pain localized to the distribution of the maxillary branch. Modified decompression of the IOC through the maxillary sinus is a safe, highly effective, and minimally invasive method to treat these patients. PMID- 29272696 TI - The role of fathers during breastfeeding. AB - OBJECTIVE: identify fathers' perceptions of their role in a breastfeeding context. SETTING: three different geographic areas (urban, semi-urban, and rural) of Quebec, a francophone province in Canada. PARTICIPANTS: 43 fathers whose children had been exclusively breastfed for a minimum of six months. METHODS: a qualitative study using semi-structured interviews was undertaken. Thematic analysis of the interviews was carried out with NVivo 11. FINDINGS: variations were identified in the role of father during breastfeeding, namely, 1) acting as partners in decision-making; 2) being responsible for the family functioning, and 3) providing emotional support to the mother. These different variants each entail challenges and tasks. KEY CONCLUSIONS: participating fathers perceived their role as much more complex than the limited role of breastfeeding facilitator that is usually attributed to them. Fathers saw themselves as stakeholders in decision-making relating to how their child was fed and they reacted to the imbalance created by breastfeeding. Their involvement occurred at several levels: that of their child, their spouse, and their family. IMPLICATIONS FOR PRACTICE: these results suggest that more attention should be given to fathers' roles in a breastfeeding context and more investigation is required into the extent to which health professionals, such as midwives and nurses, support fathers in managing these various roles and the challenges they entail. PMID- 29272697 TI - Chemo-Mobilization in Myeloma-Diminishing Returns in the Era of Novel Agent Induction? PMID- 29272698 TI - The Next Step Forward in Ubiquitin-Specific Protease 7 Selective Inhibition. AB - Ubiquitin-specific protease 7 is a validated anticancer target; thus, selective USP7 inhibitors are of great interest. In this issue of Cell Chemical Biology, Lamberto et al. (2017) and Pozhidaeva et al. (2017) report important insights into the structural inhibitor-enzyme interplay, lighting the way toward the development of selective inhibitors. PMID- 29272699 TI - A Rhomboid in the Rough: Potent Inhibitors for a Previously Undruggable Target. AB - In this issue of Cell Chemical Biology, Ticha et al. (2017) report a novel class of highly potent and selective rhomboid inhibitors. Rhomboids are implicated in several devastating human afflictions including malaria, diabetes, cancer, and Parkinson's disease (PD), making them important drug targets for future therapeutics. PMID- 29272700 TI - Multi-targeting Drug Community Challenge. PMID- 29272701 TI - A Droplet to Sense Sugar Drops. AB - Cells need to rewire their metabolic network depending on the available carbon source. Simpson-Lavy et al. (2017) have discovered that Std1, the activator of the yeast AMP kinase Snf1, condensates into granules to tune Snf1 activity. PMID- 29272702 TI - On the Race to Starvation: How Do Bacteria Survive High Doses of Antibiotics? AB - In this issue of Molecular Cell, Gutierrez et al. (2017) unravel a bacterial survival strategy that they term "density-dependent persistence" or DDP. The authors demonstrate that the majority of isogenic cells in bacterial populations survive lethal antibiotic doses once bacteria consume nutrients and enter stationary growth phase. PMID- 29272703 TI - Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes. AB - Heterochromatin is integral to cell identity maintenance by impeding the activation of genes for alternate cell fates. Heterochromatic regions are associated with histone 3 lysine 9 trimethylation (H3K9me3) or H3K27me3, but these modifications are also found in euchromatic regions that permit transcription. We discovered that resistance to sonication is a reliable indicator of the heterochromatin state, and we developed a biophysical method (gradient-seq) to discriminate subtypes of H3K9me3 and H3K27me3 domains in sonication-resistant heterochromatin (srHC) versus euchromatin. These classifications are more accurate than the histone marks alone in predicting transcriptional silence and resistance of alternate fate genes to activation during direct cell conversion. Our proteomics of H3K9me3-marked srHC and functional screens revealed diverse proteins, including RBMX and RBMXL1, that impede gene induction during cellular reprogramming. Isolation of srHC with gradient-seq provides a genome-wide map of chromatin structure, elucidating subtypes of repressed domains that are uniquely predictive of diverse other chromatin properties. PMID- 29272704 TI - AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection. AB - Enhancer elements are genomic regulatory sequences that direct the selective expression of genes so that genetically identical cells can differentiate and acquire the highly specialized forms and functions required to build a functioning animal. To differentiate, cells must select from among the ~106 enhancers encoded in the genome the thousands of enhancers that drive the gene programs that impart their distinct features. We used a genetic approach to identify transcription factors (TFs) required for enhancer selection in fibroblasts. This revealed that the broadly expressed, growth-factor-inducible TFs FOS/JUN (AP-1) play a central role in enhancer selection. FOS/JUN selects enhancers together with cell-type-specific TFs by collaboratively binding to nucleosomal enhancers and recruiting the SWI/SNF (BAF) chromatin remodeling complex to establish accessible chromatin. These experiments demonstrate how environmental signals acting via FOS/JUN and BAF coordinate with cell-type specific TFs to select enhancer repertoires that enable differentiation during development. PMID- 29272707 TI - Reply by Authors. PMID- 29272706 TI - The ATPase Fap7 Tests the Ability to Carry Out Translocation-like Conformational Changes and Releases Dim1 during 40S Ribosome Maturation. PMID- 29272708 TI - Editorial Comment. PMID- 29272709 TI - Editorial Comment. PMID- 29272705 TI - A Seed Mismatch Enhances Argonaute2-Catalyzed Cleavage and Partially Rescues Severely Impaired Cleavage Found in Fish. AB - The RNAi pathway provides both innate immunity and efficient gene-knockdown tools in many eukaryotic species, but curiously not in zebrafish. We discovered that RNAi is less effective in zebrafish at least partly because Argonaute2-catalyzed mRNA slicing is impaired. This defect is due to two mutations that arose in an ancestor of most teleost fish, implying that most fish lack effective RNAi. Despite lacking efficient slicing activity, these fish have retained the ability to produce miR-451, a microRNA generated by a cleavage reaction analogous to slicing. This ability is due to a G-G mismatch within the fish miR-451 precursor, which substantially enhances its cleavage. An analogous G-G mismatch (or sometimes also a G-A mismatch) enhances target slicing, despite disrupting seed pairing important for target binding. These results provide a strategy for restoring RNAi to zebrafish and reveal unanticipated opposing effects of a seed mismatch with implications for mechanism and guide-RNA design. PMID- 29272710 TI - Editorial Comment. PMID- 29272711 TI - Editorial Comment. PMID- 29272713 TI - User-identified electronic cigarette behavioral strategies and device characteristics for cigarette smoking reduction. AB - BACKGROUND: There is limited evidence on how cigarette smokers use electronic cigarettes (ECIGs) for smoking cessation and reduction. This study used concept mapping, a participatory mixed-methods research approach, to identify ECIG use behaviors and device characteristics perceived to be associated with cigarette smoking cessation or reduction. METHODS: Current ECIG users aged 18-64 were recruited from seven cities selected randomly from U.S. census tract regions. Participants were invited to complete concept mapping tasks: brainstorming, sorting and rating (n=72). During brainstorming, participants generated statements in response to a focus prompt ("A SPECIFIC WAY I HAVE USED electronic cigarettes to reduce my cigarette smoking or a SPECIFIC WAY electronic cigarettes help me reduce my cigarette smoking is...") and then sorted and rated the statements. Multidimensional scaling and hierarchical cluster analyses were used to generate a cluster map that was interpreted by the research team. RESULTS: Eight thematic clusters were identified: Convenience, Perceived Health Effects, Ease of Use, Versatility and Variety, Advantages of ECIGs over Cigarettes, Cigarette Substitutability, Reducing Harms to Self and Others, and Social Benefits. Participants generated several statements that related to specific behavioral strategies used when using ECIGs for smoking reduction/complete switching behaviors such as making rapid transitions from smoking to ECIG use or using certain ECIG liquids or devices. Former smokers rated the Perceived Health Effects cluster and several behavioral strategy statements higher than current smokers. CONCLUSIONS: These results help to identify ECIG use behaviors and characteristics perceived by ECIG users to aid in cigarette smoking cessation or reduction. PMID- 29272712 TI - Acceptability of mHealth augmentation of Collaborative Care: A mixed methods pilot study. AB - OBJECTIVE: To assess the feasibility and acceptability of a mobile health platform supporting Collaborative Care. METHOD: Collaborative Care patients (n=17) used a smartphone app to transmit PHQ-9 and GAD-7 scores and sensor data to a dashboard used by one care manager. Patients completed usability and satisfaction surveys and qualitative interviews at 4weeks and the care manager completed a qualitative interview. Mobile metadata on app usage was obtained. RESULTS: All patients used the app for 4weeks, but only 35% (n=6) sustained use at 8weeks. Prior to discontinuing use, 88% (n=15) completed all PHQ-9 and GAD-7 measures, with lower response rates for daily measures. Four themes emerged from interviews: understanding the purpose; care manager's role in supporting use; benefits of daily monitoring; and privacy / security concerns. Two themes were user-specific: patients' desire for personalization; and care manager burden. CONCLUSIONS: The feasibility and acceptability of the mobile platform is supported by the high early response rate, however attrition was steep. Our qualitative findings revealed nuanced participant experiences and uncovered some concerns about mobile health. To encourage retention, attention may need to be directed toward promoting patient understanding and provider engagement, and offering personalized patient experiences. PMID- 29272714 TI - Impact of heavy metal on activity of some microbial enzymes in the riverbed sediments: Ecotoxicological implications in the Ganga River (India). AB - We studied the extracellular enzyme activity (EEA) in the riverbed sediment along a 518km gradient of the Ganga River receiving carbon and nutrient load from varied human sources. Also, we tested, together with substrate-driven stimulation, if the heavy metal accumulated in the sediment inhibits enzyme activities. Because pristine values are not available, we considered Dev Prayag, a least polluted site located 624km upstream to main study stretch, as a reference site. There were distinct increases in enzyme activities in the sediment along the study gradient from Dev Prayag, however, between-site differences were in concordance with sediment carbon(C), nitrogen (N) and phosphorus (P). Fluorescein diacetate hydrolysis (FDAase), beta-glucosidase (Glu) and protease activities showed positive correlation with C, N and P while alkaline phosphatase was found negatively correlated with P. Enzyme activities were found negatively correlated with heavy metal, although ecological risk index (ERi) varied with site and metal species. Dynamic fit curves showed significant positive correlation between heavy metal and microbial metabolic quotient (qCO2) indicating a decrease in microbial activity in response to increasing heavy metal concentrations. This study forms the first report linking microbial enzyme activities to regional scale sediment heavy metal accumulation in the Ganga River, suggests that the microbial enzyme activities in the riverbed sediment were well associated with the proportion of C, N and P and appeared to be a sensitive indicator of C, N and P accumulation in the river. Heavy metal accumulated in the sediment inhibits enzyme activities, although C rich sediment showed relatively low toxicity due probably to reduced bioavailability of the metal. The study has relevance from ecotoxicological as well as from biomonitoring perspectives. PMID- 29272715 TI - Mercury in rice (Oryza sativa L.) and rice-paddy soils under long-term fertilizer and organic amendment. AB - High levels of mercury (Hg), especially methylmercury (MeHg), in rice is of concern due to its potential of entering food chain and the high toxicity to human. The level and form of Hg in rice could be influenced by fertilizers and other soil amendments. Studies were conducted to evaluate the effect of 24 years application of chemical fertilizers and organic amendments on total Hg (THg) and MeHg and their translocation in soil, plants, and rice grain. All treatments led to significantly higher concentrations of MeHg in grain than those from the untreated control. Of nine treatments tested, chemical fertilizers combining with returning rice straw (NPK1+S) led to highest MeHg concentration in grain and soil; while the nitrogen and potassium (NK) treatment led to significantly higher THg in grain. Concentrations of soil MeHg were significantly correlated with THg in soil (r = 0.59***) and MeHg in grain (r = 0.48***). Calcium superphosphate negatively affected plant bioavailability of soil Hg. MeHg concentration in rice was heavily influenced by soil Hg levels. Phosphorus fertilizer was a main source contributing to soil THg, while returning rice straw to the field contributed significantly to MeHg in soil and rice grain. As a result, caution should be exercised in soil treatment or when utilizing Hg-contaminated soils to produce rice for human consumption. Strategic management of rice straw and phosphorus fertilizer could be effective strategies of lowering soil Hg, which would ultimately lower MeHg in rice and the risk of Hg entering food chain. PMID- 29272716 TI - Does extensive agriculture influence the concentration of trace elements in the aquatic plant Veronica anagallis-aquatica? AB - The present study describes the influence of extensive agriculture on the concentrations of As, Cr, Cu, Cd, Se, Pb and Zn in sediments and in the aquatic plant Veronica anagallis-aquatica. The investigation, spanning 4 years, was conducted on three watercourses in Slovenia (Psata, Lipsenjscica and Zerovniscica) flowing through agricultural areas. The different sampling sites were chosen on the basis of the presence of different activities in these regions: dairy farming, stock raising and extensive agriculture. The concentrations of the selected elements in sediments and V. anagallis-aquatica were below the literature background values. The distribution of the selected elements among different plant parts (roots, stems and leaves) were also investigated. The majority of the studied elements, with the exception of Zn and Cu, were accumulated mainly in root tissues. PMID- 29272717 TI - Ecotoxicity assessment of dicationic versus monocationic ionic liquids as a more environmentally friendly alternative. AB - One of the reasons why ionic liquids have received growing interest from researchers is their environmentally interesting characteristics, such as their negligible vapour pressure and their good chemical and thermal properties. In particular, dicationic ionic liquids whose thermal and electrochemical stability is higher than that of monocationic ionic liquids have begun to gain attention during recent years. In this work, monocationic and dicationic ionic liquids were synthesized, characterized and tested for their toxicity, which was assessed using the luminescent bacterium Vibrio fischeri. The results revealed that the toxicity of the ionic liquids mainly depends on the head groups and linkage chain length of their cationic structure. Introduction of a new cationic head decreased the EC50 (concentration which leads to 50% reduction in bioluminescence of the bacteria) of the ionic liquids. The results present a promising picture of dicationic ionic liquids as alternatives with lower environmental impact than their monocationic counterparts and underline the significance of designing particular structures for ionic liquids. PMID- 29272718 TI - Adsorption property of Br-PADAP-impregnated multiwall carbon nanotubes towards uranium and its performance in the selective separation and determination of uranium in different environmental samples. AB - A newer efficient U(VI) ion adsorbent was synthesized by impregnating Br-PADAP [2 (5-Bromo-2-pyridylazo)-5-(diethylamino)phenol] onto multiwall carbon nanotubes (MWCNTs). The effects of various operation conditions on uranium adsorption (i.e., pH contact time, temperature, and initial uranium concentration) were systematically evaluated using batch experiments. The results indicated that the uranium adsorption on modified MWNCTs (5.571 * 10-3g/mg * min) reached faster equilibrium than that on pristine MWNCTs (4.832 * 10-3g/mg * min), reflecting the involvement of appropriate functional groups of Br-PADAP on the chelating ion exchange mechanism of U(VI) adsorption. Modified MWNCTs (83.4mg/g) exhibited significantly higher maximum Langmuir adsorption capacity than pristine MWNCTs (15.1mg/g). Approximately 99% of uranium adsorbed onto modified MWNCTs can be desorbed by 2.5mL of 1M HNO3 solution. Therefore, Br-PADAP-modified MWNCTs can server as a promising adsorbent for efficient uranium adsorption applications in water treatment. Subsequently, the proposed solid-phase extraction (using a mini column packed with Br-PADAP/MWCNT) was successfully utilized for analysing trace uranium levels by the ICP-AES method in different environmental samples with a pre-concentration factor of 300-fold. The coexistence of other ions demonstrated an insignificant interference on the separative pre-concentration of uranium. the detection limit was recognized as 0.14MUg/L, and the relative standard deviation was approximately 3.3% (n = 7). PMID- 29272719 TI - Effects of the antidepressant, mianserin, on early development of fish embryos at low environmentally relevant concentrations. AB - Pharmaceuticals have been considered as emerging organic contaminants in the environment that might pose huge risk to the non-target aquatic organisms. Mianserin, a tetracyclic antidepressant, is present at low detectable concentrations in the aquatic environment; however, limited attention has been devoted to its potential adverse effects on the aquatic animals. In the present study, we first performed an acute toxicity test for mianserin exposure using zebrafish (Danio rerio) embryos during 4-124h post fertilization (hpf). Time dependent lethal concentrations of mianserin exposure on the zebrafish embryos were firstly determined at mg/L levels. Then, a series of sublethal concentrations of 0.01, 0.1, 1, 10, 100, and 1000MUg/L of mianserin were prepared for the short-term exposure of zebrafish embryos for 120h. The results showed that mianserin exposure reduced the body length of zebrafish larvae, in addition to altering multiple physiological and biochemical parameters in the exposed embryos/larvae. A dose-dependent inhibition of the total antioxidant capacity and total cholinesterase activity was revealed in the exposed fish larvae upon increasing the concentrations of mianserin exposure. A U-shaped concentration dependent response curve was observed for the adrenocorticotropic hormone; however, an inversed U-shaped response curve was obtained for the monoamine oxidase level in response to mianserin exposure. Activities of the total adenosine triphosphatase (T-ATPase), Na+/K+-ATPase, and Ca2+/Mg2+-ATPase were significantly increased in the fish larvae exposed to relatively high doses of mianserin; interestingly however, low dose of mianserin at 10ng/L inhibited their Na+/K+-ATPase and T-ATPase activities. Additionally, the coordinated regulation of cyclic adenosine monophosphate and protein kinase A was observed in the mianserin-exposed fish larvae, implying a reserved signaling pathway involved in the fish response to the antidepressant. Therefore, our study demonstrated that mianserin exposure significantly affected the early development of fish embryos at environmentally relevant concentrations, and suggested that the risk of pharmaceutical contamination of the aquatic environment, even at low doses, should receive more attention. PMID- 29272720 TI - Comparison of conventional and lipid emulsion formulations of amphotericin B: Pharmacokinetics and toxicokinetics in dogs. AB - The major limiting factor in the use of amphotericin B (AmB) is cumulative nephrotoxicity. In previous studies, AmB mixed with Intralipid(r) 20% (AmB-IL), a parenteral fat emulsion, reduces its toxicity, increases its efficacy and is less expensive than other commercial amphotericin B lipid formulations. The pharmacokinetics and toxicity of the conventional deoxycholate AmB formulation (Fungizone(r)) and AmB-IL were compared in dogs. The pharmacokinetic of AmB was significantly modified and renal toxicity and infusion-related side effects were reduced when the drug was prepared in fat emulsion. In addition, pharmacokinetics and toxicity were evaluated after the administration of multiple doses of AmB-IL with the purpose of determining an optimal treatment protocol in dogs. When using a consecutive day administration regime, there was a significant drug accumulation together with an increase in creatinine values after each dose. However, when using three doses per week administration regime, similar maximum and minimum plasma concentrations were maintained. During the four weeks of treatment a moderate increase in the creatinine values was observed but none of the treatments were ended prematurely. All these data suggest that Intralipid(r), similar to that seen previously in humans, favors AmB distribution to the organs, decreasing drug toxicity and increasing its therapeutic index in the dogs. The dose protocol evaluated (25mg/m2/48h/three times per week) produces maintenance of AmB plasma levels that were close to that obtained by others authors after administration of liposomal formulations of AmB and that have been demonstrated to be clinically effective. PMID- 29272721 TI - miR-1 and miR-133b expression in canine osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor in dogs and it is reported to represent 80-85% of primitive bone tumors and 3-4% of all canine tumors. Canine OS is highly comparable to human OS since it is characterized by similar genetic, biologic and clinical pathological features. MicroRNAs (miRNAs) are small non-coding RNA segments controlling post-transcriptional gene expression whose altered regulation has been described in different malignant tumors. In this study we analyzed the expression of two miRNAs with an important role in regulation of osteogenesis and tumor cell proliferation in order to define their role in canine OS development. A lower expression of miR-1 and miR 133b was seen in tumors when compared with normal bone associated to a higher expression of two target genes, respectively MET and MCL1. Accordingly, MET and MCL11 proteins presented a moderate to strong immunostaining in more than 50% of tumor samples. Our results, although obtained in a small series of cases, confirming the high molecular homology with human OS suggesting a potential role of miR-1 and miR-133b as biomarkers for canine OS treatment. PMID- 29272722 TI - Zwitterionic starch-based hydrogel for the expansion and "stemness" maintenance of brown adipose derived stem cells. AB - Brown adipose derived stem cells (BADSCs) have become a promising stem cell treatment candidate for myocardial infarction because of their efficiently spontaneous differentiation capacity towards cardiomyocytes. The lack of existing cell passage protocols motivates us to develop a neotype 3D cell expansion technique for BADSCs. In this study, "clickable" zwitterionic starch based hydrogels are developed using methacrylate modified sulfobetaine derived starch with dithiol-functionalized poly (ethylene glycol) as crosslinker via the "thiol ene" Michael addition reaction. Moreover, CGRGDS peptide is immobilized into the hydrogel via a similar "clickable" approach. Their Young's moduli range from 22.28 to 74.81 kPa depending on the concentration of precursor solutions. Excellent anti-fouling property is also presented owing to the introduction of zwitterionic moieties. BADSCs are homogeneously encapsulated in the hydrogels and then routinely cultured for 10 days. Results suggest a capacious cell proliferation and the extent increases with either the decrease of mechanical strength or the introduction of CGRGDS. More excitingly, the cell "stemness" is well maintained during this period and the expanded cells released from the hydrogels well keep the efficiently spontaneous cardiomyogenic differentiation capacity. Therefore, it is suggested that zwitterionic starch based hydrogel is able for the expansion and "stemness " maintenance of BADSCs. PMID- 29272723 TI - Inactivation of Salmonella in grape tomato stem scars by organic acid wash and chitosan-allyl isothiocyanate coating. AB - The objective of this study was to evaluate inactivation of inoculated Salmonella enterica on grape tomato stem scars exploiting integrated treatment of organic acid wash (AW) followed by chitosan-allyl isothiocyanate (CT-AIT) coating. The treatment effect on microbial loads and fruit quality during 21days storage at 10 degrees C was also determined. A bacterial cocktail containing three serotypes of Salmonella enterica was used for this study based on their association with produce-related outbreaks. Tomatoes were spot inoculated on stem scars and then immersed in an organic acid solution (700ml) containing 0.5% (v/v) each of acetic (AA) and formic acid (FA) to wash under mild agitation for 1min at ambient temperature (22 degrees C) followed by 1min dipping in a coating solution containing 6mlAIT/g CT. AW in 0.5% organic acid (AA+FA) for 1min reduced Salmonella population by 2.7logCFU/g from an initial load of 7.8logCFU/g, while additional coating treatment of AW tomatoes reduced the pathogens on stem scars to undetectable levels (<0.7logCFU/g), achieving, in combination, a >7logCFU/g reduction for the pathogen. Although the populations of Salmonella in the controls (approx. 7.8logCFU/g stem scar) did not change significantly during 21days of storage at 10 degrees C, the populations were reduced to undetectable level in the integrated (AW plus CT-AIT) treated stem scars on day 1 and no regrowth was observed during storage. The treatment significantly (p<0.05) reduced background bacterial loads to approx. 1.3logCFU/g and the population remained unchanged through day 21 at 10 degrees C. The treatment also completely inactivated mold and yeast on day 1 with no growth reoccurrence. These results indicate that the integrated treatment can provide a safe and effective intervention strategy for grape tomatoes. PMID- 29272724 TI - LAMP-based group specific detection of aflatoxin producers within Aspergillus section Flavi in food raw materials, spices, and dried fruit using neutral red for visible-light signal detection. AB - Aflatoxins can be produced by 21 species within sections Flavi (16 species), Ochraceorosei (2), and Nidulantes (3) of the fungal genus Aspergillus. They pose risks to human and animal health due to high toxicity and carcinogenicity. Detecting aflatoxin producers can help to assess toxicological risks associated with contaminated commodities. Species specific molecular assays (PCR and LAMP) are available for detection of major producers, but fail to detect species of minor importance. To enable rapid and sensitive detection of several aflatoxin producing species in a single analysis, a nor1 gene-specific LAMP assay was developed. Specificity testing showed that among 128 fungal species from 28 genera, 15 aflatoxigenic species in section Flavi were detected, including synonyms of A. flavus and A. parasiticus. No cross reactions were found with other tested species. The detection limit of the assay was 9.03pg of A. parasiticus genomic DNA per reaction. Visual detection of positive LAMP reactions under daylight conditions was facilitated using neutral red to allow unambiguous distinction between positive and negative assay results. Application of the assay to the detection of A. parasiticus conidia revealed a detection limit of 211 conidia per reaction after minimal sample preparation. The usefulness of the assay was demonstrated in the analysis of aflatoxinogenic species in samples of rice, nuts, raisins, dried figs, as well as powdered spices. Comparison of LAMP results with presence/absence of aflatoxins and aflatoxin producing fungi in 50 rice samples showed good correlation between these parameters. Our study suggests that the developed LAMP assay is a rapid, sensitive and user-friendly tool for surveillance and quality control in our food industry. PMID- 29272725 TI - Comparison between digital PCR and real-time PCR in detection of Salmonella typhimurium in milk. AB - As a kind of zero-tolerance foodborne pathogens, Salmonella typhimurium poses a great threat to quality of food products and public health. Hence, rapid and efficient approaches to identify Salmonella typhimurium are urgently needed. Combined with PCR and fluorescence technique, real-time PCR (qPCR) and digital PCR (ddPCR) are regarded as suitable tools for detecting foodborne pathogens. To compare the effect between qPCR and ddPCR in detecting Salmonella typhimurium, a series of nucleic acid, pure strain culture and spiking milk samples were applied and the resistance to inhibitors referred in this article as well. Compared with qPCR, ddPCR exhibited more sensitive (10-4ng/MUl or 102cfu/ml) and less pre culturing time (saving 2h). Moreover, ddPCR had stronger resistance to inhibitors than qPCR, yet absolute quantification hardly performed when target's concentration over 1ng/MUl or 106cfu/ml. This study provides an alternative strategy in detecting foodborne Salmonella typhimurium. PMID- 29272727 TI - OnARTMAP: A Fuzzy ARTMAP-based Architecture. AB - Fuzzy ARTMAP (FAM) copes with the stability-plasticity dilemma by the adaptive resonance theory (ART). Despite such an advantage, Fuzzy ARTMAP suffers from a category proliferation problem, which leads to a high number of categories and a decrease in performance for unseen patterns. Such drawbacks are mainly caused by the overlapping region (noise) between classes. To overcome these drawbacks, we propose a Fuzzy ARTMAP-based architecture robust to noise, named OnARTMAP, for both online and batch learning. Our neural networks (OnARTMAP1 and OnARTMAP2) proposed for batch learning have a two-stage learning process, while our neural network (OnARTMAPo) for online and incremental learning has just a single iterative process. Two new modules are proposed, the overlapping region detection module (ORDM) and another one similar to ARTa, called ARTc. The ORDM finds the overlapping region between categories, while the ARTc computes and stores special categories for overlapping areas. In our architecture proposal, the weights for ordinary categories are estimated from data outside the overlapping area. An alternative to the second stage strategy for batch learning is presented and focuses on improving the generalization performance. On the basis of our achievements, one can infer that OnARTMAP can improve the generalization performance and decrease the number of categories. Our proposals were applied to artificial and real datasets, as well as were compared with several counterparts (Fuzzy ARTMAP, ART-EMAP, MUARTMAP, and BARTMAP). PMID- 29272726 TI - Manifold optimization-based analysis dictionary learning with an l1/2-norm regularizer. AB - Recently there has been increasing attention towards analysis dictionary learning. In analysis dictionary learning, it is an open problem to obtain the strong sparsity-promoting solutions efficiently while simultaneously avoiding the trivial solutions of the dictionary. In this paper, to obtain the strong sparsity promoting solutions, we employ the l1/2 norm as a regularizer. The very recent study on l1/2 norm regularization theory in compressive sensing shows that its solutions can give sparser results than using the l1 norm. We transform a complex nonconvex optimization into a number of one-dimensional minimization problems. Then the closed-form solutions can be obtained efficiently. To avoid trivial solutions, we apply manifold optimization to update the dictionary directly on the manifold satisfying the orthonormality constraint, so that the dictionary can avoid the trivial solutions well while simultaneously capturing the intrinsic properties of the dictionary. The experiments with synthetic and real-world data verify that the proposed algorithm for analysis dictionary learning can not only obtain strong sparsity-promoting solutions efficiently, but also learn more accurate dictionary in terms of dictionary recovery and image processing than the state-of-the-art algorithms. PMID- 29272728 TI - Epigenetic profiles associated with major depression in the human brain. AB - We conducted an epigenome-wide association study of Major Depressive Disorder (MDD) in brain-derived DNA using two analytic approaches. DNA methylation data (GSE41826) was used in differential methylation (DM) analyses controlling for age, sex, suicide status, and post-mortem interval; and in weighted gene co methylation network analyses (WGCNA) in probes mapping to transcription start sites. No probes in the DM analysis survived FDR correction. Nominally significant DM probes were enriched in synaptic function-related genes. WGCNA revealed one module correlated with MDD, enriched in genes associated with mitochondrial function. DM and WGCNA both showed enrichment of genes involved in transcription and DNA binding. PMID- 29272729 TI - Social contact as a strategy for self-stigma reduction in young adults and adolescents with mental health problems. AB - This study assessed the effectiveness of a social contact program between young adults and adolescents with and without mental health problems. It was evaluated if the development of a social contact program in a non-segregated space and respecting criteria of contact hypothesis reduced Self-Stigma and Public Stigma and, increased Self-Esteem. A pre-post intervention design was used with a sample of 47 subjects, 25 with different mental health diagnoses (Psychotic Disorder, Anxiety Disorder, Depression, Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder) and 22 without mental health problems, aged between 15 and 35 years. Five workshops of social contact and creativity were carried out during five months with a 2-h weekly meeting. The results analysis revealed a significant reduction in Self-Stigma for participants with mental health problems and may suggest a slight reduction in Public Stigma as well as a slight increase in the level of Self-Esteem of all participants. These findings suggest that programs of this nature reduce Self-Stigma and facilitate social inclusion in young adults and adolescents with and without mental health problems. PMID- 29272730 TI - Stress reactivity links childhood trauma exposure to an admixture of depressive, anxiety, and psychosis symptoms. AB - Childhood trauma exposure has been associated with a clinically relevant mixed phenotype of psychopathology composed of depressive, anxiety, and psychosis symptoms, across healthy and clinical samples. Altered stress-reactivity after exposure to childhood trauma may be a plausible underlying mechanism explaining this association. In a general population sample of female twins (T0 = 564; T1 = 483), associations between childhood trauma exposure and symptom profile (no symptoms, isolated symptoms, or a mixed phenotype) on the one hand, and daily life stress reactivity on the other were investigated. Daily life stress reactivity was measured using the Experience Sampling Method (ESM), and was defined as negative affect reactivity to minor daily life stressors. Individuals exposed to childhood trauma who reported a mixed phenotype of psychopathology showed a significant increase in emotional reactivity to daily life stress (activity and social stress), compared with trauma-exposed individuals without a mixed phenotype. In the trauma-exposed mixed phenotype group, increased emotional reactivity to event-stress predicted more severe symptoms at +/- 14 month follow up. This study found evidence that may link heightened emotional reactivity to stress in individuals with a trauma history to the risk for later comorbid psychopathology. PMID- 29272731 TI - Association between hypertensive disorders of pregnancy and the development of offspring mental and behavioural problems: A systematic review and meta-analysis. AB - Hypertensive disorders of pregnancy are a major cause of maternal and offspring morbidity and mortality worldwide. However, its effect on offspring mental and behavioural disorders is unclear. The aim of this study is to provide the best scientific evidence on the association between hypertensive disorders of pregnancy and offspring mental and behavioural problems. We systematically searched Scopus, PubMed, Cochrane, EMBASE, CINAH and PsycINFO databases. A total of 23 studies (11 included in meta-analysis) were identified. Of the 23 studies included in this review, 15 studies found that hypertensive disorders of pregnancy had a negative impact for at least one mental or behavioural disorder. The pooled effect of 11 studies included in the meta-analysis showed that preeclampsia was associated with increased risk of offspring schizophrenia. However, we found inconclusive finding on the effect of hypertensive disorders of pregnancy and other mental and behavioural disorders. Further high quality, large sample, birth cohort studies are needed to further progress this area of research. PMID- 29272732 TI - A neural model of retrospective attention in visual working memory. AB - An informative cue that directs attention to one of several items in working memory improves subsequent recall of that item. Here we examine the mechanism of this retro-cue effect using a model of short-term memory based on neural population coding. Our model describes recalled feature values as the output of an optimal decoding of spikes generated by a tuned population of neurons. This neural model provides a better account of human recall data than an influential model that assumes errors can be described as a mixture of normally distributed noise and random guesses. The retro-cue benefit is revealed to be consistent with a higher firing rate of the population encoding the cued versus uncued items, with no difference in tuning specificity. Additionally, a retro-cued item is less likely to be swapped with another item in memory, an effect that can also be explained by greater activity of the underlying population. These results provide a parsimonious account of the effects of retrospective attention on recall and demonstrate a principled method for investigating neural representations with behavioral tasks. PMID- 29272733 TI - Hepatic microabscesses during CMV reactivation in a multiple sclerosis patient after alemtuzumab treatment. AB - The anti-CD52 monoclonal antibody alemtuzumab is a highly active treatment for multiple sclerosis (MS) causing rapid depletion of B and T lymphocytes with nadir one month after last infusion. Opportunistic Cytomegalovirus (CMV) infections have been reported in MS patients treated with this drug. We report one patient who developed a CMV reactivation with hepatic involvement three weeks after the first cycle of alemtuzumab. This patient, promptly diagnosed and treated, achieved a complete recovery with valganciclovir. The possibility of this treatable opportunistic infection should be considered by neurologists in febrile patients with hepatic markers alteration after treatment with alemtuzumab. PMID- 29272734 TI - The influence of developmental timing on B cell diversity. AB - The adult adaptive immune system is comprised of a wide spectrum of lymphocyte subsets with distinct antigen receptor repertoire profiles, effector functions, turnover times and anatomical locations, acting in concert to provide optimal host protection and self-regulation. While some lymphocyte populations are replenished by bone marrow hematopoietic stem cells (HSCs) through adulthood, others emerge during a limited window of time during fetal and postnatal life and sustain through self-replenishment. Despite fundamental implications in immune regeneration, early life immunity and leukemogenesis, the impact of developmental timing on lymphocyte output remains an under explored frontier in immunology. In this review, we spotlight recent insights into the developmental changes in B cell output in mice and explore how several age specific cellular and molecular factors may shape the formation of a diverse adaptive immune system. PMID- 29272735 TI - Flip-angle based ratiometric approach for pulsed CEST-MRI pH imaging. AB - Several molecules have been exploited for developing MRI pH sensors based on the chemical exchange saturation transfer (CEST) technique. A ratiometric approach, based on the saturation of two exchanging pools at the same saturation power, or by varying the saturation power levels on the same pool, is usually needed to rule out the concentration term from the pH measurement. However, all these methods have been demonstrated by using a continuous wave saturation scheme that limits its translation to clinical scanners. This study shows a new ratiometric CEST-MRI pH-mapping approach based on a pulsed CEST saturation scheme for a radiographic contrast agent (iodixanol) possessing a single chemical exchange site. This approach is based on the ratio of the CEST contrast effects at two different flip angles combinations (180 degrees /360 degrees and 180 degrees /720 degrees ), keeping constant the mean irradiation RF power (Bavg power). The proposed ratiometric approach index is concentration independent and it showed good pH sensitivity and accuracy in the physiological range between 6.0 and 7.4. PMID- 29272736 TI - The effectiveness of clinical education models for undergraduate nursing programs: A systematic review. AB - Clinical nurse education is a major part of all undergraduate programs preparing nurses for competent professional practice. While research mostly evaluated specific clinical education models, few studies compared different type of models and limited attention has been given to the effect on student learning outcomes. This systematic review aimed to examine the effectiveness of clinical education models for undergraduate nursing programs. This systematic review utilised the Joanna Briggs Institute systematic review approach (JBI, 2014). A web-based literature search was conducted to identify research studies published from 2002 to 2015 using a three-step search strategy. All selected papers were assessed by at least two independent reviewers for inclusion criteria, methodological validity, and data extraction in the review. This systematic review included nine studies including two pre-post-test studies with a control group totalling 1893 participants including 1286 nursing students. The evidence regarding the effectiveness of clinical education models for undergraduate nursing programs is notably weak; however this review found limited evidence that the clinical facilitator model is preferable to the preceptor model and the Clinical Education Unit (CEU) model provided greater engagement and an enhanced learning environment compared with the standard facilitation model. PMID- 29272737 TI - The effect of intranasal oxytocin on neural response to facial emotions in healthy adults as measured by functional MRI: A systematic review. AB - Abnormalities in responses to human facial emotions are associated with a range of psychiatric disorders. Addressing these abnormalities may therefore have significant clinical applications. Previous meta-analyses have demonstrated effects of the neuropeptide oxytocin on behavioural response to facial emotions, and effects on brain, as measured by functional MRI. Evidence suggests that these effects may be mediated by sex and the role of eye gaze. However, the specific effect of oxytocin on brain response to facial emotions in healthy adults has not been systematically analysed. To address this question, this further systematic review was conducted. Twenty-two studies met our inclusion criteria. In men, oxytocin consistently attenuated brain activity in response to negative emotional faces, particularly fear, compared with placebo, while in women, oxytocin enhanced activity. Brain regions consistently involved included the amygdala, fusiform gyrus and anterior cingulate cortex. In some studies, oxytocin increased fixation changes towards the eyes with enhanced amygdala and/or fusiform gyrus activation. By enhancing understanding of emotion processing in healthy subjects, these pharmacoimaging studies provide a theoretical basis for studying deficits in clinical populations. However, progress to date has been limited by low statistical power, methodological heterogeneity, and a lack of multimodal studies. PMID- 29272738 TI - Monomeric amyloid-beta reduced amyloid-beta oligomer-induced synapse damage in neuronal cultures. AB - Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta (Abeta) in the brain. Abeta oligomers are believed to cause synapse damage resulting in the memory deficits that are characteristic of this disease. Since the loss of synaptic proteins in the brain correlates closely with the degree of dementia in Alzheimer's disease, the process of Abeta-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble Abeta oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons. When applied to synaptosomes Abeta oligomers increased cholesterol concentrations and caused aberrant activation of cytoplasmic phospholipase A2 (cPLA2). In contrast, Abeta monomer preparations did not affect cholesterol concentrations or activate synaptic cPLA2, nor did they damage synapses. The Abeta oligomer-induced aggregation of cellular prion proteins (PrPC) at synapses triggered the activation of cPLA2 that leads to synapse degeneration. Critically, Abeta monomer preparations did not cause the aggregation of PrPC; rather they reduced the Abeta oligomer-induced aggregation of PrPC. The presence of Abeta monomer preparations also inhibited the Abeta oligomer-induced increase in cholesterol concentrations and activation of cPLA2 in synaptosomes and protected neurons against the Abeta oligomer-induced synapse damage. These results support the hypothesis that Abeta monomers are neuroprotective. We hypothesise that synapse damage may result from a pathological Abeta monomer:oligomer ratio rather than the total concentrations of Abeta within the brain. PMID- 29272739 TI - Eyes that bind us: Gaze leading induces an implicit sense of agency. AB - Humans feel a sense of agency over the effects their motor system causes. This is the case for manual actions such as pushing buttons, kicking footballs, and all acts that affect the physical environment. We ask whether initiating joint attention - causing another person to follow our eye movement - can elicit an implicit sense of agency over this congruent gaze response. Eye movements themselves cannot directly affect the physical environment, but joint attention is an example of how eye movements can indirectly cause social outcomes. Here we show that leading the gaze of an on-screen face induces an underestimation of the temporal gap between action and consequence (Experiments 1 and 2). This underestimation effect, named 'temporal binding,' is thought to be a measure of an implicit sense of agency. Experiment 3 asked whether merely making an eye movement in a non-agentic, non-social context might also affect temporal estimation, and no reliable effects were detected, implying that inconsequential oculomotor acts do not reliably affect temporal estimations under these conditions. Together, these findings suggest that an implicit sense of agency is generated when initiating joint attention interactions. This is important for understanding how humans can efficiently detect and understand the social consequences of their actions. PMID- 29272740 TI - Understanding environmental sounds in sentence context. AB - There is debate about how individuals use context to successfully predict and recognize words. One view argues that context supports neural predictions that make use of the speech motor system, whereas other views argue for a sensory or conceptual level of prediction. While environmental sounds can convey clear referential meaning, they are not linguistic signals, and are thus neither produced with the vocal tract nor typically encountered in sentence context. We compared the effect of spoken sentence context on recognition and comprehension of spoken words versus nonspeech, environmental sounds. In Experiment 1, sentence context decreased the amount of signal needed for recognition of spoken words and environmental sounds in similar fashion. In Experiment 2, listeners judged sentence meaning in both high and low contextually constraining sentence frames, when the final word was present or replaced with a matching environmental sound. Results showed that sentence constraint affected decision time similarly for speech and nonspeech, such that high constraint sentences (i.e., frame plus completion) were processed faster than low constraint sentences for speech and nonspeech. Linguistic context facilitates the recognition and understanding of nonspeech sounds in much the same way as for spoken words. This argues against a simple form of a speech-motor explanation of predictive coding in spoken language understanding, and suggests support for conceptual-level predictions. PMID- 29272742 TI - Ordering clinical realities: Controversy and multiplicity in alcohol and other drug treatment for young adults. AB - BACKGROUND: Although young adults receiving treatment for alcohol and other drug (AOD) use often experience disadvantaged life circumstances, there has been little qualitative research into how treatment agencies understand and respond to intersections between these life circumstances and the AOD use of their clients. METHODS: This article draws on analytic techniques from science and technology studies to detail how treatment clinicians become sensitive to client life circumstances; how therapeutic plans of action are formed; and how clients respond to these processes. Ethnographic data were gathered through interviews with clinicians and agency staff, documentary analysis and field observations in a public AOD clinic treating young adults in Melbourne, Australia. RESULTS: Findings detail emerging controversies concerning dependence, dosage, mental health and AOD comorbidities, forensic treatment, and resumption of use after treatment. CONCLUSION: I argue that each controversy can be understood as a contest between aggregated, humanist and situated modes of ordering clinical phenomena. Aggregated modes of ordering are crafted for coherence at a population level and position AOD use as the primary problem in clients' lives. Humanist modes of ordering foreground clients' poor life circumstances and lack of resources, and frame treatment to address AOD use as benevolent. In situated modes of ordering, the effects of AOD use are transformed by emotional, social and material entanglements and AOD use is no longer necessarily the problem in clients' lives. I conclude that, since clinicians seem to readily abandon aggregated approaches in favour of humanist ones, and humanist modes of ordering are often ineffective insofar as they are politically disempowering and engender client resistance, the scientific task of constructing practice tools for more situated approaches in clinical AOD treatment settings seems to be a priority. PMID- 29272741 TI - Neurotensin Receptor 3/Sortilin Contributes to Tumorigenesis of Neuroendocrine Tumors Through Augmentation of Cell Adhesion and Migration. AB - Neurotensin (NTS), a 13-amino acid peptide which is distributed predominantly along gastrointestinal tract, has multiple physiologic and pathologic functions, and its effects are mediated by three distinct NTS receptors (NTSRs). Overexpression and activation of NTS signaling components, especially NTS and/or NTSR1, are closely linked with cancer progression and metastasis in various types of cancers including neuroendocrine tumors (NETs). Although deregulation of NTSR3/sortilin has been implicated in a variety of human diseases, the expression and role of NTSR3/sortilin in NETs have not been elucidated. In this study, we investigated the expression and oncogenic effect of NTSR3/sortilin in NETs. Increased protein levels of NTSR3/sortilin were noted in the majority of human clinical NETs (n=21) by immunohistochemical analyses compared with normal tissues (n=12). Expression of NTS and NTSR3/sortilin was also noted in all tested NET cell lines. In addition, small interfering RNA-mediated knockdown of NTSR3/sortilin decreased cell number without alteration of cell cycle progression and apoptosis induction in NET cell lines BON and QGP-1. Moreover, silencing of NTSR3/sortilin significantly suppressed cell adhesion and cell migration with inhibition of focal adhesion kinase and Src phosphorylation in the NET cells. Our results demonstrate increased expression of NTSR3/sortilin in NET patient tissues and a critical role of NTSR3/sortilin on NET cell adhesion and migration suggesting that NTSR3/sortilin contributes to NET tumorigenesis. PMID- 29272743 TI - Racial disparities in temporal lobe epilepsy. AB - OBJECTIVE: This study reports on epilepsy type period prevalence and black-white racial differences in a large patient population in the Southeastern United States. METHODS: For all patients visiting the University of Alabama at Birmingham's seizure monitoring unit between 2000 and 2011 (n = 3240), video EEG diagnosis was recorded along with basic demographic information. Descriptive statistics and multivariate logistic regression were used to identify factors associated with temporal lobe epilepsy (TLE) diagnosis. RESULTS: The racial distribution was 77.3% white, and 20.0% black (other races were only 2.3% of the population). Most patients had either TLE (n = 630) or PNES (n = 1150) compared to other focal (n = 424) or generalized epilepsies (n = 224). The diagnosis of TLE was significantly greater for blacks than whites (odds ratio [OR] = 1.87, 95% confidence interval [CI] 1.47-2.37). The period prevalence measures for the other conclusively diagnosed epilepsies were not significantly different. Women were disproportionately represented in the study population, and black women carried the most statistical weight for the TLE prevalence difference. INTERPRETATION: The nearly two-fold larger period prevalence of TLE among black patients is a striking finding that merits explanation. Although some selection bias exists due to a moderately lower than expected representation of blacks, socioeconomic status or access to care should not be assumed to be the only factors that might be responsible for the prevalence difference. Rather, all clues for distinct pathophysiological racial differences should be explored. PMID- 29272744 TI - Maternal avoidance, anxiety cognitions and interactive behaviour predicts infant development at 12 months in the context of anxiety disorders in the postpartum period. AB - BACKGROUND: Few studies have examined the relation between anxiety disorders in the postpartum period and cognitive as well as language development in infancy. AIMS: This longitudinal study investigated whether anxiety disorder in the postpartum period is linked to infant development at twelve months. A closer look was also taken at a possible link between maternal interaction and infant development. STUDY DESIGN: Subjects were videotaped during a Face-to-Face-Still Face interaction with their infant (M = 4.0 months). Specific maternal anxiety symptoms were measured by self-report questionnaires (Anxiety Cognition Questionnaire (ACQ), Body Sensations Questionnaire (BSQ), Mobility Inventory (MI)) to check for a connection with infant development. The Bayley Scales of Infant and Toddler Development-III (Bayley-III) were used to assess infant language and cognitive development at one year of age. SUBJECTS: n = 34 mothers with anxiety disorder (SCID-I; DSM-IV) and n = 47 healthy mothers with their infant. OUTCOME MEASURES: Infant performance on Bayley-III language and cognitive scales. RESULTS: Infants of mothers with anxiety disorder yielded significantly lower language scores than infants of controls. No significant group differences were found regarding infant cognitive development. Exploratory analyses revealed the vital role of "maternal avoidance accompanied" in infant language and cognitive development. Maternal neutral engagement, which lacks positive affect and vocalisations, turned out as the strongest negative predictor of cognitive development. Maternal anxiety cognitions and joint activity in mother-infant interaction were the strongest predictors of infant language performance. CONCLUSIONS: Results underline the importance to also consider the interaction behaviour of women with anxiety disorders to prevent adverse infant development. PMID- 29272745 TI - The Cu2+-nitrilotriacetic acid complex improves loading of alpha-helical double histidine site for precise distance measurements by pulsed ESR. AB - Site-directed spin labeling using two strategically placed natural histidine residues allows for the rigid attachment of paramagnetic Cu2+. This double histidine (dHis) motif enables extremely precise, narrow distance distributions resolved by Cu2+-based pulsed ESR. Furthermore, the distance measurements are easily relatable to the protein backbone-structure. The Cu2+ ion has, till now, been introduced as a complex with the chelating agent iminodiacetic acid (IDA) to prevent unspecific binding. Recently, this method was found to have two limiting concerns that include poor selectivity towards alpha-helices and incomplete Cu2+ IDA complexation. Herein, we introduce an alternative method of dHis-Cu2+ loading using the nitrilotriacetic acid (NTA)-Cu2+ complex. We find that the Cu2+-NTA complex shows a four-fold increase in selectivity toward alpha-helical dHis sites. Furthermore, we show that 100% Cu2+-NTA complexation is achievable, enabling precise dHis loading and resulting in no free Cu2+ in solution. We analyze the optimum dHis loading conditions using both continuous wave and pulsed ESR. We implement these findings to show increased sensitivity of the Double Electron-Electron Resonance (DEER) experiment in two different protein systems. The DEER signal is increased within the immunoglobulin binding domain of protein G (called GB1). We measure distances between a dHis site on an alpha-helix and dHis site either on a mid-strand or a non-hydrogen bonded edge-strand beta-sheet. Finally, the DEER signal is increased twofold within two alpha-helix dHis sites in the enzymatic dimer glutathione S-transferase exemplifying the enhanced alpha helical selectivity of Cu2+-NTA. PMID- 29272746 TI - Selective responses of class III plant peroxidase isoforms to environmentally relevant UV-B doses. AB - Efficient hydrogen peroxide detoxification is an essential aspect of plant defence against a large variety of stressors. Among others, class III peroxidase (POD, EC 1.11.1.7) enzymes provide this function. Previous studies have shown that PODs are present in several isoforms and have in general low substrate specificities. The aim of our work was to study how various assays based on using various substrates reflect differences in peroxidase activities of tobacco leaves due to either developmental or environmental factors. The former factor was studied comparing fully developed leaves of the 3rd and 5th nodes; and the latter was achieved using plants acclimated to low doses of supplementary UV-B (280-315 nm) in growth chambers. To investigate the above, POD activities were measured using three different, commonly used chromophore substrates: ABTS (2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid)), guaiacol (2-methoxyphenol), OPD (o phenylenediamine) and a fourth substrate, the secondary metabolite quercetin. All substrates registered a UV-B induced increase in leaf peroxidases as compared to untreated controls, although to different extents. However, age-related differences between upper and lower leaves were only detectable when either ABTS or quercetin were used as substrates. Additionally, native PAGE separation of POD isoforms followed by visualisation using one of the substrates showed that leaf acclimation to supplementary UV-B is realized via a selective activation of POD isoforms. PMID- 29272747 TI - The level of midgut penetration of two begomoviruses affects their acquisition and transmission by two species of Bemisia tabaci. AB - Begomoviruses are transmitted by whiteflies in a persistent manner, but factors responsible for the variation of virus transmission by different species are poorly understood. We examined ingestion of papaya leaf curl China virus (PaLCuCNV) and tomato yellow leaf curl virus (TYLCV) by two species of the Bemisia tabaci complex, MEAM1 and MED, and then quantified the virion concentrations in different organs/tissues in each species. We found that PaLCuCNV penetrated the midgut wall of MED less efficiently than MEAM1, resulting in lower efficiency of PalCuCNV transmission by MED than that by MEAM1, while TYLCV penetrated the midgut wall of both species and was transmitted by them at similar levels of efficiency. Virus coat protein determined the virus capacity to cross the midgut wall of a given whitefly species. These data indicate that the level of midgut penetration determines virus acquisition and transmission by whiteflies in the first instance. PMID- 29272748 TI - Strand-like structures and the nonstructural proteins 5, 3 and 1 are present in the nucleus of mosquito cells infected with dengue virus. AB - Dengue virus (DENV) is an arbovirus, which replicates in the endoplasmic reticulum. Although replicative cycle takes place in the cytoplasm, some viral proteins such as NS5 and C are translocated to the nucleus during infection in mosquitoes and mammalian cells. To localized viral proteins in DENV-infected C6/36 cells, an immunofluorescence (IF) and immunoelectron microscopy (IEM) analysis were performed. Our results indicated that C, NS1, NS3 and NS5 proteins were found in the nucleus of DENV-infected C6/36 cells. Additionally, complex structures named strand-like structures (Ss) were observed in the nucleus of infected cells. Interestingly, the NS5 protein was located in these structures. Ss were absent in mock-infected cells, suggesting that DENV induces their formation in the nucleus of infected mosquito cells. PMID- 29272749 TI - Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. AB - The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity. PMID- 29272750 TI - Substrate-derived triazolo- and azapeptides as inhibitors of cathepsins K and S. AB - Cathepsin (Cat) K is a critical bone-resorbing protease and is a relevant target for the treatment of osteoporosis and bone metastasis, while CatS is an attractive target for drugs in autoimmune diseases (e.g. rheumatoid arthritis), emphysema or neuropathic pain. Despite major achievements, current pharmacological inhibitors are still lacking in safety and may have damaging side effects. A promising strategy for developing safer reversible and competitive inhibitors as new lead compounds could be to insert non-cleavable bonds at the scissile P1-P1' position of selective substrates of CatS and CatK. Accordingly, we introduced a 1,4-disubstituted 1,2,3-triazole heterocycle that mimics most of the features of a trans-amide bond, or we incorporated a semicarbazide bond (azaGly residue) by replacing the alpha-carbon of the glycyl residue at P1 by a nitrogen atom. AzaGly-containing peptidomimetics inhibited powerfully their respective target proteases in the nM range, while triazolopeptides were weaker inhibitors (Ki in the MUM range). The selectivity of the azaGly CatS inhibitor (1b) was confirmed by using spleen lysates from wild-type vs CatS-deficient mice. Alternatively, the azaGly bradykinin-derived CatK inhibitor (2b) potently inhibited CatK (Ki = 9 nM) and impaired its kininase activity in vitro. Molecular modeling studies support that the semicarbazide bond of 2b is more favorable than the 1,2,3-triazole linkage of the bradykinin-derived pseudopeptide 2a to preserve an effective affinity towards CatK, its protease target. PMID- 29272751 TI - Schema modes and dissociation in borderline personality disorder/traits in adolescents or young adults. AB - Dramatic mental shifts in young patients with borderline personality disorder (BPD) can be understood to occur via dissociative processes found in immature schema modes. A schema mode is an organized pattern of thought, affect and behaviour based on a set of core beliefs. These maladaptive modes are not integrated into a united personality structure and can function in a dissociated form. The aim of this study was to empirically assess the relationship between dysfunctional schema modes and dissociation in BPD. Forty-two young patients with BPD confirmed by the structured clinical interview for DSM-IV Axis-II personality disorders (SCID-II) were further assessed by the Psychiatric Diagnostic Screening Questionnaire (PDSQ), DSM-IV/ICD-10 Personality Questionnaire (DIP-Q), Schema Mode Inventory (SMI) and Wessex Dissociation Scale (WDS). Pearson correlations assessed associations and stepwise regression explored the extent of these associations. The strongest correlations were found between dissociation and the following modes: Detached Protector, Angry Child, Impulsive Child, Punitive Parent, Demanding Parent, and Vulnerable Child. Stepwise regression analysis indicated that schema modes explained 58% of the variance in dissociation. The schema modes that significantly predicted dissociation were the Detached Protector and Impulsive Child modes. Key therapeutic targets in treating adolescents with BPD include detachment and impulsivity. PMID- 29272752 TI - The multidimensional schizotypy scale-brief: Scale development and psychometric properties. AB - This article reports on the development and psychometric properties of a brief version of the Multidimensional Schizotypy Scale (MSS-B). The MSS-B contains 38 items that assess positive, negative, and disorganized schizotypy. The scale was derived from the full-length Multidimensional Schizotypy Scale, and the positive, negative, and disorganized subscales were designed to provide the same content coverage as the original subscales. Scale development involved a derivation sample (n = 6265) and a separate cross-validation sample (n = 1000), both drawn from four universities and Amazon Mechanical Turk. The MSS-B was derived using classical test theory, item response theory, and differential item functioning. The three subscales exhibited high internal-consistency reliability, good item- and model-fit, good test information functions, and expected patterns of intercorrelations and associations with neuroticism, sex, and race/ethnicity. This pattern of findings was almost identical between the derivation and cross validation samples. Furthermore, the pattern of findings was closely comparable for MSS-B subscales and the full-length MSS subscales. The MSS-B appears to offer a promising brief measure for assessing schizotypy. PMID- 29272753 TI - Comorbidities contribute to the risk of cancer death among Aboriginal and non Aboriginal South Australians: Analysis of a matched cohort study. AB - BACKGROUND: Aboriginal Australians have poorer cancer survival than other Australians. Diagnoses at later stages and correlates of remote area living influence, but do not fully explain, these disparities. Little is known of the prevalence and influence of comorbid conditions experienced by Aboriginal people, including their effect on cancer survival. This study quantifies hospital recorded comorbidities using the Elixhauser Comorbidity Index (ECI), examines their influence on risk of cancer death, then considers effect variation by Aboriginality. METHODS: Cancers diagnosed among Aboriginal South Australians in 1990-2010 (N = 777) were matched with randomly selected non-Aboriginal cases by birth year, diagnostic year, sex, and primary site, then linked to administrative hospital records to the time of diagnosis. Competing risk regression summarised associations of Aboriginal status, stage, geographic attributes and comorbidities with risk of cancer death. RESULTS: A threshold of four or more ECI conditions was associated with increased risk of cancer death (sub-hazard ratio SHR 1.66, 95%CI 1.11-2.46). Alternatively, the presence of any one of a subset of ECI conditions was associated with similarly increased risk (SHR = 1.62, 95%CI 1.23 2.14). The observed effects did not differ between Aboriginal and matched non Aboriginal cases. However, Aboriginal cases experienced three times higher exposure than non-Aboriginal to four or more ECI conditions (14.2% versus 4.5%) and greater exposure to the subset of ECI conditions (20.7% versus 8.0%). CONCLUSION: Comorbidities at diagnosis increased the risk of cancer death in addition to risks associated with Aboriginality, remoteness of residence and disease stage at diagnosis. The Aboriginal cohort experienced comparatively greater exposure to comorbidities which adds to disparities in cancer outcomes. PMID- 29272754 TI - Comparison of histological findings and the results of energy-dispersive X-ray spectrometry analysis in experimental electrical injury. AB - The findings of histological examination and the results of energy-dispersive X ray spectrometry (EDX) analysis were compared to identify skin metallization in experimental electrical injury. Rats were divided into three experimental groups (n = 5, each group): control, current exposure for five seconds, and current exposure for ten seconds. A relatively high peak of copper, which was used as an electrical conductor, was detected in formalin-fixed skin samples of the two current exposure groups by EDX. There was a significant increase of the specific X-ray intensity in the two current exposure groups compared to the control group. On histological examination, epidermal nuclear elongation was observed in all samples of the two current exposure groups. However, deposition of metal was observed in two samples of each current exposure group. Metallization is an important finding for the diagnosis of electrocution. The present results suggest that EDX analysis is useful for the proof of metallization in electrocution, even where it is not identified on morphological examination. PMID- 29272755 TI - Sex and age at death estimation from the sternal end of the fourth rib. Does Iscan's method really work? AB - The fourth rib has been used commonly in order to estimate age at death and even sex in skeletal remains but many often, Iscan's estimates do not adjust to the real age of the individual. Population specific references for sex and age-at death estimation from the sternal end of the fourth rib are presented for a contemporary Mexican sample. A total of 504 ribs with known sex and age from a morgue sample were studied (444 males, 60 females, 17 to 92 years old). The height and breadth of the sternal end of the rib were sexually dimorphic (p = .000), and allowed a correct sex assignment in 73.3% to 84% of the cases from univariate and multivariate discriminant functions. With regard to age-at-death estimation, the morphological changes summarized by the phases of the sternal end of the fourth rib are correlated with known age in this sample (Spearman's Rho, p = .000). However, the original age intervals tend to underestimate age at death and inaccuracy increases with phase scored in males. Descriptive statistics for rib phase are provided for males and females, and new age-at-death estimates based on transition analysis and Bayesian statistics are provided for the male sample. The test of universally applied methods and the development of population specific references is an important task for forensic anthropology around the world. PMID- 29272756 TI - Delayed diagnosis of contralateral tension pneumothorax during robotic lung wedge resection. PMID- 29272757 TI - Putative identification of components in Zengye Decoction and their effects on glucose consumption and lipogenesis in insulin-induced insulin-resistant HepG2 cells. AB - Zengye Decoction (ZYD) is a well-known traditional medicine in China used for treating diseases associated with "Yin deficiency" such as diabetes. However, little information is available on its components, pharmacological effects and underlying mechanisms. This study was designed to identify its active components and evaluate the effects and mechanisms of ZYD on glucose consumption and lipogenesis in insulin-induced insulin-resistant (IR)-HepG2 cells. In this study, 45 compounds of ZYD were putatively identified, in which the iridoid glycosides such as catalpol, aucubin and harpagide were identified as the main components. The insulin-resistant (IR)-HepG2 cell model was established and the effect of ZYD at three doses (0.17, 0.5 and 1.5 MUg/mL) on cell growth was evaluated with an IncuCyteTM live-cell imaging system. The effects of ZYD on glucose consumption and uptake were evaluated by glucose consumption and uptake assay. Meanwhile, the effect of ZYD on lipogenesis was investigated in IR-HepG2 cells by oil red O (ORO) staining. Western blot was applied to observe the changes in some of the key factors involved in glucose metabolism and lipogenesis. It was found that the ZYD at a dose of 1.5 MUg/mL exhibited an inhibitory activity on IR-HepG2 cell growth. Besides, ZYD at doses of 0.5 and 1.5 MUg/mL accelerated the glucose consumption, glucose uptake and reduced the lipogenesis in the IR-HepG2 cells. Western blot studies revealed that ZYD phosphorylated AMP-activated protein kinase alpha subunits (AMPKalpha), upregulated hexokinase (HK), phosphorylated acetyl-CoA carboxylase alpha (pACC1) and carnitine palmitoyltransferase 1A (CPT1A) in the IR-HepG2 cells. These results indicate ZYD promotes glucose consumption and uptake, and attenuates lipogenesis in IR-HepG2 cells, which may be involved in activating AMPK and regulating its downstream factors including HK, pACC1 and CPT1A. PMID- 29272758 TI - The use of diffusional kurtosis imaging and neurite orientation dispersion and density imaging of the brain in major depressive disorder. AB - Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) are new diffusional magnetic resonance imaging (dMRI) techniques for the characterization of neural tissues in human brain. In this study, we used these dMRI techniques to evaluate the whole-brain microstructural changes in patients with major depressive disorder (MDD). Twenty-three patients with MDD and 26 healthy subjects underwent dMRI. We compared the dMRI metrics between the 2 groups and examined the relationships between the metrics and the clinical symptoms of MDD. The MDD patients showed significant fractional anisotropy reduction in the bilateral parietal, right parieto-occipital, and right superior temporal corti, compared with the controls. Mean kurtosis values were significantly reduced in MDD patients in the right superior temporal cortex and bilateral posterior thalamic radiation. Neurite density index reductions were found in the right superior temporal cortex, bilateral insulae, right inferior frontal cortex, left parahippocampal region, left middle cerebellar peduncle, and right cerebellum. Regarding the orientation dispersion index (ODI), we detected significant decreases in the left thalamus and left occipital cortex, and significant increases in the bilateral superior longitudinal fasciculi and left posterior thalamic radiation tract. Further, there were significant positive correlations between the total Hamilton Depression Rating scale-21 scores and the ODI values in the right frontal gyri. These results suggest that the DKI and NODDI methods may provide more information about microstructural abnormalities in patients with MDD than the DTI method. It is thus expected that these techniques will be adopted as the informative methods for neuroimaging study. PMID- 29272759 TI - A direct two-dimensional pressure formulation in molecular dynamics. AB - Two-dimensional (2D) pressure field estimation in molecular dynamics (MD) simulations has been done using three-dimensional (3D) pressure field calculations followed by averaging, which is computationally expensive due to 3D convolutions. In this work, we develop a direct 2D pressure field estimation method which is much faster than 3D methods without losing accuracy. The method is validated with MD simulations on two systems: a liquid film and a cylindrical drop of argon suspended in surrounding vapor. PMID- 29272760 TI - The effect of different pi-bridge configuration on bi-anchored triphenylamine and phenyl modified triphenylamine based dyes for dye sensitized solar cell (DSSC) application: A theoretical approach. AB - Twenty eight bi-anchored triphenylamine (TH-1 to TH-14) and phenyl modified triphenylamine (PH-TH-1 to PH-TH-14) based metal free organic dyes are designed for DSSC application. The electronic effect of different pi-bridge configurations in donor-pi-bridge-acceptor (D-pi-A)2 structure was theoretically simulated and verified using density functional theory (DFT) and time dependent density functional theory (TD-DFT). The triphenylamine and phenyl modified triphenylamine groups are used as donor and cyanoacrylic acid group is used as acceptor. Thiophene and cyanovinyl groups are used as pi-bridge. The ground state molecular structure was optimized by density functional theory and the electronic absorption spectra were calculated by time dependent density functional theory. The light harvesting efficiency (LHE), dye regeneration energy (DeltaGreg) and electron injection energy (DeltaGinject) are determined by computational examination. It is observed that, when the number of pi-bridge increases, the band gap of the dye decreases. Also the absorption maximum and molar extinction coefficient of the dyes are increased. Theoretical result shows that the thiophene-cyanovinyl and thiophene-thiophene-cyanovinyl-cyanovinyl configurations give broader and red shifted absorption spectrum compared to other configurations. Also the results of phenyl modified triphenylamine (PH-TH) dyes clearly show better absorption and dye regeneration energy compared to TH dyes. PMID- 29272761 TI - EphrinB2 signaling enhances osteogenic/odontogenic differentiation of human dental pulp stem cells. AB - OBJECTIVE: To investigate the role of the EphrinB2 signaling pathway in the osteogenesis/odontogenesis of human dental pulp stem cells (DPSCs). DESIGN: The endogenous expression levels of EphrinB2 and its cognate receptors EphB2 and EphB4 in DPSCs were analyzed by qRT-PCR and Western blotting after 7, 14 and 21 days of osteogenic/odontogenic induction culture. Additionally, the phosphorylation of EphrinB2, EphB4 and ERK1/2 proteins at early time-points following osteogenic induction, were also investigated by Western blots. Subsequently, we investigated whether supplementation of recombinant EphrinB2-Fc within the induction milieu can enhance the osteogenic/odontogenic differentiation of DPSCs. RESULTS: Endogenous gene and protein expression levels of EphrinB2, EphB2 and EphB4 were upregulated in induced versus non-induced DPSCs, over 21 days of osteogenic/odontogenic induction. Western blots showed increase in phosphorylated EphrinB2, EphB4 and ERK1/2 proteins at early time points following osteogenic induction. Preliminary investigation of a concentration range (0, 0.5, 1 and 2 MUg/ml) of recombinant EphrinB2-Fc within osteogenic induction media, showed that 0.5 MUg/ml was optimal for enhancing the osteogenic/odontogenic differentiation of DPSCs over a culture duration of 14 days. Subsequently, more comprehensive qRT-PCR analysis with 0.5 MUg/ml EphrinB2 Fc revealed significant upregulation of several key osteogenic marker genes in treated versus untreated DPSCs after 21 days of osteogenic/odontogenic induction. By 7 days of osteogenic induction, DPSCs treated with 0.5 MUg/ml EphrinB2-Fc exhibited significantly more calcium mineralization (Alizarin red S staining) and alkaline phosphatase activity than the untreated control. CONCLUSIONS: EphrinB2 signaling plays a key role in the osteogenic/odontogenic differentiation of DPSCs. PMID- 29272762 TI - Do we consider paid sick leave when deciding to get vaccinated? AB - This study investigated the effect of paid sick leave on workers' decisions to obtain vaccinations for the seasonal flu. Our vaccination decision model suggested that the marginal effect of paid sick leave depended on the reduced cost of obtaining a vaccination now and the expected income benefit from claiming paid sick leave after flu infection. Our hypothesis was that these effects vary according to workers' income levels. To confirm this hypothesis, we examined 11,702 participants in the National H1N1 Flu Survey (NHFS) conducted in late 2009 to early 2010 and measured the marginal effect using a Bayesian endogenous covariates regression model. The results of our estimation indicate that having paid sick leave did affect workers' vaccination decisions differently based on their income levels. Low-income workers were willing to be vaccinated because of the positive expected income benefit. High-income workers were willing to be vaccinated because the positive cost effect dominated the negative expected income benefit. PMID- 29272763 TI - Developing an adequate supply of health services: Taiwan's path to Universal Health Coverage. AB - Universal Health Coverage (UHC) calls for universal effective coverage, which emphasizes that people must have reasonably equal access to covered services. A critical question then arises: what policies can a nation adopt to assure an adequate supply of services and distribute them reasonably to each community and socioeconomic strata? Taiwan relied on incentives, public and private partnership and effective regulations to produce the adequate supply for UHC and distributed them. Taiwan's experience holds a valuable lesson for other nations. Taiwan was the last state in the 20th century to achieve UHC when it implemented the National Health Insurance (NHI) program in 1995. Political timing was crucial in the government's decision to achieve UHC, but the key to its success in providing effective coverage to its 23 million population was the readiness of the health service sector, the result of two decades of planning and development in the pre NHI period. This paper analyzes how Taiwan historically built up the supply of health services that made achieving UHC possible. We identified four key strategies adopted in the health service sector development, namely: 1) enhancing public-private partnerships in developing medical resources with tax incentives and subsidies; 2) ameliorating regional disparities in medical resource distribution through incentives and effective regulation; 3) safeguarding quality of care by regulating providers through licensing and accreditation programs; and 4) promoting an evidence-based policy-making process. PMID- 29272764 TI - Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy. AB - Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). Herein, we investigated whether near-infrared fluorescence (NIRF) imaging and positron-emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation in vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or 64Cu, and NIRF and PET imaging using the resulting probes (Dye-alphaGal-1 and 64Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA] alphaGal-1) were performed in 4T1 breast cancer-bearing mice treated with several rounds of sorafenib. Radiotherapy was performed in vitro and in vivo to identify the role of galectin-1 in radioresistance. NIRF and PET imaging both revealed significantly increased upregulation of galectin-1 in the hypoxic tumors after sorafenib treatment, which was verified by ex vivo biodistribution, western blotting, and enzyme-linked immunosorbent assays. Galectin-1 specific inhibition by thiodigalactoside dramatically improved the efficacy of radiotherapy, and overcame sorafenib-induced radiotherapy resistance. Taken together, galectin-1 is a key mediator of tumor resistance to radiotherapy. Targeted molecular imaging allows for real-time, noninvasive, and quantitative detection of the dynamic changes in galectin-1 levels in vivo; this introduces the possibility of early detection of tumor resistance to therapies. PMID- 29272765 TI - Amino-Si-rhodamines: A new class of two-photon fluorescent dyes with intrinsic targeting ability for lysosomes. AB - Noninvasive and specific visualization of lysosomes by fluorescence technology is critical for studying lysosomal trafficking in health and disease and for evaluating new cancer therapeutics that target tumor cell lysosomes. To date, there are two basic types of lysosomal probes whose lysosomal localization correlates with lysosomal acidity and endocytosis pathway, respectively. However, the former may suffer from pH-sensitive lysosomal localization and alkalization induced lysosomal enzyme inactivation, and the latter need long incubation time to penetrate cell membrane due to the energy-dependency of endocytosis process. In this work, a new class of two-photon fluorescent dyes, termed amino-Si rhodamines (ASiRs), were developed, which possess the intrinsic lysosome-targeted ability that is independent of lysosomal acidity and endocytosis pathway. As a result, ASiRs show not only the stable lysosomal localization against lysosomal pH changes and negligible interference to lysosomal function, but also excellent cell-membrane-permeability due to the energy-independent passive diffusion pathway. These merits, coupled with their excellent two-photon photophysical properties, long-term retention ability in lysosomes, and negligible cytotoxicity, make ASiRs very suitable for real-time and long-term tracking of lysosomes in living cells or tissues without interference to normal cellular processes. Moreover, the easy functionalization via amino linker further allows the construction of various fluorescent probes for biological targets of interest based on ASiR skeleton, as indicated by the cancer-targeted fluorescent probe ASiR6 as well as a fluorescent peroxynitrite probe ASiR-P. PMID- 29272767 TI - The severity and spread of adjustment problems of adolescents involved in mutually hostile interactions with others. AB - In the literature, bully-victims report a wider range of adjustment problems than "pure" bullies or victims. This may not be confined to the school context, but might be found in other settings as well. Involvement in mutually hostile interactions across everyday settings may more reflect adolescents' characteristic way of handling conflicts with others. We used data from a longitudinal study of a community sample of adolescents (N = 992). Cluster analyses for specific everyday settings and across settings yielded clusters high on both exposing others and being exposed to hostility. Adolescents in these clusters, and particularly across settings, reported a wider range of externalizing, internalizing, and academic problems, than adolescents in other cluster groups. Longitudinal analyses showed support for bidirectional relationships between mutually hostile conditions and problematic adjustment. We conclude that adolescents' mutual hostility experiences are associated with profoundly problematic adjustment. PMID- 29272768 TI - Left-behind adolescents' hopes and fears for the future in rural China. AB - The present study examined the contents of future hopes and fears among Chinese adolescents left behind by one or both of their rural-to-urban migrant parents compared to those from rural and urban nonmigrant families. Data from 1083 participants (50.2% boys; Mage = 13.50 years; SD = 1.06) indicated that adolescents reported future hopes and fears in a variety of life domains, including future education, academics, occupation, marriage and family, parents' and relatives' wellbeing, interpersonal relationships, leisure activities, wealth and self-related issues. Adolescents from both-parent-migrant families reported more hopes and fears for interpersonal relationships and more fears for parents' and relatives' wellbeing than other adolescents. Moreover, boys from migrant families reported more hopes for occupation and fewer hopes for interpersonal relationships than girls from migrant families, whereas no gender differences were found among adolescents from nonmigrant families. These results suggest the important roles of parental migration in adolescents' future thinking. PMID- 29272766 TI - Perceived control of anxiety as a moderator in the relationship between anxiety sensitivity and problematic alcohol use among adolescents. AB - The current study examined perceived control over anxiety as a moderator in the relationship between AS and (1) alcohol use frequency and (2) binge drinking frequency among 80 community-recruited adolescents (Mage = 15.40; 40% female). Eighty-five percent of adolescents reported consuming an alcohol beverage, while 39.5% reported binge drinking. Results indicated significant interactions between AS and perceived control. More specifically, when perceived control was low, higher anxiety sensitivity was related to increased frequency of alcohol use days, but not with binge drinking days. Alternatively, when perceived control over anxiety was high, elevated anxiety sensitivity was associated with a decreased in binge drinking days, but not with alcohol use days. Findings suggest that influence of perceived control over anxiety may be another important, malleable factor that should be considered in future etiological and intervention oriented work targeting anxiety sensitivity and alcohol misuse among adolescence. PMID- 29272769 TI - Influence of elevated Zn (II) on Anammox system: Microbial variation and zinc tolerance. AB - Nitrogen removal by anaerobic ammonium oxidation (Anammox) has attracted increasing attention in nowadays. An Anammox biofilter was subjected to a continuous loading of elevated Zn (II). The influence of Zn (II) on the nitrogen removal, microbial community and biofilm property was investigated in the condition of 23-26 degrees C and 3.5 h HRT. The nitrogen removal greatly decreased to 0.054 from the initial 0.502 kg m-3 d-1, with the Zn (II) addition. Anaerobic ammonia-oxidizing bacteria (AAOB) had self-adaption to Zn (II) in 1-10 mg L-1 and was significantly enhanced after long-term acclimatization, while the suppression threshold was 20 mg L-1. Soluble microbial products (SMP) increased correspondingly with Zn (II), while extracellular polymeric substance (EPS) climbed up initially and then decreased. Anammox biofilm performed the highest zinc adsorption as 158.27 mg g-1 SS in biofilm. High Zn (II) improved the microbial diversity and lowered the Candidatus Kuenenia abuandance to 1.38% from 20.89%. PMID- 29272770 TI - Pyrolysis kinetics and thermal behavior of waste sawdust biomass using thermogravimetric analysis. AB - The present study reports pyrolysis behavior of three waste biomass using thermogravimetric analysis to determine kinetic parameters at five different heating rates. Physiochemical characterization confirmed that these biomass have the potential for fuel and energy production. Pyrolysis experiments were carried out at five different heating rates (5-25 degrees C min-1). Five model-free methods such as Kissinger-Akahira-Sunose (KAS), Ozawa-Flynn-Wall (OFW), Friedman, Coats-Redfern, and distributed activation energy (DAEM) were used to calculate the kinetic parameters. The activation energy was found to be 171.66 kJ mol-1, 148.44 kJ mol-1, and 171.24 kJ mol-1 from KAS model; 179.29 kJ mol-1, 156.58 kJ mol-1, and 179.47 kJ mol-1 from OFW model; 168.58 kJ mol-1, 181.53 kJ mol-1, and 184.61 kJ mol-1 from Friedman model; and 206.62 kJ mol-1, 171.63 kJ mol-1, and 160.45 kJ mol-1 from DAEM model for PW, SW, AN biomass respectively. The calculated kinetic parameters are in good agreement with other reported biomass. PMID- 29272771 TI - Multiphysics simulation of algal growth in an airlift photobioreactor: Effects of fluid mixing and shear stress. AB - A multiphysics model has been developed to predict the effects of fluid mixing and shear stress on microalgal growth in an airlift photobioreactor. The model integrates multiphase flow dynamics, radiation transport, shear stress, and algal growth kinetics using an Eulerian approach. The model is first validated by comparing its predictions with experimental data, and then the radiation transport and algal growth kinetics submodels are added to predict biomass accumulation under different flow conditions. The simulations correctly predict biomass growth curves for a wide range of superficial gas flow rates and demonstrate that biomass productivity increases with increased gas flow rate due to better light delivery to microorganisms. However, at the higher gas flow rates considered, shear stress on microorganisms inhibits biomass growth. Lastly, it is shown that the Eulerian approach used here provides a less cumbersome computational approach and provides better predictions than the circulation time and Lagrangian approaches. PMID- 29272772 TI - Minimization of fermentation inhibitor generation by carbon dioxide-water based pretreatment and enzyme hydrolysis of guayule biomass. AB - Guayule rubber production leaves >80% biomass as ground bagasse, which can be hydrolyzed to release sugars but also fermentation inhibitors. Here inhibitor generation and sugar conversion by the CO2-H2O pretreatment and enzyme hydrolysis were studied. Different pretreatment conditions: 550-4900 psi, 160-195 degrees C, 10-60 min and fixed 66.7% water, generated widely varying amounts of inhibitors (per dry-bagasse mass): 0.014-0.252% hydroxymethylfurfural, 0.012 0.794% furfural and 0.17-8.02% acetic acid. The condition (195 degrees C/3400 psi/30 min) giving highest reducing sugar (86.9 +/- 1.5%) and cellulose (99.2 +/- 1.3%) conversions generated more inhibitors. Kluyveromyces marxianus fermentation showed complete growth and ethanol production inhibition at >=14 g/L combined inhibitors. Considering both sugars and inhibitors, the optimum condition was 180 degrees C, 1800 psi and 30 min, enabling 82.8 +/- 2.8% reducing sugar, 74.8 +/- 4.8% cellulose and 88.5 +/- 6.9% hemicellulose conversions with low levels of hydroxymethylfurfural (0.07%), furfural (0.25%) and acetic acid (3.0%). The optimized CO2-H2O pretreatment gave much lower inhibitor formation and higher sugar conversion than other pretreatment methods. PMID- 29272773 TI - Increased sugar yield from pre-milled Douglas-fir forest residuals with lower energy consumption by using planetary ball milling. AB - Impact of planetary ball milling on pre-milled wood fiber was studied to improve efficiency of energy consumption for bioconversion using post-harvest forest residuals. Crystalline cellulose decreased from 40.73% to 11.70% by ball milling. Crystallinity index of ball milled wood samples had a negative correlation with glucose yield (r = -0.97, p < .01), xylose/mannose (r = -0.96, p < .01), and a positive correlation with median particle size (r = 0.77, p < .01). Range of glucose yield and xylose/mannose yield for ball milled samples was found to be 24.45-59.67% and from 11.92% to 23.82%, respectively. Morphological changes of the lignocellulosic biomass were observed; the compact fiber bundles of the forest residuals were cleaved to smaller particles with lower aspect ratio with increasing intensity of ball milling. The required energy ranged from 0.50 to 2.15 kWh/kg for 7-30 min of milling respectively. PMID- 29272774 TI - Shifts in bacterial community composition and abundance of nitrifiers during aerobic granulation in two nitrifying sequencing batch reactors. AB - Shifts in bacterial community composition and abundance of nitrifiers during aerobic granulation, and the effects of wastewater composition on them were investigated using Illumina sequencing and quantitative PCR. The bacterial diversity decreased sharply during the post-granulation period. Although cultivated with different wastewater types, aerobic granular sludge (AGS) formed with similar bacterial structure. The bacterial structure in AGS was completely different from that of seed sludge. The minor genera in seed sludge, e.g., Arcobacter, Aeromonas, Flavobacterium and Acinetobacter, became the dominant genera in AGS. These genera have the potential to secrete excess extracellular polymer substances. Whereas, the dominant genera in seed sludge were found in less amount or even disappeared in AGS. During aerobic granulation, ammonia oxidizing archaea were gradually washed-out. While, ammonia-oxidizing bacteria, complete ammonia oxidizers and nitrite-oxidizing bacteria were retained. Overall, in this study, the bacterial genera with low relative abundance in seed sludge are important for aerobic granulation. PMID- 29272775 TI - Multi-pathway human exposure assessment of phthalate esters and DINCH. AB - Phthalate esters are substances mainly used as plasticizers in various applications. Some have been restricted and phased out due to their adverse health effects and ubiquitous presence, leading to the introduction of alternative plasticizers, such as DINCH. Using a comprehensive dataset from a Norwegian study population, human exposure to DMP, DEP, DnBP, DiBP, BBzP, DEHP, DINP, DIDP, DPHP and DINCH was assessed by measuring their presence in external exposure media, allowing an estimation of the total intake, as well as the relative importance of different uptake pathways. Intake via different uptake routes, in particular inhalation, dermal absorption, and oral uptake was estimated and total intake based on all uptake pathways was compared to the calculated intake from biomonitoring data. Hand wipe results were used to determine dermal uptake and compared to other exposure sources such as air, dust and personal care products. Results showed that the calculated total intakes were similar, but slightly higher than those based on biomonitoring methods by 1.1 to 3 times (median), indicating a good understanding of important uptake pathways. The relative importance of different uptake pathways was comparable to other studies, where inhalation was important for lower molecular weight phthalates, and negligible for the higher molecular weight phthalates and DINCH. Dietary intake was the predominant exposure route for all analyzed substances. Dermal uptake based on hand wipes was much lower (median up to 2000 times) than the total dermal uptake via air, dust and personal care products. Still, dermal uptake is not a well-studied exposure pathway and several research gaps (e.g. absorption fractions) remain. Based on calculated intakes, the exposure for the Norwegian participants to the phthalates and DINCH was lower than health based limit values. Nevertheless, exposure to alternative plasticizers, such as DPHP and DINCH, is expected to increase in the future and continuous monitoring is required. PMID- 29272776 TI - Pharmacokinetics of bisphenol S in humans after single oral administration. AB - Bisphenol S (BPS) has been introduced as a substitute for bisphenol A (BPA), and widely used in the manufacture of polycarbonate plastics, epoxy resins and thermal papers. Despite its adverse health outcomes and widespread exposure, pharmacokinetic data of BPS are not available for either animals or humans. The objective of the study is to describe pharmacokinetic characteristics of BPS in human body after a single oral administration with a compartmental pharmacokinetic model. Seven healthy young adults were orally exposed to 8.75MUg/bw of d4-BPS, and serum and urine samples were collected for 48h. The concentrations of total and unconjugated d4-BPS in samples were measured using HPLC-MS/MS. Based on the time-concentration profiles in serum and urine, non compartmental analysis was performed, and two-compartment model was constructed and validated. As a result of non-compartmental analysis, total d4-BPS was rapidly absorbed within 1h (0.7+/-0.3h) after oral administration, and excreted in urine with terminal half-life of <7h (6.8+/-0.7h). Fractional urinary excretion (Fue) of total d4-BPS for 48h was 92+/-17% (67-104%) for men and 70+/ 36% (59-77%) for women. The two-compartment model well described pharmacokinetic properties of BPS, and its parameter estimates were consistent with those from non-compartmental analysis. This study provides information on absorption, distribution, metabolism and elimination of BPS in human body, and the pharmacokinetic model can be utilized for estimating exposure dose of BPS, contributing to more realistic exposure assessment. PMID- 29272777 TI - Impacts of future urban expansion on summer climate and heat-related human health in eastern China. AB - China is the largest and most rapidly urbanizing nation in the world, and is projected to add an additional 200 million city dwellers by the end of 2030. While this rapid urbanization will lead to vast expansion of built-up areas, the possible climate effect and associated human health impact remain poorly understood. Using a coupled urban-atmospheric model, we first examine potential effects of three urban expansion scenarios to 2030 on summer climate in eastern China. Our simulations indicate extensive warming up to 5 degrees C, 3 degrees C, and 2 degrees C in regard to low- (>0%), high- (>75%), and 100% probability urban growth scenarios, respectively. The partitioning of available energy largely explains the changes in 2-m air temperatures, and increased sensible heat flux with higher roughness length of the underlying urban surface is responsible for the increase of nighttime planetary boundary layer height. In the extreme case (the low-probability expansion pathway), the agglomeration of impervious surfaces substantially reduces low-level atmospheric moisture, consequently resulting in large-scale precipitation reduction. However, the effect of near-surface warming far exceeds that of moisture reduction and imposes non-negligible thermal loads on urban residents. Our study, using a scenario-based approach that accounts for the full range of urban growth uncertainty by 2030, helps better evaluate possible regional climate effects and associated human health outcomes in the most rapidly urbanizing areas of China, and has practical implications for the development of sustainable urban regions that are resilient to changes in both mean and extreme conditions. PMID- 29272778 TI - Urinary trans-anti-7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene as the most relevant biomarker for assessing carcinogenic polycyclic aromatic hydrocarbons exposure. AB - Polycyclic aromatic hydrocarbons (PAH) are ubiquitous pollutants present as complex mixtures in the environment. Among them, benzo(a)pyrene (BaP) is classified as carcinogenic to humans by the International Agency of Research on Cancer. Taking into account all absorption ways, human biomonitoring allows PAH exposure assessment, but biomarkers both specific to carcinogenic effect and sufficiently sensitive are lacking. In this work, we proposed the urinary 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (7,8,9,10-OHBaP) stemming from hydrolysis of BaP-7,8-diol-9,10-epoxide, the ultimate carcinogenic BaP metabolite, as biomarker of PAH exposure. A simple and highly sensitive analytical method, with a limit of quantification (LQ) reaching 0.06pmol/L (0.02ng/L), was described and validated. The relevance of urinary 7,8,9,10-OHBaP concentrations adjustment by creatinine was demonstrated. In a group of 24 non occupationally PAH exposed subjects, only 15% of 7,8,9,10-OHBaP levels was below the LQ and the last daily void has been found as the best sampling time. Tobacco consumption had a significant positive effect on 7,8,9,10-OHBaP concentrations with a 90e percentile equal to 0.05nmole/mole creatinine (nmol/mol) and 0.03nmol/mol for smokers and non-smokers, respectively. In case of occupational PAH exposure, all the pre- and post-shift urinary 7,8,9,10-OHBaP levels of 7 non smoking workers in a prebaked electrodes production plant were above the LQ. Concentrations ranged from 0.05 to 0.91nmol/mol and accumulation of 7,8,9,10 OHBaP into organism of workers during the working week was clearly observed. The best sampling time was the post-shift at the end of week but samples should also be collected at pre-shift the beginning of week to assess the background level. Finally, the urinary 7,8,9,10-OHBaP elimination kinetic through the weekend was studied using non-linear mixed effect modelling. Mean apparent urinary half-life was 31.5h with low inter-individual variability. Describing key characteristics of urinary 7,8,9,10-OHBaP as PAH exposure biomarker, this work should promote its use for future large-scale biomonitoring campaigns. PMID- 29272779 TI - A concise route to access C-glycosidic tetrazolyl analogues of Kdo as bioisosteres. AB - Ulosonic acids are an important class of carbohydrates, including well-known representatives as 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo), 3-deoxy-d-glycero-d galacto-non-2-ulosonic acid (Kdn) and N-Acetylneuraminic acid (Neu5Ac). As part of the lipopolysaccharides (LPS) and capsular polysaccharides (CPS, K-antigen), these carbohydrates can be found on the surfaces of, both, Gram-positive and Gram negative bacteria. We developed a synthetic approach to access tetrazole derivatives of these compounds. Tetrazoles have shown to be ideal analogues for the bioisosteric replacement of carboxylic acids in several drugs, improving biological activity and pharmacokinetic properties. The presented route features indium-mediated allylation with subsequent [2 + 3]-cycloaddition as key steps, leading to tetrazole-derivative of Kdo and its corresponding C-4 epimer. The route is flexible enough to be adapted to the preparation of further tetrazole ulosonic acids. PMID- 29272780 TI - Arabinofuranose 1,2,5-orthobenzoate as a single precursor of linear alpha(1 -> 5) linked oligoarabinofuranosides. AB - Selectively protected mono-, di- and trisaccharide thioglycoside building blocks with unprotected primary hydroxy group at the non-reducing end, available in only one step from 3-O-benzoyl beta-d-arabinofuranose 1,2,5-orthobenzoate, were used in the synthesis of linear alpha(1 -> 5)-linked oligoarabinofuranosides up to octasaccharide. The obtained oligosaccharides contain 4-(2-chloroethoxy)phenyl (CEP) or 4-(2-azidoethoxy)phenyl (AEP) pre-spacer aglycons that allow preparation of neoglycoconjugates. PMID- 29272781 TI - A systematic review of the effectiveness of patient-based educational interventions to improve cancer-related pain. AB - BACKGROUND: Despite existing guidelines to assess and manage pain, the management of cancer-related pain is often suboptimal with patients often being undertreated. Inadequate pain management may be due to patient-related barriers. Educating patients may decrease these barriers. However, the effect of pain education on patient-related outcomes is still unclear. This review aimed to study the effect of educational interventions on cancer-related pain. DESIGN: We performed a systematic review of randomized controlled trials (RCTs) identified from Medline and Cinahl, from 1995 to May 2017. Two reviewers independently selected trials comparing educational intervention to usual care or an active control intervention. The methodological quality was assessed and data extraction was done independently. Primary outcome measures were pain intensity and interference. Secondary outcome measures were knowledge/barriers, medication adherence and self-efficacy. RESULTS: Twenty-six RCTs totaling 4735 patients met our inclusion criteria. Compared to the control group, 31% of the studies (including 19% of all patients) reported a significant difference in pain intensity in favor of the intervention group. Twelve studies measured pain interference and four (30%) found a significant improvement. With regard to secondary endpoints, significant differences in favor of the experimental arms were found for pain knowledge or barriers (15/22 studies; 68%), medication adherence (3/6 studies; 50%) and self-efficacy (1/2 studies). CONCLUSIONS: Patient-based pain educational programs may result in improvements of relevant patient-reported outcomes. However, the interventions are heterogeneous and improvement of pain was only seen in less than one third of the studies and in less than 20% of all included patients. PMID- 29272783 TI - Mammography screening: A major issue in medicine. AB - Breast cancer mortality is declining in most high-income countries. The role of mammography screening in these declines is much debated. Screening impacts cancer mortality through decreasing the incidence of number of advanced cancers with poor prognosis, while therapies and patient management impact cancer mortality through decreasing the fatality of cancers. The effectiveness of cancer screening is the ability of a screening method to curb the incidence of advanced cancers in populations. Methods for evaluating cancer screening effectiveness are based on the monitoring of age-adjusted incidence rates of advanced cancers that should decrease after the introduction of screening. Likewise, cancer-specific mortality rates should decline more rapidly in areas with screening than in areas without or with lower levels of screening but where patient management is similar. These two criteria have provided evidence that screening for colorectal and cervical cancer contributes to decreasing the mortality associated with these two cancers. In contrast, screening for neuroblastoma in children was discontinued in the early 2000s because these two criteria were not met. In addition, overdiagnosis - i.e. the detection of non-progressing occult neuroblastoma that would not have been life-threatening during the subject's lifetime - is a major undesirable consequence of screening. Accumulating epidemiological data show that in populations where mammography screening has been widespread for a long time, there has been no or only a modest decline in the incidence of advanced cancers, including that of de novo metastatic (stage IV) cancers at diagnosis. Moreover, breast cancer mortality reductions are similar in areas with early introduction and high penetration of screening and in areas with late introduction and low penetration of screening. Overdiagnosis is commonplace, representing 20% or more of all breast cancers among women invited to screening and 30-50% of screen detected cancers. Overdiagnosis leads to overtreatment and inflicts considerable physical, psychological and economic harm on many women. Overdiagnosis has also exerted considerable disruptive effects on the interpretation of clinical outcomes expressed in percentages (instead of rates) or as overall survival (instead of mortality rates or stage-specific survival). Rates of radical mastectomies have not decreased following the introduction of screening and keep rising in some countries (e.g. the United States of America (USA)). Hence, the epidemiological picture of mammography screening closely resembles that of screening for neuroblastoma. Reappraisals of Swedish mammography trials demonstrate that the design and statistical analysis of these trials were different from those of all trials on screening for cancers other than breast cancer. We found compelling indications that these trials overestimated reductions in breast cancer mortality associated with screening, in part because of the statistical analyses themselves, in part because of improved therapies and underreporting of breast cancer as the underlying cause of death in screening groups. In this regard, Swedish trials should publish the stage-specific breast cancer mortality rates for the screening and control groups separately. Results of the Greater New York Health Insurance Plan trial are biased because of the underreporting of breast cancer cases and deaths that occurred in women who did not participate in screening. After 17 years of follow-up, the United Kingdom (UK) Age Trial showed no benefit from mammography screening starting at age 39 41. Until around 2005, most proponents of breast screening backed the monitoring of changes in advanced cancer incidence and comparative studies on breast cancer mortality for the evaluation of breast screening effectiveness. However, in an attempt to mitigate the contradictions between results of mammography trials and population data, breast-screening proponents have elected to change the criteria for the evaluation of cancer screening effectiveness, giving precedence to incidence-based mortality (IBM) and case-control studies. But practically all IBM studies on mammography screening have a strong ecological component in their design. The two IBM studies done in Norway that meet all methodological requirements do not document significant reductions in breast cancer mortality associated with mammography screening. Because of their propensity to exaggerate the health benefits of screening, case-control studies may demonstrate that mammography screening could reduce the risk of death from diseases other than breast cancer. Numerous statistical model approaches have been conducted for estimating the contributions of screening and of patient management to reductions in breast cancer mortality. Unverified assumptions are needed for running these models. For instance, many models assume that if screening had not occurred, the majority of screen-detected asymptomatic cancers would have progressed to symptomatic advanced cancers. This assumption is not grounded in evidence because a large proportion of screen-detected breast cancers represent overdiagnosis and hence non-progressing tumours. The accumulation of population data in well screened populations diminishes the relevance of model approaches. The comparison of the performance of different screening modalities - e.g. mammography, digital mammography, ultrasonography, magnetic resonance imaging (MRI), three-dimensional tomosynthesis (TDT) - concentrates on detection rates, which is the ability of a technique to detect more cancers than other techniques. However, a greater detection rate tells little about the capacity to prevent interval and advanced cancers and could just reflect additional overdiagnosis. Studies based on the incidence of advanced cancers and on the evaluation of overdiagnosis should be conducted before marketing new breast-imaging technologies. Women at high risk of breast cancer (i.e. 30% lifetime risk and more), such as women with BRCA1/2 mutations, require a close breast surveillance. MRI is the preferred imaging method until more radical risk-reduction options are eventually adopted. For women with an intermediate risk of breast cancer (i.e. 10-29% lifetime risk), including women with extremely dense breast at mammography, there is no evidence that more frequent mammography screening or screening with other modalities actually reduces the risk of breast cancer death. A plethora of epidemiological data shows that, since 1985, progress in the management of breast cancer patients has led to marked reductions in stage-specific breast cancer mortality, even for patients with disseminated disease (i.e. stage IV cancer) at diagnosis. In contrast, the epidemiological data point to a marginal contribution of mammography screening in the decline in breast cancer mortality. Moreover, the more effective the treatments, the less favourable are the harm-benefit balance of screening mammography. New, effective methods for breast screening are needed, as well as research on risk-based screening strategies. PMID- 29272782 TI - Histopathological regression predicts treatment outcome in locally advanced esophagogastric adenocarcinoma. AB - BACKGROUND: Neoadjuvant chemotherapy (neoCTx) improves survival outcomes of patients with localised esophagogastric adenocarcinoma (EGA). This analysis evaluates the predictive value of histopathological response after neoCTx. METHODS: A total of 461 patients with locally advanced EGA (>=T2 and/or N+) who received neoCTx followed by surgery were analysed: 314 (68.1%) with intestinal, 94 (20.4%) with diffuse and 53 (11.5%) with mixed histological type according to Lauren classification. Histopathological response evaluation was available for 363 patients and performed locally. This analysis evaluates the predictive value of histopathological subtype on histopathological response after neoCTx. Response was correlated with survival. RESULTS: Median patients' age was 63 years, 79.8% were male. Tumours were localised in the stomach in 32.5% and EG junction in 67.5% of the patients. With a median follow-up of 49.4 months, median disease free (DFS) and overall survival (OS) were 38.0 and 66.4 months, respectively. Pathological complete response (TRG1a) was 8.8% and combined complete and subtotal regression (TRG1a/b) was 27.3% for all patients. Around 9.2% of patients with intestinal type had a TRG1a compared with 6.2% with diffuse and 10.8% with mixed type. TRG1a/b rate was higher in intestinal (31.0%) than in diffuse (15.4%) and in mixed type (21.6%). For patients with intestinal type, 3-year DFS was 78.4% with TRG1a and 54.3% with other regression grades (p = 0.031). All patients with diffuse and mixed type and TRG1a were disease free after 3 years compared with 31.1% (p = 0.056) and 47.7% (p = 0.044) with other regression grades. CONCLUSION: Histopathological subtype is predictive for histopathological response and outcome after neoCTx, with the highest response rates in intestinal differentiated EGA. PMID- 29272784 TI - Quasi-psychosis in covert Narcissistic Personality Disorder-A case report. PMID- 29272785 TI - The role of the GABAergic system in catatonia-Insights from clozapine and benzodiazepines. PMID- 29272787 TI - Overexpression of ING5 inhibits HGF-induced proliferation, invasion and EMT in thyroid cancer cells via regulation of the c-Met/PI3K/Akt signaling pathway. AB - The inhibitor of growth 5 (ING5), a novel member of the ING family, is involved in diverse biological processes such as cell growth, apoptosis and DNA repair. Recently, ING5 has been reported to be associated with cancer development. However, its specific role in thyroid cancer has yet to be elucidated. In this study, we found that the expression of ING5 was significantly down-regulated in human thyroid cancer tissues and cell lines. In addition, overexpression of ING5 markedly inhibited hepatocyte growth factor (HGF)-induced proliferation, invasion and epithelial-mesenchymal transition (EMT) of thyroid cancer cells as well as suppressed the tumor growth and metastasis in vivo. Furthermore, our data showed that the c-Met/PI3K/Akt signaling pathway was responsible for the inhibitory effect of ING5 on the thyroid cancer. Taken together, these findings provided an essential basis for the tumor-suppression role of ING5 in thyroid cancer. PMID- 29272786 TI - Autophagy enhanced antitumor effect in K562 and K562/ADM cells using realgar transforming solution. AB - Realgar transforming solution (RTS) can be produced from a biotransformation process by using microorganisms cultured with realgar in our lab. RTS has been demonstrated as a novel arsenic anti-leukemia agent in K562 and K562/ADM. However, its underlying mechanism is unclear. In this study, we showed that RTS could strongly induce apoptosis in K562 and K562/ADM cells. After the cells were treated by RTS, apoptotic population were increased compared to control and clearly distinguishable by DAPI nuclei staining. With increasing the dose of RTS, more cells arrested in S phase and G2/M phase. Secondly, we also showed that RTS could induce autophagy via up-regulation of LC3, p62/SQSTM1 and inhibition of mTOR in a much lower arsenic dosage in contrast to ATO and realgar. In addition, autophagy induced by RTS partially due to the degradation of fusion oncoprotein Bcr-Abl, which is associated with multidrug resistant in (MDR)-CML. Our results also showed that the apoptotic rate decreased when autophagic flux was attenuated by CQ via inhibiting cleaved-caspase-3 and alleviating Bcl-2 level. These suggested that RTS triggered autophagy is a pro-death process in CML and MDR-CML cells. In conclusion, our findings demonstrated that RTS could serve as a promising arsenic candidate for anti-CML/MDR-CML by inducing apoptosis and autophagy and is more potent than ATO and realgar. PMID- 29272788 TI - Combination of novel DR5 targeting agonistic scFv antibody TR2-3 with cisplatin shows enhanced synergistic antitumor activity in vitro and in vivo. AB - OBJECTIVES: To investigate the antitumor activity of a novel agonistic single chain fragment variable (scFv) antibody TR2-3 targeting death receptor 5 (DR5) combined with cisplatin in vitro and in vivo. METHODS: The in vitro cytotoxic effects of TR2-3 and cisplatin, alone or in combination on human cancer cell lines COLO205 and MDA-MB-231 were evaluated using the MTT assay. The apoptosis in cancer cells was evaluated by an Annexin V-PE apoptosis detection kit and flow cytometry. The mRNA and protein levels of DR5 were analyzed by real-time PCR and Western blot, respectively. Additionally, the in vivo antitumor activity of TR2-3 combined with cisplatin was evaluated in a xenograft model. RESULTS: The combination treatment with TR2-3 and cisplatin for 24 h on COLO205 and MDA-MB-231 cells showed significant cytotoxicity effects by MTT assay, compared with the alone treatment. Consistent with cell viability results, the cisplatin enhanced the apoptosis-inducing effects of TR2-3 in the COLO205 cells and MDA-MB-231 cells by flow cytometry. In addition, treatment with cisplatin alone for 24 h resulted in significantly up-regulating the mRNA and protein levels of DR5 in both COLO205 and MDA-MB-231 cell lines by q-PCR and Western blot assay. Moreover, the cytotoxic effects of TR2-3 can be blocked by adding the soluble DR5, and the blocking rate can be greatly reduced by co-treatment with cisplatin. These results indicated that cisplatin sensitized COLO205 and MDA-MB-231 cancer cells to TR2-3-mediated apoptosis by up-regulation of DR5 expression. Furthermore, combination therapy with TR2-3 and cisplatin enhanced tumor growth inhibition compared to treatment with TR2-3 or cisplatin alone in mice bearing COLO205 xenograft tumors. CONCLUSIONS: Our findings suggest that cisplatin enhanced the antitumor activity of TR2-3 in COLO205 and MDA-MB-231 cancer cells through up regulation of DR5 expression. The TR2-3 combined with cisplatin may be a promising treatment for cancer therapy. PMID- 29272789 TI - Cyclist-related content in novice driver education and training. AB - In Australia, the increasing public profile and policy interest in cycling contrasts with variable cycling participation rates across jurisdictions (Australian Bicycle Council, 2017) and lack of cyclist-specific infrastructure. Cyclists and drivers often share road space, usually without indication from the built environment about how to maximise each other's safety and utility. Yet despite this regular interaction, cyclists are largely absent from the driver licensing process in Australia. That is, novice drivers are not taught how to share the road with cyclists. This case study used a mixed methods approach to examine the cyclist-related content in the Graduated Driver Licensing System (GDLS) in the Australian Capital Territory (ACT). The case study was conducted in four stages: 1) content analysis of all documents used through the GDLS; 2) observations of the Road Ready course and learner driver lessons; 3) online survey; and, 4) semi-structured interviews. Cyclists are rarely mentioned in the GDLS in the ACT and references often constructed cyclists as problematic or were based in instructors' personal opinion (rather than scripted responses). Outcomes from this study have directly informed a new vulnerable road user driver licence competency in the ACT and findings include recommendations for greater inclusion of cyclists in the driver licensing system. PMID- 29272790 TI - Safety assessment on pedestrian crossing environments using MLS data. AB - In the framework of infrastructure analysis and maintenance in an urban environment, it is important to address the safety of every road user. This paper presents a methodology for the evaluation of several safety indicators on pedestrian crossing environments using geometric and radiometric information extracted from 3D point clouds collected by a Mobile Mapping System (MMS). The methodology is divided in four main modules which analyze the accessibility of the crossing area, the presence of traffic lights and traffic signs, and the visibility between a driver and a pedestrian on the proximities of a pedestrian crossing. The outputs of the analysis are exported to a Geographic Information System (GIS) where they are visualized and can be further processed in the context of city management. The methodology has been tested on approximately 30 pedestrian crossings in cluttered urban environments of two different cities. Results show that MMS are a valid mean to assess the safety of a specific urban environment, regarding its geometric conditions. Remarkable results are presented on traffic light classification, with a global F-score close to 95%. PMID- 29272791 TI - Disrupted functional connectivity of the amygdala is associated with depressive mood in type 2 diabetes patients. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) and mood disorders share pathophysiological commonalities in the central nervous system. The purpose of this study was to investigate the alterations in amygdala-based emotional processing circuits in T2DM patients with depressive mood using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: T2DM patients with depressive mood (n = 25), T2DM patients without depressive mood (n = 28) and matched healthy controls (n = 25) underwent neuropsychological testing and rs fMRI scanning. A seed-based correlation analysis was conducted to reveal the altered functional connectivity (FC) of the amygdala. The bilateral amygdala FC was compared among the three groups. Pearson correlation analyses were performed in a voxel-wise manner to investigate the relationship between amygdala FC and the clinical characteristics. RESULTS: The depressed T2DM patients exhibited the worst performance on the neuropsychological tests among the three groups. Compared to the non-depressed T2DM patients, the depressed T2DM patients showed decreased amygdala FC in the cingulate cortex, inferior frontal gyrus, fusiform gyrus, and precentral gyrus. Moreover, the amygdala FC in the cingulate cortex was associated with the Self-Rating Depression Scale (SDS) score in the T2DM patients. LIMITATIONS: Cross-sectional design. CONCLUSIONS: The current study revealed the cognitive changes and alterations in the amygdala-cingulate functional disconnections in T2DM patients with depressive mood, which will advance the understanding of the neural mechanisms underlying depression in T2DM patients. PMID- 29272792 TI - In-silico and in-vitro evaluation of human acetylcholinesterase inhibition by organophosphates. AB - Organophosphates (OP) inhibit the acetylcholinesterase (AChE) activity and devastate the nervous system of pest however its mode of action is ubiquitous and acts similarly on human AChE (hAChE). Screening of OP was carried out by molecular docking with hAChE using Glide docking module of Schrodinger suite as the structural information of hAChE and OP together as co-crystal structure is rarely available. The docking was done at three different precision levels, high throughput virtual screening (HTVS), standard precision and extra precision. The ranking was done using over all binding energy i.e. dock score and molecular modelling generalized born surface area (MM-GBSA). Investigation reported Tryptophan (Trp86) residue involved in most interactions by forming a pi-cation interaction apart from Ser203 on anionic subsite of hAChE. The top rank ligand was Phoxim ethyl phosphonate (PEP) interacting with Trp86, Gly121 and Ser203. However contact with Gly121 was lost during simulation and Asp74 appeared and sustained. Molecular dynamic simulation (GROMACS 4.5.5) of hAChE-PEP complex for 4 * 104 pico-second with SPC16 water system at 310 K temperature explained the evident role of Trp86 in stabilizing the ligand at P-site of the enzyme. Asp74 and Tyr124 were noticed in conveying H-bonds. Trp86 has shown consistent and better stability of bond based on distance between residues and ligand. The top ranked OP i.e. PEP was used to establish a dose response relationship between OP and hAChE. PEP inhibits half of the enzyme activity at concertation of 29.99 MUM (calculated by sigmoid plot) at R2 = 0.996 and P < 0.0001. PMID- 29272793 TI - Simultaneous determination of pyridaben, dinotefuran, DN and UF in eggplant ecosystem under open-field conditions: Dissipation behaviour and residue distribution. AB - A sensitive method for simultaneous determination of pyridaben, dinotefuran, DN and UF in eggplant ecosystem was established and validated through rapid resolution liquid chromatography triples quadrupole tandem mass spectrometry (RRLC-QqQ-MS/MS). Matrix-matched external calibrations were introduced to check matrix effects. Limits of quantification (LOQs) of pyridaben, dinotefuran, DN and UF in eggplant were 0.2, 0.2, 1.0 and 1.0 MUg kg-1, and 0.2, 0.2, 5.0 and 1.0 MUg kg-1 in soil, respectively. Limits of detection (LODs) of four pesticides were below 0.41 MUg L-1. The mean recoveries (n = 5) of these insecticides varied from 79.4% to 103%, and the relative standard deviations (RSDs) ranged from 2.1% to 15.3% at three levels. This method was applied to Chinese open-field samples from two representative locations, which were previously treated with these insecticides at the doses of 210-315 g a.i. ha-1 twice or three times. The dissipations of pyridaben and dinotefuran in eggplant and soil followed first order kinetics with the half-lives of 3.65-11.4 d. The residues of pyridaben and total dinotefuran (calculated as sum of dinotefuran parent, DN and UF) in eggplant were below 0.0311 mg kg-1 at the pre-harvest interval (PHI, 7 d). Presently, no maximum residue limit (MRL) of pyridaben and dinotefuran in eggplant was recommended by China, Codex Alimentarius Commission (CAC) or European Union (EU). This study was important for evaluation of environmental fate and food safety of pyridaben and dinotefuran in eggplant ecosystems, and facilitated China to establish maximum residue limits (MRLs) of pyridaben and dinotefuran in eggplant. PMID- 29272794 TI - Ozonation of norfloxacin and levofloxacin in water: Specific reaction rate constants and defluorination reaction. AB - The degradation kinetics and mechanism of two typical fluoroquinolones (FQs), norfloxacin (NF) and levofloxacin (LOF), by ozone in water were investigated. Semi-continuous mode and competition kinetics mode experiments were conducted to determine the reaction rate constants of target FQs with ozone and OH, separately. Results indicate that both NF and LOF were highly reactive toward ozone, and the reactivity was strongly impacted by the solution pH. The specific reaction rate constants of the diprotonated, monoprotonated and deprotonated species were determined to be 7.20 * 102, 8.59 * 103, 4.54 * 105 M-1 s-1 respectively for NF and 1.30 * 103, 1.40 * 104, 1.33 * 106 M-1 s-1 respectively for LOF. The reaction rate constants of target FQs toward OH were measured to be (4.81-7.41) * 109 M-1 s-1 in the pH range of 6.3-8.3. Furthermore, NF was selected as a model compound to clarify the degradation pathways, with a particular focus on the defluorination reaction. The significant release of F- ions and the formation of three F-free organic byproducts indicated that defluorination was a prevalent pathway in ozonation of FQs, while six F containing organic byproducts indicated that ozone also attacked the piperazinyl and quinolone moieties. Escherichia coli growth inhibition tests revealed that ozonation could effectively eliminate the antibacterial activity of target FQ solutions, and the residual antibacterial activity had a negative linear correlation with the released F- concentration. PMID- 29272795 TI - Simultaneous alleviation of cadmium and arsenic accumulation in rice by applying zero-valent iron and biochar to contaminated paddy soils. AB - The fates of cadmium (Cd) and arsenic (As) in paddy fields are generally opposite; thus, the inconsistent transformation of Cd and As poses large challenges for their remediation. In this study, the impacts of zero valent iron (ZVI) and/or biochar amendments on Cd and As bioavailability were examined in pot trials with rice. Comparison with the untreated soil, both Cd and As accumulation in different rice tissues decreased significantly in the ZVI-biochar amendments and the Cd and As accumulation in rice decreased with increasing ZVI contents. In particular, the concentrations of Cd (0.15 +/- 0.01 mg kg-1) and As (0.17 +/- 0.01 mg kg-1) in rice grains were decreased by 93% and 61% relative to the untreated soil, respectively. A sequential extraction analysis indicated that with increasing Fe ratios in the ZVI-biochar mixtures, bioavailable Cd and As decreased, and the immobilized Cd and As increased. Furthermore, high levels of Fe, Cd, and As were detected in Fe plaque of the ZVI-biochar amendments in comparison with the single biochar or single ZVI amendments. The ZVI-biochar mixture may have a synergistic effect that simultaneously reduces Cd and As bioavailability by increasing the formation of amorphous Fe and Fe plaque for Cd and As immobilization. The single ZVI amendment significantly decreased As bioavailability, while the single biochar amendment significantly reduced the bioavailability of Cd compared with the combined amendments. Hence, using a ZVI biochar mixture as a soil amendment could be a promising strategy for safely utilizing Cd and As co-contaminated sites in the future. PMID- 29272796 TI - Cobalt-embedded carbon nanofiber derived from a coordination polymer as a highly efficient heterogeneous catalyst for activating oxone in water. AB - Carbon fiber (CF) supported cobalt nanoparticles (NPs) are promising catalysts for activating Oxone because carbon is non-metal and earth-abundant, and CF-based catalysts exhibit a high aspect ratio, which affords more accessible and dense catalytic sites. Nevertheless, most of CF-supported catalysts are fabricated by post-synthetic methods, which involve complicated preparations. More importantly, metallic NPs are attached to the outer surface of CF rather than embedded within CF. However, there is still a great demand for developing Co-bearing carbon fibers for Oxone activation via simple and effective methods. Thus, this study proposes to develop a cobalt NP-embedded carbon nanofiber (CCNF) by a simple hydrothermal reaction of Co and nitrilotriacetic acid (NA), followed by one-step carbonization. Owing to the coordinative structure of CoNA, the derivative CCNF exhibits a fibrous carbon matrix embedded with evenly distributed and densely packed Co3O4 and magnetic Co0 nanoparticles. The fibrous structure, magnetism and embedded Co NPs enable CCNF to be a promising catalyst for Oxone activation. As degradation of Rhodamine B (RhB) is selected as a model reaction, CCNF not only rapidly activates Oxone to fully degrade RhB but also shows a much higher catalytic activity than the most common Oxone activator, Co3O4. CCNF also exhibits the lowest activation energy than any reported catalysts for Oxone activation to degrade RhB. In addition, CCNF could be re-used to activate Oxone for RhB degradation. These results indicate that CCNF is a conveniently prepared and highly effective fibrous Co/C hybrid material for activating Oxone to oxidize contaminants in water. PMID- 29272797 TI - Effect of the electronegativity on the electrosorption selectivity of anions during capacitive deionization. AB - The effect of electronegativity on the electrosorption selectivity of anions during capacitive deionization was investigated via a combination of experimental and theoretical studies. A model was developed based on chemical thermodynamics and the classic Stern's model to reveal the role of the anode potential and to describe electrosorption selectivity behavior during capacitive deionization. The effects of the anode potential on the adsorption of Cl- and ReO4- were studied and the obtained data were used to validate the model. Using the validated model, the effects of the anode potential and electronegativity of various anions, including Cl-, ReO4-, SO42- and NO3- were assessed. The experimental results for the electrosorption of Cl- and ReO4- corresponded well with the developed model. The electrosorption capacity demonstrates a logarithmic relationship with the anode potential. The model showed that the electronegativity significantly affects the selectivity. In a mixed Cl-, ReO4-, SO42- and NO3- solution, ReO4- was preferentially adsorbed over the other three anions, and the following selectivity was exhibited: ReO4- > NO3- > Cl- > SO42-. The results showed that the effect of flow rates on the electrosorption selectivity can be considered negligible when the flow rates are higher than 112 mL min-1. The anions selectivity can be further enhanced by increasing the anode potential, and electrosorption selectivity is no appreciable decline after 6 experiments. PMID- 29272798 TI - Modulation of hexavalent chromium toxicity on Omicronriganum vulgare in an acidic soil amended with peat, lime, and zeolite. AB - Dynamics of chromate (Cr(VI)) in contaminated soils may be modulated by decreasing its phytoavailability via the addition of organic matter-rich amendments, which might accelerate Cr(VI) reduction to inert chromite (Cr(III)) or high-cation exchange capacity amendments. We studied Cr(VI) phytoavailability of oregano in a Cr(VI)-spiked acidic soil non-treated (S) and treated with peat (SP), lime (SL), and zeolite (SZ). The addition of Cr(VI) increased the concentrations of Cr(VI) and Cr(III) in soils and plants, especially in the lime amended soil. The plant biomass decreased in the lime-amended soil compared to the un-spiked soil (control) due to decreased plant phosphorus concentrations and high Cr(VI) concentrations in root at that treatment. Oregano in the peat-amended soil exhibited significantly less toxic effects, due to the role of organic matter in reducing toxic Cr(VI) to Cr(III) and boosted plant vigour in this treatment. In the lime-amended soil, the parameters of soil Cr(VI), soil Cr(III), and root Cr(III) increased significantly compared to the non-amended soil, indicating that Cr(VI) reduction to Cr(III) was accelerated at high pH. Added zeolite failed to decreased Cr(VI) level to soil and plant. Oregano achieved a total uptake of Cr(III) and Cr(VI) of 0.275 mg in plant kg-1 soil in a pot in the non-amended soil. We conclude that peat as soil amendment might be considered as a suitable option for decreasing Cr(VI) toxicity in soil and plant, and that oregano as tolerant plant species has a certain potential to be used as a Cr accumulator. PMID- 29272799 TI - Female reproductive impacts of dietary methylmercury in yellow perch (Perca flavescens) and zebrafish (Danio rerio). AB - The purpose of this study was to evaluate the effects of environmentally relevant dietary MeHg exposures on adult female yellow perch (Perca flavescens) and female zebrafish (Danio rerio) ovarian development and reproduction. Yellow perch were used in the study for their socioeconomic and ecological importance within the Great Lakes basin, and the use of zebrafish allowed for a detailed analysis of the molecular effects of MeHg following a whole life-cycle exposure. Chronic whole life dietary exposure of F1 zebrafish to MeHg mimics realistic wildlife exposure scenarios, and the twenty-week adult yellow perch exposure (where whole life-cycle exposures are difficult) captures early seasonal ovarian development. For both species, target dietary accumulation values were achieved prior to analyses. In zebrafish, several genes involved in reproductive processes were shown to be dysregulated by RNA-sequencing and quantitative real-time polymerase chain reaction (QPCR), but no significant phenotypic changes were observed regarding ovarian staging, fecundity, or embryo mortality. Yellow perch were exposed to dietary MeHg for 12, 16, or 20 weeks. In this species, a set of eight genes were assessed by QPCR in the pituitary, liver, and ovary, and no exposure related changes were observed. The lack of genomic resources in yellow perch hinders the characterization of subtle molecular impacts. The ovarian somatic index, circulating estradiol and testosterone, and ovarian staging were not significantly altered by MeHg exposure in yellow perch. These results suggest that environmentally relevant MeHg exposures do not drastically reduce the reproductively important endpoints in these fish, but to capture realistic exposure scenarios, whole life-cycle yellow perch exposures are needed. PMID- 29272800 TI - Precopulatory sexual behavior of male mice is changed by the exposure to tannery effluent. AB - Although the toxic potential of tannery effluents (TE) is acknowledged, the impacts these residues have on mammals who intake water contaminated with this pollutant are not completely known. Thus, in order to broaden the knowledge about how these contaminants affect the biota, the aim of the current study is to assess different behavioral categories (e.g.: sexual odor preference, opposite sex attraction, and sexual discrimination) related to the sexual motivation and pre-copulation of male Swiss mice subjected to TE intake for 30 days, at concentrations 0.8% and 22%. The animals were subjected to locomotor performance evaluation through the Basso Mouse Scale (BMS), as well as to the open field (OF), odor preference (OPT), sexual orientation (SOT) and to scent marking tests (SMT) one week before the experiment ended. Our results evidenced that the treatments did not affect the animals' locomotor activity (in OF and BMS) or caused changes compatible to anxiogenic or anxiolytic behavior (in OF). However, mice exposed to TE (at both concentrations) presented discriminatory capacity deficit in the OPT test at the time to distinguish conspecific odors from the same sex, and from the opposite sex. They randomly explored (without preference) males and females, did not responded to stimuli in the SOT test, as well as did not appear capable of detecting female odor (in estrus phase) during the SMT. Thus, the current study was pioneer in evidencing that TE can influence the reproduction and the population dynamics of small rodents who intake water contaminated with the pollutant. PMID- 29272801 TI - Predicted persistence and response times of linear and cyclic volatile methylsiloxanes in global and local environments. AB - We investigated the response times of eight volatile methylsiloxanes (VMSs) in environmental systems at different scales from local to global, with a particular focus on overall loss rates after cessation of emissions. In part, this is driven by proposals to restrict the use of some of these compounds in certain products in Europe. The GloboPOP model estimated low absolute Arctic Contamination Potentials for all VMSs and rapid response times in all media except sediment. VMSs are predicted to be distributed predominantly in air where they react with OH radicals, leading to short response times. After cessation of emissions VMSs concentrations in the environment are expected to decrease rapidly from current levels. Response times in specific water and sediment systems were evaluated using a dynamic QWASI model. Response times were sensitive to both physico chemical properties and environmental characteristics. Degradation was predicted to play the most important role in determining response times in water and sediment. In the case of the lowest molecular weight VMSs such as L2 and D3, response times were essentially independent of environmental characteristics due to fast hydrolysis in water and sediment. However, response times for the other VMSs are system-specific. They are relatively short in shallow water bodies but increase with depth due to the diminishing role of volatilization on concentration change as volume to surface area ratio increases. In sediment, degradation and resuspension rates also contribute most to the response times. The estimated response times for local environments are useful for planning future monitoring programs. PMID- 29272802 TI - Industrial wastewater advanced treatment via catalytic ozonation with an Fe-based catalyst. AB - An Fe-based catalyst was used as a heterogeneous catalyst for the ozonation of industrial wastewater, and key operational parameters (pH and catalyst dosage) were studied. The results indicated that the Fe-based catalyst significantly improved the mineralization of organic pollutants in wastewater. TOC (total organic carbon) removal was high, at 78.7%, with a catalyst concentration of 200 g/L, but only 31.6% with ozonation alone. The Fe-based catalyst significantly promoted ozone decomposition by 70% in aqueous solution. Hydroxyl radicals (.OH) were confirmed to be existed directly via EPR (electron paramagnetic resonance) experiments, and .OH were verified to account for about 34.4% of TOC removal with NaHCO3 as a radical scavenger. Through characterization by SEM-EDS (field emission scanning electron microscope with energy-dispersive spectrometer), XRD (X-ray powder diffraction) and XPS (X-ray photoelectron spectroscopy), it was deduced that FeOOH on the surface of the catalyst was the dominant contributor to the catalytic efficiency. The catalyst was certified as having good stability and excellent reusability based on 50 successive operations and could be used as a filler simultaneously. Thereby, it is a promising catalyst for practical industrial wastewater advanced treatment. PMID- 29272803 TI - A review of functionalized carbon nanotubes and graphene for heavy metal adsorption from water: Preparation, application, and mechanism. AB - Carbon-based nanomaterials, especially carbon nanotubes and graphene, have drawn wide attention in recent years as novel materials for environmental applications. Notably, the functionalized derivatives of carbon nanotubes and graphene with high surface area and adsorption sites are proposed to remove heavy metals via adsorption, addressing the pressing pollution of heavy metal. This critical revies assesses the recent development of various functionalized carbon nanotubes and graphene that are used to remove heavy metals from contaminated water, including the preparation and characterization methods of functionalized carbon nanotubes and graphene, their applications for heavy metal adsorption, effects of water chemistry on the adsorption capacity, and decontamination mechanism. Future research directions have also been proposed with the goal of further improving their adsorption performance, the feasibility of industrial applications, and better simulating adsorption mechanisms. PMID- 29272804 TI - Outcome of epilepsy in patients with mitochondrial disorders: Phenotype genotype and magnetic resonance imaging correlations. AB - OBJECTIVES: Studies exploring the outcome of epilepsy in patients with mitochondrial disorders are limited. This study examined the outcome of epilepsy in patients with mitochondrial disorders and its relation with the clinical phenotype, genotype and magnetic resonance imaging findings. PATIENTS AND METHODS: The cohort was derived from the database of 67 patients with definite genetic diagnosis of mitochondrial disorders evaluated over a period of 11years (2006-2016). Among this, 27 had epilepsy and were included in final analysis. Data were analyzed with special reference to clinical phenotypes, genotypes, epilepsy characteristics, EEG findings, anti epileptic drugs used, therapeutic response, and magnetic resonance imaging findings. Patients were divided into three groups according to the seizure frequency at the time of last follow up: Group I- Seizure free; Group II- Infrequent seizures; Group III- uncontrolled seizures. For each group the clinical phenotype, genotype, magnetic resonance imaging and duration of epilepsy were compared. RESULTS: The phenotypes & genotypes included Mitochondrial Encephalopathy Lactic Acidosis and Stroke like episodes (MELAS) & m.3243A>G mutation (n = 10), Myoclonic Epilepsy Ragged Red Fiber syndrome (MERRF) & m.8344A>G mutation (n = 4), Chronic Progressive External Ophthalmoplegia plus &POLG1 mutation (CPEO, n = 6), episodic neuroregression due to nuclear mutations (n = 6; NDUFV1 (n = 3), NDUFA1, NDUFS2, MPV17-1 one each), and one patient with infantile basal ganglia stroke syndrome, mineralizing angiopathy &MT-ND5 mutations. Seven patients (25.9%) were seizure free; seven had infrequent seizures (25.9%), while thirteen (48.1%) had frequent uncontrolled seizures. Majority of the subjects in seizure free group had episodic neuroregression & leukoencephalopathy due to nuclear mutations (85.7%). Patients in group II with infrequent seizures had CPEO, POLG1 mutation and a normal MRI (71%) while 62% of the subjects in group III had MELAS, m.3243A>G mutation and stroke like lesions on MRI. CONCLUSIONS: A fair correlation exists between the outcome of epilepsy, clinical phenotypes, genotypes and magnetic resonance imaging findings in patients with mitochondrial disorders. The recognition of these patterns is important clinically because of the therapeutic and prognostic implications. PMID- 29272805 TI - Predictive risk factors for chronic low back pain in Parkinson's disease. AB - OBJECTIVES: Although previous studies have reported that the prevalence of low back pain in Parkinson's disease was over 50% and low back pain was often classified as chronic, risk factors of chronic low back pain have not been previously investigated. The aim of this study was to determine the predictive risk factors of chronic low back pain in Parkinson's disease. PATIENTS AND METHODS: One hundred and sixty-eight patients with Parkinson's disease and 179 controls were consecutively included in the study. Demographic data of the two groups and disease characteristics of Parkinson's disease patient group were recorded. Low back pain lasting for >=3 months was evaluated as chronic. Firstly, the bivariate correlations were calculated between chronic low back pain and all possible risk factors. Then, a multivariate regression was used to evaluate the impact of the predictors of chronic low back pain. RESULTS: The frequency of chronic low back pain in Parkinson's disease patients and controls were 48.2% and 26.7%, respectively (p < 0.001). The predictive risk factors of chronic low back pain in Parkinson's disease were general factors including age (odds ratio = 1.053, p = 0.032) and Hospital Anxiety and Depression Scale - Depression subscore (odds ratio = 1.218, p = 0.001), and Parkinson's disease-related factors including rigidity (odds ratio = 5.109, p = 0.002) and posture item scores (odds ratio = 5.019, p = 0.0001). CONCLUSION: The chronic low back pain affects approximately half of the patients with Parkinson's disease. Prevention of depression or treatment recommendations for managing depression, close monitoring of anti- parkinsonian medication to keep motor symptoms under control, and attempts to prevent, correct or reduce abnormal posture may help reduce the frequency of chronic low back pain in Parkinson's disease. PMID- 29272806 TI - A novel fluorescent probe (dtpa-bis(cytosine)) for detection of Eu(III) in rare earth metal ions. AB - In this paper, a novel fluorescent probe, dtpa-bis(cytosine), was designed and synthesized for detecting europium (Eu3+) ion. Upon addition of Eu3+ ions into the dtpa-bis(cytosine) solution, the fluorescence intensity can strongly be enhanced. Conversely, adding other rare earth metal ions, such as Y3+, Ce3+, Pr3+, Nd3+, Sm3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Yb3+ and Lu3+, into dtpa bis(cytosine) solution, the fluorescence intensity is decreased slightly. Some parameters affecting the fluorescence intensity of dtpa-bis(cytosine) solution in the presence of Eu3+ ions were investigated, including solution pH value, Eu3+ ion concentration and interfering substances. The detection mechanism of Eu3+ ion using dtpa-bis(cytosine) as fluorescent probe was proposed. Under optimum conditions, the fluorescence emission intensities of EuIII-dtpa-bis(cytosine) at 375nm in the concentration range of 0.50*10-5mol?L-1-5.00*10-5mol?L-1 of Eu3+ ion display a better linear relationship. The limit of detection (LOD) was determined as 8.65*10-7mol?L-1 and the corresponding correlation coefficient (R2) of the linear equation is 0.9807. It is wished that the proposed method could be applied for sensitively and selectively detecting Eu3+ ion. PMID- 29272807 TI - Innovative spectrophotometric methods for simultaneous estimation of the novel two-drug combination: Sacubitril/Valsartan through two manipulation approaches and a comparative statistical study. AB - Different innovative spectrophotometric methods were introduced for the first time for simultaneous quantification of sacubitril/valsartan in their binary mixture and in their combined dosage form without prior separation through two manipulation approaches. These approaches were developed and based either on two wavelength selection in zero-order absorption spectra namely; dual wavelength method (DWL) at 226nm and 275nm for valsartan, induced dual wavelength method (IDW) at 226nm and 254nm for sacubitril and advanced absorbance subtraction (AAS) based on their iso-absorptive point at 246nm (lambdaiso) and 261nm (sacubitril shows equal absorbance values at the two selected wavelengths) or on ratio spectra using their normalized spectra namely; ratio difference spectrophotometric method (RD) at 225nm and 264nm for both of them in their ratio spectra, first derivative of ratio spectra (DR1) at 232nm for valsartan and 239nm for sacubitril and mean centering of ratio spectra (MCR) at 260nm for both of them. Both sacubitril and valsartan showed linearity upon application of these methods in the range of 2.5-25.0MUg/mL. The developed spectrophotmetric methods were successfully applied to the analysis of their combined tablet dosage form ENTRESTOTM. The adopted spectrophotometric methods were also validated according to ICH guidelines. The results obtained from the proposed methods were statistically compared to a reported HPLC method using Student t-test, F-test and a comparative study was also developed with one-way ANOVA, showing no statistical difference in accordance to precision and accuracy. PMID- 29272808 TI - Insights on the interaction of Zn2+ cation with triazoles: Structures, bonding, electronic excitation and applications. AB - At present, we investigate the structures, the stability, the bonding and the spectroscopy of the Zn2+-triazole complexes (Zn2+-Tz), which are subunits of triazolate based porous materials and Zn-enzymes. This theoretical work is performed using ab initio methods and density functional theory (DFT) where dispersion correction is included. Through these benchmarks, we establish the ability and reliability of M05-2X+D3 and PBE0+D3 functionals for the correct description of Zn2+-Tz bond since these DFTs lead to close agreement with post Hartree-Fock methods. Therefore, M05-2X+D3 and PBE0+D3 functionals are recommended for the characterization of larger organometallic complexes formed by Zn and N-rich linkers. For Zn2+-Tz, we found two stable sigma-type complexes: (i) a planar structure where Zn2+ links to unprotonated nitrogen and (ii) an out-of plane cluster where carbon interacts with Zn2+. The most stable isomers consist on a coordinated covalent bond between the lone pair of unprotonated nitrogen and the vacant 4s orbital of Zn2+. The roles of covalent interactions within these complexes are discussed after vibrational, NBO, NPA charges and orbital analyses. The bonding is dominated by charge transfer from Zn2+ to Tz and intramolecular charge transfer, which plays a vital role for the catalytic activity of these complexes. These findings are important to understand, at the microscopic level, the structure and the bonding within triazolate based macromolecular porous materials and Zn-enzymes. PMID- 29272809 TI - Spectroscopic studies of ozone in cryosolutions: FT-IR spectra of 16O3 in liquid nitrogen, oxygen, argon and krypton. AB - We have measured and interpreted the IR spectra of ozone dissolved in liquid nitrogen, oxygen, argon, and krypton in the 650-4700cm-1 spectral region at 79 117K. Frequency shifts, band intensities and bandshapes of 22 spectral features of soluted ozone were analyzed. The bands of the A1 symmetry have a complex contour and possess an excess intensity with respect to the value of the purely vibrational transition moment. It was found that this effect is related to the manifestation of the Coriolis interaction. The bandshape distortion manifests itself as an additional intensity from the side of the V1 symmetry band being an intensity source in the case of the Coriolis interaction. PMID- 29272810 TI - The challenges of training, support and assessment of healthcare support workers: A qualitative study of experiences in three English acute hospitals. AB - BACKGROUND: Ever-growing demands on care systems have increased reliance on healthcare support workers. In the UK, their training has been variable, but organisation-wide failures in care have prompted questions about how this crucial section of the workforce should be developed. Their training, support and assessment has become a policy priority. OBJECTIVES: This paper examines: healthcare support workers' access to training, support and assessment; perceived gaps in training provision; and barriers and facilitators to implementation of relevant policies in acute care. DESIGN AND SETTINGS: We undertook a qualitative study of staff caring for older inpatients at ward, divisional or organisational level in three acute National Health Service hospitals in England in 2014. PARTICIPANTS: 58 staff working with older people (30 healthcare support workers and 24 staff managing or working alongside them) and 4 healthcare support worker training leads. METHODS: One-to-one semi-structured interviews included: views and experiences of training and support; translation of training into practice; training, support and assessment policies and difficulties of implementing them. Transcripts were analysed to identify themes. RESULTS: Induction training was valued, but did not fully prepare healthcare support workers for the realities of the ward. Implementation of hospital policies concerning supervision and formal assessment of competencies varied between and within hospitals, and was subject to availability of appropriate staff and competing demands on staff time. Gaps identified in training provision included: caring for people with cognitive impairment; managing the emotions of patients, families and themselves; and having difficult conversations. Access to ongoing training was affected by: lack of time; infrequent provision; attitudes of ward managers to additional support workforce training, and their need to balance this against patients' and other staff members' needs; and the use of e-learning as a default mode of training delivery. CONCLUSIONS: With the current and unprecedented policy focus on training, support and assessment of healthcare support workers, our study suggests improved training would be welcomed by them and their managers. Provision of training, support and assessment could be improved by organisational policy that promotes and protects healthcare support worker training; formalising the provision and availability of on-ward support; and training and IT support provided on a drop-in basis. Challenges in implementation are likely to be faced in all international settings where there is increased reliance on a support workforce. While recent policies in the UK offers scope to overcome some of these challenges there is a risk that some will be exacerbated. PMID- 29272811 TI - Mathematical Modeling and Experimental Evaluation for the predication of single nanofiber modulus. AB - Electrospun nanofiber matrices are widely used as scaffolds for the regeneration of different tissues due to similarities with fibrous components of the extracellular matrix. These scaffolds could act as a substrate for inducing mechanical stimuli to cells. The main mechanical stimuli factor in nanofiber scaffolds for determining the cell behaviors is stiffness of single nanofibers. This paper especially highlights the finding that the young's modulus of single nanofibers can be obtained from aligned nanofibers matrix. It is assume that, the modulus of single nanofibers are equal to modulus of completely aligned nanofibers. However, due to difficulty of producing completely aligned nanofibers, the obtained modulus of single nanofiber wouldn't have significant value. Therefore, we propose a new mathematical model to predict the stiffness of single nanofibers from non-perfectly aligned nanofibers matrix. PMID- 29272812 TI - Fatigue performance of a high-strength, degradable calcium phosphate bone cement. AB - Calcium phosphate cements (CPCs) are clinically used as injectable materials to fill bone voids and to improve hardware fixation in fracture surgery. In vivo they are dynamically loaded; nonetheless little is known about their fatigue properties. The aim of this study was to, for the first time, investigate the fatigue performance of a high-strength, degradable (brushitic) CPC, and also evaluate the effect of cement porosity (by varying the liquid to powder ratio, L/P) and the environment (air at room temperature or in a phosphate buffered saline solution, PBS, at 37 degrees C) on the fatigue life. At a maximum compressive stress level of 15MPa, the cements prepared with an L/P-ratio of 0.22 and 0.28ml/g, corresponding to porosities of approximately 12% and 20%, had a 100% probability of survival until run-out of 5 million cycles, in air. When the maximum stress level, or the L/P-ratio, was increased, the probability of survival decreased. Testing in PBS at 37 degrees C led to more rapid failure of the specimens. However, the high-strength cement had a 100% probability of survival up to approximately 2.5 million cycles at a maximum compressive stress level of 10MPa in PBS, which is substantially higher than some in vivo stress levels, e.g., those found in the spine. At 5MPa in PBS, all specimens survived to run-out. The results found herein are important if clinical use of the material is to increase, as characterisation of the fatigue performance of CPCs is largely lacking from the literature. PMID- 29272813 TI - Terrestrial Trunked Radio (TETRA) exposure of neuronal in vitro networks. AB - Terrestrial Trunked Radio (TETRA) is a worldwide common mobile communication standard, used by authorities and organizations with security tasks. Previous studies reported on health effects of TETRA, with focus on the specific pulse frequency of 17.64Hz, which affects calcium efflux in neuronal cells. Likewise among others, it was reported that TETRA affects heart rate variability, neurophysiology and leads to headaches. In contrast, other studies conclude that TETRA does not affect calcium efflux of cells and has no effect on people's health. In the present study we examine whether TETRA short- and long-term exposure could affect the electrophysiology of neuronal in vitro networks. Experiments were performed with a carrier frequency of 395MHz, a pulse frequency of 17.64Hz and a differential quaternary phase-shift keying (pi/4 DQPSK) modulation. Specific absorption rates (SAR) of 1.17W/kg and 2.21W/kg were applied. In conclusion, the present results do not indicate any effect of TETRA exposure on electrophysiology of neuronal in vitro networks, neither for short term nor long-term exposure. This applies to the examined parameters spike rate, burst rate, burst duration and network synchrony. PMID- 29272814 TI - Trends in urinary arsenic among the U.S. population by drinking water source: Results from the National Health and Nutritional Examinations Survey 2003-2014. AB - BACKGROUND: In 2001, the United States revised the arsenic maximum contaminant level for public drinking water systems from 50ug/L to 10ug/L. This study aimed to examine temporal trends in urinary arsenic concentrations in the U.S. population from 2003 to 2014 by drinking water source among individuals aged 12 years and older who had no detectable arsenobetaine - a biomarker of arsenic exposure from seafood intake. METHODS: We examined data from 6 consecutive cycles of the National Health and Nutrition Examination Survey (2003-2014; N=5848). Total urinary arsenic (TUA) was calculated by subtracting arsenobetaine's limit of detection and detectable arsenocholine from total arsenic. Additional sensitivity analyses were conducted using a second total urinary arsenic index (TUA2, calculated by adding arsenite, arsenate, monomethylarsonic acid, dimethylarsinic acid). We classified drinking water source using 24-h dietary questionnaire data as community supply (n=3427), well or rain cistern (n=506), and did not drink tap water (n=1060). RESULTS: Geometric means (GM) of survey cycles were calculated from multivariate regression models adjusting for age, gender, race/ethnicity, BMI, income, creatinine, water source, type of water consumed, recent smoking, and consumption of seafood, rice, poultry, and juice. Compared to 2003-2004, adjusted TUA was 35.5% lower in 2013-2014 among the general U.S. POPULATION: Stratified analysis by smoking status indicated that the trend in lower TUA was only consistent among non-smokers. Compared to 2003-2004, lower adjusted TUA was observed in 2013-2014 among non-smoking participants who used community water supplies (1.98 vs 1.16ug/L, p<0.001), well or rain cistern users (1.54 vs 1.28ug/L, p<0.001) and who did not drink tap water (2.24 vs 1.53ug/L, p<0.001). Sensitivity analyses showed consistent results for participants who used a community water supplier and to a lesser extent those who did not drink tap water. However, the sensitivity analysis showed overall exposure stayed the same or was higher among well or rain cistern users. Finally, the greatest decrease in TUA was among participants within the highest exposure percentiles (e.g. 95th percentile had 34% lower TUA in 2013/2014 vs 2003/2004, p<0.001). CONCLUSIONS: Overall, urinary arsenic levels in the U.S. population declined over a 12-year period that encompassed the adoption of the revised Arsenic Rule. The most consistent trends in declining exposure were observed among non-smoking individuals using public community water systems. These results suggest regulation and prevention strategies to reduce arsenic exposures in the U.S. may be succeeding. PMID- 29272815 TI - A calibration procedure for a traceable contamination analysis on medical devices by combined X-ray spectrometry and ambient spectroscopic techniques. AB - There is a strong need in the medical device industry to decrease failure rates of biomedical devices by reducing the incidence of defect structures and contaminants during the production process. The detection and identification of defect structures and contaminants is crucial for many industrial applications. The present study exploits reference-free X-ray fluorescence (XRF) analysis as an analytical tool for the traceable characterization of surface contaminants of medical devices, in particular N,N'-ethylene-bis (stearamide), an ubiquitous compound used in many industrial applications as a release agent or friction reduction additive. Reference-free XRF analysis as primary method has been proven to be capable of underpinning all other applied methods since it yields the absolute mass deposition of the selected N,N'-ethylene-bis (stearamide) contaminant whilst X-ray absorption fine structure analysis determines the chemical species. Ambient vibrational spectroscopy and mass spectroscopy methodologies such as Fourier transform infrared, Raman, and secondary ion mass spectroscopy have been used in this systematic procedure providing an extensive range of complementary analyses. The calibration procedure described in this paper was developed using specially designed and fabricated model systems varying in thickness and substrate material. Furthermore, typical real medical devices such as both a polyethylene hip liner and a silver-coated wound dressing have been contaminated and investigated by these diverse methods, enabling testing of this developed procedure. These well-characterized samples may be used as calibration standards for bench top instrumentation from the perspective of providing traceable analysis of biomaterials and surface treatments. These findings demonstrate the potential importance and usefulness of combining complementary methods for a better understanding of the relevant organic materials. PMID- 29272816 TI - Racial and ethnic differences in the prevalence of adverse childhood experiences: Findings from a low-income sample of U.S. women. AB - Despite great interest in adverse childhood experiences (ACEs), there has been limited research on racial and ethnic differences in their prevalence. Prior research in the United States suggests that the prevalence of ACEs varies along socioeconomic lines, but it is uncertain whether there are racial/ethnic differences in ACE rates among low-income populations. This study examined the distribution of ACEs in a sample of 1523 low-income women in Wisconsin that received home visiting services. Participants ranging in age from 16 to 50 years were coded into five racial/ethnic groups, including Hispanics and four non Hispanic groups: blacks, whites, American Indians, and other race. Following measurement conventions, ten dichotomous indicators of child maltreatment and household dysfunction were used to create a composite ACE score. Five other potential childhood adversities were also assessed: food insecurity, homelessness, prolonged parental absence, peer victimization, and violent crime victimization. Results from bivariate and multivariate analyses revealed that, while rates of adversity were high overall, there were significant racial/ethnic differences. Total ACE scores of American Indians were comparable to the ACE scores of non-Hispanic whites, which were significantly higher than the ACE scores of non-Hispanic blacks and Hispanics. Whites were more likely than blacks to report any abuse or neglect, and they were more likely than blacks and Hispanics to report any household dysfunction. The results underscore the need to account for socioeconomic differences when making racial/ethnic comparisons. Potential explanations for the observed differences are examined. PMID- 29272817 TI - Fatty acid transport protein 1 enhances the macrophage inflammatory response by coupling with ceramide and c-Jun N-terminal kinase signaling. AB - Macrophages are important cells that need to be controlled at the site of inflammation. Several factors are involved in chronic inflammation and its timely resolution. Free fatty acids drive the inflammatory response in macrophages and contribute to the vicious cycle of the inflammatory response. However, the identity of the uptake pathways of fatty acids is not fully clear in macrophages and how the inflammatory responses are regulated by the uptake of fatty acids remain poorly understood. We investigated the relationship between fatty acid transport protein (FATP) and the inflammatory response signaling pathway in macrophages as the first report. The FATP family has composed six isoforms, FATP1 6. We found that FATP1 is the most highly expressed isoform in macrophages. Forced expression of FATP1 enhanced production of inflammatory cytokines, such as TNFalpha and IL-6 concomitant with the increased uptake of fatty acids, increased level of ceramide, and increased phosphorylation of c-Jun N-terminal kinase (JNK). The enhancement by FATP1 was abolished by treatment with a JNK inhibitor, NF-kappaB inhibitor, or ceramide synthesis inhibitor. siRNA-mediated knockdown of FATP1 strongly inhibited the production of TNFalpha and IL-6. Similarly, an inhibitor of FATP1 inhibited the production of TNFalpha and IL-6. Finally, an inhibitor of FATP1 attenuated the production of inflammatory cytokines in bronchoalveolar lavage fluid in an LPS-induced acute lung injury in vivo mouse model. In summary, we propose that FATP1 is an important regulator of inflammatory response signaling in macrophages. Our findings suggest that ceramide-JNK signaling is important to terminate or sustain inflammation. PMID- 29272818 TI - Isorhamnetin, the active constituent of a Chinese herb Hippophae rhamnoides L, is a potent suppressor of dendritic-cell maturation and trafficking. AB - Dendritic cells (DCs) have been recognized as major targets of immunosuppressive therapies for their significant roles in connecting innate and adaptive immunity. Isorhamnetin (Iso), one of the most common flavonoid compounds extracted from the Chinese herb Hippophae rhamnoides L, has been proved to have anti-inflammatory, anticarcinogenic, and antioxidant activities in many chronic inflammatory conditions, but the effects of Iso on DCs have rarely been reported before. Here we investigated the functions and the mechanisms of Iso on bone marrow-derived DCs (BMDCs) including maturation, phagocytosis, and trafficking. Our data showed that Iso effectively inhibited the maturation of lipopolysaccharide (LPS)-treated BMDCs by down regulation of tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, IL-1beta and IL-12p70, up regulation of IL-10, and depression of costimulatory molecules CD40, CD80, and CD86, while had no effects on phagocytosis. Furthermore, Iso inhibited the migration of LPS-treated BMDCs, which may be due to its inhibition on chemokine receptor 7 (CCR7) expression. These findings strongly suggest that Iso is a potent immunosuppressive agent by inhibiting DC activation and trafficking, and may be used to prevent or treat chronic inflammation, autoimmune diseases, and graft rejections. PMID- 29272819 TI - Low-dose SKA Progesterone and Interleukin-10 modulate the inflammatory pathway in endometriotic cell lines. PMID- 29272820 TI - Production of curie quantities of 68Ga with a medical cyclotron via the 68Zn(p,n)68Ga reaction. AB - PET imaging with 68Ga-labeled tracers has seen a dramatic increase over the past five years primarily due to the increased accessibility of 68Ge/68Ga generators, the availability of tracers with superb targeting properties for labeling, straightforward labeling procedures and the approval of these tracers by regulatory entities. Available 68Ge/68Ga generators nominally deliver up to 1.85 GBq (50mCi) when fresh limiting production and distribution of 68Ga-labeled tracers to a few daily doses per generator. The focus of this study was to provide a simple and efficient method for 68Ga production in clinically relevant quantities using a low energy medical cyclotron with a solid target. PMID- 29272821 TI - Neutron activation analysis for the characterization of seawater uranium adsorbents. AB - This work details the development of an iterative neutron activation analysis (NAA) based workflow to precisely quantify metal ion uptake in an adsorbent. The workflow is iterative because it explores the dependence between independent variables defining the adsorbent fabrication procedure and the time-dependent uptake. It can be adapted to other adsorbents provided they have an affinity for ions which are amenable to efficient quantification using NAA. For this work, the ability of silver nanoparticles to mitigate the negative effects of biofouling on uranium transfer to an adsorbent was ultimately of interest, and hence motivates the development of this method. The limits of U detection and quantification were found to be 0.609 and 3.01MUgg-1, respectively; these were obtained using modest irradiation and counting times. The uncertainties arising from the NAA procedure were no more than 9.9%, far smaller than other sources of uncertainty present in the analysis. These results provided solid evidence that adsorbent shape and structure, rather than uniformity of composition, drives variability in adsorption of uranium. PMID- 29272822 TI - In vitro evaluation of the monoclonal antibody 64Cu-IgG M75 against human carbonic anhydrase IX and its in vivo imaging. AB - Specific oncology diagnostics requires new types of the selective radiopharmaceuticals, particularly those suitable for the molecular PET imaging. The aim of this work is to present a new, specific PET-immunodiagnostic radiopharmaceutical based on the monoclonal antibody IgG M75 targeting human carbonic anhydrase IX labelled with 64Cu (T1/2 = 12.70h) and its in vitro and in vivo evaluation. The antibody IgG M75 was conjugated with a non-commercial copper specific chelator "phosphinate" and then labelled with the positron emitter 64Cu. Stability of the labelled conjugated was tested in human serum. The immunoreactivity of the labelled conjugate was evaluated in vitro on a suitable cell cultures of the colorectal carcinoma (HT-29) and its imaging properties were estimated in vivo on a mouse model with inoculated colorectal carcinoma HT-29 imaged on a uPET/CT. The tested radioimmunoconjugate was obtained in a specific activity of 0.25-0.5 MBq/ug. In vitro uptake experiments revealed specific binding to the HT-29 cells (45 +/- 2.8% of the total added activity) and the measured KD value was found to be 9.2nM. Imaging clearly demonstrated significant uptake of the labelled monoclonal antibody in the tumour at 18h post administration. The radioimmunoconjugate 64Cu-PS-IgG M75 seems to be a suitable candidate for PET diagnostics of hypoxic tumours expressing human carbonic anhydrase IX. PMID- 29272823 TI - Evaluation of how a real time pre-registration health care curricula was managed through the application of a newly designed Change Management Model: A qualitative case study. AB - BACKGROUND: Curricula change in nurse education is of international importance. The pace of such change has been continuous and has triggered criticisms of inadequate preparation of practitioners. There are no change formulae for managing curricula change and despite a raft of change methods, globally change success remains low. A lack of a unified voice, undue focus on cognition, and arguably no existing models for academia and a literature gap contribute to change challenge. A new Change Management Model designed from research with emotion as its underpinning philosophy is evaluated. OBJECTIVE: Evaluation of a newly designed Change Management Model through a real time pre-registration health care curricula change. DESIGN: A qualitative case study was adopted. The single case study was the new pre-registration health care curricula. SETTING: This study took place in a Faculty of Health and Social care in one HEI in the UK. PARTICIPANTS: Four senior academics and fifteen academics across professions and specialisms involved in the curricula change took part in the study. RESULTS: The findings suggested that leadership operated differently throughout the organisation. Distributive and collective leadership created a critical mass of people to help deliver the new curricula but academics felt excluded at the strategic level. Emotion at the strategic level inhibited innovation but boosted engagement, emotional relationships and creativity at the operational level. Face to face communication was favoured for its emotional connection. A top down approach created an emotional disconnect and impacted inclusiveness, engagement, empowerment, vision and readiness for change. CONCLUSION: Testing the new model widely not only in organisations, practice and team changes but personal change in improving health and wellbeing could be beneficial. The continuing gap in knowledge on the link between emotion and curricula change, practice and organisational change and therapeutic value of the model also warrants further research. PMID- 29272824 TI - The impact of education and training interventions for nurses and other health care staff involved in the delivery of stroke care: An integrative review. AB - OBJECTIVES: The aim of this review was to explore the impact of stroke education and training of nurses and other health care staff involved in the delivery of stroke care. DESIGN: We performed an integrative review, following PRISMA guidance where possible. DATA SOURCES: We searched MEDLINE, ERIC, PubMed, AMED, EMBASE, HMIC, CINAHL, Google Scholar, IBSS, Web of Knowledge, and the British Nursing Index from 1980 to 2016. REVIEW METHODS: Any intervention studies were included if they focused on the education or training of nurses and other health care staff in relation to stroke care. Articles that appeared to meet the inclusion criteria were read in full. Data were extracted from the articles, and the study quality assessed by two researchers. We assessed risk of bias of included studies using a pre-specified tool based on Cochrane guidance. RESULTS: Our initial search identified 2850 studies of which 21 met the inclusion criteria. Six studies were randomised controlled trials, and one was an interrupted time series. Fourteen studies were quasi-experimental: eight were pretest-posttest; five were non-equivalent groups; one study had a single assessment. Thirteen studies used quality of care outcomes and eight used a patient outcome measure. None of the studies was identified as having a low risk of bias. Only nine studies used a multi-disciplinary approach to education and training and nurses were often taught alone. Interactive education and training delivered to multi-disciplinary stroke teams, and the use of protocols or guidelines tended to be associated with a positive impact on patient and quality of care outcomes. CONCLUSIONS: Practice educators should consider the delivery of interactive education and training delivered to multi-disciplinary groups, and the use of protocols or guidelines, which tend to be associated with a positive impact on both patient and quality of care outcomes. Future research should incorporate a robust design. PMID- 29272825 TI - Synchrotron infrared microspectroscopy reveals the roles of aliphatic and aromatic moieties in sorption of nitroaromatic compounds to soils. AB - A consensus on the role of organic carbon moieties as the sorptive domains for nonionic organic compounds in soils is lacking due to the extremely complicated compositions of soil matrices. In this study, synchrotron radiation-based infrared microspectroscopy (IMS) was applied to in situ probe the distributions of four nitroaromatic compounds with varying hydrophobicity (namely, 1,3 dinitrobenzene, 1,5-dinitronapthalene, 3-nitrophenanthrene and 6 nitrobenzo[a]pyrene) and their associations with aliphatic and aromatic organic carbon moieties in soils. The technique revealed that both nitro group (NO2) from the nitroaromatic compounds and organic carbon moieties were unevenly distributed in the soils at the micron scale. The spatial distribution of nitro groups was positively correlated with that of aromatic carbon (C=C) (r>0.804, p<0.01), indicating that the aromatic moieties of soil organic carbon play a key role in sorption of nitroaromatic compounds to soils. Neither nitro groups nor aromatic carbon showed a close relationship with aliphatic carbon (CH) in the spatial distribution in the soils. Meanwhile, the nitro groups from 1,3-dinitrobenzene and 1,5-dinitronapthalene exhibited a significant correlation with clay minerals (OH) in their distributions (r>0.629, p<0.01) in the soils and the correlation became insignificant for the other two compounds with high hydrophobicity. This study for the first time provides micron-scale spectroscopic evidence for the roles of organic carbon moieties in the sorption of nonionic organic compounds to soils. PMID- 29272826 TI - Impact of heavy metal bioaccumulation on antioxidant activities and DNA profile in two earthworm species and freshwater prawn from Ogun River. AB - The use of freshwater invertebrates as bioindicator of heavy metal pollution is an important tool for environmental biomonitoring. This study investigated antioxidant activities and DNA profile in two limicolous earthworms (Alma millsoni and Libyodrilus violaceus) and freshwater prawns (Macrobrachium vollenhovenii) at selected points of Ogun River, Abeokuta. Heavy metal concentrations and DNA profile in the earthworms and prawn tissues were measured using standard procedures. Zn concentration was higher than other heavy metals in A. millsoni (685.83+/-114.42mg/kg), L. violaceus (1913.3+/-1098.7mg/kg) and M. vollenhovenii (134.7+/-13.61mg/kg). Superoxide dismutase activity ranged from 62.44+/-7.16-79.82+/-11.18U/g tissues, 60.26+/-11.18-71.07+/-7.54U/g tissues and 74.07+/-16.69-87.79+/-8.50U/g tissues in A. millsoni, L. violaceus and M. vollenhovenii respectively. RAPD-PCR revealed varying DNA profile among the earthworms samples; the UPGMA dendrogram formed two distinct clusters at genetic similarity coefficient of 0.15-0.2 with one cluster consisting of Alma millsoni and Libyodrilus violaceus from Sokori, Enugada and Iberekodo sampling points and the second cluster forming two distinct sub-clusters comprising Arakanga and Ago ika's L. violaceus in one and A. millsoni in the other. High genetic variability was recorded among the earthworm species while the freshwater prawn showed no variability. Antioxidant activities and genetic variability in earthworms could serve as biomarkers of heavy metal pollution in freshwater environment. PMID- 29272827 TI - Wildland fire smoke and human health. AB - The natural cycle of landscape fire maintains the ecological health of the land, yet adverse health effects associated with exposure to emissions from wildfire produce public health and clinical challenges. Systematic reviews conclude that a positive association exists between exposure to wildfire smoke or wildfire particulate matter (PM2.5) and all-cause mortality and respiratory morbidity. Respiratory morbidity includes asthma, chronic obstructive pulmonary disease (COPD), bronchitis and pneumonia. The epidemiological data linking wildfire smoke exposure to cardiovascular mortality and morbidity is mixed, and inconclusive. More studies are needed to define the risk for common and costly clinical cardiovascular outcomes. Susceptible populations include people with respiratory and possibly cardiovascular diseases, middle-aged and older adults, children, pregnant women and the fetus. The increasing frequency of large wildland fires, the expansion of the wildland-urban interface, the area between unoccupied land and human development; and an increasing and aging U.S. population are increasing the number of people at-risk from wildfire smoke, thus highlighting the necessity for broadening stakeholder cooperation to address the health effects of wildfire. While much is known, many questions remain and require further population-based, clinical and occupational health research. Health effects measured over much wider geographical areas and for longer periods time will better define the risk for adverse health outcomes, identify the sensitive populations and assess the influence of social factors on the relationship between exposure and health outcomes. Improving exposure models and access to large clinical databases foreshadow improved risk analysis facilitating more effective risk management. Fuel and smoke management remains an important component for protecting population health. Improved smoke forecasting and translation of environmental health science into communication of actionable information for use by public health officials, healthcare professionals and the public is needed to motivate behaviors that lower exposure and protect public health, particularly among those at high risk. PMID- 29272829 TI - Evaluation of environmental and anthropogenic influences on ambient background metal and metalloid concentrations in soil. AB - There has been a global shift in environmental risk assessment towards quantifying ambient background concentrations of metals/metalloids in soil. Whilst bedrock has been shown to be a key driver of metal/metalloid variability in soil, few researchers have assessed controls of ambient background concentrations in soils of similar bedrock. A soil survey was undertaken ofGreater Melbourne, Greater Geelong, Ballarat and Mitchell in Victoria, Australia for elements of potential environmental concern: As, Cd, Cr, Cu, Ni, Hg, Pb and Zn. Samples (n=622) were collected from surface (0 to 0.1m) and sub surface (0.3 to 0.6m) soils, overlying Tertiary-Quaternary basalt, Tertiary sediments and Silurian siltstone and sandstone. In addition, background soil data from open-source environmental assessment reports (n=5512) were collated to support the understanding of natural enrichment, particularly at depths >0.6m. Factor analysis, supported by correlation analysis and auxiliary geo-spatial data, provided an improved understanding of where and how background metal/metalloid enrichment occurs in the environment. Weathering during paleoclimates was the predominant influence of background metal/metalloid variability in soils overlying similar bedrock. Other key influences of metal/metalloid variability in soil included hydraulic leaching of alkali elements, biological cycling, topography and alluvial transfer of silt and sand from mineralised regions. In addition, urbanisation positively correlated with Pb and Zn concentrations in surface soils suggesting that anthropogenic activities may have resulted in diffuse Pb and Zn contamination of urban soil. PMID- 29272828 TI - Environmental mapping using Bayesian spatial modelling (INLA/SPDE): A reply to Huang et al. (2017). PMID- 29272830 TI - Simulated nitrogen deposition affects stoichiometry of multiple elements in resource-acquiring plant organs in a seasonally dry subtropical forest. AB - Increase of anthropogenic atmospheric nitrogen (N) deposition markedly influences biogeochemical cycles of elements in a wide range of ecosystems. However, our knowledge of how N deposition affects stoichiometry of plants in forests experiencing regular seasonal droughts remains limited. Using a 3-year (2013 2015) N-manipulative experiment, we examined the stoichiometric responses of ten mineral elements, including the most limiting elements (N and P) to plant growth, base cations (K, Ca, and Mg), and trace metal cations (Mn, Zn, Cu, Al, and Fe) in resource-acquiring organs (foliage vs. absorptive roots) of Pinus elliottii to N additions in both wet and dry seasons in a seasonally dry subtropical forest. Stoichiometric responses of both organs depended on rate of N addition (generally stronger under high rate) and season. N additions increased foliar [N] and decreased foliar [P] only in dry season and the relative changes in foliar N:P ratio were twice higher in dry than wet seasons, suggesting an aggravated P limitation in dry season. The stoichiometry of absorptive roots was more responsive to N additions than that of foliage, especially for the base cations. N additions increased [Mn] and decreased Fe:Mn ratio in both organs, indicating increased risk of Mn2+ toxicity to this tree species. Our results have implications for understanding the N-induced changes in nutrient limitation of forests influenced by seasonal drought, and highlight the contrasting stoichiometric responses of above- and below-ground resource-acquiring plant organs to N loading. PMID- 29272831 TI - Hearing loss in children with e-waste lead and cadmium exposure. AB - Environmental chemical exposure can cause neurotoxicity and has been recently linked to hearing loss in general population, but data are limited in early life exposure to lead (Pb) and cadmium (Cd) especially for children. We aimed to evaluate the association of their exposure with pediatric hearing ability. Blood Pb and urinary Cd were collected form 234 preschool children in 3-7years of age from an electronic waste (e-waste) recycling area and a reference area matched in Shantou of southern China. Pure-tone air conduction (PTA) was used to test child hearing thresholds at frequencies of 0.25, 0.5, 1, 2, 4 and 8kHz. A PTA>=25dB was defined as hearing loss. A higher median blood Pb level was found in the exposed group (4.94+/-0.20 vs 3.85+/-1.81MUg/dL, p<0.001), while no significance was found for creatinine-adjusted Cd. Compared with the reference group, the exposed group had a higher prevalence of hearing loss (28.8% vs 13.6%, p<0.001). The PTA in the left, right and both ears, and hearing thresholds at average low and high frequency, and single frequency of 0.5, 1 and 2kHz were all increased in the exposed group. Positive correlations of child age and nail biting habit with Pb, and negative correlations of parent education level and child washing hands before dinner with Pb and Cd exposure were observed. Logistic regression analyses showed the adjusted OR of hearing loss for Pb exposure was 1.24 (95% CI: 1.029, 1.486). Our data suggest that early childhood exposure to Pb may be an important risk factor for hearing loss, and the developmental auditory system might be affected in e-waste polluted areas. PMID- 29272832 TI - Individual contributions, provision point mechanisms and project cost information effects on contingent values: Findings from a field validity test. AB - In many instances, Contingent Valuation practitioners rely on voluntary monetary contributions, despite the fact that they are deemed to be neither incentive compatible in theory nor demand revealing in practice. The reason is that they are suitable for most field applications and offer benefits that may outweigh their drawbacks. This paper endeavors to contribute to the literature by exploring the effect of donation payments with differing incentive structures and information levels on contingent values and on respondents' uncertainty regarding the donations declared. To this end, a field survey was conducted using a sample of 332 respondents who were randomly assigned to one of three different mechanisms: (1) individual contribution (hereinafter CVM treatment); (2) individual contribution with provision point mechanism (PPM), where the total cost of the project is unknown (hereinafter PPM treatment); and (3) individual contribution with PPM, where the total cost of the project is known (hereinafter PPM-INF treatment). The results indicate that there are no statistically significant differences in willingness to pay (WTP) estimates between the CVM and PPM treatments nor between the PPM and the PPM-INF treatments. The results also indicate that the PPM has a positive effect on respondents' certainty level, but there is no evidence that the certainty level is affected by the project information cost. The results are mixed compared to previous research efforts. Thus, further tests are necessary in field comparisons and under different information environments before any definite recommendations can be made. PMID- 29272833 TI - Turbidity composition and the relationship with microbial attachment and UV inactivation efficacy. AB - Turbidity in water can be caused by a range of different turbidity causing materials (TCM). Here the characteristics and attachment of bacteria to TCMs was assessed and the resultant impact on UV disinfection determined. TCMs represent potential vehicles for bacterial penetration of water treatment barriers, contamination of potable supplies and impact on subsequent human health. The TCMs under investigation were representative of those that may be present in surface and ground waters, both from the source and formed in the treatment process. The TCMs were chalk, Fe (III) hydroxide precipitate, kaolin clay, manganese dioxide and humic acids, at different turbidity levels representative of source waters (0, 0.1, 0.2, 0.4, 1, 2, and 5 NTU). Escherichia coli and Enterococcus faecalis attachment followed the order of Fe(III)>chalk, with little to no attachment seen for MnO2, humic acids and clay. The attachment was postulated to be due to chalk and Fe(III) particles having a more neutral surface charge resulting in elevated aggregation with bacteria compared to other TCMs. The humic acids and Fe(III) were the TCMs which influenced inactivation of E. coli and E. faecalis due to decreasing UV transmittance (UVT) with increasing TCM concentration. The presence of the Fe(III) TCM at 0.2 NTU resulted in the poorest E. coli inactivation, with 2.5 log10 reduction at UV dose of 10mJcm-2 (kd of -0.23cm2mJ-1) compared to a 3.9 log10 reduction in the absence of TCMs. E. faecalis had a greater resistance to UV irradiation than E. coli for all TCMs. Effective disinfection of drinking water is a priority for ensuring high public health standards. Uniform regulations for turbidity levels for waters pre-disinfection by UV light set by regulators may not always be appropriate and efficacy is dependent on the type, as well as the amount, of turbidity present in the water. PMID- 29272834 TI - Spatio-temporal benthic biodiversity patterns and pollution pressure in three Mediterranean touristic ports. AB - The Mediterranean Sea is one of the busiest areas worldwide in terms of maritime activity, facing considerable anthropogenic disturbance, such as pollution by hydrocarbons and heavy metals. The present study has evaluated the environmental and benthic biodiversity characteristics of three touristic ports, Cagliari (Sardinia, Italy), Heraklion (Crete, Greece) and El Kantaoui (Tunisia), based on the combined assessment of physical parameters, chemical variables (i.e. nutrients, pigments), sediment pollution and macrobenthic biodiversity. Different port sectors (leisure, fishing, passenger, cargo, shipyard) and different seasons (winter, before touristic period, after touristic period) were compared. Salinity and sediment concentration of copper and antimony were the three environmental parameters most highly correlated with benthic species composition and diversity. Both the environmental variables and the benthic biodiversity patterns were significantly different between the three ports (i.e. different geographical locations). Heraklion port was heavily polluted by AHs in surface and anoxic sediments and had the highest percentage of opportunistic species, while Cagliari had the highest levels of PAHs and UCM and low species richness. El Kantaoui port was less polluted and characterised by a richer biodiversity. The shipyard sector in Heraklion port was significantly different from all other sectors in terms of abiotic and biotic parameters. Physico-chemical and pollution variables recorded during the period after tourism (late summer) were significantly different from the ones recorded in winter. Seasonal differences were not significant between benthic species diversity patterns, but were revealed when the patterns derived from the aggregation of higher taxonomic levels were compared. The present study indicates that a regular-basis monitoring plan including evaluation of environmental health based on benthic biodiversity, can provide a basis for perceiving changes and reveal the degree of anthropogenic disturbance in port environments. PMID- 29272835 TI - Feature selection approaches for predictive modelling of groundwater nitrate pollution: An evaluation of filters, embedded and wrapper methods. AB - Recognising the various sources of nitrate pollution and understanding system dynamics are fundamental to tackle groundwater quality problems. A comprehensive GIS database of twenty parameters regarding hydrogeological and hydrological features and driving forces were used as inputs for predictive models of nitrate pollution. Additionally, key variables extracted from remotely sensed Normalised Difference Vegetation Index time-series (NDVI) were included in database to provide indications of agroecosystem dynamics. Many approaches can be used to evaluate feature importance related to groundwater pollution caused by nitrates. Filters, wrappers and embedded methods are used to rank feature importance according to the probability of occurrence of nitrates above a threshold value in groundwater. Machine learning algorithms (MLA) such as Classification and Regression Trees (CART), Random Forest (RF) and Support Vector Machines (SVM) are used as wrappers considering four different sequential search approaches: the sequential backward selection (SBS), the sequential forward selection (SFS), the sequential forward floating selection (SFFS) and sequential backward floating selection (SBFS). Feature importance obtained from RF and CART was used as an embedded approach. RF with SFFS had the best performance (mmce=0.12 and AUC=0.92) and good interpretability, where three features related to groundwater polluted areas were selected: i) industries and facilities rating according to their production capacity and total nitrogen emissions to water within a 3km buffer, ii) livestock farms rating by manure production within a 5km buffer and, iii) cumulated NDVI for the post-maximum month, being used as a proxy of vegetation productivity and crop yield. PMID- 29272836 TI - Overproduction of microbial extracellular polymeric substances in subtropical intertidal sediments in response to endocrine disrupting chemicals. AB - Microorganisms and their extracellular polymeric substances (EPS) in sediments are important in sediment stabilization and the fate of pollutants. However, how toxic organic pollutants affect bacteria and EPS in sediments, particularly in subtropical intertidal zones is poorly known. The present study aims to investigate the bacterial abundance and related EPS in simulated intertidal sandflat and mangrove sediments under the stress of endocrine disrupting chemicals (EDCs). Results showed that the temporal changes of the bacterial number in both sandflat and mangrove sediments were similar, increased from days 0 to 56 then became steady during the 84-days incubation. Bacteria exhibited an important role in the production of high molecular weight (HMW) EPS protein and the degradation of the low molecular weight (LMW) EPS protein. During incubation, the EPS polysaccharides changed from a colloidal-LMW fraction at the beginning to a more complex-HMW fraction at the end of the experiment. The increases in the concentration of HMW polysaccharides might contribute to sediment stabilization. Among different spiked EDCs, nonylphenol (NP) and 17alpha-ethinylestradiol (EE2) tended to accumulate in both sandflat and mangrove sediments and posed stresses to bacterial growth, especially the latter sediment. The persistent EDCs promoted a higher production of EPS polysaccharides and proteins in both sediments when compared to the respective control, but the EPS in the sandflat sediment was mainly in the colloidal fraction while the bound fraction was more abundant in the mangrove sediment. The present results enhance our understanding of the effects of EDCs on sediment biofilms in intertidal systems. This study also demonstrates the significance of EPS polysaccharides and proteins in sediment stabilization and provides a fundamental basis for future microbiology studies. PMID- 29272837 TI - Enhanced arsenic uptake and polycyclic aromatic hydrocarbon (PAH)-dissipation using Pteris vittata L. and a PAH-degrading bacterium. AB - This study examined the effects of P. vittata and a polycyclic aromatic hydrocarbon (PAH)-degrading bacterium (Alcaligenes sp.) on arsenic (As) uptake and phenanthrene dissipation. Bacterial inoculation substantially increased As accumulation in plants by 27.8% (frond) and 27.5% (root) at 60d, respectively, compared with the non-inoculated treatment, although temporal change of As translocation and reduction in plants was observed. Bacterial inoculation positively affected plants by improving growth, nutrition and antioxidative activities, and helped to modify soil As availability to the plants, which may benefit in plant tolerance and As accumulation. Plant and bacteria association enhanced phenanthrene dissipation from the soil, with the highest dissipation rate of 96.4% at 60d in the rhizosphere, which might be associated with enhanced bacterial population and activity inspired by the growth of plant. The result reveals that combination of P. vittata and PAH-degrading bacteria can promote As accumulation and phenanthrene dissipation, and can be exploited as a promising strategy for As and PAH co-contamination remediation. PMID- 29272838 TI - Prescribed fire and its impacts on ecosystem services in the UK. AB - The impacts of vegetation fires on ecosystems are complex and varied affecting a range of important ecosystem services. Fire has the potential to affect the physicochemical and ecological status of water systems, alter several aspects of the carbon cycle (e.g. above- and below-ground carbon storage) and trigger changes in vegetation type and structure. Globally, fire is an essential part of land management in fire-prone regions in, e.g. Australia, the USA and some Mediterranean countries to mitigate the likelihood of catastrophic wildfires and sustain healthy ecosystems. In the less-fire prone UK, fire has a long history of usage in management for enhancing the productivity of heather, red grouse and sheep. This distinctly different socioeconomic tradition of burning underlies some of the controversy in recent decades in the UK around the use of fire. Negative public opinion and opposition from popular media have highlighted concerns around the detrimental impacts burning can have on the health and diversity of upland habitats. It is evident there are many gaps in the current knowledge around the environmental impacts of prescribed burning in less fire prone regions (e.g. UK). Land owners and managers require a greater level of certainty on the advantages and disadvantages of prescribed burning in comparison to other techniques to better inform management practices. This paper addresses this gap by providing a critical review of published work and future research directions related to the impacts of prescribed fire on three key aspects of ecosystem services: (i) water quality, (ii) carbon dynamics and (iii) habitat composition and structure (biodiversity). Its overall aims are to provide guidance based on the current state-of-the-art for researchers, land owners, managers and policy makers on the potential effects of the use of burning and to inform the wider debate about the place of fire in modern conservation and land management in humid temperate ecosystems. PMID- 29272839 TI - Phytotoxicity, bioaccumulation and potential risks of plant irrigations using cyanobloom-loading freshwater. AB - The toxicity of cyanotoxins on plant has been reported. However, in eutrophic waters harmful cyanobacteria are associated with other environmental pollutants, such as persistent organic pollutants (POPs) and metals. Information on the phytotoxicity and bioaccumulation of coexisted cyanotoxins and these environmental pollutants is still lacking. In this study, the combined phytotoxicities of three types of cyanobacteria-associated pollutants, i.e., microcystin-LR (MC-LR), cadmium (Cd), 2, 4, 4'-Trichlorobiphenyl (PCB-28) were systematically investigated. After 7-days exposure, strong synergistic effects can be detected when Arabidopsis thaliana seeds and seedlings exposed to binary mixtures of MC-LR+PCB-28 and PCB-28+Cd. The strongest inhibition occurred when A. thaliana exposed to their ternary mixture under both glasshouse and semi-field conditions. Moreover, bioaccumulation of MC-LR, Cd and PCB-28 was enhanced when seedlings exposed to their binary/ternary mixtures, especially when seedlings were treated with higher concentrations of toxicants (MC-LR, 1mgL-1; Cd, 10mgL-1; PCB-28, 1MUgL-1). Additionally, pronounced toxic effects could be determined under 7-days after seedlings were irrigated with raw cyanobloom-containing water (collected from Lake Taihu in China)and its dilutions. Seeds production decreased significantly after the continuous irrigation with cyanoblooms-containing water. Collectively, this work will be an informative implication for risks of cyanoblooms and adequate utilization of freshwater containing cyanoblooms for crop irrigation. PMID- 29272840 TI - Changes in eggshell thickness and ultrastructure in the Bearded Vulture (Gypaetus barbatus) Pyrenean population: A long-term analysis. AB - The Spanish Bearded Vulture (Gypaetus barbatus) population has suffered from negative trends in a number of reproductive parameters that could jeopardize its long-term viability. From 1989 to 2012, 27 entire eggs and 63 eggshell fragments were collected from nests after breeding failure and/or fledging. Longer-term changes in eggshell thickness were made by examining 69 eggs collected in Spain from 1858 to 1911, and now held in European museums. Low levels of contamination with organochlorine pesticides and polychlorinated biphenyls were found in whole eggs and in conjunction with the high fertility rates observed in the field (66.7%) do not indicate a population suffering from the effects of organochlorine contamination. However, a decrease in the Ratcliffe Index and eggshell thickness were observed in eggs collected since 2001, increasingly so in samples post-2004, indicating an abrupt loss of egg quality. We found no significant relationship between organochlorine residues and eggshell in any of the variables measured. In contrast, we found a positive relationship between food availability and the Ratcliffe Index, eggshell thickness and eggshell surface area. A density dependent explanation of reduced egg quality could arise from ecological constraints as the decrease of food resources. The impact of sudden changes in food availability due to sanitary regulations between 2006 and 2011 could be related with the loss of Bearded Vulture egg quality. PMID- 29272841 TI - Unraveling the potential of a combined nitritation-anammox biomass towards the biodegradation of pharmaceutically active compounds. AB - In the past few years, anaerobic ammonium oxidation-based processes have attracted a lot of attention for their implementation at the mainstream line of wastewater treatment plants, due to the possibility of leading to energy autarky if combined with anaerobic digestion. However, little is known about the potential degradation of micropollutants by the microbial groups responsible of these processes and the few results available are inconclusive. This study aimed to assess the degradation capability of biomass withdrawn from a combined nitritation/anaerobic ammonium oxidation (combined N/A) pilot plant towards five pharmaceutically active compounds (ibuprofen, sulfamethoxazole, metoprolol, venlafaxine and carbamazepine). Batch experiments were performed under different conditions by selectively activating or inhibiting different microbial groups: i) regular combined N/A operation, ii) aerobic (optimal for nitrifying bacteria), iii) aerobic with allylthiourea (an inhibitor of ammonia monooxygenase, enzyme of ammonia oxidizing bacteria), iv) anoxic (optimal for anaerobic ammonium oxidizing bacteria), v) aerobic with acetate (optimal for heterotrophic bacteria) and vi) anoxic with acetate (optimal for heterotrophic denitrifying bacteria). Ibuprofen was the most biodegradable compound being significantly degraded (49-100%) under any condition except heterotrophic denitrification. Sulfamethoxazole, exhibited the highest removal (70%) under optimal conditions for nitrifying bacteria but in the rest of the experiments anoxic conditions were found to be slightly more favorable (up to 58%). For metoprolol the highest performance was obtained under anoxic conditions favoring anammox bacteria (62%). Finally, carbamazepine and venlafaxine were hardly removed (<=10% in the majority of cases). Taken together, these results suggest the specificity of different microbial groups that in combination with alternating operational parameters can lead to enhanced removal of some micropollutants. PMID- 29272842 TI - Pesticides in the rivers and streams of two river basins in northern Greece. AB - The pollution caused by pesticides, and their ecotoxicological implications were investigated in water samples from the Strymonas and Nestos river basins (Northern Greece). Chlorpyrifos was the most frequently detected pesticide in both basins (42 and 37% in the Strymonas and Nestos basins, respectively), followed by fluometuron and terbuthylazine (25 and 12%, Strymonas), and bentazone and boscalid (24 and 10%, Nestos). The Annual Average and the Maximum Allowable Concentration of Environmental Quality Standards set in European Union Directives were exceeded in several cases by alphamethrin and chlorpyrifos. Risk Quotient assessment revealed significant ecological risk towards the aquatic organisms in over 20% of the water samples. Insecticides (mostly pyrethroids and organophosphosphates) contributed more in the ecotoxicological risk than herbicides and fungicides. The three main rivers in the current study (Strymonas, Aggitis, Nestos) exhibited similar sum of RQs indicating that aquatic life in all three of them was at the same risk level. However, the sums of RQs were higher in the various streams monitored than the three rivers. PMID- 29272843 TI - Modeling long-term effects of hairy vetch cultivation on cotton production in Northwest Louisiana. AB - The use of hairy vetch as a winter cover crop for cotton production in Northwest Louisiana has contributed to sustaining cotton production as well as improving soil quality. To test the efficacy of hairy vetch (HV) cultivation as a natural N supplement for cotton production, a long-term field experiment lasting 27years was evaluated using the Denitrification-Decomposition (DNDC) model. Different N fertilization practices, including 0kgNha-1 (PL_1), HV alone (PL_2), 44.8kgNha-1 (PL_3), and 67.3kgNha-1 (PL_4), were compared to evaluate nitrogen (N) response to cotton yield. Measured crop yield from each treatment was used to calibrate and validate the model. The DNDC model was employed to test the effects of N application scenarios on cotton yields and HV incorporation on N balance under irrigated and non-irrigated conditions. In model calibration, statistical indices for the model performance on cotton seed yield showed that PL_1 had a normalized root mean square error (NRMSE) value of 24.5%, a model efficiency (ME) value of 0.51, and a correlation coefficient (r) of 0.87 (P<0.01). The DNDC model was validated with PL_2, PL_3, and PL_4. PL_2, PL_3 and PL_4 had a NRMSE of 18.6%, 16.4% and 15.8% respectively, ME value of 0.19, 0.47 and 0.52 respectively, and an r of 0.75, 0.83 and 0.85 (P<0.05) respectively. Estimates of soil organic carbon (SOC) for HV treatment showed double the SOC content during a 27-year long term experiment, while both treatments of 44.8kgNha-1 and 67.3kgNha-1 showed similar levels of SOC of a 25% increase compared to the control. Based on the scenario analysis, sustainable cotton yields do not require N fertilizer application under HV cultivated fields, and no yield differences were observed between irrigated and non-irrigated conditions. PMID- 29272844 TI - Decay of low-density polyethylene by bacteria extracted from earthworm's guts: A potential for soil restoration. AB - Low-density polyethylene (LDPE) is the most abundant source of microplastic pollution worldwide. A recent study found that LDPE decay was increased and the size of the plastic was decreased after passing through the gut of the earthworm Lumbricus terrestris (Oligochaeta). Here, we investigated the involvement of earthworm gut bacteria in the microplastic decay. The bacteria isolated from the earthworm's gut were Gram-positive, belonging to phylum Actinobacteria and Firmicutes. These bacteria were used in a short-term microcosm experiment performed with gamma-sterilized soil with or without LDPE microplastics (MP). We observed that the LDPE-MP particle size was significantly reduced in the presence of bacteria. In addition, the volatile profiles of the treatments were compared and clear differences were detected. Several volatile compounds such as octadecane, eicosane, docosane and tricosane were measured only in the treatments containing both bacteria and LDPE-MP, indicating that these long-chain alkanes are byproducts of bacterial LDPE-MP decay. PMID- 29272845 TI - Dissolution and transport of insensitive munitions formulations IMX-101 and IMX 104 in saturated soil columns. AB - Military training exercises can result in deposition of energetic residues on range soils, which ultimately can contaminate groundwater with munitions constituents. Column experiments followed by HYDRUS-1D modeling were conducted to evaluate dissolution and transport of energetic constituents from the new insensitive munitions (IM) formulations IMX-101, a mixture of 3-nitro-1,2,4 triazol-5-one (NTO), nitroguanidine (NQ), and 2, 4-dinitroanisole (DNAN), and IMX 104, a mixture of NTO, 1,3,5-hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and DNAN. NTO and DNAN are emerging contaminants associated with the development of insensitive munitions as replacements for traditional munitions. Flow interruption experiments were performed to investigate dissolution kinetics and sorption non-equilibrium between soil and solution phases. The results indicated that insensitive munitions compounds dissolved in order of their aqueous solubility, consistent with prior dissolution studies conducted in the absence of soil. Initial elution of the high concentration pulse of highly soluble NTO and NQ was followed by lower concentrations, while DNAN had generally lower and more constant concentrations in leachate. The sorption of NTO and NQ was low, while RDX, 1,3,5,7-octahydro-1,3,5,7-tetranitrotetrazocine (HMX, an impurity in technical grade RDX), and DNAN all exhibited appreciable sorption. DNAN transformation was observed, with formation of amino-reduction products 2-ANAN (2 amino-4-nitroanisole) and 4-ANAN (4-amino-2-nitroanisole). HYDRUS-1D model, incorporating one-dimensional advective-dispersive transport with particle dissolution and first-order solute transformation was used to simulate the measured breakthrough curves. Optimized dissolution parameters varied widely but were correlated between compounds in the same formulation. Determined adsorption coefficients generally agreed with values determined from batch and column studies conducted with pure NTO and DNAN, while mass-loss rate coefficients were in better agreement with ones from batch than column studies possibly due to suppression of microbial transformation during elution of high concentrations of explosives. Even in the low organic matter soils selected in this study DNAN experienced significant retardation and transformation, indicating potential for its natural attenuation. PMID- 29272846 TI - Management intensity controls soil N2O fluxes in an Afromontane ecosystem. AB - Studies that quantify nitrous oxide (N2O) fluxes from African tropical forests and adjacent managed land uses are scarce. The expansion of smallholder agriculture and commercial agriculture into the Mau forest, the largest montane forest in Kenya, has caused large-scale land use change over the last decades. We measured annual soil N2O fluxes between August 2015 and July 2016 from natural forests and compared them to the N2O fluxes from land either managed by smallholder farmers for grazing and tea production, or commercial tea and eucalyptus plantations (n=18). Air samples from 5 pooled static chambers were collected between 8:00am and 11:30am and used within each plot to calculate the gas flux rates. Annual soil N2O fluxes ranged between 0.2 and 2.9kgNha-1yr-1 at smallholder sites and 0.6-1.7kgNha-1yr-1 at the commercial agriculture sites, with no difference between land uses (p=0.98 and p=0.18, respectively). There was marked variation within land uses and, in particular, within those managed by smallholder farmers where management was also highly variable. Plots receiving fertilizer applications and those with high densities of livestock showed the highest N2O fluxes (1.6+/-0.3kgN2O-Nha-1yr-1, n=7) followed by natural forests (1.1+/-0.1kgN2O-Nha-1yr-1, n=6); although these were not significantly different (p=0.19). Significantly lower fluxes (0.5+/-0.1kgNha-1yr-1, p<0.01, n=5) were found on plots that received little or no inputs. Daily soil N2O flux rates were not correlated with concurrent measurements of water filled pore space (WFPS), soil temperature or inorganic nitrogen (IN) concentrations. However, IN intensity, a measure of exposure of soil microbes (in both time and magnitude) to IN concentrations was strongly correlated with annual soil N2O fluxes. PMID- 29272847 TI - Feasibility of using the National Marine Mammal Tissue Bank for retrospective exploratory studies of perfluorinated alkyl acids. AB - Perfluorinated alkyl acids (PFAAs) have been used for 50+ years in materials such as stain-resistant treatments for paper and clothing, lubricants, and foam fire extinguishers. PFAAs are characterized by a fully fluorinated alkyl chain with a terminal acid group. Their long half-lives and ubiquitous environmental distribution create considerable concern for wildlife and human exposure. There is interest in examining temporal trends of PFAAs using the National Marine Mammal Tissue Bank (NMMTB), but NMMTB tissues are frozen and cryohomogenized in polytetrafluoroethylene (PTFE)-based materials. Because PTFE supplies may leach PFAAs into samples, this study mimicked collection, processing and storage steps of NMMTB samples and measured PFAA leaching to determine the feasibility of using this sample archive for PFAA temporal trends. We also explored concentrations in Atlantic white-sided dolphin (Lagenorhynchus acutus, WSDs) and rough-toothed dolphin (Steno bredanensis, RTDs) blubber (n=3 and 0) and liver (n=48 and 12, respectively). The materials used in NMMTB protocols may add up to 0.968ng/g perfluorooctanoic acid (PFOA), 0.090ng/g perfluorononanoic acid (PNFA), and 0.221ng/g perfluorooctane sulfonate (PFOS) to each archived sample. Leaching of PFNA and PFOS from supplies compared to dolphin levels was negligible, but PFOA contributions were substantially higher than levels found in most dolphin liver samples. Therefore, monitoring PFOA temporal trends from the NMMTB would require careful consideration. RTDs had significantly higher levels of PFOS and PFNA than WSDs. Both species have similar life history, trophic status, and foraging behaviors in deep pelagic waters, so differences could be from latitudinal variation in contamination. RTDs stranded in Florida; WSDs stranded farther north mostly in Massachusetts. Juveniles had significantly higher levels of PFOS and PFNA than adults in both species, suggesting growth dilution as they approach maturity. PFOS significantly decreased after 2001 in both species as expected based on changes in production. PMID- 29272848 TI - Spatio-temporal variations in climate, primary productivity and efficiency of water and carbon use of the land cover types in Sudan and Ethiopia. AB - The impact of climate variability on the Net Primary Productivity (NPP) of different land cover types and the reaction of NPP to drought conditions are still unclear, especially in Sub-Saharan Africa. This research utilizes public domain data for the period 2000 through 2013 to analyze these aspects for several land cover types in Sudan and Ethiopia, as examples of data-scarce countries. Spatio-temporal variation in NPP, water use efficiency (WUE) and carbon use efficiency (CUE) for several land covers were correlated with variations in precipitation, temperature and drought at different time scales, i.e. 1, 3, 6 and 12months using Standardized Precipitation Evapotranspiration Index (SPEI) datasets. WUE and CUE were estimated as the ratios of NPP to actual evapotranspiration and NPP to Gross Primary Productivity (GPP), respectively. Results of this study revealed that NPP, WUE and CUE of the different land cover types in Ethiopia have higher magnitudes than their counterparts in Sudan. Moreover, they exhibit higher sensitivity to drought and variation in precipitation. Whereas savannah represents the most sensitive land cover to drought, croplands and permanent wetlands are the least sensitive ones. The inter annual variation in NPP, WUE and CUE in Ethiopia is likely to be driven by a drought of time scale of three months. No statistically significant correlation was found for Sudan between the inter-annual variations in these indicators with drought at any of the time scales considered in the study. Our findings are useful from the view point of both food security for a growing population and mitigation to climate change as discussed in the present study. PMID- 29272849 TI - Quantifying the contribution of riparian soils to the provision of ecosystem services. AB - Riparian areas, the interface between land and freshwater ecosystems, are considered to play a pivotal role in the supply of regulating, provisioning, cultural and supporting services. Most previous studies, however, have tended to focus on intensive agricultural systems and only on a single ecosystem function. Here, we present the first study which attempts to assess a wide range of ecological processes involved in the provision of the ecosystem service of water quality regulation across a diverse range of riparian typologies. Specifically, we focus on 1) evaluating the spatial variation in riparian soils properties with respect to distance with the river and soil depth in contrasting habitat types; 2) gaining further insights into the underlying mechanisms of pollutant removal (i.e. pesticide sorption/degradation, denitrification, etc.) by riparian soils; and 3) quantify and evaluate how riparian vegetation across different habitat types contribute to the provision of watercourse shading. All the habitats were present within a single large catchment and included: (i) improved grassland, (ii) unimproved (semi-natural) grassland, (iii) broadleaf woodland, (iv) coniferous woodland, and (iv) mountain, heath and bog. Taking all the data together, the riparian soils could be statistically separated by habitat type, providing evidence that they deliver ecosystem services to differing extents. Overall, however, our findings seem to contradict the general assumption that soils in riparian area are different from neighbouring (non-riparian) areas and that they possess extra functionality in terms of ecosystem service provision. Watercourse shading was highly habitat specific and was maximal in forests (ca. 52% shade cover) in comparison to the other habitat types (7-17%). Our data suggest that the functioning of riparian areas in less intensive agricultural areas, such as those studied here, may be broadly predicted from the surrounding land use, however, further research is required to critically test this across a wider range of ecosystems. PMID- 29272850 TI - Skin autofluorescence reflects individual seasonal UV exposure, skin photodamage and skin cancer development in organ transplant recipients. AB - IMPORTANCE: Ultraviolet radiation (UVR)-induced skin cancers varies among organ transplant recipients (OTRs). To improve individual risk assessment of skin cancer, objectively quantified skin photodamage is needed. OBJECTIVES: We measured personal UVR-exposure dose in OTRs and assessed the relation between individual UVR exposure, skin cancer and objectively measured photodamage in terms of skin autofluorescence, pigmentation, and black light-evaluated solar lentigines. MATERIALS AND METHODS: Danish OTRs with (n=15) and without a history of skin cancer (n=15) kept sun diaries from May to September and wore personal dosimeters recording time-stamped UVR doses in standard erythema doses (SED). Photodamage was quantified as skin autofluorescence with excitation at 370nm (F370) and 430nm (F430), skin pigmentation (pigment protection factor, PPF), and black light-evaluated solar lentigines. RESULTS: OTRs with skin cancer received a higher UVR dose than OTRs without skin cancer (median 116 SED vs. 67 SED, p=0.07) and UVR exposure doses were correlated with increased PPF (p=0.052) and F370 on the shoulder (F370shoulder) (p=0.04). We found that skin cancer was associated with F370shoulder (OR 10.53, CI 3.3-31,938; p=0.018) and time since transplantation (OR 1.34, CI 0.95-1.91, p=0.097). A cut-off at 7.2 arbitrary units, 89% of OTRs with skin cancer had F370shoulder values above 7.2 arbitrary units and F370shoulder was additionally related to patient age (p=0.09) and black light-evaluated solar lentigines (p=0.04). CONCLUSION: F370 autofluorescence indicates objectively measured photodamage and may be used for individual risk assessment of skin cancer development in OTRs. PMID- 29272851 TI - Biogenic synthesis, optical, catalytic, and in vitro antimicrobial potential of Ag-nanoparticles prepared using Palm date fruit extract. AB - Silver nanoparticles (AgNPs) have been synthesized via green route using an aqueous extract of Palm date fruit pericarp extract. The appearance of the yellow color and the surface resonance plasmon (SRP) band at around 400-450nm in UV Visible spectroscopy initially reveals the formation of AgNPs. The particle size, crystalline nature, and size distribution was confirmed by scanning electron microscopy (SEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED) ring patterns, energy dispersive X-ray spectroscopy (EDX), dynamic light scattering (DLS) techniques. The particles size ranged ca. 3nm to 30nm and are spherical in shape. The microbial activity of biogenic AgNPs was tested on clinical multiple drug resistance Staphylococcus aureus, Escherichia coli and Candida albicans reference strain. Zones of inhibition growth increases with [AgNPs]. The results suggest that the particle tested in this study certainly mediate the inhibition of bacterial and fungus growth. To overcome the serious problems related to environment like discharge of hazardous chemicals to water bodies, AgNPs have been found to be very important in the catalytic degradation of 4-nitrophenol. The rate of degradation strongly depends on the sun light exposure. Based on the chemical and kinetic studies, an attempt has been made to elucidate the mechanism of AgNPs formation. PMID- 29272852 TI - "Now drugs in Libya are much cheaper than food": A qualitative study on substance use among young Libyans in post-revolution Tripoli, Libya. AB - BACKGROUND: Libya is facing a rapidly growing epidemic of illicit drug use and HIV. This situation is fueled by a complex array of factors, mainly the consequences of the political and military turmoil of the Arab Spring. Although it is extensively documented in other settings that young people are one of the most vulnerable groups to both HIV and illicit drug use, no study has explored this issue among young people in Libya. The current study addresses this research gap. METHODS: This study is a qualitative study using in-depth interviews guided by a semi-structured questionnaire. We used a maximum variation, purposive sampling strategy to recruit male and female participants, aged 14-18 years, from schools, prisons, and community-based informal re-education and rehabilitation centers in Tripoli, Libya. RESULTS: In total, 31 participants were recruited: 6 females and 25 males. Sixteen participants were prisoners and residents of community-based informal re-education and rehabilitation centers, and 15 were recruited in schools. Risk factors for drug use included peer influence, the increased availability and affordability of drugs, disruption of social life and healthy recreational activities, and the distress and casualties of the war. Protective factors were religious beliefs and practices, good parent-child connectedness, and high self-esteem and future aspiration. Risk factors for HIV were insufficient knowledge related to HIV transmission and unsafe injection practices, such as sharing needles and syringes. CONCLUSION: We found individual, interpersonal, family, and structural-level factors that interplayed to shape the vulnerability of young people to drug use and HIV infection in Tripoli, Libya. Structural factors, including the increased availability and affordability of drugs, provided the frame within which other factors, such as peer influence, insufficient knowledge of substance use, and HIV, operated to increase the vulnerability of young people to drugs and HIV, while religious beliefs and parent-child connectedness acted as protective factors. Multisectoral efforts and studies to quantitatively evaluate the magnitude and distribution of these problems are urgently needed. PMID- 29272853 TI - Patients with newly diagnosed cervical cancer should be screened for anal human papilloma virus and anal dysplasia: Results of a pilot study using a STELLA computer simulation and economic model. AB - BACKGROUND: Women with cervical cancer often have anal human papillomavirus (HPV) infection and anal dysplasia. However, effectiveness of anal HPV screening is unknown. METHODS: A dynamic model was constructed using STELLA. Populations are represented as "stocks" that change according to model rates. Initial anal cytology in new cervical cancer patients, dysplasia progression and regression, cost of treating high-grade squamous intraepithelial lesions (HSIL), and lifetime costs for anal cancer care were extrapolated from the literature. Local costs of anal HPV testing and cytology were obtained. Outcomes included anal cancer rates, anal cancer deaths, screening costs and cancer care. RESULTS: Benefits in the screened group included reduction in anal cancers after three years and anal cancer deaths after four years. After 10 years, predicted costs per anal cancer prevented and anal cancer deaths were $168,796 and $210,057 and were $98,631 and $210,057 at 20 years. Predicted costs per quality of life year saved at 10 and 20 years were $9785 and $1687. Sensitivity analysis demonstrated cost-effectiveness of screening for a variety of cure rates HSIL with electrocautery. CONCLUSION: Screening for anal HPV and treatment of anal HSIL in patients with cervical cancer is cost-effective, prevents anal cancer and reduces anal cancer deaths. PMID- 29272854 TI - Oxalate induces mitochondrial dysfunction and disrupts redox homeostasis in a human monocyte derived cell line. AB - Monocytes/macrophages are thought to be recruited to the renal interstitium during calcium oxalate (CaOx) kidney stone disease for crystal clearance. Mitochondria play an important role in monocyte function during the immune response. We recently determined that monocytes in patients with CaOx kidney stones have decreased mitochondrial function compared to healthy subjects. The objective of this study was to determine whether oxalate, a major constituent found in CaOx kidney stones, alters cell viability, mitochondrial function, and redox homeostasis in THP-1 cells, a human derived monocyte cell line. THP-1 cells were treated with varying concentrations of CaOx crystals (insoluble form) or sodium oxalate (NaOx; soluble form) for 24h. In addition, the effect of calcium phosphate (CaP) and cystine crystals was tested. CaOx crystals decreased cell viability and induced mitochondrial dysfunction and redox imbalance in THP-1 cells compared to control cells. However, NaOx only caused mitochondrial damage and redox imbalance in THP-1 cells. In contrast, both CaP and cystine crystals did not affect THP-1 cells. Separate experiments showed that elevated oxalate also induced mitochondrial dysfunction in primary monocytes from healthy subjects. These findings suggest that oxalate may play an important role in monocyte mitochondrial dysfunction in CaOx kidney stone disease. PMID- 29272855 TI - A multi-country analysis on potential adaptive mechanisms to cold and heat in a changing climate. AB - BACKGROUND: Temporal variation of temperature-health associations depends on the combination of two pathways: pure adaptation to increasingly warmer temperatures due to climate change, and other attenuation mechanisms due to non-climate factors such as infrastructural changes and improved health care. Disentangling these pathways is critical for assessing climate change impacts and for planning public health and climate policies. We present evidence on this topic by assessing temporal trends in cold- and heat-attributable mortality risks in a multi-country investigation. METHODS: Trends in country-specific attributable mortality fractions (AFs) for cold and heat (defined as below/above minimum mortality temperature, respectively) in 305 locations within 10 countries (1985 2012) were estimated using a two-stage time-series design with time-varying distributed lag non-linear models. To separate the contribution of pure adaptation to increasing temperatures and active changes in susceptibility (non climate driven mechanisms) to heat and cold, we compared observed yearly-AFs with those predicted in two counterfactual scenarios: trends driven by either (1) changes in exposure-response function (assuming a constant temperature distribution), (2) or changes in temperature distribution (assuming constant exposure-response relationships). This comparison provides insights about the potential mechanisms and pace of adaptation in each population. RESULTS: Heat related AFs decreased in all countries (ranging from 0.45-1.66% to 0.15-0.93%, in the first and last 5-year periods, respectively) except in Australia, Ireland and UK. Different patterns were found for cold (where AFs ranged from 5.57-15.43% to 2.16-8.91%), showing either decreasing (Brazil, Japan, Spain, Australia and Ireland), increasing (USA), or stable trends (Canada, South Korea and UK). Heat AF trends were mostly driven by changes in exposure-response associations due to modified susceptibility to temperature, whereas no clear patterns were observed for cold. CONCLUSIONS: Our findings suggest a decrease in heat-mortality impacts over the past decades, well beyond those expected from a pure adaptation to changes in temperature due to the observed warming. This indicates that there is scope for the development of public health strategies to mitigate heat-related climate change impacts. In contrast, no clear conclusions were found for cold. Further investigations should focus on identification of factors defining these changes in susceptibility. PMID- 29272856 TI - Reproducible and efficient generation of functionally active neurons from human hiPSCs for preclinical disease modeling. AB - The use of human induced pluripotent stem cell (hiPSC)-derived neuronal cultures to study the mechanisms of neurological disorders is often limited by low efficiency and high variability in differentiation of functional neurons. Here we compare the functional properties of neurons in cultures prepared with two hiPSC differentiation protocols, both plated on astroglial feeder layers. Using a protocol with an expandable intermediate stage, only a small percentage of cells with neuronal morphology were excitable by 21-23days in culture. In contrast, a direct differentiation strategy of the same hiPSC line produced cultures in which the majority of neurons fired action potentials as early as 4-5days. By 35-38days over 80% of the neurons fired repetitively and many fired spontaneously. Spontaneous post-synaptic currents were observed in ~40% of the neurons at 4 5days and in ~80% by 21-23days. The majority (75%) received both glutamatergic and GABAergic spontaneous postsynaptic currents. The rate and degree of maturation of excitability and synaptic activity was similar between multiple independent platings from a single hiPSC line, and between two different control hiPSC lines. Cultures of rapidly functional neurons will facilitate identification of cellular mechanisms underlying genetically defined neurological disorders and development of novel therapeutics. PMID- 29272857 TI - Fosl1 overexpression directly activates trophoblast-specific gene expression programs in embryonic stem cells. AB - During early development in placental mammals, proper trophoblast lineage development is essential for implantation and placentation. Defects in this lineage can cause early pregnancy failures and other pregnancy disorders. However, transcription factors controlling trophoblast development remain poorly understood. Here, we utilize Fosl1, previously implicated in trophoblast giant cell development as a member of the AP-1 complex, to trans-differentiate embryonic stem (ES) cells to trophoblast lineage-like cells. We first show that the ectopic expression of Fosl1 is sufficient to induce trophoblast-specific gene expression programs in ES cells. Surprisingly, we find that this transcriptional reprogramming occurs independently of changes in levels of ES cell core factors during the cell fate change. This suggests that Fosl1 acts in a novel way to orchestrate the ES to trophoblast cell fate conversion compared to previously known reprogramming factors. Mapping of Fosl1 targets reveals that Fosl1 directly activates TE lineage-specific genes as a pioneer factor. Our work suggests Fosl1 may be used to reprogram ES cells into differentiated cell types in trophoblast lineage, which not only enhances our knowledge of global trophoblast gene regulation but also may provide a future therapeutic tool for generating induced trophoblast cells from patient-derived pluripotent stem cells. PMID- 29272858 TI - National Study of Excellence and Innovation in Physical Therapist Education: Part 2-A Call to Reform. PMID- 29272859 TI - Moving From Volume-based to Value-based Rehabilitation Care. PMID- 29272883 TI - INFLUENCE OF RADON PROGENY ON DOSE RATE MEASUREMENTS STUDIED AT PTB'S RADON REFERENCE CHAMBER. AB - The responses of electronic dose rate meters were investigated in a large volume radon chamber at PTB in a wide range of radon activity concentrations. The measurements were conducted under controlled laboratory conditions and measured dose rate data are compared with Monte-Carlo simulations. Consequences concerning environmental monitoring are described. A further result is that the direct measurement of the dose rates produced by radon progeny in air is hardly possible in radon atmospheres with high activity concentrations, because the major contribution of measured dose rates is produced by radon progeny on the housing of the dose rate instruments. The latter effect largely depends on the ability of surfaces to absorb radon progeny. The Monte-Carlo simulations revealed quantitative results on the height of the single contributions to the total dose rate measured in the radon chamber. When environmental dose rate measurements are performed, the plate-out on detectors can be neglected. PMID- 29272884 TI - DOSE EVALUATION FOR DIGITAL X-RAY IMAGING OF PREMATURE NEONATES. AB - X-ray radiography is a commonly used diagnostic method for premature neonates. However, because of higher radiosensitivity and young age, premature neonates are more sensitive to the detrimental effects of ionising radiation. Therefore, it is important to monitor and optimise radiation doses at the neonatal intensive care unit (NICU). The number of x-ray examinations, dose-area product (DAP) and effective doses are evaluated for three Dutch NICUs using digital flat panel detectors. Thorax, thorax-abdomen and abdomen protocols are included in this study. Median number of examinations is equal to 1 for all three hospitals. Median DAP ranges between 0.05 and 1.02 MUGy m2 for different examination types and different weight categories. These examinations result in mean effective doses between 4 +/- 4 and 30 +/- 10 MUSv per examination. Substantial differences in protocols and doses can be observed between hospitals. This emphasises the need for up-to-date reference levels formulated specifically for premature neonates. PMID- 29272885 TI - COMPARING TWO MEASUREMENTS OF THE SAME COSMIC-RAY NEUTRON SPECTRUM USING STANDARD BONNER SPHERES AND HIGH-SENSITIVITY BONNER CYLINDERS. AB - Ground-level cosmic-ray neutron spectra in Taiwan were measured using two neutron spectrometers, standard Bonner spheres and homemade high-sensitivity Bonner cylinders. The Bonner sphere system consisted of 12 polyethylene spheres of various diameters and four extended-range spheres that contained embedded metal shells. A set of 16 similarly designed Bonner cylinders was assembled based on a large cylindrical 3He proportional counter, showing an efficiency ~18 times higher than that of the central probe of the Bonner spheres. However, these Bonner cylinders were not fully symmetrical and exhibited angular dependence in their responses to incoming neutrons. Focusing on the low-intensity neutron background, this study presents a systematic comparison between Bonner spheres and cylinders in terms of their response characteristics, counting statistics, and unfolded neutron spectra. The comparison indicated that the neutron probe of the Bonner spheres had a small but non-negligible counting noise that required subtraction from the recorded data. According to the response functions calculated for isotropic neutron incidence, the neutron spectrum determined using the high-sensitivity Bonner cylinders agreed well with that measured using the Bonner spheres. The annual effective doses from cosmic-ray neutrons at the location were determined to be 30.5 and 30.8 MUSv by using the Bonner sphere and cylinder spectrometers, respectively, which corresponded to respective total neutron fluxes of 5.39 * 10-3 and 5.43 * 10-3 cm-2s-1. PMID- 29272886 TI - Algorithm to Manage Inconclusive RBC Antibodies by Reflex Manual Testing. AB - Objectives: Inconclusive RBC antibody identification (ABID) may delay RBC crossmatch. An increased number of inconclusive ABID was observed, and an algorithm was developed to improve ABID efficiency. Methods: RBC antibody screen (AS) and ABID were initially performed using solid-phase RBC adherence assay (SPRCA) and manual tube method. A retrospective analysis of AS and ABID results was performed pre- and postalgorithm implementation. Results: The number of inconclusive ABID results decreased from 26 to six per month pre- and postimplementation, respectively. SPRCA became the primary AS method, and manual tube became the gold standard for ABID. SPRCA was used for ABID upon reference specialist secondary review and allowed identification of 30 specific RBC antibodies, for which no patients developed signs or symptoms of a hemolytic transfusion reaction. Conclusions: RBC reference workflow using SPRCA and manual tube methods for AS and ABID decreases "inconclusive" ABID without adverse events. PMID- 29272887 TI - The 11q-Gain/Loss Aberration Occurs Recurrently in MYC-Negative Burkitt-like Lymphoma With 11q Aberration, as Well as MYC-Positive Burkitt Lymphoma and MYC Positive High-Grade B-Cell Lymphoma, NOS. AB - Objectives: The latest revision of lymphoma's World Health Organization classification describes the new provisional entity "Burkitt-like lymphoma with 11q aberration" (BLL, 11q) as lacking MYC rearrangement, but harboring the specific11q-gain/loss aberration. We report genetic characteristics of 11 lymphoma cases with this aberration. Methods: Classical cytogenetics, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism/array comparative genomic hybridization. Results: The 11q aberrations were described as duplication, inversion, and deletion. Array comparative genomic hybridization showed two types of duplication: bigger than 50 megabase pairs (Mbp) and smaller than 20 Mbp, which were associated with bulky tumor larger than 20 cm and amplification of the 11q23.3 region, including KMT2A. Six cases revealed a normal FISH status of MYC and were diagnosed as BLL,11q. Five cases showed MYC rearrangement and were diagnosed as Burkitt lymphoma (BL) or high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Conclusions: The 11q-gain/loss is not specific for BLL, 11q, but occurs recurrently in MYC positive BL and MYC-positive HGBL. PMID- 29272888 TI - Overexpression of SOX11 and TFE3 in Solid-Pseudopapillary Neoplasms of the Pancreas. AB - Objectives: To characterize the expression of SOX11 and TFE3 proteins in solid pseudopapillary neoplasms (SPNs) and their histologic mimickers. Methods: Immunohistochemistry for SOX11, TFE3, and beta-catenin was performed on 31 cases of surgically resected SPNs. Neuroendocrine tumors, acinar cell carcinomas, and pancreatoblastomas served as controls. Results: Nuclear immunoreactivity for SOX11 was detected in all SPNs and five of 31 control tumors. Nuclear immunoreactivity for TFE3 was detected in 30 SPNs and three control tumors. Nuclear immunoreactivity for beta-catenin was detected in all SPNs and four control tumors. The combination of three markers as immunohistochemical panels resulted in optimal sensitivity and specificity. Conclusions: Both SOX11 and TFE3 were overexpressed in SPNs and may be involved in the pathogenesis. Clinically, SOX11 and TFE3 can be potentially used as diagnostic markers in distinguishing indeterminate SPNs from their histologic mimickers. PMID- 29272890 TI - Through the patient's eyes: 25 years of quality and safety research and the challenges ahead. PMID- 29272889 TI - Assessment of the Measurement Error in Cyclosporine Levels Drawn Between Peripheral and Central Sources. AB - Objectives: Cyclosporine is often monitored by drug levels drawn through central venous catheters (CVCs), which may be falsely elevated due to reversible drug adsorption onto the catheter. Therefore, we assessed the correlation between cyclosporine levels drawn peripherally and through CVCs. Methods: Bone marrow transplantation patients had a weekly collection of both peripheral and CVC draws from dual-lumen catheters simultaneously to assess cyclosporine levels after research ethics approval. Our primary outcome was the proportion of paired samples that were incongruent-defined as the mean of the CVC level being greater than 2 standard deviations from the peripheral level mean. Results: After approaching 27 eligible patients, 20 patients (77.8%) provided samples. Of 53 paired samples, seven were incongruent (13.2%). Peripheral and CVC levels correlated (r = 0.91) and agreed well. Conclusion: Despite potential for preanalytical error due to adsorption, cyclosporine infusion and monitoring via CVCs produce results similar to monitoring via peripheral blood draws. PMID- 29272891 TI - HCC Risk Scores: Useful or Not? AB - The advent and efficacy of surveillance for hepatocellular carcinoma (HCC) has necessitated the refinement of assessing who is at risk for this cancer. Initially, risk was assessed for all individuals with hepatitis B and all those with cirrhosis. However, the majority of these individuals do not develop HCC so that providing surveillance for all is a waste of resources. There are now many different scores that have been developed that allow better identification of who is at risk and who is not. Specific models have been developed for hepatitis B before and on treatment, for hepatitis C before and after treatment, and for cirrhosis in general. There are also models for assessing risk in the general population. Some models can only be applied to patients coming from the population in which the score was developed (e.g., hepatitis B). Others are more generalizable. Many lack external validation. With some exceptions, the models do not attempt to assess the score at which surveillance should start. Overall, the models provide some useful guidance as to who does not need to undergo surveillance, but the long-term performance and how changes in risk score correlate with changes in HCC risk has not been completely assessed. PMID- 29272892 TI - Overdiagnosis: An Understudied Issue in Hepatocellular Carcinoma Surveillance. AB - Overdiagnosis, the detection of clinically insignificant disease that would not otherwise impact the patient's lifespan, is a phenomenon that has been described in several solid tumors, such as prostate, breast, thyroid, and lung cancers. Population-based efforts to reduce hepatocellular carcinoma (HCC) mortality in cirrhosis patients by screening and early detection may result in the overdiagnosis of HCC. One of the harms of overdiagnosis is subsequent overtreatment, which can result in increased costs, as well as physical side effects, psychological harms, and poorer quality of life. In this review, the authors explore the potential for overdiagnosis in HCC. PMID- 29272893 TI - Timing, Management, and Outcomes of Liver Transplantation in Primary Sclerosing Cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease that often progresses to secondary biliary cirrhosis and end-stage liver disease. Short of liver transplantation (LT), there is no effective treatment for PSC. PSC accounts for approximately 5% of total adult LTs in the US and is currently the fifth most common indication for LT. Patient and graft survival for PSC is among the highest for all indications for LT. The main factors that impact outcomes after LT for PSC include biliary strictures, rejection, and recurrence of PSC. Recurrent PSC (rPSC) develops in 20% of LT recipients within 5 years of LT and is associated with negative patient and graft survival. LT is a viable option for recipients who develop rPSC and progress to graft failure. PMID- 29272894 TI - The Microbiome in Primary Sclerosing Cholangitis: Current Evidence and Potential Concepts. AB - The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease has inspired hypothetical models in which gut bacteria or bacterial products are key players in PSC pathogenesis. Several studies using high-throughput sequencing technology to characterize the gut microbiota in PSC have been published over the past years. They all report reduced diversity and significant shifts in the overall composition of the gut microbiota. However, it remains unclear as to whether the observed changes are primary or secondary to PSC development and further studies are needed to assess the biological implications of the findings. In the present article, we review the published data in perspective of similar studies in other diseases. We discuss aspects of methodology and study design that are relevant to interpretation of the data. Furthermore, we propose that interpretation and further assessments of findings are structured into conceptual compartments, and elaborate three such possible concepts relating to immune function (the "immunobiome"), host metabolism (the "endobiome"), and dietary and xenobiotic factors (the "xenobiome") in PSC. PMID- 29272895 TI - Clinical Trial Design for Alcoholic Hepatitis. AB - Alcoholic hepatitis (AH) is an acute and clinically distinct manifestation of alcoholic liver disease. While severe AH causes 30% or higher mortality in 3 months, treatment options are limited and ineffective. Recent advances on the understanding of the pathomechanisms of AH have identified numerous potential targets for new therapeutic interventions. Many of those targets are currently under preclinical testing and/or in human clinical trials for nonalcoholic steatohepatitis. Thus, the field of AH should be ready to launch new efforts and targeted clinical trials for this underserved patient population. There are remaining challenges in designing clinical trials in AH that include definition of the severity of disease, common data elements in clinical trial design, and selection of clinically meaningful endpoints. Future efforts and consensus meetings between regulatory agencies, academic and clinical experts, and industry will be instrumental to advance this emerging and greatly needed field of clinical investigations. PMID- 29272896 TI - Salvage Therapies for Autoimmune Hepatitis: A Critical Review. AB - Several salvage therapies have been identified for autoimmune hepatitis refractory or recalcitrant to conventional therapy; however, the optimal salvage strategy remains unclear. High-dose prednisolone is currently recommended as the front-line salvage therapy, with alternative immunosuppressive therapies reserved for continuing treatment failure. Of the second-line therapies, the calcineurin inhibitors, cyclosporine and tacrolimus, and mycophenolate mofetil are preferred and have the most accrued clinical data. However, none of these have undergone rigorous clinical evaluation via randomized clinical trials. Tacrolimus is generally preferred over cyclosporine because of its higher potency and increased utility in organ transplantation. Mycophenolate is particularly useful for azathioprine intolerance but also for nonresponse to standard treatment. Subjects with progressive liver failure should undergo liver transplantation evaluation. The appropriate timing, dosing, and monitoring of salvage therapies require determination. Several promising immunosuppressive therapies have been developed for autoimmune diseases including molecular agents that may enhance regulatory T cell activity and function. PMID- 29272897 TI - Multifunctional YY1 in Liver Diseases. AB - The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression, depending on the cellular context. While YY1 is ubiquitously expressed and highly conserved between species, its role varies among the diverse cell types and includes proliferation, differentiation, and apoptosis. Upregulated YY1 expression is found in pathogenic conditions, such as human hepatocellular carcinoma and hepatitis B virus infection, and its roles in the molecular pathogenic mechanisms in liver (i.e., fibrosis, carcinogenesis, viral-induced injury) are currently being elucidated. The most recent studies have revealed that YY1 is deeply involved in such dysregulated cellular metabolisms as glycometabolism, lipid metabolism, and bile acid metabolism, which are all involved in various diseases. In this review, we will summarize the current knowledge on YY1 in liver diseases, providing a focused discussion on the characterized and probable underlying mechanisms, as well as a reasoned evaluation of the potential for YY1-mediated pathology as drug targets in liver disease therapies. PMID- 29272899 TI - Systematic Review and Meta-Analysis: Prevalence of Small Intestinal Bacterial Overgrowth in Chronic Liver Disease. AB - The authors conducted a meta-analysis of the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with chronic liver disease (CLD) and controls. Using the search terms "small intestinal bacterial overgrowth (SIBO)" and "chronic liver disease (CLD)" or "cirrhosis," 19 case-control studies were identified. Utilizing breath tests, the prevalence of SIBO in CLD was 35.80% (95% CI, 32.60-39.10) compared with 8.0% (95% CI, 5.70-11.00) in controls. Using culture techniques, the prevalence was 68.31% (95% CI, 59.62-76.00) in CLD patients as compared with 7.94% (95% CI, 3.44-12.73) in controls. No difference between cirrhotic and noncirrhotic patients was found. SIBO is significantly more frequent in CLD patients as compared with controls. The association of SIBO and CLD was not confined to patients with advanced CLD, suggesting that SIBO is not a consequence of advanced liver disease but may play a role in the progression of CLD. PMID- 29272900 TI - The Effectiveness of Hands-on Health Informatics Skills Exercises in the Multidisciplinary Smart Home Healthcare and Health Informatics Training Laboratories. AB - OBJECTIVE: This article aimed to evaluate the effectiveness of newly established innovative smart home healthcare and health informatics laboratories, and a novel laboratory course that focuses on experiential health informatics training, and determine students' self-confidence to operate wireless home health monitoring devices before and after the hands-on laboratory course. MATERIALS AND METHODS: Two web-based pretraining and posttraining questionnaires were sent to 64 students who received hands-on training with wireless remote patient monitoring devices in smart home healthcare and health informatics laboratories. RESULTS: All 64 students completed the pretraining survey (100% response rate), and 49 students completed the posttraining survey (76% response rate). The quantitative data analysis showed that 95% of students had an interest in taking more hands-on laboratory courses. Sixty-seven percent of students had no prior experience with medical image, physiological data acquisition, storage, and transmission protocols. After the hands-on training session, 75.51% of students expressed improved confidence about training patients to measure blood pressure monitor using wireless devices. Ninety percent of students preferred to use a similar experiential approach in their future learning experience. Additionally, the qualitative data analysis demonstrated that students were expecting to have more courses with hands-on exercises and integration of technology-enabled delivery and patient monitoring concepts into the curriculum. CONCLUSION: This study demonstrated that the multidisciplinary smart home healthcare and health informatics training laboratories and the hands-on exercises improved students' technology adoption rates and their self-confidence in using wireless patient monitoring devices. PMID- 29272901 TI - A Multisite Survey Study of EMR Review Habits, Information Needs, and Display Preferences among Medical ICU Clinicians Evaluating New Patients. AB - OBJECTIVE: The electronic chart review habits of intensive care unit (ICU) clinicians admitting new patients are largely unknown but necessary to inform the design of existing and future critical care information systems. METHODS: We conducted a survey study to assess the electronic chart review practices, information needs, workflow, and data display preferences among medical ICU clinicians admitting new patients. We surveyed rotating residents, critical care fellows, advanced practice providers, and attending physicians at three Mayo Clinic sites (Minnesota, Florida, and Arizona) via email with a single follow-up reminder message. RESULTS: Of 234 clinicians invited, 156 completed the full survey (67% response rate). Ninety-two percent of medical ICU clinicians performed electronic chart review for the majority of new patients. Clinicians estimated spending a median (interquartile range (IQR)) of 15 (10-20) minutes for a typical case, and 25 (15-40) minutes for complex cases, with no difference across training levels. Chart review spans 3 or more years for two-thirds of clinicians, with the most relevant categories being imaging, laboratory studies, diagnostic studies, microbiology reports, and clinical notes, although most time is spent reviewing notes. Most clinicians (77%) worry about overlooking important information due to the volume of data (74%) and inadequate display/organization (63%). Potential solutions are chronologic ordering of disparate data types, color coding, and explicit data filtering techniques. The ability to dynamically customize information display for different users and varying clinical scenarios is paramount. CONCLUSION: Electronic chart review of historical data is an important, prevalent, and potentially time-consuming activity among medical ICU clinicians who would benefit from improved information display systems. PMID- 29272902 TI - [Assess Capabilities Among Chronically Mentally Ill People: First Test Results on a Draft German Version of the OxCAP-MH as Part of the BAESCAP Study]. PMID- 29272898 TI - Liver Sinusoidal Endothelial Cell: An Update. AB - This update focuses on two main topics. First, recent developments in our understanding of liver sinusoidal endothelial cell (LSEC) function will be reviewed, specifically elimination of blood-borne waste, immunological function of LSECs, interaction of LSECs with liver metastases, LSECs and liver regeneration, and LSECs and hepatic fibrosis. Second, given the current emphasis on rigor and transparency in biomedical research, the update discusses the need for standardization of methods to demonstrate identity and purity of isolated LSECs, pitfalls in methods that might lead to a selection bias in the types of LSECs isolated, and questions about long-term culture of LSECs. Various surface markers used for immunomagnetic selection are reviewed. PMID- 29272903 TI - Clinical outcomes of endoscopic submucosal dissection for superficial esophageal neoplasms extending to the cervical esophagus. AB - BACKGROUND: The feasibility and safety of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms extending to the cervical esophagus currently remain unknown because of the limited number of cases. We aimed to clarify the clinical outcomes of these cases. METHODS: This was a case series study conducted at a single institution that enrolled 26 consecutive patients with superficial esophageal neoplasms extending to the cervical esophagus who underwent ESD between July 2003 and December 2015. RESULTS: En bloc and complete resection rates were both 100 % and no major intraprocedural complications occurred. Thirteen patients were treated with prophylactic steroid therapy. The incidence of postoperative stricture in patients with a circumferential mucosal defect of more than three-quarters was 72.7 %. Four patients required entire circumferential resection, with perforation occurring after endoscopic balloon dilation (EBD) in two and EBD being required for more than 1 year in the other two. CONCLUSIONS: ESD including the cervical esophagus is technically feasible. Circumferential resection may cause refractory postoperative stricture or post EBD perforation, so needs to be avoided where possible. PMID- 29272904 TI - Early removal of biflanged metal stents in the management of pancreatic walled off necrosis: a prospective study. AB - BACKGROUND AND STUDY AIMS: Dedicated stents placed under endoscopic ultrasound (EUS) guidance have shown promise for the management of pancreatic walled-off necrosis (WON). A long duration of stent placement may increase the risk of adverse events. We prospectively evaluated the effects of (i) early removal of biflanged metal stents (BFMSs) and (ii) additional stenting of the pancreatic duct with plastic stents in patients with ductal leaks, on the risk of WON recurrence. PATIENTS AND METHODS: Symptomatic patients with pancreatic WON underwent EUS-guided BFMS placement, followed by necrosectomy, when required, from Day 3. A 5 Fr plastic stent was placed in patients with ductal leak. BFMS was removed when the WON cavity had collapsed completely. Patients were followed up at 3-month intervals. RESULTS: BFMS placement was successful in all 88 patients. A total of 64 patients (72.7 %) underwent necrosectomy (median 3 sessions). All BFMSs were removed at a median of 3.5 weeks (range 3 - 17 weeks). Ductal disconnection and leak occurred in 53/87 (60.9 %) and 61/87 (70.1 %) patients, respectively. A 5 Fr stent was placed in 56/61 patients (91.8 %) with ductal leak. Overall, 22 patients (25.0 %) had adverse events (17 mild, 1 moderate, 3 severe, 1 fatal). Recurrence was noted in 8/88 (9.1 %) at a median follow-up of 22 months. The recurrence rate was higher in patients with ductal disconnection than in those without (13.2 % vs. 2.9 %; P = 0.08), and was similar in patients with vs. without pancreatic duct stenting (7.1 % vs. 12.9 %; P = 0.44). Seven recurrences (87.5 %) partially regressed on follow-up and did not require therapy; in one case, drainage with a plastic stent was performed. CONCLUSIONS: Short-term BFMS placement is an effective therapy for pancreatic WON. The majority of recurrences developed in patients with ductal disconnection and did not require therapy. Additional pancreatic duct stents probably do not influence the recurrence rate. PMID- 29272905 TI - Artificial intelligence may help in predicting the need for additional surgery after endoscopic resection of T1 colorectal cancer. AB - BACKGROUND AND STUDY AIMS: Decisions concerning additional surgery after endoscopic resection of T1 colorectal cancer (CRC) are difficult because preoperative prediction of lymph node metastasis (LNM) is problematic. We investigated whether artificial intelligence can predict LNM presence, thus minimizing the need for additional surgery. PATIENTS AND METHODS: Data on 690 consecutive patients with T1 CRCs that were surgically resected in 2001 - 2016 were retrospectively analyzed. We divided patients into two groups according to date: data from 590 patients were used for machine learning for the artificial intelligence model, and the remaining 100 patients were included for model validation. The artificial intelligence model analyzed 45 clinicopathological factors and then predicted positivity or negativity for LNM. Operative specimens were used as the gold standard for the presence of LNM. The artificial intelligence model was validated by calculating the sensitivity, specificity, and accuracy for predicting LNM, and comparing these data with those of the American, European, and Japanese guidelines. RESULTS: Sensitivity was 100 % (95 % confidence interval [CI] 72 % to 100 %) in all models. Specificity of the artificial intelligence model and the American, European, and Japanese guidelines was 66 % (95 %CI 56 % to 76 %), 44 % (95 %CI 34 % to 55 %), 0 % (95 %CI 0 % to 3 %), and 0 % (95 %CI 0 % to 3 %), respectively; and accuracy was 69 % (95 %CI 59 % to 78 %), 49 % (95 %CI 39 % to 59 %), 9 % (95 %CI 4 % to 16 %), and 9 % (95 %CI 4 % - 16 %), respectively. The rates of unnecessary additional surgery attributable to misdiagnosing LNM-negative patients as having LNM were: 77 % (95 %CI 62 % to 89 %) for the artificial intelligence model, and 85 % (95 %CI 73 % to 93 %; P < 0.001), 91 % (95 %CI 84 % to 96 %; P < 0.001), and 91 % (95 %CI 84 % to 96 %; P < 0.001) for the American, European, and Japanese guidelines, respectively. CONCLUSIONS: Compared with current guidelines, artificial intelligence significantly reduced unnecessary additional surgery after endoscopic resection of T1 CRC without missing LNM positivity. PMID- 29272906 TI - Stylet slow-pull versus standard suction for endoscopic ultrasound-guided fine needle aspiration of solid pancreatic lesions: a multicenter randomized trial. AB - BACKGROUND AND STUDY AIM: Standard endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) procedures involve use of no-suction or suction aspiration techniques. A new aspiration method, the stylet slow-pull technique, involves slow withdrawal of the needle stylet to create minimum negative pressure. The aim of this study was to compare the sensitivity of EUS-FNA using stylet slow-pull or suction techniques for malignant solid pancreatic lesions using a standard 22 gauge needle. PATIENTS AND METHODS: Consecutive patients presenting for EUS-FNA of pancreatic mass lesions were randomized to the stylet slow-pull or suction techniques using a 22-gauge needle. Both techniques were standardized for each pass until an adequate specimen was obtained, as determined by rapid on-site cytology examination. Patients were crossed over to the alternative technique after four nondiagnostic passes. RESULTS: Of 147 patients screened, 121 (mean age 64 +/- 13.8 years) met inclusion criteria and were randomized to the stylet slow-pull technique (n = 61) or the suction technique (n = 60). Technical success rates were 96.7 % and 98.3 % in the slow-pull and suction groups, respectively (P > 0.99). The sensitivity for malignancy of EUS-FNA was 82 % in the slow-pull group and 69 % in the suction group (P = 0.10). The first-pass diagnostic rate (42.6 % vs. 38.3 %; P = 0.71), acquisition of core tissue (60.6 % vs. 46.7 %; P = 0.14), and the median (range) number of passes to diagnosis (2 1 2 3 vs. 1 1 2; P = 0.71) were similar in the slow-pull and suction groups, respectively. CONCLUSIONS: The stylet slow-pull and suction techniques both offered high and comparable diagnostic sensitivity with a mean of 2 passes required for diagnosis of solid pancreatic lesions. The endosonographer may choose either technique during FNA. PMID- 29272907 TI - Management decision based on lymphovascular involvement leads to favorable outcomes after endoscopic treatment of esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) invading the muscularis mucosae (MM) and submucosa up to 200 um (SM1) has a risk of metastasis. The aims of this study were to investigate the long-term outcome of endoscopic submucosal dissection (ESD) for MM/SM1 ESCC and to assess the management after ESD in our hospital. METHODS: This was a retrospective cohort study conducted at a single institution. Patients with MM or SM1 ESCC who were treated with ESD were included. Additional prophylactic therapy was added if lymphovascular involvement (LVI) was noted in the ESD specimens. RESULTS: A total of 102 patients were analyzed. The median length of follow-up was 71.5 months (range 9 - 144 months) and the median number of CTs was 6 (range 0 - 24). LVI was found in 21 patients (20.6 %), and 12 patients underwent additional prophylactic therapy. The 5-year overall survival, disease-specific survival, and tumor-free survival rates were 84.1 %, 97.5 %, and 82.1 %, respectively. A total of 26 patients died, but only 2 of them died from ESCC. The cumulative metastasis rate was 11.8 %, and LVI was a significant predictor of metastasis (hazard ratio 5.42, 95 % confidence interval 1.39 - 21.18; P = 0.02). There were no differences between patients with MM ESCC and those with SM1 ESCC. CONCLUSIONS: The long-term outcome after ESD for MM/SM1 ESCC was favorable with additional prophylactic therapy and strict adherence to follow-up. These results indicate that our management decision based on LVI is a valid approach and that ESD can be offered as a therapeutic option to MM/SM1 ESCCs. PMID- 29272908 TI - Do Medicare Advantage Plans Minimize Costs? Investigating the Relationship Between Benchmarks, Costs, and Rebates. AB - Issue: Medicare Advantage (MA), the program that allows people to receive their Medicare benefits through private health plans, uses a benchmark-and-bidding system to induce plans to provide benefits at lower costs. However, prior research suggests medical costs, profits, and other plan costs are not as low under this system as they might otherwise be. Goal: To examine how well the current system encourages MA plans to bid their lowest cost by examining the relationship between costs and bonuses (rebates) and the benchmarks Medicare uses in determining plan payments. Methods: Regression analysis using 2015 data for HMO and local PPO plans. Findings: Costs and rebates are higher for MA plans in areas with higher benchmarks, and plan costs vary less than benchmarks do. A one dollar increase in benchmarks is associated with 32-cent-higher plan costs and a 52-cent-higher rebate, even when controlling for market and plan factors that can affect costs. This suggests the current benchmark-and-bidding system allows plans to bid higher than local input prices and other market conditions would seem to warrant. Conclusion: To incentivize MA plans to maximize efficiency and minimize costs, Medicare could change the way benchmarks are set or used. PMID- 29272909 TI - History of the Mexican College of Clinical Immunology and Allergy A.C PMID- 29272910 TI - "Chucho" Perez Martin: An Endearing Friend PMID- 29272911 TI - ? PMID- 29272913 TI - ? PMID- 29272912 TI - The Mexican Guidelines on Urticaria PMID- 29272914 TI - Synthesis and Characterization of a Magnetically Active 19F Molecular Beacon. AB - Gene expression is used extensively to describe cellular characteristics and behaviors; however, most methods of assessing gene expression are unsuitable for living samples, requiring destructive processes such as fixation or lysis. Recently, molecular beacons have become a viable tool for live-cell imaging of mRNA molecules in situ. Historically, beacon-mediated imaging has been limited to fluorescence-based approaches. We propose the design and synthesis of a novel molecular beacon for magnetic resonance detection of any desired target nucleotide sequence. The biologically compatible synthesis incorporates commonly used bioconjugation reactions in aqueous conditions and is accessible for laboratories without extensive synthesis capabilities. The resulting beacon uses fluorine (19F) as a reporter, which is broadened, or turned "off", via paramagnetic relaxation enhancement from a stabilized nitroxide radical spin label when the beacon is not bound to its nucleic acid target. Therefore, the 19F NMR signal of the beacon is quenched in its hairpin conformation when the spin label and the 19F substituent are held in proximity, but the signal is recovered upon beacon hybridization to its specific complementary nucleotide sequence by physical separation of the radical from the 19F reporter. This study establishes a path for magnetic resonance-based assessment of specific mRNA expression, providing new possibilities for applying molecular beacon technology in living systems. PMID- 29272915 TI - Shape-Dependent Dissolution and Cellular Uptake of Silver Nanoparticles. AB - The cellular uptake and dissolution of trigonal silver nanoprisms (edge length 42 +/- 15 nm, thickness 8 +/- 1 nm) and mostly spherical silver nanoparticles (diameter 70 +/- 25 nm) in human mesenchymal stem cells (hMSC's) and human keratinocytes (HaCaT cells) were investigated. Both particles are stabilized by polyvinylpyrrolidone (PVP), with the prisms additionally stabilized by citrate. The nanoprisms dissolved slightly in pure water but strongly in isotonic saline or at pH 4, corresponding to the lowest limit for the pH during cellular uptake. The tips of the prisms became rounded within minutes due to their high surface energy. Afterward, the dissolution process slowed down due to the presence of both PVP stabilizing Ag{100} sites and citrate blocking Ag{111} sites. On the contrary, nanospheres, solely stabilized by PVP, dissolved within 24 h. These results correlate with the finding that particles in both cell types have lost >90% of their volume within 24 h. hMSC's took up significantly more Ag from nanoprisms than from nanospheres, whereas HaCaT cells showed no preference for one particle shape. This can be rationalized by the large cellular interaction area of the plateletlike nanoprisms and the bending stiffness of the cell membranes. hMSC's have a highly flexible cell membrane, resulting in an increased uptake of plateletlike particles. HaCaT cells have a membrane with a 3 orders of magnitude higher Young's modulus than for hMSC. Hence, the energy gain due to the larger interaction area of the nanoprisms is compensated for by the higher energy needed for cell membrane deformation compared to that for spheres, leading to no shape preference. PMID- 29272916 TI - Solution Properties of Amphoteric Random Copolymers Bearing Pendant Sulfonate and Quaternary Ammonium Groups with Controlled Structures. AB - Amphoteric random copolymers P(AMPS/APTAC50)x, where x = 41, 89, and 117, composed of sodium 2-acrylamido-2-methylpropanesulfonate (AMPS) and 3 acrylamidopropyltrimethylammonium chloride (APTAC) were prepared via reversible addition-fragmentation chain transfer radical polymerization. P(AMPS/APTAC50)x can dissolve in pure water to form small interpolymer aggregates. In aqueous solutions of NaCl, P(AMPS/APTAC50)x can dissolve in the unimer state. Amphoteric random copolymer P(AMPS/APTAC50)c with high molecular weight was prepared via conventional free-radical polymerization. Although P(AMPS/APTAC50)c cannot dissolve in pure water, it can dissolve in aqueous solutions of NaCl. In amphoteric random copolymers with high molecular weight, the possibility of continuous sequences of monomers with the same charge may increase, which may cause strong interactions between polymer chains. When fetal bovine serum (FBS) and polyelectrolytes were mixed in phosphate-buffered saline, the hydrodynamic radius and light-scattering intensity increased. There was no interaction between P(AMPS/APTAC50)x and FBS because corresponding increases could not be observed. PMID- 29272918 TI - Nonperturbative response functions: A tool for the interpretation of four-wave mixing signals beyond third order. AB - Considering an electronic two-level system coupled to vibrational degrees of freedom and driven by short and intense non-overlapping laser pulses, we introduce the concept of nonperturbative response functions. These response functions are expressed in terms of effective electronic transition dipole moments which depend on the strength of the field-matter coupling and on the pulse durations. It is shown that the nonlinear polarization representing four wave-mixing signals can elegantly be expressed in terms of these nonperturbative response functions to all orders in the field-matter coupling. The nonperturbative response functions generalize the interpretative power of the familiar third-order response functions to four-wave-mixing experiments with intense laser pulses. PMID- 29272917 TI - Purification and Characterization of Peptides Inhibiting MMP-1 Activity with C Terminate of Gly-Leu from Simulated Gastrointestinal Digestion Hydrolysates of Tilapia (Oreochromis niloticus) Skin Gelatin. AB - Tilapia skin gelatin hydrolysates (TSGHs) were prepared by simulated gastrointestinal digestion and separated by gel filtration and semi-preparative reversed-phase high-performance liquid chromatography. The anti-photoaging effects were evaluated using an ultraviolet radiation B (UVB)-induced mouse embryonic fibroblast (MEF) photoaging model in vitro. Three fractions from TSGHs with high inhibitory intercellular matrix metalloproteinase-1 (MMP-1) activities and reactive oxygen species (ROS) production were obtained. Three key peptides, GYTGL, LGATGL, and VLGL, were identified, and their C terminate was Gly-Leu. Three peptides were synthesized and exhibited a significant inhibition of intercellular MMP-1 activity and ROS production. Furthermore, three peptides inhibiting MMP-1 activities were evaluated through their docking of S1' and S3' active pockets of MMP-1. Hydrogen bonds and C terminate Gly-Leu played important roles. Finally, the protective effects of three peptides on intercellular collagen in UVB-induced MEFs were compared. Our results indicated that tilapia gelatin peptides exhibited potential activities to prevent and regulate photoaging. PMID- 29272919 TI - Structural and magnetic properties of FeGen-/0 (n = 3-12) clusters: Mass-selected anion photoelectron spectroscopy and density functional theory calculations. AB - The structural, electronic, and magnetic properties of FeGen-/0 (n = 3-12) clusters were investigated by using anion photoelectron spectroscopy in combination with density functional theory calculations. For both anionic and neutral FeGen (n = 3-12) clusters with n <= 7, the dominant structures are exohedral. The FeGe8-/0 clusters have half-encapsulated boat-shaped structures, and the opening of the boat-shaped structure is gradually covered by the additional Ge atoms to form Gen cage from n = 9 to 11. The structures of FeGe10 /0 can be viewed as two Ge atoms symmetrically capping the opening of the boat shaped structure of FeGe8, and those of FeGe12-/0 are distorted hexagonal prisms with the Fe atom at the center. Natural population analysis shows that there is an electron transfer from the Ge atoms to the Fe atom at n = 8-12. The total magnetic moment of FeGen-/0 and local magnetic moment of the Fe atom have not been quenched. PMID- 29272920 TI - Absolute vibrational excitation cross sections for 1-18 eV electron scattering from condensed dimethyl phosphate (DMP). AB - Absolute cross sections (CSs) for vibrational excitation by 1-18 eV electrons incident on condensed dimethyl phosphate (DMP) were measured with a high resolution electron energy loss (EEL) spectrometer. Absolute CSs were extracted from EEL spectra of DMP condensed on multilayer film of Ar held at about 20 K under ultra-high vacuum (~1 * 10-11 Torr). Structures observed in the energy dependence of the CSs around 2, 4, 7, and 12 eV were compared with previous results of gas- and solid-phase experiments and with theoretical studies on dimethyl phosphate and related molecules. These structures were attributed to the formation of shape resonances. PMID- 29272921 TI - Charge transport and dipolar relaxations in phosphonium-based ionic liquids. AB - The role of anions in charge transport and localized dipolar relaxations in tributyloctylphosphonium ionic liquids is investigated by broadband dielectric spectroscopy and rheology. The dielectric spectra are quantitatively described by a combination of the random barrier model which accounts for ion transport and empirical Havriliak-Negami functions to characterize dipolar relaxations. Two secondary relaxations are observed at temperatures below the calorimetric glass transition temperature, where the primary structural relaxation is essentially frozen at the relevant experimental time scales. The faster process has an anion independent activation energy of 30 kJ/mol and is attributed to libration motion of the phosphonium cation. The slower relaxation is similar to a process previously assigned to a Johari-Goldstein relaxation in imidazolium-based ionic liquids; however, the activation energy is significantly higher in the phosphonium systems. For the charge transport dominated regime, it is observed that variation of the anion results in differences in the dc ionic conductivity and characteristic charge transport rates by ~2.5 decades. Upon scaling by the calorimetric glass transition temperature, both transport quantities are observed to coincide. From these results, a picture of glass transition assisted hopping emerges as the underlying microscopic mechanism of ion conduction, in agreement with recent results obtained for other classes of aprotic ionic liquids. PMID- 29272922 TI - Connecting structurally and dynamically detected signatures of supramolecular Debye liquids. AB - The monohydroxy alcohol 2-ethyl-1-hexanol mixed with the halogen-substituted alkyl halides 2-ethyl-1-hexyl chloride and 2-ethyl-1-hexyl bromide was studied using synchrotron-based x-ray scattering. In the diffraction patterns, an oxygen related prepeak appears. The concentration dependence of its intensity, shape, and position indicates that the formation of the hydrogen-bonded associates of monohydroxy alcohols is largely hindered by the halogen alkane admixture. Using dielectric spectroscopy and high-resolution rheology on the same liquid mixtures, it is shown that these structural features are correlated with the relaxation mechanisms giving rise to supramolecular low-frequency dynamics. PMID- 29272923 TI - Comparison of two protic ionic liquid behaviors in the presence of an electric field using molecular dynamics. AB - The effects of an external electric field on two ionic liquids (ILs) are investigated using molecular dynamics electrospray simulations of ethylammonium nitrate (EAN) and ethanolammonium nitrate (EOAN). In the absence of an external electric field, long alkyl chains were observed in EAN but not in EOAN. When the electric field was applied, the anions of both ILs formed a barrier along the applied field, but only in EAN did this barrier result in a static bilayer composed of two parallel layers of cations and anions. The primary hydrogen bonds (HBs) connecting the EAN cations and anions were formed between the ammonium and the nitrate groups. In contrast, they were formed between the ammonium as well as the hydroxyl groups and the nitrate groups in EOAN. The applied electric field was found effective in reducing the number of O1-HO?O type HBs but was less effective against the N-HN?O type HBs. It was observed that the N-C1-CM backbone angles of EAN allowed for greater storage of the energy supplied by the electric field in the form of torsional degree of freedom compared to the N-C1-CM angles of EOAN. The combination of stronger HBs and higher energy storage in the N-C1-CM covalent angle in EAN results in a stronger resistance of ion emission from the bulk compared to EOAN. PMID- 29272924 TI - Mean field theory of the swap Monte Carlo algorithm. AB - The swap Monte Carlo algorithm combines the translational motion with the exchange of particle species and is unprecedentedly efficient for some models of glass former. In order to clarify the physics underlying this acceleration, we study the problem within the mean field replica liquid theory. We extend the Gaussian Ansatz so as to take into account the exchange of particles of different species, and we calculate analytically the dynamical glass transition points corresponding to the swap and standard Monte Carlo algorithms. We show that the system evolved with the standard Monte Carlo algorithm exhibits the dynamical transition before that of the swap Monte Carlo algorithm. We also test the result by performing computer simulations of a binary mixture of the Mari-Kurchan model, both with standard and swap Monte Carlo. This scenario provides a possible explanation for the efficiency of the swap Monte Carlo algorithm. Finally, we discuss how the thermodynamic theory of the glass transition should be modified based on our results. PMID- 29272925 TI - Communication: Spectroscopic characterization of a strongly interacting C(2)H group on the EMIM+ cation in the (EMIM+)2X- (X = BF4, Cl, Br, and I) ternary building blocks of ionic liquids. AB - To unravel the intermolecular interactions at play in the assemblies of EMIM based ionic liquids, we report the vibrational spectra of the cryogenically cooled, cationic ternary complexes with halide ions, (EMIM+)2X-, X = Cl, Br, and I. This series specifically addresses the spectral response of the acidic C(2)H group upon complexation with an atomic anion, which is isolated by selective deuteration at this position. Unlike the behavior of the related BF4- complex, the halide systems display large (~175 cm-1) red-shifts and dramatic (~30X) intensity enhancements in the C(2)D stretch (relative to that of the bare d(2) EMIM+ cation), which are largest for the chloride anion. Electronic structure calculations indicate that, while the spectroscopic signatures of the interaction follow those expected for a traditional hydrogen bond to the C(2)H group, the C-H X docking arrangement deviates substantially from linearity due to a "double contact" motif involving a weaker interaction to the nearby methyl group [Hunt et al., Chem. Soc. Rev. 44(5), 1257-1288 (2015)]. PMID- 29272926 TI - Coupling discrete and continuum concentration particle models for multiscale and hybrid molecular-continuum simulations. AB - Hybrid molecular-continuum simulation techniques afford a number of advantages for problems in the rapidly burgeoning area of nanoscale engineering and technology, though they are typically quite complex to implement and limited to single-component fluid systems. We describe an approach for modeling multicomponent hydrodynamic problems spanning multiple length scales when using particle-based descriptions for both the finely resolved (e.g., molecular dynamics) and coarse-grained (e.g., continuum) subregions within an overall simulation domain. This technique is based on the multiscale methodology previously developed for mesoscale binary fluids [N. D. Petsev, L. G. Leal, and M. S. Shell, J. Chem. Phys. 144, 084115 (2016)], simulated using a particle-based continuum method known as smoothed dissipative particle dynamics. An important application of this approach is the ability to perform coupled molecular dynamics (MD) and continuum modeling of molecularly miscible binary mixtures. In order to validate this technique, we investigate multicomponent hybrid MD-continuum simulations at equilibrium, as well as non-equilibrium cases featuring concentration gradients. PMID- 29272927 TI - Electron detachment of hydrogen anion in collisions with hydrogen molecule studied by surface hopping classical trajectory calculations. AB - We employ the on-the-fly surface hopping classical trajectory algorithm to study the electron detachment process in low-energy H- + H2 collisions. The ground state and the first-excited-state Local Complex Potentials (LCPs) calculated by the generalized diatomics-in-molecule method are used for the full three dimensional nonadiabatic nuclear dynamics. Two kinds of nonadiabatic effects are taken into account: discrete-discrete transitions and discrete-continuous transitions. Discrete-discrete nonadiabatic transition probabilities are calculated by means of the adiabatic-potential-based formula within the Landau Zener model for each individual trajectory computed along real parts of the LCPs. Discrete-continuous (electron detachment) nonadiabatic transition probabilities are calculated via quasi-stationary widths which are related to the imaginary parts of the LCPs of both the electronic states of the H3- anion. Two mechanisms of the electron detachment process are treated and discussed: the direct mechanism based on quasi-stationarity of the ground state and the indirect mechanism based on both nonadiabatic transitions from the ground state to the first excited state and quasi-stationarity of the excited state. It is shown that the direct mechanism prevails at low collision energies, while the indirect mechanism makes a substantial contribution at relatively high collision energies, roughly higher than 5 eV. At collision energies higher than 2 eV, the electron detachment probability has rather high values and this affects noticeably other inelastic processes in these collisions. The electron detachment cross section in H- + H2 collisions is calculated for the collision energy range from 1 to 100 eV and a reasonable agreement with available experimental data is obtained. PMID- 29272928 TI - From properties to materials: An efficient and simple approach. AB - We present an inverse-design method, the poor man's materials optimization, that is designed to identify materials within a very large class with optimized values for a pre-chosen property. The method combines an efficient genetic-algorithm based optimization, an automatic approach for generating modified molecules, a simple approach for calculating the property of interest, and a mathematical formulation of the quantity whose value shall be optimized. In order to illustrate the performance of our approach, we study the properties of organic molecules related to those used in dye-sensitized solar cells, whereby we, for the sake of proof of principle, consider benzene as a simple test system. Using a genetic algorithm, the substituents attached to the organic backbone are varied and the best performing molecules are identified. We consider several properties to describe the performance of organic molecules, including the HOMO-LUMO gap, the sunlight absorption, the spatial distance of the orbitals, and the reorganisation energy. The results show that our method is able to identify a large number of good candidate structures within a short time. In some cases, chemical/physical intuition can be used to rationalize the substitution pattern of the best structures, although this is not always possible. The present investigations provide a solid foundation for dealing with more complex and technically relevant systems such as porphyrins. Furthermore, our "properties first, materials second" approach is not limited to solar-energy harvesting but can be applied to many other fields, as briefly is discussed in the paper. PMID- 29272929 TI - Communication: Predicting virial coefficients and alchemical transformations by extrapolating Mayer-sampling Monte Carlo simulations. AB - Virial coefficients are predicted over a large range of both temperatures and model parameter values (i.e., alchemical transformation) from an individual Mayer sampling Monte Carlo simulation by statistical mechanical extrapolation with minimal increase in computational cost. With this extrapolation method, a Mayer sampling Monte Carlo simulation of the SPC/E (extended simple point charge) water model quantitatively predicted the second virial coefficient as a continuous function spanning over four orders of magnitude in value and over three orders of magnitude in temperature with less than a 2% deviation. In addition, the same simulation predicted the second virial coefficient if the site charges were scaled by a constant factor, from an increase of 40% down to zero charge. This method is also shown to perform well for the third virial coefficient and the exponential parameter for a Lennard-Jones fluid. PMID- 29272930 TI - Mesoscopic-microscopic spatial stochastic simulation with automatic system partitioning. AB - The reaction-diffusion master equation (RDME) is a model that allows for efficient on-lattice simulation of spatially resolved stochastic chemical kinetics. Compared to off-lattice hard-sphere simulations with Brownian dynamics or Green's function reaction dynamics, the RDME can be orders of magnitude faster if the lattice spacing can be chosen coarse enough. However, strongly diffusion controlled reactions mandate a very fine mesh resolution for acceptable accuracy. It is common that reactions in the same model differ in their degree of diffusion control and therefore require different degrees of mesh resolution. This renders mesoscopic simulation inefficient for systems with multiscale properties. Mesoscopic-microscopic hybrid methods address this problem by resolving the most challenging reactions with a microscale, off-lattice simulation. However, all methods to date require manual partitioning of a system, effectively limiting their usefulness as "black-box" simulation codes. In this paper, we propose a hybrid simulation algorithm with automatic system partitioning based on indirect a priori error estimates. We demonstrate the accuracy and efficiency of the method on models of diffusion-controlled networks in 3D. PMID- 29272931 TI - Photodissociation of van der Waals complexes of iodine X-I2 (X = I2, C2H4) via charge-transfer state: A velocity map imaging investigation. AB - The photodissociation of van der Waals complexes of iodine X-I2 (X = I2, C2H4) excited via Charge-Transfer (CT) band has been studied with the velocity map imaging technique. Photodissociation of both complexes gives rise to translationally "hot" molecular iodine I2 via channels differing by kinetic energy and angular distribution of the recoil directions. These measured characteristics together with the analysis of the model potential energy surface for these complexes allow us to infer the back-electron-transfer (BET) in the CT state to be a source of observed photodissociation channels and to make conclusions on the location of conical intersections where the BET process takes place. The BET process is concluded to provide an I2 molecule in the electronic ground state with moderate vibrational excitation as well as X molecule in the electronic excited state. In the case of X = I2, the BET process converts anion I2- of the CT state into the neutral I2 in the repulsive excited electronic state which then dissociates promptly giving rise to a pair of I atoms in the fine states 2P1/2. In the case of C2H4-I2, the C2H4 molecules appear in the triplet T1 electronic state. Conical intersection for corresponding BET process becomes energetically accessible after partial twisting of C2H4+ frame in the excited CT state of complex. The C2H4(T)-I2 complex gives rise to triplet ethylene as well as singlet ethylene via the T-S conversion. PMID- 29272932 TI - Self-consistent assessment of Englert-Schwinger model on atomic properties. AB - Our manuscript investigates a self-consistent solution of the statistical atom model proposed by Berthold-Georg Englert and Julian Schwinger (the ES model) and benchmarks it against atomic Kohn-Sham and two orbital-free models of the Thomas Fermi-Dirac (TFD)-lambdavW family. Results show that the ES model generally offers the same accuracy as the well-known TFD-15vW model; however, the ES model corrects the failure in the Pauli potential near-nucleus region. We also point to the inability of describing low-Z atoms as the foremost concern in improving the present model. PMID- 29272933 TI - Parallel replica dynamics method for bistable stochastic reaction networks: Simulation and sensitivity analysis. AB - Stochastic reaction networks that exhibit bistable behavior are common in systems biology, materials science, and catalysis. Sampling of stationary distributions is crucial for understanding and characterizing the long-time dynamics of bistable stochastic dynamical systems. However, simulations are often hindered by the insufficient sampling of rare transitions between the two metastable regions. In this paper, we apply the parallel replica method for a continuous time Markov chain in order to improve sampling of the stationary distribution in bistable stochastic reaction networks. The proposed method uses parallel computing to accelerate the sampling of rare transitions. Furthermore, it can be combined with the path-space information bounds for parametric sensitivity analysis. With the proposed methodology, we study three bistable biological networks: the Schlogl model, the genetic switch network, and the enzymatic futile cycle network. We demonstrate the algorithmic speedup achieved in these numerical benchmarks. More significant acceleration is expected when multi-core or graphics processing unit computer architectures and programming tools such as CUDA are employed. PMID- 29272934 TI - Towards a quantum chemical protocol for the prediction of rovibrational spectroscopic data for transition metal molecules: Exploration of CuCN, CuOH, and CuCCH. AB - High accuracy electronic structure computations for small transition metal containing molecules have been a long term challenge. Due to coupling between electronic and nuclear wave functions, even experimental/theoretical identification of the ground electronic state requires tremendous efforts. Quartic force fields (QFFs) are effective ab initio tools for obtaining reliable anharmonic spectroscopic properties. However, the method that employs complete basis set limit extrapolation ("C"), consideration of core electron correlation ("cC"), and inclusion of scalar relativity ("R") to produce the energy points on the QFF, the composite CcCR methodology, has not yet been utilized to study inorganic spectroscopy. This work takes the CcCR methodology and adapts it to test whether such an approach is conducive for the closed-shell, copper containing molecules CuCN, CuOH, and CuCCH. Gas phase rovibrational data are provided for all three species in their ground electronic states. Equilibrium geometries and many higher-order rovibrational properties show good agreement with earlier studies. However, there are notable differences, especially in computation of fundamental vibrational frequencies. Even with further additive corrections for the inner core electron correlation and coupled cluster with full single, double, and triple substitutions (CCSDT), the differences are still larger than expected indicating that more work should follow for predicting rovibrational properties of transition metal molecules. PMID- 29272935 TI - A neural-network potential through charge equilibration for WS2: From clusters to sheets. AB - In the present work, we use a machine learning method to construct a high dimensional potential for tungsten disulfide using a charge equilibration neural network technique. A training set of stoichiometric WS2 clusters is prepared in the framework of density functional theory. After training the neural-network potential, the reliability and transferability of the potential are verified by performing a crystal structure search on bulk phases of WS2 and by plotting energy-area curves of two different monolayers. Then, we use the potential to investigate various triangular nano-clusters and nanotubes of WS2. In the case of nano-structures, we argue that 2H atomic configurations with sulfur rich edges are thermodynamically more stable than the other investigated configurations. We also studied a number of WS2 nanotubes which revealed that 1T tubes with armchair chirality exhibit lower bending stiffness. PMID- 29272936 TI - Dissociative electron attachment to 2,4,6-trichloroanisole and 2,4,6 tribromoanisole molecules. AB - 2,4,6-trichloroanisole and 2,4,6-tribromoanisole were investigated by means of electron transmission spectroscopy and two different types of dissociative electron attachment spectrometers. The results obtained were interpreted with the support of density functional theory calculations. The dominant dissociative decay channels of the temporary molecular negative ions lead to the formation of Cl- and Br- in the low electron energy region. Formation of long-lived parent anions is observed at thermal electron energies. Their relative intensity depends on the experimental time window, ~36 MUs in the case of the static magnet mass analyzer and ~200 MUs for the quadrupole mass analyzer employed. The results obtained may be useful for rapid detection of these compounds in wine and pharmaceutical industries, as well as other branches connected to the food industry, e.g., packaging. PMID- 29272937 TI - Structure, spectroscopy, and dynamics of the phenol-(water)2 cluster at low and high temperatures. AB - Aqueous solutions are complex due to hydrogen bonding (HBing). While gas-phase clusters could provide clues on the solution behavior, most neutral clusters were studied at cryogenic temperatures. Recent results of Shimamori and Fujii provide the first IR spectrum of warm phenol-(H2O)2 clusters. To understand the temperature (T) effect, we have revisited the structure and spectroscopy of phenol-(H2O)2 at all T. While older quantum chemistry work concluded that the cyclic isomers are the most stable, the inclusion of dispersion interactions reveals that they are nearly isoenergetic with isomers forming pi-HBs with the phenyl ring. Whereas the OH-stretch bands were previously assigned to purely local modes, we show that at low T they involve a concerted component. We have calculated the (static) anharmonic IR spectra for all low-lying isomers, showing that at the MP2 level, one can single out one isomer (udu) as accounting for the low-T spectrum to 3 cm-1 accuracy. Yet no isomer can explain the substantial blueshift of the phenyl-OH band at elevated temperatures. We describe the temperature effect using ab initio molecular dynamics with a density functional and basis-set (B3LYP-D3/aug-cc-pVTZ) that provide a realistic description of OH?O vs. OH?pi HBing. From the dipole moment autocorrelation function, we obtain good description for both low- and high-T spectra. Trajectory visualization suggests that the ring structure remains mostly intact even at high T, with intermittent switching between OH?O and OH?pi HBing and lengthening of all 3 HBs. The phenyl OH blueshift is thus attributed to strengthening of its OH bond. A model for three beads on a ring suggests that this shift is partly offset by the elimination of coupling to the other OH bonds in the ring, whereas for the two water molecules these two effects nearly cancel. PMID- 29272938 TI - Novel rubidium poly-nitrogen materials at high pressure. AB - First-principles crystal structure search is performed to predict novel rubidium poly-nitrogen materials at high pressure by varying the stoichiometry, i.e., relative quantities of the constituent rubidium and nitrogen atoms. Three compounds of high nitrogen content, RbN5, RbN2, and Rb4N6, are discovered. Rubidium pentazolate (RbN5) becomes thermodynamically stable at pressures above 30 GPa. The charge transfer from Rb to N atoms enables aromaticity in cyclo-N5- while increasing the ionic bonding in the crystal. Rubidium pentazolate can be synthesized by compressing rubidium azide (RbN3) and nitrogen (N2) precursors above 9.42 GPa, and its experimental discovery is aided by calculating the Raman spectrum and identifying the features attributed to N5- modes. The two other interesting compounds, RbN2 containing infinitely long single-bonded nitrogen chains and Rb4N6 consisting of single-bonded N6 hexazine rings, become thermodynamically stable at pressures exceeding 60 GPa. In addition to the compounds with high nitrogen content, Rb3N3, a new compound with 1:1 RbN stoichiometry containing bent N3 azides is found to exist at high pressures. PMID- 29272939 TI - A mapping variable ring polymer molecular dynamics study of condensed phase proton-coupled electron transfer. AB - We investigate the mechanisms of condensed phase proton-coupled electron transfer (PCET) using Mapping-Variable Ring Polymer Molecular Dynamics (MV-RPMD), a recently developed method that employs an ensemble of classical trajectories to simulate nonadiabatic excited state dynamics. Here, we construct a series of system-bath model Hamiltonians for the PCET, where four localized electron-proton states are coupled to a thermal bath via a single solvent mode, and we employ MV RPMD to simulate state population dynamics. Specifically, for each model, we identify the dominant PCET mechanism, and by comparing against rate theory calculations, we verify that our simulations correctly distinguish between concerted PCET, where the electron and proton transfer together, and sequential PCET, where either the electron or the proton transfers first. This work represents a first application of MV-RPMD to multi-level condensed phase systems; we introduce a modified MV-RPMD expression that is derived using a symmetric rather than asymmetric Trotter discretization scheme and an initialization protocol that uses a recently derived population estimator to constrain trajectories to a dividing surface. We also demonstrate that, as expected, the PCET mechanisms predicted by our simulations are robust to an arbitrary choice of the initial dividing surface. PMID- 29272940 TI - Applicability of transfer tensor method for open quantum system dynamics. AB - Accurate simulations of open quantum system dynamics is a long standing issue in the field of chemical physics. Exact methods exist, but are costly, while perturbative methods are limited in their applicability. Recently a new black-box type method, called transfer tensor method (TTM), was proposed [J. Cerrillo and J. Cao, Phys. Rev. Lett. 112, 110401 (2014)]. It allows one to accurately simulate long time dynamics with a numerical cost of solving a time-convolution master equation, provided many initial system evolution trajectories are obtained from some exact method beforehand. The possible time-savings thus strongly depend on the ratio of total versus initial evolution lengths. In this work, we investigate the parameter regimes where an application of TTM would be most beneficial in terms of computational time. We identify several promising parameter regimes. Although some of them correspond to cases when perturbative theories could be expected to perform well, we find that the accuracy of such approaches depends on system parameters in a more complex way than it is commonly thought. We propose that the TTM should be applied whenever system evolution is expected to be long and accuracy of perturbative methods cannot be ensured or in cases when the system under consideration does not correspond to any single perturbative regime. PMID- 29272941 TI - Direct evaluation of boson dynamics via finite-temperature time-dependent variation with multiple Davydov states. AB - Recent advances in quantum optics allow for exploration of boson dynamics in dissipative many-body systems. However, the traditional descriptions of quantum dissipation using reduced density matrices are unable to capture explicit information of bath dynamics. In this work, efficient evaluation of boson dynamics is demonstrated by combining the multiple Davydov Ansatz with finite temperature time-dependent variation, going beyond what state-of-the-art density matrix approaches are capable to offer for coupled electron-boson systems. To this end, applications are made to excitation energy transfer in photosynthetic systems, singlet fission in organic thin films, and circuit quantum electrodynamics in superconducting devices. Thanks to the multiple Davydov Ansatz, our analysis of boson dynamics leads to clear revelation of boson modes strongly coupled to electronic states, as well as in-depth description of polaron creation and destruction in the presence of thermal fluctuations. PMID- 29272942 TI - Structural origin of hardness decrease in irradiated sodium borosilicate glass. AB - Mechanical properties such as hardness and modulus of sodium borosilicate (NBS) glasses in irradiation conditions were studied extensively in recent years. With irradiation of heavy ions, a trend that the hardness of NBS glasses decreased and then stabilized with increase of dose has been reported. Variations in network structures were suggested for the decrease of hardness after irradiation. However, details of these variations in a network of glass are not clear yet. In this paper, molecular dynamics was applied to simulate the network variations in a type of NBS glass and the changes in hardness after xenon irradiation. The simulation results indicated that hardness variation decreased with fluence in an exponential law, which was consistent with experimental results. The origin of hardness decrease after irradiation might be attributed to the break of Biv-O links that could be derived from the (1) decrease of average coordinate number of boron, (2) decrease of Si-O-Biv bonds, and (3) increase of non-bridging oxygen. PMID- 29272943 TI - Electronic structure of SmO and SmO- via slow photoelectron velocity-map imaging spectroscopy and spin-orbit CASPT2 calculations. AB - The chemi-ionization reaction of atomic samarium, Sm + O -> SmO+ + e-, has been investigated by the Air Force Research Laboratory as a means to modify local electron density in the ionosphere for reduction of scintillation of high frequency radio waves. Neutral SmO is a likely unwanted byproduct. The spectroscopy of SmO is of great interest to aid in interpretation of optical emission spectra recorded following atmospheric releases of Sm as part of the Metal Oxide Space Cloud (MOSC) observations. Here, we report a joint experimental and theoretical study of SmO using slow photoelectron velocity-map imaging spectroscopy of cryogenically cooled SmO- anions (cryo-SEVI) and high-level spin orbit complete active space calculations with corrections from second order perturbation theory (CASPT2). With cryo-SEVI, we measure the electron affinity of SmO to be 1.0581(11) eV and report electronic and vibrational structure of low lying electronic states of SmO in good agreement with theory and prior experimental work. We also obtain spectra of higher-lying excited states of SmO for direct comparison to the MOSC results. PMID- 29272944 TI - Molecular characteristics of stress overshoot for polymer melts under start-up shear flow. AB - Stress overshoot is one of the most important nonlinear rheological phenomena exhibited by polymeric liquids undergoing start-up shear at sufficient flow strengths. Despite considerable previous research, the fundamental molecular characteristics underlying stress overshoot remain unknown. Here, we analyze the intrinsic molecular mechanisms behind the overshoot phenomenon using atomistic nonequilibrium molecular dynamics simulations of entangled linear polyethylene melts under shear flow. Through a detailed analysis of the transient rotational chain dynamics, we identify an intermolecular collision angular regime in the vicinity of the chain orientation angle theta ~ 20 degrees with respect to the flow direction. The shear stress overshoot occurs via strong intermolecular collisions between chains in the collision regime at theta = 15 degrees -25 degrees , corresponding to a peak strain of 2-4, which is an experimentally well known value. The normal stress overshoot appears at approximately theta = 10 degrees , at a corresponding peak strain roughly equivalent to twice that for the shear stress. We provide plausible answers to several basic questions regarding the stress overshoot, which may further help understand other nonlinear phenomena of polymeric systems. PMID- 29272945 TI - Diffusion and interactions of interstitials in hard-sphere interstitial solid solutions. AB - Using computer simulations, we study the dynamics and interactions of interstitial particles in hard-sphere interstitial solid solutions. We calculate the free-energy barriers associated with their diffusion for a range of size ratios and densities. By applying classical transition state theory to these free energy barriers, we predict the diffusion coefficients, which we find to be in good agreement with diffusion coefficients as measured using event-driven molecular dynamics simulations. These results highlight that transition state theory can capture the interstitial dynamics in the hard-sphere model system. Additionally, we quantify the interactions between the interstitials. We find that, apart from excluded volume interactions, the interstitial-interstitial interactions are almost ideal in our system. Lastly, we show that the interstitial diffusivity can be inferred from the large-particle fluctuations alone, thus providing an empirical relationship between the large-particle fluctuations and the interstitial diffusivity. PMID- 29272946 TI - Anisotropic stress inhibits crystallization in Cu-Zr glass-forming liquids. AB - Liquids attain a metastable state without crystallizing by cooling rapidly to a given temperature below the melting point. With increasing supercooling, the nucleation rate would show an increase based on the prediction of the classical nucleation theory. It is generally thought that the nucleation rate will reach the maximum upon approaching the glass transition temperature, Tg, for glass forming liquids. We report that there exists a supercooled region above Tg in which the crystallization has actually been severely suppressed. Our molecular dynamics simulations show that the growth of embryos in the supercooled Cu60Zr40 melt is subjected to a strong anisotropic stress associated with the dynamic heterogeneity. Its long-range effect drives the embryo to grow into a ramified morphology so that the interface energy dominates over the embryo growth, leading to the suppression of nucleation. PMID- 29272947 TI - Multivariable extrapolation of grand canonical free energy landscapes. AB - We derive an approach for extrapolating the free energy landscape of multicomponent systems in the grand canonical ensemble, obtained from flat histogram Monte Carlo simulations, from one set of temperature and chemical potentials to another. This is accomplished by expanding the landscape in a Taylor series at each value of the order parameter which defines its macrostate phase space. The coefficients in each Taylor polynomial are known exactly from fluctuation formulas, which may be computed by measuring the appropriate moments of extensive variables that fluctuate in this ensemble. Here we derive the expressions necessary to define these coefficients up to arbitrary order. In principle, this enables a single flat-histogram simulation to provide complete thermodynamic information over a broad range of temperatures and chemical potentials. Using this, we also show how to combine a small number of simulations, each performed at different conditions, in a thermodynamically consistent fashion to accurately compute properties at arbitrary temperatures and chemical potentials. This method may significantly increase the computational efficiency of biased grand canonical Monte Carlo simulations, especially for multicomponent mixtures. Although approximate, this approach is amenable to high throughput and data-intensive investigations where it is preferable to have a large quantity of reasonably accurate simulation data, rather than a smaller amount with a higher accuracy. PMID- 29272948 TI - Channel branching ratios in CH2CN- photodetachment: Rotational structure and vibrational energy redistribution in autodetachment. AB - We report photoelectron spectra of CH2CN-, recorded at photon energies between 13 460 and 15 384 cm-1, which show rapid intensity variations in particular detachment channels. The branching ratios for various spectral features reveal rotational structure associated with autodetachment from an intermediate anion state. Calculations using equation-of-motion coupled-cluster method with single and double excitations reveal the presence of two dipole-bound excited anion states (a singlet and a triplet). The computed oscillator strength for the transition to the singlet dipole-bound state provides an estimate of the autodetachment channel contribution to the total photoelectron yield. Analysis of the different spectral features allows identification of the dipole-bound and neutral vibrational levels involved in the autodetachment processes. For the most part, the autodetachment channels are consistent with the vibrational propensity rule and normal mode expectation. However, examination of the rotational structure shows that autodetachment from the nu3 (v = 1 and v = 2) levels of the dipole-bound state displays behavior counter to the normal mode expectation with the final state vibrational level belonging to a different mode. PMID- 29272949 TI - A dynamic correlation dressed complete active space method: Theory, implementation, and preliminary applications. AB - Complete Active Space SCF (CASSCF) theory may provide poor 0th order descriptions due to the lack of dynamic correlation. The most popular post-CASSCF approaches for recovering dynamic correlation are methods which keep the configuration interaction coefficients fixed at the CASSCF level and use internal contraction. This may result in severe inaccuracies where the wavefunction changes considerably under the influence of dynamic correlation. In this paper, we propose and compare several variants of a straightforward method of the "perturb then-diagonalize" type that is aimed at keeping this balance while remaining computationally tractable and numerically stable. The method is loosely based on the theory of intermediate Hamiltonians and has been given the acronym "dynamic correlation dressed CAS" (DCD-CAS), with the second-order treatment, DCD-CAS(2), being the most practically useful member of the family. The dynamic correlation energy is treated to second order with a 0th order Hamiltonian based on Dyall's Hamiltonian. The method is orbitally invariant with respect to unitary transformations in the occupied, active, and virtual subspaces. It yields the ground- and low-lying excited states at the same time. Detailed numerical evaluations show that DCD-CAS(2) is superior to NEVPT2 for the difficult situations mentioned above while being very close to it when CASSCF provides a good 0th order description. PMID- 29272950 TI - Reliability assessment for large-scale molecular dynamics approximations. AB - Molecular dynamics (MD) simulations are used in biochemistry, physics, and other fields to study the motions, thermodynamic properties, and the interactions between molecules. Computational limitations and the complexity of these problems, however, create the need for approximations to the standard MD methods and for uncertainty quantification and reliability assessment of those approximations. In this paper, we exploit the intrinsic two-scale nature of MD to construct a class of large-scale dynamics approximations. The reliability of these methods is evaluated here by measuring the differences between full, classical MD simulations and those based on these large-scale approximations. Molecular dynamics evolutions are non-linear and chaotic, so the complete details of molecular evolutions cannot be accurately predicted even using full, classical MD simulations. This paper provides numerical results that demonstrate the existence of computationally efficient large-scale MD approximations which accurately model certain large-scale properties of the molecules: the energy, the linear and angular momenta, and other macroscopic features of molecular motions. PMID- 29272951 TI - Molecular geometries and other properties of H2O?AgI and H3N?AgI as characterised by rotational spectroscopy and ab initio calculations. AB - The rotational spectra of H3N?AgI and H2O?AgI have been recorded between 6.5 and 18.5 GHz by chirped-pulse Fourier-transform microwave spectroscopy. The complexes were generated through laser vaporisation of a solid target of silver or silver iodide in the presence of an argon gas pulse containing a low concentration of the Lewis base. The gaseous sample subsequently undergoes supersonic expansion which results in cooling of rotational and vibrational motions such that weakly bound complexes can form within the expanding gas jet. Spectroscopic parameters have been determined for eight isotopologues of H3N?AgI and six isotopologues of H2O?AgI. Rotational constants, B0; centrifugal distortion constants, DJ, DJK or DeltaJ, DeltaJK; and the nuclear quadrupole coupling constants, chiaa(I) and chibb(I) - chicc(I) are reported. H3N?AgI is shown to adopt a geometry that has C3v symmetry. The geometry of H2O?AgI is Cs at equilibrium but with a low barrier to inversion such that the vibrational wavefunction for the v = 0 state has C2v symmetry. Trends in the nuclear quadrupole coupling constant of the iodine nucleus, chiaa(I), of L?AgI complexes are examined, where L is varied across the series (L = Ar, H3N, H2O, H2S, H3P, or CO). The results of experiments are reported alongside those of ab initio calculations at the CCSD(T)(F12*)/AVXZ level (X = T, Q). PMID- 29272952 TI - Assessment by Monte Carlo computer simulations of the phase behavior of hard spherocylinders confined within cylindrical cavities. AB - The phase behavior of hard spherocylinders (HSCs) confined in cylindrical cavities is studied using Monte Carlo simulations in the canonical ensemble. Results are presented for different values of the particles' aspect ratio l/sigma, where l and sigma are the length and diameter of the cylinder and hemispherical caps, respectively. Finite cavities with periodic boundary conditions along the principal axis of the cavities have been considered, where the cavity's principal axis is along the z-direction. We first focus our study in the structure induced by varying the degree of confinement, determining the HSC phase diagram for aspect ratios l/sigma = 3, 5, 7, and 9, at a fixed packing fraction eta = 0.071. By compressing the cavities along the radial direction, the isotropic phase becomes stable before the nematic phase as the length of the cavities is increased, resulting in a second-order transition. The occurrence of phase transitions has also been determined by varying eta for constant values of the cavity's length L. Systems with low aspect ratios, l/sigma = 3, 5, 7, and 9, exhibit first-order transitions with chiral, paranematic, and isotropic phases, whereas for larger HSCs, l/sigma = 50, 70, and 100, the transitions are second order with paranematic, nematic, and isotropic phases, in contrast with the behavior of non-confined systems, with first-order transitions for isotropic, nematic, smectic-A, and solid phases. PMID- 29272953 TI - The Big Five personality factors and psychological well-being following stroke: a systematic review. AB - PURPOSE: To identify and appraise studies investigating the relationship between the Big Five personality factors and psychological well-being following stroke and evidence for personality change. METHODS: Systematic searches of six databases (PsychINFO, CINAHL, Ovid Medline, Cochrane, PubMed, and Web of Science) were conducted from inception to June 2017. Studies involving adult stroke samples that employed a validated measure of at least one of the Big Five personality factors were included. Two reviewers independently assessed the eligibility and methodological quality of studies. RESULTS: Eleven studies were identified that assessed associations between personality and psychological well being after stroke (nine studies) or post-stroke personality change (two studies). A consistent finding was that higher neuroticism was significantly related to poorer psychological well-being. The evidence for the other Big Five factors was mixed. In terms of personality change, two cross-sectional studies reported high rates of elevated neuroticism (38-48%) and low extraversion (33 40%) relative to normative data. Different questionnaires and approaches to measuring personality (i.e., self vs. informant ratings, premorbid personality vs. current personality) complicated comparisons between studies. CONCLUSIONS: People high on neuroticism are at increased risk of poor psychological well-being after stroke. Prospective longitudinal studies are needed to address the limited research on post-stroke personality change. Implications for rehabilitation High neuroticism is associated with poorer psychological well-being after stroke. Assessing personality characteristics early after stroke may help to identify those at risk of poor psychological outcomes. PMID- 29272954 TI - Couple adjustment to a stressful life event: a dyadic investigation of the roles of positive reframing and perceived benefits. AB - BACKGROUND AND OBJECTIVES: This study examines positive reframing (a form of meaning making), perceived benefits (a form of meanings made) and adjustment in couples who experienced a stressful life event in the past year. This study tested whether couple members' scores were nonindependent and whether one's own perceived benefits was predicted by their own positive reframing (actor effect) as well as their partner's positive reframing (partner effect). Further, this study tested actor and partner effects for the link between perceived benefits and adjustment and whether positive reframing (the initial variable) works through perceived benefits (the mediator) to affect adjustment (the outcome) at the dyadic level. DESIGN: A standard dyadic design was used. METHODS: Eighty couples completed measures of positive reframing, perceived benefits, and adjustment (depression, anxiety, positive affect, life satisfaction, and relationship satisfaction). RESULTS: Partners' scores on study variables were related, and although only actor effects were found for the path between positive reframing and perceived benefits, both actor and partner effects were found for the path between perceived benefits and adjustment. Mediation was found for actor actor and actor-partner indirect effects. CONCLUSIONS: Results indicate that a greater focus on interpersonal factors is needed to further meaning-making theory and inform practice. PMID- 29272956 TI - Benzopyran derivatives from endophytic Daldinia eschscholzii JC-15 in Dendrobium chrysotoxum and their bioactivities. AB - Five new benzopyran derivatives (2-6) and a new natural product (1) were isolated from endophytic Daldinia eschscholzii in Dendrobium chrysotoxum and determined as (R)-2,3-dihydro-2,5-dihydroxy-2-methylchromen-4-one (1), (2R, 4S)-2,3-dihydro-2 methyl-benzopyran-4,5-diol (2), (R)-3-methoxyl-1-(2,6-dihydroxy phenyl)-butan-1 one (3), 7-O-alpha-d-ribosyl-5-hydroxy-2-methyl-4H-chromen-4-one (4), 7-O-alpha-d ribosyl-2,3-dihydro-5-hydroxy-2-methyl-chromen-4-one (5), daldinium A (6). These compounds were evaluated for their antimicrobial activity, anti acetylcholinesterase, nitric oxide inhibition, anticoagulant, photodynamic antimicrobial activities and glucose uptake of adipocytes. Some compounds showed photoactive antimicrobial activities and glucose uptake stimulating activities. PMID- 29272955 TI - Laribacter hongkongensis: clinical presentation, epidemiology and treatment. A review of the literature and report of the first case in Denmark. AB - BACKGROUND: Laribacter hongkongensis is an emerging pathogen related to gastroenteritis that can cause invasive and even fatal disease. The aim of this review is to describe the clinical presentation, epidemiology, treatment options and implications for the clinical microbiology laboratory. METHODS: We searched Pubmed using the term Laribacter hongkongensis with limitations human and language English, and identified 35 publications with eight reports on human cases. RESULTS: We describe our first case of prolonged, travel-related gastroenteritis where Laribacter hongkongensis was isolated as the sole pathogen. Our review suggests that L. hongkongensis causes non-bloody acute diarrhoea with potential for invasive disease, since three cases of bacteraemia and one case of dialysis related peritonitis have been described previously. L. hongkongensis has primarily been described in Asia, but reports from Europe, North America and Australia suggests a worldwide distribution. Broad culturing with subsequent identification by the MALDI-TOF is the current strategy for detection of L. hongkongensis. Phenotypic susceptibility testing is necessary to guide the treatment choice. Few resistance genes have been described in L. hongkongensis. CONCLUSION: L. hongkongensis should be considered a potential cause of acute and prolonged diarrhoea. Clinicians must be aware of the test methods in the local clinical microbiology laboratory, since L. hongkongensis is difficult to detect and easily overlooked. PMID- 29272957 TI - Monanchoxymycalin C with anticancer properties, new analogue of crambescidin 800 from the marine sponge Monanchora pulchra. AB - A new pentacyclic guanidine alkaloid, monanchoxymycalin C (1) was isolated from a new collection of marine sponge Monanchora pulchra along with the known monanchoxymycalin A (2). The structure of 1 was elucidated on the basis of spectroscopic data. Monanchoxymycalin C exhibits cytotoxic activity against human cancer HeLa cells at low micromolar concentrations, induces apoptosis-related death of malignant cells and inhibits cancer cell colony formation. In addition, synergistic and additive effects have been observed in combination with cisplatin. PMID- 29272959 TI - Deep Snow Immersion Deaths. AB - In brief Three snowboarders died in separate but nearly identical accidents after becoming buried head down in deep snow. After extricating each patient, the ski patrol immediately began cardiopulmonary resuscitation. On arrival at the emergency department, each patient was asystolic, apneic, cold, and stiff. Vigorous resuscitation and active rewarming were not successful in reviving the patients. These deaths indicate a need for education about the hazards of deep powder, tree wells, and snowboarding outside groomed areas. Equipment changes might also contribute to the sport's safety. PMID- 29272958 TI - Reduced neural baroreflex sensitivity is related to enhanced endothelial function in patients with end-stage liver disease. AB - OBJECTIVES: Reduced baroreflex sensitivity (BRS) is a frequent complication in end-stage liver disease, but the underlying mechanism is unknown. We investigated the mechanical and neural components of BRS. Increased nitric oxide (NO) production has been reported in end-stage liver failure. Based on earlier experiments, we hypothesised that enhanced endothelial function might affect baroreflex function. Therefore, we explored the relation between endothelial function and the components of BRS. MATERIALS AND METHODS: We enrolled 24 patients and 23 controls. BRS was determined by the spontaneous sequence method. Mechanical component was characterised by the distensibility coefficient (DC) of common carotid artery. Neural component was estimated as the ratio of integrated BRS and DC. Endothelial function was quantified by flow-mediated dilation (FMD) of the brachial artery. RESULTS: Integrated BRS was reduced in patients [7.00 (5.80-9.25) vs. 11.1 (8.50-14.80) ms/mmHg]. The mechanical component was not different in the two groups, whereas neural component showed significant reduction in patients (3.54 +/- 1.20 vs. 4.48 +/- 1.43 ms/10-3). FMD was higher in patients (9.81 +/- 3.77 vs. 5.59 +/- 1.36%). FMD and neural BRS were directly related in controls (r = 0.62), but inversely related in patients (r = -0.49). CONCLUSIONS: Baroreflex impairment in end-stage liver disease might be explained by deterioration of the neural component, while the mechanical component appears to be preserved. Endothelial NO may enhance BRS in health; however, central endothelial overproduction of NO likely contributes to the reduction of neural component of BRS in patients awaiting liver transplantation. PMID- 29272960 TI - Top 15 Tips to Do the Slope Safe. PMID- 29272961 TI - Superficial Heat and Cold. AB - In brief The wide array of superficial heat and cold modalities offers physicians many options for treating sports-related injuries. Appropriate application of heat and cold therapies can reduce the impact of an injury by relieving pain, reducing swelling, and encouraging rehabilitation. PMID- 29272962 TI - QuikQuiz. PMID- 29272965 TI - Mall Walking. PMID- 29272964 TI - A Skin-Deep Diagnosis. PMID- 29272966 TI - Do the Slopes Safely. PMID- 29272967 TI - Pearls. PMID- 29272968 TI - Spondylolisthesis in the Young Athlete. AB - In brief Young athletes with persistent unexplained low-back pain or tight hamstrings should be evaluated for possible spondylolisthesis. Although the physical examination is often unrevealing, hamstring tightness is a common finding in symptomatic patients. Anteroposterior, lateral, and possibly right and left oblique x-rays of the lumbosacral spine will suggest the diagnosis. The degree of vertebral slippage and the presence or absence of symptoms will determine whether conservative therapy or operative intervention is appropriate. PMID- 29272969 TI - Going With the Grain. PMID- 29272970 TI - Forum. PMID- 29272971 TI - Examining the beneficial effect of neuropsychological assessment on adult patient outcomes: a systematic review. AB - OBJECTIVE: Neuropsychological assessment (NPA) addresses important aspects of diagnosis, prognosis, treatment, and rehabilitation planning. This review set out to determine the impact of NPA on the adult patient's outcome, by examining how and whether NPA influences diagnostic decision-making and surgical planning, how NPA can be used to predict patient outcome, and how clients, referrers, and significant others perceive the value of NPA. METHOD: Eligible studies were selected according to pre-defined selection criteria and accessed via the electronic databases Medline and PsycInfo. RESULTS: Eighty-one studies were included, with 14 examining the influence of NPA on diagnosis, 62 in predicting outcomes, and 5 addressing the perceptions of NPA by users. The evidence was generally supportive of the value of NPA for its ability to increase the accuracy of diagnoses, to assist with decisions regarding surgical planning, to predict patient outcomes, and in its clinical benefit as reported by physicians and patients. CONCLUSION: The review demonstrated the benefit of NPA in assisting with diagnosis and prognosis, and showed positive findings with regard to consumer perceptions of NPA. The neuropsychological literature would materially benefit from high-quality randomized control trials of NPA to definitively demonstrate the efficacy of this measure in clinical management. PMID- 29272972 TI - Defining the functional gastrointestinal disorders is challenging: are clinical symptoms alone sufficient? PMID- 29272973 TI - Correction to: NPDS report 2016. PMID- 29272974 TI - Home oxygen therapy: re-thinking the role of devices. AB - INTRODUCTION: A range of devices are available for delivering and monitoring home oxygen therapy (HOT). Guidelines do not give indications for the choice of the delivery device but recommend the use of an ambulatory system in subjects on HOT whilst walking. Areas covered: We provide a clinical overview of HOT and review traditional and newer delivery and monitoring devices for HOT. Despite relevant technology advancements, clinicians, faced with many challenges when they prescribe oxygen therapy, often remain familiar to traditional devices and continuous flow delivery of oxygen. Some self-filling delivery-less devices could increase the users' level of independence with ecological advantage and, perhaps, reduced cost. Some newer portable oxygen concentrators are being available, but more work is needed to understand their performances in different diseases and clinical settings. Pulse oximetry has gained large diffusion worldwide and some models permit long-term monitoring. Some closed-loop portable monitoring devices are also able to adjust oxygen flow automatically in accordance with the different needs of everyday life. This might help to improve adherence and the practice of proper oxygen titration that has often been omitted because difficult to perform and time-consuming. Expert commentary: The prescribing physicians should know the characteristics of newer devices and use technological advancements to improve the practice of HOT. PMID- 29272975 TI - Purification and identification of 4-allylbenzene-1,2-diol: an antilisterial and biofilm preventing compound from the leaves of Piper betle L. var Pachaikodi. AB - Antibiotic-resistant food-borne Listeriosis has been rising with up to 30% mortality threat in humans since several decades. Hence, discovering antilisterial from the extracts of ethnomedicinal plants may be of value as a novel antidote. In our preceding study, we reported that ethanolic extract of Piper betle L. var Pachaikodi leaves exhibited antibacterial activity towards Listeria monocytogenes MTCC 657. Consequently in the present study, the bioactive molecule responsible for anti-Listeria activity was purified and identified as 4 allylbenzene-1,2-diol. This identified bioactive compound may have significance while used as antimicrobials and/or food additives in food processing sector as evidenced by dual action: biofilm inhibition and pore formation on cell membrane. PMID- 29272976 TI - Recent advancements in nanoparticle based drug delivery for gastrointestinal disorders. AB - INTRODUCTION: The emergent field of nanoparticles has presented a wealth of opportunities for improving the treatment of human diseases. Recent advances have allowed for promising developments in drug delivery, diagnostics, and therapeutics. Modified delivery systems allow improved drug delivery over traditional pH, microbe, or receptor dependent models, while antibody association allows for more advanced imaging modalities. Nanoparticles have potential clinical application in the field of gastroenterology as they offer several advantages compared to the conventional treatment systems including target drug delivery, enhanced treatment efficacy, and reduced side effects. Areas covered: The aim of this review article is to summarize the recent advancements in developing nanoparticle technologies to treat gastrointestinal diseases. We have covered the application of nanoparticles in various gastrointestinal disorders including inflammatory bowel disease and colorectal cancer. We also have discussed how the gut microbiota affects the nanoparticle based drug delivery in the gastrointestinal tract. Expert opinion: Nanoparticles based drug delivery offers a great platform for targeted drug delivery for gastrointestinal disorders. However, it is influenced by the presence of microbiota, drug interaction with nanoparticles, and cytotoxicity of nanoparticles. With the advancements in nanoparticle technology, it may be possible to overcome these barriers leading to efficient drug delivery for gastrointestinal disorders based on nanoparticle platform. PMID- 29272977 TI - Association between serum levels of testosterone and biomarkers of subclinical atherosclerosis. AB - OBJECTIVE: To investigate the association between serum levels of testosterone and biomarkers of subclinical atherosclerosis based on data from 119 middle-aged men of the general population. METHODS: Testosterone, Apolipoprotein A-1 (ApoA 1), Apolipoprotein B (ApoB), Apolipoprotein B-to-Apolipoprotein A-1 ratio (ApoB to-ApoA-1), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were measured. Data were also gathered based on age, BMI, waist circumference, smoking, alcohol consumption, and family history of cardiovascular diseases. Men were classified into two groups based on testosterone levels: hypogonadal (testosterone <=12 nmol/L) and eugonadal men (testosterone >12 nmol/L). RESULTS: When compared to eugonadal, the hypogonadal men were significantly older (56 years vs. 55 years, p = .03), had greater BMI (28 kg/cm2 vs. 26 kg/cm2, p = .01), and higher waist circumference (104 cm vs. 100 cm, p = .01). Moreover, ApoB, ApoB to-ApoA-1 ratio, and hsCRP were significantly higher in hypogonadal men compared to eugonadal men (1.1 g/L vs. 1.0 g/L, p = .03), (0.8 vs. 0.7, p = .03), (3.3 mg/L vs. 2.0 mg/L, p = .01), respectively. On the other hand, ApoA-1 and fibrinogen levels did not differ significantly between groups (p > .05). In an adjusted multivariate regression analysis model, only ApoB showed a significant negative association with testosterone levels (beta = -0.01; 95% CI = -0.02, 1.50; p = .04). CONCLUSION: Testosterone levels showed an inverse relation to ApoB, a biomarker implicated in subclinical atherosclerosis. These findings support the hypothesis that low testosterone levels play a role in atherosclerosis. PMID- 29272978 TI - Critical care toxicology. Diagnosis and management of the critically poisoned patient, 2nd ed. PMID- 29272979 TI - Serum level of interleukin-6 (IL-6) and N-terminal propeptide of procollagen type I (PINP) in patients with liver diseases. AB - INTRODUCTION: The aim of this study was to evaluate the concentration of interleukin-6 and N-terminal propeptide of procollagen type I and their relationship in liver diseases of different etiologies. MATERIAL AND METHODS: Serum samples were obtained from 30 healthy volunteers and patients suffering from alcoholic cirrhosis (AC) - 31, non-alcoholic cirrhosis (NAC) - 28 and toxic hepatitis (HT) - 23 patients. Cirrhotic patients were classified according to Child-Pugh score. IL-6 and PINP concentrations were determined according to the electrochemiluminescence immunoassay. RESULTS: The mean serum IL-6 concentration was significantly higher in AC (mean +/- SD:21.52 +/- 15.01 pg/mL), NAC (20.07 +/ 32.12 pg/mL) and HT (15.14 +/- 17.18 pg/mL) when compared to the control group (C) (1.67 +/- 0.42 pg/mL) (Mann-Whitney U test: p < .001 for all comparisons). The mean serum PINP concentration was significantly higher only in patients with AC (104.32 +/- 54.50 ng/mL) in comparison with the control group (54.70 +/- 19.83 ng/mL; p < .001). The mean values of IL-6 and PINP significantly differed between liver diseases (ANOVA rank Kruskal-Wallis test: p = .020 and p < .001, respectively). Accordingly, the serum levels of IL-6 and PINP were significantly higher in patients with AC than that in NAC (p < .001 and p = .022, respectively). IL-6 and PINP concentrations appeared to vary depending on the severity of liver damage (p < .001 for both). The concentrations of IL-6 and PINP were significantly higher in class C (31.88 +/- 21.51 pg/mL; 132.73 +/- 65.63 ng/mL, respectively) than that in class A (6.12 +/- 9.00 pg/mL; 57.32 +/- 28.85 ng/mL, respectively) (p < .001 for both). There were also significant differences in IL-6 concentrations between Child-Pugh class B (27.88 +/- 24.45 pg/mL) and class A (6.12 +/- 9.00 pg/mL; p < .001). CONCLUSIONS: We conclude that serum concentrations of IL-6 and PINP change in liver diseases, and those changes reflect the severity of liver disease. PMID- 29272980 TI - An isoindole alkaloid from Portulaca oleracea L. AB - A novel isoindole alkaloid named oleraisoindole (1), together with six known compounds, 7'-ethoxy-trans-feruloyltyramine (2), N-trans-feruloyltyramine (3), N trans-feruloyl-3-methoxytyramine (4), N-trans-p-coumaroyltyramine (5) aurantiamide (6) and ferulic acid methyl ester (7) were isolated from Portulaca oleracea L. Compounds 2 and 7 were isolated for the first time from this plant. Compound 1 was identified using spectroscopic methods including HR-ESI-TOF-MS, 1D NMR, 2D-NMR. It was tested in a nitric oxide (NO) inhibition assay and was shown to inhibit NO production in RAW 264.7 cells induced by LPS. PMID- 29272981 TI - Occupational therapy students' views on addressing sexual health. AB - BACKGROUND: Sexual health is an important issue in daily life, but little is known about occupational therapy (OT) students' views on these matters. AIM: To explore occupational therapy students' views on addressing sexual health in their future professional role. MATERIAL AND METHODS: A descriptive qualitative study involving 37 OT students in 5 focus groups was performed and analyzed using content analysis. RESULTS: Three categories: 'Sexual health is part of occupational therapy and but not of the OT educational program'; 'Need for knowledge to identify and intervene related to sexual health problems'; and finally, 'Communication about sexual health-unknown, untried, but necessary', formed the theme, 'Willing to try, wanting to know more, and recognizing not only the difficulties and challenges but also the importance of sexual health in OT practice'. CONCLUSIONS: OT-students consider sexual health as part of OT practice, but experience lack of knowledge of sexual health related to disease/disability, cultural diversity, and age and sexual orientation. Educational programs need to cover these matters, including how to address sexual health in OT-practice, to enhance OT's future competence related to promotion of sexual health for clients. SIGNIFICANCE: Knowledge on students' views are vital to guide education on this important, rather neglected, area. PMID- 29272983 TI - Sub-inhibitory concentration of essential oils induces antibiotic resistance in Staphylococcus aureus. AB - Fourteen Staphylococcus aureus wild strains were stressed with sub-inhibitory concentration of five essential oils: Leptospermum scoparium (manuka), Origanum majorana (marjoram), Origanum vulgare (oregano), Satureja montana (winter savoury) and Thymus vulgaris (thyme). Antibiotics susceptibility profiles of the strains were determined by agar disk diffusion method before and after EOs treatment. The following antibiotics were employed: amoxicillin-clavulanic acid, amikacin, ampicillin, amoxicillin, aztreonam, ceftazidime, cephalothin, ciprofloxacin, colistin, cefotaxime, doxycycline, enrofloxacin, erythromycin, gentamicin, cephalexin, neomycin, piperacillin, rifampin, streptomycin, trimethoprim-sulphamethoxazole, tetracycline and tobramycin. Before EOs treatment, strains were susceptible to all antibiotics except for aztreonam and colistin. After exposure to sub-inhibitory EOs concentration of manuka, marjoram and oregano, several modifications in antibiotics susceptibility profiles were detected. Conversely, few modifications were induced by winter savoury and thyme EOs. Moreover, occurrence of resistances seems uncorrelated with drug classes as low concentration of EO could induce phenotypic changes in susceptible bacteria leading to antibiotic resistance phenomena. PMID- 29272982 TI - The significance of serum IgG4 and CA19-9, autoantibodies in diagnosis and differential diagnosis of IgG4-related sclerosing cholangitis. AB - OBJECTIVE: To investigate the value of serum levels of IgG4 and CA19-9, and autoantibodies in the diagnosis of IgG4-related sclerosing cholangitis (IgG4-SC). METHODS: We detected the serum IgG4 and CA19-9 of 45 IgG4-SC patients, 173 non IgG4-SC patients and 48 healthy controls by immunoassay and chemiluminescence, respectively, with antinuclear antibody (ANA), anti-neutrophil antibody (ANCA), anti-smooth muscle antibody (SMA) and anti-mitochondrial antibody (AMA) level detected by indirect immunofluorescence. Then analyze the detection results. RESULTS: (1) The positive rates of ANA, ANCA, SMA and AMA in patients with IgG4 SC were 40%, 6.67%, 0 and 2.22%. Among them, the positive rate of ANA was significantly higher than that of the healthy control group (p < .01), and the positive rate of ANA, ANCA, SMA and AMA were significantly different from that of the non-IgG4-SC group (p < .05). (2) Serum levels of IgG4 and CA19-9 increased significantly in patients with IgG4-SC compared with the healthy controls (p < .01). The areas under the ROC curve (AUC) of IgG4 and CA19-9 were 0.9750 and 0.6498, respectively (p < .05). CONCLUSION: The high levels of serum IgG4 and CA19-9, and autoantibodies detections are of great important clinical value in diagnosis and differential diagnosis of IgG4-SC. PMID- 29272984 TI - Low 25-hydroxyvitamin D levels in postmenopausal female patients with benign paroxysmal positional vertigo. AB - OBJECTIVE: Several studies have reported the association of benign paroxysmal positional vertigo (BPPV) with vitamin D deficiency. This study aimed to evaluate serum 25-hydroxy vitamin D (25 (OH) D) levels in native Chinese postmenopausal women with de novo idiopathic BPPV and to investigate the possible relationship between the occurrence of BPPV and low 25 (OH) D levels. METHODS: This retrospective study comprised of 85 postmenopausal women with de novo idiopathic BPPV and 80 age-matched healthy controls. All subjects had bone mineral density (BMD) and serum 25 (OH) D levels measurements recorded, and the results were compared. RESULTS: The prevalence of reduced BMD (T score <-1.0) was significantly higher in female patients with BPPV than in healthy controls (71.8% vs. 51.2%, p = .004). The mean serum 25 (OH) D levels were also significantly lower in female patients with BPPV than in healthy controls (19.1 +/- 5.2 vs. 22.5 +/- 5.8, p < .001). The regression analyses demonstrated that vitamin D deficiency was associated with BPPV with an odds ratio of 2.1 (95% confidence interval = 1.1-3.1, p = .031). CONCLUSION: Our study suggests that low 25 (OH) D may be a risk factor for BPPV in postmenopausal women. PMID- 29272985 TI - The expression of thymic stromal lymphopoietin in patients and animal models with eosinophilic otitis media. AB - OBJECTIVE: In the present study, we aimed to clarify the expression of thymic stromal lymphopoietin (TSLP), a key trigger of Th2-type allergic disease, in the middle ear mucosa of eosinophilic otitis media (EOM). METHODS: An immunohistological study of TSLP was conducted in patients with EOM and in animal models of EOM constructed by intraperitoneal and intratympanic injection of ovalbumin for 7 and 14 days. In addition, the messenger RNA (mRNA) expression of TSLP in the middle ear mucosa of the animal models was analyzed using real-time PCR, and was compared with that of the control animals. RESULTS: Immunoreactivities for TSLP were observed in the middle ear mucosa around the tympanic ostium of the eustachian tube of patients with EOM. In the animal model, strong immunoreactivity for TSLP was also observed in the eustachian tube epithelium, and mRNA expression of TSLP in the seven-day stimulated animals was significantly higher than that in the controls. CONCLUSION: The present study indicates that the presence of epithelium-derived TSLP in the eustachian tubes plays an important role in the onset of EOM. PMID- 29272986 TI - Genetic divergence of isolated populations of the native micromoth Bucculatrix mirnae (Lepidoptera: Bucculatricidae) in the arid environments of Northern Chile. AB - Analysis of maternally inherited genes is especially helpful in population studies of host-specialized insects, as female dispersal is key to find an adequate host plant to ensure larval survival. Bucculatrix mirnae (Lepidoptera: Bucculatricidae) is a little-known Neotropical micromoth native to the arid environments of northern Chile whose hypermetamorphic larvae are miners and skeletonizers on leaves of two species of Baccharis (Asteraceae) shrubs. This micromoth has been detected in three isolated locations embracing a narrow geographic range: two from the coastal valleys of the Atacama Desert near sea level and one from the western slopes of the Andes at about 3000 m elevation. As the dispersal of B. mirnae is mostly restricted to the small adult stage, the altitudinal gradient and desert areas among the three localities could be effective barriers, triggering genetic differentiation among populations. Sequences of the DNA barcode fragment of the cytocrome oxidase subunit I mitochondrial gene were analyzed to assess for the first time the patterns of genetic variation of B. mirnae. Fifteen haplotypes, each exclusive to one locality, were found in the 71 specimens analyzed. Genetic divergence (K2P) between haplotypes of different localities was at least 2.0%. A Bayesian analysis with sequences of congeneric species grouped all the B. mirnae haplotypes in a clade, in which three well-supported locality-specific haplogroups were found. In concordance with this pattern, an analysis of molecular variance showed that the highest genetic variation was found among populations. Furthermore, all the population pairwise comparisons (FST) were significant. These results suggest that female migration between isolated populations of B. mirnae is absent. This pattern must be considered in the current scenario of habitat destruction and modification in the arid environments of northern Chile. PMID- 29272987 TI - The practicalities of establishing a porcine isolated heart model. AB - BACKGROUND: The isolated heart apparatus is over 100 years old, but remains a useful research tool today. While designs of many large animal systems have been described in the literature, trouble-shooting and refining such a model to yield a stable, workable system has not been previously described. This paper outlines the issues, in tabular form, that our group encountered in developing our own porcine isolated heart rig with the aim of assisting other workers in the field planning similar work. The paper also highlights some of the modern applications of the isolated heart apparatus. Methods Landrace pigs (50-80 kg) were used in a pilot project to develop the model. The model was then used in a study examining the effects of various cardioplegic solutions on function after reanimation of porcine hearts. During the two projects, non-protocol issues were documented as well as their solutions. These were aggregated in this paper. RESULTS: Issues faced by the group without explicit literature solutions included pig size selection, animal acclimatisation, porcine transoesophageal echocardiography, cannulation and phlebotomy for cross-clamping, cardioplegia delivery, heart suspension and rig tuning. CONCLUSION: Prior recognition of issues and possible solutions faced by workers establishing a porcine isolated heart system will speed progress towards a useable system for research. The isolated heart apparatus remains applicable in transplant, ischaemia reperfusion, heart failure and organ preservation research. PMID- 29272988 TI - The influence of the subarcuate artery in the superior semicircular canal dehiscence and its frequency on stillbirths: illustrative cases and systematic review. AB - : Literature describes that on the 25th gestational week the labyrinth is fully formed and with adult size. However, recent studies have shown that the cranial and labyrinth development continues until 3 years of age. OBJECTIVES: To demonstrate through tomographic study the frequency of semicircular canal dehiscence on nine specimens of stillbirths between 32 and 40 weeks and, through literature review, present another possible etiology for its cause. METHODS: Tomographic study of the temporal bone of 9 specimens of stillbirths between 32 and 40 weeks. RESULTS: A frequency of 88.89% of alterations were found in our study, with 44% presenting bilateral alterations and 44% unilateral alteration; 11.11% had no dehiscence. CONCLUSION: The tomographic study showed superior semicircular canal dehiscence (SSCD) in 88% of the specimens studied, protrusion of the superior semicircular canal (SSC) in all fetuses, and an enlarged SSC that may be caused by the expansion process provoked by the subarcuate artery entering the subarcuate canaliculus, leading to SSCD. PMID- 29272989 TI - Seeking health under palm trees: Ayurveda in Kerala. AB - Movement for healthcare, mostly termed 'medical tourism', has been a sector of enormous potential in South Asia over the past years attracting many international clients. Kerala, a state in southern India, advertises 'Kerala Ayurveda' as one of its particular attractions. The objective of this paper is to study and understand the public health view on movements for healthcare and/or wellness across borders with a particular focus on the quality of treatments offered and on issues of ethics that concern patients from across different countries, but also the providers of Ayurveda treatments. To gain insights into local perspectives, interviews were conducted with Ayurveda practitioners at Ayurveda resorts in Kerala, in particular in Kovalam and Varkala, both in Thiruvananthapuram district. The analysis of our interviews shows that - perhaps not surprisingly in a world characterised by global capitalism - marketing plays an important role in attracting clients to resorts. Market considerations led to a transformation of how Ayurveda is presented to potential customers. This in turn has undermined the significance of Ayurveda within the tourism industry of Kerala. Arguably, representatives of the state view this as an opportunity rather than considering the importance of further developing Ayurveda as a medical practice. PMID- 29272990 TI - Coronary sinus signal amplitude predicts left atrial scarring. AB - BACKGROUND: Left atrial scarring is recognised as a critical component in the maintenance of atrial fibrillation and is associated with the failure of interventional treatment. Diminished bipolar voltage (LV) has been proposed as a useful tool for left atrial scar quantification. We hypothesised that, due to its anatomic location, signals on the coronary sinus catheter might be used to predict the amount of left atrial low voltage. METHODS AND RESULTS: A total of 124 patients (42% women, average age 66 +/- 9 years) were included. Forty-one with paroxysmal and 83 with persistent atrial fibrillation. Left atrial low voltage (<0.5 mV, measured during sinus rhythm) area size and distribution varied considerably among the included patients (mean: 34.9%; maximum: 94.6%; minimum: 0.4%). Spearman correlation revealed a strong negative correlation between bipolar voltage of the signals on the coronary sinus catheter and the amount of left atrial scarring (R = -0.778, p < .0001). The optimal CS voltage cut off for prediction of left atrial low-voltage size of >=50% was 1.9 mV with an area-under the receiver-operating-characteristic (ROC) curve of 0.982, a sensitivity of 97% and a specificity of 98%. CONCLUSIONS: There is a strong negative correlation between the size of left atrial low-voltage areas (LVA) and coronary sinus signal amplitude. With increasing left atrial LVA size, CS signal amplitudes decrease, and vice versa. On the basis of these findings, average CS signal amplitudes of <=1.9 mV can be used as a predictor for a left atrial low-voltage size of >=50%. PMID- 29272991 TI - Bone Regeneration of Osteoporotic Vertebral Body Defects Using Platelet-Rich Plasma and Gelatin beta-Tricalcium Phosphate Sponges. AB - The objective of the present study was to investigate the effect of platelet-rich plasma (PRP) combined with gelatin beta-tricalcium phosphate (beta-TCP) sponge on bone generation in a lumbar vertebral body defect of ovariectomized rat. After creating critical-size defects in the center of the anterior vertebral body, the defects were filled with the following materials: (1) no material (control group), (2) gelatin beta-TCP sponge with PRP (PRP sponge group), and (3) gelatin beta-TCP sponge with phosphate-buffered saline (PBS sponge group). Microcomputed tomography and histological evaluation were performed immediately after surgery and at 4, 8, and 12 weeks to assess bone regeneration. Biomechanical test was also performed at postoperative week 12. In the PRP sponge group, both imaging and histological examination showed that visible osteogenesis was first induced and additional growth of bone tissue was observed in the transplanted sponge, compared with the PBS sponge group. There was no negative effect of either PRP sponge or PBS sponge transplantation on bone tissue generation around the periphery of the defect. Biomechanical test showed increased stiffness of the affected vertebral bodies in the PRP sponge group. These results indicate that PRP-impregnated gelatin beta-TCP sponge is effective for facilitating bone regeneration in lumbar vertebral bone defect under osteoporotic condition. PRP combined with gelatin beta-TCP sponges could be potentially useful for developing a new approach to vertebroplasty for osteoporotic vertebral fracture. PMID- 29272993 TI - Effect of maturation time on dormancy and germination of Citrullus colocynthis (Cucurbitaceae) seeds from the Arabian hyper-arid deserts. AB - BACKGROUND: Light and temperatures of germination greatly affect germination of several Cucurbitaceae species. Environmental conditions prevailing at seed maturation time can affect dormancy and germination requirements. Citrullus colocynthis seeds have a deep dormancy. This perennial prostrate shrub grows all over the year in the arid Arabian deserts. We explored if seed dormancy and germination requirements of C. colocynthis depend on time of fruit collection. Matured seeds were collected at five different times during 2014/2015 year from a population around Dubai city. Fresh seeds were germinated at three temperature regimes in both continuous darkness and alternating 12 h light/12 h darkness. Impacts of seed storage and other treatments on germination were applied on seeds collected in March and exhibited deep dormancy. RESULTS: March collected seeds almost did not germinate in both light and dark at the three temperatures, but those of the other collections responded differently to both light and temperatures. At the lowest temperatures, seeds of all collections did not germinate in light, but those of June, October and December collections germinated in dark. There were negative correlations between final germination and seed length, width, mass and coat thickness. Physical scarification, water soaking and seed storage did not break dormancy of March collection. CONCLUSIONS: Germination of C. colocynthis is very sensitive to light and incubation temperature as well as to the environmental conditions associated with the time of seed maturation. It is important to investigate the effects of environmental factors prevailing during seed maturation under controlled conditions to understand exact reasons for unusual seed dormancy and germination requirements of C. colocynthis, which seems to be very sensitive to maternal environment. PMID- 29272994 TI - What's the uptake? Pragmatic RCTs may be used to estimate uptake, and thereby population impact of interventions, but better reporting of trial recruitment processes is needed. AB - BACKGROUND: Effectiveness of interventions in pragmatic trials may not translate directly into population impact, because of limited uptake by clinicians and/or the public. Uptake of an intervention is influenced by a number of factors. METHODS: We propose a method for calculating population impact of clinical interventions that accounts for the intervention uptake. We suggest that population impact may be estimated by multiplying the two key components: (1) the effectiveness of the intervention in pragmatic trials (trial effect); and, (2) its uptake in clinical practice. We argue that participation rates in trials may be a valid proxy for uptake in clinical practice and, in combination with trial effectiveness estimates, be used to rank interventions by their likely population impact. We illustrate the method using the example of four interventions to decrease antibiotic prescription for acute respiratory infections in primary care: delayed prescribing, procalcitonin test, C-Reactive Protein, shared decision making. RESULTS: In order to estimate uptake of interventions from trial data we need detailed reporting on the recruitment processes used for clinician participation in the trials. In the antibiotic prescribing example, between 75 and 91% of the population would still be prescribed or consume antibiotics because effective interventions were not taken up. Of the four interventions considered, we found that delayed prescribing would have the highest population impact and shared decision making the lowest. CONCLUSION: Estimates of uptake and population impact of an intervention may be possible from pragmatic RCTs, provided the recruitment processes for these trials are adequately reported (which currently few of them are). Further validation of this method using empirical data on intervention uptake in the real world would support use of this method to decide on public funding of interventions. PMID- 29272992 TI - From Otic Induction to Hair Cell Production: Pax2EGFP Cell Line Illuminates Key Stages of Development in Mouse Inner Ear Organoid Model. AB - Producing hair cells of the inner ear is the major goal of ongoing research that combines advances in developmental and stem cell biology. The recent advent of an inner ear organoid protocol-resulting in three-dimensional stem cell-derived tissues resembling vestibular sensory epithelia-has sparked interest in applications such as regeneration, drug discovery, and disease modeling. In this study, we adapted this protocol for a novel mouse embryonic stem cell line with a fluorescent reporter for Pax2 expression. We used Pax2EGFP/+ organoid formation to model otic induction, the pivotal developmental event when preplacodal tissue adopts otic fate. We found upregulation of Pax2 and activation of ERK downstream of fibroblast growth factor signaling in organoid formation as in embryonic inner ear development. Pax2 expression was evident from the EGFP reporter beginning at the vesicle formation stage and persisting through generation of the sensory epithelium. The native ventralizing signal sonic hedgehog was largely absent from the cell aggregates as otic vesicles began to form, confirming the dorsal vestibular organoid fate. Nonetheless, cochlear- or vestibular-like neurons appeared to delaminate from the derived otic vesicles and formed synaptic contacts with hair cells in the organoids. Cell lines with transcriptional reporters such as Pax2EGFP/+ facilitate direct evaluation of morphological changes during organoid production, a major asset when establishing and validating the culture protocol. PMID- 29272995 TI - Primary care challenges of an obscure case of "Alice in Wonderland" syndrome in a patient with severe malaria in a resource-constrained setting: a case report. AB - BACKGROUND: "Alice in Wonderland" syndrome (AIWS) is a rare neurological abnormality characterized by distortions of visual perceptions, body schema and experience of time. AIWS has been reported in patients with various infections such as infectious mononucleosis, H1N1 influenza, Cytomegalovirus encephalitis, and typhoid encephalopathy. However, AIWS occurring in a patient with severe malaria is less familiar and could pose serious primary care challenges in a low income context. CASE PRESENTATION: A 9-year-old male of black African ethnicity was brought by his parents to our primary care hospital because for 2 days he had been experiencing intermittent sudden perceptions of his parents' heads and objects around him either "shrinking" or "expanding". The visual perceptions were usually brief and resolved spontaneously. One week prior to the onset of the visual problem, he had developed an intermittent high grade fever that was associated with other severe constitutional symptoms. Based on the historical and clinical data that were acquired, severe malaria was suspected and this was confirmed by hyperparasitaemia on blood film analysis. The patient was treated with quinine for 10 days. Apart from a single episode of generalized tonic-clonic seizures that was observed on the first day of treatment, the overall clinical progress was good. The visual illusions completely resolved and no further abnormalities were recorded during 3 months of follow-up. CONCLUSION: Symptoms of AIWS usually resolve spontaneously or after treatment of an underlying cause. In our case, the successful treatment of severe malaria coincided with a complete regression of AIWS whose aetiology was poorly-elucidated given the resource constraints. In any case, the good outcome of our patient aligns with previous reports on acute AIWS that highlight a limited need for excessive investigation and treatment modalities which are, in passing, predominantly unaffordable in resource-limited primary care settings. PMID- 29272996 TI - Spontaneous first trimester miscarriage rates per woman among parous women with 1 or more pregnancies of 24 weeks or more. AB - BACKGROUND: The purpose of this study was to quantify spontaneous first trimester miscarriage rates per woman among parous women. A vast amount of data has accumulated regarding miscarriage rates per recognized pregnancy as well as about recurrent miscarriage. This is the second study of miscarriage rates per woman in a parous population and the first study of recurrent and non-recurrent, spontaneous first trimester miscarriage rates per woman in a large parous population. METHODS: Extraction of the following variables from all delivery room admissions from both Hadassah Medical Centers in Jerusalem Israel, 2004-2014: # of first trimester spontaneous miscarriages, # live births; # living children; age on admission, pre-pregnancy height and weight, any smoking this pregnancy, any alcohol or drug abuse this pregnancy, blood type, history of ectopic pregnancy, history of cesarean surgery (CS) and use of any fertility treatment(s). RESULTS: Among 53,479 different women admitted to labor and delivery ward, 43% of women reported having had 1 or more first trimester spontaneous miscarriages; 27% reported having had one, 10% two, 4% three, 1.3% four, 0.6% five and 0.05% reported having 6-16 spontaneous first trimester miscarriages. 18.5% had one or more first trimester miscarriages before their first live birth. Eighty-one percent of women with 11 or more living children experienced one or more first trimester miscarriages. First trimester miscarriage rates rose with increasing age, increasing parity, after previous ectopic pregnancy, after previous cesarean surgery, with any smoking during pregnancy and pre-pregnancy BMI >=30. CONCLUSIONS: Miscarriages are common among parous women; 43% of parous women report having experienced one or more first trimester spontaneous miscarriages, rising to 81% among women with 11 or more living children. One in every 17 parous women have three or more miscarriages. Depending on her health, nutrition and lifestyle choices, even a 39 year old parous woman with a history of 3 or more miscarriages has a good chance of carrying a future pregnancy to term but she should act expediently. PMID- 29272998 TI - Risk factors and outcome of patients with eclampsia at a tertiary hospital in Egypt. AB - BACKGROUND: Eclampsia is a major cause of maternal and neonatal morbidity and mortality in low and middle income countries. The aim of this study was to assess the risk factors and maternal and perinatal outcome in patients with eclampsia in order to get reliable data that helps in reducing the incidence and improving the outcome in an area with high incidence of eclampsia. METHODS: Retrospective study including 250 patients diagnosed with eclampsia at Minia Maternity University Hopsital, Minia, Egypt in the period between January 2013 and December 2014.We analyzed the data obtained from medical records of these patients including patient characteristics, medical, obstetric, current pregnancy history, data on hospital admission, treatment given at hospital and maternal and perinatal outcome. Statistical analysis was done using SPSS version 21. RESULTS: During the study period, 21690 women gave birth in the hospital; of which 250 cases of eclampsia were diagnosed (1.2%).Four women died (case fatality rate 1.6%). The main risk factors identified were young age, nulliparity, low level of education, poor ante-natal attendance and pre-existing medical problems. The most common complication was HELLP syndrome (15.6%). Magnesium sulphate therapy was given to all patients but there was lack of parenteral anti-hypertensive therapy. Forty six cases delivered vaginally (18.4%). Assisted delivery was performed in 22 (8.8%) cases and caesarean section in 177 (70.8%) cases; 151(60.4%) primary caesarean sections and 26 (10.4%) intra-partum. Perinatal deaths occurred in 11.9% on cases. Prematurity and poor neonatal services were the main cause. CONCLUSION: Morbidity and mortality from eclampsia are high in our setting. Improving ante-natal and emergency obstetric and neonatal care is mandatory to improve the outcome. PMID- 29272997 TI - Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat. AB - BACKGROUND: The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. Specifically, we aimed to identify genomic regions associated with Metabolic Syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems. RESULTS: We compared two Lyon rat strains, Lyon Hypertensive (LH) which is susceptible to MetS, and Lyon Low pressure (LL), which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (Lyon Normotensive, LN) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. Consideration of regulatory information effectively identified regions with liver associated genes and rat orthologues of human GWAS variants related to obesity and metabolic traits. We attempted to find possible causative variants and compared them with the candidate genes proposed by previous studies. In strain specific regions with conserved regulation, we found a significant enrichment for published evidence to obesity-one of the metabolic symptoms shown by the Lyon strains-amongst the genes assigned to promoters with strain-specific variation. CONCLUSIONS: Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems. PMID- 29272999 TI - Missed opportunities for improving practice performance in adult immunizations: a meta-narrative review of the literature. AB - BACKGROUND: We sought to characterize how the term "missed opportunities" is reported in the literature in the context of immunization rates and to assess how missed opportunities can be operationalized. METHODS: Peer-reviewed literature searches were conducted in April - May, 2015, to answer: "What methods research studies used to operationalize missed opportunities to vaccinate?" A meta narrative review methodology was used. RESULTS: Seven studies met inclusion criteria. The methodologies for quantifying missed opportunities fell into two general categories based on: 1. the number of healthcare encounters per patient without appropriate vaccination services, defined as a number of visits per patient with no vaccination related services (Missed opportunities per patient); 2. vaccination status as "non-vaccinated" among a group of patients who had a healthcare encounter where the vaccination should/could have had happened (Missed opportunities per population). CONCLUSIONS: Our study provided an initial overview of the methods reported in the literature, and concluded that the quantifiable missed opportunity holds promise as a measurable outcome (variable) for research and quality improvement projects aimed to increase adult immunization recommendation and uptake in primary care. PMID- 29273000 TI - Age-based partitioning of individual genomic inbreeding levels in Belgian Blue cattle. AB - BACKGROUND: Inbreeding coefficients can be estimated either from pedigree data or from genomic data, and with genomic data, they are either global or local (when the linkage map is used). Recently, we developed a new hidden Markov model (HMM) that estimates probabilities of homozygosity-by-descent (HBD) at each marker position and automatically partitions autozygosity in multiple age-related classes (based on the length of HBD segments). Our objectives were to: (1) characterize inbreeding with our model in an intensively selected population such as the Belgian Blue Beef (BBB) cattle breed; (2) compare the properties of the model at different marker densities; and (3) compare our model with other methods. RESULTS: When using 600 K single nucleotide polymorphisms (SNPs), the inbreeding coefficient (probability of sampling an HBD locus in an individual) was on average 0.303 (ranging from 0.258 to 0.375). HBD-classes associated to historical ancestors (with small segments <= 200 kb) accounted for 21.6% of the genome length (71.4% of the total length of the genome in HBD segments), whereas classes associated to more recent ancestors accounted for only 22.6% of the total length of the genome in HBD segments. However, these recent classes presented more individual variation than more ancient classes. Although inbreeding coefficients obtained with low SNP densities (7 and 32 K) were much lower (0.060 and 0.093), they were highly correlated with those obtained at higher density (r = 0.934 and 0.975, respectively), indicating that they captured most of the individual variation. At higher SNP density, smaller HBD segments are identified and, thus, more past generations can be explored. We observed very high correlations between our estimates and those based on homozygosity (r = 0.95) or on runs-of-homozygosity (r = 0.95). As expected, pedigree-based estimates were mainly correlated with recent HBD-classes (r = 0.56). CONCLUSIONS: Although we observed high levels of autozygosity associated with small HBD segments in BBB cattle, recent inbreeding accounted for most of the individual variation. Recent autozygosity can be captured efficiently with low-density SNP arrays and relatively simple models (e.g., two HBD classes). The HMM framework provides local HBD probabilities that are still useful at lower SNP densities. PMID- 29273001 TI - How general practitioners perceive and assess self-care in patients with multiple chronic conditions: a qualitative study. AB - BACKGROUND: It is not known how general practitioners (GPs) perceive the concept of self-care and how they assess self-care ability in patients with multiple chronic conditions. As a part of the strategy to improve the care of people living with chronic conditions, disease management programs in Denmark require GPs and other health care workers to assess and support patients' self-care ability. The aim of the present study was to explore GPs' perceptions and assessment of self-care ability in patients with multiple chronic conditions who have difficulty following a given treatment. METHODS: A qualitative study conducted through in-depth, semi-structured interviews with a purposive sample of 12 GPs in rural areas of Denmark with economically disadvantaged populations. The interviews involved 36 complex patient cases selected by the GPs themselves. Our analysis followed the principles of systematic text condensation. RESULTS: Most GPs in our study had a health-related perception of self-care, but some had a broader perception encompassing the situational context of the patient's life. The GPs' assessments of patients' self-care ability were based on information from the ongoing and often long-term relationships with the patients. GPs identified four major factors that influenced patients' self-care ability, which accumulated and fluctuated over time: multimorbidity, cognitive resources, material resources, and the patients' social contexts. CONCLUSIONS: The GPs in this study had dual perceptions of self-care, related to both the chronic health conditions and to the broader situational contexts of their patients' lives. GPs' assessments of self-care ability depended largely on their experiences from the doctor-patient relationship, and they emphasized that the factors affecting self care ability were highly dynamic over the patient's lifetime. However, these findings might be resisted by the Danish disease management programs, which tend to have a static and more narrow, health-related view of patient self-care. The Danish programs require GPs to assess self-care ability upfront at the beginning of treatment and do not consider whether a relationship with the patient is established. If GPs' perceptions and assessments of self-care ability are not included in chronic disease management models, there is a risk that they vill be insufficiently implemented in general practice. PMID- 29273002 TI - Mining and expression analysis of candidate genes involved in regulating the chilling requirement fulfillment of Paeonia lactiflora 'Hang Baishao'. AB - BACKGROUND: The artificial enlargement of the planting area and ecological amplitude of ornamentals for horticultural and landscape applications are significant. Herbaceous peony (Paeonia lactiflora Pall.) is a world-famous ornamental with attractive and fragrant flowers and is mainly planted in temperate and cool areas. Comparatively higher winter temperatures in the subtropical and tropical Northern Hemisphere result in a deficit of chilling accumulation for bud dormancy release, which severely hinders "The southward plantation of herbaceous peony". Studies on the dormancy, chilling requirement (CR) and relevant molecular mechanisms of peony are needed to enhance our ability to extend the range of this valuable horticultural species. RESULTS: Based on natural and artificial chilling experiments, and chilling hour (CH) and chilling unit (CU) evaluation systems, the lowest CR of 'Hang Baishao' was between 504.00 and 672.00 CHs and the optimal CR was 672.00 CHs and 856.08 CUs for achieving strong sprouting, growth and flowering performance. Transcriptome sequencing and gene identification by RNA-Seq were performed on 'Hang Baishao' buds during the dormancy and sprouting periods. Six gene libraries were constructed, and 66 temperature- and photoperiod-associated unigenes were identified as the potential candidate genes that may regulate or possibly determine CR characteristics. The difference in the expression patterns of SUPPRESSPOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) between the winters of 2012-2013 and 2015-2016, and the difference of CR fulfillment periods also between these two winters represented the interesting congruent relationships. This correlation was also observed for WRKY DNA-BINDING PROTEIN 33 (WRKY 33). CONCLUSIONS: Combined with the results acquired from all of experiments, 'Hang Baishao' was confirmed to be a superb peony resource that have significantly low CR characteristics. The two genes of SOC1 and WRKY33 are likely involved in determining the CR amount and fulfillment period of 'Hang Baishao'. HEAT SHOCK PROTEIN, OSMOTIN and TIMING OF CAB EXPRESSION 1 also deserve attention for the CR research. This study could contribute to the knowledge of the deep factors and mechanisms that regulate CR characteristics, and may be beneficial for breeding new germplasms that have low CRs for landscape or horticulture applications in subtropical regions. PMID- 29273003 TI - An integrated and comparative approach towards identification, characterization and functional annotation of candidate genes for drought tolerance in sorghum (Sorghum bicolor (L.) Moench). AB - BACKGROUND: Drought is the most disastrous abiotic stress that severely affects agricultural productivity worldwide. Understanding the biological basis of drought-regulated traits, requires identification and an in-depth characterization of genetic determinants using model organisms and high throughput technologies. However, studies on drought tolerance have generally been limited to traditional candidate gene approach that targets only a single gene in a pathway that is related to a trait. In this study, we used sorghum, one of the model crops that is well adapted to arid regions, to mine genes and define determinants for drought tolerance using drought expression libraries and RNA-seq data. RESULTS: We provide an integrated and comparative in silico candidate gene identification, characterization and annotation approach, with an emphasis on genes playing a prominent role in conferring drought tolerance in sorghum. A total of 470 non-redundant functionally annotated drought responsive genes (DRGs) were identified using experimental data from drought responses by employing pairwise sequence similarity searches, pathway and interpro-domain analysis, expression profiling and orthology relation. Comparison of the genomic locations between these genes and sorghum quantitative trait loci (QTLs) showed that 40% of these genes were co-localized with QTLs known for drought tolerance. The genome reannotation conducted using the Program to Assemble Spliced Alignment (PASA), resulted in 9.6% of existing single gene models being updated. In addition, 210 putative novel genes were identified using AUGUSTUS and PASA based analysis on expression dataset. Among these, 50% were single exonic, 69.5% represented drought responsive and 5.7% were complete gene structure models. Analysis of biochemical metabolism revealed 14 metabolic pathways that are related to drought tolerance and also had a strong biological network, among categories of genes involved. Identification of these pathways, signifies the interplay of biochemical reactions that make up the metabolic network, constituting fundamental interface for sorghum defence mechanism against drought stress. CONCLUSIONS: This study suggests untapped natural variability in sorghum that could be used for developing drought tolerance. The data presented here, may be regarded as an initial reference point in functional and comparative genomics in the Gramineae family. PMID- 29273004 TI - Impact of HPV vaccination with Gardasil(r) in Switzerland. AB - BACKGROUND: Gardasil(r), a quadrivalent vaccine targeting low-risk (6, 11) and high-risk (16, 18) human papillomaviruses (HPV), has been offered to 11-14 year old schoolgirls in Switzerland since 2008. To evaluate its success and its potential impact on cervical cancer screening, HPV genotypes were examined in 18 year-old girls five years later (sub-study 1) and in outpatients participating to cervical cancer screening before and after vaccine implementation (sub-study 2). METHODS: For sub-study 1, 3726 females aged 18 in 2013 were invited to fill a questionnaire on personal demographics and HPV risk factors and to provide a self collected cervicovaginal sample for HPV genotyping and Chlamydia trachomatis PCR. Personal data were evaluated by univariable and multivariable statistics. In sub study 2, the proportion of the vaccine-type HPV among anogenital HPV was examined with archived genotyping data of 8039 outpatients participating to cervical cancer screening from 1999 till 2015. The yearly evolution of this proportion was evaluated by segmented logistic regression. RESULTS: 690 (18.5%) women participated to sub-study 1 and 327 (8.8%) provided a self-collected sample. Prevalence of Chlamydia trachomatis (4.6%) and demographics confirmed that the subjects were representative of sexually-active Swiss young women. Vaccine (five year coverage: 77.5%) was preferentially accepted by contraceptive-pill users (P = 0.001) and samples were mainly provided by sexually-active subjects (P < 0.001). The proportion (4%) of the vaccine-type HPV in this population was lower than in sub-study 2 outpatients (n = 849, <26 years old) in the pre-vaccine era (25.7%). The proportion of the high-risk vaccine-type HPV decreased significantly (59%, P = 0.0048) in the outpatients during the post-vaccine era, yet this decrease was restricted to those aged less than 26 years (n = 673, P < 0.0001). CONCLUSIONS: The low proportion of vaccine-type HPV in 18-year-old females and its rapid decrease in young women participating to cervical cancer screening extend the success of HPV vaccination to Switzerland. Our data suggest that cervical cancer screening is now entering a stage of reduced proportion of HPV16 and/or 18 in samples reported positive by cytology. In view of the high likelihood of reduced clinical specificity of cytology, primary screening modalities involving HPV testing and cytology should now be re-evaluated in Switzerland. PMID- 29273005 TI - CSmetaPred: a consensus method for prediction of catalytic residues. AB - BACKGROUND: Knowledge of catalytic residues can play an essential role in elucidating mechanistic details of an enzyme. However, experimental identification of catalytic residues is a tedious and time-consuming task, which can be expedited by computational predictions. Despite significant development in active-site prediction methods, one of the remaining issues is ranked positions of putative catalytic residues among all ranked residues. In order to improve ranking of catalytic residues and their prediction accuracy, we have developed a meta-approach based method CSmetaPred. In this approach, residues are ranked based on the mean of normalized residue scores derived from four well-known catalytic residue predictors. The mean residue score of CSmetaPred is combined with predicted pocket information to improve prediction performance in meta predictor, CSmetaPred_poc. RESULTS: Both meta-predictors are evaluated on two comprehensive benchmark datasets and three legacy datasets using Receiver Operating Characteristic (ROC) and Precision Recall (PR) curves. The visual and quantitative analysis of ROC and PR curves shows that meta-predictors outperform their constituent methods and CSmetaPred_poc is the best of evaluated methods. For instance, on CSAMAC dataset CSmetaPred_poc (CSmetaPred) achieves highest Mean Average Specificity (MAS), a scalar measure for ROC curve, of 0.97 (0.96). Importantly, median predicted rank of catalytic residues is the lowest (best) for CSmetaPred_poc. Considering residues ranked <=20 classified as true positive in binary classification, CSmetaPred_poc achieves prediction accuracy of 0.94 on CSAMAC dataset. Moreover, on the same dataset CSmetaPred_poc predicts all catalytic residues within top 20 ranks for ~73% of enzymes. Furthermore, benchmarking of prediction on comparative modelled structures showed that models result in better prediction than only sequence based predictions. These analyses suggest that CSmetaPred_poc is able to rank putative catalytic residues at lower (better) ranked positions, which can facilitate and expedite their experimental characterization. CONCLUSIONS: The benchmarking studies showed that employing meta-approach in combining residue-level scores derived from well-known catalytic residue predictors can improve prediction accuracy as well as provide improved ranked positions of known catalytic residues. Hence, such predictions can assist experimentalist to prioritize residues for mutational studies in their efforts to characterize catalytic residues. Both meta-predictors are available as webserver at: http://14.139.227.206/csmetapred/ . PMID- 29273006 TI - miR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/ beta-catenin/EMT signaling cascade in gastric cancer. AB - BACKGROUND: EphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, this study aims to identify microRNAs that target it and serve as key regulators of gastric carcinogenesis. METHODS: We identified several potential microRNAs targeting EphA2 by bioinformatics websites and then analyzed the role of miR-302b in modulating EphA2 in vitro and in vivo of GC, and it's mechanism. RESULTS: Our analysis identified miR-302b, a novel regulator of EphA2, as one of the most significantly downregulated microRNA (miRNA) in GC tissues. Overexpression of miR-302b impaired GC cell migratory and invasive properties robustly and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro. miR-302b exhibited anti-tumor activity by reversing EphA2 regulation, which relayed a signaling transduction cascade that attenuated the functions of N cadherin, beta-catenin, and Snail (markers of Wnt/beta-catenin and epithelial mesenchymal transition, EMT). This modulation of EphA2 also had distinct effects on cell proliferation and migration in GC in vivo. CONCLUSIONS: miR-302b serves as a critical suppressor of GC cell tumorigenesis and metastasis by targeting the EphA2/Wnt/beta-catenin/EMT pathway. PMID- 29273007 TI - Efficacy and safety of weekly nab-paclitaxel plus gemcitabine in Chinese patients with metastatic adenocarcinoma of the pancreas: a phase II study. AB - BACKGROUND: This phase II bridging study assessed the safety and efficacy of nab paclitaxel/gemcitabine (Metastatic Pancreatic Adenocarcinoma Clinical Trial [MPACT] regimen) in Chinese patients with metastatic pancreatic cancer (MPC). METHODS: This 3-part sequential study evaluated nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. Part 1 evaluated safety. Part 2 evaluated efficacy using Simon's optimal 2-stage design: if >2 responses were observed in Stage 1 (n = 28), 54 additional patients would be enrolled in Stage 2. If >9 responses were observed, the study was complete. Otherwise, nab-paclitaxel/gemcitabine would be compared with gemcitabine alone in Part 3. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival (OS), and safety. RESULTS: Eighty-three patients were treated. The prespecified primary endpoint was met: the independently assessed ORR in Stages 1 + 2 was 35% (95% CI, 24.8-46.2); therefore, Part 3 was not initiated. The median DOR was 8.9 months (95% CI, 6.01 8.94). The median OS and progression-free survival were 9.2 (95% CI, 7.6-11.1) and 5.5 (95% CI, 5.29-7.16) months, respectively. The 12-month OS rate was 30%. In an updated analysis, the median OS was 9.3 months and the 12-month OS rate was 32%. Longer OS was observed in patients with baseline neutrophil-to-lymphocyte ratio <= 5 vs > 5. The most common grade >= 3 adverse events were leukopenia (35%), neutropenia (34%), anemia (15%), thrombocytopenia (10%), and fatigue (13%). Grade 3 peripheral neuropathy occurred in 7% of patients (no grade 4 reported). CONCLUSIONS: The MPACT regimen of nab-paclitaxel/gemcitabine is efficacious in Chinese patients with MPC. No new safety signals were observed. TRIAL REGISTRATION: NCT02135822 , May 8, 2014. PMID- 29273008 TI - Implementation of guidelines for multidisciplinary team management of pregnancy in women with pre-existing diabetes or cardiac conditions: results from a UK national survey. AB - BACKGROUND: Despite numerous publications stating the importance of multidisciplinary care for women with pre-existing medical conditions, there is a lack of evidence regarding structure or processes of multidisciplinary working, nor impact on maternal or infant outcomes. This study aimed to evaluate the implementation of guidelines for multidisciplinary team (MDT) management in pregnant women with pre-existing diabetes or cardiac conditions. These conditions were selected as exemplars of increasingly common medical conditions in pregnancy for which MDT management is recommended to prevent or reduce adverse maternal and fetal outcomes. METHODS: National on-line survey sent to clinicians responsible for management or referral of women with pre-existing diabetes or cardiac conditions in UK National Health Service (NHS) maternity units. The survey comprised questions regarding the organisation of MDT management for women with pre-existing diabetes or cardiac conditions. Content was informed by national guidance. RESULTS: One hundred seventy-nine responses were received, covering all health regions in England (162 responses) and 17 responses from Scotland, Wales and Northern Ireland. 132 (74%) related to women with diabetes and 123 (69%) to women with cardiac conditions. MDT referral was reportedly standard practice in most hospitals, particularly for women with pre-existing diabetes (88% of responses vs. 63% for cardiac) but there was wide variation in relation to MDT membership, timing of referral and working practices. These inconsistencies were evident within and between maternity units across the UK. Reported membership was medically dominated and often in the absence of midwifery/nursing and other allied health professionals. Less than half of MDTs for women with diabetes met the recommendations for membership in national guidance, and although two thirds of MDTs for women with cardiac disease met the core recommendations for membership, most did not report having the extended members: midwives, neonatologists or intensivists. CONCLUSIONS: The wide diversity of organisational management for women with pre-existing diabetes or cardiac conditions is of concern and merits more detailed inquiry. Evidence is also required to support and better define the recommendations for MDT care. PMID- 29273009 TI - Overweight in children and its perception by parents: cross-sectional observation in a general pediatric outpatient clinic. AB - BACKGROUND: Childhood overweight is a growing problem in industrialized countries. Parents play a major role in the development and the treatment of overweight in their children. A key factor here is the perception of their child's weight status. As we know of other studies, parental perception of children's weight status is very poor. This study aimed to determine factors associated with childhood overweight and parental misperception of weight status. The height and weight of children, as reported by parents were compared with measured data. METHODS: The study was conducted at a general pediatric outpatient clinic in Vienna, Austria. A total of 600 children (aged 0-14 years) participated in the study. Collection of data was performed by means of a questionnaire comprising items relating to parental weight and social demographics. The parents were also asked to indicate their children's weight and height, as well as the estimated weight status. Children were weighed and measured and BMI was calculated, allowing a comparison of estimated values and weight categories with the measured data. RESULTS: Parental BMI, parental weight and a higher birth weight were identified as factors associated with childhood overweight. No association with the parents' educational status or citizenship could be proven. We compared parents' estimations of weight and height of their children with measured data. Here we found, that parental estimated values often differ from measured data. Using only parental estimated data to define weight status leads to misclassifications. It could be seen that parents of overweight children tend to underestimate the weight status of their children, compared to parents of children with normal weight. CONCLUSIONS: Pediatricians should bear in mind that parental assessment often differs from the measured weight of their children. Hence children should be weighed and measured regularly to prevent them from becoming overweight. This is of particular importance in children with higher birth weight and children of overweight parents. TRIAL REGISTRATION: Study was not registered. The study was approved by the Ethic committee of the city of Vienna. (EK 13-146-VK). PMID- 29273010 TI - Genetic diversity of Leishmania donovani that causes cutaneous leishmaniasis in Sri Lanka: a cross sectional study with regional comparisons. AB - BACKGROUND: Leishmania donovani is the etiological agent of visceral leishmaniasis (VL) in the Indian subcontinent. However, it is also known to cause cutaneous leishmaniasis (CL) in Sri Lanka. Sri Lankan L. donovani differs from other L. donovani strains, both at the molecular and biochemical level. To investigate the different species or strain-specific differences of L. donovani in Sri Lanka we evaluated sequence variation of the kinetoplastid DNA (kDNA). METHODS: Parasites isolated from skin lesions of 34 CL patients and bone marrow aspirates from 4 VL patients were genotyped using the kDNA minicircle PCR analysis. A total of 301 minicircle sequences that included sequences from Sri Lanka, India, Nepal and six reference species of Leishmania were analyzed. RESULTS: Haplotype diversity of Sri Lankan isolates were high (H d = 0.757) with strong inter-geographical genetic differentiation (F ST > 0.25). In this study, L. donovani isolates clustered according to their geographic origin, while Sri Lankan isolates formed a separate cluster and were clearly distinct from other Leishmania species. Within the Sri Lankan group, there were three distinct sub clusters formed, from CL patients who responded to standard antimony therapy, CL patients who responded poorly to antimony therapy and from VL patients. There was no specific clustering of sequences based on geographical origin within Sri Lanka. CONCLUSION: This study reveals high levels of haplotype diversity of L. donovani in Sri Lanka with a distinct genetic association with clinically relevant phenotypic characteristics. The use of genetic tools to identify clinically relevant features of Leishmania parasites has important therapeutic implications for leishmaniasis. PMID- 29273012 TI - A prospective, observational cohort study of patients presenting to an emergency department with acute shoulder trauma: the Manchester emergency shoulder (MESH) project. AB - BACKGROUND: Fracture and dislocation of the shoulder are usually identifiable through the use of plain radiographs in an emergency department. However, other significant soft tissue injuries can be missed at initial presentation. This study used contrast enhanced magnetic resonance arthrography (MRA) to determine the pattern of underlying soft tissue injuries in patients with traumatic shoulder injury, loss of active range of motion, and normal plain radiography. METHODS: A prospective, observational cohort study. Twenty-six patients with acute shoulder trauma and no identifiable radiograph abnormality were screened for inclusion. Those unable to actively abduction their affected arm to 90 degrees at initial presentation and at two week's clinical review were consented for MRA. RESULTS: Twenty patients (Mean age 44 years, 4 females) proceeded to MRA. One patient had no abnormality, three patients showed minimal pathology. Four patients had an isolated bony/labral injury. Eight patients had injuries isolated to the rotator cuff. Four patients had a combination of bony and rotator cuff injury. Four patients were referred to a specialist shoulder surgeon following MRA and underwent surgery. CONCLUSIONS: Significant soft tissue pathology was common in our cohort of patients with acute shoulder trauma, despite the reassurance of normal plain radiography. These patients were unable to actively abduct to 90 degrees both at initial presentation and at two week's post injury review. A more aggressive management and diagnostic strategy may identify those in need of early operative intervention and provide robust rehabilitation programmes. PMID- 29273011 TI - Time course study of the response to LPS targeting the pig immune gene networks. AB - BACKGROUND: Stress is a generic term used to describe non-specific responses of the body to all kinds of challenges. A very large variability in the response can be observed across individuals, depending on numerous conditioning factors like genetics, early influences and life history. As a result, there is a wide range of individual vulnerability and resilience to stress, also called robustness. The importance of robustness-related traits in breeding strategies is increasing progressively towards the production of animals with a high level of production under a wide range of climatic conditions and management systems, together with a lower environmental impact and a high level of animal welfare. The present study aims at describing blood transcriptomic, hormonal, and metabolic responses of pigs to a systemic challenge using lipopolysaccharide (LPS). The objective is to analyze the individual variation of the biological responses in relation to the activity of the HPA axis measured by the levels of plasma cortisol after LPS and ACTH in 120 juvenile Large White (LW) pigs. The kinetics of the response was measured with biological variables and whole blood gene expression at 4 time points. A multilevel statistical analysis was used to take into account the longitudinal aspect of the data. RESULTS: Cortisol level reaches its peak 4 h after LPS injection. The characteristic changes of white blood cell count to LPS were observed, with a decrease of total count, maximal at t=+4 h, and the mirror changes in the respective proportions of lymphocytes and granulocytes. The lymphocytes / granulocytes ratio was maximal at t=+1 h. An integrative statistical approach was used and provided a set of candidate genes for kinetic studies and ongoing complementary studies focused on the LPS-stimulated inflammatory response. CONCLUSIONS: The present study demonstrates the specific biomarkers indicative of an inflammation in swine. Furthermore, these stress responses persist for prolonged periods of time and at significant expression levels, making them good candidate markers for evaluating the efficacy of anti inflammatory drugs. PMID- 29273013 TI - A next generation sequencing based approach to identify extracellular vesicle mediated mRNA transfers between cells. AB - BACKGROUND: Exosomes and other extracellular vesicles (EVs) have emerged as an important mechanism of cell-to-cell communication. However, previous studies either did not fully resolve what genetic materials were shuttled by exosomes or only focused on a specific set of miRNAs and mRNAs. A more systematic method is required to identify the genetic materials that are potentially transferred during cell-to-cell communication through EVs in an unbiased manner. RESULTS: In this work, we present a novel next generation of sequencing (NGS) based approach to identify EV mediated mRNA exchanges between co-cultured adipocyte and macrophage cells. We performed molecular and genomic profiling and jointly considered data from RNA sequencing (RNA-seq) and genotyping to track the "sequence varying mRNAs" transferred between cells. We identified 8 mRNAs being transferred from macrophages to adipocytes and 21 mRNAs being transferred in the opposite direction. These mRNAs represented biological functions including extracellular matrix, cell adhesion, glycoprotein, and signal peptides. CONCLUSIONS: Our study sheds new light on EV mediated RNA communications between adipocyte and macrophage cells, which may play a significant role in developing insulin resistance in diabetic patients. This work establishes a new method that is applicable to examining genetic material exchanges in many cellular systems and has the potential to be extended to in vivo studies as well. PMID- 29273014 TI - "Hypothyroidism screening during first trimester of pregnancy". AB - BACKGROUND: Subclinical hypothyroidism is defined as an elevated thyroid stimulating hormone level with a normal thyroxin level without signs or symptoms of hypothyroidism. Although it is well accepted that overt hypothyroidism has a deleterious impact on pregnancy, recent studies indicate that subclinical hypothyroidism may affect maternal and fetal health. Studies suggest an association between miscarriage and preterm delivery in euthyroid women positive for anti-peroxidase antibodies and/or anti-thyroglobulin antibodies. A proposal of a new set-point to diagnose SCH was recently published. The aim of this research was to determine the optimal thyroid-stimulating hormone cut-off point to screen for subclinical hypothyroidism in the first trimester of gestation in a population of our clinical area and to determine the diagnostic value of this screening test for detecting anti-thyroid peroxidase antibodies. METHODS: This cross-sectional study determines the cutoff point for SCH screening and evaluates its usefulness to detect TPO Ab using the Receiver Operating Characteristics (ROC) curve. Prevalence of SCH was calculated using as cut-off 2.5 mIU/L, 4 mIU/L, and our TSH 97.5th percentile. The ability to detect positive anti thyroglobulin antibodies (TG Ab) and anti-thyroid peroxidase antibodies (TPO Ab) in patients with levels of TSH >97.5th percentile was determined by ROC curves. RESULTS: The mean, range and standard deviation of TSH was 2.15 +/- 1.34 mIU/L (range 0.03-8.82); FT4 was 1.18 +/- 0.13 ng/dL (range 0.94-1.3); TG Ab was 89.87 +/- 413.56 IU/mL (range 0.10-4000); and TPO Ab was 21.61 +/- 46.27 IU/mL(range 0.10-412.4). The ROC. analysis of the ability of the TSH level to predict the presence of positive TPO Ab found an AUC of 0.563. CONCLUSION: In our population, the TSH cutoff value for gestational SCH screening is 4.7 mIU/L. Using the SEGO recommended 2.5 mIU/L TSH cut-off point, the prevalence of SCH is 37%. Applying the ATA 2017 recommended cutoff point of 4 mIU/L, the prevalence of SCH is 9.6%. Finally, when the cut-off of 4.7 mIU/L (our 97.5th centile) was used, the SCH prevalence is 5%. TSH levels in the first trimester of pregnancy are not useful to detect TPO Ab. PMID- 29273015 TI - Diagnostic accuracy of 18F-FDG PET/CT and MR imaging in patients with adenoid cystic carcinoma. AB - BACKGROUND: The aim of this study was to evaluate the value of 18F-FDG PET/CT (PET/CT) and MRI for local and/or whole-body restaging of adenoid cystic carcinoma of the head and neck (ACC). METHODS: Thirty-six patients with ACC underwent conventional MRI of the head and neck and a whole-body PET/CT and were analysed with regards to detection of a local tumor recurrence, lymph node or distant metastases. A consensus interpretation of all available imaging data was used as reference standard. Sensitivity, specificity, diagnostic accuracy, positive and negative predictive values were calculated for MRI and PET/CT. RESULTS: The sensitivity of PET/CT and MRI was 96% (89%), specificity 89% (89%), PPV 96% (96%), NPV 89% (73%) and accuracy 94% (89%) for detection of local tumors. Additionally, PET/CT revealed lymph node metastases in one patient and distant metastases in 9/36 patients. In three patients secondary primaries were found. CONCLUSIONS: Whole-body PET/CT in addition to MRI of the head and neck improves detection of local tumour and metastastic spread in ACC. PMID- 29273016 TI - Buffering zone of implantable Collamer lens sizing in V4c. AB - BACKGROUND: The purpose of this study was to identify factors related to the unexpected vault in V4c implantable collamer lens (ICL; STAAR Surgical) implantation. METHODS: V4c ICLs were implanted in 43 eyes of 43 patients for the correction of myopia. The implanted V4c ICL sizes were determined individually with our previous V4 ICL sizing nomogram based on the sulcus-to-sulcus diameter (STS), and the V4 ICL sizes were then converted to V4c ICL sizes with a size converting table. We defined the "normal-sizing group" as having a pre-converted ICL size larger than the STS, and the "under-sizing group" as having a pre converted ICL size smaller than the STS. Refractive outcomes, safety and parameters related to postoperative vault were compared between the two groups. RESULTS: The value of "actual ICL size - STS" differed significantly between the normal-sizing and under-sizing groups (p < 0.001), but postoperative vault did not differ significantly (p = 0.442). The demographics, implanted ICL characteristics, effectiveness indexes, safety indexes, and parameters related to postoperative vault did not differ significantly between the two groups (p > 0.05). Two patients in the normal-sizing group exhibited over-vaulting; these patients had shallow anterior chambers and were implanted with high-dioptric power ICLs. CONCLUSIONS: The achievement of acceptable vault in both normal sizing and under-sizing groups indicates the existence of a buffering zone in V4c ICL sizing. The smaller size of V4c ICLs should be considered in patients susceptible to over-vaulting, such as those with shallow anterior chambers and high-dioptric-power ICLs. PMID- 29273017 TI - Vitamin D levels in schoolchildren: a cross-sectional study in Kuwait. AB - BACKGROUND: Ongoing studies in the Middle East, particularly in the Arabian Gulf countries, have reported extremely low levels of serum vitamin D across age and gender. In Kuwait, vitamin D deficiency is prevalent in adolescent girls and in adult women. A number of risk factors have been reported, among which gender, age, and obesity are a few. Because adequate vitamin D status is necessary to promote bone mineral accrual in childhood, and because low vitamin D levels have been associated with a wide range of health problems, there is concern that growing children with low vitamin D may be at higher risk for developing diseases. The aim of this study was to assess vitamin D levels in elementary schoolchildren. METHODS: Kuwaiti schoolchildren were recruited and assessed for their serum vitamin D, 25(OH)D, parathyroid hormone (PTH) and adjusted serum calcium (adj-Ca). Anthropometric measurements and data on lifestyle and health status were recorded during an interview. RESULTS: In a total of 199 schoolchildren, median (IQR) age was 8.5 (7.0-9.5 years), 25(OH)D was 30 (22-39 nmol/L), PTH was 4.7 (3.8-5.9 pmol/L), and adj-Ca was 2.39 (2.33-2.44 mmol/L). Boys had higher levels of 25(OH)D (18.3% vs 6.6% had levels >=50 nmol/L) and lower levels of PTH (94.6% vs 80.2% had levels <7 pmol/L) than girls. Significant risk factors for 25(OH)D levels <25 nmol/L included being <=8.5 years old (OR 4.95, 95% CI: 1.92-12.74), having PTH >=7 pmol/L (OR 2.28, 95% CI: 1.17-4.46), being female (OR 2.44, 95% CI: 1.22-4.88), and being overweight or obese (OR 2.18, 95% CI: 1.11-4.26). CONCLUSIONS: The results show relatively low levels of 25(OH)D in young schoolchildren in Kuwait, with lower levels in girls. Given the association of 25(OH)D with a wide range of ailments, it is necessary to further examine the causes and risk factors of low vitamin D in this age group to prevent associated health problems. PMID- 29273018 TI - Outcomes of and barriers to cataract surgery in Sao Paulo State, Brazil. AB - BACKGROUND: Cataract is the leading cause of blindness in developing countries and identification of the barriers to accessing treatment is essential for developing appropriate public healthcare interventions. To evaluate the barriers to cataract surgery after diagnosis and assess the postoperative outcomes in Sao Paolo State, Brazil. METHODS: This prospective study evaluated cataract patients from 13 counties in Sao Paulo State in 2014. Cataract was diagnosed in the community by a mobile ophthalmic unit and patients were referred to a hospital for management. Gender, age, distance to the hospital and local municipal health structure were evaluated as possible barriers. Data were analyzed for postoperative outcomes and the impact on blindness and visual impairment. RESULTS: Six hundred patients were diagnosed with cataract with a mean age of 68.8+/-10.3 years and 374 (62.3%) were females. Two hundred and fifty-four (42.3%) patients presented to the referral hospital. One hundred forty-four (56.7%) underwent surgery, 56 (22.0%) decided not to undergo surgery, 40 (15.7%) required only YAG-Laser and 14 (5.5%) required a spectacle prescription only. Visual acuity increased statistically significantly from 1.07+/-0.73 logMAR at presentation to 0.25+/-0.41 logMAR at the final visit after intraocular lens implantation (p=0.000). There was a statistically significantly decrease from 17 (11.8%) blind patients and 55 (38.2%) visually impaired patients at presentation to 2 (1.4%) and 5 (3.5%) patients respectively after treatment (p=0.000). CONCLUSION: Less than half of the individuals with cataract presented to the hospital for surgery. Among the patients who underwent treatment, there was an overall decrease in the number of blind individuals and visually impaired individuals. The barriers to cataract surgery were older age, greater distance to the hospital, municipalities with fewer inhabitants and less ophthalmic services. PMID- 29273019 TI - Perceived social risk in medical decision-making for physical child abuse: a mixed-methods study. AB - BACKGROUND: The medical literature reports differential decision-making for children with suspected physical abuse based on race and socioeconomic status. Differential evaluation may be related to differences of risk indicators in these populations or differences in physicians' perceptions of abuse risk. Our objective was to understand the contribution of the child's social ecology to child abuse pediatricians' perception of abuse risk and to test whether risk perception influences diagnostic decision-making. METHODS: Thirty-two child abuse pediatrician participants prospectively contributed 746 consultations from for children referred for physical abuse evaluation (2009-2013). Participants entered consultations to a web-based interface. Participants noted their perception of child race, family SES, abuse diagnosis. Participants rated their perception of social risk for abuse and diagnostic certainty on a 1-100 scale. Consultations (n = 730) meeting inclusion criteria were qualitatively analyzed for social risk indicators, social and non-social cues. Using a linear mixed-effects model, we examined the associations of social risk indicators with participant social risk perception. We reversed social risk indicators in 102 cases whilst leaving all injury mechanism and medical information unchanged. Participants reviewed these reversed cases and recorded their social risk perception, diagnosis and diagnostic certainty. RESULTS: After adjustment for physician characteristics and social risk indicators, social risk perception was highest in the poorest non minority families (24.9 points, 95%CI: 19.2, 30.6) and minority families (17.9 points, 95%CI, 12.8, 23.0). Diagnostic certainty and perceived social risk were associated: certainty increased as social risk perception increased (Spearman correlation 0.21, p < 0.001) in probable abuse cases; certainty decreased as risk perception increased (Spearman correlation (-)0.19, p = 0.003) in probable not abuse cases. Diagnostic decisions changed in 40% of cases when social risk indicators were reversed. CONCLUSIONS: CAP risk perception that poverty is associated with higher abuse risk may explain documented race and class disparities in the medical evaluation and diagnosis of suspected child physical abuse. Social risk perception may act by influencing CAP certainty in their diagnosis. PMID- 29273020 TI - Trends in cause and place of death for children in Portugal (a European country with no Paediatric palliative care) during 1987-2011: a population-based study. AB - BACKGROUND: Children and adolescents dying from complex chronic conditions require paediatric palliative care. One aim of palliative care is to enable a home death if desired and well supported. However, there is little data to inform care, particularly from countries without paediatric palliative care, which constitute the majority worldwide. METHODS: This is an epidemiological study analysing death certificate data of decedents aged between 0 and 17 years in Portugal, a developed Western European country without recognised provision of paediatric palliative care, from 1987 to 2011. We analysed death certificate data on cause and place of death; the main outcome measure was home death. Complex chronic conditions included cancer, cardiovascular, neuromuscular, congenital/genetic, respiratory, metabolic, gastro-intestinal, renal, and haematology/immunodeficiency conditions. Multivariate analysis determined factors associated with home death in these conditions. RESULTS: Annual deaths decreased from 3268 to 572. Of 38,870 deaths, 10,571 were caused by complex chronic conditions, their overall proportion increasing from 23.7% to 33.4% (22.4% to 45.4% above age 1-year). For these children, median age of death increased from 0.5 to 4.32-years; 19.4% of deaths occurred at home, declining from 35.6% to 11.5%; factors associated with home death were year of death (adjusted odds ratio 0.89, 95% confidence interval 0.89-0.90), age of death (6-10 year-olds 21.46, 16.42-28.04, reference neonates), semester of death (October-March 1.18, 1.05 1.32, reference April-September), and cause of death (neuromuscular diseases 1.59, 1.37-1.84, reference cancer), with wide regional variation. CONCLUSIONS: This first trend analysis of paediatric deaths in Portugal (an European country without paediatric palliative care) shows that palliative care needs are increasing. Children are surviving longer and, in contrast with countries where paediatric palliative care is thriving, there is a long-term trend of dying in hospital instead of at home. Age, diagnosis, season and region are associated with home death, and should be considered when planning services to support families choosing this option. Priorities should address needs of the youngest children, those with cancer, neuromuscular and cardiovascular conditions, as well as inequities related to place of residence. PMID- 29273021 TI - Randomised controlled trial to improve health and reduce substance use in established psychosis (IMPaCT): cost-effectiveness of integrated psychosocial health promotion. AB - BACKGROUND: There is mounting evidence that people with severe mental illness have unhealthy lifestyles, high rates of cardiovascular and metabolic diseases, and greater risk of early mortality. This study aimed to assess the cost effectiveness of a health promotion intervention seeking to improve physical health and reduce substance use in people with psychosis. METHODS: Participants with a psychotic disorder, aged 18-65 years old and registered on an enhanced care approach programme or equivalent were recruited from community mental health teams in six mental health trusts in England. Participants were randomisation to either standard community mental health team care (treatment as usual) or treatment as usual with an integrated health promotion intervention (IMPaCT). Cost-effectiveness and cost-utility analyses from health and social care and societal perspectives were conducted alongside a cluster randomised controlled trial. Total health and social care costs and total societal costs at 12 and 15 months were calculated as well as cost-effectiveness (incremental cost effectiveness ratios and cost-effectiveness acceptability curves) at 15 months based on quality of life (SF-36 mental and physical health components, primary outcome measures) and quality adjusted life years (QALYs) using two measures, EQ 5D-3 L and SF-36. Data were analysed using bootstrapped regressions with covariates for relevant baseline variables. RESULTS: At 12-15 months 301 participants had full data needed to be included in the economic evaluation. There were no differences in adjusted health and social care costs (L95, 95% CI L1410 to L1599) or societal costs (L675, 95% CI -L1039 to L2388) between the intervention and control arms. Similarly, there were no differences between the groups in the SF-36 mental component (-0.80, 95% CI -3.66 to 2.06), SF-36 physical component (-0.68, 95% CI -3.01 to 1.65), QALYs estimated from the SF-36 (-0.00, -0.01 to 0.00) or QALYs estimated from the EQ-5D-3 L (0.00, 95% CI -0.01 to 0.02). Cost-effectiveness acceptability curves for all four outcomes and from both cost perspectives indicate that the probability of the health promotion intervention being cost-effective does not exceed 0.4 for willingness to pay thresholds ranging from L0-L50,000. CONCLUSIONS: Alongside no evidence of additional quality of life/clinical benefit, there is also no evidence of cost effectiveness. TRIAL REGISTRATION: ISRCTN58667926 . Date retrospectively registered: 23/04/2010. Recruitment start date: 01/03/2010. PMID- 29273022 TI - On-line hemodiafiltration did not induce an overproduction of oxidative stress and inflammatory cytokines in intensive care unit-acute kidney injury. AB - BACKGROUND: Though on-line intermittent hemodiafiltration (OL-IHDF) is a routine therapy for chronic dialysis patients, it is not yet widespread used in critically ill patients. This study was undergone to evaluate efficiency and tolerance of OL-IHDF and to appreciate inflammatory consequences of its use in intensive care unit (ICU)-acute kidney injury (AKI) patients. METHODS: In this prospective cohort study conducted in a medical academic ICU in France, 30 AKI patients who underwent OL-IHDF were included. OL-HDF used an ultrapure water production: AQ 1250 line with double reverse osmosis, a generator 5008 with a 1.8m2 dialyzer with Polysulfone membrane (Fresenius Medical Care). Tolerance and efficiency of OL-IHDF were evaluated as well as its inflammatory risk by the measurement of plasma concentrations of proinflammatory (Interleukin 6, IL1beta, IL8, Interferon gamma) and anti-inflammatory (IL4, IL10) cytokines, Epidermal growth factor (EGF), Vascular Endothelial growth factor (VEGF) and Macrophage Chemoattractive Protein-1 (MCP-1) before and after sessions. RESULTS: Intradialytic hypotensive events were observed during 27/203 OL-IHDF sessions accounting for a mal-tolerated session's rate at 13.3%. Mean delivered urea Kt/V per session was 1.12 +/- 0.27 with a percentage of reduction for urea, creatinine, beta2-microglobulin and cystatine C at 61.6 +/- 8.8%, 55.3 +/- 6.7%, 51.5 +/- 8.7% and 44.5 +/- 9.8% respectively. Production of superoxide anion by leukocytes, mean levels of pro- and anti-inflammatory cytokines and plasmatic concentrations of EGF, VEGF and MCP-1 did not differ before and after OL-IHDF sessions. We observed however a significant decrease of mean TNFalpha plasmatic concentrations from 8.2 +/- 5.8 to 4.8 +/- 3.5 pg/ml at the end of OL-IHDF. CONCLUSIONS: OL-IHDF was not associated with an increase in pro and anti inflammatory cytokines, oxidative stress or EGF, VEGF and MCP-1 in AKI patients and seems therefore a secure and feasible modality in ICUs. PMID- 29273023 TI - An overview of systematic reviews on the collaboration between physicians and nurses and the impact on patient outcomes: what can we learn in primary care? AB - BACKGROUND: Primary care needs to be strengthened in order to address the many societal challenges. Group practices in primary care foster collaboration with other health care providers, which encourages care co-ordination and leads to a higher quality of primary care. Nursing roles and responsibilities expanded over time and nurses have been found to often provide equal high-quality chronic patient care compared to physicians, even with higher patient satisfaction. Inter professional collaboration between primary care physicians and nurses is a possible strategy to achieve the desired quality outcomes in a strengthened primary care system. The objective of this research is to synthesize the evidence presented in literature on the impact of collaboration between physicians and nurses on patient outcomes in primary care or in comparable care settings. METHODS: A systematic review of peer-reviewed reviews was performed in four databases: COCHRANE, MEDLINE, EMBASE and CINAHL. All studies from 1970 until May 22 2016 were included in the search strategy. Titles, abstracts and full texts were respectively reviewed. At least two of the three authors independently reviewed each of the 277 abstracts and 58 full texts retrieved in the searches to identify those which contained all the inclusion criteria. Two authors independently appraised the methodological quality of the reviews, using the AMSTAR quality appraisal tool. RESULTS: A total of eleven systematic reviews met all the inclusion criteria and almost fifty different patient outcomes were described. In most reviews, it was concluded that nurses do have added value. Blood pressure, patient satisfaction and hospitalization are patient outcomes where three or more systematic reviews concluded better results when physicians and nurses collaborated, compared to usual care. Colorectal screening, hospital length of stay and health-related quality of life are outcomes where collaboration appeared not to be effective. CONCLUSIONS: Collaboration between physicians and nurses may have a positive impact on a number of patient outcomes and on a variety of pathologies. To address future challenges of primary care, there is a need for more integrated inter-professional collaboration care models with sufficiently educated nurses. PMID- 29273024 TI - Is unplanned out-of-hospital birth managed by paramedics 'infrequent', 'normal' and 'uncomplicated'? AB - BACKGROUND: Unplanned out-of-hospital birth is often perceived as precipitate in nature, 'infrequent', 'normal' and 'uncomplicated'. However, international studies report unplanned out-of-hospital birth is associated with increased rates of maternal and neonatal morbidity and mortality. This research describes intrapartum, immediate postpartum and neonatal care provided by paramedics in Queensland, Australia. The objectives were to (1) determine the number of cases where the paramedic documented birth or imminent birth during the study period (2) to describe the incidence of births prior to or during paramedic care (3) to detail any risk factors and/or complications recorded by paramedics during these cases, (4) identify paramedic pain management practices for intrapartum care, and (5) to examine the maternal and neonatal outcomes as documented by paramedics. METHOD: A retrospective analysis of Queensland Ambulance Service (QAS) de identified patient care records, generated from clinical case data between the 1st of Jan 2010 and 31st of Dec 2011, was undertaken. Descriptive analysis and x 2 tests were used to test associations between categorical variables, and the Wilcoxon rank-sum for associates between continuous variables which were not normally distributed. Content analysis was utilised to code free text fields. RESULTS: Six thousand one hundred thirty-five records were identified as intrapartum cases. This represented approximately 0.5% of the annual QAS caseload; 5722 were classified as maternal records and 413 were neonatal records. Paramedics recorded antenatal and/or intrapartum complications in 27.3% (n = 1563) of cases. Abnormal maternal vital signs were recorded in 30.1% (n = 1725) of cases. Of the 5722 women attended by paramedics during their labour, a birth occured in 10.8% (n = 618) of cases. Parity was documented in 41.4% (n = 256) of mothers who birthed. Neonatal records were available for 66.8% (n = 413) of actual births, 60.0% (n = 248) recorded a full set of neonatal vital signs and an Apgar score. When an Apgar score was recorded, 21.8% (n = 91) scored <=7 out of 10. CONCLUSIONS: The research described intrapartum, immediate postpartum and neonatal care provided by paramedics and identified factors that may complicate paramedic clinical management of labouring and birthing women. Further research is required to determine if there are opportunities to improve the paramedic management of such cases. PMID- 29273025 TI - Exhaled breath condensate metabolome clusters for endotype discovery in asthma. AB - BACKGROUND: Asthma is a complex, heterogeneous disorder with similar presenting symptoms but with varying underlying pathologies. Exhaled breath condensate (EBC) is a relatively unexplored matrix which reflects the signatures of respiratory epithelium, but is difficult to normalize for dilution. METHODS: Here we explored whether internally normalized global NMR spectrum patterns, combined with machine learning, could be useful for diagnostics or endotype discovery. Nuclear magnetic resonance (NMR) spectroscopy of EBC was performed in 89 asthmatic subjects from a prospective cohort and 20 healthy controls. A random forest classifier was built to differentiate between asthmatics and healthy controls. Clustering of the spectra was done using k-means to identify potential endotypes. RESULTS: NMR spectra of the EBC could differentiate between asthmatics and healthy controls with 80% sensitivity and 75% specificity. Unsupervised clustering within the asthma group resulted in three clusters (n = 41,11, and 9). Cluster 1 patients had lower long-term exacerbation scores, when compared with other two clusters. Cluster 3 patients had lower blood eosinophils and higher neutrophils, when compared with other two clusters with a strong family history of asthma. CONCLUSION: Asthma clusters derived from NMR spectra of EBC show important clinical and chemical differences, suggesting this as a useful tool in asthma endotype-discovery. PMID- 29273026 TI - Genetic diversity and structure related to expansion history and habitat isolation: stone marten populating rural-urban habitats. AB - BACKGROUND: Population genetic diversity and structure are determined by past and current evolutionary processes, among which spatially limited dispersal, genetic drift, and shifts in species distribution boundaries have major effects. In most wildlife species, environmental modifications by humans often lead to contraction of species' ranges and/or limit their dispersal by acting as environmental barriers. However, in species well adapted to anthropogenic habitat or open landscapes, human induced environmental changes may facilitate dispersal and range expansions. In this study, we analysed whether isolation by distance and deforestation, among other environmental features, promotes or restricts dispersal and expansion in stone marten (Martes foina) populations. RESULTS: We genotyped 298 martens from eight sites at twenty-two microsatellite loci to characterize the genetic variability, population structure and demographic history of stone martens in Poland. At the landscape scale, limited genetic differentiation between sites in a mosaic of urban, rural and forest habitats was mostly influenced by isolation by distance. Statistical clustering and multivariate analyses showed weak genetic structuring with two to four clusters and a high rate of gene flow between them. Stronger genetic differentiation was detected for one stone marten population (NE1) located inside a large forest complex. Genetic differentiation between this site and all others was 20% higher than between other sites separated by similar distances. The genetic uniqueness index of NE1 was also twofold higher than in other sites. Past demographic history analyses showed recent expansion of this species in north-eastern Poland. A decrease in genetic diversity from south to north, and MIGRAINE analyses indicated the direction of expansion of stone marten. CONCLUSIONS: Our results showed that two processes, changes in species distribution boundaries and limited dispersal associated with landscape barriers, affect genetic diversity and structure in stone marten. Analysis of local barriers that reduced dispersal and large scale analyses of genetic structure and demographic history highlight the importance of isolation by distance and forest cover for the past colonization of central Europe by stone marten. This confirmed the hypothesis that human landscape changes (deforestation) accelerated stone marten expansion, to which climate warming probably has also been contributing over the last few decades. PMID- 29273027 TI - Effects of 12-week supplementation of Citrus bergamia extracts-based formulation CitriCholess on cholesterol and body weight in older adults with dyslipidemia: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUNDS: Recent experiments suggest that Citrus bergamia extracts could benefit people with dyslipidemia and obesity but this needs to be further validated. METHODS: A total of 98 people age-matched older adults (65 years) with elevated blood lipids were enrolled to receive 12-week supplementation of a Citrus bergamia extracts-based formulation (CitriCholess)(n = 48) and placebo (n = 50). RESULTS: No group differences were found in baseline bodyweight, body mass index (BMI), blood cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and glucose levels. CitriCholess supplementation resulted in lower levels than placebo in TG (1.83 +/- 0.92 vs. 1.95 +/- 1.34 mmol/L, P = 0.612), TC (5.14 +/- 0.98 vs. 5.44 +/- 0.77 mmol/L, P = 0.097), and LDL-C (3.13 +/- 0.74 vs. 3.43 +/- 0.62 mmol/L, P = 0.032). Compared to placebo, CitriCholess also resulted in greater reductions in body weight (-0.604 +/- 0.939 vs. 0.06 +/- 0.74 kg, P < 0.01), waist circumferences (-0.60 +/- 1.349 cm vs. -0.16 +/- 1.503 cm, P < 0.01) and BMI (-0.207 +/- 0.357 vs. 0.025 +/- 0.274, P < 0.01). Additionally, females had a significantly higher level of HDL-C than males. TC was significantly correlated with LDL-C, and to a less degree, with TG. TG was inversely correlated with HDL-C. Body weight and waist circumference were negatively correlated with HDL-C and positively correlated with glucose. CONCLUSION: 12-week supplementation of CitriCholess could benefit lipid metabolism and weight management in old adults with dyslipidemia. PMID- 29273028 TI - Implementation of a novel population panel management curriculum among interprofessional health care trainees. AB - BACKGROUND: Gaps in chronic disease management have led to calls for novel methods of interprofessional, team-based care. Population panel management (PPM), the process of continuous quality improvement across groups of patients, is rarely included in health professions training for physicians, nurses, or pharmacists. The feasibility and acceptance of such training across different healthcare professions is unknown. We developed and implemented a novel, interprofessional PPM curriculum targeted to diverse health professions trainees. METHODS: The curriculum was implemented annually among internal medicine residents, nurse practitioner students and residents, and pharmacy residents co located in a large, academic primary care site. Small groups of interprofessional trainees participated in supervised quarterly seminars focusing on chronic disease management (e.g., diabetes mellitus, hypertension, or chronic obstructive pulmonary disease) or processes of care (e.g., emergency department utilization for nonacute conditions or chronic opioid management). Following brief didactic presentations, trainees self-assessed their clinic performance using patient level chart review, presented individual cases to interprofessional staff and faculty, and implemented subsequent feedback with their clinic team. We report data from 2011 to 2015. Program evaluation included post-session participant surveys regarding attitudes, knowledge and confidence towards PPM, ability to identify patients for referral to interprofessional team members, and major learning points from the session. Directed content analysis was performed on an open-ended survey question. RESULTS: Trainees (n = 168) completed 122 evaluation assessments. Trainees overwhelmingly reported increased confidence in using PPM and increased knowledge about managing their patient panel. Trainees reported improved ability to identify patients who would benefit from multidisciplinary care or referral to another team member. Directed content analysis revealed that trainees viewed team members as important system resources (n = 82). CONCLUSIONS: Structured interprofessional training in PPM is both feasible and acceptable to trainees across multiple professions. Curriculum participants reported improved panel management skills, increased confidence in using PPM, and increased confidence in identifying candidates for interprofessional care. The curriculum could be readily exported to other programs and contexts. PMID- 29273029 TI - In vitro biological properties and health benefits of a novel sulfated polysaccharide isolated from Cymodocea nodosa. AB - BACKGROUND: During the last few decades, there has been a growing interest in the search for novel bioactive compounds from marine origins. METHODS: The present study is the first to determine the molecular characterization which it was deposited in the genebank database, to investigate and evaluate the biological properties of sulfated polysaccharide from Cymodocea nodosa (CNSP) seagrass. RESULTS: The results revealed that CNSP had high activity in total antioxidant assay (59.03 mg ascorbic acid equivalents/g extract), reducing power (OD = 0.3), DPPH radical scavenging (IC50 = 1.22 mg/ml) and ABTS radical scavenging (IC50 = 1.14 mg/ml). It was also noted to exhibit antimicrobial activity against a wide range of microorganisms, with important inhibition zones. The results revealed that CNSP was able to inhibit the proliferation of Hela cell lines with a dose dependent manner. CONCLUSION: Overall, the results presented in this study demonstrate that CNSP has several attractive antioxidant, antimicrobial and antiproliferative properties with potential benefits towards health. PMID- 29273030 TI - The use of empirical research in bioethics: a survey of researchers in twelve European countries. AB - BACKGROUND: The use of empirical research methods in bioethics has been increasing in the last decades. It has resulted in discussions about the 'empirical turn of bioethics' and raised questions related to the value of empirical work for this field, methodological questions about its quality and rigor, and how this integration of the normative and the empirical can be achieved. The aim of this paper is to describe the attitudes of bioethics researchers in this field towards the use of empirical research, and examine their actual conduct: whether they use empirical research methods (and if so, what methods), and whether (and how) they have made attempts at integrating the empirical and the normative. METHODS: An anonymous online survey was conducted to reach scholars working in bioethics/biomedical ethics/ethics institutes or centers in 12 European countries. A total of 225 bioethics researchers participated in the study. Of those, 200 questionnaires were fully completed, representing a response rate of 42.6%. The results were analysed using descriptive statistics. RESULTS: Most respondents (n = 175; 87.5%) indicated that they use or have used empirical methods in their work. A similar proportion of respondents (61.0% and 59.0%) reported having had at least some training in qualitative or quantitative methods, respectively. Among the 'empirical researchers', more than a fifth (22.9%) had not received any methodological training. It appears that only 6% or less of the 'empirical researchers' considered themselves experts in the methods (qualitative or quantitative) that they have used. Only 35% of the scholars who have used empirical methods reported having integrated empirical data with normative analysis, whereas for their current projects, 59.8% plan to do so. CONCLUSIONS: There is a need to evaluate the current educational programs in bioethics and to implement rigorous training in empirical research methods to ensure that 'empirical researchers' have the necessary skills to conduct their empirical research in bioethics. Also imperative is clear guidance on the integration of the normative and the empirical so that researchers who plan to do so have necessary tools and competences to fulfil their goals. PMID- 29273031 TI - Knowledge and possession of take-home naloxone kits among street-involved youth in a Canadian setting: a cohort study. AB - BACKGROUND: The distribution of take-home naloxone (THN) kits has been an important strategy in reducing overdose fatalities among people who use drugs. However, little is known about the use of THN among youth who are street involved. The present study explores knowledge and possession of THN among street involved youth in a Canadian setting. METHODS: Data were derived from the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth age 14-28 at enrollment in Vancouver, Canada. Participants completed a standardized questionnaire, which included items related to knowledge and possession of THN, sociodemographic characteristics, and substance use-related factors. Multivariable logistic regression models were used to identify factors independently associated with knowledge and possession of THN. RESULTS: Between December 2014 and November 2016, 177 youth were interviewed, including 68 females (38.4%). While 126 (71.2%) participants reported knowledge of THN, only 40 (22.6%) possessed a THN kit. Caucasian/white ethnicity was found to be positively associated with both knowledge and possession of THN (both p < 0.05). Public injection drug use in the last 6 months was found to be positively associated with knowledge of THN, while daily heroin use and daily methamphetamine use were associated with possession of THN (all p < 0.05). Male gender was negatively associated with possession of THN (p < 0.05). CONCLUSIONS: These findings highlight important gaps between knowledge and possession of THN among youth and the need to increase participation in THN programs among specific populations including non-white and male youth. Further research is needed to gain a better understanding of the barriers that may prevent certain youth from acquiring THN kits. PMID- 29273032 TI - Self-sampling for human papillomavirus DNA detection: a preliminary study of compliance and feasibility in BOLIVIA. AB - BACKGROUND: Cervical cancer incidence and mortality rates in Bolivia are among the highest in Latin America. This investigation aims to evaluate the possibility of using simple devices, e.g. a cotton swab and a glass slide, for self-sampling in order to detect human papillomavirus (HPV) DNA by PCR in cervico-vaginal cells. METHODS: In the first phase of our study we evaluated the use of a glass slide as a transport medium for cervical cells. A physician took paired-cervical samples from 235 women. One sample was transported in Easyfix(r) solution and the other sample was smeared over a glass slide. Both were further analyzed and compared for human DNA recovery and HPV detection. A kappa value was determined to evaluate the agreement between the HPV DNA detection rates. In the second phase of the study, 222 women from the urban, peri-urban and rural regions of Cochabamba were requested to perform self-sampling using the following devices: a cotton swab combined with a glass slide, and a vaginal tampon. Women gave their opinion about the self-sampling technique. Finally, the agreement for high risk HPV detection between self- and physician-collected samples was performed in 201 samples in order to evaluate the self-sampling technique. RESULTS: Firstly, the comparison between Easyfix(r) solution and the glass slide to transport clinical samples gave a good agreement for HPV DNA detection (kappa = 0.71, 95% CI 0.60 0.81). Secondly, self-sampling, especially with cotton swab combined with glass slide, would generally be preferred over clinician sampling for a screening program based on HPV detection. Finally, we showed a good agreement between self- and physician collected samples for high risk-HPV detection (kappa = 0.71, 95% CI 0.55-0.88). CONCLUSIONS: Simple devices such as a cotton swab and a glass slide can be used to perform self-sampling and HPV DNA detection. Furthermore, most Bolivian women preferred self-sampling over clinician-sampling for cervical cancer screening. PMID- 29273033 TI - Determinants of facility readiness for integration of family planning with HIV testing and counseling services: evidence from the Tanzania service provision assessment survey, 2014-2015. AB - BACKGROUND: Global policy reports, national frameworks, and programmatic tools and guidance emphasize the integration of family planning and HIV testing and counseling services to ensure universal access to reproductive health care and HIV prevention. However, the status of integration between these two services in Tanzanian health facilities is unclear. This study examined determinants of facility readiness for integration of family planning with HIV testing and counseling services in Tanzania. METHODS: Data from the 2014-2015 Tanzania Service Provision Assessment Survey were analyzed. Facilities were considered ready for integration of family planning with HIV testing and counseling services if they scored >= 50% on both family planning and HIV testing and counseling service readiness indices as identified by the World Health Organization. All analyses were adjusted for clustering effects, and estimates were weighted to correct for non-responses and disproportionate sampling. Descriptive, bivariate, and multivariate logistic regression analyses were performed. RESULTS: A total of 1188 health facilities were included in the study. Of all of the health facilities, 915 (77%) reported offering both family planning and HIV testing and counseling services, while only 536 (45%) were considered ready to integrate these two services. Significant determinants of facility readiness for integrating these two services were being government owned [AOR = 3.2; 95%CI, 1.9 5.6], having routine management meetings [AOR = 1.9; 95%CI, 1.1-3.3], availability of guidelines [AOR = 3.8; 95%CI, 2.4-5.8], in-service training of staff [AOR = 2.6; 95%CI, 1.3-5.2], and availability of laboratories for HIV testing [AOR = 17.1; 95%CI, 8.2-35.6]. CONCLUSION: The proportion of facility readiness for the integration of family planning with HIV testing and counseling in Tanzania is unsatisfactory. The Ministry of Health should distribute and ensure constant availability of guidelines, availability of rapid diagnostic tests for HIV testing, and the provision of refresher training to health providers, as these were among the determinants of facility readiness. PMID- 29273034 TI - Data distribution in public veterinary service: health and safety challenges push for context-aware systems. AB - BACKGROUND: Today's globalised and interconnected world is characterized by intertwined and quickly evolving relationships between animals, humans and their environment and by an escalating number of accessible data for public health. The public veterinary services must exploit new modeling and decision strategies to face these changes. The organization and control of data flows have become crucial to effectively evaluate the evolution and safety concerns of a given situation in the territory. This paper discusses what is needed to develop modern strategies to optimize data distribution to the stakeholders. MAIN TEXT: If traditionally the system manager and knowledge engineer have been concerned with the increase of speed of data flow and the improvement of data quality, nowadays they need to worry about data overflow as well. To avoid this risk an information system should be capable of selecting the data which need to be shown to the human operator. In this perspective, two aspects need to be distinguished: data classification vs data distribution. Data classification is the problem of organizing data depending on what they refer to and on the way they are obtained; data distribution is the problem of selecting which data is accessible to which stakeholder. Data classification can be established and implemented via ontological analysis and formal logic but we claim that a context-based selection of data should be integrated in the data distribution application. Data distribution should provide these new features: (a) the organization of situation types distinguishing at least ordinary vs extraordinary scenarios (contextualization of scenarios); (b) the possibility to focus on the data that are really important in a given scenario (data contextualization by scenarios); and (c) the classification of which data is relevant to which stakeholder (data contextualization by users). SHORT CONCLUSION: Public veterinary services, to efficaciously and efficiently manage the information needed for today's health and safety challenges, should contextualize and filter the continuous and growing flow of data by setting suitable frameworks to classify data, users' roles and possible situations. PMID- 29273035 TI - Describing objectively measured physical activity levels, patterns, and correlates in a cross sectional sample of infants and toddlers from South Africa. AB - BACKGROUND: Physical activity is considered to have health benefits across the lifespan but levels, patterns, and correlates have not been well described in infants and toddlers under the age of two years. METHODS: This study aimed to describe objectively and subjectively measured physical activity in a group of South African infants aged 3- to 24-months (n = 140), and to investigate individual and maternal correlates of physical activity in this sample. Infants' physical activity was measured using an Axivity AX3 wrist-worn accelerometer for one week and the mean vector magnitude was calculated. In addition, mothers reported the average amount of time their infant spent in various types of activities (including in front of the TV), their beliefs about infants' physical activity, access to equipment in the home environment, and ages of motor development milestone attainment. Analysis of variance (ANOVA) and pair-wise correlations were used to test age and sex differences and associations with potential correlates. RESULTS: There were significant age and sex effects on the distribution of time spent at different physical activity intensities (Wilks' lambda = 0.06, p < 0.01). In all cases, the trend was for boys to spend more time in higher intensity physical activity and less time in lower intensity activity than girls; and for time spent in higher intensity activities to be higher in older children. Time spent outside was higher in boys, and this reached significance at 18-months (F = 3.84, p = 0.02). Less concern around floor play was associated with higher physical activity at 12-months in females only (p = 0.03, r = 0.54), and no other maternal beliefs were correlated with physical activity. The majority (94%) of children were exceeding TV time recommendations. When controlling for age and sex, overall TV time was positively associated with BMI z-score (beta=0.01, p = 0.05). CONCLUSION: This study is the first to show sex and age differences in the patterns of physical activity, and to report on objectively measured and maternal reported physical activity and sedentary behaviour in the first two years of life in South Africa infants. Infants and toddlers should be provided with as many opportunities to be active through play as possible, and TV time should be limited. PMID- 29273036 TI - Sport and ageing: a systematic review of the determinants and trends of participation in sport for older adults. AB - BACKGROUND: The global population is ageing. As ageing is often associated with a decline in health, there is a need to further develop preventative health measures. Physical activity can positively influence older adults' (aged 50 years and older) health. Previous research on the relationship between physical activity and health for older adults has mainly focused on physical activity in general, and not specific types of exercise. Due to the social nature of sport, it may assist in improving physical, mental and social health for older adults. Sport, as a form of physical activity, has not been widely explored as a physical activity opportunity for older adults. This review concurrently explored two research questions: the determinants and the trends of sport participation for community dwelling older adults. METHODS: Two parallel systematic searches of nine electronic databases were conducted in December 2015 for the two research questions. English language quantitative and qualitative studies that provided specific results for community dwelling older adults' sport participation were included and a quality ratings assessment was undertaken. RESULTS: There were 10,171 studies initially identified for the first research question and 1992 studies for the second research question. This culminated in 18 and 8 studies respectively that met the inclusion criteria. The most frequently mentioned determinants of participation were health and using sport to negotiate the ageing process. The most frequently mentioned trends of sport participation were the effect of historical sport participation on current participation, and sport participation across the lifespan. The main themes for both research questions had contrasting results, for example, participation in sport could improve health, but poor health was also a limitation of sport participation. CONCLUSIONS: This review demonstrates that older adults are a heterogeneous age group, and therefore require different strategies than other age groups to successfully participate in sport. It is recommended that the main findings from this review are incorporated into specific strategies to develop age appropriate sporting opportunities for older adults, so that sport can be presented as a viable physical activity option for this age group. PMID- 29273037 TI - Economic and organizational impact of a clinical decision support system on laboratory test ordering. AB - BACKGROUND: We studied the impact of a clinical decision support system (CDSS) implemented in a few wards of two Italian health care organizations on the ordering of redundant laboratory tests under different perspectives: (1) analysis of the volume of tests, (2) cost analysis, (3) end-user satisfaction before and after the installation of the CDSS. METHODS: (1) and (2) were performed by comparing the ordering of laboratory tests between an intervention group of wards where a CDSS was in use and a second (control) group where a CDSS was not in use; data were compared during a 3-month period before (2014) and a 3-month period after (2015) CDSS installation. To measure end-user satisfaction (3), a questionnaire based on POESUS was administered to the medical staff. RESULTS: After the introduction of the CDSS, the number of laboratory tests requested decreased by 16.44% and costs decreased by 16.53% in the intervention group, versus an increase in the number of tests (+3.75%) and of costs (+1.78%) in the control group. Feedback from practice showed that the medical staff was generally satisfied with the CDSS and perceived its benefits, but they were less satisfied with its technical performance in terms of slow response time. CONCLUSIONS: The implementation of CDSSs can have a positive impact on both the efficiency of care provision and health care costs. The experience of using a CDSS can also result in good practice to be implemented by other health care organizations, considering the positive result from the first attempt to gather the point of view of end-users in Italy. PMID- 29273038 TI - Anti-stress and neuronal cell differentiation induction effects of Rosmarinus officinalis L. essential oil. AB - BACKGROUND: Mood disorder accounts for 13 % of global disease burden. And while therapeutic agents are available, usually orally administered, most have unwanted side effects, and thus making the inhalation of essential oils (EOs) an attractive alternative therapy. Rosmarinus officinalis EO (ROEO), Mediterranean ROEO reported to improve cognition, mood, and memory, the effect on stress of which has not yet been determined. Here, the anti-stress effect of ROEO on stress was evaluated in vivo and in vitro. METHODS: Six-week-old male ICR mice were made to inhale ROEO and subjected to tail suspension test (TST). To determine the neuronal differentiation effect of ROEO in vitro, induction of ROEO-treated PC12 cells differentiation was observed. Intracellular acetylcholine and choline, as well as the Gap43 gene expression levels were also determined. RESULTS: Inhalation of ROEO significantly decreased the immobility time of ICR mice and serum corticosterone level, accompanied by increased brain dopamine level. Determination of the underlying mechanism in vitro revealed a PC12 differentiation-induction effect through the modulation of intracellular acetylcholine, choline, and Gap43 gene expression levels. ROEO activates the stress response system through the NGF pathway and the hypothalamus-pituitary adrenal axis, promoting dopamine production and secretion. The effect of ROEO may be attributed to its bioactive components, specifically to alpha-pinene, one of its major compounds that has anxiolytic property. CONCLUSIONS: The results of this study suggest that ROEO inhalation has therapeutic potential against stress related psychiatric disorders. PMID- 29273039 TI - Including pork in the Mediterranean diet for an Australian population: Protocol for a randomised controlled trial assessing cardiovascular risk and cognitive function. AB - BACKGROUND: The Mediterranean diet is characterised by the high consumption of extra virgin olive oil, fruits, vegetables, grains, legumes and nuts; moderate consumption of fish, poultry, eggs and dairy; and low consumption of red meat and sweets. Cross sectional, longitudinal and intervention studies indicate that a Mediterranean diet may be effective for the prevention of cardiovascular disease and dementia. However, previous research suggests that an Australian population may find red meat restrictions difficult, which could affect long term sustainability of the diet. METHODS: This paper outlines the protocol for a randomised controlled trial that will assess the cardiovascular and cognitive benefits of a Mediterranean diet modified to include 2-3 weekly serves of fresh, lean pork. A 24-week cross-over design trial will compare a modified Mediterranean diet with a low-fat control diet in at-risk men and women. Participants will follow each of the two diets for 8 weeks, with an 8-week washout period separating interventions. Home measured systolic blood pressure will be the primary outcome measure. Secondary outcomes will include body mass index, body composition, fasting blood lipids, C-reactive protein, fasting plasma glucose, fasting serum insulin, erythrocyte fatty acids, cognitive function, psychological health and well-being, and dementia risk. DISCUSSION: To our knowledge this research is the first to investigate whether an alternate source of protein can be included in the Mediterranean diet to increase sustainability and feasibility for a non-Mediterranean population. Findings will be significant for the prevention of cardiovascular disease and age-related decline, and may inform individuals, clinicians and public health policy. TRIAL REGISTRATION: ACTRN12616001046493 . Registered 5 August 2016. PMID- 29273040 TI - Multiple constraints compromise decision-making about implantable medical devices for individual patients: qualitative interviews with physicians. AB - BACKGROUND: Little research has examined how physicians choose medical devices for treating individual patients to reveal if interventions are needed to support decision-making and reduce device-associated morbidity and mortality. This study explored factors that influence choice of implantable device from among available options. METHODS: A descriptive qualitative approach was used. Physicians who implant orthopedic and cardiovascular devices were identified in publicly available directories and web sites. They were asked how they decided what device to use in a given patient, sources of information they consulted, and how patients were engaged in decision-making. Sampling was concurrent with data collection and analysis to achieve thematic saturation. Data were analyzed using constant comparative technique by all members of the research team. RESULTS: Twenty-two physicians from five Canadian provinces (10 cardiovascular, 12 orthopedic; 8, 10 and 4 early, mid and late career, respectively) were interviewed. Responses did not differ by specialty, geographic region or career stage. Five major categories of themes emerged that all influence decision-making about a range of devices, and often compromise choice of the most suitable device for a given patient, potentially leading to sub-optimal clinical outcomes: lack of evidence on device performance, patient factors, physician factors, organizational and health system factors, and device and device market factors. In the absence of evidence from research or device registries, tacit knowledge from trusted colleagues and less-trusted industry representatives informed device choice. Patients were rarely engaged in decision-making. Physician preference for particular devices was a barrier to acquiring competency in devices potentially more suitable for patients. Access to suitable devices was further limited to the number of comparable devices on the market, local inventory and purchasing contract specifications. CONCLUSIONS: This study revealed that decision-making about devices is complex, cognitively challenging and constrained by several factors limiting access to and use of devices that could optimize patient outcomes. Further research is needed to assess the impact of these constraints on clinical outcomes, and develop interventions that optimize decision-making about device choice for treating given patients. PMID- 29273041 TI - Integrative health care - What are the relevant health outcomes from a practice perspective? A survey. AB - BACKGROUND: Integrative health care (IHC) is an innovative approach to health care delivery. There is increasing focus on and demand for the evaluation of IHC practices. To ensure such evaluations capture their full scope, a clear understanding of the types of outcomes relevant to an IHC approach is needed. The objective was to describe the health domains and health outcomes relevant to IHC practices in Canada. METHODS: An online survey of Canadian IHC clinics. Survey questions were informed by the IN-CAM Health Outcomes Database. Descriptive statistics were used to summarize the data. Chi square tests were used to compare responses between clinic types and patient groups served. RESULTS: Surveys were completed by 21 clinics (response rate: 50%). Physical, psychological, social, individualized and holistic were identified as applicable health domains by more than 90% of the clinics. Spiritual domain was the least relevant (70% of clinics). A number of relevant outcomes within each domain were identified. A core set of outcomes were identified and included: fatigue, anxiety, stress, and patient-provider relationship, and quality of life. Clinics with primarily conventional health practitioners were less likely to address overall well-being (p = 0.04), while clinics that provided care to a specialized patient population (i.e. cancer patients) or a mix of general and specialized patients were less likely to address religious practices (p = 0.04) or spiritual experiences (p = 0.007). CONCLUSIONS: Outcomes across health domains should be considered in the evaluation of IHC models to generate an understanding of the full scope of effectiveness of IHC approaches. The core set of outcomes identified may facilitate this task. Ethics approval (Ethics ID REB14-0495) was received from the Conjoint Health Research Ethics Board at the University of Calgary. PMID- 29273042 TI - Coronavirus and paramyxovirus in bats from Northwest Italy. AB - BACKGROUND: Bat-borne virus surveillance is necessary for determining inter species transmission risks and is important due to the wide-range of bat species which may harbour potential pathogens. This study aimed to monitor coronaviruses (CoVs) and paramyxoviruses (PMVs) in bats roosting in northwest Italian regions. Our investigation was focused on CoVs and PMVs due to their proven ability to switch host and their zoonotic potential. Here we provide the phylogenetic characterization of the highly conserved polymerase gene fragments. RESULTS: Family-wide PCR screenings were used to test 302 bats belonging to 19 different bat species. Thirty-eight animals from 12 locations were confirmed as PCR positive, with an overall detection rate of 12.6% [95% CI: 9.3-16.8]. CoV RNA was found in 36 bats belonging to eight species, while PMV RNA in three Pipistrellus spp. Phylogenetic characterization have been obtained for 15 alpha- CoVs, 5 beta CoVs and three PMVs; moreover one P. pipistrellus resulted co-infected with both CoV and PMV. A divergent alpha-CoV clade from Myotis nattereri SpA is also described. The compact cluster of beta-CoVs from R. ferrumequinum roosts expands the current viral sequence database, specifically for this species in Europe. To our knowledge this is the first report of CoVs in Plecotus auritus and M. oxygnathus, and of PMVs in P. kuhlii. CONCLUSIONS: This study identified alpha and beta-CoVs in new bat species and in previously unsurveyed Italian regions. To our knowledge this represents the first and unique report of PMVs in Italy. The 23 new bat genetic sequences presented will expand the current molecular bat borne virus databases. Considering the amount of novel bat-borne PMVs associated with the emergence of zoonotic infections in animals and humans in the last years, the definition of viral diversity within European bat species is needed. Performing surveillance studies within a specific geographic area can provide awareness of viral burden where bats roost in close proximity to spillover hosts, and form the basis for the appropriate control measures against potential threats for public health and optimal management of bats and their habitats. PMID- 29273043 TI - Psychometric properties of the FACT-M questionnaire in patients with Merkel cell carcinoma. AB - BACKGROUND: No validated disease-specific questionnaires exist to capture health related quality of life (HRQoL) in patients with Merkel cell carcinoma (MCC). The Functional Assessment of Cancer Therapy - Melanoma (FACT-M) is validated in patients with melanoma, which shares many similarities with MCC. This paper reports the psychometric properties of the FACT-M in the metastatic MCC population. METHODS: Data were collected as part of a single-arm, open-label, multicenter trial involving patients with metastatic MCC who had failed at least one previous line of chemotherapy. FACT-M and EQ-5D were administered at baseline, Week 7, Week 13, and Week 25. An optional interview was administered at the same time points. MCC-specific FACT-M scores were derived following a combined quantitative and qualitative approach. Reliability and construct validity of original and additional MCC-specific FACT-M scores were assessed at baseline. Capacity to detect change in tumor size was assessed from baseline to Week 7. Minimally important differences (MIDs) were computed using distribution and anchor-based methods. RESULTS: Baseline assessments were available in 70 patients (mean age: 70 years; 74.3% male); 19 patients were interviewed at baseline. Additional MCC-specific scores were as follows: Physical Function score (six items), Psychological Impact score (six items), and MCC summary score (12 items). FACT-M original and additional MCC-specific scores both demonstrated acceptable psychometric properties: high reliability (Cronbach's alpha: 0.81 0.96), good convergent validity (correlations above 0.4 observed for 88% of items of the Melanoma surgery scale, 75% of items of the Melanoma scale, and 100% of items of the other FACT-M domains). Some evidence of floor/ceiling effects and poor discriminant ability was found. Higher scores (better HRQoL) on all FACT-M domains were observed in patients with better functioning (assessed by ECOG performance score), supporting clinical validity. Despite the small sample for responsiveness analysis (n = 37), the majority of FACT-M scores showed sensitivity to changes in tumor size at Week 7 with small to moderate effect sizes. MIDs were consistent with previously reported values in the literature for FACT-M domains. CONCLUSIONS: FACT-M is suitable to capture HRQoL in patients with metastatic MCC, thus making it a potential candidate for assessing HRQoL in MCC trials. TRIAL REGISTRATION: This study is a post-hoc analysis conducted on data collected in Part A of the JAVELIN Merkel 200 trial. This trial was registered on 2 June 2014 with ClinicalTrials.gov as NCT02155647 . PMID- 29273044 TI - A randomized controlled trial of exercise during pregnancy on maternal and neonatal outcomes: results from the PAMELA study. AB - BACKGROUND: Women are encouraged to be physically active during pregnancy. Despite available evidence supporting antenatal physical activity to bring health benefits for both the mother and child, the most effective way to prevent some maternal and fetal outcomes is still unclear. The purpose of this study was to evaluate the efficacy of an exercise intervention to prevent negative maternal and newborn health outcomes. METHODS: A randomized controlled trial (RCT) nested into the 2015 Pelotas (Brazil) Birth Cohort Study was carried-out with 639 healthy pregnant women, 213 in the intervention group (IG) and 426 in the control (CG) group. An exercise-based intervention was conducted three times/week for 16 weeks from 16-20 to 32-36 weeks' gestation. The main outcomes were preterm birth and pre-eclampsia. Gestational age was calculated based on several parameters, including routine ultrassounds and/or last menstrual period and categorized as < 37 weeks and >= 37 weeks for evaluation of preterm birth. Pre-eclampsia was self reported. Secondary outcomes were gestational weight gain, gestational diabetes, birth weight, infant length, and head circumference. Analyses were performed by intention-to-treat (ITT) and per protocol (70% of the 48 planned exercise sessions). Odds ratio were derived using unconditional logistic regression. RESULTS: The IG and CG did not differ at baseline regarding their mean age (27.2 years +/- 5.3 vs. 27.1 years +/- 5.7) and mean pre-pregnancy body mass index (25.1 +/- 3.9 vs. 25.2 +/- 4.1 kg/m2). The mean adherence to the exercise intervention was 27 +/- 17.2 sessions (out of a potential 48) with 40.4% attending > = 70% of the recommended exercise sessions. A total of 594 participants (IG:198; CG: 396) were included in the ITT and 479 (IG: 83; CG: 396) were included in the per protocol analyses. There were no significant differences in the incidence of preterm birth and pre-eclampsia between groups in the ITT and per protocol analysis. There were also no differences between the two groups in mean gestational weight gain, gestational diabetes, birth weight, infant length, and head circumference. CONCLUSIONS: While the RCT did not support the benefits of exercise performed during pregnancy on preeclampsia and preterm birth, the exercise program also did not present adverse impacts on newborn health. Our findings may contribute to promote intervention strategies that motivate health providers to encourage pregnant women to be more physically active. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02148965 , registered on 22 May 2014. PMID- 29273045 TI - Doctors' opinion on the contribution of coordination mechanisms to improving clinical coordination between primary and outpatient secondary care in the Catalan national health system. AB - BACKGROUND: Clinical coordination is considered a health policy priority as its absence can lead to poor quality of care and inefficiency. A key challenge is to identify which strategies should be implemented to improve coordination. The aim is to analyse doctors' opinions on the contribution of mechanisms to improving clinical coordination between primary and outpatient secondary care and the factors influencing their use. METHODS: A qualitative descriptive study in three healthcare networks of the Catalan national health system. A two-stage theoretical sample was designed: in the first stage, networks with different management models were selected; in the second, primary care (n = 26) and secondary care (n = 24) doctors. Data were collected using semi-structured interviews. Final sample size was reached by saturation. A thematic content analysis was conducted, segmented by network and care level. RESULTS: With few differences across networks, doctors identified similar mechanisms contributing to clinical coordination: 1) shared EMR facilitating clinical information transfer and uptake; 2) mechanisms enabling problem-solving communication and agreement on clinical approaches, which varied across networks (joint clinical case conferences, which also promote mutual knowledge and training of primary care doctors; virtual consultations through EMR and email); and 3) referral protocols and use of the telephone facilitating access to secondary care after referrals. Doctors identified organizational (insufficient time, incompatible timetables, design of mechanisms) and professional factors (knowing each other, attitude towards collaboration, concerns over misdiagnosis) that influence the use of mechanisms. DISCUSSION: Mechanisms that most contribute to clinical coordination are feedback mechanisms, that is those based on mutual adjustment, that allow doctors to exchange information and communicate. Their use might be enhanced by focusing on adequate working conditions, mechanism design and creating conditions that promote mutual knowledge and positive attitudes towards collaboration. PMID- 29273046 TI - Development and validation of a patient-reported questionnaire assessing systemic therapy induced diarrhea in oncology patients. AB - BACKGROUND: Systemic therapy-induced diarrhea (STID) is a common side effect experienced by more than half of cancer patients. Despite STID-associated complications and poorer quality of life (QoL), no validated assessment tools exist to accurately assess STID occurrence and severity to guide clinical management. Therefore, we developed and validated a patient-reported questionnaire (STIDAT). METHODS: The STIDAT was developed using the FDA iterative process for patient-reported outcomes. A literature search uncovered potential items and questions for questionnaire construction used by oncology clinicians to develop questions for the preliminary instrument. The instrument was evaluated on its face validity and content validity by patient interviews. Repetitive, similar and different themes uncovered from patient interviews were implemented to revise the instrument to the version used for validation. Patients starting high-risk STID treatments were monitored using the STIDAT, bowel diaries and EORTC QLQ-C30. The STIDAT was evaluated for construct validity using exploratory factor analysis (EFA) using minimal residual method with Promax rotation, reliability and consistency. A weighted scoring system was developed and a receiver-operating characteristic (ROC) curve evaluated the tool's ability to detect STID occurrence. Median scores and variability were analysed to determine how well it differentiates between diarrhea severities. A post-hoc analysis determined how diarrhea severity impacted QoL of cancer patients. RESULTS: Patients defined diarrhea based on presence of watery stool. The STIDAT assessed patient's perception of having diarrhea, daily number of bowel movements, daily number of diarrhea episodes, antidiarrheal medication use, the presence of urgency, abdominal pain, abdominal spasms or fecal incontinence, patient's perception of diarrhea severity, and QoL. These dimensions were sorted into four clusters using EFA - patient's perception of diarrhea, frequency of diarrhea, fecal incontinence and abdominal symptoms. Cronbach's alpha was 0.78; kappa ranged from 0.934-0.952, except for abdominal spasms (kappa = 0.0455). The positive predictive value was 96.4%, with the minimum score of 1.35 predicting a positive STID occurrence. Patients with moderate or severe diarrhea experience significant decreases in QoL compared to those with no diarrhea. CONCLUSIONS: This is the first patient reported questionnaire that accurately predicts the occurrence and severity of diarrhea in oncology patients via assessing several bowel habit dimensions. PMID- 29273047 TI - Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia. AB - BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells. METHODS: We examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. RESULTS: In this study, we observed that pretreatment with donepezil suppressed the TNFalpha-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFalpha-induced intracellular Ca2+ elevation through the nicotinic alpha7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFalpha-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFalpha-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFalpha treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. CONCLUSIONS: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain. PMID- 29273048 TI - PROPEL: implementation of an evidence based pelvic floor muscle training intervention for women with pelvic organ prolapse: a realist evaluation and outcomes study protocol. AB - BACKGROUND: Pelvic Organ Prolapse (POP) is estimated to affect 41%-50% of women aged over 40. Findings from the multi-centre randomised controlled "Pelvic Organ Prolapse PhysiotherapY" (POPPY) trial showed that individualised pelvic floor muscle training (PFMT) was effective in reducing symptoms of prolapse, improved quality of life and showed clear potential to be cost-effective. However, provision of PFMT for prolapse continues to vary across the UK, with limited numbers of women's health physiotherapists specialising in its delivery. Implementation of this robust evidence from the POPPY trial will require attention to different models of delivery (e.g. staff skill mix) to fit with differing care environments. METHODS: A Realist Evaluation (RE) of implementation and outcomes of PFMT delivery in contrasting NHS settings will be conducted using multiple case study sites. Involving substantial local stakeholder engagement will permit a detailed exploration of how local sites make decisions on how to deliver PFMT and how these lead to service change. The RE will track how implementation is working; identify what influences outcomes; and, guided by the RE-AIM framework, will collect robust outcomes data. This will require mixed methods data collection and analysis. Qualitative data will be collected at four time-points across each site to understand local contexts and decisions regarding options for intervention delivery and to monitor implementation, uptake, adherence and outcomes. Patient outcome data will be collected at baseline, six months and one year follow-up for 120 women. Primary outcome will be the Pelvic Organ Prolapse Symptom Score (POP-SS). An economic evaluation will assess the costs and benefits associated with different delivery models taking account of further health care resource use by the women. Cost data will be combined with the primary outcome in a cost effectiveness analysis, and the EQ-5D-5L data in a cost utility analysis for each of the different models of delivery. DISCUSSION: Study of the implementation of varying models of service delivery of PFMT across contrasting sites combined with outcomes data and a cost effectiveness analysis will provide insight into the implementation and value of different models of PFMT service delivery and the cost benefits to the NHS in the longer term. PMID- 29273049 TI - Estimating species pools for a single ecological assemblage. AB - BACKGROUND: The species pool concept was formulated over the past several decades and has since played an important role in explaining multi-scale ecological patterns. Previous statistical methods were developed to identify species pools based on broad-scale species range maps or community similarity computed from data collected from many areas. No statistical method is available for estimating species pools for a single local community (sampling area size may be very small as <= 1 km2). In this study, based on limited local abundance information, we developed a simple method to estimate the area size and richness of a species pool for a local ecological community. The method involves two steps. In the first step, parameters from a truncated negative trinomial model characterizing the distributional aggregation of all species (i.e., non-random species distribution) in the local community were estimated. In the second step, we assume that the unseen species in the local community are most likely the rare species, only found in the remaining part of the species pool, and vice versa, if the remaining portion of the pool was surveyed and was contrasted with the sampled area. Therefore, we can estimate the area size of the pool, as long as an abundance threshold for defining rare species is given. Since the size of the pool is dependent on the rarity threshold, to unanimously determine the pool size, we developed an optimal method to delineate the rarity threshold based on the balance of the changing rates of species absence probabilities in the sampled and unsampled areas of the pool. RESULTS: For a 50 ha (0.5 km2) forest plot in the Barro Colorado Island of central Panama, our model predicted that the local, if not regional, species pool for the 0.5 km2 forest plot was nearly the entire island. Accordingly, tree species richness in this pool was estimated as around 360. When the sampling size was smaller, the upper bound of the 95% confidence interval could reach 418, which was very close to the flora record of tree richness for the island. A numerical test further demonstrated the power and reliability of the proposed method, as the true values of area size and species richness for the hypothetical species pool have been well covered by the 95% confidence intervals of the true values. CONCLUSIONS: Our method fills the knowledge gap on estimating species pools for a single local ecological assemblage with little information. The method is statistically robust and independent of sampling size, as proved by both empirical and numerical tests. PMID- 29273050 TI - Responses to provision of personalised cancer risk information: a qualitative interview study with members of the public. AB - BACKGROUND: It is estimated that nearly 600,000 cancer cases in the UK could have been avoided in the past five years if people had healthier lifestyles. A number of theories of behaviour change suggest that before people will change health behaviours, they must accept that a risk applies to them. This study aimed to explore the views of the public on receiving personalised cancer risk information and the potential for that information to motivate behaviour change. METHODS: We conducted 27 interviews with members of the public (mean age 49 +/- 23 years). Each participant completed a questionnaire to allow calculation of their risk of developing the most common cancers (10 for women, 8 for men). During the interviews we presented their risk using a web-based tool developed for the study and discussions covered their views on receiving that information. Each interview was audio-recorded and then analysed using thematic analysis. RESULTS: Participants generally viewed the concept of personalised cancer risk positively. The first reaction of almost all when presented with their 10-year risk of an individual cancer without any further context was that it was low and not concerning. Views on what constituted a high risk ranged widely, from 0.5 to 60%. All felt seeing the impact of changes in lifestyle was helpful. For some this led to intentions to change behaviour, but reductions in risk were not always motivating as the risks were considered low and differences small. CONCLUSIONS: Provision of personalised cancer risk was well received and may be a useful addition to other cancer prevention initiatives. Further work is needed in particular to develop ways to present cancer risk that reflect the general perception of what constitutes a risk high enough to motivate behaviour change and help patients contextualise a less well known health risk by providing a frame of reference. PMID- 29273052 TI - Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. AB - BACKGROUND: Microglia are major players in the pathogenesis of multiple sclerosis (MS) and may play a dual role in disease progression. The activation status of microglia in vivo is highly dynamic and occurs as a continuum, with the pro inflammatory and anti-inflammatory phenotypes on either end of this spectrum. Little is known about in vivo dynamics of microglia phenotypes in MS due to the lack of diagnostic tools. Positron emission tomography (PET) imaging is a powerful non-invasive technique that allows real-time imaging of microglia activation phenotypes in the central nervous system, depending on the availability of selective PET tracers. Our objective is to investigate and characterize the expression of the purinergic receptors P2Y12R and P2X7R as potential targets for PET tracer development and subsequent PET imaging in order to evaluate the dynamics of microglia status in vivo. METHODS: We used immunohistochemical analysis to explore the expression of P2Y12R and P2X7R in experimental autoimmune encephalomyelitis (EAE) post-mortem tissues and different stages of well-characterized MS lesions. We evaluated by quantitative real-time polymerase chain reaction the expression of P2Y12R and P2X7R in human polarized microglia, and we performed autoradiography binding assay with radiolabeled P2Y12R and P2X7R antagonists using MS and rat EAE tissues. RESULTS: Here, we demonstrate that P2X7R is associated with a pro-inflammatory phenotype of human microglia in vitro, and is highly expressed in microglia in MS lesions as well as during the peak of EAE. In contrast, P2Y12R was associated with an anti inflammatory phenotype in human microglia in vitro and was expressed at lower levels in active inflammatory MS lesions compared to normal-appearing white matter (NAWM) and similarly in EAE, while its expression increased in the remission phase of EAE. Binding of radiolabeled tracers specific for P2Y12R and P2X7R on ex vivo tissues validated the value of these receptors as PET imaging targets for microglia phenotypes in vivo. CONCLUSION: Our results suggest that P2Y12R and P2X7R are excellent targets for PET imaging to discriminate distinct microglia phenotypes in MS. Ultimately, this may provide insight into the role of microglia in disease progression and monitor novel treatment strategies to alter microglia phenotype. PMID- 29273051 TI - A role for B cells in organic dust induced lung inflammation. AB - BACKGROUND: Agriculture organic dust exposures induce lung disease with lymphoid aggregates comprised of both T and B cells. The precise role of B cells in mediating lung inflammation is unknown, yet might be relevant given the emerging role of B cells in obstructive pulmonary disease and associated autoimmunity. METHODS: Using an established animal model, C57BL/6 wild-type (WT) and B-cell receptor (BCR) knock-out (KO) mice were repetitively treated with intranasal inhalation of swine confinement organic dust extract (ODE) daily for 3 weeks and lavage fluid, lung tissues, and serum were collected. RESULTS: ODE-induced neutrophil influx in lavage fluid was not reduced in BCR KO animals, but there was reduction in TNF-alpha, IL-6, CXCL1, and CXCL2 release. ODE-induced lymphoid aggregates failed to develop in BCR KO mice. There was a decrease in ODE-induced lung tissue CD11c+CD11b+ exudative macrophages and compensatory increase in CD8+ T cells in lavage fluid of BCR KO animals. Compared to saline, there was an expansion of conventional B2-, innate B1 (CD19+CD11b+CD5+/-)-, and memory (CD19+CD273+/-CD73+/-) B cells following ODE exposure in WT mice. Autoreactive responses including serum IgG anti-citrullinated protein antibody (ACPA) and anti malondialdehyde-acetaldehyde (MAA) autoantibodies were increased in ODE treated WT mice as compared to saline control. B cells and serum immunoglobulins were not detected in BCR KO animals. CONCLUSIONS: Lung tissue staining for citrullinated and MAA modified proteins were increased in ODE-treated WT animals, but not BCR KO mice. These studies show that agriculture organic dust induced lung inflammation is dependent upon B cells, and dust exposure induces an autoreactive response. PMID- 29273054 TI - Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor. AB - BACKGROUND: Our previous studies showed that vasoconstrictor applied topically to rat skin minutes before irradiation completely prevented radiodermatitis. Here we report on a Phase IIa study of topically applied NG12-1 vasoconstrictor to prevent radiodermatitis in post-lumpectomy breast cancer patients who received at least 40 Gray to the whole breast using standard regimens. METHODS: Patients had undergone surgery for Stage Ia, Ib, or IIa infiltrating ductal or lobular carcinoma of the breast or ductal carcinoma in situ. NG12-1 formulation was applied topically to the same 50-cm2 treatment site within the radiation field 20 min before each daily radiotherapy fraction. RESULTS: Scores indicated significant reductions in radiodermatitis at the NG12-1 treatment site versus control areas in the same radiotherapy field. The mean dermatitis score for all subjects was 0.47 (SD 0.24) in the NG12-1-treated area versus 0.72 (SD 0.22) in the control area (P = 0.022). Analysis by two independent investigators indicated radiodermatitis reductions in 9 of the 9 patients with scorable radiodermatitis severity, and one patient with insufficient radiodermatitis to enable scoring. There were no serious adverse events from NG12-1 treatment. CONCLUSIONS: Thirty, daily, NG12-1 treatments, topically applied minutes before radiotherapy, were well tolerated and conferred statistically significant reductions in radiodermatitis severity (P = 0.022). TRIAL REGISTRATION: NCT01263366 ; clinicaltrials.gov. PMID- 29273053 TI - Are respiratory complications of Plasmodium vivax malaria an underestimated problem? AB - BACKGROUND: Respiratory complications are uncommon, but often life-threatening features of Plasmodium vivax malaria. This study aimed to estimate the prevalence and lethality associated with such complications among P. vivax malaria patients in a tertiary hospital in the Western Brazilian Amazon, and to identify variables associated with severe respiratory complications, intensive care need and death. Medical records from 2009 to 2016 were reviewed aiming to identify all patients diagnosed with P. vivax malaria and respiratory complications. Prevalence, lethality and risk factors associated with WHO defined respiratory complications, intensive care need and death were assessed. RESULTS: A total of 587 vivax malaria patients were hospitalized during the study period. Thirty (5.1%) developed respiratory complications. Thirteen (43.3%) developed severe respiratory complications, intensive care was required for 12 (40%) patients and 5 (16.6%) died. On admission, anaemia and thrombocytopaenia were common findings, whereas fever was unusual. Patients presented different classes of parasitaemia and six were aparasitaemic on admission. Time to respiratory complications occurred after anti-malarials administration in 18 (60%) patients and progressed very rapidly. Seventeen patients (56.7%) had comorbidities and/or concomitant conditions, which were significantly associated to higher odds of developing severe respiratory complications, need for intensive care and death (p < 0.05). CONCLUSION: Respiratory complications were shown to be associated with significant mortality in this population. Patients with comorbidities and/or concomitant conditions require special attention to avoid this potential life threatening complication. PMID- 29273055 TI - Nonradiographic axial spondyloarthritis: clinical and therapeutic relevance. AB - Current classification criteria for axial spondyloarthritis (axSpA) provide for the inclusion of patients with a wide range of presentations and manifestations. While not considered a formal subclassification, patients are often divided into radiographic or nonradiographic axSpA based on the presence or absence of radiographic sacroiliitis. This review will focus on nonradiographic axSpA and will discuss clinical manifestations of disease that distinguish, or in many cases do not distinguish, this entity from other individuals with axSpA. This review will also cover treatment paradigms for nonradiographic axSpA, particularly the use of biologic therapies, where current data suggest that nonradiographic disease should be managed largely the same as radiographic disease, or classical ankylosing spondylitis. PMID- 29273056 TI - Cost-effective larval diet mixtures for mass rearing of Anopheles arabiensis Patton (Diptera: Culicidae). AB - BACKGROUND: Larval nutrition, particularly diet quality, is a key driver in providing sufficient numbers of high quality mosquitoes for biological control strategies such as the sterile insect technique. The diet currently available to mass rear Anopheles arabiensis, referred here to as the "IAEA diet", is facing high costs and difficulties concerning the availability of the bovine liver powder component. To promote more affordable and sustainable mosquito production, the present study aimed to find alternative diet mixtures. Eight cheaper diet mixtures comprised of varying proportions of tuna meal (TM), bovine liver powder (BLP), brewer's yeast (BY), and chickpea (CP) were developed and evaluated through a step by step assessment on An. arabiensis larvae and adult life history traits, in comparison to the IAEA diet which served as a basis and standard. RESULTS: Four mixtures were found to be effective regarding larval survival to pupation and to emergence, egg productivity, adult body size and longevity. These results suggest that these different diet mixtures have a similar nutritional value that support the optimal development of An. arabiensis larvae and enhance adult biological quality and production efficiency, and thus could be used for mass rearing. CONCLUSIONS: Our study demonstrated that four different diet mixtures, 40 to 92% cheaper than the IAEA diet, can result in a positive assessment of the mosquitoes' life history traits, indicating that this mosquito species can be effectively mass reared with a significant reduction in costs. The mixture comprised of TM + BY + CP is the preferred choice as it does not include BLP and thus reduces the cost by 92% compared to the IAEA diet. PMID- 29273057 TI - CENP-B protects centromere chromatin integrity by facilitating histone deposition via the H3.3-specific chaperone Daxx. AB - BACKGROUND: The main chromatin unit, the nucleosome, can be modulated by the incorporation of histone variants that, in combination with posttranslational histones modifications, determine epigenetics properties of chromatin. Understanding the mechanism that creates a histone variants landscape at different genomic elements is expected to elevate our comprehension of chromatin assembly and function. The Daxx chaperone deposits transcription-associated histone H3.3 at centromeres, but mechanism of centromere-specific Daxx targeting remains unclear. RESULTS: In this study, we identified an unexpected function of the constitutive centromeric protein CENP-B that serves as a "beacon" for H3.3 incorporation. CENP-B depletion reduces Daxx association and H3.3 incorporation at centromeres. Daxx/CENP-B interaction and Daxx centromeric association are SUMO dependent and requires SIMs of Daxx. Depletion of SUMO-2, but not SUMO-1, decreases Daxx/CENP-B interaction and reduces centromeric accumulation of Daxx and H3.3, demonstrating distinct functions of SUMO paralogs in H3.3 chaperoning. Finally, disruption of CENP-B/Daxx-dependent H3.3 pathway deregulates heterochromatin marks H3K9me3, ATRX and HP1alpha at centromeres and elevates chromosome instability. CONCLUSION: The demonstrated roles of CENP-B and SUMO-2 in H3.3 loading reveal a novel mechanism controlling chromatin maintenance and genome stability. Given that CENP-B is the only centromere protein that binds centromere-specific DNA elements, our study provides a new link between centromere DNA and unique epigenetic landscape of centromere chromatin. PMID- 29273058 TI - Goats in the city: prevalence of Giardia duodenalis and Cryptosporidium spp. in extensively reared goats in northern India. AB - BACKGROUND: Various characteristics of goats mean they are highly suitable livestock for backyard rearing by people with limited resources. They are a popular livestock choice in India, where they are often kept to supplement an already scarce income. In these settings, hygiene and sanitation standards tend to be low, and weakens the interface between humans and animals, thus reducing the barrier between them and thereby increasing the likelihood that zoonotic and anthroponotic infections will occur. RESULTS: This study reports an investigation of the occurrence of Cryptosporidium spp. and Giardia duodenalis in goats being reared in different settings in urban and peri-urban areas in northern India, and addressed the zoonotic potential of these important protozoan parasites shed from goats living close to humans. The overall prevalence of G. duodenalis was 33.8 and 0.5% for Cryptosporidium spp.; the relatively low prevalence of cryptosporidiosis may reflect that most samples were derived from adult animals. The prevalence of G. duodenalis excretion was found to be similar to that reported in other studies. However, although other studies have reported a predominance of non-zoonotic Assemblage E in goats, in this study potentially zoonotic Assemblages predominated [Assemblage A (36%) and Assemblage B (32%)]. CONCLUSIONS: The results of this study indicate that in this area where goats and humans are living in close proximity, there may be sharing of intestinal parasites, which can be detrimental for both host species. PMID- 29273059 TI - Biomechanical properties of 3D-printed bone scaffolds are improved by treatment with CRFP. AB - BACKGROUND: One of the major challenges in orthopedics is to develop implants that overcome current postoperative problems such as osteointegration, proper load bearing, and stress shielding. Current implant techniques such as allografts or endoprostheses never reach full bone integration, and the risk of fracture due to stress shielding is a major concern. To overcome this, a novel technique of reverse engineering to create artificial scaffolds was designed and tested. The purpose of the study is to create a new generation of implants that are both biocompatible and biomimetic. METHODS: 3D-printed scaffolds based on physiological trabecular bone patterning were printed. MC3T3 cells were cultured on these scaffolds in osteogenic media, with and without the addition of Calcitonin Receptor Fragment Peptide (CRFP) in order to assess bone formation on the surfaces of the scaffolds. Integrity of these cell-seeded bone-coated scaffolds was tested for their mechanical strength. RESULTS: The results show that cellular proliferation and bone matrix formation are both supported by our 3D-printed scaffolds. The mechanical strength of the scaffolds was enhanced by trabecular patterning in the order of 20% for compression strength and 60% for compressive modulus. Furthermore, cell-seeded trabecular scaffolds modulus increased fourfold when treated with CRFP. CONCLUSION: Upon mineralization, the cell-seeded trabecular implants treated with osteo-inductive agents and pretreated with CRFP showed a significant increase in the compressive modulus. This work will lead to creating 3D structures that can be used in the replacement of not only bone segments, but entire bones. PMID- 29273060 TI - 'We all want to succeed, but we've also got to be realistic about what is happening': an ethnographic study of relationships in trial oversight and their impact. AB - BACKGROUND: The oversight and conduct of a randomised controlled trial involves several stakeholders, including a Trial Steering Committee (TSC), Trial Management Group (TMG), Data Monitoring Committee (DMC), funder and sponsor. We aimed to examine how the relationships between these stakeholders affect the trial oversight process and its rigour, to inform future revision of Good Clinical Practice guidelines. METHODS: Using an ethnographic study design, we observed the oversight processes of eight trials and conducted semi-structured interviews with members of the trials' TSCs and TMGs, plus other relevant informants, including sponsors and funders of trials. Data were analysed thematically, and findings triangulated and integrated to give a multi perspective account of current oversight practices in the UK. RESULTS: Eight TSC and six TMG meetings from eight trials were observed and audio-recorded, and 66 semi-structured interviews conducted with 52 purposively sampled key informants. Five themes are presented: (1) Collaboration within the TMG and role of the CTU; (2) Collaboration and conflict between oversight committees; (3) Priorities; (4) Communication between trial oversight groups and (5) Power and accountability. There was evidence of collaborative relationships, based on mutual respect, between CTUs, TMGs and TSCs, but also evidence of conflict. Relationships between trial oversight committees were influenced by stakeholders' priorities, both organisational and individual. Good communication following specific, recognised routes played a central role in ensuring that relationships were productive and trial oversight efficient. Participants described the possession of power over trials as a shifting political landscape, and there was lack of clarity regarding the roles and accountability of each committee, the sponsor and funder. Stakeholders' perceptions of their own power over a trial, and the power of others, influenced relationships between those involved in trial oversight. CONCLUSIONS: Recent developments in trial design and conduct have been accompanied by changes in roles and relationships between trial oversight groups. Recognising and respecting the value of differing priorities among those involved in running trials is key to successful relationships between committees, funders and sponsors. Clarity regarding appropriate lines of communication, roles and accountability is needed. We present 10 evidence-based recommendations to inform updates to international trial guidance, particularly the Medical Research Council guidelines. PMID- 29273061 TI - Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option? AB - Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by neoplastic cells. While most cancer cells rely on telomerase re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10-15%) employs telomerase-independent strategies, collectively referred to as Alternative Lengthening of Telomeres (ALT). ALT mechanisms involve different types of homology-directed telomere recombination and synthesis. These processes are facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture. Although the functional consequences of telomerase and ALT up-regulation are similar in that they both prevent overall telomere shortening in tumors, these telomere maintenance mechanisms (TMMs) differ in several aspects which may account for their differential prognostic significance and response to therapy in various tumor types. Therefore, reliable methods for detecting telomerase activity and ALT are likely to become an important pre-requisite for the use of treatments targeting one or other of these mechanisms. However, the question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies is still open. Here we review the latest discoveries in terms of mechanisms of ALT activation and maintenance in human tumors, methods for ALT identification in cell lines and human tissues and biomarkers validation. Then, original results on sensitivity to rational based pre-clinical and clinical anti-tumor drugs in ALT vs hTERT positive cells will be presented. PMID- 29273062 TI - Enhanced expressions of neurodegeneration-associated factors, UPS impairment, and excess Abeta accumulation in the hippocampus of mice with persistent cerebral toxocariasis. AB - BACKGROUND: Toxocariasis is a worldwide zoonotic parasitic disease mainly caused by Toxocara canis. Humans can be infected by accidental ingestion of T. canis embryonated ovum-contaminated food, water, or encapsulated larvae in paratenic hosts' viscera or meat. Since humans and mice are paratenic hosts of T. canis, the wandering larvae might cause mechanical tissue damage and excretory-secretory antigens may trigger inflammatory injuries to local organs. Long-term residence of T. canis larvae in a paratenic host's brain may cause cerebral toxocariasis (CT) that contributes to cerebral damage, neuroinflammation and neuropsychiatric disorders in mice and clinical patients. Since the hippocampus has been long recognized as being responsible for learning and memory functions, parasitic invasion of this site may cause neuroinflammatory and neurodegenerative disorders. The present study intended to assess pathological changes, expressions of neurodegeneration-associated factors (NDAFs), including transforming growth factor (TGF)-beta1, S100B, glial fibrillary acidic protein (GFAP), transglutaminase type 2 (TG2), claudin-5, substance P (SP) and interleukin (IL) 1beta, and the ubiquitin-proteasome system (UPS) function in the hippocampus and associated cognitive behavior in ICR mice orally inoculated with a high, medium or low-dose of T. canis embryonated ova during a 20-week investigation. RESULTS: Results indicated although there were insignificant differences in learning and memory function between the experimental mice and uninfected control mice, possibly because the site where T. canis larvae invaded was the surrounding area but not the hippocampus per se. Nevertheless, enhanced expressions of NDAF, persistent UPS impairment and excess amyloid beta (Abeta) accumulation concomitantly emerged in the experimental mice hippocampus at 8, 16 and 20 weeks post-infection. CONCLUSIONS: We thus postulate that progressive CT may still progress to neurodegeneration due to enhanced NDAF expressions, persistent UPS impairment and excess Abeta accumulation in the hippocampus. PMID- 29273063 TI - Nitrous oxide (N2O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial. AB - BACKGROUND: The first line of pharmacological treatment for severe depressive disorders in young people is selective serotonin reuptake inhibitors (SSRIs). However, beneficial clinical effects are rarely observed before several weeks into treatment. Nitrous oxide (N2O) has a long-standing safety record for pain relief and has been used in adults and young people. In adults with severe treatment-resistant depression, a single dose of N2O had significant antidepressant effects, with maximum antidepressant effects observed 24 h after administration. However, the antidepressant effects of N2O have never been investigated in adolescents with a confirmed diagnosis of depression in a prospective trial. The aims of this study are to (1) investigate whether a single inhaled N2O administration leads to antidepressant effects in adolescents with depression at 24 h, (2) determine whether combined N2O and SSRI administration (commenced after N2O intervention) provides a clinically significant improvement in mood over and above the benefits from SSRI administration alone, and, (3) investigate whether the effect seen following N2O administration can be used as a predictor of SSRI treatment response. METHODS/DESIGN: In this study, we will use a single-blind, randomised, placebo-controlled design. Patients aged between 12 and 17 years with major depressive disorder will be recruited. This study will consist of two phases: phase A and phase B. During phase A, participants will be randomised to receive either inhaled N2O or placebo (air) for 1 h. In phase B, participants will receive open-label pharmacological treatment with the SSRI fluoxetine and will be followed over a 12-week period. Participants will undertake mood assessments at 2 and 24 h after N2O or placebo administration (phase A) and weekly during the 12-week follow up in phase B. DISCUSSION: We expect an antidepressant effect from a single dose of inhaled N2O compared with placebo at 24 h after administration. Additionally, we expect that subjects treated with N2O will also show greater improvements than the placebo group after 6 and 12 weeks into fluoxetine treatment because of potential additive antidepressant effects. Such findings would be of clinical importance because currently children and adolescents often do not experience any symptom alleviation for several weeks following the initiation of SSRIs. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12616001568404 . Registered on 14 November 2016. PMID- 29273064 TI - The Asian fish tapeworm Schyzocotyle acheilognathi is widespread in baitfish retail stores in Michigan, USA. AB - BACKGROUND: The Asian fish tapeworm Schyzocotyle acheilognathi (Yamaguti, 1934) is an important fish pathogen because of its wide range of intermediate and definitive hosts and its pathological consequences. This study was designed to determine if baitfish are a likely vector contributing to the expansion of the invasive Asian fish tapeworm. RESULTS: We collected live baitfish for examination from 78 retail stores in Michigan between September 2015 and June 2016. A total of 5400 baitfish (90 lots, 60 fish/lot) were examined, including 42 emerald shiners [Notropis atherinoides (Rafinesque, 1818)] lots, 30 fathead minnow [Pimephales promelas (Rafinesque, 1820)] lots, 11 golden shiners [Notemigonus crysoleucas (Mitchill, 1814)] lots, 3 sand shiners [Notropis stramineus (Cope, 1865)] lots, 1 lot each of spottail shiners [Notropis hudsonius (Clinton, 1824)], Northern redbelly dace [Phoxinus eos (Cope, 1861)], and blacknose dace [Rhinichthys atratulus (Hermann, 1804)] and 1 lot of mixed two species: weed shiners [Notropis texanus (Girard, 1856)] and sand shiners. CONCLUSIONS: Based on its scolex and strobilar morphology combined with gene sequence analysis, S. acheilognathi was only found in emerald shiners, golden shiners and sand shiners. The mean within lot prevalence and abundance of infection was highest in emerald shiners (20.3 +/- 14.0 and 1.15 +/- 1.34), followed by golden shiners (8.3 +/- 10.7 and 0.89 +/- 1.27) and sand shiners (1.3 +/- 2.6 and 0.02 +/- 0.05). However, the mean intensity of S. acheilognathi in emerald shiners was lower (4.3 +/- 2.6) than that of golden shiners (6.6 +/- 6.7). S. acheilognathi-infected fish exhibited enlargement of the abdomen, distension of the intestinal wall, and intestinal occlusion and hemorrhage. This finding suggests that live baitfish are a likely vector by which the invasive Asian tapeworm's range is expanding. PMID- 29273065 TI - Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice. AB - BACKGROUND: Chemoresistance is a major obstacle that limits the benefits of 5 Fluorouracil (5-Fu)-based chemotherapy for colon cancer patients. Autophagy is an important cellular mechanism underlying chemoresistance. Recent research advances have given new insights into the use of natural bioactive compounds to overcome chemoresistance in colon cancer chemotherapy. As one of the multitargeted and safer phytomedicines, curcumin has been reported to work as cancer-specific chemosensitizer, presumably via induction of autophagic signaling pathways. The precise therapeutic effect of curcumin on autophagy in determining tumorous cells' fate, however, remains unclear. This study was conducted to investigate the differential modulations of the treatments either with 5-Fu alone or 5-Fu combined with curcumin on cellular autophagic responses and viabilities in the human colon cancer cells HCT116 and HT29, and explore molecular signaling transductions underlying the curcumin-mediated autophagic changes and potentiation of 5-Fu's cytotoxicity in vitro and in vivo. METHODS: Cell proliferation assay and morphology observation were used to identify the cytotoxicity of different combinations of curcumin and 5-Fu in HCT116 and HT29 cells. Cell immunofluorescence assay, Flow cytometry and Western blot were employed to detect changes of autophagy and the autophagy-related signaling pathways in the colon cancer cells and/or xenograft mice. RESULTS: Curcumin could significantly augment the cytotoxicity of 5-Fu to the tumorous cells, and the pre treatment with curcumin followed by 5-Fu (pre-Cur) proved to be the most effective one compared to other two combinations. The chemosensitizing role of curcumin might attribute to the autophagy turnover from being activated in 5-Fu mono-treatment to being inhibited in the pre-Cur treatment as indicated by the changes in expression of beclin-1, p62 and LC3II/LC3I and the intensity of Cyto ID Green staining. The autophagic alterations appeared to be contributed by down regulation of not only the phospho-Akt and phospho-mTOR expressions but the phospho-AMPK and phospho-ULK1 levels as well. The cellular activation of AMPK by addition of A-769662 to the pre-Cur combination resulted in reversed changes in expressions of the autophagy protein markers and apoptotic status compared to those of the pre-Cur combination treatment. The findings were validated in the xenograft mice, in which the tumor growth was significantly suppressed in the mice with 25-day combination treatment, and meanwhile expressions of the autophagy markers, P-AMPK and P-ULK1 were all reversely altered in line with those observed in HCT116 cells. CONCLUSION: Pre-treatment with curcumin followed by 5-Fu may mediate autophagy turnover both in vitro and in vivo via AMPK/ULK1 dependent autophagy inhibition and AKT modulation, which may account for the increased susceptibility of the colon cancer cells/xenograft to the cytotoxicity of 5-Fu. PMID- 29273066 TI - Co-regulation of transcription by BRG1 and BRM, two mutually exclusive SWI/SNF ATPase subunits. AB - BACKGROUND: SWI/SNF is a large heterogeneous multi-subunit chromatin remodeling complex. It consists of multiple sets of mutually exclusive components. Understanding how loss of one sibling of a mutually exclusive pair affects the occupancy and function of the remaining complex is needed to understand how mutations in a particular subunit might affect tumor formation. Recently, we showed that the members of the ARID family of SWI/SNF subunits (ARID1A, ARID1B and ARID2) had complex transcriptional relationships including both antagonism and cooperativity. However, it remains unknown how loss of the catalytic subunit(s) affects the binding and genome-wide occupancy of the remainder complex and how changes in occupancy affect transcriptional output. RESULTS: We addressed this gap by depleting BRG1 and BRM, the two ATPase subunits in SWI/SNF, and characterizing the changes to chromatin occupancy of the remaining subunit and related this to transcription changes induced by loss of the ATPase subunits. We show that depletion of one subunit frequently leads to loss of the remaining subunit. This could cause either positive or negative changes in gene expression. At a subset of sites, the sibling subunit is either retained or gained. Additionally, we show genome-wide that BRG1 and BRM have both cooperative and antagonistic interactions with respect to transcription. Importantly, at genes where BRG1 and BRM antagonize one another we observe a nearly complete rescue of gene expression changes in the combined BRG/BRM double knockdown. CONCLUSION: This series of experiments demonstrate that mutually exclusive SWI/SNF complexes have heterogeneous functional relationships and highlight the importance of considering the role of the remaining SWI/SNF complexes following loss or depletion of a single subunit. PMID- 29273067 TI - Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. AB - BACKGROUND: Secukinumab, an anti-interleukin-17A monoclonal antibody, improved the signs and symptoms of ankylosing spondylitis (AS) in two phase 3 studies (MEASURE 1 and MEASURE 2). Here, we present 52-week results from the MEASURE 3 study assessing the efficacy and safety of secukinumab 300 and 150 mg subcutaneous maintenance dosing, following an intravenous loading regimen. METHODS: A total of 226 patients were randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 300 mg (IV 300 mg) or 150 mg (IV-150 mg) every 4 weeks, or matched placebo. Patients in the placebo group were re-randomized to subcutaneous secukinumab at a dose of 300 or 150 mg at week 16. The primary endpoint was the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) response rate at week 16 in the IV-300 mg or IV-150 mg versus placebo. Other endpoints assessed through week 52 included improvements in ASAS40, ASAS 5/6, Bath Ankylosing Spondylitis Disease Activity Index, and ASAS partial remission responses, as well as the change from baseline in high-sensitivity C-reactive protein levels. Statistical analyses followed a predefined hierarchical hypothesis testing strategy to adjust for multiplicity of testing, with non-responder imputation used for binary variables and mixed-model repeated measures for continuous variables. RESULTS: The primary efficacy endpoint was met; the ASAS20 response rate was significantly greater at week 16 in the IV-300 mg (60.5%; P < 0.01) and IV-150 mg (58.1%; P < 0.05) groups versus placebo (36.8%). All secondary endpoints were met at week 16, except ASAS partial remission in the IV-150 mg group. Improvements achieved with secukinumab in all clinical endpoints at week 16 were also sustained at week 52. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period. During the entire treatment period, pooled incidence rates of Candida infections and grade 3-4 neutropenia were 1.8% for both of these adverse events in secukinumab-treated patients. CONCLUSIONS: Secukinumab (300 mg and 150 mg dose groups) provided rapid, significant and sustained improvement through 52 weeks in the signs and symptoms of patients with AS. The safety profile was consistent with previous reports, with no new or unexpected findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02008916 . Registered on 8 December 2013. EUDRACT 2013-001090-24. Registered on 24 October 2013). The study was not retrospectively registered. PMID- 29273068 TI - Exploring patient and family involvement in the lifecycle of an orphan drug: a scoping review. AB - BACKGROUND: Patients and their families have become more active in healthcare systems and research. The value of patient involvement is particularly relevant in the area of rare diseases, where patients face delayed diagnoses and limited access to effective therapies due to the high level of uncertainty in market approval and reimbursement decisions. It has been suggested that patient involvement may help to reduce some of these uncertainties. This review explored existing and proposed roles for patients, families, and patient organizations at each stage of the lifecycle of therapies for rare diseases (i.e., orphan drug lifecycle). METHODS: A scoping review was conducted using methods outlined by Arksey and O'Malley. To validate the findings from the literature and identify any additional opportunities that were missed, a consultative webinar was conducted with members of the Patient and Caregiver Liaison Group of a Canadian research network. RESULTS: Existing and proposed opportunities for involving patients, families, and patient organizations were reported throughout the orphan drug lifecycle and fell into 12 themes: research outside of clinical trials; clinical trials; patient reported outcomes measures; patient registries and biorepositories; education; advocacy and awareness; conferences and workshops; patient care and support; patient organization development; regulatory decision making; and reimbursement decision-making. Existing opportunities were not described in sufficient detail to allow for the level of involvement to be assessed. Additionally, no information on the impact of involvement within specific opportunities was found. Based on feedback from patients and families, documentation of existing opportunities within Canada is poor. CONCLUSIONS: Opportunities for patient, family, and patient organization involvement exist throughout the orphan drug lifecycle. However, based on the information found, it is not possible to determine which opportunities would be most effective at each stage. PMID- 29273069 TI - Single-walled carbon nanotubes modulate pulmonary immune responses and increase pandemic influenza a virus titers in mice. AB - BACKGROUND: Numerous toxicological studies have focused on injury caused by exposure to single types of nanoparticles, but few have investigated how such exposures impact a host's immune response to pathogen challenge. Few studies have shown that nanoparticles can alter a host's response to pathogens (chiefly bacteria) but there is even less knowledge of the impact of such particles on viral infections. In this study, we performed experiments to investigate if exposure of mice to single-walled carbon nanotubes (SWCNT) alters immune mechanisms and viral titers following subsequent influenza A virus (IAV) infection. METHODS: Male C57BL/6 mice were exposed to 20 MUg of SWCNT or control vehicle by intratracheal instillation followed by intranasal exposure to 3.2 * 104 TCID50 IAV or PBS after 3 days. On day 7 mice were euthanized and near infrared fluorescence (NIRF) imaging was used to track SWCNT in lung tissues. Viral titers, histopathology, and mRNA expression of antiviral and inflammatory genes were measured in lung tissue. Differential cell counts and cytokine levels were quantified in bronchoalveolar lavage fluid (BALF). RESULTS: Viral titers showed a 63-fold increase in IAV in SWCNT + IAV exposed lungs compared to the IAV only exposure. Quantitation of immune cells in BALF indicated an increase of neutrophils in the IAV group and a mixed profile of lymphocytes and neutrophils in SWCNT + IAV treated mice. NIRF indicated SWCNT remained in the lung throughout the experiment and localized in the junctions of terminal bronchioles, alveolar ducts, and surrounding alveoli. The dual exposure exacerbated pulmonary inflammation and tissue lesions compared to SWCNT or IAV single exposures. IAV exposure increased several cytokine and chemokine levels in BALF, but greater levels of IL-4, IL-12 (P70), IP-10, MIP-1, MIP-1alpha, MIP-1beta, and RANTES were evident in the SWCNT + IAV group. The expression of tlr3, ifnbeta1, rantes, ifit2, ifit3, and il8 was induced by IAV alone but several anti-viral targets showed a repressed trend (ifits) with pre-exposure to SWCNT. CONCLUSIONS: These findings reveal a pronounced effect of SWCNT on IAV infection in vivo as evidenced by exacerbated lung injury, increased viral titers and several cytokines/chemokines levels, and reduction of anti-viral gene expression. These results imply that SWCNT can increase susceptibility to respiratory viral infections as a novel mechanism of toxicity. PMID- 29273070 TI - The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) framework: protocol to determine a core outcome set for efficacy and effectiveness trials of alcohol screening and brief intervention. AB - BACKGROUND: The evidence base to assess the efficacy and effectiveness of alcohol brief interventions (ABI) is weakened by variation in the outcomes measured and by inconsistent reporting. The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) project aims to develop a core outcome set (COS) and reporting guidance for its use in future trials of ABI in a range of settings. METHODS/DESIGN: An international Special Interest Group was convened through INEBRIA (International Network on Brief Interventions for Alcohol and Other Drugs) to inform the development of a COS for trials of ABI. ORBITAL will incorporate a systematic review to map outcomes used in efficacy and effectiveness trials of ABI and their measurement properties, using the COnsensus based Standards for the selection of health Measurement INstruments (COSMIN) criteria. This will support a multi-round Delphi study to prioritise outcomes. Delphi panellists will be drawn from a range of settings and stakeholder groups, and the Delphi study will also be used to determine if a single COS is relevant for all settings. A consensus meeting with key stakeholder representation will determine the final COS and associated guidance for its use in trials of ABI. DISCUSSION: ORBITAL will develop a COS for alcohol screening and brief intervention trials, with outcomes stratified into domains and guidance on outcome measurement instruments. The standardisation of ABI outcomes and their measurement will support the ongoing development of ABI studies and a systematic synthesis of emerging research findings. We will track the extent to which the COS delivers on this promise through an exploration of the use of the guidance in the decade following COS publication. PMID- 29273071 TI - Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis. AB - BACKGROUND: Individuals at risk of rheumatoid arthritis (RA) demonstrate systemic autoimmunity in the form of anti-citrullinated peptide antibodies (ACPA). MicroRNAs (miRNAs) are implicated in established RA. This study aimed to (1) compare miRNA expression between healthy individuals and those at risk of and those that develop RA, (2) evaluate the change in expression of miRNA from "at risk" to early RA and (3) explore whether these miRNAs could inform a signature predictive of progression from "at-risk" to RA. METHODS: We performed global profiling of 754 miRNAs per patient on a matched serum sample cohort of 12 anti cyclic citrullinated peptide (CCP) + "at-risk" individuals that progressed to RA. Each individual had a serum sample from baseline and at time of detection of synovitis, forming the matched element. Healthy controls were also studied. miRNAs with a fold difference/fold change of four in expression level met our primary criterion for selection as candidate miRNAs. Validation of the miRNAs of interest was conducted using custom miRNA array cards on matched samples (baseline and follow up) in 24 CCP+ individuals; 12 RA progressors and 12 RA non progressors. RESULTS: We report on the first study to use matched serum samples and a comprehensive miRNA array approach to identify in particular, three miRNAs (miR-22, miR-486-3p, and miR-382) associated with progression from systemic autoimmunity to RA inflammation. MiR-22 demonstrated significant fold difference between progressors and non-progressors indicating a potential biomarker role for at-risk individuals. CONCLUSIONS: This first study using a cohort with matched serum samples provides important mechanistic insights in the transition from systemic autoimmunity to inflammatory disease for future investigation, and with further evaluation, might also serve as a predictive biomarker. PMID- 29273073 TI - Pulmonary tumor thrombotic microangiopathy successfully treated with corticosteroids: a case report. AB - BACKGROUND: Pulmonary tumor thrombotic microangiopathy is a special type of tumor thromboembolism. We report the case of a patient who developed pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. Almost all patients with pulmonary tumor thrombotic microangiopathy die within 1 week of the onset of dyspnea; however, the prognosis in this case was better, with 10 weeks of survival from presentation. CASE PRESENTATION: A 62-year-old Japanese man was referred to our hospital with a 4-week history of dyspnea on exertion and severe pulmonary hypertension. Five years previously, he had undergone distal gastrectomy for gastric cancer. He was afebrile, normotensive, and hypoxemic. A physical examination was unremarkable except for purpura on his upper extremities and trunk. Blood tests showed anemia and disseminated intravascular coagulation. Chest computed tomography revealed diffuse ground-glass opacities with emphysema in his upper lungs, moderate pleural effusions, mediastinal lymphadenopathy, and enlargement of the right ventricle and main pulmonary artery. A computed tomography pulmonary angiogram showed no evidence of pulmonary embolism. Lung perfusion scintigraphy showed multiple segmental defects. Although recurrence of gastric cancer was confirmed from the results of bone marrow biopsy, bronchoscopy was not performed due to bleeding diathesis. He was treated with corticosteroids, antibiotics, and platelet transfusion, following which resolution of the abnormal lung shadows and right ventricular pressure overload along with partial alleviation of respiratory failure was observed. Because of his poor performance status, he was eventually transited to palliative care and died 6 weeks after admission. Necropsy of the lung confirmed the diagnosis of pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. CONCLUSIONS: Pulmonary tumor thrombotic microangiopathy should be considered in the differential diagnosis of patients with cancer who present with severe pulmonary hypertension. In pulmonary tumor thrombotic microangiopathy, local inflammation in pulmonary microvasculature may contribute to pulmonary hypertension, and regulation of inflammation using corticosteroids may help improve the prognosis. PMID- 29273072 TI - Monitoring adherence to guidelines of antibiotic use in pediatric pneumonia: the MAREA study. AB - BACKGROUND: Children are the most vulnerable population exposed to the use of antibiotics often incorrectly prescribed for the treatment of infections really due to viruses rather than to bacteria. We designed the MAREA study which consisted of two different studies: i) a surveillance study to monitor the safety/efficacy of the antibiotics for the treatment of pneumonia (CAP), pharyngotonsillitis and acute otitis media in children younger than 14 yrs old, living in Liguria, North-West Italy and ii) a pre-/post-interventional study to evaluate the appropriateness of antibiotic prescription for the treatment these infections. In this paper, we show only results of the appropriateness study about the antibiotic prescription for the treatment of pneumonia. METHODS: Patients included in this study met the following inclusion criteria: i) admission to the Emergency/Inpatient Dpt/outpatient clinic of primary care pediatricians for pneumonia requiring antibiotics, ii) informed written consent. The practice of prescribing antibiotics was evaluated before-and-after a 1 day educational intervention on International/National recommendations. RESULTS: Global adherence to guidelines was fulfilled in 45%: main reason for discordance was duration (shorter than recommended). Macrolide monotherapy and cephalosporins were highly prescribed; ampicillin/amoxicillin use was limited. 61% of patients received >1 antibiotic; parenteral route was used in 33%. After intervention, i) in all CAP, cephalosporin prescription decreased (-23%) and the inappropriate macrolide prescriptions was halved and, ii) in not hospitalized CAP (notH-CAP), macrolides were prescribed less frequently (-25%) and global adherence to guidelines improved (+39%); and iii) in H-CAP antibiotic choice appropriateness increase. CONCLUSION: Prescribing practices were sufficiently appropriate but widespread preference for multidrug empirical regimens or macrolide in monotherapy deserve closer investigation. PMID- 29273074 TI - Use of prescription drugs and risk of postoperative red blood cell transfusion in breast cancer patients: a Danish population-based cohort study. AB - BACKGROUND: Several frequently used prescription drugs may affect bleeding risk. We investigated use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and statins and risk of postoperative red blood cell transfusion in breast cancer patients. METHODS: Using Danish population-based registries, we identified a cohort of women who underwent surgery for primary breast cancer (n = 22,238) during 2005-2012 and ascertained their use of aspirin, NSAIDs, SSRIs, and statins. For each drug, patients were categorized as users if they filled >=1 prescription in the 60 days prior to surgery. We calculated the 14-day risk of red blood cell transfusion and relative risks (RRs) with 95% confidence intervals (CIs), comparing users with nonusers for each drug and adjusting for age, cancer stage, and Charlson Comorbidity Index score. RESULTS: In our cohort, 1385 (6.2%) women were aspirin users, 1794 (8.0%) were NSAID users, 1110 (4.9%) were SSRI users, and 2053 (9.1%) were statin users. The overall risk of red blood cell transfusion was 1.3%. The 14-day risk of RBC transfusion was 3.5% among aspirin users versus 1.1% among aspirin nonusers (adjusted RR = 1.9, 95% CI: 1.4-2.7), and 1.8% among SSRI users versus 1.2% among SSRI nonusers (adjusted RR = 1.2, 95% CI: 0.7-1.9). Red blood cell transfusion risk was increased among NSAID users, but not in a sensitivity analysis with a 30-day exposure window. Red blood cell transfusion risk was not increased among SSRI and statin users. CONCLUSIONS: Primary breast cancer surgery confers a low risk of RBC transfusion. Still, use of aspirin and possibly NSAIDs, but not SSRIs and statins, is associated with increased red blood cell transfusion. This increased risk is not explained by differences in age, stage, or comorbidity level. PMID- 29273075 TI - Management of pneumothorax in hemodynamically stable preterm infants using high frequency oscillatory ventilation: report of five cases. AB - BACKGROUND: Despite an increased use of non-invasive ventilatory strategies and gentle ventilation, pneumothorax remains a common complication in preterm infants. The ventilator management of infants with air leaks remains challenging in terms of both prevention and treatment. Recently the safety and efficacy of expectant management avoiding chest tube drainage to treat large air leak in preterm infants hemodynamically stable has been reported. CASE PRESENTATION: In the present study, we report five cases of preterm infants with birth weight <= 1250 g affected by respiratory distress syndrome and treated with nasal continuous positive airway pressure as first intention. They were intubated for worsening of respiratory distress with increasing oxygen requirement and concomitant increase of respiratory rate and PCO2 values due to occurrence of pneumothorax, and they were successfully treated using high-frequency oscillatory ventilation without chest tube insertion. CONCLUSION: In our experience high frequency oscillatory ventilation provided a conservative management of a significant pneumothorax in preterm newborns hemodynamically stable and requiring mechanical ventilation. This approach allowed us to avoid the increasing of air leak and the insertion of chest tube drainage and all the subsequent associated risks. PMID- 29273076 TI - Highly conformal combined radiotherapy with cisplatin and gemcitabine for treatment of loco-regionally advanced cervical cancer - a retrospective study. AB - BACKGROUND: Cisplatin and gemcitabine combined with conventional radiation therapy in the treatment of cervical cancer patients results in a favorable outcome but with excess toxicity. The purpose of this study was to evaluate the toxicity profile of dual chemotherapy and highly conformal external beam radiotherapy with image guided adaptive brachytherapy. METHODS: Seventeen patients with cervical carcinoma FIGO stage IB2-IIIB were treated with curative intent between 2011 and 2015. A total dose of 50.4 Gy was prescribed to the elective pelvic nodal volume. Patients with 18FDG-PET/CT positive lymph nodes (n = 15; 83.3%) received an additional boost to a total dose of 62 Gy. Chemotherapy prescription goals were: concomitant during 5 weeks of external beam radiotherapy (EBRT) 40 mg/m2 cisplatin and 125 mg/m2 gemcitabine, followed by adjuvant chemotherapy from week 10 (2 cycles 50 mg/m2 cisplatin and 1000 mg/m2 gemcitabine). EBRT was followed by 3-4 fractions (6 Gy per fraction) of intrauterine image guided adaptive brachytherapy. Toxicities were graded according to the common terminology criteria for adverse events (CTCAE v 4.0). RESULTS: One (6%) patient developed acute grade 3 diarrhea. We did not record any other acute or late gastrointestinal or urogenital toxicity higher that grade 3. Most common acute hematological toxicity was anemia grade 2 recorded in 10 (59%) patients. There was only one case of grade 3 neutropenia (6%). The number of patients that received the complete chemotherapy regimen was gradually declining during the course of therapy. From week 2 to 5, gemcitabine was omitted in 4 (24%),7 (41%), 8 (47%), and 12 (71%) patients respectively, similarly, cisplatin was omitted in 2 (12%),3 (18%),1 (6%) and 7 (41%) patients respectively. Adjuvant chemotherapy was omitted in 8 patients (47%). During a median follow-up time of 20 months (5 to 63 months) 6 (35%) patients developed disease relapse with 5 (29%) of them in the form of systemic disease. CONCLUSIONS: In contrast to previous findings cisplatin and gemcitabine in combination with highly conformal radiation therapy seems to have an acceptable toxicity profile. Further studies are needed to determine the optimal dosage of the proposed therapy concept. PMID- 29273077 TI - Undertaking a randomised controlled trial in the police setting: methodological and practical challenges. AB - BACKGROUND: There has been an increased drive towards Evidence Based Policing in recent years. Unlike in other public sector services, such as health and education, randomised controlled trials in the police setting are relatively rare. This paper discusses some of the methodological and practical challenges of conducting a randomised controlled trial in the police setting in the UK, based on our experience of the Connect trial. This pragmatic, cluster-randomised controlled trial investigated the effectiveness of a face-to-face training intervention for frontline officers in comparison to routine training. The primary outcome was the number of incidents which resulted in a police response reported to North Yorkshire Police control room in a 1-month period up to 6 months after delivery of training. MAIN TEXT: The methodological and practical challenges that we experienced whilst conducting the Connect trial are discussed under six headings: establishing the unit of randomisation; population of interest and sample size; co-production of evidence; time frame; outcomes; and organisational issues. CONCLUSION: Recommendations on the conduct of future randomised controlled trials in the police setting are made. To understand the context in which research is undertaken, collaboration between police and academia is needed and police officers should be embedded within trial management groups. Engagement with police data analysts to understand what data is available and facilitate obtaining trial data is also recommended. Police forces may wish to review their IT systems and recording practices. Pragmatic trials are encouraged and time frames need to allow for trial set-up and obtaining relevant ethical approvals. TRIAL REGISTRATION: ISRCTN Registry, ID: ISRCTN11685602 . Retrospectively registered on 13 May 2016. PMID- 29273079 TI - United Kingdom Frozen Shoulder Trial (UK FROST), multi-centre, randomised, 12 month, parallel group, superiority study to compare the clinical and cost effectiveness of Early Structured Physiotherapy versus manipulation under anaesthesia versus arthroscopic capsular release for patients referred to secondary care with a primary frozen shoulder: study protocol for a randomised controlled trial. AB - BACKGROUND: Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy. METHODS: We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods. DISCUSSION: The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014. PMID- 29273080 TI - Activation timing of postural muscles of lower legs and prediction of postural disturbance during bilateral arm flexion in older adults. AB - BACKGROUND: Activation timings of postural muscles of lower legs and prediction of postural disturbance were investigated in young and older adults during bilateral arm flexion in a self-timing task and an oddball task with different probabilities of target presentation. Arm flexion was started from a standing posture with hands suspended 10 cm below the horizontal level in front of the body, in which postural control focused on the ankles is important. METHODS: Fourteen young and 14 older adults raised the arms in response to the target sound signal. Three task conditions were used: 15 and 45% probabilities of the target in the oddball task and self-timing. Analysis items were activation timing of postural muscles (erector spinae, biceps femoris, and gastrocnemius) with respect to the anterior deltoid (AD), and latency and amplitude of the P300 component of event-related brain potential. RESULTS: For young adults, all postural muscles were activated significantly earlier than AD under each condition, and time of preceding gastrocnemius activation was significantly longer in the order of the self-timing, 45 and 15% conditions. P300 latency was significantly shorter, and P300 amplitude was significantly smaller under the 45% condition than under the 15% condition. For older adults, although all postural muscles, including gastrocnemius, were activated significantly earlier than AD in the self-timing condition, only activation timing of gastrocnemius was not significantly earlier than that of AD in oddball tasks, regardless of target probability. No significant differences were found between 15 and 45% conditions in onset times of all postural muscles, and latency and amplitude of P300. CONCLUSION: These results suggest that during arm movement, young adults can achieve sufficient postural preparation in proportion to the probability of target presentation in the oddball task. Older adults can achieve postural control using ankle joints in the self-timing task. However, in the oddball task, older adults experience difficulty predicting the timing of target presentation, which could be related to deteriorated cognitive function, resulting in reduced use of the ankle joints for postural control. PMID- 29273081 TI - Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice. AB - BACKGROUND: Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. METHODS: Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO4-/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. RESULTS: Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. CONCLUSIONS: By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice. PMID- 29273082 TI - Low frequency of BRAF and KRAS mutations in Chinese patients with low-grade serous carcinoma of the ovary. AB - BACKGROUND: Mounting evidence has shown that KRAS and BRAF are somatic mutations associated with low grade serous carcinoma (LGSC) of the ovary. However, the frequency of KRAS or BRAF mutation was variable in literatures, with a frequency of 16-54% for KRAS mutation and 2-33% for BRAF mutation. Meanwhile, the prognostic significance of KRAS or BRAF mutation remains controversial. METHODS: Codons 12 and 13 of exon 2 of KRAS gene and exon 15 of BRAF gene were analyzed using direct Sanger sequencing in 32 cases of LGSC of the ovary. The associations between KRAS or BRAF mutation and clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) were statistically analyzed. RESULTS: KRAS mutation was observed in nine cases (9/32, 28%) and BRAF mutation in two cases (2/32, 6%). KRAS and BRAF mutations were mutually exclusive. Neither KRAS nor BRAF mutation was statistically associated with OS or DFS in our cohort, although there was a favorable prognostic trend in patients with KRAS G12D mutation than those with KRAS G12 V mutation or wild-type KRAS for OS. CONCLUSIONS: The present study indicated a low frequency of BRAF or KRAS mutation in Chinese patients with LGSC of the ovary, and neither KRAS nor BRAF mutation is a prognostic factor. PMID- 29273078 TI - Practical considerations for choosing a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized by the triad of beta-amyloid plaques, neurofibrillary tangles, and neurodegeneration. Genetic mutations and risk factors have been identified that are either causal or modify the disease progression. These genetic and pathological features serve as basis for the creation and validation of mouse models of AD. Efforts made in the past quarter century have produced over 100 genetically engineered mouse lines that recapitulate some aspects of AD clinicopathology. These models have been valuable resources for understanding genetic interactions that contribute to disease and cellular reactions that are engaged in response. Here we focus on mouse models that have been widely used stalwarts of the field or that are recently developed bellwethers of the future. Rather than providing a summary of each model, we endeavor to compare and contrast the genetic approaches employed and to discuss their respective advantages and limitations. We offer a critical account of the variables which may contribute to inconsistent findings and the factors that should be considered when choosing a model and interpreting the results. We hope to present an insightful review of current AD mouse models and to provide a practical guide for selecting models best matched to the experimental question at hand. PMID- 29273083 TI - Effectiveness, costs and cost-effectiveness of chiropractic care and physiotherapy compared with information and advice in the treatment of non specific chronic low back pain: study protocol for a randomised controlled trial. AB - BACKGROUND: Low back pain is a global public health problem and a leading cause of disability all over the world. The lifetime prevalence of low back pain is 70 80% and a significant proportion of people affected develop chronic low back pain (CLBP). Besides a severe negative impact on people's health and health-related quality of life, CLBP is associated with substantial costs for society. Medical costs for the management of CLBP and costs for production losses due to absenteeism from work are sizeable. Pharmaceuticals, physical activity, manipulation, and multidisciplinary rehabilitation interventions are examples of widely used treatments for CLBP. However, the scientific basis to recommend the use of one treatment over another is limited and more research is needed to study the effects, costs and cost-effectiveness of treatments for CLBP in clinical practice. The aim of the study is to evaluate the effectiveness (back pain related functional limitation, back pain intensity, general health, health related quality of life, and working status), costs (medical costs and costs for production losses) and cost-effectiveness of chiropractic care and physiotherapy when added to information and advice in the treatment of patients with non specific CLBP in Sweden. METHODS/DESIGN: This is a pragmatic randomised controlled trial, where participants are recruited through six primary care rehabilitation units (PCRUs) in Stockholm County Council, Sweden. Individuals with non-specific CLBP are individually randomised to one of four treatment groups: 'information and advice'; 'physiotherapy, and information and advice'; 'chiropractic care, and information and advice'; or 'chiropractic care, physiotherapy, and information and advice'. A sample size of 600 participants will be recruited during a period of 33 months. A computer-based questionnaire is used to collect data on back pain-related functional limitation (Oswestry Disability Index), pain intensity (Numeric Rating Scale), general health (self rated health), health-related quality of life (EQ-5D-3L), and working status (measured as percentage of full-time work). Data will be collected at baseline, and at 3, 6, and 12 months after baseline. DISCUSSION: The results from our study should be considered when producing evidence-based guidelines and recommendations on which treatment strategies to use for CLBP. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN15830360 . Registered prospectively on 2 February 2017. PMID- 29273084 TI - Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats. AB - BACKGROUND: This study aims at characterizing the in vitro metabolism of cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of cryptolepine in male Sprague Dawley (SD) rats. METHODS: The in vitro metabolic profiles of cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of cryptolepine. Pharmacokinetic parameters of cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. RESULTS: Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of cryptolepine. Unchanged cryptolepine detected in urine was negligible. The Pharmacokinetic profile of cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. CONCLUSIONS: Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half life. PMID- 29273085 TI - Adult human periodontal ligament-derived stem cells delay retinal degeneration and maintain retinal function in RCS rats. AB - BACKGROUND: Retinal degeneration (RD) is a leading cause of irreversible blindness, affecting millions of people worldwide. Stem cell transplantation has been considered a promising therapy for retinal degenerative diseases. This study aimed to investigate the therapeutic potential of human periodontal ligament derived stem cells (hPDLSCs) for intervention in the progress of this degeneration in the Royal College Surgeons (RCS) rat. METHODS: hPDLSCs were injected into the subretinal space of 3-week-old RCS rats. Control animals received a phosphate-buffered saline injection or were untreated. Retinal function was assessed by electroretinography recording. Eyes were collected afterward for histology and molecular studies. RESULTS: Retinal function maintenance was observed at 2 weeks and persisted for up to 8 weeks following hPDLSC transplantation. Retinal structure preservation was demonstrated in hPDLSC transplanted eyes at 4 and 8 weeks following transplantation, as reflected in the preservation of outer nuclear layer thickness and gene expression of Rho, Crx, and Opsin. The percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic photoreceptors was significantly lower in the hPDLSC-injected retinas than in those of the control groups. hPDLSCs were also found to express multiple neurotrophic factors, including vascular endothelial growth factor, bioactive basic fibroblast growth factor, brain derived neurotrophic factor, neurotrophin-3, insulin-like growth factor 1, nerve growth factor, and glial cell line-derived neurotrophic factor. CONCLUSIONS: Our findings suggest that hPDLSC transplantation is effective in delaying photoreceptor loss and provides significant preservation of retinal function in RCS rats. This study supports further exploration of hPDLSCs for treating RD. PMID- 29273086 TI - Immunoprivileged no more: measuring the immunogenicity of allogeneic adult mesenchymal stem cells. AB - BACKGROUND: Autologous and allogeneic adult mesenchymal stem/stromal cells (MSCs) are increasingly being investigated for treating a wide range of clinical diseases. Allogeneic MSCs are especially attractive due to their potential to provide immediate care at the time of tissue injury or disease diagnosis. The prevailing dogma has been that allogeneic MSCs are immune privileged, but there have been very few studies that control for matched or mismatched major histocompatibility complex (MHC) molecule expression and that examine immunogenicity in vivo. Studies that control for MHC expression have reported both cell-mediated and humoral immune responses to MHC-mismatched MSCs. The clinical implications of immune responses to MHC-mismatched MSCs are still unknown. Pre-clinical and clinical studies that document the MHC haplotype of donors and recipients and measure immune responses following MSC treatment are necessary to answer this critical question. CONCLUSIONS: This review details what is currently known about the immunogenicity of allogeneic MSCs and suggests contemporary assays that could be utilized in future studies to appropriately identify and measure immune responses to MHC-mismatched MSCs. PMID- 29273087 TI - Comparison of multiple transcriptomes exposes unified and divergent features of quiescent and activated skeletal muscle stem cells. AB - BACKGROUND: Skeletal muscle satellite (stem) cells are quiescent in adult mice and can undergo multiple rounds of proliferation and self-renewal following muscle injury. Several labs have profiled transcripts of myogenic cells during the developmental and adult myogenesis with the aim of identifying quiescent markers. Here, we focused on the quiescent cell state and generated new transcriptome profiles that include subfractionations of adult satellite cell populations, and an artificially induced prenatal quiescent state, to identify core signatures for quiescent and proliferating. METHODS: Comparison of available data offered challenges related to the inherent diversity of datasets and biological conditions. We developed a standardized workflow to homogenize the normalization, filtering, and quality control steps for the analysis of gene expression profiles allowing the identification up- and down-regulated genes and the subsequent gene set enrichment analysis. To share the analytical pipeline of this work, we developed Sherpa, an interactive Shiny server that allows multi scale comparisons for extraction of desired gene sets from the analyzed datasets. This tool is adaptable to cell populations in other contexts and tissues. RESULTS: A multi-scale analysis comprising eight datasets of quiescent satellite cells had 207 and 542 genes commonly up- and down-regulated, respectively. Shared up-regulated gene sets include an over-representation of the TNFalpha pathway via NFKbeta signaling, Il6-Jak-Stat3 signaling, and the apical surface processes, while shared down-regulated gene sets exhibited an over-representation of Myc and E2F targets and genes associated to the G2M checkpoint and oxidative phosphorylation. However, virtually all datasets contained genes that are associated with activation or cell cycle entry, such as the immediate early stress response genes Fos and Jun. An empirical examination of fixed and isolated satellite cells showed that these and other genes were absent in vivo, but activated during procedural isolation of cells. CONCLUSIONS: Through the systematic comparison and individual analysis of diverse transcriptomic profiles, we identified genes that were consistently differentially expressed among the different datasets and shared underlying biological processes key to the quiescent cell state. Our findings provide impetus to define and distinguish transcripts associated with true in vivo quiescence from those that are first responding genes due to disruption of the stem cell niche. PMID- 29273088 TI - Low-intensity pulsed ultrasound prevents muscle atrophy induced by type 1 diabetes in rats. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) induces serious skeletal muscle atrophy. Low-intensity pulsed ultrasound (LIPUS) is a common treatment for skeletal muscle injury and is effective in accelerating the rate of muscle growth. However, to the best of our knowledge, whether LIPUS can improve skeletal muscle atrophy in type 1 diabetic rats has not been investigated. METHODS: The rats were randomly divided into four groups: the normal control group (NC); the sham-treated diabetic control group (DC); the diabetic, insulin-treated group (DI) as a positive control; and the diabetic LIPUS therapy group (DL). The DL rats were treated with LIPUS (1 MHz, 30 mW/cm2) on the gastrocnemius for 20 min/day. RESULTS: After 6 weeks, the rats in the DC group showed severe muscle atrophy. However, LIPUS significantly improved type 1 diabetes-induced muscle atrophy, as evidenced by significantly enhanced muscle cross-sectional area, muscle mass, and strength. Moreover, compared with the DC group, LIPUS significantly activated Akt and upregulated the expression of mTOR, and LIPUS downregulated the expression of MSTN, its receptor ActRIIB, and FoxO1. CONCLUSIONS: These results indicate that LIPUS improved muscle atrophy induced by type 1 diabetes, and the MSTN/Akt/mTOR&FoxO1 signaling pathway may play a role in this improvement. PMID- 29273089 TI - Famitinib versus placebo in the treatment of refractory metastatic colorectal cancer: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial. AB - BACKGROUND: Metastatic colorectal cancer (mCRC) patients with progressive disease after all available standard therapies need new medication for further treatment. Famitinib is a small-molecule multikinase inhibitor, with promising anticancer activities. This multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial was designed to evaluate the safety and efficacy of famitinib in mCRC. METHODS: Famitinib or placebo was administered orally once daily. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality-of-life (QoL), and safety. RESULTS: Between July 18, 2012 and Jan 22, 2014, a total of 167 patients were screened, and 154 patients were randomized in a 2:1 ratio to receive either famitinib (n = 99) or placebo (n = 55). The median PFS was 2.8 and 1.5 months in the famitinib and placebo groups (hazard ratio = 0.60, 95% confidence interval = 0.41-0.86, P = 0.004). The DCR was 59.8% and 31.4% (P = 0.002) and the ORR was 2.2% and 0.0% (P = 0.540) in the famitinib and placebo groups, respectively. The most frequent grade 3-4 adverse events were hypertension (11.1%), hand-foot syndrome (10.1%), thrombocytopenia (10.1%), and neutropenia (9.1%). Serious adverse events occurred in 11 (11.1%) patients in the famitinib group and 5 (9.1%) in the placebo group (P = 0.788). The median OS of the famitinib and placebo groups was 7.4 and 7.2 months (P = 0.657). CONCLUSION: Famitinib prolonged PFS in refractory mCRC patients with acceptable tolerability. Trial registration This study was registered on ClinicalTrials.gov (NCT01762293) and was orally presented in the 2015 ASCO-Gastrointestinal Symposium. PMID- 29273090 TI - Exercise and reproductive function in polycystic ovary syndrome: protocol of a systematic review. AB - BACKGROUND: Although many post-participation outcomes in different types of physical training (e.g., aerobic and strength) have been previously investigated for the treatment of polycystic ovary syndrome, there is no recent systematic review of the relationship between various types of intervention and the reproductive function of women with PCOS. The current paper describes a systematic review protocol on the benefits of physical exercise and dietary or drug interventions on endocrinological outcomes in women with PCOS. METHODS: PubMed/MEDLINE, Science Direct, Bireme, Scopus, Web of Science, ProQuest, Cochrane Library (Cochrane Systematic Reviews Database, Cochrane Central Register of Controlled Studies (CENTRAL) databases will be searched. Studies randomized controlled trials reporting on intervening changes in exercise interventions with or without interventions compared such as diet, medication and acupuncture on the menstrual cycle, and fertility in women with PCOS will be included. Results will be on the decrease of the characteristics of hyperandrogenism, insulin resistance, and obesity. Studies published since 2010 and in the English language will be included. DISCUSSION: This systematic review will identify improvement strategies and types of interventions that are geared toward improving endocrine and consequently metabolic parameters. Thus, the use of such strategies may increase the types of low-cost non-drug therapies that aid in the treatment of PCOS. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017058869. PMID- 29273091 TI - Mesenchymal stem cells decrease lung inflammation during sepsis, acting through inhibition of the MAPK pathway. AB - BACKGROUND: Sepsis is a severe medical condition that ranks among the top 10 causes of death worldwide and which has permanently high incidence rates. Mesenchymal stem cells (MSCs) have been found to be potent modulators of immune responses. More importantly, there is evidence that MSCs have a beneficial effect on preclinical models of polymicrobial sepsis. However, the changes caused by the MSCs in the effector cells of the host immune system remain unclear. METHODS: A mouse model of sepsis (male C57BL/6 mice) with three experimental groups was used for experiments in vivo: a control group, an untreated septic group, and a septic group treated with MSCs. In vitro experiments were performed using a cell line of pulmonary macrophages (RAW 264.7) co-cultured with MSCs and stimulated with lipopolysaccharide (LPS). RESULTS: In vivo we demonstrated that treatment with MSCs was able to reduce the expression of cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB), and thereby decrease the production of inflammatory cytokines. In vitro experiments using a co-culture of macrophages with MSCs showed a decrease in COX-2 and NF-kappaB, and showed that this reduction was directly related to the ability of MSCs to inhibit phosphorylation of ERK, RSK, and p38, enzymes that belong to the family of mitogen-activated protein kinases (MAPKs). CONCLUSIONS: This study demonstrated that MSCs are able to inhibit the MAPK pathway activation, modulating the inflammatory response during sepsis. This understanding that MSCs can remodel the response of host cells and improve the course of sepsis is essential for developing new treatments for this pathology. PMID- 29273093 TI - Patient-related outcome of unstable pelvic ring fractures stabilized with a minimal invasive screw-rod system. AB - BACKGROUND: Clinical and radiological outcomes of operatively treated unstable pelvic ring fractures are well documented, whereas little is known about the patient's related outcome. The purpose of this study is to evaluate the patient reported outcome after minimal invasive treatment of pelvic ring fractures using the SF-36 and EQ-5D medical outcome scores. METHODS: Patients with unstable pelvic ring fractures treated in our trauma department with a minimal invasive screw-rod system between 01/2004 and 12/2014 were included. Next to patient data (sex, age), injury related details (fracture type, additional injuries, Injury Severity Score (ISS)) as well as operation details (method, time to operation, general complications, adverse events associated with the surgical procedure, revision surgery, fracture reduction) were assessed. The patient related outcome was evaluated using the SF-36 and the EQ-5D score. RESULTS: A total of 105 patients (57 men; 48 women; mean age 56 +/- 21 years) were identified as candidates for the study. 60 patients completed the SF-36 and EQ-5D score after a mean follow-up of five years (60.5 months (14-142 months)). Of these patients 77% were multiply injured with a mean ISS of 26 +/- 19. Within the respondent group 22% showed type B and 78% type C pelvic ring fractures. In 82% the dorsal pelvic ring fracture was stabilized using a minimally invasive transiliac internal fixator, in 18% an iliolumbar fixation was performed respectively. The mean physical component score of the SF-36 was 37.9 +/- 12.0, the mean mental component score was 49.8 +/- 12.5. The mean EQ-5D VAS reached 70.5 +/- 24.4. CONCLUSION: Patients being multiply injured and treated with minimal invasive treated dorsal pelvic ring fractures were suffering more especially concerning physical domains compared to the healthy reference population. Nevertheless, the overall patient-related outcome is comparable to pelvic ring fractures in general. TRIAL REGISTRATION NUMBER: Clinical Trial Registry University of Regensburg Z-2017-0878-3 . Registered 22. July 2017. Retrospectively registered. PMID- 29273092 TI - Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study. AB - BACKGROUND: In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. METHODS: We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. RESULTS: Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. CONCLUSIONS: Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE. PMID- 29273094 TI - B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies. AB - BACKGROUND: The phenotypic severity of congenital muscular dystrophy dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of alpha-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. METHODS: Using linkage mapping and whole exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. RESULTS: The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of alpha-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. CONCLUSIONS: In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay. PMID- 29273095 TI - Acupuncture for chronic prostatitis/chronic pelvic pain syndrome: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition affecting men of all ages. Acupuncture may be an effective treatment option for CP/CPPS, but evidence is limited. We propose to evaluate the effectiveness of acupuncture in a rigorously conducted trial. METHODS: Ten hospitals will recruit 440 participants with CP/CPPS in China from October 2017 to December 2019. Participants will be randomly allocated to acupuncture or sham acupuncture with a 1:1 ratio using computerized simple random sampling. The whole study consists of 2-week baseline, 8-week treatment, and 24-week follow up. Twenty 30-mintute sessions of acupuncture or sham acupuncture treatment will be provided between week 1 and 8. The two co-primary outcomes are the proportion of responders at week 8 and week 32. Secondary outcomes include proportion of responders in the two groups at different time points; change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score; change in the NIH-CPSI subscales; change in the International Prostate Symptom Score; change in the Hospital Anxiety and Depression Scale; expectation assessments; proportions of participants in each response category of the Global Response Assessment; change in the International Index of Erectile Function 5; change in the five-level EuroQol five-dimensional questionnaire and a visual analogue scale; and changes in peak and average urinary flow rate. DISCUSSION: This study will provide robust evidence on whether acupuncture is effective for relieving symptoms of CP/CPPS. TRIALS REGISTRATION: ClinicalTrials.gov, NCT03213938. Registered on 5 July 2017. PMID- 29273097 TI - Current State of Research and Summary of Preceding Summits. AB - During its 25th anniversary year, the National Alopecia Areata Foundation (NAAF) undertook a project to completely re-evaluate their research program and to help focus and direct future directions of alopecia areata (AA) research to better meet the goals of individuals with and the scientists working to discover mechanisms of disease and better treatments for AA. This project was embodied in five research summits in 2008, 2009, 2010, 2012, and 2014 as part of the NAAF's main strategic initiative, the Alopecia Areata Treatment Development Program, to accelerate progress toward a viable treatment. The sixth summit, "Building and Crossing the Translational Bridge," was held in 2016 and highlighted strong clinical data on the efficacy of topical and oral JAK inhibitors in mouse models and human AA. The advances discussed in this most recent summit provide real hope for a reliable and relatively safe treatment for AA. This work validates the last 10 years of research translating basic research of AA into new treatments based on the firm foundation of modern immunologic and genetic research. PMID- 29273098 TI - Hair Follicle Immune Privilege Revisited: The Key to Alopecia Areata Management. AB - The collapse of the immune privilege (IP) of the anagen hair bulb is now accepted as a key element in AA pathogenesis, and hair bulb IP restoration lies at the core of AA therapy. Here, we briefly review the essentials of hair bulb IP and recent progress in understanding its complexity. We discuss open questions and why the systematic dissection of hair bulb IP and its pharmacological manipulation (including the clinical testing of FK506 and alpha-melanocyte stimulating hormone analogs) promise to extend the range of future therapeutic options in AA and other IP collapse-related autoimmune diseases. PMID- 29273099 TI - Tofacitinib for the Treatment of Severe Alopecia Areata in Adults and Adolescents. AB - Alopecia areata (AA) is an autoimmune disease affecting people of all ages. There is currently no cure for AA, and a highly efficacious therapy for severe AA has been elusive. Recently, scientific advances have identified the Janus kinase pathway as a target for treatment. Both Janus kinase inhibitors approved by the US Food and Drug Administration, tofacitinib and ruxolitinib, have shown promise in open-label clinical trials. This review summarizes the results of long-term use of tofacitinib in severe AA. PMID- 29273096 TI - Genetic variation in human drug-related genes. AB - BACKGROUND: Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classic pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. METHODS: Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional variants in 806 drug-related genes, including 628 known drug targets. We further computed the likelihood of 1236 FDA-approved drugs to be affected by functional variants in their targets in the whole ExAC population as well as different geographic sub-populations. RESULTS: We find that most genetic variants in drug-related genes are very rare (f < 0.1%) and thus will likely not be observed in clinical trials. Furthermore, we show that patient risk varies for many drugs and with respect to geographic ancestry. A focused analysis of oncological drug targets indicates that the probability of a patient carrying germline variants in oncological drug targets is, at 44%, high enough to suggest that not only somatic alterations but also germline variants carried over into the tumor genome could affect the response to antineoplastic agents. CONCLUSIONS: This study indicates that even though many variants are very rare and thus likely not observed in clinical trials, four in five patients are likely to carry a variant with possibly functional effects in a target for commonly prescribed drugs. Such variants could potentially alter drug efficacy. PMID- 29273100 TI - An Overview of the Biology of Platelet-Rich Plasma and Microneedling as Potential Treatments for Alopecia Areata. AB - Platelet-rich plasma and microneedling have been investigated recently as potential therapeutic options for the treatment of hair disorders. Evidence from laboratory studies indicates that these treatments enhance growth factor production that in turn facilitates hair follicle development and cycling. Several small studies and case reports have presented encouraging findings regarding the use of these treatments for alopecia areata. Future investigations will be needed to validate these therapeutic techniques for patients with alopecia areata and further refine which subtypes of the disease these methods are best indicated for. PMID- 29273101 TI - Treatment of Alopecia Areata with Simvastatin/Ezetimibe. AB - Alopecia areata (AA) is an autoimmune disorder characterized by T lymphocytic infiltrates around the bulbar region of hair follicles. Statins have surfaced as potential therapeutic agents for AA, partly because of their modulation of the JAK/STAT pathway. Some data indicate that statins are a possible option for acute, but not chronic, longstanding AA. Animal studies suggest that treatment with statins increases CD4+/CD25+/Foxp3+ populations in AA-affected mice. PMID- 29273102 TI - Building and Crossing the Translational Bridge: 2016 Alopecia Areata Research Summit Highlights. AB - Alopecia areata (AA) is a common autoimmune skin disease that results in the loss of hair on the scalp and elsewhere on the body and affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. The National Alopecia Areata Foundation conducts research summits every 2 years to review progress and create new directions in its funded and promoted research. The Foundation brings together scientists from all disciplines to get a broad and varied perspective. These AA research summits are part of the Foundation's main strategic initiative, the AA Treatment Development Program, to enhance the understanding of AA and accelerate progress toward a viable treatment. PMID- 29273103 TI - Emerging Unconventional Therapies for Alopecia Areata. AB - Alopecia areata is a prevalent autoimmune skin disease with no cure or indicated treatment options. In the absence of an approved treatment, some patients are eager to try unconventional therapies, despite the very limited research evaluating their safety and efficacy. Recently emerging unconventional therapies for alopecia areata discussed include antihistamines, cryotherapy, and low-dose naltrexone. PMID- 29273104 TI - Quantifying Alopecia Areata via Texture Analysis to Automate the SALT Score Computation. AB - Quantifying alopecia areata in real time has been a challenge for clinicians and investigators. Although several scoring systems exist, they can be cumbersome. Because there are more clinical trials in alopecia areata, there is an urgent need for a quantitative system that is reproducible, standardized, and simple. In this article, a computer imaging algorithm to recreate the Severity of Alopecia Tool scoring system in an automated way is presented. A pediatric alopecia areata image set of four view-standardized photographs was created, and texture analysis was used to distinguish between normal hair and bald scalp. By exploiting local image statistics and the similarity of hair appearance variations across the pediatric alopecia examples, we then used a reference set of hair textures, derived from intensity distributions over very small image patches, to provide global context and improve partitioning of each individual image into areas of different hair densities. This algorithm can mimic a Severity of Alopecia Tool (score) and may also provide more information about the continuum of changes in density of hair seen in alopecia areata. PMID- 29273105 TI - The Utility and Validity of the Alopecia Areata Symptom Impact Scale in Measuring Disease-Related Symptoms and their Effect on Functioning. AB - Alopecia areata (AA) is an autoimmune disease that causes hair loss. Although persons with the disease can be physically described as having varying degrees of hair loss, the condition has significant ramifications on an individual's well being. We previously reported the preliminary psychometric properties of the Alopecia Areata Symptom Impact Scale (AASIS), a disease-specific measure that asks participants about their AA symptoms and how these symptoms interfere with their daily functioning. The goals of this article are to provide a detailed description of the development of the AASIS items and to offer a psychometric update for the measure. Preliminary items for the AASIS were developed on the basis of responses from 1,649 participants to 125 health-related quality-of-life questions/items from the National Alopecia Areata Registry. Clinicians affiliated with the registry were asked to rate the relevance of these items for content validity. Cluster analysis and clinician ratings were used to reduce the number of items. The resulting 13-item AASIS was administered to 452 participants, who were also cognitively debriefed. Results showed that the AASIS is a valid and reliable measure of AA symptoms and their impact on functioning. PMID- 29273106 TI - Race and Alopecia Areata amongst US Women. AB - Few studies have examined the clinical epidemiology of alopecia areata (AA) in regard to patient race, and therefore, any disparities in incidence or prevalence of disease are largely unexplored. We sought to investigate potential racial disparities amongst two large cohorts of women. We conducted a cross-sectional analysis from the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII), wherein participants self-reported a diagnosis of AA. We determined odds ratios for AA by race in a multivariate analysis. Among 63,960 women from NHS and 88,368 women from NHSII with information on race and diagnosis of AA, we identified 418 and 738 cases of AA, respectively. In NHS, the multivariate-adjusted odds ratio for AA was 2.72 (95% confidence interval 1.61-4.61) amongst black women as compared with white women. In NHSII, the multivariate-adjusted odds ratio was 5.48 (95% confidence interval 4.10-7.32) amongst black as compared with white women. In a secondary analysis designating participants by Hispanic ethnicity, in NHSII the multivariate odds ratio was 1.94 (95% CI 1.24-3.02) in Hispanic compared with non-Hispanic white women. In this study, we found increased odds of AA based on self-reported race in black and Hispanic women as compared with white women. Further studies are needed to explore the mechanism of this racial disparity related to AA. PMID- 29273107 TI - Why Finding a Treatment for Alopecia Areata Is Important: A Multifaceted Perspective. AB - Alopecia areata is an autoimmune disease that alters one's appearance. Some define it as a cosmetic disease despite evidence that substantial psychosocial burden is associated with it. As a physician, support group leader, consultant for the National Alopecia Areata Foundation, and patient, I discuss the evidence behind the psychosocial impact of alopecia areata and the importance of comprehensive treatment. PMID- 29273108 TI - Large-Scale Epitope Identification Screen and Its Potential Application to the Study of Alopecia Areata. PMID- 29273109 TI - Big Data Reveal Insights into Alopecia Areata Comorbidities. AB - Autoimmune diseases create a substantial burden of disease, and alopecia areata is among the more prevalent forms. Comorbidities are medical conditions that tend to occur together and may provide etiologic insights, suggest novel therapeutic strategies, and help patients and family members understand the risk of other health conditions. It is well established that having one autoimmune disease increases risk for others because of an underlying shared biology. Precision medicine initiatives are creating vast amounts of data that allow us to efficiently identify comorbidities. A survey across various datasets suggests that patients with autoimmune disease, and patients with alopecia areata in particular, may have comorbid neuropsychiatric and metabolic conditions. PMID- 29273110 TI - Cytokine Targeted Therapeutics for Alopecia Areata: Lessons from Atopic Dermatitis and Other Inflammatory Skin Diseases. AB - Alopecia areata is a T-cell-mediated disease that shares phenotypic similarities with other inflammatory diseases, particularly atopic dermatitis, and lacks safe, effective, mechanism-specific treatments. Increasing data suggests that alopecia areata harbors contributions of T helper type 1, T helper type 2, T helper type 17/IL-23, and phosphodiesterase pathways. Antagonism of these axes is undergoing evaluation, and might elucidate the underlying molecular circuitry of alopecia areata, advancing the translational revolution for this disease. PMID- 29273111 TI - Alopecia Areata: The Clinical Situation. AB - In the absence of an approved treatment by the US Food and Drug Administration, choosing one of the many off-label treatments available for a child, teen, or adult with alopecia areata (AA) can be challenging. The physician or midlevel provider treating a patient with AA needs to take into consideration the age of the patient, location of hair loss, disease extent and activity, and any ongoing medical or psychological issues. Many patients and their families have now also heard the "buzz" about evolving research, particularly with JAK inhibitors, for the treatment of AA. This means that today's clinic visit with the AA patient should include not only a discussion about traditionally used off-label treatments but also evolving therapies and clinical research opportunities. PMID- 29273112 TI - The Anatomy of Friendship. AB - Friendship is the single most important factor influencing our health, well being, and happiness. Creating and maintaining friendships is, however, extremely costly, in terms of both the time that has to be invested and the cognitive mechanisms that underpin them. Nonetheless, personal social networks exhibit many constancies, notably in their size and their hierarchical structuring. Understanding the processes that give rise to these patterns and their evolutionary origins requires a multidisciplinary approach that combines social and neuropsychology as well as evolutionary biology. PMID- 29273113 TI - Effects of a Social Empowerment Intervention on Economic Vulnerability for Adolescent Refugee Girls in Ethiopia. AB - PURPOSE: This article examines the effects of a girls' social empowerment program, Creating Opportunities through Mentoring, Parental Involvement and Safe Spaces, on economic vulnerability of participating adolescent refugee girls in Ethiopia. METHODS: Adolescents aged 13-19 years from three refugee camps were randomly assigned to either a treatment (n = 457) or control (n = 462) condition. Participants in the treatment condition received 40 fixed-curriculum, mentor facilitated sessions once a week over a period of 10 months, whereas those in the control condition were not exposed to the curriculum. Caregivers of girls in the treatment arm also participated in 10 discussion sessions held once a month over the same period, where they learned about issues relevant to adolescent girls' well-being and safety. Data were collected from adolescent girls at baseline and approximately 10 months following intervention initiation. RESULTS: Using logistic regression modeling, we found that, following the intervention, girls in the treatment arm were no more or less likely than those in the control arm to attend school, work for pay, work for pay while not being enrolled in school, or engage in transactional sexual exploitation. CONCLUSIONS: Findings suggest that stand-alone social empowerment programs may not reduce economic vulnerability for adolescent girls without simultaneously implementing economic empowerment programs or taking additional measures to address broader structural barriers. PMID- 29273114 TI - Assessing the Association Between Depression and Savings for Kenyan Youth Using a Validated Child Depression Inventory Measure. AB - PURPOSE: The Child Depression Inventory (CDI) is a commonly used measure of depression among youth and has been used in studies conducted in sub-Saharan Africa demonstrating positive effects of financial asset-building interventions on physical and mental health outcomes. However, before we can be certain that asset building does indeed improve mental health functioning, we must first be sure that the instruments used to measure mental health in this population are valid and culturally appropriate. METHODS: This two-part study used baseline data from a sample of youth (N = 1,348, 13-18 years) participating in the YouthSave Impact Study Kenya to clarify the psychometric properties of the 10-item CDI (study A), and then used the 10-item CDI to assess the relationship between financial assets and mental health functioning among this sample of adolescents (study B). RESULTS: Factor analysis on the 10-item CDI indicated a one-factor eight-item measure with excellent model fit. Invariance testing indicated that the measure performed differently for male and female respondents. Finally, using the latent structure as the dependent variable, the second part of the analysis established that cash savings were associated with depression. Female and male adolescents with savings reported lower depression (female beta = -.17, p <= .003; male beta = -.12, p <= .020) than other youth. CONCLUSION: This study identified a reasonable one-factor eight-item depression measure that was noninvariant across gender. This validated measure was used to confirm the association between financial assets and mental health outcomes, hence, supporting the hypothesis that financial assets are associated with mental health outcomes. PMID- 29273116 TI - Integrating Economic Strengthening and Family Coaching to Reduce Work-Related Health Hazards Among Children of Poor Households: Burkina Faso. AB - PURPOSE: This is the first randomized controlled trial in Burkina Faso testing the effect of economic strengthening alone and in combination with family coaching on child's hazardous work and work-related health outcomes. The study also tests the association between different forms of hazardous work and child's health outcomes. METHODS: A total of 360 households from 12 villages participated in the study. Villages were randomly assigned to three study arms: economic intervention alone, economic intervention integrated with family coaching, and control. In each household, one female caregiver and one child aged 10-15 years were interviewed. Data were collected at baseline, 12 months, and 24 months. We ran multilevel mixed-effects models that account for both within-individual correlation over time and clustering of subjects within villages. RESULTS: Compared with the control group, at 24 months, children in the integrated arm experienced significant reduction in exposure to hazardous work and some forms of hazards and abuse. Results for children in the economic strengthening-only arm were more modest. In most cases, child's health was significantly associated not with specific forms of work per se, but with child's exposure to hazards and abuse while doing this form of work. We found no significant effect of intervention on child's work-related health. CONCLUSIONS: Economic strengthening combined with family coaching on child protection issues, rather than implemented alone, may be more effective in reducing child's exposure to hazardous work. Additional research is needed to understand gender differences and causal links between different forms of child work and health hazards. PMID- 29273115 TI - Cost-Effectiveness of a Savings-Led Economic Empowerment Intervention for AIDS Affected Adolescents in Uganda: Implications for Scale-up in Low-Resource Communities. AB - PURPOSE: Nearly 12 million children and adolescents in sub-Saharan Africa have lost one or both parents to AIDS. Within sub-Saharan Africa, Uganda has been greatly impacted, with an estimated 1.2 million orphaned children, nearly half of which have experienced parental loss due to the epidemic. Cost-effective and scalable interventions are needed to improve developmental outcomes for these children, most of whom are growing up in poverty. This article examines the direct impacts and cost-effectiveness of a savings-led family economic empowerment intervention, Bridges to the Future, that employed varying matched savings incentives to encourage investment in Ugandan children orphaned by AIDS. METHODS: Using data from 48 primary schools in southwestern Uganda, we calculate per-person costs in each of the two treatment arms-Bridges (1:1 match savings) versus Bridges PLUS (1:2 match savings); estimate program effectiveness across outcomes of interest; and provide the ratios of per-person costs to their corresponding effectiveness. RESULTS: At the 24-month postintervention initiation, children in the two treatment arms showed better results in health, mental health, and education when compared to the usual care condition; however, no statistically significant differences were found between treatment arms with the exception of school attendance rates which were higher for those in Bridges PLUS. Owing to the minimal cost difference between the Bridges and Bridges PLUS arms, we did not find substantial cost-effectiveness differences across the two treatment arms. CONCLUSION: After 24 months, an economic intervention that incorporated matched savings yielded positive results on critical development outcomes for adolescents orphaned by AIDS in Uganda. The 1:1 and 1:2 match rates did not demonstrate variable levels of cost-effectiveness at 24-month follow-up, suggesting that governments intending to incorporate savings-led interventions within their social protection frameworks may not need to select a higher match rate to see positive developmental outcomes in the short term. Further research is required to understand intervention impacts and cost-effectiveness after a longer follow-up period. PMID- 29273117 TI - Welcome to the Annals 2018: New and improved? Time will tell. PMID- 29273118 TI - Atopic dermatitis yardstick: Practical recommendations for an evolving therapeutic landscape. AB - The implementation of treatment guidelines for atopic dermatitis is challenging, in part because of different guidance documents being used by different groups of specialists and in part because the language of guidelines often reflects the evidence base rather than the practical "how to." The Atopic Dermatitis Yardstick is part of a series developed in response to the need to proactively address the loss of disease control for atopic illnesses at all levels of severity. It presents a comprehensive update on how to conduct a sustained step-up in therapy for the patient with inadequately controlled or poorly controlled atopic dermatitis. Patient profiles, based on current guidelines and the authors' combined clinical experience, provide a practical and clinically meaningful guide to aid physicians in helping their patients achieve the goal of clear to almost clear. The intent is not to replace guidelines but to complement their recommendations incorporating the latest research and therapies. PMID- 29273119 TI - Extended smoking cessation counseling service utilization in the Medicare population 2012-2014. PMID- 29273120 TI - Urticarial vasculitis and autoimmune thyroid disease: Do we have enough data? PMID- 29273121 TI - Zika virus infection as a trigger of atopic dermatitis. PMID- 29273122 TI - Authors' response. PMID- 29273123 TI - Protracted severe food anaphylaxis: Should we incriminate expired epinephrine pen or clonal mast cell disorder? PMID- 29273124 TI - Authors' response. PMID- 29273125 TI - Clinical approach to the patient with refractory atopic dermatitis. PMID- 29273126 TI - Moving toward a more precise treatment of atopic dermatitis. PMID- 29273127 TI - Role of behavioral health in management of pediatric atopic dermatitis. AB - OBJECTIVE: To describe the behavioral components and complications in treating pediatric patients with atopic dermatitis (AD) and the critical role of behavioral health professionals in addressing disease impact and behavioral aspects of disease management for these patients and families. DATA SOURCES: Studies and review articles were selected from medical and psychology databases for relevance to pertinent topics. RESULTS: AD has significant negative effects in affected individuals and their families on quality of life, behavioral, emotional, and sleep disturbances, and family functioning. Effective treatment strategies for AD are available, but the challenges for children and parents in coping with disease-related concerns and in following through with the multiple aspects of treatment are considerable. A biopsychosocial model, which incorporates the interplay among biological, psychological, and social dimensions of medical care, can be implemented in various treatment settings to achieve an integrated medical and behavioral health care approach. By sharing a family orientation, using a stress and coping model, and taking into account children's developmental capabilities and concerns, medical and behavioral health care providers are equipped to bring an in-depth understanding and different evidence based therapeutic tools to address emotional, behavioral, and interpersonal challenges imposed by moderate to severe AD in children and families. CONCLUSION: Behavioral health and medical providers working together to provide integrated care play a critical role in helping children and families cope with the burdens imposed by AD, successfully manage the disease, and achieve optimal quality of life for affected children and their families. PMID- 29273128 TI - Administration of influenza vaccines to egg allergic recipients: A practice parameter update 2017. PMID- 29273129 TI - USP's revisions to sterile compounding standards and FDA guidance; impacts on mixing of allergen extracts. PMID- 29273130 TI - Efficacy and safety of birch pollen immunotherapy for local allergic rhinitis. AB - BACKGROUND: Local allergic rhinitis (LAR) is a relatively new disease. OBJECTIVE: To ascertain the effects of allergen-specific immunotherapy in LAR. METHODS: A randomized, double-blind, placebo-controlled trial of birch subcutaneous allergen immunotherapy (AIT) for LAR was performed in 28 patients. The therapy was performed for 24 months in 15 patients with AIT and 13 patients given placebo. The primary end point was decrease in symptom medication score (SMS). In addition, we monitored serum-specific immunoglobulin E (IgE), serum-specific immunoglobulin G4, nasal-specific IgE to Bet v 1, and safety and quality-of-life parameters. RESULTS: After 24 months of treatment, there was a significant decrease in the median area under the curve for SMS of the active group vs the placebo group: 2.14 (range, 1.22-4.51) vs 6.21 (range, 5.12-7.89), at the P < .05 level. During AIT, the active group showed a significant decrease in SMS of up to 65% vs baseline. A significant increase in immunoglobulin G4 and decrease in nasal-specific IgE were observed in the active group during AIT compared with the placebo group. AIT was well-tolerated and without systemic reactions. CONCLUSION: This study demonstrates that AIT for birch pollen in patients with LAR was clinically effective and exhibited good tolerance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03157505. PMID- 29273131 TI - Association between atopic dermatitis and serious cutaneous, multiorgan and systemic infections in US adults. AB - BACKGROUND: Atopic dermatitis (AD) is associated with barrier disruption, immune dysregulation, and immunosuppressing treatments that can increase the association with an unusual number of infections. OBJECTIVE: To determine whether adults with AD have an unusually large number of serious infections and related outcomes. METHODS: Data from the 2002 to 2012 National Inpatient Sample were analyzed, including an approximately 20% sample of all US hospitalizations (n = 72,108,077 adults). Prevalence of serious infections in hospitalized patients with vs without AD, length of stay, cost of care, and inpatient mortality secondary to serious infections were determined. RESULTS: The prevalence of serious infections expressed as a percentage (95% confidence interval) was higher in adults hospitalized with than in those without AD (42.1% [41.6-42.6] vs 25.4% [25.2 25.6]; P = .0002). In logistic regression models with multiple predictors (multivariable logistic regression models), AD was associated with 32 of 38 infections examined. Associated cutaneous infections included eczema herpeticum (odds ratio [95% confidence interval] adjusted for other predictors: 67.93 [47.93 96.28]), erysipelas (11.15 [9.47-13.1]), and cellulitis (4.53 [4.42-4.64]). Associated respiratory infections included aspergillosis (1.51 [1.21-1.88]) and tuberculosis (1.57 [1.41-1.76]). AD was associated with extracutaneous, multiorgan, and systemic infections, including infectious arthropathy (2.01 [1.84 2.20]), endocarditis (1.25 [1.12-1.39]), encephalitis (1.65 [1.40-1.96]), and methicillin-resistant Staphylococcus aureus infections (3.29 [3.17-3.42]). Patients with AD hospitalized with vs without any serious infection had an increased geometric mean cost of inpatient care ($8,273 [8,126-8,423] vs $7,179 [7,052-7,307]) and length of stay (5.3 days [5.2-5.3] vs 3.9 [3.9-4.0]; P = .0002), with $11 to $228 million excess annual costs from hospitalization with serious infections in adults with AD. CONCLUSION: Adults with AD had increased cutaneous, respiratory, multiorgan, and systemic infections, which were associated with a considerable cost burden. PMID- 29273132 TI - Preliminary psychometric analyses and clinical performance of a caregiver self efficacy scale for food allergy self-management. AB - BACKGROUND: Food allergy health-related quality of life has been defined, but self-efficacy is poorly described. OBJECTIVE: To examine the preliminary reliability, validity, and clinical performance of a novel food allergy self efficacy index. METHODS: An 8-item Food Allergy Self-Efficacy Questionnaire (FASEQ) was adapted for food allergy-related themes and coadministered with the Food Allergy Quality of Life Parental Burden (FAQL-PB) index to caregivers self reporting a food allergic child (group A) and those with children followed up at a food allergy referral center clinic (group B). FASEQ split-half reliability, 2 week recall, factor analysis, and construct and discriminative validity were assessed. Multiple linear regression was used to explore predictive associations between the FAQL-PB and the FASEQ. RESULTS: Among 2,308 caregivers, the mean FASEQ score was 2.69 (95% CI, 2.66-2.73) and was lower (better) among group A (mean FASEQ score, 2.52; 95% CI, 2.49-2.56) vs group B (mean FASEQ score, 3.75; 95% CI, 3.66-3.84; P < .001). The FASEQ Cronbach alpha was 0.87, and the 2-week intraclass correlation coefficient (ICC) was 0.75. Total and 6 of 8 individual FASEQ domain scores were significantly lower among caregivers with children having anaphylaxis or epinephrine use vs none and peanut or tree nut allergy vs milk or egg allergy, demonstrating good discriminative validity. Total FASEQ score was associated with FAQL-PB score (ICC, 0.13; 95% CI, 0.06-0.19; P < .001), with 6 of 8 FASEQ individual domains significantly associated (ICC range, -0.17 to 0.3; P < .01 for all). Factor analysis revealed 2 domains (medical care and social functioning) with construct validity. CONCLUSION: We present preliminary evidence the FASEQ is a valid tool to assess caregiver food allergy self efficacy. Self-efficacy is a distinct but related concept that captures aspects of self-management that are an important companion to health-related quality of life. PMID- 29273133 TI - Recent advances in atopic dermatitis. PMID- 29273134 TI - Reliability of allergy skin testing. AB - BACKGROUND: Percutaneous allergen skin testing remains an established benchmark for diagnosing atopic disease. The reliability of skin testing depends greatly on the performance of allergen extracts used, methods used, and the presence of antihistamine medications. OBJECTIVE: To determine the differential effect of cetirizine on 2 different concentrations of histamine control solution and 5 common allergens used for percutaneous skin testing. METHODS: Twelve individuals underwent skin testing with histamine (1 and 6 mg/mL), control diluent, and 5 common aeroallergens. Wheal and flare measurements were measured in a masked fashion by a single operator. Cetirizine was administered for 4 consecutive days to determine the effect on both histamine and allergen wheal and flare responses. RESULTS: A total of 384 skin tests were performed on 12 volunteers. Cetirizine began to suppress wheal and flare responses at 1 hour (P < .05), with maximum suppression at day 5 (P < .05). Wheal and flare responses returned to greater than 90% baseline within 4 days of not taking cetirizine. Suppression was more apparent with 1 vs 6 mg/mL of histamine (62% vs 33%). Four of the 12 individuals taking cetirizine had a positive skin test result using 6 mg/mL of histamine control when the 1-mg/mL histamine test result was negative. Importantly, twice as many individuals had false-negative allergen responses using 6 mg/mL of histamine vs the 1 mg/mL as a positive control, although this finding did not reach statistical significance. CONCLUSION: The use of a 6-mg/mL histamine control for some percutaneous skin test devices may result in more false-negative allergen responses because of the inability to detect the presence of antihistamines. PMID- 29273135 TI - Complex relationships between vitamin D and allergic sensitization among Puerto Rican 2-year-old children. AB - BACKGROUND: In the United States, Puerto Ricans have a higher prevalence of asthma than other Latino ethnicities. Low vitamin D levels for children living in northern climates could be a factor. OBJECTIVE: To assess serum 25-hydroxyvitamin D [25(OH)D] distributions (a marker of vitamin D) and associations among vitamin D, allergic sensitization, early wheeze, and home/demographic factors. METHODS: Puerto Rican infants born in New York City, with a maternal history of atopy, were enrolled in a birth cohort. Blood was collected at age 2 years (n = 154; 82 males and 72 females). Serum 25(OH)D and immunoglobulin E (IgE) (indoor allergen specific and total) were determined using immunoassays. Home/demographic characteristics and respiratory symptoms were assessed by questionnaire. RESULTS: The median concentration of 25(OH)D was 22.6 ng/mL; 32% were at risk of deficiency or inadequacy (<12 or 12-19 ng/mL). Serum 25(OH)D levels were lower in the heating (a surrogate for less sun exposure in colder months) compared with nonheating (26.1 vs 22.7 ng/mL, P = .02) season, but were not associated with allergen-specific IgE levels or with level of acculturation (measured by maternal birthplace). However, low 25(OH)D levels (below median) were associated with high total IgE >100 IU/mL (P = .01). Also, 25(OH)D concentrations differed between children who attended daycare and those who did not (21.8 vs 24.5 ng/mL; t test, P = .02). Serum 25(OH)D was not associated with wheeze or asthma by 2 years of age (P = .43). CONCLUSION: Vitamin D deficiency, possibly linked with allergic pathways, may partially explain the trajectory for disproportionate asthma burden among Puerto Ricans, especially those born and raised in colder climates. PMID- 29273136 TI - Allergic disease in patients with common variable immunodeficiency at a tertiary care referral center. PMID- 29273137 TI - Acute generalized exanthematous pustulosis with multisystem manifestations: Pinpoint pustules and purulent lakes. PMID- 29273138 TI - Validation of a novel sampling technology for airborne allergens in low-income urban homes. PMID- 29273139 TI - Counting All Homeless Youth Today So We May No Longer Need To Tomorrow. PMID- 29273140 TI - Erratum. PMID- 29273142 TI - Important Information for Prospective JID Authors (and JID Readers, and JID Reviewers, and JID Editors). PMID- 29273141 TI - The Optimal Age for Screening Adolescents and Young Adults Without Identified Risk Factors for HIV. AB - PURPOSE: To assess the optimal age at which a one-time HIV screen should begin for adolescents and young adults (AYA) in the U.S. without identified HIV risk factors, incorporating clinical impact, costs, and cost-effectiveness. METHODS: We simulated HIV-uninfected 12-year-olds in the U.S. without identified risk factors who faced age-specific risks of HIV infection (.6-71.3/100,000PY). We modeled a one-time screen ($36) at age 15, 18, 21, 25, or 30, each in addition to current U.S. screening practices (30% screened by age 24). Outcomes included retention in care, virologic suppression, life expectancy, lifetime costs, and incremental cost-effectiveness ratios in $/year-of-life saved (YLS) from the health-care system perspective. In sensitivity analyses, we varied HIV incidence, screening and linkage rates, and costs. RESULTS: All one-time screens detected a small proportion of lifetime infections (.1%-10.3%). Compared with current U.S. screening practices, a screen at age 25 led to the most favorable care continuum outcomes at age 25: proportion diagnosed (77% vs. 51%), linked to care (71% vs. 51%), retained in care (68% vs. 44%), and virologically suppressed (49% vs. 32%). Compared with the next most effective screen, a screen at age 25 provided the greatest clinical benefit, and was cost-effective ($96,000/YLS) by U.S. standards (<$100,000/YLS). CONCLUSIONS: For U.S. AYA without identified risk factors, a one time routine HIV screen at age 25, after the peak of incidence, would optimize clinical outcomes and be cost-effective compared with current U.S. screening practices. Focusing screening on AYA ages 18 or younger is a less efficient use of a one-time screen among AYA than screening at a later age. PMID- 29273143 TI - Get with the Program! Stemness and Reprogramming in Melanoma Metastasis. AB - Cancer cells are highly plastic and adopt multiple phenotypic states that contribute to tumor progression. Heppt et al. demonstrate that the homeodomain transcription factor Msh homeobox 1 reprograms melanoma cells to a precursor state associated with melanoma progression and increased liver metastasis. Identification of this new role for Msh homeobox 1 may facilitate the development of new therapies that limit melanoma dissemination. PMID- 29273144 TI - Opsin3-A Link to Visible Light-Induced Skin Pigmentation. AB - Skin pigmentation is primarily dependent on melanogenesis, a physiological process that occurs in melanosomes of melanocytes. Solar radiation modulates pigmentation through variety of signaling pathways, but the mechanism of visible light-induced hyperpigmentation remains uncharacterized. Passeron's group recently reported that visible light stimulates opsin3-regulated calcium dependent microphthalmia-associated transcription factor activation that increases pigment gene expression and that it also causes the clustering of melanogenic enzymes. Together, these processes possibly contribute to long lasting hyperpigmentation in the melanocompetent skins. PMID- 29273145 TI - Emergence and Evolution of Mutational Hotspots in Sun-Damaged Skin. AB - In this issue, Albibas et al. investigate the mutational nature of p53 immunopositive patches, commonly observed in sun-damaged skin. p53-immunopositive patches have long been suspected to be lineal precursors to actinic keratoses and cutaneous squamous cell carcinomas. However, the mutations actually giving rise to p53-immunopositive patches, and their relationship to skin cancer, have never been defined. The considerable clinical and economic costs of monitoring and treating sun-damaged skin demand we better understand the evolution of these common premalignancies. PMID- 29273146 TI - The Ticking CLOCK of HSV-2 Pathology. AB - Herpes simplex virus type 2 (HSV-2) is the causative agent of genital herpes. Matsuzawa et al have demonstrated that, in a mouse model, HSV-2 pathology is influenced by the time infection occurs. Increased expression of the HSV-2 receptor Nectin-1 under the control of CLOCK coincided with an increase in viral titer suggesting that HSV-2 infection is regulated by the host circadian clock. PMID- 29273147 TI - Back to the Future: Looking at the Skin to Predict Death-A Lesson from Psoriasis. AB - Noe et al. have documented that an objective measure of psoriasis severity, the body surface area as assessed at a single time point, could predict the risk of all-cause mortality in psoriatic patients. The results have important implications for disease management. Socioeconomic variables may, in part, confound the association between severe psoriasis and increased mortality. PMID- 29273148 TI - JAK-ing up the Response to KIT Inhibition. AB - Only a subset of patients with KIT-mutant melanoma derives clinical benefit from KIT inhibition, and the development of resistance is common. Efforts to improve the efficacy of KIT inhibition are limited by a lack of understanding of the mechanisms underlying response and resistance to treatment. Findings from Delyon et al. suggest that signal transducer and activator of transcription 3 activation may be an important mediator of response to nilotinib. PMID- 29273149 TI - PXR: A New Player in Atopic Dermatitis. AB - Epidemiological evidence suggests that environmental pollutants contribute to atopic dermatitis, but mechanistic details are currently lacking. Elentner et al. show that PXR, a key transcription factor involved in pollutant metabolism, drives features of subclinical atopic dermatitis. These observations provide new insight into how environmental insults may predispose individuals to atopic dermatitis. PMID- 29273151 TI - Cells to Surgery Quiz: January 2018. PMID- 29273150 TI - Research Techniques Made Simple: Murine Models of Human Psoriasis. AB - Psoriasis vulgaris is a common, inflammatory skin disease affecting approximately 3% of the population in the United States. The etiology of psoriasis and its associated comorbidities are complex and the result of complicated interactions between the skin, immune system, disease-associated susceptibility loci, and multiple environmental triggers. The modeling of human disease in vivo through the use of murine models represents a powerful, indispensable tool for investigating the immune and genetic mechanisms contributing to a clinical disease phenotype. Nevertheless, modeling a complex, multigenic disease like psoriasis in mice has proven to be extremely challenging and is associated with significant limitations. Over the last four decades, more than 40 unique mouse models for psoriasis have been described. These models can be categorized into three major types: acute (inducible), genetically engineered (transgenic), and xenograft (humanized). The purpose of this Research Techniques Made Simple article is to provide an overview of the common types of psoriasis-like mouse models currently in use and their inherent advantages and limitations. We also highlight the need for improved psoriasis mouse model systems and several key factors to be considered as this field of laboratory science advances. PMID- 29273152 TI - SnapshotDx Quiz: January 2018. PMID- 29273153 TI - Electronic Alerts for Acute Kidney Injury. PMID- 29273154 TI - Developmental Origins of CKD: Big Problems From Small Packages. PMID- 29273155 TI - Decision Making in Medicine: The Physician and the Family. PMID- 29273156 TI - Adult-Onset Proximal Tubule Dysfunction. PMID- 29273157 TI - AJKD Atlas of Renal Pathology: Adenovirus Infection. PMID- 29273158 TI - Diabetes: mapping the titanic struggle ahead. PMID- 29273159 TI - Iodine supplementation in pregnant women and child neurodevelopment - Author's reply. PMID- 29273160 TI - Iodine supplementation in pregnant women and child neurodevelopment. PMID- 29273161 TI - Questioning the safety and benefits of evolocumab - Authors' reply. PMID- 29273162 TI - Questioning the safety and benefits of evolocumab. PMID- 29273163 TI - Linoleic acid and diabetes prevention. PMID- 29273164 TI - Linoleic acid and diabetes prevention - Authors' reply. PMID- 29273167 TI - Correction to Lancet Diabetes Endocrinol 2018; 6: 17-26. PMID- 29273166 TI - Access to diabetes technology: the role of clinician attitudes. PMID- 29273168 TI - Advances and new technologies in the treatment of burn injury. PMID- 29273169 TI - Uncertainty about whether failure rates are comparable between implant-supported and tooth-supported 3-unit fixed dental prostheses. PMID- 29273170 TI - Insufficient evidence about the effects of fluoride supplements taken during pregnancy in preventing childhood caries. PMID- 29273171 TI - Resorbable plates and titanium plates might result in similar levels of postoperative pain after orthognathic surgery. PMID- 29273172 TI - Intra-articular injections of platelet-rich plasma may improve pain associated with temporomandibular disorders compared with arthrocentesis and arthroscopy. PMID- 29273173 TI - Causality and complex disease: The example of multiple sclerosis. PMID- 29273174 TI - Genitourinary Health of Sexually Abused Girls and Boys: A Matched-Cohort Study. AB - OBJECTIVE: To compare genitourinary health problems of children and adolescents with a substantiated report of sexual abuse with those of the general pediatric population. STUDY DESIGN: Via a prospective matched-cohort design, administrative databases between January 1996 and March 2013 were used to document genitourinary problems of 882 sexually abused children and those of 882 matched controls. Generalized linear mixed models determined the association between a substantiated sexual abuse and diagnoses for sexually transmitted infections and urinary and genital health problems. RESULTS: Adjusted results revealed that up to 12 years after a sexual abuse was substantiated, abused girls had, respectively, 2.1 and 1.4 times more diagnoses for urinary and genital health problems compared with girls from the general population, whereas no difference was found for sexually transmitted infections. Sexually abused boys had an equivalent number of diagnoses as those from the general population for all 3 outcomes. Depending on the genitourinary health problem, abused girls and those from the general population had between 2.5 and 11 times more diagnoses than abused boys or those from the general population. CONCLUSIONS: This study showed that substantiated childhood sexual abuse is associated with more urinary and genital health problems among girls but not boys. Early prevention and intervention efforts may mitigate the problems such that they do not persist or worsen over time and into adulthood. PMID- 29273175 TI - Variability in State-Based Recommendations for Management of Alpha Thalassemia Trait and Silent Carrier Detected on the Newborn Screen. AB - We conducted an inventory of state-based recommendations for follow-up of alpha thalassemia silent carrier and trait identified on newborn screen. We found wide variability in the nature and timing of these recommendations. We recommend a standardized recommendation to guide pediatricians in evidenced-based care for this population. PMID- 29273176 TI - Local recurrence after microwave thermosphere ablation of malignant liver tumors: results of a surgical series. AB - BACKGROUND: Microwave thermosphere ablation is a new treatment modality that creates spherical ablation zones using a single antenna. This study aims to analyze local recurrence associated with this new treatment modality in patients with malignant liver tumors. METHODS: This is a prospective clinical study of patients who underwent microwave thermosphere ablation of malignant liver tumors between September 2014 and March 2017. Clinical, operative, and oncologic parameters were analyzed using Kaplan-Meier survival and Cox proportional hazards model. RESULTS: One hundred patients underwent 301 ablations. Ablations were performed laparoscopically in 87 and open in 13 patients. Pathology included neuroendocrine liver metastasis (n = 115), colorectal liver metastasis (n = 100), hepatocellular cancer (n = 21), and other tumor types (n = 65). Ninety-day morbidity was 7% with one not procedure-related mortality. Median follow-up was 16 months with 65% of patients completing at least 12 months of follow-up. The rate of local tumor recurrence rate per lesion was 6.6% (20/301). Local tumor, new hepatic, and extrahepatic recurrences were detected in 15%, 40%, and 40% of patients, respectively. Local recurrence rate per pathology was 12% for both colorectal liver metastasis (12/100) and other metastatic tumors (8/65). No local recurrence was observed to date in the neuroendocrine liver metastasis and in the limited number of patients with hepatocellular cancers. Tumor size >3 cm and tumor type were independent predictors of local recurrence. CONCLUSION: This is the first study to analyze local recurrence after microwave thermosphere ablation of malignant liver tumors. Short-term local tumor control rate compares favorably with that reported for radiofrequency and other microwave technologies in the literature. PMID- 29273177 TI - Simulation center best practices: A review of ACS-accredited educational institutes' best practices, 2011 to present. AB - BACKGROUND: Since the inception of American College of Surgeons' Accredited Educational Institute (ACS-AEI) Consortium, accreditation reviews have identified best practices in simulation-based education and center operations. A review of best practices would support the communication of these best practices, offer recognition of exemplar institutes, and facilitate discussion and sharing of resources amongst AEIs. METHODS: We examined 5 years of ACS AEI accreditation best practices identified across all standards and criteria. The goal was to identify resources that could be shared among AEIs and recognize AEI champions that have promoted best practices in surgical simulation. RESULTS: From 149 site reviews (July 2011-June 2016), reviewers identified 197 best practices across 83 AEIs (52.9% of all sites reviewed received a best practice). A total of 52.5% of best practices were associated with curriculum development, delivery of effective education and assessment, and 25 available resources were identified that could be shared among AEIs. The majority of best practices (n = 117, 59.3%) were identified at 24 AEIs, with the highest number of best practices identified at Banner Simulation Center and New Orleans Learning Center (10 each over 2 reviews). Twenty-two other institutes presented 97 best practices, with between 3 to 8 per institute (mean = 4.4, standard deviation = 1.6). Specific best practices, criteria, and AEI champions are highlighted. CONCLUSION: Review of AEI accreditation best practices identified common themes for surgical simulation programs and identified tools that could be shared to advance all programs and champion AEIs that have promoted best practices in surgical simulation. PMID- 29273178 TI - Successful parathyroidectomy guided by intraoperative parathyroid hormone monitoring for primary hyperparathyroidism is preserved in mild and moderate renal insufficiency. AB - BACKGROUND: The effect of altered parathyroid hormone metabolism in renal insufficiency on intraoperative parathyroid hormone monitoring during parathyroidectomy is not well known. This study evaluates operative outcomes in patients undergoing parathyroidectomy guided by intraoperative parathyroid hormone monitoring for primary hyperparathyroidism with mild and moderate renal insufficiency. METHODS: A retrospective review of prospectively collected data in 604 patients with sporadic primary hyperparathyroidism undergoing parathyroidectomy guided by intraoperative parathyroid hormone monitoring was performed. Patients were stratified by stage of chronic kidney disease (CKD); those with overt secondary hyperparathyroidism (CKD stages IV and V) were excluded. Rates of bilateral neck exploration, multiglandular disease, and long term operative outcomes, including success, failure, and recurrence were compared. RESULTS: Of the 604 patients, 38% (230/604) had normal renal function or stage I CKD, 44% (268/604) had stage II CKD, and 18% (106/604) had stage III CKD. Overall, there were no differences in the rates of bilateral neck exploration or multiglandular disease or in rates of operative success, failure, or recurrence in patients with normal renal function and stages I to III CKD. CONCLUSION: Parathyroidectomy guided by intraoperative parathyroid hormone monitoring is performed with high operative success uniformly in primary hyperparathyroidism patients with mild and moderate renal insufficiency with outcomes similar to those with normal renal function. PMID- 29273179 TI - Discussion. PMID- 29273181 TI - Effectiveness of Implementing Initial Education Strategies to Promote Awareness and Healthy Habits in Childhood Obesity: A Quality Improvement Project. AB - BACKGROUND: Rising incidence and prevalence of childhood obesity and related costly health consequences suggest the need for an effective training tool at the primary care level. Evidence-based studies show how a healthy diet and physical activity help reduce the incidence of obesity. METHODS: The objective for this quality improvement project was to evaluate the effectiveness of an evidence based educational tool in improving healthy eating and physical activity habits among overweight and obese children in a primary care setting over 3 months. RESULTS: There was a positive statistically significant change in behavior in eating more fruits and vegetables and decreased intake of sugary drinks and sedentary habits (p < .05). CONCLUSION: After receiving education on the importance of healthy lifestyle changes with regard to nutrition and physical activity, pediatric patients adopted better diet and physical activity habits. However, there was little effect on reducing body mass index in a 3-month timeframe. PMID- 29273180 TI - [Multiple facets of ADA2 deficiency: Vasculitis, auto-inflammatory disease and immunodeficiency: A literature review of 135 cases from literature]. AB - Deficiency of adenosine deaminase 2 (DADA2) is a recently described auto inflammatory disorder. It is an autosomal recessive inherited disease, caused by mutations in the ADA2 gene (formerly known as CECR1) encoding ADA2 enzyme. Besides its role in the purine metabolism, it has been postulated that ADA2 may act as a growth factor for endothelial cells and in the differenciation of monocytes. Thus, deficiency of ADA2 would lead to endothelial damage and a skewing of monocytes into M1 pro-inflammatory macrophage, causing DADA2 manifestations. Three core clinical features have been described: inflammatory vascular signs, hematologic abnormalities and immunodeficiency. Clinically, patients display intermittent fever, cutaneous vascular manifestations, such as livedo, ischemic strokes, arthralgia and abdominal pain crisis. Corticosteroids and immunosuppressive agents (i.e. cyclophosphamide, azathioprine, ciclosporin, methotrexate) appear to be poorly effective. Although the mechanism has not been elucidated, anti-TNF agents have been proven efficient in DADA2 and should therefore be used as first line therapy for vasculitis. Role of anti-platelet and anticoagulant therapies in stroke-prophylaxis remains to be discussed, as those patients display a high risk of intracranial bleeding. PMID- 29273182 TI - [Peripheral arterial disease: Treatment]. AB - Medical management of peripheral arterial disease (PAD) patients is aimed at limb symptom relief and reducing systemic major adverse events risk. For the first purpose: exercise therapy is recommended in case of claudication; multidisciplinary evaluation for surgical options is mandatory in case of critical limb ischaemia. Reducing cardiac and stroke risk can be achieved through: statin prescription in most of the cases; antiplatelet agents in symptomatic PAD patients; cardio-vascular risk factors control. PMID- 29273184 TI - Editorial commentary: Treatment of refractory angina: An ongoing challenge. PMID- 29273183 TI - [Diagnosis of lower limb peripheral artery disease]. AB - Lower limb peripheral artery disease is highly prevalent worldwide and in France. Three different stages can be found: asymptomatic stage, exercise ischemia stage, rest ischemia stage. This review based on current recommendations presents how to diagnose the different stages (Ankle brachial index, Toe-brachial index, oxymetry at rest and exercise oxymetry) in order to manage these patients. PMID- 29273185 TI - Living well with dementia. PMID- 29273186 TI - Operative Management of AO Type 44 Ankle Fractures: Determinants of Outcome. AB - The consequences of inadequate treatment of ankle fractures can be disastrous. We assessed the radiologic and functional outcomes, postoperative quality of life (QOL), and its determinants for patients treated operatively for AO type 44 ankle fractures. Evidence is lacking concerning the management of posterior malleolus fractures and syndesmotic injuries. Our retrospective adult cohort study included 432 AO/OTA type 44 ankle fractures (431 patients). The median follow-up period was 52 months. Outcomes were assessed from the medical records, radiographs, American Orthopaedic Foot and Ankle Society (AOFAS) ankle scale (functional outcome), and EuroQol EQ-5D questionnaires. The median AOFAS scale score was 88; 27.9% of patients reported restricted mobility and 40.4% pain or discomfort. In 8.8%, radiographic failure was observed. The presence of posterior malleolus fractures was significantly associated with poor functional outcomes, and a postoperative step-off correlated with radiologic failure, poor functional outcome, and poor postoperative QOL. Late syndesmotic screw removal was associated with worse EQ-5D time trade-off QOL scores. A substantial number of patients experienced functional impairment, discomfort, and pain. Syndesmotic injury was associated with ankle joint failure and poor functional outcomes. Our data indicate that all displaced posterior malleolus fracture fragments affecting the posterior articular tibial surface in patients aged <=65 years require anatomic reduction. PMID- 29273187 TI - Distal Syme Hallux Amputation for Tip of Toe Wounds and Gangrene Complicated by Osteomyelitis of the Distal Phalanx: Surgical Technique and Outcome in Consecutive Cases. AB - Distal hallux gangrene and neuropathic ulceration associated with digit deformity frequently result in osteomyelitis of the distal phalanx. Ideal treatment would involve limited resection to preserve function. We describe our surgical technique and retrospective results for distal Syme hallux amputation with plantar flap closure. An institutional review board-approved review was conducted on cases performed over 8 years. A total of 15 consecutive patients (16 digits) with hallux soft tissue loss who had undergone distal Syme hallux amputation were included. In each case, initial resection removed the distal hallux wound, nail bed, and distal phalanx. The proximal phalanx tip was remodeled, allowing margin biopsy and reduction of prominence. Of the 16 digits, 5 (31.3%) had hammertoe deformity and 1 (6.3%) was excessively long. Positive probe-to-bone status was identified in 8 of the 16 digits (50.0%). All 8 ulcers (100.0%) that probed to bone had histologic or culture results consistent with distal phalanx osteomyelitis. A proximal margin biopsy was taken in 12 of 16 digits (75.0%), and proximal phalanx osteomyelitis was observed in 4 of 12 proximal margin biopsies (33.3%). Two digits (12.5%) failed to heal. Three digits (18.8%) required a more proximal amputation, and the remaining 13 (81.3%) were found to be well-healed and functional at the final follow-up examination. The mean follow-up period was 27.6 (range 8 to 97) months. We have found distal Syme hallux amputation to be an effective treatment when used judiciously for distal hallux gangrene and osteomyelitis associated with neuropathic ulceration. This procedure permits bone biopsy for early diagnosis, confirmation of clean margins, removal of nonviable tissue and the abnormal toenail, and some deformity correction. PMID- 29273188 TI - Ruptured Pseudoaneurysm of the Lateral Plantar Artery After Tibiotalocalcaneal Fusion With Retrograde Nail-A Rare Complication. AB - We report a rare presentation of a ruptured pseudoaneurysm of the lateral plantar artery following tibiotalocalcaneal fusion with a retrograde nail at 1 month after the index surgery. Although case reports of pseudoaneurysms of larger arteries such as the anterior tibial artery and posterior tibial artery after ankle surgery (e.g., ankle arthroscopy, implant removal, Ilizarov application) have been reported, we report a rare complication of a pseudoaneurysm of the lateral plantar artery. We discuss the anatomic considerations of the lateral plantar artery in the foot and the entry point of the retrograde nail to avoid this unusual complication. PMID- 29273189 TI - Soft Tissue Sarcoma Response to Two Cycles of Neoadjuvant Chemotherapy: A Multireader Analysis of MRI Findings and Agreement with RECIST Criteria and Change in SUVmax. AB - RATIONALE AND OBJECTIVES: When soft tissue sarcomas are treated with neoadjuvant chemotherapy, the number of cycles of chemotherapy is usually dependent on the tumor's initial response. Popular methods to assess tumor response include Response Evaluation Criteria in Solid Tumors (RECIST) criteria, which rely solely on tumor size, and maximum standardized uptake value (SUVmax) reduction in positron emission tomography (PET), which requires an expensive and high radiation test. We hypothesized that contrast-enhanced magnetic resonance imaging (MRI) may offer a good alternative by providing additional information beyond tumor size. MATERIALS AND METHODS: Following IRB approval, a retrospective review identified patients with soft tissue sarcomas who underwent both PET and MRI before and after two cycles of neoadjuvant chemotherapy. Five readers independently examined the MRI exams for: changes in size, T2 or T1 signal, necrosis and degree of enhancement. Readers then made a subjective binary assessment of tumor response to therapy. Each reader repeated the anonymized randomized reading at least 2 weeks apart. 18 F-FDG PET exams were interpreted by a nuclear medicine specialist. The maximum standardized uptake values (SUVmax) for pre and post-chemotherapy exams were compared. Intra- and inter-reader agreement was assessed using Cohen's kappa and Light's kappa, respectively. . RESULTS: Twenty cases were selected for this multireader study, of which 9 (45%) were responders and 11 were nonresponders by SUVmax. Using all MRI criteria, 43% were classified as responders based on MRI and 1.5% were classified as responders by RECIST criteria. Using PET as the reference, the sensitivity and the specificity of the MRI diagnosis for response using all findings were 50% and 63%, respectively. There was fair to moderate intrareader (kappa = 0.37) and inter-reader (kappa = 0.48) agreement for the MRI diagnosis of response. None of the individual MRI signal characteristics were significantly different between the PET responders and nonresponders. Additionally, no MRI findings were significantly different between those with and without good clinical responses. CONCLUSION: By our assessment, there is a poor correlation between tumor response by RECIST criteria and PET SUVmax. In addition, varying MR features did not help in diagnosing tumor response. Imaging of tumor response remains a challenging area that requires further research. PMID- 29273190 TI - Comment on: changes in bowel habits and patient-scored symptoms after Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch. PMID- 29273192 TI - Erratum to "Structure-activity relationships among DNA ligase inhibitors; characterization of a selective uncompetitive DNA ligase I inhibitor" [DNA Repair 60C (2017) 29-39]. PMID- 29273191 TI - A Simple Community-Based Risk-Prediction Score for Sudden Cardiac Death. AB - BACKGROUND: Although sudden cardiac death is a leading cause of death in the United States, most victims of sudden cardiac death are not identified as at risk prior to death. We sought to derive and validate a population-based risk score that predicts sudden cardiac death. METHODS: The Atherosclerosis Risk in Communities (ARIC) Study recorded clinical measures from men and women aged 45-64 years at baseline; 11,335 white and 3780 black participants were included in this analysis. Participants were followed over 10 years and sudden cardiac death was physician adjudicated. Cox proportional hazards models were used to derive race specific equations to estimate the 10-year sudden cardiac death risk. Covariates for the risk score were selected from available demographic and clinical variables. Utility was assessed by calculating discrimination (Harrell's C-index) and calibration (Hosmer-Lemeshow chi-squared test). The white-specific equation was validated among 5626 Framingham Heart Study participants. RESULTS: During 10 years' follow-up among ARIC participants (mean age 54.4 years, 52.4% women), 145 participants experienced sudden cardiac death; the majority occurred in the highest quintile of predicted risk. Model covariates included age, sex, total cholesterol, lipid-lowering and hypertension medication use, blood pressure, smoking status, diabetes, and body mass index. The score yielded very good internal discrimination (white-specific C-index 0.82; 95% confidence interval [CI], 0.78-0.85; black-specific C-index 0.75; 95% CI, 0.68-0.82) and very good external discrimination among Framingham participants (C-index 0.82; 95% CI, 0.79 0.86). Calibration plots indicated excellent calibration in ARIC (white-specific chi-squared 5.3, P = .82; black-specific chi-squared 4.1, P = .77), and a simple recalibration led to excellent fit within Framingham (chi-squared 2.1, P = 0.99). CONCLUSIONS: The proposed risk scores may be used to identify those at risk for sudden cardiac death within 10 years and particularly classify those at highest risk who may merit further screening. PMID- 29273193 TI - Predictors of obturator functioning and satisfaction in Turkish patients using an obturator prosthesis after maxillectomy. AB - OBJECTIVE: The aim of this study was to determine the sociodemographic, behavioral, and clinical factors affecting obturator function and satisfaction using the obturator functioning scale (OFS) in maxillectomy patients rehabilitated with obturator prostheses. STUDY DESIGN: The study sample consisted of 41 maxillectomy patients. The OFS was translated into Turkish and adapted for assessing obturator functioning and patient satisfaction among Turkish patients. Data were collected from patients' medical records and self-completed questionnaires, including the Turkish version of the OFS, sociodemographic and behavioral characteristics. Descriptive statistics, Mann-Whitney U test, Spearman's correlation coefficient, and backward stepwise multiple linear regression were used for data analysis. RESULTS: Internal consistency (Cronbach's alpha = 0.85) and test-retest reliability (intraclass correlation coefficient = 0.86) were acceptable for the OFS. The most frequently reported problem was "difficulty chewing." Bivariate analysis revealed significant differences in total OFS scores in terms of surgery type, defect size, and education level, except for the other clinical and sociodemographic characteristics and behavioral factors. Education level and surgery type were found to be the most important predictors of patient satisfaction and functioning of the obturator. CONCLUSIONS: The Turkish version of the OFS might be a useful tool for clinicians to identify patients who are at risk for poor functioning of the obturator, lack of satisfaction, and unmet needs. PMID- 29273194 TI - Evaluation of clinical and radiographic indices as predictors of osteoporotic fractures: a 10-year longitudinal study. AB - OBJECTIVES: The aim of the study was to evaluate 2 radiographic and 3 clinical indices as predictors of future osteoporotic fractures. STUDY DESIGN: In a prospective, longitudinal study with a 10-year fracture follow-up, the 2 radiographic indices mandibular cortical erosion (normal, mild/moderate erosion, and severe erosion of the inferior cortex) and cortex thickness were assessed using panoramic radiographs of 411 women, age 62 to 78 years. The clinical indices were the fracture assessment tool FRAX, the osteoporosis index of risk (OSIRIS), and the osteoporosis self-assessment tool (OST). RESULTS: The relative risks (RRs) for future fracture were significant for FRAX greater than 15%, 4.1 (95% confidence interval [CI] 2.4-7.2), and for severely eroded cortices, 1.7 (95% CI 1.1-2.8). Cortical thickness less than 3 mm, OSIRIS, and OST were not significant fracture predictors (RR 1.1, 1.4, and 1.5, respectively). For the 5 tested fracture predictors, Fisher's exact test gave the following P values for differences between fracture and nonfracture groups: FRAX <.001, cortical erosion 0.023, OST 0.078, OSIRIS 0.206, and cortical thickness 0.678. The area under the curve was 0.69 for FRAX less than 15%, 0.58 for cortical erosion, and 0.52 for cortical thickness. Adding OSIRIS and OST did not change the area under the curve significantly. CONCLUSIONS: FRAX and severely eroded cortices predicted fracture but cortical thickness, OSIRIS, and OST did not. PMID- 29273195 TI - It is not about lip retraction. PMID- 29273196 TI - Comparison of the burr and chemically induced periodontal defects using different field-of-view sizes and voxel resolutions. AB - OBJECTIVE: This study assessed the use of different voxel resolutions in a cone beam computed tomography (CBCT) unit for the detection of artificially induced periodontal bone defects created using burr, burr and chemicals, and only chemicals. STUDY DESIGN: Seven dry skulls were used in this study. In total, 65 dehiscence defects, 43 fenestration defects, and 76 control sites with no periodontal defects were examined. Images were obtained from a CBCT unit (3 D Accuitomo; J Morita Mfg. Corp., Kyoto, Japan), using 3 field-of-view (FOV) sizes (4 * 4 cm; 6 * 6 cm; and 8 * 8 cm) and 4 scan modes (standard, high-definition, high-fidelity, and low-dose). RESULTS: Overall, kappa coefficients for interobserver agreement on burr-induced periodontal defects ranged from 0.336 to 0.795, with the lowest kappa value (indicating a fair degree of agreement) obtained for images acquired in standard mode with a voxel size of 0.160 mm3. kappa coefficients for the detection of periodontal defects were highest (indicating moderate to high degrees of interobserver agreement) for smaller voxel sizes and high-resolution images. Statistical comparison among groups (burr, burr + chemicals, and chemicals only) was performed using 1-way analysis of variance with post hoc tests. CONCLUSIONS: The CBCT scan mode may affect the diagnosis of periodontal defects. The technique used to create periodontal defects also affected diagnosis. For this kind of experiment, burr-induced or burr + chemical-induced defects should be used, rather than those induced solely using a chemical technique. PMID- 29273197 TI - Relationship between estrogen and body composition, energy, and endocrine factors in obese women with normal and low REE. AB - OBJECTIVE: The aim of this study was to investigate the relationship between estrogen and leptin, thyroid (T3), Uncoupling Protein2 (UCP2), sex hormone binding globulin (SHBG), and resting energy expenditure(REE) in obese subjects with normal and low REE, and to investigate the relationship of estrogen with body composition and energy intake. METHOD: A total 49 subjects (25-50 years old) were selected. Anthropometric measurements, body composition, and resting energy expenditure were measured. Fasted circulating leptin, T3, SHBG and UCP2 levels were also measured. Subjects were divided to three groups: BMI > 30 and low resting energy expenditure (group I, n = 16), BMI > 30 and normal resting energy expenditure (group II, n = 17), and non-obese women as the control group (group III, n = 16). RESULT: A significant association was observed between estrogen and REE in obese women with normal REE. There was a significant association between estrogen and leptin in groups I (beta = 0.98, p < .0001), and II (beta = 0.84, P < .0001). However, no significant association was observed between estrogen and T3 and UCP2 protein in the three groups. Regression analyses demonstrated no correlation between fat mass, percent fat mass, and plasma estrogen. Plasma estrogen was not correlated with caloric intake or macronutrients of the diet. CONCLUSION: Estrogen has been shown to affect metabolism and hemostasis in obesity and increases resting energy expenditure via leptin. Production of UCP2 in PBMC is not affected by estrogen. PMID- 29273198 TI - Enlarged adipocytes in subcutaneous adipose tissue associated to hyperandrogenism and visceral adipose tissue volume in women with polycystic ovary syndrome. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is an androgen excess disorder associated with obesity and adipose tissue disturbances. Our aim was to evaluate gene expression of adipocytokines and adipocyte characteristics in abdominal subcutaneous adipose tissue (SAT) of PCOS women. DESIGN: Twelve PCOS (PCOSw) and 12 control (Cw) premenopausal women (BMI 20-35 kg/m2) were included, with measurements of whole-body composition assessed by dual-energy X-ray absorptiometry, and abdominal subcutaneous and visceral adipose tissue (VAT) volume, by magnetic resonance imaging. An oral glucose tolerance test was performed with measurements of glucose and insulin, and sex steroids, lipid profile and serum adipocytokines were determined in the fasting sample. Adipocytokine gene expression, mean adipocyte area and macrophage infiltration were evaluated in SAT biopsies. RESULTS: Both groups were comparable in age and BMI. Trunk fat mass amount (p = .043), serum and SAT leptin/adiponectin ratio (p = .034 and p = .028, respectively) and adipocyte area (p = .015) were higher in PCOSw compared to Cw. Interestingly, trunk fat mass was positively correlated with adipocyte area in PCOSw (r = 0.821, p = .023), while the inverse correlation was found in Cw (r = -0.786, p = .021). Only in PCOSw, adipocyte area was positively correlated with serum testosterone (r = 0.857, p = .014) and visceral adipose tissue volume (r = 0.857, p = .014). CONCLUSIONS: Our results indicate that PCOS women present adipose tissue dysfunction in the subcutaneous compartment, characterized by an alteration in adipocyte size and leptin/adiponectin expression and secretion, probably associated with higher androgen concentrations. PMID- 29273199 TI - Linkage of Medicare Records to the Interagency Registry of Mechanically Assisted Circulatory Support. AB - BACKGROUND: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is a United States registry for adults receiving durable United States Food and Drug Administration-approved mechanical circulatory support devices (MCSDs). We merged INTERMACS records with Medicare claims to investigate the uncertainty of penetrance of Medicare beneficiaries within INTERMACS. METHODS: INTERMACS records and Medicare claims (January 1, 2008, through December 31, 2013) from the Centers for Medicare and Medicaid (CMS) were linked using a deterministic matching methodology. RESULTS: There was annual growth of CMS and INTERMACS centers performing durable MCSD implants among adults from 2008 through 2013 (54% and 87% increase, respectively). The number of CMS centers outnumbered INTERMACS centers throughout all years, with the 68% to 88% of CMS centers being represented in INTERMACS. Although annual patient volume was greatest for INTERMACS, the absolute number of patients significantly increased annually across both data sets from 2008 through 2013 (149% increase in CMS; 268% increase in INTERMACS). As a proportion of all INTERMACS registrants, Medicare beneficiary representation grew from 30% in 2008 to a high of 48% in 2010 and remained stable thereafter. Representation within INTERMACS of MCSDs implanted in Medicare beneficiaries more than doubled, from 36% in 2008 to 77% in 2013. CONCLUSIONS: Using a merged data set of MCSDs implanted between 2008 and 2013, we report that the vast majority of CMS centers and Medicare beneficiaries receiving MCSDs are increasingly captured in INTERMACS. Accordingly, contemporary studies in INTERMACS are relevant and generalizable to the Medicare population. PMID- 29273200 TI - Long-Term Survival Prediction for Coronary Artery Bypass Grafting: Validation of the ASCERT Model Compared With The Society of Thoracic Surgeons Predicted Risk of Mortality. AB - BACKGROUND: The recently developed American College of Cardiology Foundation Society of Thoracic Surgeons (STS) Collaboration on the Comparative Effectiveness of Revascularization Strategy (ASCERT) Long-Term Survival Probability Calculator is a valuable addition to existing short-term risk-prediction tools for cardiac surgical procedures but has yet to be externally validated. METHODS: Institutional data of 654 patients aged 65 years or older undergoing isolated coronary artery bypass grafting between 2005 and 2010 were reviewed. Predicted survival probabilities were calculated using the ASCERT model. Survival data were collected using the Social Security Death Index and institutional medical records. Model calibration and discrimination were assessed for the overall sample and for risk-stratified subgroups based on (1) ASCERT 7-year survival probability and (2) the predicted risk of mortality (PROM) from the STS Short Term Risk Calculator. Logistic regression analysis was performed to evaluate additional perioperative variables contributing to death. RESULTS: Overall survival was 92.1% (569 of 597) at 1 year and 50.5% (164 of 325) at 7 years. Calibration assessment found no significant differences between predicted and actual survival curves for the overall sample or for the risk-stratified subgroups, whether stratified by predicted 7-year survival or by PROM. Discriminative performance was comparable between the ASCERT and PROM models for 7-year survival prediction (p < 0.001 for both; C-statistic = 0.815 for ASCERT and 0.781 for PROM). Prolonged ventilation, stroke, and hospital length of stay were also predictive of long-term death. CONCLUSIONS: The ASCERT survival probability calculator was externally validated for prediction of long-term survival after coronary artery bypass grafting in all risk groups. The widely used STS PROM performed comparably as a predictor of long-term survival. Both tools provide important information for preoperative decision making and patient counseling about potential outcomes after coronary artery bypass grafting. PMID- 29273201 TI - Hybrid Palliation: Outcomes After the Comprehensive Stage 2 Procedure. AB - BACKGROUND: The comprehensive stage 2 procedure (CS2) follows initial hybrid stage 1 palliation for patients with single-ventricle physiology. The goal of this study was to describe CS2 outcomes and differences between survivors of CS2 (s-CS2) and nonsurvivors (nons-CS2). METHOD: All patients in The Society of Thoracic Surgeons Congenital Heart Surgery Database who underwent CS2 as index operation from 2010 to 2016 were included. Preoperative, operative, and postoperative data were analyzed, stratified by operative mortality (in-hospital or within 30 days of the operation), with univariate comparisons using chi2, Fisher exact, or Wilcoxon rank sum tests. RESULTS: Of 209 patients (49 centers) who met inclusion criteria, 141 patients had the diagnosis of hypoplastic left heart syndrome. Overall operative mortality was 12.4% (26 of 209). s-CS2 had a lower prevalence of preoperative extracorporeal membrane oxygenation use (0.0% vs 7.7%, p = 0.02) and less frequently underwent concomitant tricuspid valve procedures at the time of the operation (1.1% vs 11.5%, p = 0.01) than nons-CS2. Postoperatively, the prevalence of any of six The Society of Thoracic Surgeons Congenital Heart Surgery Database major complications was higher in nons-CS2 than in s-CS2 (53.9% vs 23.0%, p < 0.01), including a higher prevalence of renal failure (7.7% vs 0.6%, p = 0.04) and postoperative extracorporeal membrane oxygenation use (46.2% vs 2.7%, p < 0.01). There were no other preoperative, operative, or postoperative differences between the two groups. CONCLUSIONS: Operative mortality associated with the CS2 procedure is substantial, especially for patients receiving extracorporeal membrane oxygenation support after CS2. No obvious modifiable variables were noted between patients who died and those who survived. PMID- 29273202 TI - Modes of Interaction of Pleckstrin Homology Domains with Membranes: Toward a Computational Biochemistry of Membrane Recognition. AB - Pleckstrin homology (PH) domains mediate protein-membrane interactions by binding to phosphatidylinositol phosphate (PIP) molecules. The structural and energetic basis of selective PH-PIP interactions is central to understanding many cellular processes, yet the molecular complexities of the PH-PIP interactions are largely unknown. Molecular dynamics simulations using a coarse-grained model enables estimation of free-energy landscapes for the interactions of 12 different PH domains with membranes containing PIP2 or PIP3, allowing us to obtain a detailed molecular energetic understanding of the complexities of the interactions of the PH domains with PIP molecules in membranes. Distinct binding modes, corresponding to different distributions of cationic residues on the PH domain, were observed, involving PIP interactions at either the "canonical" (C) and/or "alternate" (A) sites. PH domains can be grouped by the relative strength of their C- and A-site interactions, revealing that a higher affinity correlates with increased C-site interactions. These simulations demonstrate that simultaneous binding of multiple PIP molecules by PH domains contributes to high-affinity membrane interactions, informing our understanding of membrane recognition by PH domains in vivo. PMID- 29273203 TI - Transcriptome-wide Identification and Validation of Interactions between the miRNA Machinery and HuR on mRNA Targets. AB - The 3' untranslated region (UTR) of mRNAs is the primary regulatory region that mediates post-transcriptional control by microRNAs and RNA-binding proteins in the cytoplasm. Aside from individual sequence-specific binding and regulation, examples of interaction between these factors at particular 3' UTR sites have emerged. However, the whole picture of such higher-order regulatory modules across the transcriptome is lacking. Here, we investigate the interactions between HuR, a ubiquitous RNA-binding protein, and Ago2, a core effector of the miRNA pathway, at the transcriptome-wide level. Using HITS-CLIP, we map HuR and miRNA binding sites on human 3' UTRs and assess their co-occurrence. In addition, we demonstrate global effects of HuR knockdown on Ago2 occupancy, suggesting a co regulatory relationship. Focusing on sites of Ago2-HuR overlap, 13 candidates were screened in luciferase reporter assays. Eleven sites showed miRNA-dependent repression, as confirmed in Dicer-null cells. To test for HuR's role in co regulation, we measured the reporters in HuR KO cells. Three of the miRNA sites demonstrated altered activities, indicating that HuR has an effect on miRNA repression at those sites. Our study presents an efficient search and validation system for studying miRNA-HuR interactions, which expands our understanding of the combinatorial post-transcriptional control of gene expression at the 3' UTR. PMID- 29273205 TI - Dissociating location-based and object-based cue validity effects in object-based attention. AB - Encoding predictive information and allocating visual attention according to the probability distribution is one of the marvelous achievements of our visual system. Unlike previous studies on object-based attention in which the validity of location-based cues and that of object-based cues covaried, we differentiate the two and examine whether our visual system can calculate the usefulness of the cue based on, separately and independently, the probability distribution of location on one hand and object that contains multiple locations on the other. We adopted the cueing paradigm with the double-rectangle display (Egly, Driver, & Rafal, 1994) and manipulated cue validity with respect to a particular location or the object as a whole. Results showed a spatial-cueing effect when location based cues were informative and a same-object advantage when object-based cues were informative. We thus demonstrate here that different kinds of cue validity (location-based vs. object-based) determine different attention effects respectively (spatial-cueing effect vs. object-based advantage). PMID- 29273204 TI - Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination. AB - Antibody Fab fragments have been exploited with significant success to facilitate the structure determination of challenging macromolecules as crystallization chaperones and as molecular fiducial marks for single particle cryo-electron microscopy approaches. However, the inherent flexibility of the "elbow" regions, which link the constant and variable domains of the Fab, can introduce disorder and thus diminish their effectiveness. We have developed a phage display engineering strategy to generate synthetic Fab variants that significantly reduces elbow flexibility, while maintaining their high affinity and stability. This strategy was validated using previously recalcitrant Fab-antigen complexes where introduction of an engineered elbow region enhanced crystallization and diffraction resolution. Furthermore, incorporation of the mutations appears to be generally portable to other synthetic antibodies and may serve as a universal strategy to enhance the success rates of Fabs as structure determination chaperones. PMID- 29273206 TI - Cardiovascular Health and Cognitive Decline 2 Decades Later in Men with Preexisting Coronary Artery Disease. AB - Cardiovascular health (CVH) factors are associated with lower risk of cardiovascular disease, stroke, and mortality. We investigated the association between a modified CVH metrics score and change in cognitive functions 2 decades later in patients with pre-existing coronary artery disease. A subset of 200 men (mean age at baseline 57.3 +/- 6.3 years) who previously participated in a secondary prevention trial (1990 to 1997) underwent cognitive evaluation 14.6 +/- 1.9 years after baseline (mean age 72.3 +/- 6.2 years, T1 evaluation), and were re-evaluated for cognitive performance 19.9 +/- 1.0 years after baseline (mean age 77.2 +/- 6.4 years, T2 evaluation). A CVH metrics score at baseline was calculated, including 3 health parameters and 4 health behaviors. We have scored each of these CVH metrics into best (2 points), intermediate (1 point), and poor (0 points) levels. Cognitive function was assessed using the NeuroTrax Computerized Battery. A linear mixed model was used to assess change in cognitive functions between T1 and T2 cognitive evaluations. Among the 200 patients, 68 (34.0 %) had <=7 (bottom group), 85 (42.5%) had 8 to 9 (middle group), and 47 (23.5%) had >=10 (top group) CVH metrics points. After adjustments, the top group of CVH score versus others was associated with slower decline in the overall cognitive performance composite z-score (0.23 +/- 0.09, p = 0.009) and on tests of executive and visual spatial functions (0.23 +/- 0.11, p = 0.047, and 0.49 +/- 0.17, p = 0.004, respectively). In conclusion, an inverse association was observed between the score of best CVH metrics and cognitive decline. Lifestyle factors are important predictors of late-life decline in cognitive function among high-risk patients. PMID- 29273207 TI - Comparison of 1-Year Outcomes of Triple (Aspirin + Clopidogrel + Cilostazol) Versus Dual Antiplatelet Therapy (Aspirin + Clopidogrel + Placebo) After Implantation of Second-Generation Drug-Eluting Stents into One or More Coronary Arteries: from the DECREASE-PCI Trial. AB - This study sought to evaluate the impact of triple antiplatelet therapy on clinical outcomes in patients treated with second-generation drug-eluting stents (DES) for coronary artery disease. There are limited data regarding the impact of triple antiplatelet therapy in patients who underwent implantation of second generation DES. We planned to randomly assign 2,110 patients treated with second generation DES to triple (aspirin, clopidogrel, and cilostazol) and dual (aspirin, clopidogrel, and placebo) antiplatelet therapy groups. The primary end point was a composite of death, myocardial infarction, ischemic stroke, or target vessel revascularization (TVR) at 1 year since randomization. The study was stopped early owing to slow enrollment. In total, 404 patients (202 patients each in the triple and dual antiplatelet therapy groups) were finally enrolled. At 1 year, the primary end point had occurred in 3.6% and 9.4% of patients in the triple and dual antiplatelet therapy groups, respectively (hazard ratio [HR] of the triple group 0.396; 95% confidence interval [CI] 0.166 to 0.949; p = 0.038). There was no significant difference between the 2 groups regarding the occurrence of a composite of all-cause death, myocardial infarction, or ischemic stroke (HR 0.583; 95% CI 0.229 to 1.481; p = 0.256). However, the rates of TVR were significantly lower in the triple antiplatelet therapy group than in the dual antiplatelet therapy group (HR 0.118; 95% CI 0.015 to 0.930; p = 0.043). In conclusion, triple antiplatelet therapy with cilostazol after implantation of second-generation DES improved clinical outcomes, mainly by reducing TVR. PMID- 29273208 TI - Malignant Early Repolarization. AB - A 27-year-old man presents with successfully resuscitated ventricular fibrillation. Structural and electrical causes of ventricular fibrillation in the young are presented along with a diagnostic strategy. Electrocardiographic features of malignant early repolarization are discussed. PMID- 29273209 TI - Brain activity-induced neuronal glucose uptake/glycolysis: Is the lactate shuttle not required? AB - The astrocyte-neuron lactate shuttle (ANLS) hypothesis posits that during neuronal activation, astrocytic glycolysis consumes glucose and generates lactate, with the latter then imported by neurons as a preferred fuel. The hypothesis has been controversial, with multiple theoretical postulates for and against, and with empirical evidence that were either supportive or otherwise. Recent findings using direct in vivo imaging of lactate and glucose uptake as well as associated metabolic changes in neurons have now placed important constraints on the hypothesis. Here, I review these recent findings and discuss their implications on neuronal energetics. PMID- 29273210 TI - Corrigendum to "Prognostic relevance of estrogen receptor alpha, beta and aromatase expression in non-small cell lung cancer" [Steroids 113 (2016) 5-13]. PMID- 29273211 TI - Reply to letter to the editor: Epicardial adipose tissue, alcohol consumption, and coronary artery disease severity. PMID- 29273213 TI - The intravascular ventricular assist system: A promising therapy in advanced heart failure. PMID- 29273214 TI - Advancing ventricular assist device technology: One size fits all, but age still matters. PMID- 29273212 TI - Factors contributing to variation in the use of multimodality treatment in patients with gastric cancer: A Dutch population based study. AB - BACKGROUND: Substantial variation in the use of (neo) adjuvant treatment in patients with gastric cancer exists. The aim of this study was to identify underlying (organizational and process) factors associated with the use of perioperative therapy. PATIENTS AND METHODS: Patients with resectable gastric cancer who underwent surgery between 2012 and 2014 were selected from the Dutch Upper gastrointestinal Cancer Audit (DUCA). The proportion of perioperatively treated patients was defined per hospital. Five hospitals with the lowest percentage (LP group) and 5 hospitals with the highest percentage (HP group) of perioperative therapy were identified. In the selected hospitals additional information was obtained from patients' medical records using a structured list with predefined variables. RESULTS: In total, 429 patients (231 in LP group, 198 in HP group) from 9 different hospitals were included. Perioperative therapy was given in 16.0% of patients in the LP group compared to 40.4% in the HP group. In the LP group, patients were enrolled in a clinical trial less frequently (10.8% versus 26.8%, P<.001), and a higher percentage grade III-IV toxicity was observed during neoadjuvant treatment (25.7% versus 46.3%, P=.007). Multivariable analysis showed that, besides known casemix factors, consultation with >=3 upper GI specialists prior to treatment decision was positively associated with initiating perioperative therapy (OR 2.08, 95% CI 1.19-3.66). CONCLUSION: Results of this study confirm considerable hospital variation in the use of perioperative therapy in patients with gastric cancer. Besides known casemix factors, use of perioperative therapy was associated with the level of involvement of multidisciplinary care. PMID- 29273215 TI - Patient-centered outcomes with next-generation left ventricular assist devices: One small step, not a giant leap. PMID- 29273216 TI - A case of an obstructive inflow thrombus in a HeartMate 3 from the left ventricle into the pump. PMID- 29273217 TI - Characterizing Autoimmune Disease-associated Diffuse Large B-cell Lymphoma in a SEER-Medicare Cohort. AB - BACKGROUND: Severe immune dysregulation such as seen in autoimmune (AI) disease is known to act as a significant risk factor for diffuse large B-cell lymphoma (DLBCL). However, little is known about the demographics or clinical outcomes of DLBCL that arises in the setting of AI disease. PATIENTS AND METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database for patients with a diagnosis from 1999 to 2009 linked to their Medicare claims data through 2011 to characterize the presentation, treatment, and survival patterns in DLBCL patients, including those with rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjogren syndrome, and other B-cell-mediated AI diseases. We examined the baseline clinical characteristics for patients with B-cell-mediated AI disease, plotted the overall survival and lymphoma-related survival (LRS) for these groups, and compared the median survival times. RESULTS: Patients with DLBCL and AI disease were more commonly female. However, patients with DLBCL and rheumatoid arthritis, SLE, Sjogren syndrome, or other B-cell AI diseases did not differ from other DLBCL patients in any other baseline presenting features and received similar first-line treatment. A trend toward decreased LRS was seen in patients with SLE and DLBCL compared with all other groups, but this difference was not statistically significant in this cohort. CONCLUSION: In the present retrospective claims-based cohort of older patients with DLBCL, concomitant AI disease was uncommon and was more likely to occur in female DLBCL patients, which likely reflects the greater incidence of AI disease in women. The possibility of lower LRS for SLE patients should be explored in future studies. PMID- 29273218 TI - Clinical predictors and prevalence of receiving special preschool/school support in children with repaired esophageal atresia. AB - BACKGROUND/PURPOSE: In a sparsely investigated field, we aimed to evaluate the use of special preschool/school support among children with repaired esophageal atresia (EA) and/or tracheoesophageal fistula (TEF), the predicting clinical factors for this support, and level of school absence. METHODS: Data on 119 EA/TEF children 2-17years old were collected through medical records and questionnaires (response rate 95%). Logistical regression analysis identified clinical predictors of special preschool/school support in the population without genetic disorders (n=105). Nominal hypothesis testing was performed using Fisher's exact test (p<0.05). RESULTS: Of the 119 children, 35.3% received special preschool/school support; 26.8% educational support, 21.8% support with nutritional intake issues and 13.4% received both types of support. Educational support was independently predicted by birth weight<2500g (p=0.026) and associated anomalies (p=0.049), nutritional intake support by gastrostomy insertion (p=0.0028), and both types of supports by major revisional surgery (p=0.0081). School absence >=1month/year, present in 25.5% of the children, was more frequently reported in children receiving preschool/school support, in preschoolers and in those with persistent respiratory problems (p<0.05). CONCLUSIONS: Special preschool/school support is provided for approximately one third of EA/TEF children. In EA/TEF children without genetic disorders, use of this support is predicted by congenital and surgical factors, and related to frequent school absence. PMID- 29273219 TI - Cryptic changes in immune response and fitness in Tribolium castaneum as a consequence of coevolution with Beauveria bassiana. AB - Immunity is a key trait in host defence against parasites and is thus likely to be under selection during host-parasite coevolution. Broadly, the immune system consists of several lines of defence including physiological innate immunity, physical barriers such as the cuticle, avoidance behaviours and in some cases antimicrobial secretions. The defence conferring the highest fitness benefit may be situation specific and depend on the taxon and infection route of the parasite. We carried out a host-parasite coevolution experiment between the red flour beetle T. castaneum, which possesses a comprehensive immune system including the ability to secrete antimicrobial compounds into its environment, and the generalist entomopathogenic fungus Beauveria bassiana. We measured levels of external immunity (benzoquinone secretion) and an internal immune trait, phenoloxidase (PO) activity throughout and in F2 to beetles at the end of the experiment. Survival (a proxy for resistance) of F2 coevolved and control beetles exposed to the fungus was also measured. No change in external immunity or survival was observed as a consequence of host-parasite coevolution, however, PO responses in evolved beetles showed increased flexibility dependent on the route of infection of the parasite. This more flexible PO response appeared to result in beetle populations being better able to cope with the parasite, buffering their fitness during the course of the coevolution experiment. This represents a subtle but significant adaptation to the presence of a parasite over evolutionary time. PMID- 29273220 TI - Simulation of Low Density Lipoprotein (LDL) permeation into multilayer coronary arterial wall: Interactive effects of wall shear stress and fluid-structure interaction in hypertension. AB - Due to increased atherosclerosis-caused mortality, identification of its genesis and development is of great importance. Although, key factors of the origin of the disease is still unknown, it is widely believed that cholesterol particle penetration and accumulation in arterial wall is mainly responsible for further wall thickening and decreased rate of blood flow during a gradual progression. To date, various effective components are recognized whose simultaneous consideration would lead to a more accurate approximation of Low Density Lipoprotein (LDL) distribution within the wall. In this research, a multilayer Fluid-Structure Interaction (FSI) model is studied to simulate the penetration of LDL into the arterial wall. Distention impact on wall properties is taken into account by considering FSI and Wall Shear Stress (WSS) dependent endothelium properties. The results show intensified permeation of LDL whilst the FSI approach is applied. In addition, luminal distension prompted by FSI reduces WSS along lumen/wall interface, especially in hypertension. This effect leads to a lowered endothelial resistance against LDL permeation, comparing to the case in which WSS effect is overlooked. The results are in an acceptable consistency with the clinical researches on WSS effect on atherosclerosis development. PMID- 29273221 TI - A modular approach to creating large engineered cartilage surfaces. AB - Native articular cartilage has limited capacity to repair itself from focal defects or osteoarthritis. Tissue engineering has provided a promising biological treatment strategy that is currently being evaluated in clinical trials. However, current approaches in translating these techniques to developing large engineered tissues remains a significant challenge. In this study, we present a method for developing large-scale engineered cartilage surfaces through modular fabrication. Modular Engineered Tissue Surfaces (METS) uses the well-known, but largely under utilized self-adhesion properties of de novo tissue to create large scaffolds with nutrient channels. Compressive mechanical properties were evaluated throughout METS specimens, and the tensile mechanical strength of the bonds between attached constructs was evaluated over time. Raman spectroscopy, biochemical assays, and histology were performed to investigate matrix distribution. Results showed that by Day 14, stable connections had formed between the constructs in the METS samples. By Day 21, bonds were robust enough to form a rigid sheet and continued to increase in size and strength over time. Compressive mechanical properties and glycosaminoglycan (GAG) content of METS and individual constructs increased significantly over time. The METS technique builds on established tissue engineering accomplishments of developing constructs with GAG composition and compressive properties approaching native cartilage. This study demonstrated that modular fabrication is a viable technique for creating large-scale engineered cartilage, which can be broadly applied to many tissue engineering applications and construct geometries. PMID- 29273223 TI - Personalised screening: is this the way forward? AB - Screening with mammography has been implemented in many countries across the world with most offering 2-yearly examinations between the ages of 50-69 years. Robust modelling tools that include breast density and single nucleotide polymorphisms (SNPs) have been developed to predict which women are most likely to develop breast cancer. Mammographic sensitivity is poor in women with the densest category of breast tissue, and even women with heterogeneously dense tissue may benefit from additional supplemental imaging. Digital breast tomosynthesis (DBT), automated breast ultrasound (ABUS), contrast-enhanced mammography (CESM) or abbreviated (ABB) magnetic resonance imaging (MRI) all offer the opportunity to increase cancer detection, especially in women with dense breasts at increased risk of cancer. DBT increases cancer detection by around 15% with a corresponding reduction in recall rates; ABUS has been shown to increase cancer detection by between 2-4/1,000 depending on the cohort being examined and results in increased recalls, which tend to fall in subsequent screening rounds; CESM has very high sensitivity almost matching MRI with slightly improved specificity; ABB-MRI has been shown to be virtually equivalent to standard protocol MRI examinations, making this a technique that could be considered as a screening tool in high-risk women. This article reviews the literature to establish the current status of these techniques. The cost effectiveness of these techniques requires further investigation and screening trials should report the nature of any additional tumours that are found. PMID- 29273224 TI - Morphological characteristics of the reversed halo sign that may strongly suggest pulmonary infarction. AB - AIM: To analyse the morphological characteristics of the reversed halo sign (RHS) on unenhanced chest computed tomography (CT), which raise suspicion of pulmonary infarction (PI) associated with pulmonary embolism (PE), and to compare these characteristics with those observed in the RHS caused by other diseases. MATERIAL AND METHODS: CT images of 145 patients (250 RHSs) were reviewed retrospectively. Sixty-four patients had the RHS due to PI; in 81 immunocompetent patients, the RHS was caused by alternative pulmonary diseases. All PIs secondary to PE were confirmed at CT angiography. Other diagnoses were confirmed using published criteria. Two independent thoracic radiologists, who were blinded patient demographics, clinical data, and final diagnoses, analysed the morphological CT features of the RHSs. RESULTS: Seventy-four RHSs were found in the PI group and 176 RHSs in the group of other diseases. Single RHSs were associated more frequently with PI compared with the group without PIs; three or more lesions were seen only in patients with other diseases. Low-attenuation areas inside the RHS, with or without reticulation, were observed in 94.59% of PI-associated lesions, and in no patient in the group without PI (p<0.001). Subpleural involvement (p<0.001) and lower-lung predominance (p=0.001) were also associated more frequently with PI. Pleural effusion was observed in 64.06% of patients with PI and in only 6.17% of those with other diseases (p<0.001). CONCLUSIONS: A single RHS with low-attenuation areas inside the halo, with or without reticulation, is highly suggestive of PI. Lower-lung predominance and pleural effusion also suggest PI. PMID- 29273222 TI - Photophysics of diphenyl-pyrazole compounds in solutions and alpha-synuclein aggregates. AB - BACKGROUND: Recently diphenyl-pyrazole (DPP) compounds and especially anle138b were found to reduce the aggregation of alpha-synuclein or Tau protein in vitro as well as in a mouse model of neurodegenerative diseases [1,2]. Direct interaction of the DPPs with the fibrillar structure was identified by fluorescence spectroscopy. Thereby a strong dependence of the fluorescence on the surroundings could be identified [3]. METHODS: Stationary and time-resolved emission experiments were performed on DPP compounds substituted by different halogens. RESULTS: The compounds reveal a pronounced dependence of the fluorescence on the surrounding solvent. In non-polar solvents they show strong emission in the blue part of the spectrum while in polar and proton donating solvents, such as water or acetic acid a dual fluorescence can be observed where a red-shifted emission points to a charge transfer in the excited state with large dipole moment. Non-radiative processes including photochemical reactions are observed for DPP substituted with heavy halogens. Upon binding of anle138b and its derivatives to protein fibrils in aqueous buffer, strong enhancement of the fluorescence at short wavelengths is found. CONCLUSION: The investigations of the DPPs in different surroundings lead to a detailed model of the fluorescence characteristics. We propose a model for the binding in fibrils of different proteins, where the DPP is located in a hydrophobic groove independent of the specific sequence of the amino acids. GENERAL SIGNIFICANCE: These investigations characterize the binding site of the DPP anle138b in protein aggregates and contribute to the understanding of the therapeutic mode of action of this compound. PMID- 29273225 TI - Breast density: why all the fuss? AB - The term "breast density" or mammographic density (MD) denotes those components of breast parenchyma visualised at mammography that are denser than adipose tissue. MD is composed of a mixture of epithelial and stromal components, notably collagen, in variable proportions. MD is most commonly assessed in clinical practice with the time-honoured method of visual estimation of area-based percent density (PMD) on a mammogram, with categorisation into quartiles. The computerised semi-automated thresholding method, Cumulus, also yielding area based percent density, is widely used for research purposes; however, the advent of fully automated volumetric methods developed as a consequence of the widespread use of digital mammography (DM) and yielding both absolute and percent dense volumes, has resulted in an explosion of interest in MD recently. Broadly, the importance of MD is twofold: firstly, the presence of marked MD significantly reduces mammographic sensitivity for breast cancer, even with state-of-the-art DM. Recognition of this led to the formation of a powerful lobby group ('Are You Dense') in the US, as a consequence of which 32 states have legislated for mandatory disclosure of MD to women undergoing mammography. Secondly, it is now widely accepted that MD is in itself a risk factor for breast cancer, with a four to sixfold increased relative risk in women with PMD in the highest quintile compared to those with PMD in the lowest quintile. Consequently, major research efforts are underway to assess whether use of MD could provide a major step forward towards risk-adapted, personalised breast cancer prevention, imaging, and treatment. PMID- 29273226 TI - Do ultrasound guided trochanteric bursa injections of corticosteroid for greater trochanteric pain syndrome provide sustained benefit and are imaging features associated with treatment response? AB - AIM: To assess intra-bursal corticosteroid injections (ICSI) efficacy and duration of action in the management of greater trochanteric pain syndrome (GTPS). The secondary aim was to identify patient and ultrasound (US) features predictive of treatment response. MATERIALS AND METHODS: Consecutive prospectively recruited patients undergoing US-guided ICSI therapy for GTPS received baseline pre-injection questionnaires assessing pain at rest and activity, demographics and comorbidities. Baseline US and radiography findings were reported prospectively. Follow-up was performed at 6 weeks and 6 and 12 months, and change in pain scores assessed using the Wilcoxon signed rank test. Logistic regression examined associations between demographics, US findings, and a clinically significant reduction in pain score (>=50%). RESULTS: Over 6 months, 127 patients were recruited with a median age of 63.5 years and 90% were female. The greatest pain reduction was between baseline and 6 weeks at activity (median 8 versus 5, p<0.001). The majority of patients noted a reduction in pain score, but the percentage of patients receiving a >=50% reduction at 6 weeks, 6 months, and 12 months for pain at rest was 41%, 37%, and 36%, respectively. Regression models suggested only gluteus medius bursitis was weakly associated with pain reduction. CONCLUSION: ICSIs confer a benefit in pain reduction to a large proportion of patients in the short term, but this may not be reduced by a clinically significant amount. This small effect size and lack of predictive imaging features suggests initial management including subsequent steroid injection could be provided without imaging guidance in the majority of cases. PMID- 29273227 TI - The effect of individual radiographers on rates of attendance to breast screening: a 7-year retrospective study. AB - AIM: To establish whether individual radiographers had significantly different rescreening rates whilst controlling for other known confounding factors. MATERIALS AND METHODS: Women aged 50-69 years were identified from a state-wide screening database at their first screening attendance during the study period (2007-2013). The radiographer performing this index screen and potential confounding factors were recorded and subsequent screening behaviour was assessed. Clients with abnormal screens and those known to have died during the time period were excluded. A univariate analysis of the data from 160,028 women was assessed using the chi-square test to compare those women who attended their next mammography with non-re-attenders. Logistic regression was used to calculate the likelihood of "re-attendance success" across a range of variables. The probability of re-attendance for 11 randomly selected radiographers was determined from the logistic regression model, whilst controlling for other variables. RESULTS: Comparison of non-re-attenders (n=49,698) with 110,330 (69%) women attending the next round of screening revealed significant differences, including radiographer (Wald statistics=1188, p<0.000) even when all other known factors were controlled. CONCLUSION: This large, population-level study demonstrates that individual radiographer factors appear to influence a women's decision to return for their next screening round. Further research is required to identify reasons for differing rescreen rates and provide education and retraining of individual radiographers as appropriate. PMID- 29273228 TI - Utility of apparent diffusion coefficient as an imaging biomarker for assessing the proliferative potential of invasive ductal breast cancer. AB - AIM: To determine the clinical utility of apparent diffusion coefficient (ADC) metrics for the non-invasive assessment of tumour proliferation indicated by Ki 67 labelling index (LI) in invasive ductal breast cancer. MATERIALS AND METHODS: Eighty patients with 80 histopathologically proven invasive ductal breast cancers underwent diffusion-weighted imaging with b-values of 0 and 800 s/mm2 at a 3-T system. ADC metrics including ADCmean, ADCmedian, ADCmin, ADCmax, and DeltaADC (ADCmax-ADCmin) were recorded from the entire tumour volume on ADC maps, and correlated with the Ki-67 LI. Ki-67 staining of >=14% was considered to indicate high proliferation and <14% was considered to indicate low proliferation. RESULTS: ADCmin, ADCmax, and DeltaADC showed significant correlations with the Ki 67 LI (for all tumours, r=-0.311, 0.436, and 0.551, respectively; for luminal/human epidermal growth factor receptor 2 (HER2)-negative group, r=-0.437, 0.512, and 0.639, respectively; all p<0.01), whereas ADCmean and ADCmedian showed no significant correlation (both p>0.05). Receiver operating characteristic (ROC) curve analysis for the differentiation of high- from low-proliferation groups showed that DeltaADC yielded the highest area under the ROC curve for the whole tumour population (0.825; 95% confidence interval [CI]: 0.724, 0.901), as well as for the luminal/HER2-negative group (0.844; 95% CI: 0.692, 0.940). CONCLUSION: DeltaADC may serve as a promising imaging biomarker for the prediction of Ki-67 proliferation status in invasive ductal breast cancer. PMID- 29273229 TI - HRCT morphological characteristics distinguishing minimally invasive pulmonary adenocarcinoma from invasive pulmonary adenocarcinoma appearing as subsolid nodules with a diameter of <=3 cm. AB - AIM: To differentiate retrospectively the morphological characteristics at high resolution computed tomography (CT) between minimally invasive pulmonary adenocarcinoma (MIA) and invasive pulmonary adenocarcinoma (IAC) appearing as subsolid nodules (SNs) with a diameter of <=3 cm and to provide information to help operative decision-making. MATERIALS AND METHODS: The patient notes of 260 patients with SNs of <=3 cm in diameter (98 with MIA and 162 with IAC) confirmed at surgery and histopathology from September 2008 to June 2012 were reviewed retrospectively at the Department of Radiology, Weifang Respiratory Disease Hospital. Sixty-seven patients had pure ground-glass nodules (PGGNs) and 193 had mixed ground-glass nodules (MGGNs). Patients were grouped according to the final pathology: minimally invasive MIA and IAC. The HRCT characteristics were compared between the two groups. RESULTS: There were statistically significant differences in the pattern, shape, diameter of solid components, proportion of solid components, CT radiodensity values of the ground-glass and solid components, borders, margins, air bronchograms, microvascular signs, and pleural indentations of the nodules between the two groups (all p<0.05). Multivariate and receiver operating characteristic (ROC) analyses indicated significant predictors of MIAs were as follows: small lesion diameter (<=14.7 mm), solid components <=7 mm, <50% of solid components, low CT radiodensity values of the solid components (<=-107 HU), air bronchograms in the ground-glass opacity components, and microvascular signs. CONCLUSION: The morphological characteristics at high-resolution CT can be used to differentiate between MIAs and IACs appearing as SNs with a diameter of <=3 cm and provide information to help operative decision-making. PMID- 29273230 TI - Exploring the Neural Bases of Primary Muscle Tension Dysphonia: A Case Study Using Functional Magnetic Resonance Imaging. AB - : Primary muscle tension dysphonia (pMTD) is a voice disorder that occurs in the absence of laryngeal pathology. Dysregulated activity of the paralaryngeal muscles is considered the proximal cause; however, the central origin of this aberrant laryngeal muscle activation is unclear. The Trait Theory (Roy and Bless, 2000a,b) proposed that specific personality traits can predispose one to laryngeal motor inhibition and pMTD, and this inhibition is mediated by a hyperactive "behavioral inhibition system (BIS)" composed of limbic system structures (and associated prefrontal connections). This case study used functional magnetic resonance imaging to detect brain activation changes associated with successful management of pMTD, thereby evaluating possible neural correlates of this poorly understood disorder. METHOD: A 61-year-old woman with moderate-to-severe pMTD underwent functional magnetic resonance imaging scans before and immediately after successful treatment using manual circumlaryngeal techniques. Experimental stimuli were blocks of repeated vowel production and overt sentence reading. RESULTS: Significantly greater activation was observed pre- versus posttreatment in all regions of interest during sentence production, that is, periaqueductal gray, amygdala, hypothalamus, anterior cingulate cortex, hippocampus, dorsolateral prefrontal cortex, Brodmann area 10, and premotor and inferior sensorimotor cortex. CONCLUSIONS: Our findings are compatible with overactivation of neural regions associated with the BIS (cingulate cortex, amygdala, hypothalamus, periaqueductal gray) and motor inhibition networks (eg, [pre-]supplementary motor area) along with the dorsolateral prefrontal cortex and medial prefrontal cortex. Heightened input from limbic regions combined with dysfunctional prefrontal regulation may interfere with laryngeal motor preparation, initiation, and execution thereby contributing to disordered voice in pMTD. PMID- 29273231 TI - Voice Acoustic Analysis of Pediatric Vocal Nodule Patients Using Ratios Calculated With Biomedical Image Segmentation. AB - OBJECTIVE: The aim of this study was to determine nodules using newly developed software with a computer-assisted visual process technique for the calculation of size. The effects of the ratios of nodule base and width were evaluated with voice acoustic analysis. METHODS: A total of 72 patients with pediatric vocal nodule were evaluated. Nodules were marked with the ImageJ News program on photographs obtained from the video recordings in the videostroboscopic examination and classified according to the Shah et al scale. Segmentation was applied automatically. The ratios were taken as base of nodule/width and base of nodule/vocal cord. In the voice acoustic analysis, basic frequencies (mean F0), jitter (local %), shimmer (local %), and harmonicity (mean harmonics-to-noise [mean HNR]) were evaluated. RESULTS: A statistically significant negative correlation was determined between the mean F0 value and the nodule base/width ratio (P = 0.042, r = -0.240). A negative statistically significant relationship was determined between jitter (%) and vocal nodule base/width (P = 0.009, r = 0.305). A statistically significant positive correlation was determined between mean HNR and vocal nodule base/width (P = 0.034, r = 0.324). In discriminant analysis, correct classification of the Shah et al scale degrees of the classifying variables was 73.6%. CONCLUSION: Through collaboration with the biomedical engineering department, the results of this study determined new ratios in patients with pediatric vocal nodule. In voice acoustic analysis, the mean F0 was more affected by the width of the nodule, mean HNR was affected by the length of the base of the nodule, and jitter (%) was affected by the width of the nodule. PMID- 29273232 TI - The Impact of Double Source of Vibration Semioccluded Voice Exercises on Objective and Subjective Outcomes in Subjects with Voice Complaints. AB - PURPOSE: The present study reports the effects of double source of vibration semioccluded vocal tract exercises (SOVTEs) on subjective and objective variables in subjects with voice complaints. METHODS: Eighty-four participants with voice complaints were randomly assigned to one of four treatment groups: (1) water resistance therapy, (2) tongue trills, (3) lip trills, and (4) raspberry (tongue and lip trills at the same time). Before and after voice therapy, participants underwent aerodynamic, electroglottographic, and acoustic assessments. Measures for the Vocal Tract Discomfort Scale (VTDS), self-assessment of resonant voice quality, and sensation of muscle relaxation were also obtained. Three assessment sessions were conducted: (1) before the therapy session (Pre), (2) immediately after the voice therapy session (Post 1), and (3) 1 week after home practice (Post 2). RESULTS: Significant differences between baseline (Pre) and both post measures were found for the perception of muscle relaxation and resonant voice quality. No significant differences between Post 1 and Post 2 for any exercises were observed. This indicates that all voice exercises improved subjective self perceived voice quality immediately after exercises and that improvement remained stable after 1 week of practice. Water resistance therapy and raspberry attained the highest effect. A significant decrease for all exercises was also observed for VTDS values after 1 week of practice. Although some significant changes were observed in objective variables, no clear patterns could be detected. CONCLUSIONS: SOVTEs with secondary source of vibration may reduce vocal symptoms related to physical discomfort in subjects with voice complaints. Objective variables apparently do not fully reflect subjective positive outcomes, or they are not sensitive enough to capture changes. No significant differences between four observed SOVTEs were observed. PMID- 29273233 TI - Eligibility of cardiac resynchronization therapy patients for subcutaneous implantable cardioverter defibrillators. AB - The eligibility for subcutaneous implantable cardioverter-defibrillators (S-ICD) was assessed among patients already implanted with cardiac resynchronization therapy (CRT). We included 20 patients (15 men, age 73+/-10years, LVEF 35+/-10%). Seventeen (85%) patients were eligible for S-ICDs: 11 (55%) patients on only 1 vector and 6 (30%) patients on 2 or 3 vectors. Patients who were eligible on 2-3 vectors had narrower paced QRS than patients who were not eligible or were eligible on only one vector (133+/-18ms vs 167+/-17ms, p=0.007). If necessary, S ICD implantation could be considered in most patients with CRT. PMID- 29273234 TI - Body surface activation mapping of electrical dyssynchrony in cardiac resynchronization therapy patients: Potential for optimization. AB - BACKGROUND: Electrical synchronization is likely improved by cardiac resynchronization therapy (CRT), but is difficult to quantify with 12-lead ECG. We aimed to quantify changes in electrical synchrony and potential for optimization with CRT using a body-surface activation mapping (BSAM) system. METHODS: Standard deviation of activation times (SDAT) was calculated in 94 patients using BSAM at baseline CRT (CRTbl), native, and different CRT configurations. RESULTS: SDAT decreased 20% from native to CRTbl (p<0.01) and an additional 26% (p<0.01) at optimal CRT (CRTopt), the minimal SDAT setting. Patients with LBBB and patients with QRS duration >=150ms had higher native SDAT and greater decrease with CRTbl (p<0.01); however, the improvement from CRTbl to CRTopt was similar in all four groups (range: 24-28%). CRTopt was achieved with biventricular pacing in 52% and LV-only pacing in 44%. We propose that improved wavefront fusion demonstrated by BSAMs contributed substantially to the improved electrical synchrony. CONCLUSION: Optimization potential is similar regardless of pre-CRT QRS morphology or duration. BSAM could possibly improve CRT response by individualizing device programming to minimize electrical dyssynchrony. PMID- 29273235 TI - Retraction notice to Inhibition of proliferation and induction of apoptosis by 2 benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide in adult T-cell leukemia cells. PMID- 29273236 TI - Effect of tooth substrate and porcelain thickness on porcelain veneer failure loads in vitro. AB - STATEMENT OF PROBLEM: Bonded porcelain veneers are widely used esthetic restorations. High success and survival rates have been reported, but failures do occur. Fractures are the commonest failure mode. Minimally invasive or thin veneers have gained popularity. Increased enamel and porcelain thickness improve the strength of veneers bonded to enamel, but less is known about dentin or mixed substrates. PURPOSE: The purpose of this in vitro study was to measure the influences of tooth substrate type (all-enamel, all-dentin, or half-dentin-half enamel) and veneer thickness on the loads needed to cause initial and catastrophic porcelain veneer failure. MATERIAL AND METHODS: Model discoid porcelain veneer specimens of varying thicknesses were bonded to the flattened facial surfaces of incisors with different enamel and dentin tooth substrates, artificially aged, and loaded to failure with a small sphere. Initial and catastrophic fracture events were identified and analyzed statistically and fractographically. RESULTS: Fracture events included initial Hertzian cracks, intermediate radial cracks, and catastrophic gross failure. All specimens retained some porcelain after catastrophic failure. Cement failure occurred at the cement-porcelain interface not at the cement-tooth interface. Porcelain veneers bonded to enamel were substantially stronger and more damage-tolerant than those bonded to dentin or mixed substrates. Increased porcelain thickness substantially raised the loads to catastrophic failure on enamel substrates but only moderately raised the loads to catastrophic failure on dentin or mixed substrates. The veneers bonded to half-dentin-half-enamel behaved remarkably like those bonded wholly to dentin. CONCLUSIONS: Porcelain veneers bonded to enamel were substantially stronger and more damage-tolerant than those bonded to dentin or half-enamel-half dentin. PMID- 29273237 TI - Correlation of serum sialyl Tn antigen values determined by immunoassay and SRM based method. AB - We previously identified four glycan tumor marker candidates using a HPLC-based method. One candidate was sialyl Tn (STN), NeuAcalpha2-6-GalNAc. In this study, glycans were prepared from sera by hydrazine treatment followed by fluorescent labeling with aminopyridine. Pyridylaminated-STN levels of 147 gastric cancer, 85 pancreatic cancer and 10 cholangiocarcinoma patients together with 102 normal controls were accurately quantified using HPLC separation followed by selected reaction monitoring (SRM) assay, which used a stable isotope, tetradeuterium labeled pyridylamino glycan as an internal standard. Additionally, STN values were also quantified using conventional competitive inhibition radioimmunoassay (RIA). The two STN levels determined by RIA and SRM gave a similar distribution pattern in sera. STN levels were increased in sera from cancer patients compared to those from normal controls. Moreover, the STN levels in sera of cancer patients determined by the two different assay procedures showed a good correlation (i.e., correlation coefficient >0.9). Our results suggest it may be better to determine STN levels using SRM instead of RIA. PMID- 29273238 TI - Fast and accurate enzyme activity measurements using a chip-based microfluidic calorimeter. AB - Recent developments in microfluidic and nanofluidic technologies have resulted in development of new chip-based microfluidic calorimeters with potential use in different fields. One application would be the accurate high-throughput measurement of enzyme activity. Calorimetry is a generic way to measure activity of enzymes, but unlike conventional calorimeters, chip-based calorimeters can be easily automated and implemented in high-throughput screening platforms. However, application of chip-based microfluidic calorimeters to measure enzyme activity has been limited due to problems associated with miniaturization such as incomplete mixing and a decrease in volumetric heat generated. To address these problems we introduced a calibration method and devised a convenient protocol for using a chip-based microfluidic calorimeter. Using the new calibration method, the progress curve of alkaline phosphatase, which has product inhibition for phosphate, measured by the calorimeter was the same as that recorded by UV visible spectroscopy. Our results may enable use of current chip-based microfluidic calorimeters in a simple manner as a tool for high-throughput screening of enzyme activity with potential applications in drug discovery and enzyme engineering. PMID- 29273239 TI - Percutaneous pulmonary valve implantation in small conduits: A multicenter experience. AB - BACKGROUND: Guidelines allow percutaneous pulmonary valve implantation (PPVI) in conduits above 16mm diameter. Balloon dilatation of a conduit to a diameter>110% of the original implant size is also not recommended. We analyzed patients undergoing PPVI in such conditions. METHODS AND RESULTS: Nine patients (May 2008 July 2016) from 8 institutions underwent PPVI in conduits <16mm diameter. Five patients with 16-18mm conduit diameter underwent PPVI after over-expansion of the conduit>110%. Mean age and weight of the 14 patients was 12.1 (7.7 to 16) years and 44.9 (19 to 83) kg. Median conduit diameter at PPVI was 12 (10 to 17) mm. Median systolic right ventricular pressure was 70 (40 to 94) mmHg. Procedure was successful in all cases. A confined conduit rupture occurred in 7 patients (50%) and was treated with covered stent in 6. One patient experienced dislocation of 2 pulmonary artery stents that were parked distally. The post-implantation median systolic right ventricular pressure was 36 (28 to 51) mmHg. A fistula between right-ventricle outflow and aorta was found in one patient, secondary to undiagnosed conduit rupture. This was closed surgically. After a median follow-up of 20.16 (6.95 to 103.61) months, all the patients are asymptomatic with no significant RVOT stenosis. CONCLUSIONS: PPVI is feasible in small conduits but rate of ruptures is high. Although such ruptures remain contained and can be managed with covered stents in our experience, careful selection of patients and high level of expertise are necessary. More studies are needed to better assess the risk of PPVI in this population. PMID- 29273240 TI - Balloon angioplasty versus stenting for pulmonary vein stenosis after pulmonary vein isolation for atrial fibrillation: A meta-analysis. AB - BACKGROUND: The incidence of pulmonary vein stenosis (PVS) as complication after pulmonary vein isolation (PVI) for atrial fibrillation (AF) has decreased in the last decade. However, as PVI for AF is becoming more prevalent, the incidence remains considerable in absolute terms. The purpose of this meta-analysis is to investigate the optimal approach for management of PVS after PVI for AF. METHODS AND RESULTS: We searched electronic scientific databases for studies comparing plain balloon angioplasty (BA) versus stenting for PVS after PVI for AF. Aggregate data were pooled to perform a meta-analysis. The primary and secondary outcomes were restenosis requiring repeated intervention and procedure-related complications, respectively. A total of 4 studies, treating 315 PVS in 188 patients (BA, n=171 versus stent, n=144 PVS) were considered. After a median follow-up of 32months, the overall incidence of restenosis was 46%. A percutaneous therapy with BA was associated with a higher risk for restenosis requiring repeat intervention compared to stent (risk ratio - RR, 95% confidence interval [95% CI]=2.18 [1.64-2.89], p<0.001). Procedure-related complications were comparable between BA and stent (RR [95% CI]=0.96 [0.19-4.96], p=0.96). The time to diagnosis of PVS after PVI for AF did not modify the treatment effect for the primary outcome with BA versus stent (p for interaction=0.16). CONCLUSIONS: In patients presenting PVS after PVI for AF, a percutaneous therapy with BA is associated with higher risk for restenosis requiring repeat intervention as compared to stent. These percutaneous therapies display comparable safety. PMID- 29273241 TI - A meta-analysis of transcatheter device closure of perimembranous ventricular septal defect. AB - BACKGROUND: While transcatheter device closure of ventricular septal defects (VSDs) is gaining popularity, concerns remain about adverse events; particularly heart block in peri-membranous VSDs (pmVSDs). The aim of this study is to ascertain outcomes of transcatheter device closure of pmVSDs through a meta analysis of current literature. METHODS: A PubMed and Scopus search for studies in English on device closure of pmVSDs published till end-February 2017 was performed. Exclusion criteria included case series already included in multi centre studies, sample size <5, and VSD acquired following myocardial infarction. Pooled estimates of success and complications was obtained using the random effects model. RESULTS: A total of 54 publications comprising 6762 patients with pmVSDs were included. The mean age of patients ranged from 1.6 to 37.4years. The pooled estimate of successful device implantation is 97.8% (95% CI: 96.8 to 98.6). The most common complication is residual shunt (15.9%; 95% CI: 10.9 to 21.5). Other complications include arrhythmias (10.3%; 95% CI: 8.3 to 12.4) and valvular defects (4.1%; 95% CI: 2.4 to 6.1). The pooled estimate of complete atrioventricular block (cAVB) is 1.1% (95% CI: 0.5 to 1.9). CONCLUSION: Our meta analysis suggests that device closure of pmVSDs is a safe and effective procedure. The complication of cAVB is low but significant. The risk is expected to further reduce with newer devices which are less stiff with improved profiles. Further studies validating this will be useful in formulating guidelines for device closure of pmVSDs. PMID- 29273242 TI - Is early and fast blood pressure control important in hypertension management? AB - Control of blood pressure (BP) in hypertension is recognized as a key measure in the management of cardiovascular (CV) risk and is a cornerstone of preventive strategies. It is not defined, however, whether an initiation of the antihypertensive treatment in the early stages of hypertension (such as prehypertension or high-normal BP), may bring benefits for the long-term prevention of CV events. In addition, it has not been thoroughly addressed the issue whether achievement of a prompt BP reduction in hypertensive patients may contribute to reduce CV damage and events. The aim of this article is to critically examine data from studies exploring these important questions. Our conclusion is that the available evidence, though not very extensive, supports the prevailing benefits associated with early BP control. We also discuss the therapeutic strategies to achieve early control of BP. Finally, we believe that this aspect deserves to be more thoroughly addressed in upcoming international guidelines. PMID- 29273243 TI - Mapping coastal marine debris using aerial imagery and spatial analysis. AB - This study is the first to systematically quantify, categorize, and map marine macro-debris across the main Hawaiian Islands (MHI), including remote areas (e.g., Niihau, Kahoolawe, and northern Molokai). Aerial surveys were conducted over each island to collect high resolution photos, which were processed into orthorectified imagery and visually analyzed in GIS. The technique provided precise measurements of the quantity, location, type, and size of macro-debris (>0.05m2), identifying 20,658 total debris items. Northeastern (windward) shorelines had the highest density of debris. Plastics, including nets, lines, buoys, floats, and foam, comprised 83% of the total count. In addition, the study located six vessels from the 2011 Tohoku tsunami. These results created a baseline of the location, distribution, and composition of marine macro-debris across the MHI. Resource managers and communities may target high priority areas, particularly along remote coastlines where macro-debris counts were largely undocumented. PMID- 29273244 TI - Bacterial keratitis treated by strengthened antibiotic eye drops: An 18 months review of clinical cases and antibiotic susceptibilities. AB - PURPOSE: To describe, in patients treated for infectious keratitis, the microorganisms identified and their antibiotic susceptibility over a period of 18 months. METHOD: Retrospective, descriptive, non-comparative study. Medical and biological data were extracted from the patients' file treated with strengthened antibiotic eye drops at Angers University Hospital between January 2015 and June 2016. The main elements noted were the bacteria involved and their susceptibility to antibiotics. Patients' visual acuity at the start and end of treatment was compared. RESULTS: Forty-eight patients were included. Almost one bacterium was identified in 31 patients, totalling 43 pathogens of 24 different species. The most frequently found microorganisms were Gram-positive cocci (55.8%), including Staphylococcus Aureus (14.0%) and Epidermidis (14.0%). All Gram-negative bacilli amounted to 30.2% of the identified bacteria, including 9.3% of Pseudomonas aeruginosa. None of the Gram-positive cocci were resistant to vancomycin and all Gram-negative bacilli were susceptible to ceftazidime and amikacin. Following treatment with at least one of the three antibiotic eye drops produced by our pharmacy (amikacin at 50mg/mL, ceftazidime at 50mg/mL and vancomycin at 25mg/mL), patients' visual acuity was significantly improved (P=0.043). CONCLUSION: The study helped identify the bacterial ecology of patients admitted for infectious keratitis. Among the bacteria identified, none were found to be resistant to any of the three strengthened antibiotic eye drops produced by the hospital pharmacy. These eye drops allowed for a rapid and effective treatment of patients and the improvement of their visual acuity before even identifying the bacteria. PMID- 29273246 TI - Asthma. AB - Asthma-one of the most common chronic, non-communicable diseases in children and adults-is characterised by variable respiratory symptoms and variable airflow limitation. Asthma is a consequence of complex gene-environment interactions, with heterogeneity in clinical presentation and the type and intensity of airway inflammation and remodelling. The goal of asthma treatment is to achieve good asthma control-ie, to minimise symptom burden and risk of exacerbations. Anti inflammatory and bronchodilator treatments are the mainstay of asthma therapy and are used in a stepwise approach. Pharmacological treatment is based on a cycle of assessment and re-evaluation of symptom control, risk factors, comorbidities, side-effects, and patient satisfaction by means of shared decisions. Asthma is classed as severe when requiring high-intensity treatment to keep it under control, or if it remains uncontrolled despite treatment. New biological therapies for treatment of severe asthma, together with developments in biomarkers, present opportunities for phenotype-specific interventions and realisation of more personalised treatment. In this Seminar, we provide a clinically focused overview of asthma, including epidemiology, pathophysiology, clinical diagnosis, asthma phenotypes, severe asthma, acute exacerbations, and clinical management of disease in adults and children older than 5 years. Emerging therapies, controversies, and uncertainties in asthma management are also discussed. PMID- 29273245 TI - Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial. AB - BACKGROUND: In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. METHODS: In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. FINDINGS: Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1.24 [95% CI 1.05-1.46]; p=0.0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1.14 [95% CI 0.97-1.35]; p=0.1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. INTERPRETATION: In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. FUNDING: The Netherlands Organization for Health Research and Development. PMID- 29273247 TI - Taking a long view on fertility treatments. PMID- 29273249 TI - Effectiveness, Implementation and Real-World Experience with Extended-Release Naltrexone (XR-NTX): A Special Issue of JSAT. PMID- 29273248 TI - Substrate cleavage and duration of action of botulinum neurotoxin type FA ("H, HA"). AB - Botulinum neurotoxin (BoNT) type FA is the only known naturally occurring chimeric BoNT of domains of BoNT/A and BoNT/F. BoNT/FA consists of an F5-like light chain (LC), a unique heavy chain (HC) translocation domain, and a HC receptor binding domain similar to BoNT/A1. Previous analyses of purified BoNT/FA have indicated a 5-10-fold greater potency in cultured human or rat neurons as compared to BoNT/A1 and a 400-500-fold greater potency compared to BoNT/B1. However, in vivo potency in mice was about 5-fold lower than BoNT/A1 or/B1. In this report, species specificity was examined by cell-based assays using primary neurons from mice and examining VAMP1 and 2 cleavage. The data indicated similar potency of BoNT/FA in primary mouse spinal cord neurons as previously observed in primary rat and human induced pluripotent stem cell (hiPSC) derived neuronal cell models, and equal enzymatic cleavage of mouse VAMP1 and 2 isoforms. Since the duration of action of BoNTs is due to continuous enzymatic activity of the LC in the neuronal cytosol, BoNT/FA was expected to have a short duration of action due to its F-type LC. In this report the duration of action of BoNT/FA was compared to that of BoNT/F1,/F5, and/B1 in both hiPSC derived neurons and in the in vivo mouse model. The data indicate a duration of action of BoNT/FA similar to BoNT/B1, while BoNT/F5 had a short duration of action similar to BoNT/F1. PMID- 29273250 TI - Clinical Utility of Continuous Radial Magnetic Resonance Imaging Acquisition at 3 T in Real-time Patellofemoral Kinematic Assessment: A Feasibility Study. AB - PURPOSE: To compare patellar instability with magnetic resonance imaging analysis using continuous real-time radial gradient-echo (GRE) imaging in the assessment of symptomatic patients and asymptomatic subjects. METHODS: Symptomatic patients with suspected patellofemoral maltracking and asymptomatic volunteers were scanned in real time by a radial 2-dimensional GRE sequence at 3 T in axial orientation at the patella level through a range of flexion-extension. The degree of lateral maltracking, as well as the associated tibial tubercle-trochlear groove distance and trochlea depth, was measured. Patellar lateralization was categorized as normal (<=2 mm), mild (>2 to <=5 mm), moderate (>5 to <=10 mm), or severe (>10 mm). The patellofemoral cartilage was also assessed according to the modified Outerbridge grading system. RESULTS: The study included 20 symptomatic patients (13 women and 7 men; mean age, 36 +/- 12.8 years) and 10 asymptomatic subjects (3 women and 7 men; mean age, 33.1 years). The mean time to perform the dynamic component ranged from 3 to 7 minutes. Lateralization in the symptomatic group was normal in 10 patients, mild in 1, moderate in 8, and severe in 1. There was no lateral tracking greater than 3 mm in the volunteer group. Lateral maltracking was significantly higher in symptomatic patients than in asymptomatic subjects (4.4 +/- 3.7 mm vs 1.5 +/- 0.71 mm, P = .007). Lateral tracking significantly correlated with tibial tubercle-trochlear groove distance (r = 0.48, P = .006). There was excellent agreement on lateral tracking between the 2 reviewers (intraclass correlation coefficient, 0.979; 95% confidence interval, 0.956-0.990). CONCLUSIONS: The inclusion of a dynamic radial 2-dimensional GRE sequence is a rapid and easily performed addition to the standard magnetic resonance imaging protocol and allows dynamic quantitative assessment of patellar instability and lateral maltracking in symptomatic patients. With a paucity of reported data using this technique confirming that these results reach clinical significance, future work is required to determine how much lateral tracking is clinically significant. LEVEL OF EVIDENCE: Level III, case control. PMID- 29273251 TI - Outcomes and Complications Following Endoscopically Assisted Percutaneous Achilles Tendon Repair. AB - PURPOSE: To review functional and clinical outcomes as well as complications in patients who underwent endoscopically assisted percutaneous Achilles tendon repair using 4-strand core suture configuration via a 6-portal technique. METHODS: A retrospective chart review with prospectively collected data was performed in 23 consecutive patients who underwent endoscopically assisted percutaneous Achilles tendon repair between 2008 and 2015. The minimum follow-up to be included in the study was 24 months. The primary outcome was Foot and Ankle Ability Measure (FAAM), Activities of Daily Living (ADL) and Sports subscales; Short Form-36 (SF-36), physical and mental component summaries (PCS and MCS); and visual analog scale (VAS). The secondary outcomes included tourniquet time, recovery time, and complications. RESULTS: Twenty-three patients (18 males and 5 females, all unilateral) with the mean age of 36.7 years were included and 6 patients were repaired using an open technique because they did not meet the inclusion criteria owing to presenting late in the clinic (injury more than 2-3 weeks). The average time to final follow-up was 54.1 months. The average tourniquet time was 41.3 minutes. There was significant improvement of VAS (7.9/10 to 0.1/10), SF-36 (PCS, 32.5-44.7, and MCS, 47.9-51.4), and FAAM (ADL, 26.1.0-83.0, and Sports, 0-61.7). The average time to return to activities of daily living, work, and sports were 8.0 weeks, 8.8 weeks, and 5.7 months, respectively. The postoperative morbidity included superficial wound infection at the portal (1 patient with underlying type 2 diabetes, 4.3%) and there was no rerupture, deep vein thrombosis, sural nerve injury, and painful scar in this study. CONCLUSIONS: Endoscopically assisted percutaneous Achilles tendon repair has significant improvement in terms of functional outcomes as measured with the FAAM, SF-36, and VAS. This technique is safe and feasible with minimal postoperative pain and morbidities, early return to activities, and satisfactory functional outcomes. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29273252 TI - Supercritical Carbon Dioxide-Sterilized Bone Allograft in the Treatment of Tunnel Defects in 2-Stage Revision Anterior Cruciate Ligament Reconstruction: A Histologic Evaluation. AB - PURPOSE: To examine the histologic properties of supercritical carbon dioxide (sCO2)-sterilized bone allograft for tunnel grafting and determine in vivo graft quality, as well as graft incorporation and remodeling, in 2-stage revision anterior cruciate ligament (ACL) surgery. METHODS: Histologic evaluation was performed in 12 subjects undergoing 2-stage revision ACL reconstruction. In the first stage, the femoral and tibial tunnels were debrided, tunnel dimensions were measured, and tunnels were grafted with sCO2-sterilized bone allograft. In the second stage, revision ACL reconstruction was performed and bone biopsy specimens were taken from the tibia. Tissue, bone, and graft volumes were measured, and histomorphometric analysis was performed. RESULTS: The mean time between the 2 stages was 8.8 months (range, 5.6-21.3 months). In the second stage, bone graft material was easily identified by its necrotic appearance comprising mature lamellar bone devoid of osteocyte nuclei within osteocyte lacunae. In all tissue samples, host-bone apposition of predominantly mature lamellar bone was noted on the surface of graft fragments in keeping with "creeping substitution." In several regions in 3 cases, osteoblastic and osteoclastic activity was evident in keeping with ongoing creeping substitution and remodeling. The mean bone volume over tissue volume was 68% (range, 33%-92%), and the mean graft volume over bone volume was 41% (range, 19%-70%). The mean graft volume (8 cases) harvested at less than 7 months (44%; 95% confidence interval, 31.4%-56.8%) was not significantly different than the mean graft volume (4 cases) harvested at greater than 10 months (34%; 95% confidence interval, 14.3%-54.2%; P = .214). CONCLUSIONS: The sCO2-sterilized bone allograft showed graft incorporation and remodeling through creeping substitution. CLINICAL RELEVANCE: The initial bone apposition and graft fragment bridging appear to provide a strong environment for ACL graft fixation resulting in technically successful 2-stage revision ACL reconstruction. PMID- 29273253 TI - Elbow Arthroscopy: 30-Day Postoperative Complication Profile and Associated Risk Factors. AB - PURPOSE: To analyze (1) the incidence and type of complications after elbow arthroscopy, (2) the incidence of returning to the operating room (OR) after elbow arthroscopy, and (3) patient and risk factors for complications across a national surgical outcome database. METHODS: Patients who underwent elbow arthroscopy from January 2005 through December 2014 were identified in the American College of Surgeons National Surgical Quality Improvement Program database by use of Current Procedural Terminology codes. Basic patient demographic data and medical comorbidities were recorded. Postoperative adverse events and a return to the OR occurring within 30 days after the index procedure were identified, and patient and procedural risk factors were investigated. RESULTS: Five hundred thirty elbow arthroscopy cases were available for analysis. The aggregate rate of 30-day adverse events was 2.83%, whereas the rate of any patient having an adverse event was 1.89%. The most common adverse event was deep infection (0.57%). Univariate analyses showed that renal disease, preoperative steroid use, higher American Society of Anesthesiologists (ASA) class, and preoperative diagnosis were associated with the occurrence of an adverse event. Multivariate analyses showed that increasing ASA class, specifically ASA class 3 and class 4, was an independent predictor of a postoperative adverse event. Furthermore, 0.94% of cases required a return to the OR. Univariate analyses showed that preoperative steroid use and diagnosis of trauma were associated with a return to the OR. These findings were confirmed by multivariate analyses. CONCLUSIONS: Overall, the incidence of 30-day postoperative adverse events (1.89%) and need to return to the OR (0.94%) is low. Increased ASA class is an independent risk factor for the occurrence of a postoperative adverse event; preoperative steroid use and diagnoses relating to a traumatic or inflammatory cause are predictive of the need to return to the OR. These results can assist surgeons in patient selection, preoperative optimization, and preoperative risk stratification. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29273254 TI - Sex-Dependent Differences in Preoperative, Radiographic, and Intraoperative Characteristics of Patients Undergoing Hip Arthroscopy: Results From the Multicenter Arthroscopic Study of the Hip Group. AB - PURPOSE: To compare preoperative, radiographic, and intraoperative findings between male and female patients undergoing hip arthroscopy. METHODS: We performed a retrospective review of a multicenter registry of patients undergoing hip arthroscopy between January 2014 and January 2017. Perioperative data from patients who consented to undergo surgery and completed preoperative patient reported outcome questionnaires were analyzed to determine the effect of sex on preoperative symptoms, patient-reported outcomes, radiographic measures, and surgical procedures. RESULTS: A total of 1,437 patients (902 female and 535 male patients) with a mean age of 34 years were enrolled in the study. Female patients reported greater pain preoperatively on a visual analog scale (55.42 vs 50.40, P = .001) and deficits in functional abilities as per the modified Harris Hip Score (53.40 vs 57.83, P < .001) and International Hip Outcome Tool 12 (31.21 vs 38.51, P = .001) than male patients. There was a significant difference in the alpha angle (67.6 degrees in male patients vs 59.5 degrees in female patients, P < .001) corresponding with a higher prevalence of cam deformity in male patients (94.6% vs 84.5%, P < .001). Male patients had less range of motion in flexion ( 5.67 degrees , P < .001), internal rotation (-8.23 degrees , P < .001), and external rotation (-4.52 degrees , P < .001) than female patients. Acetabular chondroplasty was performed in 58% of male patients versus 40.2% of female patients (P < .001). Acetabuloplasty was performed in 59.1% of male patients versus 43.9% of female patients (P < .001). CONCLUSIONS: Male and female patients undergoing hip arthroscopy differ statistically in terms of preoperative hip function, hip morphology, and self-reported functional deficits, as well as the prevalence of surgical procedures. However, they do not differ significantly in terms of symptom localization, duration, or onset. The observed differences in preoperative functional scores between sexes, although statistically significant, may not represent clinically meaningful differences. LEVEL OF EVIDENCE: Level III, retrospective cross-sectional study. PMID- 29273255 TI - Revision Multiligament Knee Reconstruction: Clinical Outcomes and Proposed Treatment Algorithm. AB - PURPOSE: To (1) assess clinical outcomes of revision multiligament knee injury (MLKI) reconstruction at a minimum of 2 years' follow-up and (2) present a standardized treatment algorithm used in treating revision MLKI patients. METHODS: A retrospective review of our institution's MLKI database was performed to identify all patients who underwent revision MLKI reconstructions (>=2 ligaments reconstructed) after implementation of a standardized treatment algorithm in 2000 and had a minimum of 2 years' follow-up. Patient demographic information, injury description (mechanism of injury, neurovascular status, knee dislocation grade, associated chondral or meniscal injury), surgical technique (repair vs reconstruction, staged vs nonstaged, concomitant procedures), mechanism of failure, knee stability, and range of motion, as well as International Knee Documentation Committee and Lysholm scores, were obtained. RESULTS: We assessed 23 patients (8 female and 15 male patients), with an average age of 26.7 +/- 11.5 years at primary surgery and 30.8 +/- 11.0 years at revision surgery. The mean follow-up period was 7.5 +/- 5.3 years. Of the 23 patients, 10 (43.4%) underwent staged revision procedures: isolated bone grafting in 3, osteotomy in 4, hardware removal with osteochondral allograft in 1, hardware removal with bone grafting in 1, and meniscus repair for a locked knee in 1. The average International Knee Documentation Committee and Lysholm scores were 74.5 +/- 22.3 and 79.4 +/- 20.2, respectively. High-energy injury and increasing age at revision surgery were the only risk factors found to be associated with significantly worse outcomes (P < .05). CONCLUSIONS: Patients with recurrent instability after MLKI reconstruction present with many concomitant pathologies, including limb malalignment, bone tunnel widening, retained hardware, meniscal incompetence, and cartilage defects. Revision MLKI reconstruction can provide these patients with modest functional outcomes when a standardized treatment algorithm is used focusing on identification and treatment of the concomitant pathology, often in a staged manner. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29273256 TI - Preoperative Radiographic Risk Factors for Incomplete Arthroscopic Supraspinatus Tendon Repair in Massive Rotator Cuff Tears. AB - PURPOSE: To determine if preoperative imaging findings of massive rotator cuff (RC) tears were associated with (1) incomplete arthroscopic repair and (2) the use of advanced mobilization techniques (interval slides) and/or the use of a load-sharing rip stop repair construct. METHODS: Eighty-six consecutive patients who underwent arthroscopic repair for massive RC tears performed by a single surgeon between July 2013 and July 2015 were retrospectively evaluated. Previously proposed radiographic risk factors for irreparability (acromiohumeral distances, tangent sign, and the Goutallier stage of fatty infiltration for the supraspinatus) were analyzed. Associations between preoperative imaging characteristics and intraoperative results of RC surgery were determined using binary logistic regressions and Fisher's exact tests. The interobserver reliability of imaging characteristics was determined using intraclass correlation coefficients (ICCs). RESULTS: Seventy-six massive RC tears were fully reparable (88%). In the case of 10 RC tears (12%), a complete repair was not obtained. Inability to obtain a complete repair of the supraspinatus was associated with a positive tangent sign (30% irreparable) versus a negative tangent sign (6.3% irreparable, odds ratio [OR] = 6.3, P = .0102) and with Goutallier grade 3-4 fatty infiltration of the supraspinatus (42.9% irreparable) versus grade 0-2 fatty infiltration (5.7% irreparable, OR = 11.8, P = .001). Advanced arthroscopic techniques (interval slides or load-sharing rip stop) for dealing with poor-quality or retracted tendon were used in 62% of cases; however, no associations were found between preoperative imaging characteristics and these techniques. Interobserver reliability was moderate (ICC = 0.75-0.90) for the tangent sign (ICC = 0.78) and high-grade (Goutallier 3-4) fatty infiltration of the supraspinatus (ICC = 0.74). CONCLUSIONS: A positive tangent sign and/or high grade fatty infiltration (Goutallier 3-4) of the supraspinatus were risk factors for incomplete RC repair. However, these were not completely predictive of reparability because the majority of massive RC tears with these imaging characteristics were still fully reparable. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 29273257 TI - Are Outcomes After Meniscal Repair Age Dependent? A Systematic Review. AB - PURPOSE: To determine if the failure rate and functional outcome after arthroscopic meniscus suture repair are age dependent. METHODS: A systematic review was conducted using a computerized search of the electronic databases MEDLINE and ScienceDirect in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Extracted data from each included study were recorded on a standardized form. Studies were included if they (1) were English-language studies in peer-reviewed journals, (2) used a distinct age cut-off to evaluate outcome of meniscal surgery for those above and below the specified cut-off, and (3) used meniscal repairs using suture based technique with inside-out, outside-in, or all-inside techniques. Review papers, case reports, technique papers, non-English language publications, abstracts, and data on meniscal repairs using meniscal screws, arrows, or darts were excluded. RESULTS: 15 of 305 identified articles met the inclusion/exclusion criteria. There were 1,141 menisci treated in 1,063 patients. Seven and 8 studies met the inclusion/exclusion criteria for analysis for the age thresholds of 25 years and 30 years, respectively, demonstrating no difference in failure rates relative to age threshold. Four of 6 studies that met analysis criteria found no difference in failure rates above or below an age threshold of 35 years. No significant difference in failure in patients younger than 40 than patients older than 40 was found for 4 of the 5 studies in that arm of the review. CONCLUSIONS: Analysis of the composite data in this systematic review reveals that no significant difference exists when evaluating meniscal repair failure rate as a function of age above or below the given age thresholds. LEVEL OF EVIDENCE: Level IV, systematic review of level III and IV studies. PMID- 29273259 TI - Contemporary Application of Point-of-Care Echocardiography in the Emergency Department. AB - Point-of-care echocardiography is revolutionizing the management of patients presenting with undifferentiated shock and cardiac arrest in the emergency department (ED). Its primary purpose is to aid the clinician in rapidly ruling in and ruling out life-threatening diagnoses at the bedside. In addition, it has become an important component of the clinical examination for stable patients seen in the ED with nonspecific signs and symptoms such as shortness of breath or syncope. Although first described to facilitate the diagnosis of pericardial effusions and cardiac standstill, ED echocardiography has since evolved and is now widely used by emergency physicians to help diagnose other important cardiovascular pathologic conditions that may be contributing to undifferentiated shock, such as left ventricular failure and right ventricular dilatation resulting from pulmonary embolism. The use of echocardiography in the ED continues to expand, with advanced applications that include valvular assessment, diastolic dysfunction, and regional wall motion abnormalities, as well as the use of point-of-care transesophageal echocardiography. As the diffusion of these new skills continues and becomes routine, it will alter the practice of emergency medicine and the interaction with consulting cardiologists. PMID- 29273258 TI - Super-mini percutaneous nephrolithotomy for renal stone less than 25mm in pediatric patients: Could it be an alternative to shockwave lithotripsy? AB - AIM: To evaluate the efficacy of 2 different techniques: shock wave lithotripsy (SWL) vs. super-mini percutaneous nephrolithotomy (SMP), in terms of success as well as complication rates in pediatric renal stones sizing<25mm. PATIENTS AND METHODS: A total of 219 children (aging between 1-17 years) undergoing 2 different treatment modalities (SWL vs. SMP) for kidney stones<25mm were included. Depending on the type of the procedure applied, children were divided into 2 different groups: group 1 (n=108), children treated with SWL, and group 2 (n=111), children treated with SMP. All treatment related parameters (stone free rates, number of sessions, treatment duration, hospitalization, presence of the residual fragments, complications as well as the need for additional interventions) were noted and evaluated between 2 groups in a comparative manner. RESULTS: Evaluation of our data have clearly demonstrated that the percentage of residual fragments after SWL was significantly higher when compared with SMP. Although SWL required several sessions under general anesthesia in a certain per cent of the cases (54.6%), SMP was successful in one session in all of the cases. Last but not least, in addition to the similar minor complication rates observed in both group of cases, no major complication observed in any case and no case in both groups again required blood transfusion after these 2 procedures with no significant drop rates in hemoglobin levels. CONCLUSIONS: Although SWL is still the preferred treatment modality for the majority of kidney stones in children due to its safe and non-invasive nature, SMP modality may be applied as a valuable alternative in this specific patient population for its excellent stone free rates obtained in a single session and acceptable complication rates in the minimal invasive management of stones<25mm. PMID- 29273261 TI - Genotype-driven phase I study of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation for locally advanced rectal cancer. AB - PURPOSE: We aimed to identify the maximum tolerated dose (MTD) of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation according to the UGT1A1*28 genotype in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy were screened for the UGT1A1*28 genotype. Twenty-six patients with either the *1*1 or *1*28 genotype were eligible for dose escalation of irinotecan, and patients with a *28*28 genotype were excluded. The starting dose of weekly irinotecan was 50 mg/m2 for the two genotype groups, whereas the dose of capecitabine was fixed at 625 mg/m2. Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis (total dose of 50 Gy in 25 fractions). RESULTS: The dose of weekly irinotecan was escalated to 95 mg/m2 in patients with the *1*1 genotype and to 80 mg/m2 in those with the *1*28 genotype. Dose-limiting toxicities (DLTs) were observed in 2/2 *1*1 patients at 95 mg/m2 and 2/3 *1*28 patients at 80 mg/m2. No DLT cases were observed among the three *1*1 patients at 80 mg/m2, and one DLT case was observed among the six patients with *1*28 at 65 mg/m2. Hence, 80 mg/m2 and 65 mg/m2 were the MTDs for the two groups. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. CONCLUSION: A higher dose of weekly irinotecan in combination with capecitabine-based CRT is feasible under the guidance of the UGT1A1*28 genotype. Further clinical trials at these dose levels are warranted. PMID- 29273260 TI - Predicting hypoxia status using a combination of contrast-enhanced computed tomography and [18F]-Fluorodeoxyglucose positron emission tomography radiomics features. AB - BACKGROUND AND PURPOSE: Hypoxia is a known prognostic factor in head and neck cancer. Hypoxia imaging PET radiotracers such as 18F-FMISO are promising but not widely available. The aim of this study was therefore to design a surrogate for 18F-FMISO TBRmax based on 18F-FDG PET and contrast-enhanced CT radiomics features, and to study its performance in the context of hypoxia-based patient stratification. METHODS: 121 lesions from 75 head and neck cancer patients were used in the analysis. Patients received pre-treatment 18F-FDG and 18F-FMISO PET/CT scans. 79 lesions were used to train a cross-validated LASSO regression model based on radiomics features, while the remaining 42 were held out as an internal test subset. RESULTS: In the training subset, the highest AUC (0.873+/ 0.008) was obtained from a signature combining CT and 18F-FDG PET features. The best performance on the unseen test subset was also obtained from the combined signature, with an AUC of 0.833, while the model based on the 90th percentile of 18F-FDG uptake had a test AUC of 0.756. CONCLUSION: A radiomics signature built from 18F-FDG PET and contrast-enhanced CT features correlates with 18F-FMISO TBRmax in head and neck cancer patients, providing significantly better performance with respect to models based on 18F-FDG PET only. Such a biomarker could potentially be useful to personalize head and neck cancer treatment at centers for which dedicated hypoxia imaging PET radiotracers are unavailable. PMID- 29273262 TI - Long-term quality of life in inoperable non-small cell lung cancer patients treated with conventionally fractionated compared to hyperfractionated accelerated radiotherapy - Results of the randomized CHARTWEL trial. AB - BACKGROUND AND PURPOSE: To evaluate the quality of life (QoL) of patients with inoperable non-small cell lung cancer treated with conventionally fractionated radiotherapy (CF) vs. continuous hyperfractionated accelerated radiotherapy weekend-less (CHARTWEL). MATERIAL AND METHODS: The largest monocentric subgroup of the phase III CHARTWEL trial was analyzed up to three years after randomization. QoL was assessed with the European Organization for Research and Treatment of Cancer QoL Core Questionnaire (QLQ-C30) and lung cancer module (QLQ LC13) and compared using linear mixed models. QoL interrelations with recurrence, metastasis, and death were explored by multi-state modeling. RESULTS: 160 patients (98%) provided at least one QoL assessment. Average treatment differences of CF vs. CHARTWEL over three years were -5.4 points (95%CI [ 13.6,2.8], p = 0.19) in global QoL, 11.9 ([2.8,21.0], p = 0.01) in fatigue, 13.4 ([3.5,23.3], p = 0.009) in pain, 10.5 ([1.3,19.6], p = 0.03) in dyspnea, and 5.2 ([-2.7,13.0], p = 0.19) in dysphagia. At 12 months, the probabilities of being disease-free with good, good or moderate, any global QoL, or alive were 5.1%, 20.3%, 34.2%, 54.4% under CF and 10.4%, 21.0%, 37.5%, 65.3% under CHARTWEL. CONCLUSIONS: Over three years, QoL was similar or more favorable under CHARTWEL compared to CF. Modeling QoL together with disease states provided additional insight into treatment comparisons. PMID- 29273263 TI - Optocapacitive Generation of Action Potentials by Microsecond Laser Pulses of Nanojoule Energy. AB - Millisecond pulses of laser light delivered to gold nanoparticles residing in close proximity to the surface membrane of neurons can induce membrane depolarization and initiate an action potential. An optocapacitance mechanism proposed as the basis of this effect posits that the membrane-interfaced particle photothermally induces a cell-depolarizing capacitive current, and predicts that delivering a given laser pulse energy within a shorter period should increase the pulse's action-potential-generating effectiveness by increasing the magnitude of this capacitive current. Experiments on dorsal root ganglion cells show that, for each of a group of interfaced gold nanoparticles and microscale carbon particles, reducing pulse duration from milliseconds to microseconds markedly decreases the minimal pulse energy required for AP generation, providing strong support for the optocapacitance mechanism hypothesis. PMID- 29273265 TI - The safety and efficacy of laparoscopic hepatectomy in obese patients. AB - BACKGROUND: Obesity is generally reported to increase the risk of surgical complications. There have been few reports of laparoscopic hepatectomy (LH) in obese patients. The purpose of this study was to compare the safety and efficacy of (1) LH versus open hepatectomy (OH) in obese patients and (2) LH in obese patients versus LH in non-obese patients. METHODS: We introduced LH at our institution in April 2014. LH was performed in 63 obese patients and 108 non obese patients from April 2014 to May 2017. OH was performed in 79 obese patients from January 2010 to May 2017. This study retrospectively compared the short-term outcomes of the LH obese group with those of the OH obese group and the LH non obese group. RESULTS: In patient characteristics, the LH obese group included a significantly higher percentage of patients with liver cirrhosis than the OH obese group. The LH obese group had fewer patients with a history of abdominal surgery but more with liver cirrhosis than the LH non-obese group. For short-term outcomes, the LH obese group had significantly less blood loss, fewer intraoperative transfusions, fewer positive surgical margins, and shorter postoperative hospital stays than the OH obese group. In contrast, only operation time was significantly different (longer) in the LH obese group than in the LH non-obese group. There were no significant differences in morbidity or mortality between the LH obese group and either the OH obese or the LH non-obese groups. CONCLUSION: LH in obese patients is safe and effective. PMID- 29273264 TI - Early Elective Delivery Disparities between Non-Hispanic Black and White Women after Statewide Policy Implementation. AB - BACKGROUND: In 2011, Oregon implemented a policy that reduced the state's rate of early (before 39 weeks' gestation) elective (without medical need) births. OBJECTIVE: This analysis measured differential policy effects by race, examining whether Oregon's policy was associated with changes in non-Hispanic Black-White disparities in early elective cesarean and labor induction. METHODS: We used Oregon birth certificate data, defining prepolicy (2008-2010) and postpolicy (2012-2014) periods, including non-Hispanic Black and White women who gave birth during these periods (n = 121,272). We used longitudinal spline models to assess policy impacts by race and probability models to measure policy-associated changes in Black-White disparities. RESULTS: We found that the prepolicy Black White differences in early elective cesarean (6.1% vs. 4.3%) were eliminated after policy implementation (2.8% vs. 2.5%); adjusted models show decreases in the odds of elective early cesarean among Black women after the policy change (adjusted odds ratio, 0.47; 95% confidence interval, 0.22-1.00; p = .050) and among White women (adjusted odds ratio, 0.79; 95% confidence interval, 0.67-0.93; p = .006). Adjusted probability models indicated that policy implementation resulted in a 1.75-percentage point narrowing (p = .011) in the Black-White disparity in early elective cesarean. Early elective induction also decreased, from 4.9% and 4.7% for non-Hispanic Black and non-Hispanic White women to 3.8% and 2.5%, respectively; the policy was not associated with a statistically significant change in disparities. CONCLUSIONS: A statewide policy reduced racial disparities in early elective cesarean, but not early elective induction. Attention to differential policy effects by race may reveal changes in disparities, even when that is not the intended focus of the policy. PMID- 29273266 TI - In-vitro and in-vivo measurement of the animal's middle ear acoustical response by partially implantable fiber-optic sensing system. AB - The main obstacle in realization of a totally implantable hearing aid is a lack of reliable implantable microphone. In this paper we have described a potentially miniature fiber-optic vibrometer based on a modified Michelson interferometer, designed to serve as a middle-ear microphone for totally implantable cochlear- or middle-ear hearing aids. A model of the sensing system was used for in-vitro and in-vivo investigation of acoustical response of sheep's middle-ear ossicles. Surgical and implantation procedure of introducing the sensing optical fiber into the middle-ear and its aiming at the incus was investigated and described here in detail. The frequency responses of the incus was measured while a cadaver and living sheep was exposed to the sinusoidal acoustical excitation of 40-90dB SPL, in the frequency range from 100Hz to 10kHz. The amplitude of the incus vibration was found to be in the range between 10pm to 100nm, strongly depending on the frequency, with a lot of resonant peaks, corresponding mainly to the natural outer ear canal gain. The noise floor in the experiments was about 2pm/Hz1/2, but recently we have decreased it to < 0.5pm/Hz1/2, which corresponds to a minimal detectable sound level of 31-35dB(A) SPL for humans. The histological examination of temporal bones of cadaver animals and the intensity of in-vivo optical signal demonstrated that the aiming of the sensing fiber to the target has been preserved for five months after the implantation. PMID- 29273267 TI - Sexual and gender minority health: Nursing's overdue coming out. PMID- 29273268 TI - Isolation and screening of bacterial isolates from wastewater treatment plants to decolorize azo dyes. AB - The discharge of dye-contaminated wastewater into natural waterways presents a substantial risk to human and environmental health, therefore necessitating the treatment and removal of toxic dyes from colored wastewaters before their release into the ecosystem. The aim of this study was to isolate and characterize bacterial strains capable of decolorizing and/or degrading azo dyes commonly applied in textile production (monoazo dye Reactive Orange 16 and diazo dye Reactive Green 19) from activated sludge systems used in the treatment of (textile) wastewater. Following a prescreening of 125 isolates for their decolorization potential five strains were retained for further evaluation of decolorization rate and effects of physicochemical parameters using a microtiter plate method. Of those five strains, one strain belonging to the genus Acinetobacter (ST16.16/164) and another belonging to Klebsiella (ST16.16/034) outperformed the other tested strains. Both strains exhibited strong decolorization ability (>80%) within a wide temperature range (20 degrees C-40 degrees C) and retained good decolorization activity at temperatures as low as 10 degrees C (especially strain ST16.16/034). Among the different pH values tested (pH 4, 7 and 10), highest dye removal for both strains occurred at pH 7, with decolorization efficiency remaining relatively high under alkaline conditions (pH 10), and neither isolates decolorization efficiency was negatively impacted by high salt or high dye concentration. Furthermore, both strains displayed the highest rate of decolorization and were able to completely (ST16.16/034) or partly (ST16.16/164) degrade the azo dyes. Altogether, our results support the use of these bacteria in the treatment of industrial wastewaters containing azo dyes. PMID- 29273270 TI - Is pulsed dosing the answer to treatment of Clostridium difficile infection? PMID- 29273269 TI - Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. AB - BACKGROUND: Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin. METHODS: In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1-5, then once daily on alternate days on days 7-25) or vancomycin (125 mg oral capsules, four times daily on days 1-10), stratified by baseline C difficile infection severity, cancer presence, age (>=75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967. FINDINGS: Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1.0-20.7], p=0.030; odds ratio 1.62 [95% CI 1.04-2.54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug. INTERPRETATION: Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection. FUNDING: Astellas Pharma, Inc. PMID- 29273271 TI - Clozapine use in patients with schizophrenia and a comorbid substance use disorder: A systematic review. AB - Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200-600mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users. PMID- 29273272 TI - IFPA meeting 2017 workshop report: Clinical placentology, 3D structure-based modeling of placental function, placental bed, and treating placental dysfunction. AB - Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2017 there were four themed workshops, all of which are summarized in this report. These workshops discussed new knowledge and technological innovations in the following areas of research: 1) placental bed; 2) 3D structural modeling; 3) clinical placentology; 4) treatment of placental dysfunction. PMID- 29273273 TI - Utility of DNA methylation to assess placental health. AB - DNA methylation (DNAm), a mitotically stable epigenetic mark, can influence as well as reflect gene expression. DNAm has been gaining interest for use as a biomarker for many conditions including placental insufficiency, specifically preeclampsia (PE) and intrauterine growth restriction (IUGR). Additionally, DNAm may retain a "memory" of earlier in utero exposures and hence provide insight into pathogeneses occurring earlier in gestation. This review will discuss the placental DNA methylome, the uses of DNAm to assess placental health, and considerations and limitations to understand in epigenome-wide association studies (EWAS). PMID- 29273274 TI - Response to Letter to the Editor regarding article titled "Polysomnography results versus clinical factors to predict postoperative respiratory complications following pediatric adenotonsillectomy". PMID- 29273275 TI - Modulatory effect of voriconazole on the production of proinflammatory cytokines in experimental cryptococcosis in mice with severe combined immunodeficiency. AB - Cryptococcosis is a subacute or chronic disease. For many years, amphotericin B has been used in severe fungal infections. Voriconazole is a triazole with high bioavailability, a large distribution volume, and excellent penetration of the central nervous system (CNS). The objective of this study was to evaluate the production of pro-inflammatory cytokines in the lungs during an experimental infection caused by C. neoformans in murine model (SCID) that was treated with amphotericin B and voriconazole. After intravenous inoculation with 3.0*105 viable yeast cells, the animals were treated with amphotericin B and voriconazole. The daily treatments began 24hours after inoculation and lasted 15 days. We evaluated the survival curve and we measured the levels of TNF-alpha, IL 6 and IL-10. For all treatments, there was a significant increase in survival compared to the untreated group of animals and the group treated with voriconazole (maximum concentration). The levels of pro-inflammatory cytokines were significantly lower in the groups treated with voriconazole (maximum concentration) and amphotericin B (minimum concentration). Under the conditions studied, we can suggest by that the production of pro-inflammatory cytokines mediated by amphotericin B and voriconazole is dependent on the concentration administered. PMID- 29273276 TI - Aldosterone as a mediator of microvascular and macrovascular damage in a population of normotensive to early-stage hypertensive individuals. AB - We investigated whether aldosterone concurrently mediates microvascular and macrovascular impairment, in a population of treatment-naive young- to middle aged individuals free from cardiovascular comorbidities. Newly diagnosed, never treated essential hypertensive patients and normotensive individuals participated in the study. Pulse wave velocity (PWV) and augmentation index were estimated with applanation tonometry. Microalbuminuria was determined from 24-hour urine collections. Laboratory tests included measurement of plasma renin activity, serum aldosterone, and high-sensitivity C-reactive protein. In 221 individuals aged 42.0 +/- 12.3 years, classification in the highest aldosterone tertile was associated with the highest levels of blood pressure (BP), PWV, and high sensitivity C-reactive protein (P < .05 for all). These individuals also exhibited twice the prevalence of microalbuminuria, compared to the first tertile (P = .081). Multivariate analysis showed that the positive association between PWV and increasing aldosterone tertiles remained significant after adjustment for BP and other parameters (P = .035). Likewise, aldosterone independently predicted microalbuminuria (P = .026) in the logistic regression analysis. In treatment naive individuals whose BP ranges from normal to early-stage hypertension, significant interactions exist between aldosterone and indices of microvascular and macrovascular damage. These findings suggest that aldosterone concurrently modulates microvascular and macrovascular function from the very early stages of essential hypertension and is dynamically implicated in the pathogenesis of hypertensive vascular disease. PMID- 29273278 TI - Co-expression of PDGF-B and VEGFR-3 strongly correlates with poor prognosis in hepatocellular carcinoma patients after hepatectomy. AB - BACKGROUND: The ability to evaluate the prognosis of hepatocellular carcinoma (HCC) patients following hepatectomy with biological markers is of great importance. METHODS: In this study, we collected samples from 90 patients with HCC after hepatectomy. Immunohistochemistry was used to detect the expression of PDGF-B and VEGFR-3 in these HCC samples. RESULTS: According to the immunohistochemical results, PDGF-B and VEGFR-3 staining were significantly associated with clinical features. Additionally, a significant association between high PDGF-B and VEGFR-3 levels and shorter overall survival was noted, when PDGF-B and VEGFR-3 co-expression been analyzed. CONCLUSION: These results suggest that the correlative expression level of PDGF-B and VEGFR-3 has strong value in the prognosis of HCC patients following hepatectomy. PMID- 29273279 TI - Re-Defining 'Reactive' lymphadenopathies: How molecular lessons have changed our minds. PMID- 29273277 TI - Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity predominant spinal muscular atrophy-2. AB - INTRODUCTION: The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2. PATIENTS: The proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19 months, the son was unable to walk at age 3 years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5 years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression. INVESTIGATIONS AND RESULTS: Next-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family. DISCUSSION: BICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA. PMID- 29273280 TI - epidemix-An interactive multi-model application for teaching and visualizing infectious disease transmission. AB - Mathematical models of disease transmission are used to improve our understanding of patterns of infection and to identify factors influencing them. During recent public and animal health crises, such as pandemic influenza, Ebola, Zika, foot and-mouth disease, models have made important contributions in addressing policy questions, especially through the assessment of the trajectory and scale of outbreaks, and the evaluation of control interventions. However, their mathematical formulation means that they may appear as a "black box" to those without the appropriate mathematical background. This may lead to a negative perception of their utility for guiding policy, and generate expectations, which are not in line with what these models can deliver. It is therefore important for policymakers, as well as public health and animal health professionals and researchers who collaborate with modelers and use results generated by these models for policy development or research purpose, to understand the key concepts and assumptions underlying these models. The software application epidemix (http://shinyapps.rvc.ac.uk) presented here aims to make mathematical models of disease transmission accessible to a wider audience of users. By developing a visual interface for a suite of eight models, users can develop an understanding of the impact of various modelling assumptions - especially mixing patterns - on the trajectory of an epidemic and the impact of control interventions, without having to directly deal with the complexity of mathematical equations and programming languages. Models are compartmental or individual-based, deterministic or stochastic, and assume homogeneous or heterogeneous-mixing patterns (with the probability of transmission depending on the underlying structure of contact networks, or the spatial distribution of hosts). This application is intended to be used by scientists teaching mathematical modelling short courses to non-specialists - including policy makers, public and animal health professionals and students - and wishing to develop hands-on practicals illustrating key concepts of disease dynamics and control. PMID- 29273281 TI - [Skin, a target for autoimmune, infectious and drug induced diseases]. PMID- 29273282 TI - Hemodialysis Access Maintenance in the Medicare Population: An Analysis Over a Decade of Trends by Provider Specialty and Site of Service. AB - PURPOSE: To evaluate annual national trends in hemodialysis access maintenance procedures in the Medicare population by specialty and setting. METHODS: Medicare Physician Supplier Procedure Summary Master Files between 2005 and 2015 were analyzed for procedure codes of hemodialysis access angiography and percutaneous thrombectomy. Using physician specialty codes, component procedure volume for endovascular services were queried for radiology, medicine, and surgery. Data entries were analyzed by provider specialty and place of service. Average submitted and allowed charges per intervention were extracted. Linear regression modeling was used to identify trends in number of and allowed charges by specialty and practice setting. RESULTS: Between 2005 and 2015, the frequency of dialysis access angiography for Medicare fee-for-service beneficiaries increased by a total of 74.71% (211,181 to 368,955). Specialty-specific analysis demonstrated volume increases of 220.21% (22,128 to 101,109) for surgery, 249.02% (32,690 to 114,094) for medicine, and 2.81% (135,564 to 139, 367) for radiology. By 2015, an increased trend from hospital-based to non-hospital-based procedures associated with significantly higher reimbursement rates to providers (+18,798 non-hospital-based cases/year, $46.95/year, P <= .001) was also observed, with medicine performing the highest volume of non-hospital-based procedures. In this period, there was also a modest total overall increase of percutaneous thrombectomy procedures by 7.75% (61,485 to 66,250). CONCLUSIONS: The frequency of endovascular hemodialysis access maintenance procedures in the Medicare fee for-service program has increased from 2005 to 2015, with the majority market share transitioning from radiologists to non-radiologists. Similarly, most access maintenance in this time period changed from hospital-based to non-hospital-based interventions. PMID- 29273283 TI - Stereotactic Radiofrequency Ablation for Breast Cancer Liver Metastases. AB - PURPOSE: To evaluate outcomes in patients with liver metastases from breast cancer treated with stereotactic radiofrequency (RF) ablation. MATERIALS AND METHODS: A retrospective analysis of 29 stereotactic RF ablation treatment sessions in 26 consecutive patients with 64 biopsy-proven breast cancer liver metastases (BCLMs) was conducted. Patients were included only if systemic treatment failed and all visible BCLMs were treatable. RESULTS: Primary and secondary technical success rates were 96.9% (62 of 64) and 100%, respectively. There were no perioperative mortalities. Local recurrence was identified in 5 tumors (7.8%), with no significant differences among tumor sizes (P = .662): < 3 cm (9.3%), 3-5 cm (0%), and > 5 cm (8.3%). Median estimated overall survival (OS) from first stereotactic ablation treatment was 29.3 months +/- 8.9 (95% confidence interval [CI], 11.9-46.8 mo; mean, 28.7 mo) after a median follow-up of 23.1 months (mean, 31.3 mo; range, 0.1-100.8 mo). No significant differences in OS (P = .223) were observed among tumor volumes < 50 cm3 (median, 84.9 mo +/- 53.1; mean, 58.4 mo), 50-100 cm3 (median, 37.8 mo +/- 5.7; mean, 36.3 mo), and > 100 cm3 (median, 17.1 mo +/- 3.5; mean, 21.8 mo). Numbers of metastases did not affect estimated OS, with a median OS of 32.7 months +/- 10.4 (mean, 35.8 mo) for single lesions vs 17.7 months +/- 3.2 (mean, 25.9 mo) for 2/3 lesions and a mean of 68.4 months +/- 17.23 for > 3 lesions (P = .113). CONCLUSIONS: Multiple electrode stereotactic RF ablation proved to be a safe minimally invasive alternative to surgical liver resection in selected patients with BCLMs. PMID- 29273284 TI - Accumulation and exchange of parasites during adaptive radiation in an ancient lake. AB - In the ancient Lake Baikal, Russia, amphipod crustaceans have undergone a spectacular adaptive radiation, resulting in a diverse community of species. A survey of microsporidian parasites inhabiting endemic and non-endemic amphipod host species at the margins of Lake Baikal indicates that the endemic amphipods harbour many microsporidian parasite groups associated with amphipods elsewhere in Eurasia. While these parasites may have undergone a degree of adaptive radiation within the lake, there is little evidence of host specificity. Furthermore, a lack of reciprocal monophyly indicates that exchanges of microsporidia between Baikalian and non-Baikalian hosts have occurred frequently in the past and may be ongoing. Conversely, limitations to parasite exchange between Baikalian and non-Baikalian host populations at the margins of the lake are implied by differences in parasite prevalence and lack of shared microsporidian haplotypes between the two host communities. While amphipod hosts have speciated sympatrically within Lake Baikal, the parasites appear instead to have accumulated, moving into the lake from external amphipod populations on multiple occasions to exploit the large and diverse community of endemic amphipods in Lake Baikal. PMID- 29273285 TI - The Danish Head and Neck Cancer fast-track program: a tertiary cancer centre experience. AB - INTRODUCTION: During the 1990s, all Nordic countries except for Denmark experienced a general increase in 5-year survival rates for cancer patients. In 2007, the Danish National Board of Health in collaboration with national multidisciplinary cancer groups and the Danish regions initiated fast-track clinical pathway solutions. OBJECTIVES: The objectives of this study were 1) to present the setup of the head and neck cancer (HNC) fast-track program at Odense University Hospital (OUH) as an example of the Danish model and 2) to present patient characteristics, diagnostic outcome, cancer detection rate, and duration of the fast-track patient courses. MATERIALS AND METHODS: From 1st July 2012 to 1st September 2015, all patients referred to the HNC fast-track program at OUH for diagnostics and treatment were consecutively included in the study resulting in 3165 patient courses. RESULTS: The overall malignancy detection rate was 40.6% and for HNC it was 29.2%. The overall median fast-track course duration was 12 days (range 0-74). Overall 2990 (94.5%) of 3165 patients completed their fast track course within the maximally permitted course duration. DISCUSSION AND CONCLUSION: Based on our findings, it was concluded that: 1) a HNC fast-track program build on pre-booked slots for diagnostics and treatment is feasible and can secure acceptable course durations for more than 90% of patient courses, 2) by using private ENT specialists as a 'filter-function', an acceptable detection rate can be achieved. PMID- 29273286 TI - Genetic analysis of virulence and antimicrobial-resistant plasmid pOU7519 in Salmonella enterica serovar Choleraesuis. AB - BACKGROUND: Zoonotic Salmonella enterica serovar Choleraesuis (S. Choleraesuis), causing paratyphoid in pigs and bacteremia in humans, commonly carry a virulence plasmid and sometimes a separate antimicrobial-resistant plasmid or merging together. This study aimed to analyze the likely mechanism of how to form a virulence-resistance chimera of plasmid in S. Choleraesuis. METHODS: Whole plasmid sequence of pOU7519 in S. Choleraesuis strain OU7519 was determined using shotgun cloning and sequencing. Sequence annotation and comparison were performed to determine the sequence responsible for the formation of a chimeric virulence resistance pOU7519. Other chimeric plasmids among the collected strains of S. Choleraesuis were also confirmed. RESULTS: The sequence of pOU719, 127,212 bp long, was identified to be a chimera of the virulence plasmid pSCV50 and a multidrug-resistant plasmid pSC138 that have been found in S. Choleraesuis strain SC-B67. The pOU7519 is a conjugative plasmid carrying various mobile DNAs, including prophages, insertion sequences, integrons and transposons, especially a Tn6088-like transposon. By dissecting the junction site of the pSCV50-pSC138 chimera in pOU7519, defective sequences at integrase gene scv50 (int) and its attachment site (att) were found, and that likely resulted in a stable chimera plasmid due to the failure of excision from the pSCV50-pSC138 chimera. Similar structure of chimera was also found in other large plasmids. CONCLUSION: The deletion of both the int and att sties could likely block chimera excision, and result in an irreversible, stable pSCV50-pSC138 chimera. The emergence of conjugative virulence and antimicrobial-resistant plasmids in S. Choleraesuis could pose a threat to health public. PMID- 29273287 TI - Rat spinal ganglia in assessment of protective action of antioxidants: A morphological study. AB - BACKGROUND AND OBJECTIVE: Mercury pollution is one of the most pressing environmental problems. Therefore, the impact of mercury on human body, the nervous system in particular, remains topical. The aim of the study was to identify the morphological characteristics of neurons and neuroglia in spinal ganglia of rats receiving antioxidants in the presence of small doses of mercury (II) chloride. MATERIALS AND METHODS: A total of 100 white Wistar rats were divided into 5 series (10 groups), with 10 animals in each group. The first series comprised intact animals receiving saline solution instead of drugs administered in other series (control). In the second series 10 injections of mercury (II) chloride were performed (group of short-term neurointoxication) and 50 injections (group of long-term neurointoxication). In the third to the fifth series, the short- and long-term neurointoxication was followed by 10 daily injection of the drugs: unithiolum, thiotriazolinum and mildronate respectively. Spinal ganglia were obtained two weeks after the completion of drugs administration and studied microscopically and ultramicroscopically. RESULTS: Administration of thiotriazolinum, unithiolum and mildronate mitigated manifestations of toxic effects of mercury (II) chloride on spinal ganglia. Unithiolum and thiotriazolinum activated synthetic processes, while mildronate had a positive effect on restoration of cells metabolism. CONCLUSIONS: Morphological data show that unithiolum and thiotriazolinum action decreases toxic effects of mercury chloride and are similar. They demonstrate pronounced activation of synthetic processes in sensory neurons and satellite cells of spinal ganglia. Mildronate also restores cell ultrastructure and has more pronounced effect on their energetic processes and interaction between neurons and satellite cells. PMID- 29273288 TI - Cementation of a Dual Mobility Construct in Recurrently Dislocating and High Risk Patients Undergoing Revision Total Arthroplasty. AB - BACKGROUND: Recurrent instability remains a challenge after revision total hip arthroplasty (THA). We report the outcomes of cementing a cementless dual mobility (DM) component into a stable acetabular shell for the treatment and/or prevention of instability in revision THA. METHODS: Eighteen patients (18 THAs) undergoing revision THA with a specific monoblock DM construct cemented into a new acetabular component or an existing well-fixed component from 2011 to 2014 were retrospectively reviewed. Tumor prostheses and total femoral replacements were excluded. In 9 patients (50%), components were implanted specifically for recurrent dislocations. Mean age was 64 years; mean follow-up was 3 years. Patients underwent an average of 4 prior hip operations (range 2-6). RESULTS: No cemented DM cups dissociated at the cement-cup interface. Three patients (17%) experienced a postoperative dislocation. One required a revision to constrained liner and 2 underwent open reduction with retention of the DM construct. Harris Hip Scores improved from 53 to 82 postoperatively (P < .001). CONCLUSION: Cementation of a monoblock cup DM construct, an off-label use as the construct is not specifically made for cementation, into a well-fixed acetabular component provides an alternative to enhance prosthetic stability in (1) recurrently dislocating THAs with well fixed, well-positioned acetabular components and (2) complex acetabular reconstructions in which constraint should be avoided. While not a perfect solution in this series, DM constructs provide a number of advantages including no added constraint at the interface and a large effective femoral head to diminish prosthetic impingement. PMID- 29273289 TI - Inpatient Consults and Complications During Primary Total Joint Arthroplasty in a Bundled Care Model. AB - BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) are implementing changes in hospital reimbursement models for total joint arthroplasty (TJA), moving to value-based bundled payments from the fee-for-service model. The purpose of this study is to identify consults and complications during the perioperative period that increase financial burden. METHODS: We combined CMS payment data for inpatient, professional, and postoperative with retrospective review of patients undergoing primary TJA and developed profiles of patients included in the Comprehensive Care for Joint Replacement bundle undergoing TJA. Statistical comparison of episode inpatient events and payments was conducted. Multiple regression analysis was adjusted for length of stay, disposition, and Charlson-Deyo comorbidity profile. RESULTS: Median total payment was $21,577.36, which exceeded the median bundle target payment of $20,625.00. Adjusted analyses showed that psychiatry consults (increase of $73,123.32; P < .001), internal medicine consults ($5789.38; P <= .001), pulmonary embolism ($35,273.68; P < .001), intensive care unit admission ($14,078.37; P < .001), and deep vein thrombosis ($9471.26; P = .019) resulted in increased payments using multivariate analysis adjusted for length of stay, Charlson-Deyo comorbidities, and discharge disposition. CONCLUSION: Patients with inpatient complications such as pulmonary embolism and/or deep vein thrombosis, intensive care unit admission, and medical/psychiatric consultation exceeded the CMS target. Although study results showed typical complication rates, acute inpatient consultation significantly increased utilization beyond the CMS target even when adjusted for length of stay, patient comorbidities, and discharge. Needed medical care should continue to be a priority for inpatients, and allowance for individual outliers should be considered in policy discussions. PMID- 29273290 TI - Risk Factors and Costs Associated With Clostridium difficile Colitis in Patients With Prosthetic Joint Infection Undergoing Revision Total Hip Arthroplasty. AB - BACKGROUND: With the increased demand for primary total hip arthroplasty (THA) and corresponding rise in revision procedures, it is imperative to understand the factors contributing to the development of Clostridium difficile colitis. We aimed to provide a detailed analysis of: (1) the incidence of; (2) the demographics, lengths of stay, and total costs for; and (3) the risk factors and mortality associated with the development of C. difficile colitis after revision THA. METHODS: The National Inpatient Sample database was queried for all individuals diagnosed with a periprosthetic joint infection and who underwent all component revision THA between 2009 and 2013 (n = 40,876). Patients who developed C. difficile colitis during their inpatient hospital stay were identified. Multilevel logistic regression analysis was conducted to assess the association between hospital- and patient-specific characteristics and the development of C. difficile colitis. RESULTS: The overall incidence of C. difficile colitis after revision THA was 1.7%. These patients were significantly older (74 vs 65 years), had greater lengths of hospital stay (19 vs 9 days), accumulated greater costs ($51,641 vs $28,282), and were more often treated in an urban hospital compared to their counterparts who did not develop C. difficile colitis (P < .001 for all). Patients with colitis also had a significantly higher in-hospital mortality compared to those without (5.6% vs 1.4%; P < .001). CONCLUSION: While C. difficile colitis infection is an uncommon event following revision THA, it can have potentially devastating consequences. Our analysis demonstrates that this infection is associated with a longer hospital stay, higher costs, and greater in hospital mortality. PMID- 29273291 TI - Balanced Flexion and Extension Gaps Are Not Always of Equal Size. AB - BACKGROUND: It has been widely accepted in total knee arthroplasty (TKA) that flexion and extension gaps in the disarticulated knee during surgery should be equalized. We hypothesized that tensioning during assessment of the flexion gap can induce temporary widening of the gap due to posterior tibial translation. We aimed to describe posterior tibial translation at flexion gap (90 degrees ) assessments and assess the correlation of tibial translation with laxity (flexion space increase) using constrained and non-constrained inserts. METHODS: Imageless navigation was used to measure flexion angle, tibial position relative to the femoral axis, and lateral/medial laxity in 30 patients undergoing primary TKA. Trialing was conducted using posteriorly stabilized and cruciate retaining trials of the same size to elucidate the association of posterior tibial translation with changes in joint capsule laxity at 90 degrees knee flexion. RESULTS: All patients demonstrated posterior tibial translation during flexion gap assessment relative to their subsequent final implantation [mean +/- standard deviation (range), 11.3 +/- 4.4 (4-21) mm]. Positive linear correlation [r = 0.69, 95% confidence interval (CI) 0.44-0.84, P <= .001] was demonstrated between translations [8.7 +/- 2.4 (3-13) mm] and laxity changes [2.9 degrees +/- 2.0 degrees (-0.7 degrees to 7.4 degrees )] at 90 degrees of flexion. CONCLUSION: Posterior tibial translation can cause artifactual widening of the flexion gap during gap balancing in posteriorly stabilized TKA, which can be of sufficient magnitude to alter femoral component size selection for some patients. Recognition and management of these intra-operative dynamics for optimal kinematics could be feasible with the advent of robotic applications. PMID- 29273292 TI - Reduction of Particles in the Operating Room Using Ultraviolet Air Disinfection and Recirculation Units. AB - BACKGROUND: Airborne bacteria are a major source for wound contamination during total joint arthroplasty. Crystalline ultraviolet C (C-UVC) filter units were designed to disinfect and recirculate air in the operating room (OR). This preliminary study assessed the particle reducing capacity of C-UVC units in a highly controlled OR setting. METHODS: A particle counter was deployed in a positive-pressure OR to measure total and viable particle counts (TPC/VPC). Thirty 23-minute experiments were performed. At 4 designated times a person would walk through the door to mimic OR traffic. Ten experiments were performed as controls, 10 experiments used a C-UVC unit 4 meters (m) from the door, and 10 cases with the C-UVC unit at 8 m. Outcomes included overall, change (Delta), and maximum TPC/VPC. Mann-Whitney U-tests determined statistical differences in TPC/VPC. RESULTS: Compared to controls, the cases with the C-UVC unit at 4 m had significantly lower particle levels. Overall TPC/VPC, changes in TPC/VCP, and maximum TPC/VPC were all significantly lower (P < .05) in the C-UVC unit (4 m) group compared to the controls. The C-UVC at 8 m significantly reduced TPC in all 3 outcomes (P < .05) compared to controls; however, it did not significantly reduce changes in VPC (P = .107) and maximum VPC (P = .052). There were no significant differences in any outcomes between the 4 m and 8 m group. CONCLUSION: C-UVC units have shown to be capable of significantly reducing TPC and VPC in a highly controlled OR setting. Reducing airborne particles using C UVC units may reduce infection rates following total joint arthroplasty. PMID- 29273293 TI - Distinct features of trampoline-related orthopedic injuries in children aged under 6 years. AB - INTRODUCTION: Concern has been growing about trampoline-related injuries among young children. Several published policy statements have repeatedly recommended that children younger than 6 years should not use trampolines. However, few studies have investigated the injuries caused by trampoline-related accidents among young children. This study aimed to identify the distinct features of trampoline-related orthopedic injuries in children younger than 6 years. METHODS: We retrospectively reviewed the medical records of pediatric patients aged between 0 and 16 years who visited our regional emergency center due to trampoline-related orthopedic injuries between 2012 and 2015. Patients were divided into two groups: a preschool group (younger than 6 years) and a school group (older than 6 years). We compared the features of the injuries in the two groups. RESULTS: Among 208 patients, 108 (52%) were male and 100 (48%) were female. The mean age was 5.4 years. The preschool group accounted for 66%. There were no seasonal variations. Fractures were sustained in 96 patients (46%). The anatomical locations of injuries differed significantly between the two age groups. Proximal tibia fractures were more frequent in the preschool group than the school group (34% and 6%, respectively). Distal tibia fractures were more prevalent in the school group than the preschool group (44% vs. 13%, respectively). Surgical treatment was needed more frequently in the school group (p = 0.035, hazard ratio 2.52, 95% confidence interval: 1.03-6.17). Most of the injuries (82%) occurred at trampoline parks. CONCLUSIONS: The anatomical locations of trampoline-related orthopedic injuries differed significantly between age groups. Fractures were more common around the knee in younger children and the ankle in older children. PMID- 29273294 TI - Thresholds and Targets for Hypertension Management in Adults With Type 2 Diabetes Should Remain at 130/80 mmHg: What's the Evidence? AB - Hypertension and diabetes are common comorbidities and are both modifiable risk factors for cardiovascular disease and death. Lowering blood pressure reduces target organ damage and prevents cardiovascular disease outcomes. The harmonized Canadian clinical practice guidelines for managing hypertension in people with diabetes provides health-behaviour advice and medical therapy recommendations for a threshold blood pressure of 130/80 mmHg and above and to target blood pressure to below 130/80 mmHg. We have reviewed the studies supporting these recommendations and others, and they appear to be at odds with the guidelines, including those for elderly people and patients with pre-existing cardiovascular disease. PMID- 29273295 TI - Deoxynucleoside 5-monophosphate N-glycosidase from a phylogenetically distant metazoa, sponge. AB - Deoxynucleoside 5-monophosphate N-glycosidase or DNPH1 (former name Rcl) is a nucleotide hydrolase whose expression in mammalian cancer tissues has been associated with its tumorigenic potential. Therefore, the enzyme has been studied principally in rat and human models. We found the corresponding gene also in the freshwater sponge Ephydatia muelleri, an animal phylogenetically very distant from mammals. Here we report the expression and characterization of the recombinant DNPH1 from E. muelleri. The ancient homolog of mammalian enzyme in a sponge showed the substrate specificity and catalytic efficiency similar to that in higher animals. E. muelleri DNPH1 is inhibited by the purine nucleotides with different numbers of 5'-phosphate groups (n = 1-4). Our results demonstrate that GTP but also dGTP are the best inhibitors, followed by all other purine nucleotides that were tested. Hence, the functioning of DNPH1 in cells where the natural ATP and GTP concentrations are much higher than those of the substrates, dNMPs, should normally be downregulated. We demonstrate for the first time the existence of biologically relevant natural inhibitors of DNPH1, namely ATP and GTP. PMID- 29273296 TI - An archaeal aminoacyl-tRNA synthetase complex for improved substrate quality control. AB - Aminoacyl-tRNA synthetases (aaRSs) decode genetic information by coupling tRNAs with cognate amino acids. In the archaeon Methanothermobacter thermautotrophicus arginyl- and seryl-tRNA synthetase (ArgRS and SerRS, respectively) form a complex which enhances serylation and facilitates tRNASer recycling through its association with the ribosome. Yet, the way by which complex formation participates in Arg-tRNAArg synthesis is still unresolved. Here we utilized pull down and surface plasmon resonance experiments with truncated ArgRS variants to demonstrate that ArgRS uses its N-terminal domain to establish analogous interactions with both SerRS and cognate tRNAArg, providing a rationale for the lack of detectable SerRS*[ArgRS*tRNAArg] complex. In contrast, stable ternary ArgRS*[SerRS*tRNASer] complex was easily detected supporting the model wherein ArgRS operates in serylation by modulating SerRS affinity toward tRNASer. We also found that the interaction with SerRS suppresses arginylation of unmodified tRNAArg by ArgRS, which, by itself, does not discriminate against tRNAArg substrates lacking posttranscriptional modifications. Hence, there is a fundamentally different participation of the protein partners in Arg-tRNA and Ser tRNA synthesis. Propensity of the ArgRS*SerRS complex to exclude unmodified tRNAs from translation leads to an attractive hypothesis that SerRS*ArgRS complex might act in vivo as a safeguarding switch that improves translation accuracy. PMID- 29273297 TI - Loss of vascular smooth muscle cell autophagy exacerbates angiotensin II associated aortic remodeling. AB - OBJECTIVE: The pathophysiologic processes of abdominal aortic aneurysms (AAAs) and atherosclerosis often intersect. Given that anomalies in vascular smooth muscle cell (SMC) autophagy have been noted in models of atherosclerosis, we sought to evaluate the potential role that SMC autophagy may play in the initiation and progression of AAAs. METHODS: Studies were conducted in ATG7flx/flxSM22alpha-Cretg/+ (SMC ATG7 knockout [SMC-ATG7-KO]) and ATG7WT/WT; SM22alpha-Cretg/+ (SMC ATG7 wild-type [SMC-ATG7-WT]) littermates that were continuously infused with angiotensin II (Ang II; 1.5 mg/kg/d) for up to 12 weeks. Mortality, morbidity, hemodynamics, and aortic remodeling were documented. RESULTS: During the 12-week observation window, all of the Ang II-treated SMC-ATG WT mice (n = 6) survived, whereas 10 of the 19 Ang II-treated SMC-ATG-KO mice had died by week 7 (log-rank test, P < .001). Mean arterial pressure (128.07 +/- 3.4 mm Hg for Ang II-treated SMC-ATG-KO vs 138.5 +/- 5.87 mm Hg for Ang II-treated SMC-ATG-WT mice) and diastolic arterial pressure (109.7 +/- 2.55 mm Hg for Ang II treated SMC-ATG7-KO vs 119.4 +/- 2.12 mm Hg for Ang II-treated SMC-ATG7-WT mice) were significantly different between the two groups (P < .01). Cardiac rupture, myocardial infarct, end-organ damage, pleural effusion, and venous distention were noted in Ang II-treated SMC-ATG7-KO but not in Ang II-treated SMC-ATG7-WT mice. Although the suprarenal aortic diameters of the Ang II-treated SMC-ATG7-KO group demonstrated a trending increase (at week 4, 1.26 +/- 0.06 mm [n = 14] for Ang II-treated SMC-ATG-KO mice vs 1.09 +/- 0.02 mm [n = 5] for Ang II-treated SMC ATG-WT mice; P < .05), only 2 of the 19 developed abdominal aortic dissections. CONCLUSIONS: Mice with SMC ATG7 deficiency that are chronically infused with Ang II do not tend to develop dissecting AAA but do exhibit adverse aortic remodeling and appreciable cardiac failure-associated mortality. PMID- 29273298 TI - Recruitment and therapeutic application of macrophages in skeletal muscles after hind limb ischemia. AB - OBJECTIVE: Peripheral arterial disease can cause not only ischemia but also skeletal muscle damage. It has been known that macrophages (MPs) play an important role in coordinating muscle repair; however, phenotype transition of monocyte-MP in ischemic muscle has not been well defined. Hence, the purpose of this study was to examine the temporal recruitment of MPs and to explore their therapeutic effect on ischemic muscle regeneration. METHODS: Unilateral femoral artery excision was performed on C57BL/6 mice. Myeloid cells were isolated from the ischemic muscles, characterized using flow cytometry. Bone marrow-derived MPs were injected (2 * 106 cells) into the ischemic gastrocnemius muscle 24 hours after injury. Blood flow recovery was measured using laser speckle imaging. Functional outcome was evaluated by assessing the contractile force of ischemic muscles. Histologic analysis included quantification of myofiber size, collagen deposition, number of inflammatory and MyoD-expressing cells, and capillary density. RESULTS: Neutrophils and inflammatory monocytes-MPs were present at day 1 after injury. The mature MPs then remained elevated as the dominant population from day 5 to day 21 with the observation of regenerating fibers. Functional measurements revealed that the force production was significantly enhanced after treatment with proinflammatory M1 MPs (94.9% vs 77.9%; P < .05), and this was consistent with increased myofiber size, capillary- fiber ratio, and perfusion (78.6% vs 39.9%; P < .05). Moreover, the percentage of MyoD-expressing nuclei was significantly higher at day 4, indicating that M1 MPs may hasten muscle repair. Whereas early delivery of anti-inflammatory M2 MPs improved myofiber size, this was accompanied by persistent fibrosis suggesting ongoing tissue remodeling, and lower force production was observed. CONCLUSIONS: We demonstrated the dynamics of myeloid cells in skeletal muscle after ischemic insult, and the administration of exogenous M1 MPs in a temporally coordinated manner successfully improved angiogenesis and skeletal muscle regeneration. Our results suggested that cell therapy using MPs may be a promising adjunctive therapeutic approach for peripheral arterial disease. PMID- 29273299 TI - [Self-intermittent-catheterization and urinary retentions in Parkinsonian syndromes]. AB - INTRODUCTION: Lower urinary tract symptoms are common in Parkinson diseases, especially chronic urinary retention. In case of significant and symptomatic postvoid residual, a specific treatment is necessary in order to empty the bladder and nowadays the gold standard of such neurogenic bladder is based on self-intermittent-catheterizations, if possible at all. We carried out a retrospective study about feasibility and outcomes of self-intermittent catheterizations in this population. METHODS: Retrospective study with qualitative and quantitative, clinical and instrumental (urodynamic) assessment, of lower urinary tract symptoms as urinary retention in extrapyramidal syndromes. RESULTS: Overall, 42 patients with parkinsonian syndrome performing self intermittent-catheterization were assessed. Twenty-one had idiopathic Parkinson's disease, 17 multiple system atrophy, 1 vascular Parkinson, 1 iatrogenic Parkinson and 2 not yet determined parkinsonian syndromes. All the patients had urinary retention characterized by a postvoiding residual volume more than 150mL. All the patients were symptomatic and reported voiding dysfunction (30/42), overactive bladder syndrome (20/42), stress urinary incontinence (6/42). The cystometry showed detrusor overactivity (15/42), bladder-sphincter dyssynergia (15/42), detrusor underactivity (14/42), sphincter deficiency (4/42) or bladder compliance alteration (3/42). Each patient have learned and well controlled self intermittent-catheterization technique. Fourteen (33%) stopped self-intermittent catheterization prematurely in the following months because of functional impact of neurological worsening. CONCLUSION: Even if one third of the patients had stopped self-intermittent-catheterization because of neurological deterioration, this technique remains the gold standard for the treatment of urinary chronic retention in parkinsonian patients. LEVEL OF EVIDENCE: 4. PMID- 29273300 TI - Highly sensitive determination of iron (III) ion based on phenanthroline probe: Surface-enhanced Raman spectroscopy methods. AB - In this paper, we introduced Raman spectroscopy techniques that were based on the traditional Fe3+ determination method with phenanthroline as a probe. Interestingly, surface-enhanced Raman spectroscopy (SERS)-based approach exhibited excellent sensitivities to phenanthroline. Different detection mechanisms were observed for the RR and SERS techniques, in which the RR intensity increased with increasing Fe3+ concentration due to the observation of the RR effect of the phenanthroline-Fe2+ complex, whereas the SERS intensity increased with decreasing Fe3+ concentration due to the observation of the SERS effect of the uncomplexed phenanthroline. More importantly, the determination sensitivity was substantially improved in the presence of a SERS-active substrate, giving a detection limit as low as 0.001MUg/mL, which is 20 times lower than the limit of the UV-vis and RR methods. Furthermore, the proposed SERS method was free from other ions interference and can be used quality and sensitivity for the determination of the city tap water. PMID- 29273301 TI - The Association Between Natural Environments and Depressive Symptoms in Adolescents Living in the United States. AB - PURPOSE: Exposure to nature and natural environments may be beneficial for mental health; however, most population-based studies have been conducted among adults whereas few have focused on adolescents. We aimed to investigate the relationship between both greenness (vegetation) and blue space (water), and depressive symptoms among teenagers in the United States. METHODS: The study population included 9,385 participants ages 12-18 in the 1999 wave of the Growing Up Today Study. We characterized greenness exposure using the Normalized Difference Vegetation Index at a 250-m and 1,250-m radius around a subject's residence using data from the moderate-resolution imaging spectroradiometer onboard the National Aeronautics and Space Administration's Terra satellite. Exposure to blue space was defined as the presence of blue space within a 250-m and 1,250-m radius and distance to the nearest blue space. We used logistic regression models to examine associations with high depressive symptoms, measured using self-reported responses to the McKnight Risk Factor Survey. RESULTS: An interquartile range higher peak greenness in the 1,250-m buffer was associated with 11% lower odds of high depressive symptoms (95% confidence interval .79-.99). Although not statistically significant, this association was stronger in middle school students than in high school students. No such association was seen for blue spaces. CONCLUSIONS: Surrounding greenness, but not blue space, was associated with lower odds of high depressive symptoms in this population of more than 9,000 U.S. adolescents. This association was stronger in middle school students than in high school students. Incorporating vegetation into residential areas may be beneficial for mental health. PMID- 29273302 TI - Reasons for Vaping Among U.S. 12th Graders. AB - INTRODUCTION: Vaping has recently increased in popularity among adolescents. Little is known about heterogeneity of vapers, particularly in terms of why they vape. Identifying major subgroups of adolescent vapers by reasons for vaping is important to understand adolescent vaping behavior and to identify those most at risk for other substance use. METHODS: Monitoring Future data from 2015 and 2016 were used in a latent class analysis to identify subgroups of 12th graders based on their endorsement of 10 potential reasons for vaping. Multinomial regression with a latent class outcome was used to predict class membership. RESULTS: Three distinct classes of vapers were identified: adolescents who were (1) Vaping to Experiment (29.4%), (2) Vaping to Replace Cigarettes (7.3%), and (3) Vaping for Taste + Entertainment (63.4%). Vaping only flavors was associated with lower odds of membership and cigarette use was associated with higher odds of membership in the Vaping to Replace Cigarettes subgroup, and marijuana was associated with lower odds of membership in the Vaping to Experiment subgroup, compared with the Vaping for Taste + Entertainment subgroup. CONCLUSIONS: This study identified multiple subgroups of vapers based on reasons for vaping. Whereas a small subgroup vaped for reasons related to cigarette use, most adolescent vapers reported vaping for reasons unrelated to cigarette use. There were considerable differences in primary reasons for vaping and risk for traditional cigarette and other substance use, suggesting different intervention strategies may be needed for different subgroups of vapers. PMID- 29273303 TI - The impact of two triggered palliative care consultation approaches on consult implementation in oncology. AB - INTRODUCTION: Studies show palliative care delivered concurrently with cancer treatment improves outcomes, yet palliative care integration with inpatient oncology is underused. A promising approach to improve integration is a triggered palliative care consultation (TPCC). This study evaluated the impact of two TPCC approaches on consistency and quality of consult implementation, operationalized as uptake and timeliness, on solid tumor medical and gynecologic oncology services at an academic hospital. METHODS: The study timeframe was 2010-2016. TPCC in gynecologic oncology began in 2014 and was supported by a single strategy (written guideline); TPCC in medical oncology began in 2015 and was supported by multiple strategies (e.g. training, chart review). Palliative care consult information was chart abstracted and linked to hospital encounter data. We compared the effect of a single strategy vs. usual care, and multiple strategies vs. a single strategy on implementation. Difference-in-differences modified Poisson regression models evaluated whether implementation differed after TPCC; we estimated adjusted relative risk (aRR), controlling for patient demographic and clinical characteristics. RESULTS: Overall, 8.8% of medical oncology and 11.0% of gynecologic oncology inpatient encounters involved palliative care consultation. In regression analyses, TPCC supported by a single strategy in gynecologic oncology was associated with greater uptake vs. usual care (aRR: 1.45, p < .05), and TPCC supported by multiple strategies in medical oncology was associated with greater uptake vs. a single strategy (aRR: 2.34, p < .001). CONCLUSION: Across two inpatient oncology services, TPCC supported by multiple strategies had the greatest impact on uptake. How strategies affect sustained use of palliative care consults remains to be investigated. PMID- 29273304 TI - Redundancy and robustness versus division of labour and specialization in innate immunity. AB - Apparent redundancy is a recurrent theme in innate immunity in various domains including inflammatory cytokines, chemokines and pattern recognition receptors. While sharing core function, different mediators may subserve distinct functions related for instance to production and release (e.g. IL-1alpha versus IL-1beta), predominantly local versus systemic function (e.g. PTX3 versus C-reactive protein) or fine tuning of innate and adaptive responses (chemokines). Based on hard-wired phagocyte recruitment and regulation by a wide spectrum of chemokines and conventional or atypical receptors, I argue that trafficking of phagocytic cells is a robust output of the chemokine system, resistant to genetic or environmental variation. In general, I speculate that the apparent overlap and redundancy observed in core functions represents an evolutionary strategy to preserve robust essential core outputs in the face of genetically or environmentally caused variation. PMID- 29273305 TI - The production of IL-6 in acute epileptic seizure: A video-EEG study. AB - Experimental and clinical reports highlight the role of cytokines in pathophysiological processes in underpinning epilepsy, but the clinical data remains somewhat limited. The levels of Interleukin (IL)-6 were measured in serum from 49 patients with refractory epilepsy [temporal lobe epilepsy (TLE, n=23), extratemporal lobe epilepsy (XLE, n=22), and idiopathic generalized epilepsy (IGE, n=4)] before and after the first verified seizure (IS; index seizure) during inpatient video-electroencephalographic (VEEG) monitoring. The levels of IL-6 increased significantly at all time points between 3h and 24h after the IS compared to the baseline. IL-6 concentrations were significantly higher at the 3h and 6h time point after tonic-clonic seizures (TCS) compared to the situation with simple partial and complex partial seizures. An IS duration longer than 100s, low baseline IL-6 level and <10 seizures/month in patients with TLE were associated with an increase in IL-6 concentrations during the 24h after the IS. In patients with TLE, the maximum change in IL-6 levels after IS was significantly higher than in XLE. If the baseline level of IL-6 was low (under 5pg/ml), seizures induced a significant elevation in both absolute and relative values in TLE patients but not in XLE. In patients with <=10 seizures per month during the last year, the maximum change was higher than in patients with >10 seizures. If the total seizure burden during registration was >=100s, the IL-6 increase was significantly higher than if it were under 100s. The results of this study highlight the complexity of factors involved in the seizure induced production of the inflammatory cytokine, IL-6. The major factor is the epilepsy type i.e. increased production of IL-6 in TLE compared to XLE. The response to a single seizure in TLE is dependent on the previous seizure frequency and the baseline IL-6 concentration. PMID- 29273306 TI - Robotic hysterectomy and pelvic lymphadenectomy without Trendelenburg position (BMI 36). PMID- 29273307 TI - Sentinel lymph node biopsy in endometrial cancer-Feasibility, safety and lymphatic complications. AB - OBJECTIVE: To compare the rate of lymphatic complications in women with endometrial cancer undergoing sentinel lymph node biopsy versus a full pelvic and infrarenal paraaortic lymphadenectomy, and to examine the overall feasibility and safety of the former. METHODS: A prospective study of 188 patients with endometrial cancer planned for robotic surgery. Indocyanine green was used to identify the sentinel lymph nodes. In low-risk patients the lymphadenectomy was restricted to removal of sentinel lymph nodes whereas in high-risk patients also a full lymphadenectomy was performed. The impact of the extent of the lymphadenectomy on the rate of complications was evaluated. RESULTS: The bilateral detection rate of sentinel lymph nodes was 96% after cervical tracer injection. No intraoperative complication was associated with the sentinel lymph node biopsy per se. Compared with hysterectomy alone, the additional average operative time for removal of sentinel lymph nodes was 33min whereas 91min were saved compared with a full pelvic and paraaortic lymphadenectomy. Sentinel lymph node biopsy alone resulted in a lower incidence of leg lymphedema than infrarenal paraaortic and pelvic lymphadenectomy (1.3% vs 18.1%, p=0.0003). CONCLUSION: The high feasibility, the absence of intraoperative complications and the low risk of lymphatic complications supports implementing detection of sentinel lymph nodes in low-risk endometrial cancer patients. Given that available preliminary data on sensitivity and false negative rates in high-risk patients are confirmed in further studies, we also believe that the reduction in lymphatic complications and operative time strongly motivates the sentinel lymph node concept in high risk endometrial cancer. PMID- 29273308 TI - Cost effectiveness of neoadjuvant chemotherapy followed by interval cytoreductive surgery versus primary cytoreductive surgery for patients with advanced stage ovarian cancer during the initial treatment phase. AB - OBJECTIVE: Advanced stage epithelial ovarian cancer (AEOC) can be treated with either neoadjuvant chemotherapy (NACT) or primary cytoreductive surgery (PCS). Although randomized controlled trials show that NACT is non-inferior in overall survival compared to PCS, there may be improvement in short-term morbidity. We sought to investigate the cost-effectiveness of NACT relative to PCS for AEOC from the US Medicare perspective. METHODS: A cost-effectiveness analysis using a Markov model with a 7-month time horizon comparing (1) 3cycles of NACT with carboplatin and paclitaxel (CT), followed by interval cytoreductive surgery, then 3 additional cycles of CT, or (2) PCS followed by 6cycles of CT. Input parameters included probability of chemotherapy complications, surgical complications, treatment completion, treatment costs, and utilities. Model outcomes included costs, life-years gained, quality-adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratios (ICER), in terms of cost per life-year gained and cost per QALY gained. We accounted for differences in surgical complexity by incorporating the cost of additional procedures and the probability of undergoing those procedures. Probabilistic sensitivity analysis (PSA) was performed via Monte Carlo simulations. RESULTS: NACT resulted in a savings of $7034 per patient with a 0.035 QALY increase compared to PCS; therefore, NACT dominated PCS in the base case analysis. With PSA, NACT was the dominant strategy more than 99% of the time. CONCLUSIONS: In the short-term, NACT is a cost effective alternative compared to PCS in women with AEOC. These results may translate to longer term cost-effectiveness; however, data from randomized control trials continues to mature. PMID- 29273310 TI - Evaluation of fimC and bdha based duplex PCR for specific identification and differentiation of Burkholderia pseudomallei from near-neighbor Burkholderia species. AB - Assays for the rapid detection and accurate differentiation of Burkholderia pseudomallei from near-neighbor species are urgently needed in melioidosis endemic regions due to the high associated mortality and biowarfare importance of the pathogen. PCR-based methods have revolutionized this field due to the accuracy, sensitivity, and specificity that are achievable in a rapid way. In this study, a compound molecular detection system, consisting of a duplex PCR assay, was developed for the specific identification of Burkholderia pseudomallei and differentiation from other Burkholderia species. For accurate identification of B. pseudomallei, we deciphered and adopted a novel gene termed putative fimbrial chaperone (fimC). d-beta hydroxybutyrate dehydrogenase (bdha), reported previously by our group for sequence-based differentiation of B. pseudomallei from other Burkholderia species, was employed as a genus-specific target. Enforcement of an internal amplification control in the PCR format ruled out possible false negative results in the assay. Thus, the developed PCR assay was highly specific (100%) in its detection features, and a clear detection sensitivity of 10 pg/MUl for purified gDNA and 3 * 103 CFU/ml for B. pseudomallei spiked urine was recorded. Successful identification of B. pseudomallei from an experimental mouse model at both the genus and species level revealed the accurate diagnostic efficiency of the duplex PCR method. PMID- 29273311 TI - Investigating barriers to genetic counseling and germline mutation testing in women with suspected hereditary breast and ovarian cancer syndrome and Lynch syndrome. AB - OBJECTIVE: The aim of the current study was to explore barriers to genetic counseling and testing in women with gynecological cancers deemed at significant risk of carrying a germline mutation. METHODS: A qualitative study using semi structured interviews and inductively analysed thematically. Eight patients with ovarian or endometrial cancer participated in individual semi-structured telephone interviews that assessed motivation for genetic counseling and testing, perceived benefits and barriers, timing of the approach, perceptions of the referral process to genetic services and locus of control in relation to cancer and health. RESULTS: Analysis of the interview transcripts revealed five themes relating to perceptions of genetic counseling and testing: Lack of importance; Level of information received; Timing of referral processes; Fear and anxiety; Resistance to and perceptions of counseling. CONCLUSIONS: Participants had a limited understanding of hereditary cancer syndromes and did not appreciate the benefits of genetic testing. A consistent approach at the time of referral to genetic services is needed to ensure that the level and format of information is appropriate for patients. PRACTICE IMPLICATIONS: The rationale for genetic testing needs to be better explained to patients and the timing of referral should be based both on treatment priorities and patient preferences. PMID- 29273312 TI - Effect of cryopreservation on the pre-hatching behavior in the Mexican fruit fly Anastrepha ludens Loew (Diptera, Tephritidae). AB - In a sampling of untreated embryos of the economically important fruit pest species, Anastrepha ludens, the cumulative hatch percentage in the lab was noted to be ~85%. Approximately 70% of the larvae had eclosed through the posterior pole of the egg. This process is effected by the act of Pole Reversal (PR) of the fully developed pre-hatch larva from the wider anterior to the narrower posterior pole of the egg. Investigation of the effects of cryopreservation and various pretreatments prior to cryostorage on the PR behavior was prompted by the observation of significantly lower proportion of cryopreserved embryos exhibiting the PR behavior. Pretreatments (dechorionation and permeabilization) followed by vitrification resulted in delayed hatching, reflecting a slower embryonic development rate of ~10 h. A smaller proportion of the treated embryos either eclosed from the anterior end of the egg or did not eclose at all despite complete development and prehatch gnawing activity. In the untreated controls, 24.0% of the embryos eclosed from the anterior pole. After permeabilization and cryopreservation, 83% and 55% (adjusted hatch) of the embryos were noted to hatch this way, respectively. An analysis of the hatch count after the treatments shows that factors contributing to the embryos' inability to properly invert polarity is not solely due to cryopreservation but also due to the pretreatment procedures including dechorionation and permeabilization. In fact, the permeabilization pre treatment contributed the highest to this phenomenon lending support to the view that chemical toxicity rather than physical effects of cryopreservation play a major role in post-cryopreservation effects. PMID- 29273313 TI - Momentary smoking context as a mediator of the relationship between SES and smoking. AB - There is a well-established socioeconomic gradient in smoking behavior: those with lower socioeconomic status smoke more. However, much less is known about the mechanisms explaining how SES is linked to smoking. This study takes a social ecological perspective by examining whether socioeconomic status affects smoking behavior by differential exposure to places where smoking is allowed. Exposure to smoking restrictions was assessed in real-time using Ecological Momentary Assessment methods. A sample of 194 daily smokers, who were not attempting to quit, recorded their smoking and information about situational and contextual factors for three weeks using an electronic diary. We tested whether a smoker's momentary context mediated the relationship between socioeconomic status (educational attainment) and cigarettes smoked per day (CPD). Momentary context was operationalized as the proportion of random assessments answered in locations where smoking was allowed versus where smoking was not allowed. Data were analysed using multilevel regression (measurements nested within participants) with a lower level mediation model (2-1-1 mediation). Although no significant direct effect of SES on CPD were observed, there was a significant indirect effect of SES on CPD via the momentary context. Compared to participants with higher education, lower educated participants were more likely to encounter places where smoking was allowed, and this in turn, was associated with a higher number of CPD. These findings suggest that SES is associated with smoking at least partially via differential exposure to smoking-friendly environments, with smokers from lower SES backgrounds accessing more places where smoking is allowed. Implications for current smoke-free legislation are discussed. PMID- 29273314 TI - Antibiotic Drug Use and the Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Population-Based Case-Control Study. PMID- 29273309 TI - The satisfactory growth and development at 2 years of age of the INTERGROWTH-21st Fetal Growth Standards cohort support its appropriateness for constructing international standards. AB - BACKGROUND: The World Health Organization recommends that human growth should be monitored with the use of international standards. However, in obstetric practice, we continue to monitor fetal growth using numerous local charts or equations that are based on different populations for each body structure. Consistent with World Health Organization recommendations, the INTERGROWTH-21st Project has produced the first set of international standards to date pregnancies; to monitor fetal growth, estimated fetal weight, Doppler measures, and brain structures; to measure uterine growth, maternal nutrition, newborn infant size, and body composition; and to assess the postnatal growth of preterm babies. All these standards are based on the same healthy pregnancy cohort. Recognizing the importance of demonstrating that, postnatally, this cohort still adhered to the World Health Organization prescriptive approach, we followed their growth and development to the key milestone of 2 years of age. OBJECTIVE: The purpose of this study was to determine whether the babies in the INTERGROWTH-21st Project maintained optimal growth and development in childhood. STUDY DESIGN: In the Infant Follow-up Study of the INTERGROWTH-21st Project, we evaluated postnatal growth, nutrition, morbidity, and motor development up to 2 years of age in the children who contributed data to the construction of the international fetal growth, newborn infant size and body composition at birth, and preterm postnatal growth standards. Clinical care, feeding practices, anthropometric measures, and assessment of morbidity were standardized across study sites and documented at 1 and 2 years of age. Weight, length, and head circumference age- and sex-specific z-scores and percentiles and motor development milestones were estimated with the use of the World Health Organization Child Growth Standards and World Health Organization milestone distributions, respectively. For the preterm infants, corrected age was used. Variance components analysis was used to estimate the percentage variability among individuals within a study site compared with that among study sites. RESULTS: There were 3711 eligible singleton live births; 3042 children (82%) were evaluated at 2 years of age. There were no substantive differences between the included group and the lost-to-follow up group. Infant mortality rate was 3 per 1000; neonatal mortality rate was 1.6 per 1000. At the 2-year visit, the children included in the INTERGROWTH-21st Fetal Growth Standards were at the 49th percentile for length, 50th percentile for head circumference, and 58th percentile for weight of the World Health Organization Child Growth Standards. Similar results were seen for the preterm subgroup that was included in the INTERGROWTH-21st Preterm Postnatal Growth Standards. The cohort overlapped between the 3rd and 97th percentiles of the World Health Organization motor development milestones. We estimated that the variance among study sites explains only 5.5% of the total variability in the length of the children between birth and 2 years of age, although the variance among individuals within a study site explains 42.9% (ie, 8 times the amount explained by the variation among sites). An increase of 8.9 cm in adult height over mean parental height is estimated to occur in the cohort from low-middle income countries, provided that children continue to have adequate health, environmental, and nutritional conditions. CONCLUSION: The cohort enrolled in the INTERGROWTH-21st standards remained healthy with adequate growth and motor development up to 2 years of age, which supports its appropriateness for the construction of international fetal and preterm postnatal growth standards. PMID- 29273315 TI - Staphylococcus aureus Triggers Induction of miR-15B-5P to Diminish DNA Repair and Deregulate Inflammatory Response in Diabetic Foot Ulcers. AB - Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes in which bacterial presence, including the frequent colonizer Staphylococcus aureus, contributes to inhibition of healing. MicroRNAs (miRs) play a role in healing and host response to bacterial pathogens. However, the mechanisms by which miR response to cutaneous S. aureus contributes to DFU pathophysiology are unknown. Here, we show that S. aureus inhibits wound closure and induces miR-15b-5p in acute human and porcine wound models and in chronic DFUs. Transcriptome analyses of DFU tissue showed induction of miR-15b-5p to be critical, regulating many cellular processes, including DNA repair and inflammatory response, by suppressing downstream targets IKBKB, WEE1, FGF2, RAD50, MSH2, and KIT. Using a human wound model, we confirmed that S. aureus-triggered miR-15b-5p induction results in suppression of the inflammatory- and DNA repair-related genes IKBKB and WEE1. Inhibition of DNA repair and accumulation of DNA breaks was functionally confirmed by the presence of the pH2AX within colonized DFUs. We conclude that S. aureus induces miR-15b-5p, subsequently repressing DNA repair and inflammatory response, showing a mechanism of inhibition of healing in DFUs previously unreported, to our knowledge. This underscores a previously unknown role of DNA damage repair in the pathophysiology of DFUs colonized with S. aureus. PMID- 29273316 TI - Quantitative Assessment and Interpretation of Vaginal Conditions. AB - INTRODUCTION: Few means exist to provide quantitative and reproducible assessment of vaginal conditions from biomechanical and functional standpoints. AIM: To develop a new approach for quantitative biomechanical characterization of the vagina. METHODS: Vaginal tactile imaging (VTI) allows biomechanical assessment of soft tissue and function along the entire length of the anterior, posterior, and lateral vaginal walls. This can be done at rest, with applied vaginal deformation, and with pelvic muscle contraction. RESULTS: Data were analyzed for 42 subjects with normal pelvic floor support from an observational case controlled clinical study. The average age was 52 years (range = 26-90 years). We introduced 8 VTI parameters to characterize vaginal conditions: (i) maximum resistance force to insertion (newtons), (ii) insertion work (millijoules), (iii) maximum stress-to-strain ratio (elasticity; kilopascals per millimeter), (iv) maximum pressure at rest (kilopascals), (v) anterior-posterior force at rest (newtons), (vi) left-right force at rest (newtons), (vii) maximum pressure at muscle contraction (kilopascals), and (viii) muscle contraction force (newtons). We observed low to moderate correlation of these parameters with subject age and no correlation with subject weight. 6 of 8 parameters demonstrated a P value less than .05 for 2 subject subsamples divided by age (<=52 vs >52 years), which means 6 VTI parameters change with age. CONCLUSIONS: VTI allows biomechanical and functional characterization of the vaginal conditions that can be used for (i) understanding "normal" vaginal conditions, (ii) quantification of the deviation from normality, (iii) personalized treatment (radiofrequency, laser, or plastic surgery), and (iv) assessment of the applied treatment outcome. Egorov V, Murphy M, Lucente V, et al. Quantitative Assessment and Interpretation of Vaginal Conditions. Sex Med 2018;6:39-48. PMID- 29273317 TI - Surface coating affects uptake of silver nanoparticles in neural stem cells. AB - The rapid development and widespread applications of nanotechnology necessitates the design towards safe nanoparticles. Surface structure is among the most important physicochemical characteristics of metallic nanoparticles affecting their mode of action in certain biological or environmental compartments. This study aimed to investigate how different surface coatings affect the cytotoxicity and cellular uptake of silver nanoparticles (AgNPs) in murine neural stem cells (mNSCs). Different AgNPs were prepared by stabilisation with surface coatings encompassing sodium bis(2-ethylhexyl)-sulfosuccinate (AOT), cetyltrimethylammonium bromide (CTAB), poly(vinylpyrrolidone) (PVP), poly-l lysine (PLL), and bovine serum albumin (BSA). The obtained results revealed that AgNPs stabilized with different surface coating caused different cytotoxicity effects and internalization pattern in mNSCs. Macropinocytosis was determined as the main uptake mechanism in mNSCs for all of the tested AgNP types. These findings contribute to the overall knowledge essential to the safety assessment of novel nanomaterials. PMID- 29273318 TI - Reply. PMID- 29273319 TI - Physician Assistants and Nurse Practitioners in Ophthalmology-Has the Time Come? PMID- 29273320 TI - Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics. PMID- 29273321 TI - Nanomedicine for the cardiac myocyte: Where are we? AB - Biomedical achievements in the last few decades, leading to successful therapeutic interventions, have considerably improved human life expectancy. Nevertheless, the increasing load and the still suboptimal outcome for patients with cardiac dysfunction underlines the relevance of continuous research to develop novel therapeutics for these diseases. In this context, the field of nanomedicine has attracted a lot of attention due to the potential novel treatment possibilities, such as controlled and sustained release, tissue targeting, and drug protection from degradation. For cardiac myocytes, which constitute the majority of the heart by mass and are the contractile unit, new options have been explored in terms of the use of nanomaterials (NMs) for therapy, diagnosis, and tissue engineering. This review focuses on the advances of nanomedicine targeted to the cardiac myocyte: first presenting the NMs used and the principal cardiac myocyte-based afflictions, followed by an overview of key advances in the field, including NMs interactions with the cardiac myocyte, therapy delivery, diagnosis based on imaging, and tissue engineering for tissue repair and heart-on-a-chip devices. PMID- 29273322 TI - Radiologic and Functional Analysis of Compensatory Lung Growth After Living-Donor Lobectomy. AB - BACKGROUND: Whether compensatory lung growth occurs in adult humans is controversial. The aim of this study was to confirm compensatory lung growth by analyzing ipsilateral residual lung after lower lobectomy in living lung transplant donors with quantitative and qualitative computed tomography assessments. METHODS: Chest computed tomography and pulmonary function tests were performed in 31 eligible donors before and 1 year after donor lobectomy. Ipsilateral residual lung volume was measured with three-dimensional computed tomography volumetry. The computed tomography-estimated volumes of low, middle, and high attenuations in the lung were calculated. Assessment of the D value, a coefficient of the cumulative size distribution of low-density area clusters, was performed to evaluate the structural quality of the residual lung. RESULTS: Postoperative pulmonary function test values were significantly larger than preoperative estimated values. Although postoperative total volume, low attenuation volume, middle attenuation volume, and high attenuation volume of the ipsilateral residual lung were significantly larger than the preoperative volumes, with 50.2%, 50.0%, 41.5%, and 43.1% increase in the median values, respectively (all p < 0.0001), the differences in D values before and after donor lobectomy were not significant (p = 0.848). The total volume of ipsilateral residual lung was increased by more than 600 mL (50%). CONCLUSIONS: The volume of ipsilateral residual lung increased, but its structural quality did not change before and after donor lobectomy. The existence of compensatory lung growth in adult humans was suggested by quantitative and qualitative computed tomography assessments. PMID- 29273323 TI - Durability of Aortic Valve Cusp Repair With and Without Annular Support. AB - BACKGROUND: To determine the value of aortic valve repair rather than replacement for valve dysfunction, we assessed late outcomes of various repair techniques in the contemporary era. METHODS: From January 2001 to January 2011, aortic valve repair was planned in 1,124 patients. Techniques involved commissural figure-of-8 suspension sutures (n = 63 [6.2%]), cusp repair with commissuroplasty (n = 481 [48%]), debridement (n = 174 [17%]), free-margin plication (n = 271 [27%]) or resection (n = 75) or both, or annulus repair with resuspension (n = 230 [23%]), root reimplantation (n = 252 [25%]), or remodeling (n = 35 [3.5%]). RESULTS: Planned repair was aborted for replacement in 115 patients (10%); risk factors included greater severity of aortic regurgitation (AR; p = 0.0002) and valve calcification (p < 0.0001). In-hospital outcomes for the remaining 1,009 patients included death (12 [1.2%]), stroke (13 [1.3%]), and reoperation for valve dysfunction (14 [1.4%]). Freedom from aortic valve reoperation at 1, 5, and 10 years was 97%, 93%, and 90%, respectively. Figure-of-8 suspension sutures, valve resuspension, and root repair and replacement were least likely to require reoperation; cusp repair with commissural sutures, plication, and commissuroplasty was most likely (p < 0.05). Survival at 1, 5, and 10 years was 96%, 92%, and 83%. Immediate postoperative AR grade was none-mild (94%), moderate (5%), and severe (1%). At 10 years after repair, AR grade was none (20%), mild (33%), moderate (26%), and severe (21%). Patients undergoing root procedures were less likely to have higher-grade postoperative AR (p < 0.0001). CONCLUSIONS: Valve repair is effective and durable for treating aortic valve dysfunction. Greater severity of AR preoperatively is associated with higher likelihood of repair failure. Commissural figure-of-8 suspension sutures and repair with annular support have the best long-term durability. PMID- 29273324 TI - Temporal Expression of c-fos and Genes Coding for Neuropeptides and Enzymes of Amino Acid and Amine Neurotransmitter Biosynthesis in Retina, Pineal and Hypothalamus of a Migratory Songbird: Evidence for Circadian Rhythm-Dependent Seasonal Responses. AB - This study investigated whether, in photoperiodic songbirds, the circadian pacemaker system (CPS) connects to the seasonal photoperiodic responses, by changes at transcriptional level in the level and 24-h rhythm of its constituent neurotransmitters. We used black-headed buntings (Emberiza melanocephala), which exhibit distinct seasonal states in captivity under appropriate photoperiods and hence served as a useful model system. Under short days, buntings remain in the photosensitive state (Pse) (winter phenotype: non-migratory, non-breeding). Under long days, however, buntings undergo through early-photostimulated (spring phenotype: pre-migratory, pre-breeding), late photostimulated (summer phenotype: migratory, breeding) and photorefractory (autumn phenotype: post-breeding) states. During all four seasonal states, we measured in the retina, pineal and hypothalamus, which together form avian CPS, 4-hourly mRNA expression of c-fos (a neuronal-activity marker) and of genes coding for neuropeptides (vasoactive intestinal peptide, vip; somatostatin, sst; neuropeptide Y, npy) and for intermediary enzymes of amino acid (glutamate: glutaminase, gls and glutamic oxaloacetic transaminase 2, got2; GABA: glutamic acid decarboxylase, gad65) and amine (dopamine: tyrosine hydroxylase, th) neurotransmitters biosynthetic pathway. There was a significant alteration in level and 24-h pattern of mRNA expression, albeit with seasonal differences in presence, waveform parameters and phase relationship of 24-h rhythm, of different genes. Particularly, mRNA expression of all candidate genes (except hypothalamic vip, pineal gls and retinal th) was arrhythmic in late photostimulated state. These results underscore that circadian rhythm of peptide, amino acid and amine neurotransmitter biosynthesis in CPS plays a critical role in the photoperiodic regulation of seasonal states in birds. PMID- 29273325 TI - Application of Europium-Doped Very Small Iron Oxide Nanoparticles to Visualize Neuroinflammation with MRI and Fluorescence Microscopy. AB - Our recent studies demonstrated that electrostatically stabilized very small superparamagnetic iron oxide particles (VSOPs) are promising MRI probes for detecting various pathological aspects of autoimmunity in the central nervous system (CNS). However, investigation of the precise tissue and cellular distribution of VSOP has been technically limited due to the need to use iron detection methods for VSOP visualization. Therefore, we assessed here the utility of europium (Eu)-doped VSOP as an MRI tool for in vivo investigations in the animal model experimental autoimmune encephalomyelitis (EAE), and as a tool to investigate histopathological processes in the CNS using fluorescence microscopy. We demonstrated that Eu-VSOP display the same properties as VSOP in terms of revealing inflammation-mediated changes by binding to brain endothelium in vitro, and in terms of visualizing brain lesions in EAE in vivo. MRI examinations with Eu-VSOP confirm that at peak disease particles accumulated inside the choroid plexus, and in cerebellar and meningeal lesions. Importantly, Eu-VSOP-based MRI showed for the first time in a longitudinal setup that particles were absent from the choroid plexus in mice during remission of EAE, but accumulated again during subsequent relapse. Within the choroid plexus, Eu-VSOP were associated both with monocytes/macrophages present in the plexus stroma, and associated with epithelial cells. Using Eu-VSOP, we demonstrated for the first time the involvement of the choroid plexus in relapses. Thus, Eu-VSOP have the potential to reveal various aspects of choroid plexus involvement in neuroinflammation, including monocyte recruitment from the blood and alterations of the choroid plexus epithelium. PMID- 29273326 TI - Individual- and ejaculate-specific sperm traits in ant males. AB - Sperm cells are the most morphologically diverse cells across animal taxa. Within species, sperm and ejaculate traits have been suggested to vary with the male's competitive environment, e.g., level of sperm competition, female mating status and quality, and also with male age, body mass, physiological condition, and resource availability. Most previous studies have based their conclusions on the analysis of only one or a few ejaculates per male without investigating differences among the ejaculates of the same individual. This masks potential ejaculate-specific traits. Here, we provide data on the length, quantity, and viability of sperm ejaculated by wingless males of the ant Cardiocondyla obscurior. Males of this ant species are relatively long-lived and can mate with large numbers of female sexuals throughout their lives. We analyzed all ejaculates across the individuals' lifespan and manipulated the availability of mating partners. Our study shows that both the number and size of sperm cells transferred during copulations differ among individuals and also among ejaculates of the same male. Sperm quality does not decrease with male age, but the variation in sperm number between ejaculates indicates that males need considerable time to replenish their sperm supplies. Producing many ejaculates in a short time appears to be traded-off against male longevity rather than sperm quality. PMID- 29273327 TI - Quantitative proteomics reveals divergent responses in Apis mellifera worker and drone pupae to parasitization by Varroa destructor. AB - Varroa destructor is a haemophagous ectoparasite of honeybees and is considered a major causal agent of colony losses in Europe and North America. Although originating in Eastern Asia where it parasitizes Apis cerana, it has shifted hosts to the western honeybee Apis mellifera on which it has a greater deleterious effect on the individual and colony level. To investigate this important host-parasite interaction and to determine whether Varroa causes different effects on different castes we conducted a label free quantitative proteomic analysis of Varroa-parasitized and non-parasitized drone and worker Apis mellifera pupae. 1195 proteins were identified in total, of which 202 and 250 were differentially abundant in parasitized drone and worker pupae, respectively. Both parasitized drone and worker pupae displayed reduced abundance in proteins associated with the cuticle, lipid transport and innate immunity. Proteins involved in metabolic processes were more abundant in both parasitized castes although the response in workers was more pronounced. A number of caste specific responses were observed including differential abundance of numerous cytoskeletal and muscle proteins, which were of higher abundance in parasitized drones in comparison to parasitized workers. Proteins involved in fatty acid and carbohydrate metabolism were more abundant in parasitized workers as were a large number of ribosomal proteins highlighting either potentially divergent responses to Varroa or a different strategy by the mite when parasitizing the different castes. This data improves our understanding of this interaction and may provide a basis for future studies into improvements to therapy and control of Varroasis. PMID- 29273328 TI - Elevation of serum pyruvate kinase M2 (PKM2) in IBD and its relationship to IBD indices. AB - OBJECTIVES: Endoscopy remains the gold standard to diagnose and evaluate inflammatory bowel disease (IBD) activity. Current biomarkers or their combinations cannot adequately predict IBD risk, diagnosis, progression or relapse, and response to therapy. Pyruvate kinase M2 (PKM2) is emerging as a significant mediator of the inflammatory process. We aimed to assess levels of serum PKM2 in healthy and newly diagnosed IBD patients and its relationship with IBD indices and microbiota changes. DESIGN AND METHODS: IBD serum samples from newly diagnosed patients were collected and analyzed using a PKM2-ELISA and correlated with disease activity scores, IBD disease type, and intestinal microbiota. Furthermore, we tested the genetic and protein expression of PKM2 in an in vitro intestinal cell model of inflammation. RESULTS: Serum PKM2 levels were 6-fold higher in IBD patients compared to healthy controls, with no sensitivity to disease phenotype (Crohn's Disease or Ulcerative Colitis) or localization of inflammation. Serum PKM2 had considerably less interindividual variability than established IBD fecal biomarkers. A positive Pearson correlation (r=0.6121) existed between serum PKM2 and Bacteroidetes fecal levels in Crohn's disease (CD), while a negative (r=-0.6128) correlation was observed with Actinobacteria fecal levels. Furthermore, LPS (500ng/mL) significantly increased PKM2 expression in vitro, which was significantly suppressed by an anti inflammatory flaxseed bioactive agent. CONCLUSION: Our data suggests PKM2 as a putative biomarker for IBD and the dysbiosis of microflora in CD. Investigations involving larger number of clinical patients are necessary to validate its use as a serum biomarker of IBD. PMID- 29273329 TI - Validation of the Friedewald formula for the estimation of low density lipoprotein cholesterol in a sub-Saharan African population. AB - BACKGROUND: Low density lipoprotein cholesterol (LDL-C) levels are used to estimate cardiovascular disease (CVD) risk and to guide prescriptions. To circumvent the challenges of direct LDL-C measurement, guidelines recommend the use of Friedewald formula derived LDL-C levels. Despite reported limitations of this formula, its validity in sub-Saharan Africans has not been adequately investigated. OBJECTIVE: To assess the validity of the Friedewald formula derived against directly (homogeneous) measured LDL-C in adult Cameroonians. METHODS: We reviewed the fasting lipid profiles of 2500 patients, performed between March 2012 and January 2016 using enzymatic colorimetric method (reference), at the Douala General Hospital laboratory. The Friedewald formula was used to calculate LDL-C from total cholesterol, high density lipoprotein cholesterol and triglyceride levels. Calculated LDL-C values were compared to the reference values, and clinical significance of differences between the two methods was assessed using total error allowable (TEa). RESULTS: The difference between means of calculated and the reference LDL-C values was neither statistically nor clinically significant (3.33+/-1.51 vs. 3.33+/-1.25mmol/l; p=0.704). The calculated LDL-C correlated positively with the measured LDL-C value (r=0.749) and both methods showed a good agreement on Bland-Altman plot. Conversely, there was only moderate agreement (kappa=0.478, 95% CI: 0.455-0.502) between the two values in the stratification of cardiovascular risk according to the National Cholesterol Education Program/Adult Treatment Panel III. Consequently, 40.6% of the participants were misclassified. CONCLUSION: Friedewald formula is technically accurate but has a modest clinical accuracy which can translate into a substantial misclassification of patients' cardiovascular risk and subsequent inappropriate therapeutic decisions. PMID- 29273330 TI - Monitoring of morphotoxic, cytotoxic and genotoxic potential of mancozeb using Allium assay. AB - The present experiment was designed to monitor the morphotoxic, cytotoxic and genotoxic potential of Mancozeb (fungicide) in non-target plants using bulbs of Allium cepa. Mancozeb is classified as a contact fungicide and is registered for use on a variety of crop plants. In the present monitoring, Allium cepa bulbs were exposed to different concentrations of mancozeb viz., 10, 30, 50, 70, 90, 110, 130 and 150 ppm for 24 and 48 h. The potential morphotoxic and cytotoxic effects of mancozeb were examined by determining the average root number, average root length, mitotic index, relative abnormality rate (%) and frequency of abnormalities (%). A progressive significant concentration and time dependent inhibition of the average root number, average root length indicated the morphotoxic nature. The cytotoxic effect was significantly increased for 48 h treatment as compared to 24 h treatment time, by reducing the mitotic index of meristematic cells. The results indicated an indirect genotoxic effect by inducing different types of chromosomal abnormalities, likely sticky, disoriented and fragmented chromosomes. Thus indicating that the investigated fungicide have genotoxic potential due to abnormal DNA condensation and chromosome coiling by spindle inactivation. The observations of cyto and genotoxic effects suggest that the fungicide mancozeb is clastogenic agent. Thus the different concentrations used in the field could be harmful for the end-receptors of food-chain and needs constant monitoring and management for the better development of crop plants. PMID- 29273331 TI - Systemic biopolymer-delivered vascular endothelial growth factor promotes therapeutic angiogenesis in experimental renovascular disease. AB - We recently developed a therapeutic biopolymer composed of an elastin-like polypeptide (ELP) fused to vascular endothelial growth factor (VEGF) and showed long-term renoprotective effects in experimental renovascular disease after a single intra-renal administration. Here, we sought to determine the specificity, safety, efficacy, and mechanisms of renoprotection of ELP-VEGF after systemic therapy in renovascular disease. We tested whether kidney selectivity of the ELP carrier would reduce off-target binding of VEGF in other organs. In vivo bio distribution after systemic administration of ELP-VEGF in swine was determined in kidneys, liver, spleen, and heart. Stenotic-kidney renal blood flow and glomerular filtration rate were quantified in vivo using multi-detector computed tomography (CT) after six weeks of renovascular disease, then treated with a single intravenous dose of ELP-VEGF or placebo and observed for four weeks. CT studies were then repeated and the pigs euthanized. Ex vivo studies quantified renal microvascular density (micro-CT) and fibrosis. Kidneys, liver, spleen, and heart were excised to quantify the expression of angiogenic mediators and markers of progenitor cells. ELP-VEGF accumulated predominantly in the kidney and stimulated renal blood flow, glomerular filtration rate, improved cortical microvascular density, and renal fibrosis, and was accompanied by enhanced renal expression of VEGF, downstream mediators of VEGF signaling, and markers of progenitor cells compared to placebo. Expression of angiogenic factors in liver, spleen, and heart were not different compared to placebo-control. Thus, ELP efficiently directs VEGF to the kidney after systemic administration and induces long-term renoprotection without off-target effects, supporting the feasibility and safety of renal therapeutic angiogenesis via systemic administration of a novel kidney-specific bioengineered compound. PMID- 29273332 TI - Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. AB - Globally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age. PMID- 29273333 TI - Modifying styrene-maleic acid co-polymer for studying lipid nanodiscs. AB - Recently, styrene-maleic acid copolymer lipid nanodiscs have become an increasingly popular tool for the study of membrane proteins. In the work we report here, we have developed a novel method for the efficient preparation of labeled nanodiscs, under chemically mild conditions, by modification of the hydrolyzed styrene-maleic acid copolymer. This protocol is designed to be easily accessible to biochemistry laboratories. We use this procedure to prepare various fluorescent nanodiscs labeled with different fluorophores. By studying the development of Forster resonance energy transfer, we demonstrate the rapid exchange of co-polymer between nanodiscs. This demonstration, in conjunction of previous work, indicates that the lipid nanodiscs prepared using this polymer are very dynamic structures with rapid exchange of the different components. PMID- 29273334 TI - Fusogenic properties of the Ectodomain of HCV E2 envelope protein. AB - The steps leading from hepatitis C virus (HCV) attachment to the hepatocytes to the fusion of viral and cellular membranes remain uncharacterized. In this regard, we have studied the mechanism underlying the HCV fusion process using liposomes and a truncated form of E2 protein lacking the transmembrane region, E2661 (amino acids 384-661). E2661 has been previously obtained by using the baculovirus expression system and shown to behave as an independent folding domain (M. Rodriguez-Rodriguez, D. Tello, B. Yelamos, J. Gomez-Gutierrez, B. Pacheco, S. Ortega, A.G. Serrano, D.L. Peterson, F. Gavilanes, Structural properties of the ectodomain of hepatitis C virus E2 envelope protein, Virus Res. 139 (2009) 91-99). This form has been used in lipid-protein interaction studies with different model vesicles, at different pHs and by employing a variety of fluorescent assays. The obtained results indicate that E2661 induces vesicle aggregation, lipid mixing and liposome leakage, reaching higher values in the presence of negatively charged phospholipids and cholesterol at acidic pH. Therefore, the results of these studies would be indicative of an HCV infection process through receptor mediated endocytosis. Accordingly, E2 might be important in the HCV initial infective steps, interacting with the target membranes and giving rise to their subsequent destabilization. PMID- 29273335 TI - Membrane-induced initial structure of alpha-synuclein control its amyloidogenesis on model membranes. AB - Amyloid fibrillation causes serious neurodegenerative diseases and amyloidosis; however, the detailed mechanisms by which the structural states of precursor proteins in a lipid membrane-associated environment contribute to amyloidogenesis still remains to be elucidated. We examined the relationship between structural states of intrinsically-disordered wild-type and mutant alpha-synuclein (alphaSN) and amyloidogenesis on two-types of model membranes. Highly-unstructured wild type alphaSN (alphaSNWT) and a C-terminally-truncated mutant lacking negative charges (alphaSN103) formed amyloid fibrils on both types of membranes, the model membrane mimicking presynaptic vesicles (Mimic membrane) and the model membrane of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC membrane). Unstructured alphaSNWT and alphaSN103 both bound to Mimic membranes in a helical conformation with similar binding affinity. Promotion and then inhibition of amyloidogenesis of alphaSNWT were observed as the concentration of Mimic lipids increased. We explain this by the two-state binding model: at lower lipid concentrations, binding of alphaSNWT to membranes enhances amyloidogenicity by increasing the local concentration of membrane-bound alphaSN and so promoting amyloid nucleation; at higher lipid concentrations, membrane-bound alphaSNWT is actually in a sense diluted by increasing the number of model membranes, which blocks amyloid fibrillation due to an insufficient bound population for productive nucleation. Meanwhile, alphaSN103 formed amyloid fibrils over the whole concentration of Mimic lipids used here without inhibition, revealing the importance of helical structures for binding affinity and negatively charged unstructured C-terminal region for modulating amyloidogenesis. We propose that membrane binding-induced initial conformations of alphaSN, its overall charge states, and the population of membrane-bound alphaSN are key determinants of amyloidogenesis on membranes. PMID- 29273336 TI - Self-Appraised Readiness of Senior and Graduating General Surgery Residents to Perform Thoracic Surgery. AB - OBJECTIVE: General surgeons perform up to 50% of noncardiac thoracic surgery (TS). Although data show consistent TS case volume during general surgery (GS) residency it is unknown whether this operative trend will persist given potentially limited subspecialty exposure. We sought to determine if certain aspects of residency programs and resident characteristics were associated with trainees' perceived comfort in performing certain basic TS procedures. DESIGN: An anonymous survey was distributed to GS residents regarding program characteristics, presence of a TS residency, and intent to pursue thoracic surgical training, and estimated case volumes of individual procedures. Comfort levels for performing video-assisted thoracoscopic surgical (VATS) procedures, open lobectomy, elective thoracotomy, and sternotomy were attained through a 5 point Likert-type scale. SETTING: This survey was administered at 50 training programs with responses recorded via an online form. PARTICIPANTS: Fourth- and fifth-year GS residents in the United States. RESULTS: Of 272 respondents 58% were fourth-year residents, 62% of residents trained at university-affiliated programs, and 64% reported a TS residency program at their institution and 16% stated intent to pursue TS. Fifth-year residents performed significantly more cases than fourth-year residents despite no difference in median comfort levels. Residents intending to pursue TS performed significantly more cases and were more comfortable performing a thoracotomy, sternotomy, VATS wedge resection/biopsy, and VATS decortication/pleurodesis (p = 0.044, <0.001, 0.045, 0.025). No characteristics were associated with comfort performing a lobectomy via thoracoscopic or open (thoracotomy) approaches. CONCLUSION: Most senior or graduating GS residents state they are comfortable performing certain thoracic procedures with those pursuing additional thoracic surgical training more comfortable overall. No characteristics were associated with comfort performing a lobectomy. These findings may advise residency curriculum design to ensure continued thoracic surgical exposure and recommend against non-fellowship trained surgeons performing a pulmonary lobectomy. PMID- 29273337 TI - Randomized Trial of Smartphone-Based Evaluation for an Obstetrics and Gynecology Clerkship. AB - OBJECTIVE: We hypothesized that compared to paper evaluations, a smartphone-based quick response (QR) evaluation tool would improve timeliness of feedback, enhance efficacy of giving and receiving feedback, and be as easy to use. DESIGN: We performed a randomized controlled trial of student and instructor experience with two evaluation tools in the OB/GYN clerkship at University of Washington School of Medicine (UWSOM). Sites were randomized to the QR or paper tool; students at QR sites received individualized QR codes at the beginning of the clerkship. Instructors and students completed postintervention surveys regarding the evaluation tool and associated feedback. We compared responses between groups using chi-squared tests. SETTING: Participating clerkship sites included primary, tertiary, private practice and institutional settings affiliated with the University of Washington in the Washington, Wyoming, Alaska, Montana and Idaho region. PARTICIPANTS: Of the 29 OB/GYN UWSOM clerkship sites, 18 agreed to participate and were randomized. Of 29 eligible instructors, 25 (86%) completed the survey, with n = 18 using QR and n = 7 using paper. Of 161 eligible students, 102 (63%) completed the survey, with n = 54 using QR and n = 48 using paper. RESULTS: Compared to those using paper evaluations, instructors using QR evaluations were significantly more likely to agree that the evaluation tool was easy to understand (100% QR vs 43% paper, p = 0.002), the tool was effective in providing feedback (78% QR vs 29% paper, p = 0.002), and they felt comfortable approaching students with the tool (89% QR vs 43% paper, p = 0.002). Compared to those using paper evaluations, students using QR evaluations were less likely to agree the tool was effective in eliciting feedback (QR 43% vs paper 55%, p = 0.042). CONCLUSION: Instructors found QR evaluations superior to paper evaluations for providing feedback to medical students, whereas students found QR evaluations less effective for feedback. PMID- 29273338 TI - Increased Academic Productivity of Orthopaedic Surgery Residents Following 2011 Duty Hour Reform. AB - BACKGROUND: In 2003 and again in 2011, the Accreditation Council for Graduate Medical Education (ACGME) mandated increasingly stringent resident duty hour restrictions. With less time required at the hospital, residents theoretically have more time for other academic activities, such as research. Our study seeks to examine whether the number of research publications by orthopaedic residents increased following implementation of the 2011 ACGME duty hour restrictions. DESIGN: Pubmed was queried using publicly available alumni lists from programs across the United States. The years 2008 to 2011 were included to assess pre-2011 productivity. The years 2012 to 2015 were included in the post 2011 group. Paired t tests were used to assess differences between groups. Statistical significance was set to p < 0.05 a priori. SETTING: A total of 10 orthopedic surgery residency programs across the United States. PARTICIPANTS: The study group was composed of 5 of the 2015 top 20 National Institutes of Health (NIH) funded programs and 5 programs without NIH funding. RESULTS: When corrected for number of residents per year, there were 0.290 publications per resident/year from 2008 to 2011 increasing to 0.528 publications per resident/year from 2012 to 2015 following implementation of the 2011 work hour restrictions (p = 0.033). When corrected for number of residents per year, there remained no difference in publications per resident from 2008 to 2011 (p = 0.81) or from 2012 to 2015 (p = 0.10) between NIH and non-NIH funded programs. CONCLUSION: There has been little data to support the theory that resident work hour restrictions have improved education or patient care in any meaningful way. In our study, there was a statistically significant increase in publications after 2011; however, the number of publications between NIH funded and non-NIH funded programs did not differ. Our study is the first to demonstrate that with increasing duty hour restrictions, orthopaedic surgery residents may be using more of their free time to conduct research. PMID- 29273339 TI - Simulation-Based Laparoscopic Surgery Crisis Resource Management Training Predicting Technical and Nontechnical Skills. AB - OBJECTIVES: To develop a unique simulation-based assessment using a laparoscopic inferior vena cava (IVC) injury scenario that allows for the safe assessment of urology resident's technical and nontechnical skills, and investigate the effect of personality traits performance in a surgical crisis. METHODS: Urology residents from our institution were recruited to participate in a simulation based training laparoscopic nephrectomy exercise. Residents completed demographic and multidimensional personality questionnaires and were instructed to play the role of staff urologist. A vasovagal response to pneumoperitoneum and an IVC injury event were scripted into the scenario. Technical and nontechnical skills were assessed by expert laparoscopic surgeons using validated tools (task checklist, GOALS, and NOTSS). RESULTS: Ten junior and five senior urology residents participated. Five residents were unable to complete the exercise safely. Senior residents outperformed juniors on technical (checklist score 15.1 vs 9.9, p < 0.01, GOALS score 18.0 vs 13.3, p < 0.01) and nontechnical performance (NOTSS score 13.8 vs 10.1, p = 0.03). Technical performance scores correlated with NOTSS scores (p < 0.01) and pass/fail rating correlated with technical performance (p < 0.01 for both checklist and GOALS), NOTSS score (p = 0.02), and blood loss (p < 0.01). Only the conscientiousness dimension of the big five inventory correlated with technical score (p = 0.03) and pass/fail rating (p = 0.04). CONCLUSIONS: Resident level of training and laparoscopic experience correlated with technical performance during a simulation-based laparoscopic IVC injury crisis management scenario, as well as multiple domains of nontechnical performance. Personality traits of our surgical residents are similar and did not predict technical skill. PMID- 29273340 TI - Corrigendum to "The expression of G protein-coupled receptor kinase 5 and its interaction with dendritic marker microtubule-associated protein-2 after status epilepticus" [Epilepsy Res. 138 (2017) 62-70]. PMID- 29273342 TI - The association of ribosomal protein L18 (RPL18) with infectious bursal disease virus viral protein VP3 enhances viral replication. AB - Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive avian disease caused by IBD virus (IBDV). IBDV VP3 is a multifunctional protein playing a key role in virus assembly and pathogenesis. To investigate the role of VP3 in pathogenesis, we transfected DF-1 cells with pRK5 FLAG-vp3 and found that VP3 enhanced type I interferon expression and suppressed IBDV replication. Furthermore we found that VP3 interacted with chicken Ribosomal Protein L18 (chRPL18) in host cells and knockdown of chRPL18 by RNAi significantly promoted Type I interferon expression and inhibited IBDV replication. Moreover, our data show that chicken double-stranded RNA-activated protein kinase (chPKR) interacted with both VP3 and chRPL18. Thus chRPL18 in association with VP3 and chPKR affects viral replication. PMID- 29273341 TI - Current concepts on immunopathogenesis of hepatitis B virus infection. AB - Hepatitis B virus (HBV) infection is a leading cause of liver damage and hepatic inflammation. Upon infection, effective antiviral responses by CD8+ T cells, CD4+ T cells, Natural killer (NK) cells, and monocytes can lead to partial or complete eradication of the viral infection. To date, many studies have shown that the production of inhibitory cytokines such as Interleukin 10 (IL-10), Transforming growth factor beta (TGF-beta), along with dysfunction of the dendritic cells (DCs), and the absence of efficient innate immune responses could lead to T cell exhaustion, development of persistent infection, and inability to eradicate the viral infection from liver. Understanding the immunopathogenesis of the virus could be useful in providing further insights toward novel strategies in the eradication of HBV infection. PMID- 29273343 TI - [The concerning attitudes and beliefs of nursing students toward antidepressants and depression]. PMID- 29273344 TI - The effects of oxytocin on social cognition in borderline personality disorder. AB - INTRODUCTION: Deficits in social cognition and interpersonal difficulties are key features in borderline personality disorder. Social cognition refers to the function of perceiving and adequately dealing with social signals, leading to the establishment and maintenance of healthy and positive social relationships. Evidence suggests that oxytocin (OT) may improve social cognition and human social behavior. Recently, several studies have highlighted the beneficial effects of oxytocin in several psychiatric conditions involving social cognition deficits such as schizophrenia, autism or social phobia. However, despite growing interest, the effects of oxytocin in patients with borderline personality disorder are far from being clearly demonstrated. OBJECTIVE: The objective of this work was to review and discuss studies investigating the interest of oxytocin in alleviating social cognition deficits in patients with borderline personality disorder (recognition of emotion, trust and cooperation, affective and cognitive empathy, emotional expression and social problem-solving). METHOD: A systematic review of the literature was conducted up to September 31, 2016 on the Pubmed, Science direct, Medline and Scopus databases using "borderline personality disorder" and "oxytocin" as keywords. To be included, studies were to include patients with borderline personality disorder; to investigate social cognition and to investigate the effect of oxytocin on social cognition in patients with TPB. RESULTS: The initial search yielded 52 articles. Among them, 11 studies were selected according to the PRISMA criteria. The effect of oxytocin on social cognition in patients with borderline personality disorder was mainly investigated in relation to recognition of emotions and trust and cooperation. We did not find any studies investigating the effect of oxytocin on affective and cognitive empathy, emotional expression or social problem-solving abilities. In patients with borderline personality disorder, oxytocin had a beneficial impact on recognition and discrimination of emotions and on hypervigilance towards social threats. However, oxytocin could hinder trust and cooperation. CONCLUSIONS: These data lead us to consider oxytocin as a treatment for emotion recognition deficit and hypervigilance towards social threats in borderline personality disorder. A beneficial effect of oxytocin of this nature may be obtained only in patients without deficits in trust and cooperation because of a risk of aggravating relational instability. There was no current evidence for the interest of oxytocin in enhancing affective and cognitive empathy in borderline personality disorder. Further studies are needed to evaluate the clinical interest of combining oxytocin with psychotherapeutic approaches such as dialectical behavioral therapy or mentalisation-based treatment. PMID- 29273345 TI - [Depression and cardiovascular diseases in type 2 diabetic women: A case-control study]. PMID- 29273346 TI - Characterization of Water Self-Diffusion in Human Stratum Corneum. AB - The stratum corneum (SC) is the outermost layer of human skin and primary barrier to water loss and chemical exposure. It consists of keratin-filled corneocytes of large aspect ratio surrounded by a thin matrix of highly organized lipophilic molecules. In the presence of water, the corneocytes swell and permeability for many chemicals increases. The role of hydration and SC structure on water self diffusion was investigated using the pulsed-gradient stimulated echo nuclear magnetic resonance technique. Proton (1H) self-diffusion, associated with water inside the corneocytes, was determined in human SC as a function of hydration, with and without lipid extraction, at 20 degrees C to 40 degrees C. SC layers were oriented either parallel or perpendicular to the field-gradient direction. Self-diffusion in the direction parallel to the long dimension of the corneocytes is unaffected by lipid extraction and consistent with a free-volume diffusion model. The effect of temperature corresponds with the activation energy of water in wool. Self-diffusion perpendicular to the long dimension of the corneocytes was less dependent on hydration and smaller than in the parallel direction, except at low hydration, when diffusion is insensitive to orientation. Corneocyte diffusion predicted by 2 microscopic SC models in common use are compared with our results. PMID- 29273347 TI - Bile Acid as an Effective Absorption Enhancer for Oral Delivery of Epidermal Growth Factor Receptor-Targeted Hybrid Peptide. AB - The aim of this study was to improve the oral absorption of epidermal growth factor receptor-targeted hybrid peptide using bile acid as an absorption enhancer. The oral formulation of this peptide was formed through electrostatic interactions between the cationic peptide and anionic bile acid. Comparative studies of in vitro cell permeability and in vivo antitumor effects of peptide and peptide/bile acid complex were performed in Caco-2 cells and in a xenograft mouse model of human gastric cancer. The in vitro permeability of peptide/bile acid complex across Caco-2 cell monolayers was significantly enhanced to about 5.0-fold over those of peptide alone. Furthermore, in vivo mouse xenograft model treated with peptide/bile acid complex showed a 1.6-fold reduction in the mean tumor volume as compared with the peptide alone. A preliminary safety evaluation of blood cells counts, liver enzyme levels, and histopathology of gastrointestinal tissues and main organs showed that the peptide/bile acid complex did not induce any acute toxicity. These results suggest that bile acid is an effective absorption enhancer for improving the oral bioavailability and bioactivity of epidermal growth factor receptor-targeted hybrid peptide. PMID- 29273348 TI - The Role of FENO in the Diagnosis and Control of Asthma. Expert Multidisciplinary Group Debate during the Asthma Meeting Point 2017. PMID- 29273349 TI - Nebulized tranexamic acid as a therapeutic alternative in pulmonary hemorrhage. PMID- 29273350 TI - The association of age with perioperative morbidity and mortality among men undergoing radical prostatectomy. AB - INTRODUCTION: Older age is considered a relative contraindication to radical prostatectomy (RP). However, data are limited regarding the impact of age on perioperative outcomes following RP. We examined the association of age with perioperative outcomes following RP to inform risk-stratification and management. MATERIALS AND METHODS: We identified 35,968 men aged 18 to 89 years who underwent RP from 2010 to 2015 in the National Surgical Quality Improvement Program (NSQIP) database. The associations of age with 30-day complications and perioperative morbidity were evaluated using logistic regression, adjusted for patient features. Age was modeled both as a categorical and nonlinear continuous variable. RESULTS: Median age at surgery was 63 years (IQR: 58-67). Increasing age was associated with greater rates of perioperative morbidity. Compared to men aged<60 years, men aged 70 to 89 years had statistically significantly higher rates of 30-day complications (6.4% vs. 4.4%, P<0.0001), perioperative blood transfusion (6.0% vs. 3.7%, P<0.0001), readmission (4.9% vs. 3.9%, P<0001), and 30-day mortality (0.3% vs. 0.1%, P<0.0001). In multivariable analyses, older age was independently associated with increased risks of perioperative morbidity. Moreover, there was a nonlinear relationship of age with perioperative morbidity, wherein rates of 30-day complications, perioperative blood transfusion, and readmission increased after approximately 70 years of age. CONCLUSIONS: In this national cohort, we observed a nonlinear association of age with perioperative morbidity, with increasing rates of 30-day complications, perioperative blood transfusion, and readmission after approximately 70 years of age. These results have implications for risk-stratification, patient counseling, and treatment selection among older men. PMID- 29273351 TI - To oophorectomy or not to oophorectomy: Practice patterns among urologists treating bladder cancer. AB - OBJECTIVES: Classically, radical cystectomy (RC) involves hysterectomy and bilateral salpingo-oophorectomy (BSO). Current understanding of ovarian cancer pathogenesis and effect of premature oophorectomy has lead to a shift within gynecology toward risk-reducing salpingectomy without oophorectomy in the absence of gynecologic malignancy. The purpose of this study was to assess knowledge base and practice patterns of urologic oncologists with regard to management of the gynecological organs at the time of RC. MATERIALS AND METHODS: An anonymous and voluntary electronic survey was distributed to members of the Society of Urologic Oncology (SUO). Demographic data, training, practice setting and duration, experience, rationale for BSO, and knowledge assessment of ovarian cancer pathogenesis/risks associated with BSO was collected. RESULTS: A total of 159/660 (24%) SUO members responded of whom 110 (69%) were academic urologists and 58 (36%) involved in training urologic oncology fellows. Of all, 75% had performed an ovarian-sparing RC. Furthermore, 14% were aware that salpingectomy alone reduces the risk of ovarian cancer, whereas 95%, 66%, and 26% were aware that BSO increases the risk of osteoporosis, cardiovascular disease, and all-cause mortality, respectively. Reasons for BSO at the time of RC included concern for urothelial carcinoma metastasis (54%), development of future gynecologic pathology (50%), and facilitation of pelvic lymph node dissection (36%). CONCLUSIONS: Many urologic oncologists remain unaware of the benefits of risk reducing salpingectomy and the risks associated with BSO, identifying a potential area for further education in the urologic community. PMID- 29273352 TI - Evaluation of different ranges of LH:FSH ratios in polycystic ovarian syndrome (PCOS) - Clinical based case control study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine and metabolic disorder among reproductive aged women, leading to infertility. One of the common clinical manifestations in PCOS is that there is a difference in the range of LH production in different case of PCOS and accordingly variability in LH:FSH ratio was observed. OBJECTIVE: The aim of the present study was to evaluate different ranges of LH:FSH ratios in PCOS. EXPERIMENTAL DESIGN: In this cross sectional study, a consecutive series of 745 women (aged 28.11 +/- 0.2) who were subjected to infertility treatment at specialist infertility clinics in central Travancore region were considered. About 50 healthy females (aged 27.58 +/- 0.4) with regular menstrual cycles were regarded as control. The data were collected from hospital records using subject's written informed consent. RESULTS: PCOS patients were observed to have different ranges of LH:FSH ratios from < 1 range to 4.6-5.5 and subjects were classified into 7 PCO subgroups on the basis of their LH:FSH ratios. In whole PCO group, body weight, LH, FSH, LH:FSH ratio, insulin, HbA1c, estradiol, testosterone and TSH were significantly (P < .05) increased whereas progesterone and SHBG levels were significantly (P < .05) decreased in comparison to control. In various PCO subgroups as LH levels and LH:FSH ratios were increased, levels of insulin, testosterone and AMH were increased and SHBG levels were decreased accordingly. CONCLUSION: This finding suggested a dependence of insulin, LH and testosterone in initiating the hormonal imbalances in PCOS. PMID- 29273353 TI - Another failure in predicting sepsis outcomes in the emergency department. PMID- 29273354 TI - A comparison of alcohol positive and alcohol negative trauma patients requiring an emergency laparotomy. AB - BACKGROUND: The effect of alcohol exposure on patients undergoing a laparotomy for trauma is unknown. The purpose of this study was to compare outcomes of morbidity and mortality between alcohol positive and alcohol negative trauma patients who required emergent laparotomies using the National Trauma Data Bank (NTDB). METHODS: A retrospective database analysis was performed using 28,354 NTDB incident trauma cases, from 2007 through 2012, who had been tested for alcohol and who required abdominal operations (using ICD-9-CM procedure codes) within 24h of presentation. Variables used: age, gender, admission year, alcohol presence, ISS, GCS, injury type & mechanism, discharge status, hospital LOS, ICU stay, ventilator use, and hospital complications. RESULTS: In adjusted analyses, there were no statistically significant differences between the alcohol positive and alcohol negative cohorts when evaluating in-hospital mortality (OR, 0.93; 95% CI: 0.84-1.03), likelihood of earlier hospital discharge (HR, 1.02; 95% CI: 0.99 1.05), and the all-inclusive category of in-hospital complications (OR, 1.04; 95% CI: 0.97-1.12). CONCLUSIONS: After adjusting for age, gender, admission year, ISS, GCS, and injury mechanism, there were no major differences between the alcohol positive and alcohol negative cohorts when it came to in-hospital mortality, likelihood of earlier hospital discharge, and most of the in-hospital complications measured among adult trauma patients requiring emergency laparotomies. PMID- 29273355 TI - What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM. AB - BACKGROUND: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. METHODS: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. FINDINGS: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-gamma; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5DeltaD32 deletion and shared HLA-B*07, C*07 non protective alleles. INTERPRETATION: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection. PMID- 29273357 TI - Regulatory RNA Editing Sites in Cancer: Prediction and Beyond. PMID- 29273356 TI - Global Transcriptome Analysis of RNA Abundance Regulation by ADAR in Lung Adenocarcinoma. AB - Despite tremendous advances in targeted therapies against lung adenocarcinoma, the majority of patients do not benefit from personalized treatments. A deeper understanding of potential therapeutic targets is crucial to increase the survival of patients. One promising target, ADAR, is amplified in 13% of lung adenocarcinomas and in-vitro studies have demonstrated the potential of its therapeutic inhibition to inhibit tumor growth. ADAR edits millions of adenosines to inosines within the transcriptome, and while previous studies of ADAR in cancer have solely focused on protein-coding edits, >99% of edits occur in non protein coding regions. Here, we develop a pipeline to discover the regulatory potential of RNA editing sites across the entire transcriptome and apply it to lung adenocarcinoma tumors from The Cancer Genome Atlas. This method predicts that 1413 genes contain regulatory edits, predominantly in non-coding regions. Genes with the largest numbers of regulatory edits are enriched in both apoptotic and innate immune pathways, providing a link between these known functions of ADAR and its role in cancer. We further show that despite a positive association between ADAR RNA expression and apoptotic and immune pathways, ADAR copy number is negatively associated with apoptosis and several immune cell types' signatures. PMID- 29273358 TI - Impact of hospital volume on mortality in patients with severe torso injury. AB - BACKGROUND: Whether a positive volume-outcome relationship exists in the context of trauma remains controversial. Heterogeneity in the definition of hospital volume in previous studies is one of the main reasons for this inconclusiveness. We investigated whether hospital volume is associated with mortality in patients with severe torso injury using two different definitions of hospital volume. MATERIALS AND METHODS: This retrospective cohort study used the Diagnosis Procedure Combination database in Japan. Patients who were admitted to tertiary emergency centers with severe torso injury and underwent emergency surgery or interventional radiology treatment for the torso injury upon admission from April 1, 2010 to March 31, 2014 were included. Hospital volume was defined as the annual number of admissions with severe torso injury (HV-torso) or the annual number of total trauma admissions (HV-all). The main outcome was 28-d mortality. Multivariable logistic regression models fitted with generalized estimating equations were used to evaluate relationships between hospital volume and 28-d mortality. RESULTS: Overall, 7725 patients were included. The 28-d mortality rate was 15.3%. The HV-torso was significantly associated with reduced 28-d mortality (adjusted odds ratio = 0.59; 95% confidence interval = 0.44-0.79). However, there was no significant association between the HV-all and mortality (adjusted odds ratio = 1.02; 95% confidence interval = 0.72-1.46). CONCLUSIONS: The HV-torso was significantly associated with reduced mortality in patients with severe torso injury. In contrast, the HV-all had no significant relationship with their mortality. Regionalization of trauma care for severe torso injury may be beneficial for patients with severe torso injury. PMID- 29273359 TI - Antioxidant supplementation and atrial arrhythmias in critically ill trauma patients. AB - BACKGROUND: The purpose of this study is to determine if antioxidant supplementation influences the incidence of atrial arrhythmias in trauma intensive care unit (ICU) patients. MATERIALS AND METHODS: In this retrospective pre-post study, critically ill injured patients aged >=18 years, admitted to a single-center trauma ICU for >=48 hours were eligible for inclusion. The control group consists of patients admitted from January 2000 to September 2005, before routine antioxidant supplementation in our ICU. The antioxidant group consists of patients admitted from October 2005 to June 2011 who received an antioxidant protocol for >=48 hours. The primary outcome is the incidence of atrial arrhythmias in the first 2 weeks of hospitalization or before discharge. RESULTS: Of the 4699 patients, 1622 patients were in the antioxidant group and 2414 patients were in the control group. Adjusted for age, sex, year, injury severity, past medical history, and medication administration, the unadjusted incidence of atrial arrhythmias was 3.02% in the antioxidant group versus 3.31% in the control group, with no adjusted difference in atrial arrhythmias among those exposed to antioxidants (odds ratio: 1.31 [95% confidence interval: 0.46, 3.75], P = 0.62). Although there was no change in overall mortality, the expected adjusted survival of patients in those without antioxidant therapy was lower (odds ratio: 0.65 [95% confidence interval: 0.43, 0.97], P = 0.04). CONCLUSIONS: ICU antioxidant supplementation did not decrease the incidence of atrial arrhythmias, nor alter the time from admission to development of arrhythmia. A longer expected survival time was observed in the antioxidant group compared with the control group but without a change in overall mortality between groups. PMID- 29273360 TI - The diagnostic value of hepcidin to predict the presence and severity of appendicitis in children. AB - BACKGROUND: The aim of this study was to determine the diagnostic capacity of hepcidin in pediatric acute appendicitis and its accuracy as a predictor of the severity of appendicitis. MATERIALS AND METHODS: In children with appendicitis (n = 39), leukocytes, platelet count, and the serum levels of C-reactive protein (CRP) and hepcidin were compared to a control group (n = 25) of patients with unspecific abdominal pain. Additionally, parameters were compared between children with simple (n = 17) and complicated appendicitis (n = 22). Receiver operation characteristic analyses of the different parameters were performed and the areas under the curve (AUCs) calculated. RESULTS: Leukocytes and serum hepcidin levels were significantly higher in children with acute appendicitis versus control group (13.7 +/- 5.7 versus 9.8 +/- 3.9 G/L, P = 0.005 and 31.3 +/- 21.7 versus 20.4 +/- 14 ng/mL, P = 0.039). AUCs for hepcidin, leukocytes, and CRP were 0.654, 0.711, and 0.619, respectively. Complicated appendicitis was associated with significantly higher hepcidin concentrations compared to simple appendicitis (38.5 +/- 17.6 ng/mL versus 21.6 +/- 23.4 ng/mL, P < 0.001). A combination of leukocytes, CRP, and hepcidin had the highest AUC (0.914) to predict complicated appendicitis. CONCLUSIONS: Increased serum levels of hepcidin were found in children with appendicitis compared to controls. While hepcidin was useful to identify patients with complicated appendicitis as it does not seem appropriate to distinguish between simple appendicitis and other causes for acute abdominal pain. PMID- 29273361 TI - Surgical Apgar score for predicting complications after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Surgical Apgar score (SAS) was recently proposed as a simple predictor of postoperative complications. A few studies have shown the utility of the SAS in some kinds of surgeries, but it has not been investigated in patients undergoing hepatectomy for hepatocellular carcinoma (HCC). METHODS: This study included 158 patients undergoing hepatectomy for HCC. The association between SAS and postoperative complications was examined. The patients had postoperative morbidities classified as Clavien-Dindo grade II or higher. Multivariate regression analysis was performed to identify independent factors that significantly influenced the development of postoperative complications. RESULTS: Postoperative complications developed in 28 (17.7%) of the 158 patients. The proportion of cases with complications was significantly inversely correlated with SAS (Spearman rank correlation 0.829). The SAS was significantly lower in cases with complications than those without complications (5.6 +/- 1.3 points versus 6.6 +/- 1.3 points, P = 0.0004). Comparisons between patients with and without complication showed that preoperative serum albumin level and operation time, as well as SAS, were associated with complications. Multivariate analysis revealed that postoperative complications significantly correlated with the SAS. CONCLUSIONS: This study demonstrated the clinical utility of SAS in predicting the development of postoperative complications after hepatectomy for HCC. PMID- 29273362 TI - The risk factors of venous thromboembolism in massively transfused patients. AB - BACKGROUND: Massive transfusion protocols (MTPs) are necessary for hemodynamically unstable trauma patients with active bleeding. Thrombotic events have been associated with blood transfusion; however, the risk factors for the development of venous thromboembolism (VTE) in trauma patients receiving MTP are unknown. METHODS: A retrospective review was conducted by reviewing the electronic medical records of all trauma patients admitted to a Level I trauma center who received MTP from 2011 to 2016. Data were collected on patient demographics, mechanism of injury, injury severity scores, quantity of blood products transfused during MTP activation, incidence of VTE, intensive care unit length of stay (LOS), hospital LOS, and ventilator days. The primary outcome was VTE. RESULTS: Of the 59 patients who had MTP activated, 15 (25.4%) developed a VTE during their hospital admission. Patients who developed VTE were compared with those who did not. Age (40 y versus 35 y, P = 0.59), sex (60% versus 73% male, P = 0.52), and mechanism of injury (47% versus 59% blunt, P = 0.40) were similar. Intensive care unit LOS, hospital LOS, and ventilator days were longer in the patients who were diagnosed with a VTE. Multivariable analysis revealed an increase in the odds for developing a VTE with increasing packed red blood cell transfusion (adjusted odds ratio = 2.61, P = 0.03). CONCLUSIONS: The risk for VTE in trauma patients requiring massive transfusion is proportional to the number of packed red blood cells transfused. Liberal screening protocols and maintenance of a high index of suspicion for VTE in these high-risk patients is justified. PMID- 29273363 TI - LMR predicts outcome in patients after preoperative chemoradiotherapy for stage II-III rectal cancer. AB - BACKGROUND: Recently, lymphocyte-to-monocyte ratio (LMR) has attracted attention as a new marker of the chronic systemic inflammatory response and has been associated with patient prognosis in those who underwent chemoradiotherapy (CRT) for several solid cancers. This study aimed to evaluate the association between LMR and the prognosis of patients with rectal cancer. METHODS: A total of 183 stage II-III rectal cancer patients who underwent preoperative CRT followed by surgical R0 resection were retrospectively reviewed. The LMR was calculated from pre- and post-CRT blood samples. To determine the optimal cutoff value for pre- and post-CRT LMR for predicting relapse-free survival (RFS) and overall survival (OS), a receiver operator characteristic curve was used. Cox's proportional hazard models were applied to identify risk factors for recurrence and overall mortality. RESULTS: Low LMR was observed in 54 patients (pre-CRT <4.0) and 29 patients (post-CRT <1.5). Although pre-CRT LMR correlated with tumor size and ypT stage, post-CRT LMR showed no correlation to any pathologic features. Median follow-up term was 66.3 months; the 5-year RFS and OS of all patients were 72.5% and 88.7%, respectively. We found that a low pre-CRT LMR was an independent risk factor for OS (hazard ratio, 2.83; 95% confidence interval 1.03-8.13; P = 0.043). CONCLUSIONS: In rectal cancer patients who have undergone preoperative CRT, a low pre-CRT LMR is a poor prognostic factor for OS. PMID- 29273364 TI - Establishment of laparoscopic live donor nephrectomy in a porcine model: techniques and outcomes in 44 pigs. AB - BACKGROUND: Laparoscopic live donor nephrectomy has replaced open donor nephrectomy in most patients due to numerous benefits. A live animal model is required to equip surgeons with the necessary skills to perform such a procedure with minimal risk of complications. The aim of this study was to establish the technique for laparoscopic live donor nephrectomy in a porcine (Sus scrofa) model. MATERIALS AND METHODS: This study was approved by the Animal Ethics Committee of the university. Forty-four pigs underwent laparoscopic live donor nephrectomy. The left kidney was removed with a standardized four-port technique, with a small suprapubic incision to facilitate kidney delivery. RESULTS: All 44 procedures were performed successfully, with no intraoperative complications or conversion to open surgery. There was no apparent damage to any of the kidney grafts. The mean surgical time was 118.3 (+/-20.7) minutes. There was a small, but statistically insignificant, decrease in surgical time throughout the duration of the study. Several subjects had minor variations in the anatomy of the renal vasculature. CONCLUSIONS: This series has developed and proven a training model for laparoscopic donor nephrectomy in pigs. This training model will allow surgeons to develop laparoscopic proficiency in a live donor, to be used in conjunction with human cadaveric training. PMID- 29273365 TI - Sinusoidal protection by sphingosine-1-phosphate receptor 1 agonist in liver ischemia-reperfusion injury. AB - BACKGROUND: Functional and structural damages in sinusoidal endothelial cells (SECs) have a crucial role during hepatic ischemia-reperfusion injury (IRI). In regulating endothelial function, sphingosine-1-phosphate receptor 1 (S1PR1), which is a G protein-coupled receptor, has an important role. The present study aimed to clarify whether SEW2871, a selective S1PR1 agonist, can attenuate hepatic damage caused by hepatic IRI, focusing on SEC functions. METHODS: In vivo, using a 60-min partial-warm IRI model, mice were treated with SEW2871 or without it (with vehicle). In vitro, isolated SECs pretreated with SEW2871 or without it (with vehicle) were incubated with hydrogen peroxide. RESULTS: Compared with the IRI + vehicle group, SEW2871 administration significantly improved serum transaminase levels and liver damage, attenuated infiltration of Ly-6G and mouse macrophage antigen-1-positive cells, suppressed the expression of vascular cell adhesion molecule-1 and proinflammatory cytokines in the liver, and enhanced the expressions of endothelial nitric oxide synthase (eNOS) and vascular endothelial (VE) cadherin in the liver (eNOS/beta-actin [median]: 0.24 versus 0.53, P = 0.008; VE-cadherin/beta-actin [median]: 0.21 versus 0.94, P = 0.008). In vitro, compared with the vehicle group, pretreatment of SECs with SEW2871 significantly increased the expressions of eNOS and VE-cadherin (eNOS/beta-actin [median]: 0.22 versus 0.29, P = 0.008; VE-cadherin/beta-actin [median]: 0.38 versus 0.67, P = 0.008). As results of investigation of prosurvival signals, SEW2871 significantly increased Akt phosphorylation in SECs and decreased lactate dehydrogenase levels in supernatants of SECs. CONCLUSIONS: These results indicate that S1PR1 agonist induces attenuation of hepatic IRI, which might be provided by preventing SEC damage. S1PR1 may be a therapeutic target for the prevention of early sinusoidal injury after hepatic IRI. PMID- 29273366 TI - Effects of semielemental diet containing whey peptides on Peyer's patch lymphocyte number, immunoglobulin A levels, and intestinal morphology in mice. AB - BACKGROUND: Enteral nutrition (EN) is the gold standard of nutritional therapy for critically ill or severely injured patients, because EN promotes gut and hepatic immunity, thereby preventing infectious complications as compared with parenteral nutrition. However, there are many EN formulas with different protein and fat contents. Their effects on gut-associated lymphoid tissue remain unclear. Recently, semielemental diets (SEDs) containing whey peptides as a nitrogen source have been found to be beneficial in patients with malabsorption or pancreatitis. Herein, we examined the influences of various dietary formulations on gut immunity to clarify the advantages of SEDs over elemental diets. METHODS: Forty-four male Institute of Cancer Research mice were randomized to four groups: chow (CH: n = 5), intragastric total parenteral nutrition (IG-TPN: n = 13), elemental diet (ED: n = 13), and SED (n = 13). The CH group received CH diet ad libitum, whereas the IG-TPN, ED (Elental, Ajinomoto, Japan), and SED (Peptino, Terumo, Japan) groups were given their respective diets for 5 day via gastrostomy. After 5 days, the mice were killed to obtain whole small intestines. Peyer's patch (PP) lymphocytes were harvested and counted. Their subpopulations were evaluated by flow cytometry. Immunoglobulin A (IgA) levels in intestinal and respiratory tract washings were measured with enzyme-linked immunosorbent assay. Villous height (VH) and crypt depth in the distal intestine were measured by light microscopy. RESULTS: SED increased the PP cell number and intestinal or respiratory IgA levels to those of CH mice, while ED partially restored these parameters. The IG-TPN group showed the lowest PP cell number and IgA levels among the four groups. VH was significantly greater in the CH than in the other groups. VH in the ED and SED groups also exceeded in the IG-TPN group, while being similar in these two groups. No significant crypt depth differences were observed among the four groups. CONCLUSIONS: SED administration can be recommended for patients unable tolerate complex enteral diets or a normal diet in terms of not only absorption and tolerability but also maintenance of gut immunity. PMID- 29273367 TI - The rat groin flap model redesigned for evaluating treatment effects on ischemia reperfusion injury. AB - BACKGROUND: Although there is a wide application of the rat extended groin flap (epigastric skin flap) in studying different clinical issues, inconsistency arises between studies because many parameters of the extended groin flap have not been well defined. MATERIALS AND METHODS: The flap is based on the superficial inferior epigastric vessels, which give into a lateral and a medial branch distally. Herein, three steps were taken to redesign this model: First, the ventral vascular anatomy was visualized through an imaging study to determine the flap borders. Second, different ischemic durations were induced on five groups of Lewis rats (n = 5 in each group) by clamping the femoral artery; group 1 (sham group) received no ischemic insult after elevation and was immediately repositioned, and groups 2, 3, 4, and 5 received 12-, 14-, 16-, and 18-hour ischemia, respectively. Percentage of necrosis area was measured after 5 days. Third, the redesigned groin flap model was tested with the ischemic postconditioning for validation. RESULTS: The flap borders were determined such that both branches of the superficial inferior epigastric vessels were always included to ensure blood supply consistency. As the 14-hour ischemia induced the least variation in necrotic area on rats, it was chosen for further studies. In addition, ischemic postconditioning after 14-hr ischemia resulted in significant reduction of necrosis in this model. CONCLUSIONS: We have redesigned the extended groin flap model with better-defined borders and consistent vascular anatomy. The ischemia duration was calibrated with predictable necrosis pattern and the practicality was demonstrated. With this model, precise assessment of treatment efficacies on ischemia-reperfusion injury could be achieved in future studies. PMID- 29273368 TI - Enhanced vascular regeneration with chemically/physically treated bovine/human pericardium in rodents. AB - BACKGROUND: Glutaraldehyde-treated pericardia for cardiovascular applications have poor long-term clinical results. The efficacy of a combined physical/chemical treatment to improve pericardium biocompatibility and vascular regeneration was assessed and compared with detergent treatment and two commercial bovine pericardia: PeriGuard (DGBP) and Edwards pericardium (nDGBP). The physical and chemical process was applied to bovine and human pericardia (DBP DHP), and the detergent process was applied to bovine (DDBP). MATERIAL AND METHODS: Native (NBP) and treated bovine tissues were assessed for decellularization (HE/DAPI/DNA/alpha-Gal and MHC-1 staining) and mechanical integrity ex vivo. Twenty Wistar rats received subcutaneous patches of each bovine tissue to assess immunogenic response up to 4 months (flow cytometry). Ten additional rats received four subcutaneous bovine-treated patches (one/condition) to evaluate the inflammatory reaction (CD3/CD68 immunostaining), calcification (von Kossa staining/calcium quantification), and integration assessment (Hematoxylin and eosin staining). Finally, 15 rodents received a patch on the aorta (DBP n = 5, DHP n = 5, and DGBP n = 5), and vascular biocompatibility and arterial wall regeneration were assessed after 4 months (CD3/CD68/CD31/ASMA and Miller staining). RESULTS: DBP reached the higher level of decellularization, no immunogenic response whereas maintaining mechanical properties. DBP induced the lowest level grade of inflammation after 2 months (P < 0.05) concomitantly for better remodeling. No complications occurred with DBP and DHP where vascular regeneration was confirmed. Moreover, they induced a low level of CD3/CD68 infiltrations. CONCLUSIONS: This process significantly reduces immunogenicity and improves biocompatibility of bovine and human pericardia for better vascular regeneration. PMID- 29273369 TI - Carbon monoxide and hydrogen sulphide reduce reperfusion injury in abdominal compartment syndrome. AB - BACKGROUND: Carbon monoxide (CO)- and hydrogen sulphide-releasing molecules (CORM 3 and GYY4137, respectively) have been shown to be potent antioxidant and antiinflammatory agents at the tissue and systemic level. We hypothesized that both CORM-3 and GYY4137 would reduce the significant organ dysfunction associated with abdominal compartment syndrome (ACS). MATERIAL AND METHODS: Randomized trial was conducted where ACS was maintained for 2 hours in 27 rats using an abdominal plaster cast and intraperitoneal CO2 insufflation at 20 mmHg. Three experimental groups underwent ACS and received an experimental molecule at the time of decompression: inactive CORM-3, active CORM-3, and GYY4137, whereas three groups underwent no ACS to serve as a sham. Sinusoidal perfusion, inflammatory response and cell death were quantified in exteriorized livers. Respiratory, liver, and renal dysfunction was assessed biochemically. RESULTS: Hepatocellular death and the number of activated leukocytes within postsinusoidal venules were significantly increased in rats with ACS (16-fold increase, 17-fold leukocyte activation, respectively, P < 0.05). Administration of CORM-3 or GYY4137 resulted in a significant decrease of both parameters (P = 0.03 and P = 0.009). ACS resulted in an increase in markers of renal and liver injury; CORM-3 or GYY4137 partially restored levels to those seen in sham animals. Myeloperoxidase was significantly elevated in the ACS group in lung, liver, and small intestine (P = 0.0002, P = 0.01, and P = 0.08, respectively). CORM-3 treatment, but not GYY4137, was able to completely block the response (65 +/- 11 U/ml and 92 +/- 18 U/ml, respectively versus 110 +/- 10U/ml in the ACS group, lung tissue). CONCLUSIONS: We have demonstrated the effect of two molecules, CO and hydrogen sulphide, on tempering the reperfusion-associated metabolic and organ derangements in ACS. CORM-3 demonstrated a greater effect than GYY4137 and was able to restore most of the measured parameters to levels comparable to sham. PMID- 29273370 TI - Is there a "weekend effect" in emergency general surgery? AB - BACKGROUND: Weekend admission is associated with increased mortality across a range of patient populations and health-care systems. The aim of this study was to determine whether weekend admission is independently associated with serious adverse events (SAEs), in-hospital mortality, or failure to rescue (FTR) in emergency general surgery (EGS). METHODS: An observational study was performed using the National Inpatient Sample in 2012-2013; the largest all-payer inpatient database in the United States, which represents a 20% stratified sample of hospital discharges. The inclusion criteria were all inpatients with a primary EGS diagnosis. Outcomes were SAE, in-hospital mortality, and FTR (in-hospital mortality in the population of patients that developed an SAE). Multivariable logistic regression were used to adjust for patient- (age, sex, race, payer status, and Charlson comorbidity index) and hospital-level (trauma designation and hospital bed size) characteristics. RESULTS: There were 1,344,828 individual patient records (6.7 million weighted admissions). The overall rate of SAE was 15.1% (15.1% weekend, 14.9% weekday, P < 0.001), FTR 5.9% (6.2% weekend, 5.9% weekday, P = 0.010), and in-hospital mortality 1.4% (1.5% weekend, 1.3% weekday, P < 0.001). Within logistic regression models, weekend admission was an independent risk factor for development of SAE (adjusted odds ratio 1.08, 1.07 1.09), FTR (1.05, 1.01-1.10), and in-hospital mortality (1.14, 1.10-1.18). CONCLUSIONS: This study found evidence that outcomes coded in an administrative data set are marginally worse for EGS patients admitted at weekends. This justifies further work using clinical data sets that can be used to better control for differences in case mix. PMID- 29273371 TI - Response to: what is the mechanism of prolonged ileus after colectomy for inflammatory bowel disease within the ERAS protocol? PMID- 29273372 TI - Preischemic transfusion of old packed RBCs exacerbates early-phase warm hepatic ischemia reperfusion injury in rats. AB - BACKGROUND: Hepatic innate immune cells are considered to play a central role in the early phase of hepatic ischemia reperfusion (IR) injury. Transfusion of old red blood cells (RBCs) is known to prime immune cells, and transfusion before IR may exacerbate liver injury because of the expected hyperresponsiveness of immune cells. MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were divided into four groups: sham operation (Sham); hepatic IR only (IR Control); and two transfusion groups, preischemic (Pre-T) and postischemic (Post-T), in which allogeneic RBCs stored for 2 weeks were transfused before hepatic IR or after reperfusion, respectively. Partial hepatic ischemia was induced for 90 min, and reperfusion was allowed for 120 min. Serum alanine transaminase levels, area of necrosis, and apoptotic cells were then assessed. Inflammatory (tumor necrosis factor alpha, interleukin 1 beta [IL-1beta], IL-6, IL-10, and cyclooxygenase 2) and oxidative mediators (heme oxygenase 1, superoxide dismutase, and glutathione peroxidase 1) were assessed for elucidating the relevant mechanisms underlying the hepatic injury. RESULTS: Pre-T, but not Post-T, showed increased serum alanine transaminase levels than IR Control (P < 0.05). Area of necrosis was more severe in Pre-T than in IR Control or Post-T (P < 0.01), and apoptotic cells were also more abundant in Pre-T than in IR Control (P < 0.01). tumor necrosis factor alpha and IL-6 levels were higher in Pre-T than in IR Control or Post-T (P < 0.05), with no significant difference in cytoprotective protein levels. CONCLUSIONS: Preischemic transfusion of old RBCs aggravated hepatic injury. Inflammatory cytokines seemed to play a crucial role in liver injury exacerbation. Our results indicate that transfusion before hepatic ischemia may be detrimental. PMID- 29273373 TI - Robotic-assisted single-port donor nephrectomy using the da Vinci single-site platform. AB - BACKGROUND: Although single-port donor nephrectomy offers improved cosmetic outcomes, technical challenges have limited its application to selected centers. Our center has performed over 400 single-port donor nephrectomies. The da Vinci single-site robotic platform was utilized in an effort to overcome the steric, visualization, ergonomic, and other technical limitations associated with the single-port approach. MATERIALS AND METHODS: Food and Drug Administration device exemption was obtained. Selection criteria for kidney donation included body mass index <35, left kidney donors, and <=2 renal arteries. After colonic mobilization using standard single-port techniques, the robotic approach was utilized for ureteral complex and hilar dissection. RESULTS: Three cases were performed using the robotic single-site platform. Average total operative time was 262 +/- 42 min including 82 +/- 16 min of robotic use. Docking time took 20 +/- 10 min. Blood loss averaged 77 +/- 64 mL. No intraoperative complications occurred, and all procedures were completed with our standard laparoscopic single-port approach. CONCLUSIONS: This is the first clinical experience of robotic-assisted donor nephrectomy utilizing the da Vinci single-site platform. Our experience supported the safety of this approach but found that the technology added cost and complexity without tangible benefit. Development of articulating instruments, energy, and stapling devices will be necessary for increased application of robotic single-site surgery for donor nephrectomy. PMID- 29273374 TI - Protective effects of glutathione on oxidative injury induced by hydrogen peroxide in intestinal epithelial cells. AB - BACKGROUND: Reactive oxygen species are increased in multiple gastrointestinal diseases and contribute to their pathogenesis. glutathione (GSH) is an antioxidant that helps to prevent reactive oxygen species-mediated mucosal damage. This study examines the mechanisms by which GSH attenuates hydrogen peroxide (H2O2)-induced injury in intestinal epithelial cells. METHODS: IEC-6 cells were cultured and treated with H2O2 +/- GSH. Inflammation was measured by nuclear factor kappa-B (NF-kappaB) P65 expression, NF-kappaB nuclear translocation, ikappaBalpha phosphorylation, and interleukin 1 beta secretion. Terminal deoxynucleotidyl transferase-mediated UTP end-labeling staining and cleaved caspase-3 were used to assess apoptosis. The role of P38 mitogen activated protein kinase (P38 MAPK) signaling was examined using the P38 MAPK agonist U46619 and inhibitor SB203580 in H2O2 and GSH-treated cells. Phosphorylated and total P38 MAPKs and cleaved caspase-3 were measured by Western blot. Data are means +/- standard deviation, statistical significance P < 0.05 by student's t-test, or one-way analysis of variance. RESULTS: Pretreatment with GSH attenuates the activation of NF-kappaB and P38 MAPK signaling pathways by H2O2. GSH also decreased H2O2-mediated increases in interleukin 1 beta secretion, cleaved caspase-3 activation, and apoptosis in IEC-6 cells. SB203580 attenuated the increase in apoptosis and cleaved caspase-3 in H2O2-treated cells. The increase in apoptotic index and cleaved caspase-3 observed in U46619-treated cells was also diminished by GSH. CONCLUSIONS: GSH appears to ameliorate oxidative injury in intestinal epithelial cells by attenuating H2O2-mediated activation of NF-kappaB and P38 MAPK signaling pathways that regulate intestinal inflammation and apoptosis. PMID- 29273375 TI - The impact of lipomatous tumors on type 2 diabetes: are adipose-derived tumors metabolically active? AB - BACKGROUND: The metabolic and immunologic properties of adipose tissue are linked to the pathogenesis of type 2 diabetes mellitus. Lipomatous tumors, such as liposarcomas, are rare but can reach significant size. We hypothesized that some lipomatous tumors are metabolically active and can alter systemic glucose homeostasis. METHODS: We performed a retrospective study of patients who underwent resection of a lipomatous tumor at a tertiary cancer referral center (2004-2015). We divided patients into nondiabetics, well-controlled diabetics (hemoglobin A1c [HbA1c] < 7), and poorly controlled diabetics (HbA1c >= 7). We compared patient demographics, tumor characteristics, and measures of glycemic control among these groups before and after tumor resection. RESULTS: We reviewed 217 operations for lipomatous tumors. No differences were observed in tumor characteristics in patients with and without diabetes. However, tumor characteristics differed significantly between the well-controlled and poorly controlled diabetics groups. Patients with poorly controlled diabetes had larger tumors that were more likely to be malignant, retroperitoneal, and well differentiated. Tumor resection had no detectable impact on diabetes, as assessed by HbA1c, and requirement for diabetic medications. CONCLUSIONS: Poorly controlled diabetes was linked to the presence of large, malignant, and retroperitoneal lipomatous tumors. However, in limited follow-up, no detectable impact of tumor resection was apparent on glycemic control. These data suggest that most lipomatous tumors do not exert a clinically relevant impact on glucose homeostasis. PMID- 29273376 TI - Validation of the American Joint Committee on Cancer eighth edition staging system in patients undergoing hepatectomy for hepatocellular carcinoma: a US population-based study. AB - BACKGROUND: The American Joint Committee on Cancer (AJCC) eighth edition staging system for hepatocellular carcinoma (HCC) has incorporated several significant changes. This study aims to evaluate the newly proposed staging system and assess its strengths and weaknesses. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified patients with pathologically confirmed stage I-III HCC diagnosed between 2004 and 2014. RESULTS: After all exclusion criteria were applied, AJCC seventh and eighth edition staging was possible in 4931 patients. According to the AJCC eighth edition staging system, stages IB and II did not differ significantly in terms of overall survival (OS) and cause-specific survival (CSS) (P = 0.928 and 0.872, respectively). On the basis of the above results, we reclassified T1a, T1b, and T2 into several subgroups. According to the modified AJCC eighth edition staging system, OS and CSS among the five groups of patients differed significantly. For OS predication, the Akaike information criterion values for the AJCC seventh, eighth, and modified eighth edition staging systems were 29,288.24, 29,282.85, and 27,182.21, respectively, and the c-indices for the AJCC seventh, eighth, and modified eighth edition staging systems were 0.5716, 0.5805, and 0.6082, respectively. Regarding CSS, the Akaike information criterion values for the AJCC seventh, eighth, and modified eighth edition staging systems were 21,701.11, 21,682.12, and 20,313.26, respectively, and the c-indices for the AJCC seventh, eighth, and modified eighth edition staging systems were 0.5983, 0.6117, and 0.6436, respectively. CONCLUSIONS: This is the first large-scale validation of the AJCC eighth edition staging system for patients undergoing hepatectomy. Our study revealed that there was a lack of discrepancy in the outcomes for stage IB and II tumors for AJCC eighth edition staging system of HCC. Our modified AJCC eighth edition staging system allows for finer stratification of patients undergoing hepatectomy according to more detailed tumor size and vascular invasion classifications. PMID- 29273377 TI - Incidence and risk factors associated with a high comprehensive complication index score after splenectomy in cirrhotic patients with hypersplenism. AB - BACKGROUND: Postoperative complications after splenectomy are not rare and can be serious in cirrhotic patients. The purpose of this study was to assess postoperative complications using the comprehensive complication index (CCI) after splenectomy in cirrhotic patients and identify risk factors for those who developed a high postoperative CCI score. MATERIALS AND METHODS: This retrospective study included 208 adult patients with viral hepatitis-related cirrhosis, who underwent elective splenectomy at our hospital from January 2002 to June 2012. The primary outcome was the CCI score. A CCI score >30 was considered to be a high CCI score. RESULTS: The median CCI score in this cohort was 25.6 (range: 8.7-62.9), and 66 patients (31.7%) had a CCI score >30. Univariable and multivariable analyses showed that the risk factors independently associated with a high CCI score were a history of hypertension and a model for end-stage liver disease (MELD) score >=10 prior to splenectomy. CONCLUSIONS: A high CCI score is common in cirrhotic patients undergoing splenectomy. The CCI is a useful grading system to assess postoperative morbidity in cirrhotic patients undergoing splenectomy. Preoperative blood pressure control is recommended and cirrhotic patients with an elevated MELD score should consider other treatment options for hypersplenism. PMID- 29273378 TI - Safety and efficacy of preoperative abdominal Aortic balloon occlusion in placenta increta and/or percreta. AB - BACKGROUND: With the increase of cesarean deliveries globally, the incidence of placenta adhesive disorder has been on the rise greatly which is associated closely with maternal and infant morbidity and mortality. We sought to investigate the safety and efficacy of preoperative transfemoral balloon occlusion of abdominal aorta in cesarean section of women with placenta increta or percreta. METHODS: We conducted a retrospective study of 31 patients with placenta increta or percreta diagnosed by ultrasound and/or magnetic resonance imaging. The observation group included 19 patients who received transfemoral abdominal aorta balloon occlusion for preoperative prophylaxis, while the other 12 patients in the control group did not receive any preoperative interventional managements. Clinical outcomes were compared between the two groups. RESULTS: Patients in observation group had significantly less estimated blood loss during surgery than those in control group (1.2 L versus 3.15 L, P = 0.006). The average transfusion volume of the observation group was significantly lower than the control group (0.8 L versus 1.95 L, P = 0.017). Seventy-nine percent (15 of 19) patients in the observation group and 50% (6 of 12) in the control group had their uterus successfully retained (P = 0.093). No peripheral tissues including bladder, ureter, and bowel were injured in all patients. Neonatal weight and Apgar scores of 1 min and 5 min had no statistical difference (P = 0.513 and P = 1, respectively) between the two groups. The mean radiation exposure time of fetus in the observation group was 22.68 +/- 8.07 s and mean radiation exposure dose was 4.20 +/- 1.49 mGy. Both operation time and postoperative hospital stay had no statistical difference between the two groups (2 versus 2.75 h, P = 0.063; 7.0 versus 6.5 d, P = 0.846). No patients had long-term complications after 6-8 wk follow-up. CONCLUSIONS: Application of preoperative transfemoral abdominal aorta balloon occlusion during cesarean section is a safe and effective strategy for patients with placenta increta and/or percreta. It could reduce intraoperative blood loss and enhance the possibility of uterus preservation and ensure the safety of life from severe complications. PMID- 29273379 TI - AK03, a new recombinant fibrinogenase prevents abdominal adhesions in a rat model without systemic side effects. AB - BACKGROUND: Abdominal adhesions are one of the most common complications after abdominal surgery, and fibrin is suspected to be a crucial component. The aim of the current study was an in vivo evaluation of a new recombinant fibrinogenase (AK03) in two animal models. METHODS: Sixty-four rats were randomly divided into four groups (sodium chloride [NaCl], icodextrin, AK03 low dose, and AK03 high dose) and evaluated at two time endpoints. Adhesion model comprised both a visceral defect (terminal ileum) and parietal defect. Test (AK03) and control substances (NaCl and icodextrin) were administered intraperitoneally after setting the intraabdominal defects. A second dose was administered 24 h after surgery. Plasma fibrinogen values were taken at baseline and after 7 and 21 d, respectively. Rats were sacrificed after 7 or 21 d for macroscopic (Diamond score) and immunohistochemical investigations. RESULTS: After 7 and 21 d, the Diamond score of postsurgical adhesions were significantly lower in both AK03 treated groups compared with NaCl control group (P = 0.02). There were no unspecific systemic side effects in both treatment groups and no decrease in plasma fibrinogen concentration. In none of the four groups was there any evidence for impaired wound repair. Microscopically in the area of the parietal defect, we saw less cluster of differentiation 3+ T-lymphocytes and cluster of differentiation 68+ macrophages in both groups receiving AK03 compared with the NaCl and icodextrin control groups. CONCLUSIONS: The results of this study indicate that the new recombinant fibrinogenase AK03 effectively prevents peritoneal adhesions without causing side effects, notably systemic fibrinogen depletion, bleeding, or impaired wound repair. Due to these results, future clinical studies may be promising. PMID- 29273380 TI - Tumor-associated macrophages correlate with phenomenon of epithelial-mesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients. AB - BACKGROUND: Tumor-associated macrophages (TAMs) are associated with poor outcomes in multiple solid cancers and play important roles in cancer progression. Epithelial-mesenchymal transition (EMT) may account for metastasis and recurrence. However, the association between TAMs and EMT is not clarified in triple-negative breast cancer (TNBC). The aim of this study was to investigate the effects of TAMs on EMT in TNBC. MATERIAL AND METHODS: We studied specimens from 278 patients with TNBC. TAMs marker cluster of differentiation 163 and EMT related marker E-cadherin were detected by immunohistochemistry in TNBC tissues, and their clinical significance was evaluated from the patients' medical records. RESULTS: TNBC patients with polarized cluster of differentiation 163+ TAMs infiltration and low level of E-cadherin had a significantly higher risk of aggressive features, including recurrence, histologic differentiation, and lymph node metastasis. Infiltration of TAMs was also negatively correlated with E cadherin in TNBC tissues. Multivariate analysis indicated that infiltration of TAMs and low expression of E-cadherin were independent prognostic factors of overall survival and disease-free survival in TNBC patients. CONCLUSIONS: High infiltration of TAMs was associated with low expression of E-cadherin and could be used as an unfavorable prognostic factor for patients with TNBC. PMID- 29273381 TI - A Filippov model describing the effects of media coverage and quarantine on the spread of human influenza. AB - Mass-media reports on an epidemic or pandemic have the potential to modify human behaviour and affect social attitudes. Here we construct a Filippov model to evaluate the effects of media coverage and quarantine on the transmission dynamics of influenza. We first choose a piecewise smooth incidence rate to represent media reports being triggered once the number of infected individuals exceeds a certain critical level [Formula: see text] . Further, if the number of infected cases increases and exceeds another larger threshold value [Formula: see text] ( [Formula: see text] ), we consider that the incidence rate tends to a saturation level due to the protection measures taken by individuals; meanwhile, we begin to quarantine susceptible individuals when the number of susceptible individuals is larger than a threshold value Sc. Then, for each susceptible threshold value Sc, the global properties of the Filippov model with regard to the existence and stability of all possible equilibria and sliding-mode dynamics are examined, as we vary the infected threshold values [Formula: see text] and [Formula: see text] . We show generically that the Filippov system stabilizes at either the endemic equilibrium of the subsystem or the pseudoequilibrium on the switching surface or the endemic equilibrium [Formula: see text] depending on the choice of the threshold values. The findings suggest that proper combinations of infected and susceptible threshold values can maintain the number of infected individuals either below a certain threshold level or at a previously given level. PMID- 29273383 TI - SEEG-guided radiofrequency thermocoagulation. AB - We propose expert recommendations on the use of SEEG-guided radiofrequency thermocoagulation (RF-TC) based on an exhaustive literature review. This technique consists in performing a RF-TC lesion using a SEEG depth electrode at the end of the recording. It is indicated when conventional surgical resection of the ictal onset zone is not possible. SEEG guided RF-TC can also be considered as a diagnostic tool since an improvement, even limited, has a high positive predictive value concerning the good outcome after surgery. It is possible to perform SEEG only in the purposes of performing RF-TC. An over-implantation of the presumed ictal onset zone is possible when such a procedure is planned. The RF-TC target should only be defined based on the ictal activity, except when a type II focal cortical dysplasia electrophysiological interictal signature is recorded. A single or multiple coagulations should always be performed between contiguous electrode contacts. The power delivered by the generator should be increased until the impedance suddenly changes, which indicates that the thermocoagulation has occurred. The procedure should be performed under clinical monitoring without anesthesia and after systematically testing neurological functions by electric stimulation on each target. Multiple SEEG-guided RF-TC can be proposed in a single patient, for example, in cases of relapse after a previous effective procedure. Conventional resection surgery remains feasible after a RF-TC procedure. PMID- 29273382 TI - Abeta oligomer eliminating compounds interfere successfully with pEAbeta(3-42) induced motor neurodegenerative phenotype in transgenic mice. AB - Currently, there are no causative or disease modifying treatments available for Alzheimer's disease (AD). Previously, it has been shown that D3, a small, fully d enantiomeric peptide is able to eliminate low molecular weight Abeta oligomers in vitro, enhance cognition and reduce plaque load in AD transgenic mice. To further characterise the therapeutic potential of D3 towards N-terminally truncated and pyroglutamated Abeta (pEAbeta(3-42)) we tested D3 and its head-to-tail tandem derivative D3D3 both in vitro and in vivo in the new mouse model TBA2.1. These mice produce human pEAbeta(3-42) leading to a strong, early onset motor neurodegenerative phenotype. In the present study, we were able to demonstrate 1) strong binding affinity of both D3 and D3D3 to pEAbeta(3-42) in comparison to Abeta(1-42) and 2) increased affinity of the tandem derivative D3D3 in comparison to D3. Subsequently we tested the therapeutic potentials of both peptides in the TBA2.1 animal model. Truly therapeutic, non-preventive treatment with D3 and D3D3 clearly slowed the progression of the neurodegenerative TBA2.1 phenotype, indicating the strong therapeutic potential of both peptides against pEAbeta(3 42) induced neurodegeneration. PMID- 29273384 TI - Surgical technique. AB - In SEEG, as for any surgical procedure, the benefit/risk ratio is a key-point. This implies rigorous clinical practice in terms of indication, information delivered to the patient, and surgical technique. Numerous technical options may be used to achieve this goal. All are valuable, as long as they are executed with rigor and consistency. Intracranial bleeding represents the main risk of the procedure (1-4% of cases). The procedure also carries a risk of infection (0.8%), death (total of 6 reported cases in all the literature, <0.002%), and of minor and transient side effects. SEEG is performed under general anesthesia. MRI is the gold standard morphological imaging, used for targeting and for trajectory calculations. It is strictly necessary to use some form of vascular imaging to minimize the peroperative bleeding risk. SEEG can be performed on a frame-based, or frameless, basis, using stereotactic instrumentation, or a neurosurgical robot. Literature does not provide any data in favour of one of these techniques compared to the other. The minimal acceptable bone thickness is considered to be 2mm. Postoperatively, as soon as any non-preexisting neurological deficit is noticed, neuroimaging must immediately be performed. It is recommended to perform a postoperative imaging during the 24hours after implantation. The numerous current possibilities, in terms of imaging and technology, give rise to many possible stereotactic strategies for performing SEEG implantation. None of these strategies can be considered as superior to the other. The guarantee of the best possible result is provided by the care with which these procedures are done. PMID- 29273385 TI - Glycosaminoglycan fragments as a measure of disease burden in the mucopolysaccharidosis type I mouse. AB - Glycosaminoglycan (GAG) catabolism involves endo-hydrolysis of polysaccharides followed by the sequential removal of the non-reducing end residue from the resulting oligosaccharides by exo-enzymes. In the inherited metabolic disorder, mucopolysaccharidosis type I (MPS I), a deficiency in the exo-enzyme, alpha-l iduronidase, prevents removal of alpha-l-iduronic acid residues from the non reducing end of the GAGs, heparan sulphate (HS) and dermatan sulphate (DS). The excretion of partially degraded HS and DS in urine of MPS I patients has long been recognized, but the question of whether they do indeed reflect GAG load in a particular tissue has not been addressed - an important issue in the context of biomarkers for assessment of disease burden in MPS I. Therefore, we measured specific low molecular weight HS and DS oligosaccharides with terminal alpha-l iduronic acid residues, in the brain, liver, kidney, serum and urine, and correlated these findings with total GAG in the MPS I mouse model. Six oligosaccharides were identified in the urine, ranging from di- to pentasaccharides. Of these, five were observed in the kidney, four in the liver and brain, with the three most abundant in urine also seen in serum. These oligosaccharides accounted for just 0.1-2% of total GAG, with a disaccharide showing the best correlation with total GAG. The oligosaccharides and total GAG were most abundant in the liver, with the least observed in the brain. The concentration of oligosaccharides as a percentage of total GAG in urine was similar to that observed in the kidney, and both revealed a similar ratio of HS:DS, suggesting that the oligosaccharide storage pattern in urine is a reflection of that in the kidney. Serum, liver and brain had a similar ratio of HS:DS, which was lower to that seen in the urine and kidney. The distribution of oligosaccharides when ranked from most to least abundant, was also the same between serum, liver and brain suggesting that serum more closely reflects the oligosaccharides of the brain and liver and may therefore be a more informative measurement of disease burden than urine. The accumulation of HS and DS oligosaccharides was observed in the brain as early as one month of age, with the disaccharide showing a continuous increase with age. This demonstrates the progressive nature of the disease and as such this disaccharide could prove to be a useful biomarker to measure disease burden in MPS I. PMID- 29273386 TI - Total shoulder arthroplasty with minimum 5-year follow-up: does the presence of subchondral cysts in the glenoid increase risk of failure? AB - BACKGROUND: This study evaluated the effect of cystic changes in the glenoid on postoperative outcomes and implant survival after total shoulder arthroplasty (TSA). MATERIALS AND METHODS: From 2004 to 2012, 75 patients underwent TSA for primary osteoarthritis with minimum 5-year follow-up. Preoperative 3-dimensional models based on computed tomography imaging were created for all patients. A qualitative evaluation of cystic osteoarthritis was performed through survey grading by 3 fellowship-trained shoulder surgeons. The extent of cyst formation in the glenoid (no cysts, small, medium, or large) was assigned for every patient. In addition, quantitative evaluation was performed on 3-dimensional glenoid models. Functional outcomes, radiographic findings, and the need for revision were compared between group 1 (large and medium cysts) and group 2 (small and no cysts). RESULTS: Qualitative evaluation of cyst formation resulted in the following distribution: no cysts in 8 patients (11%), small cyst formation in 27 (36%), medium cysts in 19 (25%), and large cysts in 21 patients (28%; kappa = 0.605). The difference in total cyst volume between group 1 and group 2 was significant (P = .004). The overall revision rate was 7% (5 of 75). All revised patients were in the groups with medium or large cysts. There were no statistical differences in American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder Assessment scores or presence of radiographic loosening among the study groups. CONCLUSION: Qualitative computed tomography evaluation of cystic osteoarthritis correlates with quantitative analysis of cyst volume. Severe cyst formation portends a higher risk of failure at midterm follow-up. Cystic disease did not affect functional outcome or the presence of radiographic glenoid loosening. PMID- 29273387 TI - Experience and volume are determinantive factors for operative management of supracondylar humeral fractures in children. AB - BACKGROUND: We compared radiographic and operative results of pediatric patients undergoing surgical treatment of displaced supracondylar humeral fracture (SCHF) according to the surgeon's experience. METHODS: During an 11-year period (2006 2016), we reviewed the medical records of 236 patients operated on for Gartland III SCHF in our institution. Operative (operative time, time to implants removal) and radiographic parameters (Baumann and lateral capitellohumeral angles) were assessed. A malalignment was defined if there was a difference in the Baumann angle or lateral capitellohumeral angles >15 degrees or if malrotation existed compared with normative values. We compared surgeon experience and volume (number of patients operated on by year). RESULTS: In patients operated on by less experienced surgeons (<1 year, n = 69), operative time (61 vs. 41 minutes) and time to implant removal (48 vs. 40 days) were significantly longer (P < .001). Radiographic parameters did not differ between less and more experienced surgeons. Operative parameters improved through the 20 first cases of the younger surgeons. In surgeons managing fewer than 5 patients per year, malalignment and conversion to open reduction were more frequent (all P < .05). CONCLUSION: Experience and volume are 2 crucial parameters influencing the quality of management of pediatric patients undergoing surgical treatment for displaced SCHF. They should be taken into account in daily practice, especially when making the decision to operate on these patients out of day time. PMID- 29273388 TI - Assessing glenosphere position: superior approach versus deltopectoral for reverse shoulder arthroplasty. AB - BACKGROUND: The anterosuperior (AS) approach for reverse total shoulder arthroplasty (RTSA) has been reported as a risk factor for baseplate malposition because of potential difficulty in glenoid exposure. The objective of this study was to compare glenoid baseplate position between the AS and deltopectoral (DP) approaches in relation to the surgeon's experience and to evaluate the effect of placement on clinical outcomes. METHODS: There were 109 shoulders that underwent RTSA for cuff tear arthropathy or osteoarthritis with cuff tearing by a single surgeon. The AS approach was used in 87 shoulders. Clinical, radiographic, and functional outcomes were assessed for all patients with a minimum of 2 years of follow-up. Initial postoperative radiographs of all 109 shoulders were assessed for baseplate positioning. RESULTS: The mean change in glenoid inclination was 3.0 degrees inferior with the AS approach and 2.5 degrees inferior with the DP approach (P = .68). Pain scores (P = .14), range of motion, and American Shoulder and Elbow Surgeons scores (P = .16) improved in both groups, without a difference between approach. Scapular notching was noted in 68.5% of AS shoulders and 72.4% of DP shoulders (P = .78). Over time, there was a trend to place the glenoid baseplate more caudal with less inferior tilt. DISCUSSION AND CONCLUSION: Both approaches produce similar baseplate position, clinical outcomes, and rates of scapular notching when they are used for RTSA. Attempts to inferiorize the glenoid baseplate through the AS approach may increase the risk of superior inclination. PMID- 29273389 TI - Surgery for the fractured clavicle: factors predicting nonunion. AB - BACKGROUND: This study identifies the reasons for failure after plate osteosynthesis of midshaft clavicle fractures, complication rates, and time to radiographic union. METHODS: A retrospective review of 84 consecutive patients who had undergone surgical fixation for a midshaft clavicle fracture was performed. RESULTS: There were 82 patients who were included for analysis and operated on by 11 different surgeons using a mixture of locking (63%) and nonlocking (37%) plates. The rate of osteosynthesis failure was 12.2%. A logistical regression analysis found that failure of osteosynthesis had no relationship to type of plate used (P = .82), gender (P = .42), number of proximal (P = .96) or distal (P = .63) screws to the fracture, or length of plate (P = .42). Smoking was found to be the only risk factor (P = .02) that increased failure rates after midshaft clavicle osteosynthesis. CONCLUSION: Smoking was the only identifiable risk factor to increase failure rates in clavicle osteosynthesis. Preoperative counseling can identify those at increased risk of implant failure and can help improve clinical results by implementing a smoking cessation plan. PMID- 29273391 TI - Acanthamoeba in the eye, can the parasite hide even more? Latest developments on the disease. AB - Acanthamoeba spp. is a free living protozoan in the environment, but can cause serious diseases. Acanthamoeba keratitis (AK), a severe and painful eye infection, must be treated as soon as possible to prevent ulceration of the cornea, loss of visual acuity, and eventually blindness or enucleation. Although the disease affects principally contact lens (CLs) wearers, it is recognized nowadays as a cause of keratitis also in non-CLs wearers. Although the number of infections caused by these amoebae is low, AK is an emerging disease presenting an extended number of cases each year worldwide mostly due to the increasing use of CLs, but also to better diagnostic methods and awareness. There are two principal causes that lead to severe outcomes: misdiagnosis or late diagnosis of the causal agent, and lack of a fully effective therapy due to the existence of a highly resistant cyst stage of Acanthamoeba. Recent studies have reported different genotypes that have not been previously associated with this disease. In addition, Acanthamoeba can act as a reservoir for phylogenetically diverse microorganisms. In this regard, recently giant viruses called Pandoravirus have been found within genotypes producing keratitis. What potential risk this poses is not yet known. This review focuses on an overview of the present status and future prospects of this re-emerging pathology, including features of the parasite, epidemiology, clinical aspects, diagnosis, and treatment. PMID- 29273390 TI - Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial. AB - OBJECTIVES: Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established. DESIGN, MATERIALS, METHODS: The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss. RESULTS: In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 +/- 0.21 (mean +/- SD) for those with CLI versus 0.63 +/- 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI. CONCLUSIONS: Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822. PMID- 29273392 TI - Corrigendum to "pH-triggered chitosan nanogels via an ortho ester-based linkage for efficient chemotherapy" [Acta Biomater. 60 (2017) 232-243]. PMID- 29273394 TI - STING, DCs and the link between innate and adaptive tumor immunity. AB - Cancer and the immune system are intimately related. Much of the bulk of tumors is comprised of stromal leukocytes with immune functions, which serve to both promote and inhibit tumor growth, invasion and metastasis. The T lymphocytes of the adaptive immune system are essential for tumor immunity, and these T cells are generated by cross-priming against tumor associated antigens. Dendritic cells (DCs) are essential in this process, serving as the cellular link between innate and adaptive immunity. As a prerequisite for priming of adaptive immune responses, DCs must take up tumor antigens, process them and present them in the context of the major histocompatibility complex (MHC). DCs also serve as sensors of innate activation signals from cancer that are necessary for their activation and effective priming of cancer specific T cells. Here we discuss the role of DCs in the sensing of cancer and in priming the adaptive response against tumors. Furthermore, we present the essential role of the Stimulator of Interferon Genes (STING) signaling pathway in producing type I interferons (IFNs) that are essential in this process. PMID- 29273395 TI - Hybrid peptide-small molecule oxytocin analogs are potent and selective agonists of the oxytocin receptor. AB - Oxytocin (OT) is a peptide hormone agonist of the oxytocin receptor (OTR) that has been proposed as a therapeutic to treat a number of social and emotional disorders in addition to its current clinical use to induce labor and treat postpartum bleeding. OT is administered intravenously and intranasally rather than orally, in part because its low passive permeability causes low oral bioavailability. Non-peptidic OTR agonists have also been reported, but none with the exquisite potency of the peptide based agonists. In this report, we describe the OTR agonist activity and exposed polarity of a set of truncated OT analogs as well as hybrid peptide-small molecule analogs of OT. Examples of both truncated analogs and peptide-small molecule hybrid analogs are potent and selective OTR agonists. Hybrid agonist 13, which is 232 Da smaller than OT, still retains subnanomolar potency, full agonist activity, and selectivity over V1a. While these compounds were designed to address the low permeability of OT and other full length analogs, we found that reduction in molecular weight and the removal or replacement of the three amino acid tail of OT did not have a significant effect on passive permeability. PMID- 29273393 TI - Macrophages: Key orchestrators of a tumor microenvironment defined by therapeutic resistance. AB - Macrophages have emerged as promising therapeutic targets in cancer. Within tumor tissue, macrophages foster tumor development, invasion, and metastasis. As the phenotype of macrophages is inherently pliable and dependent on cues received from the surrounding microenvironment, macrophages co-evolve with malignant and other non-malignant cells during cancer progression. In doing so, they establish a microenvironment that is therapeutically resistant and thwarts the productivity of T cell immunosuveillance. Strategies designed to deplete, inhibit, or redirect macrophages with anti-tumor activity are being explored to reverse the pro-tumor properties of macrophages that are commonly observed in cancer. In this review, we discuss our current understanding of the mechanisms that regulate macrophage recruitment to tumors, their impact on the tumor microenvironment, and their promise as therapeutic targets for improving the efficacy of cytotoxic- and immune-based therapies. PMID- 29273396 TI - Spyglass-guided pancreatic stent placement for intraductal papillary mucinous neoplasm with recurrent pancreatitis. PMID- 29273398 TI - Long-term RF exposure on behavior and cerebral glucose metabolism in 5xFAD mice. AB - Given the increased public concern about the deleterious biological consequences of radiofrequency electromagnetic fields (RF-EMFs), the involvement of RF-EMFs in neurodegenerative diseases, especially Alzheimer's disease (AD), has received increased consideration. To investigate the effect of long-term RF-EMF exposure on AD progression, we exposed 5xFAD mice to 1950 MHz RF-EMF at a specific absorption rate of 5.0 W/kg for 2 h/day and 5 days/week for 8 months. Behavioral changes were assessed by an open field test and an object recognition memory task after RF exposure was terminated. In addition, cerebral glucose metabolism was analyzed in the brains of the 5xFAD mice using 18F-deoxyglucose positron emission tomography. The hyperactivity-like and anxiolytic behaviors of the 5xFAD mice in open field tests were rescued by RF exposure. Furthermore, long-term RF-EMF exposure improved the cognitive deficits of 5xFAD mice that were observed in the object recognition memory test. Consistent with the behavioral changes, glucose metabolism in the hippocampus and amygdala regions of the brains of 5xFAD mice following RF exposure was significantly increased compared to glucose metabolism in the brains of sham-exposed mice. These data suggest that long-term exposure to RF-EMF might exert beneficial effects on AD in 5xFAD mice. PMID- 29273397 TI - Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition. AB - Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called alpha-synuclein. Accumulations of alpha-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of dopaminergic neurons and reduced activation of microglial cells. Taken together, here we demonstrate that histone acetylation is disease-dependently altered in PD, likely due the effects of dopaminergic neurodegeneration and microglial infiltration; yet SIRT 2 remains relatively unaltered with disease. Given the stable nature of SIRT 2 expression with disease and the effects of SIRT 2 inhibitor treatment on degenerating dopaminergic neurons and activated microglia detected in vitro, SIRT 2 inhibitors warrant further investigation as potential therapeutics for the treatment of the PD. PMID- 29273399 TI - Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome. AB - Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150Glued. The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein. To test the hypothesis that the G71A mutation in the DCTN1 gene is sufficient to cause Perry syndrome, we generated DCTN1G71A transgenic mice. These mice initially developed normally, but young animals showed decreased exploratory activity and aged animals showed impaired motor coordination. These behavioral defects parallel apathy-like symptoms and parkinsonism encountered in Perry syndrome. TDP-43 aggregates were not detected in the substantia nigra and cerebral cortex of the transgenic mice, although pathological aggregates of TDP 43 have been considered a major neuropathological feature of Perry syndrome. Our study reveals that a single mutation in the DCTN1 gene recapitulates symptoms of Perry syndrome patients, and provides evidence that DCTN1G71A transgenic mice represent a novel rodent model of Perry syndrome. PMID- 29273400 TI - NRF2/HO-1 activation via ERK pathway involved in the anti-neuroinflammatory effect of Astragaloside IV in LPS induced microglial cells. AB - The anti-neuroinflammatory effect of Astragaloside IV (ASI) has been reported, but its underlying mechanisms are unclear. This study is further to explore the underlying mechanism of ASI on anti-neuroinflammatory effect in LPS induced microglia cells. The result showed ASI significantly reduced the production of inflammatory mediators NO, TNF-alpha and IL-6 in BV2 and primary microglial cells. Western blot analysis showed ASI did not inhibit the MAPK activation, on the contrary, the results showed ASI can obviously induce the ERK activation. We also examined the NRF2 and HO-1 activation which were reported to exert anti neuroinflammatory effect and the results presented it could induce the activation of HO-1 downstream NRF2 in BV2 microglial cells. Further study indicated the NRF2/HO-1 activation via ERK pathway activation. After NRF2 siRNA or HO-1 inhibitor treatment, the anti-neuroinflammatory effect of ASI was attenuated obviously compared with the normal group. Taken together, this study demonstrated that the activation of NRF2/HO-1 via ERK signaling pathway is a novel mechanism of ASI which exerted anti-neuroinflammatory activity in microglia cells, it could be an attractive candidate for the regulation of inflammatory responses in the brain. PMID- 29273401 TI - Effect of streptozotocin-induced diabetes on motor representations in the motor cortex and corticospinal tract in rats. AB - Motor disorders in patients with diabetes are associated with diabetic peripheral neuropathy, which can lead to symptoms such as lower extremity weakness. However, it is unclear whether central motor system disorders can disrupt motor function in patients with diabetes. In a streptozotocin-induced rat model of type 1 diabetes, we used intracortical microstimulation to evaluate motor representations in the motor cortex, recorded antidromic motor cortex responses to spinal cord stimulation to evaluate the function of corticospinal tract (CST) axons, and used retrograde labeling to evaluate morphological alterations of CST neurons. The diabetic rats exhibited size reductions in the hindlimb area at 4 weeks and in trunk and forelimb areas after 13 weeks, with the hindlimb and trunk area reductions being the most severe. Other areas were unaffected. Additionally, we observed reduced antidromic responses in CST neurons with axons projecting to lumbar spinal segments (CST-L) but not in those with axons projecting to cervical segments (CST-C). This was consistent with the observation that retrograde labeled CST-L neurons were decreased in number following tracer injection into the spinal cord in diabetic animals but that CST-C neurons were preserved. These results show that diabetes disrupts the CST system components controlling hindlimb and trunk movement. This disruption may contribute to lower extremity weakness in patients. PMID- 29273402 TI - An algorithm for the classification of mRNA patterns in eosinophilic esophagitis: Integration of machine learning. AB - BACKGROUND: Diagnostic evaluation of eosinophilic esophagitis (EoE) remains difficult, particularly the assessment of the patient's allergic status. OBJECTIVE: This study sought to establish an automated medical algorithm to assist in the evaluation of EoE. METHODS: Machine learning techniques were used to establish a diagnostic probability score for EoE, p(EoE), based on esophageal mRNA transcript patterns from biopsies of patients with EoE, gastroesophageal reflux disease and controls. Dimensionality reduction in the training set established weighted factors, which were confirmed by immunohistochemistry. Following weighted factor analysis, p(EoE) was determined by random forest classification. Accuracy was tested in an external test set, and predictive power was assessed with equivocal patients. Esophageal IgE production was quantified with epsilon germ line (IGHE) transcripts and correlated with serum IgE and the Th2-type mRNA profile to establish an IGHE score for tissue allergy. RESULTS: In the primary analysis, a 3-class statistical model generated a p(EoE) score based on common characteristics of the inflammatory EoE profile. A p(EoE) >= 25 successfully identified EoE with high accuracy (sensitivity: 90.9%, specificity: 93.2%, area under the curve: 0.985) and improved diagnosis of equivocal cases by 84.6%. The p(EoE) changed in response to therapy. A secondary analysis loop in EoE patients defined an IGHE score of >=37.5 for a patient subpopulation with increased esophageal allergic inflammation. CONCLUSIONS: The development of intelligent data analysis from a machine learning perspective provides exciting opportunities to improve diagnostic precision and improve patient care in EoE. The p(EoE) and the IGHE score are steps toward the development of decision trees to define EoE subpopulations and, consequently, will facilitate individualized therapy. PMID- 29273403 TI - Zika virus: An emerging infectious disease with serious perinatal and neurologic complications. AB - Zika virus (ZIKV) is a flavivirus that is primarily transmitted by Aedes aegypti, the mosquito vector also important in transmission of the flaviviruses responsible for dengue fever, yellow fever, and chikungunya. Because of occurrence in the same geographic regions, serologic cross-reactivity, and similar but often less severe clinical manifestations, such as dengue and chikungunya infections, ZIKV infection likely has gone undetected, misdiagnosed, or both for many years. ZIKV is somewhat unique among flaviviruses in its ability to also be transmitted through sexual contact, nonsexual body fluids, and perinatally. The relatively recent detection of the link between ZIKV infection and Guillain-Barre syndrome and fetal neurological defects, including microcephaly, has prompted intense efforts aimed at the development of new and specific diagnostic tests. Infection with ZIKV has been postulated to lead to a more severe clinical course from other structurally related viruses, especially dengue, and vice versa because of a phenomenon termed antibody-dependent enhancement. Inactivated whole virus, DNA, RNA, and vectored vaccine approaches to prevent ZIKV infection are in development, as are treatments for active disease that are safe in pregnant women. Here we summarize the important epidemiologic and clinical features of ZIKV infection, as well as the progress and challenges in developing rapid point-of-care diagnostic tests and vaccines to prevent disease. We used electronic databases to identify relevant published data regarding ZIKV MeSH searches. PMID- 29273404 TI - Superior Biochemical Recurrence and Long-term Quality-of-life Outcomes Are Achievable with Robotic Radical Prostatectomy After a Long Learning Curve-Updated Analysis of a Prospective Single-surgeon Cohort of 2206 Consecutive Cases. AB - BACKGROUND: Our earlier analysis suggested that robot-assisted radical prostatectomy (RARP) achieved superiority over open radical prostatectomy (ORP) in terms of positive surgical margin (PSM) rates and functional outcomes. OBJECTIVE: With larger sample size and longer follow-up, the objective of this study update is to assess whether our previous findings are upheld and whether the improved PSM rates for RARP after an initial learning curve compared with ORP as observed in our earlier analysis-ultimately resulted in improved biochemical control. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study comparing two surgical techniques; 2271 consecutive men underwent RARP (1520) or ORP (751) at a single centre from 2006 to 2016. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic and clinicopathological data were prospectively collected. The EPIC-QOL questionnaire was administered at baseline and 1.5, 3, 6, 12, and 24 mo. Multivariate linear regression modelled the difference in quality of life (QOL) domains against case number; logistic and Cox regression modelled the differences in PSM and biochemical recurrence (BCR) hazard ratios (HR), respectively. RESULTS AND LIMITATIONS: A total of 2206 men were included in BCR/PSM analysis and 1045 consented for QOL analysis. Superior pT2 surgical margins, early and late sexual outcomes, and early urinary outcomes were upheld and became more robust (narrowing of 95% confidence intervals [CIs]). The risk of BCR was initially higher for RARP, improved after 191 RARPs, and was 35% lower (hazard ratio [HR] 0.65, 95% CI 0.47-0.90) at final RARP, plateauing after 226 RARPs. Improved late (12-24 mo) urinary bother scores (adjusted mean difference [AMD]=4.7, 95% CI 1.3-8.0) and irritative-obstructive scores (AMD=3.8, 95% CI 0.9 5.6) at final RARP were demonstrated. Limitations include observational single surgeon data, possible residual confounding, and short follow-up. CONCLUSIONS: The results from this updated analysis demonstrate that RARP can be beneficial for patients of high-volume surgeons, although more randomised studies and studies with survival outcomes are needed. PATIENT SUMMARY: Robot-assisted radical prostatectomy was able to improve functional and oncological outcomes in this single surgeon's learning curve. PMID- 29273405 TI - Re: Molecular Classification of Urothelial Carcinoma: Global mRNA Classification Versus Tumour-cell Phenotype Classification. PMID- 29273406 TI - Re: Radical Cystectomy (Bladder Removal) Against Intravesical BCG Immunotherapy for High-risk Non-muscle Invasive Bladder Cancer (BRAVO): A Protocol for a Randomised Controlled Feasibility Study. PMID- 29273407 TI - Re: What Are We Missing? False-negative Cancers at Multiparametric MR Imaging of the Prostate. PMID- 29273408 TI - Prostate Artery Embolisation: Poor Design and Reporting Impact the Value of Current Systematic Reviews. PMID- 29273409 TI - Re: Active Surveillance in Younger Men with Prostate Cancer. PMID- 29273411 TI - Re: Bimal Bhindi, Igor Frank, Ross J. Mason, et al. Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis. Eur Urol 2017;72:660-4. PMID- 29273410 TI - Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens. AB - BACKGROUND: Patients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy have had few treatment options and uniformly poor outcomes. Atezolizumab (anti-programmed death-ligand 1) was approved in the USA for cisplatin-ineligible and platinum-treated mUC based on IMvigor210, a phase 2, single-arm, two-cohort study. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab by the number of prior lines of systemic therapy in patients with pretreated mUC. DESIGN, SETTING, AND PARTICIPANTS: IMvigor210 enrolled 315 patients with mUC with progression during or following platinum based therapy at 70 international sites between May 2014 and November 2014. Key inclusion criteria included age >=18 yr, creatinine clearance >=30ml/min, and Eastern Cooperative Oncology Group performance status 0-1, with no limit on prior lines of treatment. INTERVENTION: Patients in this cohort received atezolizumab 1200mg intravenously every 3 wk until loss of clinical benefit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Centrally assessed Response Evaluation Criteria In Solid Tumors v1.1 objective response rate (ORR), median duration of response, overall survival (OS), and adverse events were evaluated by prior treatment. Potential differences between subgroups were evaluated using log-rank (for OS) and chi-square (for ORR and adverse events frequencies) testing. RESULTS AND LIMITATIONS: Three hundred and ten patients were efficacy and safety evaluable (median follow-up, 21 mo). Objective responses and prolonged OS occurred across all prespecified subgroups; median duration of response was not reached in most subgroups. In patients without prior systemic mUC therapy (first line subgroup), ORR was 25% (95% confidence interval: 14-38), and median OS was 9.6 mo (95% confidence interval: 5.9-15.8). No significant differences in efficacy or toxicity by therapy line were observed. CONCLUSIONS: Atezolizumab demonstrated comparable efficacy and safety in previously treated patients with mUC across all lines of therapy evaluated. PATIENT SUMMARY: We investigated effects of previous treatment in patients with metastatic urothelial carcinoma that progressed after platinum-based therapy. Atezolizumab was active and tolerable no matter how many treatment regimens patients had received. ClinicalTrials.gov, NCT02108652. PMID- 29273413 TI - Two new bis-iridoids isolated from Scabiosa stellata and their antibacterial, antioxidant, anti-tyrosinase and cytotoxic activities. AB - This study presents the chemical profile investigation of a 70% ethanol extract obtained from Scabiosa stellata, a medicinal herbaceous traditionally used to treat heel cracks. A 13C NMR-based dereplication methodology was firstly applied on centrifugal partition chromatography-generated fractions in order to quickly identify the major compounds of the extract. The dereplication process was then completed by semi-preparative high-performance liquid chromatography in order to identify unknown or minor compounds. Two new bis-iridoids, namely 7-O-caffeoyl sylvestroside I (1) and 7-O-(p-coumaroyl)-sylvestroside I (2), together with ten known compounds (3-12) were isolated. Their structures were elucidated by spectroscopic methods including NMR and HR-ESI-MS. The antibacterial, anti tyrosinase and DPPH radical scavenging activities of the crude extract, fractions, and isolated compounds were evaluated. A significant antibacterial activity was observed for nine isolated compounds, particularly 1 and 2 which yielded MIC values of 31.2MUg/mL against Enterococcus faecalis and 62.5MUg/mL against Staphylococcus epidermidis. The cytotoxic activity of these new bis iridoids was evaluated on a fibrosarcoma cell line (HT1080) and only compound 1 exhibited a moderate cytotoxic activity (IC50 35.9MUg/mL). PMID- 29273412 TI - Versatility of microglial bioenergetic machinery under starving conditions. AB - Microglia are highly dynamic cells in the brain. Their functional diversity and phenotypic versatility brought microglial energy metabolism into the focus of research. Although it is known that microenvironmental cues shape microglial phenotype, their bioenergetic response to local nutrient availability remains unclear. In the present study effects of energy substrates on the oxidative and glycolytic metabolism of primary - and BV-2 microglial cells were investigated. Cellular oxygen consumption, glycolytic activity, the levels of intracellular ATP/ADP, autophagy, mTOR phosphorylation, apoptosis and cell viability were measured in the absence of nutrients or in the presence of physiological energy substrates: glutamine, glucose, lactate, pyruvate or ketone bodies. All of the oxidative energy metabolites increased the rate of basal and maximal respiration. However, the addition of glucose decreased microglial oxidative metabolism and glycolytic activity was enhanced. Increased ATP/ADP ratio and cell viability, activation of the mTOR and reduction of autophagic activity were observed in glutamine-supplemented media. Moreover, moderate and transient oxidation of ketone bodies was highly enhanced by glutamine, suggesting that anaplerosis of the TCA-cycle could stimulate ketone body oxidation. It is concluded that microglia show high metabolic plasticity and utilize a wide range of substrates. Among them glutamine is the most efficient metabolite. To our knowledge these data provide the first account of microglial direct metabolic response to nutrients under short-term starvation and demonstrate that microglia exhibit versatile metabolic machinery. Our finding that microglia have a distinct bioenergetic profile provides a critical foundation for specifying microglial contributions to brain energy metabolism. PMID- 29273414 TI - Bioactive chemical constituents of Duboscia macrocarpa Bocq., and X-ray diffraction study of 11beta, 12beta-epoxyfriedours-14-en-3alpha-ol. AB - A new gamma-lactone triterpenoid, Evodoulolide (1) and a new triterpenoid Duboscic acid B (2), along with five known compounds, maslinic acid (3), arboreic acid (4), (E)-3-(4-hydroxyphenyl)-N-[2-(4-hydroxyphenyl) ethyl] prop-2-enamide (5), (E)-heptacos-19-enoic acid (6) and 11beta,12beta-epoxyfriedours-14-en-3alpha ol (7) were isolated from the trunk wood of Duboscia macrocarpa. Their structures were elucidated from extensive 1D- and 2D-NMR and MS and by comparison of their spectra with published data. Compounds 1, 3, 5 and 6 exhibited significant alpha glucosidase inhibitory activity. Compound 5 was found to be a potent inhibitor (IC50=5.1+/-0.1MUM) of alpha-glucosidase as compared to acarbose (IC50=625.0+/ 1MUM) used as standard drug. These compounds did not show anti-glycation activity using the BSA-MG glycation model or inhibition against the alpha-chymotrypsin enzyme. The chemotaxonomic connotation of the isolated secondary metabolites is also herein described. The single-crystal X-ray and absolute configuration diffraction analysis of 11alpha, 12alpha-epoxyfriedours-14-en-3-ol (7) is also described here for the first time. PMID- 29273415 TI - Design, synthesis, and opioid activity of arodyn analogs cyclized by ring-closing metathesis involving Tyr(allyl). AB - Kappa (kappa) opioid receptor selective antagonists are useful pharmacological tools in studying kappa opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe1-3,Arg4,d-Ala8]Dyn A-(1-11)NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective kappa opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617-5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al. Eur J Pharmacol 2007;569:84-89). To restrict its conformational mobility, explore possible bioactive conformations and potentially increase its metabolic stability we synthesized cyclic arodyn analogs on solid phase utilizing a novel ring-closing metathesis (RCM) reaction involving allyl-protected Tyr (Tyr(All)) residues. This approach preserves the aromatic functionality and directly constrains the side chains of one or more of the Phe residues. The novel cyclic arodyn analog 4 cyclized between Tyr(All) residues incorporated in positions 2 and 3 exhibited potent kappa opioid receptor antagonism in the [35S]GTPgammaS assay (KB = 3.2 nM) similar to arodyn. Analog 3 cyclized between Tyr(All) residues in positions 1 and 2 also exhibited nanomolar kappa opioid receptor antagonist potency (KB = 27.5 nM) in this assay. These are the first opioid peptides cyclized via RCM involving aromatic residues, and given their promising pharmacological activity represent novel lead peptides for further exploration. PMID- 29273416 TI - Evaluation of 18F-labeled exendin(9-39) derivatives targeting glucagon-like peptide-1 receptor for pancreatic beta-cell imaging. AB - beta-cell mass (BCM) is known to be decreased in subjects with type-2 diabetes (T2D). Quantitative analysis for BCM would be useful for understanding how T2D progresses and how BCM affects treatment efficacy and for earlier diagnosis of T2D and development of new therapeutic strategies. However, a noninvasive method to measure BCM has not yet been developed. We developed four 18F-labeled exendin(9-39) derivatives for beta-cell imaging by PET: [18F]FB9-Ex(9-39), [18F]FB12-Ex(9-39), [18F]FB27-Ex(9-39), and [18F]FB40-Ex(9-39). Affinity to the glucagon-like peptide-1 receptor (GLP-1R) was evaluated with dispersed islet cells of ddY mice. Uptake of exendin(9-39) derivatives in the pancreas as well as in other organs was evaluated by a biodistribution study. Small-animal PET study was performed after injecting [18F]FB40-Ex(9-39). FB40-Ex(9-39) showed moderate affinity to the GLP-1R. Among all of the derivatives, [18F]FB40-Ex(9-39) resulted in the highest uptake of radioactivity in the pancreas 30 min after injection. Moreover, it showed significantly less radioactivity accumulated in the liver and kidney, resulting in an overall increase in the pancreas-to-organ ratio. In the PET imaging study, pancreas was visualized at 30 min after injection of [18F]FB40 Ex(9-39). [18F]FB40-Ex(9-39) met the basic requirements for an imaging probe for GLP-1R in pancreatic beta-cells. Further enhancement of pancreatic uptake and specific binding to GLP-1R will lead to a clear visualization of pancreatic beta cells. PMID- 29273417 TI - An appraisal on synthetic and pharmaceutical perspectives of pyrazolo[4,3 d]pyrimidine scaffold. AB - Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956. PMID- 29273418 TI - Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression. AB - In this study we investigated the protective effects and possible mechanisms of pirfenidone (PF) in paraquat (PQ)-induced lung injury and fibrosis in mice. Lung injury was induced by injection of PQ (20 mg/kg). Thereafter, mice orally received water and PF (100 and 200 mg/kg) for four weeks. After 28 days, the inflammation and fibrosis were determined in the lungs by analysis of histopathology, bronchoalveolar lavage fluid (BALF) cell count, lung wet/dry weight ratio, hydroxyproline content, and oxidative stress biomarkers. Expression of several genes involved in fibrogenesis and modulation of reactive oxygen species (ROS) production, such as TGF-beta1, alpha-SMA, collagen Ialpha and IV, NOX1, NOX4, iNOS, and GPX1 were determined using RT-qPCR. PF significantly decreased the lung fibrosis and edema, inflammatory cells infiltration, TGF-beta1 concentration, and amount of hydroxyproline in the lung tissue. PF dose dependently improved the expression level of the studied genes to the near normal. Decreasing of lung lipid peroxidation and catalase activity, and increasing of SOD activity in the treated mice were significant compared to the control group. Pirfenidone ameliorate paraquat induced lung injury and fibrosis partly through inhibition of inflammation and oxidative stress, and downregulation of genes encoding for profibrotic cytokines and enzymatic systems for ROS production. PMID- 29273419 TI - Development and use of microbial-based cleaning products (MBCPs): Current issues and knowledge gaps. AB - Cleaning products containing microbes as active ingredients are becoming increasingly prevalent as an alternative to chemical-based cleaning products. These microbial-based cleaning products (MBCPs) are being used in domestic and commercial settings (i.e., households and businesses) and institutional settings (e.g., hospitals, schools, etc.), in a variety of cleaning activities (hard surface cleaning, odour control, degreasing, septic tank treatments, etc.). They are typically described as "environmentally friendly" and "non-toxic". Publicly available information sources (scientific literature, patent databases, commercial websites) were searched for information on microbial species contained in MBCPs, their mode of action, cleaning applications in which they are used, and their potential impacts on human health and the environment. Although information was found providing a broad indication of microbial genera/species used, information on specific species/strains and quantities produced and sold is generally lacking. This makes it difficult to conduct a meaningful examination of any risks to human health and the environment from the production and use of MBCPs and to determine how effective current policies and regulatory frameworks are in addressing these issues. These and other challenges were addressed at an international workshop in Ottawa, Canada in June 2013 by a number of stakeholders, including industry, government, academic and non-governmental organizations. PMID- 29273420 TI - Allergens of permanent hair dyes induces epidermal damage, skin barrier loss and IL-1 alpha increase in epidermal in vitro model. AB - Allergic and irritant skin reactions caused by topical exposure to permanent hair dyes are a common problem. For regulatory and ethnical purposes, it is required to perform chemical safety assessment following the replacement, reduction, and refinement of animal testing (3Rs). Permanent hair dyes are formed by a mixture of ingredients that vary from low to extreme skin sensitizing potency and that inter-react to form unknown by-products. Because of the complex reaction, this cytotoxic mechanism has not yet been elucidated and is the subject of this study. Here, we topically exposed p-phenylenediamine (PPD), Resorcinol (RES), Hydrogen Peroxide (H2O2) alone or as a mixture to RhE and evaluated parameters related to skin irritation such as epidermal viability, keratinocytes damage, barrier loss and IL-1 alpha. Our data indicates that ingredients tested alone did not lead to an increase of cytotoxic parameters related to skin irritation. However, when the mixture of PPD/H2O2/RES and PPD/H2O2 was applied to the RhE, some of the parameters such as morphological changes including the presence of apoptotic cells, barrier loss and increased IL- 1 alpha release were observed. The results indicate that the mixture of ingredients used in permanent hair dyes have an irritant effect in RhE while the ingredients alone not. PMID- 29273421 TI - Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis. AB - BACKGROUND: Knowledge of between-session variability of nitrogen multiple-breath washout (N2MBW) indices is crucial when designing longitudinal interventional studies and in disease monitoring using N2MBW as end-point. Such information is currently sparse. METHODS: Monthly triplets of N2MBW were prospectively obtained from 14 children with CF during one year. Linear mixed models were used to analyze variability. Our aim was to assess between-session variability of N2MBW indices from repeated measurements and compare LCI derived from different software packages currently in use (TestPoint(r) vs. Spiroware(r)). RESULTS: Baseline LCI (median; range) was 9.37 (6.82; 12.08). Between-session differences in LCI measurements were up to 25%. Intra Class Correlation-Coefficient was 0.82. There was no systematic difference between LCI measurements derived from the two software packages (p=0.18); however, variability was significantly higher using Spiroware(r). CONCLUSIONS: We report between-session variability of LCI using N2MBW in school-age children and adolescents with CF. LCI changes exceeding 25% may be considered clinically relevant. TestPoint(r) and Spiroware(r) can be used interchangeably in longitudinal studies. PMID- 29273422 TI - Med-Score 24: A multivariable prediction model for poststernotomy mediastinitis 24 hours after admission to the intensive care unit. AB - OBJECTIVES: Mediastinitis is a serious complication of heart surgery. In this study, we developed a bedside risk score for poststernotomy mediastinitis. METHODS: Data were prospectively collected from 4625 patients admitted to our intensive care unit after heart surgery (January 2005-June 2011). Mediastinitis was defined according to Centers for Disease Control and Prevention criteria. A logistic model was constructed in a randomly selected subgroup of 2618 patients and validated in a second cohort of 1352, as well as in a prospective cohort of 2615 (June 2011-December 2015). Model discriminatory power was assessed according to the area under the receiver operating characteristic curve (AUROC). The beta coefficients of the model were used to define 3 levels of mediastinitis risk as a score designated Med-Score 24. Its performance to predict mediastinitis was compared with that of the logistic EuroSCORE and Society of Thoracic Surgeons score. RESULTS: Ninety-four (2.36%) patients developed mediastinitis. The risk factors identified as predictive of mediastinitis (AUROC 0.80) were 4 preoperative variables (age >70 years, chronic obstructive lung disease, obesity, and antiplatelet therapy) and 3 perioperative variables (prolonged ischemia, emergency reoperation, and prolonged intubation). AUROCs for the Society of Thoracic Surgeons score and logistic EuroSCORE were 0.63 and 0.55, respectively, both differing significantly from the area calculated for Med-Score 24 (P < .001). CONCLUSIONS: The score developed showed excellent predictive power 24 hours after admission to the intensive care unit for mediastinitis risk. This simple tool helps stratify patients according to this risk, thus identifying high risk patients for preventive measures. In our patient cohort, Med-Score 24 performed better than other scores used for this purpose. PMID- 29273424 TI - Recurrent pancreatitis due to autoimmune hypertriglyceridemia in a patient with Graves' disease. PMID- 29273423 TI - Hispanic and African American adult brain tumor patients treated at Harbor-UCLA Medical Center compared to Los Angeles County and Torrance, California. AB - The objective of this study is to shed light on racial disparities among Hispanic and African American adult brain tumor patients treated at Harbor-UCLA Medical Center compared to the general populations of Los Angeles County (LAC) and Torrance, California (CA). A retrospective review of patients admitted to the neurosurgery service at Harbor-UCLA Medical Center during years 2006 through 2010 was performed. Government census data was queried and pertinent national statistics were retrieved. Brain tumor patients at Harbor-UCLA were compared to the general populations of LAC and Torrance. A total of 271 patients were included in the study. The mean age was 46.9 years. Hispanics comprised the majority of neurosurgical patients (n = 151, 55.7%), followed by African Americans (n = 35, 12.9%). A greater percentage of Hispanic patients were treated at Harbor-UCLA relative to the general Hispanic populations of LAC and Torrance (p < .001). A greater percentage of African American patients were treated at Harbor-UCLA relative to the general African American populations of LAC and Torrance (p = .035 and p < .001, respectively). Our data revealed significant racial disparities amid the Harbor-UCLA Hispanic and African American patient populations compared to the general Angeleno populations of LAC and Torrance. PMID- 29273425 TI - Supercharged green fluorescent protein delivers HPV16E7 DNA and protein into mammalian cells in vitro and in vivo. AB - Macromolecules including DNA and proteins serve as important human therapeutics but are limited by their general inability to cross cell membranes. Supercharged proteins have been known as potent tools for delivery of macromolecules into mammalian cells. Thus, the use of these delivery systems is important to reduce the human papillomavirus (HPV)-associated malignancies through improvement of vaccine modalities. In this study, we used a supercharged green fluorescent protein (+36 GFP) for delivery of the full-length HPV16 E7 DNA and protein into mammalian cells and evaluated immune responses, and protective/therapeutic effects of different formulations in C57BL/6 tumor mice model. Our results showed that the complexes of E7 DNA/+36 GFP and also E7 protein/+36 GFP form stable nanoparticles through non-covalent binding with an average size of ~ 200-300 nm. The efficient delivery of E7 DNA or protein by +36 GFP was detected in HEK-293T cell line for 4 h and 24 h post-transfection. Mice immunization with E7 protein/+36 GFP nanoparticles elicited a higher Th1 cellular immune response with the predominant IgG2a and IFN-gamma levels than those induced by E7 protein, E7 DNA, E7 DNA/+36 GFP and control groups (p < .05). Moreover, the E7 DNA/+36 GFP and E7 protein/+36 GFP nanoparticles similarly protected mice against TC-1 tumor challenge (~67%) as compared to E7 DNA and E7 protein (~33%), respectively. These data suggest that +36 GFP may provide a promising platform to improve protein and DNA delivery in vitro and in vivo. PMID- 29273426 TI - Diabetes among asian americans with BMI less than or equal to 23. AB - Lowering the BMI overweight cut point to 23 for Asian Americans (AA) is helpful, but careful monitoring for diabetes across the whole BMI spectrum is still required for AA; One in every 17 AA with a BMI < 23 has diabetes. Twenty one percent of all AA with diabetes has a BMI < 23. PMID- 29273427 TI - Patients lacking glycemic control place more burdens on health services with the use of medications. AB - INTRODUCTION: DM spending in the world is high, and Brazilian studies of public spending caused by DM are scarce. OBJECTIVE: To estimate the annual direct cost for the municipal health sphere, related to DM2 treatment, in patients with and without glycemic control. METHOD: A cross-sectional study carried out in a city in the interior of Minas Gerais state, with patients with DM2, being municipal PHS users. Data were collected from the computerized system of the municipality and patient records, and analyzed using the IBM SPSS v.19 statistical package. The response variable was categorized into controlled A1c (<=7%) and uncontrolled A1c (>7%). RESULTS: Glycemic control in 56.6% of the patients was unsatisfactory; the mean cost of pharmacotherapy for DM2 was US$ 3.14 per year for patients in the control group and US$ 45.54 per year for uncontrolled patients. CONCLUSION: Patients with unsatisfactory glycemic control are more expensive for the municipal health system. PMID- 29273428 TI - Prevalence of prediabetes and diabetes among older adults in Ecuador: Analysis of the SABE survey. AB - AIMS: To examine the prevalence of prediabetes and diabetes among subjects aged 60 years and older in Ecuador. MATERIALS AND METHODS: The present study used data from the National Survey of Health, Wellbeing, and Aging to describe the prevalence of prediabetes and diabetes among older adults. Logistic regression models were assembled to examine the association between certain demographic and health characteristics of participants and prediabetes and diabetes prevalence rates. RESULTS: Of 2298 participants, the prevalence of prediabetes and diabetes was 36.9% (95% CI: 34.2%-39.6%) and 16.7% (95% CI: 14.9%-18.7%) among older adults in Ecuador, respectively. Notably, higher diabetes prevalence rates were seen among women, black subjects, residents in the urban coastal region, and obese participants than those without. In general, the prevalence of diabetes widely varied across provinces of the country, with higher rates seen in provinces along the coastal region of the country. After adjustment for age, gender, and BMI, residents in the urban coast, subjects with greater number of comorbidities, and those classified as having hypertension, and hypertriglyceridemia had significantly higher odds of having diabetes than those without. CONCLUSIONS: Prediabetes and diabetes are prevalent among older adults in Ecuador. The increased prevalence of these metabolic disorders was particularly associated with obesity. Thus, the present findings may assist health care authorities to implement healthy lifestyle interventions among older Ecuadorians at risk for diabetes. PMID- 29273429 TI - Sex differences in long-term quality of life after stroke: Influence of mood and functional status. AB - OBJECTIVE: To evaluate long-term quality of life (QoL) in patients who have experienced a stroke and to analyse differences in QoL between sexes. METHODS: We conducted a descriptive, cross-sectional, observational study to gather sociodemographic variables and risk factors; data were also obtained on QoL, mood, and functional status using validated scales. The study was approved by our centre's ethics committee. RESULTS: Our final sample included 124 patients; mean age was 71.30+/-11.99 years. In the QoL study, the EuroQol-5D dimensions in which participants presented most problems were anxiety/depression (66.7%) and pain/discomfort (62.2%). We found significant inter-sex differences in the dimensions of mobility and usual activities (P=.016 and P=.005, respectively). Women also achieved substantially poorer EuroQoL-5D index values than men (0.45+/ 0.45 vs. 0.65+/-0.38; P=.013). QoL was found to be associated with dependence for the activities of daily living (r=0.326; P=.001) and depressed mood (r=-0.514; P<.0001). According to the predictive model for the EQ-5D index, 72% of the score on QoL items is explained by functional status, dependence for the activities of daily living (basic and instrumental), and depressed mood. Being married, in contrast, seems to be a protective factor. CONCLUSION: Stroke survivors have poor long-term QoL; this is more marked in women than in men, especially in the dimensions of mobility and usual activities. PMID- 29273430 TI - Evaluating lay perception of prophylactic mesh placement: there are risks, benefits, and alternatives. PMID- 29273431 TI - Endoscopic resolution of gastric perforation with pancreas penetration by a fish bone. PMID- 29273432 TI - The alpha helix 1 from the first conserved region of HIV1 gp120 is reconstructed in the short NQ21 peptide. AB - Investigations of short peptides that can be used in the next phase of synthetic HIV1 vaccine development are an urgent goal, as well as investigations of peptides that can be used in immunological tests with the aim to check the titer of antibodies against the alpha helix 1 from the first conserved region of HIV1 gp120 that are known to cause antibody-dependent cellular cytotoxicity (ADCC). The aim of this work was to study the structure of the NQ21 peptide corresponding to the less mutable part of the first conserved region of HIV1 gp120 (residues 94 114). The NQ21 peptide and its conjugate with biotin (biotin-NQ21) are absolutely alpha-helical in phosphate buffer solutions at pH = 6.8, 7.4 and 8.0, as well as in the dried form, according to the results of surface-enhanced Raman scattering (SERS) spectroscopy. Results of the native gel electrophoresis and thermal analysis under the control of spectrofluorometer and near UV circular dichroism (CD) showed that the peptide exists in form of octamers and tetramers at pH = 7.4, that is important information for further vaccine development. Strong signal of interacting Trp residues in oligomers in the far UV CD obscures the signal from secondary structure, but becomes less intensive during the heating. PMID- 29273433 TI - Membrane-damaging activities of mannosylated ovalbumin are involved in its antibacterial action. AB - Mannosylated ovalbumin (Man-OVA) prepared by modification of carboxyl groups with p-aminophenyl alpha-d-mannopyranoside shows an increase of net positive charge, which may enhance its binding to bacterial membrane. Thus, we aimed to investigate whether Man-OVA exerts antibacterial activity on Escherichia coli and Staphylococcus aureus via membrane-perturbing effect. Man-OVA inhibited the growth of E. coli and S. aureus, whereas ovalbumin (OVA) did not show any antibacterial activity. Moreover, Man-OVA induced an increase in the membrane permeability of E. coli and S. aureus, which was positively correlated to its bactericidal action. Morphological examination using scanning electron microscopy revealed that Man-OVA disrupted the bacterial membrane integrity. Destabilization of the lipopolysaccharide (LPS) layer and inhibition of lipoteichoic acid (LTA) biosynthesis in the cell wall increased the bactericidal effect of Man-OVA. In contrast to OVA, Man-OVA also induced leakage of bacterial membrane-mimicking liposomes. Color transformation of phospholipid/polydiacetylene membrane assay revealed that the membrane-interaction mode of Man-OVA was distinct from that of OVA. LPS and LTA suppressed the membrane-damaging activity of Man-OVA, whereas an increase in the Man-OVA concentration attenuated the inhibitory action of LPS and LTA. Taken together, our data indicate that the bactericidal activity of Man-OVA depends strongly on its ability to induce membrane permeability. PMID- 29273434 TI - Sex disparities in health and health care utilization after Parkinson diagnosis: Rethinking PD associated disability. AB - OBJECTIVE: To examine sex differences and trends in comorbid disease and health care utilization in individuals with newly diagnosed Parkinson disease (PD). DESIGN: Retrospective cohort study. PARTICIPANTS: Over 133,000 Medicare beneficiaries with a new PD diagnosis in 2002 followed through 2008. METHODS: We compared the prevalence and cumulative incidence of common medical conditions, trends in survival and health care utilization between men and women with PD. RESULTS: Female PD patients had higher adjusted incidence rate ratio (IRR) of depression (IRR: 1.28, 1.25-1.31), hip fracture (IRR: 1.51, 1.45-1.56), osteoporosis (3.01, 2.92-3.1), and rheumatoid/osteoarthritis (IRR: 1.47, 1.43 1.51) than men. In spite of greater survival, women with PD used home health and skilled nursing facility care more often, and had less outpatient physician contact than men throughout the study period. CONCLUSIONS: Women experience a unique health trajectory after PD diagnosis as suggested by differing comorbid disease burden and health care utilization compared to men. Future studies of sex differences in care needs, care quality, comorbidity related disability, PD progression, and non-clinical factors associated with disability are needed to inform research agendas and clinical guidelines that may improve quality survival for women with PD. PMID- 29273435 TI - Severe abnormal behavior incidence after administration of neuraminidase inhibitors using the national database of medical claims. AB - An earlier study using the number of abnormal behaviors reported to the study group as the numerator and the number of influenza patient prescribed each neuraminidase inhibitor (NI) estimated by respective pharmaceutical companies found no significant difference among incidence rates of the most severe abnormal behaviors by type of NI throughout Japan. However, the dataset for the denominator used in that earlier study was the estimated number of prescriptions. In the present study, to compare the incidence rates of abnormal behavior more precisely among influenza patients administered several sorts of NI or administered no NI, we used data obtained from the National Database of Electronic Medical Claims (NDBEMC) as the denominator to reach a definitive conclusion. Results show that patients not administered any NI (hereinafter un administered) or those administered peramivir sometimes showed higher risk of abnormal behavior than those administered oseltamivir, zanamivir, or laninamivir. However, the un-administered or peramivir patients were fewer than those taking other NI. Therefore, accumulation of data through continued research is expected to be necessary to reach a definitive conclusion about the relation between abnormal behavior and NI in influenza patients. Since severe abnormal behaviors with all types of NI or of un-administered patients have been reported, there are some risks in the administration of NI or even in un-administered cases. Therefore, we infer that the policy mandating package inserts in all types of NI. PMID- 29273436 TI - Gastro-protective effect of edible plant Artemisia argyi in ethanol-induced rats via normalizing inflammatory responses and oxidative stress. AB - PHARMACOLOGICAL RELEVANCE: Artemisia argyi, a kind of ethnic drug, has a long term use on gastric diseases and syndromes. AIM OF THE STUDY: The aim of the study is to validate the traditional uses of A. argyi scientifically and to discover more efficient nature derived gastro-protective ethnomedicine and further elucidate the possible mechanisms. MATERIALS AND METHODS: Sixty rats were randomly divided into control, model (ethanol-induced), reference (omeprazole treated) and A. argyi extract (AT) (0.3, 0.1, 0.033g/mL) treated groups, respectively. The levels of biochemical indexes in tissues and serum and the activities of pepsin in gastric contents were measured after the sacrifice of rats. Moreover, the anti-inflammatory effects in LPS-induced RAW 264.7 cells of the isolated compounds were determined. RESULTS: The studies indicated that A. argyi extract could exert strong protective effects on gastric mucosa in ethanol induced rat model by regulating the levels of inflammatory factors, superoxide dismutase, and malonaldehyde, which were superior to those of positive control at 0.3g/mL. The isolated flavonoids could down-regulate the levels of pro inflammatory cytokines on LPS-induced RAW 264.7 macrophage cells and eliminate free radicals in the anti-oxidative tests. The effects of eupatilin and jaceosidin, which were substituted by additional methoxy groups, were predominant, indicting the importance of methoxy to the activities. CONCLUSION: The results confirmed that A. argyi can protect ethanol-induced rats from gastric mucosal injury through inhibiting inflammatory responses and ameliorating oxidative stress. A. argyi is suitable for people with gastric mucosal injuries or unhealthy dietary habits as a necessary dietary supplement, which will promote the planting and application of A. argyi in both agriculture and food industry. PMID- 29273437 TI - Action of the hydroethanolic extract of the flowers of Acmella oleracea (L.) R.K. Jansen on the reproductive performance of Wistar females rats: A popular female aphrodisiac from the Amazon. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The species Acmella oleracea (L.) R.K. Jansen (Asteraceae), popularly known as jambu, is marketed in fairs as a female aphrodisiac and has several pharmacological activities already confirmed, among them the sexual stimulant action. The objective of this study was to evaluate the effects of the oral administration of the hydroethanolic extract of A. oleracea flowers (EHAo) on wistar rats during the pre-mating, mating, and pre-implantation period. MATERIAL AND METHODS: During the treatment period, measurements of feed intake, water intake, weight, estrous cycle, behavior, reproductive parameters, biochemical parameters, hematological parameters, and histopathology of ovaries were performed daily. RESULTS: In the gas chromatography analysis - mass spectrometry characterization, the compound (2E, 6Z, 8E) -N-isobutyldeca-2,6,8 trienamide (spilanthol) was detected as the majority compound at the 84% concentration. In the conditions of this study, EHAo did not cause maternal toxicity. However, in the estrous cycle, the frequency of the Proestrous (P) and Estrous (E) phase was significantly increased with the doses of 88.91 and 444.57mg/kg of the EHAo in relation to the control. On the other hand, the metaestrous (M) and diestrous (D) phases showed a significant reduction in their frequency in the groups treated with EHAo. Water intake increased significantly (p < 0.01), as well as the triglyceride levels, the total cholesterol and fractions (p < 0.05), and the percentage of neutrophils (p < 0.05). CONCLUSION: It is concluded, therefore, that the treatment with EHAo, which is one of the forms popularly used, is safe in the concentrations and time of treatment studied as it is able to influence the estrous cycle without altering folliculogenesis and fertility. PMID- 29273438 TI - Curcuma comosa reduces visceral adipose tissue and improves dyslipidemia in ovariectomized rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma comosa Roxb. (C. comosa) or Wan chak motluk Zingiberaceae family, is widely used in Thai traditional medicine for treatment of gynecological problems as well as relief of postmenopausal symptoms. Since C. comosa contains phytoestrogen and causes lipid lowering effect by an unknown mechanism, we investigated its effect on adiposity and lipid metabolism in estrogen-deprived rats. MATERIALS AND METHODS: Adult female rats were ovariectomized (OVX) and received daily doses of either a phytoestrogen from C. comosa [(3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol; DPHD], C. comosa extract, or estrogen (17beta-estradiol; E2) for 12 weeks. Adipose tissue mass, serum levels of lipids and adipokines were determined. In addition, genes and proteins involved in lipid synthesis and fatty acid oxidation in visceral adipose tissue were analyzed. RESULTS: Ovariectomy for 12 weeks elevated level of serum lipids and increased visceral fat mass and adipocyte size. These alterations were accompanied with the up-regulation of lipogenic mRNA and protein expressions including LXR-alpha, SREBP1c and their downstream targets. OVX rats showed decrease in proteins involved in fatty acid oxidation including AMPK-alpha and PPAR-alpha in adipose tissue, as well as alteration of adipokines; leptin and adiponectin. Treatments with E2, DPHD or C. comosa extract in OVX rats prevented an increase in adiposity, down-regulated lipogenic genes and proteins with marked increases in the protein levels of AMPK-alpha and PPAR-alpha. These findings indicated that their lipid lowering effects were mediated via the suppression of lipid synthesis in concert with an increase in fatty acid oxidation. CONCLUSIONS: C. comosa exerts a lipid lowering effect in the estrogen deficient rats through the modulations of lipid synthesis and AMPK-alpha activity in adipose tissues, supporting the use of this plant for health promotion in the post-menopausal women. PMID- 29273439 TI - Enhanced extended state observer-based control for systems with mismatched uncertainties and disturbances. AB - This paper presents an enhanced Extended State Observer (ESO)-based control strategy to deal with the disturbance attenuation problem for a class of non integral-chain systems subject to non-linear mismatched uncertainties and external disturbances. The proposed control strategy does not assume the integral chain form and it is formed by a state-feedback plus a dynamic disturbance compensation term, which is designed to reject the disturbance effect in the system output. From a theoretical point of view, the proposed strategy is reduced to the conventional ESO when the integral chain form and the matched condition hold. In this sense, this paper is presented as an extension of the ESO principles to cover a wider class of systems. The theoretical results show that the internal zero-dynamics plays an important role in ESO-based control design. Also, the closed-loop stability is analyzed and some numerical simulations show the effectiveness of the proposal in comparison with previous ESO-based techniques. PMID- 29273441 TI - MRI screening of the internal auditory canal: Is gadolinium necessary to detect intralabyrinthine schwannomas? AB - OBJECTIVE: Non-contrast MRI of the internal auditory canal (IAC) using high resolution T2WI (T2 weighted image) has been proposed as the primary screening study in patients with sudden or asymmetric sensorineural hearing loss (ASNHL). However, there are concerns that non-contrast MRI may not detect labyrinthine pathology, specifically intralabyrinthine schwannomas (ILSs). The purpose of this study was to determine if non-contrast high-resolution T2WI alone are adequate to exclude these uncommon intralabyrinthine tumors. METHODS: 31 patients with ILSs and 36 patients without inner ear pathology that had dedicated MRI of the IAC performed with both non-contrast T2WI and post-contrast T1WI (T1 weighted image) were identified. Three board-certified neuroradiologists reviewed only the T2WI from these 67 cases. When an ILS was identified, its location and size were recorded. Sensitivity, specificity, and accuracy were calculated using the post contrast T1WI as the "gold standard." A consensus review of cases with discordant results was conducted. RESULTS: The sensitivity, specificity, and accuracy were 1.0, 1.0, and 1.0 for Observer 1; 0.84, 1.0, and 0.96 for Observer 2; 0.90, 1.0, and 0.98 for Observer 3. The 5 ILSs with discordant results were correctly identified upon consensus review. The median size of the ILSs was 4.4mm (+/ 2.9mm) and most (18/31) were intracochlear in location. CONCLUSION: Non-contrast high-resolution T2WI alone can detect ILSs with 84-100% sensitivity, suggesting that gadolinium may be unnecessary to exclude ILSs on screening MRI. These findings have implications for reducing cost, time, and adverse events associated with gadolinium administration in patients presenting with sudden or ASNHL. LEVEL OF EVIDENCE: 4. PMID- 29273440 TI - PITX1 promotes chondrogenesis and myogenesis in mouse hindlimbs through conserved regulatory targets. AB - The PITX1 transcription factor is expressed during hindlimb development, where it plays a critical role in directing hindlimb growth and the specification of hindlimb morphology. While it is known that PITX1 regulates hindlimb formation, in part, through activation of the Tbx4 gene, other transcriptional targets remain to be elucidated. We have used a combination of ChIP-seq and RNA-seq to investigate enhancer regions and target genes that are directly regulated by PITX1 in embryonic mouse hindlimbs. In addition, we have analyzed PITX1 binding sites in hindlimbs of Anolis lizards to identify ancient PITX1 regulatory targets. We find that PITX1-bound regions in both mouse and Anolis hindlimbs are strongly associated with genes implicated in limb and skeletal system development. Gene expression analyses reveal a large number of misexpressed genes in the hindlimbs of Pitx1-/- mouse embryos. By intersecting misexpressed genes with genes that have neighboring mouse PITX1 binding sites, we identified 440 candidate targets of PITX1. Of these candidates, 68 exhibit ultra-conserved PITX1 binding events that are shared between mouse and Anolis hindlimbs. Among the ancient targets of PITX1 are important regulators of cartilage and skeletal muscle development, including Sox9 and Six1. Our data suggest that PITX1 promotes chondrogenesis and myogenesis in the hindlimb by direct regulation of several key members of the cartilage and muscle transcriptional networks. PMID- 29273442 TI - Pharmaceutical interactions between antiretroviral and antimalarial drugs used in chemoprophylaxis. AB - Human immunodeficiency virus (HIV) is the causative agent of the Acquired Immunodeficiency Syndrome (AIDS). The pandemic is believed to have originated within the Northern Congo basin covering large parts of the Democratic Republic of Congo, the Republic of Congo, the Central African Republic, Cameroon and Gabon. Although over decades, HIV-1 has spread throughout the World leaving no country unaffected, sub-Saharan Africa remains the region with more than 80% of all infected individuals. The HIV-2 epidemic has largely remained restricted to West Africa along the Upper Guinean forests. Co-incident with these regions of highest HIV distribution is a part of the malaria belt and therefore, co infections are common. In this review we carve out the consequences of HIV transmission prevention and synchronous malaria prophylaxis during occupational or leisure travelling activities within this World region. In particular, we elaborate on considering pre-existing drug resistances of both, the malaria parasites and the immunodeficiency viruses, when determining a combination for prophylactic and, if necessary, post-expositional measures with a focus on the compatibility of both medications. PMID- 29273444 TI - Terminal addition in a cellular world. AB - Recent advances in our understanding of evolutionary development permit a reframed appraisal of Terminal Addition as a continuous historical process of cellular-environmental complementarity. Within this frame of reference, evolutionary terminal additions can be identified as environmental induction of episodic adjustments to cell-cell signaling patterns that yield the cellular molecular pathways that lead to differing developmental forms. Phenotypes derive, thereby, through cellular mutualistic/competitive niche constructions in reciprocating responsiveness to environmental stresses and epigenetic impacts. In such terms, Terminal Addition flows according to a logic of cellular needs confronting environmental challenges over space-time. A reconciliation of evolutionary development and Terminal Addition can be achieved through a combined focus on cell-cell signaling, molecular phylogenies and a broader understanding of epigenetic phenomena among eukaryotic organisms. When understood in this manner, Terminal Addition has an important role in evolutionary development, and chronic disease might be considered as a form of 'reverse evolution' of the self same processes. PMID- 29273443 TI - Some facts on south asian schistosomiasis and need for international collaboration. AB - In this review, we are discussing South Asian schistosomiasis; more specifically species which are responsible for schistosomiasis in India or South Asia Schistosoma indicum, S. spindale, S. nasale, S. incognitum, S. gimvicum (S.haematobium), Bivitellobilharzia nairi, Orientobilharzia bomfordi, O. dattai, O. turkestanicum and O.harinasutai, their survival strategies such as mild pathology to the host, producing low egg number and utilizing fresh water snails (Indoplanorbis exustus and Lymnaea luteola) in stagnant water bodies like ponds, lakes, ditches, low laying areas, marshy lands and rice fields. Presently, correct identification of blood fluke species, their immature stages, male schistosomes and their intermediate host details like strain variations, susceptibilities, ecologies are not well studied. Species like B. nairi, O. bomfordi, O. harinasutai (Lymnaea rubiginosa intermediate host for O.harinasutai in Thailand) are also not well studied. Moreover, snail species like Oncomalania spp are not from South Asia, but species of Tricula or Neotricula are reported from this geography, which gives indications of S. mekongi like blood fluke presence in the area. Although in humans, cercarial dermatitis is rampant in rural population with occasional reporting of schistosome eggs in stools, human schistosomiasis is considered absent from this region, despite finding a foci (now dead) of urinary schistosomiasis in Gimvi village of Ratnagiri district, Maharashtra, India. There is great difficulty in diagnosing the infection in man and animals due to low egg production, hence development of a single step antigen detection test is the need of the hour. Interestingly, lethal effect of praziquantel was seen against S.haematobium and S.mansoni. However, this drug failed to cause significant reduction of S. incognitum and S. spindale experimentally suggesting some differences in the biology of two groups of the schistosomes. Triclabendazole showed adulticidal effect at a dose rate of 20 mg/kg body against female schistosome worms, but at lower dose (10 mg/kg body wt) of the drug, a dose that is used in treating bovine fascioliasis, it is providing chances of drug resistance of the persisting schistosomes against triclabendazole. Though the South Asian institutes have all the facilities to tackle issues related to existing schistosomes, it is recommended to develop an international collaboration by establishing an international centre on schistosomiasis in India. PMID- 29273445 TI - Selective pressure on the protein-coding genes of the pufferfish is correlated with phenotypic traits. AB - The pufferfish accumulates neurotoxic tetrodotoxin in its body and inflates by filling its stomach with water. These traits are unique to this species, and may be a result of adaptation post-divergence of Tetraodontidae. However, evolution of the protein-coding genes in the pufferfish has not yet been well elucidated. Detection of positive selection on these genes can help us understand the mechanisms associated with functional evolution. We downloaded well-annotated gene information of two pufferfish species, Takifugu rubripes and Tetraodon nigroviridis, from the public ENSEMBL database. In order to detect selective pressure on protein-coding sequences, we performed dN/dS estimation using codeml within the PAML software package. We selected one to one orthologous genes among seven fish species (Gasterosteus aculeatus, Oryzias latipes, Poecilia formosa, Takifugu rubripes, Tetraodon nigroviridis, and Xiphophorus maculatus). Results of dN/dS analysis on orthologous genes indicate that pufferfish showed high non synonymous substitution rate for positively selected genes, and the evolutionary rate was faster during the diversification of two pufferfishes after divergence. Additionally, a candidate mechanism for regulation of neuro-toxicity of tetrodotoxin was identified from functional annotation of positively selected genes. These results support positive selection on protein-coding genes of the pufferfish with the acquisition of specific phenotypic traits. PMID- 29273446 TI - Stress hyperglycemia in general surgery: Why should we care? AB - AIMS: To determine the frequency of increasing levels of stress hyperglycemia and its associated complications in surgery patients without a history of diabetes. METHODS: We reviewed hospital outcomes in 1971 general surgery patients with documented preoperative normoglycemia [blood glucose (BG) <140mg/dL] who developed stress hyperglycemia (BG >140mg/dL or >180mg/dL) within 48h after surgery between 1/1/2010 and 10/31/2015. RESULTS: A total of 415 patients (21%) had >=1 episode of BG between 140 and 180mg/dL and 206 patients (10.5%) had BG>180mg/dL. The median length of hospital stay (LOS) was 9days [interquartile range (IQR) 5,15] for BG between 140 and 180mg/dL and 12days (IQR 6,18) for BG>180mg/dL compared to normoglycemia at 6days (IQR 4,11), both p<0.001. Patients with BG 140-180mg/dL had higher rates of complications with an odds ratio (OR) of 1.68 [95% confidence interval (95% CI) 1.15-2.44], and those with BG>180mg/dL had more complications [OR 3.46 (95% CI 2.24-5.36)] and higher mortality [OR 6.56 (95% CI 2.12-20.27)] compared to normoglycemia. CONCLUSION: Increasing levels of stress hyperglycemia are associated with higher rates of perioperative complications and hospital mortality in surgical patients without diabetes. PMID- 29273447 TI - Introduction of new food textures during complementary feeding: Observations in France. AB - INTRODUCTION: Complementary feeding plays a crucial role in the development of infants and toddlers and studies suggest benefits specific to the introduction of food textures. OBJECTIVES: Evaluate the recommendations given to parents, their practices, and their attitudes towards the introduction of food textures during complementary feeding in France. METHODS: This was a cross-sectional pilot study conducted in 2013. One hundred and eighty-one parents with at least one child aged 6-36 months living in France completed an ad hoc questionnaire. RESULTS: Eighty-eight percent of the parents surveyed received oral information on complementary feeding, but only 46% received such information on the introduction of food textures. Pediatricians were the most frequently listed source of oral information on complementary feeding. More than half the parents also looked for additional information in books and on the internet. While oral recommendations matched parents' practices, they seemed to occur at a later age compared to infants' physiological ability to handle new textures. The quality of information on food texture advice available in paper and electronic formats evaluated using a 4-point scale was found to be limited. Introducing new food texture was spontaneously reported as the most common difficulty in complementary feeding (16%). Fear of choking when first introducing food pieces was reported by 54% of the parents. CONCLUSIONS: The parents' lack of information on the introduction of food textures, as well as their fear that their child may choke, should encourage providing new recommendations in France. PMID- 29273448 TI - [Pain in children with neurological impairment: A review from the French Pediatric Neurology Society]. AB - Management of pain is one of the major expectations of children with neurological impairment and their families. The medical literature is poor on this topic accounting for approximately 0.15 % of the publications on pain in general. The objective of the French Pediatric Neurology Society was to review the current knowledge on this topic. Bibliographic research was conducted with PubMed and RefDoc for publications between 1994 and 2014 in French or English. A total of 925 articles were retrieved and 92 were selected for review. Pain is common in this population: a 2-week survey indicated that pain occurs in 50-75 % of children. Pain negatively impacts the quality of life of children and their parents. Children with neurological impairment express their pain with pain expression patterns and specific patterns common to children (change of tone, abnormal movements, spasticity, paradoxical reactions, such as laughter, self injury or vasomotor dysfunction). Some children with neurological impairment are able to use self-report pain scales. If not, observational measures should be used. Behavioral rating scales specifically designed for this population are more sensitive than others. Scales must be selected according to children's communication skills, type of pain, and the context. Sometimes behavioral changes are the only expression of pain: any change in sleep, tone, feeding, or mood must suggest pain in this population. Management of pain remains difficult. There are no specific guidelines. Procedural pain management guidelines and the usual analgesic drugs can be used in children with neurological impairment with specific concerns regarding tolerance and side effects. These children are particularly at risk for neuropathic pain. A multidisciplinary approach is helpful, involving physicians, nurses, physiotherapists, psychologists and parents. PMID- 29273449 TI - Iatrogenic aortic dissection - Follow the image! PMID- 29273450 TI - Helicobacter pylori Depletes Cholesterol in Gastric Glands to Prevent Interferon Gamma Signaling and Escape the Inflammatory Response. AB - BACKGROUND & AIMS: Despite inducing an inflammatory response, Helicobacter pylori can persist in the gastric mucosa for decades. H pylori expression of cholesterol alpha-glucosyltransferase (encoded by cgt) is required for gastric colonization and T-cell activation. We investigated how cgt affects gastric epithelial cells and the host immune response. METHODS: MKN45 gastric epithelial cells, AGS cells, and human primary gastric epithelial cells (obtained from patients undergoing gastrectomy or sleeve resection or gastric antral organoids) were incubated with interferon gamma (IFNG) or interferon beta (IFNB) and exposed to H pylori, including cagPAI and cgt mutant strains. Some cells were incubated with methyl beta-cyclodextrin (to deplete cholesterol from membranes) or myriocin and zaragozic acid to prevent biosynthesis of sphingolipids and cholesterol and analyzed by immunoblot, immunofluorescence, and reverse transcription quantitative polymerase chain reaction analyses. We compared gene expression patterns among primary human gastric cells, uninfected or infected with H pylori P12 wt or P12Deltacgt, using microarray analysis. Mice with disruption of the IFNG receptor 1 (Ifngr1-/- mice) and C57BL6 (control) mice were infected with PMSS1 (wild-type) or PMSS1Deltacgt H pylori; gastric tissues were collected and analyzed by reverse transcription quantitative polymerase chain reaction or confocal microscopy. RESULTS: In primary gastric cells and cell lines, infection with H pylori, but not cgt mutants, blocked IFNG-induced signaling via JAK and STAT. Cells infected with H pylori were depleted of cholesterol, which reduced IFNG signaling by disrupting lipid rafts, leading to reduced phosphorylation (activation) of JAK and STAT1. H pylori infection of cells also blocked signaling by IFNB, interleukin 6 (IL6), and IL22 and reduced activation of genes regulated by these signaling pathways, including cytokines that regulate T-cell function (MIG and IP10) and anti-microbial peptides such as human beta-defensin 3 (hBD3). We found that this mechanism allows H pylori to persist in proximity to infected cells while inducing inflammation only in the neighboring, non-infected epithelium. Stomach tissues from mice infected with PMSS1 had increased levels of IFNG, but did not express higher levels of interferon-response genes. Expression of the IFNG-response gene IRF1 was substantially higher in PMSS1Deltacgt-infected mice than PMSS1-infected mice. Ifngr1-/- mice were colonized by PMSS1 to a greater extent than control mice. CONCLUSIONS: H pylori expression of cgt reduces cholesterol levels in infected gastric epithelial cells and thereby blocks IFNG signaling, allowing the bacteria to escape the host inflammatory response. These findings provide insight into the mechanisms by which H pylori might promote gastric carcinogenesis (persisting despite constant inflammation) and ineffectiveness of T-cell-based vaccines against H pylori. PMID- 29273453 TI - Predicting Pediatric Emergency Severity Index Level Based on Emergency Department Pre-Arrival Information. AB - PURPOSE: This study examines the use of phone referral information to predict Emergency Severity Index triage levels as a proxy to anticipate emergency department nursing resource allocation in a pediatric hospital. It also assesses the relationship between these pre-arrival triage levels and hospital admission. DESIGN AND METHODS: Emergency nurses with specialized training used standardized phone referral information to assign triage levels to 481 patients before their arrival. Upon patient arrival, independent triage levels were assigned. The two levels were then compared and patient disposition was collected. Descriptive statistics and Cohen's kappa were used to assess agreement between the two emergency severity index levels. RESULTS: Moderate agreement was found between the pre-arrival and arrival triage levels. The majority of patients (71.3%) with a pre-arrival triage level of 1 or 2 (the most acute levels) were admitted to the hospital. These patients were also more likely to be admitted to the intensive care unit than were patients with a pre-arrival triage level>=3. CONCLUSIONS AND PRACTICE IMPLICATIONS: The ability to predict triage levels for incoming patients could give the emergency department charge nurse the ability to plan ahead so that appropriate nursing staffing is available upon arrival. The knowledge that patients assigned a pre-arrival triage level of 1 or 2 are more likely to be admitted gives the emergency department the ability to plan for bed placement and inpatient nursing resources earlier, potentially resulting in decreased emergency department length of stay. More study on these potential benefits is needed. PMID- 29273451 TI - Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice. AB - BACKGROUND & AIMS: Intraductal papillary mucinous neoplasias (IPMNs) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression. METHODS: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreERT2;Ptenflox/flox;R26RYFP or PtenDeltaDuct/DeltaDuct mice) and used PtenDeltaDuct/+ and Pten+/+ mice as controls. We also generated KrasG12D;PtenDeltaDuct/DeltaDuct and KrasG12D;PtenDeltaDuct/+ mice. Pancreata were collected when mice were 28 weeks to 14.5 months old and analyzed by histology, immunohistochemistry, and electron microscopy. We performed multiplexed droplet digital polymerase chain reaction to detect spontaneous Kras mutations in PtenDeltaDuct/DeltaDuct mice and study the effects of Ras pathway activation on initiation and progression of IPMNs. We obtained 2 pancreatic sections from a patient with an invasive pancreatobiliary IPMN and analyzed the regions with and without the invasive IPMN (control tissue) by immunohistochemistry. RESULTS: Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions with histologic and molecular features of human IPMNs. PtenDeltaDuct/DeltaDuct mice developed IPMNs of several subtypes. In PtenDeltaDuct/DeltaDuct mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. KrasG12D;PtenDeltaDuct/DeltaDuct mice all developed invasive IPMNs within 1 month. In KrasG12D;PtenDeltaDuct/+ mice, 70% developed IPMN, predominately of the pancreatobiliary subtype, and 63.3% developed PDAC. In all models, IPMNs and PDAC expressed the duct-specific lineage tracing marker yellow fluorescent protein. In immunohistochemical analyses, we found that the invasive human pancreatobiliary IPMN tissue had lower levels of PTEN and increased levels of phosphorylated (activated) ERK compared with healthy pancreatic tissue. CONCLUSIONS: In analyses of mice with ductal cell specific disruption of Pten, with or without activated Kras, we found evidence for a ductal cell origin of IPMNs. We also showed that PTEN loss and activated Kras have synergistic effects in promoting development of IPMN and progression to PDAC. PMID- 29273452 TI - Development and Validation of a Model to Determine Risk of Progression of Barrett's Esophagus to Neoplasia. AB - BACKGROUND & AIMS: A system is needed to determine the risk of patients with Barrett's esophagus for progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). We developed and validated a model to determine of progression to HGD or EAC in patients with BE, based on demographic data and endoscopic and histologic findings at the time of index endoscopy. METHODS: We performed a longitudinal study of patients with BE at 5 centers in United States and 1 center in Netherlands enrolled in the Barrett's Esophagus Study database from 1985 through 2014. Patients were excluded from the analysis if they had less than 1 year of follow-up, were diagnosed with HGD or EAC within the past year, were missing baseline histologic data, or had no intestinal metaplasia. Seventy percent of the patients were used to derive the model and 30% were used for the validation study. The primary outcome was development of HGD or EAC during the follow-up period (median, 5.9 years). Survival analysis was performed using the Kaplan-Meier method. We assigned a specific number of points to each BE risk factor, and point totals (scores) were used to create categories of low, intermediate, and high risk. We used Cox regression to compute hazard ratios and 95% confidence intervals to determine associations between risk of progression and scores. RESULTS: Of 4584 patients in the database, 2697 were included in our analysis (84.1% men; 87.6% Caucasian; mean age, 55.4 +/- 20.1 years; mean body mass index, 27.9 +/- 5.5 kg/m2; mean length of BE, 3.7 +/- 3.2 cm). During the follow-up period, 154 patients (5.7%) developed HGD or EAC, with an annual rate of progression of 0.95%. Male sex, smoking, length of BE, and baseline-confirmed low-grade dysplasia were significantly associated with progression. Scores assigned identified patients with BE that progressed to HGD or EAC with a c statistic of 0.76 (95% confidence interval, 0.72-0.80; P < .001). The calibration slope was 0.9966 (P = .99), determined from the validation cohort. CONCLUSIONS: We developed a scoring system (Progression in Barrett's Esophagus score) based on male sex, smoking, length of BE, and baseline low-grade dysplasia that identified patients with BE at low, intermediate, and high risk for HGD or EAC. This scoring system might be used in management of patients. PMID- 29273454 TI - Effects of non-contingent cocaine on 3 alpha-androstanediol. II. Disruption of lordosis of proestrous rats. AB - Drug use influences sexual behavior, performance, and can be associated with increased sexual risk-taking. Our prior results using an animal model indicate that progestogens contribute to hormonally-mediated changes in sexual behavior of female rodents during acute cocaine exposure. Androgens, such as testosterone, and its metabolite 3alpha-androstanediol (3alpha-diol), and estradiol, are known to influence male sexual behavior, but can also alter the expression of sexual behavior of female rodents. As such, we investigated the influence of endogenous androgen and estradiol fluctuations on cocaine-mediated changes in motor behavior and sexual receptivity of rats during diestrous or proestrous phases of the estrous cycle. Female rats were administered saline or cocaine (5, 10, or 20mg/kg, i.p.). Motor behavior was observed in the first 30min following drug administration, and then sexual responding was assessed for 15min. Cocaine decreased aggressive behavior in response to attempted mounts by a male among non receptive (diestrous) rats and inhibited sexual behavior among sexually receptive (proestrous) rats. Cocaine dose-dependently altered concentrations of testosterone metabolites (estradiol and 3alpha-diol), but not testosterone, which correlated to motor and sexual behaviors of diestrous and proestrous rats, respectively. These data suggest that actions of 3alpha-diol may be involved in female sexual and motor behavior in response to cocaine, in a cycle-dependent manner. PMID- 29273455 TI - Social media as a shield: Facebook buffers acute stress. AB - Facebook remains the most widely used social media platform. Research suggests that Facebook may both enhance and undermine psychosocial constructs related to well-being, and that it may impair physiological stress recovery. However, little is known about its influence on stress reactivity. Using novel experimental methods, this study examined how Facebook influences reactivity to an acute social stressor. Facebook users (n=104, 53 males, mean age 19.50, SD=1.73) were randomly assigned to use their own Facebook account or sit quietly with the option of reading electronic magazines before experiencing an acute social stressor. All participants showed significant changes in subjective and physiological stress markers in response to the stressor. However, participants who used Facebook experienced lower levels of psychosocial stress, physiological stress, and rated the stressor as less threatening (p's<0.05) when controlling for gender and emotional investment in the website compared to controls. Results suggest that Facebook use may buffer stress-in particular psychosocial stress-if used before experiencing an acute social stressor. This study is among the first to incorporate both objective and subjective measures in investigating the complex relationship between Facebook use and well-being. PMID- 29273456 TI - The antipsychotic trifluoperazine reduces marble-burying behavior in mice via D2 and 5-HT2A receptors: Implications for obsessive-compulsive disorder. AB - Trifluoperazine, a typical antipsychotic drug, not only antagonizes dopamine D2 receptors but also enhances serotonin 5-HT2 receptor-mediated behavior. Moreover, trifluoperazine suppresses human purinergic receptor P2X7 responses and calmodulin. However, the effect of trifluoperazine on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder (OCD), has not been studied. Here, we examined the effect of trifluoperazine on marble burying behavior in mice. Oral administration of paroxetine, a selective serotonin reuptake inhibitor, significantly reduced marble-burying behavior without affecting total locomotor activity. Similar results were obtained for trifluoperazine (3mg/kg). The D2 receptor agonist, quinpirole (0.03mg/kg, intraperitoneal [i.p.]), and 5-HT2A receptor antagonist, ketanserin (0.3mg/kg, i.p.), significantly counteracted this reduction of marble-burying behavior by trifluoperazine. These results show that trifluoperazine reduces marble-burying behavior via D2 and 5-HT2A receptors, and may be a useful drug for the treatment of OCD. PMID- 29273457 TI - The effects of ketamine on sexual behavior, anxiety, and locomotion in female rats. AB - The present study characterized the effects of ketamine on sexual behavior and anxiety in female rats. In Experiment 1, female subjects received an injection of ketamine (10.0mg/kg) or saline 30min prior to a sexual partner-preference test during which each female subject was given the opportunity to interact with a female stimulus or a sexually vigorous male stimulus. Immediately afterwards, female subjects were tested for locomotion in an open field test. Ketamine treated subjects spent significantly more time with the male stimulus than saline treated subjects. No other measures of mating behavior (i.e., paced mating behavior, lordosis) were affected by ketamine. Ketamine also had no effect on locomotion. In Experiment 2, female subjects received an injection of ketamine (10.0mg/kg), or saline daily for 10days to investigate the possibility that sexual dysfunction emerges only after repeated exposure. Similar to the results of Experiment 1, ketamine-treated subjects spent significantly more time with the male stimulus than saline-treated subjects. Chronic ketamine treatment also decreased the likelihood of leaving the male after mounts, without affecting any other measures of sexual behavior. Chronic ketamine had no effect on locomotion. In Experiment 3, female subjects received an injection of ketamine (10.0mg/kg) or saline and were tested for anxiety in an elevated plus maze test and for locomotion in an open field test. Acute ketamine had no effect on anxiety or locomotion. In Experiment 4, female subjects received an injection of ketamine (10.0mg/kg) or saline daily for 10days to investigate the possibility that anxiety emerges only after repeated exposure. Chronic ketamine exposure had no effect on any measure of anxiety. However, chronic ketamine exposure increased locomotion. The results from these experiments indicate that unlike other medications prescribed for depression, neither acute nor chronic ketamine treatment causes anxiety or disruption of sexual behavior. PMID- 29273458 TI - Testing environment shape differentially modulates baseline and nicotine-induced changes in behavior: Sex differences, hypoactivity, and behavioral sensitization. AB - In those who use nicotine, the likelihood of dependence, negative health consequences, and failed treatment outcomes differ as a function of gender. Women may be more sensitive to learning processes driven by repeated nicotine exposure that influence conditioned approach and craving. Sex differences in nicotine's influence over overt behaviors (i.e. hypoactivity or behavioral sensitization) can be examined using passive drug administration models in male and female rats. Following repeated intravenous (IV) nicotine injections, behavioral sensitization is enhanced in female rats compared to males. Nonetheless, characteristics of the testing environment also mediate rodent behavior following drug administration. The current experiment used a within-subjects design to determine if nicotine induced changes in horizontal activity, center entries, and rearing displayed by male and female rats is detected when behavior was recorded in round vs. square chambers. Behaviors were recorded from each group (males-round: n=19; males square: n=18; females-square: n=19; and females-round: n=19) immediately following IV injection of saline, acute nicotine, and repeated nicotine (0.05mg/kg/injection). Prior to nicotine treatment, sex differences were apparent only in round chambers. Following nicotine administration, the order of magnitude for the chamber that provided enhanced detection of hypoactivity or sensitization was contingent upon both the dependent measure under examination and the animal's biological sex. As such, round and square testing chambers provide different, and sometimes contradictory, accounts of how male and female rats respond to nicotine treatment. It is possible that a central mechanism such as stress or cue sensitivity is impacted by both drug exposure and environment to drive the sex differences observed in the current experiment. Until these complex relations are better understood, experiments considering sex differences in drug responses should balance characteristics of the testing environment to provide a complete interpretation of drug-induced changes to behavior. PMID- 29273459 TI - Mirtazapine impairs acquisition and reinstatement of cocaine-induced place preference in rats. AB - Exposure to cues previously associated with drug use and the environment can trigger intense craving and drug-seeking, often leading to relapse in individuals with substance use disorders. Several studies suggest that the decrease in the effects of the cues and the environment could help maintain abstinence from drug use in individuals abusing drugs. Mirtazapine, an antagonist of the noradrenergic (NE) alpha2 receptor and the 5-HT2A/C and 5-HT3 receptors has demonstrated efficacy in reducing the rewarding effect of different drugs. The purpose of the present study was to investigate whether the mirtazapine, blocks the acquisition and reinstatement of cocaine-induced conditioned place preference (CPP). In this study, 120 Wistar male rats were utilized and we use the CPP as a behavioral tool to measure the context-rewarding effect of an unconditioned stimulus such as cocaine. Mirtazapine was dosed for 30 or 60 consecutive days prior to treatment with cocaine or during the extinction phase. We found that dosing with mirtazapine for 30 consecutive days caused a time-related reduction in acquisition or reinstatement of preference for the cocaine-paired chamber. When the duration of treatment is increased (60 days), reductions in preference for the cocaine-paired chamber were potentiated. These observations support its potential clinical anti-addictive properties against drugs. PMID- 29273460 TI - Black Mothers Living With HIV Picture the Social Determinants of Health. AB - The purpose of our study was to explore the social determinants of health for Black mothers living with HIV in the southeastern region of the United States. In this exploratory study, we used qualitative methods of in-depth interviewing and photo elicitation at three time points to provide a comprehensive examination of the meaning that the constructs held for participants (n = 18). The social determinants of health, identified primarily as positive health determinants by the participants, included social support, religion, animal companions, and the physical environment. The social determinants of health identified as mixed determinants, having both positive and negative qualities, were transportation and housing. Each of these social determinants is presented with definitions and exemplars. Additionally, aspects of each determinant of health that may be meaningfully addressed through process and structural level interventions are explored. PMID- 29273461 TI - Evolution of Survival in Cardiac Arrest with Age in Elderly Patients: Is Resuscitation a Dead End? AB - BACKGROUND: Even if age is not considered the key prognostic factor for survival in cardiac arrest (CA), some studies question whether cardiopulmonary resuscitation (CPR) in the elderly could be futile. OBJECTIVE: The aim of this study was to describe differences in out-of-hospital CA survival rates according to age stratification based on the French National CA registry (ReAC). The second objective was to analyze the differences in resuscitation interventions according to age. METHODS: We performed a retrospective cohort study based on data extracted from the ReAC. All 18,249 elderly patients (>65 years old) with non traumatic CA recorded between July 2011 and March 2015 were included. Patients' ages were stratified into 5-year increments. RESULTS: Cardiopulmonary resuscitation (CPR) was started significantly more often in younger patients (p = 0.019). Ventilation and automated external defibrillation by bystanders were started without any difference between age subgroups (p = 0.147 and p = 0.123, respectively). No difference in terms of rate of external chest compressions or ventilation initiation was found between the subgroups (p = 0.357 and p = 0.131, respectively). Advanced cardiac life support was started significantly more often in younger patients (p = 0.023). Total CPR duration, return of spontaneous circulation, and survival at hospital admission and at 30 days or hospital discharge decreased significantly with age (p < 10-3). The survival decrease was linear, with a loss of 3% survival chances each 5-year interval. CONCLUSIONS: This study found that survival in older persons decreased linearly by 3% every 5 years. However, this diminished rate of survival could be the consequence of a shorter duration and less advanced life support. PMID- 29273462 TI - Fibroblast activation proteins-alpha suppress tumor immunity by regulating T cells and tumor-associated macrophages. AB - Fibroblast activation protein-alpha (FAPalpha) is a type-II cell-surface-bound integral transmembrane serine protease and selectively overexpressed by tumor associated stromal fibroblasts (TAFs), which are the main components in the tumor microenvironment, in >90% of malignant epithelial carcinomas. FAPalpha regulates the immunosuppression of tumor cells in the tumor microenvironment. Regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are the major immunosuppressive cells in the tumor microenvironment. However, the effect of FAPalpha on Tregs and TAMs is unknown. The non-enzymatic function of FAPalpha on Treg and TAM was investigated. In this study, we confirm that FAPalpha can promote the generation of Tregs and TAMs, which suggests that FAPalpha plays a immunosuppressive role in the tumor microenvironment and provides evidence for FAP alpha as a potent immunotherapeutic target for cancer. PMID- 29273463 TI - Two novel susceptibility loci for type 2 diabetes mellitus identified by longitudinal exome-wide association studies in a Japanese population. AB - Recent genome-wide association studies identified genetic variants that confer susceptibility to type 2 diabetes mellitus (T2DM). However, few longitudinal genome-wide association studies of this metabolic disorder have been reported to date. Therefore, we performed a longitudinal exome-wide association study of T2DM, using 24,579 single nucleotide polymorphisms (SNPs) and repeated measurements from 6022 Japanese individuals. The generalized estimating equation model was applied to test relations of SNPs to three T2DM-related parameters: prevalence of T2DM, fasting plasma glucose level, and blood glycosylated hemoglobin content. Three SNPs that passed quality control were significantly (P<2.26*10-7) associated with two of the three T2DM-related parameters in additive and recessive models. Of the three SNPs, rs6414624 in EVC and rs78338345 in GGA3 were novel susceptibility loci for T2DM. In the present study, the SNP of GGA3 was predicted to be a genetic variant whose minor allele frequency has recently increased in East Asia. PMID- 29273464 TI - Widening and Rotation of Carotid Artery with Age: Geometric Approach. AB - BACKGROUND: The anatomy and geometry of the carotid artery may play an important role in the pathogenesis of internal carotid artery (ICA) stenosis, but the exact nature of this role remains elusive. To clarify this issue, we sought to investigate age-related changes in the anatomy and geometry of the carotid artery in a Korean population. MATERIALS AND METHODS: We conducted a retrospective study of 300 subjects who underwent carotid contrast-enhanced magnetic resonance angiography at our clinic between 2014 and 2016. The subjects were divided into 7 groups according to age. The carotid arteries were segmented using semiautomated methods to obtain various measurements of carotid anatomy and geometry, as suggested by Thomas et al. The various age groups were compared for different parameters, including ICA angle, bifurcation angle, and vessel volume and diameter. RESULTS: Analysis of variance showed that with an increase in age, there were significant increases in vessel volume and diameter of the common carotid artery and ICA as well as the carotid bifurcation (P = .000). Significant age-related increase was also noted in the ICA angle and bifurcation angle (P = .000). The anatomical position of the ICA in subjects aged over 60 years was significantly higher than that in subjects below 40 years (12.5% versus .03%, P < .0001). CONCLUSIONS: Age-related increases were noted in vessel volume and diameter of the carotid artery and ICA as well as the bifurcation angle. The widening and rotation of the carotid artery increased with age. PMID- 29273465 TI - 68Ga activity calibrations for nuclear medicine applications in Cuba. AB - The realization and dissemination of the 68Ga activity measurement unit in Cuba is presented. Firstly, the implementation of the Triple to Double Coincidence Ratio (TDCR) method is described for the calibration of the activity concentration of a 68Ga solution using a HidexTM commercial liquid scintillation counter and a FORTRAN code developed for the calculation of the 68Ga counting efficiencies in the given measurement system. The relative expanded uncertainty (k = 2) associated with the 68Ga activity concentration obtained with the TDCR method is equal to 2%. With the aim to validate this measurement uncertainty estimate, the method is also applied to an Amersham standard solution of 22Na - a positron emitter with a similar decay mode to the 68Ga disintegration scheme from the point of view of type of emitted particles detected in the measurement system. The observed difference between the measured 22Na activity concentration by the TDCR method and the corresponding reference value traceable to NIST is equal to 0.16%. Outcomes of transferring the 68Ga activity standard, realized with the TDCR method, to the secondary standard radionuclide calibrator Capintec CRCTM 15R and to three radionuclide calibrators used for 68Ga PET applications in a hospital are also shown. PMID- 29273466 TI - The impact of replacing sugar- by artificially-sweetened beverages on brain and behavioral responses to food viewing - An exploratory study. AB - Several studies indicate that the outcome of nutritional and lifestyle interventions can be linked to brain 'signatures' in terms of neural reactivity to food cues. However, 'dieting' is often considered in a rather broad sense, and no study so far investigated modulations in brain responses to food cues occurring over an intervention specifically aiming to reduce sugar intake. We studied neural activity and liking in response to visual food cues in 14 intensive consumers of sugar-sweetened beverages before and after a 3-month replacement period by artificially-sweetened equivalents. Each time, participants were presented with images of solid foods differing in fat content and taste quality while high-density electroencephalography was recorded. Contrary to our hypotheses, there was no significant weight loss over the intervention period and no changes were observed in food liking or in neural activity in regions subserving salience and reward attribution. However, neural activity in response to high-fat, sweet foods was significantly reduced from pre-to post-intervention in prefrontal regions often linked to impulse control. This decrease in activity was associated with weight loss failure, suggesting an impairment in individuals' ability to exert control and adjust their solid food intake over the intervention period. Our findings highlight the need to implement multidisciplinary approaches when aiming to help individuals lose body weight. PMID- 29273467 TI - The effect of premedication with peppermint oil capsules (Colpermin) prior to colonoscopy: A double blind randomized placebo-controlled trial. AB - BACKGROUND AND STUDY AIMS: Colonoscopy is the cornerstone of diagnosing colonic diseases. Investigators have evaluated the effectiveness of antispasmodic agents in colonoscopy with conflicting evidence. The aim of this study is to determine the efficacy of enteric coated peppermint oil capsules (Colpermin(r)), an antispasmodic agent, on outcomes during colonoscopy. PATIENTS AND METHODS: A total of 80 patients undergoing elective colonoscopy were recruited and randomized in a double blinded fashion to receive either placebo or peppermint oil capsules administered 4 h prior to the procedure. RESULTS: Peppermint oil capsules did not affect caecal intubation time when compared with placebo. Patients' tolerance, endoscopist's satisfaction and demand on sedation were also not affected. CONCLUSION: This randomized controlled trial does not support the routine use of peppermint oil capsules prior to colonoscopy as a tool for procedure optimization, and patients' and endoscopist's satisfaction. PMID- 29273468 TI - Systematic gastric biopsy in iron deficiency anaemia. AB - BACKGROUND AND STUDY AIMS: Gastric biopsies are recommended in patients with iron deficiency anaemia to identify atrophic gastritis. However, in practice, only duodenal biopsies are routinely performed. The aim of our study was to determine the value of gastric biopsies in iron deficiency anaemia. PATIENTS AND METHODS: A prospective study including all patients referred for gastrointestinal endoscopy for iron deficiency anaemia from May 2008 to September 2014 was performed. All patients having endoscopic lesions which may explain occult bleeding were excluded, as well as patients using non-steroidal anti-inflammatory drugs or anticoagulation treatment. Two fundic biopsies, two antral biopsies, and one biopsy from the lesser curve were taken in all patients. Following entities were particularly looked for: chronic gastritis, Helicobacter pylori infection, intestinal metaplasia, endocrine hyperplasia and villous atrophy. In cases where intestinal metaplasia was present in the fundus and associated with endocrine hyperplasia and glandular atrophy, immunohistochemical study was performed to confirm autoimmune gastritis. RESULTS: One hundred seventy-seven patients (mean age 50 years, range: 15-90) were included. Chronic gastritis was found in 149 cases (84%). Infection by Helicobacter pylori was found in 107 cases (60%). Fundic intestinal metaplasia was observed in 25 patients (14%) and was associated with Helicobacter pylori infection in 52% of cases. Atrophic gastritis was observed in 14 cases (8%) and autoimmune gastritis was confirmed in 5 cases by immunohistochemical study. One patient had on gastric biopsy a carcinoma with signet ring cells. CONCLUSION: Intestinal metaplasia was frequently observed and was mostly related to Helicobacter pylori infection. These patients require monitoring, especially if they are young because it represents a pre neoplastic condition. However, in our study autoimmune gastritis often described in the literature in case of iron deficiency anaemia was rarely seen raising the question of relative cost-efficiency of fundic biopsies during iron deficiency anaemia. PMID- 29273469 TI - Circulating triacylglycerols but not pancreatic fat associate with insulin secretion in healthy humans. AB - BACKGROUND: Loss of adequate insulin secretion for the prevailing insulin resistance is critical for the development of type 2 diabetes and has been suggested to result from circulating lipids (triacylglycerols [TG] or free fatty acids) and/or adipocytokines or from ectopic lipid storage in the pancreas. This study aimed to address whether circulating lipids, adipocytokines or pancreatic fat primarily associates with lower insulin secretion. SUBJECTS/METHODS: Nondiabetic persons (n=73), recruited from the general population, underwent clinical examinations, fasting blood drawing to measure TG and adipocytokines and oral glucose tolerance testing (OGTT) to assess basal and dynamic insulin secretion and sensitivity indices. Magnetic resonance imaging and 1H-magnetic resonance spectroscopy were used to measure body fat distribution and ectopic fat content in liver and pancreas. RESULTS: In age-, sex- and BMI-adjusted analyses, total and high-molecular-weight adiponectin were the strongest negative predictors of fasting beta-cell function (BCF; beta=-0.403, p=0.0003 and beta= 0.237, p=0.01, respectively) and adaptation index (AI; beta=-0.210, p=0.006 and beta=-0.133, p=0.02, respectively). Circulating TG, but not pancreatic fat content, related positively to BCF (beta=0.375, p<0.0001) and AI (beta=0.192, p=0.003). Similar results were obtained for the disposition index (DI). CONCLUSIONS: The association of serum lipids and adiponectin with beta-cell function may represent a compensatory response to adapt for lower insulin sensitivity in nondiabetic humans. PMID- 29273471 TI - Exposure- and Dose-response Analyses in Dose Selection and Labeling of FDA approved Biologics. AB - PURPOSE: Biological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure-response and dose-response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016. METHODS: We extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure-response/dose-response analyses. We also examined how exposure-response/dose-response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization. FINDINGS: A total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose-response relationship. In support of doses that were described in labeling, exposure-response analyses for efficacy were performed more commonly (53%) than dose-response analyses (21%). This trend was apparent after 2012. IMPLICATIONS: This is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose-response analyses have been often used as the rationale for dose selection of registrational studies, although exposure-response analyses are becoming more prevalent in support of the dosing guidelines in labeling. PMID- 29273470 TI - Relative Bioavailability of Silybin A and Silybin B From 2 Multiconstituent Dietary Supplement Formulations Containing Milk Thistle Extract: A Single-dose Study. AB - PURPOSE: The purpose of this study was to compare the bioavailability between 2 milk thistle-containing dietary supplements, Product B and IsaGenesis, in healthy volunteers. METHODS: Bioavailability between Product B, originally formulated as a powdered capsule, and IsaGenesis, reformulated as a soft gel, were compared by measuring silybin A and silybin B as surrogate pharmacokinetic markers for differences in absorption and bioavailability. For this randomized, open-label, crossover pharmacokinetic study, 12 healthy volunteers consumed a single-dose serving of each supplement separated by at least a 7-day washout period. Serial blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and analyzed via LC-MS/MS. FINDINGS: Rapid absorption and elimination of silybin A and silybin B have been observed after oral administration of both Product B and IsaGenesis. However, the absorption rate and extent, as indicated by mean the Cmax and mean plasma AUC, were significantly higher for the IsaGenesis soft gel formulation. The dose-corrected mean Cmax was 365% and 450% greater for silybin A and B, respectively, relative to powdered Product B. The time to Tmax was reached, on average, at least 1 hour earlier with IsaGenesis relative to Product B for both silybin A and silybin B. IMPLICATIONS: The IsaGenesis soft gel formulation provided substantially greater absorption and bioavailability of silybin A and silybin B relative to the powdered Product B supplement. ClinicalTrials.gov Identifier: NCT02529605. PMID- 29273472 TI - The 2017 ACR Workforce Survey: Management Trends and Strategic Needs. AB - The 2017 ACR Workforce Survey included questions for group leaders about management trends and areas in which they need more help from the ACR. Respondents identified point of care ultrasound as the area in which they need the most help. Most respondents gave positive or neutral answers regarding their role in the management of radiology allied health professionals and radiology information technology, and most believed their role and influence in decision making in the organization were not decreasing. PMID- 29273473 TI - Radiology Architecture Project Primer. AB - The rapid pace of technologic advancement and increasing expectations for patient and family-friendly environments make it common for radiology leaders to be involved in imaging remodel and construction projects. Most radiologists and business directors lack formal training in architectural and construction processes but are expected to play significant and often leading roles in all phases of an imaging construction project. Avoidable mistakes can result in significant increased costs and scheduling delays; knowledgeable participation and communication can result in a final product that enhances staff workflow and morale and improves patient care and experience. This article presents practical guidelines for preparing for and leading a new imaging architectural and construction project. We share principles derived from the radiology and nonradiology literature and our own experience over the past decade completely remodeling a large pediatric radiology department and building a full-service outpatient imaging center. PMID- 29273474 TI - An Assessment of Radiology Residency Program Websites. AB - PURPOSE: When prospective radiology residents decide where to apply to residency, many will use the Internet as a resource to garner information. Therefore, it is important for residency programs to produce and maintain an informative and comprehensive website. Here, we review 179 radiology residency program websites for 19 criteria including various aspects related to the residency application process, benefits, didactics, research, clinical training, and faculty leadership. METHODS: We evaluated 179 radiology residency program websites for the inclusion of 19 different criteria. Criteria for information not available directly on the website and links with no information were considered not present. RESULTS: Only 12 of the 179 (6.7%) program websites had at least 80% of the 19 criteria. In addition, 41 programs (23%) had less than 50% of the criteria listed on their websites. Websites ranged from having 16% of the criteria to as much as 95%. CONCLUSION: Although previous studies have shown that prospective radiology resident applicants are influenced by intangibles like current resident satisfaction and academic reputation, they have also shown that applicants are influenced by the educational curriculum, clinical training, program resources, research opportunities, and quality of faculty. Therefore, it is imperative to provide online resources for prospective candidates in an attempt for residency programs to remain competitive in recruiting high-quality US medical student graduates. These findings suggest there is room for improving the comprehensiveness of information provided on radiology residency program websites. PMID- 29273475 TI - Plectin controls biliary tree architecture and stability in cholestasis. AB - BACKGROUND & AIMS: Plectin, a highly versatile cytolinker protein, controls intermediate filament cytoarchitecture and cellular stress response. In the present study, we investigate the role of plectin in the liver under basal conditions and in experimental cholestasis. METHODS: We generated liver-specific plectin knockout (PleDeltaalb) mice and analyzed them using two cholestatic liver injury models: bile duct ligation (BDL) and 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC) feeding. Primary hepatocytes and a cholangiocyte cell line were used to address the impact of plectin on keratin filament organization and stability in vitro. RESULTS: Plectin deficiency in hepatocytes and biliary epithelial cells led to aberrant keratin filament network organization, biliary tree malformations, and collapse of bile ducts and ductules. Further, plectin ablation significantly aggravated biliary damage upon cholestatic challenge. Coincidently, we observed a significant expansion of A6-positive progenitor cells in PleDeltaalb livers. After BDL, plectin-deficient bile ducts were prominently dilated with more frequent ruptures corresponding to an increased number of bile infarcts. In addition, more abundant keratin aggregates indicated less stable keratin filaments in PleDeltaalb hepatocytes. A transmission electron microscopy analysis revealed a compromised tight junction formation in plectin-deficient biliary epithelial cells. In addition, protein profiling showed increased expression of the adherens junction protein E-Cadherin, and inefficient upregulation of the desmosomal protein desmoplakin in response to BDL. In vitro analyses revealed a higher susceptibility of plectin-deficient keratin networks to stress-induced collapse, paralleled by elevated activation of p38 MAP kinase. CONCLUSION: Our study shows that by maintaining proper keratin network cytoarchitecture and biliary epithelial stability, plectin plays a critical role in protecting the liver from stress elicited by cholestasis. LAY SUMMARY: Plectin is a cytolinker protein capable of interconnecting all three cytoskeletal filament systems and linking them to plasma membrane-bound junctional complexes. In liver, the plectin-controlled cytoskeleton mechanically stabilizes epithelial cells and provides them with the capacity to adapt to increased bile pressure under cholestasis. PMID- 29273476 TI - Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. AB - BACKGROUND & AIMS: Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1beta release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. METHODS: Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd-/-) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd-/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. RESULTS: GSDMD and its pyroptosis inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd-/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1beta, TNF-alpha, and MCP-1 [CCL2]) and persistent activation of the NF-KB signaling pathway. Gsdmd-/- mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparalpha, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. CONCLUSION: As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-KB activation, and lipogenesis. LAY SUMMARY: Non-alcoholic fatty liver disease has become one of the most feared chronic liver diseases, because it is the most rapidly growing indication for adult liver transplantation and a major cause of hepatocellular carcinoma. However, the mechanisms involved in the transformation of simple steatosis to steatohepatitis remain unclear. Herein, we show that gasdermin D driven pyroptosis is prominent in patients with non-alcoholic steatohepatitis (NASH), and gasdermin-N domain remains a potential biomarker for the diagnosis of NASH. Gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-KB signaling pathway, revealing potential treatment targets for NASH in humans. PMID- 29273478 TI - Anesthetic Management of Patients With Carcinoid Syndrome and Carcinoid Heart Disease: The Mount Sinai Algorithm. PMID- 29273479 TI - Perioperative Management of Dual Antiplatelet Therapy. PMID- 29273477 TI - Transfusion Requirements in Cardiac Surgery III (TRICS III): Study Design of a Randomized Controlled Trial. AB - OBJECTIVES: To determine if a restrictive transfusion threshold is noninferior to a higher threshold as measured by a composite outcome of mortality and serious morbidity. DESIGN: Transfusion Requirements in Cardiac Surgery (TRICS) III was a multicenter, international, open-label randomized controlled trial of two commonly used transfusion strategies in patients having cardiac surgery using a noninferiority trial design (ClinicalTrials.gov number, NCT02042898). SETTING: Eligible patients were randomized prior to surgery in a 1:1 ratio. PARTICIPANTS: Potential participants were 18 years or older undergoing planned cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. INTERVENTIONS: Five thousand patients; those allocated to a restrictive transfusion group received a red blood cell (RBC) transfusion if the hemoglobin concentration (Hb) was less than 7.5 g/dL intraoperatively and/or postoperatively. Patients allocated to a liberal transfusion strategy received RBC transfusion if the Hb was less than 9.5 g/dL intraoperatively or postoperatively in the intensive care unit or less than 8.5 g/dL on the ward. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or new onset renal dysfunction requiring dialysis at hospital discharge or day 28, whichever comes first. The primary outcome was analyzed as a per-protocol analysis. The trial monitored adherence closely as adherence to the transfusion triggers is important in ensuring that measured outcomes reflect the transfusion strategy. CONCLUSION: By randomizing prior to surgery, the TRICS III trial captured the most acute reduction in hemoglobin during cardiopulmonary bypass. PMID- 29273480 TI - High Ionized Calcium Concentration Is Associated With Prolonged Length of Stay in the Intensive Care Unit for Postoperative Pediatric Cardiac Patients. AB - OBJECTIVE: There has been controversy regarding the beneficial effects of calcium on myocardial contractility and the harmful effects on myocardial cells, especially in children. The aim of this study was to investigate an association between ionized calcium concentration (iCa) and outcomes for pediatric patients after cardiac surgery. DESIGN: A retrospective, single-center study from May 2013 to December 2014. SETTING: Referral high-volume pediatric cardiac center in a tertiary teaching hospital. PATIENTS: Patients <72 months old with congenital heart disease who underwent palliative or definitive surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The association between pH-corrected iCa within 24 hours after surgery and intensive care unit (ICU) length of stay (ILOS) was defined as the primary outcome. The highest iCa (iCamax), lowest iCa (iCamin), and time-weighted average iCa (iCaave) were stratified and compared with the outcomes. The authors reviewed 5,468 ionized calcium measurements from 357 consecutive pediatric patients during the study period. One patient died at postoperative day 34 in the ICU. Significant differences in ILOS were observed among patients after cardiopulmonary bypass (CPB) according to iCaave, iCamax, and iCamin but not among patients without CPB. Patients with CPB and an iCaave value of 1.31-to-1.40 mmol/L, 1.41-to-1.50 mmol/L, 1.51-to-1.60 mmol/L, and >1.60 mmol/L stayed in the ICU for 7 (interquartile range [IQR] 4-10) days, 8 (IQR 6 16) days, 10 (IQR 8-14) days, and 19 (IQR 12-38) days, respectively, which was significantly longer than the ILOS of 5 (4-8) days for patients with an iCaave of 1.21-to-1.30 mmol/L. Even after adjustment for other predictors of ILOS using multivariable analyses, there were significant relationships of ILOS with iCaave and iCamin values of >1.50 mmol/L among patients with CPB. CONCLUSIONS: Higher iCa within 24 hours after congenital cardiac surgery using CPB was independently associated with longer LOS in the ICU. PMID- 29273481 TI - A novel and highly sensitive real-time nested RT-PCR assay in a single closed tube for detection of enterovirus. AB - The sensitivity of qRT-PCR assay is not adequate for the detection of the samples with lower viral load, particularly in the cerebrospinal fluid (CSF) of patients. Here, we present the development of a highly sensitive real-time nested RT-PCR (RTN RT-PCR) assay in a single closed tube for detection of human enterovirus (HEV). The clinical performance of both RTN RT-PCR and qRT-PCR was also tested and compared using 140 CSF and fecal specimens. The sensitivities of RTN RT-PCR assay for EV71, Coxsackievirus A (CVA)16, CVA6 and CVA10 achieved 10-8 dilution with a corresponding Ct value of 38.20, 36.45, 36.75, and 36.45, respectively, which is equal to traditional two-step nested RT-PCR assay and approximately 2-10 fold lower than that of qRT-PCR assay. The specificity of RTN RT-PCR assay was extensively analyzed insilico and subsequently verified using the reference isolates and clinical samples. Sixteen qRT-PCR-negative samples were detected by RTN RT-PCR and a variety of enterovirus serotypes was identified by sequencing of inner PCR products. We conclude RTN RT-PCR is more sensitive than qRT-PCR for the detection of HEV in clinical samples. PMID- 29273483 TI - Growth hormone receptor (GHR) gene polymorphism and scoliosis in Prader-Willi syndrome. AB - OBJECTIVE: A growth hormone receptor (GHR) gene polymorphism impacts sensitivity to endogenous and exogenous growth hormone (GH) to moderate growth and development. Increased sensitivity may accelerate spinal growth and contribute to scoliosis, particularly in GH-deficient and treated populations such as Prader Willi syndrome (PWS). Therefore, we examined the relationship between GHR genotype and scoliosis (case and control) in PWS cohorts. DESIGN: We utilized a case-control design in a study of 73 subjects (34M; 39F) with genetically confirmed PWS in 32 individuals previously diagnosed with moderate to severe scoliosis (mean age=16.9+/-10.2years; age range of 1 to 41years) and 41 adults with no evidence of scoliosis (mean age=30.8+/-9.7years; age range of 18 to 56years). The GHR gene polymorphism was determined using PCR specific primers to capture the two recognized GHR gene fragment sizes [i.e., full length (fl) or exon 3 deletions (d3)]. RESULTS: Twenty-three (72%) of the 32 case subjects with scoliosis required surgical correction with an approximately equal balance for gender and PWS genetic subtype among cases and 41 control subjects without scoliosis. The GHR d3/d3 genotype was identified in N=2 of 8 (25%) cases with scoliosis and the d3/fl genotype was identified in N=11 of 25 (44%) cases with scoliosis but the distribution difference did not statistically differ. The GHR fl/fl genotype was correlated with a significantly faster rate and heavier weight gain among case subjects. CONCLUSION: Our examination of demographic and genetic markers associated with scoliosis and surgical repair in PWS found no evidence to support differences in gender, PWS genetic subtype or GHR d3 allele distributions among the case vs control groups. Those with fl/fl alleles were heavier than those with d3/d3 or d3/fl genotypes and warrant further study with a larger sample size and possibly to include other vulnerable populations requiring growth hormone treatment. PMID- 29273482 TI - A novel host-protein assay outperforms routine parameters for distinguishing between bacterial and viral lower respiratory tract infections. AB - Bacterial and viral lower respiratory tract infections (LRTIs) are often clinically indistinguishable, leading to antibiotic overuse. We compared the diagnostic accuracy of a new assay that combines 3 host-biomarkers (TRAIL, IP-10, CRP) with parameters in routine use to distinguish bacterial from viral LRTIs. Study cohort included 184 potentially eligible pediatric and adult patients. Reference standard diagnosis was based on adjudication by an expert panel following comprehensive clinical and laboratory investigation (including respiratory PCRs). Experts were blinded to assay results and assay performers were blinded to reference standard outcomes. Evaluated cohort included 88 bacterial and 36 viral patients (23 did not fulfill inclusion criteria; 37 had indeterminate reference standard outcome). Assay distinguished bacterial from viral LRTI patients with sensitivity of 0.93+/-0.06 and specificity of 0.91+/ 0.09, outperforming routine parameters, including WBC, CRP and chest x-ray signs. These findings support the assay's potential to help clinicians avoid missing bacterial LRTIs or overusing antibiotics. PMID- 29273484 TI - The IGF-p53 connection in cancer. AB - Healthy tissue growth depends on a well-controlled and context-appropriate balance of cellular proliferation, cell cycle arrest, and programmed cell death (apoptosis). Disturbance of this balance by activation of oncogenes, inactivation/mutation of tumor suppressor genes, or inhibition of apoptosis can promote tumorigenesis. This mini-review will focus on evidence for the contribution of insulin-like growth factor (IGF) signaling and its regulation by the transcription factor, p53, to tumor development and progression. PMID- 29273485 TI - A first-in-man phase 1 trial for long-acting TransCon Growth Hormone. AB - TransCon growth hormone (GH) is a sustained-release inactive prodrug consisting of unmodified GH transiently bound to an inert carrier molecule designed to release fully active GH over a one-week period. This was a first-in-man phase 1 randomized trial was to evaluate the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose of TransCon GH as compared to equivalent doses of daily GH (Omnitrope) or placebo in healthy adults. Forty-four healthy male adults were randomized to 4 cohorts of 11 subjects, distributed in a 7:2:2 ratio (TransCon GH: Omnitrope: placebo). A single injection of 4 possible TransCon GH doses (i.e., 0.04, 0.08, 0.16, or 0.24mg GH/kg/wk) or two different Omnitrope doses (i.e., 0.08 or 0.16mg GH/kg/wk divided into 7 equal daily doses) were administered with subjects evaluated for adverse events, immunogenicity, and GH and insulin-like growth factor-1 (IGF-1) levels. TransCon GH was well tolerated; no serious adverse events occurred, no injection site reaction differences between TransCon GH, Omnitrope, or placebo were identified, no nodules or lipoatrophy were reported, and no anti-GH binding antibodies or ECG changes were detected. Overall, the exposure of GH (Cmax) and IGF-1 (AUC0-168h) following administration of equivalent doses of TransCon GH and Omnitrope were similar. GH and IGF-1 kinetics showed a dose-proportional increase following a single SC administration of TransCon GH and indicated that the prodrug is suitable for weekly administration. These results support advancement of TransCon GH to pediatric and adult GHD trials. Clinical trial registration numbers: NCT01010425 (clinicaltrials.gov). PMID- 29273487 TI - High-value dermatology: 5 Laboratory tests to reconsider. PMID- 29273486 TI - Merkel cell carcinomas infiltrated with CD33+ myeloid cells and CD8+ T cells are associated with improved outcome. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumor of the skin that has an aggressive behavior. Immunity is the main regulator of MCC development, and many interactions between lymphocytes and tumor cells have been proven. However, the impact of tumor-infiltrating myeloid cells needs better characterization. OBJECTIVE: To characterize tumor-infiltrating myeloid cells in MCC and their association with other immune effectors and patient outcome. METHODS: MCC cases were reviewed from an ongoing prospective cohort study. In all, 103 triplicate tumor samples were included in a tissue microarray. Macrophages, neutrophils, and myeloid-derived suppressor cells were characterized by the following markers: CD68, CD33, CD163, CD15, CD33, and human leukocyte antigen-DR. Associations of these cell populations with programmed cell death ligand 1 expression, CD8 infiltrates, and vascular density were assessed. Impact on survival was analyzed by log-rank tests and a Cox multivariate model. RESULTS: The median density of macrophages was 216 cells/mm2. CD68+ and CD33+ macrophage densities were associated with CD8+ T-cell infiltrates and programmed cell death ligand 1 expression. In addition, MCC harboring CD8+ T cell infiltrates and brisk CD33+ myeloid cell infiltrates were significantly and independently associated with improved outcomes (recurrence-free and overall survival). LIMITATIONS: Sampling bias and the retrospective design were potential study limitations. CONCLUSION: Infiltration of CD33+ myeloid cells and CD8+ T lymphocytes defines a subset of MCC associated with improved outcome. PMID- 29273488 TI - Repeated Amblyomma testudinarium tick bites are associated with increased galactose-alpha-1,3-galactose carbohydrate IgE antibody levels: A retrospective cohort study in a single institution. AB - BACKGROUND: Alpha-gal syndrome is a hypersensitivity reaction to red meat mediated by IgE antibody specific to galactose-alpha-1,3-galactose carbohydrate (alpha-gal). Amblyomma tick bites are associated with this condition, but the pathophysiology is not understood. OBJECTIVE: To clarify the mechanism of development of alpha-gal syndrome after tick bites. METHODS: We compared alpha gal antibody levels between patients with and without a history of tick bites and examined histologic stainings of tick bite lesions between patients with and without detectable alpha-gal IgE antibody. RESULTS: Patients who had >=2 tick bites had higher levels of alpha-gal IgE antibody compared with those with only 1 tick bite or healthy individuals. On histologic investigation, greater numbers of basophils and eosinophils, but not mast cells, were observed infiltrating lesions of patients with >=2 tick bites compared with those with 1 tick bite. Type 2 cytokine-producing T-cell infiltration was predominantly observed in such patients. LIMITATIONS: The study was conducted at a single institution in Japan. CONCLUSION: In Amblyomma tick bite lesions, basophils; eosinophils; and type 2, cytokine-producing T cells infiltrate the skin and alpha-gal IgE antibodies are produced. These findings provide a potential mechanistic connection between Amblyomma bites and red meat hypersensitivity. PMID- 29273490 TI - Descriptive survival study of nail melanoma patients treated with functional surgery versus distal amputation. PMID- 29273489 TI - Inflammatory dermatoses, infections, and drug eruptions are the most common skin conditions in hospitalized cancer patients. AB - BACKGROUND: Dermatologic conditions cause morbidity and mortality among hospitalized cancer patients. An improved understanding is critical for implementing clinical and research programs in inpatient oncodermatology. OBJECTIVE: To characterize inpatient dermatology consultations at a large comprehensive cancer center. METHODS: Retrospective database query of new admissions and medical record review of initial inpatient dermatology consultations comparing inpatients consulted and not consulted during January December 2015. RESULTS: In total, 412 of 11,533 inpatients received 471 dermatology consultations (54% male, median age 59.5 years). Patients with hematologic cancers were 6 times more likely to receive dermatologic consultations compared with nonhematologic cancers (odds ratio 6.56, 95% confidence interval 5.35-8.05, P < .0001). Patients consulted by a dermatologist had a significantly longer length of stay than inpatients not consulted by dermatology (median 11 vs 5 days, P < .0001). Among the 645 dermatologic conditions diagnosed, the most common categories were inflammatory diseases, infections, and drug reactions; the most frequent conditions were contact dermatitis, herpes zoster, and chemotherapy-induced drug eruptions. LIMITATIONS: The study's retrospective nature and single-institution setting are potential limitations. CONCLUSION: Hematologic malignancies are a significant risk factor for dermatology inpatient consultations. A significantly longer length of stay was associated with dermatology consultations, suggesting high comorbidities in these patients. Increased dermatologic care of these inpatients might improve quality of life, dermatologic health, and ability to receive anticancer agents. PMID- 29273491 TI - Supervision, autonomy, and medical error in the teaching clinic. PMID- 29273492 TI - Micro-computed Tomographic Evaluation of the Shaping Ability of XP-endo Shaper, iRaCe, and EdgeFile Systems in Long Oval-shaped Canals. AB - INTRODUCTION: This study evaluated the shaping ability of the XP-endo Shaper (FKG Dentaire SA, La Chaux-de-Fonds, Switzerland), iRaCe (FKG Dentaire SA), and EdgeFile (EdgeEndo, Albuquerque, NM) systems using micro-computed tomographic (micro-CT) technology. METHODS: Thirty long oval-shaped canals from mandibular incisors were matched anatomically using micro-CT scanning (SkyScan1174v2; Bruker microCT, Kontich, Belgium) and distributed into 3 groups (n = 10) according to the canal preparation protocol (ie, XP-endo Shaper, iRaCe, and EdgeFile systems). Coregistered images, before and after preparation, were evaluated for morphometric measurements of the volume, surface area, structure model index (SMI), untouched walls, area, perimeter, roundness, and diameter. Data were statistically compared between groups using the 1-way analysis of variance post hoc Tukey test and within groups with the paired sample t test (alpha = 5%). RESULTS: Within groups, preparation significantly increased all tested parameters (P < .05). No statistical difference was observed in the mean percentage increase of the volume (~52%) and surface area (10.8%-14.2%) or the mean percentage of the remaining unprepared canal walls between groups (8.17%-9.83%) (P > .05). The XP endo Shaper significantly altered the overall geometry of the root canal to a more conical shape (SMI = 2.59) when compared with the other groups (P < .05). After preparation protocols, changes in area, perimeter, roundness, and minor and major diameters of the root canals in the 5 mm of the root apex showed no difference between groups (P > .05). CONCLUSIONS: The XP-endo Shaper, iRaCe, and EdgeFile systems showed a similar shaping ability. Despite the XP-endo Shaper had significantly altered the overall geometry of the root canal to a more conical shape, neither technique was capable of completely preparing the long oval-shaped canals of mandibular incisors. PMID- 29273493 TI - Does the Orifice-directed Dentin Conservation Access Design Debride Pulp Chamber and Mesial Root Canal Systems of Mandibular Molars Similar to a Traditional Access Design? AB - INTRODUCTION: Despite the increasing reports on mechanical aspects of contracted endodontic access cavities (CECs), we believe that the biological aspects (debridement) have not been adequately investigated. This study examined if 1 type of CEC (orifice-directed dentin conservation [DDC] access) was able to debride the pulp chamber, root canals, and isthmus of mesial roots of mandibular molars similar to a traditional endodontic access cavity (TEC). METHODS: Mandibular molars (N = 32) were selected and divided randomly into 2 experimental groups (n = 12) after micro-computed tomographic scanning (group 1: TEC and group 2: DDC) and histologic controls (n = 8). After instrumentation to a size 30/0.06 taper using 3% sodium hypochlorite as irrigant, specimens were processed for histologic evaluation, and the remaining pulp tissue (RPT) was measured from the pulp chamber, root canal, and isthmus at all root thirds. Data were analyzed using 1-way analysis of variance, Kruskal-Wallis, and appropriate post hoc tests (P = .05). RESULTS: The RPT in the pulp chamber was significantly higher in DDC compared with TEC (P < .05). Comparing the root thirds in each group, there was no significant difference in the RPT within the root canals or the isthmus (P > .05). The RPT within the root canals and isthmus was not significantly different between the 2 access cavity designs at any root third (P > .05). CONCLUSIONS: Debridement of the pulp chamber was significantly compromised in DDC. The type of access cavity did not influence the amount of RPT in the root canals and isthmus. PMID- 29273494 TI - Anesthetic Efficacy of Gow-Gates Nerve Block, Inferior Alveolar Nerve Block, and Their Combination in Mandibular Molars with Symptomatic Irreversible Pulpitis: A Prospective, Randomized Clinical Trial. AB - INTRODUCTION: The purpose of this prospective, randomized clinical trial was to evaluate the anesthetic efficacy of the Gow-Gates nerve block (GGNB), the inferior alveolar nerve block (IANB), and their combination for mandibular molars in patients with symptomatic irreversible pulpitis. METHODS: One hundred fifty patients diagnosed with symptomatic irreversible pulpitis of a mandibular molar were selected. The patients randomly received 2 GGNB injections, 2 IANB injections, or 1 GGNB injection plus 1 IANB injection of 1.8 mL 2% lidocaine with 1:80,000 epinephrine. Access cavity preparation was initiated 15 minutes after injections. Lip numbness was a requisite for all of the patients. Success was specified as no or mild pain on the basis of Heft-Parker visual analog scale recordings during access cavity preparation or initial instrumentation. Data were analyzed with the chi-square, Kruskal-Wallis, and analysis of variance tests. RESULTS: The success rates of anesthesia were 40%, 44%, and 70% for the GGNB, IANB, and GGNB + IANB groups, respectively. There was no statistically significant difference in the success rate of anesthesia between the GGNB and IANB groups (P > .05). The anesthesia success rate for the GGNB + IANB group was significantly different from those of the GGNB and IANB groups (P < .05). CONCLUSIONS: A combination of GGNB and IANB could improve the efficacy of anesthesia in mandibular molars with symptomatic irreversible pulpitis, but it would still require supplemental anesthesia. Further research may be needed to confirm the results of this study. PMID- 29273496 TI - Corrigendum to "Spinal fusion limits upper body range of motion during gait without inducing compensatory mechanisms in adolescent idiopathic scoliosis patients" [Gait Posture 57 (2017) 1-6]. PMID- 29273495 TI - Influence of Apical Diameter on the Outcome of Regenerative Endodontic Treatment in Teeth with Pulp Necrosis: A Review. AB - INTRODUCTION: The aim of this review was to evaluate whether the apical diameter of teeth with necrotic pulp affects the outcomes of regenerative endodontic treatment and to determine the minimal apical size needed to obtain proper pulp revascularization. METHODS: A literature search was performed from January 1, 2001, to November 25, 2016. Studies that satisfied the inclusion criteria were subjected to data extraction and analysis. RESULTS: In total, 14 studies with 85 patients were included. There were 10 case reports, 3 case series, and 1 prospective cohort study. The apical diameters of the teeth were divided into 3 groups: a narrow-sized group (group N), <0.5 mm (n = 10); a medium-sized group (group M), 0.5-1.0 mm (n = 25); and a wide-sized group (group W), >1.0 mm (n = 60). In group N, 1 tooth failed, 2 teeth completely healed, and 7 teeth incompletely healed. In group M, 2 teeth were excluded, and 1 tooth failed. In group W, 3 teeth were excluded, and 4 teeth failed. The clinical success rates were 90%, 95.65%, and 92.98% in groups N, M, and W, respectively. CONCLUSIONS: Within the limitations, the teeth with apical diameters <1.0 mm achieved clinical success after regenerative endodontic treatment. Meanwhile, the teeth with apical diameters of 0.5-1.0 mm attained the highest clinical success rate, which may be related to other potential factors, including patient age, pulp necrosis etiology, preoperative apical radiolucency, procedure details, follow-up period, and sample size. PMID- 29273497 TI - Methotrexate in patients with rheumatoid arthritis in Spain: Subanalysis of the AR Excellence project. AB - OBJECTIVE: The AR Excellence project evaluates clinical monitoring in patients with rheumatoid arthritis (RA) in Spain. The aim of the study was to analyze the use of methotrexate (MTX) in the AR Excellence cohort and to compare it with current recommendations. PATIENTS AND METHODS: We collected data from RA patients who initiated treatment with MTX. They included demographics, dose and routes of administration, switching among them, highest dose in each route, combinations with other disease-modifying antirheumatic drugs (DMARDs), time to combination with another DMARD (either conventional or biological) and adverse events. RESULTS: Six hundred twenty-five patients with RA (mean age 55 years; 70.6% women) were included, with an average disease duration of 21 months. Ninety percent of the patients initiated treatment with MTX. Therapy was begun with a mean dose of 11mg per week; this initial dose was increased in 58% of the individuals. The average time to reach the full dose of MTX (20mg a week) was 6,67 months. Time to combination of MTX with another DMARD, either synthetic or biological, was 3 months. In all, 67.4% of the patients received oral MTX and the route was subcutaneous in 18.6%. In 12% of the cases, there was a change in the route of administration after a period of 6 months. In 544 patients, folate supplements were added to MTX; MTX-related adverse events were detected in 17.3% of the patients. CONCLUSION: MTX is currently the pivotal treatment in RA. The subanalysis of the AR Excellence project demonstrates that MTX escalation to its full doses is not done with adequate speed. The subcutaneous route is used in a small proportion of patients. PMID- 29273499 TI - Combination Therapy Is the New Gene Therapy? PMID- 29273498 TI - Engineering Protein-Secreting Plasma Cells by Homology-Directed Repair in Primary Human B Cells. AB - The ability to engineer primary human B cells to differentiate into long-lived plasma cells and secrete a de novo protein may allow the creation of novel plasma cell therapies for protein deficiency diseases and other clinical applications. We initially developed methods for efficient genome editing of primary B cells isolated from peripheral blood. By delivering CRISPR/CRISPR-associated protein 9 (Cas9) ribonucleoprotein (RNP) complexes under conditions of rapid B cell expansion, we achieved site-specific gene disruption at multiple loci in primary human B cells (with editing rates of up to 94%). We used this method to alter ex vivo plasma cell differentiation by disrupting developmental regulatory genes. Next, we co-delivered RNPs with either a single-stranded DNA oligonucleotide or adeno-associated viruses containing homologous repair templates. Using either delivery method, we achieved targeted sequence integration at high efficiency (up to 40%) via homology-directed repair. This method enabled us to engineer plasma cells to secrete factor IX (FIX) or B cell activating factor (BAFF) at high levels. Finally, we show that introduction of BAFF into plasma cells promotes their engraftment into immunodeficient mice. Our results highlight the utility of genome editing in studying human B cell biology and demonstrate a novel strategy for modifying human plasma cells to secrete therapeutic proteins. PMID- 29273500 TI - Seek and You Will Not Find: Ending the Hunt for Replication-Competent Retroviruses during Human Gene Therapy. PMID- 29273502 TI - miR-25 Tough Decoy Enhances Cardiac Function in Heart Failure. AB - MicroRNAs are promising therapeutic targets, because their inhibition has the potential to normalize gene expression in diseased states. Recently, our group found that miR-25 is a key SERCA2a regulating microRNA, and we showed that multiple injections of antagomirs against miR-25 enhance cardiac contractility and function through SERCA2a restoration in a murine heart failure model. However, for clinical application, a more stable suppressor of miR-25 would be desirable. Tough Decoy (TuD) inhibitors are emerging as a highly effective method for microRNA inhibition due to their resistance to endonucleolytic degradation, high miRNA binding affinity, and efficient delivery. We generated a miR-25 TuD inhibitor and subcloned it into a cardiotropic AAV9 vector to evaluate its efficacy. The AAV9 TuD showed selective inhibition of miR-25 in vitro cardiomyoblast culture. In vivo, AAV9-miR-25 TuD delivered to the murine pressure overload heart failure model selectively decreased expression of miR-25, increased levels of SERCA2a protein, and ameliorated cardiac dysfunction and fibrosis. Our data indicate that miR-25 TuD is an effective long-term suppressor of miR-25 and a promising therapeutic candidate to treat heart failure. PMID- 29273501 TI - Selective alpha-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson's Disease. AB - Progressive neuronal death in brainstem nuclei and widespread accumulation of alpha-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Reduction of alpha-synuclein levels is therefore a potential therapy for PD. However, because alpha-synuclein is essential for neuronal development and function, alpha-synuclein elimination would dramatically impact brain function. We previously developed conjugated small interfering RNA (siRNA) sequences that selectively target serotonin (5-HT) or norepinephrine (NE) neurons after intranasal administration. Here, we used this strategy to conjugate inhibitory oligonucleotides, siRNA and antisense oligonucleotide (ASO), with the triple monoamine reuptake inhibitor indatraline (IND), to selectively reduce alpha synuclein expression in the brainstem monoamine nuclei of mice after intranasal delivery. Following internalization of the conjugated oligonucleotides in monoamine neurons, reduced levels of endogenous alpha-synuclein mRNA and protein were found in substantia nigra pars compacta (SNc), ventral tegmental area (VTA), dorsal raphe nucleus (DR), and locus coeruleus (LC). alpha-Synuclein knockdown by ~20%-40% did not cause monoaminergic neurodegeneration and enhanced forebrain dopamine (DA) and 5-HT release. Conversely, a modest human alpha-synuclein overexpression in DA neurons markedly reduced striatal DA release. These results indicate that alpha-synuclein negatively regulates monoamine neurotransmission and set the stage for the testing of non-viral inhibitory oligonucleotides as disease-modifying agents in alpha-synuclein models of PD. PMID- 29273503 TI - [Is the research of posttransfusional alloantibodies still relevant?] AB - : The decision of November 6th, 2006 defining the principles of best practices recommends that posttransfusional red cell alloantibodies research is performed after one to three months after. In the University hospital of Brest, the haemovigilance unit takes charge of sending the medical prescription within the required time and centralizing the results. We wished to estimate if the realization of this research still remains relevant. METHODS: A prospective analysis was performed in 2015. We evaluated the realization rate, the red cell alloantibodies rate and the recipient adverse reactions with the diagnostic category: alloimmunization (delayed serological transfusion reaction, DSTR). RESULTS: In 2015, 2162 prescriptions were sent to the 3271 transfused patients. One thousand and eighteen red cell alloantibodies research were done, i.e. a return rate of 61%. Among them, 12 alloantibodies appeared (0.9%) within an average of 56 days. Thirty-three other alloantibodies appeared and were discovered most frequently before a new transfusion. In 10 cases, a posttransfusional research was done that was negative. A survey was conducted among GHCOH members to describe the practices in these health institutions. Twelve questionnaires were analysed. Ten institutions performed a posttransfusional alloantibodies research by issuing a prescription at the patient's exit with a return rate between 0.14 and 16%; 1 institution has a centralized organization with a return rate of 68.3%; 1566 red cell alloantibodies research were performed and among them, 24 alloantibodies appeared (1.53%). CONCLUSION: These results indicate that to be effective, the management of this biological test must be centralized. Despite this, the red cell alloantibodies rate remains very low (0.9 and 1.53%) and raises the question of the relevance of this systematic testing after transfusion, which is in any case mandatory before a new transfusion of red blood cells. PMID- 29273504 TI - Fibroblast growth factor 21 ameliorates vascular calcification by inhibiting osteogenic transition in vitamin D3 plus nicotine-treated rats. AB - FGF21, a special member of FGF superfamily, has been proven to have pleiotropic metabolic effects and many potential therapeutic action in various metabolic disorders. Vascular calcification (VC), a perplexing clinical issue, is a major risk factor for many cardiovascular diseases, especially for patients with some metabolic diseases. However, the role of FGF21 on VC in vivo remains unclear. Thus, in this study, we observed the effect and mechanism of FGF21 on VC induced by vitamin D3 plus nicotine (VDN) treated rats. After four weeks' treatment, the calcium overload is mainly manifested in the increased blood pressure, aortic calcium content and ALP activity. Also, the HE and Alizarin-red S staining showed the structural damage of calcified vessel walls. In addition, the level of endogenous FGF21/beta-Klotho/FGFR1 axis was up-regulated in the aortas of VC rats. Furthermore, exogenous FGF21 treatment significantly ameliorated the aortic injury and calcification in VC rats, and the level of beta-Klotho and FGFR1 were furtherly increase. Moreover, FGF21 inhibited the osteogenic transition of VSMCs by down-regulating the expression of bone-associated proteins such as osteopontin (OPN), osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2), together with restored the expression of SM22alpha and SM alpha-actin, which are two of lineage markers in VSMCs. We provide the first evidence that FGF21 can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs in rats. FGF21 might be an efficient endogenous vasoprotective factor for calcification. PMID- 29273505 TI - Identification and characterization of a novel prolyl oligopeptidase in filarial parasite Setaria cervi. AB - A 75 kDa serine protease having prolyl oligopeptidase activity has been purified from Setaria cervi, a bovine filarial parasite. The MALDI-MS/MS analysis of the purified protein revealed 6 peptides showing nearest match S9A (prolyl oligopeptidase) family protein from Plesiocystis pacifica. The ScPOP was found to be unique compared to mammalian POP with respect to its kinetic properties. To elucidate its role, filarial parasites were exposed to specific inhibitor of POP, Z-Pro-prolinal (ZPP) for 8 h. The inhibition of POP induced calcium signaling via phospholipase c stimulation which further triggered mitochondrial mediated apoptosis in filarial parasites. PMID- 29273506 TI - Bromodomain-containing protein 7 deficiency augments atherosclerotic lesions in ApoE-/- mice. AB - Atherosclerotic plaque formation is characterized by the persistence of lipid laden macrophages on the inner walls of arteries. Chronic inflammation and imbalanced macrophage function are likely to play a critical role. Herein, we investigated whether bromodomain-containing protein 7 (Brd7), a member of the bromodomain-containing protein family, regulates atherosclerosis, and if so, which mechanisms are responsible for the process. We found that Brd7 is expressed in mouse atherosclerotic plaques, and mostly in macrophages. Inhibition of Brd7 accelerates atherosclerotic lesion formation in ApoE-/- mice by promoting NF kappaB-mediated inflammation. Furthermore, Brd7 inhibition alters the phenotype of macrophages and promotes plaque instability, at least partly via STAT6 signaling. Our data define a previously undescribed role of Brd7 in the development of atherosclerosis. PMID- 29273507 TI - Organic anion transporter 1 (OAT1/SLC22A6) enhances bioluminescence based on d luciferin-luciferase reaction in living cells by facilitating the intracellular accumulation of d-luciferin. AB - Bioluminescence (BL) imaging based on d-luciferin (d-luc)-luciferase reaction allows noninvasive and real-time monitoring of luciferase-expressing cells. Because BL intensity depends on photons generated through the d-luc-luciferase reaction, an approach to increase intracellular levels of d-luc could improve the detection sensitivity. In the present study, we showed that organic anion transporter 1 (OAT1) is useful, as a d-luc transporter, in boosting the BL intensity in luciferase-expressing cells. Functional screening of several transporters showed that the expression of OAT1 in HEK293 cells stably expressing Pyrearinus termitilluminans luciferase (HEK293/eLuc) markedly enhanced BL intensity in the presence of d-luc. When OAT1 was transiently expressed in HEK293 cells, intracellular accumulation of d-luc was higher than that in control cells, and the specific d-luc uptake mediated by OAT1 was saturable with a Michaelis constant (Km) of 0.23 MUM. The interaction between OAT1 and d-luc was verified using 6-carboxyfluorescein, a typical substrate of OAT1, which showed that d-luc inhibited the uptake of 6-carboxyfluorescein mediated by OAT1. BL intensity was concentration-dependent at steady states in HEK293/eLuc cells stably expressing OAT1, and followed Michaelis-Menten kinetics with an apparent Km of 0.36 MUM. In addition, the enhanced BL was significantly inhibited by OAT1-specific inhibitors. Thus, OAT1-mediated transport of d-luc could be a rate-limiting step in the d-luc-luciferase reaction. Furthermore, we found that expressing OAT1 in HEK293/eLuc cells implanted subcutaneously in mice also significantly increased the BL after intraperitoneal injection of d-luc. Our findings suggest that because OAT1 is capable of transporting d-luc, it can also be used to improve visualization and monitoring of luciferase-expressing cells. PMID- 29273508 TI - Prevalence, quantification and isolation of pathogenic shiga toxin Escherichia coli O157:H7 along the production and supply chain of pork around Hubei Province of China. AB - Shiga toxin Escherichia coli (STEC) O157:H7 is an important zoonotic food borne pathogen causing gastroenteritis that may lead to life threatening hemorragic colitis (HC) and hemorrhagic uremic syndrome (HUS). 325 meat and tissue samples were tested for enumeration of O157:H7 strains using most probable number (MPN) PCR targeting their specific genes flicH7 and rfbO157 followed by isolation, sereotyping and pathogenicity testing. The overall prevalence of O157:H7 was 41.3% (134/325) along the production and supply chain of pork (PSCP), being higher in supply chain (59%, 118/200) as compared to pig farms (12.8%, 16/125). Along the PSCP, the highest prevalence was found in slaughter houses (86.25%, 69/80) followed by wet- (53.3%, 32/60) and super-markets (28.3%, 17/60). The MPN values ranged from 3 to 1100 MPN/g in overall positive samples, being higher in slaughter houses followed by wet and super markets. Except from intestine and meat samples of slaughter house, the MPN was found higher in summer as compared to winter samples. Eight STEC O157:H7 isolated from meat and liver samples were tested in Balb/C mice for pathogenicity. After development of clinical signs and symptoms, 50-83.3% mortality was produced in the infected mice. Histopathological investigations revealed visible necrosis of intestinal epithelial cells, shedding of cellular debris in the intestine, while in the kidney, necrosis of renal cortical portion of tubular epithelial cells was observed. STEC O157:H7 is prevalent along PSCP around Hubei of China in different proportions being alarmingly higher in supply chain and markets which is a matter of concern for public health. PMID- 29273509 TI - Diversity of virulence genes in multidrug resistant Pseudomonas aeruginosa isolated from burn wound infections. AB - Multidrug resistant Pseudomonas aeruginosa has frequently been reported as the cause of nosocomial outbreaks of burn wound infections. The pathogenesis of P. aeruginosa is partly due to the production of several cell-associated and extracellular virulence factors. A total of 93 P. aeruginosa isolated from burn wound infections were investigated for antimicrobial susceptibility and distribution of virulence genes. All (100%) isolates were resistant to one or more antimicrobial agents. The most frequent resistance found against ampicillin (91.4%), co-trimoxazole (77.4%), gentamicin (68.8%), cefotaxime (50.5%), aztreonam and piperacillin (41.9%). A total of 88 (94.6%) isolates were resistant to at least three different classes of antimicrobial agents and considered as multidrug resistance MDR. All isolates carried at least two or more different virulence genes. The most prevalent virulence gene was toxA (97.8%), followed by plcH (96.7%), phzI (96.7%), exoY (93.1%) and phzII (90.3%). exoU was not detected in P. aeruginosa isolates. The frequency of pilB (17.2%), exoT (20.4%), pilA (24.7%) and phzS/phzH (27.9%) was lower than other virulence genes. Twenty nine (31.2%) isolates had simultaneously 8 virulence genes, 22 (23.7%) isolates had 6 virulence genes and 19 (20.4%) isolates had 7 virulence genes. All MDR isolates carried at least 5 virulence factors. These results indicate a high frequency and heterogeneity of virulence gene profiles among multidrug resistant P. aeruginosa isolates recovered from burn wound infections. Therefore, appropriate surveillance and control measures are essential to prevent the further spread of these isolates in hospitals. PMID- 29273511 TI - Anti-biofilm and anti-virulence potential of 3,7-dimethyloct-6-enal derived from Citrus hystrix against bacterial blight of rice caused by Xanthomonas oryzae pv. oryzae. AB - The present investigation for the first time explains the anti biofilm and anti virulence potential of Kaffir lime oil (KLO) and its major constituent, Citronellal (3,7-dimethyloct-6-enal) against Xanthomonas oryzae pv. oryzae, causal organism of bacterial blight disease of rice. KLO at 500 ppm showed potential activity against X. oryzae pv. oryzae. Among the major components identified, citronellal (CIT) at 75 MUM concentration was found to significantly inhibit biofilm along with the swimming and swarming potential of X. oryzae pv. oryzae. In contrary, CIT did not affect the metabolic status and growth kinetics of the bacterial cells. Gene expression analysis showed down regulation in motA, cheD, cheY, flgF, gumC, xylanase, endogluconase, cellulose, cellobiosidase, virulence and rpfF transcript levels by citronellal treatment. However, an insignificant effect of 75 MUM CIT treatment was observed on motB, flgE, pilA, estY, pglA, protease and lytic genes expression. Finally, the observations recorded were in confirmity with the virulence leaf clip test as lesion length was significantly decreased (39%) in CIT treatment as compared to the control leaves inoculated with only X. oryzae pv. oryzae. Overall, the findings obtained advocate the use of CIT for promising anti biofilm and anti virulence activity which in turn can be used for managing the blight disease in rice. PMID- 29273510 TI - Epigallocatechin gallate can attenuate human alveolar epithelial cell injury induced by alpha-haemolysin. AB - Staphylococcus aureus (S. aureus) is a common cause of hospital-acquired infection and has become an epidemic globally. Alpha-haemolysin (alpha haemolysin), a pore-forming toxin, is one of the most important virulence factors secreted by most S. aureus strains. alpha-haemolysin monomers form a 232.4-kDa membrane-inserted heptamer by self-assembling to cause host cell lysis and death. Consequently, alpha-haemolysin plays a significant role in the pathogenesis of S. aureus, and it could be the target for the treatment of staphylococcal infection. In this study, epigallocatechin gallate (EGCg), a natural compound with little anti-S. aureus activity, was shown to reduce the haemolytic activity of alpha haemolysin by inhibiting the self-assembly of the heptamer. When EGCg was added into a co-cultured system of human alveolar epithelial (A549) cells and bacterial suspension, alpha-haemolysin-induced cell injury was significantly attenuated. These results indicate that EGCg could effectively reduce the cytotoxicity of the toxin by interacting with alpha-haemolysin. This study provides the basis for the development of anti-virulence drugs for the treatment of S. aureus infection. PMID- 29273512 TI - Recombinant M2e-HA2 fusion protein induced immunity responses against intranasally administered H9N2 influenza virus. AB - Influenza is a highly contagious respiratory tract disease and is considered a serious community health problem. Influenza viruses possess multiple conserved epitopes which are used for designing universal vaccines. To this aim, the gene coding for N-terminal part of M2e (SLLTEVET) and HA2 (GLFGAIAGF), was synthesized, linked by a (Gly4Ser)4 peptide linker, and cloned into pGS-21a vector. Afterwards, the construct was transferred into E. coli BL21 (DE3) cells to produce the designed antigenic protein called M2e-HA2. Immunization of mice with these peptides significantly induced humoral immune responses against the influenza virus. Three weeks after the last booster, mice were inoculated intranasally with 1 * 106 EID50 of H9N2 virus. The results indicated that the recombinant M2e-HA2 fusion protein could protect mice against H9N2 virus. PMID- 29273513 TI - Zerumbone protects human skin keratinocytes against UVA-irradiated damages through Nrf2 induction. AB - Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2-10 MUM) substantially suppressed UVA (15 J/cm2)-induced HaCaT cell death and lactate dehydrogenase release in a dose dependent manner. UVA-induced excessive ROS production, DNA single-strand breaks, apoptotic DNA fragmentation and a dysregulated Bax/Bcl-2 ratio were remarkably reversed by zerumbone in keratinocytes. Zerumbone-mediated cytoprotective properties were associated with increased nuclear translocation of nuclear factor E2-related factor-2 (Nrf2) and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by induction of heme oxygenase-1 (HO-1) and gamma-glutamyl cysteine ligase (gamma GCLC) genes in zerumbone-treated keratinocytes. Zerumbone-induced Nrf2 transcriptional activation was mediated by the p38 MAPK, PI3K/AKT and PKC signaling cascades. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished zerumbone-mediated cytoprotective effects, as evidenced by impaired antioxidant genes, uncontrolled ROS/apoptotic DNA fragmentation and keratinocytes death, following UVA irradiation. In vivo evidence demonstrated that zerumbone treatment to nude mice (55 and 110 MUg/day) significantly ameliorated UVA (15 J/cm2/every 2-day/14-day) cytotoxicity via increased nuclear localization of Nrf2 and Nrf2-dependent antioxidant genes (HO-1 and gamma-GCLC) in UVA-treated skin tissues. Our findings emphasized the significance of Nrf2/ARE-signaling in zerumbone-mediated induction of antioxidant genes against UVA-toxicity. The molecular evidence suggests zerumbone can be a natural medicine to treat/prevent UVA-induced skin damage/photoaging. PMID- 29273514 TI - Erratum to "Population and performance analyses of four major populations with Illumina's FGx Forensic Genomics System" [Forensic Sci. Int.: Genet. 30 (2017) 81 92]. PMID- 29273515 TI - Nasal vs Oronasal CPAP for OSA Treatment: A Meta-Analysis. AB - BACKGROUND: Nasal CPAP is the "gold standard" treatment for OSA. However, oronasal masks are frequently used in clinical practice. The aim of this study was to perform a meta-analysis of all randomized and nonrandomized trials that compared nasal vs oronasal masks on CPAP level, residual apnea-hypopnea index (AHI), and CPAP adherence to treat OSA. METHODS: The Cochrane Central Register of Controlled Trials, Medline, and Web of Science were searched for relevant studies in any language with the following terms: "sleep apnea" and "CPAP" or "sleep apnea" and "oronasal mask" or "OSA" and "oronasal CPAP" or "oronasal mask" and "adherence." Studies on CPAP treatment for OSA were included, based on the following criteria: (1) original article; (2) randomized or nonrandomized trials; and (3) comparison between nasal and oronasal CPAP including pressure level, and/or residual AHI, and/or CPAP adherence. RESULTS: We identified five randomized and eight nonrandomized trials (4,563 patients) that reported CPAP level and/or residual AHI and/or CPAP adherence. Overall, the random-effects meta analysis revealed that as compared with nasal, oronasal masks were associated with a significantly higher CPAP level (Hedges' g, -0.59; 95% CI, -0.82 to -0.37; P < .001) (on average, +1.5 cm H2O), higher residual AHI (Hedges' g, -0.34; 95% CI, -0.52 to -0.17; P < .001) (+2.8 events/h), and a poorer adherence (Hedges' g, 0.50; 95% CI, 0.21-0.79; P = .001) (-48 min/night). CONCLUSIONS: Oronasal masks are associated with a higher CPAP level, higher residual AHI, and poorer adherence than nasal masks. TRIAL REGISTRY: PROSPERO database; No.: CRD42017064584; URL: https://www.crd.york.ac.uk/prospero/. PMID- 29273516 TI - Current and future technological advances in transdermal gene delivery. AB - Transdermal gene delivery holds significant advantages as it is able to minimize the problems of systemic administration such as enzymatic degradation, systemic toxicity, and poor delivery to target tissues. This technology has the potential to transform the treatment and prevention of a range of diseases. However, the skin poses a great barrier for gene delivery because of the "bricks-and-mortar" structure of the stratum corneum and the tight junctions between keratinocytes in the epidermis. This review systematically summarizes the typical physical and chemical approaches to overcome these barriers and facilitate gene delivery via skin for applications in vaccination, wound healing, skin cancers and skin diseases. Next, the advantages and disadvantages of different approaches are discussed and the insights for future development are provided. PMID- 29273517 TI - miRNA delivery for skin wound healing. AB - The wound healing has remained a worldwide challenge as one of significant public health problems. Pathological scars and chronic wounds caused by injury, aging or diabetes lead to impaired tissue repair and regeneration. Due to the unique biological wound environment, the wound healing is a highly complicated process, efficient and targeted treatments are still lacking. Hence, research-driven to discover more efficient therapeutics is a highly urgent demand. Recently, the research results have revealed that microRNA (miRNA) is a promising tool in therapeutic and diagnostic fields because miRNA is an essential regulator in cellular physiology and pathology. Therefore, new technologies for wound healing based on miRNA have been developed and miRNA delivery has become a significant research topic in the field of gene delivery. PMID- 29273518 TI - D2A-Ala peptide derived from the urokinase receptor exerts anti-tumoural effects in vitro and in vivo. AB - D2A-Ala is a synthetic peptide that has been created by introducing mutations in the original D2A sequence, 130IQEGEEGRPKDDR142 of human urokinase receptor (uPAR). In vitro, D2A-Ala peptide displays strong anti-tumoural properties inhibiting EGF-induced chemotaxis, invasion and proliferation of a human fibrosarcoma cell line, HT 1080, and a human colorectal adenocarcinoma cell line, HT 29. D2A-Ala exerts its effects by preventing EGF receptor (EGFR) phosphorylation. To test D2A-Ala in vivo, this peptide was PEGylated generating polyethyleneglycol (PEG)-D2A-Ala peptide. PEGylation did not alter the inhibitory properties of D2A-Ala. Human tumour xenografts in the immunodeficient nude mice using HT 1080 and HT 29 cell lines showed that PEG-D2A-Ala significantly prevents tumour growth decreasing size, weight and density of tumours. The most efficient doses of the peptide were 5 and 10 mg/kg, thereby relevant for possible development of the peptide into a drug against cancer in particular tumours expressing EGFR. PMID- 29273519 TI - Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy. AB - Adenosine monophosphate-activated protein kinase (AMPK) has been studied for its myriad metabolic and mitochondrial benefits in several chronic diseases. Recent studies have uncovered its therapeutic potential against mitochondrial dysfunction in cultured dorsal root ganglion (DRG) neurons isolated from streptozotocin (STZ) induced diabetic rats. The present study is aimed at evaluating the pharmacological efficacy of berberine (BRB), a natural AMPK activator against experimental diabetic neuropathy (DN) phenotype developed in STZ (55 mg/kg, i.p.) induced diabetic rats and neurotoxicity in high-glucose (30 mM) stimulated neuro 2a (N2A) cells. Diabetic-rats have shown reduced expression of p-AMPK (Thr 172) in sciatic nerves with a consequent reduction in mitochondrial biogenesis and autophagy. BRB (50 & 100 mg/kg, po) administration to diabetic rats for 2-weeks rescued mitochondrial functional deficits and autophagy impairment by increasing the p-AMPK expression. BRB administration also augmented the NEF-2 related factor 2 (Nrf2) mediated endogenous antioxidant defence systems to restrain neuronal damage and neuroinflammation. These effects after BRB administration resulted in enhanced conduction velocity, improved nerve blood flow and attenuated hyperalgesia. Similarly, BRB exposure (5 & 10 MUM) to N2A cells attenuated high glucose induced ROS generation, mitochondrial membrane depolarization through the promotion of Nrf2 mediated antioxidant defence systems. BRB exposure augmented peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) mediated mitochondrial biogenesis in neuronal cells. Results from this study signify the importance of mitoprotection conferred by BRB in DN and can be used as a preliminary basis for further molecular exploration. PMID- 29273520 TI - Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. AB - Opioids evoke analgesia through activation of opioid receptors (predominantly the MU opioid receptor) in the central nervous system. Opioid receptors are abundant in multiple regions of the central nervous system and the peripheral nervous system including enteric neurons. Opioid-related adverse effects such as constipation, nausea, and vomiting pose challenges for compliance and continuation of the therapy for chronic pain management. In the post-operative setting opioid-induced depression of respiration can be fatal. These critical limitations warrant a better understanding of their underpinning cellular and molecular mechanisms to inform the design of novel opioid analgesic molecules that are devoid of these unwanted side-effects. Research efforts on opioid receptor signalling in the past decade suggest that differential signalling pathways and downstream molecules preferentially mediate distinct pharmacological effects. Additionally, interaction among opioid receptors and, between opioid receptor and non-opioid receptors to form signalling complexes shows that opioid induced receptor signalling is potentially more complicated than previously thought. This complexity provides an opportunity to identify and probe relationships between selective signalling pathway specificity and in vivo production of opioid-related adverse effects. In this review, we focus on current knowledge of the mechanisms thought to transduce opioid-induced gastrointestinal adverse effects (constipation, nausea, vomiting) and respiratory depression. PMID- 29273521 TI - The pathology and pathophysiology of vascular dementia. AB - Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, neuropsychological and neuroimaging measures in life but more importantly pathological confirmation. Factors defining subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes as well as time after the initial vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis, lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cerebrum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease. Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity, VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly define microvascular disease and vascular substrates of dementia. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 29273522 TI - Matrix metalloproteinase-13: A special focus on its regulation by signaling cascades and microRNAs in bone. AB - Bone remodeling is an orchestrated process involving osteoblasts and osteoclasts to maintain mineral homeostasis in the internal milieu, mediated chiefly by matrix metalloproteinases (MMPs). MMP13, one amongst the MMPs plays a premier role in bone remodeling, and mutations in MMP13 have been implicated in various pathologies including cancer and arthritis. Transcriptional activation of MMP13 gene is tightly regulated by several signaling cascade components. Post transcriptional regulators such as microRNAs (miRNAs) have also been shown to regulate MMP13 expression under physiological and pathological conditions. Hence, this review provides an outline of the structure of MMP13 gene and its regulation by signaling components, transcription factors and miRNAs in bone. PMID- 29273523 TI - Isolation, characterization and bioactive potential of sulfated galactans from Spyridia hypnoides (Bory) Papenfuss. AB - The sulfated galactans (SG) of mass 16 kDa was purified from S.hypnoides through anion exchange and gel permeation chromatography. The biochemical properties of SG including carbohydrate, 3,6 anhydrogalactose, sulfate, uronic acid, moisture, ash, carbon, hydrogen, nitrogen contents were estimated. In the purified SG, the presence of major sugars such as galactose and glucose were identified through HPLC and it was further structurally characterised through FT-IR and NMR spectroscopy. Anticoagulant activity of SG was estimated as 25.36 & 2.46 IU at 25 MUg/ml (aPTT & PT). SG also showed potential dose dependent antioxidant activity against free radicals such as DPPH (56.41% at 2 mg/ml), hydroxyl radicals (65.58% at 3 mg/ml) and superoxide radicals (73.12% at 0.6 mg/ml). The maximum metal chelating and total antioxidant property (76.42%, 66.81%) was exhibited at 1 mg/ml. The results indicate that the SG from red seaweed represents a good source of polysaccharide with significant anticoagulant and antioxidant properties. PMID- 29273524 TI - Physicochemical characterization and in vitro hypoglycemic activities of polysaccharides from Sargassum pallidum by microwave-assisted aqueous two-phase extraction. AB - Microwave-assisted aqueous two-phase extraction (MAATPE) was applied for simultaneous extraction and separation of polysaccharides from Sargassum pallidum (SPPs). The optimal extraction parameters, physicochemical properties, and hypoglycemic activities in vitro of SPPs were investigated. The results revealed that the optimal extraction conditions were as follows: 21.0% ethanol (w/w) and 22.0% ammonium sulfate (w/w) for ATPS, ratio of material to liquid 1:60 (g/mL), extraction time 15 min, microwave power 830 W, and extraction temperature 95 degrees C. Under the optimal these conditions, the maximum yields of SPPs were 0.75 +/- 0.04% of the top phase (SPP-1) and 6.81 +/- 0.33% of the bottom phase (SPP-2). SPP-1 and SPP-2 were homogeneous with molecular weights of 1518.6 and 50.6 kDa, respectively. SPP-1 mainly consisted of fucose, galactose, mannose, and glucuronic acid with a molar ratio of 4.97:9.75:6.44:6.07, whereas SPP-2 was mainly composed of fucose, galactose, glucose, and mannose with a molar ratio of 4.20:2.88:18.05:7.83. SPP-1 and SPP-2 exhibited favorable alpha-amylase and alpha glucosidase inhibitory activities, and could remarkably improve glucose consumption in insulin resistance (IR) model cells. Notably, SPP-1 exhibited stronger alpha-glucosidase inhibitory activity than SPP-2, and even was comparable with acarbose. PMID- 29273525 TI - Probing the interaction of zero valent iron nanoparticles with blood system by biophysical, docking, cellular, and molecular studies. AB - Human exposure to nanoparticles (NPs) is inevitable as NPs become more widely applied and, as a result, nanotoxicology study is now gaining attention. Herein, the interaction of zero valent iron NPs (ZVFe-NPs) with human hemoglobin (Hb) was evaluated using a variety of techniques including fluorescence spectroscopy, far circular dichroism (CD) spectroscopy as well as docking study. Also, the cytotoxicity of ZVFe-NPs on the human lymphocyte cell line as a model of blood system cell line was investigated by 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), acridine orange/ethidium bromide (AO/EB) staining, flow cytometry, and real-time PCR assays. Fluorescence studies revealed that ZVFe-NPs bind to Hb via hydrogen bonds and induced conformational changes of Hb in a static denaturation mechanism. CD experiment showed that Hb retained its native structure in the presence of ZVFe-NP. Molecular docking study also demonstrated that polar residues of Hb provide convenient medium to establish hydrogen bonds with water molecules on ZVFe-NP surface. Likewise, it was also revealed that ZVFe-NPs impaired the viability of lymphocyte cells through apoptotic pathway. For NPs to move into the clinical area, it is crucial that nanotoxicology research provide pivotal information about the adverse effect of NPs against biological systems. PMID- 29273526 TI - Activation of the capsaicin-receptor TRPV1 by the acetaminophen metabolite N arachidonoylaminophenol results in cytotoxicity. AB - AIMS: The anandamide reuptake inhibitor N-arachidonoylaminophenol (AM404) and the reactive substance N-acetyl-p-benzoquinone imine (NAPQI) are both metabolites of acetaminophen and may contribute to acetaminophen-induced analgesia by acting at TRPV1 expressed in the peripheral or central nervous system. While NAPQI slowly sensitizes and activates TRPV1 by interacting with distinct intracellular cysteine residues, detailed properties of AM404 as an agonist of TRPV1 have not yet been reported on. We explored the effects of AM404 on recombinant human TRPV1 and in rodent dorsal root ganglion (DRG) neurons. MATERIALS AND METHODS: HEK 293 cells expressing different isoforms of recombinant TRPV1 and rodent DRG neurons were employed for patch clamp and calcium imaging experiments. Cytotoxicity was assessed by propidium iodide and Annexin V staining on TRPV1-HEK 293 cells and with trypan blue staining on DRG neurons. KEY FINDINGS: AM404 activates hTRPV1 at concentrations >1MUM and in a concentration-dependent manner. AM404 also potentiates TRPV1-mediated currents evoked by heat and anandamide. Moreover, AM404-evoked currents are potentiated by NAPQI. While the partly capsaicin insensitive rabbit (o) TRPV1 fails to respond to AM404, AM404-sensitivity is restored by insertion of the capsaicin binding-domain of rat TRPV1 into oTRPV1. In DRG neurons, AM404-evoked calcium influx as well as cell death is mediated by TRPV1. SIGNIFICANCE: AM404 gates TRPV1 by interacting with the vanilloid-binding site, and TRPV1 is the main receptor for AM404 in DRG neurons. While direct activation of TRPV1 requires high concentrations of AM404, it is possible that synergistic effects of AM404 with further TRPV1-agonists may occur at clinically relevant concentrations. PMID- 29273527 TI - The role of physical exercise on Sestrin1 and 2 accumulations in the skeletal muscle of mice. AB - AIMS: Sestrins, a class of stress-related proteins, is involved in the control of aging-induced organic dysfunctions and metabolic control. However, the factors that modulate the levels of Sestrins are poorly studied. Here, we evaluated the effects of acute and chronic aerobic exercise on Sestrin 1 (Sesn1) and Sesn2 protein contents in the skeletal muscle of mice. MAIN METHODS: Male C57BL/6J mice performed an acute or chronic (4weeks) exercise protocols on a treadmill running at 60% of the peak workload. Then, the quadriceps muscle was removed and analyzed by Western blot. Bioinformatics analysis was also performed to evaluate Sesn1 and Sesn2 mRNA in the skeletal muscle and phenotypic pattern in a large panel of isogenic strains of BXD mice. KEY FINDINGS: While acute aerobic exercise increased Sesn1 accumulation and induced a discrete augment of Sesn2 protein content and AMPK threonine phosphorylation, chronic exercise reduced the basal levels of Sesn1 and Sesn2 as well as of AMPK threonine phosphorylation in the quadriceps muscles of C57BL/6J mice. In accordance with these experimental approaches, transcriptomic analysis revealed that Sesn1 and Sesn2 mRNA levels in the skeletal muscle were inversely correlated with the locomotor activity in several strains of BXD mice. SIGNIFICANCE: Our data suggest that physical exercise has role on Sestrin1 and Sestrin2 expression on skeletal muscle, providing new insights into the mechanism by which physical exercise affects stress-related proteins in skeletal muscles. PMID- 29273528 TI - Greater occipital nerve cryoneurolysis in the management of intractable occipital neuralgia. AB - OBJECTIVE: To assess technical feasibility of cryoneurolysis of the greater occipital nerve in the management of occipital neuralgia. METHODS: Six patients suffering from unilateral refractory greater occipital neuralgia and who underwent 7 GON cryoneurolysis were assessed between October 2015 and January 2017. All procedures were performed under CT guidance and local anesthesia. A planning CT was performed with contrast enhancement to plan needle target and identify surrounding major vascular structures. A 12G coaxial needle (Inomed) was then inserted and targeted the first bend of the GON under and lateral to the obliquus capitis inferior muscle. A 2.0mm cryoprobe was then inserted in the coaxial and sensitive stimulation at 100Hz was performed. One to three freezing cycles were performed in one session. RESULTS: Technical feasibility was 100% as cryoneurolysis could be performed in all 7 cases with accurate sensitive nerve stimulation prior to freezing cycle. One patient benefited from a second session after failure of the first session. More than 50% pain reduction was achieved at day 7 in all cases, and 5 of 6 cases at one and three months follow-up. CONCLUSION: Cryoneurolysis of the GON in the management of refractory GON neuralgia is feasible. Initial results are promising as 5/7 cases benefited from a 3-month pain alleviation period. PMID- 29273529 TI - Congenital involvement of the central nervous system by the Zika virus in a child without microcephaly - spectrum of congenital syndrome by the Zika virus. PMID- 29273530 TI - Feasibility of improved motion-sensitized driven-equilibrium (iMSDE) prepared 3D T1-weighted imaging in the diagnosis of vertebrobasilar artery dissection. AB - BACKGROUND AND PURPOSE: This study was to evaluate the diagnostic value of improved motion-sensitized driven-equilibrium (iMSDE)-prepared 3D T1-weighted magnetic resonance imaging (MRI) (iMSDE-3DMRI) in intracranial vertebrobasilary dissection (VBD) and to compare iMSDE-3DMRI images with those obtained using 2D high-resolution (HR) MRI with respect to their diagnostic performance in VBD. MATERIALS AND METHODS: We retrospectively reviewed 105 lesions from 102 patients who underwent multimodal imaging and contrast-enhanced iMSDE-3DMRI (CE-iMSDE 3DMRI). The 2D-HRMRI protocol comprised four axial HR images. The CE-iMSDE-3DMRI images were reformatted in the axial, coronal, and sagittal planes. The 2D-HRMRI based diagnosis was compared with the final diagnosis. The 2D-HRMRI and CE-iMSDE 3DMRI images were examined independently for the diagnosis performance of dissection. RESULTS: VBD was confirmed in 66 lesions in 63 patients; 17 patients had confirmed atherosclerosis, and 22 had no lesions in the vertebrobasilar artery. Diagnostic performances of 2D-HRMRI (AUC, 0.839+/-0.04; sensitivity, 94.0; specificity, 79.5; diagnostic accuracy, 88.6) CE-iMSDE-3DMRI (AUC, 0.847+/ 0.04; sensitivity, 84.8; specificity, 84.6; diagnostic accuracy, 84.7) and 2D HRMRI+CE-iMSDE-3DMRI (AUC, 0.893+/-0.03; sensitivity, 97.0; specificity, 85.0; diagnostic accuracy, 92.5) were good. Comparisons of the diagnostic performance of 2D-HRMRI andCE-iMSDE-3DMRI showed that combined interpretation of 2D-HRMRI and iMSDE-3DMRI yields a significantly higher diagnostic performance than that of 2D HRMRI (P=0.042). CONCLUSIONS: CE-iMSDE-3DMRI showed good diagnostic performance for the diagnosis of intracranial VBD. These results suggest that CE-iMSDE-3DMRI can be used in combination with 2D-HRMRI for the diagnosis of intracranial VBD. PMID- 29273531 TI - CNS aspergilloma mimicking tumors: Review of CNS aspergillus infection imaging characteristics in the immunocompetent population. AB - BACKGROUND AND PURPOSE: CNS Aspergillosis is very rare and difficult to diagnose clinically and on imaging. Our objective was to elucidate distinct neuroimaging pattern of CNS aspergillosis in the immunocompetent population that helps to differentiate from other differential diagnosis. METHODS: Retrospective analysis of brain imaging findings was performed in eight proven cases of central nervous system aspergillosis in immunocompetent patients. Immunocompetent status was screened with clinical and radiological information. Cases were evaluated for anatomical distribution, T1 and T2 signal pattern in MRI and attenuation characteristics in CT scan, post-contrast enhancement pattern, internal inhomogeneity, vascular involvement, calvarial involvement and concomitant paranasal, cavernous sinus or orbital extension. All patients were operated and diagnosis was confirmed on histopathology. RESULTS: The age range was 19-50 years with mean age of 33.7 years. Concomitant sinonasal disease was seen in six patients (75%). Three patients had orbital extensions. Most of the lesions (n=7) were profoundly hypointense in T2-weighted imaging. The most common enhancement pattern was bright, solid and homogenous enhancement (n=7). Cavernous extension with ICA encasement was always associated with paranasal sinus disease. Six patients showed demineralization or complete resorption of involved bone. All of the fungal masses appear hyperdense on available CT scan images. CONCLUSION: CNS aspergillus infection in immunocompetent patients has distinct imaging features as compared to CNS aspergillosis in immunocompromised patients. A high index of suspicion in proper clinical settings, even with immunocompetent status and typical imaging features allow us to diagnose CNS aspergillosis in such patients. PMID- 29273532 TI - Eagle's syndrome: A rare cause of cervical internal carotid pseudo-aneurysmal dissection. PMID- 29273533 TI - Spontaneous healing of a symptomatic basilar artery dissection. PMID- 29273534 TI - Altered functional connectivity of the subthalamic nucleus during self-initiated movement in Parkinson's disease. AB - BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) have difficulty performing self-initiated movements. The neural mechanism of this deficiency remains unclear. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the functional connectivity of the subthalamic nucleus (STN) during self-initiated movement in patients with PD. MATERIALS AND METHODS: fMRI were acquired from patients with PD and age- and sex-matched healthy control subjects during a self-initiated right hand tapping task. We selected the bilateral sensorimotor subregions of the STN as regions of interest for our connectivity analysis. RESULTS AND CONCLUSIONS: We found that the STN contralateral to voluntary hand movement exhibited enhanced connectivity with the midbrain, thalamus, putamen, and so on in patients with PD compared to control subjects. In contrast, the STN ipsilateral to the hand movement exhibited enhanced connectivity with the midbrain and insula in PD patients compared to control subjects. Connectivity between the STN contralateral to the hand movement and the primary motor cortex and supplementary motor area was positively correlated with the severity of bradykinesia. Our findings suggest that STN related connectivity in the hyperdirect and indirect basal ganglia pathways is strengthened during self-initiated movement in patients with PD. These disrupted network connections may contribute to bradykinesia. PMID- 29273535 TI - Primary versus secondary mechanical thrombectomy for anterior circulation stroke in children: An update. AB - This review of the literature on the use of mechanical thrombectomy (MT) in children with acute ischemic stroke from occlusion of the internal carotid artery and the proximal middle cerebral artery (MCA) compares the efficacy and safety of primary and secondary MT. We analyzed the data reported for 24 case reports from 20 relevant articles published up to 31 December 2016 and the data of a patient treated at our institution. Eighteen cases received primary MT and 7 received secondary MT. The proportions of complete MCA recanalization, small infarcts, and asymptomatic intracranial hemorrhage were similar in both MT groups (73% [11/15] vs. 67% [4/6], 58% [7/12] vs. 60% [3/5], and 15% [2/13] vs. 17% [1/6], respectively). The proportion of favorable neurological outcomes was higher for the primary MT group (69% [11/16] vs. 43% [3/7]). We found no substantial differences in efficacy and safety between primary and secondary MT for anterior circulation stroke in children. PMID- 29273536 TI - Variability of stroke patients meeting endovascular stroke trial criteria in a non-clinical trial setting. AB - BACKGROUND: Five randomized trials proving the efficacy and safety of mechanical embolectomy for ischemic stroke within 8hours used differing radiological methods to select patients. We aimed to evaluate the proportion of patients in clinical practice that would meet radiological criteria for inclusion in these trials. METHODS: Retrospective study of ischemic stroke patients at a large academic medical center who were considered for endovascular stroke therapy based on confirmed intracranial large vessel occlusion from April 2010-November 2014. All patients underwent computed tomography (CT) perfusion and CT angiogram. RESULTS: Of 119 patients, median age was 69 years (IQR 57-79) and median NIHSS 18 (IQR 14 21). Most patients had ASPECTS>=6 (n=105, 88.2%). All 119 patients met radiological criteria for MR CLEAN while 105 (88.2%) met criteria for SWIFT PRIME, 96 (80.7%) for REVASCAT, 80/116 (69.0%) for EXTEND-IA, and 74 (62.2%) for ESCAPE. About half (n=58,48.7%) were treated with IV rtPA and 66 (56%) underwent endovascular therapy. Any intracranial hemorrhage was more common in patients undergoing endovascular therapy than in those who were not (36% vs. 17%, P=0.034). The frequency of symptomatic intracranial hemorrhage (ICH) did not significantly differ between these groups (6% vs. 4%, P=0.691). CONCLUSIONS: The proportion of patients with acute stroke and large vessel occlusion presenting within 8 hours that would meet radiological criteria for endovascular stroke trials varies considerably (62-100%) in a cohort outside of clinical trials from an academic comprehensive stroke center. Thus, the radiological criteria used for candidate selection in daily practice will greatly influence the proportion of patients treated with endovascular therapy. PMID- 29273537 TI - Symptom-based screening of children with household tuberculosis contact. PMID- 29273538 TI - Planning ahead to avert a respiratory winter avalanche. PMID- 29273539 TI - Effectiveness of WHO's pragmatic screening algorithm for child contacts of tuberculosis cases in resource-constrained settings: a prospective cohort study in Uganda. AB - BACKGROUND: Tuberculosis is a leading cause of global childhood mortality; however, interventions to detect undiagnosed tuberculosis in children are underused. Child contact tracing has been widely recommended but poorly implemented in resource-constrained settings. WHO has proposed a pragmatic screening approach for managing child contacts. We assessed the effectiveness of this screening approach and alternative symptom-based algorithms in identifying secondary tuberculosis in a prospectively followed cohort of Ugandan child contacts. METHODS: We identified index patients aged at least 18 years with microbiologically confirmed pulmonary tuberculosis at Old Mulago Hospital (Kampala, Uganda) between Oct 1, 1995, and Dec 31, 2008. Households of index patients were visited by fieldworkers within 2 weeks of diagnosis. Coprevalent and incident tuberculosis were assessed in household contacts through clinical, radiographical, and microbiological examinations for 2 years. Disease rates were compared among children younger than 16 years with and without symptoms included in the WHO pragmatic guideline (presence of haemoptysis, fever, chronic cough, weight loss, night sweats, and poor appetite). Symptoms could be of any duration, except cough (>21 days) and fever (>14 days). A modified WHO decision-tree designed to detect high-risk asymptomatic child contacts was also assessed, in which all asymptomatic contacts were classified as high risk (children younger than 3 years or immunocompromised [HIV-infected]) or low risk (aged 3 years or older and immunocompetent [HIV-negative]). We also assessed a more restrictive algorithm (ie, assessing only children with presence of chronic cough and one other tuberculosis-related symptom). FINDINGS: Of 1718 household child contacts, 126 (7%) had coprevalent tuberculosis and 24 (1%) developed incident tuberculosis, diagnosed over the 2-year study period. Of these 150 cases of tuberculosis, 95 (63%) were microbiologically confirmed with a positive sputum culture. Using the WHO approach, 364 (21%) of 1718 child contacts had at least one tuberculosis-related symptom and 85 (23%) were identified as having coprevalent tuberculosis, 67% of all coprevalent cases detected (diagnostic odds ratio 9.8, 95% CI 6.8-14.5; p<0.0001). 1354 (79%) of 1718 child contacts had no symptoms, of whom 41 (3%) had coprevalent tuberculosis. The WHO approach was effective in contacts younger than 5 years: 70 (33%) of 211 symptomatic contacts had coprevalent disease compared with 23 (6%) of 367 asymptomatic contacts (p<0.0001). This approach was also effective in contacts aged 5 years and older: 15 (10%) of 153 symptomatic contacts had coprevalent disease compared with 18 (2%) of 987 asymptomatic contacts (p<0.0001). More coprevalent disease was detected in child contacts recommended for screening when the study population was restricted by HIV-serostatus (11 [48%] of 23 symptomatic HIV-seropositive child contacts vs two [7%] of 31 asymptomatic HIV-seropositive child contacts) or to only culture-confirmed cases (47 [13%] culture confirmed cases of 364 symptomatic child contacts vs 29 [2%] culture confirmed cases of 1354 asymptomatic child contacts). In the modified algorithm, high-risk asymptomatic child contacts were at increased risk for coprevalent disease versus low-risk asymptomatic contacts (14 [6%] of 224 vs 27 [2%] of 1130; p=0.0021). The presence of tuberculosis infection did not predict incident disease in either symptomatic or asymptomatic child contacts: in symptomatic contacts, eight (5%) of 169 infected contacts and six (5%) of 111 uninfected contacts developed incident tuberculosis (p=0.80). Among asymptomatic contacts, incident tuberculosis occurred in six (<1%) of 795 contacts infected at baseline versus four (<1%) of 518 contacts uninfected at baseline, respectively (p=1.00). INTERPRETATION: WHO's pragmatic, symptom-based algorithm was an effective case-finding tool, especially in children younger than 5 years. A modified decision-tree identified 6% of asymptomatic child contacts at high risk for subclinical disease. Increasing the feasibility of child-contact tracing using these approaches should be encouraged to decrease tuberculosis-related paediatric mortality in high-burden settings, but this should be partnered with increasing access to microbiological point-of care testing. FUNDING: National Institutes of Health, Tuberculosis Research Unit, AIDS International Training and Research Program of the Fogarty International Center, and the Center for AIDS Research. PMID- 29273540 TI - Combined disc pelletisation and thermal treatment of MSWI fly ash. AB - An environmentally friendly and cost efficient way for the management of municipal solid waste incineration (MSWI) fly ash represents its thermal co treatment together with combustible waste. However, the safe introduction and storage of MSWI fly ash in the waste bunker is challenging and associated with severe problems (e.g. dust emissions, generation of undefined lumps and heat in case of moistened MSWI fly ash). Therefore, the aim of this study is to investigate the suitability of pelletisation as a pretreatment of MSWI fly ash. In particular, MSWI fly ash was characterised after sampling, pelletisation and thermal treatment and the transfer of constituents to secondary fly ash and flue gas was investigated. For this purpose, MSWI fly ash pellets with a water content of about 0.15 kg/kg and a diameter of about 8 mm have been produced by disc pelletiser and treated in an electrically heated pilot-scale rotary kiln at different temperatures, ranging from 450 degrees C to 1050 degrees C. The total contents of selected elements in the MSWI fly ash before and after thermal treatment and in the generated secondary fly ash have been analysed in order to understand the fate of each element. Furthermore, leachable contents of selected elements and total content of persistent organic pollutants of the thermally treated MSWI fly ash were determined. Due to the low total content of Hg (0.7 mg/kg) and the low leachate content of Pb (<0.36 mg/kg), even at the lowest treatment temperature of 450 degrees C, thermally treated MSWI fly ash pellets can be classified as non-hazardous waste. However, temperatures of at least 650 degrees C are necessary to decrease the toxic equivalency of PCDD/F and DL-PCB. The removal of toxic heavy metals like Cd and Pb is significantly improved at temperatures of 850 degrees C, 950 degrees C or even 1050 degrees C. The observed metal removal led to relatively high contents of e.g. Cu (up to 11,000 mg/kg), Pb (up to 91,000 mg/kg) and Zn (up to 21,000 mg/kg) in the secondary fly ash. This metal enriched secondary fly ash might represent a potential raw material for metal recovery (e.g. via acidic leaching). Due to the high content of total dissolved solids observed in the leachate of thermally treated MSWI fly ash pellets, a wet extraction procedure is suggested to enable its safe disposal at non-hazardous waste landfills. PMID- 29273541 TI - Effect of bacterial inoculants on phytomining of metals from waste incineration bottom ash. AB - Waste incineration bottom ash is considered a secondary resource for valuable trace elements (TE), which is currently neglected in most European countries. Phytomining could potentially recover valuable TE from such waste materials but is still at an exploratory stage with many challenges. The use of bioaugmentation to improve plant growth and TE accumulation of metal-tolerant high biomass plants growing on waste incineration bottom ash was evaluated. Bacterial strains that were previously isolated from rhizosphere, roots and contaminated soil were selected according to their plant growth promoting characteristics and tolerance to the bottom ash substrate. Those selected bacterial strains were tested for their beneficial effects on Nicotiana tabacum and Salix smithiana with regards to phytomining. The rhizobacterial strain Rhodococcus erythropolis P30 enhanced the shoot dry weight of N. tabacum by on average 57% compared to the control plants. Several bacterial inoculants enhanced biomass production and the nutritional status of S. smithiana. Moreover, those bacterial strains previously described to enhance biomass production of N. tabacum and members of the Salicaceae on TE contaminated soils, also enhanced biomass production of these species on bottom ash. However, bacterial inoculants could not enhance trace element accumulation in plants. PMID- 29273542 TI - Valorization of a pharmaceutical organic sludge through different composting treatments. AB - Nowadays, the agricultural reuse of pharmaceutical sludge is still limited due to environmental and agronomic issues (e.g. low stabilization of the organic matter, phytotoxicity). The aim of the present study was to evaluate the characteristics of a pharmaceutical sludge derived from the daptomycin production and to study the possibility of improving its quality through composting. The pharmaceutical sludge showed high content of macronutrients (e.g. total Kjeldahl N content was 38 g kg-1), but it was also characterized by high salinity (7.9 dS m-1), phytotoxicity (germination index was 36.7%) and a low organic matter stabilization. Two different mixtures were prepared (mixture A: 70% sludge + 30% wood chips w/w, mixture B: 45% sludge + 45% wood chips + 10% cereal straw w/w) and treated through static composting using two different aeration systems: active and passive aeration. The mixtures resulted in the production of two different compost, and the evolution of process management parameters was different. The low total solids and organic matter content of mixture A led to the failure of the process. The addition of cereal straw in mixture B resulted in increased porosity and C/N ratio and, consequently, in an optimal development of the composting process (e.g. the final organic matter loss was 54.1% and 63.1% for the passively and actively aerated treatment, respectively). Both passively and actively aerated composting of mixture B improved the quality of the pharmaceutical sludge, by increasing its organic matter stabilization and removing phytotoxicity. PMID- 29273544 TI - Competition, trait-mediated facilitation, and the structure of plant-pollinator communities. AB - In plant-pollinator communities many pollinators are potential generalists and their preferences for certain plants can change quickly in response to changes in plant and pollinator densities. These changes in preferences affect coexistence within pollinator guilds as well as within plant guilds. Using a mathematical model, we study how adaptations of pollinator preferences influence population dynamics of a two-plant-two-pollinator community interaction module. Adaptation leads to coexistence between generalist and specialist pollinators, and produces complex plant population dynamics, involving alternative stable states and discrete transitions in the plant community. Pollinator adaptation also leads to plant-plant apparent facilitation that is mediated by changes in pollinator preferences. We show that adaptive pollinator behavior reduces niche overlap and leads to coexistence by specialization on different plants. Thus, this article documents how adaptive pollinator preferences for plants change the structure and coexistence of plant-pollinator communities. PMID- 29273545 TI - On how role versatility boosts an STI. AB - The prevalence of the HIV-1 infection has decayed in the last decades in western heterosexual populations. However, among men who have sex with men (MSM) the prevalence is still high, despite intensive campaigns and treatment programs that keep infected men as undetectable (Beyrer et al. 2012). Promiscuity and condom fatigue (Adam et al. 2005), which are not unique to the MSM community, are making unprotected anal intercourse (UAI) more common and sexually transmitted infections (STIs) presumably harder to track. Yet, MSM communities are peculiar in the sense that men can adopt fixed (insertive or receptive) or versatile (both practices) roles. Some old theoretical work (Wiley & Herschkorn 1989, Van Druten et al. 1992, Trichopoulos et al. 1998) predicted that the transmission of HIV-1 would be enhanced in MSM populations engaged more in role versatility than in role segregation, in which fixed roles are predominantly adopted. These predictions were based on the assumption that the probability of acquisition from unprotected insertive anal (UIA) sex was neglectable. However, as later shown (Vittinghoff et al. 1999, Goodreau et al. 2005), this assumption is inappropriate and HIV-1 may still be acquired via UIA sex. Here I show through a stochastic model that the increase of the HIV-1 prevalence among MSM due to role versatility holds under a stronger assumption of bidirectional virus transmission. PMID- 29273543 TI - Acute effects of lead on porcine neonatal Sertoli cells in vitro. AB - Environmental pollution is one of the main factors responsible for reducing fertility in males. Lead is one of the major heavy metal contaminants that impairs several organs; it preferentially accumulates in male reproductive organs and alters sperm quality both in vivo and in vitro. However, the underlying mechanisms remain unclear. Sertoli cells (SCs) provide structural and physiological support to spermatogenic cells within seminiferous tubules. Therefore, changes in SCs affect the developing germ cells and alter spermatogenesis. This study aimed to assess whether exposure to subtoxic doses of adversely affects SC functioning in higher mammals. Purified and functional porcine neonatal SCs were exposed to lead acetate at three different concentrations. Lead exposure decreased the mRNA expression and protein levels of inhibin B and anti-Mullerian hormone (AMH) compared to control, indicating loss of FSH-r integrity in terms of 17-beta-oestradiol production under FSH stimulation. In addition, we observed an increase in the mRNA levels of Akt and mTOR, and the phosphorylation of p38 and Akt in SCs exposed to lead at all concentrations compared to unexposed control SCs. In conclusion, lead is toxic to SCs, even at low concentrations, and is expected to alter spermatogenesis. PMID- 29273546 TI - Needs of relatives of critically ill patients in an academic hospital in Chile. AB - OBJECTIVE: To identify the importance of the needs of family members of patients in an intensive care unit (ICU). METHOD: Descriptive, comparative and cross sectional study based on a secondary data analysis of 251 relatives of ICU patients at a university hospital in Santiago, Chile. Using non-random sampling, the 'Critical Care Family Needs Inventory' was used to establish the family needs, as well as a sociodemographic questionnaire that included: age, gender, educational level, patient relationship and previous ICU experience. A descriptive statistical analysis, Student's T test and ANOVA were performed. RESULTS: The most important family needs related to the dimensions of 'security' (mean=3.90) and 'information' (mean=3.76), while those of minor importance with 'support' (mean=3.09). In the latter, differences were observed at an older age (P<.05), an educational level (P<.001) and relationship with the patient (P<.05). CONCLUSIONS: The most relevant needs for family members in the ICU are related to safety and information. Less important needs are influenced by certain sociodemographic variables. Identifying the degree of importance of family needs will allow the health team to improve its relationship with families in ICUs. PMID- 29273547 TI - [Molecular characterisation defines several subtypes of pancreatic ductal adenocarcinoma]. AB - Multi-omics high throughput analyses lead to the description of multiple molecular subtypes of pancreatic adenocarcinoma with major prognostic impact for most of them. There is no consensual multilevel integrative classification yet like in colon or breast cancers. Genomic classifications have identified a tumor subtype (15% of the patients) with deficient homologous DNA repair-system leading to increase sensitivity to platinum-based therapies and possibly to PARP inhibitors and immunotherapies. Transcriptomic classifications are still debated but all have identified an aggressive subtype with a very poor prognosis, presumably unfit for a surgical approach. Finally, approaches based on metabolomic or proteomic profiling have identified subtypes with a particular sensitivity to compounds targeting the hallmarks metabolomics or oncogenic pathways of each subtype. These classifications were mostly based on tumor cell but the micro-environment is also very heterogeneous and several types of stroma will be described soon. Subtype determination in daily practice remains a major challenge as most technologies used to build these classifications are very expensive, requires dedicated bio-informatics analysis pipelines and are not adapted to routine samples that are mostly formal in fixed paraffin embedded biopsies, in which tumor cells are highly contaminated by the cell from the microenvironment and the clot. PMID- 29273548 TI - [Epidemiology of pancreatic cancer]. AB - Actually, pancreatic cancer is a major challenge in digestive oncology. Its prognosis remains very poor with a five-year net survival less than 10%. Although if pancreatic cancer incidence was low, data from French digestive cancer registries show a dramatic increase in recent years, more marked in women (annual variation of +3.6% between 1982 and 2012) than in men (+2.3%). The currently recognized risk factors like tobacco or obesity cannot explain this evolving epidemiology. Moreover, progress in understanding pancreatic carcinogenesis is still insufficient. Except for familial aggregation, systematic screening couldn't be proposed. PMID- 29273549 TI - Older and wiser? Age differences in foraging and learning by an endangered passerine. AB - Birds use cues when foraging to help relocate food resources, but natural environments provide many potential cues and choosing which to use may depend on previous experience. Young animals have less experience of their environment compared to adults, so may be slower to learn cues or may need to sample the environment more. Whether age influences cue use and learning has, however, received little experimental testing in wild animals. Here we investigate effects of age in a wild population of hihi (Notiomystis cincta), a threatened New Zealand passerine. We manipulated bird feeders using a novel colour cue to indicate a food reward; once hihi learned its location, we rotated the feeder to determine whether the birds followed the colour or returned to the previous location. Both age groups made fewer errors over trials and learned the location of the food reward, but juveniles continued to sample unrewarding locations more than adults. Following a second rotation, more adults preferred to forage from the hole indicated by the colour cue than juveniles, despite this no longer being rewarding. Overall, juveniles spent longer in the feeder arena to reach the same proportion of foraging time as adults. Combined, these results suggest that juveniles and adults may use an "explore and exploit" foraging strategy differently, and this affects how efficiently they forage. Further work is needed to understand how juveniles may compensate for their inexperience in learning and foraging strategies. PMID- 29273550 TI - Fighting cichlids: Dynamic of intrasexual aggression in dyadic agonistic encounters. AB - Aggression is an extremely complex behaviour and female aggression is understudied when compared to males. Despite the fact that it has been suggested that conflict among females may be more frequently resolved peacefully, in many species females show high levels of aggression. We used Cichlasoma dimerus to describe dynamics and conflict outcome in intrasexual agonistic encounters. We performed encounters of two sex-matched animals in a neutral arena and we recorded agonistic interactions during one hour. All aggressive and submissive behaviours were described and quantified to perform the ethogram. Encounters followed three phases: pre-contest, contest and post-resolution. Latency, time of resolution and frequency of aggressive displays did not differ between sexes. Relative variations in size between female opponents better explained aggression outcome in each contest, since higher levels of aggression occurred in dyads of more similar fish. However, this was not observed in males, suggesting that probably morphological characteristics could be less relevant in male conflict resolution. Altogether these results suggest that in this ethological context, C. dimerus females are as aggressive as males and that they have similar motivation towards territorial aggression, emphasizing the need of deepening the study of aggression in females and not only in males. PMID- 29273551 TI - Cosmetic, minimally invasive, partial matricectomy of ingrown toenails with granulation tissue. PMID- 29273552 TI - Ageing of the bony orbit is a major cause of age-related intraorbital fat herniation. AB - We evaluated the relationship between infraorbital fat herniation and age-related changes in the bony orbit and orbital fat density using computed tomography. Two hundred and sixty-five patients were enrolled (60 patients were evaluated for changes in the bony orbit and 205 for changes in orbital fat density). Five measurements using parasagittal sections and one measurement using three dimensional images were obtained. Intraorbital fat herniation length was positively correlated with orbital rim inclination. Lowering of the inferior orbital rim, which is connected to the orbicularis retaining ligament, tear trough ligament and orbital septum, can cause mechanical stretching of the lower eyelid and may contribute to infraorbital fat herniation. A strong and significant negative correlation was observed between orbital fat density and age, indicating that existing orbital fat can accommodate an enlargement in bony orbit volume without orbital fat hyperplasia/hypertrophy. In other words, an increased orbital fat volume may be a by-product of the adaptation of orbital fat to changes in bony orbit volume. Mechanical stretching of the lower eyelid due to ageing of the bony orbit and weakening of the lower eyelid due to age-related factors such as dermal/fat/muscle atrophy and loss of muscle tone can together result in anterior drooping of the lower eyelid. Therefore, age-related changes in the bony orbit contribute to intraorbital fat herniation. PMID- 29273553 TI - Association between FASN gene polymorphisms ultrasound carcass traits and intramuscular fat in Qinchuan cattle. AB - Fatty acid synthase (FASN) is an enzyme involved with fat deposition and fatty acid composition in cattle. This study was conducted to detect single nucleotide polymorphisms (SNPs) of the FASN gene and explore their relationships with ultrasound carcass traits in order to assess the potential use of the FASN gene for the breeding selection of Qinchuan cattle for desirable carcass traits. The frequencies of SNP g.12740C>T, g.13192T>C and g.13232C>T were identified in 525 individual Qinchuan cattle which were also assessed for backfat depth, eye muscle area and intramuscular fat by ultrasound. According to the PIC values, g.13192T>C possessed an intermediate polymorphism (0.25T, g.12740C>T possessed low polymorphism (PIC<0.25). Chi-square tests showed that g.13192T>C were in Hardy-Weinberg disequilibrium (c2C was associated with a greater eye muscle area and the TT genotype at g.13232C>T was associated with greater intramuscular fat. When these genotypes were combined there was no difference in eye muscle area and intramuscular fat between the diplotypes. The H2H2 diplotype was associated with carcass traits that are likely to provide economic advantage in Qinchuan cattle. Variations in the FASN genes and their corresponding genotypes may be considered as molecular markers for economic traits in cattle breeding. PMID- 29273554 TI - Competitive endogenous RNA in colorectal cancer: A systematic review. AB - Colorectal cancer is one of the most common malignant tumours. Competitive endogenous RNA (ceRNA) networks have been hypothesized, in which various RNAs regulate each other's expression using microRNA response elements (MREs). Recent evidence has highlighted the crucial regulatory roles of ceRNA networks in colorectal cancer. In this review, we summarize the present research methods as well as the currently known ceRNA competitors and targets in colorectal cancer. In addition, we discuss the significance of ceRNA and shortcomings of current studies of colorectal cancer. PMID- 29273555 TI - Novel noncontiguous duplications identified with a comprehensive mutation analysis in the DMD gene by DMD gene-targeted sequencing. AB - Genomic rearrangements, such as intragenic deletions and duplications, are the most prevalent types of mutation in the DMD gene, and DMD mutations underlie Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Using multiplex ligation dependent probe amplification (MLPA) and DMD gene-targeted sequencing, we performed a molecular characterization of two cases of complex noncontiguous duplication rearrangements that involved inverted duplications. The breakpoint sequences were analyzed to investigate the mechanisms of the rearrangement. The two cases shared the same duplication events (Dup-nml Dup/inv), and both involved microhomology and small insertions at the breakpoints. Additionally, in case 1, SNP sequencing results indicated that the de novo duplication mutation arose in the allele that originated from the grandfather. This study has identified a novel type of DMD complex rearrangement and provides insight into the molecular basis of this genomic rearrangement. PMID- 29273556 TI - Mining Ferula gummosa transcriptome to identify miRNAs involved in the regulation and biosynthesis of terpenes. AB - Ferula gummosa is a well-known medicinal and industrial plant for its oleo-gum resin named galbanum. So far, there is no information about the role of miRNAs on the production of terpenes as the major secondary metabolite of galbanum. In the present study, RNA-seq data on the root and flower of the plant were used to predict miRNAs and their targets using computational approaches. Additionally, biological network analyses were used to unravel the direct or indirect regulatory effects of miRNAs on the targets involved in terpene biosynthesis. For the first time, 220 miRNAs from 94 families have been reported in F. gummosa. miR5658, miR1533, miR5021, miR414, and miR1436 are the top five miRNAs with high abundance. Gene ontology (GO) analysis of the identified targets showed that in the biological process category, the miRNA-regulated genes were highly involved in transcription. According to the KEGG and PlantCyc results, six miRNAs from five miRNA families including miR2919, miR5251, miR838, miR5021, and miR5658 were found to be related to the pathway of terpene biosynthesis. Moreover, network analysis showed that three terpene-regulating TFs namely SPL7, SPL11, and ATHB13 are putatively regulated by three miRNAs including miR1533, miR5021, and miR5658 respectively. Differential gene expression results showed that the expression levels of these miRNAs are negatively correlated to the expression levels of both TFs and their co-expressed terpene biosynthesis genes. PMID- 29273557 TI - Overweight/obesity status in preschool children associates with worse asthma but robust improvement on inhaled corticosteroids. AB - BACKGROUND: Overweight/obesity (OW) is linked to worse asthma and poorer inhaled corticosteroid (ICS) response in older children and adults. OBJECTIVE: We sought to describe the relationships between OW and asthma severity and response to ICS in preschool children. METHODS: This post hoc study of 3 large multicenter trials involving 2- to 5-year-old children compared annualized asthma symptom days and exacerbations among normal weight (NW) (body mass index: 10th-84th percentiles) versus OW (body mass index: >=85th percentile) participants. Participants had been randomized to daily ICS, intermittent ICS, or daily placebo. Simple and multivariable linear regression was used to compare body mass index groups. RESULTS: Within the group not treated with a daily controller, OW children had more asthma symptom days (90.7 vs 53.2, P = .020) and exacerbations (1.4 vs 0.8, P = .009) thanNW children did. Within the ICS-treated groups, OW and NW children had similar asthma symptom days (daily ICS: 47.2 vs 44.0 days, P = .44; short term ICS: 61.8 vs 52.9 days, P = .46; as-needed ICS: 53.3 vs 47.3 days, P = .53), and similar exacerbations (daily ICS: 0.6 vs 0.8, P = .10; short-term ICS: 1.1 vs 0.8 days, P = .25; as-needed ICS: 1.0 vs 1.1, P = .72). Compared with placebo, daily ICS in OW led to fewer annualized asthma symptom days (90.7 vs 41.2, P = .004) and exacerbations (1.4 vs 0.6, P = .006), while similar protective ICS effects were less apparent among NW. CONCLUSIONS: In preschool children off controller therapy, OW is associated with greater asthma impairment and exacerbations. However, unlike older asthmatic patients, OW preschool children do not demonstrate reduced responsiveness to ICS therapy. PMID- 29273558 TI - Risk Factors for Late Screening Mammography. AB - BACKGROUND: Breast cancer has the highest incidence of cancers in women in the United States. Previous research has shown that screening mammography contributes to reduced breast cancer mortality. This study aimed to clarify why late screening might occur in an at-risk population. MATERIALS AND METHODS: This study was a prospective cross-sectional study including 758 patients presenting to our radiology department for routine screening mammography who completed a 30 question survey regarding personal characteristics and mammography history. Univariate and multivariate logistic regression were performed to determine whether survey responses correlated with late screening. RESULTS: Of the 758 patients, 184 (24%) were noncompliant with screening mammography guidelines. Risk factors for late screening included younger age (P = 0.001), white race/ethnicity (P = 0.03), self-reported lack of financial means or health insurance (P = 0.005), lack of satisfaction with a previous mammogram experience (P = 0.001), inadequate mammography education by a physician (P = 0.001), and lack of awareness/comprehension of screening mammography guidelines (P = 0.002). CONCLUSION: Many factors contribute to late screening mammography. Although some are outside physician control, others can be influenced: patient education regarding screening mammography guidelines, and patient satisfaction with the mammography experience. This study highlights the importance of communication with and education of patients. PMID- 29273559 TI - High specificity of spot urinary free metanephrines in diagnosis and prognosis of pheochromocytomas and paragangliomas by HPLC with electrochemical detection. AB - BACKGROUND: The metanephrines (MNs) in plasma and urine were proposed as biomarkers for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). However, plasma free MNs and 24h urinary fractionated MNs were not satisfactory enough in specificity for the diagnosis of PPGLs. Moreover, the collection of 24h urine was inconvenient. This work examined the diagnostic and prognostic efficiency of free MNs in spot urine for PPGLs. METHODS: We measured free MNs concentration in spot urine and plasma of 28 PPGLs patients and 155 control subjects by HPLC with electrochemical detection. Postoperative free MNs levels in spot urine and plasma of 14 PPGLs patients were also determined. Creatinine (Cr) concentration was used for the correction of urine volume. RESULTS: The specificity of spot urinary free MNs/Cr in the diagnosis of PPGLs was significantly higher than that of plasma free MNs [normetanephrine (NMN), 98.7% (95.4%-99.8%) vs 93.0% (87.4%-96.6%); metanephrine (MN), 93.6% (88.5%-96.9%) vs 84.5% (77.5%-90.0%)]. Meanwhile, the positive likelihood ratios for spot urinary free NMN/Cr and MN/Cr were 69.21 and 13.29, compared with 12.68 and 5.30 for plasma free NMN and MN, respectively. For the PPGLs patients underwent surgery, the plasma free MNs level appeared an abnormal elevation and yielded false positive results for some patients. Our findings were validated in an independent cohort, resulting in the specificity of 100% for both urinary free NMN/Cr and MN/Cr, and 97.3% and 83.8% for plasma free NMN and MN, respectively. CONCLUSIONS: Spot urinary free MNs/Cr, superior to plasma free MNs, presented a promising biomarker for the diagnosis and prognosis of PPGLs. PMID- 29273560 TI - Transnational social movement theory and the waning war on drugs: Case studies from UNGASS 2016. AB - BACKGROUND: The United Nations Convention against Illicit Traffic in Narcotic Drugs 1988 ("1988 Convention") expresses a strong normative preference for criminalising drug possession. Historically, the United Nations offices responsible for overseeing the treaties have held that decriminalisation of drug possession is contrary to the treaties. Leading up to and during UNGASS 2016, however, rather than emphasise criminalisation, the high-ranking officials from the drug control offices emphasised the treaties' allowance of alternatives to punishment for drug possession offences. METHODS: This paper applies transnational social movement theory to analyse the political opportunity structure for drug law reform at the UN. Data was collected from documents created by important United Nations agencies in the lead up to UNGASS 2016. By analysing the statements of prominent UN officials within a social movement theory framework, we can assess whether those responsible for administering global drug policy are offering concession to drug law reform social movement and whether a political opportunity structure is opening up for drug law reformers to pursue further reforms. RESULTS: from the United Nations documents demonstrated significant reference to local drug law reforms and the benefits of non-punitive treatment of drug users. However, given the strong normative preference and mandatory language ("shall") in the 1988 Convention, policy leaders at the UN can only offer very moderate concessions to drug law reformers - primarily the advocacy of alternatives to incarceration. Such policies still suffer many problems caused by using the criminal justice system to funnel people into treatment. Indeed, many other offices at the UN explicitly drew attention to the problem of pre-trial punishment in their contributions to UNGASS 2016. CONCLUSION: A schism is developing at the UN as other UN offices are pointing out that advocating for alternatives to punishment is inadequate due to the many problems of "pre-trial punishment". Social movement theory suggests that this schism represents an opening of the political opportunity structure as advocates for drug law reform can now more forcefully criticise, and even breach, the treaties and will have high-level support at the UN. PMID- 29273561 TI - Cross-linked enzyme aggregates (CLEAs) of halohydrin dehalogenase from Agrobacterium radiobacter AD1: Preparation, characterization and application as a biocatalyst. AB - Halohydrin dehalogenase from Agrobacterium radiobacter AD1 (HheC) shows great potential to produce valuable optically pure epoxides and beta-substituted alcohols. However, this enzyme has been reported to be very sensitive and less stable under oxidative conditions. Enzyme immobilization represents a powerful means to overcome this limitation and provides the enzyme characteristics of a biocatalyst. In this study, the crude extract of HheC was directly subjected to enzyme immobilization using a carrier-free cross-linked enzyme aggregates (CLEAs) method. The results showed that under the optimized conditions, the obtained HheCCLEAs retained more than 90% activity of the free enzyme; preserved more than 50% of their original activity after storage at 4 degrees C for 2 months, even in the absence of a reducing agent; displayed a strong tolerance to organic solvents with fully active after incubation in the presence of 50% cyclohexane and n-hexane for 5 h; the presence of organic solvents could minimize the negative effect of enzyme immobilization on the enzntioselectivity of HheC. Most importantly, HheCCLEAs maintained more than 70% activity after 10 reusability cycles. The utility of HheCCLEAs as a valuable biocatalyst was exhibited by the kinetic resolution of azide-mediated ring-opening reaction of rac-1,2-epoxy-2 methylbutane. These results indicated that HheCCLEAs overcame some disadvantages of free enzymes to become biocatalysts. Together with further engineering of the enzyme, HheCCLEAs could become a promising biocatalyst for the synthesis of valuable chiral compounds. PMID- 29273562 TI - Novel approaches to microbial enhancement of oil recovery. AB - Microbially enhanced oil recovery (MEOR) was shown to be feasible in a number of laboratory experiments and field trials. However, it has not been widely used in the oil industry because necessary conditions cannot always be easily established in an oil reservoir. Novel approaches to MEOR, which are based on newly discovered biosurfactant-mediated MEOR-mechanisms, are discussed in this review. Particularly, the possibility of combining MEOR with chemical enhancement of oil recovery in heterogeneous oil reservoirs, which involves rock surface wettability shifts and emulsion inversions, is discussed. In wider (centimeter/millimeter scale) rock pores, the activity of (bio)surfactants and microbial cells attached to oil may allow releasing trapped oil blobs through oil-in-water emulsification. After no more oil can be emulsified, the addition of alkali or surfactants, which turn rock surface oil-wet, may help release oil droplets trapped in narrow (micrometer-scale) pores through coalescence of the droplets and water-in-oil emulsification. Experiments demonstrating the possibility of (bio)surfactant mediated enhancement of immiscible gas-driven oil recovery are also reviewed. Interestingly, very low (bio)surfactant concentrations were shown to be needed for enhancement of immiscible gas-driven oil recovery. Some possible side effects of MEOR, such as unintended bioplugging and microbially influenced corrosion (MIC), are discussed as well. PMID- 29273563 TI - Is it safe to use Acorus calamus as a source of promising bioactive compounds in prevention and treatment of cardiovascular diseases? AB - Acorus calamus has a rich history in natural medicine, and offers many health benefits. The plant has anti-inflammatory, antimicrobial, diuretic, antiurolithiatic and other properties. Moreover, various parts, especially the rhizome and roots, are sources of a range of bioactive phenolic compounds with beneficial effects on the cardiovascular system. This review article summarizes the current knowledge of the chemical composition of different parts of A. calamus and their roles in the prevention and treatment of cardiovascular diseases. However, as no human studies have been performed, the review only includes in vitro and animal studies. The paper also briefly reviews the toxicity of A. calamus and its products for human health, especially regarding the cardiovascular system. PMID- 29273564 TI - Ascorbyl stearate and ionizing radiation potentiate apoptosis through intracellular thiols and oxidative stress in murine T lymphoma cells. AB - Ascorbyl stearate (Asc-s) is a derivative of ascorbic acid with better anti tumour efficacy compared to its parent compound ascorbic acid. In this study, we have examined radio-sensitizing effect of Asc-s in murine T cell lymphoma (EL4) cells at 4 Gy. Asc-s and radiation treatment reduced cell proliferation, induced apoptosis in a dose dependent manner by arresting the cells at S/G2-M phase of cell cycle. It also decreased the frequency of cancer stem cells per se, with significantly higher decrease in combination with radiation treatment./Further, Asc-s and radiation treatment increased the level of reactive oxygen species (ROS), drop in mitochondrial membrane potential (MMP) and increased caspase-3 activity resulting in apoptosis of EL4 cells. Further it also significantly decreased GSH/GSSG ratio due to binding of Asc-s with thiols. The increase in oxidative stress induced by Asc-s and radiation treatment was abrogated by thiol antioxidants in EL4 cells. Interestingly, this redox modulation triggered significant increase in protein glutathionylation in a time dependent manner. Asc s treatment resulted in glutathionylation of IKK, p50-NF-kB and mutated p53, thereby inhibiting cancer progression during oxidative stress. Asc-s quenches GSH ensuing Asc-s + GSH adduct thereby further modulating GSH/GSSG ratio as evident from HPLC and docking studies. The anti-tumour effect of Asc-s along with radiation was studied by injecting EL4 cells in synegenicC57/BL6 male mice. Intraperitoneal injection of Asc-s followed by radiation exposure at 4 Gy to the tumour bearing mice resulted in radio-sensitization which is evident from significant regression of tumour as evident from tumour burden index. The survival study supports the data that Asc-s pre-treatment enhances radio sensitization in murine lymphoma. Our data, suggest that Asc-s and ionizing radiation induced cell cycle arrest and apoptosis by perturbing redox balance through irreversible complexes of thiols with Asc-s, disturbed mitochondrial membrane permeability and activation of caspase-3 in EL4 cells. PMID- 29273565 TI - Identification of d-amino acid oxidase and propiverine interaction partners and their potential role in the propiverine-mediated nephropathy. AB - Propiverine, a frequently-prescribed pharmaceutical for the treatment of symptoms associated with overactive bladder syndrome, provoked massive intranuclear and cytosolic protein inclusions in rat proximal tubule epithelium, primarily consisting of the peroxisomal targeting signal 1 (PTS1) containing protein d amino acid oxidase (DAAO). As this type of nephropathy was also observed for other drugs, the aim was to determine whether propiverine interferes with trafficking and/or import of peroxisomal proteins. To elucidate this, DAAO- and propiverine-specific interaction partners from human HEK293 and rat WKPT cell lines and rat kidney and liver homogenate were determined using co immunoprecipitation with subsequent nano-ESI-LC-MS/MS analyses. Corroboration of the role of DAAO- and/or propiverine-specific interaction partners in the drug induced DAAO accumulation was sought via specific immunofluorescence staining of rat kidney sections from control and propiverine-treated rats. Above analyses demonstrated the interaction of propiverine with several protein classes, foremost peroxisomal proteins (DAAO, MFE2, HAOX2) and proteins of the protein quality control system, i.e. chaperones (HSP70 and DnaJ co-chaperones), proteases and proteasomal proteins (regulatory subunits of the 26S proteasome; Rpn1/2). The immunofluorescence analysis revealed mislocalization of many PTS1-proteins (DAAO, CAT, MFE2, ACOX1, EHHADH) in rat renal sections, strongly suggesting that propiverine primarily binds to PTS1 proteins resulting in the formation of PTS1 but not PTS2 or peroxisomal membrane protein (PMP) accumulations. Moreover, chaperones involved in peroxisomal trafficking (HSC70, DnaJB1) and peroxisomal biogenesis factor proteins (PEX3, PEX5, PEX7), also presented with distinct mislocalization patterns. Concomitantly, an increased number of peroxisomes was observed, suggestive of a compensatory mechanism for the presumably suboptimally functioning peroxisomes. Overall, the data presented suggested that propiverine interacts exclusively with DAAO or with a selected number of PTS1 proteins. The consequence of this interaction is the abrogated trafficking and peroxisomal import of PTS1 proteins concomitant with their nuclear and cytosolic accumulation due to inhibited degradation and imbalanced protein homeostasis. PMID- 29273566 TI - Nutritional shortage augments cisplatin-effects on murine melanoma cells. AB - Melanoma incidence increases every year worldwide and is responsible for 80% of skin cancer deaths. Due to its metastatic potential and resistance to almost any treatments such as chemo, radio, immune and targeted-therapy, the patients still have a poor prognosis, especially at metastatic stage. Considering that, it is crucial to find new therapeutic approaches to overcome melanoma resistance. Here we investigated the effect of cisplatin (CDDP), one of the chemotherapeutic agents used for melanoma treatment, in association with nutritional deprivation in murine melanoma cell lines. Cell death and autophagy were evaluated after the treatment with cisplatin, nutritional deprivation and its association using an in vitro model of murine melanocytes malignant transformation to metastatic melanoma. Our results showed that nutritional deprivation augmented cell death induced by cisplatin in melanoma cells, especially at the metastatic subtype, with slight effects on melanocytes. Mechanistic studies revealed that although autophagy was present at high levels in basal conditions in melanoma cells, was not essential for cell death process that involved mitochondrial damage, reactive oxygen species production and possible glycolysis inhibition. In conclusion, nutritional shortage in combination with chemotherapeutic drugs as cisplatin can be a valuable new therapeutic strategy to overcome melanoma resistance. PMID- 29273567 TI - 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate induced autophagic cell death in human PC3 cells. AB - The autophagy of human prostate cancer cells (PC3 cells) induced by a new anthraquinone derivative, 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy] 9,10-anthraquinone ditrifluoroactate (PA) was investigated, and the relationship between autophagy and reactive oxygen species (ROS) generation was studied. The results indicated that PA induced PC3 cell death in a time- and dose-dependent manner, could inhibit PC3 cell growth by G1 phase cell cycle arrest and corresponding decrease in the G2/M cell population and induced S-phase arrest accompanied by a significant decrease G2/M and G1 phase numbers after PC3 cells treated with PA for 48 h, and increased the accumulation of autophagolysosomes and microtubule-associated protein LC3-ll, a marker of autophagy. However, these phenomenon were not observed in the group pretreated with the autophagy inhibitor 3-MA or Bafilomycin A1 (BAF), suggesting that PA induced PC3 cell autophagy. In addition, we found that PA triggered ROS generation in cells, while the levels of ROS decreased in the N-acetylcysteine (NAC) co-treatment, indicating that PA mediated autophagy was partly blocked by NAC. In summary, the autophagic cell death of human PC3 cells mediated by PA-triggered ROS generation. PMID- 29273568 TI - Hantavirus Gc induces long-term immune protection via LAMP-targeting DNA vaccine strategy. AB - Hemorrhagic fever with renal syndrome (HFRS) occurs widely throughout Eurasia. Unfortunately, there is no effective treatment, and prophylaxis remains the best option against the major pathogenic agent, hantaan virus (HTNV), which is an Old World hantavirus. However, the absence of cellular immune responses and immunological memory hampers acceptance of the current inactivated HFRS vaccine. Previous studies revealed that a lysosome-associated membrane protein 1 (LAMP1) targeting strategy involving a DNA vaccine based on the HTNV glycoprotein Gn successfully conferred long-term immunity, and indicated that further research on Gc, another HTNV antigen, was warranted. Plasmids encoding Gc and lysosome targeted Gc, designated pVAX-Gc and pVAX-LAMP/Gc, respectively, were constructed. Proteins of interest were identified by fluorescence microscopy following cell line transfection. Five groups of 20 female BALB/c mice were subjected to the following inoculations: inactivated HTNV vaccine, pVAX-LAMP/Gc, pVAX-Gc, and, as the negative controls, pVAX-LAMP or the blank vector pVAX1. Humoral and cellular immunity were assessed by enzyme-linked immunosorbent assays (ELISAs) and 15-mer peptide enzyme-linked immunospot (ELISpot) epitope mapping assays. Repeated immunization with pVAX-LAMP/Gc enhanced adaptive immune responses, as demonstrated by the specific and neutralizing antibody titers and increased IFN gamma production. The inactivated vaccine induced a comparable humoral reaction, but the negative controls only elicited insignificant responses. Using a mouse model of HTNV challenge, the in vivo protection conferred by the inactivated vaccine and Gc-based constructs (with/without LAMP recombination) was confirmed. Evidence of pan-epitope reactions highlighted the long-term cellular response to the LAMP-targeting strategy, and histological observations indicated the safety of the LAMP-targeting vaccines. The long-term protective immune responses induced by pVAX-LAMP/Gc may be due to the advantage afforded by lysosomal targeting after exogenous antigen processing initiation and major histocompatibility complex (MHC) class II antigen presentation trafficking. MHC II-restricted antigen recognition effectively primes HTNV-specific CD4+ T-cells, leading to the promotion of significant immune responses and immunological memory. An epitope spreading phenomenon was observed, which mirrors the previous result from the Gn study, in which the dominant IFN-gamma-responsive hot-spot epitopes were shared between HLA-II and H2d. Importantly, the pan-epitope reaction to Gc indicated that Gc should be with potential for use in further hantavirus DNA vaccine investigations. PMID- 29273569 TI - Forensic face recognition as a means to determine strength of evidence: A survey. AB - This paper surveys the literature on forensic face recognition (FFR), with a particular focus on the strength of evidence as used in a court of law. FFR is the use of biometric face recognition for several applications in forensic science. It includes scenarios of ID verification and open-set identification, investigation and intelligence, and evaluation of the strength of evidence. We present FFR from operational, tactical, and strategic perspectives. We discuss criticism of FFR and we provide an overview of research efforts from multiple perspectives that relate to the domain of FFR. Finally, we sketch possible future directions for FFR. PMID- 29273570 TI - Instability and poor recovery of cannabinoids in urine, oral fluid, and hair. AB - Cannabinoids including, but not limited to Delta9-tetrahydrocannabinol, 11 hydroxytetrahydrocannabinol, and (-)-11-nor-Delta9-tetrahydrocannabinol-9 carboxylic acid are known to toxicologists and synthetic chemists as difficult compounds because they are subject to numerous degradative pathways. It is the purpose of this short review article to discuss common pathways that result in the disappearance of cannabinoids - such as conjugate formation, adsorption to surfaces, chemical reactions, microbial action, thermal decomposition, chemical bonding, photosensitivity, sample handling, analytical methodology, and micelle trapping - and to point out possible ways to avoid such degradation. PMID- 29273571 TI - Toward a systematic classification of textile damages. AB - The accuracy of textile damage analyses was evaluated by laboratory tests carried out by trained experts. The analyzed damages were prepared by various methods, including stabbing, cutting, shooting, heating/burning, etc. A number of damages were aged by household washing and tumble-drying procedures, addition of blood, or burying. The samples were analyzed by routine laboratory evaluation. The results indicate that the properties of a damage provide a good indication of the way a textile had been damaged. Nevertheless, scoring of the answers is not straightforward. Results indicated that examiners evaluated damages on different levels of specificity and thereby showed the latent need for a more systematic approach to damage classification. The second part of the current contribution therefore presents the classification scheme we developed. This classification scheme aims to guide examiners during examination and accommodates the vast majority of textile damages observed in forensic casework. Each of the proposed classes is defined, relevant literature in each of the classes is reviewed, and the characteristics that can be expected after different damaging actions are explained. Finally, we share some ideas for further investigations. PMID- 29273572 TI - Facebook Groups as a Powerful and Dynamic Tool in Medical Education: Mixed-Method Study. AB - BACKGROUND: Social networking sites, in particular Facebook, are not only predominant in students' social life but are to varying degrees interwoven with the medical curriculum. Particularly, Facebook groups have been identified for their potential in higher education. However, there is a paucity of data on user types, content, and dynamics of study-related Facebook groups. OBJECTIVE: The aim of this study was to identify the role of study-related Facebook group use, characterize medical students that use or avoid using Facebook groups (demographics, participation pattern, and motivation), and analyze student posting behavior, covered topics, dynamics, and limitations in Facebook groups with regards to educational usage. METHODS: Using a multi-method approach (interviews, focus groups, and qualitative and quantitative analysis of Facebook posts), we analyzed two representative Facebook groups of medical preclinical semesters at Ludwig-Maximilians-University (LMU) Munich. Facebook primary posts and replies over one semester were extracted and evaluated by using thematic content analysis. We developed and applied a coding scheme for studying the frequency and distribution of these posts. Additionally, we interviewed students with various degrees of involvement in the groups, as well as "new minorities," students not registered on Facebook. RESULTS: Facebook groups seem to have evolved as the main tool for medical students at LMU to complement the curriculum and to discuss study-related content. These Facebook groups are self-organizing and quickly adapt to organizational or subject-related challenges posed by the curriculum. A wide range of topics is covered, with a dominance of organization related posts (58.35% [6916/11,853] of overall posts). By measuring reply rates and comments per category, we were able to identify learning tips and strategies, material sharing, and course content discussions as the most relevant categories. Rates of adequate replies in these categories ranged between 78% (11/14) and 100% (13/13), and the number of comments per post ranged from 8.4 to 13.7 compared with the average overall reply rate of 68.69% (1167/1699) and 3.9 comments per post. User typology revealed social media drivers (>30 posts per semester) as engines of group function, frequent users (11-30 posts), and a majority of average users acting rather as consumers or lurkers (1-10 posts). CONCLUSIONS: For the moment, the medical faculty has no active involvement in these groups and therefore no influence on accuracy of information, professionalism, and ethical issues. Nevertheless, faculty could in the future benefit by extracting relevant information, identifying common problems, and understanding semester-related dynamics. PMID- 29273573 TI - Medication Adherence and Technology-Based Interventions for Adolescents With Chronic Health Conditions: A Few Key Considerations. AB - The number of children and adolescents with chronic health conditions (CHCs) has doubled over the past two decades. Medication adherence is a key component of disease management within these groups. Low adherence to prescribed medications is a known problem in adolescents with CHCs and is related to health outcomes, including quality of life, disease complications, and mortality. Adolescence is a critical time to create routines and health behaviors that optimize disease self management and transition to adult care. The mounting interest in the development and use of mobile health tools provides novel opportunities to connect patients, particularly adolescents, with their providers outside of the clinic and to improve health outcomes. There is growing evidence to support the efficacy of technology-based approaches, in particular text-messaging and mobile apps, to improve adherence behavior in adolescents, although cost-effectiveness and long term health benefits remain unclear. In this short viewpoint article, we review some important considerations for promoting medication adherence in adolescents with CHCs using technology-based approaches. PMID- 29273575 TI - Insights From Google Play Store User Reviews for the Development of Weight Loss Apps: Mixed-Method Analysis. AB - BACKGROUND: Significant weight loss takes several months to achieve, and behavioral support can enhance weight loss success. Weight loss apps could provide ongoing support and deliver innovative interventions, but to do so, developers must ensure user satisfaction. OBJECTIVE: The aim of this study was to conduct a review of Google Play Store apps to explore what users like and dislike about weight loss and weight-tracking apps and to examine qualitative feedback through analysis of user reviews. METHODS: The Google Play Store was searched and screened for weight loss apps using the search terms weight loss and weight track*, resulting in 179 mobile apps. A content analysis was conducted based on the Oxford Food and Activity Behaviors taxonomy. Correlational analyses were used to assess the association between complexity of mobile health (mHealth) apps and popularity indicators. The sample was then screened for popular apps that primarily focus on weight-tracking. For the resulting subset of 15 weight tracking apps, 569 user reviews were sampled from the Google Play Store. Framework and thematic analysis of user reviews was conducted to assess which features users valued and how design influenced users' responses. RESULTS: The complexity (number of components) of weight loss apps was significantly positively correlated with the rating (r=.25; P=.001), number of reviews (r=.28; P<.001), and number of downloads (r=.48; P<.001) of the app. In contrast, in the qualitative analysis of weight-tracking apps, users expressed preference for simplicity and ease of use. In addition, we found that positive reinforcement through detailed feedback fostered users' motivation for further weight loss. Smooth functioning and reliable data storage emerged as critical prerequisites for long-term app usage. CONCLUSIONS: Users of weight-tracking apps valued simplicity, whereas users of comprehensive weight loss apps appreciated availability of more features, indicating that complexity demands are specific to different target populations. The provision of feedback on progress can motivate users to continue their weight loss attempts. Users value seamless functioning and reliable data storage. PMID- 29273574 TI - Consumer Adoption of Future MyData-Based Preventive eHealth Services: An Acceptance Model and Survey Study. AB - BACKGROUND: Constantly increasing health care costs have led countries and health care providers to the point where health care systems must be reinvented. Consequently, electronic health (eHealth) has recently received a great deal of attention in social sciences in the domain of Internet studies. However, only a fraction of these studies focuses on the acceptability of eHealth, making consumers' subjective evaluation an understudied field. This study will address this gap by focusing on the acceptance of MyData-based preventive eHealth services from the consumer point of view. We are adopting the term "MyData", which according to a White Paper of the Finnish Ministry of Transport and Communication refers to "1) a new approach, a paradigm shift in personal data management and processing that seeks to transform the current organization centric system to a human centric system, 2) to personal data as a resource that the individual can access and control." OBJECTIVE: The aim of this study was to investigate what factors influence consumers' intentions to use a MyData-based preventive eHealth service before use. METHODS: We applied a new adoption model combining Venkatesh's unified theory of acceptance and use of technology 2 (UTAUT2) in a consumer context and three constructs from health behavior theories, namely threat appraisals, self-efficacy, and perceived barriers. To test the research model, we applied structural equation modeling (SEM) with Mplus software, version 7.4. A Web-based survey was administered. We collected 855 responses. RESULTS: We first applied traditional SEM for the research model, which was not statistically significant. We then tested for possible heterogeneity in the data by running a mixture analysis. We found that heterogeneity was not the cause for the poor performance of the research model. Thus, we moved on to model-generating SEM and ended up with a statistically significant empirical model (root mean square error of approximation [RMSEA] 0.051, Tucker-Lewis index [TLI] 0.906, comparative fit index [CFI] 0.915, and standardized root mean square residual 0.062). According to our empirical model, the statistically significant drivers for behavioral intention were effort expectancy (beta=.191, P<.001), self-efficacy (beta=.449, P<.001), threat appraisals (beta=.416, P<.001), and perceived barriers (beta=-.212, P=.009). CONCLUSIONS: Our research highlighted the importance of health-related factors when it comes to eHealth technology adoption in the consumer context. Emphasis should especially be placed on efforts to increase consumers' self-efficacy in eHealth technology use and in supporting healthy behavior. PMID- 29273576 TI - Opinion: redefining the role of the physician in laboratory medicine in the context of emerging technologies, personalised medicine and patient autonomy ('4P medicine'). AB - The role of clinical pathologists or laboratory-based physicians is being challenged on several fronts-exponential advances in technology, increasing patient autonomy exercised in the right to directly request tests and the use of non-medical specialists as substitutes. In response, clinical pathologists have focused their energies on the pre-analytical and postanalytical phases of Laboratory Medicine thus emphasising their essential role in individualised medical interpretation of complex laboratory results. Across the European Union, the role of medical doctors is enshrined in the Medical Act. This paper highlights the relevance of this act to patient welfare and the need to strengthen training programmes to prevent an erosion in the quality of Laboratory Medicine provided to patients and their physicians. PMID- 29273577 TI - Effect of Single Dose of RANKL Antibody Treatment on Acute Charcot Neuro osteoarthropathy of the Foot. PMID- 29273578 TI - Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog. AB - OBJECTIVE: Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion. RESULTS: Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ~35 min with a half-life of ~0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by >=20 mg/dL (9-14 min) to PG >=70 mg/dL (within 6-10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44-56%). CONCLUSIONS: Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen. PMID- 29273579 TI - A decade of outpatient antimicrobial use in older adults in Ontario: a descriptive study. AB - BACKGROUND: Antimicrobials are frequently prescribed to community-dwelling older adults. Our aim was to examine the prevalence, quantity and indications of antimicrobial prescriptions to older residents of Ontario. METHODS: We conducted a population-based analysis of outpatient antimicrobial prescriptions to residents of Ontario aged 65 years or more from 2006 to 2015. Antimicrobial prescriptions, infectious disease diagnoses and prescriber information were determined from linked health care databases. Our analyses were primarily focused on antibiotics, which account for most antimicrobial use. RESULTS: We identified 2 879 779 unique Ontario residents aged 65 years or more over our study period. On average, 40.7% (range 40.1%-41.5%) of older adult outpatients in any given year received 1 or more antibiotic prescriptions. Antibiotic use remained stable over the study period, averaging 25.1 (range 24.1-25.6) defined daily doses per 1000 person-days per year. Selection of antibiotics evolved, with increasing use of penicillins and decreasing use of fluoroquinolones and macrolides. For 65.7% of prescriptions, no infectious disease diagnoses were identified within 7 days of the prescription. Among prescriptions with an associated diagnosis, upper respiratory tract infection was most common (18.9%), followed by urinary tract infection (6.2%), skin/soft-tissue infection (4.3%), lower respiratory tract infection (4.2%) and other infection (1.2%). Most antibiotics were prescribed by family physicians. INTERPRETATION: Antibiotic use among older adult outpatients in Ontario remained stable between 2006 and 2015. Current methods of measuring use are not capable of accurately determining indication, and, thus, additional data sources to monitor the appropriateness of community antimicrobial use are needed. PMID- 29273581 TI - Mortality Differences Associated With Treatment Responses in CANTOS and FOURIER: Insights and Implications. PMID- 29273580 TI - The two TRAPP complexes of metazoans have distinct roles and act on different Rab GTPases. AB - Originally identified in yeast, transport protein particle (TRAPP) complexes are Rab GTPase exchange factors that share a core set of subunits. TRAPPs were initially found to act on Ypt1, the yeast orthologue of Rab1, but recent studies have found that yeast TRAPPII can also activate the Rab11 orthologues Ypt31/32. Mammals have two TRAPP complexes, but their role is less clear, and they contain subunits that are not found in the yeast complexes but are essential for cell growth. To investigate TRAPP function in metazoans, we show that Drosophila melanogaster have two TRAPP complexes similar to those in mammals and that both activate Rab1, whereas one, TRAPPII, also activates Rab11. TRAPPII is not essential but becomes so in the absence of the gene parcas that encodes the Drosophila orthologue of the SH3BP5 family of Rab11 guanine nucleotide exchange factors (GEFs). Thus, in metazoans, Rab1 activation requires TRAPP subunits not found in yeast, and Rab11 activation is shared by TRAPPII and an unrelated GEF that is metazoan specific. PMID- 29273582 TI - The role of chloroplasts in plant pathology. AB - Plants have evolved complex tolerance systems to survive abiotic and biotic stresses. Central to these programmes is a sophisticated conversation of signals between the chloroplast and the nucleus. In this review, we examine the antagonism between abiotic stress tolerance (AST) and immunity: we propose that to generate immunogenic signals, plants must disable AST systems, in particular those that manage reactive oxygen species (ROS), while the pathogen seeks to reactivate or enhance those systems to achieve virulence. By boosting host systems of AST, pathogens trick the plant into suppressing chloroplast immunogenic signals and steer the host into making an inappropriate immune response. Pathogens disrupt chloroplast function, both transcriptionally-by secreting effectors that alter host gene expression by interacting with defence related kinase cascades, with transcription factors, or with promoters themselves and post-transcriptionally, by delivering effectors that enter the chloroplast or alter the localization of host proteins to change chloroplast activities. These mechanisms reconfigure the chloroplast proteome and chloroplast-originating immunogenic signals in order to promote infection. PMID- 29273583 TI - Chloroplast signaling and quality control. AB - Although chloroplasts contain their own genetic system and are semi-autonomous cell organelles, plastid biogenesis and homeostasis are heavily dependent on the nucleo-cytosolic compartment. These two cellular compartments are closely co ordinated through a complex signaling network comprising both anterograde and retrograde signaling chains. Developmental changes or any perturbation in the chloroplast system induced by a particular stress resulting from changes in environmental conditions such as excess light, elevated temperature, nutrient limitation, pathogen infection, give rise to specific signals. They migrate out of the chloroplast and are perceived by the nucleus where they elicit changes in expression of particular genes that allow for the maintenance of plastid homeostasis toward environmental cues. These genes mainly include those of photosynthesis-associated proteins, chaperones, proteases, nucleases and immune/defense proteins. Besides this transcriptional response, a chloroplast quality control system exists that is involved in the repair and turnover of damaged plastid proteins. This system degrades aggregated or damaged proteins and it can even remove entire chloroplasts when they have suffered heavy damage. This response comprises several processes such as plastid autophagy and ubiquitin proteasome mediated proteolysis that occurs on the plastid envelope through the action of the ubiquitin-proteasome system. PMID- 29273584 TI - Vibrio cholerae amino acids go on the defense. AB - Gram-negative bacteria remodel their surfaces to interact with the environment, particularly to protect pathogens from immune surveillance and host defenses. The enzyme AlmG is known to be involved in remodeling the Vibrio cholerae surface, but its specific role was not clear. A new study characterizes AlmG at the molecular level, showing it defies phylogenetic expectations to add amino acids to lipopolysaccharide (LPS). This LPS modification plays a pivotal role in V. cholerae resistance to antimicrobial peptides, weapons of the innate immune system against infections. PMID- 29273585 TI - Reconstructed ancestral enzymes reveal that negative selection drove the evolution of substrate specificity in ADP-dependent kinases. PMID- 29273587 TI - Pharmacokinetics of the Cardioprotective Drug Dexrazoxane and Its Active Metabolite ADR-925 with Focus on Cardiomyocytes and the Heart. AB - Dexrazoxane (DEX), the only cardioprotectant approved against anthracycline cardiotoxicity, has been traditionally deemed to be a prodrug of the iron chelating metabolite ADR-925. However, pharmacokinetic profile of both agents, particularly with respect to the cells and tissues essential for its action (cardiomyocytes/myocardium), remains poorly understood. The aim of this study is to characterize the conversion and disposition of DEX to ADR-925 in vitro (primary cardiomyocytes) and in vivo (rabbits) under conditions where DEX is clearly cardioprotective against anthracycline cardiotoxicity. Our results show that DEX is hydrolyzed to ADR-925 in cell media independently of the presence of cardiomyocytes or their lysate. Furthermore, ADR-925 directly penetrates into the cells with contribution of active transport, and detectable concentrations occur earlier than after DEX incubation. In rabbits, ADR-925 was detected rapidly in plasma after DEX administration to form sustained concentrations thereafter. ADR 925 was not markedly retained in the myocardium, and its relative exposure was 5.7-fold lower than for DEX. Unlike liver tissue, myocardium homogenates did not accelerate the conversion of DEX to ADR-925 in vitro, suggesting that myocardial concentrations in vivo may originate from its distribution from the central compartment. The pharmacokinetic parameters for both DEX and ADR-925 were determined by both noncompartmental analyses and population pharmacokinetics (including joint parent-metabolite model). Importantly, all determined parameters were closer to human than to rodent data. The present results open venues for the direct assessment of the cardioprotective effects of ADR-925 in vitro and in vivo to establish whether DEX is a drug or prodrug. PMID- 29273586 TI - Incremental effects of antihypertensive drugs: instrumental variable analysis. AB - OBJECTIVES: To assess the incremental effects of adding extra antihypertensive drugs from a new class to a patient's regimen. DESIGN: Instrumental variable analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). To account for confounding by indication-when treatments seem less effective if they are administered to sicker patients-randomization status was used as the instrumental variable. Patients' randomization status was either intensive (systolic blood pressure target <120 mm Hg) or standard (systolic blood pressure target <140 mm Hg) treatment. Results from instrumental variable models were compared with those from standard multivariable models. SETTING: Secondary data analysis of a randomized clinical trial conducted at 102 sites in 2010-15. PARTICIPANTS: 9092 SPRINT participants with hypertension and increased cardiovascular risk but no history of diabetes or stroke. MAIN OUTCOMES MEASURES: Systolic blood pressure, major cardiovascular events, and serious adverse events. RESULTS: In standard multivariable models not adjusted for confounding by indication, addition of an antihypertensive drug from a new class was associated with modestly lower systolic blood pressure (-1.3 mm Hg, 95% confidence interval 1.6 to -1.0) and no change in major cardiovascular events (absolute risk of events per 1000 patient years, 0.5, 95% confidence interval -1.5 to 2.3). In instrumental variable models, the addition of an antihypertensive drug from a new class led to clinically important reductions in systolic blood pressure (-14.4 mm Hg, -15.6 to -13.3) and fewer major cardiovascular events (absolute risk -6.2, 10.9 to -1.3). Incremental reductions in systolic blood pressure remained large and similar in magnitude for patients already taking drugs from zero, one, two, or three or more drug classes. This finding was consistent across all subgroups of patients. The addition of another antihypertensive drug class was not associated with adverse events in either standard or instrumental variable models. CONCLUSIONS: After adjustment for confounding by indication, the addition of a new antihypertensive drug class led to large reductions in systolic blood pressure and major cardiovascular events among patients at high risk for cardiovascular events but without diabetes. Effects on systolic blood pressure persisted across all levels of baseline drug use and all subgroups of patients. PMID- 29273588 TI - Loneliness and tiredness resulting from the European Working Time Regulations. PMID- 29273589 TI - Attenuation of PERK enhances glucose-stimulated insulin secretion in islets. AB - PERK is a pancreatic endoplasmic reticulum (ER) kinase. Its complete deletion in pancreatic beta cells induces insulin deficiency; however, the effects of partial Perk suppression are unclear. We investigated the effect of partial PERK suppression using the specific PERK inhibitors GSK2606414 and GSK2656157. Low dose GSK2606414 treatment for 24 h enhanced glucose-stimulated insulin secretion (GSIS), islet insulin content and calcium transit in mouse (at 40 nM) and human (at 50-100 nM) pancreatic islets. GSK2606414 also induced the expression of the ER chaperone BiP and the release of calcium from the ER. When Bip expression was inhibited using a Bip siRNA, the GSK2606414-induced augmentation of the ER calcium level, islet insulin contents, glucose-stimulated cytosolic calcium transit and GSIS were abrogated. In both wild-type and insulin-deficient Atg7 knockout mice, 8 weeks of GSK2656157 treatment enhanced GSIS and improved hyperglycemia without affecting body weight. In conclusion, partial PERK inhibition induced BiP expression in islets, increased glucose-stimulated calcium transit and islet insulin contents and enhanced GSIS, suggesting that low-dose PERK inhibitors could potentially be used to treat insulin deficiency. PMID- 29273590 TI - BASHH HIV and Blood Borne Virus Specialist Interest Group. PMID- 29273593 TI - Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study. AB - BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare cerebral vasculopathy characterized by bilateral internal carotid artery stenosis and often leads to stroke in children or young adults. Although familial inheritance is well recognized, the genetic basis of MMD remains poorly understood. METHODS: A 2 stage genome-wide association study was conducted involving 1492 cases and 5084 controls. In the discovery stage, logistic regression was used to test associations, and imputation was conducted based on genotyped single-nucleotide polymorphisms (SNPs). In the validation stage, the top significant SNPs were again genotyped in an independent cohort. Fixed-effects inverse variance-weighted meta-analysis was used in the combined discovery and validation samples. Furthermore, association analysis was conducted in subgroups using patient clinical data. RESULTS: The study identified 10 novel risk loci with genome-wide significance (P<5*10-8) and confirmed a previously reported locus on 17q25. No significant SNP showed evidence of heterogeneity between the 2 stages. Cumulatively, these SNPs explained 14.76% of disease risk variance-a substantial proportion of the 39.02% of risk variance explained by all genome-wide genotyped SNPs. One SNP, rs9916351 in RNF213 (Pcombined=4.57*10-54; odds ratio, 1.96), showed a stronger genetic effect on early-onset than late-onset MMD (P=0.003). Two novel SNPs in genes regulating homocysteine metabolism, rs9651118 in MTHFR (Pcombined=2.49*10-19; odds ratio, 0.65) and rs117353193 in TCN2 (Pcombined=6.15*10-13; odds ratio, 1.43), were associated with high-serum homocysteine in MMD cases. Additionally, another SNP associated with MMD (rs2107595 in HDAC9; Pcombined=1.49*10-29; odds ratio, 1.64) was previously implicated in large-vessel disease. Tissue enrichment analysis showed that the genes of associated loci were highly expressed in the immune system (false discovery rate, <0.05). CONCLUSIONS: This study identifies several novel susceptibility genes for MMD. The association with homocysteine metabolism and the immune system enrichment of susceptibility gene expression suggest that therapeutic interventions targeting these pathways may be effective approaches for MMD treatment. PMID- 29273595 TI - PROMIS GH (Patient-Reported Outcomes Measurement Information System Global Health) Scale in Stroke: A Validation Study. AB - BACKGROUND AND PURPOSE: The International Consortium for Health Outcomes Measurement recently included the 10-item PROMIS GH (Patient-Reported Outcomes Measurement Information System Global Health) scale as part of their recommended Standard Set of Stroke Outcome Measures. Before collection of PROMIS GH is broadly implemented, it is necessary to assess its performance in the stroke population. The objective of this study was to evaluate the psychometric properties of PROMIS GH in patients with ischemic stroke and intracerebral hemorrhage. METHODS: PROMIS GH and 6 PROMIS domain scales measuring same/similar constructs were electronically collected on 1102 patients with ischemic and hemorrhagic strokes at various stages of recovery from their stroke who were seen in a cerebrovascular clinic from October 12, 2015, through June 2, 2017. Confirmatory factor analysis was performed to evaluate the adequacy of 2-factor structure of component scores. Test-retest reliability and convergent validity of PROMIS GH items and component scores were assessed. Discriminant validity and responsiveness were compared between PROMIS GH and PROMIS domain scales measuring the same or related constructs. Analyses were repeated stratified by stroke subtype and modified Rankin Scale score <2 versus >=2. RESULTS: There was moderate internal reliability (ordinal alpha, 0.82-0.88) and marginal model fit for the 2-factor solution for component scores (root mean square error of approximation, 0.11). Convergent validity was good with significant correlations between all PROMIS GH items and PROMIS domain scales (P<0.001 for all). There was excellent discrimination for all PROMIS GH items and component scores across modified Rankin Scale levels. Good responsiveness (effect size, >0.5) was demonstrated for 8 of the 10 PROMIS GH items. Reliability and validity remained consistent across stroke subtype and disability level (modified Rankin Scale, <2 versus >=2). CONCLUSIONS: PROMIS GH exhibits acceptable performance in patients with stroke. Our findings support International Consortium for Health Outcomes Measurement recommendation to use PROMIS GH as part of the standard set of outcome measures in stroke. PMID- 29273594 TI - Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men. AB - BACKGROUND AND PURPOSE: We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). METHODS: Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke. RESULTS: The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers (P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant (P=0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16-0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS: Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885. PMID- 29273598 TI - Correction to: Early Elevated Troponin Levels After Ischemic Stroke Suggests a Cardioembolic Source. PMID- 29273596 TI - Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat. AB - BACKGROUND AND PURPOSE: The NLRP3 (nucleotide binding and oligomerization domain like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. METHODS: SAH was induced by endovascular perforation in male Sprague Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKIIalpha (calcium/calmodulin-dependent protein kinase II alpha) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed. RESULTS: DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIalpha and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIalpha, p-TAK1 (phosphorylated transforming growth factor-beta-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIalpha small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH. CONCLUSIONS: DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH. PMID- 29273597 TI - Intravenous Thrombolysis for Stroke and Presumed Stroke in Human Immunodeficiency Virus-Infected Adults: A Retrospective, Multicenter US Study. AB - BACKGROUND AND PURPOSE: Human immunodeficiency virus (HIV) infection has been shown to increase both ischemic and hemorrhagic stroke risks, but there are limited data on the safety and outcomes of intravenous thrombolysis with tPA (tissue-type plasminogen activator) for acute ischemic stroke in HIV-infected patients. METHODS: A retrospective chart review of intravenous tPA-treated HIV patients who presented with acute stroke symptoms was performed in 7 large inner city US academic centers (various search years between 2000 and 2017). We collected data on HIV, National Institutes of Health Stroke Scale score, ischemic stroke risk factors, opportunistic infections, intravenous drug abuse, neuroimaging findings, and modified Rankin Scale score at last follow-up. RESULTS: We identified 33 HIV-infected patients treated with intravenous tPA (mean age, 51 years; 24 men), 10 of whom were stroke mimics. Sixteen of 33 (48%) patients had an HIV viral load less than the limit of detection while 10 of 33 (30%) had a CD4 count <200/mm3. The median National Institutes of Health Stroke Scale score at presentation was 9, and mean time from symptom onset to tPA was 144 minutes (median, 159). The median modified Rankin Scale score for the 33 patient cohort was 1 and for the 23-patient actual stroke cohort was 2, measured at a median of 90 days poststroke symptom onset. Two patients had nonfatal hemorrhagic transformation (6%; 95% confidence interval, 1%-20%), both in the actual stroke group. Two patients had varicella zoster virus vasculitis of the central nervous system, 1 had meningovascular syphilis, and 7 other patients were actively using intravenous drugs (3 cocaine, 1 heroin, and 3 unspecified), none of whom had hemorrhagic transformation. CONCLUSIONS: Most HIV-infected patients treated with intravenous tPA for presumed and actual acute ischemic stroke had no complications, and we observed no fatalities. Stroke mimics were common, and thrombolysis seems safe in this group. We found no data to suggest an increased risk of intravenous tPA-related complications because of concomitant opportunistic infections or intravenous drug abuse. PMID- 29273599 TI - Effects of drinking on late-life brain and cognition. AB - Alcohol consumption is common in Western countries and has been increasing in older adults. Latest figures from Great Britain suggest 75% of those over 65 years drink, an increase from 71% 10 years ago. Chronic heavy intake is a well established cause of brain atrophy and dementia, with a recent long-term prospective study from the USA reporting a doubling of the odds of later severe memory impairment in those with a history of an alcohol use disorder. Drinking of moderate amounts has been reported to be protective for brain health in a number of epidemiological studies, including some claims of possibly reducing dementia risk. Rigorous recent research has questioned this belief, with new evidence of harmful associations in moderate drinkers compared with abstainers. This has raised suspicion that reported protective effects of moderate drinking were due to confounding by socioeconomic class and intelligence. Clinicians should look out for cognitive impairment in heavy drinkers, considering that abstinence may induce a degree of clinical improvement. Discussions with patients regarding moderate drinking should be informed by recent research. Health benefits of moderate drinking at least for cognitive function are questionable, and if they exist are probably limited to one unit of alcohol daily with respect to other body systems. PMID- 29273600 TI - Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice. AB - RATIONALE: Aortic valve disease is a cell-mediated process without effective pharmacotherapy. CNP (C-type natriuretic peptide) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo. OBJECTIVE: The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease. METHODS AND RESULTS: In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein-coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used Npr2+/- and Npr2+/-;Ldlr-/- mice and wild-type littermate controls to examine the valvular effects of deficient CNP/NPR2 signaling in vivo, in the context of both moderate and advanced aortic valve disease. Myofibrogenesis in cultured Npr2+/- fibroblasts was insensitive to CNP treatment, whereas aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with bicuspid aortic valves than those with tricuspid valves. CONCLUSIONS: Our data establish CNP/NPR2 signaling as a novel regulator of aortic valve development and disease and elucidate the therapeutic potential of targeting this pathway to arrest disease progression. PMID- 29273601 TI - Infographic: Genetic testing and research. PMID- 29273602 TI - Monitoring Mycobacterium bovis in Eurasian badgers (Meles meles) killed by vehicles in Northern Ireland between 1998 and 2011. PMID- 29273604 TI - Regulators seek input on reasons for high drug costs. PMID- 29273605 TI - User fee act, pending legislation focus on drug costs. PMID- 29273603 TI - Tenuous Inhibitory GABAergic Signaling in the Reticular Thalamus. AB - Maintenance of a low intracellular Cl- concentration ([Cl-]i) is critical for enabling inhibitory neuronal responses to GABAA receptor-mediated signaling. Cl- transporters, including KCC2, and extracellular impermeant anions ([A]o) of the extracellular matrix are both proposed to be important regulators of [Cl-]i Neurons of the reticular thalamic (RT) nucleus express reduced levels of KCC2, indicating that GABAergic signaling may produce excitation in RT neurons. However, by performing perforated patch recordings and calcium imaging experiments in rats (male and female), we find that [Cl-]i remains relatively low in RT neurons. Although we identify a small contribution of [A]o to a low [Cl-]i in RT neurons, our results also demonstrate that reduced levels of KCC2 remain sufficient to maintain low levels of Cl- Reduced KCC2 levels, however, restrict the capacity of RT neurons to rapidly extrude Cl- following periods of elevated GABAergic signaling. In a computational model of a local RT network featuring slow Cl- extrusion kinetics, similar to those we found experimentally, model RT neurons are predisposed to an activity-dependent switch from GABA-mediated inhibition to excitation. By decreasing the activity threshold required to produce excitatory GABAergic signaling, weaker stimuli are able to propagate activity within the model RT nucleus. Our results indicate the importance of even diminished levels of KCC2 in maintaining inhibitory signaling within the RT nucleus and suggest how this important activity choke point may be easily overcome in disorders such as epilepsy.SIGNIFICANCE STATEMENT Precise regulation of intracellular Cl- levels ([Cl-]i) preserves appropriate, often inhibitory, GABAergic signaling within the brain. However, there is disagreement over the relative contribution of various mechanisms that maintain low [Cl-]i We found that the Cl- transporter KCC2 is an important Cl- extruder in the reticular thalamic (RT) nucleus, despite this nucleus having remarkably low KCC2 immunoreactivity relative to other regions of the adult brain. We also identified a smaller contribution of fixed, impermeant anions ([A]o) to lowering [Cl-]i in RT neurons. Inhibitory signaling among RT neurons is important for preventing excessive activation of RT neurons, which can be responsible for generating seizures. Our work suggests that KCC2 critically restricts the spread of activity within the RT nucleus. PMID- 29273606 TI - Pharmacists, technicians will soon need LGBTQ education to practice in D.C. PMID- 29273607 TI - Benzodiazepine use and cognitive decline in the elderly. AB - PURPOSE: Published evidence on the relationship between benzodiazepine exposure and altered cognition in the geriatric population is reviewed. SUMMARY: Benzodiazepines constitute one of the most commonly prescribed medication classes and are used primarily for management of anxiety and insomnia. Despite strong recommendations based on high-quality evidence warning of the potential cognitive adverse effects of benzodiazepine use, particularly in patients 65 years of age or older, published literature suggests that a substantial proportion of the U.S. geriatric population use these medications in a chronic fashion. The body of evidence suggesting that benzodiazepine use may be a modifiable risk factor for dementia continues to grow. Evidence exists to suggest that benzodiazepine use in the elderly population is associated with cognitive decline, dementia, and Alzheimer's disease, although evidence regarding the correlation between benzodiazepine use and dementia is conflicting; the more recent studies in this area have focused on eliminating causation bias. Pharmacists in a variety of settings can educate patients and assist providers in selecting an appropriate medication regimen for anxiety or insomnia that is tailored to each elderly patient's needs and takes into account the immediate and long-term safety of the patient. CONCLUSION: Investigations of the association between benzodiazepine therapy and cognitive decline in elderly patients have yielded mixed findings. Stronger links have emerged from studies examining longer- rather than shorter acting benzodiazepines, longer rather than shorter durations of use, or earlier rather than later exposure. Questions remain about causality and the impact of confounders on study interpretation. PMID- 29273608 TI - Topiramate in the treatment of cocaine use disorder. AB - PURPOSE: The literature on topiramate use in cocaine-dependent patients was reviewed. SUMMARY: Six randomized, double-blind, controlled clinical trials evaluating the use of topiramate in patients who were cocaine dependent were analyzed. The results from the studies indicated that topiramate, when used in combination with cognitive behavioral therapy, may be effective in reducing short term cocaine use and should be considered as a possible treatment option. Other trials suggested that topiramate was not effective in patients with a dual diagnosis of opioid and cocaine dependence. Two trials suggested that short-term abstinence assisted by pharmacotherapy is a predictor of longer-term (6 months and 1 year, respectively) abstinence. Cocaine use is dependent on multiple factors; therefore, a reduction in use or craving is not definitively associated with abstinence. However, decreased use reduces potential patient harm and the amount of money spent on illicit cocaine. The findings of this literature review should be used to encourage the completion of more trials that are appropriately designed. Topiramate was shown to be effective for increasing cocaine abstinence, the proportion of cocaine nonuse days, and the proportion of patients to attain 3 consecutive weeks of cocaine abstinence and decreasing the abuse liability of cocaine. Conflicting results in clinical trials do not provide a definitive answer regarding topiramate's efficacy in managing cocaine dependence. CONCLUSION: Available research neither validates nor invalidates the hypothesis that topiramate is efficacious in attaining abstinence in cocaine-dependent patients. PMID- 29273609 TI - Bone marrow edema associated with everolimus. AB - PURPOSE: The case of a patient who experienced bone marrow edema and pain in both feet and a compression fracture of one heel bone after several months of everolimus use is reported. SUMMARY: A 62-year-old woman with a grade 1 metastatic pancreatic neuroendocrine tumor (pNET) developed bilateral lower extremity edema and pain approximately 4 months after initiation of treatment with everolimus, an inhibitor of mammalian (or mechanistic) target of rapamycin (mTOR). The patient was referred for orthopedic evaluation, which resulted in diagnosis of bone marrow edema and a compression fracture of the calcaneus on the basis of magnetic resonance imaging results. The case was discussed with a clinical pharmacist, and after an in-depth analysis to rule out potential alternative causes for the patient's edema and pain, everolimus was discontinued. The patient had a full recovery from the presenting symptoms within 10 days of discontinuation of everolimus. Analysis of this case using the adverse drug reaction probability scale of Naranjo et al. yielded a score of 6, indicating a probable adverse reaction to everolimus. A hypothesized mechanism for everolimus induced bone pain includes marrow edema and hyperemia from reduced intraosseous perfusion, which have been previously reported in association with mTOR inhibitor use. CONCLUSION: Bone marrow edema developed and a fracture occurred in a patient taking everolimus for a metastatic pNET, with complete resolution of lower extremity swelling and pain within 2 weeks of everolimus discontinuation. PMID- 29273610 TI - Stability of extemporaneously prepared preservative-free prochlorperazine nasal spray. AB - PURPOSE: The stability of an extemporaneously prepared preservative-free prochlorperazine 5-mg/mL nasal spray was evaluated. METHODS: The preservative free prochlorperazine nasal spray was prepared by adding 250 mg of prochlorperazine edisylate to 50 mL of citrate buffer in a low-density polyethylene nasal spray bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated using the major degradant prochlorperazine sulfoxide and by performing forced-degradation studies. For chemical stability studies, 3 100-MUL samples of the preservative free prochlorperazine from 5 nasal spray bottles stored at room temperature were collected at days 0, 20, 30, 45, and 60 and were assayed in triplicate using the stability-indicating HPLC method. Microbiological testing involved antimicrobial effectiveness testing based on United States Pharmacopeia (USP) chapter 51 and quantitative microbiological enumeration of aerobic bacteria, yeasts, and mold based on USP chapter 61. Samples for microbiological testing were collected at days 0, 30, and 60. RESULTS: The stability-indicating HPLC method clearly identified the degradation product prochlorperazine sulfoxide without interference from prochlorperazine. All tested solutions retained over 90% of the initial prochlorperazine concentration for the 60-day study period. There were no detectable changes in color, pH, and viscosity in any sample. There was no growth of bacteria, yeast, and mold for 60 days in all samples tested. CONCLUSION: An extemporaneously prepared preservative-free nasal spray solution of prochlorperazine edisylate 5 mg/mL was physically, chemically, and microbiologically stable for 60 days when stored at room temperature in low density polyethylene bottles. PMID- 29273611 TI - Physical compatibility of fosfomycin for injection with select i.v. drugs during simulated Y-site administration. AB - PURPOSE: The results of a study to determine the physical compatibility of ZTI-01 (fosfomycin for injection) in 0.9% sodium chloride or 5% dextrose during simulated Y-site administration with 37 i.v. antimicrobials and 58 nonantimicrobials are reported. METHODS: Fosfomycin, an epoxide antibiotic with broad-spectrum activity against multidrug-resistant bacteria, is marketed in the United States only in an oral formulation with limited bioavailability, but an i.v. formulation is in development. Fosfomycin for injection and other evaluated drugs were reconstituted according to manufacturer recommendations and further diluted with 0.9% sodium chloride or 5% dextrose to the final desired concentrations. Y-site administration was simulated in glass culture tubes. Incompatibility was defined as changes in visual characteristics or a change in turbidity of >0.5 nephelometric turbidity units over the 120-minute observation period. RESULTS: Of the 95 drugs tested, 16 were incompatible with fosfomycin in 0.9% sodium chloride, and 18 were incompatible with fosfomycin in 5% dextrose; incompatibility was observed with 10 of 37 antimicrobials, including the 3 commercially available amphotericin B products, anidulafungin, caspofungin, ceftaroline, ciprofloxacin, daptomycin, doxycycline, and isavuconazonium sulfate. CONCLUSION: Fosfomycin for injection at a concentration of 30 mg/mL was physically compatible with 73 of 95 (77%) of the i.v. drugs tested at concentrations used clinically in both 0.9% sodium chloride injection and 5% dextrose injection. Twenty-two drugs were deemed incompatible in at least 1 of the 2 diluents. PMID- 29273612 TI - Interprofessional care collaboration for patients with heart failure. AB - PURPOSE: An innovative collaborative care model to improve transitions of care (TOC) for patients with heart failure (HF) is described. SUMMARY: As part of a broad effort by New Hanover Regional Medical Center (NHRMC) to reduce avoidable 30-day hospital readmissions and decrease associated healthcare costs through a team-centered, value-based approach to patient care, an interprofessional team was formed to help reduce hospital readmissions among discharged patients with HF. The team consists of 5 TOC pharmacists, 4 community paramedics, and 4 advanced care practitioners (ACPs) who collaborate to coordinate care and prevent 30-day readmissions among patients with HF transitioning from the hospital to the community setting. Each team member plays an integral role in providing high quality postdischarge care. The TOC pharmacist ensures that patients have access to all needed medications, provides in-home medication reconciliation services, makes medication recommendations, and alerts the team of potential medication related issues. Community paramedics conduct home visits consisting of physical and mental health assessments, diet and disease state education, reviews of medication bottles and education on proper medication use, and administration of i.v. diuretics to correct volume status under provider orders. The ACPs offer close clinic follow-up (typically initiated within 7 days of discharge) as well as long-term HF management and education. CONCLUSION: At NHRMC, collaboration among healthcare professionals, including a TOC pharmacist, community paramedics, and ACPs, has assisted in the growth and expansion of services provided to patients with HF. PMID- 29273613 TI - Implementation of a prioritized scoring tool to improve time to pharmacist intervention. AB - PURPOSE: The implementation of a prioritized scoring tool to improve time to pharmacist intervention is described. SUMMARY: At the Ohio State University Wexner Medical Center, pharmacists are accepted providers of therapeutic drug monitoring of vancomycin and aminoglycosides. At the onset of this initiative and despite the implementation of an integrated electronic medical record (EMR), management of pharmacokinetically monitored medications was conducted using a paper monitoring form. The potential for transcription errors during this process provided an opportunity for improvement. For these reasons, the department of pharmacy focused its initial efforts for a patient scoring system on the pharmacokinetics scoring module. Adjustment of associated medications based on pharmacokinetic values was a core function of pharmacists of the institution and was expected to be conducted without fail. Vancomycin was used as the index surrogate pharmacokinetically monitored medication within the module for testing and validation because of the clear expectations and standardized resources available to pharmacists to complete the task. The pharmacokinetics scoring module was designed specifically for the function of dosing management, searching throughout the EMR and concisely displaying the information a pharmacist needs to make a clinical decision. Importantly, integration of the scoring module reduced the time to intervention from hours to minutes. The median time to intervention was reduced to within a clinical working shift (8 hours) with the scoring module versus 24 hours or longer with the paper monitoring system. CONCLUSION: The implementation of an internally developed pharmacokinetics scoring module built into the EMR substantially reduced the time to clinical intervention for pharmacokinetic monitoring of vancomycin drug levels. PMID- 29273614 TI - Pharmacy in Israel. PMID- 29273615 TI - Longitudinally extensive transverse myelitis after Campylobacter jejuni enteritis. AB - Campylobacter jejuni infection is well-known to precipitate Guillain-Barre syndrome through an immune-mediated attack on the peripheral nervous system. Molecular mimicry between C. jejuni lipo-oligosaccharides on the surface of infectious agents and human gangliosides in the peripheral nerves induces cross reactive immune responses. Although gangliosides also occur in the central nervous system (CNS), autoimmune CNS disorders rarely follow Cjejuni infections. However, longitudinally extensive transverse myelitis commonly has a parainfectious cause, triggered by a wide range of micro-organisms including viruses and bacteria. We report a patient who developed longitudinally extensive transverse myelitis after Cjejuni enteritis associated with antiganglioside antibodies. PMID- 29273616 TI - Epilepsy and psychosis: a practical approach. AB - The psychoses of epilepsy can be classified according to their temporal relationship with seizures, namely as ictal, postictal and interictal psychosis. Interictal psychosis is the most common and may resemble schizophrenia. They can be challenging to diagnose and to manage, especially given the perception that some antipsychotic drugs may exacerbate seizures, while some antiepileptic medications may worsen psychosis. The current uncertainty around their best management means that some patients may not receive appropriate care. We propose a practical stepwise approach to managing psychosis in patients with epilepsy, summarising the key clinical features. We provide a framework for diagnosis, investigation and management of psychosis in the acute and long term. We also summarise the available evidence on the risk of psychosis with current antiepileptic drugs and the risk of seizures with antipsychotic drugs. PMID- 29273617 TI - FDA Approves Trastuzumab Biosimilar. AB - On December 1, the FDA approved a second cancer biosimilar, trastuzumab-dkst. The drug was approved to treat patients with HER2-positive breast and metastatic stomach cancers. PMID- 29273618 TI - At the ends of their tethers! How coiled-coil proteins capture vesicles at the Golgi. AB - Cells face a complex problem: how to transfer lipids and proteins between membrane compartments in an organized, timely fashion. Indeed, many thousands of membrane and secretory proteins must traffic out of the ER to different organelles to function, while others are retrieved from the plasma membrane having fulfilled their roles [Nat. Rev. Mol. Cell Biol. (2013) 14, 382-392]. This process is highly dynamic and failure to target cargo accurately leads to catastrophic consequences for the cell, as is clear from the numerous human diseases associated with defects in membrane trafficking [Int. J. Mol. Sci. (2013) 14, 18670-18681; Traffic (2000) 1, 836-851]. How then does the cell organize this enormous transfer of material in its crowded internal environment? And how specifically do vesicles carrying proteins and lipids recognize and fuse with the correct compartment? PMID- 29273619 TI - Approaches to single-molecule studies of metalloprotein electron transfer using scanning probe-based techniques. AB - The single-molecule properties of metalloproteins have provided an intensely active research area in recent years. This brief review covers some of the techniques used to prepare, measure and analyse the electron transfer properties of metalloproteins, concentrating on scanning tunnelling microscopy-based techniques and advances in attachment of proteins to electrodes. PMID- 29273620 TI - Gene expression regulation by heat-shock proteins: the cardinal roles of HSF1 and Hsp90. AB - The ability to permit gene expression is managed by a set of relatively well known regulatory mechanisms. Nonetheless, this property can also be acquired during a life span as a consequence of environmental stimuli. Interestingly, some acquired information can be passed to the next generation of individuals without modifying gene information, but instead by the manner in which cells read and process such information. Molecular chaperones are classically related to the proper preservation of protein folding and anti-aggregation properties, but one of them, heat-shock protein 90 (Hsp90), is a refined sensor of protein function facilitating the biological activity of properly folded client proteins that already have a preserved tertiary structure. Interestingly, Hsp90 can also function as a critical switch able to regulate biological responses due to its association with key client proteins such as histone deacetylases or DNA methylases. Thus, a growing amount of evidence has connected the action of Hsp90 to post-translational modifications of soluble nuclear factors, DNA, and histones, which epigenetically affect gene expression upon the onset of an unfriendly environment. This response is commanded by the activation of the transcription factor heat-shock factor 1 (HSF1). Even though numerous stresses of diverse nature are known to trigger the stress response by activation of HSF1, it is still unknown whether there are different types of molecular sensors for each type of stimulus. In the present review, we will discuss various aspects of the regulatory action of HSF1 and Hsp90 on transcriptional regulation, and how this regulation may affect genetic assimilation mechanisms and the health of individuals. PMID- 29273622 TI - State Medicaid Payment Levels and the Federal "Equal Access" Statute. PMID- 29273623 TI - Increased Medicaid Payment and Participation by Office-Based Primary Care Pediatricians. AB - BACKGROUND AND OBJECTIVES: Whether the Medicaid primary care payment increase of 2013 to 2014 changed physician participation remains unanswered amid conflicting evidence. In this study, we assess national and state-level changes in Medicaid participation by office-based primary care pediatricians before and after the payment increase. METHODS: Using bivariate statistical analysis, we compared survey data collected from 2011 to 2012 and 2015 to 2016 by the American Academy of Pediatrics from state-stratified random samples of pediatrician members. RESULTS: By 4 of 5 indicators, Medicaid participation increased nationally from 2011 and 2012 to 2015 and 2016 (n = 10 395). Those accepting at least some new patients insured by Medicaid increased 3.0 percentage points (ppts) to 77.4%. Those accepting all new patients insured by Medicaid increased 5.9 ppts to 43.3%, and those accepting these patients at least as often as new privately insured patients increased 5.7 ppts to 55.6%. The average percent of patients insured by Medicaid per provider panel increased 6.0 ppts to 31.3%. Nonparticipants dropped 2.1 ppts to 14.6%. Of the 27 studied states, 16 gained in participation by 1 or more indicators, 11 gained by 2 or more, and 3 gained by all 5. CONCLUSIONS: Office-based primary care pediatricians increased their Medicaid participation after the payment increase, in large part by expanding their Medicaid panel percentage. Continued monitoring of physician participation in Medicaid at the national and state levels is vital for guiding policy to optimize timely access to appropriate health care for >37 million children insured by Medicaid. PMID- 29273621 TI - RecQ and Fe-S helicases have unique roles in DNA metabolism dictated by their unwinding directionality, substrate specificity, and protein interactions. AB - Helicases are molecular motors that play central roles in nucleic acid metabolism. Mutations in genes encoding DNA helicases of the RecQ and iron-sulfur (Fe-S) helicase families are linked to hereditary disorders characterized by chromosomal instabilities, highlighting the importance of these enzymes. Moreover, mono-allelic RecQ and Fe-S helicase mutations are associated with a broad spectrum of cancers. This review will discuss and contrast the specialized molecular functions and biological roles of RecQ and Fe-S helicases in DNA repair, the replication stress response, and the regulation of gene expression, laying a foundation for continued research in these important areas of study. PMID- 29273624 TI - Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis. AB - Noncoding transcription is a defining feature of active enhancers, linking transcription factor (TF) binding to the molecular mechanisms controlling gene expression. To determine the relationship between enhancer activity and biological outcomes in breast cancers, we profiled the transcriptomes (using GRO seq and RNA-seq) and epigenomes (using ChIP-seq) of 11 different human breast cancer cell lines representing five major molecular subtypes of breast cancer, as well as two immortalized ("normal") human breast cell lines. In addition, we developed a robust and unbiased computational pipeline that simultaneously identifies putative subtype-specific enhancers and their cognate TFs by integrating the magnitude of enhancer transcription, TF mRNA expression levels, TF motif P-values, and enrichment of H3K4me1 and H3K27ac. When applied across the 13 different cell lines noted above, the Total Functional Score of Enhancer Elements (TFSEE) identified key breast cancer subtype-specific TFs that act at transcribed enhancers to dictate gene expression patterns determining growth outcomes, including Forkhead TFs, FOSL1, and PLAG1. FOSL1, a Fos family TF, (1) is highly enriched at the enhancers of triple negative breast cancer (TNBC) cells, (2) acts as a key regulator of the proliferation and viability of TNBC cells, but not Luminal A cells, and (3) is associated with a poor prognosis in TNBC breast cancer patients. Taken together, our results validate our enhancer identification pipeline and reveal that enhancers transcribed in breast cancer cells direct critical gene regulatory networks that promote pathogenesis. PMID- 29273625 TI - The nuclear matrix protein HNRNPU maintains 3D genome architecture globally in mouse hepatocytes. AB - Eukaryotic chromosomes are folded into higher-order conformations to coordinate genome functions. In addition to long-range chromatin loops, recent chromosome conformation capture (3C)-based studies have indicated higher levels of chromatin structures including compartments and topologically associating domains (TADs), which may serve as units of genome organization and functions. However, the molecular machinery underlying these hierarchically three-dimensional (3D) chromatin architectures remains poorly understood. Via high-throughput assays, including in situ Hi-C, DamID, ChIP-seq, and RNA-seq, we investigated roles of the Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU), a nuclear matrix (NM) associated protein, in 3D genome organization. Upon the depletion of HNRNPU in mouse hepatocytes, the coverage of lamina-associated domains (LADs) in the genome increases from 53.1% to 68.6%, and a global condensation of chromatin was observed. Furthermore, disruption of HNRNPU leads to compartment switching on 7.5% of the genome, decreases TAD boundary strengths at borders between A (active) and B (inactive) compartments, and reduces chromatin loop intensities. Long-range chromatin interactions between and within compartments or TADs are also significantly remodeled upon HNRNPU depletion. Intriguingly, HNRNPU mainly associates with active chromatin, and 80% of HNRNPU peaks coincide with the binding of CTCF or RAD21. Collectively, we demonstrated that HNRNPU functions as a major factor maintaining 3D chromatin architecture, suggesting important roles of NM-associated proteins in genome organization. PMID- 29273626 TI - MinION-based long-read sequencing and assembly extends the Caenorhabditis elegans reference genome. AB - Advances in long-read single molecule sequencing have opened new possibilities for 'benchtop' whole-genome sequencing. The Oxford Nanopore Technologies MinION is a portable device that uses nanopore technology that can directly sequence DNA molecules. MinION single molecule long sequence reads are well suited for de novo assembly of complex genomes as they facilitate the construction of highly contiguous physical genome maps obviating the need for labor-intensive physical genome mapping. Long sequence reads can also be used to delineate complex chromosomal rearrangements, such as those that occur in tumor cells, that can confound analysis using short reads. Here, we assessed MinION long-read-derived sequences for feasibility concerning: (1) the de novo assembly of a large complex genome, and (2) the elucidation of complex rearrangements. The genomes of two Caenorhabditis elegans strains, a wild-type strain and a strain containing two complex rearrangements, were sequenced with MinION. Up to 42-fold coverage was obtained from a single flow cell, and the best pooled data assembly produced a highly contiguous wild-type C. elegans genome containing 48 contigs (N50 contig length = 3.99 Mb) covering >99% of the 100,286,401-base reference genome. Further, the MinION-derived genome assembly expanded the C. elegans reference genome by >2 Mb due to a more accurate determination of repetitive sequence elements and assembled the complete genomes of two co-extracted bacteria. MinION long-read sequence data also facilitated the elucidation of complex rearrangements in a mutagenized strain. The sequence accuracy of the MinION long read contigs (~98%) was improved using Illumina-derived sequence data to polish the final genome assembly to 99.8% nucleotide accuracy when compared to the reference assembly. PMID- 29273627 TI - Precise and efficient nucleotide substitution near genomic nick via noncanonical homology-directed repair. AB - CRISPR/Cas9, which generates DNA double-strand breaks (DSBs) at target loci, is a powerful tool for editing genomes when codelivered with a donor DNA template. However, DSBs, which are the most deleterious type of DNA damage, often result in unintended nucleotide insertions/deletions (indels) via mutagenic nonhomologous end joining. We developed a strategy for precise gene editing that does not generate DSBs. We show that a combination of single nicks in the target gene and donor plasmid (SNGD) using Cas9D10A nickase promotes efficient nucleotide substitution by gene editing. Nicking the target gene alone did not facilitate efficient gene editing. However, an additional nick in the donor plasmid backbone markedly improved the gene-editing efficiency. SNGD-mediated gene editing led to a markedly lower indel frequency than that by the DSB-mediated approach. We also show that SNGD promotes gene editing at endogenous loci in human cells. Mechanistically, SNGD-mediated gene editing requires long-sequence homology between the target gene and repair template, but does not require CtIP, RAD51, or RAD52. Thus, it is considered that noncanonical homology-directed repair regulates the SNGD-mediated gene editing. In summary, SNGD promotes precise and efficient gene editing and may be a promising strategy for the development of a novel gene therapy approach. PMID- 29273628 TI - Marijuana use and fecundability in a North American preconception cohort study. AB - BACKGROUND: The influence of marijuana use on human fertility has not been well studied. We evaluated the association between female and male use of marijuana and fecundability in Pregnancy Study Online, a prospective cohort of North American couples. METHODS: Female participants completed a baseline questionnaire on which they reported lifestyle and behavioural factors, including frequency of marijuana use within the previous 2 months. Male partners completed an optional baseline questionnaire on similar factors, including marijuana use. Women completed follow-up questionnaires every 8 weeks for 12 months or until pregnancy, initiation of fertility treatment or loss to follow-up, whichever came first. The analysis was restricted to 4194 women (1125 couples) with <=6 cycles of pregnancy attempt time at study enrolment (2013-2017). Fecundability ratios (FR) and 95% CIs were estimated using proportional probabilities regression models, with adjustment for potential confounders. RESULTS: Men (14.2%) were more likely than women (11.6%) to be marijuana users. FRs for female marijuana use <1 and >=1 time/week relative to non-use were 0.99 (95% CI 0.85 to 1.16) and 0.98 (95% CI 0.80 to 1.20), respectively. FRs for male marijuana use <1 and >=1 time/week relative to non-use were 0.87 (95% CI 0.66 to 1.15) and 1.24 (95% CI 0.90 to 1.70), respectively. Associations for frequent marijuana use (>=1 time/week) were attenuated among non-smoking men (FR=1.21, 95% CI 0.84 to 1.74), but stronger among men reporting intercourse >=4 times/week (FR=1.35, 95% CI 0.72 to 2.53). CONCLUSIONS: In this preconception cohort study, there was little overall association between female or male marijuana use and fecundability. PMID- 29273629 TI - Do flexible work policies improve parents' health? A natural experiment based on the UK Millennium Cohort Study. AB - BACKGROUND: There is limited evidence of the impact of policies to promote work family balance on family health. Exploiting the introduction of the UK Flexible Working Act (2003), we examined whether a policy that grants parents the right to request flexible work influences their health and well-being. METHODS: Using the UK Millennium Cohort Study, we focus on 6424 mothers employed in 2001-2002, when the cohort child was 9 months old, until their child's seventh birthday. We used a difference-in-differences (DiD) approach to compare changes in outcomes before and after the policy among mothers most likely to benefit and mothers unlikely to benefit from the policy. RESULTS: Flexible working increased in a small group of mothers (n=548) whose employer did not offer work flexibility before the reform (treatment group). By contrast, among mothers whose employer already offered flexible work before the reform (control group, n=5810), there was little change or a slight decline in flexible working. DiD estimates suggest that the policy was associated with an increase in flexible working (37.5 percentage points, 95% CI 32.9 to 41.6), but it had no impact on self-rated health (-1.6 percentage points, 95% CI -4.4 to 1.1), long-term illness (-1.87 percentage points, 95% CI 4.3 to 0.5) or life satisfaction scores (beta=0.04, 95% CI -0.08 to 0.16). CONCLUSION: The Flexible Working Act increased flexible working only among a small group of mothers who had not yet the right to request work flexibility, but it had no impact on their health and well-being. Policies promoting work flexibility may require stronger incentives for both parents and employers. PMID- 29273631 TI - NHS consults public on plans to restrict access to over-the-counter drugs. PMID- 29273630 TI - Associations between neighbourhood characteristics and depression: a twin study. AB - BACKGROUND: Depression is an important contributor to the global burden of disease. Besides several known individual-level factors that contribute to depression, there is a growing recognition that neighbourhood environment can also profoundly affect mental health. This study assessed associations between three neighbourhood constructs-socioeconomic deprivation, residential instability and income inequality-and depression among adult twin pairs. The twin design is used to examine the association between neighbourhood constructs and depression, controlling for selection factors (ie, genetic and shared environmental factors) that have confounded purported associations. METHODS: We used multilevel random intercept Poisson regression among 3738 same-sex twin pairs from a community based twin registry to examine the association between neighbourhood constructs and depression. The within-pair association controls for confounding by genetic and environmental factors shared between twins within a pair, and is the main parameter of interest. Models were adjusted for individual-level income, education and marital status, and further by neighbourhood-level population density. RESULTS: When twins were analysed as individuals (phenotypic model), all neighbourhood constructs were significantly associated with depression. However, only neighbourhood socioeconomic deprivation showed a significant within-pair association with depression. A 10-unit within-pair difference in neighbourhood socioeconomic deprivation was associated with 6% greater depressive symptoms (1.06, 95% CI 1.01 to 1.11); the association did not substantially change in adjusted models. CONCLUSION: This study provides new evidence linking neighbourhood socioeconomic deprivation with greater depression. Future studies should employ longitudinal designs to better test social causation versus social selection. PMID- 29273633 TI - OTX1 regulates cell cycle progression of neural progenitors in the developing cerebral cortex. AB - The progenitor cells in the cerebral cortex coordinate proliferation and mitotic exit to generate the correct number of neurons and glial cells during development. However, mechanisms for regulating the mitotic cycle of cortical progenitors are not fully understood. Otx1 is one of the homeobox-containing transcription factors frequently implicated in the development of the central nervous system. Mice bearing a targeted deletion of Otx1 exhibit brain hypoplasia and a decrease in the number of cortical neurons. We hypothesized that Otx1 might be crucial to the proliferation and differentiation of cortical progenitors. Otx1 knockdown by in utero electroporation in the mouse brain reduced the proportion of the G1 phase while increasing the S and M phases of progenitor cells. The knockdown diminished Tbr1+ neurons but increased GFAP+ astrocytes in the early postnatal cortex as revealed by lineage tracing study. Tbr2+ basal progenitors lacking Otx1 were held at the transit-amplifying stage. In contrast, overexpression of wildtype Otx1 but not an astrocytoma-related mutant Y320C inhibited proliferation of the progenitor cells in embryonic cortex. This study demonstrates that Otx1 is one of the key elements regulating cortical neurogenesis, and a loss-of-function in Otx1 may contribute to the overproduction of astrocytes in vivo. PMID- 29273632 TI - Oncogenic Ras Isoforms Signaling Specificity at the Membrane. AB - How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kalpha/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher KRAS mRNA levels. As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Kalpha/Akt signaling. We propose that full activation of both MAPK and PI3Kalpha/Akt proliferative pathways by oncogenic KRas4B-but not by HRas or NRas-may help explain why the KRas4B isoform is especially highly populated in certain cancers. We further discuss pharmacologic implications. Cancer Res; 78(3); 593-602. (c)2017 AACR. PMID- 29273635 TI - Prevalence, Characteristics, and Outcomes of Valvular Heart Disease in Patients With Atrial Fibrillation: Insights From the ORBIT-AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation). AB - BACKGROUND: The presence of valvular heart disease (VHD) may affect the risk of stroke and mortality in patients with atrial fibrillation (AF). Community-based estimates of prevalence and outcomes of specific forms of VHD in patients with AF are lacking. METHODS AND RESULTS: We examined the prevalence of VHD, anticoagulation use, mortality, stroke/transient ischemic attack, and bleeding among a community cohort of patients with AF. Significant VHD was defined as follows: (1) moderate/severe mitral stenosis or mechanical valve; (2) bioprosthetic valve, surgical repair, or balloon valvuloplasty; and (3) moderate/severe aortic regurgitation or stenosis, mitral regurgitation, or tricuspid regurgitation. Proportional hazards models were performed to test the association between VHD groups and outcomes. Among 9748 patients with AF, 2705 (27.7%) had significant VHD. Anticoagulation use was highest among patients with mitral stenosis/mechanical valve (91.8%). Compared with individuals with no significant VHD, individuals with aortic regurgitation/aortic stenosis, mitral regurgitation, or tricuspid regurgitation (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42) had the highest risk of death. There were no differences in stroke or transient ischemic attack and major bleeding among individuals with and without significant VHD. Patients with AF and aortic stenosis had the highest risk of death (hazard ratio, 1.32; 95% confidence interval, 1.08-1.62). CONCLUSIONS: Significant VHD is common among patients with AF in community practice. In a community cohort of patients with AF and CHA2DS2-VASc score >=2, most were anticoagulated. Individuals with AF and moderate-to-severe biological VHD have more comorbidities and a higher mortality risk; however, stroke and major bleeding are similar among those with and without significant VHD. PMID- 29273634 TI - Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice. AB - Deubiquitinases are proteases with a wide functional diversity that profoundly impact multiple biological processes. Among them, the ubiquitin-specific protease 36 (USP36) has been implicated in the regulation of nucleolar activity. However, its functional relevance in vivo has not yet been fully described. Here, we report the generation of an Usp36-deficient mouse model to examine the function of this enzyme. We show that Usp36 depletion is lethal in preimplantation mouse embryos, where it blocks the transition from morula to blastocyst during embryonic development. USP36 reduces the ubiquitination levels and increases the stability of the DEAH-box RNA helicase DHX33, which is critically involved in ribosomal RNA synthesis and mRNA translation. In agreement with this finding, O propargyl-puromycin incorporation experiments, Northern blot, and electron microscopy analyses demonstrated the role of USP36 in ribosomal RNA and protein synthesis. Finally, we show that USP36 down-regulation alters cell proliferation in human cancer cells by inducing both apoptosis and cell cycle arrest, and that reducing DHX33 levels through short hairpin RNA interference has the same effect. Collectively, these results support that Usp36 is essential for cell and organism viability because of its role in ribosomal RNA processing and protein synthesis, which is mediated, at least in part, by regulating DHX33 stability. PMID- 29273636 TI - Acute Coronary Syndrome: The Risk to Young Women. AB - BACKGROUND: Although acute coronary syndrome (ACS) mainly occurs in patients >50 years, younger patients can be affected as well. We used an age cutoff of 45 years to investigate clinical characteristics and outcomes of "young" patients with ACS. METHODS AND RESULTS: Between October 2010 and April 2016, 14 931 patients with ACS were enrolled in the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries) registry. Of these patients, 1182 (8%) were aged <=45 years (mean age, 40.3 years; 15.8% were women). The primary end point was 30-day all-cause mortality. Percentage diameter stenosis of <=50% was defined as insignificant coronary disease. ST-segment-elevation myocardial infarction was the most common clinical manifestation of ACS in the young cases (68% versus 59.6%). Young patients had a higher incidence of insignificant coronary artery disease (11.4% versus 10.1%) and lesser extent of significant disease (single vessel, 62.7% versus 46.6%). The incidence of 30-day death was 1.3% versus 6.9% for the young and older patients, respectively. After correction for baseline and clinical differences, age <=45 years was a predictor of survival in men (odds ratio, 0.24; 95% confidence interval, 0.10-0.58), but not in women (odds ratio, 1.35; 95% confidence interval, 0.50-3.62). This pattern of reversed risk among sexes held true after multivariable correction for in-hospital medications and reperfusion therapy. Moreover, younger women had worse outcomes than men of a similar age (odds ratio, 6.03; 95% confidence interval, 2.07 17.53). CONCLUSION: ACS at a young age is characterized by less severe coronary disease and high prevalence of ST-segment-elevation myocardial infarction. Women have higher mortality than men. Young age is an independent predictor of lower 30 day mortality in men, but not in women. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/. Unique identifier: NCT01218776. PMID- 29273637 TI - New-Onset Atrial Fibrillation After Coronary Artery Bypass Graft and Long-Term Risk of Stroke: A Meta-Analysis. AB - BACKGROUND: New-onset atrial fibrillation (NOAF) after coronary artery bypass graft is related to an increased short-term risk of stroke and mortality. We investigated whether the long-term risk of stroke is increased. METHODS AND RESULTS: We performed a systematic review and meta-analysis of studies that included patients who had coronary artery bypass graft and who afterwards developed NOAF during their index admission; these patients did not have previous atrial fibrillation. The primary outcome was risk of stroke at 6 months or more in patients who developed NOAF compared with those who did not. Odds ratios, relative risk, and hazard ratios were considered equivalent; outcomes were pooled on the log-ratio scale using a random-effects model and reported as exponentiated effect-sizes. We included 16 studies, comprising 108 711 participants with a median follow-up period of 2.05 years. Average participant age was 66.8 years, with studies including an average of 74.8% males. There was an increased long term risk of stroke in the presence of NOAF (unadjusted studies effect sizes=1.36, 95% confidence interval, 1.12-1.65, P=0.001, adjusted studies effect sizes=1.25, 95% confidence interval, 1.09-1.42, P=0.001). There was evidence of moderate effect variation because of heterogeneity in studies reporting unadjusted (P=0.021, I2=49.8%) and adjusted data (P=0.081, I2=49.1%), and publication bias in the latter group (Egger's test, P=0.031). Sensitivity analysis on unadjusted data by study quality, design, and surgery did not alter the effect direction. CONCLUSIONS: Presence of NOAF in patients post-coronary artery bypass graft is associated with increased long-term risk of stroke compared with patients without NOAF. Further studies may show whether the increased risk is mediated by atrial fibrillation and whether anticoagulation reduces risk. PMID- 29273638 TI - Contemporary Trends in the Use and Outcomes of Surgical Treatment of Tricuspid Regurgitation. AB - BACKGROUND: Tricuspid regurgitation (TR), if untreated, is associated with an adverse impact on long-term outcomes. In recent years, there has been an increasing enthusiasm about surgical and transcatheter treatment of patients with severe TR. We aim to evaluate the contemporary trends in the use and outcomes of tricuspid valve (TV) surgery for TR using the National Inpatient Sample. METHODS AND RESULTS: Between January 1, 2003 and December 31, 2014, an estimated 45 477 patients underwent TV surgery for TR in the United States, of whom 15% had isolated TV surgery and 85% had TV surgery concomitant with other cardiac surgery. There was a temporal upward trend to treat sicker patients during the study period. Patients who underwent isolated TV repair or replacement had a distinctly different clinical risk profile than those patients who underwent TV surgery simultaneous with other surgery. Isolated TV replacement was associated with high in-hospital mortality (10.9%) and high rates of permanent pacemaker implantation (34.1%) and acute kidney injury requiring dialysis (5.5%). Similarly, isolated TV repair was also associated with high in-hospital mortality (8.1%) and significant rates of permanent pacemaker implantation (10.9%) and new dialysis (4.4%). Isolated TV repair and TV replacement were both associated with protracted hospitalizations and substantial cost. CONCLUSIONS: In contemporary practice, surgical treatment of TR remains underused and is associated with high operative morbidity and mortality, prolonged hospitalizations, and considerable cost. PMID- 29273639 TI - Adverse Effects on beta-Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long-Term Cardiac Function. AB - BACKGROUND: Ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor-mediated signaling of the postischemic heart. The current article examines the effect of IPC or IPoC on the regulation and coupling of beta-adrenergic receptors and their effects on postischemic left ventricular function. METHODS AND RESULTS: The beta-adrenergic signal transduction was analyzed in 3-month-old Wistar rats for each of the intervention strategies (Sham, ischemia/reperfusion, IPC, IPoC) immediately and 7 days after myocardial infarction. Directly after the infarction a cardioprotective potential was demonstrated for both IPC and IPoC: the infarct size was reduced, apoptosis and production of reactive oxygen species were lowered, and the myocardial tissue was preserved. Seven days after myocardial ischemia, only IPC hearts showed significant functional improvement. Along with a deterioration in fractional shortening, IPoC hearts no longer responded adequately to beta-adrenergic stimulation. The stabilization of beta-adrenergic receptor kinase-2 via increased phosphorylation of Mdm2 (an E3-ubiquitin ligase) was responsible for desensitization of beta-adrenergic receptors and identified as a characteristic specific to IPoC hearts. CONCLUSIONS: Immediately after myocardial infarction, rapid and transient activation of beta-adrenergic receptor kinase-2 may be an appropriate means to protect the injured heart from excessive stress. In the long term, however, induction and stabilization of beta-adrenergic receptor kinase-2, with the resultant loss of positive inotropic function, leads to the functional picture of heart failure. PMID- 29273640 TI - Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer. AB - The major facilitator superfamily (MFS) effluxers are prominent mediators of antimicrobial resistance. The biochemical characterization of MFS proteins is hindered by their complex membrane environment that makes in vitro biochemical analysis challenging. Since the physicochemical properties of proteins drive the fitness of an organism, we posed the question of whether we could reverse that relationship and derive meaningful biochemical parameters for a single protein simply from fitness changes it confers under varying strengths of selection. Here, we present a physiological model that uses cellular fitness as a proxy to predict the biochemical properties of the MFS tetracycline efflux pump, TetB, and a family of single amino acid variants. We determined two lumped biochemical parameters roughly describing Km and Vmax for TetB and variants. Including in vivo protein levels into our model allowed for more specified prediction of pump parameters relating to substrate binding affinity and pumping efficiency for TetB and variants. We further demonstrated the general utility of our model by solely using fitness to assay a library of tet(B) variants and estimate their biochemical properties. PMID- 29273641 TI - Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment for Helicobacter pylori: a retrospective cohort analysis. PMID- 29273642 TI - Transcriptional and functional profiling defines human small intestinal macrophage subsets. AB - Macrophages (Mfs) are instrumental in maintaining immune homeostasis in the intestine, yet studies on the origin and heterogeneity of human intestinal Mfs are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMos), were largely replaced within 3 wk, whereas two subsets with features of mature Mfs, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptional analysis showed that all Mf subsets were markedly distinct from PBMos and dendritic cells. Compared with PBMos, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMos. PMID- 29273644 TI - Trump says tax bill "essentially repealed Obamacare". PMID- 29273643 TI - Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion. AB - Respiratory syncytial virus-bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma. PMID- 29273646 TI - Question 1: UK-WHO versus customised growth charts for the identification of at risk small for gestational age infants: which one should we use? PMID- 29273645 TI - Stratification of knee osteoarthritis: two major patient subgroups identified by genome-wide expression analysis of articular cartilage. AB - INTRODUCTION: Osteoarthritis (OA) is a heterogeneous and complex disease. We have used a network biology approach based on genome-wide analysis of gene expression in OA knee cartilage to seek evidence for pathogenic mechanisms that may distinguish different patient subgroups. METHODS: Results from RNA-Sequencing (RNA-Seq) were collected from intact knee cartilage at total knee replacement from 44 patients with OA, from 16 additional patients with OA and 10 control patients with non-OA. Results were analysed to identify patient subsets and compare major active pathways. RESULTS: The RNA-Seq results showed 2692 differentially expressed genes between OA and non-OA. Analysis by unsupervised clustering identified two distinct OA groups: Group A with 24 patients (55%) and Group B with 18 patients (41%). A 10 gene subgroup classifier was validated by RT qPCR in 16 further patients with OA. Pathway analysis showed increased protein expression in both groups. PhenomeExpress analysis revealed group differences in complement activation, innate immune responses and altered Wnt and TGFbeta signalling, but no activation of inflammatory cytokine expression. Both groups showed suppressed circadian regulators and whereas matrix changes in Group A were chondrogenic, in Group B they were non-chondrogenic with changes in mechanoreceptors, calcium signalling, ion channels and in cytoskeletal organisers. The gene expression changes predicted 478 potential biomarkers for detection in synovial fluid to distinguish patients from the two groups. CONCLUSIONS: Two subgroups of knee OA were identified by network analysis of RNA Seq data with evidence for the presence of two major pathogenic pathways. This has potential importance as a new basis for the stratification of patients with OA for drug trials and for the development of new targeted treatments. PMID- 29273647 TI - Assessment of human placenta as an ex-vivo vascular model for testing of liquid embolic agent injections with adjunctive techniques. AB - PURPOSE: This project sought to test the utility of post-delivery human placenta (HP) as a vascular model for liquid embolic agent (LEA) simulation, along with adjunctive techniques. MATERIALS AND METHODS: Twelve LEA injections were performed under fluoroscopy in HP with two reflux control methods: dual lumen 'mini' balloon-catheter (n=9); and injection after proximal nBCA plug formation through a second microcatheter ('pressure cooker') (n=3). Measured outcomes included liquid embolic agent (LEA) advancement and reflux. Reflux was categorized into three grades: grade 0=no reflux; grade 1=occlusion of side branches without reflux beyond the balloon or plug; and grade 2=reflux beyond the balloon or plug. RESULTS: Simulation success was greater when a balloon was used rather than with a nBCA plug (89% vs 33%, P=0.054). In eight successful balloon assisted injections, the reflux grades were: 50% grade 0; 12.5% grade 1; and 37.5% grade 2. The one successful nBCA plug injection had grade 2 reflux. All grade 2 balloon injections occurred when the balloon was positioned across a vessel bifurcation. CONCLUSIONS: HP provides excellent simulation for liquid embolic agents with a dual lumen balloon catheter. PMID- 29273648 TI - Determinants of completion of advance directives: a cross-sectional comparison of 649 outpatients from private practices versus 2158 outpatients from a university clinic. AB - OBJECTIVES: To compare outpatients from private practices and outpatients from a university clinic regarding the determinants of completion of advance directives (AD) in order to generalise results of studies from one setting to the other. Five determinants of completion of AD were studied: familiarity with AD, source of information about AD, prior experiences with own life-threatening diseases or family members in need of care and motives in favour and against completion of AD. DESIGN: Observational cross-sectional study. SETTING: Private practices and a university clinic in Germany in 2012. PARTICIPANTS: 649 outpatients from private practices and 2158 outpatients from 10 departments of a university clinic. OUTCOME MEASURES: Completion of AD, familiarity with AD, sources of information about AD (consultation), prior experiences (with own life-threatening disease and family members in need of care), motives in favour of or against completion of AD, sociodemographic data. RESULTS: Determinants of completion of AD did not differ between outpatients from private practices versus university clinic outpatients. Prior experience with severe disease led to a significantly higher rate of completion of AD (33%/36% with vs 24%/24% without prior experience). Participants with completion of AD had more often received legal than medical consultation before completion, but participants without completion of AD are rather aiming for medical consultation. The motives in favour of or against completion of AD indicated inconsistent patterns. CONCLUSIONS: Determinants of completion of AD are comparable in outpatients from private practices and outpatients from a university clinic. Generalisations from university clinic samples towards a broader context thus seem to be legitimate. Only one-third of patients with prior experience with own life-threatening diseases or family members in need of care had completed an AD as expression of their autonomous volition. The participants' motives for or against completion of AD indicate that ADs are considered a kind of 'negative autonomy' as instruments to prevent particular forms of therapy. Interactive, repeated and situation-based AD discussions might reach a higher percentage of patients and concurrently enable personal volitions and thereby strengthen individual 'positive autonomy'. PMID- 29273649 TI - Epidemiology of cancers in Lahore, Pakistan, among children, adolescents and adults, 2010-2012: a cross-sectional study part 2. AB - OBJECTIVES: To estimate the cancer incidence by age group for the Lahore district population within the Punjab Cancer Registry (PCR), Pakistan. The average annual population of Lahore was 9.8 million in 2010-2012. This is a sequel to a study published earlier. DESIGN: A cross-sectional study. SETTING: The registry has 19 centres in Lahore reporting their data to the coordinating office located within the Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH&RC), Lahore, Pakistan. PARTICIPANTS: Data existing in the PCR database, based on a confirmed diagnosis of cancer from 1 January 2010 to 31 December 2012, among the Lahore residents, were reviewed. OUTCOME MEASURES: Cancer counts and the age standardised incidence rates (ASIR) per 100 000 population were computed by gender, cancer site/type and age group (0-14, 15-19 and >=20 years). RESULTS: Between 2010 and 2012, of the 15 840 new cancers diagnosed, 57% were in females. The ASIRs in age groups 0-14, 15-19 and >=20 years, among females, were: 6.1, 8.4 and 170.7, respectively, and among males, 9.3, 12.2 and 104.5, respectively. The common diagnoses in children, adolescents and adults were: (1) among females: leukaemia: 2.2; bone tumour: 1.4 and breast cancer: 79.2, respectively, and (2) among males: leukaemia: 3.6; bone tumour: 2.4 and prostate cancer: 10.7, respectively. CONCLUSIONS: The ASIR was higher in adult women than in men, but it was lower in girls and young women than their corresponding male counterparts. Leukaemia was the most common diagnosis in children and bone tumour in adolescents, regardless of gender. Among women, breast cancer and, in men, prostate cancer, were the leading cancer types, in adults. These estimates could be used for the expansion of health coverage in the region including setting-up low cost, diagnostic tests for early detection of cancers. PMID- 29273650 TI - Clinical efficacy and effectiveness of 3D printing: a systematic review. AB - OBJECTIVE: To evaluate the clinical efficacy and effectiveness of using 3D printing to develop medical devices across all medical fields. DESIGN: Systematic review compliant with Preferred Reporting Items for Systematic Reviews and Meta Analyses. DATA SOURCES: PubMed, Web of Science, OVID, IEEE Xplore and Google Scholar. METHODS: A double-blinded review method was used to select all abstracts up to January 2017 that reported on clinical trials of a three-dimensional (3D) printed medical device. The studies were ranked according to their level of evidence, divided into medical fields based on the International Classification of Diseases chapter divisions and categorised into whether they were used for preoperative planning, aiding surgery or therapy. The Downs and Black Quality Index critical appraisal tool was used to assess the quality of reporting, external validity, risk of bias, risk of confounding and power of each study. RESULTS: Of the 3084 abstracts screened, 350 studies met the inclusion criteria. Oral and maxillofacial surgery contained 58.3% of studies, and 23.7% covered the musculoskeletal system. Only 21 studies were randomised controlled trials (RCTs), and all fitted within these two fields. The majority of RCTs were 3D-printed anatomical models for preoperative planning and guides for aiding surgery. The main benefits of these devices were decreased surgical operation times and increased surgical accuracy. CONCLUSIONS: All medical fields that assessed 3D printed devices concluded that they were clinically effective. The fields that most rigorously assessed 3D-printed devices were oral and maxillofacial surgery and the musculoskeletal system, both of which concluded that the 3D-printed devices outperformed their conventional comparators. However, the efficacy and effectiveness of 3D-printed devices remain undetermined for the majority of medical fields. 3D-printed devices can play an important role in healthcare, but more rigorous and long-term assessments are needed to determine if 3D-printed devices are clinically relevant before they become part of standard clinical practice. PMID- 29273651 TI - Associations of social environment, socioeconomic position and social mobility with immune response in young adults: the Jerusalem Perinatal Family Follow-Up Study. AB - OBJECTIVES: Immune response to cytomegalovirus (CMV) impacts adult chronic disease. This study investigates associations of childhood and adulthood social environment, socioeconomic position (SEP) and social mobility with CMV response in young adults. DESIGN: Historical prospective study design. SETTING: Subcohort of all 17 003 births to residents of Jerusalem between 1974 and 1976. PARTICIPANTS: Participants included 1319 young adults born in Jerusalem with extensive archival and follow-up data, including childhood and adulthood SEP related factors and anti-CMV IgG titre levels and seroprevalence measured at age 32. MAIN EXPOSURE AND OUTCOME MEASURES: Principal component analysis was used to transform correlated social environment and SEP-related variables at two time points (childhood and adulthood) into two major scores reflecting household (eg, number of siblings/children, religiosity) and socioeconomic (eg, occupation, education) components. Based on these components, social mobility variables were created. Linear and Poisson regression models were used to investigate associations of components and mobility with anti-CMV IgG titre level and seroprevalence, adjusted for confounders. RESULTS: Lower levels of household and socioeconomic components in either childhood or adulthood were associated with higher anti-CMV IgG titre level and seropositivity at age 32. Compared with individuals with stable favourable components, anti-CMV IgG titre level and risk for seropositivity were higher in stable unfavourable household and socioeconomic components (household: beta=3.23, P<0.001; relative risk (RR)=1.21, P<0.001; socioeconomic: beta=2.20, P=0.001; RR=1.14, P=0.01), downward household mobility (beta=4.32, P<0.001; RR=1.26, P<0.001) and upward socioeconomic mobility (beta=1.37, P=0.04; RR=1.19, P<0.001). Among seropositive individuals, associations between household components and mobility with anti-CMV IgG titre level were maintained and associations between socioeconomic components and mobility with anti-CMV IgG titre level were attenuated. CONCLUSIONS: Our study provides evidence that accumulating low SEP from childhood through adulthood and social mobility may compromise immune response in young adulthood. PMID- 29273653 TI - Perfusion index in healthy newborns during critical congenital heart disease screening at 24 hours: retrospective observational study from the USA. AB - OBJECTIVE: To describe the distribution of perfusion index (PI) in asymptomatic newborns at 24 hours of life when screening for critical congenital heart disease (CCHD) using an automated data selection method. DESIGN: This is a retrospective observational study. SETTING: Newborn nursery in a California public hospital with ~3500 deliveries annually. METHODS: We developed an automated programme to select the PI values from CCHD screens. Included were term and late preterm infants who were screened for CCHD from November 2013 to January 2014 and from May 2015 to July 2015. PI measurements were downloaded every 2 s from the pulse oximeter and median PI were calculated for each oxygen saturation screen in our cohort. RESULTS: We included data from 2768 oxygen saturation screens. Each screen had a median of 29 data points (IQR 17 to 49). The median PI in our study cohort was 1.8 (95% CI 1.8 to 1.9) with IQR 1.2 to 2.7. The median preductal PI was significantly higher than the median postductal (1.9 vs 1.8, p=0.03) although this difference may not be clinically significant. CONCLUSION: Using an automated data selection method, the median PI in asymptomatic newborns at 24 hours of life is 1.8 with a narrow IQR of 1.2 to 2.7. This automated data selection method may improve accuracy and precision compared with manual data collection method. Further studies are needed to establish external validity of this automated data selection method and its clinical application for CCHD screening. PMID- 29273652 TI - Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation. AB - OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710). PMID- 29273654 TI - Effects of a school-based stroke education program on stroke-related knowledge and behaviour modification-school class based intervention study for elementary school students and parental guardians in a Japanese rural area. AB - OBJECTIVES: This study aimed to determine the effect of a stroke education programme on elementary school students and their parental guardians in a rural area in Japan that has high stroke mortality. DESIGN: School class based intervention study. SETTING: Eleven public elementary schools in Tochigi Prefecture, Japan. PARTICIPANTS: 268 students aged 11-12 years and 267 parental guardians. INTERVENTIONS: Students received lessons about stroke featuring animated cartoons and were instructed to communicate their knowledge about stroke to their parental guardians using material (comic books) distributed in the lessons. Stroke knowledge (symptoms, risk factors and attitude towards stroke) and behavioural change for risk factors were assessed at baseline, immediately after the programme and at 3 months. We also evaluated behavioural change for risk factors among parental guardians. RESULTS: The percentage of students with all correct answers for stroke symptoms, risk factors and the recommended response to stroke was significantly increased at 3 months P<0.001). We observed a significant increase in the percentage of guardians who chose all correct symptoms (P<0.001: 61.0% vs 85.4%) and risk factors (P<0.001: 41.2% vs 59.9%) at 3 months compared with baseline. The percentage of parental guardians with a high behavioural response to improving risk factors was significantly increased at 3 months compared with baseline (P<0.001). CONCLUSIONS: In a rural population with high stroke mortality, stroke education can improve knowledge about stroke in elementary school students and their parental guardians. ETHICS AND DISSEMINATION: We conducted the intervention as a part of compulsory education; this study was not a clinical trial. This study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (M27-026). PMID- 29273655 TI - Politics, policies and processes: a multidisciplinary and multimethods research programme on policies on the social determinants of health inequity in Australia. AB - INTRODUCTION: The development and implementation of multisectoral policy to improve health and reduce health inequities has been slow and uneven. Evidence is largely focused on the facts of health inequities rather than understanding the political and policy processes. This 5-year funded programme of research investigates how these processes could function more effectively to improve equitable population health. METHODS AND ANALYSIS: The programme of work is organised in four work packages using four themes (macroeconomics and infrastructure, land use and urban environments, health systems and racism) related to the structural drivers shaping the distribution of power, money and resources and daily living conditions. Policy case studies will use publicly available documents (policy documents, published evaluations, media coverage) and interviews with informants (policy-makers, former politicians, civil society, private sector) (~25 per case). NVIVO software will be used to analyse the documents to see how 'social and health equity' is included and conceptualised. The interview data will include qualitative descriptive and theory-driven critical discourse analysis. Our quantitative methodological work assessing the impact of public policy on health equity is experimental that is in its infancy but promises to provide the type of evidence demanded by policy-makers. ETHICS AND DISSEMINATION: Our programme is recognising the inherently political nature of the uptake, formulation and implementation of policy. The early stages of our work indicate its feasibility. Our work is aided by a Critical Policy Reference Group. Multiple ethics approvals have been obtained with the foundation approval from the Social and Behavioural Ethics Committee, Flinders University (Project No: 6786).The theoretical, methodological and policy engagement processes established will provide improved evidence for policy-makers who wish to reduce health inequities and inform a new generation of policy savvy knowledge on social determinants. PMID- 29273656 TI - Pathways to diagnosis of a second primary cancer: protocol for a mixed-methods systematic review. AB - INTRODUCTION: As cancer survivors continue to live longer, the incidence of second primary cancers (SPCs) will also rise. Relatively little is understood about the diagnostic pathway for SPCs, how people appraise, interpret symptoms and seek help for a second different cancer and the experiences (including challenges) of healthcare providers relating to SPCs. This study aims to systematically appraise and synthesise the literature on the pathways to diagnosis of an SPC and the associated patient and healthcare provider experiences. METHODS: The approach taken includes systematic searches of published and unpublished literature without any date or language restrictions. MEDLINE, Embase, CAB Abstracts, MEDLINE In-Process and non-indexed citations, PsycINFO, Epub Ahead of Print, In-Process and other non-indexed citations, Ovid MEDLINE Daily, CINAHL, ASSIA, Sociological Abstracts, Web of Science, PROSPERO and grey literature will be searched to identify observational, systematic reviews, mixed methods and qualitative studies of interest. Titles, abstracts and full texts will be screened against the inclusion-exclusion criteria by at least two reviewers independently. Relevant outcomes of interest and study and population characteristics will be extracted. Synthesis will be used guided by the Pathways to Treatment model and the Olesen model of time intervals. ETHICS AND DISSEMINATION: Ethical approval is not required. This systematic review will provide a deeper understanding of the complex and heterogeneous diagnostic pathways of SPCs, while identifying common themes across the diagnostic interval, routes to diagnosis and patient and healthcare provider experiences. These findings will help provide a nuanced picture of the diagnostic pathway for SPCs that may inform policy and consistent practice. In particular, approaches to early diagnosis for an SPC; including the timing and reasons behind the decision by the patient to seek care,the challenges faced by healthcare providers, and in the development of future interventions to reduce the delay in patient time-to presentation. PROSPERO REGISTRATION NUMBER: CRD42016051692. PMID- 29273657 TI - Optimising technology to measure functional vision, mobility and service outcomes for people with low vision or blindness: protocol for a prospective cohort study in Australia and Malaysia. AB - INTRODUCTION: Orientation and mobility (O&M) specialists assess the functional vision and O&M skills of people with mobility problems, usually relating to low vision or blindness. There are numerous O&M assessment checklists but no measures that reduce qualitative assessment data to a single comparable score suitable for assessing any O&M client, of any age or ability, in any location. Functional measures are needed internationally to align O&M assessment practices, guide referrals, profile O&M clients, plan appropriate services and evaluate outcomes from O&M programmes (eg, long cane training), assistive technology (eg, hazard sensors) and medical interventions (eg, retinal implants). This study aims to validate two new measures of functional performance vision-related outcomes in orientation and mobility (VROOM) and orientation and mobility outcomes (OMO) in the context of ordinary O&M assessments in Australia, with cultural comparisons in Malaysia, also developing phone apps and online training to streamline professional assessment practices. METHODS AND ANALYSIS: This multiphase observational study will employ embedded mixed methods with a qualitative/quantitative priority: corating functional vision and O&M during social inquiry. Australian O&M agencies (n=15) provide the sampling frame. O&M specialists will use quota sampling to generate cross-sectional assessment data (n=400) before investigating selected cohorts in outcome studies. Cultural relevance of the VROOM and OMO tools will be investigated in Malaysia, where the tools will inform the design of assistive devices and evaluate prototypes. Exploratory and confirmatory factor analysis, Rasch modelling, cluster analysis and analysis of variance will be undertaken along with descriptive analysis of measurement data. Qualitative findings will be used to interpret VROOM and OMO scores, filter statistically significant results, warrant their generalisability and identify additional relevant constructs that could also be measured. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Human Research Ethics Committee at Swinburne University (SHR Project 2016/316). Dissemination of results will be via agency reports, journal articles and conference presentations. PMID- 29273658 TI - Qualitative investigation of the perceptions and experiences of nursing and allied health professionals involved in the implementation of an enriched environment in an Australian acute stroke unit. AB - OBJECTIVE: An enriched environment embedded in an acute stroke unit can increase activity levels of patients who had stroke, with changes sustained 6 months post implementation. The objective of this study was to understand perceptions and experiences of nursing and allied health professionals involved in implementing an enriched environment in an acute stroke unit. DESIGN: A descriptive qualitative approach. SETTING: An acute stroke unit in a regional Australian hospital. PARTICIPANTS: We purposively recruited three allied health and seven nursing professionals involved in the delivery of the enriched environment. Face to-face, semistructured interviews were conducted 8 weeks post-completion of the enriched environment study. One independent researcher completed all interviews. Voice-recorded interviews were transcribed verbatim and analysed by three researchers using a thematic approach to identify main themes. RESULTS: Three themes were identified. First, staff perceived that 'the road to recovery had started' for patients. An enriched environment was described to shift the focus to recovery in the acute setting, which was experienced through increased patient activity, greater psychological well-being and empowering patients and families. Second, 'it takes a team' to successfully create an enriched environment. Integral to building the team were positive interdisciplinary team dynamics and education. The impact of the enriched environment on workload was diversely experienced by staff. Third, 'keeping it going' was perceived to be challenging. Staff reflected that changing work routines was difficult. Contextual factors such as a supportive physical environment and variety in individual enrichment opportunities were indicated to enhance implementation. Key to sustaining change was consistency in staff and use of change management strategies. CONCLUSION: Investigating staff perceptions and experiences of an enrichment model in an acute stroke unit highlighted the need for effective teamwork. To facilitate staff in their new work practice, careful selection of change management strategies are critical to support clinical translation of an enriched environment. TRIAL REGISTRATION NUMBER: ANZCTN12614000679684; Results. PMID- 29273659 TI - PTED study: design of a non-inferiority, randomised controlled trial to compare the effectiveness and cost-effectiveness of percutaneous transforaminal endoscopic discectomy (PTED) versus open microdiscectomy for patients with a symptomatic lumbar disc herniation. AB - INTRODUCTION: Lumbosacral radicular syndrome is often caused by a disc herniation. The standard surgical technique to remove a disc herniation is open microdiscectomy. An alternative technique is percutaneous transforaminal endoscopic discectomy (PTED), which is less invasive. In the Netherlands, PTED is not currently considered as standard care, and therefore not reimbursed within public health insurance. A pragmatic, multicentre, non-inferiority, randomised controlled trial has been designed to determine the effectiveness and cost effectiveness of PTED versus open microdiscectomy for the treatment of lumbar disc herniation. METHOD AND ANALYSIS: In total, 682 patients between 18 and 70 years of age with >10 weeks of radiating pain or with >6 weeks of excessive radiating pain are to be recruited from participating centres. Patients must have an indication for surgery based on an MRI demonstrating compression of the nerve root from a lumbar disc herniation. Patients are to be randomised to PTED or open microdiscectomy. The primary outcome is self-reported leg pain measured by the 0 100 mm Visual Analogue Scale. Secondary outcomes include self-reported health and functional status, back pain, self-perceived recovery and a physical examination. Outcomes will be measured the day following surgery, at 2, 4 and 6 weeks, and at 3, 6, 9, 12 and 24 months. Physical examination will be performed at 6 weeks, and 3 and 12 months. An economic evaluation will be performed from a societal perspective and cost questionnaires will be used (eg, EQ-5D-5L). The data will be analysed longitudinally; the non-inferiority margin for the primary outcome is 5. Bootstrapping techniques will be used for the economic evaluation. ETHICS AND DISSEMINATION: This study has received approval of the Medical Ethical Committee of the VU Medical Centre Amsterdam: NL50951.029.14. The results will be published in an international peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT02602093; Pre-results, recruiting stage. PMID- 29273660 TI - Prevalence and trends of thinness, overweight and obesity among children and adolescents aged 3-18 years across Europe: a protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Increasing prevalence of both thinness and excess weight during childhood and adolescence is a significant public health issue because of short term health consequences and long-term tracking of weight status. Monitoring weight status in Europe may serve to identify countries and regions where rates of these disorders are either slowing down or increasing to evaluate recent policies aimed at appropriate body weight, and to direct future interventions. This study protocol provides a standardised and transparent methodology to improve estimating trends of thinness, overweight and obesity in children aged 3 18 years and adolescents across the European region between 2000 and 2017. METHODS AND ANALYSIS: This protocol is guided by the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and the Cochrane Collaboration Handbook. To identify relevant studies, a search will be conducted in MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science databases. From the selected studies, relevant references will be screened as supplemental sources. Finally, open search in websites from health institutions will be conducted to identify weight status data not published in scientific journals. Cross-sectional, follow-up studies and panel surveys reporting weight status (objectively measured height and weight) according to the International Obesity Task Force criteria, and written in English or Spanish will be included. Subgroup analyses will be carried out by gender, age, study year and country or European region. DISCUSSION: This study will provide a comprehensive description of weight status of children and adolescents across Europe from 2000 to 2017. The results will be disseminated in a peer-reviewed journal. This study will use data exclusively from published research or institutional literature, so institutional ethical approval is not required. PROSPERO REGISTRATION NUMBER: CRD42017056917. PMID- 29273661 TI - Design and rationale of the Cardiovascular Health and Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study: two randomised controlled trials of text messaging to improve secondary prevention for coronary heart disease and diabetes. AB - INTRODUCTION: Mobile health interventions have the potential to promote risk factor management and lifestyle modification, and are a particularly attractive approach for scaling across healthcare systems with limited resources. We are conducting two randomised trials to evaluate the efficacy of text message-based health messages in improving secondary coronary heart disease (CHD) prevention among patients with or without diabetes. METHODS AND ANALYSIS: The Cardiovascular Health And Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study are multicentre, single-blind, randomised controlled trials of text messaging versus standard treatment with 6 months of follow-up conducted in 37 hospitals throughout 17 provinces in China. The intervention group receives six text messages per week which target blood pressure control, medication adherence, physical activity, smoking cessation (when appropriate), glucose monitoring and lifestyle recommendations including diet (in CHAT-DM). The text messages were developed based on behavioural change techniques, using models such as the information-motivation-behavioural skills model, goal setting and provision of social support. A total sample size of 800 patients would be adequate for CHAT Study and sample size of 500 patients would be adequate for the CHAT-DM Study. In CHAT, the primary outcome is the change in systolic blood pressure (SBP) at 6 months. Secondary outcomes include a change in proportion of patients achieving a SBP <140 mm Hg, low-density lipoprotein cholesterol (LDL-C), physical activity, medication adherence, body mass index (BMI) and smoking cessation. In CHAT-DM, the primary outcome is the change in glycaemic haemoglobin (HbA1C) at 6 months. Secondary outcomes include a change in the proportion of patients achieving HbA1C<7%, fasting blood glucose, SBP, LDL-C, BMI, physical activity and medication adherence. ETHICS AND DISSEMINATION: The central ethics committee at the China National Center for Cardiovascular Disease and the Yale University Institutional Review Board approved the CHAT and CHAT-DM studies. Results will be disseminated via usual scientific forums including peer-reviewed publications. TRIAL REGISTRATION NUMBER: CHAT (NCT02888769) and CHAT-DM (NCT02883842); Pre results. PMID- 29273662 TI - Healthcare to parents of young terrorism survivors: a registry-based study in Norway. AB - OBJECTIVES: To assess changes in parents' short-term and long-term primary and specialised healthcare consumption following a terrorist attack threatening the lives of their children. DESIGN: Registry-based study comparing parental healthcare service consumption in the 3 years before and the 3 years after a terrorist attack. SETTING: The aftermath of the Utoya terrorist attack. The regular, publicly funded, universal healthcare system in Norway. INTERVENTION: Parents learning of a terrorist attack on their adolescent and young adult children. PARTICIPANTS: Mothers (n=226) and fathers (n=141) of a total of 263 survivors of the Utoya terrorist attack (54.6% of all survivors 13-33 years, n=482). MAIN OUTCOME MEASURES: We report primary and specialised somatic and mental healthcare service consumption in the early (0-6 months) and delayed (>6 36 months) aftermath of the attack, both in terms of frequency of services consumed (assessed by age-adjusted negative binomial hurdle regression) and proportions of mothers and fathers provided for (mean semiannual values). The predisaster and postdisaster rates were compared by rate ratios (RRs), and 95% CI were generated through bootstrap replications. RESULTS: Frequency of primary healthcare service consumption increased significantly in both mothers and fathers in the early aftermath of the attack (mothers: RR=1.97, 95% CI 1.76 to 2.23; fathers: RR=1.73, 95% CI 1.36 to 2.29) and remained significantly elevated throughout the delayed aftermath. In the specialised mental healthcare services, a significant increase in the frequency of service consumption was observed in mothers only (early: RR=7.00, 95% CI 3.86 to 19.02; delayed: RR=3.20, 95% CI 1.49 to 9.49). In specialised somatic healthcare, no significant change was found. CONCLUSION: Following terrorist attacks, healthcare providers must prepare for increased healthcare needs in survivors and their close family members, such as parents. Needs may present shortly after the attack and require long-term follow up. PMID- 29273664 TI - Postmarketing studies for novel drugs approved by both the FDA and EMA between 2005 and 2010: a cross-sectional study. AB - OBJECTIVES: To characterise postmarketing studies for drugs that were newly approved by the US Food and Drug Administration and the European Medicines Agency. DESIGN AND SETTING: Cross-sectional analysis of postmarketing studies registered in ClinicalTrials.gov until September 2014 for all novel drugs approved by both regulators between 2005 and 2010. Regulatory documents from both agencies were used. PRIMARY AND SECONDARY OUTCOME MEASURES: All identified postmarketing studies were classified according to planned enrolment, funding, status and geographical location, and we determined whether studies studied the originally approved indication. RESULTS: Overall, 69 novel drugs approved between 2005 and 2010 were eligible for inclusion. A total of 6679 relevant postmarketing studies were identified; 5972 were interventional (89.4%). The median number of studies per drug was 55 (IQR 33-119) and median number of patients to be enrolled per study was 60 (IQR 28-183). Industry was the primary sponsor of 2713 studies (40.6%) and was a primary or secondary sponsor in 4176 studies (62.5%). In all, 2901 studies (43.4%) were completed, 487 (7.3%) terminated, 1013 (15.2%) active yet not recruiting, 1895 (28.4%) recruiting and 319 (4.8%) not yet recruiting. A total of 80% of studies were conducted in only one country and 84.4% took place in Europe and/or North America; 2441 (36.5%) studied another indication than the originally approved indication. Studies designed in the originally approved indication were found to be more industry-sponsored than others 68.7%vs53.7%; P<0.0001. CONCLUSIONS: Postmarketing pharmaceutical research was highly variable and predominantly located in North America and Europe. Postmarketing studies were frequently designed to study indications other than the originally approved one. Although some findings were reassuring, others question the lack of coordination of postmarketing research. PMID- 29273665 TI - Crowd medical services in the English Football League: remodelling the team for the 21st century using a realist approach. AB - OBJECTIVES: To evaluate the new model of providing care based on demand. This included reconfiguration of the workforce to manage workforce supply challenges and meet demand without compromising the quality of care. DESIGN: Currently the Sports Ground Safety Authority recommends the provision of crowd medical cover at English Football League stadia. The guidance on provision of services has focused on extreme circumstances such as the Hillsborough disaster in 1989, while the majority of demand on present-day services is from patients with minor injuries, exacerbations of injuries and pre-existing conditions. A new model of care was introduced in the 2009/2010 season to better meet demand. A realist approach was taken. Data on each episode of care were collected over 14 consecutive football league seasons at Millwall FC divided into two periods, preimplementation of changes and postimplementation of changes. Data on workforce retention and volunteer satisfaction were also collected. SETTING: The data were obtained from one professional football league team (Millwall FC) located in London, UK. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was to examine the demand for crowd medical services. The secondary outcome was to remodel the service to meet these demands. RESULTS: In total, 981 episodes of care were recorded over the evaluation period of 14 years. The groups presenting, demographic and type of presentation did not change over the evaluation. First aiders were involved in 87.7% of episodes of care, nurses in 44.4% and doctors 17.8%. There was a downward trend in referrals to hospital. Workforce feedback was positive. CONCLUSIONS: The new workforce model has met increased service demands while reducing the number of referrals to acute care. It involves the first aid workforce in more complex care and key decision-making and provides a flexible registered healthcare professional team to optimise the skill mix of the team. PMID- 29273663 TI - Meta-ethnography to understand healthcare professionals' experience of treating adults with chronic non-malignant pain. AB - OBJECTIVES: We aimed to explore healthcare professionals' experience of treating chronic non-malignant pain by conducting a qualitative evidence synthesis. Understanding this experience from the perspective of healthcare professionals will contribute to improvements in the provision of care. DESIGN: Qualitative evidence synthesis using meta-ethnography. We searched five electronic bibliographic databases from inception to November 2016. We included studies that explore healthcare professionals' experience of treating adults with chronic non malignant pain. We used the GRADE-CERQual framework to rate confidence in review findings. RESULTS: We screened the 954 abstracts and 184 full texts and included 77 published studies reporting the experiences of over 1551 international healthcare professionals including doctors, nurses and other health professionals. We abstracted six themes: (1) a sceptical cultural lens, (2) navigating juxtaposed models of medicine, (3) navigating the geography between patient and clinician, (4) challenge of dual advocacy, (5) personal costs and (6) the craft of pain management. We rated confidence in review findings as moderate to high. CONCLUSIONS: This is the first qualitative evidence synthesis of healthcare professionals' experiences of treating people with chronic non malignant pain. We have presented a model that we developed to help healthcare professionals to understand, think about and modify their experiences of treating patients with chronic pain. Our findings highlight scepticism about chronic pain that might explain why patients feel they are not believed. Findings also indicate a dualism in the biopsychosocial model and the complexity of navigating therapeutic relationships. Our model may be transferable to other patient groups or situations. PMID- 29273666 TI - Clinical characteristics, one-year change in ejection fraction and long-term outcomes in patients with heart failure with mid-range ejection fraction: a multicentre prospective observational study in Catalonia (Spain). AB - OBJECTIVES: The aim of this study was to analyse baseline characteristics and outcome of patients with heart failure and mid-range left ventricular ejection fraction (HFmrEF, left ventricular ejection fraction (LVEF) 40%-49%) and the effect of 1-year change in LVEF in this group. SETTING: Multicentre prospective observational study of ambulatory patients with HF followed up at four university hospitals with dedicated HF units. PARTICIPANTS: Fourteen per cent (n=504) of the 3580 patients included had HFmrEF. INTERVENTIONS: Baseline characteristics, 1 year LVEF and outcomes were collected. All-cause death, HF hospitalisation and the composite end-point were the primary outcomes. RESULTS: Median follow-up was 3.66 (1.69-6.04) years. All-cause death, HF hospitalisation and the composite end point were 47%, 35% and 59%, respectively. Outcomes were worse in HF with preserved ejection fraction (HFpEF) (LVEF>50%), without differences between HF with reduced ejection fraction (HFrEF) (LVEF<40%) and HFmrEF (all-cause mortality 52.6% vs 45.8% and 43.8%, respectively, P=0.001). After multivariable Cox regression analyses, no differences in all-cause death and the composite end point were seen between the three groups. HF hospitalisation and cardiovascular death were not statistically different between patients with HFmrEF and HFrEF. At 1-year follow-up, 62% of patients with HFmrEF had LVEF measured: 24% had LVEF<40%, 43% maintained LVEF 40%-49% and 33% had LVEF>50%. While change in LVEF as continuous variable was not associated with better outcomes, those patients who evolved from HFmrEF to HFpEF did have a better outcome. Those who remained in the HFmrEF and HFrEF groups had higher all-cause mortality after adjustment for age, sex and baseline LVEF (HR 1.96 (95% CI 1.08 to 3.54, P=0.027) and HR 2.01 (95% CI 1.04 to 3.86, P=0.037), respectively). CONCLUSIONS: Patients with HFmrEF have a clinical profile in-between HFpEF and HFrEF, without differences in all cause mortality and the composite end-point between the three groups. At 1 year, patients with HFmrEF exhibited the greatest variability in LVEF and this change was associated with survival. PMID- 29273667 TI - User involvement in adolescents' mental healthcare: protocol for a systematic review. AB - INTRODUCTION: User involvement has become a growing importance in healthcare. The United Nations state that adolescents have a right to be heard, and user involvement in healthcare is a legal right in many countries. Some research provides an insight into the field of user involvement in somatic and mental healthcare for adults, but little is known about user involvement in adolescents' mental healthcare, and no overview of the existing research evidence exists. METHODS AND ANALYSIS: The aim of this systematic review is to provide an overview of existing research reporting on experiences with and the effectiveness and safety issues associated with user involvement for adolescents' mental healthcare at the individual and organisational level. A systematic literature search and assessment of published research in the field of user involvement in adolescents' mental healthcare will be carried out. Established guidelines will be used for data extraction (Cochrane Collaboration guidelines, Strengthening the Reporting of Observational studies in Epidemiology and Critical Appraisal Skills Programme (CASP)), critical appraisal (Cochrane Collaboration guidelines and Pragmatic Explanatory Continuum Indicator Summary) and reporting of results (Preferred Reporting Items for Systematic reviews and Meta-Analyses, Consolidated Standards of Reporting Trials and CASP). Confidence in the research evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. Adolescents are included as coresearchers for the planning and carrying out of this systematic review. This systematic review will provide an overview of the existing research literature and thereby fill a knowledge gap. It may provide various stakeholders, including decision-makers, professionals, individuals and their families, with an overview of existing knowledge in an underexplored field of research. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review as we are not collecting primary data. The results will be published in a peer-reviewed journal and at conference presentations and will be shared with stakeholder groups. PMID- 29273668 TI - Investigating fractional exhaled nitric oxide (FeNO) in chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO): a scoping review protocol. AB - INTRODUCTION: During the last decade, many articles have been published, including reviews on fractional exhaled nitric oxide (FeNO) use and utility in clinical practice and for monitoring and identifying eosinophilic airway inflammation, especially in asthma, and evaluating corticosteroid responsiveness. However, the exact role of FeNO in patients with chronic obstructive pulmonary disease (COPD) and its ability to distinguish patients with COPD and those having concomitant asthma, that is, asthma-COPD overlap (ACO) is still unclear and needs to be defined. Due to the broad topics of FeNO in chronic airway disease, we undertook a scoping review. The present article describes the protocol of a scoping review of peer-reviewed published literature specific to FeNO in COPD/ACO over the last decade. METHODS AND ANALYSIS: We used Joanna Briggs Institute Reviewers' Manual scoping review methodology as well as Levac et al's and Arksey et al's framework as guides. We searched a variety of databases, including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, Web of Science, and BioSciences Information Service (BIOSIS) on 29 June 2016. Additional studies will be recognised by exploring the reference list of identified eligible studies. Screening of eligible studies will be independently performed by two reviewers and any disagreement will be solved by the third reviewer. We will analyse the gathered data from article bibliographies and abstracts. ETHICS AND DISSEMINATION: To investigate the body of published studies regarding the role of FeNO in patients with COPD and its usefulness in the clinical setting, a scoping review can be used as a modern and pioneer model, which does not need ethics approval. By this review, new insights for conducting new research specific to FeNO in COPD/ACO population will emerge. The results of this study will be reported in the scientific meetings and conferences, which aim to provide information to the clinicians, primary care providers and basic science researchers. PMID- 29273669 TI - Recognition of mental disorders: findings from a cross-sectional study among medical students in Singapore. AB - OBJECTIVES: To assess recognition of five mental disorders (alcohol abuse, dementia, depression, obsessive-compulsive disorder (OCD) and schizophrenia) among a sample of medical students using a vignette-based approach. Socio demographic predictors of correct recognition were also explored. DESIGN: Cross sectional online survey. PARTICIPANTS: Medical students studying in Singapore. METHODS: This was a cross-sectional online study among medical students (n=502) who were randomly assigned one of the five vignettes. Students were instructed to read the vignette, then answer the open text question, 'What do you think the person in the vignette is suffering from?' Multiple logistic regression was performed to determine the predictors of correct recognition. RESULTS: 81.7% could correctly recognise the condition described in the vignette. Depression was most well recognised (93.0%), followed by alcohol abuse (89.0%), OCD (87.1%) and dementia (79.2%), while only 60.0% of students correctly recognised schizophrenia. Females were significantly more likely to correctly recognise the disorders, while the odds of correct recognition were significantly higher among fourth-year and fifth-year students compared with first-year students. Compared with depression, dementia and schizophrenia were significantly more likely to be mislabelled. CONCLUSION: While overall correct recognition was high (81.7%), this did vary by disorder, where schizophrenia (60%) was the most poorly recognised condition. Given that primary care providers are often the first professional help-seeking source for people with mental health problems, medical students should be equipped with the skills and ability to recognise signs and symptoms of various mental illnesses. PMID- 29273670 TI - Using a retrospective cross-sectional study to analyse unintentional fatal drowning in Australia: ICD-10 coding-based methodologies verses actual deaths. AB - OBJECTIVES: Fatal drowning estimates using a single underlying cause of death (UCoD) may under-represent the number of drowning deaths. This study explores how data vary by International Classification of Diseases (ICD)-10 coding combinations and the use of multiple underlying causes of death using a national register of drowning deaths. DESIGN: An analysis of ICD-10 external cause codes of unintentional drowning deaths for the period 2007-2011 as extracted from an Australian total population unintentional drowning database developed by Royal Life Saving Society-Australia (the Database). The study analysed results against three reporting methodologies: primary drowning codes (W65-74), drowning-related codes, plus cases where drowning was identified but not the UCoD. SETTING: Australia, 2007-2011. PARTICIPANTS: Unintentional fatal drowning cases. RESULTS: The Database recorded 1428 drowning deaths. 866 (60.6%) had an UCoD of W65-74 (accidental drowning), 249 (17.2%) cases had an UCoD of either T75.1 (0.2%), V90 (5.5%), V92 (3.5%), X38 (2.4%) or Y21 (5.9%) and 53 (3.7%) lacked ICD coding. Children (aged 0-17 years) were closely aligned (73.9%); however, watercraft (29.2%) and non-aquatic transport (13.0%) were not. When the UCoD and all subsequent causes are used, 67.2% of cases include W65-74 codes. 91.6% of all cases had a drowning code (T75.1, V90, V92, W65-74, X38 and Y21) at any level. CONCLUSION: Defining drowning with the codes W65-74 and using only the UCoD captures 61% of all drowning deaths in Australia. This is unevenly distributed with adults, watercraft and non-aquatic transport-related drowning deaths under represented. Using a wider inclusion of ICD codes, which are drowning-related and multiple causes of death minimises this under-representation. A narrow approach to counting drowning deaths will negatively impact the design of policy, advocacy and programme planning for prevention. PMID- 29273671 TI - How is defensive medicine understood and experienced in a primary care setting? A qualitative focus group study among Danish general practitioners. AB - OBJECTIVES: Recent years have witnessed a progressive increase in defensive medicine (DM) in several Western welfare countries. In Danish primary and secondary care, documentation on the extent of DM is lacking. Before investigating the extent of DM, we wanted to explore how the phenomenon is understood and experienced in the context of general practice in Denmark. The objective of the study was to describe the phenomenon of DM as understood and experienced by Danish general practitioners (GPs). DESIGN: A qualitative methodology was employed and data were generated through six focus group interviews with three to eight GPs per group (n=28) recruited from the Region of Southern Denmark. Data were analysed using a thematic content analysis inspired by a hermeneutic-phenomenological focus on understanding and meaning. RESULTS: DM is understood as unnecessary and meaningless medical actions, carried out mainly because of external demands that run counter to the GP's professionalism. Several sources of pressure to act defensively were identified by the GPs: the system's pressure to meet external regulations, demands from consumerist patients and a culture among GPs and peers of infallibility and zero-risk tolerance. CONCLUSIONS: GPs understand DM as unnecessary and meaningless actions driven by external demands instead of a focus on the patient's problem. GPs consider defensive actions to be carried out as a result of succumbing to various sources of pressure deriving from the system, the patients, the GPs themselves and peers. PMID- 29273673 TI - Reduced SERCA activity underlies dysregulation of Ca2+ homeostasis under atmospheric O2 levels. AB - Unregulated increases in cellular Ca2+ homeostasis are a hallmark of pathophysiological conditions and a key trigger of cell death. Endothelial cells cultured under physiologic O2 conditions (5% O2) exhibit a reduced cytosolic Ca2+ response to stimulation. The mechanism for reduced plateau [Ca2+]i upon stimulation was due to increased sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) mediated reuptake rather than changes in Ca2+ influx capacity. Agonist-stimulated phosphorylation of the SERCA regulatory protein phospholamban was increased in cells cultured under 5% O2. Elevation of cytosolic and mitochondrial [Ca2+] and cell death after prolonged ionomycin treatment, as a model of Ca2+ overload, were lower when cells were cultured long-term under 5% compared with 18% O2. This protection was abolished by cotreatment with the SERCA inhibitor cyclopiazonic acid. Taken together, these results demonstrate that culturing cells under hyperoxic conditions reduces their ability to efficiently regulate [Ca2+]i, resulting in greater sensitivity to cytotoxic stimuli.-Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. Reduced SERCA activity underlies dysregulation of Ca2+ homeostasis under atmospheric O2 levels. PMID- 29273674 TI - Alternative routes for synthesis of N-linked glycans by Alg2 mannosyltransferase. AB - Asparagine ( N)-linked glycosylation requires the ordered, stepwise synthesis of lipid-linked oligosaccharide (LLO) precursor Glc3Man9GlcNAc2-pyrophosphate dolichol (Glc3Man9Gn2-PDol) on the endoplasmic reticulum. The fourth and fifth steps of LLO synthesis are catalyzed by Alg2, an unusual mannosyltransferase (MTase) with two different MTase activities; Alg2 adds both an alpha1,3- and alpha1,6-mannose onto ManGlcNAc2-PDol to form the trimannosyl core Man3GlcNAc2 PDol. The biochemical properties of Alg2 are controversial and remain undefined. In this study, a liquid chromatography/mass spectrometry-based quantitative assay was established and used to analyze the MTase activities of purified yeast Alg2. Alg2-dependent Man3GlcNAc2-PDol production relied on net-neutral lipids with a propensity to form bilayers. We further showed addition of the alpha1,3- and alpha1,6-mannose can occur independently in either order but at differing rates. The conserved C-terminal EX7E motif, N-terminal cytosolic tail, and 3 G-rich loop motifs in Alg2 play crucial roles for these activities, both in vitro and in vivo. These findings provide insight into the unique bifunctionality of Alg2 during LLO synthesis and lead to a new model in which alternative, independent routes exist for Alg2 catalysis of the trimannosyl core oligosaccharide.-Li, S. T., Wang, N., Xu, X.-X., Fujita, M., Nakanishi, H., Kitajima, T., Dean, N., Gao, X.-D. Alternative routes for synthesis of N-linked glycans by Alg2 mannosyltransferase. PMID- 29273672 TI - CD1a presentation of endogenous antigens by group 2 innate lymphoid cells. AB - Group 2 innate lymphoid cells (ILC2) are effectors of barrier immunity, with roles in infection, wound healing, and allergy. A proportion of ILC2 express MHCII (major histocompatibility complex II) and are capable of presenting peptide antigens to T cells and amplifying the subsequent adaptive immune response. Recent studies have highlighted the importance of CD1a-reactive T cells in allergy and infection, activated by the presentation of endogenous neolipid antigens and bacterial components. Using a human skin challenge model, we unexpectedly show that human skin-derived ILC2 can express CD1a and are capable of presenting endogenous antigens to T cells. CD1a expression is up-regulated by TSLP (thymic stromal lymphopoietin) at levels observed in the skin of patients with atopic dermatitis, and the response is dependent on PLA2G4A. Furthermore, this pathway is used to sense Staphylococcus aureus by promoting Toll-like receptor-dependent CD1a-reactive T cell responses to endogenous ligands. These findings define a previously unrecognized role for ILC2 in lipid surveillance and identify shared pathways of CD1a- and PLA2G4A-dependent ILC2 inflammation amenable to therapeutic intervention. PMID- 29273675 TI - Vitamin E and lycopene reduce coal burning fluorosis-induced spermatogenic cell apoptosis via oxidative stress-mediated JNK and ERK signaling pathways. AB - Although fluoride has been widely used in toothpaste, mouthwash, and drinking water to prevent dental caries, the excessive intake of fluoride can cause fluorosis which is associated with dental, skeletal, and soft tissue fluorosis. Recent evidences have drawn the attention to its adverse effects on male reproductive system that include spermatogenesis defect, sperm count loss, and sperm maturation impairment. Fluoride induces oxidative stress through the activation of mitogen activated protein kinase (MAPK) cascade which can lead to cell apoptosis. Vitamin E (VE) and lycopene are two common antioxidants, being protective to reactive oxygen species (ROS)-induced toxic effects. However, whether and how these two antioxidants prevent fluoride-induced spermatogenic cell apoptosis are largely unknown. In the present study, a male rat model for coal burning fluorosis was established and the histological lesions and spermatogenic cell apoptosis in rat testes were observed. The decreased expression of clusterin, a heterodimeric glycoprotein reported to regulate spermatogenic cell apoptosis, was detected in fluoride-treated rat testes. Interestingly, the co-administration with VE or lycopene reduced fluorosis mediated testicular toxicity and rescued clusterin expression. Further, fluoride caused the enhanced Jun N-terminal kinase (JNK, c-Jun) and extracellular signal regulated protein kinase (ERK) phosphorylation, which was reduced by VE or lycopene. Thus, VE and lycopene prevent coal burning fluorosis-induced spermatogenic cell apoptosis through the suppression of oxidative stress-mediated JNK and ERK signaling pathway, which could be an alternative therapeutic strategy for the treatment of fluorosis. PMID- 29273676 TI - Resveratrol attenuates high glucose-induced nucleus pulposus cell apoptosis and senescence through activating the ROS-mediated PI3K/Akt pathway. AB - BACKGROUND: Diabetes mellitus is closely correlated with disc degeneration. Nucleus pulposus (NP) cell apoptosis and senescence are typical cellular features within the degenerative disc. Resveratrol is a newly identified phytoalexin that has protective effects on cartilaginous tissue. OBJECTIVE: To investigate the whether resveratrol can protect against high glucose-induced NP cell apoptosis and senescence, and the potential mechanism in this process. METHODS: Rat NP cells were cultured in either 10% FBS culture medium (control group) or 10% FBS with a high glucose concentration (0.2 M, experiment group) for 3 days. Resveratrol or the combination of resveratrol and LY294002 was added into the culture medium of experiment group to investigate the effects of resveratrol and the PI3K/Akt pathway. RESULTS: High glucose significantly promoted NP cell apoptosis and NP cell senescence compared with the control group. Resveratrol exhibited protective effects against high glucose-induced NP cell apoptosis and senescence. Further analysis showed that resveratrol suppressed reactive oxygen species (ROS) generation and increased the activity of the PI3K/Akt pathway under the high glucose condition. However, the LY294002 had no significant effects on ROS content in the resveratrol-treated high glucose group. CONCLUSION: Resveratrol can attenuate high glucose-induced NP cell apoptosis and senescence, and the activation of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process. PMID- 29273677 TI - Study of analgesic effect of earthworm extract. AB - Pain represents a major clinical problem and one which has exercised generations of healthcare professionals. Earthworms are used as a traditional Chinese medicine, and have been applied pharmacologically and clinically since a long time in China. However, the analgesic effects of earthworm extract (EE) are seldom studied. Hence, we evaluated the analgesic effects of EE in mice. The obtained data showed that EE increased pain threshold and exhibited peripheral but not central analgesic effects in mice; evidenced by increased inhibition ratio in acetic acid writhing test and formalin test, whereas only slight increase in inhibition ratio in hot plate test and tail immersion test. In addition, EE decreased serum norepinephrine (NE), 5-hydroxytryptamine (5-HT), and nitric oxide (NO) synthase (NOS) concentration, similar to other analgesic drugs like morphine and aspirin. In a nutshell, the obtained data have demonstrated that EE has peripheral analgesic properties and could be used as a promising analgesic drug. PMID- 29273678 TI - Static compression down-regulates N-cadherin expression and facilitates loss of cell phenotype of nucleus pulposus cells in a disc perfusion culture. AB - Mechanical compression often induces degenerative changes of disc nucleus pulposus (NP) tissue. It has been indicated that N-cadherin (N-CDH)-mediated signaling helps to preserve the NP cell phenotype. However, N-CDH expression and the resulting NP-specific phenotype alteration under the static compression and dynamic compression remain unclear. To study the effects of static compression and dynamic compression on N-CDH expression and NP-specific phenotype in an in vitro disc organ culture. Porcine discs were organ cultured in a self-developed mechanically active bioreactor for 7 days and subjected to static or dynamic compression (0.4 MPa for 2 h once per day). The noncompressed discs were used as controls. Compared with the dynamic compression, static compression significantly down-regulated the expression of N-CDH and NP-specific markers (laminin, brachyury, and keratin 19); decreased the Alcian Blue staining intensity, glycosaminoglycan and hydroxyproline contents; and declined the matrix macromolecule (aggrecan and collagen II) expression. Compared with the dynamic compression, static compression causes N-CDH down-regulation, loss of NP-specific phenotype, and the resulting decrease in NP matrix synthesis. PMID- 29273680 TI - IGF system in sarcomas: a crucial pathway with many unknowns to exploit for therapy. AB - The insulin-like growth factor (IGF) system has gained substantial interest due to its involvement in regulating cell proliferation, differentiation and survival during anoikis and after conventional and targeted therapies. However, results from clinical trials have been largely disappointing, with only a few but notable exceptions, such as trials targeting sarcomas, especially Ewing sarcoma. This review highlights key studies focusing on IGF signaling in sarcomas, specifically studies underscoring the properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. This review discusses the potential roles of IGF2 mRNA-binding proteins (IGF2BPs), discoidin domain receptors (DDRs) and metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) in regulating the IGF system. Deeper investigation of these novel regulators of the IGF system may help us to further elucidate the spatial and temporal control of the IGF axis, as understanding the control of this axis is essential for future clinical studies. PMID- 29273681 TI - Sorcin is involved during embryo implantation via activating VEGF/PI3K/Akt pathway in mice. AB - Our earlier studies have demonstrated the cyclic variation and also the altered expression of sorcin in endometrium during early-to-mid-secretory phase transition in women with unexplained infertility. The current study was undertaken to establish the functional role of sorcin in endometrial receptivity in mice. Results indicated that sorcin was highly expressed during the window of implantation in mice and functional blockage of sorcin caused significant reduction in number of implanted blastocyst. The receptivity markers (i.e.Integrin beta3, HBEGF, IGFBP1, WNT4 and Cyclin E)) were found to be downregulated in sorcin knocked down uterine horn on day 5 as compared to untreated horn. The reduced attachment and expansion of BeWo spheroids on RL95-2 endometrial cells with sorcin knock down, in in vitro model of endometrium trophoblast interaction further supported these findings. Uterine sorcin expression pattern during estrous cycle and in delayed implantation mice model suggested the upregulation of sorcin by estrogen. The functional blockade of sorcin induced the intracellular Ca+2 levels in endometrial epithelial cells (EECs), which indicated that altered Ca+2 homeostasis might be responsible for implantation failure. Sorcin silencing led to significant reduction in the expression of angiogenic factor VEGF and its downstream effector molecules i.e. PI3K, Akt and NOS. The migratory and invasive properties of HUVECs were abrogated by anti-VEGF or by adding culture media from sorcin blocked EECs, which indicated that sorcin might mediate angiogenesis during implantation. Taken together, sorcin is involved in the regulation of Ca+2-mediated angiogenesis via VEGF/PI3K/Akt pathway in endometrial cells and plays a crucial role in preparing the endometrium for implantation. PMID- 29273679 TI - The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes. AB - The mammalian HoxD cluster lies between two topologically associating domains (TADs) matching distinct enhancer-rich regulatory landscapes. During limb development, the telomeric TAD controls the early transcription of Hoxd genes in forearm cells, whereas the centromeric TAD subsequently regulates more posterior Hoxd genes in digit cells. Therefore, the TAD boundary prevents the terminal Hoxd13 gene from responding to forearm enhancers, thereby allowing proper limb patterning. To assess the nature and function of this CTCF-rich DNA region in embryos, we compared chromatin interaction profiles between proximal and distal limb bud cells isolated from mutant stocks where various parts of this boundary region were removed. The resulting progressive release in boundary effect triggered inter-TAD contacts, favored by the activity of the newly accessed enhancers. However, the boundary was highly resilient, and only a 400-kb deletion, including the whole-gene cluster, was eventually able to merge the neighboring TADs into a single structure. In this unified TAD, both proximal and distal limb enhancers nevertheless continued to work independently over a targeted transgenic reporter construct. We propose that the whole HoxD cluster is a dynamic TAD border and that the exact boundary position varies depending on both the transcriptional status and the developmental context. PMID- 29273682 TI - Downregulation of decidual SP1 and P300 is associated with severe preeclampsia. AB - Preeclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria after 20 weeks of gestation, affecting 5-7% of pregnancies worldwide. So far, the etiology of PE remains poorly understood. Abnormal decidualization is thought to contribute to the development of PE. SP1 belongs to the Sp/KLF superfamily and can recruit P300 to regulate the transcription of several genes. SP1 is also very important for decidualization as it enhances the expression of tissue factor. In this study, we investigated the expression of SP1 and P300 in deciduae and their relationship with PE. A total of 42 decidua samples were collected, of which 21 were from normal pregnant (NP) and 21 from severe PE. SP1 and P300 expression in deciduae and the levels of SP1 and P300 in cultured human endometrial stromal cells (hESCs) and primary hESCs during decidualization were determined. To further investigate the role of SP1 and P300 in human decidualization, RNA interference was used to silence SP1 and P300 in hESCs and primary hESCs. The following results were obtained. We found that the expressions of SP1 and P300 were reduced in decidual tissues with PE compared to those from NP. In the in vitro model of induction of decidualization, we found an increase in both SP1 and P300 levels. Silencing of SP1 and P300 resulted in abnormal decidualization and a significant reduction of decidualization markers such as insulin-like growth factor-binding protein1 and prolactin. Furthermore, the expression of vascular endothelial growth factor was also decreased upon SP1 and P300 silencing. Similar results were observed in primary hESCs. Our results suggest that SP1 and P300 play an important role during decidualization. Dysfunction of SP1 and P300 leads to impaired decidualization and might contribute to PE. PMID- 29273683 TI - Functional implications of corticosteroid-binding globulin N-glycosylation. AB - Corticosteroid-binding globulin (CBG) is a plasma carrier of glucocorticoids. Human and rat CBGs have six N-glycosylation sites. Glycosylation of human CBG influences its steroid-binding activity, and there are N-glycosylation sites in the reactive center loops (RCLs) of human and rat CBGs. Proteolysis of the RCL of human CBG causes a structural change that disrupts steroid binding. We now show that mutations of conserved N-glycosylation sites at N238 in human CBG and N230 in rat CBG disrupt steroid binding. Inhibiting glycosylation by tunicamycin also markedly reduced human and rat CBG steroid-binding activities. Deglycosylation of fully glycosylated human CBG or human CBG with only one N-glycan at N238 with Endo H-reduced steroid-binding affinity, while PNGase F-mediated deglycosylation does not, indicating that steroid binding is preserved by deamidation of N238 when its N-glycan is removed. When expressed in N-acetylglucosaminyltransferase-I deficient Lec1 cells, human and rat CBGs, and a human CBG mutant with only one glycosylation site at N238, have higher (2-4 fold) steroid-binding affinities than when produced by sialylation-deficient Lec2 cells or glycosylation-competent CHO-S cells. Thus, the presence and composition of an N-glycan in this conserved position both appear to influence the steroid binding of CBG. We also demonstrate that neutrophil elastase cleaves the RCL of human CBG and reduces its steroid binding capacity more efficiently than does chymotrypsin or the Pseudomonas aeruginosa protease LasB. Moreover, while glycosylation of N347 in the RCL limits these activities, N-glycans at other sites also appear to protect CBG from neutrophil elastase or chymotrypsin. PMID- 29273684 TI - SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy. AB - c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125's protection against DN. To test the role of NRF2 in SP600125's effect, streptozotocin-induced C57BL/6 wild-type (WT) and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125's protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK induced Keap1 expression. PMID- 29273685 TI - IGF1 receptor and thyroid-associated ophthalmopathy. AB - Thyroid-associated ophthalmopathy (TAO) is a vexing and poorly understood autoimmune process involving the upper face and tissues surrounding the eyes. In TAO, the orbit can become inflamed and undergo substantial remodeling that is disfiguring and can lead to loss of vision. There are currently no approved medical therapies for TAO, the consequence of its uncertain pathogenic nature. It usually presents as a component of the syndrome known as Graves' disease where loss of immune tolerance to the thyrotropin receptor (TSHR) results in the generation of activating antibodies against that protein and hyperthyroidism. The role for TSHR and these antibodies in the development of TAO is considerably less well established. We have reported over the past 2 decades evidence that the insulin-like growth factorI receptor (IGF1R) may also participate in the pathogenesis of TAO. Activating antibodies against IGF1R have been detected in patients with GD. The actions of these antibodies initiate signaling in orbital fibroblasts from patients with the disease. Further, we have identified a functional and physical interaction between TSHR and IGF1R. Importantly, it appears that signaling initiated from either receptor can be attenuated by inhibiting the activity of IGF1R. These findings underpin the rationale for therapeutically targeting IGF1R in active TAO. A recently completed therapeutic trial of teprotumumab, a human IGF1R inhibiting antibody, in patients with moderate to severe, active TAO, indicates the potential effectiveness and safety of the drug. It is possible that other autoimmune diseases might also benefit from this treatment strategy. PMID- 29273686 TI - Ovarian aging is associated with gray matter volume and disability in women with MS. AB - OBJECTIVE: To determine if ovarian aging as measured by levels of anti-Mullerian hormone (AMH) is associated with pattern of multiple sclerosis (MS) progression in women. METHODS: Women with MS and healthy controls were included from a longitudinal research cohort with up to 10 years follow-up. Plasma AMH levels were measured by ELISA for baseline and years 3, 5, and 8-10. Mixed effects logistic and linear regression models were employed, with adjustments for age, disease duration, and other covariables as appropriate. RESULTS: AMH levels were similar (0.98-fold difference, 95% confidence interval [CI] 0.69-1.37, p = 0.87) in women with MS (n = 412, mean age 42.6 years) and healthy controls (n = 180, mean age 44 years). In a multivariable model of women with MS, including adjustments for age, body mass index, and disease duration, 10-fold lower AMH level was associated with 0.43-higher Expanded Disability Status Scale (EDSS) score (95% CI 0.15-0.70, p = 0.003), 0.25-unit worse MS Functional Composite z score (95% CI -0.40 to -0.10, p = 0.0015), and 7.44 mm3 lower cortical gray matter volume (95% CI -14.6 to -0.30; p = 0.041) at baseline. In a multivariable random-intercept-random-slope model using all observations over time, 10-fold decrease in AMH was associated with a 0.27 increase in EDSS (95% CI 0.11-0.43, p = 0.006) and 5.48 mm3 (95% CI 11.3-0.33, p = 0.065) and 4.55 mm3 (95% CI 9.33 0.23, p = 0.062) decreases in total gray and cortical gray matter, respectively. CONCLUSION: As a marker of ovarian aging, lower AMH levels were associated with greater disability and gray matter loss in women with MS independent of chronological age and disease duration. PMID- 29273687 TI - Ophthalmoscopy in the 21st century: The 2017 H. Houston Merritt Lecture. AB - Although the usefulness of viewing the ocular fundus is well-recognized, ophthalmoscopy is infrequently and poorly performed by most nonophthalmologist physicians, including neurologists. Barriers to the practice of ophthalmoscopy by nonophthalmologists include not only the technical difficulty related to direct ophthalmoscopy, but also lack of adequate training and discouragement by preceptors. Recent studies have shown that digital retinal fundus photographs with electronic transmission and remote interpretation of images by an ophthalmologist are an efficient and reliable way to allow examination of the ocular fundus in patients with systemic disorders such as diabetes mellitus. Ocular fundus photographs obtained without pharmacologic dilation of the pupil using nonmydriatic fundus cameras could be of great value in emergency departments (EDs) and neurologic settings. The Fundus Photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department (FOTO-ED) study showed that ED providers consistently failed to correctly identify relevant ocular funduscopic findings using the direct ophthalmoscope, and that nonmydriatic fundus photography was an effective alternate way of providing access to the ocular fundus in the ED. Extrapolating these results to headache clinics, outpatient neurology clinics, and adult and pediatric primary care settings seems self-evident. As technology advances, nonmydriatic ocular fundus imaging systems will be of higher quality and more portable and affordable, thereby circumventing the need to master the use of the ophthalmoscope. Visualizing the ocular fundus is more important than the method used. Ocular fundus photography facilitates nonophthalmologists' performance of this essential part of the physical examination, thus helping to reestablish the value of doing so. PMID- 29273688 TI - Abnormal beta power is a hallmark of explicit movement control in functional movement disorders. AB - OBJECTIVE: To determine whether sensorimotor beta-frequency oscillatory power is raised during motor preparation in patients with functional movement disorders (FMD) and could therefore be a marker of abnormal "body-focused" attention. METHODS: We analyzed motor performance and beta-frequency cortical oscillations during a precued choice reaction time (RT) task with varying cue validity (50% or 95% congruence between preparation and go cues). We compared 21 patients with FMD with 13 healthy controls (HCs). RESULTS: In HCs, highly predictive cues were associated with faster RT and beta desynchronization in the contralateral hemisphere (contralateral slope -0.045 [95% confidence interval (CI) -0.057 to 0.033] vs ipsilateral -0.033 [95% CI -0.046 to -0.021], p < 0.001) and with a tendency for reaching lower contralateral end-of-preparation beta power (contralateral -0.482 [95% CI -0.827 to -0.137] vs ipsilateral -0.328 [95% CI 0.673 to 0.016], p = 0.069). In contrast, patients with FMD had no improvement in RTs with highly predictive cues and showed an impairment of beta desynchronization and lateralization before movement. CONCLUSIONS: Persistent beta synchronization during motor preparation could reflect abnormal explicit control of movement in FMD. Excessive attention to movement itself rather than the goal might maintain beta synchronization and impair performance. PMID- 29273690 TI - Take-home message: improve naloxone supply. PMID- 29273689 TI - Multiple pathways of reserve simultaneously present in cognitively normal older adults. AB - OBJECTIVE: To examine neural correlates of intellectual activity underlying multiple pathways imparting reserve by testing that higher intellectual activity is associated with lower brain amyloid pathology, greater gray matter (GM) volume, and differential task-evoked brain activation levels as a function of amyloid positivity status among clinically intact older adults. METHODS: Eighty two cognitively normal older adults and 46 healthy young participants underwent fMRI during task switching. All older participants completed 18F-florbetaben-PET and an individual's amyloid positivity status was determined. To assess GM volume, T1-weighted high-resolution structural images were processed using voxel based morphometry. As lifestyle factors, intellectual activity was estimated by a composite score of vocabulary, reading ability, and years of education. RESULTS: Across all older participants, intellectual activity was associated with lower amyloid deposition in lateral and medial frontoparietal and temporal lobes but higher amyloid deposition in superior frontal and parietal cortices, larger GM volume across widespread brain regions, and reduced brain activation during task switching. These patterns of associations, however, differed by amyloid positivity status. While the patterns of associations remained similar among amyloid-negative older adults, among amyloid-positive older adults, intellectual activity was associated with increased amyloid deposition in frontoparietal cortices and increased activation during task. CONCLUSIONS: Intellectual activity simultaneously exerts both neuroprotective and compensatory effects via multiple neural pathways that promote optimal brain aging and help maintain normal cognition during amyloid accumulation. PMID- 29273691 TI - Neuropsychological outcome after subtemporal versus transsylvian approach for selective amygdalohippocampectomy in patients with mesial temporal lobe epilepsy: a randomised prospective clinical trial. AB - OBJECTIVE: To compare the effects of different surgical approaches for selective amygdalohippocampectomy in patients with pharmacoresistant mesial temporal lobe epilepsy with regard to the neuropsychological outcome and to replicate an earlier study employing a matched-pair design. METHOD: 47 patients were randomised to subtemporal versus transsylvian approaches. Memory, language, attentional and executive functions were assessed before and 1 year after surgery. Multivariate analyses of variance (MANOVAs) with presurgical and postsurgical assessments as within-subject variables and approach and side of surgery as between-subject factors were calculated. Additionally, the frequencies of individual performance changes based on reliable change indices were analysed. RESULTS: Seizure freedom International League Against Epilepsy (ILAE) 1a, was achieved in 62% of all patients without group difference. MANOVAs revealed no significant effects of approach on cognition. Tested separately for each parameter, verbal recognition memory declined irrespective of approach. Post hoc tests revealed that on group level, the subtemporal approach was associated with a worse outcome for verbal learning and delayed free recall as well as for semantic fluency. Accordingly, on individual level, more patients in the subtemporal group declined in verbal learning. Left side of surgery was associated with decline in naming regardless of approach. CONCLUSION: The main analysis did not confirm the effects of approach on memory outcome seen in our previous study. Post hoc testing, however, showed greater memory losses with the subtemporal approach. Previous findings were replicated for semantic fluency. The discrepant results are discussed on the background of the different study designs. PMID- 29273693 TI - The Christmas gift of genetic uncertainty. PMID- 29273692 TI - Efficacy of intensive aphasia therapy in patients with chronic stroke: a randomised controlled trial. AB - OBJECTIVE: Recent evidence has fuelled the debate on the role of massed practice in the rehabilitation of chronic post-stroke aphasia. Here, we further determined the optimal daily dosage and total duration of intensive speech-language therapy. METHODS: Individuals with chronic aphasia more than 1 year post-stroke received Intensive Language-Action Therapy in a randomised, parallel-group, blinded assessment, controlled trial. Participants were randomly assigned to one of two outpatient groups who engaged in either highly-intensive practice (Group I: 4 hours daily) or moderately-intensive practice (Group II: 2 hours daily). Both groups went through an initial waiting period and two successive training intervals. Each phase lasted 2 weeks. Co-primary endpoints were defined after each training interval. RESULTS: Thirty patients-15 per group-completed the study. A primary outcome measure (Aachen Aphasia Test) revealed no gains in language performance after the waiting period, but indicated significant progress after each training interval (gradual 2-week t-score change [CI]: 1.7 [+/-0.4]; 0.6 [+/-0.5]), independent of the intensity level applied (4-week change in Group I: 2.4 [+/-1.2]; in Group II: 2.2 [+/-0.8]). A secondary outcome measure (Action Communication Test) confirmed these findings in the waiting period and in the first training interval. In the second training interval, however, only patients with moderately-intensive practice continued to make progress (Time-by-Group interaction: P=0.009, eta2=0.13). CONCLUSIONS: Our results suggest no added value from more than 2 hours of daily speech-language therapy within 4 weeks. Instead, these results demonstrate that even a small 2-week increase in treatment duration contributes substantially to recovery from chronic post-stroke aphasia. PMID- 29273694 TI - 18F-FDG and Amyloid PET in Dementia. AB - We present a case of memory loss and aphasia in a 72-y-old man and discuss how PET imaging supported a diagnosis of Alzheimer dementia despite conflicting clinical findings. PMID- 29273696 TI - EDUCATORS' FORUM: WELCOME TO A NEW SECTION IN THE JNMT. PMID- 29273695 TI - Cardiac Displacement During 13N-Ammonia Myocardial Perfusion PET/CT: Comparison Between Adenosine- and Regadenoson-Induced Stress. AB - This study investigated differences in cardiac displacement during adenosine stress versus regadenoson stress in 13N-ammonia (13NH3) MP PET/CT scans. Methods: In total, 61 myocardial perfusion PET/CT scans were acquired using either adenosine (n = 30) or regadenoson (n = 31) as a stressor. For both groups, cardiac displacement during rest and stress was measured 3-dimensionally, relative to either a fixed reference frame or the previous frame, in each 1-min frame of a list-mode PET acquisition of 25 min. All stress scans were additionally evaluated for the presence of motion artifacts. Also, the tolerability of the agents and the occurrence of side effects were compared between groups. Results: Significantly larger cardiac displacement during stress was detected in the adenosine group than in the regadenoson group, reflected by both maximal cardiac displacement (P = 0.022) and mean cardiac displacement (P = 0.001). The duration of the movement was typically shorter in the regadenoson group. Frames with cardiac displacement of at least 5 mm were observed nearly twice as frequently when adenosine was used instead of regadenoson. Conclusion: The displacement during regadenoson stress is of lower amplitude and shorter duration than that during adenosine stress and may therefore contribute to a lower incidence of motion artifacts on PET/CT scans. PMID- 29273697 TI - Nuclear Medicine Technology Undergraduate Research Methods. AB - Introduction: The purpose of this article is to introduce nuclear medicine technology (NMT) educators to a method of incorporating research methodologies into the curriculum. Methods: The research methodology in the NMT program at Indiana University (IU) is taught in five steps (1. Introduction to research articles and statistics 2. Mock project and individual project design 3. Data collection 4. Writing the research paper 5. Presenting the abstract and mentoring new students). These steps could be combined for programs of shorter length or with credit hour restrictions. Results: All IU NMT students (100%) presented their research abstracts as part of a continuing education program for technologists. Seventeen of twenty-five (68%) presented their abstracts at a regional professional meeting. Six of twenty-five (24%) presented their research abstracts at a national professional meeting. Three of those six (50%) received travel grants. Two students submitted their research for publication and one was successful. Conclusion: The goal of incorporating a research methodology program into the nuclear medicine program should be to introduce undergraduates to the research process and instill excitement for new technologists to continue participation in research throughout their career. PMID- 29273698 TI - Effective Dose in Nuclear Medicine Studies and SPECT/CT: Dosimetry Survey Across Quebec Province. AB - The aims of the current study were to draw a portrait of the delivered dose in selected nuclear medicine studies in Quebec province and to assess the degree of change between an earlier survey performed in 2010 and a later survey performed in 2014. Methods: Each surveyed nuclear medicine department had to complete 2 forms: the first, about the administered activity in selected nuclear medicine studies, and the second, about the CT parameters used in SPECT/CT imaging, if available. The administered activities were converted into effective doses using the most recent conversion factors. Diagnostic reference levels were computed for each imaging procedure to obtain a benchmark for comparison. Results: The distributions of administered activity in various nuclear medicine studies, along with the corresponding distribution of the effective doses, were determined. Excluding 131I for thyroid studies, 67Ga-citrate for infectious workups, and combined stress and rest myocardial perfusion studies, the remainder of the 99mTc based studies delivered average effective doses clustered below 10 mSv. Between the 2010 survey and the 2014 survey, there was a statistically significant decrease in delivered dose from 18.3 to 14.5 mSv. 67Ga-citrate studies for infectious workups also showed a significant decrease in delivered dose from 31.0 to 26.2 mSv. The standardized CT portion of SPECT/CT studies yielded a mean effective dose 14 times lower than the radiopharmaceutical portion of the study. Conclusion: Between 2010 and 2014, there was a significant decrease in the delivered effective dose in myocardial perfusion and 67Ga-citrate studies. The CT portions of the surveyed SPECT/CT studies contributed a relatively small fraction of the total delivered effective dose. PMID- 29273699 TI - False-Positive Findings on Dopamine Transporter SPECT Due to Therapeutic Dextroamphetamine and Amphetamine. AB - Dopamine transporter SPECT is an accurate adjunct to clinical evaluation for Parkinson disease when the diagnosis is difficult. Dopaminergic medications may significantly affect dopamine transporter availability and, thus, uptake of dopamine transporter tracers. A patient had a false-positive dopamine transporter SPECT result while she was taking dextroamphetamine and amphetamine for attention deficit hyperactivity disorder. The SPECT findings normalized after amphetamine therapy was withheld. An accurate medication history combined with knowledge of drugs that interfere with dopamine transporter imaging is critical to ensure accuracy. PMID- 29273700 TI - Statistics Refresher for Molecular Imaging Technologists Part 1: Testing the Test. AB - Molecular imaging technologists are faced with statistics on a daily basis because they image patients who have been selected for diagnostic testing based on analysis of how well the test performs, and because technical factors can influence the performance of any diagnostic test. Choosing what test procedure to perform on which patient is a matter of understanding the patient's pretest likelihood of disease, the performance characteristics of the diagnostic test, and other clinical factors which may impact the usefulness of the results. Terms such as sensitivity, specificity, accuracy, and predictive value are used to describe how a diagnostic test performs, or how it compares to other diagnostic tests. While nuclear medicine and PET technologists study these concepts in training programs, applying this learning to daily patient care can be daunting given that new tracers and technologies are continuously moving into clinical practice. Research advances continue to challenge diagnostic paradigms with new patient populations, increasingly sophisticated technology, and the advent of large databases with which to study population outcomes. This article is part I of a two-part series. The purpose of this article is to provide a refresher about basic clinical statistics that are useful in understanding how diagnostic testing is optimally applied in the patient care setting. PMID- 29273701 TI - Impact of Nuclear Laboratory Personnel Credentials & Continuing Education on Nuclear Cardiology Laboratory Quality Operations. AB - Background/Objectives: The specific credentials and continuing education (CME/CE) of nuclear cardiology laboratory medical and technical staff are important factors in the delivery of quality imaging services that have not been systematically evaluated. Methods: Nuclear cardiology accreditation application data from the Intersocietal Accreditation Commission (IAC) was used to characterize facilities performing myocardial perfusion imaging by setting, size, previous accreditation and credentials of the medical and technical staff. Credentials and CME/CE were compared against initial accreditation decisions (grant or delay) using multivariable logistic regression. Results: Complete data were available for 1913 nuclear cardiology laboratories from 2011-2014. Laboratories with initial positive accreditation decisions had a greater prevalence of Certification Board in Nuclear Cardiology (CBNC) certified medical directors and specialty credentialed technical directors. Certification and credentials of the medical and technical directors, respectively, staff CME/CE compliance, and assistance of a consultant with the application were positively associated with accreditation decisions. Conclusion: Nuclear cardiology laboratories directed by CBNC-certified physicians and NCT- or PET-credentialed technologists were less likely to receive delay decisions for MPI. CME/CE compliance of both the medical and technical directors was associated with accreditation decision. Medical and technical directors' years of experience were not associated with accreditation decision. PMID- 29273702 TI - Goals of the SNMMI-TS Quality Committee. PMID- 29273703 TI - Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort. AB - Frailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. However, younger individuals (under 65 years) are less-studied in this respect. Also, the relationship between frailty and cause-specific mortality in community settings is understudied. We used a 42-item Rockwood-based frailty index (FI) in the Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks. The FI was independently associated with increased risk for all-cause mortality in younger (<65 years; HR per increase in one deficit 1.11, 95%CI 1.07-1.17) and older (>=65 years; HR 1.07, 95%CI 1.04-1.10) women and in younger men (HR 1.05, 95%CI 1.01-1.10). In cause-specific mortality analysis, the FI was strongly predictive of CVD mortality in women (HR per increase in one deficit 1.13, 95%CI 1.09-1.17), whereas in men the risk was restricted to deaths from other causes (HR 1.07, 95%CI 1.01-1.13). In conclusion, the FI is a strong mortality predictor especially among younger individuals and its associations with cause-specific mortality are sex-specific. PMID- 29273704 TI - Mitogen-activated protein kinases, Fus3 and Kss1, regulate chronological lifespan in yeast. AB - Using a systems-based approach, we have identified several genes not previously evaluated for a role(s) in chronological aging. Here, we have thoroughly investigated the chronological lifespan (CLS) of three of these genes (FUS3, KSS1 and HOG1) and their protein products, each of which have well-defined cell signaling roles in young cells. The importance of FUS3 and KSS1 in CLS are largely unknown and analyzed here for the first time. Using both qualitative and quantitative CLS assays, we show that deletion of any of the three MAPK's increases yeast lifespan. Furthermore, combined deletion of any MAPK and TOR1, most prominently fus3Delta/tor1Delta, produces a two-stage CLS response ending in lifespan increase greater than that of tor1Delta. Similar effects are achieved upon endogenous expression of a non-activatable form of Fus3. We speculate that the autophagy-promoting role of FUS3, which is inherently antagonistic to the role of TOR1, may in part be responsible for the differential aging phenotype of fus3Delta/tor1Delta. Consistent with this notion we show that nitrogen starvation, which promotes autophagy by deactivating Tor1, results in decreased CLS if FUS3 is deleted. Taken together, these results reveal a previously unrealized effect of mating-specific MAPKs in the chronological lifespan of yeast. PMID- 29273705 TI - High-Intensity Exercise Acutely Increases Substantia Nigra and Prefrontal Brain Activity in Parkinson's Disease. AB - BACKGROUND Pathologic alterations in resting-state brain activity patterns exist among individuals with Parkinson's disease (PD). Since physical exercise alters resting-state brain activity in non-PD populations and improves PD symptoms, we assessed the acute effect of exercise on resting-state brain activity in exercise trained individuals with PD. MATERIAL AND METHODS Resting-state functional magnetic resonance imaging (fMRI) was collected twice for 17 PD participants at the conclusion of an exercise intervention. The acute effect of exercise was examined for PD participants using the amplitude of low frequency fluctuation (ALFF) before and after a single bout of exercise. Correlations of clinical variables (i.e., PDQ-39 quality of life and MDS-UPDRS) with ALFF values were examined for the exercise-trained PD participants. RESULTS An effect of acute exercise was observed as an increased ALFF signal within the right ventromedial prefrontal cortex (PFC), left ventrolateral PFC, and bilaterally within the substantia nigra (SN). Quality of life was positively correlated with ALFF values within the vmPFC and vlPFC. CONCLUSIONS Given the role of the SN and PFC in motor and non-motor symptoms in PD, the acute increases in brain activity within these regions, if repeated frequently over time (i.e., exercise training), may serve as a potential mechanism underlying exercise-induced PD-specific clinical benefits. PMID- 29273706 TI - Delayed Diagnosis of Ureteral Injury Following Penetrating Abdominal Trauma: A Case Report and Review of the Literature. AB - BACKGROUND Ureteral injuries are considered to be uncommon in cases of trauma. The possibility of damage to the ureters may not be considered in the setting of acute trauma when life-threatening injuries take clinical management priority. A case of acute ureteral injury is described in a patient with acute penetrating gunshot abdominal injury that had a delay in diagnosis, with a review of the literature. CASE REPORT A 29-year-old woman presented to our hospital with a missed ureteral injury following a self-inflicted gunshot injury to the abdomen. She underwent abdominal computed tomography (CT) imaging and a retrograde pyelogram, which showed complete transection of the left upper ureter with contrast extravasation and the formation of a large urinoma. She underwent a percutaneous nephrostomy and drainage of the urinoma. An end-to-end ureteric anastomosis with excision of the intervening injured ureter, or ureteroureterostomy, was performed three weeks following the diagnosis. CONCLUSIONS Ureteral injuries following trauma are rare, but a delay in diagnosis can be associated with clinical morbidity. A high index of clinical suspicion is important for early identification of ureteral injury in cases of acute abdominal trauma. PMID- 29273707 TI - Pre-critical fluctuations and what they disclose about heterogeneous crystal nucleation. AB - Heterogeneous crystal nucleation is ubiquitous in nature and at the heart of many industrial applications. At the molecular scale, however, major gaps in understanding this phenomenon persist. Here we investigate through molecular dynamics simulations how the formation of precritical crystalline clusters is connected to the kinetics of nucleation. Considering heterogeneous water freezing as a prototypical scenario of practical relevance, we find that precritical fluctuations connote which crystalline polymorph will form. The emergence of metastable phases can thus be promoted by templating crystal faces characteristic of specific polymorphs. As a consequence, heterogeneous classical nucleation theory cannot describe our simulation results, because the different substrates lead to the formation of different ice polytypes. We discuss how the issue of polymorphism needs to be incorporated into analysis and comparison of heterogeneous and homogeneous nucleation. Our results will help to interpret and analyze the growing number of experiments and simulations dealing with crystal polymorph selection. PMID- 29273708 TI - Rainbow peacock spiders inspire miniature super-iridescent optics. AB - Colour produced by wavelength-dependent light scattering is a key component of visual communication in nature and acts particularly strongly in visual signalling by structurally-coloured animals during courtship. Two miniature peacock spiders (Maratus robinsoni and M. chrysomelas) court females using tiny structured scales (~ 40 * 10 MUm2) that reflect the full visual spectrum. Using TEM and optical modelling, we show that the spiders' scales have 2D nanogratings on microscale 3D convex surfaces with at least twice the resolving power of a conventional 2D diffraction grating of the same period. Whereas the long optical path lengths required for light-dispersive components to resolve individual wavelengths constrain current spectrometers to bulky sizes, our nano-3D printed prototypes demonstrate that the design principle of the peacock spiders' scales could inspire novel, miniature light-dispersive components. PMID- 29273710 TI - Urinary potassium is a potential biomarker of disease activity in Ulcerative colitis and displays in vitro immunotolerant role. AB - We evaluated the in-vitro effect of potassium on CD4+ T cells and the role of urinary potassium as a potential biomarker of disease activity in patients with ulcerative colitis (UC). This prospective observational cohort study included healthy controls (n = 18) and UC patients [n = 30, median age: 40 (IQR: 28-46) years, 17 males)] with active disease(assessed by Mayo score) from September 2015 May 2016. Twenty-four hours urinary potassium along with fecal calprotectin (FCP) were estimated in UC patients (at baseline and follow-up after 3-6 months) and controls. In healthy volunteers, we also assessed the effect of potassium on CD4+ T cells differentiated in the presence of Th17 polarizing condition. UC patients had significantly higher FCP (368.2 +/- 443.04 vs 12.44 +/- 27.51, p < 0.001) and significantly lower urinary potassium (26.6 +/- 16.9 vs 46.89 +/- 35.91, p = 0.01) levels than controls. At follow-up, a significant increase in urinary potassium among patients who had clinical response [n = 22, 21.4 (14.4-39.7) to 36.5 (20.5-61.6), p = 0.04] and remission [n = 12, 18.7 (9.1-34.3) to 36.5 (23.4 70.5), p = 0.05] was accompanied with a parallel decline in FCP. On in-vitro analysis, potassium under Th17 polarizing conditions significantly inhibited IL 17 and interferon-[Formula: see text] expression while favoring the induction of FoxP3+ T cells. Therefore, urinary potassium levels are inversely associated with disease activity in UC with in-vitro data supporting an immune-tolerant role of potassium. PMID- 29273709 TI - Protein conformational flexibility modulates kinetics and thermodynamics of drug binding. AB - Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery. PMID- 29273711 TI - LUCS (Light-Up Cell System), a universal high throughput assay for homeostasis evaluation in live cells. AB - Observations of fluorescent cyanine dye behavior under illumination at 500 nm lead to a novel concept in cell biology allowing the development of a new live cell assay called LUCS, for Light-Up Cell System, measuring homeostasis in live cells. Optimization of the LUCS process resulted in a standardized, straightforward and high throughput assay with applications in toxicity assessment. The mechanisms of the LUCS process were investigated. Electron Paramagnetic Resonance experiments showed that the singlet oxygen and hydroxyl radical are involved downstream of the light effect, presumably leading to deleterious oxidative stress that massively opens access of the dye to its intracellular target. Reversible modulation of LUCS by both verapamil and proton availability indicated that plasma membrane proton/cation antiporters, possibly of the MATE drug efflux transport family, are involved. A mechanistic model is presented. Our data show that intracellular oxidation can be controlled by tuning light energy, opening applications in regulatory purposes, anti-oxidant research, chemotherapy efficacy and dynamic phototherapy strategies. PMID- 29273712 TI - Lack of acclimatization to chronic hypoxia in humans in the Antarctica. AB - The study was carried out at Concordia Station (Antarctic Plateau). The aim was to investigate the respiratory and haematological responses to hypoxia in healthy subjects living at constant altitude. Thirteen men and women (34.1 +/- 3.1 years) were exposed for 10 months to hypobaric hypoxia (oxygen level equivalent to 3800 m asl). These unique conditions enable a greater accuracy of monitoring human responses to chronic hypoxia than can be achieved elsewhere. Blood haemoglobin and erythropoietin concentrations were determined at sea level (Pre), and after 3, 7, 20, 90 and 300 days at altitude. Blood gas analysis, base excess and arterial oxygen saturation were measured at Pre, and after 150 and 300 days at altitude. Erythropoietin returned quickly to baseline level after a transient increase in the first days. Blood haemoglobin concentration started increasing at day 7 and remained markedly higher for the entire duration of the mission. At day 150 the blood carbon dioxide partial pressure was markedly reduced, and consequently blood pH remained higher at negative base excess until day 300. The arterial oxygen saturation remained lower than Pre throughout. In conclusion, humans display little capacity of hypoxia acclimatization even after ten months of constant exposure to low oxygen partial pressure. PMID- 29273713 TI - Ferromagnetic Phase in Nonequilibrium Quantum Dots. AB - By nonperturbatively solving the nonequilibrium Anderson two-impurity model with the hierarchical equations of motion approach, we report a robust ferromagnetic (FM) phase in series-coupled double quantum dots, which can suppress the antiferromagnetic (AFM) phase and dominate the phase diagram at finite bias and detuning energy in the strongly correlated limit. The FM exchange interaction origins from the passive parallel spin arrangement caused by the Pauli exclusion principle during the electrons transport. At very low temperature, the Kondo screening of the magnetic moment in the FM phase induces some nonequilibrium Kondo effects in magnetic susceptibility, spectral functions and current. In the weakly correlated limit, the AFM phase is found still stable, therefore, a magnetic-field-free internal control of spin states can be expected through the continuous FM-AFM phase transition. PMID- 29273714 TI - Electron beam induced removal of PMMA layer used for graphene transfer. AB - We demonstrate the development of an effective technique to remove the poly methyl methacrylate (PMMA) layer used for transferring graphene synthesized by a chemical vapor deposition (CVD). This was achieved utilizing electron-beam bombardment and following developing processes, prior to the use of conventional organic solvents. Field-effect transistors were fabricated on the transferred graphene in order to explore their Dirac points and carrier motilities in the ambient condition - the results were then compared with those from the conventional wet chemical treatment. It was found that the Dirac points were located close to the zero gate bias when compared to those from the acetone and the acetic acid treatments. Most significantly, the field-effect mobility reached as high as 6770 cm2/Vs and 7350 cm2/Vs on average for holes and electrons, respectively, which is more than seven times improvement in comparison to conventional acetone treatments for CVD-grown graphene devices. PMID- 29273715 TI - Type-II Dirac semimetal stabilized by electron-phonon coupling. AB - There is major interest, in condensed matter physics, in understanding the role of topology: remarkable progress has been made in classifying topological properties of non-interacting electrons, and on understanding the interplay between topology and electron-electron interactions. We extend such studies to interactions with the lattice, and predict non-trivial topological effects in infinitely long-lived polaron bands. Specifically, for a two-dimensional many band model with realistic electron-phonon coupling, we verify that sharp level crossings are possible for polaron eigenstates, and prove that they are responsible for a novel type of sharp transition in the ground state of the polaron that can occur at a fixed momentum. Furthermore, they result in the appearance of Dirac cones stabilized by electron-phonon coupling. Thus, electron phonon coupling opens an avenue to create and control Dirac and Weyl semimetals. PMID- 29273716 TI - Effects of prey density, temperature and predator diversity on nonconsumptive predator-driven mortality in a freshwater food web. AB - Nonconsumptive predator-driven mortality (NCM), defined as prey mortality due to predation that does not result in prey consumption, is an underestimated component of predator-prey interactions with possible implications for population dynamics and ecosystem functioning. However, the biotic and abiotic factors influencing this mortality component remain largely unexplored, leaving a gap in our understanding of the impacts of environmental change on ecological communities. We investigated the effects of temperature, prey density, and predator diversity and density on NCM in an aquatic food web module composed of dragonfly larvae (Aeshna cyanea) and marbled crayfish (Procambarus fallax f. virginalis) preying on common carp (Cyprinus carpio) fry. We found that NCM increased with prey density and depended on the functional diversity and density of the predator community. Warming significantly reduced NCM only in the dragonfly larvae but the magnitude depended on dragonfly larvae density. Our results indicate that energy transfer across trophic levels is more efficient due to lower NCM in functionally diverse predator communities, at lower resource densities and at higher temperatures. This suggests that environmental changes such as climate warming and reduced resource availability could increase the efficiency of energy transfer in food webs only if functionally diverse predator communities are conserved. PMID- 29273717 TI - Strain profiling and epidemiology of bacterial species from metagenomic sequencing. AB - Microbial communities are often composed by complex mixtures of multiple strains of the same species, characterized by a wide genomic and phenotypic variability. Computational methods able to identify, quantify and classify the different strains present in a sample are essential to fully exploit the potential of metagenomic sequencing in microbial ecology, with applications that range from the epidemiology of infectious diseases to the characterization of the dynamics of microbial colonization. Here we present a computational approach that uses the available genomic data to reconstruct complex strain profiles from metagenomic sequencing, quantifying the abundances of the different strains and cataloging them according to the population structure of the species. We validate the method on synthetic data sets and apply it to the characterization of the strain distribution of several important bacterial species in real samples, showing how its application provides novel insights on the structure and complexity of the microbiota. PMID- 29273718 TI - Successful reconstruction of whole mitochondrial genomes from ancient Central America and Mexico. AB - The northern and southern peripheries of ancient Mesoamerica are poorly understood. There has been speculation over whether borderland cultures such as Greater Nicoya and Casas Grandes represent Mesoamerican outposts in the Isthmo Colombian area and the Greater Southwest, respectively. Poor ancient DNA preservation in these regions challenged previous attempts to resolve these questions using conventional genetic techniques. We apply advanced in-solution mitogenome capture and high-throughput sequencing to fourteen dental samples obtained from the Greater Nicoya sites of Jicaro and La Cascabel in northwest Costa Rica (n = 9; A.D. 800-1250) and the Casas Grandes sites of Paquime and Convento in northwest Mexico (n = 5; A.D. 1200-1450). Full mitogenome reconstruction was successful for three individuals from Jicaro and five individuals from Paquime and Convento. The three Jicaro individuals belong to haplogroup B2d, a haplogroup found today only among Central American Chibchan speakers. The five Paquime and Convento individuals belong to haplogroups C1c1a, C1c5, B2f and B2a which, are found in contemporary populations in North America and Mesoamerica. We report the first successfully reconstructed ancient mitogenomes from Central America, and the first genetic evidence of ancestry affinity of the ancient inhabitants of Greater Nicoya and Casas Grandes with contemporary Isthmo-Columbian and Greater Southwest populations, respectively. PMID- 29273719 TI - Resequencing of the Leishmania infantum (strain JPCM5) genome and de novo assembly into 36 contigs. AB - Leishmania parasites are the causative of leishmaniasis, a group of potentially fatal human diseases. Control strategies for leishmaniasis can be enhanced by genome based investigations. The publication in 2005 of the Leishmania major genome sequence, and two years later the genomes for the species Leishmania braziliensis and Leishmania infantum were major milestones. Since then, the L. infantum genome, although highly fragmented and incomplete, has been used widely as the reference genome to address whole transcriptomics and proteomics studies. Here, we report the sequencing of the L. infantum genome by two NGS methodologies and, as a result, the complete genome assembly on 36 contigs (chromosomes). Regarding the present L. infantum genome-draft, 495 new genes have been annotated, a hundred have been corrected and 75 previous annotated genes have been discontinued. These changes are not only the result of an increase in the genome size, but a significant contribution derives from the existence of a large number of incorrectly assembled regions in current chromosomal scaffolds. Furthermore, an improved assembly of tandemly repeated genes has been obtained. All these analyses support that the de novo assembled L. infantum genome represents a robust assembly and should replace the currently available in the databases. PMID- 29273720 TI - Access to stereodefined (Z)-allylsilanes and (Z)-allylic alcohols via cobalt catalyzed regioselective hydrosilylation of allenes. AB - Hydrosilylation of allenes is the addition of a hydrogen atom and a silyl group to a carbon-carbon double bond of an allene molecule and represents a straightforward and atom-economical approach to prepare synthetically versatile allylsilanes and vinylsilanes. However, this reaction generally produces six possible isomeric organosilanes, and the biggest challenge in developing this reaction is to control both regioselectivity and stereoselectivity. The majorities of the developed allene hydrosilylation reactions show high selectivity towards the production of vinylsilanes or branched allylsilanes. By employing a cobalt catalyst generated from readily available and bench-stable cobalt precursor and phosphine-based ligands, here we show that this reaction proceeds under mild conditions in a regioselective and stereoselective manner, and affords synthetically challenging, but valuable linear cis-allylsilanes with excellent stereoselectivity (generally cis to trans ratios: >98:2). This cobalt catalyzed (Z)-selective allene hydrosilylation provides a general approach to access molecules containing stereodefined (Z)-alkene units. PMID- 29273721 TI - Topographical diversity of common skin microflora and its association with skin environment type: An observational study in Chinese women. AB - This study evaluated cutaneous microbial distribution, and microbial co occurrence at different body sites and skin environments in Chinese women (39.6 +/- 11.9 years, N = 100) during the winter season. Microbial distribution (Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis, Lactobacillus, Pseudomonadaceae, and Malassezia furfur), association with biomarkers (antimicrobial peptides: LL-37, beta-defensins [HBD-2, HBD-3]), and claudin-1) and skin biophysical parameters (transepidermal water loss, pH, skin scaliness and roughness, sebum and hydration levels) were also determined. Skin sites (glabella [GL], hand-back [HB], interdigital web-space [IS], antecubital fossa [AF], volar forearm [VF], back [BA]) were classified as normal, oily or dry based on two-step cluster analysis and exposed or unexposed (uncovered or covered by clothes, respectively) based on seasonal apparel. Pseudomonadaceae and Staphylococcus aureus had the highest and lowest detection rate respectively at all sites. Cluster analysis identified skin sites as 'normal' (HB, BA, AF, VF), 'dry' (IS) and 'oily' (GL). Bacterial alpha diversity was higher in exposed (HB, IS, and GL) compared with unexposed sites (BA, AF and VF). Co-occurrence of Staphylococcus aureus with any of the other five microorganisms was lower in dry and oily skin versus normal skin. Skin exposure, biophysical/barrier profile and biomarkers were found to be associated with bacterial distribution and co occurrence. PMID- 29273722 TI - Cell Assembly in Self-foldable Multi-layered Soft Micro-rolls. AB - Multi-layered thin films with heterogeneous mechanical properties can be spontaneously transformed to realise various three-dimensional (3D) geometries. Here, we describe micro-patterned all-polymer films called micro-rolls that we use for encapsulating, manipulating, and observing adherent cells in vitro. The micro-rolls are formed of twin-layered films consisting of two polymers with different levels of mechanical stiffness; therefore they can be fabricated by using the strain engineering and a self-folding rolling process. By controlling the strain of the films geometrically, we can achieve 3D tubular architectures with controllable diameters. Integration with a batch release of sacrificial hydrogel layers provides a high yield and the biocompatibility of the micro-rolls with any length in the release process without cytotoxicity. Thus, the multiple cells can be wrapped in individual micro-rolls and artificially reconstructed into hollow or fibre-shaped cellular 3D constructs that possess the intrinsic morphologies and functions of living tissues. This system can potentially provide 3D bio-interfaces such as those needed for reconstruction and assembly of functional tissues and implantable tissue grafts. PMID- 29273723 TI - Dehydrogenative desaturation-relay via formation of multicenter-stabilized radical intermediates. AB - In organic molecules, the reactivity at the carbon atom next to the functional group is dramatically different from that at other carbon atoms. Herein, we report that a versatile copper-catalyzed method enables successive dehydrogenation or dehydrogenation of ketones, aldehydes, alcohols, alpha,beta unsaturated diesters, and N-heterocycles to furnish stereodefined conjugated dienecarbonyls, polyenecarbonyls, and nitrogen-containing heteroarenes. On the basis of mechanistic studies, the copper-catalyzed successive dehydrogenation process proceeds via the initial alpha,beta-desaturation followed by further dehydrogenative desaturation of the resultant enone intermediate, demonstrating that the reactivity at alpha-carbon is transferred through carbon-carbon double bond or longer pi-system to the carbon atoms at the positions gamma, epsilon, and eta to carbonyl groups. The dehydrogenative desaturation-relay is ascribed to the formation of an unusual radical intermediate stabilized by 5- or 7,- or 9-center pi-systems. The discovery of successive dehydrogenation may open the door to functionalizations of the positions distant from functional groups in organic molecules. PMID- 29273724 TI - Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation. AB - Prevalence of pancreatic ductal carcinoma (PDC) is nearly twice in patients with diabetes mellitus, but the reason for this close association remains obscure. Recently promoter methylation of E-cadherin1 (CDH1) and CDKN2A genes, encoding E cadherin and P16 respectively, are invoked in development of PDC. It is still unclear whether diabetes affects such epigenetic changes and malignant behavior in PDC. In this study, we studied whether diabetes influences the clinico pathological profile and methylation status of CDH1 and CDKN2A genes in patients with PDC. PDC subjects were divided into 3 groups; 59 cases without diabetes (non DM), 17 cases with short-term diabetes (short-DM)(diabetes duration 3 yrs>) and 33 cases with long-term diabetes (long-DM)(?3 yrs). Compared to non-DM or short DM, long-DM was associated with a higher histological grade of malignancy and a higher tumor stage. Promoter methylation of both CDH1 and CDKN2A was encountered more frequently in PDC patients with long-DM than non-DM or short DM. Cases with CDH1 promoter methylation showed reduced E-cadherin expression and worsened survival. We consider that the presence of long-DM has a negative impact on the prognosis of PDC patients which may be relevant to a high frequency of promoter methylation of CDH1. PMID- 29273725 TI - Functional shift with maintained regenerative potential following portal vein ligation. AB - Selective portal vein ligation (PVL) allows the two-stage surgical resection of primarily unresectable liver tumours by generating the atrophy and hypertrophy of portally ligated (LL) and non-ligated lobes (NLL), respectively. To evaluate critically important underlying functional alterations, present study characterised in vitro and vivo liver function in male Wistar rats (n = 106; 210 250 g) before, and 24/48/72/168/336 h after PVL. Lobe weights and volumes by magnetic resonance imaging confirmed the atrophy-hypertrophy complex. Proper expression and localization of key liver transporters (Ntcp, Bsep) and tight junction protein ZO-1 in isolated hepatocytes demonstrated constantly present viable and well-polarised cells in both lobes. In vitro taurocholate and bilirubin transport, as well as in vivo immunohistochemical Ntcp and Mrp2 expressions were bilaterally temporarily diminished, whereas LL and NLL structural acinar changes were divergent. In vivo bile and bilirubin-glucuronide excretion mirrored macroscopic changes, whereas serum bilirubin levels remained unaffected. In vivo functional imaging (indocyanine-green clearance test; 99mTc mebrofenin hepatobiliary scintigraphy; confocal laser endomicroscopy) indicated transitionally reduced global liver uptake and -excretion. While LL functional involution was permanent, NLL uptake and excretory functions recovered excessively. Following PVL, functioning cells remain even in LL. Despite extensive bilateral morpho-functional changes, NLL functional increment restores temporary declined transport functions, emphasising liver functional assessment. PMID- 29273726 TI - delta-Subunit Containing GABAA Receptors Modulate Respiratory Networks. AB - Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic delta-subunit containing GABAA receptors (deltaGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of deltaGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function in the preBotzinger Complex (preBotC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBotC deltaGABAARs in anesthetized rats and wild-type mice decreased breathing rate. In deltaGABAAR knockout (Gabrd -/-) mice, however, deltaGABAARs activation had no effect on breathing rate. We then found that during active wakefulness associated with behaviors and movements, diaphragm activation was higher in the Gabrd -/- compared to wild-type mice, but not in other states. These findings identify that deltaGABAARs modulate the respiratory network, which is critical to understand how deltaGABAARs change breathing in pathological conditions affecting extra-synaptic GABAA receptor function such as exposure to anesthetics and neurosteroids. PMID- 29273727 TI - Radiosensitization of Prostate Cancers In Vitro and In Vivo to Erbium-filtered Orthovoltage X-rays Using Actively Targeted Gold Nanoparticles. AB - Theoretical investigations suggest that gold nanoparticle (GNP)-mediated radiation dose enhancement and radiosensitization can be maximized when photons interact with gold, predominantly via photoelectric absorption. This makes ytterbium (Yb)-169, which emits photons with an average energy of 93 keV (just above the K-edge of gold), an ideal radioisotope for such purposes. This investigation tests the feasibility of tumor-specific prostate brachytherapy achievable with Yb-169 and actively targeted GNPs, using an external beam surrogate of Yb-169 created from an exotic filter material - erbium (Er) and a standard copper-filtered 250 kVp beam. The current in vitro study shows that treatment of prostate cancer cells with goserelin-conjugated gold nanorods (gGNRs) promotes gonadotropin releasing hormone receptor-mediated internalization and enhances radiosensitivity to both Er-filtered and standard 250 kVp beams, 14 and 10%, respectively. While the degree of GNP-mediated radiosensitization as seen from the in vitro study may be considered moderate, the current in vivo study shows that gGNR treatment plus Er-filtered x-ray irradiation is considerably more effective than radiation treatment alone (p < 0.0005), resulting in a striking reduction in tumor volume (50% smaller) 2 months following treatment. Overall, the current results provide strong evidence for the feasibility of tumor-specific prostate brachytherapy with Yb-169 and gGNRs. PMID- 29273728 TI - Allopurinol and risk of benign prostatic hyperplasia in a Finnish population based cohort. AB - BACKGROUND: Metabolic syndrome and obesity are linked with hyperuricemia, and it has also been proposed that oxidative stress associated with hyperuricemia may promote benign prostatic hyperplasia (BPH). However, it is currently unknown whether use of antihyperuricemic medication is associated with risk of developing BPH. We studied the association between BPH and use of antihyperuricemic allopurinol in a Finnish population-based cohort. METHODS: The study cohort consisted of 74,754 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Information on gout and BPH medication usage (5alpha-reductase inhibitors, 5ARIs) during 1996-2014 was obtained from the National medication reimbursement database. Information on BPH diagnoses from in- and outpatient hospital visits and BPH-related surgery was obtained from the National Health Care Registry. Men with a record of BPH at baseline was excluded. We used Cox regression to analyze risk of starting BPH medication, having a recorded diagnosis or undergoing BPH surgery by allopurinol use with adjustment for age and simultaneous use of statins, antidiabetic or antihypertensive drugs and aspirin or other NSAIDs. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. RESULTS: Men using allopurinol had a decreased risk for all three BPH endpoints: BPH medication (HR 0.81; 95% CI 0.75 0.88), BPH diagnosis (HR 0.78; 95% CI 0.71-0.86) and BPH-related surgery (HR 0.67; 95% CI 0.58-0.76) after multivariable adjustment. The risk association did not change by cumulative use. The risk decrease disappeared after 1-2 years lag time. Only BMI modified the risk association; the risk decrease was observed only among men with BMI above the median (27.3 kg/m2); p for interaction <0.05 for each endpoint. CONCLUSIONS: We found that allopurinol use is associated with lowered risk of BPH medication, diagnosis and surgery. A possible explanation could be antioxidative effects of urate-lowering allopurinol. PMID- 29273729 TI - Antimicrobial peptide capsids of de novo design. AB - The spread of bacterial resistance to antibiotics poses the need for antimicrobial discovery. With traditional search paradigms being exhausted, approaches that are altogether different from antibiotics may offer promising and creative solutions. Here, we introduce a de novo peptide topology that-by emulating the virus architecture-assembles into discrete antimicrobial capsids. Using the combination of high-resolution and real-time imaging, we demonstrate that these artificial capsids assemble as 20-nm hollow shells that attack bacterial membranes and upon landing on phospholipid bilayers instantaneously (seconds) convert into rapidly expanding pores causing membrane lysis (minutes). The designed capsids show broad antimicrobial activities, thus executing one primary function-they destroy bacteria on contact. PMID- 29273730 TI - The F-box protein FKF1 inhibits dimerization of COP1 in the control of photoperiodic flowering. AB - In Arabidopsis thaliana, CONSTANS (CO) plays an essential role in the regulation of photoperiodic flowering under long-day conditions. CO protein is stable only in the afternoon of long days, when it induces the expression of FLOWERING LOCUS T (FT), which promotes flowering. The blue-light photoreceptor FLAVIN-BINDING, KELCH REPEAT, F-BOX1 (FKF1) interacts with CO and stabilizes it by an unknown mechanism. Here, we provide genetic and biochemical evidence that FKF1 inhibits CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1)-dependent CO degradation. Light-activated FKF1 has no apparent effect on COP1 stability but can interact with and negatively regulate COP1. We show that FKF1 can inhibit COP1 homo-dimerization. Mutation of the coiled-coil domain in COP1, which prevents dimer formation, impairs COP1 function in coordinating flowering time. Based on these results, we propose a model whereby the light- and day length-dependent interaction between FKF1 and COP1 controls CO stability to regulate flowering time. PMID- 29273731 TI - GAREM1 regulates the PR interval on electrocardiograms. AB - PR interval is the period from the onset of P wave to the start of the QRS complex on electrocardiograms. A recent genomewide association study (GWAS) suggested that GAREM1 was linked to the PR interval on electrocardiograms. This study was designed to validate this correlation using additional subjects and examined the function of Garem1 in a mouse model. We analyzed the association of rs17744182, a variant in the GAREM1 locus, with the PR interval in 5646 subjects who were recruited from 2 Korean replication sets, Yangpyeong (n = 2471) and Yonsei (n = 3175), and noted a significant genomewide association by meta analysis (P = 2.39 * 10-8). To confirm the function of Garem1 in mice, Garem1 siRNA was injected into mouse tail veins to reduce the expression of Garem1. Garem1 transcript levels declined by 53% in the atrium of the heart (P = 0.029), and Garem1-siRNA injected mice experienced a significant decrease in PR interval (43.27 ms vs. 44.89 ms in control, P = 0.007). We analyzed the expression pattern of Garem1 in the heart by immunohistology and observed specific expression of Garem1 in intracardiac ganglia. Garem1 was expressed in most neurons of the ganglion, including cholinergic and adrenergic cells. We have provided evidence that GAREM1 is involved in the PR interval of ECGs. These findings increase our understanding of the regulatory signals of heart rhythm through intracardiac ganglia of the autonomic nervous system and can be used to guide the development of a therapeutic target for heart conditions, such as atrial fibrillation. PMID- 29273732 TI - Decisional conflict and regret: shared decision-making about pregnancy affected by beta-thalassemia major in Southeast of Iran. AB - To study the effect of shared decision-making (SDM) on decisional conflict (DC) scores immediately after consultation and to assess the decisional regret (DR) scores in the first 3 months following women's decision regarding termination of pregnancy. This quasi-experimental study was conducted during August 3rd-February 20th, 2016. We included 80 women whose fetuses were diagnosed with beta thalassemia major (beta-TM) through chorionic villi sampling and were referred to the only prenatal diagnosis center at Ali-Asghar Hospital, Zahedan, Iran. While the control group went through the routine procedures, the intervention group received a 90-min counseling session based on SDM. The demographic characteristics form and DC scale were filled out immediately after the consultation session. After 3 months, the women were contacted via telephone call to collect data on their level of DR. The mean DC score was significantly (P = < 0.0025) lower in the intervention group (8.47 +/- 4.63) compared with the control group (44.10 +/- 14.5). Moreover, the mean score of DR was significantly (P = 0.004) lower in the intervention group (9.37 +/- 15.44) compared with the control group (24.37 +/- 23.42). SDM consultation can help women experience significantly lower levels of DC and DR. PMID- 29273733 TI - Knockdown of long non-coding RNA H19 inhibits multiple myeloma cell growth via NF kappaB pathway. AB - Long non-coding RNAs (lncRNAs) are implicated in the complex network of cancer including Multiple myeloma (MM) and play important roles in tumor development. lncH19 was significantly up-regulated in multiple cancer types, suggesting it is a potential oncogene. However, the exact functions and downstream mechanisms are largely unknown. This study aimed to investigate whether H19 participates in the cell growth of MM and elucidate the underlying mechanism. We found that H19 was abnormally overexpressed in MM cell lines and sorted CD138+ MM bone marrow tissues. H19 knockdown induced by shRNA transfection significantly inhibited proliferation, viability and colony formation in MM cells, as well as inactivated NF-kappaB pathway. Moreover, combination treatment of H19 knockdown and NF-kappaB suppression (induced by specific inhibitor PDTC) produced synergistically inhibitory effects. Bone marrow expression of H19 was positively associated with circulating IL-6 or IL-8 level in the same MM patients. And patients with high expression of H19 had a lower survival rate. Taken together, we confirmed the abnormal upregulation of a novel lncRNA, H19, in human MM. H19 was involved in MM cell growth. The linkage between H19 and NF-kappaB pathway may provide a novel interpretation for the mechanism of H19's growth regulation in MM. PMID- 29273734 TI - RNA-Seq reveals seven promising candidate genes affecting the proportion of thick egg albumen in layer-type chickens. AB - Eggs with a much higher proportion of thick albumen are preferred in the layer industry, as they are favoured by consumers. However, the genetic factors affecting the thick egg albumen trait have not been elucidated. Using RNA sequencing, we explored the magnum transcriptome in 9 Rhode Island white layers: four layers with phenotypes of extremely high ratios of thick to thin albumen (high thick albumen, HTA) and five with extremely low ratios (low thick albumen, LTA). A total of 220 genes were differentially expressed, among which 150 genes were up-regulated and 70 were down-regulated in the HTA group compared with the LTA group. Gene Ontology (GO) analysis revealed that the up-regulated genes in HTA were mainly involved in a wide range of regulatory functions. In addition, a large number of these genes were related to glycosphingolipid biosynthesis, focal adhesion, ECM-receptor interactions and cytokine-cytokine receptor interactions. Based on functional analysis, ST3GAL4, FUT4, ITGA2, SDC3, PRLR, CDH4 and GALNT9 were identified as promising candidate genes for thick albumen synthesis and metabolism during egg formation. These results provide new insights into the molecular mechanisms of egg albumen traits and may contribute to future breeding strategies that optimise the proportion of thick egg albumen. PMID- 29273735 TI - The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling. AB - Splenic marginal zone B cells (MZB) shuttle between the blood-filled marginal zone for antigen collection and the follicle for antigen delivery. However, it is unclear how MZBs migrate directionally from the marginal zone to the follicle. Here, we show that murine MZBs migrate up shear flow via the LFA-1 (alphaLbeta2) integrin ligand ICAM-1, but adhere or migrate down the flow via the VLA-4 integrin (alpha4beta1) ligand VCAM-1. MZBs lacking Arhgef6 (Pak-interacting exchange factor (alphaPIX)) or functional LFA-1 are impaired in shuttling due to mislocalization toward the VCAM-1-rich red pulp. Sphingosine-1-phosphate (S1P) signaling through the S1PR3 receptor inhibits MZB migration up the flow, and deletion of S1pr3 in Arhgef6 -/- mice rescues mislocalized MZBs. These findings establish shear flow as a directional cue for MZB migration to the follicle, and define S1PR3 and VCAM-1 as counteracting forces that inhibit this migration. PMID- 29273737 TI - Hydrolytic activity determination of Tail Tubular Protein A of Klebsiella pneumoniae bacteriophages towards saccharide substrates. AB - In this paper, the enzymatic activity, substrate specificity and antibiofilm feature of bacteriophage dual-function tail proteins are presented. So far, tail tubular proteins A-TTPAgp31 and TTPAgp44-have been considered as structural proteins of Klebsiella pneumoniae bacteriophages KP32 and KP34, respectively. Our results show that TTPAgp31 is able to hydrolyze maltose as well as Red-starch. The activity of 1 uM of the protein was calculated as 47.6 milli-Units/assay relating to the alpha-amylase activity. It degrades capsular polysaccharides (cPS), slime polysaccharides (sPS) and lipopolysaccharide (LPS) of K. pneumoniae PCM 2713 and shows antibiofilm reactivity towards S. aureus PCM 519 and E. faecalis PCM 2673. TTPAgp44 hydrolyses trehalose and cPS of E. faecium PCM 1859. TTPAgp44's activity was also observed in the antibiofilm test against P. aeruginosa PCM 2710 and B. subtilis PCM 2021. TTPAgp31 has been identified as alpha-1,4-glucosidase whereas, TTPAgp44 exhibits trehalase-like activity. Both proteins contain aspartate and glutamate residues in the beta-stranded region which are essential for catalytic activity of glycoside hydrolases. The significant novelty of our results is that for the first time the bacteriophage tubular proteins are described as the unique enzymes displaying no similarity to any known phage hydrolases. They can be used as antibacterial agents directed against bacterial strains producing exopolysaccharides and forming a biofilm. PMID- 29273736 TI - VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses. AB - Glutamate is the major excitatory transmitter in the vertebrate nervous system. To maintain synaptic efficacy, recycling synaptic vesicles (SV) are refilled with glutamate by vesicular glutamate transporters (VGLUTs). The dynamics and mechanism of glutamate uptake in intact neurons are still largely unknown. Here, we show by live-cell imaging with pH- and chloride-sensitive fluorescent probes in cultured hippocampal neurons of wild-type and VGLUT1-deficient mice that in SVs VGLUT functions as a glutamate/proton exchanger associated with a channel like chloride conductance. After endocytosis most internalized Cl- is substituted by glutamate in an electrically, and presumably osmotically, neutral manner, and this process is driven by both the Cl- gradient itself and the proton motive force provided by the vacuolar H+-ATPase. Our results shed light on the transport mechanism of VGLUT under physiological conditions and provide a framework for how modulation of glutamate transport via Cl- and pH can change synaptic strength. PMID- 29273738 TI - Generic wound signals initiate regeneration in missing-tissue contexts. AB - Despite the identification of numerous regulators of regeneration in different animal models, a fundamental question remains: why do some wounds trigger the full regeneration of lost body parts, whereas others resolve by mere healing? By selectively inhibiting regeneration initiation, but not the formation of a wound epidermis, here we create headless planarians and finless zebrafish. Strikingly, in both missing-tissue contexts, injuries that normally do not trigger regeneration activate complete restoration of heads and fin rays. Our results demonstrate that generic wound signals have regeneration-inducing power. However, they are interpreted as regeneration triggers only in a permissive tissue context: when body parts are missing, or when tissue-resident polarity signals, such as Wnt activity in planarians, are modified. Hence, the ability to decode generic wound-induced signals as regeneration-initiating cues may be the crucial difference that distinguishes animals that regenerate from those that cannot. PMID- 29273739 TI - Crude phosphorylation mixtures containing racemic lipid amphiphiles self-assemble to give stable primitive compartments. AB - It is an open question how the chemical structure of prebiotic vesicle-forming amphiphiles complexified to produce robust primitive compartments that could safely host foreign molecules. Previous work suggests that comparingly labile vesicles composed of plausibly prebiotic fatty acids were eventually chemically transformed with glycerol and a suitable phosphate source into phospholipids that would form robust vesicles. Here we show that phosphatidic acid (PA) and phosphatidylethanolamine (PE) lipids can be obtained from racemic dioleoyl glycerol under plausibly prebiotic phosphorylation conditions. Upon in situ hydration of the crude phosphorylation mixtures only those that contained rac DOPA (not rac-DOPE) generated stable giant vesicles that were capable of encapsulating water-soluble probes, as evidenced by confocal microscopy and flow cytometry. Chemical reaction side-products (identified by IR and MS and quantified by 1H NMR) acted as co-surfactants and facilitated vesicle formation. To mimic the compositional variation of such primitive lipid mixtures, self assembly of a combinatorial set of the above amphiphiles was tested, revealing that too high dioleoyl glycerol contents inhibited vesicle formation. We conclude that a decisive driving force for the gradual transition from unstable fatty acid vesicles to robust diacylglyceryl phosphate vesicles was to avoid the accumulation of unphosphorylated diacylglycerols in primitive vesicle membranes. PMID- 29273741 TI - Topological guiding of elastic waves in phononic metamaterials based on 2D pentamode structures. AB - A topological state with protected propagation of elastic waves is achieved by appropriately engineering a phononic metamaterial based on 2D pentamode structures in silicon. Gapless edge states in the designed structure, which are characterized by pseudospin-dependent transport, provide backscattering-immune propagation of the elastic wave along bend paths. The role of the states responsible for forward and backward transfer can be interchanged by design. PMID- 29273740 TI - RNA sequencing provides insights into the evolution of lettuce and the regulation of flavonoid biosynthesis. AB - Different horticultural types of lettuce exhibit tremendous morphological variation. However, the molecular basis for domestication and divergence among the different horticultural types of lettuce remains unknown. Here, we report the RNA sequencing of 240 lettuce accessions sampled from the major horticultural types and wild relatives, generating 1.1 million single-nucleotide polymorphisms (SNPs). Demographic modeling indicates that there was a single domestication event for lettuce. We identify a list of regions as putative selective sweeps that occurred during domestication and divergence, respectively. Genome-wide association studies (GWAS) identify 5311 expression quantitative trait loci (eQTL) regulating the expression of 4105 genes, including nine eQTLs regulating genes associated with flavonoid biosynthesis. GWAS for leaf color detects six candidate loci responsible for the variation of anthocyanins in lettuce leaves. Our study provides a comprehensive understanding of the domestication and the accumulation of anthocyanins in lettuce, and will facilitate the breeding of cultivars with improved nutritional value. PMID- 29273742 TI - The interaction of fat mass and obesity associated gene polymorphisms and dietary fiber intake in relation to obesity phenotypes. AB - Controversies surrounding the effectiveness of fiber intake for prevention of obesity can be attributed to differences in the genetic makeup of individuals. This study aims to examining the interaction between dietary fiber intake and common fat mass and obesity-associated (FTO) single-nucleotide polymorphisms (SNPs), in relation to obesity. Subjects of this nested case-control study were selected from among adult participants of the Tehran Lipid and Glucose Study. Cases (n = 627) were individually matched with controls, who had normal weight. Six selected SNPs (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973, and rs3751812) were genotyped by tetra-refractory mutation system-polymerase chain reaction analysis. Genetic risk scores (GRS) were calculated using the weighted method. A significant interaction was observed between total fiber intake and the GRS in relation to obesity (Pinteraction = 0.01); the difference in the risk for obesity was more pronounced in individuals with GRS >= 6 who consumed >= 14 grams of fiber a day (OR: 2.74, CI: 2.40-3.35 vs Ref.; P trend = 0.0005) than in individuals with GRS < 6 (P trend = 0.34). Dietary fiber intakes modified the association of FTO SNPs and the GRS with general obesity, an effect which was more pronounced in those who consumed high levels of dietary fiber and had a high number of risk alleles. PMID- 29273743 TI - Motion and Interaction of Magnetic Dislocations in Alternating Magnetic Field. AB - The behavior of magnetic dislocations (MDs) in an alternating harmonic magnetic field in iron garnets has been experimentally investigated. The results are presented for single-crystal plates in which the drift of domain walls is observed in fields of sound frequencies. It is found that MDs in a stripe domain structure are able to move not only along but also across domain walls. A pairwise interaction between magnetic dislocations when they approach each other to distances on the order of the sizes of the cores of MDs is revealed. The processes of the annihilation, mutual passing of magnetic dislocations through each other and overtaking are found. The features of the dynamic behavior of MDs are explained using a mechanism based on the presence of vertical Bloch lines in a structure of domain walls. MDs are formed at nucleation centers, and their nucleation field is lower than the drift-starting field, which corresponds to previously proposed dislocational mechanism of the drift. The dependencies of quantitative parameters of the drift and MDs on amplitude and frequency of the pumping field are determined. The behavior of MDs should be considered when analyzing the mechanisms for magnetization and temperature-dependent phase transitions in magnetic layers. PMID- 29273744 TI - Pitavastatin nanoparticle-engineered endothelial progenitor cells repair injured vessels. AB - Endothelial progenitor cells (EPC) participate in vessel recovery and maintenance of normal endothelial function. Therefore, pitavastatin-nanoparticles (NPs) engineered EPC may be effective in repairing injured vasculature. Pitavastatin loaded poly(lactic-co-glycolic) acid (PLGA) NPs were obtained via ultrasonic emulsion solvent evaporation with PLGA as the carrier encapsulating pitavastatin. The effects and mechanism of pitavastatin-NPs on EPC proliferation in vitro were evaluated. Then, EPC that internalized pitavastatin-NPs were transplanted into rats after carotid artery injury. EPC homing, re-endothelialization, and neointima were evaluated by fluorescence labeling, evans Blue and hematoxylin/eosin (H&E) staining. Pitavastatin-NPs significantly improved EPC proliferation compared with control and pitavastatin group. Those effects were blocked by pretreatment with the pharmacological phosphoinositide 3-kinase (PI3K) blockers LY294002. After carotid artery injury, more transplanted EPC were detected in target zone in Pitavastatin-NPs group than pitavastatin and control group. Re-endothelialization was promoted and intimal hyperplasia was inhibited as well. Thus, pitavastatin-NPs promote EPC proliferation via PI3K signaling and accelerate recovery of injured carotid artery. PMID- 29273745 TI - Imaging the square of the correlated two-electron wave function of a hydrogen molecule. AB - The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2 two-electron wave function in which electron-electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources. PMID- 29273746 TI - Intraindividual Behavioral Variability Predicts Foraging Outcome in a Beach dwelling Jumping Spider. AB - Animal personality, defined as consistent differences between individuals in behavior, has been the subject of hundreds if not thousands of papers. However, little work explores the fitness consequences of variation in behavior within individuals, or intraindividual variability (IIV). We probe the effects of behavioral IIV on predator-prey interaction outcomes in beach-dwelling jumping spiders (Terralonus californicus). Prior studies have found that spiders with higher body condition (body mass relative to size) behave more variably. Thus, we hypothesized that jumping spider activity level IIV would relate positively to foraging performance. To address this, we tested for associations between activity IIV, average activity level, and two measures of foraging success in laboratory mesocosms: change in spider mass and the number of prey killed. Activity IIV positively correlated with the mass that spiders gained from prey, but not with the number of prey killed. This suggests that spiders with high IIV consumed a greater proportion of their prey or used less energy. Interestingly, average activity level (personality) predicted neither metric of foraging success, indicating that behavioral IIV can predict metrics of success that personality does not. Therefore, our findings suggest that IIV should be considered alongside personality in studies of predator-prey interactions. PMID- 29273747 TI - Residues His172 and Lys238 are Essential for the Catalytic Activity of the Maleylacetate Reductase from Sphingobium chlorophenolicum Strain L-1. AB - Maleylacetate reductase (PcpE), the last enzyme in the pentachlorophenol biodegradation pathway in Sphingobium chlorophenolicum L-1, catalyzes two consecutive reductive reactions, reductive dehalogenation of 2 chloromaleylacetate (2-CMA) to maleylacetate (MA) and subsequent reduction of MA to 3-oxoadipate (3-OXO). In each reaction, one molecule of NADH is consumed. To better understand its catalytic function, we undertook a structural model-based site-directed mutagenesis and steady-state kinetics study of PcpE. Our results showed that the putative catalytic site of PcpE is located in a positively charged solvent channel at the interface of the two domains and the binding of 2 CMA/MA involves seven basic amino acids, His172, His236, His237, His241 and His251, Lys140 and Lys238. Mutagenesis studies showed that His172 and Lys238 are essential for the catalytic activity of PcpE. However, the mutation of His236 to an alanine can increase the catalytic efficiency (k cat /K m ) of PcpE by more than 2-fold, implying that PcpE is still in an early stage of molecular evolution. Similar to tetrachlorobenzoquinone reductase (PcpD), PcpE is also inhibited by pentachlorophenol in a concentration-dependent manner. Furthermore, our studies showed that PcpE exhibits an extremely low but detectable level of alcohol dehalogenase activity toward ethanol and supports the notion that it is evolved from an iron-containing alcohol dehydrogenase. PMID- 29273748 TI - Molecular understanding of polyelectrolyte binders that actively regulate ion transport in sulfur cathodes. AB - Polymer binders in battery electrodes may be either active or passive. This distinction depends on whether the polymer influences charge or mass transport in the electrode. Although it is desirable to understand how to tailor the macromolecular design of a polymer to play a passive or active role, design rules are still lacking, as is a framework to assess the divergence in such behaviors. Here, we reveal the molecular-level underpinnings that distinguish an active polyelectrolyte binder designed for lithium-sulfur batteries from a passive alternative. The binder, a cationic polyelectrolyte, is shown to both facilitate lithium-ion transport through its reconfigurable network of mobile anions and restrict polysulfide diffusion from mesoporous carbon hosts by anion metathesis, which we show is selective for higher oligomers. These attributes allow cells to be operated for >100 cycles with excellent rate capability using cathodes with areal sulfur loadings up to 8.1 mg cm-2. PMID- 29273749 TI - Publisher Correction: Puerarin attenuates diabetic kidney injury through the suppression of NOX4 expression in podocytes. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29273750 TI - Elimination of Antibiotic Resistant Surgical Implant Biofilms Using an Engineered Cationic Amphipathic Peptide WLBU2. AB - Antibiotics are unable to remove biofilms from surgical implants. This high antibiotic tolerance is related to bacterial persisters, a sub-population of bacteria phenotypically tolerant to antibiotics secondary to a reduced metabolic state. WLBU2 is an engineered cationic amphipathic peptide designed to maximize antimicrobial activity with minimal mammalian cell toxicity. The objective of this study was to test the ability of WLBU2 to remove Staphylococcus aureus surgical implant biofilms. WLBU2 effectively treated S. aureus biofilms formed by a variety of clinical MSSA and MRSA strains and created culture-negative implants in the in vitro biofilm model. Blocking bacterial metabolism by inhibiting oxidative phosphorylation did not affect WLBU2 killing compared to decreased killing by cefazolin. In the surgical implant infection animal model, WLBU2 decreased biofilm mass as compared to control, untreated samples. WLBU2 could rapidly eliminate implants in vitro and had sufficient efficacy in vivo with minimal systemic toxicity. PMID- 29273751 TI - Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1. AB - Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-kappaB/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-kappaB/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders. PMID- 29273752 TI - Alternative dominance of the parental genomes in hybrid cells generated through the fusion of mouse embryonic stem cells with fibroblasts. AB - For the first time, two types of hybrid cells with embryonic stem (ES) cell-like and fibroblast-like phenotypes were produced through the fusion of mouse ES cells with fibroblasts. Transcriptome analysis of 2,848 genes differentially expressed in the parental cells demonstrated that 34-43% of these genes are expressed in hybrid cells, consistent with their phenotypes; 25-29% of these genes display intermediate levels of expression, and 12-16% of these genes maintained expression at the parental cell level, inconsistent with the phenotype of the hybrid cell. Approximately 20% of the analyzed genes displayed unexpected expression patterns that differ from both parents. An unusual phenomenon was observed, namely, the illegitimate activation of Xist expression and the inactivation of one of two X-chromosomes in the near-tetraploid fibroblast-like hybrid cells, whereas both Xs were active before and after in vitro differentiation of the ES cell-like hybrid cells. These results and previous data obtained on heterokaryons suggest that the appearance of hybrid cells with a fibroblast-like phenotype reflects the reprogramming, rather than the induced differentiation, of the ES cell genome under the influence of a somatic partner. PMID- 29273754 TI - Diagnosis and typing of influenza using fluorescent barcoded probes. AB - In this work, we explore a new hybridization technology using barcoded probes which has large-scale multiplexing capability. We used influenza virus to test whether the technology has application in virus diagnostics. Typing of influenza virus strains is an important aspect of global health surveillance. Standard typing procedures use serological or amplification-based assays performed sequentially. By comparison, the hybridization technology was correctly able to detect, type and subtype influenza A and B virus strains directly from clinical samples in a single reaction without prior virus isolation or amplification. Whilst currently not as sensitive as amplification-based assays, these results are a first-step towards application of this technology to the detection and typing of influenza and other viruses. PMID- 29273753 TI - Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non proteinogenic amino acid. AB - Hundreds of non-proteinogenic (np) amino acids (AA) are found in plants and can in principle enter human protein synthesis through foods. While aminoacyl-tRNA synthetase (AARS) editing potentially provides a mechanism to reject np AAs, some have pathological associations. Co-crystal structures show that vegetable-sourced azetidine-2-carboxylic acid (Aze), a dual mimic of proline and alanine, is activated by both human prolyl- and alanyl-tRNA synthetases. However, it inserts into proteins as proline, with toxic consequences in vivo. Thus, dual mimicry increases odds for mistranslation through evasion of one but not both tRNA synthetase editing systems. PMID- 29273755 TI - Anomalous Decay of Nanomechanical Modes Going Through Nonlinear Resonance. AB - Because of the small size of nanomechanical systems, their vibrations become nonlinear already for small amplitudes. Many nontrivial aspects of the vibration dynamics arise from the coexistence of several nonlinearly coupled modes. We show that such coupling can lead to anomalous decay of the modes where they go through nonlinear resonance, so that their amplitude-dependent frequencies become commensurate. We demonstrate the possibility of a strongly nonmonotonic dependence of the decay rate on the amplitude if one of the modes serves as a thermal reservoir for another mode. Where the decay of both modes is slow compared to the rate of resonant energy exchange, the decay is accompanied by amplitude oscillations. Depending on the initial conditions, with increasing time it can display an extremely sharp or a comparatively smooth crossover between different regimes. The results provide insight into recent experimental results by several groups and suggest new ways of characterizing and controlling nanomechanical systems. PMID- 29273756 TI - Chromatin state changes during neural development revealed by in vivo cell-type specific profiling. AB - A key question in developmental biology is how cellular differentiation is controlled during development. While transitions between trithorax-group (TrxG) and polycomb-group (PcG) chromatin states are vital for the differentiation of ES cells to multipotent stem cells, little is known regarding the role of chromatin states during development of the brain. Here we show that large-scale chromatin remodelling occurs during Drosophila neural development. We demonstrate that the majority of genes activated during neuronal differentiation are silent in neural stem cells (NSCs) and occupy black chromatin and a TrxG-repressive state. In neurons, almost all key NSC genes are switched off via HP1-mediated repression. PcG-mediated repression does not play a significant role in regulating these genes, but instead regulates lineage-specific transcription factors that control spatial and temporal patterning in the brain. Combined, our data suggest that forms of chromatin other than canonical PcG/TrxG transitions take over key roles during neural development. PMID- 29273757 TI - Quantitative predictions of diverse wrinkling patterns in film/substrate systems. AB - A basic characteristic of stiff film/soft substrate systems is their ability to experience large deformation under compressive stresses, which inevitably leads to formation of patterns on the surface. Such pattern formation is the result of loss of stability and symmetry breaking. Knowledge on how such instabilities arise and evolve is essential to describe, understand, predict, and ultimately to design complex functional materials and structures, for example the fabrication of stretchable electronic devices and micro/nano-scale surface patterning control. In this paper, quantitative predictions of various instability pattern formations and evolutions, which involve highly nonlinear deformation and multiple bifurcations, will be presented based on advanced mechanical models and methods, from planar to curved geometry. The results can provide further insight into fundamental understanding in a whole view of a variety of surface patterning morphology and imply a potential way to facilitate the design of functional materials and structures by quantitatively harnessing surface instabilities. PMID- 29273759 TI - Orientation in Virtual Reality Does Not Fully Measure Up to the Real-World. AB - Adult participants learned to reorient to a specific corner inside either a real or virtual rectangular room containing a distinct featural object in each corner. Participants in the virtual-reality (VR) condition experienced an immersive virtual version of the physical room using a head-mounted display (HMD) and customized manual wheelchair to provide self-movement. Following a disorientation procedure, people could reorient by using either the geometry of the room and/or the distinct features in the corners. Test trials in which the different spatial cues were manipulated revealed participants encoded features and geometry in both the real and VR rooms. However, participants in the VR room showed less facility with using geometry. Our results suggest caution must be taken when interpreting the nuances of spatial cue use in virtual environments. Reduced reliability of geometric cues in VR environments may result in greater reliance on feature cues than would normally be expected under similar real-world conditions. PMID- 29273758 TI - The sleep EEG spectrum is a sexually dimorphic marker of general intelligence. AB - The shape of the EEG spectrum in sleep relies on genetic and anatomical factors and forms an individual "EEG fingerprint". Spectral components of EEG were shown to be connected to mental ability both in sleep and wakefulness. EEG sleep spindle correlates of intelligence, however, exhibit a sexual dimorphism, with a more pronounced association to intelligence in females than males. In a sample of 151 healthy individuals, we investigated how intelligence is related to spectral components of full-night sleep EEG, while controlling for the effects of age. A positive linear association between intelligence and REM anterior beta power was found in females but not males. Transient, spindle-like "REM beta tufts" are described in the EEG of healthy subjects, which may reflect the functioning of a recently described cingular-prefrontal emotion and motor regulation network. REM sleep frontal high delta power was a negative correlate of intelligence. NREM alpha and sigma spectral power correlations with intelligence did not unequivocally remain significant after multiple comparisons correction, but exhibited a similar sexual dimorphism. These results suggest that the neural oscillatory correlates of intelligence in sleep are sexually dimorphic, and they are not restricted to either sleep spindles or NREM sleep. PMID- 29273760 TI - Urotensin II-induced store-operated Ca2+ entry contributes to glomerular mesangial cell proliferation and extracellular matrix protein production under high glucose conditions. AB - Glomerular mesangial cell (GMC) proliferation and matrix expansion are pathological hallmarks of a wide range of kidney diseases, including diabetic nephropathy. Although the circulating level of peptide hormone urotensin II (UII) and kidney tissue expression of UII and UII receptors (UTR) are increased in diabetic nephropathy, it remains unclear whether UII regulates GMC growth and extracellular matrix (ECM) accumulation. In this study, we tested the hypothesis that UII-induced Ca2+ signaling controls GMC proliferation and ECM production under normal and high glucose conditions. Mouse GMCs cultured under normal glucose conditions proliferated and synthesized ECM proteins in response to stimulation by mouse UII. UII-induced GMC proliferation and ECM protein synthesis were dependent on TRPC4 channel-mediated store-operated Ca2+ entry (SOCE) and sequential activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Ca2+/cAMP response element-binding protein (CREB) transcription factor. Under high glucose conditions, GMCs synthesized UII. Moreover, proliferation and ECM production in high glucose-challenged GMCs were attenuated by selective UTR antagonist, TRPC4 channel blocker, and CaMKII and CREB-binding protein/p300 inhibitors. These findings indicate that UII-induced SOCE via TRPC4 channels stimulates CaMKII/CREB-dependent GMC proliferation and ECM protein production. Our data also suggest that UII synthesis contributes to GMC proliferation and ECM accumulation under high glucose conditions. PMID- 29273761 TI - New Seeding Approach Reduces Costs and Time to Outplant Sexually Propagated Corals for Reef Restoration. AB - The use of sexually propagated corals is gaining popularity as an approach for reef restoration. However, manually attaching substrates with recently settled corals to the reef using binding materials is both time-consuming and expensive, limiting the use of this technique to small spatial scales. We present a novel approach whereby young corals are 'seeded' on the reef without the need for manual attachment to the benthos. We tested two tetrapod-shaped concrete substrates (7.9 and 9.8 cm in diameter) on which coral larvae were settled. The tetrapods were efficiently deployed by wedging them in reef crevices, in 1.5 to 7% of the time required for traditional outplanting techniques. Seeding tetrapods was most effective in reefs with moderately to highly complex topographies, where they rapidly became lodged in crevices or cemented to the benthos by encrusting organisms. After one year, average recruit survival was 9.6% and 67% of tetrapods still harboured at least one coral colony, and overall, this approach resulted in a 5 to 18 fold reduction in outplanting costs compared to common outplanting methods. This seeding approach represents a substantial reduction in costs and time required to introduce sexually propagated corals to reefs, and could possibly enable larger scale reef restoration. PMID- 29273762 TI - Analysis of ENSO's response to unforced variability and anthropogenic forcing using CESM. AB - Understanding how the El Nino-Southern Oscillation (ENSO) may change with climate is a major challenge, given the internal variability of the system and relatively short observational record. Here we analyze the effect of coupled internal variability on changes in ENSO under anthropogenic global warming using the Community Earth System Model (CESM). We present results from a ~5000 year control run with constant pre-industrial conditions and a 50-member climate change ensemble experiment, consisting of historical hindcasts (1850-2005) and future projections to 2100 following representative concentration pathway 8.5 (RCP8.5). Given this large single-model ensemble, we are able to use simple statistical analyses to compare the effects of anthropogenic climate change with the effects of natural modulations in ENSO sea surface temperature (SST) metrics, as well as how internal variability may change with global warming. Changes in eastern Pacific ENSO SST metrics due to climate change are secondary to the model's natural modulations; however, central Pacific ENSO amplitude significantly decreases, to an extent comparable with natural modulations. We also assess the sensitivity of internal variability estimates to ensemble size. The primary role of natural modulations in this ensemble highlights the importance of careful assessment of ocean-atmosphere internal variability in ENSO projections. PMID- 29273764 TI - Alternating-magnetic-field induced enhancement of diffusivity in Ni-Cr alloys. AB - For applying an alternating magnetic field (AMF) in materials processing it is of high significance to understand the physical mechanisms behind the change in diffusivity in the AMF. In this work, the effect of the AMF on interdiffusion in a Ni-Cr alloy was investigated with a diffusion couple. The interdiffusion coefficient was found to increase with increasing AMF intensity. The faster diffusivity is a consequence of the enhancement of the dislocation density in the diffusion couples that was confirmed by the broadening of X-ray diffraction peaks. The higher dislocation density is attributed to the magnetoplastic effect (MPE). Theoretical considerations on the relation of MPE, dislocation density and diffusivity are in agreement with the experimental results. PMID- 29273763 TI - Interactions between GHRH and GABAARs in the brains of patients with epilepsy and in animal models of epilepsy. AB - Growth hormone releasing hormone (GHRH) has recently been shown to increase the level of gamma-aminobutyric acid (GABA) and activate GABA receptors (GABARs) in the cerebral cortex. GABA is an inhibitory neurotransmitter that can inhibit seizures. Does GHRH enhance the inhibitory effect of GABA to prevent epilepsy by increasing the GABA level and activating GABARs? In this study, patients with epilepsy and C57/BL6 mice with epilepsy induced by kainic acid (KA) or pentylenetetrazol (PTZ) served as the research subjects. Western blots were used to observe the differences in GHRH expression between the normal group and the epilepsy group, immunofluorescence was performed to explore the localization of GHRH in the brain, and coimmunoprecipitation was used to observe the interaction between GHRH and GABARs. GHRH expression was significantly increased in both patients with temporal lobe epilepsy (TLE) and in two mouse models induced by KA or PTZ compared with that in the normal groups (P < 0.05 or P < 0.01). GHRH was expressed in neurons in both humans and mice. Additionally, GHRH co-localized with presynaptic and postsynaptic sites of inhibitory neurons. Coimmunoprecipitation confirmed that GHRH interacted with GABAAalpha1 and GABAAbeta2 + 3. GHRH may play an important role in inhibiting seizures by activating GABAARs. PMID- 29273765 TI - Discovery of novel solid solution Ca3Si3-x O3+x N4-2x : Eu2+ phosphors: structural evolution and photoluminescence tuning. AB - Discovery of novel phosphors is one of the main issues for improving the color rendering index (CRI) and correlated color temperature (CCT) of white light emitting diodes (w-LEDs). This study mainly presents a systematic research on the synthesis, crystal structure variation and photoluminescence tuning of novel (oxy)nitride solid solution Ca3Si3-x O3+x N4-2x : Eu2+ phosphors. XRD refinements show that lattice distortion occurs when x value diverges the optimum one (x = 1). The lattice distortion causes a widening of emission spectrum and an increase of Stokes shift (DeltaSS), which leads to a bigger thermal quenching. With decrease of x value, the emission spectrum shows an obvious red-shift from 505.2 to 540.8 nm, which is attributed to the crystal field splitting. The enhanced crystal field splitting also broadens the excitation spectrum, making it possible to serve as the phosphor for near ultraviolet (n-UV) LEDs. A 3-phosphor conversion w-LED lamp was fabricated with the as-prepared phosphor, which exhibits high CRI (Ra = 85.29) and suitable CCT (4903.35 K). All these results indicate that the Ca3Si3-x O3+x N4-2x : Eu2+ phosphor can serve as the green phosphor for n-UV w-LEDs, with a tunable spectrum by controlling the crystal structure and morphology. PMID- 29273766 TI - NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor alpha1. AB - Thyroid hormone receptor alpha (THRA) gene mutations, via dominant negative mode, cause erythroid abnormalities in patients. Using mice expressing a dominant negative TRalpha1 mutant (TRalpha1PV; Thra1 PV/+ mice), we showed that TRalpha1PV acted directly to suppress the expression of key erythroid genes, causing erythroid defects. The nuclear receptor corepressor 1 (NCOR1) was reported to mediate the dominant negative effects of mutated TRalpha1. However, how NCOR1 could regulate TRalpha1 mutants in erythroid defects in vivo is not known. In the present study, we crossed Thra1 PV/+ mice with mice expressing a mutant Ncor1 allele (NCOR1DeltaID; Ncor1 DeltaID mice). TRalpha1PV mutant cannot bind to NCOR1DeltaID. The expression of NCOR1DeltaID ameliorated abnormalities in the peripheral blood indices, and corrected the defective differentiation potential of progenitors in the erythroid lineage. The defective terminal erythropoiesis of lineage-negative bone marrow cells of Thra1 PV/+ mice was rescued by the expression of NCOR1DeltaID. De-repression of key erythroid genes in Thra1 PV/+ Ncor1 DeltaID/DeltaID mice led to partial rescue of terminal erythroid differentiation. These results indicate that the inability of TRalpha1PV to recruit NCOR1DeltaID to form a repressor complex relieved the deleterious actions of TRalpha1 mutants in vivo. NCOR1 is a critical novel regulator underpining the pathogenesis of erythroid abnormalities caused by TRalpha1 mutants. PMID- 29273767 TI - The rs2108622 polymorphism is related to the early risk of ischemic stroke in non valvular atrial fibrillation subjects under oral anticoagulation. AB - Oral anticoagulant treatments, such as vitamin K antagonists (VKAs), are the main treatments administered to atrial fibrillation (AF) patients in order to prevent ischemic stroke (IS). However, the genes involved in the VKA metabolism can undergo variations in a single nucleotide (SNP). These SNPs may then affect the VKA target enzyme (VKORC1), VKA degradation enzyme (CYP2C9), and vitamin K bioavailability enzyme (CYP4F2). We genotyped these SNPs in a cohort of patients with non-valvular AF who were under VKA treatment after suffering an IS. Clinical variables, CHADS2-VASC score and data about the international normalized ratio (INR) within the therapeutic range were all recorded. DNA was extracted from blood and genotyping was carried out by DNA sequencing. The main endpoint was the time from VKA onset to IS. Of a total of 356 consecutive IS patients monitored, 33 were included in the study. The median time to the event was 2248.0 days (interquartile range [IQR] 896.3-3545.3). The median CHADS2-VASC score was 4.0 (IQR 3.0-6.0). When we considered the risk of IS within 2 years under VKA treatment, we found that only the rs2108622 AA genotype was significantly associated with this endpoint (early IS) (hazard ratio 6.81, 95% CI 1.37-33.92, p = 0.019). Kaplan-Meier curve analysis also showed a significant relationship between early IS and rs2108622 AA genotype (Log rank p = 0.022). The CYP4F2 gene rs2108622 polymorphism was associated with a risk of early IS in NV-AF patients under VKA treatment. PMID- 29273768 TI - Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan. AB - Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders. PMID- 29273770 TI - Quantum Hall states observed in thin films of Dirac semimetal Cd3As2. AB - A well known semiconductor Cd3As2 has reentered the spotlight due to its unique electronic structure and quantum transport phenomena as a topological Dirac semimetal. For elucidating and controlling its topological quantum state, high quality Cd3As2 thin films have been highly desired. Here we report the development of an elaborate growth technique of high-crystallinity and high mobility Cd3As2 films with controlled thicknesses and the observation of quantum Hall effect dependent on the film thickness. With decreasing the film thickness to 10 nm, the quantum Hall states exhibit variations such as a change in the spin degeneracy reflecting the Dirac dispersion with a large Fermi velocity. Details of the electronic structure including subband splitting and gap opening are identified from the quantum transport depending on the confinement thickness, suggesting the presence of a two-dimensional topological insulating phase. The demonstration of quantum Hall states in our high-quality Cd3As2 films paves a road to study quantum transport and device application in topological Dirac semimetal and its derivative phases. PMID- 29273769 TI - Differential miRNA expression in the three-spined stickleback, response to environmental changes. AB - miRNAs play important role in the various physiological and evolutionary processes, however, there is no data allowing comparison of evolutionary differences between various ecotypes adapted to different environmental conditions and specimen demonstrating immediate physiological response to the environmental changes. We compared miRNA expression profiles between marine and freshwater stickleback populations of the three-spined stickleback to identify the evolutionary differences. To study the immediate physiological response to foreign environment, we explored the changes induced by transfer of marine sticklebacks into freshwater environment and vice versa. Comparative analysis of changes in miRNA expression suggested that they are driven by three independent factors: (1) non-specific changes in miRNA expression under different environmental conditions; (2) specific response to freshwater conditions in the marine stickleback ecotype; (3) specific response to extreme osmotic conditions for both marine and freshwater ecotypes during the contact with non-native environment. Gene Ontology enrichment analysis of differential expressed miRNA targets supports our current hypothesis. PMID- 29273771 TI - 96 perfusable blood vessels to study vascular permeability in vitro. AB - Current in vitro models to test the barrier function of vasculature are based on flat, two-dimensional monolayers. These monolayers do not have the tubular morphology of vasculature found in vivo and lack important environmental cues from the cellular microenvironment, such as interaction with an extracellular matrix (ECM) and exposure to flow. To increase the physiological relevance of in vitro models of the vasculature, it is crucial to implement these cues and better mimic the native three-dimensional vascular architecture. We established a robust, high-throughput method to culture endothelial cells as 96 three dimensional and perfusable microvessels and developed a quantitative, real-time permeability assay to assess their barrier function. Culture conditions were optimized for microvessel formation in 7 days and were viable for over 60 days. The microvessels exhibited a permeability to 20 kDa dextran but not to 150 kDa dextran, which mimics the functionality of vasculature in vivo. Also, a dose dependent effect of VEGF, TNFalpha and several cytokines confirmed a physiologically relevant response. The throughput and robustness of this method and assay will allow end-users in vascular biology to make the transition from two-dimensional to three-dimensional culture methods to study vasculature. PMID- 29273773 TI - Intravitreal injections of anti-VEGF agents and antibiotic prophylaxis for endophthalmitis: A systematic review and meta-analysis. AB - We performed a systematic review and meta-analysis to determine whether the use of local antibiotics is a beneficial prophylactic treatment for endophthalmitis in patients treated with anti-VEGF agents. We searched the MEDLINE and EMBASE databases, and the Cochrane Library over the period January 2007 to December 2016. The search terms used included "Endophthalmitis", "Antibiotic" and "Intravitreal injection". Studies in which the patients were treated exclusively with intravitreal injections of anti-VEGF were selected. Eight studies fit the inclusion criteria, which included a total of 276,774 injections; 109,178 (39.45%) were associated with the use of antibiotics and 114,821 (60.55%) were not associated with the use of antibiotics. Our meta-analysis indicated a significant risk for endophthalmitis that was 1.70 times greater with the use of antibiotics than that without antibiotics, with a confidence interval of 1.08 to 2.66 (p = 0.02). A meta-regression indicated that the location (operating rooms versus outpatient clinics) of injection did not have a significant effect on the incidence of endophthalmitis. The prophylactic use of antibiotics when administering anti-VEGF intravitreal injections may contribute to a greater incidence of endophthalmitis. This finding, in addition to reducing costs, would eliminate a treatment that has been shown to be unnecessary and even harmful to patients. PMID- 29273772 TI - Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. AB - Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau mediated pathology. PMID- 29273774 TI - Magnetization jump in one dimensional J - Q 2 model with anisotropic exchange. AB - We investigate the adiabatic magnetization process of the one-dimensional J - Q 2 model with XXZ anisotropy g in an external magnetic field h by using density matrix renormalization group (DMRG) method. According to the characteristic of the magnetization curves, we draw a magnetization phase diagram consisting of four phases. For a fixed nonzero pair coupling Q, (i) when g < -1, the ground state is always ferromagnetic in spite of h; (ii) when g > -1 but still small, the whole magnetization curve is continuous and smooth; (iii) if further increasing g, there is a macroscopic magnetization jump from partially- to fully polarized state; (iv) for a sufficiently large g, the magnetization jump is from non- to fully-polarized state. By examining the energy per magnon and the correlation function, we find that the origin of the magnetization jump is the condensation of magnons and the formation of magnetic domains. We also demonstrate that while the experienced states are Heisenberg-like without long range order, all the jumped-over states have antiferromagnetic or Neel long-range orders, or their mixing. PMID- 29273776 TI - Publisher Correction: A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29273775 TI - Cropping System Conversion led to Organic Carbon Change in China's Mollisols Regions. AB - Land use change driven by diet, globalization, and technology advancement have greatly influenced agricultural production and environment in the mollisols region of China, with a marked impact on the depletion of soil organic matter, a signature property of mollisols. Here we report findings on soil organic carbon (SOC) change in three different cropping systems (soybean, soybean/maize, corn) in Northeast China during a 10-year time span. The results indicated that the decline rate of SOC in recent ten years (0.27 g kg-1 yr-1) has slowed down considerably compared to previous decades (1.12 g kg-1 yr-1). Crop system conversion from soybean monocropping to corn monocropping or break system was the critical factor for SOC change, and the background SOC was the second influence factor. When approaching a SOC turning point, conversion from low carbon input crop system (soybeans monocropping) to high carbon input crop system helped slow down the SOC decline (break crop) or even improve SOC (corn monocropping) in mollisols regions. This result implied that imported soybean has brought benefit for Northeast China. But for sustainable goal in China's mollisols region, straw returning, optimized nitrogen fertilization and no tillage are all necessary whatever in continues maize or rotation system. PMID- 29273777 TI - Entropy is a Simple Measure of the Antibody Profile and is an Indicator of Health Status: A Proof of Concept. AB - We have previously shown that the diversity of antibodies in an individual can be displayed on chips on which 130,000 peptides chosen from random sequence space have been synthesized. This immunosignature technology is unbiased in displaying antibody diversity relative to natural sequence space, and has been shown to have diagnostic and prognostic potential for a wide variety of diseases and vaccines. Here we show that a global measure such as Shannon's entropy can be calculated for each immunosignature. The immune entropy was measured across a diverse set of 800 people and in 5 individuals over 3 months. The immune entropy is affected by some population characteristics and varies widely across individuals. We find that people with infections or breast cancer, generally have higher entropy values than non-diseased individuals. We propose that the immune entropy as measured from immunosignatures may be a simple method to monitor health in individuals and populations. PMID- 29273778 TI - Methylation-regulated decommissioning of multimeric PP2A complexes. AB - Dynamic assembly/disassembly of signaling complexes are crucial for cellular functions. Specialized latency and activation chaperones control the biogenesis of protein phosphatase 2A (PP2A) holoenzymes that contain a common scaffold and catalytic subunits and a variable regulatory subunit. Here we show that the butterfly-shaped TIPRL (TOR signaling pathway regulator) makes highly integrative multibranching contacts with the PP2A catalytic subunit, selective for the unmethylated tail and perturbing/inactivating the phosphatase active site. TIPRL also makes unusual wobble contacts with the scaffold subunit, allowing TIPRL, but not the overlapping regulatory subunits, to tolerate disease-associated PP2A mutations, resulting in reduced holoenzyme assembly and enhanced inactivation of mutant PP2A. Strikingly, TIPRL and the latency chaperone, alpha4, coordinate to disassemble active holoenzymes into latent PP2A, strictly controlled by methylation. Our study reveals a mechanism for methylation-responsive inactivation and holoenzyme disassembly, illustrating the complexity of regulation/signaling, dynamic complex disassembly, and disease mutations in cancer and intellectual disability. PMID- 29273780 TI - Extracellular ATP elicits DORN1-mediated RBOHD phosphorylation to regulate stomatal aperture. AB - In addition to acting as a cellular energy source, ATP can also act as a damage associated molecular pattern in both animals and plants. Stomata are leaf pores that control gas exchange and, therefore, impact critical functions such as photosynthesis, drought tolerance, and also are the preferred entry point for pathogens. Here we show the addition of ATP leads to the rapid closure of leaf stomata and enhanced resistance to the bacterial pathogen Psuedomonas syringae. This response is mediated by ATP recognition by the receptor DORN1, followed by direct phosphorylation of the NADPH oxidase RBOHD, resulting in elevated production of reactive oxygen species and stomatal closure. Mutation of DORN1 phosphorylation sites on RBOHD eliminates the ability of ATP to induce stomatal closure. The data implicate purinergic signaling via DORN1 in the control of stomatal aperture with important implications for the control of plant photosynthesis, water homeostasis, pathogen resistance, and ultimately yield. PMID- 29273781 TI - Altered gene expression and metabolism in fetal umbilical cord mesenchymal stem cells correspond with differences in 5-month-old infant adiposity gain. AB - The intrauterine period is a critical time wherein developmental exposure can influence risk for chronic disease including childhood obesity. Using umbilical cord-derived mesenchymal stem cells (uMSC) from offspring born to normal-weight and obese mothers, we tested the hypothesis that changes in infant body composition over the first 5 months of life correspond with differences in cellular metabolism and transcriptomic profiles at birth. Higher long-chain acylcarnitine concentrations, lipid transport gene expression, and indicators of oxidative stress in uMSC-adipocytes were related to higher adiposity at 5 months of age. In uMSC-myocytes, lower amino acid concentrations and global differential gene expression for myocyte growth, amino acid biosynthesis, and oxidative stress were related to lower infant percent fat-free mass at 5 months of age, particularly in offspring of obese mothers. This is the first evidence of human infant adipocyte- or myocyte-related alterations in cellular metabolic pathways that correspond with increased adiposity and lower fat-free mass in early infancy. These pathways might reflect the effects of an adverse maternal metabolic environment on the fetal metabolome and genome. Our findings suggest that programmed differences in infant stem cell metabolism correspond with differences in body composition in early life, a known contributor to obesity risk. PMID- 29273782 TI - AraBAD Based Toolkit for Gene Expression and Metabolic Robustness Improvement in Synechococcus elongatus. AB - As a novel chemical production platform, controllable and inducible modules in Synechococcus elongatus plus the ability of working in diurnal conditions are necessary. To the endeavors, inducible promoters, such as PTrc, have been refined from Escherichia coli, but the inducer isopropyl-beta-D-thiogalactoside may cause several side-effects. Meanwhile, to promote the efficiency, photomixotrophic cultivation has been applied in S. elongatus with the additional organic carbon sources. In this study, we developed L-arabinose based modules consisted of both the PBAD inducible promoter and the metabolism of L-arabinose in S. elongatus, since L-arabinose is an ideal heterologous feedstock for its availability and economic and environmental benefits. As expected, we achieved homogeneous and linear expression of the exogenous reporter through the PBAD promoter, and the biomass increased in diurnal light condition via introducing L-arabinose metabolism pathway. Moreover, the combined AraBAD based toolkit containing both the PBAD inducible module and the L-arabinose metabolism module could obtain gene expression and metabolic robustness improvement in S. elongatus. With the only additive L-arabinose, the novel strategy may generate a win-win scenario for both regulation and metabolism for autotrophic bio-production platforms. PMID- 29273779 TI - Reading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration. AB - Salamanders exhibit an extraordinary ability among vertebrates to regenerate complex body parts. However, scarce genomic resources have limited our understanding of regeneration in adult salamanders. Here, we present the ~20 Gb genome and transcriptome of the Iberian ribbed newt Pleurodeles waltl, a tractable species suitable for laboratory research. We find that embryonic stem cell-specific miRNAs mir-93b and mir-427/430/302, as well as Harbinger DNA transposons carrying the Myb-like proto-oncogene have expanded dramatically in the Pleurodeles waltl genome and are co-expressed during limb regeneration. Moreover, we find that a family of salamander methyltransferases is expressed specifically in adult appendages. Using CRISPR/Cas9 technology to perturb transcription factors, we demonstrate that, unlike the axolotl, Pax3 is present and necessary for development and that contrary to mammals, muscle regeneration is normal without functional Pax7 gene. Our data provide a foundation for comparative genomic studies that generate models for the uneven distribution of regenerative capacities among vertebrates. PMID- 29273783 TI - Clay content and pH: soil characteristic associations with the persistent presence of chronic wasting disease in northern Illinois. AB - Environmental reservoirs are important to infectious disease transmission and persistence, but empirical analyses are relatively few. The natural environment is a reservoir for prions that cause chronic wasting disease (CWD) and influences the risk of transmission to susceptible cervids. Soil is one environmental component demonstrated to affect prion infectivity and persistence. Here we provide the first landscape predictive model for CWD based solely on soil characteristics. We built a boosted regression tree model to predict the probability of the persistent presence of CWD in a region of northern Illinois using CWD surveillance in deer and soils data. We evaluated the outcome for possible pathways by which soil characteristics may increase the probability of CWD transmission via environmental contamination. Soil clay content and pH were the most important predictive soil characteristics of the persistent presence of CWD. The results suggest that exposure to prions in the environment is greater where percent clay is less than 18% and soil pH is greater than 6.6. These characteristics could alter availability of prions immobilized in soil and contribute to the environmental risk factors involved in the epidemiological complexity of CWD infection in natural populations of white-tailed deer. PMID- 29273784 TI - Integrated transcriptional analysis unveils the dynamics of cellular differentiation in the developing mouse hippocampus. AB - The ability to assign expression patterns to the individual cell types that constitute a tissue is a major challenge. This especially applies to brain, given its plethora of different, functionally interconnected cell types. Here, we derived cell type-specific transcriptome signatures from existing single cell RNA data and integrated these signatures with a newly generated dataset of expression (bulk RNA-Seq) of the postnatal developing mouse hippocampus. This integrated analysis allowed us to provide a comprehensive and unbiased prediction of the differentiation drivers for 11 different hippocampal cell types and describe how the different cell types interact to support crucial developmental stages. Our results provide a reliable resource of predicted differentiation drivers and insights into the multifaceted aspects of the cells in hippocampus during development. PMID- 29273786 TI - A landscape of commitment. PMID- 29273785 TI - Construction of engineered corpus cavernosum with primary mesenchymal stem cells in vitro. AB - Various methods have been used to reconstruct the penis. The objective of this study was to investigate the feasibility of constructing engineered corpus cavernosum with primary mesenchymal stem cells (MSCs) in a rabbit model in vitro. Acellular corporal matrices (ACMs) were obtained from adult rabbit penile tissues through an established decellularization procedure. MSCs were separated, purified, and then seeded on ACMs to construct engineered corpus cavernosum. The seeded ACMs were subsequently cultured in an incubator for 14 days. Histological analyses showed that MSCs seeded on the ACMs had proliferated and were well distributed. Detection of CD31, vWF, smooth muscle actin (SMA), and myosin protein as well as vWF and myosin mRNA revealed that the MSCs had differentiated into endothelial cells and smooth muscle cells. In addition, cell morphology of the engineered corpus cavernosum was directly observed by transmission electron microscopy. This study demonstrated that engineered corpus cavernosum could be successfully constructed using primary MSCs in vitro. This technology represents another step towards developing engineered corpus cavernosum in vitro. PMID- 29273787 TI - N6-methyladenine is an epigenetic marker of mammalian early life stress. AB - Recent evidence described 6-methyladenine (6 mA) as a novel epigenetic regulator in a variety of multicellular species, including rodents; however, its capacity to influence gene expression in the mammalian brain remains unknown. We examined if 6 mA is present and regulated by early life stress associated with predator odor exposure (POE) within the developing rat amygdala. Our results provide evidence that 6 mA is present in the mammalian brain, is altered within the Htr2a gene promoter by early life stress and biological sex, and increased 6 mA is associated with gene repression. These data suggest that methylation of adenosine within mammalian DNA may be used as an additional epigenetic biomarker for investigating the development of stress-induced neuropathology. PMID- 29273788 TI - Structure of a Wbl protein and implications for NO sensing by M. tuberculosis. AB - Mycobacterium tuberculosis causes pulmonary tuberculosis (TB) and claims ~1.8 million human lives per annum. Host nitric oxide (NO) is important in controlling TB infection. M. tuberculosis WhiB1 is a NO-responsive Wbl protein (actinobacterial iron-sulfur proteins first identified in the 1970s). Until now, the structure of a Wbl protein has not been available. Here a NMR structural model of WhiB1 reveals that Wbl proteins are four-helix bundles with a core of three alpha-helices held together by a [4Fe-4S] cluster. The iron-sulfur cluster is required for formation of a complex with the major sigma factor (sigmaA) and reaction with NO disassembles this complex. The WhiB1 structure suggests that loss of the iron-sulfur cluster (by nitrosylation) permits positively charged residues in the C-terminal helix to engage in DNA binding, triggering a major reprogramming of gene expression that includes components of the virulence critical ESX-1 secretion system. PMID- 29273789 TI - Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model. AB - Reduced clearance of lipoproteins by HDL scavenger receptor class B1 (SR-B1) plays an important role in occlusive coronary artery disease. However, it is not clear how much microvascular dysfunction contributes to ischemic cardiomyopathy. Our aim was to determine the distribution of vascular dysfunction in vivo in the coronary circulation of male mice after brief exposure to Paigen high fat diet, and whether this vasomotor dysfunction involved nitric oxide (NO) and or endothelium derived hyperpolarization factors (EDHF). We utilised mice with hypomorphic ApoE lipoprotein that lacked SR-B1 (SR-B1-/-/ApoER61h/h, n = 8) or were heterozygous for SR-B1 (SR-B1+/-/ApoER61h/h, n = 8) to investigate coronary dilator function with synchrotron microangiography. Partially occlusive stenoses were observed in vivo in SR-B1 deficient mice only. Increases in artery-arteriole calibre to acetylcholine and sodium nitroprusside stimulation were absent in SR B1 deficient mice. Residual dilation to acetylcholine following L-NAME (50 mg/kg) and sodium meclofenamate (3 mg/kg) blockade was present in both mouse groups, except at occlusions, indicating that EDHF was not impaired. We show that SR-B1 deficiency caused impairment of NO-mediated dilation of conductance and microvessels. Our findings also suggest EDHF and prostanoids are important for global perfusion, but ultimately the loss of NO-mediated vasodilation contributes to atherothrombotic progression in ischemic cardiomyopathy. PMID- 29273791 TI - Tailoring Optical Gradient Force and Optical Scattering and Absorption Force. AB - The introduction of the concept of gradient force and scattering and absorption force is an important milestone in optical trapping. However the profiles of these forces are usually unknown, even for standard setups. Here, we successfully calculated them analytically via multipole expansion and numerically via Mie theory and fast Fourier transform. The former provides physical insight, while the latter is highly accurate and efficient. A recipe to create truly conservative energy landscapes is presented. These may open up qualitatively new features in optical manipulation. PMID- 29273790 TI - TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma. AB - Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor alpha (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients. PMID- 29273792 TI - Timing and pacing of the Late Devonian mass extinction event regulated by eccentricity and obliquity. AB - The Late Devonian envelops one of Earth's big five mass extinction events at the Frasnian-Famennian boundary (374 Ma). Environmental change across the extinction severely affected Devonian reef-builders, besides many other forms of marine life. Yet, cause-and-effect chains leading to the extinction remain poorly constrained as Late Devonian stratigraphy is poorly resolved, compared to younger cataclysmic intervals. In this study we present a global orbitally calibrated chronology across this momentous interval, applying cyclostratigraphic techniques. Our timescale stipulates that 600 kyr separate the lower and upper Kellwasser positive delta13C excursions. The latter excursion is paced by obliquity and is therein similar to Mesozoic intervals of environmental upheaval, like the Cretaceous Ocean-Anoxic-Event-2 (OAE-2). This obliquity signature implies coincidence with a minimum of the 2.4 Myr eccentricity cycle, during which obliquity prevails over precession, and highlights the decisive role of astronomically forced "Milankovitch" climate change in timing and pacing the Late Devonian mass extinction. PMID- 29273793 TI - Optimising monitoring efforts for secretive snakes: a comparison of occupancy and N-mixture models for assessment of population status. AB - A fifth of reptiles are Data Deficient; many due to unknown population status. Monitoring snake populations can be demanding due to crypsis and low population densities, with insufficient recaptures for abundance estimation via Capture-Mark Recapture. Alternatively, binomial N-mixture models enable abundance estimation from count data without individual identification, but have rarely been successfully applied to snake populations. We evaluated the suitability of occupancy and N-mixture methods for monitoring an insular population of grass snakes (Natrix helvetica) and considered covariates influencing detection, occupancy and abundance within remaining habitat. Snakes were elusive, with detectability increasing with survey effort (mean: 0.33 +/- 0.06 s.e.m.). The probability of a transect being occupied was moderate (mean per kilometre: 0.44 +/- 0.19 s.e.m.) and increased with transect length. Abundance estimates indicate a small threatened population associated to our transects (mean: 39, 95% CI: 20 169). Power analysis indicated that the survey effort required to detect occupancy declines would be prohibitive. Occupancy models fitted well, whereas N mixture models showed poor fit, provided little extra information over occupancy models and were at greater risk of closure violation. Therefore we suggest occupancy models are more appropriate for monitoring snakes and other elusive species, but that population trends may go undetected. PMID- 29273794 TI - Prediction of aesthetic reconstruction effects in edentulous patients. AB - The aim of the study is to establish a virtual prediction method to predict aesthetic reconstruction effects in edentulous patients. The facial soft tissue surface data before and after wearing complete dentures of ten edentulous patients were acquired with a facial Three-dimension scanner. Then, the two sets of scanned data were entered into the same coordinate system. Manual interaction was performed to extract the external boundary of the perioral appearance deformation area, and the proportional relationships of key facial anatomical features were measured. A virtual prediction software module was developed based on back-propagation neural networks and a Laplacian deformation algorithm. Virtual prediction of the aesthetic reconstruction effects in the overall appearance of the lower third of the face was performed in 10 edentulous patients. The mean accuracy of the virtual predictions was approximately 0.769 +/ 0.205 mm, and there were statistically significant differences between the 10 patients (p < 0.05). The scope of the changes in facial appearance of edentulous patients was smaller than the scope of the lower third of the face. This method can achieve the virtual prediction of soft tissue appearance in the lower third of the face after wearing complete dentures to an extent. PMID- 29273795 TI - Fusimonas intestini gen. nov., sp. nov., a novel intestinal bacterium of the family Lachnospiraceae associated with diabetes in mice. AB - Our previous study shows that an anaerobic intestinal bacterium strain AJ110941P contributes to type 2 diabetes development in mice. Here we phylogenetically and physiologically characterized this unique mouse gut bacterium. The 16S rRNA gene analysis revealed that the strain belongs to the family Lachnospiraceae but shows low sequence similarities ( < 92.5%) to valid species, and rather formed a distinct cluster with uncultured mouse gut bacteria clones. In metagenomic database survey, the 16S sequence of AJ110941P also matched with mouse gut derived datasets (56% of total datasets) with > 99% similarity, suggesting that AJ110941P-related bacteria mainly reside in mouse digestive tracts. Strain AJ110941P shared common physiological traits (e.g., Gram-positive, anaerobic, mesophilic, and fermentative growth with carbohydrates) with relative species of the Lachnospiraceae. Notably, the biofilm-forming capacity was found in both AJ110941P and relative species. However, AJ110941P possessed far more strong ability to produce biofilm than relative species and formed unique structure of extracellular polymeric substances. Furthermore, AJ110941P cells are markedly long fusiform-shaped rods (9.0-62.5 um) with multiple flagella that have never been observed in any other Lachnospiraceae members. Based on the phenotypic and phylogenetic features, we propose a new genus and species, Fusimonas intestini gen. nov., sp. nov. for strain AJ110941P (FERM BP-11443). PMID- 29273796 TI - Interactive effects of music and prefrontal cortex stimulation in modulating response inhibition. AB - Influential hypotheses propose that alterations in emotional state influence decision processes and executive control of behavior. Both music and transcranial direct current stimulation (tDCS) of prefrontal cortex affect emotional state, however interactive effects of music and tDCS on executive functions remain unknown. Learning to inhibit inappropriate responses is an important aspect of executive control which is guided by assessing the decision outcomes such as errors. We found that high-tempo music, but not low-tempo music or low-level noise, significantly influenced learning and implementation of inhibitory control. In addition, a brief period of tDCS over prefrontal cortex specifically interacted with high-tempo music and altered its effects on executive functions. Measuring event-related autonomic and arousal response of participants indicated that exposure to task demands and practice led to a decline in arousal response to the decision outcome and high-tempo music enhanced such practice-related processes. However, tDCS specifically moderated the high-tempo music effect on the arousal response to errors and concomitantly restored learning and improvement in executive functions. Here, we show that tDCS and music interactively influence the learning and implementation of inhibitory control. Our findings indicate that alterations in the arousal-emotional response to the decision outcome might underlie these interactive effects. PMID- 29273798 TI - Flat lens effect on seismic waves propagation in the subsoil. AB - We show that seismic energy simulated by an artificial source that mainly propagates Rayleigh surface waves, is focused in structured soil made of a grid of holes distributed in the ground. We carry out large-scale field tests with a structured soil made of a grid consisting of cylindrical and vertical holes in the ground and a low frequency artificial source (<10 Hz). This allows the identification of a distribution of energy inside the grid, which can be interpreted as the consequence of a dynamic anisotropy akin to an effective negative refraction index. Such a flat lens reminiscent of what Veselago and Pendry envisioned for light opens avenues in seismic metamaterials to counteract partially or totally the most devastating components of seismic signals. PMID- 29273797 TI - Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation. AB - Bone marrow-derived mesenchymal stem cells (MSC) have been promoted for multiple therapeutic applications. Many beneficial effects of MSCs are paracrine, dependent on extracellular vesicles (EVs). Although MSC-derived EVs (mEVs) are beneficial for acute lung injury and pulmonary fibrosis, mechanisms of mEV uptake by lung fibroblasts and their effects on myofibroblastic differentiation have not been established. We demonstrate that mEVs, but not fibroblast EVs (fEVs), suppress TGFbeta1-induced myofibroblastic differentiation of normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. MEVs display increased time and dose-dependent cellular uptake compared to fEVs. Removal or blocking of Thy 1, or blocking Thy-1-beta integrin interactions, decreased mEV uptake and prevented suppression of myofibroblastic differentiation. MicroRNAs (miRs) 199a/b 3p, 21-5p, 630, 22-3p, 196a-5p, 199b-5p, 34a-5p and 148a-3p are selectively packaged in mEVs. In silico analyses indicated that IPF lung fibroblasts have increased expression of genes that are targets of mEV-enriched miRs. MiR-630 mimics blocked TGFbeta1 induction of CDH2 in normal and IPF fibroblasts, and antagomiR-630 abrogated the effect of mEV on CDH2 expression. These data suggest that the interaction of Thy-1 with beta integrins mediates mEV uptake by lung fibroblasts, which blocks myofibroblastic differentiation, and that mEVs are enriched for miRs that target profibrotic genes up-regulated in IPF fibroblasts. PMID- 29273799 TI - RNA-seq identifies a diminished differentiation gene signature in primary monolayer keratinocytes grown from lesional and uninvolved psoriatic skin. AB - Keratinocyte (KC) hyper-proliferation and epidermal thickening are characteristic features of psoriasis lesions, but the specific contributions of KCs to plaque formation are not fully understood. This study used RNA-seq to investigate the transcriptome of primary monolayer KC cultures grown from lesional (PP) and non lesional (PN) biopsies of psoriasis patients and control subjects (NN). Whole skin biopsies from the same subjects were evaluated concurrently. RNA-seq analysis of whole skin identified a larger number of psoriasis-increased differentially expressed genes (DEGs), but analysis of KC cultures identified more PP- and PN-decreased DEGs. These latter DEG sets overlapped more strongly with genes near loci identified by psoriasis genome-wide association studies and were enriched for genes associated with epidermal differentiation. Consistent with this, the frequency of AP-1 motifs was elevated in regions upstream of PN-KC decreased DEGs. A subset of these genes belonged to the same co-expression module, mapped to the epidermal differentiation complex, and exhibited differentiation-dependent expression. These findings demonstrate a decreased differentiation gene signature in PP/PN-KCs that had not been identified by pre genomic studies of patient-derived monolayers. This may reflect intrinsic defects limiting psoriatic KC differentiation capacity, which may contribute to compromised barrier function in normal-appearing uninvolved psoriatic skin. PMID- 29273800 TI - Developing and diagnosing climate change indicators of regional aerosol optical properties. AB - Given the importance of aerosol particles to radiative transfer via aerosol radiation interactions, a methodology for tracking and diagnosing causes of temporal changes in regional-scale aerosol populations is illustrated. The aerosol optical properties tracked include estimates of total columnar burden (aerosol optical depth, AOD), dominant size mode (Angstrom exponent, AE), and relative magnitude of radiation scattering versus absorption (single scattering albedo, SSA), along with metrics of the structure of the spatial field of these properties. Over well-defined regions of North America, there are generally negative temporal trends in mean and extreme AOD, and SSA. These are consistent with lower aerosol burdens and transition towards a relatively absorbing aerosol, driven primarily by declining sulfur dioxide emissions. Conversely, more remote regions are characterized by increasing mean and extreme AOD that is attributed to increased local wildfire emissions and long-range (transcontinental) transport. Regional and national reductions in anthropogenic emissions of aerosol precursors are leading to declining spatial autocorrelation in the aerosol fields and increased importance of local anthropogenic emissions in dictating aerosol burdens. However, synoptic types associated with high aerosol burdens are intensifying (becoming more warm and humid), and thus changes in synoptic meteorology may be offsetting aerosol burden reductions associated with emissions legislation. PMID- 29273801 TI - Environmental conditions during winter predict age- and sex-specific differences in reproductive success of a trans-Saharan migratory bird. AB - Previous studies have linked winter habitat with subsequent breeding phenology and physical condition of migratory birds, but few have found delayed effects of winter habitat on subsequent reproductive success. The aim of this study was to test if African winter habitat is related to subsequent reproductive success of house martins (Delichon urbicum) breeding at a colony in Spain. We measured stable isotope (delta2H, delta13C, delta15N) values from feathers moulted in West Africa and used confirmatory path analysis to test if isotopic values of winter grown feathers were related to reproductive success through the mediation of breeding phenology and body condition. We conducted separate analyses for males, females and age classes (yearlings vs >= 2 years old). Experienced males wintering in habitats of higher rainfall (as inferred from lower feather delta2H values) were in better body condition and produced more offspring during the subsequent breeding season. In contrast, we did not find any effect of winter habitat on reproductive success of young males or females. These findings provide evidence consistent with a complex causal link between winter habitat quality and subsequent breeding success of long-distance migratory songbirds. PMID- 29273802 TI - Multiple Cryptic Binding Sites are Necessary for Robust Fibronectin Assembly: An In Silico Study. AB - The mechanism of assembly of the extracellular matrix protein fibronectin (FN) into elastic, insoluble fibrils is still poorly understood. FN fibrillogenesis requires cell-generated forces, which expose cryptic FN-FN binding sites buried in FN Type III domains. The number and location of cryptic binding sites have been debated, but experimental evidence suggests multiple domains may contain FN FN binding sites. The requirement of cell-dependent forces to generate FN fibrils restricts investigation of the mechanism of assembly. To address this, we use a recently developed biophysical model of fibrillogenesis to test competing hypotheses for the location and number of cryptic FN-FN binding sites and quantify the effect of these molecular alterations on assembled FN fibril properties. Simulations predict that a single FN-FN binding site facilitates either negligible fibrillogenesis or produces FN fibrils that are neither robust nor physiological. However, inclusion of multiple FN-FN binding sites predicts robust fibrillogenesis, which minimally depends on individual domain properties. Multiple FN-FN binding site models predict a heterogeneous fibril population that contains two distinct phenotypes with unique viscoelastic properties, which we speculate may play a key role in generating heterogeneous mechanical signaling in the extracellular matrix of developing and regenerating tissues. PMID- 29273803 TI - Mapping regulatory variants in hiPSC models. PMID- 29273804 TI - Is H3K4me1 at enhancers correlative or causative? PMID- 29273805 TI - Bacterial genomics of plant adaptation. PMID- 29273809 TI - A re-engineered immunotoxin shows promising preclinical activity in ovarian cancer. AB - RG7787 is a re-engineered mesothelin-targeted immunotoxin with reduced immunogenicity composed of a humanized anti-mesothelin Fab fragment and a B-cell epitope silenced 24 kD fragment of Pseudomonas exotoxin A. High prevalence of mesothelin-positive cases and a large unmet medical need make ovarian cancer a promising indication for the clinical development of RG7787. However, ovarian cancer patients also frequently have elevated serum levels of the cancer antigen 125 (CA-125). In principle this could pose a problem, since the binding sites for CA-125 and RG7787 on mesothelin were reported to overlap. However, we show here that RG7787 can readily displace even excess amounts of CA-125 in different cellular assays. Moreover when tested in-vitro on a panel of 12 ovarian cancer cell lines, RG7787 had high cytotoxic activity on COV644, Caov-4, and SNU-119 cells and fully inhibited growth of EFO-21, KURAMOCHI, OVSAHO, and Caov-3 cells with potency values ranging from 1 to 86 pM. Finally, we evaluated the in-vivo efficacy of RG7787 in OvCa6668, a patient-derived ovarian cancer model with high levels of CA-125 expression. RG7787 had moderate monotherapy efficacy but in combination with standard chemotherapies (cisplatin, paclitaxel) achieved pronounced tumor regressions. In summary our data support clinical testing of RG7787 in ovarian cancer. PMID- 29273808 TI - Near-field spectroscopic investigation of dual-band heavy fermion metamaterials. AB - Broadband tunability is a central theme in contemporary nanophotonics and metamaterials research. Combining metamaterials with phase change media offers a promising approach to achieve such tunability, which requires a comprehensive investigation of the electromagnetic responses of novel materials at subwavelength scales. In this work, we demonstrate an innovative way to tailor band-selective electromagnetic responses at the surface of a heavy fermion compound, samarium sulfide (SmS). By utilizing the intrinsic, pressure sensitive, and multi-band electron responses of SmS, we create a proof-of-principle heavy fermion metamaterial, which is fabricated and characterized using scanning near field microscopes with <50 nm spatial resolution. The optical responses at the infrared and visible frequency ranges can be selectively and separately tuned via modifying the occupation of the 4f and 5d band electrons. The unique pressure, doping, and temperature tunability demonstrated represents a paradigm shift for nanoscale metamaterial and metasurface design. PMID- 29273810 TI - Hierarchical Porous Chitosan Sponges as Robust and Recyclable Adsorbents for Anionic Dye Adsorption. AB - Biomass waste treatment and detrimental dye adsorption are two of the crucial environmental issues nowadays. In this study, we investigate to simultaneously resolve the aforementioned issues by synthesizing chitosan sponges as adsorbents toward rose bengal (RB) dye adsorption. Through a temperature-controlled freeze casting process, robust and recyclable chitosan sponges are fabricated with hierarchical porosities resulted from the control of concentrations of chitosan solutions. Tested as the adsorbents for RB, to the best of our knowledge, the as prepared chitosan sponge in this work reports the highest adsorption capacity of RB (601.5 mg/g) ever. The adsorption mechanism, isotherm, kinetics, and thermodynamics are comprehensively studied by employing statistical analysis. Importantly and desirably, the sponge type of chitosan adsorbents exceedingly facilitates the retrieving and elution of chitosan sponges for recyclable uses. Therefore, the chitosan sponge adsorbent is demonstrated to possess dramatically squeezable capability with durability for 10,000 cycles and recyclable adsorption for at least 10 cycles, which provides an efficient and economical way for both biomass treatment and water purification. PMID- 29273812 TI - Diurnal cloud cycle biases in climate models. AB - Clouds' efficiency at reflecting solar radiation and trapping the terrestrial radiation is strongly modulated by the diurnal cycle of clouds (DCC). Much attention has been paid to mean cloud properties due to their critical role in climate projections; however, less research has been devoted to the DCC. Here we quantify the mean, amplitude, and phase of the DCC in climate models and compare them with satellite observations and reanalysis data. While the mean appears to be reliable, the amplitude and phase of the DCC show marked inconsistencies, inducing overestimation of radiation in most climate models. In some models, DCC appears slightly shifted over the ocean, likely as a result of tuning and fortuitously compensating the large DCC errors over the land. While this model tuning does not seem to invalidate climate projections because of the limited DCC response to global warming, it may potentially increase the uncertainty of climate predictions. PMID- 29273806 TI - Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. AB - We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms. PMID- 29273811 TI - The stringent response promotes biofilm dispersal in Pseudomonas putida. AB - Biofilm dispersal is a genetically programmed response enabling bacterial cells to exit the biofilm in response to particular physiological or environmental conditions. In Pseudomonas putida biofilms, nutrient starvation triggers c-di-GMP hydrolysis by phosphodiesterase BifA, releasing inhibition of protease LapG by the c-di-GMP effector protein LapD, and resulting in proteolysis of the adhesin LapA and the subsequent release of biofilm cells. Here we demonstrate that the stringent response, a ubiquitous bacterial stress response, is accountable for relaying the nutrient stress signal to the biofilm dispersal machinery. Mutants lacking elements of the stringent response - (p)ppGpp sythetases [RelA and SpoT] and/or DksA - were defective in biofilm dispersal. Ectopic (p)ppGpp synthesis restored biofilm dispersal in a ?relA ?spoT mutant. In vivo gene expression analysis showed that (p)ppGpp positively regulates transcription of bifA, and negatively regulates transcription of lapA and the lapBC, and lapE operons, encoding a LapA-specific secretion system. Further in vivo and in vitro characterization revealed that the PbifA promoter is dependent on the flagellar sigma factor FliA, and positively regulated by ppGpp and DksA. Our results indicate that the stringent response stimulates biofilm dispersal under nutrient limitation by coordinately promoting LapA proteolysis and preventing de novo LapA synthesis and secretion. PMID- 29273813 TI - Proximity of signallers can maintain sexual signal variation under stabilizing selection. AB - How sexual communication systems can evolve under stabilizing selection is still a paradox in evolutionary biology. In moths, females emit a species-specific sex pheromone, consisting of a blend of biochemically related components, to which males are attracted. Although males appear to exert strong stabilizing selection on female pheromone, these blends seem to have evolved rapidly, as evidenced by ~120,000 moth species. Here we propose and test a "proximity model" wherein two females that vary in their relative attractiveness to males, can both benefit from calling in close proximity to each other. In a field study, we show that (1) artificially selected unattractive females can achieve mating rates comparable to attractive females if they signal in close proximity to attractive females, and (2) attractive females benefit from higher mating rates when signalling in close proximity to unattractive females. We propose that frequency-dependent behavioural and spatial interactions can sustain signal variation within populations even when these signals are under stabilizing selection. PMID- 29273814 TI - The crucial role of the TRPM7 kinase domain in the early stage of amelogenesis. AB - Transient receptor potential melastatin-7 (TRPM7) is a bi-functional protein containing a kinase domain fused to an ion channel. TRPM7 is highly expressed in ameloblasts during tooth development. Here we show that TRPM7 kinase-inactive knock-in mutant mice (TRPM7 KR mice) exhibited small enamel volume with opaque white-colored incisors. The TRPM7 channel function of ameloblast-lineage cells from TRPM7 KR mice was normal. Interestingly, phosphorylation of intracellular molecules including Smad1/5/9, p38 and cAMP response element binding protein (CREB) was inhibited in ameloblasts from TRPM7 KR mice at the pre-secretory stage. An immunoprecipitation assay showed that CREB was bound to TRPM7, suggesting that direct phosphorylation of CREB by TRPM7 was inhibited in ameloblast-lineage cells from TRPM7 KR mice. These results indicate that the function of the TRPM7 kinase domain plays an important role in ameloblast differentiation, independent of TRPM7 channel activity, via phosphorylation of CREB. PMID- 29273815 TI - Hydrothermal transformation of SnSe crystal to Se nanorods in oxalic acid solution and the outstanding thermoelectric power factor of Se/SnSe composite. AB - The present work demonstrates the synthesis of one-dimensional (1D) Se nanorods with ~50 nm diameter by hydrothermal transformation of SnSe crystals in oxalic acid solution and suggests the reaction mechanism for this chemical transformation. SnSe particles react with oxalic acid to generate numerous Se nuclei, which crystallize into Se nanorods due to the intrinsic character of the 1D growth of Se. The resulting Se/SnSe composite exhibits outstanding thermoelectric power factor without the aid of any rare dopants, which is higher than both undoped polycrystalline SnSe and SnSe doped with Pb and Cu. PMID- 29273816 TI - Novel Mealtime Duration Measures: Reliability and Preliminary Associations With Clinical Feeding and Swallowing Performance in Self-Feeding Children With Cerebral Palsy. AB - Purpose: The purpose of this study is to examine (a) the reliability of newly developed measures of mealtime duration and (b) their relationship to clinical feeding/swallowing performance in children with spastic cerebral palsy (SCP). Method: Seventeen self-feeding children (9 boys, 8 girls) with SCP (age range = 5;1 [years;months] to 17;6, Gross Motor Function Classification System range = I IV) were assessed during mealtimes using the Dysphagia Disorder Survey (DDS; Sheppard, Hochman, & Baer, 2014). Children were divided into 2 groups, children with primarily unilateral or bilateral brain involvement. Duration measures included mealtime duration and total sip/bite duration for each bolus type (liquid and solid). Results: Excellent intra- and inter-rater reliability for all duration measures was observed (intraclass correlation coefficient [ICC] = 1.00 and 0.955, respectively, for mealtime duration; ICC = 1.00 and 0.963, respectively, for solid/bite duration; ICC = 1.00 and 0.957, respectively, for liquid/sip duration). Positive correlations were found between total mealtime duration and DDS Part 1, rs = .514 [.045-.797], p = .035; Part 2, rs = .528 [.064 .804], p = .029; and total scores, rs = .665 [.271-.868], p = .004, and between total solid/bite duration and DDS Part 1, rs = .579 [.137-.828], p = .015; Part 2, rs = .620 [.199-.847], p = .007; and total scores, rs = .762 [.444-.909], p < .001. Children with unilateral brain involvement exhibited significantly lower DDS total (p = .049) and Part 2 scores (p = .026), indicating better feeding/swallowing performance/skills. They also had shorter mealtime duration (p = .019) and solid/bite duration (p = .025) compared with children with bilateral involvement. Conclusions: Our new mealtime duration measures are reliable and correlate with feeding/swallowing performance in a sample of self-feeding children with SCP. Therefore, they may be useful supplements to feeding/swallowing assessments for this population. Supplemental Material: https://doi.org/10.23641/asha.5715076. PMID- 29273817 TI - Evaluation of Language Predictors of Main Concept Production in Spanish/English Bilingual Discourse Using Nicholas and Brookshire Stimuli. AB - Purpose: A conceptual framework of bilingual aphasia assessment requires an understanding of the variables that influence discourse in bilingual speakers. This study aimed to determine predictors of main concept (MC) production, a measure of discourse completeness, as well as the effect of language dominance on MCs. Method: The Nicholas and Brookshire (1993) picture stimuli were used to elicit English and Spanish discourse in 83 young bilinguals. Participant-reported variables (e.g., proficiency self-ratings) and measured language variables (e.g., correct information units [CIUs] in discourse) were entered into regressions to determine potential MC predictors. A repeated-measures analysis of variance evaluated MCs within and across dominance groups categorized by speaking self ratings. Results: Measured language variables (number of CIUs, naming accuracy) were most predictive of MCs. The participant-reported variable most associated with MC production was self-rating of speaking proficiency. Spanish- and English dominant groups produced more MCs in their dominant language; the balanced group produced more English MCs. Between-groups differences were observed. Conclusions: Two measures related to lexical retrieval (CIUs and naming) were most predictive of MC production across languages. Participant ratings of speaking proficiency were also highly correlated to MCs. They also accurately reflected dominance, though balanced bilinguals overestimated their Spanish abilities. Supplemental Material: https://doi.org/10.23641/asha.5708605. PMID- 29273818 TI - Do Transmasculine Speakers Present With Gender-Related Voice Problems? Insights From a Participant-Centered Mixed-Methods Study. AB - Purpose: The purpose of this study was to investigate whether there are indications of gender-related voice problems in our transmasculine participants and to analyze how discrepancies between participant self-evaluations and researcher-led examinations can be best negotiated to ensure a participant centered interpretation. Method: We conducted a participant-centered mixed methods study combining qualitative content analyses of semistructured interviews, acoustical voice analyses, and an examination of gender attributions to voice. Fourteen German-speaking transmasculine people, 14 cisfemale control persons, and 7 cismale control persons participated. The data were examined for indications of gender-related voice problems pertaining to vocal gender presentation and gender attribution to voice received from others. Results: Eleven participants (79%) presented with indications of gender-related voice problems. Problems included dissatisfaction with gender-related voice features, difficulties with control of vocal gender presentation, and mismatch between desired gender attribution and gender attributions received from others. Discrepancies between participant self-evaluations and researcher-led examinations were observed in a number of cases. Conclusion: Transmasculine speakers may experience a range of gender-related voice problems. Research and clinical practice with transmasculine people need to be adapted to better match the diversity of the population and the complexity of the processes that shape the production of speaker vocal gender in interaction. PMID- 29273820 TI - Effects of caffeine on reaction time are mediated by attentional rather than motor processes. AB - BACKGROUND: Caffeine has a well-established effect on reaction times (RTs) but the neurocognitive mechanisms underlying this are unclear. METHODS: In the present study, 15 female participants performed an oddball task after ingesting caffeine or a placebo, and electroencephalographic data were obtained. Single trial P3b latencies locked to the stimulus and to the response were extracted and mediation models were fitted to the data to test whether caffeine's effect on RTs was mediated by its effect on either type of P3b latencies. RESULTS: Stimulus locked latencies showed clear evidence of mediation, with approximately a third of the effect of caffeine on RTs running through the processes measured by stimulus-locked latencies. Caffeine did not affect response-locked latencies, so could not mediate the effect. DISCUSSION: These findings are consistent with caffeine's effect on RTs being a result of its effect on perceptual-attentional processes, rather than motor processes. The study is the first to apply mediation analysis to single-trial P3b data and this technique holds promise for mental chronometric studies into the effects of psychopharmacological agents. The R code for performing the single trial analysis and mediation analysis are included as supplementary materials. PMID- 29273819 TI - Nanomaterials: certain aspects of application, risk assessment and risk communication. AB - Development and market introduction of new nanomaterials trigger the need for an adequate risk assessment of such products alongside suitable risk communication measures. Current application of classical and new nanomaterials is analyzed in context of regulatory requirements and standardization for chemicals, food and consumer products. The challenges of nanomaterial characterization as the main bottleneck of risk assessment and regulation are presented. In some areas, e.g., quantification of nanomaterials within complex matrices, the establishment and adaptation of analytical techniques such as laser ablation inductively coupled plasma mass spectrometry and others are potentially suited to meet the requirements. As an example, we here provide an approach for the reliable characterization of human exposure to nanomaterials resulting from food packaging. Furthermore, results of nanomaterial toxicity and ecotoxicity testing are discussed, with concluding key criteria such as solubility and fiber rigidity as important parameters to be considered in material development and regulation. Although an analysis of the public opinion has revealed a distinguished rating depending on the particular field of application, a rather positive perception of nanotechnology could be ascertained for the German public in general. An improvement of material characterization in both toxicological testing as well as end-product control was concluded as being the main obstacle to ensure not only safe use of materials, but also wide acceptance of this and any novel technology in the general public. PMID- 29273821 TI - The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research. AB - RATIONALE: Consideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health. OBJECTIVE: The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA. RESULTS: Kratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems. CONCLUSIONS: Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use. PMID- 29273822 TI - Management of idiopathic spinal epidural lipomatosis: a case report and review of the literature. AB - BACKGROUND: Spinal epidural lipomatosis (SEL) is a rare pathologic growth of histologically normal unencapsulated adipose tissue in the epidural space. Although rare, SEL can compress the spinal cord or nerve roots causing myelopathy or radiculopathy. While SEL has been associated with long-term exposure to endogenous or exogenous steroids and obesity, idiopathic forms of SEL are much rarer. CASE REPORT: In this report, we present the first case of SEL isolated to the cervical region compressing the spinal cord in a healthy, non-obese, preadolescent patient. CONCLUSION: Idiopathic SEL in the pediatric population is a rare entity. This is the first case of epidural lipomatosis isolated to the cervical region in an adult or child patient. In refractory, symptomatic cases of idiopathic SEL, surgical decompression is often required. PMID- 29273823 TI - Preoperative anxiety in children undergoing neurosurgical operations and proposed effective interventions. PMID- 29273824 TI - Accuracy of the third molar maturity index in assessing the legal age of 18 years: a systematic review and meta-analysis. AB - The age estimation is a complex procedure required in the daily practice of legal medicine. The maturity of third molars stands out by the age of 18 because these teeth are still in development. This systematic review aimed to assess the accuracy of the third molar maturity index (I 3M), proposed by Cameriere et al. (2008), in discriminating whether an individual is under or over 18 years. Seven electronic databases were screened: PubMed, Scopus, ISI Web of Science, Cochrane Library, LILACS, SIGLE, and CAPES. Eligible studies included an assessment of I 3M accuracy at the 0.08 cut-off value. The quality assessment was performed by using QUADAS 2. Three meta-analyses (MA) were accomplished: overall, one for males and another for females. From 2397 articles identified, 16 met the eligibility criteria. Of these, two showed high risk of bias, one in the reference standard domain and the other in the flow and timing domain. The percentage of individuals correctly classified ranged from 72.4 to 96.0%. The overall MA showed pooled sensitivity of 0.86 (0.84 to 0.87; p = 0.0000) and pooled specificity of 0.93 (0.92 to 0.94; p = 0.0000). The AUC (area under the summary receiver operator characteristics curve) and DOR (diagnostic odds ratio) values were, respectively, 0.9652 and 104.68, indicating an overall high discrimination effect. Separately, better results of accuracy were found for males. High heterogeneity was achieved for both sensibility (94.6%) and specificity (88.8%). We conclude that the I 3M is a suitable and useful method for estimating adulthood regarding forensic purposes, regardless of gender. PMID- 29273825 TI - Localization and subcellular association of Grapevine Pinot Gris Virus in grapevine leaf tissues. AB - Despite the increasing impact of Grapevine Pinot gris disease (GPG-disease) worldwide, etiology about this disorder is still uncertain. The presence of the putative causal agent, the Grapevine Pinot Gris Virus (GPGV), has been reported in symptomatic grapevines (presenting stunting, chlorotic mottling, and leaf deformation) as well as in symptom-free plants. Moreover, information on virus localization in grapevine tissues and virus-plant interactions at the cytological level is missing at all. Ultrastructural and cytochemical investigations were undertaken to detect virus particles and the associated cytopathic effects in field-grown grapevine showing different symptom severity. Asymptomatic greenhouse grown grapevines, which tested negative for GPGV by real time RT-PCR, were sampled as controls. Multiplex real-time RT-PCR and ELISA tests excluded the presence of viruses included in the Italian certification program both in field grown and greenhouse-grown grapevines. Conversely, evidence was found for ubiquitous presence of Grapevine Rupestris Stem Pitting-associated Virus (GRSPaV), Hop Stunt Viroid (HSVd), and Grapevine Yellow Speckle Viroid 1 (GYSVd 1) in both plant groups. Moreover, in every field-grown grapevine, GPGV was detected by real-time RT-PCR. Ultrastructural observations and immunogold labelling assays showed filamentous flexuous viruses in the bundle sheath cells, often located inside membrane-bound organelles. No cytological differences were observed among field-grown grapevine samples showing different symptom severity. GPGV localization and associated ultrastructural modifications are reported and discussed, in the perspective of assisting management and control of the disease. PMID- 29273807 TI - Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. AB - Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. PMID- 29273826 TI - FRAX-based intervention and assessment thresholds in seven Latin American countries. AB - : Age-specific intervention and assessment thresholds were developed for seven Latin American countries. The intervention threshold ranged from 1.2% (Ecuador) to 27.5% (Argentina) at the age of 50 and 90 years, respectively. In the Latin American countries, FRAX offers a substantial advance for the detection of subjects at high fracture risk. INTRODUCTION: Intervention thresholds are proposed using the Fracture Risk Assessment (FRAX) tool. We recommended their use to calculate the ten-year probability of fragility fracture (FF) in both, men and women with or without the inclusion of bone mineral density (BMD). The purpose of this study is to compute FRAX-based intervention and BMD assessment thresholds for seven Latin American countries in men and women >= 40 years. METHODS: The intervention threshold (IT) was set at a 10-year probability of a major osteoporotic fracture (MOF) equivalent to a woman with a prior FF and a body mass index (BMI) equal to 25.0 kg/m2 without BMD or other clinical risk factors. The lower assessment threshold was set at a 10-year probability of a MOF in women with BMI equal to 25.0 kg/m2, no previous fracture and no clinical risk factors. The upper assessment threshold was set at 1.2 times the IT. RESULTS: For the seven LA countries, the age-specific IT varied from 1.5 to 27.5% in Argentina, 3.8 to 25.2% in Brazil, 1.6 up to 20.0% in Chile, 0.6 to 10.2% in Colombia, 0.9 up to 13.6% in Ecuador, 2.6 to 20.0% in Mexico, and 0.7 up to 22.0% in Venezuela at the age of 40 and 90 years, respectively. CONCLUSIONS: In the LA countries, FRAX-based IT offers a substantial advance for the detection of men and women at high fracture risk, particularly in the elderly. The heterogeneity of IT between the LA countries indicates that country-specific FRAX models are appropriate rather than a global LA model. PMID- 29273828 TI - Skeletal Radiology: The Year in Review 2017. PMID- 29273827 TI - Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis. AB - : Intestinal fractional calcium absorption (FCA) was assessed before and after vitamin D3 treatment. Serum 1,25(OH)2D concentration was significantly increased by plain vitamin D3 and reduced by eldecalcitol. The 1alpha hydroxyl calcidiol and eldecalcitol treatments increased FCA, which may be induced through direct stimulation of vitamin D receptors in the intestine. INTRODUCTION: To assess the effects of vitamin D3 compounds on intestinal FCA and calcium-regulating hormones in post-menopausal osteoporosis, a randomized open-label prospective study was conducted. METHODS: Forty eligible patients were allocated randomly into four groups: eldecalcitol (ELD; 0.75 MUg/day), 1alpha hydroxyl calcidiol (ALF; 1 MUg/day), plain vitamin D3 (800 IU/day), and control. Before and after the 4-week treatment, intestinal FCA was estimated by using a double isotope method, and serum concentrations of calcium-regulating hormones and a bone turnover marker were measured. RESULTS: The baseline FCA value of the participants was 21.5 +/- 7.9% (mean +/- SD) and was significantly correlated with serum 1,25(OH)2D (calcitriol) concentration. After the treatment, the FCA significantly increased by 59.5% (95% CI, 41.6 to 77.4%) in the ELD group and by 45.9% (27.9 to 63.8%) in the ALF group, whereas no significant change in the plain vitamin D3 group was found. Unlike the baseline FCA, post-treatment FCA exhibited no significant correlation with serum calcitriol concentration. Parathyroid hormone levels were suppressed by ALF and plain vitamin D3 but were sustained in the ELD and control groups. Serum calcitriol tended to be suppressed by ELD, whereas plain vitamin D3 treatment increased both serum 25(OH)D and calcitriol concentrations. CONCLUSION: These findings suggest that oral administration of vitamin D3 analogues (ALF and ELD) stimulates FCA but plain vitamin D3 does not. Those effects of vitamin D3 compounds on FCA were independent of serum calcitriol concentration, suggesting that ALF and ELD may directly stimulate intestinal vitamin D receptors. PMID- 29273830 TI - A posterior labral cyst associated with an anterior labral tear of the hip. AB - Paralabral cysts are often associated with labral and other intraarticular hip pathology; MRI as well as diagnostic ultrasound can assist in diagnosis. Although often considered a coincidental finding, paralabral cysts can be a separate pain generator about the hip through compression of surrounding anatomy. They can also be initially mistaken for malignancy or other pathology by providers unfamiliar with their appearance. We present the case of an active 33-year-old female with right hip pain secondary to a large symptomatic posterior acetabular paralabral cyst with concomitant anterior labral tear. Following diagnosis on MRI, treatment included ultrasound-guided aspiration of the cyst, followed by arthroscopic anterior labral repair and separate cyst decompression from a posterior portal. The patient had complete resolution of her symptoms. PMID- 29273829 TI - Isolated subcutaneous nontuberculous mycobacterial infection: a rare case initially mischaracterized as a soft tissue malignancy. AB - The occurrence of nontuberculous mycobacterial (NTM) infection is rare, and the involvement of the musculoskeletal system is even less common. However, the incidence of soft tissue and skin NTM infection is increasing, particularly in patients who undergo injections and minor surgical procedures. Given the non specific clinical manifestations of NTM infection, the lack of knowledge among physicians regarding this rare infection could lead to inaccurate and delayed diagnosis. Herein, we present a case of an isolated subcutaneous NTM infection caused by Mycobacterium abscessus in the upper back of an immunocompetent 68-year old woman. The clinical presentation, magnetic resonance imaging findings (including diffusion-weighted imaging), and pathologic findings of subcutaneous NTM infection are described and compared with those of tuberculosis and tumor presentations to provide a more accurate clinical picture for a differential diagnosis. PMID- 29273831 TI - Synergism between apolipoprotein E E4 allele and paraoxonase (PON1) 55-M allele is associated with risk of systemic lupus erythematosus. AB - Evidences indicate that abnormal lipid metabolism and lipid peroxidation can affect the progression of complications in systemic lupus erythematosus (SLE) patients. Apolipoprotein E (ApoE) and paraoxonase-1 (PON1) play important role in lipid metabolism and protection of lipid peroxidation. The polymorphisms of ApoE and paraoxonase (PON1) L55M (Met < Leu) allele genes lead to disorders in lipid metabolism and are related to atherosclerosis. This study is the first investigation to examine the possible association between ApoE and PON1-L55M polymorphisms and correlation with serum arylesterase (ARE) activities of PON, levels of malondialdehyde (MDA), neopterin, and lipid lipoprotein in SLE patients from Iranian western population. The present case-control study consisted of 107 SLE patients and 101 gender- and age-matched, unrelated, healthy controls from Iran's western population. The ApoE and PON1-L55M genotypes were identified using PCR-RFLP method. The serum level of MDA, neopterin, lipid levels, and ARE activity were determined by HPLC, commercial kits, and spectrophotometry, respectively. Our results showed that ApoE epsilon4 and PON1-55M alleles act synergistically to increase the risk of SLE by 1.47 times (p = 0.038). We found that the frequency of ApoE E3/E4 genotype was higher in SLE patients (11.2%) compared with control subjects (5%), although the difference was not significant (p = 0.087). This study for the first time not only demonstrates that ApoE E4 and PON-55M alleles synergistically increase the risk of SLE but also reveals that serum levels of MDA, neopterin, and LDL-C are high in SLE patients. This information may be in value for evaluating SLE progression and in the elucidation of the mechanisms of the disease pathogenesis. PMID- 29273832 TI - Early hearing loss detection in rheumatoid arthritis and primary Sjogren syndrome using extended high frequency audiometry. AB - The aim of this study is to evaluate the hearing behavior of rheumatoid arthritis (RA) and primary Sjogren syndrome (PSS) patients and compare them with a healthy control group and with each other. A comparative cross-sectional study was performed with a group of 117 female RA patients, a group of 60 female PSS patients, and a 251 female healthy control group. Every subject underwent a series of studies including high-frequency audiometry, speech audiometry, and tympanometry. The high-frequency audiometry measured 250 to 16,000 Hz. The 117 patients with RA and the 60 with PSS were diagnosed according to American College of Rheumatology criteria / ACR 2010, and the validated classification of the American-European Consensus Group. Hearing loss was present in 36.8% of the RA group in 500-3000 Hz, 68.4% in 4000-8000 Hz, and 94.9% in 10,000-16,000 Hz. Hearing loss was present in 60% of the PSS group in 500-3000 Hz, 70% in 4000-8000 Hz, and 100% in 10,000-16,000 Hz. The hearing impairment prevalence of both groups was significantly different (p < 0.05) when compared with the healthy control group. We also compared the hearing thresholds between RA and PSS patients, finding a significant hearing threshold increase in 500-3000 Hz of the PSS group. This study consolidates the association between RA and PSS with hearing impairment. A deeper hearing loss was reported in PSS than in RA patients, demonstrating a greater auditory and speech recognition repercussion. PMID- 29273833 TI - Prospective Observational Study on the Association Between Serum Mannose-Binding Lectin Levels and Severe Outcome in Critically Ill Patients with Pandemic Influenza Type A (H1N1) Infection. AB - BACKGROUND: Mannose-binding lectin (MBL) plays an important role in the innate immune response. In addition to activating the complement, MBL can induce cytokine production and contribute to a deleterious inflammatory response with severe A(H1N1)pdm09 virus infection. Our aim was to determine if serum MBL levels correlate with the risk of mortality in intensive care units (ICU) patients with A(H1N1)pdm09 infection. METHODS: Prospective observational study was performed in ICU patients with acute respiratory distress syndrome due to influenza A(H1N1)pdm09 virus. Demographic characteristics and severity indices were recorded at ICU admission. MBL was assayed from blood drawn at influenza diagnosis within 24-48 h following the ICU admission. Outcomes were compared according to MBL levels. Results are expressed as median and interquartile range. RESULTS: Serum MBL levels were studied in 27 patients (age: 56 [IQR 29] years) with severe A(H1N1)pdm09 infection and in 70 healthy controls. Median admission SAPSII and SOFA scores were 49 [IQR 26] and 12 [IQR 5], respectively. Mortality rate after a 30-day was 37%. MBL was significantly higher in non-survivors (3741 [IQR 2336] ng/ml) vs survivors (215 [IQR 1307] ng/ml), p = 0.006, as well as control group (1814 [IQR 2250] ng/ml), p = 0.01. In contrast, MBL levels in survivors group were significantly lower than the controls group (215 [IQR 1307] ng/ml vs. 1814 [IQR 2250] ng/ml, p = 0.005). MBL cut-off > 1870 ng/ml had a sensitivity of 80% and a specificity of 88.2% for mortality [AUC = 0.82 (95% CI 0.63-0.94)]. Kaplan-Meier analysis demonstrated a strong association between MBL levels and mortality (log-rank 7.8, p = 0.005). MBL > 1870 ng/ml was independently associated with mortality (HR = 8.7, 95% CI 1.2-29.1, p = 0.007). CONCLUSIONS: This study shows that baseline MBL > 1870 ng/ml is associated with higher mortality in ICU patients with severe A(H1N1)pdm09 infection. PMID- 29273834 TI - The effect of tar spot pathogen on host plant carbon balance and its possible consequences on a tundra ecosystem. AB - In Arctic tundra, plant pathogens have substantial effects on the growth and survival of hosts, and impacts on the carbon balance at the scale of ecological systems. To understand these effects on carbon dynamics across different scales including plant organ, individual, population and ecosystem, we focused on two primary factors: host productivity reduction and carbon consumption by the pathogen. We measured the effect of the pathogen on photosynthetic and respiratory activity in the host. We also measured respiration and the amount of carbon in the pathogen. We constructed a model based on these two factors, and calculated pathogenic effects on the carbon balance at different organismal and ecological scales. We found that carbon was reduced in infected leaves by 118% compared with healthy leaves; the major factor causing this loss was pathogenic carbon consumption. The carbon balance at the population and ecosystem levels decreased by 35% and 20%, respectively, at an infection rate of 30%. This case study provides the first evidence that a host plant can lose more carbon through pathogenic carbon consumption than through a reduction in productivity. Such a pathogenic effect could greatly change ecosystem carbon cycling without decreasing annual productivity. PMID- 29273835 TI - Competition between cheatgrass and bluebunch wheatgrass is altered by temperature, resource availability, and atmospheric CO2 concentration. AB - Global change drivers (elevated atmospheric CO2, rising surface temperatures, and changes in resource availability) have significant consequences for global plant communities. In the northern sagebrush steppe of North America, the invasive annual grass Bromus tectorum (cheatgrass) is expected to benefit from projected warmer and drier conditions, as well as increased CO2 and nutrient availability. In growth chambers, we addressed this expectation using two replacement series experiments designed to test competition between B. tectorum and the native perennial bunchgrass Pseudoroegneria spicata. In the first experiment, we tested the effects of elevated temperature, decreased water and increased nutrient availability, on competition between the two species. In the second, we tested the effects of elevated atmospheric CO2 and decreased water availability on the competitive dynamic. In both experiments, under all conditions, P. spicata suppressed B. tectorum, though, in experiment one, warmer and drier conditions and elevated nutrient availability increased B. tectorum's competitiveness. In experiment two, when grown in monoculture, both species responded positively to elevated CO2. However, when grown in competition, elevated CO2 increased P. spicata's suppressive effect, and the combination of dry soil conditions and elevated CO2 enhanced this effect. Our findings demonstrate that B. tectorum competitiveness with P. spicata responds differently to global change drivers; thus, future conditions are unlikely to facilitate B. tectorum invasion into established P. spicata communities of the northern sagebrush steppe. However, disturbance (e.g., fire) to these communities, and the associated increase in soil nutrients, elevates the risk of B. tectorum invasion. PMID- 29273836 TI - Return to sports after reverse shoulder arthroplasty-the Swiss perspective. AB - PURPOSE: This patient survey evaluated the return to previous sports activities in Swiss patients up to five years after reverse shoulder arthroplasty (RSA). METHODS: We screened our local shoulder arthroplasty registry for patients registered with a unilateral RSA due to rotator cuff deficiency between May 2010 and May 2015. Revision cases and patients already known as unwilling or unable to complete a German language questionnaire were excluded. Eligible patients received a paper questionnaire asking about their past and current sports activities, return time point and level of activity. RESULTS: Of 305 patients, 89% responded at a mean post-operative follow-up of 2.9 years (SD 1.1). The respondents had a mean age of 77.1 years (SD 7.8) and included 62% females. The overall rate of patients returning to a previous sports activity was 77%. Sixty one percent (166/271) participated in regular sports activities before the onset of their shoulder disorders. After RSA, 47% (127/271) participated in at least one sport type with the most frequent activities including hiking (66), swimming (53), cycling (45) and callisthenics (43). Most patients carried out their main sports activity after surgery with a moderate level of intensity (83%) and between one to three times per week (69%). Forty-two percent of the respondents indicated that returning to sports was among their key demands after RSA. CONCLUSIONS: Returning to previous sports activities is an important expectation of RSA patients, and the majority do. Patient expectations of post-operative sports activity need to be addressed when planning RSA. PMID- 29273837 TI - Diaphyseal long bone nonunions - types, aetiology, economics, and treatment recommendations. AB - The intention of the current article is to review the epidemiology with related socioeconomic costs, pathophysiology, and treatment options for diaphyseal long bone delayed unions and nonunions. Diaphyseal nonunions in the tibia and in the femur are estimated to occur 4.6-8% after modern intramedullary nailing of closed fractures with an even much higher risk in open fractures. There is a high socioeconomic burden for long bone nonunions mainly driven by indirect costs, such as productivity losses due to long treatment duration. The classic classification of Weber and Cech of the 1970s is based on the underlying biological aspect of the nonunion differentiating between "vital" (hypertrophic) and "avital" (hypo-/atrophic) nonunions, and can still be considered to represent the basis for basic evaluation of nonunions. The "diamond concept" units biomechanical and biological aspects and provides the pre-requisites for successful bone healing in nonunions. For humeral diaphyseal shaft nonunions, excellent results for augmentation plating were reported. In atrophic humeral shaft nonunions, compression plating with stimulation of bone healing by bone grafting or BMPs seem to be the best option. For femoral and tibial diaphyseal shaft fractures, dynamization of the nail is an atraumatic, effective, and cheap surgical possibility to achieve bony consolidation, particularly in delayed nonunions before 24 weeks after initial surgery. In established hypertrophic nonunions in the tibia and femur, biomechanical stability should be addressed by augmentation plating or exchange nailing. Hypotrophic or atrophic nonunions require additional biological stimulation of bone healing for augmentation plating. PMID- 29273838 TI - Ethnic inequalities in health between Arabs and Jews in Israel: the relative contribution of individual-level factors and the living environment. AB - OBJECTIVES: Ethnic inequalities in health (EIH) are unjust public health problem that emerge across societies. In Israel, despite uniform healthcare coverage, marked EIH persist between Arabs and Jews. METHODS: We draw on the ecosocial approach to examine the relative contributions of individual socioeconomic status (SES), psychosocial and health behavioral factors, and the living environment (neighborhood problems, social capital, and social participation) to explaining ethnic differences in self-rated health (SRH). Data were derived from two nationwide studies conducted in 2004-2005 of stratified samples of Arabs (N = 902) and Jews (N = 1087). RESULTS: Poor SRH was significantly higher among Arabs after adjustment for age and gender [odds ratio and 95% confidence interval (CI) = 1.94 (1.57-2.40)]. This association was reversed following adjustment for all possible mediators: OR (95% CI) = 0.70(0.53-0.92). The relative contribution of SES and the living environment was sizable, each attenuating the EIH by 40%, psychosocial factors by 25%, and health behaviors by 16%. CONCLUSIONS: Arabs in Israel have poorer SRH than Jews. Polices to reduce this inequality should mainly focus on improving the SES and the living conditions of the Arabs, which might enhance health behaviors and well-being. PMID- 29273840 TI - ETS-NOCV decomposition of the reaction force for double-proton transfer in formamide-derived systems. AB - The analysis of the electronic-structure changes along IRC paths for double proton-transfer reactions in the formamide dimer (R1), formamide-thioformamide system (R2), and the thioformamide dimer (R3) was performed based on the extended transition-state natural orbitals for chemical valence (ETS-NOCV) partitioning of the reaction force, considering the intra-fragments strain and the inter fragments interaction terms, and further-the electrostatic, Pauli-repulsion and orbital interaction components, with the latter being decomposed into the NOCV components. Two methods of the system partitioning into the fragments were considered ('reactant perspective'/bond-formation, 'product perspective' / bond breaking). In agreement with previous studies, the results indicate that the major changes in the electronic structure occur in the transition state region; the bond-breaking processes are, however, initiated already in the reactant region, prior to entering the TS region. The electrostatic contributions were identified as the main factor responsible for the increase in the activation barrier in the order R1 < R2 < R3. PMID- 29273839 TI - Laminar shear stress inhibits high glucose-induced migration and invasion in human bladder cancer cells. AB - High glucose has been known to play a pathogenic role in the development and progression of bladder cancer in diabetics, whereas the leading cause of death in such patients is mainly attributed to hyperglycemia-enhanced metastasis. In addition to the impact of glucose, cancer cells may be affected by laminar shear stress (LSS) generated from interstitial, blood, and/or lymphatic fluid flows during metastasis. Although the effect of flow-induced mechanical force on cancer pathophysiology has been extensively investigated, very little is understood regarding the cells that are simultaneously stimulated by LSS and hyperglycemia. To address this issue, the influence of LSS on bladder cancer cell motility in a hyperglycemic environment was examined. Based on the results of cell movement and protein expression analyses, we found that both cell migration and invasion were up- and downregulated by 25 mM glucose and 12 dynes/cm2 LSS, respectively. Furthermore, the motility of the cells with simultaneous hyperglycemic and LSS stimulations was significantly reduced compared with that of the cells stimulated by high glucose alone (P < 0.05), demonstrating that the LSS rather than hyperglycemia played the dominant role in regulation of cell motility. These results implied that LSS with an intensity >= 12 dynes/cm2 may serve as a feasible tool to reduce bladder cancer motility in diabetics. PMID- 29273842 TI - Evaluation of Graphene/WO3 and Graphene/CeO x Structures as Electrodes for Supercapacitor Applications. AB - The combination of graphene with transition metal oxides can result in very promising hybrid materials for use in energy storage applications thanks to its intriguing properties, i.e., highly tunable surface area, outstanding electrical conductivity, good chemical stability, and excellent mechanical behavior. In the present work, we evaluate the performance of graphene/metal oxide (WO3 and CeO x ) layered structures as potential electrodes in supercapacitor applications. Graphene layers were grown by chemical vapor deposition (CVD) on copper substrates. Single and layer-by-layer graphene stacks were fabricated combining graphene transfer techniques and metal oxides grown by magnetron sputtering. The electrochemical properties of the samples were analyzed and the results suggest an improvement in the performance of the device with the increase in the number of graphene layers. Furthermore, deposition of transition metal oxides within the stack of graphene layers further improves the areal capacitance of the device up to 4.55 mF/cm2, for the case of a three-layer stack. Such high values are interpreted as a result of the copper oxide grown between the copper substrate and the graphene layer. The electrodes present good stability for the first 850 cycles before degradation. PMID- 29273843 TI - Estimating the Reference Incremental Cost-Effectiveness Ratio for the Australian Health System. AB - BACKGROUND: Spending on new healthcare technologies increases net population health when the benefits of a new technology are greater than their opportunity costs-the benefits of the best alternative use of the additional resources required to fund a new technology. OBJECTIVE: The objective of this study was to estimate the expected incremental cost per quality-adjusted life-year (QALY) gained of increased government health expenditure as an empirical estimate of the average opportunity costs of decisions to fund new health technologies. The estimated incremental cost-effectiveness ratio (ICER) is proposed as a reference ICER to inform value-based decision making in Australia. METHODS: Empirical top down approaches were used to estimate the QALY effects of government health expenditure with respect to reduced mortality and morbidity. Instrumental variable two-stage least-squares regression was used to estimate the elasticity of mortality-related QALY losses to a marginal change in government health expenditure. Regression analysis of longitudinal survey data representative of the general population was used to isolate the effects of increased government health expenditure on morbidity-related, QALY gains. Clinical judgement informed the duration of health-related quality-of-life improvement from the annual increase in government health expenditure. RESULTS: The base-case reference ICER was estimated at AUD28,033 per QALY gained. Parametric uncertainty associated with the estimation of mortality- and morbidity-related QALYs generated a 95% confidence interval AUD20,758-37,667. CONCLUSION: Recent public summary documents suggest new technologies with ICERs above AUD40,000 per QALY gained are recommended for public funding. The empirical reference ICER reported in this article suggests more QALYs could be gained if resources were allocated to other forms of health spending. PMID- 29273845 TI - No need for NMDA receptor antibody screening in neurologically asymptomatic patients with ovarian teratomas. PMID- 29273844 TI - Attitudes, perceptions, and use of marijuana in youth with multiple sclerosis. AB - BACKGROUND: Studies have shown a negative impact on cognition and brain volume in marijuana-using adult multiple sclerosis (MS) patients and healthy adolescents. Given that onset of MS during childhood and adolescence negatively impacts brain growth and the normal maturation of neuronal networks, the addition of marijuana exposure in these youth may be even more harmful. OBJECTIVE: Determine attitudes toward and prevalence of recreational marijuana use in MS youth. METHODS: We surveyed 52 consecutive pediatric-onset MS patients from three pediatric MS centers in the United States. Participants answered a structured questionnaire to capture attitudes toward marijuana and personal use habits, if present. RESULTS: Nearly half reported use of marijuana, with the majority beginning to use in mid to-late adolescence. The most popular reasons for using marijuana were relaxation (72%), improvement of medical problems (64%), and stress reduction (52%). Over half (64%) of marijuana users perceived it to have negative effects on memory and focus. Cost and access were not barriers to use, despite all respondents being less than age 21. CONCLUSION: Youth with MS endorse recreational marijuana as safe, and many use marijuana frequently despite appreciating a negative impact on memory. More detailed understanding of the long-term impact of marijuana use in youth with MS is needed. PMID- 29273846 TI - Intrathecal oligoclonal bands synthesis in multiple sclerosis: is it always a prognostic factor? AB - BACKGROUND: Oligoclonal IgM (OCMB) and IgG (OCGB) bands were found to be associated with poor multiple sclerosis (MS) prognosis. OBJECTIVE: We aimed to evaluate the prognostic value of OCMB/OCGB in a cohort of Sardinian MS patients. MATERIALS AND METHODS: We recruited patients from the University of Cagliari. They underwent lumbar puncture for diagnostic purposes. Demographic and the following clinical data were recorded: clinical course; time to reach EDSS 3 and 6; EDSS at last follow-up; and MS treatments. The influence of gender, clinical course, age at onset, treatments, and OCGB/OCMB on reaching EDSS 3 was analysed using Cox regression. Kaplan-Meier curves were used to study the time to reach EDSS 3 considering OCMB/OCGB and therapies. RESULTS: The enrolled number of subjects was 503. The variables influencing the achievement of EDSS 3.0 were: male gender (p = 0.005); progressive course (p = 0.001); age at onset (p < 0.001); and disease-modifying drugs (p < 0.001). The OCGB/OCMB status was not significant. Kaplan-Meier analysis showed no difference in time to reach EDSS 3 for patients with and without OCGB or OCMB in both treated and non-treated groups. CONCLUSION: Our study did not confirm the poor prognostic value of OCMB/OCGB. These results may be influenced by the peculiar genetic background associated with the risk of MS in Sardinians. PMID- 29273847 TI - Clinical and histologic evaluation of different approaches to gain keratinized tissue prior to implant placement in fully edentulous patients. AB - OBJECTIVES: This work aimed to investigate the effectiveness and predictability of different treatment modalities for gain of keratinized tissue (KT) in fully edentulous jaws prior to dental implant placement: apically positioned flap (APF), APF plus xenogeneic collagen matrix (XCM), and APF plus free gingival graft (FGG). MATERIALS AND METHODS: In fully edentulous patients with insufficient zones of KT at the prospective implant positions, four treatment modalities were performed in the lower jaw: APF, XCM, FGG, and an untreated control group (control). APF and XCM were applied in the first molar positions, FGG and control in the canine positions. Assessed outcomes up to 3 months post surgery included changes in width of KT (over a 3-month period), histomorphometric analysis of harvested soft-tissue biopsies (at 3 months postoperatively), and patient-reported outcomes measures (PROMs). RESULTS: For the primary outcome, changes in KT width demonstrated an increase of 1.93 +/- 1.6 mm (APF), whereas XCM and FGG showed an increase of 4.63 +/- 1.25 mm and 3.64 +/- 2.01, respectively. Histomorphometric analyses revealed a thickness of the epithelium ranging between 375 +/- 122 MUm (APF), 410 +/- 116 MUm (XCM), 336 +/- 122 MUm (FGG), and 413 +/- 109 MUm (control). All biopsies showed a regular muco periosteal structure with a keratinized epithelium of comparable thickness in all groups. CONCLUSION: All three methods were suitable to increase the width of KT, although APF alone rendered roughly 50% less gain compared to XCM and FGG. CLINICAL RELEVANCE: The use of XCM in conjunction with an APF represents a valuable treatment option for the gain of keratinized tissue in edentulous sites. PMID- 29273848 TI - Redox Imbalance in Intestinal Fibrosis: Beware of the TGFbeta-1, ROS, and Nrf2 Connection. AB - Intestinal fibrosis, a common complication of inflammatory bowel diseases, becomes clinically apparent in ~ 40% of patients with Crohn's disease and ~ 5% of those with ulcerative colitis. Fibrosis, a consequence of local chronic inflammation, is characterized by excessive deposition of extracellular matrix (ECM) proteins by activated myofibroblasts, which are modulated by pro-fibrotic and anti-fibrotic factors. Fibrosis depends on the balance between production and degradation of ECM proteins. Although the transforming growth factor (TGF) beta1/Smad pathway is the major driving force of fibrosis, several pro-fibrogenic and anti-fibrogenic endogenous factors appear to interact directly with this pathway such as reactive oxygen species (ROS) and nuclear factor-erythroid 2 related factor 2 (Nrf2), which are connected with TGF-beta1 during fibrosis development in several organs, including the intestine. Nrf2 is a ubiquitous master transcription factor that upregulates the expression of antioxidant enzymes and cytoprotective proteins mediated by antioxidant response elements (AREs). Here, I describe and discuss the links among TGF-beta1, ROS, and Nrf2 AREs in the pathogenesis of intestinal fibrosis. PMID- 29273850 TI - Using a noise monitoring station in a small quarry located in an urban area. AB - Mining plays an important role in Brazilian exports. On the other hand, large urban centers like Sao Paulo, with approximately 21 million inhabitants, also demand an increasing domestic consumption of natural resources, such as construction aggregate. There are many quarries located in the surroundings of urban centers in Brazil, competing with the growth of urbanized areas. Such proximity leads to a series of conflicts involving quarries and surrounding communities, where the increase in noise levels is highlighted. Operations in quarries, in general, are intermittent. Noisier equipment, such as drilling rigs and primary crushers, operates only a few hours during the day, while other operations, such as screening and secondary and tertiary crushing, are more constant. This paper presents a study carried out in a quarry located near Sao Paulo, where in addition to conventional short term noise measurements at surrounding receptors, one noise monitoring station was installed, allowing to identify the noisiest moments during the quarry operating time. Through data transmitted by wireless technology, it was possible to follow the noise variations emitted from mining activities in real time and observe the noisiest events that were recorded for events that exceeded the established standards. A mobile application associated to this monitoring station facilitated the quarry's manager and employees to access immediately the monitoring information. Therefore, by using this system, it was possible to evaluate the effectiveness of noise reduction measures already taken and indicate what steps still need to be held. PMID- 29273849 TI - Effects of autophagy on acid-sensing ion channel 1a-mediated apoptosis in rat articular chondrocytes. AB - Rheumatoid arthritis (RA) is a degenerative joint disease that is caused by multiple pathogenic factors. However, the precise etiology of RA is still unknown. Our previous studies demonstrated that acid-sensing ion channel 1a (ASIC1a)-mediated articular chondrocyte apoptosis played a key role in the progression of RA. In this study, we aim to explore whether ASIC1a mediates autophagy or not and the effect of autophagy on ASIC1a-mediated apoptosis. Primary articular chondrocytes, extracted from rat knee joints, were exposed to different concentrations of concentrated hydrochloric acid for different time intervals in vitro. The results indicated that extracellular acid treatment induced autophagy of rat articular chondrocytes. Moreover, inhibition of ASIC1a with either psalmotoxin 1 or ASIC1a short hairpin RNA reduced the autophagy flux. The results suggested that ASIC1a mediated acid-induced autophagy. Pretreatment with autophagy antagonist 3-methyladenine decreased the autophagy, but increased the apoptosis mediated by ASIC1a. Furthermore, knockdown of Beclin 1 by small interfering RNA attenuated autophagy but potentiated ASIC1a-mediated apoptosis of rat articular chondrocytes. Taken together, these findings suggested that both inhibition and silencing of autophagy could enhance ASIC1a-mediated apoptosis in rat articular chondrocytes, and therefore, autophagy is likely to be a new mechanism involved in ASIC1a-mediated apoptosis of articular chondrocytes during the pathogenesis of RA. PMID- 29273851 TI - ? PMID- 29273852 TI - Seasonal dynamics of freshwater pathogens as measured by microarray at Lake Sapanca, a drinking water source in the north-eastern part of Turkey. AB - Monitoring drinking water quality is an important public health issue. Two objectives from the 4 years, six nations, EU Project MUAqua were to develop hierarchically specific probes to detect and quantify pathogens in drinking water using a PCR-free microarray platform and to design a standardised water sampling program from different sources in Europe to obtain sufficient material for downstream analysis. Our phylochip contains barcodes (probes) that specifically identify freshwater pathogens that are human health risks in a taxonomic hierarchical fashion such that if species is present, the entire taxonomic hierarchy (genus, family, order, phylum, kingdom) leading to it must also be present, which avoids false positives. Molecular tools are more rapid, accurate and reliable than traditional methods, which means faster mitigation strategies with less harm to humans and the community. We present microarray results for the presence of freshwater pathogens from a Turkish lake used drinking water and inferred cyanobacterial cell equivalents from samples concentrated from 40 into 1 L in 45 min using hollow fibre filters. In two companion studies from the same samples, cyanobacterial toxins were analysed using chemical methods and those dates with highest toxin values also had highest cell equivalents as inferred from this microarray study. PMID- 29273853 TI - Antisense transcription regulates the expression of sense gene via alternative polyadenylation. AB - Natural antisense transcripts (NAT) and alternative polyadenylation (APA) of messenger RNA (mRNA) are important contributors of transcriptome complexity, each playing a critical role in multiple biological processes. However, whether they have crosstalk and function collaboratively is unclear. We discovered that APA enriched in human sense-antisense (S-AS) gene pairs, and finally focused on RNASEH2C-KAT5 S-AS pair for further study. In cis but not in trans over expression of the antisense KAT5 gene promoted the usage of distal polyA (pA) site in sense gene RNASEH2C, which generated longer 3' untranslated region (3'UTR) and produced less protein, accompanying with slowed cell growth. Mechanistically, elevated Pol II occupancy coupled with SRSF3 could explain the higher usage of distal pA site. Finally, NAT-mediated downregulation of sense gene's protein level in RNASEH2C-KAT5 pair was specific for human rather than mouse, which lacks the distal pA site of RNASEH2C. We provided the first evidence to support that certain gene affected phenotype may not by the protein of its own, but by affecting the expression of its overlapped gene through APA, implying an unexpected view for understanding the link between genotype and phenotype. PMID- 29273854 TI - Imidacloprid slows the development of preference for rewarding food sources in bumblebees (Bombus impatiens). AB - Bee pollination is economically and ecologically vital and recent declines in bee populations are therefore a concern. One possible cause of bee declines is pesticide use. Bumblebees exposed to imidacloprid, a neonicotinoid pesticide, have been shown to be less efficient foragers and collect less pollen on foraging trips than unexposed bees. We investigated whether bumblebees (Bombus impatiens) chronically exposed to imidacloprid at field-realistic levels of 2.6 and 10 ppb showed learning deficits that could affect foraging. Bumblebees were tested for their ability to associate flower colour with reward value in a simulated foraging environment. Bumblebees completed 10 foraging trips in which they collected sucrose solution from artificial flowers that varied in sucrose concentration. The reward quality of each artificial flower was predicted by corolla colour. Unexposed bumblebees acquired a preference for feeding on the most rewarding flower colour on the second foraging trip, while bumblebees exposed at 2.6 and 10 ppb did not until their third and fifth trip, respectively. The delay in preference acquisition in exposed bumblebees may be due to reduced flower sampling and shorter foraging trips. These results show that bumblebees exposed to imidacloprid are slow to learn the reward value of flowers and this may explain previously observed foraging inefficiencies associated with pesticide exposure. PMID- 29273855 TI - Metal concentrations in homing pigeon lung tissue as a biomonitor of atmospheric pollution. AB - Atmospheric pollution in urban areas is a major worldwide concern with potential adverse impacts on wildlife and humans. Biomonitoring can provide direct evidence of the bioavailability and bioaccumulation of toxic metals in the environment that is not available with mechanical air monitoring. The current study continues our evaluation of the usefulness of homing pigeon lung tissue as a biomonitor of atmospheric pollution. Homing pigeons (1-2, 5-6, and 9-10+ year old (yo)) collected from Guangzhou during 2015 were necropsied and concentrations of cadmium (Cd), lead (Pb), and mercury (Hg) were measured in lung tissue. Lung Cd and Pb concentrations were significantly greater in 9-10+-year-old pigeons compared with those in other age groups, indicating their bioavailability and bioaccumulation. Lung Pb and Cd concentrations measured in 5-yo pigeons collected from Guangzhou during 2015 were significantly lower than concentrations reported in 5-yo homing pigeons collected from Guangzhou during 2011 and correlated with concentrations measured using mechanical air monitoring. In addition to temporal differences, spatial differences in concentrations of Cd, Pb, and Hg reported in ambient air samples and in pigeon lung tissues collected from Beijing and Guangzhou are discussed. PMID- 29273856 TI - Treatment patterns and low-density lipoprotein cholesterol (LDL-C) goal attainment among patients receiving high- or moderate-intensity statins. AB - BACKGROUND: European clinical guidelines recommend a low-density lipoprotein cholesterol (LDL-C) goal of < 70 mg/dL. Statin use varies and past studies suggest low rates of real-world goal attainment. This study describes LDL-C goal attainment among atherosclerotic CV disease (ASCVD) patients with various utilization patterns of moderate- or high-intensity statins in routine care. METHODS: This retrospective cohort study used electronic medical records data from the QuintilesIMS(r) Disease Analyzer (> 2 million individuals annually) to identify ASCVD (coronary atherosclerosis, stable/unstable angina, myocardial infarction, ischemic stroke, transient ischemic attack, aneurysm, peripheral artery disease) patients on moderate-/high-intensity statin in Germany. Proportion of patients with LDL-C < 70 mg/dL was determined using the lowest LDL C value for each patient (index) in 2012, 2013, and 2014, while on statin. Treatment patterns were assessed for patients with at least 1 year of post-index follow-up. Results were stratified by year and treatment pattern [no change, switch, dose up-/down-titration, discontinuation (>= 90 day gap)]. RESULTS: In > 14,000 patients assessed in each year (mean age 71 years, 35% female, 8-12% taking high-intensity statins), approximately 80% had LDL-C >= 70 mg/dL. Treatment patterns were assessed for most (88-93%) patients. Approximately 79-81% of patients made no change to statin regimens, 1% switched statins, 14-16% discontinued; 1% of moderate-intensity patients up-titrated, and 3% of all patients down-titrated. LDL-C goal attainment in these treatment pattern groups was 20, 16-24, 17, 11-14, and 17-19%, respectively. CONCLUSIONS: Majority of ASCVD patients had LDL-C >= 70 mg/dL while on moderate-/high-intensity statins. Despite low LDL-C goal attainment, few patients changed their treatment regimens. PMID- 29273857 TI - Development of a dietary formulation of the SHetA2 chemoprevention drug for mice. AB - Development of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity. C57bl/6 J mice were monitored on modified American Institute of Nutrition (AIN)76A diet mixed with SHetA2 in a 3:1 ratio with Kolliphor HS15, a self-emulsifying drug delivery system (SEDDS) to deliver 37.5, 62.5, 125, 187 or 250 mg SHetA2/kg/day. Blood and tissues were evaluated after 1, 3 and 6 weeks. The 187 mg/kg/day dose was identified as optimal based on achievement of maximum blood and tissue drug levels in the effective micromolar range without evidence of toxicity. The 250 mg/kg/day group exhibited lower drug levels and the highest intestinal drug content suggesting that an upper limit of intestinal absorption had been surpassed. Only this highest dose resulted in liver and kidney function tests that were outside of the normal range, and significant reduction of cyclin D1 protein in normal cervical tissue. SHetA2 reduced cyclin D1 to greater extents in cancer compared to non cancer cell cultures. Given this differential effect, optimal chemoprevention without toxicity would be expected to occur at doses that reduced cyclin D1 in neoplastic, but not in normal tissues. These findings support further development of SHetA2 as a chemoprevention agent and potential food additive. PMID- 29273858 TI - If Squeezed, a Camel Passes Through the Eye of a Needle: Voltage-Mediated Stretching of Dendrimers Facilitates Passage Through a Nanopore. AB - Herein, we report uni-molecular observations of electric potential- and electrolyte-dependent elasticity of poly(amidoamine) (PAMAM)-G1.5 dendrimers containing sodium carboxylate surface groups, using the electric field-assisted migration through the alpha-hemolysin nanopore (alpha-HL). Although at moderate transmembrane potentials the dendrimer (~ 2.5 nm in diameter) is sterically excluded from translocation across the constriction region of the nanopore (~ 1.5 nm in diameter), we found a threshold for its translocation that depends on both the electrolyte pH and ionic strength. We posit that the decreased repulsive intramolecular interactions among dendrimer's branches at low when compared to neutral pH, caused mainly by the protonation of surface groups on the dendrimer, determine a larger propensity of the dendrimer to collapse and deform. This in turns enables the dendrimer to adopt more favorably conformations that facilitate its optimal squeezing through the alpha-HL's constriction region at low pH, despite the fact that the estimated net force acting on it becomes approximately one order of magnitude lower than at neutral pH. Experiments performed in a low ionic strength buffer, which decreases Coulombic screening, enhance the intramolecular forces on the dendrimer and renders the dendrimer stiffer than in high ionic strength buffer, confirming the dendrimer elastic properties-dependent threshold for deformation inside the nanopore. PMID- 29273859 TI - The Effect of Novel Glucose Monitoring System (Flash Glucose Monitoring) on Mental Well-being and Treatment Satisfaction in Japanese People with Diabetes. AB - INTRODUCTION: FreeStyle Libre (Abbot Diabetes Care Ltd) has been launched as a novel glucose monitoring system called flash glucose monitoring (FGM) in Europe. Several reports are becoming available on its usefulness and safety. To date, however, reports from Asian countries have not been made available. In this study, we evaluated its usefulness in Japanese people with diabetes in terms of its mental well-being and patient satisfaction outcomes. METHODS: Individuals with type 1 and 2 diabetes treated with insulin were enrolled, and they performed self-monitoring of blood glucose. All participants were subjected to FGM for 14 days and compared for changes in mental well-being using the WHO-Five Well-Being Index (WHO-5) (1998 version) as well as in patient satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) before and after implementation of FGM. RESULTS: The study included a total of 80 subjects (type 1/2 diabetes, 57/23). The WHO-5 scores were significantly improved from 15.5 +/- 4.1 at baseline to 17.2 +/- 4.5 after implementation of FGM (P < 0.001); the DTSQ scores also were significantly improved from 24.8 +/- 6.0 to 26.7 +/- 5.2 (P = 0.001). In type 1 diabetes, both the WHO-5 and DTSQ scores were significantly improved from baseline (P = 0.001, P = 0.001), while neither the WHO-5 scores nor the DTSQ scores were improved in type 2 diabetes. CONCLUSIONS: The study results suggest that FGM has the potential to improve mental well-being and treatment satisfaction among individuals with type 1 diabetes. PMID- 29273860 TI - Maternal depression symptoms and internalising problems in the offspring: the role of maternal and family factors. AB - Maternal depression symptoms (MDS) are a robust risk factor for internalising problems (IP) in the offspring. However, the relative importance of MDS and other factors associated with it (i.e. other types of maternal psychopathology, maternal parenting practices, family characteristics) is not well understood. To (a) identify a group of children with high levels of IP between 6 and 12 years using combined maternal and teacher assessments and (b) to quantify the associations between trajectories of MDS during early childhood and children's IP trajectories before and after controlling for family factors associated with MDS. MDS and family factors were assessed in a population-based sample in Canada (n = 1537) between 5 months and 5 years. The outcome variable was membership in trajectories of teacher- and mother-rated IP between ages 6 and 12 years. Family factors were included as covariates in a multinomial logistic regression model. There was a strong association between MDS and children's atypically high levels of IP in unadjusted analyses [OR 4.14 (95% CI 2.60; 6.61)]. The association was reduced, but remained strong [2.60 (1.55; 4.36)] when maternal psychopathology, maternal parenting, and family socioeconomic status were entered in the model. MDS, maternal anxiety, and low parental self-efficacy were associated with offspring's high IP trajectories. MDS is associated with high levels of children's IP independently of other maternal and family characteristics. Intervention targeting maternal psychopathology and parenting self-efficacy and testing the impact on children's IP would provide information on the putative causal pathways between maternal and offspring's symptomatology. PMID- 29273862 TI - Heterorhizy and fine root architecture of rabbiteye blueberry (Vaccinium virgatum) softwood-cuttings. AB - All fine root systems consist of individual fine roots. Individual roots have morphological, anatomical, and functional heterogeneity (heterorhizy). Heterorhizy plays crucial roles in plant ecosystems. However, in many species, the heterorhizy and fine root system architecture based on individual root units are unclear. This study investigated heterorhizy along the root system architecture of Vaccinium virgatum Ait (rabbiteye blueberry) softwood-cuttings (propagated from annual shoots in growing season) using protoxylem groups (PGs), a classification according to the number of protoxylem poles, as an indicator of individual root traits. Individual roots of rabbiteye blueberry varied from monarch to heptarch. The frequency of roots with larger number of PGs decreased but those with smaller number of PGs increased from adventitious roots toward lateral roots with different branching levels. This architecture were stable among cultivars, collecting position of the cuttings, or indole acetic acids treatment. Individual root sizes and secondary growth were positively correlated with the PGs. These results indicate that branching itself strongly and broadly controls individual root traits. The individual roots were classified into two types: monarch and diarch roots with small size and lacking secondary growth (thought to be hair roots in core Ericaceae) and triarch or more PG roots with large size and showing secondary growth. These heterogeneous individual roots responded differently to the experimental factors. In particular, elongation of the large roots significantly contributed to increased total root length. These results mean that heterorhizic plasticity is a determinant of root system development and heterorhizic variation exists even under practical cutting condition. In conclusion, we demonstrated heterorhizy of rabbieye blueberry cuttings based on the strong relationships of PG, individual root morphology and growth potential, and root system architecture. This study also supports strong connection between root morphology and functional roles intermediated by the PG. PMID- 29273861 TI - Dynamic and epistatic QTL mapping reveals the complex genetic architecture of waterlogging tolerance in chrysanthemum. AB - MAIN CONCLUSION: 37 unconditional QTLs, 51 conditional QTLs and considerable epistatic QTLs were detected for waterlogging tolerance, and six favourable combinations were selected accelerating the possible application of MAS in chrysanthemum breeding. Chrysanthemum is seriously impacted by soil waterlogging. To determine the genetic characteristics of waterlogging tolerance (WAT) in chrysanthemum, a population of 162 F1 lines was used to construct a genetic map to identify the dynamic and epistatic quantitative trait loci (QTLs) for four WAT traits: wilting index (WI), dead leaf ratio (DLR), chlorosis score (Score) and membership function value of waterlogging (MFVW). The h B2 for the WAT traits ranged from 0.49 to 0.64, and transgressive segregation was observed in both directions. A total of 37 unconditional consensus QTLs with 5.81-18.21% phenotypic variation explanation (PVE) and 51 conditional consensus QTLs with 5.90-24.56% PVE were detected. Interestingly, three unconditional consensus QTLs were consistently identified across different stages, whereas no conditional consensus QTLs were consistently expressed. In addition, considerable epistatic QTLs, all with PVE values ranging from 0.01 to 8.87%, were detected by a joint analysis of WAT phenotypes. These results illustrated that the QTLs (genes) controlling WAT were environmentally dependent and selectively expressed at different times and indicated that both additive and epistatic effects underlie the inheritance of WAT in chrysanthemum. The findings of the current study provide insights into the complex genetic architecture of WAT, and the identification of favourable alleles represents an important step towards the application of molecular marker-assisted selection (MAS) and QTL pyramiding in chrysanthemum WAT breeding programmes. PMID- 29273863 TI - [Exophthalmos and chorioretinal folds]. PMID- 29273864 TI - [Testing and approach when non-organic visual loss is suspected]. AB - Approximately 5% of the patients in the ophthalmological practice suffer from non organic vision loss. In children non-organic vision loss has been observed from the age of 6 years. In order to be able to make a rapid diagnosis knowledge of the relevant clinical tests is decisive. If a patient shows signs of non-organic visual loss, diagnostic externalization of the visual function is crucial. Depending on the symptoms there are various tests, which can be used to differentiate between organic and non-organic disorders. For therapeutic and economic reasons an early diagnosis of a non-organic visual loss is crucial. Ophthalmologists need to differentiate between malingering and augmentation, where the patient is aware of the fraud and tries to gain personal benefit from it, and somatoform disorders. In the latter, a more sensitive approach is recommended. PMID- 29273865 TI - [Tintelnotia destructans: new enemy at the gates]. AB - Tintelnotia destructans is a fungal species described for the first time in 2016, which can cause infections of the nails and of the cornea. We describe the second known case worldwide of Tintelnotia destructans-associated keratitis and its therapy. A good sensitivity for amphotericin B and voriconazole was demonstrated in the resistogram for the first time and the successful clinical course was confirmed. The present case study also shows the importance of intensive diagnostics in atypical microbial keratitis. PMID- 29273866 TI - [Closed-circuit television systems : Current importance and tips on adaptation and prescription]. AB - Closed-circuit television systems (CCTVs) have become an indispensable tool in rehabilitating low vision patients. Compared to optical visual aids, apart from providing maximum magnification these devices have the additional advantage of improved contrast sensitivity and an enlarged field of view. They are often the only visual aid enabling patients to regain reading ability. Our data reflect a decrease in the number of prescriptions caused by improved counseling of low vision patients. Any prescription of reading aids must be preceded by comprehensive testing and counseling. More recent developments, such as electronic magnifiers are becoming increasingly more important but they are no substitute for CCTV. PMID- 29273867 TI - A New Multi-Mode Perfusion System for Ex Vivo Heart Perfusion Study. AB - Ex vivo heart perfusion has been shown to be an effective means of facilitating the resuscitation and assessment of donor hearts for cardiac transplantation. Over the last ten years however, only a few ex vivo perfusion systems have been developed for this application. While results have been promising, a system capable of facilitating multiple perfusion strategies on the same platform has not yet been realized. In this paper, the design, development and testing of a novel and modular ex vivo perfusion system is described. The system is capable of operating in three unique primary modes: the traditional Langendorff Mode, Pump Supported Working-Mode, and Passive Afterload Working-Mode. In each mode, physiological hemodynamic parameters can be produced by managing perfusion settings. To evaluate heart viability, six experiments were conducted using porcine hearts and measuring several parameters including: pH, aortic pressure, lactate metabolism, coronary vascular resistance (CVR), and myocardial oxygen consumption. Pressure-volume relationship measurements were used to assess left ventricular contractility in each Working Mode. Hemodynamic and metabolic conditions remained stable and consistent across 4 h of ex vivo heart perfusion on the ex vivo perfusion system, validating the system as a viable platform for future development of novel preservation and assessment strategies. PMID- 29273868 TI - Involvement of TLR3-Dependent PGES Expression in Immunosuppression by Human Bone Marrow Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (MSCs) are known for their prostaglandin E2 (PGE2) mediated immunosuppressive function but the precise molecular mechanisms underlying PGE2 biosynthesis during inflammation have not been completely elucidated. In this study, we have investigated the involvement of PGE2 pathway members in PGE2 production by bone marrow (BM)-MSCs in response to inflammatory stimuli, and their role in immunosuppression mediated by BM-MSCs. We found that IFN-gamma and TNF-alpha increased cyclooxygenase (COX)-2 expression but not that of prostaglandin E synthase (PGES), or PGE2 production. On the other hand, the toll like receptor 3 (TLR3) stimulant poly(I:C) increased expression of both COX 2 and PGES, resulting in a significant increase in PGE2 levels. This effect was reversed upon COX-2 inhibition with indomethacin or PGES downregulation by siRNA. Reduced PGE2 levels decreased MSC's capacity to inhibit hPBMC proliferation. In addition, administration of MSCs with inhibited PGES expression into mice with graft-versus-host disease (GVHD) did not reduce mortality. In summary, the present study reveals that upregulation of PGES via TLR3 is critical for BM-MSCs mediated immunosuppression by PGE2 secretion via the COX-2/PGE2 pathway. These results provide a basis for understanding the molecular mechanisms underlying the PGE2-mediated immunosuppressive properties of MSCs. PMID- 29273869 TI - Indocyanine green fluorescence imaging techniques and interventional radiology during laparoscopic anatomical liver resection (with video). AB - BACKGROUND: To accomplish laparoscopic anatomical liver resection, intraoperative liver segmentation is necessary. Tattooing method or Glissonian approach will be used in a similar way to that in open liver resection. Moreover, in liver segment detection, the fluorescence of indocyanine green (ICG) means it has been recognized as a useful dye. In laparoscopy, however, there are technical difficulties in performing these conventional methods, so development of new techniques is necessary for liver segment identification. We report a pilot study using interventional radiology technique for laparoscopic intraoperative liver segmentation. METHODS: Just prior to liver parenchymal resection, angiography was performed using a hybrid operation room. A catheter was inserted from the right femoral artery into the targeted arterial branch. After confirming the perfusion area by arteriography, embolic solution containing ICG was injected, and the branch was embolized. ICG fluorescence was observed by PINPOINT, a near-infrared imaging system. RESULTS: Immediately after embolic solution injection, we were able to observe ICG fluorescence on the surface of the liver to be resected. This visual effect continued during liver parenchymal resection. We were able to confirm the intra-parenchymal boundary by observing ICG fluorescence on the cut surface of the resecting side and accomplished precise anatomical liver resection. CONCLUSIONS: Our novel technique provides advances in laparoscopic anatomical liver resection performance. As two-dimensional laparoscopy lacks depth perception, additional visual information, such as ICG fluorescence imagery, is helpful as a navigation tool for precise laparoscopic anatomical liver resection. PMID- 29273871 TI - Using outcomes data to justify instituting new technology: a single institution's experience. AB - BACKGROUND: The PILLAR II trial demonstrated PINPOINT is safe, feasible to use with no reported adverse events and resulted in no anastomotic leaks in patients who had a change in surgical plan based on PINPOINT's intraoperative assessment of tissue perfusion during colorectal resection. Whether the cost savings associated with this reduction in anastomotic complications can offset the cost of investing in PINPOINT is unknown. METHODS: We performed a retrospective analysis of all patients (N = 347) undergoing colectomy with primary anastomosis from January 2015 to April 2016. These patients were stratified based on whether fluorescence imaging was used intraoperatively. The clinical outcomes of these patients were then evaluated based on their development of an anastomotic leak or stricture. The direct hospital costs per case were then calculated, and the economic impact of using fluorescence imaging was examined to assess whether decreased direct costs would justify the initial expenditures to purchase new technology (PINPOINT System, NOVADAQ, Canada). RESULTS: Fluorescence imaging in colorectal surgery using PINPOINT reduced the anastomotic failure rate in patients who underwent colon resection. The PINPOINT group (n = 238) had two (0.84%) anastomotic failures, while the non-PINPOINT group (n = 109) had six (5.5%) anastomotic failures. In the PINPOINT group, 11 (4.6%) patients had a change in the resection margin based on the results of the fluorescence imaging, and none of these patients experienced an anastomotic failure. Cost per case was less in the PINPOINT group secondary to fewer direct costs associated with complications. CONCLUSIONS: These results validate the findings of the PILLAR II trial and confirm the decrease in direct costs due to reduction in anastomotic failures as a result of using PINPOINT justified the expense of the new technology after just 143 cases. PMID- 29273870 TI - Risk factors for pulmonary morbidities after minimally invasive esophagectomy for esophageal cancer. AB - BACKGROUND: Pulmonary morbidities after esophagectomy are still common and are a major cause of surgery-related mortality. The relationship between minimally invasive esophagectomy (MIE) and pulmonary morbidities is not clear. The current study aimed to examine the incidence of pulmonary morbidities after MIE and to clarify the associated risk factors. METHODS: Between May 2011 and December 2016, 184 patients underwent MIE for esophageal cancer. Clinical data were prospectively collected and analyzed. Patient- and surgery-related factors, relating to pulmonary complications, were compared between the complicated and uncomplicated cases. RESULTS: The incidence of any pulmonary morbidity following MIE was 17.9%. Univariate analysis showed that past heavy smoking [Brinkman index (BI) >= 1000], presence of neoadjuvant therapy, advanced clinical stage (stage III, IV), and intraoperative bleeding >= 600 g were candidates for being postoperative pulmonary morbidity risk factors. Multivariate analysis suggested that BI >= 1000 and advanced clinical stage were independent risk factors for causing pulmonary morbidities. CONCLUSIONS: Past heavy smoking and advanced stage are independent risk factors for pulmonary morbidities after MIE. When performing MIE for such cases, various preoperative precautions and careful postoperative monitoring are necessary. PMID- 29273873 TI - Video review program enhances resident training in laparoscopic inguinal hernia: a randomized blinded controlled trial. AB - BACKGROUND: The purpose was to determine if a standardized video review program for residents improves operative performance. METHODS: Participation was offered to surgical residents rotating on a minimally invasive service. Residents were randomized to either the video review group or no video review group. Every participant in the video review group underwent video reviews with an attending surgeon for 30 min once weekly during their 1-month rotation. A blinded surgeon evaluated performance in the operating room using validated assessment tools. The amount of time the resident spent as primary surgeon was recorded. One-way analysis of variance was used to compare the video and no video review groups. Differences were considered statistically significant for p values < 0.05. RESULTS: Sixteen residents were randomized to the video review group (n = 8) or the no video review group (n = 8). Residents in the video review cohort significantly improved in creating a working space (p = 0.04), hernia sac reduction (p = 0.01), mesh placement (p = 0.01), knowledge of the procedure (p = 0.01), and overall competence (p = 0.02). Residents in the no video review group did not significantly improve in five of seven categories. The video review group significantly increased the time spent as primary surgeon (p = 0.02). CONCLUSION: Video review with a coach proved to be beneficial for residents when learning laparoscopic inguinal hernia repairs. We conclude that systematic video review is a good supplemental tool in resident surgical training. PMID- 29273872 TI - Comparison of oral and intravenous lansoprazole for the prevention of bleeding from artificial ulcers after endoscopic submucosal dissection for gastric tumors: a prospective randomized phase II study (KDOG 0802). AB - BACKGROUND: Very few studies have evaluated the effectiveness of oral proton-pump inhibitors for the prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric tumors. The aim of our study was to establish the non inferiority of lansoprazole orally disintegrating (OD) tablets to intravenous lansoprazole for the prevention of bleeding from artificial ulcers after ESD. PATIENTS AND METHODS: Consecutive patients who underwent ESD for gastric tumors were randomly assigned to receive lansoprazole OD tablets (OD group) or intravenous lansoprazole (IV group). In the OD group, lansoprazole OD tablets (30 mg) were given orally once daily for 8 weeks (56 days), starting on the day before ESD. In the IV group, lansoprazole (30 mg) was given as a continuous intravenous infusion twice daily for 3 days, starting on the day before ESD, and lansoprazole OD tablets (30 mg) were given orally once daily on days 4-56. The primary endpoint was the incidence of bleeding events within 8 weeks after ESD. RESULTS: Among 310 enrolled patients, 304 patients (152 in the OD group and 152 in the IV group) were included in the analysis. Endoscopic hemostasis was performed in 38 patients (19 in the OD group and 19 in the IV group). The incidence of bleeding events within 8 weeks after ESD did not differ significantly between the groups (p = 0.487). Endoscopic hemostasis was performed at second-look endoscopy in 17 patients (11.2%) in the OD group and 19 patients (12.5%) in the IV group (difference, 1.3 percentage points; 90% confidence interval, - 4.8-7.4%; non-inferiority, p < 0.001). CONCLUSIONS: The effectiveness of lansoprazole OD tablets for the prevention of bleeding from artificial ulcers after ESD was similar to that of intravenous lansoprazole. Lansoprazole OD tablets are thus considered a treatment option in patients who undergo ESD. PMID- 29273874 TI - Safety and feasibility of the robotic platform in the management of surgical sequelae of chronic pancreatitis. AB - BACKGROUND/AIM: The application of minimally invasive surgery to chronic pancreatitis (CP) procedures is uncommon. Our objective was to report the safety and feasibility of the robotic approach in the treatment of surgical sequelae of CP, and provide insights into the technique, tricks, and pitfalls associated with the application of robotics to this challenging disease entity. METHODS: A retrospective review of a prospectively maintained database of patients undergoing robotic-assisted resections and/or drainage procedures for CP at the University of Pittsburgh between May 2009 and January 2017 was performed. A video of a robotic Frey procedure is also shown. RESULTS: Of 812 robotic pancreatic resections and reconstructions 39 were for CP indications. These included 11 total pancreatectomies [with and without auto islet transplantation], 8 Puestow procedures, 4 Frey procedures, 6 pancreaticoduodenectomies, and 10 distal pancreatectomies. Median age was 49, and 41% of the patients were female. The most common etiology for CP was idiopathic pancreatitis (n = 16, 46%). Median operative time was 324 min with a median estimated blood loss of 250 ml. None of the patients required conversion to laparotomy. A Clavien III-IV complication rate was experienced by 5 (13%) patients, including one reoperation. Excluding the eleven patients who underwent TP, rate of clinically relevant postoperative pancreatic fistula was 7% (Grade B = 2, Grade C = 0). No 30 or 90 day mortalities were recorded. The median length of hospital stay was 7 days. CONCLUSIONS: Use of the robotic platform is safe and feasible when tackling complex pancreatic resections for sequelae of chronic pancreatitis. PMID- 29273875 TI - Robotic total pancreatectomy with splenectomy: technique and outcomes. AB - BACKGROUND: Robotic total pancreatectomy (TP) represents a minimally invasive approach to a major intra-abdominal operation. Its utility, technique, and outcomes are evolving. METHODS: In this video, we describe a systematic approach to a robotic total pancreatectomy performed for multifocal intraductal papillary mucinous neoplasm (IPMN). Additionally, we reviewed the National Cancer Database (NCDB) to examine the outcomes of robotic TP compared to laparoscopic and open TP between 2010 and 2014. RESULTS: The patient is a 61-year-old female who was diagnosed with multifocal IPMN. A total of 6 robotic ports were placed and the da Vinci Xi robotic system was used with the patient supine. The approach entailed as follows: (1) Diagnostic laparoscopy; (2) Entry into the lesser sac; (3) Division of the short gastric vessels; (4) Exposure and dissection of the inferior pancreas border; (5) Dissection and transection of the splenic artery; (6) Mobilization of the pancreas tail/spleen; (7) Exposure of the splenic vein superior mesenteric vein confluence; (8) Kocher maneuver; (9) Release of the ligament of Treitz and transection of the proximal jejunum; (10) Transection of the distal stomach; (11) Portal lymphadenectomy; (12) Dissection and transection of the gastroduodenal artery; (13) Superior mesenteric vein exposure/dissection of the uncinate process; (14) Hepaticojejunostomy; (15) Cholecystectomy; and (16) Gastrojejunostomy. NCDB database review of 73 patients who underwent robotic TP revealed similar rates of margin negative resections and retrieved lymph nodes between robotic, laparoscopic, and open TP, whereas robotic and laparoscopic TP were associated with shorter in-hospital stay and reduced mortality at 30 and 90 days compared to open TP. Overall median survival of pancreatic adenocarcinoma patients who underwent TP was similar between robotic, laparoscopic, and open approaches. CONCLUSION: Robotic total pancreatectomy with splenectomy offers a minimally invasive approach to a major abdominal operation and is feasible in a stepwise, reproducible technique. It is associated with improved postoperative outcomes and equivalent oncologic outcomes compared to open TP. PMID- 29273876 TI - Surgeon-performed endoscopic retrograde cholangiopancreatography. Outcomes of 2392 procedures at two tertiary care centers. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a common procedure that, in the United States, is traditionally performed by gastroenterologists. We hypothesized that when performed by well-trained surgeons, ERCP can be performed safely and effectively. The objectives of the study were to assess the rate of successful cannulation of the duct of interest and to assess the 30-day complication and mortality rates. METHODS: We retrospectively reviewed the charts of 1858 patients who underwent 2392 ERCP procedures performed by five surgeons between August 2003 and June 2016 in two centers. Demographic and historical data, indications, procedure-related data and 30-day complication and mortality data were collected and analyzed. RESULTS: The mean age was 53.4 (range 7-102) years and 1046 (56.3%) were female. 1430 (59.8%) of ERCP procedures involved a surgical endoscopy fellow. The most common indication was suspected or established uncomplicated common bile duct stones (n = 1470, 61.5%), followed by management of an existing biliary or pancreatic stent (n = 370, 15.5%) and acute biliary pancreatitis (n = 173, 7.2%). A therapeutic intervention was performed in 1564 (65.4%), a standard sphincterotomy in 1244 (52.0%), stent placement in 705 (29.5%) and stone removal in 638 (26.7%). When cannulation was attempted, the rate of successful cannulation was 94.1%. When cannulation was attempted during the patient's first ERCP the cannulation rate was 92.4%. 94 complications occurred (5.4%); the most common complication was post-ERCP pancreatitis in 75 (4.2%), significant gastrointestinal bleeding in 7 (0.4%), ascending cholangitis in 11 (0.6%) and perforation in 1 (0.05%). 11 mortalities occurred (0.5%) but none of which were ERCP-related. CONCLUSION: When performed by well-trained surgical endoscopists, ERCP is associated with high success rate and acceptable complication rates consistent with previously published reports and in line with societal guidelines. PMID- 29273877 TI - Robotic versus laparoscopic colectomy for stage I-III colon cancer: oncologic and long-term survival outcomes. AB - BACKGROUND: While short-term data suggest that robotic resections are safe for oncologic operations, long-term outcomes remain uncertain. This study evaluates the impact of robotic and laparoscopic approaches on oncologic and survival outcomes in partial and total colectomies for colon cancer. METHODS: The US National Cancer Database (2010-2012) was reviewed for patients with stage I-III adenocarcinoma of the colon, who underwent robotic and laparoscopic partial or total colectomies. Lymph node retrieval, surgical margins, and survival were compared between surgical approaches with linear and logistic regressions. Propensity score matching was then used to create comparable laparoscopic and robotic cohorts and compare survivor functions. RESULTS: Of 15,112 patients, 5.1% underwent robotic approaches (n = 765, conversion rate 10.6%), and 94.9% laparoscopic (n = 14,347, conversion rate 15.1%). Robotic approach was associated with Hispanic race (p = 0.009), private insurance (p = 0.001), and earlier stage (p = 0.028). There was no difference in number of lymph nodes retrieved (p = 0.6200) or negative surgical margins (p = 0.6700). In multivariate analysis, robotic approaches were associated with an improved hazard of mortality (HR 0.79, p = 0.027). Linear regression found no difference in lymph node retrieval (- 0.39, p = 0.285). Logistic regression found no difference in rates of positive margins (OR 1.09, p = 0.649). After propensity score matching, robotic approaches were associated with improved survival in stage II (5YS 66.9% vs. 56.8%, p = 0.0189) and III disease (5YS 78.6% vs. 64.9%, p = 0.0241). CONCLUSION: Robotic approaches to partial and total colectomies for stage I-III colon cancer offer comparable oncologic outcomes as laparoscopic approaches. Relative to laparoscopic approaches, robotic approaches appear to offer improved long-term survival. PMID- 29273879 TI - Correction to: Simultaneous detection of severe acute respiratory syndrome, Middle East respiratory syndrome, and related bat coronaviruses by real-time reverse transcription PCR. AB - Unfortunately, the concentration unit of plasmids was published incorrectly in the original publication of the article. The concentration unit, 'copies/ml' should be corrected to 'copies/MUl'. This changes do not affect to the analytic sensitivity of the method because the detection limits of 50-100 copies/MUL and 5 100 copies/MUL using pUC57-SARS-pS2 (a template for SARS-CoV) and pGEM-MERS-S2 (a template for MERS-CoV), respectively, were as sensitive as other real-time PCR methods [1]. PMID- 29273878 TI - Laparoscopic common bile duct exploration. PMID- 29273880 TI - Computational analysis of the effect of polymerase acidic (PA) gene mutation F35L in the 2009 pandemic influenza A (H1N1) virus on binding aspects of mononucleotides in the endonuclease domain. AB - An F35L mutation in the N-terminal domain of the polymerase acidic protein (PA Nter), which contains the active site of the endonuclease, has been reported to result in higher polymerase activity in mouse-adapted strains of the 2009 pandemic influenza A H1N1 virus. We modeled wild and mutant complexes of uridine 5'-monophosphate (UMP) as the endonuclease substrate and performed molecular dynamics simulations. The results demonstrated that the F35L mutation could result in a changed orientation of a helix containing active site residues and improve the ligand affinity in the mutant strain. This study suggests a molecular mechanism of enhanced polymerase activity. PMID- 29273881 TI - Altered White-Matter Microstructure in Conduct Disorder Is Specifically Associated with Elevated Callous-Unemotional Traits. AB - Adolescents with conduct disorder (CD) and elevated callous-unemotional (CU) traits have been reported to present with a more severe and persistent pattern of antisocial behaviour than those with low levels of CU traits. However, relatively few studies have investigated whether there are differences in brain structure between these subgroups.We acquired diffusion tensor imaging data and used tract based spatial statistics (TBSS) to compare adolescents with CD and high levels of CU traits (CD/CU+; n = 18, CD and low levels of CU traits (CD/CU-; n = 17) and healthy controls (HC; n = 32) on measures of fractional anisotropy (FA), axial (AD), radial (RD) and mean (MD) diffusivity. Compared to CD/CU- adolescents, those with CD/CU+ presented increased FA and reduced RD and MD (lower diffusivity) in several tracts including: body and splenium of the corpus callosum, right inferior longitudinal fasciculus, ILF; right inferior fronto occipital fasciculus, IFOF; left superior longitudinal fasciculus, SLF; left cerebral peduncle, bilateral internal capsule, left superior and posterior corona radiata, bilateral thalamic radiation and left external capsule. In addition, relative to CD/CU- individuals, adolescents with CD/CU+ showed lower diffusivity (indexed by reduced RD and MD) in left uncinate fasciculus and bilateral fornix. Finally, relative to healthy controls, CD/CU+ individuals showed lower diffusivity (reduced RD) in the genu and body of the corpus callosum and left anterior corona radiata. These results suggest that CD/CU+ individuals present with white-matter microstructural abnormalities compared to both CD/CU- individuals and age-matched healthy controls. This finding is consistent with emerging evidence suggesting that CD/CU+ represents a distinct subtype of CD, and illustrates the importance of accounting for heterogeneity within CD populations. PMID- 29273882 TI - The oral microbiome-the relevant reservoir for acute pediatric appendicitis? AB - PURPOSE: The oral microbiome has been related to numerous extra oral diseases. Recent studies detected a high abundance of oral bacteria in inflamed appendices in pediatric patients. To elucidate the role of oral bacteria in acute pediatric appendicitis, we studied the oral and appendiceal microbiome of affected children compared to healthy controls. METHODS: Between January and June 2015, 21 children undergoing appendectomy for acute appendicitis and 28 healthy controls were prospectively enrolled in the study. All individuals underwent thorough dental examination and laboratory for inflammatory parameters. Samples of inflamed appendices and the gingival sulcus were taken for 16S rDNA sequencing. RT-qPCR of Fusobacterium nucleatum, Peptostreptococcus stomatis, and Eikenella corrodens was performed and their viability was tested under acidic conditions to mimic gastric transfer. RESULTS: In phlegmonous appendices, Bacteroidetes and Porphyromonas were discovered as dominant phylum and genus. In sulcus samples, Firmicutes and Streptococcus were detected predominantly. P. stomatis, E. corrodens, and F. nucleatum were identified in each group. Viable amounts of P. stomatis were increased in sulci of children with acute appendicitis compared to sulci of healthy controls. In inflamed appendices, viable amounts of E. corrodens and F. nucleatum were decreased compared to sulci of children with appendicitis. Postprandial viability could be demonstrated for all tested bacteria. CONCLUSION: In children with acute appendicitis, we identified several oral bacterial pathogens. Based on postprandial viability of selected species, a viable migration from the oral cavity through the stomach to the appendix seems possible. Thus, the oral cavity could be a relevant reservoir for acute appendicitis. PMID- 29273883 TI - Calcification of the iliac arteries: a marker for leakage risk in rectal anastomosis-a blinded clinical trial. AB - PURPOSE: Anastomotic leakage (AL) is associated with increased morbidity and mortality after colorectal surgery. Calcification of the arteries has been identified as a risk factor for cardiovascular events and can be reliably measured on computed tomography using software assistance. The aim of this prospective study was to prove the value of calcium scoring of the iliac arteries as a predictor of AL after rectal anastomosis. METHODS: Consecutive patients who underwent colorectal resection with rectal anastomosis were analyzed. Diagnostic computed tomography images were used to detect calcification of the arteries supplying the rectal anastomosis. Logistic regression analysis was used to determine the relationship between vascular calcification and AL. RESULTS: Of 139 included and analyzed patients, AL occurred in 15 (11%). The volume and calcium scores were significantly higher in the infrarenal aorta, the left and right common iliac artery, and the left internal iliac artery. In univariate analysis, calcification of the left internal iliac artery and both internal iliac arteries combined correlated with the occurrence of the primary endpoint. A receiver operating curve analysis led to the cut-off values of 30 and 6 for the volume score and calcium score, respectively. They provide a negative predictive value of 0.97 and a positive predictive value of 0.19. CONCLUSIONS: Calcification in the iliac arteries appears to be a good marker for the risk of leakage after rectal anastomosis. The calcification scoring system is easy to calculate after computed tomography and may aid in patient selection to create a protective ileostomy. PMID- 29273884 TI - One decade of rectal prolapse surgery: a national study. AB - PURPOSE: We aimed to investigate the development of common procedures used as treatment for rectal prolapse over a decade and to determine if the choice of primary operation affects the reoperation rate. METHODS: This is a retrospective analysis of operative data from a National Data Registry, Landspatientregisteret (LPR), from the period of January 1, 2004 to December 31, 2014. All hospitalized surgical treatments are registered in LPR. RESULTS: Sixteen hundred and twenty five patients with rectal prolapse underwent 1834 operations. There were 94% women and mean age at surgery was 71.6 +/- 18.1 years, with no difference over the 11 years. The types of operations performed differed (p < 0.0001), with an increase in overall number of operations and increasing use of laparoscopic procedures. There were 209 reoperations, of which 129 patients were primarily operated with a perineal procedure. The mean age at reoperation was 72.8 +/- 17.3 years. The most frequently used reoperation was laparoscopic rectopexy. The overall reoperation rate was 16%: 10% for both open and laparoscopic rectopexy, and for perineal procedures 26% (p < 0.001). The overall 30-day mortality was 2.1% and there was no difference in mortality between the procedures (p = 0.23). CONCLUSIONS: The overall number of rectal prolapse operations was increasing. There was a clear trend towards extended use of laparoscopic rectopexy both as primary procedure and as reoperation. The highest reoperation rates were for the perineal procedures. PMID- 29273885 TI - Estimation of Supercapacitor Energy Storage Based on Fractional Differential Equations. AB - In this paper, new results on using only voltage measurements on supercapacitor terminals for estimation of accumulated energy are presented. For this purpose, a study based on application of fractional-order models of supercapacitor charging/discharging circuits is undertaken. Parameter estimates of the models are then used to assess the amount of the energy accumulated in supercapacitor. The obtained results are compared with energy determined experimentally by measuring voltage and current on supercapacitor terminals. All the tests are repeated for various input signal shapes and parameters. Very high consistency between estimated and experimental results fully confirm suitability of the proposed approach and thus applicability of the fractional calculus to modelling of supercapacitor energy storage. PMID- 29273886 TI - Lignin peroxidase mediated silver nanoparticle synthesis in Acinetobacter sp. AB - Metals present in environment render the bacteria to attain certain resistance machinery to survive, one of which is transformation of metal ions to nano forms. Various enzymes and proteins have been suggested to play significant role in synthesis of silver nanoparticles (AgNPs) in bacteria. In present study, we have purified lignin peroxidase from secreted enzyme extract of Acinetobacter sp. employing diethyl aminoethyl cellulose ion exchange and Biogel P-150 gel filtration column chromatography. The purified fraction has a specific activity of 1.571 U/mg with substrate n-propanol and 6.5-fold purification. The tetrameric enzyme, with molecular weight of 99 kDa, consisted of dimers of two polypetides of 23.9 and 24.6 kDa as revealed by native and SDS-PAGE. On exposure to purified enzyme, spherical polydispersed AgNPs of ~ 50 nm were obtained as observed under transmission electron microscope. Optimum activity of the purified enzyme was obtained at pH 2 and 60 degrees C with n-propanol as substrate. This is the first report describing the reduction of extracellular silver ions by lignin peroxidase purified from Acinetobacter sp. PMID- 29273887 TI - Post-myocardial infarction exercise training beneficially regulates thyroid hormone receptor isoforms. AB - Thyroid hormone receptors (TRs) play a critical role in the expression of genes that are major determinants of myocardial contractility, including alpha-myosin heavy chain (alpha-MHC) and beta-MHC. After myocardial infarction (MI), changes in myocardial TRs consistently correlate with changes in thyroid hormone (TH) target gene transcription, and this is thought to play a key role in the progression to end-stage heart failure. Interestingly, post-MI exercise training has been shown to beneficially alter TH-target gene transcription and preserve cardiac function without changing serum TH. Therefore, in this study, we investigated whether mild exercise training alters expression of alpha1 and beta1 TR isoforms in post-MI rats. Seven-week-old male Sprague-Dawley rats underwent coronary ligation or sham operation, and were assigned to 3 groups (n = 10): sham, sedentary MI (MI-Sed), and exercise MI (MI-Ex). Treadmill training was initiated 1 week post-MI, and gradually increased up to 16 m/min, 5 degrees incline, 50 min/day, 5 days/week, and lasted for a total of 8 weeks. Real-time polymerase chain reaction and gel electrophoresis were performed to quantify changes in TR isoforms. Our results illustrated that mRNA expression of TR-alpha1 and TR-beta1 was higher in both MIs; however, protein electrophoresis data showed that TR-alpha1 was 1.91-fold higher (P < 0.05) and TR-beta1 was 1.62-fold higher (P < 0.05) in the MI-Ex group than in the MI-Sed group. After MI, TR-alpha1 and TR-beta1 protein levels are significantly decreased in the surviving non infarcted myocardium. Moderate-intensity exercise training significantly increases TR-alpha1 and TR-beta1 protein expression, which in turn may upregulate alpha-MHC and improve myocardial contractile function and prognosis. PMID- 29273888 TI - Identification of pleiotropic genetic variants affecting osteoporosis risk in a Korean elderly cohort. AB - Pleiotropy has important implications for understanding the genetic basis and risk assessment of osteoporosis. Our aim was to identify pleiotropic genetic variants associated with the development of osteoporosis and predict osteoporosis risk by leveraging pleiotropic variants. We evaluated the effects of 21 conventional risk factors and 185 single-nucleotide polymorphisms (SNPs) in 63 inflammation- and metabolism-related genes on osteoporosis risk in a community based Korean cohort study of 1025 participants, the Hallym Aging Study. Ten nongenetic factors, including sex (female) and hematocrit level, and 12 SNPs across ten genes showed evidence of association with incident osteoporosis in 270 initially osteoporosis-free subjects who completed a 6-year follow up. Three gene variants, rs1801282 (PPARG-Pro12Ala, hazard ratio (HR) = 3.26, P = 0.008), rs1408282 (near EPHA7, HR = 1.87, P = 0.002), and rs2076212 (PNPLA3-Gly115Cys, HR = 2.24, P = 0.024), were associated with significant differences in survival among the three genotype groups (P diff = 0.042, 0.003, and 0.048, respectively). Individuals in the highest polygenic risk score tertile were 27.9 fold more likely to develop osteoporosis than those in the lowest tertile (P = 0.004). The PPARG gene in particular was a hub pleiotropic gene in the epistasis network. Our findings highlight pleiotropic modulations of metabolism- and inflammation related genes in the development of osteoporosis and demonstrate the contribution of pleiotropic genetic variants in prediction of osteoporosis risk. PMID- 29273889 TI - Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions. AB - Osteoclasts and foreign body giant cells (FBGCs) are derived from common progenitors and share properties such as multi-nucleation capacity induced by cell-cell fusion; however, mechanisms underlying lineage determination between these cells remain unclear. Here we show that, under inflammatory conditions, osteoclasts are stimulated in a manner similar to M1 macrophages, while formation of FBGCs, which exhibit M2-like phenotypes, is inhibited in a manner similar to that seen in M1/M2 macrophage polarization. FBGC/osteoclast polarization was inhibited by conditional knockout of tumor necrosis factor receptor associated factor 6 (Traf6) in adults in vivo and in vitro. Traf6-null mice were previously reported to die soon after birth, but we found that Traf6 deletion in adults did not cause lethality but rather inhibited osteoclast activation and prevented FBGC inhibition under inflammatory conditions. Accordingly, basal osteoclastogenesis was significantly inhibited by Traf6 deletion in vivo and in vitro and accompanied by increased bone mass. Lipopolysaccharide-induced osteoclast formation and osteolysis were significantly inhibited in Traf6 conditional knockout mice. Our results suggest that Traf6 plays a crucial role in regulating M1 osteoclast and M2 FBGC polarization and is a potential therapeutic target in blocking FBGC inhibition, antagonizing osteolysis in inflammatory conditions, and increasing bone mass without adverse effects in adults. PMID- 29273890 TI - Subventricular zone involvement at recurrence is a strong predictive factor of outcome following high grade glioma reirradiation. AB - We aimed to assess the efficacy of stereotactic irradiation for patients with recurrent high-grade glioma (HGG) and identify predictive factors of progression free survival (PFS) and overall survival (OS) following reirradiation. We identified 32 patients with recurrent brain HGG who had been treated with either single-dose (stereotactic radiosurgery) or fractionated stereotactic radiotherapy between April 2008 and October 2015. Median follow up was 21.4 months (range 12.9 23.2) and median PFS was and 3.3 months (95% CI [2.3-4.7]), respectively. OS was 90.40% (95% CI [73.09-96.80]) at 6 months and 79.55% (95% CI [59.9-90.29]) at 12 months. Univariate analysis showed that biological effective dose at isocenter <= 76 Gy was a poor prognostic factor for both OS (83.33 vs. 100% at 6 months, p = 0.032) and median PFS (2.7 vs. 4.7 months, p = 0.025), as was gross tumor volume (GTV) above 1 cm3 for OS (86.15 vs. 94.12% at 6 months, p = 0.043). Contact with the subventricular zone (SVZ) was also a poor prognostic factor for median PFS (2.3 vs. 4.7 months, p = 0.002). Multivariate analysis showed that SVZ contact remained a poor prognostic factor for PFS (hazard ratio = 3.44, 95% CI [1.21 9.82], p = 0.021). Results suggest that reirradiation is a safe and effective treatment option for recurrent HGG in patients with a good Karnosfsky Performance Scale score, a long progression-free interval since first radiation and limited GTV, and that contact to SVZ is a strong prognostic factor for PFS. PMID- 29273891 TI - PedsQL Neurofibromatosis Type 1 Module for children, adolescents and young adults: feasibility, reliability, and validity. AB - The objective of the present study was to report on the measurement properties of the Pediatric Quality of Life Inventory (PedsQL) Neurofibromatosis Type 1 Module for pediatric patients ages 5-25 from the perspectives of patients and parents. The 104-item PedsQL NF1 Module and 23-item PedsQL Generic Core Scales were completed in a multi-site national study by 323 patients and 335 parents (343 families). Patients were diagnosed with NF1 using the National Institutes of Health diagnostic criteria. In addition to a Total Scale Score, 18 unidimensional scales were derived measuring skin itch bother, skin sensations, pain, pain impact, pain management, cognitive functioning, speech, fine motor, balance, vision, perceived physical appearance, communication, worry, treatment anxiety, medicines, stomach discomfort, constipation, and diarrhea. The PedsQL NF1 Module Scales evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report alpha = 0.98; parent proxy-report alpha = 0.98), and good to excellent reliability for the 18 individual scales (patient self-report alpha = 0.71-0.96; parent proxy-report alpha = 0.73-0.98). Intercorrelations with the Generic Core Scales supported construct validity. Factor analysis supported the unidimensionality of the 18 individual scales. The PedsQL NF1 Module Scales demonstrated acceptable to excellent measurement properties, and may be utilized as standardized metrics to assess NF1-specific symptoms and problems in clinical research and practice in children, adolescents, and young adults. PMID- 29273892 TI - Low-level laser therapy in the management of plantar fasciitis: a randomized controlled trial. AB - This study aimed at estimating the extent to which a combination therapy of low level laser therapy (LLLT) with exercise and orthotic support (usual care) affects functional ability in the patient with plantar fasciitis (PF) when compared to usual care alone. Participants with PF were randomly allocated into two groups: LLLT (n = 27) and control (n = 22). All the participants received home exercise program with orthotic support. In addition, the LLLT group received a gallium-aluminum-arsenide laser with a 850-nm wavelength for ten sessions, three times a week. Functional outcomes were measured by function subscale of American Orthopedic Foot and Ankle Society Score (AOFAS-F) and 12-min walking test including walking speed, cadence, and activity-related pain using visual analog scale (VAS).The scores were recorded at baseline, third week, and third month after the treatment. Analysis was performed using repeated measures ANOVA and an intention to treat approach using multiple imputations. There was a significant improvement in AOFAS-F total score at 3 weeks in both groups (LLLT, p < 0.001; control, p = 0.002), but the improvements were seen only for the LLLT group for AOFAS-F total score (p = 0.04) and two individual items of AOFAS-F (walking distance (p < 0.001) and walking surface (p = 0.01)) at 3 months. The groups were comparable with each other for both walking speed and cadence at all assessment times (p > 0.05). Both groups showed significant reduction in pain over 3 months (LLLT, p < 0.001; control, p = 0.01); however, the LLLT group had lower pain than the control group at 3 months (p = 0.03). The combination therapy of LLLT with usual care is more effective to improve functional outcomes and activity-related pain when compared to usual care alone. PMID- 29273893 TI - Intraoperative Doppler sonogram in pediatric liver transplants: a pictorial review of intraoperative and early postoperative complications. AB - A spectrum of vascular complications can be seen in pediatric liver transplant patients, including occlusion and hemodynamically significant narrowing of the vessels that provide inflow to or outflow from the graft. Intraoperative Doppler ultrasound (US) has the potential benefit of identifying vascular complications in pediatric liver transplant patients prior to abdominal closure. Importantly, intraoperative Doppler US can be used as a problem-solving tool in situations such as position-dependent kinking of the portal or hepatic veins, or in suspected vasospasm of the hepatic artery. Furthermore, this technique can be used for real-time reassessment after surgical correction of vascular complications. This pictorial review of intraoperative Doppler US in pediatric liver transplant patients illustrates normal findings and common vascular complications, including examples after surgical correction, in the perioperative period. PMID- 29273894 TI - Medicaid Expansion, Chronic Disease, and the Next Chapter of Health Reform. PMID- 29273895 TI - Smear Campaign: Misattribution of Pancytopenia to a Tick-Borne Illness. AB - We report the case of a 51-year-old woman presenting with a targetoid rash and pancytopenia after a tick bite. Initial evaluation was notable for severe neutropenia on the complete blood cell count differential, a positive Lyme IgM antibody, and a peripheral blood smear demonstrating atypical lymphocytes. While her pancytopenia was initially attributed to tick-borne illness, peripheral flow cytometry showed 7% myeloblasts, and a bone marrow biopsy confirmed 60% blasts. The patient was ultimately diagnosed with acute myelogenous leukemia, in addition to early, localized Lyme disease. This case highlights the differential diagnosis for pancytopenia, cytopenia patterns for different tick-borne illnesses, the risk of premature closure in internal medicine, and management of Lyme disease in hosts with altered immunity. PMID- 29273896 TI - Baby Boomers and Beds: a Demographic Challenge for the Ages. AB - The United States is facing a significant demographic transition, with about 10,000 baby boomers turning age 65 each day. At the same time, the nation is experiencing a similarly striking transition in hospital capacity, as the supply of hospital beds has declined in recent decades. The juxtaposition of population aging and hospital capacity portends a potentially widening divergence between supply and demand for hospital care. We provide a closer look at current hospital capacity and a rethinking of the future role of hospital beds in meeting the needs of an aging population. PMID- 29273897 TI - Impact of flash glucose monitoring on hypoglycaemia in adults with type 1 diabetes managed with multiple daily injection therapy: a pre-specified subgroup analysis of the IMPACT randomised controlled trial. AB - AIMS/HYPOTHESIS: Evidence for the effectiveness of interstitial glucose monitoring in individuals with type 1 diabetes using multiple daily injection (MDI) therapy is limited. In this pre-specified subgroup analysis of the Novel Glucose-Sensing Technology and Hypoglycemia in Type 1 Diabetes: a Multicentre, Non-masked, Randomised Controlled Trial' (IMPACT), we assessed the impact of flash glucose technology on hypoglycaemia compared with capillary glucose monitoring. METHODS: This multicentre, prospective, non-masked, RCT enrolled adults from 23 European diabetes centres. Individuals were eligible to participate if they had well-controlled type 1 diabetes (diagnosed for >=5 years), HbA1c <= 58 mmol/mol [7.5%], were using MDI therapy and on their current insulin regimen for >=3 months, reported self-monitoring of blood glucose on a regular basis (equivalent to >=3 times/day) for >=2 months and were deemed technically capable of using flash glucose technology. Individuals were excluded if they were diagnosed with hypoglycaemia unawareness, had diabetic ketoacidosis or myocardial infarction in the preceding 6 months, had a known allergy to medical-grade adhesives, used continuous glucose monitoring (CGM) within the previous 4 months or were currently using CGM or sensor-augmented pump therapy, were pregnant or planning pregnancy or were receiving steroid therapy for any disorders. Following 2 weeks of blinded (to participants and investigator) sensor wear by all participants, participants with sensor data for more than 50% of the blinded wear period (or >=650 individual sensor results) were randomly assigned, in a 1:1 ratio by a central interactive web response system (IWRS) using the biased-coin minimisation method, to flash sensor-based glucose monitoring (intervention group) or self-monitoring of capillary blood glucose (control group). The control group had two further 14 day blinded sensor-wear periods at the 3 and 6 month time points. Participants, investigators and staff were not masked to group allocation. The primary outcome was the change in time in hypoglycaemia (<3.9 mmol/l) between baseline and 6 months in the full analysis set. RESULTS: Between 4 September 2014 and 12 February 2015, 167 participants using MDI were enrolled. After screening and the baseline phase, participants were randomised to intervention (n = 82) and control groups (n = 81). One woman from each group was excluded owing to pregnancy; the full analysis set included 161 randomised participants. At 6 months, mean time in hypoglycaemia was reduced by 46.0%, from 3.44 h/day to 1.86 h/day in the intervention group (baseline adjusted mean change, -1.65 h/day), and from 3.73 h/day to 3.66 h/day in the control group (baseline adjusted mean change, 0.00 h/day), with a between-group difference of -1.65 (95% CI -2.21, -1.09; p < 0.0001). For participants in the intervention group, the mean +/- SD daily sensor scanning frequency was 14.7 +/- 10.7 (median 12.3) and the mean number of self-monitored blood glucose tests performed per day reduced from 5.5 +/- 2.0 (median 5.4) at baseline to 0.5 +/- 1.0 (median 0.1). The baseline frequency of self-monitored blood glucose tests by control participants was maintained (from 5.6 +/- 1.9 [median 5.2] to 5.5 +/- 2.6 [median 5.1] per day). Treatment satisfaction and perception of hypo/hyperglycaemia were improved compared with control. No device-related hypoglycaemia or safety-related issues were reported. Nine serious adverse events were reported for eight participants (four in each group), none related to the device. Eight adverse events for six of the participants in the intervention group were also reported, which were related to sensor insertion/wear; four of these participants withdrew because of the adverse event. CONCLUSIONS/INTERPRETATION: Use of flash glucose technology in type 1 diabetes controlled with MDI therapy significantly reduced time in hypoglycaemia without deterioration of HbA1c, and improved treatment satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov NCT02232698 FUNDING: Abbott Diabetes Care, Witney, UK. PMID- 29273899 TI - The wicked ocean. PMID- 29273898 TI - Pseudo-patella baja: a minor yet frequent complication of total knee arthroplasty. AB - PURPOSE: One of the complications in total knee arthroplasty (TKA) is pseudo patella baja (PPB). PPB is present when there is no shortening of the patellar tendon, but the joint line is elevated. The purpose of this study is to investigate the incidence of PPB after TKA and its clinical effects. METHODS: A case series of 158 patients undergoing TKA surgery between 1999 and 2012 at the 2nd Department of Orthopaedics and Traumatology, Pisa were retrospectively reviewed. Surgeries were performed by three senior surgeons, using the same surgical procedure for the implantation of a cemented posterior stabilized prosthesis. Lateral radiographs at 30 degrees knee flexion were evaluated and the presence of PPB defined as modified Blackburne-Peel Index (mBPI) of < 0.54. All the patients were clinically evaluated using the Knee Society Score (KSS) and the Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC). Anterior knee pain was evaluated by visual analogue scale (VAS) and range of motion (ROM) was assessed through clinical examination. RESULTS: The cohort group consisted of 158 patients, 109 (69.0%) female and 49 (31.0%) male. Median age at time of surgery was 74 years (range 36-87) and median follow-up was 66 months (range 12-163 months). Bilateral TKA surgery was performed in 50 patients, resulting in a total of 208 implants for investigation. On radiological evaluation, 139 (66.8%) showed no abnormalities (no joint line elevation and no patellar tendon shortening) and 55 (26.4%) presented joint line elevation with absence of patellar tendon shortening (PPB). No significant differences were found between the groups in terms of the KSS, WOMAC score, VAS or ROM. CONCLUSION: Post TKA PPB is a relatively common complication. Careful preoperative planning, adequate soft tissue release, optimal cutting of bone components, on the femoral side in particular, and the use of thin polyethylene inserts can help to avoid this complication. LEVEL OF EVIDENCE: IV. PMID- 29273901 TI - Systematic Review of Combined Pharmacotherapy for the Treatment of Alcohol Use Disorder in Patients Without Comorbid Conditions. AB - BACKGROUND: Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder. OBJECTIVES: The objective of this review was to identify combinations of pharmacological treatments for alcohol use disorder, and assess the strength of clinical evidence for these treatments. METHODS: We conducted searches using PubMed, EMBASE(r) through Ovid(r) (1974 to present), MEDLINE(r) through Ovid(r) (1946 to present), and Psychinfo(r) through Ovid(r) (1806 to present). Our primary search included the terms "alcoholism" and "drug therapy, combination". Search results were restricted to human subjects and English language. Search criteria were not restricted based on study design or patient age. Studies were evaluated for randomization, blinding, group similarity, power determination, outcome reporting, and number of patients analyzed. RESULTS: Nine hundred and eighty-four publications were initially screened for inclusion after duplicates were removed. The search identified 16 publications evaluating drug combinations for the treatment of alcohol use disorder. The majority of published trials included naltrexone combined with one of the following: gabapentin, ondansetron, acamprosate, gamma-hydroxybutyrate, sertraline, quetiapine, or escitalopram plus gamma-hydroxybutyrate. Other combinations included 5-hydroxytryptophan with carbidopa/levodopa, gamma-hydroxybutyrate with disulfiram, acamprosate with disulfiram, and mirtazapine with quetiapine. Interpretation of results across studies was limited by low statistical power, and heterogeneity of drug combinations and outcome measures. Drug combination effect sizes were comparable to those observed in single-agent trials. CONCLUSIONS: No significant benefit for the use of combinations over single agents was observed. However, benefit may be observed when combined pharmacological interventions address specific symptoms of alcohol use disorder known to be influenced by combination components, or when combinations are used in specific subpopulations in which combination components demonstrate benefit. PMID- 29273900 TI - Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. AB - In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS. PMID- 29273902 TI - AMPK-dependent nitric oxide release provides contractile support during hyperosmotic stress. AB - In different pathological situations, cardiac cells undergo hyperosmotic stress (HS) and cell shrinkage. This change in cellular volume has been associated with contractile dysfunction and cell death. Given that nitric oxide (NO) is a well recognized modulator of cardiac contractility and cell survival, we evaluated whether HS increases NO production and its impact on the negative inotropic effect observed during this type of stress. Superfusing cardiac myocytes with a hypertonic solution (HS: 440 mOsm) decreased cell volume and increased NO sensitive DAF-FM fluorescence compared with myocytes superfused with an isotonic solution (IS: 309 mOsm). When cells were exposed to HS in addition to different inhibitors: L-NAME (NO synthase inhibitor), nitroguanidine (nNOS inhibitor), and Wortmannin (eNOS inhibitor) cell shrinkage occurred in the absence of NO release, suggesting that HS activates nNOS and eNOS. Consistently, western blot analysis demonstrated that maintaining cardiac myocytes in HS promotes phosphorylation and thus, activation of nNOS and eNOS compared to myocytes maintained in IS. HS induced nNOS and eNOS activation and NO production were also prevented by AMPK inhibition with Dorsomorphin (DORSO). In addition, the HS-induced negative inotropic effect was exacerbated in the presence of either L-NAME, DORSO, ODQ (guanylate cyclase inhibitor), or KT5823 (PKG inhibitor), suggesting that NO provides contractile support via a cGMP/PKG-dependent mechanism. Our findings suggest a novel mechanism of AMPK-dependent NO release in cardiac myocytes with putative pathophysiological relevance determined, at least in part, by its capability to reduce the extent of contractile dysfunction associated with hyperosmotic stress. PMID- 29273903 TI - So, you think you want to be an editor. PMID- 29273905 TI - Fully automated focused infrared microashing combined with use of ICP-based instruments for rapid analysis of multiple elements in biological samples. AB - A fully automated focused infrared microashing sample preparation system was proposed for preparation of biological samples with high organic matter content for the determination of multiple elements combined with inductively coupled plasma optical emission spectroscopy and inductively coupled plasma mass spectrometry. The whole ashing procedure, including sample transfer, carbonization and oxidation of the sample, dissolution of ash, constant volume control, and homogenization of the solution, was automatically controlled. Gold plated infrared tubes were used to produce and focus infrared radiation to heat the sample. Ozone was used to accelerate the carbonization of samples at a lower temperature to avoid the production of large amounts of empyreumatic oil. In addition, the self-designed double-layer tube serves as a site for ashing and carbonization of the sample and as a container for dissolving ash, as well as for holding the solution. This is the only container in the entire system to reduce the risk of pollution. Eight biological certified reference materials were used as examples to evaluate the performance of the proposed device. A sample ashing pretreatment cycle, from solid sample to liquid solution, took only 40 min and simultaneously treated 12 samples. Except for individual results, the relative errors between the certified values and recorded values for 38 micro and trace elements, including Ca, Mg, Na, P, Li, Be, Sc, Ti, V, Mn, Co, Ni, Cu, Zn, Rb, Sr, Y, Mo, Ag, Cs, Ba, Tl, Th, U, and rare earth elements, were typically less than 30%. The relative standard deviations for five determinations were typically less than 15%. Graphical abstract Automated dry ashing sample preparation system. ICP inductively coupled plasma. PMID- 29273904 TI - Advanced LC-MS-based methods to study the co-occurrence and metabolization of multiple mycotoxins in cereals and cereal-based food. AB - Liquid chromatography (LC) coupled with mass spectrometry (MS) is widely used for the determination of mycotoxins in cereals and cereal-based products. In addition to the regulated mycotoxins, for which official control is required, LC-MS is often used for the screening of a large range of mycotoxins and/or for the identification and characterization of novel metabolites. This review provides insight into the LC-MS methods used for the determination of co-occurring mycotoxins with special emphasis on multiple-analyte applications. The first part of the review is focused on targeted LC-MS approaches using cleanup methods such as solid-phase extraction and immunoaffinity chromatography, as well as on methods based on minimum cleanup (quick, easy, cheap, effective, rugged, and safe; QuEChERS) and dilute and shoot. The second part of the review deals with the untargeted determination of mycotoxins by LC coupled with high-resolution MS, which includes also metabolomics techniques to study the fate of mycotoxins in plants. PMID- 29273906 TI - 3D super-localization of intracellular organelle contacts at live single cell by dual-wavelength synchronized fluorescence-free imaging. AB - A fluorescence-free real-time three-dimensional (3D) super-localization method for the analysis of 3D structure of organelles (e.g., mitochondria-associated endoplasm reticulum [mito-ER] contacts) in live single cells under physiological conditions was developed with dual-wavelength enhanced dark-field microscopy. The method was applied to live single cells under physiological conditions to analyze the complex 3D mito-ER contact region by choosing an optimum nanotag with distinct scattering properties. Combining dual-view with enhanced dark-field microscopy provided concurrent images of different scattering wavelengths of nanotag-labeled mitochondria and ER. The reconstructed super-localized images resolved controversy over the distance between the intracellular organelles at functional contacts. The distance between mitochondria and ER was measured to be 45 nm, which was ~ 50% greater than in a previous report using electron microscopic tomography, and was a better fit for the likely features of these structures. These results indicate that this method was a reliable and convenient approach for investigating the 3D structure of organelles, such as mito-ER contacts in live single cells, and provided accurate information under physiological conditions. Graphical abstract Fluorescence-free enhanced dark field 3D super-resolution microscopy (3D SRM) method, with dual-wavelength simultaneous imaging (DWSI) for 3D analysis of mitochondria-endoplasmic reticulum (Mito-ER) at their functional contact site. PMID- 29273907 TI - Comparison of the atmospheric- and reduced-pressure HS-SPME strategies for analysis of residual solvents in commercial antibiotics using a steel fiber coated with a multiwalled carbon nanotube/polyaniline nanocomposite. AB - A low-cost, sensitive and reliable reduced-pressure headspace solid-phase microextraction (HS-SPME) setup was developed and evaluated for direct extraction of residual solvents in commercial antibiotics, followed by determination by gas chromatography with flame ionization detection (GC-FID). A stainless steel narrow wire was made porous and adhesive by platinization by a modified electrophoretic deposition method and coated with a polyaniline/multiwalled carbon nanotube nanocomposite. All experimental variables affecting the extraction efficiency were investigated for both atmospheric-pressure and reduced-pressure conditions. Comparison of the optimal experimental conditions and the results demonstrated that the reduced-pressure strategy leads to a remarkable increase in the extraction efficiency and reduction of the extraction time and temperature (10 min, 25 degrees Sigma vs 20 min, 40 degrees Sigma). Additionally, the reduced pressure strategy showed better analytical performances compared with those obtained by the conventional HS-SPME-GC-FID method. Limit of detections, linear dynamic ranges, and relative standard deviations of the reduced-pressure HS-SPME procedure for benzene, toluene, ethylbenzene, and xylene (BTEX) in injectable solid drugs were obtained over the ranges of 20-100 pg g-1, 0.02-40 MUg g-1, and 2.8-10.2%, respectively. The procedure developed was successful for the analysis of BTEX in commercial containers of penicillin, ampicillin, ceftriaxone, and cefazolin. Graphical abstract Schematic representation of the developed RP-HS SPME setup. PMID- 29273908 TI - Evaluating the solvation properties of metal-containing ionic liquids using the solvation parameter model. AB - Ionic liquids (IL) have been utilized as gas chromatography stationary phases due to their high thermal stability, negligible vapor pressure, wide liquid range, and the ability to solvate a range of analytes. In this study, the solvation properties of eight room temperature ILs containing various transition and rare earth metal centers [e.g., Mn(II), Co(II), Ni(II), Nd(III), Gd(III), and Dy(III)] are characterized using the Abraham solvation parameter model. These metal containing ILs (MCILs) consist of the trihexyl(tetradecyl)phosphonium cation and functionalized acetylacetonate ligands chelated to various metals. They are used in this study as gas chromatographic stationary phases to investigate the effect of the metal centers on the separation selectivities for various analytes. In addition, two MCILs comprised of tetrachloromanganate and tris(trifluoromethylphenylacetylaceto)manganate anions were used to study the effect of chelating ligands on the selectivity of the stationary phases. Depending on the metal center and chelating ligand, significant differences in solvation properties were observed. MCILs containing Ni(II) and Mn(II) metal centers exhibited higher retention factors and higher peak asymmetry factors for amines (e.g., aniline and pyridine). Alcohols (e.g., phenol, p-cresol, 1-octanol, and 1-decanol) were strongly retained on the MCIL stationary phase containing Mn(II) and Dy(III) metal centers. This study presents a comprehensive evaluation into how the solvation properties of ILs can be varied by incorporating transition and rare earth metal centers into their structural make-up. In addition, it provides insight into how these new classes of ILs can be used for solute-specific gas chromatographic separations. Graphical abstract The solvation properties of eight metal-containing ionic liquids (MCILs) comprised of transition and rare-earth metal centers are evaluated for the first time using gas chromatography. The results reveal that metals comprising the MCILs provide unique separation selectivities for various analytes and that these materials can be exploited as stationary phases in solute-specific gas chromatographic separations. PMID- 29273910 TI - Erratum to: Ion Binding to Transport Proteins using Isothermal Titration Calorimetry. PMID- 29273909 TI - Emergency department visits among patients with left ventricular assist devices. AB - Continuous-flow left ventricular assist devices (LVADs) are increasingly implanted to support patients with end-stage heart failure. These patients are at high risk for complications, many of which necessitate emergency care. While rehospitalization rates have been described, there is little data regarding emergency department (ED) visits. We hypothesize that ED visits are frequent and often require admission after LVAD implantation. We performed a retrospective review of patients in our health-care system followed by the advanced heart failure service for LVAD management after implantation between January 2011 and July 2015. We accounted for all ED visits in our system through February 2016, 7 months after the last implantation included. Clinically relevant demographic variables and ED visit details were recorded and analyzed to describe this population. We identified 81 patients with complete data, among whom there were 283 visits (3.49 visits/patient), occurring at a rate of approximately 7.3 ED visits per patient per year alive with LVAD. The most common reason for an ED visit is a complication related to bleeding (18% of visits), followed by chest pain (14%) and dizziness or syncope (13%). Thirty-six percent of patients were discharged from the ED without hospital admission. A growing populace with implanted LVADs represents an important population within emergency medicine. They are at risk for significant complications and frequently present to the ED. While many of these visits may be managed without hospital admission, this specialized patient group represents a potential area for improvement in provider education. PMID- 29273911 TI - Computational investigation of double nitrogen doping on graphene. AB - Density functional theory (DFT) calculations were performed to study doping of two nitrogen atoms at different positions on a finite-sized graphene model of C82H24. We examined 21 structures of double nitrogen doped graphene to calculate their relative stabilities. The structure with two nitrogen atoms located apart is the most stable among the positional isomers considered in this study. For double nitrogen doping within a six-membered ring, the 1,4-position is more preferred than 1,3- or 1,2-positions for the finite-sized single layer graphene sheet. Our computational study supports the experimental observation of two nitrogen atoms at the 1,3- and 1,4-positions in a single six-membered ring of graphene. Furthermore, the structures with N-N bond are the least stable among two nitrogen doped graphene structures. The effects of nitrogen doping and the positions of two nitrogen atoms on the HOMO-LUMO energy gap of pristine graphene were analyzed. PMID- 29273912 TI - Excess mortality in people with mental illness: findings from a Northern Italy psychiatric case register. AB - PURPOSE: People with mental disorders show mortality rates up to 22.2 times higher than that of the general population. In spite of progressive increase in life expectancy observed in the general population, the mortality gap of people suffering from mental health problems has gradually widened. The aim of this paper was to study mortality rates in people suffering from mental illness in a cohort of people (16,981 subjects) in the local mental health register of the province of Modena during the decade 2006-2015. METHODS: Standardized Mortality Ratios (SMRs) were calculated to compare the mortality of people with mental disorders to the mortality of people living in the province of Modena and the excess of mortality was studied in relation to the following variables: gender, age group, diagnosis and causes of death. In addition, Poisson regression analysis was performed to study the association between patient characteristics and mortality. RESULTS: An overall excess mortality of 80% was found in subjects under the care of mental health services as compared to the reference population (SMR = 1.8, 95% CI 1.7-1.9). Subjects in the 15-44 year group presented the highest SMR (9.2, 95% CI 6.9-11.4). The most prevalent cause of death was cancer (28.1% of deaths). At the Poisson regression, the diagnosis "Substance abuse and dependence" showed the highest relative risk (RR) (4.00). Moreover, being male, single, unemployed and with a lower qualification was associated with higher RRs. CONCLUSIONS: Our study confirms that subjects with mental illness have higher SMR. Noteworthy, the overall higher risk of mortality was observed in the younger age group. PMID- 29273913 TI - Effectiveness of working memory training among children with dyscalculia: evidence for transfer effects on mathematical achievement-a pilot study. AB - We examined whether the working memory (WM) capacity of developmentally dyscalculic children can be improved by a WM training program and whether outcomes relate to mathematical performance. The experimental design comprised two groups with developmental dyslexia with grade 4 schooling: an experimental group (n = 14; mean age = 129.74 months) and a control group (n = 14; mean age = 126.9 months). All participants were assessed on measures of WM, mathematic attainment, and nonverbal mental ability (Raven test) before and after training. The WM training program focused on manipulating and maintaining arithmetic information. The results show that both WM and mathematical performances improved significantly after intervention, indicating a strong relationship between these two constructs. The control group improved slightly in Raven's progressive matrices and a reading number task. These findings are discussed in terms of near and far transfer toward trained and untrained skills and stress the positive impact of WM training on learning mathematics in children with dyscalculia. PMID- 29273914 TI - Myeloid neoplasms with t(12;22)(p13;q12)/MN1-EVT6: a systematic review of 12 cases. AB - t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality involving the ETS transcription factor ETV6 and meningioma 1 (MN1) genes. In this study, we analyzed the clinical, cytogenetic, and molecular features of five new patients with the t(12;22)/MN1-EVT6 who presented with acute myeloid leukemia or chronic myelomonocytic leukemia. We subsequently reviewed the literature and identified seven additional cases reported with t(12;22)/MN1-EVT6. Our data suggest that neoplasms carrying the t(12;22)/MN1-ETV6, although rare, can commonly present as myeloid neoplasms at the initial diagnosis, including acute myeloid leukemia (n = 8), myelodysplastic syndrome (n = 2), and myelodysplastic/myeloproliferative neoplasms (n = 2). There were five men and seven women with a median age of 43 years (range, 15-63 years) at initial diagnosis. Cytogenetics revealed t(12;22) as the sole abnormality in five patients, with the remaining seven patients harboring additional chromosomal aberrations. Of the five patients who received known therapy regimens, all of them had poor response to the idarubicin/mitoxantrone + cytarabine regimen. Of the seven patients with follow up information, six patients died with a median overall survival time of only 5 months (range, 1-12 months) after the emergence of t(12;22). In summary, patients with t(12;22) are frequently associated with myeloid neoplasms, poor response to chemotherapy, and inferior outcome. PMID- 29273915 TI - Cyclin D1 mRNA as a molecular marker for minimal residual disease monitoring in patients with mantle cell lymphoma. AB - Chromosomal translocation t(11;14)(q13;q32) is a characteristic molecular marker of mantle cell lymphoma (MCL) and leads to the fusion of the immunoglobulin heavy chain enhancer-promoter with the cyclin D1 gene. Both aberrant cyclin D1 expression and underlying chromosomal aberration may be used as molecular targets for monitoring minimal residual disease (MRD). The present study aims to assess the usefulness of quantitative cyclin D1 gene expression compared to the standardised but more technologically demanding DNA-based method for immunoglobulin heavy chain (IGH) or t(11;14) clone-specific gene rearrangement quantification in a cohort of bone marrow (BM) and peripheral blood (PB) samples from patients with MCL. We simultaneously evaluated DNA-MRD and cyclin D1 expression levels in 234 samples from 57 patients. We observed that both in DNA MRD positive and negative BM/PB pairs from the same time points the expression levels of cyclin D1 are lower in PB than in BM (median 19*, BM/PB range 0.41 352). The correlation of cyclin D1 transcript levels with DNA-MRD or with flow cytometry was good only in samples with a very high infiltration. In DNA-MRD negative BM samples, we observed a significant heterogeneity of cyclin D1 expression (in the range of more than three orders of magnitude). This is in contrast to previous reports demonstrating the usefulness of cyclin D1 for MRD monitoring that did not use DNA-based method as a reference. In PB, the specificity of cyclin D1 expression was better due to a lower physiological background. In conclusion, we show that cyclin D1 is unsuitable for MRD monitoring in BM. PMID- 29273916 TI - Characterization of ecto-nucleotidases in human oviducts with an improved approach simultaneously identifying protein expression and in situ enzyme activity. AB - Extracellular ATP and its hydrolysis product adenosine modulate various reproductive functions such as those taking place in oviducts, including contraction, beating of cilia, and maintenance of fluid composition that, in turn, influences sperm capacitation and hyperactivation, as well as oocyte and embryo nourishing. Ecto-nucleotidases are the enzymes that regulate extracellular ATP and adenosine levels, thus playing a role in reproduction. We have optimized a convenient method for characterizing ecto-nucleotidases that simultaneously localizes the protein and its associated enzyme activity in the same tissue slice and characterizes ecto-nucleotidases in human oviducts. The technique combines immunofluorescence and in situ histochemistry, allowing precise identification of ecto-nucleotidases at a subcellular level. In oviducts, remarkably, ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and NTPDase3, with the ability to hydrolyze ATP to AMP, are expressed in ciliated epithelial cells but with different subcellular localization. Ecto-5'nucleotidase/CD73 is also expressed apically in ciliated cells. CD73, together with alkaline phosphatase, also expressed apically in oviductal epithelium, complete the hydrolysis sequence by dephosphorylating AMP to adenosine. The concerted action of these enzymes would contribute to the local increase of adenosine concentration necessary for sperm capacitation. The use of this method would be an asset for testing new potential therapeutic drugs with inhibitory potential, which is of great interest presently in the field of oncology and in other clinical disciplines. PMID- 29273917 TI - Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. AB - Sepsis is a serious medical condition that can lead to multi-organ failure and shock, and it is associated with increased mortality. Acute kidney injury (AKI) is a frequent complication of sepsis in critically ill patients, and often requires renal replacement therapy. The pathophysiology of AKI in sepsis has not yet been fully defined. In the past, classic theories were mainly focused on systemic hemodynamic derangements, underscoring the key role of whole kidney hypoperfusion due to reduced renal blood flow. However, a growing body of experimental and clinical evidence now shows that, at least in the early phase of sepsis-associated AKI, renal blood flow is normal, or even increased. This could suggest a dissociation between renal blood flow and kidney function. In addition, the scant data available from kidney biopsies in human studies do not support diffuse acute tubular necrosis as the predominant lesion. Instead, increasing importance is now attributed to kidney damage resulting from a complex interaction between immunologic mechanisms, inflammatory cascade activation, and deranged coagulation pathways, leading to microvascular dysfunction, endothelial damage, leukocyte/platelet activation with the formation of micro-thrombi, epithelial tubular cell injury and dysfunction. Moreover, the same processes, through maladaptive responses leading to fibrosis acting from the very beginning, may set the stage for progression to chronic kidney disease in survivors from sepsis-associated AKI episodes. The aim of this narrative review is to summarize and discuss the latest evidence on the pathophysiological mechanisms involved in septic AKI, based on the most recent data from the literature. PMID- 29273918 TI - A review of atypical subtrochanteric femoral fractures in Northern Ireland between 2010 and 2014. AB - The term atypical femoral fractures most commonly occur in the subtrochanteric area. Concerns exist regarding the role of bisphosphonate treatment in their aetiology. Which surgical intervention provides the best outcome remains contentious. We reviewed all atypical subtrochanteric femoral fractures treated in Northern Ireland over 5 years, specifically investigating incidence, prodromal symptoms, association with bisphosphonates and optimal fixation methods. All subtrochanteric fractures treated in the region were identified and reviewed for atypical features. Case notes and imaging were then reviewed for each patient. A total of 364 subtrochanteric femoral fractures were identified during the 5-year study period. Twenty-six of these met the criteria for an atypical fracture (7%). Thirteen patients (50%) had presented with prodromal symptoms prior to complete fracture, six of which had radiological evidence of an incomplete fracture of the lateral cortex. Thirteen patients had a history of bisphosphonate treatment. All were treated operatively, with twenty-five cephalomedullary nails and one dynamic hip screw. Twenty-one patients had follow-up for greater than 2 months, nine of which (42.9%) achieved radiological union with a mean time to union of 297 days. Dynamically locked nails had a higher union rate than statically locked (80% versus 33.3%). Four patients required major revision surgery (15.4%). The quality of reduction was statistically significant in predicting need for revision. Atypical fractures often present with prodromal symptoms. Complete fractures are difficult to successfully manage with longer than expected times to union. Treatment with a dynamically locked, cephalomedullary with a good reduction provided the best results. PMID- 29273919 TI - Microbial diversity of saline environments: searching for cytotoxic activities. AB - In order to select halophilic microorganisms as a source of compounds with cytotoxic activities, a total of 135 bacterial strains were isolated from water and sediment samples collected from the Zipaquira salt mine in the Colombian Andes. We determined the cytotoxic effects of 100 crude extracts from 54 selected organisms on the adherent murine mammary cell carcinoma 4T1 and human mammary adenocarcinoma MCF-7 cell lines. These extracts were obtained from strains of Isoptericola, Ornithinimicrobium, Janibacter, Nesterenkonia, Alkalibacterium, Bacillus, Halomonas, Chromohalobacter, Shewanella, Salipiger, Martellela, Oceanibaculum, Caenispirillum and Labrenzia. The extracts of 23 strains showed an IC50 of less than 100 MUg mL-1. They were subsequently analyzed by LC/MS allowing dereplication of 20 compounds. The cytotoxic effect was related to a complex mixture of diketopiperazines present in many of the extracts analyzed. The greatest cytotoxic activity against both of the evaluated cell lines was obtained from the chloroform extract of Labrenzia aggregata USBA 371 which had an IC50 < 6 MUg mL-1. Other extracts with high levels of cytotoxic activity were obtained from Bacillus sp. (IC50 < 50 MUg mL-1) which contained several compounds such as macrolactin L and A, 7-O-succinoylmacrolactin F and iturin. Shewanella chilikensis USBA 344 also showed high levels of cytotoxic activity against both cell lines in the crude extract: an IC50 < 15 MUg mL-1 against the 4T1 cell line and an IC50 < 68 MUg mL-1 against the MCF-7 cell line. Nesterenkonia sandarakina CG 35, which has an IC50 of 118 ug mL-1 against 4T1, is a producer of diketopiperazines and 1-acetyl-beta-carboline. Also, Ornithinimicrobium kibberense CG 24, which has IC50 < 50 MUg mL-1, was a producer of diketopiperazines and lagunamycin. Our study demonstrates that these saline environments are habitats of halophilic and halotolerant bacteria that have previously unreported cytotoxic activity. PMID- 29273920 TI - Particulate matter concentration levels during intense haze event in an urban environment. AB - This study assessed concentration levels of particulate matter (PM) in the ambient environment of Ilorin metropolis, Nigeria, during haze episodes. Meteorological data (wind speed and direction, rainfall data, sunshine data, relative humidity and temperature) were obtained. Aerocet 531S particle counter (MetOne Instruments, USA) was used to measure four mass concentration ranges of PM (PM1.0, PM2.5, PM10 and the total suspended particles (TSP)) in 10 locations taking into consideration land use patterns. Surfer(r) version 8 (Golden Software LLC, USA) was used to model the spatial variation of particulate matter concentration levels using kriging interpolation griding method. Human exposure assessment was done using the total respiratory deposition dose (TRDD) estimates and statutory limit breach (SLB) approaches. The appearance of dominating weak southern atmospheric wind flow was observed as wind speed ranged from 0 to 6.811 m/s while solar radiation periods ranged from 0.3 to 3.5 h/day. The relative humidity of the metropolis ranged between 28 and 57%, while daily temperature was 15 to 36 degrees C. Highest concentration levels of PM measured were 73.4, 562.7, 7066.3 and 9907.8 MUg/m3 for PM1.0, PM2.5, PM10 and TSP, respectively. Very strong negative correlations existed between the PM concentration levels and microclimatic parameters. Spatial variation of the concentration level as modelled using Surfer(r) version 8 indicated that particulate concentration level increases from south to north. Concentration levels of PM for the 24-h averaging period were generally above the 24-h threshold limit value set by the regulatory agencies for all the locations. PMID- 29273921 TI - Is It Possible a Conservative Approach After Radiochemotherapy in Locally Advanced Rectal Cancer (LARC)? A Systematic Review of the Literature and Meta analysis. AB - BACKGROUND: Locally advanced rectal cancer is usually treated with a preoperative approach with radiochemotherapy followed by surgery. Patients obtaining a pathologic complete response have a very favorable long-term prognosis. This study was intended to assess whether major surgery can reduce tumor recurrences and prolong survival of patients with a complete response after radiochemotherapy. METHODS: Computerized literature search was performed to identify relevant articles. Comparative studies reporting the outcomes of non operative and operative management in patients after neoadjuvant treatment were reviewed. Data synthesis was performed using Review Manager 5.0 software. RESULTS: Twelve non-randomized comparative studies with a total of 1812 patients were suitable for analysis. There was no significant difference in overall survival at 3 and 5 years (odds ratio [OR] 1.31; 95% CI 0.64-2.69; p = 0.46 and 1.48; 95% CI 1.00-2.20; p = 0.50) and in disease-free survival at 3 and 5 years (odds ratio [OR] 1.20; 95% CI 0.68-2.14; p = 0.53 and 1.22; 95% CI 0.86-1.74; p = 0.26, respectively) between locally advanced rectal cancer patients treated with and without operative approach. CONCLUSIONS: Major surgery does not seem to improve prognosis in patients obtaining a complete response after radiochemotherapy. Clinical trials, using clear criteria to identify complete response patients, are needed to recommend non-operative approach. PMID- 29273922 TI - Predictors of cut-out after cephalomedullary nail fixation of pertrochanteric fractures: a retrospective study of 813 patients. AB - BACKGROUND: Cut-out is the most common mechanical complication of the osteosynthesis of pertrochanteric fractures. This complication determines a significant increase in morbidity in elderly patient. Cut-out is defined as the varus collapse of the femoral head-neck fragment with the extrusion of the cephalic screw. Surgical treatment of cut-out might lead to further complications, longer rehabilitation, increased social burden and healthcare system costs. The aim of the study is to identify the predictors of cut-out to prevent its occurrence. MATERIALS AND METHODS: Study population included all patients affected by extracapsular fracture of the proximal femur who were admitted and treated with short cephalomedullary nailing at the Cattinara Hospital-ASUITS of Trieste between 2009 and 2014. A retrospective analysis of clinical and radiographic data was carried out and cut-out cases recorded. The data collected on the study population were analyzed to find an eventual correlation with the occurrence of cut-out. The independent variables were age, gender, side of the fracture, ASA class, Evans classification, nailing system, quality of reduction, TAD, CalTAD, and Parker ratio. RESULTS: The study population counted 813 cases, with an F:M ratio of 4:1 and a mean age of 84.7 years. The cut-out was recorded in 18 cases (2.2%). There was no statistically significant association between cut-out and age, sex, side of fracture, ASA class, and nailing system. The Evans classification, the quality of reduction, the TAD, the CalTAD, and the Parker's ratio demonstrated a significant correlation at univariate analysis with cut-out. The results of multivariate analysis confirmed that TAD, Parker AP, and quality of reduction were independently significantly correlated to cut-out. CONCLUSION: The results of the present study demonstrate that good quality of reduction and correct position of the lag screw are likely to decrease the risk of cut-out complication. A nomogram for cut-out prediction is proposed for clinical validation. PMID- 29273923 TI - The Association Between Weight Loss and Quality of Life 1 and 5 Years After Laparoscopic Roux-en-Y Gastric Bypass in Danish Bariatric Patients. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is effective to achieve significant weight loss, as well as improvement of comorbidity and quality of life (QoL) in obese patients. Several studies have examined whether weight loss can predict the change in QoL after LRYGB but results vary and follow-up is short. The aim of this study was to examine the association between weight loss and change in QoL at 1- and 5-year follow-up after LRYGB. METHODS: The study was a cohort study with 1- and 5-year follow-up, based on data consecutively recorded at the Private Hospital Molholm, Denmark. Before LRYGB (baseline), 3371 severely obese patients filled in the questionnaire that included information on weight and QoL. The patients were invited to fill in a similar questionnaire at 1- and at 5-year follow-up. The response rate at 1 and 5 years was 71 and 63%, respectively. RESULTS: Among the respondents, there was a positive, significant association between weight loss and change in QoL at both 1- and 5-year follow-up after LRYGB. Weight loss and change in QoL peaked after 1 year but remained significantly different from baseline at 5-year follow-up. CONCLUSION: This study showed that weight loss after LRYGB predicts the change in QoL of patients 1 and 5 years after surgery. Furthermore, both weight loss and change in QoL peaked after 1 year but remained significant at 5-year follow-up. PMID- 29273924 TI - Changes in Physical Activities and Body Composition after Roux-Y Gastric Bypass Surgery. AB - PURPOSE: Given the importance of physical activities for health outcomes, it is still unclear whether bariatric surgery per se and the standard care after surgery would result in an increase of physical activity level. This study aimed to determine physical activities preoperatively and at 6 and 12 months postoperatively among female patients who underwent bariatric surgery, and to investigate its relationship with body composition changes. MATERIAL AND METHODS: Thirty-four women who had Roux-Y gastric bypass (RYGB) surgery completed the study. Physical activity was measured objectively for 7 consecutive days by using an ActiGraph GT3X+ accelerometer. Body composition was estimated by using multifrequency bioimpedance analysis. RESULTS: The percentage of time spent in moderate-to-vigorous physical activity (MVPA) changed significantly from preoperatively to 6 months postoperatively; however, no difference was observed at 12 months. No significant changes were detected for other physical activity variables. Multivariable regression analysis suggested that the percentage of time spent in sedentary activity was associated with fat-free mass loss at 6 months (beta = - 0.323; 95% CI = - 0.649 to 0.003) and 12 months (beta = - 0.510; 95% CI = - 0.867 to - 0.154) postoperatively. CONCLUSION: The overall MVPA increased at 6 months post-RYGB surgery; however, this change was not maintained at 12 months. Despite the considerable body mass loss postoperatively, most of the subjects were classified as being physically inactive and did not change their sedentary behavior. These findings indicate that female patients undergoing bariatric surgery should be encouraged to increase their physical activity level. PMID- 29273925 TI - Safety and Effectiveness of Single-Anastomosis Duodenal Switch Procedure: 2-Year Result from a Single US Institution. AB - BACKGROUND: Single-anastomosis duodenal switch (DS) was introduced by Sanchez Pernaute et al. as a modification of the biliopancreatic diversion with duodenal switch. We have published preliminary results of the loop DS as the first report of the procedure in the USA. This study aims to evaluate the loop DS procedures again, in terms of weight loss, comorbidity resolution, complication rate, and address the nutritional concerns. METHODS: A retrospective chart review was performed on initial 128 patients who underwent laparoscopic or robot-assisted laparoscopic single-stage loop DS between December 17, 2013 and September 23, 2016. Sixteen additional patients were prospectively enrolled from September 24, 2016 to May 4, 2017. RESULTS: A total of 102 female and 38 male patients were included in this study with a mean age of 41.2 +/- 9.6 years. The mean body mass index (BMI) at the time of procedure was 57.3 +/- 9.2 kg/m2. Percentage of total weight loss was 23.1, 37.1, 42.9, and 44.7% at 6, 12, 18, and 24 months, respectively. Percentage of excess BMI loss was 41.9, 68.1, 76.6, and 80.8% at 6, 12, 18, and 24 months, respectively. Mean levels of HbA1c, triglyceride, and LDL cholesterol decreased significantly after the loop DS. Regarding the fat-soluble vitamins, majority of patients had vitamin A and E levels in the normal range. However, 42 to 56% of the patients had low levels of vitamin D at 6, 12, and 24 months following the procedure. Mean length of hospital stay was 4.1 +/- 2.7 days. Thirty-day readmission rate was 7.6% (n = 11), and 30-day reoperation rate was 6.9% (n = 10). CONCLUSIONS: Loop DS seems to be effective in weight loss and is a feasible operation in the super-obese population. However, close monitoring of liver enzymes is warranted in addition to nutritional follow-up. PMID- 29273926 TI - A Dutch Nationwide Bariatric Quality Registry: DATO. AB - INTRODUCTION: In the Netherlands, the number of bariatric procedures increased exponentially in the 90s. To ensure and improve the quality of bariatric surgery, the nationwide Dutch Audit for Treatment of Obesity (DATO) was established in 2014. The audit was coordinated by the Dutch Institute for Clinical Auditing (DICA). This article provides a review of the aforementioned process in establishing a nationwide registry in the Netherlands. MATERIALS AND METHODS: In collaboration with the DATO's scientific committee and other stakeholders, an annual list of several external quality indicators was formulated. This list consists of volume, process, and outcome indicators. In addition to the annual external indicators, the database permits individual hospitals to analyze their own data. The dashboard provides several standardized reports and detailed quality indicators, which are updated on a weekly base. RESULTS: Since the start, all 18 Dutch bariatric centers participated in the nationwide audit. A total of 21,941 cases were registered between 2015 and 2016. By 2016, the required variables were registered in 94.3% of all cases. A severe complicated course was seen in 2.87%, and mortality in 0.05% in 2016. The first-year follow-up shows a > 20% TWL in 86.1% of the registered cases. DISCUSSION: The DATO has become rapidly a mature registry. The well-organized structure of the national audit institution DICA and governmental funding were essential. However, most important were the bariatric teams themselves. The authors believe reporting the results from the registry has already contributed to more knowledge and acceptance by other health care providers. PMID- 29273927 TI - Response to: Commentary: "Gluteal Augmentation with Silicone Implants: A New Proposal for Intramuscular Dissection". PMID- 29273928 TI - Sexuality Among Women Treated for Breast Cancer: A Survey of Three Surgical Procedures. PMID- 29273929 TI - Correcting Nasojugal Groove with Autologous Cultured Fibroblast Injection: A Pilot Study. AB - BACKGROUND: A new commercial drug that contains autologous cultured fibroblasts has been developed and approved by the United States Food and Drug Administration for improving the appearance of nasolabial folds. However, the treatment requires three sessions every 3-6 weeks. It is known that the skin overlying the nasojugal groove is thinner, and the wrinkle is generally shallower than nasolabial folds. Therefore, we hypothesized that the nasojugal groove could be improved by just one treatment session. Therefore, the purpose of this study was to evaluate the efficacy and safety of autologous cultured fibroblast injection to correct nasojugal grooves. METHODS: Forty-six subjects with nasojugal grooves were enrolled in this study. They were injected with autologous cultured fibroblasts or placebo in one session. Blinded evaluators and subjects assessed the efficacy using a validated wrinkle assessment scale at 4, 12, and 24 weeks after the injection. Information of adverse events was collected at each visit. RESULTS: Based on the evaluators' assessment at 24 weeks after the injection, 76% of subjects treated with autologous cultured fibroblasts showed improvement whereas 0% of subjects treated with placebo showed improvement (P < 0.0001). Based on self-assessment at 24 weeks after the injection, 72% of subjects treated with autologous cultured fibroblasts and 45% of subjects treated with placebo showed improvement (P = 0.0662). There were no serious adverse events related to autologous cultured fibroblast injection. CONCLUSIONS: Autologous cultured fibroblast injection might be effective and safe to correct nasojugal grooves. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29273930 TI - Response to: Commentary on: "Gluteal Augmentation with Silicone Implants: A New Proposal for Intramuscular Dissection". PMID- 29273931 TI - Comparison of Periorbital Anthropometry Between Beauty Pageant Contestants and Ordinary Young Women with Korean Ethnicity: A Three-Dimensional Photogrammetric Analysis. AB - BACKGROUND: The purpose of this study is to investigate the differences in the periorbital anthropometry between national Beauty Pageant Contestants and Ordinary Young Women with Korean ethnicity. METHODS: Forty-three Beauty Pageant Contestants who were elected for the national beauty contest and forty-eight Ordinary Young Women underwent 3D photography. The authors analyzed 3D photogrammetric measures regarding periorbital soft tissue. RESULTS: The palpebral fissure width was significantly higher in the Beauty Pageant Contestants than the Ordinary Young Women (27.7 +/- 1.2 vs. 26.3 +/- 1.6 mm) (p < 0.001). The palpebral fissure height was also significantly higher in the Beauty Pageant Contestants (11.5. +/- 1.0 vs. 9.1 +/- 1.2 mm) (p < 0.001). The intercanthal width and upper eyelid height were smaller for the Beauty Pageant Contestants (intercanthal width, 34.3 +/- 1.86 mm vs. 36.7 +/- 3.1 mm; upper eyelid height, 11.5 +/- 1.4 mm vs. 13.4 +/- 2.3 mm) (p < 0.05). The nasal width and midfacial width were significantly smaller in the Beauty Pageant Contestants (nasal width, 38.0 +/- 1.8 vs. 39.5 +/- 2.2 mm; midfacial width 144.5 +/- 3.9 vs. 146.9 +/- 5.2 mm) (p < 0.05). The eyebrow showed significantly different features between the two groups in terms of vertical position in the upper face and the shape of the brow apex. The interpupillary distance, binocular distance, slant of palpebral fissure and width of pretarsal crease showed no significant difference between the two groups. CONCLUSION: Periorbital features in Beauty Pageant Contestants are wide-set eyes, larger palpebral fissure in width and height, relatively small upper eyelid height and intercanthal width, and relatively small nose and facial width compared to normal women. Our anthropometric results can be referable values for Asian eyelid surgery and help surgeons to establish individualized surgical planning. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29273932 TI - Treatment of Gigantomastia Using a Medial-Lateral Bipedicle Reduction Mammoplasty: The Role of Doppler-Assisted Preoperative Perforator Identification. AB - The purpose of this study is to introduce a breast reduction technique designed to reduce the incidence of postoperative nipple-areola complex ischemia and necrosis following reduction mammoplasty, while at the same time allowing all the other goals of breast reduction to be realized. This is achieved through preoperative detection of perforating vessels supplying the nipple-areola complex using a hand-held Doppler. The horizontally based parenchymal pedicle is designed to include these perforators whether originating from the internal mammary artery, lateral thoracic artery or both. This technique provides freedom in pedicle shaping and fixation to the pectoral fascia to achieve the best breast contour. The study included 50 patients equally divided into two groups: the study group (using preoperative Doppler for detection of perforators) and control group (without preoperative Doppler). The average body mass index of our patients was 32.4 and 29.8 for study and control groups, respectively. The average suprasternal notch to nipple distance was 40.8 cm in the study group and 38.9 cm in the control group. In all cases of the study group, both medial and lateral pedicles were used each of them containing one perforator. The average resection weight per side was 1433.6 g for the study group and 1173.2 g for the control group. None of the study group cases experienced NAC necrosis, while four cases of the control group experienced NAC necrosis (3 partial and 1 total). The horizontally based parenchymal pedicle constructed with the aid of preoperative perforator identification with a Doppler is an effective technique for breast reduction that results in a very low rate of postoperative ischemia and necrosis of the nipple-areola complex. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29273933 TI - Neck Contouring Without Rhytidectomy in the Presence of Excess Skin. AB - BACKGROUND: Patients with severe neck skin laxity due to excess submental adipose tissue have required either standard rhytidectomy or direct excision of neck skin with Z-plasty and submental lipectomy. Our recent experiences with four patients who declined cervicofacial rhytidectomy demonstrate that submental lipectomy and platysmarrhaphy appear to obtain sufficient improvement. METHODS: The submental area, submandibular area, and lateral neck are injected with local anesthetic. An incision is made in the submental area anterior to the existing crease, and the incision is taken through the subcutaneous tissue to the underlying fat. The skin is undermined in the deep subcutaneous plane. The lateral fat that cannot be visualized directly is suctioned using a number 2 cannula. Supra-platysmal and subplatysmal excess fat are excised under direct vision. The anterior bellies of the digastric muscle are excised partially or completely to obtain a flat contour if necessary. The submaxillary gland is partially or totally removed as indicated. The platysmarrhaphy is performed, and a TLS drain is placed in position and brought out through the left post-auricular sulcus using the attached trocar. The submental incision is then closed without skin excision. RESULT: Non-excisional surgical neck rejuvenation was performed on four patients with significant skin laxity. There was adequate improvement in the cervicomental angle and neck profile contour in all patients, indicating that significant improvement may be achieved without skin excision. CONCLUSION: Patients with excess skin can achieve acceptable results with submental lipectomy and platysmarrhaphy without rhytidectomy or direct excision of neck skin. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29273934 TI - Ethnic Rhinoplasty in Female Patients: The Neoclassical Canons Revisited. AB - BACKGROUND: Despite the substantial amount of research devoted to objectively defining facial attractiveness, the canons have remained a paradigm of aesthetic facial analysis, yet their omnipresence in clinical assessments revealed their limitations outside of a subset of North American Caucasians, leading to criticism about their validity as a standard of facial beauty. In an effort to introduce more objective treatment planning into ethnic rhinoplasty, we compared neoclassical canons and other current standards pertaining to nasal proportions to anatomic proportions of attractive individuals from seven different ethnic backgrounds. METHODS: Beauty pageant winners (Miss Universe and Miss World nominees) between 2005 and 2015 were selected and assigned to one of seven regionally defined ethnic groups. Anteroposterior and lateral images were obtained through Google, Wikipedia, Miss Universe, and Miss World Web sites. Anthropometry of facial features was performed via Adobe Photoshop TM. Individual facial measurements were then standardized to proportions and compared to the neoclassical canons. RESULTS: Our data reflected an ethnic-dependent preference for the multiple fitness model. Wide-set eyes, larger mouth widths, and smaller noses were significantly relevant in Eastern Mediterranean and European ethnic groups. Exceptions lied within East African and Asian groups. CONCLUSION: As in the attractive face, the concept of the ideal nasal anatomy varies between different ethnicities. Using objective criteria and proportions of beauty to plan and execute rhinoplasty in different ethnicities can help the surgeon plan and deliver results that are in harmony with patients' individual background and facial anatomy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29273935 TI - Introducing a new bond reactivity index: Philicities for natural bond orbitals. AB - In the present work, a new methodology defined for obtaining reactivity indices (philicities) is proposed. This is based on reactivity functions such as the Fukui function or the dual descriptor, and makes it possible to project the information from reactivity functions onto molecular orbitals, instead of onto the atoms of the molecule (atomic reactivity indices). The methodology focuses on the molecules' natural bond orbitals (bond reactivity indices) because these orbitals have the advantage of being localized, allowing the reaction site of an electrophile or nucleophile to be determined within a very precise molecular region. This methodology provides a "philicity" index for every NBO, and a representative set of molecules has been used to test the new definition. A new methodology has also been developed to compare the "finite difference" and the "frontier molecular orbital" approximations. To facilitate their use, the proposed methodology as well as the possibility of calculating the new indices have been implemented in a new version of UCA-FUKUI software. In addition, condensation schemes based on atomic populations of the "atoms in molecules" theory, the Hirshfeld population analysis, the approximation of Mulliken (with a minimal basis set) and electrostatic potential-derived charges have also been implemented, including the calculation of "bond reactivity indices" defined in previous studies. Graphical abstract A new methodology defined for obtaining bond reactivity indices (philicities) is proposed and makes it possible to project the information from reactivity functions onto molecular orbitals. The proposed methodology as well as the possibility of calculating the new indices have been implemented in a new version of UCA-FUKUI software. In addition, this version can use new atomic condensation schemes and new "utilities" have also been included in this second version. PMID- 29273937 TI - Correction to: Hydroxychloroquine dosing in immune-mediated diseases: implications for patient safety. AB - The given and family name of a co-author R. Adams Dudley was swapped in the published article. The correct given name is R. Adams and the family name is Dudley. PMID- 29273936 TI - A Multinational Cluster Randomised Controlled Trial to Assess the Efficacy of '11+ Kids': A Warm-Up Programme to Prevent Injuries in Children's Football. AB - OBJECTIVE: The objective of this study was to assess the efficacy of a newly developed warm-up programme ('11+ Kids') regarding its potential to reduce injuries in children's football. METHODS: Children's football teams (under 9 years, under 11 years, and under 13 years age groups) from Switzerland, Germany, the Czech Republic and the Netherlands were invited. Clubs were randomised to an intervention group and a control group, and followed for one season. The intervention group replaced their usual warm-up by '11+ Kids', while the control group warmed up as usual. The primary outcome was the overall risk of football related injuries. Secondary outcomes were the risks of severe and lower extremity injuries. We calculated hazard ratios using extended Cox models, and performed a compliance analysis. RESULTS: In total, 292,749 h of football exposure of 3895 players were recorded. The mean age of players was 10.8 (standard deviation 1.4) years. During the study period, 374 (intervention group = 139; control group = 235) injuries occurred. The overall injury rate in the intervention group was reduced by 48% compared with the control group (hazard ratio 0.52; 95% confidence interval 0.32-0.86). Severe (74% reduction, hazard ratio 0.26; 95% confidence interval 0.10-0.64) and lower extremity injuries (55% reduction, hazard ratio 0.45; 95% confidence interval 0.24-0.84) were also reduced. Injury incidence decreased with increasing compliance. CONCLUSION: '11+ Kids' is efficacious in reducing injuries in children's football. We observed considerable effects for overall, severe and lower extremity injuries. The programme should be performed at least once per week to profit from an injury preventive effect. However, two sessions per week can be recommended to further increase the protective benefit. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02222025. PMID- 29273938 TI - Mesenchymal stem cells injections for knee osteoarthritis: a systematic overview. AB - Numerous systematic reviews investigating the effects of mesenchymal stem cells (MSCs) in treating knee osteoarthritis (OA) have been published with controversial conclusion. The purpose of the overview was (1) to perform an overview of systematic reviews investigating MSCs for knee OA and (2) to synthesize evidence qualitatively to assess confidence in the review findings. A systematic search of systematic reviews published through Aug 2017 was conducted using the MEDLINE, EMBASE and Cochrane Library. The methodological quality and risk of bias of included systematic reviews was assessed by AMSTAR instrument and ROBIS tool, respectively. Best evidence choice procedure was conducted according to the Jadad decision algorithm. The systematic reviews with high methodological quality and low risk of bias were selected ultimately for further evidence synthesis based on the CERQual tool. Four systematic reviews were eligible for inclusion. According to the ROBIS tool, there was one systematic review with low risk of bias and three with high risk of bias. Thus, only one systematic review conducted by Pas et al. with highest AMSTAR score and low risk of bias was selected. For all outcomes after evidence synthesis via the CERQual tool, confidence for decision making was either low (self-reported measurement and MRI/histological outcome) or moderate (adverse events). The present study demonstrates that moderate confidence could be placed in safety of MSCs therapy for knee OA, but with low confidence in efficacy outcomes due to limitations of the current evidence. Further high-quality studies with high internal and external validity are still required. PMID- 29273939 TI - Impact of tissue transport on PET hypoxia quantification in pancreatic tumours. AB - BACKGROUND: The clinical impact of hypoxia in solid tumours is indisputable and yet questions about the sensitivity of hypoxia-PET imaging have impeded its uptake into routine clinical practice. Notably, the binding rate of hypoxia sensitive PET tracers is slow, comparable to the rate of diffusive equilibration in some tissue types, including mucinous and necrotic tissue. This means that tracer uptake on the scale of a PET imaging voxel-large enough to include such tissue and hypoxic cells-can be as much determined by tissue transport properties as it is by hypoxia. Dynamic PET imaging of 20 patients with pancreatic ductal adenocarcinoma was used to assess the impact of transport on surrogate metrics of hypoxia: the tumour-to-blood ratio [TBR(t)] at time t post-tracer injection and the trapping rate k 3 inferred from a two-tissue compartment model. Transport quantities obtained from this model included the vascular influx and efflux rate coefficients, k 1 and k 2, and the distribution volume v d =k 1/(k 2+k 3). RESULTS: Correlations between voxel- and whole tumour-scale k 3 and TBR values were weak to modest: the population average of the Pearson correlation coefficients (r) between voxel-scale k 3 and TBR (1 h) [TBR(2 h)] values was 0.10 [0.01] in the 20 patients, while the correlation between tumour-scale k 3 and TBR(2 h) values was 0.58. Using Patlak's formula to correct uptake for the distribution volume, correlations became strong (r=0.80[0.52] and r=0.93, respectively). The distribution volume was substantially below unity for a large fraction of tumours studied, with v d ranging from 0.68 to 1 (population average, 0.85). Surprisingly, k 3 values were strongly correlated with v d in all patients. A model was proposed to explain this in which k 3 is a combination of the hypoxia-sensitive tracer binding rate k b and the rate k eq of equilibration in slow-equilibrating regions occupying a volume fraction 1-v d of the imaged tissue. This model was used to calculate the proposed hypoxia surrogate marker k b. CONCLUSIONS: Hypoxia-sensitive PET tracers are slow to reach diffusive equilibrium in a substantial fraction of pancreatic tumours, confounding quantification of hypoxia using both static (TBR) and dynamic (k 3) PET imaging. TBR is reduced by distribution volume effects and k 3 is enhanced by slow equilibration. We proposed a novel model to quantify tissue transport properties and hypoxia-sensitive tracer binding in order to improve the sensitivity of hypoxia-PET imaging. PMID- 29273940 TI - Investigation of Clostridium difficile ribotypes in symptomatic patients of a German pediatric oncology center. AB - : In a German pediatric oncology unit, the attending physicians diagnosed 27 cases of Clostridium difficile-associated disease (CDI) from January 01, 2010 to October 31, 2013. This refers to a CDI incidence density of 2.0/1000 inpatient days. According to the hospital hygiene standard, symptomatic patients with CDI were kept in contact isolation. Most patients (median age 8.2 years) suffered from acute lymphoblastic leukemia; 88.9% were treated with broad-spectrum antibiotics during the preceding 4 weeks. 29.6% received intravenous morphine/metamizole and parenteral nutrition due to severe chemotherapy-induced mucositis. None of the patients experienced severe complications such as lower gastrointestinal tract bleeding, sepsis, or toxic megacolon. Genotyping of the isolates derived from symptomatic patients revealed many different ribotypes without detection of the hypervirulent 027 strain and did not point at hospital transmission as an important promoter of CDI in our unit. CONCLUSION: Under strict standard hygiene and contact isolation for symptomatic patients, genotyping of clinical isolates revealed that in pediatric cancer patients, CDI is not necessarily based on nosocomial transmission. The rate of CDI-related severe complications was low. What is Known: * Pediatric cancer patients face an increased risk of Clostridium difficile-associated disease due to immunosuppression, cancer chemotherapy, mucositis, and dysbiosis following intravenous broad-spectrum antimicrobial treatment. * C. difficile may be transmitted from patient to patient. What is New: * Under strict standard hygiene and contact isolation for symptomatic patients, genotyping of clinical isolates revealed that in pediatric cancer patients, CDI is not necessarily based on nosocomial transmission. * The rate of CDI-related severe complications was low. PMID- 29273941 TI - Associations between metabolic syndrome components and markers of inflammation in Welsh school children. AB - : We investigated the multivariate dimensionality and strength of the relationship between metabolic syndrome (MetS) and inflammation in children. Caucasian school children (N = 229; 12-14 years) from Wales were tested on several health indicators including measures of body composition, inflammation, fasting glucose regulation, blood pressure, and lipids. The multivariate association between MetS and inflammation was investigated via canonical correlation analysis. Data were corrected for non-normality by log transformation, and sex-specific z-scores computed for variables where there was a significant sex difference. Structure r's were interpreted to determine the dimensions of MetS and inflammation responsible for significant canonical variates. The overall multivariate association between MetS and inflammation was significant (Wilks' Lambda = 0.54, p < 0.001). The relationship was explained primarily by the waist circumference dimension of MetS (CC = 0.87) and inflammatory markers of fibrinogen (CC = 0.52) and C-reactive protein (CC = 0.50). The pattern of results was similar regardless of whether variables were adjusted for sex differences. CONCLUSION: Central adiposity is the strongest predictor of the inflammatory aspect of cardiovascular disease risk in Caucasian adolescents. Future research into MetS and cardiometabolic risk should consider multivariate statistical approaches, in order to identify the separate contributions of each dimension in interrelationships and to identify which dimensions are influenced by preventive interventions. What is Known: * Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes. Markers of inflammation are also potential predictors of later development of CVD and type 2 diabetes. * The contribution of individual markers in interrelationships between MetS and inflammation is unknown. What is New: * We uniquely demonstrate that within a multivariate model, waist circumference is the primary link between MetS variables and markers of inflammation in children. * Waist circumference may therefore be a useful population-level screening tool to identify future risk of CVD. PMID- 29273942 TI - Repeated early-life exposure to inter-parental conflict increases risk of preadolescent mental health problems. AB - : This study investigated the association between inter-parental conflict at a single occasion, or repeated over early childhood, and children's internalizing and externalizing problems at 10-11 years; and examined potential mechanisms via social risk, maternal mental health, and parenting. Data were five time points from the Baby cohort of the Longitudinal Study of Australian Children (N = 3696, recruited in 2004). Verbal or physical inter-parental conflict was measured at 0 1, 2-3, 4-5, and 6-7 years. Internalizing and externalizing problems (Strengths and Difficulties Questionnaire) were measured via mother-, father-, teacher-, and child-report at 10-11 years. A series of regression models accounted for social risk at 0-1 years, parenting, and maternal psychological distress at 8-9 years. Physical and verbal inter-parental conflict (reported by 16 and 33% of mothers, respectively) consistently predicted mother-, father-, and child-reported externalizing and internalizing problems, and teacher-reported externalizing (but not internalizing) problems (adjusted regression coefficients [beta] = 0.4-1.1). Repeated compared to single report of verbal conflict was associated with more behavior problems (adjusted mean = 0.8-1.1 compared to 0.4-0.6). CONCLUSION: Children are sensitive to inter-parental conflict, with long-term negative effects for child mental health even when reported at one time point within the first 6 years of life. What is Known: * Studies of children born prior to 1990 show that children exposed to verbal conflict or severe forms of family violence are at greater risk of mental health problems. What is New: * Physical and verbal inter-parental conflict reported once or at multiple time points over the first 6 years of life was associated with externalizing and internalizing problems reported by mothers, fathers, children, and teachers. * Associations between inter-parental conflict and child problems were not explained by family social risk, maternal mental health, or parenting. PMID- 29273943 TI - Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS). AB - : Patients with PTEN hamartoma tumor syndrome (PHTS) are at increased risk of developing benign and malignant tumors, including thyroid carcinoma. Benign thyroid lesions and single cases of thyroid carcinoma have been reported in children with PHTS. We conducted a retrospective, single-centered study including children and adolescents with a molecularly proven diagnosis of PTEN. Our cohort consists of 16 patients, with a mean age at diagnosis PHTS of 5.7 years. Twelve of 16 cases exhibited thyroid abnormalities (75%). In seven patients, thyroid abnormalities were already present at first ultrasound screening, in five cases they occurred during follow-up. Eight patients underwent thyroidectomy. Histopathology included nodular goiter, follicular adenoma, papillary microcarcinoma in a boy of six and follicular carcinoma in a girl of 13 years. Two patients had autoimmune thyroid disease. CONCLUSION: Thyroid disease is common in children with PHTS. Physicians caring for patients with early thyroid abnormalities and additional syndromal features should be aware of PHTS as a potentially underlying disorder. Ultrasound screening should be performed immediately after diagnosis of PHTS and repeated yearly or more frequently. Because of possible early cancer development, we recommend early surgical intervention in the form of total thyroidectomy in cases of suspicious ultrasound findings. What is Known: * PHTS patients are at high risk of developing benign and malignant tumors. * Individual cases of thyroid carcinoma in children have been reported. What is New: * Thyroid disease is even more common in children with PHTS (75%) than previously expected. * Frequently thyroid disease is the first organ pathology requiring diagnostic workup and therefore children with PHTS should be examined for thyroid disease right after diagnosis and receive follow-up on a regular basis throughout life. PMID- 29273945 TI - Evaluations of Structural Interventions for HIV Prevention: A Review of Approaches and Methods. AB - Structural interventions alter the social, economic, legal, political, and built environments that underlie processes affecting population health. We conducted a systematic review of evaluations of structural interventions for HIV prevention in low- and middle-income countries (LMICs) to better understand methodological and other challenges and identify effective evaluation strategies. We included 27 peer-reviewed articles on interventions related to economic empowerment, education, and substance abuse in LMICs. Twenty-one evaluations included clearly articulated theories of change (TOCs); 14 of these assessed the TOC by measuring intermediary variables in the causal pathway between the intervention and HIV outcomes. Although structural interventions address complex interactions, no evaluation included methods designed to evaluate complex systems. To strengthen evaluations of structural interventions, we recommend clearly articulating a TOC and measuring intermediate variables between the predictor and outcome. We additionally recommend adapting study designs and analytic methods outside traditional epidemiology to better capture complex results, influences external to the intervention, and unintended consequences. PMID- 29273944 TI - Health status of Polish children and adolescents after cancer treatment. AB - : In the last 40 years, considerable progress was made in the treatment of childhood cancer. Nearly 80% of children achieve long-term clinical remission or are permanently cured. This improvement is however not without sacrifice. This is the first Polish study analyzing the general health status and epidemiology of organ late effects in the cohort of Polish childhood and adolescent cancer survivors monitored by doctors and registered in the on-line national database for late effects (N = 1761). This tool collects information on previous therapy and current health status (medical history, physical examination, laboratory tests) of cancer survivors. The survivors are invited to take part in the follow up examination 5 years after the end of treatment. In the study group, 207 survivors (11.75%) had no complaints; whereas in 1554 cases (88.25%), one or more symptoms/complaints suggesting organ dysfunction were reported. In the whole group, the circulatory problems were most common (31.7%); more than 20% of survivors presented complaints or abnormal function of the urinary tract and had skin, dental, skeletal/muscular problems, or difficulty with chewing. Obesity or short stature alone (21.4%) and a variety of endocrine problems (short stature, obesity, thyroid dysfunction, and gonads toxicity) were present in 323 patients (118 females 15.0% and 205 males 21.0%). Gonadal dysfunction, as the only problem, occurred in 75 girls (9.6%) and 131 boys (13.4%). In our cohort, severe or life-threatening health conditions (3 and 4 grade according to toxicity criteria) were present in low percentage, i.e., 0.2% in the circulatory system, 0.3% in the respiratory tract and, 0.7% in kidney insufficiency. CONCLUSION: Our findings indicate that many childhood cancer survivors demonstrate numerous complaints, even a short time after treatment, suggesting the importance of regular follow-up examinations in subsequent years. What is Known: * Contemporary studies indicate that a significant number of childhood cancer survivors present different long-term side effects which influence their quality of life. What is New: * This is the first nationwide study performed in the largest cohort of Polish childhood cancer survivors concerning general health status and frequency of organ dysfunction. PMID- 29273946 TI - A Randomized Controlled Trial of Intensive Case Management (Project Bridge) for HIV-Infected Probationers and Parolees. AB - Individuals on probation and parole are disproportionately at high risk for HIV infection and experience significant barriers to accessing health care. This study was a two-group randomized controlled trial conducted at a community corrections office and was designed to link HIV positive probationers/parolees to HIV treatment in the community. HIV positive participants were assigned to one of the two treatment conditions: (1) Project Bridge (PB), an intensive case management intervention; or (2) treatment as usual (TAU), involving standard referral to treatment. We hypothesized that PB would be more effective than TAU in terms of initiating individuals in community HIV treatment. We found no difference in rates of, or time to, treatment initiation when comparing the PB to TAU (all ns > 0.05). Additionally, there was no statistically significant difference between HIV medication regiment initiation by treatment condition (p > 0.05). Despite limitations, we found that probationers and parolees were willing to be screened and linked to treatment. PMID- 29273947 TI - Correction to: Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage. AB - The original version of this paper unfortunately captured the names of Florian Gessler and Volker Seifert incorrectly and are now corrected in this paper. PMID- 29273949 TI - Brain pulsations enlightened. PMID- 29273948 TI - ICP curve morphology and intracranial flow-volume changes: a simultaneous ICP and cine phase contrast MRI study in humans. AB - BACKGROUND: The intracranial pressure (ICP) curve with its different peaks has been extensively studied, but the exact physiological mechanisms behind its morphology are still not fully understood. Both intracranial volume change (DeltaICV) and transmission of the arterial blood pressure have been proposed to shape the ICP curve. This study tested the hypothesis that the ICP curve correlates to intracranial volume changes. METHODS: Cine phase contrast magnetic resonance imaging (MRI) examinations were performed in neuro-intensive care patients with simultaneous ICP monitoring. The MRI was set to examine cerebral arterial inflow and venous cerebral outflow as well as flow of cerebrospinal fluid over the foramen magnum. The difference in total flow into and out from the cranial cavity (Flowtot) over time provides the DeltaICV. The ICP curve was compared to the Flowtot and the DeltaICV. Correlations were calculated through linear and logarithmic regression. Student's t test was used to test the null hypothesis between paired samples. RESULTS: Excluding the initial ICP wave, P1, the mean R 2 for the correlation between the DeltaICV and the ICP was 0.75 for the exponential expression, which had a higher correlation than the linear (p = 0.005). The first ICP peaks correlated to the initial peaks of Flowtot with a mean R 2 = 0.88. CONCLUSION: The first part, or the P1, of the ICP curve seems to be created by the first rapid net inflow seen in Flowtot while the rest of the ICP curve seem to correlate to the DeltaICV. PMID- 29273950 TI - What experiments on pinned nanobubbles can tell about the critical nucleus for bubble nucleation. AB - The process of homogeneous bubble nucleation is almost impossible to probe experimentally, except near the critical point or for liquids under large negative tension. Elsewhere in the phase diagram, the bubble nucleation barrier is so high as to be effectively insurmountable. Consequently, there is a severe lack of experimental studies of homogenous bubble nucleation under conditions of practical importance (e.g., cavitation). Here we use a simple geometric relation to show that we can obtain information about the homogeneous nucleation process from Molecular Dynamics studies of bubble formation in solvophobic nanopores on a solid surface. The free energy of pinned nanobubbles has two extrema as a function of volume: one state corresponds to a free-energy maximum ("the critical nucleus"), the other corresponds to a free-energy minimum (the metastable, pinned nanobubble). Provided that the surface tension does not depend on nanobubble curvature, the radius of the curvature of the metastable surface nanobubble is independent of the radius of the pore and is equal to the radius of the critical nucleus in homogenous bubble nucleation. This observation opens the way to probe the parameters that determine homogeneous bubble nucleation under experimentally accessible conditions, e.g. with AFM studies of metastable nanobubbles. Our theoretical analysis also indicates that a surface with pores of different sizes can be used to determine the curvature corrections to the surface tension. Our conclusions are not limited to bubble nucleation but suggest that a similar approach could be used to probe the structure of critical nuclei in crystal nucleation. PMID- 29273952 TI - Modification of pomegranate waste with iron ions a green composite for removal of Pb from aqueous solution: equilibrium, thermodynamic and kinetic studies. AB - Pomegranate waste modified with Fe2+ and Fe3+ ions followed with carbonization were used as an adsorbent to remove the Pb2+ ions from aqueous solution. To optimum the highest adsorption efficiency, adsorption experiments were conducted on iron modified carbons by batch technique. The characteristic of composite was studied by scanning electron microscope (SEM) and Fourier transform infrared spectrometer (FT-IR). The best pH for control of chemical adsorption was selected within pH of 6.0-6.5. It was observed that the contact time of 90 min, initial concentration 50.0 ppm, and adsorbent dose, 1.0 g/100 ml solution was found to be optimum conditions. On this condition, the maximum adsorption capacity was obtained 27.5 and 22.5 mg/g for Fe2+ and Fe3+ impregnated pomegranate peel carbons (PPC), respectively. The value of Cid, 1.584 for Fe2+-PPC and 0.552 for Fe3+-PPC, indicates that the effect of the boundary layer is more important in adsorption of Pb2+ by Fe2+-PPC and the pore diffusion is the rate limiting mechanism after 30 min. Thermodynamic parameters of Gibbs free energy, enthalpy, and entropy of Pb2+ adsorption on iron-modified carbons suggest that the adsorption process is favorable and spontaneous under the optimum condition. PMID- 29273951 TI - Neuroinflammatory responses in Alzheimer's disease. AB - Neuroinflammatory responses in Alzheimer's disease (AD) are complex and not fully understood. They involve various cellular and molecular players and associate interaction between the central nervous system (CNS) and the periphery. Amyloid peptides within the senile plaques and abnormally phosphorylated tau in neurofibrillary tangles are able to initiate inflammatory responses, in brain of AD patients and in mouse models of this disease. The outcome of these responses on the pathophysiology of AD depends on several factors and can be either beneficial or detrimental. Thus, understanding the role of neuroinflammation in AD could help to develop safer and more efficient therapeutic strategies. This review discusses recent knowledge on microglia responses toward amyloid and tau pathology in AD, focusing on the role of Toll-like receptors and NOD-like receptor protein 3 (NLRP3) inflammasome activation in microglial cells. PMID- 29273954 TI - Late breast cancer treatment-related symptoms and functioning: associations with physical activity adoption and maintenance during a lifestyle intervention for rural survivors. AB - PURPOSE: Physical activity may be difficult for survivors with poorer functioning following primary treatment. The study examined whether late symptoms of breast cancer treatment impact PA adoption (0-6 months) and maintenance (6-18 months) during a weight management intervention, and whether late symptoms influence PA when accounting for overall functioning. METHODS: Secondary analyses were conducted using a sample of survivors participating in a weight management intervention and who provided valid weight and accelerometer data at baseline and 6 months (N = 176). The Breast Cancer Prevention Trial Symptom Checklist (BCPT) assessed late treatment-related symptoms. SF-12 Physical Component Scale (PCS) and Mental Component Scale (MCS) scores assessed functioning. RESULTS: Change in bouted moderate to vigorous physical activity (MVPA) min/week from baseline to 6 months was not associated with BCPT scales (all p values > 0.05). When adding SF 12 scores to the model, change in bouted MVPA min/week was significantly associated with the PCS (p = 0.045). Change in MVPA min/week from 6 to 18 months was significantly associated with cognitive symptoms (p = 0.004), but not musculoskeletal or vasomotor symptoms (p values > 0.05). When adding 6-month SF 12 scores to the model, MVPA min/week was significantly associated with PCS (p = 0.001) and MCS (p = 0.028); however, BCPT cognitive problems score became non significant (p > 0.05). CONCLUSIONS: Poorer physical functioning was associated with lower PA adoption, and poorer mental and physical functioning was associated with lower maintenance of PA, while late symptoms generally were not. Interventionists should consider level of functioning when identifying individual PA goals during weight management interventions. PMID- 29273953 TI - A Review of "Polychaeta" Chemicals and their Possible Ecological Role. AB - Despite the many publications concerning the isolation of substances and the many reviews of marine natural products, some groups of organisms remain poorly studied, including "Polychaeta". In response, this review covers articles published through December 2016 that address marine natural products produced from polychaetes, with a focus on antipredatory strategies, competitors, fouling, and pathogens. A total of 121 compounds were isolated from 1934 to 2016, which includes halogenated aromatics, proteins, amino acids and Lumazine derivatives most notably-with a defensive function were found in the literature, most frequently in the families Sabellidae, Terebellidae, Glyceridae, and Nereididae. The period of highest discovery of natural products in defensive actions for the group was the 2000s. Polychaetes were addressed in 26 revisions of the total 51 articles analyzed and are less reported than other marine invertebrates such as sponges, cnidarians, mollusks, and tunicates. In sum, the present review provides a basis for future research on the marine chemical ecology of polychaetes. PMID- 29273955 TI - Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma. AB - PURPOSE: Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor-stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated. METHODS: A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). RESULTS: TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles. CONCLUSIONS: Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients. PMID- 29273956 TI - Interventions are needed to support patient-provider decision-making for DCIS: a scoping review. AB - PURPOSE: Prognostic and treatment uncertainty make ductal carcinoma in situ (DCIS) complex to manage. The purpose of this study was to describe research that evaluated DCIS communication experiences, needs and interventions among DCIS patients or physicians. METHODS: MEDLINE, EMBASE, CINAHL and The Cochrane Library were searched from inception to February 2017. English language studies that evaluated patient or physician DCIS needs, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings. RESULTS: A total of 51 studies published from 1997 to 2016 were eligible for review, with a peak of 8 articles in year 2010. Women with DCIS lacked knowledge about the condition and its prognosis, although care partners were more informed, desired more information and experienced decisional conflict. Many chose mastectomy or prophylactic mastectomy, often based on physician's recommendation. Following treatment, women had anxiety and depression, often at levels similar to those with invasive breast cancer. Disparities were identified by education level, socioeconomic status, ethnicity and literacy. Physicians said that they had difficulty explaining DCIS and many referred to DCIS as cancer. Despite the challenges reported by patients and physicians, only two studies developed interventions designed to improve patient-physician discussion and decision-making. CONCLUSIONS: As most women with DCIS undergo extensive treatment, and many experience treatment-related complications, the paucity of research on PE to improve and support informed decision-making for DCIS is profound. Research is needed to improve patient and provider discussions and decision-making for DCIS management. PMID- 29273957 TI - Oncological strategies for locally advanced rectal cancer with synchronous liver metastases, interval strategy versus rectum first strategy: a comparison of short term outcomes. AB - BACKGROUND: The goal of treatment for patients with synchronous liver metastases (SLM) from rectal cancer is to achieve a complete resection of both tumor locations. For patients with symptomatic locally advanced rectal cancer with resectable SLM at diagnosis, our usual strategy has been the rectum first approach (RF). However, since 2014, we advocate for the interval approach (IS) that involves the administration of chemo-radiotherapy followed by the resection of the SLM in the interval of time between rectal cancer radiation and rectal surgery. METHODS: From 2010 to 2016, 16 patients were treated according to this new strategy and 19 were treated according RF strategy. Data were collected prospectively and analyzed with an intention-to-treat perspective. Complete resection rate, duration of the treatment and morbi-mortality were the main outcomes. RESULTS: The complete resection rate in the IS was higher (100%, n = 16) compared to the RF (74%, n = 14, p = 0.049) and the duration of the strategy was shorter (6 vs. 9 months, respectively, p = 0.006). The incidence of severe complications after liver surgery was 14% (n = 2) in the RF and 0% in the IS (p = 1.000), and after rectal surgery was 24% (n = 4) and 12% (n = 2), respectively (p = 1.000). CONCLUSION: The IS is a feasible and safe strategy that procures higher level of complete resection rate in a shorter period of time compared to RF strategy. PMID- 29273959 TI - Epidural venous thrombosis as differential diagnosis in back pain patients. AB - Epidural venous thrombosis is a rare clinical entity with a characteristic constellation of findings in contrast-enhanced MRI, which should be considered in the differential diagnosis in the case of clinical symptoms that are initially indicative of disc herniation. The most important distinctive feature between epidural venous thrombosis and disc herniation is their topographical location in relation to the vertebral venous plexus. Particularly where morphological imaging shows a space-occupying lesion in close proximity to the internal vertebral venous plexus and a central contrast medium defect, epidural venous thrombosis should be taken into consideration. PMID- 29273958 TI - Biomarkers in breast cancer: A consensus statement by the Spanish Society of Medical Oncology and the Spanish Society of Pathology. AB - This consensus statement revises and updates the recommendations for biomarkers use in the diagnosis and treatment of breast cancer, and is a joint initiative of the Spanish Society of Medical Oncology and the Spanish Society of Pathology. This expert group recommends determining in all cases of breast cancer the histologic grade and the alpha-estrogen receptor (ER), progesterone receptor, Ki 67 and HER2 status, in order to assist prognosis and establish therapeutic options, including hormone therapy, chemotherapy and anti-HER2 therapy. One of the four available genetic prognostic platforms (MammaPrint(r), Oncotype DX(r), Prosigna(r) or EndoPredict(r)) may be used in node-negative ER-positive patients to establish a prognostic category and decide with the patient whether adjuvant treatment may be limited to hormonal therapy. Newer technologies including next generation sequencing, liquid biopsy, tumour-infiltrating lymphocytes or PD-1 determination are at this point investigational. PMID- 29273960 TI - Stent-assisted coiling of intracranial aneurysms using LEO stents: long-term follow-up in 153 patients. AB - PURPOSE: Coiling associated with placement of a self-expandable intracranial stent has improved the treatment of intracranial wide-necked aneurysms. Little is known, however, about the durability of this treatment. The purpose of this report is to present our experience with the LEO stent and to evaluate the complications, effectiveness, and long-term results of this technique. METHODS: We analyzed the records of 155 intracranial unruptured aneurysms that were treated by stent-assisted coiling with a LEO stent between 2008 and 2012. Procedural, early post-procedural, and delayed complications were recorded. Clinical and angiographic follow-up of patients was conducted over a period of at least 36 months. RESULTS: No procedural mortality was observed. One-month morbidity was observed in 14 out of 153 patients (9,15%). One hundred thirty eight patients (with 140 aneurysms) had clinical and angiographic follow-up for more than 36 months. No aneurysm rupture was observed during follow-up. Four patients presented an intra-stent stenosis at 8 months, and 6 patients who had an early recurrence were retreated. Final results showed 85% complete occlusion, 13% neck remnants, and 2% stable incomplete occlusion. CONCLUSION: Stent-assisted coiling with the LEO stent is a safe and effective treatment for unruptured intracranial aneurysms. The long-term clinical outcomes with the LEO stent are excellent with a high rate of complete occlusion that is stable over time. PMID- 29273961 TI - Experimental Evaluation of Preservation Techniques for Benzene, Toluene, Ethylbenzene, and Total Xylenes in Water Samples. AB - An experiment was designed to address the validity of the prescribed maximum allowable holding-time limit of 14 days when acidified at < 2 pH and maintained at 4 degrees C to prevent significant loss of benzene, toluene, ethyl benzene, and xylenes (BTEX) in preserved water samples. Preservation methods prescribed by the United State Environmental Protection Agency were used as well as adaptions of that procedure to determine stability between 3 and 21 days. Water samples preserved at 4 degrees C and pH of < 2 with hydrochloric acid did not result in unacceptable (> 15%) BTEX losses during the study as defined by procedures and statistical methods described by the American Society for Testing and Materials International. In addition, water samples preserved only with acid (pH < 2) at ambient temperatures (20-27 degrees C) also provided acceptable results during the 21-day study. These results have demonstrated the acceptability of BTEX data derived from water samples exceeding the standard holding-time and/or temperature limits. PMID- 29273962 TI - Testing the Underlying Chemical Principles of the Biotic Ligand Model (BLM) to Marine Copper Systems: Measuring Copper Speciation Using Fluorescence Quenching. AB - Speciation of copper in marine systems strongly influences the ability of copper to cause toxicity. Natural organic matter (NOM) contains many binding sites which provides a protective effect on copper toxicity. The purpose of this study was to characterize copper binding with NOM using fluorescence quenching techniques. Fluorescence quenching of NOM with copper was performed on nine sea water samples. The resulting stability constants and binding capacities were consistent with literature values of marine NOM, showing strong binding with [Formula: see text] values from 7.64 to 10.2 and binding capacities ranging from 15 to 3110 nmol mg [Formula: see text] Free copper concentrations estimated at total dissolved copper concentrations corresponding to previously published rotifer effect concentrations, in the same nine samples, were statistically the same as the range of free copper calculated for the effect concentration in NOM-free artificial seawater. These data confirms the applicability of fluorescence spectroscopy techniques for NOM and copper speciation characterization in sea water and demonstrates that such measured speciation is consistent with the chemical principles underlying the biotic ligand model approach for bioavailability-based metals risk assessment. PMID- 29273963 TI - Transglycosylation of gallic acid by using Leuconostoc glucansucrase and its characterization as a functional cosmetic agent. AB - Gallic acid glycoside was enzymatically synthesized by using dextransucrase and sucrose from gallic acid. After purification by butanol partitioning and preparative HPLC, gallic acid glucoside was detected at m/z 355 (C13, H16, O10, Na)+ by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The yield of gallic acid glucoside was found to be 35.7% (114 mM) by response surface methodology using a reaction mixture of 319 mM gallic acid, 355 mM sucrose, and 930 mU/mL dextransucrase. The gallic acid glucoside obtained showed 31% higher anti-lipid peroxidation and stronger inhibition (Ki = 1.23 mM) against tyrosinase than that shown by gallic acid (Ki = 1.98 mM). In UVB irradiated human fibroblast cells, gallic acid glucoside lowered matrix metalloproteinase-1 levels and increased the collagen content, which was indicative of a stronger anti-aging effect than that of gallic acid or arbutin. These results indicated that gallic acid glucoside is likely a superior cosmetic ingredient with skin-whitening and anti-aging functions. PMID- 29273964 TI - HRCT texture analysis for pure or part-solid ground-glass nodules: distinguishability of adenocarcinoma in situ or minimally invasive adenocarcinoma from invasive adenocarcinoma. AB - PURPOSE: To distinguish between adenocarcinoma in situ (AIS)-minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) showing pure or part-solid ground-glass nodules (GGNs) by high-resolution computed tomography (HRCT) texture analysis. MATERIALS AND METHODS: This retrospective study included 101 consecutive patients with 115 pure or part-solid GGNs <= 3 cm diameter, which were surgically resected and pathologically diagnosed with AIS, MIA, or IAC (48 AIS-MIA and 67 IAC) between April 2011 and March 2015. Each tumor was manually segmented on axial CT images, and the following texture features were calculated: volume, mass, mean CT value, variance, skewness, kurtosis, entropy, uniformity, and percentile CT numbers (10th, 25th, 50th, 75th, 90th, 95th percentiles). The differences between AIS-MIA and IAC were statistically evaluated using univariate, multivariate, and receiver operating characteristic analysis. RESULTS: Compared with IAC, AIS-MIA had significantly greater skewness, kurtosis, and uniformity, whereas in the other parameters, AIS-MIA demonstrated significantly lower values than those of IAC. Multivariate analysis revealed that independent differentiators were the 90th percentile CT numbers (P < 0.001) and entropy (P = 0.005) with an excellent accuracy (area under the curve, 0.90). CONCLUSIONS: The 90th percentile CT numbers and entropy can accurately distinguish AIS-MIA from IAC. PMID- 29273965 TI - Effects of alpha7 Nicotinic Receptor Activation on Cell Survival in Rat Organotypic Hippocampal Slice Cultures. AB - Glutamatergic signaling via N-methyl-D-aspartate receptors (NMDARs) is important for physiological functioning, but can also induce cell death via excitotoxic mechanisms in many neuropathological diseases, such as stroke. Altering the cellular response to excitotoxic insults by modulating the downstream effects of NMDAR activation represents a promising therapeutic approach. For example, alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) signaling has been shown to be able to change NMDA-induced neurotoxicity in some models. However, both neuroprotective and neurotoxic effects have been reported. In this study, we examined the effect of co-activation of alpha7 nAChRs on NMDA-mediated cell death in rat organotypic hippocampal slice cultures (OHSCs). Our results show that alpha7 nAChR stimulation did not significantly influence NMDA-induced excitotoxic cell damage as measured by propidium iodide uptake. However, treatment of OHSCs with the alpha7 nAChR agonist choline alone induced an increase in the propidium iodide signal. Both the alpha7 nAChR antagonist methyllycaconitine (MLA) and the NMDAR antagonist (RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) were able to block this effect in the dentate gyrus and hippocampal subfield CA3. PMID- 29273966 TI - Molecular characterization of AmiC, a positive regulator in acetamidase operon of Mycobacterium smegmatis. AB - Mycobacterium smegmatis, a rapidly growing non-pathogenic mycobacterium, is currently used as a model organism to study mycobacterial genetics. Acetamidase of M. smegmatis is the highly inducible enzyme of Mycobacteria, which utilizes several amide compounds as sole carbon and nitrogen sources. The acetamidase operon has a complex regulatory mechanism, which involves three regulatory proteins, four promoters, and three operator elements. In our previous study, we showed that over-expression of AmiA leads to a negative regulation of acetamidase by blocking the P2 promoter. In this study, we have identified a new positive regulatory protein, AmiC that interacts with AmiA through protein-protein interaction. Gel mobility shift assay showed that AmiC protein inhibits AmiA from binding to the P2 promoter. Interaction of AmiC with cis-acting elements identified its binding ability to multiple regulatory regions of the operon such as P3, OP3, and P1 promoter/operator. Consequently, the addition of inducer acetamide to AmiC complexe trips the complexes, causing AmiC to appear to be the sensory protein for the amides. Homology modeling and molecular docking studies suggest AmiC as a member of Periplasmic binding proteins, which preferentially bind to the inducers and not to the suppressor. Over-expression of AmiC leads to down-regulation of the negative regulator, amiA, and constitutive up-regulation of acetamidase. Based on these findings, we conclude that AmiC positively regulates the acetamidase operon. PMID- 29273967 TI - Molecular characteristics of a novel HSP60 gene and its differential expression in Manila clams (Ruditapes philippinarum) under thermal and hypotonic stress. AB - The Manila clam Ruditapes philippinarum inhabits the intertidal zone and must therefore tolerate broad fluctuations in water temperature and salinity. Heat shock protein 60 (HSP60) is an evolutionarily conserved, multi-functional protein that plays a significant role in protecting organisms from harmful stress conditions. We cloned the R. philippinarum HSP60 (RpHSP60) gene and analyzed its transcriptional responses to thermal and low-salinity stresses. The complete sequence of RpHSP60 cDNA was 1777 nucleotides, containing a 1728-bp open reading frame encoding a polypeptide of 576-amino acids, with a calculated molecular mass of 61.25 kDa and predicted isoelectric point of 5.08. Comparisons of amino acid sequences and three-dimensional structures of HSP60 revealed that RpHSP60 was highly conserved in the signature HSP60-family domains. RpHSP60 mRNA was detected in all the tested tissues of R. philippinarum, with the highest expression levels in hemocytes. We measured RpHSP60 mRNA levels in the gills under thermal and low salinity stresses using quantitative real-time reverse transcription-polymerase chain reaction. Following the thermal challenge, RpHSP60 mRNA was significantly upregulated at 6 h, and then progressively downregulated under high-temperature stress (30 degrees C), while only slight fluctuations were observed under low temperature stress (-1 degrees C). Under low-salinity (17 ppt) stress, RpHSP60 mRNA levels were significantly increased at 3, 72, and 96 h (P < 0.05). These results suggest that HSP60 of R. philippinarum may play important roles in responding to high-temperature and low-salinity stresses. PMID- 29273969 TI - Within-person adaptivity in frugal judgments from memory. AB - Humans can exploit recognition memory as a simple cue for judgment. The utility of recognition depends on the interplay with the environment, particularly on its predictive power (validity) in a domain. It is, therefore, an important question whether people are sensitive to differences in recognition validity between domains. Strategic, intra-individual changes in the reliance on recognition have not been investigated so far. The present study fills this gap by scrutinizing within-person changes in using a frugal strategy, the recognition heuristic (RH), across two task domains that differed in recognition validity. The results showed adaptive changes in the reliance on recognition between domains. However, these changes were neither associated with the individual recognition validities nor with corresponding changes in these validities. These findings support a domain adaptivity explanation, suggesting that people have broader intuitions about the usefulness of recognition across different domains that are nonetheless sufficiently robust for adaptive decision making. The analysis of metacognitive confidence reports mirrored and extended these results. Like RH use, confidence ratings covaried with task domain, but not with individual recognition validities. The changes in confidence suggest that people may have metacognitive access to information about global differences between task domains, but not to individual cue validities. PMID- 29273968 TI - In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics. AB - PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software. RESULTS: Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compared with the CYP2C9*1/*1 genotype, HLM incubations from CYP2C9*3/*3 and CYP2C9*2/*2 donors showed ~ 10- and 3-fold decrease in siponimod metabolism, respectively. Simulations of enzyme contribution predicted that in the CYP2C9*1/*1 genotype, CYP2C9 is predominantly responsible for siponimod metabolism (~ 81%), whereas in the CYP2C9*3/*3 genotype, its contribution is reduced to 11%. The predicted exposure increase of siponimod with fluconazole 200 mg was 2.0-2.4-fold for CYP2C9*1/*1 genotype. In context of single dosing, the predicted mean area under the curve (AUC) is 2.7-, 3.0- and 4.5-fold higher in the CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, compared with the CYP2C9*1/*1 genotype. CONCLUSION: .Enzyme phenotyping with correlation analysis confirmed the predominant role of CYP2C9 in the biotransformation of siponimod and demonstrated the functional consequence of CYP2C9 genetic polymorphism on siponimod metabolism. Simulation of fluconazole inhibition closely predicted a 2-fold AUC change (ratio within ~ 20% deviation) to the observed value. In silico simulation predicted a significant reduction in siponimod clearance in the CYP2C9*2/*2 and CYP2C9*3/*3 genotypes based on the in vitro metabolism data; the predicted exposure was close (within 30%) to the observed results for the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes. PMID- 29273970 TI - Renal replacement therapy for children throughout the world: the need for a global registry. AB - BACKGROUND: To describe the factors affecting the incidence of renal replacement therapy (RRT) among children, information from RRT registries is required. We aimed to give an overview of existing pediatric RRT registries worldwide, identify regions with a need to commence or increase data collection on pediatric RRT, and provide a rationale for developing a global RRT registry. METHODS: A survey assessing pediatric RRT registry status was sent to International Pediatric Nephrology Associateion (IPNA) members in 127 countries in January 2016. The survey was complemented by a systematic literature search for active pediatric RRT registries. RESULTS: Complete survey responses were retrieved from 94 countries (representing 86.2% of the world childhood population), with 84 (81.2%) having the means to provide RRT to children, given that there are no other limitations such as financial, social, or religious restraints. Fifty-one (35.3%) countries had national registries for both dialysis and transplantation, nine (30.0%) either had a dialysis or a transplant registry, six participated in international registries only (2.7%), and in 18 (13.2%), children on RRT were not followed in any registry. The search identified 92 pediatric RRT registries, primarily national registries located in Europe, North America, and Asia. CONCLUSIONS: Although pediatric RRT can be provided in 84 countries representing 81.2% of the world's childhood population, national pediatric RRT registries are unavailable in many countries. To improve knowledge about the incidence and outcomes of pediatric RRT around the globe, an international population-based pediatric RRT registry has recently been initiated. PMID- 29273971 TI - Stereological study of developing glomerular forms during human fetal kidney development. AB - BACKGROUND: Human fetal kidney development is a complex and stepwise process. The number, shape, size and distribution of glomeruli provide important information on kidney organization. The aim of this study was to quantify glomerular developing forms during human fetal kidney development using stereological methods. METHODS: Kidney tissue specimens of 40 human fetuses with gestational ages ranging from 9 to 40 weeks were analyzed. Specimens were divided into eight groups based on gestational age, each corresponding to 1 lunar month. Stereological methods were used at the light microscopy level to estimate volume, surface and numerical density of the glomerular developing forms. RESULTS: During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Volume, surface and numerical densities of vesicular forms and S shaped bodies decreased gradually in parallel with gradual increases in estimated stereological parameters for vascularized glomeruli. Volume density and surface density of vascularized glomeruli increased gradually during fetal kidney development, and numerical density increased until the seventh lunar month. A relative decrease in vascularized glomeruli per unit volume of cortex occurred during the last 3 lunar months. Nephrogenesis began to taper off by 32 weeks and was completed by 36 weeks of gestation. The last sample in which we observed vesicles was from a fetus aged 32 weeks, and the last sample with S-shaped bodies was from a fetus aged 36 weeks. CONCLUSIONS: The present study is one of few quantitative studies conducted on human kidney development. Knowledge of normal human kidney morphogenesis during development could be important for future medical practice. Events occurring during fetal life may have significant consequences later in life. PMID- 29273972 TI - The first report of Japanese antimicrobial use measured by national database based on health insurance claims data (2011-2013): comparison with sales data, and trend analysis stratified by antimicrobial category and age group. AB - PURPOSE: Our objective was to evaluate the utility of the national database (NDB) based on health insurance claims data for antimicrobial use (AMU) surveillance in medical institutions in Japan. METHODS: The population-weighted total AMU expressed as defined daily doses (DDDs) per 1000 inhabitants per day (DID) was measured by the NDB. The data were compared with our previous study measured by the sales data. Trend analysis of DID from 2011 to 2013 and subgroup analysis stratified by antimicrobial category and age group were performed. RESULTS: There was a significant linear correlation between the AMUs measured by the sales data and the NDB. Total oral and parenteral AMUs (expressed in DID) were 1.04-fold from 12.654 in 2011 to 13.202 in 2013 and 1.13-fold from 0.734 to 0.829, respectively. Percentage of oral form among total AMU was high with more than 94% during the study period. AMU in the children group (0-14 years) decreased from 2011 to 2013 regardless of dosage form, although the working age group (15-64 years) and elderly group (65 and above years) increased. Oral AMU in the working age group was approximately two-thirds of those in the other age groups. In contrast, parenteral AMU in the elderly group was extremely high compared to the other age groups. CONCLUSIONS: The trend of AMU stratified by antimicrobial category and age group were successfully measured using the NDB, which can be a tool to monitor outcome indices for the national action plan on antimicrobial resistance. PMID- 29273973 TI - Re: Blood mercury concentration in relation to metabolic and weight phenotypes using the KNHANES 2011-2013 data. PMID- 29273974 TI - Reply to comment to: Blood mercury concentration in relation to metabolic and weight phenotypes using the KNHANES 2011-2013 data. PMID- 29273975 TI - Influence of Elastic Stiffness and Surface Adhesion on Bouncing of Nanoparticles. AB - Granular collisions are characterized by a threshold velocity, separating the low velocity regime of grain sticking from the high-velocity regime of grain bouncing: the bouncing velocity, v b . This parameter is particularly important for nanograins and has applications for instance in astrophysics where it enters the description of collisional dust aggregation. Analytic estimates are based on the macroscopic Johnson-Kendall-Roberts (JKR) theory, which predicts the dependence of v b on the radius, elastic stiffness, and surface adhesion of grains. Here, we perform atomistic simulations with model potentials that allow us to test these dependencies for nanograin collisions. Our results not only show that JKR describes the dependence on materials parameters qualitatively well, but also point at considerable quantitative deviations. These are the most pronounced for small adhesion, where elastic stiffness does not influence the value of the bouncing velocity. PMID- 29273976 TI - Geographic Variability in Diagnosis and Antibiotic Prescribing for Acute Respiratory Tract Infections. AB - INTRODUCTION: Antibiotic prescribing rates vary substantially across regions in the USA. Whether these differences are driven primarily by a greater tendency to treat certain infections (i.e., overtreatment) in certain regions or differences in the tendency to diagnose certain infections (i.e., overdiagnosis) is poorly understood. METHODS: We examined data from 2012 to 2013 using the National Ambulatory Medical Care Survey, which is a nationally representative sample of visits to office-based physicians. For each of nine geographic regions, we examined the relationship between the visit rate/1000 population for respiratory diagnoses for which antibiotics were prescribed to the visit rate/1000 population for selected respiratory diagnoses where antibiotic therapy may be warranted. RESULTS: The visit rate for all respiratory conditions resulting in an antibiotic prescription was lowest (109/1000 population) in the Pacific Region and highest (176/1000, 95% CI 138-213) in the East South Central Region. The diagnosis rate for selected respiratory conditions where antibiotic therapy may be warranted was also lowest (119/1000, 95% CI 91-147) in the Pacific Region and highest (189/1000, 95% CI 153-225) in the East South Central Region. CONCLUSION: Antibiotic prescribing rates for respiratory conditions vary by region and are strongly associated with the rate with which selected respiratory conditions are diagnosed. PMID- 29273977 TI - Negative IgG Varicella Zoster Virus Antibody Status: Immune Responses Pre and Post Re-immunization. AB - INTRODUCTION: Varicella zoster virus (VZV) causes chicken pox and herpes zoster and is a self-limiting disease in healthy children. Vaccination is recommended for children, adolescents, and adults. This study discusses a healthy pediatric patient with negative immunoglobulin (Ig) G VZV antibody (Ab) status after two doses of varicella vaccine and then subsequently re-immunized. Since measurement of serum IgG titers alone may not reflect vaccine protection, we further evaluated cell-mediated and humoral immune responses before and after re immunization. METHODS: Blood lymphocyte distributions (CD3+CD4+, CD3+CD8+, CD19+, CD4+CD60+, CD8+CD60+), total serum IgG and IgE levels, and VZV-IgG, IgM, and IgE Ab levels were measured in a healthy girl (14 year-old) pre- and post-VZV re immunization (weeks 1-8) [flow microfluorimetry, nephelometry, ELISA, enzyme immunoassay (EIA)]. RESULTS: Pre-re-immunization numbers of T cells (CD3+CD4+, CD3+CD8+, CD4+CD60+, CD8+CD60+) and B cells (CD19+) were within normal ranges. After re-immunization, numbers of T cells remained relatively unchanged; however, numbers of CD19+ B cells increased (48%). Total serum IgG was low (757 mg/dl), and total serum IgE was normal (30 IU/ml). Pre-reimmunization, VZV IgG and IgM Ab levels were negative (< 0.90 and < 0.90 antibody index, respectively), and VZV IgE levels were undetectable. After re-immunization, VZV IgG Ab levels were positive (690.70 Ab index), VZV IgM Ab levels were negative (<= 0.90), and VZV IgE levels remained undetectable. CONCLUSION: Vaccination with the VZV vaccine may boost IgG but not IgE-specific viral responses and concurrently increase the numbers of CD19+ B cells. PMID- 29273979 TI - Impacts of biofouling on the removal of pharmaceutically active compounds by a nanofiltration membrane. AB - The impacts of biofouling on the retention of pharmaceutically active compounds (PhACs) by a commercially available nanofiltration membrane (NF 270) were systematically studied. Biofouling was achieved through inoculating live and dead Pseudomonas aeruginosa into artificial wastewater. In comparison to a clean membrane, an increase in PhAC rejection during biofouling with live cells was observed. However, the rejection behaviors presented more complex changes during biofouling with dead cells: PhAC rejection was below the clean membrane in the early biofouling stage; however, in the later stage, PhAC rejection was above the clean membrane. In addition, PhAC rejection behaviors present the similar tendency as salt rejection under both biofouling conditions. In addition, solute rejections were much lower for biofouling with dead cells than those for biofouling with live cells. Combined with biofilm characterization under both biofouling conditions, we could conclude that biofilm enhanced osmotic pressure (BEOP) due to higher cell counts and biofilm thickness led to a decrease in PhAC retention, especially for the dead cells. In addition, more dominant steric exclusion in the later stage of biofouling due to higher extracellular polymeric substances (EPS) concentration on the membrane surface resulted in an increase in PhAC retention. PMID- 29273978 TI - Challenges and Solution of Invasive Aspergillosis in Non-neutropenic Patients: A Review. AB - Invasive aspergillosis (IA) is a serious opportunistic infection, which has increasingly been recognized as an emerging disease of non-neutropenic patients. In this group of patients, the diagnosis of IA can be challenging owing to the lack of specificity of symptoms, the difficulty in discriminating colonization from infection, and the lower sensitivity of microbiological and radiological tests compared with immunocompromised patients. The aim of this article is to present to clinicians a critical review on the management of IA in non neutropenic patients. PMID- 29273980 TI - Biorational substitution of piperonyl butoxide in organic production: effectiveness of vegetable oils as synergists for pyrethrums. AB - Piperonyl butoxide is a semi-synthetic synergist for natural pyrethrum and synthetic pyrethroid insecticides in phytochemicals and biocides. As such it is used in large quantities for crop treatments, stored grain protection, disinfestation of grain storage facilities and indoor uses. Piperonyl butoxide is consequently a regular contaminant in stored grains, and subsequently in corresponding cereal food products and meat via feed uses. Therefore it is regularly monitored and its MRL is ongoing a reassessment. It is also considered as a possible human carcinogen and a suspected endocrine disruptor. For all these reasons and considerations most of the countries have already banned its use in Organic Farming as France in 2017. Thus, ecological substitution of with biorational and sustainable solutions is required. Vegetable oils have been described as exhibiting similar potency and synergistic effects. We have reviewed the literature and have proceeded to ecotoxicological efficacy tests in order to determine the best and most durable substitution candidates. Sesame and rape seed oil were determined to be the most efficient. PMID- 29273981 TI - Compound washing remediation and response surface analysis of lead-contaminated soil in mining area by fermentation broth and saponin. AB - The development of eluent is the key to soil washing remediation, and a compound eluent was constructed using the prepared citric acid fermentation broth and saponin in this study. It displayed a good washing performance for Pb, Cu, Cr, and Cd in red soil, and the removal rates, especially Pb, gained an improvement compared with a single eluent. Based on this, the compound eluent was applied to remediation of Pb-contaminated soil in mining area; the desorption of Pb is a heterogeneous diffusion process, and Pb in large particle size soil is relatively easy to remove. An available response surface analysis model was established; its P < 0.0001 is very significant, and the P of the missing item is 0.1152. The degree of influence of three significant factors on removal of Pb is liquid-to solid ratio > washing time > saponin concentration, and liquid-to-solid ratio and washing time show interaction. Moreover, the Pb removal rate can reach 56.20% under the optimized conditions: 0.25% saponin concentration, 20 mL/g liquid-to solid ratio, and 320-min washing time, which is close to the predicted value of 56.20% with a difference of 1.41%. In addition, most of the active Pb was removed and environmental risks were lowered after washing. PMID- 29273982 TI - Spatiotemporal characteristics of aerosols and their trends over mainland China with the recent Collection 6 MODIS and OMI satellite datasets. AB - With the rapid development of China's economy and high rate of industrialization, environmental pollution has become a major challenge for the country. The present study is aimed at analyzing spatiotemporal heterogeneities and changes in trends of different aerosol optical properties observed over China. To achieve this, Collection 6 Level 3 data retrieved from the Moderate Resolution Imaging Spectroradiometer (MODIS; 2002-2016) and Ozone Monitoring Instrument (OMI; 2005 2016) sensors were used to investigate aerosol optical depth (AOD550), Angstrom exponent (AE470-660), and Absorption Aerosol Index (AAI). The spatial distribution of annual mean AOD550 was noticed to be high over economically and industrialized regions of the east, south, and northeast of China, while low aerosol loadings were located over rural and less-developed areas of the west and northeast of China. High AE470-660 (> 1.0) values were characterized by the abundance of fine-mode particles and vice versa, likely attributed to large anthropogenic activities. Similarly, high AOD with corresponding high AE and low AAI was characterized over the urban-industrialized regions of the central, east, and south of China during most of the months, being more pronounced in June and July. On seasonal scale, AOD values were found to be high during spring, followed by the summer and autumn, and low during the winter season. It is also evident that all aerosol parameters showed a single-peak frequency distribution in all seasons over entire China. Further, the annual, monthly, and seasonal spatial trends revealed a decreasing trend in AOD over most regions of China, except in the southwest of China, which showed a positive increasing trend. Significant increasing trends were noted in AAI for all the seasons, particularly during autumn and winter, resulting in a large amount of the absorbing type of aerosols produced from biomass burning and desert dust. PMID- 29273983 TI - Heavy metal contamination in the muscle of Aegean chub (Squalius fellowesii) and potential risk assessment. AB - Especially after the industrial revolution, the amount of contaminants released in aquatic ecosystems has considerably increased. For this reason, the necessity to carry on research on the existence of contaminants, specifically heavy metals, has emerged. In this study, heavy metal concentrations in muscle tissues of Aegean chub, which was an endemic species of south western part of Turkey, gathered from Tersakan River were examined. Heavy metal concentrations of the samples were analyzed with ICP-MS. Estimated daily intakes (EDI), target hazard quotient (THQ), and carcinogenic risk (CR) of elements were calculated. The heavy metals detected in muscle tissues were Zn > Cu > Cr > Mn > Pb > Cd, consecutively. According to the results of the applied health risk assessment (EDI, THQ and CR) for heavy metal exposure from fish consumption in children and adults, it was determined that there was no any significant threat to human health. PMID- 29273984 TI - Comparative toxicity of azo dyes to two infaunal organisms (Hexagenia spp. and Tubifex tubifex) in spiked-sediment exposures. AB - Azo dyes are synthetic compounds used as industrial colorants, and some are predicted to be inherently toxic, bioaccumulative, and/or persistent based upon their chemical composition. This study addresses data gaps in current research which include the need to evaluate the toxicity of hydrophobic azo dyes to benthic invertebrates. The toxicity of a solvent dye, Sudan Red G (SRG), and two disperse dyes, Disperse Yellow 7 (DY7) and Disperse Orange 13 (DO13), to Hexagenia spp. and Tubifex tubifex was assessed in spiked-sediment exposures. The dye compounds appeared to degrade readily in the equilibrium and exposure periods, suggesting a limited persistence of the parent compounds in the environment under test conditions. Although azo dye degradation products could not be reliably quantified, one was detected in DY7 sediment samples that elicited toxic effects to Hexagenia and Tubifex, providing evidence that DY7 degrades. Hexagenia survival and growth endpoints responded with similar sensitivity to the dyes, but DY7 was the most toxic, with a 21-day IC25 (concentration associated with 25% inhibition) for growth of 9.6 MUg/g. Comparatively, Tubifex reproduction was the most sensitive endpoint for all dyes with 28-day IC25s for young production ranging from 1.3 to 11.8 MUg/g. At sublethal concentrations, toxic effects to Tubifex differed between dyes: the solvent dye exerted an effect primarily on gametogenesis (cocoon production), while disperse dyes, most notably DY7, caused effects on embryogenesis (development of worm inside the cocoon). This study indicates that there could be potential hazard to oligochaetes based on the observed effect concentrations, but given the lack of environmental measurements, the risk of these compounds is unknown. Further research is required to determine if degradation products were formed in all dye samples and whether toxicity was caused by the parent molecules, which have limited persistence under test conditions, or by their degradation products. To avoid underestimating toxicity, this study stresses the need to use an infaunal deposit feeder such as the oligochaete Tubifex in sediment toxicity assessments where highly hydrophobic compounds are present. PMID- 29273985 TI - Water and sediment quality assessment in the Colastine-Corralito stream system (Santa Fe, Argentina): impact of industry and agriculture on aquatic ecosystems. AB - The present study focuses on the evaluation of metal (chromium, copper, and lead), arsenic, and pesticide (atrazine and endosulfan) contamination in freshwater streams of one of the most important agricultural and industrial areas of central-eastern Argentina, which has not been reported earlier. The environmental fate of inorganic microcontaminants and pesticides was assessed. Samples were collected monthly for a year. Pesticide concentrations were measured in water; metal and arsenic concentrations were measured in water and sediments, and physicochemical variables were analyzed. In most cases, metals and arsenic in water exceeded the established guideline levels for the protection of aquatic biota: 98 and 56.25% of the samples showed higher levels of Cr and Pb, while 81.25 and 85% of the samples presented higher values for Cu and As, respectively. Cr, Pb, Cu, and As exceeded 181.5 times, 41.6 times, 57.5 times, and 12.9 times, respectively, the guideline level values. In sediment samples, permitted levels were also surpassed by 40% for Pb, 15% for As, 4% for Cu, and 2% for Cr. Geoaccumulation Index (Igeo) demonstrated that most of the sediment samples were highly polluted by Cr and Cu and very seriously polluted by Pb, which indicates progressive deterioration of the sediment quality. Atrazine never exceeded them, but 27% of the 48 water samples contained total endosulfan that surpassed the guidelines. The findings of this study suggest risk to the freshwater biota over prolong periods and possible risk to humans if such type of contaminated water is employed for recreation or human use. Improper disposal of industrial effluents and agricultural runoffs need to be controlled, and proper treatment should be done before disposal to avoid further deterioration of the aquifers of this area. PMID- 29273986 TI - Evaluation of the methods for quantifying particle wash-off loadings in urban impervious surfaces at small scales. AB - Quantifying road-deposited sediment (RDS) wash-off is critical in estimating pollutant load and for supporting the designs of urban storm water low-impact development (LID) best management practices (BMPs). The objective of this study was to identify a simple and effective small-scale wash-off load estimation and prediction method suitable for BMP engineering. The reliabilities, complexities, and applicabilities of four prediction methods (i.e., the event mean concentration (EMC) equation method, the exponential equation method, and the RDS mass difference before and after rainfall event method, and the RDS index model) were tested for three sites (i.e., a newly built area, and built-up area, and conservation area) during five natural rainfall events. Taking the calculations by the EMC method as standard results revealed the following. (1) The degree of agreement of the methods with the standard results in descending order was exponential equation method > RDS index model > RDS mass difference. (2) The degree of complexity of the studied methods in descending order was exponential equation method > the EMC equation method > the RDS index model > the RDS mass difference. (3) When considering the applicability of the models in terms of LID BMP engineering, the RDS index model could be considered optimal for supporting the design of urban storm water BMPs. PMID- 29273987 TI - Higher cation exchange capacity determined lower critical soil pH and higher Al concentration for soybean. AB - Low soil pH and aluminum (Al) toxicity induced by soil acidification are the main obstacles in many regions of the world for crop production. The purpose of this study was to reveal the mechanisms on how the properties of the soils derived from different parent materials play role on the determination of critical soil pH and Al concentration for soybean crops. A set of soybean pot experiment was executed in greenhouse with a soil pH gradient as treatment for each of four soils to fulfill the objectives of this study. The results indicated that plant growth parameters were affected adversely due to Al toxicity at low soil pH level in all soils. The critical soil pH varied with soil type and parent materials. They were 4.38, 4.63, 4.74, and 4.95 in the Alfisol derived from loss deposit, and the Ultisols derived from Quaternary red earth, granite, and Tertiary red sandstone, respectively. The critical soil exchangeable Al was 2.42, 1.82, 1.55, and 1.44 cmolc/kg for the corresponding soils. At 90% yield level, the critical Al saturation was 6.94, 10.36, 17.79, and 22.75% for the corresponding soils. The lower critical soil pH and Al saturation, and higher soil exchangeable Al were mainly due to greater soil CEC and exchangeable base cations. Therefore, we recommended that critical soil pH, soil exchangeable Al, and Al saturation should be considered during judicious liming approach for soybean production. PMID- 29273988 TI - Grey relational analysis for evaluating the effects of different rates of wine lees-derived biochar application on a plant-soil system with multi-metal contamination. AB - In this study, grey relational analysis (GRA) was used to investigate the effects of different application rates of wine lees-derived biochar on a plant-soil system with multi-metal contamination. A pot experiment was conducted to determine rice growth in multi-metal-contaminated soil amended with samples of wine lees-derived biochar, and 47 indicators (including soil properties, microbial activity, and plant physiology) were selected as evaluation indexes to assess the plant-soil system. The results indicated that higher wine lees-derived biochar application rates (2% W/W) were favorable for soil fertility, the bioconcentration factor (BF), and the mobility factor (MF, %) (with the exception of Cr, Zn, and Hg), but an application of 1% produced the highest plant growth, enzymatic activities, and bacterial diversity. The richness of the bacterial communities was reduced in the soil amended with the wine lees-derived biochar. According to the GRA assessment, the 1% application rate of wine lees-derived biochar was more suitable for restoring the holistic plant-soil system than were the application rates of 0, 0.5, and 2% (W/W). Furthermore, this study shows that GRA is a useful method for evaluating plant-soil systems. PMID- 29273989 TI - Electrochemical advanced oxidation processes as decentralized water treatment technologies to remediate domestic washing machine effluents. AB - Water scarcity is one of the major concerns worldwide. In order to secure this appreciated natural resource, management and development of water treatment technologies are mandatory. One feasible alternative is the consideration of water recycling/reuse at the household scale. Here, the treatment of actual washing machine effluent by electrochemical advanced oxidation processes was considered. Electrochemical oxidation and electro-Fenton technologies can be applied as decentralized small-scale water treatment devices. Therefore, efficient decolorization and total organic abatement have been followed. The results demonstrate the promising performance of solar photoelectro-Fenton process, where complete color and organic removal was attained after 240 min of treatment under optimum conditions by applying a current density of 66.6 mA cm-2. Thus, electrochemical technologies emerge as promising water-sustainable approaches. PMID- 29273990 TI - Distribution, contamination and accumulation of heavy metals in water, sediments, and freshwater shellfish from Liuyang River, Southern China. AB - Heavy metal distributions in water, sediments, and freshwater shellfish collected from Liuyang River in China have been investigated. The concentrations of heavy metals including Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Cd, and Pb were determined by ICP-MS. The distribution pattern of heavy metals in sediments was different from that in water. Large coefficients of variation of heavy metal concentrations were observed in water due to the susceptibility to discharge fluctuation and seasonal variation. Multivariate statistical analysis such as Pearson's correlation analysis, hierarchical cluster analysis (HCA), and principal component analysis (PCA) were employed to identify the possible sources of heavy metals in sediments. These heavy metals were categorized into three distinct groups, one was derived from natural existence and two were associated with anthropogenic activities. Five shellfish species including three species of gastropod mollusks (Parafossarulus eximius, Semisulcospira cancellata, and Pomacea canaliculata) and two species of bivalve mollusks (Corbicula fluminea and Anodonta woodiana) were collected and investigated. The distribution pattern of heavy metals in shellfish species was visualized by the nonmetric multidimensional scaling (NMDS) plot. The metal pollution index (MPI) values for the shellfish species were in the descending order of C. fluminea > A. woodiana > S. cancellata > P. eximius > P. canaliculata. PMID- 29273992 TI - Multi-scale analysis of the relationship between landscape patterns and a water quality index (WQI) based on a stepwise linear regression (SLR) and geographically weighted regression (GWR) in the Ebinur Lake oasis. AB - Water quality is highly dependent on landscape characteristics. This study explored the relationships between landscape patterns and water quality in the Ebinur Lake oasis in China. The water quality index (WQI) has been used to identify threats to water quality and contribute to better water resource management. This study established the WQI and analyzed the influence of landscapes on the WQI based on a stepwise linear regression (SLR) model and geographically weighted regression (GWR) models. The results showed that the WQI was between 56.61 and 2886.51. The map of the WQI showed poor water quality. Both positive and negative relationships between certain land use and land cover (LULC) types and the WQI were observed for different buffers. This relationship is most significant for the 400-m buffer. There is a significant relationship between the water quality index and landscape index (i.e., PLAND, DIVISION, aggregation index (AI), COHESION, landscape shape index (LSI), and largest patch index (LPI)), demonstrated by using stepwise multiple linear regressions under the 400-m scale, which resulted in an adjusted R 2 between 0.63 and 0.88. The local R 2 between the LPI and LSI for forest grasslands and the WQI are high in the Akeqisu River and the Kuitun rivers and low in the Bortala River, with an R 2 ranging from 0.57 to 1.86. The local R 2 between the LSI for croplands and the WQI is 0.44. The local R 2 values between the LPI for saline lands and the WQI are high in the Jing River and low in the Bo River, Akeqisu River, and Kuitun rivers, ranging from 0.57 to 1.86. PMID- 29273991 TI - Augmentation with potential endophytes enhances phytostabilization of Cr in contaminated soil. AB - The contamination of soil with heavy metals is a major environmental problem worldwide. The combined use of plants and their associated microbes has gained popularity in recent years for their potential to remediate heavy metal contaminated soil. In the current study, the effect that augmentation of soil with plant growth-promoting endophytes has on the phytostabilization of chromium (Cr)-contaminated soil was investigated. Three potential endophytic bacterial strains (Enterobacter sp. HU38, Microbacterium arborescens HU33, and Pantoea stewartii ASI11) were inoculated individually as well as in combination to Leptochloa fusca and Brachiaria mutica vegetated in Cr-contaminated soil. The accumulation of Cr in the root and shoot of the plants was determined. Moreover, bacterial persistence in the rhizosphere and endosphere was determined. Augmentation with potential endophytes significantly increased root length (24 45%), shoot height (39-64%), chlorophyll content (20-55%), and the overall biomass (32-61%) of the plants. Although L. fusca and B. mutica showed potential to accumulate Cr in their root and shoot, endophytic augmentation increased uptake, translocation, and accumulation of Cr in the roots and shoots of both plant species. However, L. fusca showed more potential to phytostabilize Cr as compared to B. mutica. Furthermore, the potential endophytes showed more survival and persistence within the roots than in the rhizosphere and shoot interior. This study provides useful evidence of endophyte-assisted phytoremediation to be the most sustainable and affordable approach for in situ remediation of Cr contaminated soil. PMID- 29273993 TI - Migration of epoxidized soybean oil from polyvinyl chloride/polyvinylidene chloride food packaging wraps into food simulants. AB - Epoxidized soybean oil (ESBO) has been used in polyvinyl chloride (PVC)/polyvinylidene chloride (PVDC) food packaging cling film as a plasticizer and stabilizer. The aim of this study was to investigate the migration of ESBO from PVC/PVDC cling film, based on gas chromatography mass spectrometry (GC-MS). The specific migration of ESBO was evaluated using various food simulants (water, 4% acetic acid, 50% ethanol and n-heptane) for PVC and PVDC wrap products. ESBO did not migrate into water and 4% acetic acid for all the tested samples. However, it was released into 50% ethanol and n-heptane in several PVC/PVDC wraps, with maximum migration levels of 38.4 +/- 0.7 and 37.4 +/- 0.8 MUg/mL, respectively. These results demonstrate that ESBO is capable of being released from PVC/PVDC wrap into amphiphilic/oily food and its migration should be regularly monitored. PMID- 29273995 TI - Applied Mycology Can Contribute to Sustainable Rural Livelihoods: Building upon China's Matsutake Management Initiatives. AB - Matsutake mushrooms are an important part of rural livelihoods and forest ecosystems across large parts of China, as well as elsewhere in East Asia, Northern Europe and North America. Mushroom harvesters have developed sophisticated understandings of matsutake ecology and production, and are applying this knowledge in various innovative management strategies. At the same time, Chinese government agencies and scientists are promoting matsutake-based livelihoods to support development and conservation goals. We collaborated with matsutake harvesters in one Yunnan community to carry out a systematic experiment on a popular shiro-level management technique: covering matsutake shiros with either plastic or leaf litter. Our experimental results suggest that although leaf litter coverings are superior to plastic coverings, shiros that are left uncovered may produce the highest yields. Complementing our experimental work is a multi-sited household survey of existing matsutake management practices across Yunnan, which shows that a high proportion of harvesters are already engaged in a broad range of potentially beneficial management strategies. Though both findings highlight limitations of previous initiatives led by government and research actors in China, this existing body of work is an important foundation and opportunity for developing applied mycology in the region. In and beyond China, working with communities to develop site-specific management strategies through rigorous and participatory scientific inquiry can provide salient benefits for both scientists and resource users. PMID- 29273994 TI - Effects of low-level engineered nanoparticles on the quorum sensing of Pseudomonas aeruginosa PAO1. AB - The toxicity of engineered nanoparticles (ENPs) on bacteria has aroused much interest. However, few studies have focused on the effects of low-level ENPs on bacterial group behaviors that are regulated by quorum sensing (QS). Herein, we investigated the effects of nine ENPs (Ag, Fe, ZnO, TiO2, SiO2, Fe2O3, single wall carbon nanotubes (SWCNTs), graphene oxide (GO), and C60) on QS in Pseudomonas aeruginosa PAOl. An ENP concentration of 100 MUg L-1 did not impair bacterial growth. However, concentrations of 100 MUg L-1 of Ag and GO ENPs induced significant increases in 3OC12-HSL in the culture and significantly promoted protease production and biofilm formation of PAO1. C4-HSL synthase and its transcription factors were less sensitive to 100 MUg L-1 Ag and GO ENPs compared with 3OC12-HSL. Fe ENPs induced a significant increase in the 3OC12-HSL concentration, similar to Ag and GO ENPs. However, Fe ENPs did not induce any significant increase in protease production or biofilm formation. Different size distributions, chemical compositions, and aggregation states of the ENPs had different effects on bacterial QS. These whole circuit indicators could clarify the effects of ENPs on bacterial QS. This study furthers our understanding of the effects of low-level ENPs on bacterial social behaviors. PMID- 29273996 TI - Visitor Preferences for Visual Changes in Bark Beetle-Impacted Forest Recreation Settings in the United States and Germany. AB - Extensive outbreaks of tree-killing insects are increasing across forests in Europe and North America due to climate change and other factors. Yet, little recent research examines visitor response to visual changes in conifer forest recreation settings resulting from forest insect infestations, how visitors weigh trade-offs between physical and social forest environment factors, or how visitor preferences might differ by nationality. This study explored forest visitor preferences with a discrete choice experiment that photographically simulated conifer forest stands with varying levels of bark beetle outbreaks, forest and visitor management practices, and visitor use levels and compositions. On-site surveys were conducted with visitors to State Forest State Park in Colorado (n = 200), Lake Bemidji State Park in Minnesota (n = 228), and Harz National Park in Germany (n = 208). Results revealed that the condition of the immediate forest surrounding was the most important variable influencing visitors' landscape preferences. Visitors preferred healthy mature forest stands and disliked forests with substantial dead wood. The number of visitors was the most important social factor influencing visitor landscape preferences. Differences in the influence of physical and social factors on visual preferences existed between study sites. Findings suggest that both visual forest conditions and visitor use management are important concerns in addressing landscape preferences for beetle-impacted forest recreation areas. PMID- 29273997 TI - The Effect of a Clinical Decision Support System on Improving Adherence to Guideline in the Treatment of Atrial Fibrillation: An Interrupted Time Series Study. AB - To evaluate the effect of a computerized Decision Support System (CDSS) on improving adherence to an anticoagulation guideline for the treatment of atrial fibrillation (AF). This study had an interrupted time series design. The adherence to the guideline was assessed at fortnightly (two weeks) intervals from January 2016 to January 2017, 6 months before and 6 months after intervention. Newly diagnosed patients with AF were included in the offices of ten cardiologists. Stroke and major bleeding risks were calculated by the CDSS which was implemented via a mobile application. Treatment recommendations based on the guideline were shown to cardiologists. The segmented regression model was used to evaluate the effect of CDSS on level and trend of guideline adherence for the treatment of AF. In our analysis, 373 patients were included. The trend of adherence to the anticoagulation guideline for the treatment of AF was stable in the pre-intervention phase. After the CDSS intervention, mean of the adherence to the guideline significantly increased from 48% to 65.5% (P-value < 0.0001). The trend of adherence to the guideline was stable in the post-intervention phase. Our results showed that the CDSS can improve adherence to the anticoagulation guideline for the treatment of AF. Registration ID: IRCT2016052528070N1. PMID- 29273998 TI - Incidence and Risk Factors of Cholangitis after Hepaticojejunostomy. AB - BACKGROUND: After hepatobiliary-pancreatic surgery, hepaticojejunostomy cholangitis is a rare condition; the true incidence rate of postoperative cholangitis is unknown. Therefore, our study aimed to determine the incidence rate and timing of postoperative cholangitis after biliary-enteric anastomosis, and to evaluate risk factors and management strategies. METHODS: Our single center retrospective study included 583 patients who had undergone biliary enteric anastomosis for hepatobiliary-pancreatic diseases. Demographic and treatment data were extracted from the medical records, and the association between potential risk factors and the development of postoperative cholangitis evaluated using a prospectively collected database. RESULTS: Postoperative cholangitis developed in 45/583 patients (incidence rate, 7.7%), on average 18.3 +/- 27.4 months (median = 6.9 months) after surgery. On multivariate analysis, the following factors were independently associated with postoperative cholangitis after biliary-enteric anastomosis: male sex, benign condition, and postoperative complication with a Clavien-Dindo classification grade > III. Among patients with postoperative cholangitis, a biliary stricture developed in 57.8% (26/45) of cases. Percutaneous balloon dilatation (73.1%) and endoscopic stenting (11.5%) were used as initial treatment of the stricture, with surgical revision being required in only 15.4% of cases of hepaticojejunostomy stricture. CONCLUSION: Biliary-enteric anastomotic cholangitis after hepaticojejunostomy is a distinct disease process. Although non-operative management of postoperative cholangitis is successful in many cases, further research is required to better understand patient- and physician-related factors that predispose patients to postoperative cholangitis. PMID- 29273999 TI - Distal Duodenogastrostomy or Proximal Jejunogastrostomy in the Management of Ultra-Short Bowel. AB - Inflammatory bowel disease, vascular disease, volvulus, adhesions, or abdominal trauma may necessitate extensive small-bowel resection resulting in an ultra short distal duodenal or jejunal stump. If this distal duodenal or short jejunal stump is too short for stoma creation and bowel continuity restoration is hazardous or not possible at all, a distal duodenogastrostomy or proximal jejunogastrostomy in combination with drainage of the stomach is an option to prevent stump leakage. Although successful, this distal duodenogastrostomy has been described only in very few patients and in older records. We reintroduced this technique and describe a recent series of patients that confirms its usefulness in certain conditions. The technique of the distal duodenogastrostomy or proximal jejunogastrostomy with gastric drainage was used for the management of the difficult distal duodenum stump in five critically ill patients undergoing extensive bowel resection. Four patients with small-bowel ischemia and one patient suffering from perforating Crohn's disease and small-bowel volvulus were treated successfully. The gastrostomies were subsequently converted to a duodenotransversostomy (in two patients) or the patients underwent small-bowel transplantation (two patients). One patient still has a jejunogastrostomy just after the duodenal-jejunal transition. In all five patients, the distal duodenogastrostomy or proximal jejunogastrostomy in combination with gastric drainage functioned well up to restoration of bowel continuity. In one patient, distal duodenogastrostomy and transabdominal gastric drainage functioned well for 5 years. No anastomotic leakage occurred. This procedure provides a feasible solution for an ultra-short bowel at emergency laparotomy. It enhances the surgical armamentarium and provides treatment options for these patients that were perhaps previously deemed unsalvageable. PMID- 29274000 TI - The Effectiveness of a Clinical Pathway in Liver Surgery: a Case-Control Study. AB - BACKGROUND: In the field of liver surgery, evidence on the effectiveness of clinical pathways based on ERAS principles is limited. METHODS: This is a single center observational study from a prospectively maintained database. Two cohorts were formed of all patients undergoing liver surgery during a defined period before (traditional management) and after introduction of a clinical pathway. Additionally, a case-match analysis-based on approach, tumor location, and Brisbane classification of resection-was performed. A cost analysis and patient satisfaction questionnaire were carried out. RESULTS: In both the overall analysis (n = 229) as well as the case-match analysis (n = 100), hospital stay was significantly reduced from 8 to 4 days and from 6.5 to 4 days, respectively (p < 0.05). Postoperative morbidity (traditional management 11/50 vs clinical pathway 5/50; p = 1.00) and readmission rate did not increase. Cost analysis showed a significant decrease in postoperative costs in favor of the clinical pathway (traditional management ?3666.7 vs clinical pathway ?1912.2; p < 0.001). Overall, 92.3% of the survey questions were answered with satisfied (86.0%) or very satisfied (6.3%). DISCUSSION: Implementation of clinical pathway for liver surgery is feasible and safe. A clinical pathway significantly reduces hospital stay without increasing postoperative morbidity and readmission rates. Postoperative costs are significantly reduced. Patient satisfaction is high. PMID- 29274001 TI - Incidental Gallbladder Carcinoma Discovered after Laparoscopic Cholecystectomy: Identifying Patients Who will Benefit from Reoperation. AB - BACKGROUND: Despite an early radical reoperation, recurrence and poor survival are observed in up to 40% of patients with an incidentally discovered gallbladder carcinoma (I-GBC) after undergoing a laparoscopic cholecystectomy (LC). This study seeks to identify prognostic factors after re-I-GBC resection. METHODS: A retrospective review of a prospectively maintained patient database with patients who were undergoing resection for I-GBC from January 1995 to March 2017 was performed. Prognostic factors for survival were assessed by multivariate Cox analysis. RESULTS: There were 50 consecutive patients (median age 64 years; range 38-82) undergoing reoperation 45 +/- 30 days after LC. Re-resection entailed a major hepatectomy in five patients (10%) and lymphadenectomy in all patients. Ninety-day morbidity and mortality were 22 and 2%, respectively. Lymph node (LN) involvement was present in 24 (48%) patients with a mean of 5.79 +/- 14.4 LN+. Median overall survival was 40 months with 1-, 3-, 5- and 10-year survival rates of 80, 50, 41 and 36%, respectively. Independent risk factors for overall survival were T3 tumours (HR = 7.58; 95% confidence intervals (CI), 2.41-23.83.) and LN involvement (HR = 3.66; 95% CI, 1.42-9.45). Patients presenting with zero, one and two risk factors had 3-year survival rates of 85, 31 and 0%, respectively, and median overall survival of 80, 22 and 13 months, respectively (p < 0.0001). CONCLUSIONS: After I-GBC discovery following an LC, T3 tumours and tumours with LN+ are characterised by poor prognosis. The presence and the identification of these prognostic factors help identify patients in need of alternative perioperative treatments. PMID- 29274002 TI - A periodic disease transmission model with asymptomatic carriage and latency periods. AB - In this paper, the global dynamics of a periodic disease transmission model with two delays in incubation and asymptomatic carriage periods is investigated. We first derive the model system with a general nonlinear incidence rate function by stage-structure. Then, we identify the basic reproduction ratio [Formula: see text] for the model and present numerical algorithm to calculate it. We obtain the global attractivity of the disease-free state when [Formula: see text] and discuss the disease persistence when [Formula: see text]. We also explore the coexistence of endemic state in the nonautonomous system and prove the uniqueness with constants coefficients. Numerical simulations are provided to present a case study regarding the meningococcal meningitis disease transmission and discuss the influence of carriers on [Formula: see text]. PMID- 29274003 TI - Should we consider integrated approach for endometriosis-associated infertility as gold standard management? Rationale and results from a large cohort analysis. AB - PURPOSE: To evaluate reproductive and maternal-fetal outcomes after integrated approach for endometriosis-associated infertility (EAI). METHODS: We retrospectively analyzed reproductive and maternal-fetal outcomes of 277 women affected by EAI, subdividing patients in two groups: in the first one (surgery group), we included all women who underwent laparoscopic surgery for EAI; in the second one (integrated group), we included women who failed to conceive spontaneously after surgery within 6-12 months and underwent in vitro fertilization and embryo transfer (IVF). We evaluated delivery rate (DR), maternal and neonatal outcomes of the first pregnancies, and, finally, the type (spontaneous or IVF) of subsequent pregnancies. RESULTS: We did not find significant difference regarding DR between surgery and integrated groups. We found significantly lower birth weight (p < 0.001) and gestational age at delivery (p < 0.001) in integrated group respect to surgery group; conversely, we found higher rate of preterm birth (p < 0.001), small for gestational age (p = 0.003), and admission to the neonatal intensive care unit (p < 0.001) respect to surgery group. Finally, 92 women became pregnant for the second time: 8% were spontaneous and 20% were IVF pregnancies. CONCLUSIONS: We suggest the integrated approach as gold standard treatment for carefully selected patients (young, good ovarian reserve, partner with normal semen parameters) affected by EAI. As consequence, IVF should be reserved as the secondary treatment for women who fail to conceive spontaneously after surgery within 6-12 months, since it is able to increase DR significantly. PMID- 29274004 TI - Correlation between NM23 protein overexpression and prognostic value and clinicopathologic features of ovarian cancer: a meta-analysis. AB - OBJECTIVE: The prognostic value and clinicopathological features of NM23 (non metastasis 23) have previously been assessed, but the results are controversial. Here, we attempted to clarify the correlation between NM23 expression and its prognostic value and the clinicopathological features in ovarian cancer (OC). METHODS: The relevant studies were identified using PubMed, Embase, and Web of Science. We calculated the pooled odds ratio (OR) with 95% confidence intervals (CIs) for overall survival (OS), progression-free survival (PFS), and clinicopathological features. We used OS to evaluate the prognostic value of NM23 expression in patients with OC. Subgroup analyses were used to explore the source of heterogeneity. RESULTS: We included 10 studies involving 894 patients in our assessment of the association between NM23 expression and OS for OC. Our data indicated that NM23 expression was not associated with improved OS (OR 0.83, 95% CI 0.41-1.68, P = 0.61) or PFS (OR 0.7, 95% CI 0.39-1.24, P = 0.22). Elevated NM23 expression was associated with differentiation grade (OR 0.35, 95% CI 0.2 0.6, P = 0.0002) and N status (OR 0.33, 95% CI 0.14-0.78, P = 0.01), whereas there was no significant difference between NM23 expression and tumor stage (OR 1.1, 95% CI 0.45-2.66, P = 0.84). Subgroup analysis did not reveal any potential source of heterogeneity. No obvious publication bias was found. CONCLUSIONS: In OC, there is poor statistical significance between NM23 expression and OS and PFS, but NM23 expression is related to differentiation grade and N status. This meta-analysis reveals that NM23 expression is a potential factor of poor prognosis in OC. The prognostic role of NM23 in different OC stages in combination with the clinical characteristics suggests a novel approach for developing future therapeutic targets. PMID- 29274005 TI - Ethnic rhinoplasty. AB - Rhinoplasty is one of the main facial plastic procedures performed worldwide. Ethnic patients today are mainly mixed-race patients. Diagnosis is based on anatomical findings and surgery should be planned based on patients' needs and what they define as beautiful. Different surgical techniques are presented where a structural approach to rhinoplasty is explained. Very little tissue is resected and support structures of the nose are strengthened with sutures and grafts. A gradual approach to the nasal tip is also presented progressing from simple predictable techniques to more complex unpredictable ones. The final result should be noses with greater definition and refinement that are harmonious and blend in with patients' faces. PMID- 29274007 TI - Assessing and overcoming participant dishonesty in online data collection. AB - Crowdsourcing services, such as MTurk, have opened a large pool of participants to researchers. Unfortunately, it can be difficult to confidently acquire a sample that matches a given demographic, psychographic, or behavioral dimension. This problem exists because little information is known about individual participants and because some participants are motivated to misrepresent their identity with the goal of financial reward. Despite the fact that online workers do not typically display a greater than average level of dishonesty, when researchers overtly request that only a certain population take part in an online study, a nontrivial portion misrepresent their identity. In this study, a proposed system is tested that researchers can use to quickly, fairly, and easily screen participants on any dimension. In contrast to an overt request, the reported system results in significantly fewer (near zero) instances of participant misrepresentation. Tests for misrepresentations were conducted by using a large database of past participant records (~45,000 unique workers). This research presents and tests an important tool for the increasingly prevalent practice of online data collection. PMID- 29274006 TI - Chromogranin-A Regulates Macrophage Function and the Apoptotic Pathway in Murine DSS colitis. AB - : Chromogranin-A (CHGA) is elevated in inflammatory bowel disease (IBD), but little is known about its role in colonic inflammation. IBD is associated with impaired functions of macrophages and increased apoptosis of intestinal epithelial cells. We investigated CHGA expression in human subjects with active ulcerative colitis (UC) and the underlying mechanisms in Chga -/- mice. In UC, CHGA, classically activated macrophage (M1) markers, caspase-3, p53, and its associated genes were increased, while alternatively activated macrophage (M2) markers were decreased without changes in the extrinsic apoptotic pathway. CHGA correlated positively with M1 and the apoptotic pathway and negatively with M2. In the murine dextran sulfate sodium (DSS)-induced colitis, Chga deletion reduced the disease severity and onset, pro-inflammatory mediators, M1, and p53/caspase-3 activation, while it upregulated anti-inflammatory cytokines and M2 markers with no changes in the extrinsic apoptotic markers. Compared to Chga +/+ , M1 and p53/caspase-3 activation in Chga -/- macrophages were decreased in vitro, while M2 markers were increased. CHGA plays a critical role during colitis through the modulation of macrophage functions via the caspase-3/p53 pathway. Strategies targeting CHGA to regulate macrophage activation and apoptosis might be developed to treat UC patients. KEY MESSAGES: * Chromogranin-A (CHGA) is pro-hormone and is secreted in the gut. CHGA is elevated in colitis and is associated with the disease severity. The lack of GHGA has beneficial immunomodulatory properties during the development of intestinal inflammation. The lack of CHGA regulates the plasticity of macrophages and p53/caspase activation in colitis. Functional analysis of CHGA may lead to a novel therapy for IBD. PMID- 29274008 TI - Selective Impairment of Basic Emotion Recognition in People with Autism: Discrimination Thresholds for Recognition of Facial Expressions of Varying Intensities. AB - Autism spectrum disorders (ASD) are characterized by early onset qualitative impairments in reciprocal social development. However, whether individuals with ASD exhibit impaired recognition of facial expressions corresponding to basic emotions is debatable. To investigate subtle deficits in facial emotion recognition, we asked 14 children diagnosed with high-functioning autism (HFA)/AS and 17 typically developing peers to complete a new highly sensitive test of facial emotion recognition. The test stimuli comprised faces expressing increasing degrees of emotional intensity that slowly changed from a neutral to a full-intensity happiness, sadness, surprise, anger, disgust, or fear expression. We assessed individual differences in the intensity of stimuli required to make accurate judgments about emotional expressions. We found that, different emotions had different identification thresholds and the two groups were generally similar in terms of the sequence of discrimination threshold of six basic expressions. It was easier for individuals in both groups to identify emotions that were relatively fully expressed (e.g., intensity > 50%). Compared with control participants, children with ASD generally required stimuli with significantly greater intensity for the correct identification of anger, disgust, and fear expressions. These results suggest that individuals with ASD do not have a general but rather a selective impairment in basic emotion recognition. PMID- 29274009 TI - The Effects of a Peer-Delivered Social Skills Intervention for Adults with Comorbid Down Syndrome and Autism Spectrum Disorder. AB - Deficits in social skills are often exhibited in individuals with comorbid Down syndrome (DS) and autism spectrum disorder (ASD), and there is a paucity of research to help guide intervention for this population. In the present study, a multiple probe study across behaviors, replicated across participants, assessed the effectiveness of peer-delivered simultaneous prompting in teaching socials skills to adults with DS-ASD using visual analysis techniques and Tau-U statistics to measure effect. Peer-mediators with DS and intellectual disability (ID) delivered simultaneous prompting sessions reliably (i.e., > 80% reliability) to teach social skills to adults with ID and a dual-diagnoses of DS-ASD with small (Tau Weighted = .55, 90% CI [.29, .82]) to medium effects (Tau Weighted = .75, 90% CI [.44, 1]). Statistical and visual analysis findings suggest a promising social skills intervention for individuals with DS-ASD as well as reliable delivery of simultaneous prompting procedures by individuals with DS. PMID- 29274010 TI - The Challenge of Hammock Mitral Valve During Infancy: Precise Preoperative Advanced Imaging and Three-Dimensional Modeling Augments Customized Operative Valve Reconstruction. AB - Hammock mitral valve (MV), also known as anomalous mitral arcade, is a rare congenital anomaly. We report a case of a 10-month-old child who presented with congestive heart failure and was found to have severe mitral stenosis (MS) secondary to a hammock MV anomaly. Detailed advanced imaging with cardiac MRI and three-dimensional (3D) echocardiography favorably navigated a customized valve sparing surgical reconstruction of the congenitally abnormal MV. Repair of a hammock MV is technically difficult with a guarded prognosis. Surgical experience is extremely limited and variable outcomes are reported. A rare case of severe MS secondary to hammock MV deformity with successful surgical repair and review of worldwide literature are presented. PMID- 29274011 TI - Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study. AB - AIMS: Middle Eastern immigrants to western countries are at high risk of developing type 2 diabetes. However, the heritability and impact of first-degree family history (FH) of type 2 diabetes on insulin secretion and action have not been adequately described. METHODS: Citizens of Malmo, Sweden, aged 30-75 years born in Iraq or Sweden were invited to participate in this population-based study. Insulin secretion (corrected insulin response and oral disposition index) and action (insulin sensitivity index) were assessed by oral glucose tolerance tests. RESULTS: In total, 45.7% of Iraqis (616/1348) and 27.4% of native Swedes (201/733) had FH in parent(s), sibling(s) or single parent and sibling, i.e., FH+. Approximately 8% of Iraqis and 0.7% of Swedes had >= 3 sibling(s) and parent(s) with diabetes, i.e., FH++. Irrespective of family size, prediabetes and diabetes increased with family burden (FH- 29.4%; FH+ 38.8%; FH++ 61.7%) without significant differences across ethnicities. With increasing level of family burden, insulin secretion rather than insulin action decreased. Individuals with a combination of >= 3 siblings and parents with diabetes presented with the lowest levels of insulin secretion. CONCLUSIONS: The Iraqi immigrant population often present with a strong familial burden of type 2 diabetes with the worst glycemic control and highest diabetes risk in individuals with >= 3 siblings and parents with diabetes. Our data show that in a population still free from diabetes familial burden influences insulin secretion to a higher degree than insulin action and may be a logical target for intervention. PMID- 29274012 TI - Predicting substituent effects on activation energy changes by static catalytic fields. AB - Catalytic fields illustrate topology of the optimal charge distribution of a molecular environment reducing the activation energy for any process involving barrier crossing, like chemical reaction, bond rotation etc. Until now, this technique has been successfully applied to predict catalytic effects resulting from intermolecular interactions with individual water molecules constituting the first hydration shell, aminoacid mutations in enzymes or Si->Al substitutions in zeolites. In this contribution, hydrogen to fluorine (H->F) substitution effects for two model reactions have been examined indicating qualitative applicability of the catalytic field concept in the case of systems involving intramolecular interactions. Graphical abstract Hydrogen to fluorine (H->F) substitution effects on activation energy in [kcal/mol]. PMID- 29274013 TI - Fermented Soybean Meal Increases Lactic Acid Bacteria in Gut Microbiota of Atlantic Salmon (Salmo salar). AB - The main goal of the present study was to address the effect of feeding fermented soybean meal-based diet to Atlantic salmon on gut microbiota. Further, expression of genes of interest, including cathelicidin antimicrobial peptide (cath), mucin 2 (muc2), aquaporin (aqp8ab), and proliferating cell nuclear antigen (pcna), in proximal intestine of fish fed either experimental diet was analyzed. Three experimental diets, including a control fishmeal (30% FM), soybean meal (30% SBM), or fermented soybean meal diet (30% FSBM) were randomly assigned to triplicate tanks during a 50-day trial. The PCR-TTGE showed microbiota composition was influenced by experimental diets. Bands corresponding to genus Lactobacillus and Pediococcus were characteristic in fish fed the FSBM-based diet. On the other hand, bands corresponding to Isoptericola, Cellulomonas, and Clostridium sensu stricto were only observed in fish FM-based diet, while Acinetobacter and Altererythrobacter were detected in fish fed SBM-based diet. The expression of muc2 and aqp8ab were significantly greater in fish fed the FSBM based diet compared with the control group. Our results suggest feeding FSBM to Atlantic salmon may (1) boost health and growth physiology in fish by promoting intestinal lactic acid bacteria growth, having a prebiotic-like effect, (2) promote proximal intestine health by increasing mucin production, and (3) boost intestinal trans-cellular uptake of water. Further research to better understands the effects of bioactive compounds derived from the fermentation process of plant feedstuff on gut microbiota and the effects on health and growth in fish is required. PMID- 29274014 TI - Psychometric evaluation of the PainCAS Interference with Daily Activities, Psychological/Emotional Distress, and Pain scales. AB - PURPOSE: The PainCAS is a web-based clinical tool for assessing and tracking pain and opioid risk in chronic pain patients. Despite evidence for its utility within the clinical setting, the PainCAS scales have never been subject to psychometric evaluation. The current study is the first to evaluate the psychometric properties of the PainCAS Interference with Daily Activities, Psychological/Emotional Distress, and Pain scales. METHODS: Patients (N = 4797) from treatment centers and hospitals in 16 different states completed the PainCAS as part of routine clinical assessment. A subsample (n = 73) from two hospital based treatment centers also completed comparator measures. Rasch Rating Scale Models were employed to evaluate the Interference with Daily Activities and Psychological/Emotional Distress scales, and empirical evaluation included assessment of dimensionality, discrimination, item fit, reliability, information, and person-to-item targeting. Additionally, convergent and discriminant validity were evaluated through classical test theory approaches. Convergent validity of the Pain scales was evaluated through correlations with corresponding comparator items. RESULTS: One Interference with Daily Activities item was removed due to poor functioning and discrimination. The retained items from the Interference with Daily Activities and Psychological/Emotional Distress scales conformed to unidimensional Rasch measurement models, yielding satisfactory item fit, reliability, precision, and coverage. Further, results provided support for the convergent and discriminant validity of these two scales. Convergent validity between the PainCAS Pain and BPI Pain items was also strong. CONCLUSION: Taken together, results provide strong psychometric support for these PainCAS Pain scales. Strengths and limitations of the current study are discussed. PMID- 29274015 TI - Correction to: Impact of an electronic monitoring device and behavioural feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial. AB - The clinicaltrials.gov identifying number for the article titled "Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial" is NCT02234713 (https://clinicaltrials.gov/ct2/show/NCT02234713). PMID- 29274016 TI - Quantitative pulmonary blood flow measurement using 15O-H2O PET with and without tissue fraction correction: a comparison study. AB - BACKGROUND: Physiological measures per lung parenchyma, rather than per lung volume, sometimes reflect the disease status. PET images of the lung, which are usually expressed per lung volume, could confound the interpretation of the disease status, especially in cases with a prominent heterogeneity in aeration. The aim of the present study was to develop a method for measuring pulmonary blood flow (PBF) with aeration correction using 15O-H2O PET and to compare the results with those obtained using a conventional method. We obtained the voxel based tissue fraction (TF) derived from density images converted from transmission images obtained using an external 137Cs point source. Quantitative PBF values with and without the TF were calculated using 15O-H2O PET to examine contralateral lung tissue in 9 patients with unilateral lung cancer. The heterogeneity in PBF before and after TF correction was then evaluated and compared. As a measure of PBF heterogeneity, we used the skewness and kurtosis of the PBF distribution. RESULTS: The mean PBF of contralateral lung was 1.4 +/- 0.3 mL/min per mL of lung. The TF-corrected PBF was 5.0 +/- 0.6 mL/min per mL of lung parenchyma. After TF correction, the skewness and kurtosis of the PBF decreased significantly. CONCLUSIONS: The present PBF calculation method using TF correction demonstrated that the normal PBF increased significantly and the PBF distribution became uniform. The proposed TF correction method is a promising technique to account for variations in density when interpreting PBF in PET studies. PMID- 29274017 TI - Trypanosoma cruzi serinecarboxipeptidase is a sulfated glycoprotein and a minor antigen in human Chagas disease infection. AB - In this work, the presence of sulfated N-glycans was studied in a high-mannose type glycoprotein of Trypanosoma cruzi with serinecarboxipeptidase (TcSCP) activity. The immune cross-reactivity between purified SCP and Cruzipain (Cz) was evidenced using rabbit sera specific for both glycoproteins. Taking advantage that SCP co-purifies with Cz from Concanavalin-A affinity columns, the Cz-SCP mixture was desulfated, ascribing the cross-reactivity to the presence of sulfate groups in both molecules. Therefore, knowing that Cz is a sulfated glycoprotein, with antigenic sulfated epitopes (sulfotopes), SCP was excised from SDS-PAGE and the N-glycosydic chains were analyzed by UV-MALDI-TOF-MS, confirming the presence of short-sulfated high-mannose-type oligosaccharidic chains. Besides, the presence of sulfotopes was analyzed in lysates of the different parasite stages demonstrating that a band with apparent molecular weight similar to SCP was highly recognized in trypomastigotes. In addition, SCP was confronted with sera of infected people with different degrees of cardiac dysfunction. Although most sera recognized it in different groups, no statistical association was found between sera antibodies specific for SCP and the severity of the disease. In summary, our findings demonstrate (1) the presence of sulfate groups in the N glycosidic short chains of native TcSCP, (2) the existence of immune cross reactivity between Cz and SCP, purified from epimastigotes, (3) the presence of common sulfotopes between both parasite glycoproteins, and (4) the enhanced presence of sulfotopes in trypomastigotes, probably involved in parasite-host relationship and/or infection. Interestingly, we show for the first time that SCP is a minor antigen recognized by most of chronic Chagas disease patient's sera. PMID- 29274018 TI - Examining the Lesbian, Gay, and Bisexual Identity Scale Among Members of an Alternative Sexuality Special Interest Group. AB - The present study contributes to a growing body of literature developing psychometrically and theoretically grounded measures of sexual orientation minority identity. We tested psychometric properties and construct validity of a 27-item measure, the Lesbian, Gay, and Bisexual Identity Scale (LGBIS). The sample consisted of 475 adult (178 male, 237 female, 16 male-to-female, 14 female to-male, and 30 gender queer persons) members of a special interest group, the National Coalition for Sexual Freedom. Participants completed a health needs questionnaire. Prominent findings included (1) confirmatory factor-analytic, internal consistency, and inter-correlation patterns support two LGBIS factor structures; (2) men, compared primarily to women, reported elevated scores on Acceptance Concerns, Concealment Motivation, Difficulty Process, and Negative Identity; (3) queer-identifying persons tended to report low Concealment Motivation, and high Identity Affirmation and Identity Centrality scores; (4) experimenting/fluid-identifying individuals tended toward higher Identity Uncertainty and Negative Identity, and lower Identity Centrality scores; (5) LGB community involvement was negatively associated with Concealment Motivation, Identity Uncertainty, and Negative Identity, and positively associated with Identity Superiority, Identity Affirmation, and Identity Centrality scores; and (6) Acceptance Concerns, Identity Uncertainty, and Internalized Homonegativity displayed significant positive associations with such mental health symptoms as general anxiety and posttraumatic stress. The LGBIS represents a useful approach to evaluating sexual orientation minority identity. Implications for identity theory, research, and practice are provided. PMID- 29274019 TI - Switch from BAK-preserved to preservative-free latanoprost decreases anterior chamber flare in POAG patients. AB - PURPOSE: To validate the hypothesis that BAK induces low-grade inflammation in the anterior chamber, we designed a study to investigate whether switching from BAK-preserved to preservative-free latanoprost in patients with primary open angle glaucoma (POAG) would reduce the flare levels. PATIENTS: Forty-one eyes of twenty-two patients with primary open-angle glaucoma treated with BAK-preserved latanoprost for at least 6 months as monotherapy were included. Exclusion criteria included any use of topical eye drops other than latanoprost, pseudoexfoliation and pigment dispersion glaucoma, wearing of contact lenses and intraocular surgery in the past year. METHODS: At the start of the study, we measured baseline flare values. We then switched all patients to preservative free latanoprost. After 1, 2, and 3 months, a routine ophthalmological examination was performed and flare measurement repeated. RESULTS: Thirty-three eyes were followed up throughout the entire 3-month period. One month after the switch to preservative-free latanoprost, a statistically significant mean drop in flare of - 0.96 ph/ms (P = 0.025) was observed. Mean flare decreased further by - 1.31 ph/ms (P = 0.0027) after 2 months and by - 1.25 ph/ms (P = 0.0041) after 3 months. CONCLUSION: The switch from BAK-preserved to preservative-free latanoprost induced a statistically significant reduction in mean flare value. Whereas our previous study showed an increase in flare when initiating treatment with BAK-preserved eye drops, this study shows a decrease in flare upon cessation of BAK-preserved drugs. The combined evidence from the two studies strongly suggests that in humans BAK exerts its effects not only on the ocular surface, but also at the level of the anterior chamber. PMID- 29274020 TI - Short-term change in higher-order aberrations after mitomycin-C-augmented trabeculectomy. AB - PURPOSE: To investigate the changes in ocular higher-order aberrations (HOA) after trabeculectomy using mitomycin-C (MMC). METHODS: We retrospectively reviewed data for 63 eyes from 63 glaucoma patients who had undergone MMC augmented trabeculectomy. We measured intraocular pressure (IOP), refractive errors, anterior chamber depth (ACD), and HOA before surgery and 1, 2, and 4 weeks postoperatively. The patients were divided into two groups on the basis of preoperative lens status: phakic and pseudophakic group. We used a paired t test to compare preoperative and postoperative HOA values. Regression analysis was used to compare higher-order total (HOT) change and factors including ACD and age. RESULTS: For entire eye aberrations, coma-like and total HOT were significantly increased postoperatively at 1 week (P = 0.029, P = 0.005, respectively), but not after 2 or 4 weeks in the phakic group and were not significant at any time in the pseudophakic group. Corneal HOA were significantly increased postoperatively after 1, 2 weeks, but not after 4 weeks in the phakic group and were not significant in the pseudophakic group. For internal optics aberrations, HOA were significantly increased postoperatively at 1, 2, and 4 weeks in the phakic group, but were not significant at any time in the pseudophakic group. However, HOT aberration change showed no correlation with age, ACD, IOP change in either group. CONCLUSION: Following trabeculectomy, HOA changes were significantly increased postoperatively at 1, 2 weeks in the phakic group. Therefore, visual complaint-related HOA changes after trabeculectomy may be more profound in phakic patients. PMID- 29274021 TI - Clinical characteristics and ophthalmologic findings of pituitary adenoma in Korean patients. AB - PURPOSE: To investigate the clinical characteristics of and ophthalmic findings in Korean patients diagnosed with a pituitary adenoma. METHODS: The medical records of 534 patients diagnosed with a pituitary adenoma at Kyung Hee University Hospital between January 2007 and December 2016 were retrospectively reviewed. RESULTS: Mean patient age was 47.9 +/- 16.2 years. The most common symptoms at the time of presentation were headache (26.2%) and visual disturbance (12.4%). The referral rate to the ophthalmology department was 18.44% and patients most often presented to the neurosurgery department. Optic chiasm compression was identified in 23.4% of patients (54.4% of patients referred to ophthalmology, 15.0% of patients not referred to ophthalmology). Normal visual field (57%) was the most common visual field feature followed by bitemporal hemianopsia (17.8%). Optic chiasmal compression without visual field defects was found in 36.1% of patients. Tumor volume was positively correlated with visual field pattern standard deviation (PSD, p = 0.020) and best-corrected logMAR visual acuity (p = 0.000) and negatively associated with tumor volume and visual field mean deviation (MD, p = 0.000). Best-corrected visual acuity (p = 0.000), MD (p = 0.001), and PSD (p = 0.028) significantly improved after surgery. CONCLUSIONS: Pituitary adenoma patients do not always have ocular symptoms at their first presentation, even when optic chiasm compression and visual field deficits are present. Therefore, collaboration with an ophthalmologist is important when evaluating pituitary adenoma patients. PMID- 29274022 TI - Outcome of "treat and monitor" regimen of aflibercept and ranibizumab in macular edema secondary to non-ischemic branch retinal vein occlusion. AB - PURPOSE: To compare the efficacy of a modified PRN treatment regimen ("treat and monitor") of aflibercept and ranibizumab in macular edema secondary to non ischemic branch retinal vein occlusion. METHODS: Seventy eyes of 70 patients with treatment naive branch retinal vein occlusion were enrolled. All patients underwent a comprehensive ophthalmic examination, spectral-domain optical coherence tomography, and fluorescein angiography. Patients were randomized 1:1 to receive intravitreal aflibercept (34 eyes) and ranibizumab (36 eyes) with a "treat and monitor" treatment regimen with monthly follow-up for 12 months. Primary outcome measures included mean change in best corrected visual acuity (BCVA) and central foveal thickness (CFT) at month 12 compared to baseline. RESULTS: At 12 months follow-up, the mean BCVA improved from 0.58 +/- 0.13 to 0.20 +/- 0.15 logMAR (P = 0.0003) in the aflibercept group (mean injections 2.6 +/- 1.51) and from 0.52 +/- 0.11 to 0.21 +/- 0.1 logMAR (P = 0.0002) in the ranibizumab group (mean injections 2.8 +/- 1.78). No statistical difference between the two groups in terms of the visual acuity gains in eyes with macular edema secondary to non-ischemic BRVO treated with either aflibercept or ranibizumab was observed. Mean CFT reduced from 498 +/- 46 to 204 +/- 23 um (P < 0.0001) in the aflibercept group and from 488 +/- 31 to 212 +/- 29 um (P < 0.0001) in the ranibizumab group. CONCLUSION: "Treat and monitor" regimen is a real-life effective strategy in improving visual acuity after macular edema from branch vein occlusion and in reducing the number of injections. PMID- 29274023 TI - Vector analysis of femtosecond laser-assisted astigmatic keratotomy after deep anterior lamellar keratoplasty and penetrating keratoplasty. AB - PURPOSE: To compare the refractive and keratometric changes induced by femtosecond laser astigmatic keratotomy (AK) for suture-out post-keratoplasty astigmatism in deep anterior lamellar keratoplasty (group I) and penetrating keratoplasty (group II). SETTING: Dhahran Eye Specialist Hospital, Dhahran, Saudi Arabia. DESIGN: Retrospective, comparative, interventional study. METHODS: This study comprised 15 eyes in group I and 35 eyes in group II. All eyes underwent femtosecond AK for suture-out post-keratoplasty astigmatism. The refractive and keratometric measurements were evaluated before and 6 months after AK. The Alpins method for vector analysis was used to evaluate the keratometric changes induced by AK. RESULTS: The astigmatic correction was 99 and 110% in group I and group II, respectively (p = 0.743) and the success of AK was 43 and 51% in group I and group II (p = 0.966). There was a trend in the magnitude of error toward overcorrection with increased surgically induced astigmatism (r = 0.80 with p < 0.001 in group I and r = 0.70 with p < 0.001 in group II). There was no systemic misalignment in either group. The safety indices were 1.50 (0.19-26.67) and 1.27 (0.12-13.33) in group I and group II, respectively (p = 0.325). The efficacy indices were 1.00 (0.05-24.00) and 0.31 (0.04-2.50) in group I and group II, respectively (p = 0.001). CONCLUSIONS: Femtosecond laser AK has similar safety for correcting suture-out post-DALK and PKP astigmatism; however, it is more effective for DALK. There is a positive correlation between surgically induced astigmatism and magnitude of error. PMID- 29274024 TI - The effect of trabeculectomy on contrast sensitivity, corneal topography and aberrations. AB - PURPOSE: To investigate the effect of trabeculectomy on corneal topography, corneal sensitivity and aberrations. METHODS: Twenty-four eyes of 24 subjects with open-angle glaucoma who required glaucoma filtration surgery were assessed. The evaluation of corneal topography, corneal sensitivity and aberrations were done before the trabeculectomy procedure, 1 week and 1 month after the trabeculectomy. RESULTS: There were significant differences in cylindrical power (P = 0.02), contrast sensitivity at 12 cycle/degree spatial frequency (P = 0.04) as well as high order aberration (P = 0.04) and high order without spherical component (P = 0.02) following trabeculectomy. However, significant differences were found for keratometric results and Fourier index in 3 and 6 mm pupil diameters between pre- and post-trabeculectomy (P > 0.05). CONCLUSIONS: According to the findings of the current study, trabeculectomy affects contrast sensitivity at 12 cycle/degree spatial frequency, higher-order aberration and higher order without spherical component aberration 1 month after trabeculectomy. Being knowledgeable about these changes may lead to some advancement in post-surgical management of patients particularly in early stages following trabeculectomy. PMID- 29274025 TI - Simplified approach of Gokyigit's technique for complete cranial nerve third palsy. AB - PURPOSE: To evaluate a simpler approach of the medial transposition of split lateral rectus technique in patients with complete third nerve palsy. METHODS: All eyes with complet third nerve palsy were followed in our Strabismus Department between 2014 and 2016. All patients had complete oculamotor nerve palsy. All patients assed routine ophthalmologic examination. Also the ocular deviation, horizontal and vertical ocular alignments were measured at 6 m and at 1/3 m using the Krimsky corneal reflection test and alternate prism cover test with best optical correction. Same surgeon (BG) performed all procedures in general anesthesia. In this procedure, same Gokyigit's technique except upper and lower part of lateral rectus muscle was passed under the superior oblique tendon and inferior oblique tendon. Final deviation from 0 to 14 PD was considered a successful result. RESULTS: Eight patients were included in the study. The average ages were 39.4 years and male to female ratio 5:3. Patients had a preoperative horizontal deviation - 42.5 +/- 2.7 PD and postoperative horizontal deviation - 1.7 +/- 2.6 PD. All patients follow-up time were at least 6 months. CONCLUSIONS: Achieved to acceptable alignment in primary position, manage to diplopia and cosmetical appearance are the main aims of patients with third nerve palsy. PMID- 29274026 TI - Clinical and Demographic Profile of Patients Receiving Fingolimod in Clinical Practice in Germany and the Benefit-Risk Profile of Fingolimod After 1 Year of Treatment: Initial Results From the Observational, Noninterventional Study PANGAEA. AB - The population with multiple sclerosis receiving treatment in clinical practice differs from that in randomized controlled trials (RCTs). An assessment of the real-world benefit-risk profile of therapies is needed. This analysis used data from the large, noninterventional, observational German study Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) to assess prospectively baseline characteristics and outcomes after 12 months (+/- 90 days) of fingolimod treatment. Patients were divided into 2 cohorts: fingolimod starter [first received fingolimod in PANGAEA (n = 3315)] and previous study [received fingolimod before enrollment in PANGAEA in RCTs (n = 875), some of whom also had baseline data at entry into RCTs (n = 505)]. At PANGAEA baseline, patients in the fingolimod starter versus the previous study cohort had a higher annualized relapse rate [ARR (95% confidence interval): 1.79 (1.75-1.83) vs 1.32 (1.25 1.40)] and Expanded Disability Status Scale score [3.11 (3.04-3.17) vs 2.55 (2.44 2.66)]. A greater proportion in the fingolimod starter versus previous study cohort had diabetes (2.0% vs 0.7%). After 12 months of fingolimod, ARRs were lower than in the 12 months before PANGAEA enrollment in the fingolimod starter [0.386 (0.360-0.414)] and previous study [0.276 (0.238-0.320)] cohorts. Expanded Disability Status Scale scores were stable versus baseline. Adverse events were experienced by similar proportions in both cohorts during fingolimod treatment. Relevant differences exist in disease activity and comorbidities between patients receiving fingolimod in clinical practice versus RCTs. Irrespective of baseline differences indicating a higher proportion at an advanced stage of multiple sclerosis in the real world versus RCTs, fingolimod remains effective, with a manageable safety profile. PMID- 29274027 TI - Chemotherapy and echocardiographic indices in patients with non-Hodgkin lymphoma: the ONCO-ECHO study. AB - The cardiotoxicity of chemotherapy (CTx) for non-Hodgkin's lymphomas is not well recognized. In order to facilitate individual risk counseling for patients, we analyzed the effect of CTx on echocardiographic indices in regard to clinical data in patients treated for non-Hodgkin's lymphoma (NHL). A prospective multicenter ONCO-ECHO trial included 67 patients with NHL (45 patients with DLBCL (diffuse large B cell lymphoma) and 22 with non-DLBCL). Patients received standard CTx, primarily R-CHOP, CHOP, R-COP and COP regimens. Clinical data and echocardiographic indices were obtained at baseline, 3-, 6- and 12-month follow up. The primary end point representing CTx cardiotoxicity was defined as a >= 10% decrease in the left ventricular ejection fraction (LVEF) during 12-month observation. In a 12-month follow-up five (7.5%) deaths occurred, while no clinical manifestations of heart failure were reported. There was an increase in left ventricular end-systolic diameter (p = 0.002) and E/e' index (p = 0.036) in 12-month observation. Preexisting coronary artery disease was associated with significant decrease in the DeltaLVEF (p = 0.008), increase in DeltaLVEDV (p = 0.03) and DeltaLVESV (p = 0.02) and increase in the Delta left atrium diameter (p = 0.02); while history of arterial hypertension was related to significant decrease in the DeltaLVEF (p = 0.039), diabetes mellitus was related to significant increase in the DeltaE/e' index (p = 0.002). The primary end point was reported in ten (14.9%) patients. There were no independent risk factors for cardiotoxicity in the study population. Chemotherapy administered to NHL patients may induce dilatation and impaired LV diastolic function. Standard cardiovascular risk factors may predispose patients to negative LV remodeling. PMID- 29274028 TI - A cross-sectional study examining the prevalence of cachexia and areas of unmet need in patients with cancer. AB - PURPOSE: The semantics of defining cancer cachexia over the last decade has resulted in uncertainty as to the prevalence. This has further hindered the recognition and subsequent treatment of this condition. Following the consensus definition for cancer cachexia in 2011, there is now a need to establish estimates of prevalence. Therefore, the primary aim of the present study was to assess the prevalence of cachexia in an unselected cancer population. A secondary aim was to assess patient-perceived need of attention to cachexia. METHODS: A cross-sectional study in hospital patients was undertaken. Key inclusion criteria were the following: age > 18 years, cancer diagnosis, and no surgery the preceding 24 h. Data on demographics, disease, performance status, symptoms, cachexia, and patients' perceived need of attention to weight loss and nutrition were registered. RESULTS: Data were available on 386 of 426 eligible patients. Median age (IQR) was 65 years (56-72), 214 (55%) were male and 302 (78%) had a performance status of 0-1 (Eastern Cooperative Oncology Group). Prevalence of cachexia (inpatients/outpatients) was 51/22%. Prevalence was highest in patients with gastrointestinal cancer (62/42%) and lung cancer (83/36%). There was no major difference in prevalence between patients with metastatic (55/24%) and localized disease (47/19%). Twenty percent of inpatients and 15% of outpatients wanted more attention to weight loss and nutrition. Cachexia (p < 0.001), symptoms of mood disorder (p < 0.001), and male gender (p < 0.01) were independently associated with increased need of attention. CONCLUSION: Cachexia is a prevalent condition, affecting both patients with localized and metastatic cancer. Clinical attention to the condition is a sizeable unmet need. PMID- 29274029 TI - Endovascular stent-based revascularization of malignant superior vena cava syndrome with concomitant implantation of a port device using a dual venous approach. AB - PURPOSE: The aim of this paper is to evaluate the safety and efficacy of endovascular revascularization of malignant superior vena cava syndrome (SVCS) and simultaneous implantation of a totally implantable venous access port (TIVAP) using a dual venous approach. MATERIALS AND METHODS: Retrospectively, 31 patients (mean age 67 +/- 8 years) with malignant CVO who had undergone revascularization by implantation of a self-expanding stent into the superior vena cava (SVC) (Sinus XL(r), OptiMed, Germany; n = 11 [Group1] and Protege TM EverFlex, Covidien, Ireland; n = 20 [Group 2]) via a transfemoral access were identified. Simultaneously, percutaneous access via a subclavian vein was used to (a) probe the lesion from above, (b) facilitate a through-and-through maneuver, and (c) implant a TIVAP. Primary endpoints with regard to the SVC syndrome were technical (residual stenosis < 30%) and clinical (relief of symptoms) success; with regard to TIVAP implantation technical success was defined as positioning of the functional catheter within the SVC. Secondary endpoints were complications as well as stent and TIVAP patency. RESULTS: Technical and clinical success rate were 100% for revascularization of the SVS and 100% for implantation of the TIVAP. One access site hematoma (minor complication, day 2) and one port-catheter associated sepsis (major complication, day 18) were identified. Mean catheter days were 313 +/- 370 days. Mean imaging follow-up was 184 +/- 172 days. Estimated patency rates at 3, 6, and 12 months were 100% in Group 1 and 84, 84, and 56% in Group 2 (p = 0.338). CONCLUSION: Stent-based revascularization of malignant SVCS with concomitant implantation of a port device using a dual venous approach appears to be safe and effective. PMID- 29274030 TI - Fatigue among patients with renal cell carcinoma receiving adjuvant sunitinib or sorafenib: patient-reported outcomes of ECOG-ACRIN E2805 trial. AB - BACKGROUND: E2805 was a phase III trial to test whether adjuvant sunitinib or sorafenib could improve disease-free survival compared to placebo in patients with renal cell carcinoma. Patient-reported outcomes (PRO), focusing on fatigue, were evaluated as a secondary endpoint. PATIENTS AND METHODS: A total of 463 patients participated in the PRO study. Fatigue was measured by the FACIT Fatigue scale and PROMIS Fatigue SF1 measure at baseline, week 10, and week 22. The primary endpoint was change in fatigue score from baseline to week 22, measured by the FACIT Fatigue scale. Secondarily, the psychometric properties of PROMIS Fatigue SF1 were assessed in relation to the FACIT Fatigue scale. RESULTS: Fatigue got significantly worse on all arms after 2 cycles of treatment, and especially so in patients on sunitinib (- 9.6 vs. - 5.6 on sorafenib vs. - 4.7 on placebo). Fatigue remained stable during week 10 and week 22. Overall, the mean score change between baseline and week 22 was - 7.9 (p < 0.001) on sunitinib, - 6.4 (p < 0.001) on sorafenib and - 5.6 (p < 0.001) on placebo arm. The difference in score change was not statistically significant between the two experimental arms and the placebo arm (difference = - 2.34 [p = 0.110] and - 0.87 [p = 0.535] for sunitinib vs. placebo and sorafenib vs. placebo). PROMIS Fatigue SF1 had good internal consistency reliability and construct and criterion validity, and was highly correlated with the FACIT Fatigue scale score. CONCLUSIONS: Fatigue got worse during study period, especially in patients on sunitinib. The PROMIS Fatigue SF1 was highly correlated with FACIT Fatigue and produced similar results. PMID- 29274031 TI - Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure. AB - Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apoptosis, and synaptic pruning. Sex differences in microglia colonization of the developing brain have been reported, but have not been established following alcohol insult. Developmental alcohol exposure represents a neuroimmune challenge that may contribute to cognitive dysfunction prevalent in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. Most studies have investigated neuroimmune activation following adult alcohol exposure or following multiple exposures. The current study uses a single day binge alcohol exposure model (postnatal day [PD] 4) to examine sex differences in the neuroimmune response in the developing rat hippocampus on PD5 and 8. The neuroimmune response was evaluated through measurement of microglial number and cytokine gene expression at both time points. Male pups had higher microglial number compared to females in many hippocampal subregions on PD5, but this difference disappeared by PD8, unless exposed to alcohol. Expression of pro inflammatory marker CD11b was higher on PD5 in alcohol-exposed (AE) females compared to AE males. After alcohol exposure, C-C motif chemokine ligand 4 (CCL4) was significantly increased in female AE pups on PD5 and PD8. Tumor necrosis factor-alpha (TNF-alpha) levels were also upregulated by AE in males on PD8. The results demonstrate a clear difference between the male and female neuroimmune response to an AE challenge, which also occurs in a time-dependent manner. These findings are significant as they add to our knowledge of specific sex-dependent effects of alcohol exposure on microglia within the developing brain. PMID- 29274033 TI - Supplementation with an insoluble fiber obtained from carob pod (Ceratonia siliqua L.) rich in polyphenols prevents dyslipidemia in rabbits through SIRT1/PGC-1alpha pathway. AB - PURPOSE: To investigate the mechanism implicated in the effect of an insoluble fiber (obtained from carob pod) rich in polyphenols (IFCP) in lipid metabolism in the liver. METHODS: Male New Zealand rabbits were fed with the following diets for 8 weeks: control diet (CT group), dyslipidemic diet supplemented with 0.5% cholesterol + 14% coconut oil (DL group) and dyslipidemic diet containing 0.5% cholesterol + 14% coconut oil plus 3% IFCP (DL + IFCP group). RESULTS: Dyslipidemic diet with IFCP was able to reduce development of mixed dyslipidemia, liver relative weight and collagen I protein expression compared to DL rabbits. Analyses of the main enzymes implicated in cholesterol and triglycerides metabolism revealed that IFCP increased hepatic concentration of 3-hydroxy-3 methylglutaryl-CoA reductase (HMG-CoA reductase) and cytochrome P450, family 7, subfamily a, polypeptide 1C (CYP7A1) (82.34, 114.42%, respectively) as well as protein expression of LDL receptor (42.48%) in DL rabbits. Importantly, IFCP also increased hepatic lipase (HL) levels (91.43%) and decreased glycerol phosphate acyltransferase (GPAT) and sterol regulatory element-binding protein 1C (SREBP1c) liver expression levels (20.38 and 41.20%, respectively). Finally, sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) hepatic expression increased in DL + IFCP group compared with DL (159.81 and 48.00%, respectively). CONCLUSIONS: These findings show that IFCP is able to abrogate the deleterious effects of hepatic dyslipidemia by modulating SIRT1 and PGC-1alpha pathways. PMID- 29274032 TI - Impact of quadripolar LV leads on heart failure hospitalization rates among patients implanted with CRT-D: data from the Israeli ICD Registry. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an effective treatment for heart failure (HF); however, a third of patients are non-responders. The development of quadripolar left ventricular (LV) lead was shown, mainly in single manufactures' registry, to improve LV remodeling and overall mortality. However, limited reports exist on the impact of quadripolar LV leads on HF hospitalization rates in real-life cohorts. We evaluated the clinical outcomes associated with quadripolar LV leads in a large nation-wide registry including all patients implanted with a cardiac resynchronization therapy with defibrillator (CRT-D). METHODS: Between July 2010 and October 2016, 2913 consecutive patients were implanted with a CRT-D and all were prospectively enrolled in the Israeli ICD Registry. Quadripolar LV leads were implanted in 973 (33.4%) patients during this period, and their clinical outcomes were compared to CRT-D recipients implanted with a bipolar LV lead. Primary endpoint was HF hospitalization rate. RESULTS: Quadripolar leads were implanted more in patients with non-ischemic cardiomyopathy and for primary prevention indication and less in post-infarction patients and for secondary prevention of sudden death. Longer QRS duration was observed with quadripolar leads (147 +/- 23 vs 143 +/- 25; p < 0.001). Outcome event rate for 100 patient years revealed no difference in HF hospitalization rates between bipolar and quadripolar LV leads. Quadripolar lead implant led to lower cardiac mortality, with no influence on overall mortality. Multivariate analysis revealed no significant differences in study endpoints between bipolar and quadripolar LV leads. CONCLUSION: In a large real-life registry, implantation of quadripolar LV leads in patients with CRT-D did not influence HF hospitalization rates. PMID- 29274034 TI - The effects of bovine colostrum supplementation on in vivo immunity following prolonged exercise: a randomised controlled trial. AB - BACKGROUND: Bovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction, but there is a lack of research with clinically relevant in vivo measures. AIM: To investigate the effects of COL supplementation on in vivo immunity following prolonged exercise using experimental contact hypersensitivity (CHS) with the novel antigen diphenylcyclopropenone (DPCP). METHODS: In a double-blind design, 31 men were randomly assigned to COL (20 g/day) or placebo (PLA) for 58 days. Participants ran for 2 h at 60% maximal aerobic capacity on day 28 and received a primary DPCP exposure (sensitisation) 20 min after. On day 56, participants received a low dose-series DPCP challenge to elicit recall of in vivo immune-specific memory (quantified by skinfold thickness 24 and 48 h later). Analysis of the dose response curves allowed determination of the minimum dose required to elicit a positive response (i.e., sensitivity). RESULTS: There was no difference in summed skinfold thickness responses between COL and PLA at 24 h (p = 0.124) and 48 h (p = 0.405). However, sensitivity of in vivo immune responsiveness was greater with COL at 24 h (p < 0.001) and 48 h (p = 0.023) with doses ~ twofold greater required to elicit a positive response in PLA. CONCLUSIONS: COL blunts the prolonged exercise-induced decrease in clinically relevant in vivo immune responsiveness to a novel antigen, which may be a mechanism for reduced illness reports observed in the previous studies. These findings also suggest that CHS sensitivity is highly relevant to host defence. PMID- 29274035 TI - MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson's disease by targeting Nlrp3. AB - Accumulating evidences suggest that neuroinflammation is a pathological hallmark of Parkinson's disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MicroRNAs have been recently recognized as crucial regulators of inflammatory responses. Here, we found significant downregulation of microRNA-30e (miR-30e) in SNpc of MPTP induced PD mice. Next, we employed miR-30e agomir to upregulate miR-30e expression in MPTP-treated mice. Our results showed that delivery of miR-30e agomir remarkably improved motor behavioral deficits and neuronal activity, and inhibited the loss of dopamine neurons. Moreover, the increased alpha-synuclein protein expression in SNpc of MPTP-PD mice was alleviated by the upregulation of miR-30e. Further, miR-30e agomir administration also attenuated the marked increase of inflammatory cytokines, such as TNF-alpha, COX-2, iNOS, and restored the decreased secretion of BDNF in SNpc. In addition, we demonstrated for the first time that miR-30e directly targeted to Nlrp3, thus suppressing Nlrp3 mRNA and protein expression. Finally, miR-30e upregulation significantly inhibited the activation of Nlrp3 inflammasome as evident from the decreased Nlrp3, Caspase-1 and ASC expressions and IL-18 and IL-1beta secretions. Taken together, our study demonstrates that miR-30e ameliorates neuroinflammation in the MPTP model of PD by decreasing Nlrp3 inflammasome activity. These findings suggesting that miR30e may be a key inflammation-mediated molecule that could be a potential target for PD therapeutics. PMID- 29274036 TI - Synthesis, characterization, biological evaluation and molecular docking studies of 2-(1H-benzo[d]imidazol-2-ylthio)-N-(substituted 4-oxothiazolidin-3-yl) acetamides. AB - BACKGROUND: A series of 2-(1H-benzo[d]imidazol-2-ylthio)-N-(substituted 4 oxothiazolidin-3-yl) acetamides was synthesized and characterized by physicochemical and spectral means. The synthesized compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans and Aspergillus niger by tube dilution method. The in vitro cytotoxicity study of the compounds was carried out against human colorectal (HCT116) cell line. The most promising anticancer derivatives (5l, 5k, 5i and 5p) were further docked to study their binding efficacy to the active site of the cyclin-dependent kinase-8. RESULTS: All the compounds possessed significant antimicrobial activity with MIC in the range of 0.007 and 0.061 uM/ml. The cytotoxicity study revealed that almost all the derivatives were potent in inhibiting the growth of HCT116 cell line in comparison to the standard drug 5-fluorouracil. Compounds 5l and 5k (IC50 = 0.00005 and 0.00012 uM/ml, respectively) were highly cytotoxic towards HCT116 cell line in comparison to 5-fluorouracil (IC50 = 0.00615 uM/ml) taken as standard drug. CONCLUSION: The molecular docking studies of potent anticancer compounds 5l, 5k, 5i and 5p showed their putative binding mode and significant interactions with cyclin-dependent kinase-8 as prospective agents for treating colon cancer. PMID- 29274038 TI - A glance at the 2017 edition of the international Molecular Mycorrhiza Meetings. PMID- 29274037 TI - Depicting the pterygopalatine ganglion on 3 Tesla magnetic resonance images. AB - PURPOSE: The pterygopalatine ganglion has yet not been identified on medical images in living humans. The primary aim of this study was to evaluate whether the pterygopalatine ganglion could be identified on 3 T MR imaging. METHODS: This study was performed on medical images of 20 Caucasian subjects on both sides (n = 40 ganglia) with an exploratory design. 3 T MR images were assessed by two physicians for the presence and size of the pterygopalatine ganglion. The distance from the pterygopalatine ganglion to four bony landmarks was registered from fused MR and CT images. In an equivalence analysis, the distances were compared to those obtained in an anatomical cadaveric study serving as historical controls (n = 50). RESULTS: A structure assumed to be the pterygopalatine ganglion was identified on MR images in all patients on both sides by both physicians. The mean size was depth 2.1 +/- 0.5 mm, width 4.2 +/- 1.1 mm and height 5.1 +/- 1.4 mm, which is in accordance with formerly published data. Equivalence of the measurements on MR images and the historical controls was established, suggesting that the structure identified on the MR images is the pterygopalatine ganglion. CONCLUSION: Our findings suggest that the pterygopalatine ganglion can be detected on 3 T MR images. Identification of the pterygopalatine ganglion may be important for image-guided interventions targeting the pterygopalatine ganglion, and has the potential to increase the efficacy, safety and reliability for these treatments. PMID- 29274039 TI - An arbuscular mycorrhizal fungus and Epichloe festucae var. lolii reduce Bipolaris sorokiniana disease incidence and improve perennial ryegrass growth. AB - Leaf spot of perennial ryegrass (Lolium perenne) caused by Bipolaris sorokiniana is an important disease in temperate regions of the world. We designed this experiment to test for the combined effects of the arbuscular mycorrhizal (AM) fungus Claroideoglomus etunicatum and the grass endophyte fungus Epichloe festucae var. lolii on growth and disease occurrence in perennial ryegrass. The results show that C. etunicatum increased plant P uptake and total dry weight and that this beneficial effect was slightly enhanced when in association with the grass endophyte. The presence in plants of both the endophyte and B. sorokiniana decreased AM fungal colonization. Plants inoculated with B. sorokiniana showed the typical leaf spot symptoms 2 weeks after inoculation and the lowest disease incidence was with plants that were host to both C. etunicatum and E. festucae var. lolii. Plants with these two fungi had much higher activity of peroxidases (POD), superoxide dismutase (SOD) and catalase (CAT) and lower values of malondialdehyde (MDA) and hydrogen peroxide (H2O2). The AM fungus C. etunicatum and the grass endophyte fungus E. festucae var. lolii have the potential to promote perennial ryegrass growth and resistance to B. sorokiniana leaf spot. PMID- 29274040 TI - LC-MS/MS method for the quantification of masitinib in RLMs matrix and rat urine: application to metabolic stability and excretion rate. AB - Masitinib (MST) is a selective tyrosine kinase inhibitor. Validated liquid chromatography tandem mass spectrometric method (LC-MS/MS) was developed for the quantification of MST in rat liver microsomes (RLMs) matrix. The developed method was applied to metabolic stability and excretion rate studies. Reversed phase liquid chromatography was used for resolution of MST and bosutinib (IS) using C18 (50 mm * 2.1 mm, 1.8 MUm). Binary solvent system consisted of 35% solvent A (0.1% formic acid in H2O, pH: 3.2) and 65% solvent B (acetonitrile) used as mobile phase at flow rate of 0.25 mL with a total run time of 5 min. Injection volume was 5 uL. Generation of ions was done in positive ESI source and quantification of MST and IS were done using MRM mode. The developed method showed a linearity in the range of 5-200 ng/mL (r2 >= 0.9992) with LOQ and LOD of 0.25 and 0.76 ng/mL in RLMs. The intra- and inter-day precision and accuracy ranged from 0.95 to 1.49 and - 5.22 to 1.13%, respectively in RLMs. Rate of disappearance of MST during incubation with RLMs was almost linear allover incubation time. In vitro t1/2 was 50.38 min and CLin was 3.11 +/- 0.2. The developed method was applied also to measure the rate of masitinib excretion in rat urine. The method can used for further pharmacokinetic studies of MST. PMID- 29274041 TI - Intraoral Pigmented Low-Grade Adenocarcinoma, Not Otherwise Specified: Case Report and Immunohistochemical Study. AB - Salivary adenocarcinoma, not otherwise specified (AdCaNOS) is a rare malignant tumor with potential diagnostic challenge, which mainly affects the parotid glands; however, the minor salivary glands can also be involved by AdCaNOS. This paper reports a case of a 45-year-old Afro-descendant woman complaining of a slow growing mass with 6 months of evolution in the left superior vestibular fornix. Microscopic examination revealed an infiltrative epithelial neoplasm composed of predominantly solid growth pattern, arranged in a lobular configuration, admixed with glandular or ductal structures. Perineural invasion was evident. The tumor cells were polygonal or oval showing focally mild nuclear pleomorphism, and eosinophilic or clear cytoplasm. Notably, some areas exhibited intracytoplasmic pigment granules mainly in non-luminal cells, as well as sebaceous-like cells, discrete hyaline material deposition and foci of infiltration of residual salivary gland parenchyma. Tumor cells were negative for PAS, mucicarmine and Alcian blue stains. By immunohistochemistry, the tumor cells were diffuse and strongly positive for pan-cytokeratin (CK) AE1/AE3, 34betaE12 CK, vimentin, p63 and S100. CK7 and EMA strongly highlighted the ductal structures. Solid areas also showed diffuse and moderate expression of CD56. Podoplanin (D2-40), GFAP and Calponin, followed by DOG-1, were focally positive; whereas CK20, alpha-SMA, h Caldesmon, CD57, ERBB2/HER2 and p53 were negative. Ki-67 was < 2%. Consecutive serial tissue sections using CD57 confirmed the perineural invasion. Positivity for HMB-45 and MART-1/Melan-A, as well as Fontana-Masson stain (and potassium permanganate bleaching-sensitive), identified the pigment granules as melanin. To the best of our knowledge, this is the first case of intraoral low-grade AdCaNOS with intracytoplasmic melanin granules. PMID- 29274043 TI - 4Ts Score and EuroSCORE in cardiac surgery. PMID- 29274042 TI - Sclerosing Epithelioid Fibrosarcoma of the Jaw: Late Recurrence from a Low Grade Fibromyxoid Sarcoma. AB - Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon variant of fibrosarcoma that is characterized by a distinct morphology. It most frequently presents in the deep soft tissues of the lower extremities, often in intimate association with fascia and periosteum, although reports of the head and neck involvement have been reported. A minority of cases show morphological, immunohistochemical and molecular overlap with low grade fibromyxoid sarcoma (LG-FMS). Herein, we describe a case of a bland spindle cell neoplasm presenting in the jaw that was initially incompletely excised. Over the course of 20 years the tumor subsequently recurred with a SEF morphology. Molecular testing performed on both specimens subsequently confirmed the presence of an EWSR1-CREB3L1 gene fusion. This report highlights the diagnostic difficulty with LG-FMS, particularly in unusual anatomic locations; reiterates the potential for the uncommon EWSR1 CREB3L1 fusion product in LG-FMS; and, reaffirms the potential for progression and/or overlap between LG-FMS to SEF over time. PMID- 29274044 TI - Expanding anticoagulation management services to include direct oral anticoagulants. AB - Despite the ease of use of direct oral anticoagulants (DOACs), these agents remain high risk medications and their clinical efficacy can be impacted by factors such as patient adherence, drug procurement barriers, bleeding leading to discontinuation, and prescribing that deviates from approved dosing regimens. Clinical monitoring of patients on DOACs should be performed by clinicians who specialize in anticoagulation and are familiar with the nuances of DOAC dosing, monitoring, and other components of anticoagulation management including peri procedural management and care transitions. Although data for centralized warfarin management have consistently demonstrated improved clinical outcomes compared to traditional management by individual community providers, there are no published data addressing the impact of centralized management of DOACs on clinical outcomes or anticoagulation control. In addition, there is currently no consensus on how to incorporate patients on DOACs into this centralized model, despite recommendations for systematic follow-up by both the Anticoagulation Forum and the Institute for Safe Medication Practices. Based on the national recommendations and an identified institutional need, the Brigham and Women's Hospital Anticoagulation Management Service implemented a pilot program to expand services to include patients newly initiated on, or transitioned to, a DOAC. We describe our model for expansion of the AMS to include patients on DOACs. PMID- 29274045 TI - Overwork accelerates thrombotic reaction: implications for the pathogenesis of Karoshi. AB - Work-related stressors are potential causes of cardiovascular diseases (CVDs) and stroke; however, the pathophysiological mechanisms by which occupational stress induces and exacerbates CVDs remain unclear. The global thrombosis test (GTT) is a novel in vitro assay for evaluating both thrombotic reactions and subsequent thrombolysis. The time required to form an occlusive thrombus with the GTT, called as the occlusion time (OT), and the time to lyse the thrombus, the lysis time (LT), are markers of thrombotic and thrombolytic reactions, respectively. We investigated the impact of work-related stress on the thrombotic and thrombolytic reactions in 46 healthy medical residents. Off-duty or on-duty blood samples were collected on the mornings of non-work days or after the night duty on the emergent room respectively. The duration of sleep was significantly shorter during night duty than during off-duty nights [2.25 (1.0, 3.0) h vs. 6.0 (5.0, 7.0) h; p < 0.001]. Baseline OT was 310.3 (260.9, 437.7) s. whereas the on-duty OT was significantly shortened [284.2 (230.5, 355.8) s; p < 0.01]. LT was significantly prolonged during overwork conditions compared with off-duty conditions [1547 (1346, 1908) s vs. 1470 (1219, 1692) s; p < 0.05]. Overwork accelerates the thrombotic reactions. These reactions might explain the pathogenesis of overwork-related CVDs. The GTT is a good tool for evaluating of the level of fatigue. PMID- 29274047 TI - Quantitative Analysis of Uncertainty in Medical Reporting: Creating a Standardized and Objective Methodology. AB - Uncertainty in text-based medical reports has long been recognized as problematic, frequently resulting in misunderstanding and miscommunication. One strategy for addressing the negative clinical ramifications of report uncertainty would be the creation of a standardized methodology for characterizing and quantifying uncertainty language, which could provide both the report author and reader with context related to the perceived level of diagnostic confidence and accuracy. A number of computerized strategies could be employed in the creation of this analysis including string search, natural language processing and understanding, histogram analysis, topic modeling, and machine learning. The derived uncertainty data offers the potential to objectively analyze report uncertainty in real time and correlate with outcomes analysis for the purpose of context and user-specific decision support at the point of care, where intervention would have the greatest clinical impact. PMID- 29274046 TI - Outcome of thrombus aspiration in STEMI patients: a propensity score-adjusted study. AB - The use of thrombus aspiration (TA) prior to primary percutaneous coronary intervention (PPCI) has undergone a radical change in intervention guidelines. The clinical implications, however, are still under scrutiny. This study investigated the clinical effects and outcome of TA before PPCI in patients with ST-segment elevation myocardial infarction (STEMI). Overall 1027 patients with STEMI were analyzed in this retrospective, propensity score-adjusted, multicenter study. The primary endpoints were in-hospital and long-term mortality. There were 418 patients in the TA group and 609 in the conventional PPCI group. The in hospital mortality rate was significantly higher in the TA group (8.7 vs. 5.0%; P = 0.03). During long-term follow-up [median follow-up duration 689 days (IQR 405 959)] the mortality rates were similar (TA 14.3%, conventional PPCI 15.0%; P = 0.85). Survival analysis for the complete observation period revealed no significant benefit of TA [hazard ratio (HR) 1.12; 97.5% CI 0.90-0.71; P = 0.63]. There were also no significant differences between the groups in the following secondary endpoints: composite of cardiovascular death and non-fatal reinfarction at discharge (P = 0.39), post-PPCI thrombolysis in myocardial infarction flow grade-3 (P = 0.14), left ventricular ejection fraction (P = 0.47), and non-fatal reinfarction during follow-up (P = 0.17). Rehospitalization rate (1.82 vs. 10.3%; P < 0.0001) and Canadian Cardiovascular Society (CCS) grading (P = 0.02) during follow-up were significantly lower in the TA group. In our cohort the in-hospital mortality rate was significantly higher for TA patients, but during long-term follow-up the mortality rates did not differ. The incidence of rehospitalization and CCS grading were lower in the TA-treated patients. PMID- 29274049 TI - Correction to: Expression of optineurin isolated from rat-injured dental pulp and the effects on inflammatory signals in normal rat kidney cells. AB - In the original publication of the article, one of the author name was published incorrectly as "Keisuke Yamashairo" and correct name should be "Keisuke Yamashiro". PMID- 29274048 TI - A comparison of serial order short-term memory effects across verbal and musical domains. AB - Recent studies suggest that the mechanisms involved in the short-term retention of serial order information may be shared across short-term memory (STM) domains such as verbal and visuospatial STM. Given the intrinsic sequential organization of musical material, the study of STM for musical information may be particularly informative about serial order retention processes and their domain-generality. The present experiment examined serial order STM for verbal and musical sequences in participants with no advanced musical expertise and experienced musicians. Serial order STM for verbal information was assessed via a serial order reconstruction task for digit sequences. In the musical domain, serial order STM was assessed using a novel melodic sequence reconstruction task maximizing the retention of tone order information. We observed that performance for the verbal and musical tasks was characterized by sequence length as well as primacy and recency effects. Serial order errors in both tasks were characterized by similar transposition gradients and ratios of fill-in:infill errors. These effects were observed for both participant groups, although the transposition gradients and ratios of fill-in:infill errors showed additional specificities for musician participants in the musical task. The data support domain-general serial order STM effects but also suggest the existence of additional domain-specific effects. Implications for models of serial order STM in verbal and musical domains are discussed. PMID- 29274050 TI - The First CT Scan of the Brain: Entering the Neurologic Information Age. AB - Computed tomography (CT) scan of the brain transitioned clinical neurology from the educated-guess world to the real computer-age world. One of the first CT scans-published by the British neuroradiologist James Ambrose-showed an intracranial hemorrhage and also suggested the use of iodine to demonstrate abnormal blood-brain barrier. In the USA, CT scans were rapidly commercialized and first placed at Mayo Clinic and Massachusetts General Hospital in the summer of 1973. CT scanning of the brain has revolutionized diagnostic acute neurology and neurosurgery and was the overture to an even larger revolution-magnetic resonance imaging. This historical vignette discusses the development of CT scanning of the brain and its connection with neurocritical care. PMID- 29274051 TI - Stroke and Craniectomy. AB - Neurosurgical involvement in the care of major stroke complications has yielded striking results in the subtentorial region but equivocal outcomes in the supratentorial compartment. Most neurosurgeons want to see some degree of deterioration before proceeding; thus, timing will be debated. Viewpoints have changed over the years regarding surgical or medical intervention, but in many patients the procedure has not produced a definitive change in outcome other than preventing death from terminal brainstem shift. The introduction of craniectomy (and craniotomy) to treat swollen ischemic brain or intracranial hemorrhage has historical interest. PMID- 29274052 TI - Epidemiology and effect of gastrointestinal nematodes on beef cattle from tropical Argentina. AB - The aim of this work was to study the epidemiology and the harmful effect of gastrointestinal nematodes (GINs) on beef cattle in the piedmont forest and grassland region of northwestern Argentina, between March 2015 and March 2016. Sixty weaned female calves were divided into three groups: STG-calves treated systematically with 200 mcg/kg moxidectin every 40-50 days; LTG-calves treated as usually locally implemented, with 200 mcg/kg ivermectin on May 4 and August 5; and UTG-calves not receiving treatment. Moreover, a group of 20 untreated first calving cows was monitored. Eggs per gram of faeces (epg) and faeces cultures were performed. Live weight gain (LWG) was recorded. Differences among groups were compared using analysis of variance and Tukey test. At the start of the experiment, mean epg was from moderate to high (595 +/- 480); therefore, this group was treated in May. Mean UTG epg peaked (907 +/- 754) in mid-winter, decreasing toward spring. LTG epg only decreased partially after treatment, showing 54.2% of ivermectin efficacy. Epg values of STG were always negligible values (95.8% of moxidectin efficacy). The dominant nematode genus was Cooperia (81.9%), followed by Haemonchus (15.5%). The effect of treatments was evident from middle autumn, with STG showing a significantly (p < 0.002) higher LWG than the other groups. Toward the end of the trial, LWG of STG and LTG increased by 27.2 and 8.2%, respectively, to those of UTG. This preliminary study showed a winter epg peak and a negative effect of GINs on LWG, even in moderately infected calves. PMID- 29274053 TI - Pregnancy rate in water buffalo following fixed-time artificial insemination using new or used intravaginal devices with two progesterone concentrations. AB - This study evaluated the pregnancy rate (PR) after timed artificial insemination (TAI) in water buffalo (Bubalus bubalis) during both non-breeding and breeding season, using either a new or reused intravaginal device (IVD) with two different progesterone concentrations. A total of 247 dairy buffalo cows were randomly assigned using a two-by-three factorial design and four replicates to the following groups: (1) new intravaginal device (IVD-New: DIB(r), 1.0 g of P4, n = 51 or CIDR(r), 1.38 g of P4, n = 55); (2) intravaginal device previously used once (9 days) (IVD-Used1x: DIB, n = 40 or CIDR, n = 51); or (3) intravaginal device previously used twice (18 days) (IVD-Used2x: DIB, n = 27 or CIDR, n = 23). On day 0, animals received the IVD plus 10.5 MUg of buserelin acetate (GnRH) intramuscularly. On day 9, the devices were removed and 25 mg of PGF2alpha plus 500 IU of eCG was given intramuscularly. On day 11 (48 h after IVD withdrawal), animals received 10.5 MUg of GnRH and were artificially inseminated 8-12 h later. Data were analyzed using Proc Logistic of SAS(r). Animals that received IVD-New DIB, had a significantly higher PR (62.7%; P = 0.0193) compared to animals that received IVD-New-CIDR (40%). Pregnancy rate was not negatively affected by reusing both types of IVD. Overall PR (new and reused devices) was higher (P = 0.0055) in the DIB group (62.7%) compared to the CIDR group (45%). In conclusion, PR was higher in buffaloes treated with devices containing 1.0 g of P4 (DIB(r)) compared to those receiving 1.38 g of P4 (CIDR(r)). Reusing the intravaginal devices did not affect negatively PR/TAI, suggesting that P4 concentrations within the TAI protocols in water buffaloes could be reduced, without impairing their fertility. PMID- 29274054 TI - Prevalence and risk factors of mycobacterial infections in farm and trade cattle in southwestern Nigeria. AB - We evaluated the prevalence of mycobacterial infections (i.e., Mycobacterium bovis and non-tuberculous mycobacteria [NTM]) and their associated risk factors among cattle herds and trade cattle in southwestern Nigeria. Through cross sectional study design, cattle herds from three locations were screened using the single intradermal comparative cervical tuberculin test based on two diagnostic standards; more than 4 mm (? 4 mm) and more than 2 mm (? 2 mm) cut-off points. Abattoir study involved screening trade cattle for tuberculous lesions. Overall, 515 cattle from 45 herds were screened. Using > 4 mm, animal level and herd prevalence of 11.7 and 46.7% were recorded, respectively. Applying the ? 2 mm cut off, animal level and herd prevalence increased to 31.1 and 60.0%, respectively. Significantly, using the ? 2 mm cut-off, cattle in medium size herds/extensive management system (OR = 1.6; 95% CI 1.1-2.5) and Sokoto Gudali (OR = 2.3; 95% CI 1.4-3.8) were more at risk of being positive reactors, while Rahaji (OR = 0.3; 95% CI 0.1-0.7) breeds of cattle and cows in the peri-urban area (OR = 0.4; 95% CI 0.2-0.9) were less at risk of being positive reactors. Again, M. avium reactor of 21.7% was observed. In the abattoir, 1797 cattle were examined with 126 lesions suggestive of tuberculosis (TB). Culture/molecular analyses confirmed 2.2% M. bovis and 0.9% NTM infections. Risk factors associated with bovine TB among trade cattle were sex (OR = 4.0; 95% CI 1.2-13.5) and age (OR = 0.3; 95% CI 0.1-0.9). We confirm 11.7% prevalence of mycobacterial infections among populations of cattle screened with breed and herd size being major risk factors. PMID- 29274055 TI - Impact of crossbreeding Holstein and Brown Swiss cows on milk yield, composition, and fatty acid profiles in subtropics. AB - Milk yield (MY), composition, and fatty acid profiles of purebred Holstein (HO) cows, Brown Swiss (BS), and their F1 crossbreds (HS) were compared under subtropical climate in Egypt. Pure HO had significantly greater 305-MY, total-MY, and daily-MY (p < 0.05) than pure BS and crossbred HS. Furthermore, HO and HS had significantly higher peak-MY (44.2 and 43.3 kg, respectively) than BS (36.1 kg). In comparison with HO, BS had significantly higher milk fat, protein, total solids, and solid-not-fat % (p < 0.05); however, no significant differences were observed between BS and HS for milk fat %. The milk fat of BS had higher concentrations of saturated (C17:0 and C18:0) fatty acids (FA) than that of the HO and HS (p = 0.001 and 0.008, respectively). Content of C4:0, C6:0, C8:0, C12:0, and C15.0 FA did not differ between genotypes. Milk from HO and BS had significantly higher concentrations of unsaturated (C20:1 and C20:5) FA than that from HS (p < 0.05). C14:1 (myristoleic), C16:1 (palmitoleic), and C18:2 (linoleic) FA contents were similar for all genotypes. In conclusion, BS surpassed HO for all milk composition traits and some FA components; however, HS had comparable milk fat percentage with BS. There appears to be an opportunity to modify the concentration of certain FA by breeding. PMID- 29274056 TI - Documenting the absence of brucellosis in cattle, goats and dogs in a "One Health" interface in the Mnisi community, Limpopo, South Africa. AB - This study shows the absence of the world's most common bacterial zoonoses caused by Brucella abortus and Brucella melitensis in cattle, goats and dogs in an agro pastoral community in South Africa, where heifer vaccination against brucellosis with the live Strain 19 vaccine is compulsory. The study site is bordering wildlife reserves with multiple wildlife species infected with brucellosis. The results showed a low seroprevalence (1.4%) in cattle. Seroprevalence in cattle decreased with age after 4 years in females, males were less positive than females and a tissue culture from a brucellin skin test-positive male was negative. The results indicate that Brucella seropositivity in cattle is due to S19 vaccination and not natural infections. This conclusion is reinforced by the absence of Brucella seropositivity in goats (1/593 positive result) and dogs (0/315), which can be seen as potential spillover hosts. Therefore, the close proximity of brucellosis-infected wildlife is not a threat to domestic animals in this controlled setting with vaccination, fencing and movement control. PMID- 29274057 TI - Categorization difficulty modulates the mediated route for response selection in task switching. AB - Conflict during response selection in task switching is indicated by the response congruency effect: worse performance for incongruent targets (requiring different responses across tasks) than for congruent targets (requiring the same response). The effect can be explained by dual-task processing in a mediated route for response selection, whereby targets are categorized with respect to both tasks. In the present study, the author tested predictions for the modulation of response congruency effects by categorization difficulty derived from a relative speed-of-processing hypothesis. Categorization difficulty was manipulated for the relevant and irrelevant task dimensions in a novel spatial task-switching paradigm that involved judging the locations of target dots in a grid, without repetition of dot configurations. Response congruency effects were observed and they varied systematically with categorization difficulty (e.g., being larger when irrelevant categorization was easy than when it was hard). These results are consistent with the relative-speed-of-processing hypothesis and suggest that task switching models that implement variations of the mediated route for response selection need to address the time course of categorization. PMID- 29274058 TI - Increased microbial functional diversity under long-term organic and integrated fertilization in a paddy soil. AB - Microbes play key roles in diverse biogeochemical processes including nutrient cycling. However, responses of soil microbial community and functional genes to long-term integrated fertilization (chemical combined with organic fertilization) remain unclear. Here, we used pyrosequencing and a microarray-based GeoChip to explore the shifts of microbial community and functional genes in a paddy soil which received over 21-year fertilization with various regimes, including control (no fertilizer), rice straw (R), rice straw plus chemical fertilizer nitrogen (NR), N and phosphorus (NPR), NP and potassium (NPKR), and reduced rice straw plus reduced NPK (L-NPKR). Significant shifts of the overall soil bacterial composition only occurred in the NPKR and L-NPKR treatments, with enrichment of certain groups including Bradyrhizobiaceae and Rhodospirillaceae families that benefit higher productivity. All fertilization treatments significantly altered the soil microbial functional structure with increased diversity and abundances of genes for carbon and nitrogen cycling, in which NPKR and L-NPKR exhibited the strongest effect, while R exhibited the least. Functional gene structure and abundance were significantly correlated with corresponding soil enzymatic activities and rice yield, respectively, suggesting that the structural shift of the microbial functional community under fertilization might promote soil nutrient turnover and thereby affect yield. Overall, this study indicates that the combined application of rice straw and balanced chemical fertilizers was more pronounced in shifting the bacterial composition and improving the functional diversity toward higher productivity, providing a microbial point of view on applying a cost-effective integrated fertilization regime with rice straw plus reduced chemical fertilizers for sustainable nutrient management. PMID- 29274059 TI - Alterations in anaerobic ammonium oxidation of paddy soil following organic carbon treatment estimated using 13C-DNA stable isotope probing. AB - In this study, soil samples from the typical rice-wheat cropping system in Jiangsu Province, China, subjected to different fertilizer application treatments no carbon (CK), urea (UR), straw (SR), pig manure (PM), starch (ST), and glucose (GL)-were used to determine potential anaerobic ammonium oxidation (anammox) rate and its association with bacterial abundance, diversity, and activity by using DNA stable isotope probing combined with 15N isotope tracing and molecular techniques. The effects of different organic carbon sources on anammox were significant, in the following order: GL > ST, SR > UR > PM; anammox activity differed significantly across treatments; however, the 13C active anammox bacteria were only closely related to Ca. Brocadia. The anammox hydrazine synthase beta subunit functional gene sequences were highly associated with the Candidatus genus Brocadia in PM and CK treatments. The different organic carbon sources had different inhibitory effects with anammox rate, which dropped from 3.19 to 1.04 nmol dinitrogen gas g-1 dry soil h-1 among treatments. About 4.2 22.3% of dinitrogen gas emissions were attributed to anammox and indicated that a specific population of anammox bacteria was present and varied with the addition of exogenous organic compounds in paddy soils, although a small part of dinitrogen gas was emitted from the soil via anammox. PMID- 29274060 TI - Biosynthesis of mono-acylated mannosylerythritol lipid in an acyltransferase gene disrupted mutant of Pseudozyma tsukubaensis. AB - The basidiomycetous yeast genus Pseudozyma produce large amounts of mannosylerythritol lipids (MELs), which are biosurfactants. A few Pseudozyma strains produce mono-acylated MEL as a minor compound using excess glucose as the sole carbon source. Mono-acylated MEL shows higher hydrophilicity than di acylated MEL and has great potential for aqueous applications. Recently, the gene cluster involved in the MEL biosynthesis pathway was identified in yeast. Here, we generated an acyltransferase (PtMAC2) deletion strain of P. tsukubaensis 1E5 with uracil auxotrophy as a selectable marker. A PtURA5-mutant with a frameshift mutation in PtURA5 was generated as a uracil auxotroph of strain 1E5 by ultraviolet irradiation on plate medium containing 5-fluoro-orotic acid (5-FOA). In the mutant, PtMAC2 was replaced with a PtURA5 cassette containing the 5' untranslated region (UTR) (2000 bp) and 3' UTR (2000 bp) of PtMAC2 by homologous recombination, yielding strain DeltaPtMAC2. Based on TLC and NMR analysis, we found that DeltaPtMAC2 accumulates MEL acylated at the C-2' position of the mannose moiety. These results indicate that PtMAC2p catalyzes acylation at the C 3' position of the mannose of MEL. PMID- 29274061 TI - TGFbeta signaling reinforces pericyte properties of the non-endocrine mouse pituitary cell line TtT/GF. AB - The non-endocrine TtT/GF mouse pituitary cell line was derived from radiothyroidectomy-induced pituitary adenoma. In addition to morphological characteristics, because the cells are S100beta-positive, they have been accepted as a model of folliculostellate cells. However, our recent microarray analysis indicated that, in contrast to folliculostellate cells, TtT/GF cells might not be terminally differentiated, as they share some properties with stem/progenitor cells, vascular endothelial cells and pericytes. The present study investigates whether transforming growth factor beta (TGFbeta) can elicit further differentiation of these cells. The results showed that canonical (Tgfbr1 and Tgfbr2) and non-canonical TGFbeta receptors (Tgfbr3) as well as all TGFbeta ligands (Tgfb1-3) were present in TtT/GF cells, based on reverse transcription PCR. SMAD2, an intercellular signaling molecule of the TGFbeta pathway, was localized in the nucleus upon TGFbeta signaling. Furthermore, TGFbeta induced cell colony formation, which was completely blocked by a TGFbeta receptor I inhibitor (SB431542). Real-time PCR analysis indicated that TGFbeta downregulated stem cell markers (Sox2 and Cd34) and upregulated pericyte markers (Nestin and Ng2). Double immunohistochemistry using mouse pituitary tissue confirmed the presence of NESTIN/NG2 double-positive cells in perivascular areas where pericytes are localized. Our results suggest that TtT/GF cells are responsive to TGFbeta signaling, which is associated with cell colony formation and pericyte differentiation. As pericytes have been shown to regulate angiogenesis, tumorigenesis and stem/progenitor cells in other tissues, TtT/GF cells could be a useful model to study the role of pituitary pericytes in physiological and pathological processes. PMID- 29274062 TI - Metformin, beta-cell development, and novel processes following beta-cell ablation in zebrafish. AB - PURPOSE: Type 1 and 2 diabetes are characterized by a loss of insulin-producing beta-cells. Current treatments help maintain blood glucose levels but cannot provide a cure. As such, a vital target for the cure of diabetes is a way to restore beta-cell mass. The drug metformin can protect cultured beta-cells/islets from hyperglycemia-induced dysfunction and death. Further, treatment of pregnant mice with metformin results in an enhanced beta-cell fraction in the embryos; however, whether this occurs via a direct effect is unknown. METHODS: We utilized the external embryogenesis of the zebrafish to determine the direct effect of metformin treatment on the pancreas of the developing embryo and following beta cell ablation. RESULTS: During development metformin did not alter beta-cell or alpha-cell mass but had a small effect to increase delta-cell mass as measured by in situ hybridization. Further metformin significantly increased beta-cell number. Following beta-cell ablation, both glucagon and somatostatin expression were upregulated (>2-fold). Additionally, while metformin showed no effect to alter beta-cell mass or number, somatostatin expression was further increased (>5 fold). CONCLUSIONS: We showed that direct exposure to metformin during embryogenesis does not increase insulin-expressing area but does increase beta cell number. Further, we identified novel consequences of beta-cell ablation to alter the expression of other pancreatic hormones that were enhanced by metformin. Therefore, this study provides a greater understanding of the beta cell development/regenerative processes and the effect of metformin, bringing us closer to identifying how to increase beta-cells in humans. PMID- 29274064 TI - Metabolic and bone effects of high-fat diet in adult zebrafish. AB - An increase of visceral fat affects human bone health causing fragility, mechanical strength reduction, and increased propensity to fractures because of impaired bone matrix microstructure and aberrant bone cell function. Adult Danio rerio (zebrafish) represents a powerful model to study both metabolic diseases and bone metabolism. The aim of this study was to generate an obese adult zebrafish by high-fat diet and evaluate metabolic and bone tissue effects. Fish blood glucose and insulin levels were found to be altered in high-fat diet fish revealing a failure in beta-cells insulin production. Blood analysis of adipokines revealed significant alterations in adiponectin and leptin levels that are common in human and other obesity animal models. Advanced glycation end products (AGEs), derived from hyperglycemia condition, were found to be altered too. All these alterations were associated with an impaired bone metabolism. The scales of high-fat diet fish shown bone resorption lacunae associated with an intense osteoclastic tartrate-resistant acid phosphatase (TRAP) activity, whereas alkaline phosphatase (ALP) decreased. These data suggest that an imbalance of fat metabolism alters energy metabolism generating an osteoporosis-like phenotype in adult zebrafish scales. The zebrafish obesity model can contribute to elucidate in vivo the molecular mechanisms of metabolic changes in human obese patients. PMID- 29274063 TI - Effects of growth hormone on thyroid function are mediated by type 2 iodothyronine deiodinase in humans. AB - PURPOSE: Growth hormone (GH) therapy in adults alters thyroid function, and acromegaly often involves thyroid disease. The present study aimed to elucidate roles and mechanisms of GH in regulating thyroid function. METHODS: We performed two retrospective observational studies, which focused on consecutive patients with severe adult GH deficiency who received recombinant human GH (rhGH) therapy (n = 20) and consecutive patients with acromegaly who underwent transsphenoidal surgery (TSS) (n = 25). In both studies, serum free triiodothyronine (fT3), free thyroxine (fT4), and fT3/fT4 ratio were examined before and after the interventions. We subsequently administered GH to four human cell lines (HepG2, TSA201, MCF7, and HTC/C3) in vitro, and examined changes in mRNA levels of iodothyronine deiodinases (D1, D2, and D3). RESULTS: Median serum fT3 level significantly increased after rhGH therapy from 2.38 to 2.78 pg/mL (p < 0.001), and fT4 decreased from 1.115 to 1.065 ng/dL (p = 0.081). TSS significantly decreased median serum fT3 from 3.03 to 2.53 pg/mL (p < 0.001), and increased fT4 from 1.230 to 1.370 ng/dL (p < 0.001). In vitro, GH significantly increased D2 expression at the mRNA level in HTC/C3 cells (p < 0.01), as well as D2 protein and its activity. CONCLUSIONS: GH increased serum fT3 level and decreased serum fT4 level in humans. Our results suggest that its mechanism involves D2 upregulation. Considering this GH effect on thyroid hormone metabolism, data on thyroid function could be useful in the management of GH deficiency and acromegaly. PMID- 29274065 TI - Reply to letter to the editor "Blood pressure variability in primary hyperparathyroidism: more data needed". PMID- 29274066 TI - Dynamical heterogeneities and mechanical non-linearities: Modeling the onset of plasticity in polymer in the glass transition. AB - In this paper we focus on the role of dynamical heterogeneities on the non-linear response of polymers in the glass transition domain. We start from a simple coarse-grained model that assumes a random distribution of the initial local relaxation times and that quantitatively describes the linear viscoelasticity of a polymer in the glass transition regime. We extend this model to non-linear mechanics assuming a local Eyring stress dependence of the relaxation times. Implementing the model in a finite element mechanics code, we derive the mechanical properties and the local mechanical fields at the beginning of the non linear regime. The model predicts a narrowing of distribution of relaxation times and the storage of a part of the mechanical energy --internal stress-- transferred to the material during stretching in this temperature range. We show that the stress field is not spatially correlated under and after loading and follows a Gaussian distribution. In addition the strain field exhibits shear bands, but the strain distribution is narrow. Hence, most of the mechanical quantities can be calculated analytically, in a very good approximation, with the simple assumption that the strain rate is constant. PMID- 29274067 TI - Perceived Benefits of Participation and Risks of Soil Contamination in St. Louis Urban Community Gardens. AB - Community gardens are credited for promoting health within neighborhoods, by increasing healthy food intake and exercise frequency. These benefits, however, are potentially undermined as urban soils are often contaminated from industrial legacies. The purpose of this study was to examine the perceived benefits of participation and risks of soil contamination within urban community gardens, and factors associated with soil contamination concerns. Ninety-three gardeners were interviewed across 20 community gardens in St. Louis, Missouri between June and August 2015. Surveys included questions on demographics, gardening practices, and perceptions of community gardening. Multilevel logistic models assessed how gardener demographics, gardening practices, and garden characteristics were associated with soil contamination concerns. Common perceived benefits of community gardening were community building (68.8%), healthy and fresh food (35.5%), and gardening education (18.3%). Most gardeners (62.4%) were not concerned about soil contamination, but nearly half (48.4%) stated concerns about heavy metals. Black race was significantly associated with soil contamination concerns (OR 5.47, 95% CI 1.00-30.15, p = .04). Community gardens offer numerous social and health benefits. Although most gardeners were not concerned about soil contamination, black gardeners were more likely to have concerns. Garden leaders should provide resources to gardeners to learn about soil contamination and methods to manage their risk, particularly in minority neighborhoods. PMID- 29274068 TI - Individual Supervision to Enhance Reflexivity and the Practice of Patient Centered Care: Experience at the Undergraduate Level. AB - This article reports on what is at work during individual supervision of medical students in the context of teaching breaking bad news (BBN). Surprisingly, there is a relative lack of research and report on the topic of supervision, even though it is regularly used in medical training. Building on our research and teaching experience on BBN at the undergraduate level, as well as interviews of supervisors, the following key elements have been identified: learning objectives (e.g., raising student awareness of structural elements of the interview, emotion (patients and students) handling), pedagogical approach (being centered on student's needs and supportive to promote already existing competences), essentials (e.g., discussing skills and examples from the clinical practice), and enhancing reflexivity while discussing specific issues (e.g., confusion between the needs of the patient and those of the student). Individual supervision has been identified as crucial and most satisfactory by students to provide guidance and to foster a reflexive stance enabling them to critically apprehend their communication style. Ultimately, the challenge is to teach medical students to not only connect with the patient but also with themselves. PMID- 29274069 TI - New Horizons. PMID- 29274070 TI - The Combined Effect of Temperature and Host Clonal Line on the Microbiota of a Planktonic Crustacean. AB - Host-associated microbiota vary across host individuals and environmental conditions, but the relative importance of their genetic background versus their environment is difficult to disentangle. We sought to experimentally determine the factors shaping the microbiota of the planktonic Crustacean, Daphnia magna. We used clonal lines from a wide geographic distribution, which had been kept under standardized conditions for over 75 generations. Replicate populations were kept for three generations at 20 and 28 degrees C. The interaction of the host clonal line and environment (i.e., temperature) influenced microbiota community characteristics, including structure, the relative abundance of common microbial species, and the microbial richness and phylogenetic diversity. We did not find any correlation between host-associated microbiota and the geographic origin of the clones or their temperature tolerance. Our results highlight the prominent effects that host clonal lineage and its interaction with the environment has on host-associated microbiota composition. PMID- 29274071 TI - Genome-wide association analysis of lead accumulation in maize. AB - Large phenotypic variations in the lead (Pb) concentration were observed in grains and leaves of maize plants. A further understanding of inheritance of Pb accumulation may facilitate improvement of low-Pb-accumulating cultivars in maize. A genome-wide association study was conducted in a population of 269 maize accessions with 43,737 single-nucleotide polymorphisms (SNPs). The Pb concentrations in leaves and kernels of 269 accessions were collected in pot culture and field experiments in years of 2015 and 2016. Significant differences in Pb accumulation were found among individuals under different environments. Using the structure and kinship model, a total of 21 SNPs significantly associated with the Pb accumulation were identified with P < 2.28 * 10-5 and FDR < 0.05 in the pot-culture and field experiments across 2 years. Three SNPs on chromosome 4 had significant associations simultaneously with the Pb concentrations of kernels and leaves and were co-localized with the previously detected quantitative trait loci. Through ridge regression best linear unbiased prediction Pb accumulation in the association population, the prediction accuracies by cross validation were 0.18-0.59 and 0.17-0.64, depending on the k fold and the size of the training population. The results are helpful for genetic improvement and genomic prediction of Pb accumulation in maize. PMID- 29274072 TI - Simulation of phase separation with temperature-dependent viscosity using lattice Boltzmann method. AB - This paper presents an exploration of the phase separation behavior and pattern formation in a binary fluid with temperature-dependent viscosity via a coupled lattice Boltzmann method (LBM). By introducing a viscosity-temperature relation into the LBM, the coupling effects of the viscosity-temperature coefficient [Formula: see text] , initial viscosity [Formula: see text] and thermal diffusion coefficient [Formula: see text] , on the phase separation were successfully described. The calculated results indicated that an increase in initial viscosity and viscosity-temperature coefficient, or a decrease in the thermal diffusion coefficient, can lead to the orientation of isotropic growth fronts over a wide range of viscosity. The results showed that droplet-type phase structures and lamellar phase structures with domain orientation parallel or perpendicular to the walls can be obtained in equilibrium by controlling the initial viscosity, thermal diffusivity, and the viscosity-temperature coefficient. Furthermore, the dataset was rearranged for growth kinetics of domain growth and thermal diffusion fronts in a plot by the spherically averaged structure factor and the ratio of separated and continuous phases. The analysis revealed two different temporal regimes: spinodal decomposition and domain growth stages, which further quantified the coupled effects of temperature and viscosity on the evolution of temperature-dependent phase separation. These numerical results provide guidance for setting optimum temperature ranges to obtain expected phase separation structures for systems with temperature-dependent viscosity. PMID- 29274073 TI - Investigation of the Use of a Family Health History Application in Genetic Counseling. AB - The paper-based pedigree is the current standard for family health history (FHH) documentation in genetic counseling. Several tools for electronic capture of family health data have been developed to improve re-use and accessibility, data quality and standardization, ease of updating, and integration with electronic medical records. One such tool, the tablet-based Proband application, provides a flexible approach to data capture in dynamic and diverse clinical settings. This study compared Proband FHH collection to paper-based methods and investigated the usability of Proband in a clinical setting. After one use by 23 genetic counselors and students, Proband had 91% accuracy with a FHH audio scenario, which was significantly less (p < 0.001) than paper's 96% accuracy. These differences were attributed to incorrect or missing ages of grandparents (p < 0.001) and great-aunts/uncles (p = 0.012) and missing documentation of consanguinity (p < 0.001). Possible explanations for these differences include greater experience with paper FHH documentation and pre-populated prompts for consanguinity on the paper template used. Proband's perceived usability increased with use, with individual System Usability Scores increasing between first and last use (p = 0.033). We conclude that tools for dynamic, provider-driven FHH documentation such as Proband show promise for improving risk assessment accuracy and quality patient care. PMID- 29274074 TI - Evaluation of Subclinical Atherosclerosis by Ultrasound Radiofrequency Data Technology in Patients With Familial Mediterranean Fever. AB - OBJECTIVES: The aim of this study was to noninvasively demonstrate the presence of early risk associated with subclinical inflammatory activity in patients with familial Mediterranean fever (FMF) who had stable disease, using ultrasound (US) radiofrequency data technology. METHODS: A total of 110 participants, including 55 patients with FMF and 55 healthy control participants, were evaluated with Doppler US. The intima-media thickness and arterial stiffness were measured from bilateral common carotid arteries (CCAs) by the radiofrequency method. RESULTS: No statistically significant difference was found between the patients with FMF and controls in terms of the right and left CCA intima-media thickness, distensibility coefficient, compliance coefficient, alpha and beta stiffness indices, and pulsed wave velocity (P > .05). Symptom duration and diagnosis and treatment time of the patients with FMF had a negative correlation with the distensibility and compliance measurements obtained by Doppler US (r = -0.324 and -0.303), and a positive (r = 0.380 and 0.339) and statistically significant relationship was detected between the alpha stiffness index, beta stiffness index, and pulsed wave velocity (P < .05). CONCLUSIONS: Common carotid artery intima-media thickness and arterial stiffness measurements can aid in early prediction of cardiovascular disease development in patients with FMF. Radiofrequency data technology provides a noninvasive method for accurately and quantitatively showing the CCA intima-media thickness elevation and the decrease in vascular elasticity in patients with FMF. PMID- 29274076 TI - Novel POFUT1 mutation associated with hidradenitis suppurativa-Dowling-Degos disease firm up a role for Notch signalling in the pathogenesis of this disorder: reply from the authors. PMID- 29274075 TI - Optogenetic dissection of roles of specific cortical interneuron subtypes in GABAergic network synchronization. AB - KEY POINTS: An increase in the excitability of GABAergic cells has typically been assumed to decrease network activity, potentially producing overall anti epileptic effects. Recent data suggest that inhibitory networks may actually play a role in initiating epileptiform activity. We show that activation of GABAergic interneurons can elicit synchronous long-lasting network activity. Specific interneuron subpopulations differentially contributed to GABA network synchrony, indicating cell type-specific contributions of interneurons to cortical network activity. Interneurons may critically contribute to the generation of aberrant network activity characteristic of epilepsy, warranting further investigation into the contribution of distinct cortical interneuron subpopulations to the propagation and rhythmicity of epileptiform activity. ABSTRACT: In the presence of the A-type K+ channel blocker 4-aminopyrdine, spontaneous synchronous network activity develops in the neocortex of mice of either sex. This aberrant synchrony persists in the presence of excitatory amino acid receptor antagonists (EAA blockers) and is considered to arise from synchronous firing of cortical interneurons (INs). Although much attention has been given to the mechanisms underlying this GABAergic synchrony, the contribution of specific IN subtypes to the generation of these long-lasting discharges (LLDs) is incompletely understood. We employed genetically-encoded channelrhodopsin and archaerhodopsin opsins to investigate the sufficiency and necessity, respectively, of activation of parvalbumin (PV), somatostatin (SST) and vasointestinal peptide (VIP) expressing INs for the generation of synchronous neocortical GABAergic discharges. We found light-induced activation of PV or SST INs to be equally sufficient for the generation of LLDs, whereas activation of VIP INs was not. By contrast, light-induced inhibition of PV INs strongly reduced LLD initiation, whereas suppression of SST or VIP IN activity only partially attenuated LLD magnitude. These results suggest neocortical INs perform cell type-specific roles in the generation of aberrant GABAergic cortical network activity. PMID- 29274078 TI - The Pathologic Patterns Detectable by Transthoracic Ultrasonography Are Only the Pleural and Subpleural Ones and Are Not Specific: Why Compare Them With High Resolution Computed Tomography? PMID- 29274077 TI - Increasing T-type calcium channel activity by beta-adrenergic stimulation contributes to beta-adrenergic regulation of heart rates. AB - KEY POINTS: Cav3.1 T-type Ca2+ channel current (ICa-T ) contributes to heart rate genesis but is not known to contribute to heart rate regulation by the sympathetic/beta-adrenergic system (SAS). We show that the loss of Cav3.1 makes the beating rates of the heart in vivo and perfused hearts ex vivo, as well as sinoatrial node cells, less sensitive to beta-adrenergic stimulation; it also renders less conduction acceleration through the atrioventricular node by beta adrenergic stimulation. Increasing Cav3.1 in cardiomyocytes has the opposite effects. ICa-T in sinoatrial nodal cells can be upregulated by beta-adrenergic stimulation. The results of the present study add a new contribution to heart rate regulation by the SAS system and provide potential new mechanisms for the dysregulation of heart rate and conduction by the SAS in the heart. T-type Ca2+ channel can be a target for heart disease treatments that aim to slow down the heart rate ABSTRACT: Cav3.1 (alpha1G ) T-type Ca2+ channel (TTCC) is expressed in mouse sinoatrial node cells (SANCs) and atrioventricular (AV) nodal cells and contributes to heart rate (HR) genesis and AV conduction. However, its role in HR regulation and AV conduction acceleration by the beta-adrenergic system (SAS) is unclear. In the present study, L- (ICa-L ) and T-type (ICa-T ) Ca2+ currents were recorded in SANCs from Cav3.1 transgenic (TG) and knockout (KO), and control mice. ICa-T was absent in KO SANCs but enhanced in TG SANCs. In anaesthetized animals, different doses of isoproterenol (ISO) were infused via the jugular vein and the HR was recorded. The EC50 of the HR response to ISO was lower in TG mice but higher in KO mice, and the maximal percentage of HR increase by ISO was greater in TG mice but less in KO mice. In Langendorff-perfused hearts, ISO increased HR and shortened PR intervals to a greater extent in TG but to a less extent in KO hearts. KO SANCs had significantly slower spontaneous beating rates than control SANCs before and after ISO; TG SANCs had similar basal beating rates as control SANCs probably as a result of decreased ICa-L but a greater response to ISO than control SANCs. ICa-T in SANCs was significantly increased by ISO. ICa T upregulation by beta-adrenergic stimulation contributes to HR and conduction regulation by the SAS. TTCC can be a target for slowing the HR. PMID- 29274079 TI - Bioinformatics for dermatology: why we should learn about code. PMID- 29274080 TI - Observational Study Using Ultrasound to Assess Midline Labor Epidural Analgesia Placement and Analgesic Efficacy. AB - OBJECTIVES: Labor epidural analgesia failure may relate to nonmidline placement of epidural catheters. We hypothesized that greater deviations of the epidural catheter insertion point from the ultrasound (US)-determined midline would be associated with less effective labor analgesia. METHODS: A prospective ethically approved cohort study was conducted. Fifty-two healthy average-sized women receiving labor epidural analgesia, inserted by the landmark technique, were approached after delivery. Immediately after removing the epidural catheter, we determined the epidural space midline using US and compared it to the epidural catheter insertion point and to the patient-identified midline (assessed by a pinprick in 1-mm increments). Correlations between the US midline-to-catheter insertion point distance and additional epidural local anesthetic requirements (primary outcome), pain verbal numeric rating scale scores (0-10) 1 hour after epidural insertion, and maternal satisfaction with analgesia were determined. The differences in distances were assessed by a Bland-Altman analysis. RESULTS: There were no significant correlations between the US midline-to-epidural catheter insertion point distance and additional epidural local anesthetic requirements (R2 = 0.138; P = .33), pain verbal numeric rating scale scores 1 hour after the epidural (R2 = 0.121; P = .40) or maternal satisfaction (R2 = 0.085; P = .57). The Bland-Altman analysis revealed that the mean +/- SD US midline-to-epidural catheter insertion point distance and patient-identified midline distances were 0.38 +/- 0.31 and 0.35 +/- 0.46 cm, respectively. CONCLUSIONS: In our laboring population, the hypothesis that nonmidline epidural insertion is associated with less-effective labor analgesia was not confirmed in this study cohort. We found minimal differences in distances between the US midline to epidural catheter insertion point and US midline to patient-identified midline. PMID- 29274081 TI - Normative Values for Tonsils in Pediatric Populations Based on Ultrasonography. AB - OBJECTIVES: Pediatric tonsillar infections are common, particularly in adolescents. Ultrasonography (US) has high sensitivity and specificity for diagnosing peritonsillar abscesses and can diagnose tonsillitis by enlargement of the gland. In this study, we established normal tonsillar measurements and volumes according to age in pediatric populations. METHODS: Transcervical US of the peritonsillar region to measure tonsillar size and volume was performed in patients who had undergone neck US without throat symptoms from October 2016 to May 2017. Transverse and anteroposterior diameters, length, and volume were measured. RESULTS: In total, 161 patients (age range, 1 month-18 years) were enrolled in the study. The mean tonsillar volumes +/- SD were 1.58 +/- 1.26 (total), 0.30 +/- 0.14 (<1 year), 1.27 +/- 0.57 (1-<5 years), 2.06 +/- 1.09 (5 <10 years), and 2.19 +/- 1.48 (>10 years) cm3 . Mean measurements for the sums of both tonsils for the transverse diameter, anteroposterior diameter, and length were 1.98 +/- 0.61, 2.17 +/- 0.66, and 2.28 +/- 0.69 cm, respectively. Tonsillar size and volume increased according to age. Simplified models for volume estimation showed that anteroposterior diameters had the highest coefficients of determination (R2 = 0.71 and 0.74). Regression models for the tonsillar volume of 6 measurements in the multiple linear regression models showed an R2 of 0.89. Regression models for log(volume) showed an improved coefficient of determination (R2 = 0.96). CONCLUSIONS: These normal tonsillar sizes on transcervical ultrasound in pediatric patients can be used to diagnose tonsillar lesions. PMID- 29274082 TI - Understanding patient engagement in psoriasis treatment. PMID- 29274083 TI - Different views of dentists and general medical practitioners on dental care for patients with diabetes mellitus and coronary heart diseases: results of a questionnaire-based survey in a district of Germany. AB - BACKGROUND: The aim of this questionnaire-based study was to evaluate the views of dentists (Ds) and general medical practitioners (GPs) on different aspects of dental care for patients with diabetes mellitus (DM) or coronary heart disease (CHD). METHODS: Reliable and comparable questionnaires for Ds and GPs, with 23 questions, were sent to 1,000 randomly selected Ds and 1,000 randomly selected GPs. Questions were asked about patients with DM or CHD regarding their dental care and potentially related issues (e.g. antibiotic prophylaxis). The responses received within 12 weeks were evaluated and statistically analysed using chi square and Mann-Whitney U tests (P < 0.05). RESULTS: The response rate was 39% (n = 391) for Ds and 18% (n = 181) for GPs. Both groups stated that they used the medical history as well as patient interviews to assess patients. However, only 55% of Ds assumed correct identification of every at-risk patient compared with 100% of GPs (P < 0.01). Furthermore, Ds speculated that they inform their patients more often about their at-risk status than do GPs (P < 0.01). Neither Ds nor GPs appeared to be confident in their knowledge about adequate antibiotic prophylaxis. Interdisciplinary collaboration was considered insufficient, although Ds had a higher rate of regular collaboration (68% for Ds vs. 40% for GPs; P < 0.01). CONCLUSION: Ds and GPs have differing views on dental care of patients with DM or CHD, and Ds showed more interest in this issue. These results might partially explain the insufficient collaboration between Ds and GPs. PMID- 29274084 TI - Reply. PMID- 29274085 TI - 'I guess I do have to take back what I said before, about television': pregnant women's understandings and use of televisual representations of childbearing. AB - Research on television as a source of childbearing information is divided on its importance. Drawing from a sample of 64 pregnant women in the greater New York and Connecticut metropolitan area, we examine how women understand the influence of television on their expectations for pregnancy and birth. A sizable minority (44%) regularly watched reality television programmes on childbearing; all engaged in active viewing practices, such as recognising programme formula and evaluating plausibility of depictions. We find clear educational differences in how viewers believed television influenced their pregnancy knowledge: women with higher levels of education generally disavowed all television as an information source, but used reality programming to educate their children about pregnancy and for entertainment. Women who had lower educational attainment were more likely to include reality programmes as part of their comprehensive approach to information gathering. Only one woman asserted that fictional television was a good source of pregnancy information. Although many devalued television, women referenced television programmes and imagery as they described their expectations and concerns for pregnancy. A large proportion of respondents were unaware of the influence television exerted on them. Health scholars must better engage with the complexities of media use. PMID- 29274086 TI - How Well Are We Applying Quantitative Methods to Reverse Translation to Inform Early Clinical Development? AB - If we are to improve our low success rate and rising costs in the pharmaceutical industry, we need to use every tool available. Reverse translation can particularly inform discovery and early clinical development via appropriate quantitative integration of relevant data. This commentary reports on a crowd sourced survey (2017) that sought to evaluate the integration of reverse translation in pharma. The results indicate that these methods are being applied, to varying degrees, across most respondents. PMID- 29274087 TI - Human enteric viruses in a wastewater treatment plant: evaluation of activated sludge combined with UV disinfection process reveals different removal performances for viruses with different features. AB - : This study assess the quality of wastewater through the detection and quantification of important viruses causing gastroenteritis at different stages of the wastewater treatment process in an activated-sludge wastewater treatment plant with ultraviolet disinfection. Ten sampling events were carried out in a campaign along a period of 18 months collecting wastewater samples from the influent, after the activated-sludge treatment, and after the final disinfection with UV radiation. Samples were concentrated through ultracentrifugation and analysed using retro-transcription, PCR and real time quantitative PCR protocols, for detection and quantification of Group A Rotavirus (RVA), Human Astrovirus (HAstV), Norovirus Genogroup II (NoV GII) and Human Adenovirus (HAdV). HAdV (100%), NoV GII (90%), RVA (70%) and HAstV (60%) were detected in influent samples with concentration from 1.4 (NoV GII) to 8.0 (RVA) log10 gc l-1 . Activated-sludge treatment reached well quality effluents with low organic material concentration, although nonstatistical significant differences were registered among influent and postactivated sludge treatment samples, regarding the presence and concentration for most viruses. All post-UV samples were negative for NoV GII and HAstV, although RVA and HAdV were detected in 38% and 63% of those samples respectively, with concentration ranging from 2.2 to 5.5 and 3.1 to 3.4 log10 gc l-1 . SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that an activated-sludge wastewater treatment plant with UV disinfection reduces to levels below the detection limit those single-stranded RNA viruses as noroviruses and astroviruses and reach significant lower levels of rotaviruses and adenoviruses after the complete treatment process. PMID- 29274088 TI - Autopsy and biopsy study of paracoccidioidomycosis and neuroparacoccidioidomycosis with and without HIV co-infection. AB - Paracoccidioidomycosis (PCM) is a systemic mycosis prevalent among immunocompetent patients in Latin America. This study aimed to describe the frequency, demographics and clinical characteristics of central nervous system PCM (NPCM) and PCM in an endemic region, and the impact of human immunosuppression virus (HIV) co-infection. This was a retrospective study of autopsy and biopsy reports from the Medical Pathology Section of the Hospital de Clinicas, UFPR, Curitiba, Southern Brazil, between 1951 and 2014. PCM was present in 0.1% of 378,323 cases examined, with 5.7% being NPCM. Infection was prevalent in working-age men, agricultural workers and rural residents. Numbers of HIV autopsy cases increased over time, while those of PCM cases decreased. Prevalence of co-infection of HIV/PCM and HIV/NPCM was 1.6%, and 0.4%, respectively. Adrenals were affected more frequently in the NPCM group compared with the PCM group. Mortality was higher on NPCM group. The clinical course of PCM in HIV patients resembles an acute/sub-acute infection. Association of NPCM and HIV is rare, while diagnosis of NPCM is difficult, it should be considered a differential diagnosis in HIV patients who live in, or have visited, endemic areas and present with neurological symptoms. PMID- 29274089 TI - Intestinal microbiome analysis revealed dysbiosis in sickle cell disease. PMID- 29274090 TI - Case of femoral pseudarthrosis due to Scedosporium apiospermum in an immunocompetent patient with successful conservative treatment and review of literature. AB - Scedosporium apiospermum is a ubiquitous filamentous fungus, commonly found in soil, sewage and polluted waters. It is rarely pathogenic but can cause a broad spectrum of clinical diseases, which can be localised or disseminate to distant organs. The disseminated form of the disease is mostly seen among immunocompromised patients. However, some rare cases of disseminated disease have been reported in immunocompetent individuals. Treatment of these infections is challenging because of their natural resistance to many antifungal agents. Here, we report the case of a 57-year-old immunocompetent patient diagnosed with femoral pseudarthrosis due to S. apiospermum, despite having no obvious clinical sign of infection. Previously, the patient had undergone four iterative femoral surgeries following a road traffic accident which occurred 20 years before. During its last surgery for pseudarthrosis, no clinical or biological signs of infection were present. Per operative samples tested positive for S. apiospermum. The patient was successfully treated with oral voriconazole during 6 months with an excellent tolerance. We also provide a review of literature on bone and joint infections due to Scedosporium spp. (S. apiospermum, Scedosporium boydii and Scedosporium aurantiacum), discussing the evolution of their management and outcome which seems to improve since the use of voriconazole. PMID- 29274091 TI - Prognostic impact of bone marrow fibrosis and dyserythropoiesis in autoimmune hemolytic anemia. PMID- 29274092 TI - Insulinoma-associated protein 1 (INSM1) differentiates carcinoid tumourlets of the lung from pulmonary meningothelial-like nodules. PMID- 29274093 TI - Interactions between Candida albicans and Candida glabrata in biofilms: Influence of the strain type, culture medium and glucose supplementation. AB - The relationship among Candida species may be influenced by several factors. Thus, this study evaluated the interactions between Candida albicans and Candida glabrata in biofilms, varying the strain type, culture medium and glucose supplementation. Biofilms were formed for 48 hours in Sabouraud dextrose broth (SDB) or RPMI 1640, supplemented with 0%, 1% or 5% glucose. Each strain of C. albicans was combined with two strains of C. glabrata, generating four biofilm associations, which were quantified by colony-forming units (CFUs), total biomass and metabolic activity. Data were analysed by ANOVA and Tukey's HSD test (alpha = 0.05). For CFUs, all associations were classified as indifferent for biofilms formed in RPMI 1640, while for SDB the interactions were antagonistic for C. albicans and indifferent for C. glabrata. The association of reference strains resulted in a dual-species biofilm with biomass significantly higher than that observed for each single biofilm developed in SDB. The metabolic activity of dual species biofilms did not significantly differ from that found for single ones, except for co-culture of the reference strains. Glucose supplementation and culture media had a significant influence on all parameters. In conclusion, the strain type, culture medium and glucose supplementation influenced the interactions between C. albicans and C. glabrata. PMID- 29274094 TI - Folliculotropism in pigmented facial macules: Differential diagnosis with reflectance confocal microscopy. AB - Pigmented facial macules are common on sun damage skin. The diagnosis of early stage lentigo maligna (LM) and lentigo maligna melanoma (LMM) is challenging. Reflectance confocal microscopy (RCM) has been proven to increase diagnostic accuracy of facial lesions. A total of 154 pigmented facial macules, retrospectively collected, were evaluated for the presence of already-described RCM features and new parameters depicting aspects of the follicle. Melanocytic nests, roundish pagetoid cells, follicular infiltration, bulgings from the follicles and many bright dendrites and infiltration of the hair follicle (ie, folliculotropism) were found to be indicative of LM/LMM compared to non melanocytic skin neoplasms (NMSNs), with an overall sensitivity of 96% and specificity of 83%. Concerning NMSNs, solar lentigo and lichen planus-like keratosis resulted better distinguishable from LM/LMM because usually lacking malignant features and presenting characteristic diagnostic parameters, such as epidermal cobblestone pattern and polycyclic papillary contours. On the other hand, distinction of pigmented actinic keratosis (PAK) resulted more difficult, and needing evaluation of hair follicle infiltration and bulging structures, due to the frequent observation of few bright dendrites in the epidermis, but predominantly not infiltrating the hair follicle (estimated specificity for PAK 53%). A detailed evaluation of the components of the folliculotropism may help to improve the diagnostic accuracy. The classification of the type, distribution and amount of cells, and the presence of bulging around the follicles seem to represent important tools for the differentiation between PAK and LM/LMM at RCM analysis. PMID- 29274097 TI - Photovoltaic Devices Prepared through a Trihydroxy Substitution Strategy on an Unsymmetrical Squaraine Dye. AB - A series of unsymmetrical arene-1,3-squaraine (USQ) derivatives with two, three, or four hydroxy (-OH) substituents, namely, USQ-2-OH, USQ-3-OH, or USQ-4-OH, respectively, were designed and synthesized, and the effect of the number of hydroxy groups on the optoelectronic properties of USQs were investigated. Despite the three compounds having similar UV/Vis absorption and HOMO energy levels, solution-processed bulk-heterojunction (BHJ) small-molecule organic solar cells with USQ-3-OH as electron-donor materials exhibit the highest power conversion efficiency of 6.07 %, which could be mainly attributed to the higher hole mobility and smaller phase separation. It is also noteworthy that the short circuit current (Jsc ) of the USQ-3-OH-based device is as high as 14.95 mA cm-2 , which is the highest Jsc values reported for squaraine-based BHJ solar cells to date. The results also indicate that more -OH substituents on squaraine dyes do not necessarily lead to better photovoltaic performance. PMID- 29274095 TI - Alterations in CA1 hippocampal synapses in a mouse model of fragile X syndrome. AB - Fragile X Syndrome (FXS) is the major cause of inherited mental retardation and the leading genetic cause of Autism spectrum disorders. FXS is caused by mutations in the Fragile X Mental Retardation 1 (Fmr1) gene, which results in transcriptional silencing of Fragile X Mental Retardation Protein (FMRP). To elucidate cellular mechanisms involved in the pathogenesis of FXS, we compared dendritic spines in the hippocampal CA1 region of adult wild-type (WT) and Fmr1 knockout (Fmr1-KO) mice. Using diolistic labeling, confocal microscopy, and three dimensional electron microscopy, we show a significant increase in the diameter of secondary dendrites, an increase in dendritic spine density, and a decrease in mature dendritic spines in adult Fmr1-KO mice. While WT and Fmr1-KO mice had the same mean density of spines, the variance in spine density was three times greater in Fmr1-KO mice. Reduced astrocyte participation in the tripartite synapse and less mature post-synaptic densities were also found in Fmr1-KO mice. We investigated whether the increase in synaptic spine density was associated with altered synaptic pruning during development. Our data are consistent with reduced microglia-mediated synaptic pruning in the CA1 region of Fmr1-KO hippocampi when compared with WT littermates at postnatal day 21, which is the peak period of synaptic pruning in the mouse hippocampus. Collectively, these results support abnormal synaptogenesis and synaptic remodeling in mice deficient in FMRP. Deficits in the maturation and distribution of synaptic spines on dendrites of CA1 hippocampal neurons may play a role in the intellectual disabilities associated with FXS. PMID- 29274096 TI - Developmental differences between neonatal and adult human erythropoiesis. AB - Studies of human erythropoiesis have relied, for the most part, on the in vitro differentiation of hematopoietic stem and progenitor cells (HSPC) from different sources. Here, we report that despite the common core erythroid program that exists between cord blood (CB)- and peripheral blood (PB)-HSPC induced toward erythroid differentiation in vitro, significant functional differences exist. We undertook a comparative analysis of human erythropoiesis using these two different sources of HSPC. Upon in vitro erythroid differentiation, CB-derived cells proliferated 4-fold more than PB-derived cells. However, CB-derived cells exhibited a delayed kinetics of differentiation, resulting in an increased number of progenitors, notably colony-forming unit (CFU-E). The phenotypes of early erythroid differentiation stages also differed between the two sources with a significantly higher percentage of IL3R- GPA- CD34+ CD36+ cells generated from PB than CB-HSPCs. This subset was found to generate both burst-forming unit (BFU-E) and CFU-E colonies in colony-forming assays. To further understand the differences between CB- and PB-HSPC, cells at eight stages of erythroid differentiation were sorted from each of the two sources and their transcriptional profiles were compared. We document differences at the CD34, BFU E, poly- and orthochromatic stages. Genes exhibiting the most significant differences in expression between HSPC sources clustered into cell cycle- and autophagy-related pathways. Altogether, our studies provide a qualitative and quantitative comparative analysis of human erythropoiesis, highlighting the impact of the developmental origin of HSPCs on erythroid differentiation. PMID- 29274098 TI - Epstein-Barr virus exanthem in an adult patient with myelodysplastic syndrome. PMID- 29274099 TI - Effects of celastrol on Tau hyperphosphorylation and expression of HSF-1 and HSP70 in SH-SY5Y neuroblastoma cells induced by amyloid-beta peptides. AB - To observe the effects of celastrol on Tau hyperphosphorylation induced by amyloid-beta peptides (Abeta) in SH-SY5Y neuroblastoma cells, the changes of Tau hyperphosphorylation and the expression of heat shock protein 90 (HSP90), HSP70, and heat shock factor 1 (HSF-1) in SH-SY5Y cells treated with Abeta1-42 and celastrol were measured. Tau hyperphosphorylation and HSP90 expression induced by Abeta1-42 was also measured by Western blotting after HSP70 or HSF-1 knockdown by siRNA. The interaction between HSP70 and Tau or HSP70 and carboxyl terminus of HSP70 interacting protein (CHIP) was measured by co-immunoprecipitation. Compared with the control group, the expressions of HSP70 and HSF-1 were markedly decreased after the induction of Abeta1-42 , whereas the expressions of HSP90, Tau phospho S199/202, and Tau phospho S396 were markedly increased. Meanwhile, both celastrol treatment and knockdown of HSP70 or HSF-1 in SH-SY5Y cells significantly inhibited the Tau hyperphosphorylation and HSP90 expression induced by Abeta1-42 . Moreover, celastrol treatment had no effects on Abeta1-42 -induced decreased expression of HSP70 and HSF-1, Tau ubiquitination, and the interaction of HSP70/Tau and HSP70/CHIP. These results suggest that celastrol- inhibited Tau hyperphosphorylation may not be dependent on the cause of HSF-1/HSP70/CHIP mediated ubiquitination of Tau. PMID- 29274100 TI - Population exposure-safety analysis of cediranib for Phase I and II studies in patients with cancer. AB - AIMS: A multistudy analysis of cediranib, a potent, selective inhibitor of all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), was conducted to establish population exposure-safety models for the relationship of cediranib exposure to the safety endpoints, diastolic and systolic blood pressure (DBP and SBP) and diarrhoea in cancer patients. These models were applied to predict safety outcomes for different cediranib dose regimens. METHODS: Models for hypertension and diarrhoea were constructed based on data from 10 Phase I and three Phase II studies comprising 631 cancer patients following cediranib once daily oral dosing. Daily DBP and SBP were simultaneously characterized using indirect response models for predicted cediranib concentration-time courses, while daily diarrhoea events were modelled as ordered categorical variables with a proportional odds model with a Markov element for predicted average cediranib concentrations. RESULTS: For 20 mg cediranib once-daily oral administration, the mean increase in DBP and SBP was predicted to be 7 (95% CI 3-13) and 8 mmHg (95% CI 3-16), respectively, while the probability of mild diarrhoea, but not the severity, was predicted to increase over time. Severe diarrhoea was predicted to be resolved rapidly upon discontinuation of cediranib treatment. CONCLUSIONS: Maximum blood pressure increase was observed within the first few days of cediranib treatment, consistent with the pharmacokinetic profile of cediranib reaching steady state in about 5 days. The probability of diarrhoea increased with cediranib concentration but was far more dependent on the status of diarrhoea predicted on the previous day. PMID- 29274101 TI - Printing inks of electroactive polymer PEDOT:PSS: The study of biocompatibility, stability, and electrical properties. AB - Biocompatibility tests and a study of the electrical properties of thin films prepared from six electroactive polymer ink formulations based on poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) were performed. The aim was to find a suitable formulation of PEDOT:PSS and conditions for preparing thin films in order to construct printed bioelectronic devices for biomedical applications. The stability and electrical properties of such films were tested on organic electrochemical transistor (OECT)-based sensor platforms and their biocompatibility was evaluated in assays with 3T3 fibroblasts and murine cardiomyocytes. It was found that the thin films prepared from inks without an additive or any thin film post-treatment provide limited conductivity and stability for use in biomedical applications. These properties were greatly improved by using ethylene glycol and thermal annealing. Addition or post treatment by ethylene glycol in combination with thermal annealing provided thin films with electrical resistance and a stability sufficient to be used in sensing of animal cell physiology. These films coated with collagen IV showed good biocompatibility in the assay with 3T3 fibroblasts when compared to standard cell culture plastics. Selected films were then used in assays with murine cardiomyocytes. We observed that these cells were able to attach to the PEDOT:PSS films and form an active sensor element. Spontaneously beating clusters were formed, indicating a good physiological status for the cardiomyocyte cells. These results open the door to construction of cheap printed electronic devices for biointerfacing in biomedical applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1121-1128, 2018. PMID- 29274102 TI - Effect of age on Narcotrend Index monitoring during sevoflurane anesthesia in children below 2 years of age. AB - BACKGROUND: In older children, different electroencephalogram-based algorithms for measuring depth of anesthesia displayed a similar performance as in adults, but in infants they have not displayed the same reliability so far. According to the individual developmental state, the Narcotrend distinguishes "differentiated" electroencephalograms, which can be classified using the full Narcotrend Index scale, from "undifferentiated" electroencephalograms, which are classified using a scale with fewer stages. OBJECTIVE: The objective of this prospective clinical observational study was to assess the feasibility and performance of the Narcotrend monitor in children <2 years within a clinical setting. METHODS: Sixty one children aged 0-24 months undergoing general anesthesia with sevoflurane and remifentanil for elective pediatric surgery were studied. We investigated the percentage of differentiated electroencephalograms and the correlation between multiples of minimal alveolar sevoflurane concentration and the Narcotrend Index according to age groups. Prediction probability was used to evaluate the performance of the Narcotrend Index for differentiation between consciousness and unconsciousness and between different sevoflurane concentrations. RESULTS: The percentage of differentiated electroencephalograms increased with increasing age (0-3 months: 23.8%, 4-5 months: 87.5%, 6-11 months: 92.3%, 12-24 months: 100%). The overall prediction probability of Narcotrend Index was 1.0 (SE 0.05) for differentiation between awake and loss of consciousness and 1.0 (SE 0.01) for differentiation between anesthetized and return of consciousness. Spearman correlation analysis revealed a significant negative correlation between sevoflurane concentration and the Narcotrend Index (r = -0.78, P < .0001, 95%CI: 0.81 to -0.74). Overall prediction probability of Narcotrend Index to sevoflurane concentration was 0.8 (95%CI: 0.78-0.82). CONCLUSION: The Narcotrend monitor indicated a Narcotrend Index in most infants and young children starting from 4 months with significant correlation to and acceptable prediction probability for minimal alveolar sevoflurane concentration. PMID- 29274103 TI - Osteogenic differentiation of human adipose derived stem cells on chemically crosslinked carbon nanomaterial coatings. AB - Carbon nanomaterial coatings have been widely investigated for many biomedical applications including bone tissue engineering. Current methods to fabricate carbon nanomaterial coatings are limited by specific substrate requirements and the lack of strong bonds between the nanomaterials. Furthermore, few studies compare the effect of carbon nanoparticle architecture on stem cell differentiation and mineralization for osteogenic differentiation. Herein, we report a study comparing chemically crosslinked carbon nanotubes (of various diameters), graphene nanoplatelets, and graphene nanoribbons coatings for adipose derived stem cell differentiation toward an osteogenic lineage. We observed greatest autodeposition of calcium on graphene nanoribbon surfaces, while multiwalled carbon nanotubes of high diameter had the greatest influence on stem cell fate (by alkaline phosphatase activity, calcium deposition, and osteocalcin measurements). Studies indicate the cause for multiwalled carbon nanotube related stem cell differentiation, may be related to early timepoint toxicity as indicated by lactose dehydrogenase release. These results indicate suggestions for orthopedic tissue engineering applications for carbon nanomaterial coatings. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1189-1199, 2018. PMID- 29274104 TI - Designing connected marine reserves in the face of global warming. AB - Marine reserves are widely used to protect species important for conservation and fisheries and to help maintain ecological processes that sustain their populations, including recruitment and dispersal. Achieving these goals requires well-connected networks of marine reserves that maximize larval connectivity, thus allowing exchanges between populations and recolonization after local disturbances. However, global warming can disrupt connectivity by shortening potential dispersal pathways through changes in larval physiology. These changes can compromise the performance of marine reserve networks, thus requiring adjusting their design to account for ocean warming. To date, empirical approaches to marine prioritization have not considered larval connectivity as affected by global warming. Here, we develop a framework for designing marine reserve networks that integrates graph theory and changes in larval connectivity due to potential reductions in planktonic larval duration (PLD) associated with ocean warming, given current socioeconomic constraints. Using the Gulf of California as case study, we assess the benefits and costs of adjusting networks to account for connectivity, with and without ocean warming. We compare reserve networks designed to achieve representation of species and ecosystems with networks designed to also maximize connectivity under current and future ocean warming scenarios. Our results indicate that current larval connectivity could be reduced significantly under ocean warming because of shortened PLDs. Given the potential changes in connectivity, we show that our graph-theoretical approach based on centrality (eigenvector and distance-weighted fragmentation) of habitat patches can help design better-connected marine reserve networks for the future with equivalent costs. We found that maintaining dispersal connectivity incidentally through representation-only reserve design is unlikely, particularly in regions with strong asymmetric patterns of dispersal connectivity. Our results support previous studies suggesting that, given potential reductions in PLD due to ocean warming, future marine reserve networks would require more and/or larger reserves in closer proximity to maintain larval connectivity. PMID- 29274105 TI - Neural predictors of sensorimotor adaptation rate and savings. AB - In this study, we investigate whether individual variability in the rate of visuomotor adaptation and multiday savings is associated with differences in regional gray matter volume and resting-state functional connectivity. Thirty four participants performed a manual adaptation task during two separate test sessions, on average 9 days apart. Functional connectivity strength between sensorimotor, dorsal cingulate, and temporoparietal regions of the brain was found to predict the rate of learning during the early phase of the adaptation task. In contrast, default mode network connectivity strength was found to predict both the rate of learning during the late adaptation phase and savings. As for structural predictors, greater gray matter volume in temporoparietal and occipital regions predicted faster early learning, whereas greater gray matter volume in superior posterior regions of the cerebellum predicted faster late learning. These findings suggest that the offline neural predictors of early adaptation may facilitate the cognitive aspects of sensorimotor adaptation, supported by the involvement of temporoparietal and cingulate networks. The offline neural predictors of late adaptation and savings, including the default mode network and the cerebellum, likely support the storage and modification of newly acquired sensorimotor representations. PMID- 29274106 TI - Factors driving public tolerance levels and information-seeking behaviour concerning insects in the household environment. AB - BACKGROUND: The public's negative attitudes towards household insects drive tolerance for these insects and their control. Tolerance levels are important in integrated pest management (IPM), as are pest knowledge and information. The risk information seeking and processing (RISP) model describes the relationships between personal factors and information-seeking behaviour. We combined IPM and RISP to determine important relationships between factors driving insect tolerance levels and information-seeking behaviour through an online survey and tested whether this model is valid and generally applicable. RESULTS: Relationships between variables from both IPM and RISP models were tested for seven insect species. Tolerance levels were measured with two factors: willingness to pay for pest control and whether insects are tolerated. Willingness to pay for control was positively affected by age, experience, risk perception, insect characteristics, and negative emotions and affected behavioural intention, by influencing information sufficiency and information seeking behaviour. Tolerability was influenced by perception of insect characteristics and determines whether control measures are taken. CONCLUSION: It was possible to combine the RISP and IPM models. Relevant driving factors were a person's age, experience, risk perception, negative affective responses, tolerance levels, relevant channel beliefs about online forums, information sufficiency and information-seeking behaviour. There was, however, variation in important factors between different insects. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29274108 TI - Usefulness of hard X-ray microscope using synchrotron radiation for the structure analysis of insects. AB - Three-dimensional (3D) printing technology has the advantage of enabling specific visualization of creative ideas. Since synchrotron based images can provide high sensitivity and high resolution, they are a very useful technology to identify the 3D anatomy of microscale samples. X-ray images using such synchrotron radiation are grafted to 3D printing technology. We can be obtained 3D images and modeling data of an ant using synchrotron radiation, and then, it were outputted with the 3D printer. A new way to identify the usefulness of the structure analysis is then found by visualizing the micro-internal structure of diverse biomedical samples and creating an enlarged model. This study suggests methods of utilizing a 3D printed model produced through synchrotron radiation imaging in various fields such as bioengineering, medical, and education. PMID- 29274109 TI - Improved Photophysical and Photochemical Properties of Thiopheneethoxy Substituted Metallophthalocyanines on Immobilization onto Gold-speckled Silica Nanoparticles. AB - This work reports on the synthesis of tetrakis-[(thiophineethoxy) phthalocyaninato] indium(II) chloride (3). The photophysical behavior of complex 3 was compared to that of the Zn derivative (tetrakis-[(thiophineethoxy) phthalocyaninato] zinc(II) (complex 2)). The compounds were interacted with gold speckled silica (GSS) nanoparticles via Au-S self assembly to afford the conjugates (2-GSS and 3-GSS). The photophysicochemical behavior of the compounds and their conjugates were assessed. The conjugates afforded a decrease in fluorescence quantum yields and lifetimes with improved triplet and singlet oxygen quantum yields in comparison with complexes 2 and 3 alone. The complexes and their conjugates could serve as good candidates for photodynamic therapy. PMID- 29274107 TI - Tumor-associated CD204+ M2 macrophages are unfavorable prognostic indicators in uterine cervical adenocarcinoma. AB - Uterine cervical adenocarcinoma is rare, but its prevalence has increased. To improve outcomes and ensure the suitability of recent immunotherapies, the aim of this study was to evaluate the clinicopathological impact of the tumor immune microenvironment of uterine cervical adenocarcinoma. We investigated 148 adenocarcinoma cases, including 21 cases of adenocarcinoma in situ (AIS) and 127 cases of invasive adenocarcinoma, using immunohistochemistry to detect tumor infiltrating immune cells and the expression of programmed cell death 1 ligand-1 (PD-L1) and p16 on tumor cells. We then carried out correlation and survival analyses. The density of immune cells and expression levels were compared between the tumor cell nest and stroma and between AIS and invasive adenocarcinoma using digital image analysis. A higher density of tumor-infiltrating CD204+ M2 macrophages was significantly associated with shorter disease-free survival, although no other tumor-infiltrating immune cells were prognostic, including CD4+ , CD8+ , FOXP3+ , and PD-1+ lymphocytes and CD68+ macrophages. The density of stroma-infiltrating lymphocytes and macrophages was significantly higher in invasive adenocarcinoma than in AIS. The density of tumor-infiltrating lymphocytes in p16-expressing human papillomavirus (HPV)-positive tumors was significantly higher than that in HPV-negative tumors. The HPV status was not associated with patient outcome. Expression of PD-L1 on tumor cells was found only in invasive adenocarcinoma cases (17.3%). A higher density of stroma infiltrating lymphocytes and macrophages was found in PD-L1-positive tumors than in negative tumors. Patients with PD-L1-positive tumors tended to experience longer survival. It is suggested that tumor-infiltrating CD204+ M2 macrophages may predict poor prognoses in patients with cervical adenocarcinoma. PMID- 29274111 TI - Influence of ciprofloxacin-based additives on the hydrolysis of nanofiber polyurethane membranes. AB - A degradable polycarbonate urethane (PCNU) and an antimicrobial oligomer (AO) were used to generate anti-infective nanofiber scaffolds through blend electrospinning. The AO consists of two molecules of ciprofloxacin (CF) bound through hydrolysable linkages to triethylene glycol. The membranes were conceived for use as tissue engineering scaffolds for the regeneration of soft tissues for the periodontium, where there would be a need for a local dose of antibiotic to the periodontal space as the scaffold degrades in order to prevent biomaterial associated infection. Scaffolds were made using AO at 7 and 15% w/w equivalent CF, and compared to scaffolds with 15% w/w CF (with HCl counterion). AO was hydrolyzed and released CF continuously over 28 days, while the 15% w/w CF HCl scaffolds showed a burst release within hours, with no subsequent release in the subsequent 28 day period. Released CF from both the AO and CF HCl scaffolds had a similar minimum inhibitory concentration to that of off-the-shelf CF. Interestingly, the introduction of drug in either form (AO or CF HCl) was found to increase the hydrolytic stability of the electrospun degradable PCNU scaffold matrix itself. The alteration of hydrolysis kinetics was attributed to changes in the hydrogen bonding character and microstructure within the scaffolds, introduced by the presence of CF. This study has revealed that in generating in situ drug release systems, the secondary effects of the added drug on the degradation properties of the polymeric carriers must be considered, particularly for systems that act dually as tissue engineering scaffolds. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1211-1222, 2018. PMID- 29274110 TI - Metabolic correlates of cognitive function in children with unilateral Sturge Weber syndrome: Evidence for regional functional reorganization and crowding. AB - To evaluate metabolic changes in the ipsi- and contralateral hemisphere in children showing a cognitive profile consistent with early reorganization of cognitive function, we evaluated the regional glucose uptake, interhemispheric metabolic connectivity, and cognitive function in children with unilateral SWS. Interictal 2-deoxy-2[18 F]fluoro-D-glucose (FDG)-PET scans of 27 children with unilateral SWS and mild epilepsy and 27 age-matched control (non-SWS children with epilepsy and normal FDG-PET) were compared using statistical parametric mapping (SPM). Regional FDG-PET abnormalities calculated as SPM(t) scores in the SWS group were correlated with cognitive function (IQ) in left- and right hemispheric subgroups. Interhemispheric metabolic connectivity between homotopic cortical regions was also calculated. Verbal IQ was substantially (>=10 points difference) higher than non-verbal IQ in 61% of the right- and 71% of the left hemispheric SWS group. FDG SPM(t) scores in the affected hemisphere showed strong positive correlations with IQ in the left-hemispheric, but not in right hemispheric SWS group in several frontal, parietal, and temporal cortical regions. Significant positive interhemispheric metabolic connectivity, present in controls, was diminished in the SWS group. In addition, the left-hemispheric SWS group showed inverse metabolic interhemispheric correlations in specific parietal, temporal, and occipital regions. FDG SPM(t) scores in the same regions of the right (unaffected) hemisphere showed inverse correlations with IQ. These findings suggest that left-hemispheric lesions in SWS often result in early reorganization of verbal functions while interfering with ("crowding") their non verbal cognitive abilities. These cognitive changes are associated with specific metabolic abnormalities in the contralateral hemisphere not directly affected by SWS. PMID- 29274112 TI - Relationships among neuroscore, magnetic resonance imaging features, and intracranial pressure in sheep affected by slow-growing brain lesions. AB - Diagnosing high intracranial pressure by clinical and diagnostic imaging is particularly challenging for chronic or slow-growing lesions. The aim of this prospective case-control study is to determine whether the neuroscore and brain magnetic resonance imaging (MRI) are related to the direct measurement of intracranial pressure in sheep affected by intracranial slow-growing lesions due to chronic cerebral coenurosis (Coenurus cerebralis). Seventeen affected and 10 control sheep were included. All animals underwent a neurological examination, MRI of the brain, and direct measurement of intracranial pressure. The severity of clinical signs and MRI findings were scored. Data were statistically analyzed. The invasive intracranial pressure value was higher in affected animals. A severely altered neuroscore is related to an increased intracranial pressure beyond the normal threshold (P < 0.05). The volume of the calvarium was larger in affected animals than in control animals (P = 0.0001) and was positively influenced by the presence and volume of the parasitic cyst (r = 0.7881, P < 0.01). Several degrees of deviation and deformation of both the ventricular system and brain parenchyma were detected by MRI. Subjective MRI findings were not associated with intracranial hypertension. In conclusion, this study shows that in sheep affected by slow-growing lesions, severe alterations in the neuroscore and the results of objective MRI are related to an increased intracranial pressure beyond the normal threshold. PMID- 29274113 TI - Robustness of the approximate likelihood of the protracted speciation model. AB - The protracted speciation model presents a realistic and parsimonious explanation for the observed slowdown in lineage accumulation through time, by accounting for the fact that speciation takes time. A method to compute the likelihood for this model given a phylogeny is available and allows estimation of its parameters (rate of initiation of speciation, rate of completion of speciation and extinction rate) and statistical comparison of this model to other proposed models of diversification. However, this likelihood computation method makes an approximation of the protracted speciation model to be mathematically tractable: it sometimes counts fewer species than one would do from a biological perspective. This approximation may have large consequences for likelihood-based inferences: it may render any conclusions based on this method completely irrelevant. Here, we study to what extent this approximation affects parameter estimations. We simulated phylogenies from which we reconstructed the tree of extant species according to the original, biologically meaningful protracted speciation model and according to the approximation. We then compared the resulting parameter estimates. We found that the differences were larger for high values of extinction rates and small values of speciation-completion rates. Indeed, a long speciation-completion time and a high extinction rate promote the appearance of cases to which the approximation applies. However, surprisingly, the deviation introduced is largely negligible over the parameter space explored, suggesting that this approximate likelihood can be applied reliably in practice to estimate biologically relevant parameters under the original protracted speciation model. PMID- 29274114 TI - The Y137H mutation in the cytochrome P450 FgCYP51B protein confers reduced sensitivity to tebuconazole in Fusarium graminearum. AB - BACKGROUND: Fusarium graminearum is the main pathogen of Fusarium head blight (FHB), a worldwide plant disease and one of the most significant wheat diseases in China. Demethylation inhibitor (DMI) fungicides, such as tebuconazole (TEC), are widely used to control FHB, but long-term use leads to low efficacy against FHB. Earlier studies showed that DMI resistance is associated with the fungal sterol 14alpha-demethylase (cytochrome P450 CYP51) gene, and that point mutations in the CYP51 gene are the primary mechanism of resistance to DMI fungicides. The aims of this study were to clarify the molecular mechanisms of resistance to TEC and identify the binding sites on the FgCYP51B protein. RESULTS: Site-directed mutagenesis was used to change the FgCYP51B gene of wild-type strain PH-1 from tyrosine to histidine at residue 137 (Y137H) to generate a mutant transformant, which was confirmed to be resistant to TEC compared with the parental strains. A three-dimensional FgCYP51B model was constructed, and molecular docking simulation studies were conducted to identify the optimum binding mode with TEC. The wild-type FgCYP51B protein displayed stronger affinity to TEC than that of the mutated FgCYP51B in the molecular docking analysis. CONCLUSION: These results indicate that a Tyr137 amino acid mutation in the cytochrome P450 FgCYP51B could lead to resistance to TEC and that Y137 forms part of the tebuconazole-binding pocket. (c) 2017 Society of Chemical Industry. PMID- 29274115 TI - A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy. AB - BACKGROUND: DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations. METHODS: Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a history of sudden cardiac death. We performed cell transfection experiments and in vitro assembly experiments to prove the pathogenicity of this novel DES indel mutation. RESULTS: These experiments revealed a severe filament formation defect of mutant desmin supporting the pathogenicity. In addition, we labeled a skeletal muscle biopsy from the mutation carrier revealing cytoplasmic desmin positive protein aggregates. In summary, we identified and functionally characterized a pathogenic DES indel mutation causing cardiac and skeletal myopathy. CONCLUSION: Our study has relevance for the clinical and genetic interpretation of further DES indel mutations causing cardiac or skeletal myopathies and might be helpful for risk stratification. PMID- 29274116 TI - Risk of HLA Homozygous Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation. AB - Clinical application of induced pluripotent stem cells (iPS) in autologous settings has just begun. To overcome the high time and cost barriers in the individual production of autologous iPS, the use of allogeneic iPS with a homozygous human leukocyte antigen (HLA) haplotype (HLA-homo HP) has been proposed. Cord blood transplantation (CBT) is a suitable model for evaluating the allogeneic immunogenicity of iPS transplantation from HLA-homo donors. We analyzed 1,374 Japanese single cord blood transplant pairs who were retrospectively typed as HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. Among these, six pairs with donor HLA homo-patient-HLA hetero (homo-hetero) were found, all of which showed favorable neutrophil engraftment. Multivariate analysis revealed a significantly elevated engraftment risk (HR = 1.59) compared with hetero-hetero pairs with HLA 1-2 locus mismatch (789 pts) and comparative risk (HR = 1.23) compared with hetero-hetero pairs with 0 mismatch (104 pts). These results for CBT with HLA-homo HP cord blood carry an important implication, namely the possibility that HLA-homo iPS transplantation results in favorable engraftment. Furthermore, we obtained detailed information on HLA alleles and haplotypes of HLA-homo. All donor HLA-homo HPs had a common specific ethnicity and high conservation of the HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA-homo HP, and another non-shared patient HP was mismatched with 1 to 4 HLA alleles of HLA-A, -B, -C, and -DRB1 loci in the GVH direction. These findings indicate that patients possessing a single common HLA haplotype have a higher chance of yielding HLA-homo iPS. Stem Cells Translational Medicine 2018;7:173-179. PMID- 29274117 TI - Sarcoid-like granulomatosis in a patient receiving anti-TNFalpha for psoriasis. PMID- 29274118 TI - Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232. AB - The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures. PMID- 29274119 TI - Beyond abundance: How microenvironmental features and weather influence Bartonella tribocorum infection in wild Norway rats (Rattus norvegicus). AB - Norway rats (Rattus norvegicus) inhabit cities worldwide and carry a number of zoonotic pathogens. Although many studies have investigated rat-level risk factors, there is limited research on the effects of weather and environment on zoonotic pathogen transmission ecology in rats. The objective of this study was to use a disease ecology approach to understand how abiotic (weather and urban microenvironmental features) and biotic (relative rat population abundance) factors affect Bartonella tribocorum prevalence in urban Norway rats from Vancouver, British Columbia, Canada. This potentially zoonotic pathogen is primarily transmitted by fleas and is common among rodents, including rats, around the world. During a systematic rat trap and removal study, city blocks were evaluated for 48 environmental variables related to waste, land/alley use and property condition, and rat abundance. We constructed 32 weather (temperature and precipitation) variables with time lags prior to the date we captured each rat. We fitted multivariable logistic regression models with rat pathogen status as the outcome. The odds of a rat testing positive for B. tribocorum were significantly lower for rats in city blocks with one or more low-rise apartment buildings compared to blocks with none (OR = 0.20; 95% CI: 0.04-0.80; p = .02). The reason for this association may be related to unmeasured factors that influence pathogen transmission and maintenance, as well as flea vector survival. Bartonella tribocorum infection in rats was positively associated with high minimum temperatures for several time periods prior to rat capture. This finding suggests that a baseline minimum temperature may be necessary for flea vector survival and B. tribocorum transmission among rats. There was no significant association with rat abundance, suggesting a lack of density-dependent pathogen transmission. This study is an important first step to understanding how environment and weather impacts rat infections including zoonotic pathogen ecology in urban ecosystems. PMID- 29274120 TI - Structural and functional integrity of Sulla carnosa photosynthetic apparatus under iron deficiency conditions. AB - The abundance of calcareous soils makes bicarbonate-induced iron (Fe) deficiency a major problem for plant growth and crop yield. Therefore, Fe-efficient plants may constitute a solution for use on calcareous soils. We investigated the ability of the forage legume Sulla carnosa (Desf.) to maintain integrity of its photosynthetic apparatus under Fe deficiency conditions. Three treatments were applied: control, direct Fe deficiency and bicarbonate-induced Fe deficiency. At harvest, all organs of deficient plants showed severe growth inhibition, the effect being less pronounced under indirect Fe deficiency. Pigment analysis of fully expanded leaves revealed a reduction in concentrations of chlorophyll a, chlorophyll b and carotenoids under Fe deficiency. Electron transport rate, maximum and effective quantum yield of photosystem II (PSII), photochemical quenching (qP), non-photochemical quenching (qN) as well as P700 activity also decreased significantly in plants exposed to direct Fe deficiency, while qN was not affected. The effects of indirect Fe deficiency on the same parameters were less pronounced in bicarbonate-treated plants. The relative abundances of thylakoid proteins related to PSI (PsaA, Lhca1, Lhca2) and PSII (PsbA, Lhcb1) were also more affected under direct than indirect Fe deficiency. We conclude that S. carnosa can maintain the integrity of its photosynthetic apparatus under bicarbonate-induced Fe deficiency, preventing harmful effects to both photosystems under direct Fe deficiency. This suggests a high capacity of this species not only to take up Fe in the presence of bicarbonate (HCO3- ) but also to preferentially translocate absorbed Fe towards leaves and prevent its inactivation. PMID- 29274123 TI - Errata. PMID- 29274124 TI - Errata. PMID- 29274122 TI - Zoophytophagous mirids provide pest control by inducing direct defences, antixenosis and attraction to parasitoids in sweet pepper plants. AB - BACKGROUND: In addition to their services as predators, mirid predators are able to induce plant defences by phytophagy. However, whether this induction occurs in sweet pepper and whether it could be an additional benefit to their role as a biological control agent in this crop remain unknown. Here, these questions were investigated in two model insects, the mirids Nesidiocoris tenuis and Macrolophus pygmaeus. RESULTS: Plant feeding behaviour was observed in both N. tenuis and M. pygmaeus on sweet pepper and occupied 33% and 14% of total time spent on the plant, respectively. The punctures caused by mirid plant feeding induced the release of a blend of volatile organic compounds (VOCs) which repelled the herbivore pests Frankliniella occidentalis and Bemisia tabaci and attracted the whitefly parasitoid Encarsia formosa. The repellent effect on B. tabaci was observed for at least 7 days after initial exposure of the plant to N. tenuis, and attraction of E. formosa remained functional for 14 days. CONCLUSION: Plant defences induced by the feeding of mirid predators, their subsequent effects on the behaviour of both pests and natural enemies, and the persistence of these observed effects open the door to new control strategies in the sweet pepper crop. Further application of this research is discussed, such as the vaccination of plants by zoophytophagous mirids in the nursery before transplantation. (c) 2017 Society of Chemical Industry. PMID- 29274121 TI - Brain metabolic sensing and metabolic signaling at the level of an astrocyte. AB - Astrocytes support neuronal function by providing essential structural and nutritional support, neurotransmitter trafficking and recycling and may also contribute to brain information processing. In this article we review published results and report new data suggesting that astrocytes function as versatile metabolic sensors of central nervous system (CNS) milieu and play an important role in the maintenance of brain metabolic homeostasis. We discuss anatomical and functional features of astrocytes that allow them to detect and respond to changes in the brain parenchymal levels of metabolic substrates (oxygen and glucose), and metabolic waste products (carbon dioxide). We report data suggesting that astrocytes are also sensitive to circulating endocrine signals hormones like ghrelin, glucagon-like peptide-1 and leptin, that have a major impact on the CNS mechanisms controlling food intake and energy balance. We discuss signaling mechanisms that mediate communication between astrocytes and neurons and consider how these mechanisms are recruited by astrocytes activated in response to various metabolic challenges. We review experimental data suggesting that astrocytes modulate the activities of the respiratory and autonomic neuronal networks that ensure adaptive changes in breathing and sympathetic drive in order to support the physiological and behavioral demands of the organism in ever-changing environmental conditions. Finally, we discuss evidence suggesting that altered astroglial function may contribute to the pathogenesis of disparate neurological, respiratory and cardiovascular disorders such as Rett syndrome and systemic arterial hypertension. PMID- 29274126 TI - Computed tomographic contrast tenography of the digital flexor tendon sheath of the equine hindlimb. AB - Pre-surgical investigation of digital flexor tendon sheath pathology remains challenging with current standard imaging techniques. The aim of this prospective, anatomical, pilot study was to describe the anatomy of the equine hind limb digital flexor tendon sheath using a combination of computed tomography (CT) and computed tomographic contrast tenography in clinically normal cadaver limbs. Ten pairs of hind limbs with no external abnormalities were examined from the level of the tarsometatarsal joint distally. Limbs initially underwent non contrast CT examination using 120 kVp, 300 mAs, and 1.5 mm slice thickness. Sixty millilitres of ioversol iodinated contrast media and saline (final concentration 100 mg/ml) were injected using a basilar sesamoidean approach. The computed tomographic contrast tenography examination was then repeated, before dissection of the specimens to compare gross and imaging findings. The combined CT and computed tomographic contrast tenography examinations provided excellent anatomical detail of intra-thecal structures. The borders of the superficial and deep digital flexor tendons, and the manica flexoria were consistently identifiable in all limbs. Detailed anatomy including that of the mesotenons, two of which are previously undescribed, and the plantar annular ligament were also consistently identifiable. Dissection of all 10 pairs of limbs revealed there to be no pathology, in accordance with the imaging findings. In conclusion, the combination of CT and computed tomographic contrast tenography may be useful adjunctive diagnostic techniques to define digital flexor tendon sheath pathology prior to surgical exploration in horses. PMID- 29274125 TI - Ischaemic ulcers on the toes secondary to Raynaud phenomenon in a patient with systemic sclerosis successfully treated with botulinum toxin. PMID- 29274127 TI - Optimized expression and purification of NavAb provide the structural insight into the voltage dependence. AB - Voltage-gated sodium channels are crucial for electro-signalling in living systems. Analysis of the molecular mechanism requires both fine electrophysiological evaluation and high-resolution channel structures. Here, we optimized a dual expression system of NavAb, which is a well-established standard of prokaryotic voltage-gated sodium channels, for E. coli and insect cells using a single plasmid vector to analyse high-resolution protein structures and measure large ionic currents. Using this expression system, we evaluated the voltage dependence and determined the crystal structures of NavAb wild-type and two mutants, E32Q and N49K, whose voltage dependence were positively shifted and essential interactions were lost in voltage sensor domain. The structural and functional comparison elucidated the molecular mechanisms of the voltage dependence of prokaryotic voltage-gated sodium channels. PMID- 29274128 TI - The metabolic (under)groundwork of the lily bulb toward sprouting. AB - Large bulbs of Lilium longiflorum have an obligatory cold requirement to flower. Bulb cooling is widely used to induce and accelerate flowering. However, in-depth investigations of the effect of bulb cooling on major landmarks of plant development are lacking. It has been demonstrated that low temperature induces carbohydrate degradation, yet integrative studies on metabolic changes occurring in the bulb are not available. We detected that cold exposure mainly hastened bulb sprouting, rather than floral transition or blooming. Metabolite profiling of cooled and non-cooled bulbs was carried out, revealing cold-induced accumulation of soluble sugars, lipids and specific amino acids, and a significant reduction in tricarboxylic acid (TCA)-cycle elements. We observed that metabolic pathways located in the cytosol - including glycolysis, lipid synthesis and part of the gamma-Aminobutyric acid (GABA) shunt - were enhanced by cold exposure, while mitochondrial metabolism - namely the TCA cycle - was reduced by cold. We suggest a physiological model accounting for this metabolic discrepancy. PMID- 29274129 TI - Newborn screening for galactosaemia. AB - BACKGROUND: Classical galactosaemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase. This is a rare and potentially lethal condition that classically presents in the first week of life once milk feeds have commenced. Affected babies may present with any or all of the following: cataracts; fulminant liver failure; prolonged jaundice; or Escherichia coli sepsis. Once the diagnosis is suspected, feeds containing galactose must be stopped immediately and replaced with a soya-based formula. The majority of babies will recover, however a number will not survive. There are long-term complications of galactosaemia, despite treatment, including learning disabilities and female infertility. It has been postulated that galactosaemia could be detected on newborn screening and this would prevent the immediate severe liver dysfunction and sepsis. OBJECTIVES: To assess whether there is evidence that newborn screening for galactosaemia prevents or reduces mortality and morbidity and improves clinical outcomes in affected neonates and the quality of life in older children. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from electronic database searches, handsearches of relevant journals and conference abstract books. We also searched online trials registries and the reference lists of relevant articles and reviews.Date of the most recent search of Cochrane Cystic Fibrosis Group's Trials Register: 18 December 2017.Date of the most recent search of additional resources: 11 October 2017. SELECTION CRITERIA: Randomised controlled studies and controlled clinical studies, published or unpublished comparing the use of any newborn screening test to diagnose infants with galactosaemia and presenting a comparison between a screened population versus a non-screened population. DATA COLLECTION AND ANALYSIS: No studies of newborn screening for galactosaemia were found. MAIN RESULTS: No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS: We were unable to identify any eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on randomised controlled studies. However, we are aware of uncontrolled studies which support the efficacy of newborn screening for galactosaemia. There are a number of reviews and economic analyses of non-trial literature suggesting that screening is appropriate. PMID- 29274130 TI - A single center experience with romiplostim for the management of chemotherapy induced thrombocytopenia. PMID- 29274131 TI - Roles of p21, p53, cyclin D1, CDK-4, estrogen receptor alpha in aflatoxin B1 induced cytotoxicity in testicular tissue of mice. AB - This study was done in order to investigate time-dependent effect of AFB1 on expression of genes involving in cell cycle check point machinery at G, S, and M phases. For this purpose, 24 mature male Swiss albino mice were randomly divided into control and test groups. The animals in test group subdivided into three groups, which received the AFB1 at a daily dose of 20 ug/kg body weight, through intraperitoneal (i.p.) route, for 7, 14, and 21 days. The p21, p53, cyclin D1, CDK4, and ERalpha expressions at both mRNA and protein level were analyzed by using reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. Moreover, the tubular differentiation (TDI) and spermiogenesis (SPI) indices were analyzed. Finally, the testicular DNA fragmentation was assessed by using DNA Ladder test. Observations revealed that the AFB1 remarkably (P < .05) reduced cyclin D1, Cdk4, and ERalpha expression at both mRNA and protein levels. Up regulated p21 and p53 expression was revealed in AFB1-received animals, which developed time dependently. Histological examinations exhibited a significant reduction in TDI and SPI indices. Finally, the AFB1 resulted in severe DNA fragmentation. Our data showed that the AFB1 by down-regulating the cyclin D1, Cdk4, and ERalpha expression adversely affects cyclin D1/Cdk4 and cyclin D1/ERalpha interactions. Moreover, the AFB1-induced overexpression of p21 (as a kinase inhibitor), in turn results in cell cycle arrest via inhibiting the Cdk4 interaction with cyclin D1. Finally, the AFB1-induced DNA damage triggers the p53 dependent apoptosis pathway independent to p21 overexpression. PMID- 29274132 TI - Solar irradiation levels during simulated long- and short-term heat waves significantly influence heat survival, pigment and ascorbate composition, and free radical scavenging activity in alpine Vaccinium gaultherioides. AB - In the 20th century, annual mean temperatures in the European Alps rose by almost 1 K and are predicted to rise further, increasing the impact of temperature on alpine plants. The role of light in the heat hardening of plants is still not fully understood. Here, the alpine dwarf shrub Vaccinium gaultherioides was exposed in situ to controlled short-term heat spells (150 min with leaf temperatures 43-49 degrees C) and long-term heat waves (7 days, 30 degrees C) under different irradiation intensities. Lethal leaf temperatures (LT50 ) were calculated. Low solar irradiation [max. 250 photosynthetic photon flux density (PPFD)] during short-term heat treatments mitigated the heat stress, shown by reduced leaf tissue damage and higher Fv /Fm (potential quantum efficiency of photosystem 2) than in darkness. The increase in xanthophyll cycle activity and ascorbate concentration was more pronounced under low light, and free radical scavenging activity increased independent of light conditions. During long-term heat wave exposure, heat tolerance increased from 3.7 to 6.5 degrees C with decreasing mean solar irradiation intensity (585-115 PPFD). Long-term exposure to heat under low light enhanced heat hardening and increased photosynthetic pigment, dehydroascorbate and violaxanthin concentration. In conclusion, V. gaultherioides is able to withstand temperatures of around 50 degrees C, and its heat hardening can be enhanced by low light during both short- and long-term heat treatment. Data showing the specific role of light during short- and long-term heat exposure and the potential risk of lethal damage in alpine shrubs as a result of rising temperature are discussed. PMID- 29274134 TI - A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. AB - Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in AML. NPM1 mutations often co-occur with FLT3-ITDs and mutations in genes regulating DNA methylation, such as DNMT3A, TET2, and IDH1/2. It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1-mutated AML and correlated sequencing data with immunophenotypic and clinical findings. Of 84 cases (63%) that lacked monocytic differentiation ("myeloid AML"), 40 (48%) demonstrated an acute promyelocytic leukemia-like (APL-like) immunophenotype by flow cytometry, with absence of CD34 and HLA-DR and strong myeloperoxidase expression, in the absence of a PML-RARA translocation. Pathologic variants in TET2, IDH1, or IDH2 were identified in 39/40 APL-like cases. This subset of NPM1-mutated AML was associated with longer relapse-free and overall survival, when compared with cases that were positive for CD34 and/or HLA-DR. The combination of NPM1 and TET2 or IDH1/2 mutations along with an APL-like immunophenotype identifies a distinct subtype of AML. Further studies addressing its biology and clinical significance may be especially relevant in the era of IDH inhibitors and recent work showing efficacy of ATRA therapy in NPM1 and IDH1-mutated AML. PMID- 29274135 TI - 2018, Forward, Going Online and all that... PMID- 29274133 TI - Adenosine A1 receptor activates background potassium channels and modulates information processing in olfactory bulb mitral cells. AB - KEY POINTS: Adenosine is a widespread neuromodulator in the mammalian brain, but whether it affects information processing in sensory system(s) remains largely unknown. Here we show that adenosine A1 receptors hyperpolarize mitral cells, one class of principal neurons that propagate odour information from the olfactory bulb to higher brain areas, by activation of background K+ channels. The adenosine-modulated background K+ channels belong to the family of two-pore domain K+ channels. Adenosine reduces spontaneous activity of mitral cells, whereas action potential firing evoked by synaptic input upon stimulation of sensory neurons is not affected, resulting in a higher ratio of evoked firing (signal) over spontaneous firing (noise) and hence an improved signal-to-noise ratio. The study shows for the first time that adenosine influences fine-tuning of the input-output relationship in sensory systems. ABSTRACT: Neuromodulation by adenosine is of critical importance in many brain regions, but the role of adenosine in olfactory information processing has not been studied so far. We investigated the effects of adenosine on mitral cells, which are projection neurons of the olfactory bulb. Significant expression of A1 and A2A receptors was found in mitral cells, as demonstrated by in situ hybridization. Application of adenosine in acute olfactory bulb slices hyperpolarized mitral cells in wild-type but not in adenosine A1 receptor knockout mice. Adenosine-induced hyperpolarization was mediated by background K+ currents that were reduced by halothane and bupivacaine, which are known to inhibit two-pore domain K+ (K2P) channels. In mitral cells, electrical stimulation of axons of olfactory sensory neurons evoked synaptic currents, which can be considered as input signals, while spontaneous firing independent of sensory input can be considered as noise. Synaptic currents were not affected by adenosine, while adenosine reduced spontaneous firing, leading to an increase in the signal-to-noise ratio of mitral cell firing. Our findings demonstrate that A1 adenosine receptors activate two pore domain K+ channels, which increases the signal-to-noise ratio of the input output relationship in mitral cells and thereby modulates information processing in the olfactory bulb. PMID- 29274138 TI - Wurster-Type Nanographenes as Stable Diradical Dications. AB - Three new and stable diradical dications based on the 4,10-dibromoanthanthrone have been synthesized and characterized. In their dicationic state, the amines show a biradical character in the ground state. Their magnetic properties have been investigated by NMR and EPR spectroscopies. The dicationic salts shows strong and broad optical absorption in the near-infrared region. The main driving force to obtain a ground state biradical is the high steric hindrance that prevents planarization of the diphenylamines with the anthanthrone aromatic core. The radical cations are isolated in two perpendicular pi-systems as demonstrated by X-ray diffraction structures. This work provides a new bridging unit in the search for biradical bis(triarylamines) salts. PMID- 29274137 TI - Solute carrier family 35 member F2 is indispensable for papillary thyroid carcinoma progression through activation of transforming growth factor-beta type I receptor/apoptosis signal-regulating kinase 1/mitogen-activated protein kinase signaling axis. AB - Solute carrier family members control essential physiological functions and are tightly linked to human diseases. Solute carrier family 35 member F2 (SLC35F2) is aberrantly activated in several malignancies. However, the biological function and molecular mechanism of SLC35F2 in papillary thyroid carcinoma (PTC) are yet to be fully explored. Here, we showed that SLC35F2 was prominently upregulated in PTC tissues at both protein and mRNA expression level compared with matched adjacent normal tissues. Besides, the high expression of SLC35F2 was significantly associated with lymph node metastasis in patients with PTC. CRISPR/Cas9-mediated knockout of SLC35F2 attenuated the tumorigenic properties of PTC, including cell proliferation, migration and invasion and induced G1 phase arrest. In contrast, ectopic expression of SLC35F2 brought about aggressive malignant phenotypes of PTC cells. Moreover, SLC35F2 expedited the proliferation and migration of PTC cells by targeting transforming growth factor-beta type I receptor (TGFBR1) and phosphorylation of apoptosis signal-regulating kinase 1 (p ASK-1), thereby activating the mitogen-activated protein kinase signaling pathway. The malignant behaviors induced by overexpression of SLC35F2 could be abrogated by silencing of TGFBR1 using a specific inhibitor. We conducted the first study on SLC35F2 in thyroid cancer with the aim of elucidating the functional significance and molecular mechanism of SLC35F2. Our findings suggest that SLC35F2 exerts its oncogenic effect on PTC progression through the mitogen activated protein kinase pathway, with dependence on activation of TGFBR-1 and apoptosis signal-regulating kinase 1. PMID- 29274139 TI - Spatial information from cutaneous and muscle receptors contributes to perceived finger position and ownership. PMID- 29274140 TI - JAK2 exon 12 mutated polycythemia vera: Mayo-Careggi MPN Alliance study of 33 consecutive cases and comparison with JAK2V617F mutated disease. PMID- 29274142 TI - Establishment of hybridized focus measure functions as a universal method for autofocusing. AB - Exact focusing is essential for any automatic image capturing system. Performances of focus measure functions (FMFs) used for autofocusing are sensitive to image contents and imaging systems. Therefore, identification of universal FMF assumes a lot of significance. Eight FMFs were hybridized in pairs of two and implemented simultaneously on a single stack to calculate the hybrid focus measure. In total, 28 hybrid FMFs (HFMFs) and eight FMFs were implemented on stacks of images from three different imaging modalities. Performance of FMFs was found to the best at 50% region sampling. Accuracy, focus error, and false maxima were calculated to evaluate the performance of each FMF. Nineteen HFMFs provided >90% accuracy. Image distortion (noise, contrast, saturation, illumination, etc.) was performed to evaluate robustness of HFMFs. Hybrid of tenengrad variance and steerable filter-based (VGRnSFB) FMFs was identified as the most robust and accurate function with an accuracy of >=90% and a relatively lower focus error and false maxima rate. Sharpness of focus curve of VGRnSFB along with eight individual FMFs was also computed to determine the efficacy of HFMF for the optimization process. VGRnSFB HFMF may be implemented for automated capturing of an image for any imaging system. PMID- 29274141 TI - Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression. AB - With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi-treated variants produced less gammaH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6-8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure. PMID- 29274143 TI - Development and evaluation of a connective tissue phantom model for subsurface visualization of cancers requiring wide local excision. AB - Wide local excision (WLE) of tumors with negative margins remains a challenge because surgeons cannot directly visualize the mass. Fluorescence-guided surgery (FGS) may improve surgical accuracy; however, conventional methods with direct surface tumor visualization are not immediately applicable, and properties of tissues surrounding the cancer must be considered. We developed a phantom model for sarcoma resection with the near-infrared fluorophore IRDye 800CW and used it to iteratively define the properties of connective tissues that typically surround sarcoma tumors. We then tested the ability of a blinded surgeon to resect fluorescent tumor-simulating inclusions with ~1-cm margins using predetermined target fluorescence intensities and a Solaris open-air fluorescence imaging system. In connective tissue-simulating phantoms, fluorescence intensity decreased with increasing blood concentration and increased with increasing intralipid concentrations. Fluorescent inclusions could be resolved at >=1-cm depth in all inclusion concentrations and sizes tested. When inclusion depth was held constant, fluorescence intensity decreased with decreasing volume. Using targeted fluorescence intensities, a blinded surgeon was able to successfully excise inclusions with ~1-cm margins from fat- and muscle-simulating phantoms with inclusion-to-background contrast ratios as low as 2?1. Indirect, subsurface FGS is a promising tool for surgical resection of cancers requiring WLE. PMID- 29274144 TI - Linear-regression convolutional neural network for fully automated coronary lumen segmentation in intravascular optical coherence tomography. AB - Intravascular optical coherence tomography (OCT) is an optical imaging modality commonly used in the assessment of coronary artery diseases during percutaneous coronary intervention. Manual segmentation to assess luminal stenosis from OCT pullback scans is challenging and time consuming. We propose a linear-regression convolutional neural network to automatically perform vessel lumen segmentation, parameterized in terms of radial distances from the catheter centroid in polar space. Benchmarked against gold-standard manual segmentation, our proposed algorithm achieves average locational accuracy of the vessel wall of 22 microns, and 0.985 and 0.970 in Dice coefficient and Jaccard similarity index, respectively. The average absolute error of luminal area estimation is 1.38%. The processing rate is 40.6 ms per image, suggesting the potential to be incorporated into a clinical workflow and to provide quantitative assessment of vessel lumen in an intraoperative time frame. PMID- 29274146 TI - Cortical response states for enhanced sensory discrimination. AB - Brain activity during wakefulness is characterized by rapid fluctuations in neuronal responses. Whether these fluctuations play any role in modulating the accuracy of behavioral responses is poorly understood. Here, we investigated whether and how trial changes in the population response impact sensory coding in monkey V1 and perceptual performance. Although the responses of individual neurons varied widely across trials, many cells tended to covary with the local population. When population activity was in a 'low' state, neurons had lower evoked responses and correlated variability, yet higher probability to predict perceptual accuracy. The impact of firing rate fluctuations on network and perceptual accuracy was strongest 200 ms before stimulus presentation, and it greatly diminished when the number of cells used to measure the state of the population was decreased. These findings indicate that enhanced perceptual discrimination occurs when population activity is in a 'silent' response mode in which neurons increase information extraction. PMID- 29274145 TI - Review of optical coherence tomography in oncology. AB - The application of optical coherence tomography (OCT) in the field of oncology has been prospering over the past decade. OCT imaging has been used to image a broad spectrum of malignancies, including those arising in the breast, brain, bladder, the gastrointestinal, respiratory, and reproductive tracts, the skin, and oral cavity, among others. OCT imaging has initially been applied for guiding biopsies, for intraoperatively evaluating tumor margins and lymph nodes, and for the early detection of small lesions that would often not be visible on gross examination, tasks that align well with the clinical emphasis on early detection and intervention. Recently, OCT imaging has been explored for imaging tumor cells and their dynamics, and for the monitoring of tumor responses to treatments. This paper reviews the evolution of OCT technologies for the clinical application of OCT in surgical and noninvasive interventional oncology procedures and concludes with a discussion of the future directions for OCT technologies, with particular emphasis on their applications in oncology. PMID- 29274148 TI - Oral findings in Williams-Beuren syndrome. AB - BACKGROUND: Williams-Beuren syndrome (WBS; OMIM #194050) is a developmental disorder characterized by congenital heart disease, intellectual disability, dysmorphic facial features and ophthalmologic abnormalities. Oral abnormalities are also described in clinical manifestations of the disease. This paper describes orofacial features in patients with WBS. MATERIAL AND METHODS: Seventeen patients with a confirmed molecular diagnosis of WBS were examined for oral abnormalities through clinical oral evaluations and panoramic radiography. RESULTS: Malocclusion, specifically with dental midline deviation, and high arched palate were the most common findings. CONCLUSIONS: The present results contribute to knowledge on the orofacial manifestations of WBS. Since such patients with WBS may develop severe oral abnormalities, early detection and treatment can help improve their quality of life. PMID- 29274147 TI - Doc2B acts as a calcium sensor for vesicle priming requiring synaptotagmin-1, Munc13-2 and SNAREs. AB - Doc2B is a cytosolic protein with binding sites for Munc13 and Tctex-1 (dynein light chain), and two C2-domains that bind to phospholipids, Ca2+ and SNAREs. Whether Doc2B functions as a calcium sensor akin to synaptotagmins, or in other calcium-independent or calcium-dependent capacities is debated. We here show by mutation and overexpression that Doc2B plays distinct roles in two sequential priming steps in mouse adrenal chromaffin cells. Mutating Ca2+-coordinating aspartates in the C2A-domain localizes Doc2B permanently at the plasma membrane, and renders an upstream priming step Ca2+-independent, whereas a separate function in downstream priming depends on SNARE-binding, Ca2+-binding to the C2B domain of Doc2B, interaction with ubMunc13-2 and the presence of synaptotagmin-1. Another function of Doc2B - inhibition of release during sustained calcium elevations - depends on an overlapping protein domain (the MID-domain), but is separate from its Ca2+-dependent priming function. We conclude that Doc2B acts as a vesicle priming protein. PMID- 29274149 TI - Evolution of oral neoplasm in an andalusian population (Spain). AB - BACKGROUND: Head and neck cancer are one of the most common neoplasm pathologies in humans. The aim of this study was to analyze the type, characteristics, treatment and evolution of oral neoplasm or precancerous lesion in a sample of Andalusian population (Spain) derived from the Oncology Rehabilitation Hospital Unit during a period of 20 years. MATERIAL AND METHODS: A retrospective descriptive study was carried out during the years 1991 and 2011 analyzing the type, characteristics, treatment and follow-up of oral neoplasm in the Oral and Maxillofacial Surgery Unit of the Universitary Hospital Virgen del Rocio. The inclusion criteria were patients whose underlying pathology was any type of benign or malignant neoplasm or presence of precancerous lesion that, after treatment, had been referred to the Prosthetic Rehabilitation Unit. RESULTS: Of the initial analyzed sample of 60 patients, only 45 patients met the inclusion criteria. Of the final sample analyzed, 31 subjects were men (68.9%) and 14 women (31.1%) (p = 0.0169). The mean age of the sample was 57 years +/- 13.83, been more frequently in older people with more than 50 years (73.3%) (p = 0.0169). The most common type of neoplasm was epidermoid carcinoma (64.4%). The site most frequently found in squamous cell carcinoma was the floor of the mouth (31%). The most frequent treatment modality was surgery with postoperative radiotherapy (42.2%). All patients had a minimum follow-up of 5 years, and a recurrence in this period was identified in 11.1% of the sample. Multivariate logistic regression showed a statistically significant association for the variables age (p = 0.0063) and smoking (p = 0.0434). CONCLUSIONS: Epidermoid carcinoma is the most frequent tumor in the oral cavity, where increase age and smoking are confirmed as associated risk factors. PMID- 29274151 TI - Preliminary evaluation of near-infrared vein visualization technology in the screening of palatal blood vessels. AB - BACKGROUND: Avoidance from palatal blood vessel rupture is a major concern during the palatal soft tissue graft surgery. There is no defined chair-side and case specific palatal blood vessel detection approach to facilitate the harvesting process. The objective of this pilot study is to assess the feasibility of a near infrared vein visualization system in the screening process of palatal blood vessels. MATERIAL AND METHODS: An extraoral vein visualization device (AccuVein AV400) was applied to a total of 304 hemi-maxilla of 152 individuals by two blind examiners. The study groups were classified according to their maximum inter incisal measurements. The distances between the coronal border of the vessel image and the mid-palatal gingival margins of the adjacent teeth were measured and in each group. The correlations among the measurements were evaluated within groups. RESULTS: The blood vessel to the adjacent teeth measurements exhibited no statistical difference between both examiners in all subjects (p<0.001). Correlations between the examiners gradually increased in all groups as the mouth opening rates of the subjects were increased (p<0.001). CONCLUSIONS: In the current state, screening of the palatal blood vessels via near-infrared vein visualization technology seems to be not suitable for every individual due to the restrictive effect of mouth opening. However, the promising results of this preliminary study demonstrated increasing consistency between the measurements of the examiners as the inter-incisal distance increase which emphasized the need an intraoral version of the device. Considering the lack of local decision-making technology for the detection of palatal blood vessels, further studies are required for development and optimization of these systems. PMID- 29274150 TI - Occupational group, educational level, marital status and deleterious habits among individuals with maxillofacial fractures: retrospective study. AB - BACKGROUND: To investigate the occupational profile, educational level, marital status and deleterious habits to the health of patients with maxillofacial fractures of a population of northeastern Brazil. MATERIAL AND METHODS: A retrospective study of patients records admitted to the Division of Oral and Maxillofacial Surgery at the Walter Cantidio University Hospital (Fortaleza, Brazil) who sustained maxillofacial fractures was conducted in the period between 2006 and 2015. RESULTS: A total of 338 patients rendered 355 fractures. Males were the most affected (p <0.001), with prevalence in the third decade of life (p <0.001). There was a predominance of motorcycle accidents (p <0.001), home workers (p <0.001), low educational status (p = 0.032), and no cigarette use (p <0.001) or alcohol (p = 0.023). Fractures of the zygomatic-orbital complex were the most prevalent in the sample (p <0.001). CONCLUSION: The sociodemographic profile exerted a significant influence on the epidemiological profile of maxillofacial fractures in a Brazilian population during the study period. PMID- 29274152 TI - The Epidemiology, treatment, and complication of ameloblastoma in East-Indonesia: 6 years retrospective study. AB - BACKGROUND: Ameloblastoma is a neoplasm classified as a benign epithelial odontogenic tumor of the jaws, grow slowly and are locally invasive. The aim of the present study was to investigate the incidence, treatment, and complication of patients with ameloblastoma in East-Indonesia during six years retrospective study. MATERIAL AND METHODS: This retrospective study included 84 patients who were diagnosed with ameloblastoma from 2011 to 2016. There were 56 patients with treatment data available. Data from each patient, including gender, age, histologic type, the size of the tumor, radiologic form, tumor location, type of treatment, and complication were reviewed and analyzed retrospectively. RESULTS: Fourteen patients were diagnosed with unicystic ameloblastoma (25%), thirty two patients with multicystic follicular ameloblastoma (57%) and ten patients with an unspecified multicystic ameloblastoma (18%). A total of about 35 patients were treated conservatively (62.5%) and 21 patients were treated radically (37.5%). Swelling was present as a pre-operative complication in all 56 cases (100%). There were no complaints concerning speech. CONCLUSIONS: The majority findings of the histologic type were multicystic ameloblastoma and their location were in the mandible. Most ameloblastoma were treated conservatively and reconstructions were made with only titanium plates and not bone graft. PMID- 29274153 TI - Oral cancer: A multicenter study. AB - BACKGROUND: To determine the prevalence and clinicopathologic features of the oral cancer patients. MATERIAL AND METHODS: Biopsy records of the participating institutions were reviewed for oral cancer cases diagnosed from 2005 to 2014. Demographic data and site of the lesions were collected. Sites of the lesion were subdivided into lip, tongue, floor of the mouth, gingiva, alveolar mucosa, palate, buccal/labial mucosa, maxilla and mandible. Oral cancer was subdivided into 7 categories: epithelial tumors, salivary gland tumors, hematologic tumors, bone tumors, mesenchymal tumors, odontogenic tumors, and others. Data were analyzed by descriptive statistics using SPSS software version 17.0. RESULTS: Of the 474,851 accessioned cases, 6,151 cases (1.30%) were diagnosed in the category of oral cancer. The mean age of the patients was 58.37+/-15.77 years. A total of 4,238 cases (68.90%) were diagnosed in males, whereas 1911 cases (31.07%) were diagnosed in females. The male-to-female ratio was 2.22:1. The sites of predilection for oral cancer were tongue, labial/buccal mucosa, gingiva, palate, and alveolar mucosa, respectively. The three most common oral cancer in the descending order of frequency were squamous cell carcinoma, non-Hodgkin lymphoma and mucoepidermoid carcinoma. CONCLUSIONS: Although the prevalence of oral cancer is not high compared to other entities, oral cancer pose significant mortality and morbidity in the patients, especially when discovered late in the course of the disease. This study highlights some anatomical locations where oral cancers are frequently encountered. As a result, clinicians should pay attention to not only teeth, but oral mucosa especially in the high prevalence area as well since early detection of precancerous lesions or cancers in the early stage increase the chance of patient being cured and greatly reduce the mortality and morbidity. This study also shows some differences between pediatric and elderly oral cancer patients as well as between Asian and non-Asian oral cancer patients. PMID- 29274154 TI - Panoramic and skull imaging may aid in the identification of multiple myeloma lesions. AB - BACKGROUND: The purpose of this study was to investigate the presence of punched out lesions in craniofacial bones using three different radiographic protocols in a large cohort of patients. MATERIAL AND METHODS: One hundred fifty-five MM patients were evaluated using panoramic and skull (frontal and lateral) radiographs, which were performed in all patients at the time of MM diagnosis. The diagnostic potential for detecting punched-out lesions was compared among the radiographic techniques. RESULTS: MM punched-out lesions were identified in 135 (87%) panoramic radiographs, 141 (91%) frontal and 144 (93%) lateral skull radiographs. Punched out-lesions were synchronously present in skull and jawbones in 129 (83.23 %) cases. The lesions were detected exclusively in skull in 18 (11.61%) cases and exclusively in jawbones in 6 (3.87%) cases. Punched out-lesion mainly affected the skull and the jawbones in a synchronous way (p<0.001) rather than separately. CONCLUSIONS: All investigated radiographic techniques (panoramic, frontal and lateral skull approaches) demonstrated high detection rates for MM punched-out lesions in craniofacial bones. Panoramic radiography may aid to the radiographic protocols to identify multiple myeloma bone lesions. PMID- 29274155 TI - Oral appliance therapy in obstructive sleep apnea: Long-term adherence and patients experiences. AB - BACKGROUND: Despite the advances in the treatment of obstructive sleep apnea (OSA) with mandibular advancement appliances (MAA), their effectiveness is dependent on the patients compliance. Our aims were to evaluate the long-term adherence to MAA therapy and patients experiences of the treatment in OSA. MATERIAL AND METHODS: Sixty-nine patients (52 males, 17 females; Mean age: 54.4+/ 10.8 years) were included in the study. The subjects were mild (56%) and moderate (44%) OSA patients who had been treated using MAA at least 4 years prior to the study. A phone survey was used to determine the demographic characteristics of the patients, as well as to assess self-reported adherence to therapy, subjective long-term effectiveness, and patient experiences with the appliance. Descriptive statistics, Pearson Chi-square test, and independent samples t-test were used for data analysis. RESULTS: Only 22 (32%) patients reported using the appliance regularly. Most of the non-adherent patients had stopped using their appliances in the first year (55%). The mean duration of appliance use was 33.5 months (Median: 12 months). No significant differences in appliance type, OSA severity, educational level, gender, marital status, income status, employment status or place of residence existed between adherent and non-adherent subjects. Adherent subjects were significantly younger than non-adherent subjects (Age: 50.6 +/- 11.9 versus 56.1 +/- 9.9, p < 0.05). The most common reasons reported by patients were inability to adapt to the appliance (62%) and pain in the temporomandibular joint (38%). The most common factors associated with continued usage were effectiveness (100%) and ease of use (64%). CONCLUSIONS: The overall long-term nonadherence to MAA therapy in mild-to moderate OSA patients was high suggesting that barriers to MAA therapy adherence should be prevented to increase the efficiency of oral appliance treatment in OSA and achieve better outcomes for this disease. PMID- 29274156 TI - Autogenous teeth used for bone grafting: A systematic review. AB - BACKGROUND: Recently, bone graft materials using permanent teeth have come to light, and clinical and histological outcomes of this material have been confirmed by some studies. The aim of this systematic review was to evaluate the reliability of the autogenous tooth bone graft material applied to alveolar ridge augmentation procedures. MATERIAL AND METHODS: A systematic review of literature was conducted analyzing articles published between 2007 and 2017. The following four outcome variables were defined: a) implant stability b) post-operative complication c) evaluation of implant survival and failure rates, and d) histological analysis. A total of 108 articles were identified; 6 were selected for review. Based on the PICO (problem, intervention, comparison, outcome) model, the chief question of this study was: Can patients with alveolar ridge deficiency be successfully treated with the autogenous teeth used as bone graft? RESULTS: The mean primary stability of the placed implants was 67.3 ISQ and the mean secondary stability was 75.5 ISQ. The dehiscence of the wound was the most frequent complication with a rate of 29.1%. Of the 182 analyzed implants, the survival rate was 97.7% and the failure rate was 2.3%. In the histological analysis, most of studies reported bone formation. CONCLUSIONS: There is insufficient evidence regarding the effects of autogenous teeth used for bone grafting to support any definitive conclusions, although it has been shown clinically safe and good bone forming capacity, and good results are shown about implant stability. PMID- 29274157 TI - Nonsyndromic cleft lip and palate, gastric cancer and tooth agenesis. AB - BACKGROUND: To determine the frequency of nonsyndromic cleft lip and/or palate (NSCL/P) in first-degree relatives and to analyze the prevalence of tooth agenesis in patients with gastric cancer. MATERIAL AND METHODS: This cross sectional, observational, case-control study included 798 patients attended at hospital Santa Casa in Montes Claros, Minas Gerais and Alfa Institute of Gastroenterology of the Federal University of the Minas Gerais. Information on basic demographic data and tooth agenesis of both groups and their family history of NSCL/P in first-degree relatives were evaluated. The collected information was stored in a database and analyzed using statistical program SPSS version 21.0 and the values with p<0.05 were considered statistically significant. RESULTS: Of the 798 patients, 113 (14.16%) consisted of the case group and 685 of the control group (85.84%). Non-Caucasian males were the most affected, although no differences among the groups were detected. Of all participants (n=798), 66 (8.27%) presented tooth agenesis and 25 (3.13%) presented oral cleft in first degree relative. CONCLUSIONS: Our results no found increase in the frequency of tooth agenesis in patients with gastric cancer and in the frequency of NSCL/P in the first-degree relatives of patients with gastric cancer. PMID- 29274158 TI - Prospective study of the 532 nm laser (KTP) versus diode laser 980 nm in the resection of hyperplastic lesions of the oral cavity. AB - BACKGROUND: The aim of this study is to evaluate the resection of hyperplastic lesions on the buccal mucosa comparing the 532nm laser (KTP), versus diode 980nm laser, considering pain, scarring, inflammation and drug consumption that occurred postoperatively with each lasers. MATERIAL AND METHODS: A prospective study of consecutive series of 20 patients in two groups that presents hyperplastic lesions on the buccal mucosa. The choice of the KTP laser or diode 980nm laser for the surgery was made randomly. The power used was 1.5W in both groups in a continuous wave mode with a 320 MUm optical fiber. Parameters of pain, scarring, inflammation and consumption of drugs were recorded by a Numerical Rating Scale and evaluated postoperatively. These recordings were made the day of the surgery, 24 hours after, 14 and 28 days after. RESULTS: Pain and inflammation was light - moderate. The consumption of paracetamol was somewhat higher in the diode 980nm laser versus the KTP laser after 24 hours, although data was not statistically significant; significant differences were found after 28 days in regards to pain (p = 0.023) and inflammation (p = 0.023), but always in the absence parameter so we find no pain in both lasers. Scarring in the two types of laser showed no differences along the visits, with not detected scar retractable. CONCLUSIONS: Although there is a slight histological difference regarding the KTP laser in the oral soft tissues for clinical use, both wavelengths are very suitable for excision of oral fibroma. PMID- 29274159 TI - Effect of implant placement depth on the peri-implant bone defect configurations in ligature-induced peri-implantitis: An experimental study in dogs. AB - BACKGROUND: The subcrestal placement of implant platform has been considered a key factor in the preservation of crestal bone, but the influence of implant placement depth on bone remodeling combined with peri-implantitis is not fully understood. The aim of this study was to assess the effect of the crestal or subcrestal placement of implants on peri-implant bone defects of ligature-induced peri-implantitis in dogs. MATERIAL AND METHODS: Eight weeks after tooth extraction in six beagle dogs, two different types of implants (A: OsseoSpeed(TM), Astra, Molndal, Sweden; B: Integra-CP(TM), Bicon, Boston, USA) were placed at either crestal or subcrestal (-1.5 mm) positions on one side of the mandible. Ligature-induced peri-implantitis was initiated four weeks after the installation of the healing abutment connections. After 12 weeks, tissue biopsies were processed for histological analyses. RESULTS: Supra-alveolar bone loss combined with a shallow infrabony defect was observed in crestal level implants while deep and wide infrabony defects were present in subcrestal level groups. Subcrestal groups showed significantly greater ridge loss, depths and widths of infrabony defects when compared to crestal groups (P <0.001). CONCLUSIONS: Within the limitations of the animal study, it can be stated that the implants at subcrestal position displayed greater infra-osseous defect than implants at crestal position under an experimental ligature-induced peri implantitis. PMID- 29274160 TI - Correlation between the visibility of submandibular fossa and mandibular canal cortication on panoramic radiographs and submandibular fossa depth on CBCT. AB - BACKGROUND: To identify a correlation between the submandibular fossa (SF) visibility and mandibular canal (MC) cortication on panoramic image and the depth of SF measured on CBCT and also correlation between the depth of SF and vertical and horizontal location of MC on CBCT. MATERIAL AND METHODS: 500 CBCT scans and panoramic radiographs were evaluated. SF depth types were classified as type I (< 2mm); type II (2-3mm) and type III (> 3mm) on CBCT. Visibility of SF and the cortication of MC on panoramic radiographs were compared with the depth of SF on CBCT. Distances between MC and mandibular inferior, buccal and lingual cortices were measured. RESULTS: No statistically significant correlation was found between radiolucent appearances of SF, cortication of MC, and depth of SF. The deepest part of the fossa was in the second molar area followed by third and first molars. Negative weak correlations were found between B-MC, L-MC distances and depth of SF. CONCLUSION: Visibility of SF and cortication of MC on panoramic radiographs did not correlate with the depth of SF. A marked radiolucent submandibular fossa on panoramic image does not undoubtedly indicate a deep fossa, which emphasizes the importance of 3-D imaging in implant planning. PMID- 29274161 TI - Lower lip squamous cell carcinoma in patients with photosensitive disorders: Analysis of cases treated at the Brazilian National Cancer Institute (INCA) from 1999 to 2012. AB - BACKGROUND: Lower lip squamous cell carcinoma (LLSCC) is a common malignancy of the head and neck, being mainly a consequence of a chronic exposure to ultraviolet (UV) light solar radiation. Here, we evaluated the clinicopathological profile of patients with photosensitive disorders (xeroderma pigmentosum, lupus erythematosus and albinism) that developed LLSCC. MATERIAL AND METHODS: Data from patients who had a diagnosed LLSCC with a prior xeroderma pigmentosum, lupus erythematosus or albinism diagnosis that were treated at INCA from 1999 to 2012 were collected from patients medical records (n=16). The control group was composed of 68 patients with LLSCC without a medical history of photosensitivity. The clinicopathological data of this study population were collected and the association between these variables was analyzed by Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method and compared by log-rank test. All statistical analyses were performed using SPSS statistics package. RESULTS: The mean age of patients in the photosensitive and non-photosensitive groups was 42 years and 67 years, respectively (p<0.0001). A previous history of malignant diseases was more common in the photosensitive group (p=0.001). In both groups, most tumors showed a pathological stage I/II disease. Overall and cancer-specific survival were not statistically different. However, disease-free interval showed a significant difference (p=0.01) between the photosensitive and non-photosensitive patients. CONCLUSIONS: Photosensitive patients presented LLSCC at earlier age but it usually was not the primary tumor in these patients. Furthermore, a more aggressive pathological behavior was not seen when compared with tumors from non-photosensitive patients. The disease-free interval was lower in photosensitive patients, as expected. PMID- 29274162 TI - Low-level laser therapy and anesthetic infiltration for orofacial pain in patients with fibromyalgia: a randomized clinical trial. AB - BACKGROUND: To compare the analgesic effect of anesthetic infiltration of lidocaine 2% and low-level laser therapy (LLLT) by GaAlAs into tender points of patients with orofacial pain and fibromyalgia (FM). MATERIAL AND METHODS: A randomized clinical trial was performed with adults (N=66) that were allocated into two groups (1:1): Group A received LLLT irradiation by Diode Laser GaAlAs (780nm) with expositions twice a week during six weeks and Group B was treated with anesthetic infiltration of lidocaine 2% without vasoconstrictor once a week for four weeks. The pain assessment included the Visual Analogic Scale (VAS) and tenderness to palpation. RESULTS: No dropout and adverse effect was observed during the study. The pain decreased significantly in each group after the treatment (p=0.0001, beta=1.0), even though no statistical difference was found between both treatments (p=0.46, beta= 0.82). The presence of tender points decreased after both treatments, with responsively in some types of masticatory muscles (p<0.05) except posterior temporalis muscle. The patients perception showed that both treatments were effective and a few patients reported that the treatment did not improve welfare. CONCLUSIONS: The LLLT by GaAlAs and anesthetic infiltration of lidocaine 2% were equally effective to control orofacial pain in FM individuals. PMID- 29274163 TI - Masseter and temporalis muscle electromyography findings after lower third molar extraction. AB - BACKGROUND: The main clinical application of electromyography is to detect abnormalities in muscle function, to assess muscle activity for purposes of recruitment, and in the biomechanics of movement. OBJECTIVES: To analyze electromyography (EMG) findings for masticatory muscles during chewing following surgical extraction of lower third molars, and to determine any correlation between pain, inflammation, trismus, and the EMG data registered. MATERIAL AND METHODS: This prospective study included 31 patients. Surface EMG was used to study masseter and temporalis muscle function before lower third molar extraction and 72 hours and seven days after surgery. Clinical variables, pain, inflammation, and trismus were registered before and after surgery. RESULTS: Studying the area and size of the masticatory muscles, higher values were found for temporalis than masseter muscles, regardless of the surgical side, which points to the greater involvement of the temporalis muscle in mastication. Comparing the side where surgery had been performed with the non-surgical side, a sharp and statistically significant reduction in amplitude and area were noted on the surgical side reflecting major functional affectation. One week after surgery, amplitude and area had almost returned to base-line values, indicating almost complete recovery. While pain decreased progressively after surgery, inflammation peaked at 72 hours, while mouth opening reached a minimum at this time, returning to normality within the week. CONCLUSIONS: Surgical extraction of lower third molars produces changes to electromyography activity that are more evident during the first hours after surgery and closely related to the intensity of pain suffered and the patient's inflammatory responses, although they are not related to mouth opening capacity. PMID- 29274164 TI - A clinical diagnosis of oral leukoplakia; A guide for dentists. AB - BACKGROUND: In view of the many white or predominantly white lesions of the oral mucosa it is a challenge for dentists to clinically identify a leukoplakia, being a potentially (pre)malignant lesion. MATERIAL AND METHODS: Based on the available literature and experience of the authors the parameters of a clinical diagnosis of oral leukoplakia have been studied. RESULTS: A guide has been presented that should help dentists to establish a clinical diagnosis of leukoplakia as accurate as possible. CONCLUSIONS: Probably in most parts of the world dentists will need the help of a specialist for confirmation or exclusion of the clinical diagnosis of oral leukoplakia and for further management of the patient, including patient information. PMID- 29274165 TI - Epidemiologic study of odontogenic and non-odontogenic cysts in children and adolescents of a Brazilian population. AB - BACKGROUND: the objective of this study was to describe the frequency of cystic lesions in a Brazilian population of patients histopathologically diagnosed in the first and second decade of life. MATERIAL AND METHODS: Retrospective descriptive cross-sectional study was performed. Biopsy records were obtained from the archives of a Brazilian referral center between 1980 and 2016. RESULTS: A total of 2.114 biopsy records of pediatric patients were analyzed with oral and maxillofacial lesions. Data such as gender, age, anatomical location, and histopathological diagnosis were collected and categorized. Among all oral and maxillofacial lesions (n=2.114), were diagnosed 294 cases of odontogenic cysts (13.9%) and 16 cases of non-odontogenic cysts (0.8%). The most frequent lesions in each group were, respectively: radicular cyst (n=145) and epidermoid cyst (n=4). These lesions were most common in female (n=158), with a mean age of 14 years. For intraosseous lesions, the mandible (n=148) was the most affected anatomic site; moreover, the floor of the mouth (n=6) was most affected by cysts in soft tissues. CONCLUSIONS: Odontogenic cysts were relatively common in population studied, but non-odontogenic cysts were rare in these patients. PMID- 29274166 TI - Rapid screening of inorganic and organic anions in liquid by-products from hydrothermal treatment of biomass by capillary electrophoresis. AB - A simple and rapid capillary electrophoresis method with capacitively coupled contactless conductivity detection (CE-C4 D) for the simultaneous determination of inorganic and organic anions in liquid product obtained from the hydrothermal treatment of biomass residues is presented. Under the optimal analytical conditions, limits of detection ranged from 1.8 to 9.4 MUM for most target solutes and 53 MUM for citrate. Relative standard deviations were below 0.5% for migration times and within 0.6-6.5% for peak areas for all solutes. The proposed method was successfully applied for the rapid determination and screening of inorganic and organic anions in liquid product produced following differing hydrothermal treatment temperatures for banana and pineapple biomass, and the contribution of organic acid formation to acidity in the liquid was evaluated. CE C4 D could be a suitable method for the optimization or tailoring of HTT conditions for desired liquid product composition, and additionally for determination of the best variety(s) of biomass to use in such processes. PMID- 29274167 TI - Effects of Photobiomodulation on SOFAT, A T-cell-derived Cytokine, May Explain Accelerated Orthodontic Tooth Movement. AB - Orthodontic tooth movement is based on mechanical forces inducing bone remodeling, and several methods have been proposed to increase tooth movement, including photobiomodulation. This study evaluated, in an animal model, the effects of photobiomodulation on SOFAT-a secreted osteoclastogenic factor of activated T cells and RANK-L during tooth movement. The results showed that tooth displacement, RANK-L and SOFAT levels were significantly greater compared to Control group. SOFAT may play an important role in bone remodeling during orthodontic movement, possibly increasing the osteoclast cells at the compression area and bone remodeling activity. PMID- 29274168 TI - Prophylactic supplement with melatonin successfully suppresses the pathogenesis of periodontitis through normalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway. AB - Periodontitis (PD) is an inflammatory disease characterized by gingival inflammation and resorption of alveolar bone. Impaired receptor activator of nuclear factor-kappa B ligand/osteoprotegerin (RANKL/OPG) signaling caused by enhanced production of pro-inflammatory cytokines plays an essential role in the pathogenesis of PD. Considering melatonin possesses significant anti-inflammatory property, this study aimed to determine whether prophylactic treatment with melatonin would effectively normalize RANKL/OPG signaling, depress toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88)-mediated pro inflammatory cytokine activation, and successfully suppress the pathogenesis of PD. PD was induced in adult rats by placing the ligature at molar subgingival regions. Fourteen days before PD induction, 10, 50, or 100 mg/kg of melatonin was intraperitoneally injected for consecutive 28 days. Biochemical and enzyme-linked immunosorbent assay were used to detect TLR4/MyD88 activity, RANKL, OPG, interleukin 1beta, interleukin 6, and tumor necrosis factor-alpha levels, respectively. The extent of bone loss, bone mineral intensity, and calcium intensity was further evaluated by scanning electron microscopy, micro-computed tomography, and energy-dispersive X-ray spectroscopy. Results indicated that high RANKL/OPG ratio, TLR4/MyD88 activity, and pro-inflammatory cytokine levels were detected following PD. Impaired biochemical findings paralleled well with severe bone loss and reduced calcium intensity. However, in rats pretreated with melatonin, all above parameters were successfully returned to nearly normal levels with maximal change observed in rats receiving 100 mg/kg. As prophylactic treatment with melatonin effectively normalizes RANKL/OPG signaling by depressing TLR4/MyD88-mediated pro-inflammatory cytokine production, dietary supplement with melatonin may serve as an advanced strategy to strengthen oral health to counteract PD-induced destructive damage. PMID- 29274169 TI - Muscle damage protective effect by two maximal isometric contractions on maximal eccentric exercise of the elbow flexors of the contralateral arm. AB - Muscle damage after 30 maximal eccentric contractions of the elbow flexors (30MVEC) is reduced when the same exercise is performed by the opposite arm, and when two maximal voluntary isometric contractions at a long muscle length (2MVIC) are performed prior to 30MVEC by the same arm. This study investigated the hypothesis that 2MVIC would attenuate muscle damage after 30MVEC performed by the opposite arm. Untrained young (20-25 years) men were placed into 1 of 4 experimental groups that performed 2MVIC at 1 (1d), 2 (2d), 4 (4d), or 7 days (7d) before 30MVEC by the opposite arm, or one control group that performed 30MVEC only (n = 13/group). Changes in indirect muscle damage markers after 30MVEC were compared among the groups by mixed-design two-way ANOVA. Maximal voluntary concentric contraction torque, range of motion, plasma creatine kinase activity, and muscle soreness did not change significantly after 2MVIC. Changes in these variables after 30MVEC were smaller (P < .05) for 1d (eg, peak soreness: 45 +/- 21 mm) and 2d groups (46 +/- 20 mm) than control group (66 +/- 18 mm), without significant differences between 1d and 2d groups. No significant differences in the changes were found among 4d, 7d, and control groups, except for soreness showing smaller (P < .05) increases for 4d group (54 +/- 19 mm) than 7d (62 +/- 17 mm) and control groups. These results supported the hypothesis and showed that muscle damage induced by 30MVEC was reduced by 2MVIC performed 1-2 days prior to 30MVIC by the contralateral arm. PMID- 29274170 TI - The impact of Early Warning Score and Rapid Response Systems on nurses' competence: An integrative literature review and synthesis. AB - AIMS AND OBJECTIVES: To describe, interpret and synthesise the current research findings on the impact of the Early Warning Score and Rapid Response Systems on nurses' competence in identifying and managing deteriorating patients in general hospital wards. BACKGROUND: As patient safety initiatives designed to ensure the early identification and management of deteriorating patients, the Early Warning Score and Rapid Response Systems have broad appeal. However, it is still unclear how these systems impact nurses' competence when these systems are used in general hospital wards. METHODS: CINAHL, PubMed, Cochrane, EMBASE and Ovid MEDLINE databases were systematically searched for relevant articles. Articles were appraised, a thematic analysis was conducted, and similar and divergent perspectives on emergent themes and subthemes were extracted by a team of researchers. RESULTS: Thirty-six studies met the inclusion criteria. The analysis of findings showed how the Early Warning Score and Rapid Response Systems impacted three competence areas: (i) Nurses' competence in assessing and caring for patients related to the subthemes: (a) sensing clinical deterioration and (b) the development of skills and knowledge. (ii). Nurses' competence in referring patients, related to the subthemes: (a) deciding whether to summon help and (b) the language and communication lines in the referral process. (ii) Nurses' coping and mastery experiences. CONCLUSION: The impact of the Early Warning Score and Rapid Response Systems on nurses' competence in identifying and managing deteriorating patients is beneficial but also somewhat contradictory. RELEVANCE TO CLINICAL PRACTICE: A greater understanding of nurses' development of competence when using the Early Warning Score and Rapid Response Systems will facilitate the design of implementation strategies and the use of these systems to improve practice. PMID- 29274172 TI - Dissemination of scholarship across eight cohorts of doctor of nursing practice graduates. AB - AIMS AND OBJECTIVES: To evaluate the publication record across eight cohorts of post-master's Doctor of Nursing Practice graduates. BACKGROUND: Dissemination of findings from evidence-based practice is described in the American Association of the Colleges of Nursing, Doctor of Nursing Practice Essential III. Students in Doctor of Nursing Practice programmes are expected to generate deliverables (e.g., a manuscript) of evidence to improve practice or patient outcomes. DESIGN: A descriptive study was conducted to determine whether two key manuscripts (i.e., integrative review and an evidence-based quality improvement project) were disseminated in peer-reviewed journals, and if so, the length of time from graduation to publication. Co-authorship with faculty advisors and contributors was also examined. RESULTS: The number of evidence-based quality improvement publications outpaces the number of integrative reviews over this span of time. Time to publication from graduation has decreased in recent years. CONCLUSIONS: Expecting, rather than encouraging a publishable-ready manuscript as a course deliverable would further student's motivation to disseminate their scholarship. Focused attention on faculty co-authorship may help increase the number of successful student publications for both integrative reviews and evidence-based quality improvement projects and decrease the time from graduation for those publications. RELEVANCE TO CLINICAL PRACTICE: Dissemination of academic scholarly work is an expected outcome for Doctor of Nursing Practice graduates who impact clinical, operational and financial outcomes in complex healthcare delivery systems. PMID- 29274171 TI - Landscape attributes governing local transmission of an endemic zoonosis: Rabies virus in domestic dogs. AB - Landscape heterogeneity plays an important role in disease spread and persistence, but quantifying landscape influences and their scale dependence is challenging. Studies have focused on how environmental features or global transport networks influence pathogen invasion and spread, but their influence on local transmission dynamics that underpin the persistence of endemic diseases remains unexplored. Bayesian phylogeographic frameworks that incorporate spatial heterogeneities are promising tools for analysing linked epidemiological, environmental and genetic data. Here, we extend these methodological approaches to decipher the relative contribution and scale-dependent effects of landscape influences on the transmission of endemic rabies virus in Serengeti district, Tanzania (area ~4,900 km2 ). Utilizing detailed epidemiological data and 152 complete viral genomes collected between 2004 and 2013, we show that the localized presence of dogs but not their density is the most important determinant of diffusion, implying that culling will be ineffective for rabies control. Rivers and roads acted as barriers and facilitators to viral spread, respectively, and vaccination impeded diffusion despite variable annual coverage. Notably, we found that landscape effects were scale-dependent: rivers were barriers and roads facilitators on larger scales, whereas the distribution of dogs was important for rabies dispersal across multiple scales. This nuanced understanding of the spatial processes that underpin rabies transmission can be exploited for targeted control at the scale where it will have the greatest impact. Moreover, this research demonstrates how current phylogeographic frameworks can be adapted to improve our understanding of endemic disease dynamics at different spatial scales. PMID- 29274173 TI - Investigation of autophagy and differentiation of myenteric interstitial cells of Cajal in the pathogenesis of gastric motility disorders in rats with functional dyspepsia. AB - Interstitial cells of Cajal (ICC), especially myenteric interstitial cells of Cajal (ICC-MY), are key to gastrointestinal motility. However, their role in the pathogenesis of functional dyspepsia (FD) is unclear. Therefore, autophagy and differentiation of ICC-MY were investigated to elucidate the pathogenesis of gastric motility disorder in FD. FD model was induced by chronic stress via tail clamping in rats, which was assessed by the vital signs of rats, gastric emptying rate result, and histology. The ultrastructure of ICC-MY was examined using transmission electron microscope. In ICC-MY, changes in autophagic biomarkers (Beclin1 and LC3B) and differentiation biomarkers (c-kit and SCF) were evaluated with in situ hybridization, quantitative real time PCR, immunofluorescence, and Western blot, respectively. The FD model was successfully induced in rats, as evidenced by the abnormal vital signs (such as loss of appetite, liquid excreta, less activity, and slower weight gain), the decrease in gastric emptying rates, and little pathological change in gastric antrum tissue. Compared with the control group, FD caused increased organelle denaturation or reduction and increase in vacuolization. FD also promoted generation of autophagosomes in ICC MY. Moreover, increased the expression of Beclin1 and LC3B, but decreased expression of c-kit and SCF. Excessive autophagy and abnormal differentiation of ICC-MY may contribute to the pathogenesis of gastric motility disorder in FD. PMID- 29274174 TI - Prophylactic antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus can be stopped at delivery. PMID- 29274175 TI - Environmental effects on fine-scale spatial genetic structure in four Alpine keystone forest tree species. AB - Genetic responses to environmental changes take place at different spatial scales. While the effect of environment on the distribution of species' genetic diversity at large geographical scales has been the focus of several recent studies, its potential effects on genetic structure at local scales are understudied. Environmental effects on fine-scale spatial genetic structure (FSGS) were investigated in four Alpine conifer species (five to eight populations per species) from the eastern Italian Alps. Significant FSGS was found for 11 of 25 populations. Interestingly, we found no significant differences in FSGS across species but great variation among populations within species, highlighting the importance of local environmental factors. Interannual variability in spring temperature had a small but significant effect on FSGS of Larix decidua, probably related to species-specific life history traits. For Abies alba, Picea abies and Pinus cembra, linear models identified spring precipitation as a potentially relevant climate factor associated with differences in FSGS across populations; however, models had low explanatory power and were strongly influenced by a P. cembra outlier population from a very dry site. Overall, the direction of the identified effects is according to expectations, with drier and more variable environments increasing FSGS. Underlying mechanisms may include climate-related changes in the variance of reproductive success and/or environmental selection of specific families. This study provides new insights on potential changes in local genetic structure of four Alpine conifers in the face of environmental changes, suggesting that new climates, through altering FSGS, may also have relevant impacts on plant microevolution. PMID- 29274176 TI - Population genomic analysis suggests strong influence of river network on spatial distribution of genetic variation in invasive saltcedar across the southwestern United States. AB - Understanding the complex influences of landscape and anthropogenic elements that shape the population genetic structure of invasive species provides insight into patterns of colonization and spread. The application of landscape genomics techniques to these questions may offer detailed, previously undocumented insights into factors influencing species invasions. We investigated the spatial pattern of genetic variation and the influences of landscape factors on population similarity in an invasive riparian shrub, saltcedar (Tamarix L.) by analysing 1,997 genomewide SNP markers for 259 individuals from 25 populations collected throughout the southwestern United States. Our results revealed a broad scale spatial genetic differentiation of saltcedar populations between the Colorado and Rio Grande river basins and identified potential barriers to population similarity along both river systems. River pathways most strongly contributed to population similarity. In contrast, low temperature and dams likely served as barriers to population similarity. We hypothesize that large scale geographic patterns in genetic diversity resulted from a combination of early introductions from distinct populations, the subsequent influence of natural selection, dispersal barriers and founder effects during range expansion. PMID- 29274177 TI - Links between parental life histories of wild salmon and the telomere lengths of their offspring. AB - The importance of parental contributions to offspring development and subsequent performance is self-evident at a genomic level; however, parents can also affect offspring fitness by indirect genetic and environmental routes. The life history strategy that an individual adopts will be influenced by both genes and environment; and this may have important consequences for offspring. Recent research has linked telomere dynamics (i.e., telomere length and loss) in early life to future viability and longevity. Moreover, a number of studies have reported a heritable component to telomere length across a range of vertebrates, although the effects of other parental contribution pathways have been far less studied. Using wild Atlantic salmon with different parental life histories in an experimental split-brood in vitro fertilization mating design and rearing the resulting families under standardized conditions, we show that there can be significant links between parental life history and offspring telomere length (studied at the embryo and fry stage). Maternal life history traits, in particular egg size, were most strongly related to offspring telomere length at the embryonic stage, but then became weaker through development. In contrast, paternal life history traits, such as the father's growth rate in early life, had a greater association in the later stages of offspring development. However, offspring telomere length was not significantly related to either maternal or paternal age at reproduction, nor to paternal sperm telomere length. This study demonstrates both the complexity and the importance of parental factors that can influence telomere length in early life. PMID- 29274178 TI - Assessing uncertainty in the burden of hepatitis C virus: Comparison of estimated disease burden and treatment costs in the UK. AB - Hepatitis C virus (HCV) is a major and growing public health concern. We need to know the expected health burden and treatment cost, and understand uncertainty in those estimates, to inform policymaking and future research. Two models that have been important in informing treatment guidelines and assessments of HCV burden were compared by simulating cohorts of individuals with chronic HCV infection initially aged 20, 35 and 50 years. One model predicts that health losses (measured in quality-adjusted life-years [QALYs]) and treatment costs decrease with increasing initial age of the patients, whilst the other model predicts that below 40 years, costs increase and QALY losses change little with age, and above 40 years, they decline with increasing age. Average per-patient costs differ between the models by up to 38%, depending on the patients' initial age. One model predicts double the total number, and triple the peak annual incidence, of liver transplants compared to the other model. One model predicts 55%-314% more deaths than the other, depending on the patients' initial age. The main sources of difference between the models are estimated progression rates between disease states and rates of health service utilization associated with different disease states and, in particular, the age dependency of these parameters. We conclude that decision-makers need to be aware that uncertainties in the health burden and economic cost of HCV disease have important consequences for predictions of future need for care and cost-effectiveness of interventions to avert HCV transmission, and further quantification is required to inform decisions. PMID- 29274179 TI - Brief telephone interventions for problem gambling: a randomized controlled trial. AB - BACKGROUND AND AIMS: Problem gambling is a significant public health issue world wide. There is substantial investment in publicly funded intervention services, but limited evaluation of effectiveness. This study investigated three brief telephone interventions to determine whether they were more effective than standard helpline treatment in helping people to reduce gambling. DESIGN: Randomized clinical trial. SETTING: National gambling helpline in New Zealand. PARTICIPANTS: A total of 462 adults with problem gambling. INTERVENTIONS AND COMPARATOR: (1) Single motivational interview (MI), (2) single motivational interview plus cognitive-behavioural self-help workbook (MI + W) and (3) single motivational interview plus workbook plus four booster follow-up telephone interviews (MI + W + B). Comparator was helpline standard care [treatment as usual (TAU)]. Blinded follow-up was at 3, 6 and 12 months. MEASUREMENTS: Primary outcomes were days gambled, dollars lost per day and treatment goal success. FINDINGS: There were no differences across treatment arms, although participants showed large reductions in gambling during the 12-month follow-up period [mean reduction of 5.5 days, confidence interval (CI) = 4.8, 6.2; NZ$38 lost ($32, $44; 80.6%), improved (77.2%, 84.0%)]. Subgroup analysis revealed improved days gambled and dollars lost for MI + W + B over MI or MI + W for a goal of reduction of gambling (versus quitting) and improvement in dollars lost by ethnicity, gambling severity and psychological distress (all P < 0.01). MI + W + B was associated with greater treatment goal success for higher gambling severity than TAU or MI at 12 months and also better for those with higher psychological distress and lower self-efficacy to MI (all P < 0.01). TAU and MI were found to be equivalent in terms of dollars lost. CONCLUSIONS: In treatment of problem gambling in New Zealand, brief telephone interventions are associated with changes in days gambling and dollars lost similar to more intensive interventions, suggesting that more treatment is not necessarily better than less. Some client subgroups, in particular those with greater problem severity and greater distress, achieve better outcomes when they receive more intensive treatment. PMID- 29274180 TI - Association of intralipid intake in extremely low birthweight infants with neurodevelopmental outcomes. AB - AIM: To determine whether high intake of intralipid (IL) in extremely low birthweight (ELBW) neonates is associated with higher rates of neuroimpairment and Bayley III scores at two years of corrected age. METHODS: Quartiles of IL received by 389 ELBW infants were linked to neurodevelopmental outcomes. Logistic regression analyses, adjusted for confounders, were performed to determine the association between IL dose and neuroimpairment. Linear regression analyses were performed to predict Bayley III scores. RESULTS: No association was found between IL dose and neuroimpairment A significant association was found between higher IL intake and lower Bayley Cognitive, motor and language scores. Adding breast milk intake to the linear regression eliminated the associations. CONCLUSION: Higher IL intake was associated with lower cognitive, motor and language scores. Breast milk intake eliminated the latter associations, which underscores the important role of breast milk in developmental outcome. PMID- 29274181 TI - Child healthcare nurses' experiences of asking new mothers about intimate partner violence. AB - AIMS AND OBJECTIVES: To investigate child healthcare nurses' experiences of asking mothers of 8-month-old children about intimate partner violence using a two-step questionnaire. BACKGROUND: Exposure to intimate partner violence is detrimental to women and to their children, and its early detection is vital. Child health care is a promising setting for detecting intimate partner violence. DESIGN: The overall project had a quasi-experimental design and was employed in 2015 at 12 child healthcare centres in Sweden. The project aimed to test a two step method for talking about intimate partner violence with mothers (n = 198) at the child healthcare centre. In this article, we disclose the experiences of the intervention from the perspective of the nurses (n = 13) who were educated and involved in the intervention. METHODS: Data were collected by semi-structured interviews, analysed by thematic analysis. RESULTS: Five categories emerged: using the two-step questionnaire method, asking about IPV as an important issue, being comfortable in the professional role and with asking about IPV, the importance of time and place in asking about IPV and spillover effects. CONCLUSIONS: Asking mothers visiting the child health clinic about their experiences of intimate partner violence was seen as an important task. Using a questionnaire could facilitate asking, but the questionnaire must be short and easy to use. Furthermore, the time and place for initiating a talk about this sensitive topic must be carefully chosen. RELEVANCE TO CLINICAL PRACTICE: The Violence in Families questionnaire was regarded as a useful tool and could thus be implemented in practice. However, it is important to offer education to the nurses prior to implementing a routine of asking about intimate partner violence in the child healthcare setting. PMID- 29274182 TI - Screening for problem gambling within mental health services: a comparison of the classification accuracy of brief instruments. AB - BACKGROUND AND AIMS: Despite the over-representation of people with gambling problems in mental health populations, there is limited information available to guide the selection of brief screening instruments within mental health services. The primary aim was to compare the classification accuracy of nine brief problem gambling screening instruments (two to five items) with a reference standard among patients accessing mental health services. DESIGN: The classification accuracy of nine brief screening instruments was compared with multiple cut-off scores on a reference standard. SETTING: Eight mental health services in Victoria, Australia. PARTICIPANTS: A total of 837 patients were recruited consecutively between June 2015 and January 2016. MEASUREMENTS: The brief screening instruments were the Lie/Bet Questionnaire, Brief Problem Gambling Screen (BPGS) (two- to five-item versions), NODS-CLiP, NODS-CLiP2, Brief Biosocial Gambling Screen (BBGS) and NODS-PERC. The Problem Gambling Severity Index (PGSI) was the reference standard. FINDINGS: The five-item BPGS was the only instrument displaying satisfactory classification accuracy in detecting any level of gambling problem (low-risk, moderate-risk or problem gambling) (sensitivity = 0.803, specificity = 0.982, diagnostic efficiency = 0.943). Several shorter instruments adequately detected both problem and moderate-risk, but not low-risk, gambling: two three-item instruments (NODS-CLiP, three-item BPGS) and two four-item instruments (NODS-PERC, four-item BPGS) (sensitivity = 0.854-0.966, specificity = 0.901-0.954, diagnostic efficiency = 0.908-0.941). The four-item instruments, however, did not provide any considerable advantage over the three-item instruments. Similarly, the very brief (two-item) instruments (Lie/Bet and two-item BPGS) adequately detected problem gambling (sensitivity = 0.811-0.868, specificity = 0.938-0.943, diagnostic efficiency = 0.933-0.934), but not moderate-risk or low-risk gambling. CONCLUSIONS: The optimal brief screening instrument for mental health services wanting to screen for any level of gambling problem is the five-item Brief Problem Gambling Screen (BPGS). Services wanting to employ a shorter instrument or to screen only for more severe gambling problems (moderate-risk/problem gambling) can employ the NODS-CLiP or the three item BPGS. Services that are only able to accommodate a very brief instrument can employ the Lie/Bet Questionnaire or the two-item BPGS. PMID- 29274183 TI - Maximal shortening velocity during plantar flexion: Effects of pre-activity and initial stretching state. AB - We investigated the effects of the initial length of the muscle-tendon unit (MTU) and muscle pre-activation on muscle-tendon interactions during plantarflexion performed at maximal velocity. Ultrasound images of gastrocnemius medialis were obtained on 11 participants in three conditions: (a) active plantarflexion performed at maximal velocity from three increasingly stretched positions (10 degrees , 20 degrees , and 30 degrees dorsiflexion), (b) passive plantarflexion induced by a quick release of the ankle joint from the same three positions, and (c) pre-activation, which consisted of a maximal isometric contraction of the plantarflexors at 10 degrees of dorsiflexion followed by a quick release of ankle joint. During the active condition at maximal velocity, initial MTU stretch positively influenced ankle joint velocity (+15.3%) and tendinous tissues shortening velocity (+37.6%) but not the shortening velocity peak value reached by muscle fascicle. The muscle fascicle was shortened during the passive condition; however, its shortening velocity never exceeded peak velocity measured in the active condition. Muscle pre-activation resulted in a considerable increase in ankle joint (+114.7%) and tendinous tissues velocities (+239.1%), although we observed a decrease in muscle fascicle shortening velocity. During active plantarflexion at maximal velocity, initial MTU length positively influences ankle joint velocity by increasing the contribution of tendinous tissues. Although greater initial stretch of the plantarflexors (ie, 30 degrees dorsiflexion) increased the passive velocity of the fascicle during initial movement, its peak velocity was not affected. As muscle pre-activation prevented reaching the maximal muscle fascicle shortening velocity, this condition should be used to characterize tendinous tissues rather than muscle contractile properties. PMID- 29274184 TI - Prevalence of mixed genotype hepatitis C virus infections in the UK as determined by genotype-specific PCR and deep sequencing. AB - The incidence of mixed genotype hepatitis C virus (HCV) infections in the UK is largely unknown. As the efficacy of direct-acting antivirals is variable across different genotypes, treatment regimens are tailored to the infecting genotype, which may pose issues for the treatment of underlying genotypes within undiagnosed mixed genotype HCV infections. There is therefore a need to accurately diagnose mixed genotype infections prior to treatment. PCR-based diagnostic tools were developed to screen for the occurrence of mixed genotype infections caused by the most common UK genotypes, 1a and 3, in a cohort of 506 individuals diagnosed with either of these genotypes. The overall prevalence rate of mixed infection was 3.8%; however, this rate was unevenly distributed, with 6.7% of individuals diagnosed with genotype 3 harbouring genotype 1a strains and only 0.8% of samples from genotype 1a patients harbouring genotype 3 (P < .05). Mixed infection samples consisted of a major and a minor genotype, with the latter constituting less than 21% of the total viral load and, in 67% of cases, less than 1% of the viral load. Analysis of a subset of the cohort by Illumina PCR next-generation sequencing resulted in a much greater incidence rate than obtained by PCR. This may have occurred due to the nonquantitative nature of the technique and despite the designation of false-positive thresholds based on negative controls. PMID- 29274185 TI - Estimating the drink driving attributable fraction of road traffic deaths in Mexico. AB - AIM: To estimate the Drink Driving Attributable Fraction (DDAF) of road traffic injury mortality in car occupants in Mexico during 2010-13. DESIGN: A case control study was conducted to examine the presence of alcohol in analysed body fluids of car occupants killed in fatal crashes (cases) compared with car drivers tested in alcohol-testing checkpoints who were not involved in a fatal collision (controls). Two data sets were used for the period 2010-13: the forensic module of the Epidemiological Surveillance System on Addictions that included car occupants killed in a collision (cases) and a data set from alcohol-testing at police checkpoints available for matching municipalities (controls). SETTING: Mexico. PARTICIPANTS: The analysed study sample included 1718 car occupants killed in a traffic collision and 80 656 drivers tested at alcohol police checkpoints, all from 10 municipalities. MEASUREMENTS: Unadjusted and adjusted odds ratios (OR) of presence of alcohol in body fluids were obtained stratified by sex and age groups and the interaction with these two variables were assessed. The ORs were used to calculate the DDAF. FINDINGS: It was estimated that 19.5% of car occupants' deaths due to road traffic injuries were attributable to alcohol consumption [95% confidence interval (CI) = 19.1-19.9]. The adjusted OR of presence of alcohol was 6.84 (95% CI = 6.06-7.71) overall. For males it was 7.21 (95% CI = 6.35-8.18) and for females it was 4.45 (95% CI = 3.01-6.60). The ORs were similar across younger age bands (10-19 years: 9.61, 95% CI = 6.72-13.73; 20 29 years: 7.70, 95% CI = 6.28-9.4; and 30-49 years: 7.21, 95% CI = 5.98-8.70); and lower but still elevated among older people (50+ years: 3.19, 95% CI = 2.19 4.65). CONCLUSIONS: An estimated 19.5% of car occupant deaths in Mexico may have been caused by alcohol in 2010-13. PMID- 29274187 TI - Sex Differences in Diagnoses, Treatment, and Outcomes for Emergency Department Patients With Chest Pain and Elevated Cardiac Troponin. AB - OBJECTIVE: While sex differences in the treatment and outcomes of subjects with acute coronary syndromes are well documented, little is known about the impact of cardiac troponin (cTn) levels obtained in the emergency department (ED) on the observed sex differences. We sought to determine whether cTn levels by chest pain features modify sex differences in diagnosis, treatment, and outcomes in patients presenting with chest pain suggestive of ischemia. METHODS: All adults presenting to two hospitals in Vancouver, Canada, between May 2008 and March 2013 with ischemic chest pain and with cTn testing were included in the study. Outcomes were obtained through data linkage with population-based administrative data sets, including Vital Statistics (death), Discharge Abstract Database (hospitalizations), and PharmaNet (medications). Cumulative event rates for the composite major adverse cardiac event (MACE) endpoint (death, myocardial infarction [MI], incident admission for heart failure or for angina requiring diagnostic catheterization or revascularization) were estimated for each sex and cTn level using the Kaplan-Meier method; Cox models were used to estimate hazard ratios and 95% confidence interval (CIs) for 1-year MACE and 7-day catheterization. Logistic models were used to estimate odds ratios (ORs) and 95% CI for 90-day medication use. RESULTS: Over the 5-year study period, 25,539 patients presented to the ED with chest pain of which 7,272 (2,933 females and 4,339 males) met the inclusion criteria. Among patients with chest pain with cardiac features/history and cTn > 99th percentile, females were less likely to be diagnosed with MI (46.4% vs. 57.5%). Females in the cTnI > 99th percentile group had the worst outcomes with a 1-year MACE rate of 22.7% (95% CI = 18.5 27.7) versus 18.8% (95% CI = 16.2-21.6), although this difference was attenuated and not statistically significant after adjustment for baseline differences. Overall, females underwent fewer diagnostic catheterizations than males within 7 days of admission to the ED. Even when cTn was above the 99th percentile and the chest pain was cardiac in nature, 48.4% of females underwent a diagnostic catheterization compared to 64.3% of males (p < 0.001). Within 90 days of discharge, females were less likely to use the evidence-based cardiac medications. The most striking sex differences were noted when cTnI levels were > 99th percentile and when the chest pain was cardiac in nature; males filled 25% more prescriptions for statins than their female counterparts. Adjustment for baseline differences did not attenuate this difference. CONCLUSIONS: Sex differences in diagnosis and treatment after presentation to the ED with chest pain are not explained by differences in chest pain features or levels of cTn. Even when females have cardiac chest pain and cTn levels > 99th percentile, they are less likely to be diagnosed with MI, less likely to undergo diagnostic cardiac catheterization within 7 days, and less likely to use evidence-based cardiac medications, but they have the highest 1-year MACE rate. The higher MACE rate appears to be driven by the higher burden of comorbid conditions. PMID- 29274186 TI - Slow evolution of sex-biased genes in the reproductive tissue of the dioecious plant Salix viminalis. AB - The relative rate of evolution for sex-biased genes has often been used as a measure of the strength of sex-specific selection. In contrast to studies in a wide variety of animals, far less is known about the molecular evolution of sex biased genes in plants, particularly in dioecious angiosperms. Here, we investigate the gene expression patterns and evolution of sex-biased genes in the dioecious plant Salix viminalis. We observe lower rates of sequence evolution for male-biased genes expressed in the reproductive tissue compared to unbiased and female-biased genes. These results could be partially explained by the lower codon usage bias for male-biased genes leading to elevated rates of synonymous substitutions compared to unbiased genes. However, the stronger haploid selection in the reproductive tissue of plants, together with pollen competition, would also lead to higher levels of purifying selection acting to remove deleterious variation. Future work should focus on the differential evolution of haploid- and diploid-specific genes to understand the selective dynamics acting on these loci. PMID- 29274188 TI - The presence of multiple NS5A RASs is associated with the outcome of sofosbuvir and ledipasvir therapy in NS5A inhibitor-naive patients with chronic HCV genotype 1b infection in a real-world cohort. AB - It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naive patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naive patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy. PMID- 29274189 TI - The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients. AB - This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)-positive and -negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg-positive and 104 HBeAg-negative patients) who were previously treated with TDF and had post treatment follow-up for at least 6 months (median: 55, IQR 36-85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg-positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg-negative patients. Cox regression analysis revealed that the higher end-of-treatment HBsAg levels were an independent factor of virological relapse in HBeAg-positive and HBeAg negative patients. The end-of-treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg-positive and HBeAg negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg-positive and HBeAg-negative patients who achieved HBsAg <=200 IU/mL and HBsAg <=80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off-therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end-of treatment HBsAg <=80 IU/mL and <=50 IU/mL, respectively. In conclusions, the end of-treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg-positive and HBeAg-negative CHB patients. PMID- 29274190 TI - Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein more reliably distinguishes liver fibrosis stages in non-alcoholic fatty liver disease than serum Mac-2 binding protein. AB - AIM: Serum Mac-2 binding protein (M2BP) and Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+ -M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head-to-head studies have been carried out to compare the two biomarkers in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum M2BP and WFA+ -M2BP levels were compared against clinical characteristics and liver histological manifestations in the same samples collected from 213 biopsy-proven NAFLD patients. RESULTS: Median levels (range) of M2BP and WFA+ -M2BP were 1.58 (0.70-7.75) pg/mL and 0.85 (0.22-11.32) cut-off index (COI), respectively. Fibrosis stages 1, 2, 3, and 4 were determined in 136, 37, 17, and 23 patients, respectively. Median levels of both biomarkers increased stepwise with fibrosis progression. The M2BP and WFA+ -M2BP levels showed a significant positive correlation (r = 0.643, P = 2.91 * 10-26 ), but a marked discrepancy between both biomarkers was noted in five stage 4 and three stage 1 patients, who had high WFA+ -M2BP but relatively low M2BP levels. Most of these outliers had findings suggestive of more advanced fibrosis. For diagnosing any fibrosis severity, WFA+ -M2BP had greater area under the receiver operating characteristic curve (AUC) and predictive accuracy than M2BP. Among eight fibrosis markers/indices, WFA+ -M2BP yielded the second highest AUC (0.832) and the highest predictive accuracy (82.2%) to diagnose cirrhosis. In addition, WFA+ M2BP showed the second highest predictive accuracy to diagnose severe fibrosis (78.4%) and significant fibrosis (76.1%). CONCLUSION: This head-to-head comparison suggests that WFA+ -M2BP is superior to M2BP for distinguishing liver fibrosis stages in NAFLD patients. A marked discrepancy between the two biomarkers may be indicative of advanced NAFLD (UMIN000023286). PMID- 29274191 TI - Acquired coagulopathy in patients with left ventricular assist devices. AB - Chronic heart failure (HF) is a major emerging healthcare problem, associated with a high morbidity and mortality. Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage HF. Despite its great benefit, the use of LVAD is associated with a high risk of complications. Bleeding, pump thrombosis and thromboembolic events are frequently observed complications, with bleeding complications occurring in over a third of the patients. Although the design of the third-generation LVAD has improved greatly, these hemostatic complications still occur. The introduction of an LVAD into the circulatory system results in an altered hematological balance as a consequence of blood-pump interactions, changes in hemodynamics, the rheology, and the concomitant need for anticoagulation while implanted with an LVAD. The majority, if not all, LVAD patients experience a form of platelet dysfunction and impaired von Willebrand factor activity, leading to acquired coagulopathy disorders. Different diagnostic tools and treatment strategies have been reported; however, they require validation in LVAD patients. The present review focuses on acquired coagulopathies, describing the incidence, impact and underlying mechanism of acquired coagulopathy disorders in patients supported by LVADs. In addition, we will discuss diagnostic and management strategies for these acquired coagulopathies. PMID- 29274192 TI - Uptake of direct-acting antiviral treatment for chronic hepatitis C in Australia. AB - A government-funded interferon-free direct-acting antiviral (DAA) treatment programme for chronic hepatitis C virus (HCV) infection has been available in Australia since March 2016. This study assessed the levels and patterns of DAA treatment uptake during March-December 2016 in Australia and described the key features in the development of the programme. All prescriptions in Australia are submitted to the Pharmaceutical Benefits Scheme by dispensing pharmacies. Data on dispensed DAA prescriptions for a longitudinal cohort of individuals, representing a 10% random sample of the Pharmaceutical Benefits Scheme database, were used for estimating DAA treatment uptake and subgroup analyses. The estimated number of 32 400 individuals initiated DAA treatment in 2016, equating to 14% of people with chronic HCV infection in Australia. Most commonly prescribed DAA regimens included sofosbuvir/ledipasvir (56%, n = 18 020), sofosbuvir + daclatasvir (39%, n = 12 600) and sofosbuvir + other agents (4%, n = 1220). Among individuals initiated DAA treatment, 66% (n = 21 430) were men, 43% (n = 13 870) were <=50 years old and 36% (n = 11 670) had cirrhosis. DAA prescriptions were 62% (n = 20 080) by specialists, 19% (n = 6000) by general practitioners (GP) and 20% (n = 6320) by other physicians. Proportion of individuals prescribed DAA by GPs increased from 8% to 31% and proportion of individuals <=50 years old increased from 28% to 61% between March and December. In conclusion, rapid treatment scale-up was observed in the first 10 months of unrestricted DAA programme in Australia. The proportion of prescriptions by GPs increased over time, important for broadened access. A trend towards younger age treatment suggested the broadening of DAA-treated population, potentially including individuals at higher risk of HCV transmission. PMID- 29274193 TI - Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection. AB - The phase 2, open-label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6- or 8-week regimen of simeprevir, daclatasvir and sofosbuvir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early-stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early-stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty-eight patients were treated (6-week group: n = 59; 8-week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early-stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6-week group was viral relapse (11.9%; 7/59). One patient had on-treatment failure due to an early withdrawal (lost to follow-up due to incarceration). One patient with SVR12 in the 6-week group had a late viral relapse at post-treatment week 24. No clinically significant drug-drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct-acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment-naive, HCV GT1-infected patients with early-stage fibrosis or compensated cirrhosis. PMID- 29274194 TI - International comparative field study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories. AB - : Essentials AFSTYLA exhibits ~50% underestimation in activity when the one-stage (OS) assay is utilized. A field study compared the performance of AFSTYLA with Advate in factor VIII activity assays. AFSTYLA activity can be monitored with both the chromogenic substrate and the OS assay. The consistent OS underestimation allows for a conversion factor to be applied to OS results. SUMMARY: Introduction AFSTYLA (antihemophilic factor [recombinant] single chain) is a novel B-domain truncated recombinant factor VIII (rFVIII). For AFSTYLA, an approximate 50% discrepancy was observed between results of the one-stage (OS) and chromogenic substrate (ChS) FVIII activity assays. An investigation was undertaken to test whether there is a linear relationship between ChS and OS assay results that would allow reliable clinical interpretation of results independent of the assay method used. Aims To provide confidence in future clinical monitoring, this field study investigated the performance of AFSTYLA and a full-length rFVIII (Advate(r) ) in FVIII activity assays routinely performed in clinical laboratories. Methods The comparison of AFSTYLA and Advate was performed in an international, multicenter and blinded field study of simulated post infusion samples. The study documented the extent of variability between methods and laboratories and characterized the relationship between the ChS and OS assays. Results Results from 23 laboratories demonstrate that intra and interlaboratory variability in OS assays were similar for both products. When comparing within the OS assay format, there was a similar and reagent-correlated variability in response to different activators for both AFSTYLA and Advate. The OS underestimation was highly predictable and consistent across the complete range of FVIII plasma concentrations. Conclusion Post-infusion plasma AFSTYLA levels can be monitored in patients by the OS and ChS assays. The consistent and predictable difference between the two assay formats provides clinicians with adequate guidance on how to interpret the results of the OS assay using a single conversion factor. PMID- 29274195 TI - Molecular Motions and Interactions in Aqueous Solutions of Thymosin-beta4 , Stabilin C-Terminal Domain (CTD) and Their 1:1 Complex Studied by 1 H NMR Spectroscopy. AB - Wide-line 1 H NMR measurements were extended and all results were reinterpreted in a new thermodynamics-based approach to study aqueous solutions of thymosin beta4 (Tbeta4 ), stabilin C-terminal domain (CTD) and their 1:1 complex. The energy distributions of the potential barriers, which control motion of protein bound water molecules, were determined. Heterogeneous and homogeneous regions were found at the protein-water interface. The measure of heterogeneity gives a quantitative value for the portion of disordered parts in the protein. Ordered structural elements were found extending up to 20 % of the whole proteins. About 40 % of the binding sites of free Tbeta4 become involved in bonds holding the complex together. The complex has the most heterogeneous solvent accessible surface (SAS) in terms of protein-water interactions. The complex is more disordered than Tbeta4 or stabilin CTD. The greater SAS area of the complex is interpreted as a clear sign of its open structure. PMID- 29274196 TI - Musculoskeletal ultrasound for intra-articular bleed detection: a highly sensitive imaging modality compared with conventional magnetic resonance imaging. AB - : Essentials The best imaging modality for joint blood detection in hemophilia is unknown. Blood appearance and detection thresholds were studied with ultrasound and conventional MRI. Ultrasound is sensitive to low volume and concentration of blood, whereas conventional MRI is not. The findings establish the validity of ultrasound for rapid bleed detection in hemophilia care. SUMMARY: Background There is increasing demand for musculoskeletal ultrasound (MSKUS) to detect hemophilic joint bleeding, but there is uncertainty regarding blood detection concentration thresholds or if magnetic resonance imaging (MRI) is more accurate. Aims Compare the sensitivity of blood detection by MSKUS and MRI. Methods Increasing blood concentrations in plasma were imaged with MSKUS and MRI 1-2 h, 3 4 days and 7 days after blood withdrawal in vitro, and after injection into cadaveric pig joints. Additionally, effusions in the joints of two patients with hemophilia joints were imaged, followed by aspiration. MSKUS was performed using an 8-18-MHz linear transducer; MRI was performed at 3T using T1-weighted and T2 weighted fat-suppressed sequences. Images were reviewed by a hematologist certified in MSKUS and a musculoskeletal radiologist. Results MSKUS permitted the detection of blood in vitro and in pig joint spaces at concentrations as low as 5%, demonstrated by the presence of echogenic signals that were absent with plasma alone. In contrast, no differences between fluids were discernible on the T1-weighted or T2-weighted MRI images. Results were confirmed in the two patients with hemophilia. Blood clots demonstrated varying and dynamic echogenicity patterns over time and, using MRI, were visualized best with T2 sequences. Conclusion MSKUS is extremely sensitive in detecting low concentrations of intra articular blood and in discriminating between bloody and non-bloody fluid, whereas conventional MRI is not. These observations demonstrate the advantages of MSKUS over MRI in detecting intra-articular blood, and show that MSKUS is ideal for rapid bleed detection in the clinic. PMID- 29274197 TI - Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C-infected Egyptian cohort: A comparative analysis. AB - In Egypt, hepatocellular carcinoma (HCC) is the most common form of cancer and direct-acting antivirals (DAA) are administered on a large scale to patients with chronic HCV infection to reduce the risk. In this unique setting, we aimed to determine the association of DAA exposure with early-phase HCC recurrence in patients with a history of HCV-related liver cancer. This was a prospective cohort study of an HCV-infected population from one Egyptian specialized HCC management centre starting from the time of successful HCC intervention. The incidence rates of HCC recurrence between DAA-exposed and nonexposed patients were compared, starting from date of HCC complete radiological response and censoring after 2 years. DAA exposure was treated as time varying. Two Poisson regressions models were used to control for potential differences in the exposed and nonexposed group; multivariable adjustment and balancing using inverse probability of treatment weighting (IPTW). We included 116 patients: 53 treated with DAAs and 63 not treated with DAAs. There was 37.7% and 25.4% recurrence in each group after a median of 16.0 and 23.0 months of follow-up, respectively. Poisson regression using IPTW demonstrated an association between DAAs and HCC recurrence with an incidence rate ratio of 3.83 (95% CI: 2.02-7.25), which was similar in the multivariable-adjusted model and various sensitivity analyses. These results add important evidence towards the possible role of DAAs in HCC recurrence and stress the need for further mechanistic studies and clinical trials to accurately confirm this role and to identify patient characteristics that may be associated with this event. PMID- 29274198 TI - Dabigatran versus vitamin k antagonist: an observational across-cohort comparison in acute coronary syndrome patients with atrial fibrillation. AB - : Essentials Acute coronary syndrome (ACS) with atrial fibrillation (AF) is a therapeutic challenge. Dual and triple antithrombotic therapy showed a similar thrombotic risk in ACS patients with AF. The omission of aspirin during the first month did not increase the rate of ischemic events. Replacement of vitamin K antagonist by dabigatran leads to an increased thrombotic risk. SUMMARY: Background Dual antithrombotic therapy comprising a vitamin K antagonist (VKA) plus clopidogrel reduces the incidence of major bleeding compared with triple therapy (VKA + clopidogrel + aspirin) in acute coronary syndrome (ACS) patients with atrial fibrillation (AF), with a similar thrombotic risk. The oral thrombin inhibitor dabigatran (150 mg twice a day) showed superiority over VKA in non valvular AF, but data supporting its use in AF patients presenting with ACS are limited. Objective We sought to evaluate the efficacy of dabigatran vs. VKA in the management of AF patients undergoing percutaneous coronary intervention for an ACS. Methods In this open-label study, 133 consecutive patients received dabigatran plus clopidogrel. Another cohort of 133 patients treated with VKA plus clopidogrel was used as the control group. Results After propensity score adjustment, the cumulative incidence of major adverse cardiovascular events over 24 months was higher with dabigatran vs. VKA (adjusted hazard ratio, 2.28; 95% confidence interval, 1.46-3.56). Similar rates of major bleeding were found (adjusted hazard ratio, 1.17; 95% confidence interval, 0.46-2.96). Conclusions In AF patients presenting with ACS, replacement of VKA by dabigatran concurrently with clopidogrel is associated with an increased thrombotic risk, without a reduction in major bleeding. PMID- 29274199 TI - Dereplication-guided isolation of a new indole alkaloid triglycoside from the hooks of Uncaria rhynchophylla by LC with ion trap time-of-flight MS. AB - Uncaria rhynchophylla (Gou-Teng) as the monarch herb of many formulae (Fufang), e.g. "Tian-Ma-Gou-Teng-Yin," "Ling-Jiao-Gou-Teng-Yin," and "Yi-Gan-San", is a famous traditional Chinese medicine documented in the Chinese pharmacopoeia for mental and cardiovascular diseases. In the traditional Chinese medicine system, only the hook-bearing stems are used as the crude materials for Gou-Teng, and the hooks are always considered more effective than the stems. Focusing on the mono herb and its active constituents from combinatorial formulae is the core idea of reductionism of traditional Chinese medicine theory. Detailed liquid chromatography with mass spectrometry analysis on the hooks of U. rhynchophylla was performed to profile the chemical constituents based on tandem mass spectrometry fragmentation and UV absorption. Under the guidance of liquid chromatography with ion trap/time-of-flight mass spectrometry, one new indole alkaloid triglycoside (1), together with five known compounds 2-6 as the main constituents, were isolated from the hooks of U. rhynchophylla by various column chromatography methods. Compound 1 showed moderate activity on MT1 and MT2 melatonin receptors with agonistic rates of 79.6 and 46.3% at the concentration of 1 mM. This dereplication strategy can be equally applicable to rapidly disclose the active constituents of other Chinese herbs through targeted purification. PMID- 29274200 TI - Basalt fibers functionalized with gold nanoparticles for in-tube solid-phase microextraction. AB - Basalt fibers were functionalized with gold nanoparticles and characterized by scanning electron microscopy and energy-dispersive X-ray spectroscopy. An in-tube solid-phase microextraction device was developed by packing the functionalized basalt fibers in a polyether ether ketone tube. The device was connected into high performance liquid chromatography equipment with a diode array detector to build online enrichment and analysis system. Eight polycyclic aromatic hydrocarbons were used as model analytes, important factors including sampling rate, sampling volume, organic solvent content in sample, and desorption time were investigated. Linear range (0.01-20 MUg/L), detection limits (0.003-0.015 MUg/L), and enrichment factors (130-1628) were given by the online analysis method. Relative standard deviations (n = 5) of extraction repeatability on one tube and tube-to-tube repeatability were less than 5.2 and 14.7%, respectively. The analysis method was applied to detect polycyclic aromatic hydrocarbons in environmental water samples, and relative recoveries ranged from 87 to 128%. PMID- 29274201 TI - iTRAQ-Based Proteomic Analysis Reveals Protein Profile in Plasma from Children with Autism. AB - PURPOSE: Autism is a childhood neurological disorder with poorly understood etiology and pathology. This study is designed to identify differentially expressed proteins that might serve as potential biomarkers for autism. EXPERIMENTAL DESIGN: We perform iTRAQ (isobaric tags for relative and absolute quantitation) analysis for normal and autistic children's plasma of the same age group. RESULTS: The results show that 24 differentially expressed proteins were identified between autistic subjects and controls. For the first time, differential expression of complement C5 (C5) and fermitin family homolog 3 (FERMT3) are related to autism. Five proteins, that is, complement C3 (C3), C5, integrin alpha-IIb (ITGA2B), talin-1 (TLN1), and vitamin D-binding protein (GC) were validated via enzyme-linked immunosorbent assay (ELISA). By ROC (receiver operating characteristic) analysis, combinations of these five proteins C3, C5, GC, ITGA2B, and TLN1 distinguished autistic children from healthy controls with a high AUC (area under the ROC curve) value (0.982, 95% CI, 0.957-1.000, p < 0.000). CONCLUSION: These above described proteins are found involved in different pathways that have previously been linked to the pathophysiology of autism spectrum disorders (ASDs). The results strongly support that focal adhesions, acting cytoskeleton, cell adhesion, motility and migration, synaptogenesis, and complement system are involved in the pathogenesis of autism, and highlight the important role of platelet function in the pathophysiology of autism. PMID- 29274202 TI - 'Very-low-risk' bladder tumours - a new entity? AB - OBJECTIVE: To evaluate the homogeneity of the 'low-risk' bladder cancer group in an attempt to optimise follow-up protocols. PATIENTS AND METHODS: Between June 1998 and December 2008, 211 patients (mean [sd] age of 66.7 [12.8] years) underwent transurethral resection of low-risk bladder cancer. Postoperative follow-up included cystoscopy at 3 and 12 months after surgery, then annually for a total of 5 years, and then annual ultrasonography indefinitely. RESULTS: After a median follow-up of 10 years, 65 patients (30.7%) developed tumour recurrence and three (1.4%) stage progressions. In all, 84 patients (40%) had tumours of <=1 cm; these patients were significantly younger than patients with 1.1-3 cm tumours (64.6 vs 68.3 years, P = 0.03). Their 5-year recurrence-free survival rate was significantly higher (92% vs 70% in patients with larger tumours, P < 0.001). The median time to recurrence was 5.7 years in patients with smaller tumours and 3.6 years in patients with larger tumours (P = 0.03). Only 43.7% of the recurrences in patients with small tumours occurred within 5 years, compared to 75.5% in patients with larger tumours. CONCLUSIONS: Patients with low-risk bladder cancer make an inhomogeneous group. They can be stratified according to tumour size. Patients with tumours of <=1 cm are younger, have lower risk of tumour recurrence, and most of their recurrences arise beyond the recommended 5-year surveillance period. It seems that these patients can be classified separately to a 'very-low-risk' group. Follow-up in these cases can be based on prolonged non invasive evaluations. PMID- 29274203 TI - Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population. AB - INTRODUCTION: To reduce the incidence of hemophilia B (HB) which with no complete cure currently, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are effective and feasible means. However, previous studies about genetic diagnosis in HB mostly just focused on the detection of patients and carriers. Here, we established a comprehensive genetic diagnosis strategy for HB and worked it out in Chinese population. The strategy includes the detection of patients and carriers, prenatal diagnosis, and PGD. METHODS: Seven unrelated HB families from Chinese population involved in this study. Firstly, probands and available members were carried out coagulation laboratory assays, and the clinical information has been recorded. Secondly, we used DNA direct sequencing to screen the whole FIX gene of them. The pathogenicity of novel mutations was verified according to 2015 ACMG-AM guidelines. For prenatal diagnosis, a mix of DNA direct sequencing and STR linkage analysis was employed. To explore a better PGD protocol, Karyomapping was first applied in PGD of HB, comparing with conventional PCR-based methods. RESULTS: Six different pathogenic mutations including 1 novel duplication (c.660_661dup ATCA) were identified. The results of prenatal diagnosis were consistent with birth outcomes. In the PGD case, 4 of 11 embryos were confirmed to be normal and one of them was transferred and led to a healthy birth. CONCLUSIONS: The established genetic diagnosis strategy for HB in our study was comprehensive and well applied in clinic practice. Besides, we recommended that DNA direct sequencing combined with Karyomapping was a better PGD protocol. PMID- 29274204 TI - Coupling nanoliter high-performance liquid chromatography to inductively coupled plasma mass spectrometry for arsenic speciation. AB - Nanoliter high-performance liquid chromatography shows low consumption of solvents and samples, offering one of the best choices for arsenic speciation in precious samples in combination with inuctively coupled plasma mass spectrometry. A systematic investigation on coupling nanoliter high-performance liquid chromatography to inductively coupled plasma mass spectrometry from instrument design to injected sample volume and mobile phase was performed in this study. Nanoflow mobile phase was delivered by flow splitting using a conventional high pressure pump with reuse of mobile phase waste. Dead volume was minimized to 60 nL for the sheathless interface based on the previously developed nanonebulizer. Capillary columns for nanoliter high-performance liquid chromatography were found to be sensitive to sample loading volume. An apparent difference was also found between the mobile phases for nanoliter and conventional high-performance liquid chromatography. Baseline separation of arsenite, arsenate, monomethylarsenic, and dimethylarsenic was achieved within 11 min on a 15 cm C18 capillary column and within 12 min on a 25 cm strong anion exchange column. Detection limits of 0.9 1.8 MUg/L were obtained with precisions variable in the range of 1.6-4.2%. A good agreement between determined and certified values of a certified reference material of human urine (GBW 09115) validated its accuracy along with good recoveries (87-102%). PMID- 29274205 TI - Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies. AB - Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies. PMID- 29274206 TI - Comparative analysis of C-type lectin domain proteins in the ghost moth, Thitarodes xiaojinensis (Lepidoptera: Hepialidae). AB - Insects have a large family of C-type lectins involved in cell adhesion, pathogen recognition and activation of immune responses. In this study, 32 transcripts encoding C-type lectin domain proteins (CTLDPs) were identified from the Thitarodes xiaojinensis transcriptome. According to their domain structures, six CTLDPs with one carbohydrate-recognition domain (CRD) were classified into the CTL-S subfamily. The other 23 CTLDPs with two CRDs were grouped into the immulectin (IML) subfamily. The remaining three with extra regulatory domains were sorted into the CTL-X subfamily. Phylogenetic analysis showed that CTL-S and CTL-X members from different insects could form orthologous groups. In contrast, no T. xiaojinensis IML orthologues were found in other insects. Remarkable lineage-specific expansion in this subfamily was observed reflecting that these CTLDPs, as important receptors, have evolved diversified members in response to a variety of microbes. Prediction of binding ligands revealed that T. xiaojinensis, a cold-adapted species, conserved the ability of CRDs to combine with Ca2+ to keep its receptors from freezing. Comparative analysis of induction of CTLDP genes after different immune challenges indicated that IMLs might play critical roles in immune defenses. This study examined T. xiaojinensis CTLDPs and provides a basis for further studies of their characteristics. PMID- 29274207 TI - Autophagy as a universal intracellular process. A comment on the 2016 Nobel Prize in Physiology or Medicine AB - The 2016 Nobel Prize in Physiology or Medicine was awarded to molecular biologist Yoshinori Ohsumi for his work in the field of autophagy (Greek for "self eating"). This fact has once again directed the attention of many scientists to a common cellular phenomenon occurring in all eukaryotes from yeast to mammals, namely the process by which the cell digests and then recycles its components. Although the phenomenon of autophagy was discovered in mammals, a method for monitoring it by light microscopy was established in the unicellular eukaryote, the buddingy east Saccharomyces cerevisiae. The article describes the achievements of the Nobel Laureate, the mechanism of autophagy and its role in the cell physiology of organisms including the unicellular pathogen, the protozoan Toxoplasmagondii. PMID- 29274208 TI - The light microscopy and ultrastructural characteristics of Myxobolus naffari (Myxosporea, Myxobolidae) infecting the Nile carp Labeo niloticus (Cyprinidae) and its histological impact AB - During a survey of myxosporean parasites infecting freshwater fishes from the River Nile at Giza Governorates, Egypt between March and September 2016, nine out of 30 specimens of the Nile carp Labeo niloticus (Cyprinidae) were found to be naturally infected with Myxobolus naffari (Myxobolidae). Small macroscopic plasmodiaappeared embedded in the host gill tissue accompanied with fusion of the gill epithelia, and atrophy was observed at the site of infection. The host reaction was manifested by the encapsulation of the plasmodia with a thick layer of connective tissue. The plasmodia appeared as white, elongated rods between gill filaments with an intensity ranging from three to eight cysts/fish. The average dimensions of plasmodia were 1.2-2.0 (1.8 +/- 0.2) mm long * 0.4-0.7 (0.6 +/- 0.2) mm wide. The spores were oval, reaching 9.56-11.2 (10.2 +/- 0.2) MUm long and 6.5-7.7 (7.0 +/- 0.4) MUm wide with two equal-sized polar capsules regularly arranged at the anterior pole of each spore. They were 4.51-5.5 (5.1 +/ 0.4) MUm in length and 1.5-2.0 (1.7 +/- 0.2) MUm in width. Histological, semi thin sections were taken through parasite plasmodia andtransmission electron microscopic examination of ultrathin sections was performed to describe the developmental stages of the recorded parasite within the host fish. PMID- 29274209 TI - Amoebicidal or amoebostatic influence of disinfectants used in health facilities and laboratories on corneal strains of Acanthamoeba AB - Different Acanthamoeba species are amphizoic organisms distributed in wide range of habitats in natural and man-made environments; they are also detected on surfaces of equipment and accessories in health facilities. Some strains of the amoebae are causative agents of the vision-threatening human disease Acanthamoeba keratitis, mainly reported in contact lens wearers. An exceptional high resistance of Acanthamoeba trophozoites and particularly cysts to chemicals, disinfectants and drugs is believed as influencing difficulty resulting in unsuccessful therapeutic management. As Acanthamoeba keratitis is the serious medical problem worldwide, different chemicals with possible activity against environmental and clinical Acanthamoeba strains are tested. In our study, selected disinfectants used in health care settings and laboratories were tested and their efficacy against the corneal strains Acanthamoeba castellanii and A. polyphaga , and environmental A. castellanii Neff strain was assessed. Comparative assessment of results of the assays show that, apart from amoebistatic effects, the disinfectants indicated expected cysticidal efficacy. PMID- 29274210 TI - Impact of alternative treatment approach for cerebral toxoplasmosis among HIV/AIDS patients from a resource-poor setting in Burkina Faso AB - Cerebral toxoplasmosis is caused by the protozoan Toxoplasma gondii because of reactivation of latent tissue cysts in the Acquired Immunodeficiency Syndrome (AIDS) patients with severe immunosuppression. The objective of this study was to evaluate the benefit of co-trimoxazole in presumptive and prevention of cerebraltoxoplasmosis in Human Immunodeficiency Virus (HIV)/AIDS patients at Bobo Dioulasso Hospital in Burkina Faso from June 2012 to October 2014. ELISA and ELFA were performed on serum for the quantitative determination of IgG and IgM anti-T. gondii, respectively. The seroprevalence of toxoplasmosis was 29.3%. No IgM antibodies for T. gondii were found. Six patients with Toxoplasma-specific antibodies presented cerebral toxoplasmosis. All patients were infected by HIV-1 with the median of CD4+ T lymphocytes at 141 cells/MUl. No patient was under antiretroviral therapy. No case of cerebral toxoplasmosis was noted in patients receiving co-trimoxazole in prevention. Presumptive treatment of cerebral toxoplasmosis with co-trimoxazole was effective in all patients with a significant clinical improvement in 83.3%. These results attest the benefit of cotrimoxazole in cerebral toxoplasmosis treatment in countries where drug resources are limited when sulfadiazine is not available. Ours finding highlight the importance of establishing toxoplasmosis chemoprophylaxis to HIV with severe immunosuppression patients and positive Toxoplasma serology. PMID- 29274211 TI - Sensitization to the storage mites Lepidoglyphus destructor and Tyrophagus putrescentiae (Acari, Sarcoptiformes, Astigmatina) in a suburban population in Southern Poland AB - Mite infestation of stored products is a serious threat to food safety and public health. These stored product mites are not only serious pests of stored food but also cause allergies in humans. Thirty serum samples from patients living in suburban areas of Upper Silesia (South Poland) were tested for sensitization to two species of storage mites: Lepidoglyphus destructor [LD] and Tyrophagus putrescentiae [TP]. Patient antibodies against particular antigens were identified using anti-human anti-IgE monoclonal antibodies. Fifteen protein fractions from LD gave positive reactions with IgE antibodies and 18 from TP. Seven of the 30 samples showed positive reactions to a protein fraction measuring about 29 kDa from LD and six reacted with a fraction measuring about 25 kDa from TP. These findings may imply the existence of many protein fractions with allergenic properties besides the characterized allergens in the two tested species. PMID- 29274212 TI - Drug susceptibility of fungi isolated from ICU patients AB - Candida species can be a reason of infections associated with high morbidity and mortality. The risk of invasive candidosis for patients admitted to intensive care units (ICUs) is increased due to immunosuppressive states, prolonged length of stay, broad-spectrum antibiotics and Candida colonization. The aim of the study was to determine selected properties of fungi isolated from patients treated in the ICUs of hospitals in Lodz. The materials were collected from the oral cavity, the tracheostomy or endotracheal tube and urine from 16 children and 35 adult. In total, 127 samples were examined to differentiate the fungal strains with used morphological and biochemical methods. Candida species were isolated from adult patients (82.9%), but were not isolated from any of the children; C. albicans was the predominant fungus (61.7%), much less frequent were C. glabrata (12.8%), C. tropicalis (6.4%) and C. kefyr, C. dubliniensis (4.3% each).The susceptibility of fungi to antimycotic drugs revealed that almost all of the strains were susceptible to nystatin (97.9%) and to amphotericin B (72.3%), and resistant to fluconazole (72.3%) and ketoconazole (57.5%). No isolation of fungi from children remaining in ICU may be an evidence of high sanitary regime at these wards; fungi from the genus Candida are the etiological factors for ICU infections; 3/5 of them are caused by C. albicans, mostly of the code 2 576 174, characteristic for strains isolated from hospitalized patients; it is necessary to determine the species of the fungus and its susceptibility to drugs, which allows to conduct effective therapy; prophylactic administration of fluconazole leads to an increase in the number of strains resistant to this chemotherapeutic agent; in the antifungal local treatment, nystatin should be a drug of choice as the drug to which most fungi are susceptible. PMID- 29274213 TI - Coccidiosis of domestic pigeons (Columba livia domestica Gmelin, 1789) in Kano State, Nigeria AB - Pigeon coccidiosis is caused by Eimeria spp., a protozoan parasite which limits productivity by causing severe illness. Although numerous studies have been conducted on the coccidiosis of pigeons in some parts of Nigeria, there is no published data from Kano State. The intestinal contents of 144 pigeons (72 females and 72 males) were analysed for Eimeria oocysts in 2007 from 12 Local Government Areas of Kano State over the period of six months including the dry (February-April) and wet (June-August) seasons. The pigeons were divided into three groups according to age: squabs (0-4 weeks), squeakers (5-8 weeks) and youngsters (9+ weeks); each group including 48 pigeons. The results of these studies revealed an overall prevalence of 19.44%. The prevalence was higher in females (20.83%) than males (18.06%) (p<0.05). Furthermore, squabs had the highest prevalence (27.08%) followed by squeakers (20.83%), and youngsters (10.42%) (p<0.05). Infection with Eimeria spp. oocysts was higher during the wet season (8.96%) than dry season (5.98%) (p<0.05). This study provides basic information on the first detection of coccidiosis of pigeons in Kano State, Nigeria which has an implication on the sustainable pigeon production for human protein reguirement. PMID- 29274214 TI - Helminth infections in faecal samples of Apennine wolf (Canis lupus italicus) and Marsican brown bear (Ursus arctos marsicanus) in two protected national parks of central Italy AB - This article reports the results of a copromicroscopic and molecular investigation carried out on faecal samples of wolves (n=37) and brown bears (n=80) collected in two protected national parks of central Italy (Abruzzo Region). Twenty-three (62.2%) samples from wolves were positive for parasite eggs. Eight (34.78%) samples scored positive for single infections, i.e. E. aerophilus (21.74%), Ancylostoma/Uncinaria (4.34%), Trichuris vulpis (4.34%), T. canis (4.34%). Polyspecific infections were found in 15 samples (65.21%), these being the most frequent association: E. aerophilus and Ancylostoma/Uncinaria. Thirty-seven (46.25%) out of the 80 faecal samples from bears were positive for parasite eggs. Fourteen (37.83%) samples were positive for B. transfuga, and six (16.21%) of them also contained Ancylostoma/Uncinaria, one (2.7%) E. aerophilus and one (2.7%) both E. aerophilus and Ancylostoma/Uncinaria. Ofthe other samples, 19 (51.35%) were positive for Ancylostoma/Uncinaria, two (5.4%) for E. aerophilus and two (5.4%) for both. Molecular analysis found the roundworm and capillariid eggs found in wolves and bear samples to be Toxocara canis, Baylisascaris transfuga and Eucoleus aerophilus (syn. Capillaria aerophila). Considering the high prevalence of zoonotic intestinal helminths detected in this study, it is important to improve the knowledge and awareness of the general public and park operators regarding the potential health risk associated with infections in wildlife. PMID- 29274215 TI - Altitudinal distribution of Aedes indices during dry season in the dengue endemic area of Central Java, Indonesia AB - Aedes mosquitoes, mainly Aedes aegypti and Aedes albopictus, are the primary and secondary vectors of dengue viruses in Indonesia, with transmission occurring by sucking blood. The density of the vectors is influenced by season and rainfall, but limited by altitude. The aim of the study is to describe the density and distribution of dengue vectors during the dry season based on the altitudes of recent dengue cases in five regencies of Central Java Province, Indonesia. Mosquito larvae and pupae were collected from the indoor and outdoor water containers from 253 houses within 50 m of houses occupied by a dengue patient. A considerable dengue vector population was found in all localities and altitudes based on the Aedes indices: an HI of 41.7% (15.0-70.6), CI of 33.6% (8.1-69.6) and BI of 57.1 (15.0-94.1). The highest indices were found in the highest altitude settlement; as the most common larval habitat in this village was a large-sized cement tank, larvivorous fish can act as effective predators in this case. This finding indicates an expansion of the dengue problem from low to high altitudes, causing a high potential for dengue transmission in all of the localities. PMID- 29274216 TI - CHALLENGES TO INDIGENOUS HEALTH CURRICULUM DESIGN -- BRINGING THE ABORIGINAL AND TORRES STRAIT ISLANDER HEALTH CURRICULUM FRAMEWORK TO LIFE. AB - While it is our responsibility to produce culturally safe graduates with a nuanced grasp of Aboriginal and Torres Strait Islander health needs, there are central challenges in curriculum writing for indigenous health today. PMID- 29274217 TI - Evaluation of inhibitory effect of redox-active antimalarial drug against Babesia microti in mice AB - Babesiosis is an emerging, tick-transmitted disease caused by the intraerythrocytic parasite Babesia microti. In immunocompetent individuals, B. microti infection quickly resolves after antibabesial treatment. Immunocompromised patients and those of advanced age experience chronic and relapsing babesiosis, accompanied by severe complications and often, a fatal outcome. In these individuals, B. microti infection may persist despite multiple courses of treatment with antiprotozoal drugs. The increasing incidence of human babesiosis caused by B. microti, coupled with a growing number of immunosuppressed people who do not respond to standard antibabesial therapy, emphasises the need for new therapeutics for this protozoan infection with more effective mechanisms of action.Plasmodione, namely 3-[4-(trifluoromethyl)benzyl] menadione, acts as a redox cycler and disrupts the redox homeostasis of Plasmodium-infected erythrocytes. The present study was designed to evaluate the potential inhibitory effect of this novel antimalarial compound against intraerythrocytic stages of B. microti in mice. Our results demonstrate that plasmodione did not reduce the level of parasitemia in B. microti-infected mice, indicating that interfering with the parasite redox balance is not an effective strategy to restrict the division of this protozoan. The mechanism of parasite resistance to plasmodione may be based on the differences in the oxidative metabolisms of Babesia and Plasmodium parasites inside infected erythrocytes. The significance of our results is discussed in relation to the development of novel antibabesial drugs based on redox-active benzylmenadiones. PMID- 29274218 TI - HOW CAN SCHOOLS OF NURSING AND MIDWIFERY PREPARE THEIR GRADUATES TO ENCOURAGE MEDICATION ADHERENCE FOR AUSTRALIAN ABORIGINAL AND TORRES STRAIT ISLANDER CLIENTS? AB - Research undertaken in mainstream Australian studies show that the overall rate of medication non-adherence has been reported to be high, for Aboriginal and Torres Strait Islander peoples of Australia leading to adverse and critical health outcomes (AIHW 2010). PMID- 29274219 TI - USING MAPPING TOOLS TO IMPROVE ABORIGINAL PATIENT JOURNEYS. AB - Nurses and midwives play a central role in ensuring effective healthcare for Aboriginal patients in urban, rural and remote locations. However, at times they feel underequipped to fully support Aboriginal patients and their families with the skills and knowledge and resources available (Dwyer et at 2014). PMID- 29274221 TI - HOW AN EVERYDAY NURSE CRACKED COMEDY. AB - British nurse Georgie Carroll moved to Australia seeking adventure and inadvertently discovered a hidden talent for making people laugh. PMID- 29274220 TI - INCORPORATING THE NURSING AND MIDWIFERY ABORIGINAL AND TORRES STRAIT ISLANDER HEALTH CURRICULUM FRAMEWORK INTO A BN PROGRAM. AB - Preparing nursing students for authentic person-centred practice demands an awareness and understanding of Australian culture and history and the impact of these things on the health of Aboriginal and Torres Strait Islander peoples. PMID- 29274222 TI - Demonstrating the Unique Value a Study Adds. PMID- 29274223 TI - A Survey of Health Equity Practices in Early Psychosis Intervention Programs: A Starting Point for Improvement. AB - Equity has been identified as a core component of quality healthcare in Ontario. However, translating policy into practice can be challenging. This paper reports results from a province-wide survey of early psychosis intervention programs to assess the extent to which equity has been incorporated into program delivery. All 56 programs (100%) completed the survey. Results found that while most programs perceive that they are meeting equity aims, they reported limited use of practices to support this aim, and few systematically collect information on performance. Strategies to improve equity in practice are discussed. PMID- 29274224 TI - What Is Bending the Cost Curve? An Exploration of Possible Drivers and Unintended Consequences. AB - Health expenditures in most OECD countries have increased at a slower rate since 2008/2009. Potential drivers of this bending of the cost curve include: (1) changes in pharmaceuticals and technology innovations; (2) healthcare reforms, and specifically those focusing on care for complex and high-user patients and (3) government expenditure controls resulting from general economic conditions. We use publicly available National Health Expenditure data from the Canadian Institute for Health Information to assess the merits of each of these drivers, with a focus on British Columbia. We find some evidence for the effects of changes in pharmaceuticals and technology, but the dominant effect is government spending controls, which are greatest for non-Medicare-covered services. These changes suggest potential unintended consequences on access and equity that should be understood before declaring victory for healthcare expenditure control. PMID- 29274225 TI - Personal Support Workers in Canada: The New Precariat? AB - There has been much recent discussion internationally about the emergence in modern society of a new class of workers - the precariat - with a common consciousness based on features such as low wages, insecurity, short-term jobs, minority status and restricted rights. This paper critically explores the extent to which the growing, large-scale group of personal support workers (PSWs) can be viewed as part of a new precariat in terms of their position in the healthcare labour market. Drawing on currently available empirical data, this issue is examined particularly with reference to PSWs in Canada - drawing out some of the implications for government health policy in this sphere. PMID- 29274226 TI - What's Involved with Wanting to Be Involved? Comparing Expectations for Public Engagement in Health Policy across Research and Care Contexts. AB - OBJECTIVES: We explored public preferences for involvement in health policy decisions, across the contexts of medical research and healthcare. APPROACH: We e surveyed a sample of Canadians, categorizing respondents by preferences for decision control: (1) more authority; (2) more input; (3) status quo. Two generalized ordered logistic regressions assessed influences on preferences. RESULTS: The participation rate was 94%; 1,102 completed responses met quality criteria. The dominant preference was for more input (average = 52.0%), followed by status quo (average = 24.9%) and more authority (average = 21.1%), though preferences for more control were higher in healthcare (57.2%) than medical research (46.8%). Preferences for greater control were associated with constructs related to reduced trust in healthcare systems. CONCLUSION: The public expects health policy to account for public views, but not base decisions primarily on these views. More involvement was expected in healthcare than medical research policy. As opportunities for public involvement in health research grow, we anticipate increased desired involvement. PMID- 29274227 TI - A Review and Comparative Analysis of Information Targeted to the General Public on the Websites of Breast Screening Programs in Canada. AB - Organized breast screening programs in Canada recommend that women, usually 50-74 years of age, are screened regularly with mammography to reduce their risk of breast cancer death. There is increasing evidence that estimates of mortality reduction are overestimated and harms under-reported. This article will report on a review of the websites of 12 breast screening programs in Canada. The primary goal is to determine what information is provided to enable women to make an informed decision about mammography and whether choice is emphasized. All publicly available English language information was extracted from the 12 websites by two independent reviewers, using a data extraction sheet. Information extracted included eligible age, screening interval and potential benefits and harms. This review is relevant to policy makers and breast screening program staff so they can determine what additional or alternative information is required on their websites to enable women to make informed decisions. PMID- 29274228 TI - Prior Authorization and Canadian Public Utilization of Direct-Acting Oral Anticoagulants. AB - PURPOSE: Provincial public drug formularies in Canada have different mechanisms for reimbursement of direct-acting oral anticoagulants (DOACs). We investigate how these differences influence DOAC utilization and expenditure across the country. METHODS: We conducted a population-based, cross-sectional study of all out-patient prescriptions for OACs dispensed to public beneficiaries between January 1, 2010, and June 30, 2015. We calculated quarterly rates of OAC use and expenditures stratified by OAC type and province. RESULTS: The greatest increase in quarterly rates of DOAC utilization occurred in provinces with more liberal mechanism of drug coverage: Ontario by 462%, Alberta by 425% and Quebec by 1,924%. This translated to increased expenditure on overall OAC by 270%, 204% and 390%, respectively. In contrast, provinces with more stringent mechanisms had low rates of DOAC utilization and expenditure. CONCLUSIONS: DOAC utilization and expenditure is considerably different across Canada, associated with provincial difference in reimbursement mechanism. PMID- 29274229 TI - Evaluating the Implementation of The Champlain BASETM eConsult Service in a New Region of Ontario, Canada: A Cross-Sectional Study. AB - OBJECTIVE: To replicate an existing electronic consultation (eConsult) service in a new jurisdiction to test its generalizability. METHODS: We conducted a cross sectional study of all eConsults submitted by providers in the region of Mississauga Halton, Ontario, between January 5, 2015, and May 31, 2016. We compared our results to those from the original pilot in Eastern Ontario. The RE AIM model served as our study framework. RESULTS: Providers submitted 594 patient cases to 46 different specialty groups during the study period. Specialists responded in a median of 1.1 days, with 75% of cases answered within four days. Providers rated the service as having high or very high value for themselves and their patients in 92% of cases. The service yielded a net program cost of $10,321.56. CONCLUSION: Our findings resembled those of the initial implementation, though with a faster rate of uptake and lower cost because of the avoidance of start-up and administrative costs. PMID- 29274230 TI - CRISPR/Cas9 and active genetics-based trans-species replacement of the endogenous Drosophila kni-L2 CRM reveals unexpected complexity. AB - The knirps (kni) locus encodes transcription factors required for induction of the L2 wing vein in Drosophila. Here, we employ diverse CRISPR/Cas9 genome editing tools to generate a series of targeted lesions within the endogenous cis regulatory module (CRM) required for kni expression in the L2 vein primordium. Phenotypic analysis of these 'in locus' mutations based on both expression of Kni protein and adult wing phenotypes, reveals novel unexpected features of L2-CRM function including evidence for a chromosome pairing-dependent process that promotes transcription. We also demonstrate that self-propagating active genetic elements (CopyCat elements) can efficiently delete and replace the L2-CRM with orthologous sequences from other divergent fly species. Wing vein phenotypes resulting from these trans-species enhancer replacements parallel features of the respective donor fly species. This highly sensitive phenotypic readout of enhancer function in a native genomic context reveals novel features of CRM function undetected by traditional reporter gene analysis. PMID- 29274232 TI - Enantiomeric separation of type I and type II pyrethroid insecticides with different chiral stationary phases by reversed-phase high-performance liquid chromatography. AB - The enantiomeric separation of type I (bifenthrin, BF) and type II (lambda cyhalothrin, LCT) pyrethroid insecticides on Lux Cellulose-1, Lux Cellulose-3, and Chiralpak IC chiral columns was investigated by reversed-phase high performance liquid chromatography. Methanol/water or acetonitrile/water was used as mobile phase at a flow rate of 0.8 mL/min. The effects of chiral stationary phase, mobile phase composition, column temperature, and thermodynamic parameters on enantiomer separation were carefully studied. Bifenthrin got a partial separation on Lux Cellulose-1 column and baseline separation on Lux Cellulose-3 column, while LCT enantiomers could be completely separated on both Lux Cellulose 1 and Lux Cellulose-3 columns. Chiralpak IC provided no separation ability for both BF and LCT. Retention factor (k) and selectivity factor (alpha) decreased with the column temperature increasing from 10 degrees C to 40 degrees C for both BF and LCT enantiomers. Thermodynamic parameters including ?H and ?S were also calculated, and the maximum Rs were not always obtained at lowest temperature. Furthermore, the quantitative analysis methods for BF and LCT enantiomers in soil and water were also established. Such results provide a new approach for pyrethroid separation under reversed-phase condition and contribute to environmental risk assessment of pyrethroids at enantiomer level. PMID- 29274231 TI - Structural insights into the assembly and polyA signal recognition mechanism of the human CPSF complex. AB - 3' polyadenylation is a key step in eukaryotic mRNA biogenesis. In mammalian cells, this process is dependent on the recognition of the hexanucleotide AAUAAA motif in the pre-mRNA polyadenylation signal by the cleavage and polyadenylation specificity factor (CPSF) complex. A core CPSF complex comprising CPSF160, WDR33, CPSF30 and Fip1 is sufficient for AAUAAA motif recognition, yet the molecular interactions underpinning its assembly and mechanism of PAS recognition are not understood. Based on cross-linking-coupled mass spectrometry, crystal structure of the CPSF160-WDR33 subcomplex and biochemical assays, we define the molecular architecture of the core human CPSF complex, identifying specific domains involved in inter-subunit interactions. In addition to zinc finger domains in CPSF30, we identify using quantitative RNA-binding assays an N-terminal lysine/arginine-rich motif in WDR33 as a critical determinant of specific AAUAAA motif recognition. Together, these results shed light on the function of CPSF in mediating PAS-dependent RNA cleavage and polyadenylation. PMID- 29274233 TI - Efficacy of anti-programmed cell death-1 immunotherapy for skin carcinomas and melanoma metastases in a patient with xeroderma pigmentosum. AB - Xeroderma pigmentosum (XP) is an orphan disease of poor prognosis. We report one case of parallel efficacy with anti-programmed cell death-1 (PD-1) antibody on both melanoma and skin carcinoma in a patient with XP. A 17-year-old patient presented with metastatic melanoma and multiple nonmelanoma skin cancers. He was treated with pembrolizumab, a monoclonal anti-PD-1 antibody, at a dose of 2 mg kg 1 , every 3 weeks. Parallel therapeutic efficacy of anti-PD-1 was observed in metastatic melanoma and skin carcinomas, and maintained at week 24. This observation suggests anti-PD-1 may be considered in patients with XP and metastatic melanoma in addition to advanced nonmelanoma skin cancer. PMID- 29274234 TI - Lymphoedema in patients with lentigo maligna treated with imiquimod: a long-term adverse effect. PMID- 29274235 TI - The role of breakfast in adipose tissue biology. PMID- 29274236 TI - Successful steroid withdrawal guided by surveillance biopsies-A single-center experience. AB - Steroid withdrawal following renal transplantation is challenging and widely debated. This retrospective study aimed at investigating the frequency and determinants of successful steroid withdrawal guided by surveillance biopsies. We analyzed 156 pretransplant DSA-negative renal transplants receiving basiliximab induction and maintenance immunosuppression with tacrolimus-mycophenolate steroids. The absence of rejection in surveillance biopsies at 3 or 6 months post transplant initiated steroid withdrawal, which was monitored by subsequent indication and/or surveillance biopsies. The primary outcome was the frequency of successful (i.e., rejection-free) steroid withdrawal at 1 year post-transplant. In the whole study population, successful steroid withdrawal was achieved in 73 of 156 patients (47%). Steroid withdrawal was initiated in 98 of 156 patients (63%) and successful in 73 of 98 patients (74%). Subsequent clinical rejection occurred in only one of 98 patients (1%), whereas 24 of 98 patients (24%) experienced subclinical rejection. Steroid withdrawal was not initiated in 58 of 156 patients (37%) mainly due to current or prior severe (Banff TCMR >=IA) subclinical rejection. Prediction of successful steroid withdrawal by pretransplant or early post-transplant parameters was poor. In conclusion, (sub)clinical rejection-free steroid withdrawal can be expected in about half of pretransplant DSA-negative patients. As successful steroid withdrawal cannot be well predicted by pre- and early post-transplant parameters, guidance by surveillance biopsies is an attractive strategy. PMID- 29274237 TI - Lipase-catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives. AB - Novel benzoxazole derivatives were synthesized, and their antitubercular activity against sensitive and drug-resistant Mycobacterium tuberculosis strains (M. tuberculosis H37 Rv, M. tuberculosis sp. 210, M. tuberculosis sp. 192, Mycobacterium scrofulaceum, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium avium, and Mycobacterium kansasii) was evaluated. The chemical step included preparation of ketones, alcohols, and esters bearing benzoxazole moiety. All racemic mixtures of alcohols and esters were separated in Novozyme SP 435-catalyzed transesterification and hydrolysis, respectively. The transesterification reactions were carried out in various organic solvents (tert butyl methyl ether, toluene, diethyl ether, and diisopropyl ether), and depending on the solvent, the enantioselectivity of the reactions ranged from 4 to >100. The enzymatic hydrolysis of esters was performed in 2 phase tert-butyl methyl ether/phosphate buffer (pH = 7.2) system and provided also enantiomerically enriched products (ee 88-99%). The antitubercular activity assay has shown that synthesized compounds exhibit an interesting antitubercular activity. Racemic mixtures of alcohols, (+/-)-4-(1,3-benzoxazol-2-ylsulfanyl)butan-2-ol ((+/-)-3a), (+/-)-4-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((+/-)-3b), and (+/-)-4 [(5,7-dibromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((+/-)-3c), displayed as high activity against M. scrofulaceum, M. intracellulare, M. fortuitum, and M. kansasii as commercially available antituberculosis drug-Isoniazid. Moreover, these compounds exhibited twice higher activity toward M. avium (MIC 12.5) compared with Isoniazid (MIC 50). PMID- 29274238 TI - Tuning of Polyoxopalladate Macroanionic Hydration Shell via Countercation Interaction. AB - Three types of macroanion-countercation interactions in dilute solution, decided by the strength of electrostatic attraction and the change of hydration shells are reported: minor interaction between macroanions [MO8 Pd12 (SeO3 )8 ]6- (M=Zn2+ or Ni2+ ) and monovalent cations (Na+ , K+ , Rb+ , Cs+ ), leaving their hydration shells intact (solvent-separated ion-pairs); strong binding between macroanions and divalent cations (Sr2+ , Ba2+ ) to form solvent-shared ion-pairs with partial dehydration; very strong electrostatic attraction between macroanions and Y3+ ion with contact ion-pairs formation by severely breaking their original hydration shells and forming new ones. In addition, divalent cations can help the macroanions self-assemble into hollow spherical blackberry structures through counterion-mediated attraction, whereas macroanions with mono- or trivalent cations only stay as discrete ions due to either weak interaction or a small number of bound countercations. PMID- 29274239 TI - Chirality of 20-membered unclosed cryptand: Macroring distortion via lariat arm modification. PMID- 29274240 TI - Do clinical trials reflect reality? A systematic review of inclusion/exclusion criteria in trials of renal transplant immunosuppression. AB - Renal transplant recipients and donors are becoming increasingly more marginal, with more expanded criteria (ECD) and donation after circulatory death (DCD) donors and older recipients. Despite this, high-risk donors and recipients are often excluded from clinical trials, leading to uncertainty about the generalizability of findings. We extracted data regarding inclusion/exclusion criteria from 174 trials of immunosuppression in renal transplant recipients published over a 5-year period and compared criteria with those specified in published trial registries. Frequently reported donor exclusion criteria were age (16.1%), donor type and cold ischaemic time (22.4%). Common recipient exclusion criteria included upper age limit (38.5%), high panel reactive antibody (PRA) (42.5%) and previous transplantation (39.7%). Inclusion/exclusion criteria recorded in trial registries matched those reported in the manuscript in only 6 (7.8%) trials. Of registered trials, 51 (66.2%) trials included additional criteria in the manuscript, 51 (66.2%) were missing criteria in the manuscript specified in the protocol, and in 19 (24.7%) key criteria changed from the protocol to the manuscript. Our findings suggest many recent immunosuppression trials have restrictive inclusion criteria which may not be reflective of current renal transplant populations. Discrepancies between trial protocols and published reports raise the possibility of selection bias. PMID- 29274241 TI - The role of adult attachment orientation and coping in psychological adjustment to living with skin conditions. AB - BACKGROUND: Skin conditions can be associated with significant psychological distress. Investigation of attachment orientation and associated use of coping strategies is a promising perspective from which to investigate psychological adjustment to skin conditions. OBJECTIVES: To examine the role of adult attachment orientation, conceptualized as two dimensions - attachment avoidance and attachment anxiety - in psychological adjustment [appearance-related distress and skin-related quality of life (QoL)], and the mediating role of two coping strategies - defeatism and activity. METHODS: Attachment avoidance and attachment anxiety, use of coping strategies, appearance-related distress and skin-related QoL were assessed via a cross-sectional online survey in 207 adults with skin conditions. Multiple mediation analyses were performed using PROCESS pathway analysis. RESULTS: Overall, higher attachment avoidance and higher attachment anxiety were associated with higher appearance-related distress and greater impact on emotions and functioning aspects of QoL. For attachment anxiety, the relationship was fully explained by more frequent use of defeatism coping. For attachment avoidance, the relationship was partially explained by more frequent use of defeatism coping (and in the case of appearance-related distress also more frequent use of activity coping), and higher attachment avoidance was also associated with poorer psychological adjustment in a way that could not be explained by use of assessed coping strategies. CONCLUSIONS: Insecure attachment orientation (high attachment avoidance or high attachment anxiety) is linked to poorer adjustment. People with insecure attachment might benefit from psychological interventions that target underlying attachment orientation. PMID- 29274242 TI - Phosphorylation of intracellular signalling molecules in peripheral blood cells from patients with psoriasis on originator or biosimilar infliximab. AB - BACKGROUND: Psoriasis vulgaris is a chronic, inflammatory skin disease characterized by a dysregulated immune response and it is associated with substantial systemic comorbidities. Biological drugs such as tumour necrosis factor (TNF)-alpha inhibitors can ameliorate the disease but are expensive. Biosimilar drugs have the same amino-acid sequence as the originator, but differences in manufacturing can affect biological activity, efficacy and tolerability. OBJECTIVES: To explore potential differences in intracellular phosphorylation of signalling molecules in peripheral blood cells from patients with psoriasis treated with the TNF-alpha inhibitor infliximab compared with healthy controls, and to investigate if the phosphorylation pattern was influenced by switching from the originator infliximab to the biosimilar CT-P13. METHODS: By flow cytometry, we measured phosphorylation of nuclear factor kappa B, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3, before and after TNF-alpha stimulation in monocytes and T, B, natural killer and CD3+ CD56+ cells from 25 patients with psoriasis treated with infliximab and 19 healthy controls. RESULTS: At inclusion, phosphorylation levels of peripheral blood mononuclear cells (PBMCs) were increased in patients with psoriasis compared with healthy controls, even though clinical remission had already been achieved. Phosphorylation levels declined in patients on both originator infliximab and biosimilar during continued treatment. No significant differences were detected between the two medications after 12 months. CONCLUSIONS: Patients with psoriasis on infliximab have higher activation levels of PBMCs than do healthy controls, possibly reflecting systemic inflammation. Switching from the originator infliximab to biosimilar CT-P13 did not affect phosphorylation levels or clinical parameters, suggesting that CT-P13 is a noninferior treatment alternative to the originator infliximab. PMID- 29274243 TI - Novel POFUT1 mutation associated with hidradenitis suppurativa-Dowling-Degos disease firm up a role for Notch signalling in the pathogenesis of this disorder. PMID- 29274244 TI - Intracellular potassium under osmotic stress determines the dielectrophoresis cross-over frequency of murine myeloma cells in the MHz range. AB - Dielectrophoresis (DEP) has been widely studied for its potential as a biomarker free method of sorting and characterizing cells based upon their dielectric properties. Most studies have employed voltage signals from ~1 kHz to no higher than ~30 MHz. Within this range a transition from negative to positive DEP can be observed at the cross-over frequency fx01 . The value of fx01 is determined by the conductivity of the suspending medium, as well as the size and shape of the cell and the dielectric properties (capacitance, conductivity) of its plasma membrane. In this work DEP measurements were performed up to 400 MHz, where the transition from positive to negative DEP can be observed at a higher cross-over frequency fx02 . SP2/O murine myeloma cells were suspended in buffer media of different osmolarities and measurements taken of cell volume, fx01 and fx02 . Potassium-binding benzofuran isophthalate (PBFI), a potassium-sensitive fluorophore, and flow cytometry was employed to monitor relative changes in intracellular potassium concentration. In agreement with theory, it was found that fx02 is independent of the cell parameters that control fx01 and is predominantly determined by intracellular conductivity. In particular, the value of fx02 is highly correlated to that of the intracellular potassium concentration. PMID- 29274245 TI - The Gasdermin-D pore acts as a conduit for IL-1beta secretion in mice. AB - The pro-inflammatory cytokine IL-1beta is well known for its role in host defense and the initiation of potent inflammatory responses. It is processed from its inactive pro-form by the inflammatory caspase-1 into its mature bioactive form, which is then released from the cell via an unconventional secretion mechanism. Recently, gasdermin-D has been identified as a new target of caspase-1. After proteolytical cleavage of gasdermin-D, the N-terminal fragment induces pyroptosis, a lytic cell death, by forming large permeability pores in the plasma membrane. Here we show using the murine system that gasdermin-D is required for IL-1beta secretion by macrophages, dendritic cells and partially in neutrophils, and that secretion is a cell-lysis-independent event. Liposome transport assays in vitro further demonstrate that gasdermin-D pores are large enough to allow the direct release of IL-1beta. Moreover, IL-18 and other small soluble cytosolic proteins can also be released in a lysis-independent but gasdermin-D-dependent mode, suggesting that the gasdermin-D pores allow passive the release of cytosolic proteins in a size-dependent manner. PMID- 29274246 TI - The sarcopenia index: A novel measure of muscle mass in lung transplant candidates. AB - BACKGROUND: Frailty, including low muscle mass, is an emerging risk factor for poor outcomes after lung transplant. The sarcopenia index (SI)-(serum creatinine value/cystatin C value) * 100-is a novel blood test to approximate muscle mass. We sought to validate SI among lung transplant patients. METHODS: We retrospectively identified adult lung transplant recipients from 2000 through 2012 at our institution who underwent computed tomography within 1 year before transplant and had preserved blood samples. Creatinine and cystatin C values were measured using the samples and used to calculate SI. Muscle mass was estimated by computed tomographic measurement of skeletal muscle cross-sectional surface area (SA) at the L1 to L3 vertebral levels. Correlation between SI and SA was evaluated. RESULTS: Of 28 patients meeting eligibility criteria, most were white (96%) and men (54%). Median (interquartile range) body mass index, SI, and SA were 25.9 (22-30) kg/m2 , 106 (91-119), and 157 (113-195) cm2, respectively. The Pearson correlation coefficient between SI and SA was significant at L2 (0.43; P = .02) and L3 (0.41; P = .03). CONCLUSION: Sarcopenia index is a potentially objective measure for estimating muscle mass that is noninvasive and less expensive. Sarcopenia index could be considered in lung transplant candidate selection following prospective validation in larger cohorts. PMID- 29274248 TI - Stem cell education for medical students at Tongji University: Primary cell culture and directional differentiation of rat bone marrow mesenchymal stem cells. AB - Stem cells are cells that can self-renew and differentiate into a variety of cell types under certain conditions. Stem cells have great potential in regenerative medicine and cell therapy for the treatment of certain diseases. To deliver knowledge about this frontier in science and technology to medical undergraduate students, we designed an innovative practical experiment for freshmen in their second semester. The lab exercise focused on rat bone marrow mesenchymal stem cell (BMSC) isolation, cell culture and differentiation, and it aimed to help students master the aseptic techniques for cell culture, the basic methods and procedures for the primary culture and passage of BMSCs, the basic procedure for the directional differentiation of BMSCs into adipocytes and their subsequent identification by oil-red-O staining. This lab exercise is a very meaningful and useful introduction to stem cell collection and manipulation and inspires medical students to deepen their understanding of translational medicine and regenerative medicine. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):151-154, 2018. PMID- 29274247 TI - Temporal Trends in Analgesic Use in Long-Term Care Facilities: A Systematic Review of International Prescribing. AB - OBJECTIVES: To explore global changes in the prescription of analgesic drugs over time in the international long-term care (LTC) population. DESIGN: Systematic review. SETTING: We included original research articles in English, published and unpublished, that included number of participants, country and year(s) of data collection, and prescription of analgesics (analgesics not otherwise specified, opioids, acetaminophen; scheduled only, or scheduled plus as needed (PRN)). PARTICIPANTS: LTC residents. MEASUREMENTS: We searched PubMed, EMBASE, CINAHL, International Pharmaceutical Abstracts, PsycINFO, Cochrane, Web of Science, Google Scholar, using keywords for LTC facilities and analgesic medication; hand searched references of eligible papers; correspondence. Studies were quality rated using an adapted Newcastle-Ottawa scale. Pearson correlation coefficients were generated between percentage of residents prescribed an analgesic and year of data collection. If available, we investigated changes in acetaminophen and opioid prescriptions. RESULTS: Forty studies met inclusion criteria. A moderate correlation (0.59) suggested that scheduled prescription rates for analgesics have increased over time. Similar findings were reflected in scheduled prescriptions for acetaminophen and opioids. No increase was seen when analyzing scheduled plus PRN analgesics. Use of opioids (scheduled plus PRN) appears to have increased over time. CONCLUSION: Worldwide, use of opioids and acetaminophen has increased in LTC residents. Research is needed to explore whether this reflects appropriate pain management for LTC residents and if PRN medication is used effectively. PMID- 29274249 TI - Cell Wall Proteome of Sugarcane Young and Mature Leaves and Stems. AB - By characterizing the cell wall proteomes of different sugarcane organs (leaves and stems) at two developmental stages (young vs mature/apical vs basal), it is possible to address unique characteristics in each of them. Four-month-old leaves show a higher proportion of oxido-reductases and proteins related to lipid metabolism (LM), besides a lower proportion of proteins acting on polysaccharides, in comparison to 4-month-old internodes. It is possible to note that sugarcane leaves and young stems have the highest LM rate than all species, which is assumed to be linked to cuticle formation. The data generated enrich the number of cell wall proteins (CWPs) identified in sugarcane, reaching 277. To our knowledge, sugarcane has now the second higher coverage of monocot CWP in plants. PMID- 29274250 TI - An Exosome-Based Vaccine Platform Imparts Cytotoxic T Lymphocyte Immunity Against Viral Antigens. AB - Exosomes are 50-150 nm sized nanovesicles released by all eukaryotic cells. The authors very recently described a method to engineer exosomes in vivo with the E7 protein of Human Papilloma Virus (HPV). This technique consists in the intramuscular injection of a DNA vector expressing HPV-E7 fused at the C-terminus of an exosome-anchoring protein, that is, Nefmut , the authors previously characterized for its high levels of incorporation in exosomes. In this configuration, the ~11 kDa E7 protein elicited a both strong and effective antigen-specific cytotoxic T lymphocyte (CTL) immunity. Attempting to establish whether this method could have general applicability, the authors expanded the immunogenicity studies toward an array of viral products of various origin and size including Ebola Virus VP24, VP40 and NP, Influenza Virus NP, Crimean-Congo Hemorrhagic Fever NP, West Nile Virus NS3, and Hepatitis C Virus NS3. All antigens appeared stable upon fusion with Nefmut , and are uploaded in exosomes at levels comparable to Nefmut . When injected in mice, DNA vectors expressing the diverse fusion products elicited a well detectable antigen-specific CD8+ T cell response associating with a cytotoxic activity potent enough to kill peptide loaded and/or antigen-expressing syngeneic cells. These data definitely proven both effectiveness and flexibility of this innovative CTL vaccine platform. PMID- 29274252 TI - Development of hafnium metal and titanium-hafnium alloys having apatite-forming ability by chemical surface modification. AB - Hafnium (Hf) has attracted considerable attention as a component of biomedical titanium (Ti) alloys with low Young's moduli and/or shape-memory functionalities, because its cytotoxicity is as low as that of Ti. The drawback of metals is that their bone-bonding ability is generally low. It is known that apatite formation in the body is a prerequisite for bone-bonding. Although several chemical treatments have been proposed for preparing Ti for bone-bonding, there have been no similar investigations for Hf. In the present study, NaOH- and heat-treatments were applied to pure Hf and Ti-Hf alloys and their bone-bonding ability was assessed in vitro with the use of simulated body fluid (SBF). After NaOH- and heat-treatments, anatase formed on alloys with low Hf content (20-40% (atom%) Hf); mixtures of sodium titanate and hafnium titanate formed on alloys with similar Ti and Hf content (60% Hf); and hafnium oxide formed on alloys with high Hf content (80% Hf and pure Hf). Precipitates of apatite were observed on all the metals in SBF, except for the alloy with 60% Hf. We speculated that the hafnium titanate formed on this alloy had a low apatite-forming ability owing to its high negative surface charge, which inhibited P adsorption. The apatite-forming abilities of the Ti-Hf alloys strongly depended on their Hf content. The present results indicate that Hf-based materials have good potential for bone-bonding. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2519-2523, 2018. PMID- 29274251 TI - Quantitative Flow Imaging in Human Umbilical Vessels In Utero Using Nongated 2D Phase Contrast MRI. AB - BACKGROUND: Volumetric assessment of afferent blood flow rate provides a measure of global organ perfusion. Phase-contrast magnetic resonance imaging (PCMRI) is a reliable tool for volumetric flow quantification, but given the challenges with motion and lack of physiologic gating signal, such studies, in vivo on the human placenta, are scant. PURPOSE: To evaluate and apply a nongated (ng) PCMRI technique for quantifying blood flow rates in utero in umbilical vessels. STUDY TYPE: Prospective study design. STUDY POPULATION: Twenty-four pregnant women with median gestational age (GA) 30 4/7 weeks and interquartile range (IQR) 8 1/7 weeks. FIELD STRENGTH/SEQUENCE: All scans were performed on a 3.0T Siemens Verio system using the ng-PCMRI technique. ASSESSMENT: The GA-dependent increase in umbilical vein (UV) and arterial (UA) flow was compared to previously published values. Systematic error to be expected from ng-PCMRI, in the context of pulsatile UA flow and partial voluming, was studied through Monte-Carlo simulations, as a function of resolution and number of averages. STATISTICAL TESTS: Correlation between the UA and UV was evaluated using a generalized linear model. RESULTS: Simulations showed that ng-PCMRI measurement variance reduced by increasing the number of averages. For vessels on the order of 2 voxels in radius, partial voluming led to 10% underestimation in the flow. In fetuses, the average flow rates in UAs and UV were measured to be 203 +/- 80 ml/min and 232 +/ 92 ml/min and the normalized average flow rates were 140 +/- 59 ml/min/kg and 155 +/- 57 ml/min/kg, respectively. Excellent correlation was found between the total arterial flow vs. corresponding venous flow, with a slope of 1.08 (P = 0.036). DATA CONCLUSION: Ng-PCMRI can provide accurate volumetric flow measurements in utero in the human umbilical vessels. Care needs to be taken to ensure sufficiently high-resolution data are acquired to minimize partial voluming-related errors. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017. PMID- 29274253 TI - miR-200a enhances TRAIL-induced apoptosis in gastric cancer cells by targeting A20. AB - Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) triggers apoptosis by inducing the death-inducing signaling complex (DISC) formation. Recently, TNFalpha-induced protein 3 (TNFAIP3, A20) was reported to prevent TRAIL induced caspase 8 cleavage in the DISC by mediating ubiquitination of RIP1 in glioblastoma. However, whether A20 regulates caspase 8 cleavage in the DISC when TRAIL induces apoptosis in gastric cancer cells is unknown. In the present study, A20 interacted with RIP1 and DR4 in MGC803 and SGC7901 gastric cancer cells. Treatment with TRAIL promoted the A20-mediated polyubiquitination of RIP1, caspase 8 translocation into the DISC, and the interaction between caspase 8 and ubiquitinated RIP1. Inhibition of A20 expression prevented the polyubiquitination of RIP1 and promoted caspase 8 cleavage. Moreover, our data clarified that A20 is a target of miR-200a. Overexpression of miR-200a inhibited A20 expression and polyubiquitination of RIP1 and then promoted cleavage of caspase 8 and TRAIL triggered apoptosis. Taken together, our results indicate that miR-200a enhanced TRAIL-triggered apoptosis in gastric cancer cells by targeting A20. PMID- 29274254 TI - French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy: a randomized open-label trial. AB - : Essentials An immediate supply of plasma in case of trauma-induced coagulopathy is required. The Traucc trial compared French Lyophilised Plasma (FLyP) and Fresh Frozen Plasma (FFP). FLyP achieved higher fibrinogen concentrations compared with FFP. FLyP led to a more rapid coagulopathy improvement than FFP. SUMMARY: Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6 h of injury. We randomly assigned patients to receive 4 FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45 min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n = 24; FFP, n = 24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90] min). FLyP achieved a higher fibrinogen concentration 45 min after randomization compared with FFP (baseline-adjusted mean difference, 0.29 g L-1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6 h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters. PMID- 29274255 TI - Fuel-Selective Transient Activation of Nanosystems for Signal Generation. AB - The transient activation of function using chemical fuels is common in nature, but much less in synthetic systems. Progress towards the development of systems with a complexity similar to that of natural ones requires chemical fuel selectivity. Here, we show that a self-assembled nanosystem, composed of monolayer-protected gold nanoparticles and a fluorogenic peptide, is activated for transient signal generation only in case the chemical fuel matches the recognition site present at the nanoparticle surface. A modification of the recognition site in the nanosystem completely changes the chemical fuel selectivity. When two nanosystems are simultaneously present, the selectivity expressed by the system depends on the concentration of nucleotide added. PMID- 29274256 TI - Small laccase from streptomyces coelicolor-an ideal model protein/enzyme for undergraduate laboratory experience. AB - A one semester undergraduate biochemistry laboratory experience is described for an understanding of recombinant technology from gene cloning to protein characterization. An integrated experimental design includes three sequential modules: molecular cloning, protein expression and purification, and protein analysis and characterization. Students perform the tasks of cloning, expression, purification, analysis, and characterization of small laccase (SLAC) from Streptomyces coelicolor. SLAC is an extremely robust well-characterized protein/enzyme, which serves as an ideal model for undergraduate teaching laboratories. Also, this goal-oriented research-like approach helps students to unite the concepts of biochemistry and molecular biology and appreciate the utility of the methods more effectively. A student assessment before and after the course demonstrated an overall increase in learning and enthusiasm on the topic of modern protein chemistry. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):172-181, 2018. PMID- 29274257 TI - Simultaneous enantioselective determination of six pesticides in aqueous environmental samples by chiral liquid chromatography with tandem mass spectrometry. AB - A robust and sensitive method was developed for the enantiomeric analysis of six chiral pesticides (including metalaxyl, epoxiconazole, myclobutanil, hexaconazole, napropamide, and isocarbophos) in aquatic environmental samples. The optimized chromatographic conditions for the quantification of all the 12 enantiomers were performed with Chiralcel OD-RH column using mobile phase consisting of 0.1% aqueous formic acid and acetonitrile operated under reversed phase conditions and then analyzed using liquid chromatography with tandem mass spectrometry. Twelve enantiomers were detected in multiple reaction monitoring mode. Solid-phase extraction and dispersive liquid-liquid microextraction were employed in this study. Response surface methodology was applied to assist in the dispersive liquid-liquid microextraction optimization. Under the optimum conditions, recoveries of pesticides enantiomers varied from 83.0 to 103.2% at two spiked levels with relative standard deviation less than 11.5%. The concentration factors were up to 1000 times. Method detection and quantification limits varied from 0.11 to 0.48 ng/L and from 0.46 to 1.49 ng/L, respectively. Finally, this method was used to determination of the enantiomers composition of the six pesticides in environmental aqueous matrices, which will help better understand the behavior of individual enantiomer and make accurate risk assessment to ecosystems. PMID- 29274258 TI - In Situ Synthesis of 3D Flower-Like Nanocrystalline Ni/C and its Effect on Hydrogen Storage Properties of LiAlH4. AB - Lithium alanate (LiAlH4 ) is of particular interest as one of the most promising candidates for solid-state hydrogen storage. Unfortunately, high dehydrogenation temperatures and relatively slow kinetics limit its practical applications. Herein, 3D flower-like nanocrystalline Ni/C, composed of highly dispersed Ni nanoparticles and interlaced carbon flakes, was synthesized in situ. The as synthesized nanocrystalline Ni/C significantly decreased the dehydrogenation temperature and dramatically improved the dehydrogenation kinetics of LiAlH4 . It was found that the LiAlH4 sample with 10 wt % Ni/C (LiAlH4 -10 wt %Ni/C) began hydrogen desorption at approximately 48 degrees C, which is very close to ambient temperature. Approximately 6.3 wt % H2 was released from LiAlH4 -10 wt %Ni/C within 60 min at 140 degrees C, whereas pristine LiAlH4 only released 0.52 wt % H2 under identical conditions. More importantly, the dehydrogenated products can partially rehydrogenate at 300 degrees C under 4 MPa H2 . The synergetic effect of the flower-like carbon substrate and Ni active species contributes to the significantly reduced dehydrogenation temperatures and improved kinetics. PMID- 29274259 TI - Understanding the Daphnia magna-microbiota crosstalk is an essential step to improve ecotoxigenomics-based testing. PMID- 29274260 TI - Risk of sea lice in aquaculture versus the cost of treatment. PMID- 29274261 TI - Learned Discourse: Timely Scientific Opinions. PMID- 29274263 TI - Advancing the assessment of population stability as a protection goal in ecotoxicology. PMID- 29274264 TI - IEAM, SETAC, and personal investment. PMID- 29274265 TI - Editorial. AB - As nurses and midwives it's our job to look after the healthcare needs of others. Caring is the fundamental core of what nursing and midwifery is all about and is what we do well for our patients, their families, and each other. PMID- 29274266 TI - Celebrate through self care. AB - International Day of the Midwife and International Nurses Day, celebrated on 5 May and 12 May respectively, are when nurses and midwives are acknowledged for the job that they do and also thanked for the vital care they give to their patients, their patients' families and each other. Yet while nurses and midwives are good at taking care of others, sometimes they can fall short of taking care of themselves. When celebrating nurses and midwives during May it is important to take time to acknowledge your own achievements as a nurse and/or a midwife, but also review what you are doing to care for yourself. Applying a few strategies could help you live more fulfilling, productive and happier lives, professionally and personally. PMID- 29274267 TI - PENALTY RATES. AB - In February 2017, the Fair Work Commission (FWC) handed down a decision which cut penalty rates for employees in the retail, hospitality and fast food industries. In particular, it cut the level of penalty rates for working on Sundays and public holidays by 25% to 50%. PMID- 29274268 TI - DIABETES: A TICKING TIME BOMB. AB - Diabetes is fast becoming one of the biggest epidemics in the world. Nowhere is this more apparent than in Australia where approximately 1 million Australians have been diagnosed with the disease. Natalie Dragon investigates why Diabetes has become so prevalent and what is being done about it. PMID- 29274269 TI - BIRTH OF A MIDWIFE. AB - Like many experienced midwives and nurses I have a plethora of experience spanning over 13 years. I completed my nursing degree in my home town of Derry City, Northern Ireland before completing my Post Graduate Degree in Midwifery at Queens University, Belfast. PMID- 29274270 TI - HONESTY AND INTEGRITY IN AUTHORSHIP ATTRIBUTION. AB - The publication of peer reviewed journal articles, book chapters, and books have become an important hallmark of the professional, academic, social and scientific credibility of the nursing profession. PMID- 29274271 TI - TEN TIPS FOR DRESSING AND SECUREMENT OF IV DEVICE WOUNDS. AB - Nurses insert and care for more than two billion intravascular (IV) devices globally each year. A wound is created for each IV insertion, and the wound cannot heal while the IV remains. PMID- 29274274 TI - Identifying return-to-work trajectories using sequence analysis in a cohort of workers with work-related musculoskeletal disorders. AB - Objectives This study aimed to identify return-to-work (RTW) trajectories among workers with work-related musculoskeletal disorders (MSD) and examine the associations between different MSD and these RTW trajectories. Methods We used administrative workers' compensation data to identify accepted MSD lost-time claims with an injury date between 2010-2012 in British Columbia, Canada. Cox regression analyses were used to investigate differences in time to RTW between MSD. Validated day-to-day calendar measures of four RTW states (sickness absence, modified RTW, RTW, and non-RTW) were grouped into RTW trajectories spanning a one year period using sequence analysis. RTW trajectories were clustered using decision rules that identified a shared trajectory structure. Poisson regression with robust standard errors was used to estimate relative risk ratios (RR) with 95% confidence intervals (CI) between MSD and RTW trajectory clusters. Results In a cohort of 81 062 claims, 2132 unique RTW trajectories were identified and clustered into nine RTW trajectory clusters. Half of the workers sustainably returned to work within one month. Workers with back strains were most likely to have trajectories characterized by early sustained RTW, while workers with fractures or dislocations were more likely to have prolonged sickness absence trajectories (RR 4.9-9.9) or non-RTW trajectories (RR 1.4-7.6). Conclusion This is the first study that has characterized different types of RTW trajectories of workers with MSD using sequence analysis. The application of sequence analysis and the identification of RTW trajectories yielded a number of key insights not found using conventional cox regression analysis. PMID- 29274275 TI - Stat5 phosphorylation is responsible for the excessive potency of HB-EGF. AB - Heparin-binding EGF-like growth factor (HB-EGF) is a potent growth factor involved in wound healing and tumorigenesis. Despite the sequence similarity between HB-EGF and EGF, HB-EGF induces cellular proliferation and migration more potently than EGF. However, the differential regulation by HB-EGF and EGF has not been thoroughly elucidated. In this study, we compared signaling pathways activated by HB-EGF and EGF to understand the details of the molecular mechanism of the high potency induced by HB-EGF. HB-EGF specifically induced the phosphorylation of EGFR-Y1045 and activated Stat5, which is responsible for promoting cell proliferation, and migration. The competition of phosphorylated EGFR-Y1045 inhibited Stat5 activation and consequently lowered the effect of HB EGF on cell proliferation, suggesting that the phosphorylation of EGFR-Y1045 is essential for the activation of Stat5. The phosphorylation of EGFR-Y1045 and Stat5 induced by HB-EGF was prevented by sequestering the heparin-binding domain, suggesting that the heparin-binding domain is critical for HB-EGF-mediated signaling and cellular responses. In conclusion, the heparin-binding domain of HB EGF was responsible for EGFR-mediated Stat5 activation, resulting in a more potent cellular proliferation, and migration than that mediated by EGF. This molecular mechanism is useful for understanding ligand-specific EGFR signaling and developing biomedicines for wound healing or cancer therapy. PMID- 29274273 TI - Nicotinic Acetylcholine Receptor Alpha7 Subunit Mediates Vagus Nerve Stimulation Induced Neuroprotection in Acute Permanent Cerebral Ischemia by a7nAchR/JAK2 Pathway. AB - BACKGROUND The role of nicotinic acetylcholine receptor alpha7 subunit (a7nAchR) in the treatment of acute cerebral ischemia by VNS has not been thoroughly clarified to date. Therefore, this study aimed to investigate the specific role of a7nAchR and explore whether this process is involved in the mechanisms of VNS induced neuroprotection in rats undergoing permanent middle cerebral artery occlusion (PMCAO) surgery. MATERIAL AND METHODS Rats received a7nAChR antagonist (A) or antagonist placebo injection for control (AC), followed by PMCAO and VNS treatment, whereas the a7nAChR agonist (P) was utilized singly without VNS treatment but only with PMCAO pretreatment. The rats were randomly divided into 6 groups: sham PMCAO, PMCAO, PMCAO+VNS, PMCAO+VNS+A, PMCAO+VNS+AC, and PMCAO+P. Neurological function and cerebral infarct volume were measured to evaluate the level of brain injury at 24 h after PMCAO or PMCAO-sham. Moreover, the related proteins levels of a7nAChR, p-JAK2, and p-STAT3 in the ischemic penumbra were assessed by Western blot analysis. RESULTS Rats pretreated with VNS had significantly improved neurological function and reduced cerebral infarct volume after PMCAO injury (p<0.05). In addition, VNS enhanced the levels of a7nAchR, p JAK2, and p-STAT3 in the ischemic penumbra (p<0.05). However, inhibition of a7nAchR not only attenuated the beneficial neuroprotective effects induced by VNS, but also decreased levels of p-JAK2 and p-STAT3. Strikingly, pharmacological activation of a7nAchR can partially substitute for VNS-induced beneficial neurological protection. CONCLUSIONS These results suggest that a7nAchR is a pivotal mediator of VNS-induced neuroprotective effects on PMCAO injury, which may be related to suppressed inflammation via activation of the a7nAchR/JAK2 anti inflammatory pathway. PMID- 29274272 TI - The role of the Hedgehog signaling pathway in cancer: A comprehensive review. AB - The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers. PMID- 29274276 TI - Recent progress in [11 C]carbon dioxide ([11 C]CO2 ) and [11 C]carbon monoxide ([11 C]CO) chemistry. AB - [11 C]Carbon dioxide ([11 C]CO2 ) and [11 C]carbon monoxide ([11 C]CO) are 2 attractive precursors for labelling the carbonyl position (C?O) in a vast range of functionalised molecules (eg, ureas, amides, and carboxylic acids). The development of radiosynthetic methods to produce functionalised 11 C-labelled compounds is required to enhance the radiotracers available for positron emission tomography, molecular, and medical imaging applications. Following a brief summary of secondary 11 C-precursor production and uses, the review focuses on recent progress with direct 11 C-carboxylation routes with [11 C]CO2 and 11 C carbonylation with [11 C]CO. Novel approaches to generate [11 C]CO using CO releasing molecules (CO-RMs), such as silacarboxylic acids and disilanes, applied to radiochemistry are described and compared with standard [11 C]CO production methods. These innovative [11 C]CO synthesis strategies represent efficient and reliable [11 C]CO production processes, enabling the widespread use of [11 C]CO chemistry within the wider radiochemistry community. PMID- 29274277 TI - CUL4B promotes metastasis and proliferation in pancreatic cancer cells by inducing epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway. AB - This study determines whether cullin 4B (CUL4B) promotes pancreatic cancer (PC) metastasis by inducing epithelial-mesenchymal transition (EMT) via the Wnt/beta catenin signaling pathway. A total of 64 PC patients were enrolled in this study. Human PC cell lines were distributed into blank, negative control, shCUL4B, PLOC, PLOC-CUL4B, and PLOC-CUL4B + siRNA-beta-catenin groups. The expressions of CUL4B, Wnt/beta-catenin signaling pathway-related proteins, and EMT-related proteins were determined using RT-qPCR and Western blotting. The positive expressions of CUL4B and beta-catenin protein in tissues were detected by immunohistochemistry. MTT assay and flow cytometry was performed for cell proliferation and cell cycle, scratch test, and transwell assay for cell migration and invasion ability. CUL4B and beta-catenin were expressed at a higher level in PC tissues than in paracancerous tissues though paracancerous tissues had higher expressions of CUL4B and beta-catenin than normal tissues. The PLOC-CUL4B group showed increased CUL4B, Wnt, beta-catenin, LEF-1, c-Jun, Cyclin D1, N-cadherin, Vimentin, Snail, and ZEB1 expression; decreased E-cadherin expression; accelerated cell proliferation; increased S-phase cell percentages; increased cell migration ability; more liver metastases; and enlarged tumor than the PLOC and PLOC-CUL4B + siRNA-beta-catenin groups. The shCUL4B group showed decreased CUL4B, Wnt, beta catenin, LEF-1, c-Jun, Cyclin D1, N-cadherin, Vimentin, Snail, and ZEB1 expression; increased E-cadherin expression; decelerated cell proliferation; decreased S-phase cell percentages; reduced cell migration ability; less liver metastases; and decreased tumor weight than the blank and negative control groups. We demonstrate that CUL4B promotes PC metastasis by inducing EMT via the Wnt/beta-catenin signaling pathway. Therefore, CUL4B might be the clinical target for treating PC. PMID- 29274278 TI - Low synthesis of secondary compounds in the lichen Lobaria pulmonaria infected by the lichenicolous fungus Plectocarpon lichenum. PMID- 29274279 TI - RBM10: Harmful or helpful-many factors to consider. AB - RBM10 is an RNA binding motif (RBM) protein expressed in most, if not all, human and animal cells. Interest in RBM10 is rapidly increasing and its clinical importance is highlighted by its identification as the causative agent of TARP syndrome, a developmental condition that significantly impacts affected children. RBM10's cellular functions are beginning to be explored, with initial studies demonstrating a tumor suppressor role. Very recently, however, contradictory results have emerged, suggesting a tumor promoter role for RBM10. In this review, we describe the current state of knowledge on RBM10, and address this dichotomy in RBM10 function. Furthermore, we discuss what may be regulating RBM10 function, particularly the importance of RBM10 alternative splicing, and the relationship between RBM10 and its paralogue, RBM5. As RBM10-related work is gaining momentum, it is critical that the various aspects of RBM10 molecular biology revealed by recent studies be considered moving forward. It is only if these recent advances in RBM10 structure and function are considered that a clearer insight into RBM10 function, and the disease states with which RBM10 mutation is associated, will be gained. PMID- 29274280 TI - Impact of IL-22 and IL-22 receptor alpha 1 polymorphisms on preeclampsia risk in Chinese Han women. AB - Previous studies have indicated that an increased inflammatory response plays an important role in preeclampsia (PE), and rising levels of interleukin (IL)-22 can trigger inflammation and hyperproliferation, leading to increased production of several pro-inflammatory cytokines such as IL-1, IL-6, and IL-8. We aimed to investigate the association between polymorphisms of IL-22 and IL-22 receptor alpha 1 gene (IL-22RA1) and PE in Chinese Han population. Single nucleotide polymorphisms (SNPs) rs2227485 in IL-22 and rs3795299 in IL-22RA were genotyped by Taqman real-time PCR in 1071 PE patients and 1263 control subjects. Differences in genetic distribution were compared between two groups using the chi-square test. Significant differences were observed in genotypic and allelic frequencies of IL-22RA1 rs3795299 between healthy controls and PE patients (P < 0.001 by genotype; P = 0.001, odds ratio = 1.253, 95% confidence interval 1.103 1.424 by allele). There were also significant differences in genotypic and allelic frequencies of rs3795299 between late-onset/mild PE and control groups. In addition, we found obvious statistic difference for the allele of early-onset PE/the genotype of late-onset PE and control subgroups for IL-22 rs2227485. IL-22 rs2227485 and IL-22RA1 rs3795299 may be associated with the development of PE in Chinese Han population. However, further validation is required in other populations, as well as an evaluation of the association of other SNPs in IL-22 and IL-22RA1 with PE. PMID- 29274281 TI - Differential uptake of and sensitivity to diphenhydramine in embryonic and larval zebrafish. AB - The zebrafish fish embryo toxicity (FET) test is increasingly employed for alternative toxicity studies, yet our previous research identified increased sensitivity of zebrafish slightly older than embryos employed in FET methods (0-4 d postfertilization [dpf]). We identified rapid steady-state accumulation of diphenhydramine across zebrafish embryo and larval stages. However, significantly (p < 0.05) lower accumulation was observed at 48 h compared to 96 h in chorionated and dechorionated embryos (0-4 dpf), but not in zebrafish at 7 to 11 and 14 to 18 dpf. Increased uptake and toxicity of diphenhydramine was further observed in zebrafish at 7 to 11 and 14 to 18 dpf compared with 0-4 dpf embryos with chorion or dechorionated, which indicates that differential zebrafish sensitivity with age is associated with accumulation resulting from gill and other toxicokinetic and toxicodynamic changes during development. Environ Toxicol Chem 2018;37:1175-1181. (c) 2017 SETAC. PMID- 29274282 TI - Genomic data reveal cryptic lineage diversification and introgression in Californian golden cup oaks (section Protobalanus). AB - Here we study hybridization, introgression and lineage diversification in the widely distributed canyon live oak (Quercus chrysolepis) and the relict island oak (Q. tomentella), two Californian golden cup oaks with an intriguing biogeographical history. We employed restriction-site-associated DNA sequencing and integrated phylogenomic and population genomic analyses to study hybridization and reconstruct the evolutionary past of these taxa. Our analyses revealed the presence of two cryptic lineages within Q. chrysolepis. One of these lineages shares its most recent common ancestor with Q. tomentella, supporting the paraphyly of Q. chrysolepis. The split of these lineages was estimated to take place during the late Pliocene or the early Pleistocene, a time corresponding well with the common presence of Q. tomentella in the fossil records of continental California. Analyses also revealed historical hybridization among lineages, high introgression from Q. tomentella into Q. chrysolepis in their current area of sympatry, and widespread admixture between the two lineages of Q. chrysolepis in contact zones. Our results support that the two lineages of Q. chrysolepis behave as a single functional species phenotypically and ecologically well differentiated from Q. tomentella, a situation that can be only accommodated considering hybridization and speciation as a continuum with diffuse limits. PMID- 29274283 TI - Mechanistic and structural insight into promiscuity based metabolism of cardiac drug digoxin by gut microbial enzyme. AB - The recent advances in microbiome studies have revealed the role of gut microbiota in altering the pharmacological properties of oral drugs, which contributes to patient-response variation and undesired effect of the drug molecule. These studies are essential to guide us for achieving the desired efficacy and pharmacological activity of the existing drug molecule or for discovering novel and more effective therapeutics. However, one of the main limitations is the lack of atomistic details on the binding and metabolism of these drug molecules by gut-microbial enzymes. Therefore, in this study, for a well-known and important FDA-approved cardiac glycoside drug, digoxin, we report the atomistic details and energy economics for its binding and metabolism by the Cgr2 protein of Eggerthella lenta DSM 2243. It was observed that the binding pocket of digoxin to Cgr2 primarily involved the negatively charged polar amino acids and a few non-polar hydrophobic residues. The drug digoxin was found to bind Cgr2 at the same binding site as that of fumarate, which is the proposed natural substrate. However, digoxin showed a much lower binding energy (17.75 +/- 2 Kcal mol-1 ) than the binding energy (42.17 +/- 2 Kcal mol-1 ) of fumarate. This study provides mechanistic insights into the structural and promiscuity based metabolism of widely used cardiac drug digoxin and presents a methodology, which could be useful to confirm the promiscuity-based metabolism of other orally administrated drugs by gut microbial enzymes and also help in designing strategies for improving the efficacy of the drugs. PMID- 29274284 TI - Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion. AB - Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase 3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1 induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment. PMID- 29274285 TI - CsLFY is required for shoot meristem maintenance via interaction with WUSCHEL in cucumber (Cucumis sativus). AB - Cucumber (Cucumis sativus) is an agronomically important vegetable with indeterminant growth habit, in which leaves are produced from the shoot apical meristem (SAM), and unisexual flowers are generated from the leaf axils. LEAFY (LFY) and its homologs have been shown to play important roles in promoting flower development and branching. The LFY homolog gene CsLFY was cloned in cucumber. Molecular biology, developmental biology and biochemical tools were combined to explore the biological function of the LFY homologous gene CsLFY in cucumber. CsLFY was expressed in the SAM, floral meristem and floral organ primordia. Ectopic expression of CsLFY rescued the phenotype of the lfy-5 mutant in Arabidopsis. Knockdown of CsLFY by RNA interference (RNAi) led to defective shoot development and premature discontinuance of leaf initiation in cucumber. Transcription of CsWUS and putative CsLFY target genes including CsAP3 and CUM1 were significantly reduced in the CsLFY-RNAi lines. Further biochemical analyses indicated that CsLFY physically interacts with CsWUS in cucumber. These data suggested that CsLFY has a novel function in regulating shoot meristem maintenance through interaction with CsWUS, and promotes flower development via activation of CsAP3 and CUM1 in cucumber. PMID- 29274286 TI - The prevention of latanoprost on osteoclastgenesis in vitro and lipopolysaccharide-induced murine calvaria osteolysis in vivo. AB - Identification of agents that inhibit osteoclast formation and function is important for the treatment of osteolytic diseases which feature excessive osteoclast formation and bone resorption. Latanoprost (LTP), an analog of prostaglandin F2alpha, is a medication which works to lower pressure inside the eyes. Prostaglandin F2alpha was reported to regulate bone metabolism, however, the effect of LTP in osteoclastogenesis is still unknown. Here, we found that LTP suppressed RANKL-induced osteoclastogenesis in a dose-dependent manner as illustrated by TRAP activity and TRAP staining. In addition, the osteoclast function was also reduced by LTP treatment, as indicated in less osteoclastic resorption pit areas. Furthermore, LTP inhibited the mRNA expressions of osteoclast marker genes such as TRAP and cathepsin K. In order to illustrate its molecular mechanism, we examined the changing of mRNA and protein levels of NFATc1 and c-fos by LTP treatment, as well as the phosphorylation of ERK, AKT, JNK, and p38. The results suggested that LTP inhibited RANKL-induced osteoclastgenesis and function by inhibiting ERK, AKT, JNK, and p38 cascade, following by the c-fos/NFATc1 pathway. In agreement with in vitro results, using an in vivo lipopolysaccharide-induced murine calvaria osteolysis mouse model, we found that administration of LTP was able to reverse the lipopolysaccharide induced bone loss. Together, these data demonstrated that LTP attenuated the bone loss in lipopolysaccharide-induced murine calvaria osteolysis mice through inhibiting osteoclast formation and function. Our study thus provided the evidences that LTP was a potential treatment option against osteolytic bone diseases. PMID- 29274287 TI - Practical aspects of real-time pure shift HSQC experiments. AB - Pure shift NMR spectroscopy has become an efficient tool for improving resolution in proton NMR spectra by removing the effect of homonuclear couplings. The introduction of real-time acquisition methods has allowed the main drawback of pure shift NMR, the long experiment times needed, to be circumvented. Real-time methods use periodic application of J-refocusing pulse sequence elements, acquiring a single free induction decay, in contrast to previous methods that construct a pure shift interferogram by concatenating excerpts from multiple free induction decays. In the important heteronuclear single-quantum correlation experiment, implementing real-time pure shift data acquisition typically leads to the simultaneous improvement of both resolution and sensitivity. The current limitations of and problems with real-time pure shift acquisition methods are discussed here in the context of heteronuclear single-quantum correlation experiments. We aim to provide a detailed account of the technical challenges, together with a practical guide to exploiting the full potential of such methods. PMID- 29274288 TI - Biological processes dominate seasonality of remotely sensed canopy greenness in an Amazon evergreen forest. AB - Satellite observations of Amazon forests show seasonal and interannual variations, but the underlying biological processes remain debated. Here we combined radiative transfer models (RTMs) with field observations of Amazon forest leaf and canopy characteristics to test three hypotheses for satellite observed canopy reflectance seasonality: seasonal changes in leaf area index, in canopy-surface leafless crown fraction and/or in leaf demography. Canopy RTMs (PROSAIL and FLiES), driven by these three factors combined, simulated satellite observed seasonal patterns well, explaining c. 70% of the variability in a key reflectance-based vegetation index (MAIAC EVI, which removes artifacts that would otherwise arise from clouds/aerosols and sun-sensor geometry). Leaf area index, leafless crown fraction and leaf demography independently accounted for 1, 33 and 66% of FLiES-simulated EVI seasonality, respectively. These factors also strongly influenced modeled near-infrared (NIR) reflectance, explaining why both modeled and observed EVI, which is especially sensitive to NIR, captures canopy seasonal dynamics well. Our improved analysis of canopy-scale biophysics rules out satellite artifacts as significant causes of satellite-observed seasonal patterns at this site, implying that aggregated phenology explains the larger scale remotely observed patterns. This work significantly reconciles current controversies about satellite-detected Amazon phenology, and improves our use of satellite observations to study climate-phenology relationships in the tropics. PMID- 29274289 TI - Epigenetic regulation of integrin beta6 transcription induced by TGF-beta1 in human oral squamous cell carcinoma cells. AB - Overexpression of integrin alphavbeta6 is believed to play an important role in the invasion and metastasis of oral squamous cell carcinoma (OSCC). However, little is known about the molecular mechanisms leading to alphavbeta6 upregulation in OSCC. As the integrin beta6 (ITGB6) is the only partner with alphav, the expression of alphavbeta6 is dependent on ITGB6, it is, therefore, pivotal to investigate the mechanisms underlying ITGB6 overexpression in OSCC. We previously reported the cloning and characterization of human ITGB6 gene. In the current study, we further investigated the molecular mechanisms of ITGB6 expression and the upregulation by carcinogenesis related cytokine-transforming growth factor-beta1 (TGF-beta1) in OSCC cells. We first demonstrated that TGF beta1 can induce ITGB6 mRNA and protein express in a time and concentration dependent manner, and the induced-ITGB6 mRNA was not due to increase the mRNA stability, but regulated at transcriptional level. By using a luciferase reporter assay, site-mutation, RNA interference, and chromatin immunoprecipitation assay, we revealed for the first time that JunB, a member of the activator protein-1 (AP 1) family, is involved in the positive regulation to the ITGB6 transcription induced by TGF-beta1 in OSCC cells. Furthermore, our data also demonstrated that histone acetyltransferase (HAT) CBP mediated histone H3 and H4 hyperacetylation, and RNA Polymerase II recruitment to ITGB6 promoter, facilitated the binding of transcription factor JunB to ITGB6 promoter after TGF-beta1 stimulation. Collectively, these findings demonstrate that JunB and CBP-mediated histone hyperacetylation are responsible for TGF-beta1 induced ITGB6 transcription in OSCC cells, suggesting that epigenetic mechanisms are responsible for the active transcription expression of ITGB6 induced by TGF-beta1 in OSCC cells. PMID- 29274290 TI - Facile synthesis of high specific activity 4-[1-14 C]butyl-1,2 diphenylpyrazolidine-3,5-dione (phenylbutazone) using nucleophilic substitution. AB - Metabolism, environmental fate, and low concentration food residue studies would be facilitated by the use of radiolabeled test articles that can be readily quantified within complex matrices. However, radiochemical approaches for such studies require high specific activities to allow analytical detection of correspondingly low masses of test article. The synthesis of high specific activity (>50 MUCi/MUmol) [14 C]-radiolabeled phenylbutazone presents a challenge using existing methodology, mainly due to the low solvent volumes required and vigorous refluxing needed to close the pyrazolidinedione ring. Herein, we report on the significant modification of an existing method that allows the synthesis of low masses of high specific activity (>50 MUCi/MUmol) [14 C]-phenylbutazone under mild conditions with simple purification and high yield. The closure of the pyrazolidinedione ring of 1,2-diphenyl-3,5-pyrazolidinedione was accomplished as a first step with unlabeled 1,2-diphenylhydrazine and diethyl malonate in 32% yield under gram-scale conditions, which avoided the challenges of low solvent use and vigorous refluxing. Low mass of high specific activity n-[1-14 C]-butyl bromide was then added via a nucleophilic substitution reaction as a final step. Yields ranged from 65% to 92% during multiple synthetic attempts with unlabeled butyl bromide and were greatly influenced by reaction stoichiometry and the selection of base. PMID- 29274291 TI - Enriched physical environment reverses spatial cognitive impairment of socially isolated APPswe/PS1dE9 transgenic mice before amyloidosis onset. AB - AIMS: Social isolation increases the onset of Alzheimer's disease (AD). Environmental enrichment, a complicated social and physical construct, plays beneficial effects on brain plasticity and function. This study was designed to determine whether physical enrichment can reduce the deleterious consequences of social isolation on the onset of AD. METHODS: One-month-old APPswe/PS1dE9 transgenic AD model mice were singly housed in the enriched physical environment for 8 weeks and then received behavioral tests, neuropathological analyses, and Western blot of the hippocampus. RESULTS: The enriched physical environment reversed spatial cognitive decline of socially isolated APPswe/PS1dE9 mice. The functional reversal was associated with decreases in cellular apoptosis, synaptic protein loss, inflammation, and glial activation in the hippocampus, without changes in amyloid beta neuropathology. CONCLUSION: These results suggest that the enriched physical environment may serve as a nonpharmacological intervention for delaying the onset of AD accompanied with social isolation. PMID- 29274292 TI - Butyrate and docosahexaenoic acid interact in alterations of specific lipid classes in differentiating colon cancer cells. AB - Docosahexaenoic acid (DHA) and sodium butyrate (NaBt) exhibit a number of interactive effects on colon cancer cell growth, differentiation, or apoptosis; however, the molecular mechanisms responsible for these interactions and their impact on cellular lipidome are still not fully clear. Here, we show that both dietary agents together induce dynamic alterations of lipid metabolism, specific cellular lipid classes, and fatty acid composition. In HT-29 cell line, a model of differentiating colon carcinoma cells, NaBt supported incorporation of free DHA into non-polar lipids and their accumulation in cytoplasmic lipid droplets. DHA itself was not incorporated into sphingolipids; however, it significantly altered representation of individual ceramide (Cer) classes, in particular in combination with NaBt (DHA/NaBt). We observed altered expression of enzymes involved in Cer metabolism in cells treated with NaBt or DHA/NaBt, and exogenous Cer 16:0 was found to promote induction of apoptosis in differentiating HT-29 cells. NaBt, together with DHA, increased n-3 fatty acid synthesis and attenuated metabolism of monounsaturated fatty acids. Finally, DHA and/or NaBt altered expression of proteins involved in synthesis of fatty acids, including elongase 5, stearoyl CoA desaturase 1, or fatty acid synthase, with NaBt increasing expression of caveolin-1 and CD36 transporter, which may further promote DHA incorporation and its impact on cellular lipidome. In conclusion, our results indicate that interactions of DHA and NaBt exert complex changes in cellular lipidome, which may contribute to the alterations of colon cancer cell differentiation/apoptotic responses. The present data extend our knowledge about the nature of interactive effects of dietary fatty acids. PMID- 29274293 TI - Activation of KLF4 expression by small activating RNA promotes migration and invasion in colorectal epithelial cells. AB - RNA activation mediated by small double-stranded RNAs targeting promoter sequence named small activating RNAs (saRNAs) is one of the mechanisms for gene activation. Artificial regulation of gene expression through RNA activation does not affect the alteration of the genomic DNA sequences or exogenous plasmid DNA, therefore it is a relative manageable approach for gene perturbation. KLF4 is a member of zinc-finger transcription factors and its functions in colorectal cells are still controversial. In order to elucidate the functions of KLF4, we synthesized saRNAs that target the promoter regions of KLF4 and transfected into varied colorectal epithelial cell lines. We found the KLF4 gene expression is specifically increased in the human normal epithelial cell NCM460 and colorectal epithelial cancer cell Caco-2 and HCT116, but not in other human colorectal epithelial cell lines. In addition, we observed that saRNAs induced overexpression of KLF4 could promote cell migration/invasion in NCM460 and HCT116 cell lines. This effect is mediated partly by inducing EMT and facilitating nuclear translocation of beta-catenin. PMID- 29274294 TI - Using 2 H labelling to improve the NMR detectability of pyridine and its derivatives by SABRE. AB - By introducing a range of 2 H labels into pyridine and the para-substituted agents, methyl isonicotinate and isonicotinamide, we significantly improve their NMR detectability in conjunction with the signal amplification by reversible exchange process. We describe how the rates of T1 relaxation for the remaining 1 H nuclei are increased and show how this leads to a concomitant increase in the level of 1 H and 13 C hyperpolarization that can ultimately be detected. PMID- 29274295 TI - The role of cognitive bias in relation to persistent distress among women diagnosed with breast cancer. AB - OBJECTIVE: To examine if bias in attention to and interpretation of cancer related stimuli differentiates women with persistent psychological distress from those with low/transient distress following breast cancer. METHODS: One-hundred forty women classified in a prior longitudinal study as having low (n = 73) or persistent high (n = 67) distress completed 2 modified dot-probe tasks assessing attention bias and an ambiguous cues task assessing interpretation bias toward cancer-related vs neutral information. Psychological distress was assessed using the Hospital Anxiety Depression Scale. Four-way repeated analysis of variance was adopted. RESULTS: Participants with persistent high distress from the original study who continued to report high Hospital Anxiety Depression Scale scores (>=8) on recruitment into the present study comprised the persistent distress group (ie, 31 reporting high anxiety and 30 reporting high depression scores). Persistent distress and low distress groups did not differ in attentional bias toward negative-stimuli or cancer-related information, but a significant time course effect in attentional bias toward negative-stimuli or cancer-related information was observed, with women in the persistent distress group showing a significant bias away from negative-stimuli or cancer-related information under supraliminal conditions. There was a borderline difference in interpretation bias scores between low anxiety and chronic anxiety groups (P = .065), with correlation suggesting a significant positive association (r = 0.20, P = .019). CONCLUSION: Women with persistent distress may adopt avoidance strategies to cope with breast cancer. Moreover, women reporting persistent anxiety may have a tendency to negatively interpret ambiguous information, leading to illness preoccupation. These findings offer critical insight for clinicians to develop tailored interventions to help women with persistent psychological distress. PMID- 29274296 TI - T cell exhaustion in cancer: Mechanisms and clinical implications. AB - During chronic viral infection or cancer, the immune system usually induces a corresponding immune response against pathogens or cancer cells so as to prevent worsening disease. T cell exhaustion in which reduced and dysfunctional effector T cells lead to immune escape is one of the mechanisms that pathogens or cancer cells get rid of control from the immune system. In this review, we discuss some mechanisms associated with T cell exhaustion and enumerate current methods of reversing T cell exhaustion. We also summarize current targeted treatment strategies and put forward following aspects that required to research. PMID- 29274297 TI - Effect of ECM2 expression on bovine skeletal muscle-derived satellite cell differentiation. AB - Extracellular matrix components have important regulatory functions during cell proliferation and differentiation. In recent study, extracellular matrix were shown to have a strong effect on skeletal muscle differentiation. Here, we aimed to elucidate the effects of extracellular matrix protein 2 (ECM2), an extracellular matrix component, on the differentiation of bovine skeletal muscle derived satellite cells (MDSCs). Western blot and immunofluorescence analyses were used to elucidate the ECM2 expression pattern in bovine MDSCs during differentiation in vitro. CRISPR/Cas9 technology was used to activate or inhibit ECM2 expression to study its effects on the in vitro differentiation of bovine MDSCs. ECM2 expression was shown to increase gradually during bovine MDSC differentiation, and the levels of this protein were higher in more highly differentiated myotubes. ECM2 activation promoted MDSC differentiation, whereas its suppression inhibited the differentiation of these cells. Here, for the first time, we demonstrated the importance of ECM2 expression during bovine MDSC differentiation; these results could lead to treatments that help to increase beef cattle muscularity. PMID- 29274298 TI - Time-resolved monitoring of enzyme activity with ultrafast Hyper-CEST spectroscopy. AB - We propose a method to dynamically monitor the progress of an enzymatic reaction using NMR of hyperpolarized 129 Xe in a host-guest system. It is based on a displacement assay originally designed for fluorescence experiments that exploits the competitive binding of the enzymatic product on the one hand and a reporter dye on the other hand to a supramolecular host. Recently, this assay has been successfully transferred to NMR, using xenon as a reporter, cucurbit[6]uril as supramolecular host, and chemical exchange saturation transfer with hyperpolarized Xe (Hyper-CEST) as detection technique. Its advantage is that the enzyme acts on the unmodified substrate and that only the product is detected through immediate inclusion into the host. We here apply a method that drastically accelerates the acquisition of Hyper-CEST spectra in vitro using magnetic field gradients. This allows monitoring the dynamic progress of the conversion of lysine to cadaverine with a temporal resolution of ~30 s. Moreover, the method only requires to sample the very early onset of the reaction (<0.5% of substrate conversion where the host itself is required only at MUM concentrations) at comparatively low reaction rates, thus saving enzyme material and reducing NMR acquisition time. The obtained value for the specific activity agrees well with previously published results from fluorescence assays. We furthermore outline how the Hyper-CEST results correlate with xenon T2 measurements performed during the enzymatic reaction. This suggests that ultrafast Hyper-CEST spectroscopy can be used for dynamically monitoring enzymatic activity with NMR. PMID- 29274299 TI - Anti-proliferative effect of rosiglitazone in the human T-lymphocyte leukaemia cell line Jurkat cells. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in various types of human cancer cells including leukaemia cells, and activation of PPARgamma can inhibit cancer cell growth. However, whether PPARgamma is expressed in Jurkat cells, a human T-lymphocyte leukaemia cell line, and whether activation of PPARgamma affects cell biological behaviors remains to be clarified. In this study, we investigated the effect of a PPARgamma activator rosiglitazone, under clinically relevant pharmacological concentrations, on the growth and apoptosis of Jurkat cells in vitro and explored the possible mechanism. Metformin was also included as a positive control for the anti-proliferative and pro-apoptotic effects. We found that PPARgamma mRNA was transcribed in Jurkat cells. Treatment with rosiglitazone (5 uM, 10 uM, and 20 uM) or metformin (1 mM and 10 mM) inhibited cell proliferation, and induced cell cycle arrest at G0/G1 or S phase, respectively, in a dose-dependent manner. Although metformin significantly upregulated the protein levels of the pro-apoptotic markers cleaved-caspase 3 and Bax in Jurkat cells, rosiglitazone did not have such an effect. Moreover, rosiglitazone significantly upregulated the level of PPARgamma, and downregulated the expression of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) in a dose-dependent manner. Our data indicate that rosiglitazone has an anti-proliferative effect in Jurkat cells, which may be at least partly mediated via downregulating IR and IGF-1R expression. Therefore, rosiglitazone may have a potential role not only for management of hyperglycaemia but also for control of tumor progression in patients with T-lymphocyte leukaemia and diabetes. PMID- 29274300 TI - Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Cav 2.3 voltage-gated calcium channel. AB - INTRODUCTION: The relationship between blood metabolites and hemoglobin degradation products (BMHDPs) formed in the cerebrospinal fluid and the development of vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been the focus of several previous studies, but their molecular and cellular targets remain to be elucidated. METHODS: Because BMHDP-induced changes in Cav 2.3 channel function are thought to contribute to DCI after aSAH, we studied their modulation by unconjugated bilirubin (UCB) in an organotypical neuronal network from wild-type (WT) and Cav 2.3-deficient animals (KO). Murine retinae were isolated from WT and KO and superfused with nutrient solution. Electroretinograms were recorded before, during, and after superfusion with UCB. Transretinal signaling was analyzed as b wave, implicit time, and area under the curve (AUC). RESULTS: Superfusion of UCB significantly attenuated the b-wave amplitude in the isolated retina from wild type mice by 14.9% (P < 0.05), followed by gradual partial recovery (P = 0.09). Correspondingly, AUC decreased significantly with superfusion of UCB (P < 0.05). During washout, the b-wave amplitude returned to baseline (P = 0.2839). The effects of UCB were absent in Cav 2.3-deficient mice, lacking the expression of Cav 2.3 as proofed on the biochemical level. CONCLUSIONS: Ex vivo neuronal recording in the murine retina is able to detect transient impairment of transretinal signaling by UCB in WT, but not in KO. This new model may be useful to further clarify the role of calcium channels in neuronal signal alteration in the presence of BHMDPs. PMID- 29274301 TI - Rapid Formation of a Disordered Layer on Monoclinic BiVO4 : Co-Catalyst-Free Photoelectrochemical Solar Water Splitting. AB - A surface disordered layer is a plausible approach to improve the photoelectrochemical performance of TiO2 . However, the formation of a crystalline disordered layer in BiVO4 and its effectiveness towards photoelectrochemical water splitting has remained a big challenge. Here, we report a rapid solution process (within 5 s) that is able to form a disordered layer of a few nanometers thick on the surface of BiVO4 nanoparticles using a specific solution with a controllable reducing power. The disordered layer on BiVO4 alleviates charge recombination at the electrode-electrolyte interface and reduces the onset potential greatly, which in turn results in a photocurrent density of approximately 2.3 mA cm-2 at 1.23 V versus the reversible hydrogen electrode (RHE). This value is 2.1 times higher than that of bare BiVO4 . The enhanced photoactivity is attributed to the increased charge separation and transfer efficiencies, which resolve the intrinsic drawbacks of bare BiVO4 such as the short hole diffusion length of around 100 nm and poor surface oxygen evolution reactivity. PMID- 29274302 TI - Association of CYP2C9*3 with phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: A systematic review and meta-analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key enzyme in PHT metabolism. The aim of this meta-analysis was to evaluate the association between CYP2C9*3 and PHT-induced SJS/TEN. METHODS: An extensive search was performed in multiple databases, including the Cochrane Library, EMBASE, PubMed, OVID and EBSCO. Studies exploring the relationship between CYP2C9*3 and PHT-induced SJS and TEN were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for dichotomous data. Data analysis was performed using Review Manager (version 5.3). RESULTS AND DISCUSSION: Four studies, with 117 PHT-induced SJS/TEN cases and 338 matched controls (PHT-tolerant patients) or 4231 population controls (general population), were identified. SJS and TEN were found to be significantly associated with the CYP2C9*3 allele, comparing both matched controls (OR, 8.93; 95% CI, 2.63-30.36; P = .0005) with substantial heterogeneity (I2 = 46%) and population controls (OR, 8.88; 95% CI, 5.01-15.74; P < .00001). WHAT IS NEW AND CONCLUSION: A significant association between CYP2C9*3 and PHT-induced SJS/TEN was identified, especially in a Thai population. CYP2C9*3 is thus a credible predictive genetic marker of PHT-induced SJS/TEN. Further multicenter studies and large prospective observational studies are, however, still required to determine the influence of CYP2C*3 on blood levels of PHT and its metabolites, and their association with SJS/TEN. PMID- 29274303 TI - Magnetic drug targeting simulations in blood flows with fluid-structure interaction. AB - We present fluid-structure interaction simulations of magnetic drug targeting (MDT) in blood flows. In this procedure, a drug is attached to ferromagnetic particles to externally direct it to a specific target after it is injected inside the body. The goal is to minimize the healthy tissue affected by the treatment and to maximize the number of particles that reach the target location. Magnetic drug targeting has been studied both experimentally and theoretically by several authors. In recent years, computational fluid dynamics simulations of MDT in blood flows have been conducted to obtain further insight on the combination of parameters that provide the best capture efficiency. However, to this day, no computational study addressed MDT in a fluid-structure interaction setting. With this paper, we aim to fill this gap and investigate the impact of the solid deformation on the capture efficiency. PMID- 29274304 TI - Editorial Comment. PMID- 29274305 TI - Treatment adherence and level of control in moderate persistent asthma in children and adolescents treated with fluticasone and salmeterol. AB - OBJECTIVE: There is a scarcity of studies that assessed the association between adherence to combination therapy and asthma control in pediatric patients. The authors investigated the association between adherence to fluticasone propionate/salmeterol xinafoate combination-metered aerosol and the level of asthma control in children. METHODS: This was a prospective observational study of 84 patients aged 5-16 years with moderate persistent asthma, who remained uncontrolled despite the use of 1000MUg/day of inhaled nonextrafine-hydrofluoric alkane-beclomethasone dipropionate in the three months prior to study enrollment. Participants were prescribed two daily doses of FP (125MUg)/salmeterol xinafoate (25MUg) combination by metered aerosol/spacer for six months. Adherence rates were assessed using the device's dose counter after the 2nd, 4th, and 6th months of follow up. Asthma control was assessed using a simplified Global Initiative for Asthma 2014 Report classification. RESULTS: Mean adherence rates after the second, fourth, and sixth months were 87.8%, 74.9%, and 62.1% respectively, for controlled asthma, and 71.7%, 56.0%, and 47.6% respectively, for uncontrolled asthma (all p-values<=0.03). The proportion of children achieving asthma control increased to 42.9%, 67.9% and 89.3% after the 2nd, 4th and 6th months of follow up, respectively (p<=0.001). CONCLUSION: Adherence rates between 87.8% in the 2nd month and 62.1% in the 6th month were strong determinants of asthma control. PMID- 29274306 TI - Scurvy, a Not-So-Ancient Disease. PMID- 29274309 TI - Occurrence of Cryptosporidium in the water basins of nitra region, slovakia. AB - Cryptosporidium species C. parvum and C. hominis are a common cause of human diarrheal infections worldwide. In this study we attempted to detect these parasites in fish ponds and a water reservoirs in the Nitra region of Slovakia. We identified C. parvum genotype IIaA15G1R1 and genotype IIaA16G1R1 and C. hominis genotype IeA11G3T3 in these locations. Occurrence of the same genotype of C. hominis in two different locations indicates that this parasite is most likely present in the river that connects them. These results indicate a serious threat to public health of humans since these locations are used for fishing and for recreational activities. PMID- 29274308 TI - The platelet phenotype in patients with ST-segment elevation myocardial infarction is different from non-ST-segment elevation myocardial infarction. AB - It is assumed that platelets in diseased conditions share similar properties to platelets in healthy conditions, although this has never been examined in detail for myocardial infarction (MI). We examined platelets from patients with ST segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) compared with platelets from healthy volunteers to evaluate for differences in platelet phenotype and function. Platelet activation was examined and postreceptor signal transduction pathways were assessed. Platelet-derived plasma biomarkers were evaluated by receiver operator characteristic curve analysis. Maximum platelet activation through the thromboxane receptor was greater in STEMI than in NSTEMI but less through protease-activated receptor 1. Extracellular-signal related-kinase 5 activation, which can activate platelets, was increased in platelets from subjects with STEMI and especially in platelets from patients with NSTEMI. Matrix metalloproteinase 9 (MMP9) protein content and enzymatic activity were several-fold greater in platelets with MI than in control. Mean plasma MMP9 concentration in patients with MI distinguished between STEMI and NSTEMI (area under curve [AUC] 75% [confidence interval (CI) 60-91], P = 0.006) which was superior to troponin T (AUC 66% [CI 48-85, P = 0.08), predicting STEMI with 80% sensitivity (95% CI 56 94), 90% specificity (CI 68-99), 70% AUC (CI 54-86, P < 0.0001), and NSTEMI with 50% sensitivity (CI 27-70), 90% specificity (CI 68-99), 70% AUC (CI 54-86, P = 0.03). Platelets from patients with STEMI and NSTEMI show differences in platelet surface receptor activation and postreceptor signal transduction, suggesting the healthy platelet phenotype in which antiplatelet agents are often evaluated in preclinical studies is different from platelets in patients with MI. PMID- 29274310 TI - Is Bone Morphogenetic Protein-2 as Effective as Alveolar Distraction Osteogenesis for Vertical Bone Regeneration? AB - PURPOSE: The aim of this study was to assess the clinical effectiveness of alveolar distraction osteogenesis (ADO) versus recombinant human bone morphogenetic protein-2 (rh-BMP-2) for vertical ridge augmentation. Few data have been published on vertical bone regeneration using rh-BMP-2. MATERIALS AND METHODS: The authors implemented a retrospective cohort study and enrolled a sample composed of patients with deficient alveolar vertical bone height. The primary predictor variable was vertical augmentation with BMP-2 and a titanium mesh or ADO. The primary outcome variable was gain in vertical bone height (millimeters) measured using computed tomography. The secondary outcome variable was postoperative complications, namely need for further grafting before or simultaneous with implant placement, soft tissue dehiscence, paresthesia, infection, implant failure, and pain. Other outcomes included implant stability at time of placement and follow-up (implant stability quotient by resonance frequency analysis), surgical time (minutes), and total treatment time until implant placement (weeks). Other study variables included location of reconstruction (maxilla or mandible). Appropriate bivariate statistics were computed and statistical significance was set a P value less than .05. RESULTS: The retrospective review yielded 21 patients in the BMP group and 19 in the ADO group. For the BMP-2 group, the average vertical bone gain was 2.96 +/- 1.8 mm overall (maxilla, mean 3.6 +/- 3.1 mm; mandible, mean 2.32 +/- 1.8 mm). For the ADO group, this gain was 4 +/- 1.69 mm overall (maxilla, mean 2.8 +/- 1.94 mm; mandible, mean 5.2 +/- 4.67 mm). For complications, group BMP showed a statistically minor tendency for more postoperative problems, such as wound dehiscence. For implant survival, group BMP showed a 92.2% survival rate versus 96.3% in group ADO at 3 to 45 months after delivery of the prosthesis (average, 22 months). CONCLUSION: The 2 techniques showed similar values in absolute vertical bone gain. Group ADO showed a slightly better outcome in outright vertical regenerative potential, albeit with a more frequent need for regrafting before and simultaneous with implant placement. Group BMP showed a lesser need for regrafting, despite having a higher postoperative complication rate. PMID- 29274311 TI - Endoscopic-Assisted Treatment Combined With Transoral and Transbuccal Approach to Mandibular Subcondylar Fractures. AB - PURPOSE: Endoscopic treatment of maxillofacial fractures is a different way of performing open reduction and internal fixation. This report presents a case series of mandibular subcondylar fractures performed with combined endoscopic transoral and transbuccal approaches and the results. MATERIALS AND METHODS: Sixteen patients with mandibular condylar fractures were preoperatively assessed for risk and underwent open reduction and internal fixation with the endoscope assisted transoral approach. Duration of hospital stay was recorded and patients were followed for an average of 17 months for possible complications. RESULTS: No major complications were encountered in any patient. Minimal angulation was observed in 3 patients. One patient had late complaints of temporomandibular joint pain. CONCLUSION: Endoscopic-assisted mandibular condylar fracture repair includes special surgical equipment and manipulation not used in classic methods. With this approach, subcondylar fractures can be more readily manipulated through a transbuccal puncture with appropriate fixation achieved. PMID- 29274312 TI - Population genetic characterization of Cyclospora cayetanensis from discrete geographical regions. AB - Cyclospora cayetanensis is an emerging pathogen that is endemic in developing countries and responsible for many large foodborne cyclosporiasis outbreaks in North America since 1990s. Because of the lack of typing targets, the genetic diversity and population genetics of C. cayetanensis have not been investigated. In this study, we undertook a population genetic analysis of multilocus sequence typing data we recently collected from 64 C. cayetanensis specimens. Despite the extensive genetic heterogeneity in the overall C. cayetanensis population, there were significant intra- and inter-genic linkage disequilibria (LD). A disappearance of LD was observed when only multilocus genotypes were included in the population genetic analysis, indicative of an epidemic nature of C. cayetanensis. Geographical segregation-associated sub-structuring was observed between specimens from China and those from Peru and the United States. The two subpopulations had reduced LD, indicating the likely occurrence of genetic exchange among isolates in endemic areas. Further analyses of specimens from other geographical regions are necessary to fully understand the population genetics of C. cayetanensis. PMID- 29274307 TI - Vitamin K Antagonists After 6 Months of Low-Molecular-Weight Heparin in Cancer Patients with Venous Thromboembolism. AB - BACKGROUND: Low-molecular-weight heparin (LMWH) is the treatment of choice in cancer patients with venous thromboembolism. However, data on continuing LMWH treatment beyond 6 months remain scanty. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to compare the rate of venous thromboembolism recurrences and major bleeding appearing beyond the first 6 months of anticoagulant therapy in cancer patients with venous thromboembolism, according to therapy with LMWH or vitamin K antagonists (VKA). We performed a propensity score-matched cohort study. RESULTS: After propensity matching, 482 cancer patients continued to receive LMWH and 482 switched to VKA. During the course of anticoagulant therapy (mean 275.5 days), 57 patients developed venous thrombosis recurrences (recurrent pulmonary embolism 26, recurrent deep vein thrombosis 29, both 2), 28 had major bleeding, 38 had nonmajor bleeding, and 129 died. No patient died of recurrent venous thrombosis, and 5 patients died of bleeding (2 were on LMWH, 3 on VKA). Patients who continued with LMWH had a similar rate of deep vein thrombosis recurrences (relative risk [RR] 1.41; 95% confidence interval [CI], 0.68-2.93), pulmonary embolism recurrences (RR 0.73; 95% CI, 0.34-1.58), major bleeding (RR 0.96; 95% CI, 0.51-1.79), or nonmajor bleeding (RR 1.15; 95% CI, 0.55-2.40), compared with those who switched to VKA, but a higher mortality rate (RR 1.58; 95% CI, 1.13-2.20). CONCLUSIONS: In cancer patients with venous thromboembolism who completed 6 months of LMWH therapy, switching to VKA was associated with a similar risk of venous thrombosis recurrences or bleeding when compared with patients who continued LMWH. PMID- 29274313 TI - Mitral Ring Extraction due to Nickel Allergy. AB - The incidence of allergic reactions due to mechanical prosthesis or rings is not well established. We report the case of a 56-year-old man who presented a persistent urticarial rash and anaphylactic shock after a mitral valve repair operation. Prick skin tests were positive for nickel. After the nucleus from the mitral annulus was removed, the urticarial rash disappeared. PMID- 29274314 TI - An Analysis of Left Ventricular Retraining in Patients With Dextro- and Levo Transposition of the Great Arteries. AB - BACKGROUND: Patients with dextro (D)-transposition of the great arteries (TGA) who have undergone a previous atrial switch and for some patients with levo (L) TGA (ie, no ventricular septal defect or outflow tract obstruction), the left ventricle (LV) may require retraining before late arterial switch. The purpose of this study was to analyze the results of LV retraining for these two entities. METHODS: This was a retrospective review of 51 patients enrolled in an LV retraining program. There were 25 patients with D-TGA and 26 with L-TGA. The median age of the D-TGA patients was 15 years, and 22 of 25 were in New York Heart Association class III or IV. The median age of the L-TGA patients was 12 months, and 3 of 26 patients were in New York Heart Association class III or IV. RESULTS: LV retraining was successful in 13 of the 25 patients (52%) with D-TGA, and 10 these 13 patients (77%) underwent successful late arterial switch. Of the 26 patients with L-TGA, LV retraining was successful in 24 (92%), and a double switch operation was successful in 19 of 19 (100%) who subsequently underwent that procedure. A mathematical formula based on the incremental gain in left-to right ventricular pressure ratio correctly predicted the success or failure in 94% of the patients. CONCLUSIONS: The data demonstrate differences in the success of LV retraining and late arterial switch for D-TGA and L-TGA. We would propose that the LV retraining ratio may be useful in objectively selecting patients eligible for late arterial switch. PMID- 29274315 TI - Clinical Tests Have Limited Predictive Value for Chronic Ankle Instability When Conducted in the Acute Phase of a First-Time Lateral Ankle Sprain Injury. AB - OBJECTIVE: To evaluate whether a battery of clinical assessments for acute lateral ankle sprain (LAS) can be used to predict long-term recovery. DESIGN: Cohort study. SETTING: University biomechanics laboratory. PARTICIPANTS: Individuals (N=82) were assessed using a clinical test battery within 2 weeks of incurring a first-time LAS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The clinical test battery included scores on the talar glide test (degrees), the anterior drawer, talar tilt, figure of 8 for swelling (millimeters) and knee to wall (millimeters) tests, and handheld goniometric range of motion (inversion, eversion, and plantarflexion [in degrees]). Scores on the Cumberland Ankle Instability Tool taken 12 months after the clinical test battery were used to classify participants as having chronic ankle instability (CAI) or as being LAS copers. RESULTS: Forty percent of participants were designated as having CAI, with 60% being designated as LAS copers. A logistic regression analysis revealed that a combined model using scores from the talar glide, talar tilt, and anterior drawer tests in addition to plantarflexion range of motion was statistically significant (P<.01) and correctly classified cases with moderate accuracy (68.8%). The final model had moderate sensitivity (64%) and good specificity (72%). CONCLUSIONS: The clinical tests used in this investigation have limited predictive value for CAI when conducted in the acute phase of a first-time LAS injury. PMID- 29274316 TI - Comparative evaluation of neonatal bilirubin using Radiometer whole blood co oximetry and plasma bilirubin methods from Roche Diagnostics and Ortho Clinical Diagnostics. AB - BACKGROUND: Clinically significant variation has been reported within and between plasma and whole blood total bilirubin methods used to identify neonates for whom clinical intervention for hyperbilirubinemia may be required. OBJECTIVE: To evaluate total bilirubin measurements between the Radiometer whole blood co oximeter and plasma bilirubin methods from Roche Diagnostics and Ortho Clinical Diagnostics using neonatal specimens. METHODS: Total bilirubin levels were analyzed by whole blood co-oximetry (Radiometer(r) ABL90). Specimens were centrifuged and plasma analyzed for total bilirubin with a diazo method (Roche Cobas(r) C-601) and a reflectance spectrophotometric BuBc dry film method (Ortho Clinical Diagnostics VITROS(r) 350). Results were evaluated by regression, Bland Altman comparisons and t-tests. RESULTS: The patient correlation study yielded the following regression equations in MUmol/L: a) Radiometer=1.03 Roche - 3.5MUmol/L b) Radiometer=0.98 Ortho - 5.7MUmol/L c) Roche=0.97 Ortho - 2.4MUmol/L. The mean bias over the range of total bilirubin levels examined was 1.0MUmol/L for the Radiometer versus the Roche (p<=0.305); -4.4MUmol/L for the Radiometer versus Ortho (p<=0.005) and -4.4MUmol/L for the Roche versus Ortho (p<=0.002). CONCLUSIONS: Whole blood total bilirubin measurement using the Radiometer ABL90 blood gas analyzer provides accurate and precise results compared to the Roche plasma diazo method. Compared to the reflectance spectrophotometric method, results are precise and had a small but statistically significant bias of -4.4MUmol/L. PMID- 29274317 TI - Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the Mrgprx2 pathway in vitro and in vivo. AB - Pseudo-allergic reactions-adverse, non-immunologic, anaphylaxis-like sudden onset reactions mediated through an IgE-independent pathway-are activated by various basic compounds and occur at least as frequently as IgE-mediated reactions to drugs. A large family of G protein coupled receptors (Mas-related genes; Mrgprs) is closely related to pseudo-allergies. However, few therapies can directly target pseudo-allergies and related Mrgprs. Saikosaponin A (SSA) is effective in the treatment of passive cutaneous anaphylaxis (PCA), adjuvant arthritis, and delayed hypersensitiveness. In this study, we investigated the anti-pseudo allergy effect of SSA and its underlying mechanism. We examined the effect of SSA on both IgE-independent and IgE-dependent responses using PCA and active systemic anaphylaxis models, as well as in vitro-cultured mast cells. We also evaluated whether the anti-allergy effect is related to Mrgprs by using in vitro Mrgprx2 expressing HEK293 cells. SSA dose dependently suppressed compound 48/80 (C48/80) induced PCA and mast cell degranulation in mice. When SSA and C48/80 were administered together through the vein, C48/80-induced systemic anaphylaxis did not occur, and C48/80-induced shock ratio decreased dose-dependently upon SSA treatment. However, SSA did not affect IgE-dependent allergy. When administered topically 24 h before antigen challenge, Evans blue leakage and paw swelling were induced in the SSA-treated group and the vehicle group. Our in vitro studies revealed that SSA reduced C48/80-induced calcium flux and suppressed degranulation in LAD2 cells. SSA could also dose-dependently inhibit C48/80 induced Mrgprx2-expressing HEK293 cell activation. As a conclusion, SSA could inhibits IgE-independent allergy, but not IgE-dependent allergy, and this effect involves the Mrgprx2 pathway. This study provided a new sight on pseudo-allergy and its therapy. PMID- 29274318 TI - The Burden of Viruses in Pneumonia Associated With Acute Respiratory Failure: An Underappreciated Issue. AB - BACKGROUND: Pneumonia associated with mechanical ventilation (MV) results in substantial mortality and represents a leading reason for the use of antibiotics. The role of viruses in this setting is unclear. Identifying a viral cause in such instances could facilitate antibiotic stewardship. METHODS: We performed a secondary analysis of a prospective cohort with pneumonia requiring MV. We included both cases occurring in the community and hospital-onset cases and classified patients according to the cause of the pneumonia. The prevalence of viral pathogens represented the primary end point. We identified variables independently associated with isolation of a viral organism as the sole pathogen. RESULTS: The cohort included 364 patients, and a virus was the sole pathogen in 79 cases (21.7%). The most common viruses included rhinovirus/enterovirus (n = 20), influenza A (n = 12), and respiratory syncytial virus (n = 11). The rate of in-hospital death was high (37.2%) and did not differ from that seen in other patients (36.5%). The duration of MV, hospital length of stay, and 30-day readmission rates also did not differ based on the cause of pneumonia. Two variables were independently associated with recovery of a virus: an Acute Physiology and Health Evaluation II score of < 26 (adjusted odds ratio [AOR], 0.51; 95% CI, 0.28-0.93; P = .027) and stem cell transplantation (SCT) (AOR, 4.39; 95% CI, 2.03-9.50; P = .001). A sensitivity analysis excluding patients who underwent SCT did not substantially alter our observations. CONCLUSIONS: Viruses represent a major cause of pneumonia in critically ill patients requiring MV. Identifying such subjects presents an opportunity for discontinuing antibiotics. Clinicians should consider systematically evaluating patients with pneumonia requiring MV for viral pathogens. PMID- 29274319 TI - Histopathologic Findings in Lungs of Patients Treated With Extracorporeal Membrane Oxygenation. AB - BACKGROUND: The outcome of extracorporeal membrane oxygenation (ECMO) might be influenced by its complications. Only limited information is available regarding the pathologic consequences of ECMO, especially in the era of modern ECMO technology. METHODS: We studied the histopathologic findings in autopsy lungs of patients treated with ECMO compared with those without ECMO. Autopsy files were queried for cases with ECMO. An age- and sex-matched control group comprised of patients who died in the ICU without acute respiratory distress syndrome, pneumonia, or ECMO was compared with patients with ECMO for cardiac reason. Histopathology and medical records were reviewed. RESULTS: Seventy-six patients treated with ECMO (38 men; median age, 40 years) and 47 control patients (23 men; median age, 45 years) were included. Common histologic pulmonary findings in the ECMO group were pulmonary hemorrhage (63.2%), acute lung injury (60.5%), thromboembolic disease (47.4%), calcifications (28.9%), vascular changes (21.1%), and hemorrhagic infarct (21.1%). Pulmonary hemorrhage was associated with longer ECMO duration (median, 7.0 vs 3.5 months; P = .014), acute lung injury with venovenous ECMO (91.7% vs 54.7%; P = .039) and longer ECMO (6.0 vs 4.0 months; P = .044), and pulmonary calcifications with infants (50.0% vs 22.4%; P = .024). Patients with ECMO for cardiac reasons (n = 60) more frequently showed pulmonary hemorrhage (P < .001), diffuse alveolar damage (P = .044), thromboembolic disease (P = .004), hemorrhagic infarct (P = .002), pulmonary calcifications (P = .002), and vascular changes (P = .001) than patients in the non-ECMO group. CONCLUSIONS: Some findings are suspected to be associated with the patient's underlying disease, whereas others might be related to ECMO. Our results provide a better understanding of ECMO-related lung disease and might help to prevent it. PMID- 29274320 TI - The switch from cAMP-independent to cAMP-dependent arrest of meiotic prophase is associated with coordinated GPR3 and CDK1 expression in mouse oocytes. AB - Mammalian oocytes are arrested in meiotic prophase from around the time of birth until just before ovulation. Following an extended period of growth, they are stimulated to mature to the metaphase II stage by a preovulatory luteinizing hormone (LH) surge that occurs with each reproductive cycle. Small, growing oocytes are not competent to mature into fertilizable eggs because they do not possess adequate amounts of cell cycle regulatory proteins, particularly cyclin dependent kinase 1 (CDK1). As oocytes grow, they synthesize CDK1 and acquire the ability to mature. After oocytes achieve meiotic competence, meiotic arrest at the prophase stage is dependent on high levels of cAMP that are generated in the oocyte under the control of the constitutively active Gs-coupled receptor, GPR3. In this study, we examined the switch between GPR3-independent and GPR3-dependent meiotic arrest. We found that the ability of oocytes to mature, as well as oocyte CDK1 levels, were dependent on follicle size, but CDK1 expression in oocytes from preantral follicles was not acutely altered by the activity of follicle stimulating hormone (FSH). Gpr3 was expressed and active in incompetent oocytes within early stage follicles, well before cAMP is required to maintain meiotic arrest. Oocytes from Gpr3-/- mice were less competent to mature than oocytes from Gpr3+/+ mice, as assessed by the time course of germinal vesicle breakdown. Correspondingly, Gpr3-/- oocytes contained significantly lower CDK1 levels than their Gpr3+/+ counterparts that were at the same stage of follicle development. These results demonstrate that GPR3 potentiates meiotic competence, most likely by raising cAMP. PMID- 29274321 TI - Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages. AB - INTRODUCTION: Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated. METHODS: We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Abeta42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study. RESULTS: In CN subjects, study-wide significant (P < 8.3 * 10-9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls. DISCUSSION: Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes. PMID- 29274322 TI - Subpopulations of cancer stem cells found in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer and while it has a generally good prognosis, tumor recurrence remains a major clinical challenge. Studying laboratory cell lines as well as clinical specimens indicate that PTC may follow the cancer stem cell (CSC) model. However, CSC characteristics relevant in PTC initiation and progression remain largely unknown. Here we studied a population of sphere-growing tumor cells isolated from primary cultures of clinical PTC. These sphere-growing cells consisted of aldehyde dehydrogenase positive (ALDH+) and ALDH negative (ALDH-) cell subpopulations and demonstrated a hierarchical pattern of cell division. Using combinations of selective depletion, specific inhibition and cell sorting, we found that both subpopulations of the sphere cells were able to self-renew and initiate xenograft tumors independently, and fulfilled the definition of CSC. Importantly, when the subpopulations functioned together, the cancer-initiation efficiency and the xenograft tumor progression were significantly enhanced compared to either subpopulation alone. These data revealed crucial roles of ALDH CSC in PTC biology and suggested that CSC subpopulations function cooperatively to control PTC initiation and progression. Together, our study indicates that CSC subpopulations isolated from clinical specimens offer unprecedented opportunities for investigating PTC pathogenesis and developing effective therapies. PMID- 29274323 TI - AF119895 regulates NXF3 expression to promote migration and invasion of hepatocellular carcinoma through an interaction with miR-6508-3p. AB - Various studies revealed that numerous long noncoding RNAs (lncRNAs) have been found dysregulated in HCC and played important role in hepatocarcinogenesis, although the underlying mechanism still remains unclear. Herein, we reported AF119895, a new lncRNA which was identified from microarray and amplified in HCC. Functionally, AF119895 promoted migration and invasion of HCC cells both in vitro and in vivo. Furthermore, we identified that NXF3 was a downstream target of AF119895. NXF3 depletion could decrease HCC cells migration and invasion. In addition, AF119895 could act as an endogenous sponge by binding to miR-6508-3p and reduce miR-6508-3p expression. And miR-6508-3p could regulate NXF3 by interacting with its 3'UTR. These observations collectively demonstrate that AF119895 modulates the repression of NXF3 by binding to miR-6508-3p. Our results outline a novel signaling pathway mediated by AF119895 and suggest its candidacy as a new prognostic biomarker and therapeutic target of HCC. PMID- 29274324 TI - Apoptosis induction and inhibition of HeLa cell proliferation by alpha naphthoflavone and resveratrol are aryl hydrocarbon receptor-independent. AB - Human papilloma viruses 16 and 18 express E6 and E7 oncoproteins. E6 activates and redirects E6-associated protein (E6AP), an E3 ubiquitin ligase. E6AP interacts with Ube2l3, an E2 ubiquitin conjugating enzyme protein (also known as UbcH7), to promote p53 ubiquitination and degradation by the 26S proteasome. Therefore, blocking E6-mediated p53 degradation might be an alternative treatment for cervical cancer. In addition, activation of the aryl hydrocarbon receptor (AHR) induces Ube2l3 expression, resulting in p53 ubiquitination and degradation. The aim of the present study was to determine whether inhibition of AHR in HeLa cells resulted in an increase in p53 and apoptosis along with a decrease in cell proliferation. The results demonstrate that two AHR antagonists, alpha naphthoflavone (alpha-NF) and resveratrol, decreased cell proliferation, arrested cells in the gap 1/synthesis (G1/S) phases, and increased p53 levels and apoptosis. However, knocking out the Ahr gene did not abrogate the effects of alpha-NF and resveratrol. Moreover, Ahr-null cells presented similar cell proliferation rates and apoptosis levels when compared to control HeLa cells. Taken together, the results indicate that alpha-NF's and resveratrol's cytostatic and cytotoxic actions, respectively, occur through an AHR-independent mechanism, and that AHR is not required for HeLa cell proliferation. PMID- 29274325 TI - HDL acceptor capacities for cholesterol efflux from macrophages and lipid transfer are both acutely reduced after myocardial infarction. AB - BACKGROUND: The transport of lipids from the artery wall is one of the most essential anti-atherogenic functions of high-density lipoprotein (HDL). Recent reports of changes in the HDL composition, during myocardial infarction (MI), suggest that this function may be altered. METHODS: Forty-one consecutive patients with ST-segment elevation MI enrolled at the Brasilia Heart Study were selected. The following HDL-related measures were determined upon admission (D1) and on the fifth day (D5) after MI: C-reactive protein, CETP and PLTP activity, HDL composition, efflux of cholesterol from J774 macrophages to HDL, and transfer of unesterified and esterified cholesterol, triglycerides and phospholipids from a donor nanoemulsion to HDL. RESULTS: From D1 to D5, the activity of CETP decreased by 25%, but PLTP activity remained unchanged. Esterified cholesterol ( 23%) and phospholipid (-9.5%) contents of HDL decreased. Transfer of triglycerides (-36.5%) and esterified cholesterol (-14.7%) to HDL from nanoemulsions was reduced, but other lipids transfers were unchanged. Cholesterol efflux to HDL was also diminished by 8.5% (p=0.04) on D5 compared to D1. It was more pronounced in patients above the 75th percentile of C-reactive protein. CONCLUSIONS: After an MI, a simultaneous decrease in lipid transfer to HDL and in the capacity of HDL to efflux cholesterol from cells occurs. Thus, HDL with inferior atheroprotective properties may be generated in the acute post-MI period. PMID- 29274326 TI - Effect of iron supplementation on HbA1c levels in pregnant women with and without anaemia. AB - BACKGROUND: Iron deficiency anaemia has been associated with higher HbA1c levels. However, during and after iron supplementation there is a decrease in HbA1c results, causing a misinterpretation. Our aim was to analyse the effect of iron supplementation on HbA1c levels in nondiabetic pregnant women with and without anaemia. METHODS: Pregnant women in prenatal care, without gestational diabetes (GDM) or previous diabetes mellitus (DM) that performed an oral glucose tolerance test (OGTT) in the third trimester of pregnancy were invited to participate. Clinical and laboratorial analyses were performed, including standardized questionnaire, OGTT, full blood count and HbA1c. RESULTS: A total of 231 pregnant women without DM or GDM were included in the study. According to anaemia and/or iron supplementation, we divided women in: no iron and no anaemia - Group 1 (N=86); no iron and with anaemia - Group 2 (N=29); iron and no anaemia - Group 3 (N=87); iron and anaemia - Group 4 (N=29). There was statistically a significant, although no clinically relevant, difference between HbA1c values in pregnant women in Groups 1 and 4 [5.1+/-0.4% (32+/-4.4mmol/mol) and 4.8+/-0.3% (29+/ 3.3mmol/mol), P<0.01; respectively]. HbA1c values in pregnant women in Groups 1, 2 and 3 were similar, independently of anaemia [5.1+/-0.4% (32+/-4.4mmol/mol); 5.0+/-0.4% (31+/-4.4mmol/mol) and 5.0+/-0.4% (31+/-4.4mmol/mol); p>0.05; respectively]. CONCLUSIONS: Iron supplementation during pregnancy does not affect HbA1c levels and has no clinical impact in the final interpretation of results in the absence of anaemia or presence of mild anaemia. Interpreting HbA1c results in pregnant women during iron therapy and with moderate or severe anaemia still requires caution. PMID- 29274327 TI - Investigation of correlation of urinary globotriaosylceramide (Gb3) levels with markers of renal function in patients with Fabry disease. AB - Fabry disease (FD) is a disorder that results from mutations of hydrolase alpha galactosidase A. The enzymatic defect leads to accumulation of globotriaosylceramide (Gb3) in the kidney. Substrate deposition is related to tissue damage in FD, but the relation of urinary Gb3 levels in patients and the renal function markers remain not completely understood. Once nephropathy is one of the main features of FD and is marked by an insidious development, we investigated a possible correlation of Gb3 with biochemical markers of nephropathy including albuminuria, estimated glomerular filtration rate (eGFR), serum creatinine and urea, and proteinuria in male and female patients under or not enzyme replacement therapy (ERT).Gb3, proteinuria and albuminuria were increased in male and female FD patients. We found no correlation between urinary Gb3 levels and all renal function parameters evaluated in Fabry patients (in both sexes and using or not ERT). On the other hand, albuminuria showed negative correlation with eGFR only in male under or not ERT, demonstrating that albuminuria seems to be an early marker of renal function alteration. In conclusion, the results suggest that urinary Gb3 level does not reflect the renal function and that albuminuria is an important biomarker in male FD patients. PMID- 29274328 TI - Preanalytical and analytical challenges in gas chromatographic determination of cholesterol synthesis and absorption markers. AB - INTRODUCTION: Cholesterol homeostasis disruption contributes to the development of different pathologies. Non-cholesterol sterols (NCSs) serve as cholesterol synthesis markers (desmosterol and lathosterol), and cholesterol absorption surrogate markers (campesterol, stigmasterol and beta-sitosterol). The study aimed to resolve certain new pre-analytical and analytical problems and ensure a reliable and validated method. MATERIALS AND METHODS: Method optimization, validation and stability studies were executed in human serum and plasma. Freeze thaw cycles were done with and without antioxidant. Gas chromatography-mass spectrometer (GC-MS) was used for NCSs confirmation and plasticizer identification, while GC-flame ionization detector (GC-FID) was used for NCSs quantitation. RESULTS: Intra- and inter-assay variabilities for all NCSs were 2.75-9.55% and 5.80-7.75% for plasma and 3.10-5.72% and 3.05-10.92% for serum, respectively. Recovery studies showed satisfactory percentage errors for all NCSs: 93.4-105.7% in plasma and 87.5-106.9 in serum. Derivatized samples were stable up to 7days at -20 degrees C and derivatization yield was affected by presence of plasticizers. Fatty acid amids were identified as interfering plastic leachates. Statistically different NCSs concentrations were observed after the 1st freeze-thaw cycle, in antioxidant-free samples, and after the 4th cycle in antioxidant-enriched samples. CONCLUSIONS: All of the in-house procedures proved to be useful for minimizing the preanalytical and analytical variations, as proven by the validation results. PMID- 29274329 TI - Rapid amino acid quantitation with pre-column derivatization; ultra-performance reverse phase liquid chromatography and single quadrupole mass spectrometry. AB - BACKGROUND: We optimized a quantitative amino acid method with pre-column derivatization, norvaline (nva) internal standard and reverse phase ultra performance liquid chromatography by replacing the ultraviolet detector with a single quadrupole mass spectrometer (MSnva). METHOD: We used 13C15N isotopically labeled amino acid internal standards and a C18 column with 1.6MUm particles to optimize the chromatography and to confirm separation of isobaric compounds (MSlis). We compared the analytical performance of MSnva with MSlis and the original method (UVnva) with clinical samples. RESULTS: The chromatography time per sample of MSnva was 8min, detection capabilities were <1MUmol/L for most components, intermediate imprecisions at low concentrations were <10% and there was negligible carryover. MSnva was linear up to a total amino acid concentration in a sample of approximately 9500MUmol/L. The agreements between most individual amino acids were satisfactory compared to UVnva with the latter prone to outliers and suboptimal quantitation of urinary arginine, aspartate, glutamate and methionine. MSnva reliably detected argnininosuccinate, beta-alanine, citrulline and cysteine-s-sulfate. CONCLUSION: MSnva resulted in a more than fivefold increase in operational efficiency with accurate detection of amino acids and metabolic intermediates in clinical samples. PMID- 29274330 TI - A new enzyme immunoassay for the determination of highly sialylated and fucosylated human alpha1-acid glycoprotein as a biomarker of tumorigenesis. AB - BACKGROUND: Upon initiation and progression of cancer, alpha1-acid glycoprotein (AGP) possessing highly sialylated and fucosylated glycans appears in the serum, and recently has attracted a great deal of attention, as a potential biomarker of tumorigenesis in humans. METHODS: To establish a rapid and precise method for the quantitative assay of fucosylated AGP in serum samples, we developed an enzyme immunoassay (EIA) bearing an anti-AGP antibody and a fucose-binding lectin, Aleuria aurantia (AAL) with additional endeavor to improved sample handling, and antibody preparations. RESULTS: The amounts of fucosylated AGP could be determined by the present method with a good performance feature in all tested samples from both cancer patients and healthy controls. From cancer patients under chemotherapy we show that fucosylated AGP could be a clinically relevant biomarker for cancer progression or prognosis as well as for an early assessment of clinical response and treatment outcomes. Furthermore, in a different setting, fucosylated AGP also showed relevance in patients who received immunotherapy with an anti-programmed cell death-1 (PD-1) antibody. CONCLUSIONS: alpha1,3fucosylated AGP is a potential biomarker of cancer initiation, progression and response to treatment in cancer patients. PMID- 29274331 TI - Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis. AB - New therapeutic agents are needed to overcome the toxicity and suboptimal efficacy observed in current treatment of glomerulonephritis (GN). BaxB01 is a fully human monoclonal antibody targeting a disease-related immunologically distinct isoform of Macrophage migration Inhibitory Factor (MIF), designated oxidized MIF (oxMIF) and locally expressed in inflammatory conditions. We report the pharmacokinetic profile of BaxB01, and its dose and exposure-related disease modifying activity in experimentally induced rat GN. BaxB01 bound to rat oxMIF with high affinity and reduced rat macrophage migration in vitro. After intravenous administration in rats, BaxB01 demonstrated favorable pharmacokinetics, with a half-life of up to nine days. Disease modification was dose-related (>= 10mg/kg) as demonstrated by significantly reduced proteinuria and diminished histopathological glomerular crescent formation. Importantly, a single dose was sufficient to establish an exposure-related, anti-inflammatory milieu via amelioration of glomerular cellular inflammation. Pharmacodynamic modeling corroborated these findings, consistently predicting plasma exposures that were effective in attenuating both anti-inflammatory activity and reducing loss of kidney function. This pharmacologic benefit on glomerular function and structure was sustained during established disease, while correlation analyses confirmed a link between the antibody's anti-inflammatory activity and reduced crescent formation in individual rats. Finally, safety assessment in rats showed that the experimental therapeutic was well tolerated without signs of systemic toxicity or negative impact on kidney function. These data define therapeutically relevant exposures correlated with mechanism-based activity in GN, while toxicological evaluation suggests a large therapeutic index and provides evidence for achieving safe and effective exposure to a MIF isoform-directed therapeutic in nephritis-associated disease. PMID- 29274333 TI - The natural flavonoid myricetin inhibits gastric H+, K+-ATPase. AB - Myricetin (3,3',4',5,5',7-hexahydroxyflavone), a major flavonoid in berries and red wine, has been recently used as a health food supplement based on its antioxidant and antitumor properties. We report here that myricetin preferentially exerts inhibitory effects on gastric H+, K+-ATPase. Myricetin inhibited H+, K+-ATPase with a sub-micromolar IC50 value in an enzyme assay using freeze-dried tubulovesicles prepared from hog stomach. Na+, K+-ATPase and Ca2+ ATPase were also inhibited by myricetin in a dose-dependent manner, but the IC50 values for these enzymes were approximately an order of magnitude higher compared to the H+, K+-ATPase. In structure-inhibitory functional analysis of sixteen myricetin derivatives, several phenolic hydroxy groups attached to the flavonoid backbone were highlighted as essential modifications for the inhibition of P2 type ATPases. Furthermore, oral administration of myricetin significantly attenuated histamine-induced gastric acid secretion in an in vivo mouse assessment. Therefore, myricetin derivatives seem to be useful seed compounds for developing new drugs and supplements to alleviate gastric acid secretion. PMID- 29274332 TI - Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control. AB - Chronic GPR18 activation by its agonist abnormal cannabidiol (trans-4-[3-methyl-6 (1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; abn-cbd) improves myocardial redox status and function in healthy rats. Here, we investigated the ability of abn-cbd to alleviate diabetes-evoked cardiovascular pathology and the contribution of GPR18 to this effect. Four weeks after diabetes induction by streptozotocin (STZ, 55mg/kg; i.p), male Wistar rats received abn-cbd, the GPR18 antagonist (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2 ,cyclohexen-1-yl]benzene;O-1918), their combination (100ug/kg/day, i.p, each) or their vehicle for 2 weeks. Abn-cbd had no effect on diabetes-evoked cardiac hypertrophy or impaired glycemic control (hyperglycemia and hypoinsulinemia), but alleviated the associated reductions in left ventricular (LV) contractility (dP/dtmax) and relaxation (dP/dtmin) indices, and the increases in LV end diastolic pressure (LVEDP) and cardiac vagal dominance. Abn-cbd also reversed myocardial oxidative stress by restoring circulating and cardiac nitric oxide (NO) and adiponectin (ADN) levels and enhancing GPR18 expression and phosphorylation of Akt, ERK1/2 and eNOS in diabetic rats' hearts. Concurrent GPR18 blockade (O-1918) abrogated all favorable effects of abn-cbd in diabetic rats. Collectively, the current findings present evidence for abn-cbd alleviation of diabetes-evoked cardiovascular anomalies likely via GPR18 dependent restoration of cardiac adiponectin-Akt-eNOS signaling and the diminution of myocardial oxidative stress. PMID- 29274334 TI - Targeting of EGFR increase anti-cancer effects of arsenic trioxide: Promising treatment for glioblastoma multiform. AB - Glioblastoma multiform (GBM) accounts for the most common form of primary brain tumors with very limited survival rate. Drug resistance is the main challenges for good prognosis of GBM patients. Arsenic trioxide (ATO) as a multifunctional drug has been investigated for the treatment of several solid tumors. Amplification/overexpression of the epidermal growth factor receptor (EGFR) gene as a signature genetic abnormality of GBM tumors can be a chemoresistance mechanism. In this study, we use erlotinib as an EGFR inhibitor to increase the sensitivity of GBM cell lines to ATO treatment. We evaluate the effects of this combination on metabolic activity, viability, cell proliferation, colony formation, cell cycle distribution, migration, oxidative stress and reactive oxygen species production. Our results showed that combination of ATO with erlotinib synergistically reduced metabolic activity, proliferation and colony forming potential in treated GBM cell lines. This combination induced G2/M cell cycle arrest. We also found that wound-healing rate were suppressed only after combination treatment. In addition, apoptotic cell death and reactive oxygen species content significantly increased after combination treatment. The combination of ATO and erlotinib considerably interfere with survival and migration of treated GBM cell lines through cell cycle arrest and reactive oxygen species production. Present study uncovered that EGFR inhibition could overcome the resistance of glioblastoma cells to ATO treatment. PMID- 29274335 TI - CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases. AB - The cluster of differentiation 36 (CD36) is implicated in the intake of long chain fatty acids and fat storage in various cell types including the pancreatic beta cell, thus contributing to the pathogenesis of metabolic stress and diabetes. Recent evidence indicates that CD36 undergoes post-translational modifications such as acetylation-deacetylation. However, putative roles of such modifications in its functional activation and onset of beta cell dysregulation under the duress of glucolipotoxicity (GLT) remain largely unknown. Using pharmacological approaches, we validated, herein, the hypothesis that acetylation deacetylation signaling steps are involved in CD36-mediated lipid accumulation and downstream apoptotic signaling in pancreatic beta (INS-1832/13) cells under GLT. Exposure of these cells to GLT resulted in significant lipid accumulation without affecting the CD36 expression. Sulfo-n-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, significantly attenuated lipid accumulation under GLT conditions, thus implicating CD36 in this metabolic step. Furthermore, trichostatin A (TSA) or valproic acid (VPA), known inhibitors of lysine deacetylases, markedly suppressed GLT-associated lipid accumulation with no discernible effects on CD36 expression. Lastly, SSO or TSA prevented caspase 3 activation in INS-1832/13 cells exposed to GLT conditions. Based on these findings, we conclude that an acetylation-deacetylation signaling step might regulate CD36 functional activity and subsequent lipid accumulation and caspase 3 activation in pancreatic beta cells exposed to GLT conditions. Identification of specific lysine deacetylases that control CD36 function should provide novel clues for the prevention of beta-cell dysfunction under GLT. PMID- 29274336 TI - The long non-coding RNA MALAT1 activates Nrf2 signaling to protect human umbilical vein endothelial cells from hydrogen peroxide. AB - The potential effect of the long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) against hydrogen peroxide (H2O2) induced oxidative injury in endothelial cells was tested. We show that forced expression of MALAT1 using a lentiviral vector ("LV-MALAT1") significantly attenuated H2O2-induced death and apoptosis of human umbilical vein endothelial cells (HUVECs). Conversely, knocking down of MALAT1 by targeted siRNA exacerbated H2O2-induced HUVEC injury. For the mechanism study, we show that LV-MALAT1 induced Keap1 downregulation, leading to nuclear-factor-E2-related factor 2 (Nrf2) stabilization and activation. Critically, Nrf2 shRNA almost completely abolished LV-MALAT1-mediated HUVEC protection against H2O2. Significantly, H2O2 induced oxidative stress, lipid peroxidation and DNA damages in HUVECs were attenuated by LV-MALAT1, but were intensified with MALAT1 siRNA. In summary, we identified a novel signaling axis involving MALAT1, Keap1 and Nrf2, which in turn protects HUVECs from oxidative injury. PMID- 29274337 TI - Generation of three-dimensional retinal organoids expressing rhodopsin and S- and M-cone opsins from mouse stem cells. AB - PURPOSE: Three-dimensional retinal organoids can be differentiated from embryonic stem cells/induced pluripotent stem cells (ES/iPS cells) under defined medium conditions. We modified the serum-free floating culture of embryoid body-like aggregates with quick reaggregation (SFEBq) culture procedure to obtain retinal organoids expressing more rod photoreceptors and S- and M-cone opsins. METHODS: Retinal organoids differentiated from mouse Nrl-eGFP iPS cells were cultured in various mediums during photoreceptor development. To promote rod photoreceptor development, organoids were maintained in media containing 9-cis retinoic acids (9cRA). To obtain retinal organoids with M-opsin expression, we cultured in medium with 1% fetal bovine serum (FBS) supplemented with T3, BMP4, and DAPT. Section immunohistochemistry was performed to visualize the expression of photoreceptor markers. RESULTS: In three-dimensional (3D) retinas exposed to 9cRA, rhodopsin was expressed earlier and S-cone opsins were suppressed. We could maintain 3D retinas up to DD 35 in culture media with 1% FBS. The 3D retinas expressed rhodopsin, S- and M-opsins, but most cone photoreceptors expressed either S- or M-opsins. CONCLUSION: By modifying culture conditions in the SFEBq protocol, we obtained rod-dominated 3D retinas and S- and M-opsin expressing 3D retinas. PMID- 29274338 TI - Structural insights into a StART-like domain in Lam4 and its interaction with sterol ligands. AB - Sterols are essential components of cellular membranes and shape their biophysical properties. The recently discovered family of Lipid transfer proteins Anchored at Membrane contact sites (LAMs) has been suggested to carry out intracellular sterol traffic using StART-like domains. Here, we studied the second StART-like domain of Lam4p from S. cerevisiae by NMR. We show that NMR data are consistent with the StART-like domain structure, and that several functionally important regions within the domain exhibit significant conformational dynamics. NMR titration experiments confirm sterol binding to the canonical sterol-binding site and suggest a role of membrane interactions on the thermodynamics and kinetics of sterol binding. PMID- 29274339 TI - Thermodynamic and spectroscopic investigations of TMPyP4 association with guanine and cytosine-rich DNA and RNA repeats of C9orf72. AB - BACKGROUND: An expansion of the hexanucleotide repeat (GGGGCC)n.(GGCCCC)n in the C9orf72 promoter has been shown to be the cause of Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The C9orf72 repeat can form four-stranded structures; the cationic porphyrin (TMPyP4) binds and distorts these structures. METHODS: Isothermal titration calorimetry (ITC), and circular dichroism (CD) were used to study the binding of TMPyP4 to the C-rich and G-rich DNA and RNA oligos containing the hexanucleotide repeat at pH 7.5 and 0.1 M K+. RESULTS: The CD spectra of G-rich DNA and RNA TMPyP4 complexes showed features of antiparallel and parallel G-quadruplexes, respectively. The shoulder at 260 nm in the CD spectrum becomes more intense upon formation of complexes between TMPyP4 and the C-rich DNA. The peak at 290 nm becomes more intense in the c-rich RNA molecules, suggesting induction of an i-motif structure. The ITC data showed that TMPyP4 binds at two independent sites for all DNA and RNA molecules. CONCLUSIONS: For DNA, the data are consistent with TMPyP4 stacking on the terminal tetrads and intercalation. For RNA, the thermodynamics of the two binding modes are consistent with groove binding and intercalation. In both cases, intercalation is the weaker binding mode. These findings are considered with respect to the structural differences of the folded DNA and RNA molecules and the energetics of the processes that drive site-specific recognition by TMPyP4; these data will be helpful in efforts to optimize the specificity and affinity of the binding of porphyrin-like molecules. PMID- 29274340 TI - Four unreported types of glycans containing mannose-6-phosphate are heterogeneously attached at three sites (including newly found Asn 233) to recombinant human acid alpha-glucosidase that is the only approved treatment for Pompe disease. AB - Myozyme is a recombinant human acid alpha-glucosidase (rhGAA) that is currently the only drug approved for treating Pompe disease, and its low efficacy means that a high dose is required. Mannose-6-phosphate (M6P) glycosylation on rhGAA is a key factor influencing lysosomal enzyme targeting and the efficacy of enzyme replacement therapy (ERT); however, its complex structure and relatively small quantity still remain to be characterized. This study investigated M6P glycosylation on rhGAA using liquid chromatography (LC)-electrospray ionization (ESI)-high-energy collisional dissociation (HCD) tandem mass spectrometry (MS/MS). The glycans released from rhGAA were labeled with procainamide to improve mass ionization efficiency and the sensitivity of MS/MS. The relative quantities (%) of 78 glycans were obtained, and 1.0% of them were glycans containing M6P (M6P glycans). These were categorized according to their structure into 4 types: 3 newly found ones, comprising high-mannose-type M6P glycans capped with N-acetylglucosamine (GlcNAc) (2 variants, 17.5%), hybrid-type M6P glycans (2 variants, 11.2%), and hybrid-type M6P glycans capped with GlcNAc (3 variants, 6.9%), as well as high-mannose-type M6P glycans (3 variants, 64.4%). HCD-MS/MS spectra identified six distinctive M6P-derived oxonium ions. The glycopeptides obtained from protease-digested rhGAA were analyzed using nano-LC-ESI-HCD-MS/MS, and the extracted-ion chromatograms of M6P-derived oxonium ions confirmed three M6P glycosylation sites comprising Asn 140, Asn 233 (newly found), and Asn 470 attached heterogeneously to nine M6P glycans (two types), eight M6P glycans (four types), and seven M6P glycans (two types), respectively. This is the first study of rhGAA to differentiate M6P glycans and identify their attachment sites, despite rhGAA already being an approved drug for Pompe disease. PMID- 29274341 TI - The ubiquitin-specific protease USP36 is a conserved histone H2B deubiquitinase. AB - Histone H2B monoubiquitination plays a critical role in the regulation of gene transcription. Deregulation of H2B monoubiquitination contributes to human pathologies, such as cancer. Here we report that human USP36 is a novel H2Bub1 deubiquitinase. We show that USP36 interacts with H2B and deubiquitinates H2Bub1 in cells and in vitro. Overexpression of USP36 markedly reduced the levels of H2Bub1 in cells. Using the p21 gene as a model, we demonstrate that depletion of USP36 increases H2Bub1 at the p21 locus, primarily within its gene body. Consistently, knockdown of USP36 induced the expression of p21 and inhibits cell proliferation. Together, our results reveal USP36 as a novel H2B deubiquitinase and shed light on its additional functions in regulating gene expression. PMID- 29274342 TI - The modulatory role of pre-SMA in speed-accuracy tradeoff: A bi-directional TMS study. AB - Many perceptual decisions are inevitably subject to the tradeoff between speed and accuracy of choices (SAT). Sequential sampling models attribute this ubiquitous relation to random noise in the sensory evidence accumulation process, and assume that SAT is adaptively modulated by altering the decision thresholds at which the level of integrated evidence should reach for making a choice. Although, neuroimaging studies have shown a relationship between right presupplementary motor area (pre-SMA) activity and threshold setting, only a limited number of brain stimulation studies aimed at establishing the causal link, results of which were inconsistent. Additionally, these studies were limited in scope as they only examined the effect of pre-SMA activity unidirectionally through experimentally inhibiting the neural activity in this region. The current study aims to investigate the predictions of the striatal theory of SAT by experimentally assessing the modulatory effect of right pre-SMA on threshold setting bi-directionally. To this end, we applied both offline inhibition and excitation to the right pre-SMA utilizing transcranial magnetic stimulation in a within-subjects design and tested participants on a Random Dot Motion Task. Decision thresholds were estimated using the Hierarchical Drift Diffusion Model. Findings of our planned comparisons showed that right pre-SMA inhibition leads to significantly higher, whereas right pre-SMA excitation leads to significantly lower thresholds without showing any effects on the evidence integration process itself. PMID- 29274343 TI - Psychological stress level detection based on electrodermal activity. AB - This paper presents a method for detecting psychological stress levels. It aims to explore the feasibility of using a single physiological signal to create a more practical alternative for detecting stress in people than current multiple physiological signals approaches involve. In particular, the approach explored uses linear discriminant analysis (LDA) based on the electrodermal activity (EDA) signal which aims at discriminating between three stress levels: low, medium and high. We used the MIT Media lab 'stress database' from which we selected eleven 'foot' based EDA data sets for our experiments. Using this eighteen EDA features were extracted from (sixty-six) five-minutes data segments equating to three driving conditions: at rest, on the open road (highway) and city driving. After that, Fisher projection and Linear discriminant analysis (LDA) were used to classify the stress levels with feature vectors, that included both leaving one out and test cross-validation strategy. The results showed that these methods achieved recognition rate of 81.82% which we argue, while less that multiple signal systems, may be a better balance between recognition performance and computational load, that could be a promising line of research for the development of practical personal stress monitors. PMID- 29274346 TI - A new method for removal of eyelid margin molluscum. PMID- 29274344 TI - Calcium phosphate particles stimulate interleukin-1beta release from human vascular smooth muscle cells: A role for spleen tyrosine kinase and exosome release. AB - AIMS: Calcium phosphate (CaP) particle deposits are found in several inflammatory diseases including atherosclerosis and osteoarthritis. CaP, and other forms of crystals and particles, can promote inflammasome formation in macrophages leading to caspase-1 activation and secretion of mature interleukin-1beta (IL-1beta). Given the close association of small CaP particles with vascular smooth muscle cells (VSMCs) in atherosclerotic fibrous caps, we aimed to determine if CaP particles affected pro-inflammatory signalling in human VSMCs. METHODS AND RESULTS: Using ELISA to measure IL-1beta release from VSMCs, we demonstrated that CaP particles stimulated IL-1beta release from proliferating and senescent human VSMCs, but with substantially greater IL-1beta release from senescent cells; this required caspase-1 activity but not LPS-priming of cells. Potential inflammasome agonists including ATP, nigericin and monosodium urate crystals did not stimulate IL-1beta release from VSMCs. Western blot analysis demonstrated that CaP particles induced rapid activation of spleen tyrosine kinase (SYK) (increased phospho-Y525/526). The SYK inhibitor R406 reduced IL-1beta release and caspase-1 activation in CaP particle-treated VSMCs, indicating that SYK activation occurs upstream of and is required for caspase-1 activation. In addition, IL-1beta and caspase-1 colocalised in intracellular endosome-like vesicles and we detected IL 1beta in exosomes isolated from VSMC media. Furthermore, CaP particle treatment stimulated exosome secretion by VSMCs in a SYK-dependent manner, while the exosome-release inhibitor spiroepoxide reduced IL-1beta release. CONCLUSIONS: CaP particles stimulate SYK and caspase-1 activation in VSMCs, leading to the release of IL-1beta, at least in part via exosomes. These novel findings in human VSMCs highlight the pro-inflammatory and pro-calcific potential of microcalcification. PMID- 29274345 TI - Risk factors for imipenem-resistant Pseudomonas aeruginosa in neonatal intensive care units in south China. AB - This multi-centre retrospective study was designed to investigate the risk factors for infection with imipenem-resistant Pseudomonas aeruginosa in neonatal intensive care units (NICUs) in south China. All patients with confirmed P. aeruginosa infection from eight NICUs in south China were divided into two groups: imipenem-susceptible P. aeruginosa and imipenem-resistant P. aeruginosa. Data were analysed using Chi-squared test and logistic regression. In total, 188 medical records were reviewed. On multi-variate logistic analysis, the only independent risk factor was imipenem treatment within two weeks of isolation of P. aeruginosa (odds ratio 6.409, 95% confidence interval 1.926-21.333). PMID- 29274347 TI - Faster suction blister formation using 2 hair dryers. PMID- 29274348 TI - Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: Retrospective multicenter case-control study from France and Switzerland. AB - BACKGROUND: Case reports have suggested an association between dipeptidyl peptidase-4 inhibitors (DPP4is) and development of bullous pemphigoid (BP). OBJECTIVE: To evaluate the association between DPP4i treatment and development of BP. METHODS: We conducted a retrospective 1:2 case-control study, comparing case patients with diabetes and BP with age- and sex-matched control patients with diabetes issued from Swiss (Bern) and French (Marseille) dermatologic departments from January 1, 2014, to July 31, 2016. RESULTS: We collected 61 case patients with diabetes and BP and 122 controls. DPP4is were associated with an increased risk for development of BP (adjusted odds ratio, 2.64; 95% confidence interval, 1.19-5.85; P = .02), with vildagliptin showing the highest adjusted odds ratio (3.57 [95% confidence interval, 1.07-11.84; P = .04]). Stratified analysis showed a stronger association in males and patients age 80 years or older. DPP4i withdrawal and the initiation of first-line treatments led to clinical remission in 95% of cases. LIMITATIONS: This was a retrospective study in tertiary referral hospitals. We focused the analysis on DPP4i intake, without analyzing the potential isolated effect of metformin. CONCLUSIONS: DPP4is, especially vildagliptin, are associated with an increased risk for development of BP. Their use needs to be carefully evaluated, particularly in high-risk patients, such as males and those age 80 years or older. PMID- 29274349 TI - Diurnal cortisol and alpha-amylase in the daily lives of older adults with vital exhaustion. AB - OBJECTIVE: Vital exhaustion (VE) is characterised by unusual fatigue, increased irritability, and a feeling of demoralisation. It has been found a major risk factor for cardiovascular diseases, and one that is independent of subclinical or clinical manifestations of coronary heart disease or lifestyle-related risk factors. Stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system may mediate the link between VE and increased cardiovascular risk. However, no studies have yet assessed both systems simultaneously and in high-risk populations, such as older adults. METHODS: A total of 72 older adults (34 women, mean age 61.7+/-7.3) who were free of any major physical or mental illnesses filled out the Maastricht Vital Exhaustion Questionnaire (MVEQ) and the Perceived Stress Scale (PSS). To determine cortisol and alpha-amylase, participants collected saliva samples upon awakening, +30min thereafter, and at 11am, 3pm, and 8pm. RESULTS: Participants with higher VE reported lower perceived stress (beta=-0.515, p<0.001). Individuals reporting higher VE also exhibited more diminished cortisol concentrations across the day, although only by trend (beta=-0.218, p=0.092). There was no significant association between VE and diurnal alpha-amylase activity. Moreover, women had lower diurnal cortisol (beta=-0.381, p=0.004) and alpha-amylase (beta=-0.329, p=0.011) when compared to men. CONCLUSIONS: Our findings provide initial evidence for psychosocial stress to be linked to VE in older adults, while evidence for HPA alterations remains tentative. Future research is warranted to determine whether VE related hypocortisolaemia represents a specific stage of the stress adaptation process that may put individuals at risk for incident cardiovascular diseases. PMID- 29274350 TI - Visual and physical affective touch delivered by a rotary tactile stimulation device: A human psychophysical study. AB - The discovery that pleasant touch is coded by C-tactile fibers has generated considerable research interest and increased understanding of the skin as a channel for social information via cutaneous senses. However, no study has differentiated between the pleasant response to visual and tactile non-human stimulations. Our study investigated pleasant touch in which the visual and haptic touch information was obtained from an affective, but non-social experience, by a custom-built non-human device. Participants (n=19) received soft brush strokes on their lower left arm delivered by a rotary tactile stimulator (physical session) or watched a video of an arm being stroked by a rotary tactile stimulator (visual session). The brush strokes were delivered at the same velocities (0.3, 1, 3, 10, 30cm/s) and force (0.4N) in both sessions. After each trial, participants rated the pleasantness of the touch. Analysis of variance was used to assess the effects of velocity and modality (visual touch vs. physical touch) on the pleasantness rating. Participants rated strokes between 1 and 10cm/s as most pleasant under both conditions. The pleasantness rating patterns differed significantly among velocities; however, no significant differences were found between modalities. Visual and physical (without human-to-human interaction) touch elicited similar behavioral responses, including an inverted U shaped perception of pleasantness. These findings suggest that the pleasantness of touch is influenced by the velocity of the strokes in both visual and physical touch with a non-human stimulation. PMID- 29274351 TI - High-fat diet-induced hyperglutamatergic activation of the hippocampus in mice: A proton magnetic resonance spectroscopy study at 9.4T. AB - The aim of this study was to investigate the long-term neurochemical alterations in the hippocampus of mice fed a high-fat diet (HFD) while plasma leptin and corticosterone levels were monitored. Although metabolic disturbances induced by the excess intake of fat are assumed to cause depression, the relationship underlying dysfunctional adipose tissue, stress hormone release, and excitatory metabolism has not been fully understood yet. Four-week-old male C57BL/6 mice were separated into a HFD-fed group (n = 8) and low-fat diet-fed group (n = 8). Proton magnetic resonance spectroscopy was used to measure the long-term changes in neurochemicals in the hippocampus at 0, 5, and 10 weeks and blood samples were taken at the same time to assess plasma hormones levels. At the end of the experiment, magnetic resonance imaging was performed to quantify abdominal fat accumulation. At 10 weeks, corticosterone and leptin levels were significantly increased in the HFD group compared with the low-fat diet group. In addition, aspartate, glutamate, total choline, and N-acetylaspartic acid levels were significantly increased, but glutamine/glutamate ratios were substantially decreased at 10 weeks in the HFD group. These results were compatible with HFD induced acute stress responses and changes in N-methyl-d-aspartate receptor induced plasticity. These findings demonstrated that the long-term ingestion of a HFD induced hyperglutamatergic metabolism and altered glutamine-glutamate cycling. Therfore, it is suggested that hypothalamic-pituitary-adrenal dysfunction and hyperglutamatergic activation in the hippocampus resulting from the HFD. PMID- 29274352 TI - Oxytocin is present in islets and plays a role in beta-cell function and survival. AB - Oxytocin is associated mainly with modulating reproductive function. However, studies suggest that oxytocin also plays a role in endocrine pancreatic function. In the present study, islet expression of oxytocin and its related receptor was confirmed in mouse islets as well as cultured rodent and human beta-cells. Oxytocin significantly stimulated glucose-induced insulin secretion from isolated mouse islets. Similar insulinotropic actions were also observed in rodent BRIN BD11 and human 1.1B4 beta-cells. Positive effects of oxytocin on insulin secretion were almost fully annulled by the oxytocin receptor antagonist, atosiban. In terms of mechanism of insulin secretory action, oxytocin had no effect on beta-cell membrane potential or cAMP generation, but did augment intracellular calcium concentrations. In vivo administration of oxytocin to mice significantly reduced overall blood glucose levels and increased plasma insulin concentrations in response to a glucose challenge. Oxytocin also had a modest, but significant, appetite suppressive effect. As expected, streptozotocin diabetic mice had marked loss of beta-cell area accompanied by increases in alpha cell area, whilst hydrocortisone treatment increased beta-cell and overall islet areas. Both mouse models of diabetes presented with dramatically decreased percentage islet oxytocin co-localisation with insulin and increased co localisation with glucagon. More detailed studies in cultured beta-cell lines revealed direct positive effects of oxytocin on beta-cell proliferation and protection against apoptosis. Together, these data highlight a potentially important role of islet-derived oxytocin and related receptor signalling pathways on the modulation of beta-cell function and survival. PMID- 29274353 TI - Oxidative Stress in the Amygdala Contributes to Neuropathic Pain. AB - Earlier studies indicate that the central nucleus of the amygdala (CeA) contributes to neuropathic pain. Here we studied whether amygdaloid administration of antioxidants or antagonists of TRPA1 that is among ion channels activated by oxidative stress attenuates nociceptive or affective pain in experimental neuropathy, and whether this effect involves amygdaloid astrocytes or descending serotonergic pathways acting on the spinal 5-HT1A receptor. The experiments were performed in rats with spared nerve injury (SNI). Drugs were administered through a chronic cannula in the CeA or internal capsule (control site), and an intrathecal catheter. Nociception was assessed using monofilaments and affective pain using conditioned place-aversion. Antioxidants or TRPA1 antagonists in the CeA attenuated both nociceptive and affective pain in SNI animals but not in sham controls or in a control injection site. Drugs influencing astroglia (a gap junction decoupler or a D-amino acid oxidase inhibitor) in the CeA had no effect on SNI rats, whereas local anesthesia of the CeA attenuated nociception. Spinally administered 5-HT1A receptor antagonist at a dose that had no effect alone prevented the antinociceptive effect of amygdaloid TRPA1 blockers. The results suggest that injury-induced amygdaloid oxidative stress that drives TRPA1 promotes neuropathic pain behavior. This pronociceptive effect involves suppression of medullospinal serotonergic feedback-inhibition acting on the spinal 5-HT1A receptor. While the CeA is involved in mediating the nerve injury-induced pronociception, it may not be a critical relay for the recruitment of medullospinal feedback-inhibition. PMID- 29274354 TI - Ochratoxin A exposure decreased sperm motility via the AMPK and PTEN signaling pathways. AB - Ochratoxin A (OTA), a common mycotoxin found in nature, has been implicated as effecting the function of male reproductive systems. OTA exposure has been shown to decrease sperm production and quality, however, the underlying mechanisms remain unknown. In the current investigation boar sperm exposed to 10 and 100MUM OTA in vitro for 24h resulted in significantly decreased motility, in the 100MUM OTA treatment group when compared with the control group. The level of reactive oxygen species (ROS) was significantly increased in both of the OTA treatment groups. The increase in ROS activated phosphatase and the tensin homolog deleted on chromosome ten (PTEN) and inhibited the activation of protein kinase B (PKB, AKT), activated adenosine 5'-monophosphate (AMP), and activated protein kinase (AMPK) in the exposed sperm. Furthermore, activation of AMPK was enhanced by a decrease in ATPase. These changes culminated in a decline in boar sperm motility. PTEN/AMPK inhibitors significantly inhibited the expression of the two proteins in the OTA treatment group. In addition, there was increased expression of apoptosis markers in the OTA exposed sperm. In conclusion, these data suggest that OTA exposure affects the sperm motility via the AMPK and PTEN signaling pathways. PMID- 29274355 TI - Lipid-lowering and antiatherogenic effects of Vitex megapotamica (Spreng.) Moldenke in a mice experimental model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Vitex megapotamica (Spreng.) Moldenke is a deciduous tree, native of South America. Its leaves are traditionally used to treat cardiovascular diseases. This activity is related to the presence of flavonoids, the major compounds of the crude extract. AIM OF THE STUDY: This study investigated the effects of the oral administration of crude extract and standardized fractions from V. megapotamica leaves on lipid profile and on the formation of atherosclerotic plaque in C57BL/6 LDLr-KO mice treated with high-fat diet (HFD). MATERIALS AND METHODS: Male C57BL/6 LDLr-KO mice were fed with HFD (cholesterol, 1.25%) for 30 days. They were treated with hydroethanolic extract (500 or 1000mg/kg/day) or fractions (125 or 250mg/kg/day). After 30 days of treatment, it was evaluated the serum lipid profile, atherogenic index, and atherosclerotic plaque. RESULTS: All doses of the hydroethanolic extract reduced significantly the levels of total cholesterol, triglycerides, LDL-c and the atherogenic index. The n-butanolic fraction also reduced significantly the levels of total cholesterol, triglycerides, LDL-c and the atherogenic index, at all doses, with exception for the triglycerides, which only the lower dose was effective. The residual fraction reduced significantly the levels of total cholesterol, LDL-c and the atherogenic index, at all doses, with exception for the atherogenic index, which only the higher dose was effective. The atherosclerotic plaque formation was impaired only by the lower dose of the hydroethanolic extract. CONCLUSIONS: Overall, our data suggest that V. megapotamica has potential for the treatment of dyslipidemias. PMID- 29274356 TI - In vitro and in vivo evaluation of systemic and genetic toxicity of Citrus unshiu peel. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The peel of Citrus unshiu Markovich fruits (CUP), called "Jinpi" in Korea, and "Chenpi" in China, has been used for the treatment of respiratory and blood circulation disorders in traditional oriental medicine (TOM). Despite its widespread uses in TOM, no information on the safety of CUP has been reported. Thus, genotoxicity and systemic toxicity of CUP were evaluated in the current studies. MATERIALS AND METHODS: We conducted a toxicological evaluation of CUP water extracts using acute and subchronic (13-week repeated dose) toxicity tests and three genotoxicity assays (bacterial reverse mutation, mammalian chromosomal aberration, and micronuclei formation). RESULTS: In acute and subchronic toxicity tests, both the median lethal dose (LD50) and no-observed adverse-effect level (NOAEL) were more than 4000mg/kg/day in rats. None of the genotoxicity assays revealed any mutagenicity or clastogenicity in in vitro and in vivo systems. CONCLUSION: CUP water extracts were found to be nongenotoxic under our testing conditions and had low acute and subchronic toxicity. PMID- 29274357 TI - The role of temporal inversion in the perception of realistic and morphed dynamic transitions between facial expressions. AB - Recent studies suggest that video recordings of human facial expressions are perceived differently than linear morphing between the first and last frames of these records. Also, observers can differentiate dynamic expressions presented in normal versus time-reversed frame orders. To date, the simultaneous influence of dynamics (natural or linear) and timeline (normal or reversed) has not yet been tested on a wide range of dynamic emotional expressions and the transitions between them. We compared the perception of dynamic transitions between basic emotions in realistic (human-posed) and artificial (linearly morphed) stimuli which were presented in reversed or non-reversed order. The nonlinearity of realistic stimuli was demonstrated by automated facial structure analysis. The results of the behavioral study revealed that the recognition of emotions in time reversed stimuli significantly differed from recognition of the normally presented ones, and this difference was substantially higher for videos of a dynamic human face than for linear morphs. Emotions displayed at the end of the transitions were recognized better than the first-frame emotions in all types of stimuli except in the time-reversed videos, which showed a similar recognition rate for both the starting and ending emotions. Our findings suggest that nonlinearity, which is present in a realistic facial display but absent in linear morphing, is an important cue for emotion perception, and that unnatural perceptual conditions (inversion in time) make the recognition of emotions more difficult. These results confirm the ability of the human visual system to use subtle dynamic cues on an interlocutor's face, and reveal its sensitivity to the timeline organization of the displayed emotions. PMID- 29274358 TI - Is lack of attention necessary for task-irrelevant perceptual learning? AB - Perceptual learning can occur for a feature irrelevant to the training task, when it is sub-threshold and outside of the focus of attention (task-irrelevant perceptual learning, TIPL); however, TIPL does not occur when the task-irrelevant feature is supra-threshold. Here, we asked the question whether TIPL occurs when the task-irrelevant feature is sub-threshold but within the focus of spatial attention. We tested participants in three different discrimination tasks performed on a 3-dot stimulus: a horizontal Vernier task and a vertical bisection task (during pre- and post-training sessions), and a luminance task (during training). In Experiment 1 we found that attending to luminance differences within the same stimulus that contains a sub-threshold horizontal offset (an irrelevant feature during training) does not preclude TIPL, as revealed by an improvement in the Vernier task, but not in the bisection task. This conclusion was confirmed in Experiment 2, in which the 3-dot stimulus used during training did not include a horizontal offset. PMID- 29274360 TI - Disulfiram with or without metformin inhibits oesophageal squamous cell carcinoma in vivo. AB - Oesophageal squamous cell carcinoma (OSCC) is highly prevalent in developing countries but there has been little recent progress into efficacious yet affordable treatment strategies. Drug repurposing is one attractive approach for cancer therapy. Disulfiram (DSF), used to treat alcoholism, inhibits cancer growth and we previously found that DSF perturbs protein degradation/turnover pathways in vitro. This was enhanced by combining DSF with the anti-diabetic drug metformin (Met). Here, we investigated DSF with/without Met, against OSCC in vivo. Nude mice injected subcutaneously with the human OSCC cell line WHCO1, were treated with 30 mg/kg or 50 mg/kg DSF three times per week and with/without Met, for 21 days. DSF and DSF/Met-treated animals had significantly smaller tumours compared to untreated, vehicle and positive control cisplatin-treated groups. This effect for DSF was independent of copper, with no significant accumulation of copper in tumours, together with maintained proteasome activity. However, increases in total ubiquitinated proteins, LC3B-II, LAMP1 and p62 in DSF and DSF/Met groups, indicate that autophagy is inhibited. These findings show that DSF and DSF/Met significantly impede OSCC tumour growth in vivo and offer prospective alternative chemotherapy approaches for OSCC. PMID- 29274359 TI - Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. AB - Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IkappaBalpha inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-kappaB-independent manner. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol containing agents, as well as iron chelation, rescued BAY-induced cell death. BAY upregulated a variety of Nrf2 target genes related to redox regulation, particularly heme oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. SLC7A11 inhibition by erastin, sulfasalazine, or shRNA interference sensitizes BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell viability. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. BAY causes compartmentalization of HO-1 into the nucleus and mitochondrion, and followed mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this study, we first discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 pathway and HO-1 is a key mediator by responding to the cellular redox status. PMID- 29274361 TI - Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl. AB - Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively. Lusutrombopag caused a robust increase in Ba/F3-hMpl cells by activating pathways in a manner similar to that of thrombopoietin and induced colony-forming units-megakaryocyte and polyploid megakaryocytes in human CD34-positive cells. Because lusutrombopag has high species specificity for human TPOR, there was no suitable experimental animal model for drug evaluation, except for immunodeficient mouse-based xenograft models. Therefore, a novel genetically modified knock-in mouse, TPOR Ki/Shi, was developed by replacing mouse Mpl with human-mouse chimera Mpl. In TPOR-Ki/Shi mice, lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production. PMID- 29274362 TI - A new time-resolved 3D angiographic technique (4D DSA): Description, and assessment of its reliability in Spetzler-Martin grading of cerebral arteriovenous malformations. AB - BACKGROUND AND PURPOSE: The Spetzler and Martin (SM) cerebral arteriovenous malformation (AVM) classification is a widely used 5-tier classification. This common language allows specialists to exchange about AVMs and must be reliably characterized by the imaging methods. We presented an agreement study on a new method of digital subtracted 3D rotational angiography resolved in time (four dimensional DSA: 4D DSA) compared to the gold standard (two-dimensional DSA: 2D DSA) in AVM grading using the SM classification. METHODS: Ten patients with AVMs were included during one year, they had an angiographic exploration with both 4D DSA and 2D DSA. Three readers assessed the SM classification. One reader conducted a second reading. The inter-, intra-observer and intermodality agreements were calculated by Kappas. Dose to patient was reported. RESULTS: Considering the SM grade, the inter-observer agreement between 4D DSA and 2D DSA was equivalent (kappa=0.45 and 0.46), and calculated as substantial kappa=0.76 between the 2 methods. The agreement between 4D DSA and 2D DSA was calculated as moderate kappa=0.46 assessing the size of the nidus, slight kappa=0.18 analyzing the drainage and almost perfect kappa=0.95 depicting the localization. 4D DSA performed during a standard initial angiographic assessment of AVM represented approximately 6% of the total dose. CONCLUSION: The addition of this new technique 4D DSA could be performed regularly in addition to the 2D DSA if available, to assess SM grading, with an acceptable exposure to ionizing radiation. PMID- 29274363 TI - Unique features of nucleotide and codon usage patterns in mycoplasmas revealed by information entropy. AB - Currently, the comparison between GC usage pattern at the 3rd codon position and codon usage index is commonly used to estimate the roles of evolutionary forces in shaping synonymous codon usages, however, this kind of analysis often losses the information about the role of A/T usage bias in shaping synonymous codon usage bias. To overcome this limitation and better understand the interplay between nucleotide and codon usages for the evolution of bacteria at gene levels, in this study, we employed the information entropy method with some modification to estimate roles of nucleotide compositions in the overall codon usage bias for 18 mycoplasma species in combination with Davies-Bouldin index. At gene levels, the overall nucleotide usage bias represents A content as the highest, followed by T, G and C for mycoplasmas, resulting in a low GC content. This feature is universal across these species derived from different hosts, suggesting that the hosts have the limited impact on nucleotide usage bias of mycoplasmas. Information entropy and Davies-Bouldin index can better reveal that the nucleotide usage bias at the 3rd codon position is essential in shaping the overall nucleotide bias for all given mycoplasmas except M. pneumoniae M129. Davies-Bouldin index revealed that the 1st and 2nd codon position play more important role in synonymous codon usage bias than that of the 3rd position at gene levels. To our knowledge, this is the first comprehensive investigation into cooperation between nucleotide and codon usages for mycoplasma and extends our knowledge of the mechanisms that contribute to codon usage and evolution of this microorganism. PMID- 29274364 TI - Variation in reward- and error-related neural measures attributable to age, gender, race, and ethnicity. AB - Event-related potentials (ERPs) have been widely applied to the study of individual differences in reward and error processing, including recent proposals of several ERPs as possible biomarkers of mental illness. A criterion for all biomarkers, however, is that they be generalizable across the relevant populations, something which has yet to be demonstrated for many commonly studied reward- and error-related ERPs. The aim of this study was to examine variation in reward and error-related ERPs across core demographic variables: age, gender, race, and ethnicity. Data was drawn from three studies with relatively large samples (N range 207-527). Results demonstrated that ERPs varied across the demographic variables of interest. Several examples include attenuated reward related ERPs with increasing age, larger error-related ERPs for men than women, and larger ERPs to feedback after losses for individuals who identified as Hispanic/Latino. Overall, these analyses suggest systematic variation in ERPs that is attributable to core demographic variables, which could give rise to seemingly inconsistent results across studies to the extent that these sample characteristics differ. Future psychophysiological studies should include these analyses as standard practice and assess how these differences might exacerbate, mask, or confound relationships of interest. PMID- 29274365 TI - The sweetness of successful goal pursuit: Approach-motivated pregoal states enhance the reward positivity during goal pursuit. AB - Traditionally, the reward positivity (RewP) is thought to index a binary performance monitoring system sensitive to approach motivation. However, recent theoretical models have argued that feedback processing extends beyond simple "good" vs. "bad" associations, such that performance monitoring incorporates the complex, multi-step sequence of behaviors often necessary to attain rewards. The present study sought to go beyond simple stimulus-response paradigms to examine how approach-motivated states occurring in multi-step goal pursuit impacts the RewP. Additionally, outcome frequency was varied to examine how the P3, a neural marker of expectancy, influences the RewP. Using a modified monetary incentive delay paradigm, participants played a reaction time game where multiple correct responses were required to attain a reward. Additionally, each trial had the potential for a reward (approach-motivated state) or no reward (neutral state). Results revealed that RewP amplitudes were larger after reward trial win feedback than after reward trial no-win feedback across multiple stages of goal pursuit. Additionally, after for controlling outcome frequency via the P3, RewP amplitudes were larger in reward trials than in neutral trials across incremental stages of goal pursuit. The RewP appears to be sensitive to feedback indicating successfully completing sub-goals during pursuit of a goal, even when no immediate reward is given. Approach motivation enhances performance monitoring when multiple steps are needed to attain a desired outcome, which may increase the likelihood of goal acquisition and attainment. PMID- 29274366 TI - Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice. AB - Emerging data have identified certain drugs such as scopolamine as rapidly acting antidepressants for major depressive disorder (MDD) that increase glutamate release and induce neurotrophic factors through alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR) activation in rodent models. However, little research has addressed the direct mechanisms of scopolamine on AMPAR activation or vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release in the prefrontal cortex (PFC) of mice. Herein, using a chronic unpredictable stress (CUS) paradigm, acute treatment with scopolamine rapidly reversed stress-induced depression-like behaviors in mice. Our results showed that CUS-induced depression-like behaviors, accompanied by a decrease in membrane AMPAR subunit 1 (GluA1), phosphorylated GluA1 Ser845 (pGluA1 Ser845), brain derived neurotrophic factor (BDNF) and VGF (non-acronymic) and an increase in bicaudal C homolog 1 gene (BICC1) in the PFC of mice, and these biochemical and behavioral abnormalities were ameliorated by acute scopolamine treatments. However, pharmacological block of AMPAR by NBQX infusion into the PFC significantly abolished these effects of scopolamine. In addition, knock down of VGLUT1 by lentiviral-mediated RNA interference in the PFC of mice was sufficient to induce depression-like phenotype, to decrease extracellular glutamate accumulation and to cause similar molecular changes with CUS in mice. Remarkably, VGLUT1 knockdown alleviated the rapid antidepressant-like actions of scopolamine and the effects of scopolamine on membrane GluA1-mediated BDNF, VGF and BICC1 changes. Altogether, our findings suggest that VGLUT1-mediated glutamate release and membrane GluA1 activation may play a critical role in the rapid-acting antidepressant-like effects of scopolamine in mice. PMID- 29274367 TI - The effects of incretin hormones on cerebral glucose metabolism in health and disease. AB - Incretin hormones, notably glucagon-like peptide-1 (GLP-1), are gluco-regulatory hormones with pleiotropic effects also in the central nervous system. Apart from a local production of GLP-1, systemic administration of the hormone has been shown to influence a number of cerebral pathologies, including neuroinflammation. Given the brains massive dependence on glucose as its major fuel, we here review the mechanistics of cerebral glucose transport and metabolism, focusing on the deleterious effects of both hypo- and hyperglycaemia. GLP-1, when administered as long-acting analogues or intravenously, appears to decrease transport of glucose in normoglycaemic conditions, without affecting the total cerebral glucose content. During hypoglycaemia this effect seems abated, whereas during hyperglycaemia GLP-1 regulates cerebral glucose metabolism towards stable levels resembling normoglycaemia. In Alzheimer's disease, a 6-month intervention with GLP-1 maintained cerebral glucose levels at baseline levels, contrasting the decline otherwise seen in Alzheimer's. Kinetic studies suggest blood-brain barrier (BBB) glucose transport as the key player in GLP-1 mediated effects on cerebral glucose metabolism. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29274369 TI - Development and in vivo evaluation of a novel lyophilized formulation for the treatment of hemorrhagic shock. AB - Hemorrhagic shock, caused by trauma, is a leading cause of preventable death. A combination treatment of d-beta-hydroxybutyrate (BHB) and melatonin (MLT), in dimethyl sulfoxide - water, increased survival. A freeze-dried BHB-MLT formulation, with a short reconstitution time, has been developed. This intravenous formulation, prepared with an aqueous vehicle, completely eliminated dimethyl sulfoxide, thereby avoiding the potential problems associated with this solvent. The poor aqueous solubility of MLT necessitated the use of polyvinylpyrrolidine (PVP) as a complexing agent. Thus the prelyophilization solution contained BHB (2 M), MLT (21.5 mM) and PVP (40 mM). Using a combination of low-temperature X-ray diffractometry and thermal analysis, the lyophilization process parameters were optimized. Infra-red spectra revealed hydrogen bonding interaction between PVP and MLT, while BHB crystallized as BHB.0.25 H2O in the final lyophile. The formulation improved survival in a rat model of hemorrhagic shock. Based on the increase in rate of survival and longer survival time compared to untreated animals, we conclude that this formulation can serve as a promising first line of treatment for hemorrhagic shock. PMID- 29274370 TI - Sterilization of implantable polymer-based medical devices: A review. AB - This review article is focused on the sterilization techniques used for polymer based implantable medical devices as well as the regulatory aspects governing sterile medical devices. Polymeric materials are increasingly used in implantable devices due to their biodegradable and biocompatible nature. Patients and medical staff often prefer long-term implantable devices and these can be achieved using high molecular weight polymers. Sterilization of polymer-based implantable devices is critical. Since all implantable devices must be sterile, the effect of the sterilization method on the different device components (such as, the polymer, the drug, the electronics, etc.) has to be considered. A comprehensive summary of the established sterilization methods is provided along with the possible effects on polymers. In addition, novel sterilization methods are also discussed. PMID- 29274368 TI - Knockdown of Anillin Actin Binding Protein Blocks Cytokinesis in Hepatocytes and Reduces Liver Tumor Development in Mice Without Affecting Regeneration. AB - BACKGROUND & AIMS: Cytokinesis can fail during normal postnatal liver development, leading to polyploid hepatocytes. We investigated whether inhibiting cytokinesis in the liver slows tumor growth without compromising the health of normal hepatocytes. We inhibited cytokinesis in cancer cells by knocking down ANLN, a cytoskeletal scaffolding protein that regulates cytokinesis and might promote tumorigenesis, in mice with liver disease. METHODS: We analyzed clinical and gene expression data from The Cancer Genome Atlas, Oncomine, PrognoScan, and a hepatocellular carcinoma (HCC) tissue microarray. We knocked down ANLN with small interfering RNAs (siRNAs) in H2.35 liver cells and performed image analyses of cells undergoing cytokinesis. siRNAs were delivered to LAP-MYC mice, which develop hepatoblastoma, using lipid nanoparticles. H2.35 cells with knockdown of ANLN or control cells were injected into FRG mice, which develop chronic liver damage, and tumor growth was monitored. We also developed mice with inducible expression of transgenes encoding small hairpin RNAs (shRNAs) against Anln messenger RNA and studied liver tumorigenesis after administration of diethylnitrosamine and carbon tetrachloride. siRNAs against Anln messenger RNA were conjugated to N-acetylgalactosamine to reduce toxicity and increase hepatocyte tropism; their effects were studied in mouse models of liver cancer and regeneration. RESULTS: Levels of ANLN messenger RNA were increased in human HCC tissues compared to non-tumor liver tissues. siRNA knockdown of ANLN blocked cytokinesis in H2.35 liver cells. Administration of siRNA against ANLN increased survival times of LAP-MYC mice, compared to mice given a control siRNA. H2.35 liver cells with shRNA knockdown of ANLN formed tumors more slowly in FRG mice than control H2.35 cells. Mice with inducible expression of shRNAs against Anln mRNA developed fewer liver tumors after administration of diethylnitrosamine and carbon tetrachloride than control mice. Knockdown of ANLN did not affect liver regeneration after acute and chronic liver injuries. CONCLUSIONS: Knockdown of ANLN in liver cells blocks cytokinesis and inhibits development of liver tumors in mice. Agents that inhibit ANLN in the liver might be effective for prevention or treatment of HCC. PMID- 29274371 TI - Orbital rhabdomyosarcoma in a child with Leigh syndrome. AB - We present the case of a 6-year old girl with Leigh syndrome and an orbital rhabdomyosarcoma and describe her clinical course and our multidisciplinary approach to treatment. To our knowledge, this is the first report of rhabdomyosarcoma in a patient with Leigh syndrome. PMID- 29274373 TI - Congenital lymphocytic choriomeningitis virus-an underdiagnosed fetal teratogen. AB - Congenital lymphocytic choriomeningitis virus (LCMV) infection is associated with high mortality and morbidity. Although the number of cases reported in the literature has been increasing, it might still be clinically an underdiagnosed human fetal teratogen. We report 2 more cases of serologically proven congenital LCMV infection. One case presented with Aicardi-like syndrome features. Since congenital LCMV infection may mimic Aicardi syndrome, serologic testing should be considered in the workup of patients with Aicardi syndrome to rule out LCMV infection. PMID- 29274375 TI - Meta-analysis: Risk of dry mouth with second generation antidepressants. AB - OBJECTIVE: The goal of this meta-analysis was to quantify the risk of dry mouth associated with commonly prescribed antidepressant agents and examine the potential implications of medication class, dose, and pharmacodynamics and dose on risk of treatment-induced dry mouth. DATA SOURCES AND STUDY SELECTION: A PubMed search was conducted to identify double-blind, randomized, placebo controlled trials examining the efficacy and tolerability of second generation antidepressant medications for adults with depressive disorders, anxiety disorders, and OCD. DATA EXTRACTION: A random-effects meta-analysis was used to quantify the pooled risk ratio of treatment-emergent dry mouth with second generation antidepressants compared to placebo. Stratified subgroup analysis and meta-regression was utilized to further examine the effects antidepressant agent, class, dosage, indication, and receptor affinity profile on the measured risk of dry mouth. RESULTS: 99 trials involving 20,868 adults. SNRIs (Relative Risk (RR)=2.24, 95% Confidence Interval (CI): 1.95-2.58, z=11.2, p<0.001) were associated with a significantly greater risk of dry mouth (test for subgroup differences chi2=7.6, df=1; p=0.006) compared to placebo than SSRIs (RR=1.65, 95% CI: 1.39-1.95, z=5.8, p<0.001). There was a significant difference found in the risk of dry mouth between diagnostic indications within the SNRI class (test for subgroup differences chi2=9.63, df=1; p=0.002). Anxiety diagnoses (RR=2.78, 95% CI: 2.29-3.38, z=10.32, p<0.001) were associated with a greater risk of dry mouth compared to depression (RR=1.80, 95% CI: 1.48-2.18, z=5.85, p<0.001). Decreased affinity for Alpha-1 (PE=0.18, 95% CI: 0.07-0.28, z=3.26, p=0.001) and Alpha-2 (PE=0.49, 95% CI: 0.22-0.75, z=3.64, p<0.001) receptors and SERT (PE=0.07, 95% CI: 0.01-0.14, z=2.10, p<0.05) was significantly associated with increased risk of dry mouth. CONCLUSIONS: The current meta-analysis suggests that SSRIs, SNRIs, and atypical antidepressants are all associated with varying degrees of increased risk of dry mouth. SNRIs were associated with a significantly greater risk of dry mouth compared to SSRIs. PMID- 29274374 TI - The effect of subcellular localization on the efficiency of EGFR-targeted VHH photosensitizer conjugates. AB - Photodynamic therapy (PDT) is an emerging method to treat light-accessible malignancies. To increase specificity and allow dose reduction, conjugates of photosensitizers (PS) with antibodies against tumor-associated antigens have been developed for photoimmunotherapy (PIT). However, so far it is unclear whether cellular internalization of these conjugates after binding affects PIT efficacy. The use of low molecular weight llama single domain antibodies (VHHs, nanobodies) for PIT is preferred above full size antibodies because of better tumor penetration. Therefore, we functionalized the VHH 7D12, directed against the epidermal growth factor receptor (EGFR), with a PS (IRDye700DX). To assess the impact of cellular internalization on activity, the VHHs were additionally conjugated to a cell-penetrating peptide (VHH[PS]-CPP). Here we show that upon illumination with near-infrared (NIR) light, both VHH[PS] and VHH[PS]-CPP conjugates specifically induce cell death of EGFR expressing cancer cell lines and of EGFR-expressing cells derived from surgically obtained ascites from patients with high-grade serous ovarian cancer. However, VHH[PS] conjugates were significantly more effective compared to internalizing VHH[PS]-CPP suggesting that cell surface association is required for optimal therapeutic activity. PMID- 29274376 TI - Trauma: Still the Cornerstone of Acute Care Surgery Specialty. PMID- 29274372 TI - Single grading vs double grading with adjudication in the telemedicine approaches to evaluating acute-phase retinopathy of prematurity (e-ROP) study. AB - PURPOSE: To evaluate the sensitivity and specificity of single, independent, nonphysician trained reader (TR) gradings in the Telemedicine Approaches to Evaluating Acute-phase Retinopathy of Prematurity (e-ROP) study. METHODS: Secondary analyses of image grading results from 1,235 infants of birth weights <1251 g. Two of three TRs independently graded image sets; discrepancies were adjudicated by the reading center director (an ophthalmologist) to reach final grading. Sensitivity and specificity of each TR grading and final grading was calculated by comparing gradings to clinical examination results. RESULTS: Of 7,808 double graded image sets, TR1 graded 5,165; TR2, 3,787; and TR3, 6,664. Compared to final grading for referral warranted retinopathy of prematurity (RW ROP), two TRs had relatively lower sensitivity (TR1, 75% vs 79% [P = 0.03]; TR2, 73% vs 77% [P = 0.02]) and specificity (TR1, 80% vs 83% [P < 0.001]; TR2, 82% vs 83% [P = 0.09]). TR3 had similar sensitivity (83% vs 83% [P = 0.78]) and specificity (83% vs 84% [P = 0.02]). Compared to final grading, TR1 had lower sensitivity for zone I ROP (47% vs 56% [P = 0.04]) and stage >=3 ROP (71% vs 77% [P = 0.002]); TR2 had lower sensitivity for stage >=3 ROP (69% vs 77% [P < 0.001]) and lower specificity for all three components (P < 0.001); TR3 had lower sensitivity for detecting plus disease (23% vs 35% [P < 0.001]) and similar sensitivity for zone I ROP and stage >=3 ROP. CONCLUSIONS: There is a small but significant decrease in the sensitivity and specificity for RW-ROP when single reader grading is compared to double adjudicated grading. PMID- 29274377 TI - Associative versus predictive processes in Pavlovian conditioning. AB - Learning and memory are so obviously related that it is hard to see how the understanding of one could proceed without an understanding of the other. Yet, in psychology, they are studied by two different research communities. The concept of association, which is central both to the field of conditioning and to that of retrieval and forgetting, could be used to bridge the gap between the two concepts. However, the concept is quite different in the fields of learning and memory, a situation for which this article argues that the Rescorla-Wagner model is mainly to blame. By viewing Pavlovian conditioning as the outcome of a predictive process but using the traditional associative language developed in memory studies to describe this process, it has introduced an unnecessary confusion between memory and prediction within the field of learning. This confusion needs to be acknowledged so that the concepts of associations and predictions can again be differentiated. This would allow for better integration of the fields of learning and memory. PMID- 29274379 TI - Cortical and spinal conditioned media modify the inward ion currents and excitability and promote differentiation of human striatal primordium. AB - Human striatal precursor cells (HSPs) isolated from ganglionic eminence may differentiate in electrophysiologically functional excitable neuron-like cells and a number of endogenous molecules such as hormones, neurotransmitters or growth factors can actually regulate neuronal growing and differentiation. The purpose of this research was to assess, by electrophysiological and immunocytochemical analysis, if the type of culture medium could specifically impact on the neuronal differentiation potential of HSPs. Accordingly, HSPs were maintained in different inductive media such as cortical and spinal cord conditioned media, and we estimated the possible changes in the main ion currents, excitability and expression of neuronal markers indicative of neuronal differentiation. Our results have shown that 36 h exposure to each of the conditioned media, with their blend of autocrine and paracrine growth factors, was able to modify significantly the electrophysiological membrane properties and the functional expression of inward ionic currents in selected neuronal HSPs. Moreover, although both types of conditioned media determined neuronal maturation (increased neuritogenesis and increased expression of neuronal and striatal markers), each of them leads to the occurrence of different functional features. Particularly, the spinal medium caused a stronger depolarization of the membrane potential and significantly increased the amplitude of Na+ current as well as L- and N- type Ca2+ currents, definitely modifying their kinetics. In contrast, the cortical medium mainly caused a significant and more marked increase of the membrane conductance and time constant values. These results strongly support the plasticity of our cellular model that, although already committed towards a specific phenotype, it can be differently affected by the conditioned media, thereby resulting functionally modifiable according to environmental cues. PMID- 29274378 TI - Sources of maladaptive behavior in 'normal' organisms. AB - A basic assumption of most researchers is that behavior is generally functional, and indeed, in most instances the function is obvious. But in a number of cases, some behaviors of neurophysiologically 'normal' organisms appear to be maladaptive. Considerable research has been conducted to understand the basis of such behavior as well as how the frequency of such behavior can be reduced. Here we provide a brief panoramic review of the major sources of maladaptive behavior in neurophysiologically 'normal' organisms: a) altered environmental contingencies relative to those faced by ancestral generations in their environment of evolutionary adaptation, b) altered environmental contingencies within the lifespan of the animal, c) linked behaviors in which the dysfunctional behavior is a linked companion of a more valuable beneficial trait, and d) the labeling of some behaviors as 'maladaptive' when more careful examination finds that they provide net benefit. Most of our attention is on the consequences of altered contingencies across and within a generation, with altered contingencies within a generation constituting a form of associative interference. The central issue in these two cases can be framed in terms of insufficient or excessive transfer of training resulting in maladaptive behavior. We discuss the functional basis of successful and unsuccessful near transfer (i.e., stimulus and response generalization) and far transfer (including rule learning and abstraction). PMID- 29274380 TI - The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. AB - The increased production of reactive oxygen species (ROS) has been postulated to play a key role in the progression of nonalcoholic fatty liver disease (NAFLD). However, the source of ROS and mechanisms underlying the development of NAFLD have yet to be established. We observed a significant up-regulation of a minor isoform of NADPH oxidase, NOX1, in the liver of nonalcoholic steatohepatitis (NASH) patients as well as of mice fed a high-fat and high-cholesterol (HFC) diet for 8 weeks. In mice deficient in Nox1 (Nox1KO), increased levels of serum alanine aminotransferase and hepatic cleaved caspase-3 demonstrated in HFC diet fed wild-type mice (WT) were significantly attenuated. Concomitantly, increased protein nitrotyrosine adducts, a marker of peroxynitrite-induced injury detected in hepatic sinusoids of WT, were significantly suppressed in Nox1KO. The expression of NOX1 mRNA was much higher in the fractions of enriched liver sinusoidal endothelial cells (LSECs) than in those of hepatocytes. In primary cultured LSECs, palmitic acid (PA) up-regulated the mRNA level of NOX1, but not of NOX2 or NOX4. The production of nitric oxide by LSECs was significantly attenuated by PA-treatment in WT but not in Nox1KO. When the in vitro relaxation of TWNT1, a cell line that originated from hepatic stellate cells, was assessed by the gel contraction assay, the relaxation of stellate cells induced by LSECs was attenuated by PA treatment. In contrast, the relaxation effect of LSECs was preserved in cells isolated from Nox1KO. Taken together, the up-regulation of NOX1 in LSECs may elicit peroxynitrite-mediated cellular injury and impaired hepatic microcirculation through the reduced bioavailability of nitric oxide. ROS derived from NOX1 may therefore constitute a critical component in the progression of NAFLD. PMID- 29274382 TI - Mesh-Free Laparoscopic High Uterosacral Ligament Suspension during Total Laparoscopic Hysterectomy for Uterine Prolapse. AB - STUDY OBJECTIVE: To demonstrate a mesh-free approach for uterine prolapse during a hysterectomy. DESIGN: Technical video (Canadian Task Force classification III). SETTING: Benign gynecology department at a university hospital. PATIENT: A 50 year-old woman. INTERVENTION: Laparoscopic high uterosacral ligament suspension technique. MEASUREMENTS AND MAIN RESULTS: A 50-year-old woman presented with irregular vaginal bleeding and grade 3 uterine prolapse. The patient was concerned regarding the use of mesh and erosion. After counseling the patient agreed to a mesh-free single procedure. The use of mesh for the treatment of pelvic organ prolapse has become the subject of controversy and litigation. Complications of mesh erosion have resulted in the US Food and Drug Administration reclassifying transvaginal meshes as high-risk devices in 2016 [1]. Mesh erosion risk is up to 23% with hysterectomy and concomitant laparoscopic sacrocolpopexy [2] and 3% with sacrohysteropexy [3]. We present an alternative laparoscopic approach of treating uterine prolapse with high uterosacral suspension during laparoscopic hysterectomy. Our method avoids the use of mesh, sacrocervicopexy and morcellation, or an interval sacrocolpopexy. Although high uterosacral ligament suspension can be performed vaginally, it carries up to an 11% risk of ureteric injury [4]. CONCLUSION: In this video a bilateral ureterolysis is performed, before hysterectomy, isolating the uterosacral ligaments. These are then suspended to the vaginal vault in a purse string fashion using Vicryl 0 (polyglactin 910) and intracorporeal knot-tying. Postprocedure the vault is well supported with a vaginal length of 12 cm. PMID- 29274381 TI - Redox and the circadian clock in plant immunity: A balancing act. AB - Plants' reliance on sunlight for energy makes their light-driven circadian clock a critical regulator in balancing the energy needs for vital activities such as growth and defense. Recent studies show that the circadian clock acts as a strategic planner to prime active defense responses towards the morning or daytime when conditions, such as the opening of stomata required for photosynthesis, are favorable for attackers. Execution of the defense response, on the other hand, is determined according to the cellular redox state and is regulated in part by the production of reactive oxygen and nitrogen species upon pathogen challenge. The interplay between redox and the circadian clock further gates the onset of defense response to a specific time of the day to avoid conflict with growth-related activities. In this review, we focus on discussing the roles of the circadian clock as a robust overseer and the cellular redox as a dynamic executor of plant defense. PMID- 29274383 TI - Human body donation in Thailand: Donors at Khon Kaen University. AB - BACKGROUND: Culture, society and spirituality contribute to variability in the characteristics of human body donors and donation programmes worldwide. The donors and the body donation programme at Khon Kaen University, northeast Thailand, reflect all these aspects of Thailand, including the status accorded to the donors and the ceremonial acknowledgement of the donors and their families. METHODS: Data from the programme records and from surveys of samples of currently registering donors and recently received donor bodies are analysed to define the characteristics of both registering and received donors, including motivation, demography, socio-economic status, health, and use of the bodies. FINDINGS: The body donation programme at Khon Kaen University currently has a very high rate of registration of body donors, with gender and age differences in the patterns of donation. Registrants include more females than males, a long-standing pattern, and are an average age of 50 years. The bodies of 12% of registrants are received after death and include more males than females. Both sexes are of an average age of 69 years. Males had registered their donation eight years prior to death and females ten years prior. Current registrants identified altruistic motives for their decision to donate, although the coincidence of body donation by a highly revered monk with a surge in donations in 2015 suggests that Buddhism plays a primary role in motivation. The opportunity to make merit for donors and their families, and respect shown to donors and the nature of the ceremonies acknowledging the donors and their families, including the use of the Royal Flame at the cremation ceremony, all contribute to decisions to donate. CONCLUSIONS: The characteristics of body donors and the body donation programme at Khon Kaen University are reflective of Thai society and the centrality of Buddhism to Thai culture. PMID- 29274384 TI - Carthamus tinctorius L. extract improves hemodynamic and vascular alterations in a rat model of renovascular hypertension through Ang II-AT1R-NADPH oxidase pathway. AB - Carthamus tinctorius L. (CT) is widely used in Asian countries as a beverage and in folk medicine. The effects of CT extract on hemodynamics, vascular remodeling, the renin-angiotensin system (RAS) and oxidative stress in the two-kidney, one clip (2K-1C) hypertensive rat model were investigated. Renovascular hypertension was induced in male Sprague-Dawley rats and were treated with CT extract (500mg/kg/day) or captopril (5mg/kg/day) or vehicle for four weeks. CT extract or captopril reduced blood pressure, hindlimb vascular resistance, and increased hindlimb blood flow in 2K-1C hypertensive rats (p<0.05). Increases in aortic wall thickness, cross-sectional area and collagen deposition in 2K-1C rats were alleviated with CT extract or captopril treatment (p<0.05). CT extract or captopril suppressed RAS activation, including elevated serum ACE activity, and plasma Ang II level and up-regulated aortic AT1R protein expression in 2K-1C rats (p<0.05). Furthermore, CT extract or captopril reduced vascular superoxide production, aortic NADPH oxidase subunit gp91phox expression and increased plasma nitric oxide metabolite levels in 2K-1C rats (p<0.05). These findings suggest that CT extract ameliorated hemodynamic alteration and vascular remodeling in 2K 1C hypertensive rats. Possible mechanisms may involve RAS inhibitor effects and potent antioxidant activity. PMID- 29274385 TI - Live Long and Prosper: Roles of Sugar and Sugar Polymers in Seed Vigor. PMID- 29274386 TI - Auditing SNOMED CT hierarchical relations based on lexical features of concepts in non-lattice subgraphs. AB - OBJECTIVE: We introduce a structural-lexical approach for auditing SNOMED CT using a combination of non-lattice subgraphs of the underlying hierarchical relations and enriched lexical attributes of fully specified concept names. Our goal is to develop a scalable and effective approach that automatically identifies missing hierarchical IS-A relations. METHODS: Our approach involves 3 stages. In stage 1, all non-lattice subgraphs of SNOMED CT's IS-A hierarchical relations are extracted. In stage 2, lexical attributes of fully-specified concept names in such non-lattice subgraphs are extracted. For each concept in a non-lattice subgraph, we enrich its set of attributes with attributes from its ancestor concepts within the non-lattice subgraph. In stage 3, subset inclusion relations between the lexical attribute sets of each pair of concepts in each non lattice subgraph are compared to existing IS-A relations in SNOMED CT. For concept pairs within each non-lattice subgraph, if a subset relation is identified but an IS-A relation is not present in SNOMED CT IS-A transitive closure, then a missing IS-A relation is reported. The September 2017 release of SNOMED CT (US edition) was used in this investigation. RESULTS: A total of 14,380 non-lattice subgraphs were extracted, from which we suggested a total of 41,357 missing IS-A relations. For evaluation purposes, 200 non-lattice subgraphs were randomly selected from 996 smaller subgraphs (of size 4, 5, or 6) within the "Clinical Finding" and "Procedure" sub-hierarchies. Two domain experts confirmed 185 (among 223) suggested missing IS-A relations, a precision of 82.96%. CONCLUSIONS: Our results demonstrate that analyzing the lexical features of concepts in non-lattice subgraphs is an effective approach for auditing SNOMED CT. PMID- 29274387 TI - Common cues wire the spinal cord: Axon guidance molecules in spinal neuron migration. AB - Topographic arrangement of neuronal cell bodies and axonal tracts are crucial for proper wiring of the nervous system. This involves often-coordinated neuronal migration and axon guidance during development. Most neurons migrate from their birthplace to specific topographic coordinates as they adopt the final cell fates and extend axons. The axons follow temporospatial specific guidance cues to reach the appropriate targets. When neuronal or axonal migration or their coordination is disrupted, severe consequences including neurodevelopmental disorders and neurological diseases, can arise. Neuronal and axonal migration shares some molecular mechanisms, as genes originally identified as axon guidance molecules have been increasingly shown to direct both navigation processes. This review focuses on axon guidance pathways that are shown to also direct neuronal migration in the vertebrate spinal cord. PMID- 29274388 TI - IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis. AB - OBJECTIVES: B-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE). METHODS: Isolated PBMCs of SLE-patients (n=30) and healthy controls (n=21) were in vitro stimulated with CPG, IgG+IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry. RESULTS: The strongest stimulus for Granzyme B secretion of B-cells was IgG+IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B+ B-cells in particular SLE-patients with active disease and with lupus nephritis. CONCLUSIONS: The frequency of GrB+ producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis. PMID- 29274389 TI - Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade. PMID- 29274390 TI - Extracellular ATP signaling and clinical relevance. AB - Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies. PMID- 29274391 TI - Electrophysiological characteristics and pharmacological sensitivity of two lines of human induced pluripotent stem cell derived cardiomyocytes coming from two different suppliers. AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used as preclinical tool for predicting drug-induced QT prolongation and arrhythmias. This study was conducted to assess the electrophysiological characteristics and the pharmacological sensitivity of two commercialized hiPSC CMs. The baseline electrophysiological characteristics measured with a multi electrode array (MEA) technology differ between Cor.4U and iCell2: higher beat rate (+32bpm) and shorter field potential duration (FPD, -201ms) for Cor.4U. The FPD lengthening after cisapride (100nM: +65% versus +18%), quinidine (10MUM: +65% versus +31%), sotalol (30MUM: +90% versus +47%) or flecainide (3MUM: +76% versus +22%) application appeared earlier in iCell2 as compared to Cor.4U. Arrhythmia occurrence also appeared earlier in iCell2 as compared to Cor.4U for the 3 substances mentioned above. The FPD shortening recorded after verapamil or nifedipine application was similar in both hiPSC-CMs. In conclusion, Cor.4U and iCell2 hiPSC-CMs are both sensitive enough to detect drug-induced delayed or shortened repolarization and arrhythmia and can provide useful predictive cardiac electrophysiology data. Arrhythmias occurred at concentrations higher than clinical free maximum plasma concentrations with an overestimation of the risk with cisapride. However, quantitative differences of baseline electrophysiological characteristics or pharmacological sensitivity of both cell types have to be considered with caution during the interpretation of data. The new chemical entities included within a given drug development program should be evaluated in hiPSC-CMs coming from a single supplier. PMID- 29274393 TI - The Social Regulation of Pain: Autonomic and Neurophysiological Changes Associated With Perceived Threat. AB - : The analgesic effect of social support is proposed as a function of social support modulating perceived threat of painful stimuli. In the current study, we directly examined the social buffering effect in the context of the threat of pain. Eighteen healthy participants were subjected to the threat of pain while they held the hand of a close other, a stranger, or not at all. Neural and autonomic responses were recorded using electroencephalogram and heart rate, respectively. Close other hand-holding reduced pain perception. This was accompanied by decreased heart rate and frontal theta oscillation (4-8 Hz) during the threat phase preceding painful stimulation. Interestingly, decreased heart rate and frontal theta in the close other hand-holding condition were uniquely associated with greater pain reduction during subsequent nociceptive stimulation. Neural changes were source-localized to the insular cortex and the rostral ventral portions of anterior cingulate cortex, regions involved in the processing of threat and pain. Together, our data build upon work to date linking social support to pain by showing autonomic and neurophysiological changes associated with pain reduction. PERSPECTIVE: Social support may reduce pain through buffering the autonomic and neurophysiological response to the threatening quality of noxious stimuli. Results implicate that in clinical settings the caregiver could help people with chronic pain reappraise pain and related conditions as less stressful. PMID- 29274392 TI - Rightward and leftward biases in temporal reproduction of objects represented in central and peripheral spaces. AB - The basis for how we represent temporal intervals in memory remains unclear. One proposal, the mental time line theory (MTL), posits that our representation of temporal duration depends on a horizontal mental time line, thus suggesting that the representation of time has an underlying spatial component. Recent work suggests that the MTL is a learned strategy, prompting new questions of when and why MTL is used to represent temporal duration, and whether time is always represented spatially. The current study examines the hypothesis that the MTL may be a time processing strategy specific to centrally-located stimuli. In two experiments (visual eccentricity and prismatic adaptation procedures), we investigated the magnitude of the rightward bias, an index of the MTL, in central and peripheral space. When participants performed a supra-second temporal interval reproduction task, we observed a rightward bias only in central vision (within 3 degrees visual angle), but not in the peripheral space (approximately 6-8 degrees visual angle). Instead, in the periphery, we observed a leftward bias. The results suggest that the MTL may be a learned strategy specific to central space and that strategies for temporal interval estimation that do not depend on MTL may exist for stimuli perceived peripherally. PMID- 29274394 TI - Reduced methicillin-resistant Staphylococcus aureus biofilm formation in bone cavities by photodynamic therapy. AB - : Photodynamic Therapy (PDT) is a promising alternative for the treatment of infectious bone lesions in the oral cavity. The objective of this study was to evaluate the antimicrobial effectiveness of PDT using blue LED associated with curcumin in methicillin-resistant Staphylococcus aureus biofilms (MRSA) in bovine bone cavities by fluorescence spectroscopy. Standardized suspensions of MRSA culture were inoculated into bone lesions to form biofilm. Forty bone species were distributed in three distinct groups: L-C- (control); L + C- (LED for 5 min); L-C+ (curcumin incubation for 5 min) and L + C+ (PDT). Aliquots of 100 MUL were collected from the bone cavities after the treatments and were cultived in BHI for 24 h at 36 degrees C +/- 1 and bacterial colonies counting were performed. Statistical analysis were performed using the paired t-test and analysis of variance (ANOVA) for the variables studied. RESULTS: The control and PDT groups presented statistically significant differences (p < 0.001). It was possible to reduce 3.666 log10 CFU/mL of MRSA and a reduction in the fluorescence emitted after the treatments was observed. The MRSA reduction in biofilms by PDT was the most efficient treatmnent. There was a significant reduction of biofilms in the L + C- and non-PDT groups by fluorescence spectroscopy images. PMID- 29274395 TI - Adherence to Mediterranean diet and nutritional status in a sample of nonagenarians. AB - OBJECTIVE: The aim is to describe the adherence to Mediterranean diet in a sample of nonagenarians and to analyse its cross-sectional association with anthropometric and bioelectrical parameters. DESIGN: A cross-sectional design was employed in this study. The adherence to the Mediterranean diet was measured through the Mediterranean Diet Score (MedDietScore). SETTING AND PARTICIPANTS: A representative sample of nonagenarian residents in the eight municipalities belonging to Mugello (Florence, Italy). MEASUREMENTS: The tools used to investigate the nutritional status and the body composition were: weight; ulna length to estimate the height; body mass index (BMI); mid-upper arm circumference (MUAC); calf circumference (CC); waist circumference (WC); hip circumference (HC); and specific bioelectrical impedance vector analysis (BIVAsp). RESULTS: All the measurements were carried out for 298 nonagenarians (70.8% of whom were females). The mean value of MedDietScore was 34.3+/-3.6. The MedDietScore was significantly correlated with CC (r=0.127), specific resistance (Rsp, r=0.152), and specific impedance (Zsp, r=0.153) in the whole sample, as well as with height (r=-0.222), Rsp (r=0.282), and Zsp (r=0.282) in males. In the whole sample, Rsp and Zsp mean values significantly increased by quartiles of MedDietScore; these results were confirmed by vector analysis. CONCLUSIONS: The high level of adherence to Mediterranean diet could contribute to explaining the longevity of our sample. Studying the influence of dietary lifestyle in nonagenarians in depth could help to promote healthy ageing. PMID- 29274397 TI - Litigation in orthopaedic surgery: New ethical challenges. PMID- 29274396 TI - Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. AB - In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine +/- 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m2/day on days -6 to -4 and i.v. fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted. PMID- 29274398 TI - Haplotypes composed of minor frequency single nucleotide polymorphisms of the TNF gene protect from progression into sepsis: A study using the new sepsis classification. AB - OBJECTIVES: Several articles have provided conflicting results regarding the role of single nucleotide polymorphisms (SNPs) in the promoter region of the TNF gene in susceptibility to sepsis. Former articles have been based on previous definitions of sepsis. This study investigated the influence of TNF haplotypes on the development of sepsis using the new Sepsis-3 definitions. METHODS: DNA was isolated from patients suffering from infection and systemic inflammatory response syndrome. Haplotyping was performed for six SNPs of TNF. The serum levels of tumour necrosis factor alpha (TNF-alpha) of these patients were measured using an enzyme immunosorbent assay. Patients were classified into infection and sepsis categories using the Sepsis-3 definitions. Associations between the TNF haplotypes and the clinical characteristics and serum TNF-alpha levels of the patients were examined. RESULTS: The most common TNF haplotype h1 was composed of major alleles of the studied SNPs. Carriage of haplotypes composed of minor frequency alleles was associated with a lower risk of developing sepsis (odds ratio 0.41, 95% confidence interval 0.19-0.88, p=0.022), but this did not affect the 28-day outcome. Serum TNF-alpha levels were significantly higher among patients homozygous for h1 haplotypes who developed sepsis compared to infection (p=0.032); a similar result was not observed for patients carrying other haplotypes. CONCLUSIONS: Haplotypes containing minor frequency SNP alleles of TNF protect against the development of sepsis without affecting the outcome. PMID- 29274399 TI - The Inherent Fallibility of Validated Screening Tools for Social Determinants of Health. PMID- 29274400 TI - Conditional MitoTimer reporter mice for assessment of mitochondrial structure, oxidative stress, and mitophagy. AB - Assessment of structural and functional changes of mitochondria is vital for biomedical research as mitochondria are the power plants essential for biological processes and tissue/organ functions. Others and we have developed a novel reporter gene, pMitoTimer, which codes for a redox sensitive mitochondrial targeted protein that switches from green fluorescence protein (GFP) to red fluorescent protein (DsRed) when oxidized. It has been shown in transfected cells, transgenic C. elegans and Drosophila m., as well as somatically transfected adult skeletal muscle that this reporter gene allows quantifiable assessment of mitochondrial structure, oxidative stress, and lysosomal targeting of mitochondria-containing autophagosomes. Here, we generated CAG-CAT-MitoTimer transgenic mice using a transgene containing MitoTimer downstream of LoxP-flanked bacterial chloramphenicol acetyltransferase (CAT) gene with stop codon under the control of the cytomegalovirus (CMV) enhancer fused to the chicken beta-actin promoter (CAG). When CAG-CAT-MitoTimer mice were crossbred with various tissue specific (muscle, adipose tissue, kidney, and pancreatic tumor) or global Cre transgenic mice, the double transgenic offspring showed MitoTimer expression in tissue-specific or global manner. Lastly, we show that hindlimb ischemia reperfusion caused early, transient increases of mitochondrial oxidative stress, mitochondrial fragmentation and lysosomal targeting of autophagosomes containing mitochondria as well as a later reduction of mitochondrial content in skeletal muscle along with mitochondrial oxidative stress in sciatic nerve. Thus, we have generated conditional MitoTimer mice and provided proof of principle evidence of their utility to simultaneously assess mitochondrial structure, oxidative stress, and mitophagy in vivo in a tissue-specific, controllable fashion. PMID- 29274401 TI - Agressive pediatric myofibromatosis in a two-year-old child. AB - INTRODUCTION: Aggressive paediatric myofibromatosis is an autosomal recessive disease characterized by fibroblastic proliferation from cells originated in muscle-aponeurotic tissue. Its etiology is unknown, and the average age of the reported cases is 7 years old. The tumor exhibits rapid painless growth and appears attached to muscle tissue and/or bone. The treatment of choice is conservative surgical excision despite of early relapses has been reported. OBSERVATION: A 2-year-old patient, with no morbid history, presented with a large swelling in the left submandibular region, firm, neither defined limits nor inflammatory characteristics. Its size doubled 2 months after an incisional biopsy. CT images showed great compromise of the left mandibular body with expanded and thinned cortical bone. The MRI showed extension towards the pharynx. Histopathological findings were elongated fibroblastic and ovoid cells arranged in bundles and fascicles within fibromyxoid stroma, an image consistent with the diagnosis. The treatment consisted in a conservative exeresis of the tumor, preserving the jaw. Control 1 year after surgical removal shows no signs of relapse and the mandibular structure has been restored. DISCUSSION: The large size of the lesion and bone involvement at such an early age evidenced a very aggressive lesion, however, supported by a previous biopsy, we performed a conservative treatment, which only caused the loss of a dental germ, impossible to take off from the intraosseous tumor. The control of this type of lesions requires a longer follow-up. PMID- 29274402 TI - Proteome analysis of an Escherichia coli ptsN-null strain under different nitrogen regimes. AB - : The carbohydrate-uptake phosphorelay PTS system plays a key role in metabolic regulation in Bacteria controlling the utilization of secondary carbon sources. Some bacteria, such as Escherichia coli, encode a paralogous system named PTSNtr (nitrogen related PTS). PTSNtr is composed of EINtr (ptsP), NPr (ptsO), and EIIANtr (ptsN). These proteins act as a phosphorelay system from phosphoenolpyruvate to EINtr, NPr and them to EIIANtr. PTSNtr is not involved in carbohydrate uptake and it may be dedicated to performing regulatory functions. The phosphorylation state of EINtr is regulated by allosteric binding of glutamine and 2-oxoglutarate, metabolites whose intracellular levels reflect the nitrogen status. Although PTSNtr is designated as having nitrogen-sensory properties, no major effect of this system on nitrogen regulation has been described in E. coli. Here we show that an E. coli ptsN deletion mutant has impaired growth in minimal medium. Proteome analysis of the ?ptsN strain under different nitrogen regimes revealed no involvement in regulation of the canonical nitrogen regulatory (Ntr) system. The proteomic data support the conclusion that ptsN is required to balance the activities of the sigma factors RpoS and RpoD in such way that, in the absence of ptsN, RpoS-dependent genes are preferentially expressed. SIGNIFICANCE: The nitrogen related PTSNtr phosphorelay system has been hypothesized to participate in the control of nitrogen metabolism. Here we used a proteomics approach to show that an Escherichia coli ptsN null strain, which misses the final module of PTSNtr phosphorelay, has no significant effects on nitrogen metabolism under different nitrogen regimes. We noted that ptsN is required for fitness under minimal medium and for the proper balance between RpoS and sigma 70 activities in such way that, in the absence of ptsN, RpoS-dependent genes are preferentially expressed. PMID- 29274403 TI - Estradiol receptor profile and estrogen responsiveness in laryngeal cancer and clinical outcomes. AB - There is growing evidence that laryngeal cancers are responsive to sex hormones, specifically 17beta-estradiol (E2), despite controversy regarding the presence and characterization of E2 receptors (ER). Determination of sex hormone responsiveness impacts the prognosis of laryngeal cancer patients and the treatment modalities implemented by their clinicians. Discovery of membrane associated steroid hormone receptors and rapid membrane signaling opened the possibility that cancers previously labeled 'non-hormone dependent' and 'ER negative' might in fact be susceptible to the effects of E2 via these membrane receptors. ERalpha66 and ERbeta, the classical nuclear receptors, are present in the membranes of different cancer cells via a mechanism referred to as trafficking. Novel splice variants of these traditional receptors, a key example being ERalpha36, have also been found in the caveolae of cancer cells. Previous work demonstrated that ERalpha36 has a role in the tumorigenesis of laryngeal cancer, enhancing both proliferation and the anti-apoptotic effect of E2 against chemotherapeutics. The present study showed that expression of different membrane ERs in laryngeal cancer is not uniform, which may result in differential and even antagonistic responses to E2. E2 had protective or deleterious effects in different cancer cell lines, stimulating proliferation and conferring anti apoptotic potential to the cancer cells according to their receptor profile. These findings stress the importance of establishing the molecular and clinical characterization of the specific laryngeal tumor in order to tailor treatment accordingly, thus optimizing care while reducing adverse effects for individual patients. PMID- 29274404 TI - Doping control analysis of 13 steroids and structural-like analytes in human urine using Quadrupole-Orbitrap LC-MS/MS with parallel reaction monitoring (PRM) mode. AB - Anabolic androgenic steroids (AASs) and structural-like substances are commonly prohibited substances found in doping control studies that can be difficult to accurately detect. In the present study, 11 AASs and 2 structural-like substances that are commonly detected were examined. Currently, such analytes are detected using low resolution GC-MS/MS or LC-MS/MS, with detection not always possible. Herein, the high resolution Quadrupole-Orbitrap liquid chromatography-tandem mass spectrometry LC-MS/MS system Q Exactive was utilized to increase the specificity. This approach was then combined for the first time with parallel reaction monitoring (PRM) during the screening procedure. The results confirmed high specificity, with the LODs of all 13 analytes being at least 25-fold lower than corresponding MRPLs as defined by WADA. Furthermore, the extraction recoveries were above 70% and the intra- and inter-day precisions were lower than 15%. This approach was successfully applied to analyze over 10,000 samples with no false positive or false-negative results, thus suggesting that Quadrupole-Orbitrap LC MS/MS when combined with PRM is an effective method for doping control analysis. PMID- 29274406 TI - Association between non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: An observational cohort study. AB - BACKGROUND & AIMS: There are limited data on the association between non alcoholic fatty liver disease (NAFLD) and subclinical coronary atherosclerosis. This study investigated the influence of NAFLD on subclinical coronary atherosclerosis as detected by coronary computed tomography angiography (CCTA) in an asymptomatic population. METHODS: A total of 5,121 consecutive asymptomatic individuals with no prior history of coronary artery disease or significant alcohol intake voluntarily underwent abdominal ultrasonography and CCTA as part of a general health examination. Fatty liver was assessed by ultrasonography examination. The fatty liver index and NAFLD fibrosis score were also calculated. Coronary atherosclerotic plaques on CCTA were evaluated. The association between NAFLD and subclinical coronary atherosclerosis was determined by logistic regression analysis. RESULTS: Of the study participants, 1,979 (38.6%) had ultrasonography-diagnosed NAFLD. After adjustment for cardiovascular risk factors, there were no statistically significant differences in the adjusted odds ratios of NAFLD for calcified plaque (1.03; 95% CI 0.89-1.20; p = 0.673) and mixed plaque (1.15; 95% CI 0.93-1.42; p = 0.214). However, adjusted odds ratios for any atherosclerotic plaque (1.18; 95% CI 1.03-1.35; p = 0.016) and non calcified plaque (1.27; 95% CI 1.08-1.48; p = 0.003) were significantly higher in NAFLD. In addition, there was a significant association of fatty liver index >=30 with non-calcified plaque (1.37; 95% CI 1.14-1.65; p = 0.001) and NAFLD fibrosis score >=-1.455 with non-calcified plaque (1.20; 95% CI 1.08-1.42; p = 0.030). CONCLUSIONS: In this large cross-sectional study of asymptomatic individuals undergoing CCTA, NAFLD was consistently associated with non-calcified plaque, suggesting an increased cardiovascular risk. LAY SUMMARY: In asymptomatic individuals, non-alcoholic fatty liver disease (NAFLD) was an independent risk factor for non-calcified plaque, which has been known as a vulnerable plaque associated with sudden and unexpected cardiac events. Therefore, appropriate medical therapy for NAFLD was required to reduce future cardiac events. PMID- 29274407 TI - Comparison of the accuracy of AASLD and LI-RADS criteria for the non-invasive diagnosis of HCC smaller than 3 cm. AB - BACKGROUND & AIMS: Non-invasive imaging is crucial for the early diagnosis and successful treatment of hepatocellular carcinoma (HCC). Terminology and criteria for interpreting and reporting imaging results must be standardized to optimize diagnosis. The aim of this study was to prospectively compare the diagnostic accuracy of the American Association for the Study of Liver Diseases (AASLD) and the 2014 version of Liver Imaging Reporting and Data System (LI-RADS(r)) criteria for the non-invasive diagnosis of small HCC, and to evaluate the diagnostic value of ancillary features used in the LI-RADS criteria. METHODS: Between April 2009 and April 2012, patients with cirrhosis and one to three 10-30 mm nodules were enrolled and underwent computed tomography (CT) and magnetic resonance (MR) imaging. The diagnostic accuracy of both the AASLD and the LI-RADS criteria were determined based on their sensitivity, specificity, positive (PPV) and negative predictive values (NPV). RESULTS: A total of 595 nodules were included (559 [341 HCC, 61%] with MR imaging and 529 [332 HCC, 63%] with CT). Overall, no (0%) LR-1 and LR-2, 44 (33%) and 47 (41%) LR-3, 50 (53%) and 54 (55%) LR-4, 244 (94%) and 222 (91%) LR-5 and 4 (67%) and 9 (82%) LR-5V were HCC on MR imaging and CT, respectively. The sensitivity, specificity, PPV/NPV of the AASLD score was 72.5%, 87.6%, 90.2%, and 66.9% for MR imaging, and 71.4%, 77.7%, 84.3%, 61.7% for CT, respectively. For the combination of LR-5V and LR-5 nodules these measures were 72.5%, 89.9%, 91.9% and 67.5% on MRI and 66.9%, 88.3%, 90.9% and 63.3% on CT, respectively. For the combination of LR-5V, LR-5 and LR-4 nodules they were 87.1%, 69.1%, 81.6% and 77.3% on MRI and 85.8%, 66%, 81% on 73.5% on CT, respectively. CONCLUSION: The 2014 version of the LI-RADS is no more accurate than the AASLD score for the non-invasive diagnosis of small HCC in high-risk patients, but it provides important and complementary information on the probability of having HCC in high-risk patients, allowing for possible changes in the management of these patients. LAY SUMMARY: The 2014 version of Liver Imaging Reporting and Data System criteria does not outperform the American Association for the Study of Liver Diseases criteria for the non-invasive diagnosis of hepatocellular carcinoma (HCC) smaller than 3 cm. Liver Imaging Reporting and Data System offers a nodule-based evaluation of the risk of HCC, allowing possible changes in management in these patients. The added value of ancillary features appears limited for the non-invasive diagnosis of small HCC. PMID- 29274409 TI - Natural disasters-impact on physicians and researchers. PMID- 29274408 TI - Modelling the elimination of hepatitis C as a public health threat in Iceland: A goal attainable by 2020. AB - BACKGROUND & AIMS: In Iceland a nationwide program has been launched offering direct-acting antiviral (DAA) treatment for everyone living with hepatitis C virus (HCV). We estimate (i) the time and treatment scale-up required to achieve the World Health Organization's HCV elimination target of an 80% reduction in incidence; and (ii) the ongoing frequency of HCV testing and harm reduction coverage among people who inject drugs (PWID) required to minimize the likelihood of future HCV outbreaks occurring. METHODS: We used a dynamic compartmental model of HCV transmission, liver disease progression and the HCV cascade of care, calibrated to reproduce the epidemic of HCV in Iceland. The model was stratified according to injecting drug use status, age and stage of engagement. Four scenarios were considered for the projections. RESULTS: The model estimated that an 80% reduction in domestic HCV incidence was achievable by 2030, 2025 or 2020 if a minimum of 55/1,000, 75/1,000 and 188/1,000 PWID were treated per year, respectively (a total of 22, 30 and 75 of the estimated 400 PWID in Iceland per year, respectively). Regardless of time frame, this required an increased number of PWID to be diagnosed to generate enough treatment demand, or a 20% scale-up of harm reduction services to complement treatment-as-prevention incidence reductions. When DAA scale-up was combined with annual antibody testing of PWID, the incidence reduction target was reached by 2024. Treatment scale-up with no other changes to current testing and harm reduction services reduced the basic reproduction number of HCV from 1.08 to 0.59, indicating that future outbreaks would be unlikely. CONCLUSION: HCV elimination in Iceland is achievable by 2020 with some additional screening of PWID. Maintaining current monitoring and harm reduction services while providing ongoing access to DAA therapy for people diagnosed with HCV would ensure that outbreaks are unlikely to occur once elimination targets have been reached. LAY SUMMARY: In Iceland, a nationwide program has been launched offering treatment for the entire population living with hepatitis C virus (HCV). A mathematical model was used to estimate the additional health system requirements to achieve the HCV elimination targets of the World Health Organization (WHO), as well as the year that this could occur. With some additional screening of people who inject drugs, Iceland could reach the WHO targets by 2020, becoming one of the first countries to achieve HCV elimination. The model estimated that once elimination targets were reached, maintaining current monitoring and harm reduction services while providing ongoing access to DAA therapy for people diagnosed with HCV would ensure that future HCV outbreaks are unlikely to occur. PMID- 29274410 TI - CD151, a novel host factor of nuclear export signaling in influenza virus infection. AB - BACKGROUND: Despite advances in our understanding of the mechanisms of influenza A virus (IAV) infection, the crucial virus-host interactions during the viral replication cycle still remain incomplete. Tetraspanin CD151 is highly expressed in the human respiratory tract, but its pathological role in IAV infection is unknown. OBJECTIVES: We sought to characterize the functional role and mechanisms of action of CD151 in IAV infection of the upper and lower respiratory tracts with H1N1 and H3N2 strains. METHODS: We used CD151-null mice in an in vivo model of IAV infection and clinical donor samples of in vitro-differentiated human nasal epithelial cells cultured at air-liquid interface. RESULTS: As compared with wild-type infected mice, CD151-null infected mice exhibited a significant reduction in virus titer and improvement in survival that is associated with pronounced host antiviral response and inflammasome activation together with accelerated lung repair. Interestingly, we show that CD151 complexes newly synthesized viral proteins with host nuclear export proteins and stabilizes microtubule complexes, which are key processes necessary for the polarized trafficking of viral progeny to the host plasma membrane for assembly. CONCLUSIONS: Our results provide new mechanistic insights into our understanding of IAV infection. We show that CD151 is a critical novel host factor of nuclear export signaling whereby the IAV nuclear export uses it to complement its own nuclear export proteins (a site not targeted by current therapy), making this regulation unique, and holds promise for the development of novel alternative/complementary strategies to reduce IAV severity. PMID- 29274405 TI - Sex-related differences in oxidative stress and neurodegeneration. AB - Oxidative stress has been implicated in a number of neurodegenerative diseases spanning various fields of research. Reactive oxygen species can be beneficial or harmful, depending on their concentration. High levels of reactive oxygen species can lead to oxidative stress, which is an imbalance between free radicals and antioxidants. Increased oxidative stress can result in cell loss. Interestingly, sex differences have been observed in oxidative stress generation, which may underlie sex differences observed in neurodegenerative disorders. An enhanced knowledge of the role of sex hormones on oxidative stress signaling and cell loss can yield valuable information, leading to sex-based mechanistic approaches to neurodegeneration. PMID- 29274411 TI - Epidemiologic patterns of in-hospital anaphylaxis in pediatric surgical patients. PMID- 29274412 TI - The Western environment reduces innate immune cytokine production in Chinese immigrants. PMID- 29274413 TI - Are we what our mothers made us? Lessons from epigenetics. PMID- 29274415 TI - The activation and function of IL-36gamma in neutrophilic inflammation in chronic rhinosinusitis. AB - BACKGROUND: Although increased accumulation of neutrophils has been noted in chronic rhinosinusitis (CRS), the function and regulation of neutrophils in CRS are largely unknown. IL-36 family cytokines may play an important role in neutrophilic inflammation. OBJECTIVE: This study sought to investigate the expression and function of IL-36 cytokines in CRS. METHODS: Quantitative RT-PCR, immunohistochemistry, immunofluorescence, and ELISA were used to investigate the expression of IL-36 cytokines and IL-36 receptor (IL-36R) in sinonasal mucosa. The expression of IL-36R on neutrophils in polyps and blood was measured by flow cytometry. Purified blood neutrophils were cultured to investigate the regulation of IL-36R expression. The cleavage of IL-36gamma was detected by Western blotting. Dispersed nasal polyp cells were treated with IL-36gamma with or without elastase inhibitor and dexamethasone. RESULTS: Neutrophil infiltration and expression of IL-36 cytokines and IL-36R were upregulated in both CRS with and without nasal polyps. IL-36gamma was the most abundant isoform and mainly expressed by epithelial cells in CRS. Neutrophils were the principal IL-36R+ cell type in polyps. IL-36R expression was almost absent in blood neutrophils and upregulated by IL-6, IL-1beta, and Dermatophagoides pteronyssinus group 1. Elastase activity was increased in polyps and degraded full-length IL-36gamma. Consistently, the levels of cleaved IL-36gamma were increased in polyps. Full length IL-36gamma promoted the production of matrix metalloproteinase 9; IL-17A; and chemokine (C-X-C motif) ligands 1, 2, and 8 from dispersed nasal polyp cells, which was abolished by elastase inhibitor. The proinflammatory effect of IL 36gamma was not suppressed by dexamethasone. CONCLUSIONS: Increased production and activation of IL-36gamma may act on neutrophils and further exaggerate neutrophilic inflammation in CRS. PMID- 29274414 TI - Low-density lipoprotein receptor-related protein 1 attenuates house dust mite induced eosinophilic airway inflammation by suppressing dendritic cell-mediated adaptive immune responses. AB - BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP-1) is a scavenger receptor that regulates adaptive immunity and inflammation. LRP-1 is not known to modulate the pathogenesis of allergic asthma. OBJECTIVE: We sought to assess whether LRP-1 expression by dendritic cells (DCs) modulates adaptive immune responses in patients with house dust mite (HDM)-induced airways disease. METHODS: LRP-1 expression on peripheral blood DCs was quantified by using flow cytometry. The role of LRP-1 in modulating HDM-induced airways disease was assessed in mice with deletion of LRP-1 in CD11c+ cells (Lrp1fl/fl; CD11c-Cre) and by adoptive transfer of HDM-pulsed CD11b+ DCs from Lrp1fl/fl; CD11c-Cre mice to wild-type (WT) mice. RESULTS: Human peripheral blood myeloid DC subsets from patients with eosinophilic asthma have lower LRP-1 expression than cells from healthy nonasthmatic subjects. Similarly, LRP-1 expression by CD11b+ lung DCs was significantly reduced in HDM-challenged WT mice. HDM-challenged Lrp1fl/fl; CD11c Cre mice have a phenotype of increased eosinophilic airway inflammation, allergic sensitization, TH2 cytokine production, and mucous cell metaplasia. The adoptive transfer of HDM-pulsed LRP-1-deficient CD11b+ DCs into WT mice generated a similar phenotype of enhanced eosinophilic inflammation and allergic sensitization. Furthermore, CD11b+ DCs in the lungs of Lrp1fl/fl; CD11c-Cre mice have an increased ability to take up HDM antigen, whereas bone marrow-derived DCs display enhanced antigen presentation capabilities. CONCLUSION: This identifies a novel role for LRP-1 as a negative regulator of DC-mediated adaptive immune responses in the setting of HDM-induced eosinophilic airway inflammation. Furthermore, the reduced LRP-1 expression by circulating myeloid DCs in patients with eosinophilic asthma suggests a possible role for LRP-1 in modulating type 2 high asthma. PMID- 29274416 TI - Dectin-1 mediates the immunoenhancement effect of the polysaccharide from Dictyophora indusiata. AB - The polysaccharides (DIP) extracted from Dictyophora indusiate has been found featuring great anti-cancer activity through enhancing organism immunity ability, and the DIP-induced macrophages activation might be mediated via TLR4/NF-kappaB signaling pathway. In this work, we make further investigation of the effect of DIP on macrophages and whether there was another pathway to regulate the immunoenhancement effect of DIP. The results showed that DIP could activate macrophages, causing the enhancement of its phagocyte activity, and then increase the secretion of IL-1beta and TNF-alpha. It could also activate the MAPK pathway and promoted the phosphorylation and nuclear translocation of NF-kappaB p65. However, these effects of DIP on macrophage was inhibited by anti-Dectin-1, indicating that besides TLR-4, Dectin-1 act as another receptor on macrophage surface which was responsible for the activation effect of DIP. In conclusion, we further illuminate the molecular mechanism involving in the immune enhancement activities on macrophages. PMID- 29274417 TI - Chemical profile of a polysaccharide from Psidium guajava leaves and it's in vivo antitussive activity. AB - Decoction of Psidium guajava leaves has been used as medication for chronic coughs and breathlessness for ages. Despite demonstration of antitussive activity, the specific molecule responsible for this remains unidentified. Herein, we report chemical profile and antitussive activity of its water extract (WE) and a polysaccharide (F1) present therein. This polysaccharide (F1), purified from WE by precipitation with ethanol and then through Cu(II)acetate, contains Ara, Gal, Rha, Glc and GalA residues, and has a molecular mass of 156 kDa. It comprises of terminal-, (1,5)- and (1,3,5)-linked Araf; (1,3)-, (1,6)- and (1,3,6)-linked Galp alongside (1,2)- and (1,2,4)-linked Rhap residues. Oligosaccharides indicating polysaccharide structure have been generated by Smith degradation and characterized. The WE fraction suppressed citric acid induced cough efforts in guinea pigs in the dose of 50 mg kg-1. Assessment of antitussive activity of fractions prepared from WE namely F1 (polysaccharide) and F2 (ethanol soluble fraction) revealed that polysaccharide is the active component. Remarkably, tested samples do not alter the specific airway smooth muscle reactivity in animals significantly. The simple extraction method, prominent activity and favorable reactions profile suggest that this macromolecule could be an antitussive drug candidate. PMID- 29274418 TI - Extraction, purification and characterization of low molecular weight Proline iminopeptidase from probiotic L. plantarum for meat tenderization. AB - Membrane bound proline iminopeptidase (PIP) from lactic acid bacteria (LAB) L. plantarum was extracted and purified using CM-sephadex, Sephadex G-100 and Q sepharose column chromatography. PIP was purified with purification fold 7.13 and 33.5% yield. SDS-PAGE and MALDI-TOF revealed it as homodimer with molecular weight of 37.9 kDa and subunit of mass 18.9 kDa. Purified enzyme exhibited maximum activity at 45 degrees C and pH 7.0. Km and Vmax of purified PIP were 65 MUM and 25.9 nm/min/ml respectively. Inhibition by PMSF confirmed it a serine protease. Metal ions and EDTA showed no effect on enzyme activity. The enzyme mainly hydrolysed Pro-4mbetaNA. The effectiveness of enzyme in purified form, membrane bound form and in combination with other enzymes to degrade collagen resulting in pharmaceutically significant collagen hydrolysates and in meat tenderization marks its industrial importance. There are very few PIPs are characterized from LAB, and therefore this study is industrially significant and brings some new knowledge into this area. PMID- 29274419 TI - An overview of the immune modulating effects of enzymatic toxins from snake venoms. AB - Snake venoms are complex mixtures of organic and inorganic compounds, including proteins belonging to the protease (serine and metalloproteinases), oxidase (L amino acid oxidases), and phospholipase (especially phospholipases A2) enzyme classes. These toxins account for the serious deleterious effects of snake envenomations, such as tissue necrosis, neurotoxicity, and hemorrhage. In addition to their toxic effects, snake venom toxins have served as important tools for investigating the mechanisms underlying envenomation and discovering new pharmacologically active compounds with immunotherapeutic potential. In this sense, the present review discusses the new findings and therapeutic perspectives in the immune modulating potential of enzymatic toxins from snake venoms belonging to the classes metalloproteinase, serine protease, L-amino acid oxidase, and phospholipase A2. PMID- 29274420 TI - Multi-analysis of chemical transformations of lignin macromolecules from waterlogged archaeological wood. AB - A large number of archaeological wooden building poles have been excavated from the Hai Menkou site (Yunnan province, China). Lignin can be transformed and altered accompanied with significant loss of carbohydrates during this process. Elucidation of chemical and structural transformations of lignin is of primary importance for understanding both the nature of degradation processes and the structure of waterlogged archaeological wood, and crucial for developing proper consolidation technology and restoring artifacts of historical and cultural value. In this study, state-of-the-art analytical techniques, including SEM, FT IR, XRD, CP-MAS 13C NMR, 2D-HSQC NMR, 31P-NMR, CRM, GPC and TG analysis, were all employed to elucidate the structural characteristics of lignin in waterlogged and reference Pinus wood. The results interpreted by NMR analysis demonstrated the depolymerization of lignin via cleavage of beta-O-4, beta-5, -OCH3 and some LCC linkages, leading to a higher amount of free phenol OH groups in the lignin from the ancient waterlogged wood as compared to that of the reference wood. Microscopically, it was found that extensive degradation of carbohydrates in cell walls was mainly occurred in secondary cell walls, while the lignin concentrations were relatively increased in CCML and S regions in the plant cell wall of the ancient wood. PMID- 29274421 TI - Immobilization of laccase on epoxy-functionalized silica and its application in biodegradation of phenolic compounds. AB - A novel method of laccase immobilization on epoxy-functionalized silica particles was developed. Laccase from Myceliophthora thermophila was covalently immobilized onto epoxy-functionalized matrix by nucleophilic attack of amino groups of laccase to epoxy groups of the support. The enzyme loading on the support was about 30 mg/g under the optimum conditions (pH 4.5, 24 h). The effect of pH, temperature and organic solvent on immobilized enzyme activity was determined and compared with those of free enzyme. In general the immobilized enzyme was found to be stabilized compared to the free enzyme. Lineweaver-Burk plots were used to calculate kinetic parameters for ABTS oxidation. KM values were 24.0 and 25.3 MUM while vmax values were 10.0 and 1.6 MUM min-1 for free and immobilized laccase, respectively. The performance of the biocatalyst was evaluated by the degradation of phenolic compounds including phenol, p-chlorophenol and catechol. The removal efficiency of catechol by immobilized laccase was about 95% after 2 h. PMID- 29274422 TI - Roles of osmolytes in protein folding and aggregation in cells and their biotechnological applications. AB - Nature has selected osmolytes to protect intracellular macromolecules exposed to denaturing conditions and stabilize proteins. Osmolytes are small naturally occurring compounds that act as chemical chaperones under changing environmental conditions and in disease states, and are present in microorganisms, animals, and plants. In the intracellular environment osmolytes naturally accumulate at high concentrations when cells/tissues are exposed to stressful conditions, which is important because protein aggregation, misfolding, and destabilization underlie the pathogenesis of several life-threatening neurodegenerative disorders. The chaperone abilities of osmolytes suggests they may be therapeutically used for the treatment of several diseases associated with protein misfolding, and their abilities to protect proteins against denaturing stresses impinges on the fundamental problem of protein stabilization, which plagues the pharmaceutical industry, biotechnologists, and researchers. We hope that this review will encourage further research in this area and catalyze increased collaboration at the interface of chemistry and biology to decipher the mechanisms and roles of protein folding, misfolding and aggregation in the fields of health and disease. PMID- 29274423 TI - Enzymatic characterization and functional analysis of EcChi3C from ridgetail white prawn Exopalaemon carinicauda. AB - Chitinase belongs to the glycosyl hydrolases family 18 and plays key role in the development and pathogen resistance of crustaceans. In this study, the enzymatic characterization of chitinase 3C (EcChi3C) of Exopalaemon carinicauda was analyzed. In addition, we analyzed the expression profiles of EcChi3C at different tissues and different molting stages. In the all tested tissues, it was predominantly expressed in hepatopancreas, and then stomach, but poor in other tissues. In all tested molting periods, it was mainly expressed in intermolt and molting stages, but poor in other stages. The results of molting, mortality and the uropod ultrastructure of prawns after being injected with EcChi3C dsRNA were in accordance with those of the control group. In addition, there is no difference for endopodite morphology between the survival and dead individuals in experimental group. After being challenged with bacteria, the expression of EcChi3C was up-regulated significantly at 12 h and followed with a comeback at 96 h. These results suggest that EcChi3C is an important immune related gene but not a necessary gene in the molting process of E. carinicauda. PMID- 29274424 TI - Biochemical and biophysical characterization of novel GH10 xylanase prospected from a sugar cane bagasse compost-derived microbial consortia. AB - Environmental issues are promoting the development of innovative technologies for the production of renewable energy and "green products" from plant biomass residues. These technologies rely on the conversion of the plant cell wall (PCW) polysaccharides into simple sugars, which involve synergistic activities of different PCW degrading enzymes, including xylanases; these are widely applied in food and feed sectors, paper and textile industries, among others. We cloned, expressed and biochemically characterized a novel xylanase (Xyn10) from the GH10 identified in a metatranscriptome of compost-derived microbial consortia and determined its low-resolution SAXS molecular envelope in solution. Our results reveal that Xyn10 is a monomeric flexible globular enzyme, with high stability with a broad pH range from 4 to 10 and optimal activity conditions at pH 7 and 40 degrees C. Only 10% of activity loss was observed after the enzyme was incubated for 30 h at 40 degrees C with a pH ranging from 5 to 10. Moreover, Xyn10 maintained 100% of its initial activity after incubation for 120 h at 40 degrees C and 51% after incubation for 24 h at 50 degrees C (pH = 7.0). Xyn10 shows endocatalytic activity towards xylan and arabinoxylan, liberating xylose, xylobiose, 1,2-alpha-d-methylglucuronic acid decorated xylotriose, and 1,3-alpha l-arabinofuranose decorated xylobiose and xylotriose oligosaccharides. PMID- 29274425 TI - Chemical characterization and wound healing property of a beta-D-glucan from edible mushroom Piptoporus betulinus. AB - A water-soluble beta-D-glucan was obtained from fruiting bodies of Piptoporus betulinus, by hot aqueous extraction followed by freeze-thawing procedure and dialysis. Its molar mass distribution and conformational behavior in solution was assessed by size-exclusion chromatography coupled with multiangle laser light scattering, showing a polysaccharide with an average molecular weight of 2.5 * 105 Da with a random coil conformation for molecular weights below 1 * 106 Da. Typical signals of beta-(1 -> 3)-linkages were observed in NMR spectrum (delta 102.7/4.76; 102.8/4.74; 102.9/4.52; and delta 85.1/3.78; 85.0/3.77) and also signals of O-6 substitution at delta 69.2/4.22 and 69.2/3.87. The analysis of partially O-methylated alditol acetates corroborates the NMR results, indicating the presence of a beta-D-glucan with a main chain (1 -> 3)-linked, substituted at O-6 by single-units of glucose. The beta-D-glucan showed no toxicity on human colon carcinoma cell line (Caco-2) up to 1000 MUg mL-1 and promoted cell migration on in vitro scratch assay, demonstrating a potential wound healing capacity. PMID- 29274426 TI - Anti-digestion properties of amylosucrase modified waxy corn starch. AB - Amylosucrase is a valuable enzymatic tool for the preparation of resistant starch (RS). This study investigated the morphology, thermal properties and molecular structure of the RS components resulting from the digestion of amylosucrase modified starches (MSs). Morphology of starch samples suggests that the surface of MSs is partially attacked by the digestion enzymes. Besides, the peak melting temperature of RSs shows a considerable increase compared with that of the corresponding MSs. Branch chain length distributions data reveals that the long branch chains of MSs are prone to being hydrolyzed, and the branch chains with degree polymerization of 22-32 are the largest populations among the RS components. Moreover, the RS content in MSs decreases significantly after thermal treatment. Overall results demonstrates that the existence of crystalline structure with thermostable double helices is responsible for the anti-digestion properties of modified starches. PMID- 29274427 TI - Purification, in vitro antioxidant and in vivo anti-aging activities of soluble polysaccharides by enzyme-assisted extraction from Agaricus bisporus. AB - In present study, the soluble polysaccharides by enzyme-assisted extraction from Agaricus bisporus (EnAPS) and its purified fractions of EnAPS-1, -2 and -3 were successfully obtained, and the antioxidant activities and anti-aging effects were investigated. The in vitro antioxidant assay demonstrated that EnAPS-2 had superior scavenging activities on DPPH and hydroxyl radicals, chelating activities of Fe2+ and reducing power. The in vivo animal experiments showed that both EnAPS and its purifies fractions had potential anti-aging effects against the d-galctose-induced aging diseases on liver, kidney, brain and skin, possibly by increasing the antioxidant enzymes, reducing the lipid peroxidation, improving the organ functions and remitting the lipid metabolism. The conclusions demonstrated that the polysaccharides by A. bisporus might be suitable for applying functional foods and natural drugs in preventing and delaying the aging and its complications. PMID- 29274428 TI - Structural characterization of a polysaccharide from Sargassum henslowianum, and its immunomodulatory effect on gastric cancer rat. AB - A complicated sulfated fucoidan, SHPPB2, was purified from Sargassum henslowianum by DEAE-cellulose 52 and Sephacryl S-300 column chromatography. Via chemical and spectral method, SHPPB2 was found to contain mannose, glucuronic acid, galactose, xylose, and fucose, in a ratio of 17.4: 13.5: 10.5: 16.8: 41.8, as well as 21.4% of sulfate. The methylation analysis demonstrated terminal, 3-, 4-, 2, 3-, and 3, 4- linked fucose, 2-, 2, 3-, 2, 4-, and 2, 4, 6- linked mannose, terminal, 4-, 6 , 2, 4-, 3, 4-, and 3, 6- linked galactose, terminal and 4- linked xylose, and 4- linked glucuronic acid. In addition, the sulfate groups were substituted on the C 2, C-3 or C-4 of 3- and 4- linked fucose, on the C-4 or C-6 of 2- linked mannose, and on C-2 or C-3 of 4- and 6- linked galactose. With the treatment of SHPPB2 in the N-methyl-N'-nitro-nitrosoguanidine (MNNG) induced gastric cancer rats, it was observed with an increased body weight, and improved immune organ indices. Furthermore, SHPPB2 could significantly promote splenocyte proliferation induced by ConA or LPS in gastric cancer rats, and improve anti-inflammatory cytokines (IL-2, IL-4, and IL-10) secretion, but reduce pro-inflammatory cytokines (IL-6 and TNF-alpha). Taken together, it suggested that SHPPB2 could improve immune function in gastric cancer rats. Thus, it could be explored as a potential immuno therapy for gastric cancer treatment. PMID- 29274429 TI - Retinoic acid synthesis by NG2 expressing cells promotes a permissive environment for axonal outgrowth. AB - Stimulation of retinoic acid (RA) mediated signalling pathways following neural injury leads to regeneration in the adult nervous system and numerous studies have shown that the specific activation of the retinoic acid receptor beta (RARbeta) is required for this process. Here we identify a novel mechanism by which neuronal RARbeta activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Using an established rodent model of RARbeta induced axonal regeneration, we show that neuronal RARbeta activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells). These release RA in association with exosomes providing a permissive substrate to neurite outgrowth. Conversely, deletion of Raldh2 in the NG2+ cells in our in vivo regeneration model is sufficient to compromise axonal outgrowth. This hitherto unidentified RA paracrine signalling is required for axonal/neurite outgrowth and is initiated by the activation of neuronal RARbeta signalling. PMID- 29274430 TI - Divergent brain changes in two audiogenic rat strains: A voxel-based morphometry and diffusion tensor imaging comparison of the genetically epilepsy prone rat (GEPR-3) and the Wistar Audiogenic Rat (WAR). AB - Acoustically evoked seizures (e.g., audiogenic seizures or AGS) are common in models of inherited epilepsy and occur in a variety of species including rat, mouse, and hamster. Two models that have been particularly well studied are the genetically epilepsy prone rat (GEPR-3) and the Wistar Audiogenic Rat (WAR) strains. Acute and repeated AGS, as well as comorbid conditions, displays a close phenotypic overlap in these models. Whether these similarities arise from convergent or divergent structural changes in the brain remains unknown. Here, we examined the brain structure of Sprague Dawley (SD) and Wistar (WIS) rats, and quantified changes in the GEPR-3 and WAR, respectively. Brains from adult, male rats of each strain (n=8-10 per group) were collected, fixed, and embedded in agar and imaged using a 7 tesla Bruker MRI. Post-acquisition analysis included voxel-based morphometry (VBM), diffusion tensor imaging (DTI), and manual volumetric tracing. In the VBM analysis, GEPR-3 displayed volumetric changes in brainstem structures known to be engaged by AGS (e.g., superior and inferior colliculus, periaqueductal grey) and in forebrain structures (e.g., striatum, septum, nucleus accumbens). WAR displayed volumetric changes in superior colliculus, and a broader set of limbic regions (e.g., hippocampus, amygdala/piriform cortex). The only area of significant overlap in the two strains was the midline cerebellum: both GEPR-3 and WAR showed decreased volume compared to their control strains. In the DTI analysis, GEPR-3 displayed decreased fractional anisotropy (FA) in the corpus callosum, posterior commissure and commissure of the inferior colliculus (IC). WAR displayed increased FA only in the commissure of IC. These data provide a biological basis for further comparative and mechanistic studies in the GEPR-3 and WAR models, as well as provide additional insight into commonalities in the pathways underlying AGS susceptibility and behavioral comorbidity. PMID- 29274431 TI - Trajectory of inflammatory and microglial activation markers in the postnatal rabbit brain following intrauterine endotoxin exposure. AB - BACKGROUND: Maternal infection is a risk factor for periventricular leukomalacia and cerebral palsy (CP) in neonates. We have previously demonstrated hypomyelination and motor deficits in newborn rabbits, as seen in patients with cerebral palsy, following maternal intrauterine endotoxin administration. This was associated with increased microglial activation, primarily involving the periventricular region (PVR). In this study we hypothesized that maternal intrauterine inflammation leads to a pro-inflammatory environment in the PVR that is associated with microglial activation in the first 2 postnatal weeks. METHODS: Timed pregnant New Zealand white rabbits underwent laparotomy on gestational day 28 (G28). They were randomly divided to receive lipopolysaccharide (LPS; 20MUg/kg in 1mL saline) (Endotoxin group) or saline (1mL) (control saline, CS group), administrated along the wall of the uterus. The PVR from the CS and Endotoxin kits were harvested at G29 (1day post-injury), postnatal day1 (PND1, 3day post injury) and PND5 (7days post-injury) for real-time PCR, ELISA and immunohistochemistry. Kits from CS and Endotoxin groups underwent longitudinal MicroPET imaging, with [11C]PK11195, a tracer for microglial activation. RESULTS: We found that intrauterine endotoxin exposure resulted in pro-inflammatory microglial activation in the PVR of rabbits in the first postnatal week. This was evidenced by increased TSPO (translocator protein) expression co-localized with microglia/macrophages in the PVR, and changes in the microglial morphology (ameboid soma and retracted processes). In addition, CD11b level significantly increased with a concomitant decline in the CD45 level in the PVR at G29 and PND1. There was a significant elevation of pro-inflammatory cytokines and iNOS, and decreased anti-inflammatory markers in the Endotoxin kits at G29, PND1 and PND5. Increased [11C]PK11195 binding to the TSPO measured in vivo by PET imaging in the brain of Endotoxin kits was present up to PND14-17. CONCLUSIONS: Our results indicate that a robust pro-inflammatory microglial phenotype/brain milieu commenced within 24h after LPS exposure and persisted through PND5 and in vivo TSPO binding was found at PND14-17. This suggests that there may be a window of opportunity to treat after birth. Therapies aimed at inducing an anti inflammatory phenotype in microglia might promote recovery in maternal inflammation induced neonatal brain injury. PMID- 29274433 TI - Toxicity reduction of ochratoxin A by lactic acid bacteria. AB - Ochratoxin A (OTA) is a mycotoxin produced by the metabolism of fungus belonging to the genus Aspergillus and Penicillium. In this paper we report, the capacity of different cultures of lactic acid bacteria (LAB) to degrade OTA present in MRS broth at both pH 3.5 and 6.5. A study of OTA reduction during gastrointestinal digestion carried out with the LAB was also performed. Taking into account the two reduction mechanisms of OTA studied in this work as the enzymatic one and the adsorption on the cell wall, as well as at pH 3.5 and 6.5 the reduction values of OTA were in a range of 30-99%, being the strains with greater reduction (97% and 95%) Lb. rhamnosus CECT 278T and Lb. plantarum CECT 749 respectively. In the experiments carried out digesting the OTA in MRS medium with LAB, the highest bioaccessibility reduction was observed by the strain of Lb. johnsonii CECT 289, showing a mean reduction around all the gastrointestinal digestion process of 97.4%. The mass spectrometry associated to the linear ion trap method identified ochratoxin alpha (OTalpha) m/z = 256.1 and phenylalanine (Phe) m/z = 166.1 as the major metabolites of OTA degradation in LAB cultures. PMID- 29274432 TI - A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. AB - DEPDC5 is a newly identified epilepsy-related gene implicated in focal epilepsy, brain malformations, and Sudden Unexplained Death in Epilepsy (SUDEP). In vitro, DEPDC5 negatively regulates amino acid sensing by the mTOR complex 1 (mTORC1) pathway, but the role of DEPDC5 in neurodevelopment and epilepsy has not been described. No animal model of DEPDC5-related epilepsy has recapitulated the neurological phenotypes seen in patients, and germline knockout rodent models are embryonic lethal. Here, we establish a neuron-specific Depdc5 conditional knockout mouse by cre-recombination under the Synapsin1 promotor. Depdc5flox/flox Syn1Cre (Depdc5cc+) mice survive to adulthood with a progressive neurologic phenotype that includes motor abnormalities (i.e., hind limb clasping) and reduced survival compared to littermate control mice. Depdc5cc+ mice have larger brains with increased cortical neuron size and dysplastic neurons throughout the cortex, comparable to the abnormal neurons seen in human focal cortical dysplasia specimens. Depdc5 results in constitutive mTORC1 hyperactivation exclusively in neurons as measured by the increased phosphorylation of the downstream ribosomal protein S6. Despite a lack of increased mTORC1 signaling within astrocytes, Depdc5cc+ brains show reactive astrogliosis. We observed two Depdc5cc+ mice to have spontaneous seizures, including a terminal seizure. We demonstrate that as a group Depdc5cc+ mice have lowered seizure thresholds, as evidenced by decreased latency to seizures after chemoconvulsant injection and increased mortality from pentylenetetrazole-induced seizures. In summary, our neuron-specific Depdc5 knockout mouse model recapitulates clinical, pathological, and biochemical features of human DEPDC5-related epilepsy and brain malformations. We thereby present an important model in which to study targeted therapeutic strategies for DEPDC5-related conditions. PMID- 29274434 TI - Gypenosides protect retinal pigment epithelium cells from oxidative stress. AB - Oxidative stress plays a critical role in the pathogenesis of retinal degeneration. Gypenosides are the major functional components isolated from Gynostemma pentaphyllum. They have been shown to protect against oxidative stress and inflammation and have also demonstrated a protective effect on experimental optic neuritis. In order to determine the protective properties of gypenosides against oxidative stress in human retinal pigment epithelium (RPE) cells, ARPE-19 cells were treated with H2O2 or H2O2 plus gypenosides for 24 h. ARPE-19 cells co treated with gypenosides had significantly increased cell viability and decreased cell death rate when compared to cells treated with H2O2 alone. The level of GSH, the activities of SOD and catalase, and the expression of NRF2 and antioxidant genes were notably decreased, while there were marked increases in ROS, MDA and pro-inflammatory cytokines in ARPE-19 cells exposed to H2O2; co-treatment with gypenosides significantly counteract these changes. Our study suggests that gypenosides protect RPE cells from oxidative damage and offer therapeutic potential for the treatment of retinal degeneration. PMID- 29274435 TI - Dietary cumulative acute risk assessment of organophosphorus, carbamates and pyrethroids insecticides for the Brazilian population. AB - Cumulative acute dietary risk assessments of organophosphorus (OPs), carbamates (CBs) and pyrethroids (PYs) were conducted for the Brazilian population. Residue data for 30786 samples of 30 foods were obtained from two national monitoring programs and one University laboratory, and consumption data from a national survey conducted among persons 10 years or older. Acephate and methamidophos were used as index compounds (IC) for OPs, oxamyl for CBs and deltamethrin for PYs. Exposures were estimated using the Monte Carlo Risk Assessment (MCRA 8.2) software. Orange and orange juice (mainly containing methidathion), pasta and salted bread (mainly pirimiphos-methyl) contributed most to the OPs intake. Rice accounted for 80% of the CBs intake (teenagers), mainly due to aldicarb. Pasta, salted bread and beans contributed most to the PYs intake (9-14%), mainly due to bifenthrin. The intake did not exceed the ARfD at the 99.9th percentile for OPs, CBs and PYs, and the risks from the exposure were not considered of health concern. When food consumption data become available for children under age 10, studies in the cumulative exposure should be conducted, as this age group is the most critical among the population, mainly due to their higher food consumption per kg body weight. PMID- 29274436 TI - Bacillus spore-based oral carriers loading curcumin for the therapy of colon cancer. AB - Oral drug delivery has attracted substantial attention due to its advantages over other administration routes. Bacillus spores, as oral probiotic agents, are applied widely. In this paper, a novel Bacillus spore-based oral colon targeted carrier loading curcumin was developed for colon cancer treatment. Curcumin was linked covalently with the outer coat of Bacillus spore and folate, respectively (SPORE-CUR-FA). Bacillus spores are capable of delivering drugs to the colon area through gastric barrier, taking the advantage of its tolerance to the harsh conditions and disintegration of the outer coat of spores after germination in the colon. The drug release in vitro and in vivo of SPORE-CUR-FA was investigated. Results showed that SPORE-CUR-FA had the characteristics of colon targeted drug release. Pharmacokinetic studies confirmed that Bacillus spore based carriers could efficiently improve the oral bioavailability of curcumin. In vitro and in vivo anti-tumor studies showed that SPORE-CUR-FA had substantial ability for inhibiting colon cancer cells. These findings suggest that this Bacillus spore-based oral drug delivery system has a great potential for the treatment of colon cancer. PMID- 29274437 TI - Convection enhanced delivery of chemotherapeutic drugs into brain tumour. AB - Convection enhanced delivery (CED) of chemotherapeutic drugs can successfully bypass the blood-brain barrier (BBB). However, the treatment efficacy is significantly variable in clinic owing to the absence of proper drugs and the lack of understanding on the local drug transport. In this study, mathematical modelling is employed to investigate the suitability of six chemotherapeutic drugs from the perspective of intratumoural transport, including fluorouracil, carmustine, cisplatin, methotrexate, doxorubicin and paclitaxel. The convection/diffusion/reaction model coupled with Darcy's law is applied to a 3-D realistic brain tumour model that is extracted from magnetic resonance (MR) images. The modelling demonstrates the advantages of CED in enhancing the convective flow of interstitial fluid and reducing the drug concentration dilution caused by the fluid loss from blood stream in the tumour region around the infusion site. The delivery outcomes of the drug in CED treatments are strongly dependent on its physicochemical properties. Convection is more effective in determining the transport of paclitaxel and methotrexate in brain tumour. Paclitaxel exhibits its superiority in drug penetration and accumulation, resulting in the largest effective delivery volume as compared to the other studied drugs. Nanocarrier and diagnostic ultrasound are able to enhance the drug penetration for achieving improved delivery outcomes. Results obtained in this study can serve as a guide for optimising CED treatment regimens. PMID- 29274438 TI - The treatment of spinal cord injury in rats using bone marrow-derived neural-like cells induced by cerebrospinal fluid. AB - This study aimed to evaluate the effect of bone mesenchymal stem cells (BMSCs) and BMSC neural-like cells (BMSC-Ns) on the spinal cord injury (SCI) in the rat model of SCI. BMSC-Ns were prepared from the third passage of BMSCs by induction of healthy cerebrospinal fluid (CSF) of an adult human. The SCI rat model was established through a surgical procedure, and after 7 days the rats were randomly divided into 3 (A, B and C) groups. Groups A (BMSC-Ns) and B (BMSCs) were treated with 1 * 106/20 MUl cells, while group C (saline) was treated with saline, all via intracerebroventricular injection. After transplantation, the BBB score of group A was significantly higher than that of group B, which in turn was significantly higher than that of group C (P < .05). The levels of Bdnf, Ngf, Ntf3 were statistically significantly higher in group A than those in groups B and C (P < .05). The levels of 5-HT, NA, Ach, DA, GABA in group A were significantly higher than those in groups B and C, whereas the level of Glu was significantly lower in group A than that in groups B and C (P < .05). The histopathological data showed remarkably less necrosis of the spinal cord in group A, compared to that in groups B and C. Transplanting BMSC-Ns or BMSCs into the lateral ventricles improved the neurological function of rats with SCI. Moreover, BMSC-Ns were significantly more effective than BMSCs, which provides a possible approach for the treatment of SCI. PMID- 29274439 TI - Visualization of Arc promoter-driven neuronal activity by magnetic resonance imaging. AB - Visualization of direct neuronal activity to understand brain function is one of the most important challenges in neuroscience. We have previously demonstrated that in vivo and in vitro gene expression of the ferritin reporter system could be detected by magnetic resonance imaging (MRI). In addition, increased neuronal activity induces Arc, an immediate early gene, and insertion of a destabilized fluorescent reporter dVenus under Arc promoter control has been used for monitoring neuronal activities in the brain by optical imaging. In this study, to visualize Arc promoter-driven neuronal activities directly, we generated transgenic mice and cell lines that express a destabilized fusion reporter ferritin-mKate2 under Arc promoter control. When transgenic mice and cell lines were treated with pilocarpine, a non-selective muscarinic agonist, an increase in T2-weighted image signal was successfully found in neuronal cells. There was a difference in peak time between MRI and fluorescence imaging, which might result from the binding process of iron with ferritin. Visualization of Arc promoter driven neuronal activity is essential to understand neural mechanisms underlying cognitive processes and complex behaviors, and could be a useful tool for therapeutic approaches in the brain by MRI. PMID- 29274440 TI - Cortical frequency-specific plasticity is independently induced by intracortical circuitry. AB - Auditory learning induces frequency-specific plasticity in the auditory cortex. Both the auditory cortex and thalamus are involved in the cortical plasticity; however, the precise role of the intracortical circuity remains unclear until the contributions of the thalamocortical inputs are controlled. Here, we induced cortical plasticity by local activation of the primary auditory cortex (AI) via intracortical electrical stimulation (ES) in C57 mice and found a similar pattern of cortical plasticity was induced by ESAI when the auditory thalamus was inactivated or remained active during the ESAI. The best frequencies (BFs) of the recorded cortical neurons shifted towards the BFs of the electrically stimulated ones. In addition, the BF shifts were linearly correlated to the BF differences between the recorded and stimulated cortical neurons. More importantly, the ratio of the linear function with thalamic inactivation was nearly the same as the ratio of the linear function in the control condition. Our data show that cortical frequency-specific plasticity was induced by ESAI with or without the thalamic inactivation; thus intracortical circuitry can be independently responsible for cortical frequency-specific plasticity. PMID- 29274441 TI - Intraocular pressure lowering effect and structure-activity relationship of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds in ocular normotensive rats: Insight on possible link with hypotensive activity. AB - In an effort to find new ocular hypotensive drug candidates, a total of 27 condensed benzimidazoles based compounds were screened. This study was done in normotensive rats and rebound tonometry was used to estimate IOP. All compounds were topically applied as a single drop, unilaterally, at 3 different concentrations (0.1%, 0.2% and 0.4%). The contralateral eye was instilled with vehicle and served as control. The IOP reduction was measured up to 6h. It was observed that with a single topical instillation, compounds RU 551, RU 555, RU839 (pyrimido[1,2-a]benzimidazole derivatives), and RU 615 (imidazo[1,2 a]benzimidazole derivative) showed significant IOP lowering activities in ocular normotensive rats. All other compounds showed none, weak and inconsistent IOP lowering effect. The relationship between ability of IOP lowering and hypotensive activities was studied. According to the pharmacophore analysis, the class of pyrimido[1,2-a]benzimidazole is more promising than the class of imidazo[1,2 a]benzimidazole as a source of compounds with high IOP lowering activity. Pharmacophore analysis also showed that the critical features of high IOP lowering activity are methoxyphenyl and [phenyl]alkyl fragments, and non conjugated six-membered heterocyclic ring. PMID- 29274442 TI - The effect of 2-hydroxypropyl-beta-cyclodextrin on the intestinal permeation through mucus. AB - In addition to its important role in preventing the interaction of toxic agents with the intestinal lining, the intestinal mucus layer can impede the permeation of drugs. The purpose of this study was to evaluate whether the presence of HP beta-CD in the intraluminal environment could influence the permeation of drugs through a layer of mucus. To this end, a new artificial membrane insert system incorporating a fixed mucus layer was developed to monitor the permeation of methylparaben (log P=1.96) and heptylparaben (log P=4.83). While the transport of methylparaben remained unaffected by the mucus layer, the transport of heptylparaben was significantly impeded by the mucus layer. In presence of relatively low concentrations of HP-beta-CD, however, this negative effect of mucus on the permeation of heptylparaben disappeared. Importantly, the impact of the mucus layer was found to depend on the composition of the solvent system used. The colloidal structures present in simulated intestinal media were able to neutralize the impeding effect of mucus on heptylparaben permeation observed when using simple phosphate buffers. These findings advocate the use of biorelevant media when studying the impact of the mucus layer on drug permeation. PMID- 29274443 TI - Gynecologic Bleeding Complications in Postmenarchal Female Adolescents Receiving Antithrombotic Medications. AB - STUDY OBJECTIVE: The prevalence, clinical features, and management of gynecologic bleeding complications and health care provider awareness of these in postmenarchal adolescents receiving antithrombotic medications has rarely been addressed in the literature. We sought to address these issues in a review of our experience in a pediatric tertiary care center. DESIGN, SETTING, AND PARTICIPANTS: A retrospective chart review was conducted with institutional review board approval from 2004 to 2014, on eligible postmenarchal adolescents receiving antithrombotic medications. Descriptive statistics were used. RESULTS: Sixty-eight adolescents received antithrombotic medications (thromboembolism in 67 of 68; 99%; cardiac causes in 4 of 68; 6%), which included enoxaparin, warfarin, unfractionated heparin, alteplase, fondaparinux, and aspirin. Heavy menstrual bleeding (HMB) screening questions were documented by treating hematologists in 52 of 68 patients (76%; 95% confidence interval, 65%-86%). Adolescent gynecology consult was requested for 25 of 68 patients (37%). After antithrombotic medications were started, 13 of 68 (19%) developed HMB. Anemia was found in 43% of patients tested (18 of 42); 50% (9 of 18) and 78% patients (14 of 18) received packed red blood cell transfusion and iron therapy, respectively. Five patients (5 of 68; 7%) developed hemorrhagic ovarian cysts, 40% (2 of 5) were treated with surgery, 16% (1 of 5) received transfusions, and 100% (5 of 5) received or continued progesterone-only therapy with no recurrence. CONCLUSION: Adolescents receiving antithrombotic medications are at risk of developing gynecologic bleeding complications, which can result in anemia, hospitalization, transfusions, or surgery. Provider awareness/screening of HMB as a bleeding complication of antithrombotic medications is less than optimal. Future prospective studies in adolescents receiving antithrombotic medications are needed to better evaluate provider awareness and the prevalence of gynecologic bleeding complications, which can lead to effective management. PMID- 29274444 TI - Rare Giant Intradural Extramedullary Ependymoma. AB - A 23-year-old female was admitted to our hospital because she had suffered from back pain for 3 years and paralysis of both lower limbs for 10 days. Neurologic examination showed sensory disturbance and complete paralysis in bilateral lower extremities with negative Babinski sign. Contrast-enhanced magnetic resonance imaging showed there was an enhanced intradural lesion between T2 and T12, which pressed the spinal cord. The lesion was resected completely by laminectomy approach, and the tumor was totally intradural extramedullary. Postoperative pathologic findings confirmed that the lesion was ependymoma. Preoperative symptoms recovered slightly after surgery. The back pain disappeared and muscle strength of both lower extremities returned to level 4 one year after the operation. Meanwhile, her sensory function in both legs improved but was not completely normal. Intradural extramedullary primary ependymomas are rare. To our knowledge, this case is the largest one ever reported in the literature. PMID- 29274445 TI - Acute Effects of Electrical Stimulation of the Bed Nucleus of the Stria Terminalis/Internal Capsule in Obsessive-Compulsive Disorder. AB - BACKGROUND: Deep brain stimulation (DBS) has been introduced as a treatment option for treatment-resistant obsessive-compulsive disorder (OCD). However, the optimal stimulation target and the corresponding stimulation settings remain unclear. Furthermore, there is limited knowledge about the acute effects of DBS. METHODS: In 3 patients with treatment-resistant OCD, DBS electrodes were implanted in the bed nucleus of the stria terminalis (BNST)/internal capsule (IC). On the next day, different electrode pairs (BNST only, IC only, and BNST/IC) were stimulated at different voltages (1, 2, and 3.5 V) for 5 minutes each. Afterwards, patients rated their perceived OCD symptoms and various emotional states on corresponding visual analog scales. RESULTS: Across locations, low voltage stimulation (1 and 2 V) was associated with reduction of OCD symptoms (i.e., anxiety and tension), in particular when the IC was stimulated. High voltage stimulation (3.5 V), in particular when BNST was involved, led to less reduction of OCD symptoms. Moreover, 3.5-V stimulation of the BNST (BNST only and BNST/IC) induced higher levels of anxiety, tension, and discomfort. Subjects also reported an increase in vegetative sensations. CONCLUSIONS: In summary, we demonstrate that both stimulation site and voltage settings show sweet spots (2 V at IC or BNST/IC) at which OCD symptom severity decreased while negative effects were minimal. Stimulation of IC fibers might be relevant both for acute and chronic effects. Whether acute effects are useful for outcome prediction remains to be shown in future studies. PMID- 29274446 TI - Progressively Enlarging Cerebellar Hematoma Concurrent with T-DM1 Treatment. AB - BACKGROUND: Trastuzumab emtansine, an antibody-drug conjugate commonly abbreviated as T-DM1, is accepted as effective therapy for trastuzumab-resistant metastatic HER2-positive breast cancer. T-DM1 significantly increases progression free and overall survival when compared with lapatinib plus capecitabine in patients with HER2-positive breast cancer previously treated with trastuzumab and a taxane. Among the common side effects related to T-DM1, thrombocytopenia and mucosal hemorrhage are seen, although they are infrequently judged to be clinically significant. Intracranial hemorrhages are extremely rare, and only 3 cases of hematomas have been reported in association with T-DM1 and remote radiotherapy, 2 of them with progressive enlargement. OBJECTIVE: Herein we describe a patient who presented with a cerebellar hematoma that progressively enlarged over 8 months during treatment with T-DM1 and only a few months after whole-brain radiation therapy plus a stereotactic radiosurgery boost for a HER2 positive breast cancer cerebellar metastasis. The pathology of the hematoma was similar to that in previous cases and suggested a unique pathophysiology related to an interaction between T-DMI and radiation therapy. CONCLUSIONS: A progressively enlarging intraparenchymal hematoma can be seen just a few months after delivery of radiation therapy for a metastatic brain lesion in HER2 positive breast cancer patients who are receiving T-DM1. In such patients, even a small focus of hemorrhage on magnetic resonance images should prompt close follow up with serial imaging. PMID- 29274447 TI - Risk Factor Analysis for Poor Outcomes in Supraorbital Keyhole Aneurysm Clipping for Ruptured Anterior Circulation Aneurysms. AB - BACKGROUND: The transciliary keyhole approach has been actively employed for unruptured intracranial aneurysms in many institutions, although applying this technique to ruptured aneurysms remains controversial. We investigated risk factors related to poor surgical outcomes in ruptured aneurysms and attempted to clarify the differences between conventional craniotomy and keyhole surgery. METHODS: A retrospective review was performed at a single institution of medical records and images from surgeries of 188 patients who underwent keyhole surgery for ruptured anterior circulation aneurysms between July 2007 and February 2015. RESULTS: The study included 116 (62%) female and 72 (38%) male patients; age range was 23-86 years. Preoperative clinical grades were good in almost all patients except for a few patients with poor clinical grades. Mean aneurysm size was 5.5 mm, and the most common aneurysm location was the anterior communicating artery (n = 82). Most patients (n = 158; 91.5%) showed good clinical outcomes. Univariate analysis of risk factors associated with poor-grade outcomes after 3 months was performed. Hunt and Hess grade (odds ratio [OR] 13.50, P < 0.0001), World Federation of Neurosurgical Societies scale (OR 7.69, P < 0.0001), aneurysm size (OR 1.21, P = 0.019), and vasospasm (OR 6.43, P = 0.0003) were statistically significant, whereas Fisher grade, skin-to-skin time (operation time), rebleeding, and ventricle puncture were not statistically significant. CONCLUSIONS: Because incidence of poor surgical outcome of keyhole surgery is not different from known conventional craniotomy, this approach is an acceptable treatment option in a good-grade ruptured anterior circulation aneurysm. PMID- 29274448 TI - Congenital Absence of the Posterior Element of C1, C2, and C3 Along with Bilateral Absence of C4 Pedicles: Case Report and Review of the Literature. AB - BACKGROUND: Abnormalities of the posterior arch of vertebrae are rare conditions that may incidentally be found on neck radiographs. We report a case and present a comprehensive review of the literature. CASE DESCRIPTION: A 10-year-old boy presented with intermittent paresthesia in the lower extremities, mild neck pain, and episodes of drop attacks following neck flexion. Radiologic investigations depicted a complete absence of the posterior element of C1, C2, and C3 along with bilateral absence of C4 pedicles. CONCLUSIONS: The diagnosis of posterior arch abnormalities is of high-level of importance because of resultant neurologic defects. To the best of our knowledge, no case of this type has been reported in literature thus far. PMID- 29274449 TI - Proton Magnetic Resonance Spectroscopy Detection of High Lipid Levels and Low Apparent Diffusion Coefficient Is Characteristic of Germinomas. AB - BACKGROUND: The differentiation of germinoma from other tumors by conventional magnetic resonance imaging (MRI) can be very difficult. The purpose of our study was to determine whether diffusion-weighted imaging (DWI) and single-voxel proton magnetic resonance spectroscopy (1H-MRS) could provide additional useful information for a definitive diagnosis of germinomas. METHODS: Our hospital's Institutional Review Board approved this retrospective study. We reviewed imaging studies of 26 patients with histologically confirmed germinomas who were treated at our hospital between 2003 and 2016. We also studied 25 patients with pineal tumors, which included 14 nongerminomatous germ cell tumors (NGGCTs), 9 pineal parenchymal tumors (PPTs; including 3 pineocytomas, 4 PPTs of intermediate differentiation [PPTID], and 2 pineoblastomas) and 2 meningiomas. Patients underwent conventional MRI and advanced MRI, including DWI and/or 1H-MRS. RESULTS: The germinoma group comprised 24 males and 2 females, ranging in age from 9.1 to 37.7 years (average, 17.5 years; median, 14.6 years). The NGGCT group was all male, ranging in age from 5.4 to 51.9 years (mean, 20.1 years; median, 14.1 years). In the PPT group, patient age ranged from 4.5 to 64.7 years (mean, 29.9 years; median, 30.7 years). High lipid peaks detected on 1H-MRS were observed in 16 of 16 examined germinomas. In contrast, in the pineocytomas, PPTID, pineoblastomas, and meningiomas, lipid peaks were small or absent in 10 of 10 examined tumors. In the NGGCT group, high lipid peaks on 1H-MRS were observed in 11 of 12 examined tumors; however, no tumors showed high intensity on DWI, with all low to high mixed intensity. ADC was statistically lower in the germinoma group compared with the NGGCT group (P = 0.0002). CONCLUSIONS: Lower ADC values and high lipid peaks detected on 1H-MRS are characteristics of germinomas. PMID- 29274450 TI - Does Obesity Affect Perioperative and Postoperative Morbidity and Complication Rates After Minimal Access Spinal Technologies in Surgery for Lumbar Degenerative Disc Disease. AB - OBJECTIVE: The impact of obesity on spine surgery has been studied extensively, but only a few investigations have been focused on minimally invasive spinal fusion techniques and complication rates in normal-weight, preobese, or obese patients. Obesity was found to be a risk factor for intraoperative complications. Published data tend to favor minimal access surgery techniques (MAST) for obese patients. In a prospective study, we assessed the perioperative and postoperative complications of MAST in a large population of 187 patients. METHODS: We evaluated perioperative and postoperative complication rates in minimally invasive surgery (MIS) fusion techniques of the lumbar spine in obese, preobese, and normal-weight patients, classified by body mass index (BMI). Lumbar MIS fusion was performed by interbody fusion procedures and posterolateral fusion. In cases of spinal stenosis, a laminotomy was performed (146 patients). Any harmful event occurring during or after surgery was included in the statistical analysis. RESULTS: No infection or severe wound healing disorder was encountered in the series. No significant difference in terms of cerebrospinal fluid leakage, blood loss, drainage, or length of hospital stay between the 3 BMI groups was encountered. More clinically insignificant hematomas were encountered in the preobese and obese groups (P = 0.013) than in the normal-weight patients. No significant difference was registered between the BMI or age groups regarding overall complication rates. CONCLUSION: We conclude that preobese and obese patients are good candidates for MAST because BMI did not affect complication rates or duration of surgery. PMID- 29274451 TI - Treatment of Progressive Herpes Zoster-Induced Vasculopathy with Surgical Revascularization: Effects on Cerebral Hemodynamics. AB - BACKGROUND: Herpes zoster ophthalmicus (HZO) is caused by reactivation of the herpes simplex virus in the trigeminal nerve. HZO-initiated cerebral vasculopathy is well characterized; however, there are no documented cases that report the efficacy of surgical revascularization for improving cerebral hemodynamics following progressive HZO-induced vasculopathy. We present a case in which quantitative anatomic and hemodynamic imaging were performed longitudinally before and after surgical revascularization in a patient with HZO and vasculopathic changes. CASE DESCRIPTION: A 57-year-old female with history of right-sided HZO presented with left-sided hemiparesis and dysarthria and multiple acute infarcts. Angiography performed serially over a 2-month duration revealed progressive middle cerebral artery stenosis, development of new moyamoya-like lenticulostriate collaterals, and evidence of fibromuscular dysplasia in cervical portions of the internal carotid artery. Hemodynamic imaging revealed right hemisphere decreased blood flow and cerebrovascular reserve capacity. In addition to medical therapy, right-sided surgical revascularization was performed with the intent to reestablish blood flow. Follow-up imaging 13 months post revascularization demonstrated improved blood flow and vascular reserve capacity in the operative hemisphere, which paralleled symptom resolution. CONCLUSIONS: HZO can lead to progressive, symptomatic intracranial stenoses. This report suggests that surgical revascularization techniques can improve cerebral hemodynamics and symptomatology in patients with aggressive disease when medical management is unsuccessful; similar procedures could be considered in managing HZO patients with advanced or progressive vasculopathy. PMID- 29274452 TI - Visualization of Needle-Tip Localization by Ultrasound Guidance with Contrast Bubble in Lumbar Selective Nerve Root Block: Clinical Pilot Study. AB - BACKGROUND: Epidural steroid injection for low back and leg pain has been shown to result in a positive clinical outcome. Lumbosacral selective nerve root block (SNRB) via a transforaminal approach is commonly performed under fluoroscopic guidance. However, ultrasound guidance is an alternative to overcome the radiologic disadvantages. This study examined the accuracy of needle-tip localization under ultrasound guidance with a contrast bubble, compared with fluoroscopic guidance. OBJECTIVE: The primary objectives were to envisage the needle-tip localization with an air bubble by ultrasound and also to determine the accuracy of needle-tip location in transforaminal lumbar SNRB for low back and leg pain patients who were not surgical candidates. METHODS: A prospective study of 30 SNRBs was conducted. An air bubble was produced and was used to envisage the needle-tip location under ultrasound guidance. Finally, the needle tip was confirmed by fluoroscopy. The accuracy of needle-tip location was statistically analyzed. RESULTS: Twenty-four SNRBs were performed at L4-5 and 6 SNRBs at L3-4. The accuracy of needle-tip localization was 80%. CONCLUSION: In order to avoid radiation exposure during the SNRB procedure, ultrasound guidance might be an alternative. Despite being accepted practice, there is a steep learning curve involved in the use of ultrasound guidance for lumbar SNRB, and proper training is crucial. A contrast bubble is a prospective enhancement for better visualization of ultrasound guidance. PMID- 29274453 TI - Comparative Cohort Study of Percutaneous Pedicle Screw Implantation without Versus with Navigation in Patients Undergoing Surgery for Degenerative Lumbar Disc Disease. AB - BACKGROUND: The major limitation of computer-based three-dimensional fluoroscopy is increased radiation exposure of patients and operating room staff. Combining spine navigation with intraoperative three-dimensional fluoroscopy (io3DF) can likely overcome this shortcoming, while increasing pedicle screw accuracy rate. We compared data from a cohort of patients undergoing lumbar percutaneous pedicle screw placement using io3DF alone or in combination with spine navigation. METHODS: This study consisted of 168 patients who underwent percutaneous pedicle screw implantation between 2009 and 2016. The primary endpoint was to compare pedicle screw accuracy between the 2 groups. Secondary endpoints were to compare radiation exposure of patients and operating room staff, duration of surgery, and postoperative complications. RESULTS: In group 1, 438 screws were placed without navigation guidance; in group 2, 276 screws were placed with spine navigation. Mean patient age in both groups was 58.6 +/- 14.1 years. The final pedicle accuracy rate was 97.9% in group 1 and 99.6% in group 2. Average radiation dose per patient was significantly larger in group 1 (571.9 mGym2) than in group 2 (365.6 mGym2) (P = 0.000088). Surgery duration and complication rate were not significantly different between the 2 groups (P > 0.05). CONCLUSIONS: io3DF with spine navigation minimized radiation exposure of patients and operating room staff and provided an excellent percutaneous pedicle screw accuracy rate with no permanent complications compared with io3DF alone. This setup is recommended, especially for patients with a complex degenerative spine condition. PMID- 29274454 TI - The Prevalence of Cerebrovascular Abnormalities Detected in Various Diagnostic Subgroups of Spontaneous Subarachnoid Hemorrhage in the Modern Era. AB - OBJECTIVE: To determine prevalence of cerebrovascular abnormalities in diagnostic subgroups of spontaneous subarachnoid hemorrhage (SAH) in a regional neurosurgical center in the modern era. METHODS: Data of 609 consecutive patients with spontaneous SAH in a 3-year period (August 2010 to August 2013) were prospectively collected. Patients were divided into 3 diagnostic subgroups: computed tomography (CT) positive for SAH; CT negative but positive cerebrospinal fluid examination by spectrophotometry for SAH; CT negative for SAH and inconclusive cerebrospinal fluid examination. All patients fit for intervention underwent CT angiography with or without digital subtraction angiography to identify vascular abnormalities for subsequent treatment. RESULTS: Of 609 patients, 554 were fit for further investigation and consideration of further intervention; 514 patients had confirmed SAH. Mean patient age was 54.0 years; 61.5% of patients were women. Of patients, 390 (75.9%) showed vascular abnormalities on angiography. There were 438 patients (85.2%) with confirmed SAH diagnosed on CT scan (group 1). Vascular abnormalities were detected in 81.1% of patients; 18.9% of patients with positive CT scan had no identifiable cause of SAH. Of patients with confirmed SAH, 76 (14.8%) had negative CT scan but positive lumbar puncture (group 2); 46.1% of patients in this group had vascular abnormalities. Three patients with inconclusive cerebrospinal fluid examination had lesions requiring treatment. Median length of hospital stay in group 1 patients was longer than median length of hospital stay in group 2 patients. CONCLUSIONS: Frequency of vascular abnormalities in spontaneous SAH is lower than the traditionally quoted figure, which has diagnostic and prognostic implications for patient management. PMID- 29274455 TI - Biomechanical analysis of the shoulder of swimmers after a maximal effort test. AB - OBJECTIVES: To compare the kinematics and electromyography of the periscapular muscles in swimmers before and after a 3-min maximal effort test. PARTICIPANTS: 16 competitive swimmers. MAIN OUTCOME MEASUREMENTS: Infrared cameras were used to record kinematics in the scapular plane in synchronization with the electromyography system. RESULTS: There was an increase in internal rotation in all angles (p < 0.05), an increase of the anterior tilt, with 120 degrees of elevation (p = 0.04). The serratus anterior showed a decrease in the intervals of 120-90 degrees and 60-30 degrees (p = 0.04; p = 0.02). There was a linear relationship between the variation before and after the maximal effort of the anterior tilt in relation to the variation of muscular activation of the transverse trapezius (p = 0.01) and the lower trapezius (42%, p = 0.01); an internal rotation in 120 degrees and 90 degrees of elevation in relation to the transverse trapezius (p = 0.01); and an internal rotation in 60 degrees and 30 degrees of elevation in relation to the serratus anterior (p = 0.04, p = 0.03). CONCLUSION: A maximal 3-min effort test resulted in altered scapular biomechanics. More studies are needed to verify if the changes correspond to a risk factor for injuries. PMID- 29274456 TI - Molecular characterization of extended spectrum beta-lactamase-producing Enterobacteriaceae strains isolated from a tertiary care hospital. AB - Infectious diseases caused by ESBL producing Enterobacteriaceae are an emerging problem worldwide which increases the empirical treatment failure, hospital cost, rate of morbidity and mortality. This also leads to the Hospital infection outbreak. Present study was undertaken to determine the frequency of blaTEM, blaCTX-M and blaSHV genes among Enterobacteriaceae. A total of 751 non-repeated clinical isolates of Enterobacteriaceae family were included in this study. Antibiotic susceptibility test was done and minimal inhibitory concentration (MIC) against four antibiotics was carried out. Five hundred fifteen multi drug resistant isolates were tested for ESBL by CLSI confirmatory method. Isolates showing ESBL positive by phenotypic method were screened for blaTEM, blaCTX-M and blaSHV genes by monoplex PCR. Two blaTEM and two blaCTX-M amplified products were selected randomly for sequencing. Sequencing data was submitted to NCBI data base. Of the 515 MDR isolates, 140 showed ESBL production by phenotypic method. All the ESBL producing isolates showed resistant to ceftazidime (100%). IMP, TGC and CL drugs could be preferred for the treatment of ESBL producers as these drugs showed a lower rate of resistance. blaTEM gene was the predominant (96.42%) followed by blaCTX-M (75%) and blaSHV (17.85%). All the three bla genes were occurred in 22 (17.14%) isolates. All the phenotypically confirmed ESBL producers were found contain any one of the three bla genes. It is concluded from the study that the blaTEM was predominantly found in Enterobacteriaceae and blaCTX-M gene also seemed to emerging. PMID- 29274457 TI - Unique biomarkers as a potential predictive tool for differentiation of Bacillus cereus group based on real-time PCR. AB - The aim of the study was to develop unique biomarkers for qPCR detection of Bacillus cereus group. Clinical and soil isolates were identified by specifically designed biomarkers - Lipoprotein (OPL-114-lipo), Methyltransferase (MT-17) and S layer homology domain protein (151-1BC). In order to design biomarkers, we used 120 bacterial strains grouped into B. cereus and non-Bacillus group. The B. cereus group was confirmed by 108 strains of B. cereus and B. thuringiensis (30 reference and 78 wild), along with 3 strains of B. mycoides, B. pseudomycoides, and B. weihenstephanensis; while the non-Bacillus group was composed of 9 Gram positive and Gram-negative strains. Direct analysis of samples revealed specificity towards identification and characterization of B. cereus group. The newly developed markers OPL-114-lipo and MT-17 showed specificity of 95% and 81%, respectively in identification of B. cereus. They are efficient tools to identify contaminated sources and the degree of bacterial contamination. Environmental and food samples do not require band isolation, re-amplification, sequencing or sequence identification. Thus, reducing the time and cost of analysis. Hence, it will be an alternative approach to traditional culture methods. Commercial food processing industries will be able to employ these biomarkers specific for B. cereus group as a detection tool to reduce economic loss due to B. cereus contamination. PMID- 29274458 TI - Detection of virulence genes determining the ability to adhere and invade in Campylobacter spp. from cattle and swine in Poland. AB - The aim of the study was to determine the prevalence of virulence genes responsible for the adhesion (flaA, cadF and racR) and invasion (virB11, iam and pldA) in Campylobacter isolates from cattle and swine and determine their adherence and invasion abilities. The studies conducted revealed high prevalence rate of adherence and invasion associated genes irrespective of the isolates origin. All Campylobacter strains of swine and cattle origin adhered to HeLa cells at mean level 0.1099% +/- SD 0.1341% and 0.0845% +/- SD 0.1304% of starting viable inoculum, respectively. However swine isolates exhibited higher invasion abilities (0.0012% +/- SD 0.0011%) compared to bovine isolates (0.00038% +/- SD 0.00055%). The results obtained revealed significantly positive correlation between invasion and adherence abilities of swine origin isolates (R = 0.4867 in regard to C. jejuni and R = 0.4507 in regard to C. coli) and bovine origin isolates (R = 0.726 in regard to C. jejuni). Bacterial virulence is multifactorial and it is affected by the expression of virulence genes. Moreover the presence of virulence genes determines the ability of Campylobacter isolates to adhere and invade the cells. PMID- 29274459 TI - Killing of S. aureus in murine peritoneal macrophages by Ascorbic acid along with antibiotics Chloramphenicol or Ofloxacin: Correlation with inflammation. AB - Alarming increase of death due to S. aureus sepsis demands newer treatment strategies. Enhancement of antibiotic resistant S. aureus strains caused increased mortality. Only antibiotic treatment for Staphylococcal sepsis has been found insufficient to improve outcomes. In the innate immune response, phagocytosis mediated killing of pathogen and further triggering of intracellular signaling cascades by the PRRs culminates in the release of a variety of pro inflammatory cytokines, which orchestrate together in the early host response to infection. Increased production of inflammatory cytokines not only delineate pathogen burden but also affects host cell by triggering inflammation. Therefore, combinational therapy of Ascorbic acid is used along with antibiotics Ofloxacin (OFX) or Chloramphenicol (CHL) to kill S. aureus by mouse peritoneal macrophages. For this ROS like H2O2, superoxide anion and NO production was accessed, TLR2 and COX2 expression was monitored. Pro-inflammatory cytokines along with antioxidant levels were also analyzed. Ascorbic acid along with antibiotics OFX or CHL promoted bacterial clearance at early infection by increasing H2O2 and O2-.NO production has been found to decrease, providing protection against harmful per oxynitril ion. Increase in TLR-2 expression resulted in enhanced phagocytosis and subsequently more killing. Treatment with Ascorbic acid decreased proinflammatory cytokines and inflammatory markers like iNOS and COX2. This combination increased antioxidant enzymes like SOD, Catalase, GSH as well as decreased LPO, thus balancing ROS and antioxidant status inside the cell. Thus in-vitro augmentation of bacterial clearance along with regulated inflammation as found by decrease in proinflammatory cytokines like TNF-alpha IFN-gamma,IL-6 and inflammatory markers like COX2 may be considered as a novel and important therapeutic strategy. PMID- 29274460 TI - Human endogenous retrovirus env genes: Potential blood biomarkers in lung cancer. AB - Lung cancer, the leading cause of cancer mortality, needs urgent development of newly qualified diagnostic and therapeutic biomarkers. Recently, Human Endogenous Retroviruses (HERVs) have been introduced for cancer diagnosis. In this case control study, we have collected blood samples from 60 lung cancer patients and 20 healthy controls. Quantitative gene expression analysis of various HERV env genes, including HERV-R, HERV-H, HERV-K, and HERV-P was performed by real-time PCR. Results indicate that expression of all four HERV env mRNAs is significantly increased in the blood of lung cancer patients than healthy controls (P values<0.01). Furthermore, we have observed a positive and significant pairwise correlation between the expressions of four HERV env genes. The level of HERV env transcript in the blood of adenocarcinoma patients was generally much higher than squamous cell carcinoma (SCC) and small-cell lung cancer (SCLC) patients. Also, the expression of three HERV P, HERV H, and HERV K in the blood of lung cancer patients could significantly differentiate between adenocarcinoma and other types of lung cancer. In conclusion, these four HERV families could be considered as promising non-invasive blood-based biomarkers for prognosis, early detection, and monitoring of lung cancer. PMID- 29274461 TI - Identification of a KPC-9-producing Klebsiella pneumoniae ST258 cluster among KPC 2-producing isolates of an ongoing outbreak in Northwestern Greece: a retrospective study. PMID- 29274462 TI - Performance of the BacT/Alert Virtuo Microbial Detection System for the culture of sterile body fluids: prospective multicentre study. AB - OBJECTIVES: Continuous monitoring blood culture systems are commonly used for sterile body fluid cultures. In this multicentre study, we evaluated the performance of the new-generation BacT/Alert Virtuo system compared to the BacT/Alert 3D and conventional culture for the recovery of microorganisms from sterile body fluids. METHODS: Peritoneal, cerebrospinal, pericardial, pleural and synovial fluids from adult patients submitted for culture were collected from three different centres. Specimens were inoculated into two bottles of the same bottle type (SA, SN, FA Plus or FN Plus) in equal volumes for simultaneous incubation in the Virtuo and 3D instruments. Each specimen was also Gram stained and seeded to solid media. RESULTS: A total of 811 specimens were inoculated to 1257 bottle pairs. The Virtuo and 3D showed equivalent recovery of clinically significant microorganisms (127/155, 81.9%, vs. 126/155, 81.3%, respectively). Solid media cultures recovered fewer pathogens than either continuous monitoring system (95/155, 61.3%, p <0.001), including significantly fewer Enterobacteriaceae and enterococci. The Virtuo was significantly faster than the 3D in median time to detection of isolates from the same specimen (12.5 (range, 2.8-101.5) hours vs. 15.5 (range, 4.3-78.5) hours, p <0.001). Direct specimen Gram stain detected the eventual pathogen in 30 (26.1%) of 115 significant positive specimens. CONCLUSIONS: The BacT/Alert Virtuo system was equivalent to the 3D system in organism recovery from sterile body fluid culture but showed faster detection of growth as a result of design enhancements. PMID- 29274464 TI - C. difficile infection - Can we do better? PMID- 29274463 TI - How to: Surveillance of Clostridium difficile infections. AB - BACKGROUND: The increasing incidence of Clostridium difficile infections (CDI) in healthcare settings in Europe since 2003 has affected both patients and healthcare systems. The implementation of effective CDI surveillance is key to enable monitoring of the occurrence and spread of C. difficile in healthcare and the timely detection of outbreaks. AIMS: The aim of this review is to provide a summary of key components of effective CDI surveillance and to provide some practical recommendations. We also summarize the recent and current national CDI surveillance activities, to illustrate strengths and weaknesses of CDI surveillance in Europe. SOURCES: For the definition of key components of CDI surveillance, we consulted the current European Society of Clinical Microbiology and Infectious Diseases (ESCMID) CDI-related guidance documents and the European Centre for Disease Prevention and Control (ECDC) protocol for CDI surveillance in acute care hospitals. To summarize the recent and current national CDI surveillance activities, we discussed international multicentre CDI surveillance studies performed in 2005-13. In 2017, we also performed a new survey of existing CDI surveillance systems in 33 European countries. CONTENT: Key components for CDI surveillance are appropriate case definitions of CDI, standardized CDI diagnostics, agreement on CDI case origin definition, and the presentation of CDI rates with well-defined numerators and denominators. Incorporation of microbiological data is required to provide information on prevailing PCR ribotypes and antimicrobial susceptibility to first-line CDI treatment drugs. In 2017, 20 European countries had a national CDI surveillance system and 21 countries participated in ECDC-coordinated CDI surveillance. Since 2014, the number of centres with capacity for C. difficile typing has increased to 35 reference or central laboratories in 26 European countries. IMPLICATIONS: Incidence rates of CDI, obtained from a standardized CDI surveillance system, can be used as an important quality indicator of healthcare at hospital as well as country level. PMID- 29274465 TI - Laboratory preparedness and response with a focus on arboviruses in Europe. AB - BACKGROUND: The global health burden of arboviruses is continuously rising, which results in increasing pressure on local and (inter)national laboratory infrastructures. Timely and accurate diagnosis of cases is one of the main pillars for public health and clinical responses to an arbovirus emergence. AIMS AND SOURCES: This narrative review aims to summarize recent advances and to identify needs in laboratory preparedness and response activities, with a focus on viruses transmitted by arthropods in Europe. The review is based on evidence extracted from PubMed searches, Public Health and clinical laboratory experiences from the authors and the authors' opinions substantiated by peer-reviewed scientific literature. CONTENT: We illustrate the importance of inter-epidemic laboratory preparedness activities to ensure adequate Public Health and clinical responses. We describe the status of arbovirus endemicity and emergence in Europe thereby highlighting the need for preparedness for these viruses. We discuss the components and pitfalls of an adequate laboratory preparedness and response and the broader context of the current landscape of international research, clinical and laboratory preparedness networks. The complexity of arbovirus laboratory preparedness and response is described. IMPLICATIONS: Outbreak preparedness plans need to look beyond national reference laboratories, to include first-line responding onsite hospital laboratories and plans for strengthening of such local capacity and capability as required depending on the nature of the outbreak. In particular, the diagnosis of arbovirus infections is complicated by the existence of geographic overlap of circulation of numerous arboviruses, the overlap in clinical manifestation between many arboviruses and other aetiologies and the existence of cross-reactivity between related arboviruses in serology testing. Inter-epidemic preparedness activities need strong national and international networks addressing these issues. However, the current mushrooming of European preparedness networks requires governance to bring the European preparedness and response to a next level. PMID- 29274466 TI - Letter-to-the-Editor in response to "Tanton C, et al. Human papillomavirus (HPV) in young women in Britain: Population-based evidence ofthe effectiveness of the bivalent immunisation programme and burden of quadrivalent and 9-valent vaccine types. Papillomavirus Res. 2017 Jun;3:36-41.doi: 10.1016/j.pvr.2017.01.001." PMID- 29274467 TI - The incidence of Clostridioides difficile and Clostridium perfringens netF positive strains in diarrheic dogs. AB - The aim of this study was to examine the incidence of Clostridioides (previously Clostridium) difficile and Clostridium perfringens in the feces of diarrheic and non-diarrheic dogs. Also, the presence of other common canine enteropathogens was examined. Toxigenic C. difficile and C. perfringens positive for the NetF encoding gene (netF) were detected in 11 (11.9%) and seven (7.6%) diarrheic dogs, respectively. Three dogs were diagnosed simultaneously with toxigenic C. difficile and netF-positive C. perfringens. Among other enteropathogens, Giardia sp. was the most common agent detected in dogs positive for toxigenic C. difficile or netF-positive C. perfringens. The results suggest that C. difficile and C. perfringens occur more frequently as a primary cause of diarrhea. PMID- 29274468 TI - Molecular characterisation of carbapenem-resistant Enterobacter cloacae complex in Colombia: blaKPC and the 'changing landscape'. AB - OBJECTIVES: The aim of this study was to examine the population structure of representative carbapenem-resistant Enterobacter cloacae complex (CR-Ecl) isolates from eight different Colombian regions and to characterise their associated beta-lactamases. METHODS: A total of 28 CR-Ecl isolates collected in Colombia between 2009-2013 through the Colombian Nosocomial Network were included in this study. Antimicrobial susceptibility testing was performed by the broth microdilution method. Molecular detection of carbapenemase and extended-spectrum beta-lactamase (ESBL) genes and the presence of transposon Tn4401 was evaluated by PCR and DNA sequencing. Genetic relatedness was assessed by multilocus sequencing typing (MLST) and repetitive sequence-based PCR (rep-PCR). RESULTS: PCR and DNA sequencing revealed that 19/28 (68%) of the CR-Ecl isolates carried blaKPC-2. Analysis of the genetic environment found blaKPC-2 within transposon Tn4401b in 8/19 isolates (42%). Population genetic analysis using rep-PCR revealed four clonal groups. MLST showed a variety of sequence types (STs), among which ST510 was the most common (10/28 isolates; 36%). CONCLUSIONS: blaKPC-2 was discovered as the most common mechanism of carbapenem resistance in CR-Ecl and was disseminated among different STs. Although none of the previously reported major clonal complexes were identified, it appears that local strain lineages are associated with the spread of blaKPC within CR-Ecl in various regions of Colombia. PMID- 29274469 TI - Reduced susceptibility of Enterococcus spp. isolates from Cairo University Hospital to tigecycline: Highlight on the influence of proton pump inhibitors. AB - OBJECTIVES: The incidence of reduced susceptibility to tigecycline (TIG) is increasing. This study aimed to analyse the in vitro activity of TIG against Enterococcus spp. isolates recovered from hospitalised patients and to evaluate the effect of omeprazole on the in vitro antimicrobial activity of TIG against several enterococcal species. METHODS: A total of 67 Enterococcus clinical isolates were identified by MALDI-TOF/MS and multiplex PCR. Minimum inhibitory concentrations (MICs) of TIG alone and in combination with omeprazole (10, 30 and 60mg/L) were determined by broth microdilution. Antibiotic susceptibility to other antibiotics was determined by disk diffusion. The presence of van, tet(X) and tet(X1) genes was tested by multiplex PCR. RESULTS: Of the 67 Enterococcus isolates, 2 (3.0%) were resistant to TIG and 13 (19.4%) were intermediate resistant according to EUCAST. The frequencies of resistance to norfloxacin (80.6%), doxycycline (80.6%), levofloxacin (74.6%) and ciprofloxacin (71.6%) were highest, whilst that of vancomycin (25.4%) was lowest. The vanA gene was detected in 11 Enterococcus isolates (8 Enterococcus faecalis, 3 Enterococcus faecium), vanB in 3 Enterococcus isolates (2 E. faecium, 1 E. faecalis) and vanC-2/3 in 3 Enterococcus casseliflavus. Nine isolates (13.4%) were positive for tet(X1). TIG resistance occurred both in patients receiving or not TIG and/or omeprazole. Omeprazole increased TIG MICs by 4-128-fold. CONCLUSIONS: The possibility of selection of TIG-non-susceptible Enterococcus in the gut may occur with long-term use of omeprazole. Omeprazole influenced TIG activity in a concentration dependent manner. To our knowledge; this is the first report of TIG-non susceptible Enterococcus spp. in Egypt. PMID- 29274470 TI - Serotype distribution, antibiotic resistance patterns and molecular characteristics of serogroup 6 Streptococcus pneumoniae isolates collected from Chinese children before the introduction of PCV13. AB - OBJECTIVES: Streptococcus pneumoniae is an important pathogen in infectious diseases worldwide, and serogroup 6 S. pneumoniae strains are very common in China. This study investigated the serotype distribution, antibiotic resistance patterns and molecular characteristics of 215 serogroup 6 S. pneumoniae isolates collected from hospitalised children in China during 2013-2016. METHODS: Serotypes were determined using the Quellung reaction with antisera. Antibiotic resistance against 11 antimicrobials was tested by Etest or the disk diffusion method. Sequence types (STs) were assigned using multilocus sequence typing (MLST). Data analysis was performed with WHONET 5.6 software. RESULTS: The percentages of serotype 6A, 6B, 6C and 6D among the 215 serogroup 6 isolates were 50.7% (109/215), 36.3% (78/215), 12.6% (27/215) and 0.5% (1/215), respectively. All isolates were susceptible to levofloxacin and were resistant to erythromycin. No isolate was resistant to parenteral penicillin, but the intermediate and resistant rates reached 72.6% (156/215) and 5.1% (11/215), respectively, based on the oral breakpoint. Sixty-seven STs were detected, with 14 STs being newly assigned. The most common clonal complexes (CCs) were CC3173 (26.5%; 57/215), CC9789 (13.5%; 29/215), CC90 (13.0%; 28/215) and CC902 (8.8%; 19/215), and the non-susceptibility rates of these four CCs against penicillin and cefuroxime (penicillin, 98.2%, 100%, 100% and 100%, respectively; cefuroxime, 98.2%, 100%, 96.4% and 94.7%, respectively) were higher than the overall level of serogroup 6 isolates (penicillin, 77.7%; cefuroxime, 70.2%). CONCLUSIONS: Serotype 6A is the most common serotype of serogroup 6 S. pneumoniae strains in Chinese children, and different CCs/STs express diverse antibiotic resistance patterns. PMID- 29274471 TI - Five-day course of paired associative stimulation fails to improve motor function in stroke patients. AB - BACKGROUND: Non-invasive brain stimulation has been studied as a therapeutic adjunct for upper-limb recovery in patients with stroke. One type of stimulation, paired associative stimulation (PAS), has effects on plasticity in both patients and healthy participants. Lasting several hours, these effects are reversible and topographically specific. OBJECTIVE: The goal was to investigate the presence of a lasting increase in motor cortex plasticity for extensor wrist muscles - extensor carpi radialis (ECR) - and an improvement in upper-limb function after 5 days of daily PAS in patients at the subacute post-stroke stage. METHODS: A total of 24 patients (mean [SD] age 50.1 [12.1] years, weeks since stroke 10.1 [5.3]) were included in a double-blind, placebo-controlled trial and randomly assigned to the PAS or sham group (n=13 and n=11). For the PAS group, patients underwent a 5-day course of electrical peripheral stimulation combined with magnetic cortical stimulation applied to the ECR muscle in a single daily session at 0.1Hz for 30min; patients with sham treatment received minimal cortical stimulation. Both patient groups underwent 2 hr of conventional physiotherapy. Variations in the motor evoked potential (MEP) surface area of the ECR muscle and Fugl-Meyer Assessment-Upper-Limb motor scores were analysed up to day 12. RESULTS: The 2 groups did not differ in electrophysiological or motor parameters. Repeated PAS sessions seemed to affect only patients with low initial cortical excitability. We found considerable variability in PAS effects between patients and across the sessions. CONCLUSION: We failed to induce a lasting effect with PAS in the present study. PAS does not seem to be the main method for post-stroke brain stimulation. Perhaps recruitment of patients could be more selective, possibly targeting those with a wide altered ipsilesional corticomotor pathway. PMID- 29274472 TI - Protein phosphatase 2ACalpha gene knock-out results in cortical atrophy through activating hippo cascade in neuronal progenitor cells. AB - Protein phosphatase 2ACalpha (PP2ACalpha), a vital member of the protein phosphatase family, has been studied primarily as a regulator for the development, growth and protein synthesis of a lot of cell types. Dysfunction of PP2ACalpha protein results in neurodegenerative disease; however, this finding has not been directly confirmed in the mouse model with PP2ACalpha gene knock out. Therefore, in this study presented here, we generated the PP2ACalpha gene knock-out mouse model by the Cre-loxP targeting gene system, with the purpose to directly observe the regulatory role of PP2ACalpha gene in the development of mouse's cerebral cortex. We observe that knocking-out PP2ACalpha gene in the central nervous system (CNS) results in cortical neuronal shrinkage, synaptic plasticity impairments, and learning/memory deficits. Further study reveals that PP2ACalpha gene knock-out initiates Hippo cascade in cortical neuroprogenitor cells (NPCs), which blocks YAP translocation into the nuclei of NPCs. Notably, p73, directly targeted by Hippo cascade, can bind to the promoter of glutaminase2 (GLS2) that plays a dominant role in the enzymatic regulation of glutamate/glutamine cycle. Finally, we find that PP2ACalpha gene knock-out inhibits the glutamine synthesis through up-regulating the activity of phosphorylated-p73 in cortical NPCs. Taken together, it concludes that PP2ACalpha critically supports cortical neuronal growth and cognitive function via regulating the signaling transduction of Hippo-p73 cascade. And PP2ACalpha indirectly modulates the glutamine synthesis of cortical NPCs through targeting p73 that plays a direct transcriptional regulatory role in the gene expression of GLS2. PMID- 29274474 TI - Permanent His-bundle pacing: Long-term lead performance and clinical outcomes. AB - BACKGROUND: Right ventricular pacing (RVP) is associated with heart failure and increased mortality. His-bundle pacing (HBP) is a physiological alternative to RVP. OBJECTIVE: The purpose of this study was to report long-term performance and compare the clinical outcomes of permanent HBP vs RVP. METHODS: All patients requiring pacemaker implantation underwent an attempt at permanent HBP in 2011 at one hospital and RVP at the sister hospital. Patients were followed from implantation, 2 weeks, 2 months, and yearly for 5 years. Left ventricular ejection fraction (LVEF), pacing thresholds, lead revision, and generator change were tracked. Primary outcome was the combined endpoint of death or heart failure hospitalization (HFH) at 5 years. RESULTS: HBP was attempted in 94 consecutive patients and was successful in 75 (80%); 98 patients underwent RVP. LVEF remained unchanged in the HBP group (55% +/- 8% vs 57% +/- 6%; P = .13), whereas significant decline was noted in the RVP group (57% +/- 7% vs 52% +/- 11%; P = .002). Incidence of pacing-induced cardiomyopathy was significantly lower in HBP compared to RVP patients (2% vs 22%; P = .04). At 5 years, death or HFH was significantly lower in HBP compared to RVP patients with >40% ventricular pacing (32% vs 53%; hazard ratio 1.9; P = .04). At 5 years, the need for lead revisions (6.7% vs 3%) and for generator change (9% vs 1%) were higher in the HBP group. CONCLUSION: In patients undergoing pacemaker implantation, permanent HBP was associated with reduction in death or HFH during long-term follow-up compared to RVP. HBP was associated with higher rates of lead revisions and generator change. PMID- 29274473 TI - Tyro3-mediated phosphorylation of ACTN4 at tyrosines is FAK-dependent and decreases susceptibility to cleavage by m-Calpain. AB - Tyro3, a member of TAM receptor tyrosine kinase family, has been implicated in the regulation of melanoma progression and survival. In this study, we sought the molecular mechanism of Tyro3 effects avoiding endogenous background by overexpression of Tyro3 in fibroblasts that have negligible levels of Tyro3. This introduction triggers the tyrosyl-phosphorylation of ACTN4, a member of actin binding protein family involved in motility, a behavior critical for invasive progression, as shown by siRNA to Tyro3 limiting melanoma cell migration and invasion. Tyro3-mediated phosphorylation of ACTN4 required FAK activation at tyrosine 397 and the EGF receptor cascade, but not EGFR ligand binding. Using PCR based mutagenesis, the sites of Tyro3-mediated ACTN4 phosphorylation were mapped to ACTN4 tyrosine 11 and 13, and this occurs in conjunction with EGF-mediated phosphorylation on Y4 and Y31. Interestingly, Tyro3-mediated phosphorylation only slightly decreases the actin binding activity of ACTN4. However, this rendered the phosphorylated ACTN4 resistant to the m-calpain cleavage between Y13 and G14, a limited proteolysis that prevents growth factor regulation of ACTN4 interaction with F-actin. Overexpression of both WT ACTN4 and ACTN4Y11/13E, a mimic of ACTN4 phosphorylated at tyrosine 11 and 13, in melanoma WM983b cells resulted in a likely mesenchymal to amoeboidal transition. ACTN4Y11/13E-expressing cells were more amoeboidal, less migratory on collagen I gel coated surface but more invasive through collagen networks. In parallel, expression of ACTN4Y11/13E, in ACTN4 knockdown melanoma WM1158 cells resulted in an increase of invasion compared to WT ACTN4. These findings suggest that Tyro3-mediated phosphorylation of ACTN4 is involved in invasion of melanoma cells. PMID- 29274475 TI - Breast cancer in octogenarian. Are we doing our best? A population-registry based study. AB - BACKGROUND: The number of old people with breast cancer is estimated to increase during the next years in developed countries. However, management of breast cancer in octogenarians is not well established. The main objective was to evaluate if patients older than 80 years with breast cancer are receiving the most convenient treatment by using a population registry cancer analysis. PATIENTS AND METHODS: A retrospective analysis of a population cancer registry was designed. Data were retrieved from the Castellon Cancer Registry (Valencian Community, Spain). Patient records were analyzed from January 1, 1995 to December 31, 2013. Two groups were defined: group A, <80 years; and group B, >= 80 years. Survival analyses were sequentially performed into three phases. First, a non adjusted Kaplan Meier analysis was conducted. For the second survival analyses, Cox's proportional hazards model of Overall survival was used adjusting for condensed-TNM stage and adjuvant treatments. Finally, the third specific adjustment was carried out adding information of life expectancy by age for Spanish women, corresponding to year 2008 with condensed-TNM stage and Propensity Score variable, as an approximation to relative or disease-specific survival. RESULTS: The total number of included patients was 1304. Women >=80 years presented a more extended disease, larger tumors and less in situ carcinomas. A lower proportion of women >=80 years received adjuvant therapies. In the absence of any adjustment of results, the overall survival in women >=80 years was poorer than in younger patients (median of 14.1 years for <80y vs. 5.7 years for >=80y), the crude HR was 4.6 (95% CI: 2.9-7.5) p < 0.001. For second survival analysis, the HR was 2.5 (95% CI: 1.8-3.5) p < 0.001. After the third adjustment the HR was 1.7 (95% CI: 1.2-2.4) p = 0.004. CONCLUSIONS: Octogenarians with operable breast cancer are receiving suboptimal treatments, which can have repercussions on survival. New studies are required to identify a subgroup of women age >=80 years who may benefit from more aggressive treatment and a population of older women on the basis of tumor characteristics, comorbidities and life expectancy who may not need as aggressive treatment. PMID- 29274476 TI - Nanoparticle-induced inflammation can increase tumor malignancy. AB - : Nanomaterials, such as aluminum oxide, have been regarded with high biomedical promise as potential immune adjuvants in favor of their bulk counterparts. For pathophysiological conditions where elevated immune activity already occurs, the contribution of nanoparticle-activated immune reactions remains unclear. Here, we investigated the effect of spherical and wire-shaped aluminum oxide nanoparticles on primary splenocytes and observed a clear pro-inflammatory effect of both nanoparticles, mainly for the high aspect ratio nanowires. The nanoparticles resulted in a clear activation of NLRP3 inflammasome, and also secreted transforming growth factor beta. When cancer cells were exposed to these cytokines, this resulted in an increased level of epithelial-to-mesenchymal transition, a hallmark for cancer metastasis, which did not occur when the cancer cells were directly exposed to the nanoparticles themselves. Using a syngeneic tumor model, the level of inflammation and degree of lung metastasis were significantly increased when the animals were exposed to the nanoparticles, particularly for the nanowires. This effect could be abrogated by treating the animals with inflammatory inhibitors. Collectively, these data indicate that the interaction of nanoparticles with immune cells can have secondary effects that may aggravate pathophysiological conditions, such as cancer malignancy, and conditions must be carefully selected to finely tune the induced aspecific inflammation into cancer-specific antitumor immunity. STATEMENT OF SIGNIFICANCE: Many different types of nanoparticles have been shown to possess immunomodulatory properties, depending on their physicochemical parameters. This can potentially be harnessed as a possible antitumor therapy. However, in the current work we show that inflammation elicited by nanomaterials can have grave effects in pathophysiological conditions, where non-specific inflammation was found to increase cancer cell mobility and tumor malignancy. These data show that immunomodulatory properties of nanomaterials must be carefully controlled to avoid any undesired side-effects. PMID- 29274477 TI - Intrafibrillar silicified collagen scaffold promotes in-situ bone regeneration by activating the monocyte p38 signaling pathway. AB - : Intrafibrillar silicified collagen scaffold (SCS) is a promising biomaterial for bone regeneration because it promotes cell homing and angiogenesis in bone defects via monocyte modulation. In the present study, a rat femoral defect model was used to examine the contribution of monocyte signaling pathways to SCS modulation. Activation of the monocyte p38 signaling pathway by SCS resulted in monocyte differentiation into TRAP-positive mononuclear cells. These cells demonstrated increased secretion of SDF-1alpha, VEGFa and PDGF-BB, which, in turn, promoted homing of bone marrow stromal cells (BMSCs) and endothelial progenitor cells (EPCs), as well as local vascularization. Monocyte differentiation and secretion were blocked after inhibition of the p38 pathway, which resulted in reduction in cell homing and angiogenesis. Taken together, these novel findings indicate that the p38 signaling pathway is crucial in SCS modulated monocyte differentiation and secretion, which has a direct impact on SCS-induced bone regeneration. STATEMENT OF SIGNIFICANCE: Intrafibrillar silicified collagen scaffold (SCS) is a promising biomaterial for bone regeneration. The present work demonstrates that SCS possesses favorable bone regeneration potential in a rat femoral defect model. The degrading scaffold modulates monocyte differentiation and release of certain cytokines to recruit MSCs and EPCs, as well as enhances local vascularization by activating the p38 MAPK signaling pathway. These findings indicate that SCS contributes to bone defect regeneration by stimulating host cell homing and promoting local angiogenesis and osteogenesis without the need for loading cytokines or xenogenous stem cells. PMID- 29274478 TI - A compound scaffold with uniform longitudinally oriented guidance cues and a porous sheath promotes peripheral nerve regeneration in vivo. AB - : Scaffolds with inner fillers that convey directional guidance cues represent promising candidates for nerve repair. However, incorrect positioning or non uniform distribution of intraluminal fillers might result in regeneration failure. In addition, proper porosity (to enhance nutrient and oxygen exchange but prevent fibroblast infiltration) and mechanical properties (to ensure fixation and to protect regenerating axons from compression) of the outer sheath are also highly important for constructing advanced nerve scaffolds. In this study, we constructed a compound scaffold using a stage-wise strategy, including directionally freezing orientated collagen-chitosan (O-CCH) filler, electrospinning poly(epsilon-caprolactone) (PCL) sheaths and assembling O-CCH/PCL scaffolds. Based on scanning electron microscopy (SEM) and mechanical tests, a blend of collagen/chitosan (1:1) was selected for filler fabrication, and a wall thickness of 400 MUm was selected for PCL sheath production. SEM and three dimensional (3D) reconstruction further revealed that the O-CCH filler exhibited a uniform, longitudinally oriented microstructure (over 85% of pores were 20-50 MUm in diameter). The electrospun PCL porous sheath with pore sizes of 6.5 +/- 3.3 MUm prevented fibroblast invasion. The PCL sheath exhibited comparable mechanical properties to commercially available nerve conduits, and the O-CCH filler showed a physiologically relevant substrate stiffness of 2.0 +/- 0.4 kPa. The differential degradation time of the filler and sheath allows the O-CCH/PCL scaffold to protect regenerating axons from compression stress while providing enough space for regenerating nerves. In vitro and in vivo studies indicated that the O-CCH/PCL scaffolds could promote axonal regeneration and Schwann cell migration. More importantly, functional results indicated that the CCH/PCL compound scaffold induced comparable functional recovery to that of the autograft group at the end of the study. Our findings demonstrated that the O-CCH/PCL scaffold with uniform longitudinal guidance filler and a porous sheath exhibits favorable properties for clinical use and promotes nerve regeneration and functional recovery. The O-CCH/PCL scaffold provides a promising new path for developing an optimal therapeutic alternative for peripheral nerve reconstruction. STATEMENT OF SIGNIFICANCE: Scaffolds with inner fillers displaying directional guidance cues represent a promising candidate for nerve repair. However, further clinical translation should pay attention to the problem of non-uniform distribution of inner fillers, the porosity and mechanical properties of the outer sheath and the morphological design facilitating operation. In this study, a stage-wise fabrication strategy was used, which made it possible to develop an O-CCH/PCL compound scaffold with a uniform longitudinally oriented inner filler and a porous outer sheath. The uniform distribution of the pores in the O-CCH/PCL scaffold provides a solution to resolve the problem of non-uniform distribution of inner fillers, which impede the clinical translation of scaffolds with longitudinal microstructured fillers, especially for aligned-fiber-based scaffolds. In vitro and in vivo studies indicated that the O-CCH/PCL scaffolds could provide topographical cues for axonal regeneration and SC migration, which were not found for random scaffolds (with random microstructure resemble sponge-based scaffolds). The electrospun porous PCL sheath of the O-CCH/PCL scaffold not only prevented fibroblast infiltration, but also satisfied the mechanical requirements for clinical use, paving the way for clinical translation. The differential degradation time of the O-CCH filler and the PCL sheath makes O-CCH/PCL scaffold able to provide long protection for regenerating axons from compression stress, but enough space for regenerating nerve. These findings highlight the possibility of developing an optimal therapeutic alternative for nerve defects using the O-CCH/PCL scaffold. PMID- 29274479 TI - Sub-surface assessment of hydrothermal ageing in zirconia-containing femoral heads for hip joint applications. AB - : Zirconia-based materials have been used in orthopaedics since the 1980s, with large success, mainly thanks to transformation toughening. On the other hand, their main drawback is their potential sensitivity to hydrothermal ageing, i.e. tetragonal to monoclinic phase transformation on their surface in the presence of water. Hydrothermal ageing may result in roughness increase and microcracking of the surface. In this article the hydrothermal ageing behaviour of three medical grade zirconia-based materials is assessed at high temperature and extrapolated to room or body temperature. The degradation is also characterized by FIB/SEM nano-tomography to better assess sub-surface evolutions. In both zirconia and alumina-toughened zirconia (ATZ), ageing results in the presence of a homogenous transformed layer of constant thickness whose growth rate is about 8 times slower in ATZ than in zirconia. Microcracking occurs in the entire transformed layer in zirconia, but was much less relevant in ATZ. Zirconia-toughened alumina (ZTA) is much less prone to ageing. In ZTA ageing results in a thin transformed layer in which the monoclinic fraction decreases with depth. No microcracking was observed in ZTA. STATEMENT OF SIGNIFICANCE: This article details the microstructural evolution of the surface of three zirconia-based ceramics when exposed to water (hydrothermal ageing), and establishes a time-temperature equivalences of these evolutions. It shows that different zirconia-alumina composites do not degrade the same way: zirconia and alumina-toughened zirconia present a homogeneous degraded zone of constant thickness, whereas zirconia-toughened-alumina presents a gradient of transformation. These new findings will help understanding better the hydrothermal degradation of zirconia based materials, and in particular will facilitate a better prediction of the durability of zirconia-based devices such as orthopaedic implants and dental devices (implants, crowns, abutments...). PMID- 29274481 TI - Growth/no growth boundary of Clostridium perfringens from spores in cooked meat: A logistic analysis. AB - Clostridium perfringens is a major foodborne health hazard that can cause acute gastroenteritis in consumers, and is often associated with cooked meat and poultry products. Improper cooling after cooking may allow this pathogen to grow in a product, producing an enterotoxin that causes food poisoning. This study was conducted to evaluate the effect of common ingredients, including sodium tripolyphosphate (STPP), sodium lactate (NaL), and sodium chloride (NaCl), on the germination and outgrowth of C. perfringens spores in meat products. The growth/no growth test was conducted in Shahidi Ferguson Perfringens agar mixed with STPP (0-2500ppm), NaL (0-4%), and NaCl (0-4%) in microplates. Turbidity measurements at 600nm were compared before and after anaerobic incubation at 46 degrees C to evaluate growth and no growth conditions. The dichotomous responses were analyzed by logistic regression to develop a model for estimating the growth probability of C. perfringens. The probability model was used to define the threshold of growth (probability >0.1 or 0.2) of C. perfringens and validated using inoculated ground beef under optimum temperature. Inoculated ground beef was mixed with different combinations of STPP, NaL, and NaCl to observe growth or no growth of C. perfringens, and the probability was calculated from the formulation. If the threshold of growth was set to 0.2, the accuracy of the growth and no growth predictions was 95.7%, with 4.3% over-prediction of growth events (fail-safe). The results from this study suggested that proper combinations of STPP, NaL, and NaCl could be used to control the growth of C. perfringens in cooked beef under the optimum temperature. The results may also suggest that proper combinations of STPP, NaL, and NaCl in cooked meat and poultry products could be used to prevent the growth of C. perfringens during cooling. PMID- 29274482 TI - Surface decontamination of eggshells by using non-thermal atmospheric plasma. AB - In this study, the possibility of using an effective short time non-thermal plasma (NTP) treatment to inactivate Salmonella enterica serovar Enteritidis on eggshell surface was investigated. The eggshells were artificially contaminated with S. Enteritidis at an initial concentration of 107cfu/egg and then treated with an atmospheric pressure plasma jet by using air as process gas under different experimental settings with various frequencies (20-25kHz) and reference voltages (100-80%), exposure times (60-120s), distances from plasma jet (15 or 40mm) and gas flow rates (2000-3000L/h). The best result was obtained at maximum plasma power of 655W (25kHz-100% V), where S. Enteritidis concentration on egg surface was reduced below the detection limit (102cfu/egg) after 120s of treatment. The temperature remained below 35 degrees C after all plasma treatments in order to minimize the risk of egg quality alterations. Specific measurements demonstrated that there were no negative effects on egg quality after NTP treatment. The effect of plasma process on the egg cuticle was demonstrated by using scanning electron microscopy. PMID- 29274483 TI - Mathematical modelling of temperature effect on growth kinetics of Pseudomonas spp. on sliced mushroom (Agaricus bisporus). AB - The growth data of Pseudomonas spp. on sliced mushrooms (Agaricus bisporus) stored between 4 and 28 degrees C were obtained and fitted to three different primary models, known as the modified Gompertz, logistic and Baranyi models. The goodness of fit of these models was compared by considering the mean squared error (MSE) and the coefficient of determination for nonlinear regression (pseudo R2). The Baranyi model yielded the lowest MSE and highest pseudo-R2 values. Therefore, the Baranyi model was selected as the best primary model. Maximum specific growth rate (rmax) and lag phase duration (lambda) obtained from the Baranyi model were fitted to secondary models namely, the Ratkowsky and Arrhenius models. High pseudo-R2 and low MSE values indicated that the Arrhenius model has a high goodness of fit to determine the effect of temperature on rmax. Observed number of Pseudomonas spp. on sliced mushrooms from independent experiments was compared with the predicted number of Pseudomonas spp. with the models used by considering the Bf and Af values. The Bf and Af values were found to be 0.974 and 1.036, respectively. The correlation between the observed and predicted number of Pseudomonas spp. was high. Mushroom spoilage was simulated as a function of temperature with the models used. The models used for Pseudomonas spp. growth can provide a fast and cost-effective alternative to traditional microbiological techniques to determine the effect of storage temperature on product shelf-life. The models can be used to evaluate the growth behaviour of Pseudomonas spp. on sliced mushroom, set limits for the quantitative detection of the microbial spoilage and assess product shelf-life. PMID- 29274480 TI - Extracellular matrix hydrogel therapies: In vivo applications and development. AB - : Decellularized extracellular matrix (ECM) has been widely used for tissue engineering applications and is becoming increasingly versatile as it can take many forms, including patches, powders, and hydrogels. Following additional processing, decellularized ECM can form an inducible hydrogel that can be injected, providing for new minimally-invasive procedure opportunities. ECM hydrogels have been derived from numerous tissue sources and applied to treat many disease models, such as ischemic injuries and organ regeneration or replacement. This review will focus on in vivo applications of ECM hydrogels and functional outcomes in disease models, as well as discuss considerations for clinical translation. STATEMENT OF SIGNIFICANCE: Extracellular matrix (ECM) hydrogel therapies are being developed to treat diseased or damaged tissues and organs throughout the body. Many ECM hydrogels are progressing from in vitro models to in vivo biocompatibility studies and functional models. There is significant potential for clinical translation of these therapies since one ECM hydrogel therapy is already in a Phase 1 clinical trial. PMID- 29274484 TI - Effect of water activity and heating rate on Staphylococcus aureus heat resistance in walnut shells. AB - Water activity (aw) and heating rate have shown important effects on the thermo tolerance of pathogens in low moisture foods during thermal treatments. In this study, three strains were selected to compare the heat resistance in walnut shell powder and finally the most heat resistant S. aureus ATCC 25923 was chosen to investigate the influence of aw and heating rate using a heating block system (HBS). The results showed that S. aureus ATCC 25923 became more thermo-tolerant at lower aw. The D-values of S. aureus ATCC 25923 increased with decreasing water activity and heating rates (<1 degrees C/min). A significant increase in heat resistance of S. aureus ATCC 25923 in walnut shell powder was observed only for the heating rates of 0.2 and 0.5 degrees C/min but not at 1, 5 and 10 degrees C/min. There was a rapid reduction of S. aureus ATCC 25923 at elevated temperatures from 26 to 56 degrees C at a heating rate of 0.1 degrees C/min. The inactivation under non-isothermal conditions was better fitted by Weibull distribution (R2=0.97 to 0.99) than first-order kinetics (R2=0.88 to 0.98). These results suggest that an appropriate increase in moisture content of in-shell walnuts and heating rate during thermal process can improve the inactivation efficiency of pathogens in low moisture foods. PMID- 29274485 TI - Comparative evaluation of DNA extraction methods for amplification by qPCR of superficial vs intracellular DNA from Bacillus spores. AB - : This study was designed to assess the efficiency of eight extraction methods regarding their ability to release superficial (exogenous) and intracellular (endogenous) DNA from B. cereus spores for subsequent analysis by quantitative PCR (qPCR). B. cereus spore suspensions were subjected to both commercial DNA extraction kits and mechanical DNA extraction methods. The spores were observed by transmission electron microscopy to evaluate any damage caused during extraction. The efficiency of both extraction and purification were assessed using a qPCR assay targeting the bclA gene. Most of the extraction methods assessed, except the passage through the French press or the use of the QIAamp DNA Blood Mini kit without 95 degrees C treatment, allowed the amplification of significant amounts of DNA. By using propidium monoazide, which is a photoreactive DNA-binding dye, the presence of non-negligible amounts of amplifiable DNA at the spore surface was highlighted. A further set of extraction assays was then performed on spores previously treated with PMA. The results of this study show that both superficial and intracellular spore DNA can be released by extraction methods to a greater or lesser extent and then further amplified by qPCR. The Precellys extraction allowed the detection of both intracellular and superficial DNA, the DNeasy Blood & Tissue kit the specific detection of intracellular DNA, while the Instagene kit detected only superficial DNA. Of the methods tested in this study, the Precellys extraction was the most efficient in terms of further DNA detection. SIGNIFICANCE AND IMPACT OF THE STUDY: In order to verify the presence or absence of B. cereus spores in food or on surfaces in the food environment, the use of an efficient extraction method is required, followed by a qPCR analysis on the DNA released. Conversely, in order to quantify the population of Bacillus spores, any superficial DNA must be blocked, e.g. with PMA, prior to intracellular DNA extraction and further amplification. PMID- 29274486 TI - Tellurite resistance profiles and performance of different chromogenic agars for detection of non-O157 Shiga toxin-producing Escherichia coli. AB - Shiga toxin-producing Escherichia coli (STEC) are globally important food-borne pathogens. The isolation of non-O157 STEC is a significant public health challenge due to the dramatic diversity of their phenotypes and genotypes. In the present study, 476 non-O157 STEC strains representing 95 different O-serogroups were used to evaluate tellurite resistance and the performance of 12 different chromogenic agars. Of 476 strains, only 108 (22.7%) strains showed the minimal inhibitory concentration (MIC) values for potassium tellurite being higher than 4MUg/ml, and 96 (20.2%) strains harbored intact ter genes cluster. The presence of ter genes was significantly correlated with tellurite resistance. Six commercial chromogenic agars (TBX, MAC, SMAC, Rainbow(r) Agar O157, CHROMagarTM ECC, and Fluorocult O157) supported the growth of all strains. However, CT-SMAC, CHROMagarTM O157, and CHROMagarTM STEC agars exhibited 12.2%, 31.1%, and 38.0% of growth inhibition, respectively. Furthermore, 4.6%, 33.2%, and 45.0% of strains were inhibited on RBA-USDA, RBA-NT, and BCM O157 agar media. Variations in tellurite resistance and colony appearance might result in discrepant performance of non-O157 STEC recovery from different chromogenic agars. Using inclusive agars or less selective agar in combination with highly selective agar should be suggested to recover most non-O157 STEC strains, which would increase the probability of recovering STECs from complex background microflora. PMID- 29274487 TI - Refinement of the critical 7p22.1 deletion region: Haploinsufficiency of ACTB is the cause of the 7p22.1 microdeletion-related developmental disorders. AB - Non-recurrent microdeletion (<=2 Mb in size) in 7p22.1 is a rarely described cytogenetic aberration, only recently reported in patients with developmental delay/intellectual disability, short stature and microcephaly. The size of the deletions ranged from 0.37 to 1.5 Mb, and reported genotype-phenotype correlations identified a minimum deleted region of 0.37 Mb involving the FBLX18, ACTB, FSCN1, RNF216 and ZNF815P genes. The authors suggested that deletion of ACTB, which encodes beta-actin, an essential component of the cytoskeleton, could be responsible for the clinical features observed in the patients with a 7p22.1 microdeletion. Here, we describe a 23-month-old child displaying developmental delay, short stature, microcephaly and distinctive facial features. Chromosomal microarray analysis performed using high-resolution SNP-array platform revealed a de novo interstitial 60 Kb microdeletion in the 7p22.1 region (from 5,509,127 bp to 5,569,096 bp, hg19) encompassing only two genes: FBXL18 and ACTB. To the best of our knowledge, this is the smallest deletion at 7p22.1 to date reported in medical literature (Pubmed). Combining our data with phenotypic and genotypic data of cases from literature, we were able to narrow the minimal critical region, which contained only two genes, i.e., FBXL18 and ACTB. Our finding is useful to perform a more accurate genotype-phenotype correlation and strongly strengthen the hypothesis that haploinsufficiency of ACTB is the main cause of the clinical phenotype observed in the patients with 7p22.1 microdeletions, facilitating genetic diagnosis and counseling. PMID- 29274488 TI - Differentiation analysis of boron isotopic fractionation in different forms within plant organ samples. AB - As a critical micronutrient, boron (B) plays an important role in plant growth and embryonic development. To further understand the effects of B uptake, transportation and isotopic fractionation, the contents and isotopic compositions of hydro-soluble B in the sap and structural B fixed in the cell within individual plant tissues were investigated. The B isotope ratio was determined by multi-collector inductively coupled plasma mass spectrometry. The delta11B values in hydro-soluble and structural B in the investigated plant samples ranged from 1.570/00 to +11.300/00 and from +6.570/00 to +16.640/00, respectively. Different fractionation factors of the B isotopes, in the range of 0.9954-1.0150, were observed in these samples, indicating that in most plant tissues, the heavy isotope (11B) was preferentially enriched in structural B, which was fixed into the cell. However, there was a reversal in the fractionation of B isotopic compositions in the fruit samples compared with the other plant tissue samples. It is more powerful to examine the molecular mechanisms of B transport, uptake and utilization than the use of limited plant organ samples containing a mixture of hydro-soluble and structural B within different intra-plant compartments and in inter-plant interactions. These isotopic shifts, which may be used as important isotopic indicators, contribute to the surface processes interactions in the plant-soil system and the knowledge of the molecular mechanisms of B in the uptake and absorption by different plant species in nature. PMID- 29274489 TI - Branching tryptamines as a tool to tune their antiproliferative activity. AB - The influence of a series of tryptamine derivatives on the viability of normal (HEK293) and tumor (HepG2, Jurkat and SH-SY5Y) cells has been evaluated. All tryptamines tested were three different substitution types: C- and N-branching, and indole benzylation. All the derivations enhance the activity of compounds separately, although the effects of different substitutions were not additive. Thus, combinations of C- and N-branchings as well as C-branching and indole benzylation gave little or no increase in activity. PMID- 29274490 TI - Colchicine prodrugs and codrugs: Chemistry and bioactivities. AB - Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as intentions for toxicity reduction and structure-activity relationship (SAR) studying. Hybrid system of colchicine structure with nontoxic biofunctional compounds modified further affords a new entity in chemical structure with enhanced activity and selectivity. Moreover, nanocarrier formulation strategies have been used for colchicine delivery. This review paper focuses on colchicine nanoformulation, chemical synthesis of colchicine prodrugs and codrugs with different linkers, highlights linker chemical nature and biological activity of synthesized compounds. Additionally, classification of colchicine prodrugs based on type of conjugates is discussed, as biopolymers prodrugs, fluorescent prodrug, metal complexes prodrug, metal-labile prodrug and bioconjugate prodrug. Finally, we briefly summarized the biological importance of colchicine nanoformulation, colchicine prodrugs and codrugs. PMID- 29274491 TI - Photoactive platinum(II) complexes of nonsteroidal anti-inflammatory drug naproxen: Interaction with biological targets, antioxidant activity and cytotoxicity. AB - The effect on the therapeutic efficacy of Pt(II) complexes on combining non steroidal anti-inflammatory drugs (NSAIDs) is an attractive strategy to circumvent chronic inflammation mediated by cancer and metastasis. Two square planar platinum(II) complexes: [Pt(dach)(nap)Cl] (1) and [Pt(dach)(nap)2] (2), where dach = (1R,2R)-dichloro(cyclohexane-1,2-diamine) and NSAID drug naproxen (nap), have been designed for studying their biological activity. The naproxen bound to the Pt(II) centre get released upon photoirradiation with low-power UV-A light as confirmed by the significant enhancement in emission intensities of the complexes. The compounds were evaluated for their photophysical properties, photostability, reactivity with 5'-guanosine monophophosphate (5'-GMP), interactions with CT-DNA and BSA, antioxidant activity and reactive oxygen species mediated photo-induced DNA damage properties. ESI-MS studies demonstrated the formation of bis-adduct with 5'-GMP and the formation of PtII-DNA crosslinks by gel electrophoretic mobility shift assay and ITC studies. The interaction of the complexes 1 and 2 with the CT-DNA exhibits potential binding affinity (Kb ~ 104 M-1, Kapp~ 105 M-1), implying intercalation to CT-DNA through planar naphthyl ring of the complexes. Both the complexes also exhibit strong binding affinity towards BSA (KBSA~ 105 M-1). The complexes exhibit efficient DNA damage activity on irradiation at 365 nm via formation of singlet oxygen (1O2) and hydroxyl radical (*OH) under physiological conditions. Both the complexes were cytotoxic in dark and exhibit significant enhancement of cytotoxicity upon photo-exposure against HeLa and HepG2 cancer cells giving IC50 values ranging from 8 to 12 MUM for 1 and 2. The cellular internalization data showed cytosolic and nuclear localization of the complexes in the HeLa cells. PMID- 29274492 TI - The synthesis, antifungal and apoptotic effects of triazole-oxadiazoles against Candida species. AB - In search of potent and safe antifungal agents, herein, we report the synthesis, characterization and biological activities of triazole-oxadiazole compounds. The structural verification of the molecules was carried out by 1H NMR, 13C NMR and mass spectral data. The in vitro antifungal and apoptotic activity were investigated against C. albicans, C. parapsilosis, C. krusei and C. glabrata. The compounds namely N-(4-nitrophenyl)-2-[(5-(2-((4-methyl-4H-1,2,4-triazol-3 yl)thio)ethyl)-1,3,4-oxadiazol-2-yl)thio]acetamide (4e) and N-(6 fluorobenzothiazol-2-yl)-2-[(5-(2-((4-methyl-4H-1,2,4-triazol-3-yl)thio)ethyl) 1,3,4-oxadiazol-2-yl)thio]acetamide (4i) were detected as the most potent compounds against C. albicans and C. glabrata (MIC90 = 62.5 MUg/mL). According to studies on their mechanism of action, it was confirmed that compound 4i has apoptotic effect on four Candida via Annexin V-PI with flow cytometry. The MTT assay revealed that all compounds were determined to be non-toxic against healthy cells in the tested concentrations. PMID- 29274493 TI - 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity. AB - The emergence of multi- and extensively-drug resistant tubercular (MDR- and XDR TB) strains of mycobacteria has limited the use of existing therapies, therefore new drugs are needed. Dihydrofolate reductase (DHFR) has recently attracted much attention as a target for the development of anti-TB agents. This study aimed to develop selective M. tuberculosis DHFR inhibitors using rationale scaffolding design and synthesis, phenotype-oriented screening, enzymatic inhibitory study, whole cell on-target validation, molecular modeling, and in vitro DMPK determination to derive new anti-TB agents. 2,4-diamino-1-phenyl-1,3,5 triazaspiro[5.5]undeca-2,4-dienes 20b and 20c were identified as selective M. tuberculosis DHFR inhibitors, showing promising antimycobacterial activities (MIC50: 0.01 MUM and MIC90: 0.025 MUM on M. tuberculosis H37Rv). This study provided compelling evidence that compound 20b and 20c exerted whole cell antimycobacterial activity through DHFR inhibition. In addition, these two compounds exhibited low cytotoxicity and low hemolytic activity. The in vitro DMPK and physiochemical properties suggested their potential in vivo efficacy. PMID- 29274494 TI - An integrative review: Developing and measuring creativity in nursing. AB - OBJECTIVE: To analyze and synthesise the existing evidence on creativity in nursing. DESIGN: An integrative review. DATA SOURCES: A systematic search was conducted using seven English databases (PubMed, Science Direct, Web of Science, Cochrane, EBSCO, Wiley, and Medline) and the top three best Chinese databases (CNKI, Wanfang Data, and VIP). REVIEW METHODS: The combined keywords, creativity and nursing/nurse, were used to search for relevant journal articles that were written in English or Chinese from January 1995 to December 2016. The components of articles, i.e. title, abstract, full-text and the cited reference, were screened, filtered, evaluated and recorded according to the PRISMA statements and Joanna Briggs Institute Checklists. Thematic analysis was performed to synthesise evidence from the full-texts of studies. RESULTS: Fifteen quantitative and seven qualitative studies were included in this review. A joyful affective perspective enriched the conceptualization of creativity in nursing. Many intrinsic factors (e.g. learning styles, thinking styles, intrinsic passion, interest in nursing and achievement motivation) or extrinsic factors (mostly workplace problems and nurses' shortage) could influence nurses' and nursing students' creativity. Artistic expressions (e.g. painting, music, and pottery), self-directed learning and group/team work were reported to have a positive effect on creativity enhancement. None of existing instruments can adequately measure nurses' or nursing students' creativity. CONCLUSIONS: The concept of creativity requires an explicit definition, which is essential to the development and evaluation of creativity in nursing education and practice. Many factors influencing nurses' and nursing students' creativity can be implemented to achieve positive outcomes through efforts at artistic expressions, self-directed learning and teamwork. An instrument with satisfactory psychometric properties should be available for monitoring creativity development among nurses and nursing students. PMID- 29274495 TI - Reclassification of Lamprotula rochechouartii as Margaritifera rochechouartiicomb. nov. (Bivalvia: Margaritiferidae) revealed by time-calibrated multi-locus phylogenetic analyses and mitochondrial phylogenomics of Unionoida. AB - The family Margaritiferidae encompasses 12 valid species, which are distributed widely but disjunctively in the Northern Hemisphere. A lack of a well resolved and temporally calibrated phylogenetic framework of Margaritiferidae has made it difficult to discuss the evolutionary pattern and process. Phylogenetic relationships between five major clades, which were revealed in earlier studies, remain elusive and unresolved. Lamprotula rochechouartii has long been classified within the family Unionidae based on shell morphology, but our preliminary molecular study on this species made us hypothesize that it has an affinity with margaritiferids. Hence, five loci (COI, 16S, 18S, 28S and histone H3) were used to investigate the phylogenetic position of L. rochechouartii and intra-familial relationships within Margaritiferidae using various partitioning strategies. Moreover, two mitochondrial genomes were newly obtained to further resolve and validate the five-clade relationships within Margaritiferidae in a broad view of Unionoida evolution. Both five-gene and mitogenome datasets strongly advocated treating Lamprotula rochechouartii as Margaritifera rochechouartiicomb. nov. Maximum likelihood and Bayesian inference analyses using partitioned five-gene dataset resulted in various topologies, but five well-supported clades were obtained. The most probable cladistic relationships generated by five-gene dataset analyses were identical to subsequent whole mitogenome analyses except the position of M. monodonta. M. rochechouartii and M. laosensis had a well supported sister relationship and formed a basal clade splitting from the rest of the family. Based on six reliable fossils, crown age of the extant Margaritiferidae was estimated during the Late Cretaceous at 88.3 Ma (95% HPD = 66.2-117.4). But we hypothesized a much earlier origin of this family due to the Permian stem age (mean = 257 Ma, 95% HPD = 230.0-296.0) and a high extinction rate in the whole order. Biogeographic scenarios supported a Laurasian origin of extant Margaritiferidae during the Late Cretaceous, and suggested that Asian margaritiferids may have had two origins, having either Asia (M. rochechouartii, M. laosensis) or North America (M. dahurica, M. laevis, and M. middendorffi) as ancestral. The newly added Margaritiferidae species M. rochechouartii expands our recognized distribution range of modern margaritiferids. Our results indicate that whole mitogenome sequences can be used to reconstruct robust phylogenetic relationships for freshwater mussels, especially with the help of adding M-type mitogenomes. PMID- 29274496 TI - New World spittlebugs (Hemiptera: Cercopidae: Ischnorhininae): Dated molecular phylogeny, classification, and evolution of aposematic coloration. AB - The spittlebug family Cercopidae (Hemiptera: Auchenorrhyncha: Cicadomorpha: Cercopoidea) is distributed worldwide, with highest species diversity in the tropics. Several included species are economically important pests of major agricultural crops and cultivated pasture grasses. Taxonomically, Cercopidae is divided into two subfamilies: the paraphyletic Old World Cercopinae and the monophyletic New World Ischnorhininae. Results are here presented from an investigation of phylogenetic relationships within Ischnorhininae based on DNA sequences from seven loci (18S rDNA, 28S rDNA, Histone 2A, Histone 3, Wingless, Cytochrome Oxidase I, and Cytochrome Oxidase II) generated from exemplars of 119 spittlebug species. The resulting topology is used to test alternative higher level classification hypotheses of Ischnorhininae and, with fossil-calibration, dates were estimated for major events in the evolutionary history of Cercopidae, including a much earlier divergence date (around 68-50 Mya) than previously reported in the literature. In addition, for the first time in Cercopidae, ancestral states of some predation avoidances strategies were reconstructed, with results suggesting an origin of aposematic coloration in the Cercopidae ancestor, with subsequent independent losses of aposematic coloration in multiple lineages. PMID- 29274498 TI - Species delimitation within the Bothryorrhynchapion weevils: Multiple evidence from genetics, morphology and ecological associations. AB - Curculionidae is a hyperdiverse group of beetles, whose taxonomy and phylogenetics are still poorly understood, especially at the genus level. The latest work on the evolution of Apionini showed a noticeable "mess" in the subtribe Oxystomatina, where most of the morphology-based genera were found to be polyphyletic or paraphyletic. These discrepancies between classical taxonomy and molecular phylogenetics implied the need for further taxonomic revision of these groups. Here, we used sets of morphological, molecular and ecological characters to verify the taxonomic statuses and disentangle the phylogenetic relations among the Bothryorrhynchapion apionids, which are classified as a subgenus of Cyanapion. Morphological data including morphometrics, and multilocus molecular analyses confirmed the monophyly of the Bothryorrhynchapion and species statuses of five species. The morphological analyses showed that Cyanapion (Bothryorrhynchapion) protractum (Sharp, 1891) from the southeast Palaearctic is a synonym of C. (B.) gyllenhalii (Kirby). Moreover, ecological features (host plant use and presence/absence of the endosymbiotic bacteria Wolbachia) helped to unravel the relations among the examined weevils. The speciation of Bothryorrhynchapion apionids was probably affected by allopatric distribution, shifts in the preferred host plants (Vicia sp. or Lathyrus sp.) of sympatric taxa, and infection by different strains of Wolbachia. The paper presents the first comprehensive description of the species' morphology, biology and ecology, and includes a key to the species. PMID- 29274497 TI - A phylogenomic analysis of lichen-feeding tiger moths uncovers evolutionary origins of host chemical sequestration. AB - Host species utilize a variety of defenses to deter feeding, including secondary chemicals. Some phytophagous insects have evolved tolerance to these chemical defenses, and can sequester secondary defense compounds for use against their own predators and parasitoids. While numerous studies have examined plant-insect interactions, little is known about lichen-insect interactions. Our study focused on reconstructing the evolution of lichen phenolic sequestration in the tiger moth tribe Lithosiini (Lepidoptera: Erebidae: Arctiinae), the most diverse lineage of lichen-feeding moths, with 3000 described species. We built an RNA-Seq dataset and examined the adult metabolome for the presence of lichen-derived phenolics. Using the transcriptomic dataset, we recover a well-resolved phylogeny of the Lithosiini, and determine that the metabolomes within species are more similar than those among species. Results from an initial ancestral state reconstruction suggest that the ability to sequester phenolics produced by a single chemical pathway preceded generalist sequestration of phenolics produced by multiple chemical pathways. We conclude that phenolics are consistently and selectively sequestered within Lithosiini. Furthermore, sequestration of compounds from a single chemical pathway may represent a synapomorphy of the tribe, and the ability to sequester phenolics produced by multiple pathways arose later. These findings expand on our understanding of the interactions between Lepidoptera and their lichen hosts. PMID- 29274499 TI - Impact of leakage delay on bifurcation in high-order fractional BAM neural networks. AB - The effects of leakage delay on the dynamics of neural networks with integer order have lately been received considerable attention. It has been confirmed that fractional neural networks more appropriately uncover the dynamical properties of neural networks, but the results of fractional neural networks with leakage delay are relatively few. This paper primarily concentrates on the issue of bifurcation for high-order fractional bidirectional associative memory(BAM) neural networks involving leakage delay. The first attempt is made to tackle the stability and bifurcation of high-order fractional BAM neural networks with time delay in leakage terms in this paper. The conditions for the appearance of bifurcation for the proposed systems with leakage delay are firstly established by adopting time delay as a bifurcation parameter. Then, the bifurcation criteria of such system without leakage delay are successfully acquired. Comparative analysis wondrously detects that the stability performance of the proposed high order fractional neural networks is critically weakened by leakage delay, they cannot be overlooked. Numerical examples are ultimately exhibited to attest the efficiency of the theoretical results. PMID- 29274500 TI - Cortical hemodynamic changes during the Trier Social Stress Test: An fNIRS study. AB - The study of the stress response has been of great interest in the last decades due to its relationship to physical and mental health. Along with the technological progress in the neurosciences, different methods of stress induction have been developed for the special requirements regarding the acquisition of neuroimaging data. However, these paradigms often differ from ecologically valid stress inductions such as the Trier Social Stress Test (TSST) in substantial ways. In the study at hand, we used the rather robust optical imaging method of functional Near-infrared Spectroscopy (fNIRS) to assess brain activation during the TSST and two non-stressful control conditions. Additionally, we measured other stress parameters including the cortisol response and subjective stress ratings. As expected we found significant increases in subjective and physiological stress measures during the TSST in comparison to the baseline and control conditions. We found higher activation in parts of the cognitive control network (CCN) and dorsal attention network (DAN) - comprising the dorsolateral prefrontal cortex, the inferior frontal gyrus and superior parietal cortex - during the performance of the TSST in comparison to the control conditions. Further, calculation errors during the TSST as well as subjective and physiological stress parameters correlated significantly with the activation in the CCN. Our study confirms the validity of previous neuroimaging data obtained from adapted stress procedures by providing cortical activation data during a classical stress induction paradigm (i.e., the TSST) for the first time. PMID- 29274501 TI - Using diffusion MRI to discriminate areas of cortical grey matter. AB - Cortical area parcellation is a challenging problem that is often approached by combining structural imaging (e.g., quantitative T1, diffusion-based connectivity) with functional imaging (e.g., task activations, topological mapping, resting state correlations). Diffusion MRI (dMRI) has been widely adopted to analyse white matter microstructure, but scarcely used to distinguish grey matter regions because of the reduced anisotropy there. Nevertheless, differences in the texture of the cortical 'fabric' have long been mapped by histologists to distinguish cortical areas. Reliable area-specific contrast in the dMRI signal has previously been demonstrated in selected occipital and sensorimotor areas. We expand upon these findings by testing several diffusion based feature sets in a series of classification tasks. Using Human Connectome Project (HCP) 3T datasets and a supervised learning approach, we demonstrate that diffusion MRI is sensitive to architectonic differences between a large number of different cortical areas defined in the HCP parcellation. By employing a surface based cortical imaging pipeline, which defines diffusion features relative to local cortical surface orientation, we show that we can differentiate areas from their neighbours with higher accuracy than when using only fractional anisotropy or mean diffusivity. The results suggest that grey matter diffusion may provide a new, independent source of information for dividing up the cortex. PMID- 29274503 TI - Human aging reduces the neurobehavioral influence of motivation on episodic memory. AB - The neural circuitry mediating the influence of motivation on long-term declarative or episodic memory formation is delineated in young adults, but its status is unknown in healthy aging. We examined the effect of reward and punishment anticipation on intentional declarative memory formation for words using an event-related functional magnetic resonance imaging (fMRI) monetary incentive encoding task in twenty-one younger and nineteen older adults. At 24 hour memory retrieval testing, younger adults were significantly more likely to remember words associated with motivational cues than neutral cues. Motivational enhancement of memory in younger adults occurred only for recollection ("remember" responses) and not for familiarity ("familiar" responses). Older adults had overall diminished memory and did not show memory gains in association with motivational cues. Memory encoding associated with monetary rewards or punishments activated motivational (substantia nigra/ventral tegmental area) and memory-related (hippocampus) brain regions in younger, but not older, adults during the target word periods. In contrast, older and younger adults showed similar activation of these brain regions during the anticipatory motivational cue interval. In a separate monetary incentive delay task that did not require learning, we found evidence for relatively preserved striatal reward anticipation in older adults. This supports a potential dissociation between incidental and intentional motivational processes in healthy aging. The finding that motivation to obtain rewards and avoid punishments had reduced behavioral and neural influence on intentional episodic memory formation in older compared to younger adults is relevant to life-span theories of cognitive aging including the dopaminergic vulnerability hypothesis. PMID- 29274502 TI - Subtyping cognitive profiles in Autism Spectrum Disorder using a Functional Random Forest algorithm. AB - DSM-5 Autism Spectrum Disorder (ASD) comprises a set of neurodevelopmental disorders characterized by deficits in social communication and interaction and repetitive behaviors or restricted interests, and may both affect and be affected by multiple cognitive mechanisms. This study attempts to identify and characterize cognitive subtypes within the ASD population using our Functional Random Forest (FRF) machine learning classification model. This model trained a traditional random forest model on measures from seven tasks that reflect multiple levels of information processing. 47 ASD diagnosed and 58 typically developing (TD) children between the ages of 9 and 13 participated in this study. Our RF model was 72.7% accurate, with 80.7% specificity and 63.1% sensitivity. Using the random forest model, the FRF then measures the proximity of each subject to every other subject, generating a distance matrix between participants. This matrix is then used in a community detection algorithm to identify subgroups within the ASD and TD groups, and revealed 3 ASD and 4 TD putative subgroups with unique behavioral profiles. We then examined differences in functional brain systems between diagnostic groups and putative subgroups using resting-state functional connectivity magnetic resonance imaging (rsfcMRI). Chi-square tests revealed a significantly greater number of between group differences (p < .05) within the cingulo-opercular, visual, and default systems as well as differences in inter-system connections in the somato-motor, dorsal attention, and subcortical systems. Many of these differences were primarily driven by specific subgroups suggesting that our method could potentially parse the variation in brain mechanisms affected by ASD. PMID- 29274504 TI - A preliminary analysis of the effects of bisphenol A on the plant root growth via changes in endogenous plant hormones. AB - Bisphenol A (BPA) is ubiquitous in the environment worldwide, affecting plant growth and development. Endogenous plant hormones serve as switches that regulate plant growth and development. However, plants have different physiological requirements and environmental adaptive capacities during the different growth stages. Here, we investigated the effects of BPA on soybean (Glycine max L.) root growth at the three growth stages and analyzed the mechanisms underlying the effects of BPA on the root growth by assessing changes in endogenous hormone. The results showed that low concentration of BPA (1.5mgL-1) improved root growth (except at the seed-filling stage), increased indole-3-acetic acid (IAA) content at the first two growth stages, and increased zeatin (ZT) content and decreased gibberellic acid (GA3) content at the seedling stage. But low concentration of BPA caused decreased ethylene (ETH) contents and constant abscisic acid (ABA) content at all three stages. However, BPA at moderate and high concentrations (6.0 and 12.0mgL-1) inhibited root growth, causing the decreased IAA, GA3 and ETH contents and increased ABA content at all three growth stages. The change degrees of above indices were weakened with prolonging the growth stages. After BPA withdrawal, both the root growth and the hormone contents recovered (with the exception of ZT and ETH), and the recovery degrees had negative correlation with the BPA exposure concentration and had positive correlation with the growth stage. Changes in residual BPA content in the roots were also observed at different BPA concentrations and different growth stages. Our results demonstrated the effects of BPA on root growth were related to BPA-induced changes in hormone, which performed differently at various growth stages. PMID- 29274506 TI - Spectrum imaging of complex nanostructures using DualEELS: II. Absolute quantification using standards. AB - Nanometre-sized TixV(1-x)CyNz precipitates in an Fe20%Mn steel matrix with a thickness range from 14 to 40 nm are analysed using DualEELS. Their thicknesses, volumes and compositions are quantified using experimental binary standards and the process used to give robust results is described. Precisions of a few percent are achieved with accuracies that are estimated to be of a similar magnitude. Sensitivities are shown to be at 0.5-1 unit cells range in the thinnest matrix region, based on the assumption that a sub-lattice is fully populated by the element. It rises to the 1-2 unit cell range for the metals and 2-3 unit cells for the non-metal in the thickest matrix region. The sensitivities for Ti and N are greater than those for V and C respectively because the O K-edge from surface oxide needs to be separated from the V L2,3-edge, and the C K-edges from C in the matrix and amorphous C on the surface have to be separated from the C in the precipitate itself. Separation of the contributions from the bulk and the surface is demonstrated, showing that there is significant and detectable C in the matrix but no O, while there is significant O but little C in the surface oxide. Whilst applied to precipitates in steel in this work, the approach can be adapted to many multi-phase systems. PMID- 29274505 TI - Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor. AB - The endocannabinoid (eCB) system, including its receptors, ligands, and their metabolizing enzymes, plays an important role in bone physiology. Skeletal cannabinoid type 1 (CB1) receptor signaling transmits retrograde signals that restrain norepinephrine (NE) release, thus transiently stimulating bone formation following an acute challenge, suggesting a feedback circuit between sympathetic nerve terminals and osteoblasts. To assess the effect of chronic in vivo occurrence of this circuit, we characterized the skeletal phenotype of mice with a conditional deletion of the CB1 receptor in adrenergic/noradrenergic cells, including sympathetic nerves. Whereas the deletion of the CB1 receptor did not affect bone mass accrual in the distal femoral metaphysis and in vertebral bodies of young, 12-week-old mice, it substantially increased bone mass in aged, 35-week old mutant mice as compared to wild-type controls. Contrary to our expectations, specific deficiency of the CB1 receptor in sympathetic neurons led to a markedly increased bone mass phenotype, associated with an enhanced bone formation rate and reduced osteoclastogenesis. Mechanistically, the reduced skeletal eCB 'tone' in the null mice did not reflect in increased sympathetic tone and reduced bone formation, suggesting that constitutive genetic inactivation of sympathetic CB1 receptor disrupts the negative feedback loop between eCBs and NE signaling in bone. PMID- 29274507 TI - Mediterranean diet improves endothelial function in patients with diabetes and prediabetes: A report from the CORDIOPREV study. AB - BACKGROUND AND AIMS: Endothelial dysfunction (ED) plays a key role in the development of atherosclerotic cardiovascular disease (ASCVD). Likewise, type 2 diabetes (T2D) is a major CVD risk factor. Therefore, our objective was to explore whether long-term consumption of a Mediterranean diet (MedDiet) rich in olive oil or a low-fat diet (LF diet) was associated with an improvement in ED and whether the potential benefits were similar in patients with or without T2D in the CORDIOPREV clinical trial (NCT00924937). METHODS: Endothelial function was measured in 805 participants who had completed follow-up ultrasound image studies, using ultrasonography of brachial artery to calculate flow mediated vasodilatation (FMD) before and after 1.5 years of intervention with a MedDiet [35% of calories from fat (22% monounsaturated) and 50% from carbohydrates] and LF diet [28% fat (12% monounsaturated) and 55% of calories from carbohydrates]. We categorized participants as patients with T2D, prediabetes, and without T2D according to the American Diabetes Association (ADA) criteria. RESULTS: MedDiet increased FMD in patients with T2D [5.2 +/- 0.4 at 1.5 years vs. 3.8 +/- 0.4 at baseline; p=0.04] and prediabetes [4.9 +/- 0.4 vs. 3.8 +/- 0.4; p=0.04] and induced an improvement in FMD compared to LF diet in patients with diabetes [5.2 +/- 0.4 (MedDiet) vs.3.7 +/- 0.4 (LF diet); p=0.01]; whereas both diets maintained FMD stable in patients without diabetes. CONCLUSIONS: Habitual consumption of a MedDiet rich in extra virgin olive oil improves endothelial function in patients with prediabetes and diabetes. This takes great importance given that diet must be the cornerstone of treatment of patients with diabetes at high cardiovascular risk. PMID- 29274509 TI - Retelling stories: Grammatical and lexical measures for identifying monolingual spanish speaking children with specific language impairment (SLI). AB - Children with Specific Language Impairment (SLI) have grammatical and lexical difficulties when telling stories. The aim of this work was to explore whether language productivity measures, such as mean length of utterance (MLU), percentage of ungrammatical sentences (%UGS), total number of words (TNW), and number of different words (NDW) produced by young children during a story retell task, can be used to accurately differentiate monolingual Spanish-speaking children with SLI from children with typical language development (TLD). Fifty monolingual Spanish-speaking children between 4; 0 and 6; 11 years were assigned to one of two groups: 25 children with SLI and 25 TLD age-matched peers. A scripted picture book was read to each child and the child was subsequently asked to retell the story using pictures. Story retells were analyzed for MLU, %UGS, TNW, and NDW. Results showed significant differences between groups on all four measures. Children with SLI showed significantly lower MLU, TNW and NDW, and significantly higher%UGS when compared with age-matched peers with TLD. Results suggest that measures of language productivity obtained during story retells may be used to accurately detect differences in language performance and differentiate monolingual Spanish-speaking children with SLI from their typical peers. The findings from this study have clinical implications for assessment and identification of monolingual Spanish-speaking children with language impairments. PMID- 29274508 TI - A Heparin Binding Motif Rich in Arginine and Lysine is the Functional Domain of YKL-40. AB - The heparin-binding glycoprotein YKL-40 (CHI3L1) is intimately associated with microvascularization in multiple human diseases including cancer and inflammation. However, the heparin-binding domain(s) pertinent to the angiogenic activity have yet been identified. YKL-40 harbors a consensus heparin-binding motif that consists of positively charged arginine (R) and lysine (K) (RRDK; residues 144-147); but they don't bind to heparin. Intriguingly, we identified a separate KR-rich domain (residues 334-345) that does display strong heparin binding affinity. A short synthetic peptide spanning this KR-rich domain successfully competed with YKL-40 and blocked its ability to bind heparin. Three individual point mutations, where alanine (A) substituted for K or R (K337A, K342A, R344A), led to remarkable decreases in heparin-binding ability and angiogenic activity. In addition, a neutralizing anti-YKL-40 antibody that targets these residues and prevents heparin binding impeded angiogenesis in vitro. MDA-MB-231 breast cancer cells engineered to express ectopic K337A, K342A or R344A mutants displayed reduced tumor development and compromised tumor vessel formation in mice relative to control cells expressing wild-type YKL-40. These data reveal that the KR-rich heparin-binding motif is the functional heparin binding domain of YKL-40. Our findings shed light on novel molecular mechanisms underlying endothelial cell angiogenesis promoted by YKL-40 in a variety of diseases. PMID- 29274510 TI - Assessment of water-soluble thiourea-formaldehyde (WTF) resin for stabilization/solidification (S/S) of heavy metal contaminated soils. AB - Stabilization/Solidification (S/S) can be regarded as necessary for remediation of heavy metal contaminated soil. There is, however, solid agent is not very convenient to use. Water-soluble thiourea-formaldehyde (WTF) is a novel chelating agent, which has more practical applications. The process of WTF resin for S/S process of heavy metal contaminated soils was studied. Laboratory-prepared slurries, made of field soils spiked with Cd2+ and Cr6+ were treated with WTF resin. The toxicity characteristic leaching procedure (TCLP) showed that with 2 wt% WTF, in the neutral condition of soil after treatment for 7 d, the leaching concentrations of Cd2+ and Cr6+ in contaminated soil were decreased by 80.3% and 92.6% respectively. Moreover, Tessier sequence extraction procedure showed WTF resin reduced the leaching concentration by transforming heavy metal from exchange form to organic form. The structure of WTF is obtained according to elemental analysis result and reaction mechanism. Through analysis of the infrared spectrogram of WTF and WTF heavy mental chelating precipitation, WTF can form stable chelate with heavy mental through coordination. The significant groups are hydroxyl, nitrogen and sulphur function groups in WTF mainly. Toxicology test revealed that the WTF resin is nontoxic to microorganism in the soils. PMID- 29274511 TI - Continuous generation of hydroxyl radicals for highly efficient elimination of chlorophenols and phenols catalyzed by heterogeneous Fenton-like catalysts yolk/shell Pd@Fe3O4@metal organic frameworks. AB - Core/shell Fe3O4-decorated Pd nanoparticles (NPs) hybrids (Pd@Fe3O4) are prepared through a "green", and one-pot chemical process. The Pd@Fe3O4 hybrids consisted of faceted quasi-spherical Pd nanoparticles (NPs) cores (~20 nm) surrounded by close-packed Fe3O4 NPs (~7 nm). To improve the stability and avoid aggregation of Pd@Fe3O4 hybrids in water, hollow Fe-metal organic frameworks (Fe-MOFs) were applied to enwrap Pd@Fe3O4 to obtain yolk/shell structured composites. Sub-10 nm Fe3O4 and Pd NPs close to each other were distributed evenly in the MOFs shell of Pd@Fe3O4@MOFs. The yolk/shell Pd@Fe3O4@MOFs can catalyze the oxidative degradation of chlorophenols and phenols by hydroxyl radicals (OH) decomposed from H2O2. With low molar ratio of H2O2/pollutants, the pollutants are degraded and mineralized efficiently and rapidly. The outstanding catalytic efficiency of Pd@Fe3O4@MOFs is contributed by the fast and continuous generation of OH radicals in Pd@Fe3O4@MOFs suspension which is detected with the electron spin resonance spin-trap technique and a continuous-flow chemiluminescence system. Lack of consumption of hydroperoxyl radicals/superoxide radicals (HO2/O2-) in the Pd@Fe3O4@MOFs-H2O2 system might suggest that the production of OH radicals results from the electron transferring from Pd to Fe3O4 component both in the inner Pd@Fe3O4 and MOF shell, which facilitates fast Fe(III)/Fe(II) redox cycle. PMID- 29274512 TI - Arsenic release and speciation during the oxidative dissolution of arsenopyrite by O2 in the absence and presence of EDTA. AB - The oxidative decomposition of arsenopyrite is an important source of As in surface environment. This study investigated the oxidative dissolution of arsenopyrite by O2 and aqueous arsenic transformation at different pHs, dissolved oxygen (DO) contents, and temperatures in the absence and presence of EDTA. The oxidative dissolution was greatly inhibited at neutral and alkaline pH in the absence of EDTA. However, in the presence of EDTA, the oxidative dissolution rate increased linearly from pH 4 to 7. The highest dissolution rate was 3-4 times higher than that at pH 4 and 1-2 orders of magnitude higher than that at pH 7 in the absence of EDTA. This is possibly due to the lack of Fe oxyhydroxides on the surface of arsenopyrite. In the pH range of 7-10, the oxidative dissolution rate decreased linearly, possibly due to the formation of goethite and/or hematite coating. The oxidation of released arsenite (AsIII) to arsenate (AsV) took place simultaneously during the oxidative dissolution of arsenopyrite in the presence of dissolved Fe without EDTA, while no obvious aqueous AsIII oxidation was observed in the presence of EDTA, indicating that aqueous Fe species play an important role in AsIII oxidation. PMID- 29274513 TI - miR-143 inhibits intracellular salmonella growth by targeting ATP6V1A in macrophage cells in pig. AB - Salmonella infects many vertebrate species, and animals such as pigs can be colonized with Salmonella and become established carriers. Analyzing the roles of microRNA in intracellular proliferation is important for understanding the process of Salmonella infection. The objective of this study is to verify the regulation effect of miR-143 on ATP6V1A and its functions in the intracellular growth of Salmonella. A new miR-143 binding site was discovered in the 3' UTR of ATP6V1A using a newly developed prediction tool. The binding site was confirmed by binding site deletion assay. Real-time PCR results indicated that ATP6V1A was predominantly expressed in bone-marrow-derived macrophages, and the expression of miR-143 in different tissues was negatively correlated with ATP6V1A. The Salmonella proliferation assay showed that the expression of miR-143 could inhibit intracellular Salmonella growth in macrophages by target ATP6V1A. The results strongly suggest that miR-143 plays important regulatory roles in the development of Salmonella infection in animals. PMID- 29274514 TI - Distribution of single nucleotide polymorphisms and protein domain architecture of toll-like receptor-2 in Pahari cattle (Indian non-descript indigenous breed). AB - Distribution of polymorphism in TLR2 gene was studied in Pahari (Indian non descript indigenous breed) cattle of Himachal Pradesh. The complete sequence of TLR2 gene consisted of 136bp 5'-UTR, 2355bp CDS and 1316bp 3'UTR. The phylogenetic analysis revealed clustering of Indian Zebu with Bos taurus as the nearest neighbour. The nucleotide sequences of TLR2 revealed the occurrence of 19 SNPs including 47% non-synonymous and 53% synonymous SNPs within TLR domain among all bovines. The dS/dN ratio (omega)<1 at polymorphic sites revealed purifying selection and thus, indicating the presence of highly conserved domains. Two SNPs in the extracellular domain of TLR2 were predicted to have damaging effect whereas the rest have benign effect. The amino acid sequence of the coding region corresponds to a protein of 784 amino acids long with predicted molecular weight 104kDa and 6.97 pI value. The amino acid sequence analysis showed extracellular domain composed of leucine rich repeats (LRR), trans- membrane domain and Toll-IL receptor domain in the protein. The 3D structure of TLR2 is a solenoid-like having active sites buried in the concave side and forming a pocket for ligand binding. The substitution of G with T in nucleotide sequence leads to the replacement of amino acid W<->L at position 119 which has not been reported so far. These findings indicate that polymorphism may be associated with PAMPs mediated differential TLR signaling of bovine immunity and could determine the outcome of infection. PMID- 29274515 TI - Performance of waste-based amendments to reduce metal release from mine tailings: One-year leaching behaviour. AB - A one-year leaching experiment has been conducted in order to assess the effectiveness of several amendments on metal immobilization in mine tailings from an old Pb/Zn mining area of Central Spain (San Quintin mine). Demineralized water was used as leaching solution, selecting doses equivalent to the annual rainfall conditions of the studied area. Columns with mine tailings without any amendment and others treated with 10% of sugar foam (SF), 15% of drinking water treatment sludge (DWS), 30% of paper mill sludge (PMS) and 15% of olive mill waste (OMW) were used. SF, DWS and PMS amendments increased the pH of leachates from values of approximately 4 to around neutrality. Additionally, the release of sulfate ions from the oxidation of pyritic residues was decreased in some extent by SF and DWS amendments. Metal leaching was effectively reduced by the amendments reaching overall decreases with respect to the unamended columns of 79-96% for Pb, 36-100% for Zn, 50-99% for Cu and 44-100% for Cd. The effect of the amendments in leachate pH, sulfate concentration and metal release from mine tailings was kept throughout the whole experimental period. Our results showed that the application of different organic and inorganic amendments based on by products and waste materials may be a feasible alternative for the restoration of soils around abandoned metal mines. PMID- 29274516 TI - Highly efficient magnetic chicken bone biochar for removal of tetracycline and fluorescent dye from wastewater: Two-stage adsorber analysis. AB - Magnetic chicken bone biochar (MCB) was fabricated and characterised. The specific surface area, magnetisation value and pHpzc of the MCB were found to be 328 m2 g-1, 64.7 emu/g and 8.3 respectively. The adsorptive performance of MCB for rhodamine B dye (RB) and tetracycline (TC) removal in a single and two-stage stirred adsorber (TSA) was evaluated. The TSA reduced the pressure drops, mass transfer resistances, and fouling of the adsorbent. 63.0 g MCB is required to remove 75% of RB and TC in a single-stage system within 12 h. However, the optimised TSA confirmed that 33.2 g of MCB is needed to achieve 96% removal of TC and 22.2 g for RB within 180 min of 100 mgL-1 effluent solutions. The sorption was suitably described by the Freundlich mechanism. Based on the comparative performance, the MCB is considered a viable efficient and magnetically separable alternative adsorbent. PMID- 29274517 TI - Synergistic effect of fly ash in in-vessel composting of biomass and kitchen waste. AB - The present study aims to utilize coal fly ash for its property to adsorb heavy metals and thus reducing the bioavailability of the metals for plant uptake. Fly ash was incorporated into the in-vessel composting system along with organic waste. The in-vessel composting experiments were conducted in ten plastic vessels of 15 L capacity comprising varying proportions of biomass waste, kitchen waste and fly ash. In this study, maximum degradation of organic matter was observed in Vessel 3 having k value of 0.550 d-1. In vessel 10, 20% fly ash with a combination of 50% biomass waste and 30% kitchen waste along with the addition of 5% jaggery as an additive produced the best outcome with least organic matter (%C) loss and lowest value of rate constant (k). PMID- 29274518 TI - One-step treatment and resource recovery of high-concentration non-toxic organic wastewater by photosynthetic bacteria. AB - In order to achieve simple pollutant removal and simultaneous resource recovery in high-COD-non-toxic wastewater treatment, a one-step photosynthetic bacteria (PSB) method was established using batch study experiment. The effluent COD met the national discharge standard, and biomass with rich protein and high-value substances was efficiently produced. It eliminated the demand of post-treatment for conventional PSB treatment. Results showed that Rhodopseudomonas effectively treated brewery wastewater and achieved biomass proliferation. Yeast extract was the best additive for PSB growth and the effluent COD was below 80 mg/L with 400 mg/L yeast extract, meeting the national discharge standard. In addition, the PSB biomass increased by 2.6 times, and the cells were rich in protein, polysaccharide, carotenoids, bacteriochlorophyll and coenzyme Q10, reaching 420.9, 177.6, 2.53, 10.75 and 38.6 mg/g respectively. This work demonstrated the great potential of PSB for high-COD non-toxic wastewater treatment in one-step process. PMID- 29274520 TI - Managing imperfect competition by pay for performance and reference pricing. AB - I study a managed health service market where differentiated providers compete for consumers by choosing multiple service qualities, and where copayments that consumers pay and payments that providers receive for services are set by a payer. The optimal regulation scheme is two-sided. On the demand side, it justifies and clarifies value-based reference pricing. On the supply side, it prescribes pay for performance when consumers misperceive service benefits or providers have intrinsic quality incentives. The optimal bonuses are expressed in terms of demand elasticities, service technology, and provider characteristics. However, pay for performance may not outperform prospective payment when consumers are rational and providers are profit maximizing, or when one of the service qualities is not contractible. PMID- 29274519 TI - Evaluation of heterotrophic and mixotrophic cultivation of novel Micractinium sp. ME05 on vinasse and its scale up for biodiesel production. AB - Direct disposal of vinasse, a by-product of molasses fermentation plants, threatens environmental health. This study investigated the usage of vinasse as a nutrient source for the heterotrophic and mixotrophic cultivation of novel Micractinium sp. ME05. The 500-mL flask experiments resulted in higher biomass productivities under mixotrophic conditions (0.16 +/- 0.01 g L-1 day1) than the heterotrophic conditions (0.13 +/- 0.01 g L-1 day1). A 1.7-fold increase in biomass productivity was achieved by scaling up from 500-mL flasks (0.16 +/- 0.01 g L-1 day1) to 2-L flasks (0.27 +/- 0.019 g L-1 day1). The 5-L bioreactor experiments resulted in a biomass productivity of 0.32 +/- 0.2 g L-1 day1 and lipid productivity of 3.4 +/- 0.20 g L-1 day-1. This study demonstrated that Micractinium sp. ME05 can be cultivated with vinasse to produce large amounts of biomass. The FAME profile of mixotrophic Micractinium sp. ME05 cells was promising for further biodiesel production. This study highlights the feasibility of industrial by- product-vinasse as the nutrient source for biomass and lipid productions using the novel Micractinium sp. ME05 cells. PMID- 29274521 TI - Returns to specialization: Evidence from the outpatient surgery market. AB - Technological changes in medicine have created new opportunities to provide surgical care in lower cost, specialized facilities. This paper examines patient outcomes in ambulatory surgery centers (ASCs), which were developed as a low-cost alternative to outpatient surgery in hospitals. Because we are concerned that selection into ASCs may bias estimates of facility quality, we use predicted changes in federally set Medicare facility payment rates as an instrument for ASC utilization to estimate the effect of location of treatment on patient outcomes. We find that patients treated in an ASC are less likely to be admitted to a hospital or visit an emergency room a short time after outpatient surgery. The findings in this paper indicate that factors other than patient and physician heterogeneity contribute to the observed returns to specialization in the ASC market. PMID- 29274522 TI - Characterization and application of in-vacuum PIXE/EBS system for the direct elemental analysis of thick solid biological samples. AB - Utilization of combined particle-induced X-ray emission (PIXE) and elastic backscattering (EBS) spectrometry for the direct elemental analysis of thick solid biological samples was thoroughly discussed. Powdered samples pressed as pellets were directly analyzed. Combination of applying low ion beam currents, random scanning of the sample across the beam during data acquisition, and using special sample holder enabled effective minimization of local ion beam heating. This subsequently inhibited potential element loss during ion beam irradiation. Matrix elements were determined from multiple EBS spectra, which were acquired using three different ion beam energies. Subsequently, averaging of the elemental concentrations obtained was achieved using novel MultiSIMNRA software. Moreover, combined EBS spectrometry, nuclear reaction analysis (NRA), and elastic recoil detection analysis (ERDA) measurements were used to overcome the limitations of using EBS separately and subsequently obtain accurate matrix element concentrations. The validity of the PIXE/EBS system for the direct elemental analysis of thick biological samples was comprehensively evaluated. The obtained concentration values demonstrated reliable results for most investigated elements (5-15%), starting from sodium onwards. The non-satisfying results were evaluated and justified. PMID- 29274523 TI - Calculation of the detection limits for radionuclides identified in gamma-ray spectra based on post-processing peak analysis results. AB - A new method for calculating the detection limits of gamma-ray spectrometry measurements is presented. The method is applicable for gamma-ray emitters, irrespective of the influences of the peaked background, the origin of the background and the overlap with other peaks. It offers the opportunity for multi gamma-ray emitters to calculate the common detection limit, corresponding to more peaks. The detection limit is calculated by approximating the dependence of the uncertainty in the indication on its value with a second-order polynomial. In this approach the relation between the input quantities and the detection limit are described by an explicit expression and can be easy investigated. The detection limit is calculated from the data usually provided by the reports of peak-analyzing programs: the peak areas and their uncertainties. As a result, the need to use individual channel contents for calculating the detection limit is bypassed. PMID- 29274524 TI - Undergraduate nursing students' experience related to their clinical learning environment and factors affecting to their clinical learning process. AB - Clinical education is an essential part of nursing education. The purpose of this study was to explore nurse students' experiences related to cinical learning environments, factors effecting to clinical learning process. Descriptive qualitative design was used in this study, and data were collected from 2nd class nursing student (n = 14). The study took the form of in-depth interviews between August-October 2015. The qualitative interviews were analyzed by using simple content analysis. Data were analyzed manually. Experiences nurse students are described five themes. The themes of the study are (1) effecting persons to clinical learning, (2) educational atmosphere, (3) students' personal charactering, (4) the impact of education in school, and (5) students' perceptions related to clinical learning. Participants stated that they experienced many difficulties during clinical learning process. All students importantly stated that nurse teacher is very effecting to clinical learning. This study contributes to the literature by providing data on beginner nursing student' experiences about clinical learning process. The data of this present study show to Turkish nursing student is affecting mostly from persons in clinical learning. The data of this present study will guide nurse teacher when they plan to interventions to be performed to support student during clinical learning process. PMID- 29274525 TI - In vitro biomechanical and hydrodynamic characterisation of decellularised human pulmonary and aortic roots. AB - BACKGROUND AND PURPOSE OF THE STUDY: The use of decellularised biological heart valves in the replacement of damaged heart valves offers a promising solution to reduce the degradation issues associated with existing cryopreserved allografts. The purpose of this study was to assess the effect of low concentration sodium dodecyl sulphate decellularisation on the in vitro biomechanical and hydrodynamic properties of cryopreserved human aortic and pulmonary roots. METHOD: The biomechanical and hydrodynamic properties of cryopreserved decellularised human aortic and pulmonary roots were fully characterised and compared to cellular human aortic and pulmonary roots in an unpaired study. Following review of these results, a further study was performed to investigate the influence of a specific processing step during the decellularisation protocol ('scraping') in a paired comparison, and to improve the method of the closed valve competency test by incorporating a more physiological boundary condition. RESULTS: The majority of the biomechanical and hydrodynamic characteristics of the decellularised aortic and pulmonary roots were similar compared to their cellular counterparts. However, several differences were noted, particularly in the functional biomechanical parameters of the pulmonary roots. However, in the subsequent paired comparison of pulmonary roots with and without decellularisation, and when a more appropriate physiological test model was used, the functional biomechanical parameters for the decellularised pulmonary roots were similar to the cellular roots. CONCLUSION: Overall, the results demonstrated that the decellularised roots would be a potential choice for clinical application in heart valve replacement. PMID- 29274526 TI - Tailoring the mechanical and biodegradable properties of binary blends of biomedical thermoplastic elastomer. AB - Blending polymers with complementary properties capitalizes on the inherent advantages of both components, making it possible to tailor the behaviour of the resultant material. A polymer blend consisting of an elastomer and thermoplastic can help to improve the mechanical integrity of the system without compromising on its processibility. A series of blends of biodegradable Poly(L-lactide-co-E caprolactone) (PLC) and Poly-(l,l-lactide-co-glycolic acid) (PLLGA), and PLC with Poly-(d,l-lactide-co-glycolic acid) (PDLLGA) were evaluated as a potential material for a biodegradable vesicourethral connector device. Based on the Tg of the blends, PLC/PLLGA formed an immiscible mixture while PLC/PDLLGA resulted in a compatible blend. The results showed that with the blending of PLC, the failure mode of PLLGA and PDLLGA changed from brittle to ductile fracture, with an significant decreas in tensile modulus and strength. SEM images demonstrated the different blend morphologies of different compositions during degradation. Gel Permeation Chromatography (GPC) and mechanical characterization revealed the degradation behaviour of the blends in this order (fastest to slowest): PDLLGA and PLC/PDLLGA blends > PLLGA and PLC/PLLGA blends > PLC. The PLC/PLLGA (70:30) blend was recommended as a suitable for the vesicourethral connector device application, highlighting the tailoring of blends to achieve a desired mechanical performance. PMID- 29274527 TI - Rattle-type Au@Cu2-xS hollow mesoporous nanocrystals with enhanced photothermal efficiency for intracellular oncogenic microRNA detection and chemo-photothermal therapy. AB - The coupling of the localized surface plasma resonance (LSPR) between noble metals of Au, Ag and Cu and semiconductors of Cu2-xE (E = S, Se, Te) opens new regime to design photothermal (PT) agents with enhanced PT conversion efficiency. However, it is rarely explored on fabricating of engineered dual plasmonic hybrid nanosystem for combinatory therapeutic-diagnostic applications. Herein, rattle type Au@Cu2-xS hollow mesoporous nanoparitcles with advanced PT conversion efficiency are designed for cellular vehicles and chemo-photothermal synergistic therapy platform. The LSPR coupling between the Au core and Cu2-xS shell are investigated experimentally and theoretically to generate a PT conversion efficiency high to 35.2% and enhanced by 11.3% than that of Cu2-xS. By conjugating microRNA (miRNA) gene probe on the surface, it can realize the intracellular oncogenic miRNA detection. After loading of anticancer drug doxorubicin into the cavity of the Au@Cu2-xS, the antitumor therapy efficacy is greatly enhanced in vitro and in vivo due to the NIR photoactivation chemo- and photothermal synergistic therapy. The rattle-type metal-semiconductor hollow mesoporous nanostructure with efficient LSPR coupling and high cargo loading capability will be beneficial to future design of LSPR-based photothermal agents for a broad range of biomedical application. PMID- 29274528 TI - Studies on immunity and immunopathogenesis of parrot bornaviral disease in cockatiels. AB - We have demonstrated that vaccination of cockatiels (Nymphicus hollandicus) with killed parrot bornavirus (PaBV) plus recombinant PaBV-4 nucleoprotein (N) in alum was protective against disease in birds challenged with a virulent bornavirus isolate (PaBV-2). Unvaccinated birds, as well as birds vaccinated after challenge, developed gross and histologic lesions typical of proventricular dilatation disease (PDD). There was no evidence that vaccination either before or after challenge made the infection more severe. Birds vaccinated prior to challenge largely remained free of disease, despite the persistence of the virus in many organs. Similar results were obtained when recombinant N, in alum, was used for vaccination. In some rodent models, Borna disease is immune mediated thus we did an additional study whereby cyclosporine A was administered to unvaccinated birds starting 1day prior to challenge. This treatment also conferred complete protection from disease, but not infection. PMID- 29274529 TI - Normal values of abdominal muscles thickness in healthy children using ultrasonography. AB - Abdominal muscles are one of the important elements to support the lumbar spine. Evaluation of muscle thickness using ultrasonography (US) is considered to be a source of information from muscles characteristics. The purpose of this study was to demonstrate normal reference data of abdominal muscles thickness and subcutaneous fat in adolescents using US. A random sample of 160 healthy adolescents (80 boys and 80 girls) at the age range of 15-18 years was recruited. Three abdominal muscles including Transversus Abdominis (TA), Internal Oblique (IO), External Oblique (EO) and subcutaneous fat (SF) were bilaterally measured using US. The range of normal values for TA muscle thickness was between 2.31 and 2.57 mm, for IO muscle thickness was between 4.02 and 5.15 mm and for EO muscle thickness was between 2.81 and 3.17 mm. The normal patterns of abdominal muscles were found as IO > EO > TA at both sides. Boys were taller, heavier with greater body mass index (BMI) and had larger abdominal muscles thickness than girls. A weak negative correlation was found between age and muscles size [r = (-0.06) - ( 0.23), p < .05], but a significant positive correlation was found between BMI and muscle size (r = 0.21-0.68, p < .05). It seems that abdominal muscles thickness in adolescents followed the same pattern of muscle size in adults. BMI appeared to be the best predictor of muscle thickness. However, further studies are recommended to support the findings of the present study. PMID- 29274530 TI - Prevalence of psychiatric diagnoses in individuals who die by suicide or attempt suicide in China based on independent structured diagnostic interviews with different informants. AB - Many individuals who die by suicide or attempt suicide have no pre-existing psychiatric record. In these cases determination of the presence of mental illness at the time of the suicidal act depends on diagnostic interviews with different informants, but the reliability of such interviews is unknown. To address this issue, the current study from northern China conducted independent diagnostic interviews (by different psychiatrists) with a co-resident family member and another associate of 151 suicide decedents, with 120 individuals who attempted suicide, and with two proxy informants for each suicide attempter. In the suicide decedent group, 56% of interviews with family members and 50% with other associates resulted in one or more psychiatric diagnosis; the concordance (kappa) of these two respondents for the presence of any current psychiatric disorder, any mood disorder and any other psychiatric disorder were 0.35, 0.32 and 0.41, respectively. In the suicide attempt group, 47% of interviewers with suicide attempters, 31% with family members, and 15% with other associates resulted in a psychiatric diagnosis; the concordance for any current psychiatric disorder, any mood disorder and any other psychiatric disorder between the interview with the suicide attempter and the combined result of the two separate proxy informant interviews were 0.31, 0.34 and 0.39, respectively. We conclude that the concordance of the presence and type of psychiatric diagnosis of individuals with suicidal behavior based on independent structured interviews by psychiatrists with different informants is low to fair and that using multiple informants will increase the identification of psychiatric disorders. PMID- 29274531 TI - The association between pain and suicidal behavior in an English national sample: The role of psychopathology. AB - Pain has been linked with an increased risk of engaging in suicidal behavior. However, the role of common mental disorders (CMDs) and borderline personality disorder (BPD) traits in this association is largely unknown. This study was based on data from the 2007 Adult Psychiatric Morbidity Survey (N = 7403). Suicidal behavior referred to past 12-month suicidal ideation and suicide attempt. Pain was assessed in terms of the level of its interference with work activity in the past four weeks. BPD traits were assessed with the structured interview for DSM disorders questionnaire, and CMDs with the Clinical Interview Schedule Revised (CIS-R). Multivariate logistic regression and mediation analyses were conducted to analyze the association between pain and suicidal behavior, and the role of CMDs and BPD traits in this association. The prevalence of past 12 month suicidal ideation and suicide attempt increased from 2.7% to 11.5% and 0.2% to 2.4%, respectively, between no pain and extreme pain. Pain was found to be significantly associated with suicidal ideation (ORs = 1.61-2.92) and suicide attempt (ORs = 2.95-6.70). CMDs were significant mediators in the pain-suicidal behavior relationship but did not fully explain the association. BPD had little influence in this association. Assessing suicide risk in individuals with pain may be important for suicide prevention. Treating CMDs may reduce risk for suicide in these individuals but other factors leading to higher risk for suicidal behavior should also be investigated in future studies. PMID- 29274532 TI - Modeling and evaluating spatial variation of polycyclic aromatic hydrocarbons in urban lake surface sediments in Shanghai. AB - To explore the influence of rapid urbanization development on the accumulation of 16 priority PAHs in urban environment, thirty-three surface sediments from city lakes in different urbanized areas of Shanghai were collected to evaluate the occurrence characteristic and source apportionment of PAHs. The concentrations of Sigma16PAHs in lake surface sediments ranged from 55.7 to 4928 ng g-1 with a mean value of 1131 ng g-1 (standard deviation, 1228 ng g-1), of which 4-, 5- and 6 ring PAHs were the dominant components. Spatial distribution of PAHs in lake surface sediments showed a significantly declining trend along with a decreasing urbanization gradient (one-way ANOVA, p < .05). Two hotspots of sediment PAHs were mainly distributed at highly urbanized areas with intensive population density and heavy traffic activities and at burgeoning industrial towns in the suburb. Source apportionment of total PAHs identified by a constrained positive matrix factorization model revealed that vehicle emission and combustion of coal, biomass and natural gas were the absolutely predominant sources, respectively accounting for 55.0% and 40.45% of total PAHs burden in lake sediments. Land use regression (LUR) models were successfully developed to evaluate spatial variation of PAHs contamination in urban sediments based on their significant correlations with residential land, commercial land, traffic variables, industrial sources, and population density. All PAH compounds showed strong associations with one or two source indicators (the traffic congestion index and the number of industrial sources), with the fitting R2 varying from 0.529 to 0.984. Our findings suggest that energy consumption related to land use activities obviously promoted PAH accumulations in urban sediment environment during rapid development of urbanization and industrialization in Shanghai. PMID- 29274533 TI - Defective magnesium ferrite nano-platelets for the adsorption of As(V): The role of surface hydroxyl groups. AB - In this work, magnesium ferrite (MgFe2O4) nano-platelets with rich defects and abundant surface hydroxyl groups were synthesized, and used for the removal of low concentration As(V) in aqueous solution. Results from scanning electron microscopy (SEM) showed that the as-synthesized MgFe2O4 nano-platelets were consisted of many individual nanospheres. Rietveld refinement of X-ray diffraction (XRD) data indicated that the Mg2+ ions substituted the Fe3+ ions at both the octahedral and the tetrahedral sites of the crystal structure. Batch adsorption experiment showed that the equilibrium concentration of As(V) could be reduced down to 4.9 MUg.L-1 when the initial concentration of As(V) is 1 mg.L-1, which complied with the drinking water standard of WHO (10 MUg.L-1). The adsorption capacity of synthesized MgFe2O4 towards As(V) was higher than commonly used iron oxide adsorbents (Fe3O4, gamma-Fe2O3 and alpha-Fe2O3). Mechanistic studies proved that the superior adsorption capacity was attributed to: (1) increased amount of surface hydroxyl groups that resulted from the surface defects. (2) formation of tridentate hexanuclear surface complexes instead of bidentate binuclear complexes, and (3) formation of excess Mg-OH surface hydroxyl groups and As-Mg monodentate mononuclear surface complexes. This work disclosed the correlation of the superior As(V) adsorption ability with the surface hydroxyl groups in defective MgFe2O4, and propose MgFe2O4 as a potential candidate for the remediation of As-contaminated water. PMID- 29274534 TI - Metagenomic survey of bacterial diversity in the atmosphere of Mexico City using different sampling methods. AB - The identification of airborne bacteria has traditionally been performed by retrieval in culture media, but the bacterial diversity in the air is underestimated using this method because many bacteria are not readily cultured. Advances in DNA sequencing technology have produced a broad knowledge of genomics and metagenomics, which can greatly improve our ability to identify and study the diversity of airborne bacteria. However, researchers are facing several challenges, particularly the efficient retrieval of low-density microorganisms from the air and the lack of standardized protocols for sample collection and processing. In this study, we tested three methods for sampling bioaerosols - a Durham-type spore trap (Durham), a seven-day recording volumetric spore trap (HST), and a high-throughput 'Jet' spore and particle sampler (Jet) - and recovered metagenomic DNA for 16S rDNA sequencing. Samples were simultaneously collected with the three devices during one week, and the sequencing libraries were analyzed. A simple and efficient method for collecting bioaerosols and extracting good quality DNA for high-throughput sequencing was standardized. The Durham sampler collected preferentially Cyanobacteria, the HST Actinobacteria, Proteobacteria and Firmicutes, and the Jet mainly Proteobacteria and Firmicutes. The HST sampler collected the largest amount of airborne bacterial diversity. More experiments are necessary to select the right sampler, depending on study objectives, which may require monitoring and collecting specific airborne bacteria. PMID- 29274535 TI - In vitro effects of virgin microplastics on fish head-kidney leucocyte activities. AB - Microplastics are well-documented pollutants in the marine environment that result from production or fragmentation of larger plastic items. The knowledge about the direct effects of microplastics on immunity, including fish, is still very limited. We investigated the in vitro effects of microplastics [polyvinylchloride (PVC) and polyethylene (PE)] on gilthead seabream (Sparus aurata) and European sea bass (Dicentrarchus labrax) head-kidney leucocytes (HKLs). After 1 and 24 h of exposure of HKLs with 0 (control), 1, 10 and 100 mg mL-1 MPs in a rotatory system, cell viability, innate immune parameters (phagocytic, respiratory burst and peroxidase activities) and the expression of genes related to inflammation (il1b), oxidative stress (nrf2, prdx3), metabolism of xenobiotics (cyp1a1, mta) and cell apoptosis (casp3) were studied. Microplastics failed to affect the cell viability of HKLs. In addition, they provoke very few significant effects on the main cellular innate immune activities, as decrease on phagocytosis or increase in the respiratory burst of HKLs with the highest dose of microplastics tested. Furthermore, microplastics failed to affect the expression of the selected genes on sea bass or seabream, except the nrf2 which was up-regulated in seabream HKLs incubated with the highest doses. Present results seem to suggest that continue exposure of fish to PVC or PE microplastics could impair fish immune parameters probably due to the oxidative stress produced in the fish leucocytes. PMID- 29274536 TI - Are there fitness costs of adaptive pyrethroid resistance in the amphipod, Hyalella azteca? AB - Pyrethroid-resistant Hyalella azteca with voltage-gated sodium channel mutations have been identified at multiple locations throughout California. In December 2013, H. azteca were collected from Mosher Slough in Stockton, CA, USA, a site with reported pyrethroid (primarily bifenthrin and cyfluthrin) sediment concentrations approximately twice the 10-d LC50 for laboratory-cultured H. azteca. These H. azteca were shipped to Southern Illinois University Carbondale and have been maintained in pyrethroid-free culture since collection. Even after 22 months in culture, resistant animals had approximately 53 times higher tolerance to permethrin than non-resistant laboratory-cultured H. azteca. Resistant animals held in culture also lacked the wild-type allele at the L925 locus, and had non-synonymous substitutions that resulted in either a leucine isoleucine or leucine-valine substitution. Additionally, animals collected from the same site nearly three years later were again resistant to the pyrethroid permethrin. When resistant animals were compared to non-resistant animals, they showed lower reproductive capacity, lower upper thermal tolerance, and the data suggested greater sensitivity to, 4, 4'-dichlorodiphenyltrichloroethane (DDT), copper (II) sulfate, and sodium chloride. Further testing of the greater heat and sodium chloride sensitivity of the resistant animals showed these effects to be unrelated to clade association. Fitness costs associated with resistance to pyrethroids are well documented in pest species (including mosquitoes, peach potato aphids, and codling moths) and we believe that H. azteca collected from Mosher Slough also have fitness costs associated with the developed resistance. PMID- 29274537 TI - Effects of lead, cadmium, arsenic, and mercury co-exposure on children's intelligence quotient in an industrialized area of southern China. AB - Exposure to metal(loid)s can lead to adverse effects on nervous system in children. However, little is known about the possible interaction effects of simultaneous exposure to multiple metal(loid)s on children's intelligence. In addition, relationship between blood lead concentrations (<100 MUg/L) and the intelligence of children over 5 years needs further epidemiological evidence. We recruited 530 children aged 9-11 years, including 266 living in a town near an industrialized area and 264 from another town in the same city in South China as a reference. The levels of lead (Pb), cadmium (Cd), arsenic (As) and mercury (Hg) in blood (BPb, BCd, BAs, BHg) and urine (UPb, UCd, UAs, UHg) were assessed, as well as children's intelligence quotient (IQ). A significant decrease in IQ scores was identified in children from the industrialized town (p < .05), who had statistically higher geometric mean concentrations of BPb, BCd, UPb, UCd and UHg (65.89, 1.93, 4.04, 1.43 and 0.37 MUg/L, respectively) compared with children from the reference town (37.21, 1.07, 2.14, 1.02 and 0.30 MUg/L, respectively, p < .05). After adjusting confounders, only BPb had a significant negative association with IQ (B = -0.10, 95% confidence interval: -0.15 to -0.05, p < .001), which indicated that IQ decreased 0.10 points when BPb increased 1 MUg/L. Significant negative interactions between BAs and BHg, positive interaction between UPb and UCd on IQ were observed (p < .10), and BPb <100 MUg/L still negatively affected IQ (p < .05). Our findings suggest that although only BPb causes a decline in children's IQ when simultaneously exposed to these four metal(loid)s at relatively low levels, interactions between metal(loid)s on children's IQ should be paid special attention, and the reference standard in China of 100 MUg/L BPb for children above 5 years old should be revised. PMID- 29274538 TI - Transcriptomic responses of catalase, peroxidase and laccase encoding genes and enzymatic activities of oil spill inhabiting rhizospheric fungal strains. AB - Fungi are well associated with the degradation of hydrocarbons by the production of different enzymes, among which catalases (CBH), laccases (LCC) and peroxidases (LiP and MnP) are of immense importance. In this study, crude oil tolerance and enzyme secretions were demonstrated by rhizospheric fungal strains. Four most abundant strains were isolated from the rhizosphere of grasses growing in aged oil spill sites and identified through morphological characterization and molecular PCR-amplification of 5.8-28S ribosomal rRNA using ITS1 and ITS4 primers. These strains were subjected to crude oil tolerance test at 0-20% concentrations. Presence and transcriptase responses of putative genes lig (1-6), mnp, cbh (1.1, 1.1 and 11), and lcc encoding lignin peroxidase, manganese peroxidase, catalase, and laccase enzymes respectively were also studied in these strains using RT-PCR. In addition, activities of secreted enzymes by each strain were studied in aliquots. The strains were identified as Aspergillus niger asemoA (KY473958), Talaromyces purpurogenus asemoF (KY488463), Trichoderma harzianum asemoJ (KY488466), and Aspergillus flavus asemoM (KY488467) through sequencing and comparing the sequences' data at NCBI BLAST search software. All the isolated strains showed tolerance to crude oil at 20% concentration, but the growth rate reduced with increasing in oil concentrations. All the isolated strains possess the tested genes and lig 1-6 gene was overexpressed in A. niger and T. harzianum while lcc and mnp genes were moderately expressed in all the four strains. Almost 145 U.mL-1 of lignin and manganese peroxidase, 87 U.mL-1 of catalase, and 180 U.mL-1 of laccase enzymes were produced by these strains and it was also observed that these strain mostly produced studied enzymes in response to increasing crude oil concentrations. Considering the robust nature and diverse production of these catalytic enzymes by these strains, they can be exploited for various bioremediation technologies as well as other biotechnological applications. PMID- 29274539 TI - Indoor exposure to particles emitted by biomass-burning heating systems and evaluation of dose and lung cancer risk received by population. AB - Homes represent a critical microenvironment in terms of air quality due to the proximity to main particle sources and the lack of proper ventilation systems. Biomass-fed heating systems are still extensively used worldwide, then likely emitting a significant amount of particles in indoor environments. Nonetheless, research on biomass emissions are limited to their effects on outdoor air quality then not properly investigating the emission in indoor environments. To this purpose, the present paper aims to evaluate the exposure to different airborne particle metrics (including both sub- and super-micron particles) and attached carcinogenic compounds in dwellings where three different heating systems were used: open fireplaces, closed fireplaces and pellet stoves. Measurements in terms of particle number, lung-deposited surface area, and PM fraction concentrations were measured during the biomass combustion activities, moreover, PM10 samples were collected and chemically analyzed to obtain mass fractions of carcinogenic compounds attached onto particles. Airborne particle doses received by people exposed in such environments were evaluated as well as their excess lung cancer risk. Most probable surface area extra-doses received by people exposed to open fireplaces on hourly basis (56 mm2 h-1) resulted one order of magnitude larger than those experienced for exposure to closed fireplaces and pellet stoves. Lifetime extra risk of Italian people exposed to the heating systems under investigation were larger than the acceptable lifetime risk (10-5): in particular, the risk due to the open fireplace (8.8 * 10-3) was non-negligible when compared to the overall lung cancer risk of typical Italian population. PMID- 29274540 TI - Low-to-moderate intensity aerobic exercise training modulates irritable bowel syndrome through antioxidative and inflammatory mechanisms in women: Results of a randomized controlled trial. AB - Our aim was to explore the putative beneficial effects of low-to-moderate intensity exercise training program in patients with irritable bowel syndrome (IBS). This study evaluated the changes in blood oxidative stress status, inflammatory biomarkers and IBS severity symptoms following 24 weeks of moderate aerobic exercise in sedentary IBS patients. A total of 109 female volunteers (aged 18-41 yrs) who fulfilled Rome III criteria for the diagnosis of IBS were screened and 60 were randomized to exercise (EX, n = 30) and non-exercise (NON EX, n = 30) groups. Exercise intervention favorably attenuated inflammation as indicated by plasma cytokines (IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha), adenosine deaminase, oxidative stress (XO, MDA and NO) and enhanced antioxidants (SOD, CAT and GSH-Px) (P < .05), and these alterations correlate with promising improvements in IBS symptoms (P < .05). Taken together, low-to-moderate intensity exercise training program attenuates symptoms in IBS. Symptom improvement was associated with a reversal of the ratio of anti- to pro-inflammatory cytokines as well as facilitating blood redox homeostasis, suggesting an immune- and redox modulating function for exercise training. PMID- 29274541 TI - Understanding postpartum depression in adolescent mothers in Mashonaland Central and Bulawayo Provinces of Zimbabwe. AB - This study has shown evidence of significant prevalence of postpartum depression (PPD) among adolescent mothers (ADLM) (13.0%) than among adult mothers (ADM) (7.2%) (p < 0.001) in Mashonaland Central and Bulawayo provinces of Zimbabwe. The following were shown to significantly associate with PPD among ADLM: (p < 0.05): (i) abandonment by a partner, (ii) lack access to childhood needs, (iii) bad relationships within families, (iv) social insecurity, (v) prenatal depression (vi) unplanned pregnancies, (vii) lack of information about contraception, (viii) negative perception of teenage pregnancy, (ix) absence of both parents during childhood and (x) negative familial relationships during childhood [OR > 1, 95% CI; p < 0.05). PMID- 29274542 TI - Anesthetic management of an adult patient with Cor Triatriatum Sinistrum: Utility of transesophageal echocardiography. PMID- 29274543 TI - Erector spinae plane block for combined lovectomy and radical mastectomys. PMID- 29274544 TI - Erector spinae plane block and brachial plexus. PMID- 29274545 TI - Should videolaryngoscopy be the standard of care for routine tracheal intubation in obese adults? PMID- 29274546 TI - Ultrasound guided erector spinae block for postoperative analgesia in pediatric nephrectomy surgeries. PMID- 29274547 TI - Plasma neutrophil gelatinase-associated lipocalin: Biomarker of the future or just another test? PMID- 29274548 TI - Efficiently "pumping out" value-added resources from wastewater by bioelectrochemical systems: A review from energy perspectives. AB - Bioelectrochemical systems (BES) can accomplish simultaneous wastewater treatment and resource recovery via interactions between microbes and electrodes. Often deemed as "energy efficient" technologies, BES have not been well evaluated for their energy performance, such as energy production and consumption. In this work, we have conducted a review and analysis of energy balance in BES with parameters like normalized energy recovery, specific energy consumption, and net energy production. Several BES representatives based on their functions were selected for analysis, including direct electricity generation in microbial fuel cells, hydrogen production in microbial electrolysis cells, nitrogen recovery in BES, chemical production in microbial electrosynthesis cells, and desalination in microbial desalination cells. Energy performance was normalized to water volume (kWh m-3), organic removal (kWh kg COD-1), nitrogen recovery (kWh kg N-1), chemical production (kWh kg-1), or removed salt during desalination (kWh kg-1). The key operating factors such as pumping system (recirculation/feeding pumps) and external power supply were discussed for their effects on energy performance. This is an in-depth analysis of energy performance of various BES and expected to encourage more thinking, analysis, and presentation of energy data towards appropriate research and development of BES technology for resource recovery from wastewater. PMID- 29274549 TI - Lymphoblastoids cell lines - Derived iPSC line from a 26-year-old myotonic dystrophy type 1 patient carrying (CTG)200 expansion in the DMPK gene: CHUQi001 A. AB - Human immortalized Epstein-Barr virus (EBV) lymphoblastoids cells line (LCLs) from a 26-year- old male affected by an adult form of myotonic dystrophy type 1 (DM1) disease and carrying 200 CTG repeats mutation in the blood was used to generate induced pluripotent stem cells (iPSCs) using the Sendai virus expressing KLF4, OCT4, SOX2 and C-MYC. The resulting iPSCs were EBV free, expressed the pluripotency markers, could be differentiated into the three germ layers in vitro, had a normal karyotype, and retained the genetic DM1 mutation. This iPSC line could be useful for the investigation of DM1 mechanisms. PMID- 29274550 TI - A decade of progress in liver regenerative medicine. AB - Liver diseases can be caused by viral infection, metabolic disorder, alcohol consumption, carcinoma or injury, chronically progressing to end-stage liver disease or rapidly resulting in acute liver failure. In either situation, liver transplantation is most often sought for life saving, which is, however, significantly limited by severe shortage of organ donors. Until now, tremendous multi-disciplinary efforts have been dedicated to liver regenerative medicine, aiming at providing transplantable cells, microtissues, or bioengineered whole liver via tissue engineering, or maintaining partial liver functions via extracorporeal support. In both directions, new compatible biomaterials, stem cell sources, and bioengineering approaches have fast-forwarded liver regenerative medicine towards potential clinical applications. Another important progress in this field is the development of liver-on-a-chip technologies, which enable tissue engineering, disease modeling, and drug testing under biomimetic extracellular conditions. In this review, we aim to highlight the last decade's progress in liver regenerative medicine from liver tissue engineering, bioartificial liver devices (BAL), to liver-on-a-chip platforms, and then to present challenges ahead for further advancement. PMID- 29274551 TI - 90Sr specific activity of teeth of abandoned cattle after the Fukushima accident teeth as an indicator of environmental pollution. AB - 90Sr specific activity in the teeth of young cattle that were abandoned in Kawauchi village and Okuma town located in the former evacuation areas of the Fukushima-Daiichi Nuclear Power Plant (FNPP) accident were measured. Additionally, specific activity in contaminated surface soils sampled from the same area was measured. (1) All cattle teeth examined were contaminated with 90Sr. The specific activity, however, varied depending on the developmental stage of the teeth during the FNPP accident; teeth that had started development before the accident exhibited comparatively lower values, while teeth developed mainly after the accident showed higher values. (2) Values of 90Sr-specific activity in teeth formed after the FNPP accident were higher than those of the bulk soil but similar to those in the exchangeable fraction (water and CH3COONH4 soluble fractions) of the soil. The findings suggest that 90Sr was incorporated into the teeth during the process of development, and that 90Sr in the soluble and/or leachable fractions of the soil might migrate into teeth and contribute to the amount of 90Sr in the teeth. Thus, the concentration of 90Sr in teeth formed after the FNPP accident might reflect the extent of 90Sr pollution in the environment. PMID- 29274552 TI - Synthesis of tetracyclic azasugars fused benzo[e][1,3]thiazin-4-one by the tandem Staudinger/aza-Wittig/cyclization and their HIV-RT inhibitory activity. AB - Azasugar aldehydes 6a and 6b containing azido groups were prepared from D mannose. Three novel tetracyclic azasugars fused benzo[e][1,3]thiazin-4-one 9a-1, 9a-2 and 9a-3 were conveniently synthesized from 6a by the tandem intramolecular Staudinger/aza-Wittig/cyclization reaction under microwave radiation. Two unexpected elimination compounds 8b-1 and 8b-2 were achieved as the main products from 6b in the same processes. The newly synthesized azasugars were examined for their HIV reverse transcriptase (RT) inhibitory activities. The results showed that all the tested compounds could effectively inhibit RT activity. Among them, compound 8b-1 with the protective group (isopropylidene group) was the best one with the IC50 value of 0.76 MUM. The structure activity relationship analysis suggested that improvement of the molecular hydrophilicity might be beneficial for their anti-HIV RT activities. PMID- 29274553 TI - Bisecting GlcNAc restricts conformations of branches in model N-glycans with GlcNAc termini. AB - Bisected N-glycans play significant roles in tumor migration and Alzheimer's disease through modulating the action and localization of their carrier proteins. Such biological functions are often discussed in terms of the conformation of the attached N-glycans with or without bisecting GlcNAc. To obtain insights into the effects of bisecting GlcNAc on glycan conformation, a systematic NMR structural analysis was performed on two pairs of synthetic N-glycans, with and without bisecting GlcNAc. The analysis reveals that terminal GlcNAcs and bisecting GlcNAc cooperate to restrict the conformations of both the alpha1-3 and alpha1-6 branches of N-glycans. 1H and 13C chemical shift comparisons suggest that bisecting GlcNAc directly modulates local conformation. Unique NOE correlations between core-mannose and the alpha1-3 branch mannose as well as the 3JC-H constant of the glycoside linkage indicate that bisecting GlcNAc restricts the conformation of the 1-3 branch. The angles of the glycosidic bonds between core mannose and alpha1-6 branch mannose derived from 3JC-H and 3JH-H coupling constants show that terminal GlcNAcs restrict the distribution of the psi angle to 180 degrees and the bisecting GlcNAc increases the distribution of the omega angle +60 degrees in the presence of terminal GlcNAcs. It is feasible that restriction of branch conformations by bisecting GlcNAc has important consequences for protein-glycan interplay and following biological events. PMID- 29274554 TI - Functionalized metal-organic frameworks for effective removal of rocephin in aqueous solutions. AB - The porous metal-organic frameworks, MIL-101, MIL-101-SO3H and MIL-101-NH2 were used for the removal of harmful drug (rocephin) from water via adsorption. The kinetics study suggests that the adsorption onto all the MOFs follows the pseudo second-order model. The adsorption isotherms results suggest that the adsorption onto MIL-101 and MIL-101-NH2 fits well with Langmuir model and the maximum adsorption capacities are calculated to 204.08 mg g-1 and 277.78 mg g-1, respectively; while the adsorption onto MIL-101-SO3H cannot fit well with both Langmuir and Freundlich models and the maximum adsorption capacity in the experiment is 25 mg g-1. Furthermore, the effect of pH as well as the adsorption mechanism was analysed systematically. It was found that electrostatic interaction as well as hydrogen-bond interaction plays dominant roles in adsorption of rocephin, and MIL-101-NH2 with abundant amino groups can exhibit better adsorption capacity and removal percentage towards rocephin than MIL-101, MIL-101-SO3H, and some other common adsorbents. In addition, co-existed Zn(NO3)2 can induce a large improvement of rocephin adsorption performance of MIL-101-NH2. At last, MIL-101-NH2 demonstrates to be a renewable adsorbent. In conclusion, we suggest MIL-101-NH2 is a promising adsorbent for effective removal of rocephin in water. PMID- 29274555 TI - Rod-like Bi4O7 decorated Bi2O2CO3 plates: Facile synthesis, promoted charge separation, and highly efficient photocatalytic degradation of organic contaminants. AB - In this manuscript, rod-like Bi4O7 decorated Bi2O2CO3 plates were fabricated for the first time. Compared with pristine Bi2O2CO3, the tight decoration of Bi4O7 over Bi2O2CO3 plates not only strengthened the visible light absorption, but also enhanced the separation efficiency of photo-generated carriers. As expected, the heterostructured Bi4O7/Bi2O2CO3 composites have exhibited highly promoted photocatalytic activities in decomposing Rhodamine B (RhB) under visible light. The BOBC-2 sample displayed the best activity with a reaction rate constant of 0.0245 min-1, which was 3.8 times higher than that of pure Bi4O7. Besides RhB, the Bi4O7/Bi2O2CO3 composites also displayed superior activity toward colorless contaminants with stable chemical structures, such as phenol, p-tert-butylphenol, and o-phenylphenol. The activity enhancement should be ascribed to the proper energy levels of the materials and formation of heterojunction at their interfaces, which could facilitate the charge transfer and promote the separation efficiency. Following transient photocurrent response, electrochemical impedance spectroscopy, and photoluminescence emission tests all verified this. In addition, controlled experiments using various radical scavengers proved that O2- and h+ played the chief role in decomposing organic pollutants. This work may provide a new method for constructing Bi-based heterostructured photocatalysts with high activity. PMID- 29274556 TI - Surfactant mediated synthesis of bismuth selenide thin films for photoelectrochemical solar cell applications. AB - In the present report, nanostructured bismuth selenide (Bi2Se3) thin films have been successfully deposited by using arrested precipitation technique (APT) at room temperature. The effect of three different surfactants on the optostructural, morphological, compositional and photoelectrochemical properties of Bi2Se3 thin films were investigated. Optical absorption data indicates direct and allowed transition with a band gap energy varied from 1.4 eV to 1.8 eV. The X ray diffraction pattern (XRD) revealed that Bi2Se3 thin films are crystalline in nature and confirmed rhombohedral crystal structure. SEM micrographs shows morphological transition from interconnected mesh to nanospheres like and finally granular morphology. Surface topography of Bi2Se3 thin films was determined by AFM. Compositional analysis of all samples was carried out by energy dispersive X ray spectroscopy (EDS). Finally, all Bi2Se3 thin films shows good PEC performance with highest photoconversion efficiency 1.47%. In order to study the stability of Bi2Se3 thin films four cycles are repeated after gap of one week each. Further PEC performance of all Bi2Se3 thin films are also supported by electrochemical impedance (EIS) measurement study. PMID- 29274557 TI - ZIF-67 supported on marcoscale resin as an efficient and convenient heterogeneous catalyst for Oxone activation. AB - While metal organic frameworks (MOFs) are promising catalysts for aqueous chemical oxidation, MOFs are typically prepared to be nanoscale and thus less practical for solution-based reactions. Although a few attempts have developed substrate-supported MOFs, many of them are still small and none of them are developed for sulfate-radical based chemical oxidation. However, there is still an urgent demand for developing substrate-supported MOFs which are catalytically effective, conveniently prepared, and simply recyclable. In this study, a macrosphere-supported MOF is successfully fabricated using ion exchange resins as readily available, stable and functionalized macrospheres. Via equilibrating resins with 2-MIM and cobalt ions sequentially, a cobalt-based MOF, zeolitic imidazolate framework-67 (ZIF-67) nanocrystal, is grown on the resin surface via self-assembly. The resulting composite of ZIF "at" resin (abbreviated as ZIF@R) can preserve porous structures and metal coordination of ZIF-67, and also convenient features of resins, making it an advantageous heterogeneous catalyst for activating Oxone in water. As Rhodamine B (RhB) decolorization is employed as a model test for evaluating Oxone activation, ZIF@R is confirmed not only to activate Oxone for full decolorization of RhB but also to exhibit a much higher catalytic activity than Co3O4, the most typical catalyst for Oxone. ZIF@R could be also re-used to activate Oxone for RhB decolorization without activity loss. These results indicate that ZIF@R is a conveniently prepared and highly effective and stable macroscale catalyst for aqueous chemical oxidation reactions. PMID- 29274558 TI - One-step prepared cobalt-based nanosheet as an efficient heterogeneous catalyst for activating peroxymonosulfate to degrade caffeine in water. AB - Two-dimensional (2D) planar cobalt-containing materials are promising catalysts for activating peroxymonosulfate (PMS) to degrade contaminants because 2D sheet like morphology provides large reactive surfaces. However, preparation of these sheet-supported cobaltic materials typically involves multiple steps and complex reagents, making them less practical for PMS activation. In this study, a cobalt based nanosheet (CoNS) is particularly developed using a one-step hydrothermal process with a single reagent in water. The resulting CoNS can exhibit a thickness as thin as a few nanometers and 2-D morphology. CoNS is also primarily comprised of cobalt species in a coordinated form of Prussian Blue analogue, which consists of both Co3+ and Co2+. These features make CoNS promising for activating PMS in aqueous systems. As degradation of an emerging contaminant, caffeine, is selected as a representative reaction, CoNS not only successfully activates PMS to fully degrade caffeine in 20 min but also exhibits a much higher catalytic activity than the most common PMS activator, Co3O4. Via studying inhibitive effects of radical scavengers, caffeine degradation by CoNS-activated PMS is primarily attributed to sulfate radicals and hydroxyl radicals to a lesser extent. The degradation products of caffeine by CoNS-activated PMS are also identified and a potential degradation pathway is proposed. Moreover, CoNS could be also re-used to activate PMS for caffeine degradation without activity loss. These results indicate that CoNS is a conveniently prepared and highly effective and stable 2-D catalyst for aqueous chemical oxidation reactions. PMID- 29274559 TI - Nitrogen-doped mesoporous carbon-armored cobalt nanoparticles as efficient hydrogen evolving electrocatalysts. AB - A series of Co nanoparticles embedded, N-doped mesoporous carbons have been synthesized through chelate-assisted co-assembly strategy followed by thermal treatment. The preparation is based on an assembly process, with evaporation of an ethanol-water solution containing melamine formaldehyde resin (MF resin) as carbon source, nitrogen source, and chelating agent. Moreover, F127 and Co(NO3)2 are used as template and metallic precursor, respectively. The Co nanoparticles embedded, N-doped mesoporous carbon annealed at 800 degrees C (denoted as MFCo800) shows high electrocatalytic activity for hydrogen evolution reaction (HER) with high current density and low overpotential, which has the ability to operate in both acidic and alkaline electrolytes. PMID- 29274560 TI - Manufacturing of an electrochemical biosensing platform based on hybrid DNA hydrogel: Taking lung cancer-specific miR-21 as an example. AB - DNA hydrogel garnered increasing attention in the sensing and medical field owing to its native biocompatibility and mechanical stability. While electrochemistry serves as a quantitative and sensitive detection technique, electrochemical DNA hydrogel biosensor is rarely reported. Here, for the first time, we report an electrochemical biosensor based on hybrid DNA hydrogel immobilized on indium tin oxide/polyethylene terephthalate (ITO/PET) electrode for the detection of lung cancer-specific microRNA, miR-21. The biosensor is capable of detecting miR-21 at a concentration as low as 5nM (1 pmol) and linear read-out from 10nM to 50MUM. Ferrocene-tagged recognition probes were cross-linked with DNAs grafted on the polyacrylamide backbones to form the hybrid DNA hydrogel, which was further immobilized on 3-(trimethoxysilyl)propyl methacrylate (KH 570) treated ITO electrode. When the recognition probe was hybridized with the target miR-21, the hydrogel dissolved, producing a loss of ferrocene tags and a reduction in current, detected by Cyclic Voltammetry (CV) and Differential Pulse Voltammetry (DPV). The material characteristics of the biosensor were verified using contact angle meter and Energy Dispersive Spectrometer (EDS). This novel biosensor holds great promise in early sensitive clinical diagnosis for a variety of cancer specific biomarkers due to the flexible sequence design of the recognition probe. PMID- 29274561 TI - "All the King's horses and all the King's men...": What is broken should not always be put back together again. PMID- 29274562 TI - Increased platelet activation occurs in cystic fibrosis patients and correlates to clinical status. AB - Cystic fibrosis (CF) is an inflammatory lung disease. Platelets have an emerging role in inflammation, however previous studies of platelet activation in CF have generated conflicting results. In this study, we determined platelet function in CF patients and correlated platelet activation to establish clinical and laboratory parameters. Twenty-two patients, aged 20.7 to 54.4 (mean 34.0, SD 9.45) years and with a mean FEV1%pred (forced expiratory volume in one second, % of predicted) of 72 (SD 21.4, range 32-110) were recruited. A combination of platelet assays was used: platelet aggregation, platelet activation and platelet leukocyte complex formation. Platelets from CF patients exhibited significantly increased aggregation when stimulated ex-vivo, a tendency towards increased platelet upregulation of CD62P, but no increase of GPIIb/IIIa activation (PAC-1). Platelet-monocyte complex (PMC) formation was significantly increased in CF patients compared to controls, while platelet-neutrophil complex formation was not. In the CF group, platelet aggregation correlates with levels of anti neutrophil cytoplasmic antibodies (ANCA) with specificity for bactericidal/permeability-increasing protein (BPI), BPI-ANCA (r=0.56). The formation of PMCs correlates with lung function decline (1-FEV1%), CRP and BPI ANCA (r=0.61, 0.55, 0.5). We therefore confirm the presence of increased platelet activation in CF patients, and determine that further evaluation of platelet activation in relation to prognostic factors in CF is warranted. PMID- 29274563 TI - IgA anti-beta2 glycoprotein I antibodies: Experience from a large center. AB - OBJECTIVE: IgG and IgM antibodies directed at beta2-glycoprotein I are included in the classification criteria for the antiphospholipid syndrome (APS) while the IgA antibodies against beta2-glycoprotein I (IgA abeta2GPI) are not. Conflicting data about the significance of IgA abeta2GPI and APS manifestation can be found and more studies are necessary in order to define the diagnostic value of IgA abeta2GPI. In the present article, we investigated the possible role of IgA abeta2GPI as marker of APS. METHODS: A cohort of 314 patients with APS and systemic autoimmune disease was investigated for the presence of IgA abeta2GPI and its association with clinical manifestation of APS. RESULTS: Eighty-nine patients presented IgA abeta2GPI, 68 cases associated with others antiphospholipid antibodies (aPL) and in 21 cases being the only aPL present. In primary APS IgA abeta2GPI are highly coincidental with other aPL (92,2%) while most of the isolated IgA abeta2GPI were present in the SLE group (16/21). No association between IgA abeta2GPI and APS manifestations: thrombosis and pregnancy morbidity was found, while a positive association between IgA abeta2GPI and the presence of anti-nDNA, anti-RNP, anti-Sm, anti-SSA, anti-SSB antibodies was encountered. CONCLUSION: Our study does not show association between IgA abeta2GPI and APS manifestations and does not support the inclusion of IgA abeta2GPI as a classification criteria for APS. PMID- 29274564 TI - The validity and reliability of screening measures for depression and anxiety disorders in multiple sclerosis. AB - OBJECTIVE: We aimed to evaluate the validity and reliability of multiple screening measures for depression and anxiety for use in the clinical care of people with multiple sclerosis (MS). METHODS: Participants with MS completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Kessler-6 Distress Scale, PROMIS Emotional Distress Depression Short-Form 8a (PROMIS Depression) and Anxiety Short-Form 8a (PROMIS Anxiety), Generalized Anxiety Disorder 7-item Scale (GAD-7), and the Overall Anxiety and Severity Impairment Scale (OASIS). A subgroup repeated the screening measures two weeks later. All participants also completed a Structured Clinical Interview for DSM-IV TR Axis I Disorders (SCID). For the screening measures we computed sensitivity, specificity, positive predictive and negative predictive value with SCID diagnoses as the reference standard and conducted receiver operating curve (ROC) analyses; we also assessed internal consistency and test-retest reliability. RESULTS: Of 253 participants, the SCID classified 10.3% with major depression and 14.6% with generalized anxiety disorder. Among the depression measures, the PHQ-9 had the highest sensitivity (84%). Specificity was generally higher than sensitivity, and was highest for the HADS-D with a cut-point of 11 (95%). In ROC analyses the area under the curve (AUC) did not differ between depression measures. Among the anxiety measures, sensitivity was highest for the HADS-A with a cut-point of 8 (82%). Specificity ranged from 83% to 86% for all measures except the HADS-A with a cut-point of 8 (68%). The AUC did not differ between anxiety measures. CONCLUSION: Overall, performance of the depression and anxiety screening measures was very similar, with reasonable psychometric properties for the MS population, suggesting that other factors such as accessibility and ease of use could guide the choice of measure in clinical practice. PMID- 29274565 TI - Daily conformity drinking motivations are associated with increased odds of consuming alcohol mixed with energy drinks. AB - Recent research indicates that individuals drank more heavily and experienced more harms on days they consumed alcohol mixed with energy drinks (AmEDs). Limited research, thus far, has examined predictors of AmED use on a daily level. Drinking motives, or reasons for drinking, are shown to discern AmED users from non-users, but the extent to which daily drinking motives covary with AmED use has not been tested. The current study used a daily diary design to determine how motives differ between AmED and other drinking occasions. Participants included 122 college students (73.8% women) with a mean age of 20.39years. Participants completed up to 14 daily surveys, resulting in 389 drinking days (40days involved AmED use). Participants reported on their drinking motives at baseline as well as on each drinking day. Multilevel models revealed that, after controlling for other motives, AmED use was more likely on days where conformity motives were higher than usual and was less likely when enhancement motives were higher. Daily social and coping motives as well as all motives measured at baseline were unassociated with AmED use. Our findings suggest that conformity motives, or drinking to fit in with others, are the most salient drinking motive predicting AmED use on a drinking day. Given that conformity motives are often less associated with alcohol use outcomes in general, these findings highlight AmEDs as a unique alcoholic beverage. Clinicians and interventionists working with frequent AmED users should consider the unique conditions under which AmEDs are consumed. PMID- 29274566 TI - Immobilization of formaldehyde dehydrogenase in tailored siliceous mesostructured cellular foams and evaluation of its activity for conversion of formate to formaldehyde. AB - Formaldehyde dehydrogenase (FaldDH) is used as a catalyst to reduce formate to formaldehyde in a cascade reaction to convert CO2 to methanol. This enzyme, however, has low activity and is sensitive to substrate/product concentration and pH. To improve the performance of FaldDH, it can be immobilized through physical adsorption in siliceous mesostructured cellular foams (MCF), which physical properties are suitable for the immobilization of large molecules as FaldDH (molecular size of 8.6 * 8.6 * 19 nm). In this work two MCF materials were synthesized: MCF1 with a pore size of 26.8 nm and window size of 10.5 nm; and MCF2 with a pore size of 32.9 nm and window size of 13.0 nm. The surfaces of the materials were functionalized with octyl, mercaptopropyl or chloromethyl groups. FaldDH was successfully immobilized inside all the materials, yielding enzyme loadings of about 300 mg g-1 in MCF1 and more than 750 mg g-1 in MCF2. However, the enzyme was inactive upon immobilization on MCF1, whereas on MCF2 the enzyme retained its catalytic activity presumably owing to the larger pores of this material and the need for the enzyme to undergo configurational changes during the reaction. Using MCF2 functionalized with mercaptopropyl groups the activity of FaldDH was enhanced beyond that of the free enzyme. Additionally, low leakage of the enzyme from the MCF2 was observed during the reactions. Thus, tailored MCF is a highly attractive material for employment of the FaldDH enzyme. PMID- 29274567 TI - Is there consensus across international evidence-based guidelines for the psychotropic drug management of bipolar disorder during the perinatal period? AB - BACKGROUND: Clinicians treating a patient with bipolar disorder who is pregnant or breastfeeding may seek advice from bipolar management guidelines that provide recommendations for perinatal treatment. We examine the consistency of such recommendations across several evidence-based guidelines. METHODS: A literature search in the National Guideline Clearinghouse, the Cochrane Database of Systematic Reviews, PsycInfo and PubMed was undertaken using the search terms "bipolar disorder" and "guidelines," which generated 11 sets of evidence-based guidelines published by professional organizations during the 2005-2015 period. Information relevant to management during the perinatal period was reviewed by two independent reviewers, with key themes qualitatively analysed. RESULTS: There was a moderate level of agreement across guidelines regarding the potential teratogenic effects of lithium, sodium valproate and carbamazepine, with most highlighting caution in using these medications during the perinatal period. There was less agreement regarding the safety risks associated with lamotrigine, antipsychotics, and antidepressants, and little agreement regarding the risks and recommendations of medications during breastfeeding. LIMITATIONS: Some differences in recommendations are likely due to varying publication dates, with recent guidelines having more up-to-date evidence available to use when formulating recommendations. Further, due to ethical issues surrounding pregnancy and infant research, the evidence used to formulate perinatal recommendations is largely based on retrospective reports and/or case studies. It is therefore unrealistic to expect such recommendations to be entirely consistent and based on rigorous evidence. CONCLUSIONS: While there was some consistency across guidelines on key recommendations, there were also substantial inconsistencies, with the latter risking compromising clinical management. PMID- 29274568 TI - Effect of heavy atoms on photochemically induced dynamic nuclear polarization in liquids. AB - Given its short hyperpolarization time (~10-6 s) and mostly non-perturbative nature, photo-chemically induced dynamic nuclear polarization (photo-CIDNP) is a powerful tool for sensitivity enhancement in nuclear magnetic resonance. In this study, we explore the extent of 1H-detected 13C nuclear hyperpolarization that can be gained via photo-CIDNP in the presence of small-molecule additives containing a heavy atom. The underlying rationale for this methodology is the well-known external-heavy-atom (EHA) effect, which leads to significant enhancements in the intersystem-crossing rate of selected photosensitizer dyes from photoexcited singlet to triplet. We exploited the EHA effect upon addition of moderate amounts of halogen-atom-containing cosolutes. The resulting increase in the transient triplet-state population of the photo-CIDNP sensitizer fluorescein resulted in a significant increase in the nuclear hyperpolarization achievable via photo-CIDNP in liquids. We also explored the internal-heavy-atom (IHA) effect, which is mediated by halogen atoms covalently incorporated into the photosensitizer dye. Widely different outcomes were achieved in the case of EHA and IHA, with EHA being largely preferable in terms of net hyperpolarization. PMID- 29274569 TI - Risk factors for adverse driving outcomes in Dutch adults with ADHD and controls. AB - OBJECTIVE: To identify risk factors for adverse driving outcomes and unsafe driving among adults with and without ADHD in a Dutch sample. METHODS: In this cross-sectional study, validated self-report questionnaires were used to compare driving history and current driving behavior between 330 adults diagnosed with ADHD and 330 controls. RESULTS: Adults with ADHD had significantly more adverse driving outcomes when compared to controls. Having an ADHD diagnosis significantly increased the odds for having had 3 or more vehicular crashes (OR = 2.72; p = .001). Driving frequency, male gender, age, high anxiety levels, high hostility levels, and alcohol use all significantly influenced the odds for unsafe driving behavior, for having had 12 or more traffic citations, and/or for having had 3 or more vehicular crashes. CONCLUSIONS: Alcohol use, and high levels of anxiety and hostility are highly prevalent among adults with ADHD, and they mediate the risk for negative driving outcomes in this group. PMID- 29274571 TI - TaNTF2, a contributor for wheat resistance to the stripe rust pathogen. AB - Nuclear Transport Factor 2 (NTF2) functions as a critical regulator in balancing the GTP-and GDP-bound forms of Ran, a class of evolutionarily conserved small GTP binding protein. During the incompatible interaction between wheat-Puccinia striiformis f. sp. tritici (Pst), a cDNA fragment encoding a putative wheat NTF2 gene was found to be significantly induced, suggesting a potential role in wheat resistance to Pst. In this work, the full length of TaNTF2 was obtained, with three copies located on 7A, 7B and 7D chromosomes, respectively. QRT-PCR further verified the up-regulated expression of TaNTF2 in response to avirulent Pst. In addition, TaNTF2 was also induced by exogenous hormone applications, especially JA treatment. Transient expression of TaNTF2 in tobacco cells confirmed its subcellular localization in the cytoplasm, perinuclear area and nucleus. And virus induced gene silencing (VIGS) was used to identify the function of TaNTF2 during an incompatible wheat-Pst interaction. When TaNTF2 was knocked down, resistance of wheat to avirulentPst was decreased, with a bigger necrotic spots, and higher numbers of hyphal branches and haustorial mother cells. Our results demonstrated that TaNTF2 was a contributor for wheat resistance to the stripe rust pathogen, which will help to comprehensively understand the NTF2/Ran modulating mechanism in wheat-Pst interaction. PMID- 29274572 TI - Exploration of DPP-IV inhibitors with a novel scaffold by multistep in silico screening. AB - Dipeptidyl peptidase-IV (DPP-IV), an enzyme that degrades incretins-hormones that promote insulin secretion-is a therapeutic target for type 2 diabetes, with a number of its inhibitors having been launched as therapies for diabetes. Since adverse effects of these inhibitors have recently been reported, the development of novel DPP-IV inhibitors with higher efficacy and safety is required. We, therefore, screened for novel DPP-IV inhibitors using the combination of an in silico drug discovery technique and a DPP-IV assay system. We initially selected seven candidate compounds as DPP-IV inhibitors from a database consisting of four million compounds by a multistep in silico screening procedure combining pharmacophore-based screening, docking calculation and the analysis of three dimensional quantitative structure-activity relationship. We then measured the inhibitory activity of the selected compounds and identified a hit compound. In addition, we discuss the structure-activity relationship between the binding mode model and inhibitory activity of the hit compound. PMID- 29274570 TI - Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria. AB - Mitochondria are critical sources of hydrogen peroxide (H2O2), an important secondary messenger in mammalian cells. Recent work has shown that O2*-/H2O2 emission from individual sites of production in mitochondria is regulated by protein S-glutathionylation. Here, we conducted the first examination of O2* /H2O2 release rates from cardiac and liver mitochondria isolated from mice deficient for glutaredoxin-2 (GRX2), a matrix-associated thiol oxidoreductase that facilitates the S-glutathionylation and deglutathionylation of proteins. Liver mitochondria isolated from mice heterozygous (GRX2+/-) and homozygous (GRX2 /-) for glutaredoxin-2 displayed a significant decrease in O2*-/H2O2 release when oxidizing pyruvate or 2-oxoglutarate. The genetic deletion of the Grx2 gene was associated with increased protein expression of pyruvate dehydrogenase (PDH) but not 2-oxoglutarate dehydrogenase (OGDH). By contrast, O2*-/H2O2 production was augmented in cardiac mitochondria from GRX2+/- and GRX2-/- mice metabolizing pyruvate or 2-oxoglutarate which was associated with decreased PDH and OGDH protein levels. ROS production was augmented in liver and cardiac mitochondria metabolizing succinate. Inhibitor studies revealed that OGDH and Complex III served as high capacity ROS release sites in liver mitochondria. By contrast, Complex I and Complex III were found to be the chief O2*-/H2O2 emitters in cardiac mitochondria. These findings identify an essential role for GRX2 in regulating O2*-/H2O2 release from mitochondria in liver and cardiac tissue. Our results demonstrate that the GRX2-mediated regulation of O2*-/H2O2 release through the S-glutathionylation of mitochondrial proteins may play an integral role in controlling cellular ROS signaling. PMID- 29274573 TI - Effect of simulation-based emergency cardiac arrest education on nursing students' self-efficacy and critical thinking skills: Roleplay versus lecture. AB - BACKGROUND: Simulation education is a learning method for improving self-efficacy and critical thinking skills. However, not much study has been done on how to use it for education on emergency cardiac arrest situations, for which a multidisciplinary team approach is required. OBJECTIVES: This study investigated the effects of simulation education on nursing students' self-efficacy and critical thinking skills in emergency cardiac arrest situations. DESIGN: A quasi experimental research approach with a crossover design was used to compare two types of simulation instruction methods. PARTICIPANTS AND SETTING: This study was conducted with 76 nursing students divided into two groups by order of instruction methods, in November and December 2016. METHODS: Both groups of participants experienced a simulation lesson based on the same emergency scenario. Group A first completed a roleplay of an emergency cardiac arrest situation in a clinical setting, while Group B first listened to a lecture on the procedure. After ten days, Group A repeated the simulation exercise after listening to the lecture, while Group B completed the simulation exercise after the roleplay. The students' self-efficacy and critical thinking skills were measured using a questionnaire before and after each session. RESULTS: In the first session, self-efficacy and critical thinking skills scores increased greatly from pretest to posttest for Group A in comparison to Group B; no statistically significant difference was found between the two groups. In the second session, Group B showed a significant increase between pretest and posttest, while Group A showed no significant difference. CONCLUSIONS: Conducting the simulation exercise after the roleplay was a more effective teaching method than conducting it after the lecture. Moreover, having the nursing students assume various roles in realistic roleplay situations combined with simulation exercises led to a deeper understanding of clinical situations and improved their self-efficacy and critical thinking skills. PMID- 29274574 TI - Photoreactivity of graphene oxide in aqueous system: Reactive oxygen species formation and bisphenol A degradation. AB - The phototransformation and environmental implications of graphene oxide (GO) have been widely studied in order to understand its implications upon release into the environment. However, very little is known about the formation of reactive oxygen species (ROS) by GO under solar irradiation. Currently there are no studies on the mechanism of ROS formation by GO or the amount of ROS catalyzed by the nanomaterials in the environment. In this study, we carefully investigated the different types and formation mechanisms of ROS generated by GO in the presence of simulated solar irradiation. The effect of GO's photoactivity on bisphenol A (BPA), a representative organic co-pollutant, was also studied. The conduction band electron (eaq-) of GO led to the formation of different ROS including OH, O2-, and 1O2. Among the three types of ROS investigated, O2- was the most abundant species generated during simulated solar irradiation of GO. BPA was degraded, mainly due to the oxidative potential of the valence band holes produced during solar irradiation of GO. This study advances understanding of the photoactivity of GO and its potential impact on other possible environmental co pollutants. PMID- 29274575 TI - Synergistic effects between hydroxyl radicals and hydrated electrons on strengthening decomposition of an s-triazine compound: A combined experimental and theoretical study. AB - The decomposition of an environmentally recalcitrant s-triazine compound, prometry (PMT), was carried out by experimental and theoretical approaches to study the combined effects of hydroxyl radicals (OH) and hydrated electrons (eaq ). With the participation of strongly oxidative radicals OH and reductive radicals eaq- induced by electron beam (EB), PMT obtained a good decomposition performance, which was obviously better than those methods simply using OH as the single active species. The evolution of cyanuric acid (CA) during the EB and UV irradiation processes elucidate that former method could efficiently decompose such chemically stable intermediate. The experiments of radical scavengers further suggest that OH was the predominant radical during PMT degradation, while eaq- was beneficial to further decomposition and mineralization. Combined with the results of density functional theory (DFT) calculations, the strengthened synergistic effects between OH and eaq- were proven. The calculations illustrated OH could attack the carbon-branch-chains of s-trazine ring and form OH-adducts rather than nitrogen oxides. Moreover, the presence of eaq- could not only greatly change the geometry of the s-triazine ring, but also help cleaving alkyl chain on ring, thus facilitate the complete mineralization. PMID- 29274576 TI - Evidence of anaerobic coupling reactions between reduced intermediates of 4 nitroanisole. AB - Nitroaromatic compounds are widely used in agricultural pesticides, pharmaceuticals, military explosives, and other applications. They enter the environment via manufacturing and municipal wastewater discharges and releases from agricultural and military operations. Because of their ubiquity and toxicity, they are considered an important class of environmental contaminants. Nitroaromatics are known to undergo reductive transformation to aromatic amines, and under aerobic conditions they are susceptible to coupling reactions which may lead to their irreversible incorporation into soil organic matter. However, there is also evidence of coupling reactions in the absence of oxygen between reduced intermediates of the insensitive munitions compound 2,4-dinitroanisole, leading to the formation of azo dimers. The formation of such products is a concern since they may be more toxic than the original nitroaromatic compounds. The objective of this research is to provide evidence of the anaerobic formation of azo coupling products. 4-Nitroanisole was used as a model compound and was spiked into incubations containing anaerobic granular sludge with H2 as the electron donor. Using liquid chromatography, UV-Vis spectroscopy, and mass spectrometry, the formation of the azo dimer 4,4'-dimethoxyazobenzene was confirmed. However, due to the instability of the azo bond under the reducing conditions of our incubations, the azo dimer did not accumulate. Consequently, 4-aminoanisole was the major product formed in our experiment. Other minor suspected coupling products were also detected in our incubations. The results provide clear evidence for the temporal formation of at least one azo dimer in the anaerobic reduction of a model nitroaromatic compound. PMID- 29274577 TI - Assessing the suitability of a manometric test system for determining the biodegradability of volatile hydrocarbons. AB - Manometric test systems, adapted from those used to measure biochemical oxygen demand (BOD), and the OxiTop(r) test system in particular, are being increasingly used to determine the biodegradability of chemicals in accordance to OECD 301F guidelines. In this study, the suitability of the OxiTop(r) test system for determining the biodegradability of volatile hydrophobic substances has been explored. Experiments in biotic and abiotic systems were conducted with readily biodegradable complex aliphatic hydrocarbons covering a range of volatilities. Results indicated that abiotic losses of test substances were occurring due to sorption of the test substance to plastic components used in the OxiTop(r) system. A further 'plastic-free' biodegradation test system was designed using PreSens optical dissolved oxygen (DO) sensors. This significantly improved the measured biodegradation due to reduced abiotic losses and better retention of the test substance. These results highlight the importance of considering the physico chemical properties of test substances when selecting test methods and equipment. They also highlight the value of incorporating chemical analysis and abiotic controls to improve the interpretation of biodegradation studies. PMID- 29274578 TI - Predicting Ni dynamic mobilization in reservoir riparian soils prior to water submergence using DGT and DIFS. AB - The South-to-North Water Diversion Project has been initiated to address the problem of water shortages in north China. However, the environmental impact of this project is currently unclear, especially for the geochemical process of toxic trace metals in reservoir riparian soil following water submergence. The mobility of Ni in Miyun Reservoir riparian soil samples was investigated using diffusive gradients in thin films (DGT), considering five different land use types and three vertical elevations. The DGT-induced fluxes in soil (DIFS) model was applied to simulate the kinetics of Ni mobilization in the soil. The results showed that the average concentration of Ni was 36.58 mg/kg, which was slightly higher than the corresponding background values reported for both Beijing and China. Coincidentally, the highest concentrations of both total Ni and DGT-labile Ni (CDGT-Ni) were observed at the same site (recreational area), indicating that anthropogenic activities may have contributed to the release of Ni. Land use type and vertical elevation had no significant influence on CDGT-Ni. In addition, CDGT Ni was positively correlated with reducible fraction, CDGT-Fe, CDGT-Mn, and TOC, indicating that Ni in the soils was adsorbed mainly on the Fe/Mn oxides and organic matter. Moreover, the low values of R (CDGT-Ni/Csol-Ni, R < 0.25) indicated that the replenishment of Ni from the solid phase was poor, and the rate of Ni desorption was considerably lower than its depletion rate, thus leaving only a small proportion of Ni was available. PMID- 29274579 TI - 6.0 K microarray reveals differential transcriptomic responses in the dinoflagellate Prorocentrum minimum exposed to polychlorinated biphenyl (PCB). AB - Endocrine disrupting chemicals (EDCs) have toxic effects on algae; however, their molecular genomic responses have not been sufficiently elucidated. Here, we evaluated genome-scaled responses of the dinoflagellate alga Prorocentrum minimum exposed to an EDC, polychlorinated biphenyl (PCB), using a 6.0 K microarray. Based on two-fold change cut-off, we identified that 609 genes (~10.2%) responded to the PCB treatment. KEGG pathway analysis showed that differentially expressed genes (DEGs) were related to ribosomes, biosynthesis of amino acids, spliceosomes, and cellular processes. Many DEGs were involved in cell cycle progression, apoptosis, signal transduction, ion binding, and cellular transportation. In contrast, only a few genes related to photosynthesis and oxidative stress were expressed in response to PCB exposure. This was supported by that fact that there were no obvious changes in the photosynthetic efficiency and reactive oxygen species (ROS) production. These results suggest that PCB might not cause chloroplast and oxidative damage, but could lead to cell cycle arrest and apoptosis. In addition, various signal transduction and transport pathways might be disrupted in the cells, which could further contribute to cell death. These results expand the genomic understanding of the effects of EDCs on this dinoflagellate protist. PMID- 29274580 TI - Management strategies for trace organic chemicals in water - A review of international approaches. AB - To ensure an appropriate management of potential health risks and uncertainties from the release of trace organic chemicals (TOrCs) into the aqueous environment, many countries have evaluated and implemented strategies to manage TOrCs. The aim of this study was to evaluate existing management strategies for TOrCs in different countries to derive and compare underlying core principles and paradigms and to develop suggestions for more holistic management strategies to protect the environment and drinking water supplies from the discharge of undesired TOrCs. The strategies in different industrial countries were summarized and subsequently compared with regards to three particular questions: 1) Do the approaches different countries have implemented manage all or only specific portions of the universe of chemicals; 2) What implementation and compliance strategies are used to manage aquatic and human health risk and what are their pros and cons; and 3) How are site-specific watershed differences being addressed? While management strategies of the different countries target similar TOrCs, the programs differ in several important aspects, including underlying principles, the balance between aquatic or human health protection, implementation methods, and financing mechanisms used to fund regulatory programs. PMID- 29274581 TI - The visual attention span deficit in Chinese children with reading fluency difficulty. AB - With reading development, some children fail to learn to read fluently. However, reading fluency difficulty (RFD) has not been fully investigated. The present study explored the underlying mechanism of RFD from the aspect of visual attention span. Fourteen Chinese children with RFD and fourteen age-matched normal readers participated. The visual 1-back task was adopted to examine visual attention span. Reaction time and accuracy were recorded, and relevant d-prime (d') scores were computed. Results showed that children with RFD exhibited lower accuracy and lower d' values than the controls did in the visual 1-back task, revealing a visual attention span deficit. Further analyses on d' values revealed that the attention distribution seemed to exhibit an inverted U-shaped pattern without lateralization for normal readers, but a W-shaped pattern with a rightward bias for children with RFD, which was discussed based on between-group variation in reading strategies. Results of the correlation analyses showed that visual attention span was associated with reading fluency at the sentence level for normal readers, but was related to reading fluency at the single-character level for children with RFD. The different patterns in correlations between groups revealed that visual attention span might be affected by the variation in reading strategies. The current findings extend previous data from alphabetic languages to Chinese, a logographic language with a particularly deep orthography, and have implications for reading-dysfluency remediation. PMID- 29274582 TI - Bioactivity evaluation of natural product alpha-mangostin as a novel xanthone based lysine-specific demethylase 1 inhibitor to against tumor metastasis. AB - Lysine-specific demethylase 1 (LSD1), which has been reported to be overexpressed in several human cancers, has recently emerged as an attractive therapeutic target for treating cancer. To date, almost all the developed LSD1 inhibitors are chemo-synthesized molecules, while alpha-mangostin is first characterized as xanthone-based natural inhibitor in the current study with IC50 values of 2.81 +/ 0.44 MUM. Bioactivity study and docking analysis indicated that alpha-mangostin could inhibit MDA-MB-231 cells migration and evasion through inhibit intracellular LSD1 activity. These findings provides new molecular skeleton for LSD1 inhibitor study and should encourage further modification of alpha-mangostin to produce more potent LSD1 inhibitors with potential anticancer activity. PMID- 29274583 TI - A stability-study of expired ampoules manufactured more than 40 years ago. AB - Pharmaceutical manufacturers have to study the stability of drug products before marketing according to ICH guideline Q1A(R2); data of those investigations aim to set expiry dates. The expiry date on the container of a remedy assures the physician and the patient a stability of the drug in its formulation i.e. within a specification of 95-105%. Only few studies show that shelf-lives of pharmaceutical products are often longer than expiration dates. The objective of the study presented here was determining the content of nine expired ampoules manufactured in the last century and identifying the impurity profile by means of HPLC-UV and HPLC-MS, respectively. The ampoules are part of the "PEAK-collection" of long expired finished pharmaceutical products at IBMP, Nurnberg-Heroldsberg, and consists among others of epinephrine (Suprarenin and Adrenalin in Oil), etilefrine (Effortil(r)), synephrine (Sympatol(r)), caffeine and procaine (Impletol), caffeine and sodium salicylate (Caffeinum Salicylicum), dipyridamole (Persantin(r)), furosemide (Lasix(r)), and metamizole (Novalgin(r)). For chromatographic investigations methods of the European Pharmacopoeia for related substances were used; for determining the content, they were validated for linearity, precision, and accuracy. The results were compared to current reference ampoules. Five out of nine ampoules were still within the specified content limits. In Suprarenin and Adrenalin in Oil, both containing epinephrine, Impletol (procaine), and Persantin(r) (dipyridamole) contents were decreased to 70%, 74%, 79%, and 86%, respectively, and therefore out of specification. PMID- 29274584 TI - The protective effects of triptolide on age-related bone loss in old male rats. AB - BACKGROUND: Previous studies have showed that triptolide have a critical role in inhibiting osteoclast formation, bone resorption and attenuating regional osteoporosis. However, the protective role of triptolide on age-related bone loss has not been investigated. In the study, we assessed the effect of triptolide supplementation on bone microstructure and bone remolding in old male rat lumbars. METHODS: Fifty-two 22-month-old male Sprague-Dawley rats were randomly assigned to either triptolide treatment group or control group. Triptolide (15 MUg/kg/d) or normal saline was administered to the rats of assigned group for 8 weeks. Lumbar bone mineral density (BMD) and bone microstructure were analyzed by micro-CT. Fluorochrome labeling of the bones was performed to measure the mineral apposition rate (MAR) and bone formation rate (BFR). Osteoclast number was also measured by TRAP staining. Plasma level of osteocalcin and tartrate-resistant acid phosphatase 5b (Tracp 5b) was also analyzed. RESULTS: Micro-CT results revealed that triptolide-treated rats had significant higher BMD, bone volume over total volume (BV/TV), trabecular thickness (Tb.Th), bone trabecular number (Tb.N), and lower trabecular separation (Tb.Sp) compared to the control group. Although fluorochrome labeling result showed no significant difference in MAR and BFR between the groups, triptolide decreased osteoclast number in vivo. In addition, a significant higher level of plasma Tracp 5b was observed in the triptolide-treated rats. Furthermore, triptolide also reduced the expression of receptor for activation of NF-kappaB ligand (RANKL) and increased osteoprotegerin (OPG) expression in the lumbars. CONCLUSION: These results suggested that triptolide had a protective effect on age-related bone loss at least in part by reducing osteoclast number in elder rats. Therefore, triptolide might be a feasible therapeutic approach for senile osteoporosis. PMID- 29274585 TI - Knockdown of the long non-coding RNA HOTTIP inhibits colorectal cancer cell proliferation and migration and induces apoptosis by targeting SGK1. AB - More and more long non-coding RNA (lncRNA) might be serve as molecular biomarkers for tumor cell progression. HOTTIP has been recently revealed as oncogenic regulator in several cancers. However, it remains unclear about whether and how HOTTIP regulates Colorectal cancer (CRC). In the present study, we assayed the expression of HOTTIP in CRC tissues and cell lines, and detected CRC cells (HCT 116 and SW620) proliferation, migration, and apoptosis when HOTTIP was knocked down. Furthermore, we discovered the underlying mechanism. The level of HOTTIP was higher in CRC tissues and in CRC cells compared with adjacent normal tissues and normal colon tissue cell. Knockdown of HOTTIP inhibited the cell proliferation migration and induced apoptosis in HCT-116 and SW620 cell lines. In addition, luciferase reporter assay suggested that knockdown of HOTTIP could target decreasing the expression of Serum- and glucocorticoid-inducible kinase 1 (SGK1) gene, and we subsequently verified that up-regulation of the SGK1 gene promoted cell proliferation and migration and inhibited cell apoptosis in HCT-116 and SW620 cell lines. Furthermore, Knockdown of HOTTIP significantly suppressed the expression of GSK3beta, beta-catenin, c-myc, Vimentin and MMP-7, and increased the expression of E-cadherin, FoxO3a, p27 and Bim proteins in HCT-116 and SW620 cell lines, and up-regulation of the SGK1 emerged the opposite effect with knockdown of HOTTIP. The data described in this study suggest that HOTTIP may be an oncogene and a potential target in CRC. PMID- 29274586 TI - Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive deterioration of cognitive functions. The pathological hallmarks are extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles of tau protein. The cognitive deficits seen are thought to be due to synaptic dysfunction and neurochemical deficiencies. Various neurochemical abnormalities have been observed during progressive ageing, and are linked to cognitive abnormalities as seen with the sporadic form of AD. Acetylcholinesterase inhibitors are one of the major therapeutic strategies used for the treatment of AD. During the last decade, various new therapeutic strategies have shown beneficial effects in preclinical studies and under clinical development for the treatment of AD. The present review is aimed at discussing the neurobiology of AD and association of neurochemical abnormalities associated with cognitive deterioration and new therapeutic strategies for the treatment of AD. PMID- 29274587 TI - Cardioprotective effects of total flavonoids from Jinhe Yangxin prescription by activating the PI3K/Akt signaling pathway in myocardial ischemia injury. AB - The purpose of the present study was to investigate the cardioprotective effects of total flavonoids of Jinhe yangxin prescription (JHTF) on myocardial ischemia (MI) injury rats induced by Isoproterenol (ISO) and explore the potential mechanisms underlying these effects. 128 male rats were randomized into 8 groups: Control, Model, Positive, JHTF-H (2.64 g/kg/d), JHTF-M (1.32 g/kg/day), JHTF-L (0.66 g/kg/d), LY + JHTF (JHTF-H plus LY294002, an inhibitor of PI3K/Akt) and LY groups. Electrocardiogram, histopathological examination and terminal deoxynucleotidyl transferase dUTP nickend labeling (TUNEL) assay were performed. Heart weight index, markers of cardiac marker enzymes [creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI)], oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and nitric oxide (NO)] and inflammation [tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)] were also measured in each group. Proteins involved in PI3K/Akt pathway were detected by Western blot. JHTF decreased the ST elevation induced by MI, decreased serum levels of CK, CK MB, cTnI, LDH, MDA, IL-6 and TNF-alpha, and increased serum SOD, GSH-Px and NO activities. Furthermore, JHTF inhibited myocardial apoptosis, which may be related to downregulated caspase-3 and Bax, upregulated Bcl-2, and increased the protein levels of phosphorylated Akt, GSK-3beta and endothelial nitric oxide synthase (eNOS). However, all the previously mentioned effects of JHTF were blocked when JHTF was coadministered with LY294002. In conclusion, these observations indicated that JHTF has cardioprotective effects against MI, and these effects seem to be related to the activation of PI3K/Akt signaling pathway in the myocardium. PMID- 29274588 TI - alpha-asarone reduce proteinuria by restoring antioxidant enzymes activities and regulating necrosis factor kappaB signaling pathway in doxorubicin-induced nephrotic syndrome. AB - alpha-asarone is natural bioactive compound that has been reported to have many benefits and medicinal properties. The present study aimed to assess the protective effect of alpha-asarone against doxorubicin (DOX) induced nephrotic syndrome in rats. An experimental nephrotic syndrome was induced by single intravenous injection of DOX (7 mg/kg) in rats. Animals were orally administered alpha-asarone (10 and 20 mg kg-1 d-1) for 4 weeks. Blood, urine and kidney tissues were collected for analyses at the end of the study. Treatment with alpha asarone significantly improved kidney function by significantly inhibiting proteinuria, hypoalbuminemia, dyslipidemia, and restored antioxidant enzyme activities in kidney tissue. Furthermore, alpha-asarone ameliorated mRNA and protein expression of NF-kappaB, TNF-alpha, IL-6, and podocin in the kidney. Histopathological evidence also confirmed the protective effects of alpha-asarone against DOX-induced nephrotic syndrome. In conclusion, alpha-asarone has an anti nephritic effect that might be attributed to its antioxidant, hypolipidaemic and anti-inflammatory activities. PMID- 29274589 TI - Exogenous VEGF introduced by bioceramic composite materials promotes the restoration of bone defect in rabbits. AB - This study aimed to investigate the effect of exogenous vascular endothelial growth factor (VEGF) introduced by bioceramic composite materials on jawbone defect. Rabbits were randomly divided into four groups: control, sham, model, and stent. In the model group, holes of jawbone defect were created through surgery. In the stent group, rabbits with jawbone defect were treated with polyether ketone (PEK)/biphasic bioceramic ((PEK-BBC)) composite materials encapsulating VEGF. At 4, 8, and 16 weeks post-operation, HE and Van Gieson staining of jawbones were performed to characterize the repair status of the bone defect. For all time intervals, we found intact bone structures in the control and sham groups and there was no improvement in the bone defect position in the model group. However, in the stent group, we excitingly observed the growth of many osteocytes in the margin of stents at 8 and 16 weeks. RT-PCR, western blot, and immunofluorescence analysis were conducted to investigate the VEGF expression at 4, 8, and 16 weeks post-operation. At 8 weeks, the level of VEGF in the model group was sharply downregulated as compared with the control group (P < .05) and interestingly, the stent group had a much higher level of VEGF than the model group (P < .05). At 16 weeks, the VEGF expression in the model group was further reduced comparing to the control group (P < .05), which was also elevated to a relative high level by the stent treatment (P < .05). As for the sham group, the VEGF level was stable without any difference from the control group at all time intervals. Therefore, exogenous VEGF introduced by bioceramic composite materials promoted the restoration of bone defect in rabbits. PMID- 29274590 TI - Crocin potentiates antioxidant defense system and improves oxidative damage in liver tissue in diabetic rats. AB - BACKGROUND: Diabetes-induced oxidative stress has an essential role in hepatic dysfunction. The current study was aimed to potentiate the impact of crocin treatment on the anti-oxidant defenses system of hepatic tissue following un controlled hyperglycemia. METHODS: Male Wistar rats were randomly divided into four experimental groups as normal, normal treated, diabetic and diabetic treated (n = 6). Diabetes was induced by a single intravenous dose of streptozotocin into tail vein (40 mg/kg). Treated animals received crocin daily for 8 weeks intraperitoneally (40 mg/kg). At the end of the 8th week, animals were sacrificed and liver tissues were collected. After tissue preparation, malondialdehyde (MDA), nitrate and glutathione (GLT) contents and also catalase (CAT) and superoxide dismutase (SOD) enzymes activities were evaluated in all experimental animals. RESULTS: Un-controlled diabetes weakened anti-oxidant system by decreasing SOD and CAT enzymes activities and increasing MDA production. Crocin potentiated anti-oxidant defense system by increasing SOD and CAT enzymes activities and improved oxidative damage by lessening nitrate content and MDA production in hepatic tissues of diabetic animals. CONCLUSION: Crocin maybe a potential therapeutic candidate against diabetes-induced hepatic dysfunction by attenuating oxidative damage in the hepatic tissue. PMID- 29274591 TI - Extract of Citrus maxima (pummelo) leaves improve hepatoprotective activity in Wistar rats submitted to the induction of non-alcoholic hepatic steatosis. AB - Non-alcoholic fatty liver disease is a spectrum of liver changes, ranging from hepatic steatosis to hepatocellular carcinoma. The Citrus maxima (CM) has been shown to be beneficial to the organism, and these activities are attributed to the presence of phytochemical compounds. The objective of this study was to evaluate the n vitro antioxidant potential of the CM leaves extract and on Wistar rats submitted to hepatic steatosis induction by fructose-associated hyperlipid diet (FHD). For the evaluation of in vivo effects, the animals were distributed in G1 (normal diet - ND), G2 (FHD), G3 (ND + extract 50mg/kg) and G4 (FHD + extract 50 mg/kg). All the parameters were determined through classical methodologies. The extract showed a significant antioxidant potential in vitro. In the in vivo analysis, the diet used was able to induce the development of metabolic abnormalities that favored the formation of hepatic steatosis (G2). Changes in inflammatory markers, increase in markers of oxidative damage, and reduction of antioxidant defenses were also observed. In addition, the extract did not cause changes in the animals' weight gain and acted as an anti inflammatory, since G4 animals exhibited significantly reduced levels of the inflammatory markers. In the liver, the extract significantly decreased the content of fat, cholesterol and triglycerides compared to G2. The extract also showed antioxidant activity (G4) when compared to G2. The results suggest that the extract of CM leaf showed hepatoprotective, hypolipidemic, anti-inflammatory and antioxidant activities and the presence of phenolic compounds is a probable cause for such activities. PMID- 29274592 TI - Rose petal and P123 dual-templated macro-mesoporous TiO2 for a hydrogen peroxide biosensor. AB - In this work, highly ordered macro-mesoporous TiO2 has been successfully synthesized using fresh rose petals and P123 (EO20PO70EO20) as dual templates through a simple soaking and calcining process. Characterization of the as prepared TiO2 indicated that the mesoporous structure of the TiO2 was highly ordered, with a pore diameter of approximately 3nm. After electrodeposition of Pt nanoparticles onto the TiO2 as an electron transfer enhancer and the immobilization of horseradish peroxidase (HRP) onto the TiO2-modified electrode, a biosensor for detecting hydrogen peroxide (H2O2) was realized. This biosensor showed a wide linear detection range from 5MUM to 8mM and a low detection limit of 1.65MUM with good stability and high selectivity, suggesting that the sensor is well-suited for the detection of H2O2. PMID- 29274594 TI - Prospective cohort study on noise levels in a pediatric cardiac intensive care unit. AB - PURPOSE: To describe noise levels in a pediatric cardiac intensive care unit, and to determine the relationship between sound levels and patient sedation requirements. MATERIALS AND METHODS: Prospective observational study at a pediatric cardiac intensive care unit (PCICU). Sound levels were measured continuously in slow A weighted decibels dB(A) with a sound level meter SoundEarPro(r) during a 4-week period. Sedation requirement was assessed using the number of intermittent (PRNs) doses given per hour. Analysis was conducted with autoregressive moving average models and the Granger test for causality. RESULTS: 39 children were included in the study. The average (SD) sound level in the open area was 59.4 (2.5) dB(A) with a statistically significant but clinically unimportant difference between day/night hours (60.1 vs. 58.6; p-value < 0.001). There was no significant difference between sound levels in the open area/single room (59.4 vs. 60.8, p-value = 0.108). Peak noise levels were > 90 dB. There was a significant association between average (p-value = 0.030) and peak sound levels (p-value = 0.006), and number of sedation PRNs. CONCLUSION: Sound levels were above the recommended values with no differences between day/night or open area/single room. High sound levels were significantly associated with sedation requirements. PMID- 29274595 TI - Florbetapir-PET beta-amyloid imaging and associated neuropsychological trajectories in survivors of critical illness: A case series. AB - PURPOSE: Cognitive impairment resembling Alzheimer's disease is common in survivors of critical illness. We hypothesized that Intensive Care Unit (ICU) survivors with cognitive impairment would have significant amyloid and designed a pilot study to explore this relationship. MATERIALS AND METHODS: A pilot, case series of a convenience sample of 14 adult medical and surgical ICU survivors, in a clinical neuroradiology clinic. Patients underwent cognitive testing at 3months, 1year, 4years, and 6years after hospital discharge with the Repeatable Battery for the Assessment of Neuropsychological Status. They received a single PET scan using amyloid PET imaging (florbetapir F18) 2 to 4years after their ICU stay. RESULTS: Amyloid (defined as a Standard Uptake Value ratio or SUVr >1.10) was present in 2 of 14 (14%) individuals, both of whom demonstrated significant cognitive impairment yet no consistent decline over time. Of the 6 impaired patients (RBANS<78), 4 (66.7%) were amyloid negative. CONCLUSIONS: It is feasible to assess ICU survivors with amyloid imaging. In this small sample, most patients with cognitive impairment were negative on amyloid PET imaging, which raises the possibility that ICU survivors may experience a unique form of dementia not driven by an amyloid related mechanism. PMID- 29274593 TI - Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study. AB - OBJECTIVE: Because oral contraceptives (OC) tends to lessen menstrual fluid loss a route of excretion for perfluoroalkyl substances (PFASs) - we hypothesized that such use would be positively associated with PFAS concentrations. METHODS: This analysis was based on the Norwegian Mother and Child Cohort (MoBa) study. We included 1090 women from two previous substudies of women enrolled from 2003 to 2007. Characteristics of OC use were obtained at baseline: use in the past 12months, duration and recency of use, age at first use. We examined log transformed plasma concentrations of seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)). Linear regression analyses, adjusted for maternal age, menstrual cycle length, parity, and education, were used to examine whether OC use characteristics were determinants of PFAS concentrations. RESULTS: Except for PFDA and PFUnDA, women who used OCs in the 12months preceding the baseline interview had 12.9-35.7% higher PFAS concentrations than never OC users. To a lesser extent, past OC use was positively associated with PFASs (estimates ranged from 7.2-32.1%). Compared with never users, using OCs for 10 or more years was associated with increased PFAS concentrations, except for PFDA and PFUnDA (estimates for other PFASs ranged from 18.9-46.2%). We observed little effect of age at first OC use. CONCLUSIONS: This analysis shows that characteristics of OC use, and duration of use in particular, may be important considerations when investigating relationships between women's reproductive outcomes and PFASs. PMID- 29274596 TI - Pragmatic studies for acute kidney injury: Consensus report of the Acute Disease Quality Initiative (ADQI) 19 Workgroup. AB - PURPOSE: Acute kidney injury (AKI) has become a major medical and financial burden in China along with the rest of the world. There have been considerable advances in the understanding of the epidemiology and pathogenesis of AKI. However, there is no consensus regarding the optimal care for patients. The Acute Disease Quality Initiative (ADQI) 19 meeting focused on identifying and designing relevant and achievable AKI-related studies in China. MATERIALS & METHODS: The working group developed a list of preliminary questions and objectives and performed analysis of the existing literature. Relevant studies were identified through a literature search using the MEDLINE database and bibliographies of relevant research and review articles. We then used a two-step Delphi process to prioritize a research agenda and proposed specific study designs to address unmet needs. RESULTS: Important gaps in existing knowledge were identified and pragmatic studies were proposed in three distinct areas: care bundles for AKI prevention, renal replacement therapy (RRT) for AKI, and fluid management. In addition, the use of biomarkers to guide clinical trials was discussed. CONCLUSIONS: Consensus was reached on a research agenda for AKI with a specific focus on pragmatic trials in China. PMID- 29274597 TI - Healthcare costs of ICU survivors are higher before and after ICU admission compared to a population based control group: A descriptive study combining healthcare insurance data and data from a Dutch national quality registry. AB - PURPOSE: To identify subgroups of ICU patients with high healthcare utilization for healthcare expenditure management purposes such as prevention and targeted care. MATERIALS AND METHODS: We conducted a descriptive cohort study, combining a national health insurance claims database and a national quality registry database for ICUs. Claims data in the timeframe 2012-2014 were combined with the clinical data of ICU patients admitted to an ICU during 2013. A population based control group was created based on the ICU population. RESULTS: 56,760 ICU patients and 75,232 controls from the general population were included. Median healthcare costs per day alive for the ICU population were significantly higher during the year before (?8.9 (IQR ?2.4; ?32.1)) and the year after ICU admission (?15.4 (IQR ?5.4; ?51.2)) compared to the control group ((?2.8 (IQR ?0.7; ?8.8) and ?3.1 (IQR ?0.8; ?10.1)). ICU patients with more chronic conditions had significantly higher healthcare costs before and after ICU admission compared to ICU patients with less chronic conditions. CONCLUSIONS: ICU patients have three to five times higher healthcare costs per day alive compared to a control population. Our findings can be used to optimize the healthcare trajectories of ICU patients with high healthcare utilization after discharge. PMID- 29274598 TI - Transmissibility and waveform purity of whole-body vibrations in older adults. AB - BACKGROUND: This study examined the transmission power and waveform purity of vertical (synchronous) whole-body vibrations upon its propagation in the human body among older adults. METHODS: Forty community-dwelling older adults participated in the study (33 women; mean age: 60.3 (SD 5.7) years). Four vibration frequencies (25, 30, 35, 40Hz), two amplitudes (0.6 and 0.9mm), and six different postures were tested. Skin-mounted tri-axial accelerometers were placed at the medial malleolus, tibial tuberosity, greater trochanter, third lumbar vertebra, and forehead. The transmissibility of vibration was computed as the ratio of the root-mean-square-acceleration at different body sites to that of the platform. Signal purity was expressed by the percentage of total transmitted power within 1Hz of the nominal frequency delivered by the platform. FINDINGS: Vibration frequency and amplitude were inversely associated with transmissibility in all anatomical landmarks except the medial malleolus. Amplification of signals was noted at the medial malleolus in most testing conditions. The effect of posture on whole-body vibration transmission depends on its frequency and amplitude. In general, toe-standing led to the lowest transmissibility. Single leg standing had the highest vibration transmission to the hip, while erect standing had the highest transmissibility to the head. The purity of waveform of the vibration signals was well conserved as the vibrations were transmitted from the feet to the upper body. INTERPRETATION: Whole-body vibration transmissibility was highly influenced by signal frequency, amplitude and posture. These parameters should be carefully considered when prescribing whole-body vibration to older adults. PMID- 29274599 TI - Bowel obstruction in obturator hernia: A challenging diagnosis. AB - INTRODUCTION: The obturator hernia is a rare pelvic hernia that often comes in the shape of bowel obstruction caused by the presence of an intestinal segment, more often ileum, passing trough the obturator foramen of the pelvic wall (Fig. 1). This type of hernia accounts for 0.5-1.4% of all hernias. CASE PRESENTATION: We report the clinical case of a 84-year-old woman with no previous surgical interventions, who went to the emergency room complaining of vomit and nausea, bowels closed to gas and stool, which she had experienced for three previous days. Routine blood test showed impaired renal function and hydrohelectrolyte imbalance. A CT scan revealed a right ileal, strangulated obturator hernia. The patient underwent an emergency surgical intervention with laparoscopic trans abdominal peritoneal approach (TAP): after the reduction of the herniated segment, a primary suturing of the parietal defect was performed without ileal resection. DISCUSSION: Because of the non-specific symptoms the diagnosis of this kind of hernia is often unclear; female are 6-9 times more likely than men to be subject to the aforementioned pathology, mostly occurring in multiparous, emaciated, elderly woman so it is also called "the little old lady's hernia". Risk factors are loss of weight, chronic pulmonary disease and ascites which increase the abdominal pressure. An unfrequent presenting sign is a palpable mass, or the Howship-Romberg sign- a pain radiating from the inner tigh and knee but it could be misleading when confused with symptoms of gonarthrosis or lumbar vertebral disc pathology. CT scan has superior sensitivity and accuracy with respect to other radiological exams to assess the presence of an obturator hernia. CONCLUSION: Obturator hernia is a rare type of hernia due to his diagnosis, which is often unclear; a prompt suspect based for the non-specific symptoms is crucial for the diagnosis. Surgical management depends on early diagnosis and it is the only possible treatment for this pathology. PMID- 29274600 TI - Evidence of intimal tear in type A intramural hematoma of the aorta: A case series. AB - INTRODUCTION: Aortic intramural hematoma (IMH) is described as "dissection without intimal tear" due to rupture of vasa vasorum, which results in bleeding within the tunica media in the absence of intimal disruption or blood flow communication. The aim of our study is to validate perioperative evidence of intimal entry tear in patients with IMH and to suggest that this entity may represent a part of a disease and not a separate disease. PRESENTATION OF CASES: We report two patients admitted to our institution with sudden onset thoracic pain. A CT scan showed an aneurysm of the ascending aorta complicated by type A IMH. The patients underwent open operation. Surgical set-up has included right axillary artery as arterial inflow, no cross-clamp before hypothermic circulatory arrest and Kazui protocol for selective antegrade cerebral perfusion. We found no evidence of intimal flap, but we identified an intimal tear in both patients. A hemiarch procedure associated with root replacement, using two-grafts techniques was performed in both cases. The postoperative course was uneventful and the patients were discharged home. DISCUSSION: Recent data are emerging from the radiologic literature about the evidence of intimal lesions in IMH, but surgical reports are scant. The evidence of intimal tears contributes to consider as questionable the etiological role of vasa vasorum and it may justify updates in the management. CONCLUSION: We consider that IMH may represent a part of a disease (aortic dissection), depicted by radiological images in a specific single instant of its clinical evolution. PMID- 29274601 TI - Isolated medial plantar neuropathy caused by a large ganglion cyst diagnosed with MRI: A case report. AB - INTRODUCTION: Although ganglion cysts are common soft tissue tumors, nerve compression syndrome caused by a ganglion cyst in the lower extremities is very rare. Herein, we report a 57-year-old man who presented with hypoesthesia in the sole of his right foot for 6 months. We believe that reporting this rare case will help clinicians update their knowledge on possible causes of the plantar neuropathy, and avoid diagnostic delay. PRESENTATION OF CASE: The patient had pain and numbness in the inner right sole, as well as a tingling and dull sensation. Tenderness around the area of abnormal sensation was not evident. Percussion at the abductor tunnel gave a positive Tinel's sign in the medial plantar nerve. No mass was palpable in the right foot. Based on the electrophysiological findings, we diagnosed medial plantar nerve entrapment in the right foot. Magnetic resonance imaging (MRI) was conducted to identify a 5.5 cm long elongated cystic lesion as the cause of entrapment. The patient underwent surgical removal of the cystic mass, with histologic examination confirming the diagnosis of a large ganglion cyst. DISCUSSION: The feasibility of nerve conduction studies and electromyography for detection of nerve entrapment is still controversial. MRI is considered the best diagnostic modality, if biopsy is not feasible. CONCLUSION: We suggest that foot imaging and electrophysiological studies should be considered for patients with isolated median plantar neuropathy to exclude the presence of space-occupying lesions, especially when conservative treatment is not effective. PMID- 29274602 TI - Micro-Raman imaging on 4H-SiC in contact with the electrode at room temperature. AB - Raman images (30MUm*30MUm*180MUm) of a bulk 4H-SiC wafer in contact with a Ni/Au electrode film in 100nm/200nm thick were measured with Micro-Raman spectroscopy at room temperature. As the imaging area approached the interface between the SiC and electrode, the center frequency of the E2(TO) mode (778cm-1) immediately declined; in the Raman imaging, relative distribution of compressive residual stress around residual tensile stress, and linewidth were broadened due to crystal distortion. For LOPC (LO-phonon-plasmon-coupled) mode (970cm-1), center frequency showed variation right next to the interface, while linewidth decreased slowly as the imaging area approached the interface. We evaluated the temperature dependence of the line broadening and the center frequency of the LOPC mode in 4H SiC in a high-temperature region. Free carrier concentration increased with temperature, and remained almost constant in the center frequency after impurities were ionized completely. PMID- 29274603 TI - Plackett-Burman and Box-Behnken designs as chemometric tools for micro determination of l-Ornithine. AB - Plackett-Burman (PB) and Box-Behnken (BB) screening and response surface factorial designs were used to evaluate spectrophotometric and spectrofluorimetric approaches for the determination of l-Ornithine (ORN) as per se and in dietary supplements. Both approaches were based on the derivatization of the primary amino group of ORN via Hantzsch condensation reaction producing yellow coloured adducts (dihydrolutidine derivative). The reaction product was determined spectrophotometrically (method A) at lambdamax=327nm and spectrofluorimetrically (method B) at 480nm (lambdaem) after excitation at 325nm (lambdaex). A multivariate scheme was tailored to investigate the process numerical variables; reaction temperature, heating time, reagent volume, and pH implementing PB as a screening design followed by BB as an optimization strategy. Categorical factors including diluting solvent and sequence of addition were kept invariable. Responses of the reaction systems were the maximum absorbance (Y1) and maximum fluorescence intensity (Y2), correspondingly. Quality tools as well as ANOVA testing, before and after response transformation were used to decide upon the substantial variables. Following the optimization of reaction variables using desirability plots, calibration graphs were found to be rectilinear in the range of 6-14MUg/mL and 0.4-1.2MUg/mL for methods A and B, respectively. Both methods proved to be sensitive with detection limits (DL) of 337 and 85ng/mL, and quantitation limits (QL) of 1086 and 283ng/mL, for methods A and B, respectively. An interference study was performed using potential foreign species. No significant interference effect was observed on any of the proposed procedures. System performance was addressed following ICH guidelines and considering parameters such as linearity, detection and quantification limits, accuracy and precision, robustness and specificity. PMID- 29274604 TI - Interictal cardiac repolarization abnormalities in people with epilepsy. AB - BACKGROUND AND OBJECTIVE: The occurrence of cardiac electrical abnormalities such as repolarization disorders in patients with epilepsy was previously documented and may, in part, clarify the mechanism of sudden unexpected death in those patients. The aim of this study was to investigate the frequency of cardiac repolarization disorders among patients with epilepsy and whether specific demographic- or disease-related features were associated with their occurrence. SUBJECTS AND METHODS: This cross-sectional study was carried out on 1000 subjects with epilepsy who were compared with age- and sex-matched 2500 subjects without epilepsy. Clinical assessment, which included careful history taking and examination, was carried out for all participants in addition to resting 12-lead electrocardiogram (ECG) recording. Electrocardiograms were reviewed by experienced cardiologists. Electrocardiogram intervals were measured, and morphological abnormalities were identified using standard guidelines. RESULTS: Repolarization abnormalities were found in 142 (14.2%) patients with epilepsy. A statistically significant elevation in percentage of corrected QT interval (QTc) prolongation (both severe and borderline) among patients with epilepsy compared with controls was documented (8.4% vs 2%, P<0.001). Epilepsy increased the likelihood of hosting prolonged QTc more than 4 times (95% confidence interval: 3.175-6.515; odds ratio: 4.548; P<0.001). Affected patients were significantly older (95% confidence interval: 1.012-1.044; odds ratio: 1.027; P=0.001), and the abnormality was significantly more prevalent among those with poor seizure control (95% confidence interval: 1.103-2.966; odds ratio: 1.809; P=0.019). On the other hand, early repolarization (ER) pattern and Brugada type ECG pattern (BP) were significantly more prevalent in subjects without epilepsy. CONCLUSIONS: Corrected QT interval prolongation (both severe and borderline) was more prevalent among patients with epilepsy, especially if uncontrolled or elderly. Electrocardiogram should be established as a part of the diagnostic workup of epilepsy in order to identify such electrocardiographic abnormality. PMID- 29274605 TI - Alexithymia as a mediator of the relationship between child sexual abuse and psychological distress in adolescence: A short-term longitudinal study. AB - BACKGROUND: Understanding factors influencing mental health of sexually abused teenagers is essential to orient treatment with this vulnerable population. The purpose of this study was to explore alexithymia as a mediator of the relationship between child sexual abuse and psychological distress using a representative sample of teenagers, while considering gender as a potential moderator. METHODS: Teenagers participating in the Quebec Youths' Romantic Relationships Survey completed measures evaluating a history of child sexual abuse and alexithymia at baseline while psychological distress was evaluated 6 months later. RESULTS: A moderated mediated model revealed a partial mediation effect of alexithymia in the relationship between child sexual abuse and psychological distress. Gender acted as a moderator as the conditional indirect effects of child sexual abuse on mental health via alexithymia were stronger for boys. CONCLUSION: Findings underscore the relevance of assessing and targeting sexually abused victims' capacity to identify and communicate emotions to promote well-being. PMID- 29274606 TI - Combined effects of ZnO NPs and seawater acidification on the haemocyte parameters of thick shell mussel Mytilus coruscus. AB - Flow cytometry was used to investigate the immune parameters of haemocytes in thick-shell mussel Mytilus coruscus exposed to different concentrations of ZnO nanoparticles (NPs) (0, 2.5, and 10mgl-1) at two pH levels (7.3 and 8.1) for 14days following a recovery period of 7days. ZnO NPs significantly affected all of the immune parameters throughout the experiment. At high ZnO NPs concentrations, total haemocyte counting, phagocytosis, esterase, and lysosomal content were significantly decreased whereas haemocyte mortality and reactive oxygen species (ROS) were increased. Although low pH also significantly influenced all of the immune parameters of the mussels, its effect was not as strong as that of ZnO NPs. Interactive effects were observed between pH and ZnO NPs in most haemocyte parameters during the exposure period. Although a slight recovery from the stress of ZnO NPs and pH was observed for all immune parameters, significant carry-over effects of low pH and ZnO NPs were still detected. This study revealed that high concentration of ZnO NPs and low pH exert negative and synergistic effects on mussels, and these effects remain even after the mussels are no longer exposed to such stressors. PMID- 29274607 TI - Growth parameters influencing uptake of chlordecone by Miscanthus species. AB - Because of its high persistence in soils, t1/2=30years, chlordecone (CLD) was classified as a persistent organic pollutant (POP) by the Stockholm Convention in 2009.The distribution of CLD over time has been heterogeneous, ranging from banana plantations to watersheds, and contaminating all environmental compartments. The aims of this study were to (i) evaluate the potential of Miscanthus species to extract chlordecone from contaminated soils, (ii) identify the growth parameters that influence the transfer of CLD from the soil to aboveground plant parts. CLD uptake was investigated in two species of Miscanthus, C4 plants adapted to tropical climates. M. sinensis and M.*giganteus were transplanted in a soil spiked with [14C]CLD at environmental concentrations (1mgkg-1) under controlled conditions. Root-shoot transfer of CLD was compared in the two species after two growing periods (2 then 6months) after transplantation. CLD was found in all plant organs, roots, rhizomes, stems, leaves, and even flower spikes. The highest concentration of CLD was in the roots, 5398+/-1636 (M.*giganteus) and 14842+/-3210ngg-1 DW (M. sinensis), whereas the concentration in shoots was lower, 152+/-28 (M.*giganteus) and 266+/-70ngg-1 DW (M. sinensis) in soil contaminated at 1mgkg-1. CLD translocation led to an acropetal gradient from the bottom to the top of the plants. CLD concentrations were also monitored over two complete growing periods (10months) in M. sinensis grown in 8.05mgkg-1 CLD contaminated soils. Concentrations decreased in M. sinensis shoots after the second growth period due to the increase in organic matters in the vicinity of the roots. Results showed that, owing to their respective biomass production, the two species were equally efficient at phytoextraction of CLD. PMID- 29274608 TI - Antimony mobility during prolonged waterlogging and reoxidation of shooting range soil: A field experiment. AB - Due to its increasing anthropogenic use, antimony (Sb) soil pollution is of growing concern. Many soils experience fluctuating hydrological conditions, yet very little is known about how this affects the mobility of this toxic element under field conditions. In this study, we performed an outdoor lysimeter experiment to compare Sb leaching from a calcareous shooting range soil under drained and prolonged waterlogged conditions (1.5-2.75years), followed by a 1.5 year period of soil reoxidation. Waterlogging reduced Sb leachate concentrations significantly compared to drained conditions and soil solution concentrations decreased with depth due to the increased reducing conditions. This was attributed to the reduction of Sb(V) to Sb(III) and the more effective sorption of the latter to metal (hydr)oxides. However, reductive dissolution of iron (hydr)oxides released Sb into solution, although Sb concentrations never exceeded those in the drained lysimeters. On reoxidation of the soil, Sb was remobilized, but even after 1.5years under reoxidised conditions, Sb leachate and soil solution concentrations still remained below those of the drained lysimeters. Our results demonstrate that prolonged waterlogging may have an irreversible effect on Sb leachate and soil solution concentrations. PMID- 29274609 TI - Trends and seasonality of river nutrients in agricultural catchments: 18years of weekly citizen science in France. AB - Agriculture and urbanization have disturbed three-quarters of global ice-free land surface, delivering huge amounts of nitrogen and phosphorus to freshwater ecosystems. These excess nutrients degrade habitat and threaten human food and water security at a global scale. Because most catchments are either currently subjected to, or recovering from anthropogenic nutrient loading, understanding the short- and long-term responses of river nutrients to changes in land use is essential for effective management. We analyzed a never-published, 18-year time series of anthropogenic (NO3- and PO43-) and naturally derived (dissolved silica) riverine nutrients in 13 catchments recovering from agricultural pollution in western France. In a citizen science initiative, high-school students sampled catchments weekly, which ranged from 26 to 1489km2. Nutrient concentrations decreased substantially over the period of record (19 to 50% for NO3- and 14 to 80% for PO43-), attributable to regional, national, and international investment and regulation, which started immediately prior to monitoring. For the majority of catchments, water quality during the summer low-flow period improved faster than during winter high-flow conditions, and annual minimum concentrations improved relatively faster than annual maximum concentrations. These patterns suggest that water-quality improvements were primarily due to elimination of discrete nutrient sources with seasonally-constant discharge (e.g. human and livestock wastewater), agreeing with available land-use and municipal records. Surprisingly, long-term nutrient decreases were not accompanied by changes in nutrient seasonality in most catchments, attributable to persistent, diffuse nutrient stocks. Despite decreases, nutrient concentrations in almost all catchments remained well above eutrophication thresholds, and because additional improvements will depend on decreasing diffuse nutrient sources, future gains may be much slower than initial rate of recovery. These findings demonstrate the value of citizen science initiatives in quantifying long-term and seasonal consequences of changes in land management, which are necessary to identify sustainable limits and predict recovery timeframes. PMID- 29274610 TI - Spatial and temporal variations in the relationship between lake water surface temperatures and water quality - A case study of Dianchi Lake. AB - Global warming and rapid urbanization in China have caused a series of ecological problems. One consequence has involved the degradation of lake water environments. Lake surface water temperatures (LSWTs) significantly shape water ecological environments and are highly correlated with the watershed ecosystem features and biodiversity levels. Analysing and predicting spatiotemporal changes in LSWT and exploring the corresponding impacts on water quality is essential for controlling and improving the ecological water environment of watersheds. In this study, Dianchi Lake was examined through an analysis of 54 water quality indicators from 10 water quality monitoring sites from 2005 to 2016. Support vector regression (SVR), Principal Component Analysis (PCA) and Back Propagation Artificial Neural Network (BPANN) methods were applied to form a hybrid forecasting model. A geospatial analysis was conducted to observe historical LSWTs and water quality changes for Dianchi Lake from 2005 to 2016. Based on the constructed model, LSWTs and changes in water quality were simulated for 2017 to 2020. The relationship between LSWTs and water quality thresholds was studied. The results show limited errors and highly generalized levels of predictive performance. In addition, a spatial visualization analysis shows that from 2005 to 2020, the chlorophyll-a (Chla), chemical oxygen demand (COD) and total nitrogen (TN) diffused from north to south and that ammonia nitrogen (NH3-N) and total phosphorus (TP) levels are increases in the northern part of Dianchi Lake, where the LSWT levels exceed 17 degrees C. The LSWT threshold is 17.6-18.53 degrees C, which falls within the threshold for nutritional water quality, but COD and TN levels fall below V class water quality standards. Transparency (Trans), COD, biochemical oxygen demand (BOD) and Chla levels present a close relationship with LSWT, and LSWTs are found to fundamentally affect lake cyanobacterial blooms. PMID- 29274611 TI - Reductive dechlorination of DNAPL mixtures with Fe(II/III)-L and Fe(II)-C: Evaluation using a kinetic model for the competitions. AB - A kinetic model for the competitions was applied to understand the reductive dechlorination of tertiary DNAPL mixtures containing PCE, TCE, and 1,1,1-TCA. The model assumed that the mass transfer rates were sufficiently rapid that the target compounds in the solution and the DNAPL mixture were in phase equilibrium. Dechlorination was achieved using either a mixture of Fe(II), Fe(III), and Ca(OH)2 (Fe(II/III)-L) or a mixture of Fe(II) and Portland cement (Fe(II)-C). PCE in the DNAPL mixtures was gradually reduced and it was reduced more rapidly using Fe(II)-C than Fe(II/III)-L. A constant total TCE concentration in the DNAPL mixtures was observed, which implied that the rate of loss of TCE by dechlorination and possibly other processes was equal to the rate of production of TCE by PCE dechlorination. On the other hand, 1,1,1-TCA in the DNAPL mixtures was removed rapidly and its degradation rate by Fe(II/III)-L was faster than by Fe(II)-C. The coefficients in the kinetic model (ki, Ki) were observed to decrease in the order 1,1,1-TCA>PCE>TCE, for both Fe(II/III)-L and Fe(II)-C. The concentrations of target compounds in solution were the effective solubilities, because of the assumption of phase equilibrium and were calculated with Rault's Law. The concentration changes observed were an increase and then a decrease for PCE, a sharp and then gradual increase for TCE, and a dramatic decrease for 1,1,1 TCA. The fraction of initial and theoretical reductive capacity revealed that Fe(II)-C had ability to degrade target compounds. PMID- 29274612 TI - The impact of channel capture on estuarine hydro-morphodynamics and water quality in the Amazon delta. AB - Due to progressive erosion of the new Urucurituba Channel, the Amazon River has recently captured almost all discharge from the lower Araguari River (Amapa-AP, Brazil), which previously flowed directly to the Atlantic Ocean. These recent geomorphological changes have caused strong impacts on the landscape and hydrodynamic patterns near the Araguari River mouth, especially the alteration of the riverine drainage system and its water quality. Landsat images were used to assess the estuarine landscape morphodynamic, particularly the expansion of the Urucurituba Channel, 80km from the Araguari River mouth, chronicling its connection to the Amazon River. The results suggest that the Urucurituba developed by headward migration across the Amazon delta; this is perhaps the first observation of estuarine distributary network development by headward channel erosion. The rate of Urucurituba Channel width increase has been ~5m/month since 2011, increasing drainage capacity of the channel. We also collected in situ hydrodynamic measurements and analyzed 17 water quality parameters. Having 2011 as baseline, the flowrate of Araguari River has been diverted by up to 98% through Urucurituba Channel, with substantial changes in net discharge recorded at 3 monitoring stations. Statistically significant differences in water quality (p<0.05) were observed between 2011 and 2015, associated with the change in the flow pattern. Estuarine salinity and solids concentrations have increased. Overall, we demonstrate changes in landscape, hydrodynamics and water quality of the lower Araguari River. PMID- 29274613 TI - Individual and combined effects of enrofloxacin and cadmium on soil microbial biomass and the ammonia-oxidizing functional gene. AB - The negative effects of residues from antibiotics and heavy metals in agricultural soils are becoming an increasingly frequent concern. To evaluate the toxicity and interaction of antibiotics and heavy metals, enrofloxacin (ENR) and cadmium (Cd) were used as targets to study the individual effects of ENR (0.025, 0.1, 0.4mmol/kg) and Cd (0.4mmol/kg) and their combined effects (mole ratios of ENR to Cd of 1: 1, 1: 4 and 1: 16) on soil microbial biomass and function on days 7, 14, 21 and 28 of the study. The results demonstrated that microbial populations, which were counted during 4 sampling periods, were mainly in the order of bacteria>actinomycetes>fungi. The ammonia monooxygenase (amoA) gene copies of ammonia-oxidizing archaea (AOA) were more abundant than ammonia oxidizing bacteria (AOB) on days 14 and 21. Soil bacteria, fungi, and actinomycetes numbers and amoA gene abundances of AOB and AOA in soils were inhibited to varying degrees by the single and combined effects of ENR and Cd; the higher the concentration of the treatments, the stronger the inhibition. The combined toxicity of ENR and Cd on soil microbes and AOA- and AOB-amoA genes was stronger than when either chemical was used alone; the interaction effects of ENR and Cd were mainly antagonistic. Moreover, the ratios of bacteria/fungi declined significantly on days 14, 21 and 28; the proportions of AOA- and AOB-amoA were altered with the addition of ENR and Cd. Thus, ENR and Cd had significant negative effects on the soil microbial community, especially when both contaminants were present. PMID- 29274614 TI - Social cure, what social cure? The propensity to underestimate the importance of social factors for health. AB - RATIONALE: Recent meta-analytic research indicates that social support and social integration are highly protective against mortality, and that their importance is comparable to, or exceeds, that of many established behavioural risks such as smoking, high alcohol consumption, lack of exercise, and obesity that are the traditional focus of medical research (Holt-Lunstad et al., 2010). The present study examines perceptions of the contribution of these various factors to life expectancy within the community at large. METHOD: American and British community respondents (N = 502) completed an on-line survey assessing the perceived importance of social and behavioural risk factors for mortality. RESULTS: As hypothesized, while respondents' perceptions of the importance of established behavioural risks was positively and highly correlated with their actual importance, social factors were seen to be far less important for health than they actually are. As a result, overall, there was a small but significant negative correlation between the perceived benefits and the actual benefits of different social and behavioural factors. Men, younger participants, and participants with a lower level of education were more likely to underestimate the importance of social factors for health. There was also evidence that underestimation was predicted by a cluster of ideological factors, the most significant of which was respondents' respect for prevailing convention and authorities as captured by Right-Wing Authoritarianism. CONCLUSION: Findings suggest that while people generally underestimate the importance of social factors for health this also varies as a function of demographic and ideological factors. They point to a range of challenges confronting those who seek to promote greater awareness of the importance of social factors for health. PMID- 29274615 TI - Latent Semantic Analysis: A new measure of patient-physician communication. AB - RATIONALE: Patient-physician communication plays an essential role in a variety of patient outcomes; however, it is often difficult to operationalize positive patient-physician communication objectively, and the existing evaluation tools are generally time-consuming. OBJECTIVE: This study proposes semantic similarity of the patient's and physician's language in a medical interaction as a measure of patient-physician communication. Latent semantic analysis (LSA), a mathematical method for modeling semantic meaning, was employed to assess similarity in language during clinical interactions between physicians and patients. METHODS: Participants were 132 Black/African American patients (76% women, Mage = 43.8, range = 18-82) who participated in clinical interactions with 17 physicians (53% women, Mage = 27.1, range = 26-35) in a primary care clinic in a large city in the Midwestern United States. RESULTS: LSA captured reliable information about patient-physician communication: The mean correlation indicating similarity between the transcripts of a physician and patient in a clinical interaction was 0.142, significantly greater than zero; the mean correlation between a patient's transcript and transcripts of their physician during interactions with other patients was not different from zero. Physicians differed significantly in the semantic similarity between their language and that of their patients, and these differences were related to physician ethnicity and gender. Female patients exhibited greater communication similarity with their physicians than did male patients. Finally, greater communication similarity was predicted by less patient trust in physicians prior to the interaction and greater patient trust after the interaction. CONCLUSION: LSA is a potentially important tool in patient-physician communication research. Methodological considerations in applying LSA to address research questions in patient-physician communication are discussed. PMID- 29274616 TI - Integrating social justice concerns into economic evaluation for healthcare and public health: A systematic review. AB - Social justice is the moral imperative to avoid and remediate unfair distributions of societal disadvantage. In priority setting in healthcare and public health, social justice reaches beyond fairness in the distribution of health outcomes and economic impacts to encompass fairness in the distribution of policy impacts upon other dimensions of well-being. There is an emerging awareness of the need for economic evaluation to integrate all such concerns. We performed a systematic review (1) to describe methodological solutions suitable for integrating social justice concerns into economic evaluation, and (2) to describe the challenges that those solutions face. To be included, publications must have captured fairness considerations that (a) involve cross-dimensional subjective personal life experience and (b) can be manifested at the level of subpopulations. We identified relevant publications using an electronic search in EMBASE, PubMed, EconLit, PsycInfo, Philosopher's Index, and Scopus, including publications available in English in the past 20 years. Two reviewers independently appraised candidate publications, extracted data, and synthesized findings in narrative form. Out of 2388 publications reviewed, 26 were included. Solutions sought either to incorporate relevant fairness considerations directly into economic evaluation or to report them alongside cost-effectiveness measures. The majority of reviewed solutions, if adapted to integrate social justice concerns, would require their explicit quantification. Four broad challenges related to the implementation of these solutions were identified: clarifying the normative basis; measuring and determining the relative importance of criteria representing that basis; combining the criteria; and evaluating trade-offs. All included solutions must grapple with an inherent tension: they must either face the normative and operational challenges of quantifying social justice concerns or accede to offering incomplete policy guidance. Interdisciplinary research and broader collaborations are crucial to address these challenges and to support due attention to social justice in priority setting. PMID- 29274617 TI - Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27. AB - BACKGROUND: Histological subtype, (invasive ductal breast cancer (IDBC)/invasive lobular breast cancer (ILBC)), might be a marker for differential response to endocrine therapy in breast cancer. METHODS: Clinical trial MA.27 compared 5 years of adjuvant anastrozole or exemestane in postmenopausal patients with hormone receptor positive early breast cancer. We evaluated IDBC versus ILBC (based on original pathology reports) as predictor for event-free survival (EFS) and overall survival (OS). RESULTS: A total of 5709 patients (5021 with IDBC and 688 with ILBC) were included (1876 were excluded because of missing or other histological subtype). Median follow-up was 4.1 years. Overall, histological subtype did not influence OS or EFS (HR (hazard ratio) 1.14, 95% confidence interval (CI) [0.79-1.63], P = 0.49 and HR 1.04, 95% CI [0.77-1.41], P = 0.81, respectively). There was no significant difference in OS between treatment with exemestane versus treatment with anastrozole in the IDBC group (HR = 0.92, 95% CI [0.73-1.16], P = 0.46). In the ILBC group, a marginally significant difference in favour of treatment with anastrozole was seen (HR = 1.79, 95% CI [0.98-3.27], P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with ILBC on anastrozole (HR 2.1, 95% CI [0.99-4.29], P = 0.05). After stepwise selection in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, 95% CI [1.00-4.31], P = 0.05). CONCLUSION: Our data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with ILBC cancers had a better OS when treated with anastrozole versus exemestane, whereas no difference was noted for patients with IDBC. CLINICAL TRIAL INFORMATION: NCT00066573. PMID- 29274618 TI - The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. AB - BACKGROUND: In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. METHODS: Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, >=65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. RESULTS: Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged >=65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59-0.81; P = 0.0001). Median OS in the three regions was 6.5-7.8 months in the trifluridine/tipiracil arm and 4.3 6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34-0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48-0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57-1.00; P = 0.0470). Median PFS was 2.0-2.8 months for trifluridine/tipiracil and 1.7-1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. CONCLUSIONS: Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957. PMID- 29274619 TI - Circulating oncometabolite D-2-hydroxyglutarate enantiomer is a surrogate marker of isocitrate dehydrogenase-mutated intrahepatic cholangiocarcinomas. AB - Therapeutic resources are limited for advanced biliary tract cancers and prognosis remains poor. Somatic mutations in isocitrate dehydrogenase (IDH)1/2 gene are found in 5-36% of patients with intrahepatic cholangiocarcinoma (ICC). The mutant forms of IDH1/2 catalyse the non-reversible accumulation of 2 hydroxyglutarate (2HG). Increasing numbers of indirect or direct-targeted therapies are developed to IDH1/2 mutations and could be assisted by a routinely feasible, rapid and inexpensive serum 2HG measurement by liquid chromatography coupled to tandem mass spectrometry. By comparing eight patients with an IDH1/2 mutated ICC to nine patients with wild-type IDH1/2 ICC, we found significantly higher levels of 2HG in patients with IDH1/2 mutations versus the wild-type group (median, 10.9 vs. 0.8 MUmol/L, p = 0.0037). D and L-2HG enantiomer levels significantly differed between the two groups with a higher level of D-2HG (p < 0.0001) in patients with IDH1/2 mutations. Accordingly, the D/L ratio was markedly higher in the patients with IDH1/2 mutations compared with the wild-type group (38.0 vs. 0.9 MUmol/L, p < 0.0001). D-2HG measurement ensured 100% sensitivity and specificity at a cut-off of 0.6 MUmol/L. D-2HG levels were correlated with tumour burden and tumour response to treatment with IDH-targeted therapies or indirect therapies. D-2HG serum level measurement by liquid chromatography coupled to tandem mass spectrometry is a sensitive, specific, precise (a coefficient of variation <10% and an accuracy >95%), fast (9 min run per sample) and inexpensive surrogate marker of IDH1/2 somatic mutation in ICC. Systematic measurement in patients with ICC may facilitate access to, and monitoring of, IDH-driven therapies. PMID- 29274620 TI - Age-related changes of CD4+ T cell migration and cytokine expression in germ-free and SPF mice periodontium. AB - OBJECTIVE: Increasing age is a potential risk factor for periodontal tissue breakdown, which may be affected by commensal flora. The aim of this study evaluated age-related changes in CD4+ T cells, C-C chemokine ligand 5 (CCL5), interleukin (IL)-17A, and receptor activator of nuclear factor-kappa B ligand (RANKL) expression using germ-free (GF) and conventionally reared (SPF) mice. DESIGN: GF and SPF mice at 8 (n = 6/group) and 22 weeks old (n = 6/group) were used. Immunohistochemical analyses were performed to determine the effects of aging on protein expression in periodontal tissues. Age-related changes in alveolar bone were quantified using micro-CT analysis. RESULTS: SPF mice, but not GF mice, showed an age-related increase in alveolar bone loss (P < 0.01). SPF mice at 22 weeks of age increased expression of CD4+ T cells, CCL5, IL-17A, and RANKL compared to those at 8 weeks of age in connective tissue and alveolar bone surface (P < 0.01). Furthermore, there was increased CD4+ T cells, which were co expressed with IL-17A and RANKL in SPF mice at 22 weeks of age. On the other hand, the GF mice did not show any significant differences in CD4+ T cells, CCL5, IL-17A and RANKL expression between the two age groups. CONCLUSIONS: SPF mice induced an age-related increase in CD4+ T cells co- expressed with IL-17A and RANKL, with occurring alveolar bone loss. In contrast, GF mice did not show age related changes in CD4+ T cell migration and cytokine expression. PMID- 29274621 TI - Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts. AB - OBJECTIVES: Approximately 65 million adults in the US have periodontitis, causing tooth loss and decreased quality of life. Cannabinoids modulate immune responses, and endocannabinoids are prevalent during oral cavity inflammation. Targets for intervention in periodontal inflammation are cannabinoid type 1 and 2 receptors (CB1R, CB2R), particularly CB2R because its levels increase during inflammation. We previously demonstrated that SMM-189 (CB2R inverse agonist) decreased pro inflammatory cytokine production in primary microglial cells. The hypothesis of this study was that cannabinoids anandamide (AEA), HU-308 (CB2R selective agonist), and SMM-189 decrease pro-inflammatory IL-6 and MCP-1 production by primary human periodontal ligament fibroblasts (hPDLFs) stimulated with P. gingivalis LPS, TNF-alpha, or IL-1beta. DESIGN: Cytotoxic effects of cannabinoid compounds (10-4-10-6.5 M), LPS (1-1000 ng/ml), TNFalpha (10 ng/ml) and IL-1beta (1 ng/ml) were assessed by measuring effects on cellular dehydrogenase activity. IL-6 and MCP-1 production were measured using Mesoscale Discovery (MSD) Human Pro Inflammatory IL-6 and MSD Human Chemokine MCP-1 kits and analyzed using MSD Sector 2400 machine. RESULTS: EC50 values for AEA, SMM-189, and HU-308 were 16 MUM, 13 MUM, and 7.3 MUM respectively. LPS (1 MUg/ml), TNF-alpha (10 ng/ml), and IL-1beta (1 ng/ml) increased IL-6 and MCP-1 production, which were inhibited by AEA, SMM-189, and HU-308. AEA alone significantly increased IL-6, but not MCP-1 levels, but the other cannabinoids alone had no effect. CONCLUSION: The effective inhibition of LPS, TNF-alpha, IL-1beta stimulated IL-6 and MCP-1 production by CB2R ligands in hPDLFs suggests that targeting the endocannabinoid system may lead to development of novel drugs for periodontal therapy, aiding strategies to improve oral health. PMID- 29274622 TI - Inhibition of the receptor for advanced glycation promotes proliferation and repair of human periodontal ligament fibroblasts in response to high glucose via the NF-kappaB signaling pathway. AB - OBJECTIVE: To observe if inhibition of the receptor for advanced glycation endproducts (RAGE) promotes proliferation and repair of human periodontal ligament fibroblasts (hPDLFs) stimulated by high glucose. In addition, we also discuss the effects of the NF-kappaB signaling pathway in relation to this process. METHODS: Primary cultured hPDLFs were exposed to either low glucose (5.5 mmol/L) or high glucose (25 mmol/L), and RAGE expression was measured by Western blot analysis. Cells were cultured in high glucose with different concentrations of the RAGE inhibitor, FPS-ZM1. We measured cell proliferation using the Cell Counting Kit-8 and expression of collagen type 1 and fibronectin by real-time PCR and ELISA, respectively. The relative protein expression levels of NF-kappaB p65 and phosphorylated p65 were measured by Western blot analysis. RESULTS: High glucose enhanced RAGE expression and suppressed cell growth. While FPS-ZM1 increased proliferation and expression of repair-related factors in high glucose, there was a concurrent decline in the phosphorylation level of NF-kappaB p65. CONCLUSION: FPS-ZM1 rescued the proliferative capacity and repair capability of hPDLFs via the RAGE-NF-kappaB signaling pathway in response to high glucose. PMID- 29274623 TI - Automatic estimation of a scale resolution in forensic images. AB - This paper proposes a new method for an automatic detection of a resolution of a scale or a ruler with graduation marks in the shoeprint images. The method creates a vector of the correlations estimated from the co-occurrence matrices for every row in a shoeprint image. The scale resolution is estimated from maxima in Fourier spectrum of the correlations' vectors. The proposed method is evaluated on over 500 images taken at crime scenes and in a forensics laboratory. The experimental results indicate the possibility of applying the proposed method to automatically estimate the scale resolution in forensic images. The automatic detection of a scale resolution could be used to automatically rescale a forensic image before the printing this image in "one-to-one" scale. Furthermore, the proposed method could be used to automatically rescale images to an equal scale thus allowing to compare the images digitally. PMID- 29274624 TI - Interferon regulatory factor 5 (IRF5) regulates the expression of matrix metalloproteinase-3 (MMP-3) in human chondrocytes. AB - Matrix metalloproteinase-3 (MMP-3) plays a pivotal role in the destruction of articular cartilage in osteoarthritis (OA). The regulation of gene expression of MMP-3 is complicated. Interferon regulatory factor 5 (IRF5) is a member of the interferon regulatory factor family of transcription factors. Little information regarding the biological function of IRF5 on chondrocytes and the pathogenesis of OA has been reported. In the current study, for the first time, we report that IRF5 is expressed in human primary chondrocytes and human chondrosarcoma cell line SW1353 cells. In addition, IRF5 is upregulated in response to TNF-alpha treatment in a dose dependent manner. Interestingly, IRF5 is significantly higher in chondrocytes from OA patients compared to those from normal subjects. Notably, IRF5 mediates TNF-alpha- induced expression of MMP-3 in chondrocytes. Overexpression of IRF5 promotes the expression of MMP-3, however, knockdown of IRF5 reduces the expression of MMP-3. Mechanistically, IRF5 is able to enhance the transcription of MMP-3 by binding to its promoter. Also, we found that NF kappaB was involved in the effects of IRF-5 on MMP-3 expression. These findings suggest that IRF5 might be a novel pharmacological target for the treatment of OA and RA. PMID- 29274625 TI - Inhibition of myocardial hypertrophy by magnesium isoglycyrrhizinate through the TLR4/NF-kappaB signaling pathway in mice. AB - Magnesium isoglycyrrhizinate (MgIG) is a magnesium salt of the 18-alpha glycyrrhizic acid stereoisomer that has exhibited hepato-protective effects and has anti-inflammatory, antioxidant, and antiviral activities. Here, we have investigated the effects and potential mechanisms of action of MgIG, with respect to myocardial fibrosis induced by isoproterenol (ISO) in mice. Mice were administered MgIG for 14days, with concurrent ISO dosing, and were sacrificed two weeks later. Lactate dehydrogenase (LDH) and creatine kinase (CK) concentrations were measured in the blood. Pathological changes in the myocardium were observed via light microscopy. In addition, the expression of the Bax and Bcl-2 genes, and the basic fibroblast growth factor (bFGF) protein were measured via an immunohistochemical method. The RNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), c-fos, and c-jun mRNA were quantified by reverse transcription-polymerase chain reaction (RT-PCR) in the myocardial tissue. The protein expression of toll-like receptor (TLR) 4, and nuclear factor kappa B (NF-kappaB) (p65) were measured using Western blot assays. Compared with the control group, the ISO group showed significant increases in bFGF, Bax, Bcl 2, TLR4, and NF-kappaB (p65) expressions, as well as increased serum levels of LDH and CK. MgIG had a protective effect on ISO-induced myocardial fibrosis, which might be ascribed, at least in part, to the inhibition of the TLR4/NF kappaB (p65) signaling pathway. PMID- 29274626 TI - The dual regulatory function of lienal peptide on immune system. AB - Lienal peptide (LP), extracted from the spleen of healthy calves, has been reported to be a unique immune modulator which shows notable immunomodulatory effects on immune system function. This study was designed to further investigate the immunomodulatory effect of LP in vitro and in vivo. The results showed that LP significantly decreased the LPS-induced overexpression levels of pro inflammatory cytokines including IL-1beta, IL-15, TNF-alpha and MIP-1alpha, through the NF-kappaB pathway. Moreover, LP showed an immunologic enhancement effect on immunosuppressed mice which were induced by cytarabine. The percentage of activated cells for bone marrow B lymphocytes, spleen lymphocytes, NK cells and peritoneal macrophages were notably increased after LP treatment. Furthermore, the administration of LP significantly reduced DNFB-induced inflammatory cell infiltration and restored CFA-induced arthritis in rats as evidenced by decrease in paw swelling and regulation of cytokines balance in serum. In conclusion, LP has outstanding immunomodulatory activity and could be served as a potential candidate for the management of patients with immune system disorders. PMID- 29274627 TI - Regulation of ABCG2 by nuclear factor kappa B affects the sensitivity of human lung adenocarcinoma A549 cells to arsenic trioxide. AB - Arsenic trioxide (As2O3) is successfully used as an anticancer agent against acute promyelocytic leukemia and some solid tumors. However, the application of As2O3 is largely limited by its drug resistance in the treatment of non-small cell lung carcinoma (NSCLC). Therefore, it is an urgent task to enhance the sensitivity of lung cancer cells to As2O3. In this study, using human lung adenocarcinoma A549 cells as a cell culture model, we demonstrated that an adenosine triphosphate binding cassette (ABC) transporter, ABCG2, was significantly increased by As2O3 treatment, while other ABC transporters, ABCB1 and ABCC1 showed no remarkable change in the response to As2O3. After inhibition of ABCG2 by its specific inhibitor, the drug sensitivity of As2O3 to A549 cells was significantly enhanced, manifested by decreased cell viability and colony formation as well as the increased ROS production and cell apoptosis. To further understand the molecular mechanism underlying the elevation of ABCG2 expression in As2O3-treated cells, we detected the activation state of nuclear factor kappa B (NF-kappaB) pathway and its relationship with ABCG2 expression. Our results revealed that the increased expression of ABCG2 was regulated by NF-kappaB, and thus affecting the cell death of As2O3-treated A549 cells. These findings indicate that inhibition of NF-kappaB/ABCG2 pathway by specific inhibitors may be a new strategy for the improvement of As2O3 sensitivity in NSCLC treatment. PMID- 29274628 TI - Hydrogen sulfide protects neonatal rat medulla oblongata against prenatal cigarette smoke exposure via anti-oxidative and anti-inflammatory effects. AB - We previously demonstrated that hydrogen sulfide (H2S) protected neonatal rat medulla oblongata from prenatal cigarette smoke exposure (CSE) via anti-apoptotic effect. The present work further investigated the involvement of anti-oxidative and anti-inflammatory effects of H2S in the protection. Pregnant Sprague-Dawley rats were randomly divided into NaCl, CSE, CSE + NaHS (a donor of H2S) and NaHS groups. All the tests were performed with corresponding neonatal rats. Nissl staining revealed that NaHS treatment ameliorated neuronal chromatolysis in the hypoglossal nucleus and nucleus ambiguus resulted from prenatal CSE. Moreover, NaHS eliminated decrease of glutathione level, increase of malondialdehyde content and inhibition of superoxide dismutase activity within neonatal rat medulla oblongata caused by prenatal CSE. NaHS also relieved the up-regulation of tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 in the medulla oblongata of the neonatal CSE rats. These results suggest that H2S can alleviate prenatal CSE-induced injuries of neonatal rat medulla oblongata through anti oxidative and anti-inflammatory effects. PMID- 29274629 TI - Trunk sway response to consecutive slip perturbations between subjects with and without recurrent low back pain. AB - BACKGROUND: Trunk sway responses following perturbations are critical to develop adequate prevention strategies. It is unclear how postural responses with a handheld task can validly be transferred to treadmill-induced slip perturbations in subjects with recurrent low back pain (LBP). OBJECTIVE: To compare trunk sway angle, velocity, and reaction time following treadmill-induced perturbations while subjects with and without LBP held a tray. DESIGN: Cross-sectional study. METHODS: There were 30 subjects with LBP and 50 control subjects who participated in the study. Each participant stood on the treadmill while he/she held a tray to produce a functional task. Three levels of consecutive slips were introduced based on the specific duration, velocity, and displacement. RESULTS: The trunk extension angle was significantly different (F = 4.22, p = 0.04) and demonstrated a significant interaction with groups and levels of perturbation (F = 6.83, p = 0.01). However, the reaction time was not significantly different based on the levels of perturbation (F = 0.43, p = 0.51). The LBP group increased trunk extension only at level 1 slip perturbation (t = 2.86, p = 0.005). CONCLUSION: The increased trunk extension following the first perturbation indicated a delay in adjusting trunk stability in the LBP group. However, there was no group difference with higher magnitudes of perturbations. These results indicated that the LBP group was able to minimize trunk sway with higher perturbations following the first perturbation. PMID- 29274630 TI - Molecular tools for pathway engineering in Saccharomyces cerevisiae. AB - Molecular tools for the regulation of protein expression in Saccharomyces cerevisiae have contributed to rapid advances in pathway engineering for this yeast. This review considers new and enhanced additions to this toolbox, focusing on experimental approaches to modulate enzyme synthesis and enzyme fate. Methods for genome engineering, regulation of transcription, post-translational protein localization, and combinatorial screening and sensing in S. cerevisiae are highlighted, and promising new approaches are introduced. PMID- 29274631 TI - Medical Devices; Anesthesiology Devices; Classification of the External Negative Pressure Airway Aid. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the external negative pressure airway aid into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the external negative pressure airway aid's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29274632 TI - Medicare Program; Medicare Shared Savings Program: Extreme and Uncontrollable Circumstances Policies for Performance Year 2017. Interim final rule with comment period. AB - This interim final rule with comment period establishes policies for assessing the financial and quality performance of Medicare Shared Savings Program (Shared Savings Program) Accountable Care Organizations (ACOs) affected by extreme and uncontrollable circumstances during performance year 2017, including the applicable quality reporting period for the performance year. Under the Shared Savings Program, providers of services and suppliers that participate in ACOs continue to receive traditional Medicare fee-for-service (FFS) payments under Parts A and B, but the ACO may be eligible to receive a shared savings payment if it meets specified quality and savings requirements. ACOs in performance-based risk agreements may also share in losses. This interim final rule with comment period establishes extreme and uncontrollable circumstances policies for the Shared Savings Program that will apply to ACOs subject to extreme and uncontrollable events, such as Hurricanes Harvey, Irma, and Maria, and the California wildfires, effective for performance year 2017, including the applicable quality data reporting period for the performance year. PMID- 29274633 TI - Unreported Deaths Affect the 'Hispanic Paradox' and the 'Black-White Mortality Crossover.' PMID- 29274634 TI - The Multi-Generational Impacts of Medicaid. PMID- 29274635 TI - Surprise Charges for Emergency Care. PMID- 29274636 TI - Using Raman spectroscopy and chemometrics to identify the growth phase of Lactobacillus casei Zhang during batch culture at the single-cell level. AB - BACKGROUND: As microbial cultures are comprised of heterogeneous cells that differ according to their size and intracellular concentrations of DNA, proteins, and other constituents, the detailed identification and discrimination of the growth phases of bacterial populations in batch culture is challenging. Cell analysis is indispensable for quality control and cell enrichment. METHODS: In this paper, we report the results of our investigation on the use of single-cell Raman spectrometry (SCRS) for real-time analysis and prediction of cells in different growth phases during batch culture of Lactobacillus (L.) casei Zhang. A targeted analysis of defined cell growth phases at the level of the single cell, including lag phase, log phase, and stationary phase, was facilitated by SCRS. RESULTS: Spectral shifts were identified in different states of cell growth that reflect biochemical changes specific to each cell growth phase. Raman peaks associated with DNA and RNA displayed a decrease in intensity over time, whereas protein-specific and lipid-specific Raman vibrations increased at different rates. Furthermore, a supervised classification model (Random Forest) was used to specify the lag phase, log phase, and stationary phase of cells based on SCRS, and a mean sensitivity of 90.7% and mean specificity of 90.8% were achieved. In addition, the correct cell type was predicted at an accuracy of approximately 91.2%. CONCLUSIONS: To conclude, Raman spectroscopy allows label-free, continuous monitoring of cell growth, which may facilitate more accurate estimates of the growth states of lactic acid bacterial populations during fermented batch culture in industry. PMID- 29274637 TI - Large-scale production of a thermostable Rhodothermus marinus cellulase by heterologous secretion from Streptomyces lividans. AB - BACKGROUND: The gene encoding a thermostable cellulase of family 12 was previously isolated from a Rhodothermus marinus through functional screening. CelA is a protein of 260 aminoacyl residues with a 28-residue amino-terminal signal peptide. Mature CelA was poorly synthesized in some Escherichia coli strains and not at all in others. Here we present an alternative approach for its heterologous production as a secreted polypeptide in Streptomyces. RESULTS: CelA was successfully over-expressed as a secreted polypeptide in Streptomyces lividans TK24. To this end, CelA was fused C-terminally to the secretory signal peptide of the subtilisin inhibitor protein (Sianidis et al. in J Biotechnol. 121: 498-507, 2006) from Streptomyces venezuelae and a new cloning strategy developed. Optimal growth media and conditions that stall biomass production promote excessive CelA secretion. Under optimal growth conditions in nutrient broth medium, significant amounts of mature CelA (50-90 mg/L or 100-120 mg/g of dry cell weight) are secreted in the spent growth media after 7 days. A protocol to rapidly purify CelA to homogeneity from culture supernatants was developed and specific anti-sera raised against it. Biophysical, biochemical and immmuno detection analyses indicate that the enzyme is intact, stable and fully functional. CelA is the most thermostable heterologous polypeptide shown to be secreted from S. lividans. CONCLUSION: This study further validates and extends the use of the S. lividans platform for production of heterologous enzymes of industrial importance and extends it to active thermostable enzymes. This study contributes to developing a platform for poly-omics analysis of protein secretion in S. lividans. PMID- 29274638 TI - Bone regeneration using composite non-demineralized xenogenic dentin with beta tricalcium phosphate in experimental alveolar cleft repair in a rabbit model. AB - BACKGROUND: Alveolar cleft repair is performed via bone grafting procedure to restore the dental arch continuity. A suitable bone substitute materials should possess osteoinductive and osteoconductive properties, to promote new bone formation, along with a slowly resorbable scaffold that is subsequently replaced with functionally viable bone. Calcium phosphate biomaterials have long proved their efficacy as bone replacement materials. Dentin in several forms has also demonstrated its possibility to be used as bone graft replacement material in several studies. The purpose of this study was to evaluate bone regeneration pattern and quantify bone formation after grafting pre-established experimental alveolar clefts defects model in rabbits using composite xenogenic dentin and beta-TCP in comparison to beta-TCP alone. METHODS: Unilateral alveolar cleft defects were created in 16 New Zealand rabbits according to previously described methodology. Alveolar clefts were allowed 8 weeks healing period. 8 defects were filled with beta-TCP, whereas 8 defects filled with composite xenogenic dentin with beta-TCP. Bone regeneration of the healed defects was compared at the 8 weeks after intervention. Quantification of bone formation was analyzed using micro-computed tomography (uCT) and histomorphometric analysis. RESULTS: uCT and histomorphometric analysis revealed that defects filled with composite dentin/beta-TCP showed statistically higher bone volume fraction, bone mineral density and percentage residual graft volume when compared to beta-TCP alone. An improved surgical handling of the composite dentin/beta-TCP graft was also noted. CONCLUSIONS: Composite xenogenic dentin/beta-TCP putty expresses enhanced bone regeneration compared to beta-TCP alone in the reconstruction of rabbit alveolar clefts defects. PMID- 29274641 TI - Use All Forms of Media to Tell Our Story. PMID- 29274640 TI - Effectiveness of the Malnutrition Quality Improvement Initiative on Practitioner Malnutrition Knowledge and Screening, Diagnosis, and Timeliness of Malnutrition Related Care Provided to Older Adults Admitted to a Tertiary Care Facility: A Pilot Study. AB - BACKGROUND: Malnutrition is present in 30% to 50% of hospitalized patients aged 60 years or older. As few as 3.2% of patients identified as high risk have a malnutrition diagnosis documented by medical providers. The Malnutrition Quality Improvement Initiative (MQii) aims to reduce the burden of hospital malnutrition by improving the process and delivery of care. OBJECTIVE: To evaluate implementing the MQii toolkit of best practice resources for screening, diagnosis, documentation, and timeliness of malnutrition care. DESIGN: This 6 month prospective pilot included a 3-month intervention with training and education modules tailored to type of practitioner and integrated into existing teaching and clinical workflow. PARTICIPANTS/SETTING: Forty-five health care professionals from geriatric, general medicine, and general surgery units at Vanderbilt University Hospital during January to June 2016. MAIN OUTCOME MEASURES: Malnutrition knowledge by 30-item questionnaire; electronic medical record (EMR) documentation; and timeliness of malnutrition screening, diagnosis, intervention, and discharge planning. STATISTICAL ANALYSES: Analysis of variance was used to test change over time. RESULTS: Malnutrition knowledge score increased 14%, from 39% to 53% (P=0.009). All patients whose nutrition screen indicated they were malnourished/high risk had registered dietitian nutritionist diagnosis of malnutrition documented in the EMR. The proportion who had medical provider (physician, nurse practitioner, or physician assistant) malnutrition diagnosis documented in the EMR increased 11.6%, from 26.7% to 38.3% (P=0.08). About 95% of malnourished/high risk patients had a documented intervention addressing malnutrition. Inclusion of malnutrition care in the discharge plan increased 4.8%, from 70.0% to 74.8% (P=0.13). CONCLUSIONS: This pilot study demonstrated feasibility of implementing the MQii resources to improve malnutrition knowledge and professionals' skills relevant to screening, diagnosis, intervention, and timeliness of malnutrition care. By optimizing the process and delivery of malnutrition care, it is expected that the quality of clinical care provided to older adults with malnutrition or at high malnutrition risk will improve. PMID- 29274639 TI - The changing roles of community nurses: the case of health plan nurses in Israel. AB - BACKGROUND: In Israel, approximately one-third of the country's nurses work in community settings - primarily as salaried employees in Israel's four non-profit health plans. Many health system leaders believe that the roles of health plan nurses have changed significantly in recent years due to a mix of universal developments (such as population aging and academization of the profession) and Israel-specific changes (such as the introduction of extensive quality monitoring in primary care). OBJECTIVES: The main objectives of the study were to identify recent changes in the roles of health plan nurses and their current areas of activity. It also explored the experience of front-line nurses with regard to autonomy, work satisfaction, and barriers to further role development. METHODS: The study integrated interviews and surveys of nurses and other professionals conducted across 4 years. Data generated from earlier study components were used to guide questions and focus for later components. In 2013, in-depth interviews were held with 55 senior nursing and medical professionals supplemented by interviews in mid-2017 with the head nurses in the four health plans. In addition, a national survey was conducted in 2014-5 among a representative sample of 1019 community nurses who work for the health plans and who are engaged in direct patient care. Six hundred ninety-two nurses responded to the survey, yielding a response rate of 69%. The survey sample consisted of an equal number of nurses from each health plan, and the observations were weighted accordingly. FINDINGS: Senior professionals identified general themes associated with a shift in nursing roles, including a transition from reactive to initiated work, increased specialization, and a shifting of tasks from hospitals to community settings. They identified the current main areas of activity in the health plans as being: routine care, chronic care, health promotion, quality monitoring and improvement, specialized care (such as wound care), and home care. In the survey of front-line nurses, 38% of the nurses identified "caring for chronically ill patients" as their main area of activity aside from routine care; 30% did so regarding "health promotion", and 26% did so regarding "a specific area of specialization" e.g., diabetes, wound care or women's health). In response to a separate question, 77% reported "great" or "very great" involvement in quality measurement programs. Four out of five front-line nurses were satisfied with their work to a great or very great extent, and approximately three out of four of them (73%) felt that they had autonomy at work to a great or very great extent. About half of the nurses take into account, to a great or very great extent, the financial concerns of the health plans that employ them. A large majority of the nurses (85%) indicated that the nature of their work had changed substantially in recent years, with an increase in autonomy noted as one of the key changes. Perceived barriers to further role development include attitudes on the part of some physicians and nurses, an insufficient number of dedicated nursing positions, and insufficiently attractive wage levels. CONCLUSIONS: The findings, gathered over 4 years, indicate alignment between universal and Israel specific trends in health care and the evolving roles of nurses in Israel's health plans. The findings provide support for ongoing efforts in the health plans to give nurses more authority and responsibility in the management of chronically ill patients, a more central role in health promotion efforts, more advanced training - both inter-professional and nurse-specific, and more opportunity to focus on the roles and tasks that require nursing professionals. PMID- 29274642 TI - MyPlate: Meeting Consumers Where They Are, Every Season. PMID- 29274643 TI - Increased Efficacy and Safety of Enteral Nutrition Support with a Protocol (ASNET) in Noncritical Patients: A Randomized Controlled Trial. AB - BACKGROUND: Unintentional underfeeding is common in patients receiving enteral nutrition (EN), and is associated with increased risk of malnutrition complications. Protocols for EN in critically ill patients have been shown to enhance adequacy, resulting in better clinical outcomes; however, outside of intensive care unit (ICU) settings, the influence of a protocol for EN is unknown. OBJECTIVE: To evaluate the efficacy and safety of implementing an EN protocol in a noncritical setting. DESIGN: Randomized controlled clinical trial. PARTICIPANTS AND SETTINGS: This trial was conducted from 2014 to 2016 in 90 adult hospitalized patients (non-ICU) receiving exclusively EN. Patients with carcinomatosis, ICU admission, or <72 hours of EN were excluded. INTERVENTION: The intervention group received EN according to a protocol, whereas the control group was fed according to standard practice. MAIN OUTCOME MEASURES: The proportion of patients receiving >=80% of their caloric target at Day 4 after EN initiation. STATISTICAL ANALYSES PERFORMED: Student t test or Wilcoxon rank-sum test were used for continuous variables and the difference between the groups in the time to receipt of the optimal amount of nutrition was analyzed using Kaplan Meier curves. RESULTS: Forty-five patients were randomized to each group. At Day 4 after EN initiation, 61% of patients in the intervention arm had achieved the primary end point compared with 23% in the control group (P=0.001). In malnourished patients, 63% achieved the primary end point in the intervention group compared with 16% in the control group (P=0.003). The cumulative deficit on Day 4 was lower in the intervention arm compared with the control arm: 2,507 kcal (interquartile range [IQR]=1,262 to 2,908 kcal) vs 3,844 kcal (IQR=2,620 to 4,808 kcal) (P<0.001) and 116 g (IQR=69 to 151 g) vs 191 g (IQR=147 to 244 g) protein (P<0.001), respectively. The rates of gastrointestinal complications were not significantly different between groups. CONCLUSIONS: Implementation of an EN protocol outside the ICU significantly improved the delivery of calories and protein when compared with current standard practice without increasing gastrointestinal complications. PMID- 29274644 TI - The European Experience in Laparoscopic Pancreatic Resections. PMID- 29274645 TI - Laparoscopic Pancreatic Surgery: In reply to Sahakyan and colleagues. PMID- 29274646 TI - Is the Incidence of Delayed Gastric Empty Due to the Gastroenterostomy Method? PMID- 29274647 TI - Flange Gastroenterostomy: In reply to Xu and Jia. PMID- 29274648 TI - Nipple-Sparing Mastectomy. PMID- 29274649 TI - January 2018 Featured Articles, Volume 226. PMID- 29274650 TI - Correction. PMID- 29274651 TI - Correction. PMID- 29274652 TI - Retraction notice to "Poly-pathway model, a novel approach to simulate multiple metabolic states by reaction network-based model - Application to amino acid depletion in CHO cell culture". PMID- 29274653 TI - Winning the HIV War Through Prevention. PMID- 29274654 TI - Using the Social-Ecological Model of HIV Prevention to Explore HIV Testing Behaviors of Young Black College Women. AB - The purpose of our study was to explore HIV testing behaviors and attitudes among young Black women ages 18-24 years in southern North Carolina (N =17) using a semi-structured interview based on the Socio-Ecological Model. The findings showed that individual, interpersonal, social, and organizational factors contributed to participants' testing behaviors and attitudes. Understanding the factors that influence attitudes and intention for HIV testing among young Black women will inform the development of culturally congruent prevention interventions and programs. PMID- 29274655 TI - Do You PrEP? A Review of Primary Care Provider Knowledge of PrEP and Attitudes on Prescribing PrEP. AB - Oral preexposure prophylaxis (PrEP) has been proven to be a safe and effective means of preventing HIV. The purpose of our literature review was to examine primary care provider knowledge and attitudes about prescribing PrEP. PubMed, CINAHL, Web of Science, and Scopus were searched and additional articles were identified through other sources, yielding 11 articles that met inclusion criteria. Overall, there was high variability among providers regarding attitudes, knowledge, and prescriptive practices related to PrEP. PrEP continues to be an underutilized HIV prevention intervention and more research focusing on provider-specific factors is warranted. PMID- 29274656 TI - Risk factors for implant failure after fixation of proximal femoral fractures with fracture of the lateral femoral wall. AB - INTRODUCTION: To investigate potential predictors of implant failure following fixation of proximal femoral fractures with a fracture of the lateral femoral wall. MATERIALS AND METHODS: Medical records of 99 adult patients who had operative treatment for a proximal femoral fracture with a fracture of the lateral femoral wall between May 2004 and April 2015 were retrospectively analysed to determine factors associated with implant failure. Patients underwent routine surgical procedures for implantation of extramedullary or intramedullary devices. Potential predictors were age, gender, body mass index, comorbidities, type of fracture, reduction method, status of greater and lesser trochanters, course of the lateral fracture line, and presence/absence of a free bone fragment at the junction of the greater trochanter and lateral femoral wall. RESULTS: Ten (10%) implant failures were identified. Univariate analysis identified a free bone fragment at the junction of the greater trochanter and lateral femoral wall (odds ratio [OR], 21.25; 95% confidence interval [CI], 4.31-104.67; p < 0.001) and a transverse fracture line across the lateral femoral wall (primary or iatrogenic) (OR, 5.36; 95% CI, 1.29-22.30; p = 0.021) as factors associated with implant failure. Using a multivariate model, only a free bone fragment at the junction of the greater trochanter and lateral femoral wall (OR, 16.05; 95% CI, 3.06-84.23; p = 0.001) was a risk factor for implant failure. CONCLUSIONS: A free bone fragment at the junction of the greater trochanter and lateral femoral wall and a transverse fracture line across the lateral femoral wall are predictors of implant failure in proximal femoral fractures with a fracture of the lateral femoral wall. Integrity of the lateral femoral wall correlates with prognosis of proximal femoral fracture. Lateral femoral wall reconstruction may be required for effective treatment of proximal femoral fractures with a fracture of the lateral femoral wall. PMID- 29274657 TI - Historical investigations into varicocele pathophysiology and sperm migration. AB - Stephenson JD, O'Shaughnessy EJ. Hypospermia and its relationship to varicocele and intrascrotal temperature. Fertil Steril 168;19(1):110-7. "There is a frequently observed, definite relationship between varicocele and hypospermia." Moghissi KS. Human and bovine sperm migration. Fertil Steril 1968;19(1):118-22. "Van Leeuwenhoek's discovery of motile spermatozoa led to the conclusion that their migration was due to their own propellant activity." PMID- 29274658 TI - Endometrial scratching to increase pregnancy rates with intrauterine insemination. PMID- 29274659 TI - Fraternal twins after elective single-embryo transfers: a lesson in never saying "never". PMID- 29274660 TI - Mirror, mirror on the wall: Increasing young children's honesty through inducing self-awareness. AB - Previous studies have shown that in older children, promising to tell the truth increases truth-telling rates; however, in preschool-aged children, this has not been found to be effective. The current study compared promising with a novel technique of increasing children's self-awareness (by asking children to look at themselves in a mirror). It was predicted that inducing self-awareness would encourage children's honesty given that self-awareness increases adherence to social and moral norms. Children aged 3 or 4 years (N = 135) completed a modified temptation resistance paradigm where they were asked to not peek at a toy in the absence of an experimenter. Next, children were randomly assigned to one of three conditions: Self-Awareness, Promise, or Control. When questioned about whether they peeked at the toy, children in the Self-Awareness condition were significantly more likely to tell the truth about peeking compared with those in the Promise condition. There was no significant difference between the Promise and Control conditions. PMID- 29274661 TI - Perioperative Celecoxib and Postoperative Opioid Use in Hand Surgery: A Prospective Cohort Study. AB - PURPOSE: Prescription opioid abuse is an epidemic in the United States; multimodal analgesia has been suggested as a potential solution to decrease postoperative opioid use. The primary aim of this study was to determine the effect of perioperative celecoxib on opioid intake. Secondary goals were to determine whether perioperative administration of celecoxib decreased postoperative patient-reported pain and whether patient demographic characteristics could predict postoperative pain and opioid intake. METHODS: This prospective cohort study enrolled patients undergoing mass excision or carpal tunnel, trigger finger, or de Quervain release by 1 of 3 fellowship-trained hand surgeons. Patients in the experimental group were given 200 mg celecoxib tablets taken twice a day starting the day before surgery and continued for 5 days after surgery. Both groups received hydrocodone-acetaminophen tablets 5 mg/325 mg as needed after surgery. After surgery, patients completed daily opioid consumption and pain logs for 7 days and underwent a pill count. Outcomes included morphine milligram equivalents (MME) consumed and postoperative pain. RESULTS: A total of 123 patients were enrolled: 68 control patients and 54 celecoxib patients. Fifty (74%) and 37 (69%) patients, respectively, completed the study. Overall, the median number of MMEs consumed was 25 (range, 0-330). During the first postoperative week, patients in the celecoxib and control groups were similar with respect to postoperative pain experienced (median visual analog scale score, 2.0 vs 1.4, respectively) and amount of opioid taken (median MMEs = 30 vs 20, respectively). CONCLUSIONS: Patients taking perioperative celecoxib had similar postoperative pain and opioid intake compared with patients not prescribed celecoxib in the study. Regardless of study group, 4 to 10 hydrocodone tablets were sufficient to control postoperative pain for most patients undergoing soft tissue ambulatory hand surgery. This may be the result of the limited duration and mild nature of pain after outpatient elective hand surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 29274662 TI - Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice. AB - The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is normally suppressed during pregnancy. Dysregulation of the HPA axis has been proposed to play a role in postpartum depression. However, direct investigation into the relationship between the HPA axis and postpartum depression has been hindered by the lack of useful animal models. Building on our discovery of a role for the K+/Cl-co-transporter, KCC2, in the GABAergic regulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN), critical for mounting the body's physiological response to stress, we assessed the role of KCC2 in the regulation of the HPA axis during pregnancy and the postpartum period. Here we demonstrate that the normal suppression of the stress-induced activation of the HPA axis during the peripartum period involves maintenance of KCC2 in the PVN. Mice lacking KCC2 specifically in corticosterone-releasing hormone (CRH) neurons, which govern the activity of the HPA axis (KCC2/Crh mice), exhibit dysregulation of the HPA axis and abnormal postpartum behaviors. Loss of KCC2 specifically in CRH neurons in the PVN is sufficient to reproduce the depression-like phenotype and deficits in maternal behaviors during the postpartum period. Similarly, chemogenetic activation of CRH neurons in the PVN is sufficient to induce abnormal postpartum behaviors and chemogenetic silencing of CRH neurons in the PVN can ameliorate abnormal postpartum behaviors observed in KCC2/Crh mice. This study demonstrates that dysregulation of the HPA axis is sufficient to induce abnormal postpartum behaviors and deficits in maternal behaviors in mice, providing empirical support for a role of HPA axis dysfunction in the pathophysiology of postpartum depression. PMID- 29274664 TI - Competition in the Historical Niche: A Response to Scheele et al. PMID- 29274665 TI - Red ginseng extracts attenuate skin inflammation in atopic dermatitis through p70 ribosomal protein S6 kinase activation. AB - Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease with increased immunoglobulin E (IgE) levels. Activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling is known to occur in the inflammatory regions of AD skin. We previously demonstrated that red ginseng extract (RGE), as an anti-inflammatory agent, had potential for treating AD. However, it is still unclear whether RGE inhibits mTOR/p70S6K signaling. Thus, we examined the anti-inflammatory effects of RGE on IgE or interferon-gamma (IFN-gamma) induced signaling pathways. In KU812 human basophils, activation of Fcepsilon receptor type Ialpha (FCepsilonRI), also known as the high affinity IgE receptor, induced phosphorylation of both mTOR and p70S6K. Moreover, levels of phosphorylated p70S6K (p-p70S6K), but not p-mTOR, were decreased by RGE. RGE also decreased p-p70S6K levels in IFN-gamma-stimulated human keratinocytes, suppressing the IFN-gamma induced increase in levels of C-C chemokine ligand 2 mRNA. Interestingly, the increased p70S6K phosphorylation in skin lesions of AD model mice was attenuated by RGE treatment. In conclusion, RGE is a potential therapy against inflammatory responses involving the p70S6K signaling pathway. PMID- 29274663 TI - Long Noncoding RNA in Cancer: Wiring Signaling Circuitry. AB - Long noncoding RNAs (lncRNAs), which are encoded by a vast less explored region of the human genome, may hold missing drivers of cancer and have gained attention recently as a potentially crucial layer of cancer cell regulation. lncRNAs are aberrantly expressed in a broad spectrum of cancers, and they play key roles in promoting and maintaining tumor initiation and progression, demonstrating their clinical potential as biomarkers and therapeutic targets. Recent discoveries have revealed that lncRNAs act as key signal transduction mediators in cancer signaling pathways by interacting with proteins, RNA, and lipids. Here, we review the mechanisms by which lncRNAs regulate cellular responses to extracellular signals and discuss their clinical potential as diagnostic indicators, stratification markers, and therapeutic targets of combinatorial treatments. PMID- 29274666 TI - [Erratum to "Histoplasma capsulatum bone and joint infection" [Med. Mal. Infect. 47 (2017) 554-557]]. PMID- 29274667 TI - A real-time multiplex PCR for the identification and typing of Vibrio cholerae. AB - We report the development and validation of a duo-triplex real-time polymerase chain reaction (PCR) for the rapid identification and typing of Vibrio cholerae. The PCR assay targets a species-specific toxR gene present in all strains of V. cholerae and used as a marker for the species wbeO1 and wbfO139, encoding the O1 and O139 somatic antigens, and ctxA, encoding cholera toxin (CT). The two tcpA variants associated with the classical and El-Tor biotypes are used to infer biotype. The assay was evaluated using 178 isolates comprising eight different Vibrio species, including 122 isolates of V. cholerae. The PCR results of 171/178 (96.1%) isolates were concordant with the serotyping, biotyping, and expected CT results. Variants of toxR (n=3), nonfunctional wbeO1 (n=1), and CT-negative isolates of V. cholerae O1 (n=3) were likely explanations for the mismatched results. This duo-triplex real-time PCR is a reproducible and robust assay for the rapid identification and typing of V. cholerae belonging to the highly pathogenic, pandemic lineages. PMID- 29274669 TI - [Recurrent abdominal pain. Abdominal cutaneous nerve entrapment syndrome: A report of three cases]. PMID- 29274668 TI - ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis. AB - To clarify the possible involvement of intermediate ATXN1 alleles as risk factors for amyotrophic lateral sclerosis (ALS), we tested ATXN1 in a cohort of 1146 Italian ALS patients, previously screened for variants in other ALS genes, and in 529 controls. We detected ATXN1 alleles with >=33 polyglutamine repeats in 105 of 1146 patients (9.16%) and 29 of 529 controls (5.48%) (p = 0.003). The frequency of ATXN1 alleles with >=33 polyglutamine repeats was particularly high in the group of ALS patients carrying the C9orf72 expansion (12/59, 20.3%). We confirmed this result in an independent cohort of C9orf72 Italian patients (10/80 cases, 12.5%), thus finding a cumulative frequency of ATXN1 expansion of 15.82% in C9orf72 carriers (p = 2.40E-05). Our results strongly support the hypothesis that ATXN1 could act as a disease risk gene in ALS, mostly in C9orf72 expansion carriers. Further studies are needed to confirm our results and to define the mechanism by which ATXN1 might contribute to neuronal degeneration leading to ALS. PMID- 29274670 TI - Prediction of organ-confined disease after robot-assisted radical prostatectomy in patients with clinically locally-advanced prostate cancer. AB - BACKGROUND: Little is known about the preoperative predictive factors that could identify subsets of favorable patients who can be possibly cured with robot assisted radical prostatectomy (RARP) alone in locally advanced prostate cancer (LAPCa). Our study was designed to identify clinical predictors of pathologic organ-confined disease (pOCD) in RARP setting. METHODS: Between 2007 and 2013, clinicopathological and oncological data from 273 consecutive men undergoing robot-assisted RP with extended PLND for clinically LAPCa were reviewed in a single-institution, retrospectively. After exclusion of patients who received neoadjuvant hormone treatment before surgery, 186 subjects satisfied the final inclusion criteria. RESULTS: Fourty-three patients (23.1% of total cohort) with preoperative clinically LAPCa patients were down-staged to pOCD following RARP. Preoperative prostate-specific antigen (PSA) level, preoperative PSAD, positive core percent, maximal tumor volume in any core, and biopsy Gleason score were significantly associated with down-staging into pOCD following RARP. Multivariate logistic regression analysis revealed that lower preoperative PSA (<=10 ng/mL) and maximal tumor volume in any core (<=70%) were independent predictors of pOCD following RARP. CONCLUSIONS: Approximately 23% of preoperative clinically LAPCa patients were down-staged to pOCD following RARP. Preoperative PSA and maximal tumor volume in any biopsy core might be useful clinical predictors of pOCD in clinically LAPCa patients in RARP setting. PMID- 29274671 TI - Incidence rates of admissions associated with alcohol withdrawal syndrome in Spain: Analysis of minimum basic data set 1999-2010. AB - BACKGROUND: There are no data on the incidence of admissions associated with alcohol withdrawal syndrome (AWS) or about its trend over time in Spain. OBJECTIVE: To analyze the characteristics, incidence rates and trends over time of hospital admissions associated with AWS in Spanish public hospitals. MATERIAL AND METHOD: Analysis from the Spanish public hospitals minimum basic data set of hospital admissions with AWS (CIE9-MC 291.81), alcohol withdrawal delirium (CIE9 MC 291.0) and alcohol withdrawal hallucinosis (CIE9-MC 291.3), since 1999 to 2010. RESULTS: We identified 56,395 admissions associated with AWS. Mean age was 50.9 (SD 12.5) and 88% were male. The most frequent admission department was Internal Medicine (24.9%). The mean hospital stay was 12.6 days (SD 14.4) and mortality was 4.7%; 62.6% of cases developed AWS during an admission for another reason, mostly due to alcohol-related pathologies. Secondary diagnoses in patients hospitalized for AWS were related to alcohol consumption in more than half of the cases. The incidence rate of admissions associated with AWS in Spain remained stable from 1999 to 2010, with a small decline in the last 3 years of the period. The communities with the highest incidence were the Canary Islands, the Balearic Islands and Galicia. CONCLUSIONS: The incidence rate of admissions associated with AWS in Spanish public hospitals in the period 1999-2010 has remained stable with slight changes. There are differences in the incidence of AWS among the different autonomous communities. PMID- 29274672 TI - New therapeutic options in asthma. PMID- 29274673 TI - Evaluation of the outcomes following endonasal endoscopic orbital decompression in patients with Graves' ophthalmopathy. PMID- 29274674 TI - Comparative study between obstetric antiphospholipid syndrome and obstetric morbidity related with antiphospholipid antibodies. AB - BACKGROUND AND OBJECTIVES: To compare clinical, laboratory, treatment and live birth rate data between women with aPL-related obstetric complications (OMAPS) not fulfilling the Sydney criteria and women fulfilling them (OAPS). MATERIALS AND METHODS: Retrospective and prospective multicentre study. Data comparison between groups from The European Registry on Antiphospholipid Syndrome included within the framework of the European Forum on Antiphospholipid Antibody projects. RESULTS: 338 women were analysed: 247 fulfilled the Sydney criteria (OAPS group) and 91 did not (OMAPS group). In the OMAPS group, 24/91 (26.37%) fulfilled laboratory Sydney criteria (subgroup A) and 67/91 (74.63%) had a low titre and/or non-persistent aPL-positivity (subgroup B). Overall, aPL laboratory categories in OAPS vs. OMAPS showed significant differences: 34% vs. 11% (p<0.0001) for category I, 66% vs. 89% (p<0.0001) for category II. No differences were observed when current obstetric complications were compared (p=0.481). 86.20% of OAPS women were treated vs. 75.82% of OMAPS (p=0.0224), particularly regarding the LDA+LMWH schedule (p=0.006). No differences between groups were observed in live births, gestational, puerperal arterial and/or venous thrombosis. CONCLUSIONS: Significant differences were found among aPL categories between groups. Treatment rates were higher in OAPS. Both OAPS and OMAPS groups had similarly good foetal maternal outcomes when treated. The proposal to modify OAPS classification criteria, mostly laboratory requirements, is reinforced by these results. PMID- 29274675 TI - [Correlation between obstructive apnea syndrome and difficult airway in ENT surgery]. AB - INTRODUCTION: ENT patients with obstructive sleep apnea syndrome have a tendency of collapsing the upper airways in addition to anatomical obstacles. Obstructive sleep apnea syndrome is related to the increased risk of difficult airway and also increased perioperative complications. In order to identify these patients in the preoperative period, the STOP Bang questionnaire has been highlighted because it is summarized and easy to apply. OBJECTIVES: Evaluate through the STOP Bang questionnaire whether patients undergoing ENT surgery with a diagnosis of obstructive sleep apnea syndrome have a higher risk of complications, particularly the occurrence of difficult airway. CASUISTRY AND METHODS: Measurements of anatomical parameters for difficult airway and questionnaire application for clinical prediction of obstructive sleep apnea syndrome were performed in 48 patients with a previous polysomnographic study. RESULTS: The sample detected difficult airway in about 18.7% of patients, all of them with obstructive sleep apnea syndrome. This group had older age, cervical circumference > 40cm, ASA II and Cormack III/IV. Patients with obstructive sleep apnea syndrome had higher body mass index, cervical circumference, and frequent apnea. In subgroup analysis, the group with severe obstructive sleep apnea syndrome showed a significantly higher SB score compared to patients without this syndrome or with a mild/moderate obstructive sleep apnea syndrome. CONCLUSIONS: The STOP Bang questionnaire was not able to predict difficult airway and mild obstructive sleep apnea syndrome, but it identified marked obstructive sleep apnea syndrome. All patients with difficult airway had moderate and marked obstructive sleep apnea syndrome, although this syndrome did not involve difficult airway. The variables Cormack III/IV and BMI greater than 35 Kg.m-2 were able to predict difficult airway and obstructive sleep apnea syndrome, respectively. PMID- 29274676 TI - [Determination of residual mass in left ventricle by intraoperative transesophageal echocardiography after a giant and floating left atrial myxoma resection]. AB - Atrial myxoma is a benign tumor of the heart that occurs primarily in the left atrium. Floating or large left atrial myxomas frequently cause functional mitral stenosis, may also affect mitral valve structure and flow, and lead to mitral regurgitation. Systemic embolization occurs in around 30% of cases either from tumor fragmentation or complete tumor detachment hence it should be removed as soon as it is detected. Intraoperative transesophageal echocardiography has a vital importance in the surgery. After resection of myxoma, intraoperative transesophageal echocardiography must be performed to rule out residual mass. The case here reported is of a 48-year old female, who presented with giant and floating left atrial myxoma. Residue mass was detected with intraoperative transesophageal echocardiography in the left ventricle after the resection of myxoma. Subsequently, the residue mass was successfully removed. Complete resection must be required to prevent possible complications such as recurrence, embolization in atrial myxomas. Transesophageal echocardiography performed intraoperatively is vital importance to confirm that the myxoma is completely resected. PMID- 29274677 TI - Musculoskeletal and Sports Medicine Physical Medicine and Rehabilitation Curriculum Guidelines. PMID- 29274678 TI - An Introduction to Bayesian Data Analysis for Correlations. PMID- 29274679 TI - A Tale of Two Treatments for Patellofemoral Pain. PMID- 29274680 TI - Multiple sclerosis: what's it got to do with your guts? PMID- 29274681 TI - Kapil Sethi: all about water buffaloes and refusing to be boring. PMID- 29274682 TI - Linear IgA dermatosis: An atypical manifestation of a rare disease. PMID- 29274683 TI - Homogenization of the lipid profile values. AB - Analytical reports from the clinical laboratory are essential to guide clinicians about what lipid profile values should be considered altered and, therefore, require intervention. Unfortunately, there is a great heterogeneity in the lipid values reported as "normal, desirable, recommended or referenced" by clinical laboratories. This can difficult clinical decisions and be a barrier to achieve the therapeutic goals for cardiovascular prevention. A recent international recommendation has added a new heterogeneity factor for the interpretation of lipid profile, such as the possibility of measuring it without previous fasting. All this justifies the need to develop a document that adapts the existing knowledge to the clinical practice of our health system. In this regard, professionals from different scientific societies involved in the measurement and use of lipid profile data have developed this document to establish recommendations that facilitate their homogenization. PMID- 29274684 TI - Identification of novel nt-MGAM inhibitors for potential treatment of type 2 diabetes: Virtual screening, atom based 3D-QSAR model, docking analysis and ADME study. AB - In this study, a virtual screening procedure was applied to identify new potential nt-MGAM inhibitors as a possible medication for type 2 diabetes. To this aim, a series of salacinol analogues were first investigated by docking analysis for their binding to the X-ray structure of the biological target nt MGAM. Key interactions for ligand binding into the receptor active site were identified which shared common features to those found for other known inhibitors, which strengthen the results of this study. 3D QSAR model was then built and showed to be statistically significant and with a good predictive power for the training (R2 = 0.99, SD = 0.17, F = 555.3 and N = 27) and test set (Q2 = 0.81, Pearson(r) = 0.92, RMSE = 0.52, N = 08). The model was then used to virtually screen the ZINC database with the aim of identifying novel chemical scaffolds as potential nt-MGAM inhibitors. Further, in silico predicted ADME properties were investigated for the most promising molecules. The outcome of this investigation sheds light on the molecular characteristics of the binding of salacinol analogues to nt-MGAM enzyme and identifies new possible inhibitors which have the potential to be developed into drugs, thus significantly contributing to the design and optimization of therapeutic strategies against type 2 diabetes. PMID- 29274685 TI - Reversible cerebral vasoconstriction syndrome: an important and common cause of thunderclap and recurrent headaches. AB - Reversible cerebral vasoconstriction syndrome is an intracranial vascular manifestation of a wide variety of diseases. It is the second most common cause of thunderclap headache, the most common cause of recurrent severe secondary headaches, and, in patients <60 years of age, has been reported as the commonest cause of isolated convexity subarachnoid haemorrhage. Radiologically, its key feature is vasoconstriction of the intracranial vessels, a dynamic process that is typically maximal at 2 weeks, varies in its distribution over the course of the disease, and typically resolves after 3 months. It can have haemorrhagic and ischaemic complications and sometimes occurs in concert with posterior reversible encephalopathy syndrome. It also has important associations with dissection and migraine. Rarer atypical cases can present with mild headache, no headache at all, or even a comatose state. This paper provides a detailed review of this syndrome, its pathophysiology, differential diagnosis, imaging findings, and work up. It also describes the role that high-resolution magnetic resonance imaging (MRI) techniques can have in diagnosing the disease and emphasises the central role that all radiologists have in detecting this important and underdiagnosed condition. PMID- 29274687 TI - Assessment of the waste electrical and electronic equipment management systems profile and sustainability in developed and developing European Union countries. AB - The assessment of waste management systems for electrical and electronic equipment (WEEE) from developed economies (Germany, Sweden and Italy) and developing countries (Romania and Bulgaria), is discussed covering the period 2007-2014. The WEEE management systems profiles are depicted by indicators correlated to WEEE life cycle stages: collection, transportation and treatment. The sustainability of national WEEE management systems in terms of greenhouse gas emissions is presented, together with the greenhouse gas efficiency indicator that underlines the efficiency of WEEE treatment options. In the countries comparisons, the key elements are: robust versus fragile economies, the overall waste management performance and the existence/development of suitable management practices on WEEE. Over the life cycle perspective, developed economies (Germany, Sweden and Italy) manage one order of magnitude higher quantities of WEEE compared to developing countries (Romania and Bulgaria). Although prevention and reduction measures are encouraged, all WEEE quantities were larger in 2013, than in 2007. In 2007-2014, developed economies exceed the annual European collection target of 4 kg WEEE/capita, while collection is still difficult in developing countries. If collection rates are estimated in relationship with products placed on market, than similar values are registered in Sweden and Bulgaria, followed by Germany and Italy and lastly Romania. WEEE transportation shows different patterns among countries, with Italy as the greatest exporter (in 2014), while Sweden treats the WEEE nationally. WEEE reuse is a common practice in Germany, Sweden (from 2009) and Bulgaria (from 2011). By 2014, recycling was the most preferred WEEE treatment option, with the same kind of rates performance, over 80%, irrespective of the country, with efforts in each of the countries in developing special collection points, recycling facilities and support instruments. The national total and the recycling carbon footprints of WEEE are lower in 2013 than in 2007 for each country, the order in reducing the environmental impacts being: Germany, Italy, Sweden, Bulgaria and Romania. The negative values indicate savings in greenhouse gas emissions. In 2013, the GHG efficiency shows no differences of the WEEE management in the developed and developing countries. PMID- 29274686 TI - Fluid-structure interaction models based on patient-specific IVUS at baseline and follow-up for prediction of coronary plaque progression by morphological and biomechanical factors: A preliminary study. AB - Plaque morphology and biomechanics are believed to be closely associated with plaque progression. In this paper, we test the hypothesis that integrating morphological and biomechanical risk factors would result in better predictive power for plaque progression prediction. A sample size of 374 intravascular ultrasound (IVUS) slices was obtained from 9 patients with IVUS follow-up data. 3D fluid-structure interaction models were constructed to obtain both structural stress/strain and fluid biomechanical conditions. Data for eight morphological and biomechanical risk factors were extracted for each slice. Plaque area increase (PAI) and wall thickness increase (WTI) were chosen as two measures for plaque progression. Progression measure and risk factors were fed to generalized linear mixed models and linear mixed-effect models to perform prediction and correlation analysis, respectively. All combinations of eight risk factors were exhausted to identify the optimal predictor(s) with highest prediction accuracy defined as sum of sensitivity and specificity. When using a single risk factor, plaque wall stress (PWS) at baseline was the best predictor for plaque progression (PAI and WTI). The optimal predictor among all possible combinations for PAI was PWS + PWSn + Lipid percent + Min cap thickness + Plaque Area (PA) + Plaque Burden (PB) (prediction accuracy = 1.5928) while Wall Thickness (WT) + Plaque Wall Strain (PWSn) + Plaque Area (PA) was the best for WTI (1.2589). This indicated that PAI was a more predictable measure than WTI. The combination including both morphological and biomechanical parameters had improved prediction accuracy, compared to predictions using only morphological features. PMID- 29274688 TI - Considerations for Successful Treatment-free Remission in Chronic Myeloid Leukemia. AB - BCR-ABL1 tyrosine kinase inhibitors have dramatically improved outcomes for patients with chronic myeloid leukemia, and current studies are investigating whether some patients may be able to suspend therapy yet maintain response in a state known as "treatment-free remission" (TFR). Results from ongoing studies suggest that ~ 40% to 60% of patients in sustained (generally >= 2 years) deep molecular response (defined as a 4-log or deeper reduction in BCR-ABL1 transcripts, depending on the study) who attempt TFR may successfully remain off treatment. Results from TFR clinical trials, patient considerations for attempting TFR, and potential predictive factors associated with successful TFR are reviewed herein. PMID- 29274689 TI - Understanding periviable birth: A microeconomic alternative to the dysregulation narrative. AB - Periviable infants (i.e., those born in the 20th through 26th weeks of gestation) suffer much morbidity and approximately half die in the first year of life. Attempts to explain and predict these births disproportionately invoke a "dysregulation" narrative. Research inspired by this narrative has not led to efficacious interventions. The clinical community has, therefore, urged novel approaches to the problem. We aim to provoke debate by offering the theory, inferred from microeconomics, that risk tolerant women carry, without cognitive involvement, high risk fetuses farther into pregnancy than do other women. These extended high-risk pregnancies historically ended in stillbirth but modern obstetric practices now convert a fraction to periviable births. We argue that this theory deserves testing because it suggests inexpensive and noninvasive screening for pregnancies that might benefit from the costly and invasive interventions clinical research will likely devise. PMID- 29274691 TI - Overweight and obesity: effectiveness of interventions in adults. AB - OBJECTIVE: To identify the most effective interventions in overweight and obese adults. METHOD: A narrative review through a search of the literature in databases PubMed, Cochrane, Joanna Briggs Institute, EMBASE, Cuiden y Cinahl with free and controlled language (MeSH terms) using Boolean operators AND and NOT. The research was limited to articles published between 2007 and 2015. Eighteen articles were selected based on the established inclusion and exclusion criteria. RESULTS: Different types of interventions were identified based on the modification of lifestyles, mainly diet, physical activity and behavior. Major differences were found in specific content, degree of intensity of interventions, time tracking and elements evaluated. Most of studies found statistically significant weight loss but this was limited in terms of weight and number of people. Web-based interventions have no uniform effect on weight loss but achieve similar levels to face-to-face interventions in maintaining weight loss. CONCLUSIONS: The combination of personalised diet, exercise and cognitive behavioural therapy is the most effective form of intervention in overweight and obesity. There is insufficient data to indicate whether group or individual interventions are more effective. Online intervention allows greater accessibility and lower cost. PMID- 29274690 TI - Colonic Mucosal Bacteria Are Associated with Inter-Individual Variability in Serum Carotenoid Concentrations. AB - BACKGROUND: Relatively high serum carotenoid levels are associated with reduced risks of chronic diseases, but inter-individual variability in serum carotenoid concentrations is modestly explained by diet. The bacterial community in the colon could contribute to the bioaccessibility of carotenoids by completing digestion of plant cells walls and by modulating intestinal permeability. OBJECTIVE: To evaluate whether colonic bacterial composition is associated with serum and colon carotenoid concentrations. DESIGN: The study was a randomized dietary intervention trial in healthy individuals who were at increased risk of colon cancer. Colon mucosal biopsy samples were obtained before and after 6 months of intervention without prior preparation of the bowels. PARTICIPANTS/SETTING: Participants were recruited from Ann Arbor, MI, and nearby areas from July 2007 to November 2010. Biopsy data were available from 88 participants at baseline and 82 participants after 6 months. METHODS: Study participants were randomized to counseling for either a Mediterranean diet or a Healthy Eating diet for 6 months. RESULTS: At baseline, bacterial communities in biopsy samples from study participants in the highest vs the lowest tertile of total serum carotenoid levels differed by several parameters. Linear discriminant analysis effect size identified 11 operational taxonomic units that were significantly associated with higher serum carotenoid levels. In linear regression analyses, three of these accounted for an additional 12% of the variance in serum total carotenoid concentrations after including body mass index, smoking, and dietary intakes in the model. These factors together explained 36% of the inter-individual variance in serum total carotenoid concentrations. The bacterial community in the colonic mucosa, however, was resistant to change after dietary intervention with either a Mediterranean diet or Healthy Eating diet, each of which doubled fruit and vegetable intakes. CONCLUSIONS: The colonic mucosal bacterial community was associated with serum carotenoid concentrations at baseline but was not appreciably changed by dietary intervention. PMID- 29274692 TI - Cultural Adaptation of a Medication Adherence Intervention With Prisoners Living With HIV in Indonesia: A Pragmatic Approach to Intervention Development. AB - Cultural adaptation is a research strategy used to tailor evidence-informed interventions for new populations and settings. We describe a pragmatic approach used to culturally adapt a nurse-led medication adherence intervention, Adherence Through Home Education and Nursing Assessment (ATHENA), for prisoners living with HIV in Indonesia. Researchers reviewed data from completed studies in Indonesia and identified core components of the ATHENA intervention considered essential for effectiveness. Adaptations likely to render ATHENA acceptable and feasible in the Indonesian prison setting were proposed. An intervention led by nurses and peer educators was feasible and congruent with existing models in Indonesian prisons. Involving prisoners with HIV in successive developmental phases helped to ensure a good cultural fit. In the context of prisons and other freedom limiting environments, a pragmatic approach that integrates members of the target population within an anti-oppressive Freirian pedagogical framework is highly appropriate for adapting evidence-informed interventions. PMID- 29274693 TI - Apparent diffusion coefficient histogram analysis for prediction of prognosis in glioblastoma. AB - BACKGROUND: To investigate the potential to predict prognosis of glioblastoma (GBM) patients by analysis of the broader and lower values in the lower distribution of apparent diffusion coefficient (ADCL) (B&L-ADCL) values in the ADC histogram. BACKGROUND: Presurgical publicly available diffusion-weighted images (DWI) and contrast-enhanced T1-weighted images from 76 GBM patients were analyzed. With applied 2-mixture normal distribution in the ADC histogram of enhanced lesions on T1-weighted images, the mean and width of ADCL were analyzed. We dichotomized the lower mean of ADCL (L-ADCL) and the broader width of ADCL (B ADCL) at their own average. B&L-ADCL was defined as B-ADCL with L-ADCL. Progression-free survival (PFS) and overall survival (OS) were determined by using Cox proportional hazards analysis and the Kaplan-Meier method with the log rank test. The difference between PFS and OS was calculated. RESULTS: Six (7.89%) patients had B&L-ADCL values. B&L-ADCL was strongly associated with poor PFS (hazard risk: 5.747; P=0.002) and OS (hazard risk: 3.331; P=0.018). There were significant differences in PFS (median, 77 vs. 302 days; P<0.001) and OS (median, 199 vs. 472 days; P=0.004) between the patents with and without B&L-ADCL. There was no significant difference in the OS-PFS duration difference between the patients with (median, 79 days) and without B&L-ADCL (median, 132 days) (P=0.348). CONCLUSION: In this study, B&L-ADCL from pretreatment ADC analysis predicted poor PFS. B&L-ADCL may indicate higher cellularity and heterogeneity in GBM tumor tissue. PMID- 29274694 TI - Acute Type A Aortic Dissection Causing Collapse of Previous Stent Graft. AB - A 69-year-old man presented to the emergency department with back pain and paraplegia. Computed tomography showed acute type A aortic dissection with a primary tear right below the origin of the left subclavian artery. He had undergone endovascular aneurysm repair 13 months earlier, and the previously inserted endovascular graft had totally collapsed. Total arch replacement covering the primary entry tear was performed. Femoral pulse was undetected before the operation but was monitored postsurgically after cardiopulmonary bypass was weaned. The patient was discharged from the hospital on foot without an additional intervention. PMID- 29274695 TI - Diminutive Porcelain Ascending Aorta With Supravalvular Aortic Stenosis. AB - This report describes the case of a 49-year-old man with a medical history significant for congenital aortic stenosis. The patient presented with progressive shortness of breath and decreased stamina and was found to have a concentric, diminutive porcelain ascending aorta with diffuse supravalvular aortic stenosis. We describe treatment with an aortic root augmentation and Bentall procedure using hypothermic circulatory arrest. PMID- 29274696 TI - Evaluation of dermal adhesive formulations for topical application. AB - Topical delivery is one of the main challenges in the pharmaceutical technology. This study aimed to synthesize a potential adhesive polymeric excipient stable enough for pronounced skin adhesiveness to pave the skin delivery pathway. Polyacrylic acid an anionic well established polymer in the pharmaceutical field was chemically modified with sulfhydryl moieties and in a second step, this sulfhydryl bearing polymer was prone to a preactivation process. During this process, mercaptonicotinic acid was covalently bound to the sulfhydryl groups of polyacrylic acid. The obtained polymeric conjugates were characterized with respect to viscosity measurements, and evaluated in terms of skin adhesive properties with the help of tensile strength assay as well as bond strength assay. Findings exhibited promising potential of newly synthesized preactivated polyacrylic acid in terms of adhesive properties. Preactivated polyacrylic acid revealed a 15.39-fold improved adhesion compared to unmodified polymeric excipient. Therefore, the herein designed preactivated polyacrylic acid shows interesting features for skin application such as scar and wound management. PMID- 29274697 TI - A review of mathematical modeling and simulation of controlled-release fertilizers. AB - Nutrients released into soils from uncoated fertilizer granules are lost continuously due to volatilization, leaching, denitrification, and surface run off. These issues have caused economic loss due to low nutrient absorption efficiency and environmental pollution due to hazardous emissions and water eutrophication. Controlled-release fertilizers (CRFs) can change the release kinetics of the fertilizer nutrients through an abatement strategy to offset these issues by providing the fertilizer content in synchrony with the metabolic needs of the plants. Parametric analysis of release characteristics of CRFs is of paramount importance for the design and development of new CRFs. However, the experimental approaches are not only time consuming, but they are also cumbersome and expensive. Scientists have introduced mathematical modeling techniques to predict the release of nutrients from the CRFs to elucidate fundamental understanding of the dynamics of the release processes and to design new CRFs in a shorter time and with relatively lower cost. This paper reviews and critically analyzes the latest developments in the mathematical modeling and simulation techniques that have been reported for the characteristics and mechanisms of nutrient release from CRFs. The scope of this review includes the modeling and simulations techniques used for coated, controlled-release fertilizers. PMID- 29274698 TI - Mannitol treatment is not effective in therapy of rabies virus infection in mice. AB - Rabies is a deadly viral disease with an extremely high fatality rate in humans. Previously, it was suggested that an enhancement of the blood-brain barrier (BBB) permeability, which allows immune cells and/or antibodies to enter the central nervous system (CNS) tissue, is critical to clear the infection. In this study, we utilised mannitol to increase BBB permeability in mice infected with highly pathogenic silver-haired bat rabies virus (SHBRV). We found that intraperitoneal injection of mannitol causes a slight, transient increase of BBB permeability in the treated mice. SHBRV-infected mice were treated with intraperitoneally administered mannitol daily from day 3 or day 4 post-infection, but no effect of this treatment on the time of disease onset, clinical signs or survival was observed. This data indicates that the increase of BBB permeability by mannitol is not efficient in promoting CNS virus clearance in SHBRV-infected mice. PMID- 29274699 TI - HIV-1 superinfection can occur in the presence of broadly neutralizing antibodies. AB - BACKGROUND: Superinfection of individuals already infected with HIV-1 suggests that pre-existing immune responses may not adequately protect against re infection. We assessed high-risk female sex workers initially infected with HIV-1 clades A, D or A/D recombinants, to determine if HIV-1 broadly neutralizing antibodies were lacking prior to superinfection. METHODS: Six superinfected female sex workers previously stratified by HIV-1 high-risk behavior, infecting virus clade and volunteer CD4 counts were evaluated at baseline (n = 5) and at 350 days post-superinfection (n = 6); one superinfected volunteer lacked pre superinfection plasma. Retrospective plasmas were assessed for neutralization of a multi-clade panel of 12 HIV-1 viruses before superinfection, and then at quarterly intervals thereafter. Similarly stratified singly infected female sex workers were correspondingly assessed at baseline (n = 19) and 350 days after superinfection (n = 24). Neutralization of at least 50% of the 12 viruses (broad neutralization), and geometric means of the neutralization titers (IC50) were compared before and after superinfection; and were correlated with the volunteer HIV-1 superinfection status, CD4 counts, and pseudovirus clade. RESULTS: Preexisting broad neutralization occurred in 80% (4/5) of the superinfected subjects with no further broadening by 350 days after superinfection. In one of the five subjects, HIV-1 superinfection occurred when broad neutralization was lacking; with subsequent broadening of neutralizing antibodies occuring within 9 months and plateauing by 30 months after detection of superinfection. Clade B and C pseudoviruses were more sensitive to neutralization (13; [87%]); and (12; [80%]) than the locally circulating clades A (10; [67%]) and D (6; [40%]), respectively (p = 0.025). Low antibody titers correlated with clade D viruses and with >500 CD4 T cell counts, but not with the superinfection status. CONCLUSION: These data demonstrate that HIV-1 superinfection can occur both in the presence, and in the absence of broadly neutralizing antibodies. PMID- 29274701 TI - Sentinel surveillance for rotavirus in children <5 years of age admitted for Diarrheal illness to Yangon Children's Hospital, Myanmar, 2009-2014. AB - BACKGROUND: Rotavirus is the leading cause of severe acute gastroenteritis (AGE) in children <5 years of age in Myanmar. The purpose of this analysis is to report from the sentinel surveillance system for rotavirus gastroenteritis (RVGE), which collects information on the epidemiology and circulating genotypes to assess the disease burden and support vaccine introduction in Myanmar. METHODS: Prospective, active surveillance for RVGE-associated hospitalizations was conducted during 2009 -2014 at Yangon Children's Hospital. Stool samples collected from children <5 years of age admitted for AGE were screened for rotavirus antigen by ELISA (ProSpecTTM Rotavirus, OXOID-UK). G and P genotyping was performed by reverse transcription polymerase chain reaction. RESULTS: Overall, 1860/3724 (49.9%) of stool samples tested positive for rotavirus, ranging from 42-56% of hospitalized AGE cases each year. RVGE was predominant in the 6-11 months age group 889/1860 (47.8%) as compared with 12-23 months 633/1860 (34.0%), 0-5 months 226/1860 (12.2 %) and 24-59 months 112/1860 (6.0%). RVGE occurred in a seasonal cycle with peak occurrence in the cold and dry months (November to February), accounting for 65.3% (1151/1763) among enrolled AGE cases. Vomiting (84.1% Vs 67.9%; P < .01), fever (84.5% Vs 75.6%; P < .01) and dehydration (78% Vs 69%; P < .01) were more frequently observed in RVGE than non-RVGE. Genotyping revealed that G1P[8] was predominant from January to June 2009, G12P[8] was predominant throughout 2009 2012 which was replaced in 2012-2013 by G2P[4] and changed again to G1P[8] in 2013-2014 and G9P[8] in late 2014. CONCLUSIONS: Rotavirus is accounting for approximately half of AGE-associated hospitalizations among children <5 years of age in Myanmar. There is immense diversity of rotavirus strains similar to that reported previously for other countries in the region. Information gained from this surveillance system highlights consideration of rotavirus vaccine introduction into this target population. PMID- 29274702 TI - Does influenza vaccination during early pregnancy really increase the risk of miscarriage? PMID- 29274703 TI - Clinical Significance of Neutrophil/lymphocyte Ratio in Patients With Granulomatosis With Polyangiitis. AB - OBJECTIVE: To determine to neutrophil-to-lymphocyte ratio (NLR) in granulomatosis with polyangiitis (GPA) patients and to study its relation to disease manifestations and activity. METHODS: The study included 44 GPA patients and 44 matched age and sex controls. Full history taking, thorough clinical examination with more attention to ocular examination, laboratory and radiological investigations were considered. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). RESULTS: The patients (21 males and 23 females) had a mean age of 45.66+/-7.24 years, disease duration 6.8+/-3.6 years and BVAS 50.1+/-14.3. All patients had a positive cytoplasmic anti neutrophil cytoplasmic antibody (c-ANCA) while only 5 had a positive p-ANCA. The NLR was significantly increased in the GPA patients (5.1+/-2.4) compared to the control (1.5+/-0.8) (P<.0001). Ten patients with uveitis had a significantly higher NLR (6.5+/-1.9) compared to those without (4.7+/-2.4) (0.03) while those with proptosis (n=10), cutaneous manifestations (n=17) or ischemic heart disease (n=9) had a significantly lower NLR than those without (P=.0001, P=.017 and P=.046 respectively). The NLR did not significantly correlate with any of the patients' characteristics. The NLR inversely yet insignificantly correlated with the disease activity (r=-0.02, P=.93). CONCLUSION: The NLR may have a significant role in the pathogenesis of GPA, the development of uveitis or proptosis, cutaneous manifestations and ischemic heart disease. NLR may serve as a future potential companion to c-ANCA positivity in diagnosing and evaluating GPA and may play a role in the tissue-specific and clinical characteristics. PMID- 29274704 TI - Synthesis, structure-activity relationships, and mechanistic studies of 5-arylazo tropolone derivatives as novel xanthine oxidase (XO) inhibitors. AB - Xanthine oxidase (XO) is an enzyme that contains molybdenum at the active site and catalyzes the oxidation of purine bases to uric acid. Even though XO inhibitors are widely used for the treatment of hyperuricemia and gout, only very few such compounds are clinically used as drugs for the treatment of these diseases. Given the unique physicochemical properties of tropolone, i.e., its chelating effect and the pKa value that is similar to that of carboxylic acid, we have synthesized 22 5-arylazotropolone derivatives as potential XO inhibitors. In vitro enzyme-inhibitory assays for XO revealed that 3-nitro derivative 1j showed the most potent XO inhibitory activity, which is by one order of magnitude more potent than allopurinol. An enzyme-kinetic study revealed that 1j inhibited the production of uric acid by XO both competitively and non-competitively. A docking simulation study of 1j with XO suggested that the carbonyl and hydroxyl groups of the tropolone ring interact with the hydroxy group that acts as a ligand for molybdenum and the amino acid residues around the active site of XO. PMID- 29274700 TI - Erratum to "Predominance of influenza A(H3N2) virus genetic subclade 3C.2a1 during an early 2016/17 influenza season in Europe - Contribution of surveillance data from World Health Organization (WHO) European region to the WHO vaccine composition consultation for northern hemisphere 2017/18" [Vaccine 35 (2017) 4828 4835]. PMID- 29274706 TI - Recent advances in mass spectrometry-based approaches for proteomics and biologics: Great contribution for developing therapeutic antibodies. AB - Since the turn of the century, mass spectrometry (MS) technologies have continued to improve dramatically, and advanced strategies that were impossible a decade ago are increasingly becoming available. The basic characteristics behind these advancements are MS resolution, quantitative accuracy, and information science for appropriate data processing. The spectral data from MS contain various types of information. The benefits of improving the resolution of MS data include accurate molecular structural-derived information, and as a result, we can obtain a refined biomolecular structure determination in a sequential and large-scale manner. Moreover, in MS data, not only accurate structural information but also the generated ion amount plays an important rule. This progress has greatly contributed a research field that captures biological events as a system by comprehensively tracing the various changes in biomolecular dynamics. The sequential changes of proteome expression in biological pathways are very essential, and the amounts of the changes often directly become the targets of drug discovery or indicators of clinical efficacy. To take this proteomic approach, it is necessary to separate the individual MS spectra derived from each biomolecule in the complexed biological samples. MS itself is not so infinite to perform the all peak separation, and we should consider improving the methods for sample processing and purification to make them suitable for injection into MS. The above-described characteristics can only be achieved using MS with any analytical instrument. Moreover, MS is expected to be applied and expand into many fields, not only basic life sciences but also forensic medicine, plant sciences, materials, and natural products. In this review, we focus on the technical fundamentals and future aspects of the strategies for accurate structural identification, structure-indicated quantitation, and on the challenges for pharmacokinetics of high-molecular-weight protein biopharmaceuticals. PMID- 29274707 TI - High MYBL2 expression and transcription regulatory activity is associated with poor overall survival in patients with hepatocellular carcinoma. AB - PURPOSE: In this study, we aimed to assess the association between MYBL2 expression/transcription regulatory activity (TRA) and overall survival (OS) in patients with primary hepatocellular carcinoma (HCC) and to explore the factors related to B-Myb TRA. MATERIALS AND METHODS: Bioinformatic analysis was performed based on data from the cancer genome atlas-liver hepatocellular carcinoma (TCGA LIHC) and the human protein atlas (HPA). RESULTS: The death group in TCGA-LIHC had significantly higher MYBL2 RNA and exon expression than the censor group. The high MYBL2 RNA and exon expression groups had significantly worse OS (P<0.01). Univariate and multivariate analysis confirmed that high MYBL2 expression was an independent prognostic factor of unfavourable OS (HR=1.591, 95%CI: 1.119-2.262, P=0.01). One hundred and fourteen out of 188 primary HCC cases in TCGA-LIHC had elevated transcription of B-Myb's downstream genes. High B-Myb TRA was associated with poor OS (P=0.013). Elevated expression of MYBL2, LIN9, LIN52 and FOXM1 were related to the higher TRA of B-Myb in HCC. CONCLUSION: High MYBL2 expression/TRA are associated with inferior OS in patients with primary HCC. Increased expression of MYBL2, LIN9, LIN52 and FOXM1 are related to higher TRA of B-Myb in HCC. PMID- 29274709 TI - Our Journal, Our Source of Pride. PMID- 29274705 TI - Prostaglandin E2 as a Regulator of Immunity to Pathogens. AB - The body is exposed to foreign pathogens every day, but remarkably, most pathogens are effectively cleared by the innate immune system without the need to invoke the adaptive immune response. Key cellular components of the innate immune system include macrophages and neutrophils and the recruitment and function of these cells are tightly regulated by chemokines and cytokines in the tissue space. Innate immune responses are also known to regulate development of adaptive immune responses often via the secretion of various cytokines. In addition to these protein regulators, numerous lipid mediators can also influence innate and adaptive immune functions. In this review, we cover one particular lipid regulator, prostaglandin E2 (PGE2) and describe its synthesis and signaling and what is known about the ability of this lipid to regulate immunity and host defense against viral, fungal and bacterial pathogens. PMID- 29274710 TI - Notre journal, notre source de fierte. PMID- 29274708 TI - No 354 - Lignes directrices canadiennes en matiere de planification de la grossesse en presence du VIH. PMID- 29274711 TI - Excerpts from the World Medical Literature: Obstetrics. PMID- 29274712 TI - A Well-Deserved Update to the Canadian HIV Pregnancy Planning Guidelines. PMID- 29274713 TI - Extraits de la litterature medicale mondiale : obstetriques. PMID- 29274714 TI - No. 354-Canadian HIV Pregnancy Planning Guidelines. AB - OBJECTIVE: The objective of the Canadian HIV Pregnancy Planning Guidelines is to provide clinical information and recommendations for health care providers to assist Canadians affected by HIV with their fertility, preconception, and pregnancy planning decisions. These guidelines are evidence- and community-based and flexible and take into account diverse and intersecting local/population needs based on the social determinants of health. INTENDED OUTCOMES: EVIDENCE: Literature searches were conducted by a librarian using the Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases for published articles in English and French related to HIV and pregnancy and HIV and pregnancy planning for each section of the guidelines. The full search strategy is available upon request. VALUES: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the SOGC under the leadership of the principal authors, and recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care and through use of the Appraisal of Guidelines Research and Evaluation instrument for the development of clinical guidelines. BENEFITS, HARMS, AND COSTS: Guideline implementation should assist the practitioner in developing an evidence-based approach for the prevention of unplanned pregnancy, preconception, fertility, and pregnancy planning counselling in the context of HIV infection. VALIDATION: These guidelines have been reviewed and approved by the Infectious Disease Committee and the Executive and Council of the SOGC. SPONSOR: Canadian Institutes of Health Research Grant Planning and Dissemination grant (Funding Reference # 137186), which funded a Development Team meeting in 2016. RECOMMENDATIONS: PMID- 29274715 TI - No. 133-Prevention of Rh Alloimmunization. AB - OBJECTIVE: To provide guidelines on use of anti-D prophylaxis to optimize prevention of rhesus (Rh) alloimmunization in Canadian women. OUTCOMES: Decreased incidence of Rh alloimmunization and minimized practice variation with regards to immunoprophylaxis strategies. EVIDENCE: The Cochrane Library and MEDLINE were searched for English-language articles from 1968 to 200 I, relating to the prevention of Rh alloimmunization. Search terms included: Rho(D) immune globulin, Rh iso- or aile-immunization, anti-D, anti-Rh, WinRho, Rhogam, and pregnancy. Additional publications were identified from the bibliographies of these articles. All study types were reviewed. Randomized controlled trials were considered evidence of highest quality, followed by cohort studies. Key individual studies on which the principal recommendations are based are referenced. Supporting data for each recommendation is briefly summarized with evaluative comments and referenced. VALUES: The evidence collected was reviewed by the Maternal-Fetal Medicine and Genetics Committees of The Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: VALIDATION: These guidelines have been reviewed by the MaternalFetal Medicine Committee and the Genetics Committee, with input from the Rh Program of Nova Scotia. Final approval has been given by the Executive and Council of The Society of Obstetricians and Gynaecologists of Canada. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada. PMID- 29274716 TI - No 133-Prevention de l'allo-immunisation foeto-maternelle Rh. PMID- 29274717 TI - No. 283-Treatments for Overactive Bladder: Focus on Pharmacotherapy. AB - OBJECTIVE: To provide guidelines for pharmacotherapy to treat overactive bladder syndrome (OAB). OPTIONS: Pharmacotherapy for OAB includes anticholinergic (antimuscarinic) drugs and vaginal estrogen. Both oral and transdermal anticholinergic preparations are available. OUTCOMES: To provide understanding of current available evidence concerning safety and clinical efficacy of pharmacotherapy for OAB; to guide selection of anticholinergic therapy based on individual patient characteristics. EVIDENCE: The Cochrane Library and Medline were searched for articles published from 1950 to the present related to individual anticholinergic drugs. Review articles on management of refractory OAB were also examined. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to 2010. VALUES: The quality of evidence is rated and recommendations are made using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: Anticholinergics are the mainstay of pharmacotherapy for OAB. Evidence for their efficacy is mostly derived from short-term phase III randomized drug trials. Placebo response is strong, and long-term follow-up and patient subjective outcome data are lacking. Care providers need to be well acquainted with the side effects of anticholinergics and select therapy based on individual patient parameters. RECOMMENDATIONS: PMID- 29274718 TI - No 283-Traitements visant la vessie hyperactive : Accent sur la pharmacotherapie. PMID- 29274719 TI - Hyperactive Factor IX Padua: A Game-Changer for Hemophilia Gene Therapy. PMID- 29274720 TI - Clinical significance of defining borderline resectable pancreatic cancer. AB - Since the introduction of the concept of borderline resectable pancreatic cancer (BRPC), various definitions of this disease entity have been suggested. However, there are several obstacles in defining this disease category. The current diagnostic criteria of BRPC mainly focuses on its expanded 'technical resectability'; however, they are difficult to interpret because of their ambiguity using potential subjective or arbitrary terminology, In addition, limitations in current imaging technology and a lack of evidence in radiological pathological-clinical correlation make it difficult to refine the criteria. On the other hand, neoadjuvant treatment is usually applied to increase the R0 resection rate of BRPC focusing on the 'oncological curability'. However, evidence is needed concerning the effect of neoadjuvant treatment by quality controlled prospective randomized clinical trials based on a standardized radiologic and pathologic reporting system. In conclusion, there are two aspects in the current concept of BRPC, which are technical resectability and oncological curability. Although the recent evolution of surgical techniques is expanding the scope of technical resectability, it should not be overlooked that the disease entity must be defined based on the evidence of oncological curability. PMID- 29274722 TI - 11th International Symposium on Avian Endocrinology. PMID- 29274721 TI - CpG-ODN exerts a neuroprotective effect via the TLR9/pAMPK signaling pathway by activation of autophagy in a neonatal HIE rat model. AB - Hypoxic Ischemic Encephalopathy (HIE) is an injury caused to the brain due to prolonged lack of oxygen and blood supply which results in death or long-term disabilities. The main aim of this study was to investigate the role of Cytosine phospho-guanine oligodeoxynucleotide (CpG-ODN) in autophagy after HIE. Ten-day old (P10) rat pups underwent right common carotid artery ligation followed by 2.5h of hypoxia as previously described by Rice-Vannucci. At 1h post HIE, rats were intranasally administered with recombinant CpG-ODN. Time-course expression levels of endogenous key proteins, TLR9, pAMPK/AMPK, LC3II/I, and LAMP1 involved in CpG-ODN's protective effects were measured using western blot. Short (48h) and long (4w) term neurobehavior studies were performed using righting reflex, negative geotaxis, water maze, foot fault and Rota rod tests. Brain samples were collected after long term for histological analysis. Furthermore, to elucidate the pathway via which CpG-ODN confers protection, TLR9 and AMPK inhibitors were used. Time course results showed that the expression of TLR9, pAMPK/AMPK, LC3II/I, LAMP1 increased after HIE. Neurobehavioral studies showed that HIE induced a significant delay in development and resulted in cognitive and motor function deficits. However, CpG-ODN ameliorated HIE-induced outcomes and improved long term neurological deficits. In addition, CpG-ODN increased expression of pAMPK/AMPK, p-ULK1/ULK1, P-AMBRA1/AMBRA1, LC3II/I and LAMP1 while inhibition of TLR9 and AMPK reversed those effects. In summary, CpG-ODN increased HIE-induced autophagy and improved short and long term neurobehavioral outcomes which may be mediated by the TLR9/pAMPK signaling pathway after HIE. PMID- 29274723 TI - Prevalence of temporomandibular disorders discovered incidentally during routine dental examination using the Research Diagnostic Criteria for Temporomandibular Disorders. AB - OBJECTIVES: The aim of this study was to assess the prevalence of temporomandibular disorders (TMDs) discovered incidentally during routine dental examination, identify disease patterns, and evaluate patients' attitude toward accepting treatment. STUDY DESIGN: A total of 3009 patients were examined at the University Dental Hospital Sharjah (Sharjah, United Arab Emirates). Research Diagnostic Criteria for TMD (RDC/TMD) Axes I and II were used for assessment. Patients with acute/serious dysfunction symptoms underwent cone beam computed tomography examination. Magnetic resonance imaging was used to confirm the diagnosis of disk displacement. RESULTS: Non-self-reported TMD prevalence was 10.8% (n = 325). Among patients with TMDs, women were diagnosed more often (65.85%) (P < .05) and those between ages 25 and 45 years (65.54%) (P < .05). Axis I assessment revealed disk displacement with reduction (group IIa) was the most common (40.92%). Axis II chronic pain grade showed that 32.62% of patients with TMDs experienced chronic pain, whereas 66.77% had mild disability. Interest in pursuing treatment was indicated by 92.31% of patients. Cone beam computed tomography and magnetic resonance imaging assessments changed the primary diagnosis in 26.08% and 18.47% of cases, respectively. CONCLUSIONS: TMD screening during routine dental examination led to the diagnosis of non-self-reported TMDs, most commonly related to disk displacement with reduction. Radiographic assessment was important to confirm TMD diagnosis. Patients diagnosed with TMD during dental screening expressed interest in pursuing treatment. PMID- 29274724 TI - Effects of Wrist Weights on Kinematic and Myographic Movement Characteristics During a Reaching Task in Individuals With Parkinson Disease. AB - OBJECTIVE: To investigate the kinematic and myographic effects of weighted wrist cuffs on individuals with Parkinson disease (PD) during a reaching task. DESIGN: Cross-sectional study. SETTING: Biomechanics research laboratory. PARTICIPANTS: Individuals (N=39) with PD (n=19) and healthy age-matched control subjects (n=20). INTERVENTIONS: Participants were instructed to reach and grasp a can at a distance of 80% of their arm length without a wrist cuff, while wearing separate 0.5- and 1.0-kg wrist cuffs, and subsequently without a wrist cuff. MAIN OUTCOME MEASURES: Movement time, kinematic, and electromyographic data were recorded during all reach and grasp movements. Four end point coordinate strategy variables, 3 joint recruitment variables, and 2 co-contraction indices were derived from the raw data for analysis. RESULTS: Significant interaction effects were found in the trunk and index finger movement time as the weight of the cuff increased from 0.5 to 1.0kg. The group of individuals with PD showed decreased movement times in both instances, whereas the control group showed increased movement times as the weight of the wrist cuff increased from baseline to 0.5 and 1.0kg. No group difference was observed in the co-contraction index of the upper arm and forearm. CONCLUSIONS: Adoption of weighted wrist cuffs in the clinic should be cautiously undertaken because compensatory movements may be induced in the trunk of individuals with PD. PMID- 29274725 TI - Geographic Region and Profit Status Drive Variation in Hospital Readmission Outcomes Among Inpatient Rehabilitation Facilities in the United States. AB - OBJECTIVE: To examine whether there are differences in inpatient rehabilitation facilities' (IRFs') all-cause 30-day postdischarge hospital readmission rates vary by organizational characteristics and geographic regions. DESIGN: Observational study. SETTING: IRFs. PARTICIPANTS: Medicare fee-for-service beneficiaries discharged from all IRFs nationally in 2013 and 2014 (N = 1166 IRFs). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We applied specifications for an existing quality measure adopted by Centers for Medicare & Medicaid Services for public reporting that assesses all-cause unplanned hospital readmission measure for 30 days postdischarge from inpatient rehabilitation. We estimated facility-level observed and risk-standardized readmission rates and then examined variation by several organizational characteristics (facility type, profit status, teaching status, proportion of low-income patients, size) and geographic factors (rural/urban, census division, state). RESULTS: IRFs' mean risk-standardized hospital readmission rate was 13.00%+/-0.77%. After controlling for organizational characteristics and practice patterns, we found substantial variation in IRFs' readmission rates: for-profit IRFs had significantly higher readmission rates than did not-for-profit IRFs (P<.001). We also found geographic variation: IRFs in the South Atlantic and South Central census regions had the highest hospital readmission rates than did IRFs in New England that had the lowest rates. CONCLUSIONS: Our findings point to variation in quality of care as measured by risk-standardized hospital readmission rates after IRF discharge. Thus, monitoring of readmission outcomes is important to encourage quality improvement in discharge care planning, care transitions, and follow-up. PMID- 29274726 TI - Dynamic Balance Is Related to Physiological Impairments in Persons With Multiple Sclerosis. AB - OBJECTIVES: To compare physiological impairments between persons with multiple sclerosis (MS) with a history of falls and persons with MS without a history of falls, and to investigate the association between physiological impairments and dynamic balance. DESIGN: Cross-sectional study. SETTING: University motion analysis laboratory. PARTICIPANTS: Persons with MS (N=55; 27 recurrent fallers and 28 nonfallers). Participants were classified as fallers if they self-reported >=2 falls in the previous 6 months. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Physiological impairment was assessed with sensorimotor delays, spasticity, plantar cutaneous sensation, and the sensory, cerebellar, and pyramidal subscales of the Expanded Disability Status Scale (EDSS). Dynamic balance was assessed using the average and variability of margin of stability and variability of trunk accelerations. RESULTS: Compared with nonfallers, fallers had lower plantar sensation, longer sensorimotor delays, more spasticity, and more impairment in the pyramidal and cerebellar subscales of the EDSS. Additionally, these impairments were all moderately to strongly correlated with worse dynamic balance. CONCLUSIONS: This study highlights the multifactorial nature of instability in persons with MS. A better understanding of the physiological mechanisms of dynamic instability in persons with MS can be used to improve methods of monitoring disease progression, identifying which impairments to target through interventions, and appropriately evaluating intervention efficacy. PMID- 29274728 TI - Learning from TARDIS: time for more focused trials in stroke prevention. PMID- 29274729 TI - Gemcitabine directly inhibits effector CD4 T cell activation and prevents experimental autoimmune encephalomyelitis. AB - Pro-inflammatory T cells are critical to the pathogenesis of multiple sclerosis (MS). We investigated the potential for the anti-proliferative, pro-apoptotic drug gemcitabine to affect development of MS-relevant effector TH1, TH17, and Treg cells. Gemcitabine directly suppressed proliferation, activation, and induced apoptosis of all effector subsets in subtype and dose-dependent fashion. This drug also prevented development of disease in the MS model experimental autoimmune encephalomyelitis (EAE) and significantly reduced the abundance of TH1 and TH17 cells. Our results indicate that pathogenic CD4+ T cells may be viable targets by gemcitabine for therapeutic benefit in MS. PMID- 29274730 TI - Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. AB - BACKGROUND & AIM: Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation. METHODS: Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-beta induction and IFN-I receptor (IFNAR) triggering in VACV infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1+/gfp mice revealed the origin of reconstituted KC. Finally, mixed bone marrow chimeric mice were studied to specifically analyze the effect of IFNAR triggering on liver infiltrating monocytes. RESULTS: VACV infection induced local IFN-beta responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution. CONCLUSION: Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis. LAY SUMMARY: Viral infection can cause fulminant hepatitis, which in turn is a major cause of acute liver failure. Herein, we aimed to study the role of type 1 interferon responses in acute viral hepatitis. We identified that during infection with DNA-encoded viruses, type 1 interferon receptor triggering of blood monocytes delays the development of monocyte-derived Kupffer cells. This points to new therapeutic strategies for acute viral hepatitis. PMID- 29274731 TI - Simultaneous analysis of opioid analgesics and their metabolites in municipal wastewaters and river water by liquid chromatography-tandem mass spectrometry. AB - Although published literature provides a clear demonstration of widespread occurrence of opioid analgesics (OAs) in the aquatic environment, analytical methods suitable for a systematic study of this pharmaceutical class, which would include a broad spectrum of opioid analgesics and their metabolites, are still missing. In this work, a comprehensive multiresidue method for quantitative analysis of 27 opioid analgesics and their metabolites, including 2 morphine glucuronide conjugates, was developed and validated for three matrices: raw wastewater (RW), secondary effluent (SE) and river water. The method comprised different classes of opioid analgesics, including natural opiates (morphine and codeine), their semi-synthetic derivatives (hydrocodone, hydromorphone, oxycodone, oxymorphone and buprenorphine) as well as fully synthetic opioids such as methadone, fentanyl, sufentanil, propoxyphene and tramadol. The optimized enrichment procedure involved mixed-mode, strong cation-exchange sorbent in combination with a sequential elution procedure. The extracts were analyzed by reversed-phase liquid chromatography using a Synergy Polar column coupled to electrospray ionization tandem mass spectrometry (LC-MS/MS). Accurate quantification of target OAs was achieved using 19 deuterated analogues as surrogate standards. Method accuracies for RW, SE and river water varied in the range from 91 to 126%, 74 to 120% and 75 to 116%, respectively. Careful optimization of the procedure allowed reliable determination of OAs with method quantification limits in the low ng/L range (RW: 0.3-3.5 ng/L; SE: 0.2-1.9 ng/L, river water: 0.1-0.8 ng/L. The developed method was applied for analysis of RW, SE and river water samples from Croatia. The concentrations of individual OAs in municipal wastewater varied in a wide range (from < QL to 859 ng/L) and the most prevalent representatives were tramadol, codeine, morphine and methadone and their derivatives. Elevated concentrations of morphine glucuronides (up to 370 ng/L) found in raw municipal wastewater indicated their importance in the overall morphine mass balance. PMID- 29274732 TI - Corrigendum to "Molecular epidemiology of swine influenza A viruses in the Southeastern United States, highlights regional differences in circulating strains'' [Vet. Microbiol. 211 (2017) 174-179]. PMID- 29274733 TI - BDNF as a marker of response to cognitive remediation in patients with schizophrenia: A randomized and controlled trial. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is considered to be a putative biomarker for cognitive recovery in schizophrenia. However, current evidence is still scarce for pharmacological treatments, and the use of BDNF as a biomarker has only been tested once with cognitive remediation treatment (CRT). METHODS: A randomized and controlled trial (NCT02341131) with 70 schizophrenia outpatients and 15 healthy volunteers was conducted. The participants with schizophrenia were randomly assigned to either CRT or the control group. All the participants were assessed in terms of cognition, quality of life, and their serum BDNF levels at both baseline and after the intervention. Additionally, comparisons of the effects of the different genotypes of the Val66Met polymorphism at the BDNF gene on the outcome variables were also performed. RESULTS: The patients in the CRT group presented with improvements in both cognition and quality of life. However, no significant changes were detected in the serum levels of BDNF. Interestingly, we found a significant positive interaction effect between the serum BDNF levels and the different BDNF genotypes. The Val/Val group showed significantly higher serum levels after the CRT treatment. However, the interaction among the serum BDNF levels, the BDNF genotypes and the treatment condition was not statistically significant. CONCLUSIONS: The replication of the previous finding of increased serum BDNF levels after cognitive remediation in clinically stable individuals with schizophrenia was not achieved. However, our data indicated that genetic variability may be mediating serum BDNF activity in the context of CRT. PMID- 29274734 TI - Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. AB - INTRODUCTION: It has remained controversial if antipsychotic treatment is associated with increased or decreased mortality among patients with schizophrenia, and if there are any clinically meaningful differences between specific agents and routes of administration. METHODS: We linked prospectively gathered nationwide register-based data during 2006-2013 to study all-cause mortality among all patients aged 16-64years with schizophrenia in Sweden (N=29,823 in total; N=4603 in the incident cohort). Multivariate Cox regression models were adjusted for clinical and sociodemographic covariates. Sensitivity analyses with the incident cohort were conducted to control for survival bias. RESULTS: During the mean follow-up of 5.7years, 2515 patients (8.4%) died. During the maximum follow-up (7.5years), the lowest cumulative mortality was observed for second generation (SG) long-acting injection (LAI) use (7.5%). Adjusted hazard ratios (aHRs) compared to SG LAI use were 1.37 (95%CI 1.01-1.86) for first generation (FG) LAIs, 1.52 (1.13-2.05) for SG orals, 1.83 (1.33-2.50) for FG orals, and 3.39 (2.53-4.56) for nonuse of antipsychotics. Concerning specific agents, the lowest mortality was observed for once-monthly paliperidone LAI (0.11, 0.03-0.43), oral aripiprazole (0.22, 0.15-0.34), and risperidone LAI (0.31, 0.23-0.43). In pairwise comparison, LAIs were associated with 33% lower mortality than equivalent orals (0.67, 0.56-0.80). The results with incident cohort were consistent with the primary analyses. CONCLUSIONS: Among patients with schizophrenia, LAI use is associated with an approximately 30% lower risk of death compared with oral agents. SG LAIs and oral aripiprazole are associated with the lowest mortality. PMID- 29274735 TI - Neuroanatomical heterogeneity of schizophrenia revealed by semi-supervised machine learning methods. AB - : Schizophrenia is associated with heterogeneous clinical symptoms and neuroanatomical alterations. In this work, we aim to disentangle the patterns of neuroanatomical alterations underlying a heterogeneous population of patients using a semi-supervised clustering method. We apply this strategy to a cohort of patients with schizophrenia of varying extends of disease duration, and we describe the neuroanatomical, demographic and clinical characteristics of the subtypes discovered. METHODS: We analyze the neuroanatomical heterogeneity of 157 patients diagnosed with Schizophrenia, relative to a control population of 169 subjects, using a machine learning method called CHIMERA. CHIMERA clusters the differences between patients and a demographically-matched population of healthy subjects, rather than clustering patients themselves, thereby specifically assessing disease-related neuroanatomical alterations. Voxel-Based Morphometry was conducted to visualize the neuroanatomical patterns associated with each group. The clinical presentation and the demographics of the groups were then investigated. RESULTS: Three subgroups were identified. The first two differed substantially, in that one involved predominantly temporal-thalamic-peri-Sylvian regions, whereas the other involved predominantly frontal regions and the thalamus. Both subtypes included primarily male patients. The third pattern was a mix of these two and presented milder neuroanatomic alterations and comprised a comparable number of men and women. VBM and statistical analyses suggest that these groups could correspond to different neuroanatomical dimensions of schizophrenia. CONCLUSION: Our analysis suggests that schizophrenia presents distinct neuroanatomical variants. This variability points to the need for a dimensional neuroanatomical approach using data-driven, mathematically principled multivariate pattern analysis methods, and should be taken into account in clinical studies. PMID- 29274736 TI - Can we accurately classify schizophrenia patients from healthy controls using magnetic resonance imaging and machine learning? A multi-method and multi-dataset study. AB - Machine learning is a powerful tool that has previously been used to classify schizophrenia (SZ) patients from healthy controls (HC) using magnetic resonance images. Each study, however, uses different datasets, classification algorithms, and validation techniques. Here, we perform a critical appraisal of the accuracy of machine learning methodologies used in SZ/HC classifications studies by comparing three machine learning algorithms (logistic regression [LR], support vector machines [SVMs], and linear discriminant analysis [LDA]) on three independent datasets (435 subjects total) using two tissue density estimates and cortical thickness (CT). Performance is assessed using 10-fold cross-validation, as well as a held-out validation set. Classification using CT outperformed tissue densities, but there was no clear effect of dataset. LR, SVMs, and LDA each yielded the highest accuracies for a different feature set and validation paradigm, but most accuracies were between 55 and 70%, well below previously reported values. The highest accuracy achieved was 73.5% using CT data and an SVM. Taken together, these results illustrate some of the obstacles to constructing effective disease classifiers, and suggest that tissue densities and CT may not be sufficiently sensitive for SZ/HC classification given current available methodologies and sample sizes. PMID- 29274737 TI - Substantia nigra ultrastructural pathology in schizophrenia. AB - Schizophrenia is a severe mental illness affecting approximately 1% of the population worldwide. Despite its prevalence, the cause remains unknown, and treatment is not effective in all patients. Dopamine is thought to play a role in schizophrenia pathology, yet the substantia nigra (SN), the origin of dopaminergic pathways, has not been studied extensively in schizophrenia. In this study, electron microscopy was used to examine neurons, oligodendrocytes, and myelinated axons in the SN of normal controls (NCs, n=9) and schizophrenia subjects with varying response to antipsychotic drugs [SZ, n=14; treatment resistant (TR)=6, treatment responsive (RESP)=6, unknown=2]. Postmortem tissue was analyzed for qualitative and quantitative markers of ultrastuctural integrity. A significantly higher percentage of axons in the schizophrenia group had inclusions in the myelin sheath compared to NCs (SZ: 3.9+/-1.7, NC: 2.6+/ 2.0). When considering treatment response, a significantly higher percentage of axons lacked cytoplasm (TR: 9.7+/-5.5, NC: 3.5+/-2.3), contained cellular debris (TR: 7.5+/-3.2, NC: 2.3+/-1.3) or had protrusions in the myelin sheath (TR: 0.4+/ 0.5, NC: 0.2+/-0.3). The G-ratio, a measure of myelin thickness, was significantly different between treatment response groups and was greater in TR (0.72+/-0.02) as compared to NCs (0.68+/-0.03), indicating decreased myelination in TR. These findings, which suggest myelin pathology in the SN in schizophrenia, are consistent with findings elsewhere in the brain. In addition, our results suggest cytoskeletal abnormalities, which may or may not be associated with myelin pathology. PMID- 29274738 TI - Is digital photography an accurate and precise method for measuring range of motion of the shoulder and elbow? AB - BACKGROUND: Accurate measurements of shoulder and elbow motion are required for the management of musculoskeletal pathology. The purpose of this investigation was to compare three techniques for measuring motion. The authors hypothesized that digital photography would be equivalent in accuracy and show higher precision compared to the other two techniques. METHODS: Using infrared motion capture analysis as the reference standard, shoulder flexion/abduction/internal rotation/external rotation and elbow flexion/extension were measured using visual estimation, goniometry, and digital photography on 10 fresh frozen cadavers. These measurements were performed by three physical therapists and three orthopaedic surgeons. Accuracy was defined by the difference from the reference standard (motion capture analysis), while precision was defined by the proportion of measurements within the authors' definition of clinical significance (10 degrees for all motions except for elbow extension where 5 degrees was used). Analysis of variance (ANOVA), t-tests, and chi-squared tests were used. RESULTS: Although statistically significant differences were found in measurement accuracy between the three techniques, none of these differences met the authors' definition of clinical significance. Precision of the measurements was significantly higher for both digital photography (shoulder abduction [93% vs. 74%, p < 0.001], shoulder internal rotation [97% vs. 83%, p = 0.001], and elbow flexion [93% vs. 65%, p < 0.001]) and goniometry (shoulder abduction [92% vs. 74%, p < 0.001] and shoulder internal rotation [94% vs. 83%, p = 0.008]) than visual estimation. Digital photography was more precise than goniometry for measurements of elbow flexion only [93% vs. 76%, p < 0.001]. CONCLUSIONS: There was no clinically significant difference in measurement accuracy between the three techniques for shoulder and elbow motion. Digital photography showed higher measurement precision compared to visual estimation for shoulder abduction, shoulder internal rotation, and elbow flexion. However, digital photography was only more precise than goniometry for measurements of elbow flexion. Overall digital photography shows equivalent accuracy to visual estimation and goniometry, but with higher precision than visual estimation. PMID- 29274739 TI - Herbarium collection-based phylogenetics of the ragweeds (Ambrosia, Asteraceae). AB - Ambrosia (Asteraceae) is a taxonomically difficult genus of weedy, wind pollinated plants with an apparent center of diversity in the Sonoran Desert of North America. Determining Ambrosia's evolutionary relationships has been the subject of much interest, with numerous studies using morphological characters, cytology, comparative phytochemistry, and chloroplast restriction site variation to produce conflicting accounts the relationships between Ambrosia species, as well as the classification of their close relatives in Franseria and Hymenoclea. To resolve undetermined intra-generic relationships within Ambrosia, we used DNA extracted from tissues obtained from seed banks and herbarium collections to generate multi-locus genetic data representing nearly all putative species, including four from South America. We performed Bayesian and Maximum-Likelihood phylogenetic analyses of six chloroplast-genome and two nuclear-genome markers, enabling us to infer monophyly for the genus, resolve major infra-generic species clusters, as well as to resolve open questions about the evolutionary relationships of several Ambrosia species and former members of Franseria. We also provide molecular data supporting the hypothesis that A. sandersonii formed through the hybridization of A. eriocentra and A. salsola. The topology of our chloroplast DNA phylogeny is almost entirely congruent with the most recent molecular work based on chloroplast restriction site variation of a much more limited sampling of 14 North American species of Ambrosia, although our improved sampling of global Ambrosia diversity enables us to draw additional conclusions. As our study is the first direct DNA sequence-based phylogenetic analyses of Ambrosia, we analyze the data in relation to previous taxonomic studies and discuss several instances of chloroplast/nuclear incongruence that leave the precise geographic center of origin of Ambrosia in question. PMID- 29274727 TI - Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. AB - BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0.90, 95% CI 0.67-1.20, p=0.47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2.54, 95% CI 2.05-3.16, p<0.0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation. PMID- 29274740 TI - Which surgical procedure is effective for refractory chronic subdural hematoma? Analysis of our surgical procedures and literature review. AB - Refractory chronic subdural hematoma (CSDH) is rare but remains a difficulty for neurosurgeons, and no consensus on treatment procedures has been established. To discuss effective surgical procedures for refractory CSDH, we analyzed our surgical procedures and outcomes for refractory CSDH. We defined patients with refractory CSDH as those who presented with two or more recurrences. Fourteen patients with refractory CSDH were analyzed. Eight patients underwent burr-hole irrigation and closed-system drainage alone, four patients received embolization of the middle meningeal artery (MMA), and two patients with organized CSDH underwent large craniotomy with outer membranectomy as the third surgery. Two of the eight patients (25%) treated with burr-hole irrigation and drainage alone showed a third recurrence. No further recurrences were identified in patients treated with embolization of the MMA or craniotomy. However, statistical analysis showed no significant difference in cure rate between patients treated with burr hole irrigation and drainage alone and patients treated with burr-hole irrigation and drainage with embolization of the MMA (P = .42). Similarly, no significant differences in cure rate were seen between patients treated with burr-hole irrigation and drainage alone and patients treated with craniotomy (P = .62). When selecting a surgical procedure, assessing whether the CSDH is organized is crucial. Embolization of the MMA may be considered as one of the optional treatments for refractory CSDH without organized hematoma. On the other hand, for refractory cases of organized CSDH, hematoma evacuation and outer membranectomy with large craniotomy or mini-craniotomy assisted by an endoscope may be suitable, as previous reports have recommended. PMID- 29274741 TI - A novel therapeutic approach for treatment of catamenial epilepsy. AB - Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked. We determined whether progesterone increased excitatory transmission in the hippocampus via activation of progesterone receptors, which may play a role in regulating catamenial seizure exacerbation. In a double-blind study using a rat model of catamenial epilepsy, we found that treatment with RU-486, which blocks progesterone and glucocorticoid receptors, significantly attenuated neurosteroid withdrawal-induced seizures. Furthermore, progesterone treatment as well as endogenous rise in progesterone during estrous cycle increased the expression of GluA1 and GluA2 subunits of AMPA receptors in the hippocampi, and enhanced the AMPA receptor-mediated synaptic transmission of CA1 pyramidal neurons. The progesterone-induced plasticity of AMPA receptors was blocked by RU-486 treatment and progesterone also failed to increase AMPA receptor expression in progesterone receptor knockout mice. These studies demonstrate that progesterone receptor activation regulates AMPA receptor expression and may play a role in catamenial seizure exacerbation. PMID- 29274743 TI - ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway. AB - Haploinsufficiency of ANKRD11 due to deletion or truncation mutations causes KBG syndrome, a rare genetic disorder characterized by intellectual disability, autism spectrum disorder, and craniofacial abnormalities. However, little is known about the neurobiological role of ANKRD11 during brain development. Here we show that ANKRD11 regulates pyramidal neuron migration and dendritic differentiation in the developing mouse cerebral cortex. Using an in utero manipulation approach, we found that Ankrd11 knockdown delayed radial migration of cortical neurons. ANKRD11-deficient neurons displayed markedly reduced dendrite growth and branching as well as abnormal dendritic spine morphology. Ankrd11 knockdown suppressed acetylation of epigenetic molecules such as p53 and Histone H3. Furthermore, the mRNA levels of Trkb, Bdnf, and neurite growth related genes were downregulated in ANKRD11-deficient cortical neurons. The Trkb promoter region was largely devoid of acetylated Histone H3 and p53, and was instead occupied with MeCP2 and DNMT1. Overexpression of TrkB rescued abnormal dendrite growth in these cells. Our findings demonstrate a novel role for ANKRD11 in neuron differentiation during brain development and suggest an epigenetic modification as a potential key molecular feature underlying KBG syndrome. PMID- 29274744 TI - Analytic tractography: A closed-form solution for estimating local white matter connectivity with diffusion MRI. AB - White matter structures composed of myelinated axons in the living human brain are primarily studied by diffusion-weighted MRI (dMRI). These long-range projections are typically characterized in a two-step process: dMRI signal is used to estimate the orientation of axon segments within each voxel, then these local orientations are linked together to estimate the spatial extent of putative white matter bundles. Tractography, the process of tracing bundles across voxels, either requires computationally expensive (probabilistic) simulations to model uncertainty in fiber orientation or ignores it completely (deterministic). Furthermore, simulation necessarily generates a finite number of trajectories, introducing "simulation error" to trajectory estimates. Here we introduce a method to analytically (via a closed-form solution) take an orientation distribution function (ODF) from each voxel and calculate the probabilities that a trajectory projects from a voxel into each directly adjacent voxels. We validate our method by demonstrating experimentally that probabilistic simulations converge to our analytically computed transition probabilities at the voxel level as the number of simulated seeds increases. We then show that our method accurately calculates the ground-truth transition probabilities from a publicly available phantom dataset. As a demonstration, we incorporate our analytic method for voxel transition probabilities into the Voxel Graph framework, creating a quantitative framework for assessing white matter structure, which we call "analytic tractography". The long-range connectivity problem is reduced to finding paths in a graph whose adjacency structure reflects voxel-to-voxel analytic transition probabilities. We demonstrate that this approach performs comparably to the current most widely-used probabilistic and deterministic approaches at a fraction of the computational cost. We also demonstrate that analytic tractography works on multiple diffusion sampling schemes, reconstruction method or parameters used to define paths. Open source software compatible with popular dMRI reconstruction software is provided. PMID- 29274742 TI - Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum. AB - We evaluated the impact of early embryonic deletion of huntingtin (htt) from pyramidal neurons on cortical development, cortical neuron survival and motor behavior, using a cre-loxP strategy to inactivate the mouse htt gene (Hdh) in emx1-expressing cell lineages. Western blot confirmed substantial htt reduction in cerebral cortex of these Emx-httKO mice, with residual cortical htt in all likelihood restricted to cortical interneurons of the subpallial lineage and/or vascular endothelial cells. Despite the loss of htt early in development, cortical lamination was normal, as revealed by layer-specific markers. Cortical volume and neuron abundance were, however, significantly less than normal, and cortical neurons showed reduced brain-derived neurotrophic factor (BDNF) expression and reduced activation of BDNF signaling pathways. Nonetheless, cortical volume and neuron abundance did not show progressive age-related decline in Emx-httKO mice out to 24months. Although striatal neurochemistry was normal, reductions in striatal volume and neuron abundance were seen in Emx-httKO mice, which were again not progressive. Weight maintenance was normal in Emx-httKO mice, but a slight rotarod deficit and persistent hyperactivity were observed throughout the lifespan. Our results show that embryonic deletion of htt from developing pallium does not substantially alter migration of cortical neurons to their correct laminar destinations, but does yield reduced cortical and striatal size and neuron numbers. The Emx-httKO mice were persistently hyperactive, possibly due to defects in corticostriatal development. Importantly, deletion of htt from cortical pyramidal neurons did not yield age-related progressive cortical or striatal pathology. PMID- 29274745 TI - Neural phase locking predicts BOLD response in human auditory cortex. AB - Natural environments elicit both phase-locked and non-phase-locked neural responses to the stimulus in the brain. The interpretation of the BOLD signal to date has been based on an association of the non-phase-locked power of high frequency local field potentials (LFPs), or the related spiking activity in single neurons or groups of neurons. Previous studies have not examined the prediction of the BOLD signal by phase-locked responses. We examined the relationship between the BOLD response and LFPs in the same nine human subjects from multiple corresponding points in the auditory cortex, using amplitude modulated pure tone stimuli of a duration to allow an analysis of phase locking of the sustained time period without contamination from the onset response. The results demonstrate that both phase locking at the modulation frequency and its harmonics, and the oscillatory power in gamma/high-gamma bands are required to predict the BOLD response. Biophysical models of BOLD signal generation in auditory cortex therefore require revision and the incorporation of both phase locking to rhythmic sensory stimuli and power changes in the ensemble neural activity. PMID- 29274746 TI - Structural covariance networks are coupled to expression of genes enriched in supragranular layers of the human cortex. AB - Complex network topology is characteristic of many biological systems, including anatomical and functional brain networks (connectomes). Here, we first constructed a structural covariance network from MRI measures of cortical thickness on 296 healthy volunteers, aged 14-24 years. Next, we designed a new algorithm for matching sample locations from the Allen Brain Atlas to the nodes of the SCN. Subsequently we used this to define, transcriptomic brain networks by estimating gene co-expression between pairs of cortical regions. Finally, we explored the hypothesis that transcriptional networks and structural MRI connectomes are coupled. A transcriptional brain network (TBN) and a structural covariance network (SCN) were correlated across connection weights and showed qualitatively similar complex topological properties: assortativity, small worldness, modularity, and a rich-club. In both networks, the weight of an edge was inversely related to the anatomical (Euclidean) distance between regions. There were differences between networks in degree and distance distributions: the transcriptional network had a less fat-tailed degree distribution and a less positively skewed distance distribution than the SCN. However, cortical areas connected to each other within modules of the SCN had significantly higher levels of whole genome co-expression than expected by chance. Nodes connected in the SCN had especially high levels of expression and co-expression of a human supragranular enriched (HSE) gene set that has been specifically located to supragranular layers of human cerebral cortex and is known to be important for large-scale, long-distance cortico-cortical connectivity. This coupling of brain transcriptome and connectome topologies was largely but not entirely accounted for by the common constraint of physical distance on both networks. PMID- 29274747 TI - More highly myelinated white matter tracts are associated with faster processing speed in healthy adults. AB - The objective of this study was to investigate whether the estimated myelin content of white matter tracts is predictive of cognitive processing speed and whether such associations are modulated by age. Associations between estimated myelin content and processing speed were assessed in 570 community-living individuals (277 middle-age, 293 older-age). Myelin content was estimated in-vivo using the mean T1w/T2w magnetic resonance ratio, in six white matter tracts (anterior corona radiata, superior corona radiata, pontine crossing tract, anterior limb of the internal capsule, genu of the corpus callosum, and splenium of the corpus callosum). Processing speed was estimated by extracting a principal component from 5 separate tests of processing speed. It was found that estimated myelin content of the bilateral anterior limb of the internal capsule and left splenium of the corpus callosum were significant predictors of processing speed, even after controlling for socio-demographic, health and genetic variables and correcting for multiple comparisons. One SD higher in the estimated myelin content of the anterior limb of the internal capsule was associated with 2.53% faster processing speed and within the left splenium of the corpus callosum with 2.20% faster processing speed. In addition, significant differences in estimated myelin content between middle-age and older participants were found in all six white matter tracts. The present results indicate that myelin content, estimated in vivo using a neuroimaging approach in healthy older adults, is sufficiently precise to predict variability in processing speed in behavioural measures. PMID- 29274748 TI - Neural circuitry underlying sustained attention in healthy adolescents and in ADHD symptomatology. AB - Moment-to-moment reaction time variability on tasks of attention, often quantified by intra-individual response variability (IRV), provides a good indication of the degree to which an individual is vulnerable to lapses in sustained attention. Increased IRV is a hallmark of several disorders of attention, including Attention-Deficit/Hyperactivity Disorder (ADHD). Here, task based fMRI was used to provide the first examination of how average brain activation and functional connectivity patterns in adolescents are related to individual differences in sustained attention as measured by IRV. We computed IRV in a large sample of adolescents (n = 758) across 'Go' trials of a Stop Signal Task (SST). A data-driven, multi-step analysis approach was used to identify networks associated with low IRV (i.e., good sustained attention) and high IRV (i.e., poorer sustained attention). Low IRV was associated with greater functional segregation (i.e., stronger negative connectivity) amongst an array of brain networks, particularly between cerebellum and motor, cerebellum and prefrontal, and occipital and motor networks. In contrast, high IRV was associated with stronger positive connectivity within the motor network bilaterally and between motor and parietal, prefrontal, and limbic networks. Consistent with these observations, a separate sample of adolescents exhibiting elevated ADHD symptoms had increased fMRI activation and stronger positive connectivity within the same motor network denoting poorer sustained attention, compared to a matched asymptomatic control sample. With respect to the functional connectivity signature of low IRV, there were no statistically significant differences in networks denoting good sustained attention between the ADHD symptom group and asymptomatic control group. We propose that sustained attentional processes are facilitated by an array of neural networks working together, and provide an empirical account of how the functional role of the cerebellum extends to cognition in adolescents. This work highlights the involvement of motor cortex in the integrity of sustained attention, and suggests that atypically strong connectivity within motor networks characterizes poor attentional capacity in both typically developing and ADHD symptomatic adolescents. PMID- 29274749 TI - The genetic polymorphisms of TGFbeta superfamily genes are associated with litter size in a Chinese indigenous sheep breed (Hu sheep). AB - Litter size, which is a complex economic trait in sheep, is affected by polygenes. Hu sheep are a prolific native breed in China and also an ideal resource for studying the genetic mechanism that controls litter size in sheep. In this study, we investigated the genetic effects of candidate genes on litter size in a large experimental population (n = 2021) of Hu sheep. A total of 23 single nucleotide polymorphisms (SNPs) including six reported major mutations (FecB, FecXI, FecXB, FecXH, FecGI, and FecGH) and 17 novel SNPs in 10 candidate genes involved in reproduction were genotyped using KASPar technology. Genotyping showed that Hu sheep carry the FecB mutation, but not the FecXI, FecXB, FecXH, FecGH, and FecGI mutations. Among the remaining 18 SNPs, 16 tagged SNPs were selected based on the HAPLOVIEW program. Analysis of single marker association indicated a significant association between litter size in Hu sheep and three mutations in the TGFbeta superfamily (FecB, GDF9 and TGFBR2 genes). Quantitative trait modes (QTMs) analysis revealed that the FecB and GDF9 mutations exerted an additive effect, while the mutation located within TGFBR2 gene was dominant. Linear regression analysis of the association between multiple markers and litter size indicated a correlation between homozygous ewes with the GG/AA/TT genotype and larger litter size than any of the other genotypes. In conclusion, the FecB, GDF9, and TGFBR2 polymorphisms were implicated as genetic markers of potential importance in marker-assisted selection (MAS) strategies to improve litter size in Hu sheep. PMID- 29274750 TI - Rabbit seminal plasma proteome: The importance of the genetic origin. AB - The present study was conducted to characterise rabbit seminal plasma proteins (SP proteins) focusing on the influence of the genetic origin and seasonality. In addition, beta-NGF protein quantity in SP was determined. Semen samples were recovered from January to December 2014 using 6 males belonging to genotype A and six from genotype R. For each genotype, one pooled sample at the beginning, middle and end of each season was selected to develop the experiment. A total of 24 pools (3 for each season and genetic line) were analysed. SP proteins of the two experimental groups were recovered and subjected to in-solution digestion nano LC-MS/MS and bioinformatics analysis. The resulting library included 402 identified proteins validated with >=95% Confidence (unused Score >= 1.3). These data are available via ProteomeXchange with identifier PXD006308. Only 6 proteins were specifically implicated in reproductive processes according to Gene Ontology annotation. Twenty-three proteins were differentially expressed between genotypes, 11 over-expressed in genotype A and 12 in genotype R. Regarding the effect of season on rabbit SP proteome, results showed that there is no clear pattern of protein variation throughout the year. Similar beta-NGF relative quantity was observed between seasons and genotypes. In conclusion, this study generates the largest library of SP proteins reported to date in rabbits and provides evidence that genotype is related to a specific abundance of SP proteins. PMID- 29274751 TI - Reduced expression of Na+/Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice. AB - Na+/Ca2+ exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca2+ for three Na+ ions, depending on Ca2+ and Na+ electrochemical gradients across the membrane. Three mammalian NCX isoforms (NCX1, NCX2, and NCX3) are each encoded by a distinct gene. Here, we report that NCX2 and NCX3 protein and mRNA levels are relatively reduced in hippocampal CA1 of APP23 and APP-KI mice. Likewise, NCX2+/- or NCX3+/- mice exhibited impaired hippocampal LTP and memory-related behaviors. Moreover, relative to controls, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in NCX2+/- mouse hippocampus but increased in hippocampus of NCX3+/- mice. NCX2 or NCX3 heterozygotes displayed impaired maintenance of hippocampal LTP, a phenotype that in NCX2+/- mice was correlated with elevated calcineurin activity and rescued by treatment with the calcineurin (CaN) inhibitor FK506. Likewise, FK506 treatment significantly restored impaired hippocampal LTP in APP-KI mice. Moreover, Ca2+ clearance after depolarization following high frequency stimulation was slightly delayed in hippocampal CA1 regions of NCX2+/- mice. Electron microscopy revealed relatively decreased synaptic density in CA1 of NCX2+/- mice, while the number of spines with perforated synapses in CA1 significantly increased in NCX3+/- mice. We conclude that memory impairment seen in NCX2+/- and NCX3+/- mice reflect dysregulated hippocampal CaMKII activity, which alters dendritic spine morphology, findings with implications for memory deficits seen in Alzheimer's disease model mice. PMID- 29274753 TI - Multiple Sclerosis Re-Examined: Essential and Emerging Clinical Concepts. AB - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by exacerbations of neurological dysfunction due to inflammatory demyelination. Neurologic symptoms typically present in young adulthood and vary based on the site of inflammation, although weakness, sensory impairment, brainstem dysfunction, and vision loss are common. MS occurs more frequently in women and its development is complex-genetics, hormones, geography, vitamin D, and viral exposure all play roles. Early MS is characterized by relapsing-remitting course and inflammation of the white matter, although as patients age, the disease often transitions to a pathologically distinct secondary progressive phase with gradual disability accrual affecting gait, coordination, and bladder function. A minority of patients (10%) have disease that is progressive at onset. In the past decade, there has been a remarkable expansion in disease-modifying therapy for MS, but treatment of progressive disease remains a challenge. This article reviews foundational concepts in MS and emerging work that has reshaped understanding of the disease, providing new insight for therapeutic advance. PMID- 29274752 TI - Chronic paroxetine treatment prevents disruption of methamphetamine-sensitive circadian oscillator in a transgenic mouse model of Huntington's disease. AB - Circadian abnormalities seen in Huntington's disease (HD) patients are recapitulated in several HD transgenic mouse models. In mice, alongside the master clock located in the suprachiasmatic nucleus (SCN), two other oscillators may influence circadian behaviour. These are the food-entrainable oscillator (FEO) and the methamphetamine-sensitive circadian oscillator (MASCO). SCN- and MASCO- (but not FEO-) driven rhythms are progressively disrupted in the R6/2 mouse model of HD. MASCO-driven rhythms are induced by chronic treatment with low dose of methamphetamine and characterised by an increase in period length to greater than 24 h. Interestingly, the rhythms mediated by MASCO deteriorate earlier than those mediated by the SCN in R6/2 mice. Here, we used a pharmacological strategy to investigate the mechanisms underlying MASCO-driven rhythms in WT mice. In contrast to methamphetamine, chronic cocaine was ineffective in generating a MASCO-like component of activity although it markedly increased locomotion. Furthermore, neither blocking dopamine (DA) receptors (with the DA antagonist haloperidol) nor blocking neurotransmission by inhibiting the activity of vesicular monoamine transporter (with reserpine) prevented the expression of the MASCO-driven rhythms, although both treatments downregulated locomotor activity. Interestingly, chronic treatment with paroxetine, a serotonin specific reuptake inhibitor commonly used as antidepressant in HD, was able to restore the expression of MASCO-driven rhythms in R6/2 mice. Thus, MASCO-driven rhythms appear to be mediated by both serotoninergic and dopaminergic systems. This supports the idea that abnormalities in MASCO output may contribute to both the HD circadian and psychiatric phenotype. PMID- 29274754 TI - The HAS-BLED, ATRIA, and ORBIT Bleeding Scores in Atrial Fibrillation Patients Using Non-Vitamin K Antagonist Oral Anticoagulants. AB - BACKGROUND: Various bleeding risk scores have been proposed to assess the risk of bleeding in patients with atrial fibrillation taking oral anticoagulants. Limited data are available with these scores, in users of non-vitamin K antagonist oral anticoagulants. METHODS: Using the Danish registries, we evaluated and compared the risk classification properties of the Hypertension, Age, Stroke, Bleeding tendency/predisposition, Labile international normalized ratios, Elderly age/frailty, Drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess (HAS-BLED), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) scores for predicting major bleeding in 57,930 atrial fibrillation patients (44.6% female; mean age 73.5 years, standard deviation 11.4 years; mean CHA2DS2-VASc score 3.2, standard deviation 1.8). RESULTS: At 1-year follow-up, C-statistics for ATRIA, HAS-BLED, and ORBIT were approximately 0.59, with only minor differences between scores. Both ATRIA and ORBIT categorized more patients as "low risk" (both >83%, when compared with HAS-BLED, only 53%), and qualitatively, the receiver operating characteristic curves revealed higher sensitivity (62.8%) for HAS-BLED compared with ATRIA (29.7%) and ORBIT (37.1%). The clinical usefulness of scores was evaluated using decision curve analyses at a 1-year perspective. If the intervention threshold is low (<1.7%), the benefit is toward monitoring all patients. If preference is for a major bleeding risk threshold between 1.7% and 2.0%, most benefit was obtained by using HAS-BLED. The ORBIT and ATRIA scores provided better benefit for thresholds between 2.0% and 6.0%. CONCLUSION: This analysis of contemporary bleeding risk score stratification in a "real-world" non-vitamin K antagonist oral anticoagulant users population with atrial fibrillation showed modest predictive values using C statistics. The scores represent different risk thresholds, with HAS-BLED classifying least patients at low risk and achieving the highest benefit if applying a major bleeding intervention threshold of approximately 2%, whereas benefit from using either ATRIA score or ORBIT score was only evident using higher intervention thresholds. PMID- 29274755 TI - Finding Aliki: Medicine with Heart. PMID- 29274756 TI - Different Causes of Death in Patients with Myocardial Infarction Type 1, Type 2, and Myocardial Injury. AB - BACKGROUND: Data outlining the mortality and the causes of death in patients with type 1 myocardial infarction, type 2 myocardial infarction, and those with myocardial injury are limited. METHODS: During a 1-year period from January 2010 to January 2011, all hospitalized patients who had cardiac troponin I measured on clinical indication were prospectively studied. Patients with at least one cardiac troponin I value >30 ng/L underwent case ascertainment and individual evaluation by an experienced adjudication committee. Patients were classified as having type 1 myocardial infarction, type 2 myocardial infarction, or myocardial injury according to the criteria of the universal definition of myocardial infarction. Follow-up was ensured until December 31, 2014. Data on mortality and causes of death were obtained from the Danish Civil Registration System and the Danish Register of Causes of Death. RESULTS: Overall, 3762 consecutive patients were followed for a mean of 3.2 years (interquartile range 1.3-3.6 years). All cause mortality differed significantly among categories: Type 1 myocardial infarction 31.7%, type 2 myocardial infarction 62.2%, myocardial injury 58.7%, and 22.2% in patients with nonelevated troponin values (log-rank test; P < .0001). In patients with type 1 myocardial infarction, 61.3% died from cardiovascular causes, vs 42.6% in patients with type 2 myocardial infarction (P = .015) and 41.2% in those with myocardial injury (P < .0001). The overall mortality and the causes of death did not differ substantially between patients with type 2 myocardial infarction and those with myocardial injury. CONCLUSIONS: Patients with type 2 myocardial infarction and myocardial injury exhibit a significantly higher long-term mortality compared with patients with type 1 myocardial infarction . However, most patients with type 1 myocardial infarction die from cardiovascular causes in contrast to patients with type 2 myocardial infarction and myocardial injury, in whom noncardiovascular causes of death predominate. PMID- 29274757 TI - Oncologic 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: What All Physicians Need to Know. AB - Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) hybrid examinations (PET/computed tomography, PET/magnetic resonance imaging) have become the most common PET imaging tools in the evaluation of the oncologic patient. Therefore it is of paramount importance that physicians who take care of oncology patients in any capacity are familiar with the basics of when these examinations are indicated, know how to best prepare the patients, and understand the benefits and limitations of the procedure. Additionally, it is important to understand which medical conditions and medications need to be controlled to maintain the diagnostic accuracy of these tests. In this article we aim to explain what 18F-FDG is, how to best prepare our patients, what PET is, and how these examinations are interpreted. Finally, we discuss some of the limitations of these examinations. PMID- 29274758 TI - Efficacy and Safety Outcomes of Direct Oral Anticoagulants and Amiodarone in Patients with Atrial Fibrillation. AB - BACKGROUND: Direct oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P gp) and cytochrome p-450 (CYP3A4) substrates. Direct oral anticoagulant levels may be increased by the concomitant use of potent dual P-gp/CYP3A4 inhibitors, such as amiodarone, which can potentially translate into adverse clinical outcomes. We aimed to assess the efficacy and safety of drug-drug interaction by the concomitant use of DOACs and amiodarone. METHODS: We performed a systematic review of MEDLINE, the Cochrane Central Register of Clinical Trials, and Embase, limiting our search to randomized controlled trials of patients with atrial fibrillation that have compared DOACs versus warfarin for prophylaxis of stroke or systemic embolism, to analyze the impact on stroke or systemic embolism, major bleeding, and intracranial bleeding risk in patients with concomitant use of amiodarone. Risk ratio (RR) 95% confidence intervals were measured using the Mantel-Haenszel method. The fixed effects model was used owing to heterogeneity (I2) < 25%. RESULTS: Four trials with a total of 71,683 patients were analyzed, from which 5% of patients (n = 3212) were concomitantly taking DOAC and amiodarone. We found no statistically significant difference for any of the clinical outcomes (stroke or systemic embolism [RR 0.85; 95% CI, 0.67-1.06], major bleeding [RR 0.91; 95% CI, 0.77-1.07], or intracranial bleeding [RR 1.10; 95% CI, 0.68-1.78]) among patients taking DOAC and amiodarone versus DOAC without amiodarone. CONCLUSION: On the basis of the results of this meta-analysis, co administration of DOACs and amiodarone, a dual P-gp/CYP3A4 inhibitor, does not seem to affect efficacy or safety outcomes in patients with atrial fibrillation. PMID- 29274759 TI - Acute Myocardial Infarction in Patients with Paraplegia: Characteristics, Management, and Outcomes. AB - BACKGROUND: Cardiovascular disease has become a leading cause of death for patients with paraplegia. Acute myocardial infarction in patients with paraplegia has not been described in the literature. This study investigates clinical features, management strategies, and outcomes of these patients. METHODS: Acute myocardial infarction in patients with or without paraplegia was identified in the New York State Inpatient Database between 2007 and 2013. Clinical comorbidities, management strategies and their associated outcomes were compared using propensity score-matching analysis. RESULTS: Among 402,569 patients with acute myocardial infarction, 1400 had a concomitant diagnosis of paraplegia. Compared with those without, patients with paraplegia were younger, more likely to be black, and had a higher prevalence of hypertension, anemia, congestive heart failure, coagulopathy, and depression, but a lower prevalence of diabetes, hyperlipidemia, obesity, chronic lung disease, and renal failure. Patients with paraplegia were more likely to receive medical therapy without a diagnostic cardiac catheterization than those without (83.7% vs 64.5%, P < .001). Nine percent of patients with paraplegia received revascularization, which was significantly lower than that without paraplegia. In terms of the clinical outcome, patients with paraplegia had higher in-hospital mortality than those without (22.4% vs 16.8%, P < .001). Among the patients with paraplegia, the subcohort that received revascularization had lower in-hospital mortality (9.5% vs 22.0%, P < .01), had shorter length of stay (13.0 vs 16.9 days, P =.08), and higher hospital charges ($130,079 vs $92,125, P < .001) than those without revascularization. Furthermore, the paraplegic subcohort underwent coronary artery bypass grafting that was associated with higher in-hospital mortality (21.7% vs 1.7%, P < .001), longer length of stay (24.8 vs 14.2 days, P < .001), and higher hospital charges ($231,323 vs $144,449, P < .01) than subcohort that received percutaneous coronary intervention. CONCLUSIONS: Acute myocardial infarction patients with concomitant paraplegia had distinct clinical characteristics and comorbidity profiles; were less likely to receive revascularization therapy; and had higher in-hospital mortality. Acute myocardial infarction patient with paraplegia who underwent revascularization were associated with better clinical outcomes, in particular, those who were treated with percutaneous coronary intervention had significantly lower in-hospital mortality than those treated with coronary artery bypass grafting. PMID- 29274760 TI - Escaping behavior in goitered gazelle. AB - Prey species modify their behaviors in response to predation risks to minimize their vulnerability and enhance their survival. When a predation risk arises, gregarious, open-habitat-dwelling ungulates usually increase their vigilance rate and enlarge their herd sizes, which are the two antipredator responses that are most often investigated. However, other reactive responses, as well as prey risk assessments and escape strategies depending on a predator's approach behavior, are less explored. In this paper I want to discuss the responses of goitered gazelles and their escape strategies when they encountered humans or vehicles in their natural habitat in Kazakhstan. I found that in most cases adult goitered gazelles, being more experienced and habituated to dangerous situations, usually made a preflight risk assessment and stopped in mid escape for an additional scan of their surroundings. The younger, more reactive individuals behaved this way less often and instead ran immediately instead regardless of threat level. In cases with a more obvious, direct danger, all goitered gazelles, irrespective of age, galloped immediately without stopping, and ran mainly in a sideways direction almost perpendicular to or even across the path of the approaching predator. Goitered gazelles also preferred to run upward to elevated points or toward mountain foothills, where they could get higher than the perceived threat. Furthermore, this study has shown that the goitered gazelles, preferring rough open terrain of lowlands and foothills, combined escape features found in typical antipredator strategies of both open-habitat antelopes (first assessment of danger mainly through sight, then galloping to outrun the predator) and mountain dwelling ungulates (use of rough terrain as refuge, running to the highest elevation for a better view, and attempting to get higher on the slope than their pursuer). The goitered gazelles, however, did not demonstrate any freezing pattern for concealment, typical for forest-dwelling ungulates. PMID- 29274761 TI - Spatial integration during performance in pigeons. AB - We've shown that pigeons can integrate separately acquired spatial maps into a cognitive map. Integration requires an element shared between maps. In two experiments using a spatial-search task in pigeons, we test spatial combination rules when no shared element was present during training. In all three experiments, pigeons first learned individual landmark-target maps. In subsequent tests involving combinations of landmarks, we found evidence that landmarks collaborate in guiding spatial choice at test (Experiment 1). In Experiment 2, pigeons were trained on two landmarks with different proximities to the target. On tests on a compound of both landmarks, pigeons showed stronger spatial control by the more proximal landmark, a performance overshadowing effect. Extinction of the proximal landmark shifted spatial control to the non-extinguished distal landmark. This reveals that the performance overshadowing effect was associative in nature, and not due to perceptual or spatial biases. This emphasis on spatial control during performance reflects the emphasis on performance processes that were a major focus in Ralph Miller's lab. PMID- 29274762 TI - The "olfactory mirror" and other recent attempts to demonstrate self-recognition in non-primate species. AB - The recent attempt by Horowitz (2017) to develop an "olfactory mirror" test of self-recognition in domestic dogs raises some important questions about the kinds of data that are required to provide definitive evidence for self-recognition in dogs and other species. We conclude that the "olfactory mirror" constitutes a compelling analog to the mark test for mirror self-recognition in primates, but despite claims to the contrary neither dogs, elephants, dolphins, magpies, horses, manta rays, squid, nor ants have shown compelling, reproducible evidence for self-recognition in any modality. PMID- 29274763 TI - The neural response of female zebra finches (Taeniopygia guttata) to conspecific, heterospecific, and isolate song depends on early-life song exposure. AB - The auditory forebrain regions caudo-medial nidopallium (NCM) and caudo-medial mesopallium (CMM) of songbirds exhibit differential expression of the immediate early gene ZENK in response to playback of different song stimuli, and dependent on early-life auditory experience. Similarly, song preferences depend both on auditory experience and unlearned biases for particular song features. We explored the contributions of early-life auditory experience and the type of song stimuli on the Zenk response in the auditory forebrain of female zebra finches. Females were raised in three different early tutoring conditions: conspecific tutors that sang isolate song, heterospecific tutors, or conspecific tutors that sang wild-type song. At maturity, these females were exposed to one of five different playback conditions: wild-type song, isolate song, tutor song, heterospecific song, or white noise. Subsequently, the number of cells immunoreactive for ZENK in CMM and NCM was measured. We predicted that birds exposed to conspecific song early in life, and during the song playback in adulthood, would have the highest neural response. Instead, we found that the Zenk response varied across playback conditions with the highest response to conspecific wild-type and conspecific isolate song. In addition, we found a main effect of tutoring, with the lowest overall Zenk response in females tutored by males singing isolate song. Most importantly, there was a significant interaction in that females tutored by wild-type conspecific or heterospecific songs showed a similar increased response to zebra finch songs (wild-type or isolate), but females tutored by isolate song showed no differential response to conspecific song and only showed elevated Zenk response to the particular songs they were tutored with. Combined, our results indicate that unlearned response biases to conspecific song elements depend on previous auditory experience. That is, early experience appears to modulate the expression of innate biases. PMID- 29274764 TI - Foraging motivation favors the occurrence of Levy walks. AB - Levy walks are a property of random movements often observed among foraging animals (and humans), and they might confer some advantages for survival in an unpredictable environment, in comparison with Brownian walks. In animals with a nervous system, specific neurotransmitters associated with some psychological states could play a crucial role in controlling the occurrence of Levy walks. We argue that incentive motivation, a dopamine-dependent process that in vertebrates makes rewards and their predictive conditioned stimuli attractive, has behavioral effects that may favor their occurrence: incentive motivation is higher when food is unpredictable and it strongly underpins foraging activity. An individual-based computer model is used to determine whether changes in incentive motivation can influence the probability that Levy walks occur among foraging agents. Our results suggest that they are produced more often under an unpredictable than a predictable food access, and more often in strongly rather than weakly motivated foragers exposed to an unpredictable food access. Also, our motivational framework indicates that the occurrence of Levy walks are correlated with, but not causally linked to, the number of food items consumed and the ability to store fat reserves. We conclude that Levy walks can confer some advantages for survival in an unpredictable environment, provided that they appear in foragers with a high motivation to seek food. PMID- 29274765 TI - Management of postoperative pain. PMID- 29274766 TI - Infliximab trough levels and persistent vs transient antibodies measured early after induction predict long-term clinical remission in patients with inflammatory bowel disease. AB - BACKGROUND: The use of therapeutic drug monitoring has been proposed as a useful tool in the management of patients with loss of response to biological therapy in patients with inflammatory bowel disease. AIMS: To evaluate whether early, post induction anti-tumor necrosis factor trough levels and the presence of different types of anti-drug antibodies may impact long-term clinical remission in patients with inflammatory bowel disease. METHODS: We prospectively assessed anti-tumor necrosis factor trough levels and both persistent and transient anti-drug antibodies. The Harvey-Bradshaw Index and the partial Mayo score were evaluated at each visit or in case of relapse. RESULTS: At week 14, median infliximab trough levels were significantly lower in patients who experienced loss of response at week 48 as compared to patients in stable remission (1.3mcg/mL [range 0-10.2mcg/mL] vs. 10.1mcg/mL[range 0-42.8mcg/mL], P<0.0004). ROC curve identified an infliximab trough levels of 6.2mcg/mL as the cut-off value with the highest accuracy (c-index=0.864) for loss of response at week 48. At week 14 we observed a correlation between anti-drug antibodies concentration and infliximab trough levels (rs=-0.513, P=0.04). CONCLUSIONS: The results highlight the usefulness of assessing early biological TL in order to predict patients' long-term outcome. PMID- 29274767 TI - Development of corticospinal motor excitability and cortical silent period from mid-childhood to adulthood - a navigated TMS study. AB - OBJECTIVES: We characterized the maturation of the excitability of the motor cortex and corticospinal tract from childhood to adulthood using electric field (EF) navigated TMS and correlated the results with manual dexterity. METHODS: Both hemispheres of healthy right-handed children (6-9 years, n=10), preadolescents (10-12 years, n=13), adolescents (14-17 years, n=12) and young adults (22-34 years, n=12) of both genders were examined. The optimal cortical representation site and resting motor threshold (rMT) were determined for the abductor pollicis brevis muscle. Motor-evoked potential (MEP) latencies and amplitudes in relaxed and active states, input-output curves and silent period (SP) durations were determined. Manual dexterity was assessed with the Box and Block Test. RESULTS: rMT (in terms of maximal stimulator output or EF strength) decreased with age (P<0.001) and stabilized when reaching adolescence. The MEP amplitude (P=0.037) and latency increased (P<0.001) with age. Input-output curves showed age-dependent changes in several parameters. SP duration decreased with age (P<0.001), and demonstrated hemispheric asymmetry in the children (P=0.030). Manual dexterity correlated negatively with rMT (P<0.001). DISCUSSION: The excitation/inhibition balance develops with age and correlates with manual dexterity. Strong corticospinal inhibition was observed in the children and this was found to decrease with age. Interhemispheric asymmetry was only observed for SP duration in the children. Knowledge of normal development is crucial for the understanding of developmental disabilities and using estimates of effective EF may be advantageous in future pediatric studies. PMID- 29274768 TI - Evaluation of the impact of hearing loss in adults: Validation of a quality of life questionnaire. AB - OBJECTIVES: The impact of hearing loss and of auditory rehabilitation (hearing aid, cochlear implant) on quality of life is a crucial issue. Commonly used questionnaires to assess quality of life in these patients (Nijmegen, APHAB, GBI) are time-consuming, difficult for patients to fill out, and show poor sensitivity to small improvements or deterioration. The objective of the present study was to validate a dedicated quality of life scale for hearing-impaired adults with or without auditory rehabilitation. MATERIAL AND METHODS: ERSA (Evaluation du Retentissement de la Surdite chez l'Adulte: Evaluation of the Impact of Hearing Loss in Adults) is a self-administered questionnaire. It is divided into 4 domains, each comprising 5 questions graded from 1 to 10. The questions are simple, and formulated so patients will answer according to how they feel at the actual time of the session. Test-retest reliability was measured in 38 patients. Internal coherence and validity against the APHAB questionnaire as gold standard and in relation to hearing performance were measured in 122 patients at auditory assessment. Sensitivity to change in hearing was measured in 36 cochlear implant patients, before and 6 or 12 months after implantation. RESULTS: Test-retest reliability was very satisfactory (rho=0.88). Internal coherence was good for all questions. External validity, comparing ERSA to APHAB scores in the same non implanted hearing-impaired patients, was good (rho=0.52). Additionally, ERSA scores correlated with hearing performance in adverse conditions (monosyllabic words: rho=0.22; sentences in noise: rho=0.19). In patients tested before and after cochlear implantation, improvement in hearing performance in silence and in noise correlated with an improvement in ERSA score (rho=0.37 to 0.59, depending on the test), but not to GBI score. CONCLUSION: The ERSA questionnaire is easy and quick to use, reliable, and sensitive to change in hearing performance after cochlear implantation. PMID- 29274769 TI - Comparison of Video Head Impulse Test and Caloric Reflex Test in advanced unilateral definite Meniere's disease. AB - AIMS: There have been very few studies of the Video Head Impulse Test (VHIT) in patients with Meniere's Disease (MD). Some reported 100% normal VHIT results, others not. These discrepancies may be due to differences in severity. The present study compared VHIT and caloric reflex test results in advanced unilateral definite MD. MATERIAL AND METHOD: A prospective study included 37 consecutive patients, with a mean age of 56+/-12 years. Mean hearing loss was 59+/-18dB HL; 12 patients were subject to Tumarkin's otolithic crises. Abnormal caloric reflex was defined as >=20% deficit, and abnormal VHIT as presence of saccades or <0.64 gain in vertical semicircular canals and <0.78 in horizontal canals. RESULTS: All patients had normal VHIT results, and 3 had normal caloric reflex; mean caloric reflex deficit was 45%. CONCLUSION: The present study is the only one to use the August 2015 updated definition of MD. The results showed that, outside of episodes of crisis, VHIT was normal during advanced unilateral definite MD, in contrast to abnormal caloric reflex. This feature could help distinguish MD from other inner ear diseases, and it would be interesting to try to confirm this hypothesis by studying MD patients. PMID- 29274770 TI - In Defense of Sympathy, in Consideration of Empathy, and in Praise of Compassion: A History of the Present. PMID- 29274771 TI - Determination of normal expression patterns of CD86, CD210a, CD261, CD262, CD264, CD358, and CD361 in peripheral blood and bone marrow cells by flow cytometry. AB - In 2010, new monoclonal antibodies were submitted to the 9th International Workshop on Human Leukocyte Differentiation Antigens, and there are few studies demonstrating normal expression patterns of these markers. Thus, the objective of this study was to determine the normal patterns of cell expression of CD86, CD210a, CD261, CD262, CD264, CD358, and CD361 in peripheral blood (PB) and bone marrow (BM) samples by flow cytometry. In the present study, CD86 was expressed only in monocytes and B lymphocytes in PB and in monocytes and plasma cells in BM. Regarding CD210a expression, in PB samples, monocytes and NK cells showed weak expression, while neutrophils, B and T lymphocytes, and basophils showed weak and partial expression. In BM samples, expression of CD210a was observed in eosinophils, monocytes, and B and T/NK lymphocytes. Weak expression of CD210a was also observed in neutrophilic cells and plasma cells. All B cell maturation stages had weak expression of CD210a except for immature B cells, which did not express this marker. In the present study, no cell type in PB samples showed positivity for CD261 and, in BM samples, there was very weak expression in neutrophilic series, monocytes, and B lymphocytes. Conversely, plasma cells showed positivity for CD261 with a homogeneous expression. For CD262, there was weak expression in monocytes, neutrophils, and B lymphocytes in PB samples and weak expression in monocytes, B lymphocytes, and plasma cells in BM samples. The evaluation of CD264 showed very weak expression in B cells in PB samples and no expression in BM cells. Very weak expression of CD358 was observed in neutrophils, monocytes, and B lymphocytes in PB and BM samples. In addition, in BM samples, plasma cells and T lymphocytes showed weak expression of CD358. In relation to the maturation stages of B cells, there was weak expression in pro-B cel, pre-B cell, and mature B cell. In the present study, it was possible to observe expression of CD361 in all cell types analyzed in PB and BM samples. The analyzed markers presented varied profiles of expression and, in some cases, these profiles were different from those observed in other studies. Further studies are needed to evaluate these molecules, mainly in relation to a possible application in the diagnosis of hematological malignancies or as new therapeutic targets for the treatment of hematological neoplasms or autoimmune diseases. PMID- 29274772 TI - Evidence for the use of mineralocorticoid receptor antagonists in the treatment of coronary artery disease and post-angioplasty restenosis. AB - Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone have an established role in the treatment of heart failure. However, many experimental and clinical studies have shown that aldosterone also plays a pivotal role in a variety of other pathophysiological conditions within the cardiovascular system. Aldosterone has been suggested to promote inflammation, endothelial dysfunction and smooth muscle cell hyperplasia during the development of atherosclerosis, thereby promoting the development of coronary artery disease (CAD). Since CAD and subsequent ischemic cardiomyopathy are the major causes of heart failure, it is of major interest, whether pharmacological therapy with MRAs among heart failure patients will also affect the common underlying conditions, namely, atherosclerosis and subsequent coronary vessel narrowing/rarefication. Therefore, in this article, we reviewed and discussed the preclinical and clinical evidence of MRAs for the treatment of acute or chronic vascular remodeling processes, such as atherosclerosis and post-angioplasty restenosis, which determine the progression of CAD and subsequent ischemic cardiomyopathy. PMID- 29274773 TI - Nerve growth factor plays a role in the neurotherapeutic effect of a CD45+ pan hematopoietic subpopulation derived from human umbilical cord blood in a traumatic brain injury model. AB - BACKGROUND AIMS: Human umbilical cord blood (HUCB) is an important source of stem cells for therapy of hematopoietic disorders and is a potential therapy for various neurological disorders, including traumatic brain injury (TBI). The expression of nerve growth factor (NGF) and its receptors TrkA, p75NTR and alpha9beta1 integrin on an HUCB CD45+ pan-hematopoietic subpopulation was investigated in the context of its neurotherapeutic potential after TBI. METHODS: NGF and its receptors were detected on CD45+ cells by reverse transcriptase polymerase chain reaction, flow cytometry analysis and confocal microscopy. CD45+ cells were stimulated by TBI brain extracts, and NGF levels were measured by enzyme-linked immunosorbent assay. TBI mice were divided into six groups for xenogeneic intravenous transplantation, 1 day post-trauma, with 1 * 106 CD45+ cells untreated or treated with the anti-NGF neutralizing antibody K252a, a TrkA antagonist; VLO5, an alpha9beta1 disintegrin; or negative (vehicle) and positive (NGF) controls. RESULTS: The HUCB CD45+ subpopulation constitutively expresses NGF and its receptors, mainly TrkA and p75NTR and minor levels of alpha9beta1. In vitro experiments provided evidence that trauma-related mediators from brain extracts of TBI mice induced release of NGF from HUCB CD45+ cell cultures. HUCB CD45+ cells induced a neurotherapeutic effect in TBI mice, abrogated by cell treatment with either anti-NGF antibody or K252a, but not VLO5. CONCLUSIONS: These findings strengthen the role of NGF and its TrkA receptor in the HUCB CD45+ subpopulation's neurotherapeutic effect. The presence of neurotrophin receptors in the HUCB CD45+ pan-hematopoietic subpopulation may explain the neuroprotective effect of cord blood in therapy of a variety of neurological disorders. PMID- 29274774 TI - Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium. AB - Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted "lipid-coated microbubble" [LCM]/"nanoparticle-derived" [ND] (or LCM/ND) nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly class B type I), or SR-BI, making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient. PMID- 29274775 TI - [Erratum to "Management of pregnant women with first episode of genital herpes. Guidelines for clinical practice from the French college of gynecologists and obstetricians (CNGOF)" [Gynecol Obstet Fertil Senol. 45 (2017) 664-76]]. PMID- 29274776 TI - Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma. AB - Deregulation of autophagy is proposed to play a key pathogenic role in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the third leading cause of cancer death. Autophagy is an evolutionarily conserved catabolic process activated to degrade and recycle cell's components. Under stress conditions, such as oxidative stress and nutrient deprivation, autophagy is an essential survival pathway that operates in harmony with other stress response pathways. These include the redox-sensitive transcription complex Nrf2-Keap1 that controls groups of genes with roles in detoxification and antioxidant processes, intermediary metabolism, and cell cycle regulation. Recently, a functional association between a dysfunctional autophagy and Nrf2 pathway activation has been identified in HCC. This appears to occur through the physical interaction of the autophagy adaptor p62 with the Nrf2 inhibitor Keap1, thus leading to increased stabilization and transcriptional activity of Nrf2, a key event in reprogramming metabolic and stress response pathways of proliferating hepatocarcinoma cells. These emerging molecular mechanisms and the therapeutic perspective of targeting Nrf2-p62 interaction in HCC are discussed in this paper along with the prognostic value of autophagy in this type of cancer. PMID- 29274777 TI - Lithium chloride contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by stimulating autophagic flux. AB - Blood-spinal cord barrier (BSCB) disruption following spinal cord injury (SCI) significantly compromises functional neuronal recovery. Autophagy is a potential therapeutic target when seeking to protect the BSCB. We explored the effects of lithium chloride (LiCl) on BSCB permeability and autophagy-induced SCI both in a rat model of SCI and in endothelial cells subjected to oxygen-glucose deprivation. We evaluated BSCB status using the Evans Blue dye extravasation test and measurement of tight junction (TJ) protein levels; we also assessed functional locomotor recovery. We detected autophagy-associated proteins in vivo and in vitro using both Western blotting and immunofluorescence staining. We found that, in a rat model of SCI, LiCl attenuated the elevation in BSCB permeability, improved locomotor recovery, and inhibited the degradation of TJ proteins including occludin and claudin-5. LiCl significantly induced the extent of autophagic flux after SCI by increasing LC3-II and ATG-5 levels, and abolishing p62 accumulation. In addition, a combination of LiCl and the autophagy inhibitor chloroquine not only partially eliminated the BSCB-protective effect of LiCl, but also exacerbated TJ protein degradation both in vivo and in vitro. Together, these findings suggest that LiCl treatment alleviates BSCB disruption and promotes locomotor recovery after SCI, partly by stimulating autophagic flux. PMID- 29274778 TI - Inhibition of CX3CR1 reduces cell motility and viability in pancreatic adenocarcinoma epithelial cells. AB - Increased expression of the chemokine CX3CL1 and its sole receptor, CX3CR1 have been correlated with poor pancreatic cancer patient survival and time to recurrence, as well as with pancreatic perineural invasion. We have previously shown that metastasis of prostate and breast cancer is in part driven by CX3CL1, and have developed small molecule inhibitors against the CX3CR1 receptor that diminish metastatic burden. Here we ask if inhibition of this chemokine receptor affects the phenotype of PDAC tumor cells. Our findings demonstrate that motility, invasion, and contact-independent growth of PDAC cells all increase following CX3CL1 exposure, and that antagonism of CX3CR1 by the inhibitor JMS-17 2 reduces each of these phenotypes and correlates with a downregulation of AKT phosphorylation. These data suggest that PDAC tumor cell migration and growth, elements critical in metastatic progression, may susceptible to pharmacologic intervention. PMID- 29274779 TI - Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis. AB - Information of myeloid lineage-related antigen on hematopoietic stem/progenitor cells (HSPCs) is important to clarify the mechanisms regulating hematopoiesis, as well as for the diagnosis and treatment of myeloid malignancies. We previously reported that special AT-rich sequence binding protein 1 (SATB1), a global chromatin organizer, promotes lymphoid differentiation from HSPCs. To search a novel cell surface molecule discriminating early myeloid and lymphoid differentiation, we performed microarray analyses comparing SATB1-overexpressed HSPCs with mock-transduced HSPCs. The results drew our attention to membrane spanning 4-domains, subfamily A, member 3 (Ms4a3) as the most downregulated molecule in HSPCs with forced overexpression of SATB1. Ms4a3 expression was undetectable in hematopoietic stem cells, but showed a concomitant increase with progressive myeloid differentiation, whereas not only lymphoid but also megakaryocytic-erythrocytic progenitors were entirely devoid of Ms4a3 expression. Further analysis revealed that a subset of CD34+CD38+CD33+ progenitor population in human adult bone marrow expressed MS4A3, and those MS4A3+ progenitors only produced granulocyte/macrophage colonies, losing erythroid colony- and mixed colony-forming capacity. These results suggest that cell surface expression of MS4A3 is useful to distinguish granulocyte/macrophage lineage-committed progenitors from other lineage-related ones in early human hematopoiesis. In conclusion, MS4A3 is useful to monitor early stage of myeloid differentiation in human hematopoiesis. PMID- 29274780 TI - Follicle-stimulating hormone promotes the transformation of cholesterol to estrogen in mouse adipose tissue. AB - Follicle-stimulating hormone (FSH) levels increase estrogen biosynthesis in obese menopausal women. Ovariectomized mice and 3T3-L1 cells were used to explore estrogen biosynthesis in the decline of ovarian function. After ovariectomy, lipid deposition, and FSH and estrogen levels changed, and feed intake increased significantly. In mouse adipose tissue, FSH was found to have a role in accelerating lipid deposition via the peroxisome proliferators-activated receptor pathway, and in inducing estrogen biosynthesis via the steroid hormone metabolism pathway. Furthermore, FSH bound to the FSH receptor promoted CREB phosphorylation, which was activated by cAMP-PKA. Moreover, pCREB could up regulate PPARgamma and SREBP2 mRNA levels, resulting in an increased transformation of cholesterol to estrogen. Overall, this study shows that FSH induces fat deposition and promotes the transformation of cholesterol to estrogen through CREB activation by cAMP-PKA in mouse adipose tissue. Our findings provide a new understanding of menopause treatment. PMID- 29274781 TI - Ro60/SSA levels are increased and promote the progression of pancreatic ductal adenocarcinoma. AB - Ro60/SSA is a vital auto antigen that is targeted in Sjogren's syndrome and systemic lupus erythematosus (SLE). However, its role in solid cancers has rarely been reported. The present study investigated the expression and function of Ro60/SSA in the development of pancreatic ductal adenocarcinoma (PDAC) both in vitro and in vivo. Immunohistochemistry was used to examine the expression of Ro60/SSA in PDAC and normal pancreatic tissues by using tissue microarray chips. The results showed that Ro60/SSA expression was increased in PDAC tissues compared with normal pancreatic tissues. Knockdown of Ro60/SSA by siRNA transfection significantly decreased cell proliferation and invasion in vitro. Furthermore, knockdown of Ro60/SSA inhibited the growth of subcutaneous tumors in vivo. Taken together, the current study provides evidence of new function of Ro60/SSA in the development of cancer. It facilitates pancreatic cancer proliferation, migration and invasion. Therefore, it may represent a novel molecular target for the management of pancreatic cancer. PMID- 29274782 TI - The aryl hydrocarbon receptor regulates the expression of TIPARP and its cis long non-coding RNA, TIPARP-AS1. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and member of the basic helix-loop-helix-PAS family. AHR is activated by numerous dietary and endogenous compounds that contribute to its regulation of genes in diverse signaling pathways including xenobiotic metabolism, vascular development, immune responses and cell cycle control. However, it is most widely studied for its role in mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. The AHR target gene and mono-ADP-ribosyltransferase, TCDD-inducible poly-ADP-ribose polymerase (TIPARP), was recently shown to be part of a novel negative feedback loop regulating AHR activity through mono-ADP-ribosylation. However, the molecular characterization of how AHR regulates TIPARP remains elusive. Here we show that activated AHR is recruited to the TIPARP promoter, through its binding to two genomic regions that each contain multiple AHR response elements (AHREs), AHR regulates the expression of both TIPARP but also TIPARP-AS1, a long non coding RNA (lncRNA) which lies upstream of TIPARP exon 1 and is expressed in the opposite orientation. Reporter gene and deletion studies showed that the distal AHRE cluster predominantly regulated TIPARP expression while the proximal cluster regulated TIPARP-AS1. Moreover, time course and promoter activity assays suggest that TIPARP and TIPARP-AS1 work in concert to regulate AHR signaling. Collectively, these data show an added level of complexity in the AHR signaling cascade which involves lncRNAs, whose functions remain poorly understood. PMID- 29274783 TI - Steady-state structural fluctuation is a predictor of the necessity of pausing mediated co-translational folding for small proteins. AB - Translational pausing coordinates protein synthesis and co-translational folding. It is a common factor that facilitates the correct folding of large, multi-domain proteins. For small proteins, pausing sites rarely occurs in the gene body, and the 3'-end pausing sites are only essential for the folding of a fraction of proteins. The determinant of the necessity of the pausings remains obscure. In this study, we demonstrated that the steady-state structural fluctuation is a predictor of the necessity of pausing-mediated co-translational folding for small proteins. Validated by experiments with 5 model proteins, we found that the rigid protein structures do not, while the flexible structures do need 3'-end pausings to fold correctly. Therefore, rational optimization of translational pausing can improve soluble expression of small proteins with flexible structures, but not the rigid ones. The rigidity of the structure can be quantitatively estimated in silico using molecular dynamic simulation. Nevertheless, we also found that the translational pausing optimization increases the fitness of the expression host, and thus benefits the recombinant protein production, independent from the soluble expression. These results shed light on the structural basis of the translational pausing and provided a practical tool for industrial protein fermentation. PMID- 29274784 TI - Regulation of PD-L1 expression by matrix stiffness in lung cancer cells. AB - Expression of programmed death-ligand 1 (PD-L1) in tumor cells such as lung cancer cells plays an important role in mechanisms underlying evasion of an immune check point system. Lung cancer tissue with increased deposition of extracellular matrix is much stiffer than normal lung tissue. There is emerging evidence that the matrix stiffness of cancer tissue affects the phenotypes and properties of cancer cells. Nevertheless, the effects of substrate rigidity on expression of PD-L1 in lung cancer cells remain elusive. We evaluated the effects of substrate stiffness on PD-L1 expression in HCC827 lung adenocarcinoma cells by using polyacrylamide hydrogels with stiffnesses of 2 and 25 kPa. Expression of PD L1 protein was higher on the stiffer substrates (25 kPa gel and plastic dish) than on the soft 2 kPa gel. PD-L1 expression was reduced by detachment of cells adhering to the substrate. Interferon-gamma enhanced expression of PD-L1 protein cultured on stiff (25 kPa gel and plastic dishes) and soft (2 kPa gel) substrates and in the cell adhesion-free condition. As the stiffness of substrates increased, formation of actin stress fiber and cell growth were enhanced. Transfection of the cells with short interfering RNA for PD-L1 inhibited cell growth without affecting stress fiber formation. Treatment of the cells with cytochalasin D, an inhibitor of actin polymerization, significantly reduced PD-L1 protein levels. Taken together, a stiff substrate enhanced PD-L1 expression via actin-dependent mechanisms in lung cancer cells. It is suggested that stiffness as a tumor environment regulates PD-L1 expression, which leads to evasion of the immune system and tumor growth. PMID- 29274785 TI - Indirubin 3'-oxime inhibits anticancer agent-induced YB-1 nuclear translocation in HepG2 human hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a disease with poor prognosis. Nuclear accumulation of YB-1 is closely related to the malignancy of HCC. Treatment with anticancer agents often induces translocation of YB-1 from cytoplasm to nucleus and activates the expression of multidrug resistance gene 1 (MDR1). Therefore, any effective inhibitor of this phenomenon would be useful for cancer treatment. Here we examined various indirubin derivatives and found that indirubin 3'-oxime inhibits actinomycin D-induced nuclear transport of YB-1 and suppresses the activation of MDR1 gene expression in the human hepatocellular carcinoma cell line HepG2. Furthermore, use of both indirubin 3'-oxime and actinomycin D in combination increased the anticancer effect on HepG2 cells. Indirubin 3'-oxime is a novel and efficient inhibitor of anticancer agent-induced YB-1 nuclear translocation. PMID- 29274786 TI - BQ123 selectively improved tumor perfusion and enhanced nanomedicine delivery for glioblastomas treatment. AB - Blood perfusion was always lower in tumor tissues as compared with that in surrounding normal tissues which lead to inadequate nanomedicine delivery to tumors. Inspired by the upregulation of both endothelin-1 (ET1) and its ETA receptor in tumor tissues and the crucial contribution of ET1-ETA receptor signaling to maintain myogenic tone of tumor vessels, we supposed that inhibition of ET1-ETA receptor signaling might selectively improve tumor perfusion and help deliver nanomedicine to tumors. Using human U87 MG glioblastomas with abundant vessels as the tumor model, immunofluorescence staining demonstrated that ETA receptor was overexpressed by in glioblastomas tissues compared with normal brain tissues. A single administration of ETA receptor antagonist BQ123 at the dose of 0.5 mg/kg could effectively improve tumor perfusion which was evidenced by in vivo photoacoustic imaging. Additionally, a single treatment of BQ123 could significantly improve the accumulation of nanoparticles (NPs) around 115 nm in tumors with a more homogeneous distribution pattern by in vivo imaging, ex vivo imaging as well as in vivo distribution experiments. Furthermore, BQ123 successfully increased the therapeutic benefits of paclitaxel-loaded NPs and significantly elongated the survival time of orthotropic glioblastomas-bearing animal models. In summary, the present study provided a new strategy to selectively improve tumor perfusion and therefore benefit nanomedicine delivery for tumor therapy. As ET1-ETA receptor signaling was upregulated in a variety of tumors, this strategy might open a new avenue for tumor treatment. PMID- 29274787 TI - Expert surgical consensus for prenatal counseling using the Delphi method. AB - BACKGROUND: Pediatric surgeons frequently offer prenatal consultation for congenital pulmonary airway malformation (CPAM) and congenital diaphragmatic hernia (CDH); however, there is no evidence-based consensus to guide prenatal decision making and counseling for these conditions. Eliciting feedback from experts is integral to defining best practice regarding prenatal counseling and intervention. METHODS: A Delphi consensus process was undertaken using a panel of pediatric surgeons identified as experts in fetal therapy to address current limitations. Areas of discrepancy in the literature on CPAM and CDH were identified and used to generate a list of content and intervention questions. Experts were invited to participate in an online Delphi survey. Items that did not reach first-round consensus were broken down into additional questions, and consensus was achieved in the second round. RESULTS: Fifty-four surgeons (69%) responded to at least one of the two survey rounds. During round one, consensus was reached on 54 of 89 survey questions (61%), and 45 new questions were developed. During round two, consensus was reached on 53 of 60 survey questions (88%). CONCLUSIONS: We determined expert consensus to establish guidelines regarding perinatal management of CPAM and CDH. Our results can help educate pediatric surgeons participating in perinatal care of these patients. LEVEL OF EVIDENCE: V. PMID- 29274788 TI - Human d-amino acid oxidase: The inactive G183R variant. AB - In the brain, the enzyme d-amino acid oxidase (DAAO) catalyzes the oxidative deamination of d-serine, a main positive modulator of the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR). Dysregulation in d-serine signaling is implicated in the NMDAR dysfunctions observed in various brain diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, schizophrenia. A strain of ddY mice lacking DAAO activity due to the G181R substitution (DAAOG181R mice) and exhibiting increased d-serine concentration as compared to wild-type mice shows altered pain response, improved adaptative learning and cognitive functions, and larger hippocampal long-term potentiation. In past years, this mice line has been used to shed light on physiological and pathological brain functions related to NMDAR. Here, we decided to introduce the corresponding substitution in human DAAO (hDAAO). The recombinant G183R hDAAO is produced as an inactive apoprotein: the substitution alters the protein conformation that negatively affects the ability to bind the flavin cofactor in the orientation required for hydride-transfer during catalysis. At the cellular level, the overexpressed G183R hDAAO is not fully targeted to peroxisomes, forms protein aggregates showing a strong colocalization with ubiquitin, and significantly (7-fold) increases both the d serine cellular concentration and the D/(D+L)-serine ratio. Taken together, our investigation warrants caution in using DAAOG181R mice: the abolition of enzymatic activity is coupled to DAAO aggregation, a central process in different pathological conditions. The effect due to G181R substitution in DAAO could be misleading: the effects due to impairment of d-serine degradation overlap with those related to aggregates accumulation. PMID- 29274789 TI - A cuticle protein from the Pacific white shrimp Litopenaeus vannamei involved in WSSV infection. AB - White spot syndrome virus (WSSV) is a major viral pathogen in global shrimp farming, causing huge economic damage. Through penetrating the outer surface of the target tissues, WSSV enters into the cells of the target tissue to complete the replication process in the host. In the present study, a cuticle protein gene from Litopenaeus vannamei, designated as LvAMP13.4, was identified and proved to be involved in WSSV invasion. The deduced amino acid sequence of LvAMP13.4 contained a signal peptide and a conserved chitin-binding domain type 4 (ChBD4). This cuticle protein gene was mainly expressed in stomach, gill and epidermis. The expression level of LvAMP13.4 was significantly changed during WSSV infection. Silencing of LvAMP13.4 by dsRNA interference apparently reduced the mortality rate and the WSSV copy number in shrimp upon WSSV infection. Furthermore, yeast two-hybrid system and Co-IP assay were performed to confirm that LvAMP13.4 could interact with the major envelop protein VP24 of WSSV. These data indicated that LvAMP13.4 was involved in the invasion process of WSSV through interaction with VP24. The present results could provide new insights for us in understanding the role of host cuticle proteins during virus invasion. PMID- 29274791 TI - Distal internal carotid artery dissection after consumption of synthetic cannabinoid "Bonzai". PMID- 29274790 TI - JAK and STAT members in channel catfish: Identification, phylogenetic analysis and expression profiling after Edwardsiella ictaluri infection. AB - The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is one of the main pleiotropic cascades used to transmit information from extracellular receptors to the nucleus, which results in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, migration, apoptosis, and cell survival. Members of JAK family and STAT family have been extensively studied in different mammalian species because of their important roles in innate and adaptive immune responses. However, they have not been systematically studied among teleost fish species. In this study, five JAK family members and eight STAT family members were identified and characterized from channel catfish. Phylogenetic analysis was conducted to properly annotate these genes. Syntenic analysis was also conducted to establish orthology, and confirm the results from phylogenetic analysis. Compared to mammals, more members of the JAK and STAT family were identified in channel catfish genome. Expression of JAK and STAT family members was detected in healthy catfish tissues, but was induced in gill, liver, and intestine after bacterial challenge. Notably, the significant upregulation of STAT1b gene in catfish liver, gill and intestine after Edwardsiella ictaluri infection supported the notion that high STAT1 expression are involved in defense against pathogens. Collectively, the increased expression of JAK and STAT members in tested tissues suggested their crucial function in defending the host against pathogen invasion. PMID- 29274792 TI - The personal outcome measures(r). AB - BACKGROUND: The Personal Outcome Measures(r) is a person-centered tool to measure the quality of life (QOL) of people with disabilities, especially those who receive long term services and supports. While the outcomes examine people's satisfaction with their lives in a wide range of areas, the organizational supports determine if service agencies are appropriately supporting people with disabilities to ensure people with disabilities have the best possible QOL. The Personal Outcome Measures(r) has been administered to tens of thousands of people with disabilities and older adults over its twenty-five years of existence. OBJECTIVE: In order for the Personal Outcome Measures(r) to adequately measure the QOL of people with disabilities, it must continuously be refined in alignment with the advances made by people with disabilities, and the disability service system. Therefore, the purpose of this study was to re-validate the Personal Outcome Measures(r). METHODS: A Principal Components Analysis was used to analyze data from 1473 people with disabilities to determine if any indicators needed to be removed as well as the underlying structure of the Personal Outcome Measures(r). RESULTS: The analysis revealed the Personal Outcome Measures(r) has construct validity. It also found that the 21 indicators fall into five underlying factors: my human security; my community; my relationships; my choices; and, my goals. CONCLUSIONS: Taken together these twenty-one indicators and five factors represent a multifaceted and comprehensive QOL assessment that aims to improve the lives of people with disabilities. PMID- 29274793 TI - Automatic quantification of juvenile zebrafish aggression. AB - BACKGROUND: Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. The zebrafish is an ideal model for aggression research. Zebrafish are small, amenable to genetic and pharmacological manipulation, and agonistic behaviour can be measured reliably. NEW METHOD: In this study we have established a novel setup to automatically quantify aggression and locomotion in one-month old juvenile zebrafish, a stage at which fish exhibit adult-like behaviour but are small so that one camera can film several animals. RESULTS: We have validated our novel software by comparison to manual quantification of behaviour, characterised the aggression of one-month old fish, and demonstrated that we can detect alterations to aggression caused by mutation or drug application. COMPARISON WITH OTHER METHODS: The ability to record up to 12 juvenile fish allows us to speed up and standardise data acquisition compared to studies of single fish. CONCLUSIONS: This setup appears to be suitable to screen for drugs that decrease zebrafish aggression as a first step toward developing novel treatments for this behaviour. PMID- 29274794 TI - Injectable poly-L-lactic acid: Instant hydration in lukewarm water bath and use of a thin needle to filter particles. PMID- 29274795 TI - [Splenic sarcoidosis diagnosed by US-guided biopsy: About a case]. AB - INTRODUCTION: Splenic localisation of sarcoidosis is common but rare as unique location. We report a case diagnosed by US-guided biopsy. OBSERVATION: A 42-year old woman presented atypic and recidivant epigastric pain. Abdominal ultrasound showed splenic hypoechoic nodules not characterizable with CT or MRI. PET-CT revealed hypermetabolism without any other abnormal metabolic activity. US-guided biopsy with small needle achieved diagnosis of isolated splenic sarcoidosis. CONCLUSION: Diagnosis of splenic nodular sarcoidosis can be challenging without any other localization. Splenic biopsy achieved diagnosis. This procedure is associated with a low risk of complications - in particular hemorragic ones. Diagnostic splenectomy should be an exceptional intervention. PMID- 29274796 TI - [Compliance with treatment in Wilson's disease: On the interest of a multidisciplinary closer follow-up]. AB - BACKGROUND: Compliance with treatment is very important for patients who suffer from Wilson's disease, a rare genetic disorder. They can benefit a long-life and effective treatment. The purpose of our study is to identify the level of compliance in Wilson's disease patients and features associated with compliance as well. METHODS: This is a prospective study carried out in the National Reference Center for Wilson Disease (based in Paris and Lyon) over a 8 months period. Patients were evaluated on the first (M0) and last month (M8) with a questionnaire evaluating the number of missed treatment doses, a self questionnaire collecting the reasons for non-compliance, and analogic scales analyzing the doctor-patient relationship and their behavior towards the treatment. The severity of depression symptoms was investigated by the Beck Depression Inventory (BDI). A detailed phone call interview was conducted by a psychologist every two months to evaluate their compliance and feeling. RESULTS: Thirty-nine patients were included. The mean age of patients was 34 years (+/ 9.9). At M0, 84.6% had a poor compliance with treatment. They were diagnosed more recently (P=0.049) with a higher proportion involving neurological disorders (P=0.007). Age, the type of treatment and the quality of the doctor-patient relationship were not associated with the outcome; 38.5% suffered from depressive symptoms. At M8, 56.8% of patients were poor compliants and 21.6% presented depressive symptoms. CONCLUSION: Wilsons's disease patients have important problems with compliance, without necessary being depressed. A close follow-up may help them become compliant, particularly those with neurological symptoms. PMID- 29274797 TI - An inverse method to estimate emission rates based on nonlinear least-squares based ensemble four-dimensional variational data assimilation with local air concentration measurements. AB - An inverse source estimation method is proposed to reconstruct emission rates using local air concentration sampling data. It involves the nonlinear least squares-based ensemble four-dimensional variational data assimilation (NLS-4DVar) algorithm and a transfer coefficient matrix (TCM) created using FLEXPART, a Lagrangian atmospheric dispersion model. The method was tested by twin experiments and experiments with actual Cs-137 concentrations measured around the Fukushima Daiichi Nuclear Power Plant (FDNPP). Emission rates can be reconstructed sequentially with the progression of a nuclear accident, which is important in the response to a nuclear emergency. With pseudo observations generated continuously, most of the emission rates were estimated accurately, except under conditions when the wind blew off land toward the sea and at extremely slow wind speeds near the FDNPP. Because of the long duration of accidents and variability in meteorological fields, monitoring networks composed of land stations only in a local area are unable to provide enough information to support an emergency response. The errors in the estimation compared to the real observations from the FDNPP nuclear accident stemmed from a shortage of observations, lack of data control, and an inadequate atmospheric dispersion model without improvement and appropriate meteorological data. The proposed method should be developed further to meet the requirements of a nuclear emergency response. PMID- 29274798 TI - Adapting the Caesium-137 technique to document soil redistribution rates associated with traditional cultivation practices in Haiti. AB - Large-scale deforestation, intensive land use and unfavourable rainfall conditions are responsible for significant continuous degradation of the Haitian uplands. To develop soil conservation strategies, simple and cost-effective methods are needed to assess rates of soil loss from farmland in Haiti. The fallout radionuclide caesium-137 (137Cs) provides one such means of documenting medium-term soil redistribution rates. In this contribution, the authors report the first use in Haiti of 137Cs measurements to document soil redistribution rates and the associated pattern of erosion/sedimentation rates along typical hillslopes within a traditional upland Haitian farming area. The local 137Cs reference inventory, measured at an adjacent undisturbed flat area, was 670 Bq m 2 (SD = 100 Bq m-2, CV = 15%, n = 7). Within the study area, where cultivation commenced in 1992 after deforestation, three representative downslope transects were sampled. These were characterized by 137Cs inventories ranging from 190 to 2200 Bq m-2. Although, the study area was cultivated by the local farmers, the 137Cs depth distributions obtained from the area differed markedly from those expected from a cultivated area. They showed little evidence of tillage mixing within the upper part of the soil or, more particularly, of the near-uniform activities normally associated with the plough layer or cultivation horizon. They were very similar to that found at the reference site and were characterized by high 137Cs activities at the surface and much lower activities at greater depths. This situation is thought to reflect the traditional manual tillage practices which cause limited disturbance and mixing of the upper part of the soil. It precluded the use of the conversion models normally used to estimate soil redistribution rates from 137Cs measurements on cultivated soils and the Diffusion and Migration conversion model frequently used for uncultivated soils was modified for application to the cultivated soils of the study area, in order to take account of the unusual local conditions. The model was also modified to take account of the fact that cultivation in the study area commenced in 1992, rather than predating the period of weapons test fallout which extended from the mid 1950s to the 1970s. Erosion rates on the upper parts of the hillside involved in the study were found to be relatively high and ca. -23 t ha-1 y-1 with low spatial variability. In the lower, flatter areas at the bottom of the slope, deposition occurred. Deposition rates were characterized by high spatial variability, ranging from 6.0 to 71 t ha-1 y-1. Soil redistribution rates of this magnitude are a cause for concern and there is an urgent need to implement soil conservation measures to ensure the longer-term sustainability of the local agricultural practices. PMID- 29274799 TI - Leadless pacing in a young patient with cardioinhibitory vasovagal syncope. AB - Vasovagal syncope is characterized by vasodilatation and/or bradycardia and thereby a fall in arterial BP and global cerebral perfusion in response to a trigger. Although it is a benign condition, patients with frequent and traumatic episodes need treatment in order to improve quality of life. We describe the case of a 17-years-old boy suffering from cardioinhibitory syncope. At the end of a complete negative cardiac and neurological examination, a loop recorder was implanted. During the subsequent follow-up the ILR documented a 9-s pause. To improve the patient's compliance, and considering cardioinhibitory syncope as a temporary condition, a leadless pacemaker was eventually implanted. PMID- 29274800 TI - Cardiac resynchronization therapy device implantation in a patient with persistent left superior vena cava without communicating innominate vein - should we proceed from the same side? - A dilemma revisited. AB - Persistent left superior vena cava (PLSVC) is an uncommon congenital anomaly. We report a case of implantation of cardiac resynchronization therapy - pacemaker (CRT-P) device in a 38-year-old lady with idiopathic dilated cardiomyopathy. After left axillary vein puncture, we faced an unexpected entry of left subclavian to PLSVC draining into the coronary sinus (CS). The target posterolateral vein which had been identified before, seemed to have an acute angle at its entry into the CS. Hence, at this stage we were in a dilemma, whether to switch to the right side or to continue from the same side. We continued the procedure from the left side and completed it successfully after some manipulation and improvisation. PMID- 29274801 TI - Three-dimensional electroanatomical mapping for non-pulmonary vein foci in a patient with complete situs inversus and dextrocardia. AB - In patients with atrial fibrillation (AF) having congenital anatomical abnormalities, such as complete situs inversus and dextrocardia, pulmonary vein isolation (PVI) ablation can be performed safety using a three-dimensional electroanatomical mapping system. However, it is not clear whether a three dimensional electroanatomical mapping system can be used to detect non-PV ectopic beats initiating AF in patients with complete situs inversus and dextrocardia. Here, we report a 21-year-old man with complete situs inversus and dextrocardia, who showed AF caused by non-PV ectopic beats. We successfully detected the origin of the triggered activity from the non-PV foci using three-dimensional electroanatomical mapping. PMID- 29274802 TI - Susceptibility testing and detection of beta-lactam resistance mechanisms in Enterobacteriaceae: a multicentre national proficiency study. AB - A nationwide study was developed to evaluate the ability of 60 Spanish clinical microbiology laboratories to predict the underlying beta-lactam resistance mechanisms of 12 Enterobacteriaceae strains (CCS01-CCS12). Results obtained by two reference laboratories were compared with those reported by the participant laboratories that used their own routine susceptibility testing methodology. Clinical and Laboratory Standards Institute (CLSI) interpretive criteria were used in 53.3% of centres, whilst 46.7% used European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Overall categorical agreement (CA) was 85.5%. Rates of very major errors (VME), minor errors (MinE) and major errors (ME) were 5%, 9.7% and 5.5%, respectively. The lowest CA values were obtained for carbapenems (56.7-78.1%). beta-Lactam/beta-lactamase inhibitors were also problematic compounds: VME for amoxicillin/clavulanic acid were 8% (EUCAST criteria) and MinE for piperacillin/tazobactam were 45.7% (CLSI criteria). OXA-48 (CCS02, CCS10, CCS11), VIM-1 (CCS09) and KPC-3 (CCS05) were correctly identified by 75-87%, 65% and 71% of centres, respectively. Strains with an extended spectrum beta-lactamase (ESBL) plus a carbapenemase (CCS03, CCS04, CCS06) were correctly detected in 32-68% of centres. Seven percent correct identifications were recorded for CCS08 (chromosomal K1 beta-lactamase hyperexpression plus IMP 8). Strains with permeability deficiencies [CCS07 (ACT-1 plus porin deficit) and CCS12 (TEM-24 plus porin deficit)] were correctly detected in 17% and 10% of centres, respectively. The TEM-1-producer (CCS01) was detected in 40% of centres. Microbiologists should be aware of new antibiotic resistance mechanisms, and these surveillance studies are particularly useful for this purpose and for the communication of such traits. PMID- 29274803 TI - A novel non-uniform control vector parameterization approach with time grid refinement for flight level tracking optimal control problems. AB - High quality control method is essential for the implementation of aircraft autopilot system. An optimal control problem model considering the safe aerodynamic envelop is therefore established to improve the control quality of aircraft flight level tracking. A novel non-uniform control vector parameterization (CVP) method with time grid refinement is then proposed for solving the optimal control problem. By introducing the Hilbert-Huang transform (HHT) analysis, an efficient time grid refinement approach is presented and an adaptive time grid is automatically obtained. With this refinement, the proposed method needs fewer optimization parameters to achieve better control quality when compared with uniform refinement CVP method, whereas the computational cost is lower. Two well-known flight level altitude tracking problems and one minimum time cost problem are tested as illustrations and the uniform refinement control vector parameterization method is adopted as the comparative base. Numerical results show that the proposed method achieves better performances in terms of optimization accuracy and computation cost; meanwhile, the control quality is efficiently improved. PMID- 29274804 TI - A novel biochemical marker for predicting the severity of ACS with unstable angina pectoris: Asprosin. PMID- 29274806 TI - Metabolic properties of the osteoclast. AB - Osteoclasts are defined as cells capable of excavating 3-dimensional resorption pits in bone and other mineralised tissues. They are derived from the differentiation/fusion of promonocytic precursors, and are usually large, multinucleated cells. In common with other cells from this myeloid lineage such as macrophages and dendritic cells, they are adapted to function in hypoxic, acidic environments. The process of bone resorption is rapid and is presumably highly energy-intensive, since osteoclasts must actively extrude protons to dissolve hydroxyapatite mineral, whilst secreting cathepsin K to degrade collagen, as well as maintaining a high degree of motility. Osteoclasts are well known to contain abundant mitochondria but they are also able to rely on glycolytic (anaerobic) metabolism to generate the ATP needed to power their activity. Their primary extracellular energy source appears to be glucose. Excessive accumulation of mitochondrial reactive oxygen species in osteoclasts during extended periods of high activity in oxygen-poor environments may promote apoptosis and help to limit bone resorption - a trajectory that could be termed "live fast, die young". In general, however, the metabolism of osteoclasts remains a poorly-investigated area, not least because of the technical challenges of studying actively resorbing cells in appropriate conditions. PMID- 29274807 TI - Deintensification of hypoglycaemic medications-use of a systematic review approach to highlight safety concerns in older people with type 2 diabetes. AB - IMPORTANCE: Intensive treatment of older people with diabetes is common placing them at increased risk of adverse events such as hypoglycaemia and hospitalisation for drug errors. Little is known about when, how or for whom to deintensify hypoglycaemic medications. OBJECTIVE: To explore the characteristics of patients for whom deintensification is appropriate and to determine the outcome of deintensification. EVIDENCE REVIEW: Medline, Google scholar and EmBase search from 1997 to present was performed using keywords relating to diabetes mellitus, polypharmacy, hypoglycaemia, hospitalisation, deintensification, deprescribing and reduction, simplification or withdrawal of hypoglycaemic medications. Only English language articles were selected. Articles were reviewed for relevance by abstract. A manual review of citations in retrieved articles was performed in addition to the electronic literature search. FINDINGS: Those who are over treated appear to be of older age group, frail with weight loss and have multiple medical morbidities especially renal impairment and dementia. Simplification, reduction or even complete withdrawal of hypoglycaemic medications in these patients appears to be feasible without deterioration of glycaemic control. CONCLUSIONS: Over treatment is common in frail older people with multiple comorbidities and deintensification appears safe in this group of patients. Current recommendations emphasise preventing underuse rather than overuse of medications, and therefore, a change in guidelines advice may be warranted. PMID- 29274808 TI - Usefulness of Individual Shear Rate Therapy, New Treatment Option for Patients With Symptomatic Coronary Artery Disease. AB - The aim of this study was to elucidate if patients with coronary artery disease (CAD), who fail to respond to revascularization procedures, can improve from individual shear rate therapy (ISRT). The ISRT is an adaptation of the external counterpulsation with lower individual treatment pressures based on Doppler ultrasound measurements during counterpulsation. In contrast to the external counterpulsation therapy, the ISRT is based on the detection of the individual intra-arterial shear rate. Here we report about the first clinical trial of 31 patients with CAD who were enrolled for 30 sessions of ISRT. To determine the therapeutic effect of ISRT we measured the exercise capacity, the arterial stiffness, the aortic wave reflection, and the 24-hour blood pressure before and after 30 treatment sessions. After 6 weeks of accomplished ISRT the walking distance during the 6-minute walking test extended by 78 m (p = 0.007). The total exercise duration in the exercise stress electrocardiogram increased by 84 seconds (p = 0.012) but not the stress intensity (p = 0.086). The pulse wave velocity decreased by 1.2 m/s (p = 0.004) and demonstrated a decrease in arterial stiffness. Pulse wave analysis results demonstrated a progressive decrease in central blood pressure by 12 mmHg (p = 0.008), in pulse pressure by 9 mmHg (p = 0.005), and in augmentation pressure by 5.3 mmHg (p = 0.004). The 24-hour blood pressure decreased systolic by 15 mmHg (p <0.001) and diastolic by 8 mmHg (p = 0.033). The patients also benefited subjectively followed by New York Heart Association and Canadian Cardiovascular Society classifications. In conclusion, the ISRT is an effective treatment for patients with CAD to improve cardiac fitness, arterial stiffness, and to reduce blood pressure. PMID- 29274805 TI - Prospective Validation That Subgenual Connectivity Predicts Antidepressant Efficacy of Transcranial Magnetic Stimulation Sites. AB - BACKGROUND: The optimal target in the dorsolateral prefrontal cortex for treating depression with repetitive transcranial magnetic stimulation (rTMS) remains unknown. Better efficacy has been associated with stimulation sites that are 1) more anterior and lateral and 2) more functionally connected to the subgenual cingulate. Here we prospectively test whether these factors predict response in individual patients. METHODS: A primary cohort (Boston, n = 25) with medication refractory depression underwent conventional open-label rTMS to the left dorsolateral prefrontal cortex. A secondary cohort (Michigan, n = 16) underwent 4 weeks of sham followed by open-label rTMS for nonresponders (n = 12). In each patient, the location of the stimulation site was recorded with frameless stereotaxy. Connectivity between each patient's stimulation site and the subgenual cingulate was assessed using resting-state functional connectivity magnetic resonance imaging from a cohort of healthy subjects (n = 1000) and confirmed using connectivity from patients with depression (n = 38). RESULTS: In our primary cohort, antidepressant efficacy was predicted by stimulation sites that were both more anterolateral (r = .51, p < .01) and more negatively correlated with the subgenual cingulate (r = -.55, p < .005). However, subgenual connectivity was the only independent predictor of response and the only factor to predict response to active (r = -.52, p < .05) but not sham rTMS in our secondary cohort. CONCLUSIONS: This study provides prospective validation that functional connectivity between an individual's rTMS cortical target and the subgenual cingulate predicts antidepressant response. Implications for improving the cortical rTMS target for depression are discussed. PMID- 29274809 TI - Antihyperglycemic and Metabolic Effects of Ranolazine in Patients With Diabetes Mellitus. AB - The antianginal drug ranolazine, because of its unique mechanism of action, has been shown to have antihyperglycemic effects. Here, we review the reports on the antihyperglycemic and metabolic effects of ranolazine. MEDLINE was searched from 2000 to October 1, 2016 using the terms ranolazine, antihyperglycemic, diabetes, cardiology, and antianginal. Studies and reviews were included if they were in English and provided relevant data to inform practicing clinicians. Ranolazine has been shown to be effective as an antihyperglycemic while utilized as monotherapy or in combination with traditional diabetic regimens. A total of 6 studies were included in this review, with 5 being randomized controlled trials and 1 being a retrospective study. Of the 6 studies, 4 directly measured differences between baseline hemoglobin A1c (HbA1c), another measured endothelium function, and lastly the retrospective study evaluated outpatient clinic visit utilization, all-cause emergency department visits, inpatient admissions, and length of stay in a cohort of patients with angina and diabetes. In conclusion, ranolazine, because of its unique mechanism of action, may have a niche in therapy for patients with chronic stable angina pectoris and diabetes mellitus. Ranolazine has been shown to have positive antihyperglycemic and metabolic effects in patients with uncontrolled HbA1c. PMID- 29274811 TI - Face recognition of full-bodied avatars by active observers in a virtual environment. AB - Viewing faces in motion or attached to a body instead of isolated static faces improves their subsequent recognition. Here we enhanced the ecological validity of face encoding by having observers physically moving in a virtual room populated by life-size avatars. We compared the recognition performance of this active group to two control groups. The first control group watched a passive reenactment of the visual experience of the active group. The second control group saw static screenshots of the avatars. All groups performed the same old/new recognition task after learning. Half of the learned faces were shown at test in an orientation close to that experienced during learning while the others were viewed from a new viewing angle. All observers found novel views more difficult to recognize than familiar ones. Overall, the active group performed better than both other groups. Furthermore, the group learning faces from static images was the only one to be at chance level in the novel-view condition. These findings suggest that active exploration combined with a dynamic experience of the faces to learn allow for more robust face recognition and point out the value of such techniques for integrating facial visual information and enhancing recognition from novel viewpoints. PMID- 29274810 TI - CIP2A is overexpressed in human endometrioid adenocarcinoma and regulates cell proliferation, invasion and apoptosis. AB - OBJECTIVE: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that stabilizes c-Myc and promotes cell proliferation and transformation. Here, we investigated the clinical significance and biological function of CIP2A in endometrial cancer. METHOD: CIP2A expression was assessed in normal endometrium, endometrial hyperplasia, endometrial atypical hyperplasia, and endometrioid adenocarcinoma tissues using immunohistochemistry, western blot, and RT-PCR. The effect of reduced CIP2A expression was assessed by siRNA knockdown in Ishikawa and An3ca endometrial cell lines. The roles of CIP2A in proliferation, apoptosis, and the cell cycle were assessed using CCK-8 assays, colony formation assays, and flow cytometry, respectively. RESULTS: Our results show that CIP2A expression was higher in endometrioid adenocarcinoma tissues and cell lines. Furthermore, CIP2A siRNA significantly reduced the proliferation rate and invasion of Ishikawa and An3ca cells, and induced a significant level of apoptosis in Ishikawa cells. Moreover, CIP2A depletion resulted in reduced c-Myc and cyclin D1 protein levels, and increased caspase-3 expression. CONCLUSIONS: CIP2A is overexpressed in endometrioid adenocarcinoma and CIP2A promotes the malignant growth and invasion,decrease apoptosis in entometrioid adenocarcinoma cell lines. These results validate that CIP2A plays an important role in the carcinogenesis of endometrioid adenocarcinoma and establishes CIP2A as a clinically relevant oncoprotein and may presents a promising therapeutic target for cancer treatment. PMID- 29274812 TI - Cytoprotective dihydronaphthalenones from the wood of Catalpa ovata. AB - Three previously undescribed dihydronaphthalenones, 7-hydroxycatalponol, (4S)-3,4 dihydro-4-hydroxy-2-[(2R)-2,3-dihydroxy-3-methylbutylidene]naphthalen-1(2H)-one, and (6S)-5,6-dihydro-6-hydroxy-2,2-dimethyl-2H-benzo[h]chromen-4(3H)-one and one phthalide, (+/-)-3-(5-hydroxy-5-methyl-2-oxohex-3-en-1-yl)isobenzofuran-1(3H) one, were isolated from the wood of Catalpa ovata G. Don (Bignoniaceae), together with six known compounds. The structures of the previously undescribed compounds were elucidated by interpretation of 1D and 2D NMR data. The absolute configurations of the dihydronaphthalenones were deduced by analysis of the ECD data and application of Mosher ester methodology. All isolates were investigated for their cytoprotective effects against hydrogen peroxide (H2O2)-induced oxidative damage in HepG2 cells. Moreover, the mRNA expression levels of antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO1) in HepG2 cells were examined by RT-PCR analysis. As a result, catalponol and epi-catalponol showed antioxidant activities via directly scavenging of intracellular ROS and inducing the antioxidant enzymes in vitro. PMID- 29274813 TI - Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan. AB - BACKGROUND: The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The present study included 222 consecutive mCRPC patients with progression during initial androgen receptor-axis-targeted agent (ARATA) therapy with either abiraterone acetate (AA) or enzalutamide (Enz). Of these 222 patients, 108 subsequently received an alternative ARATA (AA-to-Enz, n = 49; Enz-to-AA, n = 59) and 114 received docetaxel (DTX; AA-to-DTX, n = 54; Enz-to-DTX, n = 60). RESULTS: The prostate specific antigen (PSA) level in the 114 patients receiving DTX was significantly greater than that in the 108 patients receiving ARATA. However, no significant differences were found in the remaining parameters between the 2 groups. The PSA response rate, PSA progression-free survival (PFS), and overall survival (OS) during second-line therapy in the DTX group (n = 114) were significantly superior to those for the ARATA group (n = 108; PSA response rate, 42.1% vs. 21.3%; median PSA PFS, 7.2 vs. 4.2 months; median OS, 17.5 vs. 14.5 months). Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences (PSA response rate, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX; PSA PFS, AA-to-Enz vs. Enz-to-AA, AA-to-Enz vs. AA-to-DTX, Enz-to AA vs. AA-to-DTX, and Enz-to-AA vs. Enz-to-DTX; and OS, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX). Furthermore, the introduction of DTX was independently associated with improved PSA PFS, but not OS, on multivariate analysis. CONCLUSION: Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARATA, for mCRPC patients after failure of an initial ARATA. PMID- 29274814 TI - A clinical social worker's epilepsy treatment perspective. PMID- 29274815 TI - Antidepressants in people with epilepsy: A double-edge sword! PMID- 29274816 TI - Molecular determinants of loperamide and N-desmethyl loperamide binding in the hERG cardiac K+ channel. AB - Abuse of the common anti-diarrheal loperamide is associated with QT interval prolongation as well as development of the potentially fatal arrhythmia torsades de pointes. The mechanism underlying this cardiotoxicity is high affinity inhibition of the human ether-a-go-go-related gene (hERG) cardiac K+ channel. N Desmethyl loperamide is the major metabolite of loperamide and is a close structural relative of the parent molecule. To date no information is available regarding the affinity of N-desmethyl loperamide for human cardiac ion channels. The effects of N-desmethyl loperamide on various cloned human cardiac ion channels including hERG, KvLQT1/mink and Nav1.5 were studied and compared to that of the parent. N-Desmethyl loperamide was a much weaker (7.5-fold) inhibitor of hERG compared to loperamide. However, given the higher plasma levels of the metabolite relative to the parent, it is likely that N-desmethyl loperamide can contribute, at least secondarily, to the cardiotoxicity observed with loperamide abuse. We used the recently solved cryo-EM structure of the hERG channel together with previously published inhibitors, to understand the basis of the interactions as well as the difference that a single methyl plays in the hERG channel blocking affinities of these two compounds. PMID- 29274817 TI - Cytotoxicity and inhibition of leukemic cell proliferation by sesquiterpenes from rhizomes of Mah-Lueang (Curcuma cf. viridiflora Roxb.). AB - Curcuma cf. viridiflora Roxb., also known as Mah-Lueang in Thai, belongs to the Zingiberaceae family and is grown from rhizomes. The rhizome of the plant has been used for medicinal purposes, in particular, to treat paralysis in Thai traditional medicine. However, no biologically active compounds have been reported from Mah-Lueang yet. In this study, natural compounds were isolated from Mah-Lueang and structurally determined by spectroscopic methods, including electrospray ionization mass spectrometry and nuclear magnetic resonance. The four isolated compounds were identified as furanodiene (1), dehydrocurdione (2), germacrone-4,5-epoxide (3), and zedoarondiol (4). These sesquiterpenes were investigated for antileukemic activities against KG1a and Molt4 cells. Leukemic cell proliferation is regulated by the Wilms' tumor 1 (WT1) transcription factor. Compound 1 showed the strongest cytotoxicity against both KG1a and Molt4 cells. Noncytotoxic concentrations (20% inhibitory concentration values) of all compounds were able to decrease the WT1 protein expression and total cell numbers in both cell lines. The four compounds showed good inhibitory activities for WT1 protein expression. Compounds 3 and 4 showed excellent antileukemic activities for both cell lines. In summary, four sesquiterpene compounds with antileukemic activities against the KG1a and Molt4 cell lines were identified in Mah-Lueang extracts. PMID- 29274818 TI - Population Pharmacokinetics and Dosing Simulations of Ceftazidime in Chinese Neonates. AB - An accurate dosage determination is required in neonates when antibiotics are used. The adult data cannot be simply extrapolated to the pediatric population due to significant individual differences. We aimed to identify factors impacting ceftazidime exposure in neonates and to provide drug dosing guidance to clinicians. Forty-three neonates aged less than 60 days with proven or suspected infections were enrolled in this study. After intravenous administration, blood samples were collected, and plasma ceftazidime concentration was determined using a HPLC method. Pharmacokinetic data were fitted using a nonlinear mixed-effects model approach. One-compartmental model could nicely characterize the ceftazidime in vivo behavior. The covariate test found that the postmenstrual age (day) was strongly associated with systemic drug clearance (L/h), and the effect of body weight (kg) was identified as the covariate on distribution volume (L). Compared with the base model, the addition of covariates improved the goodness-of-fit of the final model. Model validation (bootstrap, visual predictive check, and prediction-corrected visual predictive check) suggested a robust and reliable pharmacokinetic model was developed. Personalized dosage regimens were provided based on model simulations. The intravenous dose should be adjusted according to postmenstrual age, body weight, and minimum inhibitory concentration. PMID- 29274819 TI - Proliferation, Metabolic Activity, and Adipogenic Differentiation of Human Preadipocytes Exposed to 2 Surfactants In Vitro. AB - Fat grafting is a pivotal technique for tissue repair. Adipose stromal cells, including preadipocytes, play a major role in the regenerative effects attributed to fat grafting. But the benefits are impaired by the low survival of the graft due to mechanical stress during harvesting, hypoxia, and nutrient deprivation. Nonionic surfactant molecules demonstrated their efficacy in preventing and repairing mechanical damage on the cellular membrane, but it is poorly understood if and how they affect cellular viability, proliferation, and differentiation. We investigated the influence of 2 nonionic surfactants, Kolliphor(r)P188 and Kolliphor(r)EL, on cultured human preadipocytes. We analyzed their effects on metabolic activity, cell number, adipogenic differentiation, and secretion of growth factors. Kolliphor(r)P188 increased metabolic activity, while it did not influence proliferation and differentiation as well as growth factors release. Kolliphor(r)EL confirmed its cytotoxic effect at the highest concentrations applied. Contrariwise, treatment with lower concentrations significantly raised metabolic activity, induced adipogenesis, and increased insulin-like growth factor-1 and vascular endothelial growth factor secretion. The effect on differentiation was inhibited by blocking peroxisome proliferator-activated receptor gamma. Our results revealed important effects of surfactants on preadipocytes' survival, proliferation, death, and the interplay with their environment. Particularly Kolliphor(r)EL provides modes of action, which could recommend it for novel treatment to improve fat graft viability. PMID- 29274820 TI - Characterization and Stability of Trypanosoma cruzi 24-C4 (Tc24-C4), a Candidate Antigen for a Therapeutic Vaccine Against Chagas Disease. AB - Chagas disease due to chronic infection with Trypanosoma cruzi is a neglected cause of heart disease, affecting approximately 6-10 million individuals in Latin America and elsewhere. T. cruzi Tc24, a calcium-binding protein in the flagellar pocket of the parasite, is a candidate antigen for an injectable therapeutic vaccine as an alternative or a complement to chemotherapy. Previously, we reported that a genetically engineered construct from which all cysteine residues had been eliminated (Tc24-C4) yields a recombinant protein with reduced aggregation and improved analytical purity in comparison to the wild-type form, without compromising antigenicity and immunogenicity. We now report that the established process for producing Escherichia coli-expressed Tc24-C4 protein is robust and reproducibly yields protein lots with consistent analytical characteristics, freeze-thaw, accelerated, and long-term stability profiles. The data indicate that, like most proteins, Tc24-C4 should be stable at -80 degrees C, but also at 4 degrees C and room temperature for at least 30 days, and up to 7 15 days at 37 degrees C. Thus, the production process for recombinant Tc24-C4 is suitable for Current Good Manufacturing Practice production and clinical testing, based on process robustness, analytical characteristics, and stability profile. PMID- 29274821 TI - Estimation of Melting Points of Organics. AB - Unified physicochemical property estimation relationships is a system of empirical and theoretical relationships that relate 20 physicochemical properties of organic molecules to each other and to chemical structure. Melting point is a key parameter in the unified physicochemical property estimation relationships scheme because it is a determinant of several other properties including vapor pressure, and solubility. This review describes the first-principals calculation of the melting points of organic compounds from structure. The calculation is based on the fact that the melting point, Tm, is equal to the ratio of the heat of melting, DeltaHm, to the entropy of melting, DeltaSm. The heat of melting is shown to be an additive constitutive property. However, the entropy of melting is not entirely group additive. It is primarily dependent on molecular geometry, including parameters which reflect the degree of restriction of molecular motion in the crystal to that of the liquid. Symmetry, eccentricity, chirality, flexibility, and hydrogen bonding, each affect molecular freedom in different ways and thus make different contributions to the total entropy of fusion. The relationships of these entropy determining parameters to chemical structure are used to develop a reasonably accurate means of predicting the melting points over 2000 compounds. PMID- 29274822 TI - Predicting Protein-Protein Interactions of Concentrated Antibody Solutions Using Dilute Solution Data and Coarse-Grained Molecular Models. AB - Protein-protein interactions for solutions of an IgG1 molecule were quantified using static light scattering (SLS) measurements from low to high protein concentrations (c2). SLS was used to determine second osmotic virial coefficients (B22) at low c2, and excess Rayleigh profiles (Rex/K vs. c2) and zero-q structure factors (Sq=0) as a function of c2 at higher c2 for a series of conditions (pH, sucrose concentration, and total ionic strength [TIS]). Repulsive (attractive) interactions were observed at low TIS (high TIS) for pH 5 and 6.5, with increasing repulsions when 5% w/w sucrose was also present. Previously developed and refined coarse-grained antibody models were used to fit model parameters from B22 versus TIS data. The resulting parameters from low-c2 conditions were used as the sole input to multiprotein Monte Carlo simulations to predict high-c2Rex/K and Sq=0 behavior up to 150 g/L. Experimental results at high-c2 conditions were quantitatively predicted by the simulations for the coarse-grained models that treated antibody molecules as either 6 or 12 (sub) domains, which preserved the basic shape of a monoclonal antibody. Finally, preferential accumulation of sucrose around the protein surface was identified via high-precision density measurements, which self-consistently explained the simulation and experimental SLS results. PMID- 29274823 TI - Change in the temporal coordination of the finger joints with ulnar nerve block during different power grips analyzed with a sensor glove. AB - Ulnar nerve injuries can cause deficient hand movement patterns. Their assessment is important for diagnosis and rehabilitation in hand surgery cases. The purpose of this study was to quantify the changes in temporal coordination of the finger joints during different power grips with an ulnar nerve block by means of a sensor glove. In 21 healthy subjects, the onset and end of the active flexion of the 14 finger joints when gripping objects of different diameters was recorded by a sensor glove. The measurement was repeated after an ulnar nerve block was applied in a standardized setting. The change in the temporal coordination of the metacarpophalangeal (MCP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints with and without the nerve block was calculated within the same subject. In healthy subjects, the MCP joints started their movement prior to the PIP joints in the middle and ring finger, whereas this occurred in the reverse order at the index and little finger. The DIP joint onset was significantly delayed (P<0.01). With the ulnar nerve block, this coordination shifted towards simultaneous onset of all joints, independent of the grip diameter. The thumb and index finger were affected the least. With an ulnar nerve block, the PIP joints completed their movement prior to the MCP joints when gripping small objects (G1 and G2), whereas the order was reversed with larger objects (G3 and G4). The alterations with ulnar nerve block affected mainly the little finger when gripping small objects. With larger diameter objects, all fingers had a significant delay at the end of the PIP joint movement relative to the MCP and DIP joints, and the PIP and DIP joint sequence was reversed (P<0.01). Based on the significant changes in temporal coordination of finger flexion during different power grips, there are biomechanical effects of loss of function of the intrinsic muscles caused by an ulnar nerve block on the fine motor skills of the hand. This can be important for the diagnosis and rehabilitation of ulnar nerve lesions of the hand. PMID- 29274824 TI - Antituberculosis Drug-Associated DRESS: A Case Series. AB - BACKGROUND: Although antituberculosis drug-associated drug reaction with eosinophilia and systemic symptoms (DRESS) is rarely reported, its diagnosis should not be dismissed. Its management implies an early withdrawal of suspected drugs. OBJECTIVE: The objective of this study was to describe the characteristics of antituberculosis drug-associated DRESS and to identify the most likely involved drugs. METHODS: We searched for potential cases of DRESS with rifampicin, isoniazid, pyrazinamide, and ethambutol reported from January 1, 2005, to July 30, 2015, in the French pharmacovigilance database. A literature review was also performed. RESULTS: Sixty-seven cases of antituberculosis drug associated DRESS were analyzed (40 women and 27 men, median age of 61 years). Liver and kidneys were the most frequently involved organs. Two patients died from DRESS. Skin tests were performed in 11 patients and were positive in 8 cases. Discrepancies between epicutaneous tests and reintroduction of the culprit drugs were observed for 2 patients with a premature reintroduction of antituberculosis drugs in 1 case. Antituberculosis drugs were the only suspects in 20 cases. As for the literature data, rifampicin was the most suspected drug because of its larger indications, but in case of tuberculosis infections, isoniazid was the most suspected drug. CONCLUSIONS: We described the largest case series of first-line antituberculosis drug-associated DRESS in the literature. All antituberculosis drugs pose a risk of DRESS. An early withdrawal of the culprit drugs is essential. A drug allergy evaluation must be performed to optimize the second-line treatment of tuberculosis infection. PMID- 29274825 TI - Should Antibiotic Prophylaxis Be Routinely Used in Patients with Antibody Mediated Primary Immunodeficiency? PMID- 29274826 TI - Structure-activity modelling of essential oils, their components, and key molecular parameters and descriptors. AB - Many essential oil components are known to possess broad spectrum antimicrobial activity, including against antibiotic resistant bacteria. These compounds may be a useful source of new and novel antimicrobials. However, there is limited research on the structure-activity relationship (SAR) of essential oil compounds, which is important for target identification and lead optimization. This study aimed to elucidate SARs of essential oil components from experimental and literature sources. Minimum Inhibitory Concentrations (MICs) of essential oil components were determined against Escherichia coli and Staphylococcus aureus using a microdilution method and then compared to those in published in literature. Of 12 essential oil components tested, carvacrol and cuminaldehyde were most potent with MICs of 1.98 and 2.10 mM, respectively. The activity of 21 compounds obtained from the literature, MICs ranged from 0.004 mM for limonene to 36.18 mM for alpha-terpineol. A 3D qualitative SAR model was generated from MICs using FORGE software by consideration of electrostatic and steric parameters. An r2 value of 0.807 for training and cross-validation sets was achieved with the model developed. Ligand efficiency was found to correlate well to the observed activity (r2 = 0.792), while strongly negative electrostatic regions were present in potent molecules. These descriptors may be useful for target identification of essential oils or their major components in antimicrobial/drug development. PMID- 29274827 TI - Motility in the L3 stage is a poor phenotype for detecting and measuring resistance to avermectin/milbemycin drugs in gastrointestinal nematodes of livestock. AB - Motility is a commonly used in vitro phenotype for assessing anthelmintic activity of candidate compounds, and for detecting anthelmintic resistance in nematodes. Third-stage larvae (L3) of parasitic nematodes are commonly used in motility-based assays because L3 are simple to obtain and can remain viable in storage for extended periods. To improve the measurement of motility of microscopic stages of nematodes, our laboratory developed the Worminator, which quantitatively measures motility of parasites. Using the Worminator, we compared the dose-response characteristics of several avermectin/milbemycin (AM) compounds using L3 from both AM-susceptible and AM-resistant Cooperia spp. (abamectin, doramectin, eprinomectin, ivermectin, moxidectin) and Haemonchus contortus (eprinomectin, ivermectin, moxidectin). Concentrations tested with the Worminator ranged from 0.156 to 40 MUM. Differences in EC50 between AM-susceptible and AM resistant isolates of Cooperia spp. and Haemonchus contortus were small, with resistance ratios ranging from 1.00 to 1.34 for Cooperia spp., 0.99 to 1.65 for Haemonchus contortus. Larval migration inhibition assays were conducted using the same isolates and were equally ineffective for detection of resistance with resistance ratios less than 2.0. These results contrast with those of the Larval Development Assay where we obtained a resistance ratio of 16.48 using the same isolates of Haemonchus contortus. Moreover, even at the highest concentration tested (40 MUM), 100% inhibition of motility was never achieved and EC50 for Worminator assays were more than 100* higher than peak plasma levels achieved in vivo following treatment. These data demonstrate that dose-response characteristics for inhibition of motility in L3 of gastrointestinal nematodes of livestock do not significantly differ for AM-susceptible and AM-resistant isolates. These data challenge the suitability of motility as a phenotype for detecting and measuring resistance to AM drugs in gastrointestinal nematodes of livestock. PMID- 29274828 TI - Mean medical costs associated with vaginal and vulvar cancers for commercially insured patients in the United States and Texas. AB - OBJECTIVE: To estimate the average medical costs for vaginal and vulvar cancers in a commercially insured population in the U.S. and Texas. METHODS: 2011 2014U.S. MarketScan databases were used to estimate the average medical costs associated with vaginal and vulvar cancers. Women with newly diagnosed vaginal or vulvar cancer were matched to a comparison group without cancer using propensity score. Year 1 and year 2 costs after index diagnosis date were estimated. A generalized linear model was used to estimate the cost for censored months. The differential costs between groups were defined as the net costs associated with cancer diagnosis and treatment. RESULTS: The analysis included 355 women with vaginal cancer and 997 with vulvar cancer in the U.S. The year 1 and year 2 costs for vaginal cancer were $86,995 and $51,107, respectively. The year 1 and year 2 costs for vulvar cancer were $37,657 and $19,139, respectively. The major factors associated with higher monthly vaginal and vulvar cancer costs were higher Charlson Comorbidity Index score and higher medical costs prior to cancer diagnosis. Monthly costs for vaginal and vulvar cancers decreased rapidly from month 1 to month 6 after diagnosis and then remained stable. CONCLUSIONS: Seventy to 75% of all vaginal and vulvar cancers are due to HPV infections and mean medical costs associated with these cancers are substantial. These data will serve as key cost parameters in the economic evaluation of HPV vaccination dissemination and estimation of the long-term net economic benefit of promoting HPV vaccination. PMID- 29274829 TI - A 2009 fetal monitor recall that arguably should have been class I. PMID- 29274830 TI - The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids. AB - Uterine fibroids are common in women of reproductive age and can have a significant impact on quality of life and fertility. Although a number of international obstetrics/gynecology societies have issued evidence-based clinical practice guidelines for the management of symptomatic uterine fibroids, many of these guidelines do not yet reflect the most recent clinical evidence and approved indication for one of the key medical management options: the selective progesterone receptor modulator class. This article aims to share the clinical experience gained with selective progesterone receptor modulators in Europe and Canada by reviewing the historical development of selective progesterone receptor modulators, current best practices for selective progesterone receptor modulator use based on available data, and potential future uses for selective progesterone receptor modulators in uterine fibroids and other gynecologic conditions. PMID- 29274831 TI - Preoperative cesarean delivery intravenous acetaminophen treatment for postoperative pain control: a randomized double-blinded placebo control trial. AB - BACKGROUND: The United States currently has an opioid use disorder epidemic and research evaluating ways to minimize the use of opioids postsurgery are needed. One of these options is intravenous acetaminophen. If the use of preoperative intravenous acetaminophen was found to be effective for cesarean delivery, this would be beneficial for both the mother and breast-feeding neonate. OBJECTIVE: The primary study objective was to see if maternal opioid use was significantly less in the postoperative period for the study group that received 1 g of intravenous acetaminophen preoperatively compared with a control group that received placebo. The secondary objectives were to evaluate maternal length of stay and pain scores postoperatively, and assess the acetaminophen level in cord blood at delivery. STUDY DESIGN: This study was a prospective double-blinded randomized placebo-controlled trial. All pregnant patients who entered labor and delivery for a scheduled cesarean from November 2015 through April 2017 were eligible. Once consented, the medication was supplied by the pharmacy department, which performed the blinded randomization. Both the study drug of 1000 mg (1 g) of acetaminophen and placebo of normal saline were distributed as unmarked 100-mL bags administered over 15 minutes just prior to incision. No study personnel from the obstetric or anesthesia departments had any access to the randomization. Based on a power analysis using the published surgical data results, the goal was to obtain a minimum of 100 patients (50 patients in each arm). Primary data collection included demographics, number of opioid doses and morphine milligram equivalents administered to the patient postoperatively, length of stay postdelivery, pain scores, and newborn cord blood acetaminophen levels. Exclusions were maternal acetaminophen allergy, receipt of acetaminophen in the prior 24 hours, opioid use disorder, and hepatitis/liver impairment. Statistics involved chi2, Fisher exact, and the Student t test where appropriate and a P value <.05 was considered significant with all tests considered against a 2-sided alternative hypothesis. RESULTS: A total of 105 patients were evaluated with 51 who received intravenous acetaminophen and 54 who received placebo. The number of postoperative opioid medication doses administered to the study group was 11.1 (+/-8.9) compared with the number received by the control group of 10.5 (+/-8.5), P = .72. The morphine milligram equivalents in the study group was 94.2 (+/-40.4) compared with the control group of 90.7 (+/-42.1), P = .67. The length of stay and pain scores were not different between the groups. All of the umbilical cord blood values for acetaminophen were subtherapeutic. CONCLUSION: These data demonstrate that for cesarean delivery, the use of a preoperative 1-g intravenous dose of acetaminophen does not decrease the number of opioid medication doses or the morphine milligram equivalents administered postoperatively, nor does it decrease length of stay postcesarean. The administration of 1-g intravenous acetaminophen preoperatively does not result in elevated newborn cord blood levels (ClinicalTrials.govNCT02694653). PMID- 29274832 TI - Extremely preterm fetal sheep lung responses to antenatal steroids and inflammation. AB - BACKGROUND: The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood. OBJECTIVE: We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings. STUDY DESIGN: Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n = 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone + lipopolysaccharide; and (4) intraamniotic + intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation. RESULTS: Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs. CONCLUSION: Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response. PMID- 29274833 TI - Reply. PMID- 29274834 TI - ESPEN guideline clinical nutrition in neurology. AB - Neurological diseases are frequently associated with swallowing disorders and malnutrition. Moreover, patients with neurological diseases are at increased risk of micronutrient deficiency and dehydration. On the other hand, nutritional factors may be involved in the pathogenesis of neurological diseases. Multiple causes for the development of malnutrition in patients with neurological diseases are known including oropharyngeal dysphagia, impaired consciousness, perception deficits, cognitive dysfunction, and increased needs. The present evidence- and consensus-based guideline addresses clinical questions on best medical nutrition therapy in patients with neurological diseases. Among them, management of oropharyngeal dysphagia plays a pivotal role. The guideline has been written by a multidisciplinary team and offers 88 recommendations for use in clinical practice for amyotrophic lateral sclerosis, Parkinson's disease, stroke and multiple sclerosis. PMID- 29274835 TI - Underestimation of Unplanned Readmission after Colorectal Surgery: A National Analysis. AB - BACKGROUND: A significant proportion of postoperative readmission occurs at a different hospital and is therefore missed by current benchmarking. There are no national studies tracking readmission at different hospitals after colorectal surgery. This study aimed to determine the national burden of postoperative colorectal readmission, including readmission to a different hospital. STUDY DESIGN: The 2013 to 2014 Nationwide Readmissions Database was queried for adults undergoing colorectal surgery. The outcome of interest was 30-day unplanned readmission. Risk factors were identified. RESULTS: There were 79,098 patients admitted during the study period, with 7.1% (n = 5,591) readmitted and of those, 10.2% (n = 569) readmitted to a different hospital. Risk factors for readmission to a different hospital included admission to a high-volume hospital (odds ratio [OR] 1.49 [95% CI 1.17 to 1.91], p < 0.01), teaching hospital (OR 1.26 [95% CI 1.01 to 1.59], p = 0.04), nonmetropolitan hospital (OR 2.75 [95% CI 1.95 to 3.89], p < 0.01), hospitalization more than 7 days (OR 1.67 [95% CI 1.33 to 2.10], p < 0.01), and elective admission (OR 1.57 [95% CI 1.22 to 2.02], p < 0.01). Predictors of readmission to a different hospital were different than predictors of readmission. The most common reason for readmission was infection (28.4%). CONCLUSIONS: The burden of readmission to a different hospital after colorectal surgery is significant and disproportionately affects high-volume hospitals. Current quality metrics underestimate readmission, failing to capture the subpopulation readmitted to a different hospital. Interventions designed to prevent readmission need to be tailored to the unique risk factors described for different hospital readmission. Benchmarking not measuring different hospital readmission is inaccurate and should be modified. PMID- 29274836 TI - Outcomes in Children Undergoing Surgery for Congenital Pulmonary Airway Malformations in the First Year of Life. AB - BACKGROUND: Treatment of congenital pulmonary airway malformations (CPAMs) is generally surgical resection; however, there is controversy regarding the optimal timing of surgical intervention, especially in asymptomatic patients. STUDY DESIGN: Using the American College of Surgeons National Surgical Quality Improvement Program-Pediatric Participant Use Files from 2012 to 2015, children who underwent lung resection for CPAMs were identified. Outcomes in children who underwent lung resection during the neonatal period were compared with those who underwent resection beyond the neonatal period, but during the first year of life (non-neonates). RESULTS: A total of 541 patients (20.7% neonates and 79.3% non neonates) were identified. Neonates had higher rates of preoperative comorbidities and worse postoperative outcomes when compared with non-neonates (morbidity 19.6% vs 5.4%, p < 0.0001). On multivariable regression analysis, the presence of preoperative symptoms (defined as oxygen dependence or ventilatory support) was independently associated with increased morbidity (odds ratio 3.91 [range 1.6 to 9.57], p = 0.003). In a subgroup analysis of asymptomatic neonates compared with asymptomatic non-neonates, there was no difference in overall morbidity (7.4% vs 4.4%, p = 0.33). CONCLUSIONS: These data suggest that lung resection for CPAMs in the neonatal period in asymptomatic children are not associated with increased 30-day morbidity. The presence of preoperative symptoms was independently associated with increased morbidity in a multivariable regression model. More data are needed to better understand the long-term outcomes and better define the optimal timing of surgery in this patient population. PMID- 29274837 TI - Dedicated Operating Room Teams and Clinical Outcomes in an Enhanced Recovery after Surgery Pathway for Colorectal Surgery. AB - BACKGROUND: Our aim was to determine whether the establishment of a dedicated operating room team leads to improved process measure compliance and clinical outcomes in an Enhanced Recovery after Surgery (ERAS) program. Enhanced Recovery after Surgery programs involve the application of bundled best practices to improve the value of perioperative care. Successful implementation and sustainment of ERAS programs has been linked to compliance with protocol elements. STUDY DESIGN: Development of dedicated teams of anesthesia providers was a component of ERAS implementation. Intraoperative provider team networks (surgeons, anesthesiologists, and certified registered nurse anesthetists) were developed for all cases before and after implementation of colorectal ERAS. Four measures of centrality were analyzed in each network based on case assignments, and these measures were correlated with both rates of process measure compliance and clinical outcomes. RESULTS: Enhanced Recovery after Surgery provider teams led to a decrease in the closeness of anesthesiologists (p = 0.04) and significant increase in the clustering coefficient of certified registered nurse anesthetists (p = 0.005) compared with the pre-ERAS network. There was no significant change in centrality among surgeons (p = NS for all measures). Enhanced Recovery after Surgery designation among anesthesiologists and nurse anesthetists-whereby individual providers received an in-service on protocol elements and received compliance data was strongly associated with high compliance (>0.6 of measures; p < 0.001 for each group). In addition, high compliance was associated with a significant reduction in length of stay (p < 0.01), surgical site infection (p < 0.002), and morbidity (p < 0.009). CONCLUSIONS: Dedicated operating room teams led to increased centrality among anesthesia providers, which in turn not only increased compliance, but also improved several clinical outcomes. PMID- 29274838 TI - Metabolic Effect of Foregut Exclusion Demonstrated by the Impact of Gastrogastric Fistula on Recurrence of Diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) resolves in >80% of patients after Roux-en-Y gastric bypass (RYGB). It has been hypothesized that foregut exclusion is mechanistically important to this observation. This study aimed to determine whether gastrogastric (GG) fistula, with a loss of foregut exclusion, is associated with T2DM relapse, and to assess whether closure of GG fistula is associated with T2DM resolution. STUDY DESIGN: A matched cohort study of patients who experienced T2DM remission after RYGB. Cases (patients with GG fistula) were matched to controls (patients without GG fistula) based on age, BMI, weight regain, and duration from RYGB. Primary end point was T2DM relapse. Time-to-event analysis was performed to identify an association between GG fistula and time to T2DM resolution. RESULTS: One hundred and twenty-six patients (42 cases and 84 controls) were included. Cases experienced a higher rate of T2DM relapse than controls (48% vs 13%; odds ratio 18; p < 0.0001). On multivariable analysis, GG fistula remained a significant predictor of T2DM relapse after controlling for sex and insulin use (odds ratio 6.3; p = 0.02). Of the 42 cases, 20 experienced T2DM relapse, with 1 spontaneous resolution. Of 19, thirteen underwent fistula revision and experienced a higher rate of T2DM resolution than the nonrevision group (69% vs 0%; odds ratio 27; p = 0.036). Time to T2DM resolution was shorter in the revision group compared with the nonrevision group (p = 0.006). CONCLUSIONS: The RYGB patients with GG fistula have a higher rate of T2DM relapse, compared with those without GG fistula with similar BMI and weight regain. Successful fistula revision is associated with resolution of T2DM. PMID- 29274839 TI - Investigation of Financial Conflict of Interest among Published Ventral Hernia Research. AB - BACKGROUND: Discordance exists between author self-disclosure and the Open Payments Database in various surgical fields, but the effects of this discordance on study design and presentation are unknown. We hypothesized that, among ventral hernia publications, discordance exists between industry and physician self reported conflicts of interest (COIs); authors disclose relevant COIs; and disclosure and relevant COIs affect study favorability. STUDY DESIGN: We conducted a double-blinded, prospective, observational study of published articles. PubMed was searched in reverse chronological order for clinical articles pertaining to ventral hernias. Authors' self-disclosed conflicts were compared with those on the Open Payments Database. Two reviewers blinded to article disclosure status determined jointly whether the COIs were relevant to the article. Three blinded referees independently voted whether each article was favorable to discussed subject matter. The primary end point was study favorability. Secondary outcomes included disclosure status and relevance. RESULTS: One hundred articles were included. Compared with authors with no COIs, authors with a COI, self-disclosed or not, were twice as likely to write results favorable to industry. Of those with a COI, most of the articles had a relevant COI (37 of 45 [82.2%]), and 25% of relevant COIs were not disclosed by authors. Among authors with a relevant COI, study favorability remained unchanged at 68.5% (control: no COI 33.3%; p < 0.001). CONCLUSIONS: Within the ventral hernia literature, 70% of articles have a COI. Self-reporting of COI is discordant in 63% of articles. Twenty-five percent of relevant COI are not disclosed. Having a COI increases the chances that an article will cast a favorable impression on the company paying the authors by 200%. PMID- 29274840 TI - Open vs Closed Negative Pressure Wound Therapy for Contaminated and Dirty Surgical Wounds: A Prospective Randomized Comparison. AB - BACKGROUND: A new proprietary negative pressure wound device has been developed to apply negative pressure therapy to closed wounds (closed-NPWT). We postulated that closed-NPWT management of contaminated and dirty wounds would lead to faster wound healing and no significant difference in wound complications. STUDY DESIGN: An IRB approved, prospective randomized trial was performed. Patients were consented preoperatively, but not entered nor assigned treatment until intraoperative findings were known. Patients were randomly assigned to either open-NPWT or a wound closed with skin staples and external closed-NPWT. Primary outcome was time to complete wound healing, defined as complete epithelization of the wound. Secondary outcomes were wound complications including wound infection, seroma, and dehiscence. Statistical analysis was performed using chi-square test, Fisher exact test, t-test, and Wilcoxon Rank-Sum test with significance of p < 0.05. RESULTS: Twenty-five closed-NPWT and 24 open-NPWT patients were analyzed. There were no significant differences in sex, mean age, BMI, smoking history, steroid use, comorbidities, or indication for surgery in the 2 groups. One patient in the open-NPWT group and 2 patients in the closed-NPWT group developed a wound infection (p = 1.0). Four open-NPWT and 3 closed-NPWT patients died from complications unrelated to the wound. Wound healing occurred at a median of 48 days (range 6 to 126 days) for the open-NPWT group vs a median of 7 days (range 6 to 12 days) for the closed-NPWT group (p < 0.0001). CONCLUSIONS: Wound healing was significantly faster in contaminated and dirty wounds when managed with closed-NPWT. There was no difference in wound complications between the 2 treatment groups. This approach shows promise for closed management of contaminated and dirty wounds and warrants additional prospective studies with larger patient groups. PMID- 29274841 TI - Preoperative Risk Score and Prediction of Long-Term Outcomes after Hepatectomy for Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: Accurate prediction of prognosis for patients with intrahepatic cholangiocarcinoma (ICC) remains a challenge. We sought to define a preoperative risk tool to predict long-term survival after resection of ICC. STUDY DESIGN: Patients who underwent hepatectomy for ICC at 1 of 16 major hepatobiliary centers between 1990 and 2015 were identified. Clinicopathologic data were analyzed and a prognostic model was developed based on the regression beta-coefficients on data in training set. The model was subsequently assessed using a validation set. RESULTS: Among 538 patients, most patients had a solitary tumor (median tumor number 1; interquartile range 1 to 2) and median tumor size was 5.7 cm (interquartile range 4.0 to 8.0 cm). Median and 5-year overall survival was 39.0 months and 39.0%, respectively. On multivariable analyses, preoperative factors associated with long-term survival included tumor size (hazard ratio [HR] 1.12; 95% CI 1.06 to 1.18), natural logarithm carbohydrate antigen 19-9 level (HR 1.33; 95% CI 1.22 to 1.45), albumin level (HR 0.76; 95% CI 0.55 to 0.99), and neutrophil to lymphocyte ratio (HR 1.05; 95% CI 1.02 to 1.09). A weighted composite prognostic score was constructed based on these factors: [9 + (1.12 * tumor size) + (2.81 * natural logarithm carbohydrate antigen 19-9) + (0.50 * neutrophil to lymphocyte ratio) + (-2.79 * albumin)]. The model demonstrated good performance in the testing (area under the curve 0.696) and validation (0.691) datasets. The model performed better than both the T categories (area under the curve 0.532) and the cumulative stage classifications in the American Joint Committee on Cancer staging manual, 8th edition (area under the curve 0.559). When assessing risk of death within 1 year of operation, a risk score >=25 had a positive predictive value of 59.8% compared with a positive predictive value of 35.3% for American Joint Committee on Cancer staging manual, 8th edition T4 disease and 31.8% for stage IIIB disease. CONCLUSIONS: Postsurgical long-term outcomes could be predicted using a composite weighted scoring system based on preoperative clinical parameters. The preoperative risk model can be used to inform patient to provider conversations and expectations before operation. PMID- 29274842 TI - Antioxidant and anti-glycation capacities of some medicinal plants and their potential inhibitory against digestive enzymes related to type 2 diabetes mellitus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Plants preparations are used by traditional medicine in the treatment of various diseases, such as type-2 diabetes mellitus. Some medicinal plants are capable of controlling the complications of this metabolic disease at different levels, for example, providing antioxidant compounds that act against oxidative stress and protein glycation and others which are capable of inhibiting the catalysis of digestive enzymes and thus contribute to the reduction of hyperglycemia and hyperlipidemia. Our objective was to investigate the antioxidant and anti-glycation activities of some medicinal plants and their potential inhibitory against alpha-amylase, alpha glucosidase and pancreatic lipase activities. MATERIAL AND METHODS: Based on the ethnobotanical researches carried out by academic studies conducted at the Federal University of Uberlandia, ten plants traditionally used in the treatment of type-2 diabetes mellitus were selected. Ethanol (EtOH) and hexane (Hex) extracts of specific parts of these plants were used in enzymatic assays to evaluate their inhibitory potential against alpha-amylase, alpha-glucosidase and lipase, as well as their antioxidant (DPPH, ORAC and FRAP) and anti-glycation (BSA/fructose model) capacities. RESULTS: The results indicate that EtOH extract of four of the ten analyzed plants exhibited more than 70% of antioxidant and anti-glycation capacities, and alpha-amylase and lipase inhibitory activities; no extract was able to inhibit more than 40% the alpha-glucosidase activity. The EtOH extracts of Bauhinia forficata and Syzygium. cumini inhibited alpha-amylase (IC50 8.17 +/- 2.24 and 401.8 +/- 14.7 MUg/mL, respectively), whereas EtOH extracts of B. forficata, Chamomilla recutita and Echinodorus grandiflorus inhibited lipase (IC50 59.6 +/- 10.8, 264.2 +/- 87.2 and 115.8 +/- 57.1 MUg/mL, respectively). In addition, EtOH extracts of B. forficata, S. cumini, C. recutita and E. grandiflorus showed, respectively, higher antioxidant capacity (DPPH IC50 0.7 +/- 0.1, 2.5 +/- 0.2, 1.3 +/- 0.2 and 35.3 +/- 9.0 MUg/mL) and anti-glycation activity (IC50 22.7 +/- 4.4, 246.2 +/- 81.7, 18.5 +/- 2.8 and 339.0 +/- 91.0 MUg/mL). CONCLUSIONS: EtOH extracts of four of the ten species popularly cited for treatment of type 2 diabetes mellitus have shown promising antioxidant and anti-glycation properties, as well as the ability to inhibit the digestive enzymes alpha-amylase and lipase. Thus, our results open new possibilities for further studies in order to evaluate the antidiabetic potential of these medicinal plants. PMID- 29274843 TI - Oxaliplatin-induced changes in expression of transient receptor potential channels in the dorsal root ganglion as a neuropathic mechanism for cold hypersensitivity. AB - Transient receptor potential (TRP) receptors are involved in the development of chemotherapy-induced peripheral neuropathic pain, which is a common side effect of selected chemotherapeutic agents such as oxaliplatin. However, the precise contribution of TRPs to this condition remains unknown. Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, so we used a preclinical model of oxaliplatin-induced cold hypersensitivity in rats to determine the effects of oxaliplatin on TRP channels. To this end, immunohistochemistry was used to examine TRP vanilloid 1 (TRPV1), TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) expression in the rat dorsal root ganglion (DRG) after 4days of oxaliplatin treatment. Behavioral assessment using the acetone spray test showed that oxaliplatin significantly increased acute cold hypersensitivity after 4days of treatment. Double-staining immunohistochemistry showed that 4days after oxaliplatin treatment, there was increased co-expression of TRPA1 and TRPV1 in isolectin B4-positive small-sized DRG neurons, as well as a significant increase in the co-localization of TRPM8 and neurofilament 200 in medium-sized DRG neurons. In addition, in situ hybridization revealed that TRPV1 protein was co expressed with TRPA1 mRNA on day 4 after oxaliplatin administration. Thus, at an early stage following oxaliplatin treatment there is an increased expression of TRPA1 and TRPV1 in small-sized DRG neurons and of TRPM8 in medium-sized DRG neurons. Collectively, these changes may contribute to the development of oxaliplatin-induced peripheral neuropathic pain. PMID- 29274844 TI - Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein. AB - Currently, there are no therapeutic alternatives to DNA polymerase inhibitors to treat human cytomegalovirus (HCMV) infections, a major threat for immunocompromised patients and pregnant women. Here, we explored the potential to repurpose manidipine dihydrochloride (MND), a calcium antagonist clinically approved to treat hypertension, as a new anti-HCMV agent. MND emerged in a previous drug repurposing screen to find early inhibitors of HCMV replication, and now we confirm that it inhibits in the low micromolar range the replication of different HCMV strains, including clinical isolates and viruses resistant to approved DNA polymerase inhibitors. The antiviral activity of MND is specific for HCMV over different both DNA and RNA viruses. Further experiments in HCMV infected cells testing the effects of MND on viral DNA synthesis and viral proteins expression revealed that it halts the progression of the virus cycle prior to viral DNA replication and E genes expression, but after IE proteins expression. According to these results, we observed that the overall antiviral activity of MND involves a specific interference with the transactivating functions of the viral Immediate-Early 2 (IE-2) protein, an essential viral transcription factor required for the progression of HCMV replication. Given that the inhibitory concentration against HCMV is in the range of clinically relevant concentrations of MND in humans, and the mechanism of action differs from that of the other available therapeutics, this already approved drug is an attractive candidate for repurposing in alternative anti-HCMV therapeutic protocols. PMID- 29274845 TI - Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening. AB - Zika virus (ZIKV), an emerging arbovirus, has become a major human health concern globally due to its association with congenital abnormalities and neurological diseases. Licensed vaccines or antivirals against ZIKV are currently unavailable. Here, by employing a structure-based approach targeting the ZIKV RNA-dependent RNA polymerase (RdRp), we conducted in silico screening of a library of 100,000 small molecules and tested the top ten lead compounds for their ability to inhibit the virus replication in cell-based in vitro assays. One compound, 3 chloro-N-[({4-[4-(2-thienylcarbonyl)-1-piperazinyl]phenyl}amino)carbonothioyl]-1 benzothiophene-2-carboxamide (TPB), potently inhibited ZIKV replication at sub micromolar concentrations. Molecular docking analysis suggests that TPB binds to the catalytic active site of the RdRp and therefore likely blocks the viral RNA synthesis by an allosteric effect. The IC50 and the CC50 of TPB in Vero cells were 94 nM and 19.4 MUM, respectively, yielding a high selective index of 206. In in vivo studies using immunocompetent mice, TPB reduced ZIKV viremia significantly, indicating TPB as a potential drug candidate for ZIKV infections. PMID- 29274846 TI - Increased postnatal concentrations of pro-inflammatory cytokines are associated with reduced IGF-I levels and retinopathy of prematurity. AB - OBJECTIVE: Retinopathy of prematurity (ROP) is a multifactorial disease linked to low insulin-like growth factor (IGF)-I levels and perhaps to postnatal inflammation. Here, we investigated the longitudinal postnatal serum concentrations of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in relation to IGF-I levels and ROP. DESIGN: The study cohort included 52 infants born before 31 gestational weeks. The infants were screened for ROP and classified as non-ROP (n=33), non-proliferative ROP (stages 1 and 2; n=10), or proliferative ROP (stage 3, all treated for ROP; n=9). Blood samples were collected at birth, 24h after birth, and then weekly until at least 36weeks postmenstrual age (PMA) (i.e., up to 13weeks after birth). Circulating levels of IL-6 and TNF-alpha were evaluated in relation to circulating IGF-I levels and ROP. RESULTS: IL-6 levels negatively correlated with IGF-I levels between 5 and 8weeks after birth, (p<0.01 to p<0.05). At birth, the IL-6 and TNF-alpha levels were similar independent of later ROP. Twenty-four hours after birth, both IL-6 and TNF-alpha levels had increased in infants later treated for ROP (p<0.05). Postnatal, infants treated for ROP had higher IL-6 levels than infants without ROP. CONCLUSIONS: The pro-inflammatory response is associated with low IGF-I levels and the development of ROP. PMID- 29274847 TI - Comparison between euglycemic hyperinsulinemic clamp and surrogate indices of insulin sensitivity in children with growth hormone deficiency. AB - OBJECTIVE: Data about the impact of growth hormone treatment (GHT) on insulin sensitivity in children are quite controversial, due to the different surrogate indices that have been used. DESIGN: We evaluated insulin sensitivity through the euglycemic hyperinsulinemic clamp, considered the gold standard technique, in 23 children affected by growth hormone deficiency (GHD) at baseline and after 12months of GHT and in 12 controls with short stature at baseline, and we compared the clamp-derived index (M-value) with the most commonly used surrogate index of insulin sensitivity, as ISI Matsuda, and with circulating plasma markers of insulin sensitivity, as adiponectin and resistin levels. RESULTS: At baseline, no significant difference in all metabolic parameters between GHD children and control subjects was found. After 12months of GHT, GHD children showed a significant increase in fasting insulin (p<0.001) and resistin (p=0.028) and a decrease in ISI Matsuda (p<0.001) and M-value (p<0.001), without significant change in fasting glucose, HbA1c and adiponectin. In GHD children, M-value showed a significant but weak correlation with ISI Matsuda (rho 0.418, p=0.047) at baseline, while no correlation with other parameters was found. After 12months of GHT, M-value did not show any significant correlation with any other metabolic parameter analyzed. CONCLUSIONS: This study highlights the limit of the evaluation of insulin sensitivity performed through surrogate indices or circulating markers, which may lead to controversial data and do not correlate with the gold standard technique to evaluate insulin sensitivity. PMID- 29274848 TI - Mirror neuron system activation in children with developmental coordination disorder: A replication functional MRI study. AB - BACKGROUND: It has been hypothesised that abnormal functioning of the mirror neuron system (MNS) may lead to deficits in imitation and the internal representation of movement, potentially contributing to the motor impairments associated with developmental coordination disorder (DCD). AIMS: Using fMRI, this study examined brain activation patterns in children with and without DCD on a finger adduction/abduction task during four MNS activation states: observation; motor imagery; execution; and imitation. METHODS AND PROCEDURES: Nineteen boys (8.25-12.75 years) participated, including 10 children with DCD (<=16th percentile on MABC-2; no ADHD/ASD), and nine typically developing controls (>=25th percentile on MABC-2). OUTCOMES AND RESULTS: Even though children with DCD displayed deficits behaviourally on imitation (Sensory Integration & Praxis Test Subtests) and motor imagery assessments prior to scanning, no differences in MNS activation were seen between the DCD and control groups at a neurological level, with both groups activating mirror regions effectively across conditions. Small clusters of decreased activation during imitation were identified in non mirror regions in the DCD group, including the thalamus, caudate, and posterior cingulate - regions involved in motor planning and attentional processes. CONCLUSIONS AND IMPLICATIONS: The results of this study do not provide support for the MNS dysfunction theory as a possible causal mechanism for DCD. Further research to explore attentional and motor planning processes and how they may interact at a network level may enhance our understanding of this complex disorder. PMID- 29274849 TI - Predictors of carotid plaque progression over a 4-year follow-up in the Reykjavik REFINE-study. AB - BACKGROUND AND AIMS: Carotid plaque is an arterial marker suggested as a surrogate end point for cardiovascular disease. The aim of this study was to examine the association of risk factors at visit 1 with plaque formation and progression of total plaque area (TPA) during follow-up. METHODS: We examined 1894 participants (50-69 years of age) in the population-based REFINE (Risk Evaluation For INfarct Estimates)-Reykjavik study. RESULTS: Among those with no plaque at baseline, plaque formation was associated with low density lipoprotein, sex, waist, former smoker and physical activity. Furthermore, both the Icelandic Heart Association (IHA) coronary heart disease (CHD) risk score and the atherosclerotic cardiovascular disease (ASCVD) risk score were highly associated with plaque formation in these individuals (p < 0.001) and a better cardiovascular health score was protective. In those with plaque present at baseline, metabolic syndrome was associated with increased risk, while older age and statin use were associated with reduced risk of new plaque formation. Statin use was the only factor associated with the relative TPA progression, where participants not on treatment had 5.7% (p=0.029) greater rate of progression compared with statin users. CONCLUSIONS: A number of conventional risk factors at visit 1 were individually associated with plaque formation, also when combined into CHD and ASCVD risk scores, but not with the relative progression in TPA. Medical intervention with statins can reduce the relative progression rate of TPA in the general population with low grade of atherosclerosis, supporting statin use to slow progression of atherosclerosis. PMID- 29274850 TI - Latin American research in rabbit transmitted zoonoses at the beginning of the "Rabbit Plan" in Venezuela: ?Are we prepared for a new outbreak? PMID- 29274851 TI - Climate patterns and mosquito-borne disease outbreaks in South and Southeast Asia. AB - BACKGROUND: Vector-borne infectious diseases, particularly mosquito-borne, pose a substantial threat to populations throughout South and Southeast Asia. Outbreaks have affected this region several times during the early years of the 21st century, notably through outbreaks of Chikungunya and Dengue. These diseases are believed to be highly prevalent at endemic levels in the region as well. With a changing global climate, the impacts of changes in ambient temperatures and precipitation levels on mosquito populations are important for understanding the effects on risk of mosquito-borne disease outbreaks. This study aims to make use of a large data set to determine how risk of mosquito-borne infectious disease outbreaks relates to the highest monthly average temperature and precipitation for each year in South and Southeast Asia. METHODS: Generalized additive models were used in a marked point process to fit nonlinear trends relating temperature and precipitation to outbreak risk, fitting splines for temperature and precipitation. Confounding factors for nation affluence, climate type, and ability to report outbreaks were also included. RESULTS: Parabolic trends for both temperature and precipitation were observed relating to outbreak risk. The trend for temperature, which was significant, showed that outbreak risk peaks near 33.5 degrees C as the highest monthly average temperature. Though not significant, a trend for precipitation was observed showing risk peaking when the highest monthly average precipitation is 650mm. CONCLUSIONS: Peak levels of temperature and precipitation were identified for outbreak risk. These findings support the notion of a poleward shift in the distribution of mosquitoes within this region rather than a poleward expansion in geographic range. PMID- 29274852 TI - Two-stage Anaerobic Membrane Bioreactor (AnMBR) system to reduce UV absorbance in landfill leachates. AB - Landfill leachate typically contains UV-quenching organics, which hinder disinfection at POTWs. This study tested a 2-stage submerged AnMBR for the degradation of UV-absorbing compounds in landfill leachate. Leachate was treated in a thermophilic reactor (55 +/- 2 degrees C) followed by a mesophilic AnMBR (37 +/- 1 degrees C), with HRTs of 25 +/- 5 days and 40 +/- 5 days respectively. Solids were not wasted, in order to promote biomass accumulation. COD, Organic carbon, and UV254 absorbance were monitored over 13 months of operation. Known UV quenching compounds, including humic acids, fulvic acids and hydrophilic matter, were reduced by 55%. Molecular weight distribution analyses revealed that the thermophilic reactor hydrolyzed organic carbon >100 KDa into smaller fractions, which were removed in the AnMBR. The system consistently removed 50% of the total UV absorbance. This promising, new enhanced biological process may provide landfills with a feasible pretreatment alternative to expensive chemical oxidation or RO processes before discharging leachate into sewers. PMID- 29274853 TI - Improved levulinic acid production from agri-residue biomass in biphasic solvent system through synergistic catalytic effect of acid and products. AB - In this study, levulinic acid (LA) was produced from rice straw biomass in co solvent biphasic reactor system consisting of hydrochloric acid and dichloromethane organic solvent. The modified protocol achieved a 15% wt LA yield through the synergistic effect of acid and acidic products (auto-catalysis) and the designed system allowed facile recovery of LA to the organic phase. Further purification of the resulting extractant was achieved through traditional column chromatography, which yielded a high purity LA product while recovering ~85% wt. Upon charcoal treatment of the resultant fraction generated an industrial grade target molecule of ~99% purity with ~95% wt recovery. The system allows the solvent to be easily recovered, in excess of 90%, which was shown to be able to be recycled up to 5 runs without significant loss of final product concentrations. Overall, this system points to a method to significantly reduce manufacturing cost during large-scale LA preparation. PMID- 29274854 TI - Removal of antibiotic sulfamethoxazole by anoxic/anaerobic/oxic granular and suspended activated sludge processes. AB - This study investigates the removal of the antibiotic sulfamethoxazole (SMX) in two sets of anoxic/anaerobic/oxic sequencing batch reactors inoculated with either suspended or granular activated sludge. Continuously, for three months, 2 MUg/L SMX was spiked into the reactor feeds in a synthetic municipal wastewater with COD, total nitrogen (TN) and total phosphorous (TP) of 400, 43 and 7 mg/L, respectively. The presence of SMX had no significant impact on treatment performance of the suspended and granular biomass. After 12 h of hydraulic retention time, SMX removal efficiencies of 84 and 73% were obtained for the granular and suspended biomass, respectively. Mixing without aeration did not remove SMX, confirming the insignificance of SMX removal via sorption. The pseudo first order SMX removal rate constants in the granular and suspended biomass were 2.25 +/- 0.30 and 1.34 +/- 0.39 L/gVSS.d, respectively. The results suggest that granules with advantages such as elevated biomass retention and greater biomass concentration could be effective for the removal of this class of antibiotics. PMID- 29274855 TI - Influence of biochar on volatile fatty acids accumulation and microbial community succession during biosolids composting. AB - The impact of biochar amendment on volatile fatty acids (VFAs) and odor generation during the biosolids-wheat straw composting was investigated. Five treatments were design using the same mixture of biosolids-wheat straw with different dosage of biochar blending (2%, 4%, 8% and 12% on dry weight basis) and without biochar applied treatment served as control. The results of VFAs and Odour Index (OI) profile designated that compost with 8-12% biochar became more rapidly humified with less quantity of VFAs and OI generation content compared to control. Consequently, the VFAs degrading and total bacterial abundance are also significantly higher recorded in 8-12% biochar than 2% biochar and control. In addition, 8-12% biochar applied treatment has significantly maximum close correlation among the all physicochemical and gaseous emission parameters. Finally, results designated that higher dosage of biochar (8-12% biochar) was more feasible approach for biosolids composting. PMID- 29274856 TI - Effect of biochar on bio-electrochemical dye degradation and energy production. AB - The effect of coconut shell biochar on dye degradation in a microbial fuel cell (MFC) was investigated in the present study. Two different doses of biochar (0.5 g and 1 g) and one control without bio-char were studied. The highest COD removal efficiency was about 77.7% (0.5 g biochar), maximum current (1.07 mA) and voltage (722 mV) were obtained with 1 g biochar. Biofilm optical microscopy characterization revealed the micro colonies intricate plate-like structures. High adsorbent dosage might provide a high surface area for biofilm to generate electricity. BET results of coconut shell biochar showed the maximum surface area of 0.9669 m2/g and macroporosity (0.0032 cm3/g). The overall results highlighted the possibility of using biochar as an additive in MFC for efficient dye degradation. PMID- 29274857 TI - Phosphoric acid based pretreatment of switchgrass and fermentation of entire slurry to ethanol using a simplified process. AB - Switchgrass (Alamo) was pretreated with phosphoric acid (0.75 and 1%, w/w) at three temperatures (160, 175 and 190 degrees C) and time (5, 7.5 and 10 min) using a steam gun. The slurry after pretreatment was liquefied by enzymes and the released sugars were fermented in a simultaneous saccharification and co fermentation process to ethanol using ethanologenic Escherichia coli strain SL100. Among the three variables in pretreatment, temperature and time were critical in supporting ethanol titer and yield. Enzyme hydrolysis significantly increased the concentration of furans in slurries, apparently due to release of furans bound to the solids. The highest ethanol titer of 21.2 +/- 0.3 g/L ethanol obtained at the pretreatment condition of 190-1-7.5 (temperature-acid concentration-time) and 10% solids loading accounted for 190 +/- 2.9 g ethanol/kg of raw switch grass. This converts to 61.7 gallons of ethanol per ton of dry switchgrass, a value that is comparable to other published pretreatment conditions. PMID- 29274858 TI - Evaluation of microbial dynamics during post-consumption food waste composting. AB - The objective of present study was to evaluate the efficacy of bacterial consortium to boost the microbial population and enzyme activities during post consumption food waste (PCFWs) composting. Three treatments of PCFWs mixed with saw dust and 10% zeolite (dry weight basis) was design, where treatments T-2 and T-3 were applied with two distinctive bacterial consortium, respectively, while T 1 was served as control. The results showed that total aerobic proteolytic, amylolytic, cellulolytic, oil degrading and total aerobic bacteria populations were significantly higher in treatment T2 and T3 than T1. Consequently, the selected hydrolytic enzymes were also higher in T2 and T3 than T1, whose apparently gave the interesting information about rate of decomposition and end product stability. Furthermore, T2 and T3 showed significant correlations between the enzymatic activities and microbial population with other physico-chemical parameters. Based on germination assays and CO2-C evolution rate, T2 and T3 were considered phytotoxic free and highly stable final compost on day 56. PMID- 29274860 TI - Primary pyomyositis in children. AB - BACKGROUND: Pyomyositis (PM) is defined as a primary pyogenic infection of the striated skeletal muscle; although it has many dystrophic musculoskeletal complications, it is always misdiagnosed by many orthopedic surgeons. HYPOTHESIS: PM is rare in temperate climates and usually considered to be a tropical disease, until recent times, after globalization, it is possible to occur in the subtropical climate as in our country. MATERIAL AND METHODS: In the present series, the results of 15 children patients with primary pyomyositis have been reviewed. In five out of them, conservative treatment protocol alone which has been by intravenous and oral antibiotics therapy was effective. The remaining ten patients with confirmed abscess formation needed invasive procedures which have been percutaneous US-guided drainage in two patients and an open surgical drainage in the remaining 8 patients. RESULTS: Conservative treatment was successful in five cases with marked improvement within 3 days, but in the other ten patients who needed surgical treatment, all were effectively treated except three out of them who were complicated as follows; elbow stiffness in one case, hip joint septic arthritis with epiphysitis in the second case and osteomyelitis of the lower femoral end with knee joint septic arthritis in last one. DISCUSSION: Both clinical picture and laboratory investigation of PM are not specific and resembled many other differential diagnoses so the proper imaging study is of valuable importance needs to be accurately identified and treated to avoid its delayed complications. CONCLUSION: In children complaining of joint pain or muscle aches and septic-appearing, pyomyositis should be considered in the differential diagnosis. MRI is the most valuable tool for diagnosis of PM. Early diagnosis, the use of appropriate antibiotic therapy and complete drainage of the purulent material are important factors for successful treatment that leads to complete resolution of PM. LEVEL OF EVIDENCE: IV. PMID- 29274859 TI - Variable tibiofemoral articular contact stress in fixed-bearing total knee arthroplasties. AB - BACKGROUND: Rotational allowance at the tibiofemoral joint would be required during deep flexion. However, the amount of flexion and rotation has not been investigated in modern total knee arthroplasty (TKA) designs. The present study aimed to determine the contact stress in five posterior-stabilized fixed-bearing TKA designs. HYPOTHESIS: We hypothesized that the contact area and stresses at the tibiofemoral articular surfaces vary according to the type of implant design and tested condition. MATERIALS AND METHODS: The contact area and mean and peak contact stresses at the tibiofemoral articular surfaces were determined when a compressive load of 1200N was applied to a NexGen LPS Flex, Scorpio NRG, Genesis II, PFC Sigma, and Foundation implant. Measurements were performed at 0 degrees and 45 degrees flexion with 0 degrees , 5 degrees , 10 degrees , and 15 degrees rotation, and at 90 degrees and 135 degrees flexion with 0, 5 degrees , 10 degrees , 15 degrees , and 20 degrees rotation. RESULTS: The LPS Flex showed that the femoral component could not achieve 20 degrees rotation at 135 degrees flexion. The Scorpio NRG showed less than 20MPa of contact stress at all conditions. The Genesis II showed higher contact stress than 20MPa at 135 degrees flexion with 20 degrees rotation. The PFC Sigma showed that the femoral component could not achieve >10 degrees rotation at any flexion angle. The Foundation showed more than 20MPa of contact stress at 90 degrees flexion with 20 degrees rotation and at 135 degrees flexion with 10 degrees , 15 degrees , and 20 degrees rotation. DISCUSSION: Surgeons should be more aware of the variable contact conditions of the tibiofemoral articular surfaces in individual TKA designs. LEVEL OF EVIDENCE: Level IV, basic science study. PMID- 29274861 TI - Hybrid total hip arthroplasty for multiple epiphyseal dysplasia. AB - BACKGROUND: Multiple Ephiphyseal Dysplasia (MED) is a rare autosomal dominant skeletal dysplasia that causes deformation of the epiphysis of the involved joints. The hips are invariably affected and symptoms due to incapacitating early onset degenerative hip disease often begin between the second and fourth decade of life. Literature regarding the clinical and radiographical outcomes after total hip arthroplasty in this young population are very scarce. Hypothesis in patients with multiple epiphyseal dysplasia and early onset degenerative hip disease, hybrid total hip arthroplasty is a safe and reliable procedure. PATIENTS AND METHODS: We followed 10 hybrid total hip arthroplasties in 6 patients with respect to the early and medium term complications. The average age at surgery was 32 years old (17 to 41). All stems were cemented polished straight tapered stems, all cups were porous coated uncemented cups. The mean duration of follow up was 10.3 (7-14, SD2.8) years. Clinical outcomes were measured using the Charnley modification of the Merle d'Aubigne-Postel grading system and VAS scores. RESULTS: No early complications and no revisions occurred and patients significantly improved for pain, function and mobility. The Charnley, Merle d'Aubigne and Postel hip scores significantly improved from 9.6 points pre operatively (range: 8-11 points) to 17 points (range: 16-18 points) and the VAS score significantly improved after surgery from respectively 7 at rest and 8.5 during activity preoperatively to 1 at rest and 1.5 during activity postoperatively. Radiographic evaluation showed no cases of radiolucency around the cemented femoral components. No migration or subsidence of the components was noted. With regard to the acetabular component, osteolysis was noted in 4 hips, but serial radiographs showed no progression or migration of the component and the patients were completely pain free. CONCLUSION: Hybrid total hip arthroplasty is a viable treatment option in multiple epiphyseal dysplasia patients, with excellent mid-term clinical and radiographical outcomes. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 29274862 TI - Percutaneous minimally invasive repair of acromioclavicular joint dislocation using cannulated screws under ultrasonic vs. C-arm navigation: A prospective trial. AB - INTRODUCTION: To compare percutaneous minimally invasive repair (PMIR) of acute acromioclavicular (AC) joint dislocation under ultrasound guidance (PMIR-UN) vs. C-arm navigation (PMIR-CN). HYPOTHESIS: PMIR-UN has similar functional and radiographic outcomes as PMIR-CN. MATERIALS AND METHODS: We treated 48 patients with acute grade III or V AC joint dislocation with surgical reduction and fixation with Kirschner wires and cannulated screws. The patients were randomly divided into a PMIR-UN group (n=24) and a PMIR-CN group (n=24). We assessed functional outcomes, operative duration, incision length, and intraoperative radiation exposure. Shoulder joint function was evaluated with the Constant Murley score, and postoperative efficacy was evaluated using the Karlsson criteria. RESULTS: The median follow-up duration was 13 months (range, 8-18 months). Satisfactory functional outcomes were obtained in both groups. Incision length, incidence of postoperative infection, pin migration, and postoperative efficacy did not differ between the two groups. Operative duration and intraoperative radiation dose were significantly greater in the PMIR-CN group than in the PMIR-UN group (P<0.05). Kirschner wires were removed at 4 weeks after surgery, and cannulated screws were removed at 12 weeks after surgery in both groups. DISCUSSION: Based on the satisfactory results obtained in all patients, we conclude that PMIR-UN is a safe, easy, and reliable technique for the treatment of acute grade III or V AC joint dislocation. TYPE OF STUDY: Low powered prospective randomized trial. LEVEL OF EVIDENCE: Level II. PMID- 29274863 TI - Total knee arthroplasty with the Medial-Pivot knee system: Clinical and radiological outcomes at 9.5 years' mean follow-up. AB - INTRODUCTION: The "ball-in-socket" design of the Medial-Pivot knee system (MicroPort Orthopedics, Arlington, Tennessee, USA) aims to reproduce normal knee kinematics by medializing its rotational axis. The goal of this study was to measure knee range of motion (ROM) with this implant after a mean follow-up of 10 years and to report the survivorship and long-term clinical and radiological outcomes. We hypothesized the prosthetic knee would have at least 120 degrees flexion at 10 years. MATERIAL AND METHODS: This was retrospective, single-centre study of 74 Medial-Pivot knees implanted in 71 patients (average age of 69 years) between May 2005 and November 2007. All patients who received a Medial-Pivot knee were included consecutively. The mean follow-up was 10 years. Clinical and radiological assessments were performed using the Knee Society Score (KSS) and Ewald's score. Kaplan-Meir survival analysis was used to calculate survivorship. RESULTS: Seven percent of cases were lost to follow-up. The knee ROM was 110 degrees at 10 years. The survivorship was 93% for all revision causes and 95.9% when revisions due to trauma or infection were excluded. The mean KSS score was 195. Stable radiolucent lines were found in 14% of cases. No aseptic loosening was observed. CONCLUSION: Our hypothesis was not confirmed. Knee flexion at the final follow-up was comparable to other semi-constrained implant designs but was not as large as expected. The survival of the Medial-Pivot knee at 10 years is good. Its radiological and clinical outcomes are satisfactory. LEVEL OF EVIDENCE: IV (retrospective cohort study). PMID- 29274864 TI - Re: Positron Emission Tomography/Computed Tomography-based Assessments of Androgen Receptor Expression and Glycolytic Activity as a Prognostic Biomarker for Metastatic Castration-resistant Prostate Cancer. PMID- 29274865 TI - Re: Comprehensive Molecular Characterization of Muscle-invasive Bladder Cancer. PMID- 29274866 TI - Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants. AB - BACKGROUND & AIMS: Inhibitors of the hepatitis C virus (HCV) NS5A protein are a key component of effective treatment regimens, but the genetic heterogeneity of HCV has limited the efficacy of these agents and mutations lead to resistance. We directly compared the efficacy of all clinically relevant NS5A inhibitors against HCV genotype 1-7 prototype isolates and resistant escape variants, and investigated the effects of pre-existing resistance-associated substitutions (RAS) on HCV escape from treatment. METHODS: We measured the efficacy of different concentrations of daclatasvir, ledipasvir, ombitasvir, elbasvir, ruzasvir, velpatasvir, and pibrentasvir in cultured cells infected with HCV recombinants expressing genotype 1-7 NS5A proteins with or without RAS. We engineered HCV variants that included RAS identified in escape experiments, using recombinants with or without T/Y93H and daclatasvir, or that contained RAS previously reported from patients. RESULTS: NS5A inhibitors had varying levels of efficacy against original and resistant viruses. Only velpatasvir and pibrentasvir had uniform high activity against all HCV genotypes tested. RAS hotspots in NS5A were found at amino acids 28, 30, 31, and 93. Engineered escape variants had high levels of fitness. Pibrentasvir had the highest level of efficacy against variants; viruses with RAS at amino acids 28, 30, or 31 had no apparent resistance to pibrentasvir, and HCV with RAS at amino acid 93 had a low level of resistance to this drug. However, specific combinations of RAS and deletion of amino acid 32 led to significant resistance to pibrentasvir. For the remaining NS5A inhibitors tested, RAS at amino acids 28 and 93 led to high levels of resistance. Among these inhibitors, velpatasvir was more effective against variants with RAS at amino acid 30 and some variants with RAS at amino acid 31 than the other agents. Variants with the pre-existing RAS T/Y93H acquired additional NS5A changes during escape experiments, resulting in HCV variants with specific combinations of RAS, showing high fitness and high resistance. CONCLUSIONS: We performed a comprehensive comparison of the efficacy of the 7 clinically relevant inhibitors of HCV NS5A and identified variants associated with resistance to each agent. These findings could improve treatment of patients with HCV infection. PMID- 29274867 TI - Esophageal Diseases. PMID- 29274868 TI - Galectin-3 Mediates Tumor Cell-Stroma Interactions by Activating Pancreatic Stellate Cells to Produce Cytokines via Integrin Signaling. AB - BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by activated pancreatic stellate cells (PSCs), abundance of extracellular matrix (ECM), and production of cytokines and chemokines. Galectin 3 (GAL3), a beta galactoside-specific lectin, contributes to PDAC development but its effects on the stroma and cytokine production are unclear. METHODS: The effect of recombinant human GAL3 (rGAL3) on activation of PSCs, production of cytokines, and ECM proteins was determined by proliferation, invasion, cytokine array, and quantitative polymerase chain reaction. We assessed co-cultures of PDAC cells with GAL3 genetic alterations with PSCs. Production of interleukin 8 (IL8) and activities of nuclear factor (NF)-kappaB were determined by enzyme-linked immunosorbent assay and luciferase reporter analyses. We studied the effects of inhibitors of NF-kappaB and integrin-linked kinase (ILK) on pathways activated by rGAL3. RESULTS: In analyses of the Gene Expression Omnibus database and our dataset, we observed higher levels of GAL3, IL8, and other cytokines in PDAC than in nontumor tissues. Production of IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, and C-C motif chemokine ligand 2 increased in PSCs exposed to rGAL3 compared with controls. Culture of PSCs with PDAC cells that express different levels of GAL3 resulted in proliferation and invasion of PSCs that increased with level of GAL3. GAL3 stimulated transcription of IL8 through integrin subunit beta 1 (ITGB1) on PSCs, which activates NF-kappaB through ILK. Inhibitors of ILK or NF-kappaB or a neutralizing antibody against ITGB1 blocked transcription and production of IL8 from PSCs induced by rGAL3. The GAL3 inhibitor significantly reduced growth and metastases of orthotopic tumors that formed from PDAC and PSC cells co-implanted in mice. CONCLUSION: GAL3 activates PSC cells to produce inflammatory cytokines via ITGB1signaling to ILK and activation of NF-kappaB. Inhibition of this pathway reduced growth and metastases of pancreatic orthotopic tumors in mice. PMID- 29274869 TI - Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut-Brain Interaction): A Rome Foundation Working Team Report. AB - BACKGROUND & AIMS: Central neuromodulators (antidepressants, antipsychotics, and other central nervous system-targeted medications) are increasingly used for treatment of functional gastrointestinal disorders (FGIDs), now recognized as disorders of gut-brain interaction. However, the available evidence and guidance for the use of central neuromodulators in these conditions is scanty and incomplete. In this Rome Foundation Working Team report, a multidisciplinary team summarized available research evidence and clinical experience to provide guidance and treatment recommendations. METHODS: The working team summarized the literature on the pharmacology of central neuromodulators and their effects on gastrointestinal sensorimotor function and conducted an evidence-based review on their use for treating FGID syndromes. Because of the paucity of data for FGIDs, we included data for non-gastrointestinal painful disorders and specific symptoms of pain, nausea, and vomiting. This information was combined into a final document comprising a synthesis of available evidence and recommendations for clinical use guided by the research and clinical experience of the experts on the committee. RESULTS: The evidence-based review on neuromodulators in FGID, restricted by the limited available controlled trials, was integrated with open label studies and case series, along with the experience of experts to create recommendations using a consensus (Delphi) approach. Due to the diversity of conditions and complexity of treatment options, specific recommendations were generated for different FGIDs. However, some general recommendations include: (1) low to modest dosages of tricyclic antidepressants provide the most convincing evidence of benefit for treating chronic gastrointestinal pain and painful FGIDs and serotonin noradrenergic reuptake inhibitors can also be recommended, though further studies are needed; (2) augmentation, that is, adding a second treatment (adding quetiapine, aripiprazole, buspirone alpha2delta ligand agents) is recommended when a single medication is unsuccessful or produces side effects at higher dosages; (3) treatment should be continued for 6-12 months to potentially prevent relapse; and (4) implementation of successful treatment requires effective communication skills to improve patient acceptance and adherence, and to optimize the patient-provider relationship. CONCLUSIONS: Based on systematic and selectively focused review and the consensus of a multidisciplinary panel, we have provided summary information and guidelines for the use of central neuromodulators in the treatment of chronic gastrointestinal symptoms and FGIDs. Further studies are needed to confirm and refine these recommendations. PMID- 29274870 TI - Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation. AB - BACKGROUND & AIMS: Cell stress signaling pathways result in phosphorylation of the eukaryotic translation initiation factor 2 subunit alpha (EIF2S1 or EIF2A), which affects regulation of protein translation. Translation reprogramming mitigates stress by activating pathways that result in autophagy and cell death, to eliminate damaged cells. Actin is modified during stress and EIF2A is dephosphorylated to restore homeostasis. It is not clear how actin affects EIF2A signaling. We studied the actin-binding proteins villin 1 (VIL1) and gelsolin (GSN) in intestinal epithelial cells (IECs) to determine whether they respond to cell stress response and affect signaling pathways. METHODS: We performed studies with mice with disruptions in Vil1 and Gsn (double-knockout mice). Wild-type (WT) mice either were or were not (controls) exposed to cell stressors such as tumor necrosis factor and adherent-invasive Escherichia coli. Distal ileum tissues were collected from mice; IECs and enteroids were cultured and analyzed by histology, immunoblots, phalloidin staining, immunohistochemistry, electron microscopy, and flow cytometry. HT-29 cells were incubated with cell stressors such as DTT, IFN, and adherent-invasive E coli or control agents; cells were analyzed by immunoblots and quantitative polymerase chain reaction. Green fluorescent protein and green fluorescent protein tagged mutant EIF2A were expressed from a lentiviral vector. The mouse immunity-related GTPase (IRGM1) was overexpressed in embryonic fibroblasts from dynamin1 like (DNM1L) protein-knockout mice or their WT littermates. IRGM1 was overexpressed in embryonic fibroblasts from receptor interacting serine/threonine kinase 1-knockout mice or their WT littermates. Human IRGM was overexpressed in human epithelial cell lines incubated with the DNM1L-specific inhibitor Mdivi-1. Mitochondria were analyzed by semi-quantitative confocal imaging. We performed immunohistochemical analyses of distal ileum tissues from 6-8 patients with Crohn's disease (CD) and 6-8 individuals without CD (controls). RESULTS: In IECs exposed to cell stressors, EIF2A signaling reduced expression of VIL1 and GSN. However, VIL1 and GSN were required for dephosphorylation of EIF2A and recovery from cell stress. In mouse and human IECs, prolonged, unresolved stress was accompanied by continued down-regulation of VIL1 and GSN, resulting in constitutive phosphorylation of EIF2A and overexpression of IRGM1 (or IRGM), which regulates autophagy. Overexpression of IRGM1 (or IRGM) induced cell death by necroptosis, accompanied by release of damage-associated molecular patterns (DAMPs). In double-knockout mice, constitutive phosphorylation of EIF2A and over-expression of IRGM1 resulted in spontaneous ileitis that resembled human CD in symptoms and histology. Distal ileum tissues from patients with CD had lower levels of VIL1 and GSN, increased phosphorylation of EIF2A, increased levels of IRGM and necroptosis, and increased release of nuclear DAMPs compared with controls. CONCLUSIONS: In studies of intestinal epithelial tissues from patients with CD and embryonic fibroblasts from mice, along with enteroids and human IEC lines, we found that induction of cell stress alters the cytoskeleton in IECs via changes in the actin-binding proteins VIL1 and GSN. Acute changes in actin dynamics increase IEC survival, whereas long-term changes in actin dynamics lead to IEC death and intestinal inflammation. IRGM regulates necroptosis and release of DAMPs to induce gastrointestinal inflammation, linking IRGM activity with CD. PMID- 29274871 TI - Glucocorticoid receptor activation selectively influence performance of Wistar rats in Y-maze. AB - Glucocorticoid receptors (GR) are ubiquitously expressed in metazoans. Different and contrasting phenotypes have been reported upon their activation. This study investigated the behavioral phenotypes characteristic of GR stimulation in male Wistar rats. Rats in each of the four groups of rats received one of the following treatments: distilled water (control) or one of three doses of dexamethasone (treatment) injected intraperitoneally for 7 days. The Rats were afterwards subjected to the Y maze, the elevated plus maze (EPM), the Morris water maze (MWM), and the novel object recognition (NOR) test. At the end of the study, the animals were anesthetized and neural activity from the prefrontal cortex recorded. Blood was collected via cardiac puncture to evaluate the levels of plasma insulin and glucose, and the prefrontal cortexes excised to determine the levels of insulin, markers of oxidative stress, and calcium in the homogenate. This study showed that treatment with dexamethasone significantly reduced the total and percentage alternation in the Y maze, but had no significant effect on object recognition in the NOR test, long-term and short term spatial memory in the MWM, or anxiety-like behavior in the EPM. Plasma and brain insulin and calcium levels were elevated moderately following treatment with the lowest dose of dexamethasone. All doses of dexamethasone decreased brain superoxide dismutase and increased lactate dehydrogenase levels. No significant change in neural activity was observed. This study shows that activation of glucocorticoid receptors differentially affects different behavioral paradigms and provides evidence for a role for glucocorticoids in mediating insulin function in the brain. PMID- 29274872 TI - [Proton pump inhibitors and kidney]. AB - Assumed for a long time to be very well tolerated, proton pump inhibitors (PPIs) are widely prescribed for inpatients and outpatients; often beyond their validated indications. Nevertheless, many very varied side effects (pneumopathy, ischemic heart disease, dementia) have been associated with the PPIs during the last decade. Renal toxicity is mainly the occurrence of acute interstitial nephritis (AIN), related to a drug-class effect, involving cellular immunity. AINs, which occur especially in elderly patients, can be difficult to diagnose, with frequently isolated acute kidney injury, appearing with variable delay after the introduction of PPIs. Although sensitive to steroid therapy, patients frequently have an incomplete recovery of the kidney function. Very recently, the risk of chronic kidney disease (CKD) and the risk of progression of CKD among PPIs users have been well demonstrated in several large independent epidemiological studies. It is a low, but a significant side effect because of the millions of PPI prescriptions. Although further studies are needed to investigate the pathophysiological mechanisms leading the use of PPI to CKD, it is appropriate for the physicians to limit PPIs to their correct indications and to monitor renal function during these treatments. PMID- 29274873 TI - The use of unfixed bone marrow trephines for multicolour flow cytometry. AB - An adequate bone marrow aspirate is essential for a rapid diagnosis of acute leukaemia by multicolour flow cytometry enabling the simultaneous assessment of multiple antigens on the cell surface as well as intracellular or nuclear ones. In the context of acute leukaemia, it is important to have a diagnosis of the blasts lineage as soon as possible to decide the appropriate treatment. This is sometimes delayed due to difficulties in obtaining a bone marrow aspirate due to a "dry tap". In this study we evaluated retrospectively cell markers results by flow cytometry of unfixed bone marrow trephines of 65 patients with leukaemia at diagnosis and including a few after treatment. Our aims were: 1) To compare cell markers results between bone marrow trephine (BMT) and bone marrow aspirate (BMA) 24 cases and BMT with peripheral blood (PB) 14 cases in paired samples to establish if they were reproducible with results of the unfixed bone marrow trephine biopsies. 2) To ascertain a precise diagnosis in 27 (42%) of the cases in which only a bone marrow trephine was available. We demonstrated that unfixed bone marrow trephine provides an adequate and representative cell suspension for flow cytometry and it is a powerful tool when no other material (bone marrow aspirate or peripheral blood) is available to make a rapid diagnosis. Furthermore when marrow aspirate or peripheral blood paired samples were available, flow cytometry results obtained were identical across all the sample types. Applicability to the clinical laboratory: We described a method to obtain a cell suspension from core biopsies that can easily be implemented routinely in a laboratory that performs diagnostic flow cytometry immunophenotyping. This method is simple, inexpensive and it doesn't require extra equipment. PMID- 29274874 TI - Application of paramagnetic relaxation enhancements to accelerate the acquisition of 2D and 3D solid-state NMR spectra of oriented membrane proteins. AB - Oriented sample solid-state NMR (OS-ssNMR) spectroscopy is uniquely suited to determine membrane protein topology at the atomic resolution in liquid crystalline bilayers under physiological temperature. However, the inherent low sensitivity of this technique has hindered the throughput of multidimensional experiments necessary for resonance assignments and structure determination. In this work, we show that doping membrane protein bicelle preparations with paramagnetic ion chelated lipids and exploiting paramagnetic relaxation effects it is possible to accelerate the acquisition of both 2D and 3D multidimensional experiments with significant saving in time. We demonstrate the efficacy of this method for a small membrane protein, sarcolipin, reconstituted in DMPC/POPC/DHPC oriented bicelles. In particular, using Cu2+-DMPE-DTPA as a dopant, we observed a decrease of 1H T1 of sarcolipin by 2/3, allowing us to reduce the recycle delay up to 3 times. We anticipate that these new developments will enable the routine acquisition of multidimensional OS-ssNMR experiments. PMID- 29274875 TI - The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slices. AB - The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling. PMID- 29274876 TI - Roles of tau pathology in the locus coeruleus (LC) in age-associated pathophysiology and Alzheimer's disease pathogenesis: Potential strategies to protect the LC against aging. AB - The locus coeruleus (LC) is the noradrenaline (norepinephrine, NE)-containing nucleus in the brainstem and innervates into widespread brain regions. This LC-NE system plays a critical role in a variety of brain functions, including attention, arousal, emotion, cognition, and the sleep-wake cycle. The LC is one of the brain regions vulnerable to the occurrence of neurofibrillary tangles (NFTs), which is associated with "primary age-related tauopathy (PART)" that describes the pathology commonly observed in the brains of aged individuals. In Alzheimer's disease (AD), the LC is one of the first places to develop NFTs, which may act as a seed for subsequent spreading of the pathology throughout the brain upon amyloid-beta (Abeta) accumulation. As AD progresses, significant neuron loss occurs in the LC. Moreover, LC neurodegeneration is not only a consequence of AD, but also drives clinical and pathological manifestations of AD, such as microglial dysregulation, sleep disturbance, cognitive decline, and neurovascular dysfunction. Therefore, prevention of NFT pathology and neuron loss in the LC-NE system is critical for suppressing the progression of AD. We propose that targeting aging itself may be a proactive intervention against age associated changes in the LC. Such an approach could open the way for novel interventions against age-associated neurodegenerative disorders, in particular, AD. PMID- 29274877 TI - Comparisons of the therapeutic effects of three different routes of bone marrow mesenchymal stem cell transplantation in cerebral ischemic rats. AB - Bone marrow mesenchymal stem cells (BMSCs) are mainly administered via three routes: intra-arterial, intravenous and intracerebral. It has been reported that BMSC administration via each route ameliorates the functional deficits after cerebral ischemia. However, there have been no comparisons of the therapeutic benefits of BMSC administration through different delivery routes. In this study, we injected BMSCs into a rat model of transient middle cerebral artery occlusion (MCAO) through the intra-arterial, intravenous, or intracerebral route at day 7 after MCAO. Control animals received only the vehicle. Neurological function was assessed at post-ischemic days (PIDs) 1, 7, 14, 21, 28 and 35 using behavioral tests (modified Neurological Severity Score (mNSS) and the adhesive removal test). At PID 35, the rat brain tissues were processed for histochemical and immunohistochemical staining. Our results showed that BMSC transplantation via the intra-arterial, intravenous, and intracerebral routes induced greater improvement in neurological functions than the control treatments; furthermore, the intra-arterial route showed the greatest degree and speed of neurological functional recovery. Moreover, BMSCs treatment through each route enhanced reconstruction of axonal myelination in the area of the corpus callosum on the infarct side of the cerebral hemisphere, increased the expression of SYN and Ki 67, and decreased the expression of Nogo-A in the brain. These effects were more apparent in the intra-arterial group than in the intravenous and intracerebral groups. These data suggest that BMSCs transplantation, especially through intra arterial delivery, can effectively improve neurological function intra-arterial. The underlying mechanism may include the promotion of synaptogenesis, endogenous cell proliferation, and axonal regeneration. PMID- 29274878 TI - Immunochemical analysis of the expression of SV2C in mouse, macaque and human brain. AB - The synaptic vesicle glycoprotein 2C (SV2C) is an undercharacterized protein with enriched expression in phylogenetically old brain regions. Its precise role within the brain is unclear, though various lines of evidence suggest that SV2C is involved in the function of synaptic vesicles through the regulation of vesicular trafficking, calcium-induced exocytosis, or synaptotagmin function. SV2C has been linked to multiple neurological disorders, including Parkinson's disease and psychiatric conditions. SV2C is expressed in various cell types primarily dopaminergic, GABAergic, and cholinergic cells. In mice, it is most highly expressed in nuclei within the basal ganglia, though it is unknown if this pattern of expression is consistent across species. Here, we use a custom SV2C specific antiserum to describe localization within the brain of mouse, nonhuman primate, and human, including cell-type localization. We found that the immunoreactivity with this antiserum is consistent with previously-published antibodies, and confirmed localization of SV2C in the basal ganglia of rodent, rhesus macaque, and human. We observed strongest expression of SV2C in the substantia nigra, ventral tegmental area, dorsal striatum, pallidum, and nucleus accumbens of each species. Further, we demonstrate colocalization between SV2C and markers of dopaminergic, GABAergic, and cholinergic neurons within these brain regions. SV2C has been increasingly linked to dopamine and basal ganglia function. These antisera will be an important resource moving forward in our understanding of the role of SV2C in vesicle dynamics and neurological disease. PMID- 29274879 TI - Glial cell responses in a murine multifactorial perinatal brain injury model. AB - The impact of traumatic brain injury during the perinatal period, which coincides with glial cell (astrocyte and oligodendrocyte) maturation was assessed to determine whether a second insult, e.g., increased inflammation due to remote bacterial exposure, exacerbates the initial injury's effects, possibly eliciting longer-term brain damage. Thus, a murine multifactorial injury model incorporating both mechanisms consisting of perinatal penetrating traumatic brain injury, with or without intraperitoneal injection of lipopolysaccharide (LPS), an analog of remote pathogen exposure has been developed. Four days after injury, gene expression changes for different cell markers were assessed using mRNA in situ hybridization (ISH) and qPCR. Astrocytic marker mRNA levels increased in the stab-alone and stab-plus-LPS treated animals indicating reactive gliosis. Activated microglial/macrophage marker levels, increased in the ipsilateral sides of stab and stab-plus LPS animals by P10, but the differences resolved by P15. Ectopic expression of glial precursor and neural stem cell markers within the cortical injury site was observed by ISH, suggesting that existing precursors and neural stem cells migrate into the injured areas to replace the cells lost in the injury process. Furthermore, single exposure to LPS concomitant with acute stab injury affected the oligodendrocyte population in both the injured and contralateral uninjured side, indicating that after compromise of the blood-brain barrier integrity, oligodendrocytes become even more susceptible to inflammatory injury. This multifactorial approach should lead to a better understanding of the pathogenic sequelae observed as a consequence of perinatal brain insult/injury, caused by combinations of trauma, intrauterine infection, hypoxia and/or ischemia in humans. PMID- 29274880 TI - CB1 cannabinoid receptor agonist mouse VD-hemopressin(alpha) produced supraspinal analgesic activity in the preclinical models of pain. AB - Mouse VD-hemopressin(alpha) (VD-Hpalpha) is an undecapeptide that selectively activates CB1 cannabinoid receptor in in vitro functional tests, and exerts CB1 mediated central antinociception in the mouse tail-flick assay. The aim of the present study was to further investigate the analgesic properties of supraspinal mouse VD-Hpalpha in a range of preclinical pain models. Our results indicated that the classical cannabinoid agonist WIN 55,212-2 produced supraspinal analgesia in preclinical pain models, which was selectively antagonized by the CB1 antagonist/inverse agonist AM251, but not by the CB2 antagonist AM630. In contrast, in post-operative pain model and phase I of formalin test, intracerebroventricular administration of mouse VD-Hpalpha induced dose-related analgesia in mice, which were markedly reduced by pretreatment with the CB1 neutral antagonist AM4113, but not AM251, AM630 and the selective antagonists of opioid and Transient Receptor Potential Vanilloid Type 1 (TRPV1) receptors. Furthermore, in the acetic acid-induced visceral pain model, supraspinal administration of mouse VD-Hpalpha dose-dependently produced analgesic activities and the effects were significantly antagonized by both AM4113 and the TRPV1 receptor antagonist SB366791, but not AM251, AM630 and naloxone. In addition, central injection of mouse VD-Hpalpha did not have significant effect in phase II of formalin test. Taken together, the present work suggests that the CB1 receptor peptidic agonist mouse VD-Hpalpha produces supraspinal analgesia in preclinical pain models via a novel CB1 receptor-mediated mechanism, in a manner pharmacologically dissociable from WIN 55,212-2. In addition, TRPV1 receptor might also be involved in mouse VD-Hpalpha-induced analgesia in a visceral pain model. PMID- 29274881 TI - Neurobiological mechanisms of antiallodynic effect of transcranial direct current stimulation (tDCS) in a mice model of neuropathic pain. AB - BACKGROUND: Neuropathic pain is relatively common and occurs in approximately 6 8% of the population. It is associated with allodynia and hyperalgesia. Thus, non pharmacological treatments, such as transcranial direct current stimulation (tDCS) may be useful for relieving pain. OBJECTIVES: This study aimed to investigate the antiallodynic effect of tDCS in a mice model of neuropathic pain, and the underlying neurotransmission systems that could drive these effects. METHODS: Male, Swiss mice, weighing 25-35 g, were subjected to partial sciatic nerve ligation (PSNL). Allodynia was assessed using a Von Frey filament (0.6 g). First, the behavioral time-course of these mice was assessed after 5, 10, 15 and 20 min of tDCS (0.5 mA). Second, the mice that underwent PSNL were assigned to either the tDCS (0.5 mA, 15 min) or tDCS sham group, and further assigned to receive either saline or a drug (i.e., naloxone, yohimbine, a-methyl-p-tyrosine, q-chlorophenylalanine methyl ester, caffeine, 1,3-dipropyl-8-cyclopentylxanthine, AM281, AM630, flumazenil, MK-801, or lidocaine). RESULTS: The antiallodynic effect of tDCS lasted 2 h and 4 h, after 10 min and 15 or 20 min of treatment, respectively (P < .001, P < .01, and P < .05, respectively). The antiallodynic effect of tDCS was associated with all the systems that were analyzed, i.e., the opioidergic (P < .01), adenosinergic (P < .001), serotonergic (P < .01), noradrenergic (P < .001), cannabinoid (P < .001), GABAergic, and glutamatergic (P < .001) systems. Lidocaine did not reverse the antiallodynic effect of tDCS (P > .05). CONCLUSION: The antiallodynic effect of tDCS was associated with different neurotransmitters systems; the duration of these after-effects depended on the time exposure to tDCS. PMID- 29274882 TI - Neurodevelopment and behavior in neonatal OXYS rats with genetically determined accelerated senescence. AB - Study of the developmental characteristics and mechanisms of senescence is an important field in brain aging research. The OXYS strain was selected from Wistar rats in Novosibirsk, and it serves as a rat model of accelerated aging. Previously, neurodegenerative processes and aberrant behavior were reported in experiments with adult OXYS rats. In our study, neurodevelopmental reflexes, neuronal density in the prefrontal cortex and hippocampus, and global DNA methylation in the hippocampus are compared between OXYS and WAG (Wistar Albino Glaxo) neonatal pups. The development of the righting, forelimb grasp, and cliff avoidance reflexes is delayed, and body weight gain was deferred in neonatal OXYS pups. Neuronal density in the hippocampus does not differ between one-day-old OXYS and WAG pups. On the sixth day, the neuronal density in OXYS pups is reduced in the CA2 hippocampal zone, augmented in CA3 and DG, and unchanged in CA1. Six day-old OXYS pups have fewer and smaller pyramidal neurons in the prefrontal cortex as compared to WAG controls. Global DNA methylation levels in the hippocampus of OXYS newborns are significantly lower than in the WAG newborn pups. At the age of six days, the global DNA methylation level decreases in WAG pups, but does not change in OXYS pups. Thus, neonatal OXYS rats show delayed neurodevelopment accompanied by changes in the global DNA methylation pattern in the hippocampus and in neuronal density in the hippocampus and the prefrontal cortex. These changes may be related to accelerated senescence in adult OXYS rats. PMID- 29274883 TI - The locus coeruleus neuroprotective drug vindeburnol normalizes behavior in the 5xFAD transgenic mouse model of Alzheimer's disease. AB - Damage to noradrenergic neurons in the Locus coeruleus (LC) occurs contributes to neuropathology and behavioral deficits in Alzheimer's disease (AD); methods to reduce LC damage may therefore be of benefit. We previously showed that vindeburnol, a derivative of the plant alkaloid vincamine, reduced neuroinflammation, amyloid burden, and LC damage in a mouse model of AD; however, effects on behavior were not tested. We now tested the effects of vindeburnol on anxiety-like behavior in 5xFAD mice which develop robust amyloid burden at early ages. During novel object recognition testing, we observed that 5xFAD mice spent more time exploring than wildtype littermates, and that time was reduced by vindeburnol. Vindeburnol also reduced hyperlocomotion in the 5xFAD mice which may have contributed to their increased exploration times. In an open field test, vindeburnol normalized the increase of time spent in the center, and the decrease of time spent near the walls in 5xFAD mice. Vindeburnol reduced amyloid burden in the hippocampus and cortex, areas that contribute to regulation of anxiety-like behavior. In vitro, vindeburnol increased neuronal BDNF expression in a cAMP dependent manner; and inhibited phosphodiesterase activity with an EC50 near 50 MUM. These findings suggest that cAMP-mediated increases in neurotrophic factors contribute to beneficial effects of vindeburnol within the context of LC damage, which may be of value for treatment of some neuropsychiatric symptoms of AD. PMID- 29274885 TI - LaSalle D. Leffall, M.D., FACS and Leadership in American Surgery. AB - The term, Festschrift, is defined as a volume of learned articles or essays by colleagues and admirers, serving as a tribute to a scholar. The recognition of LaSalle D. Leffall, Jr., M.D., F.A.C.S. adds credence to the merits of such a tribute. PMID- 29274884 TI - Multifaceted intervention to curb in-hospital over-prescription of proton pump inhibitors: A longitudinal multicenter quasi-experimental before-and-after study. AB - BACKGROUND: Proton pump inhibitors (PPIs) are indicated for a restricted number of clinical conditions, and their misuse can lead to several adverse effects. Despite that, the proportion of overuse is alarmingly high. OBJECTIVE: To test the efficacy of a multifaceted strategy in order to achieve a significant reduction of new PPI prescriptions at discharge in hospitalized patients. DESIGN: Multicenter longitudinal quasi-experimental before-and-after study conducted from July 1st, 2014 to June 30th, 2017. PARTICIPANTS: 44,973 admissions in a network of 5 public teaching hospitals of the Italian-speaking region of Switzerland. INTERVENTION: Multifaceted strategy consisting in a continuous transparent monitoring-benchmarking and in capillary educational interventions applied in the internal medicine departments. To confirm the causality of the results we monitored the trend of new PPI prescriptions in the, not exposed to the intervention, surgery departments of the same hospital network. MAIN MEASURES: New PPI prescriptions at hospital discharge. KEY RESULTS: Over the 36month study period 44,973 patient files were analyzed. At admission, comparing internal medicine vs. surgery departments, 44.9% vs. 23.3% of patients were already being treated with a PPI. The annual rate of new PPI prescriptions, for internal medicine showed a decreasing trend: 19, 19, 18, 16% in years 2014, 2015, 2016, 2017, respectively (p<0.001, 2014 vs. 2017; p-for-trend <0.001), while an increasing rate was found in the surgery departments in the same years: 30, 29, 36, 36%, respectively (p<0.001, 2014 vs. 2017; p-for-trend <0.001). The case mix was significantly associated with the probability of new PPI prescriptions in both departments (OR1.35, 95% CI 1.26-1.44 for internal medicine and 1.24, 95% CI 1.19-1.30 for surgery). CONCLUSIONS: The introduction of a multifaceted intervention significantly reduced the time trend of PPI prescriptions at hospital discharge in internal medicine departments. Further studies are needed to confirm whether the strategy proposed could contribute to optimize the in hospital drug prescription behavior in other healthcare settings as well. PMID- 29274886 TI - Establishment of human iPSC line NCCSi003-A from CD34+cells of peripheral blood collected during apheresis of healthy donor from Indian ethnicity. AB - We present generation of iPSCs from CD34+ cells isolated from peripheral blood, collected during apheresis of a healthy female individual. We nucleofected the CD34+cells by episomal vectors containing Oct4, Sox2, L-Myc, Lin28, Klf4 and p53DD (dominant negative mutation in p53). The resultant colonies showed cobble stone appearance and stained positive for alkaline phosphatase. The colonies demonstrated presence of pluripotency markers by immunofluorescence, flow cytometry and PCR. The plasmids were lost from cells subsequently during passages as assessed by PCR. Karyotype analysis demonstrated a stable genome. The cells had capability to differentiate to cells from all three-germ lineages in vitro. PMID- 29274887 TI - Spontaneous Regression of a Recalcitrant Wart after Bivalent Papillomavirus Vaccination. PMID- 29274888 TI - Echocardiography Grading for Pulmonary Arteriovenous Malformation Screening in Children with Hereditary Hemorrhagic Telangiectasia. AB - Transthoracic contrast echocardiography (TTCE) has high sensitivity but low specificity in screening for pulmonary arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). Here we describe characteristics of TTCE that might be used to reduce the need for confirmatory computed tomography scans in children with HHT. PMID- 29274889 TI - New Onset Autoimmune Hepatitis during Anti-Tumor Necrosis Factor-Alpha Treatment in Children. AB - OBJECTIVES: To evaluate a large anti-tumor necrosis factor (TNF)-treated pediatric inflammatory bowel disease cohort for drug-induced liver injury (DILI) following presentation of an index case with suspected DILI with autoimmune features after infliximab exposure. To characterize the incidence, natural history, and risk factors for liver enzyme elevation with anti-TNF use. STUDY DESIGN: We reviewed the index case and performed a retrospective cohort study of 659 children receiving anti-TNF therapy between 2000 and 2015 at a tertiary pediatric inflammatory bowel disease center. Patients with alanine aminotransferase (ALT) >=*2 the upper limit of normal were included. The incidence, evolution, and risk factors for liver injury were examined with univariate and multivariable proportional hazards regression. Causality was assessed using the Roussel-Uclaf Causality Assessment Method. RESULTS: The index case, a teenage girl with Crohn's disease, developed elevated liver enzymes and features of autoimmune hepatitis on liver biopsy 23 weeks after starting infliximab. The injury resolved entirely within 4 months of withdrawing infliximab without additional therapy. Overall, 7.7% of our cohort developed new ALT elevations while on anti-TNF. Most ALT elevations were mild and transient and attributable to alternate etiologies. No additional clear cases of autoimmune hepatitis were identified. CONCLUSIONS: Transient liver enzyme abnormalities are relatively common among anti-TNF-treated children. Anti-TNF-related DILI with autoimmune features is rare but must be recognized so that therapy can be stopped. PMID- 29274890 TI - Molybdenum cofactor deficiency type A: Prenatal monitoring using MRI. AB - Molybdenum cofactor deficiency type A (MoCD-A) is an inborn error of metabolism presenting early after birth with severe seizures. Recently, experimental substitution treatment with cyclic pyranopterin monophosphate (cPMP) has become available. Because prenatal data is scarce, we report data of prenatal Magnetic Resonance Imaging (MRI) in two cases with MoCD-A demonstrating signs of possible early brain injury. Prenatal MRI can be used for monitoring in MoCD-A to guide decision-making in timing of delivery. PMID- 29274891 TI - Selection and ranking of patient video cases in paediatric neurology in relation to learner levels. AB - BACKGROUND: Teaching and learning with patient video cases may add authenticity, enhance diagnostic accuracy and improve chances of early diagnosis. The aim of this study is firstly to identify selection criteria for key Patient video cases (PVCs), secondly to identify trends in relevance of PVCs for learner levels and thirdly, to rank PVCs for learner levels. METHODS: Based on a literature review, we identified criteria for key PVCs for use in paediatric neurology. We then performed a multi-round Delphi analysis to obtain agreement between 28 expert clinician teachers concerning key PVCs for four learner levels. RESULTS: We identified two major criteria: key PVCs should demonstrate key movements, and these movements should be subtle and/or difficult to note. The expert clinician teachers subsequently assessed a list of 14 topics for key PVCs. We found a clear, increasing trend in relevance scores, from medical students to young residents to experienced residents and specialists. For medical students and residents, epileptic spasms, Down syndrome, developmental delay, cerebral palsy and absence epilepsy were highly ranked. For specialists, conditions like chorea, focal seizures or eye movement disorders topped the ranking list, although ranking was less clear for this group of advanced learners. DISCUSSION AND CONCLUSION: Key PVCs should demonstrate movements that are difficult to note for learners. Ranked lists of key PVCs for teaching and learning at different learner levels are now available and may help institutions build validated local libraries of PVCs. PMID- 29274892 TI - Role of resistant starch on diabetes risk factors in people with prediabetes: Design, conduct, and baseline results of the STARCH trial. AB - Dietary resistant starch (RS) might alter gastrointestinal tract function in a manner that improves human health, particularly among adults at risk for diabetes. Here, we report the design and baseline results (with emphasis on race differences) from the STARCH trial, the first comprehensive metabolic phenotyping of people with prediabetes enrolled in a randomized clinical trial testing the effect of RS on risk factors for diabetes. Overweight/obese participants (BMI>=27kg/m2 and weight<=143kg), age 35-75y, with confirmed prediabetes were eligible. Participants were randomized to consume 45g/day of RS (RS=amylose) or amylopectin (Control) for 12weeks. The study was designed to evaluate the effect of RS on insulin sensitivity and secretion, ectopic fat, and inflammatory markers. Secondary outcomes included energy expenditure, substrate oxidation, appetite, food intake, colonic microbial composition, fecal and plasma levels of short-chain fatty acids, fecal RS excretion, and gut permeability. Out of 280 individuals screened, 68 were randomized, 65 started the intervention, and 63 were analyzed at baseline (mean age 55y, BMI 35.6kg/m2); 2 were excluded from baseline analyses due to abnormal insulin and diabetes. Sex and race comparisons at baseline were reported. African-Americans had higher baseline acute insulin response to glucose (AIRg measured by frequently sampled intravenous glucose tolerance test) compared to Caucasians, despite having less visceral adipose tissue mass and intrahepatic lipid; all other glycemic variables were similar between races. Sleep energy expenditure was ~90-100kcal/day lower in African Americans after adjusting for insulin sensitivity and secretion. This manuscript provides an overview of the strategy used to enroll people with prediabetes into the STARCH trial and describes methodologies used in the assessment of risk factors for diabetes. Clinicaltrials.gov identifier: STARCH (NCT01708694). The present study reference can be found here: https://clinicaltrials.gov/ct2/show/NCT01708694. Submission Category: "Study Design, Statistical Design, Study Protocols". PMID- 29274893 TI - Cognitive and Self-regulatory Mechanisms of Obesity Study (COSMOS): Study protocol for a randomized controlled weight loss trial examining change in biomarkers, cognition, and self-regulation across two behavioral treatments. AB - Obesity is a global epidemic, yet successful interventions are rare. Up to 60% of people fail to achieve clinically meaningful, short-term weight loss (5-10% of start weight), whereas up to 72% are unsuccessful at achieving long-term weight loss (5-10% loss for >=5years). Understanding how biological, cognitive, and self regulatory factors work together to promote or to impede weight loss is clearly needed to optimize obesity treatment. This paper describes the methodology of the Cognitive and Self-regulatory Mechanisms of Obesity Study (the COSMOS trial). COSMOS is the first randomized controlled trial to investigate how changes in multiple biopsychosocial and cognitive factors relate to weight loss and one another across two weight loss treatments. The specific aims are to: 1) Confirm that baseline obesity-related physiological dysregulation is linked to cognitive deficits and poorer self-regulation, 2) Evaluate pre- to post-treatment change across time to assess individual differences in biomarkers, cognition, and self regulation, and 3) Evaluate whether the acceptance-based treatment (ABT) group has greater improvements in outcomes (e.g., greater weight loss and less weight regain, improvements in biomarkers, cognition, and self-regulation), than the standard behavioral treatment group (SBT) from pre- to post-treatment and 1-year follow-up. The results of COSMOS will provide critical information about how dysregulation in biomarkers, cognition, and/or self-regulation is related to weight loss and whether weight loss treatments are differentially associated with these factors. This information will be used to identify promising treatment targets that are informed by biological, cognitive, and self-regulatory factors in order to advance obesity treatment. PMID- 29274894 TI - The Physical Activity Daily (PAD) Trial: The rationale and design of a randomized controlled trial evaluating an internet walking program to improve maximal walking distance among patients with peripheral arterial disease. AB - BACKGROUND: Despite established guidelines for regular walking as a first line therapy for adults with peripheral arterial disease (PAD), most patients do not walk routinely. This paper presents the design specifications for a randomized clinical trial to examine the effectiveness of an internet-based walking program compared to a telephone intervention, or the combination (internet-based with telephone counseling) for promotion of regular walking in patients with PAD. METHODS: Sedentary adults with documented lower extremity PAD are being recruited from the University of Michigan Health System and the surrounding area. Participants are randomized to one of four arms in a 2*2 factorial design: 1) telephone counseling to promote walking, 2) an internet-based walking program with tailored step-count goals, 3) the combination of telephone counseling with the internet-based walking program, or 4) waitlist control. Participants receive a 4-month intervention phase, after which all participants are followed for an additional 8months to assess long-term adherence to regular walking. Outcomes are assessed at baseline, 4 and 12months. The primary outcome is walking distance assessed through a standardized treadmill protocol. Additional outcomes include change in step-counts measured with a commercial activity tracker, pain-free walking distance, and changes in health-related quality of life from baseline to follow-up. CONCLUSION: Finding effective and feasible programs to promote walking among PAD patients is warranted. This study will add to current evidence regarding use of internet based programs with and without telephone counseling to promote regular walking in this population. PMID- 29274895 TI - New insights into the fecal microbiota of children living in a slum: association with small bowel bacterial overgrowth. PMID- 29274896 TI - Impact of oxidative stress on telomere biology. AB - Telomere integrity is essential for genome stability and it regulates cell proliferation and tissue renewal. Several lines of evidence indicate that telomeres are particularly sensitive to oxidative damage. Moreover, recent studies demonstrate striking inhibitory effects of oxidative damage on telomerase activity. On the other hand, several mechanisms have been uncovered that either counteract oxidative damage at telomeres or remove the modified lesions. Here, we review the current understanding of oxidative damage and protection of telomeric DNA. We discuss how oxidative telomeric lesions impact on telomerase, the regenerative capacity of stem cells and cancer. Finally, we propose how through a better understanding of the involved pathways it may become possible to target telomerase in cancer cells in future cancer therapies. PMID- 29274897 TI - Evaluation of antioxidant activities of ethanol extract from Ligusticum subjected to in-vitro gastrointestinal digestion. AB - The Rhizome of Ligusticum chuanxiong Hort, a traditional Chinese medicine, is widely used to treat cardiovascular diseases and attenuate oxidative stress. The main bioactive compounds including tetramethylpyrazine (TMP), polyphenols, ferulic acid have been reported to be responsible for these effects. This study was to evaluate the influence of Ligusticum chuanxiong extraction (LCE) in mimic gastrointestinal tract on antioxidant activity. The effects of gastric digestion group metabolic liquid on free radical scavenging followed as DPPH > .O2- > .OH, while the clearance effects of intestine digestion group expressed as .O2-> .OH > DPPH. Furthermore, the digested extraction promoted lower cellular antioxidant activity (CAA) with dose-response correlations. Gastrointestinal digestion increased the release of bound ferulic acids and polyphenols. Content of ferulic acid in gastric and intestinal metabolic solution increased from 6.07 mg/g to 9.33 mg/g and 14.17 mg/g. The free phenolic before and after digestion were 177.38 mg/g, 179.69 mg/g and 194.99 mg/g, respectively. The simulated gastrointestinal digestion of LCE promoted a significant increase in the free phenolic acids content, antioxidant activity and CAA. PMID- 29274898 TI - Reliability and validity of the English and Malay versions of the Driving and Riding Questionnaire: a pilot study amongst older car drivers and motorcycle riders. AB - OBJECTIVES: This study aimed to examine the reliability and validity of the English and Malay versions of the Driving and Riding Questionnaire. STUDY DESIGN: An observational study with a mix-method approach by utilising both questionnaire and short debriefing interviews. METHODS: Forward and backward translations of the original questionnaire were performed. The translated questionnaire was assessed for clarity by a multidisciplinary research team, translators, and several Malay native speakers. A total of 24 subjects participated in the pilot study. Reliability (Cronbach's alpha) and validity (content validity) of the original and translated questionnaires were examined. RESULTS: The English and Malay versions of the Driving and Riding Questionnaire were found to be reliable tools in measuring driving behaviours amongst older drivers and riders, with Cronbach's alpha of 0.9158 and 0.8919, respectively. For content validity, the questionnaires were critically reviewed in terms of relevance, clarity, simplicity, and ambiguity. The feedback obtained from participants addressed various aspects of the questionnaire related to the improvement of wordings used and inclusion of visual guide to enhance the understanding of the items in the questionnaire. This feedback was incorporated into the final versions of the English and Malay questionnaires. CONCLUSION: The findings of this study demonstrated both the English and Malay versions of the Driving and Riding Questionnaire to be valid and reliable. PMID- 29274899 TI - Repolarization in perfused myocardium predicts reperfusion ventricular tachyarrhythmias. AB - BACKGROUND: Aim of the study was to find out which myocardial repolarization parameters predict reperfusion ventricular tachycardia and fibrillation (VT/VF) and determine how these parameters express in ECG. METHODS: Coronary occlusion and reperfusion (30/30min) was induced in 24 cats. Local activation and end of repolarization times (RT) were measured in 88 intramyocardial leads. Computer simulations of precordial electrograms were performed. RESULTS: Reperfusion VT/VF developed in 10 animals. Arrhythmia-susceptible animals had longer RTs in perfused areas [183(177;202) vs 154(140;170) ms in susceptible and resistant animals, respectively, P<0.05]. In logistic regression analysis, VT/VFs were associated with prolonged RTs in the perfused area (OR 1.068; 95% CI 1.012-1.128; P=0.017). Simulations demonstrated that prolonged repolarization in the perfused/border zone caused precordial terminal T-wave inversion. CONCLUSIONS: The reperfusion VT/VFs were independently predicted by the longer RT in the perfused zone, which was reflected in the terminal negative phase of the electrocardiographic T-wave. PMID- 29274900 TI - "The Operation", half a century later. PMID- 29274901 TI - Foreign Body Concealed Inside the Mouthpiece of a Metered Dose Inhaler. PMID- 29274902 TI - Is Spanish urology in 2018 mature enough to perform population screening for prostate cancer? PMID- 29274903 TI - Early versus late repair of rotator cuff tears in rats. AB - BACKGROUND: In the event of a traumatic rotator cuff tear, patients are routinely advised that early surgical intervention produces an optimal repair, despite a lack of direct evidence to support this recommendation. To address this knowledge gap, massive rotator cuff tears in rats were assessed by biomechanical and bone morphometric analyses after early or late repair. METHODS: Combined supraspinatus and infraspinatus tendon tears of the left shoulder were created in 21 adult Wistar rats, which were divided into 2 groups. The tendons of the injured shoulder in the animals in group I were surgically repaired 8 weeks after the injury. Under the same anesthesia, the same injury was created on the right shoulder, which was immediately repaired. The rats from group I were euthanized 8 weeks after the repairs. No repair was performed in the rats from group II, which were euthanized 8 weeks after the injury. Tissues from both groups were harvested and biomechanically tested for supraspinatus tendon and bone morphometry analysis of the humeral head. RESULTS: All biomechanical properties were significantly increased in the early repair group compared with the late repair group. No significant differences were observed in bone morphometry of the humeral head when early and late repair groups were compared. CONCLUSION: Early surgical repair of a massive rotator cuff tear leads to improved biomechanical properties of the tissue after healing. Proximal humerus bone morphometry was unaffected by surgical repair timing. PMID- 29274904 TI - Correlation of PROMIS Physical Function Upper Extremity Computer Adaptive Test with American Shoulder and Elbow Surgeons shoulder assessment form and Simple Shoulder Test in patients with shoulder arthritis. AB - BACKGROUND: The purpose of this study was to evaluate the Patient-Reported Outcomes Measurement Informative System Physical Function Upper Extremity Computer Adaptive Test (PROMIS PFUE CAT) measurement tool against the already validated American Shoulder and Elbow Surgeons (ASES) shoulder assessment form and the Simple Shoulder Test (SST) in patients with shoulder arthritis. METHODS: Fifty-two patients with the primary diagnosis of shoulder arthritis were asked to fill out the ASES, SST, and PROMIS PFUE CAT. The time for completion of each survey was measured to determine responder burden, and correlation between the 3 instruments was defined as excellent (>0.7), strong-moderate (0.61-0.7), moderate (0.31-0.6), and poor (0.2-0.3). RESULTS: The PROMIS PFUE CAT showed a strong moderate correlation with the SST (r = 0.64; P < .001) and a moderate correlation with the ASES (r = 0.57; P < .001). The average times to complete the SST, ASES, and PROMIS PFUE CAT were determined to be 96.9 +/- 25.1 seconds, 160.6 +/- 51.5 seconds, and 62.6 +/- 22.8 seconds, respectively. The time to complete the PROMIS PFUE CAT was significantly less than the time to complete the SST (P < .001) and the ASES (P < .001). CONCLUSION: In patients with shoulder arthritis, The PROMIS PFUE CAT demonstrated strong-moderate correlation with the SST and moderate correlation with the ASES. The time savings of the PROMIS PFUE CAT were small compared with the ASES and SST but demonstrate that moving forward, using the PROMIS PFUE CAT would not place any additional burden on the patient filling out the survey. These findings indicate that the PROMIS PFUE CAT is an appropriate measurement tool for patients with shoulder arthritis. PMID- 29274905 TI - Quadrilateral space syndrome: a review. AB - Quadrilateral space (QS) syndrome (QSS) is a relatively rare condition in which the axillary nerve and the posterior humeral circumflex artery are compressed within the QS. Fibrous bands are most commonly implicated as the cause, with true space-occupying lesions being less common. QSS is characterized by poorly localized shoulder pain and paresthesia over the lateral aspect of the shoulder and arm in a nondermatomal pattern. These symptoms are aggravated by shoulder abduction and external rotation. Point tenderness is typically present over the QS; however, diagnosis on physical examination can be difficult. Pain relief after lidocaine block of the axillary nerve within the QS is a useful finding in the evaluation of patients with suspected QSS. No definitive diagnostic imaging exists, making diagnosis difficult, although radiographs and magnetic resonance imaging are recommended to rule out other pathology. Nonoperative treatment, including nonsteroidal anti-inflammatory drugs, activity modification, and physical therapy, for at least 6 months is recommended before pursuing operative intervention. Small case series have shown that surgical decompression of the QS has good outcomes, with resolution of pain and return to sport. PMID- 29274906 TI - APTR is a prognostic marker in cirrhotic patients with portal hypertension during TIPS procedure. AB - Portal hypertension is a major cause of mortality and morbidity in cirrhotic patients. In this study, we aimed to analyze the clinical characteristics of Alu mediated p21 transcriptional regulator (APTR) during transjugular intrahepatic portosystemic shunt (TIPS) procedure. Portal and hepatic venous blood was drawn from 84 patients with liver cirrhosis and portal hypertension before and after TIPS treatment. Then, we detected biochemical, hemodynamic parameters and APTR expression before and after TIPS treatment. Indeed, TIPS treatment could markedly ameliorate the serum blood urea nitrogen (BUN) level and portal vein hemodynamics in cirrhotic patients. We found that portal venous levels of APTR was significantly decreased after TIPS treatment and its aberrant expression levels were positively correlated with Model for End Stage Liver Disease (MELD), portal hepatic venous pressure gradient (PHPG) in patients. Higher APTR expression in portal vein was associated with poor prognosis. APTR level in portal vein was an independent predictors of mortality. Our data indicated that APTR may serve as a novel biomarker for cirrhotic patients with portal hypertension before and after receiving TIPS. PMID- 29274907 TI - RNA-Seq transcriptomic analysis of the Morus alba L. leaves exposed to high-level UVB with or without dark treatment. AB - Ultraviolet-B (UVB) irradiation induces oxidative stress in plant cells due to the generation of excessive reactive oxygen species. Morus alba L. (M. abla) is an important medicinal plant used for the treatment of human diseases. Also, its leaves are widely used as food for silkworms. In our previous research, we found that a high level of UVB irradiation with dark incubation led to the accumulation of secondary metabolites in M. abla leaf. The aim of the present study was to describe and compare M. alba leaf transcriptomics with different treatments (control, UVB, UVB+dark). Leaf transcripts from M. alba were sequenced using an Illumina Hiseq 2000 system, which produced 14.27Gb of data including 153,204,462 paired-end reads among the three libraries. We de novo assembled 133,002 transcripts with an average length of 1270bp and filtered 69,728 non-redundant unigenes. A similarity search was performed against the non-redundant National Center of Biotechnology Information (NCBI) protein database, which returned 41.08% hits. Among the 20,040 unigenes annotated in UniProtKB/SwissProt database, 16,683 unigenes were assigned 102,232 gene ontology terms and 6667 unigenes were identified in 287 known metabolic pathways. Results of differential gene expression analysis together with real-time quantitative PCR tests indicated that UVB irradiation with dark incubation enhanced the flavonoid biosynthesis in M. alba leaf. Our findings provided a valuable proof for a better understanding of the metabolic mechanism under abiotic stresses in M. alba leaf. PMID- 29274908 TI - Transcriptome analysis of Cyrtotrachelus buqueti in two cities in China. AB - In order to reduce the Cyrtotrachelus buqueti population, which is a serious pest in the bamboo industry, a range of approaches is required, which will be dependent on diverse gene expression influenced by environmental factors. In this study, samples from two regions of China, Muchuan in Sichuan Province and Chishui in Guizhou Province, were investigated through RNA-seq. Approximately 44 million high-quality reads were generated and 94.2% of the data was mapped to the transcriptome. A total of 15,641 out of the 29,406 identified genes were predicted. Moreover, 348 genes were differentially expressed between the two groups of imagoes (77 upregulated and 271 downregulated). The functional analysis showed that these genes were significantly enriched in the ribosome and metabolic pathway categories. The candidate genes contributing to the reduction in C. buqueti included 41 genes involved in the ribosome constitution category, five in the one-carbon pool pathway by folate category, and five heat shock protein genes. The downregulation of these candidate genes seems to have impaired metabolic processes, such as protein, DNA, RNA, and purine synthesis, as well as carbon and folate metabolism, subsequently resulting in the observed population reduction of C. buqueti. Furthermore, temperature, heavy metal content, and pH might influence the population by altering the expressions of genes involved in these metabolic processes. PMID- 29274909 TI - Cloning and functional characterization of human Pak1 promoter by steroid hormones. AB - P21-activated kinase 1 (Pak1) is known to be involved in a plethora of functions including cell growth, survival and can lead to cell transformation and tumor progression especially in breast tissue. Multiple studies have shown Pak1 dysregulation as a change in DNA copy number as well as gene expression levels, suggesting many regulatory mechanisms at transcriptional and translational level. However, very little is known about the transcriptional regulation of the human Pak1 promoter. Here, we focus on Pak1 promoter regulation by steroid hormones along with their respective receptors that are also crucial players in breast tissue function and tumorigenesis. Our results show high Pak1 expression in breast cancer cell lines and in breast tumor tissue. It also suggests that Pak1 is hormone responsive, whose expression can be modulated by steroid hormones namely, estrogen in the form of 17beta-estradiol (E2) and progesterone (P4). Sequence analysis of a 3.2kb Pak1 proximal promoter region shows the presence of PRE (progesterone response element) and ERE (estrogen response element) half sites, that were further cloned and characterized. Results from promoter analysis showed that Pak1 promoter activity is mediated by PR via its binding to PRE present on the Pak1 promoter that was further reaffirmed in vitro by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results together suggest that it is the PR isoform B regulates Pak1 promoter. To our knowledge, this is the first study to report the detailed characterization and transcriptional regulation of the human Pak1 promoter by steroid hormones. PMID- 29274910 TI - Disruption of liver development and coagulation pathway by ochratoxin A in embryonic zebrafish. AB - Ochratoxin A (OTA) is a mycotoxin that is found in various food and feed products. The molecular mechanisms that are associated with OTA hepatotoxicity and teratogenicity have not been extensively elucidated in a developing organism. In this study, the transcriptomic profile of zebrafish embryos indicates that hemostasis and blood coagulation are the top two pathways affected by OTA. The treatment of embryos with OTA was able to decrease the expression of genes that encode coagulation factors and liver markers, including f7, f9b, cp and vtna. OTA also weakened the signal of liver-specific microRNA-122. OTA administration not only reduced the size of a developing embryonic liver, but also decreased the number of phosphorylated histone H3-positive cells by immunohistochemical staining. OTA suppressed the expression of hhex and prox1, two critical transcriptional factors during hepatoblast specification, in the developing liver, but did not alter the insulin signal in the pancreas. In vitro analysis with zebrafish liver (ZFL) cells indicated that OTA blocked the expression of f7, fgb and liver markers. In summary, OTA exposure resulted in the generation of small livers which led to deficiency of coagulation factors in embryonic zebrafish. Impairment of hhex and prox1 gene expression and hepatocyte proliferation contributed to the disruption of liver development mediated by OTA. PMID- 29274911 TI - Selective implantation of durable left ventricular assist devices as primary therapy for refractory cardiogenic shock. AB - OBJECTIVE: Surgical therapy for refractory primary cardiogenic shock is largely based on emergent placement of extracorporeal membrane oxygenation or short-term ventricular assist devices. We have adopted a strategy of routine implantation of durable left ventricular assist devices (LVAD) as initial therapy for refractory cardiogenic shock, in patients who are potential candidates for heart transplantation, and report our experience. METHODS: Retrospective review of 43 consecutive patients with refractory shock caused by acute myocardial infarction (n = 21) or acute decompensated heart failure (n = 22) who were treated with primary implantation of a durable LVAD in a single institution. RESULTS: All patients received durable LVAD (axial flow, n = 37; centrifugal, n = 4; pulsatile, n = 2), with concurrent placement of right ventricular assist device (RVAD) in 5 patients (12%). One patient had delayed RVAD implantation. Mean operative time was 362 minutes and mean cardiopulmonary bypass time was 94 minutes. Twenty patients underwent concurrent cardiac procedures. Major early adverse events included operative mortality 14% (6/43), reoperation for bleeding 7% (3/43), and stroke 4.7% (2/43). Median time on mechanical ventilation was 3.5 days, ICU stay 9 days, and hospital stay 25 days. Kaplan-Meier survival was 82.7 +/- 6.0% at 6 months and 73.9 +/- 8.0% at 12 months. Using competing analysis, the cumulative incidence of transplantation was 10.3 +/- 5.0% at 6 months and 30.8 +/- 7.9% at 1 year. CONCLUSIONS: Our data challenge the notion that patients in refractory cardiogenic shock are best served by an initial period of stabilization with temporary devices. Primary implantation of durable LVADs in cardiogenic shock can yield good midterm outcomes and may have potential benefits. PMID- 29274912 TI - Discussion. PMID- 29274914 TI - Discussion. PMID- 29274913 TI - Oral anticoagulation may not be necessary for patients discharged in sinus rhythm after the Cox Maze IV procedure. AB - OBJECTIVES: Oral anticoagulants have inherent risks. In the absence of clear evidence, anticoagulant use after surgical ablation for atrial fibrillation remains variable. This study examined patient outcomes with and without oral anticoagulants after successful surgical ablation. METHODS: From October 2011 to April 2016, 239 consecutive patients underwent biatrial Cox Maze IV operations for persistent atrial fibrillation. All patients received endocardial left atrial appendage obliteration. All patients discharged in sinus rhythm not requiring anticoagulation for preexisting or mechanical prosthetic reasons received antiplatelet therapy only. Neurologic end points were defined as any deficit of abrupt onset not resolving within 24 hours. RESULTS: Of 233 patients discharged, 57 received oral anticoagulants and 176 did not. Thirty-day mortality was 2.9%. Follow-up was 2.2 +/- 1.3 years. During follow-up, 46 of 176 patients received anticoagulation, and 130 of 176 patients did not. In patients without mechanical valves, 87% were off anticoagulation at 1 year, 77% were off anticoagulation at 2 years, and 81% were off anticoagulation at 3 years. Return to sinus rhythm off antiarrhythmic drugs at 1, 2, and 3 years was 81%, 77%, and 68%, respectively. Of patients receiving anticoagulation during follow-up, 11 of 103 (11%) had major bleeds (1 fatal) and 2 (1.9%) developed stroke. In patients without anticoagulation for the entirety of follow-up, 1 stroke occurred at 21 months and 1 stroke occurred at 23 months postoperatively. Cumulative 4-year freedom from stroke in patients without anticoagulation was 97.5%. CONCLUSIONS: Discharging patients who underwent Cox Maze IV in sinus rhythm without oral anticoagulants seems to be safe with a stroke rate of less than 1% per year. This management strategy will need further validation by prospective investigation. PMID- 29274915 TI - Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. AB - Evidence supporting that gut problems are linked to ASD symptoms has been accumulating both in humans and animal models of ASD. Gut microbes and their metabolites may be linked not only to GI problems but also to ASD behavior symptoms. Despite this high interest, most previous studies have looked mainly at microbial structure, and studies on fecal metabolites are rare in the context of ASD. Thus, we aimed to detect fecal metabolites that may be present at significantly different concentrations between 21 children with ASD and 23 neurotypical children and to investigate its possible link to human gut microbiome. Using 1H-NMR spectroscopy and 16S rRNA gene amplicon sequencing, we examined metabolite profiles and microbial compositions in fecal samples, respectively. Of the 59 metabolites detected, isopropanol concentrations were significantly higher in feces of children with ASD after multiple testing corrections. We also observed similar trends of fecal metabolites to previous studies; children with ASD have higher fecal p-cresol and possibly lower GABA concentrations. In addition, Fisher Discriminant Analysis (FDA) with leave-out validation suggested that a group of metabolites-caprate, nicotinate, glutamine, thymine, and aspartate-may potentially function as a modest biomarker to separate ASD participants from the neurotypical group (78% sensitivity and 81% specificity). Consistent with our previous Arizona cohort study, we also confirmed lower gut microbial diversity and reduced relative abundances of phylotypes most closely related to Prevotella copri in children with ASD. After multiple testing corrections, we also learned that relative abundances of Feacalibacterium prausnitzii and Haemophilus parainfluenzae were lower in feces of children with ASD. Despite a relatively short list of fecal metabolites, the data in this study support that children with ASD have altered metabolite profiles in feces when compared with neurotypical children and warrant further investigation of metabolites in larger cohorts. PMID- 29274916 TI - Healthcare reforms in Cyprus 2013-2017: Does the crisis mark the end of the healthcare sector as we know it? AB - As part of a bailout agreement with the International Monetary Fund, the European Commission and the European Central Bank (known as the Troika), Cyprus had to achieve a fiscal surplus through budget constraints and efficiency enhancement. As a result, a number of policy changes were implemented, including a reform of the healthcare sector, and major healthcare reforms are planned for the upcoming years, mainly via the introduction of a National Health System. This paper presents the healthcare sector, provides an overview of recent reforms, assesses the recently implemented policies and proposes further interventions. Recent reforms targeting the demand and supply side included the introduction of clinical guidelines, user charges, introduction of coding for Diagnosis Related Groups (DRGs) and the revision of public healthcare coverage criteria. The latter led to a reduction in the number of people with public healthcare coverage in a time of financial crises, when this is needed the most, while co-payments must be reassessed to avoid creating barriers to access. However, DRGs and clinical guidelines can help improve performance and efficiency. The changes so far are yet to mark the end of the healthcare sector as we know it. A universal public healthcare system must remain a priority and must be introduced swiftly to address important existing coverage gaps. PMID- 29274917 TI - Autophagy and proteostasis in the control of synapse aging and disease. AB - The maintenance of neuronal homeostasis is severely threatened by aging, probably partially due to compromised autophagic clearance. Hence, rejuvenating autophagy in aging neurons is considered a promising strategy to restore cognitive performance. Research in recent years has shown that autophagosome biogenesis takes place mainly in distal axons and, thus, close to presynaptic specializations, and that efficient macro-autophagy is essential for neuronal homeostasis and survival. Retrograde transport of autophagosomes might play a role in neuronal signaling processes, promoting neuronal complexity and preventing neurodegeneration. Here, we discuss recent advances concerning the intersection of aging, neurodegeneration and autophagy, and try to create a unified view of how neuronal autophagy and proteostasis might control synaptic aging and disease. PMID- 29274918 TI - Caring for Migrants and Refugees With End-Stage Kidney Disease in Europe. AB - With the number of migrants and refugees increasing globally, the nephrology community is increasingly confronted with issues relating to the management of end-stage kidney disease in this population, including medical, logistical, financial, and moral-ethical questions. Beginning with data for the state of affairs regarding refugees in Europe and grounded in moral reasoning theory, this Policy Forum Perspective contends that to improve care for this specific population, there is a need for: (1) clear demarcations of responsibilities across the societal (macro), local (meso), and individual (micro) levels, such that individual providers are aware of available resources and able to provide essential medical care while societies and local communities determine the general approach to dialysis care for refugees; (2) additional data and evidence to facilitate decision making based on facts rather than emotions; and (3) better information and education in a broad sense (cultural sensitivity, legal rights and obligations, and medical knowledge) to address specific needs in this population. Although the nephrology community cannot leverage a change in the geopolitical framework, we are in a position to generate accurate data describing the dimensions of care of refugee or migrant patients with end-stage kidney disease to advocate for a holistic approach to treatment for this unique patient population. PMID- 29274919 TI - Use of Lung Ultrasound for the Assessment of Volume Status in CKD. AB - Adequate assessment of fluid status is an imperative objective in the management of all types of patients in cardiology, intensive care, and especially nephrology. Fluid overload is one of the most common modifiable risk factors directly associated with hypertension, heart failure, left ventricular hypertrophy, and eventually, higher morbidity and mortality risk in these categories of patients. Different methods are commonly used to determine fluid status (eg, clinical assessment, natriuretic peptide concentrations, echocardiography, inferior vena cava measurements, or bioimpedance analysis). In recent years, lung ultrasonography (LUS), through the assessment of extravascular lung water, has received growing attention in clinical research. This article summarizes available studies that compare LUS with other methods for fluid status assessment in patients with kidney diseases. At the same time, it also presents the association of LUS with different outcomes (physical functioning, mortality, and cardiovascular events) in the same population. It appears that this simple bedside noninvasive technique has significant clinical potential in nephrology. PMID- 29274920 TI - [Assessing the balance of quality indicator sets of external quality assurance according to SGB V section 136]. AB - INTRODUCTION: The value and usefulness of the results of indicator-based performance measurement in healthcare for different purposes do not only depend on the methodological quality of the individual indicators but also on the composition of the indicator sets. So far, the balance of the currently used indicator sets of the German mandatory national performance measurement system for hospitals has not been systematically analyzed. MATERIAL AND METHODS: Due to the lack of a methodological gold standard for the assessment of balance and orientation of indicator sets we adapted the OECD concept of quality dimensions and defined four categories: 1) "Achieving primary goals of treatment", 2) "Avoiding adverse events", 3) "Indication" and 4) "Patient-centeredness". We defined rules for the assignment to the categories and analyzed the distribution of the 239 indicators from 29 medical areas in relation to these categories. RESULTS: 63 indicators (26.4 %) were assigned to the category "Achieving primary goals of treatment", 153 (64.0 %) to the category "Avoiding adverse events", 18 (7.5 %) to the category "Indication", one indicator (0.4 %) to the category "Patient-centeredness". Four indicators (1.7 %) addressed documentation quality. 12 of the 29 indicator sets only covered one OECD quality dimension by at least one indicator. CONCLUSIONS: The current indicator sets seem to be unbalanced with a strong focus on the category "Avoiding adverse events". As regards the goal of monitoring compliance with minimal safety standards and performing improvement interventions, the direction of the indicator sets seems to be appropriate. With respect to other goals, such as for example the identification of "excellence", further development efforts are required. One relevant reason for the dominant focus on the category "Avoiding adverse events" seems to be that data sources for a follow-up and for the inclusion of the patient perspective have not been available until recently. There is a strong demand for the consequent use of these data sources to optimize the interpretability and value of the current performance measurement. The methodological approach presented may offer useful information to assess the value of indicator sets for different purposes although further development and research is necessary. PMID- 29274921 TI - More Global More Portugal. PMID- 29274922 TI - The role of Bronchoalveolar lavage in Interstitial Lung Diseases. PMID- 29274923 TI - Erratum to "Wood Charcoal Dust Pneumoconiosis". PMID- 29274924 TI - VP2 (PTA motif) encoding DNA vaccine confers protection against lethal challenge with infectious pancreatic necrosis virus (IPNV) in trout. AB - IPNV in Atlantic salmon is represented by various strains with different virulence and immunogenicity linked to various motifs of the VP2 capsid. IPNV variant with P217, T221, A247 (PTA) motif is found to be avirulent in Atlantic salmon, but virulent in rainbow trout, and other salmonid species. This study describes a DNA vaccine delivered intramuscularly encoding the VP2 protein of infectious pancreatic necrosis virus (IPNV) with PTA motif that confers high protection in rainbow trout (Oncorhynchus mykiss). Intramuscular injection of 2, 5 and 10 MUg of DNA (pcDNA3.1-VP2) in rainbow trout fry (4-5 g), confers relative protection of 75-83% in the different vaccine groups at 30 days post vaccination (450 degrees days). The VP2 gene is expressed in spleen, kidney, muscle and liver at day 30 post-vaccination (RT-PCR), and IFN-1 and Mx-1 mRNA are upregulated at early time post vaccination, and so also for IgM, IgT, CD4 and CD8 in the head kidney of vaccinated fish compared to controls, 15 and 30 days post vaccination. Significant increase of serum anti-IPNV antibodies was found 30-90 days post-vaccination that was correlated with protection levels. Mortality corresponded with viral VP4 gene expression were significantly decreased in vaccinated and challenged fish. This shows for the first time that a VP2-encoding DNA vaccine delivered intramuscularly elicits a high level of protection alongside with high levels of circulating antibodies in rainbow trout and a lowered viral replication. PMID- 29274925 TI - Role of complement anaphylatoxin receptors in a mouse model of acute burn-induced pain. AB - The complement system is an essential component of the innate immune response. The anaphylatoxins C3a and C5a are key drivers of the complement system, acting through the receptors C3aR, C5aR1 and C5aR2 to regulate inflammation. While a role for C5a activation of C5aR1 in inflammatory and neuropathic pain has been established, the role of the complement system in burn-induced pain has not been investigated. To address this gap, we assessed the role of complement receptors C3aR, C5aR1 and C5aR2 in a mouse model of acute burn-induced pain. Superficial burn injury was induced in C57BL/6 mice by firm application of left hind paw plantar surface to a hot plate set at 52.5 degrees C for 25 s. Development of burn-induced mechanical allodynia, thermal allodynia, weight bearing changes and edema was assessed in C3aR-/-, C5aR1-/- and C5aR2-/- mice and compared to their wild type controls over three days. Burn-induced mechanical allodynia, thermal allodynia and weight bearing changes developed normally C3aR-/-, C5aR1-/- and C5aR2-/- mice. However, burn-induced edema was significantly reduced in C5aR2-/- male mice, but not C5aR2-/- female mice. These results suggest that the complement system has a limited role in the development of acute burn-induced pain. PMID- 29274926 TI - 3-Methoxytyramine: An independent prognostic biomarker that associates with high risk disease and poor clinical outcome in neuroblastoma patients. AB - INTRODUCTION: Prognosis of neuroblastoma patients is very diverse, indicating the need for more accurate prognostic parameters. The excretion of catecholamine metabolites by most neuroblastomas is used for diagnostic purposes, but their correlation with prognosis has hardly been investigated. Therefore, we performed an in-depth analysis of a panel of elevated urinary catecholamine metabolites at diagnosis and their correlation with prognosis. PATIENTS AND METHODS: Retrospective study of eight urinary catecholamine metabolites in a test (n = 96) and validation (n = 205) cohort of patients with neuroblastoma (all stages) at diagnosis. RESULTS: Multivariate analyses, including risk factors such as stage and MYCN amplification, revealed that 3-methoxytyramine (3MT) was an independent risk factor for event-free survival (EFS) and overall survival (OS). Furthermore, only 3MT appeared to be an independent risk factor for both EFS and OS in high risk patients, which was independent of modern high-risk therapy and immunotherapy. Among high-risk patients, those with elevated 3MT and older than 18 months had an extremely poor prognosis compared to patients with non-elevated 3MT and younger than 18 months (5-year EFS of 14.3% +/- 4% and 66.7% +/- 18%, respectively, p = 0.001; 5-year OS of 21.8% +/- 5% and 87.5% +/- 12%, respectively, p < 0.001). CONCLUSIONS: Elevated 3MT at diagnosis was associated with high-risk disease and poor prognosis. For high-risk patients, elevated 3MT at diagnosis was the only significant risk factor for EFS and OS. 3MT was also able to identify subgroups of high-risk patients with favourable and extremely poor prognosis. PMID- 29274927 TI - Red and processed meat consumption and breast cancer: UK Biobank cohort study and meta-analysis. AB - AIM: Red and processed meat may be risk factors for breast cancer due to their iron content, administration of oestrogens to cattle or mutagens created during cooking. We studied the associations in UK Biobank and then included the results in a meta-analysis of published cohort studies. METHODS: UK Biobank, a general population cohort study, recruited participants aged 40-69 years. Incident breast cancer was ascertained via linkage to routine hospital admission, cancer registry and death certificate data. Univariate and multivariable Cox proportional hazard models were used to explore the associations between red and processed meat consumption and breast cancer. Previously published cohort studies were identified from a systematic review using PubMed and Ovid and a meta-analysis conducted using a random effects model. RESULTS: Over a median of 7 years follow up, 4819 of the 262,195 women developed breast cancer. The risk was increased in the highest tertile (>9 g/day) of processed meat consumption (adjusted hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.08-1.35, p = 0.001). Collation with 10 previous cohort studies provided data on 40,257 incident breast cancers in 1.65 million women. On meta-analysis, processed meat consumption was associated with overall (relative risk [RR] 1.06, 95% CI 1.01-1.11) and post menopausal (RR 1.09, 95% CI 1.03-1.15), but not pre-menopausal (RR 0.99, 95% CI 0.88-1.10), breast cancer. In UK Biobank and the meta-analysis, red meat consumption was not associated with breast cancer (adjusted HR 0.99 95% CI 0.88 1.12 and RR 1.03, 95% CI 0.99-1.08, respectively). CONCLUSIONS: Consumption of processed meat, but not red meat, may increase the risk of breast cancer. PMID- 29274928 TI - Optimal adjuvant endocrine treatment of ER+/HER2+ breast cancer patients by age at diagnosis: A population-based cohort study. AB - BACKGROUND: Prior randomised controlled trials on adjuvant hormonal therapy included HER2any patients; however, a differential effect of aromatase inhibitors (AIs) versus tamoxifen (TAM) may have been missed in ER+/HER2+ patients that comprise 7-15% of all breast cancer patients. In addition, a woman's hormonal microenvironment may influence sensitivity to TAM and AIs in the adjuvant setting, which changes during menopausal transition, a process that takes years. We studied the efficacy of AIs versus TAM in ER+/HER2+ breast cancer patients grouped by age at diagnosis as a proxy for menopausal status using treatment and outcome data from the nationwide population-based Netherlands Cancer Registry (NCR). PATIENTS AND METHODS: All women diagnosed between 2005 and 2007 with endocrine-treated, TanyNanyM0, ER+/HER2+ breast cancer were identified through the NCR (n = 1155). Patients were divided by age at diagnosis: premenopausal (<=45 years; n = 326), perimenopausal (4555 years; n = 525). A time-dependent variable, indicating whether AI or TAM was received for >50% of endocrine treatment duration, was applied to subdivide groups by predominant treatment received. Recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier survival estimation and Cox regression. Hazard ratios (HRs) were adjusted for chemotherapy, trastuzumab, age at diagnosis, N-status, grade, pT-stage and ovarian ablation. RESULTS: During follow-up, 237 recurrences and 182 deaths occurred. Perimenopausal women derived significant RFS and OS benefit from AI compared with TAM, HR 0.47 (95% CI 0.25 0.91; P = 0.03) and HR 0.37 (95% CI 0.18-0.79; P = 0.01), respectively, whereas premenopausal women derived no benefit from AI compared with TAM. Treatment effects differed significantly between these age groups (interaction P = 0.03 and P = 0.02, respectively). Among postmenopausal women a small but non-significant AI benefit was observed. CONCLUSION: AI treatment, preferably without any TAM treatment, was associated with the best RFS and OS outcome in ER+/HER2+ perimenopausal breast cancer patients. PMID- 29274929 TI - ? AB - Neurocutaneous syndromes are heterogenous diseases that are diagnosed in the presence of skin and central nervous system disorders. Neurofibromatosis (NF) is one of these disorders, with autosomal dominant inheritance, that causes tumors that grow on nerves as well as other abnormalities such as skin changes and bone deformities. The most common form of NF is type I. A 6-year-old Iranian boy with neurofibromatosis was referred to the pediatric cardiology clinic due to a soft holosystolic murmur discovered on routine examination. The echocardiographic findings included a large intrapericardial, encapsulated echodense homogenous mass located in the posterior part of the pericardium, attached to the posterior aspect of the left atrium and left ventricle. The mass measured about 6.3*6.5*5.5cm and exerted a compressive effect on the left-side chambers, with mild mitral regurgitation and mild pericardial effusion. Magnetic resonance imaging confirmed these findings showing encasement of the left circumflex artery, while the open biopsy through a midsternotomy procedure showed a mildly cellular mesenchymal tumor composed of spindle cells suggestive of neurofibroma. Further resection of the mass was not performed because of the risk of coronary injury and the stable situation of the patient. Visceral involvement of neurofibroma is uncommon and rarely involves the heart. As shown in this case, besides the chance for involving the pericardium, despite its benign nature, this tumor sometimes shows unusual involvement of structures such as the coronary arteries. PMID- 29274930 TI - Immediate Stress Echocardiography for Low-Risk Chest Pain Patients in the Emergency Department: A Prospective Observational Cohort Study. AB - BACKGROUND: Evaluation and disposition of low-risk chest pain (CP) patients in the emergency department (ED) is time consuming and expensive. Low-risk CP often results in hospital admission to rule out myocardial infarction, which leads to additional costs and delays. OBJECTIVE: Our aim was to assess whether an immediate exercise stress echocardiogram (IESE) in the ED will allow safe, efficient, and cost-effective evaluation and discharge of patients with low-risk CP. METHODS: Low-risk CP patients (TIMI [Thrombolysis in Myocardial Infarction] score 0-1) presenting to the ED with normal electrocardiogram, no history of coronary artery disease, and negative troponin T received IESE. We followed these patients for major adverse cardiac events and compared them to a control cohort of similar-risk patients admitted with traditional care at 1 and 6 months. RESULTS: We enrolled 216 patients, 117 IESE and 109 control. We obtained follow up at 1 and 6 months in 94% of the IESE group and 88% in the control group. There was no difference in diagnostic catheterization or percutaneous coronary intervention between the 2 groups (6.0% and 1.7% vs. 6.4% and 1.8%; p = 0.89). Median time from triage to discharge was significantly shorter with IESE (572.6 min vs. 1466.0 min), resulting in significantly lower cost ($4380.50 vs. $6191.70). There were no adverse events related to IESE or early discharge. CONCLUSIONS: In our study, IESE for low-risk CP patients presenting to the ED has the potential to be equally safe, more expeditious, and more cost effective than admission to an observation unit. PMID- 29274931 TI - External validity of the Psychiatric Diagnostic Screening Questionnaire (PDSQ) in a clinical sample. AB - This study contributes to the convergent and discriminant validity of the Psychiatric Diagnostic Screening Questionnaire (PDSQ) by investigating its correlations with the relevant clinical scales of the Personality Assessment Inventory (PAI) and life space variables, such as relationship status, education level, job loss, and history of suicide attempts. Bivariate correlations were calculated for a sample of 254 psychiatric outpatients. The results indicated that the PDSQ scales demonstrated good to excellent convergent and discriminant validity with target scales from the PAI. They were also found to be meaningfully associated with a variety of life space variables. For example, five of the subscales and the Total Score correlated positively with a recent job loss, and eight of the subscales were negatively associated with education and/or employment status. Some incongruence with hypothesized relationships was discovered for life correlates classified as markers of psychiatric severity. Overall, these findings add to the emerging body of evidence corroborating the convergent and discriminant validity of the PDSQ. PMID- 29274932 TI - Adverse Perinatal Conditions Associated With Prenatally Detected Fetal Echogenic Bowel in Nova Scotia. AB - OBJECTIVE: This study sought to estimate the association of adverse perinatal outcomes with pregnancies complicated by fetal echogenic bowel. METHODS: Data for pregnancies complicated with echogenic bowel identified in the second trimester were derived from the tertiary referral IWK Health Centre (Halifax, NS) Viewpoint Ultrasound Database augmented by medical chart review. The study was undertaken between 2003 and 2014. Rates of positive cytomegalovirus and toxoplasmosis infection were determined using maternal serology and amniocentesis results. Rates of intrauterine growth restriction, abnormal karyotype, cystic fibrosis, antenatal bleeding, and bowel abnormalities were also determined. Neonatal information included newborn urine culture results and postnatal genetic testing. Univariate analyses compared rates of infection with isolated echogenic bowel and echogenic bowel with other ultrasound findings, with statistical significance set at P <0.05. RESULTS: There were 422 pregnancies identified prenatally with echogenic bowel (82% had isolated echogenic bowel). Of these, 92 (22%) had at least one of the foregoing associated abnormalities. Three percent of women had serologic test results positive for cytomegalovirus or toxoplasmosis, with <1% documented newborn infections. Cystic fibrosis and other genetic diagnoses were observed in 8%, intrauterine growth restriction in 14%, antenatal bleeding in 19%, and bowel abnormalities in 3% of the cases of echogenic bowel. Pregnancies with isolated echogenic bowel had an 80% reduction in risk for these significant outcomes, in contrast to a four- to 11-fold increased risk of specific outcomes when additional ultrasound findings were present. CONCLUSION: An overall rate of adverse conditions of 22% with prenatally detected echogenic bowel serves to inform women and health care providers and emphasizes the importance of careful screening fetal ultrasound studies and timely referral for comprehensive assessment with findings of echogenic bowel for evaluation for associated findings. PMID- 29274933 TI - Spontaneous Retroperitoneal Hematomas Following Uncomplicated Vaginal Deliveries: A Case Report and Literature Review. AB - INTRODUCTION: Retroperitoneal hematomas are rare in obstetrics. CASE PRESENTATION: A 36-year-old female presented two days following uncomplicated non traumatic spontaneous vaginal delivery with an acute onset of severe left lower quadrant abdominal pain. The patient was hypotensive, tachycardic, and febrile. The hemoglobin dropped post delivery to 75 g/L. A non-contrast CT scan revealed a retroperitoneal hematoma. MANAGEMENT AND OUTCOME: Conservative management approaches resulted in spontaneous remission of the retroperitoneal hematoma. PMID- 29274934 TI - Perspectives of Immigrant Women on the Gender of Provider During Childbirth. AB - OBJECTIVE: This study sought to gain an understanding of the importance and effect of provider gender for immigrant women accessing obstetrical care. METHODS: A focused ethnography was conducted using purposive sampling of 38 immigrant women from one hospital in Edmonton, Alberta. Data collection consisted of semistructured interviews conducted antenatally (n = 38); an attempt was made to conduct interviews postpartum (n = 21), and intrapartum observations were made (n = 17). Interviews were audio-recorded and transcribed verbatim. Data were managed using qualitative data analysis software and analyzed through thematic analysis. RESULTS: Study participants came from varied educational and ethnic backgrounds (predominately North/East African, Middle Eastern, and South Asian), but most were Muslim (n = 30) and married (n = 36), with a mean age of 27.7. All of the women stated that they preferred a female provider, which they explained in terms of the high value they placed on modesty, often as part of the Muslim faith. The women deemed provider competency and having safe childbirth more important, however, and said that they would accept intrapartum care from a male provider. A small minority of the women reported experiencing psychological stress as a consequence of having received care from a male provider. CONCLUSION: As a whole, our study population accepted care from male providers, yet for some women this compromise came at a price, and a small minority of women perceived it as profoundly detrimental. There is a need to identify those women for whom gender of provider is a substantial barrier, so that optimal support can be provided. PMID- 29274935 TI - Does Low PAPP-A Predict Adverse Placenta-Mediated Outcomes in a Low-Risk Nulliparous Population? the Great Obstetrical Syndromes (GOS) Study. AB - OBJECTIVE: First-trimester low concentration of pregnancy-associated plasma protein A (PAPP-A) has been associated with adverse perinatal outcomes in high risk populations. This study aimed to estimate the ability of PAPP-A to identify adverse outcomes in a low-risk population. METHODS: The study investigators recruited nulliparous women with singleton pregnancy at their 11-13-week ultrasound scan. Serum samples were collected, and maternal PAPP-A concentration was measured using the B?R?A?H?M?S PAPP-A KRYPTOR (ThermoFisher Scientific, Hennigsdorf, Germany) automated assay. PAPP-A was reported in multiple of median (MoM) adjusted for GA. Participants were followed until delivery for pregnancy outcomes including preeclampsia (PE), SGA <3rd percentile, and fetal death. Receiver operating characteristic curves with the area under the curve (AUC) were used to evaluate the predictive value of PAPP-A. The investigators calculated the detection rates (DRs) and positive predictive values (PPVs) of a PAPP-A < 0.4 MoM. RESULTS: The study investigators recruited 4739 eligible participants at a mean GA of 13 +/- 6 weeks. The investigators observed 232 (4.9%) cases of PE, 84 (1.8%) cases of SGA, and 14 (0.3%) fetal deaths. PAPP-A was moderately associated with PE (AUC 0.57; 95% CI 0.53-0.61) and SGA (AUC 0.62; 95% CI 0.56-0.69), but not with fetal death (AUC 0.43; 95% CI 0.23-0.63). PAPP-A < 0.4 MoM was observed in 364 (7.7%) participants and had poor predictive values for PE (DR 9.8%; PPV 6.3%), SGA (DR 18.1%; PPV 4.4%), and fetal death (DR 21.4%; PPV 0.9%). CONCLUSION: Isolated first trimester PAPP-A has a limited predictive value for adverse pregnancy outcomes (other than trisomies). Low PAPP-A (<0.4 MoM) should be used in combination with other markers for the prediction of PE, SGA, or fetal death, and it does not constitute an indication for low-dose aspirin. PMID- 29274936 TI - Re-polarization of nuclear spins using selective SABRE-INEPT. AB - A method is proposed for significant improvement of NMR pulse sequences used in high-field SABRE (Signal Amplification By Reversible Exchange) experiments. SABRE makes use of spin order transfer from parahydrogen (pH2, the H2 molecule in its singlet spin state) to a substrate in a transient organometallic Ir-based complex. The technique proposed here utilizes "re-polarization", i.e., multiple application of an NMR pulse sequence used for spin order transfer. During re polarization only the form of the substrate, which is bound to the complex, is excited by selective NMR pulses and the resulting polarization is transferred to the free substrate via chemical exchange. Owing to the fact that (i) only a small fraction of the substrate molecules is in the bound form and (ii) spin relaxation of the free substrate is slow, the re-polarization scheme provides greatly improved NMR signal enhancement, epsilon. For instance, when pyridine is used as a substrate, single use of the SABRE-INEPT sequence provides epsilon~260 for 15N nuclei, whereas SABRE-INEPT with re-polarization yields epsilon>2000. We anticipate that the proposed method is useful for achieving maximal NMR enhancement with spin hyperpolarization techniques. PMID- 29274937 TI - Enhancing the detection of edges and non-differentiable points in an NMR spectrum using delayed-acquisition. AB - Delayed-acquisition, which is a common technique for improving spectral resolution in Fourier transform based spectroscopies, typically relies upon differences in T2 relaxation rates that are often due to underlying differences in dynamics and/or complexities of the spin systems being studied. After an acquisition delay, the broad signals from fast T2-relaxing species are more suppressed relative to the sharp signals from slow T2-relaxing species. In this paper, an alternative source of differential "dephasing" under delayed acquisition is demonstrated that is based solely upon the mathematical properties of the line shape and is independent of the underlying spin dynamics and/or complexity. Signals associated with frequencies where the line shape either changes sharply and/or is non-differentiable at some finite order dephase at a much slower rate than those signals associated with frequencies where the line shape is smooth. Experiments employing delayed-acquisition to study interfaces in biphasic samples, to measure spatially-dependent longitudinal relaxation, and to highlight sharp features in NMR spectra are presented. PMID- 29274938 TI - Therapies for genetic extracellular matrix diseases of the skin. AB - A specialized, highly developed dermal extracellular matrix (ECM) provides the skin with its unique mechano-resilient properties and is vital for organ function. Accordingly, genetically acquired deficiency of dermal ECM proteins or proteins essential for the post-translational modification and homeostasis of the dermal ECM, results in diseases affecting the skin. Some of these diseases are lethal or lead to severe complications for the affected individuals. At present limited efficient and evidence-based treatment options exist for genetic ECM diseases of the skin. There is thus a high unmet medical need, creating an urgent demand to develop improved care for these diseases. Here, by drawing examples from the wealth of research on epidermolysis bullosa, we present the current status of biological and small molecule therapies for genetic ECM diseases with skin manifestations. We discuss challenges, and using existing data to propose strategies and future directions allowing development of more efficacious therapies and advancement of them into clinical practice. PMID- 29274940 TI - Palliative care and active disease management are synergistic in modern surgical oncology. AB - Palliative care has long been described in medical literature but only recently is being discussed in the surgical domain. Mounting evidence suggests that early integration of palliative care improves patient outcomes and this is especially true of oncology patients. Thus, the pendulum is swinging toward recognizing that palliative care and active disease management are not mutually exclusive but rather synergistic in modern surgical oncology. Here we use a patient vignette to demonstrate the new challenges and possibilities in modern surgical oncology, we then discuss the historic perspective of palliative care and describe how the paradigm is shifting. Finally, we introduce a model that may be beneficial in conceptualizing this new way of thinking about and integrating palliative care into surgical oncology. PMID- 29274939 TI - Matrix biomechanics and dynamics in pulmonary fibrosis. AB - The composition and mechanical properties of the extracellular matrix are dramatically altered during the development and progression of pulmonary fibrosis. Recent evidence indicates that these changes in matrix composition and mechanics are not only end-results of fibrotic remodeling, but active participants in driving disease progression. These insights have stimulated interest in identifying the components and physical aspects of the matrix that contribute to cell activation and disease initiation and progression. This review summarizes current knowledge regarding the biomechanics and dynamics of the ECM in mouse models and human IPF, and discusses how matrix mechanical and compositional changes might be non-invasively assessed, therapeutically targeted, and biologically restored to resolve fibrosis. PMID- 29274941 TI - Developing a robust suturing assessment: validity evidence for the intracorporeal suturing assessment tool. AB - BACKGROUND: Assessment tools specific to intracorporeal suturing are lacking. The purpose of this study was to validate a novel Intracorporeal Suturing Assessment Tool (ISAT) by comparing it with existing measures that have been reported to have validity evidence. METHODS: Videos of laparoscopic suturing were assessed by 3 blinded laparoscopic experts using the validated Global Operative Assessment of Laparoscopic Skills (GOALS) scale and the ISAT. Correlations between these instruments were calculated, and sensitivity analyses compared both tools with objective suturing scores. A factor analysis was also performed. RESULTS: The ISAT and GOALS ratings were significantly correlated with the objective suturing score (r = 0.58 and 0.61, respectively; P < .0001), and with each other (r = 0.92, P < .0001). A weighted kappa test indicated significantly higher agreement than expected between these instruments (P < .0001). All ISAT items had a factor loading approaching or greater than 0.50. CONCLUSION: The ISAT accurately assessed laparoscopic suturing skill related to other instruments. ISAT was highly correlated with GOALS, which is often used for laparoscopic performance assessment. Unlike the generic GOALS, ISAT includes specific information that can provide feedback on trainee suturing ability and targeted performance improvements. ISAT may provide a better alternative for intracorporeal suturing assessment. PMID- 29274942 TI - Discussion. PMID- 29274943 TI - The association between Staphylococcus aureus and subsequent bronchiectasis in children with cystic fibrosis. AB - BACKGROUND: Staphylococcus aureus (S. aureus) may be related to more rapid progression of cystic fibrosis (CF) lung disease. METHODS: In the AREST CF cohort study, children diagnosed with CF undergo annual bronchoscopies with bronchoalveolar lavage and ultra-low-dose, chest computed tomography (CT) up to 6 years-old. Spirometry was assessed 3-monthly from the age of 4years. Associations between de novo S. aureus acquisition before school age and CT and lung function at ages 5-7years were investigated. Models were adjusted for multiple markers of disease severity at baseline. RESULTS: De novo S. aureus acquisition at 3-years old (n/N=12/122) was associated with increased bronchiectasis score at age 5 6years. This association decreased but remained significant after adjustment for confounders. S. aureus at 3 was associated with significantly reduced FEF25-75 at age 5-7years, but not with FEV1-%-predicted. CONCLUSION: De novo S. aureus acquisition at age 3 is associated with later bronchiectasis and FEF25-75 in children with CF. PMID- 29274945 TI - Role of linguistic skills in fifth-grade mathematics. AB - The current study investigated the direct and indirect relations between basic linguistic skills (i.e., phonological skills and grammatical ability) and advanced linguistic skills (i.e., academic vocabulary and verbal reasoning), on the one hand, and fifth-grade mathematics (i.e., arithmetic, geometry, and fractions), on the other, taking working memory and general intelligence into account and controlling for socioeconomic status, age, and gender. The results showed the basic linguistic representations of 167 fifth graders to be indirectly related to their geometric and fraction skills via arithmetic. Furthermore, advanced linguistic skills were found to be directly related to geometry and fractions after controlling for arithmetic. It can be concluded that linguistic skills directly and indirectly relate to mathematical ability in the upper grades of primary education, which highlights the importance of paying attention to such skills in the school curriculum. PMID- 29274944 TI - Attentional fluctuations in preschoolers: Direct and indirect relations with task accuracy, academic readiness, and school performance. AB - Attentional control fluctuates in the presence of internal and external distractors, wandering on and off a given task. The current study investigated individual differences in attentional fluctuations in 250 preschoolers. Attentional fluctuations were assessed via intra-individual variability in response time in a Go/No-Go task. Greater fluctuations in attentional control were linked to lower task accuracy. In addition, greater attentional fluctuations predicted lower performance in a task of cognitive flexibility, the Dimensional Change Card Sort task. Attentional fluctuations were also associated with laboratory measures of academic readiness in preschool, as assessed by the Applied Problems and Letter-Word Identification subscales of the Woodcock-Johnson III Tests of Achievement, which in turn predicted teacher reports of academic performance in first grade. Attentional fluctuations also had indirect associations with emergent math skills in preschool, via cognitive flexibility, as well as indirect associations with first-grade teacher reports of academic performance, via the relations between cognitive flexibility and emergent math skills in preschool. These results suggest that consistency is an important aspect of attentional control during early childhood. PMID- 29274946 TI - More Than Meets the Eye in Using Interleukin 6 as a Marker of Inflammation and Prognostic Factor for Patients With Cirrhosis. PMID- 29274947 TI - Electrically-evoked auditory steady-state responses as neural correlates of loudness growth in cochlear implant users. AB - Loudness growth functions characterize how the loudness percept changes with current level between the threshold and most comfortable loudness level in cochlear implant users. Even though loudness growth functions are highly listener dependent, currently default settings are used in clinical devices. This study investigated whether electrically-evoked auditory steady-state response amplitude growth functions correspond to behaviorally measured loudness growth functions. Seven cochlear implant listeners participated in two behavioral loudness growth tasks and an EEG recording session. The 40-Hz sinusoidally amplitude-modulated pulse trains were presented to CI channels stimulating at a more apical and basal region of the cochlea, and were presented at different current levels encompassing the listeners' dynamic ranges. Behaviorally, loudness growth was measured using an Absolute Magnitude Estimation and a Graphic Rating Scale with loudness categories. A good correspondence was found between the response amplitude functions and the behavioral loudness growth functions. The results are encouraging for future advances in individual, more automatic, and objective fitting of cochlear implants. PMID- 29274948 TI - Associations of maternal exposure to organophosphate and pyrethroid insecticides and the herbicide 2,4-D with birth outcomes and anogenital distance at 3 months in the Odense Child Cohort. AB - In Odense Child Cohort (OCC), concentrations of the pesticide metabolites 3 phenoxybenzoic acid (3-PBA), 3,5,6-trichloro-2-pyridinol (TCPY), 2,4 Dichlorophenoxyacetic acid (2,4-D) and dialkyl phosphates (DAPs) were measured in urine samples collected in gestational week 28 in up to 858 women. Gestational length, birth weight, head and abdominal circumference were obtained from birth records and anogenital distance (AGD) was measured at age three month. We did not find consistent dose-related associations between pesticide metabolite concentrations and birth outcomes or AGD. However, females tended to have shorter abdominal circumference with higher maternal 3-PBA concentrations (beta: -0.3 (95% CI: -0.5, -0.003) cm). Further, a non-significant dose-related elongation of AGD in females was seen for 3-PBA (p-trend: 0.14) and diethyl phosphates (p trend: 0.08). In males, exposure to 2,4-D in the second compared to the first tertile showed a statistically significant shorter AGD (beta: -1.55 (-2.81, 0.28) mm). These findings may suggest a weak disturbance of sex-hormone action. PMID- 29274949 TI - What works better? Food cue exposure aiming at the habituation of eating desires or food cue exposure aiming at the violation of overeating expectancies? AB - OBJECTIVE: This study tested the role of habituation of eating desires and violation of overeating expectancies during food cue exposure in obese women. METHOD: 52 obese females were randomised into a two-session exposure condition aimed at habituation, a two-session exposure condition aimed at expectancy violation, or a no-treatment control condition. Eating in the absence of hunger of foods included during cue exposure (i.e., exposed foods) and foods not included during cue exposure (i.e., non-exposed foods), and duration of exposure were measured. RESULTS: Both cue exposure conditions ate significantly less of the exposed foods compared to the control condition, though there were no differences between both types of exposure. No differences were found between conditions regarding the eating of non-exposed foods. In addition, the duration of exposure was not different between both cue exposure conditions. CONCLUSIONS: While food cue exposure in obese women led to less eating of exposed foods, focusing on either habituation of eating desires or expectancy violation did not matter. It is discussed why exposure works. PMID- 29274950 TI - Knowledge about epilepsy in university health students: A multicenter study. AB - Even with economic development and improvements in health care around the world, it is estimated that nowadays, 50 million people have epilepsy. It is one of the most prevalent neurological diseases, yet it is still surrounded by prejudice, stigma, lack of awareness, and wrong attitudes of the population towards the disease. The aim of this study was to evaluate and compare the knowledge about epilepsy in health students from different countries: Brazil, Argentina, Portugal, United States, and South Africa. Students were asked to complete a survey regarding knowledge about epilepsy (the Epilepsy Knowledge Questionnaire). One hundred and two students participated, 62.2% of them were female. Portuguese students had significantly higher values than the American ones (p=0.025). Regarding the medical aspects, on average, students hit 63.8% of the questions, and the students from Portugal had significantly higher average than the ones from the United States (p=0.0007). Statements with lower percent of correct answers were about pathophysiology, medication, and treatment of the disease. There were no differences between the scores obtained by the students of each country in the social aspects of the disease. Statements with higher percent of mistakes were about sports practice, labor, proceedings in case of convulsion, and ability to drive vehicles. General knowledge of senior health students about epilepsy was considered low, however, regarding the medical aspects of the disease, students from Brazil and Portugal exhibited a slightly superior knowledge. Changing the way of seeing and treating people with epilepsy brings, as a consequence, increased opportunities for these people in different sectors of society. PMID- 29274951 TI - Correlation Between the Posterior Mandibular Width and the Lingual Gap Caused by Symphyseal Fractures Using a Virtual Model. AB - PURPOSE: The objective was to determine the dimensional impact, on the occlusal and articular level, of the gap produced in the lingual plate from symphyseal fractures, correlated with the dimensional change in the posterior mandibular width. MATERIALS AND METHODS: We performed an observational experimental study based on 30 computed tomography scans of patients treated by the Maxillofacial Surgery Service, Hospital Clinico Mutual de Seguridad, Santiago, Chile, between 2012 and 2016. The inclusion criteria were jaws without evidence of fractures or pathology, with an absence of orthodontic appliances, and with complete dentition to the first mandibular molar. By use of Digital Dental Service 3-dimensional planning software (DDS-Pro; Digital Dental Service, London, UK), a vertical mandibular fracture was made, leaving lingual gaps of 1, 2, and 3 mm, and the dimensional changes were recorded with regard to the posterior facial width. RESULTS: The mandibular height did not vary with regard to the lingual gap; the mandibular length was inversely proportional to the lingual gap; and the intermolar, intergonial, and intercondylar distances were directly proportional to increases in the lingual gap. CONCLUSIONS: The larger the lingual gap, the shorter the mandibular length and the larger the mandibular transverse dimensions. Special attention must be paid to the occlusal and articular level. PMID- 29274952 TI - Corrigendum to "Mortality and morbidity among hospitalized adult patients with neurological diseases in Cameroon" [J. Neurol. Sci. 381C (2017) 156-168]. PMID- 29274954 TI - An Investigation Into the Differences in Bone Density and Body Composition Measurements Between 2 GE Lunar Densitometers and Their Comparison With a 4 Component Model. PMID- 29274953 TI - Non-indigenous macrozoobenthic species on hard substrata of selected harbours in the adriatic sea. AB - The intense shipping traffic characterising the Adriatic Sea favours the spread of marine organisms. Yet, a study of 12 Adriatic ports (4 on the western side and 8 on the eastern side of the basin) found that non-indigenous species (NIS) accounted for only 4% of the benthic communities settled on hard substrates. The cirripeds Amphibalanus amphitrite and Balanus trigonus, found in 8 harbours, were the most common invaders followed by Amphibalanus eburneus, the ascidian Styela plicata, and the bivalve Magallana gigas. The highest percentage of NIS was recorded in Venice and Ploce, the harbours with the least rich native communities; the lowest percentage was retrieved in Trieste, Koper, Pula, and Rijeka, the harbours hosting the highest species diversity. In contrast, the ports of Bari and Ancona showed both high NIS percentages and highly diversified communities. PMID- 29274955 TI - Injury severity analysis in taxi-pedestrian crashes: An application of reconstructed crash data using a vehicle black box. AB - In-vehicle recording devices have enabled recent changes in methodological paradigms for traffic safety research. Such devices include event data recorders (EDRs), vehicle black boxes (VBBs), and various sensors used in naturalistic driving studies (NDSs). These technologies may help improve the validity of models used to assess impacts on traffic safety. The objective of this study is to analyze the injury severity in taxi-pedestrian crashes using the accurate crash data from VBBs, such as the time-to-collision (TTC), speed, angle, and region of the crash. VBB data from a two-year period (2010-2011) were collected from taxis operating in Incheon, South Korea. An ordered probit model was then applied to analyze the injury severity in crashes. Five variables were found to have a greater effect on injury severity: crash speed, crashes in no-median sections, crashes where the secondary impact object of pedestrians was the crash vehicle, crashes where the third impact object of pedestrians was another moving vehicle, and crashes where the third impact region of pedestrians was their head. However, injuries were less severe in crashes where the first impact region on the pedestrian was their leg, crashes with the car moving in a straight line, and crashes involving junior high school students. PMID- 29274956 TI - Epigenetic mechanisms contribute to decrease stearoyl-CoA desaturase 1 expression in the liver of dairy cows after prolonged feeding of high-concentrate diet. AB - Subacute ruminal acidosis (SARA) of dairy cattle is a widely occurring but not very overt metabolic disorder thought to impair milk composition. The enzyme stearoyl-CoA desaturase 1 (SCD1) is rate-limiting for the formation of Delta-9 unsaturated fatty acids and thus crucially involved in controlling lipid metabolism in the liver. It is known that SCD1 expression is downregulated during SARA, but the underlying molecular mechanisms are unknown. To study these mechanisms, we enrolled 12 healthy multiparous mid-lactation Holstein cows into a diet-induced SARA experiment. Six cows were fed a high-concentrate diet for 18 weeks (60% content of high-concentrate to 40% forage; HC group), whereas the others received a low-concentrate diet ad libitum (40% high-concentrate content to 60% forage; LC group). Sustained low ruminal pH values (pH 5.6 maintained for 4 h/d) and reduced milk yield performance (2.07 kg/d less than LC cows) verified that SARA had been induced in the HC group. Results showed a significantly decreased concentrations of cis-9 monounsaturated long-chain fatty acids in plasma collected from hepatic but not portal veins. This was matched by reduced SCD1 mRNA and protein concentrations in HC livers. The expression levels of genes related to lipid formation (DGAT1 and PLIN2) were downregulated during SARA, whereas those of catabolic genes (CPT1A, CPT2, and ACOX1) and some inflammatory genes were upregulated. Expression of SCD1 was downregulated through reduced transcription and abundance of the transcription factor sterol regulatory element binding protein 1 (SREBP1c).This effect was augmented by local chromatin tightening and DNA methylation at and around the SREBP1c binding site in the SCD1 promoter. Chromatin immunoprecipitation assays confirmed that SARA reduced SREBP1c binding at the SCD1 promoter; hence, epigenetic mechanisms are involved in regulating the expression of genes related to long-chain fatty acid modification, partially through downregulation of both SCD1 and SREBP1c in the liver. Our results suggest that in addition to inflammatory genes, SCD1 is also involved in SARA-induced epigenetic regulation and its associated metabolic changes. This knowledge might help to provide a target for intervening against the detrimental metabolic effects of SARA. PMID- 29274957 TI - Phenotypic, fermentation characterization, and resistance mechanism analysis of bacteriophage-resistant mutants of Lactobacillus delbrueckii ssp. bulgaricus isolated from traditional Chinese dairy products. AB - Bacteriophage infection is a large factor in dairy industrial production failure on the basis of pure inoculation fermentation, and developing good commercial starter cultures from wild dairy products and improving the environmental vigor of starter cultures by enhancing their phage resistance are still the most effective solutions. Here we used a spontaneous isolation method to obtain bacteriophage-resistant mutants of Lactobacillus delbrueckii ssp. bulgaricus strains that are used in traditional Chinese fermented dairy products. We analyzed their phenotypes, fermentation characteristics, and resistance mechanisms. The results showed that bacteriophage-insensitive mutants (BIM) BIM8 and BIM12 had high bacteriophage resistance while exhibiting fermentation and coagulation attributes that were as satisfying as those of their respective parent strains KLDS1.1016 and KLDS1.1028. According to the attachment receptor detection, mutants BIM8 and BIM12 exhibited reduced absorption to bacteriophage phiLdb compared with their respective bacteriophage-sensitive parent strains because of changes to the polysaccharides or teichoic acids connected to their peptidoglycan layer. Additionally, genes, including HSDR, HSDM, and HSDS, encoding 3 subunits of a type I restriction-modification system were identified in their respective parent strains. We also discovered that HSDR and HSDM were highly conserved but that HSDS was variable because it is responsible for the DNA specificity of the complex. The late lysis that occurred only in strain KLDS1.1016 and not in strain KLDS1.1028 suggests that the former and its mutant BIM8 also may have an activatable restriction-modification mechanism. We conclude that the L. bulgaricus BIM8 and BIM12 mutants have great potential in the dairy industry as starter cultures, and their phage-resistance mechanism was effective mainly due to the adsorption interference and restriction-modification system. PMID- 29274958 TI - Symposium review: Mining metagenomic and metatranscriptomic data for clues about microbial metabolic functions in ruminants. AB - Metagenomics and metatranscriptomics can capture the whole genome and transcriptome repertoire of microorganisms through sequencing total DNA/RNA from various environmental samples, providing both taxonomic and functional information with high resolution. The unique and complex rumen microbial ecosystem is receiving great research attention because the rumen microbiota coevolves with the host and equips ruminants with the ability to convert cellulosic plant materials to high-protein products for human consumption. To date, hundreds to thousands of microbial phylotypes have been identified in the rumen using culture-independent molecular-based approaches, and genomic information of rumen microorganisms is rapidly accumulating through the single genome sequencing. However, functional characteristics of the rumen microbiome have not been well described because there are numerous uncultivable microorganisms in the rumen. The advent of metagenomics and metatranscriptomics along with advanced bioinformatics methods can help us better understand mechanisms of the rumen fermentation, which is vital for improving nutrient utilization and animal productivity. Therefore, in this review, we summarize a general workflow to conduct rumen metagenomics and metatranscriptomics and discuss how the data can be interpreted to be useful information. Moreover, we review recent literatures studying associations between the rumen microbiome and host phenotypes (e.g., feed efficiency and methane emissions) using these approaches, aiming to provide a useful guide to include studying the rumen microbiome as one of the research objectives using these 2 approaches. PMID- 29274959 TI - Short communication: Snapshot of industry milk hauling practices in the western United States. AB - The Pasteurized Milk Ordinance (PMO) mandates milk hauling sanitation and operational practices; however, the use of vague language (i.e., "as needed") and gaps in processes lead to variability in industry practices. Our aim was to characterize industry milk hauling practices and identify areas that may be an unexplained source of contamination in the dairy processing continuum, and communicate this information with industry to cultivate best practices. The objectives of this study were to (1) survey industry hauling sanitation and operation practices in the Pacific Northwest region of the United States, and (2) quantify microbial populations [aerobic plate count (APC), lactic acid bacteria, coliforms] on the internal surfaces of transfer hoses (tanker and receiving bay) to determine their potential contribution to the microbiological quality of raw milk. Eleven facilities (78% response rate) participated in our survey. All facilities surveyed were compliant with the PMO; however, overall milk reception layout, sanitation practices, and routine maintenance greatly varied between facilities. Farm hose samples (n = 115) had significantly higher microbial loads (APC: mean 4.7 log cfu/100 cm2; median 5.1 log cfu/cm2) than receiving hose samples (n = 57; APC: mean: 2.1 log cfu/100 cm2; median 1.9 log cfu/100 cm2). Microbial populations on transfer hose surfaces did not correlate with time since last cleaning for either tanker or receiving bay hoses. Microbial content of farm hoses is likely to reflect the microbial quality of the previous milk transferred through the hose, making on-farm management practices the primary consideration to maintain low microbiological counts downstream. Upon arrival at the processor, 10% of farm hoses were missing caps. Although this did not correlate with elevated microbiological counts, uncapped farm hoses are exposed to the farm environment, provide opportunity for contamination, and are in violation of the PMO. Through observations made during our studies, manual cleaning procedures appear to be a major weakness in hauling practices and need more attention. Recognizing and communicating variability and areas of weakness allows industry to elevate their hauling sanitation and operational practices to maintain optimum milk microbiological quality. PMID- 29274960 TI - Bacterial diversity and composition of alfalfa silage as analyzed by Illumina MiSeq sequencing: Effects of Escherichia coli O157:H7 and silage additives. AB - The first objective of this study was to examine effects of adding Escherichia coli O157:H7 with or without chemical or microbial additives on the bacterial diversity and composition of alfalfa silage. The second objective was to examine associations between the relative abundance of known and unknown bacterial species and indices of silage fermentation quality. Alfalfa forage was harvested at 54% dry matter, chopped to a theoretical length of cut of 19 mm, and ensiled in quadruplicate in laboratory silos for 100 d after the following treatments were applied: (1) distilled water (control); (2) 1 * 105 cfu/g of E. coli O157:H7 (EC); (3) EC and 1 * 106 cfu/g of Lactobacillus plantarum (EC+LP); (4) EC and 1 * 106 cfu/g of Lactobacillus buchneri (EC+LB); and (5) EC and 0.22% propionic acid (EC+PA). After 100 d of ensiling, the silage samples were analyzed for bacterial diversity and composition via the Illumina MiSeq platform (Illumina Inc., San Diego, CA) and chemically characterized. Overall, Firmicutes (74.1 +/- 4.86%) was the most predominant phylum followed by Proteobacteria (20.4 +/- 3.80%). Relative to the control, adding E. coli O157:H7 alone at ensiling did not affect bacterial diversity or composition but adding EC+LP or EC+LB reduced the Shannon index, a measure of diversity (3.21 vs. 2.63 or 2.80, respectively). The relative abundance of Firmicutes (69.2 and 68.8%) was reduced, whereas that of Proteobacteria (24.0 and 24.9%) was increased by EC+LP and EC+PA treatments, relative to those of the control (79.5 and 16.5%) and EC+LB (77.4 and 18.5%) silages, respectively. Compared with the control, treatment with EC+LP increased the relative abundance of Lactobacillus, Sphingomonas, Pantoea, Pseudomonas, and Erwinia by 426, 157, 200, 194, and 163%, respectively, but reduced those of Pediococcus, Weissella, and Methylobacterium by 5,436, 763, and 250%, respectively. Relative abundance of Weissella (9.19%) and Methylobacterium (0.94%) were also reduced in the EC+LB silage compared with the control (29.7 and 1.50%, respectively). Application of propionic acid did not affect the relative abundance of Lactobacillus, Weissella, or Pediococcus. Lactate concentration correlated positively (r = 0.56) with relative abundance of Lactobacillus and negatively (r = -0.41) with relative abundance of Pediococcus. Negative correlations were detected between ammonia-N concentration and relative abundance of Sphingomonas (r = -0.51), Pantoea (r = -0.46), Pseudomonas (r = -0.45), and Stenotrophomonas (r = -0.38). Silage pH was negatively correlated with relative abundance of Lactobacillus (r = -0.59), Sphingomonas (r = -0.66), Pantoea (r = 0.69), Pseudomonas (r = -0.69), and Stenotrophomonas (r = -0.50). Future studies should aim to speciate, culture, and determine the functions of the unknown bacteria detected in this study to elucidate their roles in silage fermentation. PMID- 29274961 TI - Technical note: Development and validation of a new method for the quantification of soluble and micellar calcium, magnesium, and potassium in milk. AB - Milk mineral content is a key trait for its role in dairy processes such as cheese-making, its use as source of minerals for newborns, and for all traits involving salt-protein interactions. This study investigated a new method for measuring mineral partition between soluble and micellar fractions in bovine milk after rennet coagulation. A new whey dilution step was added to correct the quantification bias due to whey trapped in curd and excluded volume. Moreover, the proposed method allowed the quantification of the diffusible volume after milk coagulation. Milk mineral content and concentration in whey, and diluted whey were quantified by acid digestion and inductively coupled plasma optical emission spectrometry. The repeatability of the method for micellar Ca, Mg, and K was between 2.07 and 8.96%, whereas reproducibility ranged from 4.01 to 9.44%. Recovery of total milk minerals over 3 spiking levels ranged from 92 to 97%. The proposed method provided an accurate estimation of micellar and soluble minerals in milk, and curd diffusible volume. PMID- 29274962 TI - Genetic parameters for body weight from birth to calving and associations between weights with test-day, health, and female fertility traits. AB - A data set including 57,868 records for calf birth weight (CABW) and 9,462 records for weight at first insemination (IBW) were used for the estimation of direct and maternal genetic effects in Holstein Friesian dairy cattle. Furthermore, CABW and IBW were correlated with test-day production records and health traits in first-lactation cows, and with nonreturn rates in heifers. Health traits considered overall disease categories from the International Committee for Animal Recording diagnosis key, including the general disease status, diarrhea, respiratory diseases, mastitis, claw disorders, female fertility disorders, and metabolic disorders. For single-trait measurements of CABW and IBW, animal models with maternal genetic effects were applied. The direct heritability was 0.47 for CABW and 0.20 for IBW, and the direct genetic correlation between CABW and IBW was 0.31. A moderate maternal heritability (0.19) was identified for CABW, but the maternal genetic effect was close to zero for IBW. The correlation between direct and maternal genetic effects was antagonistic for CABW (-0.39) and for IBW (-0.24). In bivariate animal models, only weak genetic and phenotypic correlations were identified between CABW and IBW with either test-day production or health traits in early lactation. Apart from metabolic disorders, there was a general tendency for increasing disease susceptibilities with increasing CABW. The genetic correlation between IBW and nonreturn rates in heifers after 56 d and after 90 d was slightly positive (0.18), but close to zero when correlating nonreturn rates with CABW. For the longitudinal BW structure from birth to the age of 24 mo, random regression models with the time-dependent covariate "age in months" were applied. Evaluation criteria (Bayesian information criterion and residual variances) suggested Legendre polynomials of order 3 to modeling the longitudinal body weight (BW) structure. Direct heritabilities around birth and insemination dates were slightly larger than estimates for CABW and IBW from the single-trait models, but maternal heritabilities were exactly the same from both models. Genetic correlations between BW were close to 1 for neighboring age classes, but decreased with increasing time spans. The genetic correlation between BW at d 0 (birth date) and at 24 mo was even negative (-0.20). Random regression model estimates confirmed the antagonistic relationship between direct and maternal genetic effects, especially during calfhood. This study based on a large data set in dairy cattle confirmed genetic parameters and (co)variance components for BW as identified in beef cattle populations. However, BW records from an early stage of life were inappropriate early predictors for dairy cow health and productivity. PMID- 29274963 TI - Short communication: Evaluation of 5 different ELISA for the detection of bovine leukemia virus antibodies. AB - Although Canadian dairy herds have been infected with bovine leukemia virus (BLV) for years, recent research has put new emphasis on the potential negative effects of this infection. Consequently, BLV control is becoming more favorable; however, BLV control cannot be successful without identifying infected animals. Bovicheck BLV (Biovet, Saint-Hyacinthe, QC, Canada) is currently the only assay licensed by the Canadian Centre for Veterinary Biologics. The first goal of this study was, therefore, to determine the reproducibility of the Bovicheck BLV assay for serum samples derived from Canadian cattle. The second goal was to evaluate and compare 5 different ELISA and determine their test characteristics using serum samples from Canadian herds. The considered ELISA were Bovicheck BLV, ID Screen BLV Competition (IDvet, Grabels, France), Idexx Leukosis Serum X2 Ab Test (Idexx Europe B.V., Hoofddorp, the Netherlands), Svanovir BLV gp51-Ab (Svanova, Uppsala, Sweden), and the Serelisa BLV Ab Mono Indirect (Synbiotics, Lyon, France). Eighty serum samples from Canadian cattle provided by Prairie Diagnostic Services (PDS; Saskatoon, SK, Canada) and an additional 80 serum samples from Canadian dairy and beef herds were used for the study. The Bovicheck BLV assay yielded the same results for all PDS-derived samples, implying a high level of reproducibility and robustness of this assay. Additionally, the comparison of the assays' results showed high agreement between assays, with Cohen's kappa values between kappa = 0.91 and kappa = 1. Furthermore, using original test results of the field samples as true status, relative diagnostic sensitivity and specificity were calculated. Relative diagnostic sensitivity of all tests was 100%. False-positive results were probable; therefore, the following relative diagnostic specificities were determined: 100% for Bovicheck BLV, Idexx Leukosis Serum X2, and Svanovir BLV; 95% for ID Screen BLV; and 97% for Serelisa BLV. When considering other test characteristics, ID Screen BLV is exceptional due to considerable practical advantages. PMID- 29274964 TI - Prevalence of Salmonella enterica, Listeria monocytogenes, and pathogenic Escherichia coli in bulk tank milk and milk filters from US dairy operations in the National Animal Health Monitoring System Dairy 2014 study. AB - The dairy farm environment is a well-documented reservoir for zoonotic pathogens such as Salmonella enterica, Shiga-toxigenic Escherichia coli, and Listeria monocytogenes, and humans may be exposed to these pathogens via consumption of unpasteurized milk and dairy products. As part of the National Animal Health Monitoring System Dairy 2014 study, bulk tank milk (BTM, n = 234) and milk filters (n = 254) were collected from a total of 234 dairy operations in 17 major dairy states and analyzed for the presence of these pathogens. The invA gene was detected in samples from 18.5% of operations and Salmonella enterica was isolated from 18.0% of operations. Salmonella Dublin was detected in 0.7% of operations. Sixteen Salmonella serotypes were isolated, and the most common serotypes were Cerro, Montevideo, and Newport. Representative Salmonella isolates (n = 137) were tested against a panel of 14 antimicrobials. Most (85%) were pansusceptible; the remaining were resistant to 1 to 9 antimicrobials, and within the resistant strains the most common profile was resistance to ampicillin/clavulanic acid, ampicillin, cefoxitin, ceftiofur, ceftriaxone, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline. Listeria spp. were isolated from 19.9% of operations, and L. monocytogenes was isolated from 3.0% of operations. Serogroups 1/2a and 1/2b were the most common, followed by 4b and 4a. One or more E. coli virulence genes were detected in the BTM from 30.5% of operations and in the filters from 75.3% of operations. A combination of stx2, eaeA, and gamma-tir genes was detected in the BTM from 0.5% of operations and in the filters from 6.6% of operations. The results of this study indicate an appreciable prevalence of bacterial pathogens in BTM and filters, including serovars known to infect humans. PMID- 29274965 TI - Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Lactation performance and energy metabolism. AB - The objectives of this experiment were to evaluate the effects of feeding diets with 2 dietary cation-anion difference (DCAD) levels and supplemented with either cholecalciferol (CH) or calcidiol (CA) during late gestation on lactation performance and energetic metabolism in dairy cows. The hypothesis was that combining a prepartum acidogenic diet with calcidiol supplementation would benefit peripartum Ca metabolism and, thus, improve energy metabolism and lactation performance compared with cows fed an alkalogenic diet or cholecalciferol. Holstein cows at 252 d of gestation were blocked by parity (28 nulliparous and 51 parous cows) and milk yield within parous cows, and randomly assigned to 1 of 4 treatments arranged as a 2 * 2 factorial, with 2 levels of DCAD (positive, +130, and negative, -130 mEq/kg) and 2 sources of vitamin D, CH or CA, fed at 3 mg per 11 kg of diet dry matter (DM). The resulting treatment combinations were positive DCAD with CH (PCH), positive DCAD with CA (PCA), negative DCAD with CH (NCH), or negative DCAD with CA (NCA), which were fed for the last 21 d of gestation. After calving, cows were fed the same lactation diet. Body weight and body condition were evaluated prepartum and for the first 49 d postpartum. Blood was sampled thrice weekly prepartum, and on d 0, 1, 2, 3, and every 3 d thereafter until 30 d postpartum for quantification of hormones and metabolites. Lactation performance was evaluated for the first 49 d postpartum. Feeding a diet with negative DCAD reduced DM intake in parous cows by 2.1 kg/d, but no effect was observed in nulliparous cows. The negative DCAD reduced concentrations of glucose (positive = 4.05 vs. negative = 3.95 mM), insulin (positive = 0.57 vs. negative = 0.45 ng/mL), and insulin-like growth factor-1 (positive = 110 vs. negative = 95 ng/mL) prepartum. Treatments did not affect DM intake postpartum, but CA-supplemented cows tended to produce more colostrum (PCH = 5.86, PCA = 7.68 NCH = 6.21, NCA = 7.96 +/- 1.06 kg) and produced more fat corrected milk (PCH = 37.0, PCA = 40.1 NCH = 37.5, NCA = 41.9 +/- 1.8 kg) and milk components compared with CH-supplemented cows. Feeding the negative DCAD numerically increased yield of fat-corrected milk by 1.0 kg/d in both nulliparous and 1.4 kg/d in parous cows. Minor differences were observed in postpartum concentrations of hormones and metabolites linked to energy metabolism among treatments. Results from this experiment indicate that replacing CH with CA supplemented at 3 mg/d during the prepartum period improved postpartum lactation performance in dairy cows. PMID- 29274966 TI - Fetuin-A: A negative acute-phase protein linked to adipose tissue function in periparturient dairy cows. AB - Fetuin-A (FetA) is a free fatty acid transporter and an acute-phase protein that enhances cellular lipid uptake and lipogenesis. In nonruminants, FetA is involved in lipid-induced inflammation. Despite FetA importance in lipid metabolism and inflammation, its expression and dynamics in adipose tissue (AT) of dairy cows are unknown. The objectives of this study were to (1) determine serum and AT FetA dynamics over the periparturient period and in mid-lactation cows in negative energy balance (NEB) after a feed restriction protocol and (2) characterize how an inflammatory challenge affects adipocyte FetA expression. Blood and subcutaneous AT were collected from 16 cows with high (>=3.75, n = 8) or moderate (<=3.5, n = 8) body condition score (BCS) at -26 +/- 7 d (far off) and -8 +/- 5 d (close up) before calving and at 10 +/- 2 d after parturition (early lactation) and from 14 nonpregnant mid-lactation cows (>220 d in milk) after a feed restriction protocol. Serum FetA concentrations were 0.89 +/- 0.13 mg/mL at far off, 0.96 +/- 0.13 mg/mL at close up, and 0.77 +/- 0.13 mg/mL at early lactation and were 1.09 +/- 0.09 and 1.17 +/- 0.09 mg/mL in feed-restricted and control cows, respectively. Serum and AT FetA contents decreased at the onset of lactation when lipolysis was higher. No changes in AT and serum FetA were observed after feed restriction induced NEB in mid-lactation cows. Prepartum BCS had no effect on serum FetA, but AT expression of AHSG, the gene encoding FetA, was reduced in periparturient cows with high BCS at dry-off throughout all time points. Circulating FetA was positively associated with serum albumin and calcium and with BCS variation over the periparturient period. The dynamics of AHSG expression were analogous to the patterns of lipogenic markers ABDH5, ELOVL6, FABP4, FASN, PPARgamma, and SCD1. Expression of AHSG and FetA protein in AT was inversely correlated with AT proinflammatory markers CD68, CD44, SPP1, and CCL2. In vitro, bovine adipocytes challenged with lipopolysaccharide downregulated FetA protein expression. Adipocytes treated with FetA had lower CCL2 expression compared with those exposed to lipopolysaccharide. Overall, FetA is a systemic and local AT negative acute-phase protein linked to AT function in periparturient cows. Furthermore, FetA may support physiological adaptations to NEB in periparturient cows. PMID- 29274967 TI - Milk basic protein supplementation exerts an anti-inflammatory effect in a food allergic enteropathy model mouse. AB - To examine novel functions of milk basic protein (MBP) in T-cell-related inflammatory diseases, such as autoimmune diseases and allergies, we evaluated the effects of MBP on the causative responses of ovalbumin (OVA)-specific T cells in a food-allergic enteropathy model, OVA23-3 mice, which express an OVA-specific T-cell receptor gene. The OVA-specific CD4+ T cells of the mesenteric lymph nodes (MLN) from OVA23-3 mice were cultured with CD11c+ dendritic cells of MLN from BALB/cA mice in the absence or presence of MBP following stimulation with OVA; then the levels of CD69 expression and the levels of cytokine production by CD4+ T cells were measured to evaluate activation. The effects of MBP supplementation of OVA 23-3 mice were assessed by feeding a diet containing OVA (OVA diet) with or without MBP for 28 d. Intestinal inflammation, together with activation and cytokine production of CD4+ T cells by MLN, as well as femoral bone mineral density, were measured. In in vitro culture, MBP inhibited excess activation and IL-4 production by CD4+ T cells. The supplementation of MBP to the OVA diet attenuated OVA-specific IgE production in OVA-diet-fed OVA23-3 mice and slightly resolved developing enteropathy caused by excess IL-4 production by CD4+ T cells. Feeding OVA diet to OVA23-3 mice exhibited bone loss accompanied with enteropathy, whereas MBP supplementation prevented bone loss and increased osteoprotegerin, an osteoclastogenesis inhibitory factor, in the mice. The inhibition of T-cell-activation in both MLN and bone marrow by MBP supplementation may help prevent increased IgE levels caused by excessive IL-4 production and bone loss accompanied by enteropathy. Our findings show that MBP may help attenuate both T-cell-related inflammation and bone loss. PMID- 29274968 TI - Prevalence of lameness and leg lesions of lactating dairy cows housed in southern Brazil: Effects of housing systems. AB - Within the last few decades, the North American and European dairy industries have been collecting information about lameness and leg injury prevalence on dairy farms and have tried to develop solutions to mitigate these ailments. Few published articles report the prevalence of lameness and leg lesions in areas outside of those 2 regions, or how alternative housing systems, such as compost bedded packs, affect the prevalence of these maladies. The objectives of this study were to compare the prevalence of lameness and leg lesions on confined dairies that used freestall, compost-bedded packs, or a combination of these 2 systems in Brazil. Data were collected in the autumn and winter of 2016 from 50 dairy farms located in Parana state, including 12 compost-bedded pack dairies (CB), 23 freestall dairies (FS), and 15 freestall dairies that used compost bedded packs for vulnerable cows (FS+C). A visit to the farm consisted of a management questionnaire, an inspection of the housing areas as well as the milking parlor, and an evaluation of all lactating cows as they exited the parlor for lameness (score 1-5), hygiene (score 0-2), body condition score (score 1-5), and hock and knee lesions (score 0-1). Median 1-way chi-squared test was used to compare production systems. We found no difference between farm types in management practices related to hoof health management or average daily milk production per cow [31 (29-33.9) kg/d; median (quartile 1-3)], percentage of Holstein cattle in the herd [100% (90-100%)], conception rate [35.8% (30.2-38%)], or pregnancy rate [15% (13.7-18%)]. The CB farms were smaller [85 (49.5-146.5) milking cows] than both the FS [270 (178-327.5) milking cows] and FS+C farms [360 (150-541.5) milking cows). The overall prevalence of severe lameness (score 4 and 5) across all farms was 21.2% (15.2-28.5%) but was lower on the CB farms [14.2% (8.45-15.5%)] in comparison to the FS [22.2% (16.8-26.7%)] and the FS+C farms [22.2% (17.4-32.8%)]. Less than 1% of all cows scored on CB farms were observed with swollen or wounded knees (or both), which was lower than either the FS or FS+C farms [7.4% (3.6-11.9%) and 6.4% (2.6-11.8%) of all cows scored, respectively]. The same pattern was found for hock lesions, where the farm-level prevalence within the 3 different housing types was 0.5% (0-0.9%), 9.9% (0.8 15.3%), and 5.7% (2.6-10.9%) for CB, FS, and FS+C farms, respectively. No differences between farm systems were observed for hygiene or body condition score. On average, 2.7% (0.8-10.9%) of lactating cows had a soiled side, 15.4% (2.1-37.4%) had dirty legs and 1.7% (0-9.3%) had dirty udders. The average herd level body condition score across farms was 2.9 (2.9-3), with 0.86% of the all cows scored having a body condition score <2.5. These results indicate that lameness prevalence on confined dairies in Brazil is high and highlight the need for remedial changes in environmental design and management practices. We found that CB farms in this region had reduced lameness and lesions in relation to FS or FS+C dairies. PMID- 29274969 TI - Effect of 17beta-estradiol on milk production, hormone secretion, and mammary gland gene expression in dairy cows. AB - Estradiol inhibits milk production in dairy cows. The present study evaluated the effect of 17beta-estradiol (E2) injections on prolactin (PRL) secretion and the mammary gland response to this hormone. Eight mid-lactation cows were used in a crossover design. During each experimental period, the cows were injected daily with either E2 (2.5 mg) or soy oil (2.5 mL; control) for 7 d. For each period, blood and milk samples were collected from d -4 to 14 (relative to the first injection) to measure PRL, insulin-like growth factor-1, and cortisol concentrations. In addition, blood samples were collected during morning milking on d -4, 2, and 7 to determine the milking-induced PRL release. Mammary gland biopsies were collected on the last day of injections. Milk fat samples were collected from d 1 to 7 and on d 14. The mRNA levels of genes encoding proteins related to mammary activity (alpha-lactalbumin, beta-casein, and acetyl-coenzyme A carboxylase), apoptosis (Bax, Bcl2, and caspase-3), PRL receptors (PRLR; long and short forms), signal transducer and activator of transcription 5 (STAT5A and STAT5B), and suppressors of cytokine signaling (SOCS2 and SOCS3) were evaluated by real-time reverse transcription PCR using RNA extracted from milk fat and mammary biopsies. Milk production was decreased moderately (about 9%) by E2 injections during the treatment period. Estradiol injections increased basal PRL levels in serum and milk but did not affect milking-induced PRL release. Estradiol injections increased the plasma concentration of insulin-like growth factor-1 but did not affect cortisol concentration during the treatment period. In mammary tissue, the expression of Bcl2 was downregulated, whereas that of STAT5A and B and the Bax:Bcl2 mRNA ratio was higher during E2 injections. The total STAT5 protein content in mammary tissue was elevated by E2 injections. We found no significant difference observed for the other genes in mammary tissue or milk fat. The present data do not support the contention that E2 injections inhibit milk production by interfering with PRL signaling, but enhanced basal PRL concentration and STAT5 gene expression in mammary tissue. PMID- 29274970 TI - Control of Listeria monocytogenes in whole milk using antimicrobials applied individually and in combination. AB - Dairy product recalls and dairy-related illnesses are often the result of contamination with Listeria monocytogenes, which can occur throughout the dairy production and supply chains. The use of antimicrobial compounds is one practical approach for controlling pathogen survival and growth in foods. The goal of this study was to use fluid milk as a model system to identify listeristatic or listericidal treatments that show promise for application in fluid milk and for further evaluation in other dairy products (e.g., cheese). Caprylic acid (CA), epsilon-polylysine (EPL), hydrogen peroxide, lauric arginate (LAE), and sodium caprylate (SC) were added individually or in combination to whole milk inoculated with L. monocytogenes at ~4 log10 cfu/mL. Samples were stored at 7 degrees C for 21 d, and L. monocytogenes counts were determined weekly. Inhibitory concentrations of LAE (800 mg/L) and EPL (100-400 mg/L), as well as SC and CA (3,200 mg/L each), were identified. The addition of EPL at 800 mg/L reduced L. monocytogenes counts by >3 log10 cfu/mL from initial inoculation levels after 21 d. Addition of hydrogen peroxide to milk reduced counts by >3 log10 cfu/mL from initial inoculation within 24 h (400 and 800 mg/L) or by d 7 (200 mg/L). Although the combinatory treatments of EPL + CA, EPL + LAE, and LAE + SC were characterized as indifferent, EPL + SC worked synergistically to reduce L. monocytogenes populations in milk over 21 d. Overall, these data identify potential antimicrobial treatments to control L. monocytogenes in milk and serve as a foundation for the continued development of antimicrobial controls for L. monocytogenes in dairy products. PMID- 29274971 TI - Sensory and chemical properties of Gouda cheese. AB - Gouda cheese is a washed-curd cheese that is traditionally produced from bovine milk and brined before ripening for 1 to 20 mo. In response to domestic and international demand, US production of Gouda cheese has more than doubled in recent years. An understanding of the chemical and sensory properties of Gouda cheese can help manufacturers create desirable products. The objective of this study was to determine the chemical and sensory properties of Gouda cheeses. Commercial Gouda cheeses (n = 36; 3 mo to 5 yr; domestic and international) were obtained in duplicate lots. Volatile compounds were extracted by solid-phase microextraction and analyzed by gas chromatography-olfactometry and gas chromatography-mass spectrometry. Composition analyses included pH, proximate analysis, salt content, organic acid analysis by HPLC, and color. Flavor and texture properties were determined by descriptive sensory analysis. Focus groups were conducted to document US consumer perception followed by consumer acceptance testing (n = 149) with selected cheeses. Ninety aroma-active compounds in Gouda cheeses were detected by solid-phase microextraction/gas chromatography olfactometry. Key aroma-active volatile compounds included diacetyl, 2- and 3 methylbutanal, 2-methylpropanal, methional, ethyl butyrate, acetic acid, butyric acid, homofuraneol, delta-decalactone, and 2-isobutyl-3-methoxypyrazine. Aged cheeses had higher organic acid concentrations, higher fat and salt contents, and lower moisture content than younger cheeses. Younger cheeses were characterized by milky, whey, sour aromatic, and diacetyl flavors, whereas aged cheeses were characterized by fruity, caramel, malty/nutty, and brothy flavors. International cheeses were differentiated by the presence of low intensities of cowy/barny and grassy flavors. Younger cheeses were characterized by higher intensities of smoothness and mouth coating, whereas aged cheeses were characterized by higher intensities of fracture and firmness. American consumers used Gouda cheese in numerous applications and stated that packaging appeal, quality, and age were more important than country of origin or nutrition when purchasing Gouda cheeses. Young and medium US cheeses <=6 mo were most liked by US consumers. Three distinct consumer segments were identified with distinct preferences for cheese flavor and texture. Findings from this study establish key differences in Gouda cheese regarding age and origin and identify US consumer desires for this cheese category. PMID- 29274972 TI - Antibacterial activity of selenium-enriched lactic acid bacteria against common food-borne pathogens in vitro. AB - Selenium (Se) is an essential trace element for human health and animal nutrition. The aim of this study was to evaluate the inhibitory activities of Se enriched lactic acid bacteria (LAB), Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus, against pathogenic Salmonella typhimurium, Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes in vitro. The results indicated that the accumulation amount of Se by Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus reached 12.05 +/- 0.43 ug/mL and 11.56 +/- 0.25 ug/mL, respectively, accompanied by the relative maximum living cells when sodium selenite was 80 ug/mL. Oxford cup double plate assay showed that bacterial culture solution and cell-free culture supernatant (CFCS) from Se enriched LAB exerted stronger antibacterial activity than those from the non-Se strains. The growth of pathogenic bacterial culture with CFCS at any growth stages was worse than that without CFCS; moreover, the inhibiting effect of CFCS of Se-enriched LAB was more significant than that of non-Se strains. Results from a scanning electron microscope equipped with energy dispersion X-ray spectrometry showed that elemental Se nanoparticles, which characteristically energy peak around 1.42 keV, were deposited on the cell surfaces of Lactobacillus delbrueckii ssp. bulgaricus. In addition, CFCS of Se-enriched LAB induced more serious cell structure damage of pathogenic bacteria than did non-Se LAB. PMID- 29274973 TI - Short communication: Signs of host genetic regulation in the microbiome composition in 2 dairy breeds: Holstein and Brown Swiss. AB - This study aimed to evaluate whether the host genotype exerts any genetic control on the microbiome composition of the rumen in cattle. Microbial DNA was extracted from 18 samples of ruminal content from 2 breeds (Holstein and Brown Swiss). Reads were processed using mothur (https://www.mothur.org/) in 16S and 18S rRNA gene-based analyses. Then, reads were classified at the genus clade, resulting in 3,579 operational taxonomic units (OTU) aligned against the 16S database and 184 OTU aligned against the 18S database. After filtering on relative abundance (>0.1%) and penetrance (95%), 25 OTU were selected for the analyses (17 bacteria, 1 archaea, and 7 ciliates). Association with the genetic background of the host animal based on the principal components of a genomic relationship matrix based on single nucleotide polymorphism markers was analyzed using Bayesian methods. Fifty percent of the bacteria and archaea genera were associated with the host genetic background, including Butyrivibrio, Prevotella, Paraprevotella, and Methanobrevibacter as main genera. Forty-three percent of the ciliates analyzed were also associated with the genetic background of the host. In total, 48% of microbes were associated with the host genetic background. The results in this study support the hypothesis and provide some evidence that there exists a host genetic component in cattle that can partially regulate the composition of the microbiome. PMID- 29274974 TI - Nutritional composition and in vitro digestibility of grass and legume winter (cover) crops. AB - In dairy farming systems, growing winter crops for forage is frequently limited to annual grasses grown in monoculture. The objectives of this study were to determine how cropping grasses alone or in mixtures with legumes affects the yield, nutritional composition, and in vitro digestibility of fresh and ensiled winter crops and the yield, nutritional composition, and in vitro digestibility of the subsequent summer crops. Experimental plots were planted with 15 different winter crops at 3 locations in Virginia. At each site, 4 plots of each treatment were planted in a randomized complete block design. The 15 treatments included 5 winter annual grasses [barley (BA), ryegrass (RG), rye (RY), triticale (TR), and wheat (WT)] in monoculture [i.e., no legumes (NO)] or with 1 of 2 winter annual legumes [crimson clover (CC) and hairy vetch (HV)]. After harvesting the winter crops, corn and forage sorghum were planted within the same plots perpendicular to the winter crop plantings. The nutritional composition and the in vitro digestibility of winter and summer crops were determined for fresh and ensiled samples. Growing grasses in mixtures with CC increased forage dry matter (DM) yield (2.84 Mg/ha), but the yield of mixtures with HV (2.47 Mg/ha) was similar to that of grasses grown in monoculture (2.40 Mg/ha). Growing grasses in mixtures with legumes increased the crude protein concentration of the fresh forage from 13.0% to 15.5% for CC and to 17.3% for HV. For neutral detergent fiber (NDF) concentrations, the interaction between grasses and legumes was significant for both fresh and ensiled forages. Growing BA, RY, and TR in mixtures with legumes decreased NDF concentrations, whereas growing RG and WT with legumes did not affect the NDF concentrations of either the fresh or the ensiled forages. Growing grasses in mixtures with legumes decreased the concentration of sugars of fresh forages relative to grasses grown in monoculture. Primarily, this decrease can be attributed to low concentrations of sugars of mixtures with HV (10.5%). Growing grasses in mixtures with legumes reduced the fiber digestibility of both winter crops (75.7% to 72.8% NDF). Growing grasses in mixtures with legumes did not affect estimated DM yield, nutritional composition, or digestibility of the succeeding summer crops. In conclusion, growing grasses in mixtures with legumes as winter forage crops can increase forage estimated DM yields and its nutritional quality in dairy farming sytems. PMID- 29274975 TI - Association analysis for udder index and milking speed with imputed whole-genome sequence variants in Nordic Holstein cattle. AB - Genome-wide association testing facilitates the identification of genetic variants associated with complex traits. Mapping genes that promote genetic resistance to mastitis could reduce the cost of antibiotic use and enhance animal welfare and milk production by improving outcomes of breeding for udder health. Using imputed whole-genome sequence variants, we carried out association studies for 2 traits related to udder health, udder index, and milking speed in Nordic Holstein cattle. A total of 4,921 bulls genotyped with the BovineSNP50 BeadChip array were imputed to high-density genotypes (Illumina BovineHD BeadChip, Illumina, San Diego, CA) and, subsequently, to whole-genome sequence variants. An association analysis was carried out using a linear mixed model. Phenotypes used in the association analyses were deregressed breeding values. Multitrait meta analysis was carried out for these 2 traits. We identified 10 and 8 chromosomes harboring markers that were significantly associated with udder index and milking speed, respectively. Strongest association signals were observed on chromosome 20 for udder index and chromosome 19 for milking speed. Multitrait meta-analysis identified 13 chromosomes harboring associated markers for the combination of udder index and milking speed. The associated region on chromosome 20 overlapped with earlier reported quantitative trait loci for similar traits in other cattle populations. Moreover, this region was located close to the FYB gene, which is involved in platelet activation and controls IL-2 expression; FYB is a strong candidate gene for udder health and worthy of further investigation. PMID- 29274976 TI - Replacing ground corn with incremental amounts of liquid molasses does not change milk enterolactone but decreases production in dairy cows fed flaxseed meal. AB - We investigated the effects of replacing ground corn (GRC) with incremental amounts of liquid molasses (LM) on milk enterolactone concentration, antioxidant enzymes activity in plasma, production, milk fatty acid (FA) profile, and nutrient utilization in Jersey cows fed flaxseed meal and low-starch diets. Sixteen multiparous organically certified Jersey cows averaging (mean +/- standard deviation) 101 +/- 45 d in milk, 462 +/- 38 kg of body weight, and 19.8 +/- 3.90 kg/d of milk in the beginning of the study were randomly assigned to treatment sequences in a replicated 4 * 4 Latin square design, with 14 d for diet adaptation and 7 d for data and sample collection. Diets were fed as total mixed rations consisting (dry matter basis) of 52% grass-legume baleage, 8% grass hay, 8.5% soyhulls, 2.5% roasted soybean, 15% flaxseed meal, and 2% minerals-vitamins premix. The GRC-to-LM dietary ratios (dry matter basis) were 12:0, 8:4, 4:8, and 0:12. Orthogonal polynomials were used to test linear, quadratic, and cubic effects using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC). The milk concentration of enterolactone tended to respond cubically, thus suggesting that replacing GRC with LM did not affect this lignan in milk. The plasma activities of the antioxidant enzymes glutathione peroxidase and catalase did not differ, but superoxide dismutase activity tended to respond cubically with feeding increasing amounts of LM. Dry matter intake and yields of milk and milk fat, true protein, and lactose decreased linearly with substituting GRC for LM. Whereas the concentrations of milk fat and milk true protein did not differ across treatments, milk lactose content decreased linearly. Feeding incremental levels of LM reduced linearly the milk concentration of urea N and the amount of N excreted in urine, and tended to decrease linearly the concentration of plasma urea N. Apparent total-tract digestibilities of dry matter, organic matter, and neutral and acid detergent fiber did not differ across treatments, whereas digestibility of crude protein decreased linearly. Digestibility of starch responded linearly and quadratically, but the actual differences between treatments were too small to be biologically significant. Milk FA profile was substantially changed most notably by linear increases in cis-9,trans-11 18:2, cis-9,cis-12,cis-15 18:3, Sigma odd-chain FA, and the trans-11-to-trans-10 ratio, and linear decreases in cis-9 18:1 and cis-9,cis-12 18:2 when replacing GRC by incremental amounts of LM. PMID- 29274977 TI - Technical note: Changes in rumen mucosa thickness measured by transabdominal ultrasound as a noninvasive method to diagnose subacute rumen acidosis in dairy cows. AB - Feeding high-grain diets leads to the release and accumulation of short-chain fatty acids in the rumen. The subsequent prolonged decline in ruminal pH can lead to subacute ruminal acidosis (SARA). Accumulation of short-chain fatty acids can cause proliferation of rumen papillae to increase absorption surface, subsequently leading to a thickening of the rumen mucosa. The aim of this study was to evaluate the appropriateness of continuous measurements of the rumen mucosa thickness (RMT) as a diagnostic tool for SARA in dairy cows compared with continuous measurements of ruminal pH. The study used 6 lactating Simmental cows switched from a moderate-grain (MG) diet with 40% concentrate (dry matter basis) for 1 wk to a high-grain (HG) diet with 60% concentrate (dry matter basis) for 4 wk. Reticuloruminal pH was recorded with indwelling sensors throughout the trial. Rumen mucosa thickness was measured by transabdominal ultrasound at 4 d during the MG diet and 23 d during the HG diet. Mean RMT increased from 4.7 +/- 0.19 mm in the MG diet to 5.3 +/- 0.17 mm in the HG diet, whereas daily mean reticular pH decreased from 6.8 +/- 0.01 in the MG diet to 6.5 +/- 0.01 in the HG diet. Older cows (>3 lactations) had increased RMT, associated with higher reticular pH throughout the experiment. The higher RMT and pH level in older cows underlines their lesser susceptibility to SARA during high-grain feeding. In conclusion, RMT can successfully be measured using linear ultrasound probes, commonly used by veterinary practitioners as rectal probes. By combining noninvasive RMT measurements with the lactation number of the individual cows in a herd, this study suggests that RMT is a viable option for diagnosing SARA. Further research, using a larger number of cows with different lactations numbers, is needed to establish a cut-off RMT indicating the risk of SARA. PMID- 29274978 TI - Relative bioavailability of carnitine delivered by ruminal or abomasal infusion or by encapsulation in dairy cattle. AB - Two studies were designed to evaluate the relative bioavailability of l-carnitine delivered by different methods in dairy cattle. In experiment 1, 4 Holstein heifers were used in a split-plot design to compare ruminally or abomasally infused l-carnitine. The study included 2 main-plot periods, with infusion routes allocated in a crossover design. Within main-plot periods, each of 3 subplot periods consisted of 4-d infusions separated with 4-d rest periods. Subplot treatments were infusion of 1, 3, and 6 g of l-carnitine/d in conjunction with 6 g/d of arabinogalactan given in consideration of eventual product manufacturing. Doses increased within a period to minimize carryover risk. Treatments were solubilized in 4 L of water and delivered in two 10-h infusions daily. Blood was collected before the start of infusion period and on d 4 of each infusion period to obtain baseline and treatment l-carnitine concentrations. There was a dose * route interaction and route effect for increases in plasma carnitine above baseline, with increases above baseline being greater across all dose levels when infused abomasally compared with ruminally. Results demonstrated superior relative bioavailability of l-carnitine when ruminal exposure was physically bypassed. In experiment 2, 56 lactating Holstein cows (143 +/- 72 d in milk) were used in 2 cohorts in randomized complete block designs (blocked by parity and milk production) to evaluate 2 rumen-protected products compared with crystalline l-carnitine. Treatments were (1) control, (2) 3 g/d of crystalline l-carnitine (crystalline), (3) 6 g/d of crystalline, (4) 5 g/d of 40COAT (40% coating, 60% l carnitine), (5) 10 g/d of 40COAT, (6) 7.5 g/d of 60COAT (60% coating, 40% l carnitine), and (7) 15 g/d of 60COAT. Treatments were top-dressed to diets twice daily. Each cohort used 14-d and included a 6-d baseline measurement period with the final 2 d used for data and sample collection, and an 8-d treatment period with the final 2 d used for data and sample collection. Plasma, urine, and milk samples were analyzed for l-carnitine. Crystalline and 40COAT linearly increased plasma l-carnitine, and 60COAT tended to linearly increase plasma l-carnitine. Total excretion (milk + urine) of l-carnitine averaged 1.52 +/- 0.04 g/d in controls, increased linearly with crystalline and 40COAT, and increased quadratically with 60COAT. Crystalline increased plasma l-carnitine and l carnitine excretion more than 40COAT and 60COAT. In conclusion, preventing ruminal degradation of l-carnitine increased delivery of bioavailable carnitine to cattle, but effective ruminal protection and postruminal bioavailability is challenging. PMID- 29274979 TI - Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Vitamin D, mineral, and bone metabolism. AB - Pregnant Holstein cows, 28 nulliparous and 51 parous, were blocked by parity and milk yield and randomly allocated to receive diets that differed in dietary cation-anion difference (DCAD), +130 or -130 mEq/kg, and supplemented with either calcidiol or cholecalciferol at 3 mg/11 kg of dry matter from 255 d of gestation until parturition. Blood was sampled thrice weekly prepartum, and on d 0, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, and 30 postpartum to evaluate effects of the diets on vitamin D, mineral and bone metabolism, and acid-base status. Blood pH and concentrations of minerals, vitamin D metabolites, and bone-related hormones were determined, as were mineral concentrations and losses in urine and colostrum. Supplementing with calcidiol increased plasma concentrations of 25 hydroxyvitamin D3, 3-epi 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 1,25 dihydroxyvitamin D3, and 24,25-dihydroxyvitamin D3 compared with supplementing with cholecalciferol. Cows fed the diet with negative DCAD had lesser concentrations of vitamin D metabolites before and after calving than cows fed the diet with positive DCAD, except for 25-hydroxyvitamin D2. Feeding the diet with negative DCAD induced a compensated metabolic acidosis that attenuated the decline in blood ionized Ca (iCa) and serum total Ca (tCa) around calving, particularly in parous cows, whereas cows fed the diet with positive DCAD and supplemented with calcidiol had the greatest 1,25-dihydroxyvitamin D3 concentrations and the lowest iCa and tCa concentrations on d 1 and 2 postpartum. The acidogenic diet or calcidiol markedly increased urinary losses of tCa and tMg, and feeding calcidiol tended to increase colostrum yield and increased losses of tCa and tMg in colostrum. Cows fed the diet with negative DCAD had increased concentrations of serotonin and C-terminal telopeptide of type 1 collagen prepartum compared with cows fed the diet with positive DCAD. Concentrations of undercarboxylated and carboxylated osteocalcin and those of adiponectin did not differ with treatment. These results provide evidence that dietary manipulations can induce metabolic adaptations that improve mineral homeostasis with the onset of lactation that might explain some of the improvements observed in health and production when cows are fed diets with negative DCAD or supplemented with calcidiol. PMID- 29274981 TI - Technical note: A simple back-mounted harness for grazing dairy cows to facilitate the sulfur hexafluoride tracer gas technique. AB - We describe here a cattle harness to attach a gas collection vessel to facilitate the sulfur hexafluoride (SF6) tracer gas technique. The harness consists of 2 major components: (1) a lightweight, robust body fabricated from an equine surcingle or lunge roller with padded thoracic trapezius pressure points, a bespoke shaping shaft for spine support, and adjustable buckles on both sides; and (2) an elastic flank-strap to prevent the harness from dislodging. The spine support consists of stainless steel laminated with carbon fiber. This support minimizes the contact area with the animal's skin, relieves the spine area of pressure, and creates free flow of ambient air below the platform, reducing sweat accumulation and hence preventing skin lesions. The harness weighs approximately 1.2 kg, allows for attachment of 2 gas collection vessels (animal and background sample), and is cost effective. PMID- 29274980 TI - Lactobacillus demonstrate thiol-independent metabolism of methylglyoxal: Implications toward browning prevention in Parmesan cheese. AB - Endogenous production of alpha-dicarbonyls by lactic acid bacteria can influence the quality and consistency of fermented foods and beverages. Methylglyoxal (MG) in Parmesan cheese can contribute toward undesired browning during low temperature ripening and storage conditions, leading to the economic depreciation of affected cheeses. We demonstrate the effects of exogenously added MG on browning and volatile formation using a Parmesan cheese extract (PCE). To determine the influence of Lactobacillus on alpha-dicarbonyls, strains were screened for their ability to modulate concentrations of MG, glyoxal, and diacetyl in PCE. It was found that a major metabolic pathway of MG in Lactobacillus is a thiol-independent reduction, whereby MG is partially or fully reduced to acetol and 1,2-propanediol, respectively. The majority of lactobacilli grown in PCE accumulated the intermediate acetol, whereas Lactobacillus brevis 367 formed exclusively 1,2-propanediol and Lactobacillus fermentum 14931 formed both metabolites. In addition, we determined the inherent tolerance to bacteriostatic concentrations of MG among lactobacilli grown in rich media. It was found that L. brevis 367 reduces MG exclusively to 1,2-propanediol, which correlates to both its ability to significantly decrease MG concentrations in PCE, as well as its significantly higher tolerance to MG, in comparison to other lactobacilli screened. These findings have broader implications toward lactobacilli as a viable solution for reducing MG-mediated browning of Parmesan cheese. PMID- 29274982 TI - Symposium review: Interaction of starter cultures and nonstarter lactic acid bacteria in the cheese environment. AB - The microbiota of ripening cheese is dominated by lactic acid bacteria, which are either added as starters and adjunct cultures or originate from the production and processing environments (nonstarter or NSLAB). After curd formation and pressing, starters reach high numbers, but their viability then decreases due to lactose depletion, salt addition, and low pH and temperature. Starter autolysis releases cellular contents, including nutrients and enzymes, into the cheese matrix. During ripening, NSLAB may attain cell densities up to 8 log cfu per g after 3 to 9 mo. Depending on the species and strain, their metabolic activity may contribute to defects or inconsistency in cheese quality and to the development of typical cheese flavor. The availability of gene and genome sequences has enabled targeted detection of specific cheese microbes and their gene expression over the ripening period. Integrated systems biology is needed to combine the multiple perspectives of post-genomics technologies to elucidate the metabolic interactions among microorganisms. Future research should delve into the variation in cell physiology within the microbial populations, because spatial distribution within the cheese matrix will lead to microenvironments that could affect localized interactions of starters and NSLAB. Microbial community modeling can contribute to improving the efficiency and reduce the cost of food processes such as cheese ripening. PMID- 29274983 TI - Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Health and reproductive responses. AB - The objectives of the experiment were to evaluate the effects of feeding diets with distinct dietary cation-anion difference (DCAD) levels and supplemented with 2 sources of vitamin D during the prepartum transition period on postpartum health and reproduction in dairy cows. The hypotheses were that feeding acidogenic diets prepartum would reduce the risk of hypocalcemia and other diseases, and the benefits of a negative DCAD treatment on health would be potentiated by supplementing calcidiol compared with cholecalciferol. Cows at 252 d of gestation were blocked by parity (28 nulliparous and 52 parous cows) and milk yield within parous cows, and randomly assigned to 1 of 4 treatments arranged as a 2 * 2 factorial, with 2 levels of DCAD, positive (+130 mEq/kg) or negative (-130 mEq/kg), and 2 sources of vitamin D, cholecalciferol or calcidiol, fed at 3 mg for each 11 kg of diet dry matter. The resulting treatment combinations were positive DCAD with cholecalciferol (PCH), positive DCAD with calcidiol (PCA), negative DCAD with cholecalciferol (NCH), and negative DCAD with calcidiol (NCA), which were fed from 252 d of gestation to calving. After calving, cows were fed the same lactation diet supplemented with cholecalciferol at 0.70 mg for every 20 kg of dry matter. Blood was sampled 7 d before parturition, and at 2 and 7 d postpartum to evaluate cell counts and measures of neutrophil function. Postpartum clinical and subclinical diseases and reproductive responses were evaluated. Feeding a diet with negative DCAD eliminated clinical hypocalcemia (23.1 vs. 0%) and drastically reduced the incidence and daily risk of subclinical hypocalcemia, and these effects were observed in the first 48 to 72 h after calving. The diet with negative DCAD tended to improve the intensity of oxidative burst activity of neutrophils in all cows prepartum and increased the intensity of phagocytosis in parous cows prepartum and the proportion of neutrophils with killing activity in parous cows postpartum (58.5 vs. 67.6%). Feeding calcidiol improved the proportion of neutrophils with oxidative burst activity (60.0 vs. 68.7%), reduced the incidences of retained placenta (30.8 vs. 2.5%) and metritis (46.2 vs. 23.1%), and reduced the proportion of cows with multiple diseases in early lactation. Combining the negative DCAD diet with calcidiol reduced morbidity by at least 60% compared with any of the other treatments. Cows with morbidity had lower blood ionized Ca and serum total Ca concentrations than healthy cows. Treatments did not affect the daily risk of hyperketonemia in the first 30 d of lactation. Despite the changes in cow health, manipulating the prepartum DCAD did not influence reproduction, but feeding calcidiol tended to increase the rate of pregnancy by 55%, which reduced the median days open by 19. In conclusion, feeding prepartum cows with a diet containing a negative DCAD combined with 3 mg of calcidiol benefited health in early lactation. PMID- 29274984 TI - Production, milk and plasma fatty acid profile, and nutrient utilization in Jersey cows fed flaxseed oil and corn grain with different particle size. AB - We aimed to compare the effects of ground (GC) or cracked corn (CC), with or without flaxseed oil (FSO), on milk yield, milk and plasma fatty acid (FA) profile, and nutrient digestibility in Jersey cows fed diets formulated to contain similar starch concentrations. Twelve multiparous organic-certified Jersey cows averaging (mean +/- standard deviation) 455 +/- 41.9 kg of body weight and 152 +/- 34 d in milk and 4 primiparous organic-certified Jersey cows averaging (mean +/- standard deviation) 356 +/- 2.41 kg of body weight and 174 +/ 30 d in milk in the beginning of the experiment were used. Cows were randomly assigned to treatment sequences in a replicated 4 * 4 Latin square design with a 2 * 2 factorial arrangement of treatments. Each period lasted 24 d with 18 d for diet adaptation and 6 d for data and sample collection. Treatments were fed as total mixed rations consisting of (dry matter basis): (1) 0% FSO + 27.1% GC, (2) 0% FSO + 28.3% CC, (3) 3% FSO + 27.1% GC, and (4) 3% FSO + 28.3% CC. All cows were offered 55% of the total diet dry matter as mixed grass-legume baleage and treatments averaged 20% starch. Significant FSO * corn grain particle size interactions were observed for some variables including milk concentration of lactose and proportions of cis-9,cis-12,cis-15 18:3 in milk and plasma. The proportion of cis-9,cis-12,cis-15 18:3 in milk and plasma decreased slightly when comparing GC versus CC in 0% FSO cows, but a larger reduction was observed in 3% FSO cows. Dry matter intake did not differ and averaged 16.1 kg/d across diets. Feeding 3% FSO increased yields of milk and milk fat and lactose and feed and milk N efficiencies, but decreased fat, true protein, and MUN concentrations and apparent total-tract digestibility of fiber. The Sigma branched-chain, Sigma<16C, Sigma16C, and Sigman-6 FA decreased, whereas Sigma18C, Sigmacis-18:1, and Sigmatrans-18:1 FA increased in 3% versus 0% FSO cows. No effect of corn particle size was observed for production and milk components. However, the apparent total tract digestibility of starch was greater in GC than CC cows. Compared with CC, GC increased Sigma branched-chain, Sigma<16C, Sigma16C, Sigman-6 FA, and decreased Sigma18C and Sigma cis-18:1 FA in milk fat. Overall, results of this study are more directly applicable to dairy cows fed low starch, mixed grass legume baleage-based diets. PMID- 29274985 TI - Locator spoon. PMID- 29274987 TI - Anterior capsulorhexis opening reduction after cataract surgery with subluxated lenses. AB - BACKGROUND AND OBJECTIVE: This study sought to evaluate anterior capsulorhexis opening (ACO) reductions after surgery for a subluxated lens. Significant reduction of an ACO supports direct zonular involvement (capsular factors excluded by use of capsular tension rings [CTRs] and modern intraocular lens [IOLs]), and these findings question the long-term efficacy of subluxated lens surgery by means of cataract surgery. A small ACO due to lens mobility, non enlargement of the ACO, and no lens epithelial cell washing due to an additional risk of further zonular damage were left as additional features to evaluate the possible outcomes of this simplified but still complicated surgery. MATERIALS AND METHODS: Data from 30 patients were used in the final analysis of this prospective study. Phacoemulsifications of subluxated lenses were performed in all patients, and iris/capsule hooks and CTRs or Cionni rings were used as stabilisers of the lens. Photography of the anterior parts (performed at 1 day, 1 week, 1 month, 3 months and 6 months after surgery) was used to evaluate the anterior capsulorhexis openings. RESULTS: Small initial anterior capsulorhexis openings (13.54mm2) were achieved, and the area reduction at 6 months was 16.70% (mean area at month 6: 11.28mm2, P<0.001). The reduction of the ACO area in the pseudoexfoliation (PEX) syndrome patients was 20% relative to the initial size (13.49mm2 vs. 10.92mm2, P<0.001). Two patients exhibited marked ACO reductions, and both were referred for anterior laser capsulotomy treatment. CONCLUSIONS: A weak or partially absent zonule does not markedly affect the reduction of the anterior capsule opening if appropriate surgical techniques, support materials and IOLs are used, even in the presence of a small initial capsulorhexis opening area. Therefore, a cataract surgery approach on the subluxated lens should be used. Ocular comorbidities, particularly PEX syndrome, play more significant roles in ACO reduction, and appropriate ACO size reducing inhibitors (e.g., anterior laser capsulotomy) or other types of surgery should be used. PMID- 29274988 TI - Anaerobic biodegradation of biofuels and their impact on the corrosion of a Cu-Ni alloy in marine environments. AB - Fuel biodegradation linked to sulfate reduction can lead to corrosion of the metallic infrastructure in a variety of marine environments. However, the biological stability of emerging biofuels and their potential impact on copper nickel alloys commonly used in marine systems has not been well documented. Two potential naval biofuels (Camelina-JP5 and Fisher-Tropsch-F76) and their petroleum-derived counterparts (JP5 and F76) were critically assessed in seawater/sediment incubations containing a metal coupon (70/30 Cu-Ni alloy). Relative to a fuel-unamended control (1.2 +/- 0.4 MUM/d), Camelina-JP5 (86.4 +/- 1.6 MUM/d) and JP5 (77.6 +/- 8.3 MUM/d) stimulated much higher rates of sulfate reduction than either FT-F76 (11.4 +/- 2.7 MUM/d) or F76 (38.4 +/- 3.7 MUM/d). The general corrosion rate (r2 = 0.91) and pitting corrosion (r2 = 0.92) correlated with sulfate loss in these incubations. Despite differences in microbial community structure on the metal or in the aqueous or sediment phases, sulfate reducing bacteria affiliated with Desulfarculaceae and Desulfobacteraceae became predominant upon fuel amendment. The identification of alkylsuccinates and alkylbenzylsuccinates attested to anaerobic metabolism of fuel hydrocarbons. Sequences related to Desulfobulbaceae were highly enriched (34.2-64.8%) on the Cu Ni metal surface, regardless of whether the incubation received a fuel amendment. These results demonstrate that the anaerobic metabolism of biofuel linked to sulfate reduction can exacerbate the corrosion of Cu-Ni alloys. Given the relative lability of Camelina-JP5, particular precaution should be taken when incorporating this hydroprocessed biofuel into marine environments serviced by a Cu-Ni metallic infrastructure. PMID- 29274989 TI - Effect of ionic liquids with different cations and anions on photosystem and cell structure of Scenedesmus obliquus. AB - The rapid increase in the production and practical application of ionic liquids (ILs) could pose potential threats to aquatic systems. In this study, we investigated the effects of four ILs with different cations and anions, including 1-hexyl-3-methylimidazolium nitrate ([HMIM]NO3), 1-hexyl-3-methylimidazolium chloride ([HMIM]Cl), N-hexyl-3-metylpyridinium chloride ([HMPy]Cl), and N-hexyl-3 metylpyridinium bromide ([HMPy]Br), on photosystem and cellular structure of Scenedesmus obliquus. The results indicated that ILs are phytotoxic to S. obliquus. The contents of chlorophyll a, chlorophyll b and total chlorophyll decreased with increasing ILs concentrations. The chlorophyll fluorescence parameters of photosynthetic system II (PSII), including minimal fluorescence yield (F0), potential efficiency of PSII (Fv/Fo), maximum quantum efficiency of PSII photochemistry (Fv/Fm), yield of photochemical quantum [Y(II)], and non photochemical quenching coefficient without measuring F0' (NPQ), were all affected. This indicates that ILs could damage PSII, inhibit the primary reaction of photosynthesis, interdict the process of electron-transfer and lead to loss of heat-dissipating ability. ILs also increased cell membrane permeability of S. obliquus, influenced the cellular ultrastructure, changed the morphology of algae cells and destroyed the cell wall, cell membrane and organelles. The results indicated that imidazolium ILs had greater effect than pyridinium ILs, NO3--IL and Br--IL had greater effect than Cl--IL. To minimize threats to the environment, the structure of ILs should be taken into consideration. PMID- 29274990 TI - Physico-chemical forms of copper in water and sediments of Lake Pontchartrain basin, USA. AB - In this study, one of the largest estuaries in the Gulf Coast of USA was investigated for Cu forms and fractionations. Both the water and sediment samples in subsegments of the Lake Pontchartrain basin were collected and Cu forms in dissolved phase and sediment phase were analyzed. The BCR sequential extraction procedure was used to extract Cu in exchangeable, reducible, oxidizable and residual fractions in sediments. The results showed that the residual fraction of Cu was a major contributor in Tangipahoa River and I-10 Bridge sediments, while the residual and oxidizable fractions in the case of oil refinery sediments. Cu partitioning in Lake Pontchartrain basin water showed the decreasing trend of inert > labile > organic in both spring and summer. The release of Cu from the sediments into the water column was greater in summer as compared to spring and vice versa. Lower temperature helps in the adsorption of Cu on the surface of sediments in early spring due to low disturbance and temperature. PMID- 29274991 TI - Mercury adsorption in the Mississippi River deltaic plain freshwater marsh soil of Louisiana Gulf coastal wetlands. AB - Mercury adsorption characteristics of Mississippi River deltaic plain (MRDP) freshwater marsh soil in the Louisiana Gulf coast were evaluated under various conditions. Mercury adsorption was well described by pseudo-second order and Langmuir isotherm models with maximum adsorption capacity of 39.8 mg g-1. Additional fitting of intraparticle model showed that mercury in the MRDP freshwater marsh soil was controlled by both external surface adsorption and intraparticle diffusion. The partition of adsorbed mercury (mg g-1) revealed that mercury was primarily adsorbed into organic-bond fraction (12.09) and soluble/exchangeable fraction (10.85), which accounted for 63.5% of the total adsorption, followed by manganese oxide-bound (7.50), easily mobilizable carbonate-bound (4.53), amorphous iron oxide-bound (0.55), crystalline Fe oxide bound (0.41), and residual fraction (0.16). Mercury adsorption capacity was generally elevated along with increasing solution pH even though dominant species of mercury were non-ionic HgCl2, HgClOH and Hg(OH)2 at between pH 3 and 9. In addition, increasing background NaCl concentration and the presence of humic acid decreased mercury adsorption, whereas the presence of phosphate, sulfate and nitrate enhanced mercury adsorption. Mercury adsorption in the MRDP freshwater marsh soil was reduced by the presence of Pb, Cu, Cd and Zn with Pb showing the greatest competitive adsorption. Overall the adsorption capacity of mercury in the MRDP freshwater marsh soil was found to be significantly influenced by potential environmental changes, and such factors should be considered in order to manage the risks associated with mercury in this MRDP wetland for responding to future climate change scenarios. PMID- 29274992 TI - Accumulation of organochlorine pesticides in fat tissue of wild Nile crocodiles (Crocodylus niloticus) from iSimangaliso Wetland Park, South Africa. AB - Nile crocodiles (Crocodylus niloticus) are important apex predators in many tropical and subtropical aquatic habitats throughout much of sub-Saharan Africa. In South Africa, large crocodile populations inhabit lakes and wetlands that are impacted by organochlorine pesticides (OCPs). Despite the continued use of these compounds and their potential adverse effects on key wildlife populations in southern Africa, limited ecotoxicoloigcal data exist. In this study, we examined the accumulation of OCPs in fat tissues of live, wild Nile crocodiles from iSimangaliso Wetland Park, a region of significant biological importance. All samples (n = 15) contained multiple contaminants in highly elevated concentrations, with total residue burdens varying between 3600 and 8000 ng g-1 ww. DDT and its metabolites were the dominant compounds detected in most samples, with ?DDT concentrations ranging between 520 and 3100 ng g-1 ww. Elevated levels of other OCPs were also detected, including lindane (67-410 ng g-1 ww), aldrin (150-620 ng g-1 ww) and heptachlor (170-860 ng g-1 ww). Our findings show that crocodiles are exposed to OCPs throughout their range within iSimangaliso Wetland Park and contain some of the highest concentrations ever recorded in crocodilian tissue. Results indicate the need for a greater understanding of the impacts of OCP exposure and toxicological responses in crocodiles from iSimangaliso, and in Nile crocodile populations in general. The novel surgical technique described in this study provides an effective method for assessing relationships between contaminant body burdens and their potential reproductive and developmental consequences in crocodilians. PMID- 29274993 TI - Investigation of nanoscale zerovalent iron-based magnetic and thermal dual responsive composite materials for the removal and detection of phenols. AB - In this study, well-defined magnetic and thermal dual-responsive nanomaterials were synthesized, which contained ultrafine core-shell Fe@SiO2 nanoparticles as magnetic core and poly(N-isopropylacrylamide) (PNIPAM) as thermosensitive outer shell. The fabricated nanoparticles were characterized and investigated for the adsorption of four phenolic compounds, including bisphenol A (BPA), tetrabromobisphenol A (TBBPA), 4-tert-octylphenol (4-OP) and 4-n-nonylphenol (4 NP). The experimental results demonstrated that the excellent adsorption rates were attributed to hydrophobic effect, hydrogen-bonding interaction, and electrostatic attraction. The adsorption process followed pseudo-second-order kinetics model and nonlinear isotherms, indicating heterogeneous adsorption process. The adsorption efficiency of 4-NP using Fe@SiO2@PNIPAM was more than 90% under optimized condition within 2 h. The determined maximum adsorption amounts of BPA, TBBPA, 4-OP and 4-NP were 2.43, 6.83, 24.75, and 49.34 mg g-1, respectively. Meanwhile, a magnetic solid phase extraction (MSPE) method with Fe@SiO2@PNIPAM was established to determine these four compounds simultaneously. Under the optimal conditions, the linearity ranges were in the range of 2-200, 2 300, 2-100 and 2-100 MUg L-1 for BPA, 4-OP, TBBPA, and 4-NP, respectively, and the detection limits were in the range of 0.58-0.76 MUg L-1, respectively. The applicability of the proposed method was evaluated by analyzing three fresh water samples, and satisfactory spiked recoveries in the range 70.9-119.9% were achieved. It was proved that these adsorbents could be easily collected and recycled owing to the appropriate magnetism. The results also demonstrated that the as-prepared adsorbents had promising potential in the enrichment and analysis of detrimental organic pollutants from water. PMID- 29274994 TI - Zn isotopes fractionation during slags' weathering: One source of contamination, multiple isotopic signatures. AB - During the chemical weathering of lead blast furnace (LBF) and imperial smelting furnace (ISF) slags, possible Zn isotopes fractionation was studied as a function of pH, atmosphere (open air vs nitrogen), and time. Bulk LBF and ISF displayed heavier signatures compared to Johnson Matthey Company (JMC) Zn standard solution (i.e. 0.13 +/- 0.060/00 and 0.78 +/- 0.130/00 for LBF and ISF, resp). The Zn signatures vary greatly by changes in solution pH; heavier signatures at low pH and lighter signature at high pH. Smithsonite (ZnCO3) formation could induce a big delta Delta66ZnNitro-Open.atm of 1.130/00 at pH 10 and rapid zinc hydroxide precipitation could induce Delta66ZnNitro-Open.atm of 0.13-0.20/00 at pH 8.5. In addition, slags contain many mineral phases: ~80-84% of amorphous glassy phase (in v/v) and ~16-20% of many other crystalline phases. Zn isotope signatures in primary mineral phases can be extrapolated where the signature of the amorphous glassy phase lies between -0.350/00 and -0.420/00, and that of the overall crystalline phases was estimated to be 2.120/00 for LBF and 5.740/00 for ISF. Therefore, un-weathered slags with many mineral phases can host distinct Zn isotope signatures, which further evolve significantly during chemical weathering. One should thus carefully consider the heterogeneity of slags and the low-temperature chemical processes which lead to diverse Zn isotopic signature in the end, when using Zn isotopes as tracer of smelter's contamination. PMID- 29274995 TI - Spatial variation of PCDD/F and PCB emissions and their composition profiles in stack flue gas from the typical cement plants in China. AB - Cement production processes are important sources of unintentionally produced persistent organic pollutants (UP-POPs), such as polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs), and polychlorinated biphenyls (PCBs). The emissions of PCDD/Fs and PCBs in the stack flue gases from eight typical cement plants in China were investigated in this study, including one wet process rotary kiln, three dry process rotary kilns and four vertical shaft kilns. PCBs exhibited relatively higher mass concentrations with the dioxin-like (dl) and indicator PCBs of 0.14-17.36 and 0.42-12.90 ng/Nm3, respectively. However, PCDD/Fs contributed most to the total toxic equivalent concentrations, with the proportions exceeding 90%. The international toxicity equivalency (I-TEQ) concentrations of PCDD/Fs varied greatly from 0.01 to 0.46 ng I-TEQ/Nm3 in stack gases, two of which exceeded the exhaust gas concentration limit of 0.1 ng I TEQ/Nm3 established by the European Union Directive. In weight units, 1,2,3,4,6,7,8-HpCDF was the most abundant congener in the stack gases from various types of cement kilns, with the factions of 17.0-27.8%. TCDFs and PeCDFs were the first two most abundant homologue groups. 2,3,4,7,8-PeCDF was the largest contributor to the total I-TEQ. The emission factors of PCDD/Fs and PCBs in the eight cement kilns were estimated to be 0.01-1.35 MUg I-TEQ/t clinker and 8.20 * 10-4~8.23 * 10-2 MUg World Health Organization TEQ (W-TEQ)/t clinker, respectively. No obvious differences of the PCDD/F and PCB emission factors were found among the varied cement production technologies. PMID- 29274996 TI - Cortical control of aggression: GABA signalling in the anterior cingulate cortex. AB - Reduced top-down control by cortical areas is assumed to underlie pathological forms of aggression. While the precise underlying molecular mechanisms are still elusive, it seems that balancing the excitatory and inhibitory tones of cortical brain areas has a role in aggression control. The molecular mechanisms underpinning aggression control were examined in the BALB/cJ mouse model. First, these mice were extensively phenotyped for aggression and anxiety in comparison to BALB/cByJ controls. Microarray data was then used to construct a molecular landscape, based on the mRNAs that were differentially expressed in the brains of BALB/cJ mice. Subsequently, we provided corroborating evidence for the key findings from the landscape through 1H-magnetic resonance imaging and quantitative polymerase chain reactions, specifically in the anterior cingulate cortex (ACC). The molecular landscape predicted that altered GABA signalling may underlie the observed increased aggression and anxiety in BALB/cJ mice. This was supported by a 40% reduction of 1H-MRS GABA levels and a 20-fold increase of the GABA-degrading enzyme Abat in the ventral ACC. As a possible compensation, Kcc2, a potassium-chloride channel involved in GABA-A receptor signalling, was found increased. Moreover, we observed aggressive behaviour that could be linked to altered expression of neuroligin-2, a membrane-bound cell adhesion protein that mediates synaptogenesis of mainly inhibitory synapses. In conclusion, Abat and Kcc2 seem to be involved in modulating aggressive and anxious behaviours observed in BALB/cJ mice through affecting GABA signalling in the ACC. PMID- 29274997 TI - Electroconvulsive therapy enhances the anti-ageing hormone Klotho in the cerebrospinal fluid of geriatric patients with major depression. AB - Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associated with accelerated cellular aging as well as aging-related phenotypes and comorbidity observed in Klotho deficiency. On these grounds we investigated Klotho levels in the cerebrospinal fluid (CSF) and serum of eight geriatric patients undergoing electroconvulsive therapy (ECT) for severe depression. We hypothesize that ECT as a highly effective antidepressant treatment leads enhances Klotho levels. We found a significant difference between pre- and post-ECT CSF Klotho (792.5pg/ml vs. 991.3pg/ml, p=0.0020), but no difference in serum Klotho (602.5 vs. 594.3, p=0.32). Moreover, CSF Klotho increase positively correlated with the number of single ECT sessions that were performed in each patient (F1, 6)=7.84, p=0.031). Conjointly, the results of our exploratory study with a small sample size suggest a central nervous system-specific impact of ECT on Klotho, which may in turn partake in mediating the antidepressant effect of ECT. We suggest the modulation of neuroinflammatory processes, which have been ascribed pathophysiological relevance within the conceptual framework of the neuroinflammation hypothesis of depression, through ECT as a potential mechanism by which Klotho is enhanced in response to treatment. Further preclinical and clinical investigation should aim for a precise identification of the role of Klotho in depressive disorder. PMID- 29274998 TI - DNA methylation of APBA3 and MCF2 in borderline personality disorder: Potential biomarkers for response to psychotherapy. AB - Borderline personality disorder (BPD) is a severe and complex mental disease associated with high suicidal tendencies and hospitalization rates. Accumulating evidence suggests that epigenetic mechanisms are implicated in the etiology of BPD. A recent epigenome-wide study identified several novel genes which are epigenetically dysregulated in BPD. Those genes include APBA3 and MCF2. Psychotherapy such as Dialectical Behavior Therapy (DBT), an established treatment for BPD, provides an excellent setting to investigate environmental influences on epigenetic mechanisms in order to identify biomarkers for disease status and therapy success. However, the effects of DBT on epigenetic regulation has only been researched in one previous study analyzing BDNF. In the present study, we aimed to investigate the role of DNA methylation of APBA3 and MCF2 as possible biomarkers for treatment outcome in BPD, whilst validating the previous findings of differential DNA methylation in a cohort of 44 BPD patients and 44 well-matched healthy control individuals. Unexpectedly, we did not detect significant DNA methylation differences between patients and control individuals. However, we found a high correlation between the methylation status of APBA3 and MCF2 and therapy outcome: before DBT treatment, both genes were significantly higher methylated in patients responding to therapy compared to patients that did not respond. Our study is the first to report results pointing to possible predictive epigenetic biomarkers of DBT outcome in BPD patients. Following replication in independent cohorts, our finding could facilitate the development of more personalized therapy concepts for BPD patients by including epigenetic information. PMID- 29274999 TI - Sensing and signaling mechanisms linking dietary methionine restriction to the behavioral and physiological components of the response. AB - Dietary methionine restriction (MR) is implemented using a semi-purified diet that reduces methionine by ~80% and eliminates dietary cysteine. Within hours of its introduction, dietary MR initiates coordinated series of transcriptional programs and physiological responses that include increased energy intake and expenditure, decreased adiposity, enhanced insulin sensitivity, and reduction in circulating and tissue lipids. Significant progress has been made in cataloguing the physiological responses to MR in males but not females, but identities of the sensing and communication networks that orchestrate these responses remain poorly understood. Recent work has implicated hepatic FGF21 as an important mediator of MR, but it is clear that other mechanisms are also involved. The goal of this review is to explore the temporal and spatial organization of the responses to dietary MR as a model for understanding how nutrient sensing systems function to integrate complex transcriptional, physiological, and behavioral responses to changes in dietary composition. PMID- 29275002 TI - Respuesta de los autores. PMID- 29275000 TI - The metamorphosis of adolescent hormonal stress reactivity: A focus on animal models. AB - As adolescents transition from childhood to adulthood, many physiological and neurobehavioral changes occur. Shifts in neuroendocrine function are one such change, including the hormonal systems that respond to stressors. This review will focus on these hormonal changes, with a particular emphasis on the pubertal and adolescent maturation of the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, this review will concentrate on studies using animal models, as these model systems have contributed a great deal to our mechanistic understanding of how factors such as sex and experience with stressors shape hormonal reactivity during development. Continued study of the maturation of stress reactivity will undoubtedly shed much needed light on the stress-related vulnerabilities often associated with adolescence as well as providing us with possible strategies to mitigate these vulnerabilities. This area of research may lead to discoveries that enhance the well-being of adolescents, ultimately providing them with greater opportunities to mature into healthy adults. PMID- 29275001 TI - Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) and the Association of Crohn's Disease and Ulcerative Colitis Patients (ACCU) in the management of psychological problems in Inflammatory Bowel Disease patients. AB - AIMS: To establish recommendations for the management of psychological problems affecting patients with inflammatory bowel disease (IBD). METHODS: A meeting of a group of IBD experts made up of doctors, psychologists, nurses and patient representatives was held. The following were presented: 1) Results of a previous focal group, 2) Results of doctor and patient surveys, 3) Results of a systematic review of tools for detecting anxiety and depression. A guided discussion was then held about the most important psychological and emotional problems associated with IBD, appropriate referral criteria and situations to be avoided. The validated instrument most applicable to clinical practice was selected. A recommendations document and a Delphi survey were designed. The survey was sent to the group and to a scientific committee of the GETECCU group in order to establish the level of agreement with these recommendations. RESULTS: Fifteen recommendations were established linked to 3 key processes: 1) What steps should be taken to identify psychological problems at an IBD appointment; 2) What are the criteria for referring patients to a mental health specialist; 3) How to approach psychological problems. CONCLUSIONS: Resources should be made available to healthcare professionals so that they can treat these problems during consultations, identify the disorders which could affect the clinical course of the disease and determine their impact on the patient's life in order that these can be treated and followed up by the most suitable professional. These recommendations could serve as a basis for redesigning IBD services or processes and as justification for the training of healthcare personnel. PMID- 29275003 TI - Are "off hours" intubations a risk factor for complications during intubation? A prospective, observational study. AB - OBJECTIVE: To compare the complications and the difficulty of orotracheal intubation procedures performed in the Intensive Care Unit during the off-hours period and the on-hours period. DESIGN: A prospective, observational and non interventional cohort study covering a period of 27 months was carried out. Working days between 8:00 a. m. and 7:59 p. m. were considered "on-hours", while the remaining shifts were regarded as "off-hours". SCOPE: An 18-bed surgical in a Intensive Care Unit of a third-level hospital. PATIENTS: All orotracheal intubation patients admitted to the ICU from January 2015 to March 2017 were included. Patients were stratified into 2groups according to whether intubation was performed on-hours or off-hours. INTERVENTIONS: Non-interventional study. VARIABLES OF INTEREST: The reason for intubation, time and day on which intubation was performed, degree of intubation difficulty (number of attempts, Cormack-Lehane laryngoscopic vision, need for accessory material) and complications during intubation. RESULTS: A total of 252 patients were intubated; of these, 132 were included in the on-hours group and 120 patients in the off hours group. In the off-hours group we observed a greater percentage of urgent and emergent intubations compared to the on-hours group. However, no differences were found between the 2groups in relation to the other variables studied. CONCLUSIONS: During the off-hours period, orotracheal intubation was not associated to a greater number of complications or to greater difficulty of the technique in our Unit. PMID- 29275004 TI - Handling or being the concept: An fMRI study on metonymy representations in coverbal gestures. AB - In "Two heads are better than one," "head" stands for people and focuses the message on the intelligence of people. This is an example of figurative language through metonymy, where substituting a whole entity by one of its parts focuses attention on a specific aspect of the entity. Whereas metaphors, another figurative language device, are substitutions based on similarity, metonymy involves substitutions based on associations. Both are figures of speech but are also expressed in coverbal gestures during multimodal communication. The closest neuropsychological studies of metonymy in gestures have been nonlinguistic tool use, illustrated by the classic apraxic problem of body-part-as-object (BPO, equivalent to an internal metonymy representation of the tool) vs. pantomimed action (external metonymy representation of the absent object/tool). Combining these research domains with concepts in cognitive linguistic research on gestures, we conducted an fMRI study to investigate metonymy resolution in coverbal gestures. Given the greater difficulty in developmental and apraxia studies, perhaps explained by the more complex semantic inferencing involved for external metonymy than for internal metonymy representations, we hypothesized that external metonymy resolution requires greater processing demands and that the neural resources supporting metonymy resolution would modulate regions involved in semantic processing. We found that there are indeed greater activations for external than for internal metonymy resolution in the temporoparietal junction (TPJ). This area is posterior to the lateral temporal regions recruited by metaphor processing. Effective connectivity analysis confirmed our hypothesis that metonymy resolution modulates areas implicated in semantic processing. We interpret our results in an interdisciplinary view of what metonymy in action can reveal about abstract cognition. PMID- 29275005 TI - Behavioral and electrophysiological signatures of word translation processes. AB - Translation is a demanding process during which a message is analyzed, translated and communicated from one language to another. Despite numerous studies on translation mechanisms, the electrophysiological processes underlying translation with overt production remain largely unexplored. Here, we investigated how behavioral response patterns and spatial-temporal brain dynamics differ in a translation compared to a control within-language word-generation task. We also investigated how forward and backward translation differs on the behavioral and electrophysiological level. To address these questions, healthy late bilingual subjects performed a translation and a within-language control task while a 128 channel EEG was recorded. Behavioral data showed faster responses for translation compared to within-language word generation and faster responses for backward than forward translation. The ERP-analysis revealed stronger early ( < 200ms) preparatory and attentional processes for between than within word generation. Later (424-630ms) differences were characterized by distinct engagement of domain general control networks, namely self-monitoring and lexical access interference. Language asymmetry effects occurred at a later stage (600ms), reflecting differences in conceptual processing characterized by a larger involvement of areas implicated in attention, arousal and awareness for forward versus backward translation. PMID- 29275006 TI - Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy. AB - AIM: Duchenne Muscular Dystrophy (DMD) is associated with progressive depressed left ventricular (LV) function. However, DMD effects on myofilament structure and function are poorly understood. Golden Retriever Muscular Dystrophy (GRMD) is a dog model of DMD recapitulating the human form of DMD. OBJECTIVE: The objective of this study is to evaluate myofilament structure and function alterations in GRMD model with spontaneous cardiac failure. METHODS AND RESULTS: We have employed synchrotron X-rays diffraction to evaluate myofilament lattice spacing at various sarcomere lengths (SL) on permeabilized LV myocardium. We found a negative correlation between SL and lattice spacing in both sub-epicardium (EPI) and sub-endocardium (ENDO) LV layers in control dog hearts. In the ENDO of GRMD hearts this correlation is steeper due to higher lattice spacing at short SL (1.9MUm). Furthermore, cross-bridge cycling indexed by the kinetics of tension redevelopment (ktr) was faster in ENDO GRMD myofilaments at short SL. We measured post-translational modifications of key regulatory contractile proteins. S glutathionylation of cardiac Myosin Binding Protein-C (cMyBP-C) was unchanged and PKA dependent phosphorylation of the cMyBP-C was significantly reduced in GRMD ENDO tissue and more modestly in EPI tissue. CONCLUSIONS: We found a gradient of contractility in control dogs' myocardium that spreads across the LV wall, negatively correlated with myofilament lattice spacing. Chronic stress induced by dystrophin deficiency leads to heart failure that is tightly associated with regional structural changes indexed by increased myofilament lattice spacing, reduced phosphorylation of regulatory proteins and altered myofilament contractile properties in GRMD dogs. PMID- 29275007 TI - Fexinidazole: A New Drug for African Sleeping Sickness on the Horizon. AB - Decades after the last new chemical entity was added to the pharmacopeia for human African trypanosomiasis (or sleeping sickness), orally dosed fexinidazole stands poised to replace the current treatment regimen for Trypanosoma brucei gambiense infections, following a positive Phase 2/3 clinical trial. PMID- 29275008 TI - Response to Morley: The Influence of Climate on Survival of Paramphistome Metacercariae. PMID- 29275009 TI - Paramphistomosis of Ruminants: The Role of Free-Living Metacercariae. PMID- 29275010 TI - Interleukin-7 augments CD8+ T cells function and promotes viral clearance in chronic hepatitis C virus infection. AB - Interleukin (IL)-7 is a potent proliferation, activation, and survival cytokine for CD8+ T cells to improve viral and tumor specific CD8+ T cell responses. However, the role of IL-7 in regulation of dysfunctional hepatitis C virus (HCV) specific CD8+ T cells was not fully elucidated. Thus, a total of 53 patients with chronic hepatitis C and 24 healthy individuals were enrolled in the current study. Serum IL-7 and its receptor alpha chain CD127 expression was measured. The modulatory function of IL-7 to CD8+ T cells was investigated in both direct and indirect contact co-culture with HCVcc-infected Huh7.5 cells. Both serum IL-7 and CD127 expression on CD8+ T cells was significantly reduced in chronic HCV infected patients, which was negatively correlated with HCV RNA. Stimulation of IL-7 promoted both cytotoxicity and cytokines (interferon-gamma, tumor necrosis factor-alpha, and IL-2) production of CD8+ T cells from patients with chronic hepatitis C. Moreover, IL-7 increased proliferation of CD8+ T cells, while downregulated a critical repressor of cytokine signaling, suppressor of cytokine signaling 3 (SOCS3). The IL-7-mediated enhancement effects to CD8+ T cells were dependent on IL-6 production. The current data suggested that IL-7 induced both cytolytic and noncytolytic functions of CD8+ T cells probably via repression of SOCS3. IL-7 might be considered as one of the therapeutic candidates for treatment of chronic HCV infection. PMID- 29275011 TI - Red blood cells: The primary reservoir of macrophage migration inhibitory factor in whole blood. AB - Red blood cells are widely accepted to be inert carriers of oxygen and haemoglobin, but there is growing evidence that they play a much more critical role in immune function. Macrophage migration inhibitory factor (MIF) is a key cytokine in disease with additional oxido-reductase activity, which aids in managing oxidative stress. Although two studies have reported the presence of MIF in red blood cells, no study has quantified the levels of this protein. In this study, freshly isolated plasma, platelets, leukocytes, and red blood cells from healthy individuals were collected and the concentration of MIF was determined using an enzyme linked immunosorbent assay. This analysis demonstrated that MIF in red blood cells was present at 25 ug per millilitre of whole blood, which is greater than99% of the total MIF and 1000-fold higher concentration than plasma. This result was supported by electrophoresis and Western blot analysis, which identified MIF in its monomer structural form following sample processing. Furthermore, by assessing the level of tautomerase activity in red blood cell fractions in the presence of a MIF inhibitor, it was determined that the red blood cell-derived MIF was also functionally active. Together, these findings have implications on the effect of haemolysis during sample preparation and provide some clue into the inflammatory processes that occur following haemolysis in vivo. These results support the hypothesis that red blood cells are a major reservoir of this inflammatory protein and may play a role in inflammation. PMID- 29275012 TI - Progress in pharmacological research of chemokine like factor 1 (CKLF1). AB - Currently, the research of chemokines has penetrated into many fields of life science. A new kind of chemokines, chemokine like factor 1 (CKLF1), which is cloned through suppression subtractive hybridisation (SSH) technology is expressed widely in human body, especially in the lung and peripheral blood leukocytes. CKLF1 has a broad spectrum of chemotaxic activity for many cells, such as lymphocytes, macrophages, bone marrow cells, nerve cells and so on. In addition, CKLF1 also stimulates the regeneration of skeletal muscle cells in vivo. Collecting data derived from our and other laboratories show that CKLF1 has an important relationship with allergic diseases, autoimmune diseases, tumors, cardio-cerebrovascular diseases and so on. Therefore, there be an important theoretical purport and applied value to make a summary of pharmacological progress of CKLF1. PMID- 29275013 TI - Reduced release of TNFalpha and IP-10 after ex vivo blood stimulation with endotoxin is associated with poor outcome after stroke. AB - BACKGROUND AND AIMS: The immune response to acute cerebral ischemia plays an important role in the pathophysiology of stroke and could be a therapeutic target. Toll-like receptor 4 (TLR4) is a master regulator of innate immunity. The aim of our study was to determine the association between selected cytokine release after TLR4 activation in blood cells and the outcome after ischemic stroke. METHODS: We included 156 ischemic stroke patients (median age: 69; 40.4% female). Venous blood was collected at day 3 after the onset of stroke and stimulated ex vivo with lipopolysaccharide (LPS). The LPS-induced level of tumor necrosis factor alpha (TNFalpha) was used as a proxy of the MyD88-dependent pathway, and interferon-gamma-inducible protein 10 (IP-10) was used as a proxy of the MyD88-independent pathway. The functional outcome was assessed at 3 months after stroke onset. RESULTS: TNFalpha (median: 2.2 vs. 3.5 pg/103 monocytes, p < .01) and IP-10 release (median: 0.3 vs. 0. 6 pg/103 monocytes, p < .01) was reduced in patients with a poor outcome. In a multivariate logistic regression analysis adjusted for age, stroke severity, and pneumonia, low TNFalpha release was associated with a poor outcome (OR: 4.23, 95%CI: 1.64-10.90, p = .03). Similarly, low IP-10 release was related to an unfavorable prognosis (adjusted OR: 3.42, 95%CI: 1.49-8.21, p < .01). CONCLUSIONS: The reduced release of TNFalpha and IP-10 after ex vivo blood stimulation with endotoxin is independently associated with poor outcome after stroke. Our results suggest that the inhibition of both the MyD88-dependent pathway and MyD88-independent pathway of TLR4 signaling in blood cells correlates with an unfavorable prognosis in stroke patients. PMID- 29275014 TI - Development of a reactive oxygen species-sensitive nitric oxide synthase inhibitor for the treatment of ischemic stroke. AB - Ischemic stroke is caused by a blockage of cerebral blood flow resulting in neuronal and glial hypoxia leading to inflammatory and reactive oxygen species (ROS)-mediated cell death. Nitric oxide (NO) formed by NO synthase (NOS) is known to be protective in ischemic stroke, however NOS has been shown to 'uncouple' under oxidative conditions to instead produce ROS. Nitrones are antioxidant molecules that are shown to trap ROS to then decompose and release NO. In this study, the nitrone 5 was designed such that its decomposition product is a NOS inhibitor, 6, effectively leading to NOS inhibition specifically at the site of ROS production. The ability of 5 to spin-trap radicals and decompose to 6 was observed using EPR and LC-MS/MS. The pro-drug concept was tested in vitro by measuring cell viability and 6 formation in SH-SY5Y cells subjected to oxygen glucose deprivation (OGD). 5 was found to be more efficacious and more potent than PBN, and was able to increase phospho-Akt while reducing nitrotyrosine and cleaved caspase-3 levels. 6 treatment, but not 5, was found to decrease NO production in LPS-stimulated microglia. Doppler flowmetry on anesthetized mice showed increased cerebral blood flow upon intravenous administration of 1mg/kg of 5, but a return to baseline upon administration of 10mg/kg, likely due to its dual nature of antioxidant/NO-donor and NOS-inhibition. Mice treated with 5 after permanent ischemia exhibited a >30% reduction in infarct volume, and higher formation of 6 in ischemic tissue resulting in region specific effects limited to the infarct area. PMID- 29275015 TI - An unusual cause of ischemia after coronary bypass grafting!! AB - Coronary subclavian steal syndrome is an uncommon cause of ischemia recurrence after coronary artery bypass grafting. Endovascular treatment of subclavian artery stenosis or occlusion is increasingly common and appears to offer a safe and effective alternative to surgical revascularization. We report a case of recurrent angina after coronary artery bypass grafting for critical subclavian artery stenosis. The anomalous origin of the vertebral artery from the aortic arch was an indication for endovascular treatment. We discuss the diagnostic difficulties and the management pitfalls of subclavian artery angioplasty in this syndrome. PMID- 29275016 TI - Lesbian, Gay, Bisexual, and Transgender (LGBT) Survivorship. AB - OBJECTIVE: To discuss lesbian, gay, bisexual, and transgender (LGBT)-specific survivorship issues including: integrating sexual and gender minority identities with cancer survivor identities; coordinating medical care and disclosing identities to health care providers; dealing with late effects of treatment; and addressing LGBT family and relationship issues. DATA SOURCES: Published articles, quotes from an online survey of 311 LGBT survivors. CONCLUSION: The transition from active cancer treatment to survivorship presents challenges, and LGBT cancer survivors may face additional challenges as they enter the survivorship phase. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can improve the quality of survivorship care delivered to LGBT survivors and their caregivers by addressing the disparities and gaps in health care. PMID- 29275017 TI - Competence, confidence and knowledge retention in undergraduate nursing students A mixed method study. AB - A primary goal of nursing programs is to ensure that graduates can successfully enter into professional practice. This paper examines the relationship between competence, confidence, and knowledge retention in undergraduate nursing students. The study involved a three test quantitative component as well as a qualitative component. The quantitative component comprised a pretest, posttest immediately following the intervention, posttest three month design. The intervention was comprised of an intensive one day advanced cardiac skills knowledge and simulation activity. The three tests measured competence, confidence, and knowledge retention. The results of the study demonstrated the intervention was effective in improving perceptions of competence and confidence both immediately and at a three month timeframe. Knowledge retention also was statistically significant at a three month timeframe. This study demonstrates the value of advanced knowledge and skill for undergraduate nursing students. Despite the policy enforced reality that participants were not able to use the knowledge and skill in clinical practice, the motivational benefit of the advanced knowledge had significant positive effects on participants. PMID- 29275018 TI - A cross-sectional pilot study of student's proactive behavior in midwifery education: Validation of a developed questionnaire. AB - OBJECTIVES: Midwifery students face major challenges in adapting quickly and effectively to different clinical settings. Proactive behavior, triggered by various individual and/or contextual antecedents, could be a significant added value to cope with these challenges. DESIGN: A cross-sectional pilot study was conducted to investigate prognostic factors in proactive behavior in a group of midwifery students. SETTINGS: The setting was a Belgian University College for midwifery education. PARTICIPANTS: All second and third year midwifery students (n=156). METHODS: Students were questioned regarding several prognostic factors: four personal characteristics, seven individual antecedents and three contextual antecedents that might trigger proactive behavior. A proportional odds logistic regression analyses was used to describe the association between prognostic factors and the probability to observe proactive behavior within the group. The strength of the newly developed questionnaire was tested. RESULTS: Of all tested prognostic factors, nationality, role breadth self-efficacy, referring to the self-confidence of a midwifery-student to perform tasks that exceed expectations, and control appraisal, describing the importance attached to one's perceived control, were significantly associated with proactive behavior. The overall strength of the questionnaire was ratified. Two of the original questions were deleted, two re-formulated and for one prognostic factor the answer-options were re-formulated. CONCLUSIONS: Findings from this pilot study show that midwifery students who have a high role breadth self-efficacy and low control appraisal are more likely to show proactive behavior. Additionally, Dutch students are more likely to show proactive behavior in relation to Belgian students. The questionnaire's feasibility was examined and adjustments were made for future research in a larger study to confirm these outcomes. This study can be a support in the individual guidance of midwifery students towards proactive behavior in midwifery. PMID- 29275019 TI - Exploring the cultural competence of undergraduate nursing students in Saudi Arabia. AB - PURPOSE: To explore the cultural competence of undergraduate nursing students at a college of nursing, Saudi Arabia. DESIGN: A descriptive exploratory design was used to explore the Saudi undergraduate nursing students' level of cultural competency. METHOD: The convenience sample included 205 nursing students affiliated with a college of nursing at a health science university in Jeddah, Saudi Arabia. Data was collected using the Inventory for Assessing the Process of Cultural Competence-Revised (IAPCC-R) consisting of 25 items. The tool reported acceptable reliability of Cronbach alpha 0.89. RESULTS: The majority of students were culturally aware and dealt with people from different cultures. One-third preferred to have training on culture over a period of time. Half the students preferred studying a special course related to working with people from different cultures. Cultural desire reported the highest mean while cultural knowledge scored the lowest among the cultural competence subscales despite students being exposed to some cultural knowledge content in their training. CONCLUSIONS: Implementing the guidelines for culturally competent care assure covering all aspects of care with consideration of cultural heritage as a main concept. Comparative study of nurses' and students' perception is further recommended. PMID- 29275020 TI - [A rare complication of a permanent tattoo]. PMID- 29275021 TI - Systemic sclerosis: Annual chest CT is not necessary for all patients. PMID- 29275022 TI - [Psychiatric comorbidities in epilepsy]. AB - Psychiatric comorbidities are overrepresented in people suffering from epilepsy in comparison to the general population. There is a two-way link between epilepsy and psychiatric disorders. Psychiatric symptomatology is specific in epilepsy, according to the chronology of symptoms in relation to the seizure (inter, pre- or postictal). Easy to use, fast and efficient self-administered questionnaires are available to evaluate depressive (NDDI-E) and generalized anxiety disorder (GAD-7) symptoms. Selective serotonin reuptake inhibitors (SSRIs) are not proconvulsant and can be safely used to treat depressive or anxious disorders. PMID- 29275023 TI - [Endurance running: A rare reason for ileectomy]. PMID- 29275024 TI - [Acute liver failure secondary to diffuse liver infiltration]. PMID- 29275025 TI - [Genetic factors in alcohol dependence]. AB - Genetic factors are involved in the predisposition to alcohol dependence with an heritability of about 0.5. Sequencing or analysis of the polymorphisms of genes or the whole human genome allow to identify genetic markers of alcohol dependence. Genes of the brain pathway of motivation and reward, including DRD2 and ANKK1, are associated with alcohol dependence. Genes encoding the gabaergic receptors show variants link to alcohol dependence. Polymorphisms in the genes encoding the enzymes alcohol desydrogenases (ADH) and aldehyde-dehydrogenases (ALDH) are associated to the susceptibility or the protection of alcohol dependence. Interaction between genes and environment, via the epigenetics, influence the predisposition to alcohol dependence. PMID- 29275026 TI - [Relevance of bariatric surgery care]. AB - The relevance of care in bariatric surgery must be judged in terms of the resulting benefit/risk balance. Laparoscopic approach has been proved to reduce postoperative mortality. Postoperative mortality is less than 0.1% in France. Depending on procedures, long-term percentage of weight loss is estimated around 15-30%. Long-term mortality and cardiovascular events are reduced compared to control patients. The over-risk of suicide should be known. Long-term follow-up after bariatric surgery is poor in France. PMID- 29275027 TI - [Interferences of biotin therapy on immunoassays: It is time for a long-term solution!] PMID- 29275028 TI - [Accuracy of magnetic resonance imaging in the diagnosis of thymolipoma]. PMID- 29275029 TI - [Tinea incognita in a HIV-infected male]. PMID- 29275030 TI - Testosterone and Cardiovascular Health. AB - There is an ongoing debate in the medical community regarding the effects of testosterone on cardiovascular (CV) health. For decades, there has been conflicting evidence regarding the association of endogenous testosterone levels and CV disease (CVD) events that has resulted in much debate and confusion among health care providers and patients alike. Testosterone therapy has become increasingly widespread, and after the emergence of studies that reported increased CVD events in patients receiving testosterone therapy, the US Food and Drug Administration (FDA) released a warning statement about testosterone and its potential risk regarding CV health. Some of these studies were later found to be critically flawed, and some experts, including the American Association of Clinical Endocrinologists and an expert panel regarding testosterone deficiency and its treatment, reported that some of the FDA statements regarding testosterone therapy were lacking scientific evidence. This article summarizes the current evidence regarding the relationship between testosterone (endogenous and supplemental) and CV health. A literature review was conducted via search using PubMed and specific journal databases, including the New England Journal of Medicine and the Journal of the American College of Cardiology. Key search terms included testosterone and cardiovascular health, coronary artery disease, heart failure, androgen deprivation therapy, intima-media thickness, and adrenal androgens. Initial study selection was limited to publications within the past 10 years (January 1, 2007, through December 31, 2016); however, key publications outside of this time frame were selected if they provided important quantitative data or historical perspectives for the review of this topic. The search was further supplemented by reviewing references in selected articles. PMID- 29275031 TI - The Diagnostic Accuracy of Fractional Exhaled Nitric Oxide Testing in Asthma: A Systematic Review and Meta-analyses. AB - OBJECTIVE: To evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) measurement in individuals with suspected asthma. METHODS: We searched MEDLINE, EMBASE, PsycINFO, Cochrane databases, and SciVerse Scopus from the databases' inception through April 4, 2017, for studies that enrolled patients aged 5 years and older with suspected asthma and evaluated FeNO diagnostic accuracy. Independent reviewers selected studies and extracted data. We used the symmetric hierarchical summary receiver operating characteristic models to estimate test performance. RESULTS: We included 43 studies with a total of 13,747 patients. In adults, using FeNO cutoffs of less than 20, 20 to 29, 30 to 39, and 40 or more parts per billion, FeNO testing had sensitivities of 0.80, 0.69, 0.53, and 0.41, respectively, and specificities of 0.64, 0.78, 0.85, and 0.93, respectively. In children, using FeNO cutoffs of less than 20 and 20 to 29 parts per billion, FeNO testing had sensitivities of 0.78 and 0.61, respectively, and specificities of 0.79 and 0.89, respectively. Depending on the FeNO cutoff, the posttest odds of having asthma with a positive FeNO test result increased by 2.80 to 7.00-fold. Diagnostic accuracy was modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the overall population. CONCLUSION: Fractional exhaled nitric oxide measurement has moderate accuracy to diagnose asthma in individuals aged 5 years and older. Test performance may be modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the general population with suspected asthma. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42016047887. PMID- 29275032 TI - Diagnosis and Treatment of Infectious Enteritis in Neonatal and Juvenile Ruminants. AB - Common causes of infectious enteritis in neonate and juvenile ruminants include viral, bacterial, and protozoal pathogens. The most common presenting sign in ruminants with infectious enteritis is diarrhea. Diagnosis of the cause of enteritis has important zoonotic and herd health implications. Severity of clinical signs with similar pathogens may differ between calves and small ruminants. Treatment of enteritis involves supportive care to correct fluid and electrolyte imbalances, provision of nutritional support for neonates, prevention and treatment of endotoxemia or sepsis, and pathogen-specific treatments when relevant and available. PMID- 29275033 TI - Paratuberculosis in Cattle. AB - Paratuberculosis remains one of the most important diseases of cattle worldwide. In cattle, the disease is debilitating and is characterized by weight loss and chronic diarrhea in the later stages of infection. However, cattle in the subclinical stages of the disease often show decreased milk production and are at higher risk for development of other common production diseases. Infections with Mycobacterium avium ssp paratuberculosis are difficult to control because of long incubation periods, the absence of clinical signs until advanced stages of the disease, and the lack of completely reliable diagnostic methods in the preclinical stages of the disease. PMID- 29275034 TI - The ability to predict pregnancy loss in cattle with ELISAs that detect pregnancy associated glycoproteins is antibody dependent. AB - The concentration of circulating pregnancy associated glycoproteins (PAGs) early in pregnancy may serve as markers to predict late embryonic mortality or fetal mortality in cattle. In this study, pregnancies were established in dairy cows, by either fixed-time AI (FTAI) or fixed-time embryo transfer (FTET) with in vitro produced embryos. Circulating PAGs were measured with different combinations of antibodies in either a laboratory-based ELISA or a commercial ELISA. For the in house ELISA, three monoclonal 'trapping' antibodies (A6, J2, and L4) and two polyclonal 'detection' antisera (antibodies F2 or 45) were used to quantify PAGs in serum from the same cows. The different assays were identified as follows: 'Mix-45' (A6, J2, and L4 with 45), 'Mix-F2' (A6, J2, and L4 with F2), and 'L4 F2': (L4 with F2); the commercial assay was from IDEXX. Ovulation was synchronized and FTAI or FTET was performed on day 0 or 7, respectively. Ultrasound-based diagnosis of pregnancy and serum collections occurred on day 30. The proportion of cows that subsequently experienced pregnancy loss between days 30 and 60 was 23% (43 of 183) and 16% (21 of 131) for the FTAI or FTET groups, respectively. In the FTAI group, mean serum concentration of PAGs detected with Mix-45 was higher in cows that maintained pregnancy (9.2 +/- 0.4 ng/ml; mean +/- SEM) compared with cows that experienced pregnancy failure (3.9 +/- 0.6 ng/ml) between day 30-60 (P < .001). However, there was no difference (P > .69) in circulating concentrations of PAGs between cows that experienced loss or survival between days 30 and 60 when Mix-F2 or L4-F2 were used in an in-house ELISA. Likewise, a commercial assay also did not result in measurable differences in PAG concentrations between those animals that experienced loss or survival. Following FTET, circulating concentrations of PAGs on day 30 were lower (P < .001) in cows that experienced pregnancy failure compared to cows that maintained pregnancy when the Mix-45 and the commercial assay were used, but not with the other antibody combinations. A receiver operating characteristic curve showed that only the Mix-45 antibody combination was predictive (95% accuracy) of pregnancy loss but not the other antibody combinations following FTAI. However, both Mix-45 and the commercial assay were predictive of losses following FTET. In summary, although multiple PAG assay formats have been shown to accurately detect pregnancy, the ability to predict embryo survival during early gestation appears to be antibody dependent. PMID- 29275035 TI - Critical evaluation of quantification methods for oligonucleotides formulated in lipid nanoparticles. AB - There is a very large variety in the types of nanoparticulate lipid formulations for oligonucleotides, and remarkably, also a very large heterogeneity in the methods that are used for analyzing oligonucleotide load, encapsulation efficiency and oligonucleotide release. Furthermore, a literature survey showed that the extent to which these procedures are reported in scientific literature varies greatly, with some of them not even reporting any quantification at all. This greatly hampers the reproducibility of nanoparticle preparation between different researchers and between different laboratories, which slows down the clinical translation of such nanomedicines. In this work, a standardized extraction method from liposomes is proposed, in which potential contaminants from the carrier are removed by a simple extraction of the oligonucleotides. These extracts were then analyzed with seven commonly used methods for oligonucleotide quantification, including several absorbance based methods and the most commonly applied dye binding assay. Strikingly, differences in absolute values up to fourfold were found when the same sample was analyzed using different methods which should be taken into consideration when reports using different methods are compared. Furthermore, these results indicate that the most commonly applied method, the dye binding assay, may -without adaptations- not be suitable for short oligonucleotides like siRNAs. The found differences in quantification methods as described here underscore the need for proper documentation of methods to correctly interpret published results, which -with regard to oligonucleotide analysis- is currently lacking in many reports. PMID- 29275036 TI - Cost-Effectiveness Analysis of Primary Arthrodesis Versus Open Reduction Internal Fixation for Primarily Ligamentous Lisfranc Injuries. AB - The purpose of the present study was to determine whether surgical intervention with open reduction internal fixation (ORIF) or primary arthrodesis (PA) for Lisfranc injuries is more cost effective. We conducted a formal cost effectiveness analysis using a Markov model and decision tree to explore the healthcare costs and health outcomes associated with a scenario of ORIF versus PA for 45 years postoperatively. The outcomes assessed included long-term costs, quality-adjusted life-years (QALYs), and incremental cost per QALY gained. The costs were evaluated from the healthcare system perspective and are expressed in U.S. dollars at a 2017 price base. ORIF was always associated with greater costs compared with PA and was less effective in the long term. When calculating the cost required to gain 1 additional QALY, the PA group cost $1429/QALY and the ORIF group cost $3958/QALY. The group undergoing PA overall spent, on average, $43,192 less than the ORIF group, and PA was overall a more effective technique. Strong dominance compared with ORIF was demonstrated in multiple scenarios, and the model's conclusions were unchanged in the sensitivity analysis even after varying the key assumptions. ORIF failed to show functional or financial benefits. In conclusion, from a healthcare system's standpoint, PA would clearly be the preferred treatment strategy for predominantly ligamentous Lisfranc injuries and dislocations. PMID- 29275037 TI - Open Surgical Implantation of a Viable Intact Cryopreserved Human Placental Membrane for the Treatment of Recalcitrant Plantar Fasciitis: Case Report With Greater than 2-Year Follow-Up Duration. AB - Plantar fasciitis is one of the most common conditions encountered by a podiatric physician. Although most individuals respond well to traditional conservative and surgical remedies, a portion of patients will exhaust all available treatment options and will experience ongoing pain that can ultimately affect their quality of life. There has been an increase in scientific and clinical research surrounding the medical use of human placental membranes (HPMs) and many of these point-of-care allografts are now commercially available. We present the case of a 53-year-old female with chronic plantar fasciitis for whom both conservative therapies and surgical treatments of 1 year's duration had previously failed. After open revision with implantation of viable intact cryopreserved human placental membrane (vCPM; Grafix(r), Osiris Therapeutics, Inc., Columbia, MD), the patient was able to resume her full-work duty with minimal symptoms at the 12 and 24-month follow-up examinations. This case report highlights the use of HPMs as an adjunct approach in the treatment of recalcitrant plantar fasciitis and the need for continued research. PMID- 29275038 TI - Dermal absorption of testosterone in human and pig skin in vitro. AB - The OECD test guideline 428 for the assessment of dermal absorption in vitro has been in force for more than a decade. Various sectors of industry utilise the method for the registration of chemical products. These include the Agrochemical and Cosmetic sectors where the OECD test guideline and industry-specific guidance forms a key part of the human risk assessment process for new and existing products. This investigation has compared the dermal absorption characteristics of one of the OECD 428 reference chemicals, testosterone, in human and pig dermatomed skin. We used identical dosing and skin decontamination conditions for testosterone in Franz static diffusion cells. This included a full mass balance recovery of the dose applied and distribution of the compound in the different layers of the skin. Our investigation has shown that intact human skin provides a more effective barrier to the dermal absorption of testosterone compared with pig skin, when studied according to modern day in vitro dermal absorption guidance. PMID- 29275039 TI - Investigation of (n, p), (n, 2n) reaction cross sections for Sn isotopes for fusion reactor applications. AB - The compound Nb3Sn possess superconductivity at suitable temperatures, therefore, it is best suited to be used in the toroidal coils of superconducting magnets which holds the fusion plasma and confine it inside the reactor core. The neutron induced reaction cross-sections are required from threshold to 20MeV for different isotopes of Tin (Sn). Since limited data is available for the reactions with the Sn isotopes. Therefore, we have optimized the (n, p) and (n, 2n) reaction cross-sections for all possible Sn isotopes from threshold to 20MeV with modified input parameters in the nuclear reaction modular codes EMPIRE-3.2.2 and TALYS-1.8. These codes account for the major nuclear reaction mechanisms, including direct, pre-equilibrium, and compound nucleus contributions. The present results from 116Sn(n,p)116mIn, , 117Sn(n,p)117mIn, 118Sn(n,2n)117mSn,120Sn(n,2n)119mSn and 124Sn(n,2n)123mSn reactions calculated with nuclear modular codes: TALYS - 1.8, EMPIRE - 3.2.2 were compared with EXFOR data, systematics proposed by several authors and with the existing evaluated nuclear data library ENDF/B-VII.1, as well. The results from the present study can be used for the future development of ITER devices as well as to upgrade the nuclear model codes. PMID- 29275040 TI - Radiosynthesis and modified quality control of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) for brain tumor imaging. AB - O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is the most promising radio-labeled amino acid tracer for brain tumor imaging due to the limitation of 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) and L-methyl-[11C]methionine (11C-MET). However, it has some limitations in radiosynthesis and related quality control that make it less frequently used in many PET centers, in this study, we report a new modification of [18F]FET production using a commercially available fully automated GRP SCINTOMICS module overcoming some of the existing limitations along with a suggestion of a simplified quality control procedure with special focus placed on enantiomeric and radiochemical purity. ([18F]FET) was produced in high radiochemical and enantiomeric purity more than 99% and non-decay corrected yield 25+/-5% in about 55min. PMID- 29275041 TI - Utility of Maximum Standard Uptake Value as a Predictor for Differentiating the Invasiveness of T1 Stage Pulmonary Adenocarcinoma. AB - BACKGROUND: The present study was performed to investigate the maximum standardized uptake value (SUVmax) in 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to preoperatively distinguish invasive from less-invasive pulmonary adenocarcinoma. PATIENTS AND METHODS: A total of 106 patients with resectable pulmonary adenocarcinoma (<= 3 cm) who had undergone whole-body 18F-FDG PET/CT were enrolled. The SUVmax, diameter, and consolidation/tumor (C/T) ratio of the lung tumors were measured with 18F-FDG PET/CT and regional thin-section CT. RESULTS: Of the 106 patients, 32 had adenocarcinoma in situ (AIS), 13 had minimally invasive adenocarcinoma (MIA), and 61 had invasive adenocarcinoma (IAC). IAC lesions showed greater uptake of 18F-FDG, a larger tumor diameter, and greater C/T ratios than AIS and MIA (P < .001 for all). A multivariate analysis revealed that only the SUVmax, tumor diameter, and C/T ratio were independent risk factors for tumor invasiveness (P < .05 for all). The best cutoff values for the prediction of invasiveness were 2.15 for the SUVmax, 1.36 cm for the tumor diameter, and 0.36 for the C/T ratio. The SUVmax, tumor diameter, and C/T ratio showed similar predictive sensitivity (83.6%, 82.0%, and 88.5%, respectively). However, the SUVmax showed a greater predictive specificity than the C/T ratio (93.3% vs. 73.3%, respectively; P = .011) but similar to that of the tumor diameter. The predictive sensitivity and specificity were not improved using the 3 combined parameters compared with SUVmax alone. CONCLUSION: The present study has demonstrated that the SUVmax is a good preoperative predictor for the invasiveness of pulmonary adenocarcinoma (<= 3 cm). It will help surgeons plan low invasive treatment of preinvasive tumors. PMID- 29275042 TI - Editorial: Breakthroughs in top-down proteomics. PMID- 29275043 TI - Signatures of protein expression revealed by secretome analyses of cancer associated fibroblasts and melanoma cell lines. AB - : The imbalance of cellular homeostasis during oncogenesis together with the high heterogeneity of tumor-associated stromal cells have a marked effect on the repertoire of the proteins secreted by malignant cells (the secretome). Hence, the study of tumoral secretomes provides insights for understanding the cross talk between cells within the tumor microenvironment as well as the key effectors for the establishment of the pre-metastatic niche in distant tumor sites. In this context, we performed a proteomic analysis of the secretomes derived from four cell lines: a paired set of fibroblasts - Hs 895. T, a cell line obtained from a lung node metastatic site from a patient who had melanoma and Hs 895.Sk, a skin fibroblast cell line (derived from the same patient); two malignant metastatic melanoma cell lines - A375, a malignant melanoma cell line from primary source and SH-4, a cell line derived from pleural effusion of a patient with metastatic melanoma. Clustering of expression profiles together with functional enrichment analysis resulted in patterns that mirrored each cell type. In addition, these patterns might be the result of cell-specific protein expression programs and reveal the emergence of trends in the co-expression of functionally related proteins in cellular melanoma models. SIGNIFICANCE: Melanoma is an aggressive skin cancer and a lethal melanocytic neoplasm with increasing annual number of cases, faster than any other solid tumor. In this context, the imbalance of cellular homeostasis during oncogenesis together with the high heterogeneity of tumor-associated stromal cells have a marked effect on the repertoire of the proteins secreted by malignant cells (the secretome). Therefore, the identification of protein expression patterns in malignant cells together with functional enrichment analysis provide insights into cell-specific protein expression programs and may reveal the emergence of trends in the co-expression of functionally related proteins regardless of cell type. Moreover, the identification of networks of protein interactions together with their expression profiles can be used for the targeted analysis of co-expressed proteins, allowing the identification of regulatory motifs in melanoma protein-protein interaction networks. PMID- 29275044 TI - Functional and proteomic comparison of Bothrops jararaca venom from captive specimens and the Brazilian Bothropic Reference Venom. AB - : Snake venom is a variable phenotypic trait, whose plasticity and evolution are critical for effective antivenom production. A significant reduction of the number of snake donations to Butantan Institute (Sao Paulo, Brazil) occurred in recent years, and this fact may impair the production of the Brazilian Bothropic Reference Venom (BBRV). Nevertheless, in the last decades a high number of Bothrops jararaca specimens have been raised in captivity in the Laboratory of Herpetology of Butantan Institute. Considering these facts, we compared the biochemical and biological profiles of B. jararaca venom from captive specimens and BBRV in order to understand the potential effects of snake captivity upon the venom composition. Electrophoretic analysis and proteomic profiling revealed few differences in venom protein bands and some differentially abundant toxins. Comparison of enzymatic activities showed minor differences between the two venoms. Similar cross-reactivity recognition pattern of both venoms by the antibothropic antivenom produced by Butantan Institute was observed. Lethality and neutralization of lethality for B. jararaca venom from captive specimens and BBRV showed similar values. Considering these results we suggest that the inclusion of B. jararaca venom from captive specimens in the composition of BBRV would not interfere with the quality of this reference venom. BIOLOGICAL SIGNIFICANCE: Snakebite envenomation is a neglected tropical pathology whose treatment is based on the use of specific antivenoms. Bothrops jararaca is responsible for the majority of snakebites in South and Southeastern Brazil. Its venom shows individual, sexual, and ontogenetic variability, however, the effect of animal captivity upon venom composition is unknown. Considering the reduced number of wild-caught snakes donated to Butantan Institute in the last decades, and the increased life expectancy of the snakes raised in captivity in the Laboratory of Herpetology, this work focused on the comparative profiling of B. jararaca venom from captive snakes and the Brazilian Bothropic Reference Venom (BBRV). BBRV is composed of venom obtained upon the first milking of wild-caught B. jararaca specimens, and used to assess the potency of all bothropic antivenoms produced by Brazilian suppliers. The use of proteomic strategies, added to biochemical and neutralization tests, allowed to conclude that, despite some subtle differences detected between these two venoms, venom from captive specimens could be used in the BBRV composition without affecting its quality in antivenom potency assays. PMID- 29275045 TI - Does the administration of pilocarpine prior to venom milking influence the composition of Micrurus corallinus venom? AB - : Considering that the scarcity of venom represents a huge challenge for biochemical and functional studies of Micrurus species (coral snakes), in this report we describe for the first time the influence of pilocarpine administration prior to venom milking on the yield and protein composition of Micrurus corallinus venom. The administration of pilocarpine resulted in an increase of about 127% in the volume of venom milked, with similar protein content. Venoms showed similar protein bands distribution and intensity by SDS-PAGE and equivalents RP-HPLC profiles. Our proteomic analysis showed that venoms milked in the presence and absence of pilocarpine presented comparable protein profiles, in terms of protein composition and relative abundance. The toxins identified were assigned to 13 protein families and represent the most complete M. corallinus venom proteome described so far, in terms of number of protein families identified. Our data indicate that the administration of pilocarpine prior to venom milking increases the venom yield and does not change significantly the venom composition of M. corallinus. The employment of pilocarpine represents a useful approach to increase the yield of venom not only for Micrurus species, but also for other genera of snakes with limitations regarding the amount of venom available. SIGNIFICANCE: In this report, we evaluated the influence of pilocarpine administration prior to venom milking in the overall composition of M. corallinus venom. We showed that the use of pilocarpine 10min before M. corallinus venom milking increases venom yield by ~127%. Not only the volume of venom obtained is higher, but also the protein concentration of both venoms is similar, opposing the idea that a more diluted venom is obtained as a result of pilocarpine administration, observed in non-front-fanged snakes. Shotgun proteomics analysis revealed that venom milked with and without the use of this drug showed similar overall protein composition and relative abundances. In addition, our proteomic approach allowed the identification of 13 toxin families in M. corallinus venom, representing the most complete M. corallinus venom proteome described so far. Moreover, two of these toxin families were identified for the first time in the venom of this species. Thus, considering the scarcity of Micrurus venom for biochemical and functional studies, we highlighted the usefulness of pilocarpine administration prior to venom milking to increase the venom yield of these snakes. PMID- 29275046 TI - Plasma Testosterone and Sexual Function in Southeast Asian Men Receiving Methadone and Buprenorphine Maintenance Treatment. AB - BACKGROUND: Methadone has been recognized as an effective maintenance treatment for opioid dependence. However, its use is associated with several complications, including sexual dysfunction in men. AIM: To assess plasma testosterone and sexual function in Southeast Asian men on methadone maintenance treatment (MMT) or buprenorphine maintenance treatment (BMT). METHODS: 76 sexually active men on MMT (mean age = 43.30 +/- 10.32 years) and 31 men on BMT (mean age = 41.87 +/- 9.76 years) from a Southeast Asian community were evaluated using plasma total testosterone (TT) and prolactin levels, body mass index, social demographics, substance use measures, and depression severity scale. OUTCOMES: Prevalence and associated factors of TT level lower than the reference range in men on MMT or BMT. RESULTS: More than 1 third of men (40.8%, n = 31) on MMT had TT levels lower than the reference range, whereas 1 fourth of men (22.6%, n = 7) on BMT did. At univariate analysis, MMT vs BMT (beta = 0.298, adjusted R2 = 0.08, P = .02) and body mass index (beta = -0.23, adjusted R2 = 0.12, P = .02) were associated with changes in TT after stepwise regression. There were no significant associations with age; Opiate Treatment Index Q scores for alcohol, heroin, stimulant, tobacco, or cannabis use and social functioning domain; education levels; hepatitis C status; and severity of depression. Prolactin level did not differ between the MMT and BMT groups. CLINICAL IMPLICATIONS: The sex hormonal assay should be used regularly to check men on MMT. STRENGTHS AND LIMITATIONS: This is the first study conducted in the Southeast Asian community. Our study was limited by the lack of a healthy group as the reference for serum levels of testosterone and prolactin. CONCLUSIONS: The findings showed that plasma testosterone levels are lower in MMT than in BMT users. Hence, men who are receiving MMT should be screened for hypogonadism routinely in the clinical setting. Yee A, Loh HS, Danaee M, et al. Plasma Testosterone and Sexual Function in Southeast Asian Men Receiving Methadone and Buprenorphine Maintenance Treatment. J Sex Med 2018;15:159-166. PMID- 29275047 TI - Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats. AB - BACKGROUND: Clinical studies have shown altered sexual function in people with diabetes; basic science studies, using the streptozotocin (STZ)-induced animal model of type 1 diabetes mellitus (DM1), have consistently reported decreased sexual behavior in hyperglycemic female animals, but features of sexual motivation and aggressive behavior have not been explored in these animals. AIM: To study several parameters that denote sexual motivation in STZ-treated female rats and to compare behavioral features of sexual behavior and aggression in non paced mating (NPM) and paced mating (PM) conditions. METHODS: DM1 was induced by injecting STZ (diluted in citrate buffer) at a dose of 50 mg/kg intraperitoneally over 2 consecutive days into ovariectomized Wistar rats. 10 days later, female rats were treated with estradiol benzoate (10 MUg, -24 hours) and progesterone (3 mg, -4 hours); their sexual behavior (including lordosis quotient, lordosis intensity, and proceptivity) and aggression were evaluated under NPM and PM conditions. Body weight, blood glucose levels, and spontaneous ambulatory activity also were measured. A group of STZ-treated animals was administered a long-acting insulin analogue (glargine) every 12 hours for 8 days, and their sexual and aggressive behaviors were evaluated in NPM. OUTCOMES: We quantified body weight, blood glucose level, spontaneous ambulatory activity, and sexual and aggressive behaviors in NPM and PM; the time the female rats spent interacting with the male rat or in the male rat's chamber also was registered in PM. RESULTS: Compared with controls, STZ-treated ovariectomized rats lost body weight, had increased blood glucose levels, and had unchanged spontaneous ambulatory activity. In the PM and NPM conditions, animals showed decreased lordosis quotient and lordosis intensity, increased aggression, and unaltered proceptivity, although in NPM the effects of STZ treatment on aggression were more drastic and were completely prevented by insulin. In PM no differences were found between diabetic and control female rats in the time interacting with the male rat or in the male rat's chamber. CLINICAL TRANSLATION: These findings support the observation of increased prevalence of sexual dysfunctions and aggression in the clinical setting of DM1. STRENGTHS AND LIMITATIONS: The main strength of this study is that it analyzed sexual behavior under PM and NPM conditions and aggression in STZ-treated female rats. Its main limitations are that the model of DM1 represents only 10% of the affected population and that no specific treatment is proposed for the sexual dysfunctions. CONCLUSION: These results suggest that STZ-treated rats have decreased sexual receptivity in NPM and PM, accompanied by increased aggressiveness in NPM. Hernandez-Munive AK, Rebolledo-Solleiro D, Ventura-Aquino E, Fernandez-Guasti A. Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats. J Sex Med 2018;15:124-135. PMID- 29275048 TI - Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress. AB - BACKGROUND: Non-organic erectile dysfunction (noED) at functional imaging has been related to abnormal brain activity and requires animal models for further research on the associated molecular mechanisms. AIM: To develop a noED animal model based on chronic mild stress and investigate brain activity changes. METHODS: We used 6 weeks of chronic mild stress to induce depression. The sucrose consumption test was used to assess the hedonic state. The apomorphine test and sexual behavior test were used to select male rats with ED. Rats with depression and ED were considered to have noED. Blood oxygen level-dependent-based resting state functional magnetic resonance imaging (fMRI) studies were conducted on these rats, and the amplitude of low-frequency fluctuations and functional connectivity were analyzed to determine brain activity changes. OUTCOMES: The sexual behavior test and resting-state fMRI were used for outcome measures. RESULTS: The induction of depression was confirmed by the sucrose consumption test. A low intromission ratio and increased mount and intromission latencies were observed in male rats with depression. No erection was observed in male rats with depression during the apomorphine test. Male rats with depression and ED were considered to have noED. The possible central pathologic mechanism shown by fMRI involved the amygdaloid body, dorsal thalamus, hypothalamus, caudate putamen, cingulate gyrus, insular cortex, visual cortex, sensory cortex, motor cortex, and cerebellum. Similar findings have been found in humans. CLINICAL TRANSLATION: The present study provided a novel noED rat model for further research on the central mechanism of noED. STRENGTHS AND LIMITATIONS: The present study developed a novel noED rat model and analyzed brain activity changes based at fMRI. The observed brain activity alterations might not extend to humans. CONCLUSION: The present study developed a novel noED rat model with brain activity alterations related to sexual arousal and erection, which will be helpful for further research involving the central mechanism of noED. Chen G, Yang B, Chen J, et al. Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress. J Sex Med 2018;15:136-147. PMID- 29275049 TI - The Multiple-Slit Technique (MUST) for Penile Length and Girth Restoration. AB - BACKGROUND: Patients with severe erectile dysfunction (ED) and penile size issues, especially seen in Peyronie's disease (PD), are candidates for more invasive penile prosthesis insertion techniques that aim for penile length and girth reconstruction. AIM: To present the feasibility and safety of penile length and girth restoration based on the so-called multiple-slit technique (MUST) for patients with severe ED and significant penile shortening with or without PD. METHODS: From July 2013 through January 2016, 138 patients underwent the MUST. The International Index of Erectile Function (IIEF) and the Erectile Dysfunction Inventory of Treatment Satisfaction were completed. OUTCOMES: Outcome analysis was focused on penile length restoration, penile curvature correction, intra- and postoperative complications, and patient satisfaction. RESULTS: 138 patients underwent the procedure (103 malleable and 35 inflatable devices). Etiologies of penile shortening and narrowing were PD, severe ED, post-radical prostatectomy, and androgen-deprivation therapy with or without brachytherapy or external radiotherapy for prostate cancer, and post-penile fracture in 60.1%, 24.6%, 10.1%, 3.6%, and 2.2%, respectively. In PD cases, the mean deviation of the penile axis was 55 degrees (range = 0-90 degrees ). Mean subjective penile length loss reported was 3.2 cm (range = 1-5 cm), and shaft constriction was present in 44.9%. Median follow-up was 15.2 months (range = 6-36 months). Mean penile length gain was 3.1 cm (range = 2-5 cm). No penile prosthesis infection caused device explantation. One glans necrosis was encountered. The average IIEF score increased from 22 points at baseline to 66 points at 6-month follow-up. CLINICAL IMPLICATIONS: The MUST helps address penile size issues in cases of severe ED with concomitant conditions that impair penile length or girth. STRENGTHS AND LIMITATIONS: The strength of the study is its applicability to provide surgeons with a solution for cases in which patients have severe ED and penile size impairment owing to underlying conditions such as PD. The study is limited by the relatively short follow-up. CONCLUSIONS: The MUST is an effective, safe, and viable treatment option for a selected patient cohort. Because of the potential complications, proper counseling should take place and only experienced surgeons should perform this type of surgery. Egydio PH, Kuehhas FE. The Multiple Slit Technique (MUST) for Penile Length and Girth Restoration. J Sex Med 2018;15:261-269. PMID- 29275050 TI - Reaction specificity of keratanase II in the transglycosylation using the sugar oxazolines having keratan sulfate repeating units. AB - The reaction specificity of the transglycosylation catalyzed by keratanase II from Bacillus circulans KsT202 (KSase II) was studied by using the oxazoline derivatives having keratan sulfate repeating units. The addition of 10% organic cosolvent reduced the activity for the enzymatic transglycosylation. The oxazoline derivative of 6-O-sulfonato-N-acetyllactosamine (su-LacNAc) was processively oligomerized to the corresponding hexamer or longer by the enzyme. This result strongly implies that the enzyme has the large positively numbered subsites. In contrast, the transglycosylation of the su-LacNAc oxazoline donor with the 6-O-sulfonato-Lewis X (su-LeX) acceptor solely gave the su-LacNAc-su-LeX pentasaccharide. In addition, both the oxazoline derivatives of su-LeX and 6,6' di-O-sulfonato-LacNAc have been exclusively oligomerized to the corresponding dimers respectively. These results strongly suggest that the steric hindrance exists around the (+3)(+4) subsites in KSase II. Furthermore, KSase II-catalyzed reaction of the excess su-LeX oxazoline with the su-LacNAc gave the su-LeX-su LacNAc pentasaccharide as the sole transglycosylation product, also implying the steric hindrance at the catalytic center hampering processive shift of this pentasaccharide. Thus, KSase II has the sterically crowded structures at the catalytic center and around the (+3)(+4) subsites, which are all expected to be tunnel-like. PMID- 29275051 TI - Women in Neurosurgery: Final Frontier of Career Women's Movement. AB - In the past, women in neurosurgery were deemed "less than a minority." Pioneering women entered neurosurgical residency programs alone, facing large obstacles to become surgical experts. Recent data suggest a stark increase in the number of women neurosurgical residents. As the field of neurosurgery attempts to increase numbers of women surgeons, it must also adjust workplace culture to embrace a new group of trainees. Here, we share an account of historical numbers, as well as evidence of a changing landscape within neurosurgery and suggestions of ways to modify workplace culture based on examples set in other career paths. PMID- 29275053 TI - It's Not Just Time; Imaging Is Brain, Too: The DAWN Trial and Changing Definition of the Therapeutic Window for Acute Ischemic Stroke. PMID- 29275054 TI - Gadobutrol and the End of the Tap Test. PMID- 29275052 TI - Instrumented Spinal Stabilization without Fusion for Spinal Metastatic Disease. AB - OBJECTIVES: Spinal stabilization surgery is an integral part of the treatment of spinal metastatic disease. Bony fusion is the hallmark of spinal stabilization in non-oncology patients. Spinal oncology patients are unlikely to achieve bony fusion because of their overall prognosis and concurrent therapies. Stabilization surgery without fusion may be a reasonable approach for these patients. Literature evaluating the effectiveness of this approach is limited. The object of this study was to investigate the rate of instrumentation failure in patients undergoing posterior spinal instrumented stabilization without fusion for spinal metastatic disease. METHODS: Data from consecutive cases of spinal surgery at our institution during an 81-month period were reviewed. Demographics, clinical notes, and computed tomography findings were recorded and used to evaluate instrumentation failures. Patients who underwent separation surgery that included laminectomy and posterior spinal instrumentation without fusion for spinal metastatic disease and had follow-up computed tomography scans >3 months postoperatively were selected for the study. RESULTS: Twenty-seven patients were included in the study. Mean age was 64.85 +/- 6.53 years. Nine patients were women. A mean of 1.61 +/- 0.96 laminectomy levels was performed. A mean of 8.26 +/- 1.48 screws was inserted. The mean postoperative discharge date was 5.07 +/- 1.47 days. Mean follow-up duration was 12.17 +/- 11.73 months. None of the patients had a change in instrumentation position, pedicle screw pullout, change in spinal alignment, or progressive deformity. No patient required reoperation or instrumentation revision or replacement. CONCLUSIONS: Our experience suggests that instrumented spinal stabilization without fusion is an acceptable approach for patients with spinal metastatic disease. PMID- 29275055 TI - Unexpected Mitral Regurgitation During Coronary Artery Bypass Graft Surgery: The Multidisciplinary Management of a Mitral Valve Cleft. PMID- 29275056 TI - The Pivotal Multicenter Trial of Ultrasound-Guided Percutaneous Arteriovenous Fistula Creation for Hemodialysis Access. AB - PURPOSE: To evaluate safety and efficacy of arteriovenous fistulas (AVFs) created with a thermal resistance anastomosis device. MATERIALS AND METHODS: A prospective single-arm trial at 5 sites enrolled 107 patients. Patients underwent ultrasound (US)-guided anastomosis creation between the proximal radial artery and perforating vein with the Ellipsys Vascular Access System (Avenu Medical, Inc, San Juan Capistrano, California) followed by separate maturation procedures. Primary endpoints were brachial artery flow volume >= 500 mL/min and target vein diameter >= 4 mm in > 49% of patients and absence of device-related complications at 90 days. RESULTS: AVFs with fused anastomoses were created in 95% (102/107) of patients. Maturation procedures included anastomotic balloon dilation in 72% (77/107), brachial vein embolization in 32% (34/107), cubital vein ligation in 31% (33/107), and surgical transposition in 26% (28/107) of patients. Primary flow and diameter endpoints were achieved in 86.0% (92/107) of patients, exceeding performance goal of 49% (P < .0001). No major adverse events were attributed to the device. Cumulative patency was 91.6%, 89.3%, and 86.7% at 90 days, 180 days, and 360 days. Target dialysis veins were cephalic, basilic, and brachial veins in 74% (73/99), 24% (24/99), and 2% (2/99) of patients. Two-needle dialysis was achieved in 88% (71/81) of patients on hemodialysis at a mean 114.3 days +/- 66.2. Functional patency was 98.4%, 98.4%, and 92.3% at 90 days, 180 days, and 360 days. CONCLUSIONS: The Ellipsys(r) Vascular Access System met primary safety and efficacy endpoint goals in the US pivotal trial. PMID- 29275057 TI - Treatment satisfaction and bothersome bladder, bowel, sexual symptoms in multiple sclerosis. AB - BACKGROUND: Bladder, bowel, and sexual symptoms are common among persons with multiple sclerosis (MS). We aimed to investigate the frequency and severity of bladder, bowel, and sexual symptoms, the relationships between these symptoms, satisfaction with treatment of these symptoms, and factors associated with symptom severity and treatment satisfaction. METHODS: In the fall 2010, we surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding the severity of being bothered by bladder, bowel, and sexual symptoms, their satisfaction of health providers' inquiry and treatment with these symptoms, and whether their quality of life (QOL) had changed with the treatment. Logistic regression was used to evaluate demographic and clinical factors associated with each outcome. RESULTS: Of 9341 respondents included in the study, 7720 (77.4%) were female and their mean (SD) age was 50.3 (10.5) years. Ninety-one percent of participants were mildly, moderately or severely bothered by bladder, bowel or sexual symptoms. Severity of disability (measured using the Patient Determined Disease Steps), having a relapse in the last 6 months, and catheter use were consistently associated with being bothered (versus not bothered) by each of the three symptoms. Among respondents, 5764 (62.1%) reported that their MS health providers asked about bladder problems, 4523 (51.1%) about bowel problems, and 1890 (20.6%) about sexual problems. At most one-third of participants were completely satisfied with treatment for any of the symptoms. For those who reported how their QOL changed with treatment, 23.0% reported their QOL being better. CONCLUSION: Bladder, bowel, and sexual problems remain common among persons with MS, and treatment satisfaction is low. Health care providers should consider systematically asking about these symptoms in clinical practice. Greater efforts could be devoted to developing novel, effective therapies to manage these symptoms and thereby improve QOL. PMID- 29275058 TI - Determining reliable change on the modified fatigue impact scale (5-item version). AB - BACKGROUND: Fatigue is prevalent in Multiple Sclerosis (MS), but little research indicates how to best quantify changes in fatigue over time. OBJECTIVE: Evaluate reliable change on the abbreviated Modified Fatigue Impact Scale (MFIS-5) in MS patients. METHODS: One-hundred sixty eight MS patients completed the MFIS-5 at baseline and follow-up as part of two larger studies. Test-retest reliability scores and reliable change indices were calculated. RESULTS: Differences of 4, 5, 6, and 7 points on the MFIS-5 represent statistically meaningful change at the .70, .80, .90, and .95 confidence intervals, respectively. CONCLUSIONS: The MFIS 5 can be used to quickly and reliably assess statistically meaningful changes in fatigue among MS patients. PMID- 29275060 TI - Comparison of Rates of Growth between Unruptured and Ruptured Aneurysms Using Magnetic Resonance Angiography JSCVD-D-17-01123. PMID- 29275059 TI - Long-Term Outcomes of Stroke in a Ghanaian Outpatient Clinic. AB - BACKGROUND: Compared with high-income countries, sub-Saharan African (SSA) countries experience a comparatively higher early mortality from stroke. However, data on long-term mortality from stroke in SSA are lacking. OBJECTIVE: Our aim is to assess long-term outcomes of stroke in an SSA setting. METHODS: We conducted a retrospective analysis of longitudinal data involving 607 consecutive stroke survivor encountered at an outpatient clinic in Kumasi, Ghana, between January 2012 and June 2014. Data were closed for analysis in June 2016. Data on demography, presence of vascular risk factors, stroke type, and functional status were evaluated. We followed up subjects who were no longer attending clinic by phone to assess their vital status. Primary outcome was death after initiation of clinic care, and its predictors were determined using a Cox proportional hazards regression model. RESULTS: Mean +/- standard deviation (SD) age of cohort was 59.9 +/- 13.9 years and 50.3% were female. Of the 607 stroke survivors, 377 (62.1%) were still alive, 59 (9.7%) were confirmed to have died, whereas 171 (28.2%) were lost to follow-up at the clinic. Mean +/- SD observation time for the cohort was 32 +/- 30 months. Upon adjustment for confounders, the independent predictors of mortality were age (adjusted hazard ratio [aHR] of 1.41 [95% confidence interval 1.15-1.73] for a 10-year increase in age) and diabetes mellitus (aHR of 2.24 [1.32-3.80]). CONCLUSIONS: Diabetes mellitus, a modifiable risk factor for stroke, is associated with an increased risk of mortality among West African stroke survivors over the long term. PMID- 29275061 TI - Deterioration of Chronotropic Responses and Heart Rate Recovery Indices in Men With Erectile Dysfunction. AB - INTRODUCTION: Erectile dysfunction (ED) and cardiovascular (CV) diseases share common risk factors and ED has been accepted as an early manifestation of CV disease. Exercise stress testing (EST) is used to evaluate CV functions in men with ED. Low exercise workload, a slower heart rate recovery (HRR) after exercise, and inability to increase heart rate during EST (chronotropic incompetence) are independent negative predictors of adverse CV outcomes. AIM: To assess the association among EST parameters, ED, and testosterone levels. METHODS: The study population consisted of 41 patients with ED and 40 controls. All participants underwent treadmill EST to assess cardiac autonomic functions. HRR indices were calculated by subtracting 1st (HRR1), 2nd (HRR2), and 3rd (HRR3) minute heart rates during the recovery period from maximal heart rate. Total exercise duration, exercise capacity and chronotropic response, and plasma testosterone levels were evaluated. Erectile functions were evaluated with the Sexual Health Inventory for Men. Patients were divided into subgroups according to severity and duration of ED. MAIN OUTCOME MEASURES: Mean HRR1 (30.6 +/- 11.9 vs 36.9 +/- 9.9; P = .01), HRR2 (44.9 +/- 12.4 vs 54.9 +/- 7.8; P < .001), and HRR3 (50.1 +/- 11.7 vs 63.0 +/- 7.9; P < .001) were significantly lower in the ED than in the control group. Total exercise duration (9.4 +/- 1.9 vs 10.9 +/- 1.7 minutes; P < .001), exercise capacity (12.5 +/- 1.9 vs 13.6 +/- 1.4 metabolic equivalents; P = .004), and chronotropic response (0.88 +/- 0.1 vs 1.0 +/- 0.1; P < .001) were worse in the ED group. However, we found no association between severity and duration of ED and EST parameters. In addition, serum testosterone levels were significantly correlated with HRR1 (r = 0.36, P = .02) in men with ED. CONCLUSION: Our data suggested that cardiac autonomic functions are impaired in patients with ED. A weak correlation between cardiac autonomic dysfunction and low testosterone levels in patients with ED was noted. However, further studies are needed to elucidate the prognostic significance and clinical implications of impaired autonomic functions and testosterone replacement therapy in patients with ED. Kucukdurmaz F, Agar G, Resim S. Deterioration of Chronotropic Responses and Heart Rate Recovery Indices in Men With Erectile Dysfunction. Sex Med 2018;6:8-14. PMID- 29275063 TI - Impacts of the Affordable Care Act's Medicaid Expansion on Women of Reproductive Age: Differences by Parental Status and State Policies. AB - INTRODUCTION: We use data from the Behavioral Risk Factor Surveillance System (BRFSS) from 2012 to 2015 to estimate the effects of the Affordable Care Act's (ACA) Medicaid expansions on insurance coverage and access to care for low-income women of reproductive age (19-44). METHODS: We use two-way fixed effects difference-in-differences models to estimate the effects of Medicaid expansions on low-income (<100% of the Federal Poverty Level) women of reproductive age. Additional models are stratified to estimate effects based on women's parental status, pre-ACA state Medicaid eligibility levels, and the presence of a state Medicaid family planning waiver. RESULTS: ACA Medicaid expansions decreased uninsurance among low-income women of reproductive age by 13.2 percentage points. This decrease was driven by a decrease of 27.4 percentage points for women without dependent children, who also experienced a decrease in the likelihood of not having a personal doctor (13.3 percentage points). We find a 3.8-percentage point reduction in the likelihood of experiencing a cost barrier to care among all women, but no significant effects for other access measures or subgroups. When stratified by state policies, decreases in uninsurance were greater in states expanding from pre-ACA eligibility levels of less than 50% of Federal Poverty Level (19.4 percentage points) and in states without a Medicaid family planning waiver (17.6 percentage points). CONCLUSIONS: The ACA Medicaid expansion increased insurance coverage for low-income women of reproductive age, with the greatest effects for women without dependent children and women residing in states with relatively lower pre-ACA Medicaid eligibility levels or with no family planning waiver before the ACA. PMID- 29275062 TI - Intravenous Infusion of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Erectile Dysfunction Following Cavernous Nerve Injury in Rats. AB - INTRODUCTION: Intravenous preload (delivered before cavernous nerve [CN] injury) of bone marrow-derived mesenchymal stem cells (MSCs) can prevent or decrease postoperative erectile dysfunction (J Sex Med 2015;12:1713-1721). In the present study, the potential therapeutic effects of intravenously administered MSCs on postoperative erectile dysfunction were evaluated in a rat model of CN injury. METHODS: Male Sprague-Dawley rats were randomized into 2 groups after electric CN injury. Intravenous infusion of bone marrow-derived MSCs (1.0 * 106 cells in Dulbecco's modified Eagle's medium 1 mL) or vehicle (Dulbecco's modified Eagle's medium 1 mL) was performed 3 hours after electrocautery-induced CN injury. MAIN OUTCOME MEASURES: To assess erectile function, we measured intracavernous pressure at 4 weeks after MSC or vehicle infusion. Histologic examinations were performed to investigate neuronal innervation and inhibition of smooth muscle atrophy. Green fluorescent protein-positive bone marrow-derived MSCs were used for cell tracking. To investigate mRNA expression levels of neurotrophins in the major pelvic ganglia (MPGs), quantitative real-time polymerase chain reaction was performed. RESULTS: The decrease of intracavernous pressure corrected for arterial pressure and area under the curve of intracavernous pressure in the bone marrow-derived MSC group was significantly lower than that in the vehicle group at 4 weeks after infusion (P < .05). Retrograde neuronal tracing indicated that the MSC group had a larger number of FluoroGold-positive neurons in the MPGs compared with the vehicle group. The ratio of smooth muscle to collagen in the MSC group was significantly higher than in the vehicle group. Green fluorescent protein-positive bone marrow-derived MSCs were detected in the MPGs and injured CNs using confocal microscopy, indicating homing of cells to the MPGs and injured CNs. Brain-derived neurotrophic factor and glial cell-derived neurotrophic factor expression levels in the MPGs were significantly higher in the MSC group than in the vehicle group (P < .01). CONCLUSION: Intravenous infusion of bone marrow derived MSCs after CN injury might have therapeutic efficacy in experimental erectile dysfunction. Matsuda Y, Sasaki M, Kataoka-Sasaki Y, et al. Intravenous Infusion of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Erectile Dysfunction Following Cavernous Nerve Injury in Rats. Sex Med 2018;6:49-57. PMID- 29275064 TI - Role of Physical Activity and Exercise in Alleviating Cognitive Impairment in People With Epilepsy. AB - Many persons with epilepsy (PWE) experience problems with a wide range of cognitive functions, including learning, memory, attention, and executive control. These deficits in cognition result in diminished quality of life for PWE and are related to many factors, including the etiology of their epilepsy, recurrent seizures, side effects of antiseizure medications, or a combination of these factors. Various treatments to ameliorate cognitive deficits experienced by PWE have been implemented, although noninvasive and nonpharmacologic strategies may be more appealing options due to their relatively low cost, reduced risk of side effects, and/or reduced potential interactions with antiseizure medications. Physical activity and exercise may improve cognition in PWE but have not been well researched in this respect. To date only 1 study has directly investigated the effects of exercise on cognition in PWE, and it showed improved performance on tests of attention and executive function. The goal of the present article was to examine how increased physical activity and exercise contributes to 3 strategies (reducing seizure frequency, reducing epileptiform discharges, and decreasing symptoms of depression) that have been described as having a positive impact on cognition in PWE, as well as highlight related findings in experimental models of epilepsy. There is a definite need for more randomized controlled trials to establish greater clinical evidence for the use of physical activity and exercise in ameliorating cognitive impairment in PWE. We also need to better understand the factors contributing to reduced physical activity in PWE, as well as ways to overcome such barriers. With the available research in the area of exercise in epilepsy showing positive results, and a supportive research climate encouraging PWE to engage in greater physical activity overall, further investigations into the relationships between physical activity and cognition in epilepsy are warranted. PMID- 29275065 TI - Reduced Time in Therapeutic Range and Higher Mortality in Atrial Fibrillation Patients Taking Acenocoumarol. AB - PURPOSE: The efficacy and tolerability of vitamin K antagonists (VKAs) depends on the quality of anticoagulant control, reflected by the mean time in therapeutic range (TTR) of international normalized ratio 2.0 to 3.0. In the present study, we aimed to investigate the association between TTR and change in TTR (DeltaTTR) with the risk of mortality and clinically significant events in a consecutive cohort of atrial fibrillation (AF) patients. METHODS: We included 1361 AF patients stable on VKAs (international normalized ratio 2.0-3.0) during at least the previous 6 months. After 6 months of follow-up we recalculated TTR, calculated DeltaTTR (ie, the difference between baseline and 6-month TTRs) and investigated the association of both with the risk of mortality and "clinically significant events" (defined as the composite of stroke or systemic embolism, major bleeding, acute coronary syndrome, acute heart failure, and all-cause deaths). FINDINGS: The median DeltaTTR at 6 months of entry was 20% (interquartile range 0-34%), 796 (58.5%) patients had a TTR reduction of at least 20%, while 330 (24.2%) had a TTR <65%. During follow-up, 34 (2.5% [4.16% per year]) patients died and 61 (4.5% [7.47% per year]) had a clinically significant event. Median DeltaTTR was significantly higher in patients who died (35.5% vs 20%; P = 0.002) or sustained clinically significant events (28% vs 20%; P = 0.022). Based on Cox regression analyses, the overall risk of mortality at 6 months for each decrease point in TTR was 1.02 (95% CI, 1.01-1.04; P = 0.003), and the risk of clinically significant events was 1.01 (95% CI, 1.00-1.03; P = 0.028). Patients with TTR <65% at 6 months had higher risk of mortality (hazard ratio = 2.96; 95% CI, 1.51-5.81; P = 0.002) and clinically significant events (hazard ratio = 1.71; 95% CI, 1.01-2.88; P = 0.046). IMPLICATIONS: Our findings suggest that in AF patients anticoagulated with VKAs, a change in TTR over 6 months (ie, DeltaTTR) is an independent risk factor for mortality and clinically significant events. Even in a cohort with good anticoagulation control, the risk for mortality and clinically significant events increases with every point deterioration of TTR. PMID- 29275066 TI - Phototoxic effect of aluminium-chlorine and aluminium-hydroxide phthalocyanines on Leishmania (l.) amazonensis. AB - This study investigated the activity of photosensitive phthalocyanines on promastigotes and amastigotes of Leishmania (L.) amazonensis. Aluminum phthalocyanine chloride (AlPcCl), Aluminum phthalocyanine hydroxide (AlPcOH) and zinc phthalocyanine (PcZn) were tested in the presence (matte red LED, potency of 2.5-2.3 MUW for 30 min) and absence of light against L. amazonensis promastigotes and the parasite viability was evaluated after 24, 48 and 72 h. The amastigote forms were treated with AlPcCl and AlPcOH, following the same lighting protocols described for the promastigote forms, being evaluated after 24 h. Cytotoxicity to human erythrocytes and peritoneal macrophages was also evaluated. The results showed that AlPcCl and AlPcOH in the presence of light have antileishmania activity, with leishmanistatic effects on promastigotes and amastigotes of L. amazonensis, without causing cytotoxicity to peritoneal macrophages and erythrocytes. The concentrations that inhibited 50% of the promastigote forms after 24 h of light exposure were 0.21 +/- 0.08 MUM for AlPcCl and 0.23 +/- 0.06 MUM for AlPcOH. In 48 h and 72 h after the treatment, the IC50 of AlPcCl was 0.13 +/- 0.02 and 0.12 +/- 0.03 MUM and for AlPcOH was 0.14 +/- 0.01 MUM and 0.11 +/- 0.01 MUM, respectively. PcZn showed no activity on promastigotes of L. amazonensis. This study showed a substantial photodynamic activity of the phthalocyanines AlPcCl and AlPcOH against intracellular amastigotes forms of L. amazonensis after irradiation, presenting IC50 values of 0.62 +/- 0.06 MUM and 0.92 +/- 0.12 MUM, respectively. These results support the possibility of using photodynamic therapy for the treatment of cutaneous leishmaniasis. PMID- 29275067 TI - Modularized peptides modified HBc virus-like particles for encapsulation and tumor-targeted delivery of doxorubicin. AB - Virus-mimicking particles have made great contribution to the development of nanomedicine. Herein, several modularized peptides (lipophilic NS5A peptide, 6xHis tag, and tumor-targeting peptide RGD) were genetically inserted into the C terminus and the major immunodominant loop region (MIR) of hepatitis B core protein (HBc), respectively. This study demonstrated that the recombinant HBc based VLPs could participate in self-assembly of monodisperse nanoparticles (33.6+/-3.5nm) with well-defined morphology, and DOX can be packaged into VLNPs without any chemical modification. Moreover, the HBc-based VLPs could specifically target to cancer cells via the interaction with overexpressed integrin alphavbeta3. The treatment with DOX-loaded HBc-based VLPs showed a significant inhibition of tumor growth (90.7% TGI) and less cardiotoxicity in B16F10 tumor-bearing mice models than that with the free DOX. Importantly, the results may offer an easy way to give a variety of ideal functional modulations for VLPs, thereby extending its potential biomedicine applications. PMID- 29275068 TI - Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial. AB - BACKGROUND: Diabetic foot ulcers are serious and challenging wounds associated with high risk of infection and lower-limb amputation. Ulcers are deemed neuroischaemic if peripheral neuropathy and peripheral artery disease are both present. No satisfactory treatment for neuroischaemic ulcers currently exists, and no evidence supports one particular dressing. We aimed to assess the effect of a sucrose octasulfate dressing versus a control dressing on wound closure in patients with neuroischaemic diabetic foot ulcers. METHODS: We did a randomised, double-blind clinical trial (Explorer) in 43 hospitals with specialised diabetic foot clinics in France, Spain, Italy, Germany, and the UK. Eligible participants were inpatients or outpatients aged 18 years or older with diabetes and a non infected neuroischaemic diabetic foot ulcer greater than 1 cm2 and of grade IC or IIC (as defined by the University of Texas Diabetic Wound Classification system). We excluded patients with a severe illness that might lead to them discontinuing the trial and those who had surgical revascularisation in the month before study entry. We randomly assigned participants (1:1) via a computer-generated randomisation procedure (concealed block size two); stratified by study centre and wound area (1-5 cm2 and 5-30 cm2), to treatment with either a sucrose octasulfate wound dressing or a control dressing (the same dressing without sucrose octasulfate) for 20 weeks. Both groups otherwise received the same standard of care for a 2-week screening period before randomisation and throughout the 20-week trial. Dressings were applied by nursing staff (or by instructed relatives for some outpatients). Frequencies of dressing changes were decided by the investigator on the basis of the clinical condition of the wound. Patients were assessed 2 weeks after randomisation, then monthly until week 20 or occurrence of wound closure. The primary outcome, assessed by intention-to-treat, was proportion of patients with wound closure at week 20. This trial is registered with ClinicalTrials.gov, number NCT01717183. FINDINGS: Between March 21, 2013, and March 31, 2016, we randomly assigned 240 individuals to treatment: 126 to the sucrose octasulfate dressing and 114 to the control dressing. After 20 weeks, wound closure occurred in 60 patients (48%) in the sucrose octasulfate dressing group and 34 patients (30%) in the control dressing group (18 percentage points difference, 95% CI 5-30; adjusted odds ratio 2.60, 95% CI 1.43-4.73; p=0.002). In both groups, the most frequent adverse events were infections of the target wound: 33 wound infections in 25 (20%) patients of 126 in the sucrose octasulfate dressing group and 36 in 32 (28%) patients of 114 in the control dressing group. Minor amputations not affecting the wound site were also reported in one (1%) patient in the sucrose octasulfate dressing group and two (2%) patients in the control dressing group. Three (2%) patients assigned to the sucrose octasulfate dressing and four (4%) assigned to the control dressing died, but none of the deaths were related to treatment, procedure, wound progression, or subsequent to amputation. INTERPRETATION: A sucrose octasulfate dressing significantly improved wound closure of neuroischaemic diabetic foot ulcers without affecting safety after 20 weeks of treatment along with standard care. These findings support the use of sucrose octasulfate dressing as a local treatment for neuroischaemic diabetic foot ulcers. FUNDING: Laboratoires Urgo Medical. PMID- 29275069 TI - Treatment strategies for neuroischaemic diabetic foot ulcers. PMID- 29275071 TI - Very preterm born children at early school age: Healthcare therapies and educational provisions. AB - AIM: To explore changes in motor and cognitive outcomes in very preterm (VP; gestational age<30weeks) born children between ages five and six years, and to determine whether changes in these outcomes were associated with the use of healthcare therapies and educational provisions. STUDY DESIGN: Single-center observational cohort study. Five-year-old VP born children of a one-year-cohort of our neonatal follow-up program (N=90) were invited for re-assessments at age six. Use of healthcare therapies and educational provisions was registered at ages five and six years. Motor function (Movement Assessment Battery for Children 2 [M-ABC-2]; higher scores indicate better functioning) and IQ (Wechsler Preschool and Primary Scale for Intelligence [WPPSI-III-NL]) were assessed at both ages. RESULTS: Sixty-four VP born children were seen at ages five and at six years. In this year, 61% received healthcare therapies and/or educational provisions. M-ABC-2 scores of VP born children who received healthcare therapy and/or educational provisions were significantly higher (M=8.9 [SD=3.2]) at age six years than at age five years (M=7.5 [SD=3.3]); p<0.00). M-ABC-2 scores remained stable in the average range in VP born children without any support. IQ scores remained stable irrespective of received support. CONCLUSIONS: Improvements in motor outcomes are associated with the use of healthcare therapies and/or educational support between ages five and six years in VP born children. Future studies need to determine the efficacy of existing interventions, and to develop tailored interventions to support VP born children in the transfer period from preschool to primary education. PMID- 29275070 TI - Parent participation in the neonatal intensive care unit: Predictors and relationships to neurobehavior and developmental outcomes. AB - OBJECTIVE: To 1) define predictors of parent presence, any holding, holding in arms, and skin-to-skin care in the NICU and 2) investigate the relationships between parent participation and a) early neurobehavior and b) developmental outcomes at age 4 to 5years among preterm infants. METHODS: Eighty-one preterm infants born <=32weeks estimated gestational age were prospectively enrolled within one week of life in a level III-IV NICU. Parent (maternal and paternal) presence and holding (including holding in arms and skin-to-skin care) were tracked throughout NICU hospitalization. Neurobehavior at term equivalent age and development at 4 to 5years were determined using standardized assessments. RESULTS: The median number of days per week parents were documented to be present over NICU hospitalization was 4.0 (IQR=2.4-5.8) days; days held per week 2.8 (IQR=1.4-4.3) days [holding in arms days per week was 2.2 (IQR=1.2-3.2) days and parent skin-to-skin care days per week was 0.2 (IQR=0.0-0.7) days]. More parent presence was observed among mothers who were Caucasian, married, older, or employed and among those who had fewer children, familial support and provided breast milk (p<0.05). More holding was observed in infants with fewer medical interventions (p<0.05) and among those who were Caucasian, had a father who was employed, had fewer children and family support (p<0.05). More parent holding in the NICU was related to better reflex development at term age (p=0.02). More parent skin-to-skin care was related to better infant reflexes (p=0.03) and less asymmetry (p=0.04) at term and better gross motor development (p=0.02) at 4 5years. DISCUSSION: Social and medical factors appear to impact parent presence, holding, and skin-to-skin care in the NICU. Parent holding is related to better developmental outcomes, which highlights the importance of engaging families in the NICU. PMID- 29275072 TI - Immunohistochemical detection of vimentin in pancreatic islet beta- and alpha cells of macrosomic infants of diabetic and nondiabetic mothers. AB - BACKGROUND: Expression of the intermediate filament protein vimentin has been recently observed in the pancreatic islet beta- and alpha-cells of humans with type 2 diabetes mellitus. It was suggested that the presence of vimentin in endocrine cells may indicate islet tissue renewal, or potentially represent the dedifferentiation of endocrine cells, which could contribute to the onset of type 2 diabetes or islet cell dysfunction. AIM: To analyze the expression of vimentin in pancreatic beta- and alpha-cells of macrosomic infants of diabetic and nondiabetic mothers. SUBJECTS: Pancreatic samples of five macrosomic infants (gestational age 34-40weeks) from three diabetic and two nondiabetic mothers were compared to six control infants (32-40weeks, weight appropriate for gestational age) from normoglycemic mothers. METHODS: Pancreatic autopsy samples were examined by double immunofluorescent labeling with antibodies against vimentin and either insulin or glucagon. Alterations in the endocrine pancreas were measured using morphometric methods, then data were statistically analyzed. RESULTS: In the pancreatic islets of macrosomic infants from diabetic and nondiabetic mothers, we observed vimentin-positive cells, some of which simultaneously contained insulin or glucagon. We also quantitatively showed that the presence of such cells was associated with hypertrophy and hyperplasia of the islets, and with an increase in beta- and alpha-cell density. CONCLUSIONS: We speculate that the appearance of vimentin-positive islet cells may reflect induction of differentiation in response to the increased insulin demand, and vimentin may serve as an early marker of endocrine pancreas disorders. PMID- 29275073 TI - Orbital volume and shape in Treacher Collins syndrome. AB - Orbito-palpebral reconstruction is a challenge in Treacher Collins syndrome (TCS). This study investigates orbital phenotypes in TCS using cephalometry and orbital shape analysis. Eighteen TCS and 52 control patients were included in this study, using the Dr Warehouse database. Orbital cephalometry was based on 20 landmarks, 10 planes, 16 angles, and 22 distances. Orbits were segmented. Registration-based, age-specific mean models were generated using semi-automatic segmentation, and aligned and compared using color-coded distance maps - mean absolute distance (MAD), Hausdorff distance (HD), and Dice similarity coefficient (DSC). Symmetry was assessed by mirroring and DSC computing. Central orbital depth (COD) and medial orbital depth (MOD) allowed 100% of orbits to be classified. COD and lateral orbital depth (LOD) were different from the controls. Average MAD between TCS and controls was <=1.5 mm, while for HD it was >1.5 mm, and for DSC <1. TCS orbits were more asymmetrical than controls, and orbital volumes were smaller when age was considered as a confounding factor, and had a trend for normalization with age. This report emphasizes the importance of combining different morphometric approaches in the phenotype characterization of non-trivial structures such as the orbit, and supports composite skeletal and soft-tissue strategies for the management of the peri-orbital region. PMID- 29275074 TI - Melanotic neuroectodermal tumor of infancy (MNTI) of the head and neck: A French multicenter study. AB - OBJECTIVES: Melanotic neuroectodermal tumor of infancy (MNTI) of the head and neck is a rare entity with uncertain clinical behavior. Radical surgical resection is the current recommended treatment, however this can cause severe aesthetic and functional sequelae. The aim of this study was to clinically characterize MNTIs and to stratify risk factors that may influence locoregional recurrence. METHODS: A retrospective multicenter study, including 11 patients from eight centers with a confirmed diagnosis of MNTI, was conducted. Epidemiological, clinical, radiological, pathological, and immunohistochemical examinations were reviewed. A statistical analysis using a t-test was conducted to calculate parameters correlating with tumor recurrence. RESULTS: MNTIs mainly occurred in the maxilla, with a mean age at diagnosis of 3.18 months (range: 0-6 months). Primary surgery was performed on 10 patients, with a clear margin resection on two patients. Overall recurrence rate was 27% with a survival of 100% at time of follow-up. No statistical correlation between recurrence rate, age at diagnosis, localization, resection margins, and pathological and immunohistochemical characteristics could be established. CONCLUSION: In our study, locoregional tumor recurrence did not seem to correlate with resection margins, so a conservative surgical approach may need to be considered to avoid functional and aesthetic sequelae. PMID- 29275075 TI - Accuracy of computer-assisted orthognathic surgery. AB - INTRODUCTION: The purpose of this study was to retrospectively evaluate the difference between the planned and the actual movements of the jaws, using three dimensional (3D) software for PC-assisted orthognathic surgery, to establish the accuracy of the procedure. MATERIAL AND METHODS: A retrospective study was performed with 49 patients who had undergone PC-guided bimaxillary surgery. The accuracy of the protocol was determined by comparing planned movements of the jaws with the actual surgical movements, analysing frontal and lateral cephalometries. RESULTS: The overall results were deemed accurate, and differences among 12 of the 15 parameters were considered nonsignificant. Significant differences were reported for SNA (p = 0.008), SNB (p = 0.006), and anterior facial height (p = 0.033). The latter was significantly different in patients who had undergone genioplasty when compared with patients who had not. CONCLUSION: Virtual surgical planning presented a good degree of accuracy for most of the parameters assessed, with an average error of 1.98 mm for linear measures and 1.19 degrees for angular measures. In general, a tendency towards under-projection in jaws was detected, probably due to imperfect condylar seating. A slight overcorrection of SNA and SNB during virtual planning (approximately 2 degrees ) could be beneficial. Further progress is required in the development of 3D simulation of the soft tissue, which currently does not allow an accurate management of the facial height and the chin position. Virtual planning cannot replace the need for constant intraoperative monitoring of the jaws' movements and real-time comparisons between planned and actual outcomes. It is therefore appropriate to leave some margin for correction of inaccuracies in the virtual planning. In this sense, it may be appropriate to use only the intermediate splint, and then use the planned occlusion and clinical measurements to guide repositioning of the second jaw and chin, respectively. PMID- 29275076 TI - Dermatological manifestations in onchocerciasis: A retrospective study of 400 imported cases. AB - INTRODUCTION: Onchocerciasis is caused by Onchocerca volvulus and mainly leads to pruritus and skin and visual disorders, including blindness. Seventeen million people are infected in 38 countries; 31 of these are in sub-Saharan Africa, six in Latin America and one on the Arabian Peninsula. More than 99% of cases occur in sub-Saharan Africa where 120 million people are at risk of infection. Eye disorders have been well-documented; however, skin disorders have not been described accurately. The objective of our study was to describe the epidemiology, main skin manifestations and treatment of imported onchocerciasis. MATERIAL AND METHODS: A retrospective study was thus conducted by analysing the main demographic, clinical and treatment data regarding a cohort of 400 patients attending a reference clinical unit over a 17-year period. RESULTS: Most patients were female (55%) with mean age 37.5+/-16.7 years. All the migrants came from sub Saharan countries. The most frequently occurring dermatological symptom was pruritus. Ivermectin had been used as first-line therapy and adverse reactions had been described in 11 patients (3.2%). CONCLUSIONS: The results indicate the fact that there should be a clinical suspicion of onchocerciasis regarding immigrants from endemic areas having skin lesions compatible with the disease's profile or asymptomatic patients having eosinophilia or unexplained high IgE. Moreover, skin snips from the buttocks region were very fruitful and treatment with ivermectin was seen to be safe. This is the largest case series regarding imported onchocerciasis described up to the present time. PMID- 29275077 TI - Human Mycobacterium bovis infection in Castile and Leon (Spain), 2006-2015. AB - INTRODUCTION: The annual incidence of tuberculosis (TB) from Mycobacterium bovis in humans has considerably declined in industrialised countries since the early twentieth century. The objective of this study was to determine the epidemiological, clinical and microbiological characteristics of patients with this illness in Castile and Leon (CyL). METHODS: Retrospective study of all M. bovis TB cases in CyL over a 10-year period, comparing the risk factors, the epidemiology and the clinical course between pulmonary (PTB) and extrapulmonary TB (EPTB). RESULTS: 75 cases of TB were due to M. bovis: 45 PTB and 31 EPTB. The annual incidence of TB due to M. bovis was 0.3 cases per 100,000. It remained stable between the first and second five-year period (0.27 vs. 0.33, p=0.656). However, the overall incidence of TB fell in both five-year periods (13.58 vs. 10.71, p<0.0001). The mean age was 66.2+21.3 years, mainly men (63%) and Spanish patients (92%). PTB was significantly more frequent in men, aged over 66 years, with immunosuppressive conditions or who were smokers. Mortality was 9%, associated with higher age, immunosuppression or treatment different from that recommended by the WHO. CONCLUSIONS: The incidence of M. bovis TB in CyL was higher than that for Spain and for other European countries, and remained stable despite the decreased the TB due to MTC. It affected mostly Spanish-born patients who lived in rural areas and with a high mean age. PMID- 29275078 TI - Cost-effectiveness of adjuvant intravaginal brachytherapy in high-intermediate risk endometrial carcinoma. AB - PURPOSE: We assessed the cost-effectiveness of adjuvant intravaginal brachytherapy (IVBT) vs. observation after total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) for high-intermediate risk (HIR) endometrial carcinoma. METHODS AND MATERIALS: A Markov model was used to assess the cost effectiveness of IVBT by comparing average cumulative costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) between patients allocated to (1) 'observation' or (2) 'IVBT' after TH/BSO. We used a prototype Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) defined HIR patient in the base case analysis. We calibrated the model to match the outcomes reported in the PORTEC-1 and PORTEC-2 trials. Utilities were obtained from published estimates, and costs were calculated based on Medicare reimbursement ($5445 for IVBT). The societal willingness-to-pay threshold was set at $100,000 per QALY. The time horizon was 5 years. RESULTS: IVBT was associated with a net increase of 0.094 QALYs (4.512 vs. 4.418) as well as an increase in mean cost ($17,453 vs. $15,620) relative to observation. The ICER for IVBT was $19,500 per QALY. On one-way sensitivity analysis, IVBT remained cost-effective when its cost was less than $12,937. If the probability of vaginal recurrence in the observation arm was increased or decreased by 25%, the ICER became $1335 per QALY and $87,925 per QALY, respectively. Probabilistic sensitivity analysis revealed that IVBT was the preferred management option in 86% of simulations. CONCLUSIONS: IVBT is cost-effective compared with observation after TH/BSO for HIR endometrial carcinoma by commonly accepted willingness-to-pay thresholds. PMID- 29275079 TI - Efficacy and safety of iodine-125 radioactive seeds brachytherapy for advanced non-small cell lung cancer-A meta-analysis. AB - PURPOSE: This meta-analysis was conducted to investigate the efficacy and safety of 125I brachytherapy for locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Trials comparing 125I brachytherapy with chemotherapy in NSCLC were identified. Meta-analysis was performed to obtain pooled risk ratios for an overall response rate (ORR), disease control rate (DCR) and complications, and pooled hazard ratio for overall survival (OS). RESULTS: Fifteen studies including 1188 cases were included. The pooled result indicated that there were significant differences in ORR, DCR, and OS between 125I brachytherapy combined with chemotherapy and chemotherapy alone, but no statistic differences in gastrointestinal symptoms, leukopenia, myelosuppression, and hemoglobin reduction. Patients treated with 125I brachytherapy combined with chemotherapy have a higher relative risk of pneumothorax, bloody sputum, and pneumorrhagia compared with chemotherapy alone. Seeds migration only occurred in the group treated with 125I brachytherapy. There were significant differences in ORR, DCR, and myelosuppression between 125I brachytherapy alone and chemotherapy. CONCLUSIONS: 125I brachytherapy combined with chemotherapy can significantly enhance the clinical efficacy and improve the OS of patients with advanced NSCLC without increasing the incidence of complications of chemotherapy. 125I brachytherapy alone can significantly enhance the clinical efficacy and reduce the incidence of myelosuppression compared with chemotherapy. However, 125I brachytherapy may cause lung injury. Large sample and higher-quality randomized controlled trials are needed to confirm the pooled results of complications. PMID- 29275080 TI - Leg muscle activation patterns during walking and leg lean mass are different in children with and without developmental coordination disorder. AB - BACKGROUND: Previous studies have shown that children with developmental coordination disorder (DCD) have a higher body fat and greater gait variability. Little research has investigated the gait muscle activity and lean mass measures in children with DCD. AIMS: To compare the leg muscle activation patterns of the gait cycle and leg lean mass between children with and without DCD. METHODS: Fifty-one children were in the DCD group (38 males and 13 females; 7.95 +/- 1.04 years) and fifty-two in the control group (34 males and 18 females; 8.02 +/- 1.00 years). Peak muscle activation patterns of treadmill walking in the right leg for the eight-gait phases were measured by means of surface electromyography, an electrogoniometer, and foot contact switches. Leg lean mass measures were evaluated using a whole-body dual energy X-ray absorptiometry scan. RESULTS: Children with DCD had a lower leg lean mass and appendicular lean mass index compared to the control group. Furthermore, they exhibited a less-pronounced peak muscle activation during the heel strike (gastrocnemius medialis), early swing (biceps femoris) and late swing phases (gastrocnemius medialis) of gait. CONCLUSIONS AND IMPLICATIONS: Although lower limb total mass was similar between groups, the DCD group displayed lower lean mass measures than controls. Furthermore, children with DCD illustrated a lower leg peak muscle activation during the heel strike, early swing and late swing phases of gait when walking on a treadmill. Our results emphasize the need to incorporate lower limb phasic muscle strengthening components into gait rehabilitation programs for children with DCD. PMID- 29275081 TI - Negative reactions to monitoring: Do they undermine the ability of monitoring to protect adolescents? AB - This study focused on adolescents' negative reactions to parental monitoring to determine whether parents should avoid excessive monitoring because adolescents find monitoring behaviors to be over-controlling and privacy invasive. Adolescents (n = 242, M age = 15.4 years; 51% female) reported monitoring, negative reactions, warmth, antisocial behavior, depressive symptoms, and disclosure. Adolescents additionally reported antisocial behavior, depressive symptoms, and disclosure one to two years later. In cross-sectional analyses, less monitoring but more negative reactions were linked with less disclosure, suggesting that negative reactions can undermine parents' ability to obtain information. Although monitoring behaviors were not related to depressive symptoms, more negative reactions were linked with more depressive symptoms, suggesting that negative reactions also may increase depressive symptoms as a side effect of monitoring behavior. Negative reactions were not linked to antisocial behavior. There were no longitudinal links between negative reactions and changes in disclosure, antisocial behavior, or depressive symptoms. PMID- 29275082 TI - The thin line between protection and conviction: Experiences with child protection services and later criminal convictions among a population of adolescents. AB - Relying on official data provided by the Quebec City Youth Center, Canada, we explore the nature and intensity of officially known criminality for all youth (N = 5399) found guilty under the provisions of the Youth Criminal Justice Act between 2003 and 2012 and assess the relationship between criminality and previous episodes of child maltreatment. This article proposes to further verify the general hypothesis stating that there are empirical links between these two phenomena. The results suggest that those youth victims of specific types of child maltreatment (physical abuse, sexual abuse) seem to be found guilty of criminal acts that are significantly in line with these earlier episodes of maltreatment. These results might help to prevent potential occurrences of such a phenomenon and also contributes to the ongoing development of psychological and criminological theories assessing why and to what extent a child victim of maltreatment might later commit criminal offenses. PMID- 29275083 TI - Radiology Design Project Primer. AB - The design of hospital environments is receiving increased attention as an important contributor to patient satisfaction and experience, which have a direct impact on reimbursement. Well-designed health care environments can decrease stress, improve concentration, and contribute to improved patient outcomes and enhanced staff morale. Most radiologists and business directors lack formal training in design and may feel they have little to contribute to design planning, yet creating an optimal environment for patients requires a strong understanding of local demographics and both patient and staff needs, which is a core responsibility of radiology leadership. This article presents practical guidelines for selecting a design partner for an imaging construction project, developing a design theme and design sensibilities, and engaging a multidisciplinary radiology team in working with a designer; the goal is to enable radiology leadership to collaborate with designers to cocreate health care environments that aspire to be integral components of patient-centered care and experience. PMID- 29275084 TI - The Purse Strings of Radiology. PMID- 29275085 TI - A mixed-method evaluation of the New York State Eat Well Play Hard Community Projects: Building local capacity for sustainable childhood obesity prevention. AB - This study used a mixed-method, comparative case study approach to assess the level of capacity built for childhood obesity prevention among seven New York State Eat Well Play Hard-Community Projects (EWPH-CP). Data were collected through a self-reported survey in 2007, semi-structured interviews in 2009, and EWPH-CP program documentation throughout the 2006-2010 funding cycle. Quantitative and qualitative analyses were used along with an integrative framework for assessing local capacity building to characterize the capacity built by the study coalitions. Four coalitions rated membership characteristics as a challenge at the beginning of the funding cycle. Towards the end of the funding cycle, all seven coalitions reported activities that were initially focused on building their membership (i.e., member capacity) or positive working relationships (i.e. relational capacity), before eventually pursuing support and resources (i.e., organizational capacity) for implementing their chosen community oriented programmatic goals (i.e., programmatic capacity). Five coalitions reported environmental changes aimed at increasing physical activity or fruit and vegetable intake. Technical assistance provided to coalitions was credited with contributing to the achievement of programmatic goals. These results suggest that the coalitions succeeded in building local capacity for increasing age appropriate physical activity or fruit and vegetables intake in the target communities. PMID- 29275086 TI - A game theory approach for assessing risk value and deploying search-and-rescue resources after devastating tsunamis. AB - The current early-warning system and tsunami protection measures tend to fall short because they always underestimate the level of destruction, and it is difficult to predict the level of damage by a devastating tsunami on uncertain targets. As we know, the key to minimizing the total number of fatalities after a disaster is the deployment of search and rescue efforts in the first few hours. However, the resources available to the affected districts for emergency response may be limited. This study proposes two game theoretic models that are designed for search-and-rescue resource allocation. First, the interactions between a compounded disaster and a response agent in the affected district are modelled as a non-cooperative game, after which the risk value is derived for each district from the Nash equilibrium. The risk value represents the threat, vulnerability, and consequence of a specific disaster for the affected district. Second, the risk values for fifteen districts are collected for calculation of each district's Shapley value. Then an acceptable plan for resource deployment among all districts is made based on their expected marginal contribution. The model is verified in a simulation based upon 2011 tsunami data. The experimental results show the proposed approach to be more efficient than the proportional division of rescue resources, for dealing with compounded disaster, and is feasible as a method for planning the mobilization of resources and to improve relief efforts against devastating tsunamis. PMID- 29275087 TI - Gas chromatography-mass spectrometry metabolomic study of lipopolysaccharides toxicity on rat basophilic leukemia cells. AB - Lipopolysaccharide (LPS) can lead to uncontrollable cytokine production, fatal sepsis syndrome and depression/multiple organ failure, as pathophysiologic demonstration. Various toxic effects of LPS have been extensively reported, mainly on the toxicity of LPS in cellular level, macrophages or tumor cells, etc. This work aimed on the impact of LPS on mast cell metabolism, which focused on LPS-induced cellular metabolic profiles. Gas chromatography-mass spectrometry (GC MS) based metabolomics strategy was implemented for the endo-metabolites detection in rat basophilic leukemia (RBL-2H3) cells, treated with 10 MUg/mL LPS for 24 h, along with multiple time-dose tests of cells viability/apoptosis. Significantly changes metabolites were mainly involved the metabolism of glycine, serine, threonine and the biosynthesis of phenylalanine, tyrosine, tryptophan and pentose phosphate pathway. The endo-metabolism results illustrated that LPS treatment led to downregulation of glycine, serine and threonine metabolism besides pentose phosphate pathway in RBL-2H3 cells. This novel insight into LPS cellular metabolism, provides some heuristic guidance for elucidating the underlying mechanism of LPS-mediated disease. PMID- 29275088 TI - Genetic analysis of Southern Brazil subjects using the PowerSeqTM AUTO/Y system for short tandem repeat sequencing. AB - With the advent of Next-Generation Sequencing technology, sequencing of short tandem repeats (STRs) allows for a more detailed analysis when compared to size based fragment methods (capillary electrophoresis-CE). The implementation of high throughput sequencing can help uncover deeper genetic diversities of different populations. Subjects from the South region of Brazil present a particular and more homogeneous ancestry background when compared to other regions of the country. Both autosomal and Y- STRs have been analyzed in these individuals; however, all analyses published to date encompass data from CE-based fragment analysis. In this study, a genetic analysis of 59 individuals from Southern Brazil was performed on STR sequences. Forensically relevant STRs were PCR enriched using a prototype of the PowerSeqTM AUTO/Y system (Promega Corp.). Next generation sequencing was performed on an Illumina MiSeq instrument. The raw data (FASTQ files) were processed using a custom designed sequence processing tool, Altius. Isoalleles, which are sequence-based allelic variants that do not differ in length, were observed in nine autosomal and in six Y- STRs from the core global forensic marker set. The number of distinctive alleles based on sequence was higher when compared to those based on length, 37.3% higher in autosomal STRs and 13.8% higher in Y-STRs. The most polymorphic autosomal locus was D12S391, which presented 38 different sequence-based alleles. Among the loci in the Y chromosome, DYS389II presented the highest number of isoalleles. In comparison to CE analysis, Observed and Expected Heterozygosity, Polymorphic Information Content (PIC) and Genetic Diversity also presented higher values when the alleles were analyzed based on their sequence. For autosomal loci, Polymorphic Information Content (PIC) was 2.6% higher for sequence-based data. Diversity was 9.3% and 6.5% higher for autosomal and Y markers, respectively. In the analysis of the repeat structures for the STR loci, a new allele variant was found for allele 18 in the vWA locus. The STR flanking regions were also further investigated and sixteen variations were observed at nine autosomal STR loci and one Y-STR locus. The results obtained in this study demonstrate the importance of genetic analysis based on sequencing and highlight the diversity of the South Brazilian population when characterized by STR sequencing. PMID- 29275089 TI - A template for constructing Bayesian networks in forensic biology cases when considering activity level propositions. AB - The hierarchy of propositions has been accepted amongst the forensic science community for some time. It is also accepted that the higher up the hierarchy the propositions are, against which the scientist are competent to evaluate their results, the more directly useful the testimony will be to the court. Because each case represents a unique set of circumstances and findings, it is difficult to come up with a standard structure for evaluation. One common tool that assists in this task is Bayesian networks (BNs). There is much diversity in the way that BN can be constructed. In this work, we develop a template for BN construction that allows sufficient flexibility to address most cases, but enough commonality and structure that the flow of information in the BN is readily recognised at a glance. We provide seven steps that can be used to construct BNs within this structure and demonstrate how they can be applied, using a case example. PMID- 29275090 TI - Lessons from a study of DNA contaminations from police services and forensic laboratories in Switzerland. AB - In Switzerland, the DNA profiles of police officers collecting crime scene traces as well as forensic genetic laboratories employees are stored in the staff index of the national DNA database to detect potential contaminations. Our study aimed at making a national inventory of contaminations to better understand their origin and to make recommendations in order to decrease their occurrence. For this purpose, a retrospective questionnaire was sent to both police services and forensic genetic laboratories for each case where there was a contamination. Between 2011 and 2015, a total of 709 contaminations were detected. This represents a mean of 11.5 (9.6-13.4) contaminations per year per 1'000 profiles sent to the Swiss DNA database. Feedbacks were obtained from the police, the laboratory or both for 552/709 (78%) of the contaminations. Approximately 86% of these contaminations originated from police officers whereas only 11% were from genetic laboratories employees and 3% were associated to other sources (e.g. positive controls, stain-stain contaminations). Interestingly, a direct contact between the stain and the contaminant person occurred in only 51% of the laboratory contaminations whereas this number increased to 91% for police collaborators. The high level of indirect DNA transfer in laboratories might be explained by the presence of "DNA reservoirs" suggesting that cleaning procedures should be improved. At the police level, most contaminations originated from the person who collected the trace and likely occurred directly at the crime scene. Improving sampling practices could be beneficial to reduce these contaminations. PMID- 29275091 TI - Reductive electrografting of in situ produced diazopyridinium cations: Tailoring the interface between carbon electrodes and electroactive bacterial films. AB - Carbon electrodes were functionalized through the reduction of diazopyridinium cations that are produced from in situ diazotization of 2-, 3- and 4 aminopyridine. Diazopyridinium salts were much more rarely employed for surface functionalization than other aryldiazonium derivatives. A study combining X-ray Photoelectron Spectroscopy (XPS), contact angle, ellipsometry, Atomic Force Microscopy (AFM) measurements and electrochemical analyses demonstrates that films obtained from 4-diazopyridinium cations are hydrophilic, dense, compact but sufficiently thin to preserve fast electronic transfer rate, being then relevant to efficiently tailor the interface between the anode surface and an electroactive biofilm. Microbial Fuels Cells (MFCs) with pyridine-functionalized graphite anodes exhibit faster development and improved performances than MFCs operating with bare graphite anodes. PMID- 29275092 TI - Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies. AB - Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics. Administration of OVs to cancer-bearing hosts induces two distinct immunities: antiviral and antitumor. While antitumor immunity is beneficial, antiviral immune responses are often considered detrimental for the efficacy of OV-based therapy. The existing dogma postulates that anti-OV immune responses restrict viral replication and spread, and thus reduce direct OV-mediated killing of cancer cells. Accordingly, a myriad of therapeutic strategies aimed at mitigating anti OV immune responses is presently being tested. Here, we advocate that OV-induced antiviral immune responses hold intrinsic anticancer benefits and are essential for establishing clinically desired antitumor immunity. Thus, to achieve the optimal efficacy of OV-based cancer immunotherapies, strategic management of anti OV immune responses is of critical importance. PMID- 29275093 TI - Resting energy expenditure after Roux-en Y gastric bypass surgery. AB - BACKGROUND: The mechanisms by which Roux-en Y gastric bypass surgery (RYGB) provokes weight loss are incompletely understood. Enhanced energy expenditure may be one contributing mechanism. Previous results on changes in resting energy expenditure (REE) after RYGB are inconsistent. OBJECTIVES: The aim of the present study was to assess changes in REE after RYGB and whether REE predicts weight loss (percentage weight loss). SETTING: Obesity Clinic. METHODS: REE was measured by indirect calorimetry (mREE) before and 1 year after RYGB in 233 patients with severe obesity (175 women; all body mass index >=35.0 kg.m-2) and mREE was compared with predicted REE (pREE) and expressed as percentage of pREE (%pREE). For calculation of pREE, 2 new equations were developed from an independent reference group of overweight and obese patients (852 patients; body mass index range: 27.4-73.0 kg.m-2) that were examined in exactly the same setting as the bariatric patients that were followed-up after RYGB. The new equations were based on either anthropometric (pREE-BM, %pREE-BM) or body composition (pREE-BC; %pREE BC) parameters. RESULTS: After RYGB, absolute mREE was reduced by 20.4 +/- 11.0% (-458 +/- 277 kcal.d-1; P<.001). Compared with pREE-BM (post-%REE-BM) and pREE-BC (post-%REE-BC), mREE was 2.3 +/- 9.4% and 1.6 +/- 9.5%, respectively, higher (both P <= .03). Post-%pREE-BM and post- %pREE-BC after RYGB were positively correlated with percentage weight loss (r = .206 and r = .231; both P <= .003). CONCLUSIONS: Data indicate a slightly higher mREE than pREE after RYGB. Although the underlying mechanisms of this observation remain to be elucidated our finding may play a role for weight loss outcomes after the surgery. PMID- 29275094 TI - Progression to surgery: online versus live seminar. AB - OBJECTIVE: The objective of this study was to evaluate progression to surgery rates for live and online seminar and assess weight loss outcome comparisons at 1 year postoperation. SETTING: University Hospital Network, Allentown, PA, USA. METHODS: The entry point into our program was an information seminar where prospective patients are educated about obesity, bariatric surgery, indications and contraindications, risks and benefits, and our center's process. Between January of 2009 and November of 2011, only live information seminars were offered. In November of 2011, we started offering an online information seminar to reach those who are unable to attend a live seminar. Tracking of live versus online seminar attendance was documented in our database. RESULTS: Between November 1, 2011 and September 30, 2015, 3484 people completed an information seminar. Of those, 2744 attendees came to a live seminar while 740 completed the online seminar. A significantly higher number of live seminar attendees, 78.1% (2144/2744) progressed to an office visit compared with online seminar attendees 66.5% (492/740), P<.0001. Similarly significant, 40.1% (1101/2744) of live seminar attendees progressed to surgery versus 29.7% (220/740) of online attendees (P<.0001). Sex (78.2% female for live seminar versus 79.5% female for online seminar, P = .65) and initial body mass index (46.3 +/- 7.4 for live seminar versus 45.3 +/- 7.1 for online seminar, P = .09) were very similar between the groups. Online seminar attendees' age (42.7 +/- 12.1) was younger than that of the live seminar attendees' (47.3 +/- 12.3) (P<.0001) but has little clinical value. CONCLUSION: Our results demonstrated that live seminar attendees are more likely to progress to surgery and therefore should continue to be offered. PMID- 29275095 TI - Benefit of feeding tube placement for refractory malnutrition after bariatric surgery. PMID- 29275096 TI - Simultaneous laparoscopic 'Venetian blinds' closure and mesh-reinforced ventral hernia repair with revision of gastric band to bypass. PMID- 29275098 TI - Breast lesion classification based on supersonic shear-wave elastography and automated lesion segmentation from B-mode ultrasound images. AB - Supersonic shear-wave elastography (SWE) has emerged as a useful imaging modality for breast lesion assessment. Regions of interest (ROIs) were required to be specified for extracting features that characterize malignancy of lesions. Although analyses have been performed in small rectangular ROIs identified manually by expert observers, the results were subject to observer variability and the analysis of small ROIs would potentially miss out important features available in other parts of the lesion. Recent investigations extracted features from the entire lesion segmented by B-mode ultrasound images either manually or semi-automatically, but lesion delineation using existing techniques is time consuming and prone to variability as intensive user interactions are required. In addition, rich diagnostic features were available along the rim surrounding the lesion. The width of the rim analyzed was subjectively and empirically determined by expert observers in previous studies after intensive visual study on the images, which is time-consuming and susceptible to observer variability. This paper describes an analysis pipeline to segment and classify lesions efficiently. The lesion boundary was first initialized and then deformed based on energy fields generated by the dyadic wavelet transform. Features of the SWE images were extracted from inside and outside of a lesion for different widths of the surrounding rim. Then, feature selection was performed followed by the Support Vector Machine (SVM) classification. This strategy obviates the empirical and time-consuming selection of the surrounding rim width before the analysis. The pipeline was evaluated on 137 lesions. Feature selection was performed 20 times using different sets of 14 lesions (7 malignant, 7 benign). Leave-one-out SVM classification was performed in each of the 20 experiments with a mean sensitivity, specificity and accuracy of 95.1%, 94.6% and 94.8% respectively. The pipeline took an average of 20 s to process a lesion. The fact that this efficient pipeline generated classification accuracy superior to that of existing algorithms suggests that improved efficiency did not compromise classification accuracy. The ability to streamline the quantitative assessment of SWE images will potentially accelerate the adoption of the combined use of ultrasound and elastography in clinical practice. PMID- 29275097 TI - Time-varying effects of income on hippocampal volume trajectories in adolescent girls. AB - Children from lower-SES families exhibit smaller hippocampal volume than do their higher-SES peers. Few studies, however, have compared hippocampal developmental trajectories as a function of SES. Thus, it is unclear whether initial rank-order stability is preserved, or whether volumes diverge/converge over the course of adolescence. In a sample of 101 girls ages 10-24 years, we examined the longitudinal association between family income and parental education, proxies for SES, and changes in hippocampal volume. Hippocampal volume was obtained using MRI; using mixed modeling, we examined the effects of income and education on hippocampal volume across age. As expected, changes in volume were non-linear across development. Further, trajectories diverged in mid-adolescence, with lower income girls exhibiting reductions in hippocampal volume. Maximal income-related differences were observed at 18 years, and trajectories converged thereafter. This interaction remained significant when accounting for maternal hippocampal volume, suggesting a unique contribution of environment over potential heritable differences. In contrast, the association between parental education and offspring hippocampal volume appeared to be stable across adolescence, with higher levels of parental education predicting consistently larger hippocampal volume. These findings constitute preliminary evidence that girls from lower income homes exhibit unique trajectories of hippocampal growth, with differences most evident in late adolescence. PMID- 29275099 TI - Acetowhite region segmentation in uterine cervix images using a registered ratio image. AB - Visual inspection with acetic acid (VIA) remains a main cervical cancer screening tool in developing countries. However, it depends on the operator's experience, and its utility is often limited by the lack of trained doctors. Smart colposcope devices to automatically detect the cervical intraepithelial neoplasia (CIN, the early stage of cervical cancer) may provide a promising alternative. As the acetowhite (AW) region is the most important feature of CIN during VIA, its segmentation is considered an important procedure in the automatic detection of CIN. In this study, an automatic AW region segmentation algorithm based on the pre-acetic-acid and post-acetic-acid test images was developed. The cervix region was extracted according to a clustering algorithm from the pre-acetic acid test image. A ratio image was then obtained after registering the pre- and post-acetic acid test images to facilitate the segmentation of the AW region using a modified level set algorithm. The results showed that although the developed algorithm yielded a mean sensitivity of 71.86%, which was lower than that of the fuzzy C means (FCM) algorithm by 12.08% and the classical CV model-based level set algorithm (CV-LSA) by 4.04%, a high mean specificity (92.76%) was achieved that was greater than those of FCM and CV-LSA by 46.61% and 31.34%, respectively. Additionally, a high Jaccard index (JI) mean accuracy of 61.51% was achieved, which was greater than those of FCM and CV-LSA by 18.74% and 17.14%, respectively. This new algorithm, with an improved segmentation performance over traditional algorithms, may serve as a promising tool to advance the clinical prognosis of cervical cancer. PMID- 29275100 TI - Metabolic and vascular pattern in medial pterygoid muscle is altered by chronic stress in an animal model of hypodontia. AB - Psychological stress is an important perpetuating, worsening and risk factor for temporomandibular disorders of muscular or articular origin. Occlusion instability, by the way, is considered a risk factor of this pathology and can be reproduced in some experimental animal models. The exact physiologic mechanism underlying these relations however, remains unclear. Our purpose was to test the hypothesis that chronic stress and unilateral exodontia induce metabolic and vascular changes in the medial pterygoid muscle of rats. Adult Wistar rats were submitted to chronic unpredictable stress and/or unilateral exodontia and their plasma and medial pterygoid muscle were removed for analysis. The parameters evaluated included plasma levels of corticosterone, metabolic activity by succinate dehydrogenase, oxidative capacity by nicotinamide adenine dinucleotide diaphorase, capillary density by laminin and alfa-CD staining and reactive oxidative species production. Chronic unpredictable stress as an isolated factor, increased oxidative metabolism, capillary density and reactive oxygen species production at medial pterygoid muscle. Conversely, exodontia has a main effect in metabolism, promoting glycolytic transformation of muscle fibers. Association of both factors induced a major glycolytic pattern in muscle and vascular changes. Our findings provide insights into the mechanisms, possibly inducing metabolic and vascular alterations on medial pterygoid muscle of rats, by which chronic stress and occlusal instabilities might be involved as risk factors in the pathophysiology of temporomandibular disorders with muscular components. PMID- 29275101 TI - Effect of fiber and protein-enriched pasta formulations on satiety-related sensations and afternoon snacking in Italian healthy female subjects. PMID- 29275102 TI - Effects of high-concentration influent suspended solids on aerobic granulation in pilot-scale sequencing batch reactors treating real domestic wastewater. AB - The aim of this study was to investigate the effect of high-influent concentration suspended solids (SS) on the cultivation, structure and long-term stability of aerobic granular sludge (AGS). Cultivation and long-term stability of AGS were monitored in two pilot-scale sequencing batch reactors fed with raw (R1) and settled (R2) domestic wastewater, representing high and medium SS content, respectively. The real domestic wastewater had high chemical oxygen demand (COD) content (1100 +/- 270 mg COD L-1). Aerobic granular sludge was cultivated in 44 days (R1) and 25 days (R2) under the conditions of high settling velocity (18 m h-1) and high organic loading rate (OLR) (2.1-2.4 kg COD m3 day). The AGS in both reactors had similar structural properties during long-term operation and remained structurally and functionally stable during the last five months of operation. Comparative evaluation of the results indicated that the high influent SS content of the real domestic wastewater had a positive influence on maintaining significantly lower SVI30 and relatively lower effluent SS concentration. Moreover, a higher influent SS content resulted in smaller mature granules during the stable period. Microbial community analyses helped to understand the aerobic granular sludge structure and showed that the sludge retention time and OLR affected the granular sludge population. The high influent SS increased biomass detachment from the granular sludge surface and caused wash out of some bacteria colonizing the exterior of the granular sludge. PMID- 29275103 TI - Most rotavirus strains require the cation-independent mannose-6-phosphate receptor, sortilin-1, and cathepsins to enter cells. AB - Cathepsins, endosomal acid proteases, are transported from the trans-Golgi network to late endosomes by the mannose-6-phosphate receptor (M6PR). We have previously demonstrated that some rotavirus strains, like UK, Wa, WI61, DS-1, and YM, require the cation-dependent (CD-) M6PR and cathepsins to enter from late endosomes to the cytoplasm in MA104 cells, while other strains, like the simian strain RRV, which enter cells from maturing endosomes, do not. However, the role of other trans-Golgi network-late endosome transporters, such as the cation independent (CI-) M6PR and sortillin-1, has not been evaluated. In this work, we found that several rotavirus strains that require the CD-M6PR for cell entry are also dependent on CI-M6PR and sortilin-1. Furthermore, we showed that the infectivity of all these rotavirus strains also requires cathepsins to enter not only MA104 cells, but also human intestinal Caco-2 cells. This study identifies sortilin-1 as a novel cell factor necessary for the infectivity of a virus; in addition, our results strongly suggest that cathepsins could be common cell factors needed for the infectivity of most rotavirus strains. PMID- 29275104 TI - One-Step Prepectoral Breast Reconstruction With Dermal Matrix-Covered Implant Compared to Submuscular Implantation: Functional and Cost Evaluation. AB - BACKGROUND: The breast reconstructive subpectoral technique commonly leads to functional consequences. Recently, a new conservative prepectoral breast reconstruction (PPBR) technique was proposed and its surgical safety and aesthetic effectiveness proved. The aim of this prospective nonrandomized study was to compare the functional and economical outcomes of the PPBR procedure versus the subpectoral one. PATIENTS AND METHODS: From February 2015 to September 2016, 86 patients underwent mastectomy with immediate implant-based reconstruction. Thirty-nine patients were assigned to group 1 and received prepectoral acellular dermal matrix-wrapped implant reconstruction. The remaining 45 patients were assigned to group 2 and received a subpectoral implant or tissue expander. We recorded the operating time, length of hospital stay, analgesic consumption, postoperative pain, upper limb function, esthetic satisfaction, and quality of life. Additional surgical procedures for reconstruction completion or contralateral operation for symmetrization were also recorded. RESULTS: Compared to group 2 patients, group 1 patients showed less postoperative pain and faster upper limb functional recovery. Patients in group 1 also recorded a lower analgesic consumption and an earlier return to usual work. Moreover, the muscle sparing technique improved aesthetic outcomes and largely reduced the need for symmetrization. CONCLUSION: Immediate breast reconstruction by using prepectoral muscle-sparing acellular dermal matrix-wrapped implant resulted in lower pain intensity and significant upper limb functional advantages compared to submuscular implant placement. Furthermore, when considering a series of ascertained benefits, PPBR is also economically advantageous, although future studies should better define its cost-effectiveness. PMID- 29275105 TI - Preferred and Perceived Participation of Younger and Older Patients in Decision Making About Treatment for Early Breast Cancer: A Prospective Study. AB - BACKGROUND: Older patients are believed to prefer a more passive role in treatment decision making, but studies reporting this relation were conducted over a decade ago or were retrospective. We prospectively compared younger (40-64 years) versus older (>= 65 years) breast cancer patients' preferences for decision-making roles and their perceived actual roles. PATIENTS AND METHODS: A prospective multicenter study was conducted in Leiden, The Hague, and Tilburg over a 2-year period. Early-stage breast cancer patients were surveyed about their preferred and perceived decision-making roles (active, shared, or passive) concerning surgery type (breast-conserving vs. mastectomy) (n = 74), adjuvant chemotherapy (aCT, n = 43), and adjuvant hormonal therapy (aHT, n = 39). RESULTS: For all decisions, both age groups most frequently preferred a shared role before consultation, except for decisions about aHT, for which younger patients more commonly preferred an active role. The proportion of patients favoring an active or passive role in each decision was lower for the older than the younger patients, but none of the differences was significant. Regarding perceived actual roles, both groups most frequently reported an active role in the surgical decision after consultation. In deciding about both aCT and aHT, a larger proportion of older patients perceived having had a passive role compared to younger patients, and a greater proportion of younger patients perceived having been active. Again, differences were not statistically significant. CONCLUSION: Most older patients preferred to decide together with their clinician, but preferences varied widely. Older patients more often than younger patients perceived they had not been involved in decisions about systemic therapy. Clinicians should invite all patients to participate in decision making and elicit their preferred role. PMID- 29275106 TI - Clinical Significance of the Wild Type p53-Induced Phosphatase 1 Expression in Invasive Breast Cancer. AB - BACKGROUND: Wild type p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), inhibits p53. PPM1D amplification has been reported in breast cancer. Breast cancer can sometimes develop without a tumor protein 53 (TP53) mutation. In these cases, the p53 pathway might be disrupted by alternative mechanisms, and Wip1 is reported to be a key molecule involved. MATERIALS AND METHODS: Primary invasive ductal carcinoma specimens were obtained from 201 cases, for which archival tissue samples for immunohistochemistry were available. We evaluated Wip1 and p21 protein expression (201 cases), Wip1 mRNA expression (63 cases), PPM1D DNA copy number (71 cases) and TP53 status (36 cases) using available samples among the 201 cases, and analyzed their relationships with clinicopathological factors and prognosis. RESULTS: The nuclear expression of Wip1 protein was positive in 21 cases (10.4%). The PPM1D DNA copy number was significantly correlated with Wip1 protein expression. All cases with PPM1D amplification by single-nucleotide polymorphism comparative genomic hybridization array showed positive nuclear Wip1 expression. Wip1 protein expression was positively correlated with p21 expression. The tumors with positive Wip1 and negative p21 expression showed the poorest prognosis among all tumor types. CONCLUSION: The protein expression of Wip1 might be regulated by PPM1D amplification, independent of TP53 status. Positive Wip1 and negative p21 expression was associated with the poorest prognosis and suggests the loss of p53 function. PMID- 29275107 TI - Transferrin targeted liposomal 5-fluorouracil induced apoptosis via mitochondria signaling pathway in cancer cells. AB - The purpose of this study was to prepare transferrin (Tf) targeted liposomal 5 Fluorouracil (5FU) to improve the safety and efficacy of the drug. Liposomes were prepared using thin layer method. Morphology of liposomes was characterized by transmission electron microscopy (TEM) and their particle size was also determined. The in vitro cytotoxicity was investigated via MTT assay on HT-29 (as cancer cell) and fibroblast (as normal cell). Moreover, cytotoxicity mechanism of targeted liposomes was determined through the production of reactive oxygen species (ROS), mitochondrial membrane potential (?Psim) and release of cytochrome c. Results showed that encapsulation efficiency (EE%) was 58.66+/-0.58 and average size of liposomes was 107nm. Also, nano-particles were spherical as shown by TEM. MTT assay on HT-29 cells revealed the higher cytotoxic activity of targeted liposomes in comparison to free drug and non-targeted liposome. In contrast, comparing with cancer cells, targeted liposomes had no cytotoxic effect on normal cells. In addition, targeted liposomes induced apoptosis through activation of mitochondrial apoptosis pathways, as evidenced by decreased mitochondrial membrane potential and release of cytochrome c. Results of the study indicated that targeted liposomes would provide a potential strategy to treat colon cancer by inducing apoptosis via mitochondria signaling pathway with reducing dose of the drug and resulting fewer side-effects. PMID- 29275108 TI - Different biotransformation behaviors of perfluorooctane sulfonamide in wheat (Triticum aestivum L.) from earthworms (Eisenia fetida). AB - Perfluorooctane sulfonamide (PFOSA) is a precursor of perfluorooctane sulfonic acid (PFOS) and can be broken down to PFOS in environment and biota. In the present work, PFOSA was spiked in soil and its biodegradation in soil, uptake and metabolism in wheat (Triticum aestivum L.) and earthworms (Eisenia fetida) were investigated. The results indicated that PFOSA could be biodegraded to highly stable PFOS, which has the same perfluorinated carbon chain length as PFOSA, by microbes in soil. PFOSA could be taken up by wheat root and earthworm from soil with higher bioaccumulation ability than PFOS. In both wheat and earthworms, PFOSA also degraded to PFOS. However, other shorter-chain perfluoroalkane sulfonates (PFSAs), including perfluorohexane sulfonate (PFHxS) and perfluorobutane sulfonate (PFBS), were observed in wheat, but not in soil and earthworms, suggesting that wheat displayed distinctly different degradation mechanisms to PFOSA from soil microbes and earthworms. PMID- 29275109 TI - Superelastic and superhydrophobic bacterial cellulose/silica aerogels with hierarchical cellular structure for oil absorption and recovery. AB - Bacterial cellulose aerogels/silica aerogels (BCAs/SAs) are prepared using three dimensional self-assembled BC skeleton as reinforcement and methyltriethoxysilane derived silica aerogels as filler through vacuum infiltration and freeze drying. The BCAs/SAs possess a hierarchical cellular structure giving them superelasticity and recyclable compressibility. The BCAs/SAs can bear a compressive strain up to 80% and recover their original shapes after the release of the stress. The BCAs/SAs exhibit super-hydrophobicity with a contact angle of 152 degrees and super-oleophilicity resulting from the methyl groups on the surface of silica aerogel filler. This endows the BCAs/SAs outstanding oil absorbing capability with the quality factor Q from 8 to 14 for organic solvents and oils. Moreover, the absorbed oil can be retrieved by mechanically squeezed with a recovery of 88% related to the superelastic ability of the composites. In addition, the oil absorbing of BS/SAs could be well maintained with the quality factor Q about 11 for gasoline after harsh conditional treatment down to -200 degrees C and up to 300 degrees C. Such outstanding elastic and oleophilic properties make the BC/SAs tremendous potential for applications of oil absorbing, recovery and oil-water separation. PMID- 29275110 TI - Photodegradation of taste and odor compounds in water in the presence of immobilized TiO2-SiO2 photocatalysts. AB - Disinfection by ultraviolet (UV) radiation is a growing trend in public water treatment systems because of its effectiveness with respect to inactivation of protozoa and other pathogenic microorganisms. However, removal of different classes of organic compounds, including taste and odor compounds in water is not effective with UV irradiation. In this study, a novel TiO2-based immobilized photocatalyst is developed to enhance the UV photodegradation of two of the major taste and odor compounds, 2-methylisoborneol (MIB) and Geosmin (GSM) in water. Evonik (formerly Degussa) P-25 powder-modified TiO2 was immobilized on glass slides using TiO2-SiO2 sol-gel mixture as the binder and calcined at 500 degrees C. Several catalyst films with different Si amounts were synthesized and characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), infrared spectroscopy (IR), diffuse reflectance spectroscopy (DRS), photoluminescence spectroscopy (PL) and scanning electron microscopy (SEM). Photocatalytic degradation of MIB and GSM was investigated by irradiating aqueous solutions under UV-A light (350 nm). Generation of hydroxyl radicals (OH) was also assessed to evaluate the activity of the photocatalyst films. Catalyst films with surface ratios of Ti:Si ~6 showed similar degradations rates but better robustness compared to immobilized P25 films. PMID- 29275111 TI - Clinical impact of culture-positive preservation fluid on solid organ transplantation: A systematic review and meta-analysis. AB - Contamination of the preservation fluid (PF) used for donated organs is a potential source of post-transplant infection. However, the information on this issue is scarce. We therefore conducted a systematic review and meta-analysis to assess the incidence of culture-positive PF and its impact on solid organ transplant (SOT) recipients. Seventeen studies were identified and included. The overall incidence of culture-positive PF was 37% (95% CI: 27% to 49%), and the incidence of PF-related infections among SOT recipients with PF cultures that grew pathogenic microorganisms was 10% (95% CI: 7% to 15%). There were differences in the rates of infections due to pathogenic microorganisms between SOT recipients who received pre-emptive treatment and those who did not, but without statistical significance. The mortality rate among SOT recipients with PF related infection was 35% (95% CI: 21% to 53%). In conclusion, although contamination of the PF of donated organs is frequent, the incidence of PF related infection is relatively low. A closely clinical and microbiologic monitoring of the SOT recipient in case of culture-positive PF, regardless of the type of microorganism isolated might be do in order to establish a prompt diagnosis of PF-related infection. PMID- 29275112 TI - Outcomes of Intracorporeal Urinary Diversion after Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium. AB - PURPOSE: This study aimed to provide an update and compare perioperative outcomes and complications of intracorporeal and extracorporeal urinary diversion following robot-assisted radical cystectomy using data from the multi institutional, prospectively maintained International Robotic Cystectomy Consortium database. MATERIALS AND METHODS: We retrospectively reviewed the records of 2,125 patients from a total of 26 institutions. Intracorporeal urinary diversion was compared with extracorporeal urinary diversion. Multivariate logistic regression models using stepwise variable selection were fit to evaluate preoperative, operative and postoperative predictors of intracorporeal urinary diversion, operative time, high grade complications and 90-day hospital readmissions after robot-assisted radical cystectomy. RESULTS: In our cohort 1,094 patients (51%) underwent intracorporeal urinary diversion. These patients demonstrated shorter operative time (357 vs 400 minutes), less blood loss (300 vs 350 ml) and fewer blood transfusions (4% vs 19%, all p <0.001). They experienced more high grade complications (13% vs 10%, p = 0.02). Intracorporeal urinary diversion use increased from 9% of all urinary diversions in 2005 to 97% in 2015. Complications after this procedure decreased significantly with time (p <0.001). On multivariable analysis higher annual cystectomy volume (OR 1.02, 95% CI 1.01 1.03, p <0.002), year of robot-assisted radical cystectomy (2013-2016 OR 68, 95% CI 44-105, p <0.001) and American Society of Anesthesiologists(r) score less than 3 (OR 1.75, 95% CI 1.38-2.22, p <0.001) were associated with undergoing intracorporeal urinary diversion. The procedure was associated with a shorter operative time of 27 minutes (p = 0.001). CONCLUSIONS: The use of intracorporeal urinary diversion has increased in the last decade. A higher annual institutional volume of robot-assisted radical cystectomy was associated with intracorporeal urinary diversion as well as with shorter operative time. Although intracorporeal urinary diversion was associated with higher grade complications than extracorporeal urinary diversion, they decreased with time. PMID- 29275113 TI - Alternative Payment Models Should Risk-Adjust for Conversion Total Hip Arthroplasty: A Propensity Score-Matched Study. AB - BACKGROUND: For Medicare beneficiaries, hospital reimbursement for nonrevision hip arthroplasty is anchored to either diagnosis-related group code 469 or 470. Under alternative payment models, reimbursement for care episodes is not further risk-adjusted. This study's purpose was to compare outcomes of primary total hip arthroplasty (THA) vs conversion THA to explore the rationale for risk adjustment for conversion procedures. METHODS: All primary and conversion THAs from 2007 to 2014, excluding acute hip fractures and cancer patients, were identified in the National Surgical Quality Improvement Program database. Conversion and primary THA patients were matched 1:1 using propensity scores, based on preoperative covariates. Multivariable logistic regressions evaluated associations between conversion THA and 30-day outcomes. RESULTS: A total of 2018 conversions were matched to 2018 primaries. There were no differences in preoperative covariates. Conversions had longer operative times (148 vs 95 minutes, P < .001), more transfusions (37% vs 17%, P < .001), and longer length of stay (4.4 vs 3.1 days, P < .001). Conversion THA had increased odds of complications (odds ratio [OR] 1.75; 95% confidence interval [CI] 1.37-2.24), deep infection (OR 4.21; 95% CI 1.72-10.28), discharge to inpatient care (OR 1.52; 95% CI 1.34-1.72), and death (OR 2.39; 95% CI 1.04-5.47). Readmission odds were similar. CONCLUSION: Compared with primary THA, conversion THA is associated with more complications, longer length of stay, and increased discharge to continued inpatient care, implying greater resource utilization for conversion patients. As reimbursement models shift toward bundled payment paradigms, conversion THA appears to be a procedure for which risk adjustment is appropriate. PMID- 29275114 TI - In-Hospital Acute Kidney Injury After TKA Revision With Placement of an Antibiotic Cement Spacer. AB - BACKGROUND: There is mounting evidence that treatment of periprosthetic joint infection of the knee with an antibiotic cement spacer (ACS) may increase risk for acute kidney injury (AKI). We sought to determine the incidence, as well as potential risk factors, of in-hospital AKI in this cohort. METHODS: We retrospectively identified 75 patients that received either a static or articulating ACS at a single institution. In-hospital AKI was defined by a more than 50% rise in serum creatinine from preoperative baseline to at least 1.4 mg/dL. Our secondary outcome was percent change in creatinine from preoperative to peak postoperative value. Variables were analyzed for the outcome of AKI with univariate logistic regression. A final multivariate model for percent change in creatinine was formed while controlling for age, gender, body mass index, and baseline creatinine. RESULTS: The incidence of AKI was 14.6%, occurring at a mean of 6.3 days (2-8 days). A lower preoperative hemoglobin (odds ratio = 1.82, P = .015) significantly increased risk for AKI on univariate analysis. Diagnosis of either hypertension or diabetes also showed a strong statistical trend (P = .056). On multivariate regression, lower preoperative hemoglobin significantly correlated with a greater percent rise in creatinine postoperatively (beta = 0.30, P = .015). CONCLUSION: The incidence of AKI in patients who receive ACS is relatively high, raising clinical concern in the care of periprosthetic joint infection patients. Our results suggest that a lower baseline hemoglobin may be involved in the etiology of AKI in this population. Therefore, it may be clinically appropriate to monitor anemic patients for AKI when implanting an ACS. PMID- 29275115 TI - Results of Cemented vs Cementless Primary Total Knee Arthroplasty Using the Same Implant Design. AB - BACKGROUND: Although cemented total knee arthroplasty (TKA) continues to be the gold standard, there are patient populations with higher failure rates with cemented TKAs such as the obese, morbidly obese, and younger active males. Cementless TKA usage continues to increase because of the potential benefits of long-term biologic fixation similar to the rise in cementless total hip arthroplasty. The purpose of this study was to evaluate the clinical and radiographic results of cementless TKA using a novel highly porous cementless tibial baseplate. METHODS: This was a retrospective matched case-control study of 400 primary TKAs comparing cementless vs cemented TKAs using the same implant design (Stryker Triathlon; Stryker Inc, Mahwah, NJ). Two-hundred patients with a mean age of 64 years (range 42-88 years) and body mass index (BMI) of 33.9 kg/m2 (range 19.7-57.1 kg/m2) were matched to 200 primary cemented TKA patients with a mean age of 64 years (range 43-87 years) and BMI of 33.1 kg/m2 (range 22.2-53.2 kg/m2). The mean follow-up in the cementless group was 2.4 years (range 2-3.5 years) and in the cemented group was 5.3 years (range 2-10.9 years). Clinical and radiographic analyses were evaluated. Statistical analysis was performed using the Microsoft Excel, version 15.21.1. RESULTS: There was no statistical difference in age, BMI, and preoperative Knee Society Scores between the 2 groups (P = .22, P = .82, and P = .43, respectively). Patients in both groups had a similar incidence of postoperative complications (P = .90). Cementless group had 7 revisions with one aseptic loosening of the tibial component (0.5%). Cementless tibial baseplates demonstrated areas of increased bone density at the pegs of the tibial baseplate. The cemented group had 8 total revisions with 5 cases of aseptic loosening (2.5%). CONCLUSION: Early results of cementless TKA using a highly porous tibial baseplate designed with a keel and 4 pegs appear promising with one case of aseptic loosening at minimum 2-year follow-up. As the demographics of patients undergoing TKA change to include younger, obese, and more active patients, along with increased life expectancy, the use of a highly porous cementless tibial baseplate may be beneficial in providing long-term durable biologic fixation similar to the success of cementless total hip arthroplasty. PMID- 29275116 TI - Hospital Discharge Within 1 Day After Total Joint Arthroplasty From a Veterans Affairs Hospital Does Not Increase Complication and Readmission Rates. AB - BACKGROUND: Attempts to control costs associated with total joint arthroplasty have included efforts to shorten hospital length of stay (LOS). Concerns related to patient outcomes and safety with decreased LOS persist. The purpose of this study was to investigate whether discharge on postoperative day (POD) 1 after joint replacement is associated with increased rates of 90-day return to the operating room, and 30-day readmissions and emergency department (ED) visits. METHODS: After chart review, 447 patients admitted between January 2, 2013 and September 16, 2016 met inclusion criteria. All patients underwent one total joint arthroplasty. Patients were either discharged on POD 1 (subgroup 1) or POD 2 or 3 (subgroup 2). Statistical evaluation was performed using Wilcoxon-Mann-Whitney tests for continuous variables, and Fisher exact tests for categorical and frequency data. Statistical significance was established at P <= .05. RESULTS: Subgroup 1 had significantly fewer return trips to the operating room (P = .043) and significantly fewer 30-day readmissions (P = .033). ED visits were not significantly different between groups (P = .901). CONCLUSION: Early discharge after joint arthroplasty appears to be a viable practice and did not result in increased rates of reoperation within the 90-day global period, or rates of 30 day readmission and ED visits. Our results support the utilization of an early discharge protocol on POD 1, with no evidence that shorter LOS results in higher rates of short-term complications. PMID- 29275117 TI - Incorporating population-level genetic variability within laboratory models in toxicology: From the individual to the population. AB - Humans respond to chemical exposures differently due to many factors, such as previous and concurrent stressors, age, sex, and genetic background. The vast majority of laboratory-based toxicology studies, however, have not considered the impact of population-level variability within dose-response relationships. The lack of data dealing with the influence of genetic diversity on the response to chemical exposure provides a difficult challenge for risk assessment as individuals within the population will display a wide-range of responses following toxicant challenge. Notably, the genetic background of individuals plays a major role in the variability seen in a population-level response to a drug or chemical and, thus, there is growing interest in including genetic diversity into laboratory-models. Here we outline several laboratory-based models that can be used to assay the influence of genetic variability on an individual's response to chemicals: 1) genetically-diverse cell lines, 2) human primary cells, 3) and genetically-diverse mouse panels. We also provide a succinct review for several seminal studies to highlight the capability, feasibility, and power of each of these models. This article is intended to highlight the need to include population-level genetic diversity into toxicological study designs via laboratory-based models with the goal to provide and supplement evidence in assessing the risk posed by chemicals to the human population. As such, incorporation of genetic variability will positively impact human-based risk assessment and provide empirical data to aid and influence decision-making processes in relation to chemical exposures. PMID- 29275118 TI - Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. AB - BACKGROUND: Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR). METHODS: This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m2 per day] and oral cyclophosphamide [250 mg/m2 per day] for the first 3 days of each cycle, rituximab at 375 mg/m2 intravenously on day 0 of cycle 1 and subsequently at 500 mg/m2 on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m2) every 8 weeks for up to 2 years or undergo observation, with a central computer generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606. FINDINGS: Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47.7 months (IQR 30.4-65.8), median progression-free survival in the rituximab group (59.3 months, 95% CI 49.6-not estimable) was improved compared with the observation group (49.0 months, 39.9-60.5; hazard ratio 0.55, 95% CI 0.40-0.75; p=0.0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group. INTERPRETATION: 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy. FUNDING: French National Cancer Institute (INCa), Roche, Chugai. PMID- 29275119 TI - Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. AB - BACKGROUND: The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib. METHODS: In this randomised, phase 3, open-label trial, patients were screened for eligibility from 52 clinical centres in Canada, France, Germany, Israel, Italy, Spain, the UK, and the USA. Patients who had myelofibrosis and previous ruxolitinib treatment for at least 28 days who either required red blood cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 20 mg twice a day with at least one of grade 3 thrombocytopenia, anaemia, or bleeding at grade 3 or worse, with palpable spleen of at least 5 cm and without grade 2 or greater peripheral neuropathy were included in the study. Patients were randomly assigned (2:1) to either 24 weeks of open-label momelotinib 200 mg once a day or BAT (which could include ruxolitinib, chemotherapy, steroids, no treatment, or other standard interventions), after which all patients could receive extended momelotinib treatment. Patients were randomly assigned to treatment by an interactive web response system and the randomisation was stratified by transfusion dependence and by baseline total symptom score (TSS). Results were analysed on an intention to-treat basis. The primary endpoint was a reduction by at least 35% in the spleen volume at 24 weeks compared with baseline. Safety analyses included adverse event monitoring. The trial is registered with ClinicalTrials.gov, number NCT02101268. FINDINGS: Between June 19, 2014, and July 28, 2016, 156 patients were recruited to the study; 104 received momelotinib and 52 received BAT. BAT was ruxolitinib in 46 (89%) of 52 patients. 73 (70%) of 104 patients in the momelotinib group and 40 (77%) of 52 patients in the BAT group completed the 24 week treatment phase. Seven (7%) of 104 patients in the momelotinib group and three (6%) of 52 in the BAT group had a reduction in the spleen volume by at least 35% compared with baseline (proportion difference [Cochran-Mantel-Haenszel method], 0.01; 95% CI -0.09 to 0.10), p=0.90). The most common grade 3 or worse adverse events were anaemia (14 [14%] of 104 in the momelotinib group vs seven [14%] of 52 in the BAT group), thrombocytopenia (seven [7%] vs three [6%]), and abdominal pain (one [1%] vs three [6%]). Peripheral neuropathy occurred in 11 (11%) of 104 patients receiving momelotinib (one of which was grade 3) and in no patients in the BAT group. Serious events were reported for 36 (35%) patients in the momelotinib group and 12 (23%) of patients in the BAT group. Deaths due to adverse events were reported for six patients (6%) receiving momelotinib (acute myeloid leukaemia [n=2], respiratory failure [n=2, with one considered possibly related to momelotinib], cardiac arrest [n=1, considered possibly related to momelotinib], and bacterial sepsis [n=1]); and four patients (8%) receiving BAT (lung adenocarcinoma [n=1], myelofibrosis [n=1], and sepsis [n=2]). INTERPRETATION: In patients with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to BAT for the reduction of spleen size by at least 35% compared with baseline. FUNDING: Gilead Sciences, Inc. PMID- 29275120 TI - Don't judge a JAK2 inhibitor by spleen response alone. PMID- 29275121 TI - VE-Cadherin regulates the self-renewal of mouse embryonic stem cells via LIF/Stat3 signaling pathway. AB - With the abilities of self-renewal and differentiation, embryonic stem (ES) cells provide an unlimited source for stem cell-based therapeutics. However, the maintenance of ES cells with mouse embryonic fibroblasts (MEFs) can limit the clinical translation of ES cells. In the present study, we synthesized a fusion protein of the immunoglobulin G (IgG) fragment crystallizable region and vascular endothelial cadherin (VE-cadherin) extracellular domain (VE-cad-Fc) as a substrate for mouse ES cell culture, and we hypothesized that VE-cadherin could enhance the pluripotency and self-renewal of ES cells. Furthermore, we introduced a Stat3 reporter imaging system into ES cells and investigated the mechanism of the pluripotency enhancement mediated by VE-cadherin through cultured ES cells on VE-cad-Fc-coated plates using molecular imaging techniques. The resulting data revealed that VE-cad-Fc could activate the Stat3 signaling pathway, leading to the upregulation of stemness-related markers SSEA-1 and alkaline phosphatase (ALP). Moreover, VE-cad-Fc recovered the expression of Oct4, c-Myc, Nanog, Sox2, Tbx3 and Klf4 in differentiated ES cells, as well as enhanced the pluripotency of ES cells. In conclusion, VE-cadherin fusion protein coating methods provide an alternative towards feeder free culture of ES cells, and the strategy developed in the present study may benefit the clinical translation of ES cell-based therapeutics. PMID- 29275122 TI - Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment. AB - Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine. PMID- 29275123 TI - Small numbers are sensed directly, high numbers constructed from size and density. AB - Two theories compete to explain how we estimate the numerosity of visual object sets. The first suggests that the apparent numerosity is derived from an analysis of more low-level features like size and density of the set. The second theory suggests that numbers are sensed directly. Consistent with the latter claim is the existence of neurons in parietal cortex which are specialized for processing the numerosity of elements in the visual scene. However, recent evidence suggests that only low numbers can be sensed directly whereas the perception of high numbers is supported by the analysis of low-level features. Processing of low and high numbers, being located at different levels of the neural hierarchy should involve different receptive field sizes. Here, I tested this idea with visual adaptation. I measured the spatial spread of number adaptation for low and high numerosities. A focused adaptation spread of high numerosities suggested the involvement of early neural levels where receptive fields are comparably small and the broad spread for low numerosities was consistent with processing of number neurons which have larger receptive fields. These results provide evidence for the claim that different mechanism exist generating the perception of visual numerosity. Whereas low numbers are sensed directly as a primary visual attribute, the estimation of high numbers however likely depends on the area size over which the objects are spread. PMID- 29275124 TI - Effects of Saccade Induced Retrieval Enhancement on conceptual and perceptual tests of explicit & implicit memory. AB - The effects of saccadic horizontal (bilateral) eye movements upon tests of both conceptual and perceptual forms of explicit and implicit memory were investigated. Participants studied a list of words and were then assigned to one of four test conditions: conceptual explicit, conceptual implicit, perceptual explicit, or perceptual implicit. Conceptual tests comprised category labels with either explicit instructions to recall corresponding examples from the study phase (category-cued recall), or implicit instructions to generate any corresponding examples that spontaneously came to mind (category-exemplar generation). Perceptual tests comprised of word-fragments with either explicit instructions to complete these with study items (word-fragment-cued recall), or implicit instructions to complete each fragment with the first word that simply 'popped to mind' (word-fragment completion). Just prior to retrieval, participants were required to engage in 30 s of bilateral vs. no eye movements. Results revealed that saccadic horizontal eye movements enhanced performance in only the conceptual explicit condition, indicating that Saccade-Induced Retrieval Enhancement is a joint function of conceptual and explicit retrieval mechanisms. Findings are discussed from both a cognitive and neuropsychological perspective, in terms of their potential functional and neural underpinnings. PMID- 29275125 TI - Altered regional and integrated resting-state brain activity in general social anxiety disorder patients before and after group cognitive behavior therapy. AB - We aimed to investigate the recovery neuromechanism underlying the treatment efficacy in generalized social anxiety disorder (GSAD). We recruited fifteen patients with GSAD and nineteen healthy control (HC) participants, all of whom underwent a baseline resting-state fMRI scan. The GSAD patients underwent an additional fMRI scan after group cognitive behavior therapy (GCBT). Amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) measures were used to examine altered regional and integrated spontaneous brain activity in group comparisons. After GCBT, ALFF of the right precuneus decreased. At baseline, the GSAD group showed higher ALFF in the left precuneus and the left middle temporal gyrus (MTG) and lower ALFF in the lingual gyrus compared with the HC group. The DC of the left precuneus and the MTG were attenuated and the right putamen increased in the post-treatment group. The changes in DC in the precuneus were positively correlated with changes in clinical symptom. The abnormal ALFF of the precuneus, MTG and lingual gyrus may be the neural underpinning of GSAD, whereas the neural response to symptom remission after GCBT was achieved by a rebalance within the default mode network. PMID- 29275126 TI - An undergraduate educational model for developing sustainable nursing practice: A New Zealand perspective. AB - In this article we reflect on the concept of sustainability and in particular, sustainability within our undergraduate nursing programme. Given the complexity of global environmental change and the prediction that this will impact on health, nurses need to be responsive, knowledgeable and prepared to act on these changes (Anaker and Elf, 2014). Therefore as nurse educators we are responsible for ensuring that undergraduate nursing students are prepared for this reality. Sustainability is a relatively new concept emerging in the discipline of nursing. It is a multifaceted concept embedded within a systems framework, influenced by international, national and local factors. The concept of sustainability can be difficult to articulate and to evidence in daily nursing practice. Student nurses at the School of Nursing, Otago Polytechnic, Dunedin, are expected to meet the graduate profile indicating that they are a sustainability-practicing graduate on completion of their degree programme. As faculty staff, we have been encouraged to explore the concept of sustainability and how it relates to nursing practice. An in-depth review of the international literature, engagement of faculty colleagues, development of frameworks, and mapping of the educational content within the Bachelor of Nursing programme, has led us to develop a model for conveying and teaching sustainable practice. PMID- 29275127 TI - Factors influencing progress through the liminal phase: A model to assist transition into nurse academic life. PMID- 29275128 TI - Identification of Anatomical Risk Factors for Type II Endoleak to Guide Selective Inferior Mesenteric Artery Embolization. AB - BACKGROUND: It is unclear which patients are the best candidates for inferior mesenteric artery (IMA) embolization to reduce type II endoleak (ELII). Therefore, this study aimed to identify the anatomical risk factors for ELII after endovascular aneurysm repair (EVAR) and to determine the best candidates for preventative, preoperative IMA embolization. MATERIALS AND METHODS: Between April 2007 and September 2014, 196 patients underwent standard EVAR. Anatomical risk factors of postoperative, persistent ELII were detected using logistic regression analysis. Preoperative treatment of the IMA occlusion in patients with anatomical risk factors was performed to reduce ELII. RESULTS: ELII was detected in 48 patients (24.5%). Overall, patency of the IMA (odds ratio [OR], 4.13; P = 0.004) and lumbar artery (LA) diameter >=2.0 mm (OR, 3.30; P = 0.008) were significant risk factors for ELII, whereas an Endurant stent graft protected against ELII (OR, 0.22; P = 0.023). However, in patients with patent IMA, IMA diameter >=3.0 mm (OR, 4.09; P = 0.011), LA diameter >=2.0 mm (OR, 3.16; P = 0.043), and aortoiliac aneurysm (OR, 6.36; P = 0.026) were significant risk factors for ELII. Incidence rates of ELII in patients with and without these factors were 37.8% and 11.2%, respectively. ELII did not occur in patients with risk factors who underwent treatment of preoperative IMA occlusion. CONCLUSIONS: Patients with these risk factors are the candidates for undergoing treatment of preoperative IMA occlusion to reduce ELII. PMID- 29275129 TI - Dysbiosis of the fecal microbiota in feedlot cattle with hemorrhagic diarrhea. AB - The bovine gastrointestinal microbiota is a complex polymicrobial ecosystem that plays an important role in maintaining mucosal health. The role of mucosal microbial populations in the pathogenesis of gastrointestinal diseases has been well established in other species. However, limited information is available about changes in the fecal microbiota that occur under disease conditions, such as hemorrhagic diarrhea in feedlot cattle. The objectives of this study were to characterize the differences in fecal microbiota composition, diversity and functional gene profile between feedlot calves with, and without, hemorrhagic diarrhea. Deep fecal swabs were collected from calves with hemorrhagic diarrhea (n = 5) and from pen matched healthy calves (n = 5). Genomic DNA was extracted, and V1-V3 hypervariable region of 16S rRNA gene was amplified and sequenced using the Illumina MiSeq sequencing. When compared to healthy calves, feedlot cattle with hemorrhagic diarrhea showed significant increases in the relative abundance of Clostridium, Blautia and Escherichia, and significant decreases in the relative abundance of Flavobacterium, Oscillospira, Desulfonauticus, Ruminococcus, Thermodesulfovibrio and Butyricimonas. Linear discriminant analysis effect size (LEfSe) also revealed significant differences in bacterial taxa between healthy calves and hemorrhagic diarrhea calves. This apparent dysbiosis in fecal microbiota was associated with significant differences in the predictive functional metagenome profiles of these microbial communities. In summary, our results revealed a bacterial dysbiosis in fecal samples of calves with hemorrhagic diarrhea, with the diseased calves exhibiting less diversity and fewer observed species compared to healthy controls. Additional studies are warranted in a larger cohort of animals to help elucidate the trajectory of change in fecal microbial communities, and their predictive functional capacity, in calves with other gastrointestinal diseases. PMID- 29275130 TI - Evaluation of antibacterial and modifying action of catechin antibiotics in resistant strains. AB - Diseases caused by bacteria are today one of the great problems of present time. Access to over-the-counter medication, the indiscriminate use of antibacterials and high rates of hospitalization have contributed to the increase in cases. This picture has led to the search for new alternative drugs. Thus, secondary metabolites have been reported as a possible treatment option, being evidenced in many researches to ascertain their combination with existing drugs. This research aimed to evaluate the antibacterial effect and the antibiotic activity modifying action of the catechin compound against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus multiresistant strains. The determination of the Minimum Inhibitory Concentration (MIC) and the evaluation of the antimicrobial and potentiating effect were performed by broth microdilution. The MIC obtained forcatechin against all the used strains was indicated as not clinically relevant. The combination of catechin and antibacterial drugs, both Gram-negative and Gram-positive, was synergistic and antagonistic in some drugs. Therefore, phenolic compounds can assist in the fight against infections caused by bacteria. PMID- 29275131 TI - Preparation, characterization and evaluation of the immune effect of alginate/chitosan composite microspheres encapsulating recombinant protein of Streptococcus iniae designed for fish oral vaccination. AB - Streptococcus iniae has caused serious harm to the fish farming industry in recent years. Vaccination is a potential approach for preventing and controlling disease, being oral vaccination the most suitable vaccination route in fish. Alginate and chitosan microspheres have been widely used as controlled release systems for oral vaccination in fish. In this study, we prepared and characterized alginate/chitosan composite microspheres encapsulating the recombinant protein serine-rich repeat (rSrr) of S. iniae. We evaluated effect of these microspheres on the immune system of channel catfish. The microsphere preparation conditions were optimized by Response Surface Method and target microspheres were obtained under 1.68% alginate (w/v), the W/O ratio 3.6:7.4 (liquid paraffin with 4% Span 80, v/v) with stirring at 1000 rpm, 9.64% CaCl2 (w/v) and 0.95% chitosan (w/v) with an encapsulation efficiency of 92.38%. The stability and safety of rSrr-microspheres were evaluated in vitro and in vivo, respectively. Furthermore, compared with control group, oral vaccination with rSrr-microspheres induced higher serum antibody titers, higher lysozyme activity, higher total protein and higher expression of immune-related genes, and resulted in higher relative percent survival (RPS) with the value of 60% for channel catfish against S.iniae infection. Our results thus indicate that alginate/chitosan microspheres encapsulating rSrr can be used as oral vaccine for channel catfish, providing efficient immunoprotection against S. iniae infection. PMID- 29275132 TI - Molecular cloning of Kuruma shrimp Marsupenaeus japonicus endonuclease-reverse transcriptase and its positive role in white spot syndrome virus and Vibrio alginolyticus infection. AB - This study investigated the function of endonuclease-reverse transcriptase (mjERT) in Marsupenaeus japonicus. The 1129 bp cDNA sequence of mjERT was cloned from M. japonicus using rapid amplification of cDNA ends (RACE) PCR, and RT-qPCR analysis indicated that mjERT was highly expressed in the gills and hepatopancreas of M. japonicus. We also found that white spot syndrome virus (WSSV) or Vibrio alginolyticus challenge could enhance the expression of mjERT. When mjERT was inhibited, immune genes such as toll, p53, hemocyanin and tumor necrosis factor-alpha (TNF-alpha) were significantly down-regulated (P < .01) in the hemocytes of shrimp, while myosin was significantly up-regulated (P < .01). We demonstrated that mjERT is very important for the progression of WSSV infection and that the cumulative mortality of WSSV-infected and V. alginolyticus infected shrimps was significantly increased following mjERT RNA interfere (RNAi). Apoptosis data provided information to suggest that mjERT-dsRNA challenge caused less apoptosis in hemocytes in both the disease-free and viral group. We also revealed that mjERT-dsRNA treatment resulted in a lower phagocytosis rate in the hemocytes of V. alginolyticus-challenged shrimp. Finally, we found that the absence of mjERT had an significantly negative impact upon shrimp phenoloxidase (PO) activity, superoxide dismutase (SOD) activity and total hemocyte count (THC) following WSSV or V. alginolyticus infection, indicating a regulative role for mjERT in the innate immunity of shrimp in response to pathogenic infection. In summary, we concluded that mjERT might promote the anti-WSSV immune response of shrimp by regulating apoptosis, PO activity, THC and SOD activity, and also exert a positive role in the immune response against V. alginolyticus by regulating phagocytosis, SOD activity, PO activity and THC. PMID- 29275133 TI - Inert Gas Washout in Bronchiolitis Obliterans Following Hematopoietic Cell Transplantation. AB - BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a leading cause of chronic graft-vs-host disease (cGvHD) and is associated with mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). The nitrogen multiple breath washout test (N2-MBW) measures ventilation inhomogeneity, a biomarker of central and peripheral airway obstruction. The aim of this study was to examine ventilation inhomogeneity according to cGvHD score and histologically defined bronchiolitis obliterans (BO). METHODS: This single-center prospective cross sectional study included 225 adults (mean age, 52.8 years; median, 5.4 years [interquartile range, 2.0-11 years]) after alloHSCT. Outcomes were global (lung clearance index [LCI]) and acinar ventilation inhomogeneity index (SACIN) from N2 MBW. Patients were categorized into five groups: (1) no cGvHD and no obstruction (cGvHD overall score 0 and FEV1/FVC >= 70) (2) cGvHD and no obstruction (cGvHD overall score 1-3 and FEV1/FVC >= 70), (3) BOS with or without cGvHD (if available, no BO on histologic examination, and FEV1/FVC < 70), (4) histologically proven BO, and (5) diffuse parenchymal lung disease other than BO. RESULTS: The LCI and SACIN differed significantly between groups (P < .001) and increased progressively according to cGvHD score. In BO, the LCI and SACIN were elevated in 95.5% and 81.8% of patients, respectively, whereas FEV1/FVC was abnormal in only 56.5% of patients, respectively. CONCLUSIONS: N2-MBW is highly sensitive for detecting abnormal lung function in patients following alloHSCT. LCI and SACIN seem to be promising biomarkers of lung involvement in cGvHD. PMID- 29275134 TI - Comparative Safety of Drugs Targeting the Nitric Oxide Pathway in Pulmonary Hypertension: A Mixed Approach Combining a Meta-Analysis of Clinical Trials and a Disproportionality Analysis From the World Health Organization Pharmacovigilance Database. AB - BACKGROUND: Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension. METHODS: We combined two approaches. First, we performed a meta analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization's global database of individual case safety reports, to compare the safety profiles with real-life data. RESULTS: In the meta-analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat (P < .01 for interaction). In the disproportionality analysis, the use of riociguat was associated with fewer reports of visual disorders but increased reporting of gastrointestinal, hemorrhagic, and musculoskeletal disorders compared with sildenafil and tadalafil. Pharmacovigilance signals of hearing/vestibular disorders were heterogeneous: vestibular disorders (dizziness) were reported more frequently for riociguat, whereas hearing disorders (deafness) were reported less frequently compared with PDE5is. CONCLUSIONS: The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects. TRIAL REGISTRY: PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/. PMID- 29275136 TI - Social franchising: whatever happened to old-fashioned notions of evidence-based practice? PMID- 29275135 TI - Effect of a multifaceted social franchising model on quality and coverage of maternal, newborn, and reproductive health-care services in Uttar Pradesh, India: a quasi-experimental study. AB - BACKGROUND: How to harness the private sector to improve population health in low income and middle-income countries is heavily debated and one prominent strategy is social franchising. We aimed to evaluate whether the Matrika social franchising model-a multifaceted intervention that established a network of private providers and strengthened the skills of both public and private sector clinicians-could improve the quality and coverage of health services along the continuum of care for maternal, newborn, and reproductive health. METHODS: We did a quasi-experimental study, which combined matching with difference-in differences methods. We matched 60 intervention clusters (wards or villages) with a social franchisee to 120 comparison clusters in six districts of Uttar Pradesh, India. The intervention was implemented by two not-for-profit organisations from September, 2013, to May, 2016. We did two rounds (January, 2015, and May, 2016) of a household survey for women who had given birth up to 2 years previously. The primary outcome was the proportion of women who gave birth in a health-care facility. An additional 56 prespecified outcomes measured maternal health-care use, content of care, patient experience, and other dimensions of care. We organised conceptually similar outcomes into 14 families to create summary indices. We used multivariate difference-in-differences methods for the analyses and accounted for multiple inference. FINDINGS: The introduction of Matrika was not significantly associated with the change in facility births (4 percentage points, 95% CI -1 to 9; p=0.100). Effects for any of the other individual outcomes or for any of the 14 summary indices were not significant. Evidence was weak for an increase of 0.13 SD (95% CI 0.00 to 0.27; p=0.053) in recommended delivery care practices. INTERPRETATION: The Matrika social franchise model was not effective in improving the quality and coverage of maternal health services at the population level. Several key reasons identified for the absence of an effect potentially provide generalisable lessons for social franchising programmes elsewhere. FUNDING: Merck Sharp and Dohme Limited. PMID- 29275137 TI - Blood volume extracted from the critical patient in the first 24 hours after admission. AB - OBJECTIVE: To calculate the number of analytical tests and blood volume drawn during the first 24hours of admission to the Intensive Care Unit (ICU). To analyse values of basal haemoglobin and at 24hours, relate them to blood loss, weight variation, and scoring system. METHOD: An observational descriptive pilot study. Variables studied: age, sex, diagnosis on admission, analytical tests extracted, waste quantity before the extraction of samples, total volume blood extracted in 24hours, weight variation, APACHE, SAPS, basal haemoglobin and at 24hours. Statistical analysis with SPSS vs 20.0. Variables correlation sex, weight variation, the number of analytical tests and haemoglobin change. RESULTS: The study included 100 patients. The average number of extractions per patient/day was 7.2 (+/-2.6). The average waste quantity was 32.61ml (+/-15.8). The blood volume used for determinations was 48.18ml / 24h (+/-16.74). The haemoglobin value decreased in the first 24hours of admission, being higher in men (P<.05). The scoring systems were statistically significant for levels of haemoglobin (Hb1 -0.3; P=.001; Hb2 -0.4; P=.001). CONCLUSIONS: Of the total volume of blood extracted in ICU, 40% belongs to a volume of waste and 60% of blood is used for analytical tests. There is a decrease in haemoglobin exists 24hours after admission of the critical patient. Statistically, it has not been possible to demonstrate its relation with the number of analytical tests. PMID- 29275138 TI - Does a history of psychoactive substances abuse play a role in the level of pain of the patient with severe trauma? AB - OBJECTIVE: To analyse the influence of psychotropic substance use on the level of pain in patients with severe trauma. DESIGN: Longitudinal analytical study. SCOPE: Intensive Care Unit (ICU) of Trauma and Emergencies. PATIENTS: severe trauma, non-communicative and mechanical ventilation >48hours. Two groups of patients were created: users and non-users of psychotropic substances according to medical records. INTERVENTIONS: Measurement of pain level at baseline and during mobilization, using the Pain Indicator Behaviour Scale. VARIABLES: demographic characteristics, pain score, sedation level and type and dose of analgesia and sedation. RESULTS: Sample of 84 patients, 42 in each group. The pain level in both groups, during mobilisation, showed significant differences p=0.011, with a mean of 3.11(2.40) for the user group and 1.83(2.14) for the non user group. A relative risk of 2.5 CI (1,014-6,163) was found to have moderate / severe pain in the user group compared to the non-user group. The mean dose of analgesia and continuous sedation was significantly higher in the user group: P=.032 and P=.004 respectively. There was no difference in bolus dose of analgesia and sedation with P=.624 and P=.690 respectively. CONCLUSIONS: Patients with a history of consumption of psychoactive substances show higher levels of pain and experience a higher risk of this being moderate/severe compared to non users despite receiving higher doses of analgesia and sedation infusion. Key words: pain, multiple trauma, drug users. PMID- 29275140 TI - Peri-operative desensitization for highly sensitized heart transplant patients. PMID- 29275139 TI - Pretransplant Consolidation Is Not Beneficial for Adults with ALL Undergoing Myeloablative Allogeneic Transplantation. AB - Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR1) with chemotherapy. However, the benefit of consolidation chemotherapy remains uncertain in patients undergoing alloHCT. We compared clinical outcomes of 524 adult patients with ALL in CR1 who received >=2 (n = 109), 1 (n = 93), or 0 cycles (n = 322) of consolidation before myeloablative alloHCT from 2008 to 2012. As expected, time to alloHCT was longer with increasing cycles of consolidation. Patients receiving >=2, 1, or 0 cycles of consolidation had an adjusted 3-year cumulative incidence of relapse of 20%, 27%, and 22%; 1-year transplant-related mortality (TRM) of 16%, 18%, and 23%; adjusted 3-year leukemia-free survival (LFS) of 54%, 48%, and 47%; and 3-year overall survival (OS) of 63%, 59%, and 54% (all P values >.40). Multivariable analysis confirmed that consolidation was not prognostic for LFS (relative risk, 1.20, 95% confidence interval, .86 to 1.67; P = .28 for no consolidation; RR, 1.18, 95% confidence interval, .79 to 1.76; P = .41 for 1 cycle versus >=2 cycles = reference). Similarly, consolidation was not associated with OS, relapse, TRM, or graft-versus-host disease. We conclude that consolidation chemotherapy does not appear to provide added benefit in adult ALL patients with available donors who undergo myeloablative alloHCT in CR1. PMID- 29275141 TI - Beyond interleukin-6 in right ventricular function: Evidence for another biomarker. PMID- 29275142 TI - Isolated hyperammonemic encephalopathy in heart transplantation. PMID- 29275143 TI - Performance characteristics of the Beckman Coulter UniCel DxI 800 TSH (3rd IS) assay. AB - INTRODUCTION: Beckman Coulter recently reformulated their commercial TSH assay with primary calibration to the World Health Organization 3rd TSH international standard. An extensive evaluation of the performance characteristics for this assay was completed. METHODS: Intra-day and inter-day precision was evaluated using 3 concentrations of commercial quality control material. Linearity, reportable range, stability, sensitivity and susceptibility to common inferences were determined using pooled patient specimens. Inter-assay variability was assessed across 5 different platforms (n=47 patient specimens). RESULTS: Intra day and inter-day CVs were <10% at all concentrations evaluated. The LOQ, LOD and LOB were 0.0047MUIU/ml (10% CV), 0.0012MUIU/ml and 0.0005MUIU/ml, respectively. Variable bias was observed for the TSH3 assay when evaluated against the previous generation assay and other platforms, but overall TSH3 gave comparable results. CONCLUSIONS: The TSH3 assay for UniCel DxI 800, is precise, highly sensitive and comparable to the previous generation assay. The assay is acceptable for clinical testing. PMID- 29275144 TI - Case Presentation: Botox Versus Nerve Stimulation. AB - A woman experiencing very strong urgency and associated frequency of micturition, but no incontinence, and deep dyspareunia was eventually diagnosed with idiopathic detrusor overactivity with symptoms of overactive bladder symptom complex and potentially bladder pain syndrome. A trial of neuromodulation was unsuccessful, but injections of onabotulinum toxin A have had a good effect. PMID- 29275145 TI - Taxane-based Combination Therapies for Metastatic Prostate Cancer. AB - CONTEXT: Multiple single-agent therapies improving survival are approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC), including two chemotherapies, two androgen-signaling axis-targeting agents, an immunotherapeutic vaccine, and a radiopharmaceutical. Combination therapy can target multiple oncogenic pathways simultaneously, while potentially curbing the development of treatment resistance. OBJECTIVE: To provide a succinct overview of taxane-based combination therapies currently being evaluated for the treatment of metastatic prostate cancer. EVIDENCE ACQUISITION: We searched MEDLINE/PubMed(r) and relevant congress databases for literature focused on taxane-based combination therapies being evaluated for the treatment of metastatic prostate cancer. In addition, a systematic search of www.clinicaltrials.gov was performed to gather information regarding ongoing taxane-based combination trials in prostate cancer. This search included phase II or III trials starting after January 1, 2010, which included the terms "docetaxel" or "cabazitaxel" and "prostate", and was then manually filtered for combination studies. EVIDENCE SYNTHESIS: Single-agent therapy yields modest increments in survival. The success of combining docetaxel with androgen deprivation to improve overall survival (OS) for metastatic hormone-sensitive disease suggests the potential of similar approaches in mCRPC. Several classes of biological drugs have previously been combined with docetaxel for mCRPC in clinical trials without improvement in OS. However, combining docetaxel or cabazitaxel with newer agents with established single-agent benefit, such as radium-223, second-generation androgen pathway targeted agents, or other chemotherapies, has the potential to benefit patients when compared with taxane chemotherapy alone. Our search revealed that the majority of trials currently assessing taxanes are focused on combination therapies: a combination approach is being evaluated in 37 of 47 trials assessing docetaxel and in 18 of 34 trials assessing cabazitaxel. CONCLUSIONS: Despite prior failures, novel taxane-based combination therapies have the potential to improve outcomes in mCRPC. Challenges include the absence of validated predictive biomarkers for the selection of suitable patients and the potential for enhanced toxicity. PATIENT SUMMARY: Patients with metastatic prostate cancer have access to multiple therapies improving survival. Many advanced epithelial cancers are treated with combinations of drugs; however, prostate cancer has remained an exception. A number of clinical studies have shown that combining chemotherapy with other classes of therapy may improve patient outcomes in prostate cancer. Here, we summarize the various combinations that are tested in the clinic and review the results. PMID- 29275146 TI - Prevalence of Complications Leading to a Health Care Contact After Transrectal Prostate Biopsies: A Prospective, Controlled, Multicenter Study Based on a Selected Study Cohort. AB - BACKGROUND: Transrectal ultrasound-guided prostate biopsy (TRUS-Bx) is typically considered a safe procedure. However, infectious complications have been increasing. OBJECTIVE: To determine the contemporary rate of biopsy-related infectious and noninfectious complications after TRUS-Bx, and identify potential risk factors associated with the complications. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective multicenter study and a substudy of a trial investigating the role of magnetic resonance imaging (MRI) in prostate cancer diagnosis (multi-IMPROD, NCT02241122). INTERVENTION: TRUS-Bx was performed for all patients included in the study. Ciprofloxacin, levofloxacin, or fosfomycin was administered for antibiotic prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: On inclusion, patients completed a detailed questionnaire and underwent MRI scanning. Antibiotic prophylaxis was prospectively recorded. After collection of a rectal swab, TRUS-Bx (total of 14-18 biopsy cores) was performed and. The rectal swabs were cultured and the antimicrobial susceptibility profile of Escherichia coli strains was analyzed. Biopsy complications leading to a visit to a health care unit were recorded and potential risk factors for complications were analyzed. RESULTS AND LIMITATIONS: Twelve of the 294 patients (4.1%) had a biopsy-related complication, of which two (0.7%) were infectious and managed in the outpatient setting. Some 11% of the patients had an E. coli strain resistant to the prophylactic antibiotic administered. CONCLUSIONS: The risk of an infectious or noninfectious complication after TRUS-Bx is very low, although the FQ resistance rate in the study population was significant. Accordingly, the present TRUS-Bx procedure and antibiotic prophylaxis are efficient in guarding against biopsy complications, but regional resistance rates may affect the generalizability of the results. PATIENT SUMMARY: We examined the rate of complications after prostate biopsies in 294 patients. The risk of having a biopsy-related complication was low (4.1%). The rate of infectious complications was reasonably low (0.7%) although antibiotic resistance to the prophylactic antibiotic regimen was significant (11%). PMID- 29275147 TI - Lack of Longitudinal Association Between Thiazolidinediones and Incidence and Progression of Diabetic Eye Disease: The ACCORD Eye Study. AB - PURPOSE: To report the longitudinal association between use of thiazolidinediones (TZDs), visual acuity (VA) change, and diabetic eye disease incidence and progression. DESIGN: Cohort study ancillary to a randomized clinical trial. METHODS: We analyzed baseline and 4-year follow-up data of 2856 ACCORD trial participants with no history of proliferative diabetic retinopathy. Based on stereoscopic fundus photographs, we evaluated diabetic macular edema (DME) progression and DR progression. We also evaluated 10- and 15-letter change on the ETDRS visual acuity chart. Main outcome measures were incidence or progression of DME or DR and change in visual acuity. RESULTS: TZD use was not associated with DME incidence in either the analysis of any use (adjusted odds ratio [aOR] [95% CI]: 1.22 [0.72-2.05]) or duration of use (aOR: 1.02 [0.99-1.04]). Diabetic retinopathy (DR) incidence/progression was more common in patients with no or mild DR at baseline who were ever treated with TZDs (aOR: 1.68 [1.11-2.55]), but this association disappeared when adjusting for the time on TZD (aOR: 1.02 [1.00 1.04]). DR progression among those with moderate or worse DR at baseline was no different between TZD users and non-users. TZD usage had no effect on the ultimate visual acuity outcome. CONCLUSION: In this longitudinal study of patients with type 2 diabetes, we found no association between TZD use and visual acuity outcomes or DME progression, and no consistent evidence of increased DR progression in patients ever treated with TZDs vs those never treated with TZDs. PMID- 29275148 TI - RNA splicing and its connection with other regulatory layers in somatic cell reprogramming. AB - Understanding how cell identity is established and maintained is one of the most exciting challenges of molecular biology today. Recent work has added a conserved layer of RNA splicing and other post-transcriptional regulatory processes to the transcriptional and epigenetic networks already known to cooperate in the establishment and maintenance of cell identity. Here we summarize these findings, highlighting specifically the multitude of splicing factors that can modulate the efficiency of somatic cell reprogramming. Distinct patterns of gene expression dynamics of these factors during reprogramming suggest that further improvements in efficiency could be obtained through optimal timing of overexpression or knockdown of individual regulators. PMID- 29275149 TI - Mitochondrial networking in human blood cells with application in acute care illnesses. AB - Mitochondria are dynamic organelles that adapt in response to environmental stresses or mutations. Dynamic processes involving mitochondria include their locomotion within cells and fusion and fission events in which mitochondrial join together or split apart. Various imaging strategies have been utilized to track mitochondrial dynamics. One common limitation of most of the methods available is that the time required to perform the technique and analyze the results prohibits application to clinical diagnosis and therapy. We recently demonstrated "whole cell" mitochondrial analysis in a two-dimensional fashion with fluorescence microscopy. Our developed technique allows evaluation of whole-cell mitochondrial networking, including assessment of mitochondrial motility and rates of fission and fusion events using human blood cells (peripheral blood mononuclear cells (PBMCs)) on a clinically relevant timescale. We demonstrate this methodology in a cohort of healthy subjects as well as a cohort of hospitalized subjects having sepsis, an acute care illness. As there is increasing use of human blood cells as a proxy of organ mitochondrial function with respiration in various disease states, the addition of mitochondrial dynamics will now allow for more thorough clinical evaluation of mitochondrial networking in human disease with potential exploration of therapeutics. PMID- 29275150 TI - Local anesthetics induce interdigitation and thermotropic changes in dipalmitoylphosphatidylcholine bilayers. AB - The molecular mechanism underlying the action of local anesthetics is still elusive. Phenylethanol (PEtOH) is an ingredient of essential oils with a rose like odor and has been used as a local anesthetic. In this work, we have explored the effect of PEtOH on thermotropic behavior and organization of dipalmitoylphosphatidylcholine (DPPC) membranes utilizing differential scanning calorimetry (DSC) and small angle X-ray scattering (SAXS). Our results indicate that the phase transition temperature of DPPC exhibited decrease with increasing PEtOH concentration. This is accompanied by hysteresis (difference in phase transition between the heating and cooling scans). We defined the threshold concentration of PEtOH as the concentration at which the difference in phase transition temperature between the heating and cooling thermograms is maximum. Interestingly, changes in enthalpy, entropy, and full width at half maximum displayed biphasic behavior beyond the threshold concentration of PEtOH. The biphasic change in thermodynamic parameters corresponding to phase transtition, coupled with hysteresis, is indicative of interdigitation in DPPC bilayers. We confirmed this proposition by SAXS measurements which show formation of the interdigitated phase in DPPC bilayers at and above the threshold concentration of PEtOH. To the best of our knowledge, these results constitute the first report describing the interdigitation of membrane bilayers induced by PEtOH. We further show that the formation of interdigitated phase in DPPC bilayers depends on PEtOH concentration and temperature. Our results could be useful in ongoing efforts to address the mechanism of action of local anesthetics in model and biological membranes. PMID- 29275151 TI - Coelacanth-specific adaptive genes give insights into primitive evolution for water-to-land transition of tetrapods. AB - Coelacanth is a group of extant lobe-finned fishes in Sarcopterygii that provides evolutionary information for the missing link between ray-finned fish and tetrapod vertebrates. Its phenotypes, different from actinopterygian fishes, have been considered as primitive terrestrial traits such as cartilages in their fatty fins which are homologous with the humerus and femur. To investigate molecular evolution of coelacanth which led to its divergence into Sarcopterygii, we compared its protein coding sequences with 11 actinopterygian fishes. We identified 47 genes under positive selection specific to coelacanth, when compared to Holostei and Teleostei. Out of these, NCDN and 14 genes were associated with spatial learning and nitrogen metabolism, respectively. In homeobox gene superfamily, we identified coelacanth-specific amino acid substitutions, and also observed that one of replacements in SHOX was shared with extant tetrapods. Such molecular changes may cause primordial morphological change in the common ancestor of sarcopterygians. These results suggest that certain genes such as NCDN, MMS19, TRMT1, ALX1, DLX5 and SHOX might have played a role in the evolutionary transition between aquatic and terrestrial vertebrates. PMID- 29275152 TI - WITHDRAWN: A Review Of International Pharmacy- Based Minor Ailment Services And Proposed Service Design Model. PMID- 29275153 TI - Mechanical stiffness of TMJ condylar cartilage increases after artificial aging by ribose. AB - OBJECTIVE: Aging is accompanied by a series of changes in mature tissues that influence their properties and functions. Collagen, as one of the main extracellular components of cartilage, becomes highly crosslinked during aging. In this study, the aim was to examine whether a correlation exists between collagen crosslinking induced by artificial aging and mechanical properties of the temporomandibular joint (TMJ) condyle. To evaluate this hypothesis, collagen crosslinks were induced using ribose incubation. METHODS: Porcine TMJ condyles were incubated for 7 days with different concentrations of ribose. The compressive modulus and stiffness ratio (incubated versus control) was determined after loading. Glycosaminoglycan and collagen content, and the number of crosslinks were analyzed. Tissue structure was visualized by microscopy using different staining methods. RESULTS: Concomitant with an increasing concentration of ribose, an increase of collagen crosslinks was found. The number of crosslinks increased almost 50 fold after incubation with the highest concentration of ribose. Simultaneously, the stiffness ratio of the samples showed a significant increase after incubation with the ribose. Pearson correlation analyses showed a significant positive correlation between the overall stiffness ratio and the crosslink level; the higher the number of crosslinks the higher the stiffness. CONCLUSION: The present model, in which ribose was used to mimic certain aspects of age-related changes, can be employed as an in vitro model to study age-related mechanical changes in the TMJ condyle. PMID- 29275154 TI - Three-dimensional growth pattern of the rat mandible revealed by periodic live micro-computed tomography. AB - OBJECTIVE: We wanted to evaluate the three-dimensional (3D) mandibular growth of Sprague-Dawley rats from 4th to 16th postnatal weeks with periodic and live micro computed tomographic scanning. DESIGN: Twenty Sprague-Dawley rats were used for micro-CT scanning from 4th to 16th postnatal weeks. After 3D reconstruction of rat mandible, we performed the linear and angular measurements and the superimposition of the 3D models to evaluate the mandibular growth of rat. RESULTS: The results showed that the growth direction of the condylar and coronoid regions was superior primarily and posterior secondarily, while the condyle had minimal lateral growth. Moreover, the angular region was growing mainly toward the posterior and lateral direction, while the body and symphysis maintained small, incremental anterior-posterior growth. CONCLUSIONS: We could evaluate the amount, rate, and direction of growth using the mandibular skeletal unit. Some reference points and measurements were more relevant in properly characterizing 3D growth of the mandible. Their growth rates were the greatest between 4th and 8th postnatal weeks, a period which seems most appropriate for studies of rat mandible growth. PMID- 29275155 TI - HTR1A/1B DNA methylation may predict escitalopram treatment response in depressed Chinese Han patients. AB - BACKGROUND: The serotonin receptor 1A and 1B (HTR1A/1B) gene have been suggested to be involved in the pathogenesis of major depressive disorder (MDD) and the antidepressant treatment response. Gene expression differences were partly mediated by genetic polymorphism and DNA methylation which might be affected by environmental factors. In the present study, we attempt to identify whether HTR1A/1B DNA methylation and genetic polymorphism could predict antidepressant treatment response. METHODS: 85 Chinese Han MDD patients were clinically assessed 8 weeks after of initiating escitalopram treatment for the first time. Antidepressant treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 items (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The Illumina HiSeq platform was used to assess DNA methylation at 96 CpG sites located in HTR1A and HTR1B gene promoter regions. Six single nucleotide polymorphisms (SNPs) (HTR1A rs6294, rs116985176; HTR1B rs6296, rs6298, rs1228814, rs1778258) were genotype by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or PCR sequencing. Regression analyses were used to explore the relationship between DNA methylation and SNP and antidepressant response. RESULTS: We identified two CpG sites predictor of antidepressant treatment response (CpG 668, amplicon HTR1A_1, NC_000005.10, P = 0.025; CpG 1401, amplicon HTR1B_4, NC_000006.12, P = 0.033). The interaction of four CpG sites hypomethylation of HTR1A/1B with high recent stress might result in impaired antidepressant treatment response. What's more, the present data indicated that age, environments and antidepressant treatment might affect DNA methylation status. It was found that DNA methylation status could be influenced by antidepressant treatment in turn. However, HTR1A and HTR1B genotypes did not influence antidepressant response and DNA methylation status. CONCLUSIONS: The results suggest that HTR1A/1B DNA hypomethylation and its interaction with recent life stress might drive impaired antidepressant treatment response. Meanwhile, DNA methylation, in turn, was modified by antidepressant treatment and environments. Our results offer new evidence for the role of epigenetic and genetic polymorphism in pharmacological response to antidepressants. PMID- 29275156 TI - Aripiprazole use during pregnancy, peripartum and lactation. A systematic literature search and review to inform clinical practice. AB - BACKGROUND: Aripiprazole is used relatively frequently in women with bipolar disorder or schizophrenia in childbearing years, owing to its efficacy and relatively favorable side effect profile. As is the case for other psychotropic medications, for ethical reasons, no prospective randomized placebo controlled trial to assess aripiprazole safety during pregnancy has ever been conducted. However, animal data are available and the amount of exposure and outcome data for human fetuses and infants has recently increased, providing published prospective safety data in relatively large numbers of pregnant women treated with aripiprazole. The aim of this study was to perform a systematic literature search and review to critically evaluate the available data on the use of aripiprazole during pregnancy, peripartum and lactation. METHODS: PubMed, PsychInfo, and Cochrane Library were searched using the following search builder: (pregnancy OR pregnant OR gestation OR malformations OR perinatal OR reproduction OR organogenesis OR delivery OR breast-feeding OR lactation or peripartum or obstetric) AND aripiprazole. Reports that met the following pre-defined criteria were included in the present review: (1) published in English language in a peer reviewed journal; (2) clearly defined use of aripiprazole during pregnancy and/or lactation and/or postpartum; (3) case report, case series, prospective, retrospective or cross-sectional studies. United States and European Medicine Agency prescribing information for aripiprazole were consulted as well and all the references of selected papers were cross checked for information pertaining to the use of aripiprazole during pregnancy, peripartum and lactation. RESULTS: A total of 549 items published in a period ranging from 1995 to 2017, were retrieved from the search databases and reference cross check. One-hundred-fifty three duplicate items were removed, 176 titles were deemed as not pertinent, 220 abstracts and 122 full-text articles were assessed for eligibility and 93 titles were included for qualitative synthesis. United States and European Medicine Agency prescribing information for aripiprazole were consulted and the selected manuscript references were cross checked. No randomized placebo controlled trial was found but relatively large prospective studies, large database studies, and several case reports and case studies were identified and summarized. CONCLUSIONS: As is the case for other antipsychotics, definitive evidence on aripiprazole reproductive safety is lacking, but newer safety data are relatively reassuring. In many cases, the potential benefits of aripiprazole for patients with bipolar disorder or schizophrenia outweigh the potential risks. PMID- 29275157 TI - In vitro characterization of alkylaminophenols-induced cell death. AB - Alkylaminophenols are synthetic derivatives well known for their anticancer activity. In the previous studies, we described the activity of the series of Alkylaminophenols derivatives and their ability to induce cell death for many cancer cell lines. However, temporal heterogeneity in cell death induced by lead compounds, N-(2-hydroxy-5-nitrophenyl (4'-methylphenyl) methyl) indoline (Compound I) and 2-((3,4-dihydroquinolin-1(2H)-yl) (4-methoxyphenyl) methyl) phenol (Compound II), has never been tested on osteosarcoma cells (U2OS). Here, we address the level of cell-to-cell heterogeneity by examine whether differences in the type of compounds could influence its effects on cell death of U2OS. Here, we applied imaging, computational methods and biochemical methods to study heterogeneity, apoptosis, reactive oxygen species and caspase. Our results demonstrate that the Hill coefficient of dose-response curve of Compound II is greater than compound I in treated U2OS cells. Both Compounds trigger not only apoptotic cell death but also necro-apoptotic and necrotic cell death. The percentage of these sub-populations varies depending on compounds in which greater variance is induced by compound II than Compound I. We also identified the accumulation of compounds-induced reactive oxygen species during the treatment. This resulted in caspase 3/7 activation in turn induced apoptosis. In summary, the screening of Compound I and II molecules for heterogeneity, apoptosis, reactive oxygen species and caspase has identified compound II as promising anti-osteosarcoma cancer agent. Compound II could be a promising lead compound for future antitumor agent development. PMID- 29275158 TI - In vivo and in vitro ADMET profiling and in vivo pharmacodynamic investigations of a selective alpha7 nicotinic acetylcholine receptor agonist with a spirocyclic Delta2-isoxazoline molecular skeleton. AB - (+/-)-3-Methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate (+/ )-1 was previously characterized as the most selective agonist at alpha7 neuronal nicotinic acetylcholine receptors in a series of spirocyclic quinuclidinyl-Delta2 isoxazoline derivatives. In this study, we performed different in vitro biological assays aimed at characterizing the ADMET properties of (+/-)-1. Then, we tested the compound in vivo in behavioral studies including classical novel object recognition and inhibitory avoidance tests in the rat, and a spatial memory assay in zebrafish involving a rapid T-maze task. The results indicated an overall favorable profile for (+/-)-1 in view of potential therapeutic applications targeting the central nervous system. PMID- 29275159 TI - Anti-photoaging effects of chitosan oligosaccharide in ultraviolet-irradiated hairless mouse skin. AB - Skin photoaging (SP) is a premature skin-aging damage after repeated exposure to ultraviolet (UV) radiation, mainly characterized by oxidative stress and inflammatory disequilibrium, which makes skin show the typical symptoms of photoaging such as coarse wrinkling, dryness, irregular pigmentation and laxity. Chitosan oligosaccharide (COS), a natural polysaccharide with good humectant property, is the depolymerized product of chitosan with various biological activities, among which the antioxidant and anti-inflammatory effects have been frequently reported in recent years. However, no existing invivo study indicates whether COS has direct protective effect on UV-induced SP. In the current research, we investigated the potential preventive effect of COS against UV caused damage in hairless mouse dorsal skin. The data showed that COS, by topical application after each UV-radiation for 10weeks, effectively inhibited the undesirable changes on the skin induced by UV. To be specific, COS obviously alleviated the macroscopic and histopathological damages of mice skin, via mitigating the disrupted collagenous fibers, as well as improving the relative content of type I collagen and the amount of total collagen. Furthermore, COS effectively inhibited the levels of pro-inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6, and markedly improved the activities of antioxidant enzymes (SOD, GSH-Px, CAT), as well as the content of skin hydroxyproline and moisture. These findings demonstrated that this natural polysaccharide attenuated UV induced SP, at least in part, by virtue of favorable regulation of antioxidant and anti-inflammatory status, which presumably worked in concert to maintain the morphology and level of dermal collagen. PMID- 29275160 TI - Role of the peripheral innate immune system in the development of Alzheimer's disease. AB - Alzheimer's disease is one of the most devastating neurodegenerative diseases. The exact cause of the disease is still not known although many scientists believe in the beta amyloid hypothesis which states that the accumulation of the amyloid peptide beta (Abeta) in brain is the initial cause which consequently leads to pathological neuroinflammation. However, it was recently shown that Abeta may have an important role in defending the brain against infections. Thus, the balance between positive and negative impact of Abeta may determine disease progression. Microglia in the brain are innate immune cells, and brain-initiated inflammatory responses reflected in the periphery suggests that Alzheimer's disease is to some extent also a systemic inflammatory disease. Greater permeability of the blood brain barrier facilitates the transport of peripheral immune cells to the brain and vice versa so that a vicious circle originating on the periphery may contribute to the development of overt clinical AD. Persistent inflammatory challenges by pathogens in the periphery, increasing with age, may also contribute to the central propagation of the pathological changes seen clinically. Therefore, the activation status of peripheral innate immune cells may represent an early biomarker of the upcoming impact on the brain. The modulation of these cells may thus become a useful mechanism for modifying disease progression. PMID- 29275162 TI - Vesicle release site organization at synaptic active zones. AB - Information transfer between nerve cells (neurons) forms the basis of behavior, emotion, and survival. Signal transduction from one neuron to another occurs at synapses, and relies on both electrical and chemical signal propagation. At chemical synapses, incoming electrical action potentials trigger the release of chemical neurotransmitters that are sensed by the connected cell and here reconverted to an electrical signal. The presynaptic conversion of an electrical to a chemical signal is an energy demanding, highly regulated process that relies on a complex, evolutionarily conserved molecular machinery. Here, we review the biophysical characteristics of this process, the current knowledge of the molecules operating in this reaction and genetic specializations that may have evolved to shape inter-neuronal signaling. PMID- 29275163 TI - CAST: Its molecular structure and phosphorylation-dependent regulation of presynaptic plasticity. AB - Our brain functions rely on sophisticated communication between synapses in the nervous system. Most synapses utilize a specialized submembranous structure, the so-called 'active zone', for the efficient transmission of chemical signals. The presynaptic active zone plays pivotal roles in the precise regulation of neurotransmitter release from the nerve terminals in a temporally and spatially coordinated manner. During the last two decades, several active zone-specific proteins have been isolated and characterized, including Bassoon, Piccolo/Aczonin, RIM, Munc13-1, ELKS, and CAST. The CAST/ELKS family is capable of potent direct interactions with other active zone proteins, forming a large protein complex that seems to be a molecular basis for electron density in the presynaptic active zone. The molecular details of the integrity of the active zone been well studied, however, we are just beginning to understanding its physiological significance in higher brain functions such as learning and memory, emotion, and consciousness. Focusing on the CAST/ELKS protein family, this review describes their biochemical properties, physiological functions in brain areas such as the hippocampus, and the significance of CAST phosphorylation in presynaptic short-term plasticity. PMID- 29275164 TI - Genome-wide Analysis of Transcriptional Variability in a Large Maize-Teosinte Population. AB - Gene expression regulation plays an important role in controlling plant phenotypes and adaptation. Here, we report a comprehensive assessment of gene expression variation through the transcriptome analyses of a large maize-teosinte experimental population. Genome-wide mapping identified 25 660 expression quantitative trait loci (eQTL) for 17 311 genes, capturing an unprecedented range of expression variation. We found that local eQTL were more frequently mapped to adjacent genes, displaying a mode of expression piggybacking, which consequently created co-regulated gene clusters. Genes within the co-regulated gene clusters tend to have relevant functions and shared chromatin modifications. Distant eQTL formed 125 significant distant eQTL hotspots with their targets significantly enriched in specific functional categories. By integrating different sources of information, we identified putative trans- regulators for a variety of metabolic pathways. We demonstrated that the bHLH transcription factor R1 and hexokinase HEX9 might act as crucial regulators for flavonoid biosynthesis and glycolysis, respectively. Moreover, we showed that domestication or improvement has significantly affected global gene expression, with many genes targeted by selection. Of particular interest, the Bx genes for benzoxazinoid biosynthesis may have undergone coordinated cis-regulatory divergence between maize and teosinte, and a transposon insertion that inactivates Bx12 was under strong selection as maize spread into temperate environments with a distinct herbivore community. PMID- 29275161 TI - Aging, inflammation and the environment. AB - The aging process is driven by interrelated mechanisms that lead to the emergence of characteristic phenotypes that include changes in body composition, energy production and utilization imbalance, homeostatic dysregulation, and neurodegeneration and loss of neuroplasticity. Mainstream theories of aging all recognize that the aging phenotypes result from an imbalance between stressors and stress buffering mechanisms and a resultant loss of compensatory reserve leading to accumulation of unrepaired damage. This in turn results in increased disease susceptibility, reduced functional reserve, reduced healing capacity and stress resistance, unstable health and finally failure to thrive. The resultant physical and cognitive decline that culminates with the frailty syndrome is a tipping point of healthspan and implies a high risk of system decompensation and death. Preserving physical and cognitive function is the main focus of geriatric and gerontological research, but it is important to recognize that accomplishing this goal requires a profound understanding of the molecular, cellular and physiological mechanisms that ultimately determine functional changes. In this context, the proinflammatory state of aging plays a major role. Longitudinal studies have shown that with aging most individuals tend to develop a chronic low grade proinflammatory state, and that such a state is a strong risk factor for multimorbidity, physical and cognitive disability, frailty and death. A number of environmental factors may play an important role in modifying the proinflammatory state. We explore processes and mechanisms of aging that affect human biology and the possible links of inflammation and the environment to aging, especially those related to metabolism. We point out that longitudinal studies with a life course approach are needed to gain further mechanistic insight on the processes that lead to functional decline with aging, and the role played in this process by inflammation and environmental challenges. PMID- 29275165 TI - Oximes: Unrecognized Chameleons in General and Specialized Plant Metabolism. AB - Oximes (R1R2C=NOH) are nitrogen-containing chemical constituents that are formed in species representing all kingdoms of life. In plants, oximes are positioned at important metabolic bifurcation points between general and specialized metabolism. The majority of plant oximes are amino acid-derived metabolites formed by the action of a cytochrome P450 from the CYP79 family. Auxin, cyanogenic glucosides, glucosinolates, and a number of other bioactive specialized metabolites including volatiles are produced from oximes. Oximes with the E configuration have high biological activity compared with Z-oximes. Oximes or their derivatives have been demonstrated or proposed to play roles in growth regulation, plant defense, pollinator attraction, and plant communication with the surrounding environment. In addition, oxime-derived products may serve as quenchers of reactive oxygen species and storage compounds for reduced nitrogen that may be released on demand by the activation of endogenous turnover pathways. As highly bioactive molecules, chemically synthesized oximes have found versatile uses in many sectors of society, especially in the agro- and medical sectors. This review provides an update on the structural diversity, occurrence, and biosynthesis of oximes in plants and discusses their role as key players in plant general and specialized metabolism. PMID- 29275166 TI - Functional Divergence between Subgenomes and Gene Pairs after Whole Genome Duplications. AB - Gene loss following whole genome duplication (WGD) is often biased, with one subgenome retaining more ancestral genes and the other sustaining more gene deletions. While bias toward the greater expression of gene copies on one subgenome can explain bias in gene loss, this raises the question to what drives differences in gene expression levels between subgenomes. Differences in chromatin modifications and epigenetic markers between subgenomes in several model species are now being identified, providing an explanation for bias in gene expression between subgenomes. WGDs can be classified into duplications with higher, biased gene loss and bias in gene expression between subgenomes versus those with lower, unbiased rates of gene loss and an absence of detectable bias between subgenomes; however, the originally proposed link between these two classes and whether WGD results from an allo- or autopolyploid event is inconsistent with recent data from the allopolyploid Capsella bursa-pastoris. The gene balance hypothesis can explain bias in the functional categories of genes retained following WGD, the difference in gene loss rates between unbiased and biased WGDs, and how plant genomes have avoided being overrun with genes encoding dose-sensitive subunits of multiprotein complexes. Comparisons of gene expression patterns between retained transcription factor pairs in maize suggest the high degree of retention for WGD-derived pairs of transcription factors may instead be explained by the older duplication-degeneration-complementation model. PMID- 29275167 TI - Abscisic Acid Signaling Inhibits Brassinosteroid Signaling through Dampening the Dephosphorylation of BIN2 by ABI1 and ABI2. AB - Abscisic acid (ABA) and brassinosteroid (BR) antagonistically regulate many aspects of plant growth and development. Previous physiological studies have revealed that the inhibition of BR signaling by ABA is largely dependent on ABI1 and ABI2. However, the genetic and molecular basis of how ABI1 and ABI2 are involved in inhibiting BR signaling remains unclear. Although it is known that in the BR signaling pathway the ABA-BR crosstalk occurs in the downstream of BR receptor complex but upstream of BIN2 kinase, a negative regulator of BR signaling, the component that acts as the hub to directly mediate their crosstalk remains a big mystery. Here, we found that ABI1 and ABI2 interact with and dephosphorylate BIN2 to regulate its activity toward the phosphorylation of BES1. By in vitro mimicking ABA signal transduction, we found that ABA can promote BIN2 phosphorylation by inhibiting ABI2 through ABA receptors. RNA-sequencing analysis further demonstrated that ABA inhibits BR signaling through the ABA primary signaling components, including its receptors and ABI2, and that ABA and GSK3s co regulate a common set of stress-responsive genes. Because BIN2 can interact with and phosphorylate SnRK2s to activate its kinase activity, our study also reveals there is a module of PP2Cs-BIN2-SnRK2s in the ABA signaling pathway. Collectively, these findings provide significant insights into how plants balance growth and survival by coordinately regulating the growth-promoting signaling pathway and stress responses under abiotic stresses. PMID- 29275169 TI - Testosterone induces hyporesponsiveness by interfering with IP3 receptors in guinea pig airway smooth muscle. AB - Asthma symptoms have been associated with sex steroids. During childhood, this illness seems more frequent in boys than in girls and this tendency reverts in puberty when it is more severe in women. Testosterone (TES), at supraphysiological concentrations, relaxed pre-contracted airway smooth muscle, but its effects at physiological concentrations have not been thoroughly studied. We explored this possibility in guinea pig tracheal smooth muscle. In myocytes TES (10 nM) abolished carbachol (CCh)-induced intracellular Ca2+ concentration ([Ca2+]i) increment. Ca2+ responses to ATP were partially modified by TES while histamine's were not. These results indicate that inositol 1,4,5-trisphosphate (IP3) signaling pathway might be involved. Photolysis of caged-IP3 increased [Ca2+]i and TES abolished this effect. TES diminished reactivity of the smooth muscle to CCh and this effect was non-genomic since it was unchanged by flutamide. In tracheal smooth muscle, mRNA for each IP3 receptor (ITPR) isoform was found and, by immunofluorescence, ITPR1 and ITPR3 seems to be the main isoforms observed while ITPR2 was less prominent. Comparing the amino acid sequence of ITPR1 and the sequence of the TES binding site on the androgen receptor, we found that they share a short sequence. This domain could be responsible for the TES binding to the ITPR1 and probably for its blocking effect. We conclude that TES modifies ITPR1 function in airway smooth muscle, turning this tissue less reactive to contractile agonists that act through PLCbeta-IP3 signaling cascade. These results might be related to the low asthma prevalence in males from puberty to adulthood. PMID- 29275168 TI - Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism. AB - Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping, as well as bioinformatics analysis were performed. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C [p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*], c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygous mutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations (p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings from another family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patients from 31 unrelated families with TG mutations identified in our present and previous studies. Our observation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutations were identified, 33 of the 96 TG alleles encoded the change p.R277*. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence of truncated TG proteins and/or missense mutations located within its ACHE-like domain. PMID- 29275170 TI - Complete rehabilitation of compromised full dentitions with adhesively bonded all ceramic single-tooth restorations: Long-term outcome in patients with and without amelogenesis imperfecta. AB - OBJECTIVES: This clinical follow-up evaluated the long-term outcome of full-mouth rehabilitations with adhesively bonded all-ceramic restorations in patients suffering from amelogenesis imperfecta (AI) or affected by extensive tooth wear including a loss of the vertical dimension of occlusion. MATERIALS AND METHODS: Included for evaluation were all patients treated with adhesively bonded monolithic single-tooth restorations made of silicate or lithium disilicate ceramics; allowing a maximum four missing teeth and a facial feldspathic veneering of LDS anterior crowns. After treatment, patients have been enrolled in a recall program for dental check-ups including quality assessment of the restorations. Patients answered the oral health impact profile (OHIP-14) at their last visit. RESULTS: Seventeen patients (mean age = 35 +/- 18 years) were observed up to 16.5 years (mean: 6.2 +/- 3.8 years). 12 out of 450 restorations failed due to core fracture (n = 7), tooth fracture (n = 2), one secondary caries, one chip-off grade 3, and one fixed dental prosthesis due to discomfort. The overall mean survival rate of the single-tooth restorations was estimated 99.4% at 5 and 91.4% at 10 years. The overall mean success rate was estimated 92.6% at 5 and 81.4% at 10 years, mainly due to chip-offs and crack formation (27 out of 31 relative failures). The mean annual failure rates (AFR) range between 1.5 and 2% over the years, but non-AI patients were affected more frequently by early technical complications in the facial veneering of anteriors, resulting in an AFR ranging between 5.2 and 4%. Quality assessment revealed stable color, form and marginal integrity in all patients up to ten years. The distribution of OHIP values is comparable to the representative sample of healthy patients. CONCLUSION: Adhesively bonded single-tooth restorations provided a high clinical quality in the long-run. However, while the survival and success were excellent in AI patients, restorations in non-AI patients were affected by a higher complication rate, likely related to a higher risk profile due to a history of bruxism and tooth wear. PMID- 29275171 TI - A retrospective clinical study on the longevity of posterior Class II cast gold inlays/onlays. AB - OBJECTIVE: To investigate the longevity and reasons for failure of posterior cast Class II gold inlays and onlays among a group of Norwegian adults. The term inlay was used for both inlays and onlays. METHODS: A cohort of 138 patients regularly attending a general practice for check-up were examined in 2016. The patients had a total of 391 posterior gold inlays placed in the period 1970-2015. The inlays were categorized as successful, repaired or failed. Reasons for failure were classified as either "secondary caries", "fractures", "lost inlay" or "other". Participation was voluntary and no compensation was given. RESULTS: The mean age of the patients at placement was 50.8 years (SD: 12.7 yr). Most gold inlays were placed in molars (85.9%) and 14.1% in premolars; 49.4% of the inlays were in the maxilla and the 50.6% in the mandibula. Average length of follow-up was 11.6 years (range: 1-46 years, SD: 7.9); 82.9% were classified as successful, 10.7% as repaired and 6.4% as failed. Reasons for failure were secondary caries (41.3%), lost inlay (25.4%), fractures (23.8%) and other (9.5%). Mean annual failure rate (AFR) was 1.69% for repaired and failed inlays combined. However, if repaired inlays were considered as success, the AFR decreased to 0.57%. Multi-level Cox regression analyses identified low age of the patient and high number of restored surfaces as risk factors for failure. CONCLUSION: The present retrospective clinical study demonstrated an acceptable annual failure rate for Class II cast gold inlays. PMID- 29275172 TI - A novel liquid chromatography/mass spectrometry method for determination of neurotransmitters in brain tissue: Application to human tauopathies. AB - Neurotransmitters, small molecules widely distributed in the central nervous system are essential in transmitting electrical signals across neurons via chemical communication. Dysregulation of these chemical signaling molecules is linked to numerous neurological diseases including tauopathies. In this study, a precise and reliable liquid chromatography method was established with tandem mass spectrometry detection for the simultaneous determination of aspartic acid, asparagine, glutamic acid, glutamine, gamma-aminobutyric acid, N-acetyl-l aspartic acid, pyroglutamic acid, acetylcholine and choline in human brain tissue. The method was successfully applied to the analysis of human brain tissues from three different tauopathies; corticobasal degeneration, progressive supranuclear palsy and parkinsonism-dementia complex of Guam. Neurotransmitters were analyzed on ultra-high performance chromatography (UHPLC) using an ethylene bridged hybrid amide column coupled with tandem mass spectrometry (MS/MS). Identification and quantification of neurotransmitters was carried out by ESI+ mass spectrometry detection. We optimized sample preparation to achieve simple and fast extraction of all nine analytes. Our method exhibited an excellent linearity for all analytes (all coefficients of determination >0.99), with inter day and intra-day precision yielding relative standard deviations 3.2%-11.2% and an accuracy was in range of 92.6%-104.3%. The present study, using the above method, is the first to demonstrate significant alterations of brain neurotransmitters caused by pathological processes in the brain tissues of patient with three different tauopathies. PMID- 29275173 TI - Enhancing Evolutionary Couplings with Deep Convolutional Neural Networks. AB - While genes are defined by sequence, in biological systems a protein's function is largely determined by its three-dimensional structure. Evolutionary information embedded within multiple sequence alignments provides a rich source of data for inferring structural constraints on macromolecules. Still, many proteins of interest lack sufficient numbers of related sequences, leading to noisy, error-prone residue-residue contact predictions. Here we introduce DeepContact, a convolutional neural network (CNN)-based approach that discovers co-evolutionary motifs and leverages these patterns to enable accurate inference of contact probabilities, particularly when few related sequences are available. DeepContact significantly improves performance over previous methods, including in the CASP12 blind contact prediction task where we achieved top performance with another CNN-based approach. Moreover, our tool converts hard-to-interpret coupling scores into probabilities, moving the field toward a consistent metric to assess contact prediction across diverse proteins. Through substantially improving the precision-recall behavior of contact prediction, DeepContact suggests we are near a paradigm shift in template-free modeling for protein structure prediction. PMID- 29275174 TI - Postanoxic alpha, theta or alpha-theta coma: Clinical setting and neurological outcome. AB - AIM: The aim of this study was to determine the prognosis of 26 consecutive adults with alpha coma (AC), theta coma (TC) or alpha-theta coma (ATC) following CRA and to describe the clinical setting and EEG features of these patients. METHODS: We retrospective analyzed a prospectively collected cohort of adult patients diagnosed as having AC, TC or ATC after CRA between January 2008 and June 2016. None of patients included in this analysis underwent therapeutic hypothermia (TH). Neurological outcome was expressed as the best score 6 months after CRA using the five-point Glasgow-Pisttsburgh Cerebral Performance Categories (CPC) RESULTS: Twenty-six patients were identified with a diagnosis of postanoxic AC, TC or ATC coma. There were 20 (77%) men and 6 (23%) women. The mean age was 63 +/- 16 years. The most frequent EEG pattern was TC (21 patients, 80%), followed by AC (3 patients, 12%) and ATC (2 patients, 8%). The cardiac rhythm as primary origin of the CRA was ventricular fibrillation (VF) in 16 patients (61.5%), asystole in 8 patients (34.6%) and ventricular tachycardia (VT) in one patient (3.8%). The presence of EEG reactivity was present in 8 patients (30%). The mortality rate was 85%. Of the 4 surviving patients, two (3.8%) had moderate disability (CPC 2), one (3.8%) had severe disability (CPC 3) and one (3.8%) reached a good recovery. The age was significantly lower in survivors 46.2 +/- 10.8 versus nonsurvivors 63.3 +/- 15.5 (p = 0.04). There was increased association of EEG reactivity with survival (p = 0.07). CONCLUSION: Hypoxic ischemic AC, TC and ATC are associated with a poor prognosis and a high rate of mortality. In younger patients with AC, TC and ATC and incomplete forms showing reactivity on the EEG, there is a greater probability of clinical recovery. PMID- 29275175 TI - Increasing compositional backscattered electron contrast in scanning electron microscopy. AB - A method for increasing compositional or material contrast of a standard semiconductor BSE detector in a scanning electron microscope (SEM) by compensation of the topographic contrast component is proposed. Compensation is based on the physical properties of backscattered electron emission and topography information of the specimen's surface. Three analytical and semi empirical compensation algorithms employing different physical models and approximations are implemented and compared to conventional BSE signals to show the effectivity of the proposed compensation approach. PMID- 29275176 TI - CXCL16/ROCK1 signaling pathway exacerbates acute kidney injury induced by ischemia-reperfusion. AB - Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) resulting in an abrupt deterioration of kidney function. CXC chemokine ligand 16 (CXCL16) contributes significantly to the pathogenesis of renal injury. However, the signaling pathway mechanisms of CXCL16 in IRI-induced AKI remains obscured. In this study, we examined the role of the CXCL16/ Rho Associated Coiled-Coil Containing Protein Kinase-1 (ROCK1) signaling pathway in AKI induced by IRI. In vivo, CXCL16 was induced markedly after IRI. Mice treated with anti CXCL16 antibody displayed less severe renal dysfunction and tubular injury in response to IRI compared with vehicle-treated mice. Inhibition of CXCL16 substantially reduced apoptotic cells and suppresses caspase-3 activation in the kidneys of mice following IRI. Additionally, CXCL16 inhibition profoundly decreased the production of TNF-alpha, IL-1beta and IL-6 in the kidneys of mice post IRI. Furthermore, the level of ROCK1 protein was upregulated in the kidney in response to IRI, an effect that was abolished by CXCL16 inhibitor. Finally, treatment with Y-27632 (a ROCK1 inhibitor) attenuated deterioration of renal function and tubular damage of mice after IRI. Administration of Y-27632 ameliorated apoptosis in the IRI-treated kidneys of mice. In injured HK-2 cells, CXCL16 activated ROCK1 resulting in the upregulation of caspase-3 protein and pro inflammatory molecules, which was abolished by Y-27632. In summary, our findings demonstrate that CXCL16/ROCK1 signaling pathway may play an important role in the pathogenesis of IRI-induced AKI. PMID- 29275177 TI - Synergistic therapeutic effect of diethylstilbestrol and CX-4945 in human acute T lymphocytic leukemia cells. AB - Human acute T-lymphocytic leukemia (T-ALL) is one of the most commonly diagnosed hematological disorders, and is characterized by poor prognosis and survival rate. Despite the development of new therapeutic approaches, leukemia treatment options remain limited. In this study, we investigated the immunosuppressive and anti-proliferative effects of the synthetic estrogen diethylstilbestrol (DES), both alone and combined with the casein kinase 2 (CK2) inhibitor CX-4945. Our results indicated that DES induced caspase-dependent apoptosis in a human T-ALL cell line (Jurkat cells), while exerting no significant cytotoxicity in normal peripheral blood mononuclear cells (PBMCs). Phytohaemagglutinin and phorbol 12 myristate 13-acetate induced interleukin (IL)-2 production and activation of NF kappaB signaling pathways, which were both inhibited by DES. Moreover, DES exerted synergistic effects with CX-4945 on proliferation and IL-2 production in Jurkat cells. Our results demonstrated that DES exerts anti-proliferative and immunosuppressive effects through inhibition of CK2 and the NF-kappaB signaling pathway in human T-ALL Jurkat cells. PMID- 29275178 TI - Central administration of coagonist of GLP-1 and glucagon receptors improves dyslipidemia. AB - Coagonists of Glucagon-like peptide-1 (GLP-1) and glucagon receptors are under clinical investigation for treatment of obesity associated with diabetes. In addition to their role in glucose homeostasis, GLP-1 and glucagon modulate lipid metabolism. In this study, we have investigated the role of central GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) activation in regulation of lipid metabolism in cholesterol-fed hamsters. Hamsters were treated with coagonist alone (0.3 MUg) or in combination with either GLP-1R antagonist (0.15 MUg) or GCGR antagonist (0.3 MUg) for 4 weeks by intracerebroventricular route (icv). A pair-fed control to coagonist was included in the experiment. In a separate experiment, vagotomized hamsters were treated with coagonist (0.3 MUg) for four weeks. At the end of the treatment, plasma and hepatic lipids, bile homeostasis, and hepatic gene expression were determined. Coagonist treatment caused a reduction in plasma and liver lipids, and reduced triglyceride absorption from intestine. Also, hepatic triglyceride secretion, bile flow, and biliary cholesterol excretion were increased by the coagonist treatment. Coagonist treatment exhibited increased energy expenditure and reduced the expression of SREBP-1C, HMG-CoA reductase, SCD-1, FAS and ACC in liver. Increase in the expression of LDLR, ACOX1, CPT-1, PPAR-alpha, CYP7A1, ABCA1 and ABCB11 was also observed in liver. The effect of coagonist on lipids was partially blocked by either GLP-1R or GCGR antagonist. Coadministration of GLP-1R antagonist blocked the effect of coagonist on bile flow, while effect of coagonist on biliary cholesterol was blocked by co-administration of GCGR antagonist. Coagonist did not affect lipid metabolism in vagotomized hamsters. It appears that central administration of coagonist reduces dyslipidemia by activation of GLP-1R and GCGR, independent of its anorectic effect. PMID- 29275179 TI - Haemato-protective influence of dietary fenugreek (Trigonella foenum-graecum L.) seeds is potentiated by onion (Allium cepa L.) in streptozotocin-induced diabetic rats. AB - We have recently reported the beneficial modulation of metabolic abnormalities and oxidative stress in diabetic rats by dietary fenugreek seeds and onion. This investigation evaluated the protective influence of dietary fenugreek seeds (100 g kg-1) and onion (30 g kg-1) on erythrocytes of streptozotocin-induced diabetic rats, through modulation of reduced haematological indices and antisickling potency. This study also evaluated the altered erythrocyte membrane lipid profile and beneficial countering of increased lipid peroxidation, osmotic fragility, along with reduced membrane fluidity and deformability, nitric oxide production and echinocyte formation. Dietary fenugreek seeds and onion appeared to counter the deformity and fragility of erythrocytes partially in diabetic rats by their antioxidant potential and hypocholesterolemic property. The antisickling potency of these spices was accomplished by a substantial decrease in echinocyte population and AGEs in diabetic rats. Further insight into the factors that might have reduced the fluidity of erythrocytes in diabetic rats revealed changes in the cholesterol: phospholipid ratio, fatty acid profile, and activities of membrane-bound enzymes. Dietary fenugreek seeds and onion offered a beneficial protective effect to the red blood cells, the effect being higher with fenugreek + onion. This is the first report on the hemato-protective influence of a nutraceutical food component in diabetic situation. PMID- 29275180 TI - Effect of clozapine dose and concentration on fasting concentration of appetite regulating peptides. AB - The aim of this study is to analyze whether clozapine serum concentration may affect fasting serum levels of several appetite regulating peptides: CART, PYY(1 36), NPY, AgRP, des-acylated ghrelin, leptin and obestatin. Serum concentration of clozapine and fasting serum levels of des-acylated ghrelin, neuropeptide Y (NPY), agouti-related protein (AgRP), peptide YY (PYY(1-36)), cocaine- and amphetamine-regulated transcript (CART), leptin and obestatin were measured in 30 subjects with schizophrenia on clozapine monotherapy. Leptin concentration was negatively correlated with clozapine dose (r = -0.53, p = 0.002), while NPY concentration was negatively correlated with clozapine concentration (r = -0.55, p = 0.01). Correlations with other peptides were not significant. We cannot conclude that serum concentration of clozapine is directly associated with increased or decreased level of appetite-regulating peptides. PMID- 29275181 TI - Crystal structure of cystathionine beta-synthase from honeybee Apis mellifera. AB - Cystathionine beta-synthase (CBS), the key enzyme in the transsulfuration pathway, links methionine metabolism to the biosynthesis of cellular redox controlling molecules. CBS catalyzes the pyridoxal-5'-phosphate-dependent condensation of serine and homocysteine to form cystathionine, which is subsequently converted into cysteine. Besides maintaining cellular sulfur amino acid homeostasis, CBS also catalyzes multiple hydrogen sulfide-generating reactions using cysteine and homocysteine as substrates. In mammals, CBS is activated by S-adenosylmethionine (AdoMet), where it can adopt two different conformations (basal and activated), but exists as a unique highly active species in fruit fly Drosophila melanogaster. Here we present the crystal structure of CBS from honeybey Apis mellifera, which shows a constitutively active dimeric species and let explain why the enzyme is not allosterically regulated by AdoMet. In addition, comparison of available CBS structures unveils a substrate-induced closure of the catalytic cavity, which in humans is affected by the AdoMet dependent regulation and likely impaired by the homocystinuria causing mutation T191M. PMID- 29275182 TI - The impact of HIV-1 within-host evolution on transmission dynamics. AB - The adaptive potential of HIV-1 is a vital mechanism to evade host immune responses and antiviral treatment. However, high evolutionary rates during persistent infection can impair transmission efficiency and alter disease progression in the new host, resulting in a delicate trade-off between within host virulence and between-host infectiousness. This trade-off is visible in the disparity in evolutionary rates at within-host and between-host levels, and preferential transmission of ancestral donor viruses. Understanding the impact of within-host evolution for epidemiological studies is essential for the design of preventive and therapeutic measures. Herein, we review recent theoretical and experimental work that generated new insights into the complex link between within-host evolution and between-host fitness, revealing temporal and selective processes underlying the structure and dynamics of HIV-1 transmission. PMID- 29275183 TI - Endocrine disruptors in soil: Effects of bisphenol A on gene expression of the earthworm Eisenia fetida. AB - : Xenobiotics such as bisphenol A (BPA), are present in biosolids, which are applied as organic fertilizers in agricultural fields. Their effects on soil life have been poorly assessed, and this is particularly important in the case of earthworms, which represent the main animal biomass in this medium. In the present work we study the impacts of BPA on gene expression of Eisenia fetida, a widely used ecotoxicological model. Chronic soil tests and acute contact tests were performed, and gene expression was analyzed in total tissue and in masculine reproductive organs of the earthworms. The genes studied in this research played a role in endocrine pathways, detoxification mechanisms, stress response, epigenetics, and genotoxicity. Most of the genes were identified for the first time, providing potentially useful biomarkers for future assessments. For chronic exposures, no changes were detected in whole-body tissue; however, masculine reproductive organs showed changes in the expression of genes related to endocrine function (EcR, MAPR, AdipoR), epigenetic mechanisms (DNMTs), genotoxicity (PARP1), and stress responses (HSC70 4). For acute exposures, the expression of one epigenetic-related gene was altered for both whole-body tissues and male reproductive organs (Piwi2). Further changes were detected for whole body tissues involved in detoxification (Metallothionein), stress (HSC70 4), and genotoxicity (PARP1) mechanisms. Acute exposure effects were also tested in whole body tissues of juveniles, showing changes in the expression of Metallothionein and Piwi2. The molecular changes found in the analyzed earthworms indicate that exposure to BPA may have negative implications in their populations. Particularly interesting are the alterations related to epigenetic mechanisms, which suggest that future generations may be impacted. This study is the first to evaluate the molecular effects of BPA on soil organisms, and further assays will be necessary to better characterize the true environmental repercussions. CAPSULE: Levels of gene expression in total-body tissues and masculine reproductive organs were analyzed in earthworms after exposure to bisphenol A and we observed associated changes in detoxification, endocrine, epigenetic, genotoxic and stress pathways. PMID- 29275184 TI - Analysis of variant rs3794087 in SLC1A2 and Parkinson's disease in a Chinese Han population: A case-control study and meta-analysis. AB - Recently, a genome-wide association study of a Caucasian population identified variant rs3794087 in intron 4 of the SLC1A2 gene, which may increase the risk of essential tremor (ET). Considering the overlap in the pathological features and clinical manifestations of ET and Parkinson's disease (PD), several studies on the association between rs3794087 and PD were later performed in other populations. However, results about the role of SLC1A2 rs3794087 in PD were inconsistent. We thus performed a case-control study in a Chinese Han population to investigate the role of SLC1A2 rs3794087 in Chinese patients with PD. Overall, 1096 subjects comprising 546 patients with PD and 550 control subjects were genotyped. A meta-analysis of the data obtained from the current sample-set and those available from prior studies was performed. Taking all patients and controls into consideration, rs3794087 was found to have no significant effect on PD susceptibility in analyses using allelic (p = .486), genotype (p = .736), additive (p = .764), dominant (p = .438), and recessive (p = .878) genetic models. The results of the meta-analysis were in agreement with our findings (the pooled OR was 0.97 and 95% CI = 0.85, 1.10). Our study suggested that rs3794087 does not lead to an increased risk of PD in the Chinese Han population. The role of single nucleotide polymorphism rs3794087 in the development of PD remains to be further studied. PMID- 29275185 TI - Characteristics of gray matter morphological change in Parkinson's disease patients with semantic abstract reasoning deficits. AB - BACKGROUND: Semantic abstract reasoning(SAR) is an important executive domain that is involved in semantic information processing and enables one to make sense of the attributes of objects, facts and concepts in the world. We sought to investigate whether Parkinson's disease subjects(PDs) have difficulty in SAR and to examine the associated pattern of gray matter morphological changes. METHODS: Eighty-six PDs and 30 healthy controls were enrolled. PDs were grouped into PD subjects with Similarities preservation(PDSP, n = 62) and PD subjects with Similarities impairment(PDSI, n = 24)according to their performance on the Similarities subtest of the Wechsler Adult Intelligence Scale. Brain structural images were captured with a 3T MRI scanner. Surface-based investigation of cortical thickness and automated segmentation of deep gray matter were conducted using FreeSurfer software. RESULTS: PDs performed notably worse on the Similarities test than controls(F = 13.56, P < 0.001).In the PDSI group, cortical thinning associated with Similarities scores was found in the left superior frontal, left superior parietal and left rostral middle frontal regions. Notable atrophy of the bilateral hippocampi was observed, but only the right hippocampus volume was positively correlated with the Similarities scores of the PDSI group. DISCUSSION: PDs have difficulty in SAR, and this limitation may be associated with impaired conceptual abstraction and generalization along with semantic memory deficits. Cortical thinning in the left frontal and parietal regions and atrophy in the right hippocampus may explain these impairments among Chinese PDs. PMID- 29275186 TI - Neuroimaging of person perception: A social-visual interface. AB - The visual system is able to extract an enormous amount of socially relevant information from the face, including social categories, personality traits, and emotion. While facial features may be directly tied to certain perceptions, emerging research suggests that top-down social cognitive factors (e.g., stereotypes, social-conceptual knowledge, prejudice) considerably influence and shape the perceptual process. The rapid integration of higher-order social cognitive processes into visual perception can give rise to systematic biases in face perception and may potentially act as a mediating factor for intergroup behavioral and evaluative biases. Drawing on neuroimaging evidence, we review the ways that top-down social cognitive factors shape visual perception of facial features. This emerging work in social and affective neuroscience builds upon work on predictive coding and perceptual priors in cognitive neuroscience and visual cognition, suggesting domain-general mechanisms that underlie a social visual interface through which social cognition affects visual perception. PMID- 29275187 TI - Illuminating the covert mission of mononuclear phagocytes in their regional niches. AB - Monocytes, dendritic cells (DCs) and macrophages have been classically categorized into the mononuclear phagocyte system (MPS) based on their similar functional and phenotypic characteristics. While an increasing amount of research has revealed substantial ontogenic and functional differences among these cells, the reasons behind their heterogeneity and strategic positioning in specific niches throughout the body are yet to be fully elucidated. In this review, we outline how recent advances in intravital imaging studies have dissected this phenomenon and have allowed us to appreciate how MPS cells exploit their regional niches to specialize and maximize their functional properties. Understanding their cellular behavior in each of their specialized microenvironment will eventually allow us to target specific cells and their behavioral patterns for improved vaccine and therapeutic purposes. PMID- 29275188 TI - The effects of temperature and food availability on growth, flexibility in metabolic rates and their relationships in juvenile common carp. AB - Flexibility in phenotypic traits can allow organisms to handle environmental changes. However, the ecological consequences of flexibility in metabolic rates are poorly understood. Here, we investigated whether the links between growth and flexibility in metabolic rates vary between two temperatures. Common carp Cyprinus carpio were raised in three temperature treatments [the 18 degrees C, 28 degrees C and 28 degrees C-food control (28 degrees C-FC)] and fed to satiation of receiving food either once or twice daily for 4weeks. The morphology and metabolic rates (standard metabolic rate, SMR; maximum metabolic rate, MMR) were measured at the beginning and end of the experiment. The mean total food ingested by fish in the 28 degrees C-FC treatment was the same as that by fish in the 18 degrees C treatment at each food availability. The final SMR (not MMR and aerobic scope, AS=MMR-SMR) increased more in the 28 degrees C and 28 degrees C-FC treatments with twice-daily feedings than once-daily feedings. Fish in the 28 degrees C treatment had a higher specific growth rate (SGR) than fish in the 28 degrees C-FC and 18 degrees C treatments at both food availabilities. However, no differences in feeding efficiency (FE) were found among the three treatments in fish fed twice daily. The flexibility in SMR was related to individual differences in SGR, not with food intake and FE; individuals who increased their SMR more had a smaller growth performance with twice-daily feedings at 28 degrees C, but it did not exist at 18 degrees C. Flexibility in SMR provides a growth advantage in juvenile common carp experiencing changes in food availability and this link is temperature-dependent. PMID- 29275189 TI - Transforming growth factor-beta1 gene polymorphisms with liver cirrhosis risk: A meta-analysis. AB - Although several epidemiological studies have investigated the association of transforming growth factor-beta1 (TGF-beta1) gene polymorphisms with the susceptibility to liver cirrhosis (LC), controversial results exist. Consequently, we performed a meta-analysis to accurately evaluate the relationship of TGF-beta1-509C/T and codon 10T/C polymorphisms with the risk of LC introduced by chronic hepatitis B/V virus (HBV/HCV) infection. A total of 9 case-control studies, involving 985 LC patients and 909 controls, were recruited for meta-analysis. The results suggested a significant association between the 509C/T polymorphism and LC risk in the total population. Stratification by ethnicity revealed similar associations in Egyptian and Caucasian populations, but not in Asian populations. Subgroup analyses by different etiologies also showed similar associations in HCV-induced LC, but not in HBV-induced LC. However, the overall data failed to show a significant association between codon 10T/C polymorphism and the risk of LC in the study. We concluded that TGF-beta1 509C/T polymorphism was significantly associated with LC susceptibility, while the codon 10T/C polymorphism seemed to have a limited role in predicting the occurrence of LC induced by HBV/HCV infection. PMID- 29275190 TI - Molecular characterization of genomic DNA in mycoplasma pneumoniae strains isolated from serious mycoplasma pneumonia cases in 2016, Yunnan, China. AB - Mycoplasma pneumoniae (MP) is particularly prevalent in low-immunity school-age children. Few data have been reported on MP prevalence in Yunnan, China. This study was designed to investigate the prevalence and characterize genomic DNA of MP in a small outbreak in 2016, Southwest China. RepMP4 and RepMP2/3 genes of MP positive samples were amplified for molecular typing through sequence alignment and PCR-RFLP assay. Phylogenetic trees were constructed by MEGA5.0. The results showed that two distinct P1 types (type I and type II) were prevalent in this MP outbreak. Type I was the most prevalent type, and clustered in the same evolutionary branch of C26 (China, 2012). Only 1 MP isolate belonged to type II, and clustered in the branch of KCH405 (Japan, 2016). Fifty-nine nucleotide mutations were observed in P1 genes of type I isolates (51 in RepMP4, 8 in RepMP2/3). Ninety-five nucleotide mutations were observed in P1 genes of the type II isolates (33 in RepMP4, 62 in RepMP2/3). It is noteworthy that 31 mutation sites were clustered in an 84-bp fragment in the RepMP4 gene of type II isolates. One new fragment that appeared in two of the type I strains was not found in NCBI. Nucleotide diversity analyze results showed that RepMP4 was more likely to be genetically diverse than RepMP2/3. Two-tailed Z-test result of RepMP4 suggested positive selection between 6 P1 type I isolates and M29 (China, 2005). According to secondary structure prediction, 36 new possible protein binding sites were found and another 9 sites were lost, 2 helices were missed and 1 new helix appeared in type I isolates. As for type II isolates, 16 protein binding regions were gained and 31 were lost. This study may help to understand the intrinsic geographical relatedness and contributes further to the research of MP. PMID- 29275191 TI - Genetic diversity and distribution differ between long-established and recently introduced populations in the invasive mosquito Aedes albopictus. AB - The Asian tiger mosquito Aedes albopictus, native to South-eastern Asia, is currently the most invasive mosquito in the world. The spatio-temporal dynamics of its expansion through the genetic characterization of invasive populations has been challenged so far by the limited number of genetic markers variable enough to infer the genetic structure in recently invaded areas. Here we applied the double-digest Restriction-site Associated DNA sequencing method (ddRADseq) to mosquitoes collected in two invaded areas, Reunion Island (12 localities) and Europe (18 localities). Analyses of genetic diversity, Bayesian clustering, Maximum Likelihood inference and isolation-by-distance tests based on 1561 genome wide distributed Single Nucleotide Polymorphisms (SNPs) revealed that Reunion Island and Europe form two distinct genetic clusters, supporting no contemporary gene flow and suggesting two different and independent invasion histories. Long established populations (Reunion Island) were more genetically diverse than recently introduced European populations. The largest part of genetic variance was found at the intra-individual level (>85%) and most FIS values were positive, suggesting inbreeding at the local scale. The two invaded areas showed contrasting patterns of genetic structure. Significant isolation-by-distance was found among Reunion Island populations, suggesting that these populations are at the drift-migration equilibrium. In contrast, long-distance human-assisted transport is probably the main dispersal mechanism in Europe. PMID- 29275192 TI - Detection of Aristaless-related homeobox protein in ovarian sex cord-stromal tumors. AB - OBJECTIVE: To examine the potential of ARX as a novel biomarker of ovarian endometriosis and other ovarian pathologies. METHODS: The mRNA level of ARX in ovarian endometriosis and normal endometrium samples was determined by real-time PCR, while the protein level was determined by Western blotting and immunohistochemical staining. Immunohistochemical analysis was performed on nearly 200 tissue samples of different ovarian pathologies. GraphPad Prism was used for statistical analysis. RESULTS: The expression of ARX was significantly increased in ovarian endometriosis samples as compared to normal endometrium. Also Western blotting data showed higher ARX levels in the ovarian endometriosis samples versus normal endometrium. Immunohistochemical analysis revealed that the protein is localized in the ovarian stroma and does not originate from endometriosis. Further immunohistochemical analysis performed on several different non-neoplastic and neoplastic ovarian tissue samples revealed that in the non-neoplastic ovary ARX protein is present only in the stromal cells and their derivates (luteinized stromal cells, theca and Leydig cells) and not in granulosa cells, oocites, surface epithelium or rete ovarii, while all stromal and sex cord tumors showed strong nuclear staining for ARX. All other primary or metastatic epithelial tumors of the ovary were ARX negative. CONCLUSIONS: ARX is not associated with endometriosis and cannot be used as a biomarker for ovarian endometriosis. ARX is present in ovarian stroma and cells derived from ovarian stroma as well as in all types of sex cord-stromal tumors of the ovary and could thus be used as a marker for sex cord-stromal differentiation in ovarian tumors. PMID- 29275193 TI - Transcutaneous vagus nerve stimulation (tVNS) enhances recognition of emotions in faces but not bodies. AB - The polyvagal theory suggests that the vagus nerve is the key phylogenetic substrate enabling optimal social interactions, a crucial aspect of which is emotion recognition. A previous study showed that the vagus nerve plays a causal role in mediating people's ability to recognize emotions based on images of the eye region. The aim of this study is to verify whether the previously reported causal link between vagal activity and emotion recognition can be generalized to situations in which emotions must be inferred from images of whole faces and bodies. To this end, we employed transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique that causes the vagus nerve to fire by the application of a mild electrical stimulation to the auricular branch of the vagus nerve, located in the anterior protuberance of the outer ear. In two separate sessions, participants received active or sham tVNS before and while performing two emotion recognition tasks, aimed at indexing their ability to recognize emotions from facial and bodily expressions. Active tVNS, compared to sham stimulation, enhanced emotion recognition for whole faces but not for bodies. Our results confirm and further extend recent observations supporting a causal relationship between vagus nerve activity and the ability to infer others' emotional state, but restrict this association to situations in which the emotional state is conveyed by the whole face and/or by salient facial cues, such as eyes. PMID- 29275194 TI - Coexistence of multiple globin genes conferring protection against nitrosative stress to the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125. AB - Despite the large number of globins recently discovered in bacteria, our knowledge of their physiological functions is restricted to only a few examples. In the microbial world, globins appear to perform multiple roles in addition to the reversible binding of oxygen; all these functions are attributable to the heme pocket that dominates functional properties. Resistance to nitrosative stress and involvement in oxygen chemistry seem to be the most prevalent functions for bacterial globins, although the number of globins for which functional roles have been studied via mutation and genetic complementation is very limited. The acquisition of structural information has considerably outpaced the physiological and molecular characterisation of these proteins. The genome of the Antarctic cold-adapted bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125) contains genes encoding three distinct single-chain 2/2 globins, supporting the hypothesis of their crucial involvement in a number of functions, including protection against oxidative and nitrosative stress in the cold and O2 rich environment. In the genome of PhTAC125, the genes encoding 2/2 globins are constitutively transcribed, thus suggesting that these globins are not functionally redundant in their physiological function in PhTAC125. In the present study, the physiological role of one of the 2/2 globins, Ph-2/2HbO-2217, was investigated by integrating in vivo and in vitro results. This role includes the involvement in the detoxification of reactive nitrogen and O2 species including NO by developing two in vivo and in vitro models to highlight the protective role of Ph-2/2HbO-2217 against reactive nitrogen species. The PSHAa2217 gene was cloned and over-expressed in the flavohemoglobin-deficient mutant of Escherichia coli and the growth properties and O2 uptake in the presence of NO of the mutant carrying the PSHAa2217 gene were analysed. The ferric form of Ph-2/2HbO-2217 is able to catalyse peroxynitrite isomerisation in vitro, indicating its potential role in the scavenging of reactive nitrogen species. Here we present in vitro evidence for the detoxification of NO by Ph 2/2HbO-2217. PMID- 29275195 TI - Nitric oxide-mediated integrative alterations in plant metabolism to confer abiotic stress tolerance, NO crosstalk with phytohormones and NO-mediated post translational modifications in modulating diverse plant stress. AB - Nitric oxide (NO) is a major signaling biomolecule associated with signal transduction in plants. The beneficial role of NO in plants, exposed to several abiotic stresses shifted our understanding as it being not only free radical, released from the toxic byproducts of oxidative metabolism but also helps in plant sustenance. An explosion of research in plant NO biology during the last two decades has revealed that NO is a key signal associated with plant growth, germination, photosynthesis, leaf senescence, pollen growth and reorientation. NO is beneficial as well as harmful to plants in a dose-dependent manner. Exogenous application of NO at lower concentrations promotes seed germination, hypocotyl elongation, pollen development, flowering and delays senescence but at higher concentrations it causes nitrosative damage to plants. However, this review concentrates on the beneficial impact of NO in lower concentrations in the plants and also highlights the NO crosstalk of NO with other plant hormones, such as auxins, gibberellins, abscisic acid, cytokinins, ethylene, salicylic acid and jasmonic acid, under diverse stresses. While concentrating on the multidimensional role of NO, an attempt has been made to cover the role of NO mediated genes associated with plant developmental processes, metal uptake, and plant defense responses as well as stress-related genes. More recently, several NO-mediated post translational modifications, such as S-nitrosylation, N-end rule pathway operates under hypoxia and tyrosine nitration also occurs to modulate plant physiology. PMID- 29275196 TI - Synthesis of dipolar grafted hydroxyethyl cellulose and its application for the removal of phosphate ion from aqueous medium by adsorption. AB - A novel amphoteric graft copolymer was prepared by first grafting of a cationic monomer, (3-Acrylamidopropyl) trimethyl-ammonium chloride (APTAC) using potassium peroxydisulfate (K2S2O8) as radical initiator, followed by sulfation with chlorosulfonic acid as sulfating agent onto hydroxyethyl cellulosic (HEC) backbone. Several techniques like FTIR, 1H NMR, FESEM, XRD and TGA/DTGA studies were used to characterize the graft copolymer. The dipolar graft copolymer, sulfated hydroxyethyl cellulose-g-polyAPTAC (SHEC-g-PAPTAC) so obtained was used for phosphate ion adsorption from water medium. Various operating variables affecting the phosphate adsorption were studied which showed that the maximum phosphate adsorption was obtained at pH 5, time 45 min, temperature 50 degrees C, adsorbent dose 0.02 g and initial phosphate ion concentration 120 mg/L. Adsorption mechanism was theoretically interpreted by Density Functional Theory (DFT), using Gaussian 09 software which supports the experimentally obtained data. The adsorption follows pseudo-second-order kinetic and Langmuir isotherm model with Qmax value 46.94 mg/g. Calculation of thermodynamic parameters (negative value of Gibbs free energy change (DeltaG degrees )) indicates the spontaneous nature of the adsorption. Adsorption capacities of both hydroxyethyl cellulose-g-polyAPTAC (HEC-g-PAPTAC) and SHEC-g-PAPTAC copolymer were also compared under optimum conditions. Desorption study showed that the sulfated polymer was retained almost 86% regeneration efficiency after four adsorption desorption cycles. PMID- 29275197 TI - Carbon dots-modified chitosan based electrochemical biosensing platform for detection of vitamin D. AB - Here in, a carbon dots (CDs)-modified chitosan (CH) based biosensing platform was fabricated for vitamin D2 detection. Carbon dots were synthesized through microwave pyrolysis method, and characterized with transmission electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, and UV/VIS spectroscopy. Chitosan (1%) solution was prepared in acetic acid (1%) solution and followed by the addition of CDs to prepare the carbon dots-chitosan (CD-CH) composite. A thin film of CD-CH composite was prepared onto ITO glass substrate (CD-CH/ITO) by drop casting method. Surface of the composite film was characterized by atomic force microscopy, static contact angle measurement and cyclic voltammetry. CD-CH/ITO surface was further modified with immobilization of vitamin D2 antibody (Ab-VD2) and bovine serum albumin (BSA) to prepare BSA/Ab VD2/CD-CH/ITO bioelectrode. Electrochemical response of the bioelectrode towards vitamin D2 antigen (Ag-VD2) was carried out by differential pulse voltammetry. The biosensing electrode showed linearity within the range 10-50 ng mL-1 of Ag VD2 concentration. The sensitivity was found to be 0.2 MUA ng-1 mL cm-2, LOD was 1.35 ng mL-1, and the biosensor had a shelf-life of about 25 days. PMID- 29275198 TI - Production of cotton fabrics with durable antibacterial property by using gum tragacanth and silver. AB - A simple and inexpensive procedure has been devised to prepare antibacterial cotton fabric using silver nanoparticles (AgNPs) and bio degradable gum tragacanth (GT). For this, different concentrations of GT (2, 4 and 6 g/L) along with a constant amount of Ag (5%; according to weight of dry GT used in the solutions) were applied to investigate the efficacy of antibacterial potency against Escherichia coli and Staphylococcus aureus and their effect on physical, mechanical and biological characteristics of cotton fabric. Our study exhibited the presence of small amount of AgNPs in the composite structure was enough to increase the antibacterial activity of fabrics compared to fabric that were treated by only GT. Moreover, the treated cotton with GT-4%/Ag indicated proper tensile strength and stiffness compared to treated fabric with GT-6%/Ag composite. The biocompatibility of the GT and GT/Ag treated fabrics was verified through MTT assay on fibroblast cells. PMID- 29275199 TI - Adsorption of phosphate by the cellulose-based biomaterial and its sustained release of laden phosphate in aqueous solution and soil. AB - A new quaternary ammonium anion exchanger derived from the cellulose-based biomaterial (sugarcane bagasse) was prepared for phosphate adsorption and then the phosphate saturated bio-sorbent was used as a slow-release phosphate fertilizer in water or soil. Results indicated that the adsorption of phosphate by the quaternary ammonium based sugarcane bagasse (QA-SB) was increased with the increase of temperature, and the adsorption was optimal at pH of 4.33-5.88. The capture of phosphate by the QA-SB in fixed-bed column was calculated to be 18.9 21.4 mg/g in the background of Cl- or NO3- (100 mg/L). In particular, the amount of laden phosphate was significantly decreased to 9.1 mg/g in the presence of coexisting SO42- (100 mg/L). As a result, a stronger competitve effect of SO42- on phosphate capture was observed as compared with those of Cl-, and NO3-. Results also indicated that the laden phosphate on the QA-SB could be desorbed efficiently and the recovery of phosphate onto the regenerated QA-SB still attained about 94.5% after 4 cycles. The slow-release of laden phosphate in aqueous solution could be continuously conducted for 12 d, with 43.6% of laden phosphate (11.6 mg/g) released. In contrast, phosphate (7.4 mg/g) released in soil reached equilibrium within 4 d, accounting for only 27.8% of laden phosphate released. PMID- 29275200 TI - Long non-coding RNA CCAL promotes hepatocellular carcinoma progression by regulating AP-2alpha and Wnt/beta-catenin pathway. AB - OBJECTIVE: Long non-coding RNAs are emerging as key molecules in cancer progression. LncRNA-CCAL has shown to be highly expressed and important in regulating CRC and osteosarcoma development. Nevertheless, the expression and mechanism of CCAL in HCC is still not well understood. METHODS: qRT-PCR and ISH were used to evaluate CCAL expression in HCC tissues and cell lines. Histone H3 methylation and acetylation levels across CCAL promoter region were examined by chromatin immunoprecipitation assays. Transfection of Lv-CCAL-shRNAs into HCC cell lines was used to evaluate cellular invasion and proliferation. The influence of CCAL depletion on AP-2alpha expression and Wnt/beta-catenin pathway was analyzed by qRT-PCR, western blot and immunofluorescence. RESULTS: Higher expression of CCAL was found in HCC tumor tissues compared with normal tissues, and was associated with tumor metastasis and TNM stage. Furthermore, the decreased histone H3 methylation and increased histone H3 acetylation across CCAL promoter region contributed to the upregulation of CCAL in HCC. Moreover, the depletion of CCAL inhibited HCC cellular invasion and proliferation, and promoted cell apoptosis. In addition, CCAL depletion up-regulated AP-2alpha expression and inhibited Wnt/beta-catenin pathway activation. CONCLUSIONS: CCAL has an important role in hepatic carcinogenesis and may serve as a new target for HCC diagnosis and treatment. PMID- 29275201 TI - Interpolymer complexation of egg white proteins and carrageenan: Phase behavior, thermodynamics and rheological properties. AB - The complexation between lysozyme/carrageenan and ovalbumin/carrageenan was studied in situ using acidification. The complexes were analyzed in solutions with different NaCl concentrations and different protein/polysaccharide ratios. As the protein/polysaccharide ratio increased from 1:1 to 10:1, critical structure forming events (i.e., those associated with soluble, insoluble and large insoluble complexes) shifted to higher pH values for ovalbumin/carrageenan followed by decrease of G' values at ratios of 5:1 and 10:1. The increase in the ratio of lysozyme/carrageenan complexes suppressed the critical pH transition points that led to the formation of large insoluble complexes from pH 12.0 until 1.0, and the values of G' increased simultaneously, reaching the highest value at a ratio of 10:1. Addition of salt to the ovalbumin/carrageenan and lysozyme/carrageenan mixtures suppressed the electrostatic interaction between proteins and carrageenan at lower pH values and the critical pH transitions points, whereas at a ratio of 3:1 with a 0.01 M concentration, the coacervate yield of the complex reached 79.6% +/- 0.6 and 93.7% +/- 4.8 for the ovalbumin and lysozyme complexes, respectively. The rheological data associated with microscopy images show that interpolymer complexes with heterogeneous structures were formed for both complexes, and we suggest that complexes have a great potential to improve or extend the texture, mechanical stability, consistency, and taste of food products. PMID- 29275202 TI - Effects of gums on physical properties, microstructure and starch digestibility of dried-natural fermented rice noodles. AB - The effects of gums including carboxymethyl cellulose (CMC), xanthan gum (XG) and guar gum (GG) on physical properties, microstructure and starch digestibility of dried-natural fermented rice noodles were investigated. The gums, each at 0.05 and 0.10 g/100 g wet basis, were added to the flour during rice noodle production. Control was the sample without the addition of gums. Physical properties (color, water absorption, cooking loss and firmness), microstructure, starch composition and in vitro starch digestibility were determined. Generally, the addition of gums improved the physical qualities of rehydrated fermented rice noodles as evidenced by high water absorption and low cooking loss. CMC provided the best result for improvement of the physical properties of rice noodles. The addition of gums promoted the porous microstructure in rice noodles. In terms of starch digestibility, the addition of gums increased the rate of starch digestion and consequently provided high estimated glycemic index (GI). Samples with XG showed the highest starch digestion rate and estimated GI values when compared with CMC and GG. It is concluded that CMC, XG and GG improved the texture and cooking quality of dried-natural fermented rice noodles but they had negative effects on starch digestion rate and estimated GI. PMID- 29275203 TI - Binding interaction of isoxsuprine hydrochloride and levothyroxine to milk beta lactoglobulin; from the perspective of comparison. AB - Isoxsuprine hydrochloride (ISO) and levothyroxine (LEV) are medicines which can be utilized alone or simultaneously by pregnant women. The purpose of this work is to investigate the separate and simultaneous interaction of ISO and LEV with beta-LG. The results showed that both drugs can bind to beta-LG; the static quenching was suggested for fluorescence quenching mechanism of beta-LG.The values of binding constants (Kbeta-LG-ISO = 2.69 * 104 M-1, Kbeta-LG-LEV = 0.54 * 103 M-1 and Kbeta-LG-ISO-LEV = 2.18 * 103 M-1 at 310 K) suggested that ISO has stronger binding affinity toward beta-LG than LEV and affinity of beta-LG to LEV is increased in the presence of ISO while the presence of LEV has no significant effect on the affinity of protein to ISO. Thermodynamic parameters showed that the binding of LEV to beta-LG are hydrogen bonding and Van der Waals forces but the formation of beta-LG-ISO is hydrophobic associations. The results of FT-IR and UV-visible measurements indicated that the binding of both drugs to beta-LG may induce conformational changes of protein. In silico molecular docking analyses confirmed that ISO and LEV binds to residues located at site I and site II of beta-LG, respectively. PMID- 29275204 TI - Synthesis, characterization and study of sorption parameters of multi-walled carbon nanotubes/chitosan nanocomposite for the removal of picric acid from aqueous solutions. AB - The modification of carboxylated multi-wall carbon nanotubes (MWCNT-COOH) with chitosan (Chi) has been investigated to prepare a nanocomposite material (MWCNT Chi) for the removal of picric acid from aqueous solutions. Materials were characterized by FT-IR, TGA, DTG, FESEM, EDX, BET and zeta potential. Batch experiments such as solution pH, dosage of adsorbents, contact time, concentration of the picric acid and temperature were achieved to study sorption process. Kinetic studies were well described by pseudo-second-order kinetic model for both adsorbents. The six isotherm models: Langmuir (four linear forms), Freundlich, Tempkin, Halsey, Harkins-Jura and Dubinin-Radushkevich models were applied to determine the characteristic parameters of the adsorption process. Isotherm studies showed that the Langmuir isotherm for MWCNT-Chi and Freundlich and Halsey models for both adsorbents were found to best represent the measured sorption data. In addition, the results of Dubinin-Radushkevich model confirmed the physical adsorption. Negative DeltaG degrees values for MWCNT-Chi and positive ones for MWCNT-COOH indicated the nature of spontaneous and unspontaneous, respectively for adsorption process in the range of the studied concentrations. In addition, picric acid molecules can be desorbed from MWCNT-Chi up to 90% at pH = 9 and that the consumed MWCNT-Chi could be reutilized up to 5th cycle of regeneration. PMID- 29275205 TI - Extraction, partial characterization and bioactivity of polysaccharides from Senecio scandens Buch.-Ham. AB - Mechanochemistry was applied to improve the yield of bioactive acid polysaccharides obtained from low-cost Senecio scandens Buch.-Ham. The structural characteristics and biological activities of three novel polysaccharides from S. scandens (SP2-1, SP2-2 and SP3-2) were investigated. SP2-1 and SP2-2 with molecular weights of 267.6 and 253.1 kDa, respectively, were composed of L rhamnose, D-arabinose, D-mannose, D-xylose, D-glucose and D-galactose in various ratios, whereas SP3-2 with molecular weight of 266.6 kDa was composed of D arabinose, D-glucose and D-galactose. In vitro, SP3-2 presented the strongest DPPH, ABTS and O2- radicals scavenging activities, as well as Fe3+ reducibility. Immunological tests demonstrated that all polysaccharide fractions stimulated the production of nitric oxide (NO) and immunomodulatory cytokines (IL-1beta and TNF alpha) without cytotoxicity in macrophages and promoted splenocyte proliferation in different degree. These findings indicated that SP2-1, SP2-2 and SP3-2 have prominent antioxidant activity and potential immune response, which proved the possibility of S. scandens polysaccharides (SSP) applied in the field of functional food or medicine. PMID- 29275206 TI - Chronic Treatment with Fluoxetine or Clozapine of Socially Isolated Rats Prevents Subsector-Specific Reduction of Parvalbumin Immunoreactive Cells in the Hippocampus. AB - The dysfunction of parvalbumin-positive (PV+) interneurons, the most abundant type of hippocampal GABAergic inhibitory interneuron, has been implicated in mood disorders. We recently reported that adult male Wistar rats exposed to three weeks of social isolation show depressive- and anxiety-like behaviors and a reduced number of PV+ interneurons in all hippocampal subregions. As GABA neurotransmission has been proposed as a potential therapeutic target of antidepressant and antipsychotic medications, we examined whether treatment with the antidepressant fluoxetine (Flx) (15 mg/kg/day) or the antipsychotic clozapine (Clz) (20 mg/kg/day) during three weeks of social isolation in rats offered protection from the isolation stress-induced reduction in the number of PV+ interneurons in hippocampal subregions. Using immunofluorescence analysis, we revealed that both chronic Flx and Clz partially prevented the isolation-induced changes. Flx prevented the reduction in the number of PV+ interneurons in the CA2, CA3, without affecting the CA1 and dentate gyrus DG areas, whereas Clz prevented this decrement in the CA2, CA3 and DG regions but not in CA1 areas. Moreover, Flx increased the number of PV+ interneurons in CA1 in control animals. These findings suggest that chronic administration of Flx or Clz may offer partial protection from social isolation stress via modulation of the hippocampal GABAergic system. PMID- 29275207 TI - Gray Matter and Functional Connectivity in Anterior Cingulate Cortex are Associated with the State of Mental Silence During Sahaja Yoga Meditation. AB - Some meditation techniques teach the practitioner to achieve the state of mental silence. The aim of this study was to investigate brain regions that are associated with their volume and functional connectivity (FC) with the depth of mental silence in long-term practitioners of Sahaja Yoga Meditation. Twenty-three long-term practitioners of this meditation were scanned using Magnetic Resonance Imaging. In order to identify the neural correlates of the depth of mental silence, we tested which gray matter volumes (GMV) were correlated with the depth of mental silence and which regions these areas were functionally connected to under a meditation condition. GMV in medial prefrontal cortex including rostral anterior cingulate cortex were positively correlated with the subjective perception of the depth of mental silence inside the scanner. Furthermore, there was significantly increased FC between this area and bilateral anterior insula/putamen during a meditation-state specifically, while decreased connectivity with the right thalamus/parahippocampal gyrus was present during the meditation-state and the resting-state. The capacity of long-term meditators to establish a durable state of mental silence inside an MRI scanner was associated with larger gray matter volume in a medial frontal region that is crucial for top down cognitive, emotion and attention control. This is furthermore corroborated by increased FC of this region during the meditation-state with bilateral anterior insula/putamen, which are important for interoception, emotion, and attention regulation. The findings hence suggest that the depth of mental silence is associated with medial fronto-insular-striatal networks that are crucial for top-down attention and emotional control. PMID- 29275208 TI - Phenological application of selenium differentially improves growth, oxidative defense and ion homeostasis in maize under salinity stress. AB - The underlying mechanism of selenium (Se) mediating plant salt tolerance is not well understood and information on how plant growth and development is regulated by phenological Se application (20 and 40 mg/L) under salinity stress is scarce. In present study, we have appraised the impact of phenological Se application on growth, antioxidant defense system and ionic imbalance in maize under salinity. Salinity (12 dS m-1) reduced growth, concentration of chlorophyll and K+ in root and leaf. Contrarily, salinity increased toxic Na+, malondialdehyde (MDA) and H2O2 concentration that resulted in oxidative damage. Lower level of Se application (20 mg/L) increased growth and chlorophyll by reducing oxidative damage due to high cell concentrations of MDA and H2O2. Se reduced endogenous levels of H2O2 and MDA under salinity. Moreover, Se regulated antioxidant defense system by increasing the activities of antioxidant enzymes (SOD, POD and CAT) and influenced the concentrations of non-enzymatic antioxidants (phenolics and flavonoids). Se-induced better antioxidant system protected plants from oxidative damage. We have also recorded substantial increase in K+ and decrease in Na+ concentration in plants treated with 20 mg/L Se under salinity stress. The impact of Se on plant growth and development is linked with the growth stage of exogenous application. Foliar Se at reproductive and both vegetative and reproductive stages improved salinity tolerance in maize compared with vegetative stage. PMID- 29275209 TI - Barley ADH-1 modulates susceptibility to Bgh and is involved in chitin-induced systemic resistance. AB - The plant primary energy metabolism is profoundly reorganized under biotic stress conditions and there is increasing evidence for a role of the fermentative pathway in biotic interactions. Previously we showed via transient gene silencing or overexpression a function of barley alcohol dehydrogenase 1 (HvADH-1) in the interaction of barley with the parasitic fungus Blumeria graminis f.sp. hordei (Bgh). Here we extend our studies on stable transgenic barley events over- or under-expressing HvADH-1 to analyse ADH-1 functions at the level of whole plants. Knock-down (KD) of HvADH-1 by dsRNA interference resulted in reduced and overexpression of HvADH-1 in strongly increased HvADH-1 enzyme activity in leaves of stable transgenic barley plants. The KD of HvADH-1 coincided with a reduced susceptibility to Bgh of both excised leaves and leaves of intact plants. Overexpression (OE) of HvADH-1 results in increased susceptibility to Bgh when excised leaves but not when whole seedlings were inoculated. When first leaves of 10-day-old barley plants were treated with a chitin elicitor, we observed a reduced enzyme activity of ADH-1/-1 homodimers at 48 h after treatment in the second, systemic leaf for empty vector controls and HvADH-1 KD events, but not for the HvADH-1 OE events. Reduced ADH-1 activity in the systemic leaf of empty vector controls and HvADH-1 KD events coincided with chitin-induced resistance to Bgh. Taken together, stable HvADH-1 (KD) or systemic down-regulation of ADH-1/-1 activity by chitin treatment modulated the pathogen response of barley to the biotrophic fungal parasite Bgh and resulted in less successful infections by Bgh. PMID- 29275210 TI - Differences between seedlings and flowers in anti-ROS based heat responses of Arabidopsis plants deficient in cyclic nucleotide gated channel 2. AB - Cyclic nucleotide gated channel 2 (CNGC2) in Arabidopsis has been identified as one of the putative heat sensors which might play a key role in the regulation of heat acclimation. However, it is still not understood how CNGC2 controls heat stress responses during different growth stages. This study aimed to characterize the differences in heat stress responses between seedlings and flowers of Arabidopsis plants deficient in CNGC2. Seedlings of Arabidopsis plants deficient in CNGC2 showed enhanced tolerance to heat stress accompanied by higher accumulation of heat response proteins such as multiprotein bridging factor 1c (MBF1c), ascorbate peroxidases (APXs) and heat shock proteins (HSPs). On the other hand, seed production of these knockout lines was more sensitive to heat stress. In contrast to seedlings, accumulation of MBF1c and APX proteins in flowers of these knockout lines was lower than or almost comparable with that in WT plants under heat stress. In addition, plants deficient in CNGC2 showed dramatically higher accumulation of H2O2 in flowers, but, only slightly higher accumulation in seedlings compared with WT plants. These results suggest that the stage-dependent differences in heat stress response of Arabidopsis regulated by CNGC2 might rely on regulatory mechanisms of APX1-and MBF1c-dependent pathways and H2O2 homeostasis. PMID- 29275211 TI - Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells. AB - Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR. IH significantly increased the mRNA levels of POMC and CART in all the neuronal cells. Deletion analysis revealed that the -705 to -686 promoter region of POMC and the -950 to -929 region of CART were essential for the IH-induced promoter activity. As possible GATA factor binding sequences were found in the two regions, we performed real-time RT-PCR to determine which GATA family members were expressed and found that GATA2 and GATA3 mRNAs were predominantly expressed. Therefore, we introduced siRNAs against GATA2 and GATA3 into NB-1 cells and found that GATA2 and GATA3 siRNAs abolished the IH induced up-regulation of both POMC and CART mRNAs. These results indicate that IH stress up-regulates the mRNA levels of anorexigenic peptides, POMC and CART, in human neuronal cells via GATA2 and GATA3. IH can have an anorexigenic effect on SAS patients through the transcriptional activation of POMC and CART in the central nervous system. PMID- 29275212 TI - NRF2 facilitates breast cancer cell growth via HIF1alpha-mediated metabolic reprogramming. AB - High aerobic glycolysis not only provides energy to breast cancer cells, but also supports their anabolic growth. The redox sensitive transcription factor NRF2 is over-expressed in multiple cancers, including breast cancer. It is unclear whether NRF2 could promote breast cancer cell growth through enhancing glycolysis. In this study, we found that NRF2 and HIF1alpha mRNA and protein levels were significantly increased in MCF-7 and MDA-MB-231 breast cancer cells as compared to MCF-10A benign breast epithelial cells. Down-regulation of NRF2 decreased MCF7 and MBA-DA-231 breast cell proliferation, while it reversed by hypoxia inducible factor 1alpha (HIF1alpha). Knockdown of NRF2 inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including HK2, PFKFB3, PKM2 and LDHA. Our results further indicated that the AKT activation and AMPK inhibition were required for NRF2-mediated up regulation of glycolytic enzymes. Consistent with these results, a positive correlation existed between NRF2 or HIF1alpha and several key glycolytic genes in human breast cancer cell samples and breast cancer patients with high NRF2 or HIF1alpha expression had poorer overall survival. In conclusion, our study demonstrates that NRF2 promotes breast cancer progression by enhancing glycolysis through coactivation of HIF1alpha, implicating that NRF2 is a potential molecular target for breast cancer treatment. PMID- 29275214 TI - De novo transcriptome assembly and comparative analysis between male and benzyladenine-induced female inflorescence buds of Plukenetia volubilis. AB - Plukenetia volubilis is a promising oilseed crop due to its seeds being rich in unsaturated fatty acids, especially alpha-linolenic acid. P. volubilis is monoecious, with separate male and female flowers on the same inflorescence. We previously reported that male flowers were converted to female flowers by exogenous cytokinin (6-benzyladenine, 6-BA) treatment in P. volubilis. To identify candidate genes associated with floral sex differentiation of P. volubilis, we performed de novo transcriptome assembly and comparative analysis on control male inflorescence buds (MIB) and female inflorescence buds (FIB) induced by 6-BA using Illumina sequencing technology. A total of 57,664 unigenes with an average length of 979 bp were assembled from 104.1 million clean reads, and 45,235 (78.45%) unigenes were successfully annotated in the public databases. Notably, Gene Ontology analyses revealed that 4193 and 3880 unigenes were enriched in the categories of reproduction and reproductive processes, respectively. Differential expression analysis identified 1385 differentially expressed unigenes between MIB and FIB, of which six unigenes related to cytokinin and auxin signaling pathways and 16 important transcription factor (TF) genes including MADS-box family members were identified. In particular, several unigenes encoding important TFs, such as homologs of CRABS CLAW, RADIALIS-like 1, RADIALIS-like 2, HECATE 2, WUSCHEL-related homeobox 9, and SUPERMAN, were expressed at higher levels in FIB than in MIB. The expression patterns of the 36 selected unigenes revealed by transcriptome analysis were successfully validated by quantitative real-time PCR. This study not only provides comprehensive gene expression profiles of P. volubilis inflorescence buds, but also lays the foundation for research on the molecular mechanism of floral sex determination in P. volubilis and other monoecious plants. PMID- 29275213 TI - Overexpression of miR-1290 contributes to cell proliferation and invasion of non small cell lung cancer by targeting interferon regulatory factor 2. AB - MicroRNAs are small endogenous non-coding RNAs, which can frequently emerge as regulators in many cancer types. MiR-1290 was found to be abnormally elevated in non small cell lung cancer (NSCLC). However, the underlying molecular mechanism still needs to be investigated. Here, we demonstrated that miR-1290 expression levels were remarkably upregulated in NSCLC tissues compared to adjacent normal tissues. Higher miR-1290 expression levels positively associated with lymph node metastasis and advanced tumor stage. Functional assays showed that upregulated miR-1290 expression in NSCLC cells enhanced cell proliferation, cell colony formation and invasion capacities in vitro. Furthermore, we found that miR-1290 promoted cell proliferation related protein CDK2 and CDK4 expression and enhanced Epithelial-Mesenchymal Transition (EMT) process by downregulating E-cadherin expression and upregulating N-cadherin expression. Bioinformatics analysis and luciferase reporter gene assays revealed that Interferon regulatory factor 2 (IRF2) was a direct target of miR-1290. Overexpression of miR-1290 can degrade IRF2 mRNA and downregulated IRF2 protein expression in NSCLC cells. Upregulated IRF2 could partly rescue the promoting effects induced by miR-1290 overexpression on cell proliferation and invasion of NSCLC. Additionally, we confirmed that reduced miR-1290 expression could suppress tumor growth using a tumor xenograft model in vivo. Thus, we concluded that miR-1290 may serve as a potential target of NSCLC treatment. PMID- 29275215 TI - Uncovering the basis of viability loss in desiccation sensitive Trichilia dregeana seeds using differential quantitative protein expression profiling by iTRAQ. AB - Recalcitrant seeds, unlike orthodox types, are desiccation sensitive and hence, cannot be stored using conventional seed storage methods In this study, relative changes of protein expression in T. dregeana seeds during desiccation and hydrated storage (a short- to medium-term storage method) were analysed to understand the basis of their desiccation- and storage-induced viability loss. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) were used to compare (selected) protein expression levels across fresh, partially dehydrated and stored seeds. A total of 114 proteins were significantly differentially expressed in embryonic axes of fresh seeds and those seeds exposed to dehydration and hydrated storage (which exposed seeds to a mild dehydration stress). Proteins involved in protein synthesis were up-regulated in stored and dehydrated seeds, possibly in response to dehydration-induced repair processes and/or germinative development. A range of proteins related to antioxidant protection were variably up- and down-regulated in stored and dehydrated seeds, respectively. Additionally, a class I heat shock protein was down-regulated in dehydrated and stored seeds; no late embryogenesis abundant proteins were identified in both stored and dehydrated seeds; and storage and dehydration up-regulated proteins involved in the provision of energy for cell survival. The results suggest that dehydration- and storage-induced viability loss in recalcitrant seeds may be based on proteomic changes that lead to cellular redox imbalance and increased cell energy demands. This, together with the absence/down-regulation of proteins associated with desiccation tolerance in plant tissues may form part of the proteomic footprint for desiccation sensitivity in seeds. PMID- 29275216 TI - MDPV in forensic routine cases: Psychotic and aggressive behavior in relation to plasma concentrations. AB - The new psychoactive substance 3,4-methylenedioxypyrovalerone (MDPV) belongs to the group of synthetic cathinones and is purchased mainly as "research chemical" or "bath salt" on the illegal drug market, also in South Bavaria. MDPV was detected in blood and urine samples from 2010 on in 50 authentic routine cases in a forensic setting. Plasma concentrations in 46 cases with available blood specimens ranged from approximately 1.0 to 301MUg/L (median 23.7; mean 47.9MUg/L), detected by a fully validated LC-MS/MS method. Subjects aged between 16 and 54 years (median 36; mean 35 years) and reflected experienced chronic drug users. Accused offences were mainly violent crimes such as bodily harm, robberies, homicides and acts of resistance. A lot of subjects showed highly aggressive and violent behavior with endangerment of self and others and/or psychotic symptoms as confusion, hallucinations or paranoia. The risk for such behavior rises with MDPV plasma concentrations above as low as 30MUg/L, whereby a time interval of 1.5h on average between incident and/or observation of impairment and blood sampling has to be taken into account. Comprehensive toxicological analysis proved poly-drug use in almost all cases including opiates/opioids, benzodiazepines and other sedatives, antidepressants and other stimulants, also other new psychoactive substances. Alcohol was detected only in three cases. Co-consumed benzodiazepines seem not be able to completely prevent psychotic effects despite their use as first-line treatment for patients with synthetic cathinone poisonings. The study demonstrates that relatively low plasma concentrations of MDPV could be associated with mental impairment which is relevant in the assessment of forensic cases. PMID- 29275217 TI - Fostering responsible research practices is a shared responsibility of multiple stakeholders. PMID- 29275218 TI - Myrcia sylvatica essential oil mitigates molecular, biochemical and physiological alterations in Rhamdia quelen under different stress events associated to transport. AB - The effects of pre-transport handling and addition of essential oil of Myrcia sylvatica (EOMS) during transport on stress pathways activation in Rhamdia quelen were investigated. Fish (n=400, 25.2+/-2.9g) were captured in production ponds and transferred to 100-L tank (density 100g L-1). After 24h, 10 fish were sampled (before transport group). The remaining fish were placed in plastic bags (n=30 or 32 fish per bag, density 150g L-1) containing 5L of water (control), ethanol (315MULL-1, vehicle) or EOMS (25 or 35MULL-1), in triplicate, transported for 6h and sampled (n=10 animals per group). Indicators of stress and metabolism, as well as mRNA expression of brain hormones were evaluated. Previously, full-length cDNAs, encoding specific corticotropin-releasing hormone (crh) and proopiomelanocortins (pomca and pomcb), were cloned from whole brain of R. quelen. Crh expression increased after 24h of capture and handling, whereas cortisol and glucose plasmatics enhanced their values in the control group. Transport with EOMS reduced plasma cortisol and lactate levels, while ethanol and EOMS groups increased Na+/K+-ATPase gill activity compared to control. Gene expression of crh, pomcb, prolactin and somatolactin mRNAs were lower after transport with EOMS compared to control. EOMS was able to mitigate the stress pathways activation caused by transport, maintaining a balance in body homeostasis. Thus, EOMS is recommended as sedative in procedures as transport and the pre-transport handling requires greater attention and use of tranquilizers. PMID- 29275219 TI - Internet addiction at workplace and it implication for workers life style: Exploration from Southern India. AB - BACKGROUND: Industries are focusing on digitization of their working environment. It helps in enhanced productivity as well as communication among workers. It also lead to higher usages of internet for non work related use at workplace. It affect their productivity at workplace. The present study was undertaken to explore internet use in Information technology (IT) industry and non IT industry, to see its consequence and effect on lifestyle and functioning. METHODS AND MATERIALS: 250 employees of various Government/Private sector organizations(using internet for more than a year and education level of graduation and above) were approached for the assessment using cross sectional research design. RESULTS: The average age of participants was 30.4 years. 9.2% participants falling in category of occasional problems/'at risk' for developing addiction in functioning/moderate impairment due to internet use. Statistically more participants falling in 'at risk category' had reported postponement of work and change in productivity. Sleep, meals, personal hygiene and family time were postponed more by participants who were at risk for developing internet addiction. CONCLUSIONS: The study has implications for developing a workplace based psycho-social intervention program to address the technology use issues at workplace. PMID- 29275220 TI - Using lipidomics to reveal details of lipid accumulation in developing seeds from oilseed rape (Brassica napus L.). AB - With dwindling available agricultural land, concurrent with increased demand for oil, there is much current interest in raising oil crop productivity. We have been addressing this issue by studying the regulation of oil accumulation in oilseed rape (Brassica napus L). As part of this research we have carried out a detailed lipidomic analysis of developing seeds. The molecular species distribution in individual lipid classes revealed quite distinct patterns and showed where metabolic connections were important. As the seeds developed, the molecular species distributions changed, especially in the period of early (20days after flowering, DAF) to mid phase (27DAF) of oil accumulation. The patterns of molecular species of diacylglycerol, phosphatidylcholine and acyl CoAs were used to predict the possible relative contributions of diacylglycerol acyltransferase (DGAT) and phospholipid:diacylglycerol acyltransferase to triacylglycerol production. Our calculations suggest that DGAT may hold a more important role in influencing the molecular composition of TAG. Enzyme selectivity had an important influence on the final molecular species patterns. Our data contribute significantly to our understanding of lipid accumulation in the world's third most important oil crop. PMID- 29275221 TI - Structural characterization of the nitrogenase molybdenum-iron protein with the substrate acetylene trapped near the active site. AB - The biological reduction of dinitrogen (N2) to ammonia is catalyzed by the complex metalloenzyme nitrogenase. Structures of the nitrogenase component proteins, Iron (Fe) protein and Molybdenum-iron (MoFe) protein, and the stabilized complexes these component proteins, have been determined, providing a foundation for a number of fundamental aspects of the complicated catalytic mechanism. The reduction of dinitrogen to ammonia is a complex process that involves the binding of N2 followed by reduction with multiple electrons and protons. Electron transfer into nitrogenase is typically constrained to the unique electron donor, the Fe protein. These constraints have prevented structural characterization of the active site with bound substrate. Recently it has been realized that selected amino acid substitutions in the environment of the active site metal cluster (Iron-molybdenum cofactor, FeMo-co) allow substrates to persist even in the resting state. Reported here is a 1.70A crystal structure of a nitrogenase MoFe protein alpha-96Arg?Gln variant with the alternative substrate acetylene trapped in a channel in close proximity to FeMo co. Complementary theoretical calculations support the validity of the acetylene interaction at this site and is also consistent with more favorable interactions in the variant MoFe protein compared to the native MoFe protein. This work represents the first structural evidence of a substrate trapped in the nitrogenase MoFe protein and is consistent with earlier assignments of proposed substrate pathways and substrate binding sites deduced from biochemical, spectroscopic, and theoretical studies. PMID- 29275222 TI - Perylenetetracarboxylic acid and carbon quantum dots assembled synergistic electrochemiluminescence nanomaterial for ultra-sensitive carcinoembryonic antigen detection. AB - It is important to design a nice electrochemiluminescence (ECL) biological nanomaterial for fabricating sensitive ECL immunosensor to detect tumor markers. Most reported ECL nanomaterial was decorated by a number of mono-luminophore. Here, we report a novel ECL nanomaterial assembled by dual luminophores perylenetetracarboxylic acid (PTCA) and carbon quantum dots (CQDs). In the ECL nanomaterial, graphene was chosen as nanocarrier. Significant ECL intensity increases are seen in the ECL nanomaterial, which was interpreted with the proposed synergistic promotion ECL meachanism of PTCA and CQDs. Furthermore, this ECL nanomaterial was used to label secondary antibody and fabricate a sandwiched carcinoembryonic antigen (CEA) immunosensor. The CEA immunosensor exhibits high sensitivity and the linear semilogarithmical range was from 0.001fgmL-1 to 1ngmL 1 with low detection limit 0.00026fgmL-1. And the CEA immunosensor is also suitable for various cancers' sample detection providing potential specific applications in diagnostics. PMID- 29275223 TI - Antimicrobial residues and resistance against critically important antimicrobials in non-typhoidal Salmonella from meat sold at wet markets and supermarkets in Vietnam. AB - Excessive antimicrobial usage and deficiencies in hygiene in meat production systems may result in undesirable human health hazards, such as the presence of antimicrobial drug residues and non-typhoidal Salmonella (NTS), including antimicrobial resistant (AMR) NTS. Recently, Vietnam has witnessed the emergence of integrated intensive animal production systems, coexisting with more traditional, locally-sourced wet markets. To date no systematic studies have been carried out to compare health hazards in beef, pork and chicken in different production systems. We aimed to: (1) estimate the prevalence of antimicrobial residues in beef, pork and chicken meat; (2) investigate the prevalence and levels of NTS contamination; and (3) investigate serovar distribution and AMR against critically important antimicrobials by animal species and type of retail (wet market vs. supermarket) in Vietnam. Fresh pork, beef and chicken meat samples (N=357) sourced from wet markets and supermarkets in Ho Chi Minh City (HCMC), Hanoi and Dong Thap were screened for antimicrobial residues by PremiTest, and were further investigated by Charm II. Samples from HCMC (N=113) were cultured using ISO 6579:2002/Amd 1:2007. NTS bacteria were quantified using a minimum probable number (MPN) technique. NTS isolates were assigned to serovar by Multilocus Sequence Typing (MLST), and were investigated for their phenotypic susceptibility against 32 antimicrobials. A total of 26 (7.3%) samples tested positive by PremiTest (9.5% beef, 4.1% pork and 8.4% chicken meat). Sulfonamides, tetracyclines and macrolides were detected by Charm in 3.1%, 2.8% and 2.0% samples, respectively. Overall, meat samples from wet markets had a higher prevalence of residues than those from supermarkets (9.6% vs. 2.6%) (p=0.016). NTS were isolated from 68.4% samples from HCMC. Chicken samples from wet markets had by far the highest NTS counts (median 3.2 logMPN/g). NTS isolates displayed high levels of resistance against quinolones (52.2%) and beta-lactams (49.6%), but low levels against 3rd generation cephalosporins (4.4%) and aminoglycosides (0.8%). The highest adjusted prevalence of multidrug resistance (MDR) corresponded to isolates from chicken meat and pork (OR 8.3 and 1.8, respectively) (baseline=beef). S. Kentucky was the most common serovar identified (11 from chicken, 1 from beef) and 91.7% isolates was MDR. 11/12 isolates corresponded to ST198, a worldwide-disseminated multi-resistant NTS clone. We recommend stepping up policy measures to promote responsible antimicrobial use in animal production, as well as awareness about withdrawal periods to limit the hazard of residues in animal products, and improving slaughtering/hygiene procedures to limit cross-contamination with NTS, particularly in poultry wet markets. PMID- 29275224 TI - Staging and surgical approaches in gastric cancer: A systematic review. AB - BACKGROUND: Gastric adenocarcinoma accounted for 6.8% of new cancer cases and 8.8% of cancer deaths worldwide in 2012. Although resection is the cornerstone for cure, several aspects of surgical intervention remain controversial or sub optimally applied at the population level. These include staging, extent of lymph node dissection (LND), optimal requirements of LN assessment, minimum resection margins, surgical technique (laparoscopic vs. open), relationship between surgical volumes and patient outcomes, and resection of stage IV gastric cancer. METHODS: A systematic review was conducted to inform surgical care. RESULTS: The evidence included in this systematic review consists of one guideline, seven systematic reviews and 48 primary studies. CONCLUSIONS: All patients should be discussed at a multidisciplinary team meeting and a staging CT of the chest and abdomen should always be performed. Diagnostic laparoscopy should be performed in patients at risk for stage IV disease. A D2 LND is preferred for curative-intent resection in advanced non-metastatic gastric cancer. At least 16 LNs should be assessed for adequate staging of curative-resected gastric cancer. Gastric cancer surgery should aim to achieve an RO resection margin. In the metastatic setting, surgery should only be considered for palliation of symptoms. Patients should be referred to higher volume centres, and those with adequate support to manage potential complications. Laparoscopic resections should be performed to the same standards as open resections. PMID- 29275225 TI - The efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PAbetaN) increases resistance to carbapenems in Chilean clinical isolates of KPC-producing Klebsiella pneumoniae. AB - OBJECTIVES: KPC-producing strains present a wide range of carbapenem minimum inhibitory concentrations (MICs). This variation may be due to differential expression of blaKPC and porin genes, efflux pump activity and the production of extended-spectrum beta-lactamases and/or AmpC beta-lactamases. The aim of this study was to determine the role of efflux pumps inhibited by phenylalanine arginine beta-naphthylamide (PAbetaN) in resistance to carbapenems in Chilean clinical isolates of blaKPC-harbouring Klebsiella pneumoniae. METHODS: MICs were determined by the agar dilution method for imipenem, meropenem, ertapenem and ciprofloxacin in the presence and absence of PAbetaN (25mg/L) in 17 carbapenem resistant KPC-producing K. pneumoniae strains. Outer protein membrane (OMP) profiles were determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Expression levels of the ompK35 and ompK36 genes were also determined by real-time quantitative reverse transcription PCR (qRT-PCR). RESULTS: No contribution of PAbetaN-inhibited efflux pumps to carbapenem resistance was found, unlike ciprofloxacin resistance. However, a >=4-fold increase in the MIC of at least one carbapenem was observed in 13 isolates in the presence of PAbetaN. Additionally, decreased gene expression of ompK35 and ompK36 in the presence of PAbetaN was detected, however no obvious differences in porin band intensity were observed by SDS-PAGE. CONCLUSIONS: The presence of PAbetaN resulted in an increase in carbapenem MICs unrelated to efflux pump inhibition, and a decrease in the expression of ompK35 and ompK36 genes without an obvious difference in OMP profiles observed by SDS-PAGE. Therefore, additional factors are responsible for the increase in carbapenem MIC in the presence of PAbetaN. PMID- 29275227 TI - Glycosaminoglycans in extracellular matrix organisation: are concepts from soft matter physics key to understanding the formation of perineuronal nets? AB - Conventional wisdom has it that proteins fold and assemble into definite structures, and that this defines their function. Glycosaminoglycans (GAGs) are different. In most cases the structures they form have a low degree of order, even when interacting with proteins. Here, we discuss how physical features common to all GAGs-hydrophilicity, charge, linearity and semi-flexibility underpin the overall properties of GAG-rich matrices. By integrating soft matter physics concepts (e.g. polymer brushes and phase separation) with our molecular understanding of GAG-protein interactions, we can better comprehend how GAG-rich matrices assemble, what their properties are, and how they function. Taking perineuronal nets (PNNs)-a GAG-rich matrix enveloping neurons-as a relevant example, we propose that microphase separation determines the holey PNN anatomy that is pivotal to PNN functions. PMID- 29275226 TI - Reverse-engineering organogenesis through feedback loops between model systems. AB - Biological complexity and ethical limitations necessitate models of human development. Traditionally, genetic model systems have provided inexpensive routes to define mechanisms governing organ development. Recent progress has led to 3D human organoid models of development and disease. However, robust methods to control the size and morphology of organoids for high throughput studies need to be developed. Additionally, insights from multiple developmental contexts are required to reveal conserved genes and processes regulating organ growth and development. Positive feedback between quantitative studies using mammalian organoids and insect micro-organs enable identification of underlying principles for organ size and shape control. Advances in the field of multicellular systems engineering are enabling unprecedented high-content studies in developmental biology and disease modeling. These will lead to fundamental advances in regenerative medicine and tissue-engineered soft robotics. PMID- 29275228 TI - Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B. AB - Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (Ki = 1.6 +/- 0.1 MUM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed Ki values of 0.39 +/- 0.27 and 0.20 +/- 0.01 MUM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interaction of these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB. PMID- 29275229 TI - Synthesis and biological evaluation of diarylheptanoids as potential antioxidant and anti-inflammatory agents. AB - Reactive oxygen species (ROS) are key signaling molecules and their overproduction plays an important role in the inflammation process, the secretion of inflammatory cytokines such as IL-1beta and IL-6 and the progression of inflammatory disorders. Decreasing oxidative stress represents a promising challenge in the design of antioxidant and anti-inflammatory agents. In the present study, a series of new diarylheptanoids containing allylic alcohol, amide, hydantoin or triazole fragments were synthesized and fully characterized. We evaluated the ability of these agents to block the production of intracellular ROS and the subsequent inflammatory events exerted by lipopolysaccharide (LPS) on murine macrophage RAW 264.7. Five diarylheptanoids were found to exhibit the dual required properties. PMID- 29275230 TI - Polymeric bile acid sequestrants: Review of design, in vitro binding activities, and hypocholesterolemic effects. AB - Polymeric bile acid sequestrants (BAS) have recently attracted much attention as lipid-lowering agents. These non-absorbable materials specifically bind bile acids (BAs) in the intestine, preventing bile acid (BA) reabsorption into the blood through enterohepatic circulation. Therefore, it is important to understand the structure-property relationships between the polymer sequestrant and its ability to bind specific BAs molecules. In this review, we describe pleiotropic effects of bile acids, and we focus on BAS with various molecular architectures that result in different mechanisms of BA sequestration. Here, we present 1) amphiphilic polymers based on poly(meth)acrylates, poly(meth)acrylamides, polyalkylamines and polyallylamines containing quaternary ammonium groups, 2) cyclodextrins, and 3) BAS prepared via molecular imprinting methods. The synthetic approaches leading to individual BAS preparation, as well as results of their in vitro BA binding activities and in vivo lipid-lowering activities, are discussed. PMID- 29275232 TI - Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity. AB - Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 MUM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V-FITC positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively). PMID- 29275231 TI - Development of inhibitors of receptor protein tyrosine phosphatase beta/zeta (PTPRZ1) as candidates for CNS disorders. AB - A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC50 = 0,1 MUM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity. Docking and molecular dynamics experiments have been used to analyze the binding mode and to explain the observed selectivity against PTP1B. An In vivo experiment has demonstrated that 10a can cross the BBB, thus promoting the possibility of moving forward these candidates for the development of drugs for the treatment of CNS disorders, such as drug addiction and neurodegenerative diseases. PMID- 29275233 TI - Synthesis, physicochemical properties, and biological activity of bile acids 3 glucuronides: Novel insights into bile acid signalling and detoxification. AB - Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis. PMID- 29275234 TI - A case of gastric glomus tumor resection using laparoscopy endoscopy cooperative surgery (LECS). AB - INTRODUCTION: Gastric glomus tumors are rare submucosal mesenchymal tumors. Because gastric glomus tumors are submucosal tumors and resemble gastrointestinal stromal tumors (GISTs), preoperative diagnosis is difficult. We present a case of gastric glomus tumor that was removed by laparoscopy endoscopy cooperative surgery (LECS). CASE PRESENTATION: A 67-year-old female was taken to the emergency room at our hospital due to epigastric pain. An upper gastrointestinal endoscopy revealed a submucosal tumor (SMT) located in the lesser curvature of the upper body of the stomach. Endoscopic ultrasonography revealed an intraluminal hypoechoic tumor located in the third or fourth layer of the stomach wall. Contrast-enhanced computed tomography (CECT) of the abdomen showed a 20-mm, well-enhanced, intraluminal-type tumor located in the lesser curvature of the upper body of the stomach. Laparoscopy endoscopy cooperative surgery (LECS) was performed. Immunohistochemistry revealed the expression of smooth muscle actin and vimentin, but not of keratin, S-100 protein, C-kit, or CD34. The tumor was finally diagnosed as a gastric glomus tumor. CONCLUSION: Glomus tumors are rare submucosal tumors of the stomach, and they should be considered in the differential diagnosis of gastric submucosal tumors. LECS could be a less invasive and effective method for treatment of gastric glomus tumor. PMID- 29275235 TI - Endovascular treatment of renal arterial perforation after blunt trauma: Case report. AB - INTRODUCTION: Isolated renal arterial perforation is a rare consequence of blunt abdominal trauma. Meticulous surgical control of retroperitoneal active bleeding is difficult due to oozing of soft connective tissue, the deep position of operative field, and the presence of friable vascular tissue. Therefore, endovascular treatment is often preferred. PRESENTATION OF CASE: An 83-year-old man was transferred to our trauma center due to retroperitoneal active bleeding after a car accident, in which his right upper abdomen struck the steering wheel. Contrast-enhanced abdominal computed tomography (CT) showed a retroperitoneal hematoma behind the inferior vena cava and contrast medium extravasation on the medial side of the right kidney. Selective right renal arteriography confirmed a perforation in the proximal right main renal artery, approximately 3 cm from the ostium. We successfully placed a covered stent across the perforation site. DISCUSSION: Endovascular management may reduce the likelihood of extensive abdominal surgery, surrounding organ damage, risk of bleeding, and postoperative morbidity. We regarded embolization as inappropriate for kidney salvage in our patient, and therefore used a self-expanding covered stent to treat the perforation. CONCLUSION: Endovascular management of a traumatic renal arterial injury is the best approach to preserve renal function in hemodynamically stable patients who cannot tolerate laparotomy, due to risks associated with general anesthesia, and who can tolerate anticoagulation therapy. PMID- 29275236 TI - Corrigendum to "Management of traumatic blunt IVC injury" [Int. J. Surg. Case Rep. 28 (2016) 26-30]. PMID- 29275237 TI - Management of radiation induced, bilateral Primary THA loosening with an aseptic Paprosky Type IIB acetabular defect and a contralateral septic Type IIIB acetabular defect: A case report and review of literature. AB - INTRODUCTION: Primary THA in an irradiated hip poses risk for early loosening and inadequate ingrowth.Adverse effects such as decreased vascularity and increased infection risk pose a threat. CASE PRESENTATION: Our patient was a case of post irradiation (for cervical cancer) bilateral THA loosening causing aseptic acetabular loosening on one side and catastrophic septic loosening with a Paprosky type IIIB acetabular defect with pelvic discontinuity on the contralateral side. DISCUSSION: There have been various studies documenting deleterious effects of irradiation on osseointegration and provide a challenge for long-term implant stability in THA patients. CONCLUSION: A meticulous treatment protocol with contemporary implant technology and staged bilateral stepwise management can lead to satisfactory clinical outcomes.This case report highlights on such specific nuances and principles. PMID- 29275238 TI - Simultaneous pregnancy in each uterine cavity of a double uterus in a young Nigerian multipara who presented with a retained second twin following an unsupervised preterm labor at home; Case report. AB - INTRODUCTION: Simultaneous pregnancy in each uterine cavity of a double uterus is unusual but is a recognized risk factor for preterm labour and other poor obstetrics outcomes. The work has been reported in line with the SCARE criteria. PRESENTATION OF CASE: We report an unusual case of simultaneous pregnancy in each uterine cavity of a double uterus in a young African grand multipara who presented with a retained second twin following a preterm labour at home. DISCUSSION: A double or didelphys uterus as reported in the literatures is still uncommon even in Africa. While infections are very important and always considered causes of preterm labour a high index of suspicion will help give a diagnosis of a uterine anomaly and this will lead to more precise clinical examinations and studies in cases of recurrent miscarriages and preterm birth where other causes such as infection and cervical incompetence has been ruled out. CONCLUSION: Double uterus is an important cause of recurrent preterm labourv and miscarriages as seen in the index case. Thorough pelvic examination should be conducted for women of reproductive age groups when they present for gynecological consultation to rule out the rare occurrence of double uterus and other uterine abnormalities. Health education should be intensified through different media on the reality of double uterus and its attendant complications as a means to boost ante natal care booking and attendance for early diagnosis and appropriate management of this congenital anomaly. PMID- 29275240 TI - Decomposition of moral hazard. AB - This study seeks to simulate the portion of moral hazard that is due to the income transfer contained in the coinsurance price reduction. Healthcare spending of uninsured individuals from the MEPS with a priority health condition is compared with the predicted counterfactual spending of those same individuals if they were insured with either (1) a conventional policy that paid off with a coinsurance rate or (2) a contingent claims policy that paid off by a lump sum payment upon becoming ill. The lump sum payment is set to be equal to the insurer's predicted spending under the coinsurance policy. The proportion of moral hazard that is efficient is calculated as the proportion of total moral hazard that is generated by this lump sum payment. We find that the efficient proportion of moral hazard varies from disease to disease, but is the highest for those with diabetes and cancer. PMID- 29275239 TI - Under ambient UVA exposure, pefloxacin exhibits both immunomodulatory and genotoxic effects via multiple mechanisms. AB - Pefloxacin (PFLX) is an antibiotic, which shows broad spectrum antimicrobial activities. It is an important derivative of fluoroquinolones (FLQs) group. Ultraviolet radiation (200-400nm) causes major problem for living being which comes at the earth surface naturally through sunlight and increasing regularly due to ozone depletion. PFLX was photodegraded in 5h and forms photoproduct under UVA exposure. At the non photocytotoxic dose PFLX, shows reduced phagocytosis activity, NO (nitric oxide) production, large vacuole formation and down regulated IL-6, TNF-alpha and IL-1 in BALB/c macrophages at both genes and proteins levels. At higher doses (photocytotoxic doses), PFLX induced a concentration dependent decrease in cell viability of human keratinocyte cell line (HaCaT) and peritoneal macrophages of BALB/c mice. Our molecular docking suggests that PFLX binds only to the cleaved DNA in the DNA-human TOP2A complex. Topoisomerase assay confirmed that PFLX inhibits human topoisomerase by forming an adduct with DNA. Photosensitized PFLX also caused intracellular ROS mediated DNA damage and formation of micronuclei and cyclobutane pyrimidine dimers (CPDs). Increase intracellular ROS leads to apoptosis which was proved through lysosomal destabilization and reduced mitochondrial membrane potential (MMP). Our present study shows that ambient UVA exposure in the presence of PFLX caused immunomodulatory as well as photogenotoxic effects. Therefore, patients under PFLX drug treatment should avoid sunlight exposure, especially during peak hours for their photosafety. PMID- 29275241 TI - If looks could heal: Child health and paternal investment. AB - Data from the first two waves of the Fragile Family and Child Wellbeing study indicate that infants who look like their father at birth are healthier one year later. The reason is such father-child resemblance induces a father to spend more time engaged in positive parenting. An extra day (per month) of time-investment by a typical visiting father enhances child health by just over 10% of a standard deviation. This estimate is not biased by the effect of child health on father involvement or omitted maternal ability, thereby eliminating endogeneity biases that plague existing studies. The result has implications regarding the role of a father's time in enhancing child health, especially in fragile families. PMID- 29275242 TI - Maternal cumulative exposure to extremely low frequency electromagnetic fields and pregnancy outcomes in the Elfe cohort. AB - OBJECTIVES: To study the relations between maternal cumulative exposure to extremely low frequency electromagnetic fields (ELF EMF) and the risk of moderate prematurity and small for gestational age within the Elfe cohort. METHODS: The Elfe study included 18,329 infants born at 33weeks of gestation or more in France in 2011 and was designed to follow the children until 20years of age. Gestational age and anthropometric data at birth were collected in medical records and small for gestational age was defined according to a French customized growth standard. During interviews, mothers were asked to report their job status during pregnancy. If employed, their occupation was coded according to the International Standard Classification of Occupations 1988 and the date on which they stopped their work was recorded. Cumulative exposure to ELF EMF during pregnancy was assessed, for both mothers who worked and those who did not during pregnancy, using a recently-updated job-exposure matrix (JEM). Cumulative exposure was considered as a categorical variable (<17.5, 17.5-23.8, 23.8-36.2, 36.2-61.6 or >=61.6MUT-days), a binary variable (<44.1 and >=44.1MUT-days) and a continuous variable. Associations were analyzed by logistic regression, adjusting for the mother's lifestyle factors, sociodemographic characteristics and some mother's medical history during and before pregnancy. Analyses were restricted to single births and to complete values for the pregnancy outcomes (n=16,733). RESULTS: Cumulative exposure was obtained for 96.0% of the mothers. Among them, 37.5% were classified in the 23.8-36.2MUT-days category, but high exposures were rare: 1.3% in the >=61.6MUT-days category and 5.5% in the >=44.1MUT-days category. No significant association was observed between maternal cumulative exposure and moderate prematurity and small for gestational age in this exposure range. CONCLUSION: This large population-based study does not suggest that maternal exposure to ELF EMF during pregnancy is highly associated with risks of moderate prematurity or small for gestational age. PMID- 29275243 TI - WITHDRAWN: Cytogenetics alteration in adult men involved in the recycling of electronic wastes. PMID- 29275244 TI - Environmental arsenic exposure: From genetic susceptibility to pathogenesis. AB - More than 200 million people in 70 countries are exposed to arsenic through drinking water. Chronic exposure to this metalloid has been associated with the onset of many diseases, including cancer. Epidemiological evidence supports its carcinogenic potential, however, detailed molecular mechanisms remain to be elucidated. Despite the global magnitude of this problem, not all individuals face the same risk. Susceptibility to the toxic effects of arsenic is influenced by alterations in genes involved in arsenic metabolism, as well as biological factors, such as age, gender and nutrition. Moreover, chronic arsenic exposure results in several genotoxic and epigenetic alterations tightly associated with the arsenic biotransformation process, resulting in an increased cancer risk. In this review, we: 1) review the roles of inter-individual DNA-level variations influencing the susceptibility to arsenic-induced carcinogenesis; 2) discuss the contribution of arsenic biotransformation to cancer initiation; 3) provide insights into emerging research areas and the challenges in the field; and 4) compile a resource of publicly available arsenic-related DNA-level variations, transcriptome and methylation data. Understanding the molecular mechanisms of arsenic exposure and its subsequent health effects will support efforts to reduce the worldwide health burden and encourage the development of strategies for managing arsenic-related diseases in the era of personalized medicine. PMID- 29275245 TI - Association of co-exposure to heavy metals with renal function in a hypertensive population. AB - BACKGROUND: Chronic kidney disease (CKD) is an increasing health problem worldwide. Recent studies have suggested the potential associations between exposure to metals and CKD events, particularly in participants with hypertension. However, relevant studies are limited. OBJECTIVES: We aimed to explore the associations of metal exposure with renal function in participants with essential hypertension. METHODS: Nine hundred and thirty-four participants with essential hypertension were recruited at the Department of Cardiology, Union Hospital, Wuhan, China. We measured the levels of chromium, cadmium, thallium and uranium in urine and calculated the estimated glomerular filtration rate (eGFR) for renal function. Multivariable linear regression models adjusted for potential confounders were applied. RESULTS: After adjusting for potential confounders and other metals, doubling of urinary chromium or uranium levels decreased eGFR by 2.90 (95% confidence interval, 2.04 to 3.76) and 1.87 (0.58 to 3.15) mL/min per 1.73m2, respectively. Co-exposure to chromium and uranium was found to greatly decrease eGFR, particularly in women. Compared with those in the low exposure group, women with high exposure to chromium and uranium had a 11.36 (3.66 to 19.07) mL/min per 1.73m2 adjusted decline in eGFR. Higher urinary thallium levels were positively related to elevated eGFR in men. The adjusted increase in eGFR with doubling of thallium levels was 3.12 (1.14 to 5.10) mL/min per 1.73m2. Sex difference in the associations of exposure to heavy metals with eGFR was also suggested. CONCLUSIONS: Our findings suggest that environmental exposure to chromium and uranium might contribute to a decline in eGFR in individuals with hypertension. The associations of exposure to heavy metals with eGFR might be sex different. Further studies are warranted to confirm our findings and clarify the underlying mechanisms. PMID- 29275247 TI - Light-sensitive dextran-covered PNBA nanoparticles as triggered drug delivery systems: Formulation, characteristics and cytotoxicity. AB - HYPOTHESIS: For some years, smart nano-objects are one of the main focuses of current research. In the framework of polymeric nanomedicine, o-nitrobenzyl alcohol derivatives lead to light-responsive polymeric materials. At this day, nanomedicine based on polysaccharide/poly(o-nitrobenzyl acrylate) (PNBA) copolymers have never been reported. EXPERIMENTS: For the first time, PNBA core/dextran shell nanoparticles (NPs) were formulated by evaluating two different processes: (i) nanoprecipitation of preformed Dextran-g-PNBA glycopolymers, (ii) emulsion/evaporation using azido-functionalized PNBA and alkynated dextran, carrying out (or not) an interfacial click chemistry reaction. NPs' characterization, colloidal stability in the presence of salts and of an anionic competitive surfactant (SDS) and light-induced disruption were assessed. Finally, the potential use of these NPs as photo-responsive drug delivery systems was investigated by a preliminary in vitro cytotoxicity study using Caco-2 cells. FINDINGS: Whatever the process, the photosensitive property and the colloidal stability of NPs in the presence of salts were proved. However, triazole rings between the dextran shell and the PNBA core avoid the dextran shell desorption in the presence of SDS. NPs' biocompatibility towards Caco-2 was proved and 100% cell viability was still observed after exposure to NPs following by 60 s UV irradiation. PMID- 29275246 TI - Advances in mass spectrometry imaging coupled to ion mobility spectrometry for enhanced imaging of biological tissues. AB - Tissues present complex biochemical and morphological composition associated with their various cell types and physiological functions. Mass spectrometry (MS) imaging technologies are powerful tools to investigate the molecular information from biological tissue samples and visualize their complex spatial distributions. Coupling of gas-phase ion mobility spectrometry (IMS) technologies to MS imaging has been increasingly explored to improve performance for biological tissue imaging. This approach allows improved detection of low abundance ions and separation of isobaric molecular species, thus resulting in more accurate determination of the spatial distribution of molecular ions. In this review, we highlight recent advances in the field focusing on promising applications of these technologies for metabolite, lipid and protein tissue imaging. PMID- 29275248 TI - Atoms diffusion-induced phase engineering of platinum-gold alloy nanocrystals with high electrocatalytic performance for the formic acid oxidation reaction. AB - Bimetallic noble metal nanocrystals have been widely applied in many fields, which generally are synthesized by the wet-chemistry reduction method. This work presents a purposely designed atoms diffusion induced phase engineering of PtAu alloy nanocrystals on platy Au substrate (PtAu-on-Au nanostructures) through simple hydrothermal treatment. Benefitting from the synergistic effects of component and structure, PtAu-on-Au nanostructures remarkably enhance the dehydrogenation pathway of the formic acid oxidation reaction (FAOR), and thus exhibit much higher FAOR activity and durability compared with Pt nanocrystals on platy Au substrate (Pt-on-Au nanostructures) and commercial Pd black due to an excellent stability of platy Au substrate and a high oxidation resistance of PtAu alloy nanocrystals. The atoms diffusion-induced phase engineering demonstrated in this work builds a bridge between the traditional metallurgy and modern nanotechnologies, which also provides some useful insights in developing noble metals based alloyed nanostructures for the energy and environmental applications. PMID- 29275249 TI - SnS2/SnO2 heterostructured nanosheet arrays grown on carbon cloth for efficient photocatalytic reduction of Cr(VI). AB - Nowadays, among the many heavy metal pollutants, hexavalent chromium (Cr(VI)) seriously threatens ecological systems and human health due to its high solubility, acute toxicity and potential carcinogenicity in wastewater. Meanwhile, semiconductor photocatalytic reduction is continuously gaining increasing significant research attention in the treatment of Cr(VI). Hence, we report an efficient preparation method for SnS2/SnO2 composites on carbon cloth (CC), for efficient photocatalytic reduction of aqueous Cr(VI). The morphology, composition, surface elements and optical properties of CC@SnS2/SnO2 composites were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and UV-vis diffuse reflectance spectroscopy. It was found that carbon cloth (CC) could be effectively used as a catalyst support in the obtained SnS2/SnO2 composites. In addition, the CC@SnS2 calcined 30 min exhibited the best efficiency for photocatalytic reduction of aqueous Cr(VI), which can be attributed to the formation of a heterostructure and the effective separation of photogenerated electrons (e-) and holes (h+). It was also found that acidic conditions are more favorable for the photocatalytic reduction of aqueous Cr(VI) due to the presence of abundant H+. The photocatalytic mechanism of as-prepared composites is also discussed in detail. PMID- 29275250 TI - Porous micropillar structures for retaining low surface tension liquids. AB - The ability to manipulate fluid interfaces, e.g., to retain liquid behind or within porous structures, can be beneficial in multiple applications, including microfluidics, biochemical analysis, and the thermal management of electronic systems. While there are a variety of strategies for controlling the disposition of liquid water via capillarity, such as the use of chemically modified porous adhesive structures and capillary stop valves or surface geometric features, methods that work well for low surface tension liquids are far more difficult to implement. This study demonstrates the microfabrication of a silicon membrane that can retain exceptionally low surface tension fluorinated liquids against a significant pressure difference across the membrane via an array of porous micropillar structures. The membrane uses capillary forces along the triple phase contact line to maintain stable liquid menisci that yield positive working Laplace pressures. The micropillars have inner diameters and thicknesses of 1.5-3 MUm and ~1 MUm, respectively, sustaining Laplace pressures up to 39 kPa for water and 9 kPa for FluorinertTM (FC-40). A theoretical model for predicting the change in pressure as the liquid advances along the porous micropillar structure is derived based on a free energy analysis of the liquid meniscus with capped spherical geometry. The theoretical prediction was found to overestimate the burst pressure compared with the experimental measurements. To elucidate this deviation, transient numerical simulations based on the Volume of Fluid (VOF) were performed to explore the liquid pressure and evolution of meniscus shape under different flow rates (i.e., Capillary numbers). The results from VOF simulations reveal strong dynamic effects where the anisotropic expansion of liquid along the outer micropillar edge leads to an irregular meniscus shape before the liquid spills along the micropillar edge. These findings suggest that the analytical prediction of burst Laplace pressure obtained under quasi-static condition (i.e., equilibrium thermodynamic analysis under low capillary number) is not applicable to highly dynamic flow conditions, where the liquid meniscus shape deformation by flow perturbation cannot be restored by surface tension force instantaneously. Therefore, the critical burst pressure is dependent on the liquid velocity and viscosity under dynamic flow conditions. A numerical simulation using Surface Evolver also predicts that surface defects along the outer micropillar edge can yield up to 50% lower Laplace pressures than those predicted with ideal feature geometries. The liquid retention strategy developed here can facilitate the routing and phase management of dielectric working fluids for application in heat exchangers. Further improvements in the retention performance can be realized by optimizing the fabrication process to reduce surface defects. PMID- 29275251 TI - Emerging whole-cell modeling principles and methods. AB - Whole-cell computational models aim to predict cellular phenotypes from genotype by representing the entire genome, the structure and concentration of each molecular species, each molecular interaction, and the extracellular environment. Whole-cell models have great potential to transform bioscience, bioengineering, and medicine. However, numerous challenges remain to achieve whole-cell models. Nevertheless, researchers are beginning to leverage recent progress in measurement technology, bioinformatics, data sharing, rule-based modeling, and multi-algorithmic simulation to build the first whole-cell models. We anticipate that ongoing efforts to develop scalable whole-cell modeling tools will enable dramatically more comprehensive and more accurate models, including models of human cells. PMID- 29275252 TI - Emission factors of volatile organic compounds (VOCs) based on the detailed vehicle classification in a tunnel study. AB - In order to obtain VOCs emission characteristics and emission factors from vehicle, a tunnel experiment was conducted in the Fu Gui Mountain Tunnel in Nanjing, China. The tunnel is located in the middle of city, with total length of 480m and speed limit of 50km/h. The studied vehicle fleet was composed of 87% light duty vehicles and 13% heavy duty vehicles (liquefied natural gas bus, LNGB). The emerging radio frequency identification (RFID) technology was used to divide fine vehicles type including China I, China II, China III, China IV, China V and LNGB. Ambient air samples (4-h averages) were collected inside the tunnel using 3.2L stainless-steel canisters. Samples collected in the canisters were analyzed for 97 individual VOCs using high-resolution GC-MS in the laboratory. The average tunnel emission factor for the collective light-duty vehicles was 160.79+/-65.94mg/(km*veh), and for the China I, China II, China III, China IV and China V vehicles, it was 632.07+/-259.44, 450.35+/-184.85, 205.42+/-84.32, 118.51+/-48.65, and 110.61+/-45.4mg/(km*veh), respectively. The average emission factor for heavy-duty vehicles was 358.02+/-124.86mg/(km*veh). Ethane, isopentane, propane, ethylene, toluene, propylene and 2,3-dimethylbutane were the most common VOC species in vehicle emissions. The total O3 formation potential was 373.88mg*O3/(km*veh) in the tunnel. Ethylene, propylene, m/p-xylene, toluene, and isopentane were the largest contributors to O3 production. Compared with previous studies, fuel quality increased from China II-FQ to China IV-FQ levels, while the BTEX emission levels exhibited a decreasing trend. PMID- 29275253 TI - Impact of land use changes on the storage of soil organic carbon in active and recalcitrant pools in a humid tropical region of India. AB - Quantifying soil organic carbon (SOC) dynamics is important in understanding changes in soil properties and carbon (C) fluxes. However, SOC measures all C fractions and it is not adequate to distinguish between the active C (AC) and recalcitrant or passive C (PC) fractions. It has been suggested that PC pools are the main drivers of long term soil C sink management. Therefore, the present study was undertaken with the objective of determining whether or not SOC fractions vary with land use changes under a humid tropical climate in the North East India. A chronosequence study was established consisting of natural forest, Imperata cylindrica grassland and 6, 15, 27 and 34yr old rubber (Hevea brasiliensis) plantations to determine changes in the different fractions of SOC and total SOC stock. SOC stocks significantly varied with soil depth in each land use practice. SOC stocks increased from 106Mgha-1 under 6yr to 130Mgha-1 under 34yr old rubber plantations. The SOC stocks under 34yr old plantations were 20% higher than that under I. cylindrica grassland, but 34% lower than SOC stocks recorded under natural forest soil. The proportion of AC pools decreased with increase in plantation age, AC pools being 59% of SOC stock in 6yr old stands and 33% of SOC stocks in 34yr old plantations. In contrast, the proportion of PC pools increased from 41% of SOC stock in 6yr old plantation to 67% of SOC in 34yr old plantation. In the 50-100cm soil depth, the PC pool under 27-34yr old plantations was comparable with that under natural forest but much higher than in I. cylindrica grassland. Therefore, it is concluded that old rubber plantations can play a significant role in long term soil C sink management. PMID- 29275254 TI - Diel cycles of reduced manganese and their seasonal variability in the Marque River (northern France). AB - Electrolabile reduced manganese (II) has been monitored by voltammetry during two periods of one month in summer 2014 and at the end of winter 2015 in a small river (the Marque River) located in northern France and going through a suburban area with agricultural activities. Diel variations, evolution within the one month periods and seasonal differences have been observed. Taking into consideration the multiple physical, biological and chemical reactions regulating manganese speciation in aquatic systems, it has been demonstrated that manganese speciation is probably controlled by the competition of two antagonist reactions: the photoreduction of manganese oxides (in broad sense and represented thereafter by MnOx) and the biotic oxidation of Mn(II). Depending on the season, the biological activity in the river and the amount of luminosity reaching the MnOx, either the production of reduced labile Mn(II) or the precipitation of MnOx can become the dominant process. Other punctual events such as the drop of oxygen concentration due to large inputs of biodegradable organic matter and eutrophication phenomena, rainy events and high luminosity periods can also affect the behaviour of dissolved Mn(II) in the Marque River and so, of other contaminants. PMID- 29275255 TI - Weather variables and the El Nino Southern Oscillation may drive the epidemics of dengue in Guangdong Province, China. AB - OBJECTIVE: To investigate the periodicity of dengue and the relationship between weather variables, El Nino Southern Oscillation (ENSO) and dengue incidence in Guangdong Province, China. METHODS: Guangdong monthly dengue incidence and weather data and El Nino index information for 1988 to 2015 were collected. Wavelet analysis was used to investigate the periodicity of dengue, and the coherence and time-lag phases between dengue and weather variables and ENSO. The Generalized Additive Model (GAM) approach was further employed to explore the dose-response relationship of those variables on dengue. Finally, random forest analysis was applied to measure the relative importance of the climate predictors. RESULTS: Dengue in Guangdong has a dominant annual periodicity over the period 1988-2015. Mean minimum temperature, total precipitation, and mean relative humidity are positively related to dengue incidence for 2, 3, and 4months lag, respectively. ENSO in the previous 12months may have driven the dengue epidemics in 1995, 2002, 2006 and 2010 in Guangdong. GAM analysis indicates an approximate linear association for the temperature-dengue relationship, approximate logarithm curve for the humidity-dengue relationship, and an inverted U-shape association for the precipitation-dengue (the threshold of precipitation is 348mm per month) and ENSO-dengue relationships (the threshold of ENSO index is 0.6 degrees C). The monthly mean minimum temperature in the previous two months was identified as the most important climate variable associated with dengue epidemics in Guangdong Province. CONCLUSION: Our study suggests weather factors and ENSO are important predictors of dengue incidence. These findings provide useful evidence for early warning systems to help to respond to the global expansion of dengue fever. PMID- 29275256 TI - Sources and distribution of aromatic hydrocarbons in a tropical marine protected area estuary under influence of sugarcane cultivation. AB - Goiana estuary is a well preserved marine protected area (MPA) located on the northeastern coast of Brazil. Despite its current state, human activities in the watershed represent a potential threat to long term local preservation. Dissolved/dispersed aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs) were investigated in water and sediments across the estuarine salt gradient. Concentration of aromatic hydrocarbons was low in all samples. According to results, aromatic hydrocarbons are associated to suspended particulate matter (SPM) carried to the estuary by river waters. An estuarine turbidity maximum (ETM) was identified in the upper estuary, indicating that both sediments and contaminants are trapped prior to an occasional export to the adjacent sea. PAHs distribution in sediments were associated with organic matter and mud content. Diagnostic ratios indicated pyrolytic processes as the main local source of PAHs that are probably associated with sugarcane burning and combustion engines. Low PAH concentrations probably do not cause adverse biological effects to the local biota although their presence indicate anthropogenic contamination and pressure on the Goiana estuary MPA. PMID- 29275257 TI - Natural nutrient enrichment and algal responses in near pristine micro-estuaries and micro-outlets. AB - Naturally-occurring pristine estuarine ecosystems are rare in modern environments due to anthropogenic encroachment. There are more than 100 outlets around the South African coast arising from streams flowing from small catchments close to the sea. Eight near natural systems were sampled seasonally over the period of a year to acquire baseline information on water quality and chlorophyll a status across a variety of algal guilds (benthic microalgae, phytoplankton and macroalgal cover). Albeit on a much smaller-scale, these systems represent natural surrogates of larger temporarily open/closed estuaries (TOCEs). Inorganic nutrients (ammonium, total oxidized nitrogen and soluble reactive phosphate), phytoplankton and microphytobenthos chlorophyll a, as well as macroagal percentage cover, were measured using standard methods. Algae showed a seasonal trend, with blooms of both micro- and macro-algae occurring during summer, with a dieback recorded in autumn. During summer, only one system had a phytoplankton peak in chlorophyll a above 20MUgL-1, while the microphytobenthos concentrations in three of the systems were above 100mgm-2. Summer blooms of green filamentous macroalgae occurred in all four micro-outlets and in one micro-estuary. Using a linear mixed-effects modelling approach, significant drivers for algal growth related to temperature, nutrient conditions, light availability and water residence time, all of which are known to stimulate primary production. The results show that enrichment from natural sources display similar responses from primary producers to mesotrophic and/or eutrophic water bodies, with the exception that they revert to a natural state rather than continue into a degraded state as is the case in artificially enriched systems. This importantly demonstrates how larger temporarily/open closed estuaries, most of which are anthropogenically degraded, might have functioned under a former more balanced state. Some of these larger systems now respond to nutrient enrichment by exhibiting permanent cultural eutrophication. PMID- 29275258 TI - Dioxins and furans legacy of lindane manufacture in Sabinanigo (Spain). The Bailin landfill site case study. AB - Lindane (gamma-hexachlorocyclohexane) manufacture in Spain generated nearly 200,000tonnes of HCH wastes; near 160,000tonnes were originated by the Inquinosa factory located in Sabinanigo (northern Spain) and were deposited in unlined landfill sites. This study reports for the first time the content of polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/Fs) in non-recycled HCH wastes that had been disposed in the Bailin landfill site in Sabinanigo. Samples from solid HCH powder residues (white HCH and delta-paste wastes) and the dense non-aqueous phase liquids (DNAPLs), as well as landfill leachates, soil and sediments have been characterized. White HCH wastes exhibited a toxicity of 1488ngWHO-TEQ2005.kg-1 (Sigma17 PCDD/Fs), while delta-paste wastes presented a noticeable higher toxicity (12,094ngWHO-TEQ2005.kg-1). Nevertheless, the maximum toxicity value was found for DNAPLs (37,353ngWHO-TEQ2005.L-1). Dioxins were predominant in the DNAPL waste whereas furans predominated in the landfill leachates, soil and sediments. However, in solid HCH wastes, PCDD and PCDFs contributed in a similar proportion. The PCDD/Fs congener profiles in landfill leachates, soil and sediments do not resemble the PCDD/Fs profiles found for the HCH wastes. These preliminary results will be of paramount importance in order to estimate the total quantities of PCDD/Fs disposed to the landfill site and to assess the potential mobility of PCDD/Fs, especially to groundwater and landfill leachates. Besides, this information is of great value to design periodical monitoring plans to evaluate the presence of PCDD/Fs in the impacted groundwater and leachates and finally, to evaluate the risk of PCDD/Fs for the environment and human health. PMID- 29275259 TI - Bradyrhizobium japonicum USDA110: A representative model organism for studying the impact of pollutants on soil microbiota. AB - Photobacteria phosoreum or Escherichia coli are widely used in the scientific, industrial, and regulatory industries for evaluating the toxicity of pollutants against the soil microbial community. The organisms, however, are not part of the soil microbiota and the toxicity data obtained using these organisms could be misleading. Analysis of microbiota present in the soil obtained from across the world indicates that organisms from the Bradyrhizobium genus are the most ubiquitous of all microorganisms. Playing a critical role in nitrogen fixation and soil fertility, organisms from this genus should be used for studying the toxicity of pollutants. Indeed, we propose that Bradyrhizobium japonicum USDA110 be used as a model organism for screening pollutants for toxicity against a soil microbial community. PMID- 29275260 TI - Long-term environmental monitoring infrastructures in Europe: observations, measurements, scales, and socio-ecological representativeness. AB - The challenges posed by climate and land use change are increasingly complex, with ever-increasing and accelerating impacts on the global environmental system. The establishment of an internationally harmonized, integrated, and long-term operated environmental monitoring infrastructure is one of the major challenges of modern environmental research. Increased efforts are currently being made in Europe to establish such a harmonized pan-European observation infrastructure, and the European network of Long-Term Ecological Research sites - LTER-Europe - is of particular importance. By evaluating 477 formally accredited LTER-Europe sites, this study gives an overview of the current distribution of these infrastructures and the present condition of long-term environmental research in Europe. We compiled information on long-term biotic and abiotic observations and measurements and examined the representativeness in terms of continental biogeographical and socio-ecological gradients. The results were used to identify gaps in both measurements and coverage of the aforementioned gradients. Furthermore, an overview of the current state of the LTER-Europe observation strategies is given. The latter forms the basis for investigating the comparability of existing LTER-Europe monitoring concepts both in terms of observational design as well as in terms of the scope of the environmental compartments, variables and properties covered. PMID- 29275261 TI - Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability. AB - A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8 MUMU and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with alphaAsn101, alphaThr179, alphaSer178, betaCys241, betaLys254 and betaLys352 in the colchicine-binding site of the tubulin. PMID- 29275262 TI - Design, synthesis, antibacterial evaluation and molecular docking studies of some new quinoxaline derivatives targeting dihyropteroate synthase enzyme. AB - Development of new antimicrobial agents is a good solution to overcome drug resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities. The thiazolyl 11c displayed significant antibacterial activities against P. aeruginosa (MIC, 12.5 ug/mL vs levofloxacin 12.5 ug/mL). Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of bacterial DHPS enzyme. The results provide important information for the future design of more potent antibacterial agents. PMID- 29275263 TI - NO inhibitory constituents as potential anti-neuroinflammatory agents for AD from Blumea balsamifera. AB - Our continuous search for new nitric oxide (NO) inhibitory substances as anti neuroinflammatory agents for AD resulted in the isolation of one new labdane diterpenoid and three new guaiane sesquiterpenoids, as well as ten known compounds from Blumea balsamifera. Their structures were elucidated by NMR spectroscopic data analysis and the time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. The anti neuroinflammatory effects were examined by inhibiting NO release in LPS-induced murine microglial BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the iNOS protein. PMID- 29275264 TI - Venous thromboembolism risk and postpartum lying-in: Acculturation of Indian and Chinese women. AB - OBJECTIVE: many cultures have a set time of traditional rest in the postpartum period. There is limited information on how this activity may potentially increase the risk of venous thromboembolism (VTE). We aimed to investigate VTE risk by determining the prevalence of the cultural practice of postpartum "lying in", quantifying activity and determining the factors that influence this tradition in women from China and the Indian subcontinent (India, Bangladesh, Pakistan and Sri Lanka) at an Australian tertiary referral hospital. DESIGN: we surveyed a prospective cohort of 150 women aged >= 18 years who self-identified culturally as from the Indian subcontinent or Chinese, at baseline (>= 32 weeks gestation) and at follow-up (six to eight weeks postpartum). Demographic details collected included VTE risk factors such as caesarean section, lack of graduated compression stockings (GCS), postpartum haemorrhage greater than 1000mL, comorbidities and immobility. We quantified postpartum activities and investigated factors that might influence inactivity. RESULTS: there were 100 women identifying as from the Indian subcontinent and 50 women identifying as Chinese recruited at the baseline of over 32 weeks' gestation. Most of the study participants (85%) rested in the postpartum period for cultural reasons. Of the women surveyed, 51% rested in bed as much as possible in the postpartum period. We found a significant correlation between increased number of children and decreased overall immobility or rest (P = 0.03). Overall, 91% of participants had relative live-in help, and this significantly increased the risk of immobility by more than six-fold (odds ratio [OR], 6.17; 95% CI, 1.6-23.5; P = 0.008). Furthermore, a vaginal compared to a caesarean birth increased immobility risk by almost 3.5 times (OR, 3.4; 95% CI, 1.20-9.4; P = 0.021). CONCLUSIONS: acculturation is highly individualised, however postpartum rest remains prevalent in women who identify themselves culturally as from the Indian subcontinent or as Chinese. Inactivity and comorbidities compounded the impact of cultural postpartum rest, and put women at increased risk for VTE. IMPLICATIONS FOR PRACTICE: targeted, culturally appropriate, postnatal education should include VTE-prevention information to women who intend to practise postpartum rest. PMID- 29275265 TI - Anesthetic and pharmacologic considerations in perioperative care of obese children. AB - PURPOSE: Anesthetic management of obese pediatric patients is challenging. With increasing prevalence of childhood obesity, more severely obese children with comorbidities present for surgery every day. The purpose of this review is to provide an up-to-date comprehensive narrative review on the impact of pathophysiological changes imposed by pediatric obesity on the perioperative management of obese children, especially drug dosing. This knowledge is necessary to provide safe delivery of anesthesia for severely obese children. SOURCE: MEDLINE and PubMed peer-reviewed manuscripts in obesity and pediatric anesthesia. When there was no information in pediatric literature, we included adult studies in our review. PRINCIPAL FINDINGS: Defining obesity in a growing child is based on body mass index percentiles specific to age and sex. The precursors of adult obesity-related comorbidities are often seen in obese children. Respiratory and cardiovascular comorbidities increase perioperative risk in the severely obese child [>99th percentile]. Obstructive sleep apnea is highly prevalent and requires consideration of opioid sparing techniques and careful postoperative disposition. A detailed discussion on the effect of obesity on pharmacokinetics of different commonly used anesthetics and analgesics is presented, with current recommendations on dosing. CONCLUSION: Optimal and safe anesthetic management of an obese child requires thoughtful pre-procedure assessment and meticulous perioperative management tailored to associated comorbidities, with heightened awareness of potential perioperative complications. There remains a need for improved guidelines for risk stratification, drug dosing and postoperative disposition in this patient population. PMID- 29275266 TI - Intraoperative clevidipine use to manage an acute hypertensive episode in a patient with a simultaneous kidney-pancreatic transplant. PMID- 29275267 TI - The correlation of the depth of anesthesia and postoperative cognitive impairment: A meta-analysis based on randomized controlled trials. AB - STUDY OBJECTIVE AND BACKGROUND: To comprehensively evaluate the associations between the depth of anesthesia and postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). DESIGN: Using the Cochrane evaluation system, the included studies were conducted with quality assessment. DATA SOURCES: We searched Cochrane library, Embase and PubMed databases without language restriction. The retrieval time is up to August 2017. ELIGIBILITY CRITERIA: According to the PRISMA guideline, the results associated with POCD and POD separately were compared between low and high bispectral index (BIS) groups under fixed effects model or random effects model. Besides, the risk ratio (RR) and 95% confidence intervals (95% CIs) were utilized as the effect sizes for merging the results. Furthermore, sensitivity analysis was performed to evaluate the stability of the results. Using Egger's test, publication bias was assessed for the included studies. RESULTS: Totally, 4 studies with high qualities were selected for this meta-analysis. The merged results of POCD showed no significant difference between low and high BIS groups (RR (95% CI)=0.84 (0.21, 3.45), P>0.05). Sensitivity analysis showed that the merged results of POCD were not stable (RR (95%CI)=0.41 (0.17, 0.99)-1.88 (1.09, 3.22), P=0.046). Additionally, no significant publication bias for POCD was found (P=0.385). CONCLUSION: There was no significant correlation between the depth of anesthesia and POCD. PMID- 29275268 TI - Ultrasound guided low thoracic erector spinae plane block for management of acute herpes zoster. PMID- 29275269 TI - Improving ICU services in resource-limited settings: Perceptions of ICU workers from low-middle-, and high-income countries. AB - PURPOSE: To evaluate perceptions of intensive care unit (ICU) workers from low and-middle income countries (LMICs) and high income countries (HICs). MATERIALS AND METHODS: A cross sectional design. Data collected from doctors using an anonymous online, questionnaire. RESULTS: Hundred seventy-five from LMICs and 43 from HICs participated. Barriers in LMICs were lack of formal training (Likert score median 3 [inter quartile range 3]), lack of nurses (3[3]) and low wages (3[4]). Strategies for LMICs improvement were formal training of ICU staff (4[3]), an increase in number of ICU nurses (4[2]), collection of outcome data (3[4]), as well as maintenance of available equipment [3(3)]. The most useful role of HIC ICU staff was training of LMIC staff (4[2]). Donation of equipment [2(4)], drugs [2(4)], and supplies (2[4]) perceived to be of limited usefulness. The most striking difference between HIC and LMIC staff was the perception on the lack of physician leadership as an obstacle to ICU functioning (4[3] vs. 0[2], p<0.005). CONCLUSION: LMICs ICU workers perceived lack of training, lack of nurses, and low wages as major barriers to functioning. Training, increase of nurse workforce, and collection of outcome data were proposed as useful strategies to improve LMIC ICU services. PMID- 29275270 TI - Distribution and partitioning of polybrominated diphenyl ethers in sediments from the Pearl River Delta and Guiyu, South China. AB - Polybrominated diphenyl ethers (PBDEs) were investigated by GC-NCI-MS in sediments collected from the Pearl River Delta (PRD) and Guiyu town, South China. The concentrations of ?39PBDEs and BDE 209 were in the ranges of 0.31-38.9 ng g-1 and 12.2-488 ng g-1 in the PRD, and 2.57-21,207 ng g-1 and 7.02-66,573 ng g-1 in Guiyu, respectively. The levels of PBDEs in Dongjiang River (DJ), Zhujiang River (ZJ), and Beijiang River (BJ), and Guiyu (GY) followed the order: GY > DJ > ZJ > BJ. The very high PBDE concentration (87,779 ng g-1) was detected at G1 sediment in Guiyu compared with those in sediments from other regions around the world. The PBDE mixtures detected were mainly comprised of penta-, octa-, and deca-BDEs, in which deca-BDE was the dominant constituent. The abundant congeners, excluding BDE-209, were BDE-47, BDE-99, and BDE-183, suggesting the diverse use of commercial products containing these congeners in this region. The concentrations of major congeners were significantly correlated with total organic carbon (TOC) contents (p < .01). A good regression between the logarithmic TOC-normalized BDE average concentrations and their log Kow confirmed that the sorption of PBDEs on sediment organic matter governed their spatial distribution, transport, and fate in the sediments. Furthermore, risk quotients (RQs) derived from concentrations of PBDEs in sediments from our study may pose high ecological risks to exposure of benthic organisms. PMID- 29275271 TI - Review of the fate and transformation of per- and polyfluoroalkyl substances (PFASs) in landfills. AB - A critical review of existing publications is presented i) to summarize the occurrence of various classes of per- and polyfluoroalkyl substances (PFASs) and their sources in landfills, ii) to identify temporal and geographical trends of PFASs in landfills; iii) to delineate the factors affecting PFASs in landfills; and iv) to identify research gaps and future research directions. Studies have shown that perfluoroalkyl acids (PFAAs) are routinely detected in landfill leachate, with short chain (C4-C7) PFAAs being most abundant, possibly indicating their greater mobility, and reflecting the industrial shift towards shorter-chain compounds. Despite its restricted use, perfluorooctanoic acid (PFOA) remains one of the most abundant PFAAs in landfill leachates. Recent studies have also documented the presence of PFAA-precursors (e.g., saturated and unsaturated fluorotelomer carboxylic acids) in landfill leachates at concentrations comparable to, or higher than, the most frequently detected PFAAs. Landfill ambient air also contains elevated concentrations of PFASs, primarily semi volatile precursors (e.g., fluorotelomer alcohols) compared to upwind control sites, suggesting that landfills are potential sources of atmospheric PFASs. The fate of PFASs inside landfills is controlled by a combination of biological and abiotic processes, with biodegradation releasing most of the PFASs from landfilled waste to leachate. Biodegradation in simulated anaerobic reactors has been found to be closely related to the methanogenic phase. The methane-yielding stage also results in higher pH (>7) of leachates, correlated with higher mobility of PFAAs. Little information exists regarding PFAA-precursors in landfills. To avoid significant underestimation of the total PFAS released from landfills, PFAA-precursors and their degradation products should be determined in future studies. Owing to the semi-volatile nature of some precursor compounds and their degradation products, future studies also need to include landfill gas to clarify degradation pathways and the overall fate of PFASs. PMID- 29275272 TI - Environmental occurrence and distribution of organic UV stabilizers and UV filters in the sediment of Chinese Bohai and Yellow Seas. AB - Organic UV stabilizers and UV filters are applied to industrial materials and cosmetics worldwide. In plastics they prevent photo-induced degradation, while in cosmetics they protect human skin against harmful effects of UV radiation. This study reports on the occurrence and distribution of organic UV stabilizers and UV filters in the surface sediment of the Chinese Bohai and Yellow Seas for the first time. In total, 16 out of 21 analyzed substances were positively detected. Concentrations ranged from sub-ng/g dw to low ng/g dw. The highest concentration of 25 ng/g dw was found for octocrylene (OC) in the Laizhou Bay. In the study area, characteristic composition profiles could be identified. In Korea Bay, the dominating substances were OC and ethylhexyl salicylate (EHS). All other analytes were below their method quantification limit (MQL). Around the Shandong Peninsula, highest concentrations of benzotriazole derivatives were observed in this study with octrizole (UV-329) as the predominant compound, reaching concentrations of 6.09 ng/g dw. The distribution pattern of UV-329 and bumetrizole (UV-326) were related (Pearson correlation coefficient r > 0.98, p " 0.01 around the Shandong Peninsula), indicating an identical input pathway and similar environmental behavior. PMID- 29275273 TI - Response of CH4 emissions to straw and biochar applications in double-rice cropping systems: Insights from observations and modeling. AB - Paddy soil plays an essential role in contributing to the emission of methane (CH4), a potent greenhouse gas, to the atmosphere. This study aimed to demonstrate the effects of straw incorporation and straw-derived biochar amendment on CH4 emissions from double-rice cropping fields and to explore their potential mechanisms based on in-situ field measurements conducted for a period of three years (2012-2014) and model analysis. The results showed that the improved soil aeration due to biochar amendment resulted in low CH4 emissions and that sufficient substrate carbon availability in straw amendment treatments caused high CH4 emissions. The newly developed CH4 emission module for the water and nitrogen management model (WNMM), a process-based biophysical model, performed well when simulating both daily CH4 fluxes and the annual cumulative CH4 emissions under straw incorporation and biochar amendment. Results of our study indicate that the model has a great potential for upscaling and could benefit mechanism analyses about the factors regulating CH4 emissions. Application of biochar into paddy fields provides a great opportunity to reduce CH4 emissions, and the decrease in CH4 emissions following biochar amendment with repeated crop cycles would sustain for a prolonged period. PMID- 29275274 TI - The effects of exit from work on health across different socioeconomic groups: A systematic literature review. AB - Exit from work leads to different effects on health, partially depending on the socioeconomic status (SES) of people in the work exit. Several studies on the effects of exit from work on health across socioeconomic groups have been performed, but results are conflicting. The aim of this review is to systematically review the available evidence regarding the effects of exit from work on health in high and low socioeconomic groups. A systematic literature search was conducted using Pubmed, Embase, Web of Science, CINAHL and PsycINFO. Search terms related to exit from work, health, SES and design (prospective or retrospective). Articles were included if they focused on: exit from work (early/statutory retirement, unemployment or disability pension); health (general, physical or mental health and/or health behaviour); SES (educational, occupational and/or income level); and inclusion of stratified or interaction analyses to determine differences across socioeconomic groups. This search strategy resulted in 22 studies. For general, physical or mental health and health behaviour, 13 studies found more positive effects of exit from work on health among employees with a higher SES compared to employees with a lower SES. These effects were mainly found after early/statutory retirement. In conclusion, the effects of exit from work, or more specific the effects of early/statutory retirement on health are different across socioeconomic groups. However, the findings of this review should be interpreted with caution as the studies used heterogeneous health outcomes and on each health outcome a limited number of studies was included. Yet, the positive effects of exit from work on health are mainly present in higher socioeconomic groups. Therefore, public health policies should focus on improving health of employees with a lower SES, in particular after exit from work to decrease health inequalities. PMID- 29275275 TI - The fluidity of biosocial identity and the effects of place, space, and time. AB - Public and scientific conceptions of identity are changing alongside advances in biotechnology, with important relevance to health and medicine. In particular, biological identity, once predominantly conceived as static (e.g., related to DNA, dental records, fingerprints) is now being recognized as dynamic or fluid, mirroring contemporary understandings of psychological and social identity. The dynamism of biological identity comes from the individual body's unique relationship with the world surrounding it, and therefore may best be described as biosocial. This paper reviews advances in scientific understandings of identity and presents a model that contrasts prior static approaches to biological identity from more recent dynamically-relational ones. This emerging viewpoint is of broad significance to health and medicine, particularly as medicine recognizes the significance of biography - i.e. the multiple, dense interactions imparted on a body across spatio-temporal dimensions - to phenotypic prediction, especially disease risk. PMID- 29275276 TI - Fragile x-associated premature ovarian failure in a large Turkish cohort: Findings of Hacettepe Fragile X Registry. AB - OBJECTIVE: To determine frequency of fragile X associated premature ovarian insufficiency (FXPOI) among Turkish premutation carriers. STUDY DESIGN: FMR1 premutation is the single most common genetic cause of POI (FXPOI). Fragile X Registry at Hacettepe University has been reviewed for the frequency of FXPOI among female premutation carriers. Since 1991 when FMR1 testing was available, 760 individuals from 243 families have been registered. Actual data on menstrual status of female premutation carriers were gathered and analysed. RESULTS: Among 314 premutation-bearing females in the cohort, 268 could be reached for an update of their menstrual history; 107 adults were 40 or younger and 156 were older than 40 years of age, whereas the remaining 5 patients were prepubertal. Among 263 postpubertal females with premutations, 90 women stopped menstruating before or at 40 years of age (premature ovarian failure - POF), constituting 34.2% of our cohort. Additionally, one carrier of a gray zone allele experienced FXPOI. History of twinning was present once in 18 women (5.7%) and twice in two women (0.6%), one of the latter interestingly bearing a full-mutation. CONCLUSIONS: FXPOI rates in the present cohort are higher than those reported in other populations. Higher FXPOI rates in Turkish premutation carriers might be a reflection of younger mean menopause age and higher POI rates in otherwise healthy Turkish women. Since POI is much more frequent among premutation carriers than in general population, testing for CGG repeat expansions in FMR1 should be included in the work-up. PMID- 29275277 TI - The influence of hyperglycemia on the remodeling of urethral connective tissue in pregnant rats. AB - OBJECTIVE: To analyze the distribution and quantification of the key structural extracellular matrix components of the urethral tissue in a rat model of hyperglycemia and pregnancy. STUDY DESIGN: A total of 120 female Wistar rats were distributed into the following four experimental groups: virgin, pregnant, hyperglycemic and hyperglycemic + pregnant groups. The urethra was harvested for histochemical, morphometric, immunohistochemical, Western blot and glycosaminoglycan analyses. All protocols were approved by the Institutional Animal Care and Use Committee of Botucatu Medical School (process number 828 2010). RESULTS: The hyperglycemic + pregnant group showed significantly increased stiffness in urethral tissue. The total striated muscle was decreased, with increased deposition of collagen fibers around the muscle fibers and a change in the organization of the collagen fibrils. An increase in the relative collagen type I/III ratio and a decrease in total glycosaminoglycans were also observed. CONCLUSIONS: This study provides the first line of experimental evidence supporting a metabolic relationship between hyperglycemia and urethral remodeling of connective tissue in pregnant rats. The different organization of the collagen fibrils and the profile of glycosaminoglycans found in urethral samples suggest that the pathology of the urethral fibromuscular system could be related to hyperglycemia-induced pelvic floor dysfunction in women, which has direct clinical implications with the possibility to develop new multidisciplinary treatments for improving the health care of these women. PMID- 29275278 TI - Increasing compliance with a clinical practice guideline for fetal fibronectin testing and the management of threatened preterm labour: A quality improvement project. AB - OBJECTIVE: To increase adherence to a local hospital clinical practice guideline for the use of fetal fibronectin testing in women presenting with symptoms of threatened preterm labour. STUDY DESIGN: A quality improvement project using a multi-faceted implementation strategy. SETTING: National Women's Health, Auckland City Hospital; a tertiary referral maternity unit in Auckland, New Zealand. POPULATION: All obstetricians, junior obstetric doctors and hospital employed midwives. METHODS: A pre-education audit and survey, compulsory interactive educational intervention with audit feedback and provision of reminders followed by a post-education audit and survey one year later. MAIN OUTCOME MEASURES: Number of fetal fibronectin tests performed, proportion of tests performed meeting clinical criteria for testing and proportion of results managed according to hospital guideline. RESULTS: There was a 25% increase in the number of tests performed with an increase in the proportion that met clinical criteria for testing, 76% (31/41)-93% (51/55) (OR 4.1, 95% CI 1.2-14.2). Adherence to guidelines for clinical management according to fFN results changed over time, 80% (33/41)-95% (52/55) (OR 4.2, 95% CI 1.04-17.0). Clinician knowledge on some (but not all) indications for fFN testing improved. Education and reminders did not improve understanding of clinical scenarios that may result in a false positive fFN test. CONCLUSIONS: A multi-faceted approach of audit and clinician feedback, interactive education and reminders supports the implementation of a clinical practice guideline for the use of fFN as a preterm birth prediction test for women presenting with symptoms of threatened preterm labour. PMID- 29275279 TI - Effect of immunomagnetic bead size on recovery of foodborne pathogenic bacteria. AB - Immunomagnetic separation (IMS) as a culture-free enrichment sample preparation technique has gained increasing popularity in the development of rapid detection methods for foodborne pathogens. While the use of magnetic nanoparticles in IMS is on the rise due to substantially larger surface area compared to conventional magnetic microparticles, the effects of immunomagnetic bead (IMB) size on pathogen cell recovery are not fully understood. In this study we used IMBs of different sizes (100, 500, and 1000nm diameters) to capture Salmonella Enteritidis, a common foodborne pathogen, from buffer solutions as well as food matrices (chicken carcass rinse and liquid egg white). The IMS recovery and non specific binding rate were compared. The recoveries of Salmonella cells in buffers was highest using the 100nm IMBs (88-96%), followed by the 500nm (31-89%) and 1000nm (4.1-61%) IMBs, demonstrating a significant size effect. The non specific binding rates of E. coli also increased as IMB size decreased. A 2-72% reduction in Salmonella recovery was observed in chicken carcass rinse and liquid egg white samples compared to in buffers, and this reduction was more significant using 500 and 1000nm IMBs. However, lower IMS recoveries (10-56%) was found in 100nm IMBs two months after preparation. Overall, magnetic nanoparticles yielded superior IMS efficiency to micrometer size IMBs and were less subjective to interference from food matrices. Nevertheless, their long term stability remains an obstacle towards successful use in IMS. PMID- 29275280 TI - Dynamics of biofilm formation by Listeria monocytogenes on stainless steel under mono-species and mixed-culture simulated fish processing conditions and chemical disinfection challenges. AB - The progressive ability of a six-strains L. monocytogenes cocktail to form biofilm on stainless steel (SS), under fish-processing simulated conditions, was investigated, together with the biocide tolerance of the developed sessile communities. To do this, the pathogenic bacteria were left to form biofilms on SS coupons incubated at 15 degrees C, for up to 240h, in periodically renewable model fish juice substrate, prepared by aquatic extraction of sea bream flesh, under both mono-species and mixed-culture conditions. In the latter case, L. monocytogenes cells were left to produce biofilms together with either a five strains cocktail of four Pseudomonas species (fragi, savastanoi, putida and fluorescens), or whole fish indigenous microflora. The biofilm populations of L. monocytogenes, Pseudomonas spp., Enterobacteriaceae, H2S producing and aerobic plate count (APC) bacteria, both before and after disinfection, were enumerated by selective agar plating, following their removal from surfaces through bead vortexing. Scanning electron microscopy was also applied to monitor biofilm formation dynamics and anti-biofilm biocidal actions. Results revealed the clear dominance of Pseudomonas spp. bacteria in all the mixed-culture sessile communities throughout the whole incubation period, with the in parallel sole presence of L. monocytogenes cells to further increase (ca. 10-fold) their sessile growth. With respect to L. monocytogenes and under mono-species conditions, its maximum biofilm population (ca. 6logCFU/cm2) was reached at 192h of incubation, whereas when solely Pseudomonas spp. cells were also present, its biofilm formation was either slightly hindered or favored, depending on the incubation day. However, when all the fish indigenous microflora was present, biofilm formation by the pathogen was greatly hampered and never exceeded 3logCFU/cm2, while under the same conditions, APC biofilm counts had already surpassed 7logCFU/cm2 by the end of the first 96h of incubation. All here tested disinfection treatments, composed of two common food industry biocides gradually applied for 15 to 30min, were insufficient against L. monocytogenes mono-species biofilm communities, with the resistance of the latter to significantly increase from the 3rd to 7th day of incubation. However, all these treatments resulted in no detectable L. monocytogenes cells upon their application against the mixed culture sessile communities also containing the fish indigenous microflora, something probably associated with the low attached population level of these pathogenic cells before disinfection (<102CFU/cm2) under such mixed-culture conditions. Taken together, all these results expand our knowledge on both the population dynamics and resistance of L. monocytogenes biofilm cells under conditions resembling those encountered within the seafood industry and should be considered upon designing and applying effective anti-biofilm strategies. PMID- 29275281 TI - Innovating at the food, water, and energy interface. AB - Food, energy, and water (FEW) systems are inexorably linked. Earth's changing climate and increasing competition for finite land resources are creating and amplifying challenges at the FEW nexus. Managing FEW systems to mitigate these negative impacts and stresses is a pressing policy issue. The FEW interface is often managed as three independent systems, missing disruptive opportunities for streamlined integrated management. We contend that existing technologies can be reframed and emerging technologies can be harnessed for integrated FEW management, changing the way that each resource system operates within the broader system. We discuss solutions to three main challenges to integrating FEW system management: resolving spatiotemporal disconnections over multiple scales; closing resource loops; and creating actionable information. Sustainable resource management is critical for humanity, as well as for functioning trade systems and ecological health. Embracing integrated management in FEW systems would enable policy makers and managers to more efficiently and effectively secure critical resource systems in the face of global change. PMID- 29275282 TI - Study of factors involved in the gravimetric separation process to treat soil contaminated by municipal solid waste. AB - The current research investigated the effectiveness of a gravimetric process (shaking table) to treat soil contaminated by municipal solid waste. A detailed characterization of the inorganic pollutants was performed, followed by concentrating the metals within smaller volumes using the shaking table technology. The densimetric examination of the 1-2 mm and 0.250-1 mm fractions of the contaminated soil showed that lead (Pb), copper (Cu), and tin (Sn) were mostly concentrated in the heavy fraction (metal removals > 50%). Scanning electron microscopy coupled with elemental analysis indicated the relevance of using gravimetric processes to treat this soil sample. The influence of shaking table parameters was determined using a Box-Behnken design. The tilt and washing water flow demonstrated significant effects on the motion of the 1-2 mm soil fraction and on the removal of Pb, Cu, and Sn. The results obtained under the optimal settings of the shaking table defined using the Box-Behnken methodology when treating the 1-2 mm fraction were close to those obtained when using dense media separation. The recovered mass of the concentrate was approximately 20.8% (w.w-1) of the total mass. The removals of Pb, Cu, and Sn were estimated to be 67.3%, 54.5% and 54.6% respectively. The predicted and experimental mass distributions of the medium (1-2 mm) and fine-sized (0.250-1 mm) particles were compared successively under some selected conditions. The mass distribution of both fractions showed similar tendencies in response to the forces applied by each condition. However, lowering the forces induced by the bumping action and the flowing film was recommended so as to efficiently treat the fine fraction (0.250-1 mm). The recovered mass of the concentrate (10%) was slightly lower than that obtained by dense media separation (13%). However, satisfactory removal yields were obtained for Pb, Cu, and Sn (42.7%, 23.6%, and 35% respectively). PMID- 29275283 TI - The influence of meteorological variables on CO2 and CH4 trends recorded at a semi-natural station. AB - CO2 and CH4 evolution is usually linked with sources, sinks and their changes. However, this study highlights the role of meteorological variables. It aims to quantify their contribution to the trend of these greenhouse gases and to determine which contribute most. Six years of measurements at a semi-natural site in northern Spain were considered. Three sections are established: the first focuses on monthly deciles, the second explores the relationship between pairs of meteorological variables, and the third investigates the relationship between meteorological variables and changes in CO2 and CH4. In the first section, monthly outliers were more marked for CO2 than for CH4. The evolution of monthly deciles was fitted to three simple expressions, linear, quadratic and exponential. The linear and exponential are similar, whereas the quadratic evolution is the most flexible since it provided a variable rate of concentration change and a better fit. With this last evolution, a decrease in the change rate was observed for low CO2 deciles, whereas an increasing change rate prevailed for the rest and was more accentuated for CH4. In the second section, meteorological variables were provided by a trajectory model. Backward trajectories from 1-day prior to reaching the measurement site were used to calculate distance and direction averages as well as the recirculation factor. Terciles of these variables were determined in order to establish three intervals with low, medium and high values. These intervals were used to classify the variables following their interval widths and skewnesses. The best correlation between pairs of meteorological variables was observed for the average distance, in particular with horizontal wind speed. Sinusoidal relationships with the average direction were obtained for average distance and for vertical wind speed. Finally, in the third section, the quadratic evolution was considered in each interval of all the meteorological variables. As regards the main result, the greatest increases were obtained for high potential temperature for both gases followed by low and medium boundary layer height for CO2 and CH4, respectively. Combining both meteorological variables provided increases of 22 +/- 9 and 0.070 +/- 0.019 ppm for CO2 and CH4, respectively, although the number of observations affected is small, around 7%. PMID- 29275284 TI - Harnessing landscape heterogeneity for managing future disturbance risks in forest ecosystems. AB - In order to prevent irreversible impacts of climate change on the biosphere it is imperative to phase out the use of fossil fuels. Consequently, the provisioning of renewable resources such as timber and biomass from forests is an ecosystem service of increasing importance. However, risk factors such as changing disturbance regimes are challenging the continuous provisioning of ecosystem services, and are thus a key concern in forest management. We here used simulation modeling to study different risk management strategies in the context of timber production under changing climate and disturbance regimes, focusing on a 8127 ha forest landscape in the Northern Front Range of the Alps in Austria. We show that under a continuation of historical management, disturbances from wind and bark beetles increase by +39.5% on average over 200 years in response to future climate change. Promoting mixed forests and climate-adapted tree species as well as increasing management intensity effectively reduced future disturbance risk. Analyzing the spatial patterns of disturbance on the landscape, we found a highly uneven distribution of risk among stands (Gini coefficients up to 0.466), but also a spatially variable effectiveness of silvicultural risk reduction measures. This spatial variability in the contribution to and control of risk can be used to inform disturbance management: Stands which have a high leverage on overall risk and for which risks can effectively be reduced (24.4% of the stands in our simulations) should be a priority for risk mitigation measures. In contrast, management should embrace natural disturbances for their beneficial effects on biodiversity in areas which neither contribute strongly to landscape scale risk nor respond positively to risk mitigation measures (16.9% of stands). We here illustrate how spatial heterogeneity in forest landscapes can be harnessed to address both positive and negative effects of changing natural disturbance regimes in ecosystem management. PMID- 29275285 TI - A 3DBER-S-EC process for simultaneous nitrogen and phosphorus removal from wastewater with low organic carbon content. AB - A new process was proposed by integrating a three-dimensional biofilm electrode reactor with sulfur autotrophic denitrification and electrocoagulation within the same reactor. The results indicated that under the wastewater influent condition of NO3--N = 30 mg/L, COD = 45 mg/L, total phosphorus (TP) = 1.5 mg/L, hydraulic retention time (HRT) = 8 h, and I = 400 mA, the NO3--N and TP removal of the proposed process reached 89.8% and 83.0%, respectively. It was observed that the electrocoagulation process improved phosphorus removal, while the simultaneous existence of heterotrophic, hydrogen, sulfur and iron autotrophic denitrifying bacteria led to enhanced and stabilized nitrogen removal. The Sulfuritalea hydrogenivorans sk43H and Sulfuricella denitrificans skB26 were found as the dominant denitrifying bacteria in the electrocoagulation section and the section of biofilm electrode with sulfur filler, respectively. As compared to conventional technologies, the proposed new process can achieve simultaneous, stable and deep nitrogen and phosphorus removal from wastewater treatment plant effluent with low organic carbon content. PMID- 29275286 TI - Structural identification of lipopeptide biosurfactants produced by Bacillus subtilis strains grown on the media obtained from renewable natural resources. AB - The aim of the study was to identify and characterize lipopeptide (LP) biosurfactants produced by two Bacillus subtilis strains (KP7 and I'-1a) grown on various media prepared from renewable natural resources: two different brewery wastewaters (BW#4 and BW#6), 2% beet molasses (M), apple peels extract (APE) supplemented with 0.25% of yeast extract (YE) or 0.25% peptone (P), and similarly supplemented carrot peels extract (CPE). In all used media both strains retained their individual LP production signature characterized by surfactin and iturin overproduction exhibited by KP7 and I'-1a strain, respectively. The production level and the structural diversity of synthesized LPs were dependent on the medium composition. In the CPE+YE medium it was higher than the yield obtained in Luria-Bertani (140.6 and 100.3 mg L-1, respectively). Surfactins were produced by both strains as a mixture of four homologues (C13-C16) with the domination of variant C14. All other broths prepared from renewable resources strongly stimulated the iturin production by I'-1a strain with the exception of BW media. The highest iturin concentration (428.7 mg L-1) obtained in the CPE+P culture of I'-1a strain was about seven-fold higher than in LB. In all cultures only iturin A was identified. Among four iturin homologues (C13-16) produced by I'-1a strain, the highest relative contents of C16 variant (70-80%) were calculated for samples obtained from APE+P and CPE+P media. The obtained data indicate that the waste composition has an influence on both the types and amounts of biosurfactants produced by studied B. subtilis strains. PMID- 29275287 TI - Comments on death due to non-traumatic hemoperitoneum in Milan 2002-2016, with focus on two cases of abdominal apoplexy (idiopathic spontaneous hemoperitoneum) and review of the literature. PMID- 29275288 TI - Transient postictal blindness after a focal posterior cingulate gyrus seizure. PMID- 29275289 TI - Role of fluoride induced histone trimethylation in development of skeletal fluorosis. AB - Chronic exposure to fluoride has been associated with the development of skeletal fluorosis. Limited reports are available on fluoride induced histone modification. However, the role of histone modification in the pathogenesis of skeletal fluorosis is not investigated. In the present study, we have investigated the role of fluoride induced histone modification on fluorosis development using human osteosarcoma (HOS) cell line. The expression of histone methyltransferases (EHMT1 and EHZ2) and level of global histone trimethylation (H3K9 and H3K27) have been assessed and observed to be increased significantly after fluoride exposure (8 mg/L). EpiTect chromatin immunoprecipitation (CHIP) qPCR Array (Human TGFbeta/BMP signaling pathway) was performed to assess the H3K9 trimethylation at promoter regions of pathway-specific genes. H3K9 ChIP PCR array analysis identified hyper H3K9 trimethylation in promoter regions of TGFBR2 and SMAD3. qPCR and STRING analysis was carried out to determine the repressive epigenetic effect of H3K9 trimethylation on expression pattern and functional association of identified genes. Identified genes (TGFBR2 and SMAD3) showed down regulation which confirms the repressive epigenetic effect of promoter H3K9 hyper trimethylation. Expression of two other vital genes COL1A1 and MMP13 involved in TGFBR2-SMAD signaling pathway was also found to be down-regulated with a decrease in expression of TGFBR2 and SMAD3. STRING analysis revealed functional association and involvement of identified genes TGFBR2, SMAD3, COL1A1 and MMP13 in the collagen and cartilage development/morphogenesis, connective tissue formation, bio-mineral tissue development, endochondral bone formation, bone and skeletal morphogenesis. In conclusion, present investigation is a first attempt to link fluoride induced hyper H3K9 tri-methylation mediated repression of TGFBR2 and SMAD3 with the development of skeletal fluorosis. PMID- 29275290 TI - Genetically encoded fluorescent sensors for measuring transition and heavy metals in biological systems. AB - Great progress has been made in expanding the repertoire of genetically encoded fluorescent sensors for monitoring intracellular transition metals (TMs). This powerful toolkit permits dynamic and non-invasive detection of TMs with high spatial-temporal resolution, which enables us to better understand the roles of TM homeostasis in both physiological and pathological settings. Here we summarize the recent development of genetically encoded fluorescent sensors for intracellular detection of TMs such as zinc and copper, as well as heavy metals including lead, cadmium, mercury, and arsenic. PMID- 29275291 TI - Biocatalytic reduction of activated CC-bonds and beyond: emerging trends. AB - The biocatalytic reduction of activated CC-bonds is dominated by ene-reductases from the Old Yellow Enzyme family, which gained broad practical use owing to exquisite stereoselectivity combined with wide substrate scope. Protein diversity is fostered by mining distinct protein classes and by implementing protein engineering techniques. Recent efforts are focusing on expanding the chemical complexity of the product portfolio, either through substrate functionalization or design of multi-step reactions. This review also highlights unusual chemistries catalyzed by ene-reductases and presents emerging methodologies developed to bypass the need of natural nicotinamide cofactors. PMID- 29275292 TI - Cell-cycle Checkpoints and Aneuploidy on the Path to Cancer. AB - The cell cycle is a complex sequence of events through which a cell duplicates its contents and divides, and involves many regulatory proteins for proper cellular reproduction, including cyclin proteins and cyclin-dependent kinases, oncogenes and tumor-suppressor genes, and mitotic checkpoint proteins. Mutations of any of these regulatory mechanisms can lead to reproduction of cells carrying genetic mutations or abnormal numbers of chromosomes, resulting in genomic instability. Chromosomal instability, contributing to genomic instability, refers to abnormalities in the number of chromosomes, and leads to aneuploidy. The role of aneuploidy in cancer cell development is often disputed, as conflicting hypotheses and research make it unclear as to whether aneuploidy is a cause or consequence of cancer. Here, we present an overview of the importance of cell cycle checkpoint regulation and chromosomal instability in the development of cancer, and discuss evidence for conflicting arguments for the role of aneuploidy in cancer, leading us to conclude that further investigation of this role would benefit our understanding of cancer development. PMID- 29275293 TI - Morphological Distinction of Histiocytic Sarcoma from Other Tumor Types in Bernese Mountain Dogs and Flatcoated Retrievers. AB - BACKGROUND/AIM: Histiocytic sarcoma (HS) represents a group of malignant canine tumors to which Bernese Mountain Dogs (BMD) and Flatcoated Retrievers (FCR) are predisposed. The differential diagnosis for HS is broad, encompassing round cell tumors, sarcomas and other histiocytic diseases. The aim of this study was to establish morphological and immunohistochemical criteria for routine use on formalin-fixed, paraffin-embedded samples and cytological smears for the recognition and differentiation of canine HS and its subtypes. MATERIALS AND METHODS: Retrospectively, tumor sections were reviewed from 449 BMD and 380 FCR with confirmed or suspected HS, other histiocytic conditions, or a disease of the differential diagnosis of HS. RESULTS: In a large proportion of cases, 47.5% for histology and for 46.3% cytology, the initial diagnosis was changed after the revision process. A large variation in morphological features of HS was observed in this study, making the existence of several subtypes in dogs also very likely. Furthermore, the different percentage of morphological features between BMD and FCR indicates the different mixture of cell type origins resulting possibly from genetic or environmental differences at the onset of HS in those breeds. CONCLUSION: This study stresses the value of a strictly applied and standardized scoring system for microscopic evaluation of tumor sections and smears, and the implementation of review and revision of pathological diagnoses. PMID- 29275294 TI - Effects of 2,3-Bis(4-hydroxyphenyl)-propionitrile on Induction of Polyovular Follicles in the Mouse Ovary. AB - BACKGROUND/AIM: Neonatal diethylstilbestrol (DES) treatment induces polyovular follicles (PFs), which contain more than two oocytes in a follicle, through estrogen receptor (ER) beta, not ERalpha. 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) is a specific ERbeta agonist; the effects of neonatal DPN exposure on PF induction and gene expression in the mouse ovary were examined. MATERIALS AND METHODS: Histological analysis and real-time reverse transcription-polymerase chain reaction were performed. RESULTS: The PF incidence was significantly high in the ovary of neonatally DPN-exposed mice compared to that in oil-exposed mice. The gene expression of growth differentiation factor 9 (Gdf9), Mullerian inhibiting substance, steroidogenic factor 1 (Sf1) and steroidogenic acute regulatory protein (Star) in the ovary was significantly increased in the mice neonatally exposed to 40 MUg DPN compared to oil-treated mice. CONCLUSION: Since SF1 is an important transcription factor of several genes involved in ovarian function, up-regulation of Sf1 expression by neonatal exposure to DPN, through ERbeta, might affect expression of Gdf9, Mis and Star, resulting in increased PFs in mouse ovary. PMID- 29275295 TI - EZH2 Overexpression as a Useful Prognostic Marker for Aggressive Behaviour in Thyroid Cancer. AB - BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group of genes, which are key factors in the regulation of cell proliferation and differentiation. EZH2 is overexpressed in many malignancies. We analyzed EZH2 protein expression levels in different histological subtypes of thyroid cancer to examine its utility as a prognostic factor. MATERIALS AND METHODS: We examined EZH2 protein expression by immunohistochemistry in tissue samples from 67 cases of poorly differentiated (PDTC) and 48 cases of anaplastic thyroid carcinoma (ATC), and in samples of adjacent normal and differentiated thyroid carcinoma (DTC). We examined differences in expression of EZH2 among various histological types of thyroid cancer, and the relationship between EZH2 expression and patient outcome. RESULTS: EZH2 protein was expressed in PDTC and ATC, but not in normal thyroid gland or DTC. EZH-positivity increased in the order of DTC, PDTC, and ATC (p<0.01). Higher EZH2 expression correlated with poorer survival in PDTC (p=0.004), and a similar but non-significant trend was observed in ATC (p=0.166). Multivariate analysis identified EZH2 as an independent prognostic factor similar to metastatic status in the Japanese Society of Thyroid Surgery (JSTS) classification of PDTC. CONCLUSION: EZH2 overexpression is associated with malignant potential in thyroid cancer, and may thus be a useful prognostic marker of aggressive thyroid cancer. PMID- 29275296 TI - Effect of Benifuuki Tea on Cytochrome P450-mediated Metabolic Activity in Rats. AB - BACKGROUND/AIM: Benifuuki tea has recently been used as an alternative therapy for pollinosis, and it may be consumed with pharmaceutical drugs. This study aimed to examine cytochrome P450 (CYP)-mediated food-drug interactions with Benifuuki tea in rats. MATERIALS AND METHODS: The inhibitory effects of Benifuuki tea and (-)-epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me) on CYP activities were evaluated in vitro. Midazolam pharmacokinetics was investigated after two treatments with Benifuuki tea. In an ex vivo study, CYP activities were determined after 1-week-treatment with the tea. RESULTS: Benifuuki tea and EGCG3"Me inhibited CYP2D and CYP3A activities in a concentration-dependent manner in vitro. However, MDZ metabolism did not change by Benifuuki treatment in vivo and ex vivo. In contrast, CYP2D activity was decreased ex vivo. CONCLUSION: Normal intake of Benifuuki tea is not likely to cause food-drug interactions by CYP3A inhibition or induction. In contrast, Benifuuki tea consumption may lead to food-drug interactions through the inhibition of CYP2D. PMID- 29275297 TI - The Association of MMP-8 Genotypes with Pterygium. AB - BACKGROUND/AIM: Pterygium is composed of proliferating fibrovascular tissue, and its formation and progression are closely related to the homeostasis of the extracellular microenvironment. However, few studies have examined the contribution of matrix metalloproteinases (MMP) to either diagnostic or prognostic potential in pterygium. In this study, we investigated the contribution of a polymorphism in the promoter region of MMP-8 (-799C/T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to pterygium. MATERIALS AND METHODS: In this study, 134 patients with pterygium and 268 non-cancer controls patients were collected and the MMP-8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes of each subject were examined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The results showed that the three polymorphisms investigated were not significantly associated with risk of pterygium. In addition, the stratified analysis showed that there was no interaction between MMP-8 genotype with age or gender on pterygium risk determination. CONCLUSION: Polymorphisms at MMP-8 -799C/T, Val436Ala and Lys460Thr may not mainly contribute to determining personal susceptibility to pterygium in the Taiwanese examined. PMID- 29275298 TI - Association of Antituberculosis Treatment and Lower Risk of Hyperlipidemia in Taiwanese Patients: A Population-Based Case-Control Study. AB - The association between anti-tuberculosis (TB) treatments and the risk of developing hyperlipidemia remains unclear. Data were obtained from the Longitudinal Health Insurance Database 2000 (LHID2000). The case group included patients newly diagnosed with hyperlipidemia (n=16,054) between 2006 and 2011 selected from the LHID2000. A four-fold number of hyperlipidemia-free cases (n=64,216) were matched with case patients by age, sex, and index year to create the control group. Univariable and multivariable unconditional logistic regression analyses were conducted to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between hyperlipidemia and anti-TB medication use. Patients that used isoniazid (INH) were significantly associated with a decreased risk of hyperlipidemia (OR=0.71, 95%CI=0.57-0.88). After adjustment for age, sex, urbanization level, and income as well as ethambutol, pyrazinamide, streptomycin, and anti-human immunodeficiency virus drug medications, a dose-dependent risk of hyperlipidemia was observed in the INH, rifampin (RIF), and INH and RIF groups with the ORs progressively decreasing as the cumulative dose increased. In the Taiwanese patients who used anti-TB medications, INH and RIF use was associated with a decreased risk of hyperlipidemia. PMID- 29275299 TI - Effects of Dietary and Lighting Conditions on Diurnal Locomotor Activity and Body Temperature in Microminipigs. AB - The effects of dietary and lighting conditions on diurnal rhythm of locomotor activity (LA) and body temperature (BT) using four adult male microminipigs were investigated. Different feeding times, diet and lighting conditions were applied sequentially for 3 weeks in each phase as follows: Phase I: Morning mealtime, normal diet, 12-h lights on; phase II: mealtime changed to afternoon; phase III: diet changed to high-fat diet; phase IV: lighting changed to 20-h on; and phase V: phase I repeated. LA was measured by an actigraph which was worn on the body of each pig. A BT recording module (Thermochron Type-SL) was implanted in the neck subcutaneously. Phase II increased BT compared with phase I. Phase III increased LA and BT compared with phase II. Phase IV increased LA compared with phase III. LA in phase V was higher compared with phase I. These results can be extrapolated to other diurnal animals such as humans. This study provides an example of the effects of diet and lighting on biological activities in microminipigs under low-invasive procedures measuring LA and BT, leading to low variations in these measures. PMID- 29275300 TI - Three-Dimensional Printing-based Reconstruction of a Maxillary Bone Defect in a Dog Following Tumor Removal. AB - Three-dimensional (3D) printing has been applied extensively not only in human, but also veterinary medicine. However, the technique is still used in the clinical area for a surgical plan or education prior to surgery. Thus, we report a case of reconstruction after tumor removal surgery with the use of a 3D-printed scaffold. A 12-year-old female mixed dog had a left caudal maxillary mass. Based on computed tomography images, a defect was confirmed on the maxillary bone due to the oral mass, and a surgical plan was designed to remove the oral mass and graft the 3D printed scaffold. Customized polycaprolactone/ beta tracalciumphosphate (PCL/beta-TCP) scaffold was fabricated using the micro extrusion-based 3D printer. In the operation, after the removal of the oral mass, the scaffold was grafted onto the defect site. At follow-up, 8 months after surgery, the result was successful without any special problems in the periodic CT scans and oral examinations. This case is believed to be the first case of reconstruction by using a 3D printed scaffold in the maxillary bone defect, and this 3D printing technique is thought to be very helpful for veterinary patients with bone defects and several other diseases. PMID- 29275301 TI - Cycloartobiloxanthone Induces Human Lung Cancer Cell Apoptosis via Mitochondria dependent Apoptotic Pathway. AB - BACKGROUND: Lung cancer is one of most malignant types of cancer and new anticancer agents are still required. Cycloartobiloxanthone, a flavonoid isolated from stem bark of Artocarpus gomezianus, has potential for being developed for anticancer therapy. MATERIALS AND METHODS: Cytotoxicity of cycloartobiloxanthone was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay against four human lung cancer cell lines (H23, H460, H292 and A549) and their half-maximal inhibitory concentrations (IC50) were assessed. Apoptotic induction in H460 cells was investigated by Hoechst 33342/propidium iodide (PI) staining assay and protein hallmarks of mitochondria-dependent apoptotic pathway were examined by western blot analysis. RESULTS: Cycloartobiloxanthone exhibited potent cytotoxic effect on both small and non-small cell lung cancer cells. Nuclear Hoechst/PI staining revealed that apoptotic cell death was the main mechanism of toxicity of cycloartobiloxanthone. The apoptosis-inducing potency of cycloartobiloxanthone was comparable to those of standard anticancer drugs cisplatin and etoposide at the same concentration. Protein analysis further showed that apoptosis was mediated via mitochondria-dependent pathway. p53 was activated in cells treated with cycloartobiloxanthone. Subsequently, pro apoptotic protein B-cell lymphoma 2 (BCL2)-associated X protein (BAX) was found to be significantly increased, concomitantly with the decrease of anti-apoptotic proteins BCL2 and myeloid cell leukemia 1 (MCL1). Moreover, markers of the intrinsic apoptosis pathway, namely activated caspase-9, activated caspase-3, and cleaved poly(ADP-ribose)polymerase (PARP), dramatically increased in cycloartobiloxanthone-treated cells compared to the non-treated controls. CONCLUSION: Cycloartobiloxanthone has anticancer activity against human lung cancer cells by triggering mitochondrial apoptotic caspase-dependent mechanism. This compound might have promising effects for cancer therapy. PMID- 29275302 TI - Evaluation of Vascular Proliferation in Molecular Subtypes of Breast Cancer. AB - BACKGROUND: Angiogenesis plays a pivotal role in tumor development. Although microvessel density (MVD) is the most common method used for evaluation of angiogenesis, it has several limitations. Our aim was to evaluate MVD and microvessel proliferation (MVP) in a series of invasive breast carcinomas and analyze whether angiogenesis is influenced by the molecular phenotype of each tumor. MATERIALS AND METHODS: We examined vascular proliferation using double immunohistochemistry (CD34/Ki67) in a series of 54 invasive breast carcinomas and compared the results with standard MVD, molecular subtypes and other classical parameters. RESULTS: Increased MVD and MVP values were recorded in basal-like subtype, but only the MVP value reached significance among this group of patients (p=0.0001). For all cases combined, increased MVP was significantly correlated with negative estrogen receptor (ER) status (p=0.010) and higher histological grade (p=0.002). CONCLUSION: MVP more accurately reflects the state of angiogenesis in breast cancer, compared with standard MVD. Vascular proliferation was associated with aggressive tumor features, indicating its contribution to tumor progression. The strong association between vascular proliferation and basal-like tumors suggests that this marker can be used for stratification of patients who might benefit from therapies targeting angiogenesis. PMID- 29275303 TI - Effect of Increased Intra-abdominal Pressure on Liver Histology and Hemodynamics: An Experimental Study. AB - BACKGROUND: While reduction of portal venous (PV) blood flow has been described in animal models of intra-abdominal hypertension, reports on compensatory changes in hepatic arterial (HA) flow, known as the hepatic arterial buffer response are controversial. MATERIALS AND METHODS: Pneumoperitoneum with helium was induced in 13 piglets. Hemodynamic measurements and pathological assessment were conducted at baseline and during the three subsequent phases: Phase A: 45 minutes with a stable intra-abdominal pressure of 25 mmHg; phase B: 45 minutes with a stable intra-abdominal pressure of 40 mmHg; and phase C during which the abdomen was re explored and reperfusion of the liver was allowed to take place. RESULTS: Phase B pressure was significantly greater than phase A pressure in both the PV and the inferior vena cava, demonstrating a positive association between escalating intra abdominal hypertension and the pressure in these two vessels (all p<0.001). In contrast, HA pressure was comparable between baseline and phase A, while it tended to decrease in phase B. Regarding histology, the most notable abnormality was the presence of inflammatory infiltrates and hepatocyte necrosis. CONCLUSION: Helium-insufflation increased PV pressure with a partial compensatory decrease of HA pressure. Nonetheless, findings consistent with hepatic ischemia were observed on pathology. PMID- 29275304 TI - Preventive Effects of Vitamin C on Diethylnitrosamine-induced Hepatotoxicity in Smp30 Knockout Mice. AB - Vitamin C (L-ascorbic acid) is well known as a free radical scavenger that protects cells against damage from oxidative stress. Herein, we investigated the effects of vitamin C against diethylnitrosamine (DEN)-induced hepatotoxicity. Male wild-type (C57BL/6) and senescence marker protein-30 (Smp30) knockout (KO) mice were used and divided in the following four groups: WT group (n=15): Wild type (WT) mice fed vitamin C-free diet with tap water; WV group (n=14): WT mice fed vitamin C-free diet with water supplemented with 1.5 g/kg vitamin C; KT group (n=12): Smp30 KO mice fed vitamin C-free diet with tap water; and KV group (n=13): Smp30 KO mice fed vitamin C-free diet with water supplemented with 1.5 g/kg vitamin C. A single intraperitoneal injection of DEN (5 mg/kg body weight) was injected in the second week during the experimental period. Mice were sacrificed after 17 weeks of treatment to investigate the effect of dietary vitamin C on DEN-induced hepatotoxicity. The results showed that vitamin C significantly increased the mean lifespan (p<0.05) in the WT, WV and KV groups compared with the KT group. The serum concentrations of gamma-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase did not significantly differ among groups. The WT group exhibited significantly more acute cellular swelling accompanied by centrilobular necrosis, focal lymphocyte infiltration, and eosinophilic intracytoplasmic inclusion bodies as compared with the WV and KV groups, suggesting that vitamin C had a hepatoprotective effect. Dysplastic, large, and binucleated hepatocytes were also observed in the WT group, but these pathological signs were absent from the WV and KV groups. Our experimental evidence suggests that vitamin C supplementation in Smp30 KO mice was effective for the treatment of DEN-induced hepatotoxicity. PMID- 29275305 TI - Inhibition of Formation of Azoxymethane-induced Colonic Aberrant Crypt Foci in Rats by Edible Green Algae Capsosiphon fulvescens and Brown Algae Hizikia fusiforme. AB - Capsosiphon fulvescens (green seaweed) and Hizikia fusiforme (brown seaweed) are marine algae consumed as food supplements, especially in Japan, China and Korea, and are considered traditional medicinal tonics for certain ailments. The aim of this study was to investigate the possible inhibitory effects of dietary C. fulvescens and H. fusiforme on azoxymethane (AOM)-induced colorectal cancer (CRC) in rats. F344 male rats (5 weeks, 150 g) were divided into six groups as follows. Group 1: Injected with normal saline solution and fed control diet (untreated control). Group 2: Injected with AOM and fed control diet (treated control). Group 3: Injected with AOM and fed 1% C. fulvescens diet. Group 4: Injected with AOM and fed 2% C. fulvescens diet. Group 5: Injected with AOM and fed 2% H. fusiforme diet. Group 6: Injected with AOM and fed 6% H. fusiforme diet. Test animals received subcutaneous injections of AOM (15 mg/1 ml/kg body weight) once a week for 2 weeks to induce aberrant crypt foci (ACF) in treated control and experimental groups. We evaluated the effects of dietary C. fulvescens and H. fusiforme at two different dose levels: 1 and 2% C. fulvescens, and 2 and 6% H. fusiforme, on colonic carcinogenesis by AOM in rats. Our results suggest that body weights were not significantly different amongst groups. We found that feeding C. fulvescens and H. fusiforme with a control diet significantly (p<0.05) inhibited the development of ACF in experimental groups. C. fulvescens and H. fusiforme in food also significantly (p<0.05) reduced the proliferating cell nuclear antigen labeling index in the colonic tissues of experimental groups. These results demonstrate the chemopreventive potential of C. fulvescens and H. fusiforme against CRC in an AOM-induced rats. PMID- 29275306 TI - Silver Nanoparticles Alter Cell Adhesion and Proliferation of Sheep Primary Mesothelial Cells. AB - BACKGROUND: Human exposure to engineered nanoparticles has been linked to pleural effusion, inflammation and fibrosis. Silver nanoparticles (AgNPs) are widely used in medical and domestic products, increasing the risk of occupational and domestic exposure. We assessed the influence of AgNPs on adhesion and proliferation of sheep primary pleural mesothelial cells. MATERIALS AND METHODS: Cells were used for cell adhesion (90 min) and proliferation experiments (3 days) while exposed to 20 nm and 60 nm AgNPs (0.2 MUg/ml and 2 MUg/ml) using colorimetric assays. RESULTS: Exposure to 0.2 MUg/ml of 20 nm and 60 nm AgNPs significantly increased cell adhesion, while at 2 MUg/ml this effect was not elicited. Cell proliferation was significantly increased by both 20 nm and 60 nm AgNPs at 0.2 MUg/ml, while at 2 MUg/ml this effect was only elicited by the 60 nm AgNPs. CONCLUSION: AgNPs alter the adhesive and proliferative properties of primary pleural mesothelial cells. PMID- 29275307 TI - Challenges in the Analysis of Outcomes for Surgical Compared to Radiotherapy Treatment of Prostate Cancer. AB - BACKGROUND/AIM: Prostate cancer can be treated with radical prostatectomy (RP), external-beam radiotherapy (EBRT), or brachytherapy (BT). These modalities have similar cancer-related outcomes. We used an innovative method to analyze the cost of such treatment. MATERIALS AND METHODS: We queried our Institution's Insurance Division [University of Pittsburgh Medical Center (UPMC) Health Plan] beneficiaries from 2003-2008, who were diagnosed with prostate cancer and also queried the UPMC tumor registry for all patients with prostate cancer treated at our Institution. In a de-identified manner, data from the Health Plan and Tumor Registry were merged. RESULTS: A total of 354 patients with non-metastatic disease with treatment initiated within 9 months of diagnosis were included (RP=236, EBRT=55, and BT=63). Radiotherapy-treated patients tended to be older, higher-risk, and have more comorbidities. Unadjusted median total health care expenditures during the first year after diagnosis were: RP: $16,743, EBRT: $47,256, and BT: $23,237 (p<0.0005). A propensity score-matched model comparing RP and EBRT demonstrated median total health care expenditures during year one: RP: $8,189, EBRT: $10,081; p=0.48. In a propensity-matched model comparing RP and BT, the median total health care expenditures during year one were: RP: $18,143, BT: $26,531; p=0.015 and per year during years 2 through 5 from diagnosis were: RP: $5,913, BT: $6,110; p=0.68. CONCLUSION: This pilot study demonstrates the feasibility of combining healthcare costs from the payer's perspective with clinical data from a Tumor Registry within an IDFS and represents a novel approach to investigating the economic impact of cancer treatment. PMID- 29275308 TI - Early PET-CT After Stereotactic Radiotherapy for Stage 1 Non-small Cell Lung Carcinoma Is Predictive of Local Control. AB - BACKGROUND/AIM: Radiological evaluation after stereotactic-body-radiotherapy (SBRT) for non-small-cell lung carcinoma (NSCLC) is often difficult due to lung radiation-induced image modifications on computed tomographic (CT) scan. The aim of this study was to evaluate positron-emission tomography-computed tomography (PET-CT) using fluorodeoxyglucose after SBRT in primary lung cancer. PATIENTS AND METHODS: Eighteen patients with histologically proven NSCLC were treated with SBRT. All had PET-CT evaluations before treatment, at 2 to 3 months and at 1 year post SBRT during the follow-up. RESULTS: Early PET-CT in 12/18 patients who did not experience local failure did not show any progression. No conclusion could be drawn in four cases because early PET-CT was disturbed by inflammatory reaction. Early PET-CT was not predictive of late outcome for two patients, as it showed a significant response followed by disease progression on late evaluation. CONCLUSION: Early PET response appears to correlate with local control at 1 year post SBRT. PMID- 29275309 TI - Detection of Local Recurrence with 3-Tesla MRI After Radical Prostatectomy: A Useful Method for Radiation Treatment Planning? AB - BACKGROUND/AIM: Salvage radiotherapy improves biochemical control in patients with recurrence of prostate cancer after prostatectomy. Radiotherapy target volumes of the prostatic fossa are based on empirical data and differ between different guidelines. Localization of recurrence with multiparametric magnetic resonance imaging (MRI) might be a feasible approach to localize recurrent lesions. PATIENTS AND METHODS: Twenty-one patients with biochemical recurrence after radical prostatectomy were included (median prostate-specific antigen (PSA) =0.17 ng/ml). Multi-parametric MRI was performed using a 3-T MR system. RESULTS: Lesions were detected in seven patients with a median PSA of 0.86 ng/ml (minimum= 0.31 ng/ml). Patients without detectable recurrence had a median PSA of 0.12 ng/ml. All patients with detectable lesions responded to radiotherapy. Eleven out of 14 patients without detectable recurrence also responded. Plasma flow in suspicious lesions was correlated with PSA level. CONCLUSION: Detection of recurrence at the prostatic fossa with our approach was possible in a minority of patients with a low PSA level. Clinical relevance of plasma flow in suspicious lesions should be further investigated. PMID- 29275310 TI - MMP7 Modulation by Short- and Long-term Radiotherapy in Patients with Rectal Cancer. AB - BACKGROUND/AIM: Matrix metalloproteinase 7 (MMP7) expression is highly associated with colorectal cancer and modulates tumour growth and invasion. Radiation injury induces inflammation with increases in MMP7 and in transforming growth factor beta (TGFbeta). The aim of this study was to investigate the effect on MMP7 and TGFbeta. expression in patients with rectal cancer undergoing different regimens of neoadjuvant radiotherapy (RT). PATIENTS AND METHODS: We studied 53 patients in three RT treatment groups receiving RT of 25 Gy, long-term RT 50 Gy and controls receiving no RT. Three biopsies were obtained from each patient during the treatments: before RT, after RT and after surgery. Tissue samples were formalin fixed, paraffin embedded and tissue microarrays were constructed and stained for MMP7 and TGFbeta. Mann-Whitney U-tests and Wilcoxon Z-tests were used to determine differences between patients before and after RT, and after surgery, as well as between the RT groups. RESULTS: In all three patient groups, increases of MMP7 and TGFbeta expression were observed after surgery. MMP7 expression was significantly increased in patients receiving short-term RT but TGFbeta expression was not affected by RT. CONCLUSION: 50 Gy Irradiation of rectal cancer gives less tumour activation of MMP7, whilst it is up-regulated by 25 Gy and surgery regardless of RT. PMID- 29275311 TI - Quality of Life in Patients with Bladder Cancer Undergoing Ileal Conduit: A Comparison of Women Versus Men. AB - BACKGROUND/AIM: Studies comparing health-related quality of life (HR-QoL) between patients who underwent radical cystectomy (RC) and those who underwent a different form of urinary diversion has not reached yet univocal and reliable conclusions. The aim of our study was to evaluate bladder-specific long-term HR QoL after radical cystectomy and ileal conduit. PATIENTS AND METHODS: A multicenter study was carried out on 145 consecutive patients (112 males and 33 females) undergoing RC and ileal conduit (IC). HR-QoL assessment was conducted using Italian versions of European Organisation for Research and Treatment of Cancer QLQ-C30 and EORTC BLM-30 questionnaires. RESULTS: Our data showed that women who underwent IC presented greater problems than men in cognitive functioning (mean score+/-SD: 77.3+/-27.9 vs. 87.8+/-18.6) as well in future perspective (score: 42.4+/-34.4 vs. 21.9+/-24.6). Nevertheless, men undergoing IC had more problems in sexual functioning than women (score: 23.3+/-24.5 vs. 7.0+/ 20.3) (all p<0.05). CONCLUSION: In our series, female patients presented a greater burden than male patients in cognitive functioning as well in future perspective, but lower concerns with regard to sexual function. PMID- 29275312 TI - Prognostic Impact of Splenectomy in Patients with Esophagogastric Junction Carcinoma. AB - BACKGROUND/AIM: We evaluated the survival benefit of splenectomy in patients with esophagogastric junction (ECJ) carcinoma. PATIENTS AND METHODS: We retrospectively examined clinicopathological and survival data for 60 surgically treated patients with ECJ carcinoma. RESULTS: The 5-year overall survival (OS) rate was 47%. Splenectomy was performed in 20 patients (30%). Multivariate Cox regression analysis revealed splenectomy (odds ratio (OR), 2.70; 95% confidence interval (CI)=1.06-7.17; p=0.04) and venous invasion (OR=3.03; 95%CI=1.20-9.27; p=0.02) as significant independent predictors of poorer OS. Splenic hilar lymph node metastasis was not observed. Multivariate logistic regression analysis identified perioperative blood transfusion (BTF) as a significant independent factor associated with splenectomy. CONCLUSION: The survival benefit of splenectomy in ECJ carcinoma patients may decrease with increasing frequency of perioperative BTF for blood loss. We recommend that splenectomy should be performed carefully when indicated by the extent or invasion of EGJ carcinoma. PMID- 29275313 TI - Tumor-infiltrating Lymphocytes Predict the Chemotherapeutic Outcomes in Patients with Stage IV Colorectal Cancer. AB - BACKGROUND/AIM: The anticancer immune response has been reported to contribute to the success of chemotherapy. The aim of this study was to evaluate the significance of the measurement of tumor-infiltrating lymphocytes (TILs) in the primary tumor using the method proposed by the International TILs Working Group as a prognostic marker of chemotherapeutic outcomes in patients with stage IV colorectal cancer (CRC). PATIENTS AND METHODS: A total of 57 patients with stage IV CRC who underwent palliative chemotherapy after resection of the primary tumor were enrolled. Hematoxylin and eosin (H-E)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by measuring the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. Immunohistochemistry for CD8 was also performed, and the number of immunoreactive cytotoxic T-lymphocytes (CTLs) at the invasive margin was counted. RESULTS: Thirty patients were classified into the high-TILs group, and 27 patients were classified into the low-TILs group. The high-TILs group had a significantly higher chemotherapeutic response rate (79.3% vs. 48.1%, p=0.025) and better progression-free survival (median survival time: 10.1 m vs. 7.3 m, p=0.0133) than the low-TILs group. Furthermore, the high-TILs group had a significantly better overall survival than the low-TILs group (median survival time: 35.5 m vs. 22.4 m, p=0.0221). The density of TILs evaluated using the H-E stained sections showed a strong association with the number of CTLs (p<0.001). CONCLUSION: The measurement of TILs in the primary tumor using the method proposed by the International TILs Working Group can be used as a prognostic marker of the clinical effectiveness of palliative chemotherapy in patients with stage IV CRC. PMID- 29275314 TI - Radiotherapy and Tyrosine Kinase Inhibitors in Stage IV Non-small Cell Lung Cancer: Real-life Experience. AB - AIM: To investigate the role of conventional radiotherapy (RT) and stereotactic body radiotherapy (SBRT) in patients with epidermal growth factor (EGFR)-mutant or anaplastic lymphoma kinase (ALK) rearrangement-positive metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty patients with EGFR-mutated or ALK rearrangement-positive NSCLC were treated at our Institution. Radiotherapy was delivered before, after or concomitantly with tyrosine kinase inhibitors (TKIs). Acute toxicities and overall survival (OS) were assessed. RESULTS: Radiotherapy was performed within 30 days before TKI, concomitantly with TKI and within 30 days after TKI in eight (16%), 33 (66%) and 9 (18%) cases, respectively. The median duration of TKI therapy in the whole series was 11.9 months. The median OS was 19.3 months and 1- and 2-year OS was 71.5% and 36.5%, respectively. The group treated with SBRT had a significant benefit in terms of OS (p=0.043). Only two grade 3 toxicities were reported. CONCLUSION: RT concomitantly or close to TKI administration in stage IV NSCLC was shown to be feasible and safe. Intriguing data on OS were also reported. PMID- 29275315 TI - Clinical and Prognostic Analysis of Hypopharyngeal Squamous Cell Carcinoma with Synchronous and Metachronous Multiple Malignancies. AB - BACKGROUND/AIM: To analyze the clinical features and prevalence of synchronous and metachronous second primary malignancies (SPMs) in patients with hypopharyngeal squamous cell carcinoma (HSCC), their associated risk factors, and cause-specific mortality. PATIENTS AND METHODS: We retrospectively reviewed 136 patients treated with curative intent at our hospital. Statistical analyses were performed to determine factors predictive of SPM and cause-specific mortality. RESULTS: Sixty-three of 136 patients (46.3%) developed SPM; of these, 41 (30.1%) and 42 (30.9%) had synchronous and metachronous SPMs, respectively, with patient overlap. The most common site of synchronous and metachronous SPMs was the oesophagus (65.8% and 24.4%, respectively); the corresponding overall survival rates were 34.1% and 66.5%, respectively. Furthermore, heavy drinking was significantly correlated with synchronous SPM (p<0.001). CONCLUSION: Oesophageal cancer surveillance is recommended for patients with HSCC, especially heavy drinkers. Our findings may help identify and properly manage HSCC patients at high risk of SPMs. PMID- 29275316 TI - The Positive Relationship Between gammaH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma. AB - BACKGROUND/AIM: Lung squamous cell carcinoma often arises from precancerous lesions where alterations in tumor suppressor genes and subsequent chromosomal instability are often observed due to carcinogen exposure. These tumors are often immunogenic; as such, immune checkpoint inhibitors are a promising therapeutic option. We hypothesized that the DNA damage response in tumor cells induces an immune response, thereby up-regulating programmed death-ligand 1 (PD-L1) expression on tumor cells, which in turn sensitizes them to anti-PD-1 therapy. PATIENTS AND METHODS: An immunohistochemical analysis was performed in 41 consecutive lung squamous cell carcinoma patients who underwent surgery at our institution between April 2013 and March 2014. RESULTS: The analysis revealed a high PD-L1 expression in 15 patients (37%) (p=0.028). The PD-L1 expression was positively associated with the nuclear gammaH2AX expression (p=0.02), that was confirmed by immunofluorescent staining. CONCLUSION: Our findings demonstrate that nuclear gammaH2AX expression is positively associated with the PD-L1 expression in lung squamous cell carcinoma. PMID- 29275317 TI - Totally Implantable Central Venous Port Catheters: Radiation Exposure as a Function of Puncture Site and Operator Experience. AB - BACKGROUND: Totally implantable central venous port systems provide a safe and effective, long-term means of access for administration of hyperosmolar, local irritant medication, such as chemotherapy, antibiotics and parenteral nutrition. AIM: To evaluate the combination of access site and level of experience on fluoroscopy times (FT) and dose area products (DAP) during implantation of port catheters in a large patient population. MATERIALS AND METHODS: A total of 1,870 patients (992 women, 878 men; age: 61+/-13.14 years) were reviewed investigating two groups of junior (<=50 implantations) and senior (>50) radiologists. RESULTS: Senior radiologists required less FT/DAP (0.24 s/57.3 MUGy m2 versus 0.43 s/68.2 MUGy m2, respectively; p<0.001). Right jugular vein access required the least FT/DAP (0.25 s/56.15 MUGy m2) and right-sided implantation lower FT/DAP (right: 0.26 s/56.4 MUGy m2, left: 0.40 s/85.10 MUGy m2, p<0.001). CONCLUSION: Due to DAP/FT reductions, the right jugular vein seems to be the most favorable implantation side for port systems. For further dose reduction, residents should be well-trained. PMID- 29275318 TI - Hypoxia Inducible Factor Expression and Angiogenesis - Analysis in the Pituitary Gland and Patterns of Death. AB - BACKGROUND/AIM: We investigated the expression of angiogenesis and hypoxia markers in the adenohypophysis and neurohypophysis of patients who died from various acute or chronic diseases. MATERIALS AND METHODS: Paraffin-embedded material of pituitary glands (97 patients) was investigated immunohistochemically for vascular density (CD31) and the expression of vascular endothelial growth factor (VEGF) and of hypoxia inducible factors HIF1alpha and HIF2alpha. RESULTS: Vascular density, and HIF1alpha/HIF2alpha reactivity is directly related with VEGF expression in the pituitary gland, suggesting that the HIF pathway may regulate the vascular density and blood flow in the gland under hypoxic conditions. HIF2alpha appears to be a key regulator in neurohypophysis, whilst in adenohypophysis HIF1alpha and HIF2alpha are equally expressed. Chronic conditions, including alcoholism and substance abuse, seem to activate the HIF pathway in both neuro- and adeno-hypophysis. CONCLUSION: The HIF pathway has an important role in regulating vascular density and blood flow in the pituitary gland. PMID- 29275319 TI - Rare Coexistance of Ileal Diverticulosis, Crohn's Disease and Small Bowel Adenocarcinoma: Report of a Case. AB - BACKGROUND/AIM: Adenocarcinoma is one of the most common malignant tumors of the small intestine complicating Crohn's disease. However, the coexistence of both conditions with diverticulosis of small bowel in young age makes this coincidence rare and clinical diagnosis very difficult. CASE REPORT: We report a case of a woman admitted to our Department with acute abdominal pain and fever. The surgical and histological investigation, revealed a rare coexistence that has never been mentioned in the published medical literature. CONCLUSION: Ileal diverticulosis is not frequent and often asymptomatic as well as adenocarcinoma of the small bowel. In this case, those diseases along with Crohn's disease led the patient to acute symptoms. PMID- 29275320 TI - Influence of Obesity on the Course of Malignant Neoplastic Disease in Patients After Pulmonary Metastasectomy. AB - BACKGROUND/AIM: The aim of the study was to determine whether increased body mass index (BMI) in patients operated on for lung metastases influences the course of the disease. MATERIALS AND METHODS: The retrospective data of 97 patients previously operated on for different malignancies were analyzed. There were 40 obese patients (BMI >30 kg/m2, mean 33.9+/-4.5) and 57 non-obese patients (BMI 25.8+/-2.7 kg/m2, p<0.001). Disease-free interval (DFI), the overall survival (OS) and survival after pulmonary metastasectomy were analyzed. RESULTS: DFI and OS were longer in obese than in non-obese patients (82.1+/-83.5 months vs. 43.0+/ 44.4, p<0.01 and 110.7+/-81.3 months vs. 69.9+/-52.9 p<0.005, respectively). Survival after pulmonary metastasectomy was 27.2+/-25.6 months and was longer in obese and overweight patients than in normal weight patients (20.2+/-18.4 months vs. 29.4+/-26.5, p<0.05). CONCLUSION: Being obese or overweight is a favorable prognostic factor in patients after surgical resection of lung metastases of different malignancies. PMID- 29275322 TI - Marginal cost of the calving interval in beef cows is not uniform. AB - To understand the profitability of reproduction management measures, an economic assessment based on a beef cow life simulation was proposed. It accounted for the discounted feeding costs of the dam and its calves for the different periods of their lives up to their sale and for the overall production from calves adjusted by mortality and culling. The calibration was proposed for various combinations of typical French and European situations. The maximal cash flow was observed for the lowest calving interval, corresponding to the maximal number of calves produced. The marginal cost of the calving interval was not uniform: on average, it was twice as high at a calving interval of 360 days (?1/day) as at 500 days (?0.5/day). It was also higher when age at first calving was lower and when culling was late or the replacement rate was low. The results were sensitive to the costs of the calves' diets and to the market prices for calves. These assessments may assist the evaluation of the profitability of various measures taken in the field when faced with deteriorating calving intervals in beef production. PMID- 29275321 TI - Comparison of Thoracic Radiotherapy Efficacy Between Patients With and Without EGFR-mutated Lung Adenocarcinoma. AB - To investigate the association between tumor response to thoracic radiotherapy and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma, we collected 48 patients treated between January 2010 and December 2013. Of the 18 patients with EGFR mutation, 15 (83.3%) had a single mutation, and three (16.7%) had double mutation. Different EGFR mutation subtypes exhibited different responses to radiotherapy. The identified double EGFR mutations were associated with reduction of residual tumor burden (RTB) after radiotherapy. In univariate analysis, EGFR mutations in exon 18, 20, and 21 and double EGFR mutation were significant factors predicting RTB. In multivariate analysis, exon 20 mutation was the only significant factor. Patients with EGFR mutation seemed to have longer mean overall survival (OS) compared to the group with wild-type EGFR (31.1 vs. 26.6 months, p=0.49). The median and mean OS in patients with double EGFR mutation vs. wild-type EGFR were 20.1 vs. 16.9 months and 28.9 vs. 26.6 months, respectively. Further studies with larger sample size are warranted to clarify the association of EGFR mutation status with the lung tumor response after radiotherapy. PMID- 29275323 TI - Action cameras and the Roter interaction analysis system to assess veterinarian producer interactions in a dairy setting. AB - Herd health and production management (HH&PM) are critical aspects of production animal veterinary practice; therefore, dairy veterinarians need to effectively deliver these services. However, limited research that can inform veterinary education has been conducted to characterise these farm visits. The aim of the present study was to assess the applicability of action cameras (eg, GoPro cameras) worn by veterinarians to provide on-farm recordings, and the suitability of these recordings for comprehensive communication analyses. Seven veterinarians each recorded three dairy HH&PM visits. Recordings were analysed using the Roter interaction analysis system (RIAS), which has been used to evaluate medical conversations in human and companion animal contexts, and provided insights regarding the importance of effective clinical communication. However, the RIAS has never been used in a production animal environment. Results of this pilot study indicate that on-farm recordings were suitable for RIAS coding. Dairy practitioners use a substantial amount of talk allocated to relationship-building and farmer education but that communication patterns of the same veterinarian vary considerably between farm visits. Consecutive studies using this method will provide observational data for research purposes and promise to aid in the improvement of veterinary education through identification of communication priorities and gaps in dairy advisory discussions. PMID- 29275324 TI - Use of clinical vignette questionnaires to investigate the variation in management of keratoconjunctivitis sicca and acute glaucoma in dogs. AB - There is little peer-reviewed research assessing therapeutic effectiveness in canine eye disease. Current treatments used in first opinion and ophthalmology referral practices are also somewhat poorly documented. The aim of this study was to investigate the current management of canine keratoconjunctivitis sicca (KCS) and acute primary angle-closure glaucoma (PACG) by veterinary surgeons. Questionnaires using clinical vignettes were administered to a cross section of general practitioners ('GPs') and veterinarians engaged in or training for postgraduate ophthalmology practice ('PGs'). Similar treatment recommendations for KCS (topical cyclosporine, lubricant, antibiotic) were given by both groups of veterinarians with the single exception of increased topical antibiotic use by GPs. Treatment of acute glaucoma diverged between groups: PGs were much more likely to recommend topical prostaglandin analogues and a wider array of both topical and systemic treatments were recommended by both groups. Systemic ocular hypotensive agents were suggested infrequently. Our results suggest that treatments may vary substantially in ocular conditions, particularly in conditions for which neither guidelines nor high-quality evidence exists. This study highlights the need for novel strategies to address evidence gaps in veterinary medicine, as well as for better evaluation and dissemination of current treatment experience. PMID- 29275326 TI - Current practice in early management of neonatal respiratory distress syndrome: Is it evidence-based? PMID- 29275327 TI - Standardised Frankincense extract: new possible therapeutic option for patients with relapsing-remitting multiple sclerosis. PMID- 29275325 TI - Mechanical thrombectomy in orally anticoagulated patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: To investigate the efficacy and safety of mechanical thrombectomy in patients with acute ischemic stroke according to the oral anticoagulation medication taken at the time of stroke onset. MATERIALS AND METHODS: A retrospective multicenter study of prospectively collected data based on data from the registry the Madrid Stroke Network was performed. We included consecutive patients with acute ischemic stroke treated with mechanical thrombectomy and compared the frequency of intracranial hemorrhage and the modified Rankin Scale (mRS) score at 3 months according to anticoagulation status. RESULTS: The study population comprised 502 patients, of whom 389 (77.5%) were not anticoagulated, 104 (20.7%) were taking vitamin K antagonists, and 9 (1.8%) were taking direct oral anticoagulants. Intravenous thrombolysis had been performed in 59.8% and 15.0% of non-anticoagulated and anticoagulated patients, respectively. Rates of intracranial hemorrhage after treatment were similar between non-anticoagulated and anticoagulated patients, as were rates of recanalization. After 3 months of follow-up, the mRS score was <=2 in 56.3% and 55.7% of non-anticoagulated and anticoagulated patients, respectively (P=NS). Mortality rates were similar in the two groups (13.1%and12.4%, respectively). Among anticoagulated patients, no differences were found for intracranial bleeding, mRS score, or mortality rates between patients taking vitamin K antagonists and those taking direct oral anticoagulants. CONCLUSIONS: Mechanical thrombectomy is feasible in anticoagulated patients with acute ischemic stroke. The outcomes and safety profile are similar to those of patients with no prior anticoagulation therapy. PMID- 29275328 TI - Systematic review of structural and functional brain alterations in psychosis of epilepsy. AB - This systematic review critically assesses structural and functional neuroimaging studies of psychosis of epilepsy (POE). We integrate findings from 18 studies of adults with POE to examine the prevailing view that there is a specific relationship between temporal lobe epilepsy (TLE) and POE, and that mesial temporal lobe pathology is a biomarker for POE. Our results show: (1) conflicting evidence of volumetric change in the hippocampus and amygdala; (2) distributed structural pathology beyond the mesial temporal lobe; and (3) changes in frontotemporal functional network activation. These results provide strong evidence for a revised conceptualisation of POE as disorder of brain networks, and highlight that abnormalities in mesial temporal structures alone are unlikely to account for its neuropathogenesis. Understanding POE as a disease of brain networks has important implications for neuroimaging research and clinical practice. Specifically, we suggest that future neuroimaging studies of POE target structural and functional networks, and that practitioners are vigilant for psychotic symptoms in all epilepsies, not just TLE. PMID- 29275329 TI - Amino acid residues in HIV-2 reverse transcriptase that restrict the development of nucleoside analogue resistance through the excision pathway. AB - Nucleoside reverse transcriptase (RT) inhibitors (NRTIs) are the backbone of current antiretroviral treatments. However, the emergence of viral resistance against NRTIs is a major threat to their therapeutic effectiveness. In HIV-1, NRTI resistance-associated mutations either reduce RT-mediated incorporation of NRTI triphosphates (discrimination mechanism) or confer an ATP-mediated nucleotide excision activity that removes the inhibitor from the 3' terminus of DNA primers, enabling further primer elongation (excision mechanism). In HIV-2, resistance to zidovudine (3'-azido-3'-deoxythymidine (AZT)) and other NRTIs is conferred by mutations affecting nucleotide discrimination. Mutations of the excision pathway such as M41L, D67N, K70R, or S215Y (known as thymidine-analogue resistance mutations (TAMs)) are rare in the virus from HIV-2-infected individuals. Here, we demonstrate that mutant M41L/D67N/K70R/S215Y HIV-2 RT lacks ATP-dependent excision activity, and recombinant virus containing this RT remains susceptible to AZT inhibition. Mutant HIV-2 RTs were tested for their ability to unblock and extend DNA primers terminated with AZT and other NRTIs, when complexed with RNA or DNA templates. Our results show that Met73 and, to a lesser extent, Ile75 suppress excision activity when TAMs are present in the HIV-2 RT. Interestingly, recombinant HIV-2 carrying a mutant D67N/K70R/M73K RT showed 10 fold decreased AZT susceptibility and increased rescue efficiency on AZT- or tenofovir-terminated primers, as compared with the double-mutant D67N/K70R. Molecular dynamics simulations reveal that Met73influences beta3-beta4 hairpin loop conformation, whereas its substitution affects hydrogen bond interactions at position 70, required for NRTI excision. Our work highlights critical HIV-2 RT residues impeding the development of excision-mediated NRTI resistance. PMID- 29275330 TI - Structural basis for substrate specificity of methylsuccinyl-CoA dehydrogenase, an unusual member of the acyl-CoA dehydrogenase family. AB - (2S)-methylsuccinyl-CoA dehydrogenase (MCD) belongs to the family of FAD dependent acyl-CoA dehydrogenase (ACD) and is a key enzyme of the ethylmalonyl CoA pathway for acetate assimilation. It catalyzes the oxidation of (2S) methylsuccinyl-CoA to alpha,beta-unsaturated mesaconyl-CoA and shows only about 0.5% activity with succinyl-CoA. Here we report the crystal structure of MCD at a resolution of 1.37 A. The enzyme forms a homodimer of two 60-kDa subunits. Compared with other ACDs, MCD contains an ~170-residue-long N-terminal extension that structurally mimics a dimer-dimer interface of these enzymes that are canonically organized as tetramers. MCD catalyzes the unprecedented oxidation of an alpha-methyl branched dicarboxylic acid CoA thioester. Substrate specificity is achieved by a cluster of three arginines that accommodates the terminal carboxyl group and a dedicated cavity that facilitates binding of the C2 methyl branch. MCD apparently evolved toward preventing the nonspecific oxidation of succinyl-CoA, which is a close structural homolog of (2S)-methylsuccinyl-CoA and an essential intermediate in central carbon metabolism. For different metabolic engineering and biotechnological applications, however, an enzyme that can oxidize succinyl-CoA to fumaryl-CoA is sought after. Based on the MCD structure, we were able to shift substrate specificity of MCD toward succinyl-CoA through active-site mutagenesis. PMID- 29275331 TI - Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms. AB - The complex disorder Cantu syndrome (CS) arises from gain-of-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb+) efflux assays and patch-clamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS. PMID- 29275332 TI - Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. AB - OBJECTIVE: Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone. METHODS: Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated. RESULTS: IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals. CONCLUSIONS: These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions. TRIAL REGISTRATION NUMBER: NCT02141763; Results. PMID- 29275333 TI - ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis. AB - OBJECTIVES: To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA) associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX). METHODS: Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) >=30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m2 in patients aged <13 years, 40 mg in the others, every other week. The primary outcome was response at month 2 (M2) defined as a 30% reduction of inflammation on LFP in the assessable eye with more severe baseline inflammation and no worsening on slit lamp examination. From M2 to M12, all patients received adalimumab. RESULTS: At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Chi2 test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment. CONCLUSIONS: This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy. TRIAL REGISTRATION NUMBER: NCT01385826. PMID- 29275334 TI - Effect of rituximab on a salivary gland ultrasound score in primary Sjogren's syndrome: results of the TRACTISS randomised double-blind multicentre substudy. AB - OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjogren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (>=1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI 2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results. PMID- 29275335 TI - Association of obstructive sleep apnoea with the risk of vascular outcomes and all-cause mortality: a meta-analysis. AB - OBJECTIVE: This study aimed to conduct a meta-analysis to explore and summarise the evidence regarding the association between obstructive sleep apnoea (OSA) and the subsequent risk of vascular outcomes and all-cause mortality. METHODS: Electronic databases PubMed, Embase and the Cochrane Library were searched to identify studies conducted through May 2016. Prospective cohort studies that reported effect estimates with 95% CIs of major adverse cardiac events (MACEs), coronary heart disease (CHD), stroke, cardiac death, all-cause mortality and heart failure for different levels versus the lowest level of OSA were included. RESULTS: A total of 16 cohort studies reporting data on 24 308 individuals were included. Of these, 11 studies reported healthy participants, and the remaining five studies reported participants with different diseases. Severe OSA was associated with an increased risk of MACEs (relative risk (RR): 2.04; 95% CI 1.56 to 2.66; P<0.001), CHD (RR: 1.63; 95% CI 1.18 to 2.26; P=0.003), stroke (RR: 2.15; 95% CI 1.42 to 3.24; P<0.001), cardiac death (RR: 2.96; 95% CI 1.45 to 6.01; P=0.003) and all-cause mortality (RR: 1.54; 95% CI 1.21 to 1.97; P<0.001). Moderate OSA was also significantly associated with increased risk of MACEs (RR: 1.16; 95% CI 1.01 to 1.33; P=0.034) and CHD (RR: 1.38; 95% CI 1.04 to 1.83; P=0.026). No significant association was found between mild OSA and the risk of vascular outcomes or all-cause mortality (P>0.05). Finally, no evidence of a factor-specific difference in the risk ratio for MACEs among participants with different levels of OSA compared with those with the lowest level of OSA was found. CONCLUSIONS: Severe and moderate OSAs were associated with an increased risk of vascular outcomes and all-cause mortality. This relationship might differ between genders. Therefore, further large-scale prospective studies are needed to verify this difference. PMID- 29275336 TI - Determinants of immunisation coverage of children aged 12-59 months in Indonesia: a cross-sectional study. AB - OBJECTIVES: Despite the adoption of WHO's Expanded Programme on Immunisation in Indonesia since 1977, a large proportion of children are still completely unimmunised or only partly immunised. This study aimed to assess factors associated with low immunisation coverage of children in Indonesia. SETTING: Children aged 12-59 months in Indonesia. PARTICIPANT: The socioeconomic characteristics and immunisation status of the children were obtained from the most recent Demographic and Health Survey, the 2012 Indonesia Demographic and Health Survey. Participants were randomly selected through a two-stage stratified sampling design. Data from 14 401 children aged 12-59 months nested within 1832 census blocks were included in the analysis. Multilevel logistic regression models were constructed to account for hierarchical structure of the data. RESULTS: The mean age of the children was 30 months and they were equally divided by sex. According to the analysis, 32% of the children were fully immunised in 2012. Coverage was significantly lower among children who lived in Maluku and Papua region (adjusted OR: 1.94; 95% CI 1.42 to 2.64), were 36-47 months old (1.39; 1.20 to 1.60), had higher birth order (1.68; 1.28 to 2.19), had greater family size (1.47; 1.11 to 1.93), whose mother had no education (2.13; 1.22 to 3.72) and from the poorest households (1.58; 1.26 to 1.99). The likelihood of being unimmunised was also higher among children without health insurance (1.16; 1.04 to 1.30) and those who received no antenatal (3.28; 2.09 to 5.15) and postnatal care (1.50; 1.34 to 1.69). CONCLUSIONS: Socioeconomic factors were strongly associated with the likelihood of being unimmunised in Indonesia. Unimmunised children were geographically clustered and lived among the most deprived population. To achieve WHO target of protective coverage, public health interventions must be designed to meet the needs of these high-risk groups. PMID- 29275337 TI - Risk of autism spectrum disorder in offspring following paternal use of selective serotonin reuptake inhibitors before conception: a population-based cohort study. AB - OBJECTIVE: The present study aimed to examine the association between paternal selective serotonin reuptake inhibitor (SSRI) use before conception and the risk of autism spectrum disorder (ASD) in offspring. DESIGN: A population-based cohort study. METHODS: We conducted a cohort study of 669 922 children born from 1998 to 2008, with follow-up throughout 2013. Based on Danish national registers, we linked information on paternal use of SSRIs, ASD diagnosed in children and a range of potential confounders. The children whose fathers used SSRIs during the last 3 months prior to conception were identified as the exposed. Cox regression model was used to estimate the HR for ASD in children. RESULTS: Compared with unexposed children, the exposed had a 1.62-fold higher risk of ASD (95% CI 1.33 to 1.96) and the risk attenuated after adjusting for potential confounders, especially fathers' psychiatric conditions (HR=1.43, 95% CI 1.18 to 1.74). When extending the exposure window to 1 year before conception, the increased risk persisted in children of fathers using SSRIs only from the last year until the last 3 months prior to conception (HR=1.54, 95% CI 1.21 to 1.94) but not in children of fathers using SSRIs only during the last 3 months prior to conception (HR=1.17, 95% CI 0.75 to 1.82). We also performed stratified analyses according to paternal history of affective disorders and observed no increased ASD risk among children whose father had affective disorders. Besides, the sibling analysis showed that the ASD risk did not increase among exposed children compared with their unexposed siblings. CONCLUSIONS: The mildly increased risk of ASD in the offspring associated with paternal SSRI use before conception may be attributable to paternal underlying psychiatric indications related to SSRI use or other unmeasured confounding factors. PMID- 29275338 TI - Rationale and design of the violence, injury and trauma observatory (VITO): the Cape Town VITO pilot studies protocol. AB - The establishment of violence and injury observatories elsewhere has been found to reduce the burden within a relatively short period. Currently no integrated system exists in South Africa to provide collated data on violence, to allow for targeted interventions and routine monitoring and evaluation.This research seeks to identify if bringing multiple data sources, including but not limited to data from the South African Police Service (SAPS), Forensic Pathology Services (FPS), Emergency Medical Services (EMS) and local hospital clinical databases, together are (1) feasible; (2) able to generate data for action, that is valid, reliable and robust and (3) able to lead to interventions.The violence, injury and trauma observatory (VITO) is a planned collaborative, multicentre study of clinical, police and forensic data for violence and injury in the City of Cape Town, where a local context exists of access to multiple source of health and non-health data. The VITO will initially be piloted in Khayelitsha, a periurban community characterised by increased rates of violence, where fatal and non-fatal injury data will be sourced from within the community for the period 2012-2015 and subjected to descriptive statistics and time-trend analyses. Analysed data will be visualised using story maps, data clocks, web maps and other geographical information systems-related products.This study has been approved by the University of Cape Town's Human Research Ethics Committee (HREC 861/2016). We intend to disseminate our findings among stakeholders within the local government safety cluster, non-governmental organisations working within the violence prevention sector and the afflicted communities through the SAPS and violence prevention through urban upgrading community forums. Findings from this work will serve to identify important issues and trends, influence public policy and develop evidence-based interventions. PMID- 29275339 TI - Health impact of objective burden, subjective burden and positive aspects of caregiving: an observational study among caregivers in Switzerland. AB - OBJECTIVE: To investigate associations of objective caregiver burden, subjective caregiver burden and positive aspects of caregiving with self-reported health indicators in caregiving partners of persons with a severe physical disability (spinal cord injury). DESIGN: Cross-sectional, observational. SETTING: Community, Switzerland. PARTICIPANTS: Caregiving partners of persons with spinal cord injury (n=118, response rate 19.7%). OUTCOME MEASURES: General health, role limitations due to physical health, role limitations due to mental health, pain intensity, mental health and vitality were assessed using items from the 36-Item Short Form Health Survey (SF-36). Three items were used to assess the frequency of different types of sleep problems. RESULTS: Subjective caregiver burden was associated to all self-reported health indicators. A high subjective burden was linked to poorer general health (OR 6.5, 95% CI 2.0 to 21.5), more role limitations due to physical health (OR 4.2, 95% CI 1.4 to 12.8), more role limitations due to mental health (OR 3.6, 95 % CI 1.1 to 11.7), higher pain intensity (OR 4.0, 95% CI 1.4 to 11.5), poorer mental health (coefficient -17.9, 95% CI -24.5 to -11.2), lower vitality (coefficient -20.3, 95% CI -28.4 to -12.1), and more frequent sleep problems (OR 5.3, 95% CI 1.6 to 18.4). Partners who indicated positive aspects of caregiving further reported better mental health (coefficient 6.5, 95% CI 0.2 to 12.8). Objective burden was not related to any health indicator. CONCLUSIONS: Subjective burden and lack of positive aspects of caregiving were associated with poorer physical and mental health. Caregiver health may be promoted through the strengthening of psychological and psychosocial resources. PMID- 29275341 TI - Qualitative and quantitative assessment of posterior segment optical coherence tomography images using standard photos: the Liwan Eye Study. AB - BACKGROUND/AIMS: To develop a standardised grading scheme, using standard photos, for spectral-domain ocular coherence tomography (SD-OCT) images of the posterior eye and evaluate the interobserver agreement among trained ophthalmologists in identifying pathological changes. METHODS: Subjects were recruited from Liwan District, Guangzhou, with SD-OCT data collection from June 2013 to November 2013 as part of 10-year follow-up visits from the Liwan Eye Study. All subjects underwent SD-OCT imaging of the macula with scanning lines analysed by two ophthalmologists to assess for the presence of 12 different posterior segment lesions. Per cent agreement for each lesion between the graders and quantitative measures of dome-shaped macula (DSM) height and choroidal thickness were calculated. RESULTS: A total of 679 SD-OCT images from 679 subjects were independently evaluated by the two graders. Each of the 12 lesions was successfully graded as present or absent in over 96% of images. For all lesions, per cent agreement between observers was over 90%, ranging from 90.7% for epiretinal membranes and retinal pigment epithelium thickenings to 99.7% for full thickness macular holes and retinal detachments. Quantitative measurements of DSM height and choroidal thickness at three locations of the eye all exhibited intraclass correlation scores between the two graders of greater than 0.9. CONCLUSION: Our study demonstrates high concordance between graders in characterising posterior segment lesions using SD-OCT images, validating the continued use of this imaging modality in the diagnosis of posterior eye disease. PMID- 29275340 TI - Anticipated health behaviour changes and perceived control in response to disclosure of genetic risk of breast and ovarian cancer: a quantitative survey study among women in the UK. AB - BACKGROUND: Genetic risk assessment for breast cancer and ovarian cancer (BCOC) is expected to make major inroads into mainstream clinical practice. It is important to evaluate the potential impact on women ahead of its implementation in order to maximise health benefits, as predictive genetic testing without adequate support could lead to adverse psychological and behavioural responses to risk disclosure. OBJECTIVE: To examine anticipated health behaviour changes and perceived control to disclosure of genetic risk for BCOC and establish demographic and person-specific correlates of adverse anticipated responses in a population-based sample of women. DESIGN: Cross-sectional quantitative survey study carried out by the UK Office for National Statistics in January and March 2014. SETTING: Face-to-face computer-assisted interviews conducted by trained researchers in participants' homes. PARTICIPANTS: 837 women randomly chosen from households across the UK identified from the Royal Mail's Postcode Address File. OUTCOME MEASURES: Anticipated health behaviour change and perceived control to disclosure of BCOC risk. RESULTS: In response to a genetic test result, most women (72%) indicated 'I would try harder to have a healthy lifestyle', and over half (55%) felt 'it would give me more control over my life'. These associations were independent of demographic factors or perceived risk of BCOC in Bonferroni corrected multivariate analyses. However, a minority of women (14%) felt 'it isn't worth making lifestyle changes' and that 'I would feel less free to make choices in my life' (16%) in response to BCOC risk disclosure. The former belief was more likely to be held by women who were educated below university degree level (P<0.001) after adjusting for other demographic and person-specific correlates. CONCLUSION: These findings indicate that women in the UK largely anticipate that they would engage in positive health behaviour changes in response to BCOC risk disclosure. PMID- 29275342 TI - Prevalence and possible factors associated with anaemia, and vitamin B 12 and folate deficiencies in women of reproductive age in Pakistan: analysis of national-level secondary survey data. AB - OBJECTIVE: To determine the prevalence and possible factors associated with anaemia, and vitamin B12 and folate deficiencies in women of reproductive age (WRA) in Pakistan. METHODS: A secondary analysis was conducted on data collected through the large-scale National Nutrition Survey in Pakistan in 2011. Anaemia was defined as haemoglobin levels <12 g/dL, vitamin B12 deficiency as serum vitamin B12 levels of <203 pg/mL (150 pmol/L) and folate deficiency as serum folate levels <4 ng/mL (10 nmol/L). RESULTS: A total of 11 751 blood samples were collected and analysed. The prevalence of anaemia, vitamin B12 deficiency and folate deficiency was 50.4%, 52.4% and 50.8%, respectively. After adjustment, the following factors were positively associated with anaemia: living in Sindh province (RR 1.07; 95% CI 1.04 to 1.09) P<0.00, food insecure with moderate hunger (RR 1.03; 95% CI 1.00 to 1.06) P=0.02, four or more pregnancies (RR 1.03; 95% CI 1.01 to 1.05) P<0.00, being underweight (RR 1.03; 95% CI 1.00 to 1.05) P=0.02, being overweight or obese (RR 0.95; 95% CI 0.93 to 0.97) P<0.00 and weekly intake of leafy green vegetables (RR 0.98; 95% CI 0.95 to 1.00) P=0.04. For vitamin B12 deficiency, a positive association was observed with rural population (RR 0.81; 95% CI 0.66 to 1.00) P=0.04, living in Khyber Pakhtunkhwa province (RR 1.25; 95% CI 1.11 to 1.43) P<0.00 and living in Azad Jammu and Kashmir (RR 1.50; 95% CI 1.08 to 2.08) P=0.01. Folate deficiency was negatively associated with daily and weekly intake of eggs (RR 0.89; 95% CI 0.81 to 0.98) P=0.02 and (RR 0.88; 95% CI 0.78 to 0.99) P=0.03. CONCLUSIONS: In Pakistan, anaemia, and vitamin B12 and folate deficiencies are a severe public health concern among WRA. Our findings suggest that further research is needed on culturally appropriate short-term and long-term interventions within communities and health facilities to decrease anaemia, and vitamin B12 and folate deficiencies among Pakistani women. PMID- 29275343 TI - Assessment of medium-term cardiovascular disease risk after Japan's 2011 Fukushima Daiichi nuclear accident: a retrospective analysis. AB - OBJECTIVE: To assess the medium-term indirect impact of the 2011 Fukushima Daiichi nuclear accident on cardiovascular disease (CVD) risks and to identify whether risk factors for CVD changed after the accident. PARTICIPANTS: Residents aged 40 years and over participating in annual public health check-ups from 2009 to 2012, administered by Minamisoma city, located about 10 to 40 km from the Fukushima Daiichi nuclear plant. METHODS: The sex-specific Framingham CVD risk score was considered as the outcome measure and was compared before (2009-2010) and after the accident (2011-2012). A multivariate regression analysis was employed to evaluate risk factors for CVD. RESULTS: Data from 563 individuals (60.2% women) aged 40 to 74 years who participated in the check-ups throughout the study period was analysed. After adjusting for covariates, no statistically significant change was identified in the CVD risk score postaccident in both sexes, which may suggest no obvious medium-term health impact of the Fukushima nuclear accident on CVD risk. The risk factors for CVD and their magnitude and direction (positive/negative) did not change after the accident. CONCLUSIONS: There was no obvious increase in CVD risks in Minamisoma city, which may indicate successful management of health risks associated with CVD in the study sample. PMID- 29275344 TI - Effects of a 12-week cardiovascular rehabilitation programme on systemic inflammation and traditional coronary artery disease risk factors in patients with rheumatoid arthritis (CARDIA trial): a randomised controlled trial. AB - INTRODUCTION: Patients with systemic inflammatory diseases such as rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) above the baseline risk attributable to traditional CVD risk factors seen in the general population. Exercise in cardiac rehabilitation (CR) is designed specifically for high-risk primary prevention and those with established CVD. Even though the European League Against Rheumatism guidelines state that exercise is safe for individuals with RA and exercise can reduce CVD risk, patients with RA rarely participate in CR. Thus, little is known about CR's impact on inflammatory and CVD risk in the RA population. The purpose of this trial is to determine the feasibility of a 12-week CR programme for patients with RA and whether it decreases CVD risk without exacerbating RA. METHODS AND ANALYSIS: This is a randomised controlled trial whereby 60 participants with RA will be recruited and randomly assigned to either standard of care (SOC) treatment or SOC plus a 12 week CR programme (60 min of education plus two 60 min aerobic exercise sessions/week). Exercise will be performed at 60%-80% of heart rate reserve. Outcome measures (Framingham Risk Score, resting heart rate, blood pressure, blood lipids, markers of systemic inflammation (ie, interleukin (IL) 6 and tumour necrosis factor-alpha (TNF-alpha), Clinical Disease Assessment Index, Disease Activity Score-28, physical activity levels and peak cardiorespiratory fitness) will be assessed preintervention (week-0), postintervention (week-13) and 6 months postintervention. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Nova Scotia Health Authority Research Ethics Board. Results will be submitted for publication in an appropriate peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT01534871; Pre-results. PMID- 29275345 TI - Preoxygenation with non-invasive ventilation versus high-flow nasal cannula oxygen therapy for intubation of patients with acute hypoxaemic respiratory failure in ICU: the prospective randomised controlled FLORALI-2 study protocol. AB - INTRODUCTION: Endotracheal intubation in intensive care unit (ICU) is a procedure at high risk of life-threatening complications. Among them, severe oxygen desaturation, usually defined as a drop of pulse oxymetry (SpO2) below 80%, is the most common. Preoxygenation enables delaying oxygen desaturation occurring during apnea induced by anaesthetic drugs. Data suggest that non-invasive ventilation (NIV) or high-flow nasal cannula (HFNC) oxygen therapy could further increase PaO2 before intubation procedure and prevent oxygen desaturation episodes as compared with standard oxygen. However, no recommendation favours one technique rather than the other, since they have never been compared. Hence, whether a strategy of preoxygenation with NIV or HFNC is more effective than the other in patients with acute hypoxaemic respiratory failure remains to be established. METHODS AND ANALYSIS: The FLORALI-2 study is a multicentre randomised controlled trial comparing a preoxygenation strategy with either NIV or HFNC in patients with acute hypoxaemic respiratory failure needing intubation in ICU. The 320 patients will be randomised with a ratio 1:1 in two groups according to the strategy of preoxygenation. The primary outcome is the occurrence of an episode of severe oxygen desaturation defined by a drop of SpO2 below 80% during the intubation procedure. Secondary outcomes include feasibility of the two strategies, immediate and late complications related to intubation. ETHICS AND DISSEMINATION: The study has been approved by the central ethics committee (Ethics Committee Ouest-III, Poitiers, France) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02668458; Pre-results. PMID- 29275346 TI - Clinical features and prognosis of patients with acute non-specific chest pain in emergency and cardiology departments after the introduction of high-sensitivity troponins: a prospective cohort study. AB - OBJECTIVES: To determine the incidence of clinical, cardiac-related endpoints and mortality among patients presenting to an emergency or cardiology department with non-specific chest pain (NSCP), and who receive testing with a high-sensitivity troponin. A second objective was to identify risk factors for the above-noted endpoints during 12 months of follow-up. DESIGN: A prospective multicentre study. SETTING: Emergency and cardiology departments in Southern Denmark. SUBJECTS: The study enrolled 1027 patients who were assessed for acute chest pain in an emergency or cardiology department, and in whom a myocardial infarction or another obvious reason for chest pain had been ruled out. Patients were enrolled from September 2014 to June 2015 and followed for 1 year. MAIN OUTCOME MEASURES: Clinical, cardiac-related endpoints (cardiac-related death, acute myocardial infarction, unstable angina and coronary revascularisation) and all-cause mortality. RESULTS: Over a period of 1 year, cardiac-related endpoints were found in 19 patients (1.9%): 0 patients experienced cardiac-related death, 2 (0.2%) had myocardial infarction, 4 (0.4%) had unstable angina pectoris and 17 (1.7%) underwent coronary revascularisation. All-cause mortality was observed in seven patients (0.7%). When compared with the general population, the standardised mortality ratio did not differ. The risk factors associated with the study endpoints included male gender, body mass index >25 kg/m2, previous known coronary artery disease, hypertension, hypercholesterolaemia, diabetes mellitus and the use of statins. A total of 73% of the endpoints occurred in males. CONCLUSION: The prognosis for patients with NSCP is favourable, with a 1-year mortality after discharge that is comparable with the background population. Few clinical endpoints took place during follow-up, and those that did were predominantly in males. PMID- 29275347 TI - Two-epoch cross-sectional case record review protocol comparing quality of care of hospital emergency admissions at weekends versus weekdays. AB - INTRODUCTION: The mortality associated with weekend admission to hospital (the 'weekend effect') has for many years been attributed to deficiencies in quality of hospital care, often assumed to be due to suboptimal senior medical staffing at weekends. This protocol describes a case note review to determine whether there are differences in care quality for emergency admissions (EAs) to hospital at weekends compared with weekdays, and whether the difference has reduced over time as health policies have changed to promote 7-day services. METHODS AND ANALYSIS: Cross-sectional two-epoch case record review of 20 acute hospital Trusts in England. Anonymised case records of 4000 EAs to hospital, 2000 at weekends and 2000 on weekdays, covering two epochs (financial years 2012-2013 and 2016-2017). Admissions will be randomly selected across the whole of each epoch from Trust electronic patient records. Following training, structured implicit case reviews will be conducted by consultants or senior registrars (senior residents) in acute medical specialities (60 case records per reviewer), and limited to the first 7 days following hospital admission. The co-primary outcomes are the weekend:weekday admission ratio of errors per case record, and a global assessment of care quality on a Likert scale. Error rates will be analysed using mixed effects logistic regression models, and care quality using ordinal regression methods. Secondary outcomes include error typology, error-related adverse events and any correlation between error rates and staffing. The data will also be used to inform a parallel health economics analysis. ETHICS AND DISSEMINATION: The project has received ethics approval from the South West Wales Research Ethics Committee (REC): reference 13/WA/0372. Informed consent is not required for accessing anonymised patient case records from which patient identifiers had been removed. The findings will be disseminated through peer reviewed publications in high-quality journals and through local High-intensity Specialist-Led Acute Care (HiSLAC) leads at the 121 hospitals that make up the HiSLAC Collaborative. PMID- 29275349 TI - Association between serum uric acid and atrial fibrillation: a cross-sectional community-based study in China. AB - OBJECTIVES: To investigate the effects of gender on the association of serum uric acid (SUA) levels and atrial fibrillation (AF) prevalence in a community-based Chinese population. SETTING: Data were obtained from annual Jidong Oilfield employee and family member health checkups. The Jidong community is geographically located in Tangshan City in northern China. PARTICIPANTS: A total of 9078 residents were invited to take part in the survey and provided informed consents. Individuals without data of ECG or SUA were excluded, leaving 8937 residents in our study. PRIMARY AND SECONDARY OUTCOME MEASURES: SUA was measured at baseline using the uricase-peroxidase method. Hyperuricaemia was defined as a SUA level >7.0 mg/dL in men and >5.7 mg/dL in women. AF was diagnosed based on ECG findings and/or any medical history of AF from referring physicians. The crude and independent association between SUA levels and AF prevalence was evaluated with logistic regression analysis. RESULTS: AF prevalence was 0.6% (53/8937). Participants with hyperuricaemia had a higher AF prevalence compared with those with normal SUA levels (1.1% vs 0.5%; P=0.02). Hyperuricaemia was correlated with AF after adjustment for various cardiovascular risk factors in all participants (P=0.03, OR 2.051, 95% CI 1.063 to 3.856). This correlation was particularly stronger in women compared with men (P<0.001, OR 6.366, 95% CI 2.553 to 15.871 in women and P=0.96, OR 1.025, 95% CI 0.400 to 2.626 in men). CONCLUSIONS: We demonstrated a significant association between increased SUA levels and AF prevalence in a Chinese population. Our data indicate that there is a gender-specific mechanism underlying the relationship between SUA and AF. PMID- 29275348 TI - Subgrouping and TargetEd Exercise pRogrammes for knee and hip OsteoArthritis (STEER OA): a systematic review update and individual participant data meta analysis protocol. AB - INTRODUCTION: Knee and hip osteoarthritis (OA) is a leading cause of disability worldwide. Therapeutic exercise is a recommended core treatment for people with knee and hip OA, however, the observed effect sizes for reducing pain and improving physical function are small to moderate. This may be due to insufficient targeting of exercise to subgroups of people who are most likely to respond and/or suboptimal content of exercise programmes. This study aims to identify: (1) subgroups of people with knee and hip OA that do/do not respond to therapeutic exercise and to different types of exercise and (2) mediators of the effect of therapeutic exercise for reducing pain and improving physical function. This will enable optimal targeting and refining the content of future exercise interventions. METHODS AND ANALYSIS: Systematic review and individual participant data meta-analyses. A previous comprehensive systematic review will be updated to identify randomised controlled trials that compare the effects of therapeutic exercise for people with knee and hip OA on pain and physical function to a non exercise control. Lead authors of eligible trials will be invited to share individual participant data. Trial-level and participant-level characteristics (for baseline variables and outcomes) of included studies will be summarised. Meta-analyses will use a two-stage approach, where effect estimates are obtained for each trial and then synthesised using a random effects model (to account for heterogeneity). All analyses will be on an intention-to-treat principle and all summary meta-analysis estimates will be reported as standardised mean differences with 95% CI. ETHICS AND DISSEMINATION: Research ethical or governance approval is exempt as no new data are being collected and no identifiable participant information will be shared. Findings will be disseminated via national and international conferences, publication in peer-reviewed journals and summaries posted on websites accessed by the public and clinicians. PROSPERO REGISTRATION NUMBER: CRD42017054049. PMID- 29275350 TI - Workflow interruptions and stress atwork: a mixed-methods study among physicians and nurses of a multidisciplinary emergency department. AB - OBJECTIVES: Dealing with multiple workflow interruptions is a major challenge in emergency department (ED) work. This study aimed to establish a taxonomy of workflow interruptions that takes into account the content and purpose of interruptive communication. It further aimed to identify associations of workflow interruptions with ED professionals' work stress. DESIGN: Combined data from expert observation sessions and concomitant self-evaluations of ED providers. SETTING: ED of an academic community hospital in Germany. PARTICIPANTS: Multidisciplinary sample of ED physicians and nurses. 77 matched observation sessions of interruptions and self-evaluations of work stress were obtained on 20 randomly selected days. OUTCOME MEASURES: ED professionals' stress evaluations were based on standardised measures. ED workload data on patient load, patient acuity and staffing were included as control variables in regression analyses. RESULTS: Overall mean rate was 7.51 interruptions/hour. Interruptions were most frequently caused by ED colleagues of another profession (27.1%; mean interruptions/hour rate: 2.04), by ED colleagues of the same profession (24.1%; 1.81) and by telephone/beeper (21%; 1.57). Concerning the contents of interruption events, interruptions most frequently occurred referring to a parallel case under care (30.3%, 2.07), concerning the current case (19.1%; 1.28), or related to coordination activities (18.2%, 1.24). Regression analyses revealed that interruptive communication related to parallel cases significantly increased ED providers' stress levels (beta=0.24, P=0.03). This association remained significant after controlling for ED workload. DISCUSSION: Interruptions that refer to parallel cases under care were associated with increased stress among ED physicians and nurses. Our approach to distinguish between sources and contents of interruptions contributes to an improved understanding of potential benefits and risks of workflow interruptions in ED work environments. Despite some limitations, our findings add to future research on the implications of interruptions for effective and safe patient care and work in complex and dynamic care environments. PMID- 29275352 TI - Correction: Geographical prevalence and risk factors for pterygium: a systematic review and meta-analysis. PMID- 29275353 TI - Correction: Cost-utility and budget impact analyses of the use of NEPA for chemotherapy-induced nausea and vomiting prophylaxis in Italy. PMID- 29275351 TI - Results of physician licence examination and scholarship contract compliance by the graduates of regional quotas in Japanese medical schools: a nationwide cross sectional survey. AB - OBJECTIVES: Responding to the serious shortage of physicians in rural areas, the Japanese government has aggressively increased the number of entrants to medical schools since 2008, mostly as a chiikiwaku, entrants filling a regional quota. The quota has spread to most medical schools, and these entrants occupied 16% of all medical school seats in 2016. Most of these entrants were admitted to medical school with a scholarship with the understanding that after graduation they will practise in designated areas of their home prefectures for several years. The quota and scholarship programmes will be revised by the government starting in 2018. This study evaluates the intermediate outcomes of these programmes. DESIGN: Cross-sectional survey to all prefectural governments and medical schools every year from 2014 to 2017 to obtain data on medical graduates. SETTINGS: Nationwide. PARTICIPANTS: All quota and non-quota graduates with prefecture scholarship in each prefecture, and all the quota graduates without scholarship in each medical school. PRIMARY OUTCOME MEASURES: Passing rate of the National License Examination for Physicians and the percentage of graduates who have not bought out the scholarship contract after graduation. RESULTS: Most prefectures and medical schools in Japan participated in this study (97.8%-100%). Quota graduates with scholarship were significantly more likely to pass the National License Examination for Physicians than the other medical graduates in Japan at all the years (97.9%, 96.7%, 97.4% and 94.7% vs 93.9%, 94.5%, 94.3% and 91.8%, respectively). The percentage of quota graduates with scholarship who remained in the scholarship contract 3 years after graduation was 92.2% and 89.9% for non quota graduates with scholarship. CONCLUSIONS: Quota entrants showed better academic performance than their peers. Most of the quota graduates remained in the contractual workforce. The imminent revision of the national policy regarding quota and scholarship programmes needs to be based on this evidence. PMID- 29275354 TI - Correction: A qualitative study exploring the social and environmental context of recently-acquired HIV infection among men who have sex with men in South-East England. PMID- 29275355 TI - Correction: Patient preferences for venous thromboembolism prophylaxis after injury: a discrete choice experiment. PMID- 29275356 TI - Correction: Association of asthma-chronic obstructive pulmonary disease overlap syndrome with coronary artery disease, cardiac dysrhythmia and heart failure: a population-based retrospective cohort study. PMID- 29275357 TI - Evaluation of the relative effectiveness of the 2017 updated Manchester scoring system for predicting BRCA1/2 mutations in a Southeast Asian country. AB - BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes have significant clinical implications for both risk-reducing and early surveillance management. The third and most recent revision of the Manchester scoring system (MSS3) used to distinguish patients indicated for germline BRCA1/2 testing included further adjustments for triple negative breast cancer, high-grade serous ovarian cancer and human epidermal growth factor 2 (HER2) receptor status. This study aims to evaluate the relative effectiveness of MSS3 in a Southeast Asian population. METHODS: All patients in our centre were tested using next-generation sequencing (NGS) panels that included full gene sequencing as well as coverage for large deletions/duplications in BRCA1/2. We calculated MSS1-3 scores for index patients between 2014 and 2017 who had undergone BRCA1/2 genetic testing and recorded their genetic test results. MSS1-3 outcomes were compared using receiver operating characteristic analysis, while associations with predictors were investigated using Fisher's exact test and logistics regression. Calculations were performed using Medcalc17. RESULTS: Of the 330 included patients, 47 (14.2%) were found to have a germline mutation in BRCA1 or BRCA2. A positive HER2 receptor was associated with a lower likelihood of a BRCA1/2mutation (OR=0.125, 95% CI 0.016 to 0.955; P=0.007), while high-grade serous ovarian cancer was conversely associated with an increased likelihood of a BRCA1/2 mutation (OR=5.128, 95% CI 1.431 to 18.370; P=0.012). At the 10% threshold, 43.0% (142/330) of patients were indicated for testing under MSS3, compared with 35.8% (118/330) for MSS1% and 36.4% (120/330) for MSS2. At the 10% threshold, MSS3 sensitivity was 91.5% and specificity 65.0%, significantly better than the previous MSS1 (P=0.037) and MSS2 (P=0.032) models. CONCLUSION: Our results indicate that the updated MSS3 outperforms previous iterations and relative to the Manchester population, is just as effective in identifying patients with BRCA1/2 mutations in a Southeast Asian population. PMID- 29275358 TI - Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance. AB - OBJECTIVE: Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC. DESIGN: Human HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model. RESULTS: Expression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis. CONCLUSIONS: KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC. PMID- 29275359 TI - Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis. AB - Treatment of disseminated epithelial ovarian cancer (EOC) is an unmet medical need. Therefore, the identification along with preclinical and clinical validation of new targets is an issue of high importance. In this review we focus on microRNAs that mediate metastasis of EOC. We summarize up-regulated metastasis promoting and down-regulated metastasis-suppressing microRNAs. We focus on preclinical in vitro and in vivo functions as well as their metastasis-related clinical correlations. Finally, we outline modalities for therapeutic intervention and critical issues of microRNA-based therapeutics in the context of metastatic EOC. PMID- 29275361 TI - Applications of Support Vector Machine (SVM) Learning in Cancer Genomics. AB - Machine learning with maximization (support) of separating margin (vector), called support vector machine (SVM) learning, is a powerful classification tool that has been used for cancer genomic classification or subtyping. Today, as advancements in high-throughput technologies lead to production of large amounts of genomic and epigenomic data, the classification feature of SVMs is expanding its use in cancer genomics, leading to the discovery of new biomarkers, new drug targets, and a better understanding of cancer driver genes. Herein we reviewed the recent progress of SVMs in cancer genomic studies. We intend to comprehend the strength of the SVM learning and its future perspective in cancer genomic applications. PMID- 29275362 TI - Regulation of beta-Catenin Phosphorylation by PR55beta in Adenoid Cystic Carcinoma. AB - BACKGROUND/AIM: Adenoid cystic carcinoma (AdCC) is a rare cancer of the salivary gland with high risk of recurrence and metastasis. Wnt signalling is critical for determining tumor grade in AdCC, as it regulates invasion and migration. beta catenin dephosphorylation plays an important role in the Wnt pathway, but its underlying molecular mechanism remains unclear. MATERIALS AND METHODS: Because the regulatory subunits of protein phosphatase 2A (PP2A) drive Wnt signalling via target molecules, including beta-catenin, we used qRT-PCR and immunoblot analysis to investigate the expression of these subunits in an AdCC cell line (ACCS) and a more aggressive subline (ACCS-M). RESULTS: PR55beta was highly expressed in ACCS M, suggesting its functional importance. In addition, PR55beta expression was associated with tumor grade, with ACCS-M exhibiting higher PR55beta levels. More importantly, knockdown of PR55beta in ACCS-M cells significantly reduced invasiveness and metastatic ability. Furthermore, dephosphorylation and total levels of beta-catenin were dependent on PR55beta in ACCS-M. Finally, we confirmed a correlation between PR55beta staining intensity and histopathological type in human AdCC tissues. CONCLUSION: Our study provides new insight into the interaction between PR55beta and beta-catenin and suggests that PR55beta may be a target for the clinical treatment of AdCC. PMID- 29275363 TI - Consistent Involvement of Chromosome 13 in Angiolipoma. AB - BACKGROUND/AIM: Angiolipoma is a rare benign soft tissue tumor composed of mature adipocytes and blood vessels. Genetic information on angiolipomas is scarce. With the single exception of one tumor which carried a t(X;2)(p22;p12), all angiolipomas hitherto investigated cytogenetically had normal karyotypes. MATERIALS AND METHODS: G-banding chromosome analysis was performed on three short term cultured angiolipomas. Fluorescence in situ hybridization (FISH) analysis using a commercially available RB1 deletion probe was also done. RESULTS: All three angiolipomas had abnormal karyotypes with loss or structural rearrangement of chromosome 13. The first tumor had the karyotype 46,XY, 6,del(13)(q14),+mar[cp5], the second had 44~45,XY,t(1;10;15)(p21~22;q24;q24), 13[cp5], and the third karyotype was 43,XX,t(13;22;17) (q12;q13; q22~23)[14]. FISH analysis showed heterozygous and homozygous deletion of the RB1 probe in case 2 and 3, respectively. FISH analysis failed in case 1. CONCLUSION: Chromosome 13 was consistently involved in all three angiolipomas. PMID- 29275360 TI - The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets. AB - Despite the approval of several molecular therapies in the last years, breast cancer-associated death ranks as the second highest in women. This is due to metastatic disease, which represents a challenge for treatment. A better understanding of the molecular mechanisms of metastasis is, therefore, of paramount importance. In this review we summarize the role of micro RNAs (miRs) involved in metastasis of breast cancer. We present an overview on metastasis promoting, -suppressing and context-dependent miRs with both activities. We have categorized the corresponding miRs according to their target classes, interaction with stromal cells or exosomes. The pathways affected by individual miRs are outlined in regard to in vitro properties, activity in metastasis-related in vivo models and clinical significance. Current approaches that may be suitable for therapeutic inhibition or restauration of miR activity are outlined. Finally, we discuss the delivery bottlenecks which present as a major challenge in nucleic acid (miR)-based therapies. PMID- 29275364 TI - Genetic Variations in the 3'-untranslated Regions of Genes Involved in the Cell Cycle and Apoptosis Pathways Affect Bladder Cancer Risk. AB - BACKGROUND: Key genes related to cell cycle and apoptosis pathways play critical roles in bladder cancer. Single nucleotide polymorphisms (SNPs) in the 3' untranslated regions (3'-UTR) of genes may impact microRNA (miRNA)-messenger RNA (mRNA) binding capacity and alter gene expression to contribute to the susceptibility of cancers. However, an association of genetic variations in cell cycle and apoptosis pathways with bladder cancer risk, has not been reported. MATERIALS AND METHODS: We selected SNPs in the 3'-UTR of cell cycle and apoptosis pathways genes and genotyped them with a case-control study consisting of 578 bladder cancer patients and 1,006 cancer-free subjects. Dual luciferase reporter gene assay was performed to validate the biological function of important SNPs. RESULTS: We found that 5 SNPs might change the binding ability of miRNA to their target genes, among which PPP3CC rs7431 A>G located in the 3'-untranslated regions with the minimum p-value (p=5.75*10-4). Analysis revealed that the rs7431 disrupted miR-212 and miR-132 targeting sites. Logistic regression revealed a significantly decreased risk of bladder cancer associated with the PPP3CC rs7431 A>G polymorphism with an odds ratio (OR) of 0.76 [95% confidence interval (CI)=0.66-0.89, p=5.75*10-4]. Luciferase report assay showed that both miR-212 and miR-132 could lead to significantly increased PPP3CC expression levels in the construct with the G allele compared to the A allele. CONCLUSION: PPP3CC rs7431 may alter miRNA binding ability of miR-212 and miR-132, and thus decrease bladder cancer risk. PMID- 29275366 TI - Prognostic Value of New-Generation Troponins in ST-Segment-Elevation Myocardial Infarction in the Modern Era: The RUTI-STEMI Study. AB - BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), troponins are not needed for diagnosis: symptoms and ECG data are sufficient to activate percutaneous coronary intervention. This study explored the prognostic value of new-generation troponins in a real-life cohort contemporarily treated for STEMI. METHODS AND RESULTS: We studied 1260 consecutive patients with primary STEMI treated with percutaneous coronary intervention between February 22, 2011, and August 31, 2015. We collected data on clinical characteristics and major adverse cardiovascular and cerebrovascular events (MACCEs) at 30 days and 1 year. Peak high-sensitivity troponin T and sensitive-contemporary troponin I levels were recorded. MACCEs occurred in 75 patients (6.1%) by day 30 and in 124 patients (10.8%) between day 31 and 1 year. A short-term (0-30 days) multivariable Cox regression analysis revealed that age, Killip-Kimball class, and left ventricular ejection fraction were independent predictors of MACCEs. In adjusted analysis, peak high-sensitivity troponin T and sensitive-contemporary troponin I were not significant (hazard ratio, 1.23 [95% confidence interval, 0.98-1.54] [P=0.071]; and hazard ratio, 1.15 [95% confidence interval, 0.93-1.43] [P=0.200], respectively). A long-term (31 days-1 year) multivariable Cox regression analysis revealed that age, female sex, diabetes mellitus, prior coronary artery disease, Killip-Kimball class, and left ventricular ejection fraction were statistically significantly associated with MACCEs. However, peak high-sensitivity troponin T and peak sensitive-contemporary troponin I were not significantly associated with MACCEs (hazard ratio, 1.03 [95% confidence interval, 0.88-1.20] [P=0.715]; and hazard ratio, 0.99 [95% confidence interval, 0.85-1.15] [P=0.856], respectively). CONCLUSIONS: In the modern era, new-generation troponins do not provide significant prognostic information for predicting clinical events in STEMI. We should reconsider the value of serial troponin measurements for risk stratification in STEMI. PMID- 29275365 TI - 2-Methoxyestradiol Affects Mitochondrial Biogenesis Pathway and Succinate Dehydrogenase Complex Flavoprotein Subunit A in Osteosarcoma Cancer Cells. AB - BACKGROUND/AIM: Dysregulation of mitochondrial pathways is implicated in several diseases, including cancer. Notably, mitochondrial respiration and mitochondrial biogenesis are favored in some invasive cancer cells, such as osteosarcoma. Hence, the aim of the current work was to investigate the effects of 2 methoxyestradiol (2-ME), a potent anticancer agent, on the mitochondrial biogenesis of osteosarcoma cells. MATERIALS AND METHODS: Highly metastatic osteosarcoma 143B cells were treated with 2-ME separately or in combination with L-lactate, or with the solvent (non-treated control cells). Protein levels of alpha-syntrophin and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) were determined by western blotting. Impact of 2 ME on mitochondrial mass, regulation of cytochrome c oxidase I (COXI) expression, and succinate dehydrogenase complex flavoprotein subunit A (SDHA) was determined by immunofluorescence analyses. Inhibition of sirtuin 3 (SIRT3) activity by 2-ME was investigated by fluorescence assay and also, using molecular docking and molecular dynamics simulations. RESULTS: L-lactate induced mitochondrial biogenesis pathway via up-regulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1alpha, COXI, and SIRT3 in a concentration dependent manner as a consequence of nuclear recruitment of neuronal nitric oxide synthase and nitric oxide generation. It was also proved that 2-ME inhibited SIRT3 activity by binding to both the canonical and allosteric inhibitor binding sites. Moreover, regardless of the mitochondrial biogenesis pathway, 2-ME affected the expression of SDHA. CONCLUSION: Herein, mitochondrial biogenesis pathway regulation and SDHA were presented as novel targets of 2-ME, and moreover, 2-ME was demonstrated as a potent inhibitor of SIRT3. L-lactate was confirmed to exert pro-carcinogenic effects on osteosarcoma cells via the induction of the mitochondrial biogenesis pathway. Thus, L-lactate level may be considered as a prognostic biomarker for osteosarcoma. PMID- 29275367 TI - In Vivo Validation of Patient-Specific Pressure Gradient Calculations for Iliac Artery Stenosis Severity Assessment. AB - BACKGROUND: Currently, the decision to treat iliac artery stenoses is mainly based on visual inspection of digital subtraction angiographies. Intra-arterial pressure measurements can provide clinicians with accurate hemodynamic information. However, pressure measurements are rarely performed because of their invasiveness and the time required. Therefore, the aim of the study was to test the feasibility of a computational model that can predict translesional pressure gradients across iliac artery stenoses on the basis of imaging data only. METHODS AND RESULTS: Patients (N=21) with symptomatic peripheral arterial disease and a peak systolic velocity ratio between 2.5 and 5.0 were included in the study. Patients underwent per-procedural 3-dimensional rotational angiography and hyperemic intra-arterial translesional pressure measurements. Vascular anatomical features were reconstructed from the 3-dimensional rotational angiography data into an axisymmetrical 2-dimensional computational mesh, and flow was estimated on the basis of the stenosis geometry. Computational fluid dynamics were performed to predict the pressure gradient and were compared with the measured pressure gradients. A good agreement by overlapping error bars of the predicted and measured pressure gradients was found in 21 of 25 lesions. Stratification of the stenosis on the basis of the predicted pressure gradient into hemodynamic not significant (<10 mm Hg) and hemodynamic significant (>=10 mm Hg) resulted in sensitivity, specificity, and overall predictive values of 95%, 60%, and 88%, respectively. CONCLUSIONS: The feasibility of the patient-specific computational model to predict the hyperemic translesional pressure gradient over iliac artery stenosis was successfully tested. Presented results suggest that, with further optimization and corroboration, the model can become a valuable aid to the diagnosis of equivocal iliac artery stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR5085. PMID- 29275368 TI - Use of Mineralocorticoid Receptor Antagonists in Patients With Heart Failure and Comorbid Diabetes Mellitus or Chronic Kidney Disease. AB - BACKGROUND: Perceived risks of hyperkalemia and acute renal insufficiency may limit use of mineralocorticoid receptor antagonist (MRA) therapy in patients with heart failure, especially those with diabetes mellitus or chronic kidney disease. METHODS AND RESULTS: Using clinical registry data linked to Medicare claims, we analyzed patients hospitalized with heart failure between 2005 and 2013 with a history of diabetes mellitus or chronic kidney disease. We stratified patients by MRA use at discharge. We used inverse probability-weighted proportional hazards models to assess associations between MRA therapy and 30-day, 1-year, and 3-year mortality, all-cause readmission, and readmission for heart failure, hyperkalemia, and acute renal insufficiency. We performed interaction analyses for differential effects on 3-year outcomes for reduced, borderline, and preserved ejection fraction. Of 16 848 patients, 12.3% received MRA therapy at discharge. Higher serum creatinine was associated with lower odds of MRA use (odds ratio, 0.66; 95% confidence interval, 0.61-0.71); serum potassium was not (odds ratio, 1.00; 95% confidence interval, 0.90-1.11). There was no mortality difference between groups. MRA therapy was associated with greater risks of readmission for hyperkalemia and acute renal insufficiency and lower risks of long-term all-cause readmission. Patients on MRA therapy with borderline or preserved ejection fraction had greater risks of readmission for hyperkalemia (P=0.02) and acute renal insufficiency (P<0.001); patients with reduced ejection fraction did not. CONCLUSIONS: Among patients with heart failure and diabetes mellitus or chronic kidney disease, MRA use was associated with lower risk of all cause readmission despite greater risk of hyperkalemia and acute renal insufficiency. PMID- 29275369 TI - Regional "Call 911" Emergency Department Protocol to Reduce Interfacility Transfer Delay for Patients With ST-Segment-Elevation Myocardial Infarction. AB - BACKGROUND: We evaluated the first-medical-contact-to-balloon (FMC2B) time after implementation of a "Call 911" protocol for ST-segment-elevation myocardial infarction (STEMI) interfacility transfers in a regional system. METHODS AND RESULTS: This is a retrospective cohort study of consecutive patients with STEMI requiring interfacility transfer from a STEMI referring hospital, to one of 35 percutaneous coronary intervention-capable STEMI receiving centers (SRCs). The Call 911 protocol allows the referring physician to activate 911 to transport a patient with STEMI to the nearest SRC for primary percutaneous coronary intervention. Patients with interfacility transfers were identified over a 4-year period (2011-2014) from a registry to which SRCs report treatment and outcomes for all patients with STEMI transported via 911. The primary outcomes were median FMC2B time and the proportion of patients achieving the 120-minute goal. FMC2B for primary 911 transports were calculated to serve as a system reference. There were 2471 patients with STEMI transferred to SRCs by 911 transport during the study period, of whom 1942 (79%) had emergent coronary angiography and 1410 (73%) received percutaneous coronary intervention. The median age was 61 years (interquartile range [IQR] 52-71) and 73% were men. The median FMC2B time was 111 minutes (IQR 88-153) with 56% of patients meeting the 120-minute goal. The median STEMI referring hospital door-in-door-out time was 53 minutes (IQR 37-89), emergency medical services transport time was 9 minutes (IQR 7-12), and SRC door to-balloon time was 44 minutes (IQR 32-60). For primary 911 patients (N=4827), the median FMC2B time was 81 minutes (IQR 67-97). CONCLUSIONS: Using a Call 911 protocol in this regional cardiac care system, patients with STEMI requiring interfacility transfers had a median FMC2B time of 111 minutes, with 56% meeting the 120-minute goal. PMID- 29275370 TI - Pacemaker-Mediated Programmable Hypertension Control Therapy. AB - BACKGROUND: Many patients requiring a pacemaker have persistent hypertension with systolic blood pressures above recommended levels. We evaluated a pacemaker-based Programmable Hypertension Control (PHC) therapy that uses a sequence of variably timed shorter and longer atrioventricular intervals. METHODS AND RESULTS: Patients indicated for dual-chamber pacing with office systolic blood pressure (oSBP) >150 mm Hg despite stable medical therapy were implanted with a ModeratoTM pulse generator that delivers PHC therapy. Patients were followed for 1 month (Run-In period) with conventional pacing; those with persistent oSBP >140 mm Hg were included in the study and had PHC therapy activated. The co-primary efficacy end points were changes in 24-hour ambulatory systolic blood pressure and oSBP between baseline and 3 months. Safety was assessed by tracking adverse events. Thirty-five patients met the initial inclusion criteria and underwent Moderato implantation. At 1 month, oSBP was <140 mm Hg in 7 patients who were excluded. PHC was activated in the remaining 27 patients with baseline office blood pressure 166+/-11/80+/-10 mm Hg despite an average of 3.2 antihypertensive medications. During the Run-In period, oSBP and 24-hour ambulatory systolic blood pressure decreased by 8+/-13 and 5+/-12 mm Hg (P<0.002), respectively. Compared with pre-PHC activation measurements, oSBP decreased by another 16+/-15 mm Hg and 24-hour ambulatory systolic blood pressure decreased by an additional 10+/-13 mm Hg (both P<0.01) at 3 months. No device-related serious adverse effects were noted. CONCLUSIONS: In pacemaker patients with persistent hypertension despite medical therapy, oSBP and 24-hour ambulatory systolic blood pressure are decreased by PHC therapy. Initial indications are that this therapy is a safe and promising therapy for such patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02282033. PMID- 29275371 TI - Stent and Dual Antiplatelet Therapy Duration Comparisons in the Setting of a Multicenter Randomized Controlled Trial: Can the Operator Experience Affect the Study Results? AB - BACKGROUND: Operator experience influences outcomes after percutaneous coronary intervention, but this association in the controlled setting of a randomized, clinical trial is unclear. METHODS AND RESULTS: We investigated operator-related outcomes (30-day and 2-year efficacy and safety end points) among patients undergoing percutaneous coronary intervention and randomized to different dual antiplatelet therapy durations and stent types. A total of 2003 patients were analyzed, and 7 operator groups were compared. The majority of preprocedural and postprocedural characteristics were imbalanced. The primary end point of the study, the composite of death, myocardial infarction, or cerebrovascular accidents, did not differ among operators at 30 days or 2 years. There were no significant differences also for all other individual and composite end points analyzed at 30 days and 2 years, except for 2-year stent thrombosis (P=0.048) and bleeding events (P=0.022 for Bleeding Academic Research Consortium type 2, 3, or 5). Adjusted comparisons for the main end points showed slight differences among operators at 30 days, but not at 2 years. There was no interaction of operator with dual antiplatelet therapy duration (P=0.112) or stent type (P=0.300). Results remained entirely consistent when operators were stratified by their experience. CONCLUSIONS: There was a weak signal of heterogeneity across study operators for the 30-day, but not the 2-year, main study outcomes. No clear effect of operator or operator experience was observed for the comparative efficacy and safety profile of the randomized stent types or dual antiplatelet therapy duration regimens. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286. PMID- 29275372 TI - Nitric Oxide-Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries. AB - BACKGROUND: Recent studies demonstrate that spatially restricted, local Ca2+ signals are key regulators of endothelium-dependent vasodilation in systemic circulation. There are drastic functional differences between pulmonary arteries (PAs) and systemic arteries, but the local Ca2+ signals that control endothelium dependent vasodilation of PAs are not known. Localized, unitary Ca2+ influx events through transient receptor potential vanilloid 4 (TRPV4) channels, termed TRPV4 sparklets, regulate endothelium-dependent vasodilation in resistance-sized mesenteric arteries via activation of Ca2+-dependent K+ channels. The objective of this study was to determine the unique functional roles, signaling targets, and endogenous regulators of TRPV4 sparklets in resistance-sized PAs. METHODS AND RESULTS: Using confocal imaging, custom image analysis, and pressure myography in fourth-order PAs in conjunction with knockout mouse models, we report a novel Ca2+ signaling mechanism that regulates endothelium-dependent vasodilation in resistance-sized PAs. TRPV4 sparklets exhibit distinct spatial localization in PAs when compared with mesenteric arteries, and preferentially activate endothelial nitric oxide synthase (eNOS). Nitric oxide released by TRPV4 endothelial nitric oxide synthase signaling not only promotes vasodilation, but also initiates a guanylyl cyclase-protein kinase G-dependent negative feedback loop that inhibits cooperative openings of TRPV4 channels, thus limiting sparklet activity. Moreover, we discovered that adenosine triphosphate dilates PAs through a P2 purinergic receptor-dependent activation of TRPV4 sparklets. CONCLUSIONS: Our results reveal a spatially distinct TRPV4-endothelial nitric oxide synthase signaling mechanism and its novel endogenous regulators in resistance-sized PAs. PMID- 29275373 TI - Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis. AB - BACKGROUND: Subclinical myocardial injury, as measured by high-sensitivity cardiac troponin T (hsTnT), and myocardial stress, as measured by N-terminal pro B-type natriuretic peptide (NT-proBNP), are related to glycemic control in patients with type 2 diabetes mellitus, and are strong predictors of adverse cardiovascular outcomes. We sought to determine whether antihyperglycemic therapy improves measures of myocardial injury and myocardial stress in patients with type 2 diabetes mellitus. METHODS AND RESULTS: We randomized, in a 2*2 factorial fashion, 438 patients with type 2 diabetes mellitus to insulin glargine, metformin, the combination, or placebo and measured changes in NT-proBNP and hsTnT after 12 weeks of therapy. At baseline, the median (Q1-Q3) plasma concentration was 35.4 (15.7-86.3) ng/L for NT-proBNP and 6.7 (4.6-10.1) ng/L for hsTnT. The adjusted (95% confidence interval) change in NT-proBNP concentration was 20.7% (7.9-35.0) in the insulin arm compared with 0.13% (-10.8 to 12.5) in the no-insulin arm (P=0.03 for comparison). These changes were not related to changes in fasting or postprandial glucose, glycated hemoglobin, weight, blood pressure, or inflammation. In the metformin arm, the adjusted change in NT-proBNP was 7.8% (-3.7 to 20.7) compared with 13.0% (0.72-26.8) in the no-metformin arm (P=0.58). No significant changes in hsTnT concentrations were observed for any of the treatment arms. CONCLUSIONS: Insulin glargine was associated with a significant 20.7% increase in NT-proBNP, a marker of myocardial stress, after 12 weeks of therapy. No change in hsTnT, a marker of myocardial injury, was observed. The changes were independent of substantial improvements in glucose control. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00366301. PMID- 29275374 TI - Total Bilirubin in Prognosis for Mortality in End-Stage Renal Disease Patients on Peritoneal Dialysis Therapy. AB - BACKGROUND: Evidence regarding bilirubin's antioxidant properties and predictive roles is growing. However, it is unclear whether serum bilirubin would have a prognostic impact on survival of patients with regular peritoneal dialysis. METHODS AND RESULTS: We used the Taiwan Renal Registry Data System utilizing its 2005-2012 data set. Data from patients on regular peritoneal dialysis were retrieved. The primary end point of observation was 3-year mortality. A total of 3704 patients (mean age 53.5 years, 44% male) were enrolled, and these patients were divided according to baseline serum total bilirubin levels (<0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, >0.6 mg/dL). Serum total bilirubin level was linearly related to age, incidence of hypertension, and type 2 diabetes mellitus. At the end of the observation period with a mean follow-up of 2.12+/-1.07 years, 1095 (30.6%) deaths were detected. Serum total bilirubin level and 3-year mortality rate presented a U-shaped relationship. Those with serum total bilirubin 0.5 to 0.6 mg/dL had the lowest 3-year mortality rate (24%). After adjustment for age, sex, underlying systemic disorders, medications, and laboratory discrepancies, serum total bilirubin still played an independent role for predicting 3-year mortality. CONCLUSIONS: Baseline serum total bilirubin level is significantly associated with 3-year mortality among patients receiving regular peritoneal dialysis. PMID- 29275375 TI - Etiology and Long-Term Outcome of Patients Undergoing Pericardiocentesis. AB - BACKGROUND: Pericardial effusions can be caused by a variety of disorders. The frequency of the underlying diseases varies with patient population; therefore, previously reported series are not necessarily representative of other populations. Our purpose was to examine the etiology of pericardial effusions and the survival of patients requiring pericardiocentesis at a tertiary center. METHODS AND RESULTS: We performed a retrospective observational study of 269 consecutive patients who underwent percutaneous pericardiocentesis at our university hospital between 2006 and 2016 and had prospective follow-up for up to 10 years. The most frequent etiologies were idiopathic (26%), malignancy (25%), and iatrogenicity (20%), whereas bacterial causes were very rare. The most frequent malignancies originated from the lung (53%) or breast (18%). A new cancer was diagnosed with malignant pericardial effusion as the presenting complaint for 9% of patients, whereas the pericardium was the first metastatic site of a known malignancy in 4% of patients. Survival was significantly poorer in malignancy-related versus non-malignancy-related effusions (P<0.001) and in cytology-positive versus cytology-negative effusions in the overall cohort (P<0.001). Among cancer-only patients, however, there was no significant difference in long-term survival between cytology-positive and -negative effusions. CONCLUSIONS: In this contemporary tertiary-center cohort, pericardial effusions often represent the primary instance of a new malignancy, underscoring the importance of cytological analyses of noniatrogenic effusions in patients without known cancer, as survival is significantly worse. In cancer patients, however, the presence of pericardial malignant cytology does not appear to affect outcome significantly. PMID- 29275376 TI - Programmable Hypertension Control: Another Possible Indication for Implanted Pacemakers. PMID- 29275377 TI - Mineralocorticoid Receptor Antagonists in High-Risk Heart Failure Patients With Diabetes Mellitus and/or Chronic Kidney Disease. PMID- 29275378 TI - Results of viscobubble deep anterior lamellar keratoplasty after failure of pneumatic dissection. AB - AIM: To report the outcomes of bubble formation obtained by means of intrastromal injection of ophthalmic viscoelastic device (OVD) after failure of pneumatic dissection for deep anterior lamellar keratoplasty (DALK). METHODS: DALK was performed in 140 keratoconic eyes of 130 patients by injecting air and OVD only secondarily, after pneumatic dissection had failed; the bubble formation rates after air and OVD injection were recorded; complications, best spectacle corrected visual acuity (BSCVA) and corneal tomographic parameters were evaluated 3 months, 6 months and 12 months postoperatively, as well as after complete suture removal. RESULTS: Air injection created a big bubble in 106/140 eyes (75.71%); OVD injection was not attempted in 4 eyes (perforation during cannula insertion n=2; air bubble burst n=2) and created a big bubble in 28 of the remaining 30 eyes (93.33%, 20% of the total). Manual dissection was required in 2/30 eyes (6.66%, 1.42% of the total) after failed OVD-assisted dissection.Deep folds, interface opacity and reduced BSCVA were noted in both eyes after failed OVD-assisted dissection. BSCVA was statistically better after pneumatic-assisted than after OVD-assisted dissection (P 0.01) only up to 3 months postoperatively; no statistically significant differences were recorded between the two techniques at later examinations. CONCLUSION: Intrastromal injection of OVD after failed pneumatic dissection increases considerably the success rate of bubble formation (from 75.71% to 95.71% in our series); however, when bubble formation fails, infiltration of OVD into the residual stroma makes manual dissection particularly challenging and causes severe interface haze resulting in poor visual outcomes. PMID- 29275379 TI - Correction: Gangrenous digital infarcts in a severe case of cutaneous polyarteritis nodosa. PMID- 29275380 TI - Double hit! A unique case of resistant hypertension. AB - A middle-aged woman with obesity, hyperlipidaemia and diet-controlled diabetes was referred for resistant hypertension. Her blood pressure (BP) was uncontrolled on five medications, including a diuretic. Physical exam revealed a systolic ejection murmur, and ECHO demonstrated moderate hypertrophy. Laboratory examination revealed elevated aldosterone level (20.7 ng/dL) and elevated aldosterone:renin ratio (41.4 (ng/dL)/(ng/mL/h)), meeting criteria for primary aldosteronism (PA), and confirmed by saline infusion testing. CT scan of the adrenals was non-localising. Adrenal venous sampling confirmed bilateral idiopathic adrenal hyperplasia. Concurrent primary hyperparathyroidism was demonstrated by elevated calcium and parathyroid hormone levels and localised by sestamibi scan. Idiopathic adrenal hyperplasia was treated medically with spironolactone. Her BP remained elevated until postparathyroidectomy. Evidence shows that a hyperfunctioning parathyroid gland may contribute to maintaining hyperaldosteronism in PA making this bidirectional link unique. The significance of this case is in the potential for further understanding of the pathophysiology of common causes of secondary hypertension. PMID- 29275381 TI - Maxillary chondrosarcoma mimicking torus palatinus. PMID- 29275382 TI - Intradural lumbar disc herniation detected by 3D CISS MRI. AB - A 73-year-old man who presented with right lumbosciatic pain underwent a neurosurgical operation for a voluminous L2-L3 disc herniation, seen on conventional MRI images. No disc herniation was identified in the epidural space during the surgery. Just after the operation, the patient started to present pain in the left L3 territory and was not able to walk any more. A second MRI including three-dimensional (3D) high-resolution constructive interference in steady state (CISS) sequence showed that the voluminous L2-L3 disc split the posterior longitudinal ligament and the anterior dura mater, extended intradurally and compressed the cauda equina to the right. The patient underwent a second surgery, which permitted to cure the symptoms. 3D high-resolution CISS should be considered to accurately depict intradural disc herniation in order to optimally guide the surgical approach. PMID- 29275383 TI - Solid pseudopapillary tumour (Frantz's tumour) of the pancreas in childhood: successful management of late liver metastases with sunitinib and chemoembolisation. AB - The patient is a girl aged 17 years who originally presented at age 11 years with a solid pseudopapillary tumour (SPT) in the head of the pancreas treated by an R0 pylorus-preserving Whipple procedure. The patient underwent surveillance CT every 3 months for the first year followed by MRI every 6 months. She was noted to have a new liver lesion in Couinaud segment VI highly suspicious for metastasis at 30 months. Liver wedge biopsy confirmed metastatic SPT. Two months later two new lesions were noted in Couinaud segment VII. The family preferred medical management to surgery resulting in a treatment combination of the tyrosine kinase inhibitor sunitinib and hepatic artery embolisation. The patient developed a hepatic abscess following embolisation but recovered with antibiotics. The patient has subsequently been followed with serial MRIs every 3 months, and 20 months following chemoembolisation, she has no evidence of recurrence of the metastases. PMID- 29275384 TI - Cutaneous infection with paucibacillary Mycobacterium tuberculosis treated successfully with a modified antituberculous drug regimen. AB - Tuberculosis is a serious infection that is increasing in prevalence, affecting many people worldwide. The diagnosis of cutaneous tuberculosis is challenging and requires the correlation of clinical findings with often inconclusive diagnostic testing. Extrapulmonary tuberculosis comprises approximately 10% of all cases of tuberculosis, and cutaneous tuberculosis makes up only a small proportion of these cases. Discussed here is the case of a 61-year-old immunocompetent female with a large cutaneous lesion on her index finger secondary to Mycobacterium tuberculosis Tissue cultures taken at biopsy were negative; however, empiric antimycobacterial therapy was initiated. The initial regimen was not tolerated, and antituberculous therapy was substituted for moxifloxacin and clarithromycin. The lesion improved significantly with a concurrent improvement in function. PMID- 29275385 TI - Oyster-related tenosynovitis: a rare case of Mycobacterium szulgai in the immunocompromised. AB - A 66-year-old man with a history of renal transplant on chronic immunosuppression presented to his primary care physician with a swollen right index finger. On examination, mild swelling was present. Conservative management failed and initial plain films were negative. Corticosteroid injection was performed by orthopaedics, but symptoms recurred several months later and an MRI showed flexor digitorum tenosynovitis and abscesses of the superficialis and profundus tendons. A flexor tenolysis was performed with cultures positive for Mycobacterium szulgai, a rare, non-tuberculous mycobacterial infection. Treatment was initiated with moxifloxacin, ethambutol and azithromycin daily for nearly 4 months. Repeat MRI 3 months after completion of antibiotics showed near resolution of the tenosynovitis. PMID- 29275387 TI - Syndrome of X linked intellectual disability, epilepsy, progressive brain atrophy and large head associated with SLC9A6 mutation. AB - SLC9A6 gene encodes for a sodium/hydrogen exchanger-6 protein mainly involved in endosomal trafficking and maintaining intraluminal pH. Loss of function mutations in SLC9A6 gene in children has been associated with Christianson syndrome and autism spectrum disorder. We describe a 3-year-old boy with intellectual disability, infantile-onset drug-refractory epilepsy, progressive brain atrophy and large head with a novel missense hemizygous mutation in exon 16 of the SLC9A6 gene on chromosome X. Presence of large head, early developmental regression and progressive cerebral atrophy expand the phenotypic spectrum of SLC9A6 mutations. Our case also highlights the importance of genetic testing in children with unexplained intellectual disability, epilepsy and neurodevelopmental impairments. PMID- 29275386 TI - Chickenpox: an ageless disease. AB - A 97-year-old woman presented with 4-day history of vesicular rash, initially at the feet but then spread up to the thighs bilaterally, abdomen and trunk. The initial differentials included bullous pemphigus and cellulitis by the emergency department. She was then managed as bullous pemphigus by the acute medical team and started on high-dose steroids, with no other differentials considered. When her care was taken over by the general medical team, varicella zoster virus (VZV) infection was suspected. After confirmation by the dermatology team regarding the clinical diagnosis and the positive VZV DNA swabs, she was started on acyclovir. PMID- 29275388 TI - Contemporary non-surgical approach for faecal diversion in a case of Fournier's gangrene. AB - Fournier's gangrene is a fatal necrotising fasciitis of the perineum, genitals and lower abdomen. Patients often need an aggressive surgical debridement, and in few cases, a diverting colostomy. We report the case of a 70-year-old man with multiple comorbidities diagnosed with Fournier's gangrene, who underwent debridement and had a wound complication due to faecal contamination. A novel, self-retaining rectal device was used to perform faecal diversion, which subsequently showed wound healing within a week, hence avoiding the need of a colostomy. PMID- 29275389 TI - Shah-Waardenburg syndrome: a case highlighting the importance of a holistic approach to assessing a child. AB - We present the case of a 45-day-old child with the chief complaint of failure to pass stools for 10 days. After initial investigation, the patient was found to have Hirschsprung's disease. However, with further examination and analysis, the extremely rare diagnosis of type 4 Waardenburg syndrome was made (also known as Shah-Waardenburg syndrome or Waardenburg-Hirschsprung's disease). PMID- 29275390 TI - HHV-8-associated haemophagocytic lymphohistiocytosis in a patient with advanced AIDS. AB - We present a patient with advanced AIDS admitted with recurrent shock of unclear aetiology, fevers, altered mental status and refractory cytopenias. His case posed a diagnostic challenge because evaluation of septic shock in the setting of advanced AIDS requires a time-consuming work-up for broad infectious aetiologies that can delay consideration of other diagnoses, including primary or secondary haemophagocytic lymphohistiocytosis (HLH). After this patient did not improve with supportive care and empiric antimicrobials, there was concern for HLH given that he met >=5 of the HLH consortium criteria. He underwent bone marrow biopsy, which was non-diagnostic. Empiric therapy for HLH was initiated, but unfortunately, the patient died. Autopsy revealed extensive haemophagocytosis in the spleen, bone marrow and liver, confirming the diagnosis of HLH. Postmortem, his soluble CD-25 returned 18 890 pg/mL (<1033 pg/mL), and his serum HHV-8 PCR resulted positive. The diagnosis was HLH secondary to Human Herpes Virus 8 (HHV 8) in a patient with advanced AIDS. PMID- 29275391 TI - Intractable hyperemesis gravidarum in a patient with type 1 diabetes. AB - Hyperemesis gravidarum is not uncommon. Its pathogenies is multifactorial but not fully understood. We present a case of a middle class, Caucasian pregnant woman aged 24 years with coexisting type 1 diabetes, who had severe hyperemesis gravidarum from the sixth week of pregnancy and was resistant to all standard and off-the-label treatments raising questions about the pathogenesis of hyperemesis gravidarum. She was managed with a multidisciplinary approach and was supported with total parenteral nutrition till she had an emergency caesarean section in the 29th week of pregnancy. Her vomiting stopped as soon as a small for gestational age but otherwise healthy male baby was delivered. PMID- 29275392 TI - Osteoid bezoar: a rare case causing small bowel obstruction. AB - Acute intestinal obstruction due to foreign bodies or bezoar is a rare occurrence in an adult. We report an unusual case of a 27-year-old male patient with no previous history of abdominal surgery or other medical disease, who presented with an acute episode of intestinal obstruction due to ingestion of a bone piece which was managed surgically by enterotomy, and the patient had an uneventful postoperative course. He was advised regular follow-up once in 2 weeks initially and once a month subsequently. He had no problems at the end of 6 months. PMID- 29275393 TI - Unusual case of anxiety: trichloroethylene neurotoxicity. AB - I present an uncommon case of recurrent, intractable anxiety that was presented acutely and slowly evolved into a chronic debilitating condition. A young previously fit and healthy 24-year-old patient presents with somewhat atypical symptoms of anxiety. Full medical work-up including examination, blood, ECG electrocardiogram, electroencephalogram and CT of the head was unremarkable. When the history was explored in detail, it was revealed he worked in the navy and was exposed to a neurotoxic solvent, trichloroethylene. This case highlights the importance of eliciting a detailed occupational history, particularly paying attention to patient demographics such as occupation and presenting symptoms that do not readily fit into diagnostic criteria. PMID- 29275394 TI - Idiopathic bilateral hypertrophic olivary degeneration. PMID- 29275395 TI - A rare cause of neonatal persistent jaundice. PMID- 29275396 TI - Variant of Lemierre's syndrome with internal jugular vein aneurysm. AB - Internal jugular vein (IJV) aneurysm is a rare entity, and a thrombosed aneurysm poses diagnostic and management challenges. We came across a 53-year-old woman who presented with fever, vomiting and right neck swelling for a week. Laboratory investigations showed neutrophilic leucocytosis, raised acute phase reactant and blood culture yielded Klebsiella pneumoniae Ultrasound and contrast-enhanced CT neck revealed a large fusiform aneurysm of the right IJV with filling defect extending from the aneurysm into the right transverse sinus. There was a cavity at the right lower third molar tooth. MRI confirmed the findings with additional enhancing focus at right lower periodontal region. The swelling reduced after 2 weeks of medical therapy, and follow-up imaging 4 months later showed complete resolution of the aneurysm with residual thrombosis. After extensive workup, dental infection remains the only identifiable primary source leading to thrombophlebitis of the right IJV and subsequent sequelae. PMID- 29275397 TI - Short-course high-dose ibuprofen causing both early and delayed jejunal perforations in a non-smoking man. PMID- 29275398 TI - Helping refugee children thrive: what we know and where to next. PMID- 29275399 TI - New-onset arrhythmias following transcatheter aortic valve implantation: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the prevalence and clinical impact of new-onset arrhythmias in patients following transcatheter aortic valve implantation (TAVI). METHOD: We systematically identified studies reporting new-onset arrhythmias after TAVI other than atrioventricular conduction disturbances. We summarised monitoring strategies, type and prevalence of arrhythmias and estimated their effect on risk of death or cerebrovascular events by using random-effects meta analysis. The study is registered withInternational prospective register of systematic reviews (PROSPERO) (CRD42017058053). RESULTS: Sixty-five studies (43 506 patients) reported new-onset arrhythmias following TAVI. The method of arrhythmia detection was specified only in 31 studies (48%). New-onset atrial fibrillation (NOAF) (2641 patients), bradyarrhythmias (182 patients), supraventricular arrhythmias (29 patients), ventricular arrhythmias (28 patients) and non-specified major arrhythmias (855 patients) were reported. In most studies (52 out of 65), new-onset arrhythmia detection was limited to the first month following TAVI. The most frequently documented arrhythmia was NOAF with trend of increasing summary prevalence of 11%, 14%, 14% and 25% during inhospital, 30-day, 1-year and 2-year follow-ups, respectively (P for trend=0.011). Summary prevalence estimates of NOAF at 30-day follow-up differ significantly between studies of prospective and retrospective design (8% and 21%, respectively, P=0.002). New episodes of bradyarrhythmias were documented with a summary crude prevalence of 4% at 1-year follow-up. NOAF increased the risk of death (relative risk 1.61, 95% CI 1.35 to 1.98, I2=47%) and cerebrovascular events (1.79, 95% CI 1.24 to 2.64, I2=0%). No study commented on therapeutic modifications following the detection of new-onset arrhythmias. CONCLUSIONS: Systematic identification of new-onset arrhythmias following TAVI may have considerable impact on subsequent therapeutic management and long-term prognosis in this patient population. PMID- 29275400 TI - Tubular Cell Senescence in the Donated Kidney Predicts Allograft Function, but Not Donor Remnant Kidney Function, in Living Donor Kidney Transplantation. AB - BACKGROUND: It is uncertain whether kidneys from marginal donors are suitable for live kidney transplantation. In deceased donor kidneys, tubular cell senescence affects allograft function. However, the degree of cell senescence in a living donor kidney with marginal factors has not been reported. In this study, we assessed the association of tubular cell senescence with allograft and remnant kidney function by a prospective observational clinical study. METHODS: Thirty eight living donor kidney transplantations were analyzed prospectively. Tissue sections obtained from preimplantation kidney biopsies were immunostained for p16INK4a to indicate cell senescence. Various kidney biomarkers were analyzed in urine and blood samples. RESULTS: Of the 38 donors, 21 had marginal factors. Severe tubular senescence was found in living donors with overlapping marginal criteria. Tubular senescence in living donor kidneys was significantly related to donor age and lower recipient kidney function at 1 year after transplantation independently of donor age (beta = -0.281; p = 0.050) but did not affect remnant kidney function after donation. Pretransplantation donor pre-estimated glomerular filtration rate and hypertension did not show a significant area under the curve (AUC) for prediction of high tubular senescence. High plasma levels of soluble alphaKlotho were associated with a higher predictive value for low tubular cell senescence with an AUC of 0.78 (95% CI 0.62-0.93; p < 0.01). CONCLUSIONS: The nuclear p16-staining rate in donated kidney tubules is a predictor for allograft kidney function but not donor remnant kidney function. Detection of tubular cell senescence may facilitate selection of appropriate living donor candidates. PMID- 29275401 TI - Glycemic Control Assessment in the Dialysis Patient: Is Glycated Albumin the Answer? PMID- 29275402 TI - Hand-Holding during Cystoscopy Decreases Patient Anxiety, Pain, and Dissatisfaction: A Pilot Randomized Controlled Trial. AB - OBJECTIVE: Often a sick or an anxious person can experience pain or anxiety relief if another person holds his or her hand. In this study, we conducted investigations to determine whether hand-holding during cystoscopy decreases patient anxiety, pain, and dissatisfaction while at the same time increasing patient comfort and tolerance during the procedure. PATIENTS AND METHODS: Eighty six male patients who underwent flexible cystoscopy between November 2015 and March 2017 were randomized as follows: hand-holding (group I, n = 43) or non-hand holding (group II, n = 43) during the procedure. Before flexible cystoscopy, lidocaine gel was instilled in the urethra. Patients' anxiety levels were quantified using the State-Trait Anxiety Inventory. A visual analog scale (0-10) was used for self-assessment of satisfaction, discomfort, and willingness to undergo repeat cystoscopy. RESULTS: Demographic characteristics, mean age, procedure duration, procedure indications, and preprocedural analyses did not differ significantly between the 2 groups. In group I, the postprocedural mean anxiety level, pain score, heart rate, and systolic blood pressure were significantly lower compared with those in group II (p = 0.009, p = 0.003, p = 0.022, and p = 0.014, respectively). In group I, postprocedural mean satisfaction score were higher, and patients were more likely to undergo a repeat cystoscopy, compared with those in group II (p = 0.001 and p = 0.004, respectively). CONCLUSIONS: Hand-holding during cystoscopy significantly reduced patients' feelings of anxiety, pain, discomfort, and dissatisfaction. Hand-holding served as a simple, inexpensive, and effective adjunct to sedation during cystoscopy. PMID- 29275403 TI - Missed Opportunities in Symptomatic Patients before a First Acute Coronary Syndrome: The EPIHeart Cohort Study. AB - OBJECTIVES: The aim of this study was to assess the proportion of patients with a first episode of acute coronary syndrome (ACS) reporting preceding chest pain, having previously sought medical care and undergone the performance of exams, and to identify the determinants of seeking medical advice and undergoing electrocardiogram (ECG). METHODS: Within a cohort study, 690 patients with a first episode of ACS were evaluated. A questionnaire was applied to assess chest pain within the preceding 6 months of the event and health system resources utilization. Determinants were identified by logistic regression. RESULTS: Preceding chest pain was reported by 61% of patients, 43% of these sought medical help, of whom less than half underwent ECG, and in 39% pain was attributed to a problem of the heart. Patients with hypertension were more likely to seek medical care (adjusted odds ratio, OR, 2.13, 95% CI 1.29-3.51), and former smokers (OR 0.52, 95% CI 0.28-0.99) and patients of a higher social class (OR 0.16, 95% CI 0.05-0.48) were less likely to seek medical care. The performance of ECG was associated with male sex (OR 2.56, 95% CI 1.11-5.87), health subsystem coverage (OR 3.88, 95% CI 1.11-13.53), and living in the northeastern region (OR 9.07, 95% CI 4.07-20.24), whereas cognitive impairment (OR 0.37, 95% CI 0.15-0.92) and being employed (OR 0.36, 95% CI 0.14-0.97) were inversely associated. CONCLUSIONS: These results suggest there are opportunities to improve the diagnosis of myocardial ischemia before acute coronary events. PMID- 29275404 TI - Dietary Variation in Diana Monkeys (Cercopithecus diana): The Effects of Polyspecific Associations. AB - Establishing dietary central tendencies and extremes remains an important goal of primate research. While habitat differences and spatial discontinuity are well documented contributors to dietary variation, other factors including polyspecific associations may significantly impact diet through changes in strata use and/or increased feeding competition. Here, we examine polyspecific association with closely related species as a source of dietary variation in a rain forest primate. Diana monkeys (Cercopithecus diana) in Cote d'Ivoire's Tai Forest frequently participate in mixed-species groups. We use data collected over a 5-year period on 4 Diana monkey groups to examine how association affects group diets. Groups exhibited significant differences in association rates with other guenon species, but this minimally influenced diet when food categories (fruit, invertebrates, leaves) were compared: diet overlap of 4 groups across the study period ranges from 90.8 to 98.1%. Examination of species composition within food categories is more revealing: intergroup dietary overlap decreases to 69.8-79.4% across the study period when comparing species contributing to total frugivory and folivory. These data support earlier findings that Diana monkeys maintain fruit-rich diets by competitively excluding sympatric congeners while highlighting that even selective frugivores such as Diana monkeys may exhibit remarkable dietary flexibility. Our study underscores the fact that broad categorical labels can obscure significant dietary differences. PMID- 29275405 TI - Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner. AB - BACKGROUND: After neonatal asphyxia, therapeutic hypothermia (HT) is the only proven treatment option. Although established as a neuroprotective therapy, benefit from HT has been questioned when infection is a comorbidity to hypoxic ischaemic (HI) brain injury. Gram-negative and gram-positive species activate the immune system through different pathogen recognition receptors and subsequent immunological systems. In rodent models, gram-negative (lipopolysaccharide [LPS]) and gram-positive (PAM3CSK4 [PAM]) inflammation similarly increase neuronal vulnerability to HI. Interestingly, while LPS pre-sensitisation negates the neuroprotective effect of HT, HT is highly beneficial after PAM-sensitised HI brain injury. OBJECTIVE: We aimed to examine whether systemic gram-positive or gram-negative inflammatory sensitisation affects juvenile rat pups per se, without an HI insult. METHODS: Neonatal 7-day-old rats (n = 215) received intraperitoneal injections of vehicle (0.9% NaCl), LPS (0.1 mg/kg), or PAM (1 mg/kg). Core temperature and weight gain were monitored. Brain cytokine expression (IL-6, IL-1beta, TNF-alpha, and IL-10, via PCR), apoptosis (cleaved caspase 3, via Western blots), and microglial activation (Iba1, via immunohistochemistry) were examined. RESULTS: LPS induced an immediate drop in core temperature followed by poor weight gain, none of which were seen after PAM. Furthermore, LPS induced brain apoptosis, while PAM did not. The magnitude and temporal profile of brain cytokine expression differed between LPS- and PAM injected animals. CONCLUSION: These findings reveal sepsis-like conditions and neuroinflammation specific to the inflammatory stimulus (gram-positive vs. gram negative) in the neonatal rat. They emphasise the importance of pre-clinical models being pathogen dependent, and should always be carefully tailored to their clinical scenario. PMID- 29275406 TI - Pathologic Outcomes of Candidates for Active Surveillance Undergoing Radical Prostatectomy: Results from a Contemporary Turkish Patient Cohort. AB - INTRODUCTION: To evaluate the pathological outcomes of Turkish men meeting the criteria for Active Surveillance (AS), who elected to undergo immediate radical prostatectomy (RP). MATERIAL AND METHODS: Retrospective analysis including 1,212 patients with clinically localized prostate cancer (PCa) who met the eligibility criteria for AS. The primary outcomes were pathological upstaging and pathological upgrading. RESULTS: Nine hundred ninety-one patients were eligible for analysis after the central review of the submitted data. The mean prostate specific antigen (PSA) level was 6.89 (0.51-15) ng/mL and the mean biopsy core number was 12 (8-47). The mean tumor positive core on final biopsy pathology was 1.95 (1-6) (16.6% [2.1-33.3%]). Overall, 30.6% of the men experienced a Gleason sum (GS) upgrade and 13.2% had pathological upstaging. For GS upgrade, the percentage of tumor-positive cores and free-to-total-PSA ratio were significant both in univariate analysis and multivariate logistic regression analysis. Variables predicting pathological upstaging were percentage of tumor-positive cores and PSA density, which were significant in univariate analysis. However, only PSA density was significant in multivariate logistic regression. Although biochemical recurrence-free survival was longer in patients without GS upgrade, it was not statistically significant between patients with and without any GS upgrade (mean 133.7 vs. 148.2 months, p = 0.243). A similar observation was made for patients with or without pathological upstaging (mean 117.1 vs. 148.3 months, p = 0.190). CONCLUSIONS: Upgrading and upstaging at RP are quite common among Turkish men with clinically low-risk PCa, who are candidates for AS, and a great majority of them experienced long-term PSA control. PMID- 29275407 TI - Maternal and Cord Blood Adiponectin Concentrations in Small for Gestational Age: A Meta-Analysis. AB - BACKGROUND: Adiponectin, which may have a growth-promoting effect through its insulin-sensitizing action, is thought to play a key role in fetal growth. This study was performed to determine whether maternal and/or cord blood adiponectin concentrations differ between small for gestational age (SGA) and healthy controls. METHODS: Databases were searched to identify good quality English language studies providing the number of SGA and healthy controls, and the means and standard deviations of maternal or cord blood adiponectin concentration in both groups. A meta-analysis was performed to summarize the standardized mean differences (SMDs) in maternal and cord blood adiponectin concentrations between SGA and healthy controls. RESULTS: There was no statistically significant difference in maternal blood adiponectin concentration between SGA and healthy controls (n = 8, p = 0.951). However, cord blood adiponectin concentration was significantly lower in SGA than in healthy controls (n = 6, p = 0.028), and the effect was large (i.e., SMD >0.7). CONCLUSIONS: Maternal blood adiponectin concentration is not low in SGA compared with healthy controls. However, SGA shows lower cord blood adiponectin concentration than healthy controls. PMID- 29275408 TI - Prediction of Spontaneous Puberty in Turner Syndrome Based on Mid-Childhood Gonadotropin Concentrations, Karyotype, and Ovary Visualization: A Longitudinal Study. AB - AIMS: To investigate whether karyotype, mid-childhood (6-10 years) follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, and ultrasound ovary visualization results can be used as indicators of spontaneous puberty in Turner syndrome (TS). METHODS: The analysis was based on clinical and biochemical data from 110 TS girls aged >13 years at the end of the study (1,140 visits between 1996 and 2015). The study population was divided according to karyotype: 45,X and non-45,X. RESULTS: The mean age +/- standard deviation at diagnosis was 10.7 +/- 4.0 years, and the follow-up duration was 5.9 +/- 3.3 years. Spontaneous puberty was confirmed in 48% and menarche in 20% of the subjects, less frequently in 45,X girls. The mean age at Tanner stage B2 was 13.7 +/- 2.4 years and that at menarche 14.2 +/- 1.7 years, regardless of the karyotype. The median FSH level at 6-10 years was 8.16 IU/L, which was significantly lower than <6 years and >10 years. The median LH level at 6-10 years was 0.35 IU/L, which was lower than >10 years. The chance of spontaneous menarche was decreased in girls with FSH >=6.7 IU/L between 6 and 10 years. CONCLUSIONS: Although spontaneous puberty and menarche occur more frequently in non-45,X girls, the karyotype cannot be used to predict them. However, the chance of spontaneous menarche can be predicted based on gonadotropin cut-off values. There was no correlation between ultrasound ovary visualization results and spontaneous puberty. PMID- 29275410 TI - Recurrent, Giant Renal Angiomyolipoma Treated with Selective Arterial Embolization: A Case Report. AB - Renal angiomyolipoma (AML), a rare benign mesenchymal neoplasm, is characterized by the presence of vessels, smooth muscle, and adipose tissue. Treatment should be considered for symptomatic patients or for those at risk for complications, in particular for retroperitoneal bleeding, which is correlated to the size of the tumor, grade of the angiogenic component, and presence of tuberous sclerosis complex. Herein, we report the case of a 39-year-old female with renal AML who was treated in a conservative approach by super-selective embolization. PMID- 29275409 TI - Dynamic Observation of the Morphological Changes in Paraurethral Ducts Infected with Gonococci in Men before and after Ceftriaxone Therapy Using High-Frequency Ultrasound. AB - OBJECTIVE: To observe the morphological changes in paraurethral ducts infected with gonococci in men before and after the administration of the ceftriaxone therapy using high-frequency ultrasound and determine its clinical significance. METHODS: Thirty-two male patients with gonococcal paraurethral duct infection were enrolled. Their lesions were examined using an ACUSON X300 ultrasound system before and after they were subjected to ceftriaxone therapy. RESULTS: The paraurethral duct was completely closed 3-4 days after ceftriaxone treatment in 30 patients. Paraurethral duct closure began from the blind end and proceeded gradually towards its orifice; during closure, the paraurethral duct diameter showed no apparent change. These 30 patients whose paraurethral ducts closed were considered cured. In the remaining 2 patients, the length and diameter of the paraurethral ducts showed no change before and after ceftriaxone treatment; one patient was unresponsive to ceftriaxone treatment, and the other had secondary dilatation of the paraurethral duct. These 2 patients were cured after surgery. CONCLUSION: High-frequency ultrasound enables dynamic observation of the morphological changes in paraurethral ducts infected with gonococci before and after ceftriaxone therapy. High-frequency ultrasound can provide valuable information for incision, drainage, and wedge resection of paraurethral ducts. PMID- 29275411 TI - Comorbid Conditions in Parkinson's Disease: A Population-Based Study of Statewide Parkinson's Disease Registry. AB - BACKGROUND/AIMS: In 1996, Nebraska became the first state in the United States to establish a Parkinson's disease (PD) Registry. The objectives of this study were to determine the most common comorbid conditions among PD patients receiving inpatient and outpatient services in Nebraska between 2004 and 2012, and to examine whether PD patients had increased risks of these conditions. METHODS: Statewide linkage was performed between Nebraska PD Registry data and hospital discharge database. The cohort comprised of 3,852 PD inpatients and 19,260 non-PD inpatients, and 5,217 PD outpatients and 26,085 non-PD outpatients. Referent subjects were matched to PD patients by age at initial hospital admissions or visits, gender, and county of residence using systematic random-sampling method. RESULTS: Compared to non-PD inpatients, PD inpatients were at higher risks for dementia (relative risk [RR] 2.29; 95% CI 2.14-2.45), mood disorders (RR 1.57; 95% CI 1.44-1.70), gastrointestinal disorders (RR 1.15; 95% CI 1.06-1.25), and urinary tract infections (RR 1.33; 95% CI 1.22-1.45), while PD outpatients had higher risks for spondylosis (RR 1.23; 95% CI 1.09-1.38), genitourinary disorders (RR 1.48; 95% CI 1.29-1.69), gastrointestinal disorders (RR 1.59; 95% CI 1.38 1.84), and dementia (RR 2.83; 95% CI 2.38-3.37) than non-PD outpatients. CONCLUSIONS: The findings highlight PD as a multisystem neurodegenerative disorder, and this information is crucial for creating strategies to better prevent and manage PD complications. PMID- 29275412 TI - Hypertensive Cerebral Hemorrhage in a Patient with Turner Syndrome Caused by Deletion in the Short Arm of the X Chromosome. AB - Turner syndrome is a chromosomal disorder usually caused by complete deletion of an X chromosome, with deletion in the short arm of the X chromosome being a rare cause of the condition. Patients with Turner syndrome commonly develop hypertension, and associated vascular complications such as aortic dissection or cerebral hemorrhage have been reported. Cerebral hemorrhage in Turner syndrome is a rare complication, and only a few reports have been published. In these reports, all patients have XO karyotypes or a mosaic type as the cause of Turner syndrome, while no other Turner syndrome types have been documented. In this report, we present for the first time a patient with Turner syndrome caused by deletion in the short arm of the X chromosome who experienced hypertensive hemorrhage as a late complication. PMID- 29275413 TI - Fatty Acids as Useful Serological Markers for Crohn's Disease. AB - BACKGROUND: We have previously reported that patients with Crohn's disease (CD) have a very specific erythrocyte membrane phospholipid fatty acid profile. The findings of this study suggest that the activities of enzymes involved in the metabolism of linoleic acid (LA), that is, delta-6 desaturase, are higher in CD patients than in healthy individuals. METHODS: We evaluated the utilities of various fatty acid compositions of the plasma (p-) as new serological markers for CD compared to those of erythrocyte membranes (e-). RESULTS: Fifty CD patients and 50 healthy individuals were enrolled. In both plasma and erythrocyte membranes, the weight percentages of palmitic acid (PA) were significantly higher, while those of LA were significantly lower in CD patients than in controls. Fatty acids with high sensitivity and specificity were p-PA (0.86 and 0.74) and e-PA (0.80 and 0.74). With PA and LA as a CD fatty acid index (CDFAi), that is, CDFAi = (PA/LA), the sensitivity and specificity of plasma CDFAi (p CDFAi) and e-CDFAi were 0.80 and 0.80; and 0.82 and 0.88 respectively. CONCLUSION: In CD patients, various fatty acids were specifically altered in both plasma and erythrocytes, and p-PA and p-CDFAi are potentially useful as new serological markers for CD. PMID- 29275415 TI - Comparison of Glycemic Markers in Chronic Hemodialysis Using Continuous Glucose Monitoring. AB - BACKGROUND: Glycated hemoglobin A1c (HbA1c) among diabetic hemodialysis patients continues to be the standard of care, although its limitations are well recognized. This study evaluated glycated albumin (GA) and glycated serum protein (GSP) as alternatives to HbA1c in detecting glycemic control among diabetic hemodialysis patients using continuous-glucose-monitoring (CGM)-derived glucose as reference standard. METHODS: A CGM system (iPRO) was applied for 7 days in 37 diabetic hemodialysis patients to determine glycemic control. The accuracy of GA and GSP versus HbA1c in detecting a 7-day average glucose >=184 mg/dL was evaluated via receiver-operating-characteristic (ROC) analysis. RESULTS: CGM derived glucose exhibited strong correlation (r = 0.970, p < 0.001) and acceptable agreement with corresponding capillary glucose measurements obtained by the patients themselves in 1,169 time-points over the 7-day-long CGM. The area under ROC curve (AUC) for GA, GSP, and HbA1c to detect poor glycemic control was 0.976 (0.862-1.000), 0.682 (0.502-0.862), and 0.776 (0.629-0.923) respectively. GA levels >20.3% had 90.9% sensitivity and 96.1% specificity in detecting a 7-day average glucose >=184 mg/dL. The AUC for GA was significantly higher than the AUC for GSP (difference between areas: 0.294, p < 0.001) and the AUC for HbA1c (difference between areas: 0.199, p < 0.01). CONCLUSION: Among diabetic hemodialysis patients, GA is a stronger indicator of poor glycemic control assessed with 7-day-long CGM when compared to GSP and HbA1c. PMID- 29275414 TI - A Prospective Audit of Intermittent Anti-Androgen verses Pituitary Blockade Suggests a Bipolar Androgen Type Strategy May Be Safe in Untreated Prostate Cancer. AB - OBJECTIVE: A locally advanced Gleason 4 + 4 prostate cancer patient who was on self-medication with intermittent anti-androgen monotherapy (iAAm) over 14 years suggested that raised testosterone was not dangerous and this suggestion needed investigating. PATIENTS: Others who were on AA continuously were recruited to ongoing audit of intermittent hormone therapy (IHT) and iAAm outcomes were compared with intermittent LHRH therapy (iLHRH or iMAB). RESULTS: Between 1994 and 2007, 111 patients sought IHT because of side effects of treatment. Forty-two M0 patients received IHT with iLHRHm or iMAB and 33 received iAAm (31 of these were M0). PSA nadir below 4 was necessary for entry. Overall survival was 87, 72 and 67% with iAAm and 73, 56 and 43% with iLHRH/MAB at 5, 8 and 10 years respectively. Overall survival was 61, 55 and 33% continued on iAAm and 56, 41, and 32% on iLHRH/MAB at 5, 8, and 10 years respectively. Multivariable analysis and matched case control analysis confirm that the maintenance of advantage for iAAm Testosterone levels in patients on iAAm compared to iLHRH therapy was more intense throughout treatment. CONCLUSION: These results complement recent progress in using bipolar androgen therapy to reverse castration resistance and add to the increasing acceptance that controlled testosterone exposure might be relevant in hormone-naive patients. PMID- 29275416 TI - Mechanism of Action of the Anti-Influenza Virus Active Kampo (Traditional Japanese Herbal) Medicine, Hochuekkito. AB - When the Kampo medicine, Hochuekkito (Hochu), was administered to normal mice for 2 weeks, influenza virus titer was reduced. The mechanism of action of Hochu was examined using the plaque assay method. It was suggested that Hochu may either obstruct the first stage of the infection process (adsorption and entry) or may directly target viral particles. Using the plaque assay method, these 2 modes of action could not be differentiated. Virus RNA in the infected cell was verified by quantitative real-time polymerase chain reaction. An equal inhibition effect was obtained when Hochu was preprocessed for normal cells and when they were made to act simultaneously with virus adsorption. The viral load at the cell surface following UV irradiation was higher in the Hochu-administered group as compared with that of the control. Moreover, the affinity of Hochu for the influenza virus was hundred times higher than its affinity for the host cell. The effect of entry obstruction by Hochu was observed via image analysis, where the amount of virus nucleocapsid protein (NP) invading the cell was visualized with FITC-labeled NP antibody. Hochu does not seem to have an effect on nucleic acid synthesis, viral release from infected cells, and on the subsequent second round of infection. In conclusion, Hochu binds to viral particles and forms complexes that can obstruct the entry of influenza virus into cells. PMID- 29275417 TI - Cytomorphological Findings of Follicular Dendritic Cell Sarcoma on Fine-Needle Aspiration Cytology. AB - BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm arising from follicular dendritic cells of germinal centers. The most common site of origin is lymph nodes and it may mimic a variety of tumors at that location, including carcinomas and sarcomas. Diagnosis is frequently missed on cytology as there are very few case reports describing the cytological characteristics of the lesion. Even on histology, a high degree of suspicion is required for an appropriate diagnosis. CASE: A 60-year-old male presented with a gradually increasing left submandibular mass that had been present for 3 months. Fine needle aspiration cytology (FNAC) was performed, showing many clusters as well as scattered epithelioid cells with spindled to oval nuclei, nuclear pleomorphism, grooves, inclusions, and uniformly dispersed mature lymphocytes throughout the smears. The diagnosis of FDCS was suspected and was confirmed on histopathology and immunohistochemistry. CONCLUSION: FNAC can be a cheap, easy, and helpful tool in obtaining a diagnosis of FDCS as there are few characteristic cytological features that are better recognized than histology. PMID- 29275418 TI - Opium Addiction and Ischemic Stroke in Isfahan, Iran: A Case-Control Study. AB - BACKGROUND: The effect of opium addiction (OA) on cerebrovascular disease is controversial. The aim of this study was to clarify this relationship in Iranian patients with ischemic stroke. METHODS: In a case-control study, 672 patients with ischemic stroke and 293 controls without a previous history of cerebrovascular or cardiovascular diseases were compared. OA as well as other risk factors such as diabetes mellitus (DM), hypertension (HTN), hyperlipidemia, tobacco smoking (TS) were compared between the 2 groups. RESULTS: OA percentage, TS, TS amount (pack/year), HTN and DM history were significantly higher in the case group compared to controls (p < 0.05). After regression analysis between risk factors, a significant difference remained between 2 groups with regards to HTN (OR 4.21, 95% CI 3.05-5.81, p < 0.001), TS (OR 2.33, 95% CI 1.51-3.59, p < 0.001), and OA (OR 2.36, 95% CI 1.16-4.85, p = 0.018). CONCLUSION: Our study showed OA is a risk factor for stroke. However, a follow-up study with a larger cohort is required to confirm the results. PMID- 29275420 TI - Continuing Use of Sayk's Spontaneous Cell Sedimentation Technique for Cerebrospinal Fluid Cytology in China. PMID- 29275419 TI - Family-Related Stress versus External Stressors: Differential Impacts on Alcohol and Illicit Drug Use in Young Men. AB - Intense stress increases substance use (SU). However, little is known about the extent to which distinctive forms of stress should be weighted with regard to their effects on SU. This study aimed to determine whether family-related stress factors (FSF) influenced SU in a different way than external stress factors (ESF). Data was drawn from a Swiss cohort study on SU risk factors (C-SURF), involving 5,308 young adult men. Twelve month use of alcohol and of illicit substances was assessed. FSF and ESF for the time period preceding SU were measured. FSF and ESF were both significantly associated with SU. FSF had a greater impact on the use of most substances than did ESF. The FSF with the strongest association with SU was lack of parental monitoring. Regarding ESF, the cumulative number of stressful external events had a higher impact on SU than previous physical or sexual assault by a stranger. In contrast, physical or sexual assault by a family member was not found to be associated with subsequent SU. These findings have important implications for SU prevention programmes focusing on male teenagers, as it is difficult to screen and intervene in subtle forms of maltreatment in families. PMID- 29275421 TI - Investigation of the Effect of Exercise on Headache in Migraineurs Using a Smartphone Diary. PMID- 29275422 TI - Is Central Pancreatectomy Truly Recommendable? A 9-Year Single-Center Experience. AB - AIMS: To compare the short- and long-term outcomes in patients with pancreatic benign or borderline neoplasm who underwent central pancreatectomy (CP) and distal pancreatectomy (DP). METHODS: The inclusion criteria were as follows: (1) single benign or low-grade malignant tumor; (2) tumor confined to the pancreatic neck or proximal body; and (3) tumor amenable to either CP or DP. Short and long term outcomes, including complications, pancreatic exocrine and endocrine function, and quality of life (QoL) were analyzed retrospectively. RESULTS: Sixteen patients who underwent CP and 26 patients who underwent DP were included. The median follow-up period was 53 months (range 21-117 months). Patients undergoing CP were significantly more likely to experience complications (68.7 vs. 23%, p = 0.003) especially grade B/C postoperative pancreatic fistula (62.5 vs. 23%, p = 0.011) than those undergoing DP. During the long-term follow-up, 2 patients in the DP group developed new-onset diabetes mellitus, but no patient in CP group developed this condition (8 vs. 0%, p = 0.382). Evidence of exocrine insufficiency, including severe diarrhea or steatorrhea, was not observed in either group. Both groups were equally satisfied with the overall health status and overall QoL. CONCLUSION: CP is associated with excellent pancreatic function but a significantly increased postoperative morbidity and risk compared to DP. Therefore, the indication of CP should be chosen strictly. PMID- 29275423 TI - Alcohol Screening in a National Referral Hospital: An Observational Study from Qatar. AB - BACKGROUND Alcohol consumption is a high-risk factor for several medical disorders and traffic accidents and poses a burden on outpatient clinics and emergency units. We aimed to assess the pattern of alcohol screening among patients in a multicultural setting in a national referral hospital in an Arab Middle-Eastern country. MATERIAL AND METHODS A retrospective analysis was conducted for patients who were screened with blood alcohol concentration (BAC) in the Emergency Department (ED) in the period from January 2009 to December 2012. BAC positive and negative patients were compared, and BAC positive patients were classified into mmol/L (Group 1: BAC 0.1-10.8 (less intoxicated); Group 2: BAC 10.9-21.7 (intoxicated), and Group 3: >21.7 mmol/L (intoxicated at CNS depression level). RESULTS A total of 9417 patient visits were screened for BAC during the study period (an average of 4.87 per 1000 ED visits); 38% of these tested positive. Most screened persons were males (97%) with a mean age of 37.5+/ 11.6 years. There was a steady increase in BAC screening initially (3.18 per 1000 ED visits in 2009 and 7.47 in 2012). However, the proportion of BAC-positives per total screened decreased steadily over the years, from 50% in 2008 to 33% in 2012. There were more BAC positives (92% vs. 81%, p<0.05) in patients seeking medical vs. non-medical assessment. Among BAC positives, Group 3 patients had higher HLOS (p=0.001), but the ICU-LOS was comparable. CONCLUSIONS Despite the absence of a clinical protocol for alcohol screening, this study shows that alcohol consumption has a serious impact in ED visits and hospitalizations, even in a country that partially prohibits alcohol drinking. Implementing a protocol for the screening of alcohol misuse among select hospitalized patients should be considered in the ED. PMID- 29275424 TI - Long Non-Coding RNA Prostate Cancer-Associated Transcript 7 (PCAT7) Induces Poor Prognosis and Promotes Tumorigenesis by Inhibiting mir-134-5p in Non-Small-Cell Lung (NSCLC). AB - BACKGROUND Long non-coding RNA PCAT7 has been revealed to participate in tumorigenesis of various cancers. However, the mechanism of PCAT7 in non-small cell lung cancer (NSCLC) has not been identified. Hence, this study aimed to determine the function of PCAT7 in NSCLC. MATERIAL AND METHODS The expression level of PCAT7 in 96 pairs of NSCLC tissues and 6 cell lines was detected by qRT PCR. Proliferation assay, flow cytometric analysis, transwell/migration assay, and Western blotting assay were performed to detect the relation between PCAT7 and malignant behaviors of NSCLC cells in vitro, including cell proliferation, apoptosis, migration, invasion, and epithelial-to-mesenchymal transition (EMT). Rescue assays were carried out to confirm the contribution of PCAT7 to the progression of NSCLC cells by targeting miR-134-5p. RESULTS PCAT7 was found to be overexpressed in NSCLC tissues (compared with corresponding non-tumor tissues) and NSCLC cells (compared with normal cell line 16-HBE). Overexpression of PCAT7 resulted in the promotion of tumor cell proliferation, inhibition of cells apoptosis, facilitation of cells metastasis, and formation of EMT phenotype, while PCAT7 expression deletion remarkably prohibited cell proliferation, accelerated their apoptosis, weakened metastasis, and reversed EMT to MET. miR 134-5P, as a target gene of PCAT7, restored the effects of down-regulation of PCAT7. CONCLUSIONS These findings demonstrate that PCAT7 participates in tumor progression in NSCLC by inhibiting miR-134-5p. PMID- 29275425 TI - Oropharyngeal and tongue exercises (myofunctional therapy) for snoring: a systematic review and meta-analysis. AB - PURPOSE: Oropharyngeal and tongue exercises (myofunctional therapy) have been shown to improve obstructive sleep apnea. However, to our knowledge, a systematic review has not been performed for snoring. The study objective is to perform a systematic review, with a meta-analysis, dedicated to snoring outcomes after myofunctional therapy. METHODS: PubMed/MEDLINE and three other databases were searched through November 25, 2017. Two authors independently searched the literature. Eligibility (1) patients: children or adults with snoring, (2) intervention: oropharyngeal and/or tongue exercises, (3) comparison: pre and post treatment data for snoring, (4) outcomes: snoring frequency and snoring intensity, (5) study design: publications of all study designs. RESULTS: A total of 483 articles were screened, 56 were downloaded in their full text form, and nine studies reported outcomes related to snoring. There were a total of 211 patients (all adults) in these studies. The snoring intensity was reduced by 51% in 80 patients from pre-therapy to post-therapy visual analog scale values of 8.2 +/- 2.1 (95% CI 7.7, 8.7) to 4.0 +/- 3.7 (95% CI 3.2, 4.8). Berlin questionnaire snoring intensity reduced by 36% in 34 patients from 2.5 +/- 1.0 (95% CI 2.2, 2.8) to 1.6 +/- 0.8 (95% CI 1.3, 1.9). Finally, time spent snoring during sleep was reduced by 31% in 60 patients from 26.3 +/- 18.7% (95% CI 21.6, 31.0) to 18.1 +/- 20.5% (95% CI 12.9, 23.3) of total sleep time. CONCLUSIONS: This systematic review demonstrated that myofunctional therapy has reduced snoring in adults based on both subjective questionnaires and objective sleep studies. PMID- 29275426 TI - Platelet-to-lymphocyte ratio predicts long-term survival in laryngeal cancer. AB - OBJECTIVES: Although the survival rate of laryngeal cancer is relatively high, some patients with laryngeal squamous cell carcinoma (LSCC) show the least benefit from laryngectomy, owing to few determining diagnostic tools. We aimed to identify high-risk patients according to a preoperatively determined signature of the platelet-to-lymphocyte ratio (PLR) of > 193.55, as an indicator of poor treatment outcome in LSCC patients. METHODS: We retrospectively evaluated 899 patients who underwent laryngectomy for LSCC. The patients were stratified by PLR into three subgroups: low (<= 119.55), moderate (> 119.55 and <= 193.55), and high (> 193.55). Kaplan-Meier curves were plotted to compare the intergroup cancer-specific survival (CSS). RESULTS: Patients with high PLR had significantly worse survival outcomes (5-year CSS, low vs. moderate vs. high: 75.3 vs. 68.4 vs. 53.9%; 10-year CSS, low vs. moderate vs. high: 65.0 vs. 56.0 vs. 38.6%, P < 0.001). Patients with PLR > 193.55 represented malnutrition and more advanced cancer stage.. CONCLUSION: Patients with PLR > 193.55 experience poor outcomes and represent malnutrition, more advanced cancer stage. PMID- 29275428 TI - Association of NEFA composition with insulin sensitivity and beta cell function in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort. AB - AIMS/HYPOTHESIS: Our aim was to determine the longitudinal associations of individual NEFA with the pathogenesis of diabetes, specifically with differences in insulin sensitivity and beta cell function over 6 years in a cohort of individuals who are at risk for diabetes. METHODS: In the Prospective Metabolism and Islet Cell Evaluation (PROMISE) longitudinal cohort, 477 participants had serum NEFA measured at the baseline visit and completed an OGTT at three time points over 6 years. Outcome variables were calculated using the OGTT values. At each visit, insulin sensitivity was assessed using the HOMA2 of insulin sensitivity (HOMA2-%S) and the Matsuda index, while beta cell function was assessed using the insulinogenic index over HOMA-IR (IGI/IR) and the insulin secretion-sensitivity index-2 (ISSI-2). Generalised estimating equations were used, adjusting for time, waist, sex, ethnicity, baseline age, alanine aminotransferase (ALT) and physical activity. NEFA were analysed as both concentrations (nmol/ml) and proportions (mol%) of the total fraction. RESULTS: Participants' (73% female, 70% with European ancestry) insulin sensitivity and beta cell function declined by 14-21% over 6 years of follow-up. In unadjusted models, several NEFA (e.g. 18:1 n-7, 22:4 n-6) were associated with lower insulin sensitivity, however, nearly all of these associations were attenuated in fully adjusted models. In adjusted models, total NEFA, 16:0, 18:1 n-9 and 18:2 n-6 (as concentrations) were associated with 3.7-8.0% lower IGI/IR and ISSI-2, while only 20:5 n-3 (as mol%) was associated with 7.7% higher HOMA2-%S. CONCLUSIONS/INTERPRETATION: Total NEFA concentration was a strong predictor of lower beta cell function over 6 years. Our results suggest that the association with beta cell function is due to the absolute size of the serum NEFA fraction, rather than the specific fatty acid composition. PMID- 29275427 TI - Hope vs hype: where are we in type 1 diabetes? AB - Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research. PMID- 29275429 TI - Intein-mediated assembly of tunable scaffoldins for facile synthesis of designer cellulosomes. AB - In this study, extended artificial scaffoldins possessing multiple cohesin modules were created in vivo by employing split-intein-mediated protein ligation. Artificial scaffoldins having one Clostridium thermocellum cohesin (Coht), one carbohydrate binding module (CBM) from Clostridium cellulolyticum scaffolding protein CipC, and one to five cohesins (Cohc) derived from CipC, were assembled. These scaffoldins were used to assemble cellulosomal enzyme complexes for investigating the interplay among endoglucanase, exoglucanase, and scaffoldin borne CBM, on the hydrolysis of a model microcrystalline cellulose substrate, Avicel. The cellulosomal complexes were assembled in vitro by incubating recombinant C. thermocellum endoglucanase (At) and C. cellulolyticum exoglucanase (Ec), with the various artificial scaffoldins. Under a fixed total cellulase concentration, improved hydrolysis is noted by recruiting both Ec and At on the same scaffoldin, for all scaffoldins tested, compared with free cellulases. The improvement is more profound with scaffoldins having a higher Cohc/Coht ratio (i.e., increased Ec/At ratio). Furthermore, among scaffoldins having the same Cohc/Coht ratio, highest rates of Avicel hydrolysis are noted when Coht, and hence an endoglucanase, is situated next to the CBM and not flanked by Cohc. These results point to the importance of using scaffoldins with sufficiently high numbers of cohesin units to achieve an optimal exo-/endo-glucanase ratio to create efficient designer cellulosomes. Furthermore, intein-trans-splicing is proven here to be an effective method for assembling complex scaffoldins and more intricate cellulosomes. PMID- 29275430 TI - The histone acetyltransferase Mst2 sustains the biological control potential of a fungal insect pathogen through transcriptional regulation. AB - Histone lysine acetylation orchestrates transcriptional activity essential for diverse cellular events across organisms, but it remains poorly understood how an acetylated lysine affects cellular functions in filamentous fungal pathogens. Here, we show the functions of a histone acetyltransferase that is phylogenetically close to Mst2 in fission yeast and specifically acetylates histone H3K14 in Beauveria bassiana, a fungal insect pathogen widely applied in arthropod pest management. Deletion of mst2 in B. bassiana resulted in moderate growth defects on rich and minimal media, delayed conidiation, and drastic reduction (75%) in conidiation capacity under normal culture conditions. The Deltamst2 conidia suffered slower germination, decreased hydrophobicity, attenuated virulence, and reduced thermotolerance and UV-B resistance. The Deltamst2 mutant also displayed increased sensitivities to DNA damaging, oxidative, cell wall perturbing, and osmotic stresses during conidial germination and colony growth at optimal 25 degrees C. Intriguingly, the phenotypic changes were accompanied with transcriptional repression of related gene sets, which are required for asexual development and conidial hydrophobicity or cascaded for CWI and HOG pathways, and encode the families of superoxide dismutases (SOD), catalases, heat-shock proteins, and trehalose or mannitol-metabolizing enzymes. Consequently, total SOD and catalase activities, trehalose and mannitol contents, and hydrophobicity were remarkably lowered in the hyphal cells or conidia of Deltamst2. All of these changes were well restored by targeted mst2 complementation. Our results indicate that Mst2 enables to mediate global gene transcription and/or post-translation through H3K14 acetylation and plays an essential role in sustaining the biological control potential of B. bassiana against arthropod pests. PMID- 29275431 TI - Influence of femoral bowing on range of motion after total hip arthroplasty. AB - PURPOSE: The influence of physiologic femoral bowing on range of motion (ROM) after total hip arthroplasty (THA) remains unknown. The purpose of this study was to investigate the morphology of the femur in patients who underwent THA, and to analyze the influence of femoral bowing on ROM due to implant impingement after THA. METHODS: The ROM was calculated from 100 hips in 90 patients who underwent THA using computed tomography data with a 3D dynamic analysis software. Lateral and anterior bowing angles of the femur were measured. A modular implant (Modulus system, Lima Corporate, Villanova di San Daniele del Friuli, Italy) was used for simulation. In all subjects, cup inclination, anteversion, and stem anteversion were set to 40 degrees , 15 degrees , and 30 degrees , respectively. Multiple linear regression analyses were performed to assess the relationship between the morphology of the femur and ROM. RESULTS: Lateral bowing of the femur was demonstrated to be significantly correlated with age (r = 0.361, p < 0.001) and female sex (r = 0.315, p = 0.001). Lateral bowing of the femur was significantly positively correlated with flexion and internal rotation (Int-R) with 90 degrees flexion. Anterior bowing was significantly associated with decreasing flexion, decreasing Int-R with 90 degrees flexion and increasing Int-R with 45 degrees flexion and 15 degrees adduction. CONCLUSIONS: A ROM-optimized cup position cannot be calculated from femoral stem anteversion values alone; therefore, when surgeons position the cup in relation to the femoral stem anteversion, the influence of femoral bowing may also require consideration. PMID- 29275432 TI - Aetiopathogenesis of cuff-tear arthropathy: Could juvenile joint laxity be considered a predisposing factor? AB - PURPOSE: Although many hypotheses have been formulated, aetiopathogenesis of cuff tear arthropathy (CTA) is still motive for discussion. Since prevalence of CTA is notoriously higher in women, as is joint hypermobility, we hypothesised a possible correlation between the two conditions. METHODS: One hundred thirty three (n = 133) consecutive patients with glenohumeral osteoarthritis [48 men, 85 women; mean age (SD) 72.32 (7.05)] were divided into two groups: Groups 1 (CTA) and 2 (concentric shoulder arthropathy) comprised 71 (22 men, 49 women) and 62 (26 men, 36 women), respectively. The presence of current or previous joint hypermobility was assessed using two standardised methodologies: the Beighton criteria score, and a five-item self-report questionnaire. Data were submitted to statistical analysis. RESULTS: A moderate association between Beighton criteria and the five-item self-report (phi = 0.481, p < 0.001) was detected. Beighton criteria led to a diagnosis of joint hypermobility in 16 patients (22.5%) in Group 1 and 15 (24.2%) in Group 2. According to five-item self-report questionnaire, juvenile joint laxity was diagnosed in 11 (15.5%) and 12 (19.4%) patients in Groups 1 and 2, respectively. No significant association between groups and the Beighton criteria [chi2(1) = 0.051, p = 0.82] and five-item self report questionnaire [chi2(1) = 0.67, p = 0.41] was found. CONCLUSION: Juvenile joint hyperlaxity is not a predisposing factor for cuff arthropathy. Further studies will be needed to explain CTA aetiopathogenesis. LEVELS OF EVIDENCE: III. PMID- 29275433 TI - Individual differences influence two-digit number processing, but not their analog magnitude processing: a large-scale online study. AB - Symbolic magnitude comparison is one of the most well-studied cognitive processes in research on numerical cognition. However, while the cognitive mechanisms of symbolic magnitude processing have been intensively studied, previous studies have paid less attention to individual differences influencing symbolic magnitude comparison. Employing a two-digit number comparison task in an online setting, we replicated previous effects, including the distance effect, the unit-decade compatibility effect, and the effect of cognitive control on the adaptation to filler items, in a large-scale study in 452 adults. Additionally, we observed that the most influential individual differences were participants' first language, time spent playing computer games and gender, followed by reported alcohol consumption, age and mathematical ability. Participants who used a first language with a left-to-right reading/writing direction were faster than those who read and wrote in the right-to-left direction. Reported playing time for computer games was correlated with faster reaction times. Female participants showed slower reaction times and a larger unit-decade compatibility effect than male participants. Participants who reported never consuming alcohol showed overall slower response times than others. Older participants were slower, but more accurate. Finally, higher grades in mathematics were associated with faster reaction times. We conclude that typical experiments on numerical cognition that employ a keyboard as an input device can also be run in an online setting. Moreover, while individual differences have no influence on domain-specific magnitude processing-apart from age, which increases the decade distance effect they generally influence performance on a two-digit number comparison task. PMID- 29275434 TI - A Developmental Perspective on Reentry: Understanding the Causes and Consequences of Family Conflict and Peer Delinquency during Adolescence and Emerging Adulthood. AB - Despite the uniqueness of an incarceration experience for adolescents, there remains a shortage of research on adolescents and emerging adults who have been recently released from detention centers and are returning home during the transitional time period of "reentry". Drawing from the developmental literature, the current study uses a diverse (54% Black, 20% White, 26% Other Race) longitudinal survey of 337 male adolescents living in the United States to examine the interrelationships among crime, substance use, family conflict, and peer delinquency. A series of cross-lagged dynamic panel data models using four waves of data demonstrate that while family conflict and peer delinquency relate to increased offending and substance use, conflict in the family is a major driving force behind both future family conflict and peer delinquency. Overall, findings suggest that family conflict is an overlooked, but absolutely critical, factor in explaining deviance and deviant peer associations alike for adolescents and emerging adults who have been recently incarcerated and released. PMID- 29275435 TI - Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation associated breast cancer. AB - PURPOSE: Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer. METHODS: Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of >= 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index. RESULTS: HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non deficient patients (OR 13.06, CI 1.52-11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65-160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%). CONCLUSIONS: HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents. PMID- 29275436 TI - Transcriptomic profiles of the bovine mammary gland during lactation and the dry period. AB - The initiation and maintenance of lactation are complex phenomena governed by biochemical and endocrine processes in the mammary gland (MG). Although DNA-based approaches have been used to study the onset of lactation, more comprehensive RNA based techniques may be critical in furthering our understanding of gene alterations that occur to support lactation in the bovine MG. To further determine how gene profiles vary during lactation compared with the dry period, RNA-seq transcriptomic analysis was used to identify differentially expressed genes (DEG) in bovine MG tissues from animals that were lactating and not lactating. A total of 881 DEG (605 upregulated and 276 downregulated) were identified in MG of 3 lactating Chinese Holstein dairy cows versus the 3 dry cows. The subcellular analysis showed that the upregulated genes were most abundantly located in "integral to membrane" and "mitochondrion," and the top number of downregulated genes existed in "nucleus" and "cytoplasm." The functional analysis indicated that the DEG were primarily associated with the support of lactation processes. The genes in higher abundance were most related to "metabolic process," "oxidation-reduction process," "transport" and "signal transduction," protein synthesis-related processes (transcription, translation, protein modifications), and some MG growth-associated processes (cell proliferation/cycle/apoptosis). The downregulated genes were mainly involved in immune-related processes (inflammatory/immune/defense responses). The KEGG analysis suggested that protein synthesis-related pathways (such as protein digestion and absorption; protein processing in endoplasmic reticulum; and glycine, serine, and threonine metabolism) were highly and significantly enriched in the bovine MG of lactating cows compared to dry cows. The results suggested that the dry cows had decreased capacity for protein synthesis, energy generation, and cell growth but enhanced immune response. Collectively, this reduced capacity in dry cows supports the physiological demands of the next lactation and the coordinated metabolic changes that occur to support these demands. A total of 51 identified DEG were validated by RT-PCR, and consistent results were found between RT-PCR and the transcriptomic analysis. This work provides a profile of gene-associated changes that occur during lactation and can be used to facilitate further investigation of the mechanisms underlying lactation in dairy cows. PMID- 29275438 TI - Effect of hydrophobic surface treated fumed silica fillers on a one-bottle etch and rinse model dental adhesive. AB - The objective of this study was to investigate the effect of hydrophobic surface treatment to fumed silica fillers on the bonding performance of a one-bottle etch and rinse model dental adhesive. In this study, 0.5-5 wt.% of Filler 1 and Filler 2 were loaded into BisGMA/HEMA model dental adhesive. Filler 1 was not treated, while Filler 2 was surface treated with a dimethyl silicone fluid making the silica extremely hydrophobic. The prepared adhesives were characterized through measurements of viscosity, degree of conversion, and water contact angle. SEM was utilized to observe the microstructures at the bonding interface. Micro-tensile bond strength (uTBS) test coupled with fracture surface analysis was carried out to study the mechanical properties. From the experiment, the loadings of Filler 2 is favorable to the improvement of uTBS. The uTBS of experimental adhesive with 1 wt.% Filler 2 increased 42% compared to the model adhesive without filler, and 24% compared to the experimental adhesive with 1 wt.% Filler 1. The effectively penetration of the hydrophobic compositions of the adhesive is considered as the main reason that leads to the increased bond strength, which was proved by the contact angle measurement and SEM observations. PMID- 29275437 TI - Gene expression of thyrotropin- and corticotrophin-releasing hormones is regulated by environmental salinity in the euryhaline teleost Sparus aurata. AB - In euryhaline teleosts, the hypothalamus-pituitary-thyroid and hypothalamus pituitary-interrenal axes (HPT and HPI, respectively) are regulated in response to environmental stimuli such as salinity changes. However, the molecular players participating in this physiological process in the gilthead seabream (Sparus aurata), a species of high value for aquaculture, are still not identified and/or fully characterized in terms of gene expression regulation. In this sense, this study identifies and isolates the thyrotropin-releasing hormone (trh) mRNA sequence from S. aurata, encoding prepro-Trh, the putative factor initiating the HPT cascade. In addition, the regulation of trh expression and of key brain genes in the HPI axis, i.e., corticotrophin-releasing hormone (crh) and corticotrophin releasing hormone-binding protein (crhbp), was studied when the osmoregulatory status of S. aurata was challenged by exposure to different salinities. The deduced amino acid structure of trh showed 65-81% identity with its teleostean orthologs. Analysis of the tissue distribution of gene expression showed that trh mRNA is, though ubiquitously expressed, mainly found in brain. Subsequently, regulation of gene expression of trh, crh, and crhbp was characterized in fish acclimated to 5-, 15-, 40-, and 55-ppt salinities. In this regard, the brain gene expression pattern of trh mRNA was similar to that found for the crh gene, showing an upregulation of gene expression in seabream acclimated to the highest salinity tested. Conversely, crhbp did not change in any of the groups tested. Our results suggest that Trh and Crh play an important role in the acclimation of S. aurata to hypersaline environments. PMID- 29275439 TI - Mouse-tracking evidence for parallel anticipatory option evaluation. AB - In fast-paced, dynamic tasks, the ability to anticipate the future outcome of a sequence of events is crucial to quickly selecting an appropriate course of action among multiple alternative options. There are two classes of theories that describe how anticipation occurs. Serial theories assume options are generated and evaluated one at a time, in order of quality, whereas parallel theories assume simultaneous generation and evaluation. The present research examined the option evaluation process during a task designed to be analogous to prior anticipation tasks, but within the domain of narrative text comprehension. Prior research has relied on indirect, off-line measurement of the option evaluation process during anticipation tasks. Because the movement of the hand can provide a window into underlying cognitive processes, online metrics such as continuous mouse tracking provide more fine-grained measurements of cognitive processing as it occurs in real time. In this study, participants listened to three-sentence stories and predicted the protagonists' final action by moving a mouse toward one of three possible options. Each story was presented with either one (control condition) or two (distractor condition) plausible ending options. Results seem most consistent with a parallel option evaluation process because initial mouse trajectories deviated further from the best option in the distractor condition compared to the control condition. It is difficult to completely rule out all possible serial processing accounts, although the results do place constraints on the time frame in which a serial processing explanation must operate. PMID- 29275440 TI - Enhancement of gene expression in Escherichia coli and characterization of highly stable ATP-dependent glucokinase from Pyrobaculum calidifontis. AB - The genome of the hyperthermophilic archaeon Pyrobaculum calidifontis contains an open reading frame, Pcal_1032, annotated as glucokinase. Amino acid sequence analysis showed that Pcal_1032 belonged to ROK (repressor, open reading frame, and kinase) family of sugar kinases. To examine the properties of Pcal_1032, the coding gene was cloned and expressed in Escherichia coli. However, expression of the gene was low resulting in a poor yield of the recombinant protein. A single site directed mutation in Pcal_1032 gene, without altering the amino acid sequence, resulted in approximately tenfold higher expression. Purified recombinant Pcal_1032 efficiently phosphorylated various hexoses with a marked preference for glucose. ATP was the most preferred phosphoryl group donor. Optimum temperature and pH for the glucokinase activity of Pcal_1032 were 95 degrees C and 8.5, respectively. Catalytic efficiency (k cat/K m) towards glucose was 437 mM-1 s-1. The recombinant enzyme was highly stable against temperature with a half-life of 25 min at 100 degrees C. In addition, Pcal_1032 was highly stable in the presence of denaturants. There was no significant change in the CD spectra and enzyme activity of Pcal_1032 even after overnight incubation in the presence of 8 M urea. To the best of our knowledge, Pcal_1032 is the most active and highly stable glucokinase characterized to date from archaea, and this is the first description of the characterization of a glucokinase from genus Pyrobaculum. PMID- 29275441 TI - Corrosive extracellular polysaccharides of the rock-inhabiting model fungus Knufia petricola. AB - Melanised cell walls and extracellular polymeric matrices protect rock-inhabiting microcolonial fungi from hostile environmental conditions. How extracellular polymeric substances (EPS) perform this protective role was investigated by following development of the model microcolonial black fungus Knufia petricola A95 grown as a sub-aerial biofilm. Extracellular substances were extracted with NaOH/formaldehyde and the structures of two excreted polymers studied by methylation as well as NMR analyses. The main polysaccharide (~ 80%) was pullulan, also known as alpha-1,4-; alpha-1,6-glucan, with different degrees of polymerisation. Alphalpha-(1,4)-linked-Glcp and alpha-(1,6)-linked-Glcp were present in the molar ratios of 2:1. A branched galactofuromannan with an alpha (1,2)-linked Manp main chain and a beta-(1,6)-linked Galf side chain formed a minor fraction (~ 20%). To further understand the roles of EPS in the weathering of minerals and rocks, viscosity along with corrosive properties were studied using atomic force microscopy (AFM). The kinetic viscosity of extracellular K. petricola A95 polysaccharides (~ 0.97 * 10-6 m2 s-1) ranged from the equivalent of 2% (w/v) to 5% glycerine, and could thus profoundly affect diffusion-dominated processes. The corrosive nature of rock-inhabiting fungal EPS was also demonstrated by its effects on the aluminium coating of the AFM cantilever and the silicon layer below. PMID- 29275442 TI - Development of microsatellite markers for the carnivorous plant Genlisea aurea (Lentibulariaceae) using genomics data of NGS. AB - Genlisea aurea A.St.-Hil. is a carnivorous plant endemic species to Brazil in the Lentibulariaceae family. Very few studies have addressed the genetic structure and conservation status of G. aurea and the Lentibulariaceae. Microsatellites markers are advantageous tools that can be employed to predict the vulnerability of Lentibulariaceae species. Therefore, the development of molecular markers focusing the population analyses of Genlisea for future genetic studies and conservation actions are essential. Thus, we developed simple sequence repeats (SSRs) based on in silico analyses of G. aurea draft genome assembly. We characterized 40 individuals from several populations and identified 12 loci that were polymorphic, with heterozygosity between 0.123 and 0.650. We demonstrated that the G. aurea SSR markers work cross-species in Genlisea filiformis, G. repens, G. tuberosa and G. violacea. These markers will be important for future population, phylogeographic and conservation studies in G. aurea and other Genlisea species. PMID- 29275443 TI - A framework for designing hand hygiene educational interventions in schools. AB - OBJECTIVES: Hygiene education appears to be the commonest school-based intervention for preventing infectious diseases, especially in the developing world. Nevertheless, there remains a gap in literature regarding a school specific theory-based framework for designing a hand hygiene educational intervention in schools. We sought to suggest a framework underpinned by psychosocial theories towards bridging this knowledge gap. Furthermore, we sought to propound a more comprehensive definition of hand hygiene which could guide the conceptualisation of hand hygiene interventions in varied settings. METHODS: Literature search was guided by a standardized tool and literature was retrieved on the basis of a predetermined inclusion criteria. Databases consulted include PubMed, ERIC, and EBSCO host (Medline, CINAHL, PsycINFO, etc.). Evidence bordering on a theoretical framework to aid the design of school-based hand hygiene educational interventions is summarized narratively. RESULTS: School based hand hygiene educational interventions seeking to positively influence behavioural outcomes could consider enhancing psychosocial variables including behavioural capacity, attitudes and subjective norms (normative beliefs and motivation to comply). CONCLUSIONS: A framework underpinned by formalized psychosocial theories has relevance and could enhance the design of hand hygiene educational interventions, especially in schools. PMID- 29275444 TI - Brain MRI findings in acute hepatic encephalopathy in liver transplant recipients. AB - Acute hepatic encephalopathy has significant morbidity and mortality in liver transplant recipients unless it is promptly treated. We evaluated the brain magnetic resonance (MR) imaging findings associated with acute hepatic encephalopathy in transplant recipients. We retrospectively reviewed the clinical and imaging data and outcomes of twenty-five liver transplant patients (16 male; mean age, 49.3 years) with clinically diagnosed acute hepatic encephalopathy and forty liver transplant patients (20 males; mean age, 45.5 years) without neurological symptoms suggestive of hepatic encephalopathy at our institution. Bilateral symmetric hyperintensities of the insular cortex and cingulate gyrus were observed in twenty-one patients (84.00%), bilateral symmetric extensive increased cortical signal intensity (involving two or more regions) was observed in 72.00% of the patients, leptomeningeal enhancement in 73.68%, and visualization of prominent venules in 52.00%. The most common symptom at diagnosis was rigidity (n = 14), and the plasma ammonia levels ranged from 68.63 to 192.16 MUmol/L. After active treatment, 17 patients gradually recovered, four patients suffered from mild or moderate neurologic deficits, and four patients with widespread brain edema died. The specific brain MR imaging features were bilateral symmetric increased cortical signal intensity, especially in the insular cortex and cingulate gyrus, leptomeningeal enhancement, visualization of the prominent venules, and widespread brain edema. These features may indicate poor prognosis and should alert radiologists to the possibility of acute hepatic encephalopathy in liver transplant recipients and encourage clinicians to prepare appropriate treatment in advance. PMID- 29275445 TI - Issues on the diagnosis and etiopathogenesis of mood disorders: reconsidering DSM 5. AB - The authors present a narrative review from the diagnostic and nosologic viewpoints of mood disorders (bipolar and depressive ones) by revisiting the revision from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision to DSM-5, including the following: the separation of the bipolar and depressive sections; the addition of increased energy and continuation of symptoms to the hypo/manic criteria; the elimination of mixed episodes; the creation of new categories and specifiers ("other specified bipolar and related disorder", "disruptive mood dysregulation disorder", "with anxious distress", "with mixed features", "with peripartum onset"); the categorization of hypo/manic episodes during antidepressant treatment into bipolar disorder; the elimination of the "bereavement exclusion"; the ambiguous separation between bipolar I and II; the insufficient distinction between "other specified bipolar and related disorders" and major depressive disorder; the differentiation regarding borderline personality disorder; agitation; premenstrual dysphoric disorder; and society and psychiatry. Through this analysis, we point out both the achievements and limitations of DSM-5. In addition, to examine the future direction of psychiatry, we introduce our cohort study regarding maternal depression and an outline of the National Institute of Mental Health's Research Domain Criteria project in the US. Finally, we advocate the importance of elucidating etiopathogeneses by starting from or going beyond the DSM operational diagnostic system, which has shown great efficacy. PMID- 29275446 TI - Distinct Expression of Phenotypic Markers in Placodes- and Neural Crest-Derived Afferent Neurons Innervating the Rat Stomach. AB - BACKGROUND: Visceral pain is initiated by activation of primary afferent neurons among which the capsaicin-sensitive (TRPV1-positive) neurons play an important role. The stomach is a common source of visceral pain. Similar to other organs, the stomach receives dual spinal and vagal afferent innervation. Developmentally, spinal dorsal root ganglia (DRG) and vagal jugular neurons originate from embryonic neural crest and vagal nodose neurons originate from placodes. In thoracic organs the neural crest- and placodes-derived TRPV1-positive neurons have distinct phenotypes differing in activation profile, neurotrophic regulation and reflex responses. It is unknown to whether such distinction exists in the stomach. AIMS: We hypothesized that gastric neural crest- and placodes-derived TRPV1-positive neurons express phenotypic markers indicative of placodes and neural crest phenotypes. METHODS: Gastric DRG and vagal neurons were retrogradely traced by DiI injected into the rat stomach wall. Single-cell RT-PCR was performed on traced gastric neurons. RESULTS: Retrograde tracing demonstrated that vagal gastric neurons locate exclusively into the nodose portion of the rat jugular/petrosal/nodose complex. Gastric DRG TRPV1-positive neurons preferentially expressed markers PPT-A, TrkA and GFRalpha3 typical for neural crest-derived TRPV1-positive visceral neurons. In contrast, gastric nodose TRPV1 positive neurons preferentially expressed markers P2X2 and TrkB typical for placodes-derived TRPV1-positive visceral neurons. Differential expression of neural crest and placodes markers was less pronounced in TRPV1-negative DRG and nodose populations. CONCLUSIONS: There are phenotypic distinctions between the neural crest-derived DRG and placodes-derived vagal nodose TRPV1-positive neurons innervating the rat stomach that are similar to those described in thoracic organs. PMID- 29275447 TI - Old and New Lymphocyte Players in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-gamma and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte targeting drugs in IBD patients. PMID- 29275448 TI - The Impact of Race on Survival After Hepatocellular Carcinoma in a Diverse American Population. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) incidence is increasing at differential rates depending on race. We aimed to identify associations between race and survival after HCC diagnosis in a diverse American population. METHODS: Using the cancer registry from Sylvester Comprehensive Cancer Center, University of Miami and Jackson Memorial Hospitals, we performed retrospective analysis of 999 patients diagnosed with HCC between 9/24/2004 and 12/19/2014. We identified clinical characteristics by reviewing available electronic medical records. The association between race and survival was analyzed using Cox proportional hazards regression. RESULTS: Median survival in days was 425 in Blacks, 904.5 in non Hispanic Whites, 652 in Hispanics, 570 in Asians, and 928 in others, p < 0.01. Blacks and Asians presented at more advanced stages with larger tumors. Although Whites had increased severity of liver disease at diagnosis compared to other races, they had 36% reduced rate of death compared to Blacks, [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.51-0.8, p < 0.01]. After adjusting for significant covariates, Whites had 22% (HR 0.78, 95% CI 0.61-0.99, p 0.04) reduced risk of death, compared to Blacks. Transplant significantly reduced rate of death; however, only 13.3% of Blacks had liver transplant, compared to 40.1% of Whites, p < 0.01. CONCLUSIONS: In this diverse sample of patients, survival among Blacks is the shortest after HCC diagnosis. Survival differences reflect a more advanced tumor stage at presentation rather than severity of underlying liver disease precluding treatment. Improving survival in minority populations, in whom HCC incidence is rapidly increasing, requires identification and modification of factors contributing to late-stage presentation. PMID- 29275449 TI - Lymphatic vessel involvement is predictive for lymph node metastasis and an important prognostic factor in endometrial cancer. AB - BACKGROUND: Lymphovascular space involvement is reported to be an important risk factor in endometrial cancer. This study was conducted to evaluate the separate prognostic effects of lymphatic invasion and venous invasion on the outcomes of patients with endometrial cancer. METHODS: From 2006 to 2013, 189 histologically confirmed endometrial cancer patients were examined. To study the venous invasion (v) of the endometrial cancer, Victoria blue-H&E staining-which positively stains the elastic fibers of vessels-was performed. Immunohistochemical staining with D2 40 was used to study the lymphatic invasion (ly) of the endometrial cancer. RESULTS: The median age of the patients was 57 (range 25-84) years. ly(+) and/or v(+) patients were significantly more likely to present an advanced cancer stage, G3 tumor, and deep myometrial invasion than ly(-)/v(-) patients. The incidence of lymph node metastasis was high in ly(+) patients, and that of ovarian metastasis was high in v(+) patients. Lymphatic vessel invasion was significantly correlated with regional lymph node metastasis. We found a significantly higher incidence of distant metastasis in ly(+) patients. Most recurrences in ly(+)/v(-) patients occurred in lymph nodes, while those in ly(+)/v(+) patients occurred mainly at distant organs. Finally, the prognosis was significantly poorer for ly(+) patients, in whom lymphatic invasion was an independent prognostic factor along with distant metastasis. CONCLUSIONS: Our study suggests that by separately evaluating lymphatic invasion and blood vessel invasion in endometrial cancer cases, useful information for predicting lymph node metastasis and recurrence sites as well as prognostic information can be obtained. PMID- 29275450 TI - No significant impact of response to prior androgen receptor-axis-targeted agents on the efficacy of subsequent docetaxel in patients with metastatic castration resistant prostate cancer. AB - BACKGROUND: To investigate whether the response to an androgen receptor-axis targeted (ARAT) agent is associated with the efficacy of subsequent docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: This study included 114 consecutive mCRPC patients, comprising 54 and 60 patients who progressed with abiraterone acetate (AA) and enzalutamide (Enz), respectively, before the introduction of docetaxel. The impact of the response to either ARAT agent on the activity of docetaxel was assessed. RESULTS: Following ARAT therapy, a prostate-specific antigen (PSA) response was observed in 73 of the 114 patients, of whom 33 and 40 received AA and Enz, respectively. In the 114 patients, PSA response to docetaxel was achieved in 48 (42.1%) patients, and median PSA progression-free survival (PFS) and overall survival (OS) with docetaxel were 7.2 and 17.5 months, respectively. No significant difference was noted in PSA response rate, PSA PFS or OS with docetaxel between responders and non-responders to a prior ARAT agent in the overall 114 patients, 54 receiving AA and 60 receiving Enz. Despite the absence of a significant impact of the response to a prior ARAT agent on PSA PFS or OS by univariate analysis, independent prognostic predictors were identified by multivariate analysis, as performance status (PS) for PSA PFS, and PS and visceral metastasis for OS. CONCLUSIONS: Disease control by docetaxel may not be affected by the response to a prior ARAT agent. Therefore, a prior response to an ARAT agent should not influence the decision on the subsequent introduction of docetaxel for mCRPC patients. PMID- 29275451 TI - Voice alterations in patients with Morquio A syndrome. AB - Morquio A syndrome, or mucopolysaccharidosis (MPS IV A), is an inherited lysosomal storage disorder which belongs to the group of mucopolysaccharidoses (MPSs). It is caused by N-acetylgalactosamine-6-sulfatase (GALNS) activity deficiency, which results in impaired degradation of glycosaminoglycans (GAGs), including keratan sulfate (KS) and chondroitin-6-sulfate (CS). These compounds infiltrate and disrupt the architecture of the extracellular matrix, compromising the integrity of the connective tissue. Patients with Morquio A have also been noted for exhibiting abnormalities of the larynx and vocal tract. The aim of the study was to assess voice alterations using noninvasive acoustic and electroglottographic voice analysis. Electroglottographic signal and acoustic analyses revealed considerable changes in the voices of patients with Morquio A syndrome when compared to the voices of healthy controls. Affected patients tended toward tense voice, incomplete glottal closure, increased incidence of vocal fold nodules, dysphonia, and hoarse voice. Morquio A syndrome is characterized by connective tissue disease, which adversely affects voice quality. The use of objective voice analysis makes it possible to quantitatively monitor changes in the vocal apparatus over the course of disease progression, and also allows for assessment of the effects of the enzyme replacement therapy. PMID- 29275452 TI - Mild troponin elevation in patients admitted to the emergency department with atrial fibrillation: 30-day post-discharge prognostic significance. AB - Patients with atrial fibrillation (AF) often undergo troponin (Tn) testing in the emergency department (ED), but the clinical significance of mildly elevated values remains unclear. We evaluated short-term 30-day post-discharge outcomes in AF patients according to troponin levels. Out of 2181 AF patients evaluated in the ED (June 2014 to June 2015), we included consecutive admitted patients. Patients were grouped into those with normal Tn values (<= 0.05 ng/mL), mild elevations (> 0.05-0.5 ng/mL, 10* URL) and marked elevations (> 0.5 ng/mL). Outcomes included acute coronary syndrome (ACS), revascularization, all-cause mortality and combined end point; the secondary outcome was ischemic stroke. A total of 348 patients (90.9%) had Tn testing, which was associated with longer in hospital stay (median 2.04 vs. 0.74 days in unmeasured Tn, p = 0.014); 37.1% did not have clinical suspicion of ACS. Mild Tn elevation occurred in 19.0% and 6.3% had markedly elevated values. Compared to normal values, mild elevations had higher absolute incidence, without statistical significance, of ACS (1.5 vs. 0.0%, p = 0.202), revascularization (1.5 vs. 0.0%, p = 0.202), all-cause mortality (12.1 vs. 6.9%, p = 0.200), combined end point (13.3 vs. 6.9%, p = 0.084) or ischemic stroke (4.5 vs. 2.3%, p = 0.394). Tn testing is routine in admitted AF patients, even without suspicion of ACS, and is associated with prolonged stay. Mild Tn elevation is associated with a nonsignificant trend toward higher adverse events. Larger-scale studies are needed to evaluate the cost-effectiveness of Tn testing for prognosis in admitted AF patients, as this prolongs stay and has unclear impact on patient management. PMID- 29275453 TI - Inhaled Treprostinil in Pulmonary Hypertension Associated with Lung Disease. AB - PURPOSE: Pulmonary hypertension (PH) in the setting of parenchymal lung disease adversely affects quality of life and survival. However, PH-specific drugs may result in ventilation/perfusion imbalance and currently, there are no approved PH treatments for this patient population. In the present retrospective study, data from 22 patients with PH associated with lung disease treated with inhaled treprostinil (iTre) and followed up clinically for at least 3 months are presented. METHODS: PH was defined by resting right heart catheterization as a mean pulmonary artery pressure (mPAP) >= 35 mmHg, or mPAP >= 25 mmHg associated with pulmonary vascular resistance >= 4 Woods Units. Follow-up evaluation was performed at the discretion of the attending physician. RESULTS: From baseline to follow-up, we observed significant improvement in functional class (n = 22, functional class III-IV 82 vs. 59%, p = 0.041) and 6-min walk distance (n = 11, 243 +/- 106 vs. 308 +/- 109; p = 0.022), without a deleterious effect on resting peripheral oxygen saturation (n = 22, 92 +/- 6 vs. 94 +/- 4; p = 0.014). Most of the patients (86%, n = 19/22) were using long-term nasal supplemental oxygen at baseline. During follow-up, only one patient had increased supplemental oxygen requirement. The most common adverse events were cough, headache, and diarrhea. No severe adverse event was reported. CONCLUSIONS: The results suggest that iTre is safe in patients with Group 3 PH and evidence of pulmonary vascular remodeling in terms of functional class, gas exchange, and exercise capacity. Additionally, iTre was well tolerated. The potential role of PH-specific drugs in Group 3 PH should be further assessed in larger prospective studies. PMID- 29275454 TI - Seasonal and spatial variation of arsenic in groundwater in a rhyolithic volcanic area of Lesvos Island, Greece. AB - A survey conducted in water wells located in the rhyolithic volcanic area of Mandamados, Lesvos Island, Greece, indicated that significant seasonal variation of arsenic concentration in groundwater exists mainly in wells near the coastal zone. However, there were differences among those coastal wells with regard to the processes and factors responsible for the observed seasonal variability of the element, although they are all located in a small homogeneous area. These processes and factors include (a) a higher rate of silicate weathering and ion exchange during the dry period followed by the dilution by the recharge water during the wet period, (b) enhanced desorption promoted by higher pH in summer and subsequent dilution of As by rainwater infiltration during the wet period, and (c) reductive dissolution of Mn during the wet period and by desorption under high pH values during the dry period. On the other hand, in wells located in higher-relief regions, the concentration of As in groundwater followed a fairly constant pattern throughout the year, which is probably related to the faster flow of groundwater in this part of the area due to a higher hydraulic gradient. In general, seasonal variation of As in groundwater in the study area was found to be related to geology, recharge rate, topography-distance from coast, and well depth. PMID- 29275455 TI - Early detection of metastases using whole-body MRI for initial staging and routine follow-up of myxoid liposarcoma. AB - OBJECTIVE: To define the role of whole-body MRI (WBMRI) for initial staging and routine follow-up of myxoid liposarcoma (MLS). MATERIALS AND METHODS: A retrospective review of all the patients with MLS who underwent WBMRI for initial staging and routine follow-up at our institution between October 1, 2006, and September 30, 2016 was performed. Patient demographics, clinical presentation, imaging findings, tumor histology, and occurrence and location of metastatic disease were recorded. Thirty-three patients who underwent a total of 150 WBMRI examinations were included in the study. RESULTS: Nine patients (27%) were diagnosed with metastases between 0 and 60 months (median 10; interquartile range, 7-13) from the diagnosis of the primary tumor. The initial site of metastatic disease was extrapulmonary in all patients. Only two patients developed pulmonary metastases, which were diagnosed by CT chest 9 and 29 months after the diagnosis of extrapulmonary metastases. The first metastasis was diagnosed by WBMRI in seven patients (78%), by thoracic CT in one patient, and by abdominal CT in one patient. Eight of nine patients (89%) were asymptomatic at the time of diagnosis of the metastases. In seven patients (78%), WBMRI demonstrated metastases included within the field of view of, but occult on a contemporaneous CT scan. CONCLUSION: Our 10-year institutional experience demonstrates that WBMRI facilitates early detection of extrapulmonary MLS metastases before the onset of clinical symptoms and pulmonary metastases. WBMRI also depicts extrapulmonary metastases that are occult on CT scans. The current surveillance strategies are insufficient for screening for extrapulmonary MLS metastases. PMID- 29275456 TI - Pulse-dose radiofrequency treatment in pain management-initial experience. AB - Radiofrequency procedures have been used for treating various chronic pain conditions for decades. These minimally invasive percutaneous treatments employ an alternating electrical current with oscillating radiofrequency wavelengths to eliminate or alter pain signals from the targeted site. The aim of the continuous radiofrequency procedure is to increase the temperature sufficiently to create an irreversible thermal lesion on nerve fibres and thus permanently interrupt pain signals. The pulsed radiofrequency procedure utilises short pulses of radiofrequency current with intervals of longer pauses to avert a temperature increase to the level of permanent tissue damage. The goal of these pulses is to alter the processing of pain signals, but to avoid relevant structural damage to nerve fibres, as seen in the continuous radiofrequency procedure. The pulse-dose radiofrequency procedure is a technical improvement of the pulsed radiofrequency technique in which the delivery mode of the current is adapted. During the pulse dose radiofrequency procedure thermal damage is avoided. In addition, the amplitude and width of the consecutive pulses are kept the same. The method ensures that each delivered pulse keeps the same characteristics and therefore the dose is similar between patients. The current review outlines the pulse-dose radiofrequency procedure and presents our institution's chronic pain management studies. PMID- 29275457 TI - Clinical Outcomes after Keraring Implantation for Keratoconus Management in Patients Older Than 40 Years: A Retrospective, Interventional, Cohort Study. AB - BACKGROUND: Intracorneal ring segment implantation is an effective and safe method of visual improvement in patients with keratoconus. The aim of our study was to evaluate the long-term clinical outcomes after Keraring implantation for keratoconus in patients older than 40 years. METHODS: Eleven eyes from 11 patients with keratoconus who underwent femtosecond laser-assisted Keraring implantation for keratoconus were included in this retrospective study. The uncorrected visual acuity (UCVA), corrected visual acuity, keratometric readings, central corneal thickness and thinnest corneal pachymetry were evaluated preoperatively and 6 months after the Keraring implantation. RESULTS: UCVA, BCVA and keratometric readings improved at 6 months postoperatively. CONCLUSION: Our data showed significant keratometric amelioration and visual improvement after Keraring implantation for keratoconus in patients older than 40 years at 6 months postoperatively. PMID- 29275458 TI - Maize Iranian mosaic virus shows a descending transcript accumulation order in plant and insect hosts. AB - Maize Iranian mosaic virus (MIMV) is a distinct member of the genus Nucleorhabdovirus. In this study, expression of all MIMV genes in maize for four weeks after inoculation and in inoculative planthoppers was examined using a quantitative RT-PCR (RT-qPCR) assay. Accumulation of MIMV P, gene 3, M, G and L transcripts relative to N transcripts was measured and normalized to 18S rRNA in maize plants and to the ribosomal protein S13 gene (RPS13) in planthoppers using the comparative CT method. In plants, higher levels of MIMV N transcripts were found relative to other transcripts, while MIMV L transcripts were at the lowest levels. The highest accumulation of MIMV transcripts was found at 14 days postinoculation (dpi). At 21 dpi, we found the lowest transcript levels for all genes, which increased again at 28 dpi, although in lower amounts than at 14 dpi. In Laodelphax striatellus, MIMV M, G and L transcripts accumulated at lower levels than other transcripts. The gene 3 transcript level was high in both plants and planthoppers. Our results showed that transcript accumulation for the MIMV genes was similar in both hosts and followed the pattern of sequential transcriptional attenuation from the 3' to the 5' end of the genome, similar to vertebrate rhabdoviruses. These results indicate that the regulation of virus gene transcription for this plant-infecting rhabdovirus is similar to that of some vertebrate-infecting rhabdoviruses. PMID- 29275459 TI - Sulfatase-1 knockdown promotes in vitro and in vivo aggressive behavior of murine hepatocarcinoma Hca-P cells through up-regulation of mesothelin. AB - Our previous study (Oncotarget 2016; 7:46) demonstrated that the over-expression of sulfatase-1 in murine hepatocarcinoma Hca-F cell line (a murine HCC cell with lymph node metastatic [LNM] rate of >75%) downregulates mesothelin and leads to reduction in lymphatic metastasis, both in vitro and in vivo. In current work, we investigated the effects of Sulf-1 knockdown on mesothelin (Msln) and it's effects on the in vitro cell proliferation, migration, invasion, and in vivo tumor growth and LNM rate for Hca-P cells (a murine HCC cell with LNM rate of <25%). Western blotting and qRT-PCR assay indicated that both in vitro and in vivo Sulf-1 was down-regulated by 75% and 68% and led to up regulation of Msln by 55% in shRNA-transfected-Sulf-1-Hca-P cells compared with Hca-P and nonspecific sequence control plasmid transfected Hca-P cell (shRNA-Nc-Hca-P). The in vitro proliferation, migration and invasion potentials were significantly enhanced following Sulf-1 stable down-regulation. In addition, Sulf-1 knock-down significantly promoted tumor growth and increased LNM rates of shRNA-Sulf-1-Hca-P transplanted mice by 78.6% (11 out of 14 lymph nodes were positive of cancer). Consistent with our previous work, we confirmed that Sulf-1 plays an important role in hepatocarcinoma cell proliferation, migration, invasion and metastasis. The interaction between Sulf-1 and Msln is a potential therapeutic target in the development of liver cancer therapy. PMID- 29275460 TI - Implementation of a Regional Perinatal Data Repository from Clinical and Billing Records. AB - Objectives To describe the implementation of the first phase of a regional perinatal data repository and to provide a roadmap for others to navigate technical, privacy, and data governance concerns in implementing similar resources. Methods Our implementation integrated regional physician billing records with maternal and infant electronic health records from an academic delivery hospital. These records, representing births during 2013-2015, constituted a data core supporting linkage to additional ancillary data sets. Measures obtained from pediatric follow-up, urgent care, emergency, and inpatient encounters were linked at the individual level as were measures obtained by home visitors during pre- and postnatal encounters. Residential addresses were geocoded supporting linkage to area-level measures. Results Integrated data contained regional billing records for 69,290 newborns representing approximately 81% of all regional live births and nearly 95% of live births in the region's most populous county. Billing records linked to 7293 infant delivery hospital records and 7107 corresponding maternal hospital records. Manual review demonstrated 100% validity of matches among audited records. Additionally, 2430 home visiting records were linked to the data core as were pediatric primary care, urgent care, emergency department, and inpatient visits representing 42,541 children. More than 99% of the newborn billing records were geocoded and assigned a census tract identifier. Conclusions for Practice Our approach to methodological and regulatory challenges affords opportunities for expansion of systems to integrate electronic health records originating from additional medical centers as well as individual- and area-level linkage to additional data sets relevant to perinatal health. PMID- 29275461 TI - Tumor Immuno-Environment in Cancer Progression and Therapy. AB - The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector phase of anti cancer immunity, and the overall effectiveness of immunotherapy and other forms of cancer treatment. In this chapter, we discuss the roles of key TME components during tumor progression, metastatic process and cancer therapy-induced tumor regression, as well as opportunities for their modulation to enhance the overall therapeutic benefit. PMID- 29275462 TI - Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment. AB - Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed. The mechanisms of immune escape are likely distinct in these two phenotypes, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, FoxP3+ Tregs, and evidence for T cell-intrinsic anergy. Therapeutic strategies to overcome these inhibitory mechanisms are being pursued, and anti-PD-1 mAbs have been FDA approved. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous, several of which are in clinical testing. A new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8alpha+ DCs. New strategies are being developed to engage this pathway therapeutically, such as through STING agonists. The molecular mechanisms that mediate the presence or absence of the T cell-inflamed tumor microenvironment are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/beta-catenin pathway, suggesting that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment. PMID- 29275463 TI - Regulation of CTL Infiltration Within the Tumor Microenvironment. AB - The tumor microenvironment consists of a complex milieu of cells and factors that maintain equilibrium between tumor progression and destruction. Characterization of the immune contexture in primary tumors has consistently shown that T lymphocytes are an integral predictor of improved clinical outcome. This is notably true in colorectal carcinoma where high densities of cytotoxic or memory T lymphocytes in the invasive margin and the center of the primary tumor predict better patient survival, a measure termed Immunoscore. Since a high Immunoscore and pre-existing adaptive immune response are significantly correlated with improved clinical outcome, it is essential to understand the mechanisms underlying functional T lymphocyte infiltration into the tumor. The ability of cytolytic and memory T lymphocytes to migrate into tumors is regulated by multiple strategies including T lymphocyte help, homing factors, cytokines, tumor genotype, angiogenesis, lymphangiogenesis, and neurological signals. This chapter will discuss the predominant factors that mediate T-lymphocyte infiltration into tumors and how analysis of these biomarkers determine patients' disease-related survival and predicts response to cancer therapy. PMID- 29275464 TI - The Role of Tumor Microenvironment in Cancer Immunotherapy. AB - The field of tumor immunology and immunotherapy has undergone a renaissance in the past decade do in large part to a better understanding of the tumor immune microenvironment. After suffering countless successes and setbacks in the twentieth century, immunotherapy has now come to the forefront of cancer research and is recognized as an important tool in the anti-tumor armamentarium. The goal of therapy is to aid the immune system in recognition and destruction of tumor cells by enhancing its ability to react to tumor antigens. This traditionally has been accomplished by induction of adaptive immunity through vaccination or through passive delivery of immunologic effectors as in the case of adoptive cell transfer. The recent discovery of immune "checkpoints" whose purpose is to suppress immune activity and prevent auto-immunity has created a new angle by which reactivity to tumors can be enhanced. Blockers of these checkpoints have yielded impressive clinical results and have recently been approved for use in a wide variety of malignancies. With data showing increasing rates of not only treatment response, but complete remissions, immunotherapy is poised to become an increasingly utilized therapy in the treatment of cancer. PMID- 29275465 TI - Immunogenic and Non-immunogenic Cell Death in the Tumor Microenvironment. AB - The host immune system is continuously exposed to dying cells and has evolved to distinguish between cell death events signaling potential threats and physiological apoptosis that should be tolerated. Tumors can use this distinction to their advantage, promoting apoptotic death of cancer cells to induce tolerance and evasion of immunosurveillance. On the other hand, stimuli that cause immunogenic death of cancer cells can induce an effective anti-tumor immune response. In this chapter we discuss different forms of cell death in the tumor microenvironment, and how these interact with host immune cells to impact tumor progression and cancer therapy. We focus on how cancer cells hijack aspects of cell death to promote tumor survival, and how anti-cancer treatments that activate immunogenic death modalities give strong and durable clinical efficacy. PMID- 29275466 TI - Exosomes in Cancer: Another Mechanism of Tumor-Induced Immune Suppression. AB - Exosomes are the smallest extracellular vesicles (EV) produced under physiological and pathological conditions by all cells and present in all body fluids. They are critical components of the intercellular communication network. Tumor cells release exosomes which are enriched in immunosuppressive molecules as well as biologically-active soluble factors and enzymes. Tumor-derived exosomes (TEX) interact with immune effector cells in the tumor microenvironment and in the circulation, deliver negative signals to these cells and interfere with their anti-tumor functions. By suppressing functions of immune effector cells, TEX promote tumor progression and facilitate tumor escape from the immune system. Thus, TEX can be viewed as immune checkpoint inhibitors. Silencing of TEX mediated immune inhibition without disrupting the physiologically important cellular communication networks represents a considerable challenge. Current efforts are directed at achieving a better understanding of the role exosomes play in cancer progression and/or outcome and of molecular/genetic mechanisms responsible for immunoinhibitory activity of TEX. PMID- 29275468 TI - Targeting Myeloid-Derived Suppressor Cells in Cancer. AB - Myeloid derived suppressor cells (MDSC) represent only a minor fraction of circulating blood cells but play an important role in tumor formation and progression. They are a heterogeneous group of cells that influence the tumor microenvironment by depletion of amino acids, oxidative stress, decreased trafficking of antitumor effector cells, and increased regulatory T and regulatory dendritic cell responses. Investigational treatment strategies targeting MDSCs have attempted to inhibit MDSC development and expansion (stem cell factor blockade, modulate of cell signaling, and target MDSC migration and recruitment), inhibit MDSC function (nitric oxide inhibition and reactive oxygen and nitrogen species inhibition), differentiate MDSCs into more mature cells (Vitamins A and D, all-trans retinoic acid, interleukin-2, toll-like receptor 9 inhibitors, taxanes, beta-glucan particles, tumor-derived exosome inhibition, and very small size proteoliposomes), and destroy MDSCs (cytotoxic agents, ephrin A2 degradation, anti-interleukin 13, and histamine blockers). To date, there are no Food and Drug Administration approved therapies selectively targeting MDSCs, but such therapies are likely to be implemented in the future, due to the key role of MDSCs in antitumor immunity. PMID- 29275467 TI - Chemo-Immunotherapy: Role of Indoleamine 2,3-Dioxygenase in Defining Immunogenic Versus Tolerogenic Cell Death in the Tumor Microenvironment. AB - In certain settings, chemotherapy can trigger an immunogenic form of tumor cell death. More often, however, tumor cell death after chemotherapy is not immunogenic, and may be actively tolerizing. However, even in these settings the dying tumor cells may be much more immunogenic than previously recognized, if key suppressive immune checkpoints such as indoleamine 2,3-dioxygenase (IDO) can be blocked. This is an important question, because a robust immune response to dying tumor cells could potentially augment the efficacy of conventional chemotherapy, or enhance the strength and duration of response to other immunologic therapies. Recent findings using preclinical models of self-tolerance and autoimmunity suggest that IDO and related downstream pathways may play a fundamental role in the decision between tolerance versus immune activation in response to dying cells. Thus, in the period of tumor cell death following chemotherapy or immunotherapy, the presence of IDO may help dictate the choice between dominant immunosuppression versus inflammation, antigen cross-presentation, and epitope spreading. The IDO pathway thus differs from other checkpoint-blockade strategies, in that it affects early immune responses, at the level of inflammation, activation of antigen-presenting cells, and initial cross presentation of tumor antigens. This "up-stream" position may make IDO a potent target for therapeutic inhibition. PMID- 29275469 TI - Tryptophan Catabolism and Cancer Immunotherapy Targeting IDO Mediated Immune Suppression. AB - Over the last decade, tryptophan catabolism has been firmly established as a powerful mechanism of innate and adaptive immune tolerance. The catabolism of tryptophan is a central pathway maintaining homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses. This is driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO), resulting in local depletion of tryptophan, while tryptophan catabolites accumulate, including kynurenine and its derivatives, depending on the presence of downstream enzymes in the kynurenine pathway. These metabolic modifications result in a local microenvironment that is profoundly immunosuppressive, as a result of various mechanisms whose respective role remains incompletely characterized. Drugs targeting this pathway, specifically IDO1, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. Recent studies have demonstrated favorable pharmacokinetics profiles for first generation (Indoximod NLG8189) and second-generation IDO1 inhibitors (INCB024360 and NLG919). Targeting tryptophan catabolism in combination with additional methods of therapy may improve efficacy of cancer immunotherapy. These methods include, but are not limited to vaccination, adoptive cellular therapy, checkpoint inhibitor blockade, and cyclooxygenase-2 (COX2) inhibition. Over the last decade, there has been a considerable increase in our understanding of the regulation and downstream mediators of tryptophan metabolism. This detailed understanding will expand opportunities to interfere with the pathway therapeutically on multiple levels. The object of this chapter is to highlight current and past key findings that implicate tryptophan catabolism as an important mediator of cancer immunity and discuss the development of multiple therapeutic targets. PMID- 29275470 TI - Lipid Inflammatory Mediators in Cancer Progression and Therapy. AB - Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associated with neutrophilia, lymphocytopenia and poor patient outcomes. This contrasts with lymphocyte infiltration of tumors, which is associated with improved outcomes. Lifestyle parameters such as high fat diet s and omega (omega)-6 polyunsaturated fatty acids (PUFA) intake may influence these inflammatory parameters including extramedullary myelopoiesis that can contribute to a metastatic "niche". While, tumor secretion of growth factors (GFs) and chemokines regulate tumor-immune-cell crosstalk, in this chapter, we also emphasize how lifestyle choices, including, obesity, high-fat and high omega-6 PUFA dietary content, contribute to inflammation and myeloid cell infiltration of tumors. A relationship between obesity and high-fat diets (notably the saturated fats in Western diets) and tumor incidence, metastasis, and poor outcomes is generally accepted. However, the mechanisms of dietary promotion of inflammatory microenvironments and targeted drugs to inhibit the clinical sequel remain an unmet challenge. One approach, modification of dietary intake may have a preventative or therapeutic approach to regulate tumor-associated inflammation and remains an attractive, but little studied intervention. PMID- 29275471 TI - Oncolytic Virotherapy and the Tumor Microenvironment. AB - Oncolytic viral therapy is a promising approach to treat many malignancies, including breast, colorectal, hepatocellular, and melanoma. The best results are seen when using "targeted and armed" viruses. These are viruses that have been genetically modified to selectively replicate within cancer cells and express specific transgenes that alter the tumor microenvironment to inhibit tumor progression. The products of these transgenes induce cell death, make the virus less virulent, compromise tumor vascularity, and are capable of modulating or enhancing the immune system-such as cytokines and chemokines. In addition, oncolytic viruses can induce anti-vascular effects and disrupt the extracellular matrix to improve viral spread within the tumor. Oncolytic viruses also improve crosstalk between fibroblasts, cytokine-induced killer cells, and cancer cells within the microenvironment, leading to enhanced tumor cell death. PMID- 29275473 TI - Immunotherapeutic Targeting of Tumor-Associated Blood Vessels. AB - Pathological angiogenesis occurs during tumor progression and leads in the formation of an abnormal vasculature in the tumor microenvironment (TME). The tumor vasculature is disorganized, tortuous and leaky, resulting in high interstitial pressure and hypoxia in the TME, all of which are events that support tumor growth and survival. Given the sustaining role of the tumor vasculature, it has become an increasingly attractive target for the development of anti-cancer therapies. Antibodies, tyrosine kinase inhibitors and cancer vaccines that target pro-angiogenic factors, angiogenesis-associated receptors or tumor blood vessel-associated antigens continue to be developed and tested for therapeutic efficacy. Preferred anti-angiogenic protocols include those that "normalize" the tumor-associated vasculature which reduce hypoxia and improve tumor blood perfusion, resulting in tumor cell apoptosis, decreased immunosuppression, and enhanced effector immune cell infiltration/tumoricidal action within the TME. PMID- 29275472 TI - The Impact of Housing Temperature-Induced Chronic Stress on Preclinical Mouse Tumor Models and Therapeutic Responses: An Important Role for the Nervous System. AB - In the last 10-15 years, there has been a recognition that the catecholamines (norepinephrine, NE, and epinephrine, Epi) released by the sympathetic nervous system under stressful conditions promote tumor growth through a variety of mechanisms. Tumors recruit autonomic nerves during their development and NE is then released locally in the tumor microenvironment (TME). Acting through adrenergic receptors present on a variety of cells in the TME, NE and Epi induce proliferation, resistance to apoptosis, epithelial to mesenchymal transition, metastasis of tumor cells, angiogenesis, and inflammation in the TME. These pre clinical studies have been conducted in mouse models whose care and housing parameters are outlined in "The Guide for the Care and Use of Laboratory Animals [1]. In particular, the Guide mandates that mice be housed at standardized sub thermoneutral temperatures; however, this causes a state of chronic cold-stress and elevated levels of NE. Although mice are able to maintain a normal body temperature when kept at these cool temperatures, it is becoming clear that this cold-stress is sufficient to activate physiological changes which affect experimental outcomes. We find that when mice are housed under standard, sub thermoneutral temperatures (~22 degrees C, ST), tumor growth is significantly greater than when mice are housed at thermoneutrality (~30 degrees C TT). We also find that the anti-tumor immune response is suppressed at ST and this immunosuppression can be reversed by housing mice at TT or by administration of propranolol (a beta-adrenergic receptor antagonist) to mice housed at ST. Furthermore, at ST tumors are more resistant to therapy and can also be sensitized to cytotoxic therapies by housing mice at TT or by treating mice with propranolol. The implications of these observations are particularly relevant to the way in which experiments conducted in preclinical models are interpreted and the findings implemented in the clinic. It may be that the disappointing failure of many new therapies to fulfill their promise in the clinic is related to an incomplete preclinical assessment in mouse models. Further, an expanded understanding of the efficacy of a therapy alone or in combination obtained by testing under a wider range of conditions would better predict how patients, who are under various levels of stress, might respond in a clinical setting. This may be particularly important to consider since we now appreciate that long term outcome of many therapies depends on eliciting an immune response.It is clear that the outcome of metabolic experiments, immunological investigations and therapeutic efficacy testing in tumors of mice housed at ST is restricted and expanding these experiments to include results obtained at TT may provide us with valuable information that would otherwise be overlooked. PMID- 29275474 TI - Adaptive Resistance to Cancer Immunotherapy. AB - Immunosuppressive mechanisms within the tumor microenvironment have emerged as a major impediment to cancer immunotherapy. While a broad range of secreted factors, receptors/ligands, and cell populations have been described that contribute to the immunosuppression, the involvement of these processes in immune evasion by tumors is typically considered to be an intrinsic property of the tumor. Evidence is now emerging that the processes underlying immune suppression within the tumor are, in fact, triggered by immune attack and reflect a dynamic interplay between the tumor and the host's immune system. The term adaptive resistance has been coined to describe the induction of immune suppressive pathways in the tumor following active attack on the tumor. Adaptive resistance is a scalable process where the magnitude of immune suppression matches the magnitude of the immune attack; the net balance between suppression and attack determines the durability of the anti-tumor response and tumor outcome. In this chapter, we will examine the data supporting adaptive resistance and the opposing roles of T cells in simultaneously promoting both anti-tumor immunity and immune suppression within the tumor microenvironment. The clinical implications of adaptive resistance in the design and application of immunotherapeutic strategies is also discussed. PMID- 29275475 TI - Imaging the Tumor Microenvironment. AB - The tumor microenvironment consists of tumor, stromal, and immune cells, as well as extracellular milieu. Changes in numbers of these cell types and their environments have an impact on cancer growth and metastasis. Non-invasive imaging of aspects of the tumor microenvironment can provide important information on the aggressiveness of the cancer, whether or not it is metastatic, and can also help to determine early response to treatment. This chapter provides an overview on non-invasive in vivo imaging in humans and mouse models of various cell types and physiological parameters that are unique to the tumor microenvironment. Current clinical imaging and research investigation are in the areas of nuclear imaging (positron emission tomography (PET) and single photon emission computed tomography (SPECT)), magnetic resonance imaging (MRI) and optical (near infrared (NIR) fluorescence) imaging. Aspects of the tumor microenvironment that have been imaged by PET, MRI and/or optical imaging are tumor associated inflammation (primarily macrophages and T cells), hypoxia, pH changes, as well as enzymes and integrins that are highly prevalent in tumors, stroma and immune cells. Many imaging agents and strategies are currently available for cancer patients; however, the investigation of novel avenues for targeting aspects of the tumor microenvironment in pre-clinical models of cancer provides the cancer researcher with a means to monitor changes and evaluate novel treatments that can be translated into the clinic. PMID- 29275476 TI - Lignosulfonic acid attenuates NF-kappaB activation and intestinal epithelial barrier dysfunction induced by TNF-alpha/IFN-gamma in Caco-2 cells. AB - Lentinula edodes mycelia solid culture extract (MSCE) is used as a medical food ingredient and provides beneficial effects to patients with cancer and chronic type C hepatitis. Low molecular weight lignin (LM-lignin), which is an active component of MSCE, exhibits hepatoprotective, antitumor, antiviral, and immunomodulatory effects. In this study, we investigated the effect of LM lignin/lignosulfonic acid on intestinal barrier function. Lignosulfonic acid enhanced transepithelial membrane electrical resistance in human intestinal Caco 2 cell monolayers. In Caco-2 cells treated with lignosulfonic acid, expression of claudin-2, which forms high conductive cation pores in tight junctions (TJs), was decreased. Lignosulfonic acid also attenuated the barrier dysfunction that is caused by tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in Caco-2 cells. TNF-alpha- and IFN-gamma-induced activation of NF-kappaB, such as translocation of NF-kappaB p65 into the nucleus and induction of gene expression, was inhibited by lignosulfonic acid treatment. Furthermore, lignosulfonic acid decreased the TNF-alpha- and IFN-gamma-induced increase in interleukin (IL)-1beta and IL-6 expression in Caco-2 cells. These results suggest that lignosulfonic acid not only enhances TJ barrier function but also restores TJ barrier integrity impaired by inflammatory cytokines. Therefore, lignosulfonic acid may be beneficial for the treatment of inflammation-induced intestinal barrier dysfunction observed in inflammatory bowel disease. PMID- 29275477 TI - Measuring heavy metal stress in ryegrass using helium-cadmium excitation-based photoluminescence. AB - As the chemical analysis of heavy metal uptake and toxicity in plants is time consuming, expensive, and destructive, a simple and reliable method for detecting heavy metal transfer from the soil to plants is thus necessary. We aimed to measure copper (Cu), lead (Pb), and cadmium (Cd) stress in ryegrass in vivo using plant photoluminescence based on a helium (He)-cadmium excitation source (wavelength 325 nm). The soils were combined with Cu, Pb and Cd, respectively. Fifteen ryegrass seedlings (Lolium multiflorum) were planted in each pot. After 30 days, leaves from seedlings at the fourth-leaf stage were collected and the fluorescence excitation spectra were detected using a He-Cd laser at an excitation wavelength of 325 nm. Three emission peaks that constitute known chlorophyll wavelengths, namely 450, 690, and 735 nm, were detected. These three peaks were strongly influenced by Cu, Pb, and Cd concentrations in the soil. Higher peak heights at 450 nm were observed with increasing Cu, Pb, and Cd concentrations in the soil, whereas no changes were noted at 690 and 735 nm. The P450/P690 and P450/P735 ratios were positively correlated with Cu, Pb, and Cd soil concentrations, ryegrass uptake, and DTPA-extractable Cu, Pb, and Cd in the soil. The related coefficients were all greater than 0.9. However, no correlation between the P690/P735 ratio, Cu, Pb, and Cd ryegrass uptake, and DTPA-extractable Cu, Pb, and Cd in the soil was observed. The measurement of plant photoluminescence in vivo using a He-Cd excitation source (wavelength 325 nm) may be utilized as an approach for monitoring the response of plants to specific stressors. PMID- 29275478 TI - Degradation reaction of Diazo reactive black 5 dye with copper (II) sulfate catalyst in thermolysis treatment. AB - The theme of present research demonstrates performance of copper (II) sulfate (CuSO4) as catalyst in thermolysis process to treat reactive black 5 (RB 5) dye. During thermolysis without presence of catalyst, heat was converted to thermal energy to break the enthalpy of chemical structure bonding and only 31.62% of color removal. With CuSO4 support as auxiliary agent, the thermally cleaved molecular structure was further destabilized and reacted with CuSO4. Copper ions functioned to delocalize the coordination of pi of the lone paired electron in azo bond, C=C bond of the sp2 carbon to form C-C of the sp3 amorphous carbon in benzene and naphthalene. Further, the radicals of unpaired electrons were stabilized and RB 5 was thermally decomposed to methyl group. Zeta potential measurement was carried out to analyze the mechanism of RB 5 degradation and measurement at 0 mV verified the critical chemical concentration (CCC) (0.7 g/L copper (II) sulfate), as the maximum 92.30% color removal. The presence of copper (II) sulfate catalyst has remarkably increase the RB 5 dye degradation as the degradation rate constant without catalyst, k1 is 6.5224 whereas the degradation rate constant with catalyst, k2 is 25.6810. This revealed the correlation of conversion of thermal energy from heat to break the chemical bond strength, subsequent fragmentation of RB 5 dye molecular mediated by copper (II) sulfate catalyst. The novel framework on thermolysis degradation of molecular structure of RB 5 with respect to the bond enthalpy and interfacial intermediates decomposition with catalyst reaction were determined. PMID- 29275479 TI - Potato tubers contamination with nitrate under the influence of nitrogen fertilizers and spray with molybdenum and salicylic acid. AB - A field trial was conducted through 2015 and 2016 growing seasons to study the effect of nitrogen fertilizer sources and foliar spray with molybdenum (Mo), salicylic acid (SA) and their combination on tubers yield, some chemical constituents, nutrients uptake, nitrate accumulation and nitrate reductase activity in potato tubers. N source was added at a rate of 350 kg N ha-1in five equal doses as two different forms, the first is urea and the second is ammonium sulfate plus calcium nitrate equally. SA was sprayed with three rates of 0, 75 and 150 mg l-1. Also, Mo as ammonium molybdate was sprayed using three rates 0, 50 and 100 mg l-1Mo. Both treatments of SA and Mo were applied separately as well as with each other, at three successive times 30, 50 and 70 days after planting of potato plants. Results indicated that the addition of 350 kg N ha-1 as ammonium sulfate and calcium nitrate equally caused a significant elevation (P > 0.05) in fresh weight, chlorophyll b, carotenoids, chlorophyll a, nitrate reductase activity, dry weight and NPK uptake by potato tubers compared with the same amount of nitrogen in the form of urea only. All the aforementioned characteristics were improved with increasing concentration of Mo and/or SA. The highest accumulation of nitrate was recorded under the addition of 350 kg N ha-1 as urea alone. The highest average of all the aforementioned characteristics was observed at the treatment of 350 kg N ha-1 as ammonium sulfate and calcium nitrate equally plus spraying with 100 mg l-1Mo and 150 mg l-1 SA. In contrast, this treatment gave the lowest accumulation of nitrates in potato tubers. PMID- 29275480 TI - Decision support tool for accidental pollution management. AB - Accidental river pollution can cause damage to the environment, put at risk the health of people that use the water for domestic purposes, and, not lastly, compromise dependent economic activities (e.g., agriculture). The reduction of the concentration of pollutant on any river following an accidental pollution can be achieved using dilution, by opening for certain duration the bottom gates of the reservoirs placed on the river's tributaries and releasing a significant volume of clean water in the main river. The hydraulic simulation and the pollutant transport are executed, firstly considering there is no dilution and secondly for the dilution scenario (bottom gates of the reservoirs open). A database was created, containing the results of simulations of pollutant transport for various values of the pollution characteristics in both diluted/undiluted scenarios. The database served for the implementation of a web decision support tool that presents an intuitive and easy to use GUI that allows the user to input details of the accidental pollution. Straightforward actions to be taken are presented to the end-user (e.g., "Open the bottom gates of the reservoir X at time T1 and close it at time T2") and synchronized charts show the effect of the dilution in respect to the concentration of pollutant at certain locations on the river. Using the described approach, a reduction of pollutant concentration in the river with up to 90% can be obtained. PMID- 29275481 TI - Risk assessment of heavy metals in Vembanad Lake sediments (south-west coast of India), based on acid-volatile sulfide (AVS)-simultaneously extracted metal (SEM) approach. AB - Contamination of estuarine system due to heavy metals is a severe issue in tropical countries, especially in India. For the evaluation of the risk due to heavy metals, the current study assessed spatial and temporal variation of acid volatile sulfide (AVS), simultaneously extracted metal (SEM), and total metal concentration as toxicity indicator of aquatic sediments in Vembanad Lake System (VLS), India. Surface sediment samples collected from 12 locations from the northern portion of VLS for 4 years during different seasons. The results suggest, in post-monsoon season, 91% of the sampling locations possessed high bioavailability of metals and results in toxicity to aquatic biota. The average seasonal distribution of SEM during the period of observations was in the order post-monsoon > pre-monsoon > monsoon (1.76 +/- 2.00 > 1.35 +/- 0.60 > 0.80 +/- 0.54 MUmol/g). The concentration of individual metals on ?SEM are in the order SEM Zn > SEM Cu> SEM Cd ~ SEM Pb > SEM Hg. Considering annual SigmaSEM/AVS ratio, 83% of the sites cross the critical value of 'One,' reveals that active sulfide phase of the sediment for fixing the metals is saturated. The molar ratio (differences between SEM and AVS) and its normalized organic carbon ratio reveals that in the post-monsoon season, about 42% of the sites are in the category of adverse effects are possible. The study suggests the toxicity and mobility of the metals largely depend on the available AVS, and the current situation may pose harm to benthic organisms. PMID- 29275482 TI - Paraben degradation using catalytic ozonation over volcanic rocks. AB - Parabens are widely used as antimicrobial and preservatives in pharmaceutical and personal care products and are continuously reaching the water streams. Conventional wastewater treatments are proven inefficient on the removal of this kind of contaminants from wastewater. Therefore, catalytic ozonation appears as a suitable option, due to the oxidant power of ozone and its high capacity of hydroxyl radical generation in the presence of a suitable catalyst. The main drawback of catalytic ozonation is related with the choice of stable and active catalysts at low cost. On this way, two volcanic rocks were tested to enhance the removal of a mixture of parabens by ozonation, improving their degradation. Indeed, catalytic ozonation with volcanic rock allowed total paraben degradation using a transferred ozone dose (TOD) of 55 mg/L which corresponds to a reduction of about threefold the amount of TOD comparatively with single ozonation (170 mg/L of TOD). Due to the presence of semiconductors on volcanic rock composition, the effect of UVA irradiation on paraben degradation was analyzed. The neutral and basic conditions enhanced catalytic ozonation comparatively to acid conditions. Higher pH values allowed a total methylparaben degradation with 35 mg O3/L, whereas for low pH values, 55 mg O3/L was required. The use of a radical scavenger proven that hydroxyl radicals are the main responsible for paraben degradation with catalytic ozonation. This was confirmed through the analysis of the by-products, where 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid (3,4 diHBA), 2,4-dihydroxybenzoic acid, and hydroquinone were quantified. PMID- 29275483 TI - Enhanced photocatalytic activity using GO/TiO2 catalyst for the removal of DCA solutions. AB - This work aimed to optimize high-performance photocatalysts based on graphene oxide/titanium dioxide (GO/TiO2) nanocomposites for the effective degradation of aqueous pollutants. The catalytic activity was tested against the degradation of dichloroacetic acid (DCA), a by-product of disinfection processes that is present in many industrial wastewaters and effluents. GO/TiO2 photocatalysts were prepared using three different methods, hydrothermal, solvothermal, and mechanical, and varying the GO/TiO2 ratio in the range of 1 to 10%. Several techniques were applied to characterize the catalysts, and better coupling of GO and TiO2 was observed in the thermally synthesized composites. Although the results obtained for DCA degradation showed a coupled influence of the composite preparation method and its composition, promising results were obtained with the photocatalysts compared to the limited activity of conventional TiO2. In the best case, corresponding to the composite synthesized via hydrothermal method with 5% of GO/TiO2 weight ratio, an enhancement of 2.5 times of the photocatalytic degradation yield of DCA was obtained compared to bare TiO2, thus opening more efficient ways to promote the application of photocatalytic remediation technologies. PMID- 29275484 TI - Growth, extracellular alkaline phosphatase activity, and kinetic characteristic responses of the bloom-forming toxic cyanobacterium, Microcystis aeruginosa, to atmospheric particulate matter (PM2.5, PM2.5-10, and PM>10). AB - Atmospheric particulate matter (APM), commonly seen and widely excited in environment, appears great enough to influence the biochemical processes in aquatic microorganisms and phytoplankton. Understanding the response of cyanobacteria to various factors is fundamental for eutrophication control. To clarify the response of cyanobacteria to APM, the effects of PM2.5, PM2.5-10, and PM>10 on Microcystis aeruginosa were researched. Variabilities in cell density, chlorophyll a, soluble protein, malondialdehyde, extracellular activity, and kinetic parameters of alkaline phosphatase were evaluated by lab-cultured experiments. Results showed that the PM2.5 had a slight stimulation impact on the growth and enhanced both of the 48- and 72-h extracellular alkaline phosphatase activity (APA), the affinity of alkaline phosphatase for substrate, and the 72-h maximum enzymatic reaction velocity (Vmax). Moreover, the stimulations in extracellular APA and Vmax enhanced with the increasing exposure concentrations. We also found there were no obvious distinctions on the effects of growth and alkaline phosphatase in M. aeruginosa between PM2.5-10 and PM>10 exposure groups. Obviously, inhibitory effects on growth existed in 4.0 and 8.0 mg/L PM2.5-10 and 8.0 mg/L PM>10 at 120 h. Furthermore, PM2.5-10 and PM>10 exerted inhibitory effects on the extracellular APA during the 72-h exposure. Simultaneously, the Vmax was notably inhibited and the affinity of alkaline phosphatase for substrate was more inseparable compared with control in PM2.5-10 and PM>10 treatments. Nevertheless, the inhibitors in extracellular APA and kinetic parameters were unrelated to PM2.5-10 and PM>10 exposure concentrations. Two-way ANOVA results revealed that there were significant interactions between exposure concentration and diameter of APM on the 120-h cell density, soluble protein content, APA, and 72 h APA of M. aeruginosa. These results in our study would be meaningful to further researches on relationships between APM deposition and cyanobacterial bloom. PMID- 29275485 TI - Analysis of the transmission characteristics of China's carbon market transaction price volatility from the perspective of a complex network. AB - Research on the price fluctuation transmission of the carbon trading pilot market is of great significance for the establishment of China's unified carbon market and its development in the future. In this paper, the carbon market transaction prices of Beijing, Shanghai, Tianjin, Shenzhen, and Guangdong were selected from December 29, 2013 to March 26, 2016, as sample data. Based on the view of the complex network theory, we construct a price fluctuation transmission network model of five pilot carbon markets in China, with the purposes of analyzing the topological features of this network, including point intensity, weighted clustering coefficient, betweenness centrality, and community structure, and elucidating the characteristics and transmission mechanism of price fluctuation in China's five pilot cities. The results of point intensity and weighted clustering coefficient show that the carbon prices in the five markets remained unchanged and transmitted smoothly in general, and price fragmentation is serious; however, at some point, the price fluctuates with mass phenomena. The result of betweenness centrality reflects that a small number of price fluctuations can control the whole market carbon price transmission and price fluctuation evolves in an alternate manner. The study provides direction for the scientific management of the carbon price. Policy makers should take a positive role in promoting market activity, preventing the risks that may arise from mass trade and scientifically forecasting the volatility of trading prices, which will provide experience for the establishment of a unified carbon market in China. PMID- 29275486 TI - Coagulation behavior of kaolin-anionic surfactant simulative wastewater by polyaluminum chloride-polymer dual coagulants. AB - In this study, polyaluminum chloride (PAC) and cationic polymers were used to treat kaolin suspension in the presence of sodium dodecyl benzene sulfonate (SDBS). Effects of PAC dosage, pH, and rotation rate on the coagulation efficiency and floc properties were studied. And the interaction of chemicals and kaolin-SDBS was discussed. Results showed that dual coagulants could decrease the influence of SDBS on the turbidity removal compared with PAC. PAC + polyacrylamide dual coagulant showed superior performance, and the maximal removal ratios of turbidity and dissolved organic carbon were 98.5 and 42.2%, respectively. Optimal coagulation performance was achieved at pH 5-7, where charge neutralization of Al hydrolysates and bridging of polyacrylamide were the primary mechanisms. And flocs with compact structure and small size were formed. Flocs coagulated by PAC were prone to be broken at the pH of raw water after introducing high rotation rate. After dosing polyacrylamide, floc size was enhanced under alkaline condition. Meanwhile, flocs showed stronger recoverability and an open structure because the regeneration mechanism was mainly the bridging effect of polyacrylamide. PMID- 29275487 TI - Extraction, selection and comparison of features for an effective automated computer-aided diagnosis of Parkinson's disease based on [123I]FP-CIT SPECT images. AB - PURPOSE: This work aimed to assess the potential of a set of features extracted from [123I]FP-CIT SPECT brain images to be used in the computer-aided "in vivo" confirmation of dopaminergic degeneration and therefore to assist clinical decision to diagnose Parkinson's disease. METHODS: Seven features were computed from each brain hemisphere: five standard features related to uptake ratios on the striatum and two features related to the estimated volume and length of the striatal region with normal uptake. The features were tested on a dataset of 652 [123I]FP-CIT SPECT brain images from the Parkinson's Progression Markers Initiative. The discrimination capacities of each feature individually and groups of features were assessed using three different machine learning techniques: support vector machines (SVM), k-nearest neighbors and logistic regression. RESULTS: Cross-validation results based on SVM have shown that, individually, the features that generated the highest accuracies were the length of the striatal region (96.5%), the putaminal binding potential (95.4%) and the striatal binding potential (93.9%) with no statistically significant differences among them. The highest classification accuracy was obtained using all features simultaneously (accuracy 97.9%, sensitivity 98% and specificity 97.6%). Generally, slightly better results were obtained using the SVM with no statistically significant difference to the other classifiers for most of the features. CONCLUSIONS: The length of the striatal region uptake is clinically useful and highly valuable to confirm dopaminergic degeneration "in vivo" as an aid to the diagnosis of Parkinson's disease. It compares fairly well to the standard uptake ratio-based features, reaching, at least, similar accuracies and is easier to obtain automatically. Thus, we propose its day to day clinical use, jointly with the uptake ratio-based features, in the computer-aided diagnosis of dopaminergic degeneration in Parkinson's disease. PMID- 29275488 TI - The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial. AB - BACKGROUND: We conducted the multicenter, prospective, open-label study in type 2 diabetic (T2DM) patients with renal dysfunction, to clarify the efficacy and the safety in relation to renal function and glycemic control, and the economic effect when other dipeptidyl peptidase-4 (DPP-4) inhibitors were switched to a small dose of sitagliptin depending on their renal function. METHODS: Vildagliptin, alogliptin, or linagliptin received for more than 2 months were changed to sitagliptin at 25 or 12.5 mg/day depending on their renal function in 49 T2DMs. Renal function and glycemic control, and the drug cost were assessed during 6 months. RESULTS: Estimated glomerular filtration rate was not changed in patients not on hemodialysis (n = 29). The HbA1c levels were not altered in all of the patients including those on hemodialysis (n = 20). The active glucagon like peptide-1 levels or other renal parameters were not altered significantly. There were no adverse events to be related to the drugs. The daily drug expense was reduced by 88.1 yen per patient. CONCLUSION: Switching to a small dose of sitagliptin according to the renal function in T2DM patients with renal dysfunction demonstrated the same efficacy and safety as those with other full dose DPP-4 inhibitors, indicating a therapeutic option with a high cost performance. PMID- 29275489 TI - Emphysematous cystitis complicated by unilateral hydronephrosis. PMID- 29275490 TI - A retrospective comparison of three modalities for vestibuloplasty in the posterior mandible: apically positioned flap only vs. free gingival graft vs. collagen matrix. AB - OBJECTIVES: This work aimed to comparatively evaluate the three modalities of vestibuloplasty around implants in the posterior mandible. MATERIALS AND METHODS: Forty patients who presented with a shallow vestibule and insufficient keratinized gingiva were divided into three groups: apically positioned flap only (APF group), APF with free gingival graft (FGG group), and APF with collagen matrix (CM group). The width of KT was measured at baseline, immediately after surgery (T0), and 6 months (T6) and 12 months after surgery (T12). An esthetic evaluation (color match, contour, and texture) was conducted. RESULTS: Most of the shrinkage occurred within 6 months. The FGG group demonstrated less shrinkage of KT up to 12 months compared to the APF and CM groups. The APF and CM groups exhibited a prolonged and similar rate of shrinkage. The APF and CM groups also showed significantly better esthetic profiles. CONCLUSIONS: Within the limitations of the present study, FGG may be the most predictable modality for increasing KT in the posterior mandible, but it should be emphasized that the posterior mandible does not require high esthetics. CLINICAL RELEVANCE: The effect of apically positioned flap and collagen matrix may be diminished by several factors in posterior mandible, such as low vestibule and high muscle pull. For increasing the dimension of keratinized tissue in posterior mandible, conventional free gingival graft may be more predictable compared to other options. PMID- 29275491 TI - Vancomycin and tobramycin impregnated mineralized allograft for the surgical regenerative treatment of peri-implantitis: a 1-year follow-up case series. AB - OBJECTIVES: To assess the clinical and radiographic outcomes of the regenerative treatment of peri-implantitis using a vancomycin and tobramycin impregnated allograft (VTA) after a 12-month period. MATERIAL AND METHODS: Thirteen consecutive patients who required a regenerative treatment of peri-implantitis were recruited. For the 17 implant sites, a flap was raised, and after mechanical and chemical implant decontamination, a vancomycin and tobramycin impregnated allograft was placed in the defect and then covered with a collagen membrane. Soft tissues were sutured allowing a non-submerged healing. Clinical and radiographic variables were evaluated at baseline and at 12 months after treatment. RESULTS: No signs of continuous bone loss were observed and no implant was lost, yielding a 100% survival rate. All patient's clinical examination at 12 months revealed peri-implant health showing absence of suppuration and a statistically significant reduction in terms of bleeding on probing scores (70.6%, P = 0.001). Initial probing pocket depth (7.88 +/- 1.22 mm) was significantly reduced at 12 months healing, a mean reduction of 4.23 +/- 1.47 mm (P = 0.001) was achieved. The mean radiological infrabony defect at baseline reached 4.33 +/- 1.62 mm, and was significantly reduced up to 0.56 +/- 0.88 mm, which represents an 86.99 +/- 18.2% bone fill from the original infrabony defect. CONCLUSIONS: Within the limits of the study, the application of VTA with a collagen membrane yielded positive outcomes in terms of radiographic bone fill, pocket depth reduction, and attachment gain after a 12-month period. Thus, VTA plus a collagen membrane seem to be suitable for the regenerative treatment of peri-implantitis. CLINICAL RELEVANCE: The use of locally delivered antibiotic together with the bone graft may reduce the undesirable effects related to the systemic administration and the risk of resistances. In the light of the results obtained, these grafting materials might offer new treatment strategies in the surgical regenerative treatment of peri-implantitis. PMID- 29275492 TI - Comprehensive inter-comparison of INSAT multispectral rainfall algorithm estimates and TMPA 3B42-RT V7 estimates across different climate regions of India during southwest monsoon period. AB - The main objective of this study is to validate and inter-compare two Near-Real Time Satellite Rainfall Estimates (NRT-SREs): INSAT Multispectral Rainfall Algorithm (IMSRA, simple blended product) and TMPA 3B42-RT V7 (3B42-RT, multisatellite product) across India. This study aims to provide some insight into the error characteristics of both the NRT-SREs to the algorithm developers and end users by inter-comparing the daily rainfall estimates during the southwest monsoon period of 2010-2013. This study utilizes various volumetric statistics and categorical statistics to understand and evaluate the performance of NRT-SREs in terms of both spatial and volumetric error characteristics (hit, miss, and false error) at different rainfall thresholds across different Koppen Geiger climate regions of India using the gridded gauge data provided by Indian Meteorological Department as reference dataset. A detailed statistical evaluation shows that the 3B42-RT performs comparatively better than the IMSRA across India. The results indicate that both IMSRA and 3B42-RT have a general tendency of overestimating the low rainfall rates (0-2.5 mm/day) and underestimating the high rainfall rates (> 35.5 mm/day). At lower threshold values (0 and 2.5 mm/day), it is found that the miss error is dominant in IMSRA, whereas the false error is dominant in 3B42-RT. As the threshold increases (7.5 and 35.5 mm/day), both the miss and false errors increase in both SREs. Additionally, the spatial analysis of the results clearly indicate that the performance of the tested NRT-SREs is not uniform across different climatic regions, an important aspect to be considered for development/improvement of the tested NRT-SRE algorithms. PMID- 29275493 TI - Automatic Decision Support for Clinical Diagnostic Literature Using Link Analysis in a Weighted Keyword Network. AB - We present a novel approach to recommending articles from the medical literature that support clinical diagnostic decision-making, giving detailed descriptions of the associated ideas and principles. The specific goal is to retrieve biomedical articles that help answer questions of a specified type about a particular case. Based on the filtered keywords, MeSH(Medical Subject Headings) lexicon and the automatically extracted acronyms, the relationship between keywords and articles was built. The paper gives a detailed description of the process of by which keywords were measured and relevant articles identified based on link analysis in a weighted keywords network. Some important challenges identified in this study include the extraction of diagnosis-related keywords and a collection of valid sentences based on the keyword co-occurrence analysis and existing descriptions of symptoms. All data were taken from medical articles provided in the TREC (Text Retrieval Conference) clinical decision support track 2015. Ten standard topics and one demonstration topic were tested. In each case, a maximum of five articles with the highest relevance were returned. The total user satisfaction of 3.98 was 33% higher than average. The results also suggested that the smaller the number of results, the higher the average satisfaction. However, a few shortcomings were also revealed since medical literature recommendation for clinical diagnostic decision support is so complex a topic that it cannot be fully addressed through the semantic information carried solely by keywords in existing descriptions of symptoms. Nevertheless, the fact that these articles are actually relevant will no doubt inspire future research. PMID- 29275494 TI - Differences in Pediatric Headache Prescription Patterns by Diagnosis. AB - BACKGROUND: Few studies have reported prescription patterns for headache medication. OBJECTIVE: The aim was to present the rates of specific medication prescribed to pediatric patients diagnosed with migraine, tension-type headache (TTH), and new daily persistent headache (NDPH), as well as differences in those prescription patterns by diagnosis, age, and gender. PATIENTS AND METHODS: A query using the i2b2 platform yielded 14,591 patients [migraine 10,547 (72.3%); TTH 3200 (21.9%); NDPH 844 (5.8%)] seen over a 3-year period, who were aged 4-17 years at the time of their visit and diagnosed with migraine, TTH, or NDPH. RESULTS: Sumatriptan was the most frequently prescribed medication for migraine followed by amitriptyline. The most frequently prescribed medication for both TTH and NDPH was amitriptyline, followed by sumatriptan in TTH and by topiramate in NDPH. Age and gender differences were also found in prescription patterns of each of the diagnoses. The differences in prescription patterns found between the diagnoses, as well as age and gender differences found within the diagnoses, are discussed. CONCLUSIONS: A wide range of medications are prescribed to children and adolescents with headache, with most medications prescribed for off-label use. As these medications are not Food and Drug Administration (FDA) approved for use in children and adolescents with headache, there is a need for large scale, randomized controlled trials to assess the efficacy of these medications. PMID- 29275495 TI - Analysis of Laparoscopic Sleeve Gastrectomy Learning Curve and Its Influence on Procedure Safety and Perioperative Complications. AB - PURPOSE: Laparoscopic sleeve gastrectomy (LSG) has become an attractive bariatric procedure with promising treatment effects yet amount of data regarding institutional learning process is limited. MATERIALS AND METHODS: Retrospective study included patients submitted to LSG at academic teaching hospital. Patients were divided into groups every 100 consecutive patients. LSG introduction was structured along with Enhanced Recovery after Surgery (ERAS) treatment protocol. Primary endpoint was determining the LSG learning curve's stabilization point, using operative time, intraoperative difficulties, intraoperative adverse events (IAE), and number of stapler firings. Secondary endpoints: influence on perioperative complications and reoperations. Five hundred patients were included (330 females, median age of 40 (33-49) years). RESULTS: Operative time in G1-G2 differed significantly from G3-G5. Stabilization point was the 200th procedure using operative time. Intraoperative difficulties of G1 differed significantly from G2-G5, with stabilization after the 100th procedure. IAE and number of stapler firings could not be used as predictor. Based on perioperative morbidity, the learning curve was stabilized at the 100th procedure. The morbidity rates in the groups were G1, 13%; G2, 4%; G3, 5%; G4, 5%; and G5, 2%. The reoperation rate in G1 was 3%; G2, 2%; G3, 2%; G4, 1%; and G5, 0%. CONCLUSION: The institutional learning process stabilization point for LSG in a newly established bariatric center is between the 100th and 200th operation. Initially, the morbidity rate is high, which should concern surgeons who are willing to perform bariatric surgery. PMID- 29275496 TI - Dihydropyranoaurone compound damaurone D inhibits LPS-induced inflammation and liver injury by inhibiting NF-kappaB and MAPK signaling independent of AMPK. AB - Recently, we reported the synthesis of damaurone D (DD), originally derived from Rosa damascene, and its anti-inflammatory effect in macrophages. Here, we investigated the molecular mechanism underlying the anti-inflammatory effect of DD in macrophages and further tested whether DD is protective against lipopolysaccharide (LPS)-induced liver injury. DD inhibited LPS-stimulated expression of pro-inflammatory genes and cytokine/chemokine secretion in a concentration-dependent manner in RAW 264.7 cells and thioglycolate-elicited mouse peritoneal macrophages. DD suppressed LPS-stimulated nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways, as demonstrated by reduction in IkappaB kinase alpha/beta phosphorylation, IkappaBalpha degradation, and levels of phosphorylated ERK, JNK, and p38 MAPK. The luciferase reporter activity of NF-kappaB and activator protein 1 was also attenuated by DD pretreatment. Furthermore, DD treatment induced AMP-activated protein kinase (AMPK) activation in cells and mouse liver, although the anti inflammatory effect of DD was similar in dominant-negative AMPK-overexpressing cells. Lastly, DD-treated mice were protected against LPS-induced acute liver injury, based on morphologic and immunohistochemical observations; reduction in the plasma levels of aspartate aminotransferase, TNF-alpha, and MCP-1; and a decrease in inflammatory gene expression. In summary, our findings indicate that DD can protect against LPS-stimulated inflammation and liver injury at least partly by suppression of NF-kappaB and MAPK signaling pathways. PMID- 29275497 TI - Electrospun sellulose acetate membranes decorated with curcumin-PVP particles: preparation, antibacterial and antitumor activities. AB - Curcumin (Curc) exhibits anti-inflammatory, antibacterial and antitumor activity. However, its clinical application is limited by its poor bioavailability related to its extremely low water solubility. Novel materials allowing enhanced release of Curc in aqueous medium were obtained. The new materials consisted of electrospun fibers from cellulose acetate (CA) (mean fiber diameter ca. 780 nm +/ 110 nm) with electrosprayed Curc/polyvinylpyrrolidone (Curc/PVP) particles. Scanning electron microscopy (SEM) showed that separated and evenly distributed particles of Curc/PVP were deposited on the surface of the mats and on the inner layers of the mat. X-ray diffraction studies showed that Curc was in amorphous state. In vitro studies demonstrated that Curc release was facilitated from Curc/PVP-on-CA mats (ca. 78% for 24 h) compared with the materials in which Curc was incorporated in CA fibers (17% for 24 h). Moreover, the curcumin-containing materials exhibited antibacterial activity against Gram-positive bacteria Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli). Curc/PVP-on-CA fibrous mats exhibited high in vitro cytotoxicity towards HeLa tumor cells. Therefore, the obtained materials are promising for antibacterial wound dressing applications as well as for application in local treatment of cervical tumors. PMID- 29275498 TI - Multivariate analyses of the effect of an urban wastewater treatment plant on spatial and temporal variation of water quality and nutrient distribution of a tropical mid-order river. AB - Freshwater resources are increasingly scarce due to human activities, and the understanding of water quality variations at different spatial and temporal scales is necessary for adequate management. Here, we analyze the hypotheses that (1) the presence of a wastewater treatment plant (WWTP) and (2) a polluted tributary that drains downstream from the WWTP change the spatial patterns of physicochemical variables (pH, turbidity, dissolved oxygen, and electrical conductivity) and nutrient concentrations (reactive soluble phosphorus, total phosphorus, nitrogen series, total nitrogen, and total dissolved carbon) along a mid-order river in SE Brazil and that these effects depend on rainfall regime. Six study sites were sampled along almost 4 years to evaluate the impacts of human activities, including sites upstream (1-3) and downstream (5-6) from the WWTP. The impacts were observed presenting an increasing trend from the source (site 1) towards Agua Quente stream (site 4, the polluted tributary), with signs of attenuation at site 5 (downstream from both WWTP and site 4) and the river mouth (site 6). Input of nutrients by rural and urban runoff was observed mainly at sites 2 and 3, respectively. At sites 4 and 5, the inputs of both untreated and treated wastewaters increased nutrient concentrations and changed physicochemical variables, with significant impacts to Monjolinho River. Seasonal variations in the measured values were also observed, in agreement with the pluviometric indexes of the region. Univariate analyses suggested no effect of the WWTP for most variables, with continued impacts at sites downstream, but non parametric multivariate analysis indicated that these sites were recovering to chemical characteristics similar to upstream sites, apparently due to autodepuration. Therefore, multivariate methods that allow rigorous tests of multifactor hypotheses can greatly contribute to determine effects of both point and non-point sources in river systems, thus contributing to freshwater monitoring and management. PMID- 29275499 TI - Tunnel infection diagnosed by 18 F-FDG PET/CT scan. PMID- 29275500 TI - Prolonged renal allograft survival without immunosuppressive therapy. PMID- 29275502 TI - Comparison Study of the Adequacy and Pain Scale of Ultrasound-Guided Fine-Needle Aspiration of Solid Thyroid Nodules with a 21- or 23-Gauge Needle for Liquid Based Cytology: a Single-Center Study. AB - No published study has compared the cytological adequacy between different caliber needles in liquid-based cytology (LBC) after fine-needle aspiration (FNA) of thyroid nodules. This study aimed to compare cytological adequacy, pain scale, and associated complications depending on the use of a 21- and 23-gauge needle in LBC. From January 2017 to April 2017, 88 solid thyroid nodules (STNs) in 88 patients underwent consecutive ultrasonography (US)-guided FNA (US-FNA) by a single radiologist. The selection of the needle size was randomized and changed biweekly. After FNA, the pain scale and other complications related to FNA were immediately evaluated for each patient. In all cases, adequacy and cellularity in cytology were retrospectively investigated by a single cytopathologist. Of the 88 STNs, 10 (11.4%) showed inadequate cytology: 6 for 21-gauge and 4 for 23-gauge needles. The rate of cytological adequacy was higher in the 23-gauge needle group than in the 21-gauge group, but this was not statistically significant (p = 0.318). The mean values of the pain scale in the 21- and 23-gauge needle groups were 1.8 +/- 1.3 and 1.4 +/- 1.1, respectively, but this difference was not statistically significant (p = 0.567). There were no significant complications associated with US-FNA, except for one case of mild intrathyroidal hemorrhage. In US-FNA of STNs using LBC, the use of a 23-gauge needle may be recommended rather than a 21-gauge needle. PMID- 29275503 TI - Subjective and objective measures of function and return to work: an observational study with a clinical psychiatric cohort. AB - PURPOSE: To evaluate the association between two measurement tools (Social and Occupational Functioning Assessment Scale, SOFAS and Sheehan Disability Scale, SDS), returning to work (RTW) and their inter-correlation. METHODS: 132 psychiatric patients referred to assessment of work ability participated. The association between SOFAS and SDS Work to RTW were assessed by logistic regression. Inter-correlations between SOFAS and SDS were assessed with the Spearman's rho correlation coefficient. RESULTS: SOFAS and SDS Work scores were associated with a 1-year RTW and SOFAS and SDS were inter-correlated. CONCLUSIONS: When assigning the ability to work, both subjective and objective measures of function predict RTW. PMID- 29275501 TI - Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO--MMP-9 Pathway. AB - Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation. PMID- 29275504 TI - Aedes albopictus (Skuse, 1895) (Diptera: Culicidae) in Greece: 13 years of living with the Asian tiger mosquito. AB - Aedes (Stegomyia) albopictus (Skuse, 1895) (Diptera: Culicidae), commonly known as the Asian tiger mosquito, is an invasive mosquito species of public health significance, well established in many countries worldwide. In Greece, it was first recorded in Corfu and Thesprotia between 2003 and 2004. In the following years, further distribution and establishment of Ae. albopictus in Greece have been confirmed in many Regional Units of the country. In the current study, we report the invasion history of Ae. albopictus in Greece, until 2016. The results from the entomological investigation following imported virus cases in 2014, 2015, and 2016 are also included. Moreover, its presence in Greece is demonstrated in a thematic map based on (a) information provided by pest control companies and/or citizens, (b) the official samples sent to Benaki Phytopathological Institute (BPI) and the National School of Public Health (NSPH), and PMID- 29275505 TI - The impact of a mind-body program on multiple dimensions of resiliency among geographically diverse patients with neurofibromatosis. AB - The neurofibromatoses (NF) are incurable genetic disorders that can cause nerve sheath tumors, chronic pain, and disfiguration. Patients with NF report lower quality of life and greater distress, and may benefit from programs that promote resiliency. To test effects of an 8-week mind-body program (Relaxation Response Resiliency Program for NF [3RP-NF]) on resiliency, using data derived from a larger randomized controlled trial of the 3RP-NF versus attention placebo control (Vranceanu et al. in Neurology 87:806-814, 2016). Participants (N = 63; 46 female; 52 White) were randomized to 3RP-NF (n = 32, M age = 42.86) or control (n = 31, M age = 39.90), completed intervention sessions via group videoconferencing, and provided self-report measures of resiliency (i.e., perceived coping abilities, perceived social support, gratitude, optimism, spiritual well-being, mindfulness) at baseline, post-intervention, and 6-month follow-up. All participants attended at least 6/8 sessions and 83% (N = 52) provided 6-month follow-up data. The 3RP-NF (vs. control) produced greater improvements from pre- to post-intervention in perceived coping abilities (M difference = 6.68; p = .008), perceived social support (M difference = 9.16; p = .032), and mindfulness (M difference = 2.23; p = .035), which were maintained at 6-month follow up. We did not observe group differences in spiritual well-being, optimism, or gratitude. The 3RP-NF produced sustained increases in multiple dimensions of resiliency (perceived coping abilities, perceived social support, and mindfulness). Promoting resiliency may be particularly important for a population that is underserved and living with a chronic, incurable illness. PMID- 29275506 TI - Safety and efficacy using a low-powered holmium laser for enucleation of the prostate (HoLEP): 12-month results from a prospective low-power HoLEP series. AB - PURPOSE: To analyze the 12-month outcomes of low-powered holmium laser enucleation of the prostate (LP-HoLEP) for patients with symptomatic benign prostatic obstruction (BPO). METHODS: A total of 54 patients with symptomatic BPO were treated with LP-HoLEP. All patients were treated by two experienced LP-HoLEP surgeons. A 50-W Ho:YAG laser was used at 39.6-W (2.2 J, 18 Hz). All patients were assessed preoperatively by International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), post-void residual urine (PVR), PSA, and whole prostate volume measurement by transrectal ultrasound. The patients were reassessed at 1-, 6-, and 12-month follow-up. The complications were classified according to the modified Clavien classification system. Patient data were expressed as median (interquartile range) or numbers (%). RESULTS: The median age was 72.5 (67-77.25) years and the median preoperative prostate volume 74.5 (45-110) ml. 12 (22.2%) patients were treated with ongoing anticoagulant treatment. The median operative time was 65 (41-81) min and the enucleation efficiency 1.11 (0.82-1.79) g/min, respectively. Clavien 1 (11.1%), Clavien 2 (3.7%), Clavien 3a (3.7%), and Clavien 3b (5.5%) complications occurred. At 6 month follow-up, median prostate volume (74.5 vs. 15.5 ml) and PSA (4.03 vs. 0.54 ug/l) had improved significantly compared to baseline (p <= 0.009). At 12-month follow-up, Qmax (12 vs. 29.3 ml/s), PVR (155 vs. 11.15 ml), IPSS (22 vs. 6) and QoL (5 vs. 1) had improved significantly (p < 0.001). CONCLUSIONS: LP-HoLEP is technically feasible, safe and effective for the treatment of symptomatic BPO. For experienced surgeons, power is less relevant than technique. PMID- 29275507 TI - A 12-year follow-up of ANNA/C-TRUS image-targeted biopsies in patients suspicious for prostate cancer. AB - PURPOSE: PSA screening has been rehabilitated. PSA is not specific and can be elevated by benign reasons. Additionally, a subgroup of patients with prostate hyperplasia may harbor prostate cancer (PCa). During monitoring, the clinician aims to detect significant tumors in time, submitting patients to minimal psychological and physical burden, especially in men with high serum PSA and repeat biopsies. We aimed to determine long-term outcomes with respect to ANNA/C TRUS ability to detect PCa with six targeted biopsies. METHODS: A subset of 71 patients were enrolled. During monitoring, they were subjected to primary, secondary, or even multiple prostate biopsies when needed. Protocol monitoring included PSA measurements, digital rectal examination (DRE) and imaging. RESULTS: The median follow-up was 12 years. Forty-one patients had a history of negative systematic random biopsies (1-3 sessions). Their age ranges 62-85 years, PSA 0.5 47.3 ng/ml, and the median prostate volume 11-255 cc. During monitoring, 15 patients were diagnosed with PCa. Only two harbored aggressive tumors. The median time to diagnosis was 6 years. All PCa patients are free from biochemical relapse. From the remaining 56 patients, 11 did not have any biopsies, 12 had one, 13 had two, and 20 had three or more biopsy sessions. CONCLUSIONS: ANNA/C TRUS is a useful method monitoring patients with a risk of PCa. 50-75% of the usually performed biopsy cores could be spared and, after 12 years, 97% of the patients were either without evidence of a PCa or were diagnosed with a good prognosis tumor. PMID- 29275508 TI - Preparation of electrospun polyurethane nanofiber mats for the release of doxorubicine. AB - Polyurethane (PU) and doxorubicine loaded-PU nanofiber mats were prepared by the electrospinning technique. The effect of some system and process parameters including flow rate, distance from collector, and concentration of solution on the size and morphology of nanofibers was investigated. The size, morphology and drug content of nanofiber mats were followed by scanning electron microscopy (SEM). FTIR and TGA methods were used for structural and thermal characterization, and DSC was also used for determining the form of drug within nanofiber mat. Doxorubicine release kinetics were studied in two different pHs (4.5 and 7.5) for two drug content and it was observed that there is an inverse correlation between the amounts of drug loaded and released. PMID- 29275509 TI - Examining the Links Between Challenging Behaviors in Youth with ASD and Parental Stress, Mental Health, and Involvement: Applying an Adaptation of the Family Stress Model to Families of Youth with ASD. AB - Raising a child with autism spectrum disorder (ASD) poses unique challenges that may impact parents' mental health and parenting experiences. The current study analyzed self-report data from 77 parents of youth with ASD. A serial multiple mediation model revealed that parenting stress (SIPA) and parental mental health (BAI and BDI-II) appears to be impacted by challenging adolescent behaviors (SSIS PBs) and, in turn, affect parental involvement (PRQ), controlling for social skills (SSIS-SSs). Further, the study explored the malleability of parents' mental health over the course of a social skills intervention, and provides modest evidence that parent depressive symptoms decline across intervention. This study illustrates the importance of considering the entire family system in research on youth with ASD. PMID- 29275510 TI - Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. AB - Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 uM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 MUM BPA had no effects on cell viability, but increased cytoplasmic expression of ERbeta and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFkappaB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 uM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 MUM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases. PMID- 29275511 TI - Successful limb salvage from critical limb ischemia with bilateral variant anatomy of infrapopliteal arteries. PMID- 29275512 TI - Understanding and monitoring brain injury: the role of cerebral microdialysis. PMID- 29275513 TI - Emphysematous pyelonephritis class IV. PMID- 29275514 TI - Correction to: Cerebrovascular CO2 reactivity during isoflurane-nitrous oxide anesthesia in patients with chronic renal failure. AB - In the original publication of the article, the first sentence was published incorrectly under the section "Patients and preoperative assessment". The correct sentence should read as, "The Yamaguchi University Graduate School of Medicine Ethics Committee for Human Study approved the study protocol (18th August 2004: H16-71)". PMID- 29275515 TI - Future trials on endovascular stroke treatment: the not-so-easy-to-pluck fruits. PMID- 29275516 TI - Report of the 12th Sphingolipid Club Meeting, Trabia, Italy (Sept. 7-10, 2017). AB - We present here a report of the 12th Sphingolipid Club Meeting held in Trabia, Italy, on September 7-10, 2017. The meeting accounted for the presence of 120 young and senior scientists, coming from both European and overseas countries, interested in the sphingolipid field. The scientific program consisted in a total of 41 oral and 26 poster presentations. The participants contributed actively with formal discussions and informal exchange of views all along the meeting. The original results presented confirm the importance of sphingolipid in both physiological and pathological situations, and offer a promising platform to suggest innovative therapeutic strategies for different diseases. PMID- 29275517 TI - Sarsasapogenin suppresses Abeta overproduction induced by high glucose in HT-22 cells. AB - The aim of this study is to investigate effects and potential mechanisms of sarsasapogenin (Sar), an active component purified from Rhizoma Anemarrhenae, on high glucose-induced amyloid-beta (Abeta) peptide overproduction in HT-22 cells. HT-22 cells were divided into normal glucose; high glucose (HG); HG co-treated with low, middle, and high concentration of Sar (1, 5, 25 MUmol/L); and peroxisome proliferator-activated receptor gamma (PPARgamma) agonist (10 MUmol/L pioglitazone). After treatment for 24 h, protein expression of Abeta and beta site Abeta precursor protein cleaving enzyme 1 (BACE1) and activated PPARgamma level were determined by Western blot; Abeta42 levels were also measured by using both immunofluorescence and ELISA methods. BACE1 activity and mRNA level were assessed by fluorospectrophotometry and quantitative PCR, respectively. Cell viability was assayed with a CCK-8 kit. Elevated Abeta expression and Abeta42 level were found in HG-treated HT-22 cells, accompanied by increased BACE1 protein and mRNA levels as well as enzymatic activity, which was markedly attenuated by three concentrations of Sar and pioglitazone. Moreover, HG reduced nuclear PPARgamma levels, which was reversed by middle and high concentrations of Sar as well as pioglitazone. PPARgamma antagonist GW9662 (20 MUmol/L) pretreatment reversed the effect of Sar on BACE1 protein expression in HG cultured HT-22 cells. Additionally, Sar suppressed HG-induced decreases in cell viability of HT-22 cells. High glucose can induce an increase in Abeta levels and a decrease in cell viability in HT-22 cells, while co-treatment with Sar improves these results, which is mediated likely through activation of PPARgamma and subsequent downregulation of BACE1. PMID- 29275518 TI - Borders of STN determined by MRI versus the electrophysiological STN. A comparison using intraoperative CT. AB - BACKGROUND: It is unclear which magnetic resonance imaging (MRI) sequence most accurately corresponds with the electrophysiological subthalamic nucleus (STN) obtained during microelectrode recording (MER, MER-STN). CT/MRI fusion allows for comparison between MER-STN and the STN visualized on preoperative MRI (MRI-STN). OBJECTIVE: To compare dorsal and ventral STN borders as seen on 3-Tesla T2 weighted (T2) and susceptibility weighted images (SWI) with electrophysiological STN borders in deep brain stimulation (DBS) for Parkinson's disease (PD). METHODS: Intraoperative CT (iCT) was performed after each MER track. iCT images were merged with preoperative images using planning software. Dorsal and ventral borders of each track were determined and compared to MRI-STN borders. Differences between borders were calculated. RESULTS: A total of 125 tracks were evaluated in 45 patients. MER-STN started and ended more dorsally than respective dorsal and ventral MRI-STN borders. For dorsal borders, differences were 1.9 +/- 1.4 mm (T2) and 2.5 +/- 1.8 mm (SWI). For ventral borders, differences were 1.9 +/- 1.6 mm (T2) and 2.1 +/- 1.8 mm (SWI). CONCLUSIONS: Discrepancies were found comparing borders on T2 and SWI to the electrophysiological STN. The largest border differences were found using SWI. Border differences were considerably larger than errors associated with iCT and fusion techniques. A cautious approach should be taken when relying solely on MR imaging for delineation of both clinically relevant STN borders. PMID- 29275519 TI - Investigation of the usefulness of fluorescein sodium fluorescence in stereotactic brain biopsy. AB - BACKGROUND: Intraoperative frozen section assessment, to confirm acquisition of pathological tissues, is used in stereotactic brain biopsy to minimise sampling errors. Limitations include the dependence on dedicated neuro-oncology pathologists and an increase in operative duration. We investigated the use of intraoperative fluorescein sodium, and compared it to frozen section assessment, for confirming pathological tissue samples in the stereotactic biopsy of gadolinium-contrast-enhancing brain lesions. METHODS: This prospective observational study consisted of 18 consecutive patients (12 men; median age, 63 years) who underwent stereotactic biopsy of gadolinium-contrast-enhancing brain lesions with intravenous fluorescein sodium administration. Twenty-three specimens were obtained and examined for the presence of fluorescence using a microscope with fluorescence visualisation capability. Positive and negative predictive values were calculated based on the fluorescence status of the biopsy samples with its corresponding intraoperative frozen section and definitive histopathological diagnosis. RESULTS: Nineteen specimens (83%) were fluorescent and four (17%) were non-fluorescent. All 19 fluorescent specimens were confirmed to be lesional on intraoperative frozen section assessment and were suitable for histopathological diagnosis. Three of the non-fluorescent specimens were confirmed to be lesional on intraoperative frozen section assessment. One non fluorescent specimen was non-diagnostic on frozen section and histological assessments. The positive predictive value was 100% and the negative predictive value was 25%. CONCLUSIONS: Fluorescein sodium fluorescence is as accurate as frozen section assessment in confirming sampling of pathological tissue in the stereotactic biopsy of gadolinium-contrast-enhancing brain lesions. Fluorescein sodium fluorescence-guided stereotactic biopsy is a useful addition to the neurosurgical armamentarium. PMID- 29275520 TI - Probiotic strain Stenotrophomonas acidaminiphila BJ1 degrades and reduces chlorothalonil toxicity to soil enzymes, microbial communities and plant roots. AB - Chlorothalonil, a non-systemic and broad-spectrum fungicide, is widely used to control the pathogens of agricultural plants. Although microbial degradation of chlorothalonil is known, we know little about the colonization and degradation capacity of these microbes in the natural and semi-natural soil environments. Therefore, we studied the colonization and detoxification potential of a chlorothalonil degrading Stenotrophomonas acidaminiphila probiotic strain BJ1 in the soil under green conditions. The results from polymerase chain reaction denaturing gradient gel electrophoresis demonstrated that probiotic strain BJ1 successfully colonized the soil by competing with the native biota. Moreover, the bacterial inoculation stimulated some members of indigenous soil microbial communities. Meantime, the degradation half-life of chlorothalonil decreased from 9.0 to 4.9 days in the soil environment. Moreover, the results from enzymatic activities and micronucleus test of Vicia faba root tips showed that the probiotic strain BJ1 reduced the ecotoxicity and genotoxicity of chlorothalonil in the soil. We suggest that probiotic strains like BJ1 could potentially alleviate the toxic effects of pesticides on soil microbes and plant roots under greenhouse conditions. PMID- 29275521 TI - Answer to the letter to the editor of M.N. Capoor et al. concerning "Ribosomal PCR assay of excised intervertebral discs from patients undergoing single-level primary lumbar microdiscectomy'' by Alamin TF, Munoz M, Zagel A, et al.: Eur Spine J; 2017. PMID- 29275522 TI - Intraoperative total spinal anesthesia as a complication of posterior percutaneous endoscopic cervical discectomy. AB - PURPOSE: Percutaneous endoscopic cervical discectomy (PECD) is an emerging surgical treatment for cervical disc herniation in recent years, but the complications of PECD are rarely reported. In this case report, we aimed to report two cases of total spinal anesthesia, an unusual complication of PECD. METHODS AND RESULTS: One patient became unconscious with unstable vital signs and another patient appeared with numbness of both arms and legs during PECD operation. CONCLUSIONS: From these two cases, we concluded that the operation of anchoring during PECD should be cautious and standardized, intravenous anesthesia should be chosen to enhance intraoperative anesthesia to prevent intraoperative total spinal anesthesia. PMID- 29275523 TI - Obstructive sleep apnea is associated with interdialytic weight gain and increased long-term cardiovascular events in hemodialysis patients. AB - BACKGROUND: Obstructive sleep apnea (OSA) is common in hemodialysis (HD) patients. The reasons for the high prevalence and whether OSA is associated with vascular impairment, end-organ damage, and prognosis are not completely clear. METHODS: We evaluated patients with low cardiovascular risk on HD, not treated by CPAP. Laboratory tests, sleep questionnaires (Berlin and Epworth) and polysonography studies, echocardiography, and markers of arterial stiffness and atherosclerosis were performed. After the initial evaluation, patients were followed up until cardiovascular events, renal transplantation, or death. RESULTS: Fifty-five patients (49% male, 50 +/- 9 years, body mass index 24.7 +/- 4.5 kg/m2) were included. OSA (apnea-hypopnea index >= 5 events/h) occurred in 73% of the patients. The proportion of patients with interdialytic weight gain > 2 kg was higher in patients with OSA than those without OSA (96 vs. 55%; p = 0.002). Left ventricular (LV) posterior wall thickness (10.0 +/- 1.9 vs. 11.3 +/- 1.8 mm; p = 0.04) and LV diastolic diameter (48 +/- 5 vs. 53 +/- 5 mm; p = 0.003) were higher in patients with OSA than in patients without OSA, respectively. Sleep questionnaires did not predict OSA. No significant differences were found in pulse wave velocity, carotid intima-media thickness, and ankle-brachial index between the groups. Multivariate analysis showed that interdialytic weight gain > 2 kg and LV diastolic diameter were independently associated with OSA. On follow up (median 45 months), OSA was found to be associated with a higher incidence of cardiovascular (CV) events (28 vs. 7%, log-rank = 0.042). CONCLUSIONS: OSA was associated with increased risk of CV events. Significant (> 2 kg) interdialytic weight gain was independently associated with OSA. PMID- 29275524 TI - Digestive toxicities after palliative three-dimensional conformal radiation therapy (3D-CRT) for cervico-thoracic spinal metastases. AB - OBJECTIVE: The palliative treatment for cervico-thoracic spinal metastases is based on a three-dimensional conformal radiation therapy (3D-CRT). Digestive toxicities are common and cause a clinical impact frequently underestimated in patients. We performed a retrospective study of digestive side effects occurring after palliative 3D-CRT for cervico-thoracic spinal metastases. PATIENTS AND METHODS: All patients receiving palliative 3D-CRT at Jean Bernard Center from January 2013 to December 2014 for spinal metastases between the 5th cervical vertebra (C5) and the 12th thoracic vertebra (T12) were eligible. Three dimensional conformal RT was delivered by a linear accelerator (CLINAC, Varian). Premedication to prevent digestive toxicities was not used. Adverse events ("esophagitis" and "nausea and/or vomiting") were evaluated according to the NCI CTCae (version 4). RESULTS: From January 2013 to December 2014, 128 patients met the study criteria. The median age was 68.6 years [31.8; 88.6]. Most patients (84.4%) received 30 Gy in 10 fractions. The median overall time of treatment was 13 days [3-33]. Forty patients (31.3%) suffered from grade >= 2 of "esophagitis" (35 grade 2 (27.4%) and 5 grade 3 (3.9%)). Eight patients (6.3%) suffered from grade >= 2 of "nausea and/or vomiting" (6 grade 2 (4.7%), 1 grade 3 (0.8%), and 1 grade 4 (0.8%)). CONCLUSION: The high incidence of moderate to severe digestive toxicities after palliative 3D-CRT for cervico-thoracic spinal metastases led to consider static or dynamic intensity-modulated radiation therapy (IMRT) to reduce the dose to organ at risk (the esophagus and stomach). Dosimetric studies and implementation in the clinic should be the next steps. PMID- 29275525 TI - A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer. AB - PURPOSE: This observational case registry study was designed to describe the natural history of cancer patients with medication-related osteonecrosis of the jaw (ONJ) and evaluate the ONJ resolution rate. METHODS: Adults with a diagnosis of cancer and with a new diagnosis of ONJ were enrolled and evaluated by a dental specialist at baseline and every 3 months for 2 years and then every 6 months for 3 years until death, consent withdrawal, or loss to follow-up. The primary endpoint was the rate and time course of ONJ resolution. Secondary endpoints included frequency of incident ONJ risk factors, ONJ treatment patterns, and treatment patterns of antiresorptive agents for subsequent ONJ. RESULTS: Overall, 327 patients were enrolled; 207 (63%) were continuing on study at data cutoff. Up to 69% of evaluable patients with ONJ had resolution or improvement during the study. ONJ resolution (AAOMS ONJ staging criteria) was observed in 114 patients (35%); median (interquartile range) time from ONJ onset to resolution was 7.3 (4.5-11.4) months. Most patients (97%) had received antiresorptive medication before ONJ development, 9 patients (3%) had not; 68% had received zoledronic acid, 38% had received denosumab, and 10% had received pamidronate (56% had received bisphosphonates only, 18% had received denosumab only, and 21% had exposure to both). CONCLUSIONS: These results are consistent with those observed in clinical trials evaluating skeletal-related events in patients with advanced malignancy involving bone. Longer follow-up will provide further information on ONJ recurrence and resolution rates between medically and surgically managed patients. PMID- 29275526 TI - Integrative Application of Life Cycle Assessment and Risk Assessment to Environmental Impacts of Anthropogenic Pollutants at a Watershed Scale. AB - Intense human activities have led to increasing deterioration of the watershed environment via pollutant discharge, which threatens human health and ecosystem function. To meet a need of comprehensive environmental impact/risk assessment for sustainable watershed development, a biogeochemical process-based life cycle assessment and risk assessment (RA) integration for pollutants aided by geographic information system is proposed in this study. The integration is to frame a conceptual protocol of "watershed life cycle assessment (WLCA) for pollutants". The proposed WLCA protocol consists of (1) geographic and environmental characterization mapping; (2) life cycle inventory analysis; (3) integration of life-cycle impact assessment (LCIA) with RA via characterization factor of pollutant of interest; and (4) result analysis and interpretation. The WLCA protocol can visualize results of LCIA and RA spatially for the pollutants of interest, which might be useful for decision or policy makers for mitigating impacts of watershed development. PMID- 29275527 TI - Attraction of Male Nymphs to Adult Male Volatiles in the Bronze Bug Thaumastocoris peregrinus Carpintero & Dellape (Heteroptera: Thaumastocoridae). AB - The bronze bug, Thaumastocoris peregrinus Carpintero & Dellape (Heteroptera: Thaumastocoridae), is an exotic emerging pest in Eucalyptus commercial forests in South America, Africa and southern Europe. Information on the chemical communication system and reproductive ecology of this insect is scant, and it may be relevant for designing management strategies for eucalypt plantations. Adults and nymphs usually aggregate in the field, possibly by means of chemical signals. Males emit large amounts of 3-methyl-2-butenyl butyrate, which attracts conspecific adult males but not females. The ecological role of this putative male aggregation pheromone remains unknown. Here, we report olfactometer bioassays showing that late-instar male nymphs are also attracted to synthetic 3 methyl-2-butenyl butyrate and to adult male volatile extracts, which contain this compound as the major component. As previously shown for adult females, nymphs that moulted into females were not attracted to either volatile stimulus. The intra-gender attraction of nymphs and adults may be related to the exploitation of food resources, or as a reproductive strategy for newly emerged males. Further studies on the reproductive behaviour and mating system of T. peregrinus will contribute to understanding the ecological significance of male-male, adult-nymph attraction, as well as the practical applications that may result from these findings. PMID- 29275528 TI - Lymph node dissection during radical cystectomy following prior radiation therapy: results from the SEER database. AB - PURPOSE: Population studies of patients undergoing radical cystectomy (RC) for bladder cancer (BC) suggest that a more extended lymph node dissection (LND) increases survival. However, information regarding LNDs of patients undergoing RC with a history of radiation therapy for BC is largely unknown. This study aims to define the lymph node yield (LNY) in patients undergoing RC for BC following radiation of the bladder using the surveillance epidemiology and end results (SEER) database. METHODS: Data were collected using SEER 18 registries from 1988 to 2013 to identify patients undergoing RC for BC. Data on extent and yield of LND were obtained. Logistic regression and multivariate Cox proportional hazard regression were done to identify predictors of adequate LND and all-cause mortality, respectively. RESULTS: In total, 27,451 patients were identified, of which, 27,362 (99.7%) were radiation naive and 89 (0.3%) had prior radiation therapy for BC. The average LNY in radiation naive patients (15, SD [13.5]) was slightly higher than the LNY in patients with prior radiation (12.3 SD [9.2], p = 0.157). Prior radiation was not an independent predictor of overall mortality (HR = 1.3, 95% CI [0.98-1.7]; p = 0.076). CONCLUSIONS: A lower proportion of patients with a history of radiation underwent a LND. The LNYs of radiation naive patients, and those with a history of radiation, were not statistically different; however, the proportion of irradiated patients was small. Further investigation will be required to elucidate the patient and provider characteristics that contribute to the similar LNYs. PMID- 29275529 TI - Bilateral multiple exudative retinal detachments and macular edema in a patient diagnosed with synthetic cannabinoid (Bonzai) intoxication. AB - PURPOSE: To report the first case of a patient with bilateral multiple exudative retinal detachments and macular edema after smoking Bonzai. METHODS: A 17-year old girl presented with a complaint of a sudden onset of reduced vision in both eyes. She was admitted to the emergency service 3 days ago with the symptoms of hallucination and convulsion and diagnosed with synthetic cannabinoid intoxication. RESULTS: After consultation with an internal medicine specialist, intravenous fluid treatment was initiated. Laboratory findings resolved rapidly and recovery of fundus findings was achieved at 6 months of follow-up. CONCLUSIONS: Synthetic cannabinoid abuse has been increasing in young populations in recent years and has become an important health concern. It is important for health providers to be aware of ocular signs and symptoms of intoxication. PMID- 29275531 TI - Renal phosphate handling and inherited disorders of phosphate reabsorption: an update. AB - Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na+-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH)2 vitamin D3 as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date. PMID- 29275530 TI - Histopathological classification of non-functioning pituitary neuroendocrine tumors. AB - Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify "high-risk adenomas." A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification. PMID- 29275533 TI - Correction to: Insulin and osteocalcin: further evidence for a mutual cross-talk. AB - Correction to: Endocrine https://doi.org/10.1007/s12020-017-1396-0 The article Insulin and osteocalcin: further evidence for a mutual cross-talk, written by Francesco L. Bilotta, Biagio Arcidiacono, Sebastiano Messineo, Marta Greco, Eusebio Chiefari, Domenico Britti, Tomoko Nakanishi, Daniela P. Foti, Antonio Brunetti, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 2 September 2017 without open access. PMID- 29275532 TI - Tyrosine kinase inhibitors in iodine-refractory differentiated thyroid cancer: experience in clinical practice. AB - PURPOSE: The aim of this study is to describe our clinical experience with tyrosine kinase inhibitors (TKIs) and to evaluate their efficacy and tolerability in patients with iodine-refractory differentiated thyroid cancer (DTC). METHODS: There were 17 patients (47.1% women, mean age: 65.7) with DTC iodine-refractory (9 papillary, 2 follicular and 3 Hurthle cell), treated with TKIs: 16 with sorafenib and 1 with lenvatinib as first-line treatment; 7 required second-line treatment (4 lenvatinib and 3 axitinib). Primary endpoints were progression-free survival (PFS) and radiographic response (determinate at 3, 6, 12, 18, and 24 months after the initiation of treatment) and second endpoints were determining differences in baseline characteristics depending on clinical course and describing toxicities and tolerability. RESULTS: Median PFS was 18 months. During the first 24 months of treatment with TKIs PR rate was 35.3% (only 5.8% >= 6 months) and SD >= 6 months was observed in 58.8%. There were no significant differences in baseline characteristics between patients with good and poor evolution. Adverse events (AEs) were present in 100% of patients, but most of them were grade 1 and 2. CONCLUSIONS: In our population of patients with iodine refractory DTC, treatment with sorafenib, lenvatinib, and axitinib allows the stabilization of the disease in a high percentage of cases, with acceptable tolerability. PMID- 29275535 TI - Correction to: Detectable Neuropsychological Differences in Early Preclinical Alzheimer's Disease: a Meta-Analysis. AB - Errors were discovered in the reporting of processing speed data that do not impact the interpretation of findings. PMID- 29275534 TI - Skeletal fragility induced by overtreatment of adrenal insufficiency. PMID- 29275536 TI - Palladium-Catalyzed Synthesis of (E)-5-(3-Aminoallyl)-Uridine-5'-O-Triphosphates. AB - This unit describes a simple, reliable, and efficient chemical method for the synthesis of 5-(3-aminoallyl)-2'-deoxyuridine-5'-O-triphosphate (AA-dUTP) and 5 (3-aminoallyl)-uridine-5'-O-triphosphate (AA-UTP), starting from the corresponding nucleoside triphosphate. The presented strategy involves regioselective iodination of nucleoside triphosphate using N-iodosuccinimide followed by the palladium-catalyzed Heck coupling with allylamine to provide the corresponding (E)-5-aminoallyl-uridine-5'-O-triphosphate in good yields. It is noteworthy that the protocol not only provides a high-purity product but also eliminates the use of toxic mercuric reagents. (c) 2017 by John Wiley & Sons, Inc. PMID- 29275537 TI - 3'-O-Caged 2'-Deoxynucleoside Triphosphates for Light-Mediated, Enzyme-Catalyzed, Template-Independent DNA Synthesis. AB - Synthesis, purification, and characterization of 3'-O-caged 2' deoxyribonucleoside triphosphates (dNTPs), namely 3'-O-(2-nitrobenzyl)-2'-deoxy ribonucleoside triphosphates (NB-dNTPs) and 3'-O-(4,5-dimethoxy-2-nitrobenzyl)-2' deoxy ribonucleoside triphosphates (DMNB-dNTPs), are discussed in detail. A total of eight 3'-O-caged dNTPs are synthesized with specific protocols depending on the nitrogenous base on the first carbon, i.e., adenine, guanine, thymine, and cytosine, as well as the photo-cleavable group, i.e, 2-nitrobenzyl and 4,5- dimethoxy-2-nitrobenzyl, to be attached in the 3'-O position. The purification of the synthesized compounds is done using ion-exchange and flash chromatography; this is followed by structural confirmation by nuclear magnetic resonance (NMR) and mass spectroscopy (MS). The efficiency of the designed compounds is tested by conducting and evaluating UV-cleaving experiments at 365 nm with proton NMR and LC-MS curves. Finally, the application of the 3'-O-cagged dNTPs in template independent, enzyme-catalyzed, photo-mediated oligonucleotide synthesis is demonstrated. (c) 2017 by John Wiley & Sons, Inc. PMID- 29275538 TI - Practical Synthesis of 4'-Thioribonucleosides from L-Arabinose via Novel Reductive Ring-Contraction Reaction and Pummerer-Type Thioglycosylation. AB - The detailed practical synthesis of 4'-thionucleosides starting from L-arabinose is described here. 1,4-Anhydro-2,3-O-isopropylidene-4-thioribitol, which is the key intermediate for the synthesis of 4'-thionucleosides, is obtained from L arabinose in several steps, including a novel reductive ring-contraction reaction. After oxidation of the key intermediate, the sulfoxide is subjected to Pummerer-type thioglycosylation in the presence of persilylated nucleobases to obtain the 4'-thioribonucleosides in good yield and beta-selectively. (c) 2017 by John Wiley & Sons, Inc. PMID- 29275539 TI - Synthesis of Bipartite Tetracysteine PNA Probes for DNA In Situ Fluorescent Labeling. AB - "Label-free" fluorescent probes that avoid additional steps or building blocks for conjugation of fluorescent dyes with oligonucleotides can significantly reduce the time and cost of parallel bioanalysis of a large number of nucleic acid samples. A method for the synthesis of "label-free" bicysteine-modified PNA probes using solid-phase synthesis and procedures for sequence-specific DNA in situ fluorescent labeling is described here. The concept is based on the adjacent alignment of two bicysteine-modified peptide nucleic acids on a DNA target to form a structurally optimized bipartite tetracysteine motif, which induces a sequence-specific fluorogenic reaction with commercially available biarsenic dyes, even in complex media such as cell lysate. This unit will help researchers to quickly synthesize bipartite tetracysteine PNA probes and carry out low-cost DNA in situ fluorescent labeling experiments. (c) 2017 by John Wiley & Sons, Inc. PMID- 29275540 TI - Synthesis of beta-Nicotinamide Riboside Using an Efficient Two-Step Methodology. AB - A two-step chemical method for the synthesis of beta-nicotinamide riboside (NR) is described. NR has achieved wide use as an NAD+ precursor (vitamin B3) and can significantly increase central metabolite NAD+ concentrations in mammalian cells. beta-NR can be prepared with an efficient two-step procedure. The synthesis is initiated via coupling of commercially available 1,2,3,5-tetra-O-acetyl-beta-D ribofuranose with ethyl nicotinate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). 1 H NMR showed that the product was formed with complete stereoselectivity to produce only the beta-isomer in high yield (>90% versus starting sugar). The clean stereochemical result suggests that the coupling proceeds via a cationic cis-1,2-acyloxonium-sugar intermediate, which controls addition by nucleophiles to generate predominantly beta-stereochemistry. The subsequent deprotection of esters in methanolic ammonia generates the desired product in 85% overall yield versus sugar. (c) 2017 by John Wiley & Sons, Inc. PMID- 29275541 TI - Human polyomavirus-7-associated eruption successfully treated with acitretin. AB - Advances in molecular technologies have led to the discovery of several novel human polyomaviruses (HPyVs), including human polyomavirus-7 (HPyV-7). Although low levels of HPyV-7 are shed from apparently normal skin, recent reports have described clinically significant cutaneous infection in immunocompromised patients that manifests as generalized pruritic plaques. The pruritus can be severe, and treatment options have not been described. Herein we report HPyV-7 cutaneous infection in a heart transplant patient who experienced temporary improvement with intravenous cidofovir, and complete remission with acitretin. We report a case of HPyV-7 cutaneous infection demonstrating a good response to treatment. PMID- 29275542 TI - The influence of socioeconomic deprivation on outcomes in pancreas transplantation in England: Registry data analysis. AB - Socioeconomic deprivation is associated with poorer outcomes in chronic diseases. The aim of this study was to investigate the effect of socioeconomic deprivation on outcomes following pancreas transplantation among patients transplanted in England. We included all 1270 pancreas recipients transplanted between 2004 and 2012. We used the English Index of Multiple Deprivation (EIMD) score to assess the influence of socioeconomic deprivation on patient and pancreas graft survival. Higher scores mean higher deprivation status. Median EIMD score was 18.8, 17.7, and 18.1 in patients who received simultaneous pancreas and kidney (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA), respectively (P = .56). Pancreas graft (censored for death) survival was dependent on the donor age (P = .08), cold ischemic time (CIT; P = .0001), the type of pancreas graft (SPK vs. PAK or PTA, P = .0001), and EIMD score (P = .02). The 5-year pancreas graft survival of the most deprived patient quartile was 62% compared to 75% among the least deprived (P = .013), and it was especially evident in the SPK group. EIMD score also correlated with patient survival (P = .05). When looking at the impact of individual domains of deprivation, we determined that "Environment" (P = .037) and "Health and Disability" (P = .035) domains had significant impact on pancreas graft survival. Socioeconomic deprivation, as expressed by the EIMD is an independent factor for pancreas graft and patient survival. PMID- 29275543 TI - Biophotonics: the big picture. AB - The 5th International Conference on Biophotonics (ICOB) held April 30 to May 1, 2017, in Fremantle, Western Australia, brought together opinion leaders to discuss future directions for the field and opportunities to consider. The first session of the conference, "How to Set a Big Picture Biophotonics Agenda," was focused on setting the stage for developing a vision and strategies for translation and impact on society of biophotonic technologies. The invited speakers, panelists, and attendees engaged in discussions that focused on opportunities and promising applications for biophotonic techniques, challenges when working at the confluence of the physical and biological sciences, driving factors for advances of biophotonic technologies, and educational opportunities. We share a summary of the presentations and discussions. Three main themes from the conference are presented in this position paper that capture the current status, opportunities, challenges, and future directions of biophotonics research and key areas of applications: (1) biophotonics at the nano- to microscale level; (2) biophotonics at meso- to macroscale level; and (3) biophotonics and the clinical translation conundrum. PMID- 29275545 TI - Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood-brain barrier: mechanisms of brain clearing. AB - The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood-brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels. We first demonstrate successful application of optical coherence tomography (OCT) for imaging of the lymphatic vessels in the meninges after opening of the BBB, which might be a new useful strategy for noninvasive analysis of lymphatic drainage in daily clinical practice. Also, we give information about the depth and size of the meningeal lymphatic vessels in mice. These new fundamental data with the applied focus on the OCT shed light on the mechanisms of brain clearance and the role of lymphatic drainage in these processes that could serve as an informative platform for a development of therapy and diagnostics of diseases associated with injuries of the BBB such as stroke, brain trauma, glioma, depression, or Alzheimer disease. PMID- 29275546 TI - Age, ocular magnification, and circumpapillary retinal nerve fiber layer thickness. AB - Optical coherence tomography (OCT) manufacturers graphically present circumpapillary retinal nerve fiber layer thickness (cpRNFLT) together with normative limits to support clinicians in diagnosing ophthalmic diseases. The impact of age on cpRNFLT is typically implemented by linear models. cpRNFLT is strongly location-specific, whereas previously published norms are typically restricted to coarse sectors and based on small populations. Furthermore, OCT devices neglect impacts of lens or eye size on the diameter of the cpRNFLT scan circle so that the diameter substantially varies over different eyes. We investigate the impact of age and scan diameter reported by Spectralis spectral domain OCT on cpRNFLT in 5646 subjects with healthy eyes. We provide cpRNFLT by age and diameter at 768 angular locations. Age/diameter were significantly related to cpRNFLT on 89%/92% of the circle, respectively (pointwise linear regression), and to shifts in cpRNFLT peak locations. For subjects from age 42.1 onward but not below, increasing age significantly decreased scan diameter (r= 0.28, p<0.001), which suggests that pathological cpRNFLT thinning over time may be underestimated in elderly compared to younger subjects, as scan diameter decrease correlated with cpRNFLT increase. Our detailed numerical results may help to generate various correction models to improve diagnosing and monitoring optic neuropathies. PMID- 29275544 TI - Optical coherence elastography in ophthalmology. AB - Optical coherence elastography (OCE) can provide clinically valuable information based on local measurements of tissue stiffness. Improved light sources and scanning methods in optical coherence tomography (OCT) have led to rapid growth in systems for high-resolution, quantitative elastography using imaged displacements and strains within soft tissue to infer local mechanical properties. We describe in some detail the physical processes underlying tissue mechanical response based on static and dynamic displacement methods. Namely, the assumptions commonly used to interpret displacement and strain measurements in terms of tissue elasticity for static OCE and propagating wave modes in dynamic OCE are discussed with the ultimate focus on OCT system design for ophthalmic applications. Practical OCT motion-tracking methods used to map tissue elasticity are also presented to fully describe technical developments in OCE, particularly noting those focused on the anterior segment of the eye. Clinical issues and future directions are discussed in the hope that OCE techniques will rapidly move forward to translational studies and clinical applications. PMID- 29275548 TI - Optical spectroscopic characterization of human meniscus biomechanical properties. AB - This study investigates the capacity of optical spectroscopy in the visible (VIS) and near-infrared (NIR) spectral ranges for estimating the biomechanical properties of human meniscus. Seventy-two samples obtained from the anterior, central, and posterior locations of the medial and lateral menisci of 12 human cadaver joints were used. The samples were subjected to mechanical indentation, then traditional biomechanical parameters (equilibrium and dynamic moduli) were calculated. In addition, strain-dependent fibril network modulus and permeability strain-dependency coefficient were determined via finite-element modeling. Subsequently, absorption spectra were acquired from each location in the VIS (400 to 750 nm) and NIR (750 to 1100 nm) spectral ranges. Partial least squares regression, combined with spectral preprocessing and transformation, was then used to investigate the relationship between the biomechanical properties and spectral response. The NIR spectral region was observed to be optimal for model development (83.0%<=R2<=90.8%). The percentage error of the models are: Eeq (7.1%), Edyn (9.6%), Eepsilon (8.4%), and Mk (8.9%). Thus, we conclude that optical spectroscopy in the NIR range is a potential method for rapid and nondestructive evaluation of human meniscus functional integrity and health in real time during arthroscopic surgery. PMID- 29275547 TI - Noninvasive in vivo optical coherence tomography tracking of chronic otitis media in pediatric subjects after surgical intervention. AB - In an institutional review board-approved study, 25 pediatric subjects diagnosed with chronic or recurrent otitis media were observed over a period of six months with optical coherence tomography (OCT). Subjects were followed throughout their treatment at the initial patient evaluation and preoperative consultation, surgery (intraoperative imaging), and postoperative follow-up, followed by an additional six months of records-based observation. At each time point, the tympanic membrane (at the light reflex region) and directly adjacent middle-ear cavity were observed in vivo with a handheld OCT probe and portable system. Imaging results were compared with clinical outcomes to correlate the clearance of symptoms in relation to changes in the image-based features of infection. OCT images of most all participants showed the presence of additional infection related biofilm structures during their initial consultation visit and similarly for subjects imaged intraoperatively before myringotomy. Subjects with successful treatment (no recurrence of infectious symptoms) had no additional structures visible in OCT images during the postoperative visit. OCT image findings suggest surgical intervention consisting of myringotomy and tympanostomy tube placement provides a means to clear the middle ear of infection-related components, including middle-ear fluid and biofilms. Furthermore, OCT was demonstrated as a rapid diagnostic tool to prospectively monitor patients in both outpatient and surgical settings. PMID- 29275549 TI - [Research Progress of Sudden Cardiac Death in Forensic Medicine]. AB - Sudden death (SD) is a special kind of death owing to disease, which severely threatening the lives of community population. As the most common type of SD, sudden cardiac death (SCD) has always been a crucial content of identification and research in forensic pathology. This article reviews the research progress from the aspects of epidemiology, morphology, molecular pathology and virtual anatomy of SCD in forensic medicine, so as to provide a reference for the morphological identification, determination of cause of death, and integrated control of this kind of SD. PMID- 29275550 TI - [Research Progress of Yunnan Unexplained Sudden Death]. AB - Yunnan unexplained sudden death (YUSD) has obvious spatial and temporal aggregations. With the features of sudden onset and rapid death, its causes remain unclear. However, the onset of YUSD is related to the geological and climatic conditions in specific range of altitude of incidence area, which is also influenced by the existed susceptibility gene loci or several multiple mutations in SNP loci, long-term fatigue, low dietary nutrition, trace element deficiency, poor living condition and hygienic habit, and infection by etiologic microorganism or virus among the residents live in the incidence area of YUSD. Under the continuous influence of factors above, the crowd of incidence area finally occurred unexplained sudden death that prominently shown by myocardial injury. Improvements of public health administration, living conditions, villagers' health, living habits and enhancement of indicator measurement of myocardial enzyme and electrocardiogram for the residents in the incidence area of YUSD are effective measures for prevention of YUSD. Timely identification of cause of death and in-depth genetic research are important ways to explore the causes of YUSD, enhance the effectiveness of treatment and reduce the death rate. PMID- 29275551 TI - [Expression of proBNP and NT-proBNP in Sudden Death of Coronary Heart Disease]. AB - OBJECTIVES: To study the expression change of pro-brain natriuretic peptide (proBNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in sudden death of coronary atherosclerotic heart disease, and to explore its application in forensic diagnosis. METHODS: Myocardial and blood samples were collected from normal control group, sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group (20 cases in each group). The expression of proBNP in myocardial samples were detected by immunohistochemical staining and Western blotting, and that of BNP mRNA were detected by reverse transcription PCR (RT-PCR). The content of NT-proBNP in plasma were detected by ELISA. RESULTS: Immunohistochemical staining showed positive expression of proBNP in both sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group. There was no positive expression in normal control group. For sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group, the relative expression of proBNP protein and BNP mRNA in myocardial tissue and the NT-proBNP content in plasma were higher than that of normal control group (P<0.05). The NT-proBNP content in plasma of sudden death of coronary atherosclerotic heart disease group was higher than that of single coronary stenosis group (P<0.05). CONCLUSIONS: In myocardial ischemia condition, the higher expression of proBNP in cardiac muscle cell shows that the detection of NT-proBNP in plasma can be useful to differentially diagnose the degree of coronary atherosclerotic heart disease and determine whether the sudden death due to coronary atherosclerotic heart disease. PMID- 29275552 TI - [Forensic Analysis of 6 Cases of Sudden Death due to Hyperthyroid Heart Disease]. AB - OBJECTIVES: To analyse the cases of sudden death due to hyperthyroid heart disease, and explore the general information of deaths and the forensic pathological characteristics to provide reference evidence for forensic identification of such cases. METHODS: Six cases of sudden death due to hyperthyroid heart disease between 2001 and 2016 were selected from School of Forensic Medicine, China Medical University. The general information (gender and age), clinical manifestations, medical history, anatomical and histopathological findings, biochemical parameters and cause of death were analysed retrospectively. RESULTS: Most of the 6 patients had definite history of hyperthyroidism, and they all showed certain degrees of symptoms of cardiovascular disease; had obvious incentive factors of death; histopathological examination of thyroid conformed to the performances of diffuse toxic goiter; with increase of cardiac weight, dilatation of cardiac chambers, myocardial hypertrophy and focal necrosis; postmortem biochemical analyses of pericardial fluid could be used as an additional method for diagnostic of sudden death due to hyperthyroid heart disease. CONCLUSIONS: The identification of death due to hyperthyroid heart disease should be based on the clinical history and the results of autopsy, histopathological examination, postmortem toxicology tests. The postmortem biochemical detection of thyroid and cardiac function should be performed if necessary. PMID- 29275553 TI - [Application of Ischemia Modified Albumin for Acute Ischemic Heart Disease in Forensic Science]. AB - OBJECTIVES: To explore the application value and forensic significance of ischemia modified albumin (IMA) in pericardial fluid to diagnose sudden cardiac death. METHODS: IMA level in pericardial fluid was detected in acute ischemic heart disease group (n=36), acute myocardial infarction group (n=6), cardiomyopathy group (n=4) and control group (n=15) by albumin cobalt binding method. The levels of IMA were compared among these groups. The best cut-off IMA value was estimated and the sensitivity and specificity of acute myocardial ischemia group was distinguished from control group by receiver operating characteristics (ROC) curve. RESULTS: The IMA level in acute ischemic heart disease group was significantly higher than that of control group (P<0.05). Compared with acute myocardial infarction group and cardiomyopathy group, the IMA level in acute ischemic heart disease group had no significant difference (P>0.05). The cut-off value for the identification of acute myocardial ischemia which obtained by ROC analysis was 40.65 U/mL. And the sensitivity and specificity for distinguishing acute ischemia cardiac disease was 60.0% and 80.5%, respectively. CONCLUSIONS: The IMA value in pericardial fluid can be a reference marker for the diagnosis of acute myocardial ischemia, which also can provide objective basis for the forensic identification of sudden cardiac death. PMID- 29275555 TI - [Applied Value of Electroencephalogram in Assessment of Mild Psychiatry Impairment]. AB - OBJECTIVES: To explore the applied value of electroencephalogram (EEG) in assessment of psychiatric impairment among patients with mental disorders due to traumatic brain injury. METHODS: According to the ICD-10, a total of 271 subjects were enrolled and assessed with the criterion of mental disorders due to traumatic brain injury. Activity of Daily Living Scale (ADL), Functional Activities Questionnaire (FAQ) and Social Disability Screening Schedule (SDSS) were used to evaluate the severity of patients. All the participants were tested by Wechsler Adult Intelligence Scale (WAIS) and examined by EEG. RESULTS: Totally 215 patients accomplished the study. The results of Glasgow Coma Scale (GCS), the severity of craniocerebral injury and the scores of FAQ, SDSS and ADL showed significant difference among the patients with different severity of EEG (P<0.05). The grades of psychiatric impairment showed significant difference among the patients with different abnormal EEG (P<0.05). CONCLUSIONS: EEG can reflect the severity of craniocerebral injury, assist evaluate the social function and activity of daily living of patients with mental disorders due to traumatic brain injury, and distinguish the mild psychiatric impairment grades, which suggest that EEG has a certain reference value in the assessment of psychiatric impairment. PMID- 29275554 TI - [Estimation of External Features of Eyes for the Adult Male of Han Nationality in Northeast China Based on the Characteristics of Skull]. AB - OBJECTIVES: To explore the correlation between the imaging parameters of skull and the external features of eyes. METHODS: Positive images of the head face and the frontal and lateral X-ray films were obtained from 101 cases of adult males of the Han nationality aged from 20 to 40 years old in Northeast China. The face width (x1), upper face width (x2), biorbital width (x3), all facial height (x4), upper facial height (x5), maximum breadth of skull (x6), minimum breadth of frontal bone (x7), orbital widthII(x8), anterior interorbital breadth (x9), maximum height of skull (x10), minimum width of nasal bone (x11) and orbital height (x12) were measured and the data were statistically analysed. RESULTS: Through the linear regression analysis, the regression equations of the presumed inboard canthi (y1) and outboard canthi distances (y2) were established, respectively, which were y1=0.025 x2+0.291 x3-0.011 x7+0.041 x10-0.525(R=0.613, SEE=0.222 cm) and y2=1.703-0.08 x2+0.573 x3-0.142 x4+0.421 x5+0.096 x7-0.256 x8+0.149 x9+0.071 x10(R=0.745, SEE=0.341 cm). The back-substitution check showed that the accuracy rate of two equations at +/-1SEE were 75.2% and 80.2%, respectively. CONCLUSIONS: The established regression equations of external features of eyes have high estimation accuracy, which can be used to the practical work of facial reconstruction. PMID- 29275556 TI - [Determination of Methcathinone in Urine by GC-MS]. AB - OBJECTIVES: To establish a method for the analysis of methcathinone in urine by gas chromatography-mass spectrometry (GC-MS). METHODS: Proadifen hydrochloride (internal standard) and buffer solution (pH=9) were added into the urine samples, and methcathinone was extracted by ethyl acetate. The extract was volatilized in 50 C nitrogen gas flow and the remnant was dissolved by methanol and analysed by GC-MS. RESULTS: The methcathinone in urine showed a good linear relationship in the mass concentration range of 0.02-2.00 MUg/mL. The linear equation was y=0.301 9 x+0.018 9 (r=0.999 2), and the detection limit was 0.01 MUg/mL. The recoveries of methcathinone in urine was 96.4%-99.2%, with the intra-day precision of 5.8% 7.6% and the inter-day precision of 6.0%-8.1%. CONCLUSIONS: The method is convenient and sensitive, which can be applied to the forensic identification of methcathinone in urine. PMID- 29275557 TI - [Forensic Analysis of 63 Cases of Non-violent Death Occurred in Custody]. AB - OBJECTIVES: To collect cases of non-violent death occurred in custody for analyzing the forensic characteristics and related influencing factors. METHODS: Sixty-three cases of non-violent death among detainees in custody that handled by a forensic science center from 2000 to 2015 were collected. The type, onset season, medical history, clinical manifestation, treatment and duration of related fatal diseases were analyzed retrospectively. RESULTS: The deaths due to diseases in custody were common in male, and with a high incidence in middle aged adults. The most common cause of death was cardiac death (50.8%). Chronic inflammatory diseases such as gastrointestinal perforation, pulmonary tuberculosis, pneumonia, hepatitis and pancreatitis, were common. There was a peak incidence in summer. The acute symptoms included sudden onset during sleep and sudden apsychia, and emesis, abdominal pain, fatigue, chest tightness, shortness of breath, fever and anorexia were the most common chronic symptoms. CONCLUSIONS: The management system, custody condition, medical level and rescue rudiment of custody still need improvements. It should be pay more attention to collecting the information of medical history, autopsy, histological examination and toxicological analysis, etc. PMID- 29275558 TI - [PrepFiler Express BTATM Lysis Buffer Combined with Silicon Microbeads for Rapid DNA Extraction from Bone]. AB - OBJECTIVES: To establish a convenient and rapid method for extracting DNA from bone. METHODS: Fifteen long bone samples were washed and sterilized. The skeletal fragments were obtained by electric drill, and lysed by PrepFiler Express BTATM lysis buffer. DNA was then manually extracted by silicon microbeads for further analysis. RESULTS: STR genotyping was successfully obtained in 14 out of the 15 samples, and the detection rate was 93.33%. CONCLUSIONS: The method for DNA extraction from bone established in present study is convenient, quick, effective, and with a strong applicability, which is worth spreading and applying. PMID- 29275559 TI - [Forensic Investigation in Han Population by SiFaTM 23 Plex Kit (Beta Version)]. AB - OBJECTIVES: To investigate the performance of SiFaTM 23 Plex Kit (beta version) and its population genetics of STR loci in Han population. METHODS: Genotyping was performed for 1 000 unrelated healthy Han individuals by the kit. The efficiency of the kit was tested, and the frequency data and population genetics parameter information of STR loci were analysed statistically. RESULTS: The minimum amplification system could be 6.25 MUL. In 25 MUL standard reaction system, a satisfied genotyping profiles could be obtained with the DNA content as low as 125 pg. Among the 1 000 individuals, 267 alleles were detected by 21 autosomal STR loci of the kit, which conformed to Hardy-Weinberg equilibrium. Fifteen and eleven alleles were observed at the newly added STR loci D1S1656 and D10S1248, respectively, which showed a high polymorphism information content. CONCLUSIONS: SiFaTM 23 Plex Kit (beta version) is excellent in testing blood samples. Its accuracy, repeatability and sensitivity can satisfy the need of forensic practice, which makes it be applied to forensic-related case work and DNA database establishment. PMID- 29275560 TI - [Research Progress of MALDI-TOF-IMS in Biomedicine and Its Application Prospect in Forensic Sciences]. AB - Matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF-IMS) can analysis unknown compounds in sections and obtain molecule imaging by scanning biological tissue sections, which has become a powerful tool for the research of biomarker, lipid distribution and drug metabolism, etc. This article reviews the application of this technique in protein identification, clinical application, drug discovery, lipid research and brain injury. PMID- 29275561 TI - [Application of RT-qPCR in the Study of Forensic Pathology]. AB - Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is a convenient and highly efficient method for the detection of mRNA in tissues or body fluid samples. It has the characteristics of easy operation, high sensitivity and specificity, etc. With a wide application in medicine, biology and other fields, RT-qPCR technique has made some progresses in the research field of forensic pathology. This paper reviews the application value of RT-qPCR in the study of forensic pathology and current situation, as well as the research progress at home and abroad reviews. It also summarizes the notes of samples extraction, RT-qPCR experiments and data processing, which aims to provide reference for the forensic research and its application. PMID- 29275562 TI - [Research Progress of Olfactory Event-related Potential and Its Forensic Application]. AB - Olfaction is one of the basic feelings, which plays an important role in appetite, warning of danger and emotion regulation, etc. More and more studies have shown that olfactory dysfunction may affect quality of human life. Thus, the attention of olfactory dysfunction is increasing. There are many subjective and objective methods for olfactory function detection, and olfactory event-related potential (OERP) is a more objective method. This article reviews the development, testing and analysing methods and clinical research of OERP, and explores its application prospects in forensic clinical medicine. PMID- 29275563 TI - [Understanding new progress in prosthodontics from the perspective of updates in the glossary of prosthodontic terms]. AB - Glossary of Prosthodontic Terms is a standardized vocabulary with international influence. Its ninth edition was published in J Prosthet Dent in 2017, 12 years after the last edition. During this period, great development has taken place in the dental prosthetics due to dental implant and digital dentistry as well as application of new materials and technologies. The research results of dental adhesion, aesthetic dentistry, orofacial function, and tissue regeneration has been fully applied in dental clinic. This paper attempts to capture and accurately understand the changes of some important, especially controversial academic concepts through the comparison of the seventh, eighth and ninth edition of vocabulary. Four parts including new terms, obsolete terms, terms with updated concept, and terms with the continuity of concept are used to show the important progress of prosthodontics. PMID- 29275564 TI - [Prosthodontic specialty training in the United States: what can we learn]. AB - Prosthodontics is one of the nine recognized specialties by American Dental Association. The postgraduate prosthodontic program used to train prosthodontic specialists in U S A started about 70 years ago. Compared to China which just launched the dental residency programs, the programs in U S A have more developed and relatively more mature education system. It is worthwhile for China to study and learn the U S A prosthodontic residency education program. Prosthodontics is a specialty to diagnose and treat complex dental problems, and is often considered as the 'orchestrator' directing and coordinating all the other dental specialists to manage complex situations. This specialty plays an important role in a nation's oral health system. The present article is aimed to introduce the history of US prosthodontic residency program, initial accreditation, curriculum, education standards and mechanisms of the residency program, and how the program is monitored and managed post initial accreditation, with the hope that this system can serve as a reference for China's developing its own residency program. PMID- 29275565 TI - [Expression of integrin alphavbeta3, CXC chemokine receptor 4 and CXC chemokine receptor 7 and their relationship with lymph node metastasis in squamous cell carcinoma of head and neck]. AB - Objective: To investigate the expression of integrin alphavbeta3, CXC chemokine receptor (CXCR)4 and CXCR7 and their relationship with lymph node metastasis in squamous cell carcinoma of head and neck (SCCHN). Methods: The expression of integrin alphavbeta3, CXCR4 and CXCR7 was detected by immunohistochemistry SABC in 92 cases of primary SCCHN, metastatic lymph node, normal oral mucosa tissues and normal lymph nodes. Results: The positive rate of the expression of integrin alphavbeta3, CXCR4 and CXCR7 was 75% (69/92), 81%(75/92) and 76%(70/92), respectively in primary SCCHN, and was 82%(75/92), 76%(70/92) and 65%(60/92), respectively in metastatic lymph node. The expression of integrin alphavbeta3 and CXCR4 in primary SCCHN (r=0.813, P<0.05) and lymph node metastasis (r=0.541, P<0.05) was positively correlated. Integrin alphavbeta3 and CXCR7 expression in primary SCCHN (r=0.683, P<0.05) and lymph node metastasis (r=0.708, P<0.05) was positively correlated. CXCR4 and CXCR7 expression in primary SCCHN (r=0.644, P<0.05) and lymph node metastasis (r=0.707, P<0.05) had a positive correlation. The expression level was associated with tumor size (P=0.040, 0.001, 0.009), lymph node metastasis (P=0.001, 0.000, 0.000) and surrounding tissue invasion (P=0.046, 0.002, 0.001), but not related to age (P=0.097, 0.274, 0.162), gender (P=0.103, 0.309, 0.187). Conclusions: The overexpression of integrin alphavbeta3, CXCR4 and CXCR7 in primary head and neck squamous carcinoma and metastatic lymph nodes was related to lymph node metastasis. The co-expression of integrin alphavbeta3, CXCR4 and CXCR7 may play a synergistic role in lymphatic metastasis of SCCHN. PMID- 29275566 TI - [Interaction between transcriptional factor E26 transformation specific 1 and peroxiredoxin 1 in nicotine-induced oral precancerous lesion cells]. AB - Objective: To investigate the interaction between nuclear transcriptional factor E26 transformation specific 1 (Ets1) and peroxiredoxin 1 (Prx1) in nicotine induced oral precancerous lesion cells. Methods: Human oral precancerous lesion dysplastic oral keratinocyte (DOK) cells were cultured and divided into nicotine group, control group, knockdown group and knockdown control group. The nicotine group, knockdown group and knockdown control group were treated with 1 MUmol/L nicotine for 7 days while the control group was untreated. Western blotting, co immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) were performed to detect Prx1 and Ets1 protein expression, Prx1 and Ets1 protein interaction, combined activity of Ets1 with PRDX1 gene promoter region in nicotine group and control group DOK cells. In nicotine group, DOK cells were transfected with siRNA or lentivirus to knockdown Ets1 and Prx1 expression. Prx1 and Ets1 protein expression was examined by Western blotting. Results: Nicotine increased the expression of Prx1 and Ets1 protein in DOK cells. The relative expression of Prx1 and Ets1 was 0.71+/-0.02, 0.12+/-0.01 in nicotine group and 0.53+/-0.06, 0.01+/-0.01 in control group (P=0.009, P=0.000). Co-IP showed that Prx1 could form protein complex with Ets1. The expression of Prx1 and Ets1 complex protein was increased in nicotine group. ChIP revealed that nicotine upregulated the combination of transcriptional factor Ets1 with PRDX1 gene promoter region, and the enrichment fold was 80.9+/-19.7 in nicotine group and 13.8+/-1.2 in control group (P=0.004). Ets1 and Prx1 protein expression was knocked down. The relative expression of Ets1 and Prx1 was 0.60+/-0.06, 0.48+/ 0.03 in knockdown group and 0.83+/-0.08, 0.80+/-0.06 in knockdown control group (P=0.016, P=0.002). Ets1 knockdown suppressed the expression of Prx1 (P=0.002). Conversely, Prx1 knockdown also inhibited the expression of Ets1 significantly (P=0.000). Conclusions: In oral precancerous lesion cells, Ets1 directly regulates Prx1 expression and nicotine might promote the development of oral precancerous lesion by magnifying the positive feedback signal pathway between Ets1 and Prx1. PMID- 29275567 TI - [Construction and assessment of a three-dimensional finite element model of mandibualr second molar mesialization using customized lingual appliance and mini implant]. AB - Objective: To construct a three-dimensional (3D) finite element model and analyze the biomechanical characteristics during mandibular second molar mesialization using customized lingual appliances and mini-implant. Methods: One adult student volunteer from The First Affiliated Hospital of Zhengzhou University with lower left first molar extraction was selected. After CT scanning, Mimics, Geomagic, ANSYS were employed to develop a 3D finite element model including customized lingual brackets, stainless steel lingual arch wire, buccal buckles, lower dentition, periodontal ligaments and alveolar bone. Four different loading methods (1. the force of 1.470 N loaded at the lingual side only; 2, 3, 4. the forces of 0.490, 0.735 and 0.980 N loaded at both buccal and lingual sides, respectively.) were included. The initial displacements of the lower second molar and stress distribution in the periodontal ligaments were analyzed. Results: More uniform stress distributions in the periodontal membrane of mandibular left second molar were found when the mesial force were loaded at both buccal and lingual sides than the force loaded at lingual side only. More inclination of the second molar was observed when force loaded at both sides than at lingual side only. With the values of the force increased, the mesial inclination potential of the second molar, the initial movement of the second molar and the stress distribution in the periodontal membrane increased. Under the force of 0.735 N at both buccal and lingual sides, mesially inclined initial displacements of the mandibuar second molar were observed and the stress values of von Mises was in the suitable area. Conclusions: Less second molar rotation was found when the force loaded at both buccal and lingual sides than loaded at lingual side only. However, force loaded at both sides would increase the measial inclination potential of the second molar. PMID- 29275568 TI - [Effects of T helper 1 cells and T helper 17 cells secreting cytokines on rat models of experimental periodontitis]. AB - Objectvie: To investigate the effects of secreting cytokines interferon-gamma (IFN-gamma) and interleukin-17 (IL-17) of T helper 1 cells (Th1) and T helper 17 cells (Th17) on the peripheral blood and alveolar bone destruction, so as to provide a new explanation for cellular immunity-mediated alveolar bone destruction. Methods: Eighteen eight-week-old male Sprague-Dawley rats were divided, randomly and equally, into 3 groups: lipopolysaccharide (LPS) group, ligation group and normal control group. In the LPS group, Escherichia coli LPS was injected into the alveolar mucosa on the buccalmedian site of the left upper first molar, while the right upper first molar was injected with equal volume of physiological saline as self-controls. The injections were performed every other day for four times totally. In the ligation group, the left upper first molars were ligatured with 0.2 mm orthodontic cords, while the right upper first molars were left untreated as self-controls, and supplemented with high-sugar diet to promote the periodontitis status. The rats in normal control group were fed normally. The concentrations of IFN-gamma and IL-17 in peripheral blood were measured using enzyme linked immunosorbent assay (ELISA) method at the fourth week after the start of injection and at the eighth week after ligation. The histological of periodontal tissues were observed after hematoxylin-eosin (HE) staining and osteoclast count was performed under light microscope. The histological of osteoclasts were observed after tartrate-resistant acid phosphatase (TRAP) staining. Expression of IFN-gamma and IL-17 were detected by immunohistochemical assay. Results: The concentrations of IFN-gamma in peripheral blood of LPS group [(185.0+/-50.7) ng/L] and ligation group [(202.9+/-60.4) ng/L] were significantly higher than that of normal control group [(106.3+/-17.2) ng/L](P<0.05). Meanwhile, histological examination showed inflammatory cells infiltration in the gingival epithelium, the height reduction of alveolar bone accompanied with absorption lacuna. There were significantly higher HE and TRAP stained osteoclasts in LPS group (9.50+/-1.05) and ligation group (10.83+/-1.17) than that in controlgroup (0.33+/-0.52)(P<0.05). Moreover, the expressions of IL 17 in alveolar bone absorption area of LPS group and ligation group were significantly stronger than that in control group (P<0.05). Conclusions: The rat models of experimental periodontitis and alveolar bone resorption could be successfully established by means of ligationand LPS injection, respectively. The periodontal inflammatory responses were related to secreting cytokines IFN-gamma and IL-17 of Th1 and Th17 cells, while Th17 cells might exert a positive effect on alveolar bone destruction. PMID- 29275569 TI - [Establishment of rat model with diabetes mellitus and concomitant periodontitis and the carotid artery lesions in the model rats]. AB - Objectives: To establish SD rat model with type 2 diabetes mellitus (DM) and concomitant chronic periodontitis (CP) and to evaluate the influence of periodontitis on the vascular lesions of type 2 diabetes rats. Methods: Totally 241 clean level SD rats were randomly divided into four groups, group A (normal control, NC, n=27), group B (DM, n=34), group C (CP, n=90) and group D (DM+CP, n=90). The rats of DM group were fed with high-fat and high-sugar diet for 8 to 10 weeks, and then were multiply injected with small dose streptozotocin under the condition of ice bath. Blood sugar levels after the injection were dynamically monitored at 72 h, 1 week, 2 weeks and 4 weeks, respectively. The CP model was established by means of ligation. Bilateral maxillary first and second molars were selected and ligated using 0.2 mm orthodontic wires binding with 4-0 surgical suture soaked with Porphyromonas gingivalis (Pg) suspension. After a period of 14 weeks, all the rats were put to death. Maxillary samples were subjected to methylene blue staining to observe alveolar bone loss. Bilateral carotid artery specimens were collected. The left carotid artery specimens were used to detect the prevalence of Pg using quantitative real-time PCR. The right carotid artery specimens were used to observe pathological changes. Results: Blood sugar levels of rats in group B and D increased and changed sharply after Streptozotocin injection with in 1 week. Symptoms of 'more drink, more food and body weight loss' appeared. The fasting blood glucose (FBG) was more than 7.8 mmol/L and (or) the random blood glucose (RBG) was more than 17.8 mmol/L. Both FBG and RBG became stable after 2 to 3 weeks. Levels of HbA1C in group B and D ([7.32+/-0.45]%, [9.41+/-0.45]%) were significantly higher than that of group A ([4.02+/-0.45]%) (P<0.01). Rats of group D were observed the most severe bone loss showing wider interdental space and furcation involvement. Pathological results of carotid artery tissues of group D showed the worst lesions including thinning and calcification of vessel walls, and breaking down or disappearance of elastic fibers. The prevalences of DNA of Pg in groups of A, B, C and D were 3/7, 3/7, 6/7 and 7/7, respectively. The bacteria numbers detected by quantitative real-time PCR in groups C and D were significantly higher than that of groups A and B (P<0.01). Conclusions: Rat model of type 2 DM with periodontitis was successfully established in the present study. Carotid artery specimens from DM+CP model rats showed typical vascular lesions such as calcification and fiber disorders. Pg was found in all carotid specimens and the highest bacteria numbers were detected in the composite model rats. The Pg might play a role in the progress of diabetes vascular lesions. PMID- 29275570 TI - [Three-dimensional printed miniplate used for maxillary protraction]. AB - The miniplate was designed and three-dimensional (3D) printed according to the positions of roots and tooth germs and then it was used as skeletal anchorage to protract the maxilla. The maxilla moved forward obviously after treatment. Custom designed and 3D printed miniplate could be used for maxillary protraction. PMID- 29275571 TI - [Iodine-125 seed implantation for the treatment of palatine carcinosarcoma: a case report]. PMID- 29275572 TI - [How to write and publish a scientific article in stomatology]. AB - The general principles and key points in writing of a scientific article in stomatology were interpreted based on the national guideline and the author's personal experiences in the present article. Efforts should be made by the authors focusing on core information, refinement and description of their papers. In the second half of the article, the general process of paper review was introduced. The article also gave suggestions on how to response to the reviewers' questions. It is well recognized that a good scientific journal was created by good authors, good reviewers and good editors. The author proposed that efforts by above mentioned three parties should be gathered to make more valuable, delicately designed and well performed clinical research articles be published. PMID- 29275574 TI - [Research progress in microbiological characteristics of peri-implant disease]. AB - Peri-implant disease is an inflammatory status which leads to the destruction of the soft and hard tissues around osseointegrated implants, including peri-implant mucositis and peri-implantitis. It is generally accepted that bacterial infection appears to be responsible for peri-implant lesions. This review aims to summarize the characteristics of the subgingival microbiota in healthy and diseased implants and compare the microbial composition of subgingival biofilm in teeth with periodontal disease and in diseased implant, so as to provide biological basis on the diagnosis, therapy and prevention of peri-implant disease in clinical practice. PMID- 29275575 TI - [Subclinical hypothyroidism and isolated thyroid stimulating hormone elevation should be distinguished]. PMID- 29275573 TI - [Standards and guidelines of radiation protection and safety in dental X-ray examinations]. AB - With the rapid development of imaging technology, the application of dental imaging in diagnosis, treatment planning, intraoperative surgical navigation, monitoring of treatment or lesion development and assessment of treatment outcomes is playing an essential role in oral healthcare. The increased total number of dental X-ray examinations is accompanied by a relatively significant increase in collective dose to patients as well as to dental healthcare workers, which is harmful to human bodies to a certain degree. Some radiation protection standards and guidelines in dental radiology have been published in European countries, US, Canada and Australia, etc. Adherence to these standards and guidelines helps to achieve images with diagnostic quality and avoid unnecessary and repeated exposures. However, no radiation protection standard or guideline with regard to dental X-ray examinations has been put in force so far in mainland China. Therefore, a literature review on available radiation protection standards and guidelines was conducted to provide reference to the development of radiation protection standards or guidelines in mainland China. PMID- 29275576 TI - [Clinical features of acute diffuse pulmonary exudative disorders]. AB - Objective: To analyze the clinical features of acute diffuse pulmonary exudative disorders. Methods: The data were collected from patients who were hospitalized in respiratory intensive care unit (RICU) of Beijing Chaoyang Hospital affiliated to the Capital Medical University during January 2009 to December 2011, and had acute clinical course with imaging findings of diffuse pulmonary infiltrated shadows (similar to acute respiratory distress syndrome (ARDS)). The causes of disease and clinical features were analyzed. Results: A total of 86 patients with acute diffuse pulmonary exudative disorders were included. Sixty-two (72.1%) were males, with a mean age of (58.6+/-16.4) years old; 24(27.9%) were females, with a mean age of (48.2+/-18.3) years old. The duration of the disease before administration was (11.5+/-5.2) days, and RICU stay was (15.5+/-9.5) days, with hospital mortality of 40.7% and the average hospitalization cost of 101 thousand RMB. The main cause was infection, which occurred in 53 cases (61.6%) (virus in 21 cases, bacteria in 14 cases, fungus in 11 cases, pneumocystis in 15 cases and others in 3 cases, mixed infection in 11 cases). Interstitial pneumonia occurred in 12 cases (idiopathic interstitial pneumonia in 9 cases: cryptogenic organizing pneumonia in 3 cases, the acute exacerbation of idiopathic pulmonary fibrosis in 3 cases, nonspecific interstitial pneumonia in 1 case, acute interstitial pneumonia in 2 cases, and connective tissue disease in 3 cases), aspiration pneumonia in 10 cases, acute left heart failure in 6 cases, and exogenous pulmonary ARDS in 5 cases. Conclusions: The main cause of acute diffuse pulmonary exudative disorders is pulmonary infection, followed by interstitial pneumonia. The hospital mortality and hospitalization cost are high. PMID- 29275577 TI - [Study of sevoflurane/remifentanil coadministration on improving emergence and recovery characteristics of patients following general anaesthesia with sevoflurane]. AB - Objective: To investigate the effects of remifentanil infusion on emergence and recovery characteristics of patients with thoracoscopic lobectomy following general anaesthesia with sevoflurane. Methods: One hundred patients, who were aged 37 to 65 years with American Society of Anesthesiologists (ASA) physical status 1-2, and scheduled for elective thoracoscopic lobectomy under general anaesthesia in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, from February 2016 to August 2016, were allocated to receive sevoflurane maintenance regimen(group S, n=50)or sevoflurane/remifentanil maintenance regimen(group SR, n=50)by random digital table. After routine induction and intubation, anaesthesia was maintained with 2% sevoflurane in group S and 1.5% sevoflurane/remifentanil(continuous intravenous injection at rate of 4 MUg.kg(-1).h(-1))coadministration in group SR respectively, with intermittent intravenous infusion of sulfentanil. Haemodynamic variables were collected at different time points and compared between two groups. Awaking time and extubation time, incidences of serious coughing and agitation were evaluated during emergence.Postoperative pain, nausea and cather related bladder discomfort(CRBD)were evaluated in post anesthesia care unit. Results: Compared with group S, the arterial blood pressure and heart rate were significantly lower in group SR at extubation(all P<0.05). Time to awaking and to extubation in group SR were (4.2+/-2.1) min and (4.8+/-3.1)min respectively, in group S were (12.7+/-3.4) min and (15.4+/-4.1)min.The difference between two groups were statistically significant (t=-15.040, 14.582, all P<0.05). The incidences of serious coughing and agitation in group S were 48% and 58%, which were greater than those of group SR(6% and 10%). The difference were statistically significant(chi(2)=20.294, 23.574, all P<0.05). The NRS and incidence of complaining CRBD were similar in both groups(all P>0.05). Conclusion: Compared with sevoflurane maintenence, coadministration of remifentanil and sevoflurane maintenance regimen provides better emergence and recovery which are characterized by faster awakening and extubation with a lower incidence of emergence coughing and agitation. PMID- 29275578 TI - [Application of Chinese version of ACE-III in type 2 diabetes mellitus patients with mild cognitive impairment]. AB - Objective: To investigate the application and best cut-off value of Chinese version of Addenbrooke's cognitive examination-III(ACE-III) in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment. Methods: A total of 18 T2DM patients with normal cognitive function (NCI group) and 40 T2DM patients with mild cognitive impairment (MCI group) treated in outpatient clinic or ward of Department of Neurology and Endocrinology in Fujian Medical University Union Hospital between January 2015 and February 2016 were enrolled. Mini Mental State Scale (MMSE), Montreal cognitive assessment scale (MoCA), Activity of Daily Living Scale (ADL) and the Chinese version of ACE-III were used to assess cognitive function of subjects and to assess the value of ACE-III in the diagnosis of T2DM patients with mild cognitive impairment. Results: The Cronbach's alpha of the Chinese version of ACE-III is 0.768. ACE-III and MoCA were correlative (r=0.768, P<0.001). The area under the receiver operating characteristic (ROC) curve for ACE-III was 0.906 (95%CI: 0.827-0.985). When the cut-off value for diagnosis was 87.5, the maximum Youden index was 0.769, with a sensitivity of 0.825 and a specificity of 0.944. Patients in MCI group got a lower score in the sub-items of attention/orientation, memory, verbal fluency, language and visual space of ACE-III compared to those in NCI group, and the differences were statistically significant (t=5.336, P<0.001; t=5.530, P<0.001; t=4.556, P<0.001; t=5.301, P<0.001; t=2.821, P=0.008). Conclusion: The Chinese version of ACE-III had good internal consistency reliability, and it could effectively detect impairment of general cognitive function and single cognitive domains in T2DM patients. PMID- 29275579 TI - [Risk factors associated with massive drainage after posterior spinal orthopaedic surgery for adolescent scoliosis]. AB - Objective: To identify risk factors that influence the massive drainage after posterior spinal orthopaedic surgery for adolescent scoliosis. Methods: A total of 1 461 patients from 11 to 18 years old diagnosed with adolescent scoliosis who underwent first posterior spinal orthopaedic surgery in affiliated Drum Tower Hospital, Medical School of Nanjing University between November 2010 and October 2015 were retrospectively reviewed. Patients were categorized on the basis of massive or normal drainage, with the boundary 30(th) percentile of drainage/estimated blood volume. Preoperative factors including age, gender, body mass index(BMI), ASA physical status, diagnostic type of scoliosis, main Cobb angle, laboratory tests, intraoperative factors including the number of fusion level and screws, tranexamic acid used or not, use of osteotomy and thoracoplasty, use of cell salvage technology, duration of operation, the volume of urine output, blood loss, fluid therapy and transfusion, postoperative factors including the length of hospital stay, number of transfusion, the volume of drainage, time of drain were collected. Univariate and multivariate analyses were used to determine risk factors which were independently associated with massive drainage. Results: The average drainage was (856.3+/-333.4)ml. 479(32.8%) patients had massive drainage(drainage>=30% of drainage/estimated blood volume). Multivariate analysis identified risk factors of massive drainage: BMI<17.63 kg/m(2), odds ratio(OR)=2.90, preoperative platelet count<190*10(9)/L (OR=1.67), preoperative main Cobb angle>=55 degrees(OR=1.66), number of fusion levels>=11(OR=2.33), number of screws>=15(OR=1.73), use of osteotomy(OR=1.54), intraoperative volume of crystalloids>=35.63 ml/kg(OR=1.40), intraoperative volume of colloids>=28.92 ml/kg(OR=1.82), intraoperative volume of transfusion>=19.55 ml/kg(OR=1.72), while the use of tranexamic acid(OR=0.26) was the only protective factor. Conclusion: BMI<17.63 kg/m(2,) preoperative platelet count<190*10(9)/L, preoperative main Cobb angle>=55 degrees, number of fusion levels>=11, number of screws>=15, use of osteotomy, intraoperative volume of crystalloids>=35.63 ml/kg, intraoperative volume of colloids>=28.92 ml/kg, intraoperative volume of transfusion>=19.55 ml/kg were risk factors associated with massive drainage after posterior spinal orthopaedic surgery for adolescent scoliosis, while the use of tranexamic acid could decrease the possibility of massive drainage. PMID- 29275580 TI - [Response and prognosis of neoadjuvant dose-dense or standard schedule chemotherapy with anthracyclines and taxanes for Luminal B breast cancer]. AB - Objective: To evaluate the efficacy and safety of neoadjuvant dose-dense or standard schedule chemotherapy with anthracyclines and taxanes for Luminal B (HER2-)Breast Cancer. Methods: From January 2010 to December 2014, 168 Luminal B (HER2-) breast cancer patients with stageIIA-IIIC confirmed by pathology were randomly assigned to receive one of the following regimens: (group A) concurrent TEC* 4 every 3 weeks, ( group B ) sequential EC* 4-T * 4 every 3 weeks, (group C ) dose-dense TEC* 4 every 2 weeks with G-CSF, (group D) sequential EC* 4(dose dense)-T * 4 with dose-dense every 2 weeks . Results: A total of 168 patients completed the neoadjuvant chemotherapy as planned. The pathologic complete response (pCR) was 16.8% in the 4 groups.The pCR were 30.9% and 26.1% in the group C and group D respectively, significantly higher than patients with group A and group B(9.5%and 7.1%) ( P<0.05). Median follow-up was 43 months (IQR 3-63). The 3-year disease free survival (DFS) rate was 64.7%, 55.5%, 87.8% and 92.1% and the 3-year overall survival(OS)rate was 79.4%, 77.7%, 95.1%, 97.3% in the 4 groups respectively. Patients in the dose-dense group had better 3-year DFS and 3 year OS than those with the regular group.The side-effects could be evaluated in 154 patients.The incidence of neutropenia was 29.2% and 21.9% in the group C and group D versus 65.7%and 51.3% in the regular group(P<0.05), the incidence of nervous toxicity was 54.2%, 18.9%, 60.0%, 26.8% in the 4 groups respectively. The incidence of nervous toxicity in the dose-dense group was lower than that in the regular regimen group(P<0.05). Conclusion: Neoadjuvant dose-dense chemotherapy with anthracyclines and taxanes for Luminal B (HER2-)Breast Cancer was effective and can improve the pCR, DFS and OS.Comparing the two dose dense regimens, sequentially with anthracyclines and taxanes, the incidence of nervous toxicity were lower. PMID- 29275581 TI - [Quantitative measurement of citric acid in urine using tandem liquid chromatography mass spectrometry]. AB - Objective: To find a suitable method for the determination of citric acid in the urine of patients with stones, in order to provide a new method and basis for the prevention and treatment of stone. Methods: Liquid chromatography tandem mass spectrometry was used to analyze the citric acid in urine directly. And the accuracy, stability, repeatability and other indicators of the results were detected. Results: The results showed a good linear relationship with the concentration of citric acid in urine. y=50.31x+ 0.002 6 (R(2)=0.994 21). The results were stable, reproducible [intra-day (Coefficient of Variance) CV ~1% and inter-day CV<10%], and the accuracy of which was comparable with that of the enzyme method (n=20, R=0.97). Conclusion: Using the method of this study to detect the content of citric acid in urine has the advantages of simple operation, good repeatability, accurate results, and low price. So it is worth to be popularized and applied in clinical practice. PMID- 29275582 TI - [Effect analysis on Deanxit combined with Shuganjieyu capsule in the treatment of refractory gastroesophageal reflux disease]. AB - Objective: To investigate the curative effect of Deanxit combined with Shuganjieyu capsule on the treatment of refractory gastroesophageal reflux disease. Methods: A total of 125 patients with refractory gastroesophageal reflux disease who had failed in standard lansolazole capsule treatment in the Department of Gastroenterology, First People's Hospital of Neijiang were selected. According to the symptom scores and mood scores of gastroesophageal reflux disease, patients were randomly and double-blindly divided into five groups. Group A(Lansoprazole Capsules + Mosapride Citrate + Deanxit), B(Lansoprazole Capsules + Mosapride Citrate + Shuganjieyu capsule), C(Lansoprazole Capsules + Mosapride Citrate+ Deanxit + Shuganjieyu capsule) and D(Deanxit) groups are study groups, the other was control group (Lansoprazole Capsules + Mosapride Citrate). The scores of symptoms and mood were compared after 4 weeks and 8 weeks of treatment. Results: The clinical symptoms score, HAMA and HAMD scores were significantly lower in the all study groups in comparison to the control group after 4 weeks and 8 weeks therapy. The clinical symptoms score, HAMA and HAMD scores in group C were significantly lower than those in group A and B (P<0.05), while the difference between group A and B was not statistically significant(P>0.05). The HAMA and HAMD scores of group D were significantly higher than those of group A, B, C and control group, and the differences were statistically significant (P<0.05). The total effective rate of study groups were significantly higher than those of the control group, and the difference was statistically significant (P<0.05). The total effective rate of group C was significantly higher than that of group A and B (chi(2)=6.47, P<0.05). The total effective rate of group A at the end of the 8th week was significantly higher than that of group B (chi(2)=6.52, P<0.05). The total effective rate of group D at the end of the 4th and 8th week was significantly lower than those of the group A, B, C and control group, the difference was statistically significant (chi(2)=5.85, P<0.05). Conclusions: Deanxit combined with Shuganjieyu capsule is significantly effective in treatment of refractory gastroesophageal reflux disease, which can effectively improve the total treatment efficiency, reduce the symptom scores and mood scores of gastroesophageal reflux disease patients. PMID- 29275583 TI - [Clinical application of oxycodone combined with dexmedetomidine in percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinomas]. AB - Objective: To explore the effects of oxycodone combined with dexmedetomidine in percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinomas. Methods: Sixty patients who underwent percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinomas were randomly divided into fentanyl group (group A) and oxycodone group( group B), with 30 patients in each group. Patients in group A were injected with fentanyl (2 MUg/kg), and patients in group B were injected with oxycodone (0.2 mg/kg). All the patients were injected with dexmedetomidine, with a loading dose of 0.5 MUg/kg for 10 minutes and a continuous infusion rate of 0.2 MUg.kg(-1).h(-1) until the end of the operation. The changes of heart rate (HR), mean arterial pressure (MAP), pulse oxygen saturation (SPO(2)) and bispectral index (BIS) were monitored at different time points: time when patients entering the operating room (T0), the beginning of operation (T1), 10 minutes after operation (T2), the end of operation (T3), 15 minutes after the end of operation (T4). The incidence of side effects (nausea and vomiting, respiratory depression and body movements) was assessed. The visual analogue scale (VAS) scores were also recorded at T0, T3 and an hour postoperatively. Results: Five patients of Group A had the body movements during the operation, and it was improved after injecting with fentanyl 2 MUg/kg. Compared with T0, HR in two groups decreased significantly at T2 (P<0.05). At each time point, the difference of MAP, HR, SPO(2) and BIS was not statistically significant in two groups. The incidence of Nausea and vomiting, body movements was lower in group B than that in group A(P<0.05). The VAS scores were lower in group B than that in group A at T3 and an hour postoperatively (P<0.05). Conclusion: The combination of oxycodone and dexmedetomidine can be used safely and effectively in percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinomas, and it shows more effective analgesia and less side effects. PMID- 29275584 TI - [DNA methylation modification of BRMS1 in triple-negative breast cancer and its correlation with tumor metastasis]. AB - Objective: To investigate the effect of methylation status of breast cancer metastasis suppressor gene 1 (BRMS1) on the expression of breast cancer and the biological behavior of cancer cells in triple-negative breast cancer (TNBC). Methods: The expression of BRMS1 in TNBC tissues and corresponding non-malignant tissues and its relationship with clinicopathological parameters were detected by immunohistochemistry. The mRNA and protein expression of BRMS1 in normal breast epithelial cells and TNBC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The methylation specific polymerase chain reaction (MSP) was used to detect the methylation status of BRMS1 in each cell. These cells were treated with demethylated preparations (5-Aza-dC) to re activate BRMS1 expression. Using tumor cell invasion assay to detect influence of BRMS1 demethylation on the invasion capacity of cancer cells. The data were statistically analyzed. Results: The positive expression rate of BRMS1 protein in TNBC tissues was significantly lower than that in corresponding non-malignant tissues (chi(2)= 6.635, P<0.05). The mRNA expression level of BRMS1 in patients with lymph node metastasis was significantly lower than those with no lymph node metastasis (P=0.018). The down-regulation of BRMS1 expression was related to the methylation of DNA promoter, which was statistically significant (chi(2)=14.68, P<0.05). The mRNA and protein expression of BRMS1 was also correlated with tumor size and TNM staging (P=0.000-0.003). After using 5-Aza-dC, the number of cells with invasive capacity was significantly lower than those of the control group (t=3.262-10.72, P<0.05). Conclusions: The decrease of BRMS1 expression in TNBC cells is related to the methylation of DNA. Demethylation can inhibit the invasion of breast cancer cells. PMID- 29275585 TI - [Impact of the implementation of Beijing Tobacco Control Regulation on outpatient visits for smoking cessation in Beijing Chaoyang Hospital]. AB - Objective: To investigate the impact of the implementation of Beijing Tobacco Control Regulation on outpatient visits for smoking cessation in Beijing Chaoyang Hospital. Methods: The outpatient visits and the proportion of returned cases to the total outpatient visits for smoking cessation in Beijing Chaoyang Hospital in past five years (2012-2016) that was before and after the implementation of Beijing Tobacco Control Regulation (June 1(st,) 2015) were analyzed. Time series seasonal index method was used to analyze seasonal variations in the outpatient visits. Results: From the implementation of Beijing Tobacco Control Regulation to December 31(th,) 2016, the average monthly outpatient visits for smoking cessation was significantly increased compared to that before the implementation [(101+/-37) vs (48+/-17), t=-7.486, P<0.001]. Meanwhile, the proportion of returned cases to the total outpatient visits was also significantly increased compared to that before the implementation [30.4% (582/1 912) vs 8.2% (161/1 966); chi(2)=309.8, P<0.001]. In addition, there were seasonal fluctuations in the number of outpatients from 2012 to 2016 , during which the outpatient visits started to increase in the second and third quarter (summer and fall) and peaked in June, but became less in the first and fourth quarter (spring and winter), and reached its nadir in January. Conclusions: With the implementation of Beijing Tobacco Control Regulation, the outpatient visits for smoking cessation have increased. Moreover, there is seasonal fluctuation in the outpatient visits for smoking cessation. PMID- 29275586 TI - [Relationship between screening and colorectal cancer incidence: a systematic review and meta-analysis]. AB - Objective: To explore a relationship between screening and incidence for colorectal cancer (CRC). Methods: Medline, Scopus, BIOSIS Previews, and the Cochrane Library were searched for studies, which included any randomized controlled trial (RCT) about CRC screening with a report on using endoscopy in screening arms and a usual care in control arms. Results: Nine qualified trials, four one-time and five two-or-more-time screening programs, were included in this review with 997 131 persons randomized and a median follow-up of 10-28 years. In an intention-to-screen analysis, screening was associated with a reduced incidence of advanced CRCs by 10%-60%. Compared with control groups, incidence of CRC firstly increased and then decreased following a screening procedure. Five RCT with six screening arms reported incidences at different follow-up time points, and the incidence ratios at the last time of follow-up were 0.96 (95%CI: 0.86-1.06), 0.80 (95%CI: 0.70-0.92), 1.02 (95%CI: 0.91-1.14), 0.80 (95%CI: 0.70 0.90), 0.83 (95%CI: 0.73-0.94) and 0.94 (95%CI: 0.85-1.05) at the 9.0th, 10.9th, 13.0th, 18.0th, 18.0th, and 19.5th year after baseline, respectively. Compared with population-based screening, people in the hospital/clinic-based screenings had more benefits from CRC incidence reduction, particularly for those with high endoscopy rates, more lesions detected and resected by screening. Conclusions: This study indicates that screening is likely associated with reduction of CRC incidence after 10 years since baseline screening, and this reduction seems to be highly affected by CRC risk of population screened, screening procedure program, and compliance to screening program including accepting endoscopy. PMID- 29275587 TI - [Pay attention to brain functional connectivity of resting state functional magnetic resonance imaging in Alzheimer's Disease]. PMID- 29275588 TI - [Impairments of gray matter in MRI-negative epileptic patients with different seizure types]. AB - Objective: To investigate the damage of gray matter structure in MRI-negative epilepsy patients with different symptoms by voxel-based morphometry (VBM). Methods: From June, 2009 to October, 2016, ninety MRI-negative epilepsy patients and thirty-five healthy volunteers underwent the 3T magnetic resonance imaging scan in Nanjing General Hospital. The patients were divided into three groups, including idiopathic generalized tonic-clonic seizure (I-GTCS), secondarily generalized tonic-clonic seizure (S-GTCS), and partial seizure (PS) according to different symptoms. The three-dimensional high-resolution T1 structural MRI data was obtained for the voxel-based morphometry. Data of gray matter structure from four groups were compared using one-way analysis of variance (ANOVA). An independent-sample t test was performed in order to compare gray matter volume of the three patient groups with controls respectively. According the results of ANOVA, impaired brain regions were selected as regions of interest in order to carry out correlation analysis between gray matter volume and disease duration. Results: ANOVA showed significant differences in gray matter structure of bilateral thalamus and frontal lobe between four groups (alphasim correction, P<0.01). Independent-sample t test showed that the volume of bilateral thalamus and frontal lobe decreased in all three patients groups (alphasim correction, P<0.01) .The volume of bilateral thalamus showed significantly negatively correlation with disease duration in I-GTCS patients (r=-0.466, P<0.01). Conclusions: Generalized seizures and partial seizures all can cause damage to the gray matter structure, especially in thalamus and frontal lobe. The impairments of thalamus and frontal lobe in patients with different seizure types are different with the progression of disease, which suggests that influences of different epilepsy seizures on the thalamo-cortical network are different. PMID- 29275589 TI - [Characteristics of cognitive impairment and the resting state functional MRI in patients with leukoaraiosis]. AB - Objective: To investigate the features of cognitive impairment and potential physiopathologic mechanism using neuropsychological assessment and resting state functional magnetic resonance imaging (rs-fMRI) in patients with leukoaraiosis (LA). Methods: A total of 13 patients with LA (LA group) and 13 healthy controls (NC group) from Shanxi Provincial People's Hospital between January and June 2016 were recruited. The two groups were matched for age, sex, education, and vascular risk factors. All the subjects underwent neuropsychological assessment and the scan of rs-fMRI. The neuropsychological scores and the brain areas had significant differences of cerebral spontaneous activity in resting state of the two groups were compared, and the relationship between the scores and the amplitude of low frequency fluctuation (ALFF) were evaluated in these areas. Results: LA group was associated with comprehensive cognitive impairment, including minimum mental state examination (MMSE) (LA group: 23.3+/-10.7 vs NC group: 29.7+/-0.6), montreal cognitive assessment (MoCA) (22.7+/-10.7 vs 29.5+/ 0.7), digit span test (DS) forwards (6.5+/-3.2 vs 8.7+/-1.1) and backwards (4.2+/ 2.2 vs 6.2+/-0.9), trail making test (TMT) part A (168+/-136 vs 47+/-10), immediate memory (6.1+/-3.5 vs 11.0+/-2.2) and delayed memory (4.7+/-2.8 vs 11.0+/-2.4) of auditory verbal learning test (AVLT), Stroop B (60+/-34 vs 32+/-7) and C (127+/-72 vs 48+/-12), verbal similarity test (16.5+/-8.1 vs 23.1+/-2.5) (all P<0.05). Compared with the NC group, patients with LA showed decreased ALFF in areas of the right posterior cingulate cortex (PCC), precuneus_R, cuneus, postcentral_R, precentral_R, calcarine_R (all P<0.05). After adjustment for the influences of age, sex and education, the correlation analysis showed that right PCC, precuneus_R, cuneus, postcentral_R, etc, were closely related with cognitive impairment. Conclusions: Patients with LA exhibits significant cognitive impairment, such as executive function, memory, attention and information processing speed. And cognitive impairment of LA is related to abnormal cerebral spontaneous activity, especially in areas of right PCC, precuneus_R, cuneus, etc. PMID- 29275590 TI - [Parkinson's disease: diffusion kurtosis imaging and the correlation with clinical manifestations]. AB - Objective: Using magnetic resonance diffusion kurtosis imaging (DKI) to evaluate the microstructure changes of deep brain nucleus in Parkinson's disease (PD) as well as the correlation with clinical manifestations. Methods: Thirty-two PD patients were recruited into this study. Twenty gender and age matched healthy subjects served as the control group. All participants underwent MRI examinations, including T(1)WI, T(2)WI, DWI, susceptibility weighted imaging (SWI) and DKI. The original DKI imaging data were processed offline to calculate two parametric maps, including mean kurtosis (MK) value and fractional anisotropy (FA) value. Two DKI parameters measured from head of substantia nigra were compared between the two groups using t-test or Mann-Whitney U test according to data distribution. The correlations of the two DKI parameters in the substantia nigra of PD patients with the disease duration and clinical scales were tested by Spearmen or Pearson analysis according to data distribution. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of MK value in the substantia nigra for PD. Results: MK value in the substantia nigra of PD group (1.29+/-0.05) was significant higher than that of the control group (1.26+/-0.06) (t=2.24, P=0.03). There was no significant difference in FA value between the two groups. Spearmen correlation analysis revealed that there was no significant association of two DKI parameters in substantia nigra of PD patients with the disease duration and clinical scales. Conclusion: MR DKI of deep brain nucleuses can be useful for the diagnosis of PD, but it is not suitable to evaluate the degree of PD clinical symptoms. PMID- 29275591 TI - [Dysfunctional resting-state connectivity of default mode network in adolescent patients with first-episode drug-naive major depressive disorder]. AB - Objective: To study resting-state functional connectivity (FC) of default mode network (DMN) in adolescent patients with first-episode drug-naive major depressive disorder (MDD). Methods: We enrolled thirty first-episode and drug naive adolescent MDD patients and twenty-nine adolescent healthy control (HC) participants in the First Affiliated Hospital of Zhengzhou University. There were no differences in age, sex, and education between the MDD and HC group. Resting state functional magnetic resonance images (fMRI) was performed. We selected posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) of DMN as regions of interests (ROI). The differences of these regions from the whole brain functional connectivity were analyzed. The relations between abnormalities in FCs of DMN and clinical variables were further investigated. Results: Compared to the HCs, the MDD patients had congruently reduced FCs between the PCC and cerebellum, temporal cortices, occipital cortices, fusiform, dorsolateral prefrontal cortex. MPFC not only had reduced FCs with fusiform, temporal cortices, anterior cingulate cortex, but also had enhanced FCs with occipital cortices, parietal cortices, and precentral gyrus. In addition, the increased FC between the right MPFC and right precentral gyrus was positive correlated with Hamilton Rating Scale for Depression (HAMD) scores (r=0.38, P=0.04). The reduced FC between the left middle temporal gyrus and left PCC as well as the enhanced FC between the right middle cingulum and right MPFC were positive correlated with the duration of depression since onset (r=0.39, P=0.03; r=0.38, P=0.04). Conclusions: These findings show dysfunctional DMN connectivity of adolescent MDD patients. Neurodevelopmental abnormalities in DMN may present in adolescent MDD. PMID- 29275592 TI - [The effect of follicular fluid from patients with endometriosis, follicle stimulating hormone and bone morphogenetic protein 15 on the proliferation and progesterone secretion of granular cells]. AB - Objective: The study was designed to evaluate the effect of follicular fluid from patients with endometriosis, follicle stimulating hormone (FSH), bone morphogenetic protein 15 (BMP-15) on the proliferation and progesterone secretion of human luteinized granular cells in vitro. Methods: Cumulus granulosa cells were collected from the patients who underwent in vitro fertilization and embryo transfer (IVF-ET) ovulation due to tubal or male factor infertility on the day of the retrieval. The cells in the control group were cultured with complete medium of DMEM/F-12, an extra of FSH at a dose of 12 MUg/L was added in the FSH group, an extra of BMP-15 at a dose of 6 MUg/L was added to the BMP-15 group, an extra of 5% of the follicular fluid from the patients with tubal or male factor infertility was added to the tubal group, an extra of 5% of the follicular fluid from the patients with endometriosis infertility was added to the endometriosis group, an extra of 5% of the follicular fluid from the patients with endometriosis infertility plus FSH at a dose of 12 MUg/L were added to the endometriosis plus FSH group, and an extra of 5% of the follicular fluid from the patients with endometriosis infertility plus BMP-15 at a dose of 6 MUg/L were added to the endometriosis plus BMP-15 group. Hemacytometer counting method was used to observe the growth of cells after 48 hours, and chemiluminescence method was utilized to measure the level of progesterone in culture supernatant. Results: The cell proliferation was enhanced in the FSH group, while the proliferation was inhibited in the endometriosis group and the endometriosis plus BMP-15 group, compared to the control group, both of which, were statistically significant. Compared to the control group, the progesterone levels from the culture supernatant of granular cells were significantly elevated in the FSH group, tubal group and endometriosis group. The secretion of progesterone in the endometriosis group was lower than that in the tubal group. After addition of FSH into the endometriosis group (the endometriosis plus FSH group), the secretion level of progesterone was significantly increased, compared to the control group and the endometriosis group. After adding BMP-15 into the endometriosis group (the endometriosis plus BMP-15 group), the secretion level of progesterone was increased, compared to the control group. Conclusions: FSH, but not BMP-15, was able to enhance the proliferation and progesterone secretion of granular cells. The proliferation of granular cells and secretion of progesterone were inhibited by the follicular fluid from patients with endometriosis, which was reversed by FSH. However, BMP-15 had no effect on the outcome of follicular fluid from patients with endometriosis. PMID- 29275593 TI - [Impact on the incidence of postoperative ventricular arrhythmias after cardiac resynchronization therapy defibrillator with quadripolar lead]. AB - Objective: To evaluate incidence of postoperative ventricular arrhythmias in patients who received cardiac resynchronization therapy defibrillator (CRT-D ) with left ventricular quadripolar lead. Methods: The patients received CRT-D who had complete follow-up data in Anhui Provincial Hospital from June 2013 to June 2016 were included and divided into quadripolar lead group and bipolar lead group according to the type of left ventricular lead. And ventricular arrhythmia (VA), implantable cardioverter-defibrillator (ICD) shocks treatment, antitachycardia pacing therapy (ATP), and other indicators of the two groups were compared. Prognosis of the two groups was assessed by re-hospitalization for heart failure and cardiac death. Results: Of the 220 patients enrolled in the study, 58 patients were in quadripolar lead group and 162 in bipolar lead group, and there were no significant differences in baseline characteristics between the two groups. The VA episode per patient was not significantly different between the two groups [(0.60+/-2.38) VA per person vs (0.93+/-2.24) VA per person, P=0.055]; the quadripolar lead group had significantly lower burden of VA compared with bipolar lead group [(0.22+/-0.91) per person-year vs (0.46+/-1.13) per person year, P=0.044]. Compared with bipolar lead group, there were significant reduction in both the ICD shocks per patient and the burden of ICD shocks in quadripolar lead group: [(0.12+/-0.36) shocks per person vs (0.23+/-0.52) shocks per person, P=0.034] and [(0.04+/-0.17) per person-year vs (0.12+/-0.46) per person-year, P=0.029], respectively. There were no significant differences between the two groups in both the ATP per patient and the burden of ATP: [(1.07+/-3.77) ATP per person vs (1.26+/-3.01) ATP per person, P=0.073] and [(0.38+/-1.39) per person-year vs (0.63+/-1.48) per person-year, P=0.058], respectively. And there were no significant differences between the two groups for the survival (P=0.496). Conclusion: Compared with bipolar lead group, the burden of VA could be significantly reduced after CRT-D in the quadripolar lead group. PMID- 29275594 TI - [Comparison of early clinical effects of ablation with surgery treatment in patients with hypertrophic cardiomyopathy]. AB - Objective: To compare the early clinical effect of septal myectomy and percutaneous transluminal septal myocardial ablation (PTMSA) on the left ventricular outflow obstruction and the rate of complication in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods: A total of 204 patients with HOCM who received septal reduction treatment were recruited. These patients were divided into two groups, surgery group (n=135) (65 patients with modified Morrow procedure, 70 patients with non-Morrow myomectomy) and PTMSA group (n=69). The baseline characteristics, disease status, other history of surgery and echocardiography parameters before and after septal reduction were collected, as well as the complication within 1 week after operation. Results: The mean age in surgery group was (46+/-14) years old, with 76 males (56.3%); mean age was (47+/ 11) years old and with 51 males (73.9%) in PTMSA group. There was no significant difference in age, gender, the time of symptom and diagnosis, syncope, family history and atrial fibrillation between the two groups (all P>0.05). The proportion of mitral valve prolapse in the surgery group was higher than that in PTMSA group (75.8% vs 44.2%, P<0.05). Baseline left ventricular outflow tract (LVOT) gradient was comparable (82.7 mmHg in surgery group vs 77.7 mmHg in PTMSA group, P>0.05). The mean resting LVOT gradient after septal reduction therapy was lower (16.55 mmHg in surgery group, 26.68mmHg in PTMSA group) than that before operation, with lower gradient in surgery group (P<0.05). Compared with PTMSA group, the duration of hospitalization was longer in surgery group (P<0.05). There was similar rate of operation related complications in the two groups. Conclusions: Both septal reduction therapies can improve the LVOT obstruction, more significant in surgery group, but with longer hospital stay. The rate of operation related complication is similar in both groups. PMID- 29275595 TI - [Clinical efficacy of rivaroxaban in prevention and treatment of postoperative deep vein thrombosis for severe traumatic brain injury]. AB - Objective: To explore the clinical efficacy of rivaroxaban in the prevention and treatment of postoperative deep vein thrombosis (DVT) for severe traumatic brain injury (sTBI). Methods: Patients with sTBI who met the inclusion criteria were enrolled in this study, including 119 males (75.8%) and 38 females (24.2%), aged (38.75 +/- 11.98) years old. DVT was prevented and treated according to the DVT screening and anticoagulation regimen. Intermittent venous compression was used on all of the patients to prevent DVT, and D-dimer dynamic monitoring and regular ultrasound were performed to screen for DVT. For patients with stable intracranial hemorrhage, rivaroxaban was used when the D-dimer was declining continuously and high risks exist at the same time, or the DVT was diagnosed. Drug withdrawal was performed according to the regimen. The clinical information, D-dimer dynamic changes, rivaroxaban application, DVT, and bleeding complications were analyzed retrospectively. Results: None of the patients with continuously declining D-dimer was diagnosed with DVT according to the ultrasound examination. Of the 45 patients without progressively declining D-dimer, 43 cases were diagnosed with DVT. Rivaroxaban was used in 47 cases (29.9%) to prevent DVT and 43 cases (27.4%) to treat DVT, and the medication time was (16.3+/-6.5) and (49.3 +/- 9.9) days, respectively. None was diagnosed with DVT after prophylactic administration, and 1 case relapsed after therapeutic administration. During the 6-months follow-up after injury, hematuria occurred in 3 cases, tracheotomy errhysis in 1 case and hemorrhoids bleeding in 1 case. Symptomatic pulmonary embolism, intracranial hemorrhage and fatal bleeding did not occur in any of the cases. Conclusions: The application of rivaroxaban is safe and effective in preventing and treating the postoperative DVT. PMID- 29275596 TI - [Structural changes of brain gray matter in male long-term smokers under magnetic resonance imaging]. AB - Objective: To evaluate gray matter structure changes in long-term male smokers by voxel-based morphological method. Methods: Fifty long-term smokers and 37 non smoking healthy volunteers were scanned with Siemens Skyro 3.0T magnetic resonance scanner from August 2014 to August 2016. The subjects underwent routine MRI (excluding intracranial lesions) sequences and 3D-T1 structural sequences (3D mprage). SPM8 pretreatment based on Matlab was used to analyze the structural data. All of the data were analyzed by SPM8 software. The data were compared between groups with independent sample t test. Spearman correlation analysis was used to analyze the relationship between gray matter volume (GMV) and smoking data of two groups. Results: The gray matter volume of bilateral thalamic, right supramarginal gyrus, left supramarginal gyrus and left putamen of smoking group were (0.55+/-0.07), (0.40+/-0.05), (0.48+/-0.07) and (0.14+/-0.04) voxels, respectively, and the gray matter volume of the corresponding gyri in control group were (0.61+/-0.09), (0.43+/-0.06), (0.54+/-0.07) and (0.16+/-0.03) voxels, respectively; and the gray matter volume of smoking group were all lower than those in control group (t=-3.81, -3.51, -3.86, -2.33, all P<0.05), family wise error (FWE) correction (P<0.05). The gray matter volume of bilateral thalamus, right supramarginal gyrus and left putamen was negatively correlated with smoking index (r=-0.368, -0.189, -0.274, all P<0.05), and also negatively correlated with smoking years (r=-0.391, -0.221, -0.355, all P<0.05), and bilateral thalamus gray matter volume was negatively correlated with daily cigarette smoking (r=-0.186, P<0.05). Conclusion: The changes of brain structure of smokers mainly occur on reward-related pathways and marginal systems, and related to accumulation of cigarette smoking. PMID- 29275597 TI - [Combined use of wide-detector and adaptive statistical iterative reconstruction V technique in abdominal CT with low radiation dose]. AB - Objective: To investigate the image quality and radiation dose with wide detector(80 mm) and adaptive statistical iterative reconstruction-V (ASIR-V) technique at abdominal contrast enhanced CT scan. Methods: In the first phantom experiment part, the percentage of ASIR-V for half dose of combined wide detector with ASIR-V technique as compared with standard-detector (40 mm) technique was determined. The human experiment was performed based on the phantom study, 160 patients underwent contrast-enhanced abdominal CT scan were prospectively collected and divided into the control group (n=40) with image reconstruction using 40% ASIR (group A) and the study group (n=120) with random number table. According to pre-ASIR-V percentage, the study group was assigned into three groups[40 cases in each group, group B: 0 pre-ASIR-V scan with image reconstruction of 0-100% post-ASIR-V (interval 10%, subgroups B0-B10); group C: 20% pre-ASIR-V with 20%, 40% and 60% post-ASIR-V (subgroups C1-C3); group D: 40%pre-ASIR-V with 40% and 60% post-ASIR-V (subgroups D1-D2)]. Image noise, CT attenuation values and CNR of the liver, pancreas, aorta and portal vein were compared by using two sample t test and One-way ANOVA. Qualitative visual parameters (overall image quality as graded on a 5-point scale) was compared by Mann-Whitney U test and Kruskal-Wallis H test. Results: The phantom experiment showed that the percentage of pre-ASIR-V for half dose was 40%. With the 40% pre ASIR-V, radiation dose in the study group was reduced by 35.5% as compared with the control group. Image noise in the subgroups of B2-B10, C2-C3 and D1-D2 were lower (t=-14.681--3.046, all P<0.05) while CNR in the subgroups of B4-B10, C2-3 and D1-D2 were higher(t=2.048-9.248, all P<0.05)than those in group A, except the CNR of liver in the arterial phase (AP) in C2, D1 and D2 and the CNR of pancreas in AP in D1 (t=0.574-1.327, all P>0.05). The subjective image quality scores increased gradually in the range of 0-60% post-ASIR-V and decreased with post ASIR-V larger than 70%. The overall image quality of subgroup B3-B8, C2-C3 and D1 D2 were higher than that in group A (Z=-2.229--6.533, all P<0.05). Conclusion: Compared with stand-detector together with ASIR technique, wide-detector combined with 40% pre-ASIR-V technique with 60% post-ASIR-V image reconstruction can reduce radiation dose while maintain good overall image quality. PMID- 29275598 TI - [Feasibility of susceptibility weighted imaging in the evaluation of renal fibrosis induced by unilateral ureteral obstruction in white rabbits]. AB - Objective: To evaluate the feasibility of susceptibility weighted imaging (SWI) to reflect the progression of renal fibrosis (RF) induced by unilateral ureteral obstruction (UUO) in rabbits. Methods: Total of 32 New Zealand white rabbits (aged 4-5 months) were used to establish the UUO model (RF group) and were divided into 4 subgroups (including RF-2W group, RF-4W group , RF-6W group and RF 8W group) according to the duration of obstruction(2, 4, 6 and 8 weeks). Another 8 rabbits, underwent sham operation, were used as the control group (Sham group). T2 weighted imaging (T(2)WI) and SWI sequences were performed on the rabbits at 2, 4, 6 and 8 weeks after UUO, respectively. Rabbits were sacrificed and specimens were obtained after MR examination, then hematoxylin&eosin staining and Masson staining were performed to explore the renal tubular injury and interstitial fibrosis. The relationship between the relative signal-to-noise ratio(rSNR)measured on the SWI fusion maps and the degree of renal fibrosis was analyzed. Analysis of variance was used to compare the difference of rSNRs among 5 groups. Results: The rSNRs of the inner medulla gradually decreased over time, the rSNRs of Sham group, RF-2W group, RF-4W group, RF-6W group and RF-8W group was 2.29+/-0.18, 1.73+/-0.30, 1.67+/-0.08, 1.42+/-0.28, 1.12+/-0.15, respectively (F=25.876, P<0.01). In RF-2W group, the rSNRs of the outer medulla and cortex increased when compared with those in the Sham group, then they decreased gradually over time in the other groups (F=5.230, 7.621, both P<0.05). The pathological results demonstrated that the morphology of renal tubules in Sham group was normal and no apoptosis or necrosis was seen in the tubular epithelial cells. In the RF-2W group, the main pathological manifestations included renal tubules dilatation, tubular epithelial cell degeneration or necrosis and the infiltration of inflammatory cell. In Masson staining, lots of blue areas were present in the interstitial. As the obstruction time prolonged, the renal tubular collapse, inflammatory cells and fibroblasts increased significantly. Meanwhile blue area also increased significantly in Masson staining. Conclusion: SWI can be used as a noninvasive method to evaluate the pathological progression of fibrosis in the rabbit UUO model. PMID- 29275599 TI - [Hypoxia inducible factor-1alpha deSUMOylation reduces the stemness maintenance ability of endometrial cancer stem cell and increases its chemosensitivity]. AB - Objective: To reduce the stemness maintenance ability of endometrial cancer stem cell and increase its sensitivity to chemotherapy by inducing hypoxia inducible factor 1alpha (HIF-1alpha) protein deSUMOylation. Methods: Lentiviral plasmid mediated ubiquitin carrier protein 9 (Ubc9) gene silencing was transgened into KLE endometrial carcinoma cells. The expression of Ubc9, small ubiquitin-related modifier 1(SUMO1) and HIF-1alpha protein was detected by Western blotting. Then tumor stem cells clones were cultured in 96 well plates, and these clone balls diameter were calculated. Cell cycles were determined by flow cytometry. MTT cytotoxicity assay and flow cytometry method were used to test sensitivity of cisplatin to endometrial cancer stem cell. Results: The results of Western blotting showed that Ubc9 gene was silenced well, and the covalent binding state of SUMO-1 and HIF-1alpha protein levels were significantly decreased (P<0.05). Ubc9 gene silencing in endometrial cancer cells reduced clone formation rate by (31.61+/-5.29)% down to (11.42+/-3.07)%, while the cell cycle shift from G1 to G2. IC50 of cisplatin decreased from 44.37 mg/L to 7.39 mg/L, and the rate of cell apoptosis by (41.59+/-5.37)% down to (26.22+/-4.03)%. Conclusion: The stemness maintenance ability of endometrial cancer stem cell can be reduced through deSUMOylation of HIF-1alpha protein by silencing Ubc9 gene expression, and their sensitivity to chemotherapy be enhanced, which provides a new reference for future gene therapy of endometrial carcinoma. PMID- 29275601 TI - [The need to focus on the immunological mechanism and therapy strategies of Secondary infection in sepsis]. PMID- 29275600 TI - [Effect of intermittent negative pressure on matrix metalloproteinase 9 and transforming growth factor beta of tendon-bone interface and joint fluid after reconstruction of anterior cruciate ligament in rabbits]. AB - Objective: To study the effect of intermittent negative pressure on matrix metalloproteinase 9 (MMP)-9 and transforming growth factor beta of tendon-bone interface and joint fluid after reconstruction of anterior cruciate ligament in rabbits. Methods: A total of twenty-four New Zealand white rabbits were randomly selected hind leg of negative group, contralateral hind leg as control.Reconstruction of the anterior cruciate ligament was done by autogenous semitendinosus of rabbit.Joint of the negative pressure side placed drainage tube connecting the micro-negative pressure aspirator, and maintained an intermittent, low-intensity negative pressure.Control side placed ordinary drainage tube.Drainage tube of both sides was pulled out at the same time after 5 days.After 6 weeks, joint fluid and femur-ligament-tibia complex were obtained for study of expression of MMP-9 and TGF-beta in joint fluid and tendon-bone interface. Result: Twenty-three rabbits were included in the study because of one rabbit joint infections.Detection of joint fluid showed that MMP-9 content is significantly lower in negative group than that in the control group, and the difference is statistically significant [(8.9+/-1.3) pg/L vs (12.3+/-1.8) pg/L (P=0.002)]. TGF-beta content is significantly higher in negative group in joint fluid than that in the control group, and the difference is statistically significant [(19.0+/-2.2) pg/L vs (15.2+/-1.4) pg/L (P=0.000)]. Study of immunohistochemistry in tendon-bone interface found that expression of MMP-9 is lower in negative pressure group than that in the control group, and the difference is statistically significant (P=0.000). TGF-beta expression is significantly higher in negative group in tendon-bone interface than that in the control group, and the difference is statistically significant (P=0.000). Conclusion: Intermittent negative pressure may reduce content of MMP-9 in joint fluid and expression of MMP-9 in tendon-bone interface, increase content of TGF beta in joint fluid and expression of TGF-beta in tendon-bone interface after reconstruction of anterior cruciate ligament in rabbits. PMID- 29275602 TI - [Long-term outcomes of implanting drug-eluting stents for unprotected left main coronary artery disease patients with left ventricular systolic dysfunction]. AB - Objective: To analyze the clinical characteristics and prognosis of implanting drug-eluting stents (DES) for unprotected left main (ULM) coronary artery disease patients with left ventricular systolic dysfunction (LVSD). Methods: A total of 511 ULM coronary artery disease patients who underwent DES implantation from January 2005 to January 2012 in Department of Cardiology, Beijing Anzhen Hospital were included in the study. Based on left ventricular ejection fraction (LVEF), the patients were divided into three groups: LVEF<=40% (n=104), 41%<=LVEF<=49% (n=137), and LVEF>=50% (n=270). The clinical characteristics of patients undergoing DES implantation were retrospectively compared, and the effects of LVSD on ULM coronary artery disease were analyzed. Results: After comparison of clinical baseline data among three different LVEF groups, the incidence of peripheral vascular diseases, old myocardial infarction (OMI), multi-vessel lesions, complete revascularization and chronic total occlusion (CTO) was statistically different (P=0.002, P<0.001, P<0.001, P=0.049, P=0.001, respectively). However, there was no significant difference in the incidence of other clinical characteristics (all P>0.05). In terms of survival analysis, total mortality and cardiac mortality were both remarkably higher in LVEF<=40% group than those in LVEF>=50% group (both P<0.001). There was no statistical difference of total mortality between 41%<=LVEF<=49% group and LVEF>=50% group (P>0.05), while cardiac mortality was higher in LVEF>=50% group (P=0.027) . Besides, there was no significant difference among three groups in major adverse cardiac and cerebral events (MACCE), myocardial infarction(MI), cerebral infarction and target vessel revascularization (TVR) (all P>0.05). After adjusting for multiple clinical factors, total mortality and cardiac mortality were both remarkably higher in LVEF<=40% group than those in LVEF>=50% group (P=0.002, P<0.001), while there were no statistical differences of total mortality and cardiac mortality between 41%<=LVEF<=49% group and LVEF>=50% group (both P>0.05). In terms of MACCE, MI, cerebral infarction and TVR, there were also no significant differences among three groups (all P>0.05). Conclusion: For ULM coronary artery disease patients with LVSD, implanting DES is safe and effective, but for those with severe LVSD (LVEF<=40%), DES implantation showed an increased risk of long term death and therefore should be selected with great care. PMID- 29275603 TI - [Efficacy and safety of transbronchial cryobiopsy in the etiologic diagnosis of diffuse lung disease]. AB - Objective: To assess the efficacy and safety of transbronchial cryobiopsy (TBCB) for the etiologic evaluation of diffuse lung disease (DLD). Methods: Between December 2015 to April 2017, a total of 38 patients with DLD met the inclusion criteria for TBCB in the First Affiliated Hospital of Chongqing Medical University, and 35 of them consented to undergo the procedure under rigid or flexible bronchoscopy. On the tissues obtained from the 35 patients, histopathologic and microbiological evaluations were performed, and together with clinical and radiological manifestations, diagnoses were made and the efficacy of TBCB in the diagnosis of DLD was confirmed, and then therapies were planned accordingly. Complications of the biopsy procedures were recorded. Results: Of the 35 patients who were enrolled, 24 underwent TBCB under rigid bronchoscopy and 11 under flexible bronchoscopy. Another 3 patients refused the procedure due to disinclination to invasive examinations. One single procedure of TBCB took (51.8+/-19.2) min on average, the median number of tissues obtained was 6 (5, 8), and the median area of tissues was 15 (9, 20) mm(2).Definite diagnoses were reached in 33 patients, including idiopathic nonspecific interstitial pneumonia (n=8), connective tissue disease-interstitial lung disease (n=8), occupational lung disease (n=4), idiopathic pulmonary fibrosis (n=3), interstitial pneumonia with autoimmune features (n=3), tuberculosis (n=2), cryptogenic organization pneumonia (n=1), acute interstitial pneumonia (n=1), pulmonary infection (n=1), hypersensitivity pneumonia (n=1) and sarcoidosis (n=1). Diagnostic yield was 94.3% (33 out of 35 cases diagnosed). Pneumothorax occurred in 3 patients (1 patients with mild pneumothorax , 1 moderate and 1 severe), and were resolved with thoracic puncture or pleural drainage. Bleeding occurred in all 24 patients who received TBCB under rigid bronchoscopy (11 patients with mild bleeding, 12 moderate and 1 severe) and was controlled after coagulation measures. After one month of treatment according to the diagnoses acquired with cryobiopsy, the condition was cured in 1 patient (3.0%), alleviated in 17 (51.5%), stable in 11 (33.3%), and deteriorated in 4 (12.1%). Conclusion: TBCB yields reliable diagnoses with a good safety profile. PMID- 29275604 TI - [Prevention and treatment of Horner syndrome in treatment of head and face hyperhidrosis by thoracic sympathetic nerve modulation]. AB - Objective: By summarize the Prevention and Treatment of Horner Syndrome of CT guided thoracic sympathetic nerve modulation in the treatment of head and face Hyperhidrosis, reduce the occurrence of the complications. Methods: A retrospective analysis was made on 116 patients of CT-guided thoracic sympathetic nerve modulation in the treatment of head and face Hyperhidrosis in The First Hospital of Jiaxing from January 2010 to December 2016. Analysis the reasons of Horner syndrome and external management to sum up the corresponding prevention and treatment measures. Results: Under the guidance of CT positioning, 116 patients were successfully punctured to the intended target (both sides of the R3 above the rib head), after injection of local anesthetic plus contrast agent, CT scan showed there are 39 sides of the liquid parallel to the outside of pleural (26 sides) or over (13 sides) R1 above the rib head. CT scan again after the injection of anhydrous alcohol, there are 43 sides of the liquid parallel to the outside of pleural (24 sides) or over (19 sides) R1above the rib head.After the operation, 22 sides appeared Horner syndrome, 19 of which immediately give physiological saline 5 ml into the ipsilateral Satellite ganglion.Within 2 hours Horner's syndrome completely disappeared, while 3 cases were not treated, Horner syndrome lasts for 3 months to 2 years. Conclusion: The incidence of Horner syndrome relatively high during the CT-guided thoracic sympathetic nerve modulation to treatment of head and face Hyperhidrosis. Injecting 5 ml physiological saline into the ipsilateral Satellite ganglion immediately can completely eliminate this common complications. PMID- 29275605 TI - [Research on blood distribution of Tibetan population in Ali area]. AB - Objective: To explore the distribution of ABO blood group in the healthy population in the Ali area of Tibet, and to analyze the difference of blood group distribution between the Tibetan population in Ali and the Tibet Tibetan population. Methods: The blood distribution of 509 apparent healthy volunteers of Tueti County and Gal County, Tibet, which were randomly selected from September to November in 2016; 137 Tibetan blood donors, from 2016 September to2017 July and 84 Tibetan blood donors from 2015 August to 2017 July was analyzed retrospectively. The blood type was tested by the slide method. By reviewing the Chinese and foreign language database, seven articles on Tibetan blood group distribution were obtained. And the data of the blood distribution of the Ali area population and the Tibet Tibetan population were compared. Results: The ABO phenotype frequencies of 507 apparent healthy people, 137 blood donors and 84 recipients were B>O>A>AB. The composition ratio were 36.1%, 34.5%, 21.5 %, 7.9%; 40.1%, 35.0%, 17.5%, 7.3%; 39.3%, 34.5%, 20.2%, 6.0%.There was no statistically significant difference in blood group distribution between the donors and the recipients (P>0.05). And there was no significant difference in the blood group distribution between Ali and Shigatse, Nagqu, Lhasa, Shannan. However, the differences between Ali and Qamdo, Nyingchi areas were statistically significant. Conclusion: The geographical position of the blood from the west to east, B type shows a downward trend, O type blood composition ratio shows an upward trend. PMID- 29275606 TI - [Diagnostic value of urinary free cortisol in the subclinical Cushing's syndrome in patients with adrenal incidentaloma]. AB - Objective: To evaluate the efficacy of 24 h urinary free cortisol (24 h UFC) in the diagnosis of subclinical Cushing's syndrome (SCS), and explore the best diagnostic cut-off value. Methods: The clinical data of patients with adrenal incidentaloma in Chinese PLA General Hospital between January 2008 and December 2016 was retrospectively reviewed and analyzed. All SCS patients were diagnosed based on the current Cushing's syndrome (CS) guidelines and confirmed by histopathology and then treated as study group, and additional patients with non functional adrenal adenoma (NFA) were enrolled as control group. ROC curve was used to evaluate efficacy of 24 h UFC and 24 h UFC to creatinine ratio (UFCCR), and explore their best cut-off values. Results: There were 161 patients with NFA, of which contained 84 males and 77 females, with a mean age of (51.02+/-10.49) years old. There were 88 patients with SCS, of which contained 26 males and 62 females, with a mean age of (51.74+/-10.29) years old. The 24 h UFC and UFCCR levels were significant higher in SCS group than those in NFA group[510 (363, 698) nmol vs 335 (209, 467) nmol for 24 h UFC, and 7.82(4.79, 12.13) ml vs 4.82(2.41, 6.57)ml for UFCCR, both P<0.05]. ROC analysis showed that the optimal cut-off for 24 h UFC was 480 nmol (AUC 0.716, 95% CI: 0.648-0.784, with a sensitivity of 58.0% and a specificity of 79.4%) and the optimal cut-off for UFCCR was 6.84 ml (AUC 0.729, 95% CI: 0.662-0.796, with a sensitivity of 59.1% and a specificity of 78.7%). Conclusions: The recommended cut-off points of 24 h UFC and UFCCR for diagnosing SCS in AI patients were 480 nmol and 6.84 ml, respectively. PMID- 29275607 TI - [Effect of perioperative multi-day low dose ketamine infusion on prevention of postmastectomy pain syndrome]. AB - Objective: To investigate the effects of multi-day low dose ketamine infusion for postmastectomy pain syndrome (PMPS) after breast cancer surgery. Methods: This study was a prospective randomized controlled trial. From June 2015 to May 2016 in Affiliated Yiwu Hospital of Wenzhou Medical University, 66 patients with breast cancer surgery were randomly divided into control group (group C) and ketamine group (group K). Patients in group K were infused with 0.5 mg/kg of ketamine mixed in 250 ml of 0.9% normal saline in 1 h daily for 7 days. Patients in group C were infused the same dose of 0.9% normal saline. Anesthesia induction in both groups were given intravenous midazolam, sufentanil, propofol, vecuronium and intermittent positive pressure ventilation after tracheal intubation, anesthesia was maintained with propofol and remifentanil. After awakening, all patients were monitored in postanesthesia care unit (PACU) and given patient controlled intravenous analgesia(PCIA). Pain scores were assessed using visual analogue scales (VAS) during PACU, 4 h, 24 h and 2-5 d after surgery, simultaneously analgesic requirement were recorded. Patients were evaluated Hospital Anxiety and Depression Scale (HADS) 5 d after surgery . The patients were followed up for 6 months. At 3 m, 6 m after surgery, the incidence of PMPS, the level of pain, pain site and HADS scale were assessed. Results: The VAS score uring PACU, 4 h, 24 h and 2-5 d after surgery in group K( (2.5+/-0.8), (2.4+/ 0.5), (2.4+/-0.5), (2.0+/-0.4), (1.5+/-0.5), (1.0+/-0.4), 1(1), respectively) was lower than those in group C ((2.9+/-1.0), (2.9+/-0.6), (2.6+/-0.5), (2.3+/-0.5), (1.8+/-0.6), (1.5+/-0.5), 1(0), respectively). There was statistically difference between the two groups (all P<0.05). The consumption of analgesics required at each time postoperation in group K were also lower than that of group C(all P<0.05). Followed up for 6 months, 2 lost in group C, 1 lost in group K. The incidence of PMPS in group K at 3 months and 6 months after surgery was significantly lower(25% and 22%) than that in group C(52% and 45%)(chi(2)=4.729, 3.842, all P<0.05). There were no significant difference in pain level and site between two groups of PMPS patients (all P>0.05). There were no significant difference of HADS scale preoperative and 5 d after surgery between two groups (all P>0.05); and HADS scale in group K at 3 m and 6 m after surgery was significantly lower than that in group C(all P<0.05). Conclusion: Perioperative continuous multi-day low dose ketamine infusion can effectively reduce the incidence of PMPS after breast cancer surgery. PMID- 29275608 TI - [Application of the supine position in microsurgery for lesions of the cerebellopontine angle]. AB - Objective: To validate the usefulness of the supine position in microsurgery for lesions of the cerebellopontine angle (CPA) by the retrosigmoid approach. Methods: Thirty-nine patients with lesions (22 cases of tumor, 11 cases of trigeminal neuralgia and 6 cases of hemifacial spasm) of the CPA underwent tumor resection surgery or microvascular decompression surgery (MVDS). The patients were operated on in the supine position by retrosigmoid approach with the head turned 50 to 60 degrees away from the lesion and with slight forward flexion of the neck. Results: In the supine position, the surgery spent less time in the preoperative preparation period, and had minimal cerebellar retraction, with no resection of the cerebellum. There was no pressure sore and the brachial plexus injury in these patients. Gross total resection was achieved in 18 of patients, and subtotal resection happened in 4 patients. The vascular structures were separated from the trigeminal nerve or the facial nerve in microvascular decompression and thus the preoperative symptoms alleviated. Conclusions: In the supine position, the retrosigmoid approach alleviates cerebellar retraction, increases the exposure and gives better access to the CPA lesions. The associated postoperative complications are negligible. The method is more suitable for elder, debilitated or obese patients. PMID- 29275609 TI - [The study of renal safety in elderly patients with benign prostatic hyperplasia treated with alpha receptor blockers]. AB - Objective: To investigate the renal safety in patients with benign prostatic hyperplasia treated with tamsulosin hydrochloride. Methods: A retrospective analysis of 10 cases of patients, who had renal dysfunction after treatment with long-term tamsulosin hydrochloride. Results: The average duration of oral medicine was 2 to 24 months with an average of 7.2 months. The serum creatinine after discontinuation of tamsulosin hydrochloride decreased from 132.5 MUmol/L (100-208 MUmol/L, normal 59-104 MUmol/L) to 95.7 MUmol/L (73-122 MUmol/L, normal: 59-104 MUmol/L) (F=10.385, P=0.000). Conclusion: Preliminary results show that taking tamsulosin hydrochloride might lead to renal damage in old patients with benign prostatic hyperplasia. Safety is the premise, and the right medicine should be chosen for different side effects in order to protect the safety of patient. PMID- 29275610 TI - [Effects of Oridonin combined with Capecitabine on the proliferaction of MDA-MB 231 human breast cancer cells]. AB - Objective: To investigate the effects of oridonin combined with capecitabine on the proliferaction of MDA-MB-231 human breast cancer cells. Methods: Effect of different concentrations(10, 20 and 40 MUmol/L)of oridonin, capecitabine and their combination on the proliferation of MDA-MB-231 cells after incubation for 24 or 48 h was studied. Then, the effect of 5 MUmol/L of oridonin, capecitabine and their combination on cell colony formation was detected. Finally, influence of 20 MUmol/L of oridonin, capecitabine and their combination on morphological alteration of nucleus, cell cycle and apoptosis was explored. Results: The inhibition rate on MDA-MB-231 cells after incubation with 20 MUmol/L oridonin or capecitabine for 48 h was 49.5% and 58.6%, respectively, while the inhibition rate against proliferation of MDA-MB-231 cells reached 94.6% with combination of 20 MUmol/L oridonin and capecitabine. Cells incubated with combination of oridonin and capecitabine formed fewer and smaller colonies (P<0.01). Meanwhile, cells in the combination group arrested at S and G2/M phases at the same time, and combination of two drugs caused more apoptotic cells (P<0.01). Conclusion: Oridonin combined with capecitabine can synergistically inhibit the proliferation of MDA-MB-231 human breast cancer cells. PMID- 29275611 TI - [Study on changes of calpain and myocardial damage in rats with burn-blast combined injury]. AB - : Objective: To study myocardial damage and rules of calpain change in rats with burn-blast combined injury. Methods: One hundred and twenty-eight male SD rats were randomly divided into control group, burn group, blast group, burn-blast group, with 32 rats in each group. CONTROL GROUP: 37 degrees' warm water for 12 s; Burn group: 94 degrees' boiling water for 12 s; Blast group: 5 g cyclonite explode in 75 cm distance from left chest wall of rat; Burn-blast group: burn group and blast group combined modeling method. At 6, 24, 48, 72 h observation points after injury, abdominal aorta blood samples and myocardial specimen were collected. Left ventricular ejection fraction (EF), left ventricular fractional shortening index (FS) were measured through color Doppler ultrasound instrument; Myocardial tissue was stained with hematoxylin-eosin (HE); serum cardiac troponin I (CTnI) and creatine kinase isoenzyme (CK-MB) were detected; detection of cell apoptosis in myocardial tissue was performed by terminal deoxynucleotidyl transferase-mediated dUTP notch labeling technique (Tunel). Expression levels of calpain mRNA level and protein were detected with Real-time fluorescent quantitative polymerase chain reaction (RT-PCR) and Western imprinting method analysis; calpain activity was detected by fluorescence spectrophotometry. Results: The injury of burn-blast combined injured rats was obvious, including myocardial interstitial edema, large area of myocardial cell degeneration and disintegration and the number of neutrophil infiltration increased. Cardiac function decreased 24 h after injury in burn group, blast group, burn-blast group; both EF and FS were significant lower than those of control group (all P<0.05). FS at 48, 72 h and EF at 72 h in burn-blast group were significantly lower than those of burn group, blast group at the same time points (all P<0.05); the level of cTnI in burn-blast group rose and was higher than control group at all time points, higher than the burn group, blast group at 48 h (all P<0.05). CK MB in burn-blast group rats increased after injury, lowered at 24 h and rose again at 48 h. The level was significantly higher than control group and burn group (both P<0.05). Comparing to control group, myocardial apoptosis index in burn group, blast group and burn-blast group were significantly increased (all P<0.05). Those of burn group (25.3+/-4.0) at 24 h and (28.8+/-5.3) at 48 h were significantly lowered than burn-blast group (43.3+/-9.4), (53.3+/-10.4) at same time points, and burn group (31.9+/-6.7) at 72 h was significantly higher than blast group (17.3+/-6.3) (all P<0.05). Compared to control group, Calpain mRNA and protein expression in myocardial tissue were significantly increased in burn blast group at all time points (all P<0.05). Calpain activity reached the peak at 24 h after injury, then gradually declined, and was significantly higher than control group (all P<0.05). Conclusion: Calpain expression and activity increase in burn-blast combined injured rats which leads to myocardial damage. PMID- 29275612 TI - [Prevention and treatment of electrical burn injury: much progresses achieved yet further efforts still needed]. AB - Electrical burn injury is very common, including electrical contact burn, electrical arc burn, and lightning burn, etc. Electrical burn patients account for 0.04 to 5 percent of all burn victims in the developed countries, while it hit up to 27 percent in the developing countries, much more than the global average of 4.5 percent. Historical and recent data have shown that the electrical burn injuries in China, either for the case number, the proportion of burn patients in hospital, or the population incidence per year, are much higher than those of the developed countries and the global average. Before the 1960s, conservative treatment or skin grafts after repeated debridements were used for electrical burns, resulting in high rates of amputation and severe deformity. In the 1960s, transplantation of flaps after debridement in early stage were used for repairing wrist electrical burn wounds, breaking through the traditional conservative methods. In the 1980s, local, distant and island pedicled skin or myocutaneous flaps were widely used for early stage repair of electrical burn wounds. In recent years, along with the increasing experience of evaluating the blood vessel injuries and the development of microsurgical techniques, free flaps have been more and more used to cover the deep wounds of electrical burns in early stage, leading to much better effects and shorter length of hospital stay. With the persistent efforts of the burn specialists in the last decades, great improvements have been made for the treatment of electrical burn injuries in China. Future study on decoding the full mechanism of electrical burn injury, exploring new methods to save the injured but not yet necrotic tissue, are still needed to improve the treatment and reduce amputation and deformity of electrical burn injury. PMID- 29275613 TI - [Epidemiological investigation on 2 133 hospitalized patients with electrical burns]. AB - Objective: To analyze the epidemiological characteristics of the hospitalized patients with electrical burns in Institute of Burns of Tongren Hospital of Wuhan University & Wuhan Third Hospital (hereinafter referred to as Institute of Burns of Wuhan Third Hospital), so as to provide reference for the prevention and treatment of electrical burns. Methods: Medical records of all hospitalized burn patients in Institute of Burns of Wuhan Third Hospital from January 2004 to December 2016 were collected. Genders, ages, social categories, seasons of injury, total burn areas, depths of wounds, electrical voltages of injury, sites of wound, treatment methods, amputation rates, lengths of hospital stay, operation costs, hospitalization costs, and treatment outcomes of the electrical burn patients were collected. Treatment methods, lengths of hospital stay, operation costs, and hospitalization costs of the thermal burn patients were collected and compared with those of the electrical burn patients. Electrical voltages of injury, amputation rates, operation costs, hospitalization costs, and treatment outcomes were compared and analyzed between the electrical contact burn patients and the electrical arc burn patients. Data were processed with Chi square test and Wilcoxon rank-sum test. Results: During the 13 years, 23 534 burn patients were admitted to Institute of Burns of Wuhan Third Hospital, among whom 2 133 (9.1%) were with electrical burns, without obvious variation in admission number of electrical burn patients every year. There were 1 418 patients (66.5%) with electrical contact burns and 715 patients (33.5%) with electrical arc burns. The ratio of male to female was 11.2?1.0 among the electrical burn patients with known genders. The proportions of three age groups of more than 20 years old and less than or equal to 30 years old, more than 30 years old and less than or equal to 40 years old, and more than 40 years old and less than or equal to 50 years old were relatively higher, which were 18.3% (391/2 133), 22.1% (471/2 133), and 24.6% (525/2 133), respectively. The first three social category groups in proportions were workers, peasants, and preschool children, which were 57.9% (1 235/2 133), 14.6% (311/2 133), and 6.0% (128/2 133), respectively. Among the electrical burn patients with known seasons of injury, most cases were injured in summer (659 cases, accounting for 34.1%), obviously more than the proportions in autumn (537 cases, accounting for 27.8%), spring (455 cases, accounting for 23.5%), and winter (283 cases, accounting for 14.6%), with chi(2) values from 8.414 to 149.573, P values below 0.01. The group of patients with total burn areas less than 10% total body surface area (TBSA) occupied the highest proportion (1 603 cases, accounting for 75.15%), among whom 229 (10.74%) were with scattered small wounds which were less than 1% TBSA. The percentage of electrical contact burn patients with deep wounds was 79.1% (1 122/1 418), which was obviously higher than 2.5% (18/715) of the electrical arc burn patients (chi(2)=381.741, P<0.001). Among the patients with known electrical voltages of injury, patients injured by high voltage among the electrical contact burn patients accounted for 78.4% (469/598), which was obviously higher than 8.7% (11/127) of the electrical arc burn patients (chi(2)=227.893, P<0.001). The most common wound site of the electrical burn patients was upper limbs (1 650 cases, accounting for 63.2%), followed by lower limbs (382 cases, accounting for 14.6%), head and neck (292 cases, accounting for 11.2%), trunk (247 cases, accounting for 9.5%), and hip and perineum (40 cases, accounting for 1.5%). The operation rate of electrical burn patients was 32.4% (691/2 133), obviously higher than 19.1% (3 860/20 209)of the thermal burn patients during the same period (chi(2)=210.255, P<0.001). Wounds of 116 electrical contact burn patients were repaired with free flap by vascular anastomosis, of which 9 (7.8%) failed. The length of hospital stay, the operation cost, and the hospitalization cost of electrical burn patients were (28+/-29) d, (9 534+/-16 935) and (44 258+/-93 012) Yuan, respectively, obviously longer or higher than those of the thermal burn patients during the same period [(17+/-19) d, (2 990+/-8 916) and (23 291+/-88 340) Yuan, respectively, with Z values from -21.323 to -10.996, P values below 0.001]. The amputation rate and the death rate of electrical burn patients were 3.8% (82/2 133) and 0.8% (16/2 133) respectively. Compared with those of electrical arc burn patients, the amputation rate and the operation cost of electrical contact burn patients were obviously higher (chi(2)=36.970, Z=-11.351, P values below 0.001), and the length of hospital stay of electrical contact burn patients was obviously longer (Z=-5.181, P<0.001). There were no significant differences in hospitalization cost and treatment outcome between the electrical contact burn patients and the electrical arc burn patients (Z=-1.461, chi(2)=1.673, P values above 0.05). Conclusions: The number and the proportion of hospitalized electrical burn patients in Institute of Burns of Wuhan Third Hospital were relatively high, indicating a hard task of prevention for electrical burns in Wuhan area. Working-age workers and farmers, and preschool children were the key groups in prevention from electrical burns. The length of hospital stay, the operation cost, and the hospitalization cost of electrical burn patients were obviously higher than those of thermal burn patients. The amputation rate and the operation cost of electrical contact burn patients were obviously higher than those of electrical arc burn patients, but there were no obvious differences in hospitalization cost or treatment outcome between them. Actively using tissue flaps including free flap to repair of wounds may be helpful to reduce the amputation rate, improve the results, and shorten the time of treatment. PMID- 29275614 TI - [Wound repair and functional reconstruction of high-voltage electrical burns in wrists]. AB - Objective: To explore the methods and effects of wound repair and functional reconstruction of high-voltage electrical burns in wrists. Methods: From January 2009 to June 2016, 71 patients with high-voltage electrical burns in wrists were hospitalized, with 118 wrist wounds including 21 of type I, 69 of type II, 9 of type III, and 19 of type IV. According to the wrist injuries, different surgical operations were performed. Forearm amputation was conducted in 20 wrists with necrosis in the distal end. On the basis of fasciotomy for decompression, early debridement was performed on the other 98 wrist wounds. After debridement, wounds with area ranging from 10 cm*7 cm to 30 cm*18 cm were repaired with tissue flaps with abundant blood supply. Thirty-two wounds were repaired with pedicled groin flaps, 11 wounds with pedicled paraumbilical flaps, 3 wounds with pedicled anterolateral thigh island flaps, 9 wounds with combined abdominal axial pattern flaps, 37 wounds with free skin flaps or myocutaneous flaps, and 6 wounds with flow-through descending branch of lateral femoral circumflex artery flaps, with tissue flap area ranging from 12 cm*8 cm to 34 cm*20 cm. Ulnar artery or radial artery vascular reconstruction was performed in 20 wrist wounds. Forty-one donor sites were sutured directly, while 14 were closed by thin split-thickness skin grafts from same-side thighs, and 43 were closed by thin split-thickness skin grafts from opposite-side thighs. Fifty-three wrist wounds were performed with tendon and nerve repair surgery, of which 20 were performed with simple tendon and nerve release surgery. Flexor digitorum profundus tendons and (or) flexor pollicis longus tendons were reconstructed with autologous or allogeneic tendon transplantation in 33 wrist wounds, and the median nerve was repaired with sural nerve graft in 21 wrist wounds. In 6 to 24 months after the last operation, tendon function of 53 wrist wounds which had tendon repair was evaluated with finger total active motion (TAM) method, while median nerve function of 21 wrist wounds which had median nerve repair was evaluated with integrate estimation method. Results: (1) After forearm amputation, the incisions of 20 wrists with necrosis in the distal end were healed. (2) Among the 98 tissue flaps, 90 had good blood flow, while 8 had distal necrosis, of which 6 were healed after necrotic tissue removal and skin grafting, and two were sutured directly after debridement. Infection occurred under 7 flaps, of which 3 were healed by dressing change, and 4 were healed after second debridement. Twenty wrist wounds which had radial artery or ulnar artery repair had good blood supply of hand and amputation was avoided. During follow-up of 1 to 3 years, the incisions and flaps of patients who had tissue flap repair surgery healed well. (3) The excellent and good rate of TAM in each finger of the corresponding affected limbs of 53 wrist wounds which had tendon and nerve repair surgery was 51%. (4) Twenty wrists which had simple tendon and nerve release surgery were followed up for 1 to 2 years. The strength of muscle dominated by the median nerve was restored to grade V in 1 wrist, grade IV in 3 wrists, and grade III in 2 wrists. The strength of muscle dominated by the ulnar nerve was restored to grade IV in 3 wrists, with no recovery in other wrists. Sensory function examination showed grade S0 in 4 wrists, grade S1 in 2 wrists, grade S2 in 3 wrists, grade S3 in 8 wrists, and grade S4 in 3 wrists. Twenty-one wrists which had median nerve repair were followed up for 1 to 2 years. There was no recovery in muscle strength dominated by the median nerve. Sensory function examination showed grade S0 in 3 wrists, grade S1 in 5 wrists, grade S2 in 8 wrists, and grade S3 in 5 wrists. Conclusions: It is a good method to sequentially conduct early fasciotomy for decompression, early debridement, vascular reconstruction, transplant of tissue flap with abundant blood supply, tendon and nerve repair in repairing electrical burn wounds of wrists, avoiding amputation, and reconstructing hand function according to the condition of electrical burns of wrists. PMID- 29275615 TI - [Changes of platelet rheological behavior and the interventional effects of ulinastatin in rats with high-voltage electrical burns]. AB - Objective: To explore the influence of high-voltage electrical burns on the number of platelet aggregation, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) and the interventional effects of ulinastatin in rats with high voltage electrical burns. Methods: A total of 240 Sprague-Dawley rats were divided into sham injury (SI) group, simple electrical burn (SEB) group, normal saline (NS) group, and ulinastatin (UTI) group according to the random number table, with 60 rats in each group. The electrical current was applied to the outside proximal part of left forelimb of rats and exited from the outside proximal part of right hind limb of rats. Rats in groups SEB, NS, and UTI were inflicted with high-voltage electrical burn wounds of 1 cm*1 cm at current entrances and exits, with the voltage regulator and experimental transformer. Rats in group SI were sham injured through connecting the same equipments without electricity. At 2 min post injury, rats in group NS were intraperitoneally injected with 2 mL/kg NS, and rats in group UTI were intraperitoneally injected with 2*10(4) U/kg UTI of 10 g/L. At 15 min before injury and 5 min, 1 h, 2 h, 4 h, 8 h post injury, 10 rats in each group were selected to collect 5-7 mL blood of heart respectively. Blood of 0.05 mL were collected to make fresh blood smear for observing the number of platelet aggregation, and serum were separated from the remaining blood to determine content of beta-TG and PF-4 with enzyme-linked immunosorbent assay. Data were processed with analysis of factorial design of variance, student-Newman-Keuls test, Kruskal-Wallis H test, Wilcoxon rank sum test, and Bonferroni correction. Results: (1) At 15 min before injury, the numbers of platelet aggregation of rats were close among groups SI, SEB, NS and UTI (5.9+/-1.2, 5.8+/-1.2, 5.9+/-1.3, 5.9+/-1.1, respectively, with P values above 0.05). At 5 min, 1 h, 2 h, 4 h, 8 h post injury, the numbers of platelet aggregation of rats in group SEB were 57.2+/-16.3, 59.1+/-16.9, 60.8+/-20.6, 83.6+/-24.9, and 83.4+/-30.3, respectively, obviously more than those in group SI (6.0+/-1.3, 6.0+/-1.4, 5.9+/-1.4, 5.7+/-1.1, and 5.8+/-1.3, respectively, with P values below 0.001); the numbers of platelet aggregation of rats in group UTI were 29.6+/-7.4, 31.9+/-10.1, 35.0+/-14.2, 43.0+/-13.6, and 35.2+/-11.1, respectively, obviously more than those in group NS (58.3+/-16.1, 63.9+/-18.0, 60.8+/-17.7, 74.2+/-23.0, and 82.3+/-21.9, respectively, with P values below 0.001). There was no significantly statistical difference in the number of platelet aggregation of rats in group SI between each two time points within the same group (with P values above 0.05), but the number of platelet aggregation of rats in the other 3 groups at each time point post injury was significantly more than that of the same group at 15 min before injury (with P values below 0.001). (2) At 2, 4, and 8 h post injury, beta-TG content of serum of rats in group SEB was significantly higher than that in group SI (with Z values from -3.780 to 3.477, P values below 0.05). At 5 min and 4 h post injury, beta-TG content of serum of rats in group UTI was significantly lower than that in group NS (with Z values respectively -3.477 and -3.780, P values below 0.05). There was no significantly statistical difference in beta-TG content of serum of rats in group SI at all time points of the same group (chi(2)=0.130, P >0.05). At 2, 4, and 8 h post injury, beta-TG content of serum of rats in group SEB was significantly higher than that of the same group at 15 min before injury (with Z values from 3.780 to -3.553, P values below 0.05). At 5 min, 1 h, and 4 h post injury, beta TG content of serum of rats in group NS was significantly higher than that of the same group at 15 min before injury (with Z values from -3.780 to -3.477, P values below 0.05). At 1 and 4 h post injury, beta-TG content of serum of rats in group UTI was significantly higher than that of the same group at 15 min before injury (with Z values respectively -3.250 and -3.780, P values below 0.05). (3) At 2 and 8 h post injury, PF-4 content of serum of rats in group SEB was significantly higher than that in group SI (with P values below 0.05). At 2 h post injury, PF-4 content of serum of rats in group UTI was significantly higher than that in group NS (P<0.05), and at 4 and 8 h post injury, PF-4 content of serum of rats in group UTI was significantly lower than that in group NS (with P values below 0.05). At all time points, PF-4 content of serum of rats in group SI was close (with P values above 0.05). At 2 and 8 h post injury, PF-4 content of serum of rats in group SEB was significantly higher than that of the same group at 15 min before injury (with P values below 0.05). At 1, 4, and 8 h post injury, PF-4 content of serum of rats in group NS was significantly higher than that of the same group at 15 min before injury (with P values below 0.05). There were significantly statistical differences in PF-4 content of serum of rats between all time points except for 5 min post injury and 15 min before injury (with P values below 0.05). Conclusions: Increasing number of platelet aggregation and abnormal secretion of beta-TG and PF-4 of rats with high-voltage electrical burns can lead to microcirculation disturbance. UTI can alleviate microcirculation disturbance caused by high-voltage electrical burns by reducing the number of platelet aggregation and inhibiting secretion of beta-TG and PF-4. PMID- 29275616 TI - [Clinical research of features of magnetic resonance imaging of high-voltage electrical burns in limbs at early stage]. AB - Objective: To analyze the features of magnetic resonance imaging (MRI) of patients with high-voltage electrical burns in limbs at early stage. Methods: Thirty-eight patients with high-voltage electrical burns, conforming to the study criteria, were hospitalized in our unit from March 2013 to August 2016. T(1) weighted imaging (T(1)WI), T(2)WI, fat-suppression T(2)WI plain scan, and fat suppression T(1)WI enhanced scan of MRI were performed in 78 limbs, including 56 upper limbs and 22 lower limbs at post injury hour 72. The MRI signal characteristics of electrical burns in skin and subcutaneous tissue, skeletal muscle, tendon, joint ligament, and skeleton of limbs were analyzed. " Sandwich like" necrosis and injury in skeletal muscle, injuries of tendon, joint ligament, and skeleton were observed. MRI signal characteristics of amputated upper limbs and salvaged limbs were also analyzed. All patients underwent surgery within 24 h after MRI examination, and the muscle vitality was judged during operation. Muscle tissue without reaction to electrical stimulation which was completely necrotic as shown by MRI, muscle tissue with weak reaction to electrical stimulation which was injured with blood supply as shown by MRI, and muscle tissue with edema as shown by MRI were collected, and then the pathological characteristics of muscle tissue were observed with HE staining. Results: (1) The defect area of patients at entrance of current was bigger than that at exit. The skin and subcutaneous tissue extensively unevenly thickened. T(2)WI manifested hyperintensity, and T(1)WI manifested isointensity, while fat-suppression enhanced T(1)WI manifested uneven enhancement. Zonal effusion was seen in the region of serious subcutaneous edema. (2) For complete necrosis of skeletal muscle, T(2)WI manifested hypointense, isointensity, or slight hyperintensity, and T(1)WI manifested isointensity, slight hyperintensity, or mixed signal of isointensity and slight hyperintensity, while fat-suppression enhanced T(1)WI manifested most no enhancement area with clear boundary. The MRI signals of injured skeletal muscle could be divided into two types. Type I signal was for partial necrotic muscle adjacent to the completely necrotic zone. T(2)WI manifested uneven hyperintensity or slight hyperintensity, with unclear boundary. T(1)WI manifested isointensity or slight hyperintensity. Fat-suppression enhanced T(1)WI manifested significant banding or laciness enhancement. Type II signal was for deep muscle tissue far from the complete necrotic zone. T(2)WI manifested hyperintensity, and T(1)WI manifested isointensity or main isointensity mixed with hyperintensity, while fat-suppression enhanced T(1)WI manifested uneven moderate or slight enhancement. Normal muscle signal, type I signal, and type II signal were all mixed with necrotic signal, showing " sandwich-like" change. For skeletal muscle edema, T(2)WI manifested slight hyperintensity and unclear boundary, and T(1)WI manifested hypointense, while fat-suppression enhanced T(1)WI manifested no obvious enhancement. (3) For complete necrosis of tendon, T(2)WI manifested isointensity or slight hyperintensity, and T(1)WI manifested isointensity, while fat-suppression enhanced T(1)WI manifested no enhancement. For tendon injury, T(2)WI manifested isointensity, and T(1)WI manifested isointensity or hypointense, while fat-suppression enhanced T(1)WI manifested slight enhancement. (4) Severe injury of wrist joint were manifested as complete necrosis of soft tissue around joint. T(2)WI manifested slight hyperintensity or isointensity, and T(1)WI manifested isointensity, while fat-suppression enhanced T(1)WI manifested no enhancement or slightly uneven enhancement. For completely destroyed wrist joints, the structures were not clear from outside to inside. T(2)WI manifested slight hyperintensity or isointensity, and T(1)WI manifested hypointense or isointensity, while fat-suppression enhanced T(1)WI manifested no enhancement. For elbow injury, T(2)WI manifested hyperintensity, and T(1)WI manifested isointensity or hypointense, while fat-suppression enhanced T(1)WI manifested uneven enhancement. For knee injury, T(2)WI manifested hyperintensity, and T(1)WI manifested hypointense, while fat-suppression enhanced T(1)WI manifested slight enhancement. (5) For bone edema, T(2)WI manifested isointensity, while fat-suppression T(2)WI manifested slight hyperintensity. T(1)WI manifested isointensity, and fat-suppression enhanced T(1)WI manifested patchy enhancement. (6) MRI of amputated upper limbs showed necrosis signals, type I signals, type II signals, and mixed signals of type I and type II in skeletal muscle. The necrosis signal and type I signal area of the distal end were more than 50% greater than those of the lesion. The scope of the ecological tissue was large and the boundary was not clear. There were diffuse injuries in both anterior and posterior muscles, and the ulnar and radial artery pulsation disappeared in the upper limbs. The MRI of salvaged limbs were type I signal, type II signal, mixed signals of type I and type II, and local necrosis signals of skeletal muscle. The type I signal was the main type, and the distal end showed type II signal. (7) For completely necrotic skeletal muscle as shown by MRI, surgical exploration showed loss of muscle viability, and pathological examination showed complete necrosis of striated muscle tissue. For injury area of skeletal muscle as shown by MRI, surgical exploration showed interecological muscle with activity worse than mormal muscle, and pathological examination showed normal muscle cells and muscle fiber mixed with necrotic striated muscle cells having karyopyknosis, with different degree of injury. For edema area of skeletal muscle as shown by MRI, surgical exploration showed swelling skeletal muscle and normal muscle vitality, and pathological examination showed striated muscle interstitial edema with a large number of inflammatory cells infiltration. The manifestions of MRI were consistent with the results of surgical exploration and pathological examination. Conclusions: Skeletal muscle complete necrosis, injury, and edema could be preferably differentiated by MRI, and the definite scope and depth of electrical injury, the injury of skin, tendon, joint ligament, and bone could also be displayed well on MRI. It can provide objective imaging basis for the diagnosis of high-voltage electrical burns in limbs at early stage, the establishment of clinical operation plan, and the judgment of intraoperative tissue vitality. PMID- 29275617 TI - [Treatment of patients with different degree of acute respiratory distress syndrome caused by inhalation of white smoke]. AB - Objective: To summarize the treatment experience of patients with different degree of acute respiratory distress syndrome (ARDS) caused by inhalation of white smoke from burning smoke bomb. Methods: A batch of 13 patients with different degree of ARDS caused by inhalation of white smoke from burning smoke bomb, including 2 patients complicated by pulmonary fibrosis at the late stage, were admitted to our unit in February 2016. Patients were divided into mild (9 cases), moderate (2 cases), and serious (2 cases) degree according to the ARDS Berlin diagnostic criteria. Patients with mild and moderate ARDS were conventionally treated with glucocorticoid. Patients with severe ARDS were sequentially treated with glucocorticoid and pirfenidone, and ventilator-assisted breathing, etc. were applied. The vital signs, arterial oxygenation index, changes of lung imaging, pulmonary ventilation function, general condition, and the other important organs/systems function were timely monitored according to the condition of patients. The above indexes were also monitored during the follow-up time of 10-15 months post injury. Data were processed with SPSS 18.0 statistical software. Results: (1) The symptoms of respiratory system of patients with mild and moderate ARDS almost disappeared after 3 days' treatment. Their arterial oxygenation index was decreased from post injury day 1 to 4, which almost recovered on post injury day 7 and completely recovered one month post injury. The symptoms of respiratory system of patients with severe ARDS almost disappeared at tranquillization condition 1-3 month (s) post injury. Their arterial oxygenation index was decreased from post injury day 3 to 21, which gradually recovered 1-3 month (s) post injury and was normal 15 months post injury. (2) Within 24 hours post injury, there was no obvious abnormality or only a little texture enlargement of lung in image of chest CT or X-rays of patients with mild and moderate ARDS. One patient with moderate ARDS had diffuse patchy and ground-glass like increased density shadow (pulmonary exudation for short) at post injury hour 96. Chest iconography of all patients with mild and moderate ARDS showed no abnormalities 10 months post injury. Both lungs of each of the two patients with severe ARDS showed obvious pulmonary exudation at post injury hours 45 and 75, respectively. One patient with severe ARDS showed no abnormality in chest image 10 months post injury, but there was still a small mesh-like increased density shadow in double lobes with slight adhesion of pleura in the other patient with severe ARDS 15 months post injury. (3) All patients showed severe restrictive hypoventilation when admitted to hospital. Pulmonary ventilation function of patients with mild and moderate ARDS recovered to normal one month post injury, and they could do exercises like running, etc. Pulmonary ventilation function of one patient with severe ARDS recovered to normal 6 months post injury, and the patient could do exercises like running, etc. The other patient with severe ARDS showed mild restrictive hypoventilation 15 months post injury and could do exercises like rapid walking, etc. (4) The condition of all mild and one moderate ARDS patients was better on post injury day 3, and they were transferred to the local hospital for subsequent treatment and left hospital on post injury day 21. One patient with moderate ARDS healed and left hospital on post injury day 29. Patients with severe ARDS healed and left hospital on post injury day 81. During the follow-up time of 10-15 months post injury, the other important organs/systems of all patients showed no abnormality, and there was no adverse reaction of glucocorticoid like osteoporosis, femoral head necrosis, or metabolic disorder. Two patients with severe ARDS did not have any adverse reaction of pirfenidone like liver function damage, photosensitivity, anorexia, or lethargy. Conclusions: Early enough and uninterrupted application of glucocorticoid can significantly reduce the ARDS of patients caused by inhalation of white smoke from burning smoke bomb. Sequential application of glucocorticoid and pirfenidone can effectively treat pulmonary fibrosis at the late stage. PMID- 29275618 TI - [Effects of non-muscle myosin IIA silenced bone marrow mesenchymal stem cells on lung damage of rats at early stage of smoke inhalation injury]. AB - Objective: To investigate the effects of non-muscle myosin IIA (NMIIA) silenced bone marrow mesenchymal stem cells (BMSCs) on the lung damage of rats at early stage of smoke inhalation injury. Methods: Forty Sprague-Dawley rats were divided into control, simple injury, NMIIA-BMSCs, and BMSCs groups according to the completely random method, with 10 rats in each group. Rats in control group inhaled air normally, while rats in the latter 3 groups inhaled smoke to reproduce model of smoke inhalation injury. At 30 min post injury, rats in simple injury group were injected with 1 mL normal saline via caudal vein, and rats in group BMSCs were injected with 1 mL the fifth passage of BMSCs (1*10(7)/mL), and rats in group NMIIA-BMSCs were injected with 1 mL NMIIA silenced BMSCs (1*10(7)/mL). At post injury hour (PIH) 24, abdominal aorta blood and right lung of rats in each group were harvested, and then arterial partial pressure of oxygen (PaO(2)), arterial partial pressure of carbon dioxide (PaCO(2)), and pH value were detected by blood gas analyzer. Ratio of wet to dry weight of lung was determined by dry-wet weight method. Pathological changes of lung were observed with HE staining. Bronchoalveolar lavage fluid (BALF) were collected, and then tumor necrotic factor-alpha (TNF-alpha) and interleukin-10 (IL-10) content of BALF was determined by enzyme-linked immunosorbent assay. Data were processed with one-way analysis of variance, Kruskal-Wallis H test, and least-significant difference test. Results: (1) At PIH 24, compared with those in control group, PaO(2) values of rats in simple injury, BMSCs, and NMIIA-BMSCs groups were obviously decreased (with P values below 0.05), and PaCO(2) values were obviously increased (with P values below 0.05). Compared with those in simple injury group, PaO(2) values of rats in groups NMIIA-BMSCs and BMSCs were obviously increased (with P values below 0.05), while PaCO(2) values were obviously decreased (with P values below 0.05). PaO(2) value of rats in group NMIIA-BMSCs was obviously increased as compared with that in group BMSCs (P<0.05). The pH value of arterial blood of rats in simple injury group was obviously lower than that in control group (P<0.05). (2) At PIH 24, ratios of wet to dry weight of lung of rats in control, simple injury, BMSCs, and NMIIA-BMSCs groups were 4.36+/-0.15, 7.79+/ 0.42, 5.77+/-0.18, and 5.11+/-0.20, respectively. Compared with that in control group, ratio of wet to dry weight of lung of rats was obviously increased in the other 3 groups (with P values below 0.05). Compared with that in simple injury group, ratio of wet to dry weight of lung of rats was obviously decreased in groups BMSCs and NMIIA-BMSCs (with P values below 0.05). Compared with that in group BMSCs, ratio of wet to dry weight of lung of rats in group NMIIA-BMSCs was obviously decreased (P<0.05). (3) At PIH 24, alveolar structure of rats in control group was complete without abnormality. Compared with those in simple injury group, lung injury and infiltration of inflammatory cells of rats in groups BMSCs and NMIIA-BMSCs were obviously alleviated, and alveolar structure was relatively complete with no thickening of alveolar wall. (4) At PIH 24, compared with that in control group, TNF-alpha content of BALF of rats in simple injury and BMSCs groups was obviously increased (with P values below 0.05). Compared with that in simple injury group, TNF-alpha content of BALF in groups BMSCs and NMIIA-BMSCs was obviously decreased (with P values below 0.05). Compared with that in control group, IL-10 content of BALF in simple injury, NMIIA-BMSCs and BMSCs groups were obviously increased (with P values below 0.05). Compared with that in simple injury group, IL-10 content of BALF in groups BMSCs and NMIIA-BMSCs was obviously increased (with P values below 0.05). Compared with that in group BMSCs, IL-10 content of BALF in group NMIIA-BMSCs was obviously increased (P<0.05). Conclusions: NMIIA silenced BMSCs can alleviate lung damage of rats at early stage of smoke inhalation injury, showing better effectiveness than using BMSCs only. PMID- 29275619 TI - [Role of nuclear factor-kappaB activation in sepsis-induced myocardial dysfunction]. AB - As a common complication in patients with sepsis, cardiac dysfunction may significantly increase mortality of these patients, but its mechanism is still unclear. Nuclear factor-kappaB (NF-kappaB) is a pleiotropic transcription inducing factor, which involves in the regulation of multiple biological phenomena and disease status. NF-kappaB activation participates in cardiomyocyte apoptosis, cardiomyocyte autophagy, and release of inflammatory cytokines in patients with sepsis, indicating its important role in sepsis-induced myocardial dysfunction. PMID- 29275620 TI - Direct Detection of Products from S-Adenosylmethionine-Dependent Enzymes Using a Competitive Fluorescence Polarization Assay. AB - S-Adenosylmethionine (AdoMet)-dependent methyltransferases (MTases) are an essential superfamily of enzymes that catalyze the transfer of a methyl group to several biomolecules. Alterations in the methylation of cellular components crucially impact vital biological processes, making MTases attractive drug targets for treating infectious diseases and diseases caused by overactive human encoded MTases. Several methods have been developed for monitoring the activity of MTases, but most MTase assays have inherent limitations or are not amenable for high-throughput screening. We describe a universal, competitive fluorescence polarization (FP) assay that directly measures the production of S adenosylhomocysteine (AdoHcy) from MTases. Our developed assay monitors the generation of AdoHcy by displacing a fluorescently labeled AdoHcy molecule complexed to a catalytically inert 5'-methylthioadenosine nucleosidase (MTAN D198N) variant performed in a mix-and-read format. Producing the fluorescently labeled molecule involves a one-pot synthesis by combining AdoHcy with an amine reactive rhodamine derivative, which possesses a Kd value of 11.3 +/- 0.7 nM to MTAN-D198N. The developed competitive FP assay expresses a limit of detection for AdoHcy of 6 nM and exhibits a 34-fold preference to AdoHcy in comparison to AdoMet. We demonstrate the utility of the developed assay by performing a pilot screen with the NIH Clinical Collection as well as determining the kinetic parameters of l-histidine methylation for EgtD from Mycobacterium tuberculosis. Additionally, the developed assay is applicable to other AdoMet-dependent and ATP dependent enzymes by detecting various adenosine-containing molecules including 5'-methylthioadenosine, AMP, and ADP. PMID- 29275621 TI - Large Converse Piezoelectric Effect Measured on a Single Molecule on a Metallic Surface. AB - The converse piezoelectric effect is a phenomenon in which mechanical strain is generated in a material due to an applied electrical field. In this work, we demonstrate the converse piezoelectric effect in single heptahelicene-derived molecules on the Ag(111) surface using atomic force microscopy (AFM) and total energy density functional theory (DFT) calculations. The force-distance spectroscopy acquired over a wide range of bias voltages reveals a linear shift of the tip-sample distance at which the contact between the molecule and tip apex is established. We demonstrate that this effect is caused by the bias-induced deformation of the spring-like scaffold of the helical polyaromatic molecules. We attribute this effect to coupling of a soft vibrational mode of the molecular helix with a vertical electric dipole induced by molecule-substrate charge transfer. In addition, we also performed the same spectroscopic measurements on a more rigid o-carborane dithiol molecule on the Ag(111) surface. In this case, we identify a weaker linear electromechanical response, which underpins the importance of the helical scaffold on the observed piezoelectric response. PMID- 29275622 TI - Silica Nanoparticle-Enhanced Fluorescent Sensor Array for Heavy Metal Ions Detection in Colloid Solution. AB - Sensitivity and detection limit are two vital factors that affect fluorophores based sensing and imaging system. However, it remains a challenge to improve the sensitivity and detection limit of fluorophores, largely due to their limited response and photophysical properties. In this study, we report for the first time, a novel approach to enhance the sensitivity and detection limit of probes using silica nanoparticles, also known as silica nanoparticles-enhanced fluorescence (SiEF). SiEF can drastically improve the fluorescence intensities and detection limit of fluorophores. A SiEF-improved fluorescent sensor array for rapid and sensitive identification of different heavy metal ions is achieved, and a 3D spatial dispersion graph is obtained based on the SiEF-improved fluorescent sensor array, which provides a lower concentration dependent pattern than fluorophores alone, allowing qualitative, quantitative, and sensitive detection of heavy metal ions. Furthermore, with UV lamp irradiation of the sensor-metal ion mixtures, the output signals enable direct visual of heavy metal ions with low concentration. Thus, the SiEF approach provides a simple and practical strategy for fluorescent probes to improve their sensitivity and detection limit in analytes sensing. PMID- 29275623 TI - Intensity-Dependent Photoresponse of Biphotochromic Molecule Composed of a Negative and a Positive Photochromic Unit. AB - Light-selective multiple photochromic systems are important for advanced photoswitching of chemical reactions and biological activities. While UV light has been frequently utilized to induce photochromic reactions, visible light is energetically acceptable to avoid undesired reactions. However, many of the reported multiphotochromic systems still rely on UV light to induce at least a part of photochromic reactions. In this work, we designed a biphotochromic molecule showing intensity-dependent multiple coloration with a visible-light source by incorporating two T-type photochromic units; a colorless positive photochromophore and a colored negative photochromophore in a molecule. The negative photochromophore acts as a visible-light sensitizer for the positive photochromic reaction. The compound shows an intensity-dependent color change under visible-light irradiation. The weak visible-light excitation leads to gradual decoloration from orange to yellow, whereas intense laser excitation clearly changes the color to green. This characteristic photochromism can be achieved by control of the photochromic reaction rates of the negative and positive photochromic reactions. The combination of negative and positive photochromic reactions gives attractive important insight into the development of multiresponsive optical materials. PMID- 29275625 TI - Aptamer-Decorated Self-Assembled Aggregation-Induced Emission Organic Dots for Cancer Cell Targeting and Imaging. AB - A facile and simple one-step method was developed to fabricate aptamer-decorated self-assembled organic dots with aggregation-induced emission (AIE) characteristics. With integration of the advantages of AIE aggregates with strong emission and the cell-targeting capability of aptamers, the as-prepared Apt-AIE organic nanodots can specifically target to cancer cells with good biocompatibility, high image constrast, and photostability. On the basis of this universal method, a variety of versatile organic fluorescent nanoprobes with high brightness, specific recognition, and clinical-transitional potential could be facilely constructed for biological sensing and imaging applications. PMID- 29275624 TI - Bioinspired Silicification Reveals Structural Detail in Self-Assembled Peptide Cages. AB - Understanding how molecules in self-assembled soft-matter nanostructures are organized is essential for improving the design of next-generation nanomaterials. Imaging these assemblies can be challenging and usually requires processing, e.g., staining or embedding, which can damage or obscure features. An alternative is to use bioinspired mineralization, mimicking how certain organisms use biomolecules to template mineral formation. Previously, we have reported the design and characterization of Self-Assembled peptide caGEs (SAGEs) formed from de novo peptide building blocks. In SAGEs, two complementary, 3-fold symmetric, peptide hubs combine to form a hexagonal lattice, which curves and closes to form SAGE nanoparticles. As hexagons alone cannot tile onto spheres, the network must also incorporate nonhexagonal shapes. While the hexagonal ultrastructure of the SAGEs has been imaged, these defects have not been observed. Here, we show that positively charged SAGEs biotemplate a thin, protective silica coating. Electron microscopy shows that these SiO2-SAGEs do not collapse, but maintain their 3D shape when dried. Atomic force microscopy reveals a network of hexagonal and irregular features on the SiO2-SAGE surface. The dimensions of these (7.2 nm +/- 1.4 nm across, internal angles 119.8 degrees +/- 26.1 degrees ) are in accord with the designed SAGE network and with coarse-grained modeling of the SAGE assembly. The SiO2-SAGEs are permeable to small molecules (<2 nm), but not to larger biomolecules (>6 nm). Thus, bioinspired silicification offers a mild technique that preserves soft-matter nanoparticles for imaging, revealing structural details <10 nm in size, while also maintaining desirable properties, such as permeability to small molecules. PMID- 29275626 TI - Elucidation of Excitation Energy Dependent Correlated Triplet Pair Formation Pathways in an Endothermic Singlet Fission System. AB - Singlet fission is the spin-allowed conversion of a photogenerated singlet exciton into two triplet excitons in organic semiconductors, which could enable single-junction photovoltaic cells to break the Shockley-Queisser limit. The conversion of singlets to free triplets is mediated by an intermediate correlated triplet pair (TT) state, but an understanding of how the formation and dissociation of these states depend on energetics and morphology is lacking. In this study, we probe the dynamics of TT states in a model endothermic fission system, TIPS-Tc nanoparticles, which show a mixture of crystalline and disordered regions. We observe the formation of different TT states, with varying yield and different rates of singlet decay, depending on the excitation energy. An emissive TT state is observed to grow in over 1 ns when excited at 480 nm, in contrast to excitation at lower energies where this emissive TT state is not observed. This suggests that the pathway for singlet fission in these nanoparticles is strongly influenced by the initial sub-100 fs relaxation of the photoexcited state away from the Franck-Condon point, with multiple possible TT states. On nanosecond time scales, the TT states are converted to free triplets, which suggests that TT states might diffuse into the disordered regions of the nanoparticles where their breakup to free triplets is favored. The free triplets then decay on MUs time scales, despite the confined nature of the system. Our results provide important insights into the mechanism of endothermic singlet fission and the design of nanostructures to harness singlet fission. PMID- 29275627 TI - Piezotronic Transistor Based on Topological Insulators. AB - Piezotronics and piezophototronics are emerging fields by coupling piezoelectric, semiconductor, and photon excitation effects for achieving high-performance strain-gated sensors, LEDs, and solar cells. The built-in piezoelectric potential effectively controls carrier transport characteristics in piezoelectric semiconductor materials, such as ZnO, GaN, InN, CdS, and monolayer MoS2. In this paper, a topological insulator piezotronic transistor is investigated theoretically based on a HgTe/CdTe quantum well. The conductance, ON/OFF ratio, and density of states have been studied at various strains for the topological insulator piezotronic transistor. The ON/OFF ratio of conductance can reach up to 1010 with applied strain. The properties of the topological insulator are modulated by piezoelectric potential, which is the result of the piezotronic effect on quantum states. The principle provides a method for developing high performance piezotronic devices based on a topological insulator. PMID- 29275628 TI - Plasmon-Enhanced Ultrasensitive Surface Analysis Using Ag Nanoantenna. AB - Raman scattering and fluorescence spectroscopy permeate analytic science and are featured in the plasmon-enhanced spectroscopy (PES) family. However, the modest enhancement of plasmon-enhanced fluorescence (PEF) significantly limits the sensitivity in surface analysis and material characterization. Herein, we report a Ag nanoantenna platform, which simultaneously fulfills very strong emission (an optimum average enhancement of 105-fold) and an ultrafast emission rate (~280 fold) in PES. For applications in surface science, this platform has been examined with a diverse array of fluorophores. Meanwhile, we utilized a finite element method (FEM) and time-dependent density functional theory (TD-DFT) to comprehensively investigate the mechanism of largely enhanced radiative decay. PES with a shell-isolated Ag nanoantenna will open a wealth of advanced scenarios for ultrasensitive surface analysis. PMID- 29275630 TI - Chlorine-Incorporation-Induced Formation of the Layered Phase for Antimony-Based Lead-Free Perovskite Solar Cells. AB - The environmental toxicity of Pb in organic-inorganic hybrid perovskite solar cells remains an issue, which has triggered intense research on seeking alternative Pb-free perovskites for solar applications. Halide perovskites based on group-VA cations of Bi3+ and Sb3+ with the same lone-pair ns2 state as Pb2+ are promising candidates. Herein, through a joint experimental and theoretical study, we demonstrate that Cl-incorporated methylammonium Sb halide perovskites (CH3NH3)3Sb2ClXI9-X show promise as efficient solar absorbers for Pb-free perovskite solar cells. Inclusion of methylammonium chloride into the precursor solutions suppresses the formation of the undesired zero-dimensional dimer phase and leads to the successful synthesis of high-quality perovskite films composed of the two-dimensional layered phase favored for photovoltaics. Solar cells based on the as-obtained (CH3NH3)3Sb2ClXI9-X films reach a record-high power conversion efficiency over 2%. This finding offers a new perspective for the development of nontoxic and low-cost Sb-based perovskite solar cells. PMID- 29275629 TI - Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership. AB - The RecA/LexA axis of the bacterial DNA damage (SOS) response is a promising, yet nontraditional, drug target. The SOS response is initiated upon genotoxic stress, when RecA, a DNA damage sensor, induces LexA, the SOS repressor, to undergo autoproteolysis, thereby derepressing downstream genes that can mediate DNA repair and accelerate mutagenesis. As genetic inhibition of the SOS response sensitizes bacteria to DNA damaging antibiotics and decreases acquired resistance, inhibitors of the RecA/LexA axis could potentiate our current antibiotic arsenal. Compounds targeting RecA, which has many mammalian homologues, have been reported; however, small-molecules targeting LexA autoproteolysis, a reaction unique to the prokaryotic SOS response, have remained elusive. Here, we describe the logistics and accomplishments of an academic industry partnership formed to pursue inhibitors against the RecA/LexA axis. A novel fluorescence polarization assay reporting on RecA-induced self-cleavage of LexA enabled the screening of 1.8 million compounds. Follow-up studies on select leads show distinct activity patterns in orthogonal assays, including several with activity in cell-based assays reporting on SOS activation. Mechanistic assays demonstrate that we have identified first-in-class small molecules that specifically target the LexA autoproteolysis step in SOS activation. Our efforts establish a realistic example for navigating academic-industry partnerships in pursuit of anti-infective drugs and offer starting points for dedicated lead optimization of SOS inhibitors that could act as adjuvants for current antibiotics. PMID- 29275631 TI - Efficient Intramolecular Vibrational Excitonic Energy Transfer in Ru3(CO)12 Cluster Revealed by Two-Dimensional Infrared Spectroscopy. AB - Trinuclear transition-metal carbonyl complex dodecacarbonyl triruthenium (Ru3(CO)12) is considered as one of the paradigms in cluster chemistry, which plays an important role in photocatalysis, photoenergy conversion, and synthetic chemistry. Due to structural symmetry (D3h point group), 12 carbonyl (C=O) groups in the Ru3(CO)12 complex contribute to mainly three excitonic carbonyl stretching modes: E' (radial), A2" (axial), and E' (axial). In this work, efficient intramolecular vibrational energy redistribution (IVR) processes among the three modes in this Ru-CO complex were observed to occur on the time scale of tens of picoseconds. The IVR processes were characterized in detail using a kinetic model and fitting to the waiting-time-dependent diagonal and off-diagonal signals of ultrafast two-dimensional infrared spectroscopy. In addition, the diagonal anharmonicities of the three C=O stretching modes were determined to be quite close to one another, and the coupling-induced cross peaks were invariant because this Ru3(CO)12 cluster does not show picosecond fluxionality and hence their contributions were neglected in modeling the IVR processes. Our results provide a benchmark for understanding the excitonic nature of the vibrational excited states of the carbonyl vibrators and the associated efficient vibrational energy flow pathways, in such multicentered transition-metal complexes, which are of key importance to their functions. PMID- 29275632 TI - Study of Fluorescence Quenching Ability of Graphene Oxide with a Layer of Rigid and Tunable Silica Spacer. AB - The fluorescence quenching property of graphene oxide (GO) has been newly demonstrated and applied for fluorescence imaging and biosensing. In this work, a new nanostructure was designed for effectively studying the quenching ability of GO. The key element in this design is the fabrication of a layer of rigid and thickness adjustable silica spacer for manipulating the distance between the GO and fluorophores. First, a silica core modified with organic dye molecules was prepared, followed by the formation of a silica shell with a tunable thickness. Afterward, the GO was wrapped around silica nanoparticles based on the electrostatic interaction between the negatively charged GO and positively charged silica. The quenching efficiency of GO to different dye molecules was studied at various spacer thicknesses and varying concentrations of GO. Fluorescence lifetime of fluorophores was measured to determine the quenching mechanism. We found that the quenching efficiency of GO was still around 30% when the distance between dyes and GO was increased to more than 30 nm, which indicated the long-distance quenching ability of GO and confirmed the previous theoretical calculation. The quenching mechanisms were proposed schematically based on our experimental results. We expected that the proposed nanostructure could act as a feasible model for studying GO quenching property and shed light on designing GO-based fluorescence sensing systems. PMID- 29275633 TI - Tailoring Photoisomerization Pathways in Donor-Acceptor Stenhouse Adducts: The Role of the Hydroxy Group. AB - Donor-acceptor Stenhouse adducts (DASAs) are a rapidly emerging class of visible light-activatable negative photochromes. They are closely related to (mero)cyanine dyes with the sole difference being a hydroxy group in the polyene chain. The presence or absence of the hydroxy group has far-reaching consequences for the photochemistry of the compound: cyanine dyes are widely used as fluorescent probes, whereas DASAs hold great promise for visible light-triggered photoswitching. Here we analyze the photophysical properties of a DASA lacking the hydroxy group. Ultrafast time-resolved pump-probe spectroscopy in both the visible and IR region show the occurrence of E-Z photoisomerization on a 20 ps time scale, similar to the photochemical behavior of DASAs, but on a slower time scale. In contrast to the parent DASA compounds, where the initial photoisomerization is constrained to a single position (next to the hydroxy group), 1H NMR in situ-irradiation studies at 213 K reveal that for nonhydroxy DASAs E-Z photoisomerization can take place at two different bonds, yielding two distinct isomers. These observations are supported by TD-DFT calculations, showing that in the excited state the hydroxy group (pre)selects the neighboring C2-C3 bond for isomerization. The TD-DFT analysis also explains the larger solvatochromic shift observed for the parent DASAs as compared to the nonhydroxy analogue, in terms of the dipole moment changes evoked upon excitation. Furthermore, computations provide helpful insights into the photoswitching energetics, indicating that without the hydroxy group the 4pi-electrocyclization step is energetically forbidden. Our results establish the central role of the hydroxy group for DASA photoswitching and suggest that its introduction allows for tailoring photoisomerization pathways, presumably both through (steric) fixation via a hydrogen bond with the adjacent carbonyl group of the acceptor moiety, as well as through electronic effects on the polyene backbone. These insights are essential for the rational design of novel, improved DASA photoswitches and for a better understanding of the properties of both DASAs and cyanine dyes. PMID- 29275634 TI - Adsorption of Carbon on Partially Oxidized Low-Index Cu Surfaces. AB - We use first-principles calculations to study the carbon adsorption on copper slabs of (100) and (111) surfaces predosed by oxygen atoms. Our results show that on both surfaces, an incoming carbon atom has the ability to replace and completely desorb a previously surface-adsorbed oxygen atom producing CO and CO2 molecules in the gas phase. By comparison, the (111) surface is better suited for oxygen desorption, and an incoming carbon atom can more easily bond to and desorb oxygen atoms even at low oxygen coverages. We examine this mechanism at two different temperatures for both surfaces at 0.5 ML oxygen coverage. An implication of this process is the experimentally proven cleaning effect of predosing copper surfaces with oxygen before graphene growth in the chemical vapor deposition process. Conversely, adsorption and diffusion of carbon atoms, both of which are necessary for the nucleation and growth of carbon nanotubes, may be hindered by the presence of the oxidized or partially oxidized surfaces. PMID- 29275635 TI - Reversible Laser-Induced Bending of Pseudorotaxane Crystals. AB - This study investigated the dynamic photoresponse of pseudorotaxane crystals with azobenzene and ferrocenyl groups in the axle component. X-ray crystallography showed pseudorotaxanes with a methylazobenzene group and a dibromophenylene ring in the cyclic component to exhibit twisting of the trans-azobenzene groups at torsion angles of 17 degrees and 38 degrees , respectively. Repeated alternating laser irradiation of the crystals at 360 and 445 nm produced bending of 20-30 degrees in opposite directions, with no evidence of decay. Under 445 nm irradiation, bending took place within 0.3 s. A crystal of nonsubstituted pseudorotaxane showed bending of only 2 degrees under 360 nm irradiation due to multiple pi-pi interactions between the planar trans-azobenzene groups. The pseudorotaxane crystals have two chromophores, bent rapidly and reversibly on irradiation at rates depending on the molecular structure. PMID- 29275636 TI - Criticality of Symmetry in Rational Design of Chalcogenide Perovskites. AB - Chalcogenide perovskites constitute an emerging class of promising photovoltaic materials that are stable and less toxic than popular lead-halide perovskites. Transition-metal and chalcogenide doping are the possible strategies for improving the photovoltaic properties of these materials via the band gap engineering. At the same time, doping can facilitate nonradiative charge-carrier recombination in these materials, adversely affecting their photovoltaic properties. We report a systematic study of electronic structure and nonadiabatic dynamics in transition-metal- and chalcogenide-doped barium-zirconium-sulfide based perovskites. The potential of these doping strategies to modulate the performance of photovoltaic materials is explored. Through the detailed analysis of the factors affecting the dynamics, we illustrate how symmetry (both structural and orbital) and decoherence can be critical to furnishing the most favorable properties. The noted factors of symmetry and decoherence may provide new rational design principles for efficient photovoltaics. PMID- 29275637 TI - Pore Environment Control and Enhanced Performance of Enzymes Infiltrated in Covalent Organic Frameworks. AB - In the drive toward green and sustainable methodologies for chemicals manufacturing, biocatalysts are predicted to have much to offer in the years to come. That being said, their practical applications are often hampered by a lack of long-term operational stability, limited operating range, and a low recyclability for the enzymes utilized. Herein, we show how covalent organic frameworks (COFs) possess all the necessary requirements needed to serve as ideal host materials for enzymes. The resultant biocomposites of this study have shown the ability boost the stability and robustness of the enzyme in question, namely lipase PS, while also displaying activities far outperforming the free enzyme and biocomposites made from other types of porous materials, such as mesoporous silica and metal-organic frameworks, exemplified in the kinetic resolution of the alcohol assays performed. The ability to easily tune the pore environment of a COF using monomers bearing specific functional groups can improve its compatibility with a given enzyme. As a result, the orientation of the enzyme active site can be modulated through designed interactions between both components, thus improving the enzymatic activity of the biocomposites. Moreover, in comparison with their amorphous analogues, the well-defined COF pore channels not only make the accommodated enzymes more accessible to the reagents but also serve as stronger shields to safeguard the enzymes from deactivation, as evidenced by superior activities and tolerance to harsh environments. The amenability of COFs, along with our increasing understanding of the design rules for stabilizing enzymes in an accessible fashion, gives great promise for providing "off the shelf" biocatalysts for synthetic transformations. PMID- 29275638 TI - The therapeutic role of motor imagery during the acute phase after total knee arthroplasty: a pilot study. AB - PURPOSE: The aim of this study was to measure physical and functional outcomes during the acute postoperative recovery in patients who underwent total knee arthroplasty. Motor imagery has been shown to decrease pain and promote functional recovery after both neurological and peripheral injuries. Yet, whether motor imagery can be included as an adjunct effective method into physical therapy programs following total knee arthroplasty remains a working hypothesis that we aim to test in a pilot study. METHOD: Twenty volunteers were randomly assigned to either a motor imagery or a control group. Pain, range of motion, knee girth as well as quadriceps strength and Timed Up and Go Test time were the dependent variables during pre-test and post-test. RESULTS: The motor imagery group exhibited larger decrease of ipsilateral pain and knee girth, a slightly different evolution of range of motion and an increase of ipsilateral quadriceps strength compared to the control group. No effects of motor imagery on Timed Up and Go Test scores were observed. CONCLUSION: Implementing motor imagery practice into the course of physical therapy enhanced various physical outcomes during acute postoperative recovery after total knee arthroplasty. According to this pilot study, motor imagery might be relevant to promote motor relearning and recovery after total knee arthroplasty.Partial effect-sizes should be conducted in the future. Implications for rehabilitation Adding motor imagery to physical therapy sessions during the acute period following total knee arthroplasty: * Enhances quadriceps strength. * Alleviates pain. * Enhances range of motion. * Does not have any effect on basic functional mobility. * Does not have any effect on knee girth. PMID- 29275640 TI - Lost in translation? A critical look at the role that animal models of obsessive compulsive disorder play in current drug discovery strategies. AB - INTRODUCTION: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric illness estimated to affect between 1-3% of the population. In today's literature, there are a number well-validated and convincing animal models of OCD described. Areas covered: Herein, the authors look at the role that animal models of OCD (including transgenic models, deer mouse stereotypy, quinpirole sensitization, post-training signal attenuation, and mouse marble burying) have played in determining the current directions of OCD drug discovery. Specifically, the article reviews new OCD drug therapies currently under investigation including drugs that target glutamate, dopamine, serotonin, and endocannabinoid systems. The authors review the published results of these clinical trials, and critically examine the contribution of animal models to the development of these novel therapies. Expert opinion: Nitric oxide inhibitors, oxycarbazepine, and modulators of serotonin and metabotropic glutamate receptors should be further explored in animal models as well as in clinical trials. Pregabalin, topiramate, lamotrigine, sarcosine, minocycline, L-carnosine, celecoxib, and ondansetron, which have shown promise in clinical trials, should be explored in animal models with the goal of understanding the neurobiology of their effects. A multidisciplinary, interactive approach to OCD drug discovery, where animal models generate neurobiological hypotheses that can be tested in the clinic, and vice versa, should be cultivated. PMID- 29275639 TI - Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson's disease. AB - A microsphere-gel in situ forming implant (MS-Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson's disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM-MS prepared by a modified emulsion-phase separation method and optimized by Box-Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics. We found that the RM-MS-Gel ISFI system showed no initial burst release and had a long period of in vitro drug release (60 days). An in vivo pharmacokinetic study indicated a significant reduction (p < .01) in the initial high plasma drug concentration of the RM-MS-Gel ISFI system compared to that of the single RM-MS and RM-in situ gel systems after intramuscular injection to rats. A pharmacodynamic study demonstrated a significant reduction (p < .05) in 6 hydroxydopamine-induced contralateral rotation behavior and an effective improvement (p < .05) in dopamine levels in the striatum of the lesioned side after 28 days in animals treated with the RM-MS-Gel ISFI compared with that of animals treated with saline. MS-embedded in situ phase transition gel is superior for use as a biodegradable and injectable sustained drug delivery system with a low initial burst and long period of drug release for highly hydrophilic small molecule drugs. PMID- 29275641 TI - Vaginal hyperlaxity syndrome: a new concept and challenge. PMID- 29275642 TI - Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation, optimization using central composite design and in vivo bioavailability study. AB - This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08 nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension. PMID- 29275644 TI - Renal Laceration. AB - In brief A male skateboarder experienced chest wall pain and splinting after striking a curb with the right side of his torso. X-rays revealed a nondisplaced fracture of the right ninth rib. Two days later, however, the patient returned with hematuria, and CT showed a renal laceration. This case illustrates that minor symptoms can accompany serious injury after abdominal trauma. Also, as skateboarding gains popularity, such injuries may become more frequent. PMID- 29275643 TI - Gastric cancer in Latin America. AB - Every year, cancer affects more than one million Latin Americans. The increasing incidence of cancer could be secondary to an aging population, westernization of life style, and urbanization. LA has among the highest incidence rates of gastric cancer, compared to other countries. In this review, different studies on gastric cancer and its relation with risks factors, such as infections, diet and life styles typical of LA, besides the different molecular alterations of that specific population (mainly at a genetic polymorphism level) are analyzed. An exhaustive research was made in PubMed, MEDLINE and Embase of the most relevant studies conducted in the last 27 years (1990-2017) in LA. PMID- 29275645 TI - Early Mobilization Speeds Recovery. AB - Early mobilization isn't just for elite athletes. Protected motion for sprains and strains helps patients of all activity levels avoid the deleterious effects of immobilization. PMID- 29275646 TI - Targeting Teen Health Problems. AB - While doing a teen's preparticipation exam, the physician can go beyond sports specific concerns to detect health problems in other areas. The examiner, whether through verbal queries or a questionnaire, can uncover concerns and risks for such common teen problems as drug use, sexually transmitted disease, and delayed development. PMID- 29275647 TI - The In-Line Skating Experience. PMID- 29275649 TI - QuikQuiz. PMID- 29275648 TI - Carpe Diem-Seize the Day! PMID- 29275650 TI - Pearls. AB - 'Pearls' enables sports medicine professionals to share the practical tips they've developed through treating active patients. We invite you to send your contributions to Pearls Editor, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. Selected pearls will be published, accompanied by the author's name. PMID- 29275651 TI - Neck Injuries. AB - In brief One of the most difficult on-site medical decisions is what steps to take when an athlete sustains a neck injury. A cautious examination is imperative and may involve assessing consciousness, pain, and spasm; evaluating neurologic symptoms; testing cervical range of motion; and deciding whether or not the player can return to play. Various signs and symptoms may herald serious injury and indicate the need to place the patient on a backboard before further assessment. PMID- 29275653 TI - The Low-Energy Laser, Electro-Acuscope, and Neuroprobe. AB - In brief The low-energy laser, electroacuscope, and neuroprobe are being used to promote healing and reduce the pain associated with a variety of musculoskeletal conditions including wounds, tendinitis, bursitis, and tennis elbow. Physicians should be aware that the efficacy of these new modalities remains controversial. PMID- 29275652 TI - Assessing the Threat of Anabolic Steroids. AB - Sprinter Ben Johnson's lifelong expulsion from international competition forces the sports medicine community to acknowledge, once again, the temptation performance-enhancing drugs pose for athletes. The drive to jump a little higher, run a little faster, or be a little stronger continues to compel some athletes to seek an edge through drugs. To better prepare physicians who must guide patients faced with these temptations, we gathered four medical experts to discuss current information about anabolic-androgenic steroids. PMID- 29275654 TI - Anesthesia for the Injured Hand. AB - In brief When an active patient sustains a hand or finger injury, a digital nerve block is often the appropriate anesthetic technique. A thorough knowledge of the area's anatomy, the materials needed, the proper technique, and the potential complications can help the primary care physician perform the procedure smoothly. PMID- 29275655 TI - Reversing Coronary Artery Disease. AB - In brief A low-fat diet, exercise, and other lifestyle changes can lead to regression of atherosclerosis in patients with coronary artery disease (CAD). A review of six clinical trials shows that the therapies that showed clinical benefit were those that greatly reduced patients' LDL-C blood levels. The studies help physicians better define effective strategies for not just slowing, but reversing, patients' CAD. PMID- 29275656 TI - Diagnosing an Unusual Cause of Buttock Pain. AB - In brief Osteochondroma can masquerade as a variety of more common soft-tissue overuse disorders. This case involves a 28-year-old runner who reported significant buttock pain. Deep palpation suggested a growth on his ischial tuberosity, and x-rays and CT indicated an osteochondroma. Many patients who have osteochondromas are asymptomatic and therefore require no treatment; however, complete excision relieved this patient's pain. Ruling out malignant transformation is sometimes necessary. PMID- 29275658 TI - Scanning Sports. PMID- 29275659 TI - Electronic Tools for Your Medical Bag? PMID- 29275660 TI - Stressed Out? PMID- 29275661 TI - Pearls. PMID- 29275662 TI - Primary Treatment of Ankle Trauma. AB - In brief Decreasing inflammation and pain associated with an ankle injury is the first goal of treatment. Then success depends on accurately assessing the extent of the injury. With sprains and strains, options include bracing, taping, and range-of-motion exercises. For fractures, the key is knowing when to treat conservatively and when to refer. With any ankle injury, aggressive rehabilitation often produces good results. PMID- 29275663 TI - A New Tool for Encouraging Activity. AB - In brief Promoting physical activity among patients is an essential role for physicians. Project PACE (Physician-based Assessment and Counseling for Exercise) is a practical system of matching physician counseling with patient readiness for physical activity. The PACE counseling approach will help physicians attain national goals for health promotion for the year 2000. PMID- 29275664 TI - 'Tis the Stuffing Season. PMID- 29275665 TI - QuikQuiz. PMID- 29275666 TI - Do we need a special issue about cutting edges? PMID- 29275667 TI - Trends in presentation, treatment and survival of 1777 patients with colorectal cancer over a decade: a Biobank study. AB - BACKGROUND: Most survival data in colorectal cancer (CRC) is derived from clinical trials or register-based studies. Hospital Biobanks, linked with hospital electronic records, could serve as a data-gathering method based on consecutively collected tumor samples. The aim of this Biobank study was to analyze survival of colorectal patients diagnosed and treated in a single-center university hospital over a period of 12 years, and to evaluate factors contributing to outcome. MATERIAL AND METHODS: A total of 1777 patients with CRC treated during 2001-2012 were identified from the Auria Biobank, Turku, Finland. Longitudinal clinical information was collected from various hospital electronic records and date and cause of death obtained from Statistics Finland. RESULTS: Cancer-specific, overall and disease-free survival was higher in patients diagnosed during 2004-2008 as compared with patients diagnosed in 2001-2003. Further improvement was not seen during years 2009-2012. Potential factors contributing to the improvement were introduction of multidisciplinary meetings, centralization of rectal cancer surgery, use of adjuvant chemotherapy and systematic preoperative radiotherapy of rectal cancer. The proportion of patients with stage I-IV CRC remained similar over the study period, but a marked decrease in non-metastatic rectal cancer with biopsy only (locally advanced disease) was observed. In stage I-III rectal cancer, Cox multivariate analysis suggested age, comorbidity, R1 resection, T staging and tumor grade as prognostic factors. In colon cancer, prognostic factors were age, comorbidity, gender and presence of lymph node metastases. CONCLUSIONS: Organizational changes in the treatment of CRC patients made since 2004 coincide with improved survival in CRC and a marked reduction in locally advanced rectal cancers. The clinical presentation of CRC has remained similar between 2001 and 2012. PMID- 29275668 TI - Comparison of diagnostic performance of rapid and standard polymerase chain reaction laboratory test for influenza and respiratory syncytial virus detection in nasopharyngeal swabs from symptomatic lung transplant recipients. PMID- 29275670 TI - CME Self Test. PMID- 29275669 TI - Recovering From Shoulder Pain: Tips for Swimmers. PMID- 29275672 TI - Healthy Cooking. PMID- 29275673 TI - Exercise-the Best Prescription. PMID- 29275675 TI - Sleepers: The Subtle Ills That Keep Us Awake. PMID- 29275676 TI - Blending Exercise Into Family Life. PMID- 29275677 TI - Forum. PMID- 29275678 TI - Pearls. PMID- 29275679 TI - Meningococcemia. AB - In brief Meningococcemia is a dangerous disease requiring early and aggressive treatment to prevent a potentially lethal outcome. It often occurs in relatively closed groups, including sports camps and athletic teams. A high index of suspicion must be maintained when evaluating acute febrile illness, particularly in people younger than 20. Treatment includes antibiotics and intensive care support. Prophylaxis in the intimately exposed population, and education about signs and symptoms of the disease for more peripheral contacts are critical for successfully limiting any outbreak. PMID- 29275680 TI - Blunt-Trauma Carotid Artery Injury. AB - In brief Injury to the carotid artery can occur in athletes by direct blow to the neck or by hyperextension of the neck. After such injury, symptoms may be mild or transient. Catastrophic complications such as stroke can occur if the injury is not recognized and treated. Neurologic changes such as transient weakness or transient unilateral blurred vision that occur after a hyperextension injury or a direct blow to the neck may indicate a carotid artery injury. A careful neurologic examination can help identify most carotid artery injuries, but because the symptoms of injury may not appear immediately, follow-up may be necessary. Treatment may consist of anticoagulation therapy or operative repair. PMID- 29275682 TI - Practices and Pitfalls of Corticosteroid Injection. AB - In brief Corticosteroid injection is a valuable adjunct for treating sports related inflammation. Unfortunately, these agents are not without toxicities and side effects. It's important, therefore, to choose a corticosteroid appropriate to the patient, the condition, and the size of the affected joint: For example, less soluble agents are generally better for longer-term injuries. Avoiding pitfalls may simply mean heeding the well-known contraindication of injecting into a tendon. Or it may mean monitoring blood glucose in a patient who has diabetes, immobilizing an extremity after injection, or avoiding subcutaneous injection before the target area is reached. PMID- 29275683 TI - CME Self Test. PMID- 29275685 TI - Sports Medicine Fellowships for Primary Care Physicians. PMID- 29275686 TI - Pearls. PMID- 29275687 TI - Managing Activity in Patients Who Have Diabetes. AB - In brief Control of both type I and type II diabetes involves the appropriate balance of exercise, diet, and medication. Regular, long-term exercise has many benefits for people with diabetes. Physicians can educate patients about ways to regulate and monitor blood glucose before, during, and after a workout or competition. Physicians also need to discuss the warning signs of hypoglycemia, hyperglycemia, ketoacidosis, and dehydration and how to prevent the conditions. In addition, patients who have type I diabetes need to know the effects of exercise on insulin requirements. Nutrition needs will vary for each patient, type of activity, and other factors, but food intake can be readily adjusted in conjunction with blood glucose monitoring. PMID- 29275688 TI - Roughing It on Location. AB - Despite all the rumblings in the health-care arena, medicine remains a career of man) opportunities. Whether it's tending to a neighborhood football game or helping out on a wilderness trek, doctors do have chances to work outside the office. For awhile, our "offices" were the remote, scenic sets of two adventure movies, The River Wild (R.B.) and Cliff-hanger (K.P.). PMID- 29275689 TI - Staying Active With Diabetes. PMID- 29275690 TI - Fat Phobia. PMID- 29275691 TI - Warm Up With Back-Friendly Leg Stretches. PMID- 29275692 TI - "Highlights" for Your Practice. PMID- 29275693 TI - Ready for Rigorous Activity? PMID- 29275694 TI - Grappling With Weight Cutting. AB - In response to a new state rule, the Wisconsin Minimum Weight Project was formed to curtail "weight cutting" among high school wrestlers. The project uses skinfold testing to determine a minimum competitive weight and nutrition education to help the wrestler diet safely. It serves as a model for other states and other sports. PMID- 29275695 TI - Immediate Reduction of Shoulder Dislocation. AB - In brief Anterior shoulder dislocations are common injuries in sports medicine. Associated fractures and neurovascular injuries are rare but need to be identified by physical examination and x-ray before reduction is attempted. The authors present a preferred reduction method based on the technique described by Matsen et al;5 other methods can also be used. In the patient under 30 years of age, postreduction immobilization and strengthening exercises are important to help prevent redislocation; in older patients, range-of-motion exercises are more critical. PMID- 29275697 TI - The economic cost of treatment-resistant depression in patients referred to a specialist service. AB - BACKGROUND: Patients with treatment-resistant depression (TRD) suffer very significant morbidity and are at a disadvantage concerning optimal clinical management. There are high associated societal costs. AIMS: A detailed analysis of health economic costs in the United Kingdom in a group manifesting a severe form of TRD in the 12 months before their participation in a major randomized controlled treatment trial. METHODS: The sample consisted of 118 participants from the Tavistock Adult Depression Study. Recruitment was from primary care on the basis of current major depression disorder of at least 2 years' duration and two failed treatment attempts. Service utilization was assessed based on self report and general practitioner (GP) medical records. Generalized linear models were used to identify predictors of cost. RESULTS: All participants used GP services. Use of other doctors and practice nurses was also high. The mean total societal cost was L22 124, 80% of which was due to lost work and care required of families. Level of general functioning was found to be the most consistent predictor of costs. CONCLUSIONS: Severe forms of TRD are associated with high costs in which unpaid care and lost work predominate. Treatments that improve functioning may reduce the large degree of burden. PMID- 29275696 TI - Potential of rare actinomycetes in the production of metabolites against multiple oxidant agents. AB - CONTEXT: Actinobacteria are a precious source of novel bioactive metabolites with potential pharmaceutical applications. OBJECTIVES: Representatives of 11 genera of rare Actinobacteria were selected for the evaluation of antioxidant activity. MATERIAL AND METHODS: Fermentation broths of the Actinobacteria were extracted and dosage of 10 to 2000 ug/mL were applied for in vitro antioxidant-related bioassays. Cytotoxicity was assessed at the concentration of 2.5-20 ug/mL. RESULTS: In the DPPH scavenging activity, 15 out of 52 extracts showed 17.0-26.8% activity in quantitative evaluation. Metabolites of five prominent antioxidant producing strains protected the DNA (pUC19) against UV-induced photolyzed H2O2 oxidative degradation. The potent antioxidant extracts inhibited two oxidative enzymes of xanthine oxidase in the range of 17.5-45.2% (three extracts had IC50 less than allopurinol) and lipoxygenase in the range of 36-55% (all five extracts had IC50 values less than daidzein). All these extracts could also protect eythrocytes from iron-induced hemolysis with ED50 values in a range of 0.014-1.25 mg/mL. Growth restoration of the yeast cells lacking the sod1 gene was observed by the antioxidant metabolite of Saccharothrix ecbatanensis UTMC 537 at the concentration of 1 mg/mL. CONCLUSIONS: The presence of nonidentical metabolites might be responsible for antioxidant and enzyme inhibitory activities of S. ecbatanensis, newly described actinobacterium in family Pseudonocardiaceae. The scavenging of the free electrons, protection of DNA and model yeast cells against oxidative stress, in addition to the inhibition of the oxidating enzymes are the main mechanisms of the antioxidant effect of the introduced resource in this study. PMID- 29275698 TI - Burner Syndrome. AB - In brief Burner syndrome-brachial plex us injury-is common in contact sports, especially on the football field, but not always benign. Our case report describes a 15-year-old football player who suffered burner symptoms that resolved quickly but led to shoulder weakness and neck pain a few days later. Detailed serial clinical examinations are imperative for proper classification of burner injuries. Cervical root lesions, shoulder injuries, and other plexus or nerve involvement must be excluded. Rehabilitation includes physical modalities and range-of-motion, stretching, and strengthening exercises for cervical, shoulder, and elbow muscles. Prevention measures include preseason strengthening exercises and protective devices. PMID- 29275700 TI - Cardiovascular Screening. AB - In brief While the critical task of the brief preparticipation cardiac examination is identifying life-threatening conditions, care must be taken not to exclude healthy individuals from activity. The vast majority of exams will be negative, but the physician should be alert to such potentially lethal conditions as hypertrophic cardiomyopathy, aortic stenosis, and Marfan syndrome. A history of symptoms during exertion, certain features of physical appearance, and clinical findings require referral to a cardiologist. Although the cardiac examination needn't involve complex tests, it must permit recognition of abnormal heart sounds and other signs of pathology. In the older athlete, coronary heart disease is the principal risk, and the examination should be tailored accordingly. PMID- 29275701 TI - Pearls. PMID- 29275702 TI - Heat Stress in Atlanta. AB - The weather might provide the toughest competition for endurance athletes at the Summer Olympic Games in Atlanta next month. The heat stress is likely to be higher than in any of the last several summer games. Here's a report on the expected conditions and how medical officials for the games are preparing. PMID- 29275703 TI - Minding Your Minerals. PMID- 29275705 TI - CME Self Test. PMID- 29275706 TI - Forum. PMID- 29275707 TI - Taking the Pressure Off. PMID- 29275708 TI - Visit Us on the World Wide Web. PMID- 29275710 TI - 'Activity Medicine' for Patients 8 to 80. PMID- 29275709 TI - Sidestepping Burners. PMID- 29275711 TI - Identifying Exercise Allergies. AB - In brief Exercise-related allergies vary brief from the benign rash of cholin ergic urticaria to life-threatening exercise-induced anaphylaxis. Rapid diagnosis is essential, but it can be difficult to tell the two conditions apart. The size of the wheals and the patient history provide the best clues. Giving epinephrine and taking steps to protect the patient's airway, breathing, and circulation are standard treatment for exercise-induced anaphylaxis. Effective management for less severe cases involves exercising with a partner, keeping self-injectable epinephrine on hand, and avoiding exercise before and after meals. Prophylactic antihistamines are more effective for cholinergic urticaria than for exercise induced anaphylaxis. PMID- 29275712 TI - Neck Pain. AB - In brief Most nontraumatic conditions brief that produce neck pain can be managed by primary care physicians, with physical therapy to augment rehabilitation. One key role the physician can often play is to reassure the patient that the injury is not serious. After that, the goal of immediate treatment is to minimize pain and inflammation with nonsteroidal medication and icing. Other options can include brief bed rest, narcotic analgesics, a cervical collar, and, depending on the condition, corticosteroids, local injections, acetaminophen, and moist heat. Rehabilitation to recover lost function should address the entire kinetic chain and include an aerobic component. Return to play must be gradual. Some injured or aging patients may have to cut back on activity or cross-train to maintain an active lifestyle. PMID- 29275714 TI - Exercising for Overall Fitness. PMID- 29275713 TI - Swimmer's Shoulder. AB - In brief Shoulder pain caused by impingement of subacromial tissues is a common overuse injury in swimming, especially among adolescents who may have rigorous training schedules and be skeletally immature. A case of a 14-year-old girl with swimmer's shoulder demonstrates the diagnostic work-up, which involves pertinent history, inspection, palpation, and assessment of strength, impingement, and instability. Treatment focuses on icing, relative rest, physical therapy, and modifying the swimming workout to reduce overuse and impingement. PMID- 29275715 TI - Surfing, Windsurfing, Snowboarding, and Skateboarding. AB - In brief With the rise in popularity of board sports, primary care physicians need to understand the injury risks and environmental hazards faced by surfers, windsurfers, snowboarders, and skateboarders. Physicians can play an important role by telling patients about injury prevention strategies, including using proper equipment, wearing protective gear, taking lessons, and riding in terrain and weather conditions appropriate for one's skill level. PMID- 29275717 TI - Cme Self Test. PMID- 29275719 TI - Managing Successive Minor Head Injuries. AB - In brief This case report describes a female college basketball player who experienced brief loss of consciousness with hemiparesis after being struck in the jaw during a game. When she returned to play a month later, she sustained a second mild head injury, which resulted in persistent headache, cognitive difficulties, and reversal in hand dominance. She has since recovered felly. This case addresses retum-to-play issues for the head-injured athlete, especially the risk of recurrent injury. It also illustrates the utility of neuropsychological testing when standard medical tests fail to detect any abnormalities. PMID- 29275721 TI - Fruits and Veggies. PMID- 29275720 TI - Forum. PMID- 29275722 TI - Pearls. PMID- 29275723 TI - Sports Medicine in the Workplace. AB - Physicians versed in sports medicine may want to look to industry, where primary care skills are increasingly in demand. Aggressive rehab methods honed on athletes can also return workers to the job more quickly. The result? Physicians can expand their practices while helping employers save on worker's compensation costs. PMID- 29275724 TI - When Groin Pain Signals an Adductor Strain. AB - In brief Adductor strains typically occur brief with forceful abduction of the thigh during adduction or with hyperabduction. The history and physical exam are usually diagnostic; however, other causes of acute groin pain must always be ruled out. Using CT, MRI, or ultrasound can facilitate diagnosis of difficult or unusual cases. Management of acute partial strains usually requires nonsteroidal anti-inflammatory drugs, ice, compression, physical therapy, and rest. The mainstay of treatment is early active rehabilitation and returq to competition. Surgery is often required for complete ruptures, but the treatment for such injuries remains under discussion. PMID- 29275725 TI - Solar Injury and Heat Illness. AB - In brief Children are particularly susceptible to solar injury to the skin and eyes and to heat illness-heat cramps, heat exhaustion, and heatstroke. Because sunburn during childhood is linked to subsequent skin cancer, aggressive prevention through use of sunscreens and other protective measures is critical. Physicians should screen for risk factors for heat illness, such as hypohydration, obesity, poor conditioning, and certain illnesses. Heat illness can be effectively prevented through acclimation, proper hydration, and advance event planning. PMID- 29275726 TI - How Pollution and Airborne Allergens Affect Exercise. AB - In brief Air pollution, airborne allergens, and changing weather conditions-alone or in combination-can hinder physical activity. In any active individual, high ozone levels can cause restrictive lung dysfunction, and high carbon monoxide levels can impair oxygen delivery. Sulfur dioxide worsens nasal symptoms in people who have allergies and causes bronchospasm in those who have asthma. Airway irritation from fine particulates can lead to bronchospasm. Atopic individuals suffer from the well-known effects of fungi and pollen. If a change in exercise routine or activity doesn't relieve symptoms, pharmacologic treatment may include antihistamines, immunotherapy, inhaled corticosteroids, and/or inhaled beta-2 bronchodilators. PMID- 29275727 TI - Office Diagnosis of Shoulder Disorders. AB - In brief Complex tests and procedures brief are not usually needed to identify shoulder injuries that are common in clinical practice: rotator cuff injuries, shoulder instability, and impingement syndrome, among others. The history can differentiate causes of pain or instability with questions about symptom patterns. Performing targeted physical tests such as the drop-arm test and the apprehension test establishes presence and degree of impingement or instability. A standard radiographic series that includes rotation, axillary, and supraspinatus outlet views can identify presence of associated fractures, calcification, and lesions. PMID- 29275728 TI - Must the Race Go On? PMID- 29275731 TI - CME Self Test. PMID- 29275729 TI - Exercise and Angina. PMID- 29275732 TI - Viral Myocarditis. AB - In brief Physical activity can lead to sudden death in a patient who has viral myocarditis. Vigilance is required in its detection because it is not only serious, but also rare and difficult to diagnose, given that its signs and symptoms are nonspecific. The diagnosis requires confirmation by biopsy. The natural history is highly variable; patients may develop early or late severe congestive heart failure. Treatment consists of conventional heart failure therapy including angiotensin converting enzyme (ACE) inhibitors, diuretics, and digitalis. Corticosteroid therapy seems to provide no added benefit, but should not be withheld in cases of extreme left ventricular dysfunction. Exercise restrictions are important during the acute phase, and exercise testing helps guide a safe return to activity. PMID- 29275733 TI - Pearls. PMID- 29275734 TI - Forum. PMID- 29275735 TI - Nutrition Quackery. PMID- 29275737 TI - Sports Medicine Groups 1996. PMID- 29275739 TI - Medical Information Online: What's Now? What's Coming? PMID- 29275741 TI - CME Self Test. PMID- 29275740 TI - Strengthening the Hip Abductors. PMID- 29275742 TI - Sports and Exercise During Acute Illness. AB - In brief Active people who suffer acute brief infectious illness may have questions concerning participation in exercise or sports during their illness. Many patients are reluctant to "get behind" on their training or 'let down the team." Physical activity, however, may worsen the condition, result in impaired performance, or infect others. On the other hand, some contagious diseases are relatively benign, and some activities don't affect others. Therefore, clinicians need to understand both the sport and the illness to know what level of activity to recommend. For example, solo exercise at a reduced intensity is generally safe for patients whose symptoms are above the neck. PMID- 29275743 TI - Nontraumatic Hip Pain in Active Children. AB - In brief A case report of an 8-year-old baseball player who was diagnosed with Legg-Calve-Perthes (LCP) disease gives an opportunity to consider the many nontraumatic causes of hip pain. Possibilities include slipped capital femoral epiphysis, septic arthritis, transient synovitis, juvenile rheumatoid arthritis, and bone tumor. Radiographs and bone scans are used to document and stage LCP, and to evaluate the effectiveness of treatment. Though the aggressiveness of treatment depends on the disease stage, the treatment of choice is generally nonsurgical containment of the femoral epiphysis with a cast or orthosis. PMID- 29275744 TI - Pearls. PMID- 29275746 TI - Neck Injuries. AB - In brief When a neck injury is suspected, the on-site physician must first provide basic trauma care, which includes establishing an airway as necessary, assessing breathing, and checking circulation and neurologic compromise. A few targeted questions during history taking and a directed physical exam will help rule out serious cervical injuries, which are uncommon. More common are minor injuries, such as "burners." Team physicians must also be well-versed in immobilizing and transporting the patient, administering a thorough neurologic exam, and establishing when the athlete can return to competition. PMID- 29275747 TI - Forum. PMID- 29275749 TI - An evaluation of service use outcomes in a Recovery College. AB - BACKGROUND: Recovery Colleges offer educational courses about recovery and mental health which are co-produced by mental health professionals and experts by lived experience. Previous evaluations have found positive effects of Recovery Colleges on a range of outcomes including wellbeing, recovery and quality of life. AIMS: To evaluate service use outcomes for Sussex Recovery College students who use mental health services. METHOD: The study used a controlled-before-and-after design. It used archival data to analyse service use before and after participants registered with the Recovery College (n = 463). Participants acted as their own control. RESULTS: Students used mental health services less after attending the Recovery College than before. Students who attended the Recovery College showed significant reductions in occupied hospital bed days, admissions, admissions under section and community contacts in the 18 months post compared with the 18 months before registering. Reductions in service use were greater for those who completed a course than those who registered but did not complete a course. CONCLUSION: These findings suggest that attending Recovery College courses is associated with reduced service use. The reductions equate to non cashable cost-savings of L1200 per registered student and L1760 for students who completed a course. Further research is needed to investigate causality. PMID- 29275750 TI - Responding to the Commentary on the Article: "Improving the Prediction of Maturity From Anthropometric Variables Using a Maturity Ratio". PMID- 29275753 TI - Scanning Sports. PMID- 29275751 TI - Forum. PMID- 29275754 TI - Greg Louganis and 20/20 Hindsight. PMID- 29275756 TI - CME Self Test. PMID- 29275757 TI - How I Manage Athlete's Foot. AB - Athlete's foot, or tinea pedis, is a fungal infection that commonly affects active individuals. Intense itching is the primary symptom. Rash distribution, degree of redness, type of scaling, and presence of vesicles can distinguish athlete's foot from inflammatory conditions, but there is much overlap in presentation. Antifungal creams, used consistently for a period of weeks, are generally effective; in certain cases, keratolytics or oral antifungals are necessary. Educating patients about medication use, appropriate footwear, and avoiding excessive heat and moisture can help keep the condition in tow. PMID- 29275759 TI - Healthy Muscle Gains. PMID- 29275758 TI - Pearls. PMID- 29275760 TI - The 'Super Six' Stretches for Golfers. PMID- 29275761 TI - Nerve Injuries. AB - In brief Peripheral nerve injuries are brief common active patients because many sports subject nerves to compression and traction. Patients generally present reporting weakness and paresthesia in the distribution of the damaged nerve. The most common injured nerves are the median and carpal tunnel, ulnar at the elbow, peroneal at the fibular head, long thoracic, and the suprascapular. Several of the less common nerve injuries can also be related to activity. The fact that nerve regrowth is slow often mandates patient, conservative treatment that consists of protection and activity modification. PMID- 29275762 TI - Reflex Sympathetic Dystrophy. AB - In brief Reflex sympathetic dystrophy (RSD) is an unusual pain syndrome that can arise after athletic injuries such as sprains, strains, or fractures. Classic signs-burning pain, edema, and vasomotor instability-are present in varying degrees, making the diagnosis of RSD difficult. Three case studies demonstrate typical findings. Treatment consists of early, aggressive physical therapy, adequate pain relief, and corticosteroids when appropriate. Sympathetic blockade is useful for diagnosis and therapy. Early protected range of motion for treating injuries often helps prevent RSD. PMID- 29275763 TI - Elbow Fractures. AB - In brief Elbow fractures are common injuries in active patients. When the fracture is nondisplaced, nonoperative treatment is frequently successful. Because stiffness is a common complication, early mobilization is an important aim of treatment; this may necessitate surgical fixation. This article reviews the diagnosis and treatment of fractures of the distal humerus, lateral epicondyle, medial condyle, lateral condyle, olecranon, coronoid process, radial head, and radial neck, as well as supracondylar fractures and Monteggia's fracture. PMID- 29275764 TI - Sports Medicine and Managed Care. AB - In brief Because the primary care physician is the cornerstone of the managed care system, opportunities for primary care physicians to practice sports medicine under managed care will likely increase. Access to a vast array of resources and an emphasis on patient education and preventive services has contributed to the success of sports medicine at the Kaiser Permanente Medical Care Program in California. As sports medicine enters the managed care arena, issues of efficient service delivery, cost effectiveness, and interdisciplinary care will require closer scrutiny. PMID- 29275765 TI - Assessing Acute Abdominal Pain. AB - In brief The etiology of abdominal pain is diverse, but, for immediate purposes, the team physician must simply focus on whether the process requires surgical intervention. An effective history includes a detailed description of the pain and its onset, and an accounting of associated symptoms and events. Pain from a serious condition typically arises suddenly and is continuous, progressively worse, and long lasting; begins during inactivity; and is not near the umbilicus. Portions of the physical exam that require physical contact should begin farthest away from the site of maximal pain. Auscultation should precede palpation to avoid alteration of peristalsis. PMID- 29275766 TI - Managing ACL Injuries in Children. AB - In brief ACL injuries in children result in adultlike chronic instability problems. Physical tests and radiographs guide the diagnosis. Treatment depends on whether the ACL injury is an intrasubstance tear or, what is more common, an avulsion fracture of the tibial eminence. A case report of an 11-year-old boy describes a typical avulsion injury. Treatment of avulsion injuries consists of cast immobilization and open reduction and fixation for a displaced fragment. PMID- 29275767 TI - Pearls. AB - 'Pearls' enables sports medicine professionals to share their practical tips for treating patients. We invite you to send your contributions to Pearls Editor, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. Address electronic submissions to psm@mill2.millcomm.com. Illustrations or photos are encouraged. Selected pearls will be published, accompanied by the author's name. PMID- 29275769 TI - Infectious Mononucleosis. AB - In brief A two-step infection by the Epstein-Barr virus accounts for the characteristic features of infectious mononucleosis (IM). New serologic tests for viral antigens exist, but a rapid kit test for heterophil antibody usually suffices to confirm the diagnosis. General management is supportive only. Splenic rupture is very rare, almost never fatal if diagnosed early, and, in most cases, is probably best treated by splenectomy. Athletes tend to recover from IM faster than nonathletes. When the spleen returns to normal size, the athlete can return to contact sports, though it may take 3 to 6 months for an elite athlete to regain top form. PMID- 29275770 TI - Exertional Compartment Syndrome of the Leg. AB - In brief The pain and swelling associated with exertional compartment syndrome is caused by raised intracompartmental pressures possibly induced by muscle swelling or increased osmotic pressure. Although either the acute or chronic form of exertional compartment syndrome may occur, chronic is more common. Patients typically experience pain and swelling and may also have sensory deficits or paresthesias, and motor loss or weakness. Diagnosis is confirmed by intracompartmental pressure measurements before and after exercise. Although activity modification may alleviate symptoms, fasciotomy may be required. PMID- 29275771 TI - When to Let Your Patient Back Into the Game. PMID- 29275773 TI - CME Self Test. PMID- 29275772 TI - The 'Super Six' Strengthened for Golfers. PMID- 29275775 TI - The Power of Protein. PMID- 29275776 TI - Extrahepatic cholangiocarcinoma with prolonged survival: a case report. AB - BACKGROUND: Cholangiocarcinoma has poor prognosis and short term-survival. Here, we report the case of a patient with unusually prolonged survival. CASE PRESENTATION: Our patient was a 56-year-old Arab man with a 6-month history of obstructive jaundice. A computed tomography scan of his abdomen revealed a mass at the confluence of the hepatic ducts with suspected malignant strictures on endoscopy. A positive tissue diagnosis was achieved more than 18 months after commencement of his symptoms. He remained functional throughout this period despite recurrent episodes of cholangitis. CONCLUSIONS: Cholangiocarcinoma is a presumably fatal disease, especially because patients tend to present late with unresectable disease. Many patient-related and disease-related factors may alter survival. PMID- 29275777 TI - Depression and anxiety symptom trajectories in coronary heart disease: Associations with measures of disability and impact on 3-year health care costs. AB - BACKGROUND: As mortality from coronary heart disease (CHD) falls, years lived with disability increase. Depression and anxiety are known indicators of poor outcomes in CHD, but most research has measured distress symptoms at one time point, often following acute events. Here we consider the long-term trajectories of these symptoms in established CHD, and examine their association to distinct measures of disability and impact on costs. METHODS AND RESULTS: 803 patients with diagnosis of CHD were recruited from primary care, and completed detailed assessments every 6months for 3years. Latent class growth analysis (LCGA) was used to identify 5 distinct symptom trajectories based on the Hospital Anxiety and Depression Questionnaire (HADS): 'stable low', 'chronic high', 'improving', 'worsening', and 'fluctuating'. The 'chronic high' group had highest association with reporting of chest pain (RRR 5.8, CI 2.9 to 11.7), smoking (2.9, 1.1 to 6.3), and poorer physical (0.88, 0.83-0.93) and mental (0.78, 0.73-0.84) quality of life. The 'chronic high' and 'worsening' trajectories had significantly higher health-care costs over the 'stable low' trajectory (107.2% and 95.5% increase, respectively). In addition, our trajectories were the only significant variable associated with increased health-care costs across the 3years. CONCLUSIONS: Symptoms of depression and anxiety are highly prevalent in stable CHD patients, and their long-term trajectories are the single biggest driver of health care costs. Managing morbidity in these patients, in which depression and anxiety play a key role in, should become the primary focus of policy makers and future clinical trials. PMID- 29275778 TI - Examining motivational interviewing plus nutrition psychoeducation for weight loss in primary care. AB - OBJECTIVE: Our previous randomized controlled trial found that nutrition psychoeducation (NP), an attention-control condition, produced statistically significantly more weight loss than usual care (UC), whereas motivational interviewing (MI) did not. NP, MI, and UC resulted in medium-large, medium, and negligible effects on weight loss, respectively. To examine whether weight loss could be further improved by combining MI and NP, the current study evaluated the scalable combination (MINP) with accessible web-based materials. METHODS: 31 adults with overweight/obesity, with and without binge-eating disorder (BED), were enrolled in the 3-month MINP treatment in primary care. Participants were assessed at baseline, post, and 3-month follow-up. Mixed-model analyses examined MINP effects over time and the prognostic significance of BED. RESULTS: Mixed model analyses revealed that percentage weight loss was statistically significant at post and 3-month follow-up; d'=0.59 and 0.53, respectively. BED status did not predict or moderate weight loss. Twenty-one percent (6 of 28) and 26% (7 of 27) of participants attained 5% weight loss by post-treatment and 3-month follow-up, respectively. Participants with BED had statistically significantly greater improvements in disordered eating and depression (in addition to binge-eating reductions) compared to those without BED. CONCLUSION: MINP resulted in weight and psychological improvements at post-treatment and through 3-months after treatment completion. There did not appear to be additional benefits to combining basic nutrition information with MI when compared to the previous randomized controlled trial testing nutrition psychoeducation alone. CLINICAL TRIAL REGISTRATION: NCT02578199. PMID- 29275779 TI - The predictive value of positive affect and Type D personality for adverse cardiovascular clinical outcomes in patients with non-obstructive coronary artery disease. AB - BACKGROUND: Patients with non-obstructive coronary artery disease (NOCAD) continue to experience disabling symptoms. Positive affect (PA) has shown a cardioprotective potential. Type D personality has previously been shown to have a deleterious effect on adverse outcomes in diverse cardiac populations. Little is known about the predictive value of PA and Type D personality for long-term outcomes in NOCAD patients. The aim was to investigate the effect of PA and Type D personality on clinical outcomes. METHODS: 547 patients (mean age 61 years+/-9, 48% male) who underwent a coronary angiography or CT-scan between January 2009 and February 2013 answered questionnaires concerning PA (GMS) and Type D personality (DS14). Cox proportional hazards analyses were performed. RESULTS: When analyzed dichotomously, PA was a significant predictor of need for repeat cardiac testing (HR=0.64, 95% CI: 0.41-0.99), but not emergency department (ED) admissions (HR=0.83, 95% CI: 0.52-1.32) after adjustment for age, sex, education, diagnosis by group, BMI and hypertension. Analyzed continuously, the predictive value of PA was non-significant for both repeat testing (HR=0.85, 95% CI: 0.69 1.06) and ED admissions (HR=0.98, 95% CI: 0.77-1.23). Type D personality, both continuously and dichotomously, was not significantly associated with the outcomes. Findings were also examined for men and women separately. CONCLUSION: Although Type D personality was not predictive of adverse events in this sample, PA is an interesting and important variable to take into account in NOCAD patients. Research on psychosocial factors in NOCAD patients should consider the importance of choices of endpoint, given the heterogeneity of NOCAD patients. PMID- 29275780 TI - The four week time frame for somatic symptom questionnaires reflects subjective symptom burden best. AB - OBJECTIVE: Various questionnaires are available to assess somatic symptom burden, however their assessment time frames vary largely. The aim of this study was to investigate the most relevant assessment time frame for somatic symptoms by relating somatic symptom burden, with varying time frames, to quality of life (QoL) and health anxiety as indicators for clinical relevance of symptoms. METHODS: This study was performed in data derived from a convenience sample of 3477 participants (age: 48.0 (SD 14.1), 66.4% female) of the Dutch research platform HowNutsAreTheDutch. Symptom burden was assessed using all items from the Patient Health Questionnaire-15 (PHQ-15) and 6 items of the Symptom Checklist-90 SOM (SCL-90 SOM). Five versions of the questionnaire were constructed, which evaluated symptom burden during the past 24h, 1week, 2weeks, 4weeks, and 3months. RESULTS: Symptom burden significantly increased with each step increase in time frame until 4weeks, with no further increase when comparing 4weeks and 3months. The time frame of 4weeks provided the strongest associations between somatic symptom burden and health anxiety (B=1.635; 95%CI: 1.368 to 1.938; p<=0.001). This was also true when analysing the association between QoL and the symptom groups of musculoskeletal (B=-1.54; 95%CI: -1.93 to -1.16;p<=0.001) and gastrointestinal symptoms (B=-0.71; 95%CI: -0.96 to -0.47;p<=0.001). CONCLUSION: An assessment time frame of 4weeks for somatic symptom questionnaires reflects clinically relevant somatic symptom burden in terms of QoL and health anxiety best, followed by the 3months' time frame. PMID- 29275781 TI - Physical comorbidity in patients with multiple functional somatic syndromes. A register-based case-control study. AB - BACKGROUND: Patients with multiple functional somatic syndromes show markedly reduced functioning and numerous somatic symptoms that cannot be explained by conventionally-defined physical disease. Whilst the comorbidity of functional somatic syndromes with mental disorders is well-known, knowledge about physical comorbidity and mortality is scarce. AIM: To compare number of physical diseases between patients with multiple functional somatic syndromes (operationalized as multi-organ bodily distress syndrome) and the general population with regard to: 1) All conventionally-defined physical diseases, and 2) Severe mortality associated physical diseases. MATERIALS AND METHODS: Patients with multiple functional somatic syndromes (n=239) were compared with age- and gender-matched population-based controls (n=5975). The number of physical diseases during a four year period was estimated by means of registered ICD-10 codes in relation to hospital admissions and ambulatory care. We counted individual diagnoses indicating conventionally-defined physical disease based on a previously developed diagnosis sorting algorithm and an additional clinical evaluation, excluding unspecific (symptom) diagnoses and functional somatic syndromes. An updated version of Charlson Comorbidity Index (CCI12) was used to estimate severe, mortality-associated physical diseases. RESULTS: Patients with multiple functional somatic syndromes had an increased number of conventionally-defined physical disease compared to controls (Ratio: 2.17, 95% CI: 1.96-2.41). Groups were similar as regards CCI12 (P=0.55). CONCLUSIONS: Patients with multiple functional somatic syndromes showed substantial physical comorbidity. Their burden of severe, mortality-associated physical diseases was comparable to the general population. Further research is needed to clarify the nature, clinical significance, and long-term consequences of the comorbid physical diseases. PMID- 29275782 TI - Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands. AB - OBJECTIVE: We previously described symptom-based chronic fatigue syndrome (CFS/ME) phenotypes in clinical assessment data from 7041 UK and 1392 Dutch adult CFS/ME patients. Here we aim to replicate these phenotypes in a more recent UK patient cohort, and investigate whether phenotypes are associated with 1-year treatment outcome. METHODS: 12 specialist CFS/ME services (11 UK, 1 NL) recorded the presence/absence of 5 symptoms (muscle pain, joint pain, headache, sore throat, and painful lymph nodes) which can occur in addition to the 3 symptoms (post-exertional malaise, cognitive dysfunction, and disturbed/unrefreshing sleep) that are present for almost all patients. Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes). Multinomial logistic regression models were fitted to quantify associations between phenotypes and overall change in health 1year after the start of treatment. RESULTS: Baseline data were available for N=918 UK and N=1392 Dutch patients, of whom 416 (45.3%) and 912 (65.5%) had 1-year follow-up data, respectively. 3- and 4-class phenotypes identified in the previous UK patient cohort were replicated in the new UK cohort. UK patients who presented with 'polysymptomatic' and 'pain-only' phenotypes were 57% and 67% less likely (multinomial odds ratio (MOR) 0.43 (95% CI 0.19-0.94) and 0.33 (95% CI 0.13-0.84)) to report that their health was "very much better" or "much better" than patients who presented with an 'oligosymptomatic' phenotype. For Dutch patients, polysymptomatic and pain-only phenotypes were associated with 72% and 55% lower odds of improvement (MOR 0.28 (95% CI 0.11, 0.69) and 0.45 (95% CI 0.21, 0.99)) compared with oligosymptomatic patients. CONCLUSIONS: Adult CFS/ME patients with multiple symptoms or pain symptoms who present for specialist treatment are much less likely to report favourable treatment outcomes than patients who present with few symptoms. PMID- 29275783 TI - Psychiatric comorbidities in patients with Atypical Odontalgia. AB - OBJECTIVE: Atypical Odontalgia (AO) is a condition characterized by tooth pain with no apparent cause. Although psychiatric comorbidity seems to be very common, it has rarely been studied. To clarify the influence of psychiatric comorbidity on the clinical features in patients with AO, we retrospectively evaluated their examination records. METHODS: Clinical features and psychiatric diagnoses of 383 patients with AO were investigated by reviewing patients' medical records and referral letters. Psychiatric diagnoses were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We also analyzed visual analogue scale (VAS), self-rating depression scale (SDS), and the short-form McGill pain questionnaire (SF-MPQ) scores. RESULTS: Of the 383 patients with AO, 177 (46.2%) had comorbid psychiatric disorders. The most common were depressive disorders (15.4%) and anxiety disorders (10.1%). Serious psychotic disorders such as bipolar disorder (3.0%) and schizophrenia (1.8%) were rare. Dental trigger of AO was reported in 217 (56.7%) patients. There were no significant correlations between psychiatric comorbidities and most of the demographic features. Higher VAS and SDS scores, higher frequency of sleep disturbance, and higher ratings of "Fearful" and "Punishing-cruel" descriptors of the SF-MPQ were found in patients with psychiatric comorbidity. CONCLUSIONS: About half of AO patients had comorbid psychiatric disorders. Dental procedures are not necessarily causative factors of AO. In AO patients with comorbid psychiatric disorders, pain might have a larger emotional component than a sensory one. VAS, SDS, and SF-MPQ scores might aid in the noticing of underlying comorbid psychiatric disorders in AO patients. PMID- 29275785 TI - Food allergy: Children's symptom levels are associated with mothers' psycho-socio economic variables. AB - BACKGROUND: Allergies affect children's health as well as their quality of life, stress levels, and family budget. The available literature suggests that family, social and psychological factors are affected by allergic pathologies such as rhinitis, asthma and atopic dermatitis. However, few studies have focused on quantifying such association in child food allergy. This study aims to enhance the understanding of the associations between caregiver variables and children's Food Allergy (FA). METHODS: The study involved 206 participants: 103 mothers plus 103 children with IgE mediated FA. The analyses excluded two outliers comprising 101 subjects. For statistical analyses, each dyad -mother/child- was considered to be one subject unity. A between-subjects one-way ANOVA determined the association of children's cutaneous, gastric and respiratory symptoms with anxiety, depression, perceived social support and socioeconomic factors in the mothers. RESULTS: There are significant associations between children's allergic symptoms (gastric and cutaneous) and mothers' psychological state (anxiety and depression); family budget; social interactions (with friends, family and partner); understanding of health care required by their child; and sleep disorders. Respiratory symptoms did not show any significant associations with the dependent variables. CONCLUSION: FA is a process in which children's symptoms are significantly associated with socioeconomic and psychological variables of the mothers. The presence or absence of some specific symptoms is directly associated with specific impacts on the mothers. An understanding of such dynamics supports the consideration of a comprehensive and multidisciplinary therapeutic approach to offer more ecological healthcare for "families living with FA." PMID- 29275784 TI - When is affect variability bad for health? The association between affect variability and immune response to the influenza vaccination. AB - OBJECTIVES: This study addresses methodological and theoretical questions about the association between affect and physical health. Specifically, we examine the role of affect variability and its interaction with mean levels of affect to predict antibody (Ab) levels in response to an influenza vaccination. METHODS: Participants (N=83) received the vaccination and completed daily diary measures of affect four times a day for 13days. At one and four months post-vaccination, blood was collected from the participants to assess Ab levels. RESULTS: Findings indicate that affect variability and its interaction with mean levels of affect predict an individual's immune response. Those high in mean positive affect (PA) who had more PA variability were more likely to have a lower Ab response in comparison to those who had high mean PA and less PA variability. Although it did not interact with mean negative affect (NA), NA variability on its own was associated with Ab response, whereby those with less NA variability mounted a more robust immune response. CONCLUSION: Affect variability is related to immune response to an influenza vaccination and, in some cases, interacts with mean levels of affect. These oscillations in affective experiences are critical to consider in order to unpack the intricacies of how affect influences health. These findings suggest that future researchers should consider the important role of affect variability on physical health-relevant outcomes as well as examine the moderating effect of mean affect levels. PMID- 29275786 TI - Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients. AB - OBJECTIVE: Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome (CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients. METHODS: In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF). RESULTS: Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1 1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing. CONCLUSIONS: In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS. PMID- 29275787 TI - Association between effort-reward imbalance and self-reported diabetes mellitus in older U.S. workers. AB - OBJECTIVE: Studies assessing the effects of work stress on health in older adults in the U.S. labor force are scarce. We examined the longitudinal association between work stress as measured by effort-reward imbalance (ERI) and incident diabetes over a 7-year period in U.S. working adults aged 50years and older. METHODS: We used longitudinal data from the 2006-2012 waves of the Health and Retirement Study (n=1932). Cox proportional hazard regression was used to examine whether ERI significantly predicted diabetes incidence in older adults who were diabetes-free at baseline. RESULTS: High stress level at work (ERI ratio>1.0) was found in participants who worked 55h or more a week (37.3%), had no insurance coverage (35.9%), and those working in blue collar jobs (34.4%). Participants with high ERI had a significantly higher risk of diabetes (HR=1.33, 95%CI=1.04 1.69) relative to those with low ERI, after adjustment for known predictors of adult-onset diabetes. CONCLUSION: Effort-reward imbalance was associated with increased risk of diabetes incidence after controlling for other known predictive factors, which suggests an independent non-mediated effect of work stressors. More research is required to better understand the effects of work stress in aging populations and how psychosocial disequilibrium in the work environment may impact susceptibility to chronic conditions, and in particular how change in self assessed reward might vary toward the end of a working lifetime. PMID- 29275788 TI - A systematic review of anxiety interventions in stroke and acquired brain injury: Efficacy and trial design. AB - OBJECTIVE: There is little randomized controlled trial (RCT) evidence to guide treatment for anxiety after stroke. We systematically reviewed RCTs of anxiety interventions in acquired brain injury (ABI) conditions including stroke and traumatic brain injury (TBI) in order to summarize efficacy and key aspects of trial design to help guide future RCTs. METHODS: We searched the Cochrane trial register, Medline, Embase, PsychInfo and CINAHL systematically up to August 2017. Two independent reviewers systematically selected studies and extracted data. We summarized the effect size, key study characteristics and sources of potential bias in trial design. RESULTS: 14 studies (12 stroke; one stroke & TBI; one TBI) with 928 participants were included. Meta-analysis of five psychotherapy comparisons favoured intervention over control (standardized mean difference (SMD): -0.41 [-0.79, -0.03], I2=28%); Overall effect size of pharmacotherapy comparisons favoured intervention over control (SMD: -2.12 [-3.05, -1.18], I2=89%). One comparison of mixed pharmacotherapy and psychotherapy favoured intervention over usual care (SMD: -4.79 [-5.87, -3.71]). One comparison favoured forest therapy versus urban control (SMD: -2.00 [-2.59, -1.41]). All positive studies carried high or unclear risk of bias. Sample sizes were small in all included studies. CONCLUSIONS: There is low quality evidence to suggest that psychotherapy and pharmacotherapy may be effective interventions in the treatment of anxiety after stroke based on underpowered studies that carried high risk of bias. Large-scale well-designed definitive trials are needed to establish whether pharmacological or psychotherapy works. Our review highlighted key considerations for investigators wishing to design high quality trials to evaluate treatments for anxiety after stroke. PMID- 29275789 TI - The 2-year course of Medically Unexplained Physical Symptoms (MUPS) in terms of symptom severity and functional status: results of the PROSPECTS cohort study. AB - OBJECTIVE: We assessed the 2-year course of Medically Unexplained Physical Symptoms (MUPS) in terms of symptom severity, physical functioning and mental functioning. METHODS: We used data of the PROSPECTS cohort study, consisting of 325 MUPS patients from several health care settings. Symptom severity (PHQ-15), physical functioning (RAND 36 PCS) and mental functioning (RAND 36 MCS) were assessed at baseline and 6, 12 and 24 months afterwards. We used Latent Class Growth Modeling (LCGM) to identify different course types, but as clinical usability of results was limited, we also analysed change scores and directions of change. RESULTS: LCGM identified three course trajectories for all outcomes: a "stable severe", a "stable moderate" and an "improvement" trajectory. The greater majority of participants was assigned to the stable trajectories. However, we found high levels of within-trajectory heterogeneity. Based on total change scores (using only two measurement moments), physical symptoms of 27% of the participants deteriorated, while 63% improved. Based on Minimal Clinically Important Differences these proportions were 5% and 24%. Analyses of directions of change (using all measurement moments) showed that for all outcomes almost 80% reported a fluctuating course type, with clinically important fluctuations in 35 61% of participants. CONCLUSION: Fluctuations in the course of MUPS were highly prevalent, but as fluctuations showed high interpersonal heterogeneity, these were not detected by LCGM. Improvement and deterioration rates based on change scores are in line with literature. However, based on the highly prevalent fluctuations, we conclude that temporal stability of these outcomes is limited. PMID- 29275790 TI - The clinical utility of metacognitive beliefs and processes in emotional distress in people with multiple sclerosis. AB - AIM: Multiple sclerosis (MS) is a chronic demyelinating disease that poses significant life challenges. Depression and anxiety often occur in people with MS (PwMS). An information processing model of psychopathology, the Self-Regulatory Executive Function (S-REF) model specifies that maladaptive metacognitive beliefs play a fundamental role in the development and maintenance of distress. The model also asserts that a style of thinking known as the cognitive attentional syndrome (CAS), which consists of worry and rumination, focusing on sources of threat, and unhelpful coping responses, is common across all psychological conditions. This study investigated for the first time whether metacognitive beliefs explained additional variance in distress in PwMS, after accounting for demographic, clinical, and illness appraisal variables. METHOD: One hundred and thirty-two participants with MS completed self-report questionnaires measuring distress, fatigue, pain, metacognitive beliefs, illness appraisals, and the CAS. Hierarchical regression modelling was used to test whether metacognitive beliefs accounted for distress. Mediational modelling examined if the CAS mediated the association between metacognitive beliefs and distress. RESULTS: Metacognitive beliefs made a unique contribution to distress, over and above demographic and clinical variables, and illness appraisals. The CAS fully mediated the relationship between positive metacognitive beliefs and distress, and partially mediated the relationship between negative metacognitive beliefs and distress. CONCLUSIONS: Metacognitive beliefs are associated with emotional distress in PwMS, and the CAS mediates this relationship. Future studies should examine if modification of metacognitive beliefs and processes in PwMS will lead to effective alleviation of emotional distress. PMID- 29275791 TI - The working alliance and Clinician-assisted Emotional Disclosure for rheumatoid arthritis. AB - OBJECTIVES: The working alliance predicts improvement following general psychotherapy, but how it operates in brief interventions conducted with medically ill patients is unknown. Also, the role of the working alliance may differ in emotion-focused versus educational interventions. METHODS: We report secondary analyses of a randomized clinical trial (Keefe et al.) [35], in which patients with rheumatoid arthritis (RA) received four nurse-provided sessions of either a) Clinician-assisted Emotional Disclosure (CAED), which emphasized the disclosure, expression, and processing of emotions related to stressful events; or b) Arthritis Education (AE), which provided basic education about RA. The Working Alliance Inventory was completed by both patient and nurse after each session. Patients were evaluated on multiple health measures at baseline and 1, 3, and 12months post-treatment. RESULTS: Analyses compared the alliance between interventions and related the alliance to outcomes within interventions. Patients in CAED reported a lower alliance than patients in AE. Interestingly, in CAED, lower alliance ratings predicted better outcomes (improved functioning, lower pain behaviors, lower inflammation, lower daily stress), whereas in AE, the working alliance was largely not predictive of outcomes. CONCLUSION: Having nurses encourage emotional disclosure among patients with RA reduced the patients' working alliance, but a lower alliance nonetheless predicted better patient outcomes, perhaps reflecting successful engagement in an intervention that is emotionally and relationally challenging. The level and predictive validity of the working alliance likely depends on patient, provider, and intervention factors, and further study of the working alliance in psychosocial interventions in the medical context is needed. PMID- 29275792 TI - Trajectories of anxiety symptoms and associations with incident cardiovascular disease in adults with type 2 diabetes. AB - BACKGROUND: Trajectories of anxiety symptoms in people with type 2 diabetes (T2D) and their associations with diabetes health outcomes have not been investigated. This study examined latent longitudinal trajectories of anxiety symptoms in adults with T2D and their associations with incident cardiovascular disease (CVD). METHODS: Data were from the Evaluation of Diabetes Treatment Study, a community-based cohort study of adults aged 40-76years with T2D. Anxiety and CVD were assessed by self-report at baseline and at four annual follow-up assessments. N=832 participants without cardiovascular disease at baseline and 12 month follow-up were included in the present study. Group-based trajectories of anxiety at baseline, 12-month follow-up, and 24-month follow-up were modelled using latent class growth modeling. Associations between anxiety trajectories and CVD reported at 24-, 36-, or 48-month follow-ups were examined with logistic regression analysis adjusted for sociodemographic and lifestyle characteristics. RESULTS: Four distinct anxiety trajectories were identified, reflecting chronically low (39.4%), chronically moderate-low (47.4%), chronically moderate high (11.1%), and chronically high (2.2%) anxiety. The likelihood of CVD was greater for the chronically moderate-low (OR=2.23, 95% CI=1.36-3.66), chronically moderate-high (OR=3.05, 95% CI=1.54-6.02), and chronically high (OR=3.61, 95% CI=1.09-12.00) anxiety trajectory groups compared to the chronically low anxiety group. CONCLUSION: The identified latent trajectories reflected three groups with chronic courses of anxiety symptoms at different levels of severity and one group with chronically low levels of anxiety. Chronic anxiety, even at subthreshold levels, was associated with an increased risk of CVD among people with T2D. PMID- 29275793 TI - Analysis of Evidence-Based Autism Symptoms Enhancement by Acupuncture. AB - Autism is considered as a complex developmental disability that appears during the first two years of life. It is considered as a neurological disorder that affects brain function leading to impaired development in social interaction and communication skills. Some clinical trials demonstrated that certain acupuncture points play relatively significant role in improving both signs and symptoms of this disease. Owing to limited information available about acupuncture point's combination and protocols, the present study aimed to explore the most frequently used acupuncture points and their channels for children with autism. Thirteen articles about autism enhancement were selected from 2007 to 2015. Acupoints and their channels used in these articles were analyzed according to usage frequencies. The present study identified the following main channels that contribute to autism symptoms enhancement along with the corresponding points' frequencies: Governing Vessel channel (12), Gall bladder channel (9), Kidney channel (8), Pericardium channel (7), Extra points channel (7), Liver channel (7), Heart channel (6), Conception vessel channel (6), and Bladder channel (6). On the other hand, the frequency of each corresponding acupuncture points are EX HN1 (5), GV-17 (4), PC-6 (4), LR-3 (3), KI-3 (3), HT-7 (3), Lu-9 (3), GV-20 (2), GV-24 (2), GV-24.5 (2), GB-13(2), GB-19 (2), KI-4 (2), LR-4 (2), ST-36 (2), SP-3 (2), SP-6 (2). In conclusion, the consensus is that both channels and points may have an important role in autism symptoms enhancement. Based on the present study, the specific channels and points selection and stimulation types need further investigation through clinical trials. PMID- 29275794 TI - Being Adaptive to Pain Enhances Sham Acupuncture Analgesia: A Crossover Healthy Human Study. AB - We have reported a model that distinguishes pain adaptive individuals (PA) from those who are pain non-adaptive (PNA). The present randomised, cross-over, participant-assessor blinded study aimed to determine the impact of pain adaptability on individuals' response to real and sham acupuncture. Healthy volunteers (nine PA and 13 PNA) were randomly allocated to receive real and sham acupuncture on the left hand and forearm in two separate acupuncture sessions. Pressure pain thresholds (PPTs) were measured at bilateral forearms and right leg before, immediately after and 20 minutes after the end of acupuncture. Ratings to pinprick and suprathreshold PPT were also recorded. The two groups were comparable in their demographic and baseline data. Analgesia induced by real or sham acupuncture did not differ on any outcome measures. PA responded to acupuncture needling better than PNA, and to sham needling (20% increase in PPT) better than to real acupuncture (7.9%). Those differences were at 20 min after end of acupuncture in the areas distant to the needling sites. PNA reported little changes in PPT. Being adaptive to pain was associated with enhanced distant analgesia in response to sham acupuncture. Our finding might partly explain varied acupuncture analgesia in clinical practice and trials. PMID- 29275795 TI - Comparison of Acupuncture with Ibuprofen for Pain Management in Patients with Symptomatic Irreversible Pulpitis: A Randomized Double-Blind Clinical Trial. AB - Emergency pain management in symptomatic irreversible pulpitis commonly includes use of nonnarcotic analgesics. Acupuncture has been used in dentistry to alleviate pain after tooth extraction. The aim of this randomized, double-blind, placebo controlled clinical trial was to evaluate and compare the efficacy of acupuncture therapy and ibuprofen for pain management in such patients. A total of 157 patients participated in this study and were randomly assigned to three groups, Group I-classical acupuncture with placebo tablet, Group II-sham acupuncture with placebo tablet, and Group III-sham acupuncture with ibuprofen. Before commencement of the experiment, initial pain assessment was done using a HP-VAS scale. Treatment was done by first operator, while pain assessment was done by the second operator who was blinded to the procedure performed. Acupuncture needles were inserted for 15-20 minutes at acupoints for classical acupuncture and at nonacupoints for sham acupuncture. Posttreatment pain assessment was carried out at 15, 30, 45, and 60 minutes intervals. Follow-up analysis was recorded at 12, 24, and 48 hours using VAS verbal scale. The mean final HP VAS values for Group I showed statistically significant lower pain values when compared with groups II and III (p < 0.05), with no significant difference between groups II and III. Follow-up analysis showed Group I with higher percentage of no pain, which was statistically significant when compared with other two groups. It can be concluded that classical acupuncture is more effective in pain relief (faster and prolonged) than analgesics. PMID- 29275796 TI - Antidepressant Effects of Pharmacopuncture on Behavior and Brain-Derived Neurotrophic Factor (BDNF) Expression in Chronic Stress Model of Mice. AB - OBJECTIVES: The present study aimed to investigate the antidepressant effect of the traditional Korean medical pharmacopuncture, Liver Qi Depression (HJ11), in a mouse model of depression induced by exposure to chronic immobilization stress (CIS). METHODS: Mice were subjected to 2 hours of immobilization stress daily for 14 days. They were also injected with distilled water (DW) (CIS + DW) or HJ11 at the acupoints HT7, SP6, and GV20 (CIS + HJ11) an hour before stress. The positive control group (CIS + paroxetine) was intraperitoneally injected with paroxetine (10 mg/kg, 14 days). The tail suspension test and the forced swimming test were performed to assess depression-like behaviors. Western blotting was also conducted to seek the change in brain. RESULTS: CIS + DW mice showed significantly longer immobile times in the tail suspension test and forced swimming test than sham mice that did not go through daily restraint. Immobility of CIS + HJ11 and that of CIS + paroxetine mice was significantly decreased compared with immobility of CIS + DW mice. Immunoblotting showed that HJ11 increased the expression of brain-derived neurotrophic factor both in the hippocampus and the amygdala. CONCLUSION: HJ11 improves depressive-like behaviors in the stress-induced mouse model of depression, and the results indicate that the neuroprotective effect of HJ11, identified by brain-derived neurotrophic factor expression, may play a critical role in its antidepressant effect. PMID- 29275797 TI - Simulation in Cupping Training: An Innovation Method. PMID- 29275798 TI - A Curious Oversight in Acupuncture Research. AB - Common phenomena central to acupuncture have been overlooked by previous hypotheses on how acupuncture works, with the result that the hypotheses are unable to account for acupuncture's effects. This article describes the main features overlooked and suggests how these might be investigated in future acupuncture research. PMID- 29275799 TI - Our Diversity - Celebrating a Century of the AAOMS. PMID- 29275800 TI - Editor's Perspectives - December 2017. PMID- 29275801 TI - October 16: Ether Day, National Anaesthesia Day and World Anaesthesia Day. PMID- 29275802 TI - The Lauramann Howe Russell Papers: a Window into Critical Care Medicine during the American Civil War. AB - The Civil War influenced all aspects of American society and culture, including the field of medicine and critical care. Union physician Lauramann Howe Russell's letter to his daughter, Ellen Howe, written on October 19, 1862, illustrates the changes in hospital construction, gender roles in healthcare and medical treatments which revolutionized healthcare during the Civil War. This letter offers a glimpse of the medical care of wounded soldiers during the early years of the Civil War. In describing his conversion hospital, he reveals the precursor to the new hospital construction which would greatly influence hospital design for decades to come. His description of women volunteers hints at the evolving role and growing importance of women in healthcare. Finally, the advancements in surgical and medical practice which developed during the Civil War are embodied in Russell's descriptions of his patients. His letter freezes a moment in medical history, bridging the gap between archaic medical practice and modern critical care. PMID- 29275803 TI - Publication-Based Academic Interest in Drugs and Techniques for Treatment of Postoperative Pain, 1975-2015. AB - PURPOSE: The aim of this study was to determine how drugs and their administration techniques, introduced over the past 40 years and still popular now, influenced publication-based academic interest in the treatment of postoperative pain. METHODS: Specific scientometric indices-popularity index (PI), top journal selectivity index (TJSI), and index of change (IC)-were used. Of the 61 terms searched, only those that had a PI value >=1.0 during the 2011 2015 period were selected. They include eight drugs-bupivacaine, fentanyl, ropivacaine, acetaminophen, tramadol, remifentanil, and dexamethasone-and five techniques-patient-controlled analgesia, epidural opioids, ultrasound-guided nerve blocks, continuous nerve blocks, and transversus abdominis plane block (presented according to their decreasing PI value in each category). RESULTS: Four of these drugs or techniques with the highest PI in 2011-2015 also held top positions even 20 years earlier: in 1991-1995, the PI for bupivacaine was 9.1; fentanyl, 6.6; patient-controlled analgesia, 10.4; and epidural opioids, 6.8. Since that time, their PI values slowly decreased, for the first three items by approximately 50% and much more than that (85%) with epidural opioids. Nevertheless, to this day, they continue to hold the highest degree of publication-based academic interest. The TJSI can be regarded as an index of expectations at the time of articles publication. With bupivacaine, fentanyl, patient-controlled analgesia, and epidural opioids, the TJSI exceeded the specific high threshold of 10.0 for a very long time. The TJSIs of acetaminophen, ketamine, and dexamethasone were increased with the advent of new expectations regarding the treatment of postoperative pain using these old agents. CONCLUSIONS: Two important developments related to ultrasound-guided nerve block and continuous nerve block demonstrated only a moderate degree of academic interest. In conclusion, even today, the greatest publication-based academic interest related to postoperative pain is associated with drugs and techniques introduced 40-50 years ago. PMID- 29275804 TI - From "Circe's Root" to "Spongia Soporifera": The Role of the Mandrake as True Anesthetic of Ancient Times. AB - Several ancient authors cited mandrake as a powerful and well-known narcotic drug: from Homer to Dioscorides, from Plato to Aristotle, passing from Hippocrates, Demosthenes, Theophrastus, Celsus, and Apuleius. Their detailed studies included the concrete appearance of the plant, the related recipes including mandrake as essential ingredient, the right dosages, how to administer the obtained medication, and the possible collateral effects. Even in the Middle Ages, the success of this root continued: Isidore of Seville, Theodoric of Cervia, Gilbertus Anglicus, and William from Varignana extensively reported their researches on sponges soaked with mandrake juice, which were used before surgical interventions as soporific tools. This article represents a travelogue among ancient ages to discover the anesthetic properties of the mandrake. PMID- 29275805 TI - From Dental to Mental Institutions: Did Hypoxic Anesthetics by "Dental Associations" Add More Brain-Injured Patients to America's Insane Asylums? AB - Though most patients survived the hypoxic challenge, some patients likely suffered asphyxial brain damage from GQ Colton's nitrous-oxide techniques and were admitted to insane or lunatic asylums. PMID- 29275806 TI - John Collins Warren, Surgeon of Ether Day, Entered Sulphuric Ether into The Pharmacopoeia of the Massachusetts Medical Society in 1808. AB - John Collins Warren, the surgeon of Ether Day in 1846 at Massachusetts General Hospital, entered sulphuric ether into the nationally recognized Massachusetts pharmacopeia of 1808. PMID- 29275807 TI - Precarious Distraction and Carious Extraction: Nitrous Oxide during the "Second World Billiards Tournament". AB - During the 1879 Brunswick & Balke World Billiards Tournament, Manager FC Newhall had a tooth extracted under nitrous oxide administered by GQ Colton. The dental extraction occurred at the tournament site, New York City's Cooper Institute. PMID- 29275808 TI - From Dental to Mental Institutions: Asylum-Bound Dentist Zacheus Rogers Oxygenates Nitrous Oxide. AB - American dentist Zacheus Rogers taught surgeon Edmund Andrews-and indirectly anesthesia pioneers SJ Hayes and FW Hewitt-to oxygenate anesthetics. Ironically, Rogers may have himself suffered neurologic damage by failing to oxygenate the nitrous oxide that he is speculated to have abused personally. PMID- 29275809 TI - Preface: The NEC Society. PMID- 29275811 TI - Enhancing NICU parent engagement and empowerment. AB - Within the neonatal intensive care unit (NICU), parent engagement and empowerment are of critical importance, particularly when infants are at risk of developing severe complications, such as necrotizing enterocolitis (NEC). Stakeholders within the NICU, including the fragile patients, families, clinicians, staff, and administration, benefit when parents are a valued member of their baby's care team. The 2017 NEC Symposium explored the experiences of families whose infants were impacted by NEC, the barriers to effective partnership, and promising solutions. Parents want to participate in their baby's care, and crave honest, timely, comprehensive information regarding their baby's health and potential outcomes. Clinicians and staff should implement a specific set of Family-Centered Care policies and practices within the NICU to foster a culture of collaboration with parents of premature and fragile infants. PMID- 29275810 TI - Necrotizing enterocolitis: Pathophysiology from a historical context. AB - Necrotizing enterocolitis (NEC) continues to afflict approximately 7% of preterm infants born weighing less than 1500g, though recent investigations have provided novel insights into the pathogenesis of this complex disease. The disease has been a major cause of morbidity and mortality in neonatal intensive care units worldwide for many years, and our current understanding reflects exceptional observations made decades ago. In this review, we will describe NEC from a historical context and summarize seminal findings that underscore the importance of enteral feeding, the gut microbiota, and intestinal inflammation in this complex pathophysiology. PMID- 29275812 TI - Development of the necrotizing enterocolitis society registry and biorepository. AB - Necrotizing enterocolitis (NEC) is a devastating disease affecting premature infants. New advances in diagnostic and treatment options are desperately needed. Accordingly, the NEC Society initiated a research collaborative with a group of investigators dedicated to advancing the state of NEC-associated knowledge. Recent advances in high-content molecular interrogation and bio-computation (e.g., genomics, transcriptomics, proteomics, and metabolomics) can provide new insights from afflicted infants with NEC, however, individual centers do not have sufficient cases to conduct these studies independently. The development of a NEC Society Biorepository (NSB) has emerged to advance collaboration among institutions through the shared use of biologic samples in the dedicated pursuit of molecular indicators of disease and to gain greater pathophysiologic insights through research. The NSB will provide key infrastructure across several centers to harness the potential for new discoveries, while ensuring specimens are processed consistently, appropriate clinical data is collected, and privacy is maintained. The NSB will provide a comprehensive framework for sharing biological samples and clinical data through a robust and secure system that supports the investigation of research studies on NEC. PMID- 29275813 TI - The science and necessity of using animal models in the study of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) remains one of the highest causes of mortality and of acute and long-term morbidity in premature infants. Multiple factors are involved in the pathophysiology of NEC including the immaturity of the immune system and the complex changing composition of the intestinal microbiome. This is compounded by the fact that the premature infant should ideally still be a developing fetus and has an immature intestinal tract. Because these complexities are beyond the scope of studies in single-cell cultures, animal models are absolutely essential to understand the mechanisms involved in the pathophysiology of NEC and the effects of inflammation on the immature intestinal tract. To this end, investigators have utilized many different species (e.g., rats, mice, rabbits, quails, piglets, and non-human primates) and conditions to develop models of NEC. Each animal has distinct advantages and drawbacks related to its preterm viability, body size, genetic variability, and cost. The choice of animal model is strongly influenced by the scientific question being addressed. While no model perfectly mimics human NEC, each has greatly improved our understanding of disease. Examples of recent discoveries in NEC pathogenesis and prevention underscore the importance of continued animal research in NEC. PMID- 29275814 TI - Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell's stages and biomarkers for NEC. AB - Better means to diagnose and define necrotizing enterocolitis are needed to guide clinical practice and research. Adequacy of Bell's staging system for clinical practice and clarity of cases used in NEC clinical datasets has been a topic of controversy for some time. This article provides reasons why a better global definition for NEC is needed and offers a simple alternative bedside definition for preterm NEC called the "Two out of Three" rule. Some argue that biomarkers may fill knowledge gaps and provide greater precision in defining relevant features of a clinical disease like NEC. NEC biomarkers include markers of inflammation, intestinal dysfunction, hematologic changes, and clinical features. Development and reporting of NEC biomarkers should be guided by the FDA's BEST Consensus resource, "Biomarkers, EndpointS, & other Tools" and consistently report metrics so that studies can be compared and results pooled. Current practice in the NICU would be enhanced by clinical tools that effectively inform the clinical team that a baby is at increasing risk of NEC. Ideally, these tools will incorporate both clinical information about the baby as well as molecular signals that are indicative of NEC. While meaningful biomarkers for NEC and clinical tools exist, translation into practice is mediocre. PMID- 29275815 TI - Human milk and necrotizing enterocolitis. AB - NEC is a multifactorial disease that occurs when multiple risk factors and/or stressors overlap, leading to profound inflammation and intestinal injury. Human milk feedings, both from the infant's mother and donor human milk, have been associated with reductions in NEC in preterm infants. This article will review the protective factors in human milk, clinical studies of human milk and NEC, and practices to enhance human milk use in neonatal intensive care units. PMID- 29275816 TI - Probiotics and necrotizing enterocolitis. AB - In this review, we summarize existing knowledge regarding the effects of probiotics on necrotizing enterocolitis (NEC). We review the role of the microbiome in NEC and pre-clinical data on mechanisms of probiotic action. Next, we summarize existing randomized controlled trials and observational studies of probiotics to prevent NEC. We also summarize findings from several recent meta analyses and report a new cumulative meta-analysis of probiotic trials. Finally, we review data from cohorts routinely using commercially available probiotics. Our goal is to inform clinicians about the risks and benefits of probiotics, which may be helpful for those considering use in preterm infants to prevent NEC, death, or sepsis. PMID- 29275817 TI - Anemia, red blood cell transfusions, and necrotizing enterocolitis. AB - In the past 15 years, multiple clinical studies have identified a temporal association between red blood cell (RBC) transfusions and necrotizing enterocolitis (NEC). With some variability, most of these studies indicate that up to one-third of all cases of NEC involving very low-birth weight infants may occur within 24-48h after receiving a RBC transfusion. There is also evidence that the risk of such transfusion-associated NEC may be higher in infants transfused with the greatest severity of anemia. In this article, we summarize the clinical evidence pertaining to these issues; specifically, the contribution of RBC transfusions, and the contribution of severity of underlying anemia, to the pathogenesis of a type of NEC potentially termed, "transfusion/anemia associated NEC." PMID- 29275818 TI - Neurodevelopmental considerations in surgical necrotizing enterocolitis. AB - The majority of surviving infants with surgical necrotizing enterocolitis (NEC) will have some degree of neurodevelopmental impairment. The impact of specific medial and surgical treatments for infants with severe NEC remains largely unknown but is being actively investigated. It is incumbent upon all providers caring for these infants to continue to focus on long term neurodevelopmental outcomes and to develop more widespread methods of neurodevelopmental assessment. PMID- 29275820 TI - Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. AB - During viral entry, enveloped viruses require the fusion of their lipid envelope with host cell membranes. For coronaviruses, this critical step is governed by the virally-encoded spike (S) protein, a class I viral fusion protein that has several unique features. Coronavirus entry is unusual in that it is often biphasic in nature, and can occur at or near the cell surface or in late endosomes. Recent advances in structural, biochemical and molecular biology of the coronavirus S protein has shed light on the intricacies of coronavirus entry, in particular the molecular triggers of coronavirus S-mediated membrane fusion. Furthermore, characterization of the coronavirus fusion peptide (FP), the segment of the fusion protein that inserts to a target lipid bilayer during membrane fusion, has revealed its particular attributes which imparts some of the unusual properties of the S protein, such as Ca2+-dependency. These unusual characteristics can explain at least in part the biphasic nature of coronavirus entry. In this review, using severe acute respiratory syndrome coronavirus (SARS CoV) as model virus, we give an overview of advances in research on the coronavirus fusion peptide with an emphasis on its role and properties within the biological context of host cell entry. PMID- 29275819 TI - Stem cell therapy in necrotizing enterocolitis: Current state and future directions. AB - Stem cell therapy is a promising treatment modality for necrotizing enterocolitis. Among the many promising stem cells identified to date, it is likely that mesenchymal stem cells will be the most useful and practical cell based therapies for this condition. Using acellular components such as exosomes or other paracrine mediators are promising as well. Multiple mechanisms are likely at play in the positive effects provided by these cells, and further research is underway to further elucidate these effects. PMID- 29275821 TI - Fetal growth standards: the NICHD fetal growth study approach in context with INTERGROWTH-21st and the World Health Organization Multicentre Growth Reference Study. AB - Three recently completed longitudinal cohort studies have developed intrauterine fetal growth charts, one in the United States and two international. This expert review compares and contrasts the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies, INTERGROWTH-21st and World Health Organization Multicentre Growth Reference Study conclusions in light of differences in aims, sampling frames, and analytical approaches. An area of controversy is whether a single growth reference is representative of growth, regardless of ethnic or country origin. The INTERGROWTH and World Health Organization Fetal studies used a similar approach as the World Health Organization Multicentre Growth Reference Study for infants and children, the aim of which was to create a single international reference for the best physiological growth for children aged 0-5 years. INTERGROWTH made the same assumption (ie, that there would be no differences internationally among countries or racial/ethnic groups in fetal growth when conditions were optimal). INTERGROWTH found differences in crown-rump length and head circumference among countries but interpreted the differences as not meaningful and presented a pooled standard. The World Health Organization Multicentre Growth Reference Study was designed to create a pooled reference, although they evaluated for and presented country differences, along with discussion of the implications. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Study was designed to assess whether racial/ethnic-specific fetal growth standards were needed, in recognition of the fact that fetal size is commonly estimated from dimensions (head circumference, abdominal circumference, and femur length) in which there are known differences in children and adults of differing racial/ethnic groups. A pooled standard would be derived if no racial/ethnic differences were found. Highly statistically significant racial/ethnic differences in fetal growth were found resulting in the publication of racial/ethnic-specific derived standards. Despite all 3 studies including low risk status women, the percentiles for fetal dimensions and estimated fetal weight varied among the studies. Specifically, at 39 weeks, the 50th percentile for estimated fetal weight was 3502 g for whites, 3330 g for Hispanics, 3263 g for Asians, and 3256 for blacks in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Study, compared with 3186 g for INTERGROWTH and 3403 g for World Health Organization Multicentre Growth Reference Study. When applying these standards to a clinical population, it is important to be aware that different percentages of small- and large-for-gestational-age fetuses will be identified. Also, it may be necessary to use more restrictive cut points, such as the 2.5th or 97.5th, for small-for-gestational-age or large-for-gestational age fetuses, respectively. Ideally, a comparison of diagnostic accuracy, or misclassification rates, of small-for-gestational-age and large-for-gestational age fetuses in relation to morbidity and mortality using different criteria is necessary to make recommendations and remains an important data gap. Identification of the appropriate percentile cutoffs in relation to neonatal morbidity and mortality is needed in local populations, depending on which fetal growth chart is used. On a final point, assessment of fetal growth with a one time measurement remains standard clinical practice, despite recognition that a single measurement can indicate only size. Ultimately, it is knowledge about fetal growth in addition to other factors and clinical judgment that should trigger intervention. PMID- 29275822 TI - Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers. AB - Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening. PMID- 29275823 TI - Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? AB - The placenta ages as pregnancy advances, yet its continued function is required for a successful pregnancy outcome. Placental aging is a physiological phenomenon; however, there are some placentas that show signs of aging earlier than others. Premature placental senescence and aging are implicated in a number of adverse pregnancy outcomes, including fetal growth restriction, preeclampsia, spontaneous preterm birth, and intrauterine fetal death. Here we discuss cellular senescence, a state of terminal proliferation arrest, and how senescence is regulated. We also explore the role of physiological placental senescence and how aberrant placental senescence alters placental function, contributing to the pathophysiology of fetal growth restriction, preeclampsia, spontaneous preterm labor/birth, and unexplained fetal death. PMID- 29275824 TI - Predictors of Survival After Treatment of Oligometastases After Esophagectomy. AB - BACKGROUND: Recurrent esophageal carcinoma (EC) has a dismal prognosis. However, prior studies showed that selected patients with isolated recurrence may benefit from definitive therapy. The aim of this study was to identify the predictors of postrecurrence survival (PRS) in patients with isolated EC recurrence who were treated with curative intent. METHODS: A retrospective review of a prospective database (1988 to 2015) was performed to identify all recurrent EC patients after curative esophagectomy. Demographic and clinicopathologic data were reviewed. The probability of PRS was estimated with the Kaplan-Meier method. Predictors of PRS after definitive therapy for isolated EC recurrence were determined by the multivariable Cox proportional hazards model. RESULTS: Of the 640 curative esophagectomies, 241 patients (37.7%) experienced recurrences (median follow-up 50 months). Fifty-six patients (9%) received definitive treatment of isolated EC recurrence (31 were treated surgically with or without chemotherapy-radiotherapy [CTRT] and 25 received definitive CTRT alone). Median time to recurrence (TTR) was 19 months. The 1- and 3-year PRSs were 78% and 38% (median survival 26 months). On multivariable analysis; TTR was the only significant independent predictor for survival after recurrence (hazards ratio 0.98, 95% confidence interval: 0.96 to 0.99, p = 0.034). No pronounced difference was found in disease free survival or in PRS between recurrent patients treated with operation with or without CTRT and patients who received definitive CTRT. CONCLUSIONS: A select subgroup of patients with isolated EC recurrence can be treated with curative intent. TTR was the best predictor for PRS. PMID- 29275825 TI - Leadership Oversight for Patient Safety Programs: An Essential Element. AB - Leadership in the realm of quality oversight and endorsing a culture of safety is paramount. The stakeholders, ranging from the surgeons to the Chair of the Board have to be engaged and really understand the importance of leadership support. Clarity of leadership support, innovation in process improvement as well as performance management and accountability are the foundational components of a strong culture of safety. Alignment of all stakeholders and continuous improvement that is supported by leadership will ensure the best outcomes for surgical patients. PMID- 29275826 TI - Natural History of Moderate Coronary Artery Stenosis After Surgical Revascularization. AB - BACKGROUND: It remains controversial whether grafting moderately stenosed coronary arteries (MSCAs) influences native-vessel disease progression and whether grafting may protect against late myocardial ischemia. METHODS: From 1972 to 2011, 55,567 patients underwent primary isolated coronary artery bypass grafting (CABG); 1,902 had a single coronary artery with angiographically moderate (50% to 69%) stenosis and >=1 postoperative angiogram. Disease progression was studied in 489 nongrafted, 371 internal thoracic artery (ITA) grafted, and 957 saphenous vein (SV)-grafted MSCAs, as well as patency of 376 ITA and 1,016 SV grafts to these MSCAs. RESULTS: At 1, 5, 10, and 15 years, native vessel disease progressed from moderate to severe stenosis/occlusion in 32%, 52%, 66%, and 72% of nongrafted MSCAs; 55%, 73%, 84%, and 87% of ITA-grafted MSCAs; and 67%, 82%, 90%, and 92% of SV-grafted MSCAs. After adjusting for patient characteristics, MSCA disease progressed 3.6 times faster with ITA and 10 times faster with SV grafting compared with nongrafting. At these same time points, occlusion of ITA grafts to MSCAs was 8%, 9%, 11%, and 15% and for SV grafts, 13%, 32%, 46%, and 56%; protection from myocardial ischemia by ITA-grafted versus nongrafted MSCAs was 29%, 47%, 59%, and 61%. CONCLUSIONS: Most MSCAs progress to severe stenosis or occlusion in the long term. Progression is faster in grafted than nongrafted MSCAs, more so with SV than ITA grafts. However, ITA grafts to such arteries have excellent patency, providing long-term protection from myocardial ischemia. Therefore, ITA grafting of MSCAs should be considered. PMID- 29275827 TI - Simulation and Deliberate Practice in a Porcine Model for Congenital Heart Surgery Training. AB - BACKGROUND: Surgeons in training for congenital cardiac surgery face considerable challenges owing to procedure complexity, closely scrutinized outcomes, and a steep learning curve. Simulation methods have been initiated in other surgical specialties, but have yet to be established for congenital cardiac surgery trainees. The purpose of this study was to assess high-fidelity simulation as a method to train and improve skills of resident trainees learning critical components of index congenital cardiac surgical procedures. METHODS: Using 5 neonatal piglets over a period of 2.5 days, the following procedures were simulated: Norwood procedure, arterial switch operation, neonatal Ross procedure, tetralogy of Fallot repair, systemic to pulmonary artery shunt procedures, transmediastinal coarctation repair, atrial septal defect repair, ventricular septal defect repair, and right ventricular to pulmonary artery conduit. Anastomoses were tested with saline, all procedures were timed and video recorded, and resident trainee techniques and skills were critiqued by the instructor. RESULTS: All aspects of the procedures were simulated with minimal modifications. Anastomoses were tested, and the procedure successfully replicated without the pressures of operative time. Operative techniques involving suture placement in neonatal tissue, depth perception, and patch size estimation were corrected in real time, resulting in observed improvement of surgical skills. Video review allowed for further pedagogic value through examination and documentation of competency. CONCLUSIONS: This neonatal porcine simulation model allows surgical trainees in congenital heart surgery to make and correct mistakes in a safe and controlled learning environment without compromising patient safety, thereby fostering surgeon competence and confidence. PMID- 29275828 TI - Financial Impact of Acute Kidney Injury After Cardiac Operations in the United States. AB - BACKGROUND: Acute kidney injury (AKI) after major cardiac operations is a potentially avoidable complication associated with increased morbidity, death, and costly long-term treatment. The financial impact of AKI at the population level has not been well defined. We sought to determine the incremental index hospital cost associated with the development of AKI. METHODS: All patients undergoing coronary artery bypass grafting (CABG) or valve replacement operations, or both (clinical classification software codes 43 and 44), between 2008 and 2011 were identified from the Nationwide Inpatient Sample. AKI was identified using International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes (584.xx); patients with chronic renal failure were excluded. Mean total index hospitalization costs were compared between patients with and without AKI. RESULTS: At the population level, 1,078,036 individuals underwent major cardiac procedures from 2008 to 2011, with AKI developing in 105,648 (9.8%). Specifically, AKI developed in 8.0% of CABG, 11.4% of valve replacement, and 17.0% of CABG plus valve replacement patients (p < 0.001). Death was more common among patients with AKI vs those without (13.9% vs 1.3%, p < 0.001). Mean total index hospitalization cost was $77,178 for patients with AKI vs $38,820 for those without (p < 0.001). At the national level, the overall incremental annual index hospitalization cost associated with AKI was $1.01 billion. CONCLUSIONS: AKI developed in 1 in every 10 patients nationwide after a cardiac operation. Achieving a 10% reduction in AKI in this population would likely result in an annual savings of approximately $100,000,000 in index hospital costs alone. Support for research on mechanisms to detect impending damage and prevent AKI may lead to reduced patient morbidity and death and to substantial health care cost savings. PMID- 29275829 TI - Risk Modeling to Optimize Patient Selection for Management of the Descending Thoracic Aortic Aneurysm. AB - BACKGROUND: A single-institutional study comparing early and long-term outcomes of thoracic endovascular aortic repair (TEVAR) and open surgical repair (OSR) was performed to determine the appropriate treatment option for descending thoracic aortic aneurysm (DTAA). METHODS: Between 2005 and 2014, 438 DTAA patients were treated (TEVAR, 88; OSR, 350). Acute dissection and traumatic injury were excluded. Perioperative and follow-up data were reviewed. Stratified analyses were conducted to identify patients most likely to benefit from TEVAR. A propensity score for TEVAR was developed by logistic regression, and predictive logistic and Cox regression models for death were adjusted for propensity score. RESULTS: TEVAR patients were frequently older women with emergent status, chronic obstructive pulmonary disease, or coronary artery disease. TEVAR had similar immediate (0% vs 1%; p = 0.588) and delayed (5% vs 6%, p = 1.000) motor deficits and early mortality (6% vs 12%, p = 0.121) but lower dialysis (3% vs 18%, p < 0.001), respiratory failure (10% vs 34%, p < 0.001), and intensive care unit stay (2.0 vs 5.0 days, p < 0.001). Early mortality after TEVAR was lower in septuagenarians (3% vs 16%, p < 0.02), glomerular filtration rate of less than 60 mL/min (8% vs 32%, p < 0.049), chronic obstructive pulmonary disease (6% vs 21%, p < 0.02), defined as target population that had fourfold mortality reduction (p < 0.006) attributable to TEVAR. Propensity-adjusted predictors of early mortality predictors included OSR (odds ratio [OR], 4.3; p < 0.024), target population (OR, 7.7; p < 0.001), diabetes (OR, 3; p < 0.009), peripheral vascular disease (OR, 4.7; p < 0.001), and emergent status (OR, 4.6; p < 0.001). Propensity-adjusted determinants of survival were age, glomerular filtration rate of less than 60 mL/min, peripheral vascular disease, chronic obstructive pulmonary disease, and emergent status. CONCLUSIONS: In older patients with significant comorbidities, TEVAR demonstrated superior results compared with OSR and may be preferable in this target population. PMID- 29275830 TI - Chronic tophaceous gout as the first manifestation of gout in two cases and a review of the literature. AB - OBJECTIVES: Acute gout is a common arthritis that may eventually develop into chronic tophaceous gout (CTG). CTG usually is manifested by recurrent gout attacks. The diagnosis and treatment of CTG is challenging. Although the emergence of CTG without previous gout attacks is uncommon, it is important to recognize this unusual gout presentation. METHODS: Herein, we present two cases of CTG, occurring in elderly patients with chronic kidney disease (CKD) on diuretics, who presented without a prior history of acute gout attacks. We also searched PUBMED, Ovid MEDLINE, and Google scholar (1970-2017), for "tophi as the initial manifestation of gout" and "chronic gout without previous attacks", and extracted relevant data. RESULTS: The search disclosed one retrospective study and several case reports and case series describing 96 patients. Clinical and laboratory data was extracted from 34 patients. We found that a specific group of patients, e.g., elderly patients, most often female patients, suffering from CKD, and treated with diuretics, are specifically reported in the English medical literature to present with CTG as their first manifestation of gout. CONCLUSION: The two cases and our literature review try to emphasize the many faces of chronic gout, in particular, its presentation without previous gout attacks. PMID- 29275831 TI - [Advances in the management of cervical lymphadenopathies of unknown primary: advances in diagnostic imaging and surgical modalities and new international staging system]. AB - INTRODUCTION: Cervical lymphadenopathies of unknown primary represent 3 % of head and neck cancers. Their diagnostic work up has largely changed in recent years. This review provides an update on diagnostic developments and their potential therapeutic impact. MATERIALS AND METHODS: This is a systematic review of the literature. RESULTS: In recent years, changes in epidemiology-based prognostic factors such as human papilloma virus (HPV) cancers, advances in imaging and minimally invasive surgery have been integrated in the management of cervical lymphadenopathies of unknown primary. In particular, systematic use of PET scanner and increasing practice of robotic or laser surgery have contributed to increasing detection rate of primary cancers. These allow more adapted and personalized treatments. The impact of changes in the eighth TNM staging system is discussed. CONCLUSION: The management of cervical lymphadenopathies of unknown primary cancer has changed significantly in the last 10 years. On the other hand, practice changes will have to be assessed. PMID- 29275832 TI - Re: Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy. PMID- 29275833 TI - Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen specific, Transforming Growth Factor-beta Insensitive Genetically Targeted CD8+ T cells Derived from Patients with Metastatic Castrate-resistant Disease. AB - : Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8+ T-cells by the endowment of specificity to prostate specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-beta (TGF-beta) under the control of herpes simplex virus-1 thymidine kinase. CD8+ T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(zeta) gene (PZ1) and dominant negative TGF-beta type II receptor (TbetaRIIDN), that could induce CD8+ T-cells to be PSMA reactive and insensitive to TGF-beta. Cr51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-beta insensitive CD8+ T-cells was evaluated using an immunodeficient RAG-1-/- mouse model. We found PSMA-specific, TGF-beta insensitive CD8+ T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-beta. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-beta, insensitive CD8+ T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8+ T-cell infiltration were found only in the PC3 PSMA tumor. This study verified that PSMA-specific, TGF-beta insensitive CD8+ T cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. PATIENT SUMMARY: We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor beta insensitive CD8+ T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer. PMID- 29275834 TI - Re: Morbidity and Mortality of Locally Advanced Prostate Cancer: A Population Based Analysis Comparing Radical Prostatectomy Versus External Beam Radiation. PMID- 29275835 TI - A Partner in Crime: Tumor-associated Stroma and Metastatic Prostate Cancer. PMID- 29275836 TI - A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. AB - Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORgamma). Unlike the 'master regulators' T-bet and GATA3 that orchestrate Th1 and Th2 differentiation, respectively, RORgamma controls transcription at relatively few loci in Th17 cells. Moreover, its expression is not stabilized by positive feedback loops but rather influenced by environmental cues, allowing for substantial functional plasticity. Importantly, a subset of IL-17/IFNgamma double producing Th17 cells was identified in both human and mouse models. Evidence is accumulating that these IL-17/IFNgamma double-producing cells are pathogenic drivers in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, IL-17/IFNgamma double producing cells have been identified in disorders in which the role of autoimmunity remains unclear, such as sarcoidosis. The observed plasticity of Th17 cells towards the Th1 phenotype can be explained by extensive epigenetic priming of the IFNG locus in Th17 cells. In fact, Th17 cells display an IFNG chromatin landscape that is remarkably similar to that of Th1 cells. On the other hand, pathogenic capabilities of Th17 cells can be restrained by stimulating IL 10 production and transdifferentiation into IL-10 producing T regulatory type 1 (Tr1) cells. In this review, we discuss recent advances in our knowledge on the cellular and molecular mechanisms involved in Th17 differentiation, heterogeneity and plasticity. We focus on transcriptional regulation of the Th17 expression program, the epigenetic dynamics involved, and how genetic variants associated with autoimmunity may affect immune responses through distal gene regulatory elements. Finally, the implications of Th17 cell plasticity for the pathogenesis and treatment of human autoimmune diseases will be discussed. PMID- 29275837 TI - Plasticity and heterogeneity of Th17 in immune-mediated kidney diseases. AB - Anti-neutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis, anti glomerular basement membrane (GBM) glomerulonephritis and lupus nephritis are the most common causes of rapid progressive glomerulonephritis (RPGN) in the Western world. These aggressive forms of autoimmune kidney diseases significantly contribute to end-stage renal disease and are associated with high morbidity and mortality. Moreover, patients show significant heterogeneity with respect to clinical outcome and response to therapy. T cell infiltration is a morphological hallmark of RPGN and it is a critical driver of kidney injury. Different CD4+ T cell subsets that are endowed with distinct regulatory and effector functions are involved in this detrimental inflammatory process. In particular, the identification and functional characterization of IL-17-expressing CD4+ Th17 cells have substantially advanced our understanding of organ-specific autoimmunity. In experimental models of crescentic and proliferative GN, including ANCA-associated GN, anti-GBM-GN and lupus nephritis, the Th17/IL-17 axis significantly contributes to renal tissue damage. In patients with ANCA associated GN or lupus nephritis, IL-17 serum levels correlated with disease activity. Moreover, Th17 cells are present in the kidneys of these patients and represents a topic of intense ongoing clinical and basic research. Importantly, recent studies have challenged the view of CD4+ T cells subsets as terminally differentiated homogenous cells, showing that T cells, in particular Th17 cells, are much more flexible and heterogeneous than previously thought. However, analysis of Th17 cell fate in mouse models of autoimmune kidney disease revealed a high degree of stability within these cells, an observation that is in contrast to Th17 cells in other models of autoimmune diseases including experimental autoimmune encephalomyelitis. Interestingly, anti-CD3 treatment interferes with stable Th17 cells and induces a potential regulatory phenotype in Th17 cells, highlighting the therapeutic potential of targeting pathogenic Th17 cells in autoimmunity. In this review, we discuss the current knowledge of Th17 cell plasticity and heterogeneity in autoimmune kidney diseases with a special focus on the underlying mechanisms of this process and debate if Th17 cell plasticity is beneficial or harmful to renal inflammation. PMID- 29275838 TI - Free flap surgery in Europe: an interdisciplinary survey. AB - Free flap surgery is essential for the aesthetic and functional reconstruction of various parts of the body. The aim of this study was to compare current concepts of perioperative flap management between ENT, craniomaxillofacial, and plastic surgeons. A European survey was conducted among 570 surgical departments, covering all aspects of free flap surgery. Focus was placed on antibiotic and antithrombotic drug use, aspects of osseous reconstruction, and flap monitoring strategies. One hundred and seventy-two medical units participated. A broad spectrum of anticoagulant regimens and a trend towards prolonged antibiotic prophylaxis were found. Fixation with (CAD/CAM) reconstruction plates was more popular than monocortical locking with miniplates in the mandible. Visual assessment and Doppler systems were reported to be the most common monitoring modalities. The flap loss rate was stated to be higher after osseous reconstruction. Only a few differences in perioperative flap management were identified between the different surgical fields, and osseous reconstruction appears to be the most challenging. PMID- 29275840 TI - Brain Stimulation Over the Frontopolar Cortex Enhances Motivation to Exert Effort for Reward. AB - BACKGROUND: Loss of motivation is a characteristic feature of several psychiatric and neurological disorders. However, the neural mechanisms underlying human motivation are far from being understood. Here, we investigate the role that the frontopolar cortex (FPC) plays in motivating cognitive and physical effort exertion by computing subjective effort equivalents. METHODS: We manipulated neural processing with transcranial direct current stimulation targeting the FPC while 141 healthy participants decided whether or not to engage in cognitive or physical effort to obtain rewards. RESULTS: We found that brain stimulation targeting the FPC increased the amount of both types of effort participants were willing to exert for rewards. CONCLUSIONS: Our findings provide important insights into the neural mechanisms involved in motivating effortful behavior. Moreover, they suggest that considering the motivation-related activity of the FPC could facilitate the development of treatments for the loss of motivation commonly seen in psychiatric and other neurological disorders. PMID- 29275839 TI - The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition, and Psychopathology. AB - The ventromedial prefrontal cortex (vmPFC) has been implicated in a variety of social, cognitive, and affective functions that are commonly disrupted in mental illness. In this review, we summarize data from a diverse array of human and animal studies demonstrating that the vmPFC is a key node of cortical and subcortical networks that subserve at least three broad domains of psychological function linked to psychopathology. One track of research indicates that the vmPFC is critical for the representation of reward- and value-based decision making, through interactions with the ventral striatum and amygdala. A second track of research demonstrates that the vmPFC is critical for the generation and regulation of negative emotion, through its interactions with the amygdala, bed nucleus of the stria terminalis, periaqueductal gray, hippocampus, and dorsal anterior cingulate cortex. A third track of research shows the importance of the vmPFC in multiple aspects of social cognition, such as facial emotion recognition, theory-of-mind ability, and processing self-relevant information, through its interactions with the posterior cingulate cortex, precuneus, dorsomedial PFC, and amygdala. We then present meta-analytic data revealing distinct subregions within the vmPFC that correspond to each of these three functions, as well as the associations between these subregions and specific psychiatric disorders (depression, posttraumatic stress disorder, addiction, social anxiety disorder, bipolar disorder, schizophrenia, and attention deficit/hyperactivity disorder). We conclude by describing several translational possibilities for clinical studies of vmPFC-based circuits, including neuropsychological assessment of transdiagnostic functions, anatomical targets for intervention, predictors of treatment response, markers of treatment efficacy, and subtyping within disorders. PMID- 29275842 TI - Risk of hospitalization for psychiatric disorders among siblings and parents of probands with psychotic or affective disorders: A population-based study. AB - Relatives of people diagnosed with psychotic and affective disorders have a higher risk of developing psychiatric disorders compared to the general population. This study examined the risk of hospitalization for psychiatric disorders among siblings and parents of patients affected with major psychiatric disorders. In this large population-based case-control study, 17,895 siblings and parents of 7671 hospitalized subjects with a diagnosis of narrowly defined schizophrenia (SZ), broadly defined SZ, schizoaffective disorder (SAD), bipolar disorder (BD) or unipolar depression (UD) were identified from the Israeli Psychiatric Hospitalization Registry and compared to 71,580 age and gender matched controls from the Israeli Population Registry. Results indicated that siblings of people diagnosed with broadly defined SZ had a significantly higher risk of hospitalization for broadly (OR=11.06, 95% CI=7.93-15.41) and narrowly defined SZ (OR=10.59, 95% CI=6.8-16.33), SAD (OR=9.69, 95% CI=4.76-19.73), BD (OR=7.46, 95% CI=21.8-25.52), UD (OR=2.84, 95% CI=1.01-8.00), and other psychiatric disorders (OR=1.85, 95% CI=1.16-2.93), compared to controls. Siblings of patients with BD had a significantly higher risk of hospitalization for broadly defined SZ (OR=2.92, 95% CI=1.11-7.71) and for other psychiatric disorders (OR=6.67, 95% CI=2.17-20.50), compared to controls. Parents of probands with SZ were at significantly increased risk for all disorders examined, except for UD and other psychiatric disorders, which was not significant in parents of probands with BD. This large, population-based study provides evidence for common genetic risk across different psychiatric disorders. PMID- 29275843 TI - Transdiagnostic deviant facial recognition for implicit negative emotion in autism and schizophrenia. AB - Impaired facial affect recognition (FAR) is observed in schizophrenia and autism spectrum disorder (ASD) and has been linked to amygdala and fusiform gyrus dysfunction. ASD patient's impairments seem to be more pronounced during implicit rather than explicit FAR, whereas for schizophrenia data are inconsistent. However, there are no studies comparing both patient groups in an identical design. The aim of this three-group study was to identify (i) whether FAR alterations are equally present in both groups, (ii) whether they are present rather during implicit or explicit FAR, (iii) and whether they are conveyed by similar or disorder-specific neural mechanisms. Using fMRI, we investigated neural activation during explicit and implicit negative and neutral FAR in 33 young-adult individuals with ASD, 20 subjects with paranoid-schizophrenia and 25 IQ- and gender-matched controls individuals. Differences in activation patterns between each clinical group and controls, respectively were found exclusively for implicit FAR in amygdala and fusiform gyrus. In addition, the ASD group additionally showed reduced activations in medial prefrontal cortex (PFC), bilateral dorso-lateral PFC, ventro-lateral PFC, posterior-superior temporal sulcus and left temporo-parietal junction. Although subjects with ASD showed more widespread altered activation patterns, a direct comparison between both patient groups did not show disorder-specific deficits in neither patient group. In summary, our findings are consistent with a common neural deficit during implicit negative facial affect recognition in schizophrenia and autism spectrum disorders. PMID- 29275841 TI - The Mediodorsal Thalamus: An Essential Partner of the Prefrontal Cortex for Cognition. AB - Deficits in cognition are a core feature of many psychiatric conditions, including schizophrenia, where the severity of such deficits is a strong predictor of long-term outcome. Impairment in cognitive domains such as working memory and behavioral flexibility has typically been associated with prefrontal cortex (PFC) dysfunction. However, there is increasing evidence that the PFC cannot be dissociated from its main thalamic counterpart, the mediodorsal thalamus (MD). Since the causal relationships between MD-PFC abnormalities and cognitive impairment, as well as the neuronal mechanisms underlying them, are difficult to address in humans, animal models have been employed for mechanistic insight. In this review, we discuss anatomical, behavioral, and electrophysiological findings from animal studies that provide a new understanding on how MD-PFC circuits support higher-order cognitive function. We argue that the MD may be required for amplifying and sustaining cortical representations under different behavioral conditions. These findings advance a new framework for the broader involvement of distributed thalamo-frontal circuits in cognition and point to the MD as a potential therapeutic target for improving cognitive deficits in schizophrenia and other disorders. PMID- 29275844 TI - Left ventricular assist devices versus medical management in ambulatory heart failure patients: An analysis of INTERMACS Profiles 4 and 5 to 7 from the ROADMAP study. AB - BACKGROUND: The ROADMAP study showed survival with improved functional status was better with left ventricular assist device (LVAD) therapy compared with optimal medical management (OMM) in ambulatory, non-inotrope-dependent (INTERMACS [IM] Profile 4 to 7) patients. To study more balanced cohorts and better define which patients may benefit from implantation of an LVAD, we re-evaluated the patients enrolled in ROADMAP when stratified by INTERMACS profile (Profile 4 and Profiles 5 to 7). METHODS: The primary end-point (survival on original therapy with improvement in 6-minute walk distance >=75 meters at 1 year), actuarial survival, adverse events (AEs) and health-related quality of life (HRQoL) were evaluated. RESULTS: For INTERMACS Profile 4 (IM4), more LVAD patients met the primary end point compared with OMM patients (40% vs 15%; odds ratio = 3.9 [1.2 to 12.7], p = 0.024), but there was no statistically significant difference for INTERMACS Profiles IM 5 to 7 (IM5-7). Event-free survival on original therapy at 2 years was greater for LVAD than for OMM patients in both IM4 (67% vs 28%; p < 0.001) and IM5-7 (76% vs 49%; p = 0.025) profile groups. Composite end-points of survival on original therapy with improved HRQoL or depression were better with LVAD than OMM in IM4, but not IM5-7. AEs trended higher in LVAD compared with OMM patients in both profile groups. Rehospitalization rates for LVAD vs OMM were similar between treatment arms in IM4 (82% vs 86%; p = 0.780), but were higher for LVAD in IM5-7 (93% vs 71%; p = 0.016). CONCLUSIONS: LVAD patients in IM4, but not IM5-7, are more likely to meet the primary end-point and have improvements in HRQoL and depression compared with OMM, even with AEs generally being more frequent. LVAD therapy with current technology may be beneficial in select IM4 patients, but can be deferred for most IM5-7 patients, who should be followed closely due to the high frequency of treatment failures. PMID- 29275845 TI - The wandering self: Tracking distracting self-generated thought in a cognitively demanding context. AB - We investigated how self-referential processing (SRP) affected self-generated thought in a complex working memory task (CWM) to test the predictions of a computational cognitive model. This model described self-generated thought as resulting from competition between task- and distracting processes, and predicted that self-generated thought interferes with rehearsal, reducing memory performance. SRP was hypothesized to influence this goal competition process by encouraging distracting self-generated thinking. We used a spatial CWM task to examine if SRP instigated such thoughts, and employed eye-tracking to examine rehearsal interference in eye-movement and self-generated thinking in pupil size. The results showed that SRP was associated with lower performance and higher rates of self-generated thought. Self-generated thought was associated with less rehearsal and we observed a smaller pupil size for mind wandering. We conclude that SRP can instigate self-generated thought and that goal competition provides a likely explanation for how self-generated thoughts arises in a demanding task. PMID- 29275846 TI - Factors associated with poor active anterior elevation after reverse total shoulder arthroplasty. AB - BACKGROUND: Although reverse total shoulder arthroplasty (RTSA) has been shown to reduce pain and to improve function in most patients, some still suffer from functional limitations. This study aimed to investigate the incidence of poor motion recovery after RTSA and to identify factors that may cause poor outcomes. METHODS: Seventy-six patients who underwent primary RTSA with a reverse-type Aequalis prosthesis (Tornier, Montbonnot, France) were allocated to a satisfactory or unsatisfactory group on the basis of their postoperative active anterior elevation. The average age of the patients was 69 +/- 8 years (range, 42 82 years); average follow-up period was 34 +/- 12 months (range, 24-93 months). RESULTS: Fifty-eight patients had a satisfactory outcome (satisfactory group) and 18 had an unsatisfactory outcome (unsatisfactory group). Twenty-seven patients (46.6%) in the satisfactory group and 10 (55.6%) in the unsatisfactory group had preoperative pseudoparalysis (P = .504). Pre-existing medical comorbidities, such as thyroid disease, hypertension, diabetes, and smoking, showed no significant differences. Anterior deltoid muscle belly volume also did not significantly differ between the satisfactory and unsatisfactory groups. However, mean postoperative lateral humeral offset (LHO) was -2 +/- 6 mm in the satisfactory group and 3 +/- 5 mm in the unsatisfactory group (P = .001). CONCLUSION: Satisfactory improvement of active anterior elevation was achieved in three quarters of patients who underwent RTSA using a prosthesis designed to be medialized. Of the factors we investigated, only postoperative LHO was found to be a significant risk factor for poor postoperative active anterior elevation. Therefore, surgeons should attempt to avoid increasing postoperative LHO when performing RTSA using an implant designed to be medialized. PMID- 29275847 TI - Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses. AB - New vaccine platforms are needed to address the time gap between pathogen emergence and vaccine licensure. RNA-based vaccines are an attractive candidate for this role: they are safe, are produced cell free, and can be rapidly generated in response to pathogen emergence. Two RNA vaccine platforms are available: synthetic mRNA molecules encoding only the antigen of interest and self-amplifying RNA (sa-RNA). sa-RNA is virally derived and encodes both the antigen of interest and proteins enabling RNA vaccine replication. Both platforms have been shown to induce an immune response, but it is not clear which approach is optimal. In the current studies, we compared synthetic mRNA and sa-RNA expressing influenza virus hemagglutinin. Both platforms were protective, but equivalent levels of protection were achieved using 1.25 MUg sa-RNA compared to 80 MUg mRNA (64-fold less material). Having determined that sa-RNA was more effective than mRNA, we tested hemagglutinin from three strains of influenza H1N1, H3N2 (X31), and B (Massachusetts) as sa-RNA vaccines, and all protected against challenge infection. When sa-RNA was combined in a trivalent formulation, it protected against sequential H1N1 and H3N2 challenges. From this we conclude that sa-RNA is a promising platform for vaccines against viral diseases. PMID- 29275848 TI - miR-23b Suppresses Leukocyte Migration and Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting CCL7. AB - MicroRNAs (miRNAs) are small, non-coding RNAs involved in immune response regulation. Specific miRNAs have been linked to the development of various autoimmune diseases; however, their contribution to the modulation of CNS directed cellular infiltration remains unclear. In this study, we found that miR 23b, in addition to its reported functions in the suppression of IL-17-associated autoimmune inflammation, halted the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by directly inhibiting the migration of pathogenic leukocytes to the CNS. We demonstrated that miR-23b was specifically decreased during the acute phase of EAE and that overexpression of miR-23b resulted in a defect in leukocyte migration and strong resistance to EAE. Furthermore, we found that miR-23b suppressed leukocyte migration of EAE by targeting CCL7, a chemokine that attracts monocytes during inflammation and metastasis. Finally, in the adoptive transfer model, miR-23b reduced the severity of EAE by inhibiting the migration of pathogenic T cells to the CNS rather than diminishing the encephalitogenesis of T cells. Taken together, our results characterize a novel aspect of miR-23b function in leukocyte migration, and they identify miR-23b as a potential therapeutic target in the amelioration of MS and likely other autoimmune diseases. PMID- 29275849 TI - Management of Intruded Immature Maxillary Central Incisor with Pulp Necrosis and Severe External Resorption by Regenerative Approach. AB - INTRODUCTION: Intrusive luxation is one of the most severe traumatic injuries of permanent teeth that may adversely affect the pulp and the periodontium. Pulp necrosis and root resorption are the main pathologic entities associated with this injury. The present report describes the endodontic management of an intruded immature maxillary central incisor presented with pulp necrosis and severe inflammatory root resorption by using the regenerative approach. METHODS: A 7-year-old boy with dental trauma to the anterior maxillary region was referred for the management of a traumatized maxillary central incisor. Clinical examination revealed an uncomplicated crown fracture, whereas radiographic examination showed that the tooth was immature, confirming the intrusion that was calculated between 3 and 4 mm. The tooth was left to re-erupt, but after 2 months the boy presented with intraoral swelling. Radiographic examination showed initial signs of root resorption. The tooth was treated by using a regenerative endodontic approach. RESULTS: Clinical and radiographic examinations during the initial follow-up period showed resolution of the signs and symptoms as well as inhibition of the resorption process. At the follow-up examinations, the tooth remained free of signs and symptoms and completely functional. The radiographic recall examinations showed a gradual thickening of the root canal walls but incomplete apical closure. CONCLUSIONS: The present case shows that severely injured teeth with uncertain prognosis may have a considerable percentage of chance to remain functional and free of signs and symptoms by using a regenerative endodontic procedure, confirming the efficacy of this procedure as a viable treatment option. PMID- 29275850 TI - Outcomes of Direct Pulp Capping by Using Either ProRoot Mineral Trioxide Aggregate or Biodentine in Permanent Teeth with Carious Pulp Exposure in 6- to 18 Year-Old Patients: A Randomized Controlled Trial. AB - INTRODUCTION: This study aimed to compare the success rates of direct pulp capping (DPC) by using either ProRoot Mineral Trioxide Aggregate (MTA) or Biodentine in the cariously exposed permanent teeth of 6- to 18-year-old patients. Gray discoloration was also evaluated. METHODS: Fifty-nine cariously exposed permanent teeth, including teeth with diagnosis of normal pulp, reversible pulpitis, or irreversible pulpitis, early periapical involvement, and exposure size of up to 2.5 mm, were included. Each patient with only 1 cariously exposed tooth was randomly allocated to DPC with either ProRoot MTA (n = 30) or Biodentine (n = 29). Patients were recalled every 6 months. Clinical and radiographic examinations were used to determine success. RESULTS: Fifty-five patients (mean age, 10 +/- 2 years), 27 treated with ProRoot MTA and 28 with Biodentine, were included in the analysis. At mean follow-up of 18.9 +/- 12.9 months, the success rate was 92.6% with ProRoot MTA and 96.4% with Biodentine (P > .05; difference, 4%; 95% confidence interval [CI], -8% to 16%). Biodentine was non-inferior to ProRoot MTA. Failures were distributed equally in all categories of pulpal diagnosis and occurred in teeth with no periapical involvement and small exposures (0.5 mm). The survival probabilities of DPC with ProRoot MTA and Biodentine were 0.92 (95% CI, 0.73-0.98) and 0.96 (95% CI, 0.80-0.99). No significant difference was observed between them (P > .05). Gray discoloration was observed only with ProRoot MTA (55%). CONCLUSIONS: Biodentine was non inferior to ProRoot MTA when used as a DPC material for cariously exposed permanent teeth of 6- to 18-year-old patients. However, Biodentine did not cause any gray discoloration in this study. PMID- 29275851 TI - Biocompatibility and Osteogenic/Calcification Potential of Casein Phosphopeptide amorphous Calcium Phosphate Fluoride. AB - INTRODUCTION: Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and CPP ACP with fluoride (CPP-ACFP) have been shown to provide bioavailable ions to promote mineralization. Hence, the aim of this study was to evaluate the materials' biocompatibility and osteogenic/calcification potential for endodontic applications. METHODS: Human and mouse osteoblast-like and fibroblast-like cell lines were incubated with 0.05%-3.0% w/v CPP-ACP and CPP-ACFP, and toxicity, proliferation, alkaline phosphatase, interleukin (IL)-1alpha, and IL-6 production, collagen type I, osteocalcin, and osteopontin production, and mineralization/calcification were determined. RESULTS: CPP-ACP and CPP-ACFP were non-toxic and had no significant effect on proliferation or production of the inflammatory cytokine IL-1alpha. Alkaline phosphatase activity of the osteoblast like cells was significantly increased (P < .05) by CPP-ACP and CPP-ACFP, as was the production of the osteotropic cytokine IL-6, the formation of calcium mineral deposits, and the secretion of mineralization-related proteins (collagen type I and osteocalcin). CONCLUSIONS: CPP-ACP and CPP-ACFP are biocompatible and have the potential to induce osteoblastic differentiation and mineralization. Potential applications include apexification, perforation repair, vital pulp therapy, and regenerative endodontic procedures. PMID- 29275852 TI - Required Time for Migration of Bone Marrow-derived Cells to Dental Pulp after Bone Marrow Transplantation. AB - INTRODUCTION: This study aimed to evaluate the time required for bone marrow derived cells (BMDCs) from transgenic green fluorescent protein (GFP)+ donor mice (GFP+ mice) to migrate into the dental pulp of wild-type GFP- recipient mice (GFP mice) by using bone marrow transplantation (BMT) as an in vivo model for tracking BMDCs from GFP+ mice (GFP+ BMDCs). METHODS: GFP+ BMDCs were injected into irradiated GFP- mice. Maxillary arches, tibiae, and femora from GFP- mice were isolated and processed at 24 hours, 48 hours, 4, 7, and 14 days, and 7 weeks after BMT. Confocal laser microscopy analyses were performed to assess the presence of GFP+ BMDCs in the dental pulp, and flow cytometry of BM was performed to confirm the efficiency of engraftment of GFP+ BMDCs. RESULTS: Confocal laser microscopy analyses evidenced the presence of GFP+ BMDCs in the dental pulp of GFP- mice from 14 days to 7 weeks after BMT. There was no presence of GFP+ BMDCs at 24 hours, 48 hours, 4 days, and 7 days. Flow cytometry of the BM of GFP- mice demonstrated a constant increase in the presence of GFP+ BMDCs at 24 hours, 48 hours, and 4 days after BMT, which stabilized from 7 days to 7 weeks. CONCLUSIONS: The study demonstrated the presence of GFP+ BMDCs in the dental pulp from 14 days to 7 weeks after BMT and the feasibility of using GFP+ animals and BMT as an in vivo model for tracking GFP+ BMDCs. PMID- 29275853 TI - Fractographic Analysis of a Split Tooth Presenting Radiographically as a Horizontal Root Fracture in an Unrestored Mandibular Second Molar. AB - INTRODUCTION: Spontaneously catastrophic fracture of intact unrestored molar teeth is not common. Nevertheless, cracks do occur that progress apically, resulting in the complete splitting of the tooth and root. This report describes a catastrophic fracture that occurred in an unrestored mandibular second molar resulting in a previously unreported combination of a longitudinal and horizontal root fracture, appearing radiographically as a single horizontal root fracture. METHODS: Tooth fragments were examined clinically, stereoscopically, and by scanning electron microscopy. Fractographic analysis was used to investigate the dynamics involved in fracture initiation, structural resistances encountered during progression of the fracture, and reasons for direction changes culminating in the unusual radiographic appearance. RESULT: The uniqueness of this report is that it describes fractographic evidence of factors contributing to the initiation and progression of an in vivo crack. It shows fracture markings that are evidence of the energy dissipation mechanisms. The topographic location of these markings confirmed that cracks occur in vivo in stages with different rates of progression. CONCLUSION: This analysis helps to explain why split teeth are uncommon and highlights some of the multitude of factors that have to coincide for a tooth to catastrophically fracture. The report describes the mechanism of fracture and should stimulate clinicians and researchers to investigate cracking of teeth by undertaking fractographic analysis of extracted cracked teeth. PMID- 29275854 TI - EDTA Treatment for Sodium Hypochlorite-treated Dentin Recovers Disturbed Attachment and Induces Differentiation of Mouse Dental Papilla Cells. AB - INTRODUCTION: The disturbance of cellular attachment to dentin by sodium hypochlorite (NaOCl) may hamper pulp tissue regeneration. The aims of this study were to examine the recovering effect of EDTA on the attachment/differentiation of stemlike cells and to address the mechanisms of EDTA-induced recovery under the hypothesis that attachment to the exposed dentin matrix and the subsequent activation of integrin/phosphatidylinositol 3-kinase (PI3K) signaling play a crucial role. METHODS: Mouse dental papilla (MDP) cells were cultured on bovine dentin disks treated with NaOCl (0%, 1.5%, or 6%) followed by EDTA (0%, 3%, or 17%). Cell attachment was evaluated by cell density, viability, and scanning and transmission electron microscopy. Odonto-/osteoblastic gene expression in attached MDP cells was analyzed with or without a pan-PI3K inhibitor (LY294002) using real-time polymerase chain reaction. RESULTS: NaOCl treatment (1.5%, 10 minutes) significantly diminished attached MDP cells (P < .00001), but EDTA treatment (3% and 17%, >=10 minutes) of NaOCl-pretreated dentin induced a significant increase in attached cells (P < .05). Ultrastructurally, MDP cells on EDTA-treated dentin showed attachment to exposed collagen fibers. MDP cells cultured on EDTA-treated disks (with or without 1.5% NaOCl pretreatment) showed significant up-regulation of alkaline phosphatase, dentin matrix protein 1, and dentin sialophosphoprotein messenger RNAs (P < .05). Alkaline phosphatase expression was down-regulated by LY294002 (P < .05). CONCLUSIONS: Under the present experimental conditions, 10 minutes of EDTA treatment was sufficient to recover attachment/differentiation of MDP cells on 1.5% NaOCl-pretreated dentin. EDTA-induced exposure of collagen fibers and subsequent activation of integrin/PI3K signaling may contribute, at least partly, to the recovery. PMID- 29275855 TI - Premorbid IQ subgroups in first episode non affective psychosis patients: Long term sex differences in function and neurocognition. AB - BACKGROUND: Low IQ has been associated with schizophrenia, even to the point of being posited as a possible causal factor for psychosis. However, individuals with normal and high IQ also develop psychotic illnesses. The aim of this study was to characterize premorbid IQ subgroups at first episode of psychosis (FEP). METHODS: The study sample comes from a large epidemiological, 3-year longitudinal, intervention program on psychosis containing individuals living in a catchment area in Spain. Estimated premorbid IQ (epIQ) scores were used to build low (<90), normal (90-110) and high (>110) epIQ subgroups in samples of FEP patients (N=292) and healthy controls (N=199). The epIQ subgroups were compared in sociodemographic, neuropsychological, clinical and premorbid characteristics. Long-term functional and cognitive outcome, with a focus on sex differences, were also explored. RESULTS: Low-epIQ was more frequently found in FEP patients (28.8%) than in healthy controls (14.6%). Low-epIQ patients were more likely to have worse premorbid adjustment, belong to low socioeconomic status families, have less years of education, and to be single, unemployed, and younger. They presented more severe impairments in processing speed, executive and global cognitive function. Female patients with low-epIQ showed better baseline function and more stable outcome than males. CONCLUSIONS: Our results indicate that low premorbid IQ is a morbid manifestation, easily detected in a subgroup of FEP patients that predicts poorer outcome particularly in males. This perspective provides important information for the tailoring of subgroup-specific early intervention programs for psychosis. PMID- 29275856 TI - The brief negative symptom scale (BNSS): Sensitivity to treatment effects. AB - The Brief Negative Symptom Scale (BNSS) grew out of a recommendation by the NIMH sponsored Consensus Development Conference on Negative Symptoms that a scale based on contemporary concepts be developed. We assessed sensitivity to change of the BNSS in a trial of MIN-101, which showed efficacy for negative symptoms (PANSS pentagonal model) at daily doses of 32 and 64mg/day. Using mixed-effects model for repeated measures, we examined change in BNSS total score and in the BNSS factors of anhedonia/avolition/asociality (AAA), and expressivity (EXP). Compared to placebo, the 64mg group (N=83) showed a significant decrease in BNSS total score (effect size d [ES] 0.56, p<0.01) and both factor scores (AAA ES=0.48, EXP ES=0.46, p<0.02 for both). Patients in the trial had minimal depression and positive symptom scores; covarying for disorganization, positive symptoms, or anxiety/depression did not cause a meaningful change in the significance of the BNSS total or factor scores in this group. The 32mg group (N=78) did not differ significantly from placebo (N=83) on BNSS total score (ES=0.33, p<0.09), AAA (ES=0.25, p<0.20) or EXP (ES=0.30, p<0.12) scores. These results demonstrate the BNSS is sensitive to change. PMID- 29275857 TI - Is the prevalence of anti-N-methyl-d-aspartate receptor antibodies in schizophrenia overestimated? PMID- 29275858 TI - Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease. AB - Self-reactive IgGs contribute to the pathology of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Paradoxically, IgGs are used to treat inflammatory diseases in the form of high-dose intravenous immunoglobulin (IVIG). Distinct glycoforms on the IgG crystallizable fragment (Fc) dictate these divergent functions. IgG anti-inflammatory activity is attributed to sialylation of the Fc glycan. We therefore sought to convert endogenous IgG to anti-inflammatory mediators in vivo by engineering solubilized glycosyltransferases that attach galactose or sialic acid. When both enzymes were administered in a prophylactic or therapeutic fashion, autoimmune inflammation was markedly attenuated in vivo. The enzymes worked through a similar pathway to IVIG, requiring DC-SIGN, STAT6 signaling, and FcgammaRIIB. Importantly, sialylation was highly specific to pathogenic IgG at the site of inflammation, driven by local platelet release of nucleotide-sugar donors. These results underscore the therapeutic potential of glycoengineering in vivo. PMID- 29275859 TI - Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner. AB - Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease. PMID- 29275860 TI - Antigen Identification for Orphan T Cell Receptors Expressed on Tumor Infiltrating Lymphocytes. AB - The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of peptide-human leukocyte antigen (pHLA) to screen for antigens of "orphan" T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A*02:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable the reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens and enables the facile indentification of tumor antigens through unbiased screening. PMID- 29275861 TI - Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor. AB - Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRbeta signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-gamma and tumor necrosis factor alpha (TNF-alpha) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion. PMID- 29275863 TI - Sauna use plus heat acclimation accelerates heat adaptation in females. PMID- 29275862 TI - Racial/Ethnic Discrimination and Mental Health in Mexican-Origin Youths and Their Parents: Testing the "Linked Lives" Hypothesis. AB - PURPOSE: Using a life course perspective, the present study tested the concept of "linked lives" applied to the problem of not only how racial/ethnic discrimination may be associated with poor mental health for the target of discrimination but also how discrimination may exacerbate the discrimination distress link for others in the target's social network-in this case, the family. METHODS: The discrimination-distress link was investigated among 269 Mexican origin adolescents and their parents both cross-sectionally and longitudinally. It was hypothesized that parents' discrimination experiences would adversely affect their adolescent children's mental health via a moderating effect on the target adolescent discrimination-distress link. The converse was also hypothesized for the target parents. Multilevel moderation analyses were conducted to test the moderating effect of parents' discrimination experiences on the youth discrimination-distress link. We also tested the moderating effect of youths' discrimination experiences on the parent discrimination-distress link. RESULTS: Parents' discrimination experiences significantly moderated the longitudinal association between youths' discrimination stress appraisals and mental health, such that the father's discrimination experiences exacerbated the youth discrimination-depression link. Youths' discrimination stress appraisals were not a significant moderator of the cross-sectional parent discrimination mental health association. CONCLUSIONS: Implications of these findings are discussed from a linked lives perspective, highlighting how fathers' discrimination experiences can adversely affect youths who are coping with discrimination, in terms of their mental health. PMID- 29275864 TI - Association of Tobacco Use, Alcohol Consumption and HER2 Polymorphisms With Response to Trastuzumab in HER2-Positive Breast Cancer Patients. AB - PURPOSE: Although the administration of trastuzumab has improved the survival of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, resistance remains a major clinical obstacle. We retrospectively evaluated the association of HER2 polymorphisms, tobacco use and alcohol consumption with disease-free survival (DFS) in HER2-positive breast cancer patients. PATIENTS AND METHODS: Clinicopathologic and survival data (median follow-up, 7.4 years) were collected from medical records for 236 nonmetastatic trastuzumab-treated HER2 positive breast cancer patients. Tobacco and alcohol consumption were assessed using validated questionnaires, and HER2 polymorphisms (Ile655Val and Ala1170Pro) were determined by TaqMan assay. Multivariate Cox proportional hazard models were used to analyze DFS. RESULTS: Compared to nonsmokers, patients who smoked before breast cancer diagnosis showed a worse DFS (hazard ratio [HR], 2.63, P = .001), and this association was stronger among patients who smoked > 20 cigarettes per day or who spent more than 2 decades smoking before their diagnosis (HR, 3.65, P = .01, and HR, 3.19, P = .002, respectively). Smoking during trastuzumab treatment was associated with DFS, but only among patients with estrogen receptor negative tumors (HR, 4.49, P = .02). Compared to nondrinkers, patients who consumed alcohol before breast cancer diagnosis had a significantly better DFS (HR, 0.56, P = .03). No association was observed between alcohol consumption during trastuzumab treatment and DFS. Concerning HER2 polymorphisms, patients with Ile/Val or Val/Val genotype had a significantly worse DFS than those with the Ile/Ile genotype (HR, 4.96, P = .01). CONCLUSION: Tobacco and alcohol consumption as well as HER2 Ile655Val polymorphism could influence trastuzumab response. These results need to be confirmed in a larger cohort study. PMID- 29275865 TI - A European, Observational Study of Endocrine Therapy Administration in Patients With an Initial Diagnosis of Hormone Receptor-Positive Advanced Breast Cancer. AB - BACKGROUND: Despite guideline recommendations, reports suggest that a proportion of patients with hormone receptor (HR)-positive locally advanced or metastatic breast cancer (LA/MBC) might not receive endocrine therapy. The aims of this study were to estimate the proportion of postmenopausal patients with an initial (primary) diagnosis of HR-positive LA/MBC in Europe, and to assess the administration of endocrine treatment in these patients. MATERIALS AND METHODS: Fourteen national and regional cancer registries across Europe were invited to participate in this observational study. Six registries each provided anonymized clinical information on > 5000 postmenopausal women with breast cancer diagnosed between January 2000 and December 2014, including age at diagnosis, estrogen and/or progesterone receptor status, disease stage, and receipt of endocrine therapy. The proportion of patients with an initial diagnosis of HR-positive LA/MBC and, of these, the proportion who received endocrine therapy, was calculated. RESULTS: Registries from Belgium, England, Ireland, Norway, The Netherlands, and Munich, Germany provided data. In total, 316,680 postmenopausal women were diagnosed with breast cancer, including 244,268 with known HR status and disease stage. Of these patients, 19,002 (7.8%) had a primary diagnosis of HR positive LA/MBC. This proportion ranged from 5.4% (N = 4484) in England to 12.7% (N = 4085) in Germany. Most of these patients (n = 14,157; 74.5%) received endocrine treatment, ranging from 55.5% (n = 445) in Norway to 88.1% (n = 443) in Belgium. CONCLUSION: These results indicate that a sizeable proportion of postmenopausal patients in Europe received a primary diagnosis of HR-positive LA/MBC, and that almost three-quarters received subsequent endocrine therapy as per guideline recommendations. PMID- 29275867 TI - Authors' response. PMID- 29275866 TI - Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity. AB - Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions. PMID- 29275868 TI - Ruthenium brachytherapy for uveal melanomas: Factors affecting the development of radiation complications. AB - PURPOSE: To investigate how treatment complications are related to dosimetric parameters after ruthenium-106 brachytherapy for uveal melanoma, in a large, clinically homogeneous population. METHODS AND MATERIALS: A retrospective review was performed to evaluate patients affected by small and medium size uveal melanoma, treated with ruthenium-106 brachytherapy from December 2006 to December 2014. We excluded tumors with posterior margin within 1 mm from the edge of the optic disc and foveola. Main outcome measures were occurrence and time to radiation-related maculopathy, cataract, and optic neuropathy. Secondary end points included local recurrence and distant metastases. Kaplan-Meier analysis with log-rank test and univariate Cox proportional hazards model at 3 years were performed to identify the covariates affecting the outcome of radiation complications. RESULTS: Two hundred thirty-nine patients, with sufficient data to evaluate the end points, were enrolled. Three years after plaque treatment, radiation maculopathy was found in 61 (25.5%) patients, cataract developed in 10 patients (4.2%) receiving a dose of 27 Gy or higher to the lens, and optic neuropathy was observed in 13 patients (5.4%) with an optic nerve dose exceeding 50 Gy and tumor proximity to optic disc of less than 4 mm. Tumor recurrences and tumor-related metastasis were found respectively in 20 (8.36%) and 14 (5.85%) patients. CONCLUSIONS: Radiation maculopathy occurs within a median time of 31 months in 25% of cases after plaque treatment for uveal melanoma. The most significant risk factors are total dose and distance of tumor margin from the fovea. If the distance is greater than 11.22 mm, no signs of retinal damage are detected. PMID- 29275869 TI - Image-guided interstitial high-dose-rate brachytherapy for locally recurrent uterine cervical cancer: A single-institution study. AB - PURPOSE: The aim of this study was to investigate the efficacy and safety of image-guided high-dose-rate (HDR) interstitial brachytherapy (ISBT) for reirradiation of locally recurrent uterine cervical cancer. METHODS AND MATERIALS: Between 2008 and 2015, patients receiving reirradiation using HDR-ISBT for local gross recurrence of uterine cervical cancer after definitive or postoperative radiotherapy were analyzed retrospectively. The prescription doses per fraction ranged 2.5-6.0 Gy, whereas the cumulative equivalent doses in 2 Gy fractions ranged 48.6-82.5 Gy. The effects of prognostic factors on the local control (LC), progression-free survival, and overall survival were analyzed, and late toxicity data were evaluated. RESULTS: Eighteen patients were included in the analysis, with a median followup of 18.1 months. A tumor response was obtained in all patients, with radiological and pathological complete remission seen in 12 (66.7%) patients. The 2-year LC, progression-free survival, and overall survival rates for all patients were 51.3%, 20.0%, and 60.8%, respectively. The hemoglobin level and maximum tumor diameter were shown to be statistically significant prognostic factors for LC (p = 0.028 and 0.009, respectively). Late >= Grade 2 adverse events were observed in 5 patients (27.8%). CONCLUSIONS: Image-guided HDR-ISBT for the reirradiation of locally recurrent uterine cervical cancer may play an important role for local tumor control in a subgroup of patients. However, the treatment indication must be weighed against the risk of higher-grade late toxicity. PMID- 29275871 TI - Department of Error. PMID- 29275870 TI - Personalised medicine in the UK. PMID- 29275872 TI - The long-term outcome of tick-borne encephalitis in Central Europe. AB - BACKGROUND: Information on the long-term outcome of tick-borne encephalitis (TBE) is limited. OBJECTIVES: To assess the frequency and severity of post-encephalitic syndrome (PES) at different time points after TBE, and to determine the parameters associated with unfavourable outcome. METHODS: Adult patients diagnosed with TBE in Slovenia in the period 2007-2012 were followed-up for 12 months and also examined 2-7 years after TBE. Each patient was asked to refer a person of similar age without a history of TBE to serve as control. RESULTS: A total of 420 patients and 295 control persons participated in the study. The proportion of patients with PES (defined as the presence of >= 2 subjective symptoms that newly developed or worsened since the onset of TBE and which had no other known medical explanation, and/or >= 1 objective neurological sign) was higher (P < 0.001) at the follow-up visit 6 months after the acute illness (127/304, 42%, 95% CI: 36-47%) than at 12 months (68/207, 33%, 95% CI: 26-40%); the proportion at 12 months was the same as at 2-7 years after TBE (137/420, 33%, 95% CI: 28-37%). However, the proportion of severe PES at the last two time points differed (9.7% vs 4.3%, P = 0.008). Multivariate logistic regression showed that unfavourable outcome at 6 months was associated with CSF leukocyte count (OR = 1.003, 95% CI: 1.001-1.005%, P = 0.017), at 12 months with the disease outcome at 6 months (OR = 115.473, 95% CI: 26.009-512.667%, P < 0.001), and at the final visit with disease outcome at 6 months (OR = 3.808, 95% CI: 1.151-12.593%, P = 0.028) and 12 months (OR = 26.740, 95% CI: 8.648-82.680%, P < 0.001). Unspecific symptoms that occurred within the four weeks before the final examination were more frequent and more constant in patients than in the control group. CONCLUSIONS: The frequency of PES diminished over time and stabilized 12 months after the acute illness, whereas the severity of PES continued to decline. Unfavourable outcomes at 12 months and at the final visit were strongly associated with the presence of PES at previous time points. PMID- 29275873 TI - Current and potential future distribution of the American dog tick (Dermacentor variabilis, Say) in North America. AB - The American dog tick (Dermacentor variabilis) is medically and economically important in North America. This species is found across central and eastern North America from the Gulf Coast of Mexico through southern Canada. In parts of this region, D. variabilis is a vector for pathogens that cause diseases in humans and animals. Our aim was to determine whether climate change would affect the distribution of the climatically suitable area for D. variabilis in North America, to aid monitoring for potential future spread of tick-borne pathogens. We developed a species distribution model for D. variabilis to project where climate will likely be suitable for the tick in North America using a maximum entropy method, occurrence records from museum and laboratory archives, and 10 environmental variables relevant to climate requirements for the tick. We used four emissions scenarios from the Intergovernmental Panel on Climate Change's Fifth Assessment Report and 10 climate models from the Coupled Model Intercomparison Project (phase 5) to estimate potential future climate suitability and determine how the tick's distribution could change. Our consensus model projected that the area of suitable climate in North America could increase from present by approximately 50% by 2070. In areas beyond the current northern limit of D. variabilis, climate could become more suitable for the tick than at present, possibly resulting in a northward expansion in Canada, but the potential suitability of the southern range of D. variabilis could decrease, depending on the region and climate model. Due to the ability of D. variabilis to harbor and transmit pathogens, a change in the distribution of this species could also affect the risk of human and animal diseases throughout North America, particularly in the northern range of the tick. PMID- 29275874 TI - Australian penguin ticks screened for novel Borrelia species. AB - Lyme borreliosis (or Lyme Disease) is an emerging threat to human health in the Northern Hemisphere caused by tick-borne bacteria from the Borrelia burgdorferi sensu lato (Bbsl) complex. Seabirds are important reservoir hosts of some members of the Bbsl complex in the Northern Hemisphere, and some evidence suggests this may be true of penguins in the Southern Hemisphere. While the Bbsl complex has not been detected in Australia, a novel Borrelia species ('Candidatus Borrelia tachyglossi') was recently sequenced from native ticks (Ixodes holocyclus and Bothriocroton concolor) parasitising echidnas (Tachyglossus aculeatus), suggesting unidentified borreliae may be circulating amongst native wildlife and their ticks. In the present study, we investigated whether ticks parasitising little penguins (Eudyptula novaehollandiae) harbour native or introduced Borrelia bacteria. We chose this penguin species because it is heavily exploited by ticks during the breeding season, lives in close proximity to other potential reservoir hosts (including native wildlife and migratory seabirds), and is known to be infected with other tick-borne pathogens (Babesia). We screened over 230 penguin ticks (Ixodes spp.) from colonies in south-eastern Australia, and found no evidence of Borrelia DNA. The apparent absence or rarity of the bacterium in south-eastern Australia has important implications for identifying potential tick borne pathogens in an understudied region. PMID- 29275875 TI - Subclinical Hypothyroidism and Heart Failure: Chicken or Egg? PMID- 29275876 TI - Performance Volume Thresholds for Alcohol Septal Ablation in Treating Hypertrophic Cardiomyopathy: Guidelines, Competency Statements, and Now Data. PMID- 29275877 TI - Effect of Institutional Experience on Outcomes of Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. AB - BACKGROUND: The current American College of Cardiology Foundation/American Heart Association guidelines on hypertrophic cardiomyopathy state that institutional experience is a key determinant of successful outcomes and lower complication rates of alcohol septal ablation (ASA). The aim of this study was to evaluate the safety and efficacy of ASA according to institutional experience with the procedure. METHODS: We retrospectively evaluated 1310 patients with symptomatic obstructive hypertrophic cardiomyopathy who underwent ASA and were divided into 2 groups. The first-50 group consisted of the first consecutive 50 patients treated at each centre, and the over-50 group consisted of patients treated thereafter (patients 51 and above). RESULTS: In the 30-day follow-up, there was a significant difference in the occurrence of major cardiovascular adverse events (21% in the first-50 group vs 12% in the over-50 group; P < 0.01), which was driven by the occurrence of cardiovascular deaths (2.1% vs 0.4%; P = 0.01) and implanted pacemakers (15% vs 9%; P < 0.01). In the long-term follow-up (5.5 +/- 4.1 years), the first-50 group was associated with a significantly higher occurrence of major adverse events (P < 0.01) and higher cardiovascular mortality (P < 0.01). Also, patients in the first-50 group were more likely to self-report dyspnea of New York Heart Association class III/IV (16% vs 10%), to have a left ventricular outflow gradient > 30 mm Hg (16% vs 10%) at the last clinical check up (P < 0.01 for both), and a probability of repeated septal reduction therapy (P = 0.03). CONCLUSIONS: An institutional experience of > 50 ASA procedures was associated with a lower occurrence of ASA complications, better cardiovascular survival, better hemodynamic and clinical effect, and less need for repeated septal reduction therapy. PMID- 29275878 TI - Microcatheter-Facilitated Primary Angioplasty in ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Direct stenting is the best method for achieving reperfusion in primary percutaneous coronary intervention (PPCI). We hypothesized that the use of a microcatheter (MC) during PPCI when Thrombolysis in Myocardial Infarction (TIMI) flow <= 1 after wire crossing would allow visualization of the downstream artery with an optimal TIMI 3 flow at the end of the procedure. METHODS: In this pilot study, PPCI patients with TIMI flow <= 1 after wire crossing formed the MC group (n = 60); the MC was positioned in the distal part of the culprit artery and a small amount of contrast was injected through it to determine stent size and length to treat the culprit lesion. The MC group was compared with previous consecutive patients treated using standard PPCI (n = 94; similar characteristics except for the rate of previous percutaneous coronary intervention). RESULTS: In the MC group, downstream arteries were visualized in 98% of cases and direct stenting was achieved in 72% vs 31% (P < 0.0001). Final TIMI 3 flow was similar in both groups (97%). There was less manual thrombectomy (20% vs 63%; P < 0.001) and bailout glycoprotein IIb/IIIa inhibitor use (6.7% vs 29.8%; P < 0.002). The incidence of major adverse events (death, shock, severe arrhythmia) and left ventricular ejection fraction were similar. The peak cardiac enzymes level was significantly lower in the MC group. CONCLUSIONS: The MC strategy appears feasible and safe. It could allow exploring new strategies on the basis of more systematic direct stenting and prepared reperfusion by injecting drugs through the MC before reperfusion. PMID- 29275879 TI - Cost-Effectiveness of Different Durations of Dual-Antiplatelet Use After Percutaneous Coronary Intervention. AB - BACKGROUND: There is uncertainty regarding the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). Our goal was to evaluate the cost-effectiveness of different durations of DAPT. METHODS: We created a probabilistic patient-level Markov microsimulation model to assess the discounted lifetime costs and quality-adjusted life years (QALYs) of short duration (3-6 months: short-duration group) vs standard therapy (12 months: standard-duration group) vs prolonged therapy (30-36 months: long-duration group) in patients undergoing PCI. RESULTS: The majority of patients in the model underwent PCI for stable angina (47.1%) with second-generation drug-eluting stents (62%) and were receiving clopidogrel (83.6%). Short-duration DAPT was the most effective strategy (7.163 +/- 1.098 QALYs) compared with standard-duration DAPT (7.161 +/- 1.097 QALYs) and long-duration DAPT (7.156 +/- 1.097 QALYs). However, the magnitude of these differences was very small. Similarly, the average discounted lifetime cost was CAN$24,859 +/- $6533 for short duration, $25,045 +/- $6533 for standard duration, and $25,046 +/- $6548 for long duration. Thus, in the base-case analysis, short duration was dominant, being more effective and less expensive. However, there was a moderate degree of uncertainty, because short duration was the preferred option in only ~ 55% of simulations at a willingness to pay threshold of $50,000. CONCLUSIONS: Based on a stable angina cohort receiving clopidogrel with second-generation stents, a short duration of DAPT was marginally better. However, the differences are minimal, and decisions about duration of therapy should be driven by clinical data, patient risk of adverse events, including bleeding, and cardiovascular events. PMID- 29275880 TI - Long-term Effects of Statins, Blood Pressure-Lowering, and Both on Erectile Function in Persons at Intermediate Risk for Cardiovascular Disease: A Substudy of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) Randomized Controlled Trial. AB - BACKGROUND: It is unclear whether modifying cholesterol, blood pressure, or both affect erectile dysfunction. Also, there are concerns that erectile dysfunction is worsened by common medications used to treat these risk factors. In this study, we evaluated the effect of: (1) cholesterol-lowering with a statin; (2) pharmacologic blood pressure reduction; and (3) their combination, on erectile function. METHODS: A priori, this was a secondary analysis of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) randomized controlled trial. Men were 55 years of age or older with at least 1 cardiovascular risk factor. Erectile function was measured using the erectile function domain of the International Index of Erectile Function (IIEF-EF) score. Men with incomplete scores, or who did not engage in sexual activity, were excluded. Using a 2 * 2 factorial design, participants were randomized to rosuvastatin (10 mg/d) or placebo, and to candesartan with hydrochlorothiazide (HCTZ; 16 mg/12.5 mg/d; Cand+HCTZ) or placebo. Primary outcome was change in IIEF-EF from baseline to end of study follow-up. RESULTS: Two thousand one hundred fifty-three men were included; mean age was 61.5 years, and mean follow-up was 5.8 years. Mean IIEF-EF score at baseline was 23.0 (SD 5.6). Least square mean change in the IIEF-EF score did not differ with rosuvastatin compared with placebo (-1.4; standard error [SE], 0.3 vs -1.5; SE, 0.3; P = 0.74), Cand+HCTZ compared with placebo (-1.6; SE, 0.3 vs -1.3; SE, 0.3; P = 0.10), or combination therapy compared with double placebo (P = 0.35). CONCLUSIONS: Cholesterol-lowering using a statin, and blood pressure lowering using Cand+HCTZ, either alone or in combination, do not improve or adversely affect erectile function. PMID- 29275881 TI - Cardiovascular Risk Reduction and Male Sexual Health: No Free Ride. PMID- 29275882 TI - Dysfunctional Uterine Activity in Labour and Premature Adverse Cardiac Events: Population-Based Cohort Study. AB - BACKGROUND: There exist structural and physiological commonalities between myometrial and myocardial tissue, and each can become dysfunctional, such as in the presence of cardiometabolic factors. METHODS: This population-based cohort study was comprised of 1,608,720 women with >= 1 singleton hospital live birth at 24-41 weeks' gestation in Ontario, from 1992 to 2016. The main exposure was prolonged first stage of labour; secondary exposure was prolonged second stage of labour. The main outcome was a composite of heart failure, cardiomyopathy or dysrhythmia >= 1 day after the index delivery. Cox proportional hazard regression was used to generate a hazard ratio (HR), adjusted for maternal age, parity, obstructed labour or fetal malposition, preeclampsia, income quintile, rural residence, preterm birth, and infant birth weight-each at the time of delivery; time-varying drug/tobacco use, obesity, diabetes mellitus, chronic hypertension, kidney disease, dyslipidemia-each diagnosed before or at time of delivery; as well as newly diagnosed coronary artery disease or congenital heart disease arising >= 1 day after the index delivery. RESULTS: After a median follow-up of 10.5 and 14.0 years, respectively, there were 78 composite cardiac events (2.33 per 10,000 person-years) among women with prolonged first stage of labour vs 4114 events (2.30 per 10,000 person-years) among those without prolonged labour-a crude HR of 1.07 (95% confidence interval [CI], 0.86-1.34) and an adjusted HR of 1.09 (95% CI, 0.87-1.36). Women with prolonged second stage of labour had an adjusted HR of 0.86 (95% CI, 0.75-0.99) for the composite outcome. CONCLUSIONS: Women with prolonged labour do not appear to be at a higher short-term risk of cardiac outcomes. PMID- 29275883 TI - Health Care Use and Associated Time and Out of Pocket Expenditures for Patients With Cardiovascular Disease in a Publicly Funded Health Care System. AB - BACKGROUND: The objectives of this study were to describe (1) health care use and associated patient time and out of pocket (OOP) costs over 2 years after a cardiac diagnosis, (2) the sociodemographic and clinical drivers of these costs, and (3) patient costs related to cardiac rehabilitation (CR) participation. METHODS: Secondary analysis was conducted in an observational prospective CR program evaluation cohort in Ontario, which has a publicly funded health care system. A convenience sample of patients from 1 of 3 CR programs was approached at the first visit, and consenting participants completed a survey. Participants were e-mailed surveys again 6 months and 1 and 2 years later; these later surveys assessed their cardiac care and medications and the time and OOP costs associated with care visits. Patient time was valued based on average wages in Ontario. RESULTS: Of 411 consenting patients, 240 (58.3%) completed CR, and 192 (46.7%) were retained at 2 years. Patients most often visited a general practitioner and had electrocardiography and treatment for angina. The total cost to patients over 2 years was CAD$73.70 +/- $275.84 for time and $377.01 +/- $321.72 for OOP costs ($525.93 +/- $467.08 overall). With adjustment, there were significantly higher OOP costs for women (P < 0.001) and less educated (P < 0.001) patients. Participants spent considerable money that was relatively OOP on CR visits alone ($384.78 +/- $269.67), with time costs at $379.07 +/- $1035.49 ($939.43 +/- $1333.29 overall; 1.6% share of 1 year's income). CONCLUSIONS: In conclusion, time and OOP costs are modest for patients with cardiac conditions, except for CR. Alternative delivery models are needed, in particular for low-income patients. PMID- 29275884 TI - Big Data to Assess Potential Pregnancy-Related Cardiovascular Complications of Difficult Labour-Original Investigator-Driven Research Is Not Dead! PMID- 29275885 TI - Dynamic QT Interval Changes from Supine to Standing in Healthy Children. AB - BACKGROUND: QT-interval variations in response to exercise-induced increases in heart rate have been reported in children and adults in the diagnosis of long QT syndrome (LQTS). A quick standing challenge has been proposed as an alternative provocative test in adults, with no pediatric data yet available. METHODS: A standing test was performed in 100 healthy children (mean age, 9.7 +/- 3.1 years) after 10 minutes in a supine position with continuous electrocardiographic recording. QT intervals were measured at baseline, at maximal heart rate, at maximal QT, and at each minute of a 5-minute recovery while standing. Measurements were taken in leads II/V5 and were corrected for heart rate (QTc). RESULTS: On standing, the heart rate increased by 29 +/- 10 beats per minute (bpm). The QT interval was similar at baseline and on standing (394 +/- 34 ms vs 394 +/- 34 ms; P = 1.0). However, QTc increased from 426 +/- 21 to 509 +/- 41 ms (P < 0.001). The 95th percentile for QTc at baseline and maximal heart rate was 457 ms and 563 ms, respectively. At 1 minute of recovery, the QT interval was shorter (375 +/- 31 ms) compared with baseline (394 +/- 34 ms; P < 0.001) and standing (394 +/- 34 ms; P < 0.001). QTc reached baseline values after 1 minute of recovery and remained stable thereafter (423 +/- 23 ms at 1 minute; 426 +/- 22 ms at 5 minutes; P = 1.0). CONCLUSIONS: This first characterization of QTc changes on standing in children shows substantial alterations, which are greater than those seen in adults. Two-thirds of the children would have been misclassified as having LQTS by adult criteria, indicating the need to create child-specific standards. PMID- 29275886 TI - The Extent of Left Atrial Low-Voltage Areas Included in Pulmonary Vein Isolation Is Associated With Freedom from Recurrent Atrial Arrhythmia. AB - BACKGROUND: The extent of left atrial (LA) baseline low-voltage areas (LVA-B), which may be a surrogate for fibrosis, is associated with recurrent atrial fibrillation (AF) after ablation. This study aimed to assess the relationship between the extent of LVA-B isolated by ablation (LVA-I) and AF recurrence. METHODS: The study cohort included 159 consecutive patients with drug-refractory AF who underwent an initial AF ablation with LA voltage mapping during sinus rhythm. The extent of LVA-B was quantified while excluding the pulmonary veins, LA appendage, and mitral valve area. LVA-I was quantified as the percentage of LVA-B encircled by pulmonary vein isolation. Surveillance and symptom-prompted electrocardiograms, Holter monitors, and event monitors were used to document atrial arrhythmia recurrence for a median follow-up of 712 days (1.95 years). RESULTS: Of 159 patients, 72% were men and 27% had persistent AF. The mean number of sampled bipolar voltage points was 119 +/- 56. The mean LA surface area was 102.3 +/- 37.3 cm2, and the mean LVA-B was 1.9 +/- 3.8 cm2. The mean LVA-I was 51.05% +/- 36.8% of LVA-B. In the multivariable Cox proportional hazards model adjusted for LA volume, CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age [>= 75 years], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 years], Sex [Female] score), LVA-B, and AF type, LVA-I was inversely associated with recurrent atrial arrhythmia after the blanking period (hazard ratio, 0.42/percent LVA isolated; P = 0.037). CONCLUSIONS: The extent of LVA-I is independently associated with freedom from atrial arrhythmias after AF ablation, supporting ongoing efforts to target low LA voltage areas and other fibrosis indicators to improve ablation outcomes. PMID- 29275887 TI - Subclinical Hypothyroidism Is Associated With Adverse Prognosis in Heart Failure Patients. AB - BACKGROUND: It is widely recognized that overt hyper- as well as hypothyroidism are potential causes of heart failure (HF). Additionally it has been recently reported that subclinical hypothyroidism (sub-hypo) is associated with atherosclerosis, development of HF, and cardiovascular death. We aimed to clarify the effect of sub-hypo on prognosis of HF, and underlying hemodynamics and exercise capacity. METHODS: We measured the serum levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4) in 1100 consecutive HF patients. We divided these patients into 5 groups on the basis of plasma levels of TSH and FT4, and focused on euthyroidism (0.4 <= TSH <= 4 MUIU/mL and 0.7 <= FT4 <= 1.9 ng/dL; n = 911; 82.8%) and sub-hypo groups (TSH > 4 MUIU/mL and 0.7 <= FT4 <= 1.9 ng/dL; n = 132; 12.0%). We compared parameters of echocardiography, cardiopulmonary exercise testing, and cardiac catheterization, and followed up for cardiac event rate and all-cause mortality between the 2 groups. RESULTS: Although left ventricular ejection fraction did not differ between the 2 groups, the sub-hypo group had lower peak breath-by-breath oxygen consumption and higher mean pulmonary arterial pressure than the euthyroidism group (peak breath-by breath oxygen consumption, 14.0 vs 15.9 mL/min/kg; P = 0.012; mean pulmonary arterial pressure, 26.8 vs 23.5 mm Hg, P = 0.020). In Kaplan-Meier analysis (mean 1098 days), the cardiac event rate and all-cause mortality were significantly higher in the sub-hypo group than those in the euthyroidism group (log rank, P < 0.01, respectively). In Cox proportional hazard analysis, sub-hypo was a predictor of cardiac event rate and all-cause mortality in HF patients (P < 0.05, respectively). CONCLUSIONS: Sub-hypo might be associated with adverse prognosis, accompanied by impaired exercise capacity and higher pulmonary arterial pressure, in HF patients. PMID- 29275888 TI - Avoiding Clinical Errors With Bedside Echocardiography: A Randomized Clinical Study. AB - Clinicians have strong opinions about whether they should be provided the clinical history before or after bedside testing. We hypothesized that diagnostic accuracy is improved when a concordant clinical history is provided before a diagnostic test. To investigate whether the timing (before or after) and the consistency (concordant vs discordant) of the clinical history in the setting of focused bedside echocardiography affects clinician diagnostic accuracy and management decisions. Thirty-two cardiology residents were asked to perform a bedside echocardiogram on a Vimedix 3D mannequin. Half of the histories were provided before echocardiography and half after echocardiography. Half were consistent with the echocardiographic diagnosis (concordant), and half were suggestive of a plausible alternative diagnosis (discordant). Participants were asked for a diagnosis and management plan. The primary outcome was the diagnostic accuracy of the echocardiographic images. The secondary outcome was the management plan. Overall diagnostic accuracy was 63%. If the clinical history was provided before the bedside testing, it significantly improved diagnostic accuracy if it was concordant and it diminished accuracy if it was discordant (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.16-0.80; P = 0.001). Clinical history, whether concordant or discordant, had no significant impact if provided after the images were obtained. Appropriate management was chosen 77% of the time and was chosen less often with discordant compared with concordant histories (OR, 0.25; 95% CI, 0.11-0.57; P = 0.001). Our study suggests a significant downside to clinical information received before echocardiography when the information is discordant, raising the possibility that receiving clinical information after echocardiography may be superior for diagnostic accuracy. PMID- 29275889 TI - Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists. AB - The ever-increasing use of immune checkpoint inhibitors in cancer is leading to a high incidence of autoimmune side effects. This report discusses an autoimmune fulminant myocarditis in an elderly patient with metastatic pulmonary adenocarcinoma in whom the most advanced invasive heart failure therapies were used successfully. She was treated with nivolumab. This case illustrates a severe cardiovascular complication of immunotherapy and highlights to cardiologists the importance of aggressive treatments in patients with metastatic cancers whose prognosis has improved dramatically. PMID- 29275890 TI - A Cardiac Myxoma With Intense Metabolic Activity. PMID- 29275891 TI - Transradial-Guided Percutaneous Transaxillary Intra-aortic Balloon Pump Insertion. AB - Axillary access for an intra-aortic balloon pump allows patients with advanced heart failure (HF) to sit upright and ambulate while waiting for destination therapy or bridging to heart transplantation. We describe the combination of radial access for positioning a 4F pigtail catheter to allow axillary angiography and provide a target for a micropuncture needle entry point in a fully anticoagulated patient with advanced HF. PMID- 29275892 TI - The Ongoing Quest for Optimal Thrombus Prevention After ST-Elevation Myocardial Infarction in the Modern Era. PMID- 29275893 TI - LVT Prophylaxis After Anterior ST-Elevation Myocardial Infarction: A Response to Marquis-Gravel et al. PMID- 29275894 TI - Ambulatory surgery under local anesthesia for parathyroid adenoma: Feasibility and outcome. AB - : The aim of this study was to evaluate the results of ambulatory parathyroid resection performed under local anesthesia (LA). MATERIAL AND METHODS: Outpatients undergoing parathyroid adenoma resection by a focused approach under LA were included. Results were evaluated by intraoperative serum parathormone levels (ioPTH) and the balance of phosphate and calcium postoperatively, at 3 months, 1 year and at the point date. The quality of ambulatory care was evaluated by the number of cancelled interventions, the number of patients hospitalized after surgery or during the first postoperative month. The patient data manager of the institution carried out a medico-economic analysis. RESULTS: From 2005 to 2014, 129 patients met the inclusion criteria [women: 82% (sex ratio 1:5), median age: 72 years]. There was no morbidity for 98% of patients. Twelve patients had no statistically significant drop in ioPTH: two had persistent primary hyperparathyroidism (PHP). LA failed in four patients and PTH was late to normalize in six patients. Six patients had recurrent PHP (4.6%), of which two occurred four years after excision. Outpatient treatment was successful in 95%, without deprogramming or rehospitalization. The cost of the treatment under LA and on an outpatient basis was ? 2014.90 (vs. ? 2581.47 under general anesthesia and traditional hospitalization) CONCLUSION: Excision of single parathyroid adenomas can be performed under LA in an ambulatory setting without any major risk for the patient. The risk of recurrence after the focused approach requires regular laboratory monitoring for at least five years. PMID- 29275895 TI - Persistent physical activities in leisure time over decades improve late life CVD markers. PMID- 29275896 TI - Bayesian averaging over Decision Tree models for trauma severity scoring. AB - Health care practitioners analyse possible risks of misleading decisions and need to estimate and quantify uncertainty in predictions. We have examined the "gold" standard of screening a patient's conditions for predicting survival probability, based on logistic regression modelling, which is used in trauma care for clinical purposes and quality audit. This methodology is based on theoretical assumptions about data and uncertainties. Models induced within such an approach have exposed a number of problems, providing unexplained fluctuation of predicted survival and low accuracy of estimating uncertainty intervals within which predictions are made. Bayesian method, which in theory is capable of providing accurate predictions and uncertainty estimates, has been adopted in our study using Decision Tree models. Our approach has been tested on a large set of patients registered in the US National Trauma Data Bank and has outperformed the standard method in terms of prediction accuracy, thereby providing practitioners with accurate estimates of the predictive posterior densities of interest that are required for making risk-aware decisions. PMID- 29275897 TI - Selection of the Best of 2017 in Cardiac Imaging and Structural Interventionism. PMID- 29275898 TI - Selection of the Best of 2017 in Geriatric Assessment of Elderly Patients With Aortic Stenosis. PMID- 29275899 TI - Analysis of the treatment plan evaluation process in radiotherapy through eye tracking. AB - BACKGROUND AND PURPOSE: Treatment plan evaluation is a clinical decision-making problem that involves visual search and analysis in a contextually rich environment, including delineated structures and isodose lines superposed on CT data. It is a two-step process that includes visual analysis and clinical reasoning. In this work, we used eye tracking methods to gain more knowledge about the treatment plan evaluation process in radiation therapy. MATERIALS AND METHODS: Dose distributions on a single transverse slice of ten prostate cancer treatment plans were presented to eight decision makers. Their eye movements and fixations were recorded with an EyeLink1000 remote eye-tracker. Total evaluation time, dwell time, number and duration of fixations on pre-segmented areas of interest were measured. RESULTS: The main structures receiving more and longer fixations (PTV, rectum, bladder) correspond to the main trade-offs evaluated in a typical prostate plan. Radiation oncologists made more fixations on the main structures compared to the medical physicists. Radiation oncologists fixated longer on the rectum when visited for the first time, while medical physicists fixated longer on the bladder. CONCLUSION: Our results quantify differences in the visual evaluation patterns between radiation oncologists and medical physicists, which indicate differences in their decision making strategies. PMID- 29275900 TI - Longitudinal safety evaluation of connected vehicles' platooning on expressways. AB - Connected vehicles (CV) technology has recently drawn an increasing attention from governments, vehicle manufacturers, and researchers. One of the biggest issues facing CVs popularization associates it with the market penetration rate (MPR). The full market penetration of CVs might not be accomplished recently. Therefore, traffic flow will likely be composed of a mixture of conventional vehicles and CVs. In this context, the study of CV MPR is worthwhile in the CV transition period. The overarching goal of this study was to evaluate longitudinal safety of CV platoons by comparing the implementation of managed lane CV platoons and all lanes CV platoons (with same MPR) over non-CV scenario. This study applied the CV concept on a congested expressway (SR408) in Florida to improve traffic safety. The Intelligent Driver Model (IDM) along with the platooning concept were used to regulate the driving behavior of CV platoons with an assumption that the CVs would follow this behavior in real-world. A high-level control algorithm of CVs in a managed-lane was proposed in order to form platoons with three joining strategies: rear join, front join, and cut-in joint. Five surrogate safety measures, standard deviation of speed, time exposed time-to collision (TET), time integrated time-to-collision (TIT), time exposed rear-end crash risk index (TERCRI), and sideswipe crash risk (SSCR) were utilized as indicators for safety evaluation. The results showed that both CV approaches (i.e., managed-lane CV platoons, and all lanes CV platoons) significantly improved the longitudinal safety in the studied expressway compared to the non-CV scenario. In terms of surrogate safety measures, the managed-lane CV platoons significantly outperformed all lanes CV platoons with the same MPR. Different time-to-collision (TTC) thresholds were also tested and showed similar results on traffic safety. Results of this study provide useful insight for the management of CV MPR as managed-lane CV platoons. PMID- 29275901 TI - Complications of Semiconstrained Distal Radioulnar Joint Arthroplasty. AB - PURPOSE: The Aptis total distal radioulnar joint (DRUJ) prosthesis is a semiconstrained implant designed for treatment of DRUJ arthritis and instability. The purpose of this study was to analyze short-term complications of this device. METHODS: We performed a retrospective chart review of patients undergoing semiconstrained DRUJ arthroplasty from 2007 to 2015 at a single institution. Records were analyzed for complications and the need for subsequent surgical procedures. RESULTS: Two senior hand surgeons at one institution performed 52 semiconstrained DRUJ arthroplasties over 8 years. Nineteen complications necessitating operative management occurred in 15 patients (29%). A total of 26 procedures were undertaken to address these complications. Complications included 4 periprosthetic fractures, 3 infections, 2 instances of aseptic loosening, 2 implant component failures, 1 instance of screw loosening, 3 neuromas requiring neurectomy, 2 instances of finger stiffness necessitating extensor tenolysis, and 2 cases of heterotopic ossification at the DRUJ. Three of the 52 implants were revised (6%) and 2 were explanted (4%); 3 of these (6%) were caused by deep infection. CONCLUSIONS: There is limited literature on outcomes of the semiconstrained DRUJ prosthesis. Prior studies reported low complication rates, with 0% to 5% revisions. In the current clinical series, 29% of patients required further surgery for complications, the most common reasons for which were periprosthetic fracture and infection. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29275902 TI - Synaptic Tenacity or Lack Thereof: Spontaneous Remodeling of Synapses. AB - Synaptic plasticity - the directed modulation of synaptic connections by specific activity histories or physiological signals - is believed to be a major mechanism for the modification of neuronal network function. This belief, however, has a 'flip side': the supposition that synapses do not change spontaneously in manners unrelated to such signals. Contrary to this supposition, recent studies reveal that synapses do change spontaneously, and to a fairly large extent. Here we review experimental results on spontaneous synaptic remodeling, its relative contributions to total synaptic remodeling, its statistical characteristics, and its physiological importance. We also address challenges it poses and avenues it opens for future experimental and theoretical research. PMID- 29275903 TI - Baseline Mobility is Not Associated with Decline in Cognitive Function in Healthy Community-Dwelling Older Adults: Findings From The Irish Longitudinal Study on Ageing (TILDA). AB - OBJECTIVES: Few studies examine the relationship between Timed Up-and-Go (TUG), a commonly used clinical test, and cognitive decline. This study examines whether TUG, usual gait speed (UGS), and dual-task gait speed (DTGS) predict decline in global cognition, executive function, processing speed, memory, and attention with follow-up of up to 5.9 years. DESIGN: Longitudinal study. SETTING: The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort study. PARTICIPANTS: Community-dwelling adults aged >=65 years, with Mini-Mental State Examination (MMSE) score >=18 and no known history of memory impairment, dementia, Alzheimer's disease or Parkinson's disease were included (N = 2,250). MEASUREMENTS: Participants completed mobility tasks during the baseline health assessment and cognitive tasks during interviews conducted at 2 year intervals (waves 1, 2, and 3) and health assessments (waves 1 and 3). Linear and Poisson mixed effects regression models were used to examine longitudinal associations between mobility and each cognitive test, adjusting for sociodemographics and physical and mental health. RESULTS: There was little evidence of an association between TUG, UGS, or DTGS with decline in cognitive function after adjusting for confounders. CONCLUSIONS: These mobility tasks are not sensitive predictors of cognitive decline in this high-functioning, community-dwelling sample; nonetheless, limited decline in cognitive function was observed during follow-up. Further work with longer follow-up and/or analysis of more specific and comprehensive measures associated with gait is required. PMID- 29275904 TI - The Achilles Tendon in Healthy Subjects: An Anthropometric and Ultrasound Mapping Study. AB - Ultrasonography is an inexpensive, fast, and reliable imaging technique widely used to assess the Achilles tendon. Although significant data exists regarding pathologic tendon changes, ultrasound data from healthy individuals are more limited. We aimed to better characterize ultrasound Achilles tendon measurements in healthy individuals and identify important correlating factors. The information collected included patient demographics, body habitus, activity level, foot dominance, and resting ankle angle. Ultrasound analysis was performed bilaterally on the Achilles tendons of 50 subjects using a high-frequency transducer to measure tendon width, thickness, cross-sectional area, and length. Males had a significantly larger mean tendon length, width, thickness, and cross sectional area. No statistically significant difference was found in any tendon dimension between the white and black participants. Similarly, no difference was found in any tendon parameter when comparing right versus left leg dominance. Healthy subjects had a mean ankle resting angle of 45.1 degrees +/- 24 degrees with no statistically significant difference between right and left ankles. Considering all individuals, each tendon parameter (tendon length, width, thickness, and cross-sectional area) correlated positively with subject height, weight, tibia length, and foot size. Only the Achilles cross-sectional area correlated significantly with the activity level. The resting angle of the ankle correlated positively with both tendon length and thickness. In conclusion, we found significant variations in Achilles tendon anatomy in the healthy adult population. We have thoroughly characterized significant correlations between healthy tendon dimensions and various body habitus, activity levels, and ankle parameters. Greater knowledge of the normal Achilles tendon anatomy and characterization of its variations in the healthy population will potentially allow for better pathologic diagnosis and surgical repair. PMID- 29275905 TI - Pathogen-specific responses in the bovine udder. Models and immunoprophylactic concepts. AB - Bovine mastitis is a disease of major economic effects on the dairy industry worldwide. Experimental in vivo infection models have been widely proven as an effective tool for the investigation of pathogen-specific host immune responses. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) are two common mastitis pathogens with an opposite clinical outcome of the disease. E. coli and S. aureus have proven to be valid surrogates to model clinical and subclinical mastitis respectively. Contemporary transcriptome profiling studies demonstrated that the transcriptomic response in the teat reflects the course of pathogen specific mastitis, being ultimately determined by the immune response of the mammary epithelial cells. After an experimental in vivo challenge, E. coli induces a vigorous early transcriptional response in udder tissue being quantitatively and - notably - qualitatively distinct from the much weaker response against an S. aureus infection. E. coli mastitis models proved that the local response in the infected udder quarters is accompanied by a response in non infected neighbouring udder quarters modulating systemically their immune responsiveness. Immunomodulation of the udder was investigated in animal models. Pathophysiological consequences were studied after intramammary administration of cytokines, chemokines, growth factors, steroidal anti-inflammatory drugs, or priming of tissue resident cells with pathogen-derived molecules. The latter approaches resulted only in a temporal protection of the udder, reducing transiently the risk of infection but sustained lowering of the severity of an eventually occurring mastitis. They offer an alternative to vaccination trials, which over decades also did not yield protection against new infections. PMID- 29275906 TI - Optimizing performance through stress training - An educational strategy for surgical residents. AB - BACKGROUND: Stress management programs improve efficacy in aviation, military, and professional sports; however, similar educational strategies have not been adopted in surgical training. We have evaluated the effectiveness of a stress management program for surgical residents. METHODS: From 2011 to 2016, 137 surgical residents participated in a prospective, blinded study. The intervention group (n = 65) underwent training in self-awareness, focus, relaxation, positive self-talk, visualization, and team building. All participants subsequently completed a high-stress trauma simulation, requiring diagnosis and management of a life-threatening problem. Study endpoints included measures of procedural efficiency, and physiologic and subjective measurements of anxiety. RESULTS: Residents with stress training came to an accurate diagnosis 21% faster than controls (mean diagnosis time: 2.2 vs. 2.8 min; p = 0.04), and performed with greater technical accuracy (mean OSAT scores: 9.4 vs. 8.9; p = 0.03). Both cohorts exhibited similar physiologic and subjective anxiety metrics after simulation. CONCLUSIONS: Stress management education may enhance technical performance in surgical trainees during simulation. This underscores the need for early, comprehensive stress training in surgical residency. PMID- 29275907 TI - A multimodal approach improves American Board of Surgery In-Training Examination scores. AB - BACKGROUND: There are several factors that influence ABSITE scores, but the optimal approach for remediation of poor scores is unclear. METHODS: A structured academic curriculum and focused remediation program (FRP) were implemented to improve academic performances. Within a 15-year period, ABSITE and American Board of Surgery qualifying exam (ABS QE) results were compared before and after the establishment of the program using a paired T-test. Subgroup analysis was performed for residents who completed the FRP. RESULTS: After establishing the FRP, the mean scores increased from 49.3% to 60% (p = 0.001). The proportion of first-time pass rates for the ABS QE increased from 89.5% to 100% (p = 0.18). With the subgroup analysis of FRP residents, the average improvement on the next ABSITE exam score was 51 percentile points (p = 0.003), raw score increased by 80 (p = 0.01) and percent correct increased by 7 percentage points (p = 0.006). CONCLUSIONS: A structured academic curriculum and FRP improves ABSITE scores. Additional strategies utilizing the self-regulated learning method can further assist trainees who remain struggling learners. Further study is required to determine direct correlation to the ABS QE. PMID- 29275908 TI - Centralisation for resection of the pancreatic head: A comparison of operative factors and early outcomes during the evolving unit and tertiary unit phases at a UK institution. AB - AIMS: To assess impact of centralisation on patients undergoing pancreatic head resections at a tertiary hepatobiliary (HPB) centre in the UK. METHODS: Data were analysed from a prospectively maintained database from 1998 to 2014 on all patients undergoing pancreatic head resections. Two specific time periods were defined; these were the evolving unit phase (EU) from 1998 to 2009 and finally the established tertiary unit phase (TU) from 2010 to 2014. Peri-operative factors and post-operative outcomes were analysed. RESULTS: 395 resections were undertaken during the study period. Following establishment of our tertiary HPB unit, the volume of resections undertaken increased greater than three-fold with an associated increase in case-complexity (p = 0.004). Operating time was found to increase in the TU phase compared with EU phase (p=>0.0005) whilst there was no significant difference in the rate of peri-operative transfusion, or in post operative morbidity rates. There was a significant reduction in the post operative length of stay in the TU phase (p = 0.003) with a significantly higher proportion of patients being discharged within 9 days of their procedure (p=<0.0005). There was also a significant reduction in 30-day post-operative mortality in the TU phase (0.5%) compared with the EU phase (3%) (p = 0.029). CONCLUSIONS: Data from our series of 395 cases suggests that centralisation of pancreatic cancer services to a tertiary centre does result in improved patient outcomes. The benefits of a multi-disciplinary and specialist HPB service results in a high volume, high quality unit with improved patient outcomes. PMID- 29275909 TI - Effect of a hospital-associated urinary tract infection reduction policy on general surgery patients. AB - BACKGROUND: Hospital-associated UTI rates in surgery patients have not improved despite recommendations for reducing indwelling catheter days. METHODS: We performed a retrospective review of institutional NSQIP general surgery patient data, 2006-2015. During this time, a UTI-reduction policy was implemented. Demographics, HA-UTI incidence, CA-UTI incidence, indwelling catheter days, straight catheterization rates, and mortality were examined. RESULTS: Females had significantly higher risk of HA-UTI. There was no significant change in HA-UTI (X12 = 0.02, p = .878) or indwelling catheter days (5.18 +/- 1.12 days v 3.73 +/- 0.39 days, p = .23). Straight catheterizations among those with HA-UTI increased (0.04 +/- 0.04 v 0.32 +/- 0.12, p = .029). There was no change in CA-UTI (1.38 v 1.11 CAUTI/1000 patient hospital-days P = .555) or in initial indwelling catheter days of patients with CA-UTI (7.2 SD 8.89 v 47.0 SD 7.04 days P = .961) after policy implementation. CONCLUSIONS: The reduction policy increased the number of straight catheterizations for patients developing HA-UTI, but did not reduce the number of initial indwelling catheter days, HA-UTI rates, or CA-UTI rates. PMID- 29275910 TI - Reply to: Subcutaneous implant breast reconstruction: The importance of objectively assessing the outcomes. PMID- 29275911 TI - Flap reconstruction does not increase complication rates following surgical resection of extremity soft tissue sarcoma. AB - BACKGROUND: Flap reconstruction plays an essential role in the surgical management of extremity soft tissue sarcoma (ESTS) for many patients. But flaps increase the duration and complexity of the surgery and their contribution to overall morbidity is unclear. This study directly compares the complication rates in patients with ESTS undergoing either flap reconstruction or primary wound closure and explores contributing factors. METHODS: Eight hundred and ninety seven patients who underwent ESTS resection followed by primary closure (631) or flap reconstruction (266) were included in this study. Data on patient, tumour and treatment variables and post-operative medical and surgical complications were collected. Univariate and multivariate regression analyses were performed to identify independent predictors of complications. RESULTS: Post-operative complications occurred in 33% of patients. Flap patients were significantly older, had more advanced disease and were more likely to require neoadjuvant chemo- and radiotherapy. There was no significant difference in complication rates following flap reconstruction compared to primary closure on multivariate analysis (38 vs 30.9% OR 1.12, CI 0.77-1.64, p = 0.53). Pre-operative radiation and distal lower extremity tumour location were significant risk factors in patients who underwent primary wound closure but not in those who had flap reconstruction. Patients with comorbidities, increased BMI and systemic disease were at increased risk of complications following flap reconstruction. CONCLUSIONS: Flap reconstruction is not associated with increased post-operative complications following ESTS resection. Flaps may mitigate the effects of some risk factors in selected patients. PMID- 29275912 TI - Advances in organ preserving strategies in rectal cancer patients. AB - Treatment of rectal cancer patients has been subjected to change over the past thirty years. Total mesorectal excision is considered the cornerstone of rectal cancer treatment, but is also associated with significant morbidity resulting in an impaired quality of life. The addition of neoadjuvant chemoradiotherapy to surgery has shown to improve survival and local control and may lead to a partial or even complete response (CR). This raises questions regarding the necessity for subsequent radical surgery. After careful patient selection local excision and wait-and-see approaches are explored, aiming to improve quality of life without compromising oncological outcome. A multimodality diagnostic approach for optimal staging is crucial in determining the appropriate neoadjuvant treatment regimen. Adequate endoscopic restaging of rectal tumours after multimodality treatment will aid in selecting patients who are eligible for an organ preserving approach. The role and accuracy of imaging in the detection of the primary tumour, residual rectal cancer or local recurrence seems vital. Alternative neoadjuvant regimens are currently explored to increase the rate of clinical CRs, which may support organ preserving approaches. This review aims to generate insight into the advances in diagnostics and treatment modalities in all stages of rectal cancer and will highlight future studies that may support further implementation of organ preservation treatment in rectal cancer. PMID- 29275913 TI - Re: Re: Downstream Imaging Utilization After Emergency Department Ultrasound Interpreted by Radiologists Versus Nonradiologists: A Medicare Claims-Based Study. PMID- 29275914 TI - Re: Downstream Imaging Utilization After Emergency Department Ultrasound Interpreted by Radiologists Versus Nonradiologists: A Medicare Claims-Based Study. PMID- 29275915 TI - Legislative, Payment Policy Milestones of Racial Inequality in Health Care: Medicare and Medicaid as the Final Catalyst. PMID- 29275916 TI - Trust But Verify: Online Management Tool Improves Compliance and Documentation of CT Quality Control Activities. PMID- 29275917 TI - Machine Learning and Artificial Intelligence in Radiology. PMID- 29275918 TI - Double Scan CT Rates: An Opportunity for Facility-Based Radiologist Measures in the Quality Payment Program. AB - PURPOSE: The Medicare Access and CHIP Reauthorization Act (MACRA) provides CMS flexibility to evaluate radiologists using hospital outpatient quality measures in place of conventional physician measures. We explore radiologist characteristics associated with variation in performance in two such measures: abdomen and chest CT "double scan" rates (percentage of total examinations performed both with and without intravenous contrast). METHODS: Radiologists' claims for abdomen and chest CT examinations in a facility setting were identified using 2014 Medicare Physician and Other Supplier data. Individual radiologist double scan rates were computed. Associations were explored between rates and radiologist characteristics extracted from the CMS public data sets using multivariable regression with cross-validation. RESULTS: Radiologists' double scan rates averaged 5.9% +/- 10.0% (0.0% for 52.8% of radiologists) for abdomen CT (19,867 radiologists) and 1.0% +/- 4.7% (0.0% for 91.3% of radiologists) for chest CT (18,684). At multivariable analysis, abdomen rates were best predicted by geography (lowest in Northeast, greatest in West), practice size (greatest for small practices), and specialty practice pattern (lowest for general radiologists; greatest for nuclear medicine physicians). Agreement for double scan rates among radiologists within the same practice was moderate, though slightly higher for chest (intraclass correlation = 0.70) than abdomen (0.59). CONCLUSION: Radiologists' facility double scan rates vary systematically based on an array of professional characteristics. MACRA grants CMS the authority to use these measures for evaluating radiologists, thereby aligning Medicare's hospital and physician performance programs and better incentivizing population radiation dose and cost reduction. Greater variation in abdomen CT double scan rates, compared with ubiquitously excellent chest CT performance, supports a particular role for abdomen rates in distinguishing disparities in radiologist performance. PMID- 29275919 TI - Melatonin administration lowers biomarkers of oxidative stress and cardio metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND & AIMS: Melatonin may benefit diabetic people with coronary heart disease (CHD) through its beneficial effects on biomarkers of oxidative stress and cardio-metabolic risk. This investigation evaluated the effects of melatonin administration on metabolic status in diabetic patients with CHD. METHODS: This randomized, double-blind, placebo-controlled trial was conducted and involved 60 diabetic patients with CHD. Subjects were randomly allocated into two groups to receive either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 30) or placebo (n = 30) once a day for 12 weeks. RESULTS: Compared with the placebo, melatonin supplementation resulted in significant increases in plasma glutathione (GSH) (+64.7 +/- 105.7 vs. -11.1 +/- 137.6 MUmol/L, P = 0.02) and nitric oxide (NO) (+0.9 +/- 4.7 vs. -3.3 +/- 9.6 MUmol/L, P = 0.03), and significant decreases in malondialdehyde (MDA) (-0.2 +/- 0.3 vs. +0.1 +/- 0.5 MUmol/L, P = 0.007), protein carbonyl (PCO) (-0.12 +/- 0.08 vs. +0.03 +/- 0.07 mmol/mg protein, P < 0.001) and serum high sensitivity C-reactive protein (hs-CRP) levels (-1463.3 +/- 2153.8 vs. +122.9 +/- 1230.4 ng/mL, P = 0.001). In addition, taking melatonin, compared with the placebo, significantly reduced fasting plasma glucose (-29.4 +/ 49.0 vs. -5.5 +/- 32.4 mg/dL, P = 0.03), serum insulin concentrations (-2.2 +/- 4.1 vs. +0.7 +/- 4.2 MUIU/mL, P = 0.008), homeostasis model of assessment estimated insulin resistance (-1.0 +/- 2.2 vs. +0.01 +/- 1.6, P = 0.04), total /HDL-cholesterol ratio (-0.18 +/- 0.38 vs. +0.03 +/- 0.35, P = 0.02) and systolic (-4.3 +/- 9.6 vs. +1.0 +/- 7.5 mmHg, P = 0.01) and diastolic blood pressure (-2.8 +/- 7.3 vs. +0.1 +/- 3.6 mmHg, P = 0.04). Melatonin treatment also significantly increased quantitative insulin sensitivity check index (+0.006 +/- 0.01 vs. 0.004 +/- 0.01, P = 0.01) and serum HDL-cholesterol (+2.6 +/- 5.5 vs. -0.01 +/- 4.4 mg/dL, P = 0.04). Supplementation with melatonin had no significant effect on other metabolic parameters. CONCLUSIONS: Overall, melatonin intake for 12 weeks to diabetic patients with CHD had beneficial effects on plasma GSH, NO, MDA, PCO, serum hs-CRP levels, glycemic control, HDL-cholesterol, total-/HDL-cholesterol ratio, blood pressures and parameters of mental health. Registered under ClinicalTrials.gov Identifier no. http://www.irct.ir: IRCT2017051333941N1. PMID- 29275920 TI - The effect of intermittent fasting on blood pressure variability in patients with newly diagnosed hypertension or prehypertension. AB - Intermittent fasting is a phenomenon which can be observed in most humans. The effect of intermittent fasting on blood pressure variability (BPV) has not previously been investigated. The purpose of this study was to assess the effect of fasting on blood pressure (BP) (with office, home, central, and ambulatory blood pressure monitoring [ABPM]) and on BPV. Sixty individuals were included in the study. Office, home, ABPM, and central BP measurements were performed before and during intermittent fasting. Standard deviation and coefficient variation were used for office and home BPV measurement, while the smoothness index was used to calculate ABPM variability. Patients' BP and BPV values before and during intermittent fasting were then compared. Intermittent fasting resulted in a significant decrease in office BP values and ABPM measurements but caused no significant change in home and central BP measurements. Twenty-four hour urinary sodium excretion decreased. Smoothness values obtained from ABPM measurements were low; in other words, BPV was greater. BPV was higher in patients who woke up to eat before sunrise, but BPV was low in patients with high body mass index. Intermittent fasting produced a significant decrease in BP values in terms of office and ABPM measurements in this study but caused no significant change in central BP and home measurements. We also identified an increase in BPV during intermittent fasting, particularly in patients who rose before sunrise. PMID- 29275921 TI - Patients with hypertensive responses to exercise or dobutamine stress testing differ in resting hypertensive phenotype. AB - Little is known of the importance of echocardiographic measures of resting systemic vascular resistance (SVR), cardiac output, and diastolic function in the development of a hypertensive response during dobutamine stress echocardiography. We performed a retrospective review of 325 subjects who underwent stress echocardiography and a resting echocardiogram on the same day. Logistical regressions were performed to determine associations between hypertensive response to each type of stress test and clinical and hemodynamic measurements obtained by transthoracic echocardiography. Patients with a hypertensive response to dobutamine or exercise stress modalities had Stage 1 hypertension. Those with a hypertensive response to dobutamine had a significantly elevated SVR and a lower cardiac output compared to those with a hypertensive response to exercise or a nonhypertensive response to dobutamine. An SVR >=2000 dynes * sec/cm5 showed excellent discrimination between patients who did and did not have a hypertensive response to dobutamine (c = 0.80). A hypertensive response to both stress modalities showed an association with measures of diastolic dysfunction. The hemodynamic and echocardiographic phenotypes of individuals with a hypertensive response to exercise differ from those with a hypertensive response to dobutamine. Further work is necessary to understand and guide antihypertensive therapy when a hypertensive response to stress testing is discovered and to inform choice of stress modality when resting hypertension is present. PMID- 29275922 TI - Effects of orlistat on blood pressure: a systematic review and meta-analysis of 27 randomized controlled clinical trials. AB - Obesity and high blood pressure (BP) are strongly related and weight loss is mightily associated with a significant BP decrease. The aim of the present meta analysis was to evaluate and quantify the BP decrease associated with orlistat use in randomized controlled trials. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to June 05, 2017, to identify randomized controlled trials investigating the impact of orlistat on blood pressure. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Our meta-analysis included 27 randomized controlled clinical trials which comprehended overall 8150 subjects (4419 in the orlistat group and 3731 in the control one). We observed a statistically significant decreasing effect of orlistat on both systolic BP (-1.15 mmHg [-2.11, -0.19]) and diastolic BP (-1.07 mmHg [-1.69, -0.45]), regardless of its dosage. Significant associations were found between changes in systolic BP and diastolic BP with treatment duration but not with corresponding baseline BP values. In conclusion, Orlistat use contributes weight loss associated decrease in BP in overweight and obese subjects. PMID- 29275923 TI - Global Health and Heart Failure. PMID- 29275924 TI - Pyridostigmine for the Reversal of Severe Adverse Reactions to Botulinum Toxin in Children. AB - Therapeutic botulinum toxin injections are commonly performed in pediatric otolaryngology. Aerodigestive complications from botulinum toxin injections, although rare, may be serious. Oral pyridostigmine is effective in the symptomatic treatment of these complications. We report 2 cases of aerodigestive complications arising from injection of botulinum toxin that were successfully treated with pyridostigmine. PMID- 29275925 TI - Utility of Early-Onset Sepsis Risk Calculator for Neonates Born to Mothers with Chorioamnionitis. AB - OBJECTIVES: To evaluate the performance of the early-onset sepsis (EOS) risk calculator in a cohort of neonates born to mothers with clinical chorioamnionitis, and to compare the diagnostic utility of the EOS calculator, clinical signs, and laboratory evaluations for correctly identifying EOS in this cohort. STUDY DESIGN: This was a retrospective study of neonates born at >=35 weeks of gestation to mothers with chorioamnionitis. The risk and management categories for all neonates were calculated using the EOS calculator, and these results were analyzed and compared with laboratory data and clinical signs. RESULTS: Of the 1159 neonates born to mothers with chorioamnionitis, 5 (0.43%) had culture-proven EOS. Data for calculation of EOS risk were available for 896 neonates, including the 5 neonates with culture-proven EOS. The management recommendation based on the calculator was no empiric antibiotic treatment for 67% of the neonates, including 2 of the 5 with EOS. All neonates with culture proven EOS had abnormal complete blood counts and C-reactive protein levels at 6 12 hours. Three of the 5 neonates with EOS had clinical signs of sepsis. CONCLUSIONS: The risk of EOS in neonates born to mothers with chorioamnionitis is low. The use of an EOS calculator may reduce the use of empiric antibiotics in chorioamnionitis-exposed neonates, but in our cohort, some neonates with culture confirmed EOS would have been missed. A larger study is needed to evaluate whether limiting antibiotics to chorioamnionitis-exposed neonates with clinical and/or laboratory signs of infection can safely decrease antibiotic use. PMID- 29275926 TI - Variation in Positive End-Expiratory Pressure Levels for Mechanically Ventilated Extremely Low Birth Weight Infants. AB - OBJECTIVE: To test the hypothesis that significant positive end-expiratory pressure (PEEP) level variation exists between neonatal centers. STUDY DESIGN: We performed a secondary analysis cohort study of the Nasal Intermittent Positive Pressure Ventilation trial. Our study population was extremely low birth weight infants requiring mechanical ventilation within 28 days of life. The exposure was neonatal center; 34 international centers participated in the trial. Subjects from centers with fewer than 5 eligible cases were excluded. The main outcome was the maximal PEEP level used during the first course of mechanical ventilation. Infant characteristics judged a priori to directly influence clinical PEEP level selection and all characteristics associated with PEEP at P <.05 in bivariable analyses were included with and without center in multivariable linear regression models. Variation in PEEP level use between centers following adjustment for infant characteristics was assessed. RESULTS: A total of 278 extremely low birth weight infants from 17 centers were included. Maximal PEEP ranged from 3 to 9 cm H2O, mean = 5.7 (SD = 0.9). Significant variation between centers remained despite adjustment for infant characteristics (P < .0001). Further, center alone explained a greater proportion of the PEEP level variation than all infant characteristics combined. CONCLUSIONS: Marked variation in PEEP levels for extremely low birth weight infants exists between neonatal centers. Research providing evidence-based guidance for this important aspect of respiratory care in preterm infants at high risk of lung injury is needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00433212. PMID- 29275927 TI - E-Healthcare for Celiac Disease-A Multicenter Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the (cost-)effectiveness of online consultations in follow up of patients with celiac disease (CD). STUDY DESIGN: Multicenter randomized, controlled trial involving 304 patients aged <=25 years with CD for >=1 year, randomized to an online (n = 156) or outpatient consultation (n = 148). An online consultation included questionnaires for symptom and growth measurement. Antitransglutaminase-type-2 antibodies were determined using a point-of-care (POC) test. Controls had a traditional consultation with antitransglutaminase type-2 antibodies testing in laboratories. Both groups completed questionnaires concerning CD-specific health-related quality of life (HRQOL), gluten-free diet adherence, and patient satisfaction. Six months later, participants repeated HRQOL and patient satisfaction questionnaires and the POC test. The primary outcome was anti-transglutaminase-type-2 antibodies after 6 months, and the secondary outcomes were health problems, dietary adherence, HRQOL, patient satisfaction, and costs. RESULTS: The performance of the POC test was inferior to laboratory testing (2/156 positive POC tests vs 13/148 positive laboratory tests; P = .003). Health problems were detected significantly more frequently using online consultation. The detection of growth problems and dietary transgressions was similar. HRQOL (from 1 [good] to 5 [poor]) improved after online consultation (from 3.25 to 3.16 [P = .013] vs controls from 3.10 to 3.23; P = .810). Patient satisfaction (from 1 [low] to 10 [high]) was 7.6 (online) vs 8.0 (controls; P = .001); 58% wished to continue online consultations. Mean costs per participant during the studied period were ?202 less for the online group (P < .001). CONCLUSIONS: The primary outcome could not be tested because the POC test was unreliable. Nevertheless, our results indicate that online consultations for children and young adults with CD are cost saving, increase CD-specific HRQOL, and are satisfactory for the majority. TRIAL REGISTRATION: Trialregister.nl: NTR3688. PMID- 29275928 TI - Spontaneous coronary artery dissection (SCAD): The underdiagnosed cardiac condition that plagues women. AB - Coronary heart disease (CHD) continues to be understudied, underdiagnosed, and undertreated in women. Gender and age bias complicate the evaluation of women with acute coronary syndrome (ACS). As a result, conditions like spontaneous coronary artery dissection (SCAD) are often missed. SCAD is an infrequent yet important cause of myocardial infarction (MI) with a predilection for young to middle aged women. The condition is thought to be under-reported, likely a result of both low index of suspicion as well as an unfamiliarity with SCAD's angiographic variants. Recently, the European Society of Cardiology (ESC) detailed an assessment pathway for patients with myocardial infarction with non obstructive coronary arteries (MINOCA), a subset of which includes patients with SCAD. The pathway highlights the role of cardiac magnetic resonance (CMR) in addition to intracoronary imaging for increased diagnostic yield. Early and proper diagnosis is crucial in SCAD given the potential for sudden cardiac death, as well as the increased risk for future cardiac events including recurrent dissection. In addition, SCAD has frequently been associated with underlying connective tissue disease and/or arteriopathy, most commonly fibromuscular dysplasia (FMD), which requires careful screening. The lack of consensus on investigation or treatment highlights the need for increased awareness and further research to better understand this challenging entity. PMID- 29275929 TI - Endometrial stromal sarcomas and related neoplasms: new developments and diagnostic considerations. AB - Our understanding of endometrial stromal sarcomas has evolved dramatically since their earliest descriptions from over a century ago. Initial studies focused on establishing the relationship between histological appearances of endometrial stromal sarcomas and their clinical outcomes. Studies performed in the last decade have uncovered several recurrent cytogenetic aberrations occurring in low- and high-grade endometrial stromal sarcomas. Low-grade endometrial stromal sarcomas bear close histopathological resemblance to proliferative-type endometrial stroma, and approximately half harbour t(7;17)(p15;q21) resulting in JAZF1-SUZ12 gene fusion. Less common JAZF1-PHF1, EPC1-PHF1, MEAF6-PHF1, and MBTD1 CXorf67 fusions have also been reported. The term 'high-grade endometrial stromal sarcoma' was recently re-introduced in the classification of endometrial stromal tumours after the discovery of t(10;17)(q22;p13) resulting in YWHAE-NUTM2A/B fusion and is associated with distinct morphological characteristics. This review highlights the evolution of endometrial stromal sarcoma classification schemes over time and describes the salient clinicopathological and molecular features of endometrial stromal nodule, low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. It also describes the recent characterisation of endometrial stromal sarcoma with t(X;22)(p11;q13) resulting in ZC3H7B-BCOR fusion, a noteworthy entity due to its close histological resemblance to myxoid leiomyosarcoma. We also provide insights into common challenging scenarios encountered when assessing endometrial stromal lesions in daily surgical pathology practice. PMID- 29275930 TI - Ovarian sex cord-stromal tumours: an update in recent molecular advances. AB - Sex cord-stromal tumours (SCSTs) consist of a heterogeneous group of neoplasms with diverse clinicopathological features and biological behaviour. They often present as a diagnostic challenge as they have varied and occasionally overlapping histomorphology and some may even mimic non-SCSTs. An accurate diagnosis is important for therapeutic and prognostic purposes. The use of a panel of immunohistochemical markers which are sensitive and specific for sex cord-stromal differentiation such as alpha-inhibin, calretinin, SF-1 and FOXL2, may be helpful in confirming the cellular lineage of these tumours, but is of limited utility in distinguishing between the different tumour types within this category. Additionally, the development of new therapeutic strategies in patients with SCSTs is also hampered by the infrequent occurrence of these neoplasms. Recent molecular analyses of some SCSTs has led to the discovery of novel molecular events, which may have important diagnostic, prognostic and therapeutic implications. The salient pathological features, management issues and recently described genetic aberrations in adult and juvenile granulosa cell tumours as well as Sertoli-Leydig cell tumours are discussed in this review, with particular emphasis on the clinical significance of FOXL2 and DICER1 mutations. An in-depth understanding of the molecular pathogenesis underlying SCSTs may aid in improving tumour classification and disease prognostication and also potentially lead to the discovery of more effective treatment strategies. PMID- 29275931 TI - Palliative use of furosemide in continuous subcutaneous infusion in a renal transplant patient with heart failure. PMID- 29275932 TI - An in-vitro study to assess the feasibility, validity and precision of capturing oncology facial defects with multimodal image fusion. AB - AIM: Assess the feasibility, validity and precision of multimodal image fusion to capture oncology facial defects based on plaster casts. METHODS: Ten casts of oncology facial defects were acquired. To create gold standard models, a 3D volumetric scan of each cast was obtained with a cone beam computed tomography (CBCT) scanner (NewTomVG). This was converted into surface data using open-source medical segmentation software and cropped to produce a CBCT mask using an open source system for editing meshes. For the experimental model, the external facial features were captured using stereophotogrammetry (DI4D) and the defect was recorded with a custom optical structured light scanner. The two meshes were aligned, merged and resurfaced using MeshLab to produce a fused model. Analysis was performed in MeshLab on the best fit of the fused model to the CBCT mask. The unsigned mean distance was used to measure the absolute deviation of each model from the CBCT mask. To assess the precision of the technique, the process of producing the fused model was repeated to create five models each for the casts representing the best, middle and worst results. RESULTS: Global mean deviation was 0.22 mm (standard deviation 0.05 mm). The precision of the method appeared to be acceptable although there was variability in the location of the error for the worst cast. CONCLUSION: This method for merging two independent scans to produce a fused model shows strong potential as an accurate and repeatable method of capturing facial defects. Further research is required to explore its clinical use. PMID- 29275933 TI - Speciation of organic fraction does matter for source apportionment. Part 1: A one-year campaign in Grenoble (France). AB - PM10 source apportionment was performed by positive matrix factorization (PMF) using specific primary and secondary organic molecular markers on samples collected over a one year period (2013) at an urban station in Grenoble (France). The results provided a 9-factor optimum solution, including sources rarely apportioned in the literature, such as two types of primary biogenic organic aerosols (fungal spores and plant debris), as well as specific biogenic and anthropogenic secondary organic aerosols (SOA). These sources were identified thanks to the use of key organic markers, namely, polyols, odd number higher alkanes, and several SOA markers related to the oxidation of isoprene, alpha pinene, toluene and polycyclic aromatic hydrocarbons (PAHs). Primary and secondary biogenic contributions together accounted for at least 68% of the total organic carbon (OC) in the summer, while anthropogenic primary and secondary sources represented at least 71% of OC during wintertime. A very significant contribution of anthropogenic SOA was estimated in the winter during an intense PM pollution event (PM10>50MUgm-3 for several days; 18% of PM10 and 42% of OC). Specific meteorological conditions with a stagnation of pollutants over 10days and possibly Fenton-like chemistry and self-amplification cycle of SOA formation could explain such high anthropogenic SOA concentrations during this period. Finally, PMF outputs were also used to investigate the origins of humic-like substances (HuLiS), which represented 16% of OC on an annual average basis. The results indicated that HuLiS were mainly associated with biomass burning (22%), secondary inorganic (22%), mineral dust (15%) and biogenic SOA (14%) factors. This study is probably the first to state that HuLiS are significantly associated with mineral dust. PMID- 29275934 TI - Enhanced intracellular peptide delivery by multivalent cell-penetrating peptide with bioreducible linkage. AB - Multivalent cell-penetrating peptides (CPPs) have been reported to show enhancement in cellular uptake and endosomolytic activity. However, its application was limited to trans-delivery of cargo which is lower in cellular uptake efficiency of cargo than cis-delivery. Here, we tried the cis-delivery of cargo with multivalent CPP by preparing bioreducible dimeric CPP-cargo with apoptotic activity using TatBim peptide, a fusion of Tat CPP and Bim peptide derived from Bim apoptosis-inducing protein. Dimeric TatBim was almost twice as highly internalized by cells and significantly induced apoptosis compared to monomeric TatBim. Contribution of bioreducible linkage of dimeric TatBim towards apoptotic activity was also confirmed. PMID- 29275935 TI - Highly selective peroxisome proliferator-activated receptor delta (PPARdelta) modulator demonstrates improved safety profile compared to GW501516. AB - Compound 1 regulates significantly fewer genes than the PPARdelta modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns. PMID- 29275936 TI - Downregulation of Akt2 attenuates ER stress-induced cytotoxicity through JNK-Wnt pathway in cardiomyocytes. AB - Akt, also known as protein kinase B (PKB), is a serine/threonine kinase that promotes survival and growth in response to extracellular signals. Akt1 has been demonstrated to play vital roles in cardiovascular diseases, but the role of Akt2 in cardiomyocytes is not fully understood. This study investigated the effect of Akt2 knockdown on tunicamycin (TM)-induced cytotoxicity in cardiomyocytes and the underlying mechanisms with a focus on the JNK-Wnt pathway. TM treatment significantly increased the expression of Akt2 at both mRNA and protein levels, which was shown to be mediated by the induction of reactive oxygen species (ROS). Knockdown of Akt2 expression via siRNA transfection markedly increased cell viability, decreased lactate dehydrogenase (LDH) release and reduced cell apoptosis after TM exposure. The results of western blot showed that downregulation of Akt2 also attenuated the TM-induced activation of the unfolded protein response (UPR) factors and ER stress associated pro-apoptotic proteins. In addition, Si-Akt2 transfection partially prevented the TM-induced decrease in nuclear localization of beta-catenin. By using the selective inhibitor SP-600,125 to inhibit JNK phosphorylation, we found that knockdown of Akt2-induced protection and inhibition of ER stress was mediated by reversing TM-induced decrease of Wnt through the JNK pathway. In summary, these data suggested that Akt2 play a pivotal role in regulating cardiomyocyte survival during ER stress by modulating the JNK-Wnt pathway. PMID- 29275937 TI - Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen. AB - Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo. PMID- 29275938 TI - The Prevalence of Burnout Among Nursing Home Physicians: An International Perspective. AB - Physician burnout is a critical factor influencing the quality of care delivered in various healthcare settings. Although the prevalence and consequences of burnout have been well documented for physicians in various jurisdictions, no studies to date have reported on burnout in the postacute and long-term care setting. In this exploratory study, we sought to quantify the prevalence of burnout among 3 cohorts of physicians, each practicing in nursing homes in the United States (US), Canada, or The Netherlands. International comparisons were solicited to highlight cultural and health system factors potentially impacting burnout levels. Using standard survey techniques, a total of 721 physicians were solicited to participate (Canada 393; US 110; The Netherlands 218). Physicians agreeing to participate were asked to complete the "Maslach Burnout Inventory" using the Survey Monkey platform. A total of 118 surveys were completed from The Netherlands, 59 from Canada, and 65 from the US for response rates of 54%, 15%, and 59%, respectively. While US physicians demonstrated more negative scores in the emotional exhaustion subscale compared with their counterparts in Canada and The Netherlands, there were no meaningful differences on the depersonalization and personal accomplishments subscales. Factors explaining these differences are explored as well as approaches to future research on physician burnout in postacute and long-term care. PMID- 29275940 TI - How Well Does Dual-energy CT with Fast Kilovoltage Switching Quantify CT Number and Iodine and Calcium Concentrations? AB - RATIONALE AND OBJECTIVES: Because it is imperative for understanding the performance of dual-energy computed tomography scanner to determine clinical diagnosis, we aimed to assess the accuracy of quantitative measurements using dual-energy computed tomography with fast kilovoltage switching. MATERIALS AND METHODS: Quantitative measurements were performed for 16 reference materials (physical density, 0.965-1.550 g/cm3; diameter of rod, 2.0-28.5 mm; iodine concentration, 2-15 mg/mL; and calcium concentration, 50-300 mg/mL) with varying scanning settings, and the measured values were compared to their theoretical values. RESULTS: For high-density material, the maximum differences in Hounsfield unit values in the virtual monochromatic images at 50, 70, and 100 keV were 176.2, 61.0, and -35.2 HU, respectively, and the standard deviations over short- and long-term periods were 11.1, 6.1, and 3.5 HU at maximum. The accuracy of the Hounsfield unit measurement at 50 and 70 keV was significantly higher (P < 0.05) with higher radiation output and smaller phantom size. The difference in the iodine and calcium measurements in the large phantom were up to -2.6 and -60.4 mg/mL for iodine (5 mg/mL with 2-mm diameter) and calcium (300 mg/mL) materials, and the difference was improved with a small phantom. Metal artifact reduction software improved subjective image quality; however, the quantitative values were significantly underestimated (P < 0.05) (-49.5, -26.9, and -15.3 HU for 50, 70, and 100 keV, respectively; -1.0 and -17 mg/mL for iodine and calcium concentration, respectively) compared to that acquired without a metal material. CONCLUSIONS: The accuracy of quantitative measurements can be affected by material density and the size of the object, radiation output, phantom size, and the presence of metal materials. PMID- 29275939 TI - Costs of Care of Agitation Associated With Dementia in 8 European Countries: Results From the RightTimePlaceCare Study. AB - OBJECTIVE: To estimate the additional societal costs for people living with dementia (PwD) with agitation in home care (HC) and institutional long-term care (ILTC) settings in 8 European countries. DESIGN: Cross-sectional data from the RightTimePlaceCare cohort. SETTING: HC and ILTC settings from 8 European countries (Estonia, Finland, France, Germany, Netherlands, Spain, Sweden, and England). PARTICIPANTS: A total of 1997 PwD (1217 in HC group and 780 lived in an ILTC) and their caregivers. MAIN OUTCOME MEASURES: Medical care, community care, and informal care were recorded using the Resource Utilization in Dementia (RUD) questionnaire. Agitation was assessed based on the agitation symptoms cluster defined by the presence of agitation and/or irritability and/or disinhibition and/or aberrant motor behavior items of the Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Total monthly mean cost differences due to agitation were 445? in the HC setting and 561? in the ILTC setting (P = .01 and .02, respectively). Informal care costs were the main driver in the HC group (73% of total costs) and institutional care costs were the main driver in the ILTC group (53% of total costs). After adjustments, the log link generalized linear mixed model showed an association between agitation symptoms and an increase of informal care costs by 17% per month in HC setting (P < .05). CONCLUSION: This study found that agitation symptoms have a substantial impact on informal care costs in the community care setting. Future research is needed to evaluate which strategies may be efficient by improving the cost-effectiveness ratio and reducing the burden associated with informal care in the management of agitation in PwD. PMID- 29275941 TI - Breast Imaging Outcomes following Abnormal Thermography. AB - RATIONALE AND OBJECTIVES: The study aimed to determine the outcome of patients presenting for evaluation of abnormal breast thermography. MATERIALS AND METHODS: Following Institutional Review Board approval, retrospective search identified 38 patients who presented for conventional breast imaging following a thermography detected abnormality. Study criteria included women who had mammogram and/or breast ultrasound performed for evaluation of a thermography-detected abnormality between January 1, 2000, and December 31, 2015. Patients whose mammograms and ultrasounds were initiated at an outside institution or who did not have imaging at our institution were excluded. Records were reviewed for clinical history, thermography results, mammogram and/or ultrasound findings, and pathology. Mammograms and ultrasounds were prospectively interpreted by one of 14 Mammography Quality Standards Act-certified breast imaging radiologists with 3-30 years of experience. Patient outcomes were determined by biopsy or at least 1 year of follow-up. Patient ages ranged from 23 to 70 years (mean = 50 years). RESULTS: Ninety-five percent (36 of 38) of patients did not have breast cancer. The two patients diagnosed with breast cancer had suspicious clinical symptoms including palpable mass and erythema. No asymptomatic woman had breast cancer. Negative predictive value was 100%. Of 38 patients, 79% (30 of 38) had Breast Imaging Reporting and Data System (BI-RADS) 1 or 2 assessments; 5% (2 of 38) had BI-RADS 3; and 16% (6 of 38) had BI-RADS 4 (n = 5) or BI-RADS 5 (n = 1) assessments. Two of six patients with biopsy recommendations were diagnosed with breast cancer (Positive predictive value 2 = 33.3%). All findings recommended for biopsy were ipsilateral to the reported thermography abnormality. CONCLUSIONS: No cancer was diagnosed among asymptomatic women. The 5% of patients diagnosed with cancer had co-existing suspicious clinical findings. Mammogram and/or ultrasound were useful in accurately characterizing patients with abnormal thermography. PMID- 29275943 TI - The Influence of Gender and Age on the Acoustic Voice Quality Index and Dysphonia Severity Index: A Normative Study. AB - OBJECTIVES: The Acoustic Voice Quality Index (AVQI) and the Dysphonia Severity Index (DSI) are commonly used in research and clinical practice to quantify voice quality. The aim of this study was to investigate the influence of gender and age on AVQI and again on DSI. METHODS: In total, 123 vocally healthy adults (68 females, 55 males, and age ranging between 20 and 79 years) were evaluated. RESULTS: Gender had no effects on AVQI and DSI (both P values > 0.05). Additionally, AVQI showed no significant correlation with age (P > 0.05, r2 = 0.008). However, DSI had a statistically significant correlation with age (P < 0.05), with 5% of the variance in DSI explained by the variance in age. CONCLUSIONS: AVQI values do not depend on gender and age. DSI values do not depend on gender but correlated slightly with age. This finding confirms earlier research. PMID- 29275942 TI - Short communication: Lactose enhances bile tolerance of yogurt culture bacteria. AB - Lactose is an energy source for culture bacteria. Bile tolerance is an important probiotic property. Our aim was to elucidate the effect of lactose on bile tolerance of yogurt starter culture Lactobacillus bulgaricus LB-12 and Streptococcus thermophilus ST-M5. Bile tolerance of pure cultures was determined using 0.3% oxgall in MRS THIO broth (Difco, Becton Dickinson, Sparks, MD) for L. bulgaricus and 0.3% oxgall in M17 broth (Oxoid, Basingstoke, UK) for Strep. thermophilus. Lactose was added to both broths at 0 (control), 1, 3, and 5% (wt/vol) broth. Dilutions were plated hourly for 12 h. Experiments were replicated 3 times. At 2, 4, and 12 h of incubation, lactose incorporated at all amounts, 1, 3, and 5% (wt/vol), showed higher counts of Strep. thermophilus ST-M5 compared with the control. Lactose use at 5% (wt/vol) significantly enhanced bile tolerance of both L. bulgaricus and Strep. thermophilus compared with control. PMID- 29275944 TI - Electrocardiographic patterns and long-term training-induced time changes in 2484 elite football players. AB - BACKGROUND: High-level physical training induces cardiac structural and functional changes, including 12-lead electrocardiogram modifications. OBJECTIVES: The purpose of this cross-sectional longitudinal study was to establish a quantitative electrocardiographic profile in highly trained football players. Initial and serial annual electrocardiogram monitoring over subsequent years allowed us to investigate the long-term effects of exercise on cardiac conduction and electrophysiological remodelling. METHODS: Between 2005 and 2015, serial evaluations, including 12-lead electrocardiograms, were performed in 2484 elite male football players from the French Professional Football League. A total of 6247 electrocardiograms were performed (mean 2.5+/-1.8 electrocardiograms/player). Heart rate (beats/min), atrioventricular delay (PR, ms), intraventricular conduction delay (QRS, ms), corrected QT delay (QTc) and electrical left ventricular hypertrophy (LVH) (Sokolow-Lyon index, mm) were measured, and the fixed effect of time was evaluated using panel data analysis (beta [95% confidence interval] change between two visits). RESULTS: According to European Society of Cardiology and Seattle criteria, 15% of the electrocardiogram intervals were considered abnormal. We observed 17% sinus bradycardia<50 beats/min (mean heart rate 60+/-11 beats/min), 8% first-degree atrioventricular block>200ms (mean PR 170+/-27ms), 1.5% QRS>120ms (mean QRS 87+/-19ms) and 3% prolonged QT interval (mean QTc using Bazett's formula [QTcB] 395+/-42ms). Electrical LVH (mean Sokolow-Lyon index 34+/-10mm) was noted in 37% of players. Over time, electrocardiogram changes were noted, with a significant remodelling trend in terms of decreased heart rate (-0.41 [-0.55 to -0.26] beats/min), QRS duration (-2.4 [-2.7 to -2.1] ms) and QTcB delay (-1.2 [-1.9 to -0.5] ms) (all P<0.001). CONCLUSIONS: This study describes usual electrocardiographic training induced changes in a large series of football players over the follow-up timeframe. The most frequent outliers were electrical LVH and sinus bradycardia. These results have important implications for optimizing electrocardiogram interval measurements in initial screening and during follow-up of football players, with potential cost-effective implications. PMID- 29275945 TI - The Supply of Prescription Opioids: Contributions of Episodic-Care Prescribers and High-Quantity Prescribers. AB - STUDY OBJECTIVE: We determine episodic and high-quantity prescribers' contribution to opioid prescriptions and total morphine milligram equivalents in California, especially among individuals prescribed large amounts of opioids. METHODS: This was a cross-sectional descriptive analysis of opioid prescribing patterns during an 8-year period using the de-identified Controlled Substance Utilization Review and Evaluation System (CURES) database, the California subsection of the prescription drug monitoring program. We took a 10% random sample of all patients and stratified them by the amount of prescription opioids obtained during their maximal 90-day period. We identified "episodic prescribers" as those whose prescribing pattern included short-acting opioids on greater than 95% of all prescriptions, fewer than or equal to 31 pills on 95% of all prescriptions, only 1 prescription in the database for greater than 90% of all patients to whom they gave opioids, fewer than 6 prescriptions in the database to greater than 99% of patients given opioids, and fewer than 540 prescriptions per year. We identified top 5% prescribers by their morphine milligram equivalents per day in the database. We examined the relationship between patient opioid prescriptions and provider type, with the primary analysis performed on the patient cohort who received only short-acting opioids in an attempt to avoid guideline-concordant palliative, oncologic, and addiction care, and a secondary analysis performed on all patients. RESULTS: Among patients with short-acting opioid only, episodic prescribers (14.6% of 173,000 prescribers) wrote at least one prescription to 25% of 2.7 million individuals but were responsible for less than 9% of the 10.5 million opioid prescriptions and less than 3% of the 3.9 billion morphine milligram equivalents in our sample. Among individuals with high morphine milligram equivalents use, episodic prescribers were responsible for 2.8% of prescriptions and 0.6% of total morphine milligram equivalents. Conversely, the top 5% of prescribers prescribed at least 29.8% of prescriptions and 48.8% of total morphine milligram equivalents, with a greater contribution in patients with high morphine milligram equivalents. CONCLUSION: Episodic prescribers contribute minimally to total opioid prescriptions, especially among individuals categorized as using high morphine milligram equivalents. Interventions focused on reducing opioid prescriptions in the episodic care setting are unlikely to yield important reductions in the prescription opioid supply; conversely, targeting high-quantity prescribers has the potential to create substantial reductions. PMID- 29275947 TI - GLP-1 agonist associated acute kidney injury: A case report and review. PMID- 29275946 TI - ECG Predictors of Cardiac Arrhythmias in Older Adults With Syncope. AB - STUDY OBJECTIVE: Cardiac arrhythmia is a life-threatening condition in older adults who present to the emergency department (ED) with syncope. Previous work suggests the initial ED ECG can predict arrhythmia risk; however, specific ECG predictors have been variably specified. Our objective is to identify specific ECG abnormalities predictive of 30-day serious cardiac arrhythmias in older adults presenting to the ED with syncope. METHODS: We conducted a prospective, observational study at 11 EDs in adults aged 60 years or older who presented with syncope or near syncope. We excluded patients with a serious cardiac arrhythmia diagnosed during the ED evaluation from the primary analysis. The outcome was occurrence of 30-day serous cardiac arrhythmia. The exposure variables were predefined ECG abnormalities. Independent predictors were identified through multivariate logistic regression. The sensitivities and specificities of any predefined ECG abnormality and any ECG abnormality identified on adjusted analysis to predict 30-day serious cardiac arrhythmia were also calculated. RESULTS: After exclusion of 197 patients (5.5%; 95% confidence interval [CI] 4.7% to 6.2%) with serious cardiac arrhythmias in the ED, the study cohort included 3,416 patients. Of these, 104 patients (3.0%; 95% CI 2.5% to 3.7%) had a serious cardiac arrhythmia within 30 days from the index ED visit (median time to diagnosis 2 days [interquartile range 1 to 5 days]). The presence of nonsinus rhythm, multiple premature ventricular conductions, short PR interval, first degree atrioventricular block, complete left bundle branch block, and Q wave/T wave/ST-segment abnormalities consistent with acute or chronic ischemia on the initial ED ECG increased the risk for a 30-day serious cardiac arrhythmia. This combination of ECG abnormalities had a similar sensitivity in predicting 30-day serious cardiac arrhythmia compared with any ECG abnormality (76.9% [95% CI 67.6% to 84.6%] versus 77.9% [95% CI 68.7% to 85.4%]) and was more specific (55.1% [95% CI 53.4% to 56.8%] versus 46.6% [95% CI 44.9% to 48.3%]). CONCLUSION: In older ED adults with syncope, approximately 3% receive a diagnosis of a serious cardiac arrhythmia not recognized on initial ED evaluation. The presence of specific abnormalities on the initial ED ECG increased the risk for 30-day serious cardiac arrhythmias. PMID- 29275948 TI - Item-method directed forgetting: Effects at retrieval? AB - In an item-method directed forgetting paradigm, words are presented one at a time, each followed by an instruction to Remember or Forget; a directed forgetting effect is measured as better subsequent memory for Remember words than Forget words. The dominant view is that the directed forgetting effect arises during encoding due to selective rehearsal of Remember over Forget items. In three experiments we attempted to falsify a strong view that directed forgetting effects in recognition are due only to encoding mechanisms when an item method is used. Across 3 experiments we tested for retrieval-based processes by colour coding the recognition test items. Black colour provided no information; green colour cued a potential Remember item; and, red colour cued a potential Forget item. Recognition cues were mixed within-blocks in Experiment 1 and between blocks in Experiments 2 and 3; Experiment 3 added explicit feedback on the accuracy of the recognition decision. Although overall recognition improved with cuing when explicit test performance feedback was added in Experiment 3, in no case was the magnitude of the directed forgetting effect influenced by recognition cueing. Our results argue against a role for retrieval-based strategies that limit recognition of Forget items at test and posit a role for encoding intentions only. PMID- 29275949 TI - Foraging through multiple target categories reveals the flexibility of visual working memory. AB - A key assumption in the literature on visual attention is that templates, actively maintained in visual working memory (VWM), guide visual attention. An important question therefore involves the nature and capacity of VWM. According to load theories, more than one search template can be active at the same time and capacity is determined by the total load rather than a precise number of templates. By an alternative account only one search template can be active within visual working memory at any given time, while other templates are in an accessory state - but do not affect visual selection. We addressed this question by varying the number of targets and distractors in a visual foraging task for 40 targets among 40 distractors in two ways: 1) Fixed-distractor-number, involving two distractor types while target categories varied from one to four. 2) Fixed color-number (7), so that if the target types were two, distractors types were five, while if target number increased to three, distractor types were four (etc.). The two accounts make differing predictions. Under the single-template account, we should expect large switch costs as target types increase to two, but switch-costs should not increase much as target types increase beyond two. Load accounts predict an approximately linear increase in switch costs with increased target type number. The results were that switch costs increased roughly linearly in both conditions, in line with load accounts. The results are discussed in light of recent proposals that working memory reflects lingering neural activity at various sites that operate on the stimuli in each case and findings showing neurally silent working memory representations. PMID- 29275950 TI - Sexual orientation measurement and chronic disease disparities: National Health and Nutrition Examination Survey, 2009-2014. AB - PURPOSE: To examine chronic disease disparities by sexual orientation measurement among sexual minorities. METHODS: We pooled data from the 2009-2014 National Health and Nutrition Examination Survey to examine differences in chronic disease prevalence between heterosexual and sexual minority people as defined by sexual identity, lifetime sexual behavior, 12-month sexual behavior, and concordance of lifetime sexual behavior and sexual identity. RESULTS: Self-identified lesbian women reported greater odds of asthma (adjusted odds ratio [aOR], 3.19; 95% confidence intervals [CI], 1.37-7.47) and chronic bronchitis (aOR, 2.64; 95% CI, 1.21-5.72) than self-identified heterosexual women. Self-identified sexual minority women with a history of same-sex sexual behavior reported greater odds of arthritis (aOR, 1.67; 95% CI, 1.02-2.74). Compared with heterosexual men, gay men reported greater odds of chronic bronchitis when sexual orientation was defined by sexual identity (aOR, 4.68; 95% CI, 1.90-11.56) or 12-month sexual behavior (aOR, 3.22; 95% CI, 1.27-8.20), as did bisexual men defined by lifetime sexual behavior (aOR, 2.36; 95% CI, 1.14-4.89). Bisexual men reported greater odds of asthma when measured by lifetime sexual behavior (aOR, 1.90; 95% CI, 1.12 3.19), as did self-identified heterosexual men with a history of same-sex sexual behavior (aOR, 2.21; 95% CI, 1.10-4.46). CONCLUSIONS: How we define sexual orientation influences our understanding of chronic disease prevalence. Capturing subgroups of sexual minority people in health surveillance is essential for identifying groups most at risk and developing targeted interventions to reduce chronic disease disparities. PMID- 29275951 TI - Transfemoral transcatheter aortic valve implantation and aortic calcification. PMID- 29275952 TI - Late onset of atrial fibrillation in patients undergoing mitral valve repair for type II dysfunction. AB - BACKGROUND: There are few reports regarding factors related to late-onset of atrial fibrillation (Af) after mitral valve repair, which can compromise long term outcome. We analyzed the risk factors for late Af after mitral valve repair. METHODS AND RESULTS: Between 2001 and 2015, 318 patients (214 males; median, 57.7 years) underwent mitral valve repair for degenerative mitral insufficiency (MI) without concomitant aortic valve disease in our institute. Patients with a history of paroxysmal or chronic Af preoperatively were excluded. Serial follow up echocardiography was used to evaluate cardiac function. The follow-up rate was 99%. The mean follow-up period was 6.0+/-4.1 years. There was no early death and there were nine late deaths. A total of 29 (9.1%) patients developed late Af. Freedom from late Af was 94.0% at 5 years and 82.9% at 10 years. Small ring annuloplasty, left atrial diameter, and pressure half time, which were measured at follow-up echocardiography, were considered as significant (p<0.05) risk factors for late Af. Patients who had late Af developed recurrent MI more frequently than those who did not (p<0.05). CONCLUSIONS: Remodeling of the atrium caused by functional mitral stenosis is important for late Af, as well as recurrent MI. To prevent these problems, avoiding selection of a small ring at primary mitral repair for type II dysfunction and durable repair are required. PMID- 29275953 TI - Translational research to enable personalized treatment of cystic fibrosis. AB - Translational research efforts in cystic fibrosis (CF) aim to develop therapies for all subjects with CF. To reach this goal new therapies need to be developed that target multiple aspects of the disease. To enable individuals to benefit maximally from these treatments will require improved methods to tailor these therapies specifically to individuals who suffer from CF. This report highlights current examples of translational CF research efforts to reach this goal. The use of intestinal organoids and genetics to better understand individual assessment of CFTR modulator treatment effects to ultimately enable a better personalized treatment for CF subjects will be discussed. In addition, development of viral vectors and non-viral synthetic nanoparticles for delivery of mRNA, sgRNA and DNA will be highlighted. New approaches to restore function of CFTR with early premature termination codons using nanoparticle delivery of suppressor tRNAs and new insights into mechanisms of airway epithelial repair will be reviewed as well. The state-of-the-art approaches that are discussed in this review demonstrate significant progress towards the development of optimal individual therapies for CF patients, but also reveal that remaining challenges still lie ahead. PMID- 29275954 TI - Epidemiology of CF: How registries can be used to advance our understanding of the CF population. AB - Cystic fibrosis (CF) registries work by bringing patient data together from specialist CF centres and accumulating data on a relatively rare condition over patients' lifetimes. In this review, we examine the origin of national CF registries, the use of registries for monitoring the health of the population, the power of conducting longitudinal analysis of registry data, knowledge gleaned from changing demographics, the evolving area of international comparisons of registries, strategies for sustaining registries and CF registries of the future. Examples of research undertaken using registry data and routinely reported CF registry statistics from across the world are provided. The application, utility and challenges facing CF registries in the future are discussed. PMID- 29275955 TI - Inter- and intra-observer variability of visual fragmented QRS scoring in ischemic and non-ischemic cardiomyopathy. AB - BACKGROUND: Fragmented QRS (fQRS) on a 12-lead ECG has been linked with adverse outcome. However, the visual scoring of ECGs is prone to inter- and intra observer variability. METHODS: Five observers, two experienced and three novel, assessed fQRS in 712 digital ECGs, 100 were re-evaluated to assess intra-observer variability. Fleiss and Cohen's Kappa were calculated and compared between subgroups. RESULTS: The inter-observer variability for assessing fQRS in all leads combined was substantial with a Kappa of 0.651. Experienced observers only had a better agreement with a Kappa of 0.823. Intra-observer variability ranged from 0.736 to 0.880. In the subgroup with ventricular pacing the inter-observer variability was even significantly larger when compared to ECGs with normal QRS duration (Kappa 0.493 vs 0.664, p<0.001). CONCLUSION: The visual assessment of QRS fragmentation is prone to inter- and intra-observer variability, mainly influenced by the experience of the observers, the underlying rhythm and QRS morphology. PMID- 29275956 TI - Lyme carditis: Early occurrence and prolonged recovery. AB - Lyme carditis is an uncommon manifestation of early disseminated Lyme disease. This case illustrates a 66-year-old male with complaints of fatigue, myalgias, and fever after a tick bite 3days earlier. A large erythema migrans was found on the chest wall. Initial electrocardiogram showed sinus rhythm with second degree 2:1 atrioventricular (AV) block, which progressed to intermittent complete AV block rapidly. He was treated with intravenous ceftriaxone. Over the course of 2 weeks of antibiotic therapy, the intermittent high-grade AV block improved slowly and progressively. This case highlights the importance of timely diagnosis and appropriate management to achieve a favorable prognosis. PMID- 29275957 TI - Effect of Linear Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction-12-Month Follow-Up of a Randomized, Double-Blinded, Sham-Controlled Study. AB - INTRODUCTION: Short-term data on the effect of low-intensity extracorporeal shockwave therapy (Li-ESWT) on erectile dysfunction (ED) have been inconsistent. The suggested mechanisms of action of Li-ESWT on ED include stimulation of cell proliferation, tissue regeneration, and angiogenesis, which can be processes with a long generation time. Therefore, long-term data on the effect of Li-ESWT on ED are strongly warranted. AIM: To assess the outcome at 6 and 12 months of linear Li-ESWT on ED from a previously published randomized, double-blinded, sham controlled trial. METHODS: Subjects with ED (N = 126) who scored lower than 25 points in the erectile function domain of the International Index of Erectile Function (IIEF-EF) were eligible for the study. They were allocated to 1 of 2 groups: 5 weekly sessions of sham treatment (group A) or linear Li-ESWT (group B). After a 4-week break, the 2 groups received active treatment once a week for 5 weeks. At baseline and 6 and 12 months, subjects were evaluated by the IIEF-EF, the Erectile Hardness Scale (EHS), and the Sexual Quality of Life in Men. MAIN OUTCOME MEASURES: The primary outcome measure was an increase of at least 5 points in the IIEF-EF (DeltaIIEF-EF score). The secondary outcome measure was an increase in the EHS score to at least 3 in men with a score no higher than 2 at baseline. Data were analyzed by linear and logistic regressions. RESULTS: Linear regression of the DeltaIIEF-EF score from baseline to 12 months included 95 patients (dropout rate = 25%). Adjusted for the IIEF-EF score at baseline, the difference between groups B and A was -1.30 (95% CI = -4.37 to 1.77, P = .4). The success rate based on the main outcome parameter (DeltaIIEF-EF score >= 5) was 54% in group A vs 47% in group B (odds ratio = 0.67, P = .28). Improvement based on changes in the EHS score in groups A and B was 34% and 24%, respectively (odds ratio = 0.47, P = .82). CONCLUSION: Exposure to 2 cycles of linear Li-ESWT for ED is not superior to 1 cycle at 6- and 12-month follow-ups. Fojecki GL, Tiessen S, Osther PJS. Effect of Linear Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction-12-Month Follow-Up of a Randomized, Double-Blinded, Sham Controlled Study. Sex Med 2018;6:1-7. PMID- 29275958 TI - EDEUS, a Real-Life Study on the Users of Phosphodiesterase Type 5 Inhibitors: Prevalence, Perceptions, and Health Care-Seeking Behavior Among European Men With a Focus on 2nd-Generation Avanafil. AB - INTRODUCTION: Erectile dysfunction (ED) is a multidimensional disorder with an estimated prevalence of 1% to 10% in men younger than 40 years and up to 100% in men in their 70s and 80s. AIM: To evaluate the real-life characteristics and unmet needs of men with ED, its impact on well-being, and treatment rates across Europe. METHODS: Adult men in Belgium, France, Germany, Italy, Poland, Portugal, and Spain were invited to participate in the survey. Men who did not use at least a drug for sexual health in the past 3 months, had cancer or spinal cord injuries, and/or underwent non-nerve-sparing radical prostatectomy were excluded. MAIN OUTCOME MEASURES: The 15-item International Index of Erectile Function (IIEF 15) with study-specific, self-constructed questions was used. RESULTS: Overall, 940 subjects (age = 46.2 +/- 13.4 years) were considered. Subjects (n = 778) using on-demand phosphodiesterase type 5 inhibitors (PDE5is) were designated "performers" (60%) without a formal ED diagnosis or "patients" with a medical diagnosis. Patients were older than performers, with more self-reported comorbidities; patients used a higher PDE5i dosage and purchased it from official pharmacies more often than performers did. Of avanafil users (n = 39), no differences in total IIEF or subdomain scores were observed after adjusting for confounders. However, avanafil users less often declared its use without an ED diagnosis and a physician prescription. Overall, the latter condition was associated with higher PDE5i-related satisfaction. CONCLUSION: The survey shows 2 different attitudes toward ED and PDE5i use: for recreational use and without a medical prescription or with a formal diagnosis and medical prescription. Avanafil, a 2nd-generation PDE5i with a good balance between efficacy and tolerability profile, is more frequently prescribed by doctors than self prescribed compared with other PDE5is. Because the major challenge is to decrease the high dropout of 1st-generation PDE5is, further studies will be needed to clarify this topic. Corona G, Maggi M, Jannini EA. EDEUS, a Real-Life Study on the Users of Phosphodiesterase Type 5 Inhibitors: Prevalence, Perceptions, and Health Care-Seeking Behavior Among European Men With a Focus on 2nd-Generation Avanafil. Sex Med 2018;6:15-23. PMID- 29275959 TI - mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis. AB - Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt proliferation and regeneration, CDK4/6 dependently. This triggers interleukin (IL)-6-associated reparative inflammation, inducing crypt hyper-proliferation, wound healing, and CRC. Blocking IL-6 signaling or reactivating mTORC1 reduces inflammation-induced CRC, so mTORC1 activation suppresses tumorigenesis in IBD. Conversely, mTORC1 inactivation is beneficial in APC loss-dependent CRC. Thus, IL 6 blockers or protein-rich-diet-linked mTORC1 activation may prevent IBD associated CRC. However, abolishing mTORC1 can mitigate CRC in predisposed patients with APC mutations. Our work reveals mTORC1 oncogenic and tumor suppressive roles in intestinal epithelium and avenues to optimized and personalized therapeutic regimens for CRC. PMID- 29275960 TI - Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction. AB - Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr /- mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr-/- mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics. PMID- 29275961 TI - mTORC1 Signaling: A Double-Edged Sword in Diabetic beta Cells. AB - The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of metabolic and nutrient cues that integrates environmental inputs into downstream signaling pathways to control cellular metabolism, growth, and survival. While numerous in vitro and in vivo studies reported the positive functions of mTORC1 in the regulation of beta cell survival and proliferation under physiological conditions, more recent work demonstrates the opposite in the long term; this is exemplified by the constitutive inappropriate hyper-activation of mTORC1 in diabetic islets or beta cells under conditions of increased beta cell stress and metabolic demands. These recent findings uncover mTORC1's importance as an emerging significant player in the development and progression of beta cell failure in type 2 diabetes and suggest that mTORC1 may act as a "double edge sword" in the regulation of beta cell mass and function in response to metabolic stress such as nutrient overload and insulin resistance. PMID- 29275962 TI - Fluoroquinolone-Related Neuropsychiatric Events in Hospitalized Veterans. AB - OBJECTIVE: To measure the incidence and risk factors for fluoroquinolone (ciprofloxacin, moxifloxacin, and levofloxacin)-associated psychosis or delirium in a veteran population. METHODS: A retrospective study was conducted in the Western New York Veterans Affairs Health System (2005-2013). Participants were hospitalized veterans receiving a fluoroquinolone for at least 48 hours (n = 631). Cases of delirium or psychosis were defined by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, and the Naranjo scale (score >= 1) was used to determine the probability of the adverse drug reaction being related to fluoroquinolones. A bivariate analysis of covariates followed by a multivariate logistic regression was used to determine predisposing factors to the development of delirium/psychosis. RESULTS: The mean age of the population was 71.5 years (range: 22-95). Fluoroquinolone-associated delirium/psychosis occurred in 3.7% of the inpatients studied (n = 23). The median Naranjo score was 3 indicating a possible association. Psychosis/delirium occurred in 3.6% of ciprofloxacin-treated patients (n = 14/391), 4.5% of patients-treated with moxifloxacin (n = 9/200), and 0% of those receiving levofloxacin (n = 0/40); p = 0.4. Significant risk factors for development of delirium/psychosis in patients receiving a fluoroquinolone in the multivariate logistical regression included typical antipsychotic use (OR, 5.4; 95% CI: 1.4-16.7) and age. A 10-year increase in age was associated with a 1.8-fold greater odds of a neuropsychiatric event. CONCLUSIONS: Fluoroquinolones may be more commonly associated with delirium/psychosis than originally reported in this veteran population. Caution should be used when prescribing a fluoroquinolone for patients on typical antipsychotics and those of advanced age. PMID- 29275963 TI - QT Prolongation, Torsades de Pointes, and Psychotropic Medications: A 5-Year Update. AB - BACKGROUND: Some psychotropic medications have been associated with prolongation of the QT interval and QT prolongation, especially in those with medical illness, and are linked to lethal ventricular arrhythmias, such as Torsades de Pointes (TdP). In 2013, we published a review of QT prolongation, TdP, and psychotropic medications. OBJECTIVE: We provide an update over the past 5 years on the specific concerns most relevant to clinicians who see medically ill patients. METHODS: In this nonsystematic review, we aimed to carefully and intensively identify new articles by utilizing a structured PubMed search from 2012-present. RESULTS: QT prolongation remains an imperfect, though well-established marker of risk for TdP. Among antidepressant medications, citalopram does appear to prolong the QT interval more than other selective serotonin reuptake inhibitors, though the clinical significance of this prolongation remains unclear. Escitalopram appears to prolong the QT interval to a lesser extent. Haloperidol carries a risk for QT prolongation, but the assertion that intravenous haloperidol is inherently riskier may be confounded by its primary use in medically ill populations. Among atypical antipsychotic agents, ziprasidone-and possibly iloperidone-is associated with the greatest QT prolongation, whereas aripiprazole appears safest from this standpoint. CONCLUSIONS: The evidence for clinically meaningful QT prolongation with most classes of psychiatric agents remains minimal. The most important risk reducing intervention clinicians can make is undertaking a careful analysis of other QT risk factors when prescribing psychiatric medications. PMID- 29275964 TI - Fontan Palliation for Single-Ventricle Physiology: Perioperative Management for Noncardiac Surgery and Analysis of Outcomes. PMID- 29275965 TI - Restrictive Versus Liberal Transfusion Strategies in Perioperative Blood Management: An Evidence-Based Analysis. PMID- 29275966 TI - Corrections. PMID- 29275967 TI - Effectiveness and safety of varenicline and nicotine replacement therapy among mental health patients: A retrospective cohort study. AB - OBJECTIVE: To analyse the effectiveness and safety of two smoking cessation medications (varenicline and nicotine patches) in patients with controlled psychiatric disorders in daily practice in a Smoking Cessation Service. METHODS: This is a retrospective cohort study. It was carried on at a smoking cessation clinic in Madrid and used a convenience sampling strategy. We reviewed medical records of patients diagnosed with psychiatric disorders who attended a Smoking Cessation Service. All patients received similar treatment programme: a combination of pharmacological treatment (varenicline or nicotine replacement therapy) and intensive cognitive-behavioural therapy. RESULTS: The group included 349 patients (38.4% men). Mean age (SD) 49.6 (10.5) years. 28.3 (12.8) cigarettes per day. 156 subjects achieved 9-24 weeks continuous abstinence (44.7%), in 39% of those who used nicotine patches and in 53.7% of those who used varenicline. OR: 1.64 (95% CI: 1.03-2.61; p=0.036). Success rates were higher in men; OR 1.85 (95% CI: 1.12-3.04; p=0.016). High levels of CO and high daily cigarette use were associated with poorer success rates (OR: 0.98, 95% CI: 0.96-0.99, p=0.007; and OR: 0.98, 95% CI: 0.96-1.00, p=0.045), respectively. Nausea and pruritus were the most common adverse events. No cases of suicidal ideation or behaviour were found. CONCLUSIONS: Varenicline and nicotine patches could be safe and effective smoking cessation treatments for patients with psychiatric disorders in daily clinical practice. PMID- 29275968 TI - Tuberculosis, social determinants and co-morbidities (including HIV). AB - The risk of exposure, progression to active tuberculosis (TB) and then to cure is a process affected by several risk factors. Along with well known risk factors such as human immunodeficiency virus (HIV), use of immunosuppressive drugs and being of young age, emerging risk factors such socio-economic and behavioral aspects play a significant role in increasing the susceptibility to infection, and unsuccessful treatment outcomes. This paper summarizes the effects of these socio-economic determinants and co-morbidities (including HIV) on TB infection and disease. PMID- 29275969 TI - Mobile applications in children with cerebral palsy. AB - INTRODUCTION: Cerebral palsy (CP) is one of the most common developmental disorders. Technological development has enabled a transformation of the healthcare sector, which can offer more individualised, participatory, and preventive services. Within this context of new technology applied to the healthcare sector, mobile applications, or apps, constitute a very promising tool for the management of children with CP. OBJECTIVE: The purpose of this article is to perform a systematic review of the information published about various mobile applications either directly related to CP or with potential to be useful in the context of the disease, and to describe, analyse, and classify these applications. MATERIAL AND METHODS: A literature search was carried out to gather articles published in English or Spanish between 2011 and 2017 which presented, analysed, or validated applications either specifically designed or potentially useful for CP. Furthermore, a search for mobile applications was conducted in the main mobile application markets. CONCLUSIONS: A total of 63 applications were found in biomedical databases and mobile application markets, of which 40 were potentially useful for CP and 23 were specifically designed for the condition (11 for information, 3 for evaluation, and 9 for treatment). There are numerous mobile applications either specifically designed for or with potential to be useful in the field of CP. However, despite the existing scientific evidence, the low methodological quality of scientific articles makes it impossible to generalise the use of these tools. PMID- 29275970 TI - Dorfman-Chanarin syndrome in adult patient of southern Tunisia. PMID- 29275971 TI - [Monoarthritis in Neisseria meningitidis: What instructions for contact people?] PMID- 29275972 TI - [Focus: Drug-related osteonecrosis of the jaw]. AB - Antiresorptives and antiangiogenics are treatments that have proven effective in oncology and the treatment of osteoporosis and they are increasingly prescribed. The care of these patients requires collaboration between the prescriber and the oral health professional to establish an optimized treatment plan. Therapeutic education of the patient is essential for him to understand the issues of good oral health and the adverse effects that can be caused by these treatments. The management is essentially based on the individual benefit/risk balance resulting from the general, local and inherent of the molecule risk factors. Management of drug-related osteonecrosis of the jaw should be as early as possible. PMID- 29275973 TI - Discussion. PMID- 29275974 TI - Implementation of prospective, surgeon-driven, risk-based pathway for pancreatoduodenectomy results in improved clinical outcomes and first year cost savings of $1 million. AB - BACKGROUND: Morbidity and costs after pancreatoduodenectomy remain increased, driven by postoperative pancreatic fistula (POPF). A risk-based pathway for pancreatoduodenectomy (RBP-PD) was implemented and the clinical and cost outcomes compared with that of our historic practice. METHODS: Prospective clinical and cost outcomes for our RBP-PD cohort treated from September 2014 to September 2015 were compared with a previously published cohort of pancreatoduodenectomies from January 2007 to February 2014. RESULTS: A total of 128 RBP-PD cases were compared with 808 historic controls. Apart from less blood loss, there were no significant clinical differences between the 2 groups. Overall POPF rate did not change. Average duration of stay decreased to 10 days from 12 (P < .001) despite similar readmission rates. Postsurgical interventional radiology procedures decreased to 18.0% from 26.4% (P = .048). Utilization of and duration of stay in monitored care decreased to 23.4% from 35.6% (P < .01) and to 1 day from 3 (P < .01). On multivariable analysis RBP-PD was independently associated with decreased odds of higher postoperative pancreatic fistula grade, monitored care, and prolonged duration of stay. Inpatient cost of care decreased $6,387 per patient (-11.1%, P = .016), and total 30-day costs decreased $8,565 per patient (-13.7%, P = .01), representing a total 30-day cost savings of $1.1 million. CONCLUSION: RBP-PD significantly improved patient outcomes, decreased costs of care, and likely has applicability for surgical care beyond pancreatoduodenectomy. PMID- 29275976 TI - Discussion. PMID- 29275975 TI - Daily review of AHRQ patient safety indicators has important impact on value based purchasing, reimbursement, and performance scores. AB - BACKGROUND: The Patient Safety Indicators (PSIs) Composite (PSI 90) of the Agency for Healthcare Research and Quality has been found to have low positive predictive values. Because scores can affect hospital reimbursement and ranking, our institution designed a review process to ensure accurate data and incur minimal penalties under the Hospital Value-Based Purchasing Program. METHODS: A multidisciplinary team was assembled to review PSI 90 within a performance period. The positive predictive value of each PSI was calculated. Weight-adjusted PSI rates were used to recalculate the PSI 90 Performance Period Index Value (PPIV). The adjusted PPIV was used to estimate what the achievement points and financial impact would have been if PSI review had not been implemented. Differences in PPIV, achievement points, and financial impact before and after PSI review were calculated. RESULTS: A total of 1,470 cases were flagged for PSI over a 2-year period. The positive predictive value was 63.3%. Refuting 36.7% of PSIs resulted in a decrease in the PPIV from 0.696 to 0.508, an increase in achievement points from 5 to 10, resulting in a decreased net loss of $111,773. CONCLUSION: Multidisciplinary review processes are practical and effective in identifying false-positive patient safety events. The real-time process affects hospital performance and resultant Medicare reimbursement substantially. PMID- 29275978 TI - Refining the use of MRI to predict multiple sclerosis. PMID- 29275977 TI - Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. AB - The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers. PMID- 29275980 TI - Diagnosing multiple sclerosis: art and science. PMID- 29275979 TI - Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. AB - BACKGROUND: In 2016, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network proposed modifications to the MRI criteria to define dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis in patients with clinically isolated syndrome (CIS). Changes to the DIS definition included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested. We compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for multiple sclerosis diagnosis in a large multicentre cohort of patients with CIS to provide evidence to guide revisions of multiple sclerosis diagnostic criteria. METHODS: Brain and spinal cord MRI and optic nerve assessments from patients with typical CIS suggestive of multiple sclerosis done less than 3 months from clinical onset in eight European multiple sclerosis centres were included in this retrospective study. Eligible patients were 16-60 years, and had a first CIS suggestive of CNS demyelination and typical of relapsing-remitting multiple sclerosis, a complete neurological examination, a baseline brain and spinal cord MRI scan obtained less than 3 months from clinical onset, and a follow-up brain scan obtained less than 12 months from CIS onset. We recorded occurrence of a second clinical attack (clinically definite multiple sclerosis) at months 36 and 60. We evaluated MRI criteria performance for DIS, DIT, and DIS plus DIT with a time-dependent receiver operating characteristic curve analysis. FINDINGS: Between June 16, 1995, and Jan 27, 2017, 571 patients with CIS were screened, of whom 368 met all study inclusion criteria. At the last evaluation (median 50.0 months [IQR 27.0-78.4]), 189 (51%) of 368 patients developed clinically definite multiple sclerosis. At 36 months, the two DIS criteria showed high sensitivity (2010 McDonald 0.91 [95% CI 0.85-0.94] and 2016 MAGNIMS 0.93 [0.88-0.96]), similar specificity (0.33 [0.25-0.42] and 0.32 [0.24-0.41]), and similar area under the curve values (AUC; 0.62 [0.57-0.67] and 0.63 [0.58-0.67]). Performance was not affected by inclusion of symptomatic lesions (sensitivity 0.92 [0.87 0.96], specificity 0.31 [0.23-0.40], AUC 0.62 [0.57-0.66]) or cortical lesions (sensitivity 0.92 [0.87-0.95], specificity 0.32 [0.24-0.41], AUC 0.62 [0.57 0.67]). Requirement of three periventricular lesions resulted in slightly lower sensitivity (0.85 [0.78-0.90], slightly higher specificity (0.40 [0.32-0.50], and similar AUC (0.63 [0.57-0.68]). Inclusion of optic nerve evaluation resulted in similar sensitivity (0.92 [0.87-0.96]), and slightly lower specificity (0.26 [0.18-0.34]) and AUC (0.59 [0.55-0.64]). AUC values were also similar for DIT (2010 McDonald 0.61 [0.55-0.67] and 2016 MAGNIMS 0.61 [0.55-0.66]) and DIS plus DIT (0.62 [0.56-0.67] and 0.64 [0.58-0.69]). INTERPRETATION: The 2016 MAGNIMS criteria showed similar accuracy to the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis. Inclusion of symptomatic lesions is expected to simplify the clinical use of MRI criteria without reducing accuracy, and our findings suggest that needing three lesions to define periventricular involvement might slightly increase specificity, suggesting that these two factors could be considered during further revisions of multiple sclerosis diagnostic criteria. FUNDING: UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Dutch MS Research Foundation. PMID- 29275981 TI - Evaluation by undergraduate medical students of a role-playing training program on the management of acute states of agitation. AB - OBJECTIVES: Acute states of agitation (ASAs) are frequent in daily medical practice. However, training on real ASAs raises technical and ethical issues, whereas lecture-based teaching hardly addresses some educational objectives, e.g., improving relational skills and team-based coordination. Simulation-based medical education (SBME) is a promising medium to train students on managing ASAs. We have recently implemented a role-playing training module on ASAs. In this scenario, four to five students play the role of the staff, while a trained professional actor plays the agitated patient. A subsequent standardized debriefing is conducted by a senior psychiatrist. A first wave of 219 students participated in a one-session training of this ASA module in June 2015. They completed pre-session and post-session questionnaires aiming to collect "proof-of concept" data. METHODS: The pre-session questionnaire investigated: previous experience of ASA among students during their clinical training; previous participation in a role-playing SBME; and perceived knowledge of the good practice rules for managing ASAs. The post-session questionnaire investigated among the students if: they thought having been able to appropriately manage the simulated ASA; they found the SBME medium more fitted for training than real situations; they found that the SBME session faithfully reproduced a real ASA; and the session was found useful for transmitting the skills on correct management of ASA. The average level of stress induced by the training was assessed using a numerical rating scale (0-10). RESULTS: Two hundred and six of the 219 students completed the pre-session questionnaire (63% females; response rate 96.7%). A hundred and thirty four students played the scenario and completed the post-session questionnaire (65.7% females; response rate 100%). 38.3% of the responders reported having previously experienced a situation of ASA in their practice, and 31.1% deemed to know the good practices rules for managing an ASA. In post-session, 29.9% of the participants considered that they appropriately managed the ASA, 79.9% deemed that the role-playing session faithfully reproduced a real ASA, and 97% deemed that this SBME was more fitted and useful than a real clinical situation to improve their medical skills. Bivariate analyses revealed that the post-session responses and level of stress were not influenced by previous experience on ASA, previous participation in a SBME role-playing session, or thinking to know the rules for managing ASAs. CONCLUSION: SBME role playing training appears a promising, realistic, and well-accepted method for teaching the management of ASA. PMID- 29275982 TI - Mechanisms Are Causes, Not Components: A Response to Connolly et al. PMID- 29275983 TI - The Association of Vitamin D Status in Lower Extremity Muscle Strains and Core Muscle Injuries at the National Football League Combine. AB - PURPOSE: To evaluate the association between serum vitamin D level and the prevalence of lower extremity muscle strains and core muscle injuries in elite level athletes at the National Football League (NFL) combine. METHODS: During the 2015 NFL combine, all athletes with available serum vitamin D levels were included for study. Baseline data were collected, including age, race, body mass index, position, injury history specific to lower extremity muscle strain or core muscle injury, and Functional Movement Screen scores. Serum 25-hydroxyvitamin D was collected and defined as normal (>=32 ng/mL), insufficient (20-31 ng/mL), and deficient (<20 ng/mL). Univariate regression analysis was used to examine the association of vitamin D level and injury history. Subsequent multivariate regression analysis was used to examine this relation with adjustment for collected baseline data variables. RESULTS: The study population included 214 athletes, including 78% African American athletes and 51% skilled position players. Inadequate vitamin D was present in 59%, including 10% with deficient levels. Lower extremity muscle strain or core muscle injury was present in 50% of athletes, which was associated with lower vitamin D levels (P = .03). Athletes with a positive injury history also showed significantly lower vitamin D levels as compared with uninjured athletes (P = .03). African American/black race (P < .001) and injury history (P < .001) was associated with lower vitamin D. Vitamin D groups showed no differences in age (P = .9), body mass index (P = .9), or Functional Movement Screen testing (P = .2). Univariate analysis of inadequate vitamin D levels showed a 1.86 higher odds of lower extremity strain or core muscle injury (P = .03), and 3.61 higher odds of hamstring injury (P < .001). Multivariate analysis did not reach an independent association of low vitamin D with injury history (P = .07). CONCLUSIONS: Inadequate vitamin D levels are a widespread finding in athletes at the NFL combine. Players with a history of lower extremity muscle strain and core muscle injury had a higher prevalence of inadequate vitamin D. LEVEL OF EVIDENCE: Level IV, retrospective study-case series. PMID- 29275984 TI - Independent Suture Tape Reinforcement of Small and Standard Diameter Grafts for Anterior Cruciate Ligament Reconstruction: A Biomechanical Full Construct Model. AB - PURPOSE: To compare the dynamic elongation, stiffness behavior, and ultimate failure load of standard with small diameter soft tissue grafts for anterior cruciate ligament (ACL) reconstruction with and without high-strength suture tape reinforcement. METHODS: Both a tripled "small" diameter and a "standard" quadrupled tendon graft with and without suture tape reinforcement were tested using suspensory fixation (n = 8 each group). The suture tape was passed through the suspensory fixation button on the femur and tibia to ensure independent (safety belt) fixation from the graft in vitro. The testing of the constructs included position-controlled cyclic loading, force-controlled cyclic loading at 250 N and 400 N as well as pull to failure (50 mm/min). RESULTS: Reinforcement of a small diameter graft significantly reduced dynamic elongation of 38% (1.46 +/- 0.28 mm vs 2.34 +/- 0.44 mm, P < .001) and 50% (2.55 +/- 0.44 mm vs 5.06 +/- 0.67 mm, P < .001) after the 250 N and 400 N load protocol, respectively. Reinforcement of a standard diameter tendon graft decreased dynamic elongation of 15% (1.59 +/- 0.34 mm vs 1.86 +/- 0.17 mm, P = .066) and 26% (2.62 +/- 0.44 mm vs 3.55 +/- 0.44 mm, P < .001). No significant difference was found between both reinforced models. The ultimate failure loads of small and standard diameter reinforced grafts were 1592 +/- 105 N and 1585 +/- 265 N, resulting in a 64% (P < .001) and 40% (P < .001) increase compared with their respective controls. CONCLUSIONS: Independent suture tape reinforcement of soft tissue grafts for ACL reconstruction leads to significantly reduced elongation and higher ultimate failure load according to in vivo native ACL function data without stress shielding the soft tissue graft. CLINICAL RELEVANCE: If in vitro results are translational to human knees in vivo, the suture tape reinforcement technique for ACL reconstruction may decrease the risk of graft tears, particularly in the case of small diameter soft tissue grafts. PMID- 29275985 TI - Echocardiographic Imaging for Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement has become an accepted alternative to surgery for patients with severe, symptomatic aortic stenosis who are inoperable or are at high surgical risk. Recent trials support the use of transcatheter aortic valve replacement also in patients at intermediate risk, and ongoing trials are assessing appropriateness in other patient groups. The authors review the key anatomic features integral to the transcatheter aortic valve replacement procedure and the echocardiographic imaging required for preprocedural, intraprocedural, and postprocedural assessment. PMID- 29275986 TI - Normal Reference Ranges for Transthoracic Echocardiography Following Heart Transplantation. AB - BACKGROUND: Heart function following heart transplantation (HTx) is influenced by numerous factors. It is typically evaluated using transthoracic echocardiography, but reference values are currently unavailable for this context. The primary aim of the present study was to derive echocardiographic reference values for chamber size and function, including cardiac mechanics, in clinically stable HTx patients. METHODS: The study enrolled 124 healthy HTx patients examined prospectively. Patients underwent comprehensive two-dimensional echocardiographic examinations according to contemporary guidelines. Results were compared with recognized reference values for healthy subjects. RESULTS: Compared with guidelines, larger atrial dimensions were seen in HTx patients. Left ventricular (LV) diastolic volume was smaller, and LV wall thickness was increased. With respect to LV function, both ejection fraction (62 +/- 7%, P < .01) and global longitudinal strain (-16.5 +/- 3.3%, P < .0001) were lower. All measures of right ventricular (RV) size were greater than reference values (P < .0001), and all measures of RV function were reduced (tricuspid annular plane systolic excursion 15 +/- 4 mm [P < .0001], RV systolic tissue Doppler velocity 10 +/- 6 cm/sec [P < .0001], fractional area change 40 +/- 8% [P < .0001], and RV free wall strain 16.9 +/- 4.2% [P < .0001]). Ejection fraction and LV global longitudinal strain were significantly lower in patients with previous rejection. CONCLUSION: The findings of this study indicate that the distribution of routinely used echocardiographic measures differs between stable HTx patients and healthy subjects. In particular, markedly larger RV and atrial volumes and mild reductions in both LV and RV longitudinal strain were evident. The observed differences could be clinically relevant in the assessment of HTx patients, and specific reference values should be applied in this context. PMID- 29275987 TI - Influence of hydrocarbon-stapling on membrane interactions of synthetic antimicrobial peptides. AB - Cyclization has been recognized as a valuable technique for increasing the efficacy of small molecule and peptide therapeutics. Here we report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart. The previously-described CAP, 6K-F17 (KKKKKK-AAFAAWAAFAA-NH2) was used as the backbone for incorporation of an i to i + 4 helical hydrocarbon staple through olefin ring closing metathesis. Stapled versions of 6K-F17 showed an increase in non-selective membrane interaction, where the staple itself enhances the degree of membrane interaction and rate of cell death while maintaining high potency against bacterial membranes. However, the higher averaged hydrophobicity imparted by the staple also significantly increases toxicity to mammalian cells. This deleterious effect is countered through stepwise reduction of the stapled 6K-F17's backbone hydrophobicity through polar amino acid substitutions. Circular dichroism assessment of secondary structure in various bacterial membrane mimetics reveals that a helical structure may improve - but is not an absolute requirement for - antimicrobial activity of 6K-F17. Further, phosphorus-31 static solid state NMR spectra revealed that both non-toxic stapled and linear peptides bind bacterial membranes in a similar manner that does not involve a detergent-like mechanism of lipid removal. The overall results suggest that the technique of hydrocarbon stapling can be readily applied to membrane-interactive CAPs to modulate how they interact and target biological membranes. PMID- 29275988 TI - Impact of live attenuated influenza vaccination programme for healthy children in Northern Ireland: A comparison of seven influenza seasons, 2010/11-2016/17. AB - Seasonal influenza vaccination for healthy children was introduced in Northern Ireland in the 2013/14 flu season, with an initial pilot year involving two specific cohorts, followed by rollout to all children aged 4-11 years in subsequent seasons. This study aimed to examine the impact of that programme on the burden of flu in primary care over the study period 2010/11-2016/17. Two routine indicators were used to measure impact - GP in-hour consultations and out of-hour calls for influenza and influenza-like-illness (ILI). Analysis was conducted overall and stratified by age; rates in children under 14 years of age to measure direct impact and rates in individuals 14 years and over to measure indirect impact. Seven influenza seasons were included, three pre-programme seasons (2010/11-2012/13: phase 0), one pilot season (2013/14: phase 1), and three post-programme seasons (2014/15-2016/17: phase 2). High uptake of vaccination was observed from the programme introduction, with consistent uptake of over 50% in pre-school age groups and over 75% in primary school age groups. Statistically significant reductions were found in GP in-hours consultations and in out-of-hour calls in phase 2 compared to phase 0, both overall (GP in-hours RR 0.61, 95% CI 0.38-0.98, p = .040; out-of-hours RR 0.51, 95% CI 0.27-0.97, p = .041) and in the under 14 years group (GP in-hours RR 0.38, 95% CI 0.19-0.75, p = .006; out-of-hours RR 0.39, 95% CI 0.19-0.83, p = .014). Our results suggest that there have been reductions in the burden of flu in primary care settings overall and in children aged under 14 years in the seasons since the introduction of healthy children influenza vaccination. Further seasons should be added to subsequent analyses to strengthen this evidence. PMID- 29275989 TI - Influenza vaccination in early pregnancy. PMID- 29275990 TI - Octogenarians' post-acute care use after cardiac valve surgery and recovery: clinical implications. AB - Octogenarians receiving cardiac valve surgery is increasing and recovery is challenging. Post-acute care (PAC) services assist with recovery, yet services provided in facilities do not provide adequate cardiac-focused care or long-term self-management support. The purpose of the paper was to report post-acute care discharge rates in octogenarians and propose clinical implications to improve PAC services. Using a 2003 Medicare Part A database, we studied post-acute care service use in octogenarians after cardiac valve surgery. We propose expansion of the Geriatric Cardiac Care model to include broader clinical therapy dynamics. The sample (n = 10,062) included patients over 80 years discharged from acute care following valve surgery. Post-acute care services were used by 68% of octagarians following cardiac valve surgery (1% intermediate rehabilitation, 35% skilled nursing facility, 32% home health). The large percentage of octagarians using PAC point to the importance of integrating geriatric cardiac care into post acute services to optimize recovery outcomes. PMID- 29275991 TI - Phytochrome A Negatively Regulates the Shade Avoidance Response by Increasing Auxin/Indole Acidic Acid Protein Stability. AB - The reduction in the red to far-red light ratio (R/FR) and photosynthetically active radiation caused by dense planting initiates shade avoidance responses (SARs) to help plants compete against their neighbors. However, deep shade attenuates shade-induced stem elongation to suppress excessive reversion toward skotomorphogenic development, in which photoreceptor phytochrome A (PHYA) has been known to play the major role. However, the molecular mechanism underlying PHYA function in deep shade is poorly understood. Here, we report that shade accumulated PHYA can release auxin/indole-3-acetic acid (AUX/IAA), suppressors in the auxin signaling pathway, from SCFTIR1, an auxin receptor, to weaken auxin signaling and negatively regulate shade response. Corroborating this, phyA mutants display an enhanced auxin response to deep shade and auxin treatment. Specifically, PHYA competes with TIR1 by directly binding and stabilizing AUX/IAA. Our findings illustrate a mechanistic model of how plants sense different shade levels to fine-tune auxin signaling and generate appropriate SAR. PMID- 29275992 TI - Variation in Splicing Efficiency Underlies Morphological Evolution in Capsella. AB - Understanding the molecular basis of morphological change remains a central challenge in evolutionary-developmental biology. The transition from outbreeding to selfing is often associated with a dramatic reduction in reproductive structures and functions, such as the loss of attractive pheromones in hermaphroditic Caenorhabditis elegans and a reduced flower size in plants. Here, we demonstrate that variation in the level of the brassinosteroid-biosynthesis enzyme CYP724A1 contributes to the reduced flower size of selfing Capsella rubella compared with its outbreeding ancestor Capsella grandiflora. The primary transcript of the C. rubella allele is spliced more efficiently than that of C. grandiflora, resulting in higher brassinosteroid levels. These restrict organ growth by limiting cell proliferation. More efficient splicing of the C. rubella allele results from two de novo mutations in the selfing lineage. Thus, our results highlight the potentially widespread importance of differential splicing efficiency and higher-than-optimal hormone levels in generating phenotypic variation. PMID- 29275993 TI - Long-Range Signaling Activation and Local Inhibition Separate the Mesoderm and Endoderm Lineages. AB - Specification of the three germ layers by graded Nodal signaling has long been seen as a paradigm for patterning through a single morphogen gradient. However, by exploiting the unique properties of the zebrafish embryo to capture the dynamics of signaling and cell fate allocation, we now demonstrate that Nodal functions in an incoherent feedforward loop, together with Fgf, to determine the pattern of endoderm and mesoderm specification. We show that Nodal induces long range Fgf signaling while simultaneously inducing the cell-autonomous Fgf signaling inhibitor Dusp4 within the first two cell tiers from the margin. The consequent attenuation of Fgf signaling in these cells allows specification of endoderm progenitors, while the cells further from the margin, which receive Nodal and/or Fgf signaling, are specified as mesoderm. This elegant model demonstrates the necessity of feedforward and feedback interactions between multiple signaling pathways for providing cells with temporal and positional information. PMID- 29275995 TI - Effect of parental history of diabetes on markers of inflammation, insulin resistance and atherosclerosis in first degree relatives of patients with type 2 diabetes mellitus. AB - AIM AND OBJECTIVE: To study the effect of parental history of diabetes on markers of inflammation, insulin resistance, adiposity indices and carotid intima media thickness (cIMT) in first degree relatives of patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Normal glucose tolerant (NGT) first degree relatives of T2DM patients of age group 20-40 years designated as FHpositive were enrolled in the cross sectional study. Depending on the parental history of diabetes they were divided into three groups: family history positive in father (FHfather), family history positive in mother (FHmother) and family history positive in both (FHboth). Age, sex and BMI matched controls without any history of diabetes in their parents designated as FHnegative were taken for comparison. All subjects underwent detailed clinical evaluation and biochemical investigations. cIMT and adiposity indices like visceral adipose tissue thickness (VAT) and subcutaneous adipose tissue thickness (SAT) were assessed using ultrasonography. RESULTS: No difference existed with regards to BMI, hsCRP, degree of insulin resistance, adiposity markers and cIMT between FHmother and FHfather group. Subjects in FHboth group had significantly higher degree of insulin resistance, subclinical inflammation, increased atherosclerosis and adiposity indices in contrast to those who have a single parent T2DM family history. CONCLUSIONS: hsCRP and cIMT are significantly higher in the first degree relatives of type2 diabetes mellitus patients than controls. Individuals with history of T2DM in both parents have significantly worse glycemic status, increased cIMT and adverse cardiovascular risk profile than those with T2DM history in only single parent. PMID- 29275994 TI - A Proximity Labeling Strategy Provides Insights into the Composition and Dynamics of Lipid Droplet Proteomes. AB - Lipid droplet (LD) functions are regulated by a complement of integral and peripheral proteins that associate with the bounding LD phospholipid monolayer. Defining the composition of the LD proteome has remained a challenge due to the presence of contaminating proteins in LD-enriched buoyant fractions. To overcome this limitation, we developed a proximity labeling strategy that exploits LD targeted APEX2 to biotinylate LD proteins in living cells. Application of this approach to two different cell types identified the vast majority of previously validated LD proteins, excluded common contaminating proteins, and revealed new LD proteins. Moreover, quantitative analysis of LD proteome dynamics uncovered a role for endoplasmic reticulum-associated degradation in controlling the composition of the LD proteome. These data provide an important resource for future LD studies and demonstrate the utility of proximity labeling to study the regulation of LD proteomes. PMID- 29275996 TI - How to measure monetary losses in gambling disorder? An evidence-based refinement. AB - Diverse monetary measures have been utilized across different studies in gambling disorder (GD). However, there are limited evidence-based proposals regarding the best way to assess financial losses. We investigated how different variables of monetary losses correlate with validated assessments of gambling severity and overall functioning in a large sample of subjects with GD (n = 436). We found that relative monetary variables (i.e. when financial losses were evaluated in relation to personal income) showed the most robust correlations with gambling severity and overall psychosocial functioning. Percentage of monthly income lost from gambling was the variable with the best performance. PMID- 29275997 TI - Muscle dysmorphia and the great dilemma for anabolic-androgenic steroid abuse. PMID- 29275998 TI - Does Early Coronary Angiography Improve Survival After out-of-Hospital Cardiac Arrest? A Systematic Review With Meta-Analysis. AB - BACKGROUND: In patients with out-of-hospital cardiac arrest who achieve return of spontaneous circulation, coronary angiography (CAG) might improve outcomes. We conducted a systematic review and meta-analysis to elucidate the benefit and optimal timing of early CAG in comatose out-of-hospital cardiac arrest patients with return of spontaneous circulation. METHODS: We searched MEDLINE, EMBASE, and Cochrane from 1990 to May 2017. Studies reporting survival and/or neurological survival in early (< 24-hour) vs late/no CAG were selected. We used the Clinical Advances Through Research and Information Translation (CLARITY) risk of bias in cohort studies tool and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria to assess risk of bias and quality of evidence, respectively. Results were pooled using random effects and presented as risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: After screening 9185 titles/abstracts and 631 full-text articles, we included 23 nonrandomized studies. Short (to discharge or 30 days) and long-term (1-5 years) survival were significantly improved (52% and 56%, respectively) in the early < 24-hour CAG group compared with the late/no CAG group (RR, 1.52; 95% CI, 1.32-1.74; P < 0.00001; I2, 94% and RR, 1.56; 95% CI, 1.14-2.14; P = 0.006; I2, 86%). Survival with good neurological outcome was also improved by 69% in the < 24-hour CAG group at short- (RR, 1.69; 95% CI, 1.40-2.04; P < 0.00001; I2, 93%) and intermediate-term (3-11 months; RR, 1.49; 95% CI, 1.27-1.76; P < 0.00001; I2, 67%). We found consistent benefits in the < 2-hour and < 6-hour subgroups. Early CAG was associated with significantly better outcomes in studies of patients without ST-elevation, but the results did not reach statistical significance in studies of patients with ST-elevation. CONCLUSIONS: On the basis of very low quality, but consistent evidence, early CAG (< 24 hours) was associated with significantly higher survival and better neurologic outcomes. PMID- 29275999 TI - MK2-TNF-Signaling Comes Full Circle. AB - MK2 (p38MAPK-activated protein kinase 2) is essential for tumor necrosis factor (TNF) biosynthesis, mainly operating by post-transcriptional regulation. Deletion of the gene encoding MK2 strongly reduced serum TNF and protected against endotoxic shock, demonstrating the positive role of p38MAPK/MK2 in TNF signaling at the level of ligand expression. Recent evidence indicates that MK2 directly phosphorylates the TNF receptor interactor RIPK1 and suppresses its activity, thereby limiting TNF-mediated apoptosis and necroptosis - pointing to a more complex, double-edged role of MK2 in TNF signaling. In addition, novel MK2 substrates have emerged in the DNA damage response, autophagy, and obesity, making MK2 a multifunctional kinase at the crossroads of stress response and cell death. We therefore propose a more general role of p38MAPK/MK2 signaling in the timely coordinated onset and resolution of inflammation and beyond. PMID- 29276000 TI - A standardized test to document cataplexy. AB - OBJECTIVE/BACKGROUND: Cataplexy is the pathognomonic symptom of narcolepsy type 1 (NT1). Since it is considered difficult to be directly observed or documented by clinicians, its diagnosis relies mainly on history taking. Our study aimed at testing the feasibility of a standardized video recording procedure under emotional stimulation to document cataplexy in the diagnostic work-up of suspected hypersomnia of central origin. PATIENTS/METHODS: Two-hundred-eight consecutive patients underwent the diagnostic work-up and reached the final diagnosis of NT1 (n = 133), idiopathic hypersomnia or narcolepsy type 2 (IH/NT2 group, n = 33), or subjective excessive daytime sleepiness (sEDS group, n = 42). All subjects underwent a standardized video recording procedure while watching funny movies selected according to individual preferences, and a technician blind to clinical features reviewed the recordings to identify hypotonic phenomena that were finally confirmed by patients. RESULTS: The video recording under emotional stimulation captured hypotonic phenomena in 72.2%, 9.1% and 4.8% of NT1, IH/NT2, and sEDS subjects (p < 0.0001), respectively. When tested against CSF hypocretin deficiency, the documentation of a hypotonic episode at the test showed an area under the ROC curve of 0.823 +/- 0.033 (p < 0.0001). NT1 patients under anticataplectic medications showed less frequently hypotonic episodes than untreated ones (48.0% vs 77.8%, p = 0.003). CONCLUSIONS: A standardized video recording procedure under emotional stimulation can help in the characterization of suspected hypersomnia of central origin. Further multi-center studies are warranted to extend the present findings and integrate a shared procedure for the laboratory work-up of narcolepsy. PMID- 29276001 TI - Response to "Prognosis in patients with obstructive sleep apnea with special reference to comorbidities and treatment of positive airway pressure". PMID- 29276002 TI - Intensity-based volumetric registration of magnetic resonance images and whole mount sections of the prostate. AB - OBJECTIVE: Magnetic Resonance Imaging (MRI) of the prostate provides useful in vivo diagnostic tissue information such as tumor location and aggressiveness, but ex vivo histopathology remains the ground truth. There are several challenges related to the registration of MRI to histopathology. We present a method for registration of standard clinical T2-weighted MRI (T2W-MRI) and transverse histopathology whole-mount (WM) sections of the prostate. METHODS: An isotropic volume stack was created from the WM sections using 2D rigid and deformable registration combined with linear interpolation. The prostate was segmented manually from the T2W-MRI volume and registered to the WM section volume using a combination of affine and deformable registration. The method was evaluated on a set of 12 patients who had undergone radical prostatectomy. Registration accuracy was assessed using volume overlap (Dice Coefficient, DC) and landmark distances. RESULTS: The DC was 0.94 for the whole prostate, 0.63 for the peripheral zone and 0.77 for the remaining gland. The landmark distances were on average 5.4 mm. CONCLUSION: The volume overlap for the whole prostate and remaining gland, as well as the landmark distances indicate good registration accuracy for the proposed method, and shows that it can be highly useful for registering clinical available MRI and WM sections of the prostate. PMID- 29276003 TI - "I Just Want to Do Everything Right:" Primiparous Women's Accounts of Early Breastfeeding via an App-Based Diary. AB - INTRODUCTION: Our objective was to describe the early breastfeeding experience of primiparous women. METHODS: Healthy, primiparous women intending to exclusively breastfeed downloaded a commercial infant feeding mobile application (app) during their postpartum hospitalization. Women free-texted breastfeeding thoughts and experiences through 8 weeks postpartum in the app's diary. Diary content was qualitatively coded. RESULTS: Thirty-five participants completed diaries and were included in analyses. The overarching theme was Seeking sustainability and validation. Mothers felt overwhelmed, anxious, and frustrated with the intensity and unpredictability of breastfeeding and inconsistent professional breastfeeding support. The ability to exclusively breastfeed was seen as a bellwether of maternal competence. Breastfeeding progress was primarily measured through external feedback (e.g., weight checks) and managed through strict adherence to provider feeding plans. As breastfeeding problems and intensity abated, women exhibited optimism and assumed greater independence in feeding decisions. DISCUSSION: The primiparous breastfeeding experience is fraught with internally imposed and externally reinforced pressure to produce and persevere despite inadequate breastfeeding support infrastructure. PMID- 29276004 TI - Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila. AB - Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development. PMID- 29276007 TI - Association between antioxidants and mild acute pancreatitis. AB - BACKGROUND AND STUDY AIMS: The mechanisms underlying acute pancreatitis have not been well elucidated. Over the last 20 years, there has been increasing awareness regarding the role played by oxidative stress in acute pancreatitis, but it is less well defined in human clinical trials. The aim of this study was to identify the relationship between antioxidants and acute pancreatitis. PATIENTS AND METHODS: We performed a cross-sectional trial on patients with mild acute pancreatitis. The study population consisted of 53 patients with mild acute pancreatitis and 55 healthy controls. Serum paraoxonase, arylesterase activity, total antioxidant status, total oxidant status and thiol levels were measured, and oxidative stress index was calculated. RESULTS: Paraoxonase, arylesterase activity, thiol and total antioxidant status levels were significantly lower in the acute pancreatitis group than in the control group (p = .024, p < .001, p < .001, p = .010, respectively). Oxidative stress index and total oxidant status levels were higher in the acute pancreatitis group than in the control group, but the difference was not statistically significant (p = .135, p = .253, respectively). CONCLUSIONS: This study demonstrates that decreased antioxidant levels are associated with mild acute pancreatitis. No association was observed between mild acute pancreatitis and total oxidant status. PMID- 29276008 TI - Altered kinematics of arm swing in Parkinson's disease patients indicates declines in gait under dual-task conditions. AB - OBJECTIVE: Declines in simultaneous performance of a cognitive and motor task are present in Parkinson's disease due to compromised basal ganglia function related to information processing. The aim of this project was to determine if biomechanical measures of arm swing could be used as a marker of gait function under dual-task conditions in Parkinson's disease patients. METHODS: Twenty-three patients with Parkinson's disease completed single and dual-task cognitive-motor tests while walking on a treadmill at a self-selected rate. Multiple cognitive domains were evaluated with five cognitive tests. Cognitive tests were completed in isolation (single-task) and simultaneously with gait (dual-task). Upper extremity biomechanical data were gathered using the Motek CAREN system. Primary outcomes characterizing arm swing were: path length, normalized jerk, coefficient of variation of arm swing time, and cognitive performance. RESULTS: Performance on the cognitive tasks were similar across single and dual-task conditions. However, biomechanical measures exhibited significant changes between single and dual-task conditions, with the greatest changes occurring in the most challenging conditions. Arm swing path length decreased significantly from single to dual task, with the greatest decrease of 21.16%. Jerk, characterizing smoothness, increased significantly when moving from single to dual-task conditions. CONCLUSION: The simultaneous performance of a cognitive and gait task resulted in decrements in arm swing while cognitive performance was maintained. Arm swing outcomes provide a sensitive measure of declines in gait function in Parkinson's disease under dual-task conditions. The quantification of arm swing is a feasible approach to identifying and evaluating gait related declines under dual-task conditions. PMID- 29276009 TI - Structure, electronic, optical and thermodynamic behavior on the polymerization of PMMA: A DFT investigation. AB - A density functional theory based scrutiny is implemented on the structure, electronic, optical and thermodynamic properties of the Poly (Methyl MethAcrylate) polymers (PMMA or nMMA; n = 1-5). The quantum chemical descriptors, e.g. HOMO-LUMO gap, ionization potential, chemical hardness, binding energies etc. of the PMMA polymers provides the measure for the structural and electronic properties. The parameters polarizability (alpha) and hyperpolarizability (beta) provides information for the non-linear optical (NLO) properties of the polymers. The absorption range of the PMMA polymer in the electromagnetic radiation spectrum during its growth is assessed by the UltraViolet-Visible (UV-vis) optical absorption spectra. To gain further insight on the origin of stability during the polymerization process, we have simulated frontier molecular orbitals (FMOs) and various thermodynamic properties, viz., entropy (S), enthalpy (H) and Gibbs free energy (G). PMID- 29276006 TI - WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. AB - Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ~70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways. PMID- 29276010 TI - Clinical gestalt versus prognostic scores for prognostication of patients with acute symptomatic pulmonary embolism. AB - BACKGROUND AND OBJECTIVE: To determine the accuracy of clinical gestalt to identify patients with acute symptomatic pulmonary embolism (PE) at low-risk for short-term complications. PATIENTS AND METHODS: This study included a total of 154 consecutive patients diagnosed with acute symptomatic PE in a tertiary university hospital. We compared the prognostic accuracy of the Pulmonary Embolism Severity Index (PESI), the simplified PESI (sPESI), and clinical gestalt of 1) 2senior physicians (one with and one without experience in the management of patients with PE), 2) a fourth-year resident of Pneumology, 3) a third-year resident of Pneumology, and 4) a second-year resident of Pneumology. The primary outcome was all-cause mortality during the first month after the diagnosis of PE. RESULTS: Thirty-day all-cause mortality was 8.4% (13/154; 8.4%; 95% confidence interval [CI], 4.1-12.8%). The PESI and clinical gestalt classified more patients as low-risk, compared to the sPESI (36.4%, 31.3% y 28.6%, respectively). There were no deaths in the sPESI low-risk category (negative predictive value 100%). Prognostic accuracy increased with increasing experience (84.6 vs. 92.3%; P=.049). CONCLUSIONS: The sPESI showed the best accuracy at correctly identifying low-risk patients with acute symptomatic PE. Clinical gestalt is not inferior to standardized clinical prediction rules to prognosticate patients with acute PE. PMID- 29276011 TI - Hypochromic skin lesions in Brazilian patient. PMID- 29276012 TI - Usefulness of CA125 and its kinetic parameters and positron emission tomography/computed tomography (PET/CT) with fluorodeoxyglucose ([18F] FDG) in the detection of recurrent ovarian cancer. AB - BACKGROUND AND OBJECTIVE: To assess the usefulness of cancer antigen 125 (CA125) serum levels and kinetic values, velocity (CA125vel) and doubling time (CA125dt), as well as fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), in the detection of ovarian cancer recurrence. To assess the optimal cut-off for CA125, CA125vel and CA125dt to detect relapse with [18F]FDG PET/CT. MATERIAL AND METHODS: A retrospective analysis was performed of 59 [18F]FDG-PET/CT (48 patients) for suspected recurrence of ovarian cancer. Receiver operating characteristic (ROC) curves were plotted and area-under-the curve (AUC) statistics were computed for CA125, CA125vel and CA125dt. The results obtained in the group with normal and high (>35U/ml) CA125 levels were compared. RESULTS: Forty-four cases of recurrence were diagnosed (7 had CA125 <=35U/ml), whereas 15 showed no disease. All of them were correctly catalogued by PET/CT. In ROC analysis, the discriminatory power of CA125 was relatively high (AUC 0.835) and the optimal cut-off point to reflect active disease was 23.9U/ml. The ROC analyses for the CA125vel and CA125dt showed an AUC of 0.849 and 0.728, respectively, with an optimal cut-off point of 1.96U/ml/month and 0.76 months, respectively. In patients with normal CA125 and recurrence of ovarian cancer, the CA125vel was significantly higher than in patients without recurrence (p=0.029). CONCLUSION: [18F]FDG-PET/CT is more accurate than CA125 parameters in the detection of ovarian cancer recurrence. CA125 serum levels are essential; nevertheless, CA125 kinetic values must be considered to detect relapse. Particularly in patients with CA125 within normal values, in which a higher CA125vel is indicative of recurrence. PMID- 29276005 TI - Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. AB - Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders. PMID- 29276013 TI - Outcome of Secondary Stroke Prevention in Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants. AB - BACKGROUND: Since non-vitamin K antagonist oral anticoagulants (NOACs) were released for clinical use, many studies have investigated its effectiveness in stroke prevention. In this study, to determine whether or not there is a difference in outcome in secondary stroke prevention between warfarin and NOACs, patients with embolic stroke with newly prescribed anticoagulants were prospectively analyzed. METHODS: Patients with acute ischemic stroke, who newly started anticoagulant therapy, were consecutively asked to participate in this study. Enrolled patients (76.3 +/- 11.0 years old) were classified into warfarin (n = 48), dabigatran (n = 73), rivaroxaban (n = 49), and apixaban (n = 65). The outcome in 1 year was prospectively investigated at outpatient clinic or telephone interview. Recurrence of stroke and death was considered as the critical incidence. RESULTS: The prevalence of risk factors was not different among all medicines. Patients with dabigatran showed significantly younger onset age (P < .001: 72.2 years old) and milder neurologic deficits than patients on other medicines (P < .001). Cumulative incident rates were 7.1%, 15.3%, 19.0%, and 29.7% for dabigatran, apixaban, rivaroxaban, and warfarin, respectively. Dabigatran showed relatively better outcome compared with warfarin (P = .069) and rivaroxaban (P = .055). All patients on NOACs presented lower cumulative stroke recurrence compared with warfarin. CONCLUSION: Even in the situation of secondary stroke prevention, noninferiority of NOACs to warfarin might be demonstrated. PMID- 29276014 TI - Early Selective Serotonin Reuptake Inhibitors for Recovery after Stroke: A Meta Analysis and Trial Sequential Analysis. AB - BACKGROUND: Potential benefits and risks of early (<=30 days from stroke onset) selective serotonin reuptake inhibitors (SSRIs) treatment for neurologic functional recovery after stroke are not fully understood. METHODS: We searched PubMed, Embase, and the Cochrane Library to identify randomized controlled trials that assessed SSRI medications during the initial ictus after stroke versus placebo. Primary outcome was decrease in National Institutes of Health Stroke Scale (NIHSS) score. Secondary outcomes included the improvement of Barthel index, functional independence (modified Rankin Scale score 0-2 at the end of follow-up), the incidence of depression, and adverse events including diarrhea, insomnia, hepatic enzyme disorders, seizure, and intracranial hemorrhage. We used fixed effects models or random effects models to estimate weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) according to heterogeneity. RESULTS: Eight trials were included, with 1549 patients. Compared with placebo, decrease in NIHSS was greater in SSRI-treated patients (WMD, 0.82; 95% CI, 0.31-1.33; P = .002). Trial sequential analysis showed that the cumulative z curve crossed the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. Early SSRI treatment also promoted Barthel index (WMD, 5.32; 95% CI, 1.65-8.99; P = .005) and functional independence (RR, 2.54; 95% CI, 1.82-3.55; P < .0001). There was no difference in the incidence of depression and adverse events between groups. No evidence of publication bias was detected. CONCLUSIONS: The early SSRIs treatment reduces the defective neurologic function in patients undergoing rehabilitation after stroke. PMID- 29276015 TI - Genetic analysis of 27 Y-STR loci in Han population from Hainan province, southernmost China. PMID- 29276016 TI - UK experience of herpes zoster vaccination can inform varicella zoster virus policies. PMID- 29276017 TI - Evaluation of the effect of the herpes zoster vaccination programme 3 years after its introduction in England: a population-based study. AB - BACKGROUND: In 2013, a herpes zoster vaccination programme was introduced in England for adults aged 70 years with a phased catch-up programme for those aged 71-79 years. We aimed to evaluate the effect of the first 3 years of the vaccination programme on incidence of herpes zoster and postherpetic neuralgia in this population. METHODS: In this population-based study, we extracted data from the Royal College of General Practitioners sentinel primary care network on consultations with patients aged 60-89 years for herpes zoster and postherpetic neuralgia occurring between Oct 1, 2005, and Sept 30, 2016, obtaining data from 164 practices. We identified individual data on herpes zoster vaccinations administered and consultations for herpes zoster and postherpetic neuralgia, and aggregated these data to estimate vaccine coverage and incidence of herpes zoster and postherpetic neuralgia consultations. We defined age cohorts to identify participants targeted in each year of the programme, and as part of the routine or catch-up programme. We modelled incidence according to age, region, gender, time period, and vaccine eligibility using multivariable Poisson regression with an offset for person-years. FINDINGS: Our analysis included 3.36 million person years of data, corresponding to an average of 310 001 patients aged 60-89 years who were registered at an RCGP practice each year. By Aug 31, 2016, uptake of the vaccine varied between 58% for the recently targeted cohorts and 72% for the first routine cohort. Across the first 3 years of vaccination for the three routine cohorts, incidence of herpes zoster fell by 35% (incidence rate ratio 0.65 [95% 0.60-0.72]) and of postherpetic neuralgia fell by 50% (0.50 [0.38 0.67]). The equivalent reduction for the four catch-up cohorts was 33% for herpes zoster (incidence rate ratio 0.67 [0.61-0.74]) and 38% for postherpetic neuralgia (0.62 [0.50-0.79]). These reductions are consistent with a vaccine effectiveness of about 62% against herpes zoster and 70-88% against postherpetic neuralgia. INTERPRETATION: The herpes zoster vaccination programme in England has had a population impact equivalent to about 17 000 fewer episodes of herpes zoster and 3300 fewer episodes of postherpetic neuralgia among 5.5 million eligible individuals in the first 3 years of the programme. Communication of the public health impact of this programme will be important to reverse the recent trend of declining vaccine coverage. FUNDING: Public Health England. PMID- 29276018 TI - A Study on the Applicability of the Health Action Process Approach to the Dietary Behavior of University Students in Shanxi, China. AB - OBJECTIVE: To confirm the applicability of the Health Action Process Approach in predicting and explaining the healthy dietary behavior of college students. DESIGN: Cross-sectional survey. The data were collected though the self administrated questionnaires. SETTING: Eight universities in Shanxi province, China. PARTICIPANTS: A total of 1,933 undergraduates were randomly selected using random cluster sampling from Shanxi, China (92.0% response; 31.7% males). MAIN OUTCOME MEASURES: Each variable was measured using questionnaires. ANALYSIS: Data were analyzed by 2-sample t test, linear correlation, and path analysis. Significance was set at P < .05. RESULTS: Risk perception, self-efficacy, and positive expectancy began functioning during the intention formation stage (P < .01). Outcome expectancy, self-efficacy, and behavioral intentions had a predictive role in plan formation (P < .001). Action planning, positive expectancy, and self-efficacy were effective predictors of dietary behavior (P < .001). An action plan was a mediator between behavioral intention and dietary behavior; the mediation effect was 0.086. CONCLUSIONS AND IMPLICATIONS: As a first step, application of Health Action Process Approach to the dietary behavior of Chinese college students was confirmed. Future research expanding on this study could consider including additional sociodemographic factors in the model structure using a broader study population. PMID- 29276020 TI - Improved progression-free survival in metastatic breast cancer. PMID- 29276019 TI - Nutrition Facts Use in Relation to Eating Behaviors and Healthy and Unhealthy Weight Control Behaviors. AB - OBJECTIVE: Investigate the relationship between use of Nutrition Facts labels on packaged foods and weight-related behaviors. DESIGN: Cross-sectional survey in 2015-2016. PARTICIPANTS: Young adult respondents (n = 1,817; 57% women; average age 31.0 +/- 1.6 years) to the Project Eating and Activity in Teens and Young Adults-IV survey, the fourth wave of a longitudinal cohort study. VARIABLES MEASURED: Use of Nutrition Facts labels on packaged foods; healthy, unhealthy, and extreme weight control behaviors; intuitive eating; binge eating. ANALYSIS: Linear and logistic regression models were adjusted for age, ethnicity/race, education, income, and weight status. RESULTS: In women, greater Nutrition Facts use was associated with a 23% and 10% greater likelihood of engaging in healthy and unhealthy weight control behaviors, respectively, and a 17% greater chance of engaging in binge eating. In men, greater label use was associated with a 27% and 17% greater likelihood of engaging in healthy and unhealthy weight control behaviors, respectively, and a lower level of intuitive eating. CONCLUSIONS AND IMPLICATIONS: Professionals advising patients and clients on weight management may consider possible gender differences in response to weight loss and management guidance. Since label use was related to engagement in some unhealthy behaviors in addition to healthy behaviors, it is important to consider how individuals may use labels, particularly those at risk for, or engaging in, disordered eating behaviors. Future research investigating potential relationships between Nutrition Facts use, intuitive eating, and binge eating is needed. PMID- 29276021 TI - PEGPH20 for metastatic pancreatic ductal adenocarcinoma. PMID- 29276023 TI - Salvage regimens for Hodgkin's lymphoma in the brentuximab vedotin era. PMID- 29276022 TI - Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial. AB - BACKGROUND: Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkin's lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkin's lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma and anaplastic large-T-cell lymphoma. METHODS: In this international, multicentre, single-arm, phase 1-2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkin's lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1.2 mg/kg or 1.8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331. FINDINGS: Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 [98%] with Hodgkin's lymphoma and one [2%] with anaplastic large-T-cell lymphoma; 28 [43%] during phase 1 and 37 [57%] during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1.8 mg/kg brentuximab vedotin plus 80 mg/m2 of bendamustine in two (7%) patients and diffuse rash at 1.2 mg/kg brentuximab vedotin plus 70 mg/m2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1.8 mg/kg of brentuximab vedotin and 90 mg/m2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% [95% CI 62-91]) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3-4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths. INTERPRETATION: This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant. FUNDING: Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health. PMID- 29276024 TI - Many FDA-approved cancer drugs might lack clinical benefit. PMID- 29276025 TI - Daratumumab for untreated multiple myeloma. PMID- 29276026 TI - Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML. AB - The phosphatidylinositol 3-kinase/protein kinase B (Akt)/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway is amplified in 60-80% of patients with acute myelogenous leukemia (AML). Since this complex pathway is crucial to cell functions such as growth, proliferation, and survival, inhibition of this pathway would be postulated to inhibit leukemia initiation and propagation. Inhibition of the mTORC1 pathway has met with limited success in AML due to multiple resistance mechanisms including direct insensitivity of the mTORC1 complex, feedback activation of the PI3k/Akt signaling network, insulin growth factor-1 (IGF-1) activation of PI3K, and others. This review explores the role of mTOR inhibition in AML, mechanisms of resistance, and means to improve outcomes through use of dual mTORC1/2 inhibitors or dual TORC/PI3K inhibitors. How these inhibitors interface with currently available therapies in AML will require additional preclinical experiments and conduct of well-designed clinical trials. PMID- 29276027 TI - Comments on the relationship between fibrinogen and in-hospital mortality in patients with type A acute aortic dissection. PMID- 29276028 TI - Evaluation for effects of severe acidosis on hemostasis in trauma patients using thrombelastography analyzer. AB - OBJECTIVE: To investigate effects of metabolic acidosis on hemostasis function in trauma patients using thromboelastography analyzer. METHODS: 65 critically injured patients and 19 healthy volunteers were enrolled in the study. Three samples of whole blood were collected from each patient or healthy volunteer. These three samples were acidified with 50mmol/l phosphate-buffered saline (PBS) (pH5.8) or a neutral buffer (50mmol/l phosphate, pH7.4) and acidified blood sample with target pH of 6.95, 7.15 or 7.35 was obtained respectively. These three samples with target pH value were added into thrombelastography analyzer (TEG(r) 5000 Thrombelastograph Hemostasis Analyzers; Haemoscope Corporation, Niles, Illinois, USA) respectively and variables of Clot time (r), Rate of clot formation (alpha Angle), Clot formation time (K), Coagulation Index (CI) and Maximum strength (MA) were monitored at 37 degrees C. Besides, association between TEG(r) parameters and clinicopathological features was analyzed by the Pearson chi2 test. RESULTS: In trauma patients, all 5 thrombelastographic variables, Clot time (r), Clot formation time (K), Maximum Amplitude (MA), Rate of clot formation (alpha Angle) and Coagulation Index (CI), were significantly affected by blood acidification, F(1.321,83.213)=88.960, P<0.001, F(2,128)=112.738, P<0.001, F(1.199,76.748)=37.964, P<0.001, F(1.195,76.452)=16.789, P<0.001 and F(2,128)=178.674, P<0.001. Post hoc tests showed that moderate acidosis (pH7.15) significantly elongated K time (from 2.6 to 3.4min, P=0.0013) and increased alpha Angle (from 51.9 degrees to 52.2 degrees , P=0.0040). r, MA and CI were not markedly influenced under moderate acidification. Comparing to mild acidosis (pH7.15), severe acidosis (pH6.95) induced more serious impairment to hemostasis and all 5 variables was substantially affected, r (from 5.9 to 6.8min, P<0.001), K (from 3.4 to 3.9min, P<0.001), alpha Angle (from 52.2 degrees to 50.8 degrees , P=0.002), MA (from 52.9 to 51.6mm, P<0.001) and CI (from -2.3 to -4.2, P<0.001). Additionally, higher r elongation under severe acidosis was significantly associated with an increased mortality rate and transfusion requirement (P=0.019 and 0.031). In healthy volunteers, similar effects on hemostasis were detected. Inhibition ratios of thrombelastographic parameters were significantly higher in trauma patients than in healthy volunteers indicating severer impairment of metabolic acidosis to hemostasis in critically injured patients. CONCLUSIONS: The degree of metabolic acidosis in trauma patients is positively correlated to the severity of hemostasis dysfunction. Additionally, acidosis induces more serious impairment to hemostasis in trauma patients than in healthy volunteers. Moreover, acidosis induced r time elongation is positively related to a higher death rate and increased transfusion requirement and this indicates a predictive role of TEG(r) variables for prognosis of traumatized patients. PMID- 29276029 TI - Predicting the impact of Non-Invasive Ventilation in ED Patients with CAP. PMID- 29276030 TI - The impact of prehospital assessment and EMS transport of acute aortic syndrome patients. AB - BACKGROUND: The quality of acute aortic syndrome (AAS) assessment by emergency medical service (EMS) and the incidence and prehospital factors associated with 1 month survival remain unclear. METHODS: We retrospectively analyzed the data collected for 94,468 patients with non-traumatic medical emergency excluding out of-hospital cardiac arrest during the period of 2011-2014. RESULTS: Of these transported by EMS, 22,075 had any of the AAS-related symptoms, and 330 had an EMS-assessed risk for AAS; of these, 195 received an in-hospital AAS diagnosis. Of the remaining 21,745 patients without EMS-assessed risk, 166 were diagnosed with AAS. Therefore, the sensitivity and specificity of our EMS-risk assessment for AAS was 54.0% (195/361) and 99.4% (21,579/21,714), respectively. EMS assessed the risk less frequently when patients were elderly and presented with dyspnea and syncope/faintness. Sign of upper extremity ischemia was rarely detected (6.9%) and absence of this sign was associated with lack of EMS-assessed risk. The calculation of modified aortic dissection detection risk score revealed that rigorous assessment based on this score may increase the EMS sensitivity for AAS. The 1-month survival rate was significantly higher in patients admitted to core hospitals with surgical teams for AAS than in those admitted to all other hospitals [87.5% (210/240) vs 69.4% (84/121); P<0.01]. Multiple logistic regression analysis demonstrated that Stanford type A, Glasgow coma scale <=14, and admission to core hospitals providing emergency cardiovascular surgery were associated with 1-month survival. CONCLUSIONS: Improvement of AAS survival is likely to be affected by rapid admission to appropriate hospitals providing cardiovascular surgery. PMID- 29276031 TI - In a bed or on the floor? - The effect of realistic hospital resuscitation training: A randomised controlled trial. AB - INTRODUCTION: In-hospital cardiac arrest has a poor prognosis and often occurs in patients lying in a hospital bed. A bed mattress is a soft compressible surface that may decrease cardiopulmonary resuscitation (CPR) quality. Often hospital CPR training is performed with a manikin on the floor. AIM: To study CPR quality following realistic CPR training with a manikin in a bed compared with one on the floor. METHODS: We conducted a randomised controlled study. Healthcare professionals were randomised to CPR training with a manikin in a hospital bed or one on the floor. Data on CPR quality was collected from manikins. The primary outcome measure was chest compression depth. RESULTS: In total, 108 healthcare professionals (age: 40years, female: 94%) were included. The mean chest compression depth was 39mm (standard deviation (SD): 10), for the bed group compared with 38mm (SD: 9) for the floor group, p=0.49. A post hoc analysis showed that regardless of the training method, the participants who optimised their working position by jumping onto the bed or lowering the bed had a median chest compression depth of 39mm (25th-75th percentiles: 33-45) compared with 29mm (25th-75th percentiles: 23-41) for participants who did neither, p=0.04. CONCLUSION: There was no significant difference in chest compression depth between healthcare professionals who trained CPR on a manikin in a hospital bed compared with one on the floor. Chest compression depth was too shallow in both groups. Irrespective of the training method, participants who optimised their working position performed deeper chest compressions. PMID- 29276032 TI - The utility of presepsin in diagnosis and risk stratification for the emergency patients with sepsis. AB - OBJECTIVES: To evaluate the value of presepsin in diagnosis and risk stratification of septic patients in emergency department, and investigate the utility in differentiation of gram-positive and gram-negative bacterial infection. METHODS: We enrolled 72 patients with sepsis and 23 nonbacterial patients with systemic inflammatory response syndrome (SIRS) who were admitted to the emergency department of Tianjin Medical University General Hospital. Meanwhile, 20 healthy volunteers were included. Plasma presepsin, serum PCT, C reactive protein (CRP), lactate and white blood cells (WBC) were measured, and APACHE II score were calculated upon admission. The receiver-operating characteristic curve (ROC) was computed and the area under the ROC curve was for evaluating the value to diagnose sepsis. Then the patients were grouped according to the result of culture and severity of sepsis. RESULTS: The levels of presepsin, PCT, CRP and WBC were apparently higher in sepsis patients than in nonbacterial SIRS group (P<0.05). The levels of presepsin and the APACHEII score were demonstrated the significant difference among sepsis, severe sepsis and septic shock patients (P<0.05). The area under the ROC curve of presepsin, PCT, CRP and WBC were 0.954, 0.874, 0.859 and 0.723 respectively. The cutoff of presepsin for discrimination of sepsis and nonbacterial infectious SIRS was determined to be 407pg/ml, of which the clinical sensitivity and specificity were 98.6% and 82.6%, respectively. Moreover, presepsin was significantly different between gram-positive and gram-negative bacterial infection (P<0.05). CONCLUSION: Presepsin was a promising biomarker for initially diagnosis and risk stratification of sepsis, and a potential marker to distinguish gram-positive and gram-negative bacterial infection. PMID- 29276033 TI - Crystal Structures of Anti-apoptotic BFL-1 and Its Complex with a Covalent Stapled Peptide Inhibitor. AB - BCL-2 family proteins are high-priority cancer targets whose structures provide essential blueprints for drug design. Whereas numerous structures of anti apoptotic BCL-2 protein complexes with alpha-helical BH3 peptides have been reported, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69-A resolution, revealing similarities and key differences among unliganded anti-apoptotic proteins. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by a NOXA BH3 based stapled peptide inhibitor. The crystal structure of this complex demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for therapeutic targeting so that the apoptotic blockades of BFL-1-dependent cancers can be overcome. PMID- 29276034 TI - DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants. AB - The CXXC domain, first identified as the reader of unmodified CpG dinucleotide, plays important roles in epigenetic regulation by targeting various activities to CpG islands. Here we systematically measured and compared the DNA-binding selectivities of all known human CXXC domains by different binding assays, and complemented the existing function-based classification of human CXXC domains with a classification based on their DNA selectivities. Through a series of crystal structures of CXXC domains with DNA ligands, we unravel the molecular mechanisms of how these CXXC domains, including single CXXC domains and tandem CXXC-PHD domains, recognize distinct DNA ligands, which further supports our classification of human CXXC domains and also provides insights into selective recruitment of chromatin modifiers to their respective targets via CXXC domains recognizing different genomic DNA sequences. Our study facilitates the understanding of the relationship between the DNA-binding specificities of the CXXC proteins and their biological functions. PMID- 29276035 TI - Folding and Domain Interactions of Three Orthologs of Hsp90 Studied by Single Molecule Force Spectroscopy. AB - The heat-shock protein 90 (Hsp90) molecular chaperones are highly conserved across species. However, their dynamic properties can vary significantly from organism to organism. Here we used high-precision optical tweezers to analyze the mechanical properties and folding of different Hsp90 orthologs, namely bacterial Hsp90 (HtpG) and Hsp90 from the endoplasmic reticulum (ER) (Grp94), as well as from the cytosol of the eukaryotic cell (Hsp82). We find that the folding rates of Hsp82 and HtpG are similar, while the folding of Grp94 is slowed down by misfolding of the N-terminal domain. Furthermore, the domain interactions mediated by the charged linker, involved in the conformational cycles of all three orthologs, are much stronger for Grp94 than for Hsp82, keeping the N terminal domain and the middle domain in close proximity. Thus, the ER resident Hsp90 ortholog differs from the cytosolic counterparts in basic functionally relevant structural properties. PMID- 29276036 TI - Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors. AB - Membrane dynamic processes including vesicle biogenesis depend on Arf guanosine triphosphatase (GTPase) activation by guanine nucleotide exchange factors (GEFs) containing a catalytic Sec7 domain and a membrane-targeting module such as a pleckstrin homology (PH) domain. The catalytic output of cytohesin family Arf GEFs is controlled by autoinhibitory interactions that impede accessibility of the exchange site in the Sec7 domain. These restraints can be relieved through activator Arf-GTP binding to an allosteric site comprising the PH domain and proximal autoinhibitory elements (Sec7-PH linker and C-terminal helix). Small angle X-ray scattering and negative-stain electron microscopy were used to investigate the structural organization and conformational dynamics of cytohesin 3 (Grp1) in autoinhibited and active states. The results support a model in which hinge dynamics in the autoinhibited state expose the activator site for Arf-GTP binding, while subsequent C-terminal helix unlatching and repositioning unleash conformational entropy in the Sec7-PH linker to drive exposure of the exchange site. PMID- 29276037 TI - Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance. AB - Malaria is a devastating disease in sub-Saharan Africa and is transmitted by the mosquito Anopheles gambiae. While indoor residual spraying of anticholinesterase insecticides has been useful in controlling the spread of malaria, widespread application of these compounds has led to the rise of an insecticide-resistant mosquito strain that harbors a G119S mutation in the nervous system target enzyme acetylcholinesterase. We demonstrate the atomic basis of insecticide resistance through structure determination of the G119S mutant acetylcholinesterase of An. gambiae in the ligand-free state and bound to a potent difluoromethyl ketone inhibitor. These structures reveal specific features within the active-site gorge distinct from human acetylcholinesterase, including an open channel at the base of the gorge, and provide a means for improving species selectivity in the rational design of improved insecticides for malaria vector control. PMID- 29276039 TI - Diagnosis and treatment of osteochondritis dissecans of the humeral capitellum. AB - Osteochondritis dissecans (OCD) of the humeral capitellum is a critical elbow injury in adolescent overhead throwing athletes. However, its etiology remains unknown. Medical examinations using ultrasonography found that the prevalence of capitellar OCD among adolescent baseball players was approximately from 1% to 3%. A plain anteroposterior radiograph with the elbow in 45 degrees of flexion is essential for the diagnosis of an OCD lesion. The stability of OCD lesions is evaluated on plain radiographs, computed tomography, and magnetic resonance imaging (MRI). Imaging features of the unstable lesions are an epiphyseal closure of the capitellum or a lateral epicondyle, a displaced fragment, or irregular contours of the articular surface and a high signal interface on T2-weighted MRI. A stable lesion has the potential to be healed with conservative treatment. By contrast, surgical treatment should be considered if there is no radiographic improvement within 3 months. In addition, surgery should be performed for the lesions that cause pain during daily activities, have a locking phenomenon, or which are assessed by imaging as obviously unstable. Arthroscopic debridement/loose body removal can be performed for small lesions (<=12 mm in diameter). For large lesions (>12 mm), preservation and/or reconstruction of the articular surface should be selected, such as bone-peg fixation of the lateral part of the fragment and osteochondral autograft transplantation (OAT) from the knee. In the future directions, there is no comparative study of OAT from the knee and rib. In addition, little is known about its long-term outcome, or resulting osteoarthritis. A recent meta-analysis showed that grafts harvested from the knee may lead to donor site morbidity (7.8%). Thus, a novel cartilage tissue engineering approach is anticipated. PMID- 29276040 TI - Long-term results of total hip arthroplasty using Charnley Elite-Plus stem and the effect of stem geometry on radiographic distal femoral cortical hypertrophy. AB - BACKGROUND: The Elite-Plus stem has two shape variations: roundback and flanged. The correlation between the radiographic results and stem geometry has not been previously investigated. The objective of this study was to evaluate the long term primary total hip arthroplasty results using Elite-Plus stems, and the effect of stem geometry on radiographic distal femoral cortical hypertrophy. METHODS: We retrospectively evaluated, radiographically, 156 patients (173 hips) who underwent total hip arthroplasty between April 1998 and November 2005, and were followed up for >5 years, postoperatively. Radiographic factors affecting distal femoral cortical hypertrophy were analysed using multivariable logistic regression analysis. RESULTS: The mean follow-up period was 11.6 (5-17.8) years. During follow-up, femoral components were revised in 7 hips; one was revised due to aseptic loosening. Another femoral component was loosened and waiting for revision. The 10- and 15-year survival rates for aseptic stem loosening were 100% and 98.1% (95% CI: 92.5-99.5), respectively. Distal femoral cortical hypertrophy occurred in 23 hips (14.8%), and more often with roundback type (34.1%) than with flanged type (7.2%). Distal femoral cortical hypertrophy was observed in 34.8% of hips with valgus alignment, 11.3% with neutral alignment, and 12.5% with varus alignment. Multivariable logistic regression analysis showed that roundback stem shape and valgus stem alignment significantly affected the occurrence of distal femoral cortical hypertrophy. CONCLUSIONS: The Elite-Plus stem has excellent long term clinical and radiographic results in Japanese patients. The occurrence of distal femoral cortical hypertrophy significantly depends on the shape and alignment of Elite-Plus stems. PMID- 29276038 TI - Structural and Dynamics Comparison of Thermostability in Ancient, Modern, and Consensus Elongation Factor Tus. AB - Rationally engineering thermostability in proteins would create enzymes and receptors that function under harsh industrial applications. Several sequence based approaches can generate thermostable variants of mesophilic proteins. To gain insight into the mechanisms by which proteins become more stable, we use structural and dynamic analyses to compare two popular approaches, ancestral sequence reconstruction (ASR) and the consensus method, used to generate thermostable variants of Elongation Factor Thermo-unstable (EF-Tu). We present crystal structures of ancestral and consensus EF-Tus, accompanied by molecular dynamics simulations aimed at probing the strategies employed to enhance thermostability. All proteins adopt crystal structures similar to extant EF-Tus, revealing no difference in average structure between the methods. Molecular dynamics reveals that ASR-generated sequences retain dynamic properties similar to extant, thermostable EF-Tu from Thermus aquaticus, while consensus EF-Tu dynamics differ from evolution-based sequences. This work highlights the advantage of ASR for engineering thermostability while preserving natural motions in multidomain proteins. PMID- 29276042 TI - Intestinal tight junctions are severely altered in NEC preterm neonates. AB - BACKGROUND & AIMS: Necrotizing Enterocolitis (NEC) is a severe inflammatory disorder of the intestine endangering the health and survival of preterm infants. It is well established that the gut barrier is severely damaged in NEC patients, nonetheless an in depth investigation of modifications at the transcriptional and translational levels of tight junction genes and proteins during NEC are still missing. The aim of this study was to investigate changes in the expression of tight junctions and other associated proteins during NEC and determine their correlation to the disease severity. METHODS: We examined intestinal specimens from six NEC patients and compared them with six control specimens from patients that underwent surgeries for reasons other than NEC. The expression of genes was analyzed by real time PCR and protein expression by immunohistochemistry. RESULTS: The tight junction genes ZO-1, occludin, cingulin and claudin-4 were significantly down regulated in NEC. Furthermore TLR4, BAX and SIRT1 genes were found to be significantly down regulated while HIF-1A showed a trend of up regulation in NEC patients. These changes were found to correlate with the severity of the disease. Additionally we demonstrated in an ex-vivo model that hypoxic conditions initiated a destructive process of the epithelial barrier. We also showed that the expression of the tight junction proteins ZO-1 and occludin were significantly down regulated in NEC specimens. CONCLUSIONS: The expression of tight junction proteins and their encoding genes are significantly altered in NEC. We surmise that SIRT1 and HIF-1A may play a role in controlling these effects. PMID- 29276041 TI - Cost-effectiveness of posterior lumbar interbody fusion in the Japanese universal health insurance system. AB - BACKGROUND: Globally, the cost-effectiveness of spinal surgery is becoming increasingly important. However, these data are limited to a few countries. The purpose of our study was to examine the cost/quality adjusted life year (cost/QALY) gained for posterior lumbar interbody fusion (PLIF) in the Japanese universal health insurance system. METHODS: Fifty five patients underwent PLIF for lumbar degenerative spinal canal stenosis between July 2013 and September 2015 was included. Effectiveness was measured using Euro QOL 5-dimension (EQ-5D), Short-Form 8 physical component summary (PCS), and visual analog scale (VAS). The cost was calculated from the perspective of the public healthcare payer. Effectiveness and cost were measured one year after surgery. QALYs were calculated by multiplying the utility value (EQ-5D) and life years. Only direct costs were included on the basis of actual reimbursements. Cost/QALY at a 5-year time horizon with a 2% discount rate was estimated. Sensitivity analysis was performed by varying the time horizon (2 years or 10 years). The exchange rate was defined as US $1 to Japanese 100 yen. RESULTS: Mean total cost one year after surgery was ?2,802,900 ($28029). Operative cost was ?1,779,700 ($17797). Mean gained score was 0.22 in EQ-5D, 10.3 in PCS, and -44 in VAS. Cost/QALY was ?2,697,500 ($26975). Sensitivity analysis demonstrated that cost/QALY at a 10 year time horizon was ?1,428,300 ($14283) and that cost/QALY at a 2-year time horizon was ?6,435,400 ($64354). CONCLUSIONS: Clinical outcomes after PLIF improved beyond minimum clinical improvement difference. Cost/QALY was below the widely-accepted benchmark (cost/QALY < $50000). PLIF could be regarded as cost effective interventions. PMID- 29276043 TI - Associations Between Personality Disorder Characteristics, Psychological Symptoms, and Sexual Functioning in Young Women. AB - BACKGROUND: Recently, the etiology of sexual dysfunctions in women has been approached from different angles. In clinical practice and in previous studies, it has been observed that women with sexual problems experience anxiety problems and express more rigid and perfectionistic personality traits than women without these problems. AIM: To investigate whether personality disorder characteristics according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) and psychological symptoms are associated with sexual problems in women. METHODS: 188 women 18 to 25 years old participated in this cross-sectional study. Questionnaires measuring sexual functioning (Female Sexual Function Index), personality disorder characteristics (Assessment of DSM IV-TR Personality Disorders Questionnaire), and psychological symptoms (Brief Symptom Inventory and Center for Epidemiological Studies Depression Scale) were used. OUTCOME: The main outcome measure used was sexual functioning assessed by self-report. RESULTS: Results, using analysis of variance, indicated that women with sexual problems report significantly more cluster A (specifically schizoid) and C (specifically avoidant and obsessive-compulsive) personality disorder characteristics than women without sexual problems. Furthermore, using multiple regression analyses, higher cluster A (specifically schizoid) and lower cluster B (specifically borderline and antisocial) personality disorder characteristics indicated lower levels of sexual functioning. Psychological symptoms partly mediated the effect of cluster A personality disorder characteristics on sexual functioning. CLINICAL IMPLICATIONS: The results of this study indicate that clinical practice should extend its scope by focusing more on improving adaptive personality characteristics, such as extraversion and individualism seen in cluster B personality characteristics, and decreasing the perfectionistic, introvert, and self-doubting characteristics seen in cluster C personality characteristics. STRENGTHS AND LIMITATIONS: Because of the correlational design and use of self-report measures, causal relations cannot be established between personality disorder characteristics and sexual functioning. CONCLUSION: Overall, the results indicate that personality disorder characteristics can play an important associative role in the development and maintenance of sexual functioning problems in women. Grauvogl A, Pelzer B, Radder V, van Lankveld J. Associations Between Personality Disorder Characteristics, Psychological Symptoms, and Sexual Functioning in Young Women. J Sex Med 2018;15:192-200. PMID- 29276044 TI - Intraclonal variations of resistance and phenotype in Pseudomonas aeruginosa epidemic high-risk clone ST308: A key to success within a hospital? AB - Most multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa strains belonged to epidemic high-risk (EHR) clones that succeeded worldwide in the context of hospital outbreaks. In order to study the intraclonal diversity in EHR P. aeruginosa, we selected clinical and environmental strains of the EHR clone ST308 that caused outbreak clusters over five years in a hospital and then persisted in the hospital environment during four additional years, causing sporadic infections. Unexpectedly, resistance phenotype was very diverse within the population, independently of the origin (environmental or human) and the period of isolation (during or after outbreaks). Most MDR/XDR strains belonged to clusters in pulsed-field gel electrophoresis (PFGE) while singleton strains instead displayed susceptible or moderately resistant phenotypes. High diversity was observed for motility and biofilm formation without correlation with the origin and the period. Resistance to biocides was not linked to epidemic success or to environmental persistence. Finally, the EHR clone ST308 did not display common adaptive traits, nor traits related to an origin or a period of isolation in the hospital. The major character of this EHR clone ST308 is its intraclonal diversity that probably warrants its adaptation and persistence in hospital whatever the conditions and therefore its epidemic behaviour. This diversity could result from adaptive radiation with the evolution of multiple lineages that fill available niches within a complex ecosystem such as a hospital. PMID- 29276045 TI - PhoDAGs Enable Optical Control of Diacylglycerol-Sensitive Transient Receptor Potential Channels. AB - Diacylglycerol-sensitive transient receptor potential (TRP) channels play crucial roles in a wide variety of biological processes and systems, but their activation mechanism is not well understood. We describe an optical toolkit by which activation and deactivation of these ion channels can be controlled with unprecedented speed and precision through light stimuli. We show that the photoswitchable diacylglycerols PhoDAG-1 and PhoDAG-3 enable rapid photoactivation of two DAG-sensitive TRP channels, Trpc2 and TRPC6, upon stimulation with UV-A light, whereas exposure to blue light terminates channel activation. PhoDAG photoconversion can be applied in heterologous expression systems, in native cells, and even in mammalian tissue slices. Combined laser scanning-controlled photoswitching and Ca2+ imaging enables both large-scale mapping of TRP channel-mediated neuronal activation and localized mapping in small cellular compartments. Light-switchable PhoDAGs provide an important advance to explore the pathophysiological relevance of DAG-sensitive TRP channels in the maintenance of body homeostasis. PMID- 29276046 TI - Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions. AB - Knowledge of the full target space of bioactive substances, approved and investigational drugs as well as chemical probes, provides important insights into therapeutic potential and possible adverse effects. The existing compound target bioactivity data resources are often incomparable due to non-standardized and heterogeneous assay types and variability in endpoint measurements. To extract higher value from the existing and future compound target-profiling data, we implemented an open-data web platform, named Drug Target Commons (DTC), which features tools for crowd-sourced compound-target bioactivity data annotation, standardization, curation, and intra-resource integration. We demonstrate the unique value of DTC with several examples related to both drug discovery and drug repurposing applications and invite researchers to join this community effort to increase the reuse and extension of compound bioactivity data. PMID- 29276047 TI - Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors. AB - Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12. These results highlight the importance of considering this common mode of resistance in the development of clinical analogs of THZ1, identify a covalent CDK12 inhibitor that is not susceptible to ABC transporter-mediated drug efflux, and demonstrate that target deconvolution can be accomplished through selection for resistance. PMID- 29276049 TI - Dengvaxia: age as surrogate for serostatus. PMID- 29276048 TI - Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site. AB - The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compound, MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes of inhibition. Molecular docking indicated that MMV019313 did not bind previously characterized substrate sites in PfFPPS/GGPPS. Our finding uncovers a new, selective small-molecule binding site in this important antimalarial drug target with superior druggability compared with the known inhibitor site and sets the stage for the development of Plasmodium-specific FPPS/GGPPS inhibitors. PMID- 29276050 TI - A crucial list of pathogens. PMID- 29276052 TI - Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects. AB - PURPOSE: To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype phenotype correlations. DESIGN: Cohort study. PARTICIPANTS: Retinitis pigmentosa patients from 230 families of AJ origin. METHODS: Sanger sequencing was performed to detect specific founder mutations known to be prevalent in the AJ population. Ophthalmologic analysis included a comprehensive clinical examination, visual acuity (VA), visual fields, electroretinography, color vision testing, and retinal imaging by OCT, pseudocolor, and autofluorescence fundus photography. MAIN OUTCOME MEASURES: Inheritance pattern and causative mutation; retinal function as assessed by VA, visual fields, and electroretinography results; and retinal structural changes observed on clinical funduscopy as well as by pseudocolor, autofluorescence, and OCT imaging. RESULTS: The causative mutation was identified in 37% of families. The most prevalent RP-causing mutations are the Alu insertion (c.1297_8ins353, p.K433Rins31*) in the male germ cell associated kinase (MAK) gene (39% of families with a known genetic cause for RP) and c.124A>G, p.K42E in dehydrodolichol diphosphate synthase (DHDDS) (33%). Additionally, disease-causing mutations were identified in 11 other genes. Analysis of clinical parameters of patients with mutations in the 2 most common RP-causing genes revealed that MAK patients had better VA and visual fields at relatively older ages in comparison with DHDDS patients. Funduscopic findings of DHDDS patients matched those of MAK patients who were 20 to 30 years older. Patients with DHDDS mutations were referred for electrophysiologic evaluation at earlier ages, and their cone responses became nondetectable at a much younger age than MAK patients. CONCLUSIONS: Our AJ cohort of RP patients is the largest reported to date and showed a substantial difference in the genetic causes of RP compared with cohorts of other populations, mainly a high rate of autosomal recessive inheritance and a unique composition of causative genes. The most common RP-causing genes in our cohort, MAK and DHDDS, were not described as major causative genes in other populations. The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations. PMID- 29276051 TI - Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. AB - BACKGROUND: The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. METHODS: We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. FINDINGS: We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. INTERPRETATION: Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. FUNDING: World Health Organization. PMID- 29276053 TI - Inter-observer agreement of standard joint count examination and disease global assessment in a cohort of Egyptian Rheumatoid Arthritis patients. AB - OBJECTIVES: To assess the inter-observer agreement of standard joint count between experienced Rheumatology professor (Prof) and young Rheumatology fellow (candidate), and to compare disease global assessment between professor, young candidate and patients. METHODS: This study included one hundred rheumatoid arthritis patients. For all patients independent clinical evaluation was done by two rheumatologists (professor and candidate) for detection of tenderness in 28 joints and swelling in 26 joints. The study also involved global assessment of disease activity by the provider (Prof and candidate) (EGA) as well as by the patient (PGA). The EGA was determined without previous knowledge of the patient's laboratory test results. RESULTS: A highly significant accordance (correlation) between professor and candidate was found in both the number of tender joints (p<0.001) (r=0.946), and the number of swollen joints (p<0.001) (r=0.797). Regarding swollen joints, the highest agreement was in right knee (0.929), while poor agreement was found in the right 5th MCP (0.049). Regarding tender joints, the highest analogy was in the right elbow (0.899), in contrast to the left 3rd PIP (0.462) which showed the least congruence. Agreement study using kappa measurement for disease global assessment showed: moderate agreement (between professor and candidate) (0.405), fair agreement between (professor and patient) (0.213), fair agreement between (candidate and patient) (0.367). CONCLUSION: Inter-observer reliability was better for TJCs than SJCs. Regarding SJCs agreement was better in large joints such as the knees compared to the small joints such as the MCPs. Disease global assessment may show discrepancy between patients and physicians. PMID- 29276054 TI - Drd3 Signaling in the Lateral Septum Mediates Early Life Stress-Induced Social Dysfunction. AB - Early life stress (ELS) in the form of child abuse/neglect is associated with an increased risk of developing social dysfunction in adulthood. Little is known, however, about the neural substrates or the neuromodulatory signaling that govern ELS-induced social dysfunction. Here, we show that ELS-induced downregulation of dopamine receptor 3 (Drd3) signaling and its corresponding effects on neural activity in the lateral septum (LS) are both necessary and sufficient to cause social abnormalities in adulthood. Using in vivo Ca2+ imaging, we found that Drd3 expressing-LS (Drd3LS) neurons in animals exposed to ELS show blunted activity in response to social stimuli. In addition, optogenetic activation of Drd3LS neurons rescues ELS-induced social impairments. Furthermore, pharmacological treatment with a Drd3 agonist, which increases Drd3LS neuronal activity, normalizes the social dysfunctions of ELS mice. Thus, we identify Drd3 in the LS as a critical mediator and potential therapeutic target for the social abnormalities caused by ELS. PMID- 29276056 TI - Calcium Taste Avoidance in Drosophila. AB - Many animals, ranging from vinegar flies to humans, discriminate a wide range of tastants, including sugars, bitter compounds, NaCl, and sour. However, the taste of Ca2+ is poorly understood, and it is unclear whether animals such as Drosophila melanogaster are endowed with this sense. Here, we examined Ca2+ taste in Drosophila and showed that high levels of Ca2+ are aversive. The repulsion was mediated by two mechanisms-activation of a specific class of gustatory receptor neurons (GRNs), which suppresses feeding and inhibition of sugar-activated GRNs, which normally stimulates feeding. The distaste for Ca2+, and Ca2+-activated action potentials required several members of the variant ionotropic receptor (IR) family (IR25a, IR62a, and IR76b). Consistent with the Ca2+ rejection, we found that high concentrations of Ca2+ decreased survival. We conclude that gustatory detection of Ca2+ represents an additional sense of taste in Drosophila and is required for avoiding toxic levels of this mineral. PMID- 29276055 TI - Morphometric Similarity Networks Detect Microscale Cortical Organization and Predict Inter-Individual Cognitive Variation. AB - Macroscopic cortical networks are important for cognitive function, but it remains challenging to construct anatomically plausible individual structural connectomes from human neuroimaging. We introduce a new technique for cortical network mapping based on inter-regional similarity of multiple morphometric parameters measured using multimodal MRI. In three cohorts (two human, one macaque), we find that the resulting morphometric similarity networks (MSNs) have a complex topological organization comprising modules and high-degree hubs. Human MSN modules recapitulate known cortical cytoarchitectonic divisions, and greater inter-regional morphometric similarity was associated with stronger inter regional co-expression of genes enriched for neuronal terms. Comparing macaque MSNs with tract-tracing data confirmed that morphometric similarity was related to axonal connectivity. Finally, variation in the degree of human MSN nodes accounted for about 40% of between-subject variability in IQ. Morphometric similarity mapping provides a novel, robust, and biologically plausible approach to understanding how human cortical networks underpin individual differences in psychological functions. PMID- 29276058 TI - Robot-assisted anterior pelvic exenteration in vulvovaginal malignant melanoma. AB - OBJECTIVE: Melanomas of the vulva and vagina are rare, and surgery is the gold standard of treatment [1, 2]. Since recent studies have reported pelvic exenteration by using robotic surgical system [3, 4], we showed the surgical procedures of robot-assisted anterior pelvic exenteration (rAPE) with ileal conduit urinary diversion for vulvovaginal malignant melanoma. METHODS: A 55-year old woman who received vaginal wall resection due to vaginal malignant melanoma 8months before was referred. Multiple biopsies of pigmented lesions on the vulva, vagina, and urethral orifice confirmed the recurrence, whereas preoperative image studies revealed no abnormal findings. Thus, we performed rAPE with ileal conduit urinary diversion. RESULTS: First, we performed robot-assisted bilateral inguinal and pelvic lymphadenectomy. Thereafter, we conducted en bloc resection of the bladder, uterus, vagina, and vulva through abdominal and perineal approaches (Fig. 1): Under the 4-arm robotic surgical system, prevesical space was developed and laterally dissected along the undersurface of pubic bone, to the level of levator ani muscles. Bilateral infudibulopelvic ligaments, uterine arteries and parametrium, uterosacral ligaments, and pubovesical ligaments were ligated and resected. During the wide local excision of the vulva, the rectovaginal space was dissected along the posterior vaginal wall. En bloc specimen was successfully delivered. Finally, the ileal conduit urinary diversion was performed. Total operative time was 4.5h excluding set-up and docking times of the robotic surgical system. The pathologic report ascertained clear resection margin and no lymph node involvement. CONCLUSION: rAPE with ileal conduit urinary diversion for treatment of vulvovaginal malignant melanoma is feasible (Fig. 1). PMID- 29276057 TI - Racial/ethnic differences in HPV 16/18 genotypes and integration status among women with a history of cytological abnormalities. AB - OBJECTIVE: HPV genotype distribution varies by race/ethnicity, but is unclear whether there are racial/ethnic variations in HPV 16/18 integration in the host genome. We describe HPV16/18 infection and integration status in a racially/ethnically diverse sample of women with a recent abnormal Pap test. METHODS: Patients (n=640) represent a subset of women participating in a clinical trial. Cervical swabs were tested for HPV16/18 DNA using type-specific polymerase chain reaction assays. Viral integration status was assessed using type-specific integration assays and categorized as fully integrated, fully non-integrated, or mixed. Unconditional logistic regression was used to generate unadjusted (OR) and adjusted odds ratios (aOR) to assess the association between self-reported race/ethnicity and risk of these outcomes. RESULTS: Hispanic and non-Hispanic black women had half the odds of prevalent HPV16 compared to non-Hispanic white women (aORs: 0.43 and 0.45, respectively). The prevalence odds of HPV18 was less than half among Hispanic women (aOR: 0.48), but not significantly different between black and white women (aOR: 0.72). Among women with prevalent HPV16, the odds of fully integrated viral DNA were significantly higher among black women (aORs: 2.78) and marginally higher among Hispanic women (aOR: 1.93). No racial/ethnic differences were observed for HPV18 DNA integration. CONCLUSIONS: While HPV16 and 18 infections were less prevalent among Hispanic and black women compared to whites, their HPV16 DNA was more likely to be present in a fully integrated state. This could potentially contribute to the higher rates of abnormal cytology and cervical dysplasia observed among Hispanic and black women. PMID- 29276059 TI - Clinical characteristics associated with racial disparities in endometrial cancer outcomes: A surveillance, epidemiology and end results analysis. AB - OBJECTIVES: Racial disparities exist for endometrial cancer. We examined patterns of care and factors associated with poor outcomes for Black women with endometrial cancer. METHODS: We studied 110,826 endometrial cancer patients diagnosed between 1980 and 2008 with minimum 5years follow-up in the Surveillance, Epidemiology, and End Results database. Trends over time in sociodemographics, disease characteristics and treatment factors were analyzed over four eras: 1980-1989, 1990-1999, 2000-2004, 2005-2008. Using sequential Cox proportional hazards and Fine-Gray competing risk models we determined the association between potential explanatory variables and racial disparities in all cause mortality (ACM) and cancer-specific mortality (CSM), respectively. RESULTS: Clinical characteristics of Black and White women were relatively constant over time. The unadjusted hazard ratio (HR) among Black women for ACM and CSM were 1.91 (95% CI 1.86-1.97) and 2.35 (95% CI 2.26-2.43), respectively. Adjustment for sociodemographics, disease presentation and surgery decreased the ACM HR to 1.29 (95% CI 1.24-1.34) and CSM HR to 1.18 (95% CI 1.11-1.26) without further decrease from controlling for radiotherapy. Black women were less likely to undergo operative management even when prescribed. Total and radical hysterectomy, and vaginal brachytherapy (VBT) were associated with improved ACM and CSM. Combination VBT and external beam radiotherapy was associated with improved ACM. CONCLUSION: Racial disparities in endometrial cancer survival are predominantly attributable to increased advanced stage, high-grade and aggressive histologic subtype tumors and differential use of surgery in Black women. Intensified surgical and radiation treatment is associated with improved survival, raising questions about treatment adaptations that may potentially reduce survival disparities. PMID- 29276060 TI - Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer. AB - PURPOSE/OBJECTIVE(S): Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset. MATERIALS/METHODS: We identified 3,723 patients with intermediate risk prostate cancer treated with BT between 1997 and 2013, including 1,989 and 1,734 patients with FIR and UIR disease, respectively. For the FIR cohort, Fine and Gray's competing risks regression model was used to evaluate whether there was a difference in prostate cancer specific mortality (PCSM) between BT vs. BT + supplemental therapy (ADT, EBRT, or both). For the UIR cohort, this regression model was used to evaluate whether supplemental ADT, EBRT, or both decreased PCSM beyond BT alone. Both regression models were adjusted for clinical and treatment-related factors. RESULTS: The median follow up periods were 7.7 years (interquartile range: 5.4-10.5) for the FIR cohort and 7.8 years (interquartile range: 5.3-10.6) for the UIR cohort. For the FIR cohort, there was no difference in PCSM between BT monotherapy vs. BT + supplemental therapy (adjusted hazard ratio [AHR] = 1.70; 95% CI: 0.46-6.29; P = 0.43). For the UIR cohort, supplemental EBRT (AHR = 2.66; 95% CI: 1.12-6.34; P = 0.03), ADT (AHR = 0.96; 95% CI: 0.38-2.43; P = 0.93), or both (AHR = 1.46; 95% CI: 0.42 5.01; P = 0.55) were not associated with improved PCSM compared with BT alone. CONCLUSION: In our analysis, supplemental therapies did not offer an improvement in PCSM compared with BT alone for FIR or UIR prostate cancers. Further prospective clinical trials are required to determine whether BT monotherapy may be sufficient for a subset of patients with UIR disease. PMID- 29276061 TI - Relationship between ABO blood group and outcome in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. PMID- 29276062 TI - Targeting urothelial carcinoma cells by combining cisplatin with a specific inhibitor of the autophagy-inducing class III PtdIns3K complex. AB - BACKGROUND: Cisplatin-based regimens are routinely employed for the treatment of urothelial carcinoma. However, therapeutic success is hampered by the primary presence of or the development of cisplatin resistance. This chemoresistance is executed by multiple cellular pathways. In recent years, the cellular process of autophagy has been identified as a prosurvival pathway of cancer cells. On the one hand, autophagy enables cancer cells to survive conditions of low oxygen or nutrient supply, frequently found in tumors. On the other hand, autophagy supports chemoresistance of cancer cells. Here, we aimed at investigating the involvement of autophagy for cisplatin resistance in different urothelial carcinoma cell lines. MATERIALS & METHODS: We analyzed the expression levels of different autophagy-related proteins in cisplatin-sensitive and cisplatin resistant urothelial carcinoma cell lines. Furthermore, we performed cell viability assays and caspase activity assays with cells treated with cisplatin, non-specific or specific autophagy inhibitors (chloroquine, 3-methyladenine, SAR405) or combinations thereof. RESULTS: We found that autophagy-related proteins are up-regulated in different cisplatin-resistant urothelial carcinoma cells compared to the sensitive parental cell lines. Furthermore, inhibition of autophagy, in general, or of the autophagy-inducing class III PtdIns3K complex, in particular, sensitized both sensitive and resistant urothelial carcinoma cells to cisplatin-induced cytotoxic effects. CONCLUSION: We propose that targeting the autophagic machinery might represent a suitable approach to complement or even increase cisplatin efficacy in order to overcome cisplatin resistance in urothelial carcinoma. PMID- 29276064 TI - Yoga classes may be an alternative to physiotherapy for people with chronic nonspecific low back pain [commentary]. PMID- 29276063 TI - Is sarcopenia and sarcopenic obesity associated with clinical and pathological outcomes in patients undergoing radical nephroureterectomy? AB - PURPOSE: To investigate the association between sarcopenia and sarcopenic obesity on clinical, perioperative, and oncologic outcomes in patients with upper-tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). METHODS: Retrospective review of our institutional UTUC database was performed to identify all patients who underwent radical nephroureterectomy from 2002-2016. Skeletal Muscle Index (SMI) was measured at the L3 vertebral level and standardized according to patient height (cm2/m2). Sarcopenia was defined as<55cm2/m2 for men and<39cm2/m2 for women. Sarcopenic obesity was also assessed in patients with BMI>30kg/m2. Unadjusted logistic regression and Wilcoxon rank sum tests examined the relationship between sarcopenia and variables. RESULTS: A total of 100 patients (66 men and 34 women) with a mean age of 68 years, BMI of 30, Charlson comorbidity index of 4.0, tumor size of 3.5, and SMI of 50.8cm2/m2 were included. Furthermore, 42 patients (42%) were sarcopenic, and 18 patients (18%) had sarcopenic obesity. Median EBL was 150ml, OR duration was 322 minutes, and length of stay was 5.0 days. Sarcopenia was associated with several clinical factors including decreasing BMI, male sex, and coronary artery disease, albeit without association with any perioperative or oncologic outcomes. Sarcopenic obesity was similarly associated with several clinical variables including male sex, diabetes mellitus, hyperlipidemia, as well as increased EBL (P = 0.047) and non-bladder cancer disease relapse (P = 0.049). CONCLUSIONS: This contemporary cohort of patients undergoing RNU highlights the association of nonmodifiable risk factors with sarcopenia and disease relapse with sarcopenic obesity. Larger studies are necessary to further validate these observations. PMID- 29276065 TI - Six months of strength training reduces progression of dorsiflexor muscle weakness in children with Charcot-Marie-Tooth disease [synopsis]. PMID- 29276067 TI - [Erratum to "Management of pregnant women with recurrent herpes. Guidelines for clinical practice from the French College of Gynecologists, Obstetricians (CNGOF)" [Gynecol. Obstet. Fertil. Senol. 45 (2017) 677-90]]. PMID- 29276066 TI - [Outcome of in utero transfusion in case of foetomaternal red blood cell incompatibility]. AB - OBJECTIVE: Erythrocyte allo-immunization's rate has decreased but without adapted treatment the prognosis is still poor. The aim of our study was to evaluate the fetal prognosis, the complication's rate and the risk factors of complications of the intrauterine transfusion. METHODS: Retrospective study about 37 fetus and 86 intrauterine transfusions between 2001 and 2017. Our main criterion in judging was the occurrence of procedure related complications: premature membrane rupture or premature delivery within seven days from the procedure, chorioamnionitis, abnormal fetal heart rate indicating an emergency ceasarean section within the 24hours from the procedure, in utero death or neonatal death related to the procedure. RESULTS: The survival rate was about 88.9% with a severe complication's rate of 5.8% per intrauterine transfusion and 13.5% per pregnancy. Intrauterine transfusions before 18 weeks of pregnancies was a complication risk factor: 50% of complications before 18 weeks vs. 1.3%, P=0.8*10-3. On the contrary, hydrops did not seem to be a complication risk factor (16.7% of complication with hydrops vs. 3.9%, P=0.27). The localisation of the needle insertion, intra-abdominal or placental insertion, had no effect on the fetal prognosis. CONCLUSION: Intrauterine transfusion complications are rare and it enhances the fetal prognosis. However, an early procedure is related to a higher rate of complications. PMID- 29276068 TI - What is needed to make low-density lipoprotein transport in human aorta computational models suitable to explore links to atherosclerosis? Impact of initial and inflow boundary conditions. AB - Personalized computational hemodynamics (CH) is a promising tool to clarify/predict the link between low density lipoproteins (LDL) transport in aorta, disturbed shear and atherogenesis. However, CH uses simplifying assumptions that represent sources of uncertainty. In particular, modelling blood side to wall LDL transfer is challenged by the cumbersomeness of protocols needed to obtain reliable LDL concentration profile estimations. This paucity of data is limiting the establishment of rigorous CH protocols able to balance the trade offs among the variety of in vivo data to be acquired, and the accuracy required by biological/clinical applications. In this study, we analyze the impact of LDL concentration initialization (initial conditions, ICs) and inflow boundary conditions (BCs) on CH models of LDL blood-to-wall transfer in aorta. Technically, in an image-based model of human aorta, two different inflow BCs are generated imposing subject-specific inflow 3D PC-MRI measured or idealized (flat) velocity profiles. For each simulated BC, four different ICs for LDL concentration are applied, imposing as IC the LDL distribution resulting from steady-state simulations with average conditions, or constant LDL concentration values. Based on CH results, we conclude that: (1) the imposition of realistic 3D velocity profiles as inflow BC reduces the uncertainty affecting the representation of LDL transfer; (2) different LDL concentration ICs lead to markedly different patterns of LDL transfer. Given that it is not possible to verify in vivo the proper LDL concentration initialization to be applied, we suggest to carefully set and unambiguously declare the imposed BCs and LDL concentration IC when modelling LDL transfer in aorta, in order to obtain reproducible and ultimately comparable results among different laboratories. PMID- 29276069 TI - Kinesio taping influences the mechanical behaviour of the skin of the low back: A possible pathway for functionally relevant effects. AB - Despite claims of functional benefits of kinesio tape application, little mechanistic evidence exists to support physiological pathways to achieve these benefits. As kinesio tape is adhered directly to the skin, it can be supposed that any pathway needs to first achieve effects at this level. To address this, two layers of the skin, the combined epidermis and dermis, as well as the hypodermis were studied. Specifically, -kinematic measures of skin surface stretch and retraction, as well as ultrasound measures of skin thickness, were made along all edges of kinesio tape applied over the low back. Results demonstrated that the more superficial skin layer (combined epidermis and dermis), but not the deeper hypodermis, was significantly stretched (p = .0001) and thinner (p = .0016) at either end of the tape, and significantly retracted (p < .0001) and thicker (p = .0001) along the lateral edges of the tape. These results were partly dependent upon spine posture; skin retraction along the tape edges was only apparent in neutral and flexed (but not extended) spine postures, while skin thinning at the tape ends was only apparent in neutral and extended (but not flexed) spine postures. Hypodermal thickness was not affected by kinesio tape application at any location or in any posture. In summary, measured deformations at the skin surface and within the epidermal and dermal regions provide plausible pathways through which kinesio tape could achieve its claimed benefits. PMID- 29276070 TI - A piecewise mass-spring-damper model of the human breast. AB - Previous models to predict breast movement whilst performing physical activities have, erroneously, assumed uniform elasticity within the breast. Consequently, the predicted displacements have not yet been satisfactorily validated. In this study, real time motion capture of the natural vibrations of a breast that followed, after raising and allowing it to fall freely, revealed an obvious difference in the vibration characteristics above and below the static equilibrium position. This implied that the elastic and viscous damping properties of a breast could vary under extension or compression. Therefore, a new piecewise mass-spring-damper model of a breast was developed with theoretical equations to derive values for its spring constants and damping coefficients from free-falling breast experiments. The effective breast mass was estimated from the breast volume extracted from a 3D body scanned image. The derived spring constant (ka = 73.5 N m-1) above the static equilibrium position was significantly smaller than that below it (kb = 658 N m-1), whereas the respective damping coefficients were similar (ca = 1.83 N s m-1, cb = 2.07 N s m-1). These values were used to predict the nipple displacement during bare-breasted running for validation. The predicted and experimental results had a 2.6% or less root-mean-square-error of the theoretical and experimental amplitudes, so the piecewise mass-spring-damper model and equations were considered to have been successfully validated. This provides a theoretical basis for further research into the dynamic, nonlinear viscoelastic properties of different breasts and the prediction of external forces for the necessary breast support during different sports activities. PMID- 29276071 TI - Enhancement of force patterns classification based on Gaussian distributions. AB - Description of the patterns of ground reaction force is a standard method in areas such as medicine, biomechanics and robotics. The fundamental parameter is the time course of the force, which is classified visually in particular in the field of clinical diagnostics. Here, the knowledge and experience of the diagnostician is relevant for its assessment. For an objective and valid discrimination of the ground reaction force pattern, a generic method, especially in the medical field, is absolutely necessary to describe the qualities of the time-course. The aim of the presented method was to combine the approaches of two existing procedures from the fields of machine learning and the Gauss approximation in order to take advantages of both methods for the classification of ground reaction force patterns. The current limitations of both methods could be eliminated by an overarching method. Twenty-nine male athletes from different sports were examined. Each participant was given the task of performing a one legged stopping maneuver on a force plate from the maximum possible starting speed. The individual time course of the ground reaction force of each subject was registered and approximated on the basis of eight Gaussian distributions. The descriptive coefficients were then classified using Bayesian regulated neural networks. The different sports served as the distinguishing feature. Although the athletes were all given the same task, all sports referred to a different quality in the time course of ground reaction force. Meanwhile within each sport, the athletes were homogeneous. With an overall prediction (R = 0.938) all subjects/sports were classified correctly with 94.29% accuracy. The combination of the two methods: the mathematical description of the time course of ground reaction forces on the basis of Gaussian distributions and their classification by means of Bayesian regulated neural networks, seems an adequate and promising method to discriminate the ground reaction forces without any loss of information. PMID- 29276073 TI - Corrigendum to "Regular treadmill exercise prevents sleep deprivation-induced disruption of synaptic plasticity and associated signaling cascade in the dentate gyrus" [Mol. Cell Neurosci. 56 (2013 Sep) 375-83]. PMID- 29276072 TI - Fluorescence Approaches Unravel Spatial and Temporal Aspects of GPCR Organisation, Location, and Intracellular Signalling. PMID- 29276075 TI - Steroids for sarcoidosis: How much and for how long? PMID- 29276074 TI - Kinases: Molecular Stage Directors for Schistosome Development and Differentiation. AB - Understanding schistosome biology is still a challenging mission. The reproductive biology of this parasitic trematode is closely associated with the pathologic consequences of schistosomiasis, the devastating infectious disease caused by members of the family Schistosomatidae worldwide. Recent studies of signaling mechanisms confirmed the prominent roles of protein kinases (PKs) in directing schistosome biology, and first evidence was obtained for an additional contribution of kinases with substrates different from proteins (non-PKs). This review provides an overview of the Schistosoma mansoni kinome in the context of male-female interaction and summarizes recent studies of kinases controlling development and differentiation. Due to their importance for schistosome biology, kinases represent Achilles' heels and are therefore of high value also for translational research. PMID- 29276076 TI - Robotic platform for gastric bypass is associated with more resource utilization: an analysis of MBSAQIP dataset. AB - BACKGROUND: The current literature comparing robot-assisted Roux-en-Y gastric bypass (RA-RYGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) is limited to single center retrospective series. OBJECTIVES: This study aims to compare perioperative outcomes of patients who underwent RA-RYGB with those who underwent LRYGB. SETTING: National database. METHODS: Data on patients who underwent RA RYGB and LRYGB were extracted from the 2015 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program participant use file. A 1:8 propensity score matching (RA-RYGB:LRYGB) was performed, and the 30-day outcomes of the propensity-matched cohorts were compared. RESULTS: In total, 36,158 patients met inclusion criteria, including 2660 RA-RYGB (7.4%) cases, which were propensity matched (1:8) with 21,280 LRYGB cases having similar preoperative characteristics. RA-RYGB was associated with longer median operative time (136 versus 107 min; P<.001) and a higher 30-day readmission rate (7.3% versus 6.2%; P = .03). There were no statistical differences between the RA-RYGB and LRYGB cohorts with respect to all-cause morbidity (10.6% versus 10.7%; P = .8), serious morbidity (1.2% versus 1.7%; P = .07), mortality (0.1% versus .2%; P = .2), unplanned intensive care unit admission (1.1% versus 1.3%; P = .3), reoperation (2.4% versus 2.4%; P = .97), or reintervention (3.0% versus 2.5%; P = .2) within 30 days after surgery. CONCLUSION: Based on available national data, RA-RYGB appears safe compared with a conventional laparoscopic approach for gastric bypass. However, RA-RYGB was associated with longer operative time and higher readmission rate, indicating greater resource use. Further studies are needed to better delineate the role of robotic platforms in bariatric surgery. PMID- 29276077 TI - ? PMID- 29276078 TI - Mode of action and synergistic effect of valinomycin and cereulide with amphotericin B against Candida albicans and Cryptococcus albidus. AB - Both valinomycin and cereulide are cyclic depsipeptides and are known K+ ion selective ionophores. Valinomycin and cereulide feature low minimum inhibitory concentration (MIC) values against Candida albicans and Cryptococcus albidus. This study aims at investigating the mode of action and verifying the efficacy of valinomycin or cereulide alone and in combination with amphotericin B (AmB) in vitro against both microorganisms. Based on the results from membrane permeability and fluidity assays for detection of plasma membrane permeabilization and membrane dynamics, the present study demonstrated that valinomycin and cereulide exhibit antifungal activity against C. albicans and C. albidus by interrupting membrane-associated function. The mode of action of both valinomycin and cereulide are similar with that of AmB. Time-kill kinetics assay showed that valinomycin and cereulide exhibit fungistatic activity, whereas AmB features fungicidal activity. Additionally, the combination of compounds between each cyclic peptide and AmB reached maximal fungicidal activity more rapidly than AmB alone. This result corresponded with findings of scanning electron microscopy, fractional inhibitory concentration index and minimum fungicidal concentration (MFC)/MIC ratio, indicating that combinations of the drugs show synergistic effects for inhibiting the growth of these fungal strains. Sorbitol and ergosterol assays showed that both cyclic peptides affected cell wall and membrane components due to increases in MIC value, as observed in medium with sorbitol and ergosterol. Valinomycin and cereulide may promote permeability of fungal cell wall and cell membrane when used in combination with AmB. PMID- 29276079 TI - A double sealing technique for increasing the precision of headspace-gas chromatographic analysis. AB - This paper investigates a new double sealing technique for increasing the precision of the headspace gas chromatographic method. The air leakage problem caused by the high pressure in the headspace vial during the headspace sampling process has a great impact to the measurement precision in the conventional headspace analysis (i.e., single sealing technique). The results (using ethanol solution as the model sample) show that the present technique is effective to minimize such a problem. The double sealing technique has an excellent measurement precision (RSD < 0.15%) and accuracy (recovery = 99.1%-100.6%) for the ethanol quantification. The detection precision of the present method was 10 20 times higher than that in earlier HS-GC work that use conventional single sealing technique. The present double sealing technique may open up a new avenue, and also serve as a general strategy for improving the performance (i.e., accuracy and precision) of headspace analysis of various volatile compounds. PMID- 29276080 TI - Extrathermodynamic parameters of sorption of light hydrocarbons on stationary phases prepared from tricyclononene polymers. AB - Enthalpy and entropy of adsorption of polar and non-polar solutes were measured by chromatographic technique for new stationary phases prepared from membrane polymers based on tricyclonones. Data obtained within temperature interval from 40 to 150 degrees C were used to create extrathermodynamic dependences (compensation plots, dependences of enthalpy and entropy changes on solute carbon number). Compensation plots were very similar for all the stationary phases indicating similar adsorption mechanisms. The difference between the stationary phases was elucidated using dependences of enthalpy and entropy changes on solute carbon number. Higher retentivity of the stationary phase based on polymer 1 was explained by higher both enthalpy and entropy of solute adsorption on the stationary phase. PMID- 29276081 TI - High-resolution separation of neodymium and dysprosium ions utilizing extractant impregnated graft-type particles. AB - An efficient method for rare metal recovery from environmental water and urban mines is in high demand. Toward rapid and high-resolution rare metal ion separation, a novel bis(2-ethylhexyl) phosphate (HDEHP)-impregnated graft-type particle as a filler for a chromatography column is proposed. To achieve rapid and high-resolution separation, a convection-flow-aided elution mode is required. The combination of 35 MUm non-porous particles and a polymer-brush-rich particle structure minimizes the distance from metal ion binding sites to the convection flow in the column, resulting in minimized diffusional mass transfer resistance and the convection-flow-aided elution mode. The HDEHP-impregnated graft-type non porous-particle-packed cartridge developed in this study exhibited a higher separation performance for model rare metals, neodymium (III) and dysprosium (III) ions, and a narrower peak at a higher linear velocity, than those of previous HDEHP-impregnated fiber-packed and commercially available Lewatit(r) VP OC 1026-packed cartridges. PMID- 29276082 TI - Anisotropic reversed micelles with fluorocarbon-hydrocarbon hybrid surfactants in supercritical CO2. AB - Previous work (M. Sagisaka, et al. Langmuir 31 (2015) 7479-7487), showed the most effective fluorocarbon (FC) and hydrocarbon (HC) chain lengths in the hybrid surfactants FCm-HCn (sodium 1-oxo-1-[4-(perfluoroalkyl)phenyl]alkane-2 sulfonates, where m = FC length and n = HC length) were m and n = 6 and 4 for water solubilization, whereas m 6 and n 6, or m 6 and n 5, were optimal chain lengths for reversed micelle elongation in supercritical CO2. To clarify why this difference of only a few methylene chain units is so effective at tuning the solubilizing power and reversed micelle morphology, nanostructures of water-in CO2 (W/CO2) microemulsions were investigated by high-pressure small-angle neutron scattering (SANS) measurements at different water-to-surfactant molar ratios (W0) and surfactant concentrations. By modelling SANS profiles with cylindrical and ellipsoidal form factors, the FC6-HCn/W/CO2 microemulsions were found to increase in size with increasing W0 and surfactant concentration. Ellipsoidal cross sectional radii of the FC6-HC4/W/CO2 microemulsion droplets increased linearly with W0, and finally reached ~39 A and ~78 A at W0 = 85 (close to the upper limit of solubilizing power). These systems appear to be the largest W/CO2 microemulsion droplets ever reported. The aqueous domains of FC6-HC6 rod-like reversed micelles increased in size by 3.5 times on increasing surfactant concentration from 35 mM to 50 mM: at 35 mM, FC6-HC5 formed rod-like reversed micelles 5.3 times larger than FC6-HC6. Interestingly, these results suggest that hybrid HC-chains partition into the microemulsion aqueous cores with the sulfonate headgroups, or at the W/CO2 interfaces, and so play important roles for tuning the W/CO2 interfacial curvature. The super-efficient W/CO2-type solubilizer FC6-HC4, and the rod-like reversed micelle forming surfactant FC6 HC5, represent the most successful cases of low fluorine content additives. These surfactants facilitate VOC-free, effective and energy-saving CO2 solvent systems for applications such as extraction, dyeing, dry cleaning, metal-plating, enhanced oil recovery and organic/inorganic or nanomaterial synthesis. PMID- 29276083 TI - [Left ventricular hypertrophy in chronic hemodialysis patients at CNHU-HKM of Cotonou]. AB - INTRODUCTION: Left ventricular hypertrophy (LVH) is a predictor of mortality in hemodialysis. It takes a very high proportion among cardiovascular complications. OBJECTIVE: It was to determine the frequency of LVH and identify its associated factors among chronic hemodialysis patients of CNHU-HKM. METHODS: This is a cross sectional, descriptive and analytical, which took place 1st February to 31st October 2014. The sample consisted of patients aged over 15 years, chronic hemodialysis for at least 3 months. LVH is defined by a Left Ventricular Mass Index (LVMI)>115 g/m2 for men and >95 g/m2 in women. Doppler ultrasound was performed during 15 to 20 hours after the last hemodialysis session. Factors associated as sociodemographic characteristics, history, biological data, dialysis parameters were sought by logistic regression univariate analysis. The significance level was less than 0.05. ReSULTS: The sample size was 141 patients, 39% of women with a sex-ratio of 1.6. The average age was 50.1+/-12.3 years. The frequency of hypertension was 67.4%; diabetes: 14.9%; smoking: 9.2%; the rise of the pre-dialysis blood pression: 46.8%. The frequency of LVH was 54.6% and the associated factors were: the elevation of the predialysis blood pression (P=0.04), obesity (P=0.01), central catheter (P=0.03), anemia (P=0.02) and cardiomegaly (P<0.001). CONCLUSION: LVH is frequent in hemodialysis of CNHU-HKM. It is necessary to optimize the hemodialysis sessions and to achieve better management of associated factors. PMID- 29276084 TI - Just-So Stories and Origin Myths: Phosphorylation and Structural Disorder in Circadian Clock Proteins. AB - Some longstanding dogmas in the circadian field warrant reexamination in light of recent studies focused on the role of post-translational modifications and intrinsic disorder in core circadian clock proteins of mice and fungi. Such dogmas include the role of turnover in circadian feedback loops and the origin myths describing evolutionary relatedness among circadian clocks. In this Essay, the authors recapitulate recent findings on circadian clock protein regulation by taking an unconventional approach in the form of a dialog between Wizard and Apprentice. PMID- 29276086 TI - Perioperative Management of Pheochromocytoma Resection in a Patient With Severe Aortic Stenosis. PMID- 29276085 TI - Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation. AB - Alternative mRNA processing is a critical mechanism for proteome expansion and gene regulation in higher eukaryotes. The SR family proteins play important roles in splicing regulation. Intriguingly, mammalian genomes encode many poorly characterized SR-like proteins, including subunits of the mRNA 3'-processing factor CFIm, CFIm68 and CFIm59. Here we demonstrate that CFIm functions as an enhancer-dependent activator of mRNA 3' processing. CFIm regulates global alternative polyadenylation (APA) by specifically binding and activating enhancer containing poly(A) sites (PASs). Importantly, the CFIm activator functions are mediated by the arginine-serine repeat (RS) domains of CFIm68/59, which bind specifically to an RS-like region in the CPSF subunit Fip1, and this interaction is inhibited by CFIm68/59 hyper-phosphorylation. The remarkable functional similarities between CFIm and SR proteins suggest that interactions between RS like domains in regulatory and core factors may provide a common activation mechanism for mRNA 3' processing, splicing, and potentially other steps in RNA metabolism. PMID- 29276087 TI - Acquired Factor VIII Inhibitor and Cardiopulmonary Bypass. PMID- 29276088 TI - Does an Iatrogenic Immunocompromised State Contribute to Healthcare-Associated Mycobacterium chimaera Infection From Heater-Cooler Devices? PMID- 29276089 TI - Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation (VA ECMO) in Adult Patients - Many Questions, Few Answers, and Hard Choices. PMID- 29276090 TI - Anesthesia for Lung Transplantation in Cystic Fibrosis: Retrospective Review from the Irish National Transplantation Centre. AB - Cystic fibrosis (CF) is an autosomal recessive disorder affecting approximately 1 in 2,500 live births worldwide, with double this estimated frequency in Ireland. CF is characterized by a genetic defect of the CF transmembrane regulator protein, causing impairment of chloride ion transportation. This has multisystem consequences, particularly in the lungs, where it results in intensely mucoid secretions, which increases susceptibility to infection. Lung transplantation is indicated in CF when there is progressive decline in a patient's functional reserve. In this report, the authors present a 6-year case review of allograft lung transplantations in 41 CF patients from the Irish National Centre for Lung Transplantation from 2010 through 2015. Preoperative risk factors for morbidity and major mortality are discussed. The authors' experience with intraoperative anesthetic challenges and management options are outlined, and postoperative complications are discussed. PMID- 29276091 TI - Using Intraoperative TTE Evaluates Cardiac Function During Bone Cement Placement in Orthopedic Trauma Patients. PMID- 29276092 TI - The Educational Evolution of Fellowship Training in Cardiothoracic Anesthesiology - Perspectives From Program Directors Around the United States. PMID- 29276093 TI - Heart Failure With Preserved Ejection Fraction-A Systematic Review and Analysis of Perioperative Outcomes. PMID- 29276094 TI - Measures of Blood Hemoglobin and Hematocrit During Cardiac Surgery: Comparison of Three Point-of-Care Devices. AB - OBJECTIVE: The primary objective was to compare I-Stat, HemoCue, and RapidLab in measurements of the hemoglobin concentration during cardiac surgeries using cardiopulmonary bypass. DESIGN: Prospective analysis. SETTING: Single-center, academic, tertiary care cardiovascular center. PARTICIPANTS: Thirty-four consecutive patients undergoing cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: Blood samples have been collected intraoperatively, and the hemoglobin concentration in each sample was measured, or calculated, simultaneously by the 3 point-of-care devices, HemoCue, RapidLab, and I-Stat. MEASUREMENTS AND MAIN RESULTS: Correlation coefficients from the regression analysis for HemoCue versus I-Stat, RapidLab versus HemoCue, and RapidLab versus I-Stat were 0.89, 0.96, and 0.88, respectively. Results of the Bland-Altman analysis of the hemoglobin concentration measurements for each device against one another (Fig 1) were as follows: RapidLab versus I-Stat (bias 0.42; 95% confidence interval [CI], -1.05 to 1.89), I-Stat versus HemoCue (bias 0.23; 95% CI, -1.14 to 1.59), and RapidLab versus HemoCue (bias 0.65; 95% CI, -0.17 to 1.47). It appears that I-Stat slightly underestimated the concentration of hemoglobin when compared with both RapidLab and HemoCue. The results of Bland Altman analysis of each device to a mean Z value (Fig 2) were as follows: RapidLab versus Z (bias 0.36; 95% CI, -0.29 to 1.01), I-Stat versus Z (bias 0.07; CI -0.97 to 0.84), and HemoCue versus Z (bias -0.29; 95% CI, -0.86 to 0.28). Based on the 174 paired samples used for the Pearson moment analysis, the R2 values for I-Stat versus HemoCue, I-Stat versus RapidLab, and RapidLab versus HemoCue were 0.79, 0.80, and 0.87, respectively CONCLUSIONS: These data support the interchangeability of these 3 devices for the intermittent intraoperative point-of-care assessment of hemoglobin concentrations in cardiac surgery patients. It is important, however, to consider the possible pitfalls associated with each device when making a clinical decision to transfuse. PMID- 29276095 TI - An ambivalent common bile duct. PMID- 29276096 TI - The association of variations in TLR genes and spontaneous immune control of hepatitis B virus. AB - BACKGROUND: Toll-like receptors (TLRs) are suspected to play a critical role in liver diseases and the progression of chronic hepatitis B (CHB) infection. In this study, we investigated the possible association between TLRs and hepatitis B virus (HBV) infection chronicity in Turkish population. METHODS: TLR4 (+896 A->G) (rs4986790), TLR5 (+1846 T->C) (rs5744174) and TLR9 (-1237T->C) (rs5743836) polymorphisms were screened in 131 CHB patient and 168 individuals by polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) technique. RESULTS: Of the screened polymorphisms, TT genotype of the missense variant TLR5 (rs5744174) (NM_003268.5:c.1846T>C (p.Phe616Leu) is significantly more frequent in the control group than CHB patients (P<0.001), presence of TT genotype of the upstream variant TLR9 (rs5743836) (NM_017442.3:c.-1237T>C) is more frequent in CHB group (P=0.043). However, no significant association was found for the missense variant TLR4 (rs4986790) NM_138554.4:c.896A>G (p.Asp299Gly) polymorphism and CHB in Turkish population. CONCLUSIONS: From all three analyzed SNPs association of TLR5 (rs5744174) with CHB is the most significant. Since TLR5 is associated with interferon-gamma production, a high frequency of TT at rs5744174 in controls subjects suggests that it represents a protective genotype against CHB plausibly associated with an increased interferon-gamma production. PMID- 29276097 TI - Abomasal and Third Compartment Ulcers in Ruminants and South American Camelids. AB - Abomasal ulcers are frequent incidental findings in necropsies of domestic ruminants and South American Camelids (SAC) or in slaughter animals and are a frequent cause of death in the most affected group of cattle, veal calves. Their true prevalence and significance is unknown owing to limitations in diagnosing the condition in live animals. This article discusses types of ulcers, possible causes of ulceration, and the clinical consequences, symptoms, and differential diagnoses, as well as further diagnostics in cattle, small ruminants and SAC. The limited treatment options and possibilities for prevention are reviewed. PMID- 29276098 TI - Vaccinology and Immunology: Current Knowledge, New Discoveries, and Future Directions. PMID- 29276099 TI - Lethal (3) malignant brain tumor-like 2 (L3MBTL2) protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells. AB - DNA damage contributes to renal tubular cell death during kidney injury, but how DNA damage in tubular cells is regulated is not fully understood. Lethal (3) malignant brain tumor-like 2 (L3MBTL2), a novel polycomb group protein, has been implicated in regulating chromatin architecture. However, the biological functions of L3MBTL2 are largely undefined. Here we found that L3MBTL2 was expressed in the nuclei of renal tubular epithelial cells in mice. Ablation of L3mbtl2 in renal tubular cells resulted in increases in nuclear DNA damage, p53 activation, apoptosis, tubular injury and kidney dysfunction after cisplatin treatment or unilateral ureteral obstruction. In vitro, inhibition of L3MBTL2 sequentially promoted histone gammaH2AX expression, p53 activation and apoptosis in cisplatin-treated mouse proximal tubular TKPTS cells. Inhibition of p53 activity attenuated the apoptosis induced by L3mbtl2 deficiency after cisplatin treatment both in vivo and in vitro. Intriguingly, unlike other polycomb proteins, L3MBTL2 was not recruited to DNA damage sites, but instead increased nuclear chromatin density and reduced initial DNA damage load. Thus, L3MBTL2 plays a protective role in kidney injury, in part by inhibiting the DNA damage p53-apoptosis pathway. PMID- 29276100 TI - Revisiting RAAS blockade in CKD with newer potassium-binding drugs. AB - Among patients with proteinuric chronic kidney disease (CKD), current guideline recommendations mandate the use of agents blocking the renin angiotensin aldosterone system (RAAS) as first-line antihypertensive therapy based on randomized trials demonstrating that RAAS inhibitors are superior to other antihypertensive drug classes in slowing nephropathy progression to end-stage renal disease. However, the opportunities for adequate RAAS blockade in CKD are often limited, and an important impediment is the risk of hyperkalemia, especially when RAAS inhibitors are used in maximal doses or are combined. Accordingly, a large proportion of patients with proteinuric CKD may not have the anticipated renoprotective benefits since RAAS blockers are often discontinued due to incident hyperkalemia or are administered at suboptimal doses for fear of the development of hyperkalemia. Two newer potassium binders, patiromer and sodium zirconium cyclosilicate (ZS-9), have been shown to effectively and safely reduce serum potassium levels and maintain long-term normokalemia in CKD patients receiving background therapy with RAAS inhibitors. Whether these novel potassium lowering therapies can overcome the barrier of hyperkalemia and enhance the tolerability of RAAS inhibitor use in proteinuric CKD awaits randomized trials. PMID- 29276101 TI - CD44 is required for the pathogenesis of experimental crescentic glomerulonephritis and collapsing focal segmental glomerulosclerosis. AB - A key feature of glomerular diseases such as crescentic glomerulonephritis and focal segmental glomerulosclerosis is the activation, migration and proliferation of parietal epithelial cells. CD44-positive activated parietal epithelial cells have been identified in proliferative cellular lesions in glomerular disease. However, it remains unknown whether CD44-positive parietal epithelial cells contribute to the pathogenesis of scarring glomerular diseases. Here, we evaluated this in experimental crescentic glomerulonephritis and the transgenic anti-Thy1.1 model for collapsing focal segmental glomerulosclerosis in CD44 deficient (cd44-/-) and wild type mice. For both models albuminuria was significantly lower in cd44-/- compared to wild type mice. The number of glomerular Ki67-positive proliferating cells was significantly reduced in cd44-/- compared to wild type mice, which was associated with a reduced number of glomerular lesions in crescentic glomerulonephritis. In collapsing focal segmental glomerulosclerosis, the extracapillary proliferative cellular lesions were smaller in cd44-/- mice, but the number of glomerular lesions was not different compared to wild type mice. For crescentic glomerulonephritis the influx of granulocytes and macrophages into the glomerulus was similar. In vitro, the growth of CD44-deficient murine parietal epithelial cells was reduced compared to wild type parietal epithelial cells, and human parietal epithelial cell migration could be inhibited using antibodies directed against CD44. Thus, CD44-positive proliferating glomerular cells, most likely parietal epithelial cells, are essential in the pathogenesis of scarring glomerular disease. PMID- 29276102 TI - Impact of a patient engagement tool on preventive service uptake. AB - BACKGROUND: We studied whether integrating the US Department of Health and Human Services' myHealthfinder tool, an interactive tool that recommends preventive services, into CVS Health's digital platforms could increase preventive service uptake at its retail clinic, MinuteClinic. METHODS: We used a quasi-experimental, pre-post, difference-in-differences design. In a web-based campaign, consumers in "exposed" states visiting CVS pharmacy and MinuteClinic websites could view and use the myHealthfinder tool. Consumers in "unexposed" states could not. A September 26, 2015 email campaign to registered MinuteClinic patients in exposed states described and included links to the myhealthfinder tool. We assessed consumer engagement with the myHealthfinder tool via number of website visits, myHealthfinder sessions, and myHealthfinder recommendations delivered. Using the difference-in-differences approach, we assessed mean changes in influenza, pneumococcal, and/or hepatitis A vaccine uptake, as well as other preventive services, per clinic, per month at MinuteClinics. RESULTS: In exposed states, 39,225 (1.6%) website visits included myhealthfinder use, and 13,688 personalized recommendations for preventive services were delivered. The web-based campaign was associated with an increase in mean pneumococcal vaccines (1.19 vaccines per clinic per month; 95% CI, 0.11-2.28). The email campaign resulted in a 5% increase in influenza vaccines (74.83 vaccines per clinic per month; 1.65 148.02). The myhealthfinder campaigns did not significantly change preventive service uptake for any of the other services at MinuteClinics. CONCLUSIONS: Our findings highlight the potential role of personalized patient education tools and public-private partnerships to communicate about preventive care. Getting patients to act on these recommendations was more difficult. PMID- 29276103 TI - Introduction. PMID- 29276104 TI - Determination of MIC and disk diffusion quality control guidelines for meropenem vaborbactam, a novel carbapenem/boronic acid beta-lactamase inhibitor combination. AB - Meropenem-vaborbactam is a carbapenem/cyclic boronic acid beta-lactamase inhibitor combination primarily active against Gram-negative bacilli, including those harboring class A serine carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC). A Clinical and Laboratory Standards Institute M23-A4 (Tier 2) quality control study established broth microdilution and disk diffusion ranges for reference strains. Two KPC-producing K. pneumoniae ATCC strains are recommended for quality control testing. PMID- 29276105 TI - Grip strength measurement for frailty assessment in patients with vascular disease and associations with comorbidity, cardiac risk, and sarcopenia. AB - OBJECTIVE: Frailty is associated with adverse events, length of stay, and nonhome discharge after vascular surgery. Frailty measures based on walking-based tests may be impractical or invalid for patients with walking impairment from symptoms or sequelae of vascular disease. We hypothesized that grip strength is associated with frailty, comorbidity, and cardiac risk among patients with vascular disease. METHODS: Dominant hand grip strength was measured during ambulatory clinic visits among patients with vascular disease (abdominal aortic aneurysm [AAA], carotid stenosis, and peripheral artery disease [PAD]). Frailty prevalence was defined on the basis of the 20th percentile of community-dwelling population estimates adjusted for age, gender, and body mass index. Associations between grip strength, Charlson Comorbidity Index (CCI), Revised Cardiac Risk Index (RCRI), and sarcopenia (based on total psoas area for patients with cross-sectional abdominal imaging) were evaluated using linear and logistic regression. RESULTS: Grip strength was measured in 311 participants; all had sufficient data for CCI calculation, 217 (69.8%) had sufficient data for RCRI, and 88 (28.3%) had cross sectional imaging permitting psoas measurement. Eighty-six participants (27.7%) were categorized as frail on the basis of grip strength. Frailty was associated with CCI (odds ratio, 1.86; 95% confidence interval, 1.34-2.57; P = .0002) in the multivariable model. Frail participants also had a higher average number of RCRI components vs nonfrail patients (mean +/- standard deviation, 1.8 +/- 0.8 for frail vs 1.5 +/- 0.7 for nonfrail; P = .018); frailty was also associated with RCRI in the adjusted multivariable model (odds ratio, 1.75; 95% confidence interval, 1.16-2.64; P = .008). Total psoas area was lower among patients categorized as frail vs nonfrail on the basis of grip strength (21.0 +/- 6.6 vs 25.4 +/- 7.4; P = .010). Each 10 cm2 increase in psoas area was associated with a 5.7 kg increase in grip strength in a multivariable model adjusting for age and gender (P < .0001). Adjusted least squares mean psoas diameter estimates were 25.5 +/- 1.1 cm2 for participants with AAA, 26.7 +/- 2.0 cm2 for participants with carotid stenosis, and 22.7 +/- 0.8 cm2 for participants with PAD (P = .053 for PAD vs AAA; P = .057 for PAD vs carotid stenosis; and P = .564 for AAA vs carotid stenosis). CONCLUSIONS: Grip strength is useful for identifying frailty among patients with vascular disease. Frail status based on grip strength is associated with comorbidity, cardiac risk, and sarcopenia in this population. These findings suggest that grip strength may have utility as a simple and inexpensive risk screening tool that is easily implemented in ambulatory clinics, avoids the need for imaging, and overcomes possible limitations of walking-based measures. Lower mean psoas diameters among patients with PAD vs other diagnoses may warrant consideration of specific approaches to morphomic analysis. PMID- 29276106 TI - Natural history of the proximal aorta in patients with descending thoracic aortic disease. AB - OBJECTIVE: This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease. METHODS: We examined 200 patients with descending thoracic aortic disease including acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow up (n = 108). Survival data were derived from all 200 patients in this study. RESULTS: Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 +/- 0.51 cm in the root, 3.67 +/- 0.48 cm in the ascending aorta, and 3.50 +/- 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 +/- 0.64 mm/y, 0.26 +/- 0.44 mm/y, and 0.25 +/- 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter >=4.1 cm grew faster than those <4.1 cm at the ascending aorta (P = .028) and proximal arch (P = .019). There was no difference in aortic growth rates at the aortic root (P = .887). After the index scan, five patients underwent six ascending aortic replacement procedures, leading to a 3% ascending aortic intervention rate. Overall median life expectancy was 86.15 years. CONCLUSIONS: Native ascending aortic growth in patients with descending thoracic aortic disease is slow. We suggest regular follow-up for index ascending aorta >=4.1 cm because of its larger initial size and more rapid growth. PMID- 29276108 TI - Sex-based outcomes of lower extremity bypass surgery in hemodialysis patients. AB - OBJECTIVE: The objective of this study was to compare conduit use and surgical outcomes of hemodialysis-dependent men and women after open lower extremity bypass surgery. METHODS: Using the United States Renal Data System, we studied all hemodialysis patients in the United States who underwent infrainguinal bypass surgery between January 1, 2006, and December 31, 2011. Univariate methods (chi2, analysis of variance) were employed to compare patient and bypass characteristics between men and women. Kaplan-Meier, univariate and multivariate logistic, and Cox regression analyses were employed to evaluate outcomes that included patency, graft failure, and mortality at 30 days. In addition, we compared limb salvage and patient survival rates between men and women. RESULTS: There were 9739 bypasses performed in 5927 (61%) men and 3812 (39%) women who presented most commonly with critical limb ischemia (men, 73%; women, 71%; P = .04). Bypass configurations were femoral-popliteal (48%), femoral-tibial (34%), and popliteal tibial (18%). The prevalence of autogenous conduits was higher for men (61 vs 55%; P < .001), and they were associated with higher patency compared with prosthetics (adjusted hazard ratio [aHR], 1.10; 95% confidence interval [CI], 1.01-1.19; P = .03). The risk-adjusted analyses revealed higher odds of acute graft failure for women compared with men who received prosthetic conduits (adjusted odds ratio, 1.23; 95% CI, 1.03-1.46; P = .021) but not among patients who received autogenous conduits (adjusted odds ratio, 1.07; 95% CI, 0.91-1.25; P = .41). Despite the difference in choice of conduit, there was no significant difference in primary patency (aHR, 1.00; 95% CI, 0.95-1.06; P = .90), primary assisted patency (aHR, 1.03; 95% CI, 0.97-1.10; P = .28), secondary patency (aHR, 1.01; 95% CI, 0.95-1.08; P = .75), limb salvage (aHR, 0.97; 95% CI, 0.90-1.04; P = .41), and survival (aHR, 0.97; 95% CI, 0.92-1.03; P = .45) for women compared with men. CONCLUSIONS: We found lower use of autogenous conduits in women than in men. In patients who received prosthetic conduit, acute graft failure was higher for women than for men. The benefits of autogenous conduits over prosthetic grafts underscore the need to improve the selection of appropriately sized autogenous conduits for bypass irrespective of gender. PMID- 29276109 TI - Determining patient risk factors associated with accelerated growth of popliteal artery aneurysms. AB - OBJECTIVE: The objective of this study was to determine the natural progression of popliteal artery aneurysms (PAAs) and clinical variables associated with their accelerated growth. METHODS: Retrospective chart review of 224 patients with encounters between January 2008 and May 2016 and with at least one PAA was conducted. From this group, 65 asymptomatic patients had either unilateral (n = 43) or bilateral (n = 22) PAAs that were observed for at least 1 year of medical management before intervention. We divided these aneurysms into two groups based on whether their overall growth rate was above or below the eventual mean. Aneurysm diameter was taken from duplex ultrasound and computed tomography angiography. RESULTS: There were 87 aneurysms evaluated among 65 patients. Mean age at diagnosis was 70.9 years (standard deviation [SD], 9.39 years), and 64 patients were male (98%); 50 (77%) were white and 7 (11%) were African American. The average body mass index was 27.69 (SD, 4.90). At or before initial diagnosis, 61 (94%) patients had a concomitant lower extremity or abdominal aortic aneurysm; 51 (78%) patients were current or former smokers; and 16 (25%) had atrial fibrillation. The average growth rate of all aneurysms was 1.22 mm/y (SD, 1.93 mm). The mean surveillance time from initial diagnosis to last follow-up or intervention was 3.12 years (SD, 1.66 years). Of 87 aneurysms, 25 (29%) were repaired; 18 (21%) were repaired because of size criteria, 2 (2%) because of symptom criteria (claudication or acute limb ischemia), and 5 (6%) because of both criteria. During our study window, 62 aneurysms (71%) remained asymptomatic or did not undergo an intervention. The mean initial diameter at diagnosis was 16.9 mm (SD, 5.32 mm). Within the study, 50 (57%) aneurysms presented with or developed mural thrombus. Univariate analysis identified larger initial diameter (19.2 vs 14.7 mm; P = .020), atrial fibrillation (35% vs 16%; P = .042), and mural thrombus (38% vs 20%; P < .001) as predictors of diameter expansion greater than the mean. Multivariable analysis of the significant univariate factors determined that only initial diameter (odds ratio, 5.53; P = .007) and the presence or development of mural thrombus (odds ratio, 4.00; P = .008) maintained significance. CONCLUSIONS: Patients presenting with a PAA at 20 mm or >20 mm in diameter, presence of luminal thrombus, or atrial fibrillation may need to be observed at more frequent scanning intervals than those without these risk factors. Further studies are required to validate these predictive growth factors. PMID- 29276110 TI - Imaging Features of Common Pediatric Intracranial Tumours: A Primer for the Radiology Trainee. PMID- 29276107 TI - Relationship of femoral artery ultrasound measures of atherosclerosis with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is strongly associated with peripheral artery disease (PAD). Detection of subclinical PAD may allow early interventions for or prevention of PAD in persons with CKD. Whether the presence of atherosclerotic plaque and femoral intima-media thickness (IMT) are associated with kidney function is unknown. METHODS: We performed a cross-sectional observational study of 1029 community-living adults. We measured superficial and common femoral artery IMT and atherosclerotic plaque presence by ultrasound. Estimated glomerular filtration rate (eGFR; continuous) and eGFR <60 mL/min/1.73 m2 (binary) were evaluated as outcomes. RESULTS: Mean age was 70 +/- 10 years, mean eGFR was 78 +/- 17 mL/min/1.73 m2, and 156 (15%) individuals had eGFR <60 mL/min/1.73 m2; 260 (25%) had femoral artery plaque. In models adjusted for demographics and cardiovascular risk factors, individuals with femoral artery plaque had mean eGFR approximately 3.0 (95% confidence interval, -5.3 to -0.8) mL/min/1.73 m2 lower than those without plaque (P < .01). The presence of plaque was also associated with a 1.7-fold higher odds of eGFR <60 mL/min/1.73 m2 (95% confidence interval, 1.1-2.8; P < .02). Associations were similar in persons with normal ankle-brachial index. The directions of associations were similar for femoral IMT measures with eGFR and CKD but were rendered no longer statistically significant with adjustment for demographic variables and cardiovascular disease risk factors. CONCLUSIONS: Femoral artery plaque is significantly associated with CKD prevalence in community-living individuals, even among those with normal ankle-brachial index. Femoral artery ultrasound may allow evaluation of relationships and risk factors linking PAD and kidney disease earlier in its course. PMID- 29276111 TI - Efficient detoxification of corn cob hydrolysate with ion-exchange resins for enhanced xylitol production by Candida tropicalis MTCC 6192. AB - The present study demonstrates utilization of secondary agricultural wastes for xylitol production. The highest xylan-to-xylose (70%) conversion was achieved using dilute nitric acid as catalyst followed by resin treatment. Results show that resin treatment efficiently removed nitrate salt (70%), phenolic content and 5-HMF (70%). Highest xylitol yield (85%) was achieved during fermentation using Candida tropicalis MTCC 6192 from the neutralized hemicellulosic hydrolysate medium. Good recovery (>15%) was achieved from corncob with 85% xylose to xylitol conversion during fermentation. This two-step process for transformation of agri waste to xylitol is much simpler and it could possibly be considered for up scaling after process optimization parameters. PMID- 29276112 TI - Tetramethyl ammonium hydroxide production using the microbial electrolysis desalination and chemical-production cell with long anode. AB - The aim of this study was to investigate the feasibility to improve the tetramethyl ammonium hydroxide (TMAH) production in the microbial electrolysis desalination and chemical-production cell (MEDCC) with long anode of 48 cm. Different concentrations of tetramethylammonium chloride (0.3-0.7 M) and applied voltages (1.5-3.5 V) were tested in the MEDCC. With 0.6 M of tetramethylammonium chloride as the raw material and under the applied voltage of 3.5 V, the maximum TMAH production rate in the MEDCC reached 1.13 +/- 0.12 mmol/h, which was 9.4 times higher than those previously reported in the MEDCCs. The maximum current density of 41.0 +/- 4.0 A/m2 in the MEDCC was obtained, which was the highest value in the bioelectrochemical systems using the carbon cloth or carbon brush as the anode so far. Our results should provide a promising method to improve the TMAH production and boost the MEDCC application. PMID- 29276114 TI - Acacetin protects against cardiac remodeling after myocardial infarction by mediating MAPK and PI3K/Akt signal pathway. AB - Since inhibiting cardiac remodeling is a critical treatment goal after myocardial infarction (MI), many drugs have been evaluated for this purpose. Acacetin is a flavonoid compound that has been shown to have anti-cancer, anti-mutagenic, anti inflammatory and anti-peroxidative effects. In this study, we investigated whether acacetin is able to exert a protective effect against MI. One week after anterior wall standard MI surgeries or sham surgeries were performed in mice, acacetin was administered via gavage for two weeks. The results of echocardiographic and hemodynamic evaluation revealed that cardiac dysfunction significantly improved after acacetin treatment. H&E staining indicated that the ratio of the infarct size and the cardiomyocyte cross-sectional area was decreased by acacetin. Masson's staining detected that the fibrotic area ratio was evidently lower in the acacetin-treated MI group. TUNEL assays showed that acacetin ameliorated cardiomyocyte apoptosis after MI. RT-qPCR analysis showed that levels of hypertrophic and fibrotic markers were significantly decreased after acacetin treatment. Western blot analysis of various signaling pathway proteins showed that acacetin targets the MAPK and PI3K/Akt signaling pathways. Collectively, acacetin improves mouse left ventricular function and attenuates cardiac remodeling by inhibiting of the MAPK and PI3K/Akt signaling pathway. PMID- 29276115 TI - The Cost-Effectiveness of Total Hip Arthroplasty in Patients 80 Years of Age and Older. AB - BACKGROUND: This study investigates the cost-effectiveness of total hip arthroplasty (THA) in patients 80 years old. METHODS: A Markov, state-transition model projecting lifetime costs and quality-adjusted life years (QALYs) was constructed to determine cost-effectiveness from a societal perspective. Costs (in 2016 US dollars), health state utilities, and state transition probabilities were obtained from published literature. Primary outcome was incremental cost effectiveness ratio, with a willingness-to-pay threshold of $100,000/QALY. Sensitivity analyses were performed to evaluate parameter assumptions. RESULTS: At our base-case values, THA was cost-effective compared to non-operative treatment with a total lifetime accrued cost of $186,444 vs $182,732, and a higher lifetime accrued utility (5.60 vs 5.09). Cost per QALY for THA was $33,318 vs $35,914 for non-operative management, and the incremental cost-effectiveness ratio was $7307 per QALY. Sensitivity analysis demonstrated THA to be cost effective with a utility of successful primary THA above 0.67, a peri-operative mortality risk below 0.14, and a risk of primary THA failure below 0.14. Analysis further demonstrated that THA is a cost-effective option below a base-rate mortality threshold of 0.19, corresponding to the average base-rate mortality of a 93-year-old individual. Markov cohort analysis indicated that for patients undergoing THA at age 80 there was an approximate 28% reduction in total lifetime long-term assisted living expenditure compared to non-operatively managed patients with end-stage hip osteoarthritis. CONCLUSION: The results of our model demonstrate that THA is a cost-effective option compared to non-operative management in patients >=80 years old. This analysis may inform policy regarding THA in elderly patients. PMID- 29276113 TI - Ayurveda and the science of aging. AB - Since time immemorial, humanity has been concerned with developing and preserving youthful vigor, and extending longevity by stopping or delaying the aging process. By 2030, one in five of the world population will be over 65 years old. Longevity and old age are accompanied with a variety of health challenges and population studies indicate that the elderly will use between three to five times more healthcare services compared to the younger population. Modern medicine has made a great deal of progress in understanding the aging process and in controlling age-associated health issues including heart attacks, strokes, diabetes, cancer, senility, and arthritis. Thus, every individual is now looking forward to a youthful, productive lifespan of 100 or more years filled with unlimited health and opportunity. Research by aging experts is focused on ways to go against the natural order of the aging process in order to delay it. Interventions include among other things anti-aging pills, restricted food consumption and cloning body parts to stay young and delay biological aging. Ayurveda, one of the world's most authoritative mind-body-spirit medicinal systems, offers various concepts of the aging process. This system of medicine includes therapies for healthy aging so as to create an optimal health and lengthen an individual's healthspan by living in harmony with nature. This review will explore various aspects of aging and longevity by comparing the science of aging as defined by modern medicine with the Ayurvedic treatise of Jara and Vriddhavastha. PMID- 29276116 TI - Effect of Pelvic Tilt and Rotation on Cup Orientation in Both Supine and Standing Positions. AB - BACKGROUND: The purpose of this study is to analyze the effect of pelvic tilt and rotation on radiographic measurement of cup orientation. METHODS: A total of 68 patients (79 hips) were included in this study. The patients had a computed tomography study and approximately 3 months of postoperative standing anteroposterior pelvic radiographs in both supine and standing positions. We used 2-dimensional (2D)/3-dimensional (3D) matching to measure pelvic tilt and rotation, and cup orientation. RESULTS: There was a wide range of pelvic tilt between individuals in both supine and standing positions. Supine pelvic tilt was different from standing pelvic tilt (P < .05). There were differences in cup anteversion before and after 2D/3D matching in both supine and standing positions (P < .05). Supine and standing pelvic tilt correlated with differences in cup anteversion before and after 2D/3D matching. When all 79 hips were separated into right and left side, pelvic rotation inversely correlated with the pelvic tilt adjusted difference in anteversion before and after 2D/3D matching of the right side but directly correlated with that of the left side in both supine and standing positions. CONCLUSION: This study demonstrated that the measurement of cup anteversion on anteroposterior radiographs is significantly affected by both pelvic tilt and pelvic rotation (depending on the side). Improved understanding of pelvic orientation and improved ability to measure pelvic orientation may eventually allow for desired cup positioning to potentially protect against complications associated with malposition of the cup. PMID- 29276117 TI - A Retrospective Comparison of a Medial Pivot and Posterior-Stabilized Total Knee Arthroplasty With Respect to Patient-Reported and Radiographic Outcomes. AB - BACKGROUND: Medial pivot (MP) type total knee arthroplasty (TKA) implants are designed with a highly congruent medial tibiofemoral articulation. Compared with the cam-and-post design of the posterior-stabilized (PS) TKA, the MP-TKA design has been hypothesized to better replicate the natural kinematics of the knee. We compared the MP-TKA and PS-TKA designs, with our primary outcome measures being range of motion (ROM) and patient-reported satisfaction. METHODS: This study was a retrospective comparison between the 2 groups (76 MP-TKA vs 88 PS-TKA). ROM was collected preoperatively, 6 weeks, 6 months, and 1 year postoperatively. The Forgotten Joint Score-12 (FJS-12) scores were collected at a minimum of 1 year postoperatively. RESULTS: There was no statistically significant difference in age, gender, or body mass index between the groups. We found a statistical difference in preoperative ROM (MP = 120.3 degrees , PS = 112.8 degrees , P = .002). There was no difference in DeltaROM at 6 weeks (MP = -12.36, PS = -3.79, P = .066), 6 months (MP = -4.23, PS = 2.73, P = .182), or 1 year (MP = .17, PS = 3.31, P = .499). Patients who underwent the MP-TKA scored significantly better than the PS-TKA on the FJS-12 score (MP = 59.72, PS = 44.77, P = .007). CONCLUSION: We found that patients who underwent the MP-TKA scored better on the FJS than those who underwent the PS-TKA; particularly with regard to deep knee flexion and stability of the prosthesis. The MP-TKA design may offer improved patient outcomes because of its highly congruent medial tibiofemoral articulation. PMID- 29276118 TI - Total Hip Arthroplasty in Patients With Parkinson Disease: Improved Outcomes With Dual Mobility Implants and Cementless Fixation. AB - BACKGROUND: Parkinson disease (PD) results in severe limitation in ambulation caused by abnormality of gait and posture. The rate of complications, including fractures and dislocation after total hip arthroplasty (THA), can be higher among these patients. The goal of this study was to investigate the long-term outcomes of primary and revision THAs with cementless dual mobility implants. METHODS: This retrospective study examines 59 PD patients who had surgery between 2002 and 2012. All the primary cases were performed for osteoarthritis and all patients received cementless acetabular implants with dual mobility bearing surface. The femoral stem was cemented in 4 patients who underwent revision surgery. The mean follow-up time was 8.3 years (4-14 years). RESULTS: Good to excellent pain relief was achieved in 53 of 57 patients at the 2-year follow-up and in 40 of 47 patients at their latest follow-up. The most common medical complication was cognitive impairment (12 of 57 patients). One patient sustained an intraprosthetic hip dislocation 9 years after surgery, which required revision. Four patients sustained periprosthetic femoral fractures with well-fixed stem, requiring open reduction and internal fixation. The disability had increased in 68% of the patients in the latest follow-up visit. DISCUSSION: Our study shows that elective primary or revision THA using cementless implants with dual mobility bearing surface in patients with PD provides satisfactory long-term outcomes, although many of these patients may see a general worsening of their activities over time due to PD. PMID- 29276119 TI - Not Physical Activity, but Patient Beliefs and Expectations are Associated With Return to Work After Total Knee Arthroplasty. AB - BACKGROUND: After total knee arthroplasty (TKA), 17%-60% of the patients do not or only partially return to work (RTW). Reasons for no or partial RTW remain unclear, warranting further research. Physical activity (PA) has proven beneficial effects on work participation. Therefore, we hypothesized that preoperative PA is associated with RTW after TKA. METHODS: Working TKA patients participating in an ongoing prospective cohort study were included. Preoperatively and 1 year postoperatively, patients were asked to define their work status and PA level according to the Dutch Recommendation for Health Enhancing PA and the Fitnorm. Multivariate logistic regression analysis was performed to assess the effect of PA on RTW, taking into account established prognostic factors for RTW among TKA patients. RESULTS: Of 283 eligible patients, 266 (93%) completed the questionnaires sufficiently. Preoperatively, 141 patients (54%) performed moderate PA for >=5 d/wk and 42 (16%) performed intense PA for >=3 d/wk. Concerning RTW, 178 patients (67%) reported full RTW, 59 patients (22%) partial RTW, and 29 patients (11%) no RTW. Preoperative PA was not associated with RTW. Patients who reported that their knee symptoms were not or only partially work-related had lower odds of no RTW (odds ratio 0.37, 95% confidence interval 0.17-0.81). Also, for each additional week patients expected to be absent from work, the likelihood of no RTW increased (odds ratio 1.11, 95% confidence interval 1.03-1.18). CONCLUSION: No association between preoperative PA and RTW after TKA was found. Patient beliefs and preoperative expectations did influence RTW and should be addressed to further improve RTW after TKA. PMID- 29276120 TI - Damage Assessment of Retrieved Birmingham Monoblock Cups: Is Conversion to Dual Mobility Head a Viable Revision Option? AB - BACKGROUND: A novel revision technique for failed hip resurfacings involves retention of the acetabular cup, if well-fixed, which is mated to dual-mobility (DM) prosthesis in a traditional hip replacement configuration. It is unknown whether existing damage on the retained cup will result in unacceptable wear of the DM prosthesis. METHODS: Thirty retrieved Birmingham (Smith & Nephew) monoblock cups were visually scored for damage features and area of coverage. Surface roughness measurements were obtained within each damage feature as well as reference points on each cup. Analysis of prior metal-on-metal wear was also performed to determine the maximum change in diameter of the cup. RESULTS: Scratching and grooving (deep, singular scratches) were the most common damage features. Overall bearing surface roughness was estimated as 0.059 MUm (+/-0.030 MUm) based on percent area coverage of each damage feature. Dimensional change of the bearing surface was negligible for most cups (18 of 30) but ranged from 0.20 to 0.38 mm for the most severely worn samples (5 of 30). CONCLUSION: Average surface roughness of the retrieved Birmingham cups was low, suggesting an expected 10%-20% increase in DM prosthesis wear. Similarly, dimensional change of the cup due to prior wear is not believed to significantly affect wear. Our findings support the use of a DM head in appropriate scenarios but suggest caution when applied to younger, more active patients whom may be adversely affected by increased prosthesis wear in the long term. PMID- 29276121 TI - A Randomized Seven-Year Study on Performance of the Stemmed Metal M2a-Magnum and Ceramic C2a-Taper, and the Resurfacing ReCap Hip Implants. AB - BACKGROUND: The large-diameter metal-on-metal hip prostheses were expected to have low wear and reduced dislocation rate compared to the traditional metal-on polyethylene implants. We compare 2 such prostheses, the ReCap resurfacing implant and the M2a-Magnum stemmed implant, with the C2a ceramic-on-ceramic stemmed implant as to clinical performance, serum concentrations of prosthesis metals, and the durability of the implants in a randomized, controlled clinical trial at 7 years of follow-up. METHODS: All included patients had osteoarthritis. Preoperatively, the size of the implants was estimated from a magnetic resonance imaging (MRI) scan. Follow-up data included serum cobalt and chromium concentrations, Oxford and Harris Hip Scores, leg press and abduction force, 6 minute walk distance, WOMAC and SF-36 self-assessment scores, and from the 7th postoperative year also ultrasonography (US) examination of the soft tissue adjacent to the implant as well as MRI with metal artifact reduction sequence (MARS-MRI) when indicated. RESULTS: One hundred fifty-two hips in 146 patients were included. The serum cobalt and chromium concentrations were significantly higher for the 2 metal-on-metal prostheses than for the ceramic-on-ceramic, with the M2a-Magnum as the highest. No significant difference was found between the groups concerning physical performance measurements and scores as well as dislocations and prosthesis survival. Five revisions were done and concerned all groups, for reasons of pain, high serum cobalt and chromium concentrations, cystic fluid collection around the joint, and infection. Metal concentrations, US, and MARS-MRI contributed to the decision making regarding prosthesis revision. CONCLUSION: Metal concentrations were significantly higher for the metal-on-metal prostheses than for the ceramic-on-ceramic. The clinical performance was good in all 3 prosthesis groups. Metal concentrations, US, and MARS-MRI findings were of use to identify hips needing revision. ID Number in ClinicalTrials.gov PRS: NCT00284674. PMID- 29276122 TI - A Comparison of Relative Value Units in Primary Versus Revision Total Knee Arthroplasty. AB - BACKGROUND: In total knee arthroplasty (TKA), revision cases are often technically more challenging, and require more operative time and aftercare than primary cases. These time and effort differences should therefore be appropriately compensated for when using the relative value unit (RVU) system. Therefore, the purpose of this study is to compare the mean (1) RVUs; (2) operative times; and (3) RVU/min; and (4) perform an individualized idealized surgeon annual cost difference analysis for primary vs revision TKA. METHODS: Current Procedural Terminology code 27447 identified 165,439 primary TKA patients, while Current Procedural Terminology code 27487 identified 8081 revision TKA patients from the National Surgical Quality Improvement Program database. The mean RVUs, operative times, and RVU/min were calculated. Dollar amount per minute, per case, per day, and year were also calculated. Student's t test, with a cut-off P-value of <.05, was used in order to identify any statistical differences in mean RVUs, operative times, and RVU/min. RESULTS: The mean RVUs for primary TKA was 22, while for revision TKA was 27 (P < .001). The mean operative time for primary TKA was 94 minutes, while for revision TKA was 149 minutes (P < .001). The mean RVU/min for primary TKA was 0.26, while for revision TKA was 0.22 (P < .001). The dollar amounts calculated for primary vs revision TKA were per minute ($9.33 vs $7.90), per case ($877.12 vs $1176.43), per day ($4385.60 vs $3529), and projected a $137,008.70 annual cost difference. CONCLUSION: Orthopedic surgeons are reimbursed at a higher rate per minute for primary cases compared to revision TKA (0.26 vs 0.22, P < .001). The annual difference can amount to nearly $140,000. Orthopedic surgeons can use this information to better understand the dynamics of their time, compensation, and ultimately, their practice. Furthermore, it can be argued that there needs to be a shift to increase the RVU per unit time for revision TKAs. PMID- 29276123 TI - Prospective Randomized Comparison of Posterior-Stabilized Versus Condylar Stabilized Total Knee Arthroplasty: Final Report of a Five-Year Study. AB - BACKGROUND: This report presents the minimum 5-year results of a prospective, randomized, Level of Evidence I study that evaluated cruciate-sacrificing total knee arthroplasty using either a posterior-stabilized (PS) device or a condylar stabilized (CS) device. We hypothesized that the clinical outcomes of both groups would be equivalent and that there would be differences in operative time and/or blood loss parameters. METHODS: One-hundred eleven patients undergoing total knee arthroplasty were randomized to receive either a post-cam style tibial insert (PS, n = 56) or a more congruent anterior-lipped tibial insert (CS, n = 55). All posterior cruciate ligaments were sacrificed. RESULTS: Comparison of the clinical scores and radiographic results between both groups were essentially equivalent with no statistically significant differences at the final 5-year evaluation, although the CS knee group had significantly fewer incidences of postoperative mechanical sensations (P = .01). CONCLUSION: These results demonstrate that the CS knee provides excellent clinical, functional, and radiographic outcomes that are comparable to the results achieved with the PS knee, with a lower incidence of mechanical sensations, and support the use of a CS device as an alternative to the PS device. PMID- 29276124 TI - Sex- and Gamete-Specific Patterns of X Chromosome Segregation in a Trioecious Nematode. AB - Three key steps in meiosis allow diploid organisms to produce haploid gametes: (1) homologous chromosomes (homologs) pair and undergo crossovers; (2) homologs segregate to opposite poles; and (3) sister chromatids segregate to opposite poles. The XX/XO sex determination system found in many nematodes [1] facilitates the study of meiosis because variation is easily recognized [2-4]. Here we show that meiotic segregation of X chromosomes in the trioecious nematode Auanema rhodensis [5] varies according to sex (hermaphrodite, female, or male) and type of gametogenesis (oogenesis or spermatogenesis). In this species, XO males exclusively produce X-bearing sperm [6, 7]. The unpaired X precociously separates into sister chromatids, which co-segregate with the autosome set to generate a functional haplo-X sperm. The other set of autosomes is discarded into a residual body. Here we explore the X chromosome behavior in female and hermaphrodite meioses. Whereas X chromosomes segregate following the canonical pattern during XX female oogenesis to yield haplo-X oocytes, during XX hermaphrodite oogenesis they segregate to the first polar body to yield nullo-X oocytes. Thus, crosses between XX hermaphrodites and males yield exclusively male progeny. During hermaphrodite spermatogenesis, the sister chromatids of the X chromosomes separate during meiosis I, and homologous X chromatids segregate to the functional sperm to create diplo-X sperm. Given these intra-species, intra individual, and intra-gametogenesis variations in the meiotic program, A. rhodensis is an ideal model for studying the plasticity of meiosis and how it can be modulated. PMID- 29276125 TI - Nek9 Phosphorylation Defines a New Role for TPX2 in Eg5-Dependent Centrosome Separation before Nuclear Envelope Breakdown. AB - Centrosomes [1, 2] play a central role during spindle assembly in most animal cells [3]. In early mitosis, they organize two symmetrical microtubule arrays that upon separation define the two poles of the forming spindle. Centrosome separation is tightly regulated [4, 5], occurring through partially redundant mechanisms that rely on the action of microtubule-based dynein and kinesin motors and the actomyosin system [6]. While centrosomes can separate in prophase or in prometaphase after nuclear envelope breakdown (NEBD), prophase centrosome separation optimizes spindle assembly and minimizes the occurrence of abnormal chromosome attachments that could end in aneuploidy [7, 8]. Prophase centrosome separation relies on the activity of Eg5/KIF11, a mitotic kinesin [9] that accumulates around centrosomes in early mitosis under the control of CDK1 and the Nek9/Nek6/7 kinase module [10-17]. Here, we show that Eg5 localization and centrosome separation in prophase depend on the nuclear microtubule-associated protein TPX2 [18], a pool of which localizes to the centrosomes before NEBD. This localization involves RHAMM/HMMR [19] and the kinase Nek9 [20], which phosphorylates TPX2 nuclear localization signal (NLS) preventing its interaction with importin and nuclear import. The pool of centrosomal TPX2 in prophase has a critical role for both microtubule aster organization and Eg5 localization, and thereby for centrosome separation. Our results uncover an unsuspected role for TPX2 before NEBD and define a novel regulatory mechanism for centrosome separation in prophase. They furthermore suggest NLS phosphorylation as a novel regulatory mechanism for spindle assembly factors controlled by the importin/Ran system. PMID- 29276126 TI - Polo-like Kinase Couples Cytoplasmic Protein Gradients in the C. elegans Zygote. AB - Intracellular protein gradients underlie essential cellular and developmental processes, but the mechanisms by which they are established are incompletely understood. During the asymmetric division of the C. elegans zygote, the RNA binding protein MEX-5 forms an anterior-rich cytoplasmic gradient that causes the RNA-binding protein POS-1 to form an opposing, posterior-rich gradient. We demonstrate that the polo-like kinase PLK-1 mediates the repulsive coupling between MEX-5 and POS-1 by increasing the mobility of POS-1 in the anterior. PLK 1 is enriched in the anterior cytoplasm and phosphorylates POS-1, which is both necessary and sufficient to increase POS-1 mobility. Regulation of POS-1 mobility depends on both the interaction between PLK-1 and MEX-5 and between MEX-5 and RNA, suggesting that MEX-5 may recruit PLK-1 to RNA in the anterior. The low concentration of MEX-5/PLK-1 in the posterior cytoplasm provides a permissive environment for the retention of POS-1, which depends on POS-1 RNA binding. Our findings describe a novel reaction/diffusion mechanism in which the asymmetric distribution of cytoplasmic PLK-1 couples two RNA-binding protein gradients, thereby partitioning the cytoplasm. PMID- 29276127 TI - Feature-Specific Organization of Feedback Pathways in Mouse Visual Cortex. AB - Higher and lower cortical areas in the visual hierarchy are reciprocally connected [1]. Although much is known about how feedforward pathways shape receptive field properties of visual neurons, relatively little is known about the role of feedback pathways in visual processing. Feedback pathways are thought to carry top-down signals, including information about context (e.g., figure ground segmentation and surround suppression) [2-5], and feedback has been demonstrated to sharpen orientation tuning of neurons in the primary visual cortex (V1) [6, 7]. However, the response characteristics of feedback neurons themselves and how feedback shapes V1 neurons' tuning for other features, such as spatial frequency (SF), remain largely unknown. Here, using a retrograde virus, targeted electrophysiological recordings, and optogenetic manipulations, we show that putatively feedback neurons in layer 5 (hereafter "L5 feedback") in higher visual areas, AL (anterolateral area) and PM (posteromedial area), display distinct visual properties in awake head-fixed mice. AL L5 feedback neurons prefer significantly lower SF (mean: 0.04 cycles per degree [cpd]) compared to PM L5 feedback neurons (0.15 cpd). Importantly, silencing AL L5 feedback reduced visual responses of V1 neurons preferring low SF (mean change in firing rate: 8.0%), whereas silencing PM L5 feedback suppressed responses of high-SF preferring V1 neurons (-20.4%). These findings suggest that feedback connections from higher visual areas convey distinctly tuned visual inputs to V1 that serve to boost V1 neurons' responses to SF. Such like-to-like functional organization may represent an important feature of feedback pathways in sensory systems and in the nervous system in general. PMID- 29276128 TI - Tension-Induced Error Correction and Not Kinetochore Attachment Status Activates the SAC in an Aurora-B/C-Dependent Manner in Oocytes. AB - Cell division with partitioning of the genetic material should take place only when paired chromosomes named bivalents (meiosis I) or sister chromatids (mitosis and meiosis II) are correctly attached to the bipolar spindle in a tension generating manner. For this to happen, the spindle assembly checkpoint (SAC) checks whether unattached kinetochores are present, in which case anaphase onset is delayed to permit further establishment of attachments. Additionally, microtubules are stabilized when they are attached and under tension. In mitosis, attachments not under tension activate the so-named error correction pathway depending on Aurora B kinase substrate phosphorylation. This leads to microtubule detachments, which in turn activates the SAC [1-3]. Meiotic divisions in mammalian oocytes are highly error prone, with severe consequences for fertility and health of the offspring [4, 5]. Correct attachment of chromosomes in meiosis I leads to the generation of stretched bivalents, but-unlike mitosis-not to tension between sister kinetochores, which co-orient. Here, we set out to address whether reduction of tension applied by the spindle on bioriented bivalents activates error correction and, as a consequence, the SAC. Treatment of oocytes in late prometaphase I with Eg5 kinesin inhibitor affects spindle tension, but not attachments, as we show here using an optimized protocol for confocal imaging. After Eg5 inhibition, bivalents are correctly aligned but less stretched, and as a result, Aurora-B/C-dependent error correction with microtubule detachment takes place. This loss of attachments leads to SAC activation. Crucially, SAC activation itself does not require Aurora B/C kinase activity in oocytes. PMID- 29276129 TI - Selection for Collective Aggressiveness Favors Social Susceptibility in Social Spiders. AB - Particularly socially influential individuals are present in many groups [1-8], but it is unclear whether their emergence is determined by their social influence versus the social susceptibility of others [9]. The social spider Stegodyphus dumicola shows regional variation in apparent leader-follower dynamics. We use this variation to evaluate the relative contributions of leader social influence versus follower social susceptibility in driving this social order. Using chimeric colonies that combine potential leaders and followers, we discover that leader-follower dynamics emerge from the site-specific social susceptibility of followers. We further show that the presence of leaders increases colony survival in environments where leader-follower dynamics occur. Thus, leadership is driven by the "social susceptibility" of the population majority, rather than the social influence of key group members. PMID- 29276130 TI - [Reproductive behavior of the green birdmouth wrasse Gomphosus caeruleus on a Reunion Island reef: Mode of reproduction, environmental factors and reproductive strategy alternation]. AB - The green birdmouth wrasse Gomphosus caeruleus is present all year round on the coral reefs of Reunion Island (Indian Ocean). A group of individuals was followed on one of these reefs with the objective of studying the reproduction mode of the species, the influence of environmental factors, and social behaviors on the control of reproduction. Our observations revealed that G. caeruleus is, like many Labridae, a protogynous hermaphrodite species, probably diandric, that the reproduction of G. caeruleus is, like in other reef fish species, influenced by the lunar cycle with a peak of reproductive activity during waxing gibbous phase, and that G. caeruleus displays social behavior leading to alternating haremic mating system on a single territory and lek-like mating systems without aggressions between males. These observations enhanced our knowledge of the reproduction of Labridae and reef species. PMID- 29276131 TI - [18F]PSMA-1007 PET Improves the Diagnosis of Local Recurrence and Lymph Node Metastases in a Prostate Cancer Patient With a History of Bilateral Hip Arthroplasty. PMID- 29276132 TI - Getting the Brain Into Shape: Exercise in Neurological Disorders. PMID- 29276133 TI - Lack of Acute Care Resources to Diagnose and Treat Acute Coronary Syndrome in Lower-Income Settings. PMID- 29276134 TI - Cholesterol Transport Revisited: A New Turbo Mechanism to Drive Cholesterol Excretion. AB - A fine-tuned balance between cholesterol uptake and excretion by the body is pivotal to maintain health and to remain free from the deleterious consequences of cholesterol accumulation such as cardiovascular disease. The pathways involved in intracellular and extracellular cholesterol transport are a subject of intense investigation and are being unraveled in increasing detail. In addition, insight into the complex interactions between cholesterol and bile acid metabolism has increased considerably in the last couple of years. This review provides an overview of the mechanisms involved in cholesterol uptake and excretion, with a particular emphasis on the most recent progress in this field. Special attention is given to the transintestinal cholesterol excretion (TICE) pathway, which was recently demonstrated to have a remarkably high transport capacity and to be sensitive to pharmacological modulation. PMID- 29276135 TI - [External beam radiotherapy cone beam-computed tomography-based dose calculation]. AB - In external beam radiotherapy, the dose planning is currently based on computed tomography (CT) images. A relation between Hounsfield numbers and electron densities (or mass densities) is necessary for dose calculation taking heterogeneities into account. In image-guided radiotherapy process, the cone beam CT is classically used for tissue visualization and registration. Cone beam CT for dose calculation is also attractive in dose reporting/monitoring perspectives and particularly in a context of dose-guided adaptive radiotherapy. The accuracy of cone beam CT-based dose calculation is limited by image characteristics such as quality, Hounsfield numbers consistency and restrictive sizes of volume acquisition. The analysis of the literature identifies three kinds of strategies for cone beam CT-based dose calculation: establishment of Hounsfield numbers versus densities curves, density override to regions of interest, and deformable registration between CT and cone beam CT images. Literature results show that discrepancies between the reference CT-based dose calculation and the cone beam CT-based dose calculation are often lower than 3%, regardless of the method. However, they can also reach 10% with unsuitable method. Even if the accuracy of the cone beam CT-based dose calculation is independent of the method, some strategies are promising but need improvements in the automating process for a routine implementation. PMID- 29276136 TI - Duplex Sonography of Vertebral Arteries for Evaluation of Patients with Acute Vertigo. AB - We evaluated the role of vertebral artery extracranial color-coded duplex sonography (VAECCS) in predicting vertebrobasilar stroke in consecutive patients presenting to the emergency department with vertigo of suspected ischemic origin. The final diagnosis was established by a panel of experts consisting of an emergency physician, a neurologist, and an otoneurologist. Vertebrobasilar stroke was diagnosed when an acute brain ischemic lesion congruent with symptoms was detected by neuroimaging during the index visit or a stroke was diagnosed within a 3-mo period after emergency department presentation. Among 126 patients, 28 (22%) were diagnosed with vertebrobasilar stroke. Fifteen (75%) of 20 patients with abnormal VAECCS results and 13 (12%) of 106 with normal VAECCS results had a final diagnosis of vertebrobasilar stroke. The sensitivity and specificity of VAECCS were 53.6% and 94.9%, respectively. Detecting an abnormal flow pattern at VAECCS significantly increased the risk of vertebrobasilar stroke (odds ratio = 21.5). The flow patterns most frequently related to vertebrobasilar stroke were absence of flow and high resistance pattern velocity (odds ratio = 9.3 and 22.7, respectively). VAECCS predicts vertebrobasilar stroke and could be a useful bedside screening tool in patients with vertigo. PMID- 29276137 TI - Ketamine Inhibits Ultrasound Stimulation-Induced Neuromodulation by Blocking Cortical Neuron Activity. AB - Ultrasound (US) can be used to noninvasively stimulate brain activity. However, reproducible motor responses evoked by US are only elicited when the animal is in a light state of anesthesia. The present study investigated the effects of ketamine on US-induced motor responses and cortical neuronal activity. US was applied to the motor cortex of mice, and motor responses were evaluated based on robustness scores. Cortical neuronal activity was observed by fluorescence calcium imaging. US-induced motor responses were inhibited more than 20 min after ketamine injection, and US-triggered Ca2+ transients in cortical neurons were effectively blocked by ketamine. Our results indicate that ketamine suppresses US triggered Ca2+ transients in cortical neurons and, therefore, inhibits US-induced motor responses in a deep anesthetic state. PMID- 29276138 TI - Double-Stage Delay Multiply and Sum Beamforming Algorithm Applied to Ultrasound Medical Imaging. AB - In ultrasound (US) imaging, delay and sum (DAS) is the most common beamformer, but it leads to low-quality images. Delay multiply and sum (DMAS) was introduced to address this problem. However, the reconstructed images using DMAS still suffer from the level of side lobes and low noise suppression. Here, a novel beamforming algorithm is introduced based on expansion of the DMAS formula. We found that there is a DAS algebra inside the expansion, and we proposed use of the DMAS instead of the DAS algebra. The introduced method, namely double-stage DMAS (DS-DMAS), is evaluated numerically and experimentally. The quantitative results indicate that DS-DMAS results in an approximately 25% lower level of side lobes compared with DMAS. Moreover, the introduced method leads to 23%, 22% and 43% improvement in signal-to-noise ratio, full width at half-maximum and contrast ratio, respectively, compared with the DMAS beamformer. PMID- 29276139 TI - Ultrasound Monitoring of Jugular Venous Pulse during Space Missions: Proof of Concept. AB - The jugular venous pulse (JVP) is one of the main parameters of cardiac function and is used by cardiologists in diagnosing heart failure. Its waveform comprises three positive waves (a, c and v) and two negative waves (x and y). Recently, it was found that JVP can be extrapolated from an ultrasound (US) video recording of the internal jugular vein (IJV), suggesting its application in space missions, on which US scanners are already widely used. To date, the feasibility of assessing JVP in microgravity (microG) has not been investigated. To verify the feasibility of JVP assessment in microG, we tested a protocol of self-performed B-mode ultrasound on the International Space Station (ISS). The protocol consisted of a video recording of IJV synchronized with electrocardiogram that produces a cross sectional area time trace (JVP trace) (in cm2). The scans were acquired in six experimental sessions; two pre-flight (BDC1 and -2), two in space (ISS1 and -2) and two post-flight (Houston PF1, Cologne PF2). We measured the mean and standard deviation of the JVP waves and the phase relationship between such waves and P and T waves on the electrocardiogram. We verified that such parameters had the same accuracy on Earth as they did under microG, and we compared their values. The sensitivity, specificity and accuracy of JVP trace in microgravity are higher than those on Earth. The sequence of (a, c, and v) ascents and (x and y) descents along the cardiac cycle in microG is the same as that on Earth. The cause-and effect relationship between the P and T waves on the electrocardiogram and a and v waves, respectively, of JVP is also confirmed in microG. Our experiment indicated the feasibility of deriving a JVP trace from a B-mode US examination self-performed by an astronaut in microG. PMID- 29276140 TI - Associations of Alcoholic Beverage Consumption with Dietary Intake, Waist Circumference, and Body Mass Index in US Adults: National Health and Nutrition Examination Survey 2003-2012. AB - BACKGROUND: Findings from studies of alcohol and obesity measures (eg, waist circumference [WC] and body mass index [BMI; calculated as kg/m2]) are conflicting. Residual confounding by dietary intake, inconsistent definitions of alcohol consumption across studies, and the inclusion of former drinkers in the nondrinking comparison group can contribute to the mixed literature. OBJECTIVE: This study examines associations of alcoholic beverage consumption with dietary intake, WC, and BMI. DESIGN: Cross-sectional data from the 2003-2012 National Health and Nutrition Examination Survey were analyzed. PARTICIPANTS/SETTING: Adults 20 to 79 years of age (n=7,436 men; n=6,939 women) were studied. MAIN OUTCOME MEASURES: Associations of alcoholic beverage consumption with energy (kcal), macronutrient and sugar intakes (% kcal), WC, and BMI were determined. STATISTICAL ANALYSES PERFORMED: Multivariable linear regression models were used to determine associations of average daily volume and drinking quantity (ie, drinks per drinking day) with dietary intake and obesity measures. Former and never drinkers were analyzed as distinct categories; associations of drinking with WC and BMI were examined with and without adjustment for dietary intake variables. RESULTS: Heavier-drinking men (>=3 drinks/day) and women (>=2 drinks/day) consumed less nonalcoholic energy (beta -252 kcal/day, 95% CI -346 to -159 kcal/day and beta -159 kcal/day, 95% CI -245 to -73 kcal/day, respectively) than moderate drinkers (1 to 2 drinks/day in men and 1 drink/day in women). By average daily drinking volume, differences in WC and BMI between former and moderate drinkers were +1.78 cm (95% CI 0.51 to 3.05 cm) and +0.65 (95% CI 0.12 to 1.18) in men and +4.67 cm (95% CI 2.95 to 6.39 cm) and +2.49 (95% CI 1.64 to 3.34) in women. Compared with moderate drinking, heavier drinking volume was not associated with WC or BMI among men or women. In men, drinking >=5 drinks/drinking day was associated with higher WC (beta 3.48 cm, 95% CI 1.97 to 5.00 cm) and BMI (beta 1.39, 95% CI 0.79 to 2.00) compared with men who consumed 1 to 2 drinks/drinking day. In women, WC and BMI were not significantly different for women drinking >=4 drinks/drinking day compared with 1 drink/drinking day. CONCLUSIONS: Differences in dietary intake across drinking subgroups and separation of former drinkers from nondrinkers should be considered in studies of alcohol intake in relation to WC and BMI. PMID- 29276141 TI - Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. AB - Direct cardiac reprogramming holds great promise for regenerative medicine. We previously generated directly reprogrammed induced cardiomyocyte-like cells (iCMs) by overexpression of Gata4, Mef2c, and Tbx5 (GMT) using retrovirus vectors. However, integrating vectors pose risks associated with insertional mutagenesis and disruption of gene expression and are inefficient. Here, we show that Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently and rapidly reprogram both mouse and human fibroblasts into integration-free iCMs via robust transgene expression. SeV-GMT generated 100-fold more beating iCMs than retroviral-GMT and shortened the duration to induce beating cells from 30 to 10 days in mouse fibroblasts. In vivo lineage tracing revealed that the gene transfer of SeV-GMT was more efficient than retroviral-GMT in reprogramming resident cardiac fibroblasts into iCMs in mouse infarct hearts. Moreover, SeV-GMT improved cardiac function and reduced fibrosis after myocardial infarction. Thus, efficient, non-integrating SeV vectors may serve as a powerful system for cardiac regeneration. PMID- 29276142 TI - Radial Glial Fibers Promote Neuronal Migration and Functional Recovery after Neonatal Brain Injury. AB - Radial glia (RG) are embryonic neural stem cells (NSCs) that produce neuroblasts and provide fibers that act as a scaffold for neuroblast migration during embryonic development. Although they normally disappear soon after birth, here we found that RG fibers can persist in injured neonatal mouse brains and act as a scaffold for postnatal ventricular-subventricular zone (V-SVZ)-derived neuroblasts that migrate to the lesion site. This injury-induced maintenance of RG fibers has a limited time window during post-natal development and promotes directional saltatory movement of neuroblasts via N-cadherin-mediated cell-cell contacts that promote RhoA activation. Transplanting an N-cadherin-containing scaffold into injured neonatal brains likewise promotes migration and maturation of V-SVZ-derived neuroblasts, leading to functional improvements in impaired gait behaviors. Together these results suggest that RG fibers enable postnatal V-SVZ derived neuroblasts to migrate toward sites of injury, thereby enhancing neuronal regeneration and functional recovery from neonatal brain injuries. PMID- 29276144 TI - Network biology: Describing biological systems by complex networks: Comment on "Network science of biological systems at different scales: A review" by M. Gosak et al. PMID- 29276145 TI - Corrigendum to 'Drug-resistant tuberculosis viewed from bacterial and host genomes' [International Journal of Antimicrobial Agents (2016) 353-360]. PMID- 29276143 TI - Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML. AB - Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML. PMID- 29276146 TI - Prognostic Impact of Prolonged Cross-Clamp Time in Coronary Artery Bypass Grafting. AB - BACKGROUND: The prognostic impact of cross-clamp time (XCT) in patients undergoing isolated coronary artery bypass grafting (CABG) has not been thoroughly investigated. MATERIAL AND METHODS: 2957 patients who underwent on pump isolated CABG from the prospective multicentre E-CABG study were the subjects of this analysis. RESULTS: The mean XCT in this series was 58+/ 25minutes Cross-clamp time was >60 minutes in 1134 patients (38.3%), >75minutes in 619 patients (20.9%) and >90minutes in 296 patients (10.0%). Multivariate analysis showed that XCT was an independent predictor of 30-day mortality (p<0.0001, OR 1.027, 95%CI 1.015-1.039) along with age (p<0.0001), female gender (p=0.001), pulmonary disease (p=0.001), poor mobility (p=0.002), urgency status (p=0.007), critical preoperative status (p=0.002) and participating centres (p=0.015). Adjusted risk of 30-day mortality was highest for XCT >75minutes (2.9% vs. 1.7%, p=0.002, OR 3.479, 95%CI 1.609-7.520). Analysis of 428 propensity score matched pairs showed that XCT >75minutes was associated with significantly increased risk of early mortality, prolonged use of inotropes, postoperative use of intra-aortic balloon pump, use of extracorporeal membrane oxygenation, atrial fibrillation, prolonged stay in the intensive care unit and of composite major adverse events. CONCLUSIONS: Isolated CABG is currently performed with prolonged XCT in a significant number of patients and this seems to be a determinant of poor early outcome. PMID- 29276147 TI - Evaluation of Cobalt and Chromium Levels Following Implantation of Cobalt Chromium Coronary Stents: A Pilot Study. AB - BACKGROUND: Large increases in myocardial trace elements may adversely affect metabolism and become detrimental to cardiac function. Percutaneous coronary intervention (PCI) allows for the revascularisation of obstructive coronary artery disease using drug-eluting stents. These stents are comprised of a metallic stent backbone covered in an engineered polymer which delivers a drug over a prescribed period to the vessel wall. Given the potential implications of trace metal accumulation within the myocardium, our goal is to determine if metallic coronary stents are able to cause detectable elevations in serum cobalt and/or chromium levels. METHODS: This study was a single centre, observational, pilot study with 20 patients who underwent planned PCI with implantation of a cobalt chromium drug eluting stent. Serum blood samples were drawn at baseline prior to PCI, 4hours post-stent deployment and at the time of routine follow-up after PCI. All blood samples were analysed for cobalt and chromium concentrations. The primary outcome of this study was the difference in serum cobalt and chromium levels at routine clinical follow-up. RESULTS: The mean follow up was 64.1+/-17.3 days. There was no difference in serum cobalt levels when comparing baseline and routine clinical follow up (3.32+/-2.14nmol/L vs. 3.14+/-1.00nmol/L, p=0.99) nor in chromium levels (4.24+/-2.31nmol/L vs. 2.82+/ 1.22 nmol/L, p=0.11). There was also no difference between baseline and 4hours post-PCI serum concentrations. CONCLUSIONS: Percutaneous coronary intervention with cobalt chromium coronary stents does not appear to cause an elevation in these trace element serum concentrations. PMID- 29276148 TI - Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model. AB - Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents. PMID- 29276149 TI - Real-Time and Non-invasive Monitoring of the Activation of the IRE1alpha-XBP1 Pathway in Individuals with Hemodynamic Impairment. AB - Many stressors that are encountered upon kidney injury are likely to trigger endoplasmic reticulum (ER) stress, subsequently activating transcriptional, translational and metabolic reprogramming. Monitoring early cellular adaptive responses engaged after hemodynamic impairment yields may represent a clinically relevant approach. However, a non-invasive method for detecting the ER stress response has not been developed. We combined a metabolomic approach with genetic marker analyses using urine from individuals undergoing scheduled cardiac surgery under cardiopulmonary bypass to investigate the feasibility and significance of monitoring the ER stress response in the kidney. We developed an original method based on fragment analysis that measures urinary levels of the spliced X-box binding protein 1 (sXBP1) mRNA as a proxy of inositol-requiring enzyme 1alpha (IRE1alpha) activity because sXBP1 is absolutely sensitive and specific for ER stress. The early engagement of the ER stress response after ischemic stress is critical for protecting against tissue damage, and individuals who mount a robust adaptive response are protected against AKI. The clinical consequences of our findings are of considerable importance because ER stress is involved in numerous conditions that lead to AKI and chronic kidney disease; in addition, the detection of ER stress is straightforward and immediately available in routine practice. PMID- 29276150 TI - HIV-Related Stigma Among Nursing Students Attending a College of Nursing that Promotes Nondiscriminatory Care in India. AB - Bel-Air College of Nursing in India promotes nondiscriminatory care of persons living with HIV throughout its programs, albeit with no specific intervention. We examined whether nursing students' stigmatizing attitudes were related to number of years at Bel-Air. At the start of the 2015 and 2016 academic years, 310 Bachelor's (BScN; 4-year program) and 119 Auxiliary Nurse Midwife (ANM; 2-year program) students completed the Zelaya and colleagues (2008) Stigma Scale (24 Likert-type items). Three subscales (Fear, Blame, Personal Discrimination) measured Overall Personal Stigma. The fourth subscale measured Perceived Community Discrimination. BScN students' mean Overall Personal Stigma and subscales scores declined and Perceived Community Discrimination scores increased from Year 1 to 4. For ANM students, Overall Personal Stigma, Fear, and Personal Discrimination scores were lower for Year 2 than Year 1 students. Bel-Air emphasizes effective and nondiscriminatory care throughout the entire curriculum, providing a model for reducing student nurses' stigmatizing attitudes. PMID- 29276151 TI - BMAL1 Deficiency Contributes to Mandibular Dysplasia by Upregulating MMP3. AB - Skeletal mandibular hypoplasia (SMH), one of the common types of craniofacial deformities, seriously affects appearance, chewing, pronunciation, and breathing. Moreover, SMH is prone to inducing obstructive sleep apnea syndrome. We found that brain and muscle ARNT-like 1 (BMAL1), the core component of the molecular circadian oscillator, was significantly decreased in mandibles of juvenile SMH patients. Accordingly, SMH was observed in circadian-rhythm-disrupted or BMAL1 deficient mice. RNA sequencing and protein chip analyses suggested that matrix metallopeptidase 3 (MMP3) is the potential target of BMAL1. Interestingly, in juvenile SMH patients, we observed that MMP3 was obviously increased. Consistently, MMP3 was upregulated during the whole growth period of 3-10 weeks in Bmal1-/- mice. Given these findings, we set out to characterize the underlying mechanism and found BMAL1 deficiency enhanced Mmp3 transcription through activating p65 phosphorylation. Together, our results provide insight into the mechanism by which BMAL1 is implicated in the pathogenesis of SMH. PMID- 29276152 TI - In Vitro Differentiation of Gata2 and Ly6a Reporter Embryonic Stem Cells Corresponds to In Vivo Waves of Hematopoietic Cell Generation. AB - In vivo hematopoietic generation occurs in waves of primitive and definitive cell emergence. Differentiation cultures of pluripotent embryonic stem cells (ESCs) offer an accessible source of hematopoietic cells for blood-related research and therapeutic strategies. However, despite many approaches, it remains a goal to robustly generate hematopoietic progenitor and stem cells (HP/SCs) in vitro from ESCs. This is partly due to the inability to efficiently promote, enrich, and/or molecularly direct hematopoietic emergence. Here, we use Gata2Venus (G2V) and Ly6a(SCA1)GFP (LG) reporter ESCs, derived from well-characterized mouse models of HP/SC emergence, to show that during in vitro differentiation they report emergent waves of primitive hematopoietic progenitor cells (HPCs), definitive HPCs, and B-lymphoid cell potential. These results, facilitated by enrichment of single and double reporter cells with HPC properties, demonstrate that in vitro ESC differentiation approximates the waves of hematopoietic cell generation found in vivo, thus raising possibilities for enrichment of rare ESC-derived HP/SCs. PMID- 29276153 TI - Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration. AB - The existence of slow-cycling luminal cells in the prostate has been suggested, but their identity and functional properties remain unknown. Using a bigenic mouse model to earmark, isolate, and characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC) population in the luminal cell layer as luminal progenitors. Molecular and biological characterizations show that these luminal LRCs are significantly enriched in the mouse proximal prostate, exhibit relative dormancy, display bipotency in both in vitro and in vivo assays, and express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these LRCs, compared with bulk luminal cells, maintain a lower level of androgen receptor (AR) expression and are less androgen dependent and also castration resistant in vivo. Finally, analysis of phenotypic markers reveals heterogeneity within the luminal progenitor cell pool. Our study establishes luminal LRCs as progenitors that may serve as a cellular origin for castration-resistant prostate cancer. PMID- 29276154 TI - Modeling the Pathogenesis of Charcot-Marie-Tooth Disease Type 1A Using Patient Specific iPSCs. AB - Charcot-Marie-Tooth disease type 1A (CMT1A), one of the most frequent inherited peripheral neuropathies, is associated with PMP22 gene duplication. Previous studies of CMT1A mainly relied on rodent models, and it is not yet clear how PMP22 overexpression leads to the phenotype in patients. Here, we generated the human induced pluripotent stem cell (hiPSC) lines from two CMT1A patients as an in vitro cell model. We found that, unlike the normal control cells, CMT1A hiPSCs rarely generated Schwann cells through neural crest stem cells (NCSCs). Instead, CMT1A NCSCs produced numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system, and similar results were obtained in a PMP22 overexpressing iPSC model. Therefore, despite the demyelination-remyelination and/or dysmyelination theory for CMT1A pathogenesis, developmental disabilities of Schwann cells may be considered as an underlying cause of CMT1A. Our results may have important implications for the uncovering of the underlying mechanism and the development of a promising therapeutic strategy for CMT1A neuropathy. PMID- 29276155 TI - JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation. AB - The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of alphaCD3 antibody induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response. PMID- 29276156 TI - A Phyllopod-Mediated Feedback Loop Promotes Intestinal Stem Cell Enteroendocrine Commitment in Drosophila. AB - The intestinal epithelium in the Drosophila midgut is maintained by intestinal stem cells (ISCs), which are capable of generating both enterocytes and enteroendocrine cells (EEs) via alternative cell fate specification. Activation of Delta-Notch signaling directs ISCs for enterocyte generation, but how EEs are generated from ISCs remains poorly understood. Here, we identified Phyllopod (Phyl) as a key regulator that drives EE generation from ISCs. Phyl, which is normally suppressed by Notch, functions as an adaptor protein that bridges Tramtrack 69 (Ttk69) and E3 ubiquitin ligase Sina for degradation. Degradation of Ttk69 allows the activation of the Achaete-Scute Complex (AS-C)-Pros regulatory axis, which promotes EE specification. Interestingly, expression of AS-C genes in turn further induces Phyl expression, thereby establishing a positive feedback loop for continuous EE fate specification and commitment. This positive feedback circuit-driven regulatory mechanism could represent a common strategy for reliable and irreversible cell fate determination from progenitor cells. PMID- 29276157 TI - Vaccination coverage among school children aged 14-15 years in the French department of Sarthe. AB - OBJECTIVES: Vaccinations are the main pillar of primary prevention for infectious diseases. To guide and prioritize public health interventions, the Regional Health Agency has asked the Prevention, Vaccination, and Screening Center of the Sarthe department to assess vaccination coverage (VC) at the sub-departmental level. The main objective was to measure the VC among school children aged 14-15 years in Sarthe at the sub-departmental level. PATIENTS AND METHODS: We conducted a VC evaluation survey at the administrative district level among school children aged 14-15 years in the Sarthe department during the first quarter of the 2015 2016 school year. RESULTS: Among 2384 randomly selected school children, 1171 were included in the study. At the departmental level, 85% of children were up to date for DTP, 72% for pertussis, 45% for hepatitis B, 31% for meningococcus C, 93% for measles, and 18% of girls had received at least one dose of the HPV vaccine. Vaccination coverage varied by administrative districts. CONCLUSION: At the departmental level, all VC were below national goals. Territorial disparities could be explained by sociodemographic differences or differences in medical practices. This survey allowed us to identify areas and population groups where the CV rate justified public health actions. PMID- 29276158 TI - Hospital-acquired infections documented by repeated annual prevalence surveys over 15 years. AB - OBJECTIVE: To estimate the benefits of iterative prevalence surveys in detecting trends of hospital-acquired infections (HAIs). METHODS: On the basis of the French protocol for national prevalence studies, HAI data of 15 consecutive annual surveys performed at the same period by the same group of investigators was gathered in a single database to describe the trend of HAIs in a University Hospital over a 15-year period. RESULTS: A total of 20,401 patients were included. Overall, the prevalence of patients presenting with at least one HAI acquired in our University Hospital was 5.1% [95% CI, 4.8-5.4%]. The prevalence of HAIs and antimicrobial drug use significantly decreased over time (P<0.01). CONCLUSION: Despite limitations, repeated prevalence surveys can be a useful tool for promoting control measures to better prevent HAIs. PMID- 29276160 TI - Management and Outcome of Reduced Fetal Movements-is Ultrasound Necessary? AB - OBJECTIVE: To review the management and outcome of pregnancies of women presenting to obstetrical triage with decreased fetal movements (DFM). STUDY DESIGN: A retrospective review of women presenting with DFMs to two large Canadian obstetrical centres with a combined 9490 deliveries per year. The charts were reviewed for compliance with the Canadian guidelines for demographics (age, parity, GA, comorbidities, etc.), pregnancy management (admission vs. discharge, need to deliver), and pregnancy outcomes (mortality, morbidity, GA at delivery, Apgar scores, etc.). Patients who did not comply with the Canadian guidelines (requiring the patient to count six movements within two hours) were not excluded. RESULTS: The charts of 579 patients who self-reported DFMs between January 2012 and December 2012 were reviewed. The distribution of ages was between 18 and 47 year old. The majority of these patients had no comorbidities (454/579). A significant minority of patients had FM in the triage area (231/579). The Canadian guidelines were interpreted differently in the two centres. In one (level 3), the protocol was to have a biophysical profile (BPP) on all patients prior to discharge, whereas in the other (level 2), only patients with a non-reactive non-stress test (NST) and/or oligohydramnios or intrauterine growth restriction (IUGR) underwent a BPP. All patients had an evaluation by an RN and MD and had a NST on arrival. A combination of NST and BPP was performed on 235/579. The frequency of DFM was 6.1% (level 3 centre: 5.6%, level 2 centre: 7.8%). There were 8 stillbirths on arrival. The 187 patients who had a reactive NST and a normal BPP and were sent home did not have a single stillbirth within 2 weeks. In the level 3 centre, 19 patients were sent home without a BPP and one had a stillbirth within 2 days (5%); in the level 2 hospital, there was only one stillbirth among the NST-only group (0.35%). There were 65 admissions; 46 of them (71%) were delivered, and 50% of them had a Caesarean delivery (baseline around 30%). CONCLUSIONS: This is the first study looking at the performance of the Canadian guidelines of 2007. We found that the DFM rate was compatible with the literature (6.1% vs. 5%). The frequency of stillbirth on arrival was 1.4% (8/579). Patients discharged after normal NST and BPP did extremely well (no stillbirths), whereas those admitted following DFM had a relatively high Caesarean delivery rate (50%). This study was not designed to address changes in stillbirth rate, but it outlines the patients who experience DFM and their eventual outcomes. PMID- 29276159 TI - Etiology of discharge hyponatremia in decompensated heart failure and normal admission Na+: Effect of diuretics. PMID- 29276161 TI - Impact of Vaccination History on Serological Testing in Pregnant Women. AB - OBJECTIVE: Serological testing guidelines for vaccine-preventable infectious diseases in pregnant women are heterogeneous. It is unclear how vaccination history influences health care workers' (HCWs) attitudes about testing. The aim of this study was to describe current practices in screening for rubella, hepatitis B, and varicella-zoster virus (VZV) in pregnant women in the province of Quebec. METHODS: In 2015, an electronic survey was distributed to HCWs who followed the case of at least one pregnant woman in the previous year and who could be contacted by email by their professional association. RESULTS: A total of 363 of 1084 (33%) participants were included in the analysis: general practitioners (57%), obstetrician-gynaecologists (20%), midwives (41%), and nurse practitioners (31%). For rubella, 48% of participants inquired about vaccination status, and of these, 98% offered serological testing for unvaccinated women versus 44% for vaccinated women. Similarly, of the 48% of participants who asked about hepatitis B vaccination status before offering testing, 96% ordered testing for hepatitis B surface antigen, 28% ordered testing for hepatitis B surface antibody, and 1% ordered no serological testing to unvaccinated women versus 72%, 46%, and 8%, respectively, for vaccinated women. Among the 81% of respondents who discussed VZV during prenatal care, 13% ordered serological testing if patients had a history of VZV infection, 87% if the VZV history was uncertain, and 19% if patients had a positive history of vaccination. CONCLUSION: Asking about vaccination status influences HCWs' attitudes about serological testing for rubella, hepatitis B, and VZV. In the context of increasing vaccination coverage in women of child-bearing age, it is important to clarify the impact of vaccination status in serological screening guidelines in pregnant women. PMID- 29276162 TI - HPV Unvaccinated Status and HPV Sexual Risk Behaviour are Common among Canadian Young Adult Women and Men. AB - OBJECTIVE: The current research focuses on sexual risk behaviour among young adult Canadians who have not been vaccinated against HPV. METHODS: Six hundred and forty-six Canadian university undergraduates completed a self-administered survey assessing HPV vaccination status and sexual risk behaviour. RESULTS: Five hundred and thirty-seven participants (154 men and 383 women aged 17-23) who met eligibility criteria were analyzed. 48.5% (n = 185) of female and 89.6% (n = 138) of male participants had not been vaccinated against HPV. In the unvaccinated cohort, 51.4% (n = 95) of women were coitally experienced, 49.2% (n = 91) reported experience with oral sex, and 6.5% (n = 12) reported experience with receptive anal intercourse. 55.1% (n = 76) of men were coitally experienced, 22.5% (n = 31) of men reported receptive oral sex, and 2.9% (n = 4) of men reported receptive anal intercourse. Using validated sexual risk behaviour cut offs, we determined that in the female unvaccinated population, the proportion at significantly increased risk for genital warts, cervical, anal, and oropharyngeal cancer was 11.0%, 30.0%, 6.5%, and 49.2% respectively. In the male unvaccinated population, the proportion at significantly elevated risk for genital warts and anal cancer was 27.2% and 2.9% respectively. CONCLUSION: Unvaccinated young Canadian women and men commonly engaged in sexual risk behaviours for HPV infection, engaged in sexual risk behaviours at a similar level as their vaccinated counterparts, and a substantial number were at elevated risk of HPV related morbidities at a young age. Findings contribute to an evidence-based case for redoubling efforts to encourage HPV vaccination among unvaccinated young Canadians who are at risk of HPV infection. PMID- 29276163 TI - Simulation and Classroom-Based Learning in Obstetrics and Gynaecology Residency Training. PMID- 29276164 TI - Examining the Selection Criteria of Neoadjuvant Chemotherapy Patients. AB - OBJECTIVES: To identify predictors of neoadjuvant chemotherapy (NAC) and to examine toxicities, dose reduction, interruptions, and second-line chemotherapy MATERIALS AND METHODS: A retrospective chart review of 391 patients with late stage ovarian cancer diagnosed between January 1, 2004 and December 31, 2010 was conducted. Logistic regression was used to predict chemotherapy type. Cumulative incidence of toxicities, dose reduction, and treatment interruption were calculated using the Kaplan-Meier method. Overall survival was analyzed using time-varying Cox regression models. A competing risk model was used to predict second-line chemotherapy with death as a competing risk. RESULTS: Older patients were less likely to receive primary debulking (OR 0.710; 95% CI 0.55-0.92, P = 0.0108), as were patients with longer diagnostic intervals. Clear-cell, endometrioid, and mucinous carcinoma were more likely to receive adjuvant treatment than unclassified epithelial (OR 6.964; 95% CI 2.02-24.03, P = 0.0021). Adjuvant patients experienced higher incidence of chemotherapy toxicities (P <0.0001) and treatment interruption (P = 0.016) at 3 months. There was no statistically significant difference in the incidence of chemotherapy dose reduction of >20% in the NAC and adjuvant populations (P = 0.142). Neoadjuvant patients were more likely to require more than one line of chemotherapy ([Subhazard Ratio] = 4.334; 95% CI 2.51-7.50, P <0.0001). CONCLUSION: Our study found that patients with shorter diagnostic intervals, more advanced age, and unclassified epithelial histotype were more likely to receive NAC. NAC patients did not experience a higher incidence of chemotherapy toxicities, treatment interruption, or dose reduction. There is treatment selection bias for sicker patients being treated with NAC. PMID- 29276165 TI - Caesarean Delivery Surgical Site Infection: What are Expected Rates and Potentially Modifiable Risk Factors? AB - OBJECTIVE: This study sought to determine baseline Caesarean delivery (CD) surgical site infection (SSI) rates in various patient subgroups and to identify potentially modifiable and non-modifiable risk factors for SSI. METHODS: This is a secondary analysis of a multicentre CD registry. Women who underwent CD were divided into SSI versus no SSI. SSI was defined as an infection that occurred in the part of the body where the surgery took place, within 30 days of surgery. Clinical characteristics and potential risk factors were compared between groups. RESULTS: Of 57 182 women, 3696 (6.5%) had SSI. SSI rates were higher in primary versus repeat CD (9.7% vs. 4.2%; P <0.001), and in CD after labour vs. no labour (9.5% vs. 3.8%; P <0.001). After adjustment for confounding factors, low transverse CD (adjusted OR [aOR] 0.7 [0.6-0.9]), CD performed between 7 pm and 7 am (aOR 0.9 [0.83-0.98]), primary CD (aOR 0.5 [0.5-0.6]), and intrapartum antibiotics (aOR 0.3 [0.1-0.4]) were associated with a decreased in the rate of SSI. Black race (aOR 1.9 [1.7-2.1]), tobacco use (aOR 1.4 [1.2-1.6]), increasing American Society of Anesthesiologists category (aOR 1.3 [1.1-1.6]), vertical skin incision (aOR 1.2 [1.1-1.3], emergency CD (aOR 1.3 [1.1-1.5]), and postpartum transfusion (aOR 2.7 [2.1-3.6]) were associated with an increase in the rate of SSI. CONCLUSION: This study estimates the CD SSI rates in different subgroups and serves as a baseline for future trials designed to develop preventive guidelines and protocols. PMID- 29276166 TI - Accelerated Titration of Oxytocin in Nulliparous Women with Labour Dystocia: Results of the ACTION Pilot Randomized Controlled Trial. AB - OBJECTIVE: The primary objective was to determine the feasibility of a large RCT assessing the effectiveness of an accelerated oxytocin titration (AOT) protocol compared with a standard gradual oxytocin titration (GOT) in reducing the risk of CS in nulliparous women diagnosed with dystocia in the first stage of labour. The secondary objective was to obtain preliminary data on the safety and efficacy of the foregoing AOT protocol. METHODS: This was a multicentre, double-masked, parallel-group pilot RCT. This study was conducted in three Canadian birthing centres. A total of 79 term nulliparous women carrying a singleton pregnancy in spontaneous labour, with a diagnosis of labour dystocia, were randomized to receive either GOT (initial dose 2 mU/min with increments of 2 mU/min) or AOT (initial dose 4 mU/min with increments of 4 mU/min), in a 1:1 ratio. An intention to-treat analysis was applied. RESULTS: A total of 252 women were screened and approached, 137 (54.4%) consented, and 79 (31.3%) were randomized. Overall protocol adherence was 76 of 79 (96.2%). Of the women randomized, 10 (25.6%) allocated to GOT had a CS compared with six (15.0%) allocated to AOT (Fisher exact test P = 0.27). CONCLUSION: This pilot study demonstrated that a large, multicentre RCT is not only feasible, but also necessary to assess the effectiveness and safety of an AOT protocol for labour augmentation with regard to CS rate and indicators of maternal and perinatal morbidities. PMID- 29276167 TI - Obstetric Simulation in Canada: The Need for Commitment and Leadership. PMID- 29276168 TI - Moderate Variability Does Not Rule Out Metabolic Acidemia: A Finding Which May Change How We Conceptualize Fetal Heart Rate Monitoring. PMID- 29276169 TI - Prevalence and Treatment Choices for Couples with Recurrent Pregnancy Loss Due to Structural Chromosomal Anomalies. AB - OBJECTIVE: Parental carriers of balanced structural chromosomal rearrangements such as reciprocal or Robertsonian translocations are at increased risk of recurrent pregnancy loss (RPL) due to the production of gametes with unbalanced non-viable chromosome variants. As a purported means of improving reproductive outcomes in this population, IVF and preimplantation genetic diagnosis (PGD) have been introduced as an alternative to natural conception and prenatal diagnosis. In this study, we evaluate the prevalence and treatment choices of couples with structural chromosomal rearrangement referred to a tertiary care RPL clinic. In addition, we compare the two methods of management in terms of live birth rate. METHODS: This is a retrospective chart review of 2321 couples who were referred to a highly specialized RPL clinic for ongoing clinical management between January 2005 and December 2013 (n = 23). Couples who pursued PGD through local fertility centres during this time were also included (n = 13). RESULTS: Thirty six couples (1.6%) were found to be parental carriers of a structural chromosomal rearrangement. In this cohort, couples were twice as likely to pursue natural conception compared with IVF with PGD. No significant differences were observed in live birth rate between PGD and clinical management (66.6% vs. 53.3%, P = 0.717). With PGD management, six live birth outcomes were observed, with an incidence of one birth in 5.63 years of follow-up. With clinical management, 24 live birth outcomes were observed, with an incidence of one birth in 4.09 years of follow-up. Mean time to live birth was 17.5 months and 23.3 months in clinical management and PGD, respectively. CONCLUSIONS: Among couples presenting to a tertiary RPL clinic, parental carriers of structural chromosomal rearrangement and history of RPL are more likely to pursue natural conception over IVF and PGD. With regards to reproductive outcomes, no significant difference in miscarriage rate, time to live birth, or live birth rate was observed between couples who pursued PGD compared with expectant clinical management. PMID- 29276170 TI - Fiber-Mediated Nourishment of Gut Microbiota Protects against Diet-Induced Obesity by Restoring IL-22-Mediated Colonic Health. AB - Dietary supplementation with fermentable fiber suppresses adiposity and the associated parameters of metabolic syndrome. Microbiota-generated fiber-derived short-chain fatty acids (SCFAs) and free fatty acid receptors including GPR43 are thought to mediate these effects. We find that while fermentable (inulin), but not insoluble (cellulose), fiber markedly protected mice against high-fat diet (HFD)-induced metabolic syndrome, the effect was not significantly impaired by either inhibiting SCFA production or genetic ablation of GPR43. Rather, HFD decimates gut microbiota, resulting in loss of enterocyte proliferation, leading to microbiota encroachment, low-grade inflammation (LGI), and metabolic syndrome. Enriching HFD with inulin restored microbiota loads, interleukin-22 (IL-22) production, enterocyte proliferation, and antimicrobial gene expression in a microbiota-dependent manner, as assessed by antibiotic and germ-free approaches. Inulin-induced IL-22 expression, which required innate lymphoid cells, prevented microbiota encroachment and protected against LGI and metabolic syndrome. Thus, fermentable fiber protects against metabolic syndrome by nourishing microbiota to restore IL-22-mediated enterocyte function. PMID- 29276171 TI - Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration. AB - Diet strongly affects gut microbiota composition, and gut bacteria can influence the colonic mucus layer, a physical barrier that separates trillions of gut bacteria from the host. However, the interplay between a Western style diet (WSD), gut microbiota composition, and the intestinal mucus layer is less clear. Here we show that mice fed a WSD have an altered colonic microbiota composition that causes increased penetrability and a reduced growth rate of the inner mucus layer. Both barrier defects can be prevented by transplanting microbiota from chow-fed mice. In addition, we found that administration of Bifidobacterium longum was sufficient to restore mucus growth, whereas administration of the fiber inulin prevented increased mucus penetrability in WSD-fed mice. We hypothesize that the presence of distinct bacteria is crucial for proper mucus function. If confirmed in humans, these findings may help to better understand diseases with an affected mucus layer, such as ulcerative colitis. PMID- 29276173 TI - Nutrimetry: BMI assessment as a function of development. AB - BACKGROUND AND OBJECTIVE: Adequate nutritional assessment is required to fight malnutrition (undernutrition and overfeeding) in children and adolescents. For this, joint interpretation of certain indicators (body mass index [BMI], height, weight, etc.) is recommended. This is done clinically, but not epidemiologically. The aim of this paper is to present "nutrimetry", a simple method that crosses anthropometric information allowing for bivariate interpretation at both levels (clinical and epidemiological). MATERIALS AND METHODS: Data from 41,001 children and adolescents aged 0-19 years, taken from Mexico's National Health and Nutrition Survey 2012, were analyzed. Data crossed were BMI-for-age z-scores (BAZ) with height-for-age z-scores (HAZ) according to the World Health Organization (WHO) standards. Conditional prevalences were calculated in a 3*3 grid and were compared with expected values. RESULTS: This method identified subgroups in each BAZ category showing heterogeneity of the sample with regard to WHO standards for HAZ and nutritional status. According to the method, nutritional status patterns differed among Mexican states and age and sex groups. CONCLUSION: Nutrimetry is a helpful and accessible tool to be used in epidemiology. It allows for detecting unexpected distributions of conditional prevalences, its graphical representation facilitates communication of results by geographic areas, and enriched interpretation of BAZ helps guide intervention actions according to their codes. PMID- 29276174 TI - Routine use of anticoagulation after transcatheter aortic valve replacement: Initial safety outcomes from a single-center experience. AB - BACKGROUND: Subclinical leaflet thrombosis (SCLT) can be seen in up to 12% of patients after transcatheter aortic valve replacement (TAVR). Anticoagulation appears to prevent and reverse SCLT but concerns exist about bleeding risk. METHODS: Our program adopted a strategy of routine anticoagulation after TAVR, starting warfarin on post-procedure day 0 and continuing for 3months in 10/2015. We report the initial safety and efficacy outcomes of this approach. Bleeding events were assessed using Valve Academic Research Consortium (VARC) and Bleeding Academic Research Consortium (BARC) definitions. RESULTS: The median (IQR) age of the population (n=191) was 82years (72-87) and the median (IQR) STS score was 5.6% (3-8). A total of 101 (53%) patients were discharged on anticoagulation (warfarin 97%) while 90 (47%) received antiplatelet therapy alone. The mean duration of anticoagulation therapy was 81+/-17 days. During follow-up 7 patients (4%) had a stroke or TIA, 3 (3%) in the anticoagulation group and 4 (4%) in the antiplatelet group (p=0.71). A total of 8 patients (4.2%) had BARC bleeding events during follow-up, 3 patients in the anticoagulation group (2.9%) and 5 in the antiplatelet group (5.5%, p=0.48). All bleeding events (VARC and BARC) were numerically lower in the anticoagulation group (8% versus 13%, p=0.20). CONCLUSIONS: A strategy of routine anticoagulation for 3-months after TAVR is well tolerated and associated with similar or lower bleeding risk compared to antiplatelet therapy. PMID- 29276172 TI - Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. AB - During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARgamma agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection. PMID- 29276175 TI - Impact of atrial fibrillation in patients with chronic kidney disease undergoing transcatheter aortic valve replacement: Insights of the Healthcare Cost and Utilization Project's National Inpatient Sample. AB - BACKGROUND: Limited data exists exploring the relationship between varying degrees of chronic kidney disease (CKD) and atrial fibrillation (AF) in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS: Records were selected from the 2011 to 2012 Healthcare Cost and Utilization Project's National Inpatient Sample for TAVR patients with pre-existing AF and CKD. Demographics, clinical characteristics, and TAVR-related in-hospital adverse events were identified and compared between patients with and without AF and moderate CKD (CKD stage 3-4), and between patients with and without AF and severe CKD (CKD stage 5 or end stage renal disease [ESRD]). Evaluated outcomes included major adverse cardiac and cerebrovascular events (MACCE). RESULTS: We identified a total of 293 patients with moderate CKD (stage 3 and higher) that underwent TAVR at selected U.S. hospitals between 2011 and 2012. Among these patients, 112 had a diagnosis of AF and 181 did not have AF. MACCE rates were similar among CKD 3-4 patients with and without AF (10.3% and 9.0% respectively, p=0.74). MACCE rates were similar among CKD 5/ESRD patients with and without AF (20.0% and 16.2% respectively, p=0.74). However, MACCE rates were higher in patients with CKD 5/ESRD compared with CKD 3-4 patients. Multivariate logistic regression analysis did not show that AF was an independent predictor of in-hospital MACCE. CONCLUSIONS: In a large retrospective analysis of CKD stage 3-4 or CKD 5/ESRD patients undergoing TAVR at selected U.S. hospitals, the presence of AF did not seem to be associated with increased adverse in-hospital events or length of stay. PMID- 29276176 TI - Coronary aneurysms in the acute patient: Incidence, characterization and long term management results. AB - BACKGROUND: Coronary aneurysms (1.5 times dilation the reference-vessel) are uncommon and have been diagnosed with increasing frequency with coronary angiography. The incidence varies from 1.5% to 5%. Reported complications are multiple: thrombosis, distal embolization, rupture and vasospasm, causing ischemia, heart failure or arrhythmias. However, the natural history and prognosis remains obscure. We aimed to describe the characteristics of acute patients with coronary aneurysms. METHODS: Prospective coronariography registry of patients with the diagnosis of coronary aneurysm between 2002 and 2013. Among 51,555 consecutive coronary angiograms, 414 patients with aneurysms were reported, of which 256 were considered acute (82% NSTE-ACS). RESULTS: Predominantly male (80%, mean age 65.5years), cardiovascular risk factors were common (hypertension 65%, dyslipidemia 65%, obesity 25%, diabetes mellitus 28.5%, and smokers 67%). With frequent coronary stenoses (94%), mostly with one aneurysm (80%), it was observed more frequently in the anterior descending artery. After a median follow-up of 52months, 53 died (14 cardiac causes) and 42% presented a cardiovascular event. Complications from the aneurysm were found in 4. The duration of dual antiplatelet therapy, LVEF, age and peripheral vascular disease highlighted in the multivariate analysis of death. CONCLUSION: The presence of coronary aneurysms in patients undergoing coronary angiography with an acute event is low. Patients who present them also have a large burden of atherosclerotic risk factors. In the long-term, the probability of cardiovascular complications is high, but only a small proportion are due to the aneurysm itself. A more intense and prolonged antithrombotic treatment may result in lower mortality rates. PMID- 29276177 TI - Integrin-bound talin head inhibits actin filament barbed-end elongation. AB - Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin activating domain and ABD1, whereas the C-terminal rod contains the actin anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly. PMID- 29276178 TI - The CDC50A extracellular domain is required for forming a functional complex with and chaperoning phospholipid flippases to the plasma membrane. AB - Flippases are enzymes that translocate phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn) from the outer to the inner leaflet in the lipid bilayer of the plasma membrane, leading to the asymmetric distribution of aminophospholipids in the membrane. One mammalian phospholipid flippase at the plasma membrane is ATP11C, a type IV P-type ATPase (P4-ATPase) that forms a heterocomplex with the transmembrane protein CDC50A. However, the structural features in CDC50A that support the function of ATP11C and other P4-ATPases have not been characterized. Here, using error-prone PCR-mediated mutagenesis of human CDC50A cDNA followed by functional screening and deep sequencing, we identified 14 amino acid residues that affect ATP11C's flippase activity. These residues were all located in CDC50A's extracellular domain and were evolutionarily well conserved. Most of the mutations decreased CDC50A's ability to chaperone ATP11C and other P4-ATPases to their destinations. The CDC50A mutants failed to form a stable complex with ATP11C and could not induce ATP11C's PtdSer-dependent ATPase activity. Notably, one mutant variant could form a stable complex with ATP11C and transfer ATP11C to the plasma membrane, yet the ATP11C complexed with this CDC50A variant had very weak or little PtdSer- or PtdEtn-dependent ATPase activity. These results indicated that the extracellular domain of CDC50A has important roles both in CDC50A's ability to chaperone ATP11C to the plasma membrane and in inducing ATP11C's ATP hydrolysis-coupled flippase activity. PMID- 29276179 TI - CD4+ T Cells are Exhausted and Show Functional Defects in Chronic Lymphocytic Leukemia. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. This health problem is caused due to the accumulation of mature B-lymphocytes in the peripheral blood and bone marrow. In the course of cancer, CD4+ T cells become "exhausted" and characterized with poor effector functions and the expression of multiple inhibitory receptors. OBJECTIVE: To investigate the frequency and functional properties of exhausted CD4+ T lymphocytes in patients with CLL. METHODS: Peripheral blood mononuclear cells were obtained from 25 untreated CLL patients and 15 healthy volunteers. CLL patients were clinically classified according to the Rai staging system. The frequency of CD4+/Tim-3+/PD-1+ cells was obtained by flow cytometry. To evaluate cell proliferation and cytokine production, CD4+ T cells were isolated and stimulated with phytohemagglutinin and PMA/ionomycin. Concentrations of IL-2, IFN gamma, TNF-alpha, and IL-10 were measured in the culture supernatants of stimulated cells by the ELISA technique. RESULTS: The percentage of CD4+/Tim 3+/PD-1+ cells was significantly higher in CLL patients than that of healthy controls. CD4+ T cells from CLL patients showed lower proliferative responses, a lower production of IL-2, IFN-gamma, and TNF-alpha, and a higher production of IL 10, compared to healthy controls. CD4+ T cells from CLL patients in advanced clinical stages showed more exhaustion features than those of early stages. CONCLUSION: Given that the exhaustion phase of T cells can be reversible, targeted blocking of immune inhibitory molecules could be a promising tool to restore the host immune responses against leukemic cells in CLL. PMID- 29276180 TI - CD40 Knocked Down Tolerogenic Dendritic Cells Decrease Diabetic Injury. AB - BACKGROUND: Type-1 diabetes (T1D) is an autoimmune disease in which T lymphocytes destroy insulin-producing beta-cells. Control of self-reactive T lymphocytes and recovery of diabetic injury is the end point of T1D. OBJECTIVE: To investigate generation of tolerogenic dendritic cells (tolDCs) as an innovative method of diabetes therapy. METHODS: Lentivirus vector production was achieved by GIPZ mouse CD40 shRNA, psPAX2 and pMD2G plasmids DNA. Purified bone marrow derived DCs were treated with CD40 shRNA, and expression of CD40 and mRNA level were evaluated by flow cytometry and Real-Time PCR, respectively. CD40 knock-down DCs were injected into STZ-induced diabetic mice. Blood glucose; glucose tolerance test and weight were analyzed in different groups. RESULTS: Mice treated with CD40 shRNA transfected DCs showed considerable differences in blood glucose, glucose tolerance, and weight compared to other groups. Also cytokine assays indicated an increase in IL-13 production in the CD40 shRNA group. CONCLUSION: In streptozotocin-induced diabetic mice model, administration of tolerogenic dendritic cells could improve diabetic parameters. PMID- 29276181 TI - Expression of Human Cytokine Genes Associated with Chronic Hepatitis B Disease Progression. AB - BACKGROUND: Hepatitis viruses are non-cytopathic viruses that lead to the infection and pathogenesis of liver diseases as a result of immunologically mediated events. OBJECTIVE: To investigate the expression of human inflammatory cytokines in chronic hepatitis B patients according to the severity of the infection. METHODS: We recruited a total of 120 patients, 40 of whom from cirrhotic, 40 non-cirrhotic, and 40 acute flare chronic hepatitis B and 40 healthy controls. For all groups total cellular RNA was extracted from whole blood samples, genomic DNA was eliminated, and cDNA was synthesized using the RT2 first strand kit, as instructed by the manufacturer. The real-time profiler PCR array was performed on a master cycler ep realplex and the data were analyzed using an online data analysis software. RESULTS: Non-cirrhotic chronic hepatitis B patients were found to significantly upregulate interleukin 10 receptors that regulate the balance between T helpers 1 and 2. On the other hand, patients with cirrhosis were found to have significant upregulated interleukin 3 gene expression. CONCLUSION: Our finding suggests that upregulation of anti inflammatory and downregulation of pro-inflammatory cytokines may play a role in the progression of non-cirrhotic chronic hepatitis B patients to cirrhotic and acute flare. However, a multi-center study with a larger sample size is needed to confirm our findings. PMID- 29276183 TI - The Reaction of Placental GRP78 Protein with Sera from Women with Multiple Sclerosis. AB - BACKGROUND: Multiple Sclerosis (MS) with four different types is one of the well studied autoimmune diseases of the central nervous system. Generally, two-thirds of MS patients are females who are at risk of pregnancy-related complications. Inappropriate responses of mother's immune system, such as antibody production against placental proteins, may lead to pregnancy-related disorders. The association between pregnancy complications and some autoantibodies including anti-phospholipid and anti-angiotensin II type-1 receptor antibodies are clear examples in this regard. OBJECTIVE: To investigate the probable placental antigens that might be targeted by the antibodies in the sera of MS patients. METHODS: Total placental proteins were extracted from normal fresh placentas and were separated using two-dimensional gel electrophoresis (2-DE) technique. The separated proteins were transferred onto a Polyvinylidene Fluoride (PVDF) membrane and blotted with the pooled sera of MS women or healthy controls (20 individuals in each group). The differentially blotted spot was identified by mass spectrometry and confirmed by western blot technique. RESULTS: The results indicated that the women afflicted with MS had an antibody against placental HSP 70kDa protein 5 (GRP78). CONCLUSION: In the present study, a new placental autoantigen candidate, which was targeted by antibody present in MS women sera, was found. The clinical importance of this finding regarding pregnancy complications in MS patients should be investigated by further experiments. PMID- 29276182 TI - Cytokine Profile of Leishmania Infantum Fucose-Mannose Ligand in Vaccinated Dogs in the Northwest of Iran. AB - BACKGROUND: Canine visceral leishmaniasis (CVL) caused by Leishmania infantum is endemic in the northwest and south of Iran. An appropriate vaccine can help to prevent and control visceral leishmaniasis in both humans and animals. Few studies have confirmed that the fucose-mannose ligand (FML) antigen of Leishmania donovani produced protective immunity in dogs against CVL. OBJECTIVE: To evaluate the immune responses of vaccinated dogs against FML antigen of L. infantum. METHODS: We isolated the FML antigen from native L. infantum and vaccinated the dogs with FML-saponin in an endemic area of VL in Iran to evaluate the immune responses of vaccinated dogs against this antigen. RESULTS: Our results indicated a significant increase in the expression of IFN-gamma, IL-10 and IL-13, but not IL-12A, gene transcripts in PBMCs of FML-saponin vaccinated dogs in comparison with controls. Our findings showed a significant difference in the ratio of IFN gamma/IL-10 mRNA expression in FML-saponin vaccinated dogs in comparison with two control groups. Moreover, a significant level of anti-FML antibodies was detected in serum of vaccinated dogs. CONCLUSION: These findings showed that FML-saponin stimulates both Th1 and Th2 immune responses with predominant Th1 and strong humoral immune responses to produce protective immunity against CVL. PMID- 29276184 TI - Evaluation of the miRNA-146a and miRNA-155 Expression Levels in Patients with Oral Lichen Planus. AB - BACKGROUND: Oral Lichen Planus (OLP) is a chronic autoimmune disease that could be considered as a potential premalignant status. OBJECTIVE: To evaluate the miRNA-146a and miRNA-155 expression levels in patients with oral Lichen planus lesions compared to healthy subjects with normal oral mucosa. METHODS: Forty patients with oral lichen planus and 18 healthy age and gender-matched controls were recruited in this case-control study. Oral lichen planus was diagnosed clinically and pathologically. The expression levels of two miRNAs in peripheral blood samples were determined using commercial TaqMan MicroRNA Assays. Relative quantification of gene expression was calculated by the 2-DeltaDeltact method. RESULTS: The expression levels of miRNA-146a and miRNA-155 in patients with oral Lichen planus were significantly higher than those of healthy controls. Also, a direct but insignificant correlation was found between miRNA-155 and miRNA-146a expression levels among the patient group. CONCLUSION: Our findings indicate that miRNA-146a and miRNA-155 could be potential biomarkers for the immunopathogenesis of oral lichen planus. PMID- 29276185 TI - Non-Viable Lactobacillus Casei Beneficially Modulates Poly I:C Immune Response in Co-Cultures of Human Cells. AB - BACKGROUND: Polyinosinic:polycytidylic acid (Poly-IC) has been used as a viral stimulus to mimic in vivo and in vitro infection induced by some viruses. OBJECTIVE: To determine whether non-viable Lactobacillus casei CRL431 (LcM) can modulate the immune response induced by Poly I:C in co-culture models of peripheral blood mononuclear cells (PBMC) and A549 cells. METHODS: T and NK cell activation was evaluated by flow cytometry and levels of TNF-alpha, IFN-gamma, IL 10, IL-29, and IL-17 by ELISA. Cells in direct contact with A549 (PBMC-A549) and cells with no contact with it (PBMC//A549) were used for this purpose. PBMCs alone and both co-culture systems were stimulated for 24 h with the following stimuli: LPS (10 ug/ml), LcM (106 UFC/ml), Poly I:C (2 ug/ml), Poly I:C+LcM, and LcM (3 h)+Poly I:C. Moreover, unstimulated cells were used as a control. RESULTS: Poly I:C and LcM (3 h)+Poly I:C in PBMC-A549 showed a significant increase in the percentage of CD8+ expression (p<0.05). All stimuli induced significant activation from T CD4+, CD8+ cells compared with unstimulated PBMCs in both co culture cells system. However, activation percentages were higher in direct co culture. Poly I:C induced a higher level of pro-inflammatory TNF-alpha and IFN gamma cytokines as well as IL-17 and IL-29 with lower IL-10 levels in both co culture systems while LcM induced a beneficial pattern of cytokines that would regulate Poly I:C effect. CONCLUSION: This in vitro model allowed us to highlight the potential of LcM as a modulator of anti-viral immune response and suggest its potential use in formulations against RNA respiratory viruses. PMID- 29276186 TI - IL-6/IL-10 Ratio as A Prognostic and Predictive Marker of the Severity of Inherited Epidermolysis Bullosa. AB - BACKGROUND: Recent studies have shown that cytokines have an important role in the pathogenesis of inflammatory diseases and can be used as prognostic markers. OBJECTIVE: To evaluate the IL-6/IL-10 ratio in patients with Inherited Epidermolysis Bullosa (EB) as a prognostic marker. METHODS: Serum levels of IL-6 and IL-10 were measured in 13 patients with recessive dystrophic EB (RDEB) as well as 10 with EB Simplex (EBS), and in 18 healthy subjects. Receiver Operating Characteristics (ROC) analyses were used to assess the diagnostic accuracy of the IL-6/IL-10 ratio for detecting severe form of EB. RESULTS: The IL-6/IL-10 ratio was statistically higher in RDEB patients than in EBS patients and healthy subjects. The IL-6/IL-10 ratio significantly correlated with BEBS score. CONCLUSION: Our findings suggest that IL-6/IL-10 ratio >5.6 has a good diagnostic accuracy to identify patients with the highest severity of disease. PMID- 29276188 TI - Treating the Secret Disease: Sex, Sin, and Authority in Eighteenth-Century Venereal Cases. AB - This article looks at cases of venereal disease from the early 1700s and how healers presented themselves as shrewd interpreters of patients' bodies and souls. Because the disease was so stigmatizing, patients were said to be unreliable narrators of their own symptoms and health histories. Practitioners, in turn, exhibited diagnostic expertise by sagely navigating such constraints. They characterized themselves as medical detectives who gathered clues and made diagnoses in spite of patients' alleged lies and omissions. Such work entailed moral integrity, astute observations, and the ability to persuade patients to divulge their most shameful sexual secrets. These findings illuminate how a particular disease shaped constructions of medical expertise, as well as the details of early modern medical practice that we rarely have the privilege of seeing. PMID- 29276189 TI - Managing the "Obscene M.D.": Medical Publishing, the Medical Profession, and the Changing Definition of Obscenity in Mid-Victorian England. AB - This article examines links between mid-Victorian opposition to commerce in popular works on sexual health and the introduction of a legal test of obscenity, in the 1868 trial R. v. Hicklin, that opened the public distribution of any work that contained sexual information to prosecution. The article demonstrates how both campaigning medical journals' crusades against "obscene quackery" and judicial and anti-vice groups who aimed to protect public morals responded to unruly trade in medical print by linking popular medical works with public corruption. When this link was codified, it became a double-edged sword for medical authorities. The Hicklin test provided these authorities with a blunt tool for disciplining professional medical behavior. However, it also radically narrowed the parameters through which even the most established practitioners could communicate medical information without risking censure. PMID- 29276190 TI - Between Colonial, National, and International Medicine: The Case of Bejel. AB - In the 1920s and 1930s, doctors stationed in the Middle East and North Africa debated whether bejel, a form of endemic syphilis, was an Arab version of syphilis, or a separate disease altogether. Using their clinical experience in the region, they tried to weave this unfamiliar phenomenon into a civilizational narrative, which placed European civilization at the top of a hierarchy. The assumption was that there was something inherent to Islamic societies and their hygienic habits that accounted for this difference. After World War II, the eradication of bejel was declared to be one of the objectives of both the Iraqi government and the newly founded World Health Organization. Examining the postwar life of bejel, I question how colonial legacies affected postcolonial and international medical theories and practices, on both national and international levels. PMID- 29276191 TI - Plagued by Politics: Cuba's National Sanatorium Project, 1936-59. AB - In 1936, Fulgencio Batista, the head of the Cuban military (and the de facto ruler of Cuba), founded the National Tuberculosis Council (CNT) to lead a state directed anti-tuberculosis campaign. While most national and colonial governments neglected tuberculosis until the postwar period, populist politics pushed Batista to prioritize a disease of poverty by the mid-1930s. However, national politics also undermined efforts to control the disease in Cuba. Authoritarianism facilitated Batista's considerable influence over tuberculosis policy, and he and his advisors pursued political objectives rather than following the technical advice offered by professional groups. As a result, the administration of the campaign was inefficient, nowhere more notably than in the CNT's premiere project, the Topes de Collantes National Sanatorium. Citizen and physician discontent with this project, the anti-tuberculosis campaign, and the state health sector fed into processes of political delegitimation and regime change in the 1950s. PMID- 29276193 TI - American Women Physicians in World War I. PMID- 29276197 TI - Introduction "An Exclusive Privilege ... to Complain": Framing Fashionable Diseases in the Long Eighteenth Century. PMID- 29276198 TI - The Fashioning of Fashionable Diseases in the Eighteenth Century. AB - This essay considers why the eighteenth century has particular significance for anyone concerned with the cultural forces necessary to render a disease fashionable. A brief overview of a pervasive cult of sensibility addresses the role of popular medical writing, imaginative literature, and spas in circulating a romanticized model of nervous disorders as signs of intellectual and moral superiority. Attention is drawn to the ambiguity in the term "fashionable" implying "popular," but also something that might be contrived; to what extent were Georgian fashionable diseases merely cultural constructs? Here the medicalization of masturbation suggests a limit-case. The discussion concludes with an individual case history as reported to the leading academic physician William Cullen. PMID- 29276199 TI - Experiencing, Exploiting, and Evacuating Bile: Framing Fashionable Biliousness from the Sufferer's Perspective. AB - This article examines how sufferers experienced, understood, and expressed themselves as bilious, focusing on the late Georgian era when the disease became one of the most fashionable and oft diagnosed amongst the elites. We show that responses to bile were more complex, varied, and less credulous than contemporary diatribes and subsequent historiography imply. Nonetheless, we foreground the socioculturally negotiated elements of the malady rather than its "reality." Applying Rosenberg's framing diseases model reveals biliousness as one of the most problematic conditions to frame, but one of the most malleable to self fashion. We demonstrate how Georgian Britons found functionality in their bile and "performed" being bilious. Articulate, literate sufferers deployed a range of strategies to vent or master their bile, or to render it social and serviceable, deriving various compensatory "secondary gains." We illuminate their variable success in reifying and sublimating bile, and differentiating the boundaries of biliousness vis-a-vis other complaints. PMID- 29276200 TI - Recipe Collections and the Realities of Fashionable Diseases in Eighteenth Century Elite Domestic Medicine. AB - This chapter focuses on the individualistic nature of medicine by considering manuscript recipe collections, and the concerns and rhetoric of the elite patients who wrote about fashionable diseases and experienced them. Domestic medicine in the eighteenth century was a facet of elite health care that included commercial medicine and professional assistance. Looking broadly at the fashionability of health care, including the fashionability of the consumer goods and services linked to self-management and leisure time, reveals the realities of fashionable diseases in elite lives. The sociocultural rhetoric of fashionable diseases was incorporated into the recipe collecting tradition, but experiences of suffering and a need for care continued to be at the forefront of the discourse in domestic medicine and this writing tradition. This essay argues also that domestic rhetoric and experiences of fashionable disease were significantly driven by consumerism. PMID- 29276201 TI - "The History of Half the Sex": Fashionable Disease, Capitalism, and Gender in the Long Eighteenth Century. AB - This essay examines the way in which disease was framed and narrated as fashionable in the long eighteenth century, and argues that the intensifying focus on women's fashionable disorders in the period grew in tandem with the rise of an unstable capitalism in its manifold forms. Using the satirical articles written by Henry Southern in the London Magazine-"On Fashions" (August 1825), "On Fashions in Physic" (October 1825), and "On Dilettante Physic" (January 1826)-and the literature that led to them, I analyze the role that women were now taking in the newly capitalized world of the early nineteenth century. This world was characterized by a burgeoning medical market, a periodical and print market which could adequately reflect and promote fashionable diseases and the medical market that spawned them, and the nexus of actors in the whole drama of the production, maintenance, and dissolution of fashionable diseases. PMID- 29276202 TI - Authenticity and Fashionable Disease in Eighteenth-Century Britain. AB - Throughout the eighteenth century the issue of authenticity shaped portrayals of fashionable diseases. From the very beginning of the century, writers satirized the behavior of elite invalids who paraded their delicacy as a sign of their status. As disorders such as the spleen came to be regarded as "fashionable," the legitimacy of patients' claims to suffer from distinguished diseases was called further into question, with some observers questioning the validity of the disease categories themselves. During the early and middle decades of the century, criticism was largely confined to periodicals, plays, and poetry, while medical writers wrote in defense of the authenticity of such conditions. The adoption of fashionable ailments and nervous sensibility grew increasingly popular, however, and from the 1770s onwards practitioners and novelists increasingly suggested that such diseases should not be trusted as signifiers of personal qualities or social status. PMID- 29276203 TI - "All the World Is Gone to the Assembly": Elizabeth Carter's Headaches, Nerves, and (In)Sociability. AB - Elizabeth Carter suffered from severe headaches all her life. Her letters are peppered with references to fits of "head-ach" so bad they made her bold enough to demand her own room wherever she visited, and to cherish a preference for solitude contrary to the ideal of Bluestocking sociability. Following her friends and physicians, she bowed to fashionable diagnoses in considering these headaches the result of a nervous constitution, and she was prescribed the usual remedies, including sociable trips to fashionable watering places. While positioning her sufferings within the frame of fashionable diseases, Carter tried to dissociate herself from fashionable sensibility, and struggled to gain acceptance for her pain as part of her body's "mechanism" by using a more old-fashioned, religious interpretative frame. This case study of Carter's headaches thus charts Carter's own understanding of her constitution, her body, and her pain within-and without the framework of eighteenth-century fashionable diseases. PMID- 29276204 TI - The Fat Person on the Edgware Road Omnibus: Fat, Fashion, and Public Shaming in the British Long Eighteenth Century. AB - Dieting as a fashionable undertaking in the public sphere appears in the course of the long eighteenth century. It is part of a shift to an awareness of the public stigma of obesity and marks the rise of a dieting culture focused on psychological rather than a purely somatic phenomenon. It is coterminous with the redefinition of the "reasonable" (rational) person both in law as well as in the public sphere.Reasonableness comes to define the normal within a cult of the rational; obesity comes to mark that state beyond reasonableness. Such views led and lead to the potential for psychological difficulties that come to be the hallmark of modern dieting practice. PMID- 29276206 TI - Utility of STIR-MRI in Detecting the Pain Generator in Asymmetric Bilateral Pars Fracture: A Report of 5 Cases. AB - Lumbar spondylolysis usually occurs as a stress fracture in the pars interarticularis of the vertebra. It is a prevalent sports-related disorder and a common cause of low back pain. We encountered five athletes (4 males, 1 female) with severe low back pain. Mean age was 14.5 years. All five patients were found to have bilateral pars fracture. In all cases, staging based on the findings from computed tomography scan of the right and left pars fracture was different. On short tau inversion recovery magnetic resonance imaging (STIR-MRI) of the comparatively newer more recently injured side, high signal intensity changes were obvious and dominant at the intra- and extraosseous area, which would indicate tissue edema and/or bleeding. Furthermore, the imaging findings corresponded to the side of the low back pain. In conclusion, STIR-MRI can effectively distinguish between painful pars fracture and painless pars fracture. PMID- 29276207 TI - Effects of Antrodia camphorata and Panax ginseng supplementation on anti-fatigue properties in mice. AB - Antrodia camphorata and Panax ginseng are well-known medicinal plants in Taiwan folk and traditional Chinese medicine, which have been reported for multifunctional bioactivities. However, there is limited evidence that a fixed combination formula of these two plant extracts is effective for the exercise improvement or anti-fatigue. We aimed to evaluate the potential beneficial effects of the mix formulation of these two herbal medicines (AG formulation) on fatigue and ergogenic functions following physiological challenge. Male Institute of Cancer Research (ICR) mice from four groups (n=10 per group) were orally administered AG formulation for 4 weeks at 0.984, 2.952 and 5.904 g/kg/day, which were designated the Vehicle, AG-1X, AG-3X and AG-6X groups, respectively. The anti-fatigue activity and exercise performance were evaluated using exhaustive swimming time, forelimb grip strength, and levels of serum lactate, ammonia, glucose, blood urea nitrogen (BUN) and creatine kinase (CK) after a swimming exercise. The exhaustive swimming time of the 1X, 3X or 6X AG group was significantly longer than that of the Vehicle group, and the forelimb grip strength of the 1X, 3X or 6X AG group was also significantly higher than that of the Vehicle group. AG supplementation also produced decreases in serum lactate, ammonia, BUN and CK activity after the swimming test, as well as increases in glucose. Therefore, the AG complex could be a potential formulation with an anti fatigue pharmacological effect. PMID- 29276211 TI - Treatment Patterns, Statin Intolerance, and Subsequent Cardiovascular Events Among Japanese Patients With High Cardiovascular Risk Initiating Statin Therapy. AB - BACKGROUND: This study examined treatment patterns, possible statin intolerance, and incidence of cardiovascular events (CVEs) in 2 cohorts of patients with high cardiovascular risk (i.e., patients with atherosclerotic cardiovascular disease [ASCVD] and patients with diabetes mellitus).Methods and Results:A retrospective cohort study examined adults initiating either a statin or ezetimibe from 1 January 2006 to 31 May 2014 in the Japan Medical Data Center database. The first observed statin or ezetimibe prescription defined the index date. Patients had >=12 months of pre- and post-index date plan enrollment. Two high-risk cohorts, the ASCVD cohort and diabetes cohort, were created based on diagnoses observed during the 12 months' pre-index date. Treatment patterns, possible statin intolerance, and incidence of CVEs were reported. In the ASCVD cohort (n=5,302), 32.9% discontinued therapy, 7.7% switched to a non-index statin or non-statin lipid-lowering therapy, and 11.2% augmented index therapy in the 12 months' post index date; only 0.3% were using high-intensity statins and 10% had possible statin intolerance. Also, 8.1% had any new CVE during the follow-up period. Treatment patterns and incidence of CVEs among the diabetes cohort were similar to those of the ASCVD cohort. CONCLUSIONS: High cardiovascular risk Japanese patients had frequent treatment modifications, although use of high-intensity statin doses was rare. These patterns may indicate that alternative therapies for lipid lowering are needed. PMID- 29276208 TI - The prostaglandin E2 receptor PTGER2 and prostaglandin F2alpha receptor PTGFR mediate oviductal glycoprotein 1 expression in bovine oviductal epithelial cells. AB - Oviductal glycoprotein 1 (OVGP1), an oviductin, is involved in the maintenance of sperm viability and motility and contributes to sperm capacitation in the oviduct. In this study, the regulatory effects exerted by prostaglandin E2 (PGE2) and F2alpha (PGF2alpha) on OVGP1 expression via their corresponding receptors in bovine oviductal epithelial cells (BOECs) were investigated. BOECs were cultured in vitro, and their expression of receptors of PGE2 (PTGER1, PTGER2, PTGER3, and PTGER4) and PGF2alpha (PTGFR) was measured using RT-qPCR. Ca2+ concentration was determined with a fluorescence-based method and cAMP was quantified by enzyme linked immunosorbent assays to verify activation of PTGER2 and PTGFR by their corresponding agonists in these cells. OVGP1 mRNA and protein expression was measured using RT-qPCR and western blotting, respectively, following PTGER2 and PTGFR agonist-induced activation. PTGER1, PTGER2, PTGER4, and PTGFR were found to be present in BOECs; however, PTGER3 expression was not detected. OVGP1 expression was significantly promoted by 10-6 M butaprost (a PTGER2 agonist) and decreased by 10-6 M fluprostenol (a PTGFR agonist). In addition, 3 MUM H-89 (a PKA inhibitor) and 3 MUM U0126 (an ERK inhibitor) effectively inhibited PGE2 induced upregulation of OVGP1, and 5 MUM chelerythrine chloride (a PKC inhibitor) and 3 MUM U0126 negated OVGP1 downregulation by PGF2alpha. In conclusion, this study demonstrates that OVGP1 expression in BOECs is enhanced by PGE2 via PTGER2 cAMP-PKA signaling, and reduced by PGF2alpha through the PTGFR-Ca2+-PKC pathway. PMID- 29276212 TI - Identification of Undeployed Stent in the Left Main Coronary Artery After 3 Years on Optical Coherence Tomography. PMID- 29276214 TI - New Perspective on the Treatment of Intractable Gastrointestinal Cancers: Role of Combination Therapies. AB - Unresectable gastrointestinal cancers, such as gastric, hepatocellular, biliary tract or pancreatic carcinomas, are often resistant to anti-cancer systemic therapies, and often recur locally or even after aggressive local therapies leading to dismal survival rates. Recent developments in oncology, have offered renewed hoped for the development of more efficacious therapies. For example, our understanding of the oncogenic drivers in carcinogenesis has increased exponentially, and may potentially allow personalization of therapy. In addition, a great interest has been recently to target immune checkpoints, and unleash the potential of the immune system against cancers. Finally, new radiation techniques (proton therapy) allow delivery of curative doses in a safely manner. However, optimal translation of these new therapeutic approaches will require a concerted effort in clinical trials and in preclinical studies. I will present results from clinical correlative studies and preclinical models of these diseases performed at our institution and in collaboration with other American and European investigators. The insights gained from this bench-to-the-bedside and back approach raise the hope for a more efficient development of targeted agents in gastrointestinal cancers, with the goal of increasing survival in patients afflicted with these aggressive and deadly diseases. (Presented at the 1951st Meeting, October 30th, 2017). PMID- 29276213 TI - A Literature Review of Mathematical Models of Hepatitis B Virus Transmission Applied to Immunization Strategies From 1994 to 2015. AB - A mathematical model of the transmission dynamics of infectious disease is an important theoretical epidemiology method, which has been used to simulate the prevalence of hepatitis B and evaluate different immunization strategies. However, differences lie in the mathematical processes of modeling HBV transmission in published studies, not only in the model structure, but also in the estimation of certain parameters. This review reveals that the dynamics model of HBV transmission only simulates the spread of HBV in the population from the macroscopic point of view and highlights several main shortcomings in the model structure and parameter estimation. First, age-dependence is the most important characteristic in the transmission of HBV, but an age-structure model and related age-dependent parameters were not adopted in some of the compartmental models describing HBV transmission. In addition, the numerical estimation of the force of HBV infection did not give sufficient weight to the age and time factors and is not suitable using the incidence data. Lastly, the current mathematical models did not well reflect the details of the factors of HBV transmission, such as migration from high or intermediate HBV endemic areas to low endemic areas and the kind of HBV genotype. All of these shortcomings may lead to unreliable results. When the mathematical model closely reflects the fact of hepatitis B spread, the results of the model fit will provide valuable information for controlling the transmission of hepatitis B. PMID- 29276216 TI - Malva Sylvestris Attenuates Cognitive Deficits in a Repetitive Mild Traumatic Brain Injury Rat Model by Reducing Neuronal Degeneration and Astrocytosis in the Hippocampus. AB - BACKGROUND The aim of our study was to evaluate the effect of Malva sylvestris (MS) on cognitive dysfunction in a repetitive mild traumatic brain injury (MTBI). MATERIAL AND METHODS MTBI was induced in all the study animals by hitting a metallic pendulum near the parietal-occipital area of the skull three times a day for ten days. Animals were treated with MS (250 mg/kg and 500 mg/kg) intragastrically per day for seven consecutive days. Cognitive function was estimated by the Morris water maze (MWM) method. Histopathology studies were performed on the hippocampal region by Nissl staining and anti GFAP staining. Concentrations of reactive oxygen species (ROS), and oxidative parameters including superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (LPO), and inflammatory cytokines in the brain tissues were measured. RESULTS Treatment with MS significantly improved cognitive function compared to the negative control. Histopathology studies suggested that treatment with MS significantly decreased (p<0.01) the count of neurodegenerative cells and induction of astrocytosis in the MTBI treated group compared to the negative control group. However, the concentrations of ROS and LPO, and the activities of SOD and CAT were significantly decreased in the MS treated groups of MTBI rats compared to the negative control group. Inflammatory cytokines, such as IL-1beta, IL6, and TNF-alpha were significantly decreased (p<0.01) in the brain tissues of the MTBI treated group compared to the control group of rats. CONCLUSIONS This study concluded that treatment with MS significantly improved cognitive dysfunction by reducing neurodegeneration and astrocytosis in brain tissues via decreasing oxidative stress and inflammation in neuronal cells. PMID- 29276215 TI - Deletion of both p62 and Nrf2 spontaneously results in the development of nonalcoholic steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease worldwide. However, details of pathogenetic mechanisms remain unknown. Deletion of both p62/Sqstm1 and Nrf2 genes spontaneously led to the development of NASH in mice fed a normal chow and was associated with liver tumorigenesis. The pathogenetic mechanism (s) underlying the NASH development was investigated in p62:Nrf2 double-knockout (DKO) mice. DKO mice showed massive hepatomegaly and steatohepatitis with fat accumulation and had hyperphagia-induced obesity coupled with insulin resistance and adipokine imbalance. They also showed dysbiosis associated with an increased proportion of gram-negative bacteria species and an increased lipopolysaccharide (LPS) level in feces. Intestinal permeability was elevated in association with both epithelial damage and decreased expression levels of tight junction protein zona occludens-1, and thereby LPS levels were increased in serum. For Kupffer cells, the foreign body phagocytic capacity was decreased in magnetic resonance imaging, and the proportion of M1 cells was increased in DKO mice. In vitro experiments showed that the inflammatory response was accelerated in the p62:Nrf2 double-deficient Kupffer cells when challenged with a low dose of LPS. Diet restriction improved the hepatic conditions of NASH in association with improved dysbiosis and decreased LPS levels. The results suggest that in DKO mice, activation of innate immunity by excessive LPS flux from the intestines, occurring both within and outside the liver, is central to the development of hepatic damage in the form of NASH. PMID- 29276217 TI - Roles of estrogens on myeloid-derived suppressor cells in cancer and autoimmune diseases. PMID- 29276218 TI - Signal Diversity of Receptor for Advanced Glycation End Products. AB - The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts. PMID- 29276219 TI - Indirect Calorimetry Measurement of Energy Expenditure Related to Body Position Changes in Healthy Adults. AB - Early mobilization is advocated to prevent intensive care unit-acquired physical weakness, but the patient's workload and its changes in response to body position changes have not been established. We used indirect calorimetry to determine the energy expenditure (EE) in response to body position changes, and we assessed EE's correlation with respiratory parameters in healthy volunteers: 8 males and 8 females, mean age 23.4+/-1.3 years. The subjects started in the resting supine position followed by a 30 degrees head-up position, a 60 degrees head-up position, an upright sitting position, a standing position, and the resting supine position. EE was determined in real time by indirect calorimetry monitoring the subject's respiratory rate, tidal volume (VT), and minute volume (MV). The highest values were observed immediately after the subjects transitioned from standing to supine, and this was significantly higher compared to the original supine position (1,450+/-285 vs. 2,004+/-519 kcal/day, p<0.01). Moderate correlations were observed between VT and EE (r=0.609, p<0.001) and between MV and EE (r=0.576, p<0.001). Increasing VT or MV indicates an increasing patient workload during mobilization. Monitoring these parameters may contribute to safe rehabilitation. Further studies should assess EE in critically ill patients. PMID- 29276220 TI - Metachronous Neoplasia and Local Recurrence after Colorectal Endoscopic Submucosal Dissection. AB - Several reports discussed colonoscopic surveillance after polypectomy and endoscopic mucosal resection (EMR) for colorectal polyps, but only a few reports focused on prognostic analyses, and none involved metachronous neoplasia after colorectal endoscopic submucosal dissection (ESD). We conducted the present study to assess the risk of adenoma recurrence requiring endoscopic treatment, and to establish appropriate post-ESD colonoscopic surveillance. We enrolled 116 patients who had undergone colorectal ESD at Okayama University Hospital between February 2008 and July 2014 and had been followed-up >12 months. We retrospectively analyzed clinicopathological features of 101 lesions from 101 patients. Metachronous adenomas were detected in 21 cases (20.8%). We divided the patients into 2 groups according to the occurrence of metachronous adenomas. Our comparison of clinicopathological characteristics between these groups showed that in the metachronous adenomas group the number of synchronous adenomas at index colonoscopy was high and the rate of laterally spreading tumor-nongranular (LST-NG) was higher. A multivariate analysis indicated that the number of synchronous adenomas was significantly associated with metachronous adenomas (HR: 2.54, 95%CI: 1.04-6.52, p<0.05). The colonoscopic surveillance planning after colorectal ESD should be more meticulous for patients with more synchronous adenomas. PMID- 29276221 TI - Effects of Postprandial Body Position on Gastrointestinal Motility, the Autonomic Nervous System and Subjective Comfort. AB - We examined postprandial body positions' effects on gastrointestinal motility, the autonomic nervous system and subjective comfort, i.e., whether lowering the head after a meal is beneficial for gastrointestinal motility and the prevention of pressure ulcer. We examined 10 healthy subjects and compared 3 body positions: (1) Seated upright. (2) Lying on a bed with the head at 60 degrees and knees up by 20 degrees (60 degrees position). (3) Identical to (2) until post-meal; the head was then lowered to 30 degrees (60 degrees -30 degrees position). Gastrointestinal motility was assessed as gastrointestinal sounds measured by sound-editing software. Digital plethysmography assessed autonomic nerve function as heart rate variability. The pressure ulcer risk was estimated as subjective comfort/discomfort using a visual analog scale. Gastrointestinal sounds increased post-meal. The 60 degrees -30 degrees position showed the highest number of sounds and longest cumulative sound duration. Post-meal, sympathetic activation was suggested in the 60 degrees position, whereas vagal activity was relatively preserved in the 60 degrees -30 degrees position. The 60 degrees -30 degrees position was the most comfortable, and the 60 degrees position was least comfortable. Lowering the head after a meal is beneficial to augment gastrointestinal motility and decrease the pressure ulcer risk. The 60 degrees head-up position increases the pressure ulcer risk. PMID- 29276222 TI - Lavender Essential Oil and Its Main Constituents Inhibit the Expression of TNF alpha-induced Cell Adhesion Molecules in Endothelial Cells. AB - Lavender essential oil (Lvn) has anti-inflammatory effects in an ovalbumin sensitized murine model of asthma, and inhibits inflammatory cell infiltration into the lungs. The anti-inflammatory effects of Lvn on cell adhesion molecules are not clear. Here we evaluated the effects of Lvn and its main constituents, linalyl acetate (LA) and linalool (LO), on the expression of tumor necrosis factor-alpha (TNF-alpha)-induced cell adhesion molecules in murine brain endothelial bEnd.3 cells and human umbilical vein endothelial cells (HUVECs). The bEnd.3 cells were treated with Lvn, LA, or LO and subsequently stimulated with TNF-alpha. The mRNA expression levels of cell adhesion molecules were detected using RT-PCR. E-selectin and P-selectin protein and phosphorylated-NF-kappaB p65 were detected by western blotting. The effects of Lvn on HUVECs were measured by RT-PCR. In bEnd.3 cells, Lvn and LA suppressed TNF-alpha-induced E-selectin, P selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and phosphorylated-NF-kappaB p65 in the nucleus; LO did not suppress P-selectin or phosphorylated-NF-kappaB p65. Lvn inhibited TNF-alpha-induced E-selectin mRNA in HUVECs. These results indicate that Lvn and LA inhibit TNF-alpha-induced cell adhesion molecules in endothelial cells through the suppression of NF-kappaB activation. Consequently, Lvn or other essential oils including LA may be useful as alternative anti-inflammatory medicines. PMID- 29276223 TI - Effects of (-)-epigallocatechin-3-gallate on EGFR- or Fusion Gene-driven Lung Cancer Cells. PMID- 29276224 TI - Feasibility Trial of Oral UFT after Platinum-based Adjuvant Chemotherapy in Patients with Resected Non-small Cell Lung Cancer. AB - We evaluated the feasibility of maintenance treatment using UFT (a combination of tegafur and uracil) after adjuvant platinum-based chemotherapy in patients with resected lung cancer. A prospective feasibility trial was conducted. Between 2010 and 2014, UFT was administered for 2 years sequentially after platinum-based adjuvant chemotherapy in 24 patients with resected Stage IIA-IIIA non-small cell lung cancer. The safety of UFT and the rate of treatment completion were then evaluated. The prior platinum-based chemotherapy regimens consisted of cisplatin+vinorelbine in 16 patients, carboplatin+paclitaxel in 5 and carboplatin+S-1 in one. During the subsequent UFT administration, a total of 3 patients required a dose reduction because of Grade 1 blood-stained sputum, Grade 2 numbness, and Grade 2 constipation, in one patient each. Eleven patients underwent the planned 2-year UFT administration, but 12 patients could not because of the recurrence of lung cancer in 5 patients, metachronous malignancy in one, and toxicities in 6. The completion rate for UFT administration was 64.7% (11/17). The most common type of toxicity was gastrointestinal toxicities. All of the toxicities were grade 1 or 2, and no severe toxicities were observed. UFT treatment after platinum-based chemotherapy was revealed to be feasible. PMID- 29276225 TI - The Incidence of Oral and Oropharyngeal Cancers in Betel Quid-Chewing Populations in South Myanmar Rural Areas. AB - Oral cancer is a very common disease in South and Southeast Asia. Betel quid (BQ) chewing and tobaccosmoking habits are etiological factors for oral cancer patients in these regions. We conducted an oral cancer screening in BQ-chewing endemic rural areas in South Myanmar for the early detection of oral cancer in BQ chewing and smoking individuals. We examined 105 subjects who were at high risk of oral cancer due to their oral habits (BQ users and/or smokers). Three carcinoma cases were detected, and there were 8 dysplasia cases. The carcinoma detection rate was 2.9%, and the carcinoma and precancerous lesion detection rate was 10.5%. In Myanmar, oral cancer screening has been conducted sporadically on a voluntary basis, and nationwide surveys have never been performed. There are also few reports of oral cancer screening for high-risk groups among the general population in Myanmar. Our present findings highlight the need for further screening and surveys. Education on betel quid chewing- and tobacco- related oral diseases and screening for the early detection of oral cancer are of the utmost importance in the control and prevention of oral cancer. PMID- 29276226 TI - Relationship between the Axillary Nerve and Accompanying Vessels and Proximal Humeral Locking Plates in Japanese: An MRI Study. AB - We investigated the anatomical features of the axillary nerve and its accompanying vessels with respect to the lateral wall of the greater tuberosity, focusing on the relationship between the neurovascular bundle and the proximal humeral locking plates. Magnetic resonance images of 30 Japanese patients' shoulders were examined. Oblique sagittal images across the greater tuberosity and the neurovascular bundle, which contain the axillary nerve and posterior circumflex humeral artery and vein, were obtained. The distance between the superior aspect of the greater tuberosity and the superior and inferior borders of the neurovascular bundles was measured at the anterior, middle, and posterior edges of the greater tuberosity. The neurovascular bundle was 28.5-36.7 mm, 32.6 41.3 mm, and 38.1-47.5 mm distal to the superior aspect of the greater tuberosity at the anterior, middle, and posterior edges, respectively. We evaluated the relationship between the neurovascular bundle and 3 different locking plates, which were placed at the lateral aspect of the greater tuberosity. Only 3 or four locking screws at the most proximal part could be safely inserted without axillary nerve interference. PMID- 29276227 TI - Constant Current vs. Constant Voltage Systems for Temporal Spinal Cord Stimulation for Intractable Pain. AB - Although spinal cord stimulation (SCS) is a useful treatment for chronic intractable pain, the optimal method of stimulation has not yet been established. In this prospective, crossover study, we compared the efficacy of using a constant current (CC) system with that of a constant voltage (CV) system for temporal SCS. Twenty patients were enrolled and divided into two groups. For 10 patients, a CV system was applied on Days 1-5, followed by the use of a CC system on Days 6-10. For the other 10 patients, a CC system was applied for the first five days, followed by a CV system for the subsequent five days. We evaluated the alteration of pain intensity using a visual analogue scale (VAS), the area of stimulation, the stability of effect, and patient satisfaction regarding treatment. The pain scores decreased significantly after the start of the SCS. There was no significant difference in the change in VAS between the two systems. The stimulation method used for temporal SCS did not affect the reduction of pain intensity. Patients felt a wider stimulation area by the CC system compared to the CV system. PMID- 29276228 TI - Retinal Nerve Fiber Layer Defect and Paracentral Scotoma after Internal Limiting Membrane Peeling with a Nitinol Loop. AB - Internal limiting membrane (ILM) peeling is an important maneuver in vitrectomy for macular holes (MHs). A nitinol loop is a surgical instrument designed to create an edge on the ILM and peel the ILM safely and consistently. The effect of using a nitinol loop for ILM peeling on the retina is not clear. We report here on a case of an idiopathic full-thickness MH in an adult woman, in whom retinal damage was revealed after her ILM was peeled using a nitinol loop. PMID- 29276229 TI - Severe Acute Respiratory Distress Syndrome Using Electrical Activity of the Diaphragm on Weaning from Extracorporeal Membrane Oxygenation. AB - The electrical activity of the diaphragm (EAdi) shows global diaphragmatic activation and power output from the central nervous system. We measured the EAdi as an indicator of breathing workload in a 40-year-old man suffering from severe acute respiratory distress syndrome (ARDS) secondary to influenza pneumonia in the process of weaning from extracorporeal membrane oxygenation (ECMO). Turning off the sweep gas flow immediately led to EAdi elevation, followed by hypoxia. The patient was successfully weaned from ECMO by reference to EAdi. This is the first case report to suggest that EAdi monitoring might be useful for ARDS patients during ECMO weaning. PMID- 29276230 TI - Disseminated Nontuberculous Mycobacterial Infection in a Patient with Anti-IFN gamma Autoantibodies. AB - We treated a 72-year-old Japanese female with sustained high fever and overall body exhaustion. An infectious liver cyst and right lung pneumonia were suspected causes. Hepatic cystectomy and various antibiotics did not resolve symptoms. Pneumonia exacerbation and ascitic fluid retention, left lumbar spinal osteomyelitis, and peri-gastric lymph node abscess penetrating the stomach were observed. Mycobacterium avium was identified in sputum, ascites, vertebral body abscess puncture specimen, and pus mucus secretion in the stomach. We diagnosed a disseminated nontuberculous mycobacterial infection. She seemed immunocompetent, without signs of AIDS or hematological malignancy. Serum anti-IFN-gamma autoantibodies tested positive and were suspected to be involved in the illness onset. PMID- 29276231 TI - Preconception Optimization of Glucose and Insulin Metabolism in Women Wanting to Conceive - High Rate of Spontaneous Conception Prior to Planned Assisted Reproduction. AB - Background: A hyperglycemic metabolic status with insulin resistance can have a negative effect on fertility and pregnancy outcomes. The aim of this retrospective study was to investigate disorders of glucose and insulin metabolism in women wanting to conceive who conceived spontaneously prior to planned assisted reproduction (ART). Associated risk factors of patients in terms of live births and miscarriages were also analyzed. Method: Out of total study population of 589 pregnancies, the pregnancies of 129 women wishing to have children who conceived spontaneously prior to planned ART were analyzed in more detail. A 75 g OGTT (OGTT: oral glucose tolerance test) was carried out prior to conception and after determination of pregnancy, including glucose measurement and testing of insulin resistance. If anomalies or risk factors for gestational diabetes (GDM) were detected, patients received metformin therapy prior to conception (off-label use). The course and outcome of pregnancies in the defined cohort were recorded. Results: The rate of spontaneous conception before planned ART after treatment for disorders of glucose/insulin metabolism was 21.9% (n = 129/589). 66.7% of the 129 pregnancies resulted in a live birth, 32 patients had a miscarriage. 76.0% of patients were treated with metformin (off-label use) for polycystic ovary syndrome (PCOS), positive risk profile for GDM, or abnormal glucose/insulin metabolism prior to conception. 55.8% of the cohort developed GDM. The insulin requirements of patients with GDM differed significantly depending on their metformin intake. 24.6% of GDM patients receiving metformin treatment developed GDM requiring insulin treatment compared to 53.8% who did not receive metformin medication. The PCOS rate in the study population who had live births was significantly higher (57.0%) than in the group who had miscarriages (31.3%). There were no significant differences with regard to rate of live births and rate of miscarriages with/without metformin treatment and GDM and metformin intake. Conclusion: The high rate of spontaneous conceptions in the cohort of women wishing to conceive emphasizes the importance of optimizing glucose/insulin metabolism prior to conception. The high rate of GDM in a cohort of pregnant women with a history of sterility also emphasizes the importance of expanding diagnostic testing for sterility to include the investigation of glucose metabolism and testing for insulin resistance. It is possible that PCOS patients in particular could benefit from treatment with metformin prior to conception, and this could explain the high rate of live births in this patient cohort. PMID- 29276232 TI - Storybridging: Four steps for constructing effective health narratives. AB - Objective: To develop a practical step-by-step approach to constructing narrative health interventions in response to the mixed results and wide diversity of narratives used in health-related narrative persuasion research. Method: Development work was guided by essential narrative characteristics as well as principles enshrined in the Health Action Process Approach. Results: The 'storybridging' method for constructing health narratives is described as consisting of four concrete steps: (a) identifying the stage of change, (b) identifying the key elements, (c) building the story, and (d) pre-testing the story. These steps are illustrated by means of a case study in which an effective narrative health intervention was developed for Dutch truck drivers: a high-risk, underprivileged occupational group. Conclusion: Although time and labour intensive, the Storybridging approach suggests integrating the target audience as an important stakeholder throughout the development process. Implications and recommendations are provided for health promotion targeting truck drivers specifically and for constructing narrative health interventions in general. PMID- 29276233 TI - Experimental Analysis of Allocation during Larval Development in Ambystomatid Salamanders. AB - We examined how variation in food availability and temperature influences patterns of energy allocation to growth, storage, metamorphosis, and reproduction in larval Ambystoma maculatum and A. tigrinum. In each species, an allocation vector consisting of metamorphic size, duration of larval period, fat body mass, and gonad mass was influenced by both food and temperature. Larvae grew rapidly at high food levels and high temperature, and delayed metamorphosis when grown at low temperature. High food levels resulted in larger fat bodies and decreased time to metamorphosis in A. tigrinum, and larger gonads in both species. The allocation vector collectively representing growth rate, storage, reproduction and metamorphosis differed between species: in A. maculatum, only the correlation between metamorphic size and fat body mass was significant, whereas all four variables were influenced in A. tigrinum. An interaction of food and temperature on the allocation vector was only detected for A. tigrinum. Our results indicate that interaction among allocation variables is stronger in some species than others and that these associations might be important in understanding life history variation between these species. PMID- 29276234 TI - AKD-The Time Between AKI and CKD: What Is the Role of the Pharmacist? PMID- 29276235 TI - Antithrombotic Therapy Post Endovascular Stenting for Superior Vena Cava Syndrome. PMID- 29276236 TI - Janus Kinase Inhibitors for the Treatment of Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a disease where the immune system attacks the linings of the joints, resulting in joint pain, stiffness, swelling, and destruction. Although many products are available for the treatment of RA, limitations such as adverse reactions and tolerance greatly affect adherence. Many of the current biologic disease-modifying antirheumatic drugs on the market are injectables, leaving a void to be filled for a product that can be taken orally. The most advanced of these approaches, the Janus kinase (JAK) inhibitors, are oral drugs that have not only made a breakthrough in RA, but also other skin conditions. PMID- 29276237 TI - Formulary Drug Review: Etelcalcetide. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The November 2017 monograph topics are Ertugliflozin, Glecaprevir / pibrentasvir, Neratinib, Sofosbuvir, velpatasvir, voxilaprevir and SQ C1 esterase inhibitor. The MUE is on glecaprevir, pibrentasvir. PMID- 29276238 TI - Treatment of Hypertriglyceridemia-Induced Acute Pancreatitis With Insulin, Heparin, and Gemfibrozil: A Case Series. AB - Hypertriglyceridemia is the third most common worldwide cause of acute pancreatitis. Resolving the underlying etiology is imperative for optimal management. This is especially true with regard to hypertriglyceridemia, as this etiology may cause more severe acute pancreatitis and worse symptoms than other causes of the disease. Many pharmacological treatment options for hypertriglyceridemia-induced acute pancreatitis (HTGP) have been proposed; however, the safety and efficacy for specific treatment regimens remain nebulous. At our institution, 6 patients, whose average Ranson criteria score were 5 and presenting triglyceride concentrations were 3501 mg/dL, were managed with a continuous infusion of insulin, subcutaneous heparin, and oral gemfibrozil for HTGP. Maximum insulin infusion rates ranged from 0.8 to 20.9 U/h. Half of the patients received nongemfibrozil cholesterol medication. Five patients experienced a resolution of HTGP (median day 3). The only adverse drug event was hypoglycemia in a single patient. Combination therapy with heparin, insulin, and gemfibrozil is safe and efficacious in quickly lowering serum triglyceride concentrations in HTGP. This combination warrants further study. PMID- 29276239 TI - Evaluation of Antimicrobial Stewardship-Related Alerts Using a Clinical Decision Support System. AB - Background: Information technology, including clinical decision support systems (CDSS), have an increasingly important and growing role in identifying opportunities for antimicrobial stewardship-related interventions. Objective: The aim of this study was to describe and compare types and outcomes of CDSS-built antimicrobial stewardship alerts. Methods: Fifteen alerts were evaluated in the initial antimicrobial stewardship program (ASP) review. Preimplementation, alerts were reviewed retrospectively. Postimplementation, alerts were reviewed in real time. Data collection included total number of actionable alerts, recommendation acceptance rates, and time spent on each alert. Time to de-escalation to narrower spectrum agents was collected. Results: In total, 749 alerts were evaluated. Overall, 306 (41%) alerts were actionable (173 preimplementation, 133 postimplementation). Rates of actionable alerts were similar for custom-built and prebuilt alert types (39% [53 of 135] vs 41% [253 of 614], P = .68]. In the postimplementation group, an intervention was attempted in 97% of actionable alerts and 70% of interventions were accepted. The median time spent per alert was 7 minutes (interquartile range [IQR], 5-13 minutes; 15 [12-17] minutes for actionable alerts vs 6 [5-7] minutes for nonactionable alerts, P < .001). In cases where the antimicrobial was eventually de-escalated, the median time to de escalation was 28.8 hours (95% confidence interval [CI], 10.0-69.1 hours) preimplementation vs 4.7 hours (95% CI, 2.4-22.1 hours) postimplementation, P < .001. Conclusions: CDSS have played an important role in ASPs to help identify opportunities to optimize antimicrobial use through prebuilt and custom-built alerts. As ASP roles continue to expand, focusing time on customizing institution specific alerts will be of vital importance to help redistribute time needed to manage other ASP tasks and opportunities. PMID- 29276240 TI - Compatibility, Stability, and Efficacy of Vancomycin Combined With Gentamicin or Ethanol in Sodium Citrate as a Catheter Lock Solution. AB - Background: Indwelling catheters deliver lifesaving medical treatments for many chronically ill patients but are frequently a source of infection. Treatment may include an antimicrobial agent(s) and anticoagulant solution dwelling within the catheter. In vitro determinations of solution compatibility and stability are necessary prior to use in patients. Objective: The aim of this study was to determine the physical compatibility, chemical stability, and antimicrobial activity of vancomycin (5 or 10 mg/mL) with gentamicin (1 mg/mL) or 40% ethanol in 4% sodium citrate lock solution over 72 hours. Methods: All solutions were prepared per manufacturer's instructions. Samples were studied under 4 conditions: (1) 25 degrees C with light, (2) 25 degrees C without light, (3) 37 degrees C with light, and (4) 37 degrees C without light. Physical compatibility and chemical stability were assessed at 0, 24, 48, and 72 hours. Antimicrobial susceptibility testing was conducted at 0 and 72 hours. All studies were carried out in triplicate. Results: All solution combinations under each condition remained patent from baseline to 48 hours. One solution combination of vancomycin (5 mg/mL) and ethanol (40% v/v) in 4% sodium citrate revealed a slight turbidity at 72 hours. Clarity and pH remained stable in all other solutions during the entire study period. Chemical compatibility and antibiotic activity ranged from 95% to 105% and 95% to 106% of initial baseline values, respectively, for all solutions under 4 storage conditions. Conclusions: All antibiotic-anticoagulant lock solutions were found to be physically, chemically, and microbiologically stable during the 72-hour study period except vancomycin (5 mg/mL) and ethanol (40% v/v) in 4% sodium citrate solution which showed slight turbidity at 72 hours. PMID- 29276241 TI - Development of Institutional Guidelines for Management of Gram-Negative Bloodstream Infections: Incorporating Local Evidence. AB - Background: Appropriate empirical antimicrobial therapy is associated with improved outcomes of patients with Gram-negative bloodstream infections (BSI). Objective: Development of evidence-based institutional management guidelines for empirical antimicrobial therapy of Gram-negative BSI. Methods: Hospitalized adults with Gram-negative BSI in 2011-2012 at Palmetto Health hospitals in Columbia, SC, USA, were identified. Logistic regression was used to examine the association between site of infection acquisition and BSI due to Pseudomonas aeruginosa or chromosomally mediated AmpC-producing Enterobacteriaceae (CAE). Antimicrobial susceptibility rates of bloodstream isolates were stratified by site of acquisition and acute severity of illness. Retained antimicrobial regimens had predefined susceptibility rates >=90% for noncritically ill and >=95% for critically ill patients. Results: Among 390 patients, health care associated (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.5-6.3] and hospital-acquired sites of acquisition (OR: 3.7, 95% CI: 1.6-8.4) were identified as risk factors for BSI due to P aeruginosa or CAE, compared with community acquired BSI (referent). Based on stratified bloodstream antibiogram, ceftriaxone met predefined susceptibility criteria for community-acquired BSI in noncritically ill patients (95%). Cefepime and piperacillin-tazobactam monotherapy achieved predefined susceptibility criteria in noncritically ill (95% both) and critically ill patients with health care-associated and hospital acquired BSI (96% and 97%, respectively) and critically ill patients with community-acquired BSI (100% both). Conclusions: Incorporation of site of acquisition, local antimicrobial susceptibility rates, and acute severity of illness into institutional guidelines provides objective evidence-based approach for optimizing empirical antimicrobial therapy for Gram-negative BSI. The suggested methodology provides a framework for guideline development in other institutions. PMID- 29276242 TI - Underutilization of Aldosterone Antagonists in Heart Failure. AB - Background: Treatment with an aldosterone antagonist (AA) has been shown in multiple trials to reduce heart failure (HF)-related morbidity, mortality, and hospital readmission. American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) treatment guidelines recommend the use of an AA in all HF patients with an ejection fraction <=35% and no known contraindication. Several studies have documented underuse of AA. Objectives: To determine the proportion of patients who received AA therapy consistent with the ACCF/AHA guidelines. Secondary objectives included determining the proportion of patients who received an AA inconsistent with guidelines and 30- and 90-day readmission rates. Methods: A retrospective chart review was conducted of patients admitted to an inner city academic medical center with a diagnosis of HF between August 16, 2011, and June 5, 2013. Results: A total of 346 HF admissions (87.6% African American) were evaluated. Use of an AA at discharge was consistent with guidelines in 31% of patients. A total of 121 patients (35%) were discharged on an AA. Among the remaining 225 patients who were not discharged on an AA, 170 (75.6%) had no contraindication to therapy. Sixty-one patients were readmitted within 30 days, and a total of 108 patients were readmitted within 90 days. There were no significant differences in readmission rates between patients who were discharged on AA therapy and those who were not. Conclusion: AAs are still underutilized in the treatment of HF. PMID- 29276243 TI - Stability of Procainamide Injection in Clear Glass Vials and Polyvinyl Chloride Bags. AB - Objectives: The objective of this study was to evaluate the chemical stability of procainamide hydrochloride, 100 mg/mL, when repackaged in clear glass vials or diluted to 3 mg/mL with normal saline and packaged in polyvinyl chloride (PVC) bags when stored at either 23 degrees C and exposed to light (ETL) or 5 degrees C and protected from light (PFL). Methods: Solutions were assayed using a stability indicating high-performance liquid chromatography method. Samples (5 mL) were collected from triplicate containers on days 0, 7, 14, 21, 28, 56, 91, and 193. Color/clarity and pH changes were also monitored at each time interval. Results: During the study, all samples remained clear and there was only a slight pH change. The color of the solutions stored at 23 degrees C intensified but did not correlate with a significant decrease in concentration, while solutions stored at 5 degrees C remained unchanged. Solutions repackaged in glass vials were stable for 193 days when stored at 23oC and ETL or 5oC and PFL. When further diluted to 3 mg/mL with normal saline and packaged in PVC bags, procainamide was also stable for 193 days at either 23oC and ETL or 5 degrees C and PFL. Conclusions: The stability of procainamide, 100 mg/mL, repackaged in clear glass vials was 193 days when stored at either 23oC and ETL or 5oC or PFL. If diluted further to 3 mg/mL with normal saline and packaged in PVC bags, the drug was also stable for 193 days at either 23oC and ETL or 5 degrees C and PFL. PMID- 29276244 TI - Development of a Local Health-System Pharmacy Resident Society. PMID- 29276245 TI - Challenges and Solutions to New Manager Onboarding. AB - This article outlines challenges and solutions to new managers onboarding within a department of pharmacy. PMID- 29276246 TI - Knowing What Is Coming: The Importance of Monitoring the Pharmaceutical Pipeline. PMID- 29276247 TI - In Reply to "Postoperative Pain Management With Liposomal Bupivacaine in Patients Undergoing Orthopedic Knee and Hip Arthroplasty at a Community Hospital". PMID- 29276248 TI - Letter to the Editor on "Enzyme Replacement or Substrate Reduction? A Review of Gaucher Disease Treatment Options". PMID- 29276249 TI - Response to Letter to the Editor on "Enzyme Replacement or Substrate Reduction? A Review of Gaucher Disease Treatment Options". PMID- 29276250 TI - Commentary: Exploring Novel Approaches to Staff Rewards and Recognition. PMID- 29276251 TI - Formulary Drug Review: Edaravone. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. PMID- 29276252 TI - BACE Inhibitors and Tau Protein Targeting Drugs in Prevention of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a common disease in the United States with almost 10% of people older than 65 suffering from the disease. A few drugs provide some improvement in mental function in mild-to-moderate disease, but no treatments are available to prevent the development of AD. Two new classes of drugs being investigated for the treatment or prevention of AD include drugs to decrease beta amyloid accumulation and Tau protein aggregation inhibitors. After disappointing results for treatment of AD, both classes are being tested in prevention trials. PMID- 29276253 TI - Direct and Indirect Remuneration Fees: The Controversy Continues. AB - The Centers for Medicare and Medicaid Services (CMS) initially created direct and indirect remuneration (DIR) fees with the enactment of Medicare Part D in order to track rebates and other price adjustments made to pharmacy benefit managers (PBMs). PBMs have expanded the use of these fees to "claw back" money from pharmacies on already dispensed medications. Community and specialty pharmacies claim these fees are not transparent, hurt patients and taxpayers, and negatively impact their fiscal bottom line, while PBMs assert that these fees actually reduce premiums for patients. Congress has stepped into the dispute by introducing legislation that would halt retroactive DIR fees. PMID- 29276255 TI - In Vitro Evaluation of Eslicarbazepine Delivery via Enteral Feeding Tubes. AB - Purpose: The feasibility of preparing an eslicarbazepine acetate suspension using Aptiom tablets for administration via enteral feeding tubes was evaluated. Methods: Eslicarbazepine acetate suspension (40 mg/mL) was prepared using Aptiom tablets after optimizing the tablet crushing methods and the vehicle composition. A stability-indicating high-performance liquid chromatography (HPLC) method was developed to monitor the eslicarbazepine stability in the prepared suspension. Three enteric feeding tubes of various composition and dimensions were evaluated for the delivery of the suspensions. The suspension was evaluated for the physical and chemical stability for 48 hours. Results: The reproducibility and consistency of particle size reduction was found to be best with standard mortar/pestle. The viscosity analysis and physical stability studies showed that ORA-Plus:water (50:50 v/v) was optimal for suspending ability and flowability of suspension through the tubes. The developed HPLC method was found to be stability indicating and suitable for the assay of eslicarbazepine acetate in the prepared suspension. The eslicarbazepine concentrations in separately prepared suspensions were within acceptable range (+/-3%), indicating accuracy and reproducibility of the procedure. The eslicarbazepine concentrations in suspensions before and after delivery through the enteric feeding tubes were within acceptable range (+/-4%), indicating absence of any physical/chemical interactions of eslicarbazepine with the tubes and a successful delivery of eslicarbazepine dosage via enteric feeding tubes. The stability study results showed that eslicarbazepine concentration in the suspension remained unchanged when stored at room temperature for 48 hours. Conclusion: The study presents a convenient procedure for the preparation of a stable suspension of eslicarbazepine acetate (40 mg/mL) using Aptiom tablets, for administration via enteral feeding tubes. PMID- 29276254 TI - Factors Associated With Burnout Among US Hospital Clinical Pharmacy Practitioners: Results of a Nationwide Pilot Survey. AB - Background: In health care, burnout has been defined as a psychological process whereby human service professionals attempting to positively impact the lives of others become overwhelmed and frustrated by unforeseen job stressors. Burnout among various physician groups who primarily practice in the hospital setting has been extensively studied; however, no evidence exists regarding burnout among hospital clinical pharmacists. Objective: The aim of this study was to characterize the level of and identify factors independently associated with burnout among clinical pharmacists practicing in an inpatient hospital setting within the United States. Methods: We conducted a prospective, cross-sectional pilot study utilizing an online, Qualtrics survey. Univariate analysis related to burnout was conducted, with multivariable logistic regression analysis used to identify factors independently associated with the burnout. Results: A total of 974 responses were analyzed (11.4% response rate). The majority were females who had practiced pharmacy for a median of 8 years. The burnout rate was high (61.2%) and largely driven by high emotional exhaustion. On multivariable analysis, we identified several subjective factors as being predictors of burnout, including inadequate administrative and teaching time, uncertainty of health care reform, too many nonclinical duties, difficult pharmacist colleagues, and feeling that contributions are underappreciated. Conclusions: The burnout rate of hospital clinical pharmacy providers was very high in this pilot survey. However, the overall response rate was low at 11.4%. The negative effects of burnout require further study and intervention to determine the influence of burnout on the lives of clinical pharmacists and on other health care-related outcomes. PMID- 29276256 TI - Evaluation of Insulin Use and Hypoglycemia in Hospitalized Elderly Patients. AB - Background: Routine administration of correctional insulin is no longer recommended as a primary strategy to treat hyperglycemia in hospitalized patients. Studies have demonstrated significant improvement in glycemic control in patients treated with basal and correctional insulin (B+C) versus correctional insulin alone (C). However, the effect of C or B+C on hypoglycemic events is not well understood. Objective: The objective of this study was to investigate the effect of B+C versus C on hypoglycemic events in hospitalized elderly patients. Methods: A single-center retrospective review of patients at least 65 years old that were admitted between April and July 2016, who were prescribed any type of insulin. Exclusion criteria included admission to the intensive care unit (ICU) on hospital admission, history of hypersensitivity to insulin, or insulin use for the management of hyperkalemia. Patients were divided based on the insulin regimen prescribed, B+C or C. The primary outcome of the study was the incidence of hypoglycemic episodes between groups. Secondary outcomes included severity of hypoglycemia, hospital length of stay (LOS), hospital mortality, and ICU transfer. Hypoglycemia was defined as a blood glucose level less than 70 mg/dL. Results: A total of 709 patients were included, with 144 (20.3%) prescribed B+C and 565 (79.7%) prescribed C. Incidence of hypoglycemia was greater in the B+C group than C (29.1% vs 12.6%, p=0.012). The average blood glucose readings during hypoglycemic episodes between B+C and C were 50 mg/dL and 52.5 mg/dL, respectively (p<0.01). There was no difference observed in hospital LOS. No patients required ICU admission within 24 hours of a hypoglycemic event or died during the index hospitalization. Conclusion: There is a higher incidence of hypoglycemia in elderly patients prescribed basal plus correctional insulin than correctional insulin alone. PMID- 29276257 TI - Production Standard and Stability of Compounded Del Nido Cardioplegia Solution. AB - Background: The del Nido cardioplegia solution (dNCS) was originally developed for pediatric cardiac surgery, being now also used for adult patients. Hospital pharmacies frequently resort to internal dNCS production which has led to an increase in the need for validated parameters for compounding and storage. Objective: This report defines in-house production standards, as well as the stability of dNCS under optimal storage conditions. Methods: All ingredients were sterile and United States Pharmacopeia (USP)/National Formulary (NF) certified. All final bags were quarantined at 4 degrees C for quality control, when 3 of 33 weekly bags were randomly assayed for potassium content. Each lot was only released if all 3 samples were within +/-5% of target. Stability testing was performed per USP 797 guidance. Over a 6-month period, 4 different lots and 4 bags from each lot of dNCS were assayed. Each bag was assessed for physical and chemical stability while refrigerated at 4 degrees C, at 35 degrees C in an incubator, and at 70 degrees C under 80% relative humidity. A light exposure arm was also set up at 25 degrees C under 150 lumens. Calibrators of lidocaine, mannitol, and gluconate were freshly prepared and assayed with the samples by Liquid chromatography/Mass spectrometry (LC/MS). Results: Lidocaine concentrations averaged 0.117 mg/mL (95.8% of theoretical) at 4 degrees C for 30 days. At 35 degrees C, they decayed by 67% in 30 days, while at 70 degrees C nearly 50% was lost after the first day. A first-order kinetics was observed with an Arrhenius activation energy of 25 kcal/mol. Degradation products identified under stress conditions were absent in the stable product. Conclusions: The dNCS is stable for at least 30 days under 4 degrees C refrigeration in ethylene vinyl acetate (EVA) bags. PMID- 29276258 TI - Lumbar Spine Surgeries and Medication Usage During Hospital Stay: One-Center Perspective. AB - Background: Pain after spine surgery is usually managed with opioid and nonopioids. The rate of lumbar spine surgeries (LSS) is rising, but current practices on LSS are not known. A current trend in LSS and medication usage by age group is needed to gain a better understanding of how LSS and its pain management vary by age. Objective: The aim of this study was to report current practices of LSS of discectomy, laminectomy, and fusion in patients aged 18 and older and to gain an understanding of medication use for management of LSS. Methods: This retrospective study analyzed data of the University of Kansas Medical Center from 2007 to 2014 of patients (>18 years of age) undergoing laminectomy, discectomy, and fusion. Results: A total of 19 463 patients underwent LSS between 2007 and 2014 at Kansas University hospital. For the purpose of this study, 3115 patients' medical records were observed. A 50% increase in LSS between 2007 and 2014 was noted. Specifically, more than 2-fold increase in LSS was observed in patients aged 65 years and older. Among those aged 65 years and older, laminectomy was the most commonly performed surgery (69.6%) while discectomy was the most common surgery performed among those aged 18 to 34 (82.9%) and those aged 35 to 44 (72%). The medication use also increased with a highest usage in opioids alone (55%), followed by opioids combined with other analgesics (42.7%), regardless of lumbar surgery type or age. Conclusion: The information of increase in both LSS and the medication usage over the 7 years can be used to gain a better understanding of quality, expenditure, and outcomes following LSS. This knowledge may help health care providers plan patient care and rehabilitation services for older adults, as the trajectory of lumbar spine surgery is likely to rise with growing prevalence of older adults. The information regarding increased opioid utilization may also help clinicians to refine opioid usage and consider alternative approaches to manage acute postoperative pain, in light of the current concerns related to overutilization of opioids. PMID- 29276259 TI - Formal Leadership: Thrilling (and Scary) Like a Roller Coaster Ride. PMID- 29276260 TI - ISMP Medication Error Report Analysis. AB - These medication errors have occurred in health care facilities at least once. They will happen again-perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your in-service training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site (www.ismp.org), by calling 800-FAIL-SAFE, or via e mail at ismpinfo@ismp.org. ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications. PMID- 29276261 TI - Cancer Chemotherapy Update: Bevacizumab, Etoposide, and Cisplatin Regimen for Refractory Brain Metastases. AB - The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc, 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, email: waddfour@charter.net. Regimen Name: Bevacizumab, etoposide, and cisplatin (BEEP) Origin of Name: The regimen is named for the medications it contains: bevacizumab, etoposide, and cisplatin. PMID- 29276262 TI - Formulary Drug Reviews: Plecanatide. PMID- 29276263 TI - Calcitonin Gene-Related Peptide Receptor Antagonists for Migraine Prophylaxis. AB - : Migraine is a common disorder affecting 12% of the U.S. POPULATION: Prophylaxis is recommended for patients who experience frequent migraines. Because current drugs used for prophylaxis are not 100% effective and cause adverse effects that affect compliance, new strategies have been studied to prevent headaches. One new pharmacologic strategy is to use an inhibitor of the calcitonin gene-related peptide (CGRP). As a class, the CGRP receptor inhibitors have reduced monthly migraine days and are well tolerated. This article will briefly review CGRP inhibitors in development. PMID- 29276264 TI - Highly Probable Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome Associated With Lenalidomide. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life threatening hypersensitivity reaction to medications. We report a case of a 75 year-old African American female who presented with generalized rash with desquamation and malodorous secretions. She was febrile and hypotensive, and required vasopressors for hemodynamic instability. Sepsis secondary to skin or soft tissue infection was considered initially. However, she recently was started on lenalidomide for treatment of her multiple myeloma, and her white blood cell count of 17 K/uL with 55% eosinophils along with peripheral smear showing eosinophilia suggested lenalidomide-induced rash. Lenalidomide was discontinued, and methylprednisolone was initiated. Four days after lenalidomide discontinuation, vasopressors were discontinued. Blood cultures did not exhibit any growth. The Niranjo Adverse Drug Reaction Probability Scale score of 9 suggests lenalidomide was a highly probable cause of DRESS syndrome. The temporal relation of lenalidomide administration and development of symptoms plus improvement of rash with the discontinuation of lenalidomide and reappearance on restarting lenalidomide in the follow-up clinic strengthens our suspicion of lenalidomide-induced DRESS syndrome. Cases of lenalidomide-induced DRESS syndrome are sparse; however, DRESS syndrome is fatal in approximately 10% of patients. Providers should be aware and keep a vigilant eye out for this adverse reaction with lenalidomide. PMID- 29276265 TI - Significant Published Articles for Pharmacy Nutrition Support Practice in 2016. AB - Purpose: To assist the pharmacist engaged in nutrition support therapy in staying current with pertinent literature. Methods: Several clinical pharmacists engaged in nutrition support therapy compiled a list of articles published in 2016 considered important to their clinical practice. The citation list was compiled into a single spreadsheet where the author participants were asked to assess whether the paper was considered important to nutrition support pharmacy practice. A culled list of publications was then identified whereby the majority of author participants (at least 5 out of 8) considered the paper to be important. Guideline and consensus papers from professional organizations, important to practice but not scored, were also included. Results: A total of 103 articles were identified; 10 from the primary literature were voted by the group to be of high importance. An additional 11 organizational guidelines, position, recommendation, or consensus papers were also identified. The top-ranked articles from the primary literature were reviewed. Conclusion: It is recommended that pharmacists, engaged in nutrition support therapy, be familiar with the majority of these articles as it pertains to their practice. PMID- 29276266 TI - Financial Effect of a Drug Distribution Model Change on a Health System. AB - Background: Drug manufacturers change distribution models based on patient safety and product integrity needs. These model changes can limit health-system access to medications, and the financial impact on health systems can be significant. Objective: The primary aim of this study was to determine the health-system financial impact of a manufacturer's change from open to limited distribution for bevacizumab (Avastin), rituximab (Rituxan), and trastuzumab (Herceptin). The secondary aim was to identify opportunities to shift administration to outpatient settings to support formulary change. Methods: To assess the financial impact on the health system, the cost minus discount was applied to total drug expenditure during a 1-year period after the distribution model change. The opportunity analysis was conducted for three institutions within the health system through chart review of each inpatient administration. Opportunity cost was the sum of the inpatient administration cost and outpatient administration margin. Results: The total drug expenditure for the study period was $26 427 263. By applying the cost minus discount, the financial effect of the distribution model change was $1 393 606. A total of 387 administrations were determined to be opportunities to be shifted to the outpatient setting. During the study period, the total opportunity cost was $1 766 049. Conclusion: Drug expenditure increased for the health system due to the drug distribution model change and loss of cost minus discount. The opportunity cost of shifting inpatient administrations could offset the increase in expenditure. It is recommended to restrict bevacizumab, rituximab, and trastuzumab through Pharmacy & Therapeutics Committees to outpatient use where clinically appropriate. PMID- 29276267 TI - Limited Influence of Excipients in Extemporaneous Compounded Suspensions. AB - Objective: The objective of this study was to identify whether compounding oral suspensions with SyrSpend SF based on tablets or capsules is a suitable alternative for using raw pharmaceutical materials. Methods: Suspensions based on 5 different tablets and capsules were studied in SyrSpend SF. The summary of product characteristics of these different tablets and capsules were obtained from the manufacturer. Our hypothesis was that, if the maximum beyond-use date of the study was reached, the excipient did not seem to have an influence on the stability of the active pharmaceutical ingredient (API) within the studied time frame. Results: All excipients used in flecainide acetate, labetalol HCl, and tiagabine HCl tablets as well as in celecoxib and oseltamivir capsules did not seem to influence the beyond-use date of the overall suspension based on SyrSpend SF. Conclusion: Although using raw materials as API sources is preferred, oral suspensions with SyrSpend SF prepared from crushed tablets or opened capsules could be a possible alternative. Based on this study, a wide range of different excipients does not seem to impact the beyond-use date of different APIs compounded in SyrSpend SF. PMID- 29276268 TI - Improved Outcomes and Cost Savings Associated With Pharmacist Presence in the Emergency Department. AB - Purpose: The study sought to determine whether the inclusion of a pharmacist on the emergency department (ED) resuscitation team was associated with improved compliance with the Advanced Cardiac Life Support (ACLS) guidelines and patient survival. The study also evaluated cost avoidance associated with a pharmacist providing clinical services to the ED. Methods: Cardiac arrest event records were evaluated for compliance with ACLS guidelines as well as for whether or not a pharmacist was involved as a member of the resuscitation team. Pharmacists documented all interventions performed while physically present in the ED which were utilized to associate cost avoidance. Results: When a pharmacist assisted as a member of the resuscitation team, a significant increase in the percentage of medications administered in compliance with the ACLS guidelines was noted (78% vs 67%, P = .0255). An increase in survival to hospital admission (25% vs 17.8%, P = .0155) was also noted though no significant increase in survival to hospital discharge (15% vs 4.4%, P = .6392) was observed. Over a 5-month period, pharmacists in the ED performed 1200 interventions, which created US$98 362 in cost avoidance. This extrapolates to approximately US$320 000 per year in cost avoidance. Conclusion: Inclusion of a pharmacist as a member of the resuscitation team improved compliance with medications administered according to the ACLS guidelines and increased survival to hospital admission, though survival to hospital discharge was unaffected. The presence of a pharmacist in the ED was associated with approximately US$320 000 in cost avoidance per year, if not more. PMID- 29276269 TI - Patients Given Take Home Medications Instead of Paper Prescriptions Are More Likely to Return to Emergency Department. AB - Objective: The aim of this study was to compare the 30-day emergency department (ED) return rate between patients given a Take Home Medication pack (THM) versus a standard paper prescription (SPP) prior to discharge. Methods: This was an observational, prospective cohort study in an urban, university-affiliated, level I trauma center. Patients were identified through daily pharmacy reports. Consecutive adult patients discharged from the ED with either a THM or equivalent SPP were included. For each patient, baseline characteristics including age, gender, primary care provider (PCP), primary language, ethnicity, marital status, and insurance status were recorded from the electronic medical record (EMR). Review of the EMR was used to determine whether patients returned to the ED within 30 days and whether the return visit was for all-causes or for the same complaint targeted by the THM or SPP from the index visit. Similarly, visits to other providers in the health system within 30 days were recorded. Results: A total of 711 patients were included in the study, with 268 receiving a THM and 443 receiving a SPP. In comparison with the SPP group, the THM group was more likely to have an all-cause return (Relative Risk [RR] = 1.7, P < .01). Variables associated with increased odds of returning to the ED within 30 days included study group (adjusted Odds Ratio [aOR]: 1.7), male gender (aOR: 1.6), African American ethnicity (aOR: 3.0), public insurance (aOR: 3.3), and institutional financial assistance (aOR: 5.0). The difference between study groups for index visit complaint-specific returns was not significant. Conclusions: Patients receiving a THM demonstrated a higher all-cause return rate than patients receiving a SPP. A randomized study is needed evaluating the effect of THM on return ED visits. PMID- 29276270 TI - The Evolution of Drug Information Centers and Specialists. PMID- 29276271 TI - Sodium Phosphates Injection: Osmolarity Labeling Correction. PMID- 29276272 TI - ISMP Adverse Drug Reactions: Allergic Angina Caused by Fluconazole Rhabdomyolysis Caused by Risperidone High Incidence of Hyponatremia With High-Dose Trimethoprim Sulfamethoxazole Lithium Carbonate-Induced Hypersalivation Persistent Hemorrhage After Idarucizumab Administration. AB - The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID- 29276273 TI - Drug Monographs: Avelumab and Ribociclib. AB - The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc, 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID- 29276274 TI - Formulary Drug Review: Naldemedine. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The September 2017 monograph topics are brigatinib, durvalumab, edaravone, midostaurin, and sarilumab. The MUE is on sarilumab. PMID- 29276275 TI - Chimeric Antigen Receptor T-Cell Therapy for Lymphomas. AB - It is estimated that 2.1% of the population of the United States will develop non Hodgkin lymphoma (NHL) in a lifetime. With treatment, 71% of patients with NHL live to 5 years. Because current drugs used for treatment do not cure all patients and cause serious adverse effects, new strategies have been studied to treat lymphoma. One new pharmacologic strategy is to use chimeric antigen receptor T-cell (CAR T-cell) therapy. CAR T-cell therapies are very potent. As a class, the CAR T-cell therapies have induced complete remission in 50% to 80% of patients. Most patients using CAR T-cell therapies develop cytokine release syndrome, with about 1 in 3 having a severe form of the syndrome. This article will briefly review CAR T-cell therapies in development. PMID- 29276276 TI - International Mentoring Programs: Leadership Opportunities to Enhance Worldwide Pharmacy Practice. AB - Health-system and community pharmacy practice in the United States is experiencing transformational change; however, this transformation is lagging in the international arena. As a result, efforts are being made to provide support and education to the international pharmacy leaders and practitioners. This article describes one effort, the Mandela Washington Fellows Program, and suggests areas where pharmacy leaders can be involved to help advance the practice of pharmacy on an international level. The Mandela Washington Fellows Program for young Africa leaders consists of a US-Africa pharmacy-mentoring program identified ranging from educational opportunities to collaboration for implementation of patient care programs. The specifics of the mentoring program include daily meetings, clinic and ward rounds, round table discussions with mentors, and visits to various hospital care systems. Lessons were learned and strategies for sustaining the program are discussed. These types of programs represent leadership opportunities that may not be apparent to most pharmacy directors, but expanding their view to helping international pharmacists expand their practice only strengthens the professional goal of providing patient centered pharmacy services. PMID- 29276277 TI - Impact of Developing Adult Ketamine Order Panels for the Emergency Department. AB - Background: Ketamine in adults has been identified as a safe and effective alternative for multiple indications, each with specific evidence-based dosing ranges. Emergency department (ED) providers are tasked with appropriate ordering of ketamine. A multi-institutional retrospective analysis within EDs at a large health system from November 2013 to October 2015 reviewed ED adult ketamine prescribing patterns for procedural sedation (PS), rapid sequence intubation (RSI), and analgesia. Retrospective cohort results revealed 56% (84 of 150) of PS, 64% (16 of 25) of RSI, and 81.5% (53 of 65) of analgesia ketamine doses fell within indication-specific dosing ranges. Objective: The study purpose was to evaluate the impact of standardizing ED ordering processes to increase appropriate dosing of ketamine. Methodology: Indication-specific adult ED ketamine order panels based on available clinical trial data were implemented in the electronic medical record and ED provider education conducted. Adults at least 18 years of age who received ketamine in the ED for PS, RSI, or analgesia from March 2016 to May 2016 were included. Patients were excluded if no weight or indication was documented. The primary outcome was percentage change in frequency of appropriately dosed ketamine versus the retrospective cohort. The secondary outcome was use of ketamine order panels. Mantel-Haenszel tests were used for statistical analysis. Results: Ketamine for prospective cohort adult ED patients was significantly more likely to be dosed appropriately than in the retrospective cohort (odds ratio: 2.94, 95% confidence interval: 1.1-7.8; P = .0231). Conclusion: Results suggest increased standardization with added decision support increased appropriate indication-specific dosing of ketamine for adults in the ED. PMID- 29276278 TI - Critical Appraisal of Biomedical Literature With a Succinct Journal Club Template: The ROOTs Format. AB - Journal clubs are a valuable tool to assist pharmacists in the evaluation of biomedical literature and to promote adoption of evidence-based practices. The concise ROOTs (relevance, observe validity, obtain clinically significant results, and translate results to clinical practice) method was developed to help simplify and provide structure to any journal club process. Although there are a variety of recommended practices on how to conduct journal clubs using a variety of questions and checklists, many are cumbersome and difficult to complete and present in less than 30 minutes. The concise ROOTs journal club format may be beneficial for clinicians to help them develop an efficient and consistent means to appraise evidence in clinical practice. A sample completed ROOTs template, utilizing the 2015 IMPROVE-IT trial, is provided to further assist in utilizing the template. PMID- 29276279 TI - Effect of a Rivaroxaban Patient Assistance Kit (R-PAK) for Patients Discharged With Rivaroxaban: A Randomized Controlled Trial. AB - Background: The combination of poor health literacy and a complex dosing regimen/transition for rivaroxaban in venous thromboembolism (VTE) treatment may increase the likelihood of negative clinical outcomes secondary to nonadherence. Objective: The aim was to determine if a Rivaroxaban Patient Assistance Kit (R PAK) given at hospital discharge increases proper dose transition and overall patient adherence. Methods: This prospective, randomized, controlled trial was conducted at an 859-bed academic medical center. Patients were randomized into 2 groups. In the treatment group, patients received the R-PAK with counseling at discharge, whereas patients in the control group received discharge counseling alone. In addition, patients were contacted after 21 days of therapy to assess dose transition, adherence, satisfaction, and safety. The primary outcome was percentage of patients who properly transitioned to rivaroxaban once daily on day 22. Results: Twenty-five patients were enrolled; 12 received an R-PAK, whereas 13 comprised the control group. No difference in the baseline assessment of health literacy status was noted (P = 1.00). Proper transition to daily administration on day 22 was no different between the groups (P = .891). Adherence was reported in 99.8% of R-PAK patients and 97.65% of control patients (P = .074). Side effects were rarely reported. Conclusions: The use of an R-PAK for the treatment of VTE was not associated with an improvement in transition to daily administration; however, both groups had high rates of overall adherence. Pharmacist counseling/education was provided in both groups and is an important component to include in any patient discharge, especially for medications with dose transitions. PMID- 29276280 TI - Examining the Use of Sodium Nitroprusside in Coronary Artery Bypass Grafting: Is the Benefit Worth the Cost? AB - Purpose: Sodium nitroprusside is a vasodilator frequently used in the coronary artery bypass grafting (CABG) setting. However, the price of a 50-mg vial of sodium nitroprusside increased from $5.00 in 2003 to up to $900 in 2016. The purpose of this review is to help health systems balance high-quality patient care with economic responsibility. Methods: A MEDLINE literature search was performed using the search terms "nitroprusside" and "coronary artery bypass." All English-language trials in human subjects assessing the use of sodium nitroprusside in the setting of CABG were evaluated. The references of these studies were also reviewed. Results: In the setting of CABG, sodium nitroprusside attenuates conduit vasospasm and reduces the incidence of inflammation, atrial fibrillation, and acute kidney injury after surgery. However, other vasodilators are more effective at maintaining postoperative blood pressure at goal. Conclusions: Despite its cost, sodium nitroprusside may be an appropriate agent to use during CABG operations, but other agents should be considered for treatment of postoperative hypertension. PMID- 29276281 TI - Successful Implementation of an Antimicrobial Stewardship Program at an Academic Medical Center. AB - Background: Focus on antimicrobial use and infection prevention from accrediting or regulatory bodies such as the Joint Commission, as well as regulatory agencies such as the Centers for Medicare and Medicaid Services and the Centers for Disease Control, has highlighted the need for continuing development of antimicrobial stewardship programs at healthcare facilities across the country. Methods: Our institution utilized the 2007 Infectious Diseases Society of America and the Society for Healthcare Epidemiology guidelines to direct the evaluation of its antimicrobial use and develop a successful antimicrobial stewardship program. Three baseline evaluations were conducted. Retrospective chart reviews evaluating formulary restrictions for fluroquinolones and carbepenems, a dosing optimization program for meropenem, and the intravenous to oral conversion program for fluconazole and voriconazole were completed. Results: Approximately 40% of orders for levofloxacin were not supported with a clinical justification for nonformulary use in the patient chart. Forty-nine percent of orders written for meropenem did not follow the dose optimization program. Opportunity for fluconazole and voriconazole to be converted to oral therapy when appropriate was suggested. Conclusion: The baseline evaluations revealed the need for an antimicrobial stewardship program. This article outlines the process used to assess need, plan, implement, and evaluate the impact of an antimicrobial stewardship program. PMID- 29276282 TI - Pharmacy Transitions of Care and Culture. PMID- 29276283 TI - Bivalirudin Medication Use Evaluation and Cost Savings Initiative. AB - Bivalirudin is a parenteral anticoagulant that elicits its effect through inhibition of both free and clot bound-thrombin. Inhibition of thrombin serves as a unique mechanism for anticoagulation when compared to heparin as thrombin serves as the final common pathway for the intrinsic and extrinsic coagulation cascades. Due to unclear benefit over heparin, concerns regarding reversibility, and most importantly cost its use as a parenteral anticoagulant varies by institution. A recent drug expenditure review within our institution noted a significant increase in the contribution bivalirudin had on the overall drug budget. In an effort to establish the rationale for the cost increase, a medication use evaluation was performed. While it was discovered that 625 out of 1364 days of bivalirudin therapy were potentially avoidable, an equally important discovery was the amount of waste that was associated with bivalirudin therapy. Calculating daily requirements for bivalirudin indicated that 60% of patients required less than 100 mg per day. Within this article, we describe a cost savings initiative to reduce bivalirudin waste and the resulting cost-avoidance following implementation. PMID- 29276284 TI - Navigating the New Antimicrobial Stewardship Regulations. AB - Purpose: Many health care facilities are navigating their way through the new antimicrobial stewardship standards and guidelines. The purpose of this article is to provide information for health care facilities to improve patient care. Summary: New regulations and guidelines surrounding antimicrobial stewardship have prompted facilities to review their process related to antimicrobial stewardship. In setting up a program, there are many factors to consider including involving key personnel, obtaining leadership support, identifying an infectious disease physician to chair or cochair the committee, and meeting agenda, metrics, and educational needs. Conclusion: Antimicrobial stewardship plays a vital role in both our hospital and community setting. Pharmacists are uniquely positioned to improve optimal patient care through rounding, review of patients' chart, and contribute to the improvement of antimicrobial stewardship by working with a multidisciplinary team. These efforts may improve the utilization of antimicrobial agents. PMID- 29276285 TI - Formulary Drug Review: Safinamide. PMID- 29276286 TI - Biosimilar Substitution Laws. PMID- 29276287 TI - Evaluation of Corticosteroid Dose in Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - Background: Several recent studies have shown that both lower doses and shorter durations of systemic corticosteroids have similar efficacy for treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, each trial has limitations that constrain direct applicability to a US hospital population. Objective: The aim of this study was to determine whether, in a US community hospital, low doses of corticosteroids provide the lowest risk of adverse effects without increasing length of stay or readmission rate. Methods: A single-center retrospective cohort was performed using patients meeting criteria for AECOPD. Primary endpoints included length of hospitalization, proportion of patients with >30% increase in blood glucose from baseline, and rate of 30-day readmission; multivariable regression analysis was used for comparison. The 3 inpatient cumulative dose range groups were low: <=250-mg prednisone equivalents, medium: 251 to 500 mg, and high: >=501 mg. Results: A total of 665 records were evaluated, with 369 records included. As the corticosteroid dose ranges increased, there were more patients with increased blood glucose (33.3%, 54.4%, 59.9%). When holding all other factors constant, there was a statistically significant increase in patients with elevated blood glucose with the medium- and high-dose groups as compared with the low-dose group (P < .009, P < .001), the average length of stay was 21.3 hours higher in the high-dose group as compared with the low-dose group (P < .001), and there were no significant differences in readmission rates between the dose groups. Conclusions: The lowest dose range of corticosteroids was associated with the lowest rate of impaired blood glucose without a statistically significant increase in length of stay or readmission rate. PMID- 29276288 TI - Hazardous Drug Contamination of Drug Preparation Devices and Staff: A Contamination Study Simulating the Use of Chemotherapy Drugs in a Clinical Setting. AB - Background: Hazardous drug contamination (HD) in healthcare environments continues, placing healthcare staff at risk of significantly chronic health problems, despite the use of personal protective equipment (PPE) and closed system transfer device systems (CSTDs). Objective: This study's aim was to determine how HD might spread through touch after handling contaminated vials in simulated pharmacy and nursing environments. Methods: UV fluorescent powder Glo Germ (Glo Germ Co., Moab, UT), composed of melamine resin, was used to simulate HD. Following manufacturer's exact usage specifications, five commercially available CSTDs were tested in the simulated pharmaceutical preparation environment under controlled conditions. UV fluorescence was used to detect the test medium powder that simulated HD following each trial. Photographs, using a Nikon D40X (10.2 mp) camera, were taken at selected stages of testing to document the presence of HD. Results: Transfer of the HD testing medium (Glo Germ) to IV sets, pharmacy PPE, and nursing PPE was observed in 4 of 5 CSTDs tested. The only CSTDs that showed no observable contamination was the Allison Medical Safety Enclosed Vial Adapter (SEVA) system (Littleton, CO). Conclusions: Results show residue from HD vials spread as vial was handled in a pharmacy environment in 4 of 5 CSTDs, contaminating pharmacy PPE, ancillary products, and nursing PPE. No HD residue was detected on PPE, ancillary products, or nursing PPE in the pharmacy after using the SEVA system, providing an effective means to contain HD for drug transfer from vial to delivery system. PMID- 29276289 TI - A Case of Metronidazole Injection Infiltration Without Sequelae. AB - Purpose: This report describes a case of metronidazole injection infiltration which contrasts the sole other case report in the literature at this time, as the patient described herein experienced mild signs and symptoms with prompt resolution and no significant sequelae. Summary: The patient experienced metronidazole injection infiltration during administration open to gravity via an 18-gauge peripheral catheter in the left brachial vein. The site was examined at bedside within approximately 30 minutes of the incident and was noted to be slightly edematous, erythemic, and painful in terms of a 5.5 * 6.6-cm area. No blanching, blister formation, induration, skin discoloration, or diminished capillary refill were observed. The event was conservatively managed in the form of catheter discontinuation and marking of the affected area with a patient skin marker, as hyaluronidase was not administered due to a product osmolarity of ~314 mOsM/L and pH of 5.8. A bedside evaluation the next morning revealed full resolution of the previously described symptoms. The patient was discharged from the facility 11 days later without further complications from the infiltration event. Conclusion: We describe a case of metronidazole injection infiltration which did not require pharmacologic or nonpharmacologic interventions and resulted in complete resolution. This case supplements the current literature by contrasting the sole other case report which resulted in profound necrosis near the intravenous access site. This case suggests metronidazole infiltrations may not require clinician alarm or treatment if events occur under circumstances similar to that which is presented. PMID- 29276290 TI - Doubling Pharmacist Coverage in the Intensive Care Unit: Impact on the Pharmacists' Clinical Activities and Team Members' Satisfaction. AB - Background: National professional organizations have recognized pharmacists as essential members of the intensive care unit (ICU) team. Critical care pharmacists' clinical activities have been categorized as fundamental, desirable, and optimal, providing a structure for gauging ICU pharmacy services being provided. Objective: To determine the impact the addition of a second ICU pharmacist covering 30 adult ICU beds at a large regional medical center has on the complexity of pharmacists' interventions, the types of clinical activities performed by the pharmacists, and the ICU team members' satisfaction. Methods: A prospective mixed-method descriptive study was conducted. Pharmacists recorded their interventions and clinical activities performed. A focus group composed of randomly selected ICU team members was held to qualitatively describe the impact of the additional pharmacist coverage on patient care, team dynamics, and pharmacy services provided. Results: The baseline period consisted of 33 days, and the intervention period consisted of 20 days. The average complexity of interventions was 1.72 during the baseline period (mode = 2) versus 1.69 (mode = 2) during the intervention period. The number of desirable and optimal clinical activities performed daily increased during the intervention from 8.4 (n = 279) to 16.4 (n = 328) and 2.3 (n = 75) to 8.6 (n = 171) compared with the baseline, respectively. Focus group members qualitatively described additional pharmacist coverage as beneficial. Conclusion: The additional critical care pharmacist did not increase pharmacy intervention complexity; however, more interventions were performed per day. Additional pharmacist coverage increased the daily number of desirable and optimal clinical activities performed and positively impacted ICU team members' satisfaction. PMID- 29276291 TI - Extended Stability of Epinephrine Hydrochloride Injection in Polyvinyl Chloride Bags Stored in Amber Ultraviolet Light-Blocking Bags. AB - Objective: The objective of this study was to evaluate the stability of epinephrine hydrochloride in 0.9% sodium chloride in polyvinyl chloride bags for up to 60 days. Methods: Dilutions of epinephrine hydrochloride to concentrations of 16 and 64 ug/mL were performed under aseptic conditions. The bags were then placed into ultraviolet light-blocking bags and stored at room temperature (23 degrees C-25 degrees C) or under refrigeration (3 degrees C-5 degrees C). Three samples of each preparation and storage environment were analyzed on days 0, 30, 45, and 60. Physical stability was performed by visual examination. The pH was assessed at baseline and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of epinephrine hydrochloride was evaluated using high-performance liquid chromatography. To determine the stability-indicating nature of the assay, degradation 12 months following preparation was evaluated. Samples were considered stable if there was less than 10% degradation of the initial concentration. Results: Epinephrine hydrochloride diluted to 16 and 64 ug/mL with 0.9% sodium chloride injection and stored in amber ultraviolet light-blocking bags was physically stable throughout the study. No precipitation was observed. At days 30 and 45, all bags had less than 10% degradation. At day 60, all refrigerated bags had less than 10% degradation. Overall, the mean concentration of all measurements demonstrated less than 10% degradation at 60 days at room temperature and under refrigeration. Conclusion: Epinephrine hydrochloride diluted to 16 and 64 ug/mL with 0.9% sodium chloride injection in polyvinyl chloride bags stored in amber ultraviolet light-blocking bags was stable up to 45 days at room temperature and up to 60 days under refrigeration. PMID- 29276293 TI - Pharmacists and Medical Missions. PMID- 29276292 TI - Formation of a Citywide Pharmacy Residents' Collaborative Committee. AB - Pharmacy residents undergo rigorous training to become skillful and knowledgeable independent practitioners. In addition to delivering direct clinical and operational pharmacy services, residents also participate in various administrative, educational, and scholarly activities as part of their residency experience. Throughout their training, residents may rely on individuals within their network for professional, personal, and emotional support, including residency program directors, preceptors, and co-residents from their respective institutions. Residents from nearby institutions can also serve as a vital resource. Throughout the nation, there are numerous pharmacy residency programs located within the same city or region. Fostering collaboration and relationships between residents from neighboring institutions may provide a support network to augment their training and cultivate an environment to promote work-life balance. We describe our 2-year experience in the formation of a citywide "Pharmacy Residents' Collaborative Committee." PMID- 29276294 TI - Summaries of Safety Labeling Changes Approved By FDA- Boxed Warnings Highlights April-June 2017. PMID- 29276295 TI - Cholesterol Ester Transfer Protein Inhibitor Review. AB - Treatment of blood cholesterol is part of a strategy to lower atherosclerotic cardiovascular (ASCVD) risk. While use of HMG-CoA reductase inhibitors to modify cholesterol levels is the primary means of lowering the risk of an ASCVD event, residual risk remains. A new strategy being investigated is the use of cholesterol ester transfer protein (CETP) inhibitors to raise the levels of high density lipoprotein cholesterol (HDL-C) and lower low-density lipoprotein cholesterol (LDL-C). While initial large-scale studies demonstrated no reduction of cardiovascular events, one CETP inhibitor, anacetrapib, has demonstrated a reduction in cardiovascular events in the REVEAL trial. PMID- 29276296 TI - Formulary Drug Review: Ocrelizumab. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. PMID- 29276297 TI - Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review. AB - Purpose: Benzodiazepines are the drug of choice for alcohol withdrawal syndrome (AWS); however, phenobarbital is an alternative agent used with or without concomitant benzodiazepine therapy. In this systematic review, we evaluate patient outcomes with phenobarbital for AWS. Methods: Medline, Cochrane Library, and Scopus were searched from 1950 through February 2017 for controlled trials and observational studies using ["phenobarbital" or "barbiturate"] and ["alcohol withdrawal" or "delirium tremens."] Risk of bias was assessed using tools recommended by National Heart, Lung, and Blood Institute. Results: From 294 nonduplicative articles, 4 controlled trials and 5 observational studies (n = 720) for AWS of any severity were included. Studies were of good quality (n = 2), fair (n = 4), and poor (n = 3). In 6 studies describing phenobarbital without concomitant benzodiazepine therapy, phenobarbital decreased AWS symptoms (P < .00001) and displayed similar rates of treatment failure versus comparator therapies (38% vs 29%). A study with 2 cohorts showed similar rates of intensive care unit (ICU) admission (phenobarbital: 16% and 9% vs benzodiazepine: 14%) and hospital length of stay (phenobarbital: 5.85 and 5.30 days vs benzodiazepine: 6.64 days). In 4 studies describing phenobarbital with concomitant benzodiazepine therapy, phenobarbital groups had similar ICU admission rates (8% vs 25%), decreased mechanical ventilation (21.9% vs 47.3%), decreased benzodiazepine requirements by 50% to 90%, and similar ICU and hospital lengths of stay and AWS symptom resolution versus comparator groups. Adverse effects with phenobarbital, including dizziness and drowsiness, rarely occurred. Conclusion: Phenobarbital, with or without concomitant benzodiazepines, may provide similar or improved outcomes when compared with alternative therapies, including benzodiazepines alone. PMID- 29276298 TI - Development of a Pharmacy Technician-Driven Program to Improve Vaccination Rates at an Academic Medical Center. AB - Background: Influenza and pneumococcal disease contribute substantially to the burden of preventable disease in the United States. Despite quality measures tied to immunization rates, health systems have struggled to achieve these targets in the inpatient setting. Pharmacy departments have had success through implementation of pharmacist standing order programs (SOP); however, these initiatives are labor-intensive and have not resulted in 100% immunization rates. Objective: The objective of this study was to evaluate a pilot utilizing pharmacy technician interventions, in combination with a nursing SOP, to improve vaccination rates of hospitalized patients for influenza and pneumococcal disease. Methods: A process was developed for pharmacy technicians to identify patients who were not previously screened or immunized during the weekend days on the Cardiovascular Progressive Care unit at the University of Kansas Health System. Targeted pharmacy technician interventions consisted of phone call reminders and face-to-face discussions with nursing staff. The primary study outcome was the change in immunization compliance rates between the control and intervention groups. Results: Influenza vaccine rates showed a statistically significant increase from 72.2% (52 of 72) of patients during the control group to 92.9% (65 of 70, P = .001) of patients during the intervention group. A pneumococcal vaccination rate of 81.3% (61 of 75) was observed in the control group, compared with 84.3% (59 of 70) of patients in the intervention group (P = .638). Conclusion: An improvement in inpatient influenza immunization rates can be achieved through targeted follow-up performed by pharmacy technicians, in combination with a nursing-driven SOP. PMID- 29276299 TI - Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin for Venous Thromboembolism Prophylaxis in Hemodialysis Patients. AB - Background: Enoxaparin, a low-molecular-weight heparin approved for prophylaxis in patients at risk for venous thromboembolism (VTE), offers several advantages compared with unfractionated heparin (UFH). Enoxaparin is primarily excreted through renal elimination and is currently not recommended in patients receiving hemodialysis (HD) due to potential increased bleeding complications. To date, there are limited safety and efficacy data supporting the use of enoxaparin in this patient population for VTE prophylaxis. Objective: The aim of this study was to compare the safety and efficacy of enoxaparin with UFH for deep venous thromboembolism (DVT) prophylaxis in medically ill HD patients. Methods and Results: This retrospective cohort study examined medically ill patients who received HD and were concomitantly prescribed enoxaparin or UFH for at least 2 consecutive days for VTE prophylaxis. A total of 225 patients (150 received UFH and 75 received enoxaparin) were evaluated in chronological order. The primary outcome was a composite of major, clinically relevant nonmajor, and minor bleeding based on International Society on Thrombosis and Haemostasis bleeding definitions. The secondary outcome was the occurrence of a confirmed thrombotic event. Baseline characteristics were similar between the cohorts. One patient in each cohort had a documented bleed (UFH = 0.7%, enoxaparin = 1.3%, P > .05) during the admission assessed; however, neither bleed was related to the prophylactic agent utilized. No patients developed a VTE during the index hospitalization. Conclusions: This study demonstrates that enoxaparin may be as safe and effective as UFH for VTE prophylaxis in medically ill patients receiving HD. PMID- 29276300 TI - Multilayer Model of Pharmacy Participation in the Antimicrobial Stewardship Program at a Large Academic Medical Center. AB - Purpose: Leveraging pharmacy personnel resources for the purpose of antimicrobial stewardship program (ASP) operations presents a challenging task. We describe our experience integrating all pharmacists into an ASP, and evaluate the impact on ASP interventions, antimicrobial utilization, rate of selected hospital-onset infections and readmission. Summary: During a study period (January 1 to December 31, 2015), a total of 14 552 ASP-related pharmacy interventions were performed (ASP clinical pharmacotherapy specialists [CPS] n = 4025; non-ASP CPS n = 4888; hospital pharmacists n = 5639). Sixty percent of interventions by ASP CPS were initiated utilizing the dedicated ASP phone, and 40% through prospective audit and feedback. Non-ASP CPS performed interventions during bedside rounds (dose adjustment 23%, initiate new or alternative anti-infective 21%, discontinue antibiotic(s) 12%, therapeutic drug monitoring 11%, de-escalation 4%), whereas hospital pharmacists participated at the point of verification (dose adjustment 75%, restricted antibiotic verification 15%, and reporting major drug-drug interactions 4%). The acceptance rate of interventions by providers and clinicians was >90% for all groups. Annual aggregate antimicrobial use decreased by 6.4 days of therapy/1000 patient-days (DOT/1000 PD; P = 1.0). Ceftriaxone use increased by 8.4 DOT/1000 PD (P = .029) without a significant compensatory increase in the use of antipseudomonal agents. Sustained low rates of hospital onset Clostridium difficile (CDI) and carbapenem-resistant Enterobacteriaceae (CRE) infections were observed in 2015 compared with the prior year (1.1 and 1.2 cases/1000 PD, 0.2 and 0.1 cases/1000 PD, respectively). Thirty-day readmission rate decreased by 0.6% (P = .019). Conclusions: Integration of all pharmacists into ASP activities based on the level of patient care and responsibilities is an effective strategy to expand clinical services provided by ASP. PMID- 29276301 TI - Impact of Inpatient Automatic Therapeutic Substitutions on Postdischarge Medication Prescribing. AB - Background: Automatic therapeutic substitution (ATS) is the act of therapeutic interchange, in which patients are transitioned from a nonformulary preadmission medication to an equivalent formulary medication upon admission. ATS protocols are able to provide several benefits; however, if medications are unreconciled at the time of discharge, then use may lead to duplication or omission resulting in adverse outcomes. The objective was to assess the impact of preidentified ATS protocol use during admission on duplication and omission postdischarge. Methods: This study included adults who received a preidentified ATS upon admission. The primary outcome was the incidence of duplication or omission at the time of discharge. The secondary outcome was the incidence of duplication or omission at the time of discharge in moderate-to-high readmission risk patients with completed transitions of care (TOC) services compared with incomplete TOC services. Results: A total of 689 encounters were assessed for appropriate reconciliation, duplication, or omission at time of discharge. The incidence of duplication or omission at the time of discharge was 9% (n = 62). Of the 689 encounters, 287 were assessed for the secondary outcome. The rate of duplication or omission at the time of discharge was 10% (n = 19) in the complete TOC services group and 8% (n = 8) in the incomplete TOC services group (P = .6763). Conclusion: This study identified a high rate of appropriate reconciliation of ATS protocols at the time of discharge, which illustrates ATS protocols are a safe medication use management strategy if implemented as intended. PMID- 29276302 TI - Impact of Respiratory Viral Panel Polymerase Chain Reaction Assay Turnaround Time on Length of Stay and Antibiotic Use in Patients With Respiratory Viral Illnesses. AB - Background: Respiratory viral illnesses account for many hospitalizations and inappropriate antibiotic use. Respiratory viral panels by polymerase chain reaction (RVP-PCR) provide a reliable means of diagnosis. In 2015, the RVP-PCR assay at our institution was switched from respiratory viral panel (RVP) to rapid respiratory panel (rapid RP), which has a faster turnaround time (24 hours vs 12 hours, respectively). The purpose of this study was to evaluate the effect of RVP PCR tests on duration of antibiotic use and length of stay (LOS) in hospitalized patients. Methods: We performed a retrospective chart review of patients who had a RVP-PCR ordered within a 1-year time period before and after the assay switch. Patients who were pregnant, had received antibiotics within 30 days prior to admission, were not discharged, or had not completed antibiotics by end of study period were excluded. Results: Data were obtained from a total of 140 patients (70 in each group). Of these, 25 (35.7%) in the RVP group and 28 (40.0%) in the rapid RP group had a positive result. The median LOS was 4.5 days (IQR, 3-9 days) in the RVP group and 5 days (IQR, 3-9 days) in the rapid RP group (P = .78). The median duration of antibiotic use was 4 days (IQR, 2-7 days) in the RVP group and 5 days (IQR, 1-7 days) in the rapid RP group (P = .8). Conclusion: Despite faster turnaround time, there was no significant difference in duration of antibiotic use, or LOS between the RVP and rapid RP groups. PMID- 29276303 TI - Administration of Injectable Vitamin K Orally. AB - Background: Vitamin K, or phytonadione, is available in both injectable and oral formulations. Oral vitamin K is available as 5-mg tablets, but the key drawbacks for using vitamin K tablets consist of availability of only 1 dose strength and recent tripling of the product's cost over a 2-year period. An interest exists for utilization of injectable vitamin K via oral route. Method: A literature search was performed on April 26, 2017, to identify any studies describing the use of injectable vitamin K for oral administration. The search involved PubMed and Embase and utilized various combinations of keywords vitamin K, phytonadione, IV, intravenous, injectable, and oral. The results were limited to studies that discussed oral administration of injectable vitamin K. The efficacy of the injectable preparation of vitamin K administered orally was explored in 6 studies and one cost-savings project. Results: Based on the available literature, the administration of injectable vitamin K via oral route is effective and safe. Injectable vitamin K for oral administration can be prepared as an undiluted solution or as a compounded solution. These 2 formulations have different beyond use dates depending on ingredients used. Conclusion: Information on efficacy and stability of injectable vitamin K formulations prepared for oral administration provides an additional option for health care systems when vitamin K tablets are unavailable or cost-prohibitive to use. PMID- 29276304 TI - Women's employment patterns after childbirth and the perceived access to and use of flexitime and teleworking. AB - This article sets out to investigate how flexitime and teleworking can help women maintain their careers after childbirth. Despite the increased number of women in the labour market in the UK, many significantly reduce their working hours or leave the labour market altogether after childbirth. Based on border and boundary management theories, we expect flexitime and teleworking can help mothers stay employed and maintain their working hours. We explore the UK case, where the right to request flexible working has been expanded quickly as a way to address work-life balance issues. The dataset used is Understanding Society (2009-2014), a large household panel survey with data on flexible work. We find some suggestive evidence that flexible working can help women stay in employment after the birth of their first child. More evidence is found that mothers using flexitime and with access to teleworking are less likely to reduce their working hours after childbirth. This contributes to our understanding of flexible working not only as a tool for work-life balance, but also as a tool to enhance and maintain individuals' work capacities in periods of increased family demands. This has major implications for supporting mothers' careers and enhancing gender equality in the labour market. PMID- 29276305 TI - Stable, Robust Hybrid Zero Dynamics Control of Powered Lower-Limb Prostheses. AB - To improve the quality of life for lower-limb amputees, powered prostheses are being developed. Advanced control schemes from the field of bipedal robots, such as hybrid zero dynamics (HZD), may provide great performance. HZD-based control specifies the motion of the actuated joints using output functions to be zeroed, and the required torques are calculated using input-output linearization. For one step periodic gaits, there is an analytic metric of stability. To apply HZD-based control on a powered prosthesis, several modifications must be made. Because the prosthesis and amputee are only connected via the socket, the prosthesis controller does not have access to the full state of the biped, which decentralizes the form of the input-output linearization. The differences between the amputated and contralateral sides result in a two-step periodic gait, which requires the orbital stability metric to be extended. In addition, because human gait is variable, the prosthesis controller must be robust to continuous moderate perturbations. This robustness is proved using local input-to-state stability and demonstrated with simulations of an above-knee amputee model. PMID- 29276306 TI - Early home literacy and adolescents' online reading behavior in comparative perspective. AB - Online reading behavior can be regarded as a 'new' form of cultural capital in today's digital world. However, it is unclear whether 'traditional' mechanisms of cultural and social reproduction are also found in this domain, and whether they manifest uniformly across countries at different stages of development. This article analyzes whether the early home literacy environment has an impact on informational online reading behavior among adolescents and whether this association varies between countries with different levels of digitalization and educational expansion. Data from the 2009 Programme for International Student Assessment (PISA) were used for the empirical analyses. The results of regression models with country-fixed effects indicate a positive association between literacy activities in early childhood and informational online reading at age 15. This association was quite stable across countries. These findings are discussed in light of cultural and social reproduction theory and digital divide research. PMID- 29276307 TI - In Vitro Assessment of Small Charged Pharmaceutical Aerosols in a Model of a Ventilated Neonate. AB - Aerosolized medications may benefit infants receiving mechanical ventilation; however, the lung delivery efficiency of these aerosols is unacceptably low. In vitro experiments were conducted to evaluate aerosol delivery through conventional and modified ventilation systems to the end of a 3mm endotracheal tube (ETT) under steady state and realistic cyclic flow conditions. System modifications were employed to investigate the use of small charged particles and included streamlined components, a reduction in nebulizer liquid flow rate, synchronization with inspiration, and implementation of a previously designed low flow induction charger (LF-IC), which was further modified in this study. Cyclic flow experiments implemented a modern ventilator with bias airflow and an inline flow meter, both of which are frequently excluded from in vitro tests but included in clinical practice. The modified LF-IC system demonstrated superior delivery efficiency to the end of the ETT (34%) compared with the commercial system (~1.3%) operating under cyclic ventilation conditions. These findings indicate that commercial systems still provide very low lung delivery efficiencies despite decades of innovation. In contrast, the modified system increased dose delivery to the end of the ETT by 26-fold. Despite initial concerns, the charged aerosol could be efficiently delivered through the small diameter ETT and reach the lungs. Future studies will be required to determine if the applied particle charge can eliminate expected high exhalation aerosol loss and will require the development of a realistic lung model. PMID- 29276309 TI - Associations Between Parenting Styles and Perceived Child Effortful Control Within Chinese Families in the United States, the United Kingdom, and Taiwan. AB - The current study examined the associations between parentally perceived child effortful control (EC) and the parenting styles of 122 Chinese mothers (36 first generation Chinese immigrants in the United Kingdom, 40 first-generation Chinese immigrants in the United States, and 46 Taiwanese mothers) of 5- to 7-year-old (M age = 5.82 years, SD = .805; 68 boys and 54 girls) children. The findings showed significant cultural group differences in mothers' reported authoritarian parenting style. Significant associations also emerged between mothers' reports of their children's EC and some parenting dimensions, although there were no cultural group differences in perceived child EC. Different patterns of associations between perceived child EC and parenting styles in these three groups also demonstrated heterogeneity within the Chinese population, and highlighted the need to consider differences between original and receiving societies when seeking to understand parenting and child development in different immigrant groups. PMID- 29276310 TI - Increased Larval Density Induces Accelerated Metamorphosis Independently of Growth Rate in the Frog Rana sphenocephala. AB - We grew larval Rana sphenocephala at different densities but maintained equal mean growth rates among density treatments (via equal per capita food levels) to test the hypothesis that larval density can influence metamorphic timing independently of larval growth rate. Tadpoles at high density metamorphosed earlier than tadpoles at low density despite growing at similar rates. Food reductions did not accelerate metamorphosis. These results support the hypothesis that density can be a sufficient cue to initiate metamorphosis independently of growth rate. PMID- 29276311 TI - Benchmarking of essential climate variables: Gamma index theory and results for surface albedo and aerosol optical depth. AB - This paper proposes a benchmarking method for assessing the level of spatio temporal variability of Essential Climate Variable (ECV) products against a reference taking into account acceptance criteria in terms of intensity and physical distance tolerances. This is based on a modified version of the gamma index that could be suitable for fitness-for-purpose assessment given that one can choose various criteria depending on applications. The method is first presented and then applied to both land and atmospheric ECVs. The terrestrial analysis concerns the global surface albedo, using monthly white-sky surface albedo in the visible, near-infrared and shortwave broadband spectral ranges at a spatial resolution of 0.05 degrees using three sources of products. The latter study is conducted using monthly aerosol optical depth (AOD) products at 550 nm at a spatial resolution of 1 degrees with four different datasets at the global scale. The analysis shows how the values of the gamma criteria impact the spatial and temporal results. As an example, if the Global Climate Observing System (GCOS) actual target measurements uncertainty is used as an acceptance criteria for the intensity tolerance the results show that: 1) the seasonal agreement for the surface albedo products varies over 20% to 40% of the terrestrial surface in the shortwave and near-infrared broadband and from 10% to 30% in the visible one and 2) the three aerosols optical depth products agree with the reference one for over 50% of the land surface only when the tolerance distance term is at 224km. PMID- 29276308 TI - Impacts of salvage logging on biodiversity: a meta-analysis. AB - Logging to "salvage" economic returns from forests affected by natural disturbances has become increasingly prevalent globally. Despite potential negative effects on biodiversity, salvage logging is often conducted, even in areas otherwise excluded from logging and reserved for nature conservation, inter alia because strategic priorities for post-disturbance management are widely lacking.A review of the existing literature revealed that most studies investigating the effects of salvage logging on biodiversity have been conducted less than 5 years following natural disturbances, and focused on non-saproxylic organisms.A meta-analysis across 24 species groups revealed that salvage logging significantly decreases numbers of species of eight taxonomic groups. Richness of dead wood dependent taxa (i.e. saproxylic organisms) decreased more strongly than richness of non-saproxylic taxa. In contrast, taxonomic groups typically associated with open habitats increased in the number of species after salvage logging.By analysing 134 original species abundance matrices, we demonstrate that salvage logging significantly alters community composition in 7 of 17 species groups, particularly affecting saproxylic assemblages.Synthesis and applications. Our results suggest that salvage logging is not consistent with the management objectives of protected areas. Substantial changes, such as the retention of dead wood in naturally disturbed forests, are needed to support biodiversity. Future research should investigate the amount and spatio-temporal distribution of retained dead wood needed to maintain all components of biodiversity. PMID- 29276312 TI - Assessing the fitness-for-purpose of satellite multi-mission ocean color climate data records: A protocol applied to OC-CCI chlorophyll-a data. AB - In this work, trend estimates are used as indicators to compare the multi-annual variability of different satellite chlorophyll-a (Chla) data and to assess the fitness-for-purpose of multi-mission Chla products as climate data records (CDR). Under the assumption that single-mission products are free from spurious temporal artifacts and can be used as benchmark time series, multi-mission CDRs should reproduce the main trend patterns observed by single-mission series when computed over their respective periods. This study introduces and applies quantitative metrics to compare trend distributions from different data records. First, contingency matrices compare the trend diagnostics associated with two satellite products when expressed in binary categories such as existence, significance and signs of trends. Contingency matrices can be further summarized by metrics such as Cohen's kappa index that rates the overall agreement between the two distributions of diagnostics. A more quantitative measure of the discrepancies between trends is provided by the distributions of differences between trend slopes. Thirdly, maps of the level of significance P of a t-test quantifying the degree to which two trend estimates differ provide a statistical, spatially resolved, evaluation. The proposed methodology is applied to the multi-mission Ocean Colour-Climate Change Initiative (OC-CCI) Chla data. The agreement between trend distributions associated with OC-CCI data and single-mission products usually appears as good as when single-mission products are compared. As the period of analysis is extended beyond 2012 to 2015, the level of agreement tends to be degraded, which might be at least partly due to the aging of the MODIS sensor on-board Aqua. On the other hand, the trends displayed by the OC-CCI series over the short period 2012-2015 are very consistent with those observed with VIIRS. These results overall suggest that the OC-CCI Chla data can be used for multi-annual time series analysis (including trend detection), but with some caution required if recent years are included, particularly in the central tropical Pacific. The study also recalls the challenges associated with creating a multi-mission ocean color data record suitable for climate research. PMID- 29276313 TI - Towards an Ethical Framework for Publishing Twitter Data in Social Research: Taking into Account Users' Views, Online Context and Algorithmic Estimation. AB - New and emerging forms of data, including posts harvested from social media sites such as Twitter, have become part of the sociologist's data diet. In particular, some researchers see an advantage in the perceived 'public' nature of Twitter posts, representing them in publications without seeking informed consent. While such practice may not be at odds with Twitter's terms of service, we argue there is a need to interpret these through the lens of social science research methods that imply a more reflexive ethical approach than provided in 'legal' accounts of the permissible use of these data in research publications. To challenge some existing practice in Twitter-based research, this article brings to the fore: (1) views of Twitter users through analysis of online survey data; (2) the effect of context collapse and online disinhibition on the behaviours of users; and (3) the publication of identifiable sensitive classifications derived from algorithms. PMID- 29276314 TI - Stereochemistry and Reactivity of the HPA-Imine Mannich Intermediate. AB - Homophthalic anhydride (HPA) typically reacts rapidly with benzalimines to afford the formal [4+2] adduct, a 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid. The stereochemical outcome of this reaction is consistent with an open transition state comprising an iminium species and enolized HPA, leading to a short-lived amino-anhydride intermediate. In the case of N-tert-butylbenzalimine, this Mannich-type intermediate, which would normally cyclize at low temperature to a single isomer of the delta-lactam, is intercepted by base treatment to afford beta-lactam products. A pathway featuring ketene formation followed by ring closure is implicated. PMID- 29276315 TI - A Device for Ribbon Collection for Array Tomography with Scanning Electron Microscopy. AB - "Array tomography" is a method used to observe the fine structure of cells and tissues in a three-dimensional view. In this method, serial ultrathin sections in the ribbon state (ribbons) are mounted on a solid substrate and observed by scanning electron microscopy (SEM). The method may also be used in conjunction with post-embedding immunocytochemistry. However, it is difficult to mount many serial ribbons on a substrate manually. We developed an inexpensive laboratory made device that mounts ribbons by pulling a nylon fishing line and lifting the substrate up from the water in a knife boat. Using this device, we succeeded in mounting several ribbons consisting a mean of 205.6 (SD: 37.7) serial ultrathin sections on 1.25 (SD: 0.06) * 1.25 (SD: 0.06)-cm silicon substrates. Furthermore, it was confirmed that our method is suitable for ribbons derived from water soluble resin blocks. We were also able to stain the specimens by post-embedding immunocytochemistry. Thus, our method is useful in mounting numerus sections on a substrate for array tomography with SEM. PMID- 29276316 TI - A New Electron Microscopic Method to Observe the Distribution of Phosphatidylinositol 3,4-bisphosphate. AB - Phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2] is a phosphoinositide that plays important roles in signal transduction, endocytosis, and cell migration among others. The intracellular distribution of PtdIns(3,4)P2 has mainly been studied by observing the distribution of GFP-tagged PtdIns(3,4)P2-binding protein domains in live cells and by labeling with anti-PtdIns(3,4)P2 antibody in fixed cell samples, but these methods only offer low spatial resolution results and may have pitfalls. In the present study, we developed an electron microscopic method to observe the PtdIns(3,4)P2 distribution using the SDS-treated freeze-fracture replica labeling method. The recombinant GST-tagged pleckstrin homology (PH) domain of TAPP1 was used as the binding probe, and its binding to PtdIns(3,4)P2 in the freeze-fracture replica was confirmed by using liposomes containing different phosphoinositides and by the lack of labeling by a mutant probe, in which one amino acid in the PH domain was substituted. The method was applied to NIH3T3 cell samples and showed that the increase of PtdIns(3,4)P2 in cells treated with hydrogen peroxide occurs in the cytoplasmic leaflet of the plasma membrane, except in the caveolar membrane. The present method can define the distribution of PtdIns(3,4)P2 at a high spatial resolution and will facilitate our understanding of the physiological function of this less studied phosphoinositide. PMID- 29276318 TI - Random Partition Distribution Indexed by Pairwise Information. AB - We propose a random partition distribution indexed by pairwise similarity information such that partitions compatible with the similarities are given more probability. The use of pairwise similarities, in the form of distances, is common in some clustering algorithms (e.g., hierarchical clustering), but we show how to use this type of information to define a prior partition distribution for flexible Bayesian modeling. A defining feature of the distribution is that it allocates probability among partitions within a given number of subsets, but it does not shift probability among sets of partitions with different numbers of subsets. Our distribution places more probability on partitions that group similar items yet keeps the total probability of partitions with a given number of subsets constant. The distribution of the number of subsets (and its moments) is available in closed-form and is not a function of the similarities. Our formulation has an explicit probability mass function (with a tractable normalizing constant) so the full suite of MCMC methods may be used for posterior inference. We compare our distribution with several existing partition distributions, showing that our formulation has attractive properties. We provide three demonstrations to highlight the features and relative performance of our distribution. PMID- 29276319 TI - See me through my eyes: Adolescent-parent agreement in personality predicts later self-esteem development. AB - Achieving a clear view of one's personality is a challenging but crucial developmental task during adolescence, which has enduring influences. This task might be harder if significant others see individuals differently from how the adolescents see themselves. Supporting this, the looking-glass-self theory suggests that significant others constitute a social mirror into which the individual gazes to form his/her self-view. The present study was the first to longitudinally examine whether self-other agreement in personality during adolescence (i.e., self-parent and self-friend agreement at age 12 and self mother and self-father agreement at age 17) promote self-esteem development from age 17 to 29 years (N =186, 53% boys). Results for girls consistently confirmed the hypothesized beneficial effect of self-parent agreement, while the picture was more complicated for boys. That is, for girls, self-parent agreement at age 12 and age 17 both predicted steeper increases in self-esteem. For boys, steeper self-esteem development was predicted by higher self-parent agreement at age 12, but unexpectedly, also by lower self-parent agreement at age 17. All these results remained after controlling for (self-rated) personality. Moreover, self friend agreement did not show any effects on self-esteem development, suggesting that the influence of peers' convergence with self-views during early adolescence may not be as prominent as parents'. Results are discussed from the perspective of self-view formation and maintenance during adolescence and young adulthood. The present study sheds light on the longitudinal effect of one's own view of personality being shared by important others on self-esteem development. PMID- 29276317 TI - Cryobanking of aquatic species. AB - : This review is focused on the applications of genome cryobanking of aquatic species including freshwater and marine fish, as well as invertebrates. It also reviews the latest advances in cryobanking of model species, widely used by the scientific community worldwide, because of their applications in several fields. The state of the art of cryopreservation of different cellular types (sperm, oocytes, embryos, somatic cells and primordial germ cells or early spermatogonia) is discussed focusing on the advantages and disadvantages of each procedure according to different applications. A special review on the need of standardization of protocols has also been carried out. In summary, this comprehensive review provides information on the practical details of applications of genome cryobanking in a range of aquatic species worldwide, including the cryobanks established in Europe, USA, Brazil, Australia and New Zealand, the species and type of cells that constitute these banks and the utilization of the samples preserved. Statement of relevance: This review compiles the last advances on germplasm cryobanking of freshwater and marine fish species and invertebrates, with high value for commercial aquaculture or conservation. It is reviewed the most promising cryopreservation protocols for different cell types, embryos and larvae that could be applied in programs for genetic improvement, broodstock management or conservation of stocks to guarantee culture production. PMID- 29276320 TI - A preliminary account of the Cucurbitariaceae. AB - Fresh collections, type studies and molecular phylogenetic analyses of a multigene matrix of partial nuSSU-ITS-LSU rDNA, rpb2, tef1 and tub2 sequences were used to evaluate the boundaries of Cucurbitaria in a strict sense and of several related genera of the Cucurbitariaceae. Two species are recognised in Cucurbitaria and 19 in Neocucurbitaria. The monotypic genera Astragalicola, Cucitella, Parafenestella, Protofenestella, and Seltsamia are described as new. Fenestella is here included as its generic type F. fenestrata (= F. princeps), which is lecto- and epitypified. Fenestella mackenzei and F. ostryae are combined in Parafenestella. Asexual morphs of Cucurbitariaceae, where known, are all pyrenochaeta- or phoma-like. Comparison of the phylogenetic analyses of the ITS LSU and combined matrices demonstrate that at least rpb2 sequences should be added whenever possible to improve phylogenetic resolution of the tree backbone; in addition, the tef1 introns should be added as well to improve delimitation of closely related species. PMID- 29276321 TI - Small Cues Change Savings Choices. AB - We present evidence from randomized field experiments that 401(k) savings choices are significantly affected by one- to two-sentence anchoring, goal-setting, or savings threshold cues embedded in emails sent to employees about their 401(k) plan. Even though these cues contain little to no marginal information, cues that make high savings rates salient increased 401(k) contribution rates by up to 2.9% of income in a pay period, and cues that make low savings rates salient decreased 401(k) contribution rates by up to 1.4% of income in a pay period. Cue effects persist between two months and a year after the email. PMID- 29276322 TI - Rhesus macaques (Macaca mulatta) displaying self-injurious behavior show more sleep disruption than controls. AB - Self-injurious behavior (SIB) is a pathology observed in both humans and animals. In humans, SIB has been linked to various mental health conditions that are also associated with significant sleep disruption. In rhesus macaques, SIB consists of self-directed biting which can range from mild skin abrasions to wounds requiring veterinary care. However, only one study suggests possible sleep disruption in macaques with SIB. We evaluated sleep disruption using a noninvasive system (infra-red camera and a video surveillance program) which created videos for every movement over the nighttime hours. Nighttime activity was examined in 13 macaques (three females) of which six were classified as having SIB (one female). Each monkey was studied for a total of 6 nights spanning a period of 4 months. Measures included total movement time (TMT), time moving in the first hour (HR1), time moving in the last hour (HR11), and number of videos <10 secs, >=10 secs, and >=30 secs in length. Overall, SIB monkeys had higher TMT (p < 0.01), higher HR1 (p<0.001), and generated more videos >=10 secs (p < 0.01) and >=30 secs (p < 0.01). Thus, SIB monkeys showed significant sleep disruption. A four-fold difference between SIB and control monkeys in the >=30 secs videos revealed many more significant awakenings in the SIB group. Overall higher nighttime activity, in the first hour but not in the last hour, is consistent with sleep-onset insomnia in humans. Whether increased nighttime activity contributes to the SIB condition during the day or, conversely, SIB causes higher nighttime activity remains undetermined. PMID- 29276323 TI - Long-wavelength macromolecular crystallography - First successful native SAD experiment close to the sulfur edge. AB - Phasing of novel macromolecular crystal structures has been challenging since the start of structural biology. Making use of anomalous diffraction of natively present elements, such as sulfur and phosphorus, for phasing has been possible for some systems, but hindered by the necessity to access longer X-ray wavelengths in order to make most use of the anomalous scattering contributions of these elements. Presented here are the results from a first successful experimental phasing study of a macromolecular crystal structure at a wavelength close to the sulfur K edge. This has been made possible by the in-vacuum setup and the long-wavelength optimised experimental setup at the I23 beamline at Diamond Light Source. In these early commissioning experiments only standard data collection and processing procedures have been applied, in particular no dedicated absorption correction has been used. Nevertheless the success of the experiment demonstrates that the capability to extract phase information can be even further improved once data collection protocols and data processing have been optimised. PMID- 29276325 TI - Family-Peer Linkages for Children with Intellectual Disability and Children with Learning Disabilities. AB - Family interactions are potential contexts for children with intellectual and learning disabilities to develop skillful social behaviors needed to relate effectively with peers. This study examined problem solving interactions within families of elementary school-age children (7-11 years) with intellectual disability (n = 37), specific learning disabilities (n =48), and without disabilities (n = 22). After accounting for group differences in children's behaviors and peer acceptance, across all groups, mothers' behaviors that encouraged egalitarian problem solving predicted more engaged and skillful problem solving by the children. However, mothers' controlling, directive behaviors predicted fewer of these behaviors by the children. Fathers' behaviors had mixed associations with the children's actions, possibly because they were reactive to children's unengaged and negative behaviors. For the children, greater involvement, more facilitative behaviors, and less negativity with their families were associated with greater acceptance from their peers, supporting family-peer linkages for children at risk for peer rejection. PMID- 29276326 TI - Effect of cane length and swing arc width on drop-off and obstacle detection with the long cane. AB - A repeated-measures design with block randomization was used for the study, in which 15 adults with visual impairments attempted to detect the drop-offs and obstacles with the canes of different lengths, swinging the cane in different widths (narrow vs wide). Participants detected the drop-offs significantly more reliably with the standard-length cane (79.5% +/- 6.5% of the time) than with the extended-length cane (67.6% +/- 9.1%), p <.001. The drop-off detection threshold of the standard-length cane (4.1 +/- 1.1 cm) was also significantly smaller than that of the extended-length cane (6.5+/-1.8cm), p <.001. In addition, participants detected drop-offs at a significantly higher percentage when they swung the cane approximately 3 cm beyond the widest part of the body (78.6% +/- 7.6%) than when they swung it substantially wider (30 cm; 68.5% +/- 8.3%), p <.001. In contrast, neither cane length (p =.074) nor cane swing arc width (p =.185) had a significant effect on obstacle detection performance. The findings of the study may help orientation and mobility specialists recommend appropriate cane length and cane swing arc width to visually impaired cane users. PMID- 29276324 TI - Cost Effectiveness of a School Readiness Intervention for Foster Children. AB - Objective: Many young children in foster care suffer from emotional and behavior problems due to neglect and abuse. These problems can lead to difficulties in school, and functioning in school is linked to long-term health and development. Early intervention to reduce emotional and behavioral issues can help children successfully transition to school, which can improve long-term outcomes. However, communities need information on relative costs and benefits associated with programs to make informed choices. The objective of this study was to assess cost effectiveness, over 12 months, of the Kids in Transition to School (KITS) intervention compared to usual services available to children in a foster care control group (FCC). Method: Randomized controlled trial of 192 children in foster care entering kindergarten who were randomized to KITS (n = 102) or FCC (n = 90). KITS includes school readiness groups and parent training over 4 months. Main outcomes were days free from internalizing symptoms (IFD), days free from externalizing behavior (EFD), intervention costs, public agency costs, and incremental cost effectiveness. Results: KITS significantly increased IFD and EFD compared to FCC. Average total cost of the intervention was $932 per family. The intervention did not significantly impact usual services. Average incremental cost effectiveness was $64 per IFD and $63 per EFD. Conclusions: The cost of KITS is comparable to, or less than, similar programs, and the intervention is likely to provide significant emotional and behavioral benefits and improvements in school readiness for young children in foster care. PMID- 29276327 TI - Critical, agentic and trans-media: Frameworks and findings from a foresight analysis exercise on audiences. AB - We write this article presenting frameworks and findings from an international network on audience research, as we stand 75 years from Herta Herzog's classic investigation of radio listeners, published in Lazarsfeld and Stanton's 1944 war edition of Radio Research. The article aims to contribute to and advance a rich strand of self-reflexive stock-taking and sorting of future research priorities within the transforming field of audience analysis, by drawing on the collective efforts of CEDAR - Consortium on Emerging Directions in Audience Research - a 14 country network (2015-2018) funded by the Arts and Humanities Research Council, United Kingdom, which conducted a foresight analysis exercise on developing current trends and future scenarios for audiences and audience research in the year 2030. First, we wish to present the blueprint of what we did and how we did it - by discussing the questions, contexts and frameworks for our project. We hope this is useful for anyone considering a foresight analysis task, an approach we present as an innovative and rigorous tool for assessing and understanding the future of a field. Second, we present findings from our analysis of pivotal transformations in the field and the future scenarios we constructed for audiences, as media technologies rapidly change with the arrival of the Internet of Things and changes on many levels occur in audience practices. These findings not only make sense of a transformative decade that we have just lived through but they present possibilities for the future, outlining areas for individual and collective intellectual commitment. PMID- 29276328 TI - A fully-automated multiscale kernel graph cuts based particle localization scheme for temporal focusing two-photon microscopy. AB - The temporal focusing two-photon microscope (TFM) is developed to perform depth resolved wide field fluorescence imaging by capturing frames sequentially. However, due to strong nonignorable noises and diffraction rings surrounding particles, further researches are extremely formidable without a precise particle localization technique. In this paper, we developed a fully-automated scheme to locate particles positions with high noise tolerance. Our scheme includes the following procedures: noise reduction using a hybrid Kalman filter method, particle segmentation based on a multiscale kernel graph cuts global and local segmentation algorithm, and a kinematic estimation based particle tracking method. Both isolated and partial-overlapped particles can be accurately identified with removal of unrelated pixels. Based on our quantitative analysis, 96.22% isolated particles and 84.19% partial-overlapped particles were successfully detected. PMID- 29276329 TI - Interpretable exemplar-based shape classification using constrained sparse linear models. AB - Many types of diseases manifest themselves as observable changes in the shape of the affected organs. Using shape classification, we can look for signs of disease and discover relationships between diseases. We formulate the problem of shape classification in a holistic framework that utilizes a lossless scalar field representation and a non-parametric classification based on sparse recovery. This framework generalizes over certain classes of unseen shapes while using the full information of the shape, bypassing feature extraction. The output of the method is the class whose combination of exemplars most closely approximates the shape, and furthermore, the algorithm returns the most similar exemplars along with their similarity to the shape, which makes the result simple to interpret. Our results show that the method offers accurate classification between three cerebellar diseases and controls in a database of cerebellar ataxia patients. For reproducible comparison, promising results are presented on publicly available 2D datasets, including the ETH-80 dataset where the method achieves 88.4% classification accuracy. PMID- 29276330 TI - Assessing the Relationship Between Social Vulnerability and Community Resilience to Hazards. AB - This article contributes to the disaster literature by measuring and connecting two concepts that are highly related but whose relationship is rarely empirically evaluated: social vulnerability and community resilience. To do so, we measure community resilience and social vulnerability in counties across the United States and find a correlation between high levels of vulnerability and low levels of resilience, indicating that the most vulnerable counties also tend to be the least resilient. We also find regional differences in the distribution of community resilience and social vulnerability, with the West being particularly vulnerable while the Southeast is prone to low levels of resilience. By looking at both social vulnerability and community resilience, we are able to map communities' social risks for harm from threats as well as their capacities for recovering and adapting in the aftermath of hazards. This provides a more complete portrait of the communities that might need the most assistance in emergency planning and response, as well as whether such interventions will need to be tailored toward reducing damage or finding the path to recovery. PMID- 29276331 TI - Wheeler graphs: A framework for BWT-based data structures. AB - The famous Burrows-Wheeler Transform (BWT) was originally defined for a single string but variations have been developed for sets of strings, labeled trees, de Bruijn graphs, etc. In this paper we propose a framework that includes many of these variations and that we hope will simplify the search for more. We first define Wheeler graphs and show they have a property we call path coherence. We show that if the state diagram of a finite-state automaton is a Wheeler graph then, by its path coherence, we can order the nodes such that, for any string, the nodes reachable from the initial state or states by processing that string are consecutive. This means that even if the automaton is non-deterministic, we can still store it compactly and process strings with it quickly. We then rederive several variations of the BWT by designing straightforward finite-state automata for the relevant problems and showing that their state diagrams are Wheeler graphs. PMID- 29276332 TI - Beating time: How ensemble musicians' cueing gestures communicate beat position and tempo. AB - Ensemble musicians typically exchange visual cues to coordinate piece entrances. "Cueing-in" gestures indicate when to begin playing and at what tempo. This study investigated how timing information is encoded in musicians' cueing-in gestures. Gesture acceleration patterns were expected to indicate beat position, while gesture periodicity, duration, and peak gesture velocity were expected to indicate tempo. Same-instrument ensembles (e.g., piano-piano) were expected to synchronize more successfully than mixed-instrument ensembles (e.g., piano violin). Duos performed short passages as their head and (for violinists) bowing hand movements were tracked with accelerometers and Kinect sensors. Performers alternated between leader/follower roles; leaders heard a tempo via headphones and cued their partner in nonverbally. Violin duos synchronized more successfully than either piano duos or piano-violin duos, possibly because violinists were more experienced in ensemble playing than pianists. Peak acceleration indicated beat position in leaders' head-nodding gestures. Gesture duration and periodicity in leaders' head and bowing hand gestures indicated tempo. The results show that the spatio-temporal characteristics of cueing-in gestures guide beat perception, enabling synchronization with visual gestures that follow a range of spatial trajectories. PMID- 29276333 TI - Soft drink prices, sales, body mass index and diabetes: Evidence from a panel of low-, middle- and high-income countries. AB - We take advantage of four different cross-country datasets containing data on 78 countries for the period 1999-2014, in order to assess the relationship of carbonated soft drinks' sales, as well as their prices, with body mass index (BMI), overweight, obesity and diabetes. Using an ecological study design and multivariate regression longitudinal estimation approaches, we find that carbonated soft drink sales were significantly positively related to BMI, overweight and obesity - but only in the low and lower-middle income countries. This finding was robust to a number of sensitivity and falsification checks. In this sub-sample, an increase in per capita soft drink sales by 1 litre per year was related to an increase of BMI by about 0.009 kg/m2 (p < 0.1).. This is a small effect, implying that halving annual consumption per capita in this group of countries would result in a drop of BMI by only about 0.03 kg/m2. Although soft drink prices were negatively related to weight-related outcomes in the sample of higher middle income and high income countries, this finding was not robust to falsification checks. The results thus suggest that sales restrictions to steer consumers away from soft drinks could indeed have a beneficial health effects in poorer countries, although the effect magnitude appears to be very small. However, given potential limitations of using ecological research design, results from individual level studies would be required to further ascertain the role of soft drink sales and prices in obesity and diabetes. PMID- 29276334 TI - Assistive Technology Interventions for Adolescents and Adults with Learning Disabilities: An Evidence-Based Systematic Review and Meta-Analysis. PMID- 29276335 TI - The Validation of a Beta-Binomial Model for Overdispersed Binomial Data. AB - The beta-binomial model has been widely used as an analytically tractable alternative that captures the overdispersion of an intra-correlated, binomial random variable, X. However, the model validation for X has been rarely investigated. As a beta-binomial mass function takes on a few different shapes, the model validation is examined for each of the classified shapes in this paper. Further, the mean square error (MSE) is illustrated for each shape by the maximum likelihood estimator (MLE) based on a beta-binomial model approach and the method of moments estimator (MME) in order to gauge when and how much the MLE is biased. PMID- 29276336 TI - Diagnosing Expertise: Human Capital, Decision Making, and Performance among Physicians. AB - Expert performance is often evaluated assuming that good experts have good outcomes. We examine expertise in medicine and develop a model that allows for two dimensions of physician performance: decision making and procedural skill. Better procedural skill increases the use of intensive procedures for everyone, while better decision making results in a reallocation of procedures from fewer low-risk to high-risk cases. We show that poor diagnosticians can be identified using administrative data and that improving decision making improves birth outcomes by reducing C-section rates at the bottom of the risk distribution and increasing them at the top of the distribution. PMID- 29276337 TI - Hazardous drinking and exposure to interpersonal and community violence on both sides of the U.S. -Mexico border. AB - Objective: Different patterns of heavy drinking occur by country and proximity to the U.S. Mexico border. Few studies describe the impact of violence on drinking between countries and along the border. Methods: Survey data is from U.S. Mexican origin adults living in Texas and Mexican border and non-border cities, N=4,796. Participants were asked about alcohol consumption, interpersonal physical violence (IPV) and exposure to community violence. Monthly hazardous drinking (5+/4+ for men/women) was the primary outcome. Multivariate logistic regression model comparisons identified best predictors. Results: In the U.S. hazardous drinking was associated with past year IPV (ORadj=2.5; 1.8-3.5) and community violence (ORadj=1.4; 1.1-1.8). In Mexico, IPV (ORadj=3.9; 2.0-7.4) and border proximity (ORadj=0.5; 0.4-0.8) were associated with hazardous drinking but not community violence. Conclusion: Hazardous drinking is associated with IPV in both countries, but violence did not explain border hazardous drinking differences where they existed in Mexico. PMID- 29276339 TI - Frog foams and natural protein surfactants. AB - Foams and surfactants are relatively rare in biology because of their potential to harm cell membranes and other delicate tissues. However, in recent work we have identified and characterized a number of natural surfactant proteins found in the foam nests of tropical frogs and other unusual sources. These proteins, and their associated foams, are relatively stable and bio-compatible, but with intriguing molecular structures that reveal a new class of surfactant activity. Here we review the structures and functional mechanisms of some of these proteins as revealed by experiments involving a range of biophysical and biochemical techniques, with additional mechanistic support coming from more recent site directed mutagenesis studies. PMID- 29276340 TI - Highly Stereoselective, Intermolecular Haloetherification and Haloesterification of Allyl Amides. PMID- 29276338 TI - Rural Families' Use of Multiple Child Care Arrangements from 6 to 58 Months and Children's Kindergarten Behavioral and Academic Outcomes. AB - Non-parental child care prior to kindergarten is a normative experience for the majority of children in the United States, with children commonly experiencing multiple arrangements, or more than one concurrent child care arrangement. The experience of multiple arrangements has predominantly been shown to be negatively related to young children's health and behavioral outcomes. The present study examined the use of multiple concurrent arrangements for children in the Family Life Project, a representative sample of families living in six high-poverty rural counties. Using the full sample of 1,292 children who were followed from six months to kindergarten, this study examined the associations between the number of child care arrangements averaged across six time points and children's behavioral and academic outcomes in kindergarten. After including a number of control variables, regression results suggested that a greater number of arrangements prior to kindergarten were related to higher levels of teacher reported negative behaviors, but not positive behaviors, and letter-word decoding skills, but not mathematics skills, though effect sizes were small. Moderation analyses by child care type and quality were conducted, with no evidence emerging that findings varied by type or quality of care. PMID- 29276341 TI - An X-Band Crossed-Loop EPR Resonator. AB - A copper X-band (9.22 GHz) cross loop resonator has been constructed for use with 4 mm sample tubes. The Q for the two resonators are 380 and 350, respectively. The resonator efficiency is about 1 G per square root of watt. Operation has been demonstrated with measurement of T1 by saturation recovery for samples of coal and an immobilized nitroxide radical. PMID- 29276342 TI - Machiavelli and the liberalism of fear. AB - This article revisits the long-standing question of the relations between ethics and politics in Machiavelli's work, assessing its relevance to the 'liberalism of fear' in particular in the work of Judith Shklar, Bernard Williams and also John Dunn. The article considers ways in which Machiavelli has been a 'negative' resource for liberalism - for instance, as a presumed proponent of tyranny; but also ways in which even for the liberalism of fear he might be considered a 'positive' resource, above all around the issues of political necessity and prudential judgement. PMID- 29276343 TI - For reflexivity as an epistemic criterion of ontological coherence and virtuous social theorizing. AB - This article offers an approach that combines, on the one hand, the philosophical notion of reflexivity, which is related to the ideas of self-reference and paradox, and, on the other hand, the sociological discussion of epistemic reflexivity as a problem of coherence, which was mainly initiated by certain branches of ethnomethodology and social constructionism. This combinatory approach argues for reflexivity as an epistemic criterion of ontological coherence, which suggests that social ontologies should account for the possibility of self-reflective subjectivity - for otherwise they result in a paradoxical conclusion according to which a social scientist reflects on her or his ontological commitments even though these commitments deny her or him the capacity for self-reflection. This analysis presupposes that all human sciences are categorically premised on social ontologies; and it argues for an analytical distinction between self-reflection, which refers to the agential capacity for reflecting on one's own commitments, and the epistemic criterion of reflexivity hereby proposed. These two analytically distinct though interdependent socio theoretical concepts are frequently conflated in the literature; thus, this article also aims at a 'clearing of the ground' that can be of categorical use to the human sciences. PMID- 29276344 TI - Does Far Transfer Exist? Negative Evidence From Chess, Music, and Working Memory Training. AB - Chess masters and expert musicians appear to be, on average, more intelligent than the general population. Some researchers have thus claimed that playing chess or learning music enhances children's cognitive abilities and academic attainment. We here present two meta-analyses assessing the effect of chess and music instruction on children's cognitive and academic skills. A third meta analysis evaluated the effects of working memory training-a cognitive skill correlated with music and chess expertise-on the same variables. The results show small to moderate effects. However, the effect sizes are inversely related to the quality of the experimental design (e.g., presence of active control groups). This pattern of results casts serious doubts on the effectiveness of chess, music, and working memory training. We discuss the theoretical and practical implications of these findings; extend the debate to other types of training such as spatial training, brain training, and video games; and conclude that far transfer of learning rarely occurs. PMID- 29276345 TI - The Psychology of Conspiracy Theories. AB - What psychological factors drive the popularity of conspiracy theories, which explain important events as secret plots by powerful and malevolent groups? What are the psychological consequences of adopting these theories? We review the current research and find that it answers the first of these questions more thoroughly than the second. Belief in conspiracy theories appears to be driven by motives that can be characterized as epistemic (understanding one's environment), existential (being safe and in control of one's environment), and social (maintaining a positive image of the self and the social group). However, little research has investigated the consequences of conspiracy belief, and to date, this research does not indicate that conspiracy belief fulfills people's motivations. Instead, for many people, conspiracy belief may be more appealing than satisfying. Further research is needed to determine for whom, and under what conditions, conspiracy theories may satisfy key psychological motives. PMID- 29276346 TI - From performance to performativity: The legitimization of US security contracting and its consequences. AB - Discussions about the legitimacy of private security companies (PSCs) in multilateral military interventions abound. This article looks at how the United States has sought to legitimize the outsourcing of security services to PSCs through performance-based contracting and performance assessments. Both mechanisms aim to demonstrate the effective provision of publicly desirable outcomes. However, the immaterial and socially constructed nature of security presents major problems for performance assessments in terms of observable and measurable outcomes. Performance has therefore given way to performativity - that is, the repetitive enactment of particular forms of behaviour and capabilities that are simply equated with security as an outcome. The implications of this development for the ways in which security has been conceptualized, implemented and experienced within US interventions have been profound. Ironically, the concern with performance has not encouraged PSCs to pay increased attention to their impacts on security environments and civilian populations, but has fostered a preoccupation with activities and measurable capabilities that can be easily assessed by government auditors. PMID- 29276348 TI - A quantitative model of water radiolysis and chemical production rates near radionuclide-containing solids. AB - We present a mathematical model that quantifies the rate of water radiolysis near radionuclide-containing solids. Our model incorporates the radioactivity of the solid along with the energies and attenuation properties for alpha (alpha), beta (beta), and gamma (gamma) radiation to calculate volume normalized dose rate profiles. In the model, these dose rate profiles are then used to calculate radiolytic hydrogen (H2) and hydrogen peroxide (H2O2) production rates as a function of distance from the solid-water interface. It expands on previous water radiolysis models by incorporating planar or cylindrical solid-water interfaces and by explicitly including gamma radiation in dose rate calculations. To illustrate our model's utility, we quantify radiolytic H2 and H2O2 production rates surrounding spent nuclear fuel under different conditions (at 20 years and 1000 years of storage, as well as before and after barrier failure). These examples demonstrate the extent to which alpha, beta and gamma radiation contributes to total absorbed dose rate and radiolytic production rates. The different cases also illustrate how H2 and H2O2 yields depend on initial composition, shielding and age of the solid. In this way, the examples demonstrate the importance of including all three types of radiation in a general model of total radiolytic production rates. PMID- 29276347 TI - Model-Fusion-Based Online Glucose Concentration Predictions in People with Type 1 Diabetes. AB - Accurate predictions of glucose concentrations are necessary to develop an artificial pancreas (AP) system for people with type 1 diabetes (T1D). In this work, a novel glucose forecasting paradigm based on a model fusion strategy is developed to accurately characterize the variability and transient dynamics of glycemic measurements. To this end, four different adaptive filters and a fusion mechanism are proposed for use in the online prediction of future glucose trajectories. The filter fusion mechanism is developed based on various prediction performance indexes to guide the overall output of the forecasting paradigm. The efficiency of the proposed model fusion based forecasting method is evaluated using simulated and clinical datasets, and the results demonstrate the capability and prediction accuracy of the data-based fusion filters, especially in the case of limited data availability. The model fusion framework may be used in the development of an AP system for glucose regulation in patients with T1D. PMID- 29276349 TI - Mismatch Negativity in Han Chinese Patients with Schizophrenia: A Meta-Analysis. AB - Background: Previous meta-analysis revealed that mismatch negativity(MMN) amplitude decreased in patients with schizophrenia compared with healthy controls (Cohen's d, d about 1), leading to the possibility of mismatch negativity being used as a biomarker for schizophrenia. However, it is unknown whether MMN is reliably changed in Chinese patients. It is necessary to carry out a meta analysis on MMN of Han Chinese patients with schizophrenia. Aim: To investigate whether MMN could be used as a biomarker for Han Chinese patients with schizophrenia. Methods: A literature search was conducted to identify clinical trials on MMN in Han Chinese schizophrenia patients published before May 8, 2017, by searching the Chinese language databases CNKI, WanFang Data, VIP Data and PubMed. The effects of MMN deficits were evaluated for MMN amplitude by calculating standard mean difference (SMDs) between schizophrenia patient groups and healthy control groups. Results: A total of 11 studies were included in the analysis. The total quality of all the studies were more than 6 as evaluated by Newcastle-Ottawa Scale (NOS). Meta-analysis of data from these studies had a pooled sample of 432 patients with schizophrenia and 392 healthy controls. There exists significant MMN deficit in schizophrenia patients compared to healthy controls (Cohen's d=1.004). When studies were excluded due to heterogeneity, the pooled effect size of the MMN differences between the patient group and healthy controls dropped to 0.79 (Cohen's d=0.79). Subgroup analysis showed that MMN amplitude deficits of schizophrenia over three years had the pooled effect size of 0.95, and less than three years had the pooled effect size of 0.77. Publication bias conducted via Egger regression test (t = 1.83; p = 0.101), suggested that there was no publication bias. Conclusion: The effect size of MMN amplitude between Chinese patients with schizophrenia and healthy controls is consistent with other meta-analyses published on this topic, suggesting that Han Chinese patients with schizophrenia also exhibited MMN deficits. PMID- 29276350 TI - Pleasure Experience and Emotion Expression in Patients with Schizophrenia. AB - Background: Impairments in emotional experience and expression have been observed in patients with schizophrenia. However, most previous studies have been limited to either emotional experience (especially anhedonia) or expression. Few studies have examined both the experience and expression of emotion in schizophrenia patients at the same time. Aims: The present study aimed to examine pleasure experience and emotion expression in patients with schizophrenia. In particular, we specifically examined the relationship between emotion impairments (both pleasure experience and expression) and negative symptoms. Methods: One hundred and fifty patients completed the Temporal Experience of Pleasure Scale and Emotional Expressivity Scale. Results: Schizophrenia patients exhibited deficits in experiencing pleasure, but showed intact reported emotion expression. Patients with prominent negative symptoms showed reduced anticipatory pleasure, especially in abstract anticipatory pleasure. Conclusion: The present findings suggest that patients with schizophrenia have deficits in pleasure experience, while their abilities to express emotion appear intact. Such deficits are more severe in patients with prominent negative symptoms. PMID- 29276351 TI - Abnormal Concentration of GABA and Glutamate in The Prefrontal Cortex in Schizophrenia.-An in Vivo 1H-MRS Study. AB - Background: The etiology and pathomechanism of schizophrenia are unknown. The traditional dopamine (DA) hypothesis is unable to fully explain its pathology and therapeutics. The glutamate (Glu) and gamma-aminobutyric acid (GABA) hypotheses suggest Glu or GABA concentrations are abnormal in the brains of patients with schizophrenia. Magnetic resonance spectroscopy (MRS) show glutamate level increases in the ventromedial prefrontal cortex (vmPFC) including the anterior cingulated cortex (ACC) in those with schizophrenia. Aims: To investigate the function of the glutamate system (glutamate and gamma-aminobutyric acid) in the etiology and pathomechanism of schizophrenia. Methods: 24 drug naive patients with schizophrenia and 24 healthy volunteers were matched by gender, age, and educational level. The Siemens 3T MRI system was used to collect the magnetic resonance spectroscopy (MRS) data of the subjects. The regions of interest included the left dorsolateral prefrontal cortex (IDLPFC), ventromedial prefrontal cortex (vmPFC), and anterior cingulate cortex (ACC). LCModel software was used to analyze the concentrations of gamma-aminobutyric acid (GABA), glutamate (Glu), glutamine (Gln), N-acetylaspartate (NAA), and N acetylaspartylglutamate (NAAG) in the region of interest. Meanwhile, the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) were used to assess the mental symptoms and severity of the disease. Results: The median GABA concentrations in the anterior cingulate cortex of the schizophrenia group and the healthy control group were 1.90 (Q1=1.55, Q3=2.09) and 2.16 (Q1=1.87, Q3=2.59) respectively; the mean (sd) Glu concentrations were 6.07 (2.48) and 6.54 (1.99); the median Gln concentrations were 0.36 (Q1=0.00, Q3=0.74) and 0.29 (Q1=0.00, Q3=0.59); the between-group difference of the GABA concentrations was statistically significant (Z=-2.95, p=0.003); the between group difference of the GABA/(NAA+NAAG) was statistically significant (Z=-2.72, p=0.012); the between-group difference of Glu and Gln was not statistically significant. The age of the schizophrenia group was negatively correlated with the GABA concentration in the anterior cingulate (R=-0.494, p=0.014), and negatively correlated with GABA/ (NAA+NAAG) (R=-0.473, p=0.020). Yet there was no such correlation in the control group. After calibration, no significant correlation was found between the clinical symptoms and the concentrations of the metabolites. Conclusions: The concentration of glutamate in the vemtromedial prefrontal cortex of patients with schizophrenia was abnormal, whereas the concentration of GABA in the anterior cingulate cortex decreased, supporting the hypothesis of abnormal glutamate -GABA in the brains of those individuals with schizophrenia. In patients with schizophrenia, the GABA in the anterior cingulate cortex had an accelerated decline with age. The clinical symptoms may be correlated to the metabolite concentration of the anterior cingulate cortex. PMID- 29276352 TI - Pretreatment Serum MCP-1 Level Predicts Response to Risperidone in Schizophrenia. AB - Background: Schizophrenia is a chronic debilitating disease. The pathogenesis and treatment may be associated with inflammatory cytokines. There are few studies focusing on the prediction of cytokines in response to antipsychotics. Aim: To investigate whether cytokines would predict response to antipsychotics. Methods: Cross-sectional and natural observational cohort studies were applied to:(1) compare the baseline levels of serum IL-1beta, TNF-alpha and MCP-1 between schizophrenia (n=64) and healthy controls (n=53); (2) To investigate the impact of baseline cytokines to psychopathology following olanzapine and risperidone monotherapy. Results: (1) Baseline MCP-1 level of patients with schizophrenia was significantly higher than healthy controls (t=2.62, p=0.010), while no significance was found in IL-1beta (t=1.43, p=0.154) and TNF-alpha (t=0.79, p=0.434); (2) Pretreatment level of MCP-1 significantly correlated with PANSS-G reduction following 4 weeks' of risperidone monotherapy (r =-0.658; p<0.001) but not olanzapine monotherapy (r =-0.031; p=0.855); (3) Further stepwise multiple linear regression analysis indicated that higher MCP-1 level prior to treatment was a significant predictor of less PANSS-G reduction in schizophrenia patients following risperidone monotherapy (adjusted R2= 0.409, beta = -0.658, p <0.001), but not in the olanzapine group. Conclusion: MCP-1 may play a role in the pathogenesis of schizophrenia. Pretreatment level of MCP-1 may serve as a biomarker indicating response to risperidone treatment. PMID- 29276353 TI - A Cross-Sectional Study on the Characteristics of Tardive Dyskinesia in Patients with Chronic Schizophrenia. AB - Background: Tardive dyskinesia (TD) is an abnormal involuntary movement disorder caused by patients' long-term use of antipsychotic medication. It diminishes the social functioning of patients with mental disorders, thereby affecting their compliance with antipsychotic medication. The cause and nosogenesis of TD remains unclear; furthermore, because the presentation differs greatly among individuals it often goes undiagnosed or can be easily misdiagnosed. The present study aims to evaluate the abnormal movement patterns in patients with TD, and analyze the differences among different TD patterns, in order to seek effective methods of preventing, diagnosing and treating TD. Aims: To describe the movement patterns of patients with chronic schizophrenia with TD, and analyze their clinical characteristics and risk factors. Methods: A cross-sectional study was carried out on a psychiatric unit of the Xuhui Mental Health Center with inpatients who had chronic schizophrenia as participants. Abnormal Involuntary Movement Scale (AIMS) was employed to screen for patients with schizophrenia who also had TD. These patients' movement disorders were evaluated, and they were divided into groups based on their movement patterns. Positive and Negative Syndrome Scale (PANSS) was used to assess the psychotic symptoms of patients, collect clinical information, compare the differences between the two groups and analyze the clinical characteristics and risk factors of TD. Results: (1) A total of 448 patients met the inclusion criteria for chronic schizophrenia with 46 in the TD group and 402 in the control group. After the TD group and the control group was compared, significant differences were seen between the two groups in gender, age, total duration of illness, age of onset, dosage of antipsychotic medication (daily chlorpromazine equivalent), factor scores of negative symptoms on PANSS and PANSS total scores. (2) It was possible that age, factor scores of negative symptoms in PANSS, the amount of antipsychotic medication used (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (3) There were significant differences among the number of TD patients with movement disorders in facial and oral areas (67.4%), limbs (58.7%) and torso (37%). The AIMS scores corresponding with movement disorders in different parts of the body were also significantly different. (4) Comparing TD patients with single affected area and those with multiple affected areas, we found that they had significant differences in gender, age of onset, AIMS total scores, severity scores of abnormal movements and loss of range due to abnormal movements. Conclusion: (1) Compared to the control group, the TD group had more men, was older, had a longer duration of illness, later age of onset, generally took a higher dosage of antipsychotic medication and presented with more severe negative symptoms. It is possible that age, factor scores of negative symptoms on PANSS, dosage of antipsychotic medication (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (2) The occurrence of movement disorders in facial and oral areas for patients with chronic schizophrenia with TD was the most frequent, and the symptoms were the most severe. (3) Compared to TD patients with a single affected area, TD patients with multiple affected areas may have an earlier age of onset, more severe movement disorders, and more setbacks in their movement and functioning. PMID- 29276354 TI - Multidimensional Approaches for A Case of Severe Adult Obsessive - Compulsive Disorder. AB - Obsessive-compulsive disorder (OCD) is a chronic, distressing and substantially impairing neuropsychiatric disorder, characterized by obsessions or compulsions. The current case describes a 44-year-old adult female diagnosed with OCD. The patient had an incomplete response to several SSRIs alone during her past treatment, and led a poor-quality life for at least three years. Current multidimensional approaches, including combined cognitive behavioral therapy (CBT) and the Selective Serotonin Reuptake Inhibitor (SSRI, Sertraline) with a small dose of antipsychotics (Aripiprazole) for augmentation, as well as familial support and resources from the internet were provided for the patient for six months. Standardized assessments with Yale-Brown Obsessive-Compulsive Scale (Y BOCS) every two months indicated significant reductions in obsessive and compulsive symptoms, with significant improvements in her social functioning and quality of life. A case such as this one provides preliminary support to multidimensional approaches for OCD treatment in order to achieve an optimal response, though further rigorous clinical trials are needed to provide more evidence. PMID- 29276355 TI - Psychiatry and Cinema: What Can We Learn from the Magical Screen? AB - Cinema, a vehicle of social transformation sheds light on different aspects of mental illness. Due to its dramatic and stigmatising depictions, it often spreads a negative aspect of psychiatric disorders and the patients who are suffering from them. Though it brings out a few positive and inspiring stories, they are sparse in comparison to its negative views. Here, we are going to describe the dual impact of cinema on psychiatry. PMID- 29276356 TI - Commentary on "Psychiatry and Cinema: What can We Learn from the Magical Screen?" PMID- 29276357 TI - Sample Size Calculations for Comparing Groups with Binary Outcomes. AB - Sample size is a critical parameter for clinical studies. However, to many biomedical and psychosocial investigators, power and sample size analysis seems like a magic trick of statisticians. In this paper, we continue to discuss power and sample size calculations by focusing on binary outcomes. We again emphasize the importance of close interactions between investigators and biostatisticians in setting up hypotheses and carrying out power analyses. PMID- 29276358 TI - A new look at classical inequalities involving Banach lattice norms. AB - Some classical inequalities are known also in a more general form of Banach lattice norms and/or in continuous forms (i.e., for 'continuous' many functions are involved instead of finite many as in the classical situation). The main aim of this paper is to initiate a more consequent study of classical inequalities in this more general frame. We already here contribute by discussing some results of this type and also by deriving some new results related to classical Popoviciu's, Bellman's and Beckenbach-Dresher's inequalities. PMID- 29276359 TI - Two variables functionals and inequalities related to measurable operators. AB - In this paper, we introduce two variables norm functionals of tau-measurable operators and establish their joint log-convexity. Applications of this log convexity will include interpolated Young, Heinz and Trace inequalities related to tau-measurable operators. Additionally, interpolated versions and their monotonicity will be presented as well. PMID- 29276360 TI - On the bounds of degree-based topological indices of the Cartesian product of F sum of connected graphs. AB - Topological indices are the mathematical tools that correlate the chemical structure with various physical properties, chemical reactivity or biological activity numerically. A topological index is a function having a set of graphs as its domain and a set of real numbers as its range. In QSAR/QSPR study, a prediction about the bioactivity of chemical compounds is made on the basis of physico-chemical properties and topological indices such as Zagreb, Randic and multiple Zagreb indices. In this paper, we determine the lower and upper bounds of Zagreb indices, the atom-bond connectivity (ABC) index, multiple Zagreb indices, the geometric-arithmetic (GA) index, the forgotten topological index and the Narumi-Katayama index for the Cartesian product of F-sum of connected graphs by using combinatorial inequalities. PMID- 29276361 TI - New applications of Schrodinger type inequalities in the Schrodingerean Hardy space. AB - As new applications of Schrodinger type inequalities obtained by Jiang (J. Inequal. Appl. 2016: Article ID 247, 2016) in the Schrodingerean Hardy space, we not only obtain the representation of Schrodingerean harmonic functions but also give a sufficient and necessary condition between the Schrodingerean distributional function and its derivative in the Schrodingerean Hardy space. PMID- 29276362 TI - The Effects of Genetic and Environmental Factors on Writing Development. AB - Researchers have identified sources of individual differences in writing across beginning and developing writers. The aim of the present study was to further clarify the sources of this variability by investigating the extent to which there are differences in genetic and environmental factors underlying the associations between lexical diversity, syntactic knowledge, and semantic cohesion knowledge in relation to writing. Differences were examined across two developmental phases of writing: beginning (i.e., elementary school) and developing (i.e., middle school). Participants included 262 twin pairs (Mage = 10.88 years) in elementary school and 247 twin pairs (Mage = 13.21 years) in middle school. Twins were drawn from the Florida Twin Project on Reading, Behavior, and Environment. Biometric models were conducted separately for subgroups defined by phase of writing development. Results indicated significant etiological differences in writing components across the two phases, such that effects associated with genes and non-shared environment were greater while effects associated with shared environment were lower in developing writers as compared to beginning writers. Furthermore, results showed that child-specific environment was the largest contributor to individual differences in writing components and their covariation for both beginning and developing writers. These results imply that even direct instruction about writing in schools may be having different effects on children based on their unique experiences. PMID- 29276363 TI - Does Initial Learning about the Meaning of Fractions Present Similar Challenges for Students with and without Adequate Whole-Number Skill? AB - The purposes of this study were to (a) explore whether early fractions understanding at 4th grade is differentially challenging for students with versus without adequate whole-number competence and (b) identify specific whole-number skill associated with difficulty in fractions understanding. Based on initial whole-number competence, 1,108 4th graders were classified as having (a) adequate whole-number competence (n = 775), (b) less severe whole-number difficulty (n = 201), and (c) severe whole-number difficulty (n = 132). At the end of 4th grade, they were assessed on fractions understanding and further classified as with versus without difficulty in fractions understanding. Multi-level logistic regression indicated that compared to students with adequate whole-number competence, those with less severe whole-number difficulty were almost 5 times as likely to experience difficulty with fractions understanding whereas those with severe whole-number difficulty were about 32 times as likely to experience difficulty with fractions understanding. Students with severe whole-number difficulty were about 7 times as likely to experience difficulty with fractions understanding compared to those with less severe whole-number difficulty. Among students with adequate whole-number competence, the pretest whole-number skill distinguishing those with versus without difficulty in fractions understanding was basic division facts (i.e., 2-digit dividend / 1-digit divisor) and simple multiplication (i.e., 3-digit * 1-digit without regrouping). The role of whole number competence in developing initial fractions understanding and implications for instruction are discussed. PMID- 29276364 TI - Categories and Their Role in the Science of Emotion. PMID- 29276365 TI - Patterned Plasmonic Surfaces-Theory, Fabrication, and Applications in Biosensing. AB - Low-profile patterned plasmonic surfaces are synergized with a broad class of silicon microstructures to greatly enhance near-field nanoscale imaging, sensing, and energy harvesting coupled with far-field free-space detection. This concept has a clear impact on several key areas of interest for the MEMS community, including but not limited to ultra-compact microsystems for sensitive detection of small number of target molecules, and "surface" devices for optical data storage, micro-imaging and displaying. In this paper, we review the current state of-the-art in plasmonic theory as well as derive design guidance for plasmonic integration with microsystems, fabrication techniques, and selected applications in biosensing, including refractive-index based label-free biosensing, plasmonic integrated lab-on-chip systems, plasmonic near-field scanning optical microscopy and plasmonics on-chip systems for cellular imaging. This paradigm enables low profile conformal surfaces on microdevices, rather than bulk material or coatings, which provide clear advantages for physical, chemical and biological related sensing, imaging, and light harvesting, in addition to easier realization, enhanced flexibility, and tunability. PMID- 29276366 TI - Interstitial Pneumonia with Autoimmune Features: Overview of proposed criteria and recent cohort characterization. AB - The accurate diagnosis of interstitial lung disease (ILD) is essential for optimal prognostication and management. While connective tissue disease (CTD) is among the most common causes of ILD, some patients have features suggestive of autoimmunity without meeting criteria for a specific CTD. To help define and study this disease entity more uniformly, a 2015 research statement proposed consensus-based criteria and coined the term "interstitial pneumonia with autoimmune features" (IPAF). In this review, we summarize and compare previously proposed criteria to characterize these patients, provide an overview of the IPAF criteria and highlight recent investigations aimed at characterizing IPAF cohorts. We then call attention to questions that have arisen with the application of the IPAF criteria and discuss future areas of study. PMID- 29276367 TI - A Pilot Study of the Effects of Pulley Location and Design Parameters on Hand Movements during Pulley Threading Operations. AB - Three healthy individuals participated in a laboratory experiment that required routing a thin continuous thread through a series of pulleys mounted on a vertical work surface. Task precision demand was manipulated by altering pulley outer diameter (38 mm, 76 mm, and 152 mm) and groove width (3 mm, 6 mm, and 9 mm). The target location of each destination pulley relative to the origin at the mid-sagittal plane was also manipulated. These factors were hypothesized to influence hand motion trajectories, peak speed, and task completion time. Smaller pulley diameters and larger groove widths, representing lower precision demands, were associated with smoother trajectories and a faster task completion time. These preliminary findings suggest a systematic influence of task precision demands on movement kinematics and task performance. PMID- 29276368 TI - Comparative Analysis of Inertial Sensor to Optical Motion Capture System Performance in Push-Pull Exertion Postures. AB - This study examined interactions between inertial sensor (IS) performance and physical task demand on posture kinematics in a two-handed force exertion task. Fifteen male individuals participated in a laboratory experiment that involved exerting a two-handed isometric horizontal force on an instrumented height adjustable handle. Physical task demand was operationalized by manipulating vertical handle height, target force magnitude, and force direction. These factors were hypothesized to influence average estimates of torso flexion angle measured using inertial sensors and an optical motion capture (MC) system, as well as the root mean squared errors (RMSE) between instrumentation computed over a 3s interval of the force exertion task. Results indicate that lower handle heights and higher target force levels were associated with increased torso and pelvic flexion in both, push and pull exertions. Torso flexion angle estimates obtained from IS and MC did not differ significantly. However, RMSE increased with target force intensity suggesting potential interactive effects between measurement error and physical task demand. PMID- 29276369 TI - Spatial and Temporal Patterns in Sequential Precision Reach Movements. PMID- 29276370 TI - Statistical Prediction of Hand Force Exertion Levels in a Simulated Push Task using Posture Kinematics. AB - This study explored the use of body posture kinematics derived from wearable inertial sensors to estimate force exertion levels in a two-handed isometric pushing and pulling task. A prediction model was developed grounded on the hypothesis that body postures predictably change depending on the magnitude of the exerted force. Five body postural angles, viz., torso flexion, pelvis flexion, lumbar flexion, hip flexion, and upper arm inclination, collected from 15 male participants performing simulated isometric pushing and pulling tasks in the laboratory were used as predictor variables in a statistical model to estimate handle height (shoulder vs. hip) and force intensity level (low vs. high). Individual anthropometric and strength measurements were also included as predictors. A Random Forest algorithm implemented in a two-stage hierarchy correctly classified 77.2% of the handle height and force intensity levels. Results represent early work in coupling unobtrusive, wearable instrumentation with statistical learning techniques to model occupational activities and exposures to biomechanical risk factors in situ. PMID- 29276371 TI - Normal Theory Two-Stage ML Estimator When Data Are Missing at the Item Level. AB - In many modeling contexts, the variables in the model are linear composites of the raw items measured for each participant; for instance, regression and path analysis models rely on scale scores, and structural equation models often use parcels as indicators of latent constructs. Currently, no analytic estimation method exists to appropriately handle missing data at the item level. Item-level multiple imputation (MI), however, can handle such missing data straightforwardly. In this article, we develop an analytic approach for dealing with item-level missing data-that is, one that obtains a unique set of parameter estimates directly from the incomplete data set and does not require imputations. The proposed approach is a variant of the two-stage maximum likelihood (TSML) methodology, and it is the analytic equivalent of item-level MI. We compare the new TSML approach to three existing alternatives for handling item-level missing data: scale-level full information maximum likelihood, available-case maximum likelihood, and item-level MI. We find that the TSML approach is the best analytic approach, and its performance is similar to item-level MI. We recommend its implementation in popular software and its further study. PMID- 29276372 TI - ZDHHC3 as a Risk and Mortality Marker for Breast Cancer in African American Women. AB - African American woman are 43% more likely to die from breast cancer than white women and have increased the risk of tumor recurrence despite lower incidence. We investigate variations in microsatellite genomic regions-a type of repetitive DNA and possible links to the breast cancer mortality gap. We screen 33 854 microsatellites in germline DNA of African American women with and without breast cancer: 4 are statistically significant. These are located in the 3' UTR (untranslated region) of gene ZDHHC3, an intron of transcribed pseudogene INTS4L1, an intron of ribosomal gene RNA5-8S5, and an intergenic region of chromosome 16. The marker in ZDHHC3 is interesting for 3 reasons: (a) the ZDHHC3 gene is located in region 3p21 which has already been linked to early invasive breast cancer, (b) the Kaplan-Meier estimator demonstrates that ZDHHC3 alterations are associated with poor breast cancer survival in all racial/ethnic groups combined, and (c) data from cBioPortal suggest that ZDHHC3 messenger RNA expression is significantly lower in African Americans compared with whites. These independent lines of evidence make ZDHHC3 a candidate for further investigation. PMID- 29276373 TI - Longitudinal Transcriptional Response of Glycosylation-Related Genes, Regulators, and Targets in Cancer Cell Lines Treated With 11 Antitumor Agents. AB - Cellular glycosylation processes are vital to cell functioning. In malignant cells, they are profoundly altered. We used time-course gene expression data from the NCI-60 cancer cell lines treated with 11 antitumor agents to analyze expression changes of genes involved in glycosylation pathways, genes encoding glycosylation targets or regulators, and members of cancer pathways affected by glycosylation. We also identified glycosylation genes for which pretreatment expression levels or changes after treatment were correlated with drug sensitivity. Their products are involved in N-glycosylation and O-glycosylation, fucosylation, biosynthesis of poly-N-acetyllactosamine, removal of misfolded proteins, binding to hyaluronic acid and other glycans, and cell adhesion. Tumor cell sensitivity to multiple agents was correlated with transcriptional response of C1GALT1C1, FUCA1, SDC1, MUC1; members of the MGAT, GALNT, B4GALT, B3GNT, MAN, and EDEM families; and other genes. These genes may be considered as potential candidates for drug targeting in combination therapy to enhance treatment response. PMID- 29276374 TI - Plasma Cytochrome c Detection Using a Highly Sensitive Electrochemiluminescence Enzyme-Linked Immunosorbent Assay. AB - Background: Cytochrome c is an intermembrane mitochondrial protein that is released to the bloodstream following mitochondrial injury. Methods and results: We developed an electrochemiluminescence immunoassay to measure cytochrome c in human and rat plasma, which showed high sensitivity with broad dynamic range (2 1200 ng/mL in humans and 5-500 ng/mL in rat) and high assay reproducibility (inter-assay coefficient <6% in humans and <10% in rat). In patients after blunt trauma, plasma cytochrome c directly correlated with injury severity. In rats after cardiac resuscitation, plasma cytochrome c inversely correlated with survival and responsiveness to mitochondrial protective interventions. Conclusions: The cytochrome c assays herein presented have high sensitivity, wide dynamic range, and high reproducibility well suited for biomarker of mitochondrial injury. PMID- 29276375 TI - Prophylactic intracameral levofloxacin in cataract surgery - an evaluation of safety. AB - Purpose: To evaluate posterior and anterior segment safety of an intracameral injection of levofloxacin 0.5% ophthalmic solution as prophylaxis for patients undergoing cataract extraction and intraocular lens implantation. Setting: This study was conducted at Manila Doctors Hospital, Ermita, Manila, Philippines. Design: This was a prospective interventional study. Methods: Eyes undergoing standard phacoemulsification cataract surgery with intraocular lens implantation were treated with intracameral levofloxacin 0.5% at the conclusion of surgery. Safety parameters, including best-corrected visual acuity (BCVA), endothelial cell counts, anterior chamber cells and flare, and central foveal thickness, were evaluated preoperatively and at 1 day and 1 week postoperatively. Results: A total of 50 eyes of 50 patients were included in the analysis. At 1 week postoperatively, all eyes demonstrated BCVA of 20/30 or better and 19 eyes (38%) achieved BCVA of 20/20 or better. On the first postoperative day, no corneal edema was observed, and trace to +2 cells and flare in the anterior chamber were noted in all eyes. After 1 week, all eyes had a quiet anterior chamber and endothelial cell counts decreased by an average of 225 cells/mm2, which was marginally significant (p=0.0525) when compared to other time points. Optical coherence tomography results showed no statistically significant differences between central foveal thickness measurements before and after surgery. There were also no statistically significant differences in preoperative and postoperative pachymetry. No study-related adverse events occurred. Conclusion: There were no safety concerns associated with intracameral injection of levofloxacin 0.5%, prophylactically, following cataract surgery. Further study is required to demonstrate effectiveness in endophthalmitis prevention. PMID- 29276376 TI - Short-term outcomes after EX-PRESS implantation versus trabeculectomy alone in patients with neovascular glaucoma. AB - Background: The purpose of this study was to investigate postoperative clinical outcomes in patients with neovascular glaucoma (NVG) who underwent trabeculectomy or EX-PRESS implantation and to identify predictors of successful EX-PRESS implantation. Methods: The study designed as a retrospective observational analysis and was set in a single tertiary center. Eighty-nine patients (89 eyes) with NVG, were treated using trabeculectomy alone (Trab group; n=39) or EX-PRESS implantation (EX group; n=50). All patients with a history of glaucoma surgery were excluded. The main outcome measures were postoperative intraocular pressure (IOP), visual acuity (VA), number of medications, complications, additional therapy, and success rate. Results: The mean follow-up duration was 4.6 months in the Trab group and 4.2 months in the EX group. There was no significant difference in IOP between the groups except at 1-month follow-up (P=0.045). The number of patients with early postoperative hypotony, a shallow anterior chamber, hyphema, or anterior chamber irrigation was significantly lower in the EX group than in the Trab group (P=0.016, 0.008, 0.019, and 0.014, respectively). The other outcomes, ie, VA, number of medications, and success rate, were similar between the two groups. In the EX group, the success rate was significantly lower in 15 patients with a history of vitrectomy compared to that in 35 patients without a history of vitrectomy (P=0.047). Conclusion: Implantation of an EX PRESS device may be more effective and safer than trabeculectomy alone in patients with NVG. However, a history of vitrectomy may affect the surgical success rate when using EX-PRESS. PMID- 29276377 TI - Anti-angiogenic effects of biotechnological therapies in rheumatic diseases. AB - Introduction: Angiogenesis plays a key role in the pathogenesis of numerous rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and vasculitides. Therefore, the inhibition of pathological angiogenesis may be considered a useful therapeutical approach in these rheumatic diseases. Methods: This review article is based on a literature research about the role of biotechnological therapies in angiogenesis inhibition. Results and conclusions: Several evidences have demonstrated a role for biotechnological therapies in angiogenesis inhibition. Nevertheless, further research and clinical trials are needed to better quantify the real impact of biotechnological therapies on pathological angiogenesis. PMID- 29276378 TI - Bioinformatic Analysis of Circadian Expression of Oncogenes and Tumor Suppressor Genes. AB - Background: Circadian rhythms are physiological and behavioral cycles with a period of approximately 24 hours that control various functions including gene expression. Circadian disruption is associated with a variety of diseases, especially cancer. Although some of the oncogenes and tumor suppressor genes (TSGs) are known as clock-controlled genes (CCGs), the analysis and annotation of circadian expression of most human oncogenes and TSGs are still lacking. This study aims to investigate the circadian expression of a list of human oncogenes and TSGs. Methods: A bioinformatic analysis was conducted on a gene library comprising 120 genes to investigate the circadian expression of human oncogenes and TSGs. To achieve this purpose, the genotranscriptomic data were retrieved from COSMIC and analyzed by R statistical software. Furthermore, the acquired data were analyzed at the transcriptomic and proteomic levels using several publicly available databases. Also, the significance of all analyses was confirmed statistically. Results: Altogether, our results indicated that 7 human oncogenes/TSGs may be expressed and function in a circadian manner. These oncogenes/TSGs showed a circadian expression pattern at CircaDB database and associated with at least one of the circadian genes/CCGs based on both genotranscriptomic and correlation analyses. Conclusions: Although 4 of 7 finally outputted genes have been previously reported to be clock controlled, heretofore there is no report about the circadian expression of 3 other genes. Considering the importance of oncogenes/TSGs in the initiation and progression of cancer, further studies are suggested for the identification of exact circadian expression patterns of these 3 human oncogenes/TSGs. PMID- 29276379 TI - Average annual cost of Parkinson's disease in Sao Paulo, Brazil, with a focus on disease-related motor symptoms. AB - Background: Although Parkinson's disease is the second most prevalent neurodegenerative disease worldwide, its cost in Brazil - South America's largest country - is unknown. Objective: The goal of this study was to calculate the average annual cost of Parkinson's disease in the city of Sao Paulo (Brazil), with a focus on disease-related motor symptoms. Subjects and methods: This was a retrospective, cross-sectional analysis using a bottom-up approach (ie, from the society's perspective). Patients (N=260) at two tertiary public health centers, who were residents of the Sao Paulo metropolitan area, completed standardized questionnaires regarding their disease-related expenses. We used simple and multiple generalized linear models to assess the correlations between total cost and patient-related, as well as disease-related variables. Results: The total average annual cost of Parkinson's disease was estimated at US$5,853.50 per person, including US$3,172.00 in direct costs (medical and nonmedical) and US$2,681.50 in indirect costs. Costs were directly correlated with disease severity (including the degree of motor symptoms), patients' age, and time since disease onset. Conclusion: In this study, we determined the cost of Parkinson's disease in Brazil and observed that disease-related motor symptoms are a significant component of the costs incurred on the public health system, patients, and society in general. PMID- 29276380 TI - A multicenter controlled study for dementia prevention through physical, cognitive and social activities - GESTALT-kompakt. AB - Prevention of dementia is a public health priority. Physical activity (PA) can reduce the risk of dementia, but the majority of people remain sedentary. We conducted a multicenter controlled study with older adults (60+ years). We hypothesized that an evidence-based PA intervention - GEhen, Spielen und Tanzen Als Lebenslange Tatigkeiten - kompakt [walking, playing and dancing as lifelong activities-compact] (GESTALT-kompakt) - would lead to significantly larger improvements in PA levels (step counts/Fitbit ZipTM), cognitive functions (DemTect) and social activities (Social Activity Log), compared to an active control group. Data were collected at baseline and after 3 and 12 months. The intervention group received a 12-week (1/week) multimodal and multicomponent PA program, which combined PA with cognitive and social activities. The control group received either regular gymnastics or cognitive training (1/week). A mixed linear model was chosen for analysis. A total of 87 older individuals were recruited in the GESTALT-kompakt study (68 females, average age =76.0 years, SD +/-9.2, range 52-95 years). Marginally significant differences were observed in the intervention group (n=57) in comparison to the control group (n=30), regarding improvements in PA (difference of mean changes =866.4 steps, p=0.055) after 3 months. However, their PA decreased to the baseline score value after 12 months (-866.0 steps, p=0.061). GESTALT-kompakt did not cause significant differences in cognitive functioning (-0.8620, p=0.074) and social activities ( 0.2428, p=0.288) in comparison to the control intervention from T0 to T1. Sixteen (24.2%) study participants who finished T2 reported a negative life event during the follow-up period, which severely influenced their PA behavior. GESTALT kompakt might be effective in increasing PA in the short term, but did not have a long-term impact on the PA levels, cognitive functions or social activities of the participants. We recommend PA programs with longer duration to change behavior in the long term. PMID- 29276382 TI - A facile and sensitive peptide-modulating graphene oxide nanoribbon catalytic nanoplasmon analytical platform for human chorionic gonadotropin. AB - The nanogold reaction between HAuCl4 and citrate is very slow, and the catalyst graphene oxide nanoribbon (GONR) enhanced the nanoreaction greatly to produce gold nanoparticles (AuNPs) that exhibited strong surface plasmon resonance (SPR) absorption (Abs) at 550 nm and resonance Rayleigh scattering (RRS) at 550 nm. Upon addition of the peptide of human chorionic gonadotropin (hCG), the peptide could adsorb on the GONR surface, which inhibited the catalysis. When hCG was added, peptides were separated from the GONR surface due to the formation of stable peptide-hCG complex, which led to the activation of GONR catalytic effect. With the increase in hCG concentration, the RRS and Abs signal enhanced linearly. The enhanced RRS value showed a good linear relationship with hCG concentration in the range of 0.2-20 ng/mL, with a detection limit of 70 pg/mL. Accordingly, two new GONR catalytic RRS/Abs methods were established for detecting hCG in serum samples. PMID- 29276381 TI - A new data analysis approach for measuring longitudinal changes of metabolism in cognitively normal elderly adults. AB - Introduction: Previously, we discussed several critical barriers in including [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging of preclinical Alzheimer's disease (AD) subjects. These factors included the reference region selection and intensity normalization of PET images and the within- and across-subject variability of affected brain regions. In this study, we utilized a novel FDG-PET analysis, the regional FDG time correlation coefficient, rFTC, that can address and resolve these barriers and provide a more sensitive way of monitoring longitudinal changes in metabolism of cognitively normal elderly adults. The rFTC analysis captures the within-subject similarities between baseline and follow-up regional radiotracer distributions. Methods: The rFTC trajectories of 27 cognitively normal subjects were calculated to identify 1) trajectories of rFTC decline in individual cognitively normal subjects; 2) how these trajectories correlate with the subjects' cognitive test scores, baseline cerebrospinal fluid (CSF) levels of amyloid beta (Abeta), and apolipoprotein E4 (APOE-E4) status; and 3) whether similar trajectories are observed in regional/composite standardized uptake value ratio (SUVR) values. Results: While some of the subjects maintained a stable rFTC trajectory, other subjects had declining and fluctuating rFTC values. We found that the rFTC decline was significantly higher in APOE-E4 carriers compared to noncarriers (p=0.04). We also found a marginally significant association between rFTC decline and cognitive decline measured by Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS_cog) decline (0.05). In comparison to the rFTC trajectories, the composite region of interest (ROI) SUVR trajectories did not change in any of the subjects. No individual/composite ROI SUVR changes contributed significantly to explaining changes in ADAS_cog, conversion to mild cognitive impairment (MCI), or any general changes in clinical symptoms. Conclusion: The rFTC decline may serve as a new biomarker of early metabolic changes before the MCI stage. PMID- 29276383 TI - Synthesis, structural characterization and catalytic application of citrate stabilized monometallic and bimetallic palladium@copper nanoparticles in microbial anti-activities. AB - In this research work, copper (Cu), palladium (Pd) and their bimetallic palladium@ copper (Pd@Cu) nanoparticles were synthesized using trisodium citrate as a stabilizing agent using the known chemical reduction method. The synthesized Cu, Pd and Pd@Cu nanoparticles were characterized by the ultraviolet-visible spectroscopy, scanning electron microscopy and X-ray diffraction spectroscopy, respectively. The different volumes of trisodium citrate were used for the stability of synthesized monometallic Cu, Pd and bimetallic Pd@Cu nanoparticles. The synthesized Cu, Pd and their bimetallic Pd@Cu nanoparticles were used as catalysts for the reduction of 4-nitrophenol in the presence of NaBH4. The bimetallic Pd@Cu nanoparticles had efficient catalytic activities with a high rate constant (1.812 min-1) as compared to monometallic Cu (0.3322 min-1) and Pd (0.2689 min-1) nanoparticles, respectively. The correlation coefficient (R2) was found to be 0.99 for these three nanoparticles. Meanwhile, the effect of Cu, Pd and bimetallic Pd@Cu nanoparticles was checked on the physiology of specific different micro-organism strains. The bimetallic Pd@Cu nanoparticles reported the maximum resistance at maximum level the growth of bacterial strain and had observed a smooth antibacterial graph than the monometallic analogs. PMID- 29276384 TI - Investigation of the effects of carbon-based nanomaterials on A53T alpha synuclein aggregation using a whole-cell recombinant biosensor. AB - The aggregation of alpha-synuclein (alphaS), natively unstructured presynaptic protein, is a crucial factor leading to the pathogenesis of Parkinson's disease (PD) and other related disorders. Recent studies have shown prefibrillar and oligomeric intermediates of alphaS as toxic to the cells. Herein, split luciferase complementation assay is used to design a "signal-on" biosensor to monitor oligomerization of A53T alphaS inside the cells. Then, the effect of carbon-based nanomaterials, such as graphene quantum dots (GQDs) and graphene oxide quantum dots (GOQDs), on A53T alphaS oligomerization in vitro and in living cells is investigated. In this work, for the first time, it was found that GQDs at a concentration of 0.5 MUg/mL can promote A53T alphaS aggregation by shortening the nucleation process, which is the key rate-determining step of fibrillation, thereby making a signal-on biosensor. While these nanomaterials may cross the blood-brain barrier because of their small sizes, the interaction between alphaS and GQDs may contribute to PD etiology. PMID- 29276385 TI - Green synthesis palladium nanoparticles mediated by white tea (Camellia sinensis) extract with antioxidant, antibacterial, and antiproliferative activities toward the human leukemia (MOLT-4) cell line. AB - Among nanoparticles used for medical applications, palladium nanoparticles (PdNPs) are among the least investigated. This study was undertaken to develop PdNPs by green synthesis using white tea (W.tea; Camellia sinensis) extract to produce the Pd@W.tea NPs. The Pd@W.tea NPs were characterized by UV-vis spectroscopy and X-ray diffractometry, and evaluated with transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The Pd@W.tea NPs were spherical (size 6-18 nm) and contained phenols and flavonoids acquired from the W.tea extract. Pd@W.tea NPs has good 1-diphenyl-2-picrylhydrazyl (DPPH), OH, and NO-scavenging properties as well as antibacterial effects toward Staphylococcus epidermidis and Escherichia coli. MTT assay showed that Pd@W.tea NPs (IC50 =0.006 MUM) were more antiproliferative toward the human leukemia (MOLT-4) cells than the W.tea extract (IC50 =0.894 MUM), doxorubicin (IC50 =2.133 MUM), or cisplatin (IC50 =0.013 MUM), whereas they were relatively innocuous for normal human fibroblast (HDF-a) cells. The anticancer cell effects of Pd@W.tea NPs are mediated through the induction of apoptosis and G2/M cell-cycle arrest. PMID- 29276387 TI - Delirium in hemodialysis predicts mortality: a single-center, long-term observational study. AB - Objectives: Delirium signifies underlying brain dysfunction; however, its clinical significance in hemodialysis remains unclear. In this study, we sought to determine whether the occurrence of delirium during hemodialysis was associated with higher mortality. Patients and methods: This was a retrospective, 10-year cohort study. This study was performed at the urology department located within a hospital in Oyokyo, Hirosaki. We analyzed 338 of 751 patients who underwent hemodialysis. Psychiatrists diagnosed patients with delirium according to the corresponding DSM-IV-TR criteria. Cox proportional hazard regression, which was adjusted for patient age at the time of hemodialysis initiation, sex, and the presence of diabetes mellitus, was performed. Hazard ratios (HRs) and their 95% CIs were also reported. Results: In total, 286 patients without psychiatric diseases and 52 patients with delirium were evaluated. Eighty percent of patients with delirium died within 1 year of hemodialysis initiation, while only 22% of patients without delirium died within the same time period (P<0.01). Kaplan-Meier plots demonstrated the existence of associations between delirium and all-cause mortality (global log-rank P<0.001), cardiovascular disease-related mortality (global log-rank P<0.001), and infection-related mortality (global log rank P<0.001). Moreover, Cox proportional hazard regression showed that delirium was associated with all-cause mortality (HR=1.96, 95% CI: 1.32-2.90), cardiovascular disease-related mortality (HR=2.65, 95% CI: 1.31-5.35), and infection-related mortality (HR=3.30, 95% CI: 1.34-8.10). Conclusion: Delirium is an independent predictor of death in patients undergoing hemodialysis. PMID- 29276386 TI - Guided bone regeneration with asymmetric collagen-chitosan membranes containing aspirin-loaded chitosan nanoparticles. AB - Introduction: Membranes allowing the sustained release of drugs that can achieve cell adhesion are very promising for guided bone regeneration. Previous studies have suggested that aspirin has the potential to promote bone regeneration. The purpose of this study was to prepare a local drug delivery system with aspirin loaded chitosan nanoparticles (ACS) contained in an asymmetric collagen-chitosan membrane (CCM). Methods: In this study, the ACS were fabricated using different concentrations of aspirin (5 mg, 25 mg, 50 mg, and 75 mg). The drug release behavior of ACS was studied. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used to examine the micromorphology of ACS and aspirin-loaded chitosan nanoparticles contained in chitosan-collagen membranes (ACS-CCM). In vitro bone mesenchymal stem cells (BMSCs) were cultured and critical-sized cranial defects on Sprague-Dawley rats were made to evaluate the effect of the ACS-CCM on bone regeneration. Results: Drug release behavior results of ACS showed that the nanoparticles fabricated in this study could successfully sustain the release of the drug. TEM showed the morphology of the nanoparticles. SEM images indicated that the asymmetric membrane comprised a loose collagen layer and a dense chitosan layer. In vitro studies showed that ACS CCM could promote the proliferation of BMSCs, and that the degree of differentiated BMSCs seeded on CCMs containing 50 mg of ACS was higher than that of other membranes. Micro-computed tomography showed that 50 mg of ACS-CCM resulted in enhanced bone regeneration compared with the control group. Conclusion: This study shows that the ACS-CCM would allow the sustained release of aspirin and have further osteogenic potential. This membrane is a promising therapeutic approach to guiding bone regeneration. PMID- 29276388 TI - Relevance of positive cardiovascular outcome trial results in clinical practice: perspectives from the Academy for Cardiovascular Risk, Outcomes and Safety Studies in Type 2 Diabetes (ACROSS T2D). AB - Type 2 diabetes (T2D) imposes a substantial disease burden, predominantly from cardiovascular disease (CVD), which accounts for >50% of deaths in this population and leads to a 12-year reduction in the life expectancy of a 60-year old male patient with T2D and CVD compared with the general population. The results from mandatory cardiovascular outcome trials (CVOTs) are therefore of great interest in the field. The Academy for Cardiovascular Risk, Outcomes and Safety Studies in Type 2 Diabetes meeting program aims to bring together experts from several associated disciplines to provide fair and balanced resources for those involved in the management of patients with T2D. This publication represents the opinions of the faculty on the key learnings from the meeting held in Vienna in the spring of 2017. In particular, we detail how data from the EMPA REG OUTCOME(r) [cardiovascular outcomes trial of empagliflozin] and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER(r)) (liraglutide) CVOTs can be practically interpreted across clinical specialities. It is hoped that this translation of CVOT data will achieve a dual treatment paradigm for the management of both raised glucose levels and CV risk in patients with T2D. PMID- 29276389 TI - Predictors of acute pancreatitis with low elevation of serum amylase. AB - Background and aims: Serum amylase is a traditional measure used to establish the diagnosis of acute pancreatitis (AP). The current study aimed to assess the predictors and clinical outcome of AP with low serum amylase. Methods: All patients were divided into two groups, based on their serum amylase level within the first 2 days after hospital admission: group 1 (amylase >=300 U/L) and group 2 (amylase <300 U/L). Clinical outcomes were compared between the two groups before and after 1:1 propensity score matching. Clinical and biochemical parameters were collected and evaluated as potential predictors of AP with low serum amylase. Results: A total of 464 patients were enrolled. After propensity score matching according to age, gender, time interval before admission, hematocrit, blood urea nitrogen and creatinine, 108 matched pairs of patients were selected. There was no significant statistical difference between group 2 and group 1 with respect to severity of AP, median days of stay in hospital and death. Multivariate analysis indicated that biliary etiology (odds ratio [OR]: 0.499; 95% confidence interval [CI]: 0.265-0.942; P=0.003), low-density lipoprotein cholesterol (LDL-C) (OR: 1.009; 95% CI: 1.002-1.017; P=0.017) and triglyceride levels (OR: 1.001; 95% CI: 1.0001-1.001; P=0.015) were independently associated with development of AP along with low serum amylase. Conclusion: Serum amylase level was not related to the severity of AP, median hospital stay (days) and death. Biliary etiology, LDL-C and triglyceride levels were independently associated with the development of AP with lower elevation of serum amylase. PMID- 29276390 TI - Trial-Level Regressor Modulation for Functional Magnetic Resonance Imaging Designs Requiring Strict Periodicity of Stimulus Presentations: Illustrated Using a Go/No-Go Task. AB - Computer-based assessment of many cognitive processes (eg, anticipatory and response readiness processes) requires the use of invariant stimulus display times (SDT) and intertrial intervals (ITI). Although designs with invariant SDTs and ITIs have been used in functional magnetic resonance imaging (fMRI) research, such designs are problematic for fMRI studies because of collinearity issues. This study examined regressor modulation with trial-level reaction times (RT) as a method for improving signal detection in a go/no-go task with invariant SDTs and ITIs. The effects of modulating the go regressor were evaluated with respect to the detection of BOLD signal-change for the no-go condition. BOLD signal change to no-go stimuli was examined when the go regressor was based on a (a) canonical hemodynamic response function (HRF), (b) RT-based amplitude-modulated (AM) HRF, and (c) RT-based amplitude and duration modulated (A&DM) HRF. Reaction time-based modulation reduced the collinearity between the go and no-go regressors, with A&DM producing the greatest reductions in correlations between the regressors, and greater reductions in the correlations between regressors were associated with longer mean RTs and greater RT variability. Reaction time based modulation increased statistical power for detecting group-level no-go BOLD signal-change across a broad set of brain regions. The findings show the efficacy of using regressor modulation to increase power in detecting BOLD signal-change in fMRI studies in which circumstances dictate the use of temporally invariant stimulus presentations. PMID- 29276391 TI - Some Lipid Droplets Are More Equal Than Others: Different Metabolic Lipid Droplet Pools in Hepatic Stellate Cells. AB - Hepatic stellate cells (HSCs) are professional lipid-storing cells and are unique in their property to store most of the retinol (vitamin A) as retinyl esters in large-sized lipid droplets. Hepatic stellate cell activation is a critical step in the development of chronic liver disease, as activated HSCs cause fibrosis. During activation, HSCs lose their lipid droplets containing triacylglycerols, cholesteryl esters, and retinyl esters. Lipidomic analysis revealed that the dynamics of disappearance of these different classes of neutral lipids are, however, very different from each other. Although retinyl esters steadily decrease during HSC activation, triacylglycerols have multiple pools one of which becomes transiently enriched in polyunsaturated fatty acids before disappearing. These observations are consistent with the existence of preexisting "original" lipid droplets with relatively slow turnover and rapidly recycling lipid droplets that transiently appear during activation of HSCs. Elucidation of the molecular machinery involved in the regulation of these distinct lipid droplet pools may open new avenues for the treatment of liver fibrosis. PMID- 29276392 TI - Integrative analysis of lncRNAs and miRNAs with coding RNAs associated with ceRNA crosstalk network in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is a particular subtype of breast malignant tumor with poorer prognosis than other molecular subtypes. Currently, there is increasing focus on long non-coding RNAs (lncRNAs), which can act as competing endogenous RNAs (ceR-NAs) and suppress miRNA functions involved in post transcriptional regulatory networks in the tumor. Therefore, to investigate specific mechanisms of TNBC carcinogenesis and improve treatment efficiency, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 116 TNBC tissues and 11 normal tissues from The Cancer Genome Atlas. As a result, we selected the threshold with |log2FC|>2.0 and an adjusted p-value >0.05 to obtain the differentially expressed mRNAs, miRNAs and lncRNAs. Hereafter, weighted gene co-expression network analysis was performed to identify the expression characteristics of dysregulated genes. We obtained five co-expression modules and related clinical feature. By means of correlating gene modules with protein-protein interaction network analysis that had identified 22 hub mRNAs which could as hub target genes. Eleven key dysregulated differentially expressed micro RNAs (DEmiRNAs) were identified that were significantly associated with the 22 hub potential target genes. Moreover, we found that 14 key differentially expressed lncRNAs could interact with the key DEmiRNAs. Then, the ceRNA crosstalk network of TNBC was constructed by utilizing key lncRNAs, key miRNAs, and hub mRNAs in Cytoscape software. We analyzed and described the potential characteristics of biological function and pathological roles of the TNBC ceRNA co-regulatory network; also, the survival analysis was performed for each molecule. These findings revealed that ceRNA crosstalk network could play an important role in the development and progression for TNBC. In addition, we also identified that some molecules in the ceRNA network possess clinical correlation and prognosis. PMID- 29276393 TI - miR-199a modulates cisplatin resistance in ovarian cancer by targeting Hif1alpha. AB - Resistance to chemotherapy is a primary problem for the effective treatment of ovarian cancer. Recently, increasing evidence has demonstrated that miRNAs modulate many important molecular pathways involved in chemotherapy. Previous studies demonstrated that miR-199a affected ovarian cancer cell resistance to cisplatin (DDP). However, the role of miR-199a and its target genes in determination of ovarian cancer sensitivity to DDP remains unclear. Quantitative reverse transcription polymerase chain reaction was used to detect the expression levels of miR-199a in ovarian cancer tissues and C13* and OV2008 cell lines. After transfection of miR-199a mimic or inhibitor, flow cytometry was used to detect cell apoptosis exposed to DDP. Enzyme-linked immunosorbent assay and Western blot assay were applied to detect tumor necrosis factor-alpha levels and protein expression levels of Bax, Fas, Fas-associated death domain, and caspase 8. The results indicated that the expression of miR-199a was downregulated and hypoxia-inducible factor 1alpha (Hif1alpha) upregulated in the ovarian tumors compared with those in the corresponding normal tissues. Besides, the expression levels of miR-199a were significantly higher in OV2008 cells compared with those in C13* cells. Moreover, suppression of Hif1alpha reversed the inhibiting function of miR-199a inhibitor on DDP-induced apoptosis in the OV2008 cells. However, overexpression of both miR-199a and Hif1alpha reduced DDP-induced apoptosis in C13* cells. In conclusion, miR-199a may change DDP resistance in ovarian cancer by regulating Hif1alpha. PMID- 29276394 TI - High expression of CIP2A protein is associated with tumor aggressiveness in stage I-III NSCLC and correlates with poor prognosis. AB - The aim of this work was to examine the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in non-small cell lung cancer (NSCLC) and analyze its correlation with clinical outcomes. CIP2A protein levels were detected by immunohistochemistry (IHC). One hundred and eighty-four of 209 (88.3%) primary stage I-III NSCLC specimens and 4 of 38 (10.5%) adjacent normal lung tissue specimens expressed CIP2A protein. High expression of CIP2A was detected in 38.8% (81/209) of the NSCLC specimens. Patients diagnosed histologically with late stage NSCLC (p<0.001) and malignant nodes (p=0.001) exhibited high CIP2A expression. Univariate analysis using the log-rank test identified CIP2A expression as a prognostic predictor for overall survival (p=0.005). In multivariate analyses using the Cox regression test, CIP2A expression, T stage, N stage, histological type, and chemotherapy were identified as independent prognostic factors (p=0.007, 0.001, 0.003, <0.001, and <0.001, respectively). Furthermore, Kaplan-Meier survival curves demonstrated that high CIP2A expression indicated poor prognosis in the subgroup of patients with squamous cell carcinoma (p=0.008). Similar results were noted in the subgroup of patients with adenocarcinoma, but the results did not reach statistical significance (p=0.084). We also used univariate analysis and multivariate analysis to assess the prognostic factors for overall survival in the subgroup of patients who received postoperative chemotherapy. CIP2A expression was also an independent prognostic factor in NSCLC patients who received postoperative chemotherapy (p=0.009), along with histological type (p=0.001) and N stage (p=0.034). In conclusion, adding to the accumulating evidence, our research suggested that the CIP2A expression is associated with aggressiveness and correlates with poor prognosis in NSCLC. Our findings also indicated that CIP2A might be a potential therapeutic target against NSCLC. PMID- 29276395 TI - Nuclear expression of XBP1s is correlated with breast cancer survival: a retrospective analysis based on tissue microarray. AB - An alternatively spliced transcription factor that participates in the unfolded protein response, XBP1 is a novel protein involved in cancer progression and outcome. This study aimed to investigate the relationship of spliced XBP1 (XBP1s) with the clinicopathological characteristics and prognosis of breast cancer by using tissue-microarray analysis. A consecutive series of 170 patients with breast cancer diagnosed between 2001 and 2004 in hospitals in eastern and southern China were included. Immunohistochemical staining for XBP1s was performed, and the expression of XBP1s was separately examined in nuclei and cytoplasm. We found that a higher expression of XBP1s in nuclei strongly correlated with poorer survival (46.7% versus 75%, P=0.018); however, the expression of XBP1s in the cytoplasm had no relationship with survival. Multivariate Cox regression analysis indicated that the expression of XBP1s was not an independent prognostic factor (RR 2.074, 95% CI 0.909-4.736; P=0.083). None of the other clinicopathological characteristics - age, pathology grade, T stage, N stage, TNM stage, estrogen receptor, progesterone receptor, or HER2 status - was found to be correlated with XBP1s expression in the nuclei. In conclusion, independently of other clinicopathological factors, the nuclear expression of XBP1s is correlated with shorter breast cancer survival; however, whether nuclear XBP1s is an independent prognostic biomarker needs to be confirmed by further studies with larger samples and detailed sample stratification. PMID- 29276396 TI - Naturally occurring genotypic drug-resistant mutations of HBV in Huzhou, China: a single-center study. PMID- 29276397 TI - Is cytomegalovirus infection related to inflammatory bowel disease, especially steroid-resistant inflammatory bowel disease? A meta-analysis. AB - Background: Human cytomegalovirus (HCMV) infection has been associated with inflammatory bowel disease (IBD). Numerous studies have been conducted to analyze the association between HCMV infection and risk of IBD and steroid-resistant IBD, but no clear consensus had been reached. Objectives: The aim of this study was to confirm this relationship precisely by doing a systematic review and meta analysis. Study design: We identified relevant studies through a search of PubMed and Embase. Studies were eligible for inclusion if they 1) evaluated the association between HCMV infection and IBD disease; 2) evaluated the association between HCMV infection and steroid-resistant IBD disease; 3) were case-control studies or nested case-control studies; 4) provided the numbers (or percentage) of positivity for HCMV infection in cases and controls, respectively. Data were extracted and analyzed independently by two investigators. Results and conclusion: A total of 18 studies including 1,168 patients and 951 health groups was identified, and HCMV infection was distinctly confirmed as a risk factor for the occurrence and development of IBD. When involving 17 studies including 1,306 IBD patients, a total of 52.9% of patients in the cytomegalovirus (CMV)-positive groups were observed to have steroid resistance, compared with 30.2% of patients in the CMV-negative groups. There was a significant difference in the risk of steroid resistance between people exposed to HCMV infection and those not exposed HCMV infection in IBD patients. This meta-analysis suggested that HCMV infection is associated with an increased risk for IBD and steroid-resistant IBD. PMID- 29276398 TI - Cost-effectiveness analysis of IDegLira versus basal-bolus insulin for patients with type 2 diabetes in the Slovak health system. AB - Aims: To investigate the cost-effectiveness of once-daily insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy in patients with type 2 diabetes not meeting glycemic targets on basal insulin from a healthcare payer perspective in Slovakia. Methods: Long-term clinical and economic outcomes for patients receiving IDegLira and basal-bolus therapy were estimated using the IMS CORE Diabetes Model based on a published pooled analysis of patient-level data. Results: IDegLira was associated with an improvement in quality-adjusted life expectancy of 0.29 quality-adjusted life years (QALYs) compared with basal-bolus therapy. The average lifetime cost per patient in the IDegLira arm was EUR 2,449 higher than in the basal-bolus therapy arm. Increased treatment costs with IDegLira were partially offset by cost savings from avoided diabetes-related complications. IDegLira was highly cost-effective versus basal-bolus therapy with an incremental cost-effectiveness ratio of EUR 8,590 per QALY gained, which is well below the cost-effectiveness threshold set by the law in Slovakia. Conclusion: IDegLira is cost-effective in Slovakia, providing a simple option for intensification of basal insulin therapy without increasing the risk of hypoglycemia or weight gain and with fewer daily injections than a basal-bolus regimen. PMID- 29276399 TI - Effects of a proposed physical activity and diet control to manage constipation in middle-aged obese women. AB - Background: Obesity is very common worldwide and is related to critical morbidity and mortality. It has a large number of impacts on the human body. Constipation has a prevalence from 4% to 29% in various parts of the world and is considered to be a major health problem, with an estimated incidence of 5% in males and 15% in females. There is a strong association between obesity and constipation. This study aimed to investigate the effect of physical activity and a low-calorie diet on constipation in middle-aged obese women. Methods: This study included 125 obese women (age 20-40 years) who had chronic constipation. Participants were randomly assigned to two groups. Group A included 62 women who received a suggested protocol of physical activity, a low-calorie diet, and the routine standard care for constipation, whereas Group B included 63 women who received only the standard medical care for constipation and a low-calorie diet. Both groups followed the program for 12 weeks. Changes in the Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment Quality of Life (PAC-QOL) scores, and in the body mass index (BMI) were recorded in study subjects, both at baseline and at the end of the study program. Results: There were no statistically significant differences in the baseline characteristics of patients in the two groups. After 12 weeks of intervention, both groups showed significant intra-group differences (p < 0.05) in all of the measured variables, except the BMI which showed a nonsignificant difference (p > 0.05) in Group B. Between groups comparison showed significant differences (p < 0.05) in all of the measured parameters in favor of Group A. Conclusion: Physical activity and weight reduction improve PAC-SYM and PAC-QOL scores in middle-aged, premenopausal women with constipation in the short term (up to 12 weeks). PMID- 29276400 TI - Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience. AB - Basal insulin therapy can improve glycemic control in people with type 2 diabetes. However, timely initiation, optimal titration, and proper adherence to prescribed basal insulin regimens are necessary to achieve optimal glycemic control. Even so, glycemic control may remain suboptimal in a significant proportion of patients. Unique circumstances in Asia (eg, limited resources, management of diabetes primarily in nonspecialist settings, and patient populations that are predominantly less educated) coupled with the limitations of current basal insulin options (eg, risk of hypoglycemia and dosing time inflexibility) amplify the challenge of optimal basal insulin therapy in Asia. Significant progress has been made with long-acting insulin analogs (insulin glargine 100 units/mL and insulin detemir), which provide longer coverage and less risk of hypoglycemia over intermediate-acting insulin (Neutral Protamine Hagedorn insulin). Furthermore, recent clinical evidence suggests that newer long acting insulin analogs, new insulin glargine 300 units/mL and insulin degludec, may address some of the unmet needs of current basal insulin options in terms of risk of hypoglycemia and dosing time inflexibility. Nevertheless, more can be done to overcome barriers to basal insulin therapy in Asia, through educating both patients and physicians, developing better patient support models, and improving accessibility to long-acting insulin analogs. In this study, we highlight the unique challenges associated with basal insulin therapy in Asia and, where possible, propose strategies to address the unmet needs by drawing on clinical experiences and perspectives in Asia. PMID- 29276401 TI - Cohesive Polydensified Matrix(r) hyaluronic acid volumizer injected for cheek augmentation has additional positive effect on nasolabial folds. AB - Purpose: Cohesive Polydensified Matrix(r) hyaluronic acid (CPM-HA) volumizer has been used successfully for several years to reverse biometric volume loss during facial aging. This observational study explored the additive effect on nasolabial folds when CPM-HA volumizer is injected into the neighboring cheek area. Patients and methods: In this open-label, prospective, postmarketing noninterventional study, 18 adult patients seeking esthetic enhancement of the lateral cheek hollows and cheekbone area were injected with CPM-HA volumizer integrated with lidocaine (CPM-HA-VL) in the upper or lower cheek area. Safety and performance of CPM-HA-VL up to 12 months after injection with follow-up visits at week 4 and month 3, 6, and 12 were assessed. The primary endpoint was improvement of cheek fullness on the validated Merz Aesthetics Scales. Additionally, changes in nasolabial folds were quantified using a phaseshift rapid in vivo measurement of skin optical three-dimensional (3D) in vivo measurement device. Results: Patients (94.4% female, median age 52 years, age range 39-69 years) were injected with a mean volume of 2.5+/-1.1 mL CPM-HA-VL per side. Immediately after injection, mean severity for upper and lower cheek fullness assessed on the validated MAS improved from 2.5+/-0.6 and 2.8+/-0.5, respectively, to 1.0+/-0.0, and remained unchanged through month 12. Improvement in relation to baseline was attested on the Global Aesthetics Improvement Scale for all assessments. Compared with baseline, the following assessments offered a statistical significance in the reduction of wrinkle depth of nasolabial folds (maximum depth reduction by 30.4% at 3 months) according to optical 3D in vivo measurements. Pain during injection was minimal and abated within 30 minutes. Treatment was well tolerated and led to great patient satisfaction. Conclusion: CPM-HA-VL injected into the upper and lower cheeks led to long-lasting satisfactory cosmetic results in cheek augmentation as well as in reducing depth of nasolabial folds adjacent to the injection site. PMID- 29276402 TI - Ganglion blocks as a treatment of pain: current perspectives. AB - The inputs from sympathetic ganglia have been known to be involved in the pathophysiology of various painful conditions such as complex regional pain syndrome, cancer pain of different origin, and coccygodynia. Sympathetic ganglia blocks are used to relieve patients who suffer from these conditions for over a century. Many numbers of local anesthetics such as bupivacaine or neurolytic agents such as alcohol can be chosen for a successful block. The agent is selected according to its duration of effect and the purpose of the injection. Most commonly used sympathetic blocks are stellate ganglion block, lumbar sympathetic block, celiac plexus block, superior hypogastric block, and ganglion Impar block. In this review, indications, methods, effectiveness, and complications of these blocks are discussed based on the data from the current literature. PMID- 29276403 TI - Thermal camera as a pain monitor. AB - Objectives: Today, many subjective methods are used to measure pain. Wong Baker and Hicks Facial Pain Scale is one of the most commonly used method. Clinicians grade pain according to the facial mimetic reaction of the patient. Unfortunately, there is no objective measure for monitoring pain. By using the same principle of the Wong Baker and Hicks Facial Pain Scale, in this study, we aimed to objectively measure pain by using a thermal camera to detect instant facial temperature changes. Materials and methods: Thirty volunteers who attended blood collection unit were subjected to facial thermal monitoring and measurements were obtained 5 minutes before needle puncture (BNP), during needle puncture (DNP), and after needle puncture (ANP). Data were processed with TestoIRSoft 3.8 software program and mean temperatures of the whole face (FFM) and highest temperature points (HP), horizontal line (HOR) between two pupils and first glabellar wrinkle, and bilateral lines starting from the nasolabial sulcus to oral commissure (NLS-1 at right, NLS-2 at left) were evaluated. All data were statistically analyzed with paired sample t-test. Results: Statistically, temperature measurements of HOR, NLS-1, NLS-2, HP, and FFM were significantly higher between BNP and DNP, significantly lower between ANP and DNP, and significantly higher between BNP and ANP (p<0.05). The most interesting result in our analysis was that the HP point was between the two eyebrows in 26 of the 30 volunteers. Conclusion: Our results suggest that a thermal camera can be used to objectively monitor pain and in follow-up. However, further studies involving non healthy volunteers (especially high-fever patients, children, immunosuppressive patients, and cancer and intensive care patients) should be performed. PMID- 29276404 TI - Fascia iliaca compartment block versus no block for pain control after lower limb surgery: a meta-analysis. AB - Background: The analgesic effect of fascia iliaca compartment block (FICB) versus no block (NB) after lower limb surgery (LLS) is still controversial, so we performed this meta-analysis. Materials and methods: By searching the PubMed, Embase and the Cochrane Library (last update by July 20, 2017), randomized controlled trials comparing the analgesic effect of FICB versus NB in patients receiving LLS were identified. The primary outcome was the pain scores at 4, 12, and 24 h after LLS. The dosage of morphine at 24 h was also collected. The side effect of anesthesia was assessed according to the occurrence rate of postoperative nausea and vomiting. Results: Data from 7 clinical trials that included 508 patients were summarized. The results showed that patients receiving FICB had lower pain scores at 4 h (mean difference [MD]=-1.17; 95% CI=-2.30 to 0.05; P=0.041), 12 h (MD=-0.41; 95% CI=-0.76 to -0.05; P=0.026) and 24 h (MD= 0.96; 95% CI=-1.77 to -0.15; P=0.020) after LLS. Besides, FICB could reduce the dosage of morphine at 24 h (MD=-2.06; 95% CI=-3.82 to -0.30; P=0.022) and the incidence of postoperative nausea and vomiting (relative risk rate=0.44, 95% CI=0.24-0.80, P=0.008). Conclusion: Compared with NB, FICB is an effective and safe method for alleviating the pain after LLS. More high-quality randomized controlled trials are needed to confirm this finding. PMID- 29276405 TI - Prognostic role and clinical significance of trophoblast cell surface antigen 2 in various carcinomas. AB - Introduction: Trophoblast cell surface antigen 2 (TROP2) has been linked to disease prognosis in various human cancers and plays a critical role in tumor development, progression, and metastasis. A number of relevant studies have been published on this topic. A meta-analysis of the latest literature to evaluate the value of TROP2 as a predictive prognosticator of cancer was performed. Methods: Several online databases were searched, and relevant articles were retrieved. Overall and subcategory meta-analyses were performed, and results were collated. Results: Twenty-seven articles, including 29 studies, were included, involving 4,852 cancer patients, and results showed that the above-baseline expression of TROP2 was significantly associated with poorer overall survival (OS) (pooled hazard ratio [HR]: 1.84, 95% confidence interval [CI]: 1.45-2.35), disease-free survival (DFS) (pooled HR: 2.77, 95% CI: 1.73-4.42), and progression-free survival (PFS) (pooled HR: 1.71, 95% CI: 1.25-2.35). The following clinical characteristics were also significantly linked with TROP2 overexpression: moderate/poor differentiation (pooled HR: 3.03, 95% CI: 1.99-4.63), distant metastasis (pooled HR: 2.46, 95% CI: 1.05-5.75), lymph node metastasis (pooled HR: 2.47, 95%: CI 1.72-3.56), and advanced TNM stage (pooled HR: 2.02, 95% CI: 1.38-2.95). Conclusion: TROP2 overexpression was predictive of poor prognosis in human cancers and may be an independent prognostic predictive biomarker. Further studies should be performed to confirm the significance of TROP2 in clinical practice. PMID- 29276406 TI - Observation of different tumor motion magnitude within liver and estimate of internal motion margins in postoperative patients with hepatocellular carcinoma. AB - Aims: To assess motion magnitude in different parts of the liver through surgical clips in postoperative patients with hepatocellular carcinoma and to examine the correlation between the clip and diaphragm motion. Methods: Four-dimensional computed tomography images from 30 liver cancer patients under thermoplastic mask immobilization were selected for this study. Three to seven surgical clips were placed in the resection cavity of each patient. The liver volume on computed tomography image was divided into the right upper (RU), right middle (RM), right lower (RL), hilar, and left lobes. Agreement between the clip and diaphragm motion was assessed by calculating intraclass correlation coefficient, and Bland Altman analysis (Diff). Furthermore, population-based and patient-specific margins for internal motion were evaluated. Results: The clips located in the RU lobe showed the largest motion, (7.5+/-1.6) mm, which was significantly more than in the RM lobe (5.7+/-2.8 mm, p=0.019), RL lobe (4.8+/-3.3 mm, p=0.017), and hilar lobe (4.7+/-2.7 mm, p<0.001) in the cranial-caudal direction. The mean intraclass correlation coefficient values between the clip and diaphragm motion were 0.915, 0.735, 0.678, 0.670, and the mean Diff values between them were 0.1+/ 0.8 mm, 2.3+/-1.4 mm, 3.1+/-2.0 mm, 2.4+/-1.5 mm, when clips were located in the RU lobe, RM lobe, RL lobe, and hilar lobe, respectively. The clip and diaphragm motions had high concordance when clips were located in the RU lobe. Internal margin can be reduced from 5 mm in the cranial-caudal direction based on patient population average and to 3 mm based on patient-specific margins. Conclusions: The motion magnitude of clips varied significantly depending on their location within the liver. The diaphragm was a more appropriate surrogate for tumor located in the RU lobe than for other lobes. PMID- 29276407 TI - Systemic immune-inflammation index as a useful prognostic indicator predicts survival in patients with advanced gastric cancer treated with neoadjuvant chemotherapy. AB - Background and objective: A novel systemic immune-inflammation index named SII (SII=N*P/L), which is based on neutrophil (N), platelet (P) and lymphocyte (L) counts, has emerged and reflects comprehensively the balance of host inflammatory and immune status. We aimed to evaluate the potential prognostic significance of SII in patients with advanced gastric cancer who received neoadjuvant chemotherapy. Subjects and methods: The retrospective analysis included data from 107 patients with advanced gastric cancer undergoing neoadjuvant chemotherapy and 185 patients with pathology-proven gastric cancer. The optimal cutoff value of SII by receiver operating characteristic curve stratified patients into low SII (<600*109/L) and high SII (SII >=600*109/L) groups. The clinical outcomes of disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan Meier survival curves and compared using log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic value of SII. Results: The results indicated that SII had prognostic significance using the cutoff value of 600*109/L on DFS and OS in univariate and multivariate Cox regression survival analyses. Low SII was associated with prolonged DFS and OS, and the mean DFS and OS for patients with low SII were longer than for those with high SII (57.22 vs 41.56 months and 62.25 vs 45.60 months, respectively). Furthermore, we found that patients with low SII had better 1-, 3- and 5-year rates of DFS and OS than those with high SII. In addition, patients with low SII were likely to receive DFS and OS benefits from neoadjuvant chemotherapy and postoperative chemotherapy. Conclusion: SII may qualify as a noninvasive, cost-effective, convenient and reproducible prognostic indicator for patients with advanced gastric cancer undergoing neoadjuvant chemotherapy. It may help clinicians to identify those patients who will benefit from treatment strategy decisions. PMID- 29276408 TI - ZNF259 inhibits non-small cell lung cancer cells proliferation and invasion by FAK-AKT signaling. AB - Background: Zinc finger protein 259 (ZNF259) is known to play essential roles in embryonic development and cell cycle regulation. However, its expression pattern and clinicopathological relevance remain unclear. Materials and methods: A total of 114 lung cancer specimens were collected. The ZNF259 expression was measured between the lung cancer tissues and the adjacent normal lung tissues by immunohistochemical staining and Western blotting. Moreover, the correlation of ZNF259 expression with clinicopathological features was analyzed in 114 cases of lung cancer. Additionally, ZNF259 was depleted in the lung cancer cells in order to analyze its effect in the lung cancer. Results: Immunohistochemical staining of 114 lung cancer specimens revealed significantly lower ZNF259 expression in lung cancer tissues than in adjacent normal lung tissues (53.5% vs 71.4%, P<0.001). In addition, ZNF259 downregulation was significantly associated with larger tumor size (P=0.001), advanced TNM stage (P=0.002), and positive lymph node metastasis (P=0.02). Western blotting of 20 paired lung cancer samples revealed lower ZNF259 protein levels in lung cancer tissues than in those of corresponding normal lung tissues (P=0.0032). Depletion of ZNF259 resulted in enhanced levels of p-FAK and p-AKT, CyclinD1, and MMP2, which in turn increased the proliferation and invasion of lung cancer cells. The effects of ZNF259 depletion were reversed by treatment with specific FAK or AKT inhibitors. Conclusion: ZNF259 depletion is correlated with the development of non-small cell lung cancer (NSCLC) and serves as a predictor of adverse clinical outcome in NSCLC patients. The inhibitory effect of ZNF259 on proliferation and invasion can be attributed to downregulation of CyclinD1 and MMP2 via inactivation of the FAK AKT pathway. PMID- 29276409 TI - Expression profile analysis of long noncoding RNA in ER-positive subtype breast cancer using microarray technique and bioinformatics. AB - Background: The estrogen receptor (ER)-positive subtype of breast cancer (BC) is the most common type of BC. A number of long noncoding RNAs (lncRNAs) play critical roles in cancer biology, including BC. Previous lncRNA profiling studies have focused only on triple-negative BC and HER 2-positive BC, and no studies have specifically focused on lncRNAs in ER-positive BC. In this study, we analyzed the expression profile of the lncRNAs and mRNAs found in this particular subtype of BC for the first time. Methods: We evaluated lncRNA microarray data from four pairs of primary BC and adjuvant nontumor breast tissues. Then, we screened out the differently expressed genes and measured the correlation of the expression levels of lncRNAs and ERalpha by Pearson's correlation coefficient analysis. We also performed classification and length distribution of the dysregulated lncRNAs. KEGG pathway analysis was used to understand the biological roles of these differently expressed genes. lncRNA-mRNA coexpression networks were constructed. Finally, RT-PCR was employed to validate the microarray analysis findings. Results: We screened out 2,178 differently expressed lncRNAs, and 13 lncRNAs were found to be associated with the ER expression level. Classification analysis showed that most lncRNAs belonged to intergenic lncRNA and were from 400 to 800 nt in length. Chromosome distribution showed that many of the lncRNAs were mapped to chromosome 1. In the pathway analysis, most of the genes were related to cancer-associated behaviors, such as p53 signaling pathway, cell cycle, focal adhesion, and ECM-receptor interaction. lncRNA-mRNA coexpression networks were constructed, and the lncRNAs related to ESR1, BRCA1, and BRCA2 in the two groups were significantly different. The RT-PCR results were consistent with the data obtained from the microarrays. Conclusion: These results provide useful information for exploring potential novel biomarkers as diagnosis and therapy targets for the clinical treatment of ER-positive BC. PMID- 29276410 TI - Clinical course of nonalcoholic fatty liver disease: an assessment of severity, progression, and outcomes. AB - Purpose: To identify the characteristics and initial disease severity of patients with nonalcoholic fatty liver disease (NAFLD) and assess incidence and risk factors for disease progression in a retrospective study. Methods: Patients >=18 years of age without alcoholism or other liver diseases (eg, hepatitis B/C) were selected from Geisinger Health System electronic medical record data from 2004 to 2015. Initial disease stage was stratified into uncomplicated NAFLD, advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver transplant using clinical biomarkers, diagnosis, and procedure codes. Disease progression was defined as stage progression or death and analyzed via Kaplan-Meier plots and multistate models. Results: In the NAFLD cohort (N=18,754), 61.5% were women, 39.0% had type 2 diabetes mellitus (T2DM), and the mean body mass index was 38.2+/-10.2 kg/m2. At index, 69.9% had uncomplicated NAFLD, 11.7% had advanced fibrosis, and 17.8% had cirrhosis. Of 18,718 patients assessed for progression, 17.3% progressed (11.0% had stage progression, 6.3% died without evidence of stage progression) during follow-up (median=842 days). Among subgroups, 12.3% of those without diabetes mellitus progressed vs 24.7% of those with T2DM. One-year mortality increased from 0.5% in uncomplicated NAFLD to 22.7% in HCC. After liver transplant, mortality decreased to 5.6% per year. Conclusions: In 2.3 years of follow-up, approximately 17% of patients progressed or died without evidence of stage progression. T2DM was associated with approximately twice the risk of disease progression, and mortality risk increased with disease stage. Early diagnosis and monitoring of disease progression, especially in patients with T2DM, is warranted. PMID- 29276411 TI - The use of random-effects models to identify health care center-related characteristics modifying the effect of antipsychotic drugs. AB - Purpose: A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level. Patients and methods: Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist's gender, age, length of practice experience, practice setting and type, countries' Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1) to estimate antipsychotic drugs' effectiveness (defined as the association between patients' outcome at 3 months - dependent variable, continuous - and antipsychotic drug initiation at baseline - drug A vs other antipsychotic drug); 2) to estimate the similarity between clustered data (using the intra-cluster correlation coefficient); and 3) to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term). Results: About 23% of the variance found for patients' outcome was explained by unmeasured confounding at a center level. Psychiatrists' practice experience was found to be associated with patient outcomes (p=0.04) and modified the relative effect of "drug A" (p<0.001), independent of center- or patient-related characteristics. Conclusion: Mixed models may be useful to explore how center-related characteristics modify drugs' effect estimates, but require numerous assumptions. PMID- 29276413 TI - Psychological burden among women with polycystic ovarian syndrome in Oman: a case control study. AB - Purpose: Previous studies in Euro-American populations have shown that women with polycystic ovarian syndrome (PCOS) have increased levels of "psychological burden". While PCOS has been reported in Arab countries such as Oman, there is a dearth of studies of the occurrence of psychological burden among PCOS women in the Arab region. This study aimed to compare sociodemographic and clinical characteristics of PCOS women diagnosed with non-PCOS women and prevalence of severity of depression, anxiety and stress and to explore the association between PCOS and indices of psychological disturbances after adjusting for potential confounding factors. Patients and methods: This hospital-based case-control study was conducted among women aged 16-49 years. The study included 52 women diagnosed with PCOS (as per Rotterdam 2003 criteria) and 60 control who were PCOS-free. The presence of psychological burden - depression, anxiety and stress - was quantified using Depression, Anxiety and Stress Scale-21 (DASS-21). Results: The crude odds ratios (ORs) generated by logistic regression models indicated an increased risk of depression, anxiety and stress among women with PCOS compared to controls. The adjusted OR also indicated an increased risk of depression (OR =1.10; 95% confidence interval [CI] 0.50, 2.43), anxiety (OR =1.09; 95% CI 0.47, 2.52) and stress (OR =1.45; 95% CI 0.68, 3.12), However, no statistical differences were observed along the three psychological distresses (p>0.05) between the two study groups. Conclusion: The study indicates that the presence of PCOS is associated with an increased risk of psychological burden. If this study will withstand further scrutiny, meeting psychological needs of such population would need to be contemplated. PMID- 29276412 TI - Association between coffee or caffeine consumption and fecundity and fertility: a systematic review and dose-response meta-analysis. AB - Objective: The aim was to investigate whether coffee or caffeine consumption is associated with reproductive endpoints among women with natural fertility (ie, time to pregnancy [TTP] and spontaneous abortion [SAB]) and among women in fertility treatment (ie, clinical pregnancy rate or live birth rate). Design: This study was a systematic review and dose-response meta-analysis including data from case-control and cohort studies. Methods: An extensive literature search was conducted in MEDLINE and Embase, with no time and language restrictions. Also, reference lists were searched manually. Two independent reviewers assessed the manuscript quality using the Newcastle-Ottawa Scale (NOS). A two-stage dose response meta-analysis was applied to assess a potential association between coffee/caffeine consumption and the outcomes: TTP, SAB, clinical pregnancy, and live birth. Heterogeneity between studies was assessed using Cochrane Q-test and I2 statistics. Publication bias was assessed using Egger's regression test. Results: The pooled results showed that coffee/caffeine consumption is associated with a significantly increased risk of SAB for 300 mg caffeine/day (relative risk [RR]: 1.37, 95% confidence interval [95% CI]: 1.19; 1.57) and for 600 mg caffeine/day (RR: 2.32, 95% CI: 1.62; 3.31). No association was found between coffee/caffeine consumption and outcomes of fertility treatment (based on two studies). No clear association was found between exposure to coffee/caffeine and natural fertility as measured by fecundability odds ratio (based on three studies) or waiting TTP (based on two studies). Conclusion: Results from this meta-analysis support the growing evidence of an association between coffee/caffeine intake and the risk of SAB. However, viewing the reproductive capacity in a broader perspective, there seems to be little, if any, association between coffee/caffeine consumption and fecundity. In general, results from this study are supportive of a precautionary principle advised by health organizations such as European Food Safety Authority (EFSA) and World Health Organization (WHO), although the advised limit of a maximum of two to three cups of coffee/200 300 mg caffeine per day may be too high. PMID- 29276414 TI - Perceptions and practice of epidural analgesia among women attending antenatal clinic in FETHA. AB - Background: The pain of childbirth is arguably the most severe pain that most women will endure in their lifetime. Epidural analgesia is widely used as an effective method of pain relief in labor. It provides almost complete relief of pain if administered timely, and does not affect the progress of the first stage labor. Objectives: The objective of this study was to determine the awareness and utilization of epidural analgesia in labor in pregnant women attending the antenatal clinic at Federal Teaching Hospital, Abakaliki (FETHA). Methodology: This is a cross-sectional study involving 350 women attending the antenatal clinic between April 2016 and July 2016. A total of 335 questionnaires were correctly completed, and used for analysis. Results: The average age and parity of the respondents were 27.6+/-8.2 years and 2.4+/-1.8, respectively. About 58.2% of respondents were civil servants, 98.5% were married, and 74.6% had a tertiary level of education. About 43.3% of the respondents are aware of the use of epidural analgesia in labor, but only 7.5% had used it; 95% of these were satisfied and desired to use it again. The reasons responsible for the poor uptake were desire to experience natural labor, cost, and fear of side effects. However, 70% of those who had not used it expressed the desire to use it. Conclusion: Epidural analgesia is one of the most effective methods of pain relief in labor. However, the present study indicates that knowledge and practice of epidural analgesia among parturients are low. Efforts should be made to raise awareness, dispel misconceptions, and subsidize the cost of providing this invaluable care in modern day obstetrics. PMID- 29276415 TI - CRTH2 antagonists in asthma: current perspectives. AB - Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) binds to prostaglandin D2. CRTH2 is expressed on various cell types including eosinophils, mast cells, and basophils. CRTH2 and prostaglandin D2 are involved in allergic inflammation and eosinophil activation. Orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. The biology and clinical trial data indicate that CRTH2 antagonists should be targeted toward eosinophilic asthma. This article reviews the clinical evidence for CRTH2 involvement in asthma pathophysiology and clinical trials of CRTH2 antagonists in asthma. CRTH2 antagonists could provide a practical alternative to biological treatments for patients with severe asthma. Future perspectives for this class of drug are considered, including the selection of the subgroup of patients most likely to show a meaningful treatment response. PMID- 29276416 TI - Impact of lowering ski binding settings on the outcome of the self-release test of ski bindings among female recreational skiers. AB - Background and purpose: The ability to successfully self-release the ski binding can prevent skiing-related injuries of the lower extremities. Failure of binding release associated with a knee injury is significantly higher among females compared to males. The International Standards Organization ISO 11088 standard for binding setting values allows a lowering by 15% upon request of the skier. Thus, the aim of this study was to evaluate the impact of lowered ski binding settings by 15% on the outcome of the self-release test among female recreational skiers. Materials and methods: In this randomized single-blinded study, a cohort of 20 females (24.5+/-2.7 years) performed the self-release test in the laboratory thrice with each leg under two conditions: 1) with an actual ISO 11088 setting and 2) with a setting lowered by 15%. For each attempt, torques calculated via the force plate were normalized to torques measured by a binding adjustment system (relative release torque, RRT). Results: Among 240 trials in total, more females were significantly able to self-release their ski bindings with lowered binding settings when compared to their actual ISO settings (53% vs 9%, p<0.001). Thirteen females (65%) were able to release their bindings at least once with both legs with lowered binding settings compared to only three females (15%) with their actual binding settings (p<0.001). Mean RRT of all failure of binding release trials significantly differed between lowered and actual binding settings (58.6%+/-22.2% vs 50.5%+/-20.4%, p=0.003). Conclusion: Four times more females were able to self-release their ski bindings at least once with both legs with a 15% lowered binding setting compared to their normal ISO 11088 setting. The fact that the ISO standard accepts a lowering by 15% upon request of the skier could represent an important measure to prevent knee injuries, especially for female recreational skiers. PMID- 29276417 TI - Bevacizumab in the treatment of NSCLC: patient selection and perspectives. AB - Non-small-cell lung cancer (NSCLC) represents about 85% of all lung cancers, and more than half of NSCLCs are diagnosed at an advanced stage. Chemotherapy has reached a plateau in the overall survival curve of about 10 months. Therefore, in last decade novel targeted approaches have been developed to extend survival of these patients, including antiangiogenic treatment. Vascular endothelial growth factor (VEGF) signaling pathway plays a dominant role in stimulating angiogenesis, which is the main process promoting tumor growth and metastasis. Bevacizumab (bev; Avastin(r)) is a recombinant humanized monoclonal antibody that neutralizes VEGF's biologic activity through a steric blocking of its binding with VEGF receptor. Currently, bev is the only antiangiogenic agent approved for the first-line treatment of advanced or recurrent nonsquamous NSCLC in "bev eligible" patients. The ineligibility to receive bev is related to its toxicity. In the pivotal trials of bev in NSCLC, fatal bleeding events including pulmonary hemorrhage were observed with rates higher in the chemotherapy-plus-bev group. Therefore, in order to reduce the incidence of severe pulmonary hemorrhage, numerous exclusion criteria have been characteristically applied for bev such as central tumor localization or tumor cavitation, use of anticoagulant therapy, presence of brain metastases, age of patients (elderly). Subsequent studies designed to evaluate the safety of bev have demonstrated that this agent is safe and well tolerated even in those patients subpopulations excluded from pivotal trials. This review outlines the current state-of-the-art on bev use in advanced NSCLC. It also describes patient selection and future perspectives on this antiangiogenic agent. PMID- 29276418 TI - Peripheral Artery Occlusive Disease Among Patients With Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors: A Cross-Sectional Case-Control Study. AB - Background: There were some reports of peripheral artery occlusive disease (PAOD) associated with nilotinib usage in chronic myeloid leukemia (CML). These complications in other tyrosine kinase inhibitors are revealed as unknown. Materials and methods: We determined the prevalence of PAOD in patients with CML as compared with matched-control population by cross-sectional case-control study. Peripheral artery occlusive disease was screened by ankle-brachial index (ABI). Results: In total, 78 CML and 156 matched-control patients were included. The median age was 55 years. In all, 61 (78.2%) were on imatinib and 13 (16.7%) were on nilotinib, whereas 4 patients (5.2%) were on dasatinib. Prevalence of low ABI (<0.9) was 9.0%, and nilotinib users had the highest prevalence of low ABI of 30.7%. All cases with low ABI were not shown to be clinically overt of PAOD. There were well-balanced characteristics between cases of CML and matched control except in higher levels of hypercholesterolemia in the control. Interestingly, CML had more amounts of pathologic ABI than the control (odds ratio: 2.09, 95% confidence interval: 0.71-6.21), and diagnosis of diabetes found it to be independent of the risk of PAOD. Conclusions: Peripheral artery occlusive disease was higher among patients with CML than the control, especially in patients who had diabetes. PMID- 29276419 TI - Lessons From Unilateral Loss of Cilia: Early Nasal Nitric Oxide Gas Mixing and the Role of Sinus Patency in Determining Nasal Nitric Oxide. AB - Nasal nitric oxide (nNO) measurement is a diagnostic test for primary ciliary dyskinesia (PCD). Here, we have shown the development of unilateral PCD-like symptoms associated with low nNO. A 60-year-old man had been previously healthy but developed unilateral, severe pansinusitis. He required surgical drainage of all left sinuses, and biopsies showed loss of the ciliated epithelium. At 4 weeks, he had unilateral (left-sided), profuse, clear rhinorrhea characteristic of PCD, and his surgical ostia were all patent endoscopically. His left-sided nNO was less than the right side by 37 +/- 1.2 nL/min; this difference decreased to 18 +/- 0.87 nL/min at 5 weeks and was gone by 6 weeks when his symptoms resolved. Measurements of 2- and 10-second measurements, in addition to standard nNO measurements, identified this discordance. We conclude that nNO reflects, in part, the production of NO by the ciliated epithelium, not just in the absence or occlusion of sinuses. Early (nasal/sinus volume) measures may be better for diagnosing PCD in than standard, steady-state assays in certain populations. PMID- 29276420 TI - Effects of Minerva Orthosis on Larynx Height in Young, Healthy Volunteers. AB - Background: During speech, larynx is higher in the neck for high-pitched sounds and lower for low-pitched sounds. Patients with different problems in cervical and cervicothoracic spine use cervical orthosis to limit cervical motion. This study aimed to evaluate the effects of Minerva orthosis on larynx height in young, healthy volunteers. Subjects and methods: This study included 18 subjects. Acoustic measurement of frequency variability has been assessed in 3 brace conditions: (1) without brace, (2) with brace, and (3) 30 minutes after wearing the brace. Results: Several statistically significant differences were found in the comparison between Minerva and 30 minutes after Minerva. Conclusion: When planning cervical orthosis treatment, it is important to consider the reduction in larynx height that may result from bracing for those who are already at risk of developing dysphagia and dysphonia. PMID- 29276421 TI - Adaptive Returns of Deficient Systemic Plasma Immunoglobulin G Levels as Rehabilitation Biomarker After Emergency Colectomy for Fulminant Ulcerative Colitis. AB - Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for ulcerative colitis (UC). Emergency colectomies are performed for fulminant colitis (ie, toxic megacolon, profuse bleeding, perforation, or sepsis). The RPC and IPAA involve manipulation of the proximal ileum, which may influence the essential physiological function of gut-associated lymphoid tissues. Circulating plasma immunoglobulin G (p-IgG) deficiency is observed in patients with fulminant UC. In addition, increased levels have been reported in colonic tissues of active UC compared with quiescent disease. We aimed to examine levels of p-IgG for clinical evaluation following emergency colectomies in patients with fulminant UC compared with patients with quiescent disease having elective RPC operations. In total 45 patients received an ileoanal pouch (IAP) due to UC. In all, 27 patients were men and 18 were women. The mean age was 34 years (range: 18-55). Because of fulminant UC, 26 patients had emergency subtotal colectomies with terminal ileostomy (TI). During second operation, the rectum was excised, and an IAP with diverting loop ileostomy (DLI) was performed. Nineteen patients had elective operations and had colectomies performed in conjunction with the pouch operation. Mucosectomy was performed in all groups. As a last procedure, the DLI was closed. Blood samples for immunoglobulin G (IgG) analyses were collected from each patient before the colectomy, after the colectomy with TI (before construction of the pouch), during the period with pouches (prior to DLI closure), and at 1, 2, and 3 years and at mean 13.7 years (range: 10-20) after DLI closure. Immunoglobulin G was determined by immunonephelometric assay technique. The statistics were analyzed by analysis of variance and linear regression. Preoperatively, p-IgG was significantly lower in the patients who had emergency operations compared with the group that had elective operations, 9.9 +/- 3.0 vs 11.5 +/- 3.3 g/L (P < .03). During the manipulative period with TI and/or DLI, the p-IgG levels were increased in both points, but the increase was not statistically significant (P = .26 and P = .19). During functional IAP at 1, 2, and 3 years and at mean 13.7 years (range: 10-20), there was a statistical increase in p-IgG levels (P < .002, P < .005, P < .005, and P < .0001) compared with preoperative levels. These changes did not correlate with episodes of pouchitis (P = .51). In patients having elective operations, p IgG did not change preoperatively. After 12 months with functional pouches, the p IgG levels were similar in both groups to the elective patient group preoperatively. In conclusion, p-IgG was found to be significantly lower in the emergency surgery patients compared with the elective surgery group preoperatively. This difference was probably due to increased losses and impaired gut lymphoid tissue production of IgG in the acute fulminant phase of UC. After 12 months of DLI closure, significant differences were no longer found between the emergency and elective surgery groups. Restoration and increased p-IgG levels after RPC would be due to an exaggerated response to make up for lower precolectomy values and may be interpreted as a rehabilitation biomarker. PMID- 29276422 TI - Incidence and Predictors of Mortality Among Newborns With Perinatal Asphyxia: A 4 Year Prospective Study of Newborns Delivered in Health Care Facilities in Enugu, South-East Nigeria. AB - Fatalities from perinatal asphyxia remain high in developing countries, and continually assessing its risk factors will help improve outcomes in these settings. We explored how some identified risk factors predict mortality in asphyxiated newborns, to assist clinicians in prioritizing interventions. This was a 4-year prospective study conducted at the Enugu State University Teaching Hospital, Enugu, Nigeria. All newborns who met the study criteria that were admitted to this facility in this period were enrolled and monitored. Data collected were analysed with SPSS Version 18. A total of 161 newborns with perinatal asphyxia were enrolled into the study with an in-hospital incidence rate of 12.81 per 1000 birth and a case fatality rate of 18%. Overall, the APGAR scores were severe in 10%, moderate in 22%, mild to normal in 68%, whereas the SARNAT stages were III in 24%, II in 52%, and I in 25%. In terms of mortality, 66.7%, 22.2%, and 11.1% mortalities were, respectively, observed with SARNAT scores III, II, and I (P = .003), whereas the findings with APGAR were 31.2% (severe), 25.0% (moderate), 25.0% (mild), and 18.8% (normal) (P = .030). Fatality outcome was more correlated with SARNAT (R = .280; P = .000) than APGAR (R = .247; P = .0125). The SARNAT score significantly differentiated between the degrees of asphyxia in newborns based on gestational age at delivery (P = .010), place of delivery (P = .032), and mode of delivery (P = .042). Finally, it was noted that newborns that were female (P = .007), or born outside the hospital (P = .010), or with oxygen saturations <60% (P = .001), or with heart rate <120 (P = .000), and those with respiratory rate <30 (P = .003), all have significantly higher likelihood of deaths from asphyxia. Therefore, predictors of neonatal mortality from perinatal asphyxia in our centre include being female and being born outside the hospital, as well as low oxygen saturations, heart rates, and respiratory rates at presentation. PMID- 29276423 TI - Hypoglycemia: When to Treat? AB - Hypoglycemia is the most common metabolic disorder encountered in neonates. The definition of hypoglycemia as well as its clinical significance and management remain controversial. Most cases of neonatal hypoglycemia are transient, respond readily to treatment, and are associated with an excellent prognosis. Persistent hypoglycemia is more likely to be associated with abnormal endocrine conditions, such as hyperinsulinemia, as well as possible neurologic sequelae. Manifestations of hypoglycemia include seizures which can result in noteworthy neuromorbidity in the long haul. Thus, hypoglycemia constitutes a neonatal emergency which requires earnest analytic assessment and prompt treatment. In this review, we have tried to cover the pathophysiology, the screening protocol for high-risk babies, management, long-term neurologic sequelae associated with neonatal hypoglycemia, with evidence-based answers wherever possible, and our own practices. PMID- 29276424 TI - Are they ready? Organizational readiness for change among clinical teaching teams. AB - Introduction: Curriculum change and innovation are inevitable parts of progress in postgraduate medical education (PGME). Although implementing change is known to be challenging, change management principles are rarely looked at for support. Change experts contend that organizational readiness for change (ORC) is a critical precursor for the successful implementation of change initiatives. Therefore, this study explores whether assessing ORC in clinical teaching teams could help to understand how curriculum change takes place in PGME. Methods: Clinical teaching teams in hospitals in the Netherlands were requested to complete the Specialty Training's Organizational Readiness for curriculum Change, a questionnaire to measure ORC in clinical teaching teams. In addition, change related behavior was measured by using the "behavioral support-for-change" measure. A two-way analysis of variance was performed for all response variables of interest. Results: In total, 836 clinical teaching team members were included in this study: 288 (34.4%) trainees, 307 (36.7%) clinical staff members, and 241 (28.8%) program directors. Overall, items regarding whether the program director has the authority to lead scored higher compared with the other items. At the other end, the subscales "management support and leadership," "project resources," and "implementation plan" had the lowest scores in all groups. Discussion: The study brought to light that program directors are clearly in the lead when it comes to the implementation of educational innovation. Clinical teaching teams tend to work together as a team, sharing responsibilities in the implementation process. However, the results also reinforce the need for change management support in change processes in PGME. PMID- 29276425 TI - Application of active learning modalities to achieve medical genetics competencies and their learning outcome assessments. AB - The steadily falling costs of genome sequencing, coupled with the growing number of genetic tests with proven clinical validity, have made the use of genetic testing more common in clinical practice. This development has necessitated nongeneticist physicians, especially primary care physicians, to become more responsible for assessing genetic risks for their patients. Providing undergraduate medical students a solid foundation in genomic medicine, therefore, has become all the more important to ensure the readiness of future physicians in applying genomic medicine to their patient care. In order to further enhance the effectiveness of instructing practical skills in medical genetics, the emphasis of active learning modules in genetics curriculum at medical schools has increased in recent years. This is because of the general acceptance of a better efficacy of active learner-centered pedagogy over passive lecturer-centered pedagogy. However, an objective standard to evaluate students' skill levels in genomic medicine achieved by active learning is currently missing. Recently, entrustable professional activities (EPAs) in genomic medicine have been proposed as a framework for developing physician competencies in genomic medicine. EPAs in genomic medicine provide a convenient guideline for not only developing genomic medicine curriculum but also assessing students' competency levels in practicing genomic medicine. In this review, the efficacy of different types of active learning modules reported for medical genetics curricula is discussed using EPAs in genomic medicine as a common evaluation standard for modules' learning outcomes. The utility of the EPAs in genomic medicine for designing active learning modules in undergraduate medical genetics curricula is also discussed. PMID- 29276426 TI - The Light at the End of the Tunnel-Second Generation HPMA Conjugates for Cancer Treatment. AB - It is almost four decades since N-(2-hydroxypropyl)methacrylamide (HPMA) - based copolymers arose as drug carriers. Although fundamentals have been established and significant advantages have been proved, the commercialization of this platform technology was hampered due to modest outcome of clinical trial initiated with PK1, the symbol of first generation polymer-drug conjugates. In this review, we illustrate the exciting progress and approaches offered by more effective 2nd generation HPMA-based polymer-drug conjugates in cancer treatment. For example, a new synthetic strategy endorses inert HPMA polymer with biodegradability, which permitted to prepare high molecular weight HPMA-drug conjugates with simple linear architecture while maintaining good biocompatibility. As expected, extended long-circulating pharmacokinetics and enhanced antitumor activities were achieved in several preclinical investigations. In addition, greater inhibition of tumor growth in combination regimes exhibits the remarkable capability and flexibility of HPMA-based macromolecular therapeutics. The review also discusses the main challenges and strategies for further translation development of 2nd generation HPMA-based polymer-drug conjugates. PMID- 29276427 TI - Quantitative imaging of deuterated metabolic tracers in biological tissues with nanoscale secondary ion mass spectrometry. AB - In the field of secondary ion mass spectrometry at nanometer scale (NanoSIMS), configuration of parallel detectors to routinely measure isotope ratios in sub 100 nm domains brings classical stable isotope tracer studies from the whole tissue level down to the suborganelle level. Over the past decade, the marriage of stable isotope tracers with NanoSIMS has been applied to a range of fundamental biological questions that were largely inaccessible by other means. Although multiplexed measurement of different stable isotope tracers is feasible, in practice there remains a gap in the current analytical capacity to efficiently measure stable isotopes commonly utilized in tracer studies. One such example is the measurement of deuterated tracers. The most obvious approach to measuring deuterium/hydrogen isotope ratios is at mass 2/1. However, the radius of the magnetic sector limits concomitant measurement of other masses critical to multiplexed exploration of biological samples. Here we determine the experimental parameters to measure deuterated tracers in biological samples using the C2H- polyatomic ion species (C2D-/C2H-) while operating the NanoSIMS at a reduced Mass Resolving Power of 14,000. Through control of the sputtering parameters, we demonstrate that there is an analytical window during which the C2D-/C2H- isotope ratio can be measured with sufficient precision for biological studies where the degree of D-labeling is typically well above natural abundance. We provide validation of this method by comparing the C2D measurement of D-water labeling in the murine small intestine relative to measurements of native D/H conducted in the same analytical fields. Additional proof-of-concept demonstrations include measurement of D-water, D-glucose, and D-thymidine in biological specimens. Therefore, this study provides a practical template for deuterium-based tracer studies in biological systems. PMID- 29276428 TI - Tetraquark and two-meson states at large [Formula: see text]. AB - Considering four-point correlation functions of color-singlet quark bilinears, we investigate, in the large-[Formula: see text] limit of QCD, the subleading diagrams that involve, in the s-channel of meson-meson scattering amplitudes, two quark-two-antiquark intermediate states. The latter contribute, together with gluon exchanges, to the formation, at the hadronic level, of two-meson and tetraquark intermediate states. It is shown that the two-meson contributions, which are predictable, in general, from leading-order [Formula: see text] behaviors, consistently satisfy the constraints resulting from the [Formula: see text] expansion procedure and thus provide a firm basis for the extraction of tetraquark properties from [Formula: see text]-subleading diagrams. We find that, in general, tetraquarks, if they exist in compact form, should have narrow decay widths, of the order of [Formula: see text]. For the particular case of exotic tetraquarks, involving four different quark flavors, two different types of tetraquark are needed, each having a preferred decay channel, to satisfy the consistency constraints. PMID- 29276429 TI - Prospects for the Comparative Study of International Migration using quasi longitudinal micro-data. AB - BACKGROUND: Longitudinal micro-level data about international migration behavior are notoriously difficult to collect, but data collection efforts have become more frequent in recent years. Comparative research of the patterns and processes of international migration, however, remains quite rare, especially that which compares across regions. OBJECTIVE: We highlight the promises and difficulties of comparative international migration research, by offering a detailed comparison of two prominent data collection efforts. METHODS: We systematically review existing sources of longitudinal and quasi-longitudinal individual-level and household-level data of international migration. We then compare two widely-used data sources: the Mexican Migration Project (MMP) and the Migration between Africa and Europe project (MAFE). RESULTS: Data collection efforts are increasingly diverse, yet public accessibility of data remains limited. Also, comparability of data collected across settings can be complicated. In our MMP MAFE analysis, we show some ways in which comparability can be achieved. CONCLUSIONS: A primary roadblock to international comparative research is that, with some exceptions, the public accessibility of data remains low. Even when data is public and surveys are modeled after one another, comparability is not easy due to necessary trade-offs in adapting surveys to local settings and to developments in the field. CONTRIBUTION: We demonstrate that, despite great strides in collecting quasi-longitudinal data of international migration, data accessibility still hinders the study of migration. With regards to comparability, our article provides important lessons for future data collection and analysis efforts that could improve comparability and thus advance understanding of the complex dynamics of international migration. PMID- 29276430 TI - Young adults' reasons for dropout from residential substance use disorder treatment. AB - Dropout from substance use disorder treatment is usually investigated and understood from a perspective of quantitative patient-related factors. Patients' own perspectives (user perspective) are rarely reported. This study, therefore, aimed to explore patients' own understanding of their dropout from residential substance use disorder treatment. The participants were 15 males and females, aged 19-29 years, who had dropped out of residential substance use disorder treatment at the Department of Addiction Treatment, Oslo University Hospital, Norway. Qualitative methodology with semistructured interviews was used to explore how the participants described their dropout and their reasons for doing so. Thematic analysis was used as the framework for analyzing the data derived from the interviews. Dropout had different meanings for different participants. It was understood as a break from treatment, as an end to treatment, or as a means of reduced treatment intensity. Against that background, four main themes for dropout were found: drug craving, negative emotions, personal contact, and activity. Patient and treatment factors seem to interact when participants explore reasons for their dropout. A complex pattern of variables is involved. As remedies, participants suggested that substance use disorder treatment should provide more focus on drug craving and training to understand and tolerate emotional discomfort. They also wanted closer contact with the staff during treatment, more activities, and rigorous posttreatment follow-up. These findings from the user perspective have important implications for substance use disorder treatment, clinical and social work practice, management, and research. PMID- 29276431 TI - Making home visits: Creativity and the embodied practices of home visiting in social work and child protection. AB - Although the home is the most common place where social work goes on, research has largely ignored the home visit. Drawing on a participant observation study of child protection work, this article reveals the complex hidden practices of social work on home visits. It is argued that home visits do not simply involve an extension of the social work organisation, policies and procedures into the domestic domain but the home constitutes a distinct sphere of practice and experience in its own right. Home visiting is shown to be a deeply embodied practice in which all the senses and emotions come into play and movement is central. Through the use of creativity, craft and improvisation practitioners 'make' home visits by skilfully enacting a series of transitions from the office to the doorstep, and into the house, where complex interactions with service users and their domestic space and other objects occur. Looking around houses and working with children alone in their bedrooms were common. Drawing upon sensory and mobile methods and a material culture studies approach, the article shows how effective practice was sometimes blocked and also how the home was skilfully negotiated, moved around and creatively used by social workers to ensure parents were engaged with and children seen, held and kept safe. PMID- 29276432 TI - Animal Assisted Interactions to Alleviate Psychological Symptoms in Patients on Mechanical Ventilation. AB - Mechanical ventilation is a common life support intervention for critically ill patients that can cause stressful psychological symptoms. Animal assisted interactions have been used in variety of inpatient settings to reduce symptom burden and promote overall well-being. Due to the severity of illness associated with critical care, use of highly technological equipment, and heightened concern for infection control and patient safety, animal-assisted interaction has not been widely adopted in the intensive care unit. This case study of the therapeutic interaction between a canine and a mechanically ventilated patient provides support for the promotion of animal-assisted interactions as an innovative symptom management strategy in the intensive care unit. PMID- 29276433 TI - Cell-based approaches for augmentation of tendon repair. AB - Cell-based approaches are among the principal interventions in orthobiologics to improve tendon and ligament healing and to combat degenerative processes. The number of options available for investigation are expanding rapidly and investigators have an increasing number of cell types to choose from for research purposes. However, in part due to the current regulatory environment, the list of available cells at clinicians' disposal for therapeutic purposes is still rather limited. In this review, we present an overview of the main cellular categories in current use. Notable recent developments in cell-based approaches include the introduction of diverse sources of mesenchymal stem cells, pluripotent cells of extra-embryonic origin, and the emerging popularity of fully differentiated cells such as tenocytes and endothelial cells. Delivery strategies are discussed and a succinct discussion of the current regulatory environment in the United States is presented. PMID- 29276434 TI - A Blueprint for Life and Love. PMID- 29276435 TI - Lou Gehrig and Ed Todd: Greatness Interrupted. PMID- 29276436 TI - Serum MicroRNA-27b as a Screening Biomarker for Left Ventricular Hypertrophy. AB - MicroRNA-27b (miR-27b) is frequently upregulated in pressure-overloaded hypertrophic hearts. The clinical implications of aberrant circulating miR-27b in the diagnosis and management of left ventricular hypertrophy warrant study. We investigated whether serum miR-27b is a biomarker for left ventricular hypertrophy (LVH). We used stem-loop reverse-transcription quantitative polymerase chain reaction techniques to analyze serum miR-27b levels in 200 hypertensive patients with LVH, 100 hypertensive patients without LVH, and 100 healthy volunteers. We found that serum miR-27b levels were significantly higher in the hypertensive patients with LVH than in the hypertensive patients without LVH and in the healthy volunteers. Upon receiver operating characteristic curve analysis, serum miR-27b had an area under the curve of 0.885 with 91% sensitivity and 73% specificity in distinguishing hypertensive patients with LVH from healthy volunteers (P=0.021), and an area under the curve of 0.818 with 79.1% sensitivity and 70.3% specificity in distinguishing hypertensive patients with LVH from those without LVH (P=0.036). We conclude that circulating miR-27b might serve as a specific, noninvasive biomarker in screening for LVH. PMID- 29276437 TI - Continuous Suture Technique for Aortic Valve Replacement Shortens Cross-Clamp and Bypass Times. AB - The interrupted noneverting mattress suture technique is typically used in conventional surgical aortic valve replacement. The continuous suture technique, although faster, has been associated with a higher incidence of paravalvular leak. Using a slightly modified technique to minimize this risk, we investigated whether continuous suturing would shorten aortic cross-clamp time in aortic valve replacement in comparison with interrupted suturing. We reviewed the cases and compared the perioperative data of 60 consecutive patients in Japan and Australia (35 men and 25 women; median age, 70 yr) who had undergone aortic valve replacement with or without septal myectomy. The continuous suture technique had been used in 41 patients (Group CS) and the standard interrupted suture technique in 19 (Group IS). The groups were similar in age, sex, pathologic valvular conditions, and operative urgency. In Group CS, aortic cross-clamp time (47 vs 63 min; P=0.0001) and cardiopulmonary bypass time (76 vs 89 min; P=0.04) were significantly shorter. Neither group had early paravalvular leak. Using our continuous suture technique safely shortened aortic cross-clamp time during surgical aortic valve replacement. PMID- 29276438 TI - Multimodal Imaging of Anomalous Left Coronary Artery from the Pulmonary Artery in a 75-Year-Old Woman. AB - Anomalous origin of the left coronary artery from the pulmonary artery is rare and typically results in mitral regurgitation, ventricular arrhythmias, heart failure, and sudden death. The condition most often manifests itself in early childhood, but some individuals are diagnosed much later. We describe the case of a 75-year-old woman with heart failure in whom stepwise multimodal imaging revealed anomalous origin of the left coronary artery from the pulmonary artery. PMID- 29276439 TI - Endovascular Treatment of Distal Aortic Arch Aneurysm Associated with Coarctation of Aorta in a Jehovah's Witness. AB - Late aneurysm formation in the proximal aorta or distal aortic arch is a recognized sequela of untreated stenosis of the aortic isthmus and is associated with substantial risk of aortic rupture. We describe the case of a 44-year-old man with untreated coarctation of the aorta who presented with a prestenotic dissecting thoracic aortic aneurysm. He declined surgery because he was a Jehovah's Witness. Instead, we performed emergency endovascular aortic repair in which 2 stent-grafts were placed in the descending aorta. Our experience suggests that this procedure is a useful and safe alternative to open surgery in patients who have aneurysms associated with coarctation of the aorta. PMID- 29276440 TI - Recurrent Biatrial Myxoma in a 41-Year-Old Woman after Left Atrial Myxoma Resection. AB - Bilateral recurrence of atrial myxoma has been reported only a few times. We describe the case of a 41-year-old woman who had undergone left atrial myxoma resection and presented 9 years later with myxomas in both atria. The patient underwent successful resection of both masses with resolution of symptoms. We discuss the phenomenon of recurrent biatrial myxoma. PMID- 29276441 TI - Bioresorbable Scaffolds in Spontaneous Coronary Artery Dissection: Long-Term Follow-Up in 4 Patients. AB - Spontaneous coronary artery dissection is a rare condition, and diagnosis and treatment are challenging among patients who present with acute coronary syndrome. Typically, the condition affects young females who have no underlying atherosclerotic disease. To date, few cases of bioresorbable scaffold implantation for the treatment of spontaneous coronary artery dissection have been reported. Therefore, we describe the cases of 4 patients whom we treated with scaffolds. We evaluated the long-term results by using intravascular ultrasound and optical coherence tomographic scanning. PMID- 29276442 TI - Constrictive Pericarditis 5 Months after Radiation Therapy in a 62-Year-Old Woman with Esophageal Cancer. AB - Most pericardial changes appear within a few weeks in patients who have undergone radiation therapy for thoracic neoplasms. Chronic pericardial constriction typically occurs decades later, consequent to fibrosis. Early constrictive pericarditis after chest irradiation is quite rare. We report the case of a 62 year-old woman who underwent radiation therapy for esophageal cancer and presented with constrictive pericarditis 5 months later. We searched the English language medical literature from January 1986 through December 2015 for reports of early constrictive pericarditis after irradiation for thoracic malignancies. We defined "early" as a diagnosis within one year after radiation therapy. Five cases fit our criteria, and we summarize the findings here. To our knowledge, ours is the first definitive report of a patient with esophageal cancer to present with early radiation-induced constrictive pericarditis. We conclude that constrictive pericarditis can occur early after radiation for thoracic malignancies, albeit rarely. When planning care for cancer patients, awareness of this sequela is helpful. PMID- 29276443 TI - Ruptured Sinus of Valsalva Aneurysm Associated with Situs Ambiguus, Isolated Levocardia, and Polysplenia. AB - Aneurysm of the sinus of Valsalva, a rare cardiac condition, results from dilation of an aortic sinus. Sudden aneurysm rupture can trigger rapidly progressive heart failure. We discuss the case of a 57-year-old woman with situs ambiguus, isolated levocardia, and polysplenia who presented with acute-onset heart failure. Transesophageal echocardiograms revealed an aneurysm of the right coronary sinus of Valsalva that had ruptured into the right atrial cavity. The patient underwent successful surgical repair. To our knowledge, this is the first report of a sinus of Valsalva aneurysm in a patient with this combination of congenital abnormalities. We briefly review the association between congenital heart disease, situs ambiguus, and ciliary dysfunction. PMID- 29276444 TI - Widespread Vasculopathy in a Patient with Morquio A Syndrome. AB - Morquio A syndrome (mucopolysaccharidosis IV type A), an autosomal recessive lysosomal storage disorder caused by a defective N-acetylgalactosamine 6 sulfatase gene, leads to lysosomal accumulation of keratan sulfate and chondroitin 6-sulfate. This accumulation affects multiple systems and causes notable cardiovascular manifestations, such as thickening of the left-sided valves, ventricular hypertrophy, and intimal stenosis of the coronary arteries. There have been few reports of vasculopathy in this population. We present the case of a 58-year-old woman with Morquio A syndrome who was found to have aortic dilation on a routine screening echocardiogram. Magnetic resonance images revealed multiple tortuous, dilated arteries in her head, neck, and abdomen. The diffuse vasculopathy seen in this patient should prompt further study to determine whether this is an underreported phenomenon of clinical significance or an unusual finding in this rare disorder. PMID- 29276445 TI - Spontaneous Echo Contrast in a 73-Year-Old Man with Mitral Stenosis and a Giant Left Atrium. PMID- 29276446 TI - Acupuncture Needle in the Heart. PMID- 29276447 TI - Varying Morphology of QRS Complexes: A Possible Explanation. PMID- 29276448 TI - Impact of Travel Time on Same-Day Discharge after Elective Percutaneous Coronary Intervention. PMID- 29276450 TI - Experiments in Open Innovation at Harvard Medical School: What happens when an elite academic institution starts to rethink how research gets done? PMID- 29276449 TI - Extending Models of Sensitive Parenting of Infants to Women at Risk for Perinatal Depression. AB - Objective: Recognizing that not all mothers at risk for depression engage in insensitive parenting, this study examined predictors of individual differences in sensitive parenting of infants by mothers with histories of depression, who are at elevated risk for depression during the perinatal period. Design: We examined maternal personal characteristics, context, and early infant temperament as predictors of sensitive parenting. Seventy-six women with a history of major depression were followed through pregnancy and postpartum and observed during play and feeding interactions with their 12-month-old infants. Results: Maternal personal characteristics (recurrence of clinically significant depression symptom levels during pregnancy or postpartum and higher trait anxiety), context (lower social context and lower income), and early infant temperament (higher negative affectivity, surgency/extraversion, and orienting/regulation) are often associated with less sensitive parenting, with stronger and clearer associations for play than feeding and with some differences based on whether sensitivity was defined as affective matching or rated sensitivity. Conclusions: The findings extend support for multi-determination of sensitive parenting of infants to women with histories of depression, albeit with small to medium effect sizes, and suggest ways to identify those who may be most at risk for insensitive parenting and the potential value of intervening in pregnancy to enhance subsequent sensitivity of parenting. PMID- 29276451 TI - Center of Excellence for Mobile Sensor Data-to-Knowledge (MD2K). PMID- 29276452 TI - Boston keratoprosthesis in epithelial downgrowth. AB - Introduction: To report a case of histologically proven epithelial downgrowth after multiple failed penetrating keratoplasties and glaucoma filtering surgeries that was successfully treated with Boston keratoprosthesis implantation. Materials and Methods: A 61-year-old monocular patient had severe congenital ocular syphilis with secondary glaucoma. He had undergone many intraocular surgeries with a history of epithelial downgrowth, and he presented with a failed graft after 7 penetrating keratoplasties. Implantation of a corneal graft with an aphakic type of Boston keratoprosthesis was performed, combined with anterior vitrectomy. The main outcome measures were visual acuity, ocular inflammation and media clarity. Results: Media clarity was restored and revealed severe retinal scarring and a pale optic nerve. Best corrected visual acuity of 20/400 was maintained without any further surgical intervention during 6 years follow up. No retroprosthesis membrane or epithelial growth behind the keratoprosthesis was observed. Discussion: This is, to our knowledge, the first case of long-term successful treatment of epithelial downgrowth with a Boston keratoprosthesis. This approach might be considered a suitable treatment of epithelial downgrowth. PMID- 29276453 TI - Boston Keratoprosthesis in Stevens-Johnson syndrome: a case of using infliximab to prevent tissue necrosis. AB - Purpose: To report the case of a patient with Stevens-Johnson Syndrome (SJS) with Boston Keratoprosthesis (KPro) who may have benefited from infliximab infusions. Materials and Methods: Patient A 34-year-old woman with a history of acute SJS at age 12 had three Boston KPro Type II implanted since 2003 into her right eye. The first two were followed by tissue necrosis and aqueous leak, necessitating reoperation. After the third device was implanted, monthly infliximab infusions were started. Methods: Infliximab 5 mg/kg infusions were started in January 2008, repeated after 2 weeks, and then given monthly for a year. The treatment is continuing combined with regular eye examinations. Results: While receiving infliximab, the skin around the keratoprosthesis has not shown a trace of retraction or necrosis. This is in sharp contrast to events following the two previous attempts at visual rehabilitation. The patient's vision has been generally stable for a year and is currently 20/30. Conclusion: A KPro in a patient with SJS normally has a poor long-term prognosis. However, retention of the prosthesis and visual outcome may benefit from monthly infliximab infusions. PMID- 29276454 TI - High myopia as a risk factor for post-LASIK ectasia: a case report. AB - Purpose: To describe the case of a patient developing corneal ectasia following LASIK for the correction of myopic astigmatism. Materials and Methods: A 39-year old man underwent bilateral uneventful LASIK for myopic astigmatism of -10.25 1.75 *040 OD and -8.00 -2.50 *005 OS. Preoperative corneal pachymetry was 542 micrometers OD and 543 micrometers OS. Preoperative corneal topography showed bilateral oblique bow-tie patterns. Central keratometry measurements were 45.12 D @ 124 / 43.87 D @ 34 OD and 44.87 D @ 78 / 43.12 D @ 168 OS. Keratoconus or forme fruste keratoconus were not present preoperatively. Results: The residual stromal bed was 314 micrometers OD and 295 micrometers OS. Increasing astigmatism was documented progressively after LASIK. Central keratometry and topography were performed with evidence of ectasia OD at 17 months post-operatively and early evidence of ectasia OS at last follow-up of 58 months. Conclusion: High myopia appears to be a predisposing factor in this patient. High myopia may need to be considered as an ectasia risk factor independent of amount of ablation or residual stromal bed thickness and in the absence of forme fruste keratoconus. The possibility remains that ectasia was due to an unidentified risk factor or an intrinsic corneal problem with this patient's right eye. PMID- 29276455 TI - A 25-month-old girl with vision loss, nystagmus, and anomalous head posture. PMID- 29276456 TI - Visual and anatomic outcomes of vitreoretinal surgery: results at the Boston VA and a review of the literature. AB - Introduction: The veteran population presents unique challenges in the management of vitreoretinal disorders. We compiled the surgical outcomes for the most common visually significant vitreoretinal diagnoses. Those results were then compared to visual and anatomic outcomes established in the literature. Materials and Methods: Medical records over a three-year time period, from January 2005 through December 2007, were reviewed for 208 persons who underwent vitreoretinal surgery for vitreous hemorrhage, retained lens fragment, rhegmatogenous and tractional retinal detachment, macular hole, and macular pucker at the Jamaica Plain Campus of the Veterans Affairs Boston Healthcare System in Boston, MA. A comprehensive search of the literature was conducted on Medline. Data from several large case series and meta-analyses were compared to results obtained at the VA Boston. Results: A total of 208 veterans underwent vitreoretinal surgery from January 2005 to December 2007. After excluding those with rare diagnoses and lack of adequate follow-up data, the outcomes of 181 vitreoretinal procedures were included in this study. Discussion: Overall, veterans at a regional referral center in Boston demonstrate postoperative visual and anatomic outcomes comparable to outcomes reported in the ophthalmic literature. PMID- 29276457 TI - Emerging Antimicrobial Research against Superbugs: Perspectives from a Polymer Laboratory. AB - Infectious diseases caused by drug-resistant microorganisms have become a major contributor for human morbidity and mortality. To overcome such threats, we have developed various antimicrobial agents using natural product derivatives and metallopolymers. Abundant biomass such as resin acids can be utilized to prepare cationic polymers for inhibiting a variety of bacteria. These polymers have been used in solution as well as surfaces as antimicrobial materials with low cytotoxicity. In addition, a class of charged metallopolymers have been developed to kill superbugs such as MRSA. PMID- 29276458 TI - Association of Venous Leg Ulcers With Ankle Range of Motion in People Attending Chiropractic Mobile Clinics in the Dominican Republic. AB - Objective: The goal of the study was to determine if there was an association between chronic venous disorders (CVDs), particularly venous leg ulcers, and ankle range of motion (ROM) in the Dominican Republic. Methods: Chronic venous disorders were classified using the clinical manifestations portion (C) of the CEAP (clinical manifestations, etiology, anatomy, pathophysiology) method. The legs of participants attending mobile chiropractic clinics in rural, low-income areas in the Dominican Republic were assessed for clinical signs of CVD and venous ulcers. Ankle ROM was then measured, and photographs of the legs were taken. The 6 clinical stages of CVD were divided into 3 groups: normal legs (normal), no ulcer CVD, and ulcer CVD (healed and active). Multiple linear regression of ankle ROM against CVD grouping was used to test the association. Results: Eight of the 837 patients for whom CVD classification was obtained had venous ulcers (healed or active) on at least 1 leg. About 30% relative reduction in ROM (ankle dorsiflexion plus plantar flexion) was observed between the ulcer group and the normal group. Regression analysis comparing legs with ulcers to healthy legs (normal), adjusted for age, gender, indicator for obesity, and previous leg trauma, revealed a significant decrease of approximately 14 degrees (P = .0007) in ankle ROM. Age was also found to be strongly significant in the regression analysis, 1 year of aging was associated with a decrease of 0.16 degrees (P < .0001) in ankle ROM (approximately 1.6 degrees in 10 years). Conclusion: A significant decrease was observed in ankle ROM for participants with active and healed leg venous ulcers compared with those without ulcers. There appeared to be an association between venous leg ulcers and ankle ROM in this sample. PMID- 29276459 TI - Immediate Effect of Lumbar Mobilization on Activity of Erector Spinae and Lumbar Multifidus Muscles. AB - Objective: The purpose of this study was to investigate the effect of grade IV lumbar mobilization on the activity/contraction of erector spinae (ES) and lumbar multifidus (LM) muscles in healthy people. Methods: A randomized, repeated measures design was used. Sixteen healthy subjects attended 3 testing sessions with a different intervention in each session (no intervention, grade IV central lumbar mobilization at L4, and placebo/light touch). Lying in a prone position, subjects lifted a light weight with their right arm while ultrasound images of LM and surface electromyography signals of ES were captured before and immediately after application of the intervention in the session. The contraction of LM was calculated from US images, and the root mean square was calculated from the electromyography signals of ES and used as outcome measures. Results: A significant difference was found in LM contraction between the placebo and mobilization intervention (difference = 0.04, P = .02). There was no difference for the root mean square of electromyography signals between the interventions. Conclusion: The significant difference in LM contraction was small and may not have clinical significance. Lumbar mobilization did not change the activity of ES in healthy people. Future studies with larger samples are needed to confirm our findings and to investigate the effect of mobilization on back muscles in people with low back pain. PMID- 29276460 TI - Management of Chronic Lateral Epicondylitis With Manual Therapy and Local Cryostimulation: A Pilot Study. AB - Objective: The purpose of this pilot study was to evaluate the feasibility and efficacy of adding cryostimulation to manual therapy in patients with chronic lateral epicondylitis. Methods: The control group (n = 19) was treated with manual therapy consisting of soft-tissue therapy and radial head mobilizations. The experimental group (n = 18) received cryostimulation in addition to manual therapy care similar to that for the control group. Both protocols consisted of 8 treatments over a 4-week period. Outcome measures included pain intensity (visual analog scale), pain-free grip strength (handheld dynamometer), and functional index (Patient-Rated Tennis Elbow Evaluation questionnaire). Assessments were performed at baseline, postintervention, and 3-month follow-up. Adherence and dropout rates were also considered. Results: Both groups exhibited significant improvements in pain intensity and functional index at postintervention assessments, which were maintained at follow-up. All participants attended the prescribed number of treatments, but 27% were lost at follow-up. Minor adverse events were reported after cryostimulation in 4 cases. Conclusions: This study indicated that it is feasible to complete a clinical trial evaluating the efficacy of adding cryostimulation to manual therapy in patients with chronic lateral epicondylitis. On the basis of these preliminary data, the combination of cryostimulation and manual therapy care did not provide any additional benefits in both the short term and the long term. Manual myofascial point treatment and mobilization techniques yielded positive outcomes in chronic lateral epicondylitis. Further studies should focus on the sole therapeutic effect of cryostimulation in both patients with acute and those with chronic conditions. PMID- 29276461 TI - Dietary Fiber Is Beneficial for the Prevention of Cardiovascular Disease: An Umbrella Review of Meta-analyses. AB - Objective: The purpose of this study was to review previously published meta analyses on the effectiveness of dietary fiber on cardiovascular disease. Methods: An umbrella review of all published meta-analyses was performed. A PubMed search from January 1, 1980, to January 31, 2017, was conducted using the following search strategy: (fiber OR glucan OR psyllium OR fructans) AND (meta analysis OR systematic review). Only English-language publications that provided quantitative statistical analysis on cardiovascular disease, lipid concentrations, or blood pressure were retrieved. Results: Thirty-one meta analyses were retrieved for inclusion in this umbrella review, and all meta analyses comparing highest versus lowest dietary fiber intake reported statistically significant reductions in the relative risk (RR) of cardiovascular disease mortality (RR = 0.77-0.83), as well as the incidences of cardiovascular disease (RR = 0.72-0.91), coronary heart disease (RR = 0.76-0.93), and stroke (RR = 0.83-0.93). Meta-analyses on supplementation studies using beta-glucan or psyllium fibers also reported statistically significant reductions in both total serum and low-density lipoprotein cholesterol concentrations. Conclusion: This review suggests that individuals consuming the highest amounts of dietary fiber intake can significantly reduce their incidence and mortality from cardiovascular disease. Mechanistically, these beneficial effects may be due to dietary fibers' actions on reducing total serum and low-density lipoprotein cholesterol concentrations between 9.3 to 14.7 mg/dL and 10.8 to 13.5 mg/dL, respectively. PMID- 29276462 TI - Chiropractic Care in the Management of Inactive Ankylosing Spondylitis: A Case Series. AB - Objective: This report describes chiropractic management for 3 cases of inactive ankylosing spondylitis (AS). Clinical Features: A 25-year-old woman presented with chronic, mechanical neck pain and stiffness that was ultimately diagnosed as AS. A 23-year-old man presented with chronic low back and left hip pain that was diagnosed as AS. A 31-year-old man with low back pain presented with a known diagnosis of AS. Physical examination in 2 cases failed to identify systemic findings associated with AS. In the third case, examination revealed a history of ulcerative colitis. Laboratory examination of case 2 yielded a positive HLA-B27, but cases 1 and 3 were HLA-B27 negative. The acute reactants were negative in all 3 patients, indicating an inactive phase of disease. All 3 patients underwent spinal imaging including sacroiliac joint radiography. In case 3, magnetic resonance imaging of the sacroiliac joints was performed. All 3 imaging examinations revealed bilateral, symmetric sacroiliitis. Interventions and Outcome: Patients were managed by both a medical rheumatologist and a doctor of chiropractic. Chiropractic care ranged from instrument-assisted spinal manipulation to diversified spinal and soft tissue manipulation and Cox flexion distraction. Patients were given home stretches and rehabilitation exercises. All 3 patients experienced some relief of their symptoms including pain reduction and improved activities of daily living. Conclusion: These 3 patients displayed differences and commonalities in clinical, laboratory, and imaging features. Chiropractic manipulation and rehabilitation seemed to be beneficial in reducing symptomatology and improving musculoskeletal function for these 3 patients. These findings suggest the potential for collaborative or integrative management in similar cases. PMID- 29276463 TI - Conservative Management of Possible Meniscal Derangement Using the Mulligan Concept: A Case Report. AB - Objective: The purpose of this case study was to report on the immediate effects of the combined use of mobilizations with movement and the "squeeze" technique on a patient with knee stiffness, popping, and swelling. Clinical Features: The patient presented with right knee stiffness, swelling, and a popping sensation of insidious onset. Clinical examination revealed pain with terminal knee extension and flexion, joint line tenderness, a positive Apley's compression test, and a positive Thessaly's test at 20 degrees of knee flexion. A working diagnosis was established of a meniscal pathology with the differential diagnoses of meniscal derangement and synovial plica. Intervention and Outcome: The patient received 3 total treatments using the Mulligan concept over the course of 11 days. The treatments included the application of a tibia internal rotation mobilization with movement and the "squeeze" technique to the affected knee. Patient outcomes, including the Disablement in the Physically Active Scale, the Patient-Specific Functional Scale, and the Numeric Rating Scale for pain, were collected throughout the course of treatment. The patient reported a minimal clinically important difference on the Numeric Rating Scale for pain after each treatment and on all outcomes after the third treatment. The patient reported improvement on her follow-up visit 4 days after the third treatment; the results of a clinical exam and patient outcomes supported a complete discharge after 3 treatments. Conclusion: This patient responded favorably to use of the Mulligan concept as a manual therapy technique for the treatment of symptoms related to possible meniscal derangement. PMID- 29276464 TI - Reliability of the Upper Trapezius Muscle and Fascia Thickness and Strain Ratio Measures by Ultrasonography and Sonoelastography in Participants With Myofascial Pain Syndrome. AB - Objective: The purpose of this study was to assess the intra- and interexaminer reliability of the upper trapezius muscle and fascia thickness measured by ultrasonography imaging and strain ratio by sonoelastography in participants with myofascial pain syndrome. Methods: Thirty-two upper trapezius muscles were assessed. Two examiners measured the upper trapezius thickness and strain ratio 3 times by ultrasonography and sonoelastography independently in the test session. The retest session was completed 6 to 8 days later. Results: A total of 87.5% of participants had trigger points on the right side, and 22.5% had trigger points on the left side. For the test session, the average upper trapezius thickness, fascia thickness, and strain ratio measured by first and second examiners were 11.86 mm and 11.56 mm, 1.23 mm and 1.25 mm, and 0.94 and 0.99, respectively. For the retest session, the previously mentioned parameters obtained by first and second examiners were 11.76 mm and 11.39 mm, 1.27 mm and 1.29 mm, and 0.96 and 0.99, respectively. The intraclass correlation coefficients indicated good to excellent reliability for both within-intraexaminer (0.78-0.96) and between intraexaminer (0.75-0.98) measurements. Also, the intraclass correlation coefficients and standard errors of measurement of interexaminer reliability ranged between 0.88 to 0.93 and 0.05 to 0.44 for both muscle and fascia thickness and 0.70 to 0.75 and 0.04 to 0.20 for strain ratio of upper trapezius, respectively. Conclusion: Upper trapezius thickness measurements by ultrasonography and strain ratio by sonoelastography are reliable methods in participants with myofascial pain syndrome. PMID- 29276465 TI - A Case Report of Osteochondritis Dissecans in a Rare Location: The Lateral Femoral Trochlea. AB - Objective: The purpose of this case report is to describe a rare location for knee osteochondritis dissecans (OCD). Clinical Features: A 28-year-old man presented to a chiropractic clinic with left posterolateral knee pain and swelling with joint locking after falling asleep with knees bent. A history of knee locking was reported by the patient. At presentation, he demonstrated the inability to straighten his left knee. On a pain scale of 1 to 10, he experienced level-8 stabbing pain during all knee ranges of motion with radiation to the foot. The patient was suspected of deep vein thrombosis and was sent to urgent care for evaluation. Intervention and Outcome: Deep vein thrombosis was ruled out, and additional knee imaging was obtained at our clinic. Left knee radiography and diagnostic ultrasound revealed a lateral femoral trochlea osteochondral defect with an associated osteochondral fragment. Magnetic resonance imaging of the left knee was obtained for further evaluation and confirmed the diagnosis of OCD. The patient underwent surgical treatment for loose body removal and trochlear chondroplasty. Conclusion: The diagnostic imaging findings in this case revealed a rare location for OCD, the lateral femoral trochlea. Symptoms of posterior knee pain require careful evaluation by clinicians and radiologists to ensure timely diagnosis and optimal treatment. PMID- 29276466 TI - Rehabilitative Principles in the Management of Thoracolumbar Syndrome: A Case Report. AB - Objective: The purpose of this case report was to describe the chiropractic management of thoracolumbar syndrome using multimodal therapies. Clinical Features: A 33-year-old woman with 3 weeks of back pain presented to a chiropractic clinic. Nerve tension tests and local tenderness were present in a pattern described by Maigne, and she was diagnosed with thoracolumbar syndrome (Maigne syndrome) at her initial visit. Intervention and Outcomes: The Oswestry Disability Index for low back pain (62%), STarT low back screen tool for clinical outcomes (6 points total, with a 2-point subscale), numeric pain rating scale (6/10 constant, 10/10 with provocation), and test-retest exercise audits were outcome measures. She received 3 treatment sessions, each with progressive exercise audits, and discharged with advice. At discharge, the patient scores substantially improved (Oswestry Disability Index: 8%, STarT: 1 point total, numeric pain rating scale: 1/10, 10% of the time), and she exhibited greater confidence in home care. Endurance tests were performed to establish baselines for future care, which included static back endurance test (timed 52 seconds) and side bridge endurance test (timed 43 seconds). Conclusion: The patient responded positively to chiropractic care. After a short course of care, the patient reported reduced pain, alleviated symptoms, and improved physical function. PMID- 29276468 TI - Erratum to "A Guideline of Selecting and Reporting Intraclass Correlation Coefficients for Reliability Research" [J Chiropr Med 2016;15(2):155-163]. AB - [This corrects the article DOI: 10.1016/j.jcm.2016.02.012.]. PMID- 29276467 TI - Chiropractic Management Using Multimodal Therapies on 2 Pediatric Patients With Constipation. AB - Objective: The purpose of this case report is to describe chiropractic management of 7-month-old male twins who had had constipation since birth. Clinical Features: Identical male twins presented with the chief complaint of constipation and bloating. Both patients were born premature after 29 weeks of gestation and had invasive abdominal surgeries in the right lower quadrant resulting in healed postsurgical scars. Patient A underwent ileostomy for a perforation in his ileum. Patient B underwent surgery to repair an inguinal hernia. Motion palpation restrictions indicated bilateral sacroiliac, cervical, and thoracic joint restrictions. Intervention and Outcome: The treatment plan included chiropractic manipulation, acupressure stimulation, and dynamic neuromuscular stabilization. Manipulation of the sacroiliac, cervical, and thoracic spine joint restrictions was performed using minimal force. Cross-frictional massage and myofascial manipulation and scar tissue mobilization of the abdominal scar in the right lower quadrant were performed. Acupressure stimulation was performed on both patients' feet. Both patients had improved bowel movements after the first treatment. Patient A had 5 weeks of treatment (2 visits per week). Patient B had 4 weeks of treatment (2 visits per week). The patients' clinical progress improved, and once the goal of regular bowel movements was reached, as confirmed by their mother, follow-up visits were reduced to once a week and gradually to once a month. Conclusion: Both pediatric patients with constipation responded to chiropractic care using multimodal therapies. PMID- 29276470 TI - Relationship Between Alcohol Use, Spirituality, and Coping. AB - Authors investigated a relationship between the frequency of alcohol consumption, spirituality, and coping with everyday life events in a cross-sectional, community-based sample of 320 adults in Ukraine, the country with one of the highest alcohol consumption levels in the world. Face-to-face interviews with participants took place in rural and urban locations across Eastern, Southern, and Central Ukraine. Results of the ordinary least-squares regression suggest that a higher frequency of alcohol consumption was related with the lower use of positive reappraisal (beta = -.27, p < .001), higher use of escape-avoidance (beta = .23, p < .01) and confrontive (beta = .15, p < .05) coping strategies, lower spirituality (beta = -.20, p < .001), and younger age (beta = -.11, p < .05). On the whole, current findings suggest that specific coping behaviors, younger age, and lower spirituality are involved in higher frequency of alcohol consumption among Ukrainian adults. PMID- 29276469 TI - Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer. AB - : The three-dimensional (3D) structure of the intestine is a key determinant of differentiation and function; thus, preserving this architecture is an important consideration for studies of intestinal homeostasis and disease. Over the past decade, a number of systems for 3D intestinal organoid cultures have been developed and adapted to model a wide variety of biological phenomenon. Purpose of this review: We discuss the current state of intestinal and colorectal cancer (CRC) 3D modeling, the most common methods for generating organoid cultures, and how these have yielded insights into intestinal physiology and tumor biology. Recent findings: Organoids have been used to model numerous aspects of intestinal physiology and disease. Recent adaptations have further improved disease modeling and high-throughput therapeutic screening. Summary: These studies show intestinal organoid models are a robust, highly tractable system which maintains many vital features of intestinal tissue, making them a pivotal step forward in the field of gastroenterology. PMID- 29276471 TI - Fine Particulate Air Pollution and Mortality: Response to Enstrom's Reanalysis of the American Cancer Society Cancer Prevention Study II Cohort. PMID- 29276472 TI - Optimal KI Prophylactic Dose Determination for Thyroid Radiation Protection After a Single Administration in Adult Rats. AB - A dose-response study was performed in adult rats to select an optimal stable potassium iodide (KI) dose which could be implemented in repeated prophylaxis, in case of prolonged exposure to radioactive iodine. Increasing doses of KI were given orally to rats 1 hour before internal exposure simulated by I-125 injection. I-125 incorporation in the thyroid was measured by gamma-spectrometry, and KI protection effect was modeled by pharmacological functions. The measurement method by inductively coupled plasma mass spectrometry previously developed for the quantification of stable iodine in urine was adapted to correlate KI effect with its distribution in the thyroid. More than 75% blockade of iodine I-125 incorporation in the thyroid was achieved for KI single doses above 0.5 to 0.7 mg/kg. Stable iodine content in the thyroid 24 hours after KI administration displayed a biphasic response, with a maximum level for a dose around 1 mg/kg. Besides, the urinary excretion of stable iodine is described by a sigmoid function. The change in the rate of iodine excretion for doses above 1 mg/kg KI suggests a body overload in iodine and corroborates a possible saturation of the thyroid. The results show that 1 mg/kg KI could be regarded as an optimal dose for thyroid protection. PMID- 29276473 TI - Ferric Chelate Reductase 1 Like Protein (FRRS1L) Associates with Dynein Vesicles and Regulates Glutamatergic Synaptic Transmission. AB - In the brain, AMPA receptors (AMPARs)-mediated excitatory synaptic transmission is critically regulated by the receptor auxiliary subunits. Recent proteomic studies have identified that Ferric Chelate Reductase 1 Like protein (FRRS1L), whose mutations in human lead to epilepsy, choreoathetosis, and cognitive deficits, is present in native AMPAR complexes in the brain. Here we have characterized FRRS1L in both heterologous cells and in mouse neurons. We found that FRRS1L interacts with both GluA1 and GluA2 subunits of AMPARs, but does not form dimers/oligomers, in HEK cells. In mouse hippocampal neurons, recombinant FRRS1L at the neuronal surface partially co-localizes with GluA1 and primarily localizes at non-synaptic membranes. In addition, native FRRS1L in hippocampus is localized at dynein, but not kinesin5B, vesicles. Functionally, over-expression of FRRS1L in hippocampal neurons does not change glutamatergic synaptic transmission. In contrast, single-cell knockout (KO) of FRRS1L strongly reduces the expression levels of the GluA1 subunit at the neuronal surface, and significantly decreases AMPAR-mediated synaptic transmission in mouse hippocampal pyramidal neurons. Taken together, these data characterize FRRS1L in heterologous cells and neurons, and reveal an important role of FRRS1L in the regulation of excitatory synaptic strength. PMID- 29276474 TI - Experimental Gene Therapy with Serine-Histogranin and Endomorphin 1 for the Treatment of Chronic Neuropathic Pain. AB - The insufficient pain relief provided by current pharmacotherapy for chronic neuropathic pain is a serious medical problem. The enhanced glutamate signaling via NMDA receptors appears to be one of the key events in the development of chronic pain. Although effective, clinical use of systemic NMDA antagonists is limited by adverse effects such as hallucinations and motor dysfunction. Opioids are also potent analgesics but their chronic use is accompanied by tolerance and risk of addiction. However, combination of NMDA antagonists and opioids seems to provide a stable pain relieve at subthreshold doses of both substances, eliminating development of side effects. Our previous research showed that combined delivery of NMDA antagonist Serine histrogranin (SHG) and endomorphin1 (EM1) leads to attenuation of acute and chronic pain. The aim of this study was to design and evaluate an analgesic potency of the gene construct encoding SHG and EM1. Constructs with 1SHG copy in combination with EM1, 1SHG/EM1, and 6SHG/EM1 were intraspinally injected to animals with peripheral nerve injury induced pain (chronic constriction injury, CCI) or spinal cord injury induced pain (clip compression model, SCI) and tactile and cold allodynia were evaluated. AAV2/8 particles were used for gene delivery. The results demonstrated 6SHG/EM1 as the most efficient for alleviation of pain-related behavior. The effect was observed up to 8 weeks in SCI animals, suggesting the lack of tolerance of possible synergistic effect between SHG and EM1. Intrathecal injection of SHG antibody or naloxone attenuated the analgesic effect in treated animals. Biochemical and histochemical evaluation confirmed the presence of both peptides in the spinal tissue. The results of this study showed that the injection of AAV vectors encoding combined SHG/EM constructs can provide long term attenuation of pain without overt adverse side effects. This approach may provide better treatment options for patients suffering from chronic pain. PMID- 29276475 TI - Evolution, Development and Function of Vertebrate Cone Oil Droplets. AB - To distinguish colors, the nervous system must compare the activity of distinct subtypes of photoreceptors that are maximally sensitive to different portions of the light spectrum. In vertebrates, a variety of adaptations have arisen to refine the spectral sensitivity of cone photoreceptors and improve color vision. In this review article, we focus on one such adaptation, the oil droplet, a unique optical organelle found within the inner segment of cone photoreceptors of a diverse array of vertebrate species, from fish to mammals. These droplets, which consist of neutral lipids and carotenoid pigments, are interposed in the path of light through the photoreceptor and modify the intensity and spectrum of light reaching the photosensitive outer segment. In the course of evolution, the optical function of oil droplets has been fine-tuned through changes in carotenoid content. Species active in dim light reduce or eliminate carotenoids to enhance sensitivity, whereas species active in bright light precisely modulate carotenoid double bond conjugation and concentration among cone subtypes to optimize color discrimination and color constancy. Cone oil droplets have sparked the curiosity of vision scientists for more than a century. Accordingly, we begin by briefly reviewing the history of research on oil droplets. We then discuss what is known about the developmental origins of oil droplets. Next, we describe recent advances in understanding the function of oil droplets based on biochemical and optical analyses. Finally, we survey the occurrence and properties of oil droplets across the diversity of vertebrate species and discuss what these patterns indicate about the evolutionary history and function of this intriguing organelle. PMID- 29276476 TI - Critical Points and Traveling Wave in Locomotion: Experimental Evidence and Some Theoretical Considerations. AB - The central pattern generator (CPG) architecture for rhythm generation remains partly elusive. We compare cat and frog locomotion results, where the component unrelated to pattern formation appears as a temporal grid, and traveling wave respectively. Frog spinal cord microstimulation with N-methyl-D-Aspartate (NMDA), a CPG activator, produced a limited set of force directions, sometimes tonic, but more often alternating between directions similar to the tonic forces. The tonic forces were topographically organized, and sites evoking rhythms with different force subsets were located close to the constituent tonic force regions. Thus CPGs consist of topographically organized modules. Modularity was also identified as a limited set of muscle synergies whose combinations reconstructed the EMGs. The cat CPG was investigated using proprioceptive inputs during fictive locomotion. Critical points identified both as abrupt transitions in the effect of phasic perturbations, and burst shape transitions, had biomechanical correlates in intact locomotion. During tonic proprioceptive perturbations, discrete shifts between these critical points explained the burst durations changes, and amplitude changes occurred at one of these points. Besides confirming CPG modularity, these results suggest a fixed temporal grid of anchoring points, to shift modules onsets and offsets. Frog locomotion, reconstructed with the NMDA synergies, showed a partially overlapping synergy activation sequence. Using the early synergy output evoked by NMDA at different spinal sites, revealed a rostrocaudal topographic organization, where each synergy is preferentially evoked from a few, albeit overlapping, cord regions. Comparing the locomotor synergy sequence with this topography suggests that a rostrocaudal traveling wave would activate the synergies in the proper sequence for locomotion. This output was reproduced in a two-layer model using this topography and a traveling wave. Together our results suggest two CPG components: modules, i.e., synergies; and temporal patterning, seen as a temporal grid in the cat, and a traveling wave in the frog. Animal and limb navigation have similarities. Research relating grid cells to the theta rhythm and on segmentation during navigation may relate to our temporal grid and traveling wave results. Winfree's mathematical work, combining critical phases and a traveling wave, also appears important. We conclude suggesting tracing, and imaging experiments to investigate our CPG model. PMID- 29276478 TI - Application of the Physical Disector Principle for Quantification of Dopaminergic Neuronal Loss in a Rat 6-Hydroxydopamine Nigral Lesion Model of Parkinson's Disease. AB - Stereological analysis is the optimal tool for quantitative assessment of brain morphological and cellular changes induced by neurotoxic lesions or treatment interventions. Stereological methods based on random sampling techniques yield unbiased estimates of particle counts within a defined volume, thereby providing a true quantitative estimate of the target cell population. Neurodegenerative diseases involve loss of specific neuron types, such as the midbrain tyrosine hydroxylase-positive dopamine neurons in Parkinson's disease and in animal models of nigrostriatal degeneration. Therefore, we applied an established automated physical disector principle in a fractionator design for efficient stereological quantitative analysis of tyrosine hydroxylase (TH)-positive dopamine neurons in the substantia nigra pars compacta of hemiparkinsonian rats with unilateral 6 hydroxydopamine (6-OHDA) lesions. We obtained reliable estimates of dopamine neuron numbers, and established the relationship between behavioral asymmetry and dopamine neuron loss on the lesioned side. In conclusion, the automated physical disector principle provided a useful and efficient tool for unbiased estimation of TH-positive neurons in rat midbrain, and should prove valuable for investigating neuroprotective strategies in 6-OHDA model of parkinsonism, while generalizing to other immunohistochemically-defined cell populations. PMID- 29276477 TI - Cholinergic Modulation of Cortical Microcircuits Is Layer-Specific: Evidence from Rodent, Monkey and Human Brain. AB - Acetylcholine (ACh) signaling shapes neuronal circuit development and underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. During behavior, activation of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) by ACh alters the activation state of neurons, and neuronal circuits most likely process information differently with elevated levels of ACh. In several brain regions, ACh has been shown to alter synaptic strength as well. By changing the rules for synaptic plasticity, ACh can have prolonged effects on and rearrange connectivity between neurons that outlasts its presence. From recent discoveries in the mouse, rat, monkey and human brain, a picture emerges in which the basal forebrain (BF) cholinergic system targets the neocortex with much more spatial and temporal detail than previously considered. Fast cholinergic synapses acting on a millisecond time scale are abundant in the mammalian cerebral cortex, and provide BF cholinergic neurons with the possibility to rapidly alter information flow in cortical microcircuits. Finally, recent studies have outlined novel mechanisms of how cholinergic projections from the BF affect synaptic strength in several brain areas of the rodent brain, with behavioral consequences. This review highlights these exciting developments and discusses how these findings translate to human brain circuitries. PMID- 29276479 TI - Digit Ratio (2D:4D) Predicts Self-Reported Measures of General Competitiveness, but Not Behavior in Economic Experiments. AB - The ratio of index finger length to ring finger length (2D:4D) is considered to be a putative biomarker of prenatal androgen exposure (PAE), with previous research suggesting that 2D:4D is associated with human behaviors, especially sex typical behaviors. This study empirically examines the relationship between 2D:4D and individual competitiveness, a behavioral trait that is found to be sexually dimorphic. We employ two related, but distinct, measures of competitiveness, namely behavioral measures obtained from economic experiments and psychometric self-reported measures. Our analyses are based on two independent data sets obtained from surveys and economic experiments with 461 visitors of a shopping mall (Study I) and 617 university students (Study II). The correlation between behavior in the economic experiment and digit ratios of both hands is not statistically significant in either study. In contrast, we find a negative and statistically significant relationship between psychometric self-reported measures of competitiveness and right hand digit ratios (R2D:4D) in both studies. This relationship is especially strong for younger people. Hence, this study provides some robust empirical evidence for a negative association between R2D:4D and self-reported competitiveness. We discuss potential reasons why digit ratio may relate differently to behaviors in specific economics experiments and to self reported general competitiveness. PMID- 29276480 TI - Traumatic Life Events in Relation to Cognitive Flexibility: Moderating Role of the BDNF Val66Met Gene Polymorphism. AB - Cognitive flexibility plays an important role in an individual's ability to adapt to a continuously changing environment and is considered central to goal-oriented behavior. Accordingly, increasing attention has been devoted to understanding the factors, including genetic and early life experiences, which might contribute to individual differences in this ability. In the present investigation, we examined the contribution of the BDNF Val66Met polymorphism to cognitive flexibility, as assessed by set-shifting ability on the Wisconsin Card Sorting Task (WCST), and whether this polymorphism moderated the relation between trauma experiences (including type and timing of trauma occurrence) and cognitive flexibility. Among undergraduate students (N = 239), greater frequency of total traumas experienced prior to the age 5 was associated with greater difficulties in set-shifting (as indexed by more frequent perseverative errors on the WCST) among individuals carrying the Met allele of the BDNF polymorphism, but not those who were Val homozygotes. By contrast, total traumas experienced between the age of 6 to 12 and 13 to 18 were not related to set-shifting ability, and these relations were not moderated by BDNF genotype. Moreover, greater frequency of general traumas and emotional abuse was associated with set-shifting difficulties for both male and female Met allele carriers, but not Val homozygotes. In contrast, physical punishment was related to difficulties in set-shifting, but only among male Met carriers, an effect that was likely attributed to greater frequency of this form of trauma among males. The present findings suggest that the relationship between early life trauma and later-life cognitive flexibility might depend on the presence of the BDNF Val66Met polymorphism as well as the development stage at which the trauma has occurred. Moreover, the present investigation provides further understanding into the factors (i.e., genetic and early life experiences) that might be associated with individual differences in cognitive functioning and goal-directed behaviors, such as problem-solving and decision-making. PMID- 29276481 TI - Is 8:30 a.m. Still Too Early to Start School? A 10:00 a.m. School Start Time Improves Health and Performance of Students Aged 13-16. AB - While many studies have shown the benefits of later school starts, including better student attendance, higher test scores, and improved sleep duration, few have used starting times later than 9:00 a.m. Here we report on the implementation and impact of a 10 a.m. school start time for 13 to 16-year-old students. A 4-year observational study using a before-after-before (A-B-A) design was carried out in an English state-funded high school. School start times were changed from 8:50 a.m. in study year 0, to 10 a.m. in years 1-2, and then back to 8:50 a.m. in year 3. Measures of student health (absence due to illness) and academic performance (national examination results) were used for all students. Implementing a 10 a.m. start saw a decrease in student illness after 2 years of over 50% (p < 0.0005 and effect size: Cohen's d = 1.07), and reverting to an 8:50 a.m. start reversed this improvement, leading to an increase of 30% in student illness (p < 0.0005 and Cohen's d = 0.47). The 10:00 a.m. start was associated with a 12% increase in the value-added number of students making good academic progress (in standard national examinations) that was significant (<0.0005) and equivalent to 20% of the national benchmark. These results show that changing to a 10:00 a.m. high school start time can greatly reduce illness and improve academic performance. Implementing school start times later than 8:30 a.m., which may address the circadian delay in adolescents' sleep rhythms more effectively for evening chronotypes, appears to have few costs and substantial benefits. PMID- 29276482 TI - Viewing Another Act as You Would Creates Altruistic Desires Towards that Other. AB - There has been growing evidence for the existence of distributed, frequently updating social "indices", which are related to the reputation of others and predict altruism towards them. However, the means by which the brain modifies an index based on experiences is still unknown. This work utilizes recent insights on the role of the anterior cingulate cortex during perspective taking, dorsolateral prefrontal representations of context, the temporoparietal junctions relationship with understanding another's background, and dorsomedial prefrontal activation patterns tracking reputation. It aims to show that cognitive empathy causes comparisons between a target's action and the action one would wish to do in the target's position. It also suggests that viewing a target perform the same action that one would in the target's position creates altruistic desires towards the target. By considering these comparisons as central to understanding prosocial and antisocial motivations, a variety of behavioral studies are better explained. This piece seeks to open questions and discussions on the interplay of those brain regions, suggest future approaches to relationship therapy, and establish fundamentals for multi-agent models aimed at normative sociality. PMID- 29276483 TI - Control Group Paradigms in Studies Investigating Acute Effects of Exercise on Cognitive Performance-An Experiment on Expectation-Driven Placebo Effects. AB - Introduction: Many studies report improvements in cognitive performance following acute endurance exercise compared to control group treatment. These cognitive benefits are interpreted as a result of a physiological response to exercise. However, it was also hypothesized that expectation-driven placebo effects account for these positive effects. The purpose of this study was to investigate the differences between expectations for cognitive benefits toward acute endurance exercise and multiple control group treatments. Methods: Healthy individuals (N = 247, 24.26 +/- 3.88 years) were randomized to eight different groups watching videos of a moderate, a vigorous exercise treatment or one control group treatment (waiting, reading, video-watching, stretching, myofascial release workout, and very light exercise). Then, they were introduced to three commonly used cognitive test procedures in acute exercise-cognition research (Stroop-test, Trail-Making-test, Free-recall-task). Participants rated the effect they would expect on their performance in those tasks, if they had received the treatment shortly before the task, on an 11-point Likert scale. Results: No significantly different expectations for cognitive benefits toward acute moderate exercise and control group treatments could be revealed. Participants expected significantly worse performance following vigorous exercise compared to following waiting and stretching for all cognitive tests. Significantly worse performance after vigorous exercise compared to after very light exercise was expected for Stroop and Free-recall. For Free-recall, participants expected worse performance after vigorous exercise compared to myofascial release training as well. Conclusion: Our results indicate that expectation-driven placebo effects are unlikely to cause the reported greater cognitive improvements following acute moderate and vigorous endurance exercise compared to following common control group treatments. PMID- 29276484 TI - Commentary: What Is Art Good For? The Socio-Epistemic Value of Art. PMID- 29276485 TI - Modeling Behavioral Experiment Interaction and Environmental Stimuli for a Synthetic C. elegans. AB - This paper focusses on the simulation of the neural network of the Caenorhabditis elegans living organism, and more specifically in the modeling of the stimuli applied within behavioral experiments and the stimuli that is generated in the interaction of the C. elegans with the environment. To the best of our knowledge, all efforts regarding stimuli modeling for the C. elegansare focused on a single type of stimulus, which is usually tested with a limited subnetwork of the C. elegansneural system. In this paper, we follow a different approach where we model a wide-range of different stimuli, with more flexible neural network configurations and simulations in mind. Moreover, we focus on the stimuli sensation by different types of sensory organs or various sensory principles of the neurons. As part of this work, most common stimuli involved in behavioral assays have been modeled. It includes models for mechanical, thermal, chemical, electrical and light stimuli, and for proprioception-related self-sensed information exchange with the neural network. The developed models have been implemented and tested with the hardware-based Si elegans simulation platform. PMID- 29276486 TI - Combined Computational Systems Biology and Computational Neuroscience Approaches Help Develop of Future "Cognitive Developmental Robotics". PMID- 29276487 TI - Hippocampal Transcriptomic Profiles: Subfield Vulnerability to Age and Cognitive Impairment. AB - The current study employed next-generation RNA sequencing to examine gene expression differences related to brain aging, cognitive decline, and hippocampal subfields. Young and aged rats were trained on a spatial episodic memory task. Hippocampal regions CA1, CA3, and the dentate gyrus were isolated. Poly-A mRNA was examined using two different sequencing platforms, Illumina, and Ion Proton. The Illumina platform was used to generate seed lists of genes that were statistically differentially expressed across regions, ages, or in association with cognitive function. The gene lists were then retested using the data from the Ion Proton platform. The results indicate hippocampal subfield differences in gene expression and point to regional differences in vulnerability to aging. Aging was associated with increased expression of immune response-related genes, particularly in the dentate gyrus. For the memory task, impaired performance of aged animals was linked to the regulation of Ca2+ and synaptic function in region CA1. Finally, we provide a transcriptomic characterization of the three subfields regardless of age or cognitive status, highlighting and confirming a correspondence between cytoarchitectural boundaries and molecular profiling. PMID- 29276488 TI - Prebiotic Effect of Fructooligosaccharides from Morinda officinalis on Alzheimer's Disease in Rodent Models by Targeting the Microbiota-Gut-Brain Axis. AB - Gut microbiota influences the central nervous system disorders such as Alzheimer's disease (AD). The prebiotics and probiotics can improve the host cognition. A previous study demonstrated that fructooligosaccharides from Morinda officinalis (OMO) exert effective memory improvements in AD-like animals, thereby considered as potential prebiotics; however, the underlying mechanism still remains enigma. Thus, the present study investigated whether OMO is effective in alleviating AD by targeting the microbiota-gut-brain axis. OMO was administered in rats with AD-like symptoms (D-galactose- and Abeta1-42-induced deficient rats). Significant and systematic deterioration in AD-like animals were identified, including learning and memory abilities, histological changes, production of cytokines, and microbial community shifts. Behavioral experiments demonstrated that OMO administration can ameliorate the learning and memory abilities in both AD-like animals significantly. AD parameters showed that OMO administration cannot only improve oxidative stress and inflammation disorder, but also regulate the synthesis and secretion of neurotransmitter. Histological changes indicated that OMO administration ameliorates the swelling of brain tissues, neuronal apoptosis, and down-regulation of the expression of AD intracellular markers (Tau and Abeta1-42). 16S rRNA sequencing of gut microbiota indicated that OMO administration maintains the diversity and stability of the microbial community. In addition, OMO regulated the composition and metabolism of gut microbiota in inflammatory bowel disease (IBD) mice model treated by overdosed antibiotics and thus showed the prebiotic potential. Moreover, gut microbiota plays a major role in neurodevelopment, leading to alterations in gene expression in critical brain and intestinal regions, thereby resulting in perturbation to the programming of normal cognitive behaviors. Taken together, our findings suggest that the therapeutic effect of the traditional medicine, M. officinalis, on various neurological diseases such as AD, is at least partially contributed by its naturally occurring chemical constituent, OMO, via modulating the interaction between gut ecology and brain physiology. PMID- 29276489 TI - Multi-Protection of DL0410 in Ameliorating Cognitive Defects in D-Galactose Induced Aging Mice. AB - D-galactose has been reported to accelerate senescence in rodents, accompanied by a decline in learning and memory. We used a model of D-galactose-induced amnesia for the efficacy evaluation and pharmacologic studies of active compounds against Alzheimer's disease (AD). DL0410 is a potent inhibitor against acetylcholinesterase (AChE) and, in the present study, the effect of DL0410 was evaluated in this model. We found that DL0410 could significantly improve the learning and memory of D-galactose induced aging mice in a series of behavioral tests: novel-object recognition test, nest-building test, Morris water maze test and step-through test. Pharmacologic studies were conducted from several aspects: the cholinergic system, mitochondrial respiration, oxidative stress, neuroinflammation, apoptosis and synaptic loss. The acetylcholine level and AChE activity were not altered by D-galactose but were slightly affected by DL0410 in the brain. DL0410 could significantly improve decreased mitochondrial respiration in the NADH chain and FADH2 chain, and protect mitochondrial ultrastructure. DL0410 reduced the accumulation of advanced glycation end products (AGEs) and malondialdehyde (MDA) and increase the total antioxidant capability of the brain via an increase in activity of catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD). RAGE expression was inhibited by DL0410, followed by the decreased activation of astrocytes and microglia. Subsequent phosphorylation of NF-kappaB was also reversed by DL0410, with lower expression of cyclooxygenase 2 (COX2) and iNOS. With respect to apoptosis, the activation of caspase 3 and cleavage of PARP were downregulated significantly by DL0410, after the inhibition of phosphorylation of JNK induced by inflammation and oxidative stress. Synaptic protection by DL0410 was also demonstrated. These data suggest that mitochondrial protection has a primary role in the ameliorating effect of DL0410 on the impaired learning and memory, oxidative stress, inflammation, apoptosis and synaptic loss induced by D-galactose. DL0410 is a promising candidate for the treatment of aging-related AD, and this study lays an important foundation for its further research and development. PMID- 29276490 TI - Dual Frequency Head Maps: A New Method for Indexing Mental Workload Continuously during Execution of Cognitive Tasks. AB - One goal of advanced information and communication technology is to simplify work. However, there is growing consensus regarding the negative consequences of inappropriate workload on employee's health and the safety of persons. In order to develop a method for continuous mental workload monitoring, we implemented a task battery consisting of cognitive tasks with diverse levels of complexity and difficulty. We conducted experiments and registered the electroencephalogram (EEG), performance data, and the NASA-TLX questionnaire from 54 people. Analysis of the EEG spectra demonstrates an increase of the frontal theta band power and a decrease of the parietal alpha band power, both under increasing task difficulty level. Based on these findings we implemented a new method for monitoring mental workload, the so-called Dual Frequency Head Maps (DFHM) that are classified by support vectors machines (SVMs) in three different workload levels. The results are in accordance with the expected difficulty levels arising from the requirements of the tasks on the executive functions. Furthermore, this article includes an empirical validation of the new method on a secondary subset with new subjects and one additional new task without any adjustment of the classifiers. Hence, the main advantage of the proposed method compared with the existing solutions is that it provides an automatic, continuous classification of the mental workload state without any need for retraining the classifier-neither for new subjects nor for new tasks. The continuous workload monitoring can help ensure good working conditions, maintain a good level of performance, and simultaneously preserve a good state of health. PMID- 29276491 TI - Distribution of Glycan Motifs at the Surface of Midgut Cells in the Cotton Leafworm (Spodoptera littoralis) Demonstrated by Lectin Binding. AB - Glycans are involved in many biological phenomena, including signal transduction, cell adhesion, immune response or differentiation. Although a few papers have reported on the role of glycans in the development and proper functioning of the insect midgut, no data are available regarding the localization of the glycan structures on the surface of the cells in the gut of insects. In this paper, we analyzed the spatial distribution of glycans present on the surface of the midgut cells in larvae of the cotton leafworm Spodoptera littoralis, an important agricultural pest insect worldwide. For this purpose, we established primary midgut cell cultures, probed these individual cells that are freely suspended in liquid medium with a selection of seven fluorescently labeled lectins covering a range of different carbohydrate binding specificities [mannose oligomers (GNA and HHA), GalNAc/Gal (RSA and SSA), GlcNAc (WGA and Nictaba) and Neu5Ac(alpha 2,6)Gal/GalNAc (SNA-I)], and visualized the interaction of these lectins with the different zones of the midgut cells using confocal microscopy. Our analysis focused on the typical differentiated columnar cells with a microvillar brush border at their apical side, which are dominantly present in the Lepidopteran midgut and function in food digestion and absorption, and as well as on the undifferentiated stem cells that are important for midgut development and repair. Confocal microscopy analyses showed that the GalNAc/Gal-binding lectins SSA and RSA and the terminal GlcNAc-recognizing WGA bound preferentially to the apical microvillar zone of the differentiated columnar cells as compared to the basolateral pole. The reverse result was observed for the mannose-binding lectins GNA and HHA, as well as Nictaba that binds preferentially to GlcNAc oligomers. Furthermore, differences in lectin binding to the basal and lateral zones of the cell membranes of the columnar cells were apparent. In the midgut stem cells, GNA and Nictaba bound more strongly to the membrane of these undifferentiated cells compared to the microvillar pole of the columnar cells, while SSA, HHA, WGA, and SNA-I showed stronger binding to the microvilli. Our results indicated that polarization of the midgut cells is also reflected by a specific distribution of glycans, especially between the basal and microvillar pole. The data are discussed in relation to the functioning and development of the insect midgut. PMID- 29276492 TI - Age Bias in Selection Decisions: The Role of Facial Appearance and Fitness Impressions. AB - This research examined the impact of facial age appearance on hiring, and impressions of fitness as the underlying mechanism. In two experimental hiring simulations, one with lay persons and one with Human Resource professionals, participants evaluated a chronologically older or younger candidate (as indicated by date of birth and age label) with either younger or older facial age appearance (as indicated by a photograph). In both studies, older-looking candidates received lower hireability ratings, due to less favorable fitness impressions. In addition, Study 1 showed that this age bias was reduced when the candidates provided counter-stereotypic information about their fitness. Study 2 showed that facial age-based discrimination is less prevalent in jobs with less costumer contact (e.g., back office). PMID- 29276493 TI - Learning Spoken Words via the Ears and Eyes: Evidence from 30-Month-Old Children. AB - From the very first moments of their lives, infants are able to link specific movements of the visual articulators to auditory speech signals. However, recent evidence indicates that infants focus primarily on auditory speech signals when learning new words. Here, we ask whether 30-month-old children are able to learn new words based solely on visible speech information, and whether information from both auditory and visual modalities is available after learning in only one modality. To test this, children were taught new lexical mappings. One group of children experienced the words in the auditory modality (i.e., acoustic form of the word with no accompanying face). Another group experienced the words in the visual modality (seeing a silent talking face). Lexical recognition was tested in either the learning modality or in the other modality. Results revealed successful word learning in either modality. Results further showed cross-modal recognition following an auditory-only, but not a visual-only, experience of the words. Together, these findings suggest that visible speech becomes increasingly informative for the purpose of lexical learning, but that an auditory-only experience evokes a cross-modal representation of the words. PMID- 29276494 TI - No Sensory Compensation for Olfactory Memory: Differences between Blind and Sighted People. AB - Blindness can be a driving force behind a variety of changes in sensory systems. When vision is missing, other modalities and higher cognitive functions can become hyper-developed through a mechanism called sensory compensation. Overall, previous studies suggest that olfactory memory in blind people can be better than that of the sighted individuals. Better performance of blind individuals in other sensory modalities was hypothesized to be a result of, among others, intense perceptual training. At the same time, if the superiority of blind people in olfactory abilities indeed results from training, their scores should not decrease with age to such an extent as among the sighted people. Here, this hypothesis was tested in a large sample of 94 blind individuals. Olfactory memory was assessed using the Test for Olfactory Memory, comprising episodic odor recognition (discriminating previously presented odors from new odors) and two forms of semantic memory (cued and free identification of odors). Regarding episodic olfactory memory, we observed an age-related decline in correct hits in blind participants, but an age-related increase in false alarms in sighted participants. Further, age moderated the between-group differences for correct hits, but the direction of the observed effect was contrary to our expectations. The difference between blind and sighted individuals younger than 40 years old was non-significant, but older sighted individuals outperformed their blind counterparts. In conclusion, we found no positive effect of visual impairment on olfactory memory. We suggest that daily perceptual training is not enough to increase olfactory memory function in blind people. PMID- 29276495 TI - Verbal Learning and Memory in Cannabis and Alcohol Users: An Event-Related Potential Investigation. AB - Aims: Long-term heavy use of cannabis and alcohol are known to be associated with memory impairments. In this study, we used event-related potentials to examine verbal learning and memory processing in a commonly used behavioral task. Method: We conducted two studies: first, a small pilot study of adolescent males, comprising 13 Drug-Naive Controls (DNC), 12 heavy drinkers (HD) and 8 cannabis users (CU). Second, a larger study of young adults, comprising 45 DNC (20 female), 39 HD (16 female), and 20 CU (9 female). In both studies, participants completed a modified verbal learning task (the Rey Auditory Verbal Learning Test, RAVLT) while brain electrical activity was recorded. ERPs were calculated for words which were subsequently remembered vs. those which were not remembered, and for presentations of learnt words, previously seen words, and new words in a subsequent recognition test. Pre-planned principal components analyses (PCA) were used to quantify the ERP components in these recall and recognition phases separately for each study. Results: Memory performance overall was slightly lower than published norms using the standardized RAVLT delivery, but was generally similar and showed the expected changes over trials. Few differences in performance were observed between groups; a notable exception was markedly poorer delayed recall in HD relative to DNC (Study 2). PCA identified components expected from prior research using other memory tasks. At encoding, there were no between-group differences in the usual P2 recall effect (larger for recalled than not-recalled words). However, alcohol-related differences were observed in a larger P540 (indexing recollection) in HD than DNC, and cannabis-related differences were observed in a smaller N340 (indexing familiarity) and a lack of previously seen > new words effect for P540 in Study 2. Conclusions: This study is the first examination of ERPs in the RAVLT in healthy control participants, as well as substance-using individuals, and represents an important advance in methodology. The results indicate alterations in recognition memory processing, which even if not manifesting in overt behavioral impairment, underline the potential for brain dysfunction with early exposure to alcohol and cannabis. PMID- 29276496 TI - The Interplay between Topic Shift and Focus in the Dynamic Construction of Discourse Representations. AB - Previous studies have suggested that focusing an element can enhance the activation of the focused element and bring about a number of processing benefits. However, whether and how this local prominence of information interacts with global discourse organization remains unclear. In the present study, we addressed this issue in two experiments. Readers were presented with four sentence discourses. The first sentence of each discourse contained a critical word that was either focused or unfocused in relation to a wh-question preceding the discourse. The second sentence either maintained or shifted the topic of the first sentence. Participants were told to read for comprehension and for a probe recognition task in which the memory of the critical words was tested. In Experiment 1, when the probe words were tested immediately after the point of topic shift, we found shorter response times for the focused critical words than the unfocused ones regardless of topic manipulation. However, in Experiment 2, when the probe words were tested two sentences away from the point of topic shift, we found the facilitation effect of focus only in the topic-maintained discourses, but not in the topic-shifted discourses. This suggests that the facilitation effect of focus was not immediately suppressed at the point of topic shifting, but when additional information was added to the new topic. Our findings provide evidence for the dynamic interplay between global topic structure and local salience of information and have important implications on how activation of information fluctuates in mental representation. PMID- 29276497 TI - Commentary: Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain. PMID- 29276498 TI - Role of Hyperintense Acute Reperfusion Marker for Classifying the Stroke Etiology. AB - Purpose: The hyperintense acute reperfusion marker (HARM) is a delayed enhancement of the subarachnoid or subpial space observed on post-contrast fluid attenuated inversion recovery (FLAIR) images and is associated with permeability changes to the blood-brain barrier in acute stroke. We investigated the relationship between HARM and stroke etiology based on the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. In addition, we evaluated the relationship between HARM and stroke locations with respect to vascular territories and anatomic compartments. Materials and methods: We recruited 264 consecutive patients (109 women; mean age 68.63 years) who were diagnosed with acute ischemic stroke and underwent brain magnetic resonance imaging (MRI) including post-contrast FLAIR and DWI within 7 days of symptom onset from May 2015 to March 2016 for this retrospective study. Post-contrast FLAIR images were obtained 5 min after gadolinium administration. The mean time interval between the onset of stroke symptoms and MRI acquisition in total included patients was 18 h and 7 min (median 12 h and 57 min, range 2-127 h). We analyzed the overall incidence and distribution patterns of HARM in acute ischemic stroke cases and compared the relative incidence and distribution patterns of HARM between the subgroups of stroke etiology based on conventional TOAST classification. We obtained odds ratio (OR) of HARM in different stroke locations based on vascular territories and anatomical compartments. This study was approved by our institutional review board. Results: Among the 264 patients, 67 (25.38%) patients were HARM positive and 197 (74.62%) patients were HARM negative. There was significant difference in HARM incidence among the stroke subgroups (p < 0.001). Small vessel occlusion (SVO) was associated with the HARM-negative group (p < 0.001), while large artery atherosclerosis (LAA) and cardioembolism (CE) were associated with the HARM-positive group (p = 0.001). Also, regional pattern of HARM on the same vascular territory as the acute infarction was dominantly demonstrated regardless of stroke etiology. The OR for HARM from middle cerebral artery (MCA) infarction was 1.868 [95% confidence interval (CI): 1.025-3.401]. The OR for HARM from cortical infarction was 9.475 (95% CI: 4.754-18.883) compared to other anatomic compartments. Conclusion: The presence of the HARM was significantly associated with embolic infarctions including LAA and CE. Conversely, SVO was exclusively associated with the absence of the HARM. Second, MCA and cortical infarction showed a more pronounced HARM compared to infarctions at other vascular territories and anatomic compartments. According to the results in the current study, we speculate that the presence of HARM on post-contrast FLAIR images was associated with specific stroke causes especially in embolic causes. PMID- 29276499 TI - Usability of Videogame-Based Dexterity Training in the Early Rehabilitation Phase of Stroke Patients: A Pilot Study. AB - Background: Approximately 70-80% of stroke survivors have limited activities of daily living, mainly due to dexterous problems. Videogame-based training (VBT) along with virtual reality seems to be beneficial to train upper limb function. Objective: To evaluate the usability of VBT using the Leap Motion Controller (LMC) to train fine manual dexterity in the early rehabilitation phase of stroke patients as an add-on to conventional therapy. Additionally, this study aimed to estimate the feasibility and potential efficacy of the VBT. Methods: During 3 months, 64 stroke patients were screened for eligibility, 13 stroke patients were included (4 women and 9 men; age range: 24-91 years; mean time post stroke: 28.2 days). Intervention: Nine sessions of 30 min VBT, three times per week as an add on to conventional therapy with stroke inpatients. Outcome measures: Primary outcome was the usability of the system measured with the System Usability Scale. Secondary outcomes concerning feasibility were the compliance rate calculated from the total time spent on the intervention (TT) compared to planned time, the opinion of participants via open-end questions, and the level of active participation measured with the Pittsburgh Rehabilitation Participation Scale. Regarding the potential efficacy secondary outcomes were: functional dexterity measured with the Nine Hole Peg Test (NHPT), subjective dexterity measured with the Dexterity Questionnaire 24, grip strength measured with the Jamar dynamometer, and motor impairment of the upper limb measured with the Fugl-Meyer Upper Extremity (FM-UE) scale. Results: Primarily, the usability of the system was good to excellent. The patient's perception of usability remained stable over a mean period of 3 weeks of VBT. Secondly, the compliance rate was good, and the level of active participation varied between good and very good. The opinion of the participants revealed that despite individual differences, the overall impression of the therapy and device was good. Patients showed significant improvements in hand dexterity. No changes were found in motor impairment of the upper limb (FM-UE) during intervention. Conclusion: VBT using LMC is a usable rehabilitation tool to train dexterity in the early rehabilitation phase of stroke inpatients. PMID- 29276500 TI - Initial Response to Antiepileptic Drugs in Patients with Newly Diagnosed Epilepsy As a Predictor of Long-term Outcome. AB - Objective: To investigate the correlation between initial response to antiepileptic drugs (AEDs) and long-term outcomes after 3 years in patients with newly diagnosed epilepsy. Methods: This prospective study included 204 patients with newly diagnosed epilepsy, who were followed-up for at least 36 months. The long-term seizure freedom at 36 months (36MSF) was evaluated in patients with seizure freedom 6 months (6MSF) or 12 months (12MSF) after initial treatment vs those with no seizure freedom after the initial 6 months (6MNSF) or 12 months (12MNSF). Univariate analysis and a multiple logistic regression model were used to analyze the association of potential confounding variables with the initial response to AEDs. Results: The number of patients with 36MSF was significantly higher for patients that had 6MSF (94/131, 71.8%) than those that had 6MNSF [16/73, 21.9%; chi2 = 46.862, p < 0.0001, odd ratio (OR) = 9.051]. The number of patients with 36MSF was significantly higher in patients that had 12MSF (94/118 79.7%) than those that had 12MNSF (19/86, 22.1%; chi2 = 66.720, p < 0.0001, OR = 13.811). The numbers of patients that had 36MSF were not significantly different between patients that experienced 6MSF and 12MSF or between patients that had 6MNSF and 12MNSF. Abnormalities observed in magnetic resonance imaging or computed tomography and the number of seizures before treatment correlated with poor initial 6-month response to AEDs. Significance: The initial 6-month response to AEDs is a valuable predictor of long-term response in patients with newly diagnosed epilepsy. The number of seizures before treatment and brain-imaging abnormalities are two prognostic predictors of initial 6-month seizure freedom. PMID- 29276501 TI - Host and Pathway Engineering for Enhanced Lycopene Biosynthesis in Yarrowia lipolytica. AB - Carotenoids are a class of molecules with commercial value as food and feed additives with nutraceutical properties. Shifting carotenoid synthesis from petrochemical-based precursors to bioproduction from sugars and other biorenewable carbon sources promises to improve process sustainability and economics. In this work, we engineered the oleaginous yeast Yarrowia lipolytica to produce the carotenoid lycopene. To enhance lycopene production, we tested a series of strategies to modify host cell physiology and metabolism, the most successful of which were mevalonate pathway overexpression and alleviating auxotrophies previously engineered into the PO1f strain of Y. lipolytica. The beneficial engineering strategies were combined into a single strain, which was then cultured in a 1-L bioreactor to produce 21.1 mg/g DCW. The optimized strain overexpressed a total of eight genes including two copies of HMG1, two copies of CrtI, and single copies of MVD1, EGR8, CrtB, and CrtE. Recovering leucine and uracil biosynthetic capacity also produced significant enhancement in lycopene titer. The successful engineering strategies characterized in this work represent a significant increase in understanding carotenoid biosynthesis in Y. lipolytica, not only increasing lycopene titer but also informing future studies on carotenoid biosynthesis. PMID- 29276502 TI - Composition of Micro-eukaryotes on the Skin of the Cascades Frog (Rana cascadae) and Patterns of Correlation between Skin Microbes and Batrachochytrium dendrobatidis. AB - Global amphibian decline linked to fungal pathogens has galvanized research on applied amphibian conservation. Skin-associated bacterial communities of amphibians have been shown to mediate fungal skin infections and the development of probiotic treatments with antifungal bacteria has become an emergent area of research. While exploring the role of protective bacteria has been a primary focus for amphibian conservation, we aim to expand and study the other microbes present in amphibian skin communities including fungi and other micro-eukaryotes. Here, we characterize skin-associated bacteria and micro-eukaryotic diversity found across life stages of Cascades frog (Rana cascadae) and their associated aquatic environments using culture independent 16S and 18S rRNA marker-gene sequencing. Individuals of various life stages of Cascades frogs were sampled from a population located in the Trinity Alps in Northern California during an epidemic of the chytrid fungus, Batrachochytrium dendrobatidis. We filtered the bacterial sequences against a published database of bacteria known to inhibit B. dendrobatidis in co-culture to estimate the proportion of the skin bacterial community that is likely to provide defense against B. dendrobatidis. Tadpoles had a significantly higher proportion of B. dendrobatidis-inhibitory bacterial sequence matches relative to subadult and adult Cascades frogs. We applied a network analysis to examine patterns of correlation between bacterial taxa and B. dendrobatidis, as well as micro-eukaryotic taxa and B. dendrobatidis. Combined with the published database of bacteria known to inhibit B. dendrobatidis, we used the network analysis to identify bacteria that negatively correlated with B. dendrobatidis and thus could be good probiotic candidates in the Cascades frog system. PMID- 29276504 TI - Strong Genomic and Phenotypic Heterogeneity in the Aeromonas sobria Species Complex. AB - Aeromonas sobria is a mesophilic motile aeromonad currently depicted as an opportunistic pathogen, despite increasing evidence of mutualistic interactions in salmonid fish. However, the determinants of its host-microbe associations, either mutualistic or pathogenic, remain less understood than for other aeromonad species. On one side, there is an over-representation of pathogenic interactions in the A. sobria literature, of which only three articles to date report mutualistic interactions; on the other side, genomic characterization of this species is still fairly incomplete as only two draft genomes were published prior to the present work. Consequently, no study specifically investigated the biodiversity of A. sobria. In fact, the investigation of A. sobria as a species complex may have been clouded by: (i) confusion with A. veronii biovar sobria because of their similar biochemical profiles, and (ii) the intrinsic low resolution of previous studies based on 16S rRNA gene sequences and multilocus sequence typing. So far, the only high-resolution, phylogenomic studies of the genus Aeromonas included one A. sobria strain (CECT 4245 / Popoff 208), making it impossible to robustly conclude on the phylogenetic intra-species diversity and the positioning among other Aeromonas species. To further understand the biodiversity and the spectrum of host-microbe interactions in A. sobria as well as its potential genomic diversity, we assessed the genomic and phenotypic heterogeneity among five A. sobria strains: two clinical isolates recovered from infected fish (JF2635 and CECT 4245), one from an infected amphibian (08005) and two recently isolated brook charr probionts (TM12 and TM18) which inhibit in vitro growth of A. salmonicida subsp. salmonicida (a salmonid fish pathogen). A phylogenomic assessment including 2,154 softcore genes corresponding to 946,687 variable sites from 33 Aeromonas genomes confirms the status of A. sobria as a distinct species divided in two subclades, with 100% bootstrap support. The phylogenomic split of A. sobria in two subclades is corroborated by a deep dichotomy between all five A. sobria strains in terms of inhibitory effect against A. salmonicida subsp. salmonicida, gene contents and codon usage. Finally, the antagonistic effect of A. sobria strains TM12 and TM18 suggests novel control methods against A. salmonicida subsp. salmonicida. PMID- 29276505 TI - Contribution of RaeB, a Putative RND-Type Transporter to Aminoglycoside and Detergent Resistance in Riemerella anatipestifer. AB - Riemerella anatipestifer is an important pathogenic bacterium that infects ducks. It exhibits resistance to multiple classes of antibiotics. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens and they are poorly understood in R. anatipestifer. In this study, a gene encoding the B739_0873 protein in R. anatipestifer CH-1, which belongs to the resistance-nodulation-cell division (RND) efflux pump family, was identified. With respect to the substrate specificity of B739_0873, the antibiotic susceptibility testing showed that the B739_0873 knockout strain was more sensitive to aminoglycosides and detergents than the wild-type strain. The transcription of B739_0873 was up-regulated when R. anatipestifer CH-1 was exposed to sub-inhibitory levels of these substrates. From the gentamicin accumulation assay, we concluded that B739_0873 was coupled to the proton motive force to pump out gentamicin. Furthermore, site-directed mutagenesis demonstrated that Asp 400, Asp 401, Lys 929, Arg 959, and Thr 966 were the crucial function sites of B739_0873 in terms of its ability to extrude aminoglycosides and detergents. Finally, we provided evidence that B739_0873 is co-transcribed with B739_0872, and that both B739_0872 and B739_0873 are required for aminoglycoside and detergent resistance. In view of these results, we designate B739_0873 as RaeB (Riemerella anatipestifer efflux). PMID- 29276503 TI - Synergistic Antimicrobial Interaction between Honey and Phage against Escherichia coli Biofilms. AB - Chronic wounds afford a hostile environment of damaged tissues that allow bacterial proliferation and further wound colonization. Escherichia coli is among the most common colonizers of infected wounds and it is a prolific biofilm former. Living in biofilm communities, cells are protected, become more difficult to control and eradicate, and less susceptible to antibiotic therapy. This work presents insights into the proceedings triggering E. coli biofilm control with phage, honey, and their combination, achieved through standard antimicrobial activity assays, zeta potential and flow cytometry studies and further visual insights sought by scanning electron microscopy and transmission electron microscopy. Two Portuguese honeys (PF2 and U3) with different floral origin and an E. coli-specific phage (EC3a), possessing depolymerase activity, were tested against 24- and 48-h-old biofilms. Synergic and additive effects were perceived in some phage-honey experiments. Combined therapy prompted similar phenomena in biofilm cells, visualized by electron microscopy, as the individual treatments. Honey caused minor membrane perturbations to complete collapse and consequent discharge of cytoplasmic content, and phage completely destroyed cells leaving only vesicle-like structures and debris. Our experiments show that the addition of phage to low honey concentrations is advantageous, and that even fourfold diluted honey combined with phage, presents no loss of antibacterial activity toward E. coli. Portuguese honeys possess excellent antibiofilm activity and may be potential alternative therapeutic agents in biofilm-related wound infection. Furthermore, to our knowledge this is the first study that assessed the impacts of phage-honey combinations in bacterial cells. The synergistic effect obtained was shown to be promising, since the antiviral effect of honey limits the emergence of phage resistant phenotypes. PMID- 29276506 TI - Escherichia coli O157:H7 Converts Plant-Derived Choline to Glycine Betaine for Osmoprotection during Pre- and Post-harvest Colonization of Injured Lettuce Leaves. AB - Plant injury is inherent to the production and processing of fruit and vegetables. The opportunistic colonization of damaged plant tissue by human enteric pathogens may contribute to the occurrence of outbreaks of foodborne illness linked to produce. Escherichia coli O157:H7 (EcO157) responds to physicochemical stresses in cut lettuce and lettuce lysates by upregulation of several stress response pathways. We investigated the tolerance of EcO157 to osmotic stress imposed by the leakage of osmolytes from injured lettuce leaf tissue. LC-MS analysis of bacterial osmoprotectants in lettuce leaf lysates and wound washes indicated an abundant natural pool of choline, but sparse quantities of glycine betaine and proline. Glycine betaine was a more effective osmoprotectant than choline in EcO157 under osmotic stress conditions in vitro. An EcO157 mutant with a deletion of the betTIBA genes, which are required for biosynthesis of glycine betaine from imported choline, achieved population sizes twofold lower than those of the parental strain (P < 0.05) over the first hour of colonization of cut lettuce in modified atmosphere packaging (MAP). The cell concentrations of the betTIBA mutant also were 12-fold lower than those of the parental strain (P < 0.01) when grown in hypertonic lettuce lysate, indicating that lettuce leaf cellular contents provide choline for osmoprotection of EcO157. To demonstrate the utilization of available choline by EcO157 for osmoadaptation in injured leaf tissue, deuterated (D-9) choline was introduced to wound sites in MAP lettuce; LC-MS analysis revealed the conversion of D9-choline to D-9 glycine betaine in the parental strain, but no significant amounts were observed in the betTIBA mutant. The EcO157 DeltabetTIBA-DeltaotsBA double mutant, which is additionally deficient in de novo synthesis of the compatible solute trehalose, was significantly less fit than the parental strain after their co-inoculation onto injured lettuce leaves and MAP cut lettuce. However, its competitive fitness followed a different time-dependent trend in MAP lettuce, likely due to differences in O2 content, which modulates betTIBA expression. Our study demonstrates that damaged lettuce leaf tissue does not merely supply EcO157 with substrates for proliferation, but also provides the pathogen with choline for its survival to osmotic stress experienced at the site of injury. PMID- 29276507 TI - In Silico Analysis of the Small Molecule Content of Outer Membrane Vesicles Produced by Bacteroides thetaiotaomicron Indicates an Extensive Metabolic Link between Microbe and Host. AB - The interactions between the gut microbiota and its host are of central importance to the health of the host. Outer membrane vesicles (OMVs) are produced ubiquitously by Gram-negative bacteria including the gut commensal Bacteroides thetaiotaomicron. These vesicles can interact with the host in various ways but until now their complement of small molecules has not been investigated in this context. Using an untargeted high-coverage metabolomic approach we have measured the small molecule content of these vesicles in contrasting in vitro conditions to establish what role these metabolites could perform when packed into these vesicles. B. thetaiotaomicron packs OMVs with a highly conserved core set of small molecules which are strikingly enriched with mouse-digestible metabolites and with metabolites previously shown to be associated with colonization of the murine GIT. By use of an expanded genome-scale metabolic model of B. thetaiotaomicron and a potential host (the mouse) we have established many possible metabolic pathways between the two organisms that were previously unknown, and have found several putative novel metabolic functions for mouse that are supported by gene annotations, but that do not currently appear in existing mouse metabolic networks. The lipidome of these OMVs bears no relation to the mouse lipidome, so the purpose of this particular composition of lipids remains unclear. We conclude from this analysis that through intimate symbiotic evolution OMVs produced by B. thetaiotaomicron are likely to have been adopted as a conduit for small molecules bound for the mammalian host in vivo. PMID- 29276508 TI - Biofilm Surface Density Determines Biocide Effectiveness. AB - High resistance of biofilms for chemical challenges is a serious industrial and medical problem. In this work a gradient of surface covered with biofilm has been produced and correlated to the effectiveness of different commercially available oxidative biocides. The results for thin Escherichia coli biofilms grown in rich media supplemented with glucose or lactose on glass or poly methyl methacrylate surfaces indicate that the effectiveness of hydrogen peroxide or chlorine dioxide and quaternary ammonium compounds is inversely proportional to the fraction of the surface covered with the biofilm. In areas where biofilm covered more than 90% of the available surface the biocide treatment was inefficient after 60 min of incubation. The combined effect of oxidant and surfactant increased the effectiveness of the biocide. On the other hand, the increased biofilm viscoelasticity reduced biocide effectiveness. The results emphasize differential biocide effectiveness depending on the fraction of the attached bacterial cells. The results suggest that biofilm biocide resistance is an acquired property that increases with biofilm maturation. The more dense sessile structures present lower log reductions compared to less dense ones. PMID- 29276509 TI - Anti-biofilm Properties of Bacterial Di-Rhamnolipids and Their Semi-Synthetic Amide Derivatives. AB - A new strain, namely Lysinibacillus sp. BV152.1 was isolated from the rhizosphere of ground ivy (Glechoma hederacea L.) producing metabolites with potent ability to inhibit biofilm formation of an important human pathogens Pseudomonas aeruginosa PAO1, Staphylococcus aureus, and Serratia marcescens. Structural characterization revealed di-rhamnolipids mixture containing rhamnose (Rha)-Rha C10-C10, Rha-Rha-C8-C10, and Rha-Rha-C10-C12 in the ratio 7:2:1 as the active principle. Purified di-rhamnolipids, as well as commercially available di rhamnolipids (Rha-Rha-C10-C10, 93%) were used as the substrate for the chemical derivatization for the first time, yielding three semi-synthetic amide derivatives, benzyl-, piperidine-, and morpholine. A comparative study of the anti-biofilm, antibacterial and cytotoxic properties revealed that di-Rha from Lysinibacillus sp. BV152.1 were more potent in biofilm inhibition, both cell adhesion and biofilm maturation, than commercial di-rhamnolipids inhibiting 50% of P. aeruginosa PAO1 biofilm formation at 50 MUg mL-1 and 75 MUg mL-1, respectively. None of the di-rhamnolipids exhibited antimicrobial properties at concentrations of up to 500 MUg mL-1. Amide derivatization improved inhibition of biofilm formation and dispersion activities of di-rhamnolipids from both sources, with morpholine derivative being the most active causing more than 80% biofilm inhibition at concentrations 100 MUg mL-1. Semi-synthetic amide derivatives showed increased antibacterial activity against S. aureus, and also showed higher cytotoxicity. Therefore, described di-rhamnolipids are potent anti-biofilm agents and the described approach can be seen as viable approach in reaching new rhamnolipid based derivatives with tailored biological properties. PMID- 29276512 TI - Low-Density Lipoprotein Receptor Deficiency Attenuates Neuroinflammation through the Induction of Apolipoprotein E. AB - Objective: We aimed to determine the role of the low-density lipoprotein receptor (LDLr) in neuroinflammation by inducing experimental autoimmune encephalomyelitis (EAE) in ldlr knock out mice. Methods: MOG35-55 induced EAE in male and female ldlr-/- mice was assessed clinically and histopathologically. Expression of inflammatory mediators and apolipoprotein E (apoE) was investigated by qPCR. Changes in protein levels of apoE and tumor necrosis factor alpha (TNFalpha) were validated by western blot and ELISA, respectively. Results: Ldlr-/--attenuated EAE disease severity in female, but not in male, EAE mice marked by a reduced proinflammatory cytokine production in the central nervous system of female ldlr /- mice. Macrophages from female ldlr-/- mice showed a similar decrease in proinflammatory mediators, an impaired capacity to phagocytose myelin and enhanced secretion of the anti-inflammatory apoE. Interestingly, apoE/ldlr double knock out abrogated the beneficial effect of ldlr depletion in EAE. Conclusion: Collectively, we show that ldlr-/- reduces EAE disease severity in female but not in male EAE mice, and that this can be explained by increased levels of apoE in female ldlr-/- mice. Although the reason for the observed sexual dimorphism remains unclear, our findings show that LDLr and associated apoE levels are involved in neuroinflammatory processes. PMID- 29276511 TI - Generation and Functional In Vitro Analysis of Semliki Forest Virus Vectors Encoding TNF-alpha and IFN-gamma. AB - Cytokine gene delivery by viral vectors is a promising novel strategy for cancer immunotherapy. Semliki Forest virus (SFV) has many advantages as a delivery vector, including the ability to (i) induce p53-independent killing of tumor cells via apoptosis, (ii) elicit a type-I interferon (IFN) response, and (iii) express high levels of the transgene. SFV vectors encoding cytokines such as interleukin (IL)-12 have shown promising therapeutic responses in experimental tumor models. Here, we developed two new recombinant SFV vectors encoding either murine tumor necrosis factor-alpha (TNF-alpha) or murine interferon-gamma (IFN gamma), two cytokines with documented immunostimulatory and antitumor activity. The SFV vector showed high infection rate and cytotoxicity in mouse and human lung carcinoma cells in vitro. By contrast, mouse and human macrophages were resistant to infection with SFV. The recombinant SFV vectors directly inhibited mouse lung carcinoma cell growth in vitro, while exploiting the cancer cells for production of SFV vector-encoded cytokines. The functionality of SFV vector derived TNF-alpha was confirmed through successful induction of cell death in TNF alpha-sensitive fibroblasts in a concentration-dependent manner. SFV vector derived IFN-gamma activated macrophages toward a tumoricidal phenotype leading to suppressed Lewis lung carcinoma cell growth in vitro in a concentration-dependent manner. The ability of SFV to provide functional cytokines and infect tumor cells but not macrophages suggests that SFV may be very useful for cancer immunotherapy employing tumor-infiltrating macrophages. PMID- 29276513 TI - Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization. AB - Mice transplanted with human cord blood-derived hematopoietic stem cells (HSCs) became a powerful experimental tool for studying the heterogeneity of human immune reconstitution and immune responses in vivo. Yet, analyses of human T cell maturation in humanized models have been hampered by an overall low immune reactivity and lack of methods to define predictive markers of responsiveness. Long-lived human lentiviral induced dendritic cells expressing the cytomegalovirus pp65 protein (iDCpp65) promoted the development of pp65-specific human CD8+ T cell responses in NOD.Cg-Rag1 tm1Mom -Il2rgamma tm1Wj humanized mice through the presentation of immune-dominant antigenic epitopes (signal 1), expression of co-stimulatory molecules (signal 2), and inflammatory cytokines (signal 3). We exploited this validated system to evaluate the effects of mouse sex in the dynamics of T cell homing and maturation status in thymus, blood, bone marrow, spleen, and lymph nodes. Statistical analyses of cell relative frequencies and absolute numbers demonstrated higher CD8+ memory T cell reactivity in spleen and lymph nodes of immunized female mice. In order to understand to which extent the multidimensional relation between organ-specific markers predicted the immunization status, the immunophenotypic profiles of individual mice were used to train an artificial neural network designed to discriminate immunized and non-immunized mice. The highest accuracy of immune reactivity prediction could be obtained from lymph node markers of female mice (77.3%). Principal component analyses further identified clusters of markers best suited to describe the heterogeneity of immunization responses in vivo. A correlation analysis of these markers reflected a tissue-specific impact of immunization. This allowed for an organ-resolved characterization of the immunization status of individual mice based on the identified set of markers. This new modality of multidimensional analyses can be used as a framework for defining minimal but predictive signatures of human immune responses in mice and suggests critical markers to characterize responses to immunization after HSC transplantation. PMID- 29276510 TI - Recent Successes and Future Directions in Immunotherapy of Cutaneous Melanoma. AB - The global health burden associated with melanoma continues to increase while treatment options for metastatic melanoma are limited. Nevertheless, in the past decade, the field of cancer immunotherapy has witnessed remarkable advances for the treatment of a number of malignancies including metastatic melanoma. Although the earliest observations of an immunological antitumor response were made nearly a century ago, it was only in the past 30 years, that immunotherapy emerged as a viable therapeutic option, in particular for cutaneous melanoma. As such, melanoma remains the focus of various preclinical and clinical studies to understand the immunobiology of cancer and to test various tumor immunotherapies. Here, we review key recent developments in the field of immune-mediated therapy of melanoma. Our primary focus is on therapies that have received regulatory approval. Thus, a brief overview of the pathophysiology of melanoma is provided. The purported functions of various tumor-infiltrating immune cell subsets are described, in particular the recently described roles of intratumoral dendritic cells. The section on immunotherapies focuses on strategies that have proved to be the most clinically successful such as immune checkpoint blockade. Prospects for novel therapeutics and the potential for combinatorial approaches are delineated. Finally, we briefly discuss nanotechnology-based platforms which can in theory, activate multiple arms of immune system to fight cancer. The promising advances in the field of immunotherapy signal the dawn of a new era in cancer treatment and warrant further investigation to understand the opportunities and barriers for future progress. PMID- 29276514 TI - Cross-Protective Efficacy of Influenza Virus M2e Containing Virus-Like Particles Is Superior to Hemagglutinin Vaccines and Variable Depending on the Genetic Backgrounds of Mice. AB - Influenza virus M2 extracellular domain (M2e) has been a target for developing cross-protective vaccines. However, the efficacy and immune correlates of M2e vaccination are poorly understood in the different host genetic backgrounds in comparison with influenza vaccines. We previously reported the cross-protective efficacy of virus-like particle (M2e5x VLP) vaccines containing heterologous tandem M2e repeats (M2e5x) derived from human, swine, and avian influenza viruses. In this study to gain better understanding of cross-protective influenza vaccines, we compared immunogenicity and efficacy of M2e5x VLP, H5 hemagglutinin VLP (HA VLP), and inactivated H3N2 virus (H3N2i) in wild-type strains of BALB/c and C57BL/6 mice, and CD4 and CD8 knockout (KO) mice. M2e5x VLP was superior to HA VLP in conferring cross-protection whereas H3N2i inactivated virus vaccine provided high efficacy of homologous protection. After M2e5x VLP vaccination and challenge, BALB/c mice induced higher IgG responses, lower lung viral loads, and less body weight loss when compared with those in C57BL/6 mice. M2e5x VLP but not H3N2i immune mice after primary challenges developed strong immunity against a secondary heterosubtypic virus as a model of future pandemics. M2e5x VLP and HA VLP vaccines were able to raise IgG isotypes in CD4 KO mice. T cells were found to contribute to cross-protection by playing a role in reducing lung viral loads. In conclusion, M2e5x VLP vaccination induced better cross-protection than HA VLP, and its efficacy varied depending on the genetic backgrounds of mice, supporting the important roles of T cells. PMID- 29276515 TI - Nanobodies As Novel Agents for Targeting Angiogenesis in Solid Cancers. AB - Solid cancers are dependent on angiogenesis for sustenance. The FDA approval of Bevacizumab in 2004 inspired many scientists to develop more inhibitors of angiogenesis. Although several monoclonal antibodies (mAbs) are being administered to successfully combat various pathologies, the complexity and large size of mAbs seem to narrow the therapeutic applications. To improve the performance of cancer therapeutics, including those blocking tumor angiogenesis, attractive strategies such as miniaturization of the antibodies have been introduced. Nanobodies (Nbs), small single-domain antigen-binding antibody fragments, are becoming promising therapeutic and diagnostic proteins in oncology due to their favorable unique structural and functional properties. This review focuses on the potential and state of the art of Nbs to inhibit the angiogenic process for therapy and the use of labeled Nbs for non-invasive in vivo imaging of the tumors. PMID- 29276516 TI - Myostatin Promotes Interleukin-1beta Expression in Rheumatoid Arthritis Synovial Fibroblasts through Inhibition of miR-21-5p. AB - Rheumatoid arthritis (RA) is characterized by the infiltration of a number of pro inflammatory cytokines into synovial fluid and patients with RA often develop joint destruction and deficits in muscle mass. The growth factor myostatin is a key regulator linking muscle mass and bone structure. We sought to determine whether myostatin regulates rheumatoid synovial fibroblast activity and inflammation in RA. We found that levels of myostatin and interleukin (IL)-1beta (a key pro-inflammatory cytokine in RA) in synovial fluid from RA patients were overexpressed and positively correlated. In in vitro investigations, we found that myostatin dose-dependently regulated IL-1beta expression through the ERK, JNK, and AP-1 signal-transduction pathways. Computational analysis confirmed that miR-21-5p directly targets the expression of the 3' untranslated region (3' UTR) of IL-1beta. Treatment of cells with myostatin inhibited miR-21-5p expression and miR-21-5p mimic prevented myostatin-induced enhancement of IL-1beta expression, showing an inverse correlation between miR-21-5p and IL-1beta expression during myostatin treatment. We also found significantly increased paw swelling in an animal model of collagen-induced arthritis (CIA), compared with controls; immunohistochemistry staining revealed substantially higher levels of myostatin and IL-1beta expression in CIA tissue. Our evidence indicates that myostatin regulates IL-1beta production. Thus, targeting myostatin may represent a potential therapeutic target for RA. PMID- 29276519 TI - Quaking Deficiency Amplifies Inflammation in Experimental Endotoxemia via the Aryl Hydrocarbon Receptor/Signal Transducer and Activator of Transcription 1-NF kappaB Pathway. AB - Macrophages, characterized by considerable diversity and plasticity, play a crucial role in a broad spectrum of biological processes, including inflammation. However, the molecular mechanisms underlying the diverse phenotypes of macrophages are not well defined. Here, we show that the RNA-binding protein, quaking (QKI), dynamically modulates macrophage polarization states. After lipopolysaccharide (LPS) stimulation, QKI-silenced RAW 264.7 cells displayed a pro-inflammatory M1 phenotype characterized by increased expression of iNOS, TNF alpha, and IL-6 and decreased expression of anti-inflammatory factors, such as IL 10, found in inflammatory zone (Fizz1), and chitinase-like 3 (Chil3 or Ym1). By contrast, QKI5 overexpression led to a suppressive phenotype resembling M2 macrophages, even under M1 differentiation conditions. Moreover, myeloid-specific QKI-deficient mice tended to be more susceptible to LPS-induced endotoxic shock, while the exogenous transfer of macrophages overexpressing QKI5 exerted a significant improving effect. This improvement corresponded to a higher proportion of M2 macrophages, in line with elevated levels of IL-10, and a decrease in levels of pro-inflammatory mediators, such as IL-6, TNF-alpha, and IL 1beta. Further mechanistic studies disclosed that QKI was a potent inhibitor of the nuclear factor-kappa B (NF-kappaB) pathway, suppressing p65 expression and phosphorylation. Strikingly, reduced expression of the aryl hydrocarbon receptor (Ahr) and reduced phosphorylation of signal transducer and activator of transcription 1 in QKI-deficient cells failed to restrain the transcriptional activity of NF-kappaB and NRL pyrin domain containing 3 (NLRP3) activation, while restoring QKI expression skewed the above M1-like response toward an anti inflammatory M2 state. Taken together, these findings suggest a role for QKI in restraining overt innate immune responses by regulating the Ahr/STAT1-NF-kappaB pathway. PMID- 29276518 TI - How B-Cell Receptor Repertoire Sequencing Can Be Enriched with Structural Antibody Data. AB - Next-generation sequencing of immunoglobulin gene repertoires (Ig-seq) allows the investigation of large-scale antibody dynamics at a sequence level. However, structural information, a crucial descriptor of antibody binding capability, is not collected in Ig-seq protocols. Developing systematic relationships between the antibody sequence information gathered from Ig-seq and low-throughput techniques such as X-ray crystallography could radically improve our understanding of antibodies. The mapping of Ig-seq datasets to known antibody structures can indicate structurally, and perhaps functionally, uncharted areas. Furthermore, contrasting naive and antigenically challenged datasets using structural antibody descriptors should provide insights into antibody maturation. As the number of antibody structures steadily increases and more and more Ig-seq datasets become available, the opportunities that arise from combining the two types of information increase as well. Here, we review how these data types enrich one another and show potential for advancing our knowledge of the immune system and improving antibody engineering. PMID- 29276517 TI - BP180 Is Critical in the Autoimmunity of Bullous Pemphigoid. AB - Bullous pemphigoid (BP) is by far the most common autoimmune blistering dermatosis that mainly occurs in the elderly. The BP180 is a transmembrane glycoprotein, which is highly immunodominant in BP. The structure and location of BP180 indicate that it is a significant autoantigen and plays a key role in blister formation. Autoantibodies from BP patients react with BP180, which leads to its degradation and this has been regarded as the central event in BP pathogenesis. The consequent blister formation involves the activation of complement-dependent or -independent signals, as well as inflammatory pathways induced by BP180/anti-BP180 autoantibody interaction. As a multi-epitope molecule, BP180 can cause dermal-epidermal separation via combining each epitope with specific immunoglobulin, which also facilitates blister formation. In addition, some inflammatory factors can directly deplete BP180, thereby leading to fragility of the dermal-epidermal junction and blister formation. This review summarizes recent investigations on the role of BP180 in BP pathogenesis to determine the potential targets for the treatment of patients with BP. PMID- 29276520 TI - Combined 15N-Labeling and TandemMOAC Quantifies Phosphorylation of MAP Kinase Substrates Downstream of MKK7 in Arabidopsis. AB - Reversible protein phosphorylation is a widespread posttranslational modification that plays a key role in eukaryotic signal transduction. Due to the dynamics of protein abundance, low stoichiometry and transient nature of protein phosphorylation, the detection and accurate quantification of substrate phosphorylation by protein kinases remains a challenge in phosphoproteome research. Here, we combine tandem metal-oxide affinity chromatography (tandemMOAC) with stable isotope 15N metabolic labeling for the measurement and accurate quantification of low abundant, transiently phosphorylated peptides by mass spectrometry. Since tandemMOAC is not biased toward the enrichment of acidophilic, basophilic, or proline-directed kinase substrates, the method is applicable to identify targets of all these three types of protein kinases. The MKK7-MPK3/6 module, for example, is involved in the regulation of plant development and plant basal and systemic immune responses, but little is known about downstream cascade components. Using our here described phosphoproteomics approach we identified several MPK substrates downstream of the MKK7-MPK3/6 phosphorylation cascade in Arabidopsis. The identification and validation of dynamin-related protein 2 as a novel phosphorylation substrate of the MKK7-MPK3/6 module establishes a novel link between MPK signaling and clathrin-mediated vesicle trafficking. PMID- 29276521 TI - Simulated Optimum Sowing Date for Forage Pearl Millet Cultivars in Multilocation Trials in Brazilian Semi-Arid Region. AB - Forage production is primarily limited by weather conditions under dryland production systems in Brazilian semi-arid regions, therefore sowing at the appropriate time is critical. The objectives of this study were to evaluate the CSM-CERES-Pearl Millet model from the DSSAT software suite for its ability to simulate growth, development, and forage accumulation of pearl millet [Pennisetum glaucum (L.) R.] at three Brazilian semi-arid locations, and to use the model to study the impact of different sowing dates on pearl millet performance for forage. Four pearl millet cultivars were grown during the 2011 rainy season in field experiments conducted at three Brazilian semi-arid locations, under rainfed conditions. The genetic coefficients of the four pearl millet cultivars were calibrated for the model, and the model performance was evaluated with experimental data. The model was run for 14 sowing dates using long-term historical weather data from three locations, to determine the optimum sowing window. Results showed that performance of the model was satisfactory as indicated by accurate simulation of crop phenology and forage accumulation against measured data. The optimum sowing window varied among locations depending on rainfall patterns, although showing the same trend for cultivars within the site. The best sowing windows were from 15 April to 15 May for the Bom Conselho location; 12 April to 02 May for Nossa Senhora da Gloria; and 17 April to 25 May for Sao Bento do Una. The model can be used as a tool to evaluate the effect of sowing date on forage pearl millet performance in Brazilian semi-arid conditions. PMID- 29276522 TI - Iron Deficiency Prolongs Seed Dormancy in Arabidopsis Plants. AB - The understanding of seed dormancy, germination and longevity are important goals in plant biology, with relevant applications for agriculture, food industry and also human nutrition. Reactive Oxygen Species (ROS) are key molecules involved in the release of dormancy, when their concentrations fall within the so called 'oxidative window.' The mechanisms of ROS distribution and sensing in seeds, from dormant to germinating ones, still need elucidation. Also, the impact of iron (Fe) deficiency on seed dormancy is still unexplored; this is surprising, given the known pro-oxidant role of Fe when in a free form. We provide evidence of a link between plant Fe nutrition and dormancy of progeny seeds by using different Arabidopsis ecotypes and mutants with different dormancy strengths grown in control soil or under severe Fe deficiency. The latter condition extends the dormancy in several genotypes. The focus on the mechanisms involved in the Fe deficiency-dependent alteration of dormancy and longevity promises to be a key issue in seed (redox) biology. PMID- 29276523 TI - N-P Fertilization Inhibits Growth of Root Hemiparasite Pedicularis kansuensis in Natural Grassland. AB - Fertilization has been shown to affect interactions between root hemiparasitic plants and their host plants, alleviating damage to the hosts by parasitism. However, as a majority of studies were conducted in pot cultivation, the influence of fertilizer application on root hemiparasites and the surrounding plant community in field conditions as well as relevant mechanisms remain unclear. We manipulated soil nutrient resources in a semi-arid subalpine grassland in the Tianshan Mountains, northwestern China, to explore the links between fertilization and plant community composition, productivity, survival, and growth of a weedy root hemiparasite (Pedicularis kansuensis). Nitrogen (at a low rate, LN, 30 kg N ha-1 year-1 as urea; or at a high rate, HN, 90 kg N ha-1 year-1 as urea) and phosphorus [100 kg ha-1 year-1 as Ca(H2PO4)2?H2O] were added during two growing seasons. Patterns of foliar nutrient balances were described with isometric log ratios for the different plant functional groups receiving these fertilization regimes. Fertilization with LN, HN, and P reduced above ground biomass of P. kansuensis, with above-ground biomass in the fertilization treatments, respectively, 12, 1, and 39% of the value found in the unfertilized control. Up to three times more above-ground biomass was produced in graminoids receiving fertilizers, whereas forb above-ground biomass was virtually unchanged by the fertilization regimes and forb species richness was reduced by 52% in the HN treatment. Fertilization altered foliar nutrient balances, and distinct patterns emerged for each plant functional group. Foliar [C | P,N] balance in the plant community was negatively correlated with above-ground biomass (P = 0.03). The inhibited competitiveness of P. kansuensis, which showed a much higher [C | P,N] balance, could be attributed to reduced C assimilation rather than mineral nutrient acquisition, as shown by significant increase in foliar N and P concentrations but little increase in C concentration following fertilization. PMID- 29276524 TI - Molecular Mapping of PMR1, a Novel Locus Conferring Resistance to Powdery Mildew in Pepper (Capsicum annuum). AB - Powdery mildew, caused by Leveillula taurica, is a major fungal disease affecting greenhouse-grown pepper (Capsicum annuum). Powdery mildew resistance has a complex mode of inheritance. In the present study, we investigated a novel powdery mildew resistance locus, PMR1, using two mapping populations: 102 'VK515' F2:3 families (derived from a cross between resistant parental line 'VK515R' and susceptible parental line 'VK515S') and 80 'PM Singang' F2 plants (derived from the F1 'PM Singang' commercial hybrid). Genetic analysis of the F2:3 'VK515' and F2 'PM Singang' populations revealed a single dominant locus for inheritance of the powdery mildew resistance trait. Genetic mapping showed that the PMR1 locus is located on syntenic regions of pepper chromosome 4 in a 4-Mb region between markers CZ2_11628 and HRM4.1.6 in 'VK515R'. Six molecular markers including one SCAR marker and five SNP markers were localized to a region 0 cM from the PMR1 locus. Two putative nucleotide-binding site leucine-rich repeat (NBS-LRR)-type disease resistance genes were identified in this PMR1 region. Genotyping-by sequencing (GBS) and genetic mapping analysis revealed suppressed recombination in the PMR1 region, perhaps due to alien introgression. In addition, a comparison of species-specific InDel markers as well as GBS-derived SNP markers indicated that C. baccatum represents a possible source of such alien introgression of powdery mildew resistance into 'VK515R'. The molecular markers developed in this study will be especially helpful for marker-assisted selection in pepper breeding programs for powdery mildew resistance. PMID- 29276526 TI - Invasive Macrophytes Control the Spatial and Temporal Patterns of Temperature and Dissolved Oxygen in a Shallow Lake: A Proposed Feedback Mechanism of Macrophyte Loss. AB - Submerged macrophytes can have a profound effect on shallow lake ecosystems through their ability to modify the thermal structure and dissolved oxygen levels within the lake. Invasive macrophytes, in particular, can grow rapidly and induce thermal gradients in lakes that may substantially change the ecosystem structure and challenge the survival of aquatic organisms. We performed fine-scale measurements and 3D numerical modeling at high spatiotemporal resolution to assess the effect of the seasonal growth of Potamogeton crispus L. on the spatial and temporal dynamics of temperature and dissolved oxygen in a shallow urban lake (Lake Monger, Perth, WA, Australia). Daytime stratification developed during the growing season and was clearly observed throughout the macrophyte bed. At all times measured, stratification was stronger at the center of the macrophyte bed compared to the bed edges. By fitting a logistic growth curve to changes in plant height over time (r2 = 0.98), and comparing this curve to temperature data at the center of the macrophyte bed, we found that stratification began once the macrophytes occupied at least 50% of the water depth. This conclusion was strongly supported by a 3D hydrodynamic model fitted to weekly temperature profiles measured at four time periods throughout the growing season (r2 > 0.78 at all times). As the macrophyte height increased and stratification developed, dissolved oxygen concentration profiles changed from vertically homogeneous oxic conditions during both the day and night to expression of night-time anoxic conditions close to the sediments. Spatially interpolated maps of dissolved oxygen and 3D numerical modeling results indicated that the plants also reduced horizontal exchange with surrounding unvegetated areas, preventing flushing of low dissolved oxygen water out of the center of the bed. Simultaneously, aerial imagery showed central dieback occurring toward the end of the growing season. Thus, we hypothesized that stratification-induced anoxia can lead to accelerated P. crispus dieback in this region, causing formation of a ring-shaped pattern in spatial macrophyte distribution. Overall, our study demonstrates that submerged macrophytes can alter the thermal characteristics and oxygen levels within shallow lakes and thus create challenging conditions for maximizing their spatial coverage. PMID- 29276525 TI - The Dynamics of Energy Dissipation and Xanthophyll Conversion in Arabidopsis Indicate an Indirect Photoprotective Role of Zeaxanthin in Slowly Inducible and Relaxing Components of Non-photochemical Quenching of Excitation Energy. AB - The dynamics of non-photochemical quenching (NPQ) of chlorophyll fluorescence and the dynamics of xanthophyll conversion under different actinic light conditions were studied in intact leaves of Arabidopsis thaliana. NPQ induction was investigated during up to 180 min illumination at 450, 900, and 1,800 MUmol photons m-2 s-1 (MUE) and NPQ relaxation after 5, 30, 90, or 180 min of pre illumination at the same light intensities. The comparison of wild-type plants with mutants affected either in xanthophyll conversion (npq1 and npq2) or PsbS expression (npq4 and L17) or lumen acidification (pgr1) indicated that NPQ states with similar, but not identical characteristics are induced at longer time range (15-60 min) in wild-type and mutant plants. In genotypes with an active xanthophyll conversion, the dynamics of two slowly (10-60 min) inducible and relaxing NPQ components were found to be kinetically correlated with zeaxanthin formation and epoxidation, respectively. However, the extent of NPQ was independent of the amount of zeaxanthin, since higher NPQ values were inducible with increasing actinic light intensities without pronounced changes in the zeaxanthin amount. These data support an indirect role of zeaxanthin in pH independent NPQ states rather than a specific direct function of zeaxanthin as quencher in long-lasting NPQ processes. Such an indirect function might be related to an allosteric regulation of NPQ processes by zeaxanthin (e.g., through interaction of zeaxanthin at the surface of proteins) or a general photoprotective function of zeaxanthin in the lipid phase of the membrane (e.g., by modulation of the membrane fluidity or by acting as antioxidant). The found concomitant down-regulation of zeaxanthin epoxidation and recovery of photosystem II activity ensures that zeaxanthin is retained in the thylakoid membrane as long as photosystem II activity is inhibited or down-regulated. This regulation supports the view that zeaxanthin can be considered as a kind of light stress memory in chloroplasts, allowing a rapid reactivation of photoprotective NPQ processes in case of recurrent light stress periods. PMID- 29276527 TI - Two Cassava Basic Leucine Zipper (bZIP) Transcription Factors (MebZIP3 and MebZIP5) Confer Disease Resistance against Cassava Bacterial Blight. AB - Basic domain-leucine zipper (bZIP) transcription factor, one type of conserved gene family, plays an important role in plant development and stress responses. Although 77 MebZIPs have been genome-wide identified in cassava, their in vivo roles remain unknown. In this study, we analyzed the expression pattern and the function of two MebZIPs (MebZIP3 and MebZIP5) in response to pathogen infection. Gene expression analysis indicated that MebZIP3 and MebZIP5 were commonly regulated by flg22, Xanthomonas axonopodis pv. manihotis (Xam), salicylic acid (SA), and hydrogen peroxide (H2O2). Subcellular localization analysis showed that MebZIP3 and MebZIP5 are specifically located in cell nucleus. Through overexpression in tobacco, we found that MebZIP3 and MebZIP5 conferred improved disease resistance against cassava bacterial blight, with more callose depositions. On the contrary, MebZIP3- and MebZIP5-silenced plants by virus induced gene silencing (VIGS) showed disease sensitive phenotype, lower transcript levels of defense-related genes and less callose depositions. Taken together, this study highlights the positive role of MebZIP3 and MebZIP5 in disease resistance against cassava bacterial blight for further utilization in genetic improvement of cassava disease resistance. PMID- 29276528 TI - Freedom to explore the self: How emerging adults use leisure to develop identity. AB - During a period of newly attained freedom preceding commitments expected in adulthood, emerging adults are faced with the major task of identity development. Leisure provides a context with relative freedom wherein emerging adults explore new experiences and access opportunities not always available in more constrained environments like work and school. In this case study of 40 emerging adults from 18 countries (Mage =23.14 years), qualitative interviews were used to investigate the role of leisure as a context for identity development. Results indicate five major themes for leisure-based identity development in emerging adulthood: discovering identity, forming identity, defining identity, positioning identity, and forgoing opportunities. These themes support leisure as an additional context wherein emerging adults may flourish on the pathway toward adulthood. Access to both novel and familiar leisure provide a context for emerging adults to actively direct their identity development through decisions made in leisure time. PMID- 29276531 TI - Editorial: Where are we? PMID- 29276530 TI - Inattention and hyperactivity in association with autism spectrum disorders in the CHARGE study. AB - Background: Attention deficits in young children with autism spectrum disorder (ASD) are not well understood. This study sought to determine: 1) the prevalence of ADHD symptoms in young children with ASD, typical development (TD), and developmental delay (DD) and 2) the association between ADHD symptoms and cognitive and behavioral functioning in children with ASD. Method: ADHD symptoms, defined according to Aberrant Behavior Checklist (ABC) hyperactivity subscale scores, were compared across children aged 2-5 from a large case-control study with ASD (n=548), TD (n=423), and DD (n=180). Inattention and hyperactivity items within this subscale were also explored. Within the ASD group, linear and logistic regression were used to examine how ADHD symptoms were associated with cognition as assessed by the Mullen Scales of Early Learning and adaptive functioning as assessed by the Vineland Adaptive Behavior Scales. Results: Mean hyperactivity subscale scores were lowest in children with TD (mean=3.19), higher in children with DD (12.3), and highest in children with ASD (18.2; between-group p<0.001). Among children with ASD, significant associations were observed with higher ADHD symptoms and poorer adaptive and cognitive functioning (adjusted beta for hyperactivity score in association with: Vineland composite = -5.63, p=0.0005; Mullen visual reception scale = -2.94, p=0.02; for the highest vs. lowest quartile of hyperactivity score, odds of lowest quintile of these scores was approximately doubled). Exploratory analyses highlighted associations with inattention-related items specifically. Conclusion: These results suggest ADHD symptoms may play a key role in the functioning of young children with ASD. PMID- 29276529 TI - Neurobiological Bases of Reading Disorder Part II: The Importance of Developmental Considerations in Typical and Atypical Reading. AB - Decoding-based reading disorder (RD; aka developmental dyslexia) is one of the most common neurodevelopmental disorders, affecting approximately 5-10% of school aged children across languages. Even though neuroimaging studies suggest an impairment of the left reading network in RD, the onset of this deficit and its developmental course, which may include constancy and change, is largely unknown. There is now growing evidence that the recruitment of brain networks underlying perceptual, cognitive and linguistic processes relevant to reading acquisition varies with age. These age-dependent changes may in turn impact the neurocognitive characteristics of RD observed at specific developmental stages. Here we synthesize findings from functional and structural magnetic resonance imaging (MRI) studies to increase our understanding of the developmental time course of the neural bases underlying (a)typical reading. We first provide an overview of the brain bases of typical and atypical (impaired) reading. Next we describe how the understanding of RD can be deepened through scientific attention to age effects, for example, by integrating findings from cross-sectional studies of RD at various ages. Finally, we accent findings from extant longitudinal studies that directly examine developmental reading trajectories beginning in the preliterate stage at both group and individual levels. Although science is at the very early stage of understanding developmental aspects of neural deficits in RD, evidence to date characterizes RD by atypical brain maturation. We know that reading impairment may adversely impact multiple life domains such as academic achievement and social relationships, and unfortunately, that these negative outcomes can persist and compound into adulthood. We contend that exploring the developmental trajectories of RD will contribute to a greater understanding of how neural systems support reading acquisition. Further, we propose and cite evidence that the etiology of RD can be better investigated by distinguishing primary deficits from secondary impairments unfolding along development. These exciting and modern investigatory efforts can also indirectly contribute to a centered practice of early and accurate identification and optimal intervention to support the development of foundational pre-literacy skills and fluent reading. In sum, integrating a developmental understanding into the science and practice of reading acquisition and intervention is both possible and necessary. PMID- 29276532 TI - Managing acromio-clavicular joint pain: a scoping review. AB - Background: Shoulder pain secondary to acromioclavicular joint pain is a common presentation in primary and secondary care but is often poorly managed as a result of uncertainty about optimal treatment strategies. Osteoarthritis is the commonest cause. Although acromioclavicular pain can be treated non-operatively and operatively, there appears to be no consensus on the best practice pathway of care for these patients, with variations in treatment being common place. The present study comprises a scoping review of the current published evidence for the management of isolated acromioclavicular pain (excluding acromioclavicular joint dislocation). Methods: A comprehensive search strategy was utilized in multiple medical databases to identify level 1 and 2 randomised controlled trials, nonrandomised controlled trials and systematic reviews for appraisal. Results: Four systematic reviews and two randomised controlled trials were identified. No direct studies have compared the benefits or risks of conservative versus surgical management in a controlled environment. Conclusions: High-level studies on treatment modalities for acromioclavicular joint pain are limited. As such, there remains little evidence to support one intervention or treatment over another, making it difficult to develop any evidenced-based patient pathways of care for this condition.Level of evidence: 2A. PMID- 29276534 TI - The effect of humeral polyethylene insert constraint on reverse shoulder arthroplasty biomechanics. AB - Background: There is little information on the effects of altering reverse shoulder arthroplasty (RSA) polyethylene constraint on joint load, load angle and deltoid force. The present biomechanical study aimed to investigate the effects of changing RSA polyethylene constraint on joint load, load angle, deltoid force and range of motion. Methods: A custom RSA implant capable of measuring forces across the joint with varying polyethylene constraint was tested in six cadaveric shoulders. Standard-, low- and high-constraint (retentive) polyethylene liners were tested, and joint kinematics, loads and muscle forces were recorded. Results: When polyethylene constraint was altered, joint load and load angle during active abduction were not affected significantly (p > 0.19). Additionally, the force required by the deltoid for active abduction was not affected significantly by cup constraint (p = 0.144). Interestingly, active abduction range of motion was also not affected significantly by changes in cup constraint (p > 0.45). Conclusions: Altering polyethylene cup constraint in RSA to enhance stability does not significantly alter resultant joint loads and deltoid forces. Surprisingly, terminal abduction range of motion was also not significantly different with varying cup constraint, indicating that terminal impingement may be tuberosity related rather than polyethylene. PMID- 29276533 TI - Contraindications and complications of the Latarjet procedure. AB - The Latarjet procedure is a well-known, safe and reliable technique to treat primary or recurrent anterior dislocations or subluxations, with or without hyperlaxity, with or without glenoid bone loss. Both the open and the arthroscopic methods produce excellent clinical results, with a low rate of recurrent instability. There have been concerns of a higher surgical complication rate associated with this procedure, however, large reviews reported an overall complication rate in the open Latarjet procedure of 15%. Meticulous surgical technique and a good understanding of the local anatomy can help to avoid the complications but postoperative shoulder arthritis and frequent bone block osteolysis remain unsolved additional challenges, which require further research. There are 2 main factors to further improve the clinical outcome and patient satisfaction: careful patient selection with good surgical indication, and reducing complications with adequate surgical techniques. The aim of this study is to provide the current overview of the contraindications and complications of the Latarjet procedure. PMID- 29276535 TI - Influence of screw type and length on fixation of anterior glenoid bone grafts. AB - Background: Bone-grafting procedures for recurrent shoulder instability produce low recurrence rates, although they are associated with complications such as graft non-union. Inadequate screw purchase is considered to play a causative role. However, excessive screw length can endanger neurovascular structures. The present study aimed to investigate how type and length of screws influences construct rigidity in a simplified glenoid model. Methods: Testing was performed on composite polyurethane foam models with material properties and abstract dimensions of a deficient glenoid and an bone graft. Three screw types (cannulated 3.75 mm and 3.5 mm and solid 4.5 mm) secured the graft in a bicortical-bicortical, bicortical-unicortical and unicortical-unicortical configuration. Biomechanical testing consisted of applying axial loads when measuring graft displacement. Results: At 200 N, graft displacement reached 0.74 mm, 0.27 mm and 0.24 mm for the unicortical-unicortical and 0.40 mm, 0.25 mm and 0.24 mm for the unicortical-bicortical configuration of the 3.75 mm, 3.5 mm and 4.5 mm screw types. The 3.75 mm screw incurred significant displacements in the unicortical configurations compared to the bicortical-bicortical method (p < 0.001). Conclusions: The present study demonstrates that common screw types resist physiological shear loads in a bicortical configuration. However, the 3.75 mm screws incurred significant displacements at 200 N in the unicortical configurations. These findings have implications regarding hardware selection for bone-grafting procedures. PMID- 29276536 TI - Establishing the appropriate position of proximal humerus locking plates: a cadaveric study of five plating systems and their anatomic reference measurements. AB - Background: The present study aimed to determine anatomic references for the placement of five proximal humerus locking plates. Methods: Five proximal humerus locking-plate systems were placed on six human shoulder cadavers. Plates were positioned by fluoroscopic confirmation so that the inferior oblique screw was within 5 mm of the inferomedial cortex. Plate position was measured using the superior border of the pectoralis major tendon (PMT) to the bottom of the first slotted or nonlocking hole and top of the plate to the top of the greater tuberosity. The distance from the PMT insertion to the top of the humeral head was measured as a control. Results: There was consistency within each plating system for both the distance from the PMT insertion to the first hole and the top of the plate to the greater tuberosity: Synthes first-generation [mean (SD) 13.7 mm (3.1 mm); 10 mm (1.3) mm], Synthes second-generation [28.2 mm (2.2 mm); 18.5 mm (2.7 mm)], Biomet OptiLock(r) [25.5 mm (2.7 mm); 18.7 mm (2 mm)], Stryker AxSOS(r) [5 mm (2.8 mm); 12.3 mm (3.3 mm)] and Acumed Polarus(r) [9.5 mm (1.8 mm); 14.8 mm (1.6 mm)]. Conclusions: The present study provides measurements that improve the accuracy of plate positioning for five plating systems. PMID- 29276537 TI - Open release versus radiofrequency microtenotomy in the treatment of lateral epicondylitis: a prospective randomized controlled trial. AB - Background: Optimal surgical treatment of lateral epicondylitis remains uncertain. Recently, radiofrequency microtenotomy (RFMT) has been proposed as a suitable treatment. We compared RFMT with standard open release (OR) in this prospective randomized controlled trial. Methods: In total, 41 patients with symptoms for at least 6 months were randomized into two groups: 23 patients had RFMT and 18 had OR. Two patients from RFMT withdrew. Each patient underwent Numerical Rating Scale (NRS) pain score, grip strength and Disabilities of the Arm, Shoulder and Hand (DASH) scores pre-operatively and at 6 weeks. Pain and DASH scores were repeated at 6 months and 12 months. Results: NRS pain scores improved by 4.8 points for RFMT and by 3.9 points for OR. There was a significant improvement in both groups from pre-operative scores, although there was no statistically significant difference between the groups at 1 year. Grip strength improved by 31% in the RFMT group compared to 38% in OR. There was no significant difference between the initial and 6 weeks scores or between treatments. At 1 year, DASH was 39.8 points for RFMT and 24.4 points for OR. There was a significant improvement in both groups from pre-operative scores, although there was no statistically significant difference between the groups at 1 year. Conclusions: Both groups showed significant improvements and similar benefit to the patient. The results of the present study do not show any benefit of RFMT over the standard OR. As a result of the extra expense of RFMT, we therefore recommend that OR is offered as the standard surgical management. PMID- 29276538 TI - Rotator cuff disorders: a survey of current (2016) UK physiotherapy practice. AB - Background: Shoulder pain is a common musculoskeletal presentation, with disorders of the rotator cuff (RC) regarded as the most frequent cause. Conservative treatment is often the initial management; however, findings from a previous survey showed considerable variations in clinical practice, including the use of modalities that are not supported in the literature, suggesting that research is not impacting on practice. The present study aimed to survey current UK physiotherapy practice for the management of RC disorders and to determine whether this has changed over the 5-year period since the last survey was conducted. Methods: A cross-sectional online survey of UK physiotherapists was conducted. Results: One hundred and ninety-one respondents completed the survey which showed that advice/education and some form of exercise therapy are most commonly used as a management strategy for RC disorders. There is a lack of agreement however regarding exercise prescription. The survey suggests less use of passive modalities, indicating that practice has advanced over the last 5 years in line with the current evidence. Conclusions: The present study has highlighted that the clinical practice of the survey respondents was in line with current recommendations from research. Hence, in contrast to the survey conducted 5 years previously, research appears to be impacting on practice, which is a positive finding. PMID- 29276539 TI - Triceps tendon rupture: repair and rehabilitation. AB - Triceps tendon ruptures are rare injuries and are frequently missed on initial presentation to the emergency department. In cases of complete rupture, surgical repair is recommended but no guidelines exist on the optimum reconstructive technique or rehabilitation. We present a surgical technique and rehabilitation programme for the management of these injuries. A midline posterior incision is performed, the ruptured triceps tendon is identified and mobilized, and the tendon footprint is prepared. The tendon is then repaired using bone suture anchors, with a parachute technique, and held in 40 degrees of flexion. The rehabilitation programme is divided into five phases, over a period of 12 weeks. Range of movement is gradually increased in a brace for the first 6 weeks. Rehabilitation is gradually increase in intensity, progressing from isometric extension exercises to weight-resisted exercises, and finally plyometrics and throwing exercises. Our surgical technique provides a solid tendon repair without the need for further metalwork removal. The graduated rehabilitation programme also helps to protect the integrity of the repair at the same time as enabling patients to gradually increase the strength of the triceps tendon and ultimately return to sport activities. PMID- 29276540 TI - Stuck in the middle: the impact of collaborative interprofessional communication on patient expectations. AB - A central aim of modern day healthcare is to deliver a high quality, patient centred service that addresses the expectations of its service users. However, mounting research evidence highlights a lack of patient satisfaction across a range of healthcare settings, with an overwhelming proportion of complaints relating to interprofessional communication. The link between interprofessional miscommunication and poor patient outcomes has been well documented. All too often, patients are left feeling stuck in the middle between opposing opinions, differing diagnoses and conflicting clinical outlooks. This article aims to highlight the issues surrounding interprofessional communication in healthcare, at the same time as addressing the potential facilitators and barriers for developing improved collaborative links between healthcare providers. Several key questions will be considered: (i) what are the underlying causes of interprofessional miscommunication; (ii) what do patients expect from healthcare professionals; and (iii) how might we reduce the risk of miscommunication and develop interprofessional collaboration? PMID- 29276541 TI - Fully recoverable rigid shape memory foam based on copper-catalyzed azide-alkyne cycloaddition (CuAAC) using a salt leaching technique. AB - This study is the first to employ the use of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) polymerization to form a tough and stiff, porous material from a well-defined network possessing a high glass transition temperature. The effect of the network linkages formed as a product of the CuAAC reaction, i.e., the triazoles, on the mechanical behavior at high strain was evaluated by comparing the CuAAC foam to an epoxy-amine-based foam, which consisted of monomers with similar backbone structures and mechanical properties (i.e., Tg of 115 degrees C and a rubbery modulus of 1.0 MPa for the CuAAC foam, Tg of 125 degrees C and a rubbery modulus of 1.2 MPa for the epoxy-amine foam). When each foam was compressed uniformly to 80% strain at ambient temperature, the epoxy amine foam was severely damaged after only reaching 70% strain in the first compression cycle with a toughness of 300 MJ/m3. In contrast, the CuAAC foam exhibited pronounced ductile behavior in the glassy state with three times higher toughness of 850 MJ/m3 after the first cycle of compression to 80% strain. Additionally, when the CuAAC foam was heated above Tg after each of five compression cycles to 80% strain at ambient temperature, the foam completely recovered its original shape while exhibiting a gradual decrease in mechanical performance over the multiple compression cycles. The foam demonstrated almost complete shape fixity and recovery ratios even through five successive cycles, indicative of "reversible plasticity", making it highly desirable as a glassy shape memory foams. PMID- 29276543 TI - An investigation of home advantage in the Summer Paralympic Games. AB - Purpose: There is a paucity of home advantage research set in the context of para sport events. It is this gap in the knowledge that this paper addresses by investigating the prevalence and size of home advantage in the Summer Paralympic Games. Methods: Using a standardised measure of success, we compared the performances of nations when competing at home with their own performances away from home in the competition between 1960 and 2016. Both country-level and individual sport-level analyses were conducted for this time frame. A Wilcoxon signed rank test was used to determine whether there was a genuine difference in nations' performance under host and non-host conditions. Spearman's rank-order correlation was run to assess the relationship between nation quality and home advantage. Results: Strong evidence of a home advantage effect in the Summer Paralympic Games was found at country level (p < 0.01). When examining individual sports, only athletics, table tennis, and wheelchair fencing returned a significant home advantage effect (p < 0.05). Possible explanations for these findings are discussed. The size of the home advantage effect was not significantly correlated with the quality or strength of the host nation (p > 0.10). Conclusion: While our results confirm that home advantage is prevalent in the Summer Paralympic Games at an overall country level and within specific sports, they do not explain fully why such an effect does exist. Future studies should investigate the causes of home advantage in the competition and also draw comparisons with the Summer Olympic Games to explore any differences between para sport events and able-bodied events. PMID- 29276542 TI - Different training responses to eccentric endurance exercise at low and moderate altitudes in pre-diabetic men: a pilot study. AB - This pilot study aimed (a) to evaluate the effects of eccentric exercise training at low and moderate altitudes on physical fitness in pre-diabetic men and (b) to establish whether or not oxidative stress levels and antioxidant status were associated with performance improvements. In this crossover trial, five pre diabetic men conducted nine downhill walking sessions (3 days/week, 3 consecutive weeks) at low altitude (from 1360 to 850 m) and one year later at moderate altitude (from 2447 to 2000 m). Exercise testing and the determination of parameters of oxidative stress and antioxidant capacity were performed pre- and post-training. The biological antioxidant activity of plasma (BAP) increased after eccentric training at moderate altitude (p < 0.001), whereas diacron reactive oxygen metabolites (dROMs) remained unchanged. Also, the BAP/dROMs ratio increased only after training at moderate-altitude training (p = 0.009). Maximum power output improved after training at low altitude and the changes were significantly related to baseline BAP/dROMs ratio (r = 0.90). No decrease was seen for fasting plasma glucose. Eccentric exercise training in pre-diabetic men improved performance only when performed at low altitude and this improvement was positively related to the baseline BAP/dROMs ratio. In contrast, 3 weeks of eccentric exercise training increased BAP levels and the BAP/dROMs ratio only at moderate altitude without improving the performance. Thus, one might speculate that the BAP/dROMs ratio has to increase before performance improvements occur at moderate altitude. PMID- 29276544 TI - ANALYSIS OF AGREEMENT BETWEEN EXPIRED-AIR CARBON MONOXIDE MONITORS. AB - Introduction: The current study examined the level of agreement in expired-air carbon monoxide (CO) values, focusing especially on those confirming abstinence, between the two most commonly used CO monitors, the Vitalograph BreathCO and the Bedfont piCO+ Smokerlyzer. Methods: Expired-air samples were collected via both monitors from adult dependent smokers (44 M, 34 F) participating in studies using CO values to confirm abstinence durations of: 24 hours, 12 hours, or no abstinence. All met DSM-IV nicotine dependence criteria and had a mean (SD) Fagerstrom Test of Cigarette Dependence score of 5.1 (1.8). Paired data collected across multiple visits were analyzed by regression-based Bland-Altman method of Limits of Agreement. Findings: Analysis indicated a lack of agreement in CO measurement between monitors. Overall, the Bedfont monitor gave mean (+/-SEM) readings 3.83 (+/-.23) ppm higher than the Vitalograph monitor. Mean differences between monitors were larger for those ad lib smoking (5.65+/-.38 ppm) than those abstaining 12-24 hours (1.71+/-.13 ppm). Yet, there also was not consistent agreement in classification of 24 hour abstinence between monitors. Conclusions: Systematic differences in CO readings demonstrate these two very common monitors may not result in interchangeable values, and reported outcomes in smoking research based on CO values may depend on the monitor used. PMID- 29276546 TI - Applying optimization algorithms to tuberculosis antibiotic treatment regimens. AB - Introduction: Tuberculosis (TB), one of the most common infectious diseases, requires treatment with multiple antibiotics taken over at least 6 months. This long treatment often results in poor patient-adherence, which can lead to the emergence of multi-drug resistant TB. New antibiotic treatment strategies are sorely needed. New antibiotics are being developed or repurposed to treat TB, but as there are numerous potential antibiotics, dosing sizes and potential schedules, the regimen design space for new treatments is too large to search exhaustively. Here we propose a method that combines an agent-based multi-scale model capturing TB granuloma formation with algorithms for mathematical optimization to identify optimal TB treatment regimens. Methods: We define two different single-antibiotic treatments to compare the efficiency and accuracy in predicting optimal treatment regimens of two optimization algorithms: genetic algorithms (GA) and surrogate-assisted optimization through radial basis function (RBF) networks. We also illustrate the use of RBF networks to optimize double antibiotic treatments. Results: We found that while GAs can locate optimal treatment regimens more accurately, RBF networks provide a more practical strategy to TB treatment optimization with fewer simulations, and successfully estimated optimal double-antibiotic treatment regimens. Conclusions: Our results indicate surrogate-assisted optimization can locate optimal TB treatment regimens from a larger set of antibiotics, doses and schedules, and could be applied to solve optimization problems in other areas of research using systems biology approaches. Our findings have important implications for the treatment of diseases like TB that have lengthy protocols or for any disease that requires multiple drugs. PMID- 29276547 TI - Intercomparison of Open-Path Trace Gas Measurements with Two Dual Frequency Comb Spectrometers. AB - We present the first quantitative intercomparison between two open-path dual comb spectroscopy (DCS) instruments which were operated across adjacent 2-km open-air paths over a two-week period. We used DCS to measure the atmospheric absorption spectrum in the near infrared from 6021 to 6388 cm-1 (1565 to 1661 nm), corresponding to a 367 cm-1 bandwidth, at 0.0067 cm-1 sample spacing. The measured absorption spectra agree with each other to within 5*10-4 without any external calibration of either instrument. The absorption spectra are fit to retrieve concentrations for carbon dioxide (CO2), methane (CH4), water (H2O), and deuterated water (HDO). The retrieved dry mole fractions agree to 0.14% (0.57 ppm) for CO2, 0.35% (7 ppb) for CH4, and 0.40% (36 ppm) for H2O over the two-week measurement campaign, which included 23 degrees C outdoor temperature variations and periods of strong atmospheric turbulence. This agreement is at least an order of magnitude better than conventional active-source open-path instrument intercomparisons and is particularly relevant to future regional flux measurements as it allows accurate comparisons of open-path DCS data across locations and time. We additionally compare the open-path DCS retrievals to a WMO calibrated cavity ringdown point sensor located along the path with good agreement. Short-term and long-term differences between the two systems are attributed, respectively, to spatial sampling discrepancies and to inaccuracies in the current spectral database used to fit the DCS data. Finally, the two-week measurement campaign yields diurnal cycles of CO2 and CH4 that are consistent with the presence of local sources of CO2 and absence of local sources of CH4. PMID- 29276545 TI - The beneficial effects of different types of exercise interventions on motor and cognitive functions in older age: a systematic review. AB - The decline in cognitive and motor functions with age affects the performance of the aging healthy population in many daily life activities. Physical activity appears to mitigate this decline or even improve motor and cognitive abilities in older adults. The current systematic review will focus mainly on behavioral studies that look into the dual effects of different types of physical training (e.g., balance training, aerobic training, strength training, group sports, etc.) on cognitive and motor tasks in older adults with no known cognitive or motor disabilities or disease. Our search retrieved a total of 1095 likely relevant articles, of which 41 were considered for full-text reading and 19 were included in the review after the full-text reading. Overall, observations from the 19 included studies conclude that improvements on both motor and cognitive functions were found, mainly in interventions that adopt physical-cognitive training or combined exercise training. While this finding advocates the use of multimodal exercise training paradigms or interventions to improve cognitive-motor abilities in older adults, the sizeable inconsistency among training protocols and endpoint measures complicates the generalization of this finding. PMID- 29276548 TI - Comparative Study with a Lip Balm Containing 0.5% Propolis Special Extract GH 2002 versus 5% Aciclovir Cream in Patients with Herpes Labialis in the Papular/Erythematous Stage: A Single-blind, Randomized, Two-arm Study. AB - Background and objectives: This controlled single-blind trial compared the efficacy of a lip balm with propolis special extract GH 2002 at a concentration of 0.5% in the treatment of episodes of herpes labialis with that of 5% aciclovir cream. Methods: Patients in the erythematous/papular stage were randomized: 189 patients were treated with propolis cream, 190 patients were treated with aciclovir cream (intention-to-treat population). Application was 5 times daily. The primary parameter was the difference in median time to complete encrustation or epithelialization of lesions. Secondary parameters were the development of typical herpes symptoms (eg, pain, burning and itching, tension, and swelling), the global assessment of efficacy, and the safety of application. Results: The predefined clinical situation was reached after a median of 4 days with propolis and after 5 days with aciclovir (P < 0.0001). Significant differences in favor of the study preparation were found with all secondary parameters and symptoms. No allergic reactions, local irritations, or other adverse events were observed. Conclusions: A formulation of 0.5% propolis GH 2002 extract lip balm was found to be superior in the treatment of episodes of herpes labialis over 5% aciclovir cream in patients in the papular/erythematous phase upon inclusion. EudraCT Registration No. 2006-001971-38. PMID- 29276549 TI - Heterosexual Casual Sex and STI Diagnosis: A Latent Class Analysis. AB - Casual sex is common during the emerging adult life course stage, but little research has taken a person-centered approach to investigate if casual sexual behavior influences STI rates. Using a nationally representative sample and latent class analysis, results showed three distinctive latent classes. Abstainers were the least likely to have an STI, followed by the casual sex experienced, and then the casual sex risk-takers. Once other covariates were included in the model, there was no significant difference between the abstainers and casual sex experienced classes. These results highlight the need for future research to include diverse samples of emerging adults. PMID- 29276550 TI - INFERENCE FOR SOCIAL NETWORK MODELS FROM EGOCENTRICALLY SAMPLED DATA, WITH APPLICATION TO UNDERSTANDING PERSISTENT RACIAL DISPARITIES IN HIV PREVALENCE IN THE US. AB - Egocentric network sampling observes the network of interest from the point of view of a set of sampled actors, who provide information about themselves and anonymized information on their network neighbors. In survey research, this is often the most practical, and sometimes the only, way to observe certain classes of networks, with the sexual networks that underlie HIV transmission being the archetypal case. Although methods exist for recovering some descriptive network features, there is no rigorous and practical statistical foundation for estimation and inference for network models from such data. We identify a subclass of exponential-family random graph models (ERGMs) amenable to being estimated from egocentrically sampled network data, and apply pseudo-maximum likelihood estimation to do so and to rigorously quantify the uncertainty of the estimates. For ERGMs parametrized to be invariant to network size, we describe a computationally tractable approach to this problem. We use this methodology to help understand persistent racial disparities in HIV prevalence in the US. We also discuss some extensions, including how our framework may be applied to triadic effects when data about ties among the respondent's neighbors are also collected. PMID- 29276551 TI - Gold Nanoparticles as a Probe for Amyloid-beta Oligomer and Amyloid Formation. AB - The process of amyloid-beta (Abeta) amyloid formation is pathologically linked to Alzheimer's disease (AD). The identification of Abeta amyloids and intermediates that are crucial players in the pathology of AD is critical for exploring the underlying mechanism of Abeta aggregation and the diagnosis of the disease. Herein, we performed a gold nanoparticle (AuNP)-based study to detect the formation of Abeta amyloid fibrils and oligomers. Our results demonstrate that the intensity of the surface plasmon resonance (SPR) absorption band of the AuNPs is sensitive to the quantity of Abeta40 amyloids. This allows the SPR assay to be used for detection and semi-quantification of Abeta40 amyloids, and characterization of the kinetics of Abeta amyloid formation. Furthermore, our study demonstrates that the SPR band intensity of the AuNPs is sensitive to the presence of oligomers of both Abeta40 and an Abeta40 mutant, which forms more stable oligomers. The kinetics of the stable oligomer formation of the Abeta40 mutant can also be monitored following the SPR band intensity change of AuNPs. Our results indicate that this nanoparticle based method can be used for mechanistic studies of early protein self-assembly and fibrillogenesis. PMID- 29276552 TI - Characteristics of School Districts That Participate in Rigorous National Educational Evaluations. AB - Given increasing interest in evidence-based policy, there is growing attention to how well the results from rigorous program evaluations may inform policy decisions. However, little attention has been paid to documenting the characteristics of schools or districts that participate in rigorous educational evaluations, and how they compare to potential target populations for the interventions that were evaluated. Utilizing a list of the actual districts that participated in 11 large-scale rigorous educational evaluations, we compare those districts to several different target populations of districts that could potentially be affected by policy decisions regarding the interventions under study. We find that school districts that participated in the 11 rigorous educational evaluations differ from the interventions' target populations in several ways, including size, student performance on state assessments, and location (urban/rural). These findings raise questions about whether, as currently implemented, the results from rigorous impact studies in education are likely to generalize to the larger set of school districts-and thus schools and students-of potential interest to policymakers, and how we can improve our study designs to retain strong internal validity while also enhancing external validity. PMID- 29276553 TI - Interface Engineering for Nanoelectronics. AB - Innovation in the electronics industry is tied to interface engineering as devices increasingly incorporate new materials and shrink. Molecular layers offer a versatile means of tuning interfacial electronic, chemical, physical, and magnetic properties enabled by a wide variety of molecules available. This paper will describe three instances where we manipulate molecular interfaces with a specific focus on the nanometer scale characterization and the impact on the resulting performance. The three primary themes include, 1-designer interfaces, 2 electronic junction formation, and 3-advancing metrology for nanoelectronics. We show the ability to engineer interfaces through a variety of techniques and demonstrate the impact on technologies such as molecular memory and spin injection for organic electronics. Underpinning the successful modification of interfaces is the ability to accurately characterize the chemical and electronic properties and we will highlight some measurement advances key to our understanding of the interface engineering for nanoelectronics. PMID- 29276554 TI - Regression analysis of incomplete data from event history studies with the proportional rates model. AB - This paper discusses regression analysis of a type of incomplete mixed data arising from event history studies with the proportional rates model. By mixed data, we mean that each study subject may be observed continuously during the whole study period, continuously over some study periods and at some time points, or only at some discrete time points. Therefore, we have combined recurrent event and panel count data. For the problem, we present a multiple imputation-based estimation procedure and one advantage of the proposed marginal model approach is that it can be easily implemented. To assess the performance of the procedure, a simulation study is conducted and indicates that it performs well for practical situations and can be more efficient than the existing method. The methodology is applied to a set of mixed data from a longitudinal cohort study. PMID- 29276555 TI - The Rookie Goes to Bat: Is there a "July Effect" on Stroke Treatment at Teaching Hospitals? PMID- 29276556 TI - Atrial Fibrillation Predictors on Mobile Cardiac Telemetry in Cryptogenic Ischemic Stroke. AB - Background and Purpose: The objective of our study was to evaluate magnetic resonance imaging (MRI) and echocardiographic characteristics that would identify patients with cryptogenic ischemic stroke (IS) and transient ischemic attack (TIA) who subsequently developed paroxysmal atrial fibrillation (PAF) on mobile cardiac outpatient telemetry (MCOT). Methods: All patients with cryptogenic IS or TIA seen at the Emory University Hospital and Emory University Hospital Midtown from January 1, 2009, to June 30, 2013, who underwent MCOT were included in this analysis. Location (cortical, high subcortical, or neither) of current and prior strokes on MRI and left atrial (LA) functional and anatomical echocardiographic parameters were evaluated to determine their association with subsequent detection of PAF. Results: Of 132 patients, 17 (13%) had evidence of newly diagnosed PAF on MCOT (mean duration of monitoring = 25 days). The presence (vs absence) of >=1 cortical infarct on baseline MRI was a significant predictor of identifying PAF (odds ratio: 5.2, 95% confidence interval: 1.3-19; P = .01). On baseline echocardiography, patients who had PAF (vs non-PAF) had significantly higher mean LA diameters (4.2 vs 3.7 cm, P = .03) and lower tissue Doppler velocity (a'; 5.5 vs 13.5 cm/s, P = .03). In receiver operating characteristic analysis, the ratio of LA volume index to the septal Doppler velocity (LAVI/a') of >4.6 was associated with a higher likelihood of PAF. Combining MRI with echocardiographic variables did not improve the predictive ability beyond echocardiography alone. Conclusion: Although the presence of cortical-based infarcts on MRI in patients with cryptogenic IS or TIA increases the likelihood of detecting PAF on MCOT, LA functional and anatomic parameters alone best predicted which patients subsequently had PAF. PMID- 29276557 TI - Safety and Costs of Stroke Unit Admission for Select Acute Intracerebral Hemorrhage Patients. AB - Background and Purpose: There are limited data to guide intensive care unit (ICU) versus dedicated stroke unit (SU) admission for intracerebral hemorrhage (ICH) patients. We hypothesized select patients can be safely cared for in SU versus ICU at lower costs. Methods: We conducted a retrospective cohort study of consecutive patients with predefined minor ICH (<=20 cm3, supratentorial, no coagulopathy) receiving care in either an ICU or an SU. Multiple linear regression and inverse probability weighting were used to adjust for differences in patient characteristics and nonrandom ICU versus SU assignment. The primary outcome was poor functional status at discharge (modified Rankin score [mRS] >=3). Secondary outcomes included complications, discharge disposition, hospital length of stay, and direct inpatient costs. Results: The study population included 104 patients (41 admitted to the ICU and 63 admitted to the SU). After controlling for differences in baseline characteristics, there were no differences in poor functional outcome at discharge (93% vs 85%, P = .26) or in mean mRS (2.9 vs 3.0, P = .73). Similarly, there were no differences in the rates of complications (6% vs 10%, P = .44), discharged dead or to a skilled nursing facility (8% vs 13%, P = .59), or direct patient costs (US$7100 vs US$6200, P = .33). Median length of stay was significantly longer in the ICU group (5 vs 4 days, P = .01). Conclusions: This study revealed a shorter length of stay but no large differences in functional outcome, safety, or cost among patients with minor ICH admitted to a dedicated SU compared to an ICU. PMID- 29276558 TI - Before-After Study of an Electronic Order Set for Reversal of Vitamin K Antagonist-Associated Intracerebral Hemorrhage. AB - Background: Vitamin K antagonist (VKA)-associated intracerebral hemorrhages (ICHs) are more likely to expand and are associated with higher mortality than primary ICH. Prompt reversal of anticoagulant effect with prothrombin complex concentrate (PCC) may promote hemostasis and decrease hematoma expansion. The aim of this study was to evaluate the impact of an electronic order set designed to standardize and facilitate more timely reversal of coagulopathy in VKA-associated ICH. Methods: We identified all adults who received PCC for VKA-associated ICH from June 2012 to June 2015 at University of California San Francisco Medical Center, which included a period before and after an electronic order set became available in 2014. We abstracted baseline demographics and clinical data from electronic health records. The primary outcome was time from radiographic identification of ICH to administration of PCC. Results: Thirty-one patients received PCC for VKA-associated ICH, including 17 patients before and 14 patients after the order set became available. Baseline demographics and clinical features were similar. Order set use was associated with a significant decrease in the time from identification of ICH on imaging to the administration of PCC (median 83 vs 45 minutes; P = .02), more accurate dosing (29.4% vs 92.9%; P < .01), and a shorter time from the PCC order to follow-up international normalized ratio (INR) testing (median 164 vs 85 minutes, P = .001). Conclusion: An electronic order set for administering PCC for VKA-associated ICH was associated with significantly faster time to PCC administration and increased dosing accuracy. PMID- 29276559 TI - Door-to-Needle Time in Acute Stroke Treatment and the "July Effect". AB - Intravenous thrombolysis improves outcomes in acute ischemic stroke in a time dependent fashion. As in teaching hospitals, clinical outcomes may worsen due to the arrival of new inexperienced house staff early in the academic year (July effect, JE), we evaluated the impact of the "JE" on the door-to-needle time for intravenous thrombolysis and other stroke outcomes. In this retrospective cohort study, we assessed all acute ischemic strokes treated with intravenous thrombolysis between July 2003 and June 2016. Among 101 patients, there was no detrimental July effect on the door-to-needle time, rate of thrombolysis within 60 minutes of arrival, thrombolysis of stroke mimics, post-thrombolysis intracranial hemorrhages, National Institutes of Health Stroke Scale, and modified Rankin Scale outcomes. PMID- 29276560 TI - Envenomation Seizures. AB - Insect sting-related envenomation rarely produces seizures. We present a patient with confusion and seizures that began 24 hours after a yellow jacket (wasp) sting. Given the rapid onset and resolution of symptoms, as well as accompanying dermatological and orbital features, and the lack of any infectious or structural abnormalities identified, the toxic effect of the wasp venom (and related anaphylaxis reaction) was believed to be the cause of his presentation. PMID- 29276561 TI - Jaw Dystonia and Reversible Basal Ganglia Changes as an Initial Presentation of Systemic Lupus Erythematosus. AB - Dystonia as a manifestation of neuropsychiatric lupus erythematosus (NPSLE) is uncommon. We report a 25-year-old woman who experienced progressive confusion, reduced speech, and difficulty opening her mouth approximately 2 weeks after development of a facial rash. Brain imaging showed bilateral, symmetric signal abnormalities within the basal ganglia and subcortical white matter. Despite treatment with high-dose steroids, she continued to have difficulty speaking with evidence of jaw dystonia on examination. Jaw dystonia rapidly improved with the initiation of levodopa. Repeat evaluation 3 months later exhibited the absence of jaw dystonia and near resolution of the imaging abnormalities. Our patient demonstrated a unique presentation with jaw dystonia refractory to traditional treatment for NPSLE. Such a presentation likely represents a severe variant of NPSLE requiring both immunosuppressive and symptomatic therapies. PMID- 29276562 TI - Multiple Strokes Associated With Elongation of the Hyoid Bone. AB - Hyoid bone elongation is an uncommon cause of stroke. Here, we report a case of hyoid bone elongation causing localized trauma to the internal carotid artery, resulting in multiple strokes. A 32-year-old woman presented with unilateral weakness and history of a recent stroke. Imaging revealed the greater horn of the hyoid bone extending between the external and internal carotid with associated thrombus at the carotid bifurcation and acute stroke. Carotid ultrasound demonstrated movement of the hyoid bone in and out of the space between the external carotid artery and internal carotid artery with neck rotation. Treatment involved anticoagulation and partial hyoid bone resection. After resection, the stroke symptoms had not recurred in the patient. Hyoid bone-related carotid injury is an infrequent etiology of stroke, with no established treatment guidelines. Partial hyoid bone resection and antithrombotic therapy are likely a reasonably safe and effective treatment. PMID- 29276563 TI - Clinical Problem-Solving: Lethargy and Fever in an Immunocompromised Patient. AB - We present the case of a 63-year-old woman with a glioblastoma multiforme on immunosuppressive steroid doses who developed lethargy and fever. We review the differential diagnosis and emphasize the importance of reframing the case when the clinical course differs from expectation. Once the diagnosis is evident, we discuss the incidence and clinical course in different patient populations. PMID- 29276564 TI - Dual-Energy CT Differentiates Contrast Staining From Hemorrhagic Conversion of Ischemic Stroke. PMID- 29276565 TI - Rapidly Growing Thalamic Abscess. PMID- 29276566 TI - Methotrexate-Induced Neurotoxicity: An Uncommon Stroke Mimic. PMID- 29276567 TI - Convergence Spasm in Wernicke Encephalopathy. PMID- 29276568 TI - Restricted Diffusion MRI Lesions in HIV-Associated CMV Encephalitis. PMID- 29276569 TI - Fulminant Reversible Cerebral Vasoconstriction Syndrome. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is increasingly being recognized as a diagnosis in patients presenting with thunderclap headaches. In the vast majority of the cases, the syndrome follows a benign course and patients recover completely without any significant therapeutic intervention. In the rarest of cases, RCVS follows a monophasic course with rapid worsening, severe neurological deficits, and poor outcomes. We present the case of a 25-year-old female who presented with headaches which were worsening over 1 week. She was admitted to the hospital and rapidly worsened to develop severe neurological deficits over the next day. Initial computed tomography scan showed areas of hemorrhage and multiple ischemic strokes. Computed tomography angiogram and a conventional cerebral angiogram both revealed multifocal vasoconstriction, highly suggestive of RCVS. Despite aggressive medical and surgical management, the patient continued to worsen and eventually died. Autopsy findings did not show evidence of vasculopathy or any other underlying disorder, further supporting the diagnosis of RCVS. The RCVS is usually a benign self-remitting condition which commonly affects young females and presents with an insidious onset of headaches. Rarely, it can have a fulminant course with devastating outcomes. This case illustrates an exceptionally uncommon clinical course of RCVS and the challenges in its treatment. PMID- 29276570 TI - Complete genome of a novel virulent phage ST0 lysing Escherichia coli H8. AB - Phage ST0 lysing Escherichia coli H8 was isolated from wastewater and sequenced using an Illumina HiSeq system. Genomic analyses revealed that it was virulent phages and contained a circular double-stranded DNA genome, consisting of 170,496 nucleotides with an average G + C content of 37.67%. This study may provide possible alternative materials for phage therapy. PMID- 29276571 TI - Draft genome sequence of Dethiosulfovibrio salsuginis DSM 21565T an anaerobic, slightly halophilic bacterium isolated from a Colombian saline spring. AB - A bacterium belonging to the phylum Synergistetes, genus Dethiosulfovibrio was isolated in 2007 from a saline spring in Colombia. Dethiosulfovibrio salsuginis USBA 82T (DSM 21565T= KCTC 5659T) is a mesophilic, strictly anaerobic, slightly halophilic, Gram negative bacterium with a diderm cell envelope. The strain ferments peptides, amino acids and a few organic acids. Here we present the description of the complete genome sequencing and annotation of the type species Dethiosulfovibrio salsuginis USBA 82T. The genome consisted of 2.68 Mbp with a 53.7% G + C. A total of 2609 genes were predicted and of those, 2543 were protein coding genes and 66 were RNA genes. We detected in USBA 82T genome six Synergistetes conserved signature indels (CSIs), specific for Jonquetella, Pyramidobacter and Dethiosulfovibrio. The genome of D. salsuginis contained, as expected, genes related to amino acid transport, amino acid metabolism and thiosulfate reduction. These genes represent the major gene groups of Synergistetes, related with their phenotypic traits, and interestingly, 11.8% of the genes in the genome belonged to the amino acid fermentation COG category. In addition, we identified in the genome some ammonification genes such as nitrate reductase genes. The presence of proline operon genes could be related to de novo synthesis of proline to protect the cell in response to high osmolarity. Our bioinformatics workflow included antiSMASH and BAGEL3 which allowed us to identify bacteriocins genes in the genome. PMID- 29276572 TI - Genome sequence of the model plant pathogen Pectobacterium carotovorum SCC1. AB - Bacteria of the genus Pectobacterium are economically important plant pathogens that cause soft rot disease on a wide variety of plant species. Here, we report the genome sequence of Pectobacterium carotovorum strain SCC1, a Finnish soft rot model strain isolated from a diseased potato tuber in the early 1980's. The genome of strain SCC1 consists of one circular chromosome of 4,974,798 bp and one circular plasmid of 5524 bp. In total 4451 genes were predicted, of which 4349 are protein coding and 102 are RNA genes. PMID- 29276573 TI - A Novel Framework for Groupwise Registration of fMRI Images based on Common Functional Networks. AB - Accurate registration plays a critical role in group-wise functional Magnetic Resonance Imaging (fMRI) image analysis, as spatial correspondence among different brain images is a prerequisite for inferring meaningful patterns. However, the problem is challenging and remains open, and more effort should be made to advance the state-of-the-art image registration methods for fMRI images. Inspired by the observation that common functional networks can be reconstructed from fMRI image across individuals, we propose a novel computational framework for simultaneous groupwise fMRI image registration by utilizing those common functional networks as references for spatial alignments. In this framework, firstly, individualized functional networks in each subject are inferred using Independent Component Analysis (ICA); secondly, congealing groupwise registration that takes entropy of stacked independent components (ICs) from all the subjects as objective function is applied to register individual functional maps for maximal matching. The proposed framework is evaluated by and applied to an Alzheimer's Disease (AD) fMRI dataset and shows reasonably good results. PMID- 29276574 TI - Too True to be Bad: When Sets of Studies With Significant and Nonsignificant Findings Are Probably True. AB - Psychology journals rarely publish nonsignificant results. At the same time, it is often very unlikely (or "too good to be true") that a set of studies yields exclusively significant results. Here, we use likelihood ratios to explain when sets of studies that contain a mix of significant and nonsignificant results are likely to be true or "too true to be bad." As we show, mixed results are not only likely to be observed in lines of research but also, when observed, often provide evidence for the alternative hypothesis, given reasonable levels of statistical power and an adequately controlled low Type 1 error rate. Researchers should feel comfortable submitting such lines of research with an internal meta-analysis for publication. A better understanding of probabilities, accompanied by more realistic expectations of what real sets of studies look like, might be an important step in mitigating publication bias in the scientific literature. PMID- 29276575 TI - Parochial Empathy Predicts Reduced Altruism and the Endorsement of Passive Harm. AB - Empathic failures are common in hostile intergroup contexts; repairing empathy is therefore a major focus of peacebuilding efforts. However, it is unclear which aspect of empathy is most relevant to intergroup conflict. Although trait empathic concern predicts prosociality in interpersonal settings, we hypothesized that the best predictor of meaningful intergroup attitudes and behaviors might not be the general capacity for empathy (i.e., trait empathy), but the difference in empathy felt for the in-group versus the out-group, or "parochial empathy." Specifically, we predicted that out-group empathy would inhibit intergroup harm and promote intergroup helping, whereas in-group empathy would have the opposite effect. In three intergroup contexts-Americans regarding Arabs, Hungarians regarding refugees, Greeks regarding Germans-we found support for this hypothesis. In all samples, in-group and out-group empathy had independent, significant, and opposite effects on intergroup outcomes, controlling for trait empathic concern. PMID- 29276576 TI - Digital evaluation of occlusal forces: comparison between healthy subjects and TMD patients. AB - Aim: Continuous technological innovation has provided the clinicians to access to a computerized device that can analyse the different characteristics of occlusal contacts. The purpose of this research was to use this device to study the occlusal forces comparing healthy subjects and TMD patients. Materials and methods: The study was conducted by following specific criteria to select participants; the sample was divided into two homogeneous groups: control group (CG) comprising healthy subjects, and dysfunctional group (DG) comprising TMD patients. The occlusal force analysis was performed using the computerized system T-Scan III V 5.20 T. The data were analysed with statistical methods. Results: The most significant differences emerged between the groups in the average occlusal load distribution and in the location of the centre of occlusal forces (COF). In particular, compared with the CG and the functional standard, reductions in the molar field forces on the second and first molars of 27% and 6.9%, respectively, were observed in the DG. The COF was located in the most forward position in TMD patients compared with healthy subjects. Conclusions: Although the differences in the distribution of the occlusal forces and the location of the occlusal centre of gravity were significant, the relationship between occlusal contacts and TMD remains to be fully clarified. Further research is needed to investigate whether studying occlusal force distributions in both healthy subjects and TMD patients. PMID- 29276577 TI - Are Circulating Type 2 Vaccine-derived Polioviruses (VDPVs) Genetically Distinguishable from Immunodeficiency-associated VDPVs? AB - Public health response to vaccine-derived poliovirus (VDPV) that is transmitted from person to person (circulating VDPV [cVDPV]) differs significantly from response to virus that replicates in individuals with primary immunodeficiency (immunodeficiency-associated VDPV [iVDPV]). cVDPV outbreaks require a community immunization response, whereas iVDPV chronic infections require careful patient monitoring and appropriate individual treatment. To support poliovirus outbreak response, particularly for type 2 VDPV, we investigated the genetic distinctions between cVDPV2 and iVDPV2 sequences. We observed that simple genetic measurements of nucleotide and amino acid substitutions are sufficient for distinguishing highly divergent iVDPV2 from cVDPV2 sequences, but are insufficient to make a clear distinction between the two categories among less divergent sequences. We presented quantitative approaches using genetic information as a surveillance tool for early detection of VDPV outbreaks. This work suggests that genetic variations between cVDPV2 and iVDPV2 may reflect differences in viral micro environments, host-virus interactions, and selective pressures during person-to person transmission compared with chronic infections in immunodeficient patients. PMID- 29276578 TI - New chemical and radiochemical routes to [18F]Rho6G-DEG-F, a delocalized lipophilic cation for myocardial perfusion imaging with PET. AB - New chemical and radiochemical syntheses are described for the preparation of [18F]Rho6G-DEG-F, an 18F-labeled analogue of the fluoresecent dye rhodamine 6G, which has shown promise as myocardidal perfusion imaging agent. Tosylated precursors of [18F]Rho6G-DEG-F amenable to 18F-labeling were obtained either through a two-step synthesis from rhodamine 6G lactone (33% yield), or in one step from rhodamine 575 (64% yield), then purified by preparative C18 chromatography. Manual synthesis of [18F]Rho6G-DEG-F was achieved in a single radiochemical step from either the tosylate salt or the tosylate/formate double salt in DMSO under standard nucleophillic aliphatic 18F-fluorination conditions (K[18F]F/K2CO3/Kryptofix 2.2.2.). Incorporation of the [18F]F- was found to be satisfactory (>=34% by TLC), despite the protic character of the precursor molecules. [18F]Rho6G-DEG-F was manually synthesized in final decay-corrected radiochemical yields of 11-26% (tosylate salt) and 9-21% (tosylate/formate double salt). The protocol was transferred to an automated synthesis unit, where the product was obtained in 3-9% radiochemical yield (n=3) decay corrected to start of-synthesis, >99% radiochemical purity, and a molar activity of 122-267 GBq/MUmol (3.3-7.2 Ci/MUmol). PMID- 29259761 TI - Crystallization and preliminary X-ray diffraction analysis of YejM from Salmonella typhimurium: an essential inner membrane protein involved in outer membrane directed cardiolipin transport. AB - Salmonella typhimurium is responsible for over 35% of all foodborne illness related hospitalizations in the United States. This Gram-negative bacterium possesses an inner and an outer membrane (OM), the latter allowing its survival and replication within host tissues. During infection, OM is remodeled by transport of glycerophospholipids across the periplasm and into the OM. Increased levels of cardiolipin in the OM were observed upon PhoPQ activation and led to the discovery of YejM; an inner membrane protein essential for cell growth involved in cardiolipin binding and transport to the OM. Here we report how YejM was engineered to facilitate crystal growth and X-ray diffraction analysis. Successful structure determination of YejM will help us understand how they interact and how YejM facilitates cardiolipin transport to the OM. Ultimately, yejm, being an essential gene, may lead to new drug targets inhibiting the pathogenic properties of S. typhimurium. PMID- 29276579 TI - Compositional dependency on dissolution rate and cytocompatibility of phosphate based glasses: Effect of B2O3 and Fe2O3 addition. AB - The unique property of phosphate-based glasses and fibres to be completely dissolved in aqueous media is largely dependent on the glass composition. This article focuses on investigating the effect of replacing Na2O with 3 and 5 mol% Fe2O3 on cytocompatibility, thermal and dissolution properties of P2O5-CaO-Na2O MgO-B2O3 glass system, where P2O5 content was fixed at 45 mol%. The effect of increasing Fe2O3 from 3 to 5 mol% on P2O5-CaO-Na2O-MgO glasses was also evaluated. The glass transition temperature, onset of crystallisation temperature and liquidus temperature were found to decrease with increasing Fe2O3 content and the addition of B2O3, while the thermal expansion values were found to decrease. The density of the glasses decreased with increasing Fe2O3 content. However, an increase in the density was observed by the addition of 5 mol% B2O3. The dissolution properties and mode of bulk glass and fibres were also examined which were found to decrease with increasing B2O3 and Fe2O3. However, it was found that the dissolution properties of the glasses containing both B2O3 and Fe2O3 were lower than only Fe2O3 containing glasses. The in vitro cell culture studies using human osteoblast like (MG63) cell lines revealed that the glasses containing both B2O3 and Fe2O3 maintained and showed higher cell viability as compared to the only Fe2O3 containing glasses. Glasses containing both B2O3 and Fe2O3 showed a pronounced effect on the dissolution rate of the glasses, which eventually improved the cytocompatibility properties of the glasses investigated. PMID- 29263780 TI - GAC: Gene Associations with Clinical, a web based application. AB - We present GAC, a shiny R based tool for interactive visualization of clinical associations based on high-dimensional data. The tool provides a web-based suite to perform supervised principal component analysis (SuperPC), an approach that uses both high-dimensional data, such as gene expression, combined with clinical data to infer clinical associations. We extended the approach to address binary outcomes, in addition to continuous and time-to-event data in our package, thereby increasing the use and flexibility of SuperPC. Additionally, the tool provides an interactive visualization for summarizing results based on a forest plot for both binary and time-to-event data. In summary, the GAC suite of tools provide a one stop shop for conducting statistical analysis to identify and visualize the association between a clinical outcome of interest and high dimensional data types, such as genomic data. Our GAC package has been implemented in R and is available via http://shinygispa.winship.emory.edu/GAC/. The developmental repository is available at https://github.com/manalirupji/GAC. PMID- 29276582 TI - Nonlinear Oscillatory Dynamics of the Hardening of Calcium Phosphate Bone Cements. AB - Here we report on the nonlinear, oscillatory dynamics detected in the evolution of phase composition during the setting of different calcium phosphate cements, two of which evolved toward brushite and one toward hydroxyapatite as the final product. Whereas both brushite-forming cements contained ion-doped beta tricalcium phosphate as the initial phase, the zinc-containing one yielded scholzite as an additional phase during setting and the oscillations between these two products were pronounced throughout the entire 80 h setting period, long after the hardening processes was over from the mechanical standpoint. Oscillations in the copper-containing system involved the amount of brushite as the main product of the hardening reaction and they progressed faster toward an equilibrium point than in the zinc-containing system. Initially detected with the use of in situ energy-dispersive X-ray diffractometry, the oscillations were confirmed with a sufficient level of temporal matching in an in situ Fourier transform infrared spectroscopic analysis. The kinetic reaction analysis based on the Johnson-Mehl-Avrami-Kolmogorov model indicated an edge-controlled nucleation mechanism for brushite. The hydroxyapatite-forming cement comprised gelatin as an additional phase with a role of slowing down diffusion and allowing the detection of otherwise rapid oscillations in crystallinity and in the amount of the apatitic phase on the timescale of minutes. A number of possible causes for these dynamic instabilities were discussed. The classical chemical oscillatory model should not apply to these systems unless in combination with less exotic mechanisms of physicochemical nature. One possibility is that the variations in viscosity, directly affecting diffusion and nucleation rates and accompanying growth and transformation from the lower to the higher interfacial energy per the Ostwald-Lussac rule, are responsible for the oscillatory dynamics. The conception of bone replacement materials and tissue engineering constructs capable of engaging in the dynamics of integration with the natural tissues in compliance with this oscillatory nature may open a new avenue for the future of this type of medical devices. To succeed in this goal, the mechanism of these and similar instabilities must be better understood. PMID- 29276583 TI - Utilization of chromic polydiacetylene assemblies as a platform to probe specific binding between drug and RNA. AB - Recognition of nucleic acids remains an important endeavor in biology. Nucleic acids adopt shapes ranging from A-form (RNA and GC rich DNA) to B-form (AT rich DNA). We show, in this contribution, shape-specific recognition of A-U rich RNA duplex by a neomycin (Neo)-polydiacetylene (PDA) complex. PDA assemblies are fabricated by using a well-known diacetylene (DA) monomer, 10,12-pentacosadiynoic acid (PCDA). The response of poly(PCDA) assemblies is generated by mixing with a modified neomycin-PCDA monomer (Neo-PCDA). The functionalization by neomycin moiety provides specific binding with homopolyribonucleotide poly (rA) - poly (rU) stimulus. Various types of alcohols are utilized as additives to enhance the sensitivity of poly(PCDA)/Neo-PCDA assemblies. A change of absorption spectra is clearly observed when a relatively low concentration of poly (rA)-poly (rU) is added into the system. Furthermore, poly(PCDA)/Neo-PCDA shows a clear specificity for poly (rA)-poly (rU) over the corresponding DNA duplex. The variation of linker between neomycin moiety and conjugated PDA backbone is found to significantly affect its sensitivity. We also investigate other parameters including the concentration of Neo-PCDA and the DA monomer structure. Our results provide here preliminary data for an alternative approach to improve the sensitivity of PDA utilized in biosensing and diagnostic applications. PMID- 29276584 TI - Surface Tension Sensor Meshes for Rapid Alcohol Quantification. AB - A surface tension sensor detects alcohol in solution by determining the transition of a liquid droplet from a non-wetted to a wetted state. Results from testing commercial wines are presented along with the fabrication of electrospun two-layer polymeric sensor arrays, which exhibit controlled wettability. PMID- 29276585 TI - Intestinal perforation and peritonitis due to Taenia saginata: A case report from Iran. AB - Taenia saginata (T. saginata) is one of the most common cestode in human. We report a case of intestinal perforation caused due to T. saginata infection. The patient, 54-year-old female, had intermittent abdominal pain, diarrhea and vomiting on referral. Intestinal obstruction and perforation leading to necrosis, and volvulus due to an impacted tapeworm was observed. Histopathological examinations showed acute inflammation with mucosal ulceration, and luminal exudates accompanied by an elongated and flattened segment of the helminth. Taenia infections should be considered in differential diagnosis of peritonitis and gastrointestinal tumors, particularly in endemic countries including Iran. PMID- 29276586 TI - Postoperative enterocutaneous fistula - principles in non-operative approach. AB - Introduction: Postoperative enterocutaneous fistulae could constitute a challenge when they occur following an abdominal surgery. Astute application of correct principles in its management is essential for good outcomes. Methods: A retrospective review of records of patients with enterocutaneous fistulas managed non-operatively was done. Clinical assessment, anatomic and physiologic classification of fistula, fluid resuscitation, electrolyte correction, parenteral/enteral nutrition, antibiotic use and fistula effluent monitoring, formed the basis of management. Results: (4/14)Four out of 14 patients with enterocutaneous fistulae were managed exclusively non-operatively. Their ages ranged between 34 and 63 years. Mean age 46years. All four fistulae occurred postoperatively. Laparatomy for ectopic pregnancy, bowel obstruction constituted the primary surgery. There were two high output cases and two low output cases. Initial parenteral nutrition was employed in two cases while enterals were used solely in two cases. Fistula closure was achieved in all 4 cases at durations ranging from 7 to 16 days, a mean time of 12.5 days. Conclusion: Non-operative approach to management for postoperative enterocutaneous fistulas was successful in these cases. PMID- 29276587 TI - Association between route of illicit drug administration and hospitalizations for infective endocarditis. AB - Objective: This study examined the association between the route of drug administration and being hospitalized for infective endocarditis among 4817 treatment-seeking illicit drug users in Finland. Methods: Cox regression models were used to examine the association between the route of drug administration and infective endocarditis hospitalization, adjusted for age, gender, and homelessness. Cases of infective endocarditis as a primary/main diagnosis were tracked using the 10th version of the International Classification of Disease code I33. Results: In all, 47 persons had a primary diagnosis of infective endocarditis. These 47 persons contributed a total of 95 hospitalizations and their total length of hospital stay was 1393 days. There was a statistically significant difference in hospitalizations between injectors and non-injectors (Log-Rank test p = 0.018). Univariate Cox model showed that injectors had higher hazard or risk for infective endocarditis hospitalization compared to non injectors (hazard ratio: 2.04, 95% confidence interval: 1.12-3.73, p = 0.020). After adjusting for age, gender, and homelessness in the multivariate model, the elevated hazard among injectors compared to non-injectors remained statistically significant with adjusted hazard ratio of 2.12 (95% confidence interval: 1.11 4.07, p = 0.024). Conclusion: The study findings suggested a need to boost harm reduction measures targeting high-risk injecting and other health behaviors among injecting drug users in order to reduce their hospitalizations for infective endocarditis. PMID- 29276588 TI - Ventilatory efficiency and aerobic capacity in people with multiple sclerosis: A randomized study. AB - Objectives: To assess ventilatory efficiency and aerobic capacity in people with multiple sclerosis and whether treadmill walking or progressive strength training has an effect on these parameters in this population. Methods: In all, 24 adults with multiple sclerosis with an Expanded Disability Status Scale score of <=6 completed a cardiopulmonary exercise test before and after 8 weeks of exercise. They were randomized to treadmill walking of low-to-moderate intensity (50%-70% of peak heart rate) or progressive strength training (six repetitions * two at 80% of one repetition maximum). Both groups exercised for 30 min three times per week. Primary outcome measure was ventilatory efficiency measured as the minute ventilation/carbon dioxide production (VE/VCO2) ratio and oxygen uptake efficiency slope. Secondary outcome was aerobic capacity, measured as peak oxygen uptake (VO2peak). Results: Despite low aerobic capacity, ventilatory efficiency was found to be within normal range. After 8 weeks of exercise, no significant between-group differences emerged in (1) VE/VCO2 ratio (26 +/- 2.2 to 26 +/- 2.0, 29 +/- 2.0 to 28 +/- 2.3, p = 0.66), (2) oxygen uptake efficiency slope (2697 +/- 442 to 2701 +/- 577, 2473 +/- 800 to 2481 +/- 896, p = 0.71), or (3) VO2peak in mL/kg/min (28 +/- 4.4 to 30 +/- 4.3, 29 +/- 6.7 to 29 +/- 6.4, p = 0.38) in treadmill walking and progressive strength training, respectively. There were no significant within-group differences either. No adverse events occurred during cardiopulmonary exercise test or exercise training. Conclusion: In people with mild-to-moderate multiple sclerosis, 8 weeks of treadmill walking of low-to moderate intensity or progressive strength training did not have any effect on ventilatory efficiency or aerobic capacity. Although aerobic capacity was lower than reference values, ventilatory efficiency was not reduced. PMID- 29276589 TI - Return to work in heart failure patients with suspected viral myocarditis. AB - Background: Endomyocardial biopsy is considered as the gold standard in patients with suspected myocarditis. We aimed to evaluate the impact of bioptic findings on prediction of successful return to work. Methods: In 1153 patients (48.9 +/- 12.4 years, 66.2% male), who were hospitalized due to symptoms of left heart failure between 2005 and 2012, an endomyocardial biopsy was performed. Routine clinical and laboratory data, sociodemographic parameters, and noninvasive and invasive cardiac variables including endomyocardial biopsy were registered. Data were linked with return to work data from the German statutory pension insurance program and analyzed by Cox regression. Results: A total of 220 patients had a complete data set of hospital and insurance information. Three quarters of patients were virus-positive (54.2% parvovirus B19, other or mixed infection 16.7%). Mean invasive left ventricular ejection fraction was 47.1% +/- 18.6% (left ventricular ejection fraction <45% in 46.3%). Return to work was achieved after a mean interval of 168.8 +/- 347.7 days in 220 patients (after 6, 12, and 24 months in 61.3%, 72.2%, and 76.4%). In multivariate regression analysis, only age (per 10 years, hazard ratio, 1.27; 95% confidence interval, 1.10-1.46; p = 0.001) and left ventricular ejection fraction (per 5% increase, hazard ratio, 1.07; 95% confidence interval, 1.03-1.12; p = 0.002) were associated with increased, elevated work intensity (heavy vs light, congestive heart failure, 0.58; 95% confidence interval, 0.34-0.99; p < 0.049) with decreased probability of return to work. None of the endomyocardial biopsy-derived parameters was significantly associated with return to work in the total group as well as in the subgroup of patients with biopsy-proven myocarditis. Conclusion: Added to established predictors, bioptic data demonstrated no additional impact for return to work probability. Thus, socio-medical evaluation of patients with suspected myocarditis furthermore remains an individually oriented process based primarily on clinical and functional parameters. PMID- 29276590 TI - Correlation of Gastroesophageal reflux disease Assessment Symptom Questionnaire to impedance-pH measurements in children. AB - Background: Esophageal multichannel intraluminal impedance-pH monitoring has become one of the preferred tests to correlate observed reflux-like behaviors with esophageal reflux events. The Gastroesophageal reflux disease Assessment Symptom Questionnaire is a validated tool used to distinguish infants with gastroesophageal reflux disease from healthy children. The aim of this study was to determine whether the Gastroesophageal reflux disease Assessment Symptom Questionnaire composite symptom scores and individual symptom scores correlate with outcomes in esophageal multichannel intraluminal impedance-pH monitoring. Methods: A total of 26 patients with gastroesophageal reflux disease-associated symptoms, aged 0-2 years, for whom both esophageal multichannel intraluminal impedance-pH monitoring and Gastroesophageal reflux disease Assessment Symptom Questionnaire survey results were available were included in the study. Gastroesophageal reflux disease Assessment Symptom Questionnaire score data were collected from a 7-day recall of parent's responses about the frequency and severity of gastroesophageal reflux disease symptoms, which determined the individual symptom scores. The composite symptom scores is the sum of all individual symptom scores. Multichannel intraluminal impedance-pH study results were compared to Gastroesophageal reflux disease Assessment Symptom Questionnaire data using Pearson correlation. Results: Among 26 patients, a total number of 2817 (1700 acid and 1117 non-acid) reflux episodes and 845 clinical reflux behaviors were recorded. There were significant correlations between the reflux index and the individual symptom scores for coughing/gagging/choking (r2 = 0.2842, p = 0.005), the impedance score and individual symptom scores for coughing/gagging/choking (r2 = 0.2482, p = 0.009), the reflux symptom index for acid reflux-related coughing/gagging/choking and the individual symptom scores for coughing/gagging/choking (r2 = 0.1900, p = 0.026), the impedance score and individual symptom scores for vomiting (r2 = 0.1569, p = 0.045), and the impedance score and the composite symptom scores (r2 = 0.2916, p = 0.004). However, there were no significant correlations between fussiness, irritability, or abdominal pain-related multichannel intraluminal impedance-pH results and the individual symptom scores for abdominal pain. Conclusion: The impedance scores from multichannel intraluminal impedance-pH studies correlate with coughing/gagging/choking and vomiting in infants with gastroesophageal reflux disease. There are no significant correlations among the reflux index and impedance score versus the Gastroesophageal reflux disease Assessment Symptom Questionnaire scores for abdominal pain. We conclude that in infants with gastroesophageal reflux disease, multichannel intraluminal impedance-pH studies are more likely to demonstrate an association between gastroesophageal reflux disease and symptoms of coughing, gagging, or choking compared to an association between gastroesophageal reflux disease and pain in infants. PMID- 29276591 TI - Job satisfaction among mental healthcare professionals: The respective contributions of professional characteristics, team attributes, team processes, and team emergent states. AB - Objectives: The aim of this study was to determine the respective contribution of professional characteristics, team attributes, team processes, and team emergent states on the job satisfaction of 315 mental health professionals from Quebec (Canada). Methods: Job satisfaction was measured with the Job Satisfaction Survey. Independent variables were organized into four categories according to a conceptual framework inspired from the Input-Mediator-Outcomes-Input Model. The contribution of each category of variables was assessed using hierarchical regression analysis. Results: Variations in job satisfaction were mostly explained by team processes, with minimal contribution from the other three categories. Among the six variables significantly associated with job satisfaction in the final model, four were team processes: stronger team support, less team conflict, deeper involvement in the decision-making process, and more team collaboration. Job satisfaction was also associated with nursing and, marginally, male gender (professional characteristics) as well as with a stronger affective commitment toward the team (team emergent states). Discussion and Conclusion: Results confirm the importance for health managers of offering adequate support to mental health professionals, and creating an environment favorable to collaboration and decision-sharing, and likely to reduce conflicts between team members. PMID- 29276592 TI - Sexual health knowledge and practices and STI/HIV prevalence among long-distance truck drivers in Peru. AB - Objectives: HIV and other sexually transmitted infections remain a challenge globally and many key groups have yet to be studied. Evidence shows that truck drivers may have high-risk behaviors and higher sexually transmitted infection/HIV prevalence because they are a highly mobile population. However, there is little to no information on this group in Peru. Therefore, we explored the sexual health knowledge and practices and carried out sexually transmitted infection/HIV testing among male truck drivers and their assistants in Peru. Methods: We conducted a cross-sectional study utilizing cell phone-based behavioral surveys and sexually transmitted infection testing, including HIV, syphilis, gonorrhea, and chlamydia, with truck drivers and their assistants who were traveling on two major international highways in Peru. Results: A total of 1150 truck drivers and assistants participated. Participants were middle-aged men (average age = 39.8 years), 96.0% had complete secondary education, 78.4% were in stable relationships, and 88.7% earned more than minimum wage. The majority were aware of sexually transmitted infections/HIV, but very few recognized sexually transmitted infection symptoms. Few participants (under 5%) reported recent sexually transmitted infection symptoms. Prevalence of sexually transmitted infections was also low: no one had gonorrhea; 0.1% had HIV; 0.4% had recent syphilis infection (rapid plasma reagin >=1:8); and 2.0% had chlamydia. The prevalence of these diseases is not different from that of the general population in Peru. Conclusion: When compared to other truck drivers worldwide, Peruvian truck drivers appear to have a lower risk of HIV/sexually transmitted infections. This may be since Peruvian drivers are older, more educated, have higher income, and spend fewer days away from home than their peers globally. PMID- 29276593 TI - Anterior orbital leiomyoma originating from the supraorbital neurovascular bundle. AB - Purpose: To present a young female patient with left anterior orbital leiomyoma that originates from the supraorbital neurovascular bundle. Case presentation: A 41-year-old female patient was admitted to our clinic with a complaint of swelling of the left upper eyelid. Based on the ophthalmological and imaging assessments, the excisional biopsy with the preliminary diagnosis of dermoid cyst was planned. The histopathological and immunohistochemical examinations of excised sample revealed surprisingly that the tumour was a leiomyoma. No recurrence was detected in the patient's follow-up. Conclusion: Although it is rare, orbital leiomyoma should be considered in the differential diagnosis of patients with orbital tumour. PMID- 29276594 TI - Prolonged circulatory support with an Impella assist device in the management of cardiogenic shock associated with takotsubo syndrome, severe sepsis and acute respiratory distress syndrome. AB - Severe sepsis has been known to trigger for takotsubo syndrome which is associated with profound physical or emotional stress. Severe sepsis is also associated with sepsis-induced cardiomyopathy, a reversible myocardial depression. We report a case in which a patient with takotsubo syndrome, cardiogenic shock, severe sepsis, and adult respiratory distress syndrome was managed with an Impella Cardiac Power circulatory support device for 108 h (4.5 days) because of sustained hemodynamic compromise. To the best of our knowledge, this represents the longest reported use of the Impella Cardiac Power device for the management of cardiogenic shock in a patient with takotsubo syndrome and severe sepsis. This report also highlights the importance of considering a ventricular assist device in the management of takotsubo syndrome cardiogenic shock with severe sepsis which is unresponsive to maximal medical therapy. PMID- 29276595 TI - One patient with schizophrenia showed reduced drug-induced extrapyramidal symptoms as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day. AB - Background: Schizophrenia is a chronic disease that requires long-term management with antipsychotics. Antipsychotic drugs are given by tapering their dose, extending the dosing interval, and so on, as part of a treatment strategy to minimize the adverse effects while at the same time maintaining efficacy. Methods: We report the case of one patient with schizophrenia in whom the clinical symptoms were alleviated after treatment with 6 mg paliperidone. However, the patient developed extrapyramidal syndrome, for which 3 and 6 mg paliperidone were administered alternately every other day. Extrapyramidal syndrome was assessed using the Drug-Induced Extrapyramidal Symptoms Scale, Abnormal Involuntary Movement Scale, or Barnes Akathisia Scale. Results: There was improvement in Drug-Induced Extrapyramidal Symptoms Scale score and Abnormal Involuntary Movement Scale score. However, there was almost no change in the Positive and Negative Syndrome Scale total score, positive score, negative score, or general score. Conclusion: The results indicate the possibility of lessened adverse effects as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day in the maintenance phase. PMID- 29276596 TI - Applicability of long-term electroencephalography in pre-mortem diagnosis of Creutzfeldt-Jakob disease: A case report. AB - Creutzfeldt-Jakob disease accounts for more than 90% of all sporadic prion disease cases. The molecular MM2 genotype has been divided into cortical and thalamic subtypes based on structures involved and is characterized clinically by progressive dementia without ataxia or typical electroencephalography changes. Proposed diagnostic criteria for MM2 cortical type sporadic Creutzfeldt-Jakob disease include progressive dementia, cortical hyper-intensity on diffusion weighted magnetic resonance imaging, increased cerebrospinal fluid 14-3-3 protein level, and the exclusion of other types of dementia. The presence of periodic discharges on electroencephalography in MM2 cortical type were reported in 42% of the cases. We are reporting a case of sporadic Creutzfeldt-Jakob disease cortical MM2-type presenting with rapid cognitive decline, who survived 8 months since symptom onset. Brain imaging, cerebrospinal fluid analysis, and long-term electroencephalography monitoring were obtained and diagnosis was confirmed by autopsy. Short-term electroencephalography recording, performed 5 months after symptom onset, demonstrated diffuse background slowing without epileptiform activity. Long-term video electroencephalography monitoring demonstrated generalized slowing, maximum in bilateral frontal areas, which intermittently would become rhythmic (1-2 Hz) without hemispheric predominance. If the findings do not clearly meet the proposed clinical criteria for sporadic Creutzfeldt-Jakob disease, the use of long-term electroencephalography could increase the sensitivity. We question whether the lack of the characteristic findings on electroencephalography in some cases could be due to insufficient time of recording. Application of long-term electroencephalography monitoring increases the sensitivity of electroencephalography and the certainty of pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. PMID- 29276597 TI - Urinary perforation in spina bifida: Neurosurgical and infectious consequences. AB - As the number of medically complex children increases, pediatricians and emergency physicians face challenges in evaluating complications from devices placed to treat their underlying conditions. We present a child with spina bifida who developed a perforation of his vesicostomy leading to peritonitis, septic shock, and urgent externalization of his ventriculoperitoneal shunt. Multiple consultants may need to be promptly involved in the management of children with underlying medical problems. Because procedural complications are often reported only in the surgical specialty literature, pediatricians and emergency physicians should seek information from their patients' specialists about potential problems. PMID- 29276598 TI - Giant urethrocutaneous fistula following ritual circumcision in an infant with congenital anterior urethral diverticula. AB - Circumcision is the most common operation with multiple complications. One of these complications is surgical such as urethrocutaneous fistula due to traumatic and ischemic injury during the operation. A 9-month infant with a history of swelling on the ventral aspect of the penile urethra during micturition was circumcised ritually in 3 months of birth and 6 months later was referred to Imam Reza Hospital with giant ventral fistula in the distal of the penis. PMID- 29276599 TI - Rapid resolution of left ventricular thrombus with apixaban therapy. AB - It is a common medical practice to anticoagulate an asymptomatic left ventricular mural thrombus following an ST-elevation myocardial infarction using a vitamin K antagonist. Novel oral anticoagulants have not been studied extensively in this context, and therefore, no recommendations have been made for their use. A 67 year-old male physician with no significant medical history presented to the cardiology clinic complaining of shortness of breath that had been gradually worsening over a 2-week period and was found to have an anterior wall myocardial infarction with apical left ventricular thrombus that was treated with apixaban. We present a case of rapid resolution of left ventricular thrombus with the use of apixaban for anticoagulation. Although there are no guideline recommendations for this use, there have been case series and case reports that have shown safety and efficacy. Apixaban can be used for rapid resolution of left ventricular thrombus treatment. PMID- 29276600 TI - Atraumatic bilateral rupture of the peroneus brevis tendon in recreational sport: A case report. AB - Issue: Lower extremity tendon injuries often occur in physically active individuals. Most ruptures not involving great force are diagnosed in patients presenting underlying tendon degenerations. This also applies to patients taking medications because of a disease. We have observed several cases of bilateral Achilles tendon ruptures in patients who have been taking cortisone for a long period. We treated a healthy colleague (neurologist) in our clinic who sustained ruptures of the Achilles tendon on the left side (2012) and the peroneus brevis tendon on left side (2015) and right side (2016) after minimal traumata. Aim of this report is to provide a systematic review of this case and a literature review of similar cases, as few such cases have been published. Methods: We reviewed and analysed this patient's records containing the sport-specific anamnesis, pre-existing condition, anamnesis of medications and therapy. The three injuries were magnetic resonance imaging-proven. Furthermore, the tendon's condition was examined histologically in the context of the operative treatment through lace technique of the Achilles tendon and transfer of the peroneus brevis to the peroneus longus. We also researched the literature for bilateral ruptures of the peroneal tendons. Results and conclusion: The anamnesis confirmed no underlying disease. The patient took a macrolide antibiotic about half a year prior to the first peroneal injury for an otitis media. He denied having taken any other antibiotics, especially no quinolone antibiotics. However, the patient reported cortisone intake for 2 days some months before the second peroneal injury to treat an allergic reaction. That involved no local cortisone infiltration in the lower extremity. He underwent surgery within the first 2 weeks after each trauma. Each time, postoperative follow-ups revealed a good healing process. Three months after each operation, the patient was free of complaints. Axibal and Anderson described a patient with bilateral peroneus longus and peroneus brevis ruptures, as well as an Achilles tendon rupture on the left side plus tendinopathy of the Achilles tendon on the right side of uncertain aetiology. We detected additional similar cases in patients who had taken medications, especially cortisone and levofloxacine. Further research should be conducted to clarify other risk factors to help prevent such injuries. PMID- 29276601 TI - Delayed diagnosis of a patient with Usher syndrome 1C in a Louisiana Acadian family highlights the necessity of timely genetic testing for the diagnosis and management of congenital hearing loss. AB - Advances in sequencing technologies and increased understanding of the contribution of genetics to congenital sensorineural hearing loss have led to vastly improved outcomes for patients and their families. Next-generation sequencing and diagnostic panels have become increasingly reliable and less expensive for clinical use. Despite these developments, the diagnosis of genetic sensorineural hearing loss still presents challenges for healthcare providers. Inherited sensorineural hearing loss has high levels of genetic heterogeneity and variable expressivity. Additionally, syndromic hearing loss (hearing loss and additional clinical abnormalities) should be distinguished from non-syndromic (hearing loss is the only clinical symptom). Although the diagnosis of genetic sensorineural hearing loss can be challenging, the patient's family history and ethnicity may provide critical information, as certain genetic mutations are more common in specific ethnic populations. The early identification of the cause of deafness can benefit patients and their families by estimating recurrence risks for future family planning and offering the proper interventions to improve their quality of life. Collaboration between pediatricians, audiologists, otolaryngologists, geneticists, and other specialists are essential in the diagnosis and management of patients with hearing disorders. An early diagnosis is vital for proper management and care, as some clinical manifestations of syndromic sensorineural hearing loss are not apparent at birth and have a delayed age of onset. We present a case of Usher syndrome (congenital deafness and childhood-onset blindness) illustrating the challenges encountered in the diagnosis and management of children presenting with congenital genetic sensorineural hearing loss, along with helpful resources for clinicians and families. PMID- 29276602 TI - The eyes have it: An unusual case of Escherichia coli ophthalmia neonatorum or a shifting landscape? AB - Despite dramatic declines in the incidence of ophthalmia neonatorum with universal prophylaxis, it remains a clinically important cause of eye disease in newborns. While clear guidelines exist for the treatment of the historically primary agents of ophthalmia neonatorum (Chlamydia trachomatis and Neisseria gonorrhoeae), it is less clear how to manage newborns with conjunctivitis secondary to other bacterial organisms, particularly those also frequently implicated in neonatal sepsis. We present the case of a 3-day-old well-appearing term infant with unilateral purulent conjunctivitis. The eye culture grew Escherichia coli, an unusual cause of ophthalmia neonatorum. After a limited sepsis evaluation proved negative, the infant was switched to moxifloxacin ophthalmic drops and made a full recovery. This case highlights the challenge of managing a rare presentation with minimal guideline support, as well as the need to consider other bacterial causes of neonatal conjunctivitis which are emerging in the era of routine prophylaxis in the United States. PMID- 29276603 TI - Varicose vein appearance caused by perforating vein incompetence detected after intense cycling. AB - The role of incompetent perforating veins in the aetiology of varicose veins is not well understood. Anecdotally, competitive cyclists appeared to be more prone to varicose veins than the general population. We present a case of a 63-year-old amateur competitive cyclist who acutely developed a painful varicosity of her left calf while straining during a hill climb in 106-mile cycle race. Duplex ultrasonography has shown an underlying incompetent perforating vein, feeding the varicosity directly through the underlying muscle. With no other significant venous reflux in either leg, we believe this case shows a clear causative association between the stresses put across the lower leg during competitive cycling and developing a varicose vein via an incompetent perforating vein. We believe this should lead to further investigations as to any link between cycling, perforator vein incompetence and the development of varicose veins. PMID- 29276604 TI - Spontaneous cerebrospinal fluid leak from the optic canal. AB - Objective: To present a case of successful repair of a spontaneous cerebrospinal fluid leak in a previously unreported anatomic site. Methods: Retrospective chart review. Results: A 48-year-old woman developed a spontaneous cerebrospinal fluid leak from the optic nerve sheath and underwent a multilayer endoscopic closure with no damage to the optic nerve. Conclusion: Endoscopic surgeons can successfully repair cerebrospinal fluid leaks from the optic nerve sheath without causing loss of vision. PMID- 29276605 TI - Tyramine functionalization of poly(glycerol sebacate) increases the elasticity of the polymer. AB - Poly(glycerol sebacate) (PGS) is an elastomer used widely in tissue engineering studies due to good biocompatibility. Hereby we report a tyramine functionalized PGS called PGS-TA. Tyramine adds a stronger physical bonding capability to PGS TA. Tensile tests showed that the softness and toughness of the material were similar to PGS. However, PGS-TA demonstrated 16-folds increase of elastic deformations compared to PGS processed under identical conditions. The in vitro studies demonstrated that the viability, and metabolic activity of baboon smooth muscle cells were the same as those on tissue culture polystyrene. Porous subcutaneous implants of PGS-TA substantially degraded in vivo over two weeks, showing good biodegradability and biocompatibility. We expect PGS-TA to be useful for applications in tissues and organs that are subjected to large reversible mechanical deformations. PMID- 29276606 TI - Specificity of emotion sequences in borderline personality disorder compared to posttraumatic stress disorder, bulimia nervosa, and healthy controls: an e-diary study. AB - Background: Patients with borderline personality disorder (BPD) exhibit dysregulated emotion sequences in daily life compared to healthy controls (HC). Empirical evidence regarding the specificity of these findings is currently lacking. Methods: To replicate dysregulated emotion sequences in patients with BPD and to investigate the specificity of the sequences, we used e-diaries of 43 female patients with BPD, 28 patients with posttraumatic stress disorder (PTSD), 20 patients with bulimia nervosa (BN), and 28 HC. To capture the rapid dynamics of emotions, we prompted participants every 15 min over a 24-h period to assess their current perceived emotions. We analyzed group differences in terms of activation, persistence, switches, and down-regulation of emotion sequences. Results: By comparing patients with BPD to HC, we replicated five of the seven previously reported dysregulated emotion sequences, as well as 111 out of 113 unaltered sequences. However, none of the previously reported dysregulated emotion sequences exhibited specificity, i.e., none revealed higher frequencies compared to the PTSD group or the BN group. Beyond these findings, we revealed a specific finding for patients with BN, as they most frequently switched from anger to disgust. Conclusions: Replicating previously found dysregulated and unaltered emotional sequences strengthens the significance of emotion sequences. However, the lack of specificity points to emotion sequences as transdiagnostic features. PMID- 29276608 TI - Lithium: one drug, five complications. AB - Background: Lithium poisoning could trigger multiple complications. We report the case of a lithium poisoning with five complications that are described for the first time together. Case report: A 60-year-old woman was admitted in our intensive care unit for altered consciousness. Severe lithium intoxication was diagnosed (lithium plasmatic level 8.21 mmol/l) associated with acute oliguric kidney failure. Continuous renal replacement therapy was started immediately. Orotracheal intubation was quickly required because of status epilepticus. Medullary aplasia happened 48 h after the patient was intubated. Infectious and immunological causes were ruled out and lithium poisoning was considered as the most likely etiology. Iterative blood and platelet transfusion were required. Severe polyneuropathy was diagnosed on the 5th day after admission. The patient showed a peripheral tetraparesia and cranial nerve failure while lithium plasmatic level had decreased to a therapeutic level. Conversely, urine output increased and hypernatremia promptly occurred, which led to diabetes insipidus diagnosis. Neuropathy decreased in 72 h and the patient was definitely extubated by the 11th day. Hematologic disturbances decreased and no blood transfusion would be required after the 8th day. The patient would keep sequellas of the poisoning. Thin motricity would still be altered and polyuria would remain. Diffuse alopecia was promptly observed, with no iron deficiency or thyroid disturbance. Conclusion: In addition to presenting this case report, we herein discuss the drug causality, the consequences, and the plausible pathophysiology of these five situations. PMID- 29276609 TI - Make care coordination a high priority. PMID- 29276607 TI - Ventilator-associated respiratory infection in a resource-restricted setting: impact and etiology. AB - Background: Ventilator-associated respiratory infection (VARI) is a significant problem in resource-restricted intensive care units (ICUs), but differences in casemix and etiology means VARI in resource-restricted ICUs may be different from that found in resource-rich units. Data from these settings are vital to plan preventative interventions and assess their cost-effectiveness, but few are available. Methods: We conducted a prospective observational study in four Vietnamese ICUs to assess the incidence and impact of VARI. Patients >= 16 years old and expected to be mechanically ventilated > 48 h were enrolled in the study and followed daily for 28 days following ICU admission. Results: Four hundred fifty eligible patients were enrolled over 24 months, and after exclusions, 374 patients' data were analyzed. A total of 92/374 cases of VARI (21.7/1000 ventilator days) were diagnosed; 37 (9.9%) of these met ventilator-associated pneumonia (VAP) criteria (8.7/1000 ventilator days). Patients with any VARI, VAP, or VARI without VAP experienced increased hospital and ICU stay, ICU cost, and antibiotic use (p < 0.01 for all). This was also true for all VARI (p < 0.01 for all) with/without tetanus. There was no increased risk of in-hospital death in patients with VARI compared to those without (VAP HR 1.58, 95% CI 0.75-3.33, p = 0.23; VARI without VAP HR 0.40, 95% CI 0.14-1.17, p = 0.09). In patients with positive endotracheal aspirate cultures, most VARI was caused by Gram-negative organisms; the most frequent were Acinetobacter baumannii (32/73, 43.8%) Klebsiella pneumoniae (26/73, 35.6%), and Pseudomonas aeruginosa (24/73, 32.9%). 40/68 (58.8%) patients with positive cultures for these had carbapenem-resistant isolates. Patients with carbapenem-resistant VARI had significantly greater ICU costs than patients with carbapenem-susceptible isolates (6053 USD (IQR 3806 7824) vs 3131 USD (IQR 2108-7551), p = 0.04) and after correction for adequacy of initial antibiotics and APACHE II score, showed a trend towards increased risk of in-hospital death (HR 2.82, 95% CI 0.75-6.75, p = 0.15). Conclusions: VARI in a resource-restricted setting has limited impact on mortality, but shows significant association with increased patient costs, length of stay, and antibiotic use, particularly when caused by carbapenem-resistant bacteria. Evidence-based interventions to reduce VARI in these settings are urgently needed. PMID- 29276610 TI - Care coordination in a business-to-business and a business-to-consumer model for telemonitoring patients with chronic diseases. AB - Introduction: For telemonitoring to support care coordination, a sound business model is conditional. The aim of this study is to explore the systemic and economic differences in care coordination via business-to-business and business to-consumer models for telemonitoring patients with chronic diseases. Methods: We performed a literature search in order to design the business-to-business and business-to-consumer telemonitoring models, and to assess the design elements and themes by applying the activity system theory, and describe the transaction costs in each model. The design elements are content, structure, and governance, while the design themes are novelty, lock-in, complementarities, and efficiency. In the transaction cost analysis, we looked into all the elements of a transaction in both models. Results: Care coordination in the business-to-business model is designed to be organized between the places of activity, rather than the participants in the activity. The design of the business-to-business model creates a firm lock-in but for a limited time. In the business-to-consumer model, the interdependencies are to be found between the persons in the care process and not between the places of care. The differences between the models were found in both the design elements and the design themes. Discussion: Care coordination in the business-to-business and business-to-consumer models for telemonitoring chronic diseases differs in principle in terms of design elements and design themes. Based on the theoretical models, the transaction costs could potentially be lower in the business-to-consumer model than in the business-to-business, which could be a promoting economic principle for the implementation of telemonitoring. PMID- 29276611 TI - Comprehensive knowledge and uptake of cervical cancer screening is low among women living with HIV/AIDS in Northwest Ethiopia. AB - Background: In Ethiopia, cervical cancer is ranked as the second most common type of cancer in women and it is about 8 times more common in HIV infected women. However, data on knowledge of HIV infected women regarding cervical cancer and acceptability of screening is scarce in Ethiopia. Hence, the present study was aimed at assessing the level of knowledge of about cervical cancer and uptake of screening among HIV infected women in Gondar, northwest Ethiopia. Methods: A cross sectional, questionnaire based survey was conducted on 302 HIV infected women attending the outpatient clinic of University of Gondar referral and teaching hospital from March 1 to 30, 2017. Descriptive statistics, univariate and multivariate logistic regression analysis were also performed to examine factors associated with uptake of cervical cancer screening service. Results: Overall, only 64 (21.2%) of respondent were knowledgeable about cervical cancer and screening and only 71 (23.5%) of respondents were ever screened in their life time. Age between 21 and 29 years old (AOR = 2.78, 95% CI = 1.71-7.29), perceived susceptibility to develop cervical cancer (AOR =2.85, 95% CI = 1.89-6.16) and comprehensive knowledge of cervical cancer (AOR = 3.02, 95% CI = 2.31-7.15) were found to be strong predictors of cervical cancer screening service uptake. Conclusion: The knowledge and uptake of cervical cancer screening among HIV infected women was found to be very poor. Taking into consideration the heightened importance of comprehensive knowledge in boosting up the number of participants towards cervical cancer screening services, different stakeholders working on cancer and HIV/AIDS should provide a customized health promotion intervention and awareness creation to HIV-infected women, along with improving accessibility of cervical cancer screening services in rural areas. PMID- 29276612 TI - Heritability of saccadic eye movements in spinocerebellar ataxia type 2: insights into an endophenotype marker. AB - Background: Saccade slowing has been proposed as endophenotype marker in Spinocerebellar Ataxia type 2 (SCA2), nevertheless the heritability of this trait has not been properly demonstrated. Thus the present paper was aimed to assess the heritability of different saccadic parameters in SCA2. Methods: Forty-eight SCA2 patients, 25 preclinical carriers and 24 non-SCA2 mutation carriers underwent electronystagmographical assessments of saccadic eye movements as well as neurological examination and ataxia scoring. Estimates of heritability based on the intraclass correlation coefficients were calculated for saccade velocity, accuracy and latency as well as for age at disease onset from 36, 17 and 15 sibling pairs of SCA2 patients, preclinical carriers and controls, respectively. Results: Saccade velocity was significantly reduced in SCA2 patients and preclinical carriers, whereas decreased saccade accuracy and increased saccade latency were only observed in the patients cohort. Intraclass correlation coefficient for saccade velocity was highly significant in SCA2 patients, estimating a heritability around 94%, whereas for the age at ataxia onset this estimate was around 68%. Conclusions: Electronystagmographical measure of saccade velocity showed higher familial aggregation between SCA2 patients leading the suitability of this disease feature as endophenotype marker, with potential usefulness for the search of modifier genes and neurobiological underpinnings of the disease and as outcome measure in future neuroprotective clinical trials. PMID- 29276613 TI - Vita activa in biotechnology: what we do with fungi and what fungi do with us. AB - Filamentous fungi are fascinating microorganisms. One of the reasons why it is so worthwhile to take a closer look at them is their capacity to produce secondary metabolites. Some of these substances have the potential to be of great use for mankind, such as it was the case with penicillin and its discovery in 1928. Almost a century later, the situation in healthcare could possibly turn back to the state before the development of the first antibiotics. Due to an overuse of antibiotics we are facing a surge of multiresistant bacteria that are not inhibited by any of the currently known drugs. That was part of the background why a European research project was launched in October 2013, titled "Quantitative Biology for Fungal Secondary Metabolite Producers", or "QuantFung". Fifteen young scientists embarked on a new phase in their career, moving to new work environments within Europe and dedicating their work lives intensively to the quest for useful secondary metabolites. After 4 years, the QuantFung project concluded in October this year. In this commentary, we aim to convey what it means to work in this field of fungal biotechnology and how important it is to improve the efficiency of the research therein. We introduce five out of the fifteen fellows at length and let them have their say about the adventure of science, euphoric moments, prospects and doubts. We also raise questions about the current state of research in academia, something the QuantFung fellows experienced first-hand. Being a scientist often goes beyond earning money to make one's living. This is why we also reflect on aspects of the meaning of work in our western society, where production for profit's sake is a main driver. For that we refer to one of the most distinguished thinkers of the twentieth century, to Hannah Arendt. PMID- 29276614 TI - Study profile: the Durban Diabetes Study (DDS): a platform for chronic disease research. AB - The Durban Diabetes Study (DDS) is a population-based cross-sectional survey of an urban black population in the eThekwini Municipality (city of Durban) in South Africa. The survey combines health, lifestyle and socioeconomic questionnaire data with standardised biophysical measurements, biomarkers for non-communicable and infectious diseases, and genetic data. Data collection for the study is currently underway and the target sample size is 10 000 participants. The DDS has an established infrastructure for survey fieldwork, data collection and management, sample processing and storage, managed data sharing and consent for re-approaching participants, which can be utilised for further research studies. As such, the DDS represents a rich platform for investigating the distribution, interrelation and aetiology of chronic diseases and their risk factors, which is critical for developing health care policies for disease management and prevention. For data access enquiries please contact the African Partnership for Chronic Disease Research (APCDR) at data@apcdr.org or the corresponding author. PMID- 29276615 TI - H3Africa multi-centre study of the prevalence and environmental and genetic determinants of type 2 diabetes in sub-Saharan Africa: study protocol. AB - The burden and aetiology of type 2 diabetes (T2D) and its microvascular complications may be influenced by varying behavioural and lifestyle environments as well as by genetic susceptibility. These aspects of the epidemiology of T2D have not been reliably clarified in sub-Saharan Africa (SSA), highlighting the need for context-specific epidemiological studies with the statistical resolution to inform potential preventative and therapeutic strategies. Therefore, as part of the Human Heredity and Health in Africa (H3Africa) initiative, we designed a multi-site study comprising case collections and population-based surveys at 11 sites in eight countries across SSA. The goal is to recruit up to 6000 T2D participants and 6000 control participants. We will collect questionnaire data, biophysical measurements and biological samples for chronic disease traits, risk factors and genetic data on all study participants. Through integrating epidemiological and genomic techniques, the study provides a framework for assessing the burden, spectrum and environmental and genetic risk factors for T2D and its complications across SSA. With established mechanisms for fieldwork, data and sample collection and management, data-sharing and consent for re-approaching participants, the study will be a resource for future research studies, including longitudinal studies, prospective case ascertainment of incident disease and interventional studies. PMID- 29276616 TI - H3Africa AWI-Gen Collaborative Centre: a resource to study the interplay between genomic and environmental risk factors for cardiometabolic diseases in four sub Saharan African countries. AB - Africa is experiencing a rapid increase in adult obesity and associated cardiometabolic diseases (CMDs). The H3Africa AWI-Gen Collaborative Centre was established to examine genomic and environmental factors that influence body composition, body fat distribution and CMD risk, with the aim to provide insights towards effective treatment and intervention strategies. It provides a research platform of over 10 500 participants, 40-60 years old, from Burkina Faso, Ghana, Kenya and South Africa. Following a process that involved community engagement, training of project staff and participant informed consent, participants were administered detailed questionnaires, anthropometric measurements were taken and biospecimens collected. This generated a wealth of demographic, health history, environmental, behavioural and biomarker data. The H3Africa SNP array will be used for genome-wide association studies. AWI-Gen is building capacity to perform large epidemiological, genomic and epigenomic studies across several African counties and strives to become a valuable resource for research collaborations in Africa. PMID- 29276617 TI - Antimicrobial resistance in human populations: challenges and opportunities. AB - Antimicrobial resistance (AMR) is a global public health threat. Emergence of AMR occurs naturally, but can also be selected for by antimicrobial exposure in clinical and veterinary medicine. Despite growing worldwide attention to AMR, there are substantial limitations in our understanding of the burden, distribution and determinants of AMR at the population level. We highlight the importance of population-based approaches to assess the association between antimicrobial use and AMR in humans and animals. Such approaches are needed to improve our understanding of the development and spread of AMR in order to inform strategies for the prevention, detection and management of AMR, and to support the sustainable use of antimicrobials in healthcare. PMID- 29276618 TI - The long road to elimination: malaria mortality in a South African population cohort over 21 years. AB - Background: Malaria elimination is on global agendas following successful transmission reductions. Nevertheless moving from low to zero transmission is challenging. South Africa has an elimination target of 2018, which may or may not be realised in its hypoendemic areas. Methods: The Agincourt Health and Demographic Surveillance System has monitored population health in north-eastern South Africa since 1992. Malaria deaths were analysed against individual factors, socioeconomic status, labour migration and weather over a 21-year period, eliciting trends over time and associations with covariates. Results: Of 13 251 registered deaths over 1.58 million person-years, 1.2% were attributed to malaria. Malaria mortality rates increased from 1992 to 2013, while mean daily maximum temperature rose by 1.5 degrees C. Travel to endemic Mozambique became easier, and malaria mortality increased in higher socioeconomic groups. Overall, malaria mortality was significantly associated with age, socioeconomic status, labour migration and employment, yearly rainfall and higher rainfall/temperature shortly before death. Conclusions: Malaria persists as a small but important cause of death in this semi-rural South African population. Detailed longitudinal population data were crucial for these analyses. The findings highlight practical political, socioeconomic and environmental difficulties that may also be encountered elsewhere in moving from low-transmission scenarios to malaria elimination. PMID- 29276619 TI - Association between sleep difficulties as well as duration and hypertension: is BMI a mediator? AB - Sleep difficulties and short sleep duration have been associated with hypertension. Though body mass index (BMI) may be a mediator variable, the mediation effect has not been defined. We aimed to assess the association between sleep duration and sleep difficulties with hypertension, to determine if BMI is a mediator variable, and to quantify the mediation effect. We conducted a mediation analysis and calculated prevalence ratios with 95% confidence intervals. The exposure variables were sleep duration and sleep difficulties, and the outcome was hypertension. Sleep difficulties were statistically significantly associated with a 43% higher prevalence of hypertension in multivariable analyses; results were not statistically significant for sleep duration. In these analyses, and in sex-specific subgroup analyses, we found no strong evidence that BMI mediated the association between sleep indices and risk of hypertension. Our findings suggest that BMI does not appear to mediate the association between sleep patterns and hypertension. These results highlight the need to further study the mechanisms underlying the relationship between sleep patterns and cardiovascular risk factors. PMID- 29276620 TI - Developing the science and methods of community engagement for genomic research and biobanking in Africa. AB - Historically, community engagement (CE) in research has been implemented in the fields of public health, education and agricultural development. In recent years, international discussions on the ethical and practical goals of CE have been extended to human genomic research and biobanking, particularly in the African context. While there is some consensus on the goals and value of CE generally, questions remain about the effectiveness of CE practices and how to evaluate this. Under the auspices of the Human Heredity and Health in Africa Initiative (H3Africa), the H3Africa CE working group organized a workshop in Stellenbosch, South Africa in March 2016 to explore the extent to which communities should be involved in genomic research and biobanking and to examine various methods of evaluating the effectiveness of CE. In this paper, we present the key themes that emerged from the workshop and make a case for the development of a rigorous application, evaluation and learning around approaches for CE that promote a more systematic process of engaging relevant communities. We highlight the key ways in which CE should be embedded into genomic research and biobanking projects. PMID- 29276621 TI - Developing a novel risk prediction model for severe malarial anemia. AB - As a pilot study to investigate whether personalized medicine approaches could have value for the reduction of malaria-related mortality in young children, we evaluated questionnaire and biomarker data collected from the Mother Offspring Malaria Study Project birth cohort (Muheza, Tanzania, 2002-2006) at the time of delivery as potential prognostic markers for pediatric severe malarial anemia. Severe malarial anemia, defined here as a Plasmodium falciparum infection accompanied by hemoglobin levels below 50 g/L, is a key manifestation of life threatening malaria in high transmission regions. For this study sample, a prediction model incorporating cord blood levels of interleukin-1beta provided the strongest discrimination of severe malarial anemia risk with a C-index of 0.77 (95% CI 0.70-0.84), whereas a pragmatic model based on sex, gravidity, transmission season at delivery, and bed net possession yielded a more modest C index of 0.63 (95% CI 0.54-0.71). Although additional studies, ideally incorporating larger sample sizes and higher event per predictor ratios, are needed to externally validate these prediction models, the findings provide proof of concept that risk score-based screening programs could be developed to avert severe malaria cases in early childhood. PMID- 29276622 TI - Factors affecting prevention and control of malaria among endemic areas of Gurage zone: an implication for malaria elimination in South Ethiopia, 2017. AB - Background: Globally malaria remains one of the most severe public health problems resulting in massive morbidity particularly in developing countries. Ethiopia as one of the sub-Saharan country it is highly endemic to malaria. It was noted that early detection and prompt treatment of malaria cases, selective vector control and epidemic prevention and control are the major strategies for malaria prevention and control; So far, a lot have been done and remarkable improvements were seen. However, in what extent the prevention strategy was running in the community and what factors are hindering the prevention strategy at community level was not well known in Ethiopia. Therefore this study aimed to assess measures taken to prevent malaria and associated factors among households in Gurage zone, south Ethiopia. Methods: Community based cross- sectional study was conducted in Gurage zone, southern Ethiopia. A total of 817 randomly selected households were included in the study. After checking for completeness the data was entered in to Epi info 7 and analyzed through SPSS (Statistical Package for Social Sciences) version 21. Descriptive summary was computed and presented by tables, graphs and figures. After checking for assumptions Bivariate analysis was run to look for the association between dependent and explanatory variables; and using variables which have p-value <=0.25 binary logistic regression was fitted. Association was presented in Odds ratio with 95% confidence interval and significance determined at P-value less than 0.05. Goodness of fit of the final model checked by Hosmer and Lemshow test. Results: Overall 496 (62%) of households practiced good measure of malaria prevention and control. Educated households (AOR = 2.15 (95% CI [1.21-4.67]), higher wealth index (AOR = 3.3 (95% CI [2.3-6.2]), iron corrugated house owners (AOR = 2.7 (95% CI [1.7-3.5]), who received ITN from HC (AOR = 3.6 (95% CI [1.7-4.5] and involved in malaria prevention campaign AOR = 2.6, (95% CI [1.8-3.6]) were independently and significantly determined the practice of malaria prevention measures. Conclusion: The practice of malaria prevention measures were at acceptable and comparable level to other national findings and standards. Further strengthening of the program is important. PMID- 29276623 TI - Feline vertebral angiomatosis: two cases. AB - Case series summary: Two cats aged between 1 and 2 years were presented for paraparesis, general discomfort, back pain and urinary retention. Extradural spinal cord compression at the level of T4 and T8 was evident on CT examination and on MRI. Hemilaminectomy and partial corpectomy were performed to achieve spinal cord decompression. Histopathology of the abnormal bone tissue was suggestive of vertebral angiomatosis. After initially worsening, both cats recovered their normal gait and functional urination. Both cats have been followed-up for >1 year, without any recurrence. Relevance and novel information: This is the first report of vertebral angiomatosis with complete data (CT, MRI, surgical procedures, histopathology and >1 year follow-up) and provides important information about the prognosis of this rare vascular malformation. PMID- 29276624 TI - Subcutaneous interferon beta-1a three times weekly and the natural evolution of gadolinium-enhancing lesions into chronic black holes in relapsing and progressive multiple sclerosis: Analysis of PRISMS and SPECTRIMS trials. AB - Background: Evolution of gadolinium-enhancing lesions into chronic black holes (CBH) may be reduced by interferon (IFN) therapy. Objective: The objective of this paper is to assess the effect of IFN beta-1a and placebo on CBH evolution and disability in patients with relapsing-remitting multiple sclerosis (RRMS), as well as CBH evolution in patients with secondary progressive multiple sclerosis (SPMS). Methods: A post hoc, exploratory analysis of patients with RRMS and SPMS with monthly MRI scans (months -1 to 9) from two separate placebo-controlled clinical trials of IFN beta-1a was conducted. Results: In RRMS patients, the risk of >=1 evolved CBH was lower for IFN beta-1a versus placebo (odds ratio 0.42; p = 0.024); volume of newly evolved CBH was numerically reduced. A numerically higher proportion of patients with >=1 evolving CBH vs no evolving CBH had confirmed three-month disability progression (four-year rate 55.8% vs 43.1%, respectively). Proportion of lesions evolving into CBH (patient level: 34.7% vs 12.6%, p < 0.0001; lesion level: 28.8% vs 11.0%, p < 0.0001) and evolved CBH volume (median 33.5 mm3 (Quartile 1, 0.0; Quartile 3, 173.4) vs 0.0 mm3 (0.0; 52.4); p = 0.0008) was higher for SPMS than RRMS patients treated with IFN beta-1a. Conclusion: In RRMS, IFN beta-1a significantly decreased the proportion of new T1 Gd+ lesions evolving into CBH and the risk of developing a CBH. In patients with SPMS, more lesions develop to CBH, indicating reduced repair capacity, and the natural history of lesion development appears to be unaffected by IFN beta-1a treatment. PMID- 29276626 TI - Metallic nanoislands on graphene: A metamaterial for chemical, mechanical, optical, and biological applications. AB - Graphene decorated with metallic nanoparticles exhibits electronic, optical, and mechanical properties that neither the graphene nor the metal possess alone. These composite films have electrical conductivity and optical properties that can be modulated by a range of physical, chemical, and biological signals. Such properties are controlled by the morphology of the nanoisland films, which can be deposited on graphene using a variety of techniques, including in situ chemical synthesis and physical vapor deposition. These techniques produce non-random (though loosely defined) morphologies, but can be combined with lithography to generate deterministic patterns. Applications of these composite films include chemical sensing and catalysis, energy storage and transport (including photoconductivity), mechanical sensing (using a highly sensitive piezroresistive effect), optical sensing (including so-called "piezoplasmonic" effects), and cellular biophysics (i.e sensing the contractions of cardiomyocytes and myoblasts). PMID- 29276625 TI - Epicardial delivery of autologous atrial appendage micrografts during coronary artery bypass surgery-safety and feasibility study. AB - Background: The atrial appendages are a tissue reservoir for cardiac stem cells. During on-pump coronary artery bypass graft (CABG) surgery, part of the right atrial appendage can be excised upon insertion of the right atrial cannula of the heart-lung machine. In the operating room, the removed tissue can be easily cut into micrografts for transplantation. This trial aims to assess the safety and feasibility of epicardial transplantation of atrial appendage micrografts in patients undergoing CABG surgery. Methods/design: Autologous cardiac micrografts are made from leftover right atrial appendage during CABG of 6 patients. Atrial appendage is mechanically processed to micrografts consisting of atrial appendage derived cells (AADCs) and their extracellular matrix (ECM). The micrografts are epicardially transplanted in a fibrin gel and covered with a tissue-engineered ECM sheet. Parameters including echocardiography-reflecting cardiac insufficiency are studied pre- and post-operatively as well as at 3 and 6 months of the follow up. Cardiac functional magnetic resonance imaging is performed preoperatively and at 6-month follow-up. The primary outcome measures are patient safety in terms of hemodynamic and cardiac function over time and feasibility of therapy administration in a clinical setting. Secondary outcome measures are left ventricular wall thickness, change in the amount of myocardial scar tissue, changes in left ventricular ejection fraction, plasma concentrations of N terminal pro-B-type natriuretic peptide (NT-proBNP) levels, New York Heart Association class, days in hospital, and changes in the quality of life. Twenty patients undergoing routine CAGB surgery will be recruited to serve as a control group. Discussion: This study aims to address the surgical feasibility and patient safety of epicardially delivered atrial appendage micrografts during CABG surgery. Delivery of autologous micrografts and AADCs has potential applications for cell and cell-based gene therapies. Trial registration: ClinicalTrials.gov Identifier: NCT02672163. Date of registration: 02.02.2016. PMID- 29276627 TI - Patient and public involvement in health literacy interventions: a mapping review. AB - Plain English summary: If people can read, understand and act on health information to better their health and reduce illness, they are thought to have "adequate" health literacy. Poor health literacy can mean people are less able to access health care and manage their health. Health literacy tends to worsen as adults get older, and is especially poor in adults age 65 and over. Ideally, health literacy interventions target people before age 65, to establish good skills and habits before people have many health problems associated with ageing. It is also good if researchers consult ordinary people, including patients and the public (PPI) when planning a programme to try to improve health literacy. This may help ensure individual needs are catered for.We therefore looked for studies that described any role of patient or public representatives in the research planning stages. We explored how the representatives contributed to each project. We found only 20 studies that included people other than the research team. Lack of reporting and consultation with patient and public representatives may contribute to less success when public health programmes are undertaken. Abstract: Background: Health literacy is the ability to understand, access and use health care and is a critical mediating factor that affects the health of older adults. Patient and public involvement in health and social care research, policy and design of care delivery is one mechanism that can promote production of better health literacy. This mapping review looks for and describes practices, concepts and methods that have been reported involving patients and public in the development and design of health literacy interventions for older people. Methods: Studies for the present review were selected from an inventory of health behaviour studies published between 2003 and 2013. The inventory was created by systematic searches on bibliographic databases (Medline, CINAHL, Scopus, Google) for health literacy interventions involving older people (50+ years) and resulted in screening of 5561 articles, of which 1097 met study inclusion criteria. For the research described in this article 96 of the 1097 studies specifically focused on health literacy and were independently screened by two reviewers to assess involvement of stakeholders other than investigators and participants. Results: Twenty studies included patient and/or public involvement in at least one research domain: design, management or evaluation. Involvement included volunteers, older people, patients, and/or community representatives. Conclusions: Patient and public involvement were rarely reported in studies on health literacy interventions for older people. Future intervention development needs high quality PPI, which is well reported to develop the evidence base and inform practice. PMID- 29276629 TI - Should Workers Avoid Consumption of Chilled Fluids in a Hot and Humid Climate? AB - Despite provision of drinking water as the most common method of occupational heat stress prevention, there remains confusion in hydration messaging to workers. During work site interactions in a hot and humid climate, workers commonly report being informed to consume tepid fluids to accelerate rehydration. When questioned on the evidence supporting such advice, workers typically cite that fluid absorption is delayed by ingestion of chilled beverages. Presumably, delayed absorption would be a product of fluid delivery from the gut to the intestines, otherwise known as gastric emptying. Regulation of gastric emptying is multifactorial, with gastric volume and beverage energy density the primary factors. If gastric emptying is temperature dependent, the impact of cooling is modest in both magnitude and duration (<= 5 minutes) due to the warming of fluids upon ingestion, particularly where workers have elevated core temperature. Given that chilled beverages are most preferred by workers, and result in greater consumption than warm fluids during and following physical activity, the resultant increased consumption of chilled fluids would promote gastric emptying through superior gastric volume. Hence, advising workers to avoid cool/cold fluids during rehydration appears to be a misinterpretation of the research. More appropriate messaging to workers would include the thermal benefits of cool/cold fluid consumption in hot and humid conditions, thereby promoting autonomy to trial chilled beverages and determine personal preference. In doing so, temperature-based palatability would be maximized and increase the likelihood of workers maintaining or restoring hydration status during and after their work shift. PMID- 29276628 TI - Effect of slice excitation profile on ungated steady state cardiac perfusion imaging. AB - In cardiac perfusion imaging, choice of flip angle is an important factor for steady state acquisition. This work focuses on presenting an analytical framework for understanding how non-ideal slice excitation profiles affect contrast in ungated 2D steady state cardiac perfusion studies, and to study a technique for estimating flip angle that maximizes enhanced/unenhanced myocardial contrast-to noise ratio (CNR) in single slice and multi-slice acquisitions. A numerical simulation of ungated 2D golden ratio radial spoiled gradient echo (SPGR) was created that takes into consideration the actual (Bloch simulated) slice excitation profile. The effect of slice excitation profile on myocardial CNR as a function of flip angle was assessed in phantoms and in-vivo. For fast RF pulses, the flip angle that yields maximum CNR (considering the actual slice excitation profile) was considerably higher than expected, assuming an ideal excitation. The simulation framework presented accurately predicts the flip angle yielding maximum CNR when the actual slice excitation profile is taken into consideration. The prescribed flip angle for optimal contrast in ungated 2D steady-state SPGR cardiac perfusion studies can vary significantly from that calculated when an ideal slice excitation profile is assumed. Consideration of the actual slice excitation can yield a more optimal flip angle estimate in both the single slice and multi-slice cases. PMID- 29276630 TI - Occupational Styrene Exposure on Auditory Function Among Adults: A Systematic Review of Selected Workers. AB - A review study was conducted to examine the adverse effects of styrene, styrene mixtures, or styrene and/or styrene mixtures and noise on the auditory system in humans employed in occupational settings. The search included peer-reviewed articles published in English language involving human volunteers spanning a 25 year period (1990-2015). Studies included peer review journals, case-control studies, and case reports. Animal studies were excluded. An initial search identified 40 studies. After screening for inclusion, 13 studies were retrieved for full journal detail examination and review. As a whole, the results range from no to mild associations between styrene exposure and auditory dysfunction, noting relatively small sample sizes. However, four studies investigating styrene with other organic solvent mixtures and noise suggested combined exposures to both styrene organic solvent mixtures may be more ototoxic than exposure to noise alone. There is little literature examining the effect of styrene on auditory functioning in humans. Nonetheless, findings suggest public health professionals and policy makers should be made aware of the future research needs pertaining to hearing impairment and ototoxicity from styrene. It is recommended that chronic styrene-exposed individuals be routinely evaluated with a comprehensive audiological test battery to detect early signs of auditory dysfunction. PMID- 29276632 TI - Long Working Hours in Korea: Based on the 2014 Korean Working Conditions Survey. AB - Background: Long working hours adversely affect worker safety and health. In 2004, Korea passed legislation that limited the work week to 40 hours, in an effort to improve quality-of-life and increase business competitiveness. This regulation was implemented in stages, first for large businesses and then for small businesses, from 2004 to 2011. We previously reported that average weekly working hours decreased from 2006 to 2010, based on the Korean Working Conditions Survey. Methods: In the present study, we examine whether average weekly working hours continued to decrease in 2014 based on the 2014 Korean Working Conditions Survey. Results: The results show that average weekly working hours among all groups of workers decreased in 2014 relative to previous years; however, self employed individuals and employers (who are not covered by the new legislation) in the specific service sectors worked > 60 h/wk in 2014. Conclusion: The Korean government should prohibit employees from working excessive hours and should also attempt to achieve social and public consensus regarding work time reduction to improve the safety, health, and quality-of-life of all citizens, including those who are employers and self-employed. PMID- 29276633 TI - Health and Safety at Work: Analysis from the Brazilian Documentary Film Flesh and Bone. AB - Background: The objective of this article is to make some analysis on the process of work and accidents occurring in slaughterhouses, evidenced in the Brazilian documentary film called Flesh and Bone. As such, it was necessary to discuss an alternative theoretical concept in relation to theories about health and safety at work. This alternative discussion focuses on the concepts of biopower and biopolitics. Methods: The use of audiovisual elements in research is not new, and there is already a branch of studies with methodological and epistemological variations. The Brazilian documentary Flesh and Bone was the basis for the research. The analysis of this documentary will be carried out from two complementary perspectives: "textual analysis" and "discourse analysis." Results: Flesh and Bone presents problems related to health and safety at work in slaughterhouses because of the constant exposure of workers to knives, saws, and other sharp instruments in the workplace. The results show that in favor of higher production levels, increased overseas market sales, and stricter quality controls, some manufacturers resort to various practices that often result in serious injuries, disposal, and health damages to workers. Conclusion: Flesh and Bone, by itself, makes this explicit in the form of denunciation based on the situation of these workers. What it does not make clear is that, in the context of biopolitics, the actions aimed at solving these problems or even reducing the negative impacts for this group of workers, are not efficient enough to change such practices. PMID- 29276631 TI - Workplace Violence Toward Mental Healthcare Workers Employed in Psychiatric Wards. AB - Background: Workplace violence (WPV) against healthcare workers (HCWs) employed in psychiatric inpatient wards is a serious occupational issue that involves both staff and patients; the consequences of WPV may include increased service costs and lower standards of care. The purpose of this review was to evaluate which topics have been focused on in the literature and which are new in approaching the concern of patient violence against HCWs employed in psychiatric inpatient wards, in the past 20 years. Methods: We searched for publications in PubMed and Web of Science using selected keywords. Each article was reviewed and categorized into one or more of the following four categories based on its subject matter: risk assessment, risk management, occurrence rates, and physical/nonphysical consequences. Results: Our search resulted in a total of 64 publications that matched our inclusion criteria. The topics discussed, in order of frequency (from highest to lowest), were as follows: "risk assessment," "risk management," "occurrence rates," and "physical/nonphysical consequences." Schizophrenia, young age, alcohol use, drug misuse, a history of violence, and hostile-dominant interpersonal styles were found to be the predictors of patients' violence. Conclusion: Risk assessment of violence by patients appeared the way to effectively minimize the occurrence of WPV and, consequently, to better protect mental HCWs. We found paucity of data regarding psychologic sequelae of WPV. According to these findings, we suggest the need to better investigate the psychologic consequences of WPV, with the aim of checking the effective interventions to assist HCW victims of violence and to prevent psychologic illness. PMID- 29276634 TI - A Lower Level of Physically Demanding Work Is Associated with Excellent Work Ability in Men and Women with Neck Pain in Different Age Groups. AB - Background: The aim of this study was to investigate which physical and psychosocial work demands were associated with excellent work ability in individuals with neck pain, and to investigate age and sex differences in these associations. Methods: The study sample was obtained from the Statistics Sweden cross-sectional Work Environment survey and consisted of workers who reported neck pain after work (N = 3,212). Results: The findings showed an association between excellent work ability and self-reported low exposure to lifting, twisted work posture, working with hands in shoulder level or higher, and leaning forward without support and combination of exposures containing these work demands. Low exposure to seated work and high demands showed a reversed association. The associations were present mainly among older workers and were generally stronger for men than for women. Conclusion: This study indicates that a lower level of physically demanding work is an important element to maintain excellent work ability, especially for the older worker with neck pain. PMID- 29276635 TI - Individual Fit Testing of Hearing Protection Devices Based on Microphone in Real Ear. AB - Background: Labeled noise reduction (NR) data presented by manufacturers are considered one of the main challenging issues for occupational experts in employing hearing protection devices (HPDs). This study aimed to determine the actual NR data of typical HPDs using the objective fit testing method with a microphone in real ear (MIRE) method. Methods: Five available commercially earmuff protectors were investigated in 30 workers exposed to reference noise source according to the standard method, ISO 11904-1. Personal attenuation rating (PAR) of the earmuffs was measured based on the MIRE method using a noise dosimeter (SVANTEK, model SV 102). Results: The results showed that means of PAR of the earmuffs are from 49% to 86% of the nominal NR rating. The PAR values of earmuffs when a typical eyewear was worn differed statistically (p < 0.05). It is revealed that a typical safety eyewear can reduce the mean of the PAR value by approximately 2.5 dB. The results also showed that measurements based on the MIRE method resulted in low variability. The variability in NR values between individuals, within individuals, and within earmuffs was not the statistically significant (p > 0.05). Conclusion: This study could provide local individual fit data. Ergonomic aspects of the earmuffs and different levels of users experience and awareness can be considered the main factors affecting individual fitting compared with the laboratory condition for acquiring the labeled NR data. Based on the obtained fit testing results, the field application of MIRE can be employed for complementary studies in real workstations while workers perform their regular work duties. PMID- 29276636 TI - Health Inequalities Among Korean Employees. AB - Background: Social status might be a determinant of occupational health inequalities. This study analyzed the effects of social status on both work environments and health outcomes. Methods: The study sample consisted of 27,598 wage employees aged 15 years and older from among the Korean Working Condition Survey participants in 2011. Work environments included atypical work, physical risks, ergonomic risks, work demands, work autonomy, social supports, and job rewards. Health outcomes comprised general health, health and safety at risk because of work, the World Health Organization-5 Well-being Index, work-related musculoskeletal disease, and work-related injury. Multivariable logistic regression models were used to identify the associations between social status and work environments and health outcomes. Results: Employees in the demographically vulnerable group had lower occupational status compared with their counterparts. Low social status was largely related to adverse work environments. Especially, precarious employment and manual labor occupation were associated with both adverse work environments and poor health outcomes. Conclusion: Precarious and manual workers should take precedence in occupational health equity policies and interventions. Their cumulative vulnerability, which is connected to demographics, occupational status, adverse work environments, or poor health outcomes, can be improved through a multilevel approach such as labor market, organizations, and individual goals. PMID- 29276637 TI - The Current Working Conditions in Ugandan Apparel Assembly Plants. AB - Background: The present rapid shift of industrialization from developed to developing countries requires developing countries to understand issues related to work organization, management, and working conditions. There are many factors slackening production, of which working conditions is part. A complete inquiry into the workers' working conditions can enable managements to reduce risks in the workplaces and improve productivity. Understanding and awareness of the benefits of workplace research and a probe into the working conditions in the Ugandan apparel assembly plants are urgently required. Methods: A total of 103 (70 women and 33 men) workers from five different plants were interviewed. Together with the top management of various plants, questionnaires about the workers' opinions of their physical working conditions were prepared. Data was collected using two methods: (1) questionnaire; and (2) observation of the workers during their work. Results: The results indicated that poor plant working conditions were mainly contributed by the workers' social factors and the management policies. Conclusion: The government, together with the management, should work to improve the working conditions in the apparel assembly plants, as it greatly affects both. PMID- 29276639 TI - A Cluster Randomized Controlled Trial on the Effects of Technology-aided Testing and Feedback on Physical Activity and Biological Age Among Employees in a Medium sized Enterprise. AB - Background: It has been suggested that engaging technology can empower individuals to be more proactive about their health and reduce their health risks. The aim of the present intervention was to study the effects of technology aided testing and feedback on physical activity and biological age of employees in a middle-sized enterprise. Methods: In all, 121 employees (mean age 42 +/- 10 years) participated in the 12-month three-arm cluster randomized trial. The fitness measurement process (Body Age) determined the participants' biological age in years. Physical activity was measured with the International Physical Activity Questionnaire Short Form. Results: Physical activity did not change during the intervention. Biological age (better fitness) improved in all groups statistically significantly (p < 0.001), but with no interaction effects. The mean changes (years) in the groups were -2.20 for the controls, -2.83 for the group receiving their biological age and feedback, and -2.31 for the group receiving their biological age, feedback, and a training computer. Conclusion: Technology-aided testing with feedback does not seem to change the amount of physical activity but may enhance physical fitness measured by biological age. PMID- 29276638 TI - The Effect of Various Hot Environments on Physiological Responses and Information Processing Performance Following Firefighting Activities in a Smoke-Diving Room. AB - Background: Fire service workers often implement multiple duties in the emergency conditions, with such duties being mostly conducted in various ambient temperatures. Methods: The aim of the current study was to assess the firefighters' physiological responses, information processing, and working memory prior to and following simulated firefighting activities in three different hot environments. Seventeen healthy male firefighters performed simulated firefighting tasks in three separate conditions, namely (1) low heat (LH; 29-31 degrees C, 55-60% relative humidity), (2) moderate heat (MH; 32-34 degrees C, 55 60% relative humidity), and (3) severe heat (SH; 35-37 degrees C, 55-60% relative humidity). It took about 45-50 minutes for each firefighter to finish all defined firefighting activities and the paced auditory serial addition test (PASAT). Results: At the end of all the three experimental conditions, heart rate (HR) and tympanic temperature (TT) increased, while PASAT scores as a measure of information processing performance decreased relative to baseline. HR and TT were significantly higher at the end of the experiment in the SH (159.41 +/- 4.25 beats/min; 38.22 +/- 0.10 degrees C) compared with the MH (156.59 +/- 3.77 beats/min; 38.20 +/- 0.10 degrees C) and LH (154.24 +/- 4.67 beats/min; 38.17 +/- 0.10 degrees C) conditions (p < 0.05). There was no significant difference in PASAT scores between LH and MH (p > 0.05). Nonetheless, there was a measurable difference in PASAT scores between LH and SH (p < 0.05). Conclusion: These consequences demonstrate that ambient temperature is effective in raising the physiological responses following firefighting activities. It is therefore argued that further increase of ambient temperature can impact firefighters' information processing and working memory during firefighting activity. PMID- 29276640 TI - Organizational Ostracism: A Potential Framework in Order to Deal with It. AB - Background: Organizational ostracism is defined as a violation of norms that we are suggested to acknowledge at the workplace. It results in the exclusion of one person or multiple persons, and causes damage to our innate need to belong. This kind of behaviorism can be engaged through a hierarchical or nonhierarchical relationship. Three elements interact in the framework of organizational ostracism: the actor, the target, and the institution. Our aim was to describe the different factors interacting with every element in order to produce recommendations targeting to prevent the occurrence of such behaviorism in an institution and to help targets of such a violence in order to handle this situation and go forward. As psychological impact of ostracism has frequently been studied in the literature, we focused on its impact on professional tasks. Methods: We performed a questionnaire-based study about organizational ostracism. This questionnaire was established through an online platform (https://www.sondageonline.com) and made available through the following link: https://goo.gl/forms/KrkVXe3bMEc79cau2. A keyword was sent to all participants. We created a 23-interrogation questionnaire with open and short questions. Nonwritten consent was obtained from all participants. Results: The actor of ostracism engaged in ostracism, in most of the cases, with other persons without a real purpose. The actor of ostracism had an antecedent of problematic relationship at work in 82.9% of the cases. Of the participants, 58.5% were of the view that ostracism aimed to cause hurt and isolate them. Professional isolation was observed in 58.5% of the cases; 51.2% of the participants tried to improve their work potential and explained their reaction by an intrinsic motivation. The organization atmosphere was judged to be bad in most of the cases. Conclusion: Our study showed that ostracism was mainly observed in public practice. PMID- 29276641 TI - Prevalence and Correlates of Current and Former Smoking among Urban Transit Workers. AB - Transit workers constitute a blue-collar occupational group that have elevated smoking rates relative to other sectors of employed adults in the United States. This study analyzed cross-sectional tobacco survey data from 935 workers (60% African American; 37% female) employed at an urban public transit agency in California. Prevalence of current and former smoking was 20.3% and 20.6%, respectively. Younger workers were less likely than older workers to be current or former smokers. Having a complete home smoking ban was associated with decreased likelihood of being a smoker [odds ratio (OR) = 0.04, 95% confidence interval (CI) = 0.01-0.17], as were neutral views about whether it is easy for a smoker to take a smoking break during their shift (OR = 0.50, 95% CI 0.28-0.88). Current smoking among the sample is > 50% higher than the adult statewide prevalence. Potential points of intervention identified in this study include perceived ease of worksite smoking breaks and establishing home smoking bans. Tailored cessation efforts focusing on older transit workers more likely to smoke are needed to reduce tobacco-related disparities in this workforce. PMID- 29276642 TI - Young Adult Street Vendors and Adverse Respiratory Health Outcomes in Bangkok, Thailand. AB - Air pollutants of concern include traffic-related air pollution, including particulate matter in respirable coarse and fine size fractions. There are no critical studies to date into associations between knowledge, awareness, and attitudes in using proper respiratory masks and prevalence of respiratory symptoms among urban street vendors in Thailand. In this study, we estimated adverse respiratory health outcomes among street vendors, in particular young adults, in Bangkok, Thailand, using a self-report questionnaire. Street vendors, who were not currently smoking and not having known diagnosed respiratory diseases, were recruited. They were selected from selected roadsides at Chong Nonsi, Bangkok. Participants (n = 30) reported having lower respiratory (50%), upper respiratory (37%), and other symptoms (70%). Also, 53% of participants had never used respiratory personal protective equipment (PPE: masks). Among those using PPE, all used masks not proper for particulate matter. Results suggested knowledge, awareness, and attitudes concerning proper PPE use needs to be increased among street vendors in Bangkok, Thailand. PMID- 29276643 TI - Psychological Intervention for Post-traumatic Stress Disorder among Witnesses of a Fatal Industrial Accident in a Workers' Health Center. AB - Post-traumatic stress disorder (PTSD) is a serious problem not only among workers who experience industrial accidents but also among workers who witness such accidents. Early intervention is needed to prevent prolonged psychological problems. There has been no study conducted regarding the psychological problems of and interventions for bystander workers in Korea. This study introduces the experience of intervention on psychological problems at the Busan Workers' Health Center workers who witnessed their colleagues' death. An investigation and an intervention were conducted according to the Korean Occupational Safety and Health Agency (KOSHA) Guide. In total, 21 individuals including indirect observers showed statistical differences on scores of the Impact Event Scale Revised and the Patient Health Questionnaire 9 after the intervention. Future interventions and research involving a larger sample size over a longer period are needed. The KOSHA Guide could be a useful tool for urgent psychological intervention in the event of major workplace disasters. PMID- 29276644 TI - Hepatic progenitor cell activation in liver repair. AB - The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies. PMID- 29276646 TI - Zebra migration strategies and anthrax in Etosha National Park, Namibia. AB - Partial seasonal migration is ubiquitous in many species. We documented this phenomenon in plains zebra (Equus burchelli) in Etosha National Park, Namibia (ENP), and provided a cost-benefit analysis as it relates to the spatial distribution of water, vegetation and endemic anthrax. This analysis draws upon two years of ENP zebra movement data that reveal two sub-populations: migrators and non-migrators. Migrators are shown to be behaviorally dominant in the way they utilize space and use water holes. We raise the possibility that the co existence of these two groups reflects an evolutionary process, and the size of each group maintains evolutionary equilibrium. PMID- 29276645 TI - Abnormal expression of TFIIIB subunits and RNA Pol III genes is associated with hepatocellular carcinoma. AB - The levels of the products of RNA polymerase III-dependent genes (Pol III genes), including tRNAs and 5S rRNA, are elevated in transformed and tumor cells, which potentiate tumorigenesis. TFIIB-related factor 1 (Brf1) is a key transcription factor and specifically regulates the transcription of Pol III genes. In vivo and in vitro studies have demonstrated that a decrease in Brf1 reduces Pol III gene transcription and is sufficient for inhibiting cell transformation and tumor formation. Emerging evidence indicates that dysregulation of Brf1 and Pol III genes is linked to the development of hepatocellular carcinoma (HCC) in humans and animals. We have reported that Brf1 is overexpressed in human liver cancer patients and that those with high Brf1 levels have shorter survivals. This review summarizes the effects of dysregulation of these genes on HCC and their regulation by signaling pathways and epigenetics. These novel data should help us determine the molecular mechanisms of HCC from a different perspective and guide the development of therapeutic approaches for HCC patients. PMID- 29276647 TI - Low-Dose Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin Resistant or Contraindicated Preterm Infants: Three Cases Reports. AB - Background Although indomethacin (IND) is the standard treatment for hemodynamically significant patent ductus arteriosus (hsPDA) in Japan, it may be associated with renal impairment and gastrointestinal complications. The use of paracetamol for hsPDA closure has recently increased. Unlike IND, paracetamol does not have a peripheral vasoconstrictive effect and can be given to infants with contraindications to IND. Based on limited data available from randomized trials, paracetamol and IND seem to have similar effects. However, there have been no reports of the use of paracetamol for hsPDA in Japan. Cases Our drug administration protocol was approved by the institutional ethics committee after purchasing a clinical trial insurance. In three premature infants in whom IND was contraindicated or ineffective, a 7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days after obtaining parental consents. A temporary hsPDA closure was observed in two of the three infants. However, all three infants eventually needed surgical closure. No side effects, such as hepatic and renal dysfunctions, and adverse events were reported. Conclusion The intravenous administration of paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials with optimized dose and timing of administration are needed. PMID- 29276648 TI - Sertraline-induced Hemichorea. AB - Background: Hemichorea-hemiballism is a syndrome secondary to different etiologies. Drug-induced hemichorea is a rare syndrome related to selective serotonin reuptake inhibitors. To the best of our knowledge, no previous cases of hemichorea associated with sertraline have been reported. Case Report: A 65-year old female noticed hemichorea 1 week after initiation of sertraline. After extensive investigations, other causes of hemichorea were excluded. Hemichorea remitted after sertraline withdrawal. Discussion: In our patient, temporal association and the negative clinical assessment supported a diagnosis of likely drug-induced involuntary movement. We hypothesized that enhanced serotonergic transmission in the ventral tegmental area or nigrostriatum may be involved in sertraline-induced hemichorea. PMID- 29276649 TI - Psychological Suffering in Essential Tremor: A Study of Patients and Those Who Are Close to Them. AB - Background: Although the motor and non-motor features of essential tremor (ET) have been characterized in detail, it is not known whether ET patients suffer psychologically and whether those who are close to them consider them to be suffering in this way. Methods: Fifty ET patients and 50 "close others" (COs), identified by patients "as someone who knows you well and sees you often" and who can "provide a different perspective on your well-being", reported their own depressive symptoms, daily stress, and perceptions of patient psychological suffering and patient overall suffering with validated scales. ET patients' tremor severity, duration, disability, cognition, and number of medications were also assessed. Results: ET patients reported levels of psychological suffering within the range documented in arthritis and dementia patients from previous studies, and COs perceived significantly more psychological suffering in patients than patients reported themselves. Regression models, controlling for tremor severity, duration, and disability revealed that patients' greater psychological suffering was associated with greater patient depression. The greater perceptions of COs of patient psychological and overall suffering were associated with greater CO depression and daily stress. Sensitivity analysis showed that patients' cognitive status or number of medications did not affect the results. Discussion: Multidisciplinary teams caring for ET patients should look beyond simple clinical ET indicators. They should be aware of patient experiences and perceptions of COs of psychological and overall suffering. This will help guide the development of evidence-based, supportive interventions that improve communication about the needs of ET patients and those who are close to them. PMID- 29276650 TI - Paroxysmal Kinesigenic Dyskinesia. AB - Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition associated with heterozygous mutations in the proline-rich transmembrane protein 2 (PRRT2) gene. Phenomenology Shown: In this article we illustrate the phenomenology of PKD in a male previously misdiagnosed with Tourette's syndrome. Educational Value: Regardless of the underlying phenotype, PKD is highly responsive to some antiepileptic drugs. PMID- 29276651 TI - Metallocene-Containing Homopolymers and Heterobimetallic Block Copolymers via Photoinduced RAFT Polymerization. AB - We report the synthesis of cationic cobaltocenium and neutral ferrocene containing homopolymers mediated by photoinduced reversible addition fragmentation chain transfer (RAFT) polymerization with a photocatalyst fac [Ir(ppy)3]. The homopolymers were further used as macromolecular chain transfer agents to synthesize diblock copolymers via chain extension. Controlled/"living" feature of photoinduced RAFT polymerization was confirmed by kinetic studies even without prior deoxygenation. A light switch between ON and OFF provided a spatiotemporal control of polymerization. PMID- 29276652 TI - Endometriosis: Epidemiology, Diagnosis and Clinical Management. AB - Purpose of review: Endometriosis is a disease of adolescents and reproductive aged women characterized by the presence of endometrial tissue outside the uterine cavity and commonly associated with chronic pelvic pain and infertility. Here we review the epidemiology of endometriosis as well as potential biomarkers for detection and with the goal of highlighting risk factors that could be used in combination with biomarkers to identify and treat women with endometriosis earlier.. Recent findings: Early age at menarche, shorter menstrual length, and taller height are associated with a higher risk of endometriosis while parity, higher body mass index (BMI) and smoking are associated with decreased risk. Endometriosis often presents as infertility or continued pelvic pain despite treatment with analgesics and cyclic oral contraceptive pills. Summary: Despite a range of symptoms, diagnosis of endometriosis is often delayed due to lack of non invasive, definitive and consistent biomarkers for diagnosis of endometriosis. Hormone therapy and analgesics are used for treatment of symptomatic endometriosis. However, the efficacy of these treatments are limited as endometriosis often recurs. In this review, we describe potential diagnostic biomarkers and risk factors that may be used as early non-invasive in vitro tools for identification of endometriosis to minimize diagnostic delay and improve reproductive health of patients. PMID- 29276653 TI - Prevalence of cardiovascular disease and evaluation of standard of care in type 2 diabetes: a nationwide study in primary care. AB - Objective: Cardiovascular disease (CVD) complicates type 2 diabetes. Empagliflozin and liraglutide have demonstrated improved survival in patients with type 2 diabetes and established CVD. We assessed prevalence and standard of care of patients with type 2 diabetes and established CVD managed in primary care. Patients and methods: A total of 129 general practitioners in both rural and urban areas, responsible for 348 373 patients, identified their patients with type 2 diabetes. The identification was based on a search for International Classification of Primary Health Care 2 codes in the general practitioners' electronic patient record systems. Patients with concomitant CVD were identified and characterized. Results: A total of 17 113 (4.9%) patients were diagnosed with type 2 diabetes. Type 2 diabetes with concomitant CVD was found in 3665 (21.4%) patients, with their mean age being 72 years, and 34.6% were women. Mean estimated glomerular filtration rate was 68.2 ml/min, and 22.2% had microalbuminuria or macroalbuminuria. Standard of care was fair: mean glycated hemoglobin was 52.3 mmol/mol (Diabetes Control and Complications Trial=6.9%), mean blood pressure was 131.4/75.7 mmHg, and mean low-density lipoprotein cholesterol was 2.0 mmol/l. Conclusion: In a nationwide database survey in primary care, the prevalence of CVD in patients with type 2 diabetes was high (21.4%). Standard of care was largely in accordance with national guidelines. Identification of eligible patients is possible with existing electronic patient record systems. Identifying this high-risk subgroup of patients with type 2 diabetes and optimizing their treatment might add further cardiovascular benefits as suggested by recent cardiovascular outcome trials. PMID- 29276654 TI - Contributors to Metabolic Disease Risk Following Spinal Cord Injury. AB - Spinal cord injury (SCI) induced changes in neurological function have significant impact on the metabolism and subsequent metabolic-related disease risk in injured individuals. This metabolic-related disease risk relationship is differential depending on the anatomic level and severity of the injury, with high level anatomic injuries contributing a greater risk of glucose and lipid dysregulation resulting in type 2 diabetes and cardiovascular disease risk elevation. Although alterations in body composition, particularly excess adiposity and its anatomical distribution in the visceral depot or ectopic location in non-adipose organs, is known to significantly contribute to metabolic disease risk, changes in fat mass and fat-free mass do not fully account for this elevated disease risk in subjects with SCI. There are other negative adaptations in body composition including reductions in skeletal muscle mass and alterations in muscle fiber type, in addition to significant reduction in physical activity, that contribute to a decline in metabolic rate and increased metabolic disease risk following SCI. Recent studies in adult humans suggest cold- and diet-induced thermogenesis through brown adipose tissue metabolism may be important for energy balance and substrate metabolism, and particularly sensitive to sympathetic nervous signaling. Considering the alterations that occur in the autonomic nervous system (SNS) (sympathetic and parasympathetic) following a SCI, significant dysfunction of brown adipose function is expected. This review will highlight metabolic alterations following SCI and integrate findings from brown adipose tissue studies as potential new areas of research to pursue. PMID- 29276655 TI - Polypoidal Choroidal Vasculopathy. AB - Purpose of Review: The goal of this paper is to review the recent literature of polypoidal choroidal vasculopathy (PCV) and provide an update on the epidemiology, pathophysiology, clinical findings, and management. Recent Findings: Although indocyanine-green angiography (ICGA) is still the gold standard for diagnosis of PCV, the use of en face optical coherence tomography (OCT) and OCT angiography are useful tools in the diagnosis of PCV. Studies demonstrate superior treatment outcomes with combination photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) therapy. Summary: PCV is a disease most commonly in Asians and African-Americans and presents with an orange-red nodule in the macula or the peripapillary region. While ICGA remains the most accurate method to diagnose PCV, newer non-invasive imaging modalities (eg. OCT-A and en face OCT) can be used to identify PCV lesions. The combination of PDT and anti-VEGF therapy is superior to either monotherapy. Future studies of OCT modalities and other anti-VEGF agents will be important in guiding PCV diagnosis and management, respectively. PMID- 29276656 TI - Primary Open-Angle Glaucoma Genetics in African Americans. AB - Purpose of review: Individuals of African descent are at highest risk for developing primary open-angle glaucoma (POAG), a devastating disease and major contributor of blindness worldwide. Currently, there is a large dearth of knowledge in this area despite a critical need for better understanding the underlying genetic and environmental factors afflicting this population. Here we highlight the current literature exploring the genetics of POAG in African Americans. Recent findings: Current studies have yet to replicate European POAG index variants (i.e. CDKN2B-AS1 and SIX1/SIX6) in African Americans or to definitely exclude that these loci contribute to risk in African descent populations. Recent studies have evaluated clinical features that may account for some differences in POAG risk between African Americans and European Americans. Summary: In summary, little headway has been made in elucidating the genetics of primary open-angle glaucoma in African Americans and other individuals of African descent. PMID- 29276658 TI - Optimization of rhamnolipid production from Pseudomonas aeruginosa PBS towards application for microbial enhanced oil recovery. AB - The present work reveals the potential of biosurfactant producing P. aeruginosa PBS for microbial enhanced oil recovery (MEOR). The biosurfactant production medium and culture conditions were optimized using response surface methodology. The optimization of media components and process parameters was consecutively executed in two sets of experimental runs designed by central composite rotatable design (CCRD). The maximum biosurfactant yield was attained with 2% fresh inoculum of P. aeruginosa PBS in minimal salt medium (pH 7), possessing 2.17% sodium citrate as C-source and 0.5% yeast extract as N-source, after 48 h upon incubation at 30 degrees C/150 rpm. Under optimum conditions, biosurfactant yield was increased more than threefold and turned out to be 2.65 g/L as compared to 0.82 g/L under previous conditions. The biosurfactant was characterized as a glycolipid comprising of four rhamnolipid homologs (RhaRhaC10C10, RhaRhaC8C10, RhaRhaC12C10/RhaRhaC10C12, RhaC10C10) by thin layer chromatography, fourier transform infrared spectroscopy, nuclear magnetic resonance and mass spectrometry. The produced biosurfactant was highly efficient for oil recovery application showing extreme reduction in surface tension of medium (71.80 to 23.76 mN/m), immense hydrocarbons emulsification capacity (50-60%) and greater stability at wide range of temperature (4-100 degrees C) and pH (4-10) along with an excellent (56.18 +/- 1.59%) additional oil recovery in sand-pack column lab test. PMID- 29276657 TI - Subtilisin inhibitor like protein 'ppLPI-1' from leaves of pigeonpea (Cajanus cajan, cv. BSMR 736) exhibits inhibition against Helicoverpa armigera gut proteinases. AB - Helicoverpa armigera is an orthodox rival of many crop plants affecting agricultural economy. Plant leaves found to accumulate proteinase inhibitors, although this insect pest chooses leaves for laying eggs. Plant defense response at this juncture is not fully explored. In this context, here we are reporting proteinase inhibitor (ppLPI-1) having significant homology with the I13 family from leaves of pigeonpea (cv. BSMR 736). The isolation of ppLPI-1 was carried out from leaves of field-grown pigeonpea under an outbreak of H. armigera. The acetone precipitated ppLPI-1 (125 ug) displayed substantial inhibition potential towards bovine trypsin (56.5 +/- 1.8%) and HaGPs (52.6 +/- 1.7%) on solution assay. These results were corroborated with dot-blot analysis. The molecular form of ppLPI-1 was characterized by reverse zymography and GXCP. The optimum condition was found to be pH 8 and temperature in the range of 30-40 degrees C. The protein identification via MASCOT-PMF and NCBI-BLAST search showed substantial homology with an inducible subtilisin inhibitor of Fabaceae comprising Vigna angularis (96%), Canavalia lineata (78%), Cicer arietinum (76%), Glycine max (75%), Medicago truncatula (73%) and Vicia faba (73%) consists of conserved domain of potato inhibitor I family. PMID- 29276659 TI - Bioremediation potential of hydrocarbon-utilizing fungi from select marine niches of India. AB - Ten fungal isolates with an ability to degrade crude oil were isolated from select marine substrates, such as mangrove sediments, Arabian Sea sediments, and tarballs. Out of the ten isolates, six belonged to Aspergillus, two to Fusarium and one each to Penicillium and Acremonium as identified using ITS rDNA sequencing. The selected ten fungal isolates were found to degrade the long-chain n-alkanes as opposed to short-chain n-alkanes from the crude oil. Mangrove fungus #NIOSN-M126 (Penicillium citrinum) was found to be highly efficient in biodegradation of crude oil, reducing the total crude oil content by 77% and the individual n-alkane fraction by an average of 95.37%, indicating it to be a potential candidate for the development into a bioremediation agent. PMID- 29276660 TI - Profiling of red pigment produced by Streptomyces sp. JAR6 and its bioactivity. AB - Actinomycetes strain was isolated from leaf litter soil sample and was identified as Streptomyces sp. by conventional and molecular approaches. The biologically active compound responsible for antimicrobial and anticancer activity of the strain JAR6 was elucidated by solid state fermentation followed by subsequent chromatographic and spectroscopic analysis. Extraction, purification and structural confirmation of red pigment metabolite viz undecylprodigiosin were established on the basis of spectroscopic studies and comparing the data from the literature. The biologically active compound was tested against Gram-positive and Gram-negative clinical isolates and its minimum inhibitory concentration was recorded. The antimicrobial activity of undecylprodigiosin is more prominent against Salmonella sp., Proteus mirabilis, Shigella sp. and Enterococcus sp. whereas, it was less effective against Staphylococcus aureus, Klebsiella pneumonia and Escherichia coli. The anticancer activity of undecylprodigiosin was tested against HeLa cell lines and it exhibited commendable cytotoxicity effect with IC50 value of 145 ug/ml. The present investigation reveals that undecylprodigiosin produced by Streptomyces strain JAR6 is a potent bioactive metabolite with effective pharmaceutical properties. PMID- 29276662 TI - 'Ogura'-based 'CMS' lines with different nuclear backgrounds of cabbage revealed substantial diversity at morphological and molecular levels. AB - A comprehensive study on characterization and genetic diversity analysis was carried out in 16 'Ogura'-based 'CMS' lines of cabbage using 14 agro morphological traits and 29 SSR markers. Agro-morphological characterization depicted considerable variations for different horticultural traits studied. The genotype, ZHA-2, performed better for most of the economically important quantitative traits. Further, gross head weight (0.76), head length (0.60) and head width (0.83) revealed significant positive correlation with net head weight. Dendrogram based on 10 quantitative traits exhibited considerable diversity among different CMS lines and principle component analysis (PCA) indicated that net and gross head weight, and head length and width are the main components of divergence between 16 CMS lines of cabbage. In molecular study, a total of 58 alleles were amplified by 29 SSR primers, averaging to 2.0 alleles in each locus. High mean values of Shannon's Information index (0.62), expected (0.45) and observed (0.32) heterozygosity and polymorphic information content (0.35) depicted substantial polymorphism. Dendrogram based on Jaccard's similarity coefficient constructed two major groups and eight sub-groups, which revealed substantial diversity among different CMS lines. In overall, based on agro morphological and molecular studies genotype RRMA, ZHA-2 and RCA were found most divergent. Hence, they have immense potential in future breeding programs for the high-yielding hybrid development in cabbage. PMID- 29276661 TI - Microencapsulation of reuterin to enhance long-term efficacy against food-borne pathogen Listeria monocytogenes. AB - The aim of this study was to microencapsulate the reuterin produced by Lactobacillus reuteri BPL-36 strain for its long-term efficacy against food-borne pathogen Listeria monocytogenes. Lactobacillus reuteri BPL-36 strain previously isolated from a human infant fecal sample in lab was selected for the present study based on its ability to produce reuterin. The organism displayed a broad spectrum antimicrobial activity. Reuterin concentration of 89.63 mM was obtained in the MRS-glycerol medium after 16 h incubation at 37 degrees C. The reuterin concentration required to inhibit the growth of Pseudomonas aeruginosa, Escherichia coli O157: H7, Salmonella typhi, Staphylococcus aureus, and Listeria monocytogenes was found to be 1.0, 2.0, 2.0, 4.0, and 10.0 AU/mL, respectively. Microencapsulation of reuterin to enhance long-term efficacy against food-borne pathogens was done. Results in this study indicated that the release characteristics of reuterin from the encapsulated particles were pH dependent. The release characteristics were unaffected by the storage of encapsulated reuterin at 4 degrees C for 2 weeks. The anti-listerial efficacy of the encapsulated reuterin was tested against L. monocytogenes in the BHI medium adjusted to pH 5.0 with a reuterin content equivalent to 16 mM, similar to un encapsulated (free) reuterin. Encapsulated reuterin demonstrated enhanced efficacy against L. monocytogenes for longer duration of time when compared with un-encapsulated (free) reuterin. The present work demonstrated a novel antimicrobial delivery system that ensured much better capability of inhibiting the growth of L. monocytogenes throughout 24 h incubation at 37 degrees C. PMID- 29276663 TI - Detection of viable but non-culturable Escherichia coli O157:H7 by PCR in combination with propidium monoazide. AB - The aim of this study was to evaluate the applicability of the conventional PCR detection method combined with propidium monoazide (PMA) treatment for the detection of viable but non-culturable (VBNC) state Escherichia coli O157:H7 in ground beef meatballs. Under low temperature, E. coli O157:H7 cells were induced into the VBNC state in ground beef meatballs at - 20 degrees C after 152 days. The optimal PMA concentration of 5 ug/mL was obtained in beef meatball samples, which could completely inhibit the DNA amplification on dead cells (106 cells/mL) but with no inhibition on viable cells. The established PMA-PCR assay revealed that the VBNC counts exceeded 107 CFU/mL in artificial contamination beef samples, which could be used for semi-quantitative detection of VBNC cells in beef meatball samples. This study indicated that the PMA-PCR assay might be a potential method for detection of VBNC state E. coli O157:H7 cells in food products. PMID- 29276664 TI - Subwavelength core/shell cylindrical nanostructures for novel plasmonic and metamaterial devices. AB - In this review, we introduce novel plasmonic and metamaterial devices based on one-dimensional subwavelength nanostructures with cylindrical symmetry. Individual single devices with semiconductor/metal core/shell or dielectric/metal core/multi-shell structures experience strong light-matter interaction and yield unique optical properties with a variety of functions, e.g., invisibility cloaking, super-scattering/super-absorption, enhanced luminescence and nonlinear optical activities, and deep subwavelength-scale optical waveguiding. We describe the rational design of core/shell cylindrical nanostructures and the proper choice of appropriate constituent materials, which allow the efficient manipulation of electromagnetic waves and help to overcome the limitations of conventional homogeneous nanostructures. The recent developments of bottom-up synthesis combined with the top-down fabrication technologies for the practical applications and the experimental realizations of 1D subwavelength core/shell nanostructure devices are briefly discussed. PMID- 29276665 TI - Insights since FDA Approval of Hypoglossal Nerve Stimulation for the Treatment of Obstructive Sleep Apnea. AB - Purpose: The literature on hypoglossal nerve stimulation (HNS) for the treatment of moderate-to-severe obstructive sleep apnea (OSA) was reviewed from 2014, the time of FDA approval for the Inspire Systems device, to 2017 for themes that might be useful conceptually and practically in the consideration of this new non anatomic surgical therapy. Recent Findings: there are now further follow-up articles since the 12-month results for Apnea Reduction (STAR) trial of the Inspire device, and post-approval publications which report similar and/0r improved AHI outcomes. Other emerging themes include drug-induced sedation endoscopy (DISE) as a tool in assessment of eligibility and a more detailed understanding of mechanisms for an HNS effects. Summary: The post-STAR literature provides guidelines for an integrated coordination of medicine and surgery to appropriately screen and manage patients. PMID- 29276666 TI - Reciprocal regulation of PPARgamma and RUNX2 activities in marrow mesenchymal stem cells: Fine balance between p38 MAPK and Protein Phosphatase 5. AB - Purpose of review: Post-translational modifications (PTMs), specifically serine phosphorylation, are essential for determination and tuning up an activity of many proteins, including those that are involved in the control of gene transcription. Transcription factors PPARgamma2 and RUNX2 are essential for mesenchymal stem cell (MSC) commitment to either adipocyte or osteoblast lineage. This review is summarizing current knowledge how serine phosphorylation PTMs regulate activities of both transcription factors and MSCs lineage commitment. Recent finding: Both PPARgamma2 and RUNX2 transcriptional activities are regulated by similar PTMs, however with an opposite outcome. The same p38 MAPK mediates serine phosphorylation that leads to activation of RUNX2 and inactivation of PPARgamma2. The process of protein phosphorylation is balanced with a process of protein dephosphorylation. Protein phosphatase 5 simultaneously dephosphorylates both proteins, which results in activation of PPARgamma2 and inactivation of RUNX2. Summary: This review provides a summary of the "yinyang" fine-tuned mechanism by which p38 MAPK and PP5 regulate MSCs lineage commitment. PMID- 29276667 TI - Effects of the truth FinishIt brand on tobacco outcomes. AB - Since 2000, the truth campaign has grown as a social marketing brand. Back then, truth employed branding to compete directly with the tobacco industry. In 2014, the launch of truth FinishIt reflected changes in the brand's strategy, the tobacco control environment, and youth/young adult behavior. Building on a previous validation study, the current study examined brand equity in truth FinishIt, as measured by validated multi-dimensional scales, and tobacco related attitudes, beliefs, and behavior based on two waves of the Truth Longitudinal Cohort data from 2015 and 2016. A fixed effects logistic regression was used to estimate the change in brand equity between panel survey waves 3 and 4 on past 30 day smoking among ever and current smokers. Additional models determined the effects of brand equity predicting tobacco attitudes/use at follow up among the full sample. All analyses controlled for demographic factors. A one-point increase in the brand equity scale between the two waves was associated with a 66% greater chance of not smoking among ever smokers (OR 1.66, CI 1.11-2.48, p < 0.05) and an 80% greater chance of not smoking among current smokers (OR 1.80, CI 1.05-3.10, p < 0.05). Higher overall truth brand equity at wave 3 predicted less smoking at wave 4 and more positive anti-tobacco attitudes. Being male, younger, and non-white predicted some of the tobacco related attitudes. Future research should examine long-term effects of brand equity on tobacco use and how tobacco control can optimize the use of branding in campaigns. PMID- 29276668 TI - Evaluating the association between the built environment and primary care access for new Medicaid enrollees in an urban environment using Walk and Transit Scores. AB - Worse health outcomes among those living in poverty are due in part to lower rates of health insurance and barriers to care. As the Affordable Care Act reduced financial barriers, identifying persistent barriers to accessible health care continues to be important. We examined whether the built environment as reflected by Walk ScoreTM (a measure of walkability to neighborhood resources) and Transit ScoreTM (a measure of transit access) is associated with having a usual source of care among low-income adults, newly enrolled in Medicaid. We received responses from 312 out of 1000 new Medicaid enrollees in Philadelphia, a large, densely populated urban area, who were surveyed between 2015 and 2016 to determine if they had identified a usual source of outpatient primary care. Respondents living at an address with a low Walk Scores (< 70) had 84% lower odds of having a usual source of care (OR 0.16, 95% CI 0.04-0.61). Transit scores were not associated with having a usual source of care. Walk Score may be a tool for policy makers and providers of care to identify populations at risk for worse primary care access. PMID- 29276669 TI - Bioprocess microfluidics: applying microfluidic devices for bioprocessing. AB - Scale-down approaches have long been applied in bioprocessing to resolve scale-up problems. Miniaturized bioreactors have thrived as a tool to obtain process relevant data during early-stage process development. Microfluidic devices are an attractive alternative in bioprocessing development due to the high degree of control over process variables afforded by the laminar flow, and the possibility to reduce time and cost factors. Data quality obtained with these devices is high when integrated with sensing technology and is invaluable for scale-translation and to assess the economical viability of bioprocesses. Microfluidic devices as upstream process development tools have been developed in the area of small molecules, therapeutic proteins, and cellular therapies. More recently, they have also been applied to mimic downstream unit operations. PMID- 29276670 TI - Skills and educational needs of accident and emergency nurses in Ghana: an initial needs analysis. AB - Background: The specialty of emergency medicine is highly reliant on a well trained team of providers. Ghana has recently begun a specialist training program for physicians and the need to train specialist emergency nurses has been recognized. The first step to developing this training is to conduct a needs assessment. This study was conducted to elucidate current nursing functioning and gain knowledge of the educational desires and needs for nurses in the Accident and Emergency Center (A&E) at Komfo Anokye Teaching Hospital (KATH). Methods: Three nurses from the University of Michigan (UM) worked collaboratively with the nursing leadership at KATH to conduct a needs assessment of currently practising nurses in the A&E. The UM nurses observed nursing practice in the department and KATH nurses participated in a multiple choice exam, a self-assessment questionnaire of educational desires, answered written open-ended questions and participated in focus groups. Results: KATH nurses scored relatively low on a general knowledge multiple choice exam, and indicated through the self-assessment that they would like to learn more about many topics. Open-ended questions gave further insight into areas of knowledge gaps. Several themes including Cohesion, Carrying out Orders/Decision Making and Overwhelming Volume, emerged from observations in the emergency department. Discussion: Current nurse knowledge and function as well as areas to focus on for future specialty training in emergency nursing have been identified by this needs assessment. The emergency department nurses shared an overwhelming interest in increasing their skill level, learning new methods of patient care and implementing new technologies into their clinical practice. PMID- 29276671 TI - What drives diversification of national food supplies? A cross-country analysis. AB - Little previous research has explored what drives the diversification of national food supplies (DFS) across countries and regions. We construct and analyse a cross-country dataset linking a simple DFS indicator - the share of calories supplied by nonstaple foods - with structural transformation and agroecological indicators. Panel econometric models show that several indicators of structural transformation (economic growth, urbanization and demographic change) are strong predictors of diversification within countries, yet time-invariant agroecological factors are also significantly associated with diversification, which appears to explain why some countries have exceptionally low or high DFS relative to their level of economic development. We discuss the implications of these findings for food and nutrition strategies. PMID- 29276672 TI - Combined pleuroscopy and endobronchial ultrasound for diagnosis and staging of suspected lung cancer. AB - The standard approach to staging of lung cancer in patients with pleural effusion (clinical M1a) is thoracentesis followed by pleural biopsies if the cytologic analysis is negative. If pleural biopsy findings are negative, endobronchial ultrasound-guided transbronchial needle aspiration is used to complete the staging process and, in some cases, obtain diagnosis. In this case series we report 7 patients in which a combined procedure was performed for staging of known or suspected lung cancer. We found that the combined approach was both feasible and safe in this case series. PMID- 29276673 TI - Clear cell "sugar tumor" of the lung: Diagnostic features of a rare pulmonary tumor. AB - Clear cell tumor of the lung (CCTL) is an extremely rare neoplasm with about 50 cases reported in the literature so far. CCTL belongs to a family arising from putative perivascular epithelioid cells and is otherwise named as "sugar tumor" due to its high cellular glycogen concentration. Due to its rarity, diagnostic features of this entity are not widely known and this usually leads to misdiagnosis. Herein, we report a case of benign CCTL, which was primarily evaluated intraoperatively by FNA cytology and then by a pathological examination of the resected tumor. The cytologic preparations were moderately cellular and showed multiple large, irregular, cohesive clusters of ovoid or spindle tumor cells. Cells had clear cytoplasm, showing positivity with the periodic acid Schiff (PAS) staining method owing to the glycogen (sugar) content. The rapid cytologic report excluded the possibility of malignancy and a middle lobectomy along with an anterior upper segmentectomy was performed. Immunochemistry revealed a diffuse positivity for HMB45, MART-1, SMA and focally for desmin, while specimen was negative for pancytokeratin cocktail AE1/AE3, cytokeratin7, cytokeratin20 and EMA. These findings confirmed the diagnosis of a benign CCTL. Due to its rarity and similarity with other clear cell tumors of the lung, awareness of this entity, recognition of the cytomorphologic features and familiarity with the associated clinical features can help clinicians avoid certain pitfalls in the diagnostic process. Considering its benign course, unnecessary extensive lung resections may also be avoided thus permitting conservative management of these patients. PMID- 29276674 TI - Upfront triple combination therapy-induced pulmonary edema in a case of pulmonary arterial hypertension associated with Sjogren's syndrome. AB - Clinical efficacy of combination therapy using vasodilators for pulmonary arterial hypertension (PAH) is well established. However, information on its safety are limited. We experienced a case of primary Sjogren's syndrome associated with PAH where the patient developed pulmonary edema immediately after the introduction of upfront triple combination therapy. Although the combination therapy successfully stabilized her pre-shock state, multiple ground glass opacities (GGO) emerged. We aborted the dose escalation of epoprostenol and initiated continuous furosemide infusion and noninvasive positive pressure ventilation (NPPV), but this did not prevent an exacerbation of pulmonary edema. Chest computed tomography showing diffuse alveolar infiltrates without inter lobular septal thickening suggests the pulmonary edema was unlikely due to cardiogenic pulmonary edema and pulmonary venous occlusive disease. Acute respiratory distress syndrome was also denied from no remarkable inflammatory sign and negative results of drug-induced lymphocyte stimulation tests (DLST). We diagnosed the etiological mechanism as pulmonary vasodilator-induced trans capillary fluid leakage. Following steroid pulse therapy dramatically improved GGO. We realized that overmuch dose escalation of epoprostenol on the top of dual upfront combination poses the risk of pulmonary edema. Steroid pulse therapy might be effective in cases of vasodilator-induced pulmonary edema in Sjogren's syndrome associated with PAH. PMID- 29276675 TI - An onion farmer with a case of hypersensitivity pneumonitis caused by Aspergillus niger. AB - A 62-year old man was admitted to our hospital with a 2-week complaint of a dry cough, general fatigue, and dyspnea on effort. He has been an onion farmer for several years and developed these symptoms after cleaning up onion peels with air compressors. A chest roentgenogram and computed tomography showed a ground glass shadow in the bilateral upper lung field. Cellular analysis of the bronchoalveolar lavage fluid showed elevated total cell numbers and lymphocytes. Transbronchial lung biopsies revealed a non-caseating granuloma with both epithelioid cells and Langhans giant cells. After the admission, these symptoms and radiological findings gradually improved without any treatment. Then, a returning-home provocation test was positive only when he worked cleaning up onion peels with air compressors. A. niger was cultured from his workplace and black mold from the onion peels. The precipitation antibody and the antigen were both positive for Aspergillus. Therefore, we diagnosed this case as hypersensitivity pneumonitis caused by inhalation of A. niger. Although hypersensitivity pneumonia caused by A. niger is rare, physicians should aware the possibility of this condition in farmers because A niger is ubiquitously present in several vegetables and fruits. PMID- 29276676 TI - Hamman's syndrome (spontaneous pneumomediastinum presenting as subcutaneous emphysema): A rare case of the emergency department and review of the literature. AB - Pneumomediastinum is a rare clinical entity that concerns the clinicians in the emergency department. We present a case of a patient with spontaneous pneumomediastinum (Hamman's syndrome) that presented to our hospital's emergency department with cervical subcutaneous emphysema. A conservative treatment with observation was performed. The patient after 24 hours of observation was discharged with a suggested follow-up. PMID- 29276678 TI - Understanding bicycling in cities using system dynamics modelling. AB - Background: Increasing urban bicycling has established net benefits for human and environmental health. Questions remain about which policies are needed and in what order, to achieve an increase in cycling while avoiding negative consequences. Novel ways of considering cycling policy are needed, bringing together expertise across policy, community and research to develop a shared understanding of the dynamically complex cycling system. In this paper we use a collaborative learning process to develop a dynamic causal model of urban cycling to develop consensus about the nature and order of policies needed in different cycling contexts to optimise outcomes. Methods: We used participatory system dynamics modelling to develop causal loop diagrams (CLDs) of cycling in three contrasting contexts: Auckland, London and Nijmegen. We combined qualitative interviews and workshops to develop the CLDs. We used the three CLDs to compare and contrast influences on cycling at different points on a "cycling trajectory" and drew out policy insights. Results: The three CLDs consisted of feedback loops dynamically influencing cycling, with significant overlap between the three diagrams. Common reinforcing patterns emerged: growing numbers of people cycling lifts political will to improve the environment; cycling safety in numbers drives further growth; and more cycling can lead to normalisation across the population. By contrast, limits to growth varied as cycling increases. In Auckland and London, real and perceived danger was considered the main limit, with added barriers to normalisation in London. Cycling congestion and "market saturation" were important in the Netherlands. Conclusions: A generalisable, dynamic causal theory for urban cycling enables a more ordered set of policy recommendations for different cities on a cycling trajectory. Participation meant the collective knowledge of cycling stakeholders was represented and triangulated with research evidence. Extending this research to further cities, especially in low-middle income countries, would enhance generalizability of the CLDs. PMID- 29276677 TI - Cross-sectional variations of white and grey matter in older hypertensive patients with subjective memory complaints. AB - Mild cognitive impairment and Alzheimer's dementia involve a grey matter disease, quantifiable by 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), but also white matter damage, evidenced by diffusion tensor magnetic resonance imaging (DTI), which may play an additional pathogenic role. This study aimed to determine whether such DTI and PET variations are also interrelated in a high risk population of older hypertensive patients with only subjective memory complaints (SMC). Sixty older hypertensive patients (75 +/- 5 years) with SMC were referred to DTI and FDG-PET brain imaging, executive and memory tests, as well as peripheral and central blood pressure (BP) measurements. Mean apparent diffusion coefficient (ADCmean) was determined in overall white matter and correlated with the grey matter distribution of the metabolic rate of glucose (CMRGlc) using whole-brain voxel-based analyses of FDG-PET images. ADCmean was variable between individuals, ranging from 0.82 to 1.01.10- 3 mm2 sec- 1, and mainly in relation with CMRGlc of areas involved in Alzheimer's disease such as internal temporal areas, posterior associative junctions, posterior cingulum but also insulo-opercular areas (global correlation coefficient: - 0.577, p < 0.001). Both the ADCmean and CMRGlc of the interrelated grey matter areas were additionally and concordantly linked to the results of executive and memory tests and to systolic central BP (all p < 0.05). Altogether, our findings show that cross-sectional variations in overall white brain matter are linked to the metabolism of Alzheimer-like cortical areas and to cognitive performance in older hypertensive patients with only subjective memory complaints. Additional relationships with central BP strengthen the hypothesis of a contributing pathogenic role of hypertension. PMID- 29276679 TI - Dermatological window to a disseminated disease. PMID- 29276680 TI - Oropharyngeal histoplasmosis: The diagnosis lies in the biopsy. AB - Histoplasma capsulatum, a dimorphic fungus found world-wide, is endemic to regions of the Mississippi and Ohio River valleys and portions of Central and South America. Initial infection can present with acute pulmonary symptoms or remain clinically asymptomatic, with disease course generally guided by degree of inoculum and underlying immunosuppression. A chronic, progressive course of weight loss, oral ulceration, and fatigue has been associated with elderly males. We present a 79-year-old man with a chronic, progressive course of oral lesions, odynophagia, and weight loss who was found to have histoplasmosis on oral biopsy performed for suspicions of oropharyngeal squamous cell carcinoma. Histoplasma urine antigen, serum complement fixation antibody titers, and fungal tissues were all negative despite validated sensitivities in the >90% range. Our case report highlights the critical role of tissue biopsy in establishing a diagnosis of oropharyngeal histoplasmosis. PMID- 29276681 TI - Lung malignancy in prostate cancer: A report of both metastatic and primary lung lesions. PMID- 29276682 TI - Renal pelvic cancer with spleen invasion arising in horseshoe kidney; a case report. PMID- 29276683 TI - Renal rupture - Not what it seems. PMID- 29276684 TI - Leiomyosarcoma of prostate: Case report and literature review. PMID- 29276685 TI - Bilateral renal involvement by solitary fibrous tumor - Report of a case in the post-WHO/2016 era. PMID- 29276686 TI - Huge retroperitoneal epithelioid angiomyolipoma: A case report. PMID- 29276687 TI - Toxicology: The basic science for human well-being and environmental health. PMID- 29276688 TI - Hepatoprotective effect of food preservatives (butylated hydroxyanisole, butylated hydroxytoluene) on carbon tetrachloride-induced hepatotoxicity in rat. AB - Carbon tetrachloride (CCl4), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. This study was carried out to establish the hepatoprotective measures of food preservative antioxidants butylated hydroxyanisole and butylated hydroxytolune (BHA, BHT) when mixed with food towards carbon tetrachloride (CCl4) intoxication (230 mg/ kg b wt/rat/day) in rat. Biochemical markers like serum glutamate pyruvate tranaminase (AST), serum glutamate oxaloacetate transaminase (ALT), alkaline phosphatase (ALP) and bilirubin content, antioxidant enzymes such as SOD, CAT, GPx, and malondialdehyde (MDA) as the end product of lipid peroxidanion were measured. The results had shown the elevated level of AST (121.16%), ALT (124.68%), ALP (122.41%) an, bilirubin content (57.14%) after CCl4 treatment. Marked decrease of activity of antioxidant enzymes such as SOD (85.36%), CAT (67.47%), GPx (50.7%) had indicated that the ROS mediated toxicity and pretreatment of BHA and BHT restored the activity of these enzymes. High level of MDA content with reduced GSH value was also observed due to oxidative stress. The hepatic antioxidant status was restored with the food preservative (BHA, BHT) antioxidant treatment which had indicated the significant protective effect against CCl4 induced hepatotoxicity and finally confirmed by histopathological studies. PMID- 29276689 TI - Toxic effect of Moringa peregrina seeds on histological and biochemical analyses of adult male Albino rats. AB - Moringa is multipurpose promising tree particularly for medicinal use. With its high nutritive and pharmaceutical values, every part of the tree is suitable for human consumptions. The use of vegetate parts, seeds or extracts requires toxicological evaluations to prove and verify safety uses before being added to pharmaceutical medicine, or any other products related to human diet. In this study, Moringa peregrina seeds, grown in high elevation mountain in Saint Catherin area, were investigated and evaluated for their toxicity with respect to its topological potential through histological and biochemical studies in Albino rats. Daily doses of 0, 500, 1000 and 2000 mg/kg body weight of dry seed of M. peregrina were administered orally to 4 groups of rats for 14 days. Biochemical and histopathological results were evaluated by standard methods. Measured biochemical parameters, insulin, albumin, total protein, creatinine, urea, uric acid, Follicle-stimulating hormone, Luteinizing hormone and Testosterone, revealed normal levels compared to control group. However, measured level of blood sugars, cholesterol, triglyceride and liver enzyme, displayed significant decreases. No histopathological changes were detected in the body tested organs. In consequences, intake of different doses of M. peregrina, even high one, exhibit no organ toxicity and are safe for human use. PMID- 29276690 TI - Effects of intragastrically-administered Tepary bean lectins on digestive and immune organs: Preclinical evaluation. AB - Previous work showed that Tepary bean (Phaseolus acutifolius) lectins exhibit differential cytotoxic effects on cancer cell lines by apoptosis induction. In vivo studies using a Tepary bean lectin fraction (TBLF, 50 mg/kg of body weight) after colon cancer induction in rats showed that TBLF inhibited early precancerous lesions without systemic toxicity however, loss of body weight gain and activation of immune cells were observed. In order to know more about the possible adverse effects, we evaluated the administration of TBLF on digestive and immune organs. Sprague Dawley rats were administered TBLF for six weeks and allowed to recover for two weeks. Immune activation was observed through an increased lymphocyte-granulocyte ratio, an increased number of lymphoid follicles in intestinal Peyer's patches and a slight expansion of the splenic white pulp. Atrophy was observed in small intestine villi and crypt foci of the colon without normalization after the recovery period. Pancreas histopathology showed hypertrophy after the six-week administration period, particularly vacuolation and trabecular widening; but after the two-week recovery period atrophy was observed, suggesting a partial compensatory type process. Our results show that TBLF activates the immune system and affects digestive organs through direct interaction with intestinal epithelium, and indirectly by producing pancreatic hyperfunction. Further work will focus in longer recuperation periods after TBLF treatment. PMID- 29276691 TI - Lateral flow immunoassay and enzyme linked immunosorbent assay as effective immunomethods for the detection of synthetic cannabinoid JWH-200 based on the newly synthesized hapten. AB - In recent years, the use of synthetic cannabinoids (SCs) as drugs of abuse has greatly increased. SCs are associated with a risk of severe poisoning or even death. Therefore, more rapid, cost effective and reliable methods are needed, especially for the screening of drivers after traffic accidents and for detailed toxicological analysis in forensic laboratories. In this study, we developed a lateral flow immunoassay (LFIA) and an enzyme linked immunosorbent assay (ELISA) for the detection of JWH-200 in oral fluids. For this purpose a new hapten was prepared using a ten-step synthetic route. The developed immuno methods are based on antibodies obtained from rabbit immunized with synthesized hapten conjugated to carrier protein. The proposed methods are highly sensitive (LODLFIA = 0.08 +/- 0.04 ng mL-1; LODELISA = 0.04 +/- 0.02 ng mL-1). They were applied to the quantification of JHW-200 in spiked oral fluids. The recoveries ranged from 82 to 134% for both methods. The results correlated excellently with results obtained using UHPLC-MS/MS (R2LFIA = 0.99; R2ELISA = 0.99). Our developed methods could be an important tool for analyses of JWH-200 in human oral fluids. The one-step LFIA is particularly suitable for roadside and on-site monitoring due to the rapid qualitative results it delivers, while the ELISA is especially useful for laboratory quantitative analyses of positive samples captured by LFIA. PMID- 29276692 TI - Small sample sizes in high-throughput miRNA screens: A common pitfall for the identification of miRNA biomarkers. AB - Since the discovery of microRNAs (miRNAs), circulating miRNAs have been proposed as biomarkers for disease. Consequently, many groups have tried to identify circulating miRNA biomarkers for various types of diseases including cardiovascular disease and cancer. However, the replicability of these experiments has been disappointingly low. In order to identify circulating miRNA candidate biomarkers, in general, first an unbiased high-throughput screen is performed in which a large number of miRNAs is detected and quantified in the circulation. Because these are costly experiments, many of such studies have been performed using a low number of study subjects (small sample size). Due to lack of power in small sample size experiments, true effects are often missed and many of the detected effects are wrong. Therefore, it is important to have a good estimate of the appropriate sample size for a miRNA high-throughput screen. In this review, we discuss the effects of small sample sizes in high-throughput screens for circulating miRNAs. Using data from a miRNA high-throughput experiment on isolated monocytes, we illustrate that the implementation of power calculations in a high-throughput miRNA discovery experiment will avoid unnecessarily large and expensive experiments, while still having enough power to be able to detect clinically important differences. PMID- 29276693 TI - Conducting online focus groups on Facebook to inform health behavior change interventions: Two case studies and lessons learned. AB - Background: Online social media offer great potential for research participant recruitment and data collection. We conducted synchronous (real-time) online focus groups (OFGs) through Facebook with the target population of young adult substance users to inform development of Facebook health behavior change interventions. In this paper we report methods and lessons learned for future studies. Methods: In the context of two research studies participants were recruited through Facebook and assigned to one of five 90-minute private Facebook OFGs. Study 1 recruited for two OFGs with young adult sexual and/or gender minority (SGM) smokers (range: 9 to 18 participants per group); Study 2 recruited for three groups of young adult smokers who also engage in risky drinking (range: 5 to 11 participants per group). Results: Over a period of 11 (Study 1) and 22 days (Study 2), respectively, we recruited, assessed eligibility, collected baseline data, and assigned a diverse sample of participants from all over the US to Facebook groups. For Study 1, 27 of 35 (77%) participants invited attended the OFGs, and 25 of 32 (78%) for Study 2. Participants in Study 1 contributed an average of 30.9 (SD=8.9) comments with an average word count of 20.1 (SD=21.7) words, and 36.0 (SD=12.3) comments with 11.9 (SD=13.5) words on average in Study 2. Participants generally provided positive feedback on the study procedures. Conclusions: Facebook can be a feasible and efficient medium to conduct synchronous OFGs with young adults. This data collection strategy has the potential to inform health behavior change intervention development. PMID- 29276694 TI - An optimized immunohistochemistry protocol for detecting the guidance cue Netrin 1 in neural tissue. AB - Netrin-1, an axon guidance protein, is difficult to detect using immunohistochemistry. We performed a multi-step, blinded, and controlled protocol optimization procedure to establish an efficient and effective fluorescent immunohistochemistry protocol for characterizing Netrin-1 expression. Coronal mouse brain sections were used to test numerous antigen retrieval methods and combinations thereof in order to optimize the stain quality of a commercially available Netrin-1 antibody. Stain quality was evaluated by experienced neuroanatomists for two criteria: signal intensity and signal-to-noise ratio. After five rounds of testing protocol variants, we established a modified immunohistochemistry protocol that produced a Netrin-1 signal with good signal intensity and a high signal-to-noise ratio. The key protocol modifications are as follows: *Use phosphate buffer (PB) as the blocking solution solvent.*Use 1% sodium dodecyl sulfate (SDS) treatment for antigen retrieval. The original protocol was optimized for use with the Netrin-1 antibody produced by Novus Biologicals. However, we subsequently further modified the protocol to work with the antibody produced by Abcam. The Abcam protocol uses PBS as the blocking solution solvent and adds a citrate buffer antigen retrieval step. PMID- 29276695 TI - Transient expression of CCL21as recombinant protein in tomato. AB - The main goal of this study was to investigate the possibility of expressing recombinant protein of C-C chemokine ligand 21 (CCL21) in Solanum lycopersicum via agroinfiltration. CCL21 is a chemokine can be used for anti-metastatic of cancer cell lines. To examine the expression of CCL21 protein in S. lycopersicum, the construct of ccl21 was synthesized. This construct was cloned into pBI121 and the resulting CCL21 plasmid was agro-infiltrated into S. lycopersicum leaves. Within three days after infiltration, Expression of the foreign gene was confirmed by quantitative Real-time PCR. A recombinant CCL21 protein was immunogenically detected by western blot, dot blot and ELISA assay. And results showed that the foreign gene was expressed in the transformed leaves in high level. Also scratch assay was used to investigate the role of this protein in anti-metastatic function. The results demonstrated anti-metastatic of cancer cells in the presence of this protein. PMID- 29276697 TI - Cancer cell lines involving cancer stem cell populations respond to oxidative stress. AB - Cancer cells may be more prone to the accumulation of reactive oxygen species (ROS) than normal cells; therefore increased oxidative stress can specifically kill cancer cells including cancer stem cells (CSCs). In order to generate oxidative stress in various cancer cell lines including A549, G361 and MCF-7, cultured cells were exposed to H2O2. Incubation of cancer cells with H2O2 results in concentration-dependent cell death in A549 and G361-7 cells, whereas MCF-7 cells showed higher sensitivity even at a lower H2O2 concentration. H2O2 treatment decreased the number of cells in G2/M phase and increased the number of apoptotic cells. Both CD24 negative/CD44 positive cells and CD146 positive cells were found to be present in all tested cancer cell lines, indicating that CSC populations may play role in the cellular response to oxidative stress. This study showed that inducing oxidative stress through ROS can offer a promising approach for anti-cancer therapy. PMID- 29276696 TI - Characterization of Scenedesmus obtusiusculus AT-UAM for high-energy molecules accumulation: deeper insight into biotechnological potential of strains of the same species. AB - Scenedesmus obtusiusculus AT-UAM, isolated from Cuatro Cienegas wetlands in Mexico was taxonomically, molecularly and biochemically compared to S. obtusiusculus CCAP 276/25 (Culture Collection of Algae and Protozoa, Scotland, UK). Analysis of Internal Transcribed Spacer 2 (ITS2) secondary structures confirmed that the mexican strain belongs to S. obtusiusculus with one change in the ITS2 nucleotide sequence. However, both strains exhibited different biochemical and fatty acid profiles and therefore biotechnological potential, emphasizing the need for deeper studies among strains of the same species. Furthermore, the biochemical variations of S. obtusiusculus AT-UAM under nitrogen starvation and different levels of irradiance were evaluated. The maximum lipid production (1730 mg L-1) was obtained at 613 MUmol m-2 s-1 while the highest carbohydrate content (49%) was achieved at 896 MUmol m-2 s-1. Additionally, this strain was capable of storing lipids (~52%) and carbohydrates (~40%) under outdoor condition depending on the light availability in the cultivation broth. PMID- 29276698 TI - Editorial: Charged Particles in Oncology. PMID- 29276702 TI - Interactive Prostate Shape Reconstruction from 3D TRUS Images. AB - This paper presents a two-step, semi-automated method for reconstructing a three dimensional (3D) shape of the prostate from a 3D transrectal ultrasound (TRUS) image. While the method has been developed for prostate ultrasound imaging, it can potentially be applicable to any other organ of the body and other imaging modalities. The proposed method takes as input a 3D TRUS image and generates a watertight 3D surface model of the prostate. In the first step, the system lets the user visualize and navigate through the input volumetric image by displaying cross sectional views oriented in arbitrary directions. The user then draws partial/full contours on selected cross sectional views. In the second step, the method automatically generates a watertight 3D surface of the prostate by fitting a deformable spherical template to the set of user-specified contours. Since the method allows the user to select the best cross-sectional directions and draw only clearly recognizable partial or full contours, the user can avoid time consuming and inaccurate guesswork on where prostate contours are located. By avoiding the usage of noisy, incomprehensible portions of the TRUS image, the proposed method yields more accurate prostate shapes than conventional methods that demand complete cross-sectional contours selected manually, or automatically using an image processing tool. Our experiments confirmed that a 3D watertight surface of the prostate can be generated within five minutes even from a volumetric image with a high level of speckles and shadow noises. PMID- 29276699 TI - Zika Virus: An Emerging Global Health Threat. AB - Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito Aedes species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barre syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease. PMID- 29276700 TI - An Updated View on the Rck Invasin of Salmonella: Still Much to Discover. AB - Salmonella is a facultative intracellular Gram-negative bacterium, responsible for a wide range of food- and water-borne diseases ranging from gastroenteritis to typhoid fever depending on hosts and serotypes. Salmonella thus represents a major threat to public health. A key step in Salmonella pathogenesis is the invasion of phagocytic and non-phagocytic host cells. To trigger its own internalization into non-phagocytic cells, Salmonella has developed different mechanisms, involving several invasion factors. For decades, it was accepted that Salmonella could only enter cells through a type three secretion system, called T3SS-1. Recent research has shown that this bacterium expresses outer membrane proteins, such as the Rck protein, which is able to induce Salmonella entry mechanism. Rck mimics natural host cell ligands and triggers engulfment of the bacterium by interacting with the epidermal growth factor receptor. Salmonella is thus able to use multiple entry pathways during the Salmonella infection process. However, it is unclear how and when Salmonella exploits the T3SS-1 and Rck entry mechanisms. As a series of reviews have focused on the T3SS-1, this review aims to describe the current knowledge and the limitations of our understanding of the Rck outer membrane protein. The regulatory cascade which controls Rck expression and the molecular mechanisms underlying Rck-mediated invasion into cells are summarized. The potential role of Rck-mediated invasion in Salmonella pathogenesis and the intracellular behavior of the bacteria following a Salmonella Rck-dependent entry are discussed. PMID- 29276703 TI - A Framework for Integrating Qualitative and Quantitative Data in Knowledge, Attitude, and Practice Studies: A Case Study of Pesticide Usage in Eastern Uganda. AB - Knowledge, attitude, and practice (KAP) studies guide the implementation of public health interventions (PHIs), and they are important tools for political persuasion. The design and implementation of PHIs assumes a linear KAP relationship, i.e., an awareness campaign results in the desirable societal behavioral change. However, there is no robust framework for testing this relationship before and after PHIs. Here, we use qualitative and quantitative data on pesticide usage to test this linear relationship, identify associated context specific factors as well as assemble a framework that could be used to guide and evaluate PHIs. We used data from a cross-sectional mixed methods study on pesticide usage. Quantitative data were collected using a structured questionnaire from 167 households representing 1,002 individuals. Qualitative data were collected from key informants and focus group discussions. Quantitative and qualitative data analysis was done in R 3.2.0 as well as qualitative thematic analysis, respectively. Our framework shows that a KAP linear relationship only existed for households with a low knowledge score, suggesting that an awareness campaign would only be effective for ~37% of the households. Context specific socioeconomic factors explain why this relationship does not hold for households with high knowledge scores. These findings are essential for developing targeted cost-effective and sustainable interventions on pesticide usage and other PHIs with context specific modifications. PMID- 29276701 TI - Characterization of Ixodes ricinus Fibrinogen-Related Proteins (Ixoderins) Discloses Their Function in the Tick Innate Immunity. AB - Ticks are important vectors of serious human and animal disease-causing organisms, but their innate immunity can fight invading pathogens and may have the ability to reduce or block transmission to mammalian hosts. Lectins, sugar binding proteins, can distinguish between self and non-self-oligosaccharide motifs on pathogen surfaces. Although tick hemolymph possesses strong lectin activity, and several lectins have already been isolated and characterized, little is known about the implementation of these molecules in tick immunity. Here, we have described and functionally characterized fibrinogen-related protein (FReP) lectins in Ixodes ticks. We have shown that the FReP family contains at least 27 genes (ixoderins, ixo) that could, based on phylogenetic and expression analyses, be divided into three groups with differing degrees of expansion. By using RNA interference-mediated gene silencing (RNAi) we demonstrated that IXO-A was the main lectin in tick hemolymph. Further, we found that ixoderins were important for phagocytosis of Gram-negative bacteria and yeasts by tick hemocytes and that their expression was upregulated upon injection of microbes, wounding, or after blood feeding. However, although the tick hemocytes could swiftly phagocytose Borrelia afzelii spirochetes, their transmission and burst of infection in mice was not altered. Our results demonstrate that tick ixoderins are crucial immune proteins that work as opsonins in the tick hemolymph, targeting microbes for phagocytosis or lysis. PMID- 29276704 TI - Path Dependence and Universal Health Coverage: The Case of Egypt. AB - Universal health coverage (UHC) is the big objective in health policy which several countries are seeking to achieve. Egypt is no different and its endeavors to attain UHC have been going on since the 1960s. This article discusses the status of UHC in Egypt using theories of political science and economics by analyzing the historical transformations in the Egyptian health system and its institutional settings. This article then specifically examines the path dependence theory against the sociopolitical background of Egypt and assesses any pattern between the theory and the current UHC status in Egypt. The important finding of this analysis is that the health policies and reforms in Egypt have been significantly influenced and limited by its historical institutional structure and development. Both the health policies and the institutional settings adopted a dependent path that limited Egypt's endeavors to achieve the universal coverage. This dependent path also yielded many of the present-day challenges as in the weaknesses of the healthcare financing system and the inability to extend health coverage to the poor and the informal sector. These challenges subsequently had a negative impact on the accessibility of the healthcare services. PMID- 29276705 TI - Are Exposures to Multiple Frequencies the Key to Future Radiofrequency Research? AB - There is an extensive literature investigating possible effects of exposure to radiofrequency (RF) electromagnetic fields associated with mobile phone technologies. This has not identified any public health risks with any degree of certainty. Some epidemiological studies have observed associations between heavy users of mobile phones and some types of cancer, but animal studies do not support this association, although a few studies have reported increased tumor yields. However, there is a crucial difference between epidemiology studies and laboratory work in terms of signals investigated: most people are exposed to a complex mixture of frequencies and signals at varying intensities, whereas the majority of animal studies have been performed using a single frequency or intensity. Whether this might explain the differences in outcome will be discussed, and whether there is a need for additional laboratory investigations that reproduce more accurately realistic exposure conditions will be considered. PMID- 29276706 TI - A Cyclical Approach to Continuum Modeling: A Conceptual Model of Diabetic Foot Care. AB - "Cascade" or "continuum" models have been developed for a number of diseases and conditions. These models define the desired, successive steps in care for that disease or condition and depict the proportion of the population that has completed each step. These models may be used to compare care across subgroups or populations and to identify and evaluate interventions intended to improve outcomes on the population level. Previous cascade or continuum models have been limited by several factors. These models are best suited to processes with stepwise outcomes-such as screening, diagnosis, and treatment-with a single defined outcome (e.g., treatment or cure) for each member of the population. However, continuum modeling is not well developed for complex processes with non sequential or recurring steps or those without singular outcomes. As shown here using the example of diabetic foot care, the concept of continuum modeling may be re-envisioned with a cyclical approach. Cyclical continuum modeling may permit incorporation of non-sequential and recurring steps into a single continuum, while recognizing the presence of multiple desirable outcomes within the population. Cyclical models may simultaneously represent the distribution of clinical severity and clinical resource use across a population, thereby extending the benefits of traditional continuum models to complex processes for which population-based monitoring is desired. The models may also support communication with other stakeholders in the process of care, including health care providers and patients. PMID- 29276707 TI - Reliability and Minimal Detectable Change Values for Predictions of Knee Forces during Gait and Stair Ascent Derived from the FreeBody Musculoskeletal Model of the Lower Limb. AB - FreeBody is a musculoskeletal model of the lower limb used to calculate predictions of muscle and joint contact forces. The validation of FreeBody has been described in a number of publications; however, its reliability has yet to be established. The purpose of this study was, therefore, to establish the test retest reliability of FreeBody in a population of healthy adults in order to add support to previous and future research using FreeBody that demonstrates differences between cohorts after an intervention. We hypothesized that test retest estimations of knee contact forces from FreeBody would demonstrate a high intra-class correlation. Kinematic and kinetic data from nine older participants (4 men: mean age = 63 +/- 11 years; 5 women: mean age = 49 +/- 4 years) performing level walking and stair ascent was collected on consecutive days and then analyzed using FreeBody. There was a good level of intra-session agreement between the waveforms for the individual trials of each activity during testing session 1 (R = 0.79-0.97). Similarly, overall there was a good inter-session agreement within subjects (R = 0.69-0.97) although some subjects showed better agreement than others. There was a high level of agreement between the group mean waveforms of the two sessions for all variables (R = 0.882-0.997). The intra class correlation coefficients (ICC) were very high for peak tibiofemoral joint contact forces (TFJ) and hamstring forces during gait, for peak patellofemoral joint contact forces and quadriceps forces during stair ascent and for peak lateral TFJ and the proportion of TFJ accounted for by the medial compartment during both tasks (ICC = 0.86-0.96). Minimal detectable change (MDC) of the peak knee forces during gait ranged between 0.43 and 1.53 * body weight (18-170% of the mean peak values). The smallest MDCs were found for medial TFJ share (4.1 and 5.8% for walking and stair ascent, respectively, or 4.8 and 6.7% of the mean peak values). In conclusion, the results of this study support the use of FreeBody to investigate the effect of interventions on muscle and joint contact forces at the cohort level, but care should be taken if using FreeBody at the subject level. PMID- 29276708 TI - Association between Sleep Patterns and Health in Families with Exceptional Longevity. AB - Background: Sleep patterns such as longer sleep duration or napping are associated with poor health outcomes. Although centenarians and their offspring demonstrate a delayed onset of age-related diseases, it is not known whether they have healthier sleep patterns or are protected against the negative effects of sleep disturbances. Methods: Data on sleep patterns and health history were collected from Ashkenazi Jewish subjects of the Longevity Genes Project using standardized questionnaires. Participants included individuals with exceptional longevity (centenarians) with preserved cognition (n = 348, median age 97 years), their offspring (n = 513, median age 69 years), and controls (n = 199) age matched to the offspring. Centenarians reported on their sleep patterns at age 70, while the offspring and controls on their current sleep patterns. Biochemical parameters were measured at baseline. Models were adjusted for age, sex, BMI, and use of sleep medication. Results: The offspring and controls reported similar sleep patterns, with 33% sleeping >=8 h and 17% napping in each group. At age 70, centenarians were more likely to have slept >=8 h (55%) and to have napped (28%) compared with offspring and controls, p < 0.01. Among centenarians, no association was noted between sleep patterns and health outcomes. Sleeping for >=8 h was associated with lower high-density lipoprotein cholesterol levels in the offspring and controls, and with insulin resistance in the offspring, but not with diabetes. Napping was associated with insulin resistance among the controls (p < 0.01), but not the offspring. Controls, but not offspring, who napped were 2.79 times more likely to have one or more of the following diseases: hypertension, myocardial infarction, stroke, or diabetes (OR 2.79, 95% CI 1.08 7.21, p = 0.04). Conclusion: Despite being more likely to exhibit risky sleep patterns at age 70 compared with the offspring and controls, the centenarians were protected from age-related morbidities. The offspring of centenarians did exhibit metabolic disturbances in association with less healthy sleep patterns; however, unlike the controls, they were much less likely to manifest age-related diseases. This suggests that offspring may have inherited resilience genotypes from their centenarian parents that protect them against the harmful effects of sleep disturbances. PMID- 29276710 TI - Use of Tachycardia in Patients With Submassive Pulmonary Emboli to Risk Stratify for Early Initiation of Thrombolytic Therapy: A Case Series Comparing Early Versus Late Thrombolytic Initiation. AB - Pulmonary embolism (PE) represents a prevalent cause of morbidity and mortality in the United States, with approximately 600 000 cases diagnosed annually. The mortality rate for untreated PE is as high as 30%. Right ventricular (RV) dysfunction is a sign of possible adverse outcomes with right-sided heart failure being the usual cause of death from PE. There is a spectrum of clinical presentations associated with PE diagnoses, from incidental and asymptomatic to rapid hemodynamic collapse. Despite successes in identifying patients with "high risk" PEs for aggressive thrombolytic interventions and "low-risk" PEs for outpatient anticoagulation, a significant lack of consensus exists regarding intervention modalities for PEs identified as "intermediate risk" or "submassive," defined as normotensive (systolic blood pressure >=90 mm Hg) with acute RV dysfunction and myocardial injury. In this case series, we review the management and outcomes of 2 patients with submassive PEs and sustained tachycardia in the setting of normal blood pressures, and we address the need to recognize tachycardia as an ominous RV compensatory sign, indicative of impending hemodynamic collapse, that should lead to aggressive therapy with vascular intervention. PMID- 29276712 TI - A Challenging Case of Pseudohyperkalemia in Chronic Lymphocytic Leukemia. AB - Pseudohyperkalemia is an uncommon finding in chronic lymphocytic leukemia. It is a misleading condition that could lead to iatrogenic hypokalemia when unwarranted treatment is administered. We describe an interesting case of pseudohyperkalemia in severe leukocytosis and how we identified it. PMID- 29276711 TI - Acute Kidney Injury, Immune Thrombocytopenic Purpura, and the Infection That Binds Them Together: Disseminated Histoplasmosis. AB - Untreated human immunodeficiency virus (HIV) can be complicated by opportunistic infections, including disseminated histoplasmosis (DH). Although endemic to portions of the United States and usually benign, DH can rarely act as an opportunistic infection in immunocompromised patients presenting with uncommon complications such as acute kidney injury and idiopathic thrombocytopenic purpura. We report a rare presentation of DH presenting with acute kidney injury and immune thrombocytopenic purpura in an immunocompromised patient with HIV. PMID- 29276709 TI - Tumor Heterogeneity in Breast Cancer. AB - Breast cancer is a heterogeneous disease and differs greatly among different patients (intertumor heterogeneity) and even within each individual tumor (intratumor heterogeneity). Clinical and morphologic intertumor heterogeneity is reflected by staging systems and histopathologic classification of breast cancer. Heterogeneity in the expression of established prognostic and predictive biomarkers, hormone receptors, and human epidermal growth factor receptor 2 oncoprotein is the basis for targeted treatment. Molecular classifications are indicators of genetic tumor heterogeneity, which is probed with multigene assays and can lead to improved stratification into low- and high-risk groups for personalized therapy. Intratumor heterogeneity occurs at the morphologic, genomic, transcriptomic, and proteomic levels, creating diagnostic and therapeutic challenges. Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Despite the improved knowledge of the complex genetic and phenotypic features underpinning tumor heterogeneity, there has been only limited advancement in diagnostic, prognostic, or predictive strategies for breast cancer. The current guidelines for reporting of biomarkers aim to maximize patient eligibility for targeted therapy, but do not take into account intratumor heterogeneity. The molecular classification of breast cancer is not implemented in routine clinical practice. Additional studies and in-depth analysis are required to understand the clinical significance of rapidly accumulating data. This review highlights inter- and intratumor heterogeneity of breast carcinoma with special emphasis on pathologic findings, and provides insights into the clinical significance of molecular and cellular mechanisms of heterogeneity. PMID- 29276713 TI - Participation in Recreational Athletics After Operative Fixation of Tibial Plateau Fractures: Predictors and Functional Outcomes of Those Getting Back in the Game. AB - Background: Tibial plateau fractures can be devastating traumatic injuries to the knee, particularly in active athletes. Purpose/Hypothesis: The purpose of this study was to report on the return to participation in recreational athletics after operatively managed tibial plateau fractures. In addition, this study assessed factors associated with the ability to return to participation in recreational athletics after tibial plateau fractures treated with open reduction internal fixation and compared final outcomes between patients who were able to return to recreational athletics and those who could not. The hypothesis was that returning to participation in recreational athletics would be dependent on the time from surgery after operative fixation of tibial plateau fractures. Less severe injuries would be associated with a quicker return to athletics. Study Design: Case-control study; Level of evidence, 3. Methods: All tibial plateau fractures treated by 1 of 3 surgeons at a single academic institution over an 11 year period were prospectively followed. Final outcomes were evaluated using the Short Musculoskeletal Function Assessment at latest follow-up. All complications were recorded at each follow-up. Differences between the groups were compared using Student t tests for continuous variables. Chi-square analysis was used to determine whether differences between categorical variables existed. Logistic regression was performed to assess independent variables associated with returning to participation in recreational athletics. Results: A total of 169 patients who underwent operative management of their tibial plateau fracture reported participation in recreational athletics before their injury. By the 6 month time point, 48 patients (31.6%) had returned to participation in recreational athletics, and at final follow-up (mean, 15 months), 89 patients (52.4%) had returned to participation in recreational athletics. Predictors of returning to recreational athletics included white race, female sex, social alcohol consumption, younger age, increased range of motion (ROM), low-energy Schatzker patterns (I-III), injuries not inclusive of orthopaedic polytrauma or open fractures, and no postoperative complications. White race, social alcohol consumption, and increased ROM were associated with returning to athletics at both 6-month and final follow-up. Lack of a venous thromboembolism was associated with returning to athletics at final follow-up. Patients who returned to recreational athletics had associations with better functional outcomes and emotional status than those who did not. Conclusion: The number of patients who returned to participation in recreational athletics gradually increased over time after operative fixation of tibial plateau fractures. Less severe injuries and a lack of postoperative complications were associated with a quicker return to athletics. Predictors of returning to participation in recreational athletics after operatively managed tibial plateau fractures can be used to target patients at risk of not returning to play to provide interventions aimed at improving their recovery, such as early knee range of motion, muscle strengthening, and participation in low-impact activities. PMID- 29276714 TI - Radiological Changes in the Cervical Spine in Freshman Collegiate Sumo Wrestlers. AB - Background: Sumo has long been a traditional sport in Japan and is rapidly attracting enthusiasts abroad. Sumo wrestling entails a risk of impact to the cervical spine during an initial charge. Few reports are available in the English language literature regarding radiological changes in the cervical spine in sumo wrestlers. Purpose: To examine radiological changes in the cervical spine in freshmen collegiate sumo wrestlers. Study Design: Case series; Level of evidence, 4. Methods: A total of 53 freshmen sumo wrestlers (age, 18-19 years) who belonged to the Japan Sumo Federation underwent routine radiographic examination of the cervical spine and completed questionnaires on cervical symptoms. Results: Of the 53 wrestlers, 81% showed loss of lordosis, 45% showed osteophyte formation (mainly at C3-C4), 11% showed disc space narrowing (mainly at C5-C6), and 51% showed narrowing of the cervical nerve root foramina (mainly at C3-C4). Fifty-one percent had some cervical symptoms. A correlation was found between deformity of the cervical bodies (such as intervertebral disc ballooning) and cervical symptoms, but no correlation was found between cervical degenerative changes and cervical symptoms. Conclusion: Our data suggest that loss of lordosis, osteophyte formation, and narrowing of the cervical nerve root foramina at C3-C4 were frequently present in freshmen wrestlers and may be due to the axial load incurred prior to their collegiate careers. PMID- 29276715 TI - Arthroscopic Fragment Resection for Capitellar Osteochondritis Dissecans in Adolescent Athletes: 5- to 12-Year Follow-up. AB - Background: Capitellar osteochondritis dissecans (OCD) in skeletally immature athletes has often been seen in baseball players and gymnasts. The choice of surgical procedure for unstable lesions in skeletally immature athletes remains controversial. Purpose: To investigate functional outcomes and radiographic changes in the midterm to long-term postoperative period after arthroscopic (AS) resection for small to large capitellar OCD lesions in skeletally immature athletes. Study Design: Case series; Level of evidence, 4. Methods: A total of 38 elbows in 38 patients (33 boys, 5 girls; mean age, 14 years [range, 13-15 years]) with skeletally immature elbows underwent AS resection for capitellar OCD. Patients were observed for at least 5 years (mean, 8 years [range, 5-12 years]). Elbows with a lesion width that did not exceed one-half of the radial head diameter were assigned to group 1 (n = 17 elbows), and larger lesions were assigned to group 2 (n = 21 elbows). Functional scores, patient satisfaction, range of motion (ROM), and osteoarthritis (OA) grades were evaluated between the groups. Results: All patients returned to sports activity. Functional scores at the final follow-up were not significantly different between the groups. Patient satisfaction scores were significantly higher in group 1 than in group 2. There was significant improvement in flexion ROM at the final follow-up compared with preoperative values in group 1 (P = .017), and there was a significant between group difference (group 1: 141 degrees ; group 2: 133 degrees ; P = .002). Extension ROM showed significant improvement in both groups (group 1: from -8 degrees to 3 degrees ; group 2: from -17 degrees to -1 degrees ; P < .001 for both). Group 1 tended to have better extension than group 2, but the difference was not significant. There were no elbows with severe OA in either group, but the OA grade progressed in 5 elbows (29%) in group 1 and 9 elbows (43%) in group 2, and this rate of OA progression was statistically significant between groups (P = .005). Conclusion: Both functional outcomes and radiological findings after AS fragment resection were excellent in elbows with small lesions. Although overall outcomes were acceptable in elbows with larger lesions, flexion ROM and patient satisfaction scores were significantly inferior to those in elbows with smaller lesions. PMID- 29276716 TI - Lived Experiences of Adolescent Athletes Following Sport-Related Concussion. AB - Background: Previous studies have identified the effect of sport-related concussion on health-related quality of life through the use of patient-reported outcome measures. However, there has been little research exploring the underlying mechanisms that influence these perceptions of health-related quality of life among adolescent athletes who have sustained a sport-related concussion. Purpose: To explore the psychosocial aspects of concussion among adolescent athletes. Study Design: Case series; Level of evidence, 4. Methods: A total of 12 interscholastic athletes (4 girls, 8 boys; mean +/- SD age, 15.7 +/- 1.7 years; grade level, 10.2 +/- 1.4) were interviewed via a semistructured interview protocol between 15 and 30 days postinjury. Data analysis was guided by the consensual qualitative research tradition. Themes and categories emerged through consensus by a 3-person research team, and bias was minimized through the use of multiple-analyst triangulation. Results: Participants identified numerous postconcussion symptoms that resulted in increasing difficulty with emotions (eg, irritable, easily frustrated), roles at school (eg, concentration difficulties, fatigue), and roles in their social environment (eg, letting the team down, not being able to contribute to sport). As a result, participants expressed how they tried to minimize or mask symptoms to decrease the potential of being viewed differently by their peers. Conclusion: Adolescent athletes perceived a significant effect of sport-related concussion on numerous areas of psychosocial and emotional health and well-being. Anticipatory guidance-with education regarding the possible signs and symptoms, risk factors, and recovery expectations following a concussion-is important to include in postinjury management. A better understanding of sport-related concussion and expected recovery could help to improve perceptions of this injury among interscholastic athletes. Additionally, best practices should be identified to assist health care professionals and school personnel in the development of temporary adjustments or formal academic adjustment policies in the secondary school setting, therefore ensuring that the patients receive the support that they need to maintain their roles as students. PMID- 29276717 TI - Longitudinal Associations of Sexual Fluidity and Health in Transgender Men and Cisgender Women and Men. AB - Research has just begun to study associations between sexual fluidity and health among cisgender individuals; only one cross-sectional study examined these links among transgender individuals. The goals of the current study were to prospectively examine fluidity in sexual attractions and fluidity in sexual orientation identity, and associations with health-related outcomes. Participants were a community-based sample of 45 transgender men, ages 16-51 years, who had recently begun testosterone, and 95 cisgender individuals (53 women, 42 men), ages 18-55 years, who completed surveys either in-person or via mail. Analyses tested for group differences in sexual fluidity, sociodemographic predictors of sexual fluidity among transgender men, and associations between sexual fluidity and health across the three groups. As hypothesized, transgender men reported more fluidity in sexual attractions and sexual orientation identity than did cisgender individuals. Contrary to our hypotheses, testosterone use was not significantly associated with sexual fluidity, although less education was. As hypothesized, fluidity in sexual orientation identity was associated with more adverse mental health outcomes among transgender men (depression and anxiety) and cisgender women (anxiety and stress), as well as decreased vitality among transgender men and cisgender women, and decreased social functioning among cisgender women. In contrast, fluidity in sexual attractions was only associated with less depression among cisgender women, but was not significantly associated with any other health-related outcomes. This study increases knowledge about sexual fluidity among transgender men and implications for health and can inform clinical work with this population. PMID- 29276718 TI - A Nonhuman Primate Transplantation Model to Evaluate Hematopoietic Stem Cell Gene Editing Strategies for beta-Hemoglobinopathies. AB - Reactivation of fetal hemoglobin (HbF) is a promising approach for the treatment of beta-hemoglobinopathies and the targeting of genes involved in HbF regulation is under intensive investigation. Here, we established a nonhuman primate (NHP) transplantation model to evaluate hematopoietic stem cell (HSC)-based gene editing strategies aimed at reactivating HbF. We first characterized the transient HbF induction to autologous HSC transplantation in pigtailed macaques, which was comparable in duration and amplitude to that of human patients. After validating function of the HbF repressor BCL11A in NHPs, we transplanted a pigtailed macaque with CD34+ cells electroporated with TALE nuclease mRNA targeting the BCL11A coding sequence. In vivo gene editing levels were low, but some BCL11A deletions were detected as late as 200 days post-transplantation. HbF production, as determined by F-cell staining and gamma-globin expression, was slightly increased in this animal as compared to transplant controls. We also provided proof-of-concept results for the selection of edited NHP CD34+ cells in culture following integration of the P140K/MGMT cassette at the BCL11A locus. In summary, the NHP model described here will allow the testing of novel therapeutic approaches for hemoglobinopathies and should facilitate clinical translation. PMID- 29276719 TI - Health literacy, health-related quality of life, and atrial fbrillation. AB - Atrial fbrillation (AF) is a chronic heart rhythm disorder associated with significant adverse outcomes. Health-related quality of life (HRQoL) is an established metric of health status in individuals with AF, and health literacy is highly relevant to how individuals experience HRQoL. We conducted a pilot investigation to examine the association of health literacy and health related quality of life (HRQoL) in a limited-sized cohort of individuals with AF, all of whom had AF and were >=60 years old. We used the Short-Test of Functional Health Literacy in Adults to categorize participants by health literacy status. We used the SF-36 to examine HRQoL in eight subscales and two composite scores, and related health literacy to HRQoL. In our cohort of 40 participants with AF (45% female, age 77.9 +/- 8.0 years), 62.5% had inadequate health literacy. However, we did not identify a significant association between health literacy and HRQoL. We expect our limited-sized sample is a chief limitation for why we did not see an association between health literacy and HRQoL in this convenience cohort. Further studies examining health literacy and its impact on patient-centered outcomes in AF are essential. PMID- 29276720 TI - Study of Epithelium Barrier Functions by Real-time TER Measurement. AB - Transepithelial Electrical Resistance (TER) measurement is a reliable and efficient method to quantify the permeability of barrier forming cells such as epithelial cells. Measuring the permeability of the epithelial cells will help the researchers to investigate the barrier function of epithelium in various infectious and inflammatory diseases. Here we provide a real-time and impedance based approach for measuring the permeability of epithelial cell monolayer using the Electrical Cell Substrate Impedance Sensing (ECIS(r)) instrumentation. PMID- 29276721 TI - Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays. AB - Oxidative stress has been proposed to be one of the main causes of aging and has been implicated in the pathogenesis of many diseases. Sensitivity to oxidative stress can be measured by quantifying survival following exposure to a reactive oxygen species (ROS)-generating compound such as paraquat or juglone. Sensitivity to oxidative stress is a balance between basal levels of ROS, the ability to detoxify ROS, and the ability to repair ROS-mediated damage. PMID- 29276723 TI - Cell-free Generation of COPII-coated Procollagen I Carriers. AB - The aim of this protocol is to generate COPII-coated procollagen I (PC1) carriers in a cell-free reaction. The COPII-coated PC1 carriers were reconstituted from donor membrane, cytosol, purified recombinant COPII proteins, and nucleotides. This protocol describes the preparation of donor membrane and cytosol, the assembly of the reaction, and the isolation and detection of reconstituted COPII coated carriers. This cell-free reaction can be used to test conditions that stimulate or suppress the packaging of PC1 into COPII-coated carriers. PMID- 29276722 TI - Validating Candidate Congenital Heart Disease Genes in Drosophila. AB - Genomic sequencing efforts can implicate large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system to validate candidate gene association with pathology is therefore useful. We present such a system employing Drosophila to validate candidate congenital heart disease (CHD) genes. The protocols exploit comprehensive libraries of UAS GeneX-RNAi fly strains that when crossed into a 4*Hand-Gal4 genetic background afford highly efficient cardiac-specific knockdown of endogenous fly orthologs of human genes. A panel of quantitative assays evaluates phenotypic severity across multiple cardiac parameters. These include developmental lethality, larva and adult heart morphology, and adult longevity. These protocols were recently used to evaluate more than 100 candidate CHD genes implicated by patient whole-exome sequencing (Zhu et al., 2017). PMID- 29276724 TI - Infection of Caenorhabditis elegans with Vesicular Stomatitis Virus via Microinjection. AB - Over the past 15 years, the free-living nematode, Caenorhabditis elegans has become an important model system for exploring eukaryotic innate immunity to bacterial and fungal pathogens. More recently, infection models using either natural or non-natural nematode viruses have also been established in C. elegans. These models offer new opportunities to use the nematode to understand eukaryotic antiviral defense mechanisms. Here we report protocols for the infection of C. elegans with a non-natural viral pathogen, vesicular stomatitis virus (VSV) through microinjection. We also describe how recombinant VSV strains encoding fluorescent or luciferase reporter genes can be used in conjunction with simple fluorescence-, survival-, and luminescence-based assays to identify host genetic backgrounds with differential susceptibilities to virus infection. PMID- 29276725 TI - Markerless Gene Editing in the Hyperthermophilic Archaeon Thermococcus kodakarensis. AB - The advent of single cell genomics and the continued use of metagenomic profiling in diverse environments has exponentially increased the known diversity of life. The recovered and assembled genomes predict physiology, consortium interactions and gene function, but experimental validation of metabolisms and molecular pathways requires more directed approaches. Gene function-and the correlation between phenotype and genotype is most obviously studied with genetics, and it is therefore critical to develop techniques permitting rapid and facile strain construction. Many new and candidate archaeal lineages have recently been discovered, but experimental, genetic access to archaeal genomes is currently limited to a few model organisms. The results obtained from manipulating the genomes of these genetically-accessible organisms have already had profound effects on our understanding of archaeal physiology and information processing systems, and these continued studies also help resolve phylogenetic reconstruction of the tree of life. The hyperthermophilic, planktonic, marine heterotrophic archaeon Thermococcus kodakarensis, has emerged as an ideal genetic system with a suite of techniques available to add or delete encoded activities, or modify expression of genes in vivo. We outline here techniques to rapidly and markerlessly delete a single, or repetitively delete several, continuous sequences from the T. kodakarensis genome. Our procedure includes details on the construction of the plasmid DNA necessary for transformation that directs, via homologous recombination, integration into the genome, identification of strains that have incorporated plasmid sequences (termed intermediate strains), and confirmation of plasmid excision, leading to deletion of the target gene in final strains. Near identical procedures can be employed to modify, rather than delete, a genomic locus. PMID- 29276726 TI - Drosophila Model of Leishmania amazonensis Infection. AB - This protocol describes how to generate and harvest antibody-free L. amazonensis amastigotes, and how to infect adult Drosophila melanogaster with these parasites. This model recapitulates key aspects of the interactions between Leishmania amastigotes and animal phagocytes. PMID- 29276727 TI - Translating Research to Practice in the Language Sciences. PMID- 29276728 TI - A Practice Innovations Decision Model. AB - Objective: The purpose of this commentary is to propose a flexible practice innovations decision model (PIDM) for use in health services planning and management. Method: This is an example of fuzzy decision analysis. The elements of the model are explained by applying it to the decision of whether to open a primary care clinic in retail space. The model contains 10 criteria, each of which scored as 1 (met) or 0 (not met). The scores are summed to guide the decision. Result: In this example, success was defined a priori as meeting 8 or more criteria. Sensitivity analysis and simulation can be used in practice to test the model. Conclusion: The PIDM appears to be applicable to a variety of decisions, and the fuzzy scoring combined with simulation and sensitivity analysis generates plausible results. The model should be modified as necessary for each situation in which it is applied. PMID- 29276729 TI - Editorial overview: Theories, methods, and applications of mixed emotions. PMID- 29276730 TI - The Ebb and Flow of Experience Determines the Temporal Structure of Memory. AB - Everyday life consists of a continuous stream of information, yet somehow we remember the past as distinct episodic events. Prominent models posit that event segmentation is driven by erroneous predictions about how current experiences are unfolding. Yet this perspective fails to explain how memories become integrated or separated in the absence of prior knowledge. Here, we propose that contextual stability dictates the temporal organization of events in episodic memory. To support this view, we summarize new findings showing that neural measures of event organization index how ongoing changes in external contextual cues and internal representations of time influence different forms of episodic memory. PMID- 29276731 TI - The role of the P2X7 receptor on bone loss in a mouse model of inflammation mediated osteoporosis. AB - In inflammatory autoimmune diseases, bone loss is frequent. In most cases, secondary osteoporosis is caused by treatment with systemic glucocorticoid. However, the pathogenesis behind the bone loss is presumed multifactorial. We aimed to elucidate the role of the P2X7 receptor on bone mineral density (BMD), microarchitecture, and bone strength in a standardized mouse model of inflammation-mediated osteoporosis (IMO). In total 146 mice completed our protocol, 70 wild type (WT) mice and 76 P2X7 -/- (knockout, KO). BMD at the femur and spine decreased significantly from baseline to day 20 in the WT IMO mice (p < 0.01). In the WT vehicle, KO vehicle and KO IMO, no significant BMD changes were found. Bone strength showed a lower mid-shaft max strength (p = 0.038) and also a non-significant trend towards lower strength at the femoral neck of the WT IMO group. Trabecular bone volume fraction (BV/TV) and connectivity density (CD) after 20 days were significantly decreased in the WT IMO group (p = 0.001). In contrast, the WT vehicle and KO vehicle, BV/TV and CD did no change at 20 days. Cortical bone revealed no significant microarchitectural changes after 20 days in the WT IMO group, whereas the total cortical area increased significantly in WT vehicle and KO IMO after 20 days (5.2% and 8.8%, respectively). In conclusion, the P2X7 receptor KO mice did not respond to inflammation with loss of BMD whereas the WT mice had a significant loss of BMD, bone strength and trabecular microarchitecture, demonstrating a role for the P2X7 receptor in inflammatory bone loss. PMID- 29276732 TI - Normocalcemic primary hyperparathyroidism associated with progressive cortical bone loss - A case report. AB - The existence of normocalcemic primary hyperparathyroidism (NPHP) was acknowledged at the Third and Fourth International Proceedings on primary hyperparathyroidism PHPT but data relating to its clinical presentation, natural history, and skeletal status were limited and there was no information nor guidelines as to definitive therapy. Herein are reported biochemical, hormonal, and densitometry data in a postmenopausal woman seen initially for osteoporosis who was found to have increased serum PTH levels and normal serum total and ionized calcium levels without evidence of secondary hyperparathyroidism. Over a seven year period, the patient exhibited continuing preferential cortical bone loss at the one-third site of the radius in the face of relatively stable readings at the lumbar spine and hip that led to a subtotal parathyroidectomy for parathyroid hyperplasia with resultant normalization of serum PTH. PMID- 29276733 TI - Decisive differences in the bone repair processes of the metaphysis and diaphysis in young mice. AB - Fractures are common traumatic injuries that mainly occur in the metaphyses of long bones such as the proximal humerus, distal radius, and proximal femur. However, most studies of fracture repair processes have focused on the diaphyseal region. In this study, we compared the bone repair processes of the metaphysis and the diaphysis of the mouse tibia. Bone apertures were formed in the tibial metaphysis and diaphysis. At indicated times after surgery, samples were collected, and the healing process was investigated using micro-computed tomography, as well as histological, immunohistochemical, and mRNA expression analyses. In the metaphysis, cartilage formation was not detected on the periosteal side. The bone aperture was filled with newly formed bone produced from bone marrow at day 7. In the case of the diaphysis, cartilage was formed around the aperture at day 4 and sequentially replaced by bone on the periosteal side. The bone aperture was filled with newly formed bone at day 14. In the bone marrow, expression of the osteogenic markers such as alkaline phosphatase, osteocalcin, and type I collagen, appeared earlier with metaphyseal injury than with diaphyseal injury. The mRNA expression of chondrogenesis markers was markedly upregulated in the diaphysis compared with that in the metaphysis on the periosteal side. These results indicate differences in the bone repair processes of the two regions, suggesting functional heterogeneity of the periosteum and bone marrow mesenchymal cells in response to bone fractures. PMID- 29276734 TI - Stress & the gut-brain axis: Regulation by the microbiome. AB - The importance of the gut-brain axis in regulating stress-related responses has long been appreciated. More recently, the microbiota has emerged as a key player in the control of this axis, especially during conditions of stress provoked by real or perceived homeostatic challenge. Diet is one of the most important modifying factors of the microbiota-gut-brain axis. The routes of communication between the microbiota and brain are slowly being unravelled, and include the vagus nerve, gut hormone signaling, the immune system, tryptophan metabolism, and microbial metabolites such as short chain fatty acids. The importance of the early life gut microbiota in shaping later health outcomes also is emerging. Results from preclinical studies indicate that alterations of the early microbial composition by way of antibiotic exposure, lack of breastfeeding, birth by Caesarean section, infection, stress exposure, and other environmental influences - coupled with the influence of host genetics - can result in long-term modulation of stress-related physiology and behaviour. The gut microbiota has been implicated in a variety of stress-related conditions including anxiety, depression and irritable bowel syndrome, although this is largely based on animal studies or correlative analysis in patient populations. Additional research in humans is sorely needed to reveal the relative impact and causal contribution of the microbiome to stress-related disorders. In this regard, the concept of psychobiotics is being developed and refined to encompass methods of targeting the microbiota in order to positively impact mental health outcomes. At the 2016 Neurobiology of Stress Workshop in Newport Beach, CA, a group of experts presented the symposium "The Microbiome: Development, Stress, and Disease". This report summarizes and builds upon some of the key concepts in that symposium within the context of how microbiota might influence the neurobiology of stress. PMID- 29276736 TI - Maternal separation stress leads to resilience against neuropathic pain in adulthood. AB - Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS related vulnerability for neuropathic pain and the possibly underlying etiology. In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2-12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro inflammatory cytokines and growth factors was studied by using qPCR. MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1beta) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient. PMID- 29276738 TI - Characterization, kinetic, and isotherm data for adsorption of Pb2+ from aqueous solution by adsorbent from mixture of bagasse-bentonite. AB - The usage of wastes of bagasse would be admirable from environmental and solid waste management point of view. Thus, herein, this data set present a facile method for providing an adsorbent from mixture of bagasse-bentonite. The prepared adsorbent was applied to remove Pb2+ from aqueous solution. It was conducted in laboratory scale using completely randomized design with variations in mixed mass ratio (1:0, 1:1, 1:2, 1:3, 2:1, 3:1), pH (2, 3, 4, 5, 6, 7) and contact time (5, 10, 30, 45, 90, 120, 180 min) and the adsorption technique was batch technique. The mixed adsorbent with 3:1 of mass ratio provided the highest Pb2+ adsorption efficiency of 97.31%. The optimum pH of Pb2+ adsorption was 5 and contact time was efficient at 45 min giving adsorption efficiency of 94.76% and 93.38%. The characterization data of the adsorbent were analyzed using XRF and FTIR methods. The XRF test results showed the changes of elemental content in adsorbent after the adsorption indicated that adsorbent can absorb Pb2+. The FTIR test results showed that adsorbent has a functional group that is useful in adsorption process. Adsorption of Pb2+ by adsorbent from mixture of bagasse-bentonite follows pseudo second order model with correlation coefficient value of 99.99% (R2 = 0.9999) and Freundlich isotherm model with correlation coefficient value of 90.05% (R2 = 0.9005). The acquired data indicated that the adsorption of Pb2+ by the adsorbent prepared from mixture of bagasse-bentonite is a promising technique for treating Pb-bearing wastewaters. PMID- 29276735 TI - Circuit and synaptic mechanisms of repeated stress: Perspectives from differing contexts, duration, and development. AB - The current review is meant to synthesize research presented as part of a symposium at the 2016 Neurobiology of Stress workshop in Irvine California. The focus of the symposium was "Stress and the Synapse: New Concepts and Methods" and featured the work of several junior investigators. The presentations focused on the impact of various forms of stress (altered maternal care, binge alcohol drinking, chronic social defeat, and chronic unpredictable stress) on synaptic function, neurodevelopment, and behavioral outcomes. One of the goals of the symposium was to highlight the mechanisms accounting for how the nervous system responds to stress and their impact on outcome measures with converging effects on the development of pathological behavior. Dr. Kevin Bath's presentation focused on the impact of disruptions in early maternal care and its impact on the timing of hippocampus maturation in mice, finding that this form of stress drove accelerated synaptic and behavioral maturation, and contributed to the later emergence of risk for cognitive and emotional disturbance. Dr. Scott Russo highlighted the impact of chronic social defeat stress in adolescent mice on the development and plasticity of reward circuity, with a focus on glutamatergic development in the nucleus accumbens and mesolimbic dopamine system, and the implications of these changes for disruptions in social and hedonic response, key processes disturbed in depressive pathology. Dr. Kristen Pleil described synaptic changes in the bed nuclei of the stria terminalis that underlie the behavioral consequences of allostatic load produced by repeated cycles of alcohol binge drinking and withdrawal. Dr. Eric Wohleb and Dr. Ron Duman provided new data associating decreased mammalian target of rapamycin (mTOR) signaling and neurobiological changes in the synapses in response to chronic unpredictable stress, and highlighted the potential for the novel antidepressant ketamine to rescue synaptic and behavioral effects. In aggregate, these presentations showcased how divergent perspectives provide new insights into the ways in which stress impacts circuit development and function, with implications for understanding emergence of affective pathology. PMID- 29276739 TI - Data on the impact of subclinical hypothyroidism on clinical outcomes following percutaneous coronary intervention. AB - This article contains the data showing the different influence of subclinical hypothyroidism (SCH) on the risk of cardiovascular events after percutaneous coronary intervention (PCI) in various subgroups regarding myocardial infarction, previous PCI, the stent generation, total stent length, the extent of coronary artery disease, diabetes mellitus, obesity, a lipid reduction level and a C reactive protein level. This article also contains the data showing the association between SCH and the risk of receiving repeat PCI for in-stent restenosis or de novo coronary stenosis. The data are supplemental to our original research article titled "Impact of Subclinical Hypothyroidism on Clinical Outcomes Following Percutaneous Coronary Intervention" (Lee et al., 2017) [1]. PMID- 29276740 TI - Data on color and chemical composition of dried scallop (Mizuhopecten yessoensis) produced in different areas of Hokkaido, Japan. AB - Dried scallop is used in Chinese, Japanese, and French cuisines for its unique flavor and taste. The quality of dried scallop is rated according to its clear, shiny brown color, developed by the Maillard reaction between sugars and amino acids. This article reports the colors, represented by L* and a* values, and chemical composition (water, salinity, Brix, proteins, and amino acids) of dried scallop products. The dried scallops were produced in Tokoro, Sarufutsu, and Saroma in Hokkaido, Japan. The color of the dried scallops had values of 45.7 52.0 for L* and 2.31-5.08 for a*. The salinity of the products was 15.1-17.7%. The amino acid contents were 1350.8-1668.6 mg/100 g. The data collected here are provided in table format. The data can serve as a reference for commercial dried scallop products to determine product quality. PMID- 29276737 TI - Neural EGF-like protein 1 (NELL-1): Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine. AB - Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects, two problems associated with significant morbidity. The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors. Neural EGF Like Like molecule 1 (NELL-1) is a secreted glycoprotein that has proven, both in vitro and in vivo, to be a potent osteo-inductive factor. Furthermore, it has been shown to repress adipogenic differentiation and inflammation. NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein (BMP) -2 and -9, and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis. Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering. PMID- 29276741 TI - Data on free amino acid contents in Japanese basket clams (Corbicula japonica) from Lake Abashiri and Abashirigawa River. AB - This data article provides the free amino acid contents of Japanese basket clams from different areas of Lake Abashiri and Abashirigawa River, which belong to the same water system. Abashirigawa River flows into the south side of Lake Abashiri and then runs out from the northeast side of the lake. Clams were caught in three different areas in Lake Abashiri (Memanbetsu, Yobito, and Katayama) and from one site at Abashirigawa River (Sancho). Free amino acids in the edible portion of the clams were analyzed using an automated amino acid analyzer. The clams showed high contents in beta-alanine, alanine, glutamic acid, and glycine. The clams caught in the river contains relatively higher amino acid contents. The analyzed data are provided in table format. PMID- 29276742 TI - Draft genome sequence of Anoxybacillus flavithermus KU2-6-11 isolated from hot spring in Uzon caldera (Kamchatka, Russia). AB - The Anoxybacillus flavithermus KU2-6-11 was isolated from sediments of a nameless hot spring. The hot spring is located in Uzon caldera (Kamchatka, Russia). The sequenced and annotated genome is 2,646,305 bp and encodes 2787genes. The draft genome sequence of the Anoxybacillus flavithermus KU2-6-11 has been deposited at DDBJ/EMBL/GenBank under the accession PEDM01000000 and the sequences could be found at the site https://www.ncbi.nlm.nih.gov/nuccore/PEDM01000000. PMID- 29276743 TI - Datasets for mapping pastoralist movement patterns and risk zones of Rift Valley fever occurrence. AB - Rift Valley fever (RVF) is a zoonotic disease affecting humans and animals. It is caused by RVF virus transmitted primarily by Aedes mosquitoes. The data presented in this article propose environmental layers suitable for mapping RVF vector habitat zones and livestock migratory routes. Using species distribution modelling, we used RVF vector occurrence data sampled along livestock migratory routes to identify suitable vector habitats within the study region which is located in the central and the north-eastern part of Kenya. Eleven herds monitored with GPS collars were used to estimate cattle utilization distribution patterns. We used kernel density estimator to produce utilization contours where the 0.5 percentile represents core grazing areas and the 0.99 percentile represents the entire home range. The home ranges were overlaid on the vector suitability map to identify risks zones for possible RVF exposure. Assimilating high spatial and temporal livestock movement and vector distribution datasets generates new knowledge in understanding RVF epidemiology and generates spatially explicit risk maps. The results can be used to guide vector control and vaccination strategies for better disease control. PMID- 29276744 TI - A model for habitus-adjusted paediatric weight estimation by age and data concerning the validation of this method on a large dataset of English children. AB - It is often not possible to weigh children upon arrival at an emergency room before commencing the provision of emergency care. Because drugs for children are prescribed on the basis of age and body weight, estimations of weight are necessitated. Age-based equations have been one of the most commonly used weight estimation strategies historically. Due to the variability of weight for age in children, and variations in body habitus, these methods are inaccurate by design (Young and Korotzer, 2016) [1]. PMID- 29276745 TI - Frequencies of alleles, genotypes and haplotypes of two polymorphisms in the clusterin gene in the Russian elderly population categorized by cognitive performance. AB - This article contains data on the frequencies of alleles, genotypes and haplotypes of the single nucleotide polymorphisms (SNPs) rs2279590 and rs1532278 in the CLU gene in a cohort of normal elderly from the Russian population. The SNPs have been reported to be associated with Alzheimer's disease and cognitive functions in genome-wide and candidate genes association studies. Cognitive performance in sample set was estimated by the Montreal Cognitive Assessment (MoCA). The frequencies of alleles, genotypes and haplotypes of two SNPs were calculated in 3 groups: total sample set, sample set with MoCA score less than 21 (the first quartile) and group with MoCA score more than 24 (the fourth quartile). PMID- 29276746 TI - Smart campus: Data on energy consumption in an ICT-driven university. AB - In this data article, we present a comprehensive dataset on electrical energy consumption in a university that is practically driven by Information and Communication Technologies (ICTs). The total amount of electricity consumed at Covenant University, Ota, Nigeria was measured, monitored, and recorded on daily basis for a period of 12 consecutive months (January-December, 2016). Energy readings were observed from the digital energy meter (EDMI Mk10E) located at the distribution substation that supplies electricity to the university community. The complete energy data are clearly presented in tables and graphs for relevant utility and potential reuse. Also, descriptive first-order statistical analyses of the energy data are provided in this data article. For each month, the histogram distribution and time series plot of the monthly energy consumption data are analyzed to show insightful trends of energy consumption in the university. Furthermore, data on the significant differences in the means of daily energy consumption are made available as obtained from one-way Analysis of Variance (ANOVA) and multiple comparison post-hoc tests. The information provided in this data article will foster research development in the areas of energy efficiency, planning, policy formulation, and management towards the realization of smart campuses. PMID- 29276747 TI - Housing price gradient and immigrant population: Data from the Italian real estate market. AB - The database presented here was collected by Antoniucci and Marella to analyze the correlation between the housing price gradient and the immigrant population in Italy during 2016. It may also be useful in other statistical analyses, be they on the real estate market or in another branches of social science. The data sample relates to 112 Italian provincial capitals. It provides accurate information on urban structure, and specifically on urban density. The two most significant variables are original indicators constructed from official data sources: the housing price gradient, or the ratio between average prices in the center and suburbs by city; and building density, which is the average number of housing units per residential building. The housing price gradient is calculated for the two residential sub-markets, new-build and existing units, providing an original and detailed sample of the Italian residential market. Rather than average prices, the housing price gradient helps to identify potential divergences in residential market trends. As well as house prices, two other data clusters are considered: socio-economic variables, which provide a framework of each city, in terms of demographic and economic information; and various data on urban structure, which are rarely included in the same database. PMID- 29276750 TI - Hypoxia in the Gut. PMID- 29276748 TI - Extracellular Matrix Bioscaffolds for Building Gastrointestinal Tissue. AB - Regenerative medicine is a rapidly advancing field that uses principles of tissue engineering, developmental biology, stem cell biology, immunology, and bioengineering to reconstruct diseased or damaged tissues. Biologic scaffolds composed of extracellular matrix have shown great promise as an inductive substrate to facilitate the constructive remodeling of gastrointestinal (GI) tissue damaged by neoplasia, inflammatory bowel disease, and congenital or acquired defects. The present review summarizes the preparation and use of extracellular matrix scaffolds for bioengineering of the GI tract, identifies significant advances made in regenerative medicine for the reconstruction of functional GI tissue, and describes an emerging therapeutic approach. PMID- 29276751 TI - Indian Hedgehog Suppresses Intestinal Inflammation. PMID- 29276749 TI - HIF-1alpha Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis. AB - Background & Aims: Radiation therapy in the pelvic area is associated with side effects that impact the quality of life of cancer survivors. Interestingly, the gastrointestinal tract is able to adapt to significant changes in oxygen availability, suggesting that mechanisms related to hypoxia sensing help preserve tissue integrity in this organ. However, hypoxia-inducible factor (HIF)-dependent responses to radiation-induced gut toxicity are unknown. Radiation-induced intestinal toxicity is a complex process involving multiple cellular compartments. Here, we investigated whether epithelial or endothelial tissue specific HIF-1alpha deletion could affect acute intestinal response to radiation. Methods: Using constitutive and inducible epithelial or endothelial tissue specific HIF-1alpha deletion, we evaluated the consequences of epithelial or endothelial HIF-1alpha deletion on radiation-induced enteritis after localized irradiation. Survival, radiation-induced tissue injury, molecular inflammatory profile, tissue hypoxia, and vascular injury were monitored. Results: Surprisingly, epithelium-specific HIF-1alpha deletion does not alter radiation induced intestinal injury. However, irradiated VECad-Cre+/-HIF-1alphaFL/FL mice present with lower radiation-induced damage, showed a preserved vasculature, reduced hypoxia, and reduced proinflammatory response compared with irradiated HIF-1alphaFL/FL mice. Conclusions: We demonstrate in vivo that HIF-1alpha impacts radiation-induced enteritis and that this role differs according to the targeted cell type. Our work provides a new role for HIF-1alpha and endothelium-dependent mechanisms driving inflammatory processes in gut mucosae. Results presented show that effects on normal tissues have to be taken into account in approaches aiming to modulate hypoxia or hypoxia-related molecular mechanisms. PMID- 29276752 TI - A Molecular Signature of Mouse NASH: A Step Closer to a Human Predictive Biomarker? PMID- 29276753 TI - Indian Hedgehog Suppresses a Stromal Cell-Driven Intestinal Immune Response. AB - Background & Aims: Upon intestinal epithelial damage a complex wound healing response is initiated to restore epithelial integrity and defend against pathogenic invasion. Epithelium-derived Indian Hedgehog (Ihh) functions as a critical sensor in this process. Signaling occurs in a paracrine manner because the receptor for Ihh is expressed only in the mesenchyme, but the exact Hedgehog target cell has remained elusive. The aim of this study was to elucidate further the nature of this target cell in the context of intestinal inflammation. Methods: Hedgehog activity was modulated genetically in both cell type-specific and body-wide models and the resulting animals were analyzed for gene expression profiles and sensitivity for dextran sodium sulfate (DSS) colitis. To characterize the Hedgehog target cell, Gli1-CreERT2-Rosa26-ZsGreen animals were generated, which express ZsGreen in all Hedgehog-responsive cells. These cells were characterized using flow cytometry and immunofluorescence. Results: Loss of Indian Hedgehog from the intestinal epithelium resulted in a rapid increase in expression of inflammation-related genes, accompanied by increased influx of immune cells. Animals with epithelium-specific deletion of Ihh or lacking the Hedgehog receptor Smoothened from Hedgehog target cells were more sensitive to DSS colitis. In contrast, specific deletion of Smoothened in the myeloid compartment did not alter the response to DSS. This suggests that Hedgehog signaling does not repress intestinal immunity through an effect on myeloid cells. Indeed, we found that Hedgehog-responsive cells expressed gp38, smooth muscle actin, and desmin, indicating a fibroblastic nature. Ihh signaling inhibited expression of C-X-C motif chemokine ligand 12 (CXCL12) in fibroblasts in vitro and in vivo, thereby impairing the recruitment of immune cells. Conclusions: We show that epithelium-derived Indian Hedgehog signals exclusively to fibroblasts in the intestine. Loss of Ihh leads to a rapid immune response with up-regulation of fibroblast-derived CXCL12, and migration of immune cells into the lamina propria. PMID- 29276754 TI - Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model. AB - Background & Aims: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods: A time-course study in low-density lipoprotein-receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results: High-fat diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions: An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames. PMID- 29276755 TI - Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE). PMID- 29276756 TI - Cost effectiveness of medical devices to diagnose pre-eclampsia in low-resource settings. AB - Background: Maternal mortality remains a major health challenge facing developing countries, with pre-eclampsia accounting for up to 17 percent of maternal deaths. Diagnosis requires skilled health providers and devices that are appropriate for low-resource settings. This study presents the first cost-effectiveness analysis of multiple medical devices used to diagnose pre-eclampsia in low- and middle income countries (LMICs). Methods: Blood pressure and proteinuria measurement devices, identified from compendia for LMICs, were included. We developed a decision tree framework to assess the cost-effectiveness of each device using parameter values that reflect the general standard of care based on a survey of relevant literature and expert opinion. We examined the sensitivity of our results using one-way and second-order probabilistic multivariate analyses. Results: Because the disability-adjusted life years (DALYs) averted for each device were very similar, the results were influenced by the per-use cost ranking. The most cost-effective device combination was a semi-automatic blood pressure measurement device and visually read urine strip test with the lowest combined per-use cost of $0.2004 and an incremental cost effectiveness ratio of $93.6 per DALY gained relative to a baseline with no access to diagnostic devices. When access to treatment is limited, it is more cost-effective to improve access to treatment than to increase testing rates or diagnostic device sensitivity. Conclusions: Our findings were not sensitive to changes in device sensitivity, however they were sensitive to changes in the testing rate and treatment rate. Furthermore, our results suggest that simple devices are more cost-effective than complex devices. The results underscore the desirability of two design features for LMICs: ease of use and accuracy without calibration. Our findings have important implications for policy makers, health economists, health care providers and engineers. PMID- 29276757 TI - Model-based and design-based inference goals frame how to account for neighborhood clustering in studies of health in overlapping context types. AB - Accounting for non-independence in health research often warrants attention. Particularly, the availability of geographic information systems data has increased the ease with which studies can add measures of the local "neighborhood" even if participant recruitment was through other contexts, such as schools or clinics. We highlight a tension between two perspectives that is often present, but particularly salient when more than one type of potentially health-relevant context is indexed (e.g., both neighborhood and school). On the one hand, a model-based perspective emphasizes the processes producing outcome variation, and observed data are used to make inference about that process. On the other hand, a design-based perspective emphasizes inference to a well-defined finite population, and is commonly invoked by those using complex survey samples or those with responsibility for the health of local residents. These two perspectives have divergent implications when deciding whether clustering must be accounted for analytically and how to select among candidate cluster definitions, though the perspectives are by no means monolithic. There are tensions within each perspective as well as between perspectives. We aim to provide insight into these perspectives and their implications for population health researchers. We focus on the crucial step of deciding which cluster definition or definitions to use at the analysis stage, as this has consequences for all subsequent analytic and interpretational challenges with potentially clustered data. PMID- 29276758 TI - Role of Tau Acetylation in Alzheimer's Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment. AB - Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration. PMID- 29276760 TI - From the Editor. PMID- 29276759 TI - In Vivo Multiscale and Spatially-Dependent Biomechanics Reveals Differential Strain Transfer Hierarchy in Skeletal Muscle. AB - Biological tissues have a complex hierarchical architecture that spans organ to subcellular scales and comprises interconnected biophysical and biochemical machinery. Mechanotransduction, gene regulation, gene protection, and structure function relationships in tissues depend on how force and strain are modulated from macro to micro scales, and vice versa. Traditionally, computational and experimental techniques have been used in common model systems (e.g., embryos) and simple strain measures were applied. But the hierarchical transfer of mechanical parameters like strain in mammalian systems is largely unexplored in vivo. Here, we experimentally probed complex strain transfer processes in mammalian skeletal muscle tissue over multiple biological scales using complementary in vivo ultrasound and optical imaging approaches. An iterative hyperelastic warping technique quantified the spatially-dependent strain distributions in tissue, matrix, and subcellular (nuclear) structures, and revealed a surprising increase in strain magnitude and heterogeneity in active muscle as the spatial scale also increased. The multiscale strain heterogeneity indicates tight regulation of mechanical signals to the nuclei of individual cells in active muscle, and an emergent behavior appearing at larger (e.g. tissue) scales characterized by dramatically increased strain complexity. PMID- 29276761 TI - Creating an Excellent Patient Experience Through Service Education: Content and Methods for Engaging and Motivating Front-Line Staff. AB - Service quality and patient satisfaction affect an organization's value-based payments. This new value paradigm calls for a new approach to service education and training for front-line staff. Thoughtfully conceived, department-specific content, infused with patient feedback, value creation, and science of service quality principles, was developed to give front-line staff a deeper understanding of the impact of their performance on patient experience, value creation, and value-based revenue. Feedback from nearly 1500 trainees in 60 educational sessions delivered over 7 years indicates good understanding of the content and appreciation of the targeted approach. On a 5-point scale ranging from 1 (least effective) to 5 (most effective), trainees' ratings of their understanding of service quality concepts and impact on value ranged from 4.7 to 4.9. Verbatim comments showed a positive impact on staff. Employee feedback suggests that value based service education may be useful in motivating front-line staff, improving service quality, and creating value. PMID- 29276762 TI - Live, Learn, Pass It on: A Patient Advocacy Engagement Project on the Lived Experience of Lung Cancer Survivors. AB - Introduction: The objective of this project was to engage survivor-advocates by describing their experiences living with lung cancer in an era of increasing treatment options. Methods: This was a qualitative engagement project with participants from a lung cancer advocacy organization's survivor advisory board. Interviews were conducted, transcribed, and analyzed for stages and associated experiences using interpretive phenomenological analysis and elements of narrative analysis, in partnership with the patient advocacy organization. Results: Of 27 engaged members, interviews were conducted with 19, mostly long term survivors with stage 3 or 4 lung cancer. Within the quest for patient centeredness, we identified 3 stages of the patient experience. The stage Live describes the journey of the lived experience; Learn describes the quest for knowledge, empowerment, and skills; and Pass it on describes making a difference through guiding others, building awareness, and community. Conclusions: Lung cancer survivor-advocates have an intertwined experience of their personal journey, the quest for knowledge, and developing advocacy. Future patient engagement can incorporate these findings into increasing the survivor centeredness of partnerships and research, particularly for quality of life and shared decision-making. PMID- 29276763 TI - A Description of Patient and Provider Experience and Clinical Outcomes After Heart Failure Shared Medical Appointment. AB - Background: Shared medical appointments (SMAs) are clinical visits in which several patients meet with 1 or more providers at the same time. Objective: To describe the outcomes of an interdisciplinary SMA for veterans recently discharged for heart failure (HF). Methods: A retrospective chart review for patients' readmission rates, survival, medication adherence, and medication related problems. For qualitative outcomes, we performed semistructured interviews on 12 patients who had undergone HF SMAs and their respective caregivers focusing on care satisfaction, HF knowledge, disease self-care, medication reconciliation, and peer support. Results: The cohort comprised 70 patients-49% had left ventricular function <40% and 50% were prescribed >10 medications. Medication-related problems occurred in 60% of patients. Interviews revealed overall satisfaction with HF-SMA, but patients felt overwhelmed with HF instructions, perceived lack of peer support and self-efficacy, and feelings of hopelessness related to HF. Conclusion: Shared medical appointments are well perceived. Medication problems and need for medication management are prevalent along with patient's lack of self-efficacy in HF care. Multiple HF-SMA visits may be needed to reinforce concepts, reduce confusion, and garner peer support. PMID- 29276764 TI - Relationship Between Patient Satisfaction And Physician Characteristics. AB - Background: Physician care influences patient satisfaction. Inherent physician attributes may also affect scores. Objective: To determine the relationship between physician characteristics and patient satisfaction regarding physician care and communication. Method: Observational retrospective study. We examined patient satisfaction surveys from inpatient adults across 9 questions (HCAHPS: Courtesy, Listen, and Explain; Press Ganey: Time, Concern, Informed, Friendliness, Skill, Rating) in relation to physician gender, age, ethnicity, race, and specialty. Results: We analyzed 51 896 surveys on 914 physicians. In univariate analysis, males were rated significantly more often in the highest category (top box) compared to females on Informed and Skill, and whites were rated in the top box more often than nonwhites on all questions. In multivariate analysis, there were no significant associations between ratings and physician gender, ethnicity, and race. On all questions, the odds of being rated in the top box were highest for obstetricians, second highest for surgeons, and lowest for medicine providers. On the question of Skill, the odds of being rated in the top box were higher with increasing age. Conclusion: Patient satisfaction regarding physicians is associated with physician specialty and age. PMID- 29276765 TI - Project RED Impacts Patient Experience. AB - Background: Hospitalized patients are frequently unprepared to care for themselves after discharge often leading to unplanned hospital readmission. One strategy to reduce readmission rates is improving the quality of patient education and preparation before hospital discharge. The ReEngineered Discharge (RED) is a standardized hospital-based program designed to provide patients and caregivers the information they need to continue care at home. Objectives: We sought to study the impact of the RED intervention on posthospitalization adult patient experience scores in an urban academic safety-net hospital. Methods: We conducted a descriptive study of a pilot program that compared posthospitalization survey responses to the Press Ganey survey item "Instructions were given about how to care for yourself at home." We compared the survey results for 3 groups of adult patients: those receiving the RED program, those receiving a standard discharge on the same hospital unit, and those receiving a standard discharge on other hospital units. Results: A greater percentage of adult patients who received the RED discharge program rated the quality of their discharge as "very good" as compared to those receiving a standard discharge on the same hospital unit and those receiving a standard discharge on other hospital units (61%, 35%, and 41%, respectively, P = .0001). Conclusion: Delivery of a standardized hospital discharge program resulted in a larger proportion of top box "very good" responses on a Press Ganey posthospitalization survey. Future research should examine whether hospital-based transition programs can sustain improvement in patient experience measures and whether these improvements can be observed in other patient populations. PMID- 29276766 TI - Challenges to Ethically Managing Parkinson Disease: An Interview Study of Patient Perspectives. AB - : This study investigated the current ethical issues in relation to recognizing and managing Parkinson disease (PD) from the patient's perspective. Methods: Twelve patients living with PD who were from the medical school's Patients as Educators program were recruited. Semistructured interviews were conducted to record patient experiences in order to identify potential ethical issues in relation to recognizing and managing PD. Thematic analysis was applied to the interview transcripts. Results: Four key themes emerged from the interviews. These were information giving, coping, identity, and future medical treatment. These data indicate variable experiences in relation to communication between patient and health-care professional, better support for both planning end-of life decisions and in coping with the disease's impacts on their identity. Patients with PD also struggle with access to support services and support for main carer. Implications: To ensure ethical practice in supporting patients with PD, these emerging themes need further investigation; and management guidelines relevant to PD must be informed by research in this area to ensure ethical care of patients with PD, their carers, and families. PMID- 29276767 TI - How Are We Doing?-The Experience of the Merton Home Treatment Team in Gathering Real-Time Feedback and the Impact Upon Service Provision. AB - Aims and Method: To discuss the methods involved in gathering real-time feedback (RTF) by a London Home Treatment Team. We hypothesized that RTF would lead to changes in service provision and improvements in patient and carer feedback. Patients were invited to provide RTF on discharge. Quantitative and qualitative data were collected and analyzed centrally by the Trust before being disseminated to the team and changes made based upon the results. Quantitative feedback on the team's performance in the first 6 months of RTF use was compared against data from the 6 months prior to March 2015 using 2-tailed Z tests. Results: There were significant improvements in feedback around the team visiting at the agreed times (P = .0069) and patients feeling that they had been involved in treatment decisions (P = .0371). Clinical Implications: Real-time feedback is a potentially valuable method for obtaining patient feedback and can result in service improvements if used appropriately. PMID- 29276768 TI - MD to MD Coaching: Improving Physician-Patient Experience Scores: What Works, What Doesn't. AB - With increasing national focus on patient experience scores through public reporting and the Value-Based Purchasing Program, hospitals and medical groups are challenged with initiating sustainable programs to improve their scores. Our system initiated 3 pilot programs to determine which approaches and techniques would be the most beneficial. The pilot trails included: (a) MD to MD 1:1 coaching with monthly MD-specific individual reports; (b) all staff patient experience training sessions at two of our urgent care centers; and (c) physician group patient experience training at one of our outpatient clinics. This article describes our 3 pilot initiatives and results that have been obtained. PMID- 29276769 TI - Low incidence of opportunistic Infections in Lupus Patients treated with Cyclophosphamide and Steroids in a Tertiary care setting. AB - Background: Infection is common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Our objective was to determine incidence and types of infections, particularly opportunistic infections, in SLE patients receiving cyclophosphamide, and to identify contribution of variables like demographics, steroid, other immunosuppressives, white blood cell and absolute neutrophil count to infection risk. Patients and Methods: We did retrospective chart review of SLE patients in our institute over last 10 years, who received minimum six cyclophosphamide infusions. Types of infection, cumulative steroid dose, and maintenance medications were recorded. Statistical analyses were done using SAS software. Results: 87.1% of the 31 patients were female. Mean age was 37.9 years, 48.4% Hispanic, 25.8% African American, 6.4% Asian and 19.4% were Caucasian. No one was on pneumocystis jirovecii pneumonia (PJP) prophylaxis. There were 42 episodes of infection in 31 patients. Different infections were urinary tract infections (UTI), upper respiratory infections (URI), line sepsis, bacterial pneumonia, PJP, mucocutaneous infections and viral gastroenteritis. Infection frequency was significantly higher among Asians compared to Caucasians (p =0.0152). Infection rate was significantly higher during cyclophosphosphamide induction phase (65.9%) compared to maintenance phase (34.1%) (p value=0.0041). Infection rate was higher with higher cumulative steroid dose and in patients on quarterly cyclophosphamide infusion compared to those on oral azathioprine or mycophenolate mofetil. No association found among baseline white blood cell (WBC) or absolute neutrophil count (ANC) and infection rate. Conclusion: We found higher infection rates among Asians and in patients with higher cumulative steroid dose. Single incidence of PJP noted despite absence of prophylaxis. Quarterly cyclophosphamide was associated with higher infection rates. Larger prospective studies are needed to confirm our results. PMID- 29276771 TI - Recurrent post-tonsillectomy bleeding due to an iatrogenic facial artery pseudoaneurysm. AB - This is a report of an illustrative case of recurrent post-tonsillectomy bleeding that was caused by an iatrogenic facial artery pseudoaneurysm and controlled by endovascular embolization. A 37 year-old female who underwent bilateral tonsillectomy for chronic tonsillitis had recurrent secondary hemorrhage despite multiple operative interventions to control the bleeding. Because of the recurrent nature of the bleeding, an angiography of the external carotid artery was performed demonstrating a pseudoaneurysm of the left facial artery with active extravasation. This was successfully embolized with ethylene vinyl alcohol copolymer and the bleeding did not recur. Most post-operative bleeds can be managed with bedside or intraoperative interventions. However, pseudoaneurysms should be considered in the differential diagnosis of recurrent bleeds refractory to surgical control. PMID- 29276770 TI - SPE-IMS-MS: An automated platform for sub-sixty second surveillance of endogenous metabolites and xenobiotics in biofluids. AB - Characterization of endogenous metabolites and xenobiotics is essential to deconvoluting the genetic and environmental causes of disease. However, surveillance of chemical exposure and disease-related changes in large cohorts requires an analytical platform that offers rapid measurement, high sensitivity, efficient separation, broad dynamic range, and application to an expansive chemical space. Here, we present a novel platform for small molecule analyses that addresses these requirements by combining solid-phase extraction with ion mobility spectrometry and mass spectrometry (SPE-IMS-MS). This platform is capable of performing both targeted and global measurements of endogenous metabolites and xenobiotics in human biofluids with high reproducibility (CV 6 3%), sensitivity (LODs in the pM range in biofluids) and throughput (10-s sample to-sample duty cycle). We report application of this platform to the analysis of human urine from patients with and without type 1 diabetes, where we observed statistically significant variations in the concentration of disaccharides and previously unreported chemical isomers. This SPE-IMS-MS platform overcomes many of the current challenges of large-scale metabolomic and exposomic analyses and offers a viable option for population and patient cohort screening in an effort to gain insights into disease processes and human environmental chemical exposure. PMID- 29276772 TI - Subcutaneous Injection of Oxyfluorfen Herbicide to the Forearm: Case Report. AB - Background Oxyfluorfen, a commercially available pesticide, commonly used for weed control in crop production, has been studied in terms of its toxicity, its carcinogenic properties, and its teratogenicity. We have found no reports, however, of the effects produced by an oxyfluorfen injection to the upper limb. Methods We present the case of a 40 years old psychiatric patient, who reportedly injected her forearm accidentally while fumigating her garden. She was treated with irrigation and open forearm fasciectomy. Results At 6 months, the patient had some tenderness at the scar; she wanted no further procedures done. Conclusion Oxyfluorfen appeared to produce a chemical burn to the forearm tissues including the fascia, removal of the chemical product, and a limited fasciectomy, resulted in a favorable outcome. PMID- 29276774 TI - Effect of Environmental Factors and an Emerging Parasitic Disease on Gut Microbiome of Wild Salmonid Fish. AB - The gastrointestinal tract (GIT) of fish supports a dynamic microbial ecosystem that is intimately linked to host nutrient acquisition, epithelial development, immune system priming, and disease prevention, and we are far from understanding the complex interactions among parasites, symbiotic gut bacteria, and host fitness. Here, we analyzed the effects of environmental factors and parasitic burdens on the microbial composition and diversity within the GIT of the brown trout (Salmo trutta). We focused on the emerging dangerous salmonid myxozoan parasite Tetracapsuloides bryosalmonae, which causes proliferative kidney disease in salmonid fish, to demonstrate the potential role of GIT micobiomes in the modulation of host-parasite relationships. The microbial diversity in the GIT displayed clear clustering according to the river of origin, while considerable variation was also found among fish from the same river. Environmental variables such as oxygen concentration, water temperature, and river morphometry strongly associated with both the river microbial community and the GIT microbiome, supporting the role of the environment in microbial assemblage and the relative insignificance of the host genotype and gender. Contrary to expectations, the parasite load exhibited a significant positive relationship with the richness of the GIT microbiome. Many operational taxonomic units (OTUs; n = 202) are more abundant in T. bryosalmonae-infected fish, suggesting that brown trout with large parasite burdens are prone to lose their GIT microbiome homeostasis. The OTUs with the strongest increase in infected trout are mostly nonpathogenic aquatic, anaerobic sediment/sludge, or ruminant bacteria. Our results underscore the significance of the interactions among parasitic disease, abiotic factors, and the GIT microbiome in disease etiology. IMPORTANCE Cohabiting microorganisms play diverse and important roles in the biology of multicellular hosts, but their diversity and interactions with abiotic and biotic factors remain largely unsurveyed. Nevertheless, it is becoming increasingly clear that many properties of host phenotypes reflect contributions from the associated microbiome. We focus on a question of how parasites, the host genetic background, and abiotic factors influence the microbiome in salmonid hosts by using a host-parasite model consisting of wild brown trout (Salmo trutta) and the myxozoan Tetracapsuloides bryosalmonae, which causes widely distributed proliferative kidney disease. We show that parasite infection increases the frequency of bacteria from the surrounding river water community, reflecting impaired homeostasis in the fish gut. Our results also demonstrate the importance of abiotic environmental factors and host size in the assemblage of the gut microbiome of fish and the relative insignificance of the host genotype and gender. PMID- 29276773 TI - Comparison of Zoonotic Bacterial Agents in Fleas Collected from Small Mammals or Host-Seeking Fleas from a Ugandan Region Where Plague Is Endemic. AB - Fleas (n = 407) were collected from small mammals trapped inside huts and surroundings of homesteads in five villages within the Arua and Zombo districts of Uganda. The most common flea species were Dinopsyllus lypusus (26%) and Xenopsylla cheopis (50%). Off-host fleas (n = 225) were collected inside huts by using Kilonzo flea traps. The majority of the off-host fleas were Ctenocephalides felis (80%). All fleas were examined for the presence of Bartonella spp., Rickettsia spp., and Yersinia spp. Bartonella DNA was detected in 91 fleas, with an overall prevalence of 14%. Bartonella prevalence was significantly higher in rodent or shrew fleas than in off-host fleas (22% versus 1%). The majority of Bartonella-positive fleas were of the species D. lypusus (61%), X. cheopis (20%), and Ctenophthalmus calceatus (14%). Sequencing analysis identified 12 Bartonella genetic variants, 9 of which belonged to the zoonotic pathogen B. elizabethae species complex. Rickettsia DNA was detected in 143 fleas, giving an overall prevalence of 23%, with a significantly higher prevalence in off-host fleas than in rodent or shrew fleas (56% versus 4%). The majority (88%) of Rickettsia positive fleas were C. felis and were collected from Kilonzo traps, while a small portion (10%) were X. cheopis collected from rodents. Sequencing analysis identified six Rickettsia genogroups that belonged either to zoonotic R. felis or to the closely related "Candidatus Ricksettia asemboensis" and "Candidatus Ricksettia sengalensis." Yersinia DNA was not detected in the fleas tested. These observations suggested that fleas in northwestern Uganda commonly carry the zoonotic agents B. elizabethae and R. felis and potentially play an important role in transmitting these infections to humans. IMPORTANCE Fleas play critical roles in transmitting some infections among animals and from animals to humans. Detection of pathogens in fleas is important to determine human risks for flea borne diseases and can help guide diagnosis and treatment. Our findings of high prevalence rates of B. elizabethae and R. felis in fleas in the Arua and Zombo districts of Uganda implicate these agents as potential causative agents of undiagnosed febrile illnesses in this area. PMID- 29276775 TI - Task Force on Design and Analysis in Oral Health Research: Host-Microbiome Interactions in Dysbiosis. AB - Knowledge Transfer Statement: This article discusses the proceedings of the conference organized by the Task Force on Design and Analysis in Oral Health Research on the new advances in host-microbiome interactions, analytical methods, and their implication in inflammatory periodontal disease management. PMID- 29276776 TI - Periodontitis in Chediak-Higashi Syndrome: An Altered Immunoinflammatory Response. AB - Chediak-Higashi syndrome (CHS), a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene (LYST), is associated with aggressive periodontitis. It is suggested that LYST mutations affect the toll like receptor (TLR)-mediated immunoinflammatory response, leading to frequent infections. This study sought to determine the periodontal status of patients with classic (severe) and atypical (milder) forms of CHS and the immunoregulatory functions of gingival fibroblasts in CHS patients. In contrast to aged-matched healthy controls, atypical (n = 4) and classic (n = 3) CHS patients presented with mild chronic periodontitis with no evidence of gingival ulceration, severe tooth mobility, or premature exfoliation of teeth. As a standard of care, all classic CHS patients had undergone bone marrow transplantation (BMT). Primary gingival fibroblasts obtained from atypical and BMT classic CHS patients displayed higher protein expression of TLR-2 (1.81-fold and 1.56-fold, respectively) and decreased expression of TLR-4 (-2.5-fold and -3.85-fold, respectively) at baseline when compared with healthy control gingival fibroblasts. When challenged with whole bacterial extract of Fusobacterium nucleatum, both atypical and classic CHS gingival fibroblasts failed to up regulate TLR-2 and TLR-4 expression when compared with their respective untreated groups and control cells. Cytokine multiplex analysis following F. nucleatum challenge showed that atypical CHS gingival fibroblasts featured significantly increased cytokine expression (interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, IL 12, interferon-gamma, tumor necrosis factor-alpha), whereas classic CHS cells featured similar/decreased cytokine expression when compared with treated control cells. Collectively, these results suggest that LYST mutations in CHS patients affect TLR-2 and TLR-4 expression/function, leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients. Furthermore, our results suggest that atypical CHS patients and classic CHS patients who undergo BMT early in life are less susceptible to aggressive periodontitis and that hematopoietic cells play a critical role in mitigating the risk of aggressive periodontitis in CHS. Knowledge Transfer Statement: Results from this study can be used to create awareness among clinicians and researchers that not all CHS patients exhibit historically reported aggressive periodontitis, especially if they have atypical CHS disease or have received bone marrow transplantation. LYST mutations in CHS patients may affect TLR-2 and TLR-4 expression/function leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients. PMID- 29276777 TI - Patient-Centered Dentinal Hypersensitivity Treatment Outcomes: Results from the National Dental PBRN. AB - Dentinal hypersensitivity (DH) can have a significant impact on oral health and functioning, and it is a clinical symptom commonly managed by dentists during routine clinical practice. DH symptoms are typically elicited by otherwise innocuous, nonpainful stimuli applied to exposed dentin (e.g., tactile stimuli, warming or cooling temperatures or air puffs). Treatment approaches have sought to directly target the dentinal pulp tissues or close dentinal tubules via dental office care and treatment services (fluoride varnishes, glutaraldehydes, bonding agents, sealants, oxalates, or lasers) or home care services (toothpastes or dentifrices containing fluoride or potassium nitrate compounds). The purpose of this prospective multicenter cohort study was to assess how community-based dentists from the National Dental Practice-Based Research Network (National Dental PBRN) manage DH and whether the effectiveness of DH treatments can be assessed in those settings. A total of 171 dentists recruited 1862 subjects with DH from their existing patients. Dentists then recommended and provided DH treatment as appropriate. Treatment choice was at the discretion of the dentists. Patients rated their DH pain at baseline and 1, 4, and 8 wk during the course of their treatments. They used pain intensity and unpleasantness visual analog scales and 4 labeled magnitude scales and rated their satisfaction with treatment after 8 wk. Patients were provided reminders postbaseline via email, texting, or voice mail. These patient-centered outcomes served as the principal measures for the assessment of treatment because treatments sought to alleviate DH symptoms. The patients with DH who reported pain reduction from dentist-provided treatments (glutaraldehyde/HEMA [hydroxyethyl methacrylate] compounds, oxalates, and bonding agents), dentists' advice and counseling regarding oral habits and diet, and patient-applied fluoride toothpaste reported a concomitant positive rating of satisfaction with DH treatments. The results from this study support the feasibility of engaging network practices to assess the effectiveness of clinical DH treatments. Knowledge Transfer Statement: National Dental PBRN dentists provide a range of procedures to treat dentinal hypersensitivity. In this large nonrandomized study designed to assess clinical care and to capture patient reported outcomes, about 60% of patients reported improvement in pain. This study demonstrated the feasibility of engaging network dentists and their patients to assess treatment effectiveness. Future studies will explore the feasibility of imposing randomization and measuring patient compliance with treatment in the manner that this treatment is provided. PMID- 29276778 TI - Maternal Factors Associated with Early Childhood Caries in Urban Latino Children. AB - The objective of this investigation was to describe maternal psychosocial, behavioral, and acculturation factors associated with early childhood caries in a sample of urban Latino mother-child dyads. A cross-sectional survey was conducted with 100 mothers whose children (under the age of 6 y) were patients at the Dental Center at Children's Hospital Colorado in Aurora, Colorado. All children participating in the study received an oral examination to measure decayed, missing, filled, surfaces (dmfs). Participating mothers were given the option to sign the consent form and complete the survey in English or Spanish, according to their preferred language. The survey used demographic, behavioral, knowledge, and several psychosocial variables. Bivariate analysis was conducted with dmfs as a dependent variable. The associations between independent variables and dmfs were modeled using negative binomial regression. Mean +/- SD dmfs for the entire sample was about 11 +/- 16.85. The mothers who spoke Spanish had children with significantly (P = 0.046) higher dmfs scores (15.2) compared to mothers who spoke English (7.56). Preference of Spanish language was significantly associated with self-efficacy (P = 0.0043), oral health knowledge (P = 0.0024), and 3 subscales of the health belief model: perceived severity (P = 0.057), perceived barriers (P = 0.0002), and perceived susceptibility (P = 0.008). Both in the univariate and the multivariate models, oral health behavior and preferential use of Spanish remained significantly associated with higher dmfs scores. Results of this study demonstrate that maternal oral health behaviors and preferred language are significant factors associated with early childhood caries in urban Latino children. Knowledge Transfer Statement: Results of this study indicate that maternal oral health behaviors and the level of acculturation are significantly associated with caries in urban Latino children. Caries prevention efforts in this population could use this information to tailor oral health messaging according to the level of acculturation in mothers. PMID- 29276779 TI - The Effects of Medical Well Baby Visits in Promoting Earlier First Dental Visits for Children. AB - The objective of the study was to assess the effects of medical well baby visits in promoting earlier first dental visits. We analyzed Iowa Medicaid claims data (2000-2013). The sample included 4 cohorts of children born in 2000, 2003, 2007, or 2010 and enrolled in Medicaid from birth (N = 38,211). Children were followed for 3 y. The independent variables were cohort year and medical well baby visit frequency during 3 time periods (birth to age 10 mo, ages 11-19 mo, ages 20-36 mo). We used survival analyses to estimate first dental visit rates. First dental visit rates improved significantly from 2000 to 2013, with children in latter cohorts having significantly earlier first dental visits. Children with more medical well baby visits before age 11 mo had significantly delayed first dental visit rates than children with fewer medical well baby visits. The opposite was observed for children with more medical well baby visits between ages 11 to 19 mo and ages 20 to 36 mo. First dental visit rates for Medicaid-enrolled children have improved, but there continues to be a need for early interventions to improve age 1 dental visits and other preventive oral health behaviors. Knowledge Transfer Statement: The results of this study can be used by policy makers when developing strategies to improve access to dental care for young children in Medicaid. With consideration to promoting earlier preventive dental visits for publicly insured children, this study could lead to early interventions and improved health outcomes. PMID- 29276780 TI - The role of epigenomics in personalized medicine. AB - Introduction: Epigenetics is the study of reversible modifications to chromatin and their extensive and profound effects on gene regulation. To date, the role of epigenetics in personalized medicine has been under-explored. Therefore, this review aims to highlight the vast potential that epigenetics holds. Areas covered: We first review the cell-specific nature of epigenetic states and how these can vary with developmental stage and in response to environmental factors. We then summarize epigenetic biomarkers of disease, with a focus on diagnostic tests, followed by a detailed description of current and pipeline drugs with epigenetic modes of action. Finally, we discuss epigenetic biomarkers of drug response. Expert commentary: Epigenetic variation can yield information on cellular states and developmental histories in ways that genotype information cannot. Furthermore, in contrast to fixed genome sequence, epigenetic patterns are plastic, so correcting aberrant, disease-causing epigenetic marks holds considerable therapeutic promise. While just six epigenetic drugs are currently approved for use in the United States, a larger number is being developed. However, a drawback to current therapeutics is their non-specific effects. Development of locus-specific epigenetic modifiers, used in conjunction with epigenetic biomarkers of response, will enable truly precision interventions. PMID- 29276781 TI - Recent progress in the use and tracking of transplanted islets as a personalized treatment for type 1 diabetes. AB - Introduction: Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the pancreas produces insufficient amounts of insulin. T1DM patients require exogenous sources of insulin to maintain euglycemia. Transplantation of naked or microencapsulated pancreatic islets represents an alternative paradigm to obtain an autonomous regulation of blood glucose levels in a controlled and personalized fashion. However, once transplanted, the fate of these personalized cellular therapeutics is largely unknown, justifying the development of non-invasive tracking techniques. Areas covered: In vivo imaging of naked pancreatic islet transplantation, monitoring of microencapsulated islet transplantation, visualizing pancreatic inflammation, imaging of molecular-genetic therapeutics, imaging of beta cell function. Expert commentary: There are still several hurdles to overcome before (microencapsulated) islet cell transplantation will become a mainstay therapy. Non-invasive imaging methods that can track graft volume, graft rejection, graft function (insulin secretion) microcapsule engraftment, microcapsule rupture, and pancreatic inflammation are currently being developed to design the best experimental transplantation paradigms. PMID- 29276783 TI - A method for the efficient and selective identification of 5-hydroxymethyluracil in genomic DNA. AB - Recently, 5-hydroxymethyluracil (5hmU) was identified in mammalian genomic DNA as an oxidative product of thymine by the ten-eleven translocation (TET) proteins. While the biological role of this modification remains unclear, identifying its genomic location will assist in elucidating function. Here we present a rapid and robust method to selectively tag and enrich genomic regions containing 5hmU. This method involves the selective glucosylation of 5hmU residues by the base J glucosyltransferase from trypanosomes creating glucosylhydroxymethyluracil (base J). The base J can then be efficiently and selectively pulled down by antibodies against base J or by J-binding protein 1. DNA that is enriched is suitable for analysis by quantitative PCR or sequencing. We utilized this tagging reaction to provide proof of concept for the enrichment of 5hmU containing DNA from a pool that contains modified and unmodified DNA. Furthermore, we demonstrate that the base J pull-down assay identifies 5hmU at specific regions of the trypanosome genome involved in transcriptional repression. The method described here will allow for a greater understanding of the functional role and dynamics of 5hmU in biology. PMID- 29276782 TI - Stemness-Related Markers in Cancer. AB - Cancer stem cells (CSCs), with their self-renewal ability and multilineage differentiation potential, are a critical subpopulation of tumor cells that can drive tumor initiation, growth, and resistance to therapy. Like embryonic and adult stem cells, CSCs express markers that are not expressed in normal somatic cells and are thus thought to contribute towards a 'stemness' phenotype. This review summarizes the current knowledge of stemness-related markers in human cancers, with a particular focus on important transcription factors, protein surface markers and signaling pathways. PMID- 29276785 TI - Mycobacterium abscessus disease in lung transplant recipients: Diagnosis and management. AB - Mycobacterium abscessus complex (MAbsC ) disease in lung transplant recipients is increasingly being recognized as an important cause of graft function decline and suboptimal outcomes. Lung transplant recipients appear to be at the highest risk of MAbsC among solid organ transplant recipients, as they have more intense immunosuppression, and the organisms preferentially inhabit the lungs. MAbsC is the most resistant species of rapidly growing mycobacteria and difficult to treat, causing considerable mortality and morbidity in immunocompetent and immunosuppressed patients. Herein we describe the risk factors, epidemiology, clinical features, diagnostics, and treatment strategies of MAbsC in lung transplant recipients. PMID- 29276786 TI - Endovascular Treatment for a Ruptured Lumbar Artery Aneurysm in a Patient with von Recklinghausen Disease. AB - Introduction: Vasculopathy, such as an aneurysm, stenosis, rupture, or arteriovenous fistula, in patients with neurofibromatosis type I (NF-1; von Recklinghausen disease) is well recognised. However, there has been no report regarding treatment for a ruptured lumbar artery aneurysm associated with NF-1. We present the first report of successful endovascular treatment by coil embolisation for a ruptured lumbar artery aneurysm in a patient with NF-I. Report: A 52 year old man with a history of NF-1 was referred with back pain and anaemia. The computed tomography scan showed rupture of a solitary lumbar artery aneurysm. The rupture was successfully treated by endovascular embolisation with a coil and N-butyl-2-cyanoacrylate. Discussion: Endovascular treatment with coil embolisation was performed safely in this patient. PMID- 29276784 TI - Two-dimensional digital photography for child body posture evaluation: standardized technique, reliable parameters and normative data for age 7-10 years. AB - Background: Digital photogrammetry provides measurements of body angles or distances which allow for quantitative posture assessment with or without the use of external markers. It is becoming an increasingly popular tool for the assessment of the musculoskeletal system. The aim of this paper is to present a structured method for the analysis of posture and its changes using a standardized digital photography technique. Material and methods: The purpose of the study was twofold. The first one comprised 91 children (44 girls and 47 boys) aged 7-10 (8.2 +/- 1.0), i.e., students of primary school, and its aim was to develop the photographic method, choose the quantitative parameters, and determine the intraobserver reliability (repeatability) along with the interobserver reliability (reproducibility) measurements in sagittal plane using digital photography, as well as to compare the Rippstein plurimeter and digital photography measurements. The second one involved 7782 children (3804 girls, 3978 boys) aged 7-10 (8.4 +/- 0.5), who underwent digital photography postural screening. The methods consisted in measuring and calculating selected parameters, establishing the normal ranges of photographic parameters, presenting percentile charts, as well as noticing common pitfalls and possible sources of errors in digital photography. Results: A standardized procedure for the photographic evaluation of child body posture was presented. The photographic measurements revealed very good intra- and inter-rater reliability regarding the five sagittal parameters and good reliability performed against Rippstein plurimeter measurements. The parameters displayed insignificant variability over time. Normative data were calculated based on photographic assessment, while the percentile charts were provided to serve as reference values. The technical errors observed during photogrammetry are carefully discussed in this article. Conclusions: Technical developments are allowed for the regular use of digital photogrammetry in body posture assessment. Specific child positioning (described above) enables us to avoid incidentally modified posture. Image registration is simple, quick, harmless, and cost-effective. The semi-automatic image analysis, together with the normal values and percentile charts, makes the technique reliable in terms of child's posture documentation and corrective therapy effects' monitoring. PMID- 29276787 TI - Late Disruption of a Polyethylene Terephthalate Aortic Graft 30 Years after Initial Graft Placement. AB - A 71 year old male who had undergone extra-anatomic bypass grafting between the ascending aorta and the thoraco-abdominal aorta at 41 years of age for aortic coarctation was admitted with back pain and dyspnea. A 16 mm Cooley double velour knitted polyethylene terephthalate (PET) graft was used in the initial operation in 1983. Computed tomography showed disruption of the initial PET graft perforating the right atrium, and a pseudoaneurysm at the distal anastomosis. The patient was in acute cardiac failure because of left to right shunting. A two stage operation was performed. The first stage comprised emergency re-grafting and right atrium repair, and the second stage re-grafting for the pseudoaneurysm. The patient is doing well 48 months post-operatively; however, monitoring of the patient will continue for potential PET graft rupture. PMID- 29276788 TI - A Role for Soluble IL-6 Receptor in Osteoarthritis. AB - Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane bound IL-6 receptor (mIL-6Ralpha), also known as the "classical" IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the "trans signaling" pathway. Activation of downstream signaling is transduced via these IL 6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The "shedding" of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation. PMID- 29276789 TI - Ras signaling in aging and metabolic regulation. AB - Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline. PMID- 29276791 TI - The Geometric Framework for Nutrition as a tool in precision medicine. AB - Fundamental questions in nutrition include, "What constitutes a nutritionally balanced diet?", "What are the consequences of failing to achieve diet balance?", and "How does diet balance change across the lifecourse and with individual circumstances?". Answering these questions requires coming to grips with the multidimensionality and dynamic nature of nutritional requirements, foods and diets, and the complex relationships between nutrition and health, while at the same time avoiding becoming overwhelmed by complexity. Here we illustrate the use of an integrating framework for taming the complexity of nutrition, the Geometric Framework for Nutrition (GFN), and show how this might be used to untap the full potential for nutrition to provide targeted primary interventions and treatments for the chronic diseases of aging. We first briefly introduce the concepts behind GFN, then provide an example of how GFN has been used to relate nutrition to various behavioural, physiological and health outcomes in a large mouse experiment, and end by suggesting a translational pathway to human health. PMID- 29276790 TI - A central role for hypoxia-inducible factor (HIF)-2alpha in hepatic glucose homeostasis. AB - Hepatic glucose production is regulated by hormonal and dietary factors. At fasting, 80% of glucose released into the circulation is derived from the liver, among which gluconeogenesis accounts for 55% and the rest by glycogenolysis. Studies suggest a complex mechanism involved in the regulation of hepatic glucose metabolism during fasting and post-absorptive phase. Oxygen plays a key role in numerous metabolic pathways such as TCA cycle, gluconeogenesis, glycolysis and fatty acid oxidation. Oxygenation of the gastrointestinal tract including liver and intestine is dynamically regulated by changes in the blood flow and metabolic activity. Cellular adaptation to low oxygen is mediated by the transcription factors HIF-1alpha and HIF-2alpha. HIF-1alpha regulates glycolytic genes whereas HIF-2alpha is known to primarily regulate genes involved in cell proliferation and iron metabolism. This review focuses on the role of the oxygen sensing signaling in the regulation of hepatic glucose output with an emphasis on hypoxia inducible factor (HIF)-2alpha. Recent studies have established a metabolic role of HIF-2alpha in systemic glucose homeostasis. Understanding the HIF-2alpha dependent mechanism in hepatic metabolism will greatly enhance our potential to utilize the oxygen sensing mechanisms to treat metabolic diseases. PMID- 29276792 TI - Hydration health literacy in the elderly. AB - BACKGROUND: Inadequate hydration in the elderly is associated with increased morbidity and mortality. However, few studies have addressed the knowledge of elderly individuals regarding hydration in health and disease. Gaps in health literacy have been identified as a critical component in health maintenance, and promoting health literacy should improve outcomes related to hydration associated illnesses in the elderly. METHODS: We administered an anonymous survey to community-dwelling elderly (n = 170) to gauge their hydration knowledge. RESULTS: About 56% of respondents reported consuming >6 glasses of fluid/day, whereas 9% reported drinking <=3 glasses. About 60% of respondents overestimated the amount of fluid loss at which moderately severe dehydration symptoms occur, and 60% did not know fever can cause dehydration. Roughly 1/3 were not aware that fluid overload occurs in heart failure (35%) or kidney failure (32%). A majority of respondents were not aware that improper hydration or changes in hydration status can result in confusion, seizures, or death. CONCLUSIONS: Overall, our study demonstrated that there were significant deficiencies in hydration health literacy among elderly. Appropriate education and attention to hydration may improve quality of life, reduce hospitalizations and the economic burden related to hydration-associated morbidity and mortality. PMID- 29276793 TI - Short-term consumption of a plant protein diet does not improve glucose homeostasis of young C57BL/6J mice. AB - Recently, it has become apparent that dietary macronutrient composition has a profound impact on metabolism, health and even lifespan. Work from many laboratories now suggest that dietary protein quality - the precise amino acid composition of the diet, as well as possibly the source of dietary protein - may also be critical in regulating the impact of diet on health. Perhaps in part due to the naturally low methionine content of plants, vegan diets are associated with a decreased risk of diabetes and improved insulin sensitivity, but this association is confounded by the lower overall protein intake of vegans. Here, we test the effect of consuming isocaloric rodent diets with similar amino acid profiles derived from either plant protein or dairy protein. We find that male C57BL/6J mice consuming either diet have similar glycemic control, as assessed by glucose, insulin, and pyruvate tolerance tests, and have similar overall body composition. We conclude that short-term feeding of plant protein has no positive or negative effect on the metabolic health of young male C57BL/6J mice, and suggest that dietary interventions that alter either dietary protein levels or the levels of specific essential amino acids are more likely to improve metabolic health than alterations in dietary protein source. PMID- 29276794 TI - The role of dietary patterns and exceptional parental longevity in healthy aging. AB - BACKGROUND: Individuals with exceptional longevity and their offspring manifest a lower prevalence of age-related diseases than families without longevity. However, the contribution of dietary habits to protection from disease has not been systematically assessed in families with exceptional longevity. OBJECTIVE: The aim of this study is to compare dietary patterns between individuals with parental longevity and individals without parental longevity. METHODS: Dietary intake was evaluated using the Block Brief Food Frequency Questionnaire in 234 community dwelling Ashkenazi Jewish adults aged 65 years and older who were participants of the LonGenity study, which enrolls the offspring of parents with exceptional longevity (OPEL) and offspring of parents with usual survival (OPUS). RESULTS: OPEL constituted 38% of the subjects. The two groups had similar daily intake of total calories (1119 vs. 1218 kcal, p = 0.83), grams of cholesterol (141 g vs. 143 g, p = 0.19), and grams of sodium (1324 g vs.1475 g, p = 0.45), in OPEL vs. OPUS respectively. There were also no significant differences in the intake of other macronutrients, micronutrients, nutritional supplements and consumption of various food groups between OPEL and OPUS after adjustment for age and sex. DISCUSSION: A healthy diet is associated with a lower risk of several chronic diseases. Our study revealed that dietary intake did not differ between OPEL and OPUS; thus, pointing to the role of longevity genes in protecting from disease among individuals with familial longevity. CONCLUSION: The offspring of long-lived parents do not differ in their dietary patterns compared to individuals without parental longevity. PMID- 29276795 TI - Effect of alternate day fasting on markers of bone metabolism: An exploratory analysis of a 6-month randomized controlled trial. AB - BACKGROUND: Alternate day fasting (ADF) is a novel diet therapy that reduces body weight, but its effect on bone health remains unknown. OBJECTIVE: This study examined the impact of ADF versus traditional daily calorie restriction (CR) on markers of bone metabolism in a 6-month randomized controlled trial. METHODS: Overweight and obese subjects (n = 100) were randomized to 1 of 3 groups for 6 months: 1) ADF (25% energy intake fast day, alternated with 125% intake feast day; 2) CR (75% intake every day); or 3) control (usual intake every day). RESULTS: Body weight decreased similarly (P < 0.001) by ADF (-7.8+/-1.2%) and CR (-8.8+/-1.5%), relative to controls by month 6. Lean mass, total body bone mineral content and total body bone mineral density remained unchanged in all groups. Circulating osteocalcin, bone alkaline phosphatase, and C-terminal telopeptide type I collagen (CTX) did not change in any group. IGF-1 increased (P < 0.01) in the CR group, with no change in the ADF or control group. When the data were sub-analyzed according to menopausal status, there were no differences between premenopausal or postmenopausal women for any marker of bone metabolism. CONCLUSION: These findings suggest that 6 months of ADF does not have any deleterious impact on markers of bone metabolism in obese adults with moderate weight loss. PMID- 29276796 TI - Clinical Trials Corner. PMID- 29276798 TI - A Time-Walk Correction Method for PET Detectors Based on Leading Edge Discriminators. AB - The leading edge timing pick-off technique is the simplest timing extraction method for PET detectors. Due to the inherent time-walk of the leading edge technique, corrections should be made to improve timing resolution, especially for time-of-flight PET. Time-walk correction can be done by utilizing the relationship between the threshold crossing time and the event energy on an event by event basis. In this paper, a time-walk correction method is proposed and evaluated using timing information from two identical detectors both using leading edge discriminators. This differs from other techniques that use an external dedicated reference detector, such as a fast PMT-based detector using constant fraction techniques to pick-off timing information. In our proposed method, one detector was used as reference detector to correct the time-walk of the other detector. Time-walk in the reference detector was minimized by using events within a small energy window (508.5 - 513.5 keV). To validate this method, a coincidence detector pair was assembled using two SensL MicroFB SiPMs and two 2.5 mm * 2.5 mm * 20 mm polished LYSO crystals. Coincidence timing resolutions using different time pick-off techniques were obtained at a bias voltage of 27.5 V and a fixed temperature of 20 degrees C. The coincidence timing resolution without time-walk correction were 389.0 +/- 12.0 ps (425 -650 keV energy window) and 670.2 +/- 16.2 ps (250-750 keV energy window). The timing resolution with time-walk correction improved to 367.3 +/- 0.5 ps (425 - 650 keV) and 413.7 +/- 0.9 ps (250 - 750 keV). For comparison, timing resolutions were 442.8 +/- 12.8 ps (425 - 650 keV) and 476.0 +/- 13.0 ps (250 - 750 keV) using constant fraction techniques, and 367.3 +/- 0.4 ps (425 - 650 keV) and 413.4 +/- 0.9 ps (250 - 750 keV) using a reference detector based on the constant fraction technique. These results show that the proposed leading edge based time-walk correction method works well. Timing resolution obtained using this method was equivalent to that obtained using a reference detector and was better than that obtained using constant fraction discriminators. PMID- 29276797 TI - Genetic and epigenetic determinants of inter-individual variability in responses to toxicants. AB - It is well established that genetic variability has a major impact on susceptibility to common diseases, responses to drugs and toxicants, and influences disease-related outcomes. The appreciation that epigenetic marks also vary across the population is growing with more data becoming available from studies in humans and model organisms. In addition, the links between genetic variability, toxicity outcomes and epigenetics are being actively explored. Recent studies demonstrate that gene-by-environment interactions involve both chromatin states and transcriptional regulation, and that epigenetics provides important mechanistic clues to connect expression-related quantitative trait loci (QTL) and disease outcomes. However, studies of Gene*Environment*Epigenetics further extend the complexity of the experimental designs and create a challenge for selecting the most informative epigenetic readouts that can be feasibly performed to interrogate multiple individuals, exposures, tissue types and toxicity phenotypes. We propose that among the many possible epigenetic experimental methodologies, assessment of chromatin accessibility coupled with total RNA levels provides a cost-effective and comprehensive option to sufficiently characterize the complexity of epigenetic and regulatory activity in the context of understanding the inter-individual variability in responses to toxicants. PMID- 29276799 TI - Optimization of an Adaptive SPECT System with the Scanning Linear Estimator. AB - A method for optimization of an adaptive Single Photon Emission Computed Tomography (SPECT) system is presented. Adaptive imaging systems can quickly change their hardware configuration in response to data being generated in order to improve image quality for a specific task. In this work we simulate an adaptive SPECT system and propose a method for finding the adaptation that maximizes the performance on a signal estimation task. To start with, a simulated object model containing a spherical signal is imaged with a scout configuration. A Markov-Chain Monte Carlo (MCMC) technique utilizes the scout data to generate an ensemble of possible objects consistent with the scout data. This object ensemble is imaged by numerous simulated hardware configurations and for each system estimates of signal activity, size and location are calculated via the Scanning Linear Estimator (SLE). A figure of merit, based on a Modified Dice Index (MDI), quantifies the performance of each imaging configuration and it allows for optimization of the adaptive SPECT. This figure of merit is calculated by multiplying two terms: the first term uses the definition of the Dice similarity index to determine the percent of overlap between the actual and the estimated spherical signal, the second term utilizes an exponential function that measures the squared error for the activity estimate. The MDI combines the error in estimates of activity, size, and location, in one convenient metric and it allows for simultaneous optimization of the SPECT system with respect to all the estimated signal parameters. The results of our optimizations indicate that the adaptive system performs better than a non-adaptive one in conditions where the diagnostic scan has a low photon count - on the order of thousand photons per projection. In a statistical study, we optimized the SPECT system for one hundred unique objects and demonstrated that the average MDI on an estimation task is 0.84 for the adaptive system and 0.65 for the non-adaptive system. PMID- 29276800 TI - Using Facebook as a Platform to Direct Young Black Men Who Have Sex With Men to a Video-Based HIV Testing Intervention: A Feasibility Study. AB - Objective: A randomized control pilot study was conducted with Black men who have sex with men (BMSM; N = 42) aged 18-30 years to examine the feasibility of implementing a video intervention delivered using Facebook to motivate HIV testing. Methods: At baseline, participants were unaware of their HIV status and had not tested for HIV in the past 6 months, residing in Los Angeles County. The intervention content included topics such as social influence, HIV knowledge, stigma, HIV positive knowledge, and benefits of knowing one's HIV status. Findings: Logistic regression revealed that those receiving the video intervention were 7 times more likely to have tested for HIV than those in the control group at 6-week follow-up (odds ratio [OR] = 7.00, 95% confidence interval [1.72, 28.33], p = .006). Conclusion: Data suggest that the intervention was feasible for motivating HIV testing. PMID- 29276801 TI - Psychological Well-Being and Type 2 Diabetes. AB - Positive psychological characteristics such as optimism, positive affect, gratitude, and related constructs may play an important role in health. In patients with type 2 diabetes (T2D), positive psychological constructs have been associated with superior medical outcomes, including better glucose control and lower mortality rates. The beneficial effects of positive psychological states in T2D are most likely mediated through health behaviors such as increased physical activity and adherence to a healthier diet. Furthermore, numerous studies with non-diabetic populations have shown that performing various positive psychological exercises (e.g., writing gratitude letters, performing acts of kindness) have led to greater well-being. Compared to other available treatments, these activities are simple and involve constructs that have been associated with superior adherence and diabetes-related outcomes. However, there has been minimal research on the use of positive psychological interventions in T2D, though small studies of related interventions have been linked to improvements in positive affect and, in some cases, greater health behavior adherence and lower blood sugar. Continued work is needed to ascertain whether positive psychology interventions can truly impact functioning, blood sugar, and overall health in this key population. PMID- 29276802 TI - Comparison of Tissue Stiffness Using Shear Wave Elastography in Men with Normal Testicular Tissue, Testicular Microlithiasis and Testicular Cancer. AB - Objectives: To compare elastography measurements in men with normal testicular tissue, testicular microlithiasis and testicular cancer. Methods: A total of 248 consecutive patients were included. All men provided written informed consent. Testicular stiffness was assessed using shear wave elastography (SWE). Three SWE velocity measurements were assessed in each testicle. The patients were divided into three groups; men with normal testicular tissue (n=130), men with testicular microlithiasis (n=99) and men with testicular cancer (n=19). Results: We found a higher mean velocity in the group of patients with testicular cancer (1.92 m/s (95% CI 1.82-2.03)) compared to both the group with normal tissue (0.76 m/s (95% CI: 0.75-0.78)) (p<0.001) and the group with testicular microlithiasis 0.79 m/s (95% CI: 0.77-0.81) (p<0.001). Conclusion: The presence of testicular microlithiasis increased stiffness slightly, but within the range of variation in normal testicles. Increased stiffness may indicate testicular malignancy in testicular lesions. Ultrasound elastography could be a very useful tool when investigating scrotum. PMID- 29276804 TI - How First-year Students Expressed Their Transition to College Experiences Differently Depending on the Affordances of Two Writing Contexts. AB - Drawing on theory that positions writing as a social process, this study compares how two distinct contexts influenced the linguistic features of college students' writing over time. In one context, students blogged and received comments, while in the other context students word-processed and received no comments. Systematic qualitative and quantitative analyses of these natural language posts and comments indicated the bloggers used greater rates of cognitive and intensifying expressions in their writing over time than students who word-processed. These results suggest that the affordances of the context influenced narrators' expressive writing over time. The current findings have significance for scholars seeking to understand connections between interactive media, writing processes, and audience, and for college programs across the U.S. that provide support for first-year students. PMID- 29276803 TI - Projections of temperature-related excess mortality under climate change scenarios. AB - Background: Climate change can directly affect human health by varying exposure to non-optimal outdoor temperature. However, evidence on this direct impact at a global scale is limited, mainly due to issues in modelling and projecting complex and highly heterogeneous epidemiological relationships across different populations and climates. Methods: We collected observed daily time series of mean temperature and mortality counts for all causes or non-external causes only, in periods ranging from Jan 1, 1984, to Dec 31, 2015, from various locations across the globe through the Multi-Country Multi-City Collaborative Research Network. We estimated temperature-mortality relationships through a two-stage time series design. We generated current and future daily mean temperature series under four scenarios of climate change, determined by varying trajectories of greenhouse gas emissions, using five general circulation models. We projected excess mortality for cold and heat and their net change in 1990-2099 under each scenario of climate change, assuming no adaptation or population changes. Findings: Our dataset comprised 451 locations in 23 countries across nine regions of the world, including 85 879 895 deaths. Results indicate, on average, a net increase in temperature-related excess mortality under high-emission scenarios, although with important geographical differences. In temperate areas such as northern Europe, east Asia, and Australia, the less intense warming and large decrease in cold-related excess would induce a null or marginally negative net effect, with the net change in 2090-99 compared with 2010-19 ranging from -1.2% (empirical 95% CI -3.6 to 1.4) in Australia to -0.1% (-2.1 to 1.6) in east Asia under the highest emission scenario, although the decreasing trends would reverse during the course of the century. Conversely, warmer regions, such as the central and southern parts of America or Europe, and especially southeast Asia, would experience a sharp surge in heat-related impacts and extremely large net increases, with the net change at the end of the century ranging from 3.0% (-3.0 to 9.3) in Central America to 12.7% (-4.7 to 28.1) in southeast Asia under the highest emission scenario. Most of the health effects directly due to temperature increase could be avoided under scenarios involving mitigation strategies to limit emissions and further warming of the planet. Interpretation: This study shows the negative health impacts of climate change that, under high-emission scenarios, would disproportionately affect warmer and poorer regions of the world. Comparison with lower emission scenarios emphasises the importance of mitigation policies for limiting global warming and reducing the associated health risks. Funding: UK Medical Research Council. PMID- 29276805 TI - Comparative Expression Analysis of Cytochrome P450 1A1, Cytochrome P450 1B1 and Nuclear Receptors in the Female Genital and Colorectal Tissues of Human and Pigtailed Macaque. AB - This manuscript summarizes our recent progress in examine the CYP1A1 and CYP1B1 as well as a number of nuclear receptors in the female genital and colorectal tissues of human and pigtailed macaque. Understanding the nuclear receptor mediated regulation of CYP1A1 and 1B1 expression in these tissues is necessary for identifying cancer risk factors and developing CYP1A1/1B1-targeted anti cancer therapeutics. However, there is a lack of systematic and comparative analysis of the expression profile of CYP1A1, 1B1 and NRs in the female genital and colorectal tissues of human and clinically relevant animal models. The current study aims to fill this gap. We found CYP1A1, CYP1B1 and a number of nuclear receptors were expressed in the female genital and colorectal tissues of human and macaque. However, the mRNA level and protein localization of these CYP enzymes and NRs depended on the type of tissue examined. Cytochrome P450 (CYP) 1A1 and CYP1B1 activate hormonal and environmental procarcinogens, and are associated with carcinogenesis in female genital and colorectal tissues. Understanding the nuclear receptor (NR) mediated regulation of CYP expression in these tissues is necessary for identifying cancer risk factors and developing CYP1A1/1B1-targeted anti-cancer therapeutics. The study aims to analyze the expression profile of CYP1A1, 1B1 and NRs in the female genital and colorectal tissues of human and pigtailed macaques. We found that compared to the liver, human CYP1A1 mRNA level in the genital and colorectal tissues was significantly lower, while the CYP1B1 level was significantly higher. CYP1A1 protein was mainly localized in the plasma membrane of the uterine and endocervical epithelial cells. The CYP1B1 protein was concentrated in the nucleus of genital and colorectal tissues. Fourteen NRs in the genital tract and 12 NRs in colorectal tissue were expressed at levels similar to or higher than the liver. The expression and localization of CYP1A1, CYP1B1, and NRs in macaque tissues were usually comparable to those of human tissues. In addition, menopause did not significantly alter the ectocervical mRNA levels of CYP1A1, CYP1B1, or NRs. PMID- 29276806 TI - 3-D endoscopic imaging using plenoptic camera. AB - Three-dimensional endoscopic imaging using plenoptic technique combined with F matching algorithm has been pursued in this study. A custom relay optics was designed to integrate a commercial surgical straight endoscope with a plenoptic camera. PMID- 29276807 TI - DAVE: Detecting Agitated Vocal Events. AB - DAVE is a comprehensive set of event detection techniques to monitor and detect 5 important verbal agitations: asking for help, verbal sexual advances, questions, cursing, and talking with repetitive sentences. The novelty of DAVE includes combining acoustic signal processing with three different text mining paradigms to detect verbal events (asking for help, verbal sexual advances, and questions) which need both lexical content and acoustic variations to produce accurate results. To detect cursing and talking with repetitive sentences we extend word sense disambiguation and sequential pattern mining algorithms. The solutions have applicability to monitoring dementia patients, for online video sharing applications, human computer interaction (HCI) systems, home safety, and other health care applications. A comprehensive performance evaluation across multiple domains includes audio clips collected from 34 real dementia patients, audio data from controlled environments, movies and Youtube clips, online data repositories, and healthy residents in real homes. The results show significant improvement over baselines and high accuracy for all 5 vocal events. PMID- 29276808 TI - Efficient Groupwise Registration for Brain MRI by Fast Initialization. AB - Groupwise image registration provides an unbiased registration solution upon a population of images, which can facilitate the subsequent population analysis. However, it is generally computationally expensive for performing groupwise registration on a large set of images. To alleviate this issue, we propose to utilize a fast initialization technique for speeding up the groupwise registration. Our main idea is to generate a set of simulated brain MRI samples with known deformations to their group center. This can be achieved in the training stage by two steps. First, a set of training brain MR images is registered to their group center with a certain existing groupwise registration method. Then, in order to augment the samples, we perform PCA on the set of obtained deformation fields (to the group center) to parameterize the deformation fields. In doing so, we can generate a large number of deformation fields, as well as their respective simulated samples using different parameters for PCA. In the application stage, when given a new set of testing brain MR images, we can mix them with the augmented training samples. Then, for each testing image, we can find its closest sample in the augmented training dataset for fast estimating its deformation field to the group center of the training set. In this way, a tentative group center of the testing image set can be immediately estimated, and the deformation field of each testing image to this estimated group center can be obtained. With this fast initialization for groupwise registration of testing images, we can finally use an existing groupwise registration method to quickly refine the groupwise registration results. Experimental results on ADNI dataset show the significantly improved computational efficiency and competitive registration accuracy, compared to state-of-the-art groupwise registration methods. PMID- 29276809 TI - New Advances in Human X chromosome status from a Developmental and Stem Cell Biology. AB - Recent advances in stem cell biology have dramatically increased the understanding of molecular and cellular mechanism of pluripotency and cell fate determination. Additionally, pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), arose as essential resources for disease modeling and cellular therapeutics. Despite these advancements, the epigenetic dysregulation in pluripotency such as the imprinting status, and X chromosome dosage compensation, and its consequences on future utility of PSCs yet remain unresolved. In this review, we will focus on the X chromosome regulation in human PSCs (hPSCs). We will introduce the previous findings in the dosage compensation process on mouse model, and make comparison with those of human systems. Particularly, the biallelic X chromosome activation status of human preimplantation embryos, and the regulation of the active X chromosome by human specific lincRNA, XACT, will be discussed. We will also discuss the recent findings on higher order X chromosome architecture utilizing Hi-C, and abnormal X chromosome status in hPSCs. PMID- 29276810 TI - Metalation Control of Open-Shell Character in meso-meso Linked Porphyrin meso-Oxy Radical Dimers. AB - Control of open-shell character of meso-meso linked porphyrin meso-oxy radical dimers has been demonstrated by core metalation. Namely, NiII -porphyrin dimer 6Ni exhibits a clear 1 H NMR spectrum and a distorted but rather coplanar quinonoidal structure consisting of two ruffled porphyrin rings, in accordance with the previous report. Freebase dimer 6H2 shows a similar quinonoidal structure in the solid state but displays slightly broader and temperature dependent 1 H NMR spectra, indicating a partial diradical character in solution that increases at high temperature. In sharp contrast, bis-imidazole-coordinated ZnII -porphyrin dimer 6ZnIm2 exhibits a perpendicular structure consisting of two planar ZnII -porphyrins and has been characterized as a distinct open-shell diradical on the basis of its non-observable 1 H NMR signals, a clear ESR signal, and a characteristic absorption spectrum reaching about 1700 nm. Despite the distinct diradical character, 6ZnIm2 is an extremely stable molecule. PMID- 29276811 TI - Mechanistic Insights into Hydrogen Activation by Frustrated N/Sn Lewis Pairs. AB - The mechanism of H2 activation by recently reported N/Sn Lewis pairs is unravelled using the representative iPr3 SnOTf/DABCO combination. Computations provide evidence for weak intermolecular associations between Lewis acid and Lewis base (LA/LB) in which the counteranion to cationic LA fragment plays a critical role. Two frustrated Lewis pairs (FLPs) are observed; an unprecedented counteranion-mediated noncovalent LA/LB association is characterised along with the usual FLP structure. Both the FLPs are shown to be capable of H2 activation through cooperative electron transfer processes involving the LA/LB centres. Overall, computed results are in good agreement with the experimental findings and account for the observed reactivity. Insights obtained in this study are fundamentally important for the rational design of Sn-based alternative FLP LAs. The present findings could also provide a general mechanistic framework for H2 activation by FLPs having an ion pair LA component. PMID- 29276812 TI - Stereoselective Construction of Halogenated Quaternary Carbon Centers by Bronsted Base Catalyzed [4+2] Cycloaddition of alpha-Haloaldehydes. AB - Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Bronsted base catalyzed [4+2] cycloaddition between either alpha-chloro- or alpha-bromoaldehydes and cyclic enones. The key intermediate, an alpha-halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen-bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner. PMID- 29276813 TI - Asymmetric Total Synthesis of (-)-Stemonamine and Its Stereochemical Stability. AB - The first asymmetric total synthesis of (-)-stemonamine is described. The key reactions included intramolecular acylation to construct the seven-membered ring and a tandem [2+2] cycloaddition-Dieckmann condensation reaction using an ynolate to form the fully substituted cyclopentenone moiety. Racemization and epimerization of the natural product were first experimentally demonstrated. PMID- 29276814 TI - Photooxidation of a Twisted Isoquinolinone. AB - Understanding the oxidation mechanism and positions of twistacenes and twistheteroacenes under ambient conditions is very important because such knowledge can guide us to design and synthesize novel, larger stable analogues. Herein, we demonstrated for the first time that a twisted isoquinolinone can decompose under oxygen and light at room temperature. The as-decomposed product 1 was fully characterized through conventional methods as well as single-crystal structure analysis. Moreover, the physical properties of the as-obtained product were carefully investigated and the possible formation mechanism was proposed. PMID- 29276815 TI - The Anticancer Potential of Peroxisome Proliferator-Activated Receptor Antagonists. AB - The effects on cancer-cell proliferation and differentiation mediated by peroxisome proliferator-activated receptors (PPARs) have been widely studied, and pleiotropic outcomes in different cancer models and under different experimental conditions have been obtained. Interestingly, few studies report and little preclinical evidence supports the potential antitumor activity of PPAR antagonists. This review focuses on recent findings on the antitumor in vitro and in vivo effects observed for compounds able to inhibit the three PPAR subtypes in different tumor models, providing a rationale for the use of PPAR antagonists in the treatment of tumors expressing the corresponding receptors. PMID- 29276816 TI - Tertiary-Alcohol-Directed Functionalization of Remote C(sp3 )-H Bonds by Sequential Hydrogen Atom and Heteroaryl Migrations. AB - Reported for the first time is a tertiary-alcohol-guided heteroarylation of remote C(sp3 )-H bonds. The mild and direct generation of alkoxyl radicals from alcohols is enabled by visible-light photocatalysis. A remote hydrogen atom and heteroaryl migration sequence are involved in the reaction. Many sensitive groups remain intact in the reaction, thus illustrating wide functional-group compatibility. This protocol provides a practical strategy for the late-stage modification of alkyl ketones. PMID- 29276817 TI - An Aluminum-Sulfur Battery with a Fast Kinetic Response. AB - The electrochemical performance of the aluminum-sulfur (Al-S) battery has very poor reversibility and a low charge/discharge current density owing to slow kinetic processes determined by an inevitable dissociation reaction from Al2 Cl7- to free Al3+ . Al2 Cl6 Br- was used instead of Al2 Cl7- as the dissociation reaction reagent. A 15-fold faster reaction rate of Al2 Cl6 Br- dissociation than that of Al2 Cl7- was confirmed by density function theory calculations and the Arrhenius equation. This accelerated dissociation reaction was experimentally verified by the increase of exchange current density during Al electro deposition. Using Al2 Cl6 Br- instead of Al2 Cl7- , a kinetically accelerated Al S battery has a sulfur utilization of more than 80 %, with at least four times the sulfur content and five times the current density than that of previous work. PMID- 29276818 TI - Tandem Molecular Self-Assembly in Liver Cancer Cells. AB - We herein describe the tandem molecular self-assembly of a peptide derivative (1) that is controlled by a combination of enzymatic and chemical reactions. In phosphate-buffered saline (PBS), compound 1 self-assembles first into nanoparticles by phosphatase and then into nanofibers by glutathione. Liver cancer cells exhibit higher concentrations of both phosphatase and GSH than normal cells. Therefore, the tandem self-assembly of 1 also occurs in the liver cancer cell lines HepG2 and QGY7703; compound 1 first forms nanoparticles around the cells and then forms nanofibers inside the cells. Owing to this self-assembly mechanism, compound 1 exhibits large ratios for cellular uptake and inhibition of cell viability between liver cancer cells and normal liver cells. We envision that using both extracellular and intracellular reactions to trigger tandem molecular self-assembly could lead to the development of supramolecular nanomaterials with improved performance in cancer diagnostics and therapy. PMID- 29276820 TI - Fuel-Free Bio-photoelectrochemical Cells Based on a Water/Oxygen Circulation System with a Ni:FeOOH/BiVO4 Photoanode. AB - A bio-photoelectrochemical cell (BPEC) based on a fuel-free self-circulation water-oxygen-water system was fabricated. It consists of Ni:FeOOH modified n-type bismuth vanadate (BiVO4 ) photoanode and laccase catalyzed biocathode. In this BPEC, irradiation of the photoanode generates photocurrent for photo-oxidation of water to oxygen, which is reduced to water again at the laccase biocathode. Of note, the by-products of two electrode reactions could continue to be reacted, which means the H2 O and O2 molecules are retained in an infinite loop of water oxygen-water without any sacrificial chemical components. As a result, the assembled fuel-free BPEC exhibits good performance with an open-circuit potential of 0.97 V and a maximum power density of 205 MUW cm-2 at 0.44 V. This BPEC based on a self-circulation system offers a fuel-free model to enhance multiple energy conversion and application in reality. PMID- 29276819 TI - Stabilization of the Reductase Domain in the Catalytically Self-Sufficient Cytochrome P450BM3 by Consensus-Guided Mutagenesis. AB - The multidomain, catalytically self-sufficient cytochrome P450 BM-3 from Bacillus megaterium (P450BM3 ) constitutes a versatile enzyme for the oxyfunctionalization of organic molecules and natural products. However, the limited stability of the diflavin reductase domain limits the utility of this enzyme for synthetic applications. In this work, a consensus-guided mutagenesis approach was applied to enhance the thermal stability of the reductase domain of P450BM3 . Upon phylogenetic analysis of a set of distantly related P450s (>38 % identity), a total of 14 amino acid substitutions were identified and evaluated in terms of their stabilizing effects relative to the wild-type reductase domain. Recombination of the six most stabilizing mutations generated two thermostable variants featuring up to tenfold longer half-lives at 50 degrees C and increased catalytic performance at elevated temperatures. Further characterization of the engineered P450BM3 variants indicated that the introduced mutations increased the thermal stability of the FAD-binding domain and that the optimal temperature (Topt ) of the enzyme had shifted from 25 to 40 degrees C. This work demonstrates the effectiveness of consensus mutagenesis for enhancing the stability of the reductase component of a multidomain P450. The stabilized P450BM3 variants developed here could potentially provide more robust scaffolds for the engineering of oxidation biocatalysts. PMID- 29276821 TI - An Efficient Method for the Conjugation of Hydrophilic and Hydrophobic Components by Solid-Phase-Assisted Disulfide Ligation. AB - Chemical conjugation between hydrophilic and hydrophobic components is difficult because of their extremely different solubility. Herein, we report a new versatile method with a solid-phase-assisted disulfide ligation to overcome the difficulty of conjugation attributed to solubility. The method involves two steps in a one-pot process: 1) loading of a hydrophobic molecule onto a resin in an organic solvent, and 2) release of the solid-supported hydrophobic molecule as a conjugate with a hydrophilic molecule into an aqueous solvent. This strategy allows the use of a suitable solvent system for the substrates in each step. Conjugates of a water-insoluble drug, plinabulin, with hydrophilic carriers that could not be prepared by solution-phase reactions were obtained in moderate yields (29-45 %). This strategy is widely applicable to the conjugation of compounds with solubility problems. PMID- 29276822 TI - Z-Scheme Photocatalytic Water Splitting on a 2D Heterostructure of Black Phosphorus/Bismuth Vanadate Using Visible Light. AB - Spontaneously solar-driven water splitting to produce H2 and O2 , that is, the conversion of solar energy to chemical energy is a dream of mankind. However, it is difficult to make overall water splitting feasible without using any sacrificial agents and external bias. Drawing inspiration from nature, a new artificial Z-scheme photocatalytic system has been designed herein based on the two-dimensional (2D) heterostructure of black phosphorus (BP)/bismuth vanadate (BiVO4 ). An effective charge separation makes possible the reduction and oxidation of water on BP and BiVO4 , respectively. The optimum H2 and O2 production rates on BP/BiVO4 were approximately 160 and 102 MUmol g-1 h-1 under irradiation of light with a wavelength longer than 420 nm, without using any sacrificial agents or external bias. PMID- 29276824 TI - Theranostic Nanoplatform: Triple-Modal Imaging-Guided Synergistic Cancer Therapy Based on Liposome-Conjugated Mesoporous Silica Nanoparticles. AB - Mesoporous silica nanoparticles (MSNs) have long since been investigated to provide a versatile drug-delivery platform due to their multitudinous merits. Presently, gadolinium (Gd), a T1 magnetic resonance imaging (MRI) contrast agent, was doped into MSNs as a newly emerging theranostic nanocomposite, which has received much research attention. However, it is still concerned about the dispersibility and drug leakage of MSNs. Hence, in this project, we constructed an near-infrared (NIR) irradiation-triggered, triple-modal imaging-guided nanoplatform based on doxorubicin (DOX)@Gd-doped MSNs, conjugating with indocyanine green (ICG)-loaded thermosensitive liposomes (designated as DOX@GdMSNs-ICG-TSLs). In this platform, ICG could contribute to both photodynamic therapy and photothermal therapy effects; meanwhile, it could also give play to near-infrared fluorescence imaging (NIRFI) as well as photoacoustic imaging (PAI). Consequently, NIRFI and PAI from ICG combined with the MRI function of Gd, devoted to triple-modal imaging with success. At the same time, folic acid modified thermosensitive liposomes were explored to be coated onto the surface of DOX@GdMSNs, to solve the DOX leakage as well as improve cellular uptake. Under NIR irradiation, ICG could generate heat, thus leading to the rupture of ICG-TSLs and the release of DOX. Accordingly, the multifunctional nanocomposite appeared to be a promising meritorious theranostic nanoplatform to pave a way for treating cancer. PMID- 29276823 TI - Engineering Multifunctional RNAi Nanomedicine To Concurrently Target Cancer Hallmarks for Combinatorial Therapy. AB - Cancer hallmarks allow the complexity and heterogeneity of tumor biology to be better understood, leading to the discovery of various promising targets for cancer therapy. An amorphous iron oxide nanoparticle (NP)-based RNAi strategy is developed to co-target two cancer hallmarks. The NP technology can modulate the glycolysis pathway by silencing MCT4 to induce tumor cell acidosis, and concurrently exacerbate oxidative stress in tumor cells via the Fenton-like reaction. This strategy has the following features for systemic siRNA delivery: 1) siRNA encapsulation within NPs for improving systemic stability; 2) effective endosomal escape through osmotic pressure and/or endosomal membrane oxidation; 3) small size for enhancing tumor tissue penetration; and 4) triple functions (RNAi, Fenton-like reaction, and MRI) for combinatorial therapy and in vivo tracking. PMID- 29276825 TI - Changes in Methane Flux along a Permafrost Thaw Sequence on the Tibetan Plateau. AB - Permafrost thaw alters the physical and environmental conditions of soil and may thus cause a positive feedback to climate warming through increased methane emissions. However, the current knowledge of methane emissions following thermokarst development is primarily based on expanding lakes and wetlands, with upland thermokarst being studied less often. In this study, we monitored the methane emissions during the peak growing seasons of two consecutive years along a thaw sequence within a thermo-erosion gully in a Tibetan swamp meadow. Both years had consistent results, with the early and midthaw stages (3 to 12 years since thaw) exhibiting low methane emissions that were similar to those in the undisturbed meadow, while the emissions from the late thaw stage (20 years since thaw) were 3.5 times higher. Our results also showed that the soil water-filled pore space, rather than the soil moisture per se, in combination with the sand content, were the main factors that caused increased methane emissions. These findings differ from the traditional view that upland thermokarst could reduce methane emissions owing to the improvement of drainage conditions, suggesting that upland thermokarst development does not always result in a decrease in methane emissions. PMID- 29276827 TI - Palladium-Catalyzed Regioselective C-H Alkenylation of Arylacetamides via Distal Weakly Coordinating Primary Amides as Directing Groups. AB - Herein we disclose the efficient Pd(II)-catalyzed and regioselective ortho C-H alkenylation of arylacetamide derivatives, viz. weakly coordinating aliphatic primary amides. This protocol utilizes ubiquitous free primary amides as the directing group and circumvents two troublesome steps of installation and removal of an external auxiliary. This strategy directly enables the incorporation of a synthetically versatile olefin in the products in moderate to good yields with regio- and distereoselectivity. The alkenylated acetamides can be easily manipulated and further transformed into a variety of useful derivatives. PMID- 29276826 TI - Heterologous and High Production of Ergothioneine in Escherichia coli. AB - Ergothioneine (ERG) is a histidine-derived thiol compound suggested to function as an antioxidant and cytoprotectant in humans. Therefore, experimental trials have been conducted applying ERG from mushrooms in dietary supplements and as a cosmetic additive. However, this method of producing ERG is expensive; therefore, alternative methods for ERG supply are required. Five Mycobacterium smegmatis genes, egtABCDE, have been confirmed to be responsible for ERG biosynthesis. This enabled us to develop practical fermentative ERG production by microorganisms. In this study, we carried out heterologous and high-level production of ERG in Escherichia coli using the egt genes from M. smegmatis. By high production of each of the Egt enzymes and elimination of bottlenecks in the substrate supply, we succeeded in constructing a production system that yielded 24 mg/L (104 MUM) secreted ERG. PMID- 29276828 TI - Bu4NI-Catalyzed Dehydrogenative Coupling of Diaryl Phosphinic Acids with C(sp3)-H Bonds of Arenes. AB - An efficient phosphorylation of C(sp3)-H bonds of arenes with diaryl phosphinic acids via Bu4NI-catalyzed dehydrogenative coupling has been developed. This transformation proceeds efficiently under transition-metal-free reaction conditions and represents a straightforward method to prepare valuable organophosphorus compounds from readily available arenes and diaryl phosphinic acids. PMID- 29276829 TI - Universal Mussel-Inspired Ultrastable Surface-Anchoring Strategy via Adaptive Synergy of Catechol and Cations. AB - An outstanding anchoring ligand with robust anchoring ability and universal applicability is highly desirable in materials science and surface engineering. This work reports a novel and universal mussel-inspired anchoring strategy based on a cationic amine-modified catechol ligand coupled with the 2 methacryloyloxyethyl phosphorylcholine moiety. The ligand shows substrate independent anchoring capability, and the deposited film possesses excellent antifouling properties and superior ultrasonic stability as compared to the conventional catechol ligand. Single-molecule force spectroscopy based on atomic force microscopy reveals that the enhanced ultrastable anchoring is attributed to the synergistic binding effect of cationic amine and catechol. Our results provide new nanomechanical insights into the development of novel coating strategies underwater based on amine-incorporated catechol derivatives for a wide range of materials engineering, bioengineering, and environmental applications. PMID- 29276830 TI - Diffusion-Cooperative Model for Charge Transport by Redox-Active Nonconjugated Polymers. AB - Charge transport processes in nonconjugated redox-active polymers with electrolytes were studied using a diffusion-cooperative model. For the first time, we quantitatively rationalized that the limited Brownian motion of the redox centers bound to the polymers resulted in the 103-4-fold decline of the bimolecular and heterogeneous charge transfer rate constants, which had been unexplained for half a century. As a next-generation design, a redox-active supramolecular system with high physical mobility was proposed to achieve the rate constant as high as in free solution system (>107 M-1 s-1) and populated site density (>1 mol/L). PMID- 29276831 TI - Built-In Potentials Induced by Molecular Order in Amorphous Organic Thin Films. AB - Many molecules used to fabricate organic semiconductor devices carry an intrinsic dipole moment. Anisotropic orientation of such molecules in amorphous organic thin films during the deposition process can lead to the spontaneous buildup of an electrostatic potential perpendicular to the film. This so-called giant surface potential (GSP) effect can be exploited in organic electronics applications and was extensively studied in experiment. However, presently, an understanding of the molecular mechanism driving the orientation is lacking. Here, we model the physical vapor deposition process of seven small organic molecules employed in organic light-emitting diode applications with atomistic simulations. We are able to reproduce experimental results for a wide range of strength of the GSP effect. We find that the electrostatic interaction between the dipole moments of the molecules limits the GSP strength and identify short range van der Waals interactions between the molecule and the surface during deposition as the driving force behind the anisotropic orientation. We furthermore show how the GSP effect influences the energy levels responsible for charge transport, which is important for the design of organic semiconductors and devices. PMID- 29276832 TI - Surface Photovoltage Measurements on a Particle Tandem Photocatalyst for Overall Water Splitting. AB - Surface photovoltage spectroscopy (SPS) is used to measure the photopotential across a Ru-SrTiO3:Rh/BiVO4 particle tandem overall water splitting photocatalyst. The tandem is synthesized from Ru-modified SrTiO3:Rh nanocrystals and BiVO4 microcrystals by electrostatic assembly followed by thermal annealing. It splits water into H2 and O2 with an apparent quantum efficiency of 1.29% at 435 nm and a solar to hydrogen conversion efficiency of 0.028%. According to SPS, a photovoltage develops above 2.20 eV, the effective band gap of the tandem, and reaches its maximal value of -2.45 V at 435 nm (2.44 mW cm-2), which corresponds to 96% of the theoretical limit of the photocatalyst film on the fluorine-doped tin-oxide-coated glass (FTO) substrate. Charge separation is 82% reversible with 18% of charge carriers being trapped in defect states. The unusually strong light intensity dependence of the photovoltage (1.16 V per decade) is attributed to depletion layer changes inside of the BiVO4 microcrystals. These findings promote the understanding of solar energy conversion with inorganic particle photocatalysts. PMID- 29276833 TI - On-Chip Stochastic Detection of Silver Nanoparticles without a Reference Electrode. AB - We report the electrochemical detection of 20 nm silver nanoparticles at a chip based microelectrode array (MEA) without the need for a conventional reference electrode. This is possible due to the system's open-circuit potential allowing the oxidation of silver nanoparticles in the presence of phosphate-buffered saline (PBS). The hypothesis is confirmed by modulating the open-circuit potential via addition of ascorbic acid in solution, effectively inhibiting the detection of silver nanoparticle events. Employing the reference-free detection concept, we observe a linear relationship between the nanoparticle impact frequency at the microelectrodes and the nanoparticle concentration. This allows for viable quantification of silver nanoparticle concentrations in situ. The presented concept is ideal for the development of simple lab-on-a-chip or point of-use systems enabling fast and low-cost screening of nanoparticles. PMID- 29276834 TI - New Frontiers and Challenges for Single-Cell Electrochemical Analysis. AB - Previous measurements of cell populations might obscure many important cellular differences, and new strategies for single-cell analyses are urgently needed to re-examine these fundamental biological principles for better diagnosis and treatment of diseases. Electrochemistry is a robust technique for the analysis of single living cells that has the advantages of minor interruption of cellular activity and provides the capability of high spatiotemporal resolution. The achievements of the past 30 years have revealed significant information about the exocytotic events of single cells to elucidate the mechanisms of cellular activity. Currently, the rapid developments of micro/nanofabrication and optoelectronic technologies drive the development of multifunctional electrodes and novel electrochemical approaches with higher resolution for single cells. In this Perspective, three new frontiers in this field, namely, electrochemical microscopy, intracellular analysis, and single-cell analysis in a biological system (i.e., neocortex and retina), are reviewed. The unique features and remaining challenges of these techniques are discussed. PMID- 29276836 TI - Patient-reported experiences on supportive care strategies following the introduction of the first Swedish national cancer strategy and in accordance with the new patient act. AB - INTRODUCTION: Several supportive care strategies are described in Swedish legislation and policy documents, such as the National Cancer Strategy and the Patient act. No previous systematic evaluation from a patient perspective has been performed. The aim of this study was to evaluate how these supportive care strategies are experienced by patients treated for cancer in the Stockholm Gotland region. MATERIAL AND METHODS: In this cross-sectional study, we identified patients (diagnosed with gynaecological, haematological, upper gastrointestinal and head and neck cancer during 2014) from the Swedish Cancer Register. The European Organization of Research and Treatment of Cancer, EORTC, Quality of Life Questionnaires, QLQ-C30, Information QLQ-INFO25 and a study specific questionnaire was used to collect data during follow-up after cancer treatment. We collected data on 869 cancer patients' perception of availability and access to supportive care strategies and how they were experienced. RESULTS: Among the supportive care strategies suggested in the legislation and policy documents, just over half of the patients (n = 393, 53%) reported that they had access to a contact nurse, while 43% (n = 312) had received an individual written care plan and 16% (n= 137) had been referred to palliative care. Only 29% (n = 218) of the patients reported that they had received information about patient advocacy groups and 8% (n= 62) on medical second opinions from their cancer care team. DISCUSSION: The supportive care strategies suggested in Swedish legislation and policy documents may be useful but are only available for some patients. The implementation goals for the National Cancer Strategy and the Swedish Patient act have not been reached. PMID- 29276835 TI - Sensitive, High-Throughput, and Robust Trapping-Micro-LC-MS Strategy for the Quantification of Biomarkers and Antibody Biotherapeutics. AB - For LC-MS-based targeted quantification of biotherapeutics and biomarkers in clinical and pharmaceutical environments, high sensitivity, high throughput, and excellent robustness are all essential but remain challenging. For example, though nano-LC-MS has been employed to enhance analytical sensitivity, it falls short because of its low loading capacity, poor throughput, and low operational robustness. Furthermore, high chemical noise in protein bioanalysis typically limits the sensitivity. Here we describe a novel trapping-micro-LC-MS (T-MULC-MS) strategy for targeted protein bioanalysis, which achieves high sensitivity with exceptional robustness and high throughput. A rapid, high-capacity trapping of biological samples is followed by MULC-MS analysis; dynamic sample trapping and cleanup are performed using pH, column chemistry, and fluid mechanics separate from the MULC-MS analysis, enabling orthogonality, which contributes to the reduction of chemical noise and thus results in improved sensitivity. Typically, the selective-trapping and -delivery approach strategically removes >85% of the matrix peptides and detrimental components, markedly enhancing sensitivity, throughput, and operational robustness, and narrow-window-isolation selected reaction monitoring further improves the signal-to-noise ratio. In addition, unique LC-hardware setups and flow approaches eliminate gradient shock and achieve effective peak compression, enabling highly sensitive analyses of plasma or tissue samples without band broadening. In this study, the quantification of 10 biotherapeutics and biomarkers in plasma and tissues was employed for method development. As observed, a significant sensitivity gain (up to 25-fold) compared with that of conventional LC-MS was achieved, although the average run time was only 8 min/sample. No appreciable peak deterioration or loss of sensitivity was observed after >1500 injections of tissue and plasma samples. The developed method enabled, for the first time, ultrasensitive LC-MS quantification of low levels of a monoclonal antibody and antigen in a tumor and cardiac troponin I in plasma after brief cardiac ischemia. This strategy is valuable when highly sensitive protein quantification in large sample sets is required, as is often the case in typical biomarker validation and pharmaceutical investigations of antibody therapeutics. PMID- 29276837 TI - Effects of Behavioral Activation on the Quality of Life and Emotional State of Lung Cancer and Breast Cancer Patients During Chemotherapy Treatment. AB - Research suggests that the progressive abandonment of activities in cancer patients are related to depression and worse quality of life. Behavioral activation (BA) encourages subjects to activate their sources of reinforcement and modify the avoidance responses. This study assesses the effectiveness of BA in improving quality of life and preventing emotional disorders during chemotherapy treatment. One sample of lung cancer patients and another of breast cancer patients were randomized into a BA experimental group (E.G.lung/4sess. n = 50; E.G.breast/6sess. n = 33) and a control group (C.G.lung/4sess. n = 40; C.G.breast/6sess. n = 35), respectively. In each session and in follow-ups (3/6/9 months), all participants completed different assessment scales. The results converge to show the effectiveness of BA, encouraging cancer patients to maintain rewarding activities which can activate their sources of day-to-day reinforcement and modify their experience avoidance patterns. BA appears to be a practical intervention which may improve social and role functioning and the emotional state of cancer patients during chemotherapy treatment. PMID- 29276838 TI - Complete monocular vision loss due to optic nerve involvement of blastic plasmacytoid dendritic cell neoplasm. PMID- 29276839 TI - An insight into the ecology, diversity and adaptations of Gordonia species. AB - The bacterial genus Gordonia encompasses a variety of versatile species that have been isolated from a multitude of environments. Gordonia was described as a genus about 20 years ago, and to date, 39 different species have been identified. Gordonia is recognized for symbiotic associations with multiple hosts, including aquatic (marine and fresh water) biological forms and terrestrial invertebrates. Some Gordonia species isolated from clinical specimens are known to be opportunistic human pathogens causing secondary infections in immunocompromised and immunosuppressive individuals. They are also predominant in mangrove ecosystems and terrestrial sites. Members of the genus Gordonia are ecologically adaptable and show marked variations in their properties and products. They generate diverse bioactive compounds and produce a variety of extracellular enzymes. In addition, production of surface active compounds and carotenoid pigments allows this group of microorganisms to grow under different conditions. Several isolates from water and soil have been implicated in bioremediation of different environments and plant associated species have been explored for agricultural applications. This review highlights the prevalence of the members of this versatile genus in diverse environments, details its associations with living forms, summarizes the biotechnologically relevant products that can be obtained and discusses the salient genomic features that allow this Actinomycete to survive in different ecological niches. PMID- 29276840 TI - Serum Albumin Predicts Long-Term Neurological Outcomes After Acute Spinal Cord Injury. AB - BACKGROUND: There is a need to identify reliable biomarkers of spinal cord injury recovery for clinical practice and clinical trials. OBJECTIVE: Our objective was to correlate serum albumin levels with spinal cord injury neurological outcomes. METHODS: We performed a secondary analysis of patients with traumatic spinal cord injury (n = 591) participating in the Sygen clinical trial. Serum albumin concentrations were obtained as part of routine blood chemistry analysis, at trial entry (24-72 hours), 1, 2, and 4 weeks after injury. The primary outcomes were "marked recovery" and lower extremity motor scores, derived from the International Standards for the Neurological Classification of Spinal Cord Injury. Data were analyzed with multivariable logistic and linear regression to adjust for potential confounders. RESULTS: Serum albumin was significantly associated with spinal cord injury neurological outcomes. Higher serum albumin concentrations at 1, 2, and 4 weeks were associated with higher 52-week lower extremity motor score. Similarly, the odds of achieving "marked neurological recovery" was greater for individuals with higher serum albumin concentrations. The association between serum albumin concentrations and neurological outcomes was independent of initial injury severity, treatment with GM-1, and polytrauma. CONCLUSIONS: In spinal cord injury, serum albumin is an independent marker of long-term neurological outcomes. Serum albumin could serve as a feasible biomarker for prognosis at the time of injury and stratification in clinical trials. PMID- 29276841 TI - Modified Brain Activations of the Nondamaged Hemisphere During Ipsilesional Upper Limb Movement in Persons With Initial Severe Motor Deficits Poststroke. AB - BACKGROUND: Poststroke, the ipsilesional upper limb shows slight but substantial and long-term motor deficits. OBJECTIVE: To define brain activation patterns during a gross motor flexion/extension task of the ipsilesional elbow early poststroke before and after rehabilitation, in relation to the corresponding kinematic characteristics at each time point. METHOD: Simultaneous analysis of kinematic features (amplitude, frequency, smoothness, and trajectory of movement) and of corresponding functional magnetic resonance imaging activations (block design). A total of 21 persons with subacute initial severe stroke (Fugl-Meyer score <30/66) participated twice: within the first 2 months poststroke (V0) and after 6 weeks of rehabilitation (V1). Results at both time points were compared with activation patterns and kinematics of 13 healthy controls. RESULTS: Compared with controls ( a) movements of the ipsilesional upper-limb poststroke were smaller (V0 + V1) and less smooth (V0 + V1) and ( b) participants poststroke showed additional recruitment of the contralesional middle temporal gyrus (V0) and rolandic opercularis involved in movement visualization (V0 + V1), whereas they lacked activation of the supramarginal gyrus (V0 + V1). Over time, participants poststroke showed an extended activation of the contralesional sensorimotor cortex at V0. CONCLUSION: Movements of the ipsilesional upper limb within an initially severe stroke group were not only atypical in motor outcome, but seemed to be controlled differently. Together the observed changes pointed toward an overall disturbance of the bihemispheric motor network poststroke, marked by ( a) a possible despecialization of the nondamaged hemisphere and ( b) the employment of alternative control strategies to ensure optimal task execution. PMID- 29276842 TI - Coping Strategies Used by Syrian Refugees in Jordan. AB - This study examined the coping strategies used by Syrian refugees in Jordan in relation to their demographics. A cross-sectional correlational study was conducted with a convenient sample of 550 Syrian refugees. Out of all the study participants, 88% reported seeking social support, 64.5% reported using avoidance, and 39.5% reported using problem solving. Participants who were male, single, and younger, and who had a higher education and a higher total income were satisfied with their income, were employed and free of chronic illnesses, and had higher problem-solving scores. Higher social support-seeking scores were associated with being female, older, and widowed; having a lower education and lower total income; being dissatisfied with their income; being nonemployed; and having chronic illnesses. A number of significant predictors were identified for each coping strategy. The results of this study could be used to formulate programs and develop services regarding the stressors encountered by Syrian refugees and their coping strategies. PMID- 29276843 TI - Making Your Wishes Known: Who Completes an Advance Directive and Shares It With Their Health Care Team or Loved Ones? AB - Using Andersen's health behavioral model as a framework, this study examined factors associated with the completion of advance directives and the behavior of sharing them with one's family and health care providers. Data were from the 2014 United States of Aging Survey ( N = 1,153; aged 60 or older), and multinomial logistic regression was used for analysis. We found that 73% of respondents had advance directives. However, 28% have not shared their advance directives with anyone. The sense of having completed a great deal of preparation for the future and the number of illnesses were found to be relevant to the behavior of sharing advance directives. Existing educational training and interventions can be expanded to increase public awareness and encourage people to share their completed advance directives with others. Policies mandating physicians to engage in advance directive conversations with patients during annual checkups might improve completion and sharing of advance directives. PMID- 29276844 TI - Long-Term Lifestyle Intervention in Elderly With Metabolic Syndrome. AB - The purpose of this study was to examine the effects of a long-term community based lifestyle intervention on the biochemical indicators and prevalence of metabolic syndrome among elderly adults. This was a randomized controlled trial in northern Taiwan from August 2013 to February 2015. Sixty-nine elderly adults participated in this study. There were three measurements. The experimental group participated in exercise and diet interventions. The control group participated in the exercise intervention. Repeated measurement and ANCOVA were performed to evaluate the effectiveness. After 18 months, body weight (1.06 kg), body mass index (1.21 kg/m2), waist circumference (3.32 cm), blood pressure, and prevalence (30.4%) of metabolic syndrome were significantly reduced in all subjects. There were significant differences in waist circumference and high-density lipoprotein cholesterol between the two groups. This intervention can lower the indicators and prevalence of metabolic syndrome. Exercise and diet interventions could promote further metabolic changes. PMID- 29276845 TI - Cardiometabolic comorbidities and life expectancy in people on medication for schizophrenia in Australia. AB - OBJECTIVE: This study aimed to assess the risks of people on medication for schizophrenia developing different components of the metabolic syndrome and their life expectancy, through reference to a representative population of Australians without schizophrenia. METHOD: Pharmacy payment-claim records from the Pharmaceutical Benefits Scheme were analyzed based on a representative 10% sample of Medicare numbers supplied by the Department of Human Services. Records were analyzed based on the date of supply of the prescription and the dataset included year of death information. Two major analyses were conducted for 9,533 people on medication for schizophrenia and a 1:1 sex/age matched control, followed for up to 7 years. Patient life expectancy was estimated by performing a Kaplan Meier survival analysis. RESULTS: People on medication for schizophrenia compared to controls were 1.91-times (95% CI = 1.66-2.21) and 1.28-times (95% CI = 1.15-1.43) more likely to start treatment for diabetes and hyperlipidemia, respectively, but were no more likely to start treatment for hypertension (hazard ratio = 0.87; 95% CI = 0.78-0.97). Overall, people on medication for schizophrenia were 1.32-times more likely to start treatment for one of these three comorbidities. Median life expectancy was assessed as 80 years for people on medication for schizophrenia, and 91 years for controls. CONCLUSIONS: The results for this study confirm in a large representative Australian sample of people on medication for schizophrenia, an excess risk of components of the metabolic syndrome and early death. PMID- 29276846 TI - Parents' experiences of health services for the treatment of eating disorders: a qualitative study. AB - BACKGROUND: The importance of involving parents in the treatment of eating disorders is widely recognised, however despite this, very little research has explored parents' perspectives of services. AIMS: This study aimed to explore parents' experiences following contact with services for the treatment of their child's eating disorder. METHODS: Employing qualitative methodology, 15 parents who had experience of health care services for the treatment of their daughter's eating disorder participated in either focus group or individual semi-structured interviews. RESULTS: Parents' experiences were impacted by treatment hurdles, interpersonal communication, and uncertainty. CONCLUSION: Parents' initial contact with services for the diagnosis/treatment of their child's eating disorder is important for addressing consumer expectations at an early stage. Effective communication and relevant support by health care practitioners enhanced parents' perceptions of services and alliance formation. Acknowledgement by clinicians of the logistical, emotional, and motivational challenges faced by parents can also positively impact the therapeutic alliance between parents and services. PMID- 29276847 TI - Piano jacket for perceiving and playing music for patients with cerebral palsy. AB - PURPOSE: Patients with cerebral palsy with severe motor disabilities are limited not only in everyday life activities but also in choice of their hobbies. Playing a musical instrument is for the majority not possible, even though music constitutes a central component of many relaxation activities for people with disabilities. To give affected patients the opportunity to make music and to learn piano playing through somatosensory perception, a prototype of piano jacket was developed. METHOD: A cycling jacket was equipped with boxes, each representing a musical note, incorporated into the sleeves. Each box contains vibration motors and LEDs. These can be used to translate the sequences of piano key presses performed at an external E-piano. An additional operation mode allows the user to actively play a melody himself by touching the same boxes that also incorporate touch sensor components. RESULTS: A working prototype of the piano jacket was developed. CONCLUSION: The sensory piano jacket provides patients with cerebral palsy and contractures the possibility to develop sensorimotor skills, motor abilities and participation in music-related activities. The jacket is planned to be used in music lessons. Implications for Rehabilitation The system is suitable even for patients with severe motor disabilities and especially joint contractures. Excellent handling through large easily accessible communication buttons. All building blocks are held in a garment, which allows for easy portability and gripping comfort. PMID- 29276848 TI - Survival after whole brain radiotherapy for brain metastases from lung cancer and breast cancer is poor in 6325 Dutch patients treated between 2000 and 2014. AB - BACKGROUND: Whole brain radiotherapy (WBRT) is considered standard of care for patients with multiple brain metastases or unfit for radical treatment modalities. Recent studies raised discussion about the expected survival after WBRT. Therefore, we analysed survival after WBRT for brain metastases 'in daily practice' in a large nationwide multicentre retrospective cohort. METHODS: Between 2000 and 2014, 6325 patients had WBRT (20 Gy in 4 Gy fractions) for brain metastases from non-small cell lung cancer (NSCLC; 4363 patients) or breast cancer (BC; 1962 patients); patients were treated in 15 out of 21 Dutch radiotherapy centres. Survival was calculated by the Kaplan-Meier method from the first day of WBRT until death as recorded in local hospital data registration or the Dutch Municipal Personal Records Database. FINDINGS: The median survival was 2.7 months for NSCLC and 3.7 months for BC patients (p < .001). For NSCLC patients aged <50, 50-60, 60-70 and >70 years, survival was 4.0, 3.0, 2.8 and 2.1 months, respectively (p < .001). For BC patients, survival was 4.5, 3.8, 3.2 and 2.9 months, respectively (p = .047). In multivariable analyses, higher age was related to poorer survival with hazard ratios (HR) for patients aged 50-60, 60-70 and >70 years being 1.05, 1.19 and 1.34, respectively. Primary BC (HR: 0.83) and female sex (HR: 0.85) were related to better survival (p < .001). INTERPRETATION: The survival of patients after WBRT for brain metastases from NSCLC treated in Dutch 'common radiotherapy practice' is poor, in breast cancer and younger patients it is disappointingly little better. These results are in line with the results presented in the QUARTZ trial and we advocate a much more restrictive use of WBRT. In patients with a more favourable prognosis the optimal treatment strategy remains to be determined. Prospective randomized trials and individualized prognostic models are needed to identify these patients and to tailor treatment. PMID- 29276849 TI - Male breast cancer: a nation-wide population-based comparison with female breast cancer. AB - OBJECTIVE: Describe prognostic parameters of Danish male breast cancer patients (MBCP) diagnosed from 1980-2009. Determine all-cause mortality compared to the general male population and analyze survival/mortality compared with Danish female breast cancer patients (FBCP) in the same period. MATERIAL AND METHODS: The MBCP cohort was defined from three national registers. Data was extracted from medical journals. Data for FBCP is from the DBCG database. Overall survival (OS) was quantified by Kaplan-Meier estimates. Standardized mortality ratios (SMRs) were calculated based on mortality rate among patients relative to the mortality rate in the general population. The association between SMR and risk factors were analyzed in univariate and multivariable Poisson regression models. Separate models for each gender were used for the analyses. RESULTS: We found a marked difference in OS for the two genders. For the total population of MBCP, 5- and 10-year survivals were 55.1% and 31.7%, respectively. For FBCP, the corresponding figures were 76.8% and 59.3%. Median age at diagnosis for FBCP was 61 years and 70 years for MBCP. By applying SMR, the difference in mortality between genders equalized and showed pronounced age-dependency. For males <40 years, SMR was 9.43 and for females 19.56 compared to SMR for males 80 + years (0.95) and females 80 + years (0.89). During the period 1980-2009, the risk of dying gradually decreased for FBCP (p < .0001). The risk 1980-1984 was 35% higher than 2005-2009 (RR 1.35). Although the risk of dying for MBCP was also lowest in 2005-2009, there was no clear tendency (p = .1439). The risk was highest in 1990 1994 (RR =2.48). CONCLUSION: We found better OS for FBCP than for MBCP. But SMR showed similar mortality rate for the two genders, except for very young FBCP, who had higher SMR. Furthermore, significantly improved survival over time for FBCP was observed, with no clear tendency for MBCP. PMID- 29276850 TI - Maintaining stable transfemoral amputee gait on level, sloped and simulated uneven conditions in a virtual environment. AB - PURPOSE: Describe and quantify how people with transfemoral amputations (TFA) maintain stable gait over a variety of surfaces; including, downhill and uphill, top and bottom-cross-slopes, medial-lateral translations, rolling hills and simulated rocky surfaces. METHODS: Ten TFA and ten matched people without amputations (NA) walked in a virtual environment with level, sloped and simulated uneven surfaces on a self-paced treadmill. Stability was quantified using medial lateral margin of stability (ML-MoS), step parameters, and gait variability (standard deviations for speed, temporal-spatial parameters, foot clearance and root-mean-square of medial-lateral trunk acceleration). RESULTS AND CONCLUSIONS: TFA and NA adapted to non-level conditions by changing their walking speed, step width, and foot clearance. Variability for most parameters increased across conditions, compared to level. TFA walked slower than NA with shorter, wider and longer duration steps (most differences related to speed). ML-MoS did not change compared to level; however, ML-MoS was greater on the prosthetic side than both intact side and NA limbs. Foot clearance and root-mean-square of medial-lateral trunk acceleration were greater on the prosthetic side than the intact side and NA limbs. This research provides a comprehensive analysis of the different adaptations made by people without amputations compared to people with transfemoral amputations over non-level conditions and establishes significant differences between slopes and simulated uneven surfaces for TFA. Implications for Rehabilitation Transfemoral amputation and no amputation groups adapted walking biomechanics when traversing non-level surfaces. Greatest temporal spatial gait adaptations were walking speed, step width and foot clearance. Gait parameter variability typically increased from the level condition in both groups. Transfemoral amputation group walked slower than no amputation group with shorter, wider steps and longer duration steps. This was related to speed. Transfemoral amputation group had more trunk motion variability on the prosthetic side than no amputation group; could be related to prosthetic fit. PMID- 29276851 TI - Clinical trials, ototoxicity grading scales and the audiologist's role in therapeutic decision making. AB - OBJECTIVES: Define clinical trials and adverse event (AE) monitoring from the perspective of the audiologist. Rationalise the importance of audiology's involvement before, during and after monitoring. Identify strengths and weaknesses in toxicity grading scales, and discuss factors that may influence these. DESIGN: Literature involving commonly cited grading scales used to capture ototoxicity is reviewed. Current regulations and language associated with clinical trial implementation and AE monitoring are described. Personal observations based on a variety of clinical populations are drawn from years of experience developing and employing ototoxicity monitoring protocols in a complex medical setting. RESULTS: Six commonly used grading scales for ototoxicity are systematically reviewed for strengths and weaknesses. Necessary considerations that inform selection of grading scales are presented. A review of and historical context for clinical trial development and AE monitoring is provided. CONCLUSIONS: The audiologist's role in therapeutic decision making goes beyond collection of the audiogram. Clear communication to stakeholders in ototoxicity monitoring is paramount, and toxicity grading scales are one tool to facilitate this exchange. Various factors should be considered in advance of selecting the most appropriate scale to capture hearing loss, and no scale is without limitation. PMID- 29276852 TI - Organ Donor Management: Part 1. Toward a Consensus to Guide Anesthesia Services During Donation After Brain Death. AB - Worldwide 715 482 patients have received a lifesaving organ transplant since 1988. During this time, there have been advances in donor management and in the perioperative care of the organ transplant recipient, resulting in marked improvements in long-term survival. Although the number of organs recovered has increased year after year, a greater demand has produced a critical organ shortage. The majority of organs are from deceased donors; however, some are not suitable for transplantation. Some of this loss is due to management of the donor. Improved donor care may increase the number of available organs and help close the existing gap in supply and demand. In order to address this concern, The Organ Donation and Transplantation Alliance, the Association of Organ Procurement Organizations, and the Transplant and Critical Care Committees of the American Society of Anesthesiologists have formulated evidence-based guidelines, which include a call for greater involvement and oversight by anesthesiologists and critical care specialists, as well as uniform reporting of data during organ procurement and recovery. PMID- 29276853 TI - Are habitual runners physically inactive? AB - The World Health Organisation's (WHO) physical activity guidelines recommend 150min/week of moderate- to vigorous-intensity physical activity (MVPA) accumulated in 10 min bouts. To see whether people performing habitual exercise for recreation meet these guidelines, 25 long-distance runners [mean 67 km/wk], 25 joggers [mean 28 km/wk], and 20 sedentary adults wore an ActiGraph GT3X+ accelerometer for 7 days. Sedentary time and bouts were similar in runners and sedentary adults (p > 0.46). Sedentary adults performed 20 +/- 16 min/day of MVPA (usual bout duration (W50%): 9.53 +/- 3.45min), with joggers and runners performing 45 +/- 31min (W50%: 16.92 +/- 9.53min) and 83 +/- 58min (W50%: 20.35 +/- 8.85min), respectively (p <= 0.001 versus sedentary group). Data showed that 65% of the sedentary group, 32% of joggers and 4% of long-distance runners did not meet the WHO guideline for MVPA. Failure to meet the guideline was most prominent in, but not restricted to, runners who reported <=50km running per week. Self-reported running does not ensure adults meet physical activity guidelines or offset daily sedentary behaviours. On the other hand, the sedentary group was very close in accumulating recommended bouts of MVPA in incidental activities. Future studies should assess whether modification of work and leisure physical activity would be more fruitful than encouraging recreational exercise per se in meeting physical activity guidelines. PMID- 29276854 TI - The Impact of Physical Activity on Serum Inflammatory Markers in Overweight Pubertal Boys: 24-Month Follow-Up Study. AB - PURPOSE: To investigate the differences in the pattern of changes in serum inflammatory cytokines measured annually over a 24-month period, between less active and more active overweight boys. PARTICIPANTS/METHODS: In total, 25 pubertal overweight boys were divided by their moderate to vigorous physical activity (MVPA) levels into 2 groups: less active group (LAG; n = 10; MVPA < 60 min/d) and more active group (MAG; n = 15; MVPA > 60 min/d). Physical activity was measured by 7-day accelerometry. Serum concentration of 13 inflammatory cytokines [interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-1alpha, IL-1beta, vascular endothelial growth factor, interferon-gamma, tumor necrosis factor alpha, monocyte chemotactic protein-1, epidermal growth factor, and C-reactive protein] was measured at baseline (T0), after 12 months (T1), and after 24 months (T2) from fasting blood samples. RESULTS: Serum IL-6 level was significantly higher [LAG: 1.27 (0.86, 1.98) pg/mL; MAG: 0.80 (0.52, 0.84) pg/mL] at T0 and IL 8 level [LAG: 10.26 (8.80, 11.64) pg/mL; MAG: 7.42 (6.10, 9.54) pg/mL] at T2 in LAG compared with MAG. The changes over the study period varied between different inflammatory markers. None of the slopes of any measured markers were statistically different between the LAG and MAG, although the slopes of interferon-gamma and IL-10 tended to be different between the groups. CONCLUSIONS: The pattern of changes over the study period varied between different inflammatory markers, but these changes were not different between the MVPA groups. More longitudinal studies are needed to investigate whether IL-6, IL 8, IL-10, and interferon-gamma would be the choice of inflammatory markers to study the associations between obesity and physical activity in future. PMID- 29276855 TI - Assessing Differences in Cardiorespiratory Fitness With Respect to Maturity Status in Highly Trained Youth Soccer Players. AB - PURPOSE: The purpose of the study was to examine differences in measures of cardiorespiratory fitness and determinants of running economy with respect to maturity status in a group of highly trained youth soccer players. METHODS: A total of 21 highly trained youth soccer players participated in this study. On separate visits, players' peak oxygen uptake (VO2peak), running economy at 3 different speeds [8 km.h-1, 80% gaseous exchange threshold (GET), and 95% GET], and pulmonary oxygen uptake (VO2) kinetics were determined. Players also performed a Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1). Players were categorized as either "pre-PHV" (peak height velocity) or "mid-PHV" group using the measure of maturity offset. Independent t tests and Cohen's d effect sizes were then used to assess differences between groups. RESULTS: The mid-PHV group was significantly taller, heavier, and advanced in maturity status. Absolute measures of VO2peak were greater in the mid-PHV group; however, when expressed relative to body mass, fat-free mass, and theoretically derived exponents, VO2peak values were similar between groups. Pre-PHV group presented a significantly reduced VO2 response, during relative submaximal running speeds, when theoretically derived exponents were used, or expressed as %VO2peak. VO2 kinetics (tau) were faster during a low (standing) to moderate (95% GET) transition in the pre-PHV group. Yo-Yo IR1 performance was similar between groups. CONCLUSION: Although measures of VO2peak and Yo-Yo IR1 performance are shown to be similar between groups, those categorized as pre-PHV group display a superior running economy at relative submaximal running speeds and faster taus during a low to moderate exercise transition than their more mature counterparts. PMID- 29276856 TI - Cellular Origin of [18F]FDG-PET Imaging Signals During Ceftriaxone-Stimulated Glutamate Uptake: Astrocytes and Neurons. AB - Ceftriaxone stimulates astrocytic uptake of the excitatory neurotransmitter glutamate, and it is used to treat glutamatergic excitotoxicity that becomes manifest during many brain diseases. Ceftriaxone-stimulated glutamate transport was reported to drive signals underlying [18F]fluorodeoxyglucose-positron emission tomographic ([18F]FDG-PET) metabolic images of brain glucose utilization and interpreted as supportive of the notion of lactate shuttling from astrocytes to neurons. This study draws attention to critical roles of astrocytes in the energetics and imaging of brain activity, but the results are provocative because (1) the method does not have cellular resolution or provide information about downstream pathways of glucose metabolism, (2) neuronal and astrocytic [18F]FDG uptake were not separately measured, and (3) strong evidence against lactate shuttling was not discussed. Evaluation of potential metabolic responses to ceftriaxone suggests lack of astrocytic specificity and significant contributions by pre- and postsynaptic neuronal compartments. Indeed, astrocytic glycolysis may not make a strong contribution to the [18F]FDG-PET signal because partial or complete oxidation of one glutamate molecule on its uptake generates enough ATP to fuel uptake of 3 to 10 more glutamate molecules, diminishing reliance on glycolysis. The influence of ceftriaxone on energetics of glutamate-glutamine cycling must be determined in astrocytes and neurons to elucidate its roles in excitotoxicity treatment. PMID- 29276857 TI - Mental Fatigue Impairs Physical Performance in Young Swimmers. AB - PURPOSE: This study aimed to investigate the impact of mental fatigue on heart rate variability, subjective measures of fatigue, and swimming performance in young athletes. METHODS: Sixteen swimmers [15.45 (0.51) y old, 7.35 (2.20) y of swimming experience] performed a 1500-m time trial on 2 occasions separated by an interval of at least 72 hours. The 1500-m swimming was preceded by a 30-minute treatment that consisted of performing the Stroop Color and Word test to induce mental fatigue (experimental trial) or watching an emotionally neutral video (control trial). RESULTS: Participants reported higher ratings of mental fatigue and mental effort following the Stroop test when compared with the control trial, but no differences in motivation were observed. The induction of mental fatigue impaired swimming performance, as evidenced by a slower time (1.2%) to complete the 1500-m trial. No intertrial differences were identified for rating of perceived exertion during the swimming test or in heart rate variability after the Stroop and swimming tests. CONCLUSION: The results indicate that induction of mental fatigue impairs 1500-m swimming performance without changing heart rate variability. PMID- 29276858 TI - I Have, Therefore I Love: Status Quo Preference in Mate Choice. AB - Decades of research indicate that individuals adhere to existing states ("status quo bias") and value them more ("endowment effect"). The present work is the first to investigate status quo preference within the context of trade-offs in mate choice. Across seven studies (total N = 1,567), participants indicated whether they would prefer remaining with a current partner possessing a particular set of traits (e.g., high trustworthiness, low attractiveness) or switching to an alternative partner possessing opposite traits. Preference for a given trait was highest when the individual representing the status quo (one's romantic partner or an interaction partner) possessed that trait. Concerns about hurting the partner, ambiguity avoidance, and biased construal of the partner and the alternative predicted status quo preference and disapproval of the current partner by network members eliminated this effect. These findings indicate that when it comes to matters of the heart, we tend to love what we currently have. PMID- 29276859 TI - Defining Accelerometer Nonwear Time to Maximize Detection of Sedentary Time in Youth. AB - PURPOSE: The present study examined various accelerometer nonwear definitions and their impact on detection of sedentary time using different ActiGraph models, filters, and axes. METHODS: In total, 61 youth (34 children and 27 adolescents; aged 5-17 y) wore a 7164 and GT3X+ ActiGraph on a hip-worn belt during a 90 minute structured sedentary activity. Data from GT3X+ were downloaded using the Normal filter (N) and low-frequency extension (LFE), and vertical axis (V) and vector magnitude (VM) counts were examined. Nine nonwear definitions were applied to the 7164 model (V), GT3X+LFE (V and VM), and GT3X+N (V and VM), and sedentary estimates were computed. RESULTS: The GT3X+LFE-VM was most sensitive to movement and could accurately detect observed sedentary time with the shortest nonwear definition of 20 minutes of consecutive "0" counts for children and 40 minutes for adolescents. The GT3X+N-V was least sensitive to movement and required longer definitions to detect observed sedentary time (40 min for children and 90 min for adolescents). VM definitions were 10 minutes shorter than V definitions. LFE definitions were 40 minutes shorter than N definitions in adolescents. CONCLUSION: Different nonwear definitions are needed for children and adolescents and for different model-filter-axis types. Authors need to consider nonwear definitions when comparing prevalence rates of sedentary behavior across studies. PMID- 29276860 TI - Cycling Efficiency During Incremental Cycle Ergometry After 24 Hours of Overfeeding or Fasting. AB - OBJECTIVE: The objective of this study was to determine whether net cycling efficiency (NET) is altered by 24-hour fasting or overfeeding and whether it correlates with dietary-related energy expenditure (EE) and future weight change. METHODS: In a crossover design, healthy subjects fasted or were overfed for 24 hours while in a whole-room calorimeter using five diets with doubled energy needs: standard, high-carbohydrate (75%), high-fat (60%), high-protein (30%), and low-protein (3%) diets. Graded cycling exercise at low power outputs (10-25-50 W) was performed the day before and after each dietary intervention. RESULTS: NET did not change following any dietary intervention (all P > 0.05 vs. 0). Individual changes in NET did not correlate with EE responses to dietary interventions. However, the change in NET after low-protein overfeeding was inversely correlated with baseline body fat (r = -0.60, P = 0.01); that is, NET increased in lean but decreased in overweight subjects (Delta = 0.010 +/- 0.010 vs. -0.013 +/- 0.009, P = 0.0003). Increased NET following the low-protein diet was associated with weight gain after 6 months (r = 0.60, P = 0.05). CONCLUSIONS: Despite no substantial effect of acute overfeeding or fasting on NET, the change in NET following low-protein overfeeding depends on adiposity and may influence weight change, suggesting that increased efficiency in a setting of protein scarcity is an adaptive response that may ultimately lead to weight gain. PMID- 29276861 TI - Low Circulating Levels of Neurotensin in Women with Nonalcoholic Fatty Liver Disease Associated with Severe Obesity. AB - OBJECTIVE: This study was performed to investigate neurotensin plasma levels in patients with nonalcoholic fatty liver disease (NAFLD) associated with severe obesity. METHODS: The plasma levels of neurotensin in 20 women with normal weight and 51 women with morbid obesity (MO) were measured, and women were subclassified according to their hepatic histology as having MO without NAFLD (n = 18) or MO with NAFLD (n = 33). The NAFLD group included 15 women with simple steatosis (SS) and 18 women with nonalcoholic steatohepatitis (NASH). To quantify neurotensin in plasma, a multiplex sandwich immunoassay with a Luminex magnetic bead-based platform was used. RESULTS: Neurotensin levels were significantly decreased (P = 0.001) in women with MO and NAFLD (3.62 +/- 0.85 ng/mL), compared with women with MO and normal liver function (11.65 +/- 1.95 ng/mL; P = 0.001) and women with normal weight (13.68 +/- 2.58 ng/mL; P = 0.001). There was no difference in levels between women with SS and women with NASH (P = 0.415). CONCLUSIONS: Circulating levels of neurotensin were decreased in women with NAFLD associated with MO. PMID- 29276862 TI - SNAPPE-II and risk of neonatal morbidities in very low birth weight preterm infants. AB - Ozcan B, Kavurt AS, Aydemir O, Gencturk Z, Bas AY, Demirel N. SNAPPE-II and risk of neonatal morbidities in very low birth weight preterm infants. Turk J Pediatr 2017; 59: 105-112. Illness severity scores were described to estimate the mortality and morbidity risks based on data obtained shortly after admission to an intensive care unit. The aim of this study is to evaluate Scores for Neonatal Acute Physiology-Perinatal Extension-II (SNAPPE-II) as a predictors of neonatal morbidities such as bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). A retrospective cohort study was conducted between October 2011- 2012. A total of 278 preterm infants born with gestational age (GA) < 32 weeks and birthweight (BW) < 1,500 g were given SNAPPE-II scores based on data collected within the first 12 h of admission to ICU. The main outcomes were the development of BPD and ROP. The main variable was the SNAPPE-II obtained at admission. Logistic regression and receiver-operating characteristics (ROC) curve were calculated for SNAPPE-II. The mean GA and mean BW of the whole cohort were 29.2 weeks (+/- 2.15) and 1,323 g (+/-331,4), respectively. The median SNAPPE-II value was significantly higher among patients with BPD and ROP. After logistic regression the SNAPPE-II was independent risk factor for BPD and ROP. The best discriminative cutoff value for BPD was 14.5 (sensitivity 92%) and for ROP was 23.5 (sensitivity 80%). The present study reviewed an association between SNAPPE II and neonatal morbidities including ROP and BPD. PMID- 29276863 TI - Non-suicidal self-injury behaviors' features and relationship with adolescents' daily life activities and mental status. AB - Cimen ID, Coskun A, Etiler N. Non-suicidal self-injury behaviors' features and relationship with adolescents' daily life activities and mental status. Turk J Pediatr 2017; 59: 113-121. This study investigated, characteristics of the non suicidal self-injury (NSSI) behaviors and behaviors' relationship with the sociodemographic characteristics, psychological problems and other features like daily life activities, between the ages of 12 and 17 years in the central district Izmit of Kocaeli; 555 students whose data included to study received a sociodemographic questionnaire (SQ) and Youth Self-Report (YSR). Students, who reported that they had NSSI, were additionally evaluated with the Inventory of Statements About Self-injury (ISAS). We found out a significant correlation between NSSI and the psychological problems, habits with addiction-forming potential, some daily life activities and making friends with negative characteristics. We concluded that prevention of the risk factors related to NSSI might be effective to avoid the development of this behavior. And diagnosing the behavior in the onset, might provide more effective and long-lasting results and enable the adolescent to get over this risky period with minimal harm. PMID- 29276864 TI - Low serum IGF-1 and increased cytokine levels in tracheal aspirate samples are associated with bronchopulmonary dysplasia. AB - Yilmaz C, Koksal N, Ozkan H, Dorum BA, Bagci O. Low serum IGF-1 and increased cytokine levels in tracheal aspirate samples are associated with bronchopulmonary dysplasia. Turk J Pediatr 2017; 59: 122-129. Despite developments in the perinatal and neonatal care, bronchopulmonary dysplasia (BPD) is still the most frequently seen long-term complication in preterm infants. The aim of this prospective study is to investigate the association between the development of BPD and serial measurements of IGF-1 levels and their relationship with levels of IGF-1 and cytokine in tracheal aspirate fluids. A total of 40 premature infants, born at a gestational age of <= 32 weeks, were enrolled in the study. On postnatal day-1, 3, 7, 21 and 28 serum IGF-1 levels and IGF-1 levels, IL-6, IL-8, IL-10 and TNF-alpha levels in tracheal aspirate fluid samples of intubated cases were examined. Mean gestational age of 40 patients included in the study was 29.41 +/- 2.23 weeks, and their mean birth weight was 1,256.85 +/- 311.48 g. BPD was detected in 35% of cases. Mean gestational week and birth weight of the cases that developed BPD were 30 +/- 3 weeks and 1,150 +/- 295 g, respectively. Serum IGF-1 levels on postnatal day-1, 3, 7, 21 and 28 in cases who developed BPD were significantly lower when compared with those without BPD (p < 0.01). Levels of IL 6, IL-8, IL-10, and TNF-alpha in tracheal aspirate samples were significantly higher in cases with BPD compared to those without BPD (p < 0.05). IGF-1 levels in tracheal aspirate fluid samples did not differ significantly based on the presence of BPD (p > 0.05). Severity of BPD was associated with decreased serum IGF-1 levels and increased cytokine levels in tracheal aspirate samples. PMID- 29276865 TI - High frequency oscillatory ventilation versus conventional mechanical ventilation in pediatric acute respiratory distress syndrome: A randomized controlled study. AB - El-Nawawy A, Moustafa A, Heshmat H, Abouahmed A. High frequency oscillatory ventilation versus conventional mechanical ventilation in pediatric acute respiratory distress syndrome: A randomized controlled study. Turk J Pediatr 2017; 59: 130-143. The aim of this prospective randomized study is to compare the outcomes of the early use of either high frequency oscillation (HFO) or conventional mechanical ventilation (CMV) in patients with pediatric acute respiratory distress syndrome (PARDS). We allocated two hundred PARDS patients over 5 years in 1:1 ratio to either mode. The HFO group showed a significantly higher median partial arterial oxygen pressure to fraction of inspired oxygen (PaO2/FiO2) values after 24 hours of enrollment (p=0.011), higher oxygenation index (OI) decrease percent (p=0.004) and lower cross-over rates (p < 0.001), whereas no differences in 30-day mortality, length of stay (LOS) or ventilation days (p=0.77, p=0.28, p=0.65 respectively). The second day values (after 24 hours) of both OI and PaO < sub > 2 < /sub > /FiO < sub > 2 < /sub > were found to be more significant discriminators for mortality when compared to the baseline values (cutoff values > 8.5, <=139 respectively). PARDS patients with baseline OI > 16 had a better chance of survival if initially ventilated with the HFO (p=0.004). Although the HFO mode appeared to be a safe mode with a significant better oxygenation improvement (after the first 24 hours) and fewer cross-over rates, it failed to show differences as regards mortality or LOS when compared to the CMV adopting protective lung strategy. In PARDS, HFO had a superior advantage in improving oxygenation, yet with no significant mortality improvement, as multi organ dysfunction syndrome (MODS) was the most common cause of death in our study and not refractory hypoxemia which is the main problem in PARDS; highlighting that mortality in PARDS is multi-factorial and may not depend only on how fast oxygenation improves. PMID- 29276866 TI - Association of STAT4 gene single nucleotide polymorphisms with Iranian juvenile onset systemic lupus erythematosus patients. AB - Salmaninejad A, Mahmoudi M, Aslani S, Poursani S, Ziaee V, Rezaei N. Association of STAT4 gene single nucleotide polymorphisms with Iranian juvenile-onset systemic lupus erythematosus patients. Turk J Pediatr 2017; 59: 144-149. Juvenile onset systemic lupus erythematosus (JSLE) is a complex autoimmune disease, characterized by multi-organ involvement. Single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) gene have been reported to have relationship with the risk of several autoimmune diseases. Studies have provided evidence that STAT4 may participate in the pathogenesis of JSLE. Therefore, we aimed to evaluate the association of STAT4 SNPs with JSLE in Iranian population. In this case-control study, two SNPs of STAT4 gene, including rs7574865 and rs7601754 were genotyped in 50 Iranian JSLE patients and 281 matched healthy individuals using real-time PCR allelic discrimination approach. Our experiments demonstrated that G and T alleles of rs7574865 SNP had similar distribution between patients and controls (P = 0.16). Additionally, differences in frequency of GG, GT, and TT genotypes (P = 0.14, 0.29, and 0.54, respectively) were not significant. Likewise, A and G alleles, as well as genotypes of rs7601754 SNP did not show significant differences between JSLE patients and healthy individuals. Lack of association of rs7574865 and rs7601754 SNPs in STAT4 gene with susceptibility to JSLE in Iranian population, despite their association with the risk of adult SLE in the same population, implicates on difference of genetic background of JSLE and SLE. PMID- 29276867 TI - Comparison of weight estimation methods and evaluation of usability of Broselow Luten tape in Turkish children. AB - Gultekingil-Keser A, Teksam O. Comparison of weight estimation methods and evaluation of usability of Broselow Luten tape in Turkish children. Turk J Pediatr 2017; 59: 150-154. It is controversial which method is more reliable for weight estimation of a child in an emergent situation. The aim of this study is to compare different methods and to review the applicability of Broselow Luten tape for Turkish children. This study was performed prospectively in patients presenting to pediatric emergency department. Weight estimation of patients were performed by parent, physician, nurse and Broselow Luten tape. Finally actual weight and height of the patient were measured. A total of 438 patients were eligible for the study. All estimates have a reliable correlation with actual weight. However, parent estimation is better followed by Broselow Luten tape. Correlation decreases as the weight of the child increases. When emergent care of an acutely ill child is necessary, parental estimation of the weight can be used. If it is unattainable, Broselow Luten tape can be reliably used instead of other methods especially in patients with lower weight. PMID- 29276868 TI - Rational drug use for acute bronchiolitis in emergency care. AB - Uysalol M, Haslak F, Ozunal ZG, Vehid H, Uzel N. Rational drug use for acute bronchiolitis in emergency care. Turk J Pediatr 2017; 59: 155-161. Despite the large variety of inhaled treatment options of acute bronchiolitis, there is no generally agreed treatment regime. This study aimed to determine the most appropriate treatment option. This was a double-blind randomized prospective clinical trial and has been performed in emergency department. The mean age of the 378 infants included in the study was 7.63 +/- 4.6 months, and 54.8% (207) were boys. Patients were randomized by using the lottery method for simple random sample into 5 different treatment options; 3% hypertonic saline, nebulized adrenaline, nebulized adrenaline mixed with 3% hypertonic saline, nebulized salbutamol, and as control group; normal saline (0.9% NaCl). From the first treatment time until discharge time; treatment durations, adverse events and readmission rates within the first fifteen days were recorded for each patient. Nebulized adrenaline mixed with 3% hypertonic saline, as compared with other options, were associated with a significantly higher discharge rate at 4th hours (p < 0.001) and shorter length of hospital stay (p=0.039). However, there was no significant difference between options with regard to adverse events, discharge rates at 24th hours, and readmission rates within the first fifteen days. The superiority of discharge rates at 4 hours of nebulized adrenaline mixed with 3% hypertonic saline, was evaluated as 'better acute response' and can be helpful to reduce hospitalization needs. Additionally, this option seems to be more effective to reduce length of hospital stay. PMID- 29276869 TI - Incidence, risk factors and treatment outcomes of drug extravasation in pediatric patients in China. AB - Yan YM, Gong M, Chen JL, Li D, Xu TT, Zou H, Li AQ, Fan QL, Lu QF. Incidence, risk factors and treatment outcomes of drug extravasation in pediatric patients in China. Turk J Pediatr 2017; 59: 162-168. Extravasation injury is a common phenomenon in hospitals. Failure to detect and treat extravasation injury can lead to irreversible local injuries, tissue necrosis and malfunction of the affected tissue. Until now, it is largely unknown about incidence, risk factors and treatment outcomes of extravasation in Chinese pediatric patients. The aim of this study is to explore the incidence, risk factors and summarize the characteristics and treatment outcomes of extravasation injuries resulting in drug extravasation among Chinese children in our hospital. The children undergoing infusion therapy (0-18 years) were enrolled in this study between December 2014 and June 2015 in Shanghai Children's Hospital. The patients' information including age, gender, injection site, estimated volume of solution extravasated, patient symptoms, severity of extravasation injury, treatment methods, and outcomes was collected. Multivariate logistic regression was used to identify the independent risk factors for the development of extravasation. The incidence of extravasations in pediatric patients was 1.79% (18/1,004). The severity of extravasation was labeled with grade range from Grade 1 through Grade 4: 4 cases with Grade 1, 8 cases with Grade 2, 5 cases with Grade 3, and 1 case with Grade 4. The risk factors of extravasation include infused high volume/day (>=1000 ml), received operation, infused agents with high osmolarity and poor vein condition. The severity of extravasation was related to the large volumes of drug or special drugs (high-osmolarity, high-risk, low pH, etc). All extravasations were treated with physical, pharmacological and surgical intervention according to our standard operation protocols. Systematic implementation of intervention can alleviate the extravasation injuries and improve the patients' outcome. PMID- 29276870 TI - The long-term neurodevelopmental outcomes of infants born full-term with low birth weight. AB - Tosun A, Gurbuz-Ozgur B, Aksu H, Kaynak-Turkmen M. The long-term neurodevelopmental outcomes of infants born full-term with low birth weight. Turk J Pediatr 2017; 59: 169-176. In this study, it was aimed to evaluate the neurological developments of pre-school or school-aged children together with their school successes, intelligence quotient and symptom severity of attention deficit hyperactivity disorder who were born at the 37th gestational week and above with birth weights below tenth percentile, which is called small for gestational age (SGA). A total of 74 patients with SGA and 75 healthy children were evaluated. The patients were evaluated by child neurologist and child psychiatrist. Wechsler Intelligence Scale for Children-Revised, Ankara Developmental Screening Inventory, and The Turgay DSM-IV-Based Child and Adolescent Disruptive Behavioral Disorders Screening and Rating Scale (T-DSM-IV S) were applied according to their age groups. SGA cases had been breastfed for shorter durations (p: 0.004), had walked later (p < 0.001), talked later (p < 0.001), and had encountered more vision disorders (p: 0.009) than the control group. SGA cases were determined to encounter febrile convulsions more frequently (p: 0.007). SGA cases were determined to exhibit lower school success (p < 0.001), were diagnosed with attention deficit hyperactivity disorder more frequently (p < 0.001), and their mental developments were delayed (p < 0.001). In cases with SGA, inattention (p: 0.004) and conduct disorder (p: 0.029) subscales and the total scale scores (p: 0.022) of T-DSM-IV-S were significantly lower when compared to the control group. We consider that being SGA may have a negative impact on child's behavior, attention and academic achievement in long term. PMID- 29276871 TI - Evaluation of surgically treated breast masses in children. AB - Dogan G, Soyer T, Ekinci S, Karnak I, Ciftci AO, Tanyel FC. Evaluation of surgically treated breast masses in children. Turk J Pediatr 2017; 59: 177-183. We aimed to define the diagnostic and treatment characteristics of breast masses among female children who had undergone surgical treatment in order to figure out which children should be followed conservatively or treated surgically. We reviewed retrospectively 64 female patients operated for breast masses under the age of 18 years between 1977 and 2013. Patient demographics, symptoms, physical examination findings, size of the mass and its relation with menstrual cycle, follow-up period before and after surgery, diagnostic characteristics, laboratory analysis, diagnosis before and after surgery, indications for surgery, histopathological characteristics of the mass, postoperative complications, and recurrence rate were recorded. Histopathologic investigations among 41 girls with complete hospital records showed that 26 had fibroadenoma (FA; 63.4%). Eleven girls among the other 23 cases with incomplete hospital records but with histopathological results have also had FA (47%). The majority of breast masses in childhood are FA, the frequency and duration of follow up is important. If there is a mass that will not regress, that continues to grow or does not reduce in size during follow up, and for those with family history of breast cancer to definitely exclude the possibility of malignancy, surgical treatment may be appropriate. PMID- 29276872 TI - Successful treatment of a childhood synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome with subcutaneous methotrexate: A case report. AB - Akcaboy M, Bakkaloglu-Ezgu SA, Buyukkaragoz B, Isiyel E, Kandur Y, Hasanoglu E, Buyan N. Successful treatment of a childhood synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome with subcutaneous methotrexate: A case report. Turk J Pediatr 2017; 59: 184-188. SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) is defined as a syndrome that is related to various osteoarticular manifestations and chronic dermatological conditions especially severe acne. SAPHO syndrome is a rare and unusual clinical entity in childhood and treatment choices are variable. We report an 11-year-old girl who suffered from SAPHO syndrome and successfully treated with subcutaneous methotrexate. We report our case in order to take attention to this rare clinical condition in evaluating patients and also to point out that treatment options beyond biologic agents should be the first line treatment in childhood. PMID- 29276873 TI - A case report of a 4-year-old child with glucose-6-phosphate dehydrogenase deficiency: An evidence based approach to nutritional management. AB - Pinto A, MacDonald A, Cleto E, Almeida MF, Ramos PC, Rocha JC. A case report of a 4-year-old child with glucose-6-phosphate dehydrogenase deficiency: An evidence based approach to nutritional management. Turk J Pediatr 2017; 59: 189-192. The objective was to describe the nutritional management of a 4-year-old child with glucose-6-phosphate dehydrogenase (G6PD) deficiency. A 4-year-old male child, African descent, born from non-consanguineous parents presented with a clinical history of frequent respiratory infections, usually treated with antibiotics. At 30 months of age, G6PD diagnosis was made after eating one portion (40 - 60 g) of fava beans, resulting in severe hemolytic anemia hospitalization for 5 days. Diagnosis was confirmed by G6PD activity measurement. Nutritional counseling was given to avoid dietary oxidative stressors particularly the exclusion of fava beans and accidental ingestion of other similar beans. Dietary intake of high vitamin C containing foods was discouraged and adequate hydration advised. Nutritional management is crucial in preventing acute stress events in patients with G6PD deficiency. PMID- 29276874 TI - Persistent hyperglycemia in a neonate: Is it a complication of therapeutic hypothermia? AB - Ozdemir H, Memisoglu A, Alp-Unkar Z, Arcagok B, Bilgen H, Turan S, Ozek E. Persistent hyperglycemia in a neonate: Is it a complication of therapeutic hypothermia? Turk J Pediatr 2017; 59: 193-196. The aim of this report is to present a newborn with persistent hyperglycemia requiring insulin therapy as a possible complication of therapeutic hypothermia. A term appropriate for gestational age (AGA) female infant, was born by emergency cesarean section due to abruption of placenta and was resuscitated and intubated in the delivery room. Whole body cooling was initiated according to standard cooling criteria. The patient's blood glucose increased up to 250 mg/dl on a glucose perfusion rate of 6 mg/kg/min after the second day of cooling. Insulin therapy was started due to persistent hyperglycemia and continued for 17 days. As it has been reported in adults after therapeutic cooling, persistent hyperglycemia attributed to hypothermia can also complicate therapeutic hypothermia in neonates. PMID- 29276875 TI - Drug reaction with eosinophilia and systemic symptoms in a child on multiple antiepileptics. AB - Goswami JN, Vaidya PC, Saini AG, De D, Radotra BD, Singhi PD. Drug reaction with eosinophilia and systemic symptoms in a child on multiple antiepileptics. Turk J Pediatr 2017; 59: 197-199. Drug reaction with eosinophilia and systemic symptoms (DRESS) is an adverse drug-reaction that may mimic systemic illnesses and have a fulminant presentation. We describe an 8-year-old girl with epilepsy and exposure to multiple anti-epileptics who presented with fever, extensive maculopapular rash, cervical lymphadenopathy, hepatomegaly, progressive anemia and transaminitis. Infections, autoimmune disorders and hematological or reticuloendothelial malignancies were excluded. Based on the proposed diagnostic criteria, a diagnosis of DRESS was concluded. Her skin biopsy showed atypical findings consistent with erythema multiforme. Suspected anti-epileptic drugs were discontinued. She was administered pulse methyl-prednisolone therapy and broad spectrum antibiotics along with adequate supportive management. Unfortunately, the child succumbed to nosocomial sepsis. Our case highlights the importance of early suspicion for diagnosis of pediatric DRESS, avoidance of polytherapy and institution of early immunomodulation to improve the outcomes in children in this condition. PMID- 29276876 TI - A pheochromocytoma case diagnosed as adrenal incidentaloma. AB - Vuralli D, Kandemir N, Clark G, Orhan D, Alikasifoglu A, Gonc N, Ekinci S, Ozon A. A pheochromocytoma case diagnosed as adrenal incidentaloma. Turk J Pediatr 2017; 59: 200-206. There are two problems that needs to be addressed in cases of an adrenal incidentaloma. The first is to decide whether the adrenal mass is benign or malignant, and the second is to determine whether the mass is hormonally active or not. A 17-year-old male was admitted with the complaint of progressive weight gain. Abdominal ultrasonography was performed for elevation in transaminases which revealed a hypoechoic mass located in the left adrenal gland. Hormonal investigations revealed an increase in fractionated catecholamine and metanephrine levels in 24-hour urine. Surgery was performed and pathological examination was in accordance with pheochromocytoma. Mutation analysis was carried out. This is a rare case of pheochromocytoma presenting as adrenal incidentaloma during adolescence. In view of this case, we review the approach to incidentally discovered adrenal masses and the approach to pheochromocytoma. A mutation analysis should be performed on all cases with pheochromocytoma that are diagnosed below age 20. PMID- 29276877 TI - Left upper lobe atelectasis due to plastic bronchitis. AB - Sismanlar T, Aslan AT, Oztunali C, Boyunaga O. Left upper lobe atelectasis due to plastic bronchitis. Turk J Pediatr 2017; 59: 207-209. Plastic bronchitis is a rare condition in children, characterized by expectoration of branching bronchial casts. It can cause atelectasis in the lung. Herein we reported a 4.5-year-old boy with left upper lobe atelectasis due to plastic bronchitis. Although his chest X-ray is specific for left upper left atelectasis, thoracic computerized tomography had been performed and was compatible with obliterated left upper lobe bronchus. Typical radiological appearance of the left upper lobe atelectasis is not well known by clinicians which results unnecessary further examinations such as computerized tomography which exposes high dose radiation. We want to emphasize the long-term side effects of radiation and avoid unnecessary examinations in children. PMID- 29276878 TI - The use of nasal trumpet as a non-invasive treatment method in congenital nasal stenosis. AB - Kemal O, Atmaca S, Bel-Cecen A, Duzgun B, Aygun HC. The use of nasal trumpet as a non-invasive treatment method in congenital nasal stenosis. Turk J Pediatr 2017; 59: 210-213. Newborns and infants are dependent on nasal respiration and therefore, nasal obstructions may lead to life-threatening outcomes in this age group. Although the most common cause of nasal obstruction in newborns are choanal atresia, soft tissue edema, congenital nasal bone anomalies such as narrowness of the apertura piriformis and midnasal stenosis should be kept in mind. A 5-day-old infant was referred to our clinic with the complaints of respiratory problems. Physical examination revealed nasal bone hypoplasia and saddle nose deformity. In the endoscopic examination, the septum was seen to be deviated in an 'S' shape and the nasal passages were almost completely closed. The paranasal CT examination reported significant narrowing of the airway in the central part of the nasal cavity. After application of nasal trumpet to both nasal passages, clinical recovery was determined in the patient and no pathology was determined during the follow-up period. PMID- 29276879 TI - Unilateral pityriasis rosea in a child: A rare clinical presentation. AB - Ogrum A. Unilateral pityriasis rosea in a child: A rare clinical presentation. Turk J Pediatr 2017; 59: 214-216. Pityriasis rosea is a common papulosquamous disorder with occasional variations in lesion morphology, distribution, number and course of disease. The lesions are classically arranged with their long axes parallel to the Langer's lines of cleavage and typically affect the trunk and the proximal extremities. Variations in the distribution of pityriasis rosea include inversus, localized, and unilateral forms. The unilateral form is a very rare variant of pityriasis rosea, particularly in children. We report a 15-year-old boy with pityriasis rosea demonstrating unilateral localization. PMID- 29276880 TI - Isolated thoracoschisis: Case report. AB - Ardicli B, Karaman A, Ozyazici A, Zenciroglu A, Okumus N. Isolated thoracoschisis: Case report. Turk J Pediatr 2017; 59: 217-220. Thoracoschisis is a rare congenital anomaly that refers to a congenital fissure of the chest wall. It is frequently accompanied with other congenital defects of the limbs and the abdominal wall as part of the limb-body wall complex, which is exencephaly/encephalocele and facial clefts, thoracoschisis and/or abdominoschisis and limb defects. Isolated thoracoschisis is a rare entity. We present a case of isolated thoracoschisis. A 24-week gestational age boy presented with a 3 cm chest wall defect in the left lateral 10th intercostal space and intestines herniating through the defect. There was no history of maternal drug use during pregnancy. Birth weight was 500 g. He underwent surgery. The intestines were reduced via the thoracic wall defect. PMID- 29276881 TI - Truncus arteriosus with double aortic arch: A rare association. AB - Yildirim SV, Yildirim A. Truncus arteriosus with double aortic arch: A rare association. Turk J Pediatr 2017; 59: 221-223. Truncus arteriosus (TA) is a congenital heart defect often diagnosed in neonatal period; it represents 0.7% of all congenital heart lesions. The pulmonary arteries originate generally above the coronary ostium. Aorto-pulmonary and interventricular defects are believed to represent an abnormality of conotruncal septation. TA is classified into four types, according to Van Praagh and Colette Edwards. Some of congenital heart defects may be associated with TA, such as aortic interruption. In literature, TA with a double aortic arch is observed as a very rare condition. We present here a newborn diagnosed with a combination of TA type 1 and double aortic arch. PMID- 29276882 TI - Deciphering the Dynamic Interaction Profile of an Intrinsically Disordered Protein by NMR Exchange Spectroscopy. AB - Intrinsically disordered proteins (IDPs) display a large number of interaction modes including folding-upon-binding, binding without major structural transitions, or binding through highly dynamic, so-called fuzzy, complexes. The vast majority of experimental information about IDP binding modes have been inferred from crystal structures of proteins in complex with short peptides of IDPs. However, crystal structures provide a mainly static view of the complexes and do not give information about the conformational dynamics experienced by the IDP in the bound state. Knowledge of the dynamics of IDP complexes is of fundamental importance to understand how IDPs engage in highly specific interactions without concomitantly high binding affinity. Here, we combine rotating-frame R1rho, Carr-Purcell-Meiboom Gill relaxation dispersion as well as chemical exchange saturation transfer to decipher the dynamic interaction profile of an IDP in complex with its partner. We apply the approach to the dynamic signaling complex formed between the mitogen-activated protein kinase (MAPK) p38alpha and the intrinsically disordered regulatory domain of the MAPK kinase MKK4. Our study demonstrates that MKK4 employs a subtle combination of interaction modes in order to bind to p38alpha, leading to a complex displaying significantly different dynamics across the bound regions. PMID- 29276883 TI - Light-Activatable Theranostic Agents for Image-Monitored Controlled Drug Delivery. AB - A novel drug delivery vehicle using nanodroplets activated by light irradiation for drug release in a controlled manner has been developed. The drug encapsulated in the nanodroplets was released upon phase transition from a liquid droplet to microbubbles (vaporization) by plasmonic photothermal heat from gold nanorods adsorbed on the surface of the nanodroplets. The nanodroplets were stable against aggregation and dissolution at 4 degrees C over 3 months to date. The phase transition was quantitatively analyzed by ultrasound imaging to examine the amount of drug release noninvasively. In vitro studies showed that cell death occurred only when light irradiation was performed on the drug-encapsulated nanodroplets. Ex vivo studies demonstrated a potential application of the nanodroplets for treating posterior eye diseases. Thus, it has been demonstrated that our gold-nanorod-coated light-activatable nanodroplets can be a candidate for a controlled release and a dosage-monitored drug delivery system. PMID- 29276884 TI - Catalytic Asymmetric [4+2] Cycloaddition of in Situ Generated o-Quinone Methide Imines with o-Hydroxystyrenes: Diastereo- and Enantioselective Construction of Tetrahydroquinoline Frameworks. AB - A catalytic asymmetric [4+2] cycloaddition of ortho-quinone methide imines in situ generated from o-aminobenzyl alcohols with o-hydroxystyrenes has been established under the catalysis of chiral phosphoramide, which afforded chiral tetrahydroquinolines in moderate to good yields, good enantioselectivities, and excellent diastereoselectivities (up to 82% yield, 93:7 er, all >95:5 dr). In this catalytic asymmetric [4+2] cycloaddition, the hydrogen-bonding interaction between chiral phosphoramide and two substrates was proposed to play a crucial role in controlling the enantioselectivity. This reaction not only provides a useful approach for constructing chiral tetrahydroquinoline frameworks, but also demonstrates the great practicability of ortho-quinone methide imines in catalytic asymmetric cycloadditions. PMID- 29276886 TI - Fabrication of Anti-Icing Surfaces by Short alpha-Helical Peptides. AB - We designed 12-amino acid peptides as antifreeze protein (AFP) mimetics and tuned the antifreeze activity of the peptides by their structures. Moreover, these short peptides were first immobilized to surfaces as an anti-icing coating. We discovered that the peptides with higher antifreeze activity exhibited better anti-icing performance. It is the first time that short peptides were successfully applied to fabricate anti-icing surfaces, which is certainly advantageous in comparison to the AFP anti-icing coatings previously reported. PMID- 29276885 TI - Flow Cytometric Bead Sandwich Assay Based on a Split Aptamer. AB - A few aptamers still bind their targets after being split into two moieties. Split aptamers have shown great potential in the development of aptameric sensors. However, only a few split aptamers have been generated because of lack of knowledge on the binding structure of their parent aptamers. Here, we report the design of a new split aptamer and a flow cytometric bead sandwich assay using a split aptamer instead of double antibodies. Through DMS footprinting and mutation assay, we figured out the target-binding moiety and the structure stabilizing moiety of the l-selectin aptamer, Sgc-3b. By separating the duplex strand in the structure-stabilizing moiety, we obtained a split aptamer that bound l-selectin. After optimization of one part of the split sequence to eliminate the nonspecific binding of the split sequence pair, we developed a split-aptamer-based cytometric bead assay (SACBA) for the detection of soluble l selectin. SACBA showed good sensitivity and selectivity to l-selectin and was successfully applied for the detection of spiked l-selectin in the human serum. The strategies for generating split aptamers and designing the split-aptamer based sandwich assay are simple and efficient and show good practicability in aptamer engineering. PMID- 29276887 TI - Chronoamperometry-Based Redox Cycling for Application to Immunoassays. AB - In this work, the chronoamperometry-based redox cycling of 3,3',5,5' tetramethylbenzidine (TMB) was performed by using interdigitated electrode (IDE). The signal was obtained from two sequential chronoamperometric profiles: (1) with the generator at the oxidative potential of TMB and the collector at the reductive potential of TMB, and (2) with the generator at the reductive potential of TMB and the collector at the oxidative potential of TMB. The chronoamperometry based redox cycling (dual mode) showed a sensitivity of 1.49 MUA/OD, and the redox cycling efficiency was estimated to be 94% (n = 10). The sensitivities of conventional redox cycling with the same interdigitated electrode and chronoamperometry using a single working electrode (single mode) were estimated to be 0.67 MUA/OD and 0.18 MUA/OD, respectively. These results showed that the chronoamperometry-based redox cycling (dual mode) could be more effectively used to quantify the oxidized TMB than other amperometric methods. The chronoamperometry-based redox cycling (dual mode) was applied to immunoassays using a commercial ELISA kit for medical diagnosis of the human hepatitis B virus surface antigen (hHBsAg). Finally, the chronoamperometry-based redox cycling (dual mode) provided more than a 10-fold higher sensitivity than conventional chronoamperometry using a single working electrode (single mode) when applied to a commercial ELISA kit for medical diagnosis of hHBsAg. PMID- 29276888 TI - A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt Emerging as an "F-SO2 +" Donor of Unprecedented Reactivity, Selectivity, and Scope. AB - Sulfuryl fluoride, SO2 F2 , has been found to derivatize phenols in all kinds of environments, even those in highly functional molecules. We now report that a solid fluorosulfuryl imidazolium triflate salt delivers the same "F-SO2 +" fragment to Nu-H acceptor groups in the substrates. However, this triflate salt is a far more reactive fluorosulfurylating agent than SO2 F2 and displays selectivity preferences of its own. Moreover, the new azolium triflate reagent reacts once with primary amines and anilines before the reaction stops. On the other hand, with triethylamine and two equivalents of the "F-SO2 +" donor present, it proceeds on to the bis(fluorosulfuryl)imides in good yield-two important conversions that we have never seen with sulfuryl fluoride as the electrophile. PMID- 29276895 TI - Quorumolides A-C, Three Cembranoids from Euphorbia antiquorum. AB - Three highly modified cembranoids, quorumolides A-C (1-3), were isolated from Euphorbia antiquorum. Compound 1 is the first example of a cembranoid embedding an alpha,beta-unsaturated-gamma-lactone and a tetrahydro-2H-pyran motif within the 14-membered ring. Biosynthetically, it is particularly noteworthy that the stereochemistries of C-2 and C-12 in the pyran ring of 1-3 were opposite to those of marine-derived rare cembranoids. PMID- 29276894 TI - A Structure-Based Assembly Screen of Protein Cage Libraries in Living Cells: Experimentally Repacking a Protein-Protein Interface To Recover Cage Formation in an Assembly-Frustrated Mutant. AB - Cage proteins, which assemble into often highly symmetric hollow nanoscale capsules, have great potential in applications as far reaching as drug delivery, hybrid nanomaterial engineering, and catalysis. In addition, they are promising model systems for understanding how cellular nanostructures are constructed through protein-protein interactions, and they are beginning to be used as scaffolds for synthetic biology approaches. Recently, there has been renewed interest in the engineering of protein cages, and in support of these strategies, we have recently described a fluorescence-based assay for protein cage assembly that is specific for certain oligomerization states and symmetry-related protein protein interfaces. In this work, we expand this assay to living cells and a high throughput assay for screening protein cage libraries using flow cytometry. As a proof of principle, we apply this technique to the screening of libraries of a double-alanine mutant of the mini-ferritin, DNA-binding protein from starved cells (Dps). This mutant, due to disruption of key protein-protein interactions, is unable to assemble into a cage. Randomization of residues surrounding the double mutation afforded a repacked interface and proteins with recovered cage formation, demonstrating the strength and utility of this approach. PMID- 29276896 TI - Outcome of depressive and anxiety disorders among young adults: Results from the Longitudinal Finnish Health 2011 Study. AB - PURPOSE OF THE STUDY: We investigated the outcomes and outcome predictors of depressive and anxiety disorders in a general population sample of young adults with a lifetime history of these disorders. MATERIALS AND METHODS: The study sample was derived from a nationally representative two-stage cluster sample of Finns aged 19-34 years. The original study was carried out in 2003-2005, and the follow-up in 2011. We investigated participants diagnosed with a depressive or anxiety disorder based on a SCID interview (excluding those with only a single specific phobia) (DAX-group, N = 181). The control group included those with no DSM-IV- diagnosis (N = 290). They were followed up with the M-CIDI interview assessing 12-month depressive and anxiety disorders in 2011. RESULTS: In 2011, 22.8% of the DAX-group was diagnosed with a depressive or anxiety disorder compared to 9.8% of the control group. Education was lower and quality of life worse in the DAX-group than in the control group. Those participants of the DAX group who received a diagnosis in 2011 had poorer quality of life than those in remission, which emphasizes the influence of a current disorder on the quality of life. Higher score in the Mood Disorder Questionnaire (MDQ) at baseline predicted poorer quality of life in 2011. CONCLUSIONS: Thus, depressive and anxiety disorders were persistent/recurrent in one quarter of participants, significantly affecting education and quality of life. Young adults with these disorders need support to achieve their academic goals. PMID- 29276897 TI - Waist-to-hip ratio but not body mass index predicts liver cirrhosis in women. AB - BACKGROUND: Being overweight can lead to fatty liver and end-stage liver disease. In men, higher body mass index is associated with higher risk of developing liver cirrhosis. The extent of association between overweight and liver cirrhosis in women is not fully elucidated. AIMS: This study aimed to investigate the association between overweight and liver cirrhosis in women, taking into account different measures of adipose tissue distribution. METHODS: A cohort of 1462 middle-aged women was followed over 40 years. Cases of liver cirrhosis were identified by linkage to Hospital Discharge and Death Certificate registries. The hazard ratios for different anthropometric measures and liver cirrhosis were obtained by Cox proportional hazard regression, using propensity score methods to adjust for important confounders. RESULTS: During 48,062 person-years of follow up, 11 cases of liver cirrhosis were identified. The incidence rate in women with waist-to-hip ratio >= 0.8 was 131.8 (48.1-287.0), compared to 12.0 (3.9-28.1) in women with a lower ratio. A waist-to-hip ratio >= 0.8 was associated with an increased risk of liver cirrhosis, the hazard ratio being 5.8 (95% confidence interval 1.6-21.4). No association between body mass index and liver cirrhosis was found and the hazard ratio for body mass index >25 was 1.8 (0.5-5.8). CONCLUSION: In women, an unfavorable adipose tissue distribution is more important for development of liver cirrhosis than total body fat per se. When assessing the risk for development of liver cirrhosis in women, waist-to-hip ratio is a better predictor than body mass index. PMID- 29276898 TI - [Clinical and demographic characteristics of an outpatient Russian population with chronic heart failure at the time of enrollment in the QUALIFY registry for evaluating consistency with clinical guidelines on drug therapy]. AB - BACKGROUND: Chronic heart failure is the most common condition in patients with cardiovascular diseases. Therefore, evaluating consistency of doctor's recommendations with guidelines on drug therapy is a relevant issue. AIM: To evaluate consistency of doctor's recommendations with guidelines on drug therapy for CHF. MATERIALS AND METHODS: The study presents enrollment visit data for the Russian part of the international prospective registry, QUALIFY. The study included 404 outpatient patients with CHF between February, 2013 through June, 2014. Consistency with guidelines for drug therapy was evaluated for 5 drug classes, including ACE inhibitors (ACEI), beta-blockers (BB), angiotensin receptor antagonists (ARA), mineralocorticoid receptor antagonists (MRA), and ivabradine. RESULTS: On the whole, the consistency was good in 64.9% of cases, moderate in 27.7% of cases, and poor in 7.4% of cases. Proportions of patients who received a target dose of a medicine and a dose >=50% of the target dose were low, 21.5% and 62.3% for ACEI; 15% and 50.8% for BB; 20.3% and 39.8% for ARA; and 23.4% and 78.7% for ivabradine, respectively. These values, except for BB, were lower for patients with late hospitalization (hospitalization >=6 months vs. PMID- 29276899 TI - [Left ventricular diastolic dysfunction in endovascular treatment of atrial fibrillation in patients with preserved ejection fraction]. AB - AIM: To study prevalence of left ventricular diastolic dysfunction (LVDD) and to evaluate the effect of pulmonary vein catheter isolation on left ventricular (LV) diastolic function in patients with paroxysmal and persistent forms of atrial fibrillation (AF). MATERIALS AND METHODS: 109 patients with paroxysmal (n=90; 82.6 %) and persistent (n=19; 17.4 %) AF were evaluated after 109 pulmonary vein catheter isolations. The patients were divided into two groups based on the operation efficacy. Heart ultrasound including evaluation of the LV diastolic function was performed for all patients on the day of operation and at 6 and 12 months. RESULTS: After the surgery, 61 (56.5 %) patients maintained sinus rhythm (SR) for 12 months and comprised Group 1. Group 2 consisted of patients with a relapse of AF (47 patients; 43.5 %). At baseline, LVDD with SR was observed in 53 patients (48.6 %), at 6 months - in 34 (31.2 %) patients (p=0.001), and at 12 months - in 27 patients (24.8 %) (p. PMID- 29276900 TI - [Heart failure with preserved and slightly impaired ejection fraction and cardiovascular events: Pathogenetic interrelations as a part of the cardiovascular continuum]. AB - AIM: To evaluate the effect of decompensated HF with preserved or slightly impaired EF on the risk of cardiovascular complications during a 5-year follow up. MATERIALS AND METHODS: 33 patients with arterial hypertension and HF with preserved or slightly impaired EF (NT-proBNP >=125 pg/ml, mean, 500.1+/-590.32 pg/ml and EF >=40 %, mean, 57.0+/-10.29 %) were observed for 5 years. EchoCG, markers of immune inflammation and hormonal changes (endothelin, tumor necrosis factor (TNF), interleukin-6 (IL-6), aldosterone, renin) were evaluated at baseline. The endpoint was development of acute fatal and non-fatal cardiovascular events (CVEs). The one-way regression analysis was used to identify predictors of the risk for CVEs. The ROC analysis was used to determine "threshold levels" of significant predictors for this risk. RESULTS: During the 5 year follow-up period, CVEs developed in 13 (39.4 %) patients. The CVE predictors included baseline increases in creatinine and IL-6, NT-proBNP and a greater decrease in EF (r. PMID- 29276901 TI - [Prognostic role of body composition in patients with pneumonia associated with decompensated CHF]. AB - AIM: To evaluate the effect of body composition on prediction of community acquired pneumonia caused by Str. pneumoniae in patients with decompensated CHF. MATERIALS AND METHODS: The study included 216 patients. The pneumonia agent was identified by sputum culture. Body composition with determining lean body mass and fat mass was evaluated using a bio-impedance analysis; body mass index (BMI) was calculated. Patients with BMI 18.5-24.9 kg/m2 were included into the study. Statistical analysis of obtained data was performed using the IBM SPSS Statistics 20 software. RESULTS: The in-hospital mortality was 13.4 %; the one-year mortality was 29.6 %. Fat mass strongly, negatively correlated with a fatal outcome within a year, and the degree of lean body mass shortage moderately, positively correlated with the life span of patients. CONCLUSION: Body composition is significantly predictive for patients with decompensated CHF and community-acquired pneumonia caused by Str. pneumoniae. PMID- 29276902 TI - [Role of heart rate in mechanisms of compensation and decompensation in CHF patients with sinus rhythm and atrial fibrillation and methods for safe and efficient control of heart rhythm. Part 2. Atrial fibrillation]. AB - This review focuses on the role of heart rate in patients with a combination of heart failure and atrial fibrillation and on methods for heart rate control in such patients. PMID- 29276903 TI - [Left ventricular dysfunction in hypertensive heart: Current view of the pathogenesis and treatment]. AB - The article shows major mechanisms for development of left ventricular dysfunction in patients with hypertensive heart and provides major trends in the treatment of heart failure with preserved ejection fraction in the light of state of-the art in its pathogenesis. PMID- 29276904 TI - [Current ideas of a complex relationship between atrial fibrillation and ischemic heart disease and of optimum tactics for anticoagulant therapy to prevent embolism in systemic circulation]. AB - The article discusses the issue of searching for optimum oral anticoagulants to prevent thrombosis and embolism induced by heart disease both in patients with atrial fibrillation and sinus rhythm. A complex bidirectional relationship between atrial fibrillation and coronary atherosclerosis is considered along with possible mechanisms for development of myocardial infarction in patients with atrial fibrillation. The authors provided evidence-based data which can be used in selecting an anticoagulant for prevention of heart disease induced thrombosis and embolism taking into account both the efficacy and safety established in randomized clinical studies. PMID- 29276905 TI - [Peculiarities of therapy for heart rhythm disorders in patients with chronic heart failure]. AB - This review focuses on peculiarities of therapy for heart rhythm disorders in patients with CHF. Efficacy and safety of antiarrhythmic drugs and a high incidence of pro-arrhythmic effects are discussed. It is shown that the underlying disease and severity of structural damage to the heart are of critical significance. Treatment of ventricular arrhythmias and atrial fibrillation are discussed. PMID- 29276906 TI - [Efficacy of primary prevention for atherosclerosis-induced diseases in patients with high cardiovascular risk in Russia and other European countries (Part 1)]. AB - RELEVANCE: Evaluation of the effectiveness of risk management in persons with high cardiovascular risk is an important element in reducing the death rate of the population from cardiovascular diseases (CVD). AIM: Analysis of the prevalence and level of risk factors control in patients with high CV risk CVD from the Russian centers of the primary care unit of the EUROASPIRE IV study in comparison with the general population of the study. MATERIALS AND METHODS: In this cross-sectional study, 14 European countries, including the Russian Federation, participated. Patients aged 18 to 79 years were included in the study, without clinical manifestations of atherosclerosis, who were prescribed antihypertensive therapy and/or lipid lowering therapy and/or treatment for diabetes between the ages of >=6 months and. PMID- 29276907 TI - [Regulatory adaptive status in determining the effectiveness of bisoprololum and sotalolum in patients with hypertensive disease and paroxysmal supraventricular tachycardia]. AB - AIM: To determine efficacy of bisoprolol and sotalol treatments in patients with paroxysmal supraventricular tachycardia (SVT) and essential hypertension (EH) considering effects of these treatments on the regulatory adaptive status (RAS). MATERIALS AND METHODS: The study included 49 patients with paroxysmal SVT associated with stage II-III EH randomized to two groups of either bisoprolol (6.9+/-2.2 mg/day, n=25) or sotalol (162.5+/-46.2 mg/day, n=24) treatment. Lisinopril (14.5+/-3.9 and 14.3+/-4.7 mg/day) and, if indicated, atorvastatin (15.4+/-3.8 mg/day, n=9 and 16.0+/-4.8 mg/day, n=10), and acetylsalicylic acid (91.5+/-14.7 mg/day, n=12 and 94.1+/-16.5 mg/day, n=14) were administered as a part of combination therapy. Quantitative evaluation of RAS (cardiorespiratory synchronism test), EchoCG, triplex scanning of brachiocephalic arteries, treadmill test, 6-min walk test, 24-h BP and ECG monitoring, and subjective assessment of the quality of life were performed at baseline and after 6 months of therapy. RESULTS: Both regimens of the combination drug therapy comparably improved the structural and functional status of the heart, increased exercise tolerance, effectively suppressed SVT paroxysms, and improved the quality of life. In this process, sotalol reduced RAS to a lesser extent that bisoprolol. CONCLUSION: In patients with paroxysmal SVT associated with stage II-III EH, the sotalol treatment as a part of the combination therapy may be preferable due to fewer adverse effects on RAS compared to bisoprolol. PMID- 29276908 TI - [Correlations of IL-18 and IL-6 with sodium consumption in patients with arterial hypertension and diabetes mellitus]. AB - AIM: To determine correlations of AH-associated interleukins (IL-18, IL-6) with sodium consumption in AH patients with and without DM. MATERIALS AND METHODS: The study included AH patients with and without DM (n=63) who were managed at the Municipal Clinic #64, Moscow Department of Health Care, Branch 1. Plasma levels of IL-6 and IL-18 were measured using ELISA kits (Bender Med-Systems). Salt consumption was determined using a Charlton: SaltScreener questionnaire. Statistical analyses were performed using the Statistica 10.0 software. RESULTS: Four groups were formed: Group 1, grade 2 AH and DM (n=19); Group 2, grade 2 AH and no DM (n=4); Group 3, grade 3 AH and no DM (n=28); and Group 4, grade 3 AH and DM (n=12). Group 2 was small and was excluded from further analysis due to impossibility of statistical treatment. All patients consumed more than 6 g of salt per day (approximately 10 g). Analysis of intergroup differences in selected parameters showed differences between groups in levels of cholesterol, triglycerides, LDL, and GFR. The following correlations were identified in the groups: Group 1, positive correlation of IL-18 with sodium consumption (r=0.65) and CRP level (r=0.52) and of IL-6 with LDL level (r=0.48); Group 3, positive correlation of IL-18 with IL-6 (r=0.66) and of IL-6 with CRP (r=0.52); Group 4, positive correlation of IL-18 with GFR (r=0.82) and of IL-6 with waist circumference (WC) (r=0.84) and IL-6 (r=0.73). CONCLUSION: Patients consuming more than 6 g of salt daily (approximately 10 g) with AH and DM had more pronounced inflammation, which promoted progression of kidney disease. PMID- 29276909 TI - [Management of patients with isolated aortic stenosis considering negative prognostic factors]. AB - BACKGROUND: Aortic stenosis (AS) is the most common valve defect in developed countries; its prevalence increases with age of the population. The most frequent cause for isolated AS in adults is calcification of normal tricuspid or congenital bicuspid aortic valve (AV). The only effective treatment of AS is aortic valve replacement (AVR). Major negative prognostic factors include low LV ejection fraction (EF), age older than 70, female gender, and comorbidities such as renal dysfunction, chronic obstructive pulmonary disease, and neural disorders. AIM: To study negative prognostic factors influencing outcomes of treatment for AS and to determine possibilities for managing AS patients taking into account these factors. MATERIALS AND METHODS: 120 medical records of patients who had undergone AVR for isolated AS (76 women and 44 men aged 45 to 81) were studied retrospectively, and 50 patients were examined in a late post-AV period (26 women aged 67.5 (65.0-72.0) at the time of surgery, 24 men aged 63.0 (57.0-68.0) at the time of surgery), and 84 unoperated patients (51 women and 33 men). RESULTS: Perioperative death rate was 8.76 %, 11 of 120 patients, 3 men (6.8 % of operated men) and 8 women (10.5 % of all operated women). The deceased patients aged 70 or older whereas perioperative death rate of patients younger than 70 was zero (Pchi 2 =0.004). Despite a relatively high perioperative risk, late survival of patients older than 70 who had undergone AVR was substantially and statistically significantly higher than that of unoperated AS patients. In elderly patients who died during the perioperative period of AVR, the history of valve defect was longer, and a part of the patients who did not survive AVR could have been operated at age younger than 70. Unoperated AS patients with a small LV cavity, severe LV hypertrophy, and LV EF >70 % were suggested to be isolated into a special group of risk with a special strategy for cardiosurgical treatment. PMID- 29276910 TI - [A rare case of metastatic tumor of heart from bladder cancer]. AB - The article presents a case report of metastatic heart damage which developed in association with urothelial bladder carcinoma in a 79-year old female patient. Various masses may be found in the heart. In tumors, a secondary damage to the heart is observed much more frequently than a primary damage; however, metastasis of bladder carcinoma to the heart is extremely rare. Of interest is the fact of metastatic damage to all layers of the heart, including the endocardium, pericardium, and myocardium. PMID- 29276911 TI - [Comparison of Direct Stenting Versus Stending After Pre-Dilation in ST-Elevation Myocardial Infarction]. AB - AIM: To study was to assess in-hospital outcomes of direct coronary stenting (DS) compared with stenting after predilation (PD) in patients with ST-elevation myocardial infarction (STEMI). MATERIAL AND METHODS: Data were collected from all patients (n=1103) with STEMI subjected to primary PCI in Tyumen cardiology center from 2006 to 2014. The clinical and angiographic characteristics, in-hospital outcomes, as well as predictors of no-reflow phenomenon were analyzed. The composite of in-hospital death, myocardial infarction (MI) and stent thrombosis were defined as major adverse cardiac events (MACE). RESULTS: Altogether 563 patients (51 %) underwent DS, and in 540 (49 %) stents were implanted after PD. Patients in DS group compared with those in PD group were younger (57.9+/-10.9 vs 60+/-11.5 years; p=0.001), less often had chronic kidney disease (5.2 vs 8.4 %; r=0.034), more often recieved prehospital thrombolysis (25 vs 11.9 %; p. PMID- 29276912 TI - [Antihypertensive Efficacy of Fixed Combination Azilsartan Medoxomil / Chlorthalidone in Patients With Uncontrolled Arterial Hypertension]. AB - AIM: To study effects of a fixed azilsartan medoxomil/chlorthalidone combination (Edarbi Clo) on clinical, ambulatory and central blood pressure (BP) in patients with uncontrolled arterial hypertension (AH)). MATERIALS AND METHODS: Patients (n=25) with uncontrolled AH were given fixed azilsartan medoxomil/chlorthalidone combination (40 / 12.5 mg / day) for 4 weeks. After 4 weeks, in patients who did not achieve target BP levels the dose was increased up to 40 / 25 mg / day. Duration of the study was 12 weeks. RESULTS: After 12 weeks of treatment 88 % of patients achieved target clinical BP (. PMID- 29276913 TI - [Change in the Nature of the Course of Arterial Hypertension in Patients With Chronic Arterial Insufficiency of the Extremities in Acute Thrombotic Occlusion]. AB - The article is devoted to the investigation of the mechanisms of the development of arterial hypertension (AH) in patients with atherosclerosis of the abdominal aorta and the formation of chronic lower limb ischemia (Lerish syndrome). With the development of thrombotic occlusion of arteries of the lower extremities, the nature of the course of hypertension worsens. The operational recovery of the main blood flow in the limbs positively influences the course of hypertension in the majority of patients. PMID- 29276914 TI - [Perspective Directions in Management of Severe Group Two Pulmonary Hypertension]. AB - PURPOSE: To compare immediate results of mitral valve surgery in patients with severe pulmonary hypertension with versus without concomitant pulmonary artery denervation. MATERIALS AND METHODS: From January to December 2015 30 patients were randomly assigned into two groups. Patients of one group underwent mitral valve surgery (comparison group), in the other group mitral valve surgery was accompanied by pulmonary artery ablation (ablation group). Both groups had comparable anthropometric, echocardiographic, and hemodynamics characteristics. RESULTS: There were no hospital mortality and specific ablation-related complications. Left ventricular remodeling and decrease of pulmonary artery pressure were observed in both groups at discharge. On the third day after surgery systolic and mean pulmonary artery pressure assessed by right heart catheterization were 48 and 22 versus 59 and 39 mm Hg in ablation and comparison group, respectively (p. PMID- 29276915 TI - [Progression of Atrial Fibrillation in Patients With Arterial Hypertension When Choosing Different Treatment Strategies for Arrhythmia]. PMID- 29276916 TI - [Intracellular Molecular Mechanisms of Adrenergic Regulation of Pulmonary Vein Myocardium Membrane Potential]. AB - Pulmonary vein (PV) myocardium is characterized by numerous electrophysiological properties which make this tissue highly prone to spontaneous, ectopic activity partially due to resting potential (RP) instability. PV derived ectopy frequently underlies supraventricular arrhythmias, including atrial fibrillation. It has also been demonstrated that adrenergic stimulation causes proarrhythmic alterations in PV. Selective alpha1- and beta-adrenoreceptors stimulation causes RP depolarization and hyperpolarization, respectively, at least in rats. The intracellular mechanisms of alpha1- and beta-adrenoreceptors-dependent RP drifts are not investigated. Adenylate cyclase (AC) activator forscolin similarly to selective beta-adrenoreceptors agonist isoproterenol (ISO) induced strong hyperpolarization in quiescent isolated perfused multicellular preparations of rat PV. Maximal value of hyperpolarization in PV was equal after application of both compounds. Proteinkinase A (PKA) inhibitors KT5720, H-89 and Rp-adenosine cAMP suppressed ISO-induced hyperpolarization in PV. Inhibitors of phospholipase C (U73122) or D (FIPI), similarly to proteinkinase C (PKC) inhibitor chelerythrine, failed to suppress alpha-adrenoreceptors-dependent phenylephrine induced depolarization in rat PV myocardium. These results allow us to suggest that beta-adrenoreceptors-dependent RP hyperpolarization in quiescent rat PV myocardium is only partially mediated by cAMP-dependent signal transduction pathway and by PKA. Besides, PKA-independent mechanisms also contribute to beta agonists effects in PV. In addition, alpha-adrenoreceptors-dependent depolarization in rat PV myocardium could be independent on PLC and PKC. PMID- 29276917 TI - [The Integrated Approach to Improving Efficiency and Safety of Anticoagulation Therapy in Patients With Prosthetic Mitral Valve]. AB - AIM: To assess advantages of integrated approach to improvement of efficiency and safety of warfarin therapy after heart valve replacement. MATERIALS AND METHODS: We included in this study 118 patients who had undergone simultaneous mitral valve replacement and maze procedure. Group 1 patients (n=37) underwent just sinus rhythm restoration, group 2 patients (n=54) underwent sinus rhythm restoration and participated in a patient education program, group 3 patients (n=27) underwent sinus rhythm restoration, participated in a patient education program, and were subjected to pharmacogenetic testing for warfarin sensitivity. In examination of patients we used clinical, demographic, and instrumental methods. Estimation of the time in the therapeutic range (TTR) of an international normalized ratio (INR) was used as a measure of warfarin therapy quality, and the Kaplan-Meier method was applied for analysis of hemorrhagic and thrombotic complications. RESULTS: TTR was 42 % in group 1, 68 % in group 2 (p=0.0327), and 82 % in group 3 (p=0.0019). Application of integrated approach was associated with absence of hemorrhagic and thrombotic complications within one year after heart valve replacement. CONCLUSION: The integrated approach comprising restoration of sinus rhythm, patient education, and pharmacogenetic testing for warfarin sensitivity was associated with improved anticoagulation control, and prevention of hemorrhagic and thrombotic complications. PMID- 29276919 TI - [Features of Nutrition in Groups of Healthy Young People From Families With a History of Coronary Heart Disease and Diabetes History]. PMID- 29276918 TI - [Analysis of Urine Proteome in Patients With Postinfarction Cardiosclerosis Combined With Hypertensive Disease for Assessing Endothelial Dysfunction]. AB - In our study urine protein composition of 18 healthy volunteers was compared with that of 18 patients with ischemic heart disease and concomitant hypertension. Liquid chromatography-mass-spectrometry (LC-MS) analysis of the second fraction of morning urine was carried out using nano-line high performance liquid chromatograph and hybrid mass spectrometer. The analysis revealed 23 proteins expressed in the endothelium, according to the information contained in the database Bgee, and 49 proteins, with direct functional link with the processes in the endothelium in the reconstruction of associative networks using ANDSystem program. Comparison of urine proteome of healthy people and patients with postinfarction cardiosclerosis revealed proteins specific for patients with cardiovascular disease. Thus, proteins vitronectin, syndecan-4, a histidine rich glycoprotein, endothelial protein C receptor, colony stimulating factor, cathepsin D and sekretogranin-1 may be considered as potential markers for cardiovascular diseases. Further research in this area should be conducted for clinical and experimental verification of these hypotheses. PMID- 29276920 TI - [Blood Pressure Variability. Visit-to-Visit Blood Pressure Variability]. AB - The article is devoted to the modern state of the problem of blood pressure variability (BPV). Along with discussion of classification and methods of diagnosis it contains data on prognostic value of visit-to-visit BPV. We have also reviewed effect on BPV of various regimens of antihypertensive therapy and presented evidence base supporting ability of amlodipine/perindopril fixed dose combination to lower visit-to-visit BPV. PMID- 29276921 TI - [Indapamide SR/Amlodipine Fixed Dose Combination: Novel Approach to Effective Control of Systolic Arterial Pressure]. AB - Effective control of arterial pressure (AP) is achieved only in 1/3 of patients with arterial hypertension. It is especially difficult to achieve control of systolic (S) AP in elderly patients in whom SAP is the strongest prognostic factor of cardiovascular complications. Thiazide and thiazide-like diuretics and calcium antagonists are effective for lowering of elevated SAP and pulse (P) AP including aortic PAP elevation of which is associated with high stiffness of arterial wall and is typical for elderly people. Combination of a thiazide diuretic and a calcium antagonist has been recommended by modern guidelines on arterial hypertension (AH) management but until recently it has not found wide application because of absence of a fixed preparation. Evidence base of indapamide-retard and amlodipine use in AH, their profiles of efficacy and safety are such that their combination can become an alternative variant for treatment of patients with AH. Appearance of a fixed indapamide-retard/amlodipine combination opens new perspectives of effective therapy of AH with high SAP and PAP in elderly and other patients with high stiffness of arterial wall. PMID- 29276922 TI - [Clinico-Pharmacological and Clinical Basis of Multiplicity of Intake of Novel Oral Anticoagulants]. AB - In this review we present comparison of pharmacokinetics of novel oral anticoagulants (NOAC) dabigatran, rivaroxaban, apixaban, and edoxaban, principles of selection of a regimen of their dosing for phase III clinical trials in patients with atrial fibrillation. Multiplicity of administration of NOAC depends on required level of anticoagulation, ability to maintain anticoagulation for 24 hours, relationship between minimal and maximal levels of equilibrium concentrations, efficacy and safety. Once a day administration of some drugs of this group is reasonable from positions of clinical pharmacology. It can provide not only better adherence to treatment but greater safety relative to development of bleeding. PMID- 29276923 TI - [Diagnosis and Treatment of Patients With Non-STSegment Elevation Acute Coronary Syndrome. Part 4]. PMID- 29276924 TI - [Myocardial Hypoenhancement on Multidetector Computed Tomography in Patients With Non-ST Elevation Acute Coronary Syndrome]. AB - : The purpose of our study was analysis of myocardial hypoenhancement areas (MHAs) found by multidetector computed tomography (MDCT) in patients with non-ST elevation acute coronary syndrome (NSTEACS) and comparison of these findings with results of standard methods of diagnostics of myocardial infarction and ischemia [electrocardiography (ECG) and echocardiography (ECHO)]. METHODS: MHAs were found in 18 of 21 patients with non-ST segment elevation myocardial infarction (NSTEMI) (85.7%) and only in 3 of 22 patients with unstable angina (UA) (13.6%, p. PMID- 29276925 TI - [ISCHEMIA - the Largest Ever R andomized Study in Stable Coronary Artery Disease. Baseline Characteristics of Enrolled Patients in One Russian Site]. AB - : Indications for coronary revascularization in patients with stable coronary heart disease (CHD), presented in the current international guidelines are largely based on the clinical trials conducted sometimes more than 30 years ago. ISCHEMIA is the major multicenter international randomized trial intended to answer the question about the optimal treatment strategy in stable coronary artery disease at the present time. PURPOSE: To analyze the most important baseline characteristics of patients enrolled in the ISCHEMIA study in one Russian site. METHODS: The principal inclusion criteria are a positive stress test (in our center, exercise stress echocardiography) of at least moderate risk and obstructive coronary heart disease confirmed by coronary computed tomography angiography (CCTA). Main exclusion criteria are a significant stenosis of the left main coronary artery by CCTA, clinical progression/destabilization of the ischemic heart disease, angina of IV CCS class, left ventricular ejection fraction (EF) 80% - beta blockers, >80% - ACE inhibitors/ARBs. They are at well controlled resting heart rate (. PMID- 29276926 TI - [Pathogenetic and Prognostic Role of Growth Factors in the Development of Chronic Heart Failure]. AB - AIM: To study the role of growth factors ((vascular endothelial growth factor (VEGF), platelet derived growth factor AB (PDGF-AB) and basic fibroblast growth factor (FGF-basic)) in the development and progression of chronic heart failure (CHF) in patients with ishcemic heart disease (IHD). MATERIALS AND METHODS: We included in this study 94 patients with CHF. The control group comprised 32 persons. Blood serum levels of growth factors were determined at baseline and after 12 months of observation by enzyme-linked immunosorbent assay. RESULTS: VEGF, PDGF-AB and FGF-basic play an important role in the pathogenesis and progression of heart failure in patients with IHD, determining the increased risk of adverse cardiovascular events in this pathology. Serum activity of growth factors characterizes the severity and course of CHF: with disease progression levels of VEGF and FGF-basic decrease and PDGF-AB concentration increases. Initial low level of VEGF expression regardless of the sex of the patient's sex, significantly low level of FGF-basic and significantly high PDGF-AB in men characterizes unfavorable course of CHF. CONCLUSION: A correlation has been established between blood serum levels of VEGF, PDGF-AB and FGF-basic and severity and course of CHF. PMID- 29276927 TI - [Prognostic Value of Melatonin Level, Structural and Functional Changes of the Myocardium in the Development of Complications in Patients With Heart Failure who Underwent Coronary Artery Bypass Grafting: the Possibilities of Pharmacological Cardioprotection]. AB - OBJECTIVE: To assess the significance of melatonin, NT-proBNP and morphological markers of myocardial remodeling for predicting the risk of complications after coronary artery bypass grafting (CABG) in patients with ischemic heart disease and chronic heart failure (CHF). MATERIALS AND METHODS: We included in this study 83 patients who underwent CABG in the period from September 2013 to October 2014. All patients before CABG underwent standard laboratory and instrumental examination. Concentrations of melatonin and NT-proBNP were measured in 2 days before and after surgery. The evaluation of morphological markers of myocardial remodeling (expression of MT2 melatonin receptors [MTR2], caspase-3, bcl-2) was carried out in tissue samples taken at biopsies of the right atrial appendage during CABG. RESULTS: Analysis of groups of patients with favorable and unfavorable hospital outcomes revealed no significant differences in serum levels of NT-proBNP. There was a significant decrease in the level of melatonin in the subgroup of patients with unfavorable outcome of CABG in combination with high comorbid load and high degree of apoptosis of cardiomyocytes at the background of moderate and high MTR2 expression. Comparative assessment of pharmacotherapy prior to CABG revealed favorable effect on myocardial remodeling of a combination of perindopril and amlodipine. CONCLUSION: Preoperative evaluation of the level of melatonin sulfate, apoptosis markers, and comorbid load can serve as prognostic factors of complicated course of the postoperative period after CABG in patients with CHF. The combination of perindopril and amlodipine in patients with heart failure with preserved ejection fraction exerted a significant cardioprotective effect on the myocardium, contributing to a decrease of the apoptotic dominant. PMID- 29276928 TI - [Prevalence of Markers of Chronic Kidney Disease in Patients With Arterial Hypertension: Results of Epidemiological Study CHRONOGRAF]. AB - In an noninterventional observational open multicenter program CHRONOGRAF the prevalence of markers of chronic kidney disease (CKD) was studied in 1600 patients with arterial hypertension with and without type 2 diabetes mellitus. Glomerular filtration rate (GFR) was calculated (CKD-EPI formula) and albuminuria (AU) was determined as albumin/creatinine (A/Cr) ratio in the morning portion of urine. In 49.4% of patients decreased GFR 30 mg/g was detected. Decrease of GFR 30 mg/g - in 32.6%, combination of reduced GFR and high/very high AU - in 18%. High or very high level of combined risk of progression to CKD and cardiovascular complications had 28.5% of patients. PMID- 29276929 TI - [Choice of Angiotensin Receptor Blocker at Various Stages of the Cardiovascular Continuum]. AB - We present in this paper modern views on components, physiological and pathophysiological effects of the renin-angiotensin system, pathways of its hyperactivation at various stages of the cardiovascular continuum. Special emphasis is made on angiotensin receptor blockers (sartans). Basing on results of analysis of randomized clinical trials of these agents we have outlined clinical situations in which prescription of one or another drug from this group is preferable. For patients with multiple risk factors of cardiovascular complications preferable agent is telmisartan, for patients with nephropathy - irbesartan, for survivors of acute myocardial infarction - valsartan, while for patients with clinical signs of chronic heart failure with low ejection fraction 3 agents can be designated as preferrable - losartan, valsartan, and candesartan. PMID- 29276930 TI - [Perfusion-Metabolic Myocardial Scintigraphy in Prognosis of Left Ventricular Remodeling After Complex Surgical Treatment of Ischemic Cardiomyopathy]. AB - PURPOSE: To study capabilities of perfusion-metabolic myocardial scintigraphy for prediction of the left ventricular (LV) reverse remodeling after comprehensive surgical treatment of ischemic cardiomyopathy (ICMP). METHODS: The study included ICMP patients aged 56+/-7 years (n=32) who underwent surgical correction of LV dysfunction (myocardial revascularization, LV reconstruction, and mitral valve restoration). Inclusion criteria were significant coronary artery disease; myocardial infarction; New York Heart Association (NYHA) class III-IV heart failure; LV ejection fraction (EF) <=45%; LV end-systolic index (ESI) >60 mL/m2; and LV akinesia or dyskinesia according to echocardiography. Before surgery all patients were subjected to scintigraphy with 99mTc-MIBI (to assess perfusion) and with 123I-BMIPP (to assess myocardial metabolism). Scintigraphy results were expressed as median and lower; upper quartile (Me [lQ; hQ]). The clinical status and ventricular volume indicators were evaluated before surgery, in the early post-operative period (up to 4 weeks), and in the late post-operative period (12 months). RESULTS: At 12 months after intervention patients were divided into two groups: group 1 comprised patients (n=18) with beneficial outcome of the operation that stopped LV remodeling (ESI decreased, remained unchanged, or increased by. PMID- 29276931 TI - [Medication Adherence of Elderly Patients With Chronic Heart Failure]. AB - The review is devoted to the problem of medication adherence in elderly patients with chronic heart failure. We consider here specificity of approach to management of elderly outpatients, groups of factors associated with medication adherence, and possible ways to improvement of compliance to treatment in patients from the senior age group with heart failure. PMID- 29276932 TI - [Lisinopril, Amlodipine, Rosuvastatin as a Novel Fixed Combination in the Fight Against Cardiovascular Disease]. AB - The prevalence of multicomponent therapy in treatment of cardiovascular diseases makes fixed combinations of drugs very useful. The fixed combination of rosuvastatin with ACE inhibitor lisinopril and calcium antagonist amlodipine allows to control effectively two main cardiovascular risk factors: hypercholesterolemia and arterial hypertension. The efficacy of each of the components and their combined administration in primary and secondary prevention of cardiovascular disease has been demonstrated in clinical studies. The convenience of several drugs combination in a single tablet increases adherence to therapy facilitating regular intake of all treatment components and reliably reducing the risk of cardiovascular complications. PMID- 29276933 TI - [Restoration of Sinus Rhythm in Patients With Persistent Atrial Fibrillation and Obesity: New Possibilities of Pharmacological Cardioversion]. AB - We present in this article 2 cases of successful pharmacological restoration of sinus rhythm by a new class III antiarrhythmic drug refralon in patients with obesity and persistent atrial fibrillation. In both cases, the effective use of refralon was preceded by repeated ineffective attempts of electrical cardioversion. In the article we discuss the role of obesity as the factor leading to a substantial increase of transthoracic electrical resistance, and thus significantly reducing the probability of sinus rhythm restoration by means of electrical cardioversion. The clinical examples described in this article clearly show that the use of refralon may represent a unique clinical alternative to electrical cardioversion for sinus rhythm restoration in patients with persistent atrial fibrillation, and in some cases where the success of electrical cardioversion is obviously questionable, like in patients with severe obesity, the use of refralon seems preferable. PMID- 29276934 TI - [Noncoronary Necrosis With Myocardial Rupture in a Young Woman]. AB - The article presents a clinical case of development of noncoronary myocardial necrosis with cardiac rupture in a young woman at a background of severe stress. PMID- 29276935 TI - [Rivaroxaban for Secondary Prophylaxis of Atherothrombosis Complications in Patients With Recent Acute Coronary Syndrome]. PMID- 29276936 TI - [Diagnosis and Treatment of Patients With Non-STSegment Elevation Acute Coronary Syndrome. Part 3]. PMID- 29276937 TI - Pirfenidone Inhibits Proliferation and Promotes Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the Wnt/beta-Catenin Signaling Pathway. AB - BACKGROUND Hepatocellular carcinoma (HCC) is the most important cause of cancer related deaths worldwide. Pirfenidone is an orally available small molecule with therapeutic potential for fibrotic diseases. MATERIAL AND METHODS In this study, we analyzed the effects of different pirfenidone concentrations on the proliferation of HepG2 HCC cells using Cell Counting Kit-8 (CCK-8) and colony formation assays. Flow cytometry was performed to measure the apoptotic effects of pirfenidone on HepG2 cells. Western blot analysis was performed to detect the expression of beta-catenin and p-beta-catenin. RESULTS Pirfenidone inhibited proliferation and promoted HepG2 cell apoptosis. In addition, Western blot results indicated that pirfenidone suppressed b-catenin expression in HepG2 cells. To assess the mechanism, we treated HepG2 cells with pirfenidone, and pirfenidone plus the beta-catenin activator, SB-216763. The results revealed that SB-216763 accelerated proliferation and inhibited apoptosis in HepG2 cells treated with pirfenidone. Western blot results showed that SB-216763 upregulated beta-catenin expression in HepG2 cells treated with pirfenidone. CONCLUSIONS In conclusions, pirfenidone may be a potential drug for HCC treatment. PMID- 29276940 TI - Opioid Prescribing: What Are the Numbers? PMID- 29276938 TI - (Radio)fluoroclick Reaction Enabled by a Hydrogen-Bonding Cluster. AB - We have developed a widely applicable nucleophilic (radio)fluoroclick reaction of ynamides with readily available and easy-to-handle KF(18 F). The reactions exhibited high functional-group tolerance and needed only an ambient atmosphere. This 18 F addition to C-C unsaturated bonds proceeded with extraordinarily high radiochemical yields. PMID- 29276941 TI - Rnf152 Is Essential for NeuroD Expression and Delta-Notch Signaling in the Zebrafish Embryos. AB - We report the biological functions of a zebrafish homologue of RING-finger protein 152 (rnf152) during embryogenesis. rnf152 was initially identified as a brain-enriched E3 ligase involved in early embryogenesis of zebrafish. Expression of rnf152 was ubiquitous in the brain at 24 hpf but restricted to the eyes, midbrain-hindbrain boundary (MHB), and rhombomeres at 48 hpf. Knockdown of rnf152 in zebrafish embryos caused defects in the eyes, MHB, and rhombomeres (r1-7) at 24 hpf. These defects in rnf152-deficient embryos were analyzed by whole-mount in situ hybridization (WISH) using neuroD, deltaD, notch1a, and notch3 probes. NeuroD expression was abolished in the marginal zone, outer nuclear layer (ONL), inner nuclear layer (INL), and ganglion cell layer (GCL) of the eyes at 27 hpf. Furthermore, deltaD and notch1a expression was remarkably reduced in the ONL, INL, subpallium, tectum, cerebellum, and rhombomeres (r1-7) at 24 hpf, whereas notch3 expression was reduced in the tectum, cerebellum, and rhombomeres at 24 hpf. Finally, we confirmed that expression of Notch target genes, her4 and ascl1a, also decreased significantly in these areas at 24 hpf. Thus, we propose that Rnf152 is essential for development of the eyes, midbrain and hindbrain, and that Delta-Notch signaling is involved. PMID- 29276942 TI - Humic Acid Confers HIGH-AFFINITY K+ TRANSPORTER 1-Mediated Salinity Stress Tolerance in Arabidopsis. AB - Excessive salt disrupts intracellular ion homeostasis and inhibits plant growth, which poses a serious threat to global food security. Plants have adapted various strategies to survive in unfavorable saline soil conditions. Here, we show that humic acid (HA) is a good soil amendment that can be used to help overcome salinity stress because it markedly reduces the adverse effects of salinity on Arabidopsis thaliana seedlings. To identify the molecular mechanisms of HA induced salt stress tolerance in Arabidopsis, we examined possible roles of a sodium influx transporter HIGH-AFFINITY K+ TRANSPORTER 1 (HKT1). Salt-induced root growth inhibition in HKT1 overexpressor transgenic plants (HKT1-OX) was rescued by application of HA, but not in wild-type and other plants. Moreover, salt-induced degradation of HKT1 protein was blocked by HA treatment. In addition, the application of HA to HKT1-OX seedlings led to increased distribution of Na+ in roots up to the elongation zone and caused the reabsorption of Na+ by xylem and parenchyma cells. Both the influx of the secondary messenger calcium and its cytosolic release appear to function in the destabilization of HKT1 protein under salt stress. Taken together, these results suggest that HA could be applied to the field to enhance plant growth and salt stress tolerance via post-transcriptional control of the HKT1 transporter gene under saline conditions. PMID- 29276943 TI - Nuclear Bodies Built on Architectural Long Noncoding RNAs: Unifying Principles of Their Construction and Function. AB - Nuclear bodies are subnuclear, spheroidal, and membraneless compartments that concentrate specific proteins and/or RNAs. They serve as sites of biogenesis, storage, and sequestration of specific RNAs, proteins, or ribonucleoprotein complexes. Recent studies reveal that a subset of nuclear bodies in various eukaryotic organisms is constructed using architectural long noncoding RNAs (arcRNAs). Here, we describe the unifying mechanistic principles of the construction and function of these bodies, especially focusing on liquid-liquid phase separation induced by architectural molecules that form multiple weakly adhesive interactions. We also discuss three possible advantages of using arcRNAs rather than architectural proteins to build the bodies: position-specificity, rapidity, and economy in sequestering nucleic acid-binding proteins. Moreover, we introduce two recently devised methods to discover novel arcRNA-constructed bodies; one that focuses on the RNase-sensitivity of these bodies, and another that focuses on "semi-extractability" of arcRNAs. PMID- 29276944 TI - Rice Bioactive Peptide Binding with TLR4 To Overcome H2O2-Induced Injury in Human Umbilical Vein Endothelial Cells through NF-kappaB Signaling. AB - Reactive oxygen species-induced vessel endothelium injury is crucial in cardiovascular diseases progression. Rice-derived bran bioactive peptides (RBAP) might exert antioxidant effect through unknown mechanisms. Herein, we validated the antioxidant effect and mechanism of RBAP on H2O2-induced oxidative injury in human umbilical vein endothelial cells (HUVECs). Here, HUVECs were treated with RBAP under H2O2 stimulation; the effects of RBAP on HUVECs oxidative injury were evaluated. H2O2 injury-induced cell morphology changes were ameliorated by RBAP. The effect of H2O2- on HUVEC apoptosis (percentage of apoptotic cell: 38.00 +/- 2.00 in H2O2 group vs 21.07 +/- 2.06 in RBAP + H2O2 group, P = 0.0013 compared to H2O2 group), the protein levels of cleaved caspase-3 (relative protein expression: 2.90 +/- 0.10 in H2O2 group vs 1.82 +/- 0.09 in RBAP + H2O2 group, P < 0.0001 compared to H2O2 group) and p-p65 (relative protein expression: 1.86 +/- 0.09 in H2O2 group vs 1.35 +/- 0.08 in RBAP + H2O2 group, P < 0.0001 compared to H2O2 group) could be attenuated by RBAP. RBAP exerts its protective function through binding with Toll-like receptor 4 (TLR4). Taken together, RBAP protects HUVECs against H2O2-induced oxidant injury, which provided the theoretical basis for the molecular mechanism of rice deep processing and exploitation of functional peptides. PMID- 29276945 TI - Coffee Consumption and Cardiovascular Disease: A Condensed Review of Epidemiological Evidence and Mechanisms. AB - Coffee is one of the most widely consumed beverages, and some studies have suggested it may be related to cardiovascular disease (CVD), the leading cause of poor health in the world. This review evaluates the evidence on the effect of habitual coffee consumption on CVD incidence and mortality. The review is based mostly on observational studies and meta-analyses of the literature. In healthy people, in comparison to not consuming coffee, habitual consumption of 3-5 cups of coffee per day is associated with a 15% reduction in the risk of CVD, and higher consumption has not been linked to elevated CVD risk. Moreover, in comparison to no coffee intake, usual consumption of 1-5 cups/day is associated with a lower risk of death. In people who have already suffered a CVD event, habitual consumption does not increase the risk of a recurrent CVD or death. However, hypertensive patients with uncontrolled blood pressure should avoid consuming large doses of caffeine. In persons with well-controlled blood pressure, coffee consumption is probably safe, but this hypothesis should be confirmed by further investigations. PMID- 29276947 TI - Current Resources for Evidence-Based Practice, March 2018. PMID- 29276946 TI - Zerumbone, a Cyclic Sesquiterpene from Zingiber zerumbet Induces Apoptosis, Cell Cycle Arrest, and Antimigratory Effects in SW480 Colorectal Cancer Cells. AB - Zerumbone isolated from the rhizomes of Zingiber zerumbet was investigated for the mechanisms by which it exhibits antiproliferative activity in colorectal cancer cells (SW480). The results indicated that the zerumbone suppressed cell growth and enhanced cell apoptosis. Exposure to zerumbone induced generation of reactive oxygen species, reduced the cellular antioxidant status, decreased mitochondrial membrane potential, and activated caspase 3, caspase 8, and caspase 9 (p < 0.001). It was also found that there was a decrease in the expression of Bcl 2 and elevation of Bax (p < 0.001) on exposure to zerumbone. Furthermore, treatment with 50, 75, and 100 MUM zerumbone resulted in cell cycle arrest at the G2/M phase with a value of 17.2 +/- 0.1, 19.63 +/- 0.25, and 26.66 +/- 0.25, respectively, and also distorted the microfilament network and effectively inhibited cellular migration. PMID- 29276948 TI - Editorial Comment. PMID- 29276949 TI - Editorial Comment. PMID- 29276950 TI - Mitochondrial metabolism in early neural fate and its relevance for neuronal disease modeling. AB - Modulation of energy metabolism is emerging as a key aspect associated with cell fate transition. The establishment of a correct metabolic program is particularly relevant for neural cells given their high bioenergetic requirements. Accordingly, diseases of the nervous system commonly involve mitochondrial impairment. Recent studies in animals and in neural derivatives of human pluripotent stem cells (PSCs) highlighted the importance of mitochondrial metabolism for neural fate decisions in health and disease. The mitochondria based metabolic program of early neurogenesis suggests that PSC-derived neural stem cells (NSCs) may be used for modeling neurological disorders. Understanding how metabolic programming is orchestrated during neural commitment may provide important information for the development of therapies against conditions affecting neural functions, including aging and mitochondrial disorders. PMID- 29276951 TI - Illuminating stem cell transcription factor dynamics: long-term single-cell imaging of fluorescent protein fusions. AB - Most single-cell approaches to date are based on destructive snapshot measurements which do not permit to correlate a current molecular state with future fate. However, to understand how cell fate choices are established by transcription factor networks (TFNs) regulating cell fates, TFN dynamics must be continuously monitored in single cells. Here we review how quantitative time lapse imaging can contribute to understanding TFN dependent cell fate regulation at the single-cell level. We outline potentials of the technology and highlight challenges for interpreting the dynamics of fluorescent protein reporters that may interfere with endogenous TF function. We provide an outlook on how continuous observation of TF dynamics and single-cell fates may be complemented by perturbation studies and be linked to multidimensional molecular profiling in the future. PMID- 29276952 TI - Influence of cadmium stress on root exudates of high cadmium accumulating rice line (Oryza sativa L.). AB - A hydroponic experiment with two different cadmium (Cd) accumulating rice lines of Lu527-8 (the high Cd accumulating rice line) and Lu527-4 (the normal rice line) was carried out to explore the links among Cd stress, root exudates and Cd accumulation. The results showed that (1) Cd stress increased quantities of organic acids, but had no effect on composition in root exudates of the two rice lines. In Cd treatments, the contents of every detected organic acid in root exudates of Lu527-8 were 1.76-2.43 times higher than those of Lu527-4. Significant positive correlations between organic acids contents and Cd contents in plants were observed in both rice lines, except that malic acid was only highly relevant to Lu527-8, but not to Lu527-4. (2) Both composition and quantities of amino acids in root exudates changed a lot under Cd stress and this change differed in two rice lines. In control, four amino acids (glutamic acid, glycine, tyrosine and histidine) were detected in two rice lines. Under Cd stress, eight amino acids in Lu527-8 and seven amino acids in Lu527-4 could be detected, among which phenylalanine was only secreted by Lu527-8 and alanine, methionine and lysine were secreted by both rice lines. The contents of those four newly secreted amino acids from Lu527-8 increased significantly with the increase of Cd dose and each had a high-positive correlation with Cd contents, but the same change did not appear in Lu527-4. The difference between two rice lines in secretion of organic acids and amino acids may be related to their different Cd uptake properties. PMID- 29276953 TI - Airborne polycyclic aromatic compounds contribute to the induction of the tumour suppressing P53 pathway in wild double-crested cormorants. AB - Polycyclic aromatic compounds (PACs), including polycyclic aromatic hydrocarbons (PAHs) and PAH-like compounds are known or probable environmental carcinogens released into the environment as a by-product of incomplete combustion of fossil fuels and other organic materials. Studies have shown that exposure to PACs in the environment can induce both genotoxicity and epigenetic toxicity, but few studies have related PAC exposure to molecular changes in free ranging wildlife. Previous work has suggested that double-crested cormorants (Phalacrocorax auritus; DCCO) exhibited a higher incidence of genetic mutations when their breeding sites were located in heavily industrialized areas (e.g., Hamilton Harbour, Hamilton, ON, Canada) as compared to sites located in more pristine environments, such as in Lake Erie. The aim of this study was to determine if airborne PACs from Hamilton Harbour alter the tumour-suppressing P53 pathway and/or global DNA methylation in DCCOs. Airborne PACs were measured using passive air samplers in the Hamilton Harbour area and low-resolution mass spectrometry analysis detected PACs in livers of DCCOs living in Hamilton Harbour. Further hepatic and lung transcriptional analysis demonstrated that the expression of the genes involved in the DNA repair and cellular apoptosis pathway were up-regulated in both tissues of DCCOs exposed to PACs, while genes involved in p53 regulation were down-regulated. However, global methylation levels did not differ between reference- and PAC-exposed DCCOs. Altogether, data suggest that PACs activate the P53 pathway in free-ranging DCCOs living nearby PAC-contaminated areas. PMID- 29276954 TI - Effects of high temperature on biochemical parameters, oxidative stress, DNA damage and apoptosis of pufferfish (Takifugu obscurus). AB - Water temperature is an important environmental factor that affects physiology and biochemical activities of fish. In this study, we investigated of high temperature on biochemical parameters, oxidative stress, DNA damage and apoptosis of pufferfish. Thermal stress could significantly increase the levels of AST, ALT, LDH, GLU and TG, whereas the levels of ALP and TP decrease significantly. In addition, thermal stress also decreased total blood cell count, inhibited cell viability, and subsequently lead to DNA damage and apoptosis. The mRNA levels of p53, caspase-9 and caspase-3 were up-regulated under thermal stress. These results suggested that caspase-dependent and p53 signaling pathways could play important roles in thermal stress-induced apoptosis in fish. Furthermore, the gene expression of SOD, CAT, HSP90 and C3 were induced by thermal stress. This study provides new insights into the mechanism whereby thermal stress affects physiological responses and apoptosis in pufferfish. PMID- 29276955 TI - n-Alkanes in sediments from the Yellow River Estuary, China: Occurrence, sources and historical sedimentary record. AB - : A total of 21 surface sediments from the Yellow River Estuary (YRE) and a sediment core from the abandoned Old Yellow River Estuary (OYRE) were analyzed for n-alkanes using gas chromatography-mass spectrometry (GC-MS). n-Alkanes in the range C12-C33 and C13-C34 were identified in the surface sediments and the core, respectively. The homologous series were mainly bimodal distribution pattern without odd/even predominance in the YRE and OYRE. The total n-alkanes concentrations in the surface sediments ranged from 0.356 to 0.572mg/kg, with a mean of 0.434mg/kg on dry wt. BASIS: Evaluation of n-alkanes proxies indicated that the aliphatic hydrocarbons in the surface sediments were derived mainly from a petrogenic source with a relatively low contribution of submerged/floating macrophytes, terrestrial and emergent plants. The dated core covered the time period 1925-2012 and the mean sedimentation rate was ca. 0.5cm/yr. The total n alkanes concentrations in the core ranged from 0.0394 to 0.941mg/kg, with a mean of 0.180mg/kg. The temporal evolution of n-alkanes reflected the historical input of aliphatic hydrocarbons and was consistent with local and regional anthropogenic activity. In general, the investigation on the sediment core revealed a trend of regional environmental change and the role of anthropogenic activity in environmental change. PMID- 29276956 TI - Oxygen content determines the bio-reactivity and toxicity profiles of carbon black particles. AB - In spite of the considerable efforts invested to understand the environmental health and safety (EHS) impacts of ultrafine particles, such as the representative PM2.5, there are still significant knowledge gaps to be filled. No conclusive understandings have been obtained about the physicochemical determinants in accounting for differential adverse outcomes. Here we compared the cytotoxicity of four carbon black (CB) particles with similar physicochemical properties except for their oxygen contents (C824455 < C1864 < Printex U < SB4A). We found that these four CB particles manifested in vitro and in vivo cytotoxicity reversely related to their oxygen contents, namely a hierarchy of cytotoxicity: C824455 > C1864 > Printex U > SB4A. Among these CB particles, the most significant lung injury (e.g. collapses and inflammation) and macrophagic activation were found for C824455 and C1864, in particular for C824455. All these differences in toxicity profiles, including in vitro and in vivo cytotoxicity, pro-inflammatory effects and direct damages to the lung epithelia, should be (at least partially) ascribed to the oxygen content in these CB particles that in turn determined their transformation, i.e. the different aggregation states. Nonetheless, PM2.5 likewise caused severe in vivo and in vitro toxicities to the lung cells and macrophages. This study thus offers more insights into the structure-activity relationship (SAR) and opens a new avenue to elucidate the physicochemical determinants in evoking lung injuries by ultrafine airborne particles. PMID- 29276957 TI - Microplastics contamination in molluscs from the northern part of the Persian Gulf. AB - Microplastics (MPs) are well-known emerging contaminants in the marine environment. A key route by which MPs can directly affect marine life is through ingestion. The objective of the present study was to evaluate the occurrence of MPs in marine life and seafood for human consumption in the Persian Gulf. We conducted a whole body analysis of MP (between 10 and 5000 MUm in diameter) abundance in five species of molluscs with different feeding strategies, including both gastropods and bivalves from the littoral zone of the Iranian coast of the Persian Gulf. The mean number of total encountered MPs in all species ranged from 0.2 to 21.0 particles per g of soft tissue (wet weight) and from 3.7 to 17.7 particles per individual. Overall, microfibres followed by fragments were the most common type of MP isolated in each species (respectively > 50% and ~26%). Film (~14%) and pellets (~2%) were less commonly observed. The observed MPs were classified into three size groups (ca. 10-25 MUm, 25-250 MUm and 250-5000 MUm), and 37-58% of MPs fell into the smallest size group. Fourier transform infrared (FT-IR) analysis confirmed the presence of polyethylene (PE), polyethylene terephthalate (PET), and nylon (PA). Our results indicated that molluscan shellfish from the Persian Gulf contain MPs, with higher concentrations in a predatory species, suggesting trophic transfer of MPs in the food web. The consumption of edible species may be a source of human microplastic intake. We compared our results with those previously reported for other regions of the world and identified the need for further studies in the Persian Gulf. PMID- 29276958 TI - Distribution and potential ecological risk of 50 phenolic compounds in three rivers in Tianjin, China. AB - Phenolic compounds widely exist in the surface water of many countries; however, few studies have simultaneously analyzed and evaluated broad-spectrum phenolic compounds in various components of the water environment. Therefore this study analyzed the distribution and potential ecological risk of 50 phenolic compounds in the surface water, sediment and suspended particulate matter of three important rivers in Tianjin, the main heavy industry city with high pollution in China. The qualitative results show that phenolic pollution existed extensively in the three rivers and the kinds of phenolic compounds in the water were relatively higher than in both sediment and suspended particulate matter. The quantitative results show that the phenolic pollution in the wet-season samples was serious than dry-season samples. Meanwhile, total concentrations of phenolic compounds in three components from the Dagu Drainage River (DDR) were all much higher than those in the Beitang Drainage River (BDR) and Yongdingxin River (YDXR). The highest total concentrations of phenolic compounds in three components all appeared in wet-season samples in DDR, and the highest total concentration was 1354 MUg/L in surface water, 719 MUg/kg dw in suspended particulate matter and 2937 MUg/kg dw in sediment, respectively. The ecological risk of phenolic compounds in surface water was evaluated using the quotient method, and phenolic compounds with risk quotient (RQ) > 1 (RQ > 0.3 for YDXR) were identified as priority pollutants. Five kinds of phenolic compounds were identified as priority phenolic compounds in BDR, and the order of risk was 2 cresol > 2,4-xylenol > 2-sec-butylphenol > 2-naphthol > 3-cresol. Six kinds of phenolic compounds were identified as priority phenolic compounds in DDR, and the order of risk was 2-naphthol > p-chloro-m-xylenol > 4-cresol > 3-cresol > 2,4 xylenol > 2,3,6-Trimethylphenol. In YDXR, only phenol, 2-naphthol and 2,4-xylenol were identified as priority phenolic compounds. PMID- 29276959 TI - Biota monitoring under the Water Framework Directive: On tissue choice and fish species selection. AB - The study addresses the topic of suitable matrices for chemical analysis in fish monitoring and discusses the effects of data normalization in the context of the European Water Framework Directive (WFD). Differences between species are considered by comparing three frequently monitored species of different trophic levels, i.e., chub (Squalius cephalus, n = 28), (bream, Abramis brama, n = 11), and perch (Perca fluviatilis, n = 19) sampled in the German Danube. The WFD priority substances dioxins, furans and dioxin-like polychlorinated biphenyls (PCDD/F + dl-PCB), polybrominated diphenyl ethers (PBDE), alpha hexabromocyclododecane (alpha-HBCDD), hexachlorobenzene (HCB), mercury (Hg), and perfluorooctane sulfonic acid (PFOS) as well as non-dioxin-like (ndl)-PCB were analyzed separately in fillet and carcass and whole body concentrations were calculated. Hg was analyzed in individual fish fillets and carcasses, all other substances were determined in pool samples, which were compiled on the basis of fish size (3 chub pools, 1 bream pool, 2 perch pools). The data were normalized to 5% lipid weight (or 26% dry mass in the case of Hg and PFOS) for comparison between matrices and species. Hg concentrations were generally higher in fillet than in whole fish (mean whole fish-to-fillet ratio: 0.7) whereas all other substances were mostly higher in whole fish. In the case of lipophilic substances these differences leveled after lipid normalization. Significant correlations (p <= .05) were detected between Hg and fish weight and age. Hg concentrations varied least among younger fish. PCDD/F, dl-PCB, ndl-PCB, PBDE, alpha-HBCDD and HCB correlated significantly (p <= .05) with lipid concentrations. Fillet-to whole fish conversion equations and/or conversion factors were derived for all substances except alpha-HCBDD. Although more data also for individual fish would be desirable the results are nevertheless a step on the way to translate fillet concentrations of priority substances to whole fish concentrations. PMID- 29276960 TI - Relationship between bisphenol A exposure and attention-deficit/ hyperactivity disorder: A case-control study for primary school children in Guangzhou, China. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical. Studies have shown that the exposure to BPA is associated with attention-deficit/hyperactivity disorder (ADHD) during adolescent development. However the direct clinical evidence is limited. To investigate the possible association between environmental BPA exposure and the altered behavior of children, a case-control study was conducted with children aged 6-12 years in Guangzhou, China. Two hundred fifteen children diagnosed with ADHD and 253 healthy children from Guangzhou were recruited as the case and control groups, respectively. Urinary BPA and 8-hydroxy-2' deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage) concentrations were determined by high-performance liquid chromatography/tandem spectrometry. The results showed that concentrations of urinary BPA for the case group were significantly higher than those for the control group (3.44 vs 1.70 MUg/L; 4.63 vs 1.71 MUg/g Crt. p < .001). A stepwise increase in the odds ratios for ADHD was observed with the increasing quartiles of children's urinary BPA (first quartile: reference category; second quartile adjusted OR: 1.79, 95% CI: 0.95-3.37; third quartile adjusted OR: 7.44, 95% CI: 3.91-14.1; fourth quartile adjusted OR: 9.41, 95% CI: 4.91-18.1). When the BPA levels were stratified by gender, the odds of ADHD among boys and girls increased significantly with urinary BPA concentrations (adjusted OR: 4.58, 95% CI: 2.84-7.37; adjusted OR: 2.83, 95% CI: 1.17-6.84). Urinary 8-OHdG concentrations in the ADHD children were significantly higher than those in the control group. Furthermore, the linear regression analysis results indicated that a significant relationship existed between BPA exposure and 8-OHdG levels (R = 0.257, p < .001). Our findings provide direct evidence that childhood BPA exposure may be related to ADHD and 8-OHdG concentrations for children. Moreover, BPA exposure could increase the higher occurrence of ADHD for boy than for girls. PMID- 29276961 TI - MRI determination of volumes for the upper airway and pharyngeal lymphoid tissue in preterm and term infants. AB - We aim to determine average volumes of the upper airway, adenoids and tonsils in preterm and term infants and assess for the differences according to weight, sex and ethnicity. The volumes of the upper airways, tonsils and adenoids were measured from brain MR images in 96 (49 preterm and 47 term) infants and compared using a two-tailed t-test (significant at p<0.05). The average volumes are reported for both groups. Term infants showed larger naso- and oropharyngeal volumes (independent of weight, sex, and ethnicity). No differences in hypopharyngeal, adenoidal or tonsillar volumes were found. PMID- 29276962 TI - Association between misty mesentery with baseline or new diagnosis of cancer: a matched cohort study. AB - We compared the prevalence of a baseline diagnosis of cancer in patients with and without misty mesentery (MM) and determined its association with the development of a new cancer. This was a retrospective, HIPAA-compliant, IRB-approved case control study of 148 cases and 4:1 age- and gender-matched controls. Statistical tests included chi-square, t-test, hazard models, and C-statistic. Patients with MM were less likely to have cancer at baseline (RR=0.74, p=0.003), but more likely to develop a new malignancy on follow-up (RR=2.13, p=0.003; survival analysis HR 1.74, p=0.05). MM may confer an increased probability of later developing cancer, particularly genitourinary tumors. PMID- 29276963 TI - Media use and insomnia after terror attacks in France. AB - Direct exposure to traumatic events often precipitates sleep disorders. Sleep disturbance has also been observed amongst those indirectly exposed to trauma, via mass media. However, previous work has focused on traditional media use, rather than contemporary social media. We tested associations between both traditional and social media consumption and insomnia symptoms following 2015 terror attacks in Paris France, controlling for location and post-traumatic symptomology. 1878 respondents, selected to represent the national French population, completed an internet survey a month after the Bataclan attacks (response rate 72%). Respondents indicated different media use, post-traumatic stress and insomnia. Controlling for demographics, location and PTSD, insomnia was associated with both traditional (beta 0.10, P = .001) and social media use (beta 0.12, P = .001). Associations between social media and insomnia were independent of traditional media use. Interventions targeted at social media may be particularly important following mass trauma. PMID- 29276964 TI - Disentangling the 16O cross section using light water and heavy water benchmark assemblies. AB - Fast neutron leakage spectra from the light and heavy water sphere of 30cm in diameter with neutron source in its centre were measured by a stilbene scintillation detector in the region of 1-10MeV in the distance of 85cm from the spheres surface. We use the light and heavy water to eliminate the effect of hydrogen. 252Cf with the approximate emission rate of 5.5E8 n/s was used as a neutron source for all measurements involved and was placed in the centres of the spheres. The measured neutron spectra are compared with MCNP transport code calculations in ENDF/B-VII.0, ENDF/B-VIII.b4 and JENDL-4 nuclear data libraries. Experimental results for both cases follows similar trend. The best agreement is achieved with ENDF/B-VIII.b4 library in both cases. All libraries underestimate experimental measurement in the region of 3-4MeV. Furthermore, JENDL-4 library overestimates experiment in the region of 4-6.5MeV. In addition, we performed cross section sensitivity analysis for elastic, inelastic and (n,alpha) reaction in JENDL-4 and ENDF/B-VIII.b4 libraries since they have almost independent evaluations of 16O. PMID- 29276965 TI - Development of an externally controllable sealed isotope generator. AB - An externally controllable sealed isotope generator has been proposed for radiation education activities. Column (68Ge-68Ga and 137Cs-137mBa) and solvent extraction (68Ge-68Ga)-based isotope generators were applied as radioactive sources. These generators showed high milking efficiencies and low breakthrough after repeated uses, and are expected to promote the use of isotope generators without radioactive contamination or the emission of radioactive waste. This isotope generator provides a new concept for sealed radioisotope sources. PMID- 29276966 TI - Inhibition of p38 and ERK1/2 pathways by Sparstolonin B suppresses inflammation induced melanoma metastasis. AB - BACKGROUND: Cancer related inflammation plays a fatal role in the metastatic process, which can foster tumor growth, angiogenesis and dissemination. Sparstolonin B (SsnB), derived from Chinese medicine of the tubers of Scirpus yagara, is a TLR2 and TLR4 antagonists. It has exhibited multiple activities of anti-inflammatory, anti-cancer, anti-obesity and anti-hepatitis. However, whether SsnB is involved in the regulation of inflammation-induced tumor metastasis is not well elucidated. PURPOSE: The aim of this study was to investigate the effectiveness of SsnB as a treatment of inflammation-induced tumor metastasis and identify the underlying mechanisms of its anti-tumor metastatic activity. METHOD: The anti-tumor metastatic activity in vitro was estimated by MTT, wound-healing assay, matrigel invasion analysis and extracellular matrix adhesion assay. Mice lung metastasis and hepatic metastasis experiments were performed to assess the activities in vivo. Lungs or livers were weighed and the number of metastatic nodules was determined after mice were sacrificed. The levels of pro-inflammatory cytokines in the serum, lungs and livers were detected by using enzyme-linked immunosorbent assay (ELISA). Micro-metastasis nodules in lungs or livers were analyzed by histological examination. Immunohistochemistry and western blot analysis were conducted to determine protein expression. RESULT: Herein, SsnB dose-dependently inhibited cell migration and invasion in mouse melanoma B16 cells with or without stimulation of lipopolysaccharide (LPS), Pam3csk4 or molecules from damaged tumor cells (DTC-Ms). The expression of matrix metalloproteinases (MMP)-2 was also significantly abated by SsnB in LPS-modulated B16 cells. And SsnB reduced LPS-activated B16 cells adhesion to extracellular matrix components collagen I and fibronectin in a dose-dependent manner. In vivo, SsnB obviously attenuated LPS-activated pulmonary metastasis in mice by reduction the number of metastatic nodules on the lung surfaces, lung weight and levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in serums and lungs. Moreover, in experimental hepatic metastasis model mice, SsnB remarkably repressed LPS-stimulated the number of metastatic nodules along with liver weight; and SsnB significantly suppressed LPS-activated increase levels of TNF alpha and IL-6 in livers. Immunohistochemistry analysis indicated that SsnB inhibited the expression of TLR4 in livers. Furthermore, SsnB remarkably blocked p38 and ERK1/2 signaling pathway in LPS-induced B16 cells. P38 and ERK1/2 signaling silencing, using BIRB0796 (small molecular inhibitor of p38 MAPK) and PD184352 (inhibitor of MEK1/2 kinases that activate ERK1/2), significantly abated LPS-induced migration and invasion of B16 cells. CONCLUSION: The present study reports a novel use of SsnB in mitigating TLRs ligands-induced melanoma metastasis by inhibition of p38 and ERK1/2 pathway. PMID- 29276967 TI - Synergistic effect of pyrazoles derivatives and doxorubicin in claudin-low breast cancer subtype. AB - BACKGROUND: Breast cancer is a global public health problem. For some subtypes, such as Claudin-low, the prognosis is poorer and the treatment is still a challenge. Pyrazoles are an important class of heterocyclic compounds and are promising anticancer agents based on their chemical properties. The present study was aimed not only at testing pyrazoles previously prepared by our research group in two breast cancer cell lines characterized by intermediated response to conventional chemotherapy but also at analyzing the possible synergistic effect of these pyrazoles associated with doxorubicin. METHODS: Four 1-thiocarbamoyl-3,5 diaryl-4,5-dihydro-1H pyrazoles were tested for the first time in MCF-7 and MDA MB-231 culture cells. The pyrazoles with best results in cytotoxicity were used in combination with doxorubicin and compared with this drug alone as standard. The synergic effect was analyzed using Combination Index method. In addition, cell death and apoptosis assays were carried out. RESULTS: Two pyrazoles with cytotoxic effect in MCF-7 and especially in MDA-MB-231 were identified. This activity was markedly higher in pyrazoles containing bromine and chlorine substituents. The combination of these pyrazoles with doxorubicin had a significant synergic effect in both cells tested and mainly in MDA-MB-231. These data were confirmed with apoptosis and cell death analysis. CONCLUSIONS: The synergic effect observed with combination of these pyrazoles and doxorubicin deserves special attention in Claudin-low breast cancer subtype. This should be explored in order to improve treatment results and minimize side effects. PMID- 29276968 TI - Icotinib inhibits EGFR signaling and alleviates psoriasis-like symptoms in animal models. AB - To investigate the effects of icotinib hydrochloride and a derivative cream on epidermal growth factor receptor (EGFR) signaling and within animal psoriasis models, respectively. The effect of icotinib on EGFR signaling was examined in HaCaT cells, while its effect on angiogenesis was tested in chick embryo chorioallantoic membranes (CAM). The effectiveness of icotinib in treating psoriasis was tested in three psoriasis models, including diethylstilbestrol treated mouse vaginal epithelial cells, mouse tail granular cell layer formation, and propranolol-induced psoriasis-like features in guinea pig ear skin. Icotinib treatment blocked EGFR signaling and reduced HaCaT cell viability as well as suppressed CAM angiogenesis. Topical application of icotinib ameliorated psoriasis-like histological characteristics in mouse and guinea pig psoriasis models. Icotinib also significantly inhibited mouse vaginal epithelium mitosis, promoted mouse tail squamous epidermal granular layer formation, and reduced the thickness of the horny layer in propranolol treated auricular dorsal surface of guinea pig. We conclude that icotinib can effectively inhibit psoriasis in animal models. Future clinical studies should be conducted to explore the therapeutic effects of icotinb in humans. PMID- 29276969 TI - Effects of estrogen status in osteocyte autophagy and its relation to osteocyte viability in alveolar process of ovariectomized rats. AB - Estrogen maintains osteocyte viability, whereas its deficiency induces osteocyte apoptosis. As autophagy is important for osteocyte viability, we hypothesized whether the anti-apoptotic effect of estrogen is related to autophagy in osteocytes. Thirty adult female rats were sham-operated (SHAM) or ovariectomized (OVX). After three weeks, twelve rats of SHAM and OVX groups were killed before treatment (basal period), whereas the remaining rats received estrogen (OVXE) or vehicle (OVX) for 45 days. Fragments of maxilla containing alveolar process of the first molars were embedded in paraffin or Araldite. Paraffin-sections were stained with hematoxylin/eosin for histomorphometry, or subjected to the silver impregnation method for morphological analysis of osteocyte cytoplasmic processes. Autophagy was analyzed by immunohistochemical detections of beclin-1, MAP-LC3alpha and p62, whereas apoptosis was evaluated by immunohistochemical detections of cleaved caspase-3 and BAX, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) method and by ultrastructural analysis. Araldite-semithin sections were subjected to the Sudan-black method for detection of lipids. OVX-basal group showed high frequency of caspase-3-, TUNEL- and p62 positive osteocytes accompanied with low frequency of beclin-1- and MAP-LC3alpha positive osteocytes. At 45 days, OVXE group exhibited higher number of osteocytes, higher frequency of beclin-1- and MAP-LC3alpha-positive osteocytes, and lower frequency of caspase-3, BAX-, TUNEL- and p62-positive osteocytes than OVX group. Significant reduction in bone area was observed in the OVX compared to OVXE and SHAM groups. The highest frequency of Sudan-Black-positive osteocytes and osteocytes with scarce cytoplasmic processes, or showing apoptotic features were mainly observed in OVX groups. Our results indicate that estrogen deficiency decreases autophagy and increases apoptosis, whereas estrogen replacement enhances osteocyte viability by inhibiting apoptosis and maintaining autophagy in alveolar process osteocytes. These results suggest that the anti-apoptotic effect of estrogen may be, at least in part, related to autophagy regulation in osteocytes. PMID- 29276970 TI - Cerebrospinal fluid findings in non-infectious status epilepticus. AB - OBJECTIVE: Ictal activity itself can cause pathological cerebrospinal fluid (CSF) findings. However, data regarding pathological CSF findings caused by SE itself to date remain scarce. We here evaluated the frequency and specificity of pathological CSF findings in non-infectious SE. METHODS: We performed a retrospective analysis of CSF samples in adult patients with episodes of non infectious SE, who had been admitted to the Department of Neurology, University Hospital of Cologne. The following parameters were assessed: cell count, protein, and lactate content, CSF/serum glucose quotient (QGlc), disturbances of blood brain-barrier function assessed by CSF/serum albumin quotient (QAlb), and qualitative intrathecal IgG synthesis assessed by unmatched oligoclonal bands in CSF. RESULTS: We analysed 54 episodes of non-infectious SE in which CSF had been obtained. CSF pleocytosis was infrequent (6%). Elevated CSF protein content was present in 44% of all cases, whereas elevated CSF lactate content was found in 23% of the cases. A decreased QGlc was present in 9%. Dysfunction of blood-brain barrier (BBBD) was the most frequent pathological finding, amounting to 55%. Unmatched oligoclonal bands in CSF were seen in 10% of non-infectious SE. Further analysis revealed that elevated CSF protein content was found predominantly in recfractory SE (p = 0.04). Elevated CSF lactate content was associated with shorter latency between onset of SE and CSF retrieval (p = 0.004), positive history of epilepsy (p = 0.02) and an acute symptomatic etiology (p = 0.04). BBBD was also present more often in acute symptomatic SE (p = 0.001) and was the sole pathological CSF parameter associated with clinical outcome: presence of BBBD was associated with a less favorable outcome (p = 0.02). SIGNIFICANCE: Non-infectious SE itself does not commonly cause CSF pleocytosis. Data suggest that the detection of CSF pleocytosis should prompt further diagnostics for an underlying infectious or neoplastic etiology. In contrast, elevation of CSF protein content and BBBD were found frequently in non-infectious SE. PMID- 29276971 TI - Child abuse and neglect in institutional settings, cumulative lifetime traumatization, and psychopathological long-term correlates in adult survivors: The Vienna Institutional Abuse Study. AB - Child maltreatment (CM) in foster care settings (i.e., institutional abuse, IA) is known to have negative effects on adult survivor's mental health. This study examines and compares the extent of CM (physical, emotional, and sexual abuse; physical and emotional neglect) and lifetime traumatization with regard to current adult mental health in a group of survivors of IA and a comparison group from the community. Participants in the foster care group (n = 220) were adult survivors of IA in Viennese foster care institutions, the comparison group (n = 234) consisted of persons from the Viennese population. The comparison group included persons who were exposed to CM within their families. Participants completed the Childhood Trauma Questionnaire, the Life Events Checklist for DSM 5, the PTSD Checklist for DSM-5, the International Trauma Questionnaire for ICD 11, and the Brief Symptom Inventory-18 and completed a structured clinical interview. Participants in the foster care group showed higher scores in all types of CM than the comparison group and 57.7% reported exposure to all types of CM. The foster care group had significantly higher prevalence rates in almost all mental disorders including personality disorders and suffered from higher symptom distress in all dimensional measures of psychopathology including depression, anxiety, somatization, dissociation, and the symptom dimensions of PTSD. In both groups, adult life events and some but not all forms of CM predicted PTSD and adult life events partly mediated the association of PTSD and CM. Explanations for the severe consequences of CM and IA are discussed. PMID- 29276972 TI - Identification of plasma interleukins as biomarkers for deflazacort and omega-3 based Duchenne muscular dystrophy therapy. AB - Duchenne muscular dystrophy (DMD) is a progressive and fatal disease, characterized by the absence of dystrophin, muscle degeneration and cardiorespiratory failure. Creatine kinase is the classic marker to screen for DMD. However, other markers are needed to follow disease progression and to evaluate the response to therapy over longer periods. In the present study, we aim to identify interleukins in the plasma of the mdx mice model of DMD that could serve as biomarkers to monitor dystrophy progression, at distinct stages of the disease (1, 3 and 8 months of age). We used deflazacort and omega-3 therapies to validate the biomarkers studied. Plasma levels of TNF-alpha and TGF-beta were increased in mdx mice in relation to control, at all times studied. Differences in IFN-gamma and IL-10 contents, comparing mdx x CTRL, were detected only at the early stage (1 month). IL-6 decreased at 3 and 8 months and IL-13 increased at 8 months in the mdx compared to control. Deflazacort and omega-3 reduced the plasma levels of the pro-inflammatory (TNF-alpha, INF-gamma, IL-6) and pro-fibrotic (IL 13 and TGF-beta) interleukins and increased the plasma levels of IL-10. It is suggested that TNF-alpha and TGF-beta in plasma would be the best markers to follow disease progression. IL-6, INF-gamma and IL-10 would be suitable markers to the earlier stages of dystrophy and IL-13 a suitable marker to the later stages of dystrophy. PMID- 29276973 TI - Molecular and functional characterization of tumor-induced factor (TIF): Hamster homolog of CXCL3 (GROgamma) displays tumor suppressive activity. AB - Previously our lab has created a mouse ovarian xenograft model of copy number variation (CNV)-mediated G protein-coupled receptor (GPCR) MAS-driven tumorigenesis, and RNA profiling identified a putative chemokine tumor-induced factor (Tif). Sequence analysis and chemotactic study suggested that Tif was likely to be a hamster homolog of human GROgamma (CXCL3) [IJC 125 (2009): 1316 1327]. In the present study, we report the molecular and functional characterization of the Tif gene. Genomic study of CHO-K1 cells indicated that Tif gene consisted of 4 exons, characterized with an antisense B1 element which is embedded in the fourth exon. Two Tif transcripts were identified which shared identical sequences except that a string of 71-nt derived from the antisense B1 element was deficient in the shorter transcript. Of interests, B1-like RNA ladder was detected in xenografts. Functional studies showed that TIF induced chemotaxis and neovessel formation. Pharmacological studies suggested that TIF activated Gi coupled CXCR2 and induced both calcium mobilization and ERK1/2 phosphorylation, and suppressed forskolin-stimulated cAMP accumulation. In addition, secreted matured TIF functioned as an autocrine factor and promoted anchorage-independent growth. Unexpectedly, TIF delayed the onset of tumor formation, possibly via suppressing proliferation of stromal fibroblasts. However, TIF did not exert any inhibitory effect on tumor growth. Potentially, TIF could be used for preventing cancer relapse. PMID- 29276974 TI - High resolution metabolomics to determines the risk associated with bisphenol A exposure in humans. AB - Although high BPA exposure has been correlated with several metabolic diseases, the underlying mechanisms are unclear. In the present study, a metabolomics approach was used to explore the metabolic variations caused by low or high BPA exposure in female (n = 96) and male (n = 98) urine. Fatty acid elongation and sphingolipid metabolism were affected by high BPA exposure in males and females. Fatty acid elongation and sphingolipid metabolism were further investigated among age groups consisted of 30-39 yrs old, 40-49 yrs old, and 50-59 yrs old males and females with high or low urinary BPA. High BPA-exposed males in 30 s and females in 40 s were found with significant disturbance in fatty acid elongation and sphingolipid metabolism, respectively. Additionally, females in 40 s showed elevated inflammatory metabolites: 6-ketoprostaglandin E1 and thromboxane. In the present study, we have demonstrated that environmental metabolomics is useful to elucidate the health effects of BPA exposure. PMID- 29276975 TI - Non-tip auditory-nerve responses that are suppressed by low-frequency bias tones originate from reticular lamina motion. AB - Recent cochlear mechanical measurements show that active processes increase the motion response of the reticular lamina (RL) at frequencies more than an octave below the local characteristic frequency (CF) for CFs above 5 kHz. A possible correlate is that in high-CF (>5 kHz) auditory-nerve (AN) fibers, responses to frequencies 1-3 octaves below CF ("tail" frequencies) can be inhibited by medial olivocochlear (MOC) efferents. These results indicate that active processes enhance the sensitivity of tail-frequency RL and AN responses. Perhaps related is that some apical low-CF AN fibers have tuning-curve (TC) "side-lobe" response areas at frequencies above and below the TC-tip that are MOC inhibited. We hypothesized that the tail and side-lobe responses are enhanced by the same active mechanisms as CF cochlear amplification. If responses to CF, tail frequency, and TC-side-lobe tones are all enhanced by prestin motility controlled by outer-hair-cell (OHC) transmembrane voltage, then they should depend on OHC stereocilia position in the same way. To test this, we cyclically changed the OHC stereocilia mechano-electric-transduction (MET) operating point with low frequency "bias" tones (BTs) and increased the BT level until the BT caused quasi static OHC MET saturation that reduced or "suppressed" the gain of OHC active processes. While measuring cat AN-fiber responses, 50 Hz BT level series, 70-120 dB SPL, were run alone and with CF tones, or 2.5 kHz tail-frequency tones, or side-lobe tones. BT-tone-alone responses were used to exclude BT sound levels that produced AN responses that might obscure BT suppression. Data were analyzed to show the BT phase that suppressed the tone responses at the lowest sound level. We found that AN responses to CF, tail-frequency, and side-lobe tones were suppressed at the same BT phase in almost all cases. The data are consistent with the enhancement of responses to CF, tail-frequency, and side-lobe tones all being due to the same OHC-stereocilia MET-dependent active process. Thus, OHC active processes enhance AN responses at frequencies outside of the cochlear-amplified TC-tip region in both high- and low-frequency cochlear regions. The data are consistent with the AN response enhancements being due to enhanced RL motion that drives IHC-stereocilia deflection by traditional RL-TM shear and/or by changing the RL-TM gap. Since tail-frequency basilar membrane (BM) motion is not actively enhanced, the tail-frequency IHC drive is from a vibrational mode little present on the BM, not a "second filter" of BM motion. PMID- 29276976 TI - Behavioural phenotypes in mice after prenatal and early postnatal exposure to intermediate frequency magnetic fields. AB - Electromagnetic fields are ubiquitous in the environment. Human exposure to intermediate frequency (IF) fields is increasing due to applications like electronic article surveillance systems, wireless power transfer, and induction heating cooking hobs. However, there are limited data on possible health effects of exposure to IF magnetic fields (MF). In the present study, we set out to assess cognitive and behavioural effects of IF MF in mice exposed during prenatal and early postnatal periods. Pregnant female mice were exposed continuously to 7.5kHz MFs at 12 and 120MUT, from mating until weaning of pups. Sham exposed pregnant mice were used as a control group. A behavioural teratology study was conducted on the male offspring at two months of age to detect possible effects on the developing nervous system. Body weight development did not differ between the exposure groups. The exposure did not alter spontaneous motor activity when exploring a novel cage or anxiety in novelty-suppressed feeding or marble burying tests. Improved performance in the Rotarod task was observed in the 12uT group, while the 120MUT exposure group swam more slowly than the sham exposed group in the Morris swim navigation task. However, indices of learning and memory (path length and escape latency during task acquisition and search bias during the probe test) did not differ between the exposure groups. Furthermore, the passive avoidance task did not indicate any impairment of long-term memory over a 48h interval in the exposed groups. In a post-mortem histopathological analysis, there was no evidence for an effect of IF MF exposure on astroglial reactivity or hippocampal neurogenesis. The results suggest that the IF MF used did not have detrimental effects on spatial learning and memory or histological markers of tissue reaction. The two statistically significant findings that were observed (improved performance in the Rotarod task in the 12uT group and decreased swimming speed in the 120uT group) are likely to be chance findings, as they do not form an internally consistent, dose-dependent pattern indicative of specific developmental effects. PMID- 29276977 TI - Resin-based dental sealants as a source of human exposure to bisphenol analogues, bisphenol A diglycidyl ether, and its derivatives. AB - Although studies have examined leaching of bisphenol A (BPA) from dental sealants into saliva, occurrence of BPA, bisphenol A diglycidyl ether (BADGE), and their derivatives in dental sealants themselves has not been investigated. In this study, concentrations of eight bisphenol analogues (BPs), BADGE and its derivatives (BADGEs), including BADGE?H2O, BADGE?HCl, BADGE?2H2O, BADGE?2HCl, and BADGE?H2O?HCl, were determined in 70 dental sealants collected from the U.S. market. Of the 70 dental sealants analyzed, 65 contained at least one of the target chemicals measured. BADGE?2H2O was the most abundant compound, found at concentrations of up to 1780ug/g. The geometric mean (GM) concentration of total BADGEs was 47.8ug/g, which was two to three orders of magnitude higher than that of total BPs (GM: 539ng/g). BPA was found in 46% of the sealants and BADGEs was found in 87% of the sealants analyzed. Majority of the dental sealants analyzed in this study were manufactured in the United States and Korea; no significant differences were observed in the concentrations of BPs and BADGEs between the two countries. An exposure assessment was made based on the concentrations of BPs and BADGEs measured in sealants and their application rates in dentistry. The worst case exposure scenario with the highest measured concentration of total BPs and BADGEs and application on 8 teeth at 8mg each yielded an estimated daily intake (EDI) of 1670 and 5850ng/kg.bw/day for adults and children, respectively. Although the EDI is below the specific migration limit set by the European Food Safety Authority, dental sealants are a source of exposure to BPs and BADGEs, especially in children. PMID- 29276978 TI - Identification of significant factors in fatal-injury highway crashes using genetic algorithm and neural network. AB - Identification of the significant factors of traffic crashes has been a primary concern of the transportation safety research community for many years. A fatal injury crash is a comprehensive result influenced by multiple variables involved at the moment of the crash scenario, the main idea of this paper is to explore the process of significant factors identification from a multi-objective optimization (MOP) standpoint. It proposes a data-driven model which combines the Non-dominated Sorting Genetic Algorithm (NSGA-II) with the Neural Network (NN) architecture to efficiently search for optimal solutions. This paper also defines the index of Factor Significance (Fs) for quantitative evaluation of the significance of each factor. Based on a set of three year data of crash records collected from three main interstate highways in the Washington State, the proposed method reveals that the top five significant factors for a better Fatal injury crash identification are 1) Driver Conduct, 2) Vehicle Action, 3) Roadway Surface Condition, 4) Driver Restraint and 5) Driver Age. The most sensitive factors from a spatiotemporal perspective are the Hour of Day, Most Severe Sobriety, and Roadway Characteristics. The method and results in this paper provide new insights into the injury pattern of highway crashes and may be used to improve the understanding of, prevention of, and other enforcement efforts related to injury crashes in the future. PMID- 29276979 TI - Fertility and the health of children in Indonesia. AB - We analyse the heights of children aged 2 to 12 in the Indonesian Family Life Survey (IFLS) focusing on the effect of the number of children in the family. Previous studies of the trade-off between the quantity of children and some measure of their quality have been much concerned with the endogeneity of fertility choices. Here we use the IFLS for 1993, 1997 and 2000 to exploit some unique institutional features that have influenced fertility. We find evidence that family size is influenced both from the supply side, as represented by components of the Indonesian family planning programme, and on the demand side, as represented by exposure to modern media. We use these variables as instruments for family size in regressions for the height z-scores. We find evidence for a significant negative effect of family size on height in the presence of a range of other influences. An increase of one sibling is associated with a decrease of one third of a standard deviation in the z-score of height. This effect is stronger among families with low-educated mothers and is present in both urban and rural settings. PMID- 29276980 TI - Development of a highly sensitive and specific ELISA method for the determination of l-corydalmine in SD rats with monoclonal antibody. AB - l-Corydalmine (l-CDL) is a potent analgesic constituent of the traditional Chinese medicine, Rhizoma Corydalis. However, the pharmacokinetic process and tissue distribution of l-CDL in vivo are still unknown. Therefore, it is necessary to establish a simple and sensitive method to detect l-CDL, which will be helpful to study its distribution and pharmacokinetic process. To determine this compound in biological samples, a monoclonal antibody (mAb) against l-CDL was produced and a fast and highly sensitive indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed in this study. The icELISA was applied to determine l-CDL in biological samples. The limit of detection (LOD) of the method was 0.015 ng/mL with a liner range of 1-1000 ng/mL (R2 = 0.9912). The intra- and inter-day precision were below 15% and the recoveries were within 80 117%. Finally, the developed immunoassay was successfully applied to the analysis of the distribution of l-CDL in SD rats. In conclusion, the icELISA based on the anti-l-CDL mAb could be considered as a highly sensitive and rapid method for the determination of l-CDL in biological samples. The ELISA approach may provide a valuable tool for the analysis of small molecules in biological samples. PMID- 29276981 TI - Comparative metabolism of two major compounds in Fructus Corni extracts by gut microflora from normal and chronic nephropathy rats in vitro by UPLC-Q-TOF/MS. AB - Herbal medicines are widely used as therapeutic products in many countries. Fructus Corni, a traditional herb medicine, has been clinically used to cure chronic nephropathy for thousands of years. It could be converted by gut microflora in vivo to shape its pharmacological profiles. Thus, metabolic profiles of major active constituents in Fructus Corni extracts by gut microflora from rats in healthy and nephropathy state were firstly investigated in vitro by ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) in this study. According to the features of protonated ions, five metabolites (M1, M2, M3, M5 and M6) were found and preliminarily authenticated. Intestinal bacteria were capable of converting N0 (loganin) to its aglycone M1 (loganetin). The latter was further hydrogenated to the corresponding M2 (hydrogenated loganetin) and subsequently to M3 (hydrogenated and demethylated loganetin) by demethylation; While M5 (demethylated morronisid aglycone) and M6 (dehydroxylated morronisid aglycone) were identified as the two metabolites of N4 (morronisid) through demethylation and dehydroxylation. Gut microflora from healthy and nephropathy rats could degrade loganin and morronisid to the above metabolites. However, healthy rat intestinal bacteria showed more powerful degradation and much more amounts of M1 and M6 were obtained in their samples. Additionally, this work demonstrated that UPLC-Q-TOF/MS approach connected with MetaboLynxTM analysis software was rapid and reliable for screening and authentication of natural product metabolites. PMID- 29276982 TI - A rapid and sensitive supercritical fluid chromatography/tandem mass spectrometry method for detection of ezetimibein dog plasma and its application in pharmacokinetic studies. AB - The aim of this study is to develop and validate a rapid, high-selective and sensitive supercritical fluid chromatography/tandem mass spectrometry (SFC-MS/MS) with a multiple reactions monitoring (MRM) mode method for the detection of ezetimibe in dog plasma. Several conditions were optimized systematically as follows: lipid-lipid extraction (LLE) performances were used to extract analytes from dog plasma; an ACQUITY HSS C18 SB (1.8 MUm, 3.0 * 100 mm) column was employed to separate the target compounds; the triple-quadrupole mass spectrometry equipped with electrospray ionization (ESI) source was applied to detect ezetimibe. The method, which required a relatively small volume of plasma (100 MUL), was obtained at concentration ranging from 1.0 to 100 ng/mL(r2 > 0.99). The lower limit of quantification (LLOQ)for ezetimibe was found to be as low as 1.0 ng/mL. In addition, the validations of the methodology including sensitivity, recovery, matrix effect, intra- and inter-day precision, accuracy and stability were all within acceptable limits. The Cmax, AUC0-inf and Tmax values obtained in our study were 52.2 +/- 6.3, 820.6 +/- 4.3 and 1.25 +/- 0.35 for reference formulation; 61.8 +/- 12.6, 924.2 +/- 4.7 and 2.00 +/- 0 for test formulation. In conclusion, the method developed in this study can be successfully applied to pharmacokinetic studies after oral administration of ezetimibe in dogs. PMID- 29276983 TI - UPLC-MS/MS method for the simultaneous quantification of sofosbuvir, sofosbuvir metabolite (GS-331007) and daclatasvir in plasma of HIV/HCV co-infected patients. AB - Direct-acting antiviral agents (DAAs) represent the major advance in hepatitis C virus (HCV) infection treatment leading to extremely high eradication rates in HCV mono- and HIV/HCV co-infected patients. In this scenery, availability of Therapeutic Drug Monitoring (TDM) is of interest to assess plasma concentrations to prevent either therapeutic failure due to suboptimal medication adherence and drug-drug interactions or avoid adverse events. Aim of this study was to develop and validate an Ultra-Performance Liquid Chromatography Mass Spectrometry (UPLC MS/MS) method for the simultaneous quantification of sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir in human plasma. A simple protein precipitation was applied by adding 200 MUL acetonitrile with internal standard 6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline to 100 MUL plasma sample. Drug separation was performed on analytical C-18 Luna Omega column (50 mm * 2.1 mm I.D.) with particle size of 1.6 MUm. The mobile phase consisting of water containing 0.1% formic acid and acetonitrile at flow 0.4 mL/min and a gradient run time of 3.5 min. The injection volume was 10 MUL. Anti-HCV drugs were detected in positive electrospray ionization mode. The full scan mass spectral analyses of sofosbuvir, GS-331007, daclatasvir and quinaxoline showed protonated molecule ions and transitions m/z: 530.098 -> 243.02, 260.93 -> 112.94, 739.4 -> 339.27 and 313.03 -> 77.99 respectively. The linearity of standard curves was excellent (r2 > 0.99), the absolute recovery of anti-HCV drugs ranged between 95 and 98%, and both imprecision and inaccuracy were <15% according to FDA guidelines. The UPLC-MS/MS method was applied to 16 plasma samples of as many HIV/HCV co-infected patients treated with sofosbuvir and daclatasvir. While sofosbuvir was not detectable in all samples, the median plasma concentrations of daclatasvir and GS-331007 were 223.6 +/- 319.56 ng/mL and 537.11 +/- 242.09 ng/mL, respectively. In conclusion, we describe an UPLC-MS/MS method allowing the simultaneous quantification of sofosbuvir, GS-331007 and daclatasvir in plasma samples. The method was sensitive, specific, robust, and time-saving. PMID- 29276984 TI - Genetic polymorphisms offer insight into the causal role of microRNA in coronary artery disease. AB - There is growing interest in the potential of circulating microRNAs (miRNAs), a class of small and noncoding RNA molecules, as diagnostic and/or prognostic biomarkers in coronary artery disease (CAD). Despite this promising role, there are still widespread inconsistencies among studies, and important obstacles must be overcome before miRNAs can enter clinical practice. The study of single nucleotide polymorphisms (SNPs) in the miRNA regulatory network could help shed light on the causality of associations as well as validate the value of cardiovascular miRNAs. SNPs in miRNA biogenesis or miRNA targetome genes may affect miRNA expression and circulating levels or the fidelity of the miRNA-mRNA interaction, influencing susceptibility to atherosclerotic vascular disease. This review aims to provide a general overview of the available studies that have investigated the association of miRNA gene polymorphisms with the susceptibility to CAD development and progression, and to highlight potential future research perspectives. PMID- 29276985 TI - Upregulation of miR-221 and -222 in response to increased extracellular signal regulated kinases 1/2 activity exacerbates neointimal hyperplasia in diabetes mellitus. AB - BACKGROUND AND AIMS: Diabetes is associated with accelerated arterial intimal thickening that contributes to the increased cardiovascular disease seen in this population. In healthy arteries, intimal thickening is inhibited by elevated levels of the cyclin-dependent kinase inhibitor, p27Kip1, and intimal thickening is promoted by activation of the mammalian Target of Rapamycin to promote degradation of p27Kip1 protein. Recently, we reported that two microRNAs, miR-221 and -222, which promote intimal thickening via down-regulation of mRNA encoding p27Kip1, are elevated in the arteries of diabetic patients. To determine if these miRNAs are critical to the increased intimal thickening under diabetic conditions, we examined the regulation of p27Kip1in a mouse model of diabetes. METHODS: Comparisons of p27Kip1 signaling in NONcNZO10 mice fed a diabetogenic versus control diet were performed using immunochemistry and real-time PCR. RESULTS: Vascular smooth muscle cells and arteries of diabetic mice exhibited decreased levels of p27Kip1 that derived from destabilization of p27Kip1 mRNA in an extracellular signal response kinase-1/2 (ERK-1/2) dependent manner. The activity of ERK-1/2 is increased in the arteries of diabetic mice and promotes an increase in miR-221 and -222. Inhibition of miR-221 and -222 restores normal levels of p27Kip1 mRNA and protein in the arteries of diabetic mice and reduces intimal thickening following wire injury. CONCLUSIONS: These data suggest diabetes is accompanied by increases in arterial miR-221 and -222 expression that promotes intimal thickening. Inhibition of the increased miR-221 and -222 may be efficacious in the prevention of the cardiovascular complications of diabetes. PMID- 29276986 TI - Imagined futures in living with multiple conditions: Positivity, relationality and hopelessness. AB - Hope serves as an overarching concept for a range of engagements that demonstrate the benefits of a positive outlook for coping with chronic conditions of ill health and disability. A dominant engagement through medicine has positioned hope as a desirable attribute and its opposite, hopelessness, as pathological. In this engagement hope is individual, internally located and largely cognitive and able to be learned. Attaining hope reflects a process of coming to terms with the losses associated with long-term conditions and of imagining new meanings and purposes for the future ahead. This process is characterised by a set of linear temporal stages, from loss and denial to acceptance and reappraising the life course, by an emphasis on the morally desirable exercise of self-care and by a desired outcome that, in the absence of cure, is hope. Through interviews, we aim to unsettle the privileged status given to a positive outlook through examining the expressions, contexts and negotiations of hopelessness of people living with multiple conditions of ill-health and/or disability. These narratives of hopelessness disclose the ways in which realistic imagined possibilities for the future are constrained by external structures of time and function that demand complex negotiations with places, bodies and other people. As a situated and relational narrative, hopelessness draws our attention to the need to rebalance the exclusive attention to individual, internal resources with a renewed attention to contexts and settings. Moreover, hopelessness can be generative for those living with multiple conditions in shaping alternatively framed priorities with respect to their temporal and interpersonal relations. PMID- 29276987 TI - Are life-extending treatments for terminal illnesses a special case? Exploring choices and societal viewpoints. AB - Criteria used by the National Institute for Health and Care Excellence (NICE) to assess life-extending, end-of-life (EoL) treatments imply that health gains from such treatments are valued more than other health gains. Despite claims that the policy is supported by societal values, evidence from preference elicitation studies is mixed and in-depth research has shown there are different societal viewpoints. Few studies elicit preferences for policies directly or combine different approaches to understand preferences. Survey questions were designed to investigate support for NICE EoL guidance at national and regional levels. These 'Decision Rule' and 'Treatment Choice' questions were administered to an online sample of 1496 UK respondents in May 2014. The same respondents answered questions designed to elicit their agreement with three viewpoints (previously identified and described) in relation to provision of EoL treatments for terminally ill patients. We report the findings of these choice questions and examine how they relate to each other and respondents' viewpoints. The Decision Rule questions described three policies: DA - a standard 'value for money' test, applied to all health technologies; DB - giving special consideration to all treatments for terminal illnesses; and DC - giving special consideration to specific categories of treatments for terminal illnesses e.g. life extension (as in NICE EoL guidance) or those that improve quality-of-life (QoL). Three Treatment Choices were presented: TA - improving QoL for patients with a non terminal illness; TB - extending life for EoL patients; and TC - improving QoL at the EoL. DC received most support (45%) with most respondents giving special consideration to EoL only when treatments improved QoL. The most commonly preferred treatment choices were TA (51%) and TC (43%). Overall, this study challenges claims about public support for NICE's EoL guidance and the focus on life extension at EoL and substantiates existing evidence of plurality in societal values. PMID- 29276989 TI - 'Walk like a penguin': Older Minnesotans' experiences of (non)therapeutic white space. AB - Therapeutic landscapes represent a lively field of inquiry in health geography. The health benefits of green and blue spaces feature prominently across this literature, and generate rich understanding of how it feels to encounter and move through natural environments. Juxtaposed against an abundant scholarship on green and blue (and growing attention to broader 'palettes of place' including grey and brown landscapes), white spaces - environmental snow and ice - have yet to be investigated. Research on everyday experiences of snow and ice is limited, particularly for older adults potentially more vulnerable to climactic conditions given health and mobility limitations. This study aimed to characterize white space impacts on the perceived well-being of older adults. Interviews were conducted with community-dwelling men and women (n = 125, mean age 71 years) in the Minneapolis metropolitan area from June to October 2015. Extended participant observation with a sub-sample of participants (n = 6, mean age 71 years) was conducted from September 2015 to August 2016. Qualitative thematic analyses of participant statements, experiences, and understandings of harsh winter weather conditions illuminated how white spaces can both promote and diminish physical, mental, and social well-being. White spaces were fluid and relational, with potentially therapeutic effects uniquely negotiated by each participant. The findings conceive of therapeutic landscapes as contradictory spaces that can simultaneously heal and harm. The paper enriches knowledge of how (non)therapeutic landscapes operate through dynamic, embodied, and emotional geographic experiences. Articulations of ambiguity and nuance inherent to therapeutic landscapes throughout the paper deepen understanding of social determinants of health. PMID- 29276988 TI - Neighborhood cohesion, neighborhood disorder, and cardiometabolic risk. AB - Perceptions of neighborhood disorder (trash, vandalism) and cohesion (neighbors trust one another) are related to residents' health. Affective and behavioral factors have been identified, but often in studies using geographically select samples. We use a nationally representative sample (n = 9032) of United States older adults from the Health and Retirement Study to examine cardiometabolic risk in relation to perceptions of neighborhood cohesion and disorder. Lower cohesion is significantly related to greater cardiometabolic risk in 2006/2008 and predicts greater risk four years later (2010/2012). The longitudinal relation is partially accounted for by anxiety and physical activity. PMID- 29276991 TI - Emotion regulation's relationships with depression, anxiety and stress due to imagined smartphone and social media loss. AB - A sample of 359 students participated in a web survey, administered the Emotion Regulation Questionnaire, and Depression Anxiety Stress Scale-21 (DASS-21) as a pre-test. We subsequently randomly assigned subjects to either 1) a smart phone loss group or 2) social media accounts loss group. We asked them to imagine losing two days' access to the technology in their respective group, and rate associated symptoms using the DASS-21. Compared to subjects in the smartphone loss group, social media loss subjects evidenced stronger relations between suppressive emotion regulation with depression, anxiety and stress from imagined loss. Controlling for age and gender, social media loss subjects' increased use of suppression, and decreased use of cognitive reappraisal in emotion regulation, were related to depression, stress and (for suppression only) anxiety due to imagined lost social media. Emotion regulation was not related to psychopathology for subjects in the smartphone loss scenario. Results suggest that emotion dysregulation may be associated with psychopathology from social media loss. PMID- 29276990 TI - Bright light and oxygen therapies decrease delirium risk in critically ill surgical patients by targeting sleep and acid-base disturbances. AB - This study examined the effects of bright light therapy (BLT) on the incidence of delirium in post-operative patients admitted to a surgical intensive care unit (SICU) and delineates risk and protective factors. We included 62 patients in a single-blind, randomized controlled study. The intervention group was treated with care as usual plus BLT for three consecutive days. Delirium was diagnosed by DSM-5 criteria with the Confusion Assessment Method-Intensive Care Unit (CAM ICU). Risk factors for delirium were measured, including the APACHE II score, Insomnia Severity Index (ISI), as well as hematocrit and bicarbonate levels. Results were adjusted for treatment with nasal cannula oxygen and medications. Thirteen patients developed delirium within the three days following surgery. Generalized estimating equations analysis showed a significant preventive effect of BLT on delirium, which was independent of risk or treatment factors. Higher APACHE-II and ISI scores, lower hematocrit and lower bicarbonate levels increased the risk of developing delirium. BLT plus nasal cannula oxygen significantly reduced the likelihood of delirium. BLT significantly lowered ISI scores, while nasal cannula oxygen significantly enhanced bicarbonate levels. The results indicate that BLT and supplementary oxygen therapy may protect against delirium by targeting sleep-wake and deficits in the bicarbonate buffer system. PMID- 29276992 TI - A review of epidemiologic studies on suicide before, during, and after the Holocaust. AB - The available literature on the risk of suicides related to the Holocaust (1939 1945) and its aftermath differs in its time periods, in the countries investigated, and in the robustness of its sources. Reliable information seems to indicate that the risk of suicide for Jews in Nazi Germany and Austria during the pre-war period (1933-1939) was elevated, while information on suicide during the internment in the concentration camps is fraught with problems. The latter derives from the Nazis' decision to hide the statistics on the inmates' causes of death, and from the prevailing life conditions that impeded separation between self-inflicted death and murder. Reliable studies conducted in Israel among refugees who entered pre-state Israel, 1939-1945, and post-World War II survivors reaching Israel (1948 on), show a mixed picture: suicide rates among the former were higher than comparison groups, while the latter group shows evidence of resilience. PMID- 29276993 TI - Evaluation of motor proficiency and adiponectin in adolescent students with attention deficit hyperactivity disorder after high-intensity intermittent training. AB - Attention deficit hyperactivity disorder (ADHD) is a chronic condition with frequent comorbidities such as obesity, troubled relationships, low self-esteem, and difficulty in motor proficiency. This study aims to elucidate the effect of high-intensity intermittent training on motor proficiency, adiponectin, and insulin resistance in adolescent students with ADHD disorder. Fifty adolescent students of both genders with ADHD diagnosis participated and assigned into four experimental groups (each group with 15 girls and 10 boys students; two experimental and two control groups). High-intensity intermittent training was performed continuously 3 times a week for 6 weeks in experimental groups. Serum adiponectin level significantly increased in the experimental groups of both genders after 6 weeks intermittent training while insulin resistance levels were markedly decreased. Furthermore, motor proficiency score were significantly improved in the experimental groups of both genders. In addition gender had no significant impact on adiponectin, insulin resistance and motor proficiency rating. The findings of this study suggest that high intensity intermittent training improved physiological systems in ADHD population that leads to reduce risk factors for future development of comorbidities. PMID- 29276994 TI - Transcriptomic analysis reveals transgenerational effect of hypoxia on the neural control of testicular functions. AB - There are over 400 hypoxic zones in the ocean worldwide. Both laboratory and field studies have shown that hypoxia causes endocrine disruption and reproductive impairments in vertebrates. More importantly, our recent study discovered that parental (F0) hypoxia exposure resulted in the transgenerational impairment of sperm quality in the F2 generation through the epigenetic regulation of germ cells. In the present study, we aim to test the hypothesis that the brain, as the major regulator of the brain-pituitary-gonad (BPG) axis, is also involved in the observed transgenerational effect. Using comparative transcriptomic analysis on brain tissues of marine medaka Oryzias melastigma, 45 common differentially expressed genes caused by parental hypoxia exposure were found in the hypoxic group of the F0 and F2 generations, and the transgenerational groups of the F2 generation. The bioinformatic analysis on this deregulated gene cluster further highlighted the possible involvement of the brain in the transgenerational effect of hypoxia on testicular structure, including abnormal morphologies of the epididymis and the seminal vesicle, and degeneration of the seminiferous tubule. This finding is concordant to the result of hematoxylin and eosin staining, which showed the reduction of testicular lobular diameter in the F0 and F2 generations. Our study demonstrated for the first time the involvement of the brain in the transgenerational effect of hypoxia. PMID- 29276995 TI - Characterization and pH-dependent environmental stability of arsenic trioxide containing copper smelter flue dust. AB - Increasing amounts of impurities (especially As) in Cu ores have aggravated the problem of flue dust generation in recent years. As an example from a smelter processing As-rich Cu ores, we characterized a flue dust particularly rich in As (>50 wt%) to understand its mineralogy and pH-dependent leaching behavior, with special emphasis on binding, release and solubility controls of inorganic contaminants (As, Bi, Cd, Cu, Pb, Sb, Zn). Whereas arsenolite (As2O3) was the major host for As and Sb, other contaminants were bound in sulfides, arsenates, alloys and slag-like particles. The EU regulatory leaching test (EN 12457-2) indicated that leached As, Cd, Sb and Zn significantly exceeded the limit values for landfills accepting hazardous waste. The pH-dependent leaching test (CEN/TS 14997) revealed that As, Sb and Pb exhibited the greatest leaching at pH 11-12, whereas Cd, Cu and Zn were leached most under acidic condition (pH 3) and Bi leaching was pH-independent. Mineralogical investigation of leached residue coupled with geochemical modeling confirmed that newly formed Ca, Pb and Ca-Pb arsenates (mimetite, Pb5(AsO4)3Cl) partly control the release of As and other contaminants under circumneutral and alkaline conditions and will be of key importance for the fate of smelter-derived contamination in soils or when stabilization technology is employed. PMID- 29276996 TI - B1-control receive array coil (B-RAC) for reducing B1+ inhomogeneity in abdominal imaging at 3T-MRI. AB - B1+ inhomogeneity in the human body increases as the nuclear magnetic resonance (NMR) frequency increases. Various methods have thus been developed to reduce B1+ inhomogeneity, such as a dielectric pad, a coupling coil, parallel transmit, and radio-frequency (RF) shimming. However, B1+ inhomogeneity still remains in some cases of abdominal imaging. In this study, we developed a B1-control receive array coil (B-RAC). Unlike the conventional receive array coil, B-RAC reduces B1+ inhomogeneity by using additional PIN diodes to generate the inductive loop during the RF transmit period. The inductive loop can generate dense and sparse regions of the magnetic flux, which can be used to compensate for B1+ inhomogeneity. First, B-RAC is modeled in the numerical simulation, and the spatial distributions of B1+ in a phantom and a human model were analyzed. Next, we fabricated a 12-channel B-RAC and measured receive sensitivity and B1+ maps in a 3T-MRI experiment. It was demonstrated that B-RAC can reduce B1+ inhomogeneity in the phantom and human model without increasing the maximum local specific absorption rate (SAR) in the body. B-RAC was also found to have almost the same the receive sensitivity as the conventional receive coil. Using RF shimming combined with B-RAC was revealed to more effectively reduce B1+ inhomogeneity than using only RF shimming. Therefore, B-RAC can reduce B1+ inhomogeneity while maintaining the receive sensitivity. PMID- 29276997 TI - Cancer immunotherapy in a neglected population: The current use and future of T cell-mediated checkpoint inhibitors in organ transplant patients. AB - Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population. Herein we provide a current and comprehensive review of cases in which immune checkpoint blockade was used on organ transplant recipients. Furthermore, we discuss the differences in efficacy and risk of allograft rejection between CTLA-4 and PD-1 inhibitors and make recommendations based on the limited available clinical data. We also discuss the future of immune checkpoint blockade in this subpopulation and explore the emerging data of promising combination therapies with mTOR, BRAF/MEK, and BTK/ITK inhibitors. Further clinical experience and larger clinical trials involving immune checkpoint inhibitors, whether as monotherapies or combinatorial therapies, will help develop regimens that optimize anti-tumor response and minimize the risk of allograft rejection in organ transplant patients. PMID- 29276998 TI - Pulmonary Sarcoidosis in a patient with Multiple Sclerosis on daclizumab monotherapy. AB - As new immunomodulatory therapies continue to be licensed for use in Multiple Sclerosis, it is important to remain vigilant for new, unexpected associations relating to these medications. We highlight this by reporting on a case of a 45 year-old man who developed systemic, non-specific symptoms following long term use of daclizumab and was subsequently diagnosed with sarcoidosis. We go on to briefly discuss the action of daclizumab, in particular the effect it has on CD56bright natural killer cells, a cell type that has been investigated in relation to sarcoidosis. PMID- 29276999 TI - The impact of the false ID laws on alcohol consumption among young adults: New results from the NLSY97. AB - In volume 36 of this journal, using data from the National Longitudinal Study of Youth, 1997 Cohort (NLSY97), Yoruk (2014) finds that the false ID laws with scanner provision (FSP laws) significantly reduce underage drinking. In a recent paper, Zheng (2018) argues that analyses based on the NLSY97 data fail falsification exercises and uses data from the Youth Risk Behavior Surveillance System (YRBSS) to estimate the effectiveness of the FSP laws. This paper replies to Zheng (2018) and provides new results from the NLSY97, which show that the FSP laws were effective reducing several indicators of alcohol consumption among minors. PMID- 29277000 TI - The Vaccination Kuznets Curve: Do vaccination rates rise and fall with income? AB - This paper presents a new stylized fact about the relationship between income and childhood vaccination. It shows vaccination rates first rise but then fall as income increases. This pattern is observed in WHO country-level panel data, and in US county-level panel and individual-level repeated cross-section data. This data pattern suggests that both low and high-income parents are less likely to follow the standard vaccination schedule, and that such behavior is reflected in the vaccination rate at the population level. I provide several alternative explanations as to why we observe this data pattern, including avoidance measures, medical care, and social segregation. PMID- 29277001 TI - A computational approach to unraveling TLR signaling in murine mammary carcinoma. AB - We developed an agent-based model to simulate a signaling cascade which allowed us to focus on the behavior of each class of agents independently of the other classes except when they were in physical contact. A critical piece was the ratio of the populations of agents that interact with one another, not their absolute values. This ratio reflects the effects of the density of each agent in the biological cascade as well as their size and velocity. Although the system can be used for any signaling cascade in any cell type, to validate the system we modeled Toll-like receptor (TLR) signaling in two very different types of cells; tumor cells and white blood cells. The iterative process of using experimental data to improve a computational model, and using predictions from the model to design additional experiments strengthened our understanding of how TLR signaling differs between normal white blood cells and tumor cells. The model and experimental data showed that some of the differences between the tumor cells and normal white blood cells were related to NFkappaB and TAB3 levels, and also suggested that tumor cells lacked IRAKM-dependent feedback inhibition as a negative regulator of TLR signaling. Finally, we found that these different cell types had distinctly different responses when exposed to two signals indicating that a more biologically relevant model and experimental system should address activation of multiple interconnected signaling cascades, the complexity of which further reinforces the need for a combined computational and molecular approach. PMID- 29277002 TI - Distribution of anisakid nematodes parasitizing rajiform skates under commercial exploitation in the Southwestern Atlantic. AB - In order to evaluate the infestation by anisakids present in elasmobranchs and their distribution in the Argentine Sea, this study was carried at a regional scale with the following aims: 1) to identify those anisakid species present in skates under exploitation; 2) to characterize quantitatively these infestations and 3) to determine those factors driving the variability in parasite burdens across skate species. A total of 351 skates, belonging to 3 species (218 Sympterygia bonapartii, 86 Zearaja chilensis and 47 Atlantoraja castelnaui) and from different localities of the Argentine Sea were examined for anisakids. Parasites were found in the stomach wall at high prevalence in some samples. Based on morphology and mtDNA cox2 sequences analyses (from 24 larval worms), specimens were identified as Anisakis berlandi, A. pegreffii and Pseudoterranova cattani; the last two known as potentially pathogenic for humans. Differential distribution patterns were observed across parasite and hosts species. In general, fish caught in southern and deeper waters exhibited higher loads of Anisakis spp., whereas infestation levels by P. cattani increase in larger skates. Taking into account that the mere presence of worms or their antigens in fish meat can provoke allergic responses, information on distribution of parasites and their variability is essential for the implementation of food safety practices. PMID- 29277003 TI - Eugenol enhances proliferation and migration of mouse bone marrow-derived mesenchymal stem cells in vitro. AB - Mesenchymal stem cells (MSCs) have received considerable attention in regenerative medicine during the past decade. Eugenol is a natural and versatile vegetable molecule, which has a wide variety of therapeutic effects. Although different biological and pharmaceutical functions of Eugenol are well known, its effect on MSCs has not been studied yet. Therefore, this study was focused on investigating the effect of Eugenol on the proliferation and migration of bone marrow (BM)-derived MSCs in vitro. To do so, BM-MSCs were isolated from 4 to 8 weeks old NMRI mice. Cytotoxicity of Eugenol on MSCs was evaluated by MTT assay at 24, 48 and 72 h after treatment. In addition, its effect was assessed on the proliferation and migration of MSCs using wound healing assay in vitro and quantitative gene expression analysis for Oct4, Sox2, Cyclin-D1, Rex1, Tex10, Cxcr4, Vla4 and c-Met. Results showed that Eugenol reduced the number of MSCs in a dose- and time-dependent manner. The median inhibition concentration of Eugenol on MSCs was 400 MUg/ml at 24 and 48 h and 200 MUg/ml at 72 h after treatment. Moreover, about 90% viability of MSCs was detected at concentrations <=12.5 MUg/ml. The wound healing assay and gene expression analysis demonstrated that Eugenol promoted the migratory potential of MSCs through up-regulation of c-Met. Moreover, Eugenol has enhanced the proliferation of MSCs via over-expression of Sox2, Rex1 and Tex10. In conclusion, this study revealed that Eugenol enhances the proliferation and migration of MSCs, and thus this will be beneficial to the field of regenerative medicine. PMID- 29277004 TI - Correlates of physical function among stroke survivors: an examination of the 2015 BRFSS. AB - OBJECTIVES: To identify the characteristics of stroke survivors with poor physical function. STUDY DESIGN: Cross-sectional. METHODS: Secondary data analyses were performed with the 2015 Behavioral Risk Factor Surveillance System data set. Unadjusted and adjusted logistic regressions were employed to determine the correlates of poor physical function in stroke survivors. Self-reported difficulty with walking and stairs was used as a proxy for physical function. Characteristics such as age, race, sex, difficulty doing errands alone, difficult dressing or bathing alone, health care coverage, time since last routine checkup, and reported financial difficulty with regard to health care access were examined as contributing factors to physical function. RESULTS: Approximately half of all stroke survivors reported having difficulty with walking and stairs (50.3%). As expected, the odds of reporting difficulty with walking and stairs were higher among stroke survivors aged 40 years and above (p < 0.0001). Interestingly, black/African American and multiracial respondents had higher odds of reporting difficulty with walking and stairs than whites, whereas Hispanic respondents had lower odds of reporting difficulty with walking and stairs than whites (p < 0.0001). Further analyses revealed that the disparity of physical function was preserved (p < 0.0001) after adjusting for age, race, sex, education level, family income, marital status, employment status, health insurance status, affordability of healthcare, and length of time from last doctor's visit. CONCLUSIONS: There were racial/ethnic disparities in physical function. Specifically, blacks/ African Americans had a 5.6% increase in the odds of reporting difficulty with walking and stairs than whites. Moreover, Hispanics reported significantly fewer problems than whites. Overall, similar sociocultural patterns in non-stroke and stroke populations were observed in this study. PMID- 29277005 TI - Landmarks of endosomal remodeling in the early phase of cytomegalovirus infection. AB - Cytomegaloviruses (CMVs) extensively rearrange the cellular membrane system to develop assembly compartment (AC), but the earliest events in this process are poorly characterized. Here, we demonstrate that murine CMV (MCMV) infection restrains endosomal trafficking of cargo molecules that travel along the recycling (TfR and MHC-I) and the late endosomal (EGFR, M6PR, Lamp1) circuit. Internalized cargo accumulates in Arf6-, Rab5-, Rab22A-, and Rab11-positive and Rab35-, Rab8-, and Rab10-negative juxtanuclear endosomes, suggesting the disruption of Arf/Rab regulatory cascade at the stage of sorting endosomes and the endosomal recycling compartment. Rearrangement of the endosomal system is initiated by an MCMV-encoded function very early in the infection. Our study, thus, establishes a set of landmarks of endosomal remodeling in the early phase of MCMV-infection which coincide with the Golgi rearrangement, suggesting that these perturbations are the earliest membrane reorganizations that may represent an initial step in the biogenesis of the AC. PMID- 29277007 TI - Singlet oxygen luminescence kinetics under PDI relevant conditions of pathogenic dermatophytes and molds. AB - A treatment of onychomycosis using the photodynamic effect would be a favorable alternative to currently used antimycotic drugs. This study should be considered as a first step towards development and control of an efficient photodynamic inactivation of onychomycosis causative pathogens. Here, we evaluate the usage of time-resolved 2D singlet oxygen luminescence detection in combination with 2D fluorescence scanning as a tool to understand the behavior of the photosensitizer when applied to fungi on Petri dishes. To investigate the interaction of photosensitizer with fungi in various concentrations and in different stages of live, a photodynamic inactivation was avoided by keeping the samples in darkness. Scans of singlet oxygen luminescence and photosensitizer fluorescence were performed over a period of 24days. Two different photosensitizer, a cationic porphyrin and cationic corrole and two fungi strains, the dermatophyte Trichophyton rubrum and the mold Scopulariopsis brevicaulis, were investigated in this study. The two-dimensional correlation of photosensitizer fluorescence and singlet oxygen luminescence revealed differences in the diffusion of both photosensitizer. Even though the singlet oxygen luminescence was quenched with increasing growth of fungi, it was found that the kinetics of singlet oxygen luminescence could be detected on Petri dishes for both photosensitizers and both fungi strains for up to seven days. PMID- 29277008 TI - Photodynamic therapy of mouse tumor model using chlorin e6- polyvinyl alcohol complex. AB - The use of polymeric carriers to deliver hydrophobic photosensitizers has been widely discussed as a way to improve both fluorescence diagnostic and photodynamic therapy (PDT) of cancers; however, the photophysical and pharmacokinetic parameters, as well as the PDT activity, of such modifications have, until now, only been poorly investigated. The purpose of the present study was to explore the efficacy of PDT with the formulation of the photosensitizer chlorin e6 (Ce6) in combination with polyvinyl alcohol (PVA) in comparison with Ce6 alone and with the clinical drug, Photodithazine in a mouse tumor model. We also investigated the photoactivity of the Ce6-PVA in a model reaction of tryptophan oxidation, analyzed the polymer-Ce6 interaction using fluorescence spectroscopy and atomic-force microscopy, and tested the phototoxicity in vitro. Using fluorescence imaging in vivo we found that injection to mice of Ce6 in a formulation with PVA resulted in a higher tumor-to-normal ratio and greater photobleaching when compared with either the use of Ce6 alone, or with the effects of Photodithazine. Tumor growth study and histological examination of CT26 tumors revealed fast, reproducible tumor regression and more advanced necrosis after PDT with Ce6-PVA. The higher photoactivity of the Ce6-PVA complex was confirmed in a model reaction of tryptophan oxidation and in cultured cells. Therefore, encapsulation of Ce6 in PVA represents a promising strategy for further increasing the selectivity and efficacy of PDT. PMID- 29277009 TI - Label-free sensor for automatic identification of erythrocytes using digital in line holographic microscopy and machine learning. AB - Cell types of erythrocytes should be identified because they are closely related to their functionality and viability. Conventional methods for classifying erythrocytes are time consuming and labor intensive. Therefore, an automatic and accurate erythrocyte classification system is indispensable in healthcare and biomedical fields. In this study, we proposed a new label-free sensor for automatic identification of erythrocyte cell types using a digital in-line holographic microscopy (DIHM) combined with machine learning algorithms. A total of 12 features, including information on intensity distributions, morphological descriptors, and optical focusing characteristics, is quantitatively obtained from numerically reconstructed holographic images. All individual features for discocytes, echinocytes, and spherocytes are statistically different. To improve the performance of cell type identification, we adopted several machine learning algorithms, such as decision tree model, support vector machine, linear discriminant classification, and k-nearest neighbor classification. With the aid of these machine learning algorithms, the extracted features are effectively utilized to distinguish erythrocytes. Among the four tested algorithms, the decision tree model exhibits the best identification performance for the training sets (n = 440, 98.18%) and test sets (n = 190, 97.37%). This proposed methodology, which smartly combined DIHM and machine learning, would be helpful for sensing abnormal erythrocytes and computer-aided diagnosis of hematological diseases in clinic. PMID- 29277006 TI - HIV internalization into oral and genital epithelial cells by endocytosis and macropinocytosis leads to viral sequestration in the vesicles. AB - Recently, we showed that HIV-1 is sequestered, i.e., trapped, in the intracellular vesicles of oral and genital epithelial cells. Here, we investigated the mechanisms of HIV-1 sequestration in vesicles of polarized tonsil, foreskin and cervical epithelial cells. HIV-1 internalization into epithelial cells is initiated by multiple entry pathways, including clathrin-, caveolin/lipid raft-associated endocytosis and macropinocytosis. Inhibition of HIV-1 attachment to galactosylceramide and heparan sulfate proteoglycans, and virus endocytosis and macropinocytosis reduced HIV-1 sequestration by 30-40%. T cell immunoglobulin and mucin domain 1 (TIM-1) were expressed on the apical surface of polarized tonsil, cervical and foreskin epithelial cells. However, TIM 1-associated HIV-1 macropinocytosis and sequestration were detected mostly in tonsil epithelial cells. Sequestered HIV-1 was resistant to trypsin, pronase, and soluble CD4, indicating that the sequestered virus was intracellular. Inhibition of HIV-1 intraepithelial sequestration and elimination of vesicles containing virus in the mucosal epithelium may help in the prevention of HIV-1 mucosal transmission. PMID- 29277010 TI - Ferritin based bionanocages as novel biomemory device concept. AB - Ferritin is an iron cage having protein, capable of extracting metal ions in their cages and a consequence of the electron transfer of metal ions in their cage by reduction and oxidation processes, electrochemical information storage devices can be designed. In this work, ferritin based protein biomemory substrate has been synthesized by using Amino Acid (monomer) Decorated and Light Underpinning Conjugation Approach (ANADOLUCA) method, which utilizes photosensitive electron transfer based microemulsion co-polymerization as nanobead form of ferritin. Protein substrate contains metal ions such as silver and copper or metal ion pairs namely, silver-copper (Janus bionanocage) and co polymeric shell of the photosensitive crosslinker protein. The redox behavior of bionanocages differentiates electrochemical "writing" and "erase" states depending on these metal ions (silver or copper) or metal ion pairs. The bionanocages based biomemory substrates have been immobilized using graphene modified glassy carbon electrodes and the memory functions of ferritin based bionanocages have been confirmed by chronoamperometry (CA) and open circuit potential amperometry (OCPA). The stability and durability of multi-state memory devices represent promising properties for future bioelectronic information technologies. PMID- 29277011 TI - Silk provides a new avenue for third generation biosensors: Sensitive, selective and stable electrochemical detection of nitric oxide. AB - Using heme entrapped in recombinant silk films, we have produced 3rd generation biosensors, which allow direct electron transfer from the heme center to an electrode avoiding the need for electron mediators. Here, we demonstrate the use of these heme-silk films for the detection of nitric oxide (NO) at nanomolar levels in the presence and absence of oxygen. The sensor was prepared by drop casting a silk solution on a glassy carbon electrode modified with multiwalled carbon nanotubes (MWCNT) followed by infusion with heme. The sensor was characterized by cyclic voltammetry and showed well defined and reversible Fe+/ Fe3+ redox couple activity, with NO detection by oxidation at potentials above +0.45V or reduction at potentials below - 0.7V. Evaluation of the effect of pH on the sensor response to NO reduction indicated a maximum response at pH 3. The sensor showed good linearity in the concentration range from 19 to 190nM (R2 = 0.99) with a detection limit of 2nM. The sensor had excellent selectivity towards NO with no or negligible interference from oxygen, nitrite, nitrate, dopamine and ascorbic acid and retained 86% of response after 2 months of operation and storage at room temperature. PMID- 29277012 TI - Photoelectrochemical biosensor for HEN1 RNA methyltransferase detection using peroxidase mimics PtCu NFs and poly(U) polymerase-mediated RNA extension. AB - 2'-O-methyl group on the 3' terminal nucleotide in plant microRNAs, as one kind of RNA methylations, is caused by HEN1 RNA methyltransferase (HENMT1), which is thought to be crucial for ribosome biogenesis and function. Herein, a simple and label-free PEC biosensing method was proposed for assay of HENMT1 activity and inhibitor screening based on peroxidase mimic PtCu nanoframes (PtCu NFs) catalytic signal amplification. In this work, MoS2@Graphene quantum dots/Phosphorus-doped rodlike carbon nitride (MoS2@GQDs/P-RCN) heterojunction was used as photoactive materials. With the doping of GQDs and the formation of heterojunction, the photoactivity of MoS2 is greatly improved. After the double stranded RNA (dsRNA) with 2 nt 3' overhangs was treated with HENMT1 in the presence of S-adenosyl-L-methionine, the 3' terminal nucleotide of the unmethylated dsRNA could be extended under the catalysis of the poly(U) polymerase in the existence of UTP. Poly(A) nucleotide chain modified with carboxyl group was captured on the electrode surface through hybridization reaction and acted as a bridge for the immobilization of reticular DNA functionalized PtCu NFs (PtCu@DNA). Under the catalysis effect of peroxidase mimics PtCu@DNA towards hydrogen peroxide, O2- was in situ generated as electron donor and a strong photocurrent was obtained. The proposed PEC bioassay exhibited high selectivity and low detection limit of 3.36ng/mL for HENMT1 activity assay. Furthermore, the inhibition research indicated that chlorpyrifos could inhibit the HENMT1 activity with the IC50 value of 48.32nM. PMID- 29277013 TI - Self-concept of children with cerebral palsy measured using the population specific myTREEHOUSE Self-Concept Assessment. AB - Self-concept is an individual's perception of him/herself. Research into the self concept of children with cerebral palsy (CP) has been sparse due to the lack of a population-specific self-concept instrument. Using the new myTREEHOUSE Self Concept Assessment, this study investigated the self-concept of children with CP in relation to age, gender, motor, communication and cognitive function. Children with CP aged 8-12 years (n = 50; 29 males; mean 10 years 2 months; GMFCS-E&R I = 36, II = 8, III = 5, IV = 1) completed myTREEHOUSE and a standardised intelligence measure. Most children reported positive self-concept from all three myTREEHOUSE Performance Perspectives and over half (60%) fell within the Low range for the Personal Concern Score. Self-concept was not associated with age, gender, motor function, or communication function. However, for cognitive function, associations were observed for Social Skills (Below Average > Average cognitive function; Cohen's d = 1.07) and Learning Skills (Above Average > Average cognitive function; Cohen's d = 0.95) domains when rated from a Personal Performance Perspective. As the first study of the self-concept of children with CP using a CP-specific assessment, this study offers important insights into what children with CP think about themselves. Generally, the self-concept of children with CP was sound. Future research on environmental facilitators and barriers to robust self-concept development is recommended. PMID- 29277014 TI - Effects of trichostatin A on pig SCNT blastocyst formation rate and cell number: A meta-analysis. AB - Although somatic cell nuclear transfer (SCNT) can be used to create transgenic pigs for human xenotransplantation, low efficiency limits its use. Trichostatin A (TSA) promotes SCNT embryo development, but whether TSA modifies SCNT blastocyst numbers is unclear. Thus, there is an urgent need to understand whether TSA modifies the rate and number of embryos that grow from oocytes to blastocysts in culture and what types of cell signaling pathways may be involved. Thus, we identified 63 reports, of which 13 are included in this meta-analysis. Data show that TSA significantly increased the SCNT blastocyst formation rate, but did not change blastocyst cell number. Due to study heterogeneity (I2>50%), we hypothesized that donor cells were of different backgrounds so we analyzed two donor cell subgroups: fetal and adult fibroblasts. Analysis of the fetal fibroblast subgroups showed no heterogeneity, but the adult fibroblast subgroups were heterogeneous, suggesting epigenetic reprogramming of fetal fibroblasts by TSA. Adult fibroblast heterogeneity may be complex and reprogramming by TSA is more difficult. Thus, TSA fibroblasts reprogramming is the source of heterogeneity in this meta-analysis. More work is needed to better understand how TSA influences SCNT pig embryonic development, and histone deacetylase inhibitors can be assessed with respect to SCNT pig embryos. Finally, efforts in epigenetic research may improve SCNT pig embryo outcomes. PMID- 29277015 TI - Milk fever in dairy cows is preceded by activation of innate immunity and alterations in carbohydrate metabolism prior to disease occurrence. AB - The objective of this study was to search for potential alterations in innate immunity reactants and carbohydrate and lipid metabolism in the blood of transition dairy cows before, during, and after clinical occurrence of milk fever (MF) and identify potential predictive biomarkers of disease. One hundred pregnant multiparous Holstein dairy cows were involved in the study starting from -8wks before the expected day of parturition until +8wks postpartum as part of a large retrospective longitudinal study. Health status, DMI, milk yield, and milk composition were monitored during the whole experimental period. Six healthy cows (CON) and 6 cows that showed clinical signs of MF were selected for blood analyses. Serum concentrations of lactate, non-esterified fatty acids (NEFA), beta-hydroxybutyric acid (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA) were determined. Results indicated that concentrations of serum lactate, IL-6, TNF, SAA, and Hp were greater in cows with MF than those in the CON group at different time points. Moreover, serum lactate, TNF, SAA, and Hp were greater in cows with MF starting at -8 and -4wks prior to parturition. Both principal component analysis (PCA) and partial least squares - discriminant analysis (PLS-DA) showed separated clusters between MF and CON cows at -8, -4, and disease diagnosis weeks. Overall DMI and milk production were lower in MF-affected cows. Additionally milk fat and fat:protein ratio were greater in MF. In conclusion, cows affected by MF showed alterations in some of the innate immunity reactants and metabolites related to carbohydrate metabolism several weeks prior to appearance of clinical signs of MF. Variable importance in projection plots demonstrated that TNF and SAA in the serum were the strongest discriminators between MF cows and CON ones, which might be useful as predictive biomarkers of the disease. PMID- 29277017 TI - Modifying the mechanical properties of gold nanorods by copper doping and triggering their cytotoxicity with ultrasonic wave. AB - We proposed the use of copper (Cu) doping to modify the mechanical properties of gold nanorods (AuNRs) and demonstrated the triggering of the cytotoxicity of Cu doped AuNRs with ultrasonic wave. The mechanical properties of Cu-doped AuNRs were analyzed theoretically by using the density-function calculation and it was found that Cu-Au bond is much weaker than Au-Au bond. In experiments, AuNRs without and with Cu doping were synthesized and they were found to be low cytotoxic to both human liver hepatocellular carcinoma (HepG2) cells and normal liver cells (L02). It was found that Cu-doped AuNRs can be broken into small gold nanoparticles (<5 nm) under high-power ultrasonic wave while undoped AuNRs were quite stable, although the amount of Cu doped into AuNRs was quite small (0.2%). The small gold nanoparticles are found to be with high toxicity to HepG2 cells. The cellular viability of the HepG2 cells dropped to nearly zero after being incubated with Cu-doped AuNRs (50 nM), which had been treated with a 300-W ultrasonic wave. Our findings suggest a novel method for modifying the mechanical properties of AuNRs and especially for triggering their cytotoxicity which is quite useful for in vitro therapy of cancer cells. PMID- 29277018 TI - Intracellular trafficking and therapeutic outcome of multiwalled carbon nanotubes modified with cyclodextrins and polyethylenimine. AB - Functionalized carbon nanotubes (CNTs) have been proposed in the last years as vectors for delivery of biomolecules, proteins and DNA into various cells. In this study, a new multiwalled carbon nanotube beta-cyclodextrin platform (MWCNT CD) modified with branched polyethylenimine (PEI) and doped with Rhodamine (Rhod), MWCNT-CD-PEI-Rhod, was designed and investigated as drug delivery system. The drug binding abilities of MWCNT-CD-PEI-Rhod towards Cidofovir (Cid) and DNA plasmid encoding enhanced green fluorescence protein (pCMS-EGFP) were investigated by complementary spectroscopic techniques. MWCNT-CD-PEI-Rhod showed no significative cytotoxicity and an excellent ability to entrap and delivery Cid. The present study broadens the spectrum of biological evaluation by investigating platform-treatment induced cellular response such as antiviral activity, transfection properties, cellular uptake, internalization mechanisms and cellular localization. The mechanism of cellular uptake was elucidated monitoring the dependence of intracellular red fluorescence from the assembly concentration, time and presence of specific uptake inhibitors. The biological results indicated that MWCNT-CD-PEI-Rhod loaded with Cid and/or pCMS-EGFP crossed the cell membrane via clathrin-dependent pathway and co-localized in lysosomal compartment. However, no green fluorescent protein expression of pCMS-EGFP was detected, whereas the efficient escape of Cid from lysosome and the release close to nuclear region prompted the antiviral activity. PMID- 29277016 TI - Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and compromises reendothelialization impaired by oxidized HDL through SR-B1. AB - Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL) oxidized by heme enzyme myeloperoxidase (MPO) is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL) in promoting re-endothelialization. We demonstrate that 4F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1) using human aorta endothelial cells (HAEC) and SR-B1 (-/-) mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS) activity, Akt phosphorylation and SR-B1 expression. 4F increases NO generation and diminishes oxidative stress. In vivo, 4F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/-) mice. These findings demonstrate that 4F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases. PMID- 29277019 TI - Coencapsulation of cyclodextrins into poly(anhydride) nanoparticles to improve the oral administration of glibenclamide. A screening on C. elegans. AB - This work describes the feasibility of poly(anhydride) nanoparticles as carriers for the oral administration of glibenclamide (GB) as well as the in vivo evaluation of their hypolipidemic effect in a C. elegans model. For this purpose, and in order to increase the GB payload, the drug was encapsulated in nanoparticles in presence of cyclodextrins (either betaCD or HPbetaCD). The optimized nanoparticles displayed a size of about 220 nm and a negative zeta potential (-40 mV), with a drug loading up to 52 MUg/mg. Small-angle neutron scattering studies suggested an internal fractal-like structure, based on the repetition of spherical blocks of polymeric units (about 5 nm) grouped to form the nanoparticle. X-ray diffraction study confirmed the absence of crystalline GB molecules due to its dispersion into the nanoparticles, either entrapped in the polymer chains and/or included into cyclodextrin cavities. GB-loaded nanoparticles induced a significant reduction in the fat content of C. elegans. This hypolipidemic effect was slightly higher for the nanoparticles prepared with coencapsulated HPbetaCD (8.2%) than for those prepared with betaCD (7.9%) or in the absence of cyclodextrins (7.0%). In summary, the coencapsulation of cyclodextrins into poly(anhydride) nanoparticles could be an interesting strategy to develop new oral formulations of glibenclamide. PMID- 29277020 TI - Sex estimation from the patella in an African American population. AB - The skull and pelvis have been used for the estimation of sex for unknown human remains. However, in forensic cases where skeletal remains often exhibit postmortem damage and taphonomic changes the patella may be used for the estimation of sex as it is a preservationally favoured bone. The goal of the present research was to derive discriminant function equations from the patella for estimation of sex from an historic African American population. Six parameters were measured on 200 individuals (100 males and 100 females), ranging in age from 20 to 80 years old, from the Robert J. Terry Anatomical Skeleton Collection. The statistical analyses showed that all variables were sexually dimorphic. Discriminant function score equations were generated for use in sex estimation. The overall accuracy of sex classification ranged from 80.0% to 85.0% for the direct method and 80.0%-84.5% for the stepwise method. Overall, when the Spanish and Black South African discriminant functions were applied to the African American population they showed low accuracy rates for sexing the African American sample. However, when the White South African discriminant functions were applied to the African American sample they displayed high accuracy rates for sexing the African American population. The patella was shown to be accurate for sex estimation in the historic African American population. PMID- 29277021 TI - Ultrasound guided distal adductor canal block provides effective postoperative analgesia in lower leg surgery. PMID- 29277022 TI - Is CPAP treatment not effective after supratentorial craniotomy? Author's reply. PMID- 29277023 TI - Development of an in-vivo metric to aid visual inspection of single-case design data: Do we need to run more sessions? AB - Comparing visual inspection results of graphed data reveals inconsistencies in the interpretation of the same graph among single-case experimental design (SCED) researchers and practitioners. Although several investigators have disseminated structured criteria and visual inspection aids or strategies, inconsistencies in interpreting graphed data continue to exist even for individuals considered to be experts at interpreting SCED graphs. We propose a fail safe k metric that can be used in conjunction with visual inspection, and it can be used in-vivo after each additional data point is collected within a phase to determine the optimal point in time to shift between phases (e.g., from baseline to treatment). Preliminary proof of concept data are presented to demonstrate the potential utility of the fail safe k metric with a sample of previously published SCED graphs examining the effects on noncontingent reinforcement on occurrences of problem behavior. Results showed that if the value of fail safe k is equal to or less than the number of sessions in the current phase, then the data path may not be stable and more sessions should be run before changing phases. We discuss the results in terms of using the fail safe k as an additional aid for visual inspection of SCED data. PMID- 29277024 TI - Copper redox chemistry of plant frataxins. AB - The presence of a conserved cysteine residue in the C-terminal amino acid sequences of plant frataxins differentiates these frataxins from those of other kingdoms and may be key in frataxin assembly and function. We report a full study on the ability of Arabidopsis (AtFH) and Zea mays (ZmFH-1 and ZmFH-2) frataxins to assemble into disulfide-bridged dimers by copper-driven oxidation and to revert to monomers by chemical reduction. We monitored the redox assembly disassembly process by electrospray ionization mass spectrometry, electrophoresis, UV-Vis spectroscopy, and fluorescence measurements. We conclude that plant frataxins AtFH, ZmFH-1 and ZmFH-2 are oxidized by Cu2+ and exhibit redox cysteine monomer - cystine dimer interexchange. Interestingly, the tendency to interconvert is not the same for each protein. Through yeast phenotypic rescue experiments, we show that plant frataxins are important for plant survival under conditions of excess copper, indicating that these proteins might be involved in copper metabolism. PMID- 29277025 TI - Fatigue, quality of life and walking ability in adults with cerebral palsy. AB - INTRODUCTION: Few studies on fatigue, quality of life and walking ability in adults with cerebral palsy (CP) are available. It is unclear whether these variables are associated. AIM: The aim was to study the influence of CP on fatigue, quality of life, and gait of adult patients. MATERIAL AND METHODS: Three dimensional gait analysis was performed on 24 women and 26 men, mean age 32.1 (range 21.7-67.2), 23 with unilateral and 27 with bilateral CP. The Gait Profile Score was calculated; Fatigue Severity and EQ Visual Analogue scales were used. RESULTS: Fatigue severity was higher than in controls, mean 3.8 (SD 1.8) vs 3.0 (p = 0.012). Fatigue in the unilateral group was 3.3 (SD 1.8) and in the bilateral 4.2 (SD 1.7), (p = 0.07). EQ Visual Analogue scale in the unilateral group was mean 79.5 (21.9) and in the bilateral 64.0 (20.8), p = 0.007. The group with bilateral CP tended toward crouch gait, decreased balance and low walking speed. Muscle work was shifted from the ankle to hip muscles. Fatigue correlated with the Gait Profile Score, CC = 0.31 (p = 0.038), and with knee flexion deviation, CC = 0.31 (p = 0.037). DISCUSSION: Crouch gait, increased knee flexion in stance, contributes to increased deviation in the lower extremity associated with high fatigue and low quality of life in adults with CP, effects more pronounced in those with bilateral CP. Compensation mechanisms in gait were noted. CONCLUSION: Rational follow-up programs for CP, ideally identifying risk factors early, should be established to prevent development of fatigue and deterioration of gait in adulthood. PMID- 29277026 TI - The cinnamyl alcohol dehydrogenase family in flax: Differentiation during plant growth and under stress conditions. AB - Cinnamyl alcohol dehydrogenase (CAD), which catalyzes the reduction of cinnamaldehydes to their alcohol derivatives, is represented by a large family of proteins. The aim of the study was to identify the CAD isoforms in flax (Linum usitatissimum L.) - LuCADs - and to determine their specificity to enhance knowledge of the mechanisms controlling cell wall lignification in flax under environmental stresses. On the basis of genome-wide analysis, we identified 15 isoforms (one in two copies) belonging to three major classes of the CAD protein family. Their specificity was determined at the transcriptomic level in different tissues/organs, under Fusarium infection and abiotic stresses. Considering the function of particular LuCADs, it was established that LuCAD1 and 2 belong to Class I and they take part in the lignification of maturing stem and in the response to cold and drought stress. The Class II members LuCAD3, LuCAD4, LuCAD5 and LuCAD6 play various roles in flax being putatively responsible for lignin synthesis in different organs or under certain conditions. The obtained results indicate that within Class II, LuCAD6 was the most abundant in seedlings and maturing stems, LuCAD3 in leaves, and LuCAD4 in stems. Comparative analysis showed that expression of LuCAD genes in roots after F. oxysporum infection had the greatest contribution to differentiation of LuCAD expression patterns. Surprisingly, most of the analyzed LuCAD isoforms had reduced expression after pathogen infection. The decrease in mRNA level was primarily observed for LuCAD6 and LuCAD4, but also LuCAD1 and 8. However, the induction of LuCAD expression was mostly characteristic for Class I LuCAD1 and 2 in leaves. For cold stress, a clear correlation with phylogenic class membership was observed. Low temperatures caused induction of CAD isoforms belonging to Class I and repression of LuCADs from Class III. PMID- 29277027 TI - Non-plastidial expression of a synthetic insect geranyl pyrophosphate synthase effectively increases tobacco plant biomass. AB - Designing effective synthetic genes of interest is a fundamental step in plant synthetic biology for biomass. Geranyl pyrophosphate (diphosphate) synthase (GPPS) catalyzes a bottleneck step toward terpenoid metabolism. We previously designed and synthesized a plant (Arabidopsis thaliana)-insect (Myzus persicae, Mp) GPPS- human influenza hemagglutinin (HA) cDNA, namely PTP-MpGPPS-HA (or PTP sMpGPPS-HA, s: synthetic), to localize the protein in plastids and improve plant biomass. To better understand the effects of different subcellular localizations on plant performance, herein we report PTP-sMpGPPS-HA re-design to synthesize a new MpGPPS-HA cDNA, namely sMpGPPS-HA, to express a non-plastidial sMpGPPS-HA protein. The sMpGPPS-HA cDNA driven by a 2 * S 35S promoter was introduced into Nicotiana tabacum Xanthi. PTP-MpGPPS-HA and PMDC84 vector transgenic plants were also generated as positive and negative controls, respectively. Eighteen to twenty transgenic T0 lines were generated for each sMpGPPS-HA, PTP-sMpGPPS-HA, and PMDC84. Transcriptional genotyping analysis demonstrated the expression of sMpGPPS-HA in transgenic plants. Confocal microscopy analysis of transgenic progeny demonstrated the non-plastidial localization of sMpGPPS-HA. Growth of T1 transgenic and wild-type control plants showed that the expression of sMpGPPS-HA effectively increased plant height by 50-80%, leaf numbers and sizes, and dry biomass by 60-80%. Calculation of the vegetative growth rates showed that the expression of sMpGPPS-HA increased plant height each week. Moreover, sMpGPPS-HA expression promoted early flowering and reduced leaf carotenoid levels. In conclusion, non-plastidial expression of the novel sMpGPPS-HA was effective for improving tobacco growth and biomass. Our data indicate that research examining different subcellular localizations facilitates a better understanding of in planta functions of proteins encoded by synthetic cDNAs. PMID- 29277028 TI - Are we simplifying balance evaluation in adolescent idiopathic scoliosis? AB - BACKGROUND: Clinical evaluation of the postural balance in adolescent idiopathic scoliosis has been measured by sagittal vertical axis and frontal balance. The impact of the scoliotic deformity in three planes on balance has not been fully investigated. METHODS: 47 right thoracic and left lumbar curves adolescent idiopathic scoliosis and 10 non-scoliotic controls were registered prospectively. 13 spinopelvic postural parameters were calculated from the 3-dimantional reconstructions of X-rays. 7 balance variables describing the position and sway of the center of pressure were recorded using a pressure mat. A regression analysis was used to predict sagittal vertical axis and frontal balance from the 7 balance variables. A canonical correlation analysis was performed between all the postural parameters and balance variables and the significant associations between the postural and balance variables were determined. FINDINGS: sagittal vertical axis and frontal balance were not significantly associated with the position or sway of the center of pressure (p>0.05). Canonical correlation analysis showed significant associations between the postural variables in the 3 planes and center of pressure position (R2=0.81) and sway (R2=0.62), p<0.05. INTERPRETATION: Frontal Cobbs, apical rotations, distal kyphosis, pelvic incidence, sacral slope, sagittal vertical axis, and frontal balance contributed to the postural balance in the cohort. The compensatory role of the pelvis and distal kyphosis in sagittal plane was underlined. Multidimensional analyses between the postural and balance variables showed the alignment of the thoracic, lumbar, and pelvis in the 3 planes, in addition to the global head-pelvic position impact on adolescent idiopathic scoliosis balance. PMID- 29277029 TI - Embryonic exposure to Mono(2-ethylhexyl) phthalate (MEHP) disrupts pancreatic organogenesis in zebrafish (Danio rerio). AB - Mono(2-ethylhexyl) phthalate (MEHP) is the bioactive metabolite of di(2 ethylhexyl) phthalate, a plasticizing agent and persistent environmental contaminant associated with obesity, developmental abnormalities, and oxidative stress. Nrf2 (Nfe2l2) is a transcription factor that regulates cytoprotective genes as part of the adaptive antioxidant response. We previously identified the pancreas as a sensitive target of oxidative stress during embryonic development. The goals of this study were to 1) characterize the effects of MEHP exposure on pancreatic development, and 2) determine whether oxidative stress contributes to MEHP embryotoxicity. Zebrafish (Danio rerio) embryos from AB wildtype and Tg(ins:GFP;nrf2afh318/fh318) were exposed to 0 or 200 MUg/L MEHP at 3 h post fertilization (hpf) through 168 hpf to assess pancreatic organogenesis. MEHP exposure significantly decreased beta-cell area at all timepoints (48, 72, 96, 168 hpf), but Nrf2a did not significantly protect against islet hypomorphism. Tg(gcga:GFP) embryos exposed to MEHP showed a decrease in alpha-cell area in the islet across the same timepoints. Tg(ptf1a:GFP) embryos were assessed at 80 and 168 hpf for exocrine pancreas length. MEHP exposure decreased growth of the exocrine pancreas. Expression of pancreas genes insa, sst2 and ptf1a was significantly reduced by MEHP exposure compared to controls. Glutathione (GSH) concentrations and redox potentials were quantified at 72 hpf by HPLC, but no significant changes were observed. However, expression of the GSH-related genes gstp1 and gsr were significantly altered by MEHP exposure. These data indicate that the developing pancreas is a sensitive target tissue of embryonic exposure to MEHP. PMID- 29277030 TI - Chemical and magnetic analyses on tree bark as an effective tool for biomonitoring: A case study in Lisbon (Portugal). AB - Tree bark has proven to be a reliable tool for biomonitoring deposition of metals from the atmosphere. The aim of the present study was to test if bark magnetic properties can be used as a proxy of the overall metal loads of a tree bark, meaning that this approach can be used to discriminate different effects of pollution on different types of urban site. In this study, the concentrations of As, Cd, Co, Cu, Fe, Mn, Ni, P, Pb, V and Zn were measured by ICP-OES in bark samples of Jacaranda mimosifolia, collected along roads and in urban green spaces in the city of Lisbon (Portugal). Magnetic analyses were also performed on the same bark samples, measuring Isothermal Remanent Magnetization (IRM), Saturation Isothermal Remanent Magnetization (SIRM) and Magnetic Susceptibility (chi). The results confirmed that magnetic analyses can be used as a proxy of the overall load of trace elements in tree bark, and could be used to distinguish different types of urban sites regarding atmospheric pollution. Together with trace element analyses, magnetic analyses could thus be used as a tool to provide high resolution data on urban air quality and to follow up the success of mitigation actions aiming at decreasing the pollutant load in urban environments. PMID- 29277031 TI - Antimony and arsenic partitioning during Fe2+-induced transformation of jarosite under acidic conditions. AB - Jarosite [KFe3(SO4)2(OH)6] is considered a potent scavenger for arsenic (As) and antimony (Sb) under oxidizing conditions. Fluctuations in water levels in re flooded acid sulfate soils (ASS) can lead to high Fe2+(aq) concentrations (~10-20 mM) in the soil solution under acidic to circumneutral pH conditions. This may create favorable conditions for the Fe2+-induced transformation of jarosite. In this study, synthetic arsenate [As(V)]/antimonate [Sb(V)]-bearing jarosite was subjected to Fe2+(aq) (20 mM) at pH 4.0 and 5.5 for 24 h to simulate the pH and Fe2+(aq) conditions of re-flooded freshwater ASS/acid mine drainage (AMD) affected environments at early and mid-stages of remediation, respectively. The addition of Fe2+ at pH 5.5 resulted in the formation of a metastable green rust sulfate (GR- SO4) phase within ~60 min, which was replaced by goethite within 24 h. In contrast, at pH 4.0, jarosite underwent no significant mineralogical transformation. Although the addition of Fe2+(aq) induced the dissolution/transformation of jarosite at pH 5.5 and increased the mobility of Sb during the initial stages of the experiment (Sb(aq) = ~0.05 MUmol L-1), formation of metastable green rust (GR-SO4) and subsequent transformation to goethite effectively sequestered dissolved Sb. Aqueous concentrations of As remained negligible in both pH treatments, with As being mostly repartitioned to the labile (~10%) and poorly crystalline Fe(III)-associated phases (~10-30%). The results imply that, under moderately acidic conditions (i.e. pH 5.5), reaction of Fe2+(aq) with jarosite can drive the dissolution of jarosite and increase Sb mobility prior to the formation of GR-SO4 and goethite. In addition, repartitioning of As to the labile fractions at pH 5.5 may enhance the risk of its mobilisation during future mineral transformation processes in Fe2+-rich systems. PMID- 29277032 TI - Surface-flow constructed wetlands dominated by Cladophora for reclaiming nutrients in diffuse domestic effluent. AB - In this work, a surface-flow constructed wetland (SFCW) dominated by Cladophora was used to remove and reclaim nutrients in diffuse domestic effluent (DDE) discharged from rural regions around Taihu Lake, a eutrophic shallow lake in China. Growth rate of Cladophora was investigated and linked to ambient factors and nutrient consuming rates. The growth performances of Cladophora and animal feed microbes were studied during the commissioning of SFCW. Results show that the growth rate of Cladophora was closely correlated with field temperature and surface irradiance, while surface coverage was suitable for the manipulation of SFCW. Harvest of Cladophora along with animal-feed microbes and removal of nutrients in DDE could be achieved by manipulating surface coverage to drag growth rate back at the end of linear zone and to quickly restore Cladophora biomass in the mid zone of surface growth rate. Among four stages of the commissioning, concentrating stage experienced the majority species of animal feed microbes and maximal nutrient removal; during decomposing stage, however, the reproduction of animal-feed microbes and nutrient removal were lower, whereas the density of pathogens was higher. PMID- 29277033 TI - Fate of nanoparticles during alum and ferric coagulation monitored using single particle ICP-MS. AB - In this study, aluminum sulfate, ferric sulfate, ferric chloride, and poly(diallyldimethylammonium chloride) (pDADMAC) coagulation removal of citrate stabilized silver and gold nanoparticles (NPs) and uncoated titanium dioxide, cerium dioxide, and zinc oxide NPs was investigated using a single particle (SP) ICP-MS direct monitoring technique. Zone 2 (charge neutralization) coagulation was performed in river water and more commonly used Zone 4 (sweep floc) coagulation was performed in both river and lake water with environmentally relevant concentrations of selected NPs added. SP-ICP-MS was used to detect NP and dissolved species, characterize the size distribution, and quantify particle concentration as well as dissolved species before and after treatments. Other parameters including pH, dissolved organic carbon, turbidity, and UV254 absorbance were monitored to characterize treatment efficiency. Charge neutralization (Zone 2) coagulation resulted in 48-85% removal of citrate stabilized NPs and 90-99% removal of uncoated NPs from river water. Sweep floc (Zone 4) coagulation in river water resulted in 36-94% removal of citrate stabilized NPs and 91-99% removal of uncoated NPs both with and without polymer addition. Zone 4 coagulation conditions in lake water resulted in 77-98% removal of citrate-stabilized NPs and 59-96% removal of uncoated NPs without polymer. These results indicate that NP removal depends on NP surface and stability, the nature of the source water, and the coagulant type and approach. PMID- 29277034 TI - Single and mixture toxicities of BDE-47, 6-OH-BDE-47 and 6-MeO-BDE-47 on the feeding activity of Daphnia magna: From behavior assessment to neurotoxicity. AB - Although 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47), 6-hydroxy-2,2',4,4' tetrabromodiphenyl ether (6-OH-BDE-47) and 6-methoxy-2,2',4,4'-tetrabromodiphenyl ether (6-MeO-BDE-47) clearly disrupt the endocrine system, current knowledge of their single and/or mixture toxicities on other behaviors of aquatic organisms remains limited. In the present study, Daphnia magna was used to investigate the single and mixture toxicities of BDE-47, 6-OH-BDE-47 and 6-MeO-BDE-47 as measured by inhibition of feeding during exposure and post-exposure periods. Additionally, the biochemical performance, i.e., the activities of super oxidase dismutase (SOD), glutathione peroxidase (GPx) and acetylcholinesterase (AChE) of the test organism was studied to investigate the potential mechanisms of the toxicity of the target compounds. The three target compounds produced an obvious depressive effect on feeding behavior during the exposure period, and the effect increased with increasing concentrations. D. magna was most sensitive to 6-OH-BDE-47. The toxicity of the ternary mixture showed an obvious concentration-dependent effect, whereas the binary mixture toxicity showed the characteristics of hormesis. During the post-exposure period, overcompensation occurred, indicating a short term effect of the target compounds on D. magna. Additionally, significant changes occurred in neurological responses, indicating that these compounds might have neurobehavioral toxicity in D. magna. The decrease in oxidative stress enzymes (SOD and GPx) indicated that the antioxidant response of D. magna was destroyed. PMID- 29277035 TI - Metal-free virucidal effects induced by g-C3N4 under visible light irradiation: Statistical analysis and parameter optimization. AB - Waterborne viruses with a low infectious dose and a high pathogenic potential pose a serious risk for humans all over the world, calling for a cost-effective and environmentally-friendly inactivation method. Optimizing operational parameters during the disinfection process is a facile and efficient way to achieve the satisfactory viral inactivation efficiency. Here, the antiviral effects of a metal-free visible-light-driven graphitic carbon nitride (g-C3N4) photocatalyst were optimized by varying operating parameters with response surface methodology (RSM). Twenty sets of viral inactivation experiments were performed by changing three operating parameters, namely light intensity, photocatalyst loading and reaction temperature, at five levels. According to the experimental data, a semi-empirical model was developed with a high accuracy (determination coefficient R2 = 0.9908) and then applied to predict the final inactivation efficiency of MS2 (a model virus) after 180 min exposure to the photocatalyst and visible light illumination. The corresponding optimal values were found to be 199.80 mW/cm2, 135.40 mg/L and 24.05 degrees C for light intensity, photocatalyst loading and reaction temperature, respectively. Under the optimized conditions, 8 log PFU/mL of viruses could be completely inactivated by g-C3N4 without regrowth within 240 min visible light irradiation. Our study provides not only an extended application of RSM in photocatalytic viral inactivation but also a green and effective method for water disinfection. PMID- 29277036 TI - Arsenic uptake by arugula (Eruca vesicaria, L.) cultivars as affected by phosphate availability. AB - To assess the importance of variation among arugula (Eruca vesicaria subsp. sativa) cultivars in the ability to accumulate arsenic (As) in above-ground tissues, uptake of As by 16 cultivars was measured in the field and in hydroponic culture. In the field trial on soil contaminated by past pesticide use, As soil plant uptake coefficients varied by a factor of 2.7 among different cultivars, approaching a value of one for the strongest accumulators. Compared to the field assay, hydroponically grown arugula accumulated much lower concentrations of As when nutrient solutions contained standard (high) concentrations of phosphate along with 1.0 mg L-1 As in the form of soluble arsenate. However, As accumulation was much greater in hydroponic culture using low-P nutrient solutions, an indication that phosphate strongly competed with arsenate for root uptake. Analysis of arugula roots after exposure to arsenate at 1.0 mg As L-1 and low phosphate revealed from 24 to 400 times greater As concentration in roots than tops, with S concentrations significantly greater in As-exposed than control roots. This indicated greater sulfate uptake by roots exposed to arsenate, and suggested that thiol-mediated As immobilization occurred in the roots which strongly restricted translocation to the tops. PMID- 29277037 TI - Environmental pollutant hexachlorobenzene induces hypertension in a rat model. AB - Hexachlorobenzene (HCB) is a dioxin-like environmental pollutant, widely distributed in the environment. New research links exposure to high levels of persistent organic environmental toxicants to cardiovascular disease, however little is known about the effect of HCB on vascular function and on blood pressure. The purpose of the present study was to evaluate biochemical and cardiovascular changes resulting from subchronic HCB exposure. Adult female Sprague-Dawley rats were treated with vehicle or HCB (5 or 500 mg/kg b.w) for 45 days. Systolic blood pressure (BP), recorded by tail cuff plethysmography, was significantly increased at 35, 40 and 45 days of 500 mg/kg HCB-treatment. HCB (500 mg/kg) increased arterial thickness, while both 5 and 500 mg/kg HCB decreased proliferating cell nuclear antigen (PCNA) protein levels and cellular nuclei in abdominal aortas indicating a hypertrophic process. Also, aortas from both groups of HCB-treated rats presented higher sensitivity to noradrenalin (NA) and a significant decrease in maximum contractile response. Arteries from 500 mg/kg HCB-treated rats showed a significant increase in the levels of transforming growth factor-beta1 (TGF-beta1) mRNA and angiotensin II type1 receptor (AT1), and a significant decrease in estrogen receptor alpha (ERalpha), endothelial nitric oxidide synthase (eNOS) protein expression and deiodinase II (DII) mRNA levels. In conclusion, we have demonstrated for the first time that subchronic HCB administration significantly increases BP and alters associated cardiovascular parameters in rats. In addition, HCB alters the expression of key vascular tissue molecules involved in BP regulation, such as TGF-beta1, AT1, ERalpha, eNOS and DII. PMID- 29277038 TI - An evaluation of Spanish and English on-line information sources regarding pregnancy, birth and the postnatal period. AB - OBJECTIVE: the aim of this study is to evaluate the quality of web pages found by women when carrying out an exploratory search concerning pregnancy, childbirth, the postpartum period and breastfeeding. DESIGN/SETTING: a descriptive study of the first 25 web pages that appear in the search engines Google, Yahoo and Bing, in October 2014 in the Basque Country (Spain), when entering eight Spanish words and seven English words related to pregnancy, childbirth, the postpartum period, breastfeeding and newborns. Web pages aimed at healthcare professionals and forums were excluded. The reliability was evaluated using the LIDA questionnaire, and the contents of the web pages with the highest scores were then described. FINDINGS: a total of 126 web pages were found using the key search words. Of these, 14 scored in the top 30% for reliability. The content analysis of these found that the mean score for "references to the source of the information" was 3.4 (SD: 2.17), that for "up-to-date" was 4.30 (SD: 1.97) and the score for "conflict of interest statement" was 5.90 (SD: 2.16). The mean for web pages created by universities and official bodies was 13.64 (SD: 4.47), whereas the mean for those created by private bodies was 11.23 (SD: 4.51) (F (1,124)5.27. p=0.02). The content analysis of these web pages found that the most commonly discussed topic was breastfeeding, followed by self-care during pregnancy and the onset of childbirth. CONCLUSION: in this study, web pages from established healthcare or academic institutions were found to contain the most reliable information. The significant number of web pages found in this study with poor quality information indicates the need for healthcare professionals to guide women when sourcing information online. As the origin of the web page has a direct effect on reliability, the involvement of healthcare professionals in the use, counselling and generation of new technologies as an intervention tool is increasingly essential. PMID- 29277039 TI - The development and validation of a new postpartum sexual function and dyspareunia assessment tool: The Carol Scale. AB - OBJECTIVE: The aim is to develop a new tool to evaluate postpartum sexual function and dyspareunia which will facilitate better evaluation of perineal pain in woman after vaginal delivery. DESIGN: The development and validation of the Carol Postpartum Sexual Function and Dyspareunia Assessment Scale. SETTING: The Obstetrics and Gynecology Service of a University Hospital in central Spain. PARTICIPANTS: 102 women after being attended for vaginal birth, and 5 midwife assessors. FINDINGS: 81women reinitiated sexual activity (with vaginal intercourse) during the first three months postpartum. The Carol Postpartum Sexual Function and Dyspareunia Assessment Scale (Carol Scale) was internally reliable with a Cronbach-alpha value of 0.79 (95%CI0.72-0.85). Cronbach-alpha coefficients for Carol Scale domains were: preparation for the sexual activity 0.69 (95%CI0.55-0.79), pain or discomfort on caressing the vulval area 0.86 (95%CI0.79-0.91), pain or discomfort related to vaginal intercourse 0.93 (95%CI0.90-0.95) and pain or discomfort after vaginal intercourse 0.86 (95%CI0.78 0.91). CONCLUSIONS: The Carol Postpartum Sexual Function and Dyspareunia Assessment Scale is valid and reliable for measuring sexual function and postpartum dyspareunia in women after being attended for vaginal birth. IMPLICATIONS FOR PRACTICE: The Carol Scale could be used both clinically and in research to improve the quality of care for the mother after childbirth. The scale could help to identify problems in the reinitiation of postpartum sexual activity and, therefore, could contribute to widening the clinical information about these women and help in decision making. PMID- 29277040 TI - Associations of components of sarcopenic obesity with bone health and balance in older adults. AB - OBJECTIVES: To determine characteristics of sarcopenic obesity that are independently associated with bone health and balance in older adults. STUDY DESIGN: Cross-sectional study of 168 community-dwelling older adults (mean age 67.7 +/- 8.4 years; 55% women). MAIN OUTCOME MEASURES: Appendicular lean mass (ALM), whole-body areal BMD (aBMD) and body fat percentage were assessed by dual energy X-ray absorptiometry. Peripheral quantitative computed tomography assessed muscle density and cortical volumetric BMD (vBMD), area, thickness, and strength strain index (SSI) at 66% tibial length. Hand grip strength (dynamometry) and balance path length (computerised posturography) were assessed. Obesity was defined as high body fat percentage. RESULTS: Greater lower-leg muscle density was associated with lower balance path length in men (r = -0.36; P < .01) and women (r = -0.40; P = < .01). Obese participants by body fat percentage did not differ to non-obese on bone indices, although a trend towards lower cortical vBMD was observed in obese compared with non-obese men (1041.4 +/- 39.8 vs 1058.8 +/- 36.1 mg/cm3; P = .051). In multivariable models, ALM was positively associated with all bone parameters in obese women, and with whole-body aBMD, proximal tibial cortical area and SSI in non-obese women, and both non-obese and obese men (all P < .05). Lower-leg muscle density was also positively associated with cortical vBMD (B = 2.91; 95% CI 0.02, 5.80) and area (2.70; 0.06, 5.33) in obese women. CONCLUSIONS: Amongst components of sarcopenic obesity, higher ALM is a consistent independent predictor of better bone health. Low muscle density may also compromise bone health and balance. Interventions which improve muscle mass and composition may lower fracture risk in sarcopenic obesity. PMID- 29277041 TI - New insight on the adsorption capacity of metallogels for antimonite and antimonate removal: From experimental to theoretical study. AB - Development of high capacity material for antimonite (Sb(III)) and antimonate (Sb(V)) removal is the key to solving water antimony contamination. Three dimensional Cu(II)-specific metallogels (Cu-MG), which are considered to have high density adsorption sites for antimony (Sb), were first applied to adsorb Sb(III) and Sb(V). Batch assays resulted in adsorption capacities of Cu-MG for Sb(III) and Sb(V) at 102.4 mg/g and 264.1 mg/g, respectively. In addition, the adsorption capacity for Sb(III) was up to 225.7 mg/g using in situ oxidation. Kinetic assays resulted in more than 90% removal of Sb in 30 min. X-ray photoelectron spectroscopy (XPS) revealed the adsorption of Sb depended mainly on coordination interactions of vacant orbitals of the Cu atom with the lone-pairs of the O atom of Sb(OH)3 or Sb(OH)6-. Adsorption energy based on density functional theory (DFT) confirmed that Sb(III) adsorbed as a single layer whereas Sb(V) adsorbed as a multi-layer. These findings are consistent with experimental results. In addition, DFT calculations revealed that the Cu-MG theoretical capacity for Sb(V) adsorption is higher than for Sb(III). Cu-MG is a new and promising class of adsorbents for the removal of Sb(III) and Sb(V) from contaminated water. PMID- 29277042 TI - Mechanism insight of pollutant degradation and bromate inhibition by Fe-Cu-MCM-41 catalyzed ozonation. AB - A flexible catalyst, Fe-Cu-MCM-41, was employed to enhance diclofenac (DCF) mineralization and inhibit bromate formation in catalytic ozonation process. Greater TOC removal was achieved in Fe-Cu-MCM-41/O3 process (78%) than those in Fe-MCM-41/O3 (65%), Cu-MCM-41/O3 (73%) and sole ozonation (42%). But it was interesting that both Cu-MCM-41/O3 and Fe-MCM-41/O3 achieved 93% bromate inhibition efficiency, only 71% inhibition efficiency was observed in Fe-Cu-MCM 41/O3. Influence of pH, TBA/NaHSO3 and detection of by-products were conducted to explore the mechanism. By Pyridine adsorption-IR and XPS, a relationship was found among activity of catalysts, Lewis acid sites and electron transfer effect between Fe (II/III) and Cu (I/II). Fe-Cu-MCM-41 promoted ozone decomposition to generate OH, which accounted for enhanced DCF mineralization. The consumption of aqueous O3 also suppressed the oxidative of Br- and HBrO/Br-. More HBrO/BrO- accumulated in catalytic ozonation process and less bromate generated. Bromate formation in Fe-Cu-MCM-41/O3 process was sensitive with pH value, the acidic condition was not favor for bromate formation. Both DCF mineralization and bromate inhibition were influenced by surface reaction. Moreover, Fe-Cu-MCM-41 showed excellent catalytic performance in suppressing the accumulation of carboxylic acid, especially for oxalic acid. Nearly no oxalic acid was detected during Fe-Cu-MCM-41/O3 process. PMID- 29277043 TI - Variations in the fate and risk analysis of amoxicillin and its degradation products during pig manure aerobic composting. AB - In this study, 100 mg/kg of amoxicillin (AMX) was added to pig manure during aerobic composting using a laboratory-scale reactor system, for better understanding the degradation of AMX and its potential risks. Qualitative and quantitative analysis of AMX and its main degradation products (DPs) were then conducted using solid phase extraction combined with high performance liquid chromatography-tandem mass spectrometry. Additionally, hydrolysis testing was performed to monitor DPs produced from AMX degradation under various controlled conditions. The results showed that AMX was unstable in compost and rapidly degraded into AMX penicilloic acid, AMX penilloic acid and AMX diketopiperazine, which all eventually degraded, leaving a structurally simple and stable end product, 3-(4-hydroxyphenyl) pyrazin-2-ol, which appeared to be nonallergenic and less toxic than DPs generated earlier in the composting process. Besides, AMX was more unstable and more apt to generate multiple DPs in alkaline conditions than in acidic or neutral conditions or in ultrapure water, while pH exerted a larger effect on AMX degradation than did divalent metal ions (Cu2+ and Zn2+). This study provides technical and methodological support to better achieve AMX residual treatment and to evaluate the safety of AMX DPs produced in huge quantities in compost in China. PMID- 29277044 TI - Electrocatalytic oxidative treatment of real textile wastewater in continuous reactor: Degradation pathway and disposability study. AB - Electrocatalytic treatment of real textile wastewater was investigated in continuous electrochemical reactor using dimensionally stable Ti/RuO2 anode. Effects of various parameters such as: elapsed time, current, pH, retention time on the COD removal, color removal and specific energy consumed were evaluated. Central Composite Design under RSM was used for experimental design, data analysis, optimization, interaction analysis between the various electrochemical parameters and steady state time analysis. GC-MS and UV spectrophotometric analysis of the untreated and treated wastewater were conducted to identify the oxidized and transformed/degraded compounds during the oxidation process, and a suitable degradation mechanism was proposed. Treated wastewater may contain toxic chlorinated compounds due to mediated oxidation by various hydrolyzed chlorine species. Therefore, disposability of treated wastewater was assessed by conducting toxicity bioassay test. The optimal set of operating parameters were found to be elapsed time = 124 min, current = 1.37 A, pH = 5.54 and retention time = 157.6 min to simultaneously achieve COD removal, color removal and specific energy consumed as 86.22%, 94.74% and 0.012 kW h, respectively. GC-MS analysis showed presence of chlorinated compounds in the treated wastewater. The toxicity bioassay test resulted acute toxicity with 100% mortality rate within one minute and one hour exposure with untreated and treated textile wastewater, respectively. PMID- 29277045 TI - Prediction of agenesis of the mandibular second premolar using the developmental stages of the mandibular canine, first premolar, and second molar. AB - OBJECTIVE: The aim in this study was to suggest a standard for early diagnosis of agenesis of the mandibular second premolars (L5) by estimating the developmental stages of the mandibular canines (L3), first premolars (L4), and second molars (L7). DESIGN: Among all 5136 pediatric patients aged 5-11 years who received panoramic radiographs between June 2008 and December 2009 at Seoul National University Dental Hospital, 215 control patients and 74 agenesis patients who met inclusion criteria were analyzed. The developmental stages of all L3, L4, L5, and L7 of control and agenesis patients were estimated using the method proposed by Demirjian. To identify the tooth (L3, L4, L7) with the developmental pattern most similar to that of L5, Kendall rank correlation coefficients and Bootstrap method were used. To verify that patients with agenesis of L5 show delayed development, Wilcoxon rank sum test was used. To identify the stages in which to diagnose agenesis of L5, we performed survival analysis. RESULTS: There was a significant correlation between the developmental stages of L3, L4, L7 and L5. The developmental stages of those three teeth in the agenesis group were delayed compared with those in the control group at certain ages. If the developmental stages of at least two of those three teeth reach Demirjian stage D without the calcification of L5, agenesis of L5 can be confirmed. CONCLUSIONS: Agenesis of L5 can be confirmed when two of the three teeth (L3, L4, L7) reach Demirjian stage D. PMID- 29277046 TI - The effect of intravesical instillations with Hyaluronic Acid on sexual dysfunction in women with recurrent urinary tract infections (RUTI). AB - OBJECTIVE: To determine whether sexual dysfunction in women with recurrent urinary tract infections (RUTI) improved following treatment with intravesical Hyaluronic Acid (HA) instillations. STUDY DESIGN: Ethical approval was obtained for a prospective study to be performed. Patients referred for bladder instillations to treat RUTI, and who were sexually active, were recruited to the study. A selection of validated questionnaires (ICIQ-UI, ICIQ-VS, FSDS-R, ICIQ FLUTS, O'Leary/Sant and PGI-I) were completed at baseline, three, six and 12 months after initiation of treatment with bladder instillations. Treatment consisted of weekly bladder instillations with a preparation containing HA for four weeks then monthly for two further treatments. Results were populated in SPSS for statistical analysis and statistical significance was powered for 22 patients. RESULTS: Thirty women were included in the study. FSDS-R was used to determine sexual dysfunction and showed that 57% patients with RUTI had significant sexual distress. There was a significant improvement in FSDS-R at three, six and 12 months when compared to baseline (Friedman two-way analysis p < 0.001). ICIQ FLUTS F and I scores, O'Leary/Sant, ICIQ VS and PGI-I also showed a statistically significant improvement throughout the period of follow up. A statistically significant, negative correlation was found between FSDS-R and PGI I at 12 months (r = -0.468, p = 0.009). CONCLUSION: We have reinforced previous work showing the association between RUTI and sexual dysfunction, and an improvement in bladder symptoms following treatment with HA. To our knowledge, this is the first study to prove an improvement in sexual dysfunction following intravesical treatment with HA which is sustained for up to 12 months. PMID- 29277047 TI - Association of the common SNPs in RNF212, STAG3 and RFX2 gene with male infertility with azoospermia in Chinese population. AB - OBJECTIVE: The aim of this study was to explore the association between the SNP rs4045481 in RNF212 gene, rs1050482 and rs11531577 in STAG3 gene as well as rs2288846 in RFX2 gene and male infertility with azoospermia in Chinese population. STUDY DESIGN: Two hundreds and twenty infertile patients with azoospermia and 248 fertile men were recruited in the present study. The four SNPs investigated were genotyped using polymerase chain reaction and restriction fragment length polymorphism assay. The differences in allelic and genotypic frequencies between patients and controls were evaluated by chi-square test. RESULTS: No significant differences in allele and genotype frequencies of SNP rs1050482 and rs11531577 in STAG3 gene as well as rs2288846 in RFX2 gene between patients with azoospermia and controls were observed. However, the frequencies of allele C(43.6% vs. 34.1%, P = 0.003, OR = 1.498, 95% CI 1.150-1.192) and genotype CC (24.6% vs. 12.0%, P = 0.001, OR = 2.346, 95% CI 1.448-3.858) were significantly higher in patients with azoospermia than those in controls at the rs4045481 locus in RNF212 gene. CONCULUSION: The polymorphism of SNP rs4045481 in RNF212 gene might be associated with azoospermia and genotype CC of this SNP may be a risk factor of azoospermia. PMID- 29277048 TI - Comparison of planned caesarean delivery and planned vaginal delivery in women with a twin pregnancy: A nation wide cohort study. AB - OBJECTIVE: To compare, in women with twin pregnancy with the first twin in cephalic position, neonatal morbidity and mortality rates after planned caesarean delivery (CD) versus planned vaginal delivery (VD). STUDY DESIGN: A nationwide cohort study on women pregnant with twins and the first child in cephalic position, who delivered between 32 + 0-41 + 0 weeks between 2000 and 2012 in the Netherlands, using multivariate logistic regression analysis to compare neonatal morbidity and mortality according to planned delivery mode, and looking at subgroups 32 + 0-36 + 6 and 37 + 0-41 + 0 weeks. RESULTS: We included 21,107 women, of whom 1384 (6.6%) had a planned CD. Of the 19,723 women (93.4%) who had a planned VD, 19.7% delivered by intrapartum CD. We found no significant differences in 'any mortality' (aOR planned CD vs. planned VD 1.34 (95% CI 0.63 2.60)), the outcome 'Apgar score (AS) < 4 or death within 28 days' (aOR 1.28 (95% CI 0.77-2.11) or asphyxia-related morbidity (aOR 0.57 (95% CI 0.32-1.03)). After planned CD more prematurity-related morbidity (aOR 1.55 (95% CI 1.21-1.98)), other morbidity (aOR 1.50 (95% CI 1.26-1.78)) and 'any morbidity or mortality' (aOR 1.41 (95% CI 1.20-1.66) was noted. Trauma-associated morbidity was absent after planned CD and occurred 45 times (0.2%) after planned VD. Before 36 + 6 weeks, planned CD resulted in more perinatal mortality (aOR 2.10 (95% CI 0.92 4.76)), while asphyxia-related morbidity did not differ (aOR 0.80 (95% CI 0.41 1.54). Planned CD resulted in more 'any morbidity or mortality' (aOR 1.52 (95% CI 1.25-1.84)), 'AS < 4 or death within 28 days' (aOR 1.77 (95% CI 1.02-3.09)), prematurity-related morbidity (aOR 1.73 (95% CI 1.34-2.23)), and 'other morbidity' (aOR 1.56 (95% CI 1.28-1.90)). After 37 weeks, no significance differences in mortality, 'any morbidity or mortality <28 days' (aOR 0.96 (95% CI 1 (0.67-1.38)), or 'AS < 4 or death within 28 days' (aOR 0.41 (95% CI (0.10 1.70)) were found. There was less asphyxia-related morbidity after planned CD (aOR 0.24 (95% CI 0.06-1.002)). CONCLUSION: Planned VD results in comparable neonatal outcomes as planned CD for twin pregnancy with the first twin in cephalic position, even with a low intrapartum CD rate of 19.7%. At term, a planned CD may result in less asphyxia- and trauma-related outcomes. PMID- 29277049 TI - Comparison of different aerobic granular sludge types for activated sludge nitrification bioaugmentation potential. AB - Three types of nitrifying granules were grown on media simulating anaerobic digestion dewatering reject water and compared for their potential to increase nitrification capacity when added to mainstream flocculent activated sludge treatment. An advantage of nitrification bioaugmentation with sidestream granules instead of flocculent biomass is that the granules can be selectively maintained at longer retention times than flocs and thus provide higher nitrification capacity from bioaugmentation. The three granule types and feeding conditions were: nitrifying granules with aerobic feeding, nitrifying-denitrifying granules with anoxic feeding, and nitrifying-denitrifying/phosphate-accumulating (NDN-PAO) granules with anaerobic feeding. NDN-PAO granular sludge showed the highest potential for nitrification bioaugmentation due to its better treatment performance, granule physical characteristics, and much greater production of granular mass and nitrification capacity. Dechloromonas-associated organisms were dominant in these granules; Candidatus Accumulibacter-related organisms were also present. Nitrosomonas was the dominant ammonia-oxidizing bacteria, while Candidatus Nitrotoga was an abundant nitrite-oxidizer in all granule types. PMID- 29277050 TI - Combining autohydrolysis and ionic liquid microwave treatment to enhance enzymatic hydrolysis of Eucalyptus globulus wood. AB - The combination of autohydrolysis and ionic liquid microwave treatments of eucalyptus wood have been studied to facilitate sugar production in a subsequent enzymatic hydrolysis step. Three autohydrolysis conditions (150 degrees C, 175 degrees C and 200 degrees C) in combination with two ionic liquid temperatures (80 degrees C and 120 degrees C) were compared in terms of chemical composition, enzymatic digestibility and sugar production. Morphology was measured (using SEM) and the biomass surface was visualized with confocal fluorescence microscopy. The synergistic cooperation of both treatments was demonstrated, enhancing cellulose accessibility. At intermediate autohydrolysis conditions (175 degrees C) and low ionic liquid temperature (80 degrees C), a glucan digestibility of 84.4% was obtained. Using SEM micrographs, fractal dimension (as a measure of biomass complexity) and lacunarity (as a measure of homogeneity) were calculated before and after pretreatment. High fractals dimensions and low lacunarities correspond to morphologically complex and homogeneous samples, that are better digested by enzyme cocktails. PMID- 29277051 TI - A simple method for assaying anaerobic biodegradation of dyes. AB - Anaerobic dye degradation is usually assayed using serum vials, which is time consuming and costly. In this work, a simple method was established for real-time nondestructive assay of dye biodegradation using 96-well microtiter plates with petrolatum oil to avoid the volatilization and high transmittance transparent tape to prevent the permeation of oxygen. With the anaerobic degradation of methyl red and amaranth by Shewanella oneidensis MR-1, this assay method was verified. Further experiments revealed that blocking Mtr pathway had no substantial effect on the degradation of methyl red and dose of riboflavin also failed to promote the degradation of methyl red. On the contrary, the anaerobic degradation of amaranth depended mainly on the electron transmembrane transfer through Mtr pathway. Our work clearly indicates that Mtr pathway had different effects on intra- and extra-cellular degradation of azo dyes by S. oneidensis MR 1. Such a developed method is helpful for investigating anaerobic dye decolorization. PMID- 29277052 TI - Effects of different pretreatments on compression molding of wheat straw and mechanism analysis. AB - This study investigated effects of various pretreatments on characteristics of compression molded wheat straw and molding energy consumption. And correlative mechanism was explored. Pretreatments included natural air drying, vacuum sealing, 4% ammonium hydroxide + vacuum sealing. Hemicellulose and lignin contents and crystallinity decreased following pretreatments, while surface porosities increased. Cellulose and ash levels and lower heat value were not significantly affected (P > .05), while water resistance decreased and relax density and fall strength satisfied relevant standards. Ignition index and comprehensive combustibility index of samples treated with 4% ammonium hydroxide + vacuum sealing were the greatest, and molding energy consumption was also the lowest. Optimal pretreatment time was 21 days. Mechanism analysis indicated that crystallinity affected water resistance, lignin affected combustion characteristics and hemicellulose affected molding energy consumption to the greatest extent. Overall, 4% ammonium hydroxide + vacuum sealing pretreatment had the most beneficial effect on compression molding and resulted in the lowest energy consumption. PMID- 29277053 TI - High yielding tropical energy crops for bioenergy production: Effects of plant components, harvest years and locations on biomass composition. AB - The composition of lignocellulosic feedstock, which depends on crop type, crop management, locations and plant parts, significantly affects the conversion efficiency of biomass into biofuels and biobased products. Thus, this study examined the composition of different parts of two high yielding tropical energy crops, Energycane and Napier grass, collected across three locations and years. Significantly higher fiber content was found in the leaves of Energycane than stems, while fiber content was significantly higher in the stems than the leaves of Napier grass. Similarly, fiber content was higher in Napier grass than Energycane. Due to significant differences in biomass composition between the plant parts within a crop type, neither biological conversion, including anaerobic digestion, nor thermochemical pretreatment alone is likely to efficiently convert biomass components into biofuels and biobased products. However, combination of anaerobic digestion with thermochemical conversion technologies could efficiently utilize biomass components in generating biofuels and biobased products. PMID- 29277054 TI - A solution-processed binary cathode interfacial layer facilitates electron extraction for inverted polymer solar cells. AB - The charge transfer and separation are significantly affected by the electron properties of the interface between the electron-donor layer and the carrier transporting layer in polymer solar cells (PSCs). In this study, we investigate the electron extraction mechanism of PSCs with a low temperature solution processed ZnO/PEI as electron transport layer. The incorporation of PEI layer can decrease the work function of ZnO and reduce interfacial barrier, which facilitates electron extraction and suppresses bimolecular recombination, leading to a significant performance enhancement. Furthermore, PEI layer can induce phase separation and passivite inorganic surface trap states as well as shift the interfacial energy offset between metal oxide and organic materials. This work offers a simple and effective way to improve the charge transporting property of organic photovoltaic devices. PMID- 29277055 TI - Fabrication of silver nanoparticle sponge leather with durable antibacterial property. AB - Leather product with durable antibacterial property is of great interest both from industry and consumer's point of view. To fabricate such functional leather, gallic acid modified silver nanoparticles (GA@AgNPs) were first in situ synthesized with a core-shell structure and an average size of 15.3nm. Due to its hydrophilic gallic acid surface, the GA@AgNPs possessed excellent stability and dispersibility in wide pH range from 3 to 12 and also showed effective antibacterial activity with a minimum inhibitory concentration (MIC) of around 10MUgmL-1. Then, such GA@AgNPs were used as retanning agent to be successfully filled into leather matrix during the leather manufacturing process. Moreover, taking the advantage of its high surface density of carboxyl groups, these GA@AgNPs could be further chemically cross-linked onto collagen fibers by chrome tanning agent. After retanning, the resultant leather was given a "AgNPs sponge" feature with high payload of silver nanoparticles against laundry, exhibiting high and durable antibacterial activity. PMID- 29277056 TI - Liquid marble formation and solvent vapor treatment of the biodegradable polymers polylactic acid and polycaprolactone. AB - Liquid Marbles were produced by rolling aqueous droplets on a powder bed of biodegradable polymers, namely polylactic acid (PLA), polycaprolactone (PCL) and blends of these. Solvent vapor treatment was subsequently applied with dichloromethane (DCM). This treatment aligned the polymer chains in order to form a smooth polymeric shell with enhanced mechanical and barrier properties. Whilst a wide range of potential applications for Liquid Marbles exists, the aim here is to encapsulate a solution containing a fertilizer, i.e. urea to produce a controlled release fertilizer. The influences of droplet volume, polymer particle size and solvent vapor treatment time on the liquid marble properties were investigated. Crystallinity and thermal properties were analyzed by differential scanning calorimetry (DSC), surface characteristics and shell thickness by scanning electron microscopy (SEM), mechanical strength and elasticity by compression tests and evaporation rates by thermogravimetric analysis (TGA). PMID- 29277057 TI - Novel Schiff base (DBDDP) selective detection of Fe (III): Dispersed in aqueous solution and encapsulated in silica cross-linked micellar nanoparticles in living cell. AB - This work demonstrated the synthesis of (4E)-4-(4 (diphenylamino)benzylideneamino)-1,2-dihydro-1,5- dimethyl-2-phenylpyrazol-3-one (DBDDP) for Fe (III) detection in aqueous media and in the core of silica cross linked micellar nanoparticles in living cells. The free DBDDP performed fluorescence enhancement due to Fe (III)-promoted hydrolysis in a mixed aqueous solution, while the DBDDP-doped silica cross-linked micellar nanoparticles (DBDDP SCMNPs) performed an electron-transfer based fluorescence quenching of Fe (III) in living cells. The quenching fluorescence of DBDDP-SCMNPs and the concentration of Fe (III) exhibited a linear correlation, which was in accordance with the Stern-Volmer equation. Moreover, DBDDP-SCMNPs showed a low limit of detection (LOD) of 0.1 ppm and an excellent selectivity against other metal ions. Due to the good solubility and biocompatibility, DBDDP-SCMNPs could be applied as fluorescence quenching nanosensors in living cells. PMID- 29277058 TI - The iFST: An instrumented version of the Fukuda Stepping Test for balance assessment. AB - The maintenance of the upright posture during dynamic balance requires the integration of sensory inputs regulated by the brain. After a neurological event, the assessment of balance control impairments is crucial for supporting health professionals in the design of personalized rehabilitation protocols. A commonly used test to assess balance ability is the Fukuda Stepping Test (FST). However, the clinical parameters traditionally considered are not fully representative of the patient's motor ability. The purpose of this study was to devise an instrumented version of the FST (iFST) that embodies inertial sensors and allows to obtain individual motor strategy information. Twenty-seven sub-acute stroke patients and 18 healthy adults performed a repeated stepping task with closed eyes wearing five inertial sensors located on both distal tibiae and at pelvis, sternum, and head levels. From final foot position, body rotation and linear displacements were measured. A set of indices related to upper-body stability were estimated from pelvis, sternum, and head accelerations: Root Mean Square, Attenuation Coefficients, and improved Harmonic Ratio. Two additional parameters based on upper-body angular velocities were devised to assess step-by-step repeatability and inter-segment velocity variations. The results suggest that the clinical parameters do not provide enough information about the two groups' motor strategies. Conversely, five iFST parameters were identified as predictors of patients' motor ability, discriminating not only between healthy and pathological subjects, but also between different motor deficit levels within the same pathology. The iFST could be included in the clinical routine assessment of balance impairments, supporting the design of personalized treatments. PMID- 29277059 TI - Influence of handrail height and fall direction on center of mass control and the physical demands of reach-to-grasp balance recovery reactions. AB - The ability to maintain and recover center of mass (COM) and trunk control after a destabilization is critical for avoiding falls and fall-related injuries. Handrails can significantly enhance a person's ability to recover from large destabilizations, by enabling the person to grasp and apply high forces to the rail to stabilize their COM. However, the influence of handrail height and falling direction on COM control and the demands of grasping are unknown. We investigated the effect of handrail height (34, 38, 42 in.) and fall direction (forward, backward) on COM and trunk control, and the corresponding physical demands of reach-to-grasp balance reactions. Thirteen young adults were destabilized with platform perturbations, and reached to grasp a nearby handrail to recover balance without stepping. COM kinematics and applied handrail forces were collected. COM control was evaluated in terms of: (1) COM range and peak displacement, velocity and momentum in all Cartesian axes; and (2) trunk angular displacement, velocity and momentum in the roll and pitch axes. The physical demands of grasping were estimated via resultant handrail impulse. Compared to forward-directed falling, backward-directed falling was generally associated with greater peak COM and trunk angular displacement, velocity and momentum, along with greater handrail impulse. Higher handrails generally resulted in reduced peak COM and trunk angular displacement, velocity and momentum, as well as reduced handrail impulse. These results suggest that higher handrails may provide a stability advantage within the range of handrail heights tested, with better COM control achieved with lower physical demands of grasping. PMID- 29277060 TI - Does additional patella tendon shortening influence the effects of multilevel surgery to correct flexed knee gait in cerebral palsy: A randomized controlled trial. AB - BACKGROUND: The aims of this study were to investigate if patellar tendon shortening (PTS) as a part of SEMLS (single event multilevel surgery) is effective for reduction of flexed knee gait in children with cerebral palsy (CP) and, if PTS leads to stiff knee gait. METHODS: In a randomized controlled study 22 children with flexed knee gait (age: 10.4 +/- 2.6 years, GMFCS Level I-III) were randomized and allocated to two groups (1: SEMLS + PTS; 2: SEMLS no PTS): SEMLS was performed for correction of flexed knee gait either with or without additional PTS. Before and after surgery (follow up: 12.7 +/- 1.6 months) kinematics (3-D motion analysis) and clinical parameters were compared. RESULTS: Two children were lost to follow up. Maximum knee extension improved significantly in both groups after SEMLS while the patients with additional PTS showed much more correction (SEMLS + PTS: 37.6 degrees to 11.4 degrees , p = 0.007; SEMLS no PTS: 35.1 degrees to 21.8 degrees , p = 0.016). After surgery peak knee flexion decreased significantly (14.6 degrees , p = 0.004) in the "SEMLS + PTS" group while there was no relevant change in the other group. There was a trend of increase in anterior pelvic tilt after surgery in both groups, but no statistical significant difference. After surgery knee flexion contracture (15.9 degrees , p < 0.001) and popliteal angle (27.2, p = 0.009) measured on clinical examination only decreased significantly in the "SEMLS + PTS" group. CONCLUSION: PTS is effective for correction of flexed knee gait and knee flexion contracture leading to superior stance phase knee extension. However, additional PTS may lead to stiff knee gait and a higher increase of anterior pelvic tilt. PMID- 29277061 TI - Associations among mothers' representations of their relationship with their toddlers, maternal parenting stress, and toddlers' internalizing and externalizing behaviors. AB - This study examined the array of associations among the emotional valence and the coherence of mothers' representations of their relationship with their toddlers, mothers' reported parenting stress, and toddlers' internalizing and externalizing behaviors. To evaluate maternal representations, 55 mothers were interviewed using the Five Minute Speech Sample procedure (FMSS; Magana et al., 1986), which was coded for criticism and positive comments (Magana-Amato, 1993), as well as coherence (Sher-Censor & Yates, 2015). Mothers also completed the Parenting Stress Index - Short Form (PSI; Abidin, 1997) to evaluate their parenting stress and the Child Behavior Checklist (CBCL/1.5-5; Achenbach & Rescorla, 2000) to assess their toddlers' internalizing and externalizing behaviors. Results indicated that parenting stress was associated with maternal criticism and fewer positive comments in the FMSS, but not with the coherence of mothers' FMSS. Parenting stress, criticism, and lower coherence in the FMSS were associated with maternal reports of externalizing behaviors. Only parenting stress and lower coherence in the FMSS were related to mothers' reports of internalizing behaviors of the child. Thus, the emotional valence and the coherence of mothers' representations of their relationship with their child and parenting stress may each constitute a distinct aspect of parenting and contribute to the understanding of individual differences in toddlers' internalizing and externalizing behaviors. Implications for research and practice with families of toddlers are discussed. PMID- 29277062 TI - The yeast stands alone: the future of protein biologic production. AB - Yeasts are promising alternative hosts for the manufacturing of recombinant protein therapeutics because they simply and efficiently meet needs for both platform and small-market drugs. Fast accumulation of biomass and low-cost media reduce the cost-of-goods when using yeast, which in turn can enable agile, small volume manufacturing facilities. Small, tractable yeast genomes are amenable to rapid process development, facilitating strain and product quality by design. Specifically, Pichia pastoris is becoming a widely accepted yeast for biopharmaceutical manufacturing in much of the world owing to a clean secreted product and the rapidly expanding understanding of its cell biology as a host organism. We advocate for a near term partnership spanning industry and academia to promote open source, timely development of yeast hosts. PMID- 29277063 TI - Effect of the 2015 Nepal Earthquakes on symptoms of common mental disorders among women who are pregnant. AB - BACKGROUND: Antenatal mental health problems are of concern globally not only because of the burden and limits to participation experienced by women but also because of risks for foetal neurocognitive development and adverse birth outcomes. The aim was to describe the indicative prevalence of and risk and protective factors for clinically-significant symptoms of antenatal common mental disorders (CMDs) among women who experienced the 2015 Nepal earthquakes during pregnancy. METHODS: A population-based cross-sectional study in Bhaktapur, one of 14 districts highly affected by the 2015 Nepal earthquakes. The primary outcome, clinically significant symptoms of CMDs, was ascertained using the Nepali validation of the Edinburgh Postnatal Depression Scale (EPDS-N). In order to investigate potential trauma reactions, a subset of EPDS items as indicators of trauma symptoms was constructed. Standardised instruments and study-specific questions were used to measure potential risk and protective factors. Data were collected in individual structured interviews by trained health researchers. Hierarchical multiple linear regression models were used to establish risk and protective factors for clinically significant symptoms of CMDs and indicators of post-earthquake trauma reaction. RESULTS: Overall, 497/498 eligible pregnant women provided complete data. We found that 21.9% (95% CI, 18.4; 25.8) of participants had EPDS-N scores > 12 and another 17.1% (95% CI 13.9; 20.7) scored 10-12 indicating a high prevalence of clinically significant CMD symptoms. In total, 20 factors were included in the final hierarchical multiple linear regression model and together explained 33.3% of the variance in EPDS total scores; seven factors, including earthquake experiences and lifetime experience of intimate partner violence, increased risk and five including having income generating work and a kind, and encouraging partner were protective. The association between earthquake experiences and the indicators of trauma symptoms was not significant in the hierarchical multiple linear regression analysis. LIMITATIONS: The EPDS has not yet been formally validated in Nepal for use during pregnancy. Data were collected 6 months post-earthquake, so we were not able to capture the experiences of women who had spontaneous or induced abortions or premature births in the immediate aftermath of the earthquake. CONCLUSIONS: In addition to the restoration of antenatal and obstetric services, the mental health of women who are pregnant requires specific consideration and interventions after natural disasters. This should take into account the additional adverse impact of violence perpetrated by an intimate partner. PMID- 29277064 TI - Reduced serum club cell protein as a pulmonary damage marker for chronic fine particulate matter exposure in Chinese population. AB - BACKGROUND: Exposure to fine particulate matter (PM2.5) pollution is associated with increased morbidity and mortality from respiratory diseases. However, few population-based studies have been conducted to assess the alterations in circulating pulmonary proteins due to long-term PM2.5 exposure. METHODS: We designed a two-stage study. In the first stage (training set), we assessed the associations between PM2.5 exposure and levels of pulmonary damage markers (CC16, SP-A and SP-D) and lung function in a coke oven emission (COE) cohort with 558 coke plant workers and 210 controls. In the second stage (validation set), significant initial findings were validated by an independent diesel engine exhaust (DEE) cohort with 50 DEE exposed workers and 50 controls. RESULTS: Serum CC16 levels decreased in a dose response manner in association with both external and internal PM2.5 exposures in the two cohorts. In the training set, serum CC16 levels decreased with increasing duration of occupational PM2.5 exposure history. An interquartile range (IQR) (122.0MUg/m3) increase in PM2.5 was associated with a 5.76% decrease in serum CC16 levels, whereas an IQR (1.06MUmol/mol creatinine) increase in urinary 1-hydroxypyrene (1-OHP) concentration was associated with a 5.36% decrease in serum CC16 levels in the COE cohort. In the validation set, the concentration of serum CC16 in the PM2.5 exposed group was 22.42% lower than that of the controls and an IQR (1.24MUmol/mol creatinine) increase in urinary 1-OHP concentration was associated with a 12.24% decrease in serum CC16 levels in the DEE cohort. CONCLUSIONS: Serum CC16 levels may be a sensitive marker for pulmonary damage in populations with high PM2.5 exposure. PMID- 29277065 TI - Endotoxin predictors and associated respiratory outcomes differ with climate regions in the U.S. AB - RATIONALE: Although endotoxin is a recognized cause of environmental lung disease, how its relationship with respiratory outcomes varies with climate is unknown. OBJECTIVE: To examine the endotoxin predictors as well as endotoxin association with asthma, wheeze, and sensitization to inhalant allergens in various US climate regions. METHODS: We analyzed data on 6963 participants in the National Health and Nutrition Examination Survey. Endotoxin measurements of house dust from bedroom floor and bedding were performed at the University of Iowa. Linear and logistic regression analyses were used to identify endotoxin predictors and assess endotoxin association with health outcomes. RESULTS: The overall median house dust endotoxin was 16.2 EU/mg; it was higher in mixed dry/hot-dry regions (19.7 EU/mg) and lower in mixed-humid/marine areas (14.8 EU/mg). Endotoxin predictors and endotoxin association with health outcomes significantly differed across climate regions. In subarctic/very cold/cold regions, log10-endotoxin was significantly associated with higher prevalence of wheeze outcomes (OR:1.48, 95% CI:1.19-1.85 for any wheeze, OR:1.48, 95% CI:1.22 1.80 for exercise-induced wheeze, OR:1.50, 95% CI:1.13-1.98 for prescription medication for wheeze, and OR:1.95, 95% CI:1.50-2.54 for doctor/ER visit for wheeze). In hot-humid regions, log10-endotoxin was positively associated with any wheeze (OR:1.66, 95% CI:1.04-2.65) and current asthma (OR:1.56, 95% CI:1.11 2.18), but negatively with sensitization to any inhalant allergens (OR:0.83, 95% CI:0.74-0.92). CONCLUSION: Endotoxin predictors and endotoxin association with asthma and wheeze differ across U.S. climate regions. Endotoxin is associated positively with wheeze or asthma in cold and hot-humid regions, but negatively with sensitization to inhalant allergens in hot-humid climates. PMID- 29277066 TI - Estimation of an area between the baseline and the effect curve parameter for lactate levels in the hippocampi of neonatal rats during anesthesia. AB - Naturally occurring caspase-3-dependent cell death is a widespread event in the immature nervous system. Prolonged exposure to anesthetics promotes activation of caspase-3 in the developing hippocampus. In addition, anesthetics can upregulate the levels of metabolite lactate in the adult brain. The long-lasting increase in lactate levels may affect viability of brain cells. However, it remains unknown if anesthetic-induced activation of caspase-3 is accompanied by an increase in lactate levels in the immature brain. We investigated expression of apoptotic proteins by immunoblot and estimated an area between the baseline and the effect curve (ABEC) parameter for lactate levels by high-resolution magnetic resonance spectroscopy in the hippocampi of 2-day-old Wistar rats after treatment with anesthetic urethane. Both 1.5 and 2.5 g/kg of urethane resulted in a dose dependent increase in the levels of active caspase-3 in the hippocampi in 4 h after injection. This anesthetic-induced increase in the levels of active caspase 3 was preceded by a prolonged dose-dependent rise in lactate levels. The dose dependent increase in lactate levels was not associated with the urethane-induced changes in respiratory rate in the treated rat pups. Present results evidence that the prolonged dose-dependent elevation in lactate levels in the developing brain can be induced even by urethane, which was suggested to be suitable for various physiopharmacological studies previously. The observed sequence of events after treatment with urethane suggests the possible role of lactate as a neurodamaging agent in the immature brain in case of the sustaining rise in the levels of this metabolite during prolonged anesthesia. PMID- 29277067 TI - Biochemical composition of fetal fluids in at term, normal developed, healthy, viable dogs and preliminary data from pathologic littermates. AB - A proper canine neonatal assistance, required to reduce the high perinatal loss rate, imply a full knowledge about the fetal-to-neonatal physiology. Because fetal fluids play an important role throughout mammals pregnancy, influencing fetal growth and development, fetal well being, and contributing to guarantee the most suitable environment for the fetus, the knowledge about fetal fluids biochemical composition is of major importance. At first, the biochemical composition of fetal fluids collected by normal developed, healthy and viable newborns, is necessary to depict the normal features, and represent the first step for the further detection of abnormalities associated to fetal/neonatal distress and useful for the early identification of newborns needing special attention, immediately after birth. The present study was aimed to define the biochemical composition of amniotic and allantoic fluids collected from fetus delivered by caesarean section at term of pregnancy. To reduce the possible confounding effect of maternal labor or troubles at parturition, fetal fluids were collected only from puppies born by elective caesaeran section, at term of normal pregnancies. Fetal fluids from 76 puppies, 70 normal and six pathologic newborns, born by elective caesarean section were collected and analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, lactate dehydrogenase (LDH), creatine-kinase (CK), alkaline phosphatase (ALP), creatinine, urea, amylase, lipase, gamma-glutamyl transferase (gamma-GT), triglycerides, cholesterol, total proteins, albumin, globulins, glucose, magnesium, potassium, chloride, sodium, calcium, phosphorus and osmolarity. No significant differences were found between biochemical composition of amniotic or allantoic fluid in normal and pathologic newborns, maybe due to the small number of the pathologic puppies. Although some correlations between the two fluids were found (albumin, phosphorus, glucose and triglycerides), the results showed significant differences between the amniotic and allantoic biochemical composition (for all the parameters, except of alanine aminotransferase, triglycerides, cholesterol, albumin, amylase and glucose), suggesting that diverse sources could concur to the final composition of each fluid. A wide variability within and among litters was found for both amniotic and allantoic biochemical composition, and for some parameters an influence of breed body size (amniotic amylase, cholesterol, and allantoic calcium and glucose), maternal parity (amniotic and allantoic CK, glucose, LDH, chloride) and newborn gender (allantoic phosphorus) was found. Further investigations are needed for addressing the origin of each fetal fluid biochemical composition in the dog and also to indeep possible differences in fetal fluids biochemical composition between normal and pathologic puppies, providing potential markers for the quick identification of newborns that need special surveillance and cares immediately after birth. PMID- 29277069 TI - Somatic cell count and type of intramammary infection impacts fertility from in vitro produced embryo transfer. AB - The objective of this study was to assess the impact of mastitis-causing bacteria and somatic cell count (SCC) on pregnancy per embryo transfer (P/ET) in Holstein Gir crossbred (Girolando) lactating dairy cows. Cows (n = 1397) were subjected to a timed-embryo transfer protocol. Milk samples were collected two days before embryo transfer for SCC and bacteriological culture analyses. Pregnancy diagnosis was performed on days 31 and 66 after timed-embryo transfer. The animals were grouped according to the National Mastitis Council recommendations: Gram-positive environmental (EV+), Gram-negative environmental (EV-), Gram-positive contagious (C+), coagulase-negative staphylococci (CNS) and control (no bacterial growth). Additional analysis was made by categorizing bacteria based on degree of pathogenicity (Major or Minor). Bacterial growth reduced P/ET (P < .01) at both 31 and 66 days of gestation. The P/ET was lower (P < .05) at 31 days in EV- (30.1%) and EV+ (29.9%) groups and tended (P = .09) to be lower in the C+ group (36.6%) than the control group (44.0%). The P/ET from the Major group at 31 days of gestation was lower (P = .03) compared with the Minor and control groups (32.1 vs 41.1 vs 43.2%, respectively). Cows with SCC > 400,000 cells/mL had lower P/ET (P < .01) than animals with SCC < 200,000 cells/mL at both 31 (30.4% vs 40.8%) and 66 days (24.7% vs 32.2%) of gestation. Pregnancy loss was not different between bacterial isolates and SCC categories. Elevated SCC significantly reduced P/ET, whereas environmental agents and those with Major pathogenicity yielded the greatest reduction in P/ET. PMID- 29277068 TI - Biological effects of polyphenol-rich extract and fractions from an oenological oak-derived tannin on in vitro swine sperm capacitation and fertilizing ability. AB - Although excessive ROS levels induce sperm damage, sperm capacitation is an oxidative event that requires low amounts of ROS. As the antioxidant activity of the ethanol extract (TRE) of a commercial oenological tannin (Quercus robur toasted oak wood, Tan'Activ R(r)) and its four fractions (FA, FB, FC, FD) has been recently reported, the present study was set up to investigate the biological effects of TRE and its fractions in an in vitro model of sperm capacitation and fertilization. Boar sperm capacitation or gamete coincubation were performed in presence of TRE or its fractions (0, 1, 10, 100 MUg/ml). TRE at the concentration of 10 MUg/ml (TRE10) stimulated sperm capacitation, as it increased (p < .001) the percentage of spermatozoa with tyrosine-phosphorylated protein positivity in the tail principal piece (B pattern) (67.0 +/- 10.6 vs. 48.6 +/- 9.0, mean +/- SD for TRE10 vs. Ctr respectively). Moreover T10 significantly (p < .001) increased oocyte fertilization rate (91.9 +/- 4.0 vs. 69.0 +/- 14.8, TRE10 vs. Ctr respectively). An opposite effect of TRE at the concentration of 100 MUg/ml (TRE100) on both sperm capacitation (B pattern cell percentage 33.3 +/- 29.2) and fertilizing ability (fertilization rate 4.9 +/- 8.3), associated with a higher sperm viability (66.9 +/- 9.3 vs. 35.4 +/- 10.8, TRE100 vs. Ctr respectively) (p < .001), was recorded. The potency of the TRE fractions seems to be highest in FB followed by FC, faint in FD and nearly absent in FA. Our results show that TRE and its fractions, in a different extent, exert a powerful biological effect in finely modulating capacitation and sperm fertilizing ability. PMID- 29277070 TI - Melatonin stimulates the secretion of progesterone along with the expression of cholesterol side-chain cleavage enzyme (P450scc) and steroidogenic acute regulatory protein (StAR) in corpus luteum of pregnant sows. AB - The direct effect of melatonin on porcine luteal function during the pregnancy remains unknown. The objective of the study was to analyse the molecular mechanism(s) by which melatonin directly affects progesterone (P4) production in the corpus luteum (CL) of pregnant sows. We evaluated the localization of melatonin membrane receptors (MT1 and MT2) in CL, and investigated the effect of melatonin on P4 secretion along with the expression of P4 synthesis intermediates in luteal cells. Immunohistochemistry analysis showed that MT1 and MT2 were predominantly localized in luteal cells in pregnant luteal tissues. The results of our in vitro experiments showed that melatonin from 5 to 625 pg/mL was able to significantly increase P4 release (P < 0.05) in a dose-dependent manner. And at the dose of 125 pg/mL treatment, the time-dependent effect on P4 secretion was observed. Furthermore, melatonin from 5 to 625 pg/mL up-regulated both P450scc and StAR expression (P < 0.05) in a dose-dependent manner, and the effect was also time-dependent. No difference of 3beta hydroxysteroid dehydrogenase (3beta HSD) expression was observed between control and treatment groups. In addition, melatonin induced a dose- and time-dependent promotion on cell viability. Additionally, the stimulatory effects of melatonin were blocked by luzindole, a non-selective MT1 and MT2 receptor antagonist, or partially blocked by a selective MT2 ligand, 4-phenyl-2-propionamidotetralin (4P-PDOT). The data support the presence of MT1 and MT2 in porcine CL and a regulatory role for melatonin in luteal function through MT1 and MT2-mediated signal transduction pathways. PMID- 29277071 TI - Photophysicochemical behaviour and antimicrobial properties of monocarboxy Mg (II) and Al (III) phthalocyanine-magnetite conjugates. AB - Asymmetric Mg (II) or Al (III) phthalocyanine (containing a COOH group and 3 pyridylsulfanyl units) was conjugated via an amide bond to amino functionalized magnetic nanoparticle (AIMN) to form MgPc-AIMN or AlPc-AIMN conjugate, and characterized. The photophysicochemical behaviour of the phthalocyanine-AIMN conjugates was investigated and compared to the asymmetric Pcs and to the simple mixture of Pc with AIMNs without a chemical bond, (MPc-AIMN (mixed)). The directed covalent linkage of AIMNs to the asymmetrical metallopthalocyanines afforded improvements in the singlet oxygen (FDelta) and triplet state quantum yield (FT) as well as singlet oxygen lifetimes for the MPcs-AIMN-linked conjugates compared to MPc-AIMN (mixed) and MPcs alone. The asymmetric phthalocyanines and their conjugates showed effective antimicrobial activity against Escherichia coli bacteria under illumination. PMID- 29277072 TI - A highly selective and sensitive fluorescent chemosensor and its application for rapid on-site detection of Al3. AB - In this paper, a simple naphthalene-based derivative (HL) has been designed and synthesized as a Al3+-selective fluorescent chemosensor based on the PET mechanism. HL exhibited high selectivity and sensitivity towards Al3+ over other commonly coexisting metal ions in ethanol with a detection limit of 2.72nM. The 1:1 binding stoichiometry of the complex (HL-Al3+) was determined from the Job's plot based on fluorescence titrations and the ESI-MS spectrum data. Moreover, the binding site of HL with Al3+ was assured by the 1H NMR titration experiment. The binding constant (Ka) of the complex (HL-Al3+) was calculated to be 5.06*104M-1 according to the Benesi-Hildebrand equation. In addition, the recognizing process of HL towards Al3+ was chemically reversible by adding Na2EDTA. Importantly, HL could directly and rapidly detect aluminum ion through the filter paper without resorting to additional instrumental analysis. PMID- 29277073 TI - Investigations on the spectroscopic properties of Dy3+ ions doped Zinc calcium tellurofluoroborate glasses. AB - A new series of Dy3+ doped (30-x)B2O3+30TeO2+20CaCO3+10ZnO+10ZnF2+xDy2O3 (x=0.01, 0.1, 0.5, 1, 2 and 3 in wt%) Zinc calcium tellurofluoroborate glasses were prepared and their structural, luminescence and excited state dynamics have been studied and reported. The structural properties have been characterized through XRD and FTIR studies to confirm the amorphous nature and to explore the presence of fundamental stretching vibrations. The bonding parameters (delta and beta), optical band gap, Urbach's energy, oscillator strengths and Judd-Ofelt (JO) intensity parameters were calculated from the absorption spectra. The JO intensity parameters and the Y/B intensity ratio values have been used to explore the nature of the bonding and asymmetry around the Dy-ligand field environment. The luminescence properties of the present Dy3+ doped glasses have been analyzed through luminescence excited state dynamics and radiative properties such as transition probability (A), stimulated emission cross-section (sigmaPE) branching ratio (beta) and radiative lifetime (tauR) values. The combination of dominant blue (4F9/2->6H15/2) and yellow (4F9/2->6H13/2) emissions generates white light emission in the CIE chromaticity diagram thus suggests that the present Dy3+ doped glasses are suitable for white light applications. The lifetime of the 4F9/2 excited state is found to decrease with the increase in Dy3+ ion content and the concentration quenching of the Dy3+ ions emission could be ascribed due to the resonant energy transfer and cross-relaxation processes. The non exponential behavior of the decay curves has been analyzed with Inokuti-Hirayama model and the interaction between the Dy3+ ions is of electric dipole-dipole in nature. PMID- 29277074 TI - Analysis of 19th century ceramic fragments excavated from Pirenopolis (Goias, Brazil) using FT-IR, Raman, XRF and SEM. AB - This study used Raman, FT-IR and XRF spectroscopy and SEM to analyze ceramic fragments dating from the 19th century, excavated from an old farm in the municipality of Pirenopolis, Goias, Brazil. The results show that the samples were produced in an open oven at a firing temperature below 500 degrees C, using raw materials including kaolinite, hematite, magnetite, quartz, microcline, albite, anhydrite, calcite, illite, orthoclase and MnO2. Although the analyses showed similarities in the manufacturing process and the presence of many minerals was common in all samples, multivariate statistical methods (PCA) allowed a more detailed assessment of similarities and differences in the mineral composition of the samples. The results of the PCA showed that the samples excavated in one of the slave quarters (senzalas) group with those excavated at the farmhouse, where the landowner lived, which indicates a paternalistic attitude towards captives, including the sharing of ceramic materials of everyday use. PMID- 29277075 TI - Gaze gesture based human robot interaction for laparoscopic surgery. AB - While minimally invasive surgery offers great benefits in terms of reduced patient trauma, bleeding, as well as faster recovery time, it still presents surgeons with major ergonomic challenges. Laparoscopic surgery requires the surgeon to bimanually control surgical instruments during the operation. A dedicated assistant is thus required to manoeuvre the camera, which is often difficult to synchronise with the surgeon's movements. This article introduces a robotic system in which a rigid endoscope held by a robotic arm is controlled via the surgeon's eye movement, thus forgoing the need for a camera assistant. Gaze gestures detected via a series of eye movements are used to convey the surgeon's intention to initiate gaze contingent camera control. Hidden Markov Models (HMMs) are used for real-time gaze gesture recognition, allowing the robotic camera to pan, tilt, and zoom, whilst immune to aberrant or unintentional eye movements. A novel online calibration method for the gaze tracker is proposed, which overcomes calibration drift and simplifies its clinical application. This robotic system has been validated by comprehensive user trials and a detailed analysis performed on usability metrics to assess the performance of the system. The results demonstrate that the surgeons can perform their tasks quicker and more efficiently when compared to the use of a camera assistant or foot switches. PMID- 29277076 TI - An ethical leadership program for nursing unit managers. AB - PURPOSE: The aims of this study were to evaluate the effect of an ethical leadership program (ELP) on ethical leadership, organizational citizenship behavior (OCB), and job outcomes of nursing unit managers (UMs) and to examine changes in staff nurses' perception about UMs' EL, OCB, job outcomes, and ethical work environments (EWEs) post-ELP. DESIGN: A quasi-experimental (pre- and post test design) study conducted six-month intervention (ELP) using self-reported UM survey (n=44), and staff nurses (n=158) were randomly extracted by two steps. METHODS: The Korean version of Ethical Leadership at Work for UMs' self-ethical leadership, the Ethical Leadership Scale for staff nurses' perceived ethical leadership, a 19-item OCB scale, and six dimensions of the medium-sized Copenhagen Psychosocial Questionnaire II for job outcomes and EWEs were administered at baseline and post-intervention. FINDINGS: UMs' ethical leadership scores differed significantly over time in people orientation (p=0.041) and concern for ethical leadership sustainability (p=0.002) adjusting for UM experience duration and nursing unit type. Total mean and level of power-sharing of ethical leadership among UMs with <5years of UM experience improved significantly over time. Of staff nurses' perception changes about UMs' ethical leadership, OCB, job outcomes, and EWEs, significant improvement over time appeared only in EWEs' work influence level (p=0.007). CONCLUSIONS: This study provides useful information for clinical ELP development and examining the program's effect on leadership skills and followers' outcomes. Program facilitation relies on practical training methods, participant motivation, and assessment outcome designs by controlling clinical confounding factors. Findings have implications as an attempt for intervention to promote competencies related to ethical leadership of nursing unit managers. PMID- 29277077 TI - Pharmacology training in mental health nurse education: Justification for an increase in frequency and depth in the UK. AB - This article explores the role and importance of Pharmacology within mental health nurse education. The article proposes that a lack of pharmacology content within undergraduate mental health nurse education may not fully prepare nurses for their role once qualified and as a result influence negatively upon service user care. PMID- 29277078 TI - A comparison of multicomponent electrosorption in capacitive deionization and membrane capacitive deionization. AB - In this study, the desalination performance of Capacitive Deionization (CDI) and Membrane Capacitive Deionization (MCDI) was studied for a wide range of salt compositions. The comprehensive data collection for monovalent and divalent ions used in this work enabled us to understand better the competitive electrosorption of these ions both with and without ion-exchange membranes (IEMs). As expected, MCDI showed an enhanced salt adsorption and charge efficiency in comparison with CDI. However, the different electrosorption behavior of the former reveals that ion transport through the IEMs is a significant rate-controlling step in the desalination process. A sharper desorption peak is observed for divalent ions in MCDI, which can be attributed to a portion of these ions being temporarily stored within the IEMs, thus they are the first to leave the cell upon discharge. In addition to salt concentration, we monitored the pH of the effluent stream in CDI and MCDI and discuss the potential causes of these fluctuations. The dramatic pH change over one adsorption and desorption cycle in CDI (pH range of 3.5-10.5) can be problematic in a feed water containing components prone to scaling. The pH change, however, was much more limited in the case of MCDI for all salts. PMID- 29277079 TI - Relationships between DBP concentrations and differential UV absorbance in full scale conditions. AB - Differential UV spectroscopy, defined as the difference in UV absorbance spectra before and after chlorination, has shown great potential to predict disinfection by-product (DBP) concentrations at laboratory scale. However, so far, no results have been reported on the full scale application of differential UV spectroscopy in drinking water treatment facilities. The objectives of this study are to determine if relationships can be developed between differential UV absorbance and DBP concentrations, for both regulated and unregulated DBPs, in a full-scale facility and to determine if these relationships vary throughout the year with variations in raw water quality and treatment conditions. The results show that linear and power relationships between differential UV absorbance and DBP concentrations can be developed (0.62 <= R2 <= 0.99), although differences between relationships obtained in lab- and full-scale conditions need further investigation. Finally, the relationships obtained are different from one sampling campaign to another, which raises the question of whether it is possible to determine relationships that are stable enough to be used as adequate feedback on DBP concentrations. PMID- 29277080 TI - Cyanobacterium removal and control of algal organic matter (AOM) release by UV/H2O2 pre-oxidation enhanced Fe(II) coagulation. AB - Harmful algal blooms in source water are a worldwide issue for drinking water production and safety. UV/H2O2, a pre-oxidation process, was firstly applied to enhance Fe(II) coagulation for the removal of Microcystis aeruginosa [M. aeruginosa, 2.0 (+/-0.5) * 106 cell/mL] in bench scale. It significantly improved both algae cells removal and algal organic matter (AOM) control, compared with UV irradiation alone (254 nm UVC, 5.4 mJ/cm2). About 94.7% of algae cells were removed after 5 min UV/H2O2 pre-treatment with H2O2 dose 375 MUmol/L, FeSO4 coagulation (dose 125 MUmol/L). It was also certified that low residue Fe level and AOM control was simultaneously achieved due to low dose of Fe(II) to settle down the cells as well as the AOM. The result of L9(3)4 orthogonal experiment demonstrated that H2O2 and FeSO4 dose was significantly influenced the algae removal. UV/H2O2 induced an increase of intracellular reactive oxidant species (ROS) and a decrease in zeta potential, which might contribute to the algae removal. The total microcystins (MCs) concentration was 1.5 MUg/L after UV/H2O2 pre-oxidation, however, it could be removed simultaneously with the algae cells and AOM. This study suggested a novel application of UV/H2O2-Fe(II) process to promote algae removal and simultaneously control AOM release in source waters, which is a green and promising technology without secondary pollution. PMID- 29277081 TI - Acceptance of new sanitation: The role of end-users' pro-environmental personal norms and risk and benefit perceptions. AB - Current sanitation systems are inherently limited in their ability to address the new challenges for (waste)water management that arise from the rising demand to restore resource cycles. These challenges include removal of micropollutants, water (re)use, and nutrient recovery. New opportunities to address these challenges arise from new sanitation, a system innovation that combines elements of source separation, local treatment and reuse, and less use of water. New sanitation is applied, but not yet widespread, in several residential areas in Europe. Implementation is hindered by the lack of insight into the general public's willingness to engage in new sanitation, and the resulting uncertainty about this among decision makers and other stakeholders in wastewater management. Using value-belief-norm theory as a conceptual lens, this paper addresses the individual motivations (pro-environmental personal norms) and personal drivers (benefits) and barriers (risks) for acceptance of new sanitation by the Dutch general public. The results of an online survey (N = 338) indicated that both pro environmental personal norms and risk and benefit perceptions predict consumers' willingness to accept new sanitation. More specifically, they showed that consumer acceptance is driven by perceived risks relating to the housing market and the need to change behavior, but also by environmental benefits. Overall, new sanitation was favorably evaluated by respondents: 64% indicated that they would likely use new sanitation if they were owner-occupiers. The results of this explorative study are discussed in light of the development of novel sanitation systems that are sensitive to perceptions of end-users and other key stakeholders. PMID- 29277082 TI - Routes of administration for cannabis use - basic prevalence and related health outcomes: A scoping review and synthesis. AB - BACKGROUND: Cannabis use is common, and associated with adverse health outcomes. 'Routes of administration' (ROAs) for cannabis use have increasingly diversified, in part influenced by developments towards legalization. This paper sought to review data on prevalence and health outcomes associated with different ROAs. METHODS: This scoping review followed a structured approach. Electronic searches for English-language peer-reviewed publications were conducted in primary databases (i.e., MEDLINE, EMBASE, PsycINFO, Google Scholar) based on pertinent keywords. Studies were included if they contained information on prevalence and/or health outcomes related to cannabis use ROAs. Relevant data were screened, extracted and narratively summarized under distinct ROA categories. RESULTS: Overall, there is a paucity of rigorous and high-quality data on health outcomes from cannabis ROAs, especially in direct and quantifiable comparison. Most data exist on smoking combusted cannabis, which is associated with various adverse respiratory system outcomes (e.g., bronchitis, lung function). Vaporizing natural cannabis and ingesting edibles appear to reduce respiratory system problems, but may come with other risks (e.g., delayed impairment, use 'normalization'). Vaporizing cannabis concentrates can result in distinct acute risks (e.g., excessive impairment, injuries). Other ROAs are uncommon and under-researched. CONCLUSIONS: ROAs appear to distinctly influence health outcomes from cannabis use, yet systematic data for comparative assessments are largely lacking; these evidence gaps require filling. Especially in emerging legalization regimes, ROAs should be subject to evidence-based regulation towards improved public health outcomes. Concretely, vaporizers and edibles may offer potential for reduced health risks, especially concerning respiratory problems. Adequate cannabis product regulation (e.g., purity, labeling, THC-restrictions) is required to complement ROA-based effects. PMID- 29277083 TI - Manipulation under anaesthesia and steroid injection for pain and stiffness after surgery to the first metatarsophalangeal joint. AB - AIM: To determine the effectiveness of manipulation under anaesthesia and local steroid injection to treat stiffness of the first metatarsophalangeal joint following surgery for hallux rigidus or hallux valgus. METHODS: Patients were identified who had undergone surgery for hallux rigidus or hallux valgus and subsequently were treated with manipulation and steroid injection for stiffness of their joint. Patient records were reviewed to determine the range of movement of the joint pre-operatively, immediately following the procedure and at subsequent follow up. Manchester-Oxford foot questionnaires (MOXFQ) were sent to patients to evaluate symptoms post-operatively. RESULTS: In total 35 patients were analysed, which included a total of 38 foot operations. Twenty seven had prior surgery for hallux rigidus and 11 for hallux valgus correction. The total range of movement of the joint improved following manipulation by an overall mean of 44.7 degrees (p<0.0001). At subsequent follow up, the total range of movement of the joint was still improved by 22.2 degrees (p<0.0001) overall. The mean post-operative MOXFQ score was 24.8 but no correlation was found between MOXFQ scores and range of movement. CONCLUSIONS: Manipulation under anaesthesia and local steroid injection is an effective way of treating stiffness following first ray surgery. Treatment results in an improved range of movement of the joint and patients report good function post-operatively. PMID- 29277084 TI - Sampling limits for electron tomography with sparsity-exploiting reconstructions. AB - Electron tomography (ET) has become a standard technique for 3D characterization of materials at the nano-scale. Traditional reconstruction algorithms such as weighted back projection suffer from disruptive artifacts with insufficient projections. Popularized by compressed sensing, sparsity-exploiting algorithms have been applied to experimental ET data and show promise for improving reconstruction quality or reducing the total beam dose applied to a specimen. Nevertheless, theoretical bounds for these methods have been less explored in the context of ET applications. Here, we perform numerical simulations to investigate performance of l1-norm and total-variation (TV) minimization under various imaging conditions. From 36,100 different simulated structures, our results show specimens with more complex structures generally require more projections for exact reconstruction. However, once sufficient data is acquired, dividing the beam dose over more projections provides no improvements-analogous to the traditional dose-fraction theorem. Moreover, a limited tilt range of +/-75 degrees or less can result in distorting artifacts in sparsity-exploiting reconstructions. The influence of optimization parameters on reconstructions is also discussed. PMID- 29277085 TI - Examination of core competencies of agricultural development professionals in Cambodia. AB - This cross-sectional study examined perceived level of importance, perceived level of competency in extension core competencies, and whether and how perceptions of competency vary by respondents' demographics; ascertained gaps in competency, if any; and identified ways for agricultural development professionals in Cambodia to acquire core competencies. Data were collected using a group-administered survey among 39 agricultural development professionals participating in a national workshop in December 2015. The survey consisted of 48 competencies representing eight core competencies, and each competency had level of importance and level of competency parts. The findings show that extension workers in Cambodia deemed all competencies highly or very highly important to their extension work; however, their perceived level of competency in those competencies appeared not to meet the expectations. The level of competency in all but communication skills and diversity significantly differed by gender but not by age and experience. Respondents indicated all four methods-preservice, in service, basic induction training, and participation in seminars, workshops, and webinars-equally appropriate to acquire core competencies. The findings imply that the agricultural development authority in Cambodia should review, update, or design extension education curricula incorporating the competencies highlighted in this study and train its extension cadres on those competencies. PMID- 29277086 TI - The challenges of integrating two genomes in one cell. AB - Mutualistic bacteria and mitochondria have small genomes that harbor host essential genes. A major question is why a distinct bacterial or mitochondrial genome is needed to encode these functions. The dual location of genes demand two sets of information processing systems, coordination of gene expression and elaborate transport systems. A simpler solution would be to harbor all genes in a single genome. Functional gene transfers to the host nuclear genome is uncommon in mutualistic bacteria and lost gene functions are rather rescued by co symbiotic bacteria. Recent findings suggest that the mitochondrial genome is retained to avoid conflicting signals between protein targeting pathways in the cell. However, if the selective pressure for oxygenic respiration is lost, the mitochondrial genome will start to deteriorate and soon be lost. PMID- 29277087 TI - In vivo confocal microscopy for detection of subconjunctival Onchocerca lupi infection in a dog. AB - A seven-year-old male castrated mixed-breed dog was diagnosed with bilateral subconjunctival masses. In vivo confocal microscopy facilitated visualization of Onchocerca lupi adult nematodes and their characteristic cuticular morphology. Long, thin, white nematodes were extracted during excisional biopsy. Histopathologic and parasitologic evaluation confirmed the diagnosis of O. lupi. In addition to surgical debulking of the parasitic granulomas, the dog received systemic doxycycline, prednisone, and ivermectin therapy. In vivo confocal microscopy was repeated one year after initial diagnosis, and no remaining nematodes were visible. To the authors' knowledge, this is the first report of use of in vivo confocal microscopy as a noninvasive diagnostic and monitoring tool for canine onchocerciasis. PMID- 29277088 TI - [Belching]. AB - Supragastric belching is the most important factor in the etiology of excessive belching complaints. Supragastric belching is a belching disorder with a behavioral origin. The standard diagnosis is made by monitoring the esophageal impedance. Supragastric belching has been shown to be associated with globus, as well as reflux symptoms in proton pump inhibitor non-responders in gastroesophageal reflux disease; however, the pathophysiology of supragastric belching in patients with gastroesophageal reflux disease or functional dyspepsia has not been clarified. Patient education with behavioral therapy is the treatment of choice in isolated supragastric belching. On the other hand, the best management of supragastric belching associated with globus, gastroesophageal reflux disease, and dyspepsia remains to be studied. PMID- 29277089 TI - [Rumination]. AB - Rumination syndrome is one of the functional gastroduodenal disorders. Effortless and repetitive regurgitation of recently ingested food from the stomach to the oral cavity followed by rechewing and reswallowing or spitting are the characteristic clinical features. This disorder is believed to be uncommon, but many patients with this disorder are overlooked by their physicians. Rumination might be caused by a reversal of the gastric contents through the esophagogastric junction, which is initiated by an increase in intragastric pressure. The characteristic symptoms are sufficient for the diagnosis of rumination syndrome. Postprandial high resolution esophageal impedance manometry can detect gastric pressurization exceeding 30 mmHg associated with the return of ingested material into the proximal esophagus, which is a pathognomonic finding of rumination syndrome. An extensive explanation of the condition and the underlying mechanism is the first step of the treatment of rumination syndrome. Behavioral therapy through diaphragmatic breathing is the mainstay of treatment. Further studies on the long term effects of biofeedback therapy as well as a proper strategy for refractory rumination syndrome are needed. PMID- 29277090 TI - [Vomiting]. AB - Many disorders can cause either acute or chronic vomiting. However, in most cases, vomiting is self-limited. A correct diagnosis is possible by conducting careful histories and physical examinations. In cases of severe vomiting, further testing, including laboratory studies, radiological images, endoscopic evaluation, and gastrointestinal motility tests, can also be considered. The correction of clinical consequences of vomiting should be initiated, including dehydration, electrolyte imbalances, malnutrition, and suppression of symptoms via the use empirical antiemetic treatments. Moreover, underlying disorders should be treated using dietary, pharmacological, and even surgical interventions. PMID- 29277091 TI - [Bloating]. AB - Bloating is one of the most common and troublesome problems in a large proportion of patients with gastrointestinal disorders but the mechanism is not completely understood. Several factors, including gas-producing intestinal microbiota, disturbed handling of intestinal gas, visceral hypersensitivity, abnormal viscero somatic responses, fermentable diet, and psychological factors, have been suggested as mechanisms. For an assessment, thorough medical history-taking and physical examination are the first steps. On the other hand, organic disorders should always be considered first for a differential diagnosis. The therapeutic options available are considered challenging and still limited in clinical practice. The treatment strategy may include diet modification, pharmacologic approach, psychiatric approach, biofeedback, etc. Further studies will be needed to explore the variable mechanism of bloating and develop an efficient treatment. PMID- 29277092 TI - [Gastric Cancer Recurrence in 12 Years after Surgical Resection]. AB - Recurrence of gastric cancer after 10 years of surgical resection is highly rare. There are limited data on the surveillance of patients with gastric cancer after 10 years from gastrectomy. A 50-year-old man presented to the gastroenterology clinic at our hospital for the management of abnormal findings on a routine colonoscopic exam. He had undergone gastrectomy for advanced gastric cancer 12 years ago. At presentation, colonoscopic examination revealed asymmetrically edematous and hyperemic mucosal change with luminal narrowing on transverse colon. Abdominal computed tomography showed no evidence of distant metastasis, except for focal bowel wall thickening on transverse colon. He underwent a laparoscopic right-hemicolectomy, and the resected specimen revealed a recurrent and metastatic lesion. We report a case of recurrence of gastric cancer after 10 years from surgical resection with relevant literature review. PMID- 29277093 TI - Hemosuccus Pancreaticus in the Simple Mucinous Cyst of the Pancreas. AB - Hemosuccus pancreaticus is an unusual gastrointestinal hemorrhage through the main pancreatic duct. We report a rare case of hemosuccus pancreaticus due to a simple mucinous cyst of the pancreas. A 52-year-old man who had been followed-up for a suspected branch duct intraductal papillary mucinous neoplasm (IPMN) visited the emergency room due to hematochezia. Endoscopy showed active bleeding from the ampulla. Computed tomography revealed hemorrhage in a 2.0-cm cystic mass in the pancreatic body. The patient was diagnosed with hemosuccus pancreaticus caused by bleeding into the main pancreatic duct from suspected IPMN. Elective laparoscopic distal pancreatectomy was performed. The histopathological diagnosis was a simple mucinous cyst with squamous metaplasia based upon the pathological finding involving the absence of ovarian-type stroma. In conclusion, it should be recognized that a pancreatic cyst including simple mucinous cyst may cause hemosuccus pancreaticus, and these cysts should be viewed as neoplastic and approached similarly as other mucinous pancreatic neoplasms. PMID- 29277094 TI - Superior Mesenteric Artery Syndrome Combined with Renal Nutcracker Syndrome in a Young Male: A Case Report. AB - This correction is being published to correct the author's Korean affiliation. PMID- 29277095 TI - Management and educational status of adult anaphylaxis patients at emergency department. AB - BACKGROUND/AIMS: We evaluated the management and educational status of adult anaphylaxis patients at emergency departments (EDs). METHODS: Anaphylaxis patients who visited ED from 2011 to 2013 were enrolled from three hospitals. We analyzed clinical features, prior history of anaphylaxis, management and provided education for etiology and/or prevention. For analyzing associated factors with epinephrine injection, Pearson chi-square test was used by SPSS version 21 (IBM Co.). RESULTS: A total of 194 anaphylaxis patients were enrolled. Ninety-nine patients (51%) visited ED by themselves. Time interval from symptom onset to ED visit was 62 +/- 70.5 minutes. Drug (56.2%) was the most frequent cause of anaphylaxis. Forty-seven patients (24.2%) had prior history of anaphylaxis and 33 patients had same suspicious cause with current anaphylaxis. Cutaneous (88.7%) and respiratory (72.7%) symptoms were frequent. Hypotension was presented in 114 patients (58.8%). Mean observation time in ED was 12 +/- 25.7 hours and epinephrine was injected in 114 patients (62%). In 68 patients, epinephrine was injected intramuscularly with mean dose of 0.3 +/- 0.10 mg. Associated factor with epinephrine injection was hypotension (p = 0.000). Twenty-three patients (13%) were educated about avoidance of suspicious agent. Epinephrine auto injectors were prescribed only in five patients. Only 34 (19%) and 72 (40%) patients were consulted to allergist at ED and outpatient allergy department respectively. CONCLUSION: We suggested that management and education of anaphylaxis were not fully carried out in ED. An education and promotion program on anaphylaxis is needed for medical staff. PMID- 29277096 TI - An overview of meta-analysis for clinicians. AB - The number of medical studies being published is increasing exponentially, and clinicians must routinely process large amounts of new information. Moreover, the results of individual studies are often insufficient to provide confident answers, as their results are not consistently reproducible. A meta-analysis is a statistical method for combining the results of different studies on the same topic and it may resolve conflicts among studies. Meta-analysis is being used increasingly and plays an important role in medical research. This review introduces the basic concepts, steps, advantages, and caveats of meta-analysis, to help clinicians understand it in clinical practice and research. A major advantage of a meta-analysis is that it produces a precise estimate of the effect size, with considerably increased statistical power, which is important when the power of the primary study is limited because of a small sample size. A meta analysis may yield conclusive results when individual studies are inconclusive. Furthermore, meta-analyses investigate the source of variation and different effects among subgroups. In summary, a meta-analysis is an objective, quantitative method that provides less biased estimates on a specific topic. Understanding how to conduct a meta-analysis aids clinicians in the process of making clinical decisions. PMID- 29277097 TI - Systemic review: agreement between the latent tuberculosis screening tests among patients with rheumatic diseases. AB - BACKGROUND/AIMS: To estimate the level of agreement and positivity rates of latent tuberculosis infection (LTBI) tests prior to the use of tumor necrosis factor (TNF) inhibitors in relation to underlying rheumatic diseases and endemic tuberculosis levels. METHODS: The Ovid-Medline, Embase, and Cochrane Libraries were searched for articles before October 2013 involving LTBI screening in rheumatic patients, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), and psoriatic arthritis. RESULTS: In pooled analyses, 5,224 rheumatic patients had undergone both a tuberculin skin test (TST) and an interferon-gamma release assay (IGRA) before TNF inhibitors use. The positivity of TST, QuantiFERON-TB Gold In Tube (QFT-GIT), and T-SPOT.TB (T-SPOT) tests were estimated to be 29%, 17%, and 18%, respectively. The agreement percentage between the TST and QFT-GIT, and between the TST and T-SPOT were 73% and 75%. Populations from low-to-moderate endemic TB presented with slightly less agreement (71% between TST and QFT-GIT, and 74% between TST and T SPOT) than patients from high endemic countries (73% between TST and QFT-GIT, and 81% between TST and T-SPOT). By underlying disease stratification, a lower level of agreement between TST and QFT-GIT was found among AS (64%) than among JIA (77%) and RA patients (73%). CONCLUSION: We reaffirm the current evidence for accuracy of LTBI test done by TST and IGRA among rheumatic patients is inconsistent. Our stratified analysis suggests different screening strategies might be needed in clinical settings considering the endemic status in the patient's country of origin and the precise nature of underlying diseases. PMID- 29277098 TI - Targeted Tonsillar Biopsy for Unilateral Tonsillar Enlargement. AB - BACKGROUND: Unilateral tonsillar enlargement (UTE) is not an uncommon incidental finding. Lymphoma is the most common malignancy of the tonsils in children and presents with tonsillar enlargement. METHODS: This is a retrospective case series of all cases of histopathological analysis of tonsillectomy specimens at a single pediatric tertiary hospital between 1996 and 2015. Patients either had a preoperative indication (n = 53) for pathological testing or indications based on intraoperative findings (n = 88). Of the preoperative group, 17 patients had tonsillectomy for UTE alone. In 72% of cases, the side of perceived unilateral enlargement was confirmed at histopathological assessment. RESULTS: Zero cases of suspected malignancy were identified on testing. CONCLUSION: There is a very low prevalence of unsuspected and suspected malignancy in routine and targeted examination of tonsillar specimens. It is reasonable to test based on other clinical findings and risk factors such as immunosuppression. PMID- 29277099 TI - Financial Incentives for Medicaid Beneficiaries With Diabetes: Lessons Learned From HI-PRAISE, an Observational Study and Randomized Controlled Trial. AB - PURPOSE: The Hawaii Patient Reward and Incentives to Support Empowerment (HI PRAISE) project examined the impact of financial incentives on Medicaid beneficiaries with diabetes. DESIGN: Observational pre-post study and randomized controlled trial (RCT). SETTING: Federally qualified health centers (FQHCs) and Hawaii Kaiser Permanente. PARTICIPANTS: The observational study included 2003 Medicaid beneficiaries with diabetes from FQHCs. The RCT included 320 participants from Kaiser Permanente. INTERVENTION: Participants could earn up to $320/year of financial incentives for a minimum of 1 year. MEASURES: (1) Clinical outcomes of change in hemoglobin A1c (HbA1c), blood pressure, and cholesterol; (2) compliance with American Diabetes Association (ADA) standards of diabetes care; and (3) cost effectiveness. ANALYSIS: Generalized estimating equation models were used to assess differences in clinical outcomes. General linear models were utilized to estimate the medical costs per patient/day. RESULTS: Changes in clinical outcomes in the observational study were statistically significant. Mean HbA1c decreased from 8.56% to 8.24% ( P < .0001) and low density lipoprotein decreased from 106.17 mg/dL to 98.55 mg/dL ( P < .0001). No significant differences were found between groups in the RCT. Improved ADA compliance was observed. No reduction in total health cost during the project period was demonstrated. CONCLUSION: The HI-PRAISE found no conclusive evidence that financial incentives had beneficial effect on diabetes clinical outcomes or cost saving measures. PMID- 29277100 TI - Indocyanine green MS/MS investigations using femtosecond laser-pulse photodissociation and collision-induced dissociation. AB - The dissociation reactions of indocyanine green (also known as cardiogreen) have been studied in a Fourier-transform ion-cyclotron resonance mass spectrometer by the application of unimolecular, collision-induced dissociation and photodissociation using femtosecond laser pulses. Ions were prepared by electrospray ionization (ESI) in various solvents. Depending on the properties of the solvent mixture, the mono sodiated molecule could be measured through cation exchange in various compositions. Using a mixture of methanol/water/formic acid as solvent, protonated ions, formed by exchange of sodium, are predominantly observed. A mixture of isopropanol/formic acid leads to the addition of a further sodium cation to the molecule yielding an intense bi-sodiated ion signal. The photodissociation of the stored ions was achieved using pulses at a wavelength of 790 nm and approximately 150 fs pulse duration. The results show that only fs photodissociation leads to the fragmentation of the different molecular structures, while in case of sodiated indocyanine green collision induced dissociation fails completely to observe any fragments. In all other investigated ion structures, the collision-induced-dissociation spectra show unspecified and little intense spectra. It is shown that fs-photodissociation mass spectrometry is the only method that leads to substance specific fragmentation for this sample. Furthermore, indocyanine green is known to form aggregation products. In the ion-cyclotron resonance experiment, the reactions of a dimeric cluster were also investigated. The necessary condition and the interference of the fragmentations with those of the monomer are discussed. PMID- 29277101 TI - Incidence and Management of Thrombotic and Thromboembolic Complications Following the Superior Cavopulmonary Anastomosis Procedure: A Literature Review. AB - The objective of this literature review was to estimate the incidence of thrombosis and thromboembolism associated with the superior cavopulmonary anastomosis (SCPA) procedure and its variants and to examine current thromboprophylaxis regimens utilized. MEDLINE and EMBASE were searched from inception to August 2017 for all prospective and retrospective cohort studies explicitly reporting incidence of thrombosis, thromboembolism, or shunt occlusion in neonates, infants, and children undergoing 1 or more variants of the SCPA procedure. End points included thrombotic events and thromboembolic events (strokes and pulmonary embolisms) as primary outcomes, and overall mortality as a secondary outcome, at the last available follow-up time point. Of 1303 unique references identified, 13 cohort studies were deemed eligible. Reported incidence of thrombosis and thromboembolic events ranged from 0% to 28.0% and from 0% to 12.5%, respectively. Reported incidence of major bleeding events ranged from 0% to 2.9%. Reported overall mortality ranged from 2.5% to 50.5% across studies. Thromboprophylaxis protocols varied across institutions and studies, most commonly involving unfractionated heparin (UFH), warfarin, enoxaparin, acetylsalicylic acid (ASA), or combinations of ASA and warfarin, ASA and low molecular-weight heparin (LMWH), UFH and LMWH, and UFH and ASA; several studies did not specify a protocol. Due to substantial variability in reported event rates, no clear correlation was identified between prophylaxis protocols and postoperative thrombotic complications. Despite guidance recommending postoperative UFH as standard practice, thromboprophylaxis protocols varied across institutions and studies. More robust trials evaluating different thromboprophylaxis regimens for the management of these patients are warranted. PMID- 29277102 TI - Selection and use of microsatellite markers for individual identification and meat traceability of six swine breeds in the Chinese market. AB - Meat traceability based on molecular markers is exerting a great influence on food safety and will enhance its key role in the future. This study aimed to investigate and verify the polymorphism of 23 microsatellite markers and select the most suitable markers for individual identification and meat traceability of six swine breeds in the Chinese market. The mean polymorphism information content value of these 23 loci was 0.7851, and each locus exhibited high polymorphism in the pooled population. There were 10 loci showing good polymorphism in each breed, namely, Sw632, S0155, Sw2406, Sw830, Sw2525, Sw72, Sw2448, Sw911, Sw122 and CGA. When six highly polymorphic loci were combined, the match probability value for two random individual genotypes among the pig breeds (Beijing Black, Sanyuan and Taihu) was lower than 1.151 E-06. An increasing number of loci indicated a gradually decreasing match probability value and therefore enhanced traceability accuracy. The validation results of tracing 18 blood and corresponding meat samples based on five highly polymorphic loci (Sw2525, S0005, Sw0107, Sw911 and Sw857) were successful, with 100% conformation probability, which provided a foundation for establishing a traceability system for pork in the Chinese market. PMID- 29277103 TI - Digital Diabetes Management Application Improves Glycemic Outcomes in People With Type 1 and Type 2 Diabetes. AB - BACKGROUND: Diabetes is a chronic condition that requires constant self management. As a consequence, several software platforms have been developed to facilitate the tracking of diabetes data to improve diabetes management. Our aim was to determine the real-world glycemic benefits of a mobile diabetes management platform used by individuals with type 1 and type 2 diabetes. METHODS: Mobile platform-using (n = 899) and control (n = 900) participants meeting specific minimum data criteria were randomly selected from a database of diabetes users. All results were modeled using different mixed effect generalized linear models, assigning random intercepts for each user, and adjusting the distribution assumption for each outcome. RESULTS: Users of the mobile platform increased their frequency of blood glucose monitoring (+8.8 tests per month, 95% CI [3.4, 14.1], P < .001) and had fewer hyperglycemic events and lower average glucose levels compared to the control group. In addition, a mobile user could expect a 3.5% drop in average BG (-6.4 mg/dL, 95% CI [-2.0, -10.7], P < .001) and a 10.7% decrease in hyperglycemia ( P < .001) after 2 months. CONCLUSION: Users of the mobile platform tested their BG more often and demonstrated greater improvement in blood glucose compared to users who did not use the mobile platform. This supports previous studies indicating that digital technologies can enhance diabetes care in a real-world setting. PMID- 29277104 TI - The Importance of the Hawthorne Effect on Psychological Outcomes Unveiled in a Randomized Controlled Trial of Diabetes Technology. PMID- 29277105 TI - Providers' competencies positively affect personal recovery of involuntarily admitted patients with severe mental illness: A prospective observational study. AB - OBJECTIVE: There is limited research on the patient-provider relationship in inpatient settings. The purpose of this study was to measure the effect of mental healthcare providers' recovery-promoting competencies on personal recovery in involuntarily admitted psychiatric patients with severe mental illness. METHODS: In all, 127 Dutch patients suffering from a severe mental illness residing in a high-secure psychiatric hospital reported the degree of their personal recovery (translated Questionnaire about Processes of Recovery questionnaire (QPR)) and the degree of mental healthcare providers' recovery-promoting competence (Recovery Promoting Relationship Scale (RPRS)) at two measurement points, 6 months apart. ANALYSES: (Mixed-effects) linear regression analysis was used to test the effect of providers' recovery-promoting competence on personal recovery, while controlling for the following confounding variables: age, gender drug/alcohol problems, social relationships, activities of daily living, treatment motivation and medication adherence. RESULTS: Analyses revealed a significant positive effect of providers' recovery-promoting competencies on the degree of personal recovery ( t = 8.4, p < .001) and on the degree of change in personal recovery over time ( ts > 4, p < .001). CONCLUSION: This study shows that recovery-promoting competencies of mental healthcare providers are positively associated with (a change in) personal recovery of involuntarily admitted patients. Further research is necessary on how to organize recovery oriented care in inpatient settings and how to enhance providers' competencies in a sustainable way. PMID- 29277106 TI - Factors associated with parents' levels of stress in pediatric wards. AB - Hospitalization of a child is a stressful experience, increasing parents' anxiety and deteriorating their satisfaction with the health-care services. This study aimed to assess the level of stress that parents of hospitalized children experienced and evaluate the association of parent's stress and satisfaction and identify its predictors. Three hundred and fifty-two parents whose children were hospitalized in two pediatric hospitals were enrolled in the study, from February 2015 to April 2015. The Perceived Stress Scale was used to estimate parental stress and the Pyramid Questionnaire was used for assessing parents' overall satisfaction with care. Parents expressed mild to moderate overall levels of stress. Less-stressed parents felt more satisfied. Being single ( p < .001), having lower educational level ( p = .005), one's child been hospitalized for more than 14 days ( p = .001), and one's have visited the hospital many times in the past ( p = .014) were the predictors of experiencing high levels of stress. During pediatric hospitalization, parental needs (communication, interpersonal health care, continuous information, involvement in child's care) should be considered, so as stress levels to be decreased and parents get more satisfied by the quality of health care provided. PMID- 29277107 TI - A systematic evidence synthesis of interventions to engage children and young people in consultations about their long-term conditions. AB - Children and young people with long-term conditions are not always provided with opportunities to engage fully in consultations. This systematic review examined the effectiveness or worth of methods used to engage children and young people with long-term conditions in their consultations. Searches were undertaken in October 2016 in eight databases and of the grey literature. Two reviewers independently screened the results, extracted data and assessed the quality of the studies using a validated and reliable checklist. A narrative synthesis of mixed method data was undertaken. Twelve studies were included in the review. Interventions used to engage children and young people mainly focused on face-to face outpatient consultations, with an emphasis on diabetes and asthma. Most of the interventions focused on either improving health professionals' communication skills or encouraging children's and young people's engagement through providing condition-related information or a structured way to be included in consultations. Fewer interventions were child-led or directed towards developing children's and young people's skills to become key reporters of their condition. This review has demonstrated that interventions targeted at children and young people with long-term conditions can improve their levels of engagement in consultations. There is a need for more systematic development and robust evaluation of interventions to improve children's active participation in consultations. PMID- 29277108 TI - Clinical Excellence in Palliative Care: Examples From the Published Literature. AB - BACKGROUND: With the expansion of palliative care, the concept of clinical excellence is worthy of study and has not been described well in the literature. OBJECTIVE: To apply the domains of clinical excellence, as proposed and published by the Miller Coulson Academy of Clinical Excellence, to the field of palliative care. DESIGN: Review of the literature to identify episodes of superb palliative care delivered by individuals and teams. MEASUREMENT AND MAIN RESULTS: In reviewing 821 publications, we found multiple palliative care case reports to serve as exemplars for each of the distinct domains of clinical excellence. CONCLUSIONS: The domains of excellence are relevant and applicable to the field of palliative care. This article aims to inspire clinicians-and advance the field by promoting thoughtful reflection on what clinical excellence in palliative care entails. PMID- 29277109 TI - Collective narrative practice with unaccompanied refugee minors: "The Tree of Life" as a response to hardship. AB - During the summer of 2016, in the midst of one of the biggest refugee crises in centuries, the author of this article joined the team from a shelter for unaccompanied refugee minors on Samos, Greece, in an effort to provide young boys seeking asylum in Europe with an opportunity to engage in speaking about the difficulties they have encountered in life. The team used a collective narrative methodology called the "Tree of Life", originally developed by Ncube-Mlilo and Denborough. In addition to traditional psychological treatments, collective narrative practice creates a secure foundation for addressing trauma, suffering, and hardship. This approach takes into consideration cultural differences and is easy to access for refugees with perceived stigma of traditional mental health services. The Tree of Life is a minimum of 8-hour workshop involving a strength based narrative methodology, using the tree as a metaphor. This enables participants to share and develop enriching stories about their lives, which are rooted in their cultural and social histories. The workshop conducted on Samos proved to be an effective way to invite young unaccompanied minors to speak about their difficulties in ways that were not retraumatizing, but instead made them stronger. PMID- 29277111 TI - The Value of Motion: Patient-Reported Outcome Measures Are Correlated With Range of Motion in Total Ankle Replacement. AB - BACKGROUND: The proposed benefit of total ankle replacement (TAR) over ankle fusion is preserved ankle motion, thus we hypothesized that an increase in range of motion (ROM) is positively correlated with validated patient-reported outcome measures (PROMs) in individuals receiving TAR. METHODS: Patients undergoing TAR at a single academic medical center between 2007 and 2013 were evaluated in this study. In addition to a minimum of 2-year follow-up, complete preoperative and postoperative outcome measures for the Foot and Ankle Disability Index (FADI), Short Musculoskeletal Function Assessment (SMFA) Bother and Function Indices, Visual Analog Scale (VAS), and 36-Item Short Form Health Survey (SF-36) were requisite for inclusion. Standardized weightbearing maximum dorsiflexion and plantarflexion sagittal radiographs were obtained and previously described ankle and foot measurements were performed to determine ankle ROM. RESULTS: Eighty eight patients met inclusion criteria (33 INBONE, 18 Salto-Talaris, 37 STAR). Mean time to final ROM radiographs was 43.8 months (range 24-89 months). All aforementioned PROMs improved between preoperative evaluation and most recent follow-up ( P < .01). Final ankle ROM was significantly correlated with postoperative FADI, SF-36 Mental Component Summary (MCS), SMFA Bother and Function Indices, and VAS. Additionally, dorsiflexion was positively associated with FADI, SF-36 MCS, and SMFA Function ( P < .05) but plantarflexion had no such influence on outcomes. No differences were identified with subset stratification by prosthesis type, fixed versus mobile-bearing design or etiology. CONCLUSION: In this TAR cohort with prospectively collected outcomes data, radiographic sagittal plane ankle motion was positively correlated with multiple PROMs. Disease-specific and generic health-related quality of life PROMs demonstrated improvement postoperatively in all domains when evaluating final total range of motion. Patients who undergo TAR for end-stage osteoarthritis with improvement in ROM demonstrate a direct correlation with improved patient-centric metrics and outcome scores. LEVELS OF EVIDENCE: Level III: Retrospective comparative study. PMID- 29277112 TI - Exploring of bioactive compounds in essential oil acquired from the stem and root derivatives of Hypericum triquetrifolium callus cultures. AB - The chemical profile of the essential oil of callus and cell suspension cultures derivatives from stem and root of Hypericum triquetrifolium were explored by ITEX/GC-MS. The major constituents for stem derivatives were undecane (78.44%) and 2,4,6-trimethyl-octane (9.74%) for fresh calli, 2,4-dimethyl-benzaldehyde (46.94%), 2,3-dimethyl-undecane (28.39%), 2,4-dimethyl-1-hexene (10.17%), 1,2 oxolinalool (3.64%) and limonene (3.55%) for dry calli and undecane (61.24%), octane, 2,4,6-trimethyl- (16.73%), nonane, 3-methyl-(3.74%), 2,5-diphenyl benzoquinone (3.70%) and limonene (3.60%) for cell suspension. However, for root derivatives, the dominated components were: undecane (49.94%), eucalyptol (12.07%), limonene (9.98%), toluene (9.03%) and 3-methyl-nonane (4.29%) for fresh calli, 2,4-dimethyl-benzaldehyde (29.80%), 1,1-dimethylethyl-cyclohexane (14.99%), 3-methyl-pentanal (14.99%), undecane (10.04%), beta-terpinyl acetate (8.60%), 1,2-oxolinalool (6.27%) and 2-pentyl-furan (4.09%) for dry calli, undecane (52.38%), 2,4,6-trimethyl-octane (13.81%), 3-methyl-nonane (5.73%), toluene (4.82%) and limonene (4.57%) for cell suspension derivative in root. The attained outcomes indicated that the alkane, aldehyde and monoterpene fractions dominated the chemical composition of essential oils. PMID- 29277113 TI - The downregulation of sweet taste receptor signaling in enteroendocrine L-cells mediates 3-deoxyglucosone-induced attenuation of high glucose-stimulated GLP-1 secretion. AB - CONTEXT: Sweet taste receptors (STRs) involve in regulating the release of glucose-stimulated glucagon-like peptide-1 (GLP-1). Our in vivo and in vitro studies found that 3-deoxyglucosone (3DG) inhibited glucose-stimulated GLP-1 secretion. OBJECTIVE: This study investigated the role of STRs in 3DG-induced inhibition of high glucose-stimulated GLP-1 secretion. METHODS: STC-1 cells were incubated with lactisole or 3DG for 1 h under 25 mM glucose conditions. Western blotting was used to study the expression of STRs signaling molecules and ELISA was used to analyse GLP-1 and cyclic adenosine monophosphate (cAMP) levels. RESULTS: Lactisole inhibited GLP-1 secretion. Exposure to 25 mM glucose increased the expressions of STRs subunits when compared with 5.6 mM glucose. 3DG decreased GLP-1 secretion and STRs subunits expressions, with affecting other components of STRs pathway, including the downregulation of transient receptor potential cation channel subfamily M member 5 (TRPM5) expression and the reduction of intracellular cAMP levels. CONCLUSION: 3DG attenuates high glucose-stimulated GLP 1 secretion by reducing STR subunit expression and downstream signaling components. PMID- 29277114 TI - Developing a falls prevention program for community-dwelling stroke survivors in Singapore: client and caregiver perspectives. AB - PURPOSE: Drawing on the perspectives of stroke survivors, family members and domestic helpers, this study explores participants' experiences of self-perceived fall risk factors after stroke, common fall prevention strategies used, and challenges to community participation after a fall. METHODS: Semi-structured interviews were conducted in Singapore with community-dwelling stroke survivors with a previous fall (n = 9), family caregivers (n = 4), and domestic helpers (n = 4) who have cared for a stroke survivor with a previous fall. Purposive sampling was used for recruitment; all interviews were audio-recorded with permission and transcribed. Thematic analysis was conducted using NVivo (v10) software. RESULTS: All participants shared their self-perceived intrinsic and extrinsic fall risk factors and main challenges after a fall. For stroke participants and family caregivers, motivational factors in developing safety strategies after a previous fall(s) include social connectedness, independent living and community participation. For family caregivers and domestic helpers, the stroke survivor's safety is their top priority, however this can also lead to over-protective behavior outside of the rehabilitation process. CONCLUSIONS: Reducing the risk of falls in community-dwelling stroke survivors seems to be more important than promoting community participation among caregivers. The study findings highlight that a structured and client-centered fall prevention program targeting stroke survivors and caregivers is needed in Singapore. Implications for rehabilitation Falls after stroke can lead to functional decline in gait and mobility and restricted self-care activities. Community-dwelling stroke survivors develop adaptive safety strategies after a fall and want to be socially connected. However, caregivers see the safety of the stroke survivors as their top priority and demonstrate over-protective behaviors. Fall prevention programs for community-dwelling stroke survivors should target both stroke survivors and their caregivers. A structured and client-centered fall prevention program targeting at multiple risk factors post-stroke is needed for community-living stroke survivors. PMID- 29277116 TI - Trixis angustifolia hexanic extract displays synergistic antibacterial activity against M. tuberculosis. AB - A phytochemical and antibacterial study of Trixis angustifolia, a species endemic to Mexico, was performed allowing the isolation of six flavones. The minimal inhibitory concentration (MIC) of the hexanic extract, against Mycobacterium tuberculosis H37Rv was 25 MUg/mL. The hexanic extract caused a significant inhibition of intracellular mycobacterial growth at 12.5 MUg/mL. The biodirected assay of hexane extract enabled the detection of an active fraction (AF) against M. tuberculosis (MIC = 12.5 MUg/mL), and a major flavone 1 (pebrellin) with no antimycobacterial activity (MIC > 200 MUg/mL). A subsequent combination antimicrobial assay showed a synergistic antimycobacterial effect of AF in combination with pebrellin; the results of the synergistic activity suggest that the antimycobacterial activity found in T. angustifolia is due to the combined action of diverse metabolites present in the plant. PMID- 29277115 TI - Pre-diagnostic plasma urate and the risk of amyotrophic lateral sclerosis. AB - OBJECTIVE: To prospectively examine for the first time the association between plasma urate levels measured in healthy participants and future amyotrophic lateral sclerosis (ALS) risk. METHODS: A pooled case-control study nested in five US prospective cohorts comprising 319,617 participants who provided blood, of which 275 had ALS during follow-up. Pre-diagnostic plasma urate was determined for all participants using a clinical colorimetric enzyme assay. Gender-specific multivariable-adjusted rate ratios (RR) of ALS incidence or death estimated by conditional logistic regression and pooled using inverse-variance weighting. RESULTS: In age- and matching factor-adjusted analyses, a 1 mg/dL increase in urate concentration was associated with RR = 0.88 (95% CI: [0.78, 0.997] p = 0.044). After adjustment for BMI, a strong predictor of ALS and urate levels, and other potential covariates, the RR = 0.89 (95% CI: [0.78, 1.02]; p = 0.08 for 1mg/dL increase in urate). CONCLUSION: Elevation of plasma urate was modestly inversely associated with the risk of ALS and warrants further study for a potential role in this disease. PMID- 29277117 TI - Sex differences and the influence of social factors in a Chilean urban psychiatric hospital population. AB - BACKGROUND: The epidemiological literature has reported differences by sex in the prevalence of psychiatric diagnoses. However, we know little about how other socio-demographic factors participate in these differences. AIM: To identify the socio-demographic factors that correlate with prevalent psychiatric diagnoses in women and men in a Chilean urban psychiatric hospital population. METHOD: Socio demographic information (age, educational level, marital status, family group and work status), psychiatric diagnoses and sex of the population were collected for 3,920 patients of a tertiary care hospital during a period of 8 years (2007 2014). The data were subjected to bivariate and multivariate analyses comparing the results by sex. RESULTS: Among the most prevalent psychiatric diagnoses, those significantly correlated with sex were eating disorders and major depression (women) and schizophrenia (men). Socio-demographic factors behave differently in men and women regarding those diagnoses. Among the differences, working and being married correlated directly with the diagnosis of depression only among women. Living alone correlated directly with the diagnosis of schizophrenia among men, but correlated inversely among women. CONCLUSION: Dissimilar associations between sex, psychiatric diagnosis and socio-demographic factors found in this Latin American sample invite us to reflect on how social conditions crosscut the relation between sex and psychopathology and to include gender perspectives in psychiatric practices. PMID- 29277119 TI - Brain-derived neurotropic factor (BDNF) heterozygous mice are more susceptible to synaptic protein loss in cerebral cortex during high fat diet. AB - In this study we aimed to investigate whether reduced BDNF levels aggravate the susceptibility of the brain to hazardous effects of high fat diet. For this purpose, we fed BDNF heterozygous mice and wild type littermates with normal and high fat diet for 16 weeks. Concentrations of two synaptic proteins (SNAP-25 and PSD-95) and oxidative stress parameters (MDA, SOD, CAT) were evaluated in the cortex after diet period. Interestingly, body weights of BDNF heterozygous groups fed with control diet were higher than their littermates and heterozygous mice fed with HFD were the heaviest in all experimental groups. MDA levels were significantly elevated in both HFD groups (wild type and BDNF(+/-)). Synaptic markers PSD-95 and SNAP-25 markedly decreased in BDNF(+/-) group fed with HFD compared to other groups. In conclusion, we suggest that endogenous BDNF has an important and possibly protective role in diet-induced changes in the cortex. PMID- 29277120 TI - Body Composition in Adults With Intellectual Disabilities: Implications for Practice. AB - Health care professionals require increased knowledge of health and disabilities to effectively implement health promotion initiatives at both the individual and group level for adults with intellectual disabilities (ID). The aim of this review is to examine the feasibility, reliability, and validity of various field based measurements to assess body composition among adults with ID as compared to nondisabled controls. The literature was systematically searched from 1990 to 2017 for primary articles pertaining to the subject matter that were published in the English language and included only individuals >=18 years of age. 1,989 studies were screened and 8 studies were included for review. Several field-based measurements for body composition are feasible and reliable yet none have been validated for use in adults with ID. Awareness of the various methods for assessing body composition in adults with ID in clinical practice, while simultaneously understanding their limitations, is necessary. PMID- 29277118 TI - Design and evaluation of dental films of PEGylated rosin derivatives containing sparfloxacin for periodontitis. AB - OBJECTIVE: In this study, PEGylated rosin derivatives (PRDs) namely D1 and D2 were synthesized and evaluated for their application to produce sustained-release antibacterial films containing sparfloxacin for periodontitis. SIGNIFICANCE: PRDs are biodegradable and biocompatible, and therefore sustained-release dental implant of PRD-sparfloxacin can provide an effectual treatment for periodontitis. METHODS: Films were produced by solvent casting technique and characterized for morphology, swelling-index, in vitro degradation and drug release kinetics. The impact of type of PRD, concentration of PRDs, and addition of plasticizer (dibutyl phthalate) on various film properties was evaluated. The films were also subjected to stability study at 30 degrees C and 40 degrees C for 90 days. RESULTS: Both D1 and D2 produced smooth and non-porous films with sparfloxacin. The D1 films, due to lower amount of polyethylene glycol 400 in D1, exhibited lower swelling-index, slower degradation, and slower drug release compared to D2 films. An increase in PRDs concentration decreased swelling-index, prolonged degradation time, and decreased drug release rate of films; addition of plasticizer showed the similar effect. At pH 7.6, D1 and D2 films showed complete degradation at the end of 58 and 51 days, respectively. At the end of 21 days, D1 and D2 films released 41.85% and 61.53% sparfloxacin, respectively. The drug release from D1 films followed Higuchi square-root kinetics, while D2 films released drug by the zero order kinetics. The stability conditions did not significantly alter PRDs-film properties. CONCLUSION: Results revealed that PRDs can be used successfully to produce sustained-release antibacterial films containing sparfloxacin for the treatment of periodontitis. PMID- 29277121 TI - Do patients value a hospital's innovativeness reputation? A multi-method approach to assess the relative importance of innovativeness reputation in patients' hospital choice. AB - Innovations in health care are costly and risky, but they also provide the opportunity for hospitals to increase quality of care, to distinguish themselves from competitors and to attract patients. While numerous hospitals strive to increase their innovativeness by adopting a costly innovation leader strategy, the question of whether this actually influences the patient's choice remains unanswered. To understand the role of innovativeness from the patient perspective, this study conceptualizes the construct of innovativeness reputation of hospitals and determines its relevance in patients' hospital choice decisions. In the pretest, we identified six dimensions of innovativeness reputation such as progressive work procedures and value added services. We then used three different quantitative multi-criteria decision-making methods to evaluate the relative importance of innovativeness reputation in patient choice. We collected data from 355 former German patients who had undergone elective non-emergency surgery. Overall, innovativeness reputation accounts for 11.6%-16.8% of the patient decision. Innovativeness reputation has a moderate influence on hospital choice and should be taken into account by managers. Since technical innovations are costly, hospitals should use other means to enhance their innovative image. Strategies such as emphasizing value added services can enable hospitals to increase their innovativeness reputation efficiently. PMID- 29277122 TI - Effects of Minimally Invasive Surgery for Patients With OSA on Quality of Life. AB - OBJECTIVE: To retrospectively study the effects of minimally invasive single stage multilevel surgery (MISS MLS) for treating patients with obstructive sleep apnea/hypopnea syndrome (OSA) on quality of life (QOL). METHODS: All OSA patients with multilevel obstruction who failed or refused continuous positive airway pressure (CPAP) treatment and then underwent Pillar implants and temperature controlled radiofrequency of the base of tongue (RFBOT) were enrolled. The subjective symptoms and QOL (SF-36 Taiwan Standard Version 1.0) parameters were collected preoperatively and a minimum of 3 months postoperatively. Postoperative morbidity and complications were also recorded. RESULTS: Thirty-seven patients (30 men, 7 women; mean age = 46.8 years; mean BMI = 23.9 kg/m2) were enrolled. The mean Epworth Sleepiness Scale changed from 12 +/- 4.3 to 10.6 +/- 4.3 ( P = .004, Wilcoxon signed-rank test). The mean snoring visual analog scale reduced from 9.5 +/- 1.3 to 4.0 +/- 2.0 ( P < .0001). The mean score of SF-36 increased from 65.5 +/- 19.6 to 75.2 +/- 16.7 ( P = .001). The SF-36 subscales showed statistically significant changes, especially in bodily pain, role-emotional, and general health. CONCLUSION: The study demonstrated that MISS MLS was effective on QOL in selected patients for treating OSA patients who are unresponsive to conservative OSA therapy. PMID- 29277124 TI - The Art of Health Promotion: Linking research to practice. PMID- 29277123 TI - Why Health Promotion Needs to Change. AB - If you ask most health professionals why they do what they do, they invariably speak of being of service. And being of service, for population health workers, becomes ever more meaningful as our work touches ever more lives. To wit, "Kaizen," a Japanese term meaning "change for better," sits shoulder to shoulder with our life's purpose. Health promotion professionals are high performers getting great results but we need to start working on our work. What would it take to increase our impact by 50%? And when we change our processes to accomplish that, what would we change next to get another 50% improvement? Only by stepping back and examining our processes can we see the time and motion required to make what's working now work better and be more accessible to more people next time. PMID- 29277125 TI - The Effect of Cost Sharing on an Employee Weight Loss Program: A Randomized Trial. AB - PURPOSE: To test the effects of employer subsidies on employee enrollment, attendance, and weight loss in a nationally available weight management program. DESIGN: A randomized trial tested the impact of employer subsidy: 100%; 80%, 50%, and a hybrid 50% subsidy that could become a 100% subsidy by attaining attendance targets. TRIAL REGISTRATION: NCT01756066. SETTING AND PARTICIPANTS: Twenty three thousand twenty-three employees of 2 US companies. MEASURES: The primary outcome was the percentage of employees who enrolled in the weight management program. We also tested whether the subsidies were associated with differential attendance and weight loss over 12 months, as might be predicted by the expectation that they attract employees with differing degrees of motivation. Analysis and Results: Enrollment differed significantly by subsidy level ( P < .0001). The 100% subsidy produced the highest enrollment (7.7%), significantly higher than each of the lower subsidies (vs 80% subsidy: 6.2%, P = .002; vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Enrollment in the 80% subsidy group was significantly higher than both lower subsidy groups (vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Among enrollees, there were no differences among the 4 groups in attendance or weight loss. CONCLUSION: This pragmatic trial, conducted in a real-world workplace setting, suggests that higher rates of employer subsidization help individuals to enroll in weight loss programs, without a decrement in program effectiveness. Future research could explore the cost-effectiveness of such subsidies or alternative designs. PMID- 29277126 TI - Youth Access to School Salad Bars in the United States-2011 to 2014. AB - PURPOSE: To examine differences in students' access to school salad bars across sociodemographic groups and changes in availability over time. DESIGN: Nonexperimental. SETTING: Nationally representative 2011 and 2014 YouthStyles surveys. PARTICIPANTS: A total of 833 (2011) and 994 (2014) US youth aged 12 to 17 years. MEASURES: Youth-reported availability of school salad bars. ANALYSIS: Multivariable logistic regression models were used to assess differences in school salad bar availability by sociodemographics and changes in availability from 2011 to 2014. RESULTS: Youth-reported salad bar availability differed by age in 2011 and race/ethnicity in 2014, but not by sex, income, metropolitan residence, or region in either year. Salad bars were reported by 62% of youth in 2011 and 67% in 2014; the increase was not statistically significant ( P = .07). Significant increases from 2011 to 2014 were noted among youth aged 12 to 14 years (56%-69%; P < .01), youth of non-Hispanic other races (60%-85%; P < .01), and youth in the Midwest (58%-72%; P = .01). CONCLUSION: These results suggest that youth-reported access to school salad bars does not differ significantly across most sociodemographic groups. Although overall salad bar availability did not increase significantly from 2011 to 2014, some increases were observed among subgroups. Continued efforts to promote school salad bars through initiatives such as Let's Move Salad Bars to Schools could help increase access for the nearly one-third of US youth reporting no access. PMID- 29277130 TI - An Interdisciplinary Academic Detailing Approach to Decrease Inappropriate Medication Prescribing by Physician Residents for Older Veterans Treated in the Emergency Department. AB - OBJECTIVE: To evaluate the impact of an academic detailing intervention delivered as part of a quality improvement project by a physician-pharmacist pair on (1) self-reported confidence in prescribing for older adults and (2) rates of potentially inappropriate medications (PIMs) prescribed to older adults by physician residents in a Veteran Affairs emergency department (ED). METHODS: This quality improvement project at a single site utilized a questionnaire that assessed knowledge of Beers Criteria, self-perceived barriers to appropriate prescribing in older adults, and self-rated confidence in ability to prescribe in older adults which was administered to physician residents before and after academic detailing delivered during their emergency medicine rotation. PIM rates in the resident cohort who received the academic detailing were compared to residents who did not receive the intervention. RESULTS: Sixty-three residents received the intervention between February 2013 and December 2014. At baseline, approximately 50% of the residents surveyed reported never hearing about nor using the Beers Criteria. A significantly greater proportion of residents agreed or strongly agreed in their abilities to identify drug-disease interactions and to prescribe the appropriate medication for the older adult after receiving the intervention. The resident cohort who received the educational intervention was less likely to prescribe a PIM when compared to the untrained resident cohort with a rate ratio of 0.73 ( P < .0001). CONCLUSION: Academic detailing led by a physician-pharmacist pair resulted in improved confidence in physician residents' ability to prescribe safely in an older adult ED population and was associated with a statistically significant decrease in PIM rates. PMID- 29277131 TI - Direct comparison of vasectomized males and genetically sterile Gapdhs knockout males for the induction of pseudopregnancy in mice. AB - The laboratory mouse is the most used animal model in biomedical research. Several artificial reproductive techniques, such as revitalization of cryopreserved strains, rederivation after hygienic contaminations and the production of transgenic mouse models, require the transfer of preimplantation embryos to surrogate mothers. Pseudopregnancy is essential in recipient females and is induced by mating with sterile males. Commonly, surgically vasectomized males are used for this purpose. As an alternative, genetically modified mouse strains have been identified, in which homozygous infertile males are sexually active. Here, we investigated the suitability of genetically infertile Gapdhstm1Dao males under routine laboratory conditions with respect to plug rates, pregnancy rates and frequency of born offspring after embryo transfer. Our results showed no significant differences for these aspects between Gapdhstm1Dao and vasectomized CD2F1 males. In addition, we evaluated the efforts to obtain a defined number of sterile males either by breeding of sterile mutants or surgical vasectomy, and addressed the impact of both options on animal welfare. In conclusion, infertile males of the Gapdhstm1Dao line are a reliable alternative to vasectomized males for the induction of pseudopregnancy, and can contribute to the refinement of the procedure by avoiding surgical interventions. PMID- 29277132 TI - A Second-Order Confirmatory Factor Analysis of the Moral Distress Scale-Revised for Nurses. AB - BACKGROUND: Moral distress is a growing problem for healthcare professionals that may lead to dissatisfaction, resignation, or occupational burnout if left unattended, and nurses experience different levels of this phenomenon. OBJECTIVES: This study aims to investigate the factor structure of the Persian version of the Moral Distress Scale-Revised in intensive care and general nurses. RESEARCH DESIGN: This methodological research was conducted with 771 nurses from eight hospitals in the Mazandaran Province of Iran in 2017. Participants completed the Moral Distress Scale-Revised, data collected, and factor structure assessed using the construct, convergent, and divergent validity methods. The reliability of the scale was assessed using internal consistency (Cronbach's alpha, Theta, and McDonald's omega coefficients) and construct reliability. Ethical considerations: This study was approved by the Ethics Committee of Mazandaran University of Medical Sciences. FINDINGS: The exploratory factor analysis ( N = 380) showed that the Moral Distress Scale-Revised has five factors: lack of professional competence at work, ignoring ethical issues and patient conditions, futile care, carrying out the physician's orders without question and unsafe care, and providing care under personal and organizational pressures, which explained 56.62% of the overall variance. The confirmatory factor analysis ( N = 391) supported the five-factor solution and the second order latent factor model. The first-order model did not show a favorable convergent and divergent validity. Ultimately, the Moral Distress Scale-Revised was found to have a favorable internal consistency and construct reliability. DISCUSSION AND CONCLUSION: The Moral Distress Scale-Revised was found to be a multidimensional construct. The data obtained confirmed the hypothesis of the factor structure model with a latent second-order variable. Since the convergent and divergent validity of the scale were not confirmed in this study, further assessment is necessary in future studies. PMID- 29277133 TI - Tinzaparin in intermediate dose for the treatment of superficial vein thrombosis: Results from an observational multicenter study-SeVEN study. AB - Objectives Low-molecular-weight heparins are recommended in the treatment of superficial vein thrombosis but with low grade of evidence. This study was conducted to assess the treatment outcomes of acute superficial vein thrombosis with intermediate dose of Tinzaparin. Methods Retrospective analysis of records from outpatients over a period of 16 months treated in seven centers with Tinzaparin 0.5 ml (10,000 anti-Xa IU) once daily for a period that was at the treating physician's discretion. All the patients were followed up for at least 12 weeks. Results A total of 296 patients (189 females, mean age 57.4 years) were included. Two thirds of the patients (191/296, 64.5%) received treatment for approximately five weeks (mean 36.9 days) and the remaining (105/296, 35.5%) for a shorter period (mean 16.2 days). There was no difference in patients' characteristics between the two treatment duration groups. The presence of thrombus above the knee and restricted daily activity were associated with longer period of treatment. Only one case with minor bleeding was observed. Recurrence of thrombosis over a 12-week follow-up period occurred in 6% (superficial vein thrombosis in 14 (4.7%), deep vein thrombosis in 3 (1%) and thrombus extension in the superficial veins in 1 (0.3%)). Recurrence was not related to the duration of treatment. Conclusions Intermediate dose of Tinzaparin was an effective and safe treatment for superficial vein thrombosis in the setting of real world practice. Location of thrombus and status of patients' mobilization were associated with longer duration of treatment. Future prospective randomized studies are needed to corroborate these findings. PMID- 29277135 TI - Mixed language dominance: insights from a case of unexpected fluent aphasia with semantic jargon resulting from massive left perisylvian lesion. AB - We report a right-handed patient with a massive lesion in left perisylvian language cortex, who unexpectedly presented with fluent aphasia with semantic jargon. Language deficits were assessed with a comprehensive battery of language tests. Comprehension, naming, reading, and writing were severely impaired, and verbal expression was moderately fluent with semantic jargon. Although the patient's lesion included brain areas typically essential for motor speech coordination, he was neither nonfluent nor apraxic. He exhibited strikingly unexpected aphasia with semantic jargon and prominent comprehension deficits, suggesting that this is a case of mixed dominance: the right hemisphere likely controls motor speech and basic syntactic skills, while the severely damaged left hemisphere controls semantic processing, predictably severely impaired. PMID- 29277134 TI - Customizing elastic pressure bandages for reuse to a predetermined, sub-bandage pressure: A randomized controlled trial. AB - Objective A randomized clinical trial was performed to compare the effectiveness of unmarked bandages and customized bandages with visual markers in reproducing the desired sub-bandage pressure during self-bandaging by patients. Method Ninety patients were randomly allocated to two groups ("customized bandages" and "unmarked bandages") and asked to perform self-bandaging three times. The achievement of a pressure between 35 and 45 mmHg in at least two of the three attempts was defined as adequate quality. Results Adequate quality was achieved by 33.0% when applying the unmarked bandages, and 60.0% when applying the customized bandages ( p = 0.02). Use of the customized bandage and previous experience of bandaging were independent predictors for the achievement of the predetermined sub-bandage pressure ( p = 0.005 and p = 0.021, respectively). Conclusion Customized bandages may achieve predetermined sub-bandage pressures more closely than standard, unmarked, compression bandages. Clinical trials registration ClinicalTrials.gov (NCT02729688). Effectiveness of a Pressure Indicator Guided and a Conventional Bandaging in Treatment of Venous Leg Ulcer. https://clinicaltrials.gov/ct2/show/NCT02729688. PMID- 29277136 TI - Optimal Timing for Laparoscopic Cholecystectomy After Endoscopic Retrograde Cholangiopancreatography: A Systematic Review. AB - BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy is often used as definitive treatment for common bile duct stones. The aim of this study was to investigate the optimal time interval between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. MATERIALS AND METHODS: PubMed and Embase were searched for studies comparing different time delays between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. Observational studies and randomized controlled trials were included. Primary outcome was conversion rate from laparoscopic to open cholecystectomy and secondary outcomes were complications, mortality, operating time, and length of stay. RESULTS: A total of 14 studies with a total of 1930 patients were included. The pooled estimate revealed an increase from a 4.2% conversion rate when laparoscopic cholecystectomy was performed within 24 h of endoscopic retrograde cholangiopancreatography to 7.6% for 24-72 h delay to 12.3% when performed within 2 weeks, to 12.3% for 2-6 weeks, and to a 14% conversion rate when operation was delayed more than 6 weeks. CONCLUSION: According to this systematic review, it is preferable to perform cholecystectomy within 24 h of endoscopic retrograde cholangiopancreatography to reduce conversion rate. Early laparoscopic cholecystectomy does not increase mortality, perioperative complications, or length of stay and on the contrary it reduces the risk of reoccurrence and progression of disease in the delay between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. PMID- 29277137 TI - Effects of Stress on Critical Care Nurses: A National Cross-Sectional Study. AB - BACKGROUND: Health care is a demanding field, with a high level of responsibility and exposure to emotional and physical danger. High levels of stress may result in depression, anxiety, burnout syndrome, and in extreme cases, post-traumatic stress disorder. The aim of this study was to determine which personal, professional, and organizational variables are associated with greater perceived stress among critical care nurses for purposes of developing integrative solutions to decrease stress in the future. METHODS: We conducted a correlation research survey using a cross-sectional design and an in-person survey method. The questionnaire consisted of 2 parts: (1) socioeconomic, professional, and institutional variables and (2) work stressors. Surveys were conducted between January 1, 2011, and December 1, 2015. Multistage cluster random sampling was utilized for data collection. Inclusion criteria were (1) age >=18 years, (2) registered nurse, (3) works in the intensive care unit (ICU), and (4) willing and able to complete the survey. RESULTS: We surveyed 21 767 ICU nurses in Iran and found that male sex, lower levels of peer collaboration, working with a supervisor in the unit, nurse-patient ratios, and working in a surgical ICU were positively associated with greater stress levels. Increasing age and married status were negatively associated with stress. Intensive care unit type (semi closed vs open), ICU bed number, shift time, working on holidays, education level, and demographic factors including body mass index, and number of children were not significantly associated with stress levels. CONCLUSION: As the largest study of its kind, these findings support those found in various European, North, and South American studies. Efforts to decrease workplace stress of ICU nurses by focusing on facilitating peer collaboration, improving resource availability, and staffing ratios are likely to show the greatest impact on stress levels. PMID- 29277138 TI - Electroconvulsive Therapy: The Impact of a Brief Educational Intervention on Public Knowledge and Attitudes. AB - The safety and efficacy of electroconvulsive therapy (ECT) are well established, yet efforts to educate the public about ECT advancements are lagging. The purpose of this study was to experimentally examine the impact of a brief educational intervention on public knowledge of, and attitudes toward, ECT. Participants ( n = 91) from a private liberal arts university in the upper Midwestern region of the United States were randomly assigned to either an educational intervention or a control group. The educational intervention group read a brief informational pamphlet about ECT. Both groups completed a 24-item ECT knowledge and attitude measure. Participants who read the ECT pamphlet demonstrated significantly higher levels of ECT knowledge and reported more favorable attitudes toward ECT than did the control group. Furthermore, knowledge of ECT significantly predicted attitudes toward the treatment. Educating the public about available medical treatments not only facilitates help-seeking behavior among prospective patients and their families, but also it hallmarks the informed consent process once help is sought. PMID- 29277139 TI - Perception and Practices of Nomadic Women in a Rural Community in Southwestern Nigeria to Their Children's Oral Health. AB - Introduction Nomads move from one settlement to another, thus it has been difficult to have adequate documentation about their oral health and that of their children. Aim To investigate the perception and practices of nomadic Fulani women toward their children's oral health. Methodology A cross-sectional study was conducted among 197 Fulani women using a structured interviewer administered questionnaire. Results Perceived causes of tooth decay included tooth germs/worms (23.9%) and sugar (5.1%), and 32.0%, 15.2%, and 5.1%, respectively, self medicated children with antibiotics, traditional concoctions/herbs, and analgesics for tooth decay. Two fifths (40.1%) attributed bleeding gums to tooth germs/worms. Polyurethane foam (46.7%), toothbrush (32.0%), finger (18.8%), and wooden twigs (2.5%) were aids used for cleaning children's teeth. Conclusions These mothers have suboptimal oral health knowledge, attitudes, and practices toward their children's oral health. There is a need for urgent intervention among this group of people. PMID- 29277141 TI - In silico studies of conformational dynamics of Mu opioid receptor performed using gaussian accelerated molecular dynamics. AB - G-protein-coupled receptors play a crucial role in various signaling pathways and function as targets for treating a wide spectrum of diseases. Since the twentieth century, extensive research has been conducted on the Mu opioid receptor (MOR) as a drug target. We examined the MOR inactivation and activation processes using an enhanced sampling method (Gaussian accelerated molecular dynamics), the binding pocket site area method, the root mean square deviation method, and the free energy (potential of mean force) method. This study revealed two important intermediate MOR structures (intermediate and intermediate inactive), and the results suggest that the intermediate MOR structure is responsible for the selectivity of opioids. PMID- 29277142 TI - Carriage of multidrug-resistant bacteria among pediatric patients before and during their hospitalization in a tertiary pediatric unit in Tunisia. AB - The pandemic spread of multidrug-resistant (MDR) bacteria (i.e., methicillin resistant Staphylococcus aureus (MRSA), extended-spectrum b-lactamase-producing Enterobacteriaceae (ESBLPE), vancomycin-resistant enterococci, carbapenemase producing Enterobacteriaceae (CPE), multiresistant Pseudomonas aeruginosa and multiresistant Acinetobacter baumannii) pose a threat to healthcare Worldwide. We found limited data of MDR bacteria in pediatric patients hospitalized in Tunisian tertiary healthcare.The aim of the study is to evaluate the acquisition rate of MDR acquisition during hospitalization and to explore some of the associated risk factors for both carriage and acquisition at the pediatric department, Sahloul University Hospital. During September and October 2016, newly admitted patients were screened, at admission, during care and at discharge. Risk factors for colonization were explored by multivariate analysis. Of 112 newly admitted patients, 8.92% were colonized with at least one MDR. No risk factor was identified at admission. During hospitalization, five newly acquisition MDR (4.9%) were detected and eight (7.84%) at discharge. The specie most frequently detected on admission was Escherichia coli (50%), whereas, on discharge, Escherichia coli and K. pneumoniae were the species most frequently detected (52.7%). The pediatric intensive care unit (PICU) hospitalization, the length of hospital stay (more than 3days) and age under 2 years were identified as risk factor for acquisition of MDR during hospitalization. We identified several independent risk factors for contracting MDR bacteria during hospitalization in a tertiary pediatric department. The incidence of symptomatic MDR Infection among those colonized should be under close surveillance and long-term screening for those children is required. An institutional screening program for MDR especially in PICU might be discussed in regards to cost effectiveness. PMID- 29277143 TI - Design for success: Identifying a process for transitioning to an intensive online course delivery model in health professions education. AB - : Intensive courses (ICs), or accelerated courses, are gaining popularity in medical and health professions education, particularly as programs adopt e learning models to negotiate challenges of flexibility, space, cost, and time. In 2014, the Department of Clinical Research and Leadership (CRL) at the George Washington University School of Medicine and Health Sciences began the process of transitioning two online 15-week graduate programs to an IC model. Within a year, a third program also transitioned to this model. A literature review yielded little guidance on the process of transitioning from 15-week, traditional models of delivery to IC models, particularly in online learning environments. Correspondingly, this paper describes the process by which CRL transitioned three online graduate programs to an IC model and details best practices for course design and facilitation resulting from our iterative redesign process. Finally, we present lessons-learned for the benefit of other medical and health professions' programs contemplating similar transitions. ABBREVIATIONS: CRL: Department of Clinical Research and Leadership; HSCI: Health Sciences; IC: Intensive course; PD: Program director; QM: Quality Matters. PMID- 29277145 TI - Long-term intravascular follow-up of coronary bifurcation treatment with Absorb bioresorbable vascular scaffold. PMID- 29277146 TI - Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF). AB - Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare disease that causes primary infertility. However, the genetic causes for approximately half of MMAF cases are unknown. Whole exome sequencing analysis of the 27 patients with MMAF identified several CFAP44 mutations (3 homozygous: c.2935_2944del: p.D979*, c.T1769A: p.L590Q, c.2005_2006del: p.M669Vfs*13; and putative compound heterozygous: c.G3262A: p.G1088S and c.C1718A: p.P573H.) and CFAP43 acceptor splice-site deletion (c.3661-2A>-) mutations in 5 and 1 patients, respectively. Real-time quantitative polymerase chain reaction assays also demonstrated that CFAP44 expression was very weak in patient (P)1 and P3, and CFAP43 expression was lower in P6 than in the control. Immunofluorescence analysis of CFAP43 showed lower CFAP43 protein expression levels in P6 than in the normal control. This study demonstrated that biallelic mutations in CFAP44 and CFAP43 cause MMAF. These results provide researchers with a new insight to understand the genetic etiology of MMAF and to identify new loci for genetic counselling of MMAF. PMID- 29277147 TI - Factors That Promote and Hinder Medication Adherence From the Perspective of Inmates in a Provincial Remand Center: A Mixed Methods Study. AB - Effective medication delivery to inmates within correctional facilities is essential for managing symptoms, preventing relapse, slowing disease progression, and enabling recovery. Despite its importance, medication adherence in correctional facilities is poor. This mixed methods study explores the factors that affect medication adherence from the perspective of 20 inmates at a provincial remand center in Alberta, Canada. Themes describing factors that promote or hinder medication adherence emerged: patient-related factors (addiction, social support, insight into disease, and purpose of medications), health care provider-related factors (health care provider attributes and trust in physicians), and correctional setting factors. The findings of this study inform recommendations to improve medication adherence and disease management in correctional facilities. PMID- 29277148 TI - Prostacyclins in Cardiac Surgery: Coming of Age. AB - Prostacyclin (prostaglandin I2 [PGI2]) is an eicosanoid lipid mediator produced by the endothelial cells. It plays pivotal roles in vascular homeostasis by virtue of its potent vasodilatory and antithrombotic effects. Stable pharmacological analogues of PGI2 are used for treatment of pulmonary hypertension and right ventricular failure. PGI2 dose dependently inhibits platelet activation induced by adenosine-5'-diphosphate, arachidonic acid, collagen, and low-dose thrombin. This property has led to its use as an alternative to direct thrombin inhibitors in patients with type II heparin induced thrombocytopenia (HIT) undergoing cardiac surgery. The aims of this review are the following: (1) to review the pharmacology of PGI2 and its derivatives, (2) to present the evidence for their use in pulmonary hypertension and right heart failure, and (3) to discuss their utility in the management of HIT in cardiac surgery. PMID- 29277149 TI - Creation of Data Repositories to Advance Nursing Science. AB - Data repositories are a strategy in line with precision medicine and big data initiatives, and are an efficient way to maximize data utility and form collaborative research relationships. Nurse researchers are uniquely positioned to make a valuable contribution using this strategy. The purpose of this article is to present a review of the benefits and challenges associated with developing data repositories, and to describe the process we used to develop and maintain a data repository in HIV research. Systematic planning, data collection, synthesis, and data sharing have enabled us to conduct robust cross-sectional and longitudinal analyses with more than 200 people living with HIV. Our repository building has also led to collaboration and training, both in and out of our organization. We present a pragmatic and affordable way that nurse scientists can build and maintain a data repository, helping us continue to make to our understanding of health phenomena. PMID- 29277150 TI - E. P. Pope Memorial Award to Dr. Lanny Pace. PMID- 29277153 TI - Strengths and virtues and the development of resilience: A qualitative study in Suriname during a time of economic crisis. AB - BACKGROUND: Resilience can be described as the capacity to deal with adversity and traumatic events. The current economic situation in Suriname and its social economic consequences may demand a great amount of resilience for people living in Suriname. In this explorative study, we examined the relation between strengths and resilience among the three major ethnic groups in Suriname. METHOD: Semi-structured interviews were conducted with 25 participants. We sought to gather viewpoints from community representatives, health care professionals and academic scholars about the personal resources used by people in Suriname to help them deal with the consequences of the current socio-economic crisis. RESULTS: We identified major five strengths that were associated with resilience: religiousness, hope, harmony, acceptance and perseverance. While these strengths contribute to the development of resilience, they can under certain circumstances have an ambiguous influence. CONCLUSION: Our findings suggest that religiousness is the bedrock strength for the development of resilience in Suriname. We recommend that future positive psychological interventions in non-Western countries integrate positive activities with religious elements into program interventions to achieve a better cultural fit. PMID- 29277154 TI - Comparing Behavior and Clock Gene Expression between Caterpillars, Butterflies, and Moths. AB - Circadian behavior is widely observed in insects; however, the mechanisms that drive its evolution remain a black box. While circadian activity rhythms are well characterized in adults within the order Lepidoptera (i.e., most butterfly species are day active, while most moths are night active), much less is known about daily activity and clock gene expression in the larval stage. Additionally, direct comparison of clock gene expression between day-active and night-active species reared together has not been quantified. Our study characterized the daily rhythms of caterpillar feeding and activity in addition to the gene expression of 2 central circadian clock genes, period ( per) and timeless ( tim), in larvae and adults of the day-active butterfly Danaus plexippus and the night active moth Heliothis virescens. We found that neither Danaus nor Heliothis caterpillars are strictly diurnal or nocturnal like their adult counterparts; however, we found that slight rhythms in feeding and activity can arise in response to external forces, such as temperature and host plant. Expression levels differed between genes, between butterfly larvae and adults, and between butterfly and moth species, even though expression levels of both per and tim oscillated with a similar phase over 24 hours across all treatments. Our study, the first of its kind to investigate circadian timekeeper gene expression in 2 life stages and 2 species, highlights interesting differences in core clock gene expression patterns that could have potential downstream effects on circadian rhythms. PMID- 29277155 TI - WNT Takes Two to Tango: Molecular Links between the Circadian Clock and the Cell Cycle in Adult Stem Cells. AB - Like two dancers, the circadian clock and cell cycle are biological oscillators engaged in bidirectional communication, resulting in circadian clock-gated cell division cycles in species ranging from cyanobacteria to mammals. The identified mechanisms for this phenomenon have expanded beyond intracellular molecular coupling components to include intercellular connections. However, detailed molecular mechanisms, dynamics, and physiological functions of the circadian clock and cell cycle as coupled oscillators remain largely unknown. In this review, we discuss current understanding of this connection in light of recent findings that have uncovered intercellular coupling between the circadian clock in Paneth cells and the cell cycle in intestinal stem cells via WNT signaling. This extends the impact of circadian rhythms regulating the timing of cell divisions beyond the intracellular domain of homogenous cell populations into dynamic, multicellular systems. In-depth understanding of the molecular links and dynamics of these two oscillators will identify potential targets and temporal regimens for effective chronotherapy. PMID- 29277156 TI - Supporting Aging-in-Place Well: Findings From a Cluster Analysis of the Reasons for Aging-in-Place and Perceptions of Well-Being. AB - Prior research on gerontology and housing has frequently adopted a perspective that aging-in-place is the "goal." Despite these meaningful results and policy implications, opportunities to explore consequences of aging-in-place, such as the association of this with overall well-being, have been overlooked. This study aims to fill this gap by investigating perceptions of well-being that could act as a driver or result of aging-in-place. With a nationwide random sample of non Hispanic White, older individuals (60+), living in their homes ( N = 328), three segments of senior residents based on their reasons for aging-in-place were identified. Results reinforce the importance of community-based integrative programs and policies by indicating that the three identified clusters were not homogeneous; however, inclusive community-based supports and services can provide what each cluster needs to successfully age-in-place. Discussion provides a perspective on how to support successful aging-in-place, including the role of the federal government in funding and legislation. PMID- 29277157 TI - Isolated unilateral adrenal gland hemorrhage following motor vehicle collision: a case report and review of the literature. AB - BACKGROUND: Adrenal gland trauma is a rare condition that typically stems from blunt force trauma, and is associated with multiple organ injuries. Alternatively, isolated adrenal gland trauma is extremely rare, accounting for only 1.5 to 4% of all adrenal trauma cases. While isolated adrenal trauma is a mostly self-limiting condition, it is potentially life-threatening, representing a significant cause of bleeding, and/or hypotension due to adrenal insufficiency and adrenal crisis. Due to its rare occurrence, there are no reported guidelines for monitoring and observing isolated adrenal trauma. CASE PRESENTATION: Here we report on an isolated adrenal hemorrhage from a blunt trauma without associated injuries. A 53-year-old white man presented with abdominal pain after a high speed motor vehicle accident. An initial evaluation revealed minimal abdominal pain and negative focused assessment with sonography for trauma examination; computed tomography imaging revealed a significant fluid collection consistent with adrenal hemorrhage. He was observed in our intensive care unit for 24 hours, and had stable hemoglobin and vital signs, after which he was discharged. At 1 month follow-up, he reported persistent intermittent abdominal pain, which was completely resolved by the 4-month follow-up. CONCLUSIONS: This case report demonstrates isolated adrenal gland injury resulting from significant blunt trauma to the abdomen. There are no current guidelines for monitoring isolated adrenal hemorrhage. Recognizing possible adrenal injury in blunt trauma cases is important due to potentially severe adrenal hemorrhage; therefore, we recommend follow-up with serial abdominal computed tomography until the resolution of hemorrhage and symptoms. PMID- 29277158 TI - Postoperative symbiotic in patients with head and neck cancer: a double-blind randomised trial. AB - Studies on the 'gut origin of sepsis' have suggested that stressful insults, such as surgery, can affect intestinal permeability, leading to bacterial translocation. Symbiotics have been reported to be able to improve gut permeability and modulate the immunologic system, thereby decreasing postoperative complications. Therefore we aimed to evaluate the postoperative use of symbiotics in head and neck cancer surgical patients for intestinal function and permeability, as well as the postoperative outcomes. Patients were double blind randomised into the symbiotic (n 18) or the control group (n 18). Samples were administered twice a day by nasoenteric tube, starting on the 1st postoperative day until the 5th to 7th day, and comprised 109 colony-forming units/ml each of Lactobacillus paracasei, L. rhamnosus, L. acidophilus, and Bifidobacterium lactis plus 6 g of fructo-oligosaccharides, or a placebo (6 g of maltodextrin). Intestinal function (day of first evacuation, total stool episodes, stool consistency, gastrointestinal tract symptoms and gut permeability by diamine oxidase (DAO) enzyme) and postoperative complications (infectious and non-infectious) were assessed. Results of comparison of the pre- and postoperative periods showed that the groups were similar for all outcome variables. In all, twelve patients had complications in the symbiotic group v. nine in the control group (P>0.05), and the preoperative-postoperative DAO activity ranged from 28.5 (sd 15.4) to 32.7 (sd 11.0) ng/ml in the symbiotic group and 35.2 (sd 17.7) to 34.1 (sd 12.0) ng/ml in the control group (P>0.05). In conclusion, postoperative symbiotics did not impact on intestinal function and postoperative outcomes of head and neck surgical patients. PMID- 29277159 TI - Effects of dietary methionine on productivity, reproductive performance, antioxidant capacity, ovalbumin and antioxidant-related gene expression in laying duck breeders. AB - The study investigated whether dietary methionine (Met) affects egg weight and antioxidant status through regulating gene expression of ovalbumin (OVAL), nuclear factor erythroid 2 like 2 (Nrf2) and haem oxygenase 1 (HO-1) in laying duck breeders. Longyan duck breeders (n 540, 19 weeks) were randomly assigned to six treatments with six replicates of fifteen birds each. Breeders were fed diets with six Met levels (2.00, 2.75, 3.50, 4.25, 5.00 and 5.75 g/kg) for 24 weeks. The egg weight (g), egg mass (g/d), feed conversion ratio, hatchability, 1-d duckling weight, albumen weight, albumen proportion and OVAL mRNA level improved with dietary Met levels, whereas yolk proportion decreased (P<0.05). The weight of total large yellow follicles increased linearly (P<0.001) and quadratically (P<0.05) with dietary Met concentration, and their weight relative to ovarian weight showed a linear (P<0.05) effect. Dietary Met level had a linear (P<0.05) and quadratic (P<0.001) effect on the gene expression of glutathione peroxidase (GPX1), HO-1 and Nrf2, and quadratically (P<0.05) increased contents of GPX and total antioxidant capacity (T-AOC) in liver of duck breeders. In addition, maternal dietary Met enhanced gene expression of GPX1, HO-1 and Nrf2, increased contents of GPX and T-AOC and reduced carbonylated protein in the brains of hatchlings. Overall, dietary Met concentration affected egg weight and albumen weight in laying duck breeders, which was partly due to gene expression of OVAL in oviduct magnum. A diet containing 4.0 g Met/kg would achieve optimal hepatic GPX1 and Nrf2 expression, maximise the activity of GPX and minimise lipid peroxidation. PMID- 29277160 TI - Elderly patients' and GPs' perspectives of patient-GP communication concerning polypharmacy: a qualitative interview study. AB - : AimThe aim of this study was to explore elderly patients' and general practitioners' (GPs') perceptions of communication about polypharmacy, medication safety and approaches for empowerment. BACKGROUND: To manage polypharmacy, GPs need to know patients' real medication consumption. However, previous research has shown that patients do not always volunteer all information about their medication regimen, for example, such as the intake of over-the-counter medication or the alteration or discontinuation of prescribed medication. METHOD: A qualitative interview study including patients of at least 65 years old with polypharmacy (?5 medications) and their GPs in a German Primary Healthcare Centre. The transcripts from the semi-structured interviews (n=6 with patients; n=3 with GPs) were analysed using a framework analytical approach.FindingsWe identified three themes: differing medication plans: causes?; dialogue concerning medication: whose responsibility?; supporting patients' engagement: how? While GPs stated that patients do not always report or might even conceal information, all patients reported that they could speak openly about everything with their GPs. In this context, trust might act as a double-edged sword, as it can promote open communication but also prevent patients from asking questions. Both GPs and patients could name very few ways in which patients could be supported to become more informed and active in communication concerning polypharmacy and medication safety. CONCLUSION: This study shows that patients' awareness of the significance of their active role in addressing polypharmacy needs to be increased. This includes understanding that trusting the doctor does not preclude asking questions or seeking more information. Thus, interventions which improve patients' communication skills and address specific issues of polypharmacy, particularly in elderly patients, should be designed. GPs might support patients by 'inviting' their contribution. PMID- 29277161 TI - Household access to traditional and indigenous foods positively associated with food security and dietary diversity in Botswana. AB - OBJECTIVE: To determine access to traditional and indigenous foods (TIF) and the association with household food security, dietary diversity and women's BMI in low socio-economic households. DESIGN: Sequential explanatory mixed-methods design, including a random household cross-sectional survey on household food insecurity access (HFIA), household dietary diversity (HDD) and women's BMI, followed by focus group discussions. SETTING: Two rural and two urban areas of Botswana. SUBJECTS: Persons responsible for food preparation or an adult in a household (n 400); for BMI, non-pregnant women aged 18-49 years (n 253). RESULTS: Almost two-thirds of households experienced moderate or severe food insecurity (28.8 and 37.3 %, respectively), but more than half of women were overweight or obese (26.9 and 26.9 %, respectively). Median HDD score was 6 (interquartile range 5-7) out of a total of 12. A positive correlation was found between number of TIF accessed and HDD score (r=0.457; P<0.001) and a negative correlation between number of TIF accessed and HFIA score (r=-0.272; P<0.001). There was no correlation between number of TIF accessed and women's BMI (r=-0.066; P=0.297). TIF were perceived as healthy but with declining consumption due to preference for modern foods. CONCLUSIONS: TIF may potentially have an important role in household food security and dietary diversity. There is need to explore potential benefits that may be associated with their optimal use on food security and nutrition outcomes. PMID- 29277162 TI - A European late starter: lessons from the history of reform in Irish health care. AB - The Irish health care system is unusual within Europe in not providing universal, equitable access to either primary or acute hospital care. The majority of the population pays out-of-pocket fees to access primary health care. Due to long waits for public hospital care, many purchase private health insurance, which facilitates faster access to public and private hospital services. The system has been the subject of much criticism and repeated reform attempts. Proposals in 2011 to develop a universal health care system, funded by Universal Health Insurance, were abandoned in 2015 largely due to cost concerns. Despite this experience, there remains strong political support for developing a universal health care system. By applying an historical institutionalist approach, the paper develops an understanding of why Ireland has been a European outlier. The aim of the paper is to identify and discuss issues that may arise in introducing a universal healthcare system to Ireland informed by an understanding of previous unsuccessful reform proposals. Challenges in system design faced by a late starter country like Ireland, including overcoming stakeholder resistance, achieving clarity in the definition of universality and avoiding barriers to access, may be shared by countries whose universal systems have been compromised in the period of austerity. PMID- 29277163 TI - Criterion validity and inter-rater reliability of a palliative care screening tool for patients admitted to an emergency department intensive care unit. AB - OBJECTIVE: The use of palliative care (PC) screening criteria to trigger PC consultations may optimize the utilization of PC services, improve patient comfort, and reduce invasive and futile end-of-life care. The aim of the present study was to assess the criterion validity and inter-rater reliability of a PC screening tool for patients admitted to an emergency department intensive care unit (ED-ICU). METHOD: Observational retrospective study evaluating PC screening criteria based on the presence of advanced diagnosis and the use of two "surprise questions" (traditional and modified). Patients were classified at ED-ICU admission in four categories according to the proposed algorithm. Result A total of 510 patients were included in the analysis. From these, 337 (66.1%) were category 1, 0 (0.0%) category 2, 63 (12.4%) category 3, and 110 (21.6%) category 4. Severity of illness (Simplified Acute Physiology Score III score and mechanical ventilation), mortality (ED-ICU and intrahospital), and PC-related measures (order for a PC consultation, time between admission and PC consultation, and transfer to a PC bed) were significantly different across groups, more evidently between categories 4 and 1. Category 3 patients presented similar outcomes to patients in category 1 for severity of illness and mortality. However, category 3 patients had a PC consultation ordered more frequently than did category 1 patients. The screening criteria were assessed by two independent raters (n = 100), and a substantial interrater reliability was found, with 80% of agreement and a kappa coefficient of 0.75 (95% confidence interval = 0.62, 0.88). Significance of results This study is the first step toward the implementation of a PC screening tool in the ED-ICU. The tool was able to discriminate three groups of patients within a spectrum of increasing severity of illness, risk of death, and PC needs, presenting substantial inter-rater reliability. Future research should investigate the implementation of these screening criteria into routine practice of an ED-ICU. PMID- 29277164 TI - Effect of selection for intramuscular fat on the fatty acid composition of rabbit meat. AB - Intramuscular fat (IMF) content and composition are relevant for the meat industry due to their effect on human health and meat organoleptic properties. A divergent selection experiment for IMF of Longissimus dorsi (LD) muscle was performed in rabbits during eight generations. The aim of this study is to estimate the correlated responses to selection for IMF on the fatty acid composition of LD. Response to selection for IMF was 0.34 g/100 g of LD, representing 2.4 phenotypic SD of the trait. High-IMF line showed 9.20% more monounsaturated fatty acids (MUFA) and 0.39%, 9.97% and 10.3% less n-3, n-6 and polyunsaturated fatty acids (PUFA), respectively, than low-IMF line. The main MUFA and PUFA individual fatty acids followed a similar pattern, except for C18:3n-3 that was greater in the high-IMF line. We did not observe differences between lines for the percentage of total saturated fatty acids, although high IMF line showed greater C14:0 and C16:0 and lower C18:0 percentages than low-IMF line. Heritability estimates were generally high for all fatty acids percentages, ranging from 0.43 to 0.59 with a SD around 0.08, showing an important genetic component on these traits. Genetic correlations between IMF and LD fatty acid percentages were strong and positive for C14:0, C16:1, C18:1n-9, and MUFA, ranging from 0.88 to 0.97, and strong and negative for C18:0, C18:2n-6, C20:4n-6, n-6 and PUFA, ranging from -0.83 to -0.91. These correlations were accurately estimated, with SD ranging from 0.02 to 0.06. The genetic correlations between IMF and other fatty acids were estimated with lower accuracy. In general, phenotypic and genetic correlations were of the same order. Our experiment shows that selection for IMF strongly affects the fatty acid composition of meat, due the high heritabilities of fatty acids and their high genetic correlations with IMF. PMID- 29277165 TI - Reasons and risk factors for beef calf and youngstock on-farm mortality in extensive cow-calf herds. AB - Raising calves and youngstock is an essential part of beef production. High on farm mortality (unassisted death and euthanasia) is a consequence of poor animal health and welfare, and is economically unfavourable. The present study aimed to identify the reasons and risk factors for beef calf and youngstock on-farm mortality, using registry data for the years 2013 to 2015. Cox regression models were applied for the data of four age groups: calves up to 30 days (n=21 075), calves 1 to 5 months (n=21 116), youngstock 6 to 19 months (n=22 637) and youngstock ?20 months of age (n=9582). We found that dystocia, small birth weight and older parity of the mother increased the mortality hazard in calves up to 30 days of age. A summer birth was a common protective factor against mortality for calves up to 30 days and calves 1 to 5 months of age, compared with birth in other seasons. Among calves 1 to 5 months old, being the offspring of a first parity cow was associated with significantly higher risk of death compared with calves who were the offspring of third- or higher-parity cows. A high herd-level stillbirth rate was associated with higher mortality hazard. The most commonly reported reasons for calf mortality were digestive disorders and respiratory disease. According to the models of youngstock from 6 months of age, male sex was a risk factor for mortality. Cattle having more than 10% dairy breed experienced a higher mortality risk in the ?20 months age group. No significant differences were found across regions, herd size or different breeds in any of the calf or youngstock groups. Metabolic and digestive disorders, as well as traumas and accidents, were the most common causes of mortality in beef youngstock older than 6 months. We can conclude that in young calves, animal-level factors associated with calving had a high impact on mortality. Further, timing calving for the warmer spring months would benefit calf survivability. Further studies including complementary information about farm factors adapted across the whole youngstock period is highly needed to provide sound recommendations in reducing on-farm mortality. PMID- 29277166 TI - 'Fair innings' in the face of ageing and demographic change. AB - There are now 125 million people aged 80 years and over worldwide, projected by the United Nations to grow threefold by 2050. While increases in life expectancy and rapid increases in the older-age population are considered positive developments, the consequential future health care burden represents a leading concern for health services. We revisit Williams' 'fair innings' argument from 1997, in light of technological and demographic changes, and challenge the notion that greater longevity may impose an unfair burden on younger generations. We discuss perspectives on the equity-efficiency trade-off in terms of their implications for the growing over-80 population, as well as society in general. This includes questioning the comparison of treatment cost-effectiveness in younger vs. older populations when using quality-adjusted life years and the transience of life expectancies over generations. While recognising that there will never be a clear consensus regarding societal value judgements, we present empirical evidence on the very elderly that lends support to a stronger anti ageist stance given current increases in longevity. PMID- 29277167 TI - Physicians' experiences of SBIRT training and implementation for SUD management in primary care in the UAE: a qualitative study. AB - : AimThe objective of this paper is to present a qualitative study of introducing substance misuse screening using the Screening Brief Intervention and Referral to Treatment (SBIRT) model, in primary care in Abu Dhabi. BACKGROUND: Substance misuse in the UAE is an increasing problem. However religious beliefs and fear of legal consequences have prevented this topic from being openly discussed, risk levels identified through screening and treatment options offered. METHODS: A controlled trial was undertaken which included a qualitative process study which is reported here. Qualitative interviews with primary care physicians from two intervention clinics were undertaken to explore their views, experiences and attitudes towards substance misuse management in their clinic. Physicians were trained on SBIRT and on the research project process and documentation. At completion of the project, 10 months after the training, physicians (n=17) were invited to participate in an interview to explore their experiences of training and implementation of SBIRT. Interviews were recorded and transcribed. Inductive thematic coding was applied.FindingsIn total, 11 physicians were interviewed and three main themes emerged: (1) The SBIRT screening project, (2) cultural issues and (3) patient follow-up. Findings revealed a general willingness toward the concept of screening and delivering brief interventions in primary care although increased workload and uncertainties about remuneration for the service may be a barrier to future implementation. There was a perceived problem of substance misuse that was not currently being met and a strong perception that patients were not willing to reveal substance use due cultural barriers and fear of police involvement. In conclusion this qualitative process evaluation provided essential insight into implementing SBIRT in the Middle East. In conclusion, despite physician willingness and a clinical need for a substance misuse care pathway, the reluctance among patients to admit to substance use in this culture needs to be addressed to enable successful implementation. PMID- 29277168 TI - Subclinical thiamine deficiency in patients with abdominal cancer. AB - OBJECTIVE: Thiamine is an essential coenzyme for oxidative metabolisms; however, it is not synthesized in the human body, and the average thiamine storage capacity is approximately 18 days. Therefore, thiamine deficiency (TD) can occur in any condition of unbalanced nutrition. If TD is left untreated, it causes the neuropsychiatric disorder Wernicke encephalopathy (WE). Although WE is a medical emergency, it is sometimes overlooked because most patients with WE do not exhibit all of the typical symptoms, including delirium, ataxia, and ophthalmoplegia. If all of the typical clinical symptoms of WE are absent, diagnosis of TD or WE becomes more difficult. METHOD: From a series of cancer patients, we reported three patients who developed TD without the typical clinical symptoms of WE.ResultA 69-year-old woman with pancreatic body cancer receiving chemotherapy with paclitaxel and gemcitabine for six months. Her performance status (PS) was 1. A detailed interview revealed that she had appetite loss for six months. Another 69-year-old woman with ovarian cancer received nedaplatin; her PS was 0. A detailed interview revealed that she had appetite loss for three months. A 67-year-old woman with colon cancer receiving ramucirumab in combination with second-line fluorouracil with folinic acid and irinotecan. Her PS was 1. A detailed interview revealed that she had appetite loss for three weeks. None exhibited typical clinical signs of WE, but they developed appetite loss for six months, three months, and three weeks, respectively. The diagnosis of TD was supported by abnormally low serum thiamine levels.Significance of the resultsThis report emphasizes the possibility of TD in cancer patients even when patients do not develop typical clinical signs of WE. The presence of appetite loss for more than two weeks may aid in diagnosing TD. Patients receiving chemotherapy may be at greater risk for developing TD. PMID- 29277169 TI - Evaluating the <=10:1 wholegrain criterion in identifying nutrient quality and health implications of UK breads and breakfast cereals. AB - OBJECTIVE: To evaluate the nutrient quality of breads and breakfast cereals identified using the wholegrain definition of <=10:1 carbohydrate:fibre ratio. DESIGN: Following a cross-sectional study design, nutritional information was systematically gathered from food labels of breads and breakfast cereals that met the <=10:1 carbohydrate:fibre criterion. The median nutrient content was compared with the UK Food Standards Agency's nutrient profiling standards and the associations between carbohydrate:fibre ratio and other nutrients were analysed. Subgroup analyses were undertaken for products with and without fruit, nuts and/or seeds. SETTING: Products from four major supermarket stores in the UK. SUBJECTS: Breads (n 162) and breakfast cereals (n 266). RESULTS: Breads which met the <=10:1 criterion typically contained medium fat, low saturated fat, low sugar and medium Na. Breakfast cereals typically contained medium fat, low saturated fat, high sugar and low Na. In both groups, as the carbohydrate:fibre ratio decreased, fat content increased (bread: P=0.029, r=-0.171; breakfast cereal: P=0.033, r=-0.131) and, in breakfast cereals, as the ratio increased, sugar content increased (P<0.0005, r=0.381). Breakfast cereals with fruit, nuts and/or seeds contained, per 100 g, more energy (P=0.002), fat, saturated fat and sugar (all P<0.0005), while seeded breads had more energy, fat and saturated fat (all P<0.0005). CONCLUSIONS: Overall, breads and breakfast cereals meeting the <=10:1 criterion have good nutritional quality, suggesting that the criterion could be useful in public health and/or food labelling. The utility of applying the <=10:1 criterion to products containing fruit, nuts and/or seeds is less clear and requires further research. PMID- 29277170 TI - Supplementing a yeast-derived product to enhance productive and health responses of beef steers. AB - This experiment evaluated the impacts of supplementing a yeast-derived product (Celmanax; Church & Dwight Co., Inc., Princeton, NJ, USA) on productive and health responses of beef steers, and was divided into a preconditioning (days 4 to 30) and feedlot receiving phase (days 31 to 69). In all, 84 Angus * Hereford steers were weaned on day 0 (BW=245+/-2 kg; age=186+/-2 days), and maintained in a single group from days 0 to 3. On day 4, steers were allocated according to weaning BW and age to a 21-pen drylot (4 steers/pen). Pens were randomly assigned to (n=7 pens/treatment): (1) no Celmanax supplementation during the study, (2) Celmanax supplementation (14 g/steer daily; as-fed) from days 14 to 69 or (3) Celmanax supplementation (14 g/steer daily; as-fed) from days 31 to 69. Steers had free-choice access to grass-alfalfa hay, and were also offered a corn-based concentrate beginning on day 14. Celmanax was mixed daily with the concentrate. On day 30, steers were road-transported for 1500 km (24 h). On day 31, steers returned to their original pens for the 38-day feedlot receiving. Shrunk BW was recorded on days 4, 31 and 70. Feed intake was evaluated daily (days 14 to 69). Steers were observed daily (days 4 to 69) for bovine respiratory disease (BRD) signs. Blood samples were collected on days 14, 30, 31, 33, 35, 40, 45, 54 and 69, and analyzed for plasma cortisol, haptoglobin, IGF-I, and serum fatty acids. Preconditioning results were analyzed by comparing pens that received (CELM) or not (CONPC) Celmanax during the preconditioning phase. Feedlot receiving results were analyzed by comparing pens that received Celmanax from days 14 to 69 (CELPREC), days 31 to 69 (CELRECV) or no Celmanax supplementation (CON). During preconditioning, BRD incidence was less (P=0.03) in CELM v. CONPC. During feedlot receiving, average daily gain (ADG) (P=0.07) and feed efficiency (P=0.08) tended to be greater in CELPREC and CELRECV v. CON, whereas dry matter intake was similar (P?0.29) among treatments. No other treatment effects were detected (P?0.20). Collectively, Celmanax supplementation reduced BRD incidence during the 30-day preconditioning. Moreover, supplementing Celmanax tended to improve ADG and feed efficiency during the 38-day feedlot receiving, independently of whether supplementation began during preconditioning or after feedlot entry. These results suggest that Celmanax supplementation benefits preconditioning health and feedlot receiving performance in beef cattle. PMID- 29277172 TI - The New Zealand breakfast cereal category is dynamic and responsive to consumer preferences. PMID- 29277171 TI - Post-intensive care syndrome symptoms and health-related quality of life in family decision-makers of critically ill patients. AB - OBJECTIVE: Family members of critically ill patients can suffer symptoms of post intensive care syndrome-family (PICS-F), including anxiety, depression, and posttraumatic stress disorder (PTSD) with a diminished quality of life. Our aim was to examine the relationship between coping strategies used by family decision makers (FDMs) of critically ill patients and the severity of PICS-F symptoms and to examine the relationship between FDM PICS-F symptoms and health-related quality of life (HRQOL). METHOD: A single-center, prospective, longitudinal descriptive study was undertaken of FDMs of intensive care unit (ICU) patients admitted to a large tertiary care hospital. PICS-F symptoms and coping strategy use were measured upon ICU admission (T1), 30 days (T2) after ICU admission, and 60 days (T3) after ICU admission. HRQOL was measured by the Short Form-36 version 2 at T1 and T3. RESULTS: We found a significant prevalence of anxiety (45.8%), depression (25%), and PTSD (11.1%) symptoms among FDMs over the course of the study. The patient mortality rate in our sample was 50%. The HRQOL mental summary score in FDMs was low at T1 and decreased to M = 41.72 (standard deviation = 12.47) by T3. Avoidant coping demonstrated moderate relationships with PTSD symptoms and anxiety at T3. A previous history of anxiety, depression, or PTSD was a significant predictor of PICS-F symptom severity and prevalence. PICS symptom severity at T3 explained 75% of the variance in HRQOL mental summary score. Significance of results This study describes a significant prevalence of PICS-F symptoms in FDMs with a diminished mental HRQOL. PMID- 29277173 TI - Novel Tool Selection in Left Brain-Damaged Patients With Apraxia of Tool Use: A Study of Three Cases. AB - OBJECTIVES: Recent evidence indicates that some left brain-damaged (LBD) patients have difficulties to use familiar tools because of the inability to reason about physical object properties. A fundamental issue is to understand the residual capacity of those LBD patients in tool selection. METHODS: Three LBD patients with tool use disorders, three right brain-damaged (RBD) patients, and six matched healthy controls performed a novel tool selection task, consisting in extracting a target out from a box by selecting the relevant tool among eight, four, or two tools. Three criteria were manipulated to make relevant and irrelevant tools (size, rigidity, shape). RESULTS: LBD patients selected a greater number of irrelevant tools and had more difficulties to solve the task compared to RBD patients and controls. All participants committed more errors for selecting relevant tools based on rigidity and shape than size. In some LBD patients, the difficulties persisted even in the 2-Choice condition. CONCLUSIONS: Our findings confirm that tool use disorders result from impaired technical reasoning, leading patients to meet difficulties in selecting tools based on their physical properties. We also go further by showing that these difficulties can decrease as the choice is reduced, at least for some properties, opening new avenues for rehabilitation programs. (JINS, 2018, 24, 524-529). PMID- 29277174 TI - CHARACTERISTICS OF MANAGED ENTRY AGREEMENTS IN AUSTRALIA. AB - OBJECTIVES: Australia relies on managed entry agreements (MEAs) for many medicines added to the national Pharmaceutical Benefits Scheme (PBS). Previous studies of Australian MEAs examined public domain documents and were not able to provide a comprehensive assessment of the types and operation of MEAs. This study used government documents approved for release to examine the implementation and administration of MEAs implemented January 2012 to May 2016. METHODS: We accessed documents for medicines with MEAs on the PBS between January 2012 and May 2016. Data were extracted on Anatomical Therapeutic Classification (ATC), type of MEA (financial, financial with outcomes, outcomes, and subcategories within each group), implementation and administration methods, source of MEA recommendation, and type of economic analysis. RESULTS: Of all medication indication pairs (MIPs) recommended for listing, one-third had MEAs implemented. Our study of eighty seven MIPs had 170 MEAs in place. The Government's expert health technology assessment (HTA) committee recommended MEAs for 90 percent of the eighty-seven MIPs. A total of 81 percent of MEAs were simple financial agreements: the majority either discounts (32 percent) or reimbursement caps (43 percent). Outcome-based MEAs were least common (5 percent). Ninety-two percent of MEAs were implemented and operated through legal agreements. Approximately half of the MIPs were listed on the basis of accepted claims of cost-minimization. Forty-nine percent of medicines were in ATC L group. CONCLUSION: Advice from HTA evaluations strongly influences the implementation of ways to manage uncertainties while providing access to medicines. The government relied primarily on simple financial agreements for the managed entry of medicines for which there were perceived risks. PMID- 29277175 TI - PATIENT-CENTERED DECISION MAKING: LESSONS FROM MULTI-CRITERIA DECISION ANALYSIS FOR QUANTIFYING PATIENT PREFERENCES. AB - OBJECTIVES: Patient preferences should be a central consideration in healthcare decision making. However, stories of patients challenging regulatory and reimbursement decisions has led to questions on whether patient voices are being considered sufficiently during those decision making processes. This has led some to argue that it is necessary to quantify patient preferences before they can be adequately considered. METHODS: This study considers the lessons from the use of multi-criteria decision analysis (MCDA) for efforts to quantify patient preferences. It defines MCDA and summarizes the benefits it can provide to decision makers, identifies examples of MCDAs that have involved patients, and summarizes good practice guidelines as they relate to quantifying patient preferences. RESULTS: The guidance developed to support the use of MCDA in healthcare provide some useful considerations for the quantification of patient preferences, namely that researchers should give appropriate consideration to: the heterogeneity of patient preferences, and its relevance to decision makers; the cognitive challenges posed by different elicitation methods; and validity of the results they produce. Furthermore, it is important to consider how the relevance of these considerations varies with the decision being supported. CONCLUSIONS: The MCDA literature holds important lessons for how patient preferences should be quantified to support healthcare decision making. PMID- 29277176 TI - [Establishment and Optimization of Enhanced Recovery after Surgery System ?for Lung Cancer]. AB - With the development of key techniques and programs, the concept of enhanced recovery after surgery (ERAS) has been utilized in a wide range of diseases and surgical specialties. The key technological elements of enhanced lung recovery after surgery (ELRAS), which is regarded as the mainstay of minimally invasive lung cancer surgery, consist of the airway management and the lung protection. A multidisciplinary team cooperation based on physicians, nurses and rehabilitative therapists is needed to achieve the goals of airway management and lung protection, thus establishing a comprehensive ELRAS system for lung cancer patients. Such ELRAS systems should meet the following demands: firstly, there are accurate and objective assessment models for each section in an ELRAS program; secondly, the ELRAS protocols should be made as simple and repeatable as possible; thirdly, there are rigorous evaluation systems for the clinical efficacy of an ELRAS program; finally, a question-oriented team should be constructed in an ELRAS program. In summary, the ELRAS system needs to be constantly optimized and improved in the clinical practices. PMID- 29277177 TI - [Effect of Circular RNA UBAP2 Silencing on Proliferation and Invasion of Human Lung Cancer A549 Cells and Its Mechanism]. AB - BACKGROUND: It has been proven that circular RNAs (circRNAs) play an important role on the process of many types cancer and circUBAP2 was a cancer-promoting circRNA, however, the role and mechanism in lung cancer was not clear. The aim of this study is to investigate the effects of circUBAP2 on cell proliferation and invasion of human lung cancer A549 cells. METHODS: CCK-8 assay was employed to detect the effect of circUBAP2 sliencing on cell proliferation of A549 cells. Fow cytometry was applied to detect the impact of circUBAP2 sliencing on cell cycle and cell anoikis, and Transwell invasion assay was applied to determine cell invasion of A549 cells. We also employed Western blot and Real-time PCR to determine the expressions of CDK6, cyclin D1, p27 and c-IAP1, Bcl-2, Survivin, Bax, FAK, Rac1 and MMP2, and the activities of JNK and ERK1/2, luciferase report gene assay was used to detect the targets. RESULTS: CCK-8 assay showed that the inhibition of cell proliferation in the circUBAP2-siRNA group compared to untreated group and siRNA control group. Results of cell cycle detected by flow cytometry showed that cell cycle arrestd at G0/G1 after circUBAP2 silencing, cell apoptosis rate increased also. We also found that after circUBAP2 silencing, cell invasion of A549 cells was significantly inhibited. Western blot and Real-time PCR results showed that expression of CDK6, cyclin D1, c-IAP1, Bcl-2, Survivin, FAK, Rac1 and MMP2 were down-regulated, and the expression of p27 and Bax were up regulated. Moreover, the activities of JNK and ERK1/2 were inhibited because of circUBAP2 silencing, the target genes were miR-339-5p, miR-96-3p and miR-135b-3p. CONCLUSIONS: CircUBAP2 plays an important role in the proliferation and invasion of human lung cancer. Silencing of circUBAP2 might be a novel target for molecular targeted therapy of patients with lung cancer.?. PMID- 29277178 TI - [Clinical Significance and Mechanism of PI3K p110beta Overexpression? in Non small Cell Lung Cancer]. AB - BACKGROUND: Phosphatidylinositide 3-kinases (PI3K) pathway is one of the most important pathway in cells, which plays an important role in proliferation, growth, differentiation and mobility of cells. The aberrant activation of PI3K pathway was exsited in 50%-70% cases of non-small cell lung cancer (NSCLC). As the key point in PI3K pathway, expression of PI3K plays a critical role in activity of the pathway, which is closely related with the initiation and development of NSCLC, furthermore with the response of tumor to target treatment. Our study is to analyze the clinical significance and mechanism of PI3K p110beta overexpression in NSCLC. METHODS: Expression of p110beta and other proteins in PI3K pathway were detected by immunohistochemistry in 170 cases of NSCLC. Correlation between expression of p110beta and clinicopathological characteristics of patients as well as expression of other proteins in PI3K pathway was analyzed. RESULTS: In 170 NSCLC, overexpression of p110beta was found in 41.8% of cases. Correlation between overexpression of p110beta and Ki 67 index was significant (P=0.040). No significant difference of p110 expression were observed among different cohorts of gender, age, smoking status, classification, grade and stage (P>0.05). Correlation between expression of p110beta and other proteins in PI3K pathway was various, positively correlated with PTEN loss (P<0.001) and negatively correlated with mutant EGFR (P=0.022), while not correlated with P-Akt (Ser473), HER2, ALK, ROS1 and wild type EGFR (P>0.05). CONCLUSIONS: Overexpression of p110beta is frequently detected in NSCLC. It is closely related with PTEN loss NSCLC, which shows that it plays an important role in maintaining and developing of tumors driven by PTEN loss. It initiates the proliferation of tumor cells in NSCLC without phosphorylating Akt. PIK3CB mutation is not the major cause of overexpression of p110beta. Dysregulation of receptor tyrosine kinases (RTKs) doesn't show potential of increasing p110beta level in cancer tissue, furthermore the expression of p110beta in tumors with EGFR mutation is lower than in tumors without EGFR mutation. PMID- 29277179 TI - [Detection of UGT1A1*28 Polymorphism Using Fragment Analysis]. AB - BACKGROUND: Uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1), UGT1A1*28 polymorphism can reduce UGT1A1 enzymatic activity, which may lead to severe toxicities in patients who receive irinotecan. This study tries to build a fragment analysis method to detect UGT1A1*28 polymorphism. METHODS: A total of 286 blood specimens from the lung cancer patients who were hospitalized in Guangdong General Hospital between April 2014 to May 2015 were detected UGT1A1*28 polymorphism by fragment analysis method. RESULTS: Comparing with Sanger sequencing, precision and accuracy of the fragment analysis method were 100%. Of the 286 patients, 236 (82.5% harbored TA6/6 genotype, 48 (16.8%) TA 6/7 genotype and 2 (0.7%) TA7/7 genotype. CONCLUSIONS: Our data suggest hat the fragment analysis method is robust for detecting UGT1A1*28 polymorphism in clinical practice. It's simple, time-saving, and easy-to-carry. PMID- 29277180 TI - [Expression of KIF23 and Its Prognostic Role in Non-small Cell Lung Cancer: ?Analysis Based on the Data-mining of Oncomine]. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most common cause of cancer-related death worldwide. As the overall prognosis for affected patients is still poor, there is a need for biomarkers for prediction of survival and guiding individual therapy. This study is to explore the expression and significance of kinesin family member 23 (KIF23) in NSCLC. METHODS: KIF23 data were retrieved from Oncomine NSCLC database. The prognostic value of KIF23 was retrieved from an online survival analysis tool "Kaplan-Meier Plotter" (KM plotter) database. RESULTS: In Oncomine database, there were 447 studies of different types concerning expression of KIF23, of which 67 studies were of statistically significance (64 up-regulated and 3 down-regulated). A total of 16 studies were involved KIF23 in NSCLC tissues and normal tissues, including a total of 1,189 samples. Overall, KIF23 expression in NSCLC is higher than that in normal tissues (P<0.05). Moreover, Kaplan-Meier plots of overall survival indicated that KIF23 high expression is closely associated with poor survival in NSCLC (P<0.05). Subgroup analysis revealed that KIF23 expression showed negative relation to the prognosis of pulmonary adenocarcinoma patients. Whereas, in those with squamous carcinoma KIF23 expression showed no effects on the prognosis of the patients. CONCLUSIONS: KIF23 was found highly expressed in NSCLC, which might be a marker for NSCLC prognosis. PMID- 29277181 TI - [Establishment of A Clinical Prediction Model of Prolonged Air Leak ?after Anatomic Lung Resection]. AB - BACKGROUND: Prolonged air leak (PAL) after anatomic lung resection is a common and challenging complication in thoracic surgery. No available clinical prediction model of PAL has been established in China. The aim of this study was to construct a model to identify patients at increased risk of PAL by using preoperative factors exclusively. METHODS: We retrospectively reviewed clinical data and PAL occurrence of patients after anatomic lung resection, in department of thoracic surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, from January 2016 to October 2016. 359 patients were in group A, clinical data including age, body mass index (BMI), gender, smoking history, surgical methods, pulmonary function index, pleural adhesion, pathologic diagnosis, side and site of resected lung were analyzed. By using univariate and multivariate analysis, we found the independent predictors of PAL after anatomic lung resection and subsequently established a clinical prediction model. Then, another 112 patients (group B), who underwent anatomic lung resection in different time by different team, were chosen to verify the accuracy of the prediction model. Receiver-operating characteristic (ROC) curve was constructed using the prediction model. RESULTS: Multivariate Logistic regression analysis was used to identify six clinical characteristics [BMI, gender, smoking history, forced expiratory volume in one second to forced vital capacity ratio (FEV1%), pleural adhesion, site of resection] as independent predictors of PAL after anatomic lung resection. The area under the ROC curve for our model was 0.886 (95%CI: 0.835-0.937). The best predictive P value was 0.299 with sensitivity of 78.5% and specificity of 93.2%. CONCLUSIONS: Our prediction model could accurately identify occurrence risk of PAL in patients after anatomic lung resection, which might allow for more effective use of intraoperative prophylactic strategies.?. PMID- 29277182 TI - [Application of Digital Drainage System in Postoperative Refractory Prolonged Air Leaks after Pulmonary Surgery]. AB - BACKGROUND: Postoperative prolonged air leaks is one of the most common complications secondary to pulmonary resections. Digital drainage system (DDS) is considered as an accurate and objective device which has been found to be comfortable and well tolerated by patients, economical as well. The aim of this study is to explore the application of DDS in patients with postoperative refractory prolonged air leaks after pulmonary surgery. METHODS: Prolonged air leak (PAL) is defined as air leaks lasting for more than 5 d after video-assisted surgery or more than 7 d after thoracotomy. Postoperative refractory prolonged air leak is defined as a kind of air leak lasting for twice than PAL with grade 2 or 3 air leak, or air leak with severe complications such as subcutaneous or mediastinal emphysema in our study. A total of 8 patients who had postoperative refractory prolonged air leaks after pulmonary resection were treated with digital drainage system combined with pleurodesis from January to December in 2016 in Department of Thoracic Surgery, Shanghai Pulmonary Hospital. All the relevant clinical data of patients were collected for analysis. RESULTS: In our study, 6 patients accepted lobectomy, the other 2 patients underwent segmentectomy. The average air leak and chest tube duration of the patients with postoperative refractory prolonged air leaks after pulmonary resection was (17.3+/-5.1) d. The average postoperative DDS duration was (5.6+/-3.7) d. The mean drainage volume of the patients was (2,615.6+/-1,741.2) mL and (935.0+/ 242.7) mL before and after the application of DDS. The average length of hospital stay was (18.1+/-5.0) d. CONCLUSIONS: It is safe and feasible to apply digital drainage system to patients with postoperative refractory prolonged air leaks after pulmonary resection. Compared with the conventional drainage system, digital drainage system is more accurate and objective which can offer a larger suction pressure and promote lung recruitment maneuver for pleurodesis, shortening the drainage time and length of hospital stay. PMID- 29277183 TI - [Diagnostic Utility of Electromagnetic Navigation Bronchoscopy Combined with ?Radial Probe Endobronchial Ultrasound in Peripheral Pulmonary Lesions]. AB - BACKGROUND: With the application of high resolution computed tomography (CT), a large number of peripheral lung lesions were found. It put forward new challenge on clinical diagnosis and treatment for these peripheral lung lesions. Electromagnetic navigation bronchoscopy (ENB) and radial endobronchial ultrasound probe (R-EBUS) are new technologies used for the diagnosis of peripheral lung lesions. The aim of this study is to explore the application value of ENB combined with R-EBUS in the diagnosis of peripheral pulmonary lesions. METHODS: From September 2016 to November 2017, eighteen patients with thirty peripheral pulmonary lesions in the First Affiliated Hospital of Soochow University were enrolled. The ENB was performed on these patients who were detected peripheral lung lesions by chest HR-CT. After successful navigation, the lesion's location was confirmed by R-EBUS, and specimens were acquired by needle aspiration, endoscopic cell brush and biopsy forceps. RESULTS: A total of eighteen patients with thirty lesions were enrolled in this study, the navigation success rate was 100%, the positive rate was 90%. The mean operation time was (95.61+/-28.74) min, and navigation time for each lesion was (25.90+/-11.29) min, and pneumothorax was observed in 1 case. CONCLUSIONS: ENB combined with R-EBUS for the diagnosis of peripheral pulmonary lesions is safe and effective. This technique is worth promoting. PMID- 29277184 TI - [Study on Effects and Mechanisms of Phytochemicals in Vegetables and Fruits ?in Preventing and Treating Lung Cancer]. AB - Whether in the world or China, lung cancer is a malignant tumor which is harmful to human health. There were studies showed that lung cancer is tightly related to the environment factors and life style. The epidemiology study found that eating more fruits and vegetables can prevent lung cancer. Vegetables and fruits are rich in phytochemicals such as isothiocyanates, indoles, flavonoids and so on. These phytochemicals reduce the risk of lung cancer by modulating antitumor related pathways such as inhibition of cell proliferation, induction of apoptosis, and the like. The aim of this review is to summarize the mechanisms of phytochemicals in vegetables and fruits in the pathogenesis and progression of lung cancer, so as to provide theoretical basis and direction for the prevention and treatment of lung cancer. PMID- 29277185 TI - [Mechanism and Prospect of Radiotherapy Combined with Apotatinib?in the Treatment of Non-small Cell Lung Cancer]. AB - Non-small cell lung cancer is one of the most commom malignant tumor being harmful to people's life and health. Most of the patients have developed to the last stage which not suitable for surgical indications, so radiation and chemotherapy is the main treatment strategy. In recent years, with the theory of anti-angiogenesis therapy for malignant tumors, apatinib as a promising novel medicine to treat malignant tumors, represents synergistic antitumor effects in combination with radiotherapy. The underlying mechanisms may include make blood vessel normalization, alleviating inner hypoxia, and angiogenic factors regulation. Apatinib in combination with radiotherapy may become a new and effective treatment strategy of non-small cell lung cancer. PMID- 29277186 TI - [Current Status and Progress in Molecular Imaging of Non-small Cell Lung ?Cancer for Molecular Targeted EGFR-TKI Treatment Sensitivity and ?Treatment Tolerance Prediction]. AB - More than 80% of lung cancer is non-small cell lung cancer (NSCLC), and the epidermal growth factor receptor (EGFR)-mediated signaling pathway is closely related to the occurrence and development of NSCLC. Small molecule EGFR-tyrosine kinase inhibitors (EGFR-TKI) targeting EGFR have been used in the clinical treatment of NSCLC, and positron emission tomography/computed tomgraphy (PET/CT) imaging can noninvasively monitor the expression and mutation status of EGFR in patients with NSCLC. 18F-FDG PET/CT imaging has predictive value for the activation of EGFR mutation and EGFR-TKI treatment efficacy, and in vivo can be directly observed drugs and systemic tumor targeting EGFR combined with the specific circumstances, by PET/CT imaging before and after treatment, to achieve dynamic monitoring, guide the therapy before treatment and treatment of sensitive population screening process, to achieve NSCLC EGFR-TKI precise treatment is essential. PMID- 29277187 TI - [Synchronous Multiple Primary Lung Cancer Dignosed ?by Different Phenotype genotype: A Case Report and Literature Review]. AB - In recent years, based on low-dose computed tomography (CT) scan developed for physical examination, the number of synchronous multiple primary lung cancer (SMPLC) has gradually increased. The research showed the morbidity of SMPLC up to 0.2%-8%. The current diagnostic criteria of SMPLC is Martini-Melamed criteria. SMPLC: (1) Tumours should be located distantly and separately; (2) Histological types: Different histology; If same histology, they should be located at different segment, lobe or lung and originated from carcinoma insitu. No presence of carcinoma at shared lymphatic drainage. No extrapulmonary metastases at the diagnosis. MMPLC: (1) Different histology; (2) Disease free duration more than 2 years. Originated from carcinoma in situ location of second cancer at different lobe or lung. No presence of carcinoma at shared lymphatic drainage. No extrapulmonary metastases at the diagnosis. In 2013 International association for lung cancer research (IASLC) amended and supplemented the Martini-Melamed criteria, by multidisciplinary classification of lung adenocarcinoma, epidermal growth factor receptor (EGFR), K-ras added for differential diagnosis. It also suggest that the gene mutation detection for each lesion of SMPLC is especially significant for therapeutic strategy. We herein report the case of a 60-year-old woman diagnosed with SMPLC of four adenocarcinoma and EGFR-mutated lesions, who received lung resection for each lesions. PMID- 29277188 TI - Corrigendum to "Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight" [Neurobiol. Aging 33 (2012) 831.e21-831.e31]. PMID- 29277189 TI - Exaggerated Control Demands Over Reward-Related Behavior in Anorexia Nervosa. PMID- 29277190 TI - Locus Coeruleus Hyperactivity in Posttraumatic Stress Disorder: Answers and Questions. PMID- 29277192 TI - Erratum. PMID- 29277191 TI - Symptom Changes in Posttraumatic Stress Disorder and Major Depressive Disorder After Transcranial Magnetic Stimulation: Mechanisms of Where and How in the Brain. PMID- 29277193 TI - Erratum. PMID- 29277194 TI - Erratum. PMID- 29277195 TI - It's in the Genes: A New Marker for Sex Differences in Depression and Anxiety. PMID- 29277196 TI - Can we confidently use ketamine as a clinical treatment for depression? PMID- 29277198 TI - The Future of Psychiatry Commission. PMID- 29277199 TI - The Future of Psychiatry Commission. PMID- 29277200 TI - The Future of Psychiatry Commission. PMID- 29277201 TI - The Future of Psychiatry Commission. PMID- 29277202 TI - The Future of Psychiatry Commission. PMID- 29277203 TI - The Future of Psychiatry Commission. PMID- 29277204 TI - The Future of Psychiatry Commission - Authors' reply. PMID- 29277205 TI - Barriers to medication entitlements after diagnosis of ADHD. PMID- 29277206 TI - Barriers to medication entitlements after diagnosis of ADHD - Authors' reply. PMID- 29277207 TI - Hooked on gambling: a problem of human or machine design? PMID- 29277208 TI - Pursuing functional connectivity in NMDAR1 autoantibody carriers. PMID- 29277209 TI - Pursuing functional connectivity in NMDAR1 autoantibody carriers - Authors' reply. PMID- 29277211 TI - Sarah Carpenter: cover artist and cover star, 2018. PMID- 29277212 TI - Do "animal Fluids move by Hydraulick laws"?: the politics of the hydraulic theory of emotion. PMID- 29277213 TI - Hikikomori. PMID- 29277214 TI - North American opioid crisis: decline and fall of the war on drugs. PMID- 29277215 TI - Epigenetics: a missing link in understanding psychiatric disorders? PMID- 29277216 TI - Neuroimmunology 2017: making progress over 20 years. PMID- 29277217 TI - Golden years: Badlands. PMID- 29277218 TI - After the September earthquake in Mexico: observations of a British psychiatrist. PMID- 29277219 TI - Welcome from the new Editor-in-Chief. PMID- 29277220 TI - Foreword. PMID- 29277221 TI - Wearable Cardioverter Defibrillator "The Lifevest": Device Design, Limitations, and Areas of Improvement. AB - Sudden cardiac death is a potentially fatal clinical event demanding use of emergent intervention such as defibrillation. Over the last 1 decade, development of devices such as implantable and wearable cardioverter defibrillators (WCD) has provided new avenues in the management of sudden cardiac death. Several clinical studies have commented on the therapeutic and preventive aspect of WCD, however, literature describing the device functioning and limitations is limited. In this review study, we describe the technical aspects and limitations of WCD with a focus on identifying potential areas of improvement and framework for future research studies. PMID- 29277222 TI - Discharged filtrate movement in food materials under application of electrokinetics. AB - Orange juice (OJ) and malt extract (ME) samples were treated using an electrokinetic (EK) application to investigate the impact of the pH/Lowest conductivity point (LCP) ratio of experimental materials on the water profile direction and the anolyte to catholyte filtrate ratio. After applying the electric field through samples between two electrodes, filtrate was discharged mainly towards the anode in OJ samples (acidic medium, pH/LCP < 1) and towards the cathode in ME samples (alkaline medium, pH/LCP > 1). Adjusting the orientation of electrodes depending on the results maximised dewatering efficiency under EK by 7.8% in OJ and 11.8% in ME. Changing the pH/LCP ratio by adjusting the starting pH improved dewatering efficiency under EK by 25.7%. The results are used to develop theoretical guidelines to help determine the water profile direction and filtrate outlets for different food materials based on their pH and LCP values. EK is an effective method for dewatering food materials. PMID- 29277224 TI - Free amino acids and 5'-nucleotides in Finnish forest mushrooms. AB - Edible mushrooms are valued because of their umami taste and good nutritional values. Free amino acids, 5'-nucleotides and nucleosides were analyzed from four Nordic forest mushroom species (Lactarius camphoratus, Boletus edulis, Cantharellus cibarius, Craterellus tubaeformis) using high precision liquid chromatography analysis. To our knowledge, these taste components were studied for the first time from Craterellus tubaeformis and Lactarius camphoratus. The focus was on the umami amino acids and 5'-nucleotides. The free amino acid and 5' nucleotide/nucleoside contents of studied species differed from each other. In all studied samples, umami amino acids were among five major free amino acids. The highest concentration of umami amino acids was on L. camphoratus whereas B. edulis had the highest content of sweet amino acids and C. cibarius had the highest content of bitter amino acids. The content of umami enhancing 5' nucleotides were low in all studied species. PMID- 29277223 TI - The roles of ROS production-scavenging system in Lasiodiplodia theobromae (Pat.) Griff. & Maubl.-induced pericarp browning and disease development of harvested longan fruit. AB - Effects of Lasiodiplodia theobromae on reactive oxygen species (ROS) production scavenging system during L. theobromae-induced pericarp browning and disease development of harvested "Fuyan" longans were investigated. Compared with control longans, L. theobromae-inoculated longans exhibited higher pericarp browning index and fruit disease index, higher pericarp O2- generation rate and MDA content. Moreover, L. theobromae infection also resulted in lower contents of pericarp AsA and GSH, lower levels of pericarp DPPH radical scavenging ability and reducing power. Additionally, L. theobromae infection decreased the activities of pericarp SOD, CAT and APX from day 2 to day 5. These findings suggested that L. theobromae-induced pericarp browning and disease development of harvested longans might be due to reduction of ROS scavenging ability and increase in ROS production, which might stimulate membrane lipid peroxidation, disrupt cellular membrane structure, and cause the loss of cellular compartmentalization and disease resistance, in turn, resulting in pericarp browning and disease development. PMID- 29277225 TI - The quantification of free Amadori compounds and amino acids allows to model the bound Maillard reaction products formation in soybean products. AB - The quantification of protein bound Maillard reaction products (MRPs) is still a challenge in food chemistry. Protein hydrolysis is the bottleneck step: it is time consuming and the protein degradation is not always complete. In this study, the quantitation of free amino acids and Amadori products (APs) was compared to the percentage of blocked lysine by using chemometric tools. Eighty thermally treated soybean samples were analyzed by mass spectrometry to measure the concentration of free amino acids, free APs and the protein-bound markers of the Maillard reaction (furosine, Nepsilon-(carboxymethyl)-l-lysine, Nepsilon (carboxyethyl)-l-lysine, total lysine). Results demonstrated that Discriminant Analysis (DA) and Correlated Component Regression (CCR) correctly estimated the percent of blocked lysine in a validation and prediction set. These findings indicate that the measure of free markers reflects the extent of protein damage in soybean samples and it suggests the possibility to obtain rapid information on the quality of the industrial processes. PMID- 29277227 TI - Phenolic antioxidants of foxtail and little millet cultivars and their inhibitory effects on alpha-amylase and alpha-glucosidase activities. AB - Evaluation of phenolic contents and their in vitro bioactivities of six diverse cultivars of foxtail and little millets revealed that their total phenolic content ranged from 19.42 to 24.12 umol ferulic acid equivalents/g. The soluble fraction accounted for more than 80% of the total phenolic and flavonoid contents. Ferulic, caffeic and sinapic acids were the predominant phenolic acids, and luteolin and kaempferol were major flavonoids in the soluble fractions of millets. However, ferulic and p-coumaric acids were abundant in the bound fractions. Millet cultivars exhibited relevant changes in antioxidant activities in different mechanisms. Little millet cultivars showed superior inhibition of alpha-amylase and alpha-glucosidase than foxtail millet cultivars. The soluble and bound fractions of CO7 cultivar of foxtail millet (IC50, 22.37 and 57.26 ug/ml) and CO4 cultivar of little millet (IC50, 18.97 and 55.69 ug/ml) displayed strong inhibition towards alpha-glucosidase. These results suggest the potential application of underutilized millets as functional food ingredients for regulating postprandial hyperglycemia. PMID- 29277226 TI - Comparative chemical composition, antioxidant and anticoagulant properties of phenolic fraction (a rich in non-acylated and acylated flavonoids and non-polar compounds) and non-polar fraction from Elaeagnus rhamnoides (L.) A. Nelson fruits. AB - This study focuses on two fractions from sea buckthorn (Elaeagnus rhamnoides (L.) A. Nelson) fruits: the phenolic fraction (rich in non-acylated and acylated flavonoids and non-polar compounds) and the non-polar fraction. The objective was to investigate both the chemical composition of these fractions, as well as their biological activities in vitro. The tested fractions of sea buckthorn inhibited lipid peroxidation induced by H2O2, however, the non-polar fraction reduced more powerfully the process induced by H2O2/Fe as compared to the phenolic fraction. The tested fractions of sea buckthorn fruits also inhibited carbonylation stimulated by H2O2/Fe. Moreover, the action of the phenolic fraction and non polar fraction on hemostatic parameters of plasma was also compared to activities of other phenolic fraction, in which flavonoids were the dominant compounds. Our results indicate that sea buckthorn fruits are a rich source of different secondary metabolites, i.e. triterpenes and their derivates, which possess not only antioxidant properties, but may also display anticoagulant attributes. PMID- 29277228 TI - Molecular mechanism of action of Pelargonidin-3-O-glucoside, the main anthocyanin responsible for the anti-inflammatory effect of strawberry fruits. AB - Fragaria x ananassa Duch., popularly called strawberry, is known for its worldwide consumption and important biological activities, and these effects are related to its high concentration of anthocyanins. Pelargonidin-3-O-glucoside (P3G) is a major anthocyanin found in strawberry, and was evaluated for its anti inflammatory action in experimental models. The effect of strawberry extract and P3G, on leukocyte migration, exudation levels and many inflammatory mediators, was therefore evaluated in an in vivo model. An in vitro study was also carried out to characterize the effect of P3G on mitogen-activated protein kinases, and on nuclear transcript factors NF-kappaB and AP-1. The results revealed that the strawberry and P3G have important anti-inflammatory proprieties, and the anti inflammatory mechanism of P3G involves the arrest of IkB-alpha activation and reduction in JNKMAPK phosphorylation. The results reinforce that strawberry fruits are functional foods that can act as an adjuvant in the treatment of inflammatory conditions. PMID- 29277229 TI - Selective and simultaneous determination of indigo carmine and allura red in candy samples at the nano-concentration range by flow injection analysis with multiple pulse amperometric detection. AB - A novel, unique electroanalytical method was developed for the simultaneous quantification of the dyes indigo carmine (IC) and allura red (AR) in candies by coupling flow injection analysis and multiple pulse amperometry with a cathodically pretreated boron-doped diamond electrode, using 0.30 mol L-1 H2SO4 as supporting electrolyte. A dual-potential waveform was employed, causing the electrooxidation of either IC solely or IC and AR simultaneously. Thence, subtraction of current signals was used to quantify IC and AR in the concentration ranges of 70.0-1000 nmol L-1 and 40.0-770 nmol L-1, with limits of detection of 40.0 nmol L-1 and 7.0 nmol L-1, respectively. The proposed method, which permits up to 153 determinations per hour with good precision, was successfully applied in the quantification of these dyes in samples of commercial candies; their obtained contents were similar (at a 95% confidence level) to those from a comparative HPLC method. PMID- 29277230 TI - iTRAQ-based quantitative proteomics reveals the biochemical mechanism of cold stress adaption of razor clam during controlled freezing-point storage. AB - Razor clam is a major cultivated shellfish of great economic importance and high nutritional value. Due to high corruptible potential, razor clam is generally preserved by controlled freezing-point storage (CFPS). Here, we applied isobaric tags for relative and absolute quantification (iTRAQ) labeling to investigate the biochemical mechanism of cold stress adaption in razor clam during CFPS. In total, 369 proteins were quantified, and 27 of them were identified as differentially expressed proteins during CFPS, mostly involved in energy metabolism process, DNA duplication and protein synthesis, and stress response, specifically, MAPK is the predominant pathway. Further qPCR results revealed H2A and S6K 2 alpha to be the critical post-transcriptionally regulated genes. Our results provided proteomics information with respect to the biochemical mechanism of cold stress adaption in razor clam, shed light on the further elongation of razor clams storage period, and help clarify the novel mechanisms of cold tolerance. PMID- 29277231 TI - Preparation of a broad-spectrum anti-zearalenone and its primary analogues antibody and its application in an indirect competitive enzyme-linked immunosorbent assay. AB - A broad-spectrum monoclonal antibody (mAb)-based indirect competitive enzyme linked immunosorbent assay (ic-ELISA) has been developed for rapidly screening zearalenone (ZEN) and its primary analogues in various samples using an easy sample preparation procedure. Primarily, a group-specific mAb, 6C2, was produced, which had IC50 values for ZEN, alpha-zearalenol, beta-zearalenol, alpha zearalanol, beta-zearalanol and zearalanone of 114.0, 127.4, 290.4, 114.9, 205.6 and 257.1 ng L-1, respectively. The limit of detection and limit of quantitation of this method for ZEN and its five primary analogues in various matrix samples ranged from 114.2 to 812.3 ng L-1 and 237.1 to 1653.9 ng L-1, respectively. The recoveries of the above samples spiked with ZEN and its five primary analogues were in the range of 62.9-113.6%. The CVs were less than 13.2%. A good correlation (R2 = 0.995) between the ic-ELISA results and the HPLC-MS/MS results for swine feeds supported the reliability of the developed ic-ELISA. PMID- 29277232 TI - Isolation of strawberry anthocyanins using high-speed counter-current chromatography and the copigmentation with catechin or epicatechin by high pressure processing. AB - Three anthocyanins were isolated from strawberry extract by high-speed counter current chromatography, using a biphasic mixture of tert-butyl methyl ether, n butanol, acetonitrile, water and trifluoroacetic acid (2.5:2.0:2.5:5.0:1.0%). The anthocyanins were identified as pelargonidin-3-rutinoside, cyanidin-3-glucoside and pelargonidin-3-glucoside with purity of 95.6%, 96.2% and 99.3% respectively. Additionally, the copigmentation reaction rates between pelargonidin-3-glucoside and phenolic acids (catechin or epicatechin) at pH 1.5 and 3.6, pressure 0.1 and 500 MPa, and temperature 60 degrees C were calculated. The absorbance of pelargonidin-3-glucoside at pH 3.6, with high quantity of phenolic acids was significantly increased by high pressure. The complex of pelargonidin-3 glucoside/catechin has a binding energy of 78.64 kJ/mol at pH 3.6, and 39.13 kJ/mol at pH 1.5; pelargonidin-3-glucoside/epicatechin has a binding energy of 75.34 kJ/mol at pH 1.5 and 54.47 kJ/mol at pH 3.6. The hydrogen bond and van der Waals interaction were the main forces contributing to the structures of complex. PMID- 29277233 TI - Comparison of kokumi gamma-[Glu](n>1)-Val and gamma-[Glu](n>1)-Met synthesized through transpeptidation catalyzed by glutaminase from Bacillus amyloliquefaciens. AB - A series of gamma-[Glu](n=2,3,4)-Val or gamma-[Glu](n=2,3,4)-Met were synthesized in the presence of donor (Gln) and corresponding acceptor (Val or Met) through transpeptidation catalyzed by the glutaminase from Bacillus amyloliquefaciens. Gln in excess significantly (p < .05) improved the yield of gamma-[Glu](n>1) Val/Met except for gamma-Glu-Val/Met. The Km values for transpeptidase activity to yield gamma-[Glu](n=0,1,2,3)-Val increased with an elevated n, but remained essentially the same irrespective of n value for gamma-[Glu](n=0,1,2)-Met (which were 31-44% of that for gamma-[Glu]3-Met). The highest Km value appearing when n = 3 (gamma-[Glu]3-Val or gamma-[Glu]3-Met) suggested the rising difficulty for synthesis when the number of donor increases. All the gamma-[Glu]n-Val/Met substances exhibited kokumi properties and enhanced the continuity and umami taste of soy sauce as well as the thickness, mouthfulness and umaminess of model chicken broth. These results indicate the potential of the gamma-[Glu]n-Val and gamma-[Glu]n-Met as food flavor enhancers. PMID- 29277234 TI - Special article 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. PMID- 29277237 TI - Comments on the 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease. PMID- 29277238 TI - The changing paradigm in surgery is system integration: How do we respond? AB - With expansion of health care systems across the country, close relationships need to be developed between academic medical centers and their affiliated community hospitals. This creates opportunity to integrate surgical programs across different hospitals. Herein we describe a model of surgical integration at the system level of five large hospitals. We discuss utilizing advantages that both the academic and community hospital bring to the model. A close relationship between an interdisciplinary team, which includes the academic surgical chair, a regional director liaison who was embedded in the community, individual hospital leadership, and practice plan leaders was created. Three pillars as a foundation to success were physician leadership, the use of system infrastructure and development of new processes. This resulted in development of trust, leading to successful recruitments, models of employment and expansion into novel areas of patient safety. Once created, new opportunities for programming for surgical safety across the health care were identified. PMID- 29277239 TI - Do psoas muscle area and volume correlate with postoperative complications in patients undergoing rectal cancer resection? AB - BACKGROUND: Increasingly, patients with multiple co-morbidities undergo surgery for rectal cancer. We aimed to evaluate if decreased psoas muscle area and volume, as measures for sarcopenia, were associated with postoperative morbidity. METHODS: Retrospective review of patients undergoing rectal cancer resection at a tertiary medical center (2007-2015). Variables included demographics, co morbidities, preoperative psoas muscle area and volume, and postoperative complications. RESULTS: Among 180 patients (58% male, mean age 62.7 years), 44% experienced complications (n = 79), of which 38% (n = 30) were major complications. Malnourished patients had smaller height-adjusted total psoas area than non-malnourished patients (6.4 vs. 9.5 cm2/m2, p = 0.004). Among patients with imaging obtained within 90 days of surgery, major morbidity was associated with smaller total psoas area (6.7 vs. 10.5 cm2/m2, p = 0.04) and total psoas volume (26.7 vs. 42.2 cm3/m2, p = 0.04) compared to those with minor complications. CONCLUSION: Preoperative cross-sectional imaging may help surgeons anticipate postoperative complications following rectal cancer surgery. PMID- 29277240 TI - [A mentalization-based perspective on childhood autism treatment]. AB - Mentalization is a process by which a subject makes sense of both his own mental representations and of those around him. Disturbances in the mentalization process are found in several psychiatric disorders, notably borderline personality disorders for which mentalization-based treatments (MBT) have been developed and evaluated. Children with Autism Spectrum Disorder (ASD) display a theory of mind impairments, which corresponds to disturbances in the mentalization process. Although no MBT protocol for patients with ASD has been described in the literature, such treatment appears promising to improve theory of mind and functional outcome of these children. In this paper, we propose to discuss the theoretical ground of MBT therapeutic effect in children with ASD without intellectual disabilities and to describe a clinical protocol to test this perspective. PMID- 29277241 TI - ["Evolution of paternal filicide-suicide in the province of Quebec"]. AB - OBJECTIVES: The purpose of this study was to specify the number of male filicide suicide committed in the province of Quebec between 1997 and 2012, and to evaluate whether there has been an increase in the number of male filicide suicide according to the period studied and the type of motivation to commit the crime. METHOD: The data cover all officially registered male filicides committed in the province of Quebec from 1997 to 2012, against youths under 18 years old. A total of 50 cases were divided by five years spans starting in 1997 and analyzed using the Grille d'analyse multidimensionnelle de l'homicide intrafamilial. RESULTS: The results show that among the 50 male filicides committed between 1997 and 2012, 13 of these were followed by the aggressor's suicide. Also, the likelihood of suicide committed as a result of filicide is higher among individuals who committed filicide between 2007 and 2012 and who were motivated by marital separation, compared to filicides committed between 1997 and 2001 motivated by another reason. In particular, the majority of perpetrators of filicide committed between 2007 and 2012, motivated by marital separation, committed suicide as a result of the act of committing, compared to individuals who were motivated by another reason for the same period. CONCLUSIONS: On one hand, the present study demonstrates the importance of considering self destruction and, more specifically, the suicide of these individuals. On the other hand, our study emphasizes the importance of considering the type of motivation to commit filicide, including spousal separation, which is an element of understanding specific to male filicide-suicide. PMID- 29277242 TI - [Pathological travel in a population of migrants: A retrospective study]. PMID- 29277243 TI - The significant prognostic value of circulating tumor cells in colorectal cancer: A systematic review and meta-analysis. AB - BACKGROUND: Circulating tumor cell (CTC) is a promising candidate biomarker for detection, monitoring, and survival prediction of colorectal cancer (CRC). However, the prognostic significance of CTCs in CRC is currently under debate. Here, we performed a meta-analysis to assess the prognostic value of CTC for patients diagnosed with CRC. METHODS: A comprehensive literature research had been performed in the Pubmed, Embase Databases, Cochrane Library, Elsevier Science Direct, and China National Knowledge Internet for studies reporting prognostic data of CTCs in CRC patients since December 2016. The main outcome measures were overall survival and progression-free survival. The hazard ratio (HR) and 95% CI were considered to be the effect measures. Subgroup and sensitivity analyses were also performed. We pooled in meta-analysis under a fixed-effect or random-effect model according to heterogeneity. RESULTS: A total of 15 published studies containing 3129 patients matched the selection criteria were included in this meta-analysis. Overall analyses revealed that the presence of CTCs was significantly associated with poor mortality (overall survival: HR = 2.36, 95% CI: 1.87-2.97; P = 0.006) along with aggressive disease progression (progression-free survival: HR = 1.83, 95% CI: 1.42-2.36; P < 0.00001). Further subgroup analyses demonstrated that CTC-positive patients also had poor overall survival and disease progression in different subsets, including differences in time points of blood collection, detection methods, median follow-up month, and cutoff value of CTC. CONCLUSION: Meta-analysis provides a strong evidence that the presence of CTCs was an independent prognosticator of poor survival outcomes for patients with CRC. PMID- 29277244 TI - A fuzzy logic urea dosage controller design for two-cell selective catalytic reduction systems. AB - Diesel engines have dominated in the heavy-duty vehicular and marine power source. However, the induced air pollution is a big problem. As people's awareness of environmental protection increasing, the emission regulations of diesel-engine are becoming more stringent. In order to achieve the emission regulations, the after-treatment system is a necessary choice. Specifically, the selective catalytic reduction (SCR) system has been widely applied to reduce the NOX emissions of diesel engine. Different from single-cell SCR systems, the two cell systems have various benefits from the modeling and control perspective. In this paper, the urea dosage controller design for two-cell SCR systems was investigated. Firstly, the two-cell SCR modeling was introduced. Based on the developed model, the design procedure for the fuzzy logic urea dosage controller was well addressed. Secondly, simulations and comparisons were employed via an experimental verification of the whole vehicle simulator. And the results showed that the designed controller simultaneously achieved high NOX reduction rate and low tail-pipe ammonia slip. PMID- 29277245 TI - [Molecular heterogeneity of malignant pleural mesotheliomas]. AB - Malignant pleural mesothelioma (MPM) is predominantly an occupational cancer, most often linked to asbestos exposure. Malignant pleural mesothelioma prognosis is poor with a short survival median, due to the aggressiveness of tumor cells and the weak efficiency of conventional anti-cancer therapies. Clinical, histological, and molecular data suggest tumor heterogeneity between patients as it was also shown for other cancer types. Consequently, there is an urgent need to develop new therapies that take into account this heterogeneity and the molecular characteristics of malignant pleural mesothelioma, in particular by identifying new anti-cancer drugs targeting the molecular specificities of each malignant pleural mesothelioma. Malignant pleural mesothelioma is characterized by numerous molecular alterations at the chromosomal, genetic and epigenetic levels. Molecular classification based on gene expression profile has firstly defined two tumor groups, C1 and C2, and more recently, four groups. By integrating genetic and transcriptomic analysis, a C2LN tumor subgroup of the C2 group has been identified and characterized. In addition to tumor heterogeneity between patients, intra-tumor heterogeneity is supported by several evidences. Most therapeutic strategies that take into account the tumor molecular characteristics have focused on targeted therapies based on mutated genes. A more appropriate strategy would be to consider better-defined tumor groups on the basis of several molecular alterations types as it has been proposed for the C2LN subgroup. A robust definition of homogeneous tumor groups sharing common molecular characteristics is necessary for the development of effective precision medicine for malignant pleural mesothelioma. PMID- 29277246 TI - Studying GPCR Pharmacology in Membrane Microdomains: Fluorescence Correlation Spectroscopy Comes of Age. AB - G protein-coupled receptors (GPCRs) are organised within the cell membrane into highly ordered macromolecular complexes along with other receptors and signalling proteins. Understanding how heterogeneity in these complexes affects the pharmacology and functional response of these receptors is crucial for developing new and more selective ligands. Fluorescence correlation spectroscopy (FCS) and related techniques such as photon counting histogram (PCH) analysis and image based FCS can be used to interrogate the properties of GPCRs in these membrane microdomains, as well as their interaction with fluorescent ligands. FCS analyses fluorescence fluctuations within a small-defined excitation volume to yield information about their movement, concentration and molecular brightness (aggregation). These techniques can be used on live cells with single-molecule sensitivity and high spatial resolution. Once the preserve of specialist equipment, FCS techniques can now be applied using standard confocal microscopes. This review describes how FCS and related techniques have revealed novel insights into GPCR biology. PMID- 29277247 TI - Coherence analysis of trunk and leg acceleration reveals altered postural sway strategy during standing in persons with multiple sclerosis. AB - Balance task performance is affected in persons with multiple sclerosis (PwMS), but the control strategies used to perform specific tasks are not well understood. The purpose of this study was to evaluate segmental control during quiet standing in PwMS and controls to understand whether MS alters use of the ankle and hip strategies to manage postural sway. Coherence of acceleration between the trunk and legs was evaluated with accelerometers placed on the sacrum and lower leg. Thirty-six PwMS and 20 healthy control subjects performed quiet standing with eyes open and closed while center of pressure (CoP) and acceleration of postural sway was measured. Acceleration frequencies were divided into lower frequencies (<=1.0 Hz) and higher frequencies (>1.0 Hz) to categorize sway characteristics. With eyes open, coherence was significantly lower in PwMS compared to controls at lower frequencies only. With eyes closed, coherence was significantly lower in PwMS compared to controls, who use an ankle strategy at lower frequencies only, at both lower and higher frequencies. Both groups showed decreased coherence with increasing frequency when eyes were open and closed. Coherence was significantly correlated with CoP sway area in PwMS during the eyes closed condition only. The reduced coherence in PwMS during both lower and higher frequency sway indicates PwMS utilize a mixed ankle-hip sway strategy regardless of sway frequency. This is in contrast to sway in healthy subjects which utilizes an ankle strategy at lower frequencies and a mixed strategy at higher frequencies. Lack of adaptability in segmental control strategy likely contributes to abnormal postural control, as reflected by CoP sway patterns, in PwMS. PMID- 29277249 TI - Fine-tuning the normal tissue objective in eclipse for lung stereotactic body radiation therapy. AB - The purpose of this study was to characterize the effects of the normal tissue objective (NTO) on lung stereotactic body radiation therapy (SBRT) dose distributions. The NTO is a spatially varying constraint used in Eclipse to limit dose to normal tissues by steepening the dose gradient. However, the multitude of potential NTO setting combinations challenges optimal NTO tuning. In the present study, a broad range of NTO settings are investigated for lung SBRT treatment planning with volumetric modulated arc therapy(VMAT). Ten prior lung SBRT cases were replanned using NTO priorities of 1, 50, 100, 200, 500, and 999 in combination with fall-off values of 0.01, 0.05, 0.10, 0.15, 0.20, 0.30, 0.50, 1.00, and 5.00 mm-1 and the automatic NTO. NTO distances to planning target volume (PTV), start dose, and end dose were 1 mm, 100%, and 10%, respectively, for all 600 plans. Prescription dose covered 95% of the PTV. The following metrics were recorded: conformity index (CI), ratio of the 50% prescription isodose volume to PTV (R50%), maximum dose 2 cm away from PTV (D2cm), lung volume of >=20 Gy (V20Gy), maximum PTV dose (PTVmax), and monitor units (MUs). Differences between prior plans and NTO plans were evaluated using the Wilcoxon signed-rank test. Different combinations of NTO settings resulted in wide-ranging plan quality metrics: CI (1.00 to 1.54), R50% (3.95 to 7.57), D2cm (33.4% to 67.9%), V20Gy (1.66% to 2.75%), MU (1.81 cGy-1 to 4.69 cGy-1), and PTVmax (118% to 175%). Although no settings were optimal for all metrics, a fall-off of 0.15 mm-1 and a priority of 500 best satisfied institutional criteria. Compared with prior plans, NTO plans resulted in significantly lower R50% (4.00 vs 4.35, p = 0.002), lower V20Gy (1.22% vs 1.32%, p = 0.006), and higher PTVmax (138% vs 122%, p = 0.002). All of the prior and well-tuned NTO plans met Radiation Therapy Oncology Group (RTOG) 0813 guidelines. Lung SBRT dose distributions were characterized across a range of NTO settings. NTO plans with well-tuned settings compared favorably with prior plans. PMID- 29277248 TI - Communication pathways to and from the inner ear and their contributions to drug delivery. AB - The environment of the inner ear is highly regulated in a manner that some solutes are permitted to enter while others are excluded or transported out. Drug therapies targeting the sensory and supporting cells of the auditory and vestibular systems require the agent to gain entry to the fluid spaces of the inner ear, perilymph or endolymph, which surround the sensory organs. Access to the inner ear fluids from the vasculature is limited by the blood-labyrinth barriers, which include the blood-perilymph and blood-strial barriers. Intratympanic applications provide an alternative approach in which drugs are applied locally. Drug from the applied solution enters perilymph through the round window membrane, through the stapes, and under some circumstances, through thin bone in the otic capsule. The amount of drug applied to the middle ear is always substantially more than the amount entering perilymph. As a result, significant amounts of the applied drug can pass to the digestive system, to the vasculature, and to the brain. Drugs in perilymph pass to the vasculature and to cerebrospinal fluid via the cochlear aqueduct. Conversely, drugs applied to cerebrospinal fluid, including those given intrathecally, can enter perilymph through the cochlear aqueduct. Other possible routes in or out of the ear include passage by neuronal pathways, passage via endolymph and the endolymphatic sac, and possibly via lymphatic pathways. A better understanding of the pathways for drug movements in and out of the ear will enable better intervention strategies. PMID- 29277250 TI - Effects of bilateral discectomy and bilateral discopexy on black Merino sheep rumination kinematics: TEMPOJIMS - phase 1 - pilot blinded, randomized preclinical study. AB - BACKGROUND: The temporomandibular joint interposal study (TEMPOJIMS) is a rigorous preclinical trial divided in 2 phases. In phase 1 the authors investigated the role of the TMJ disc and in phase 2 the authors evaluated 3 different interposal materials. The present work of TEMPOJIMS - phase 1, investigated the effects of bilateral discectomy and discopexy in sheep mastication and rumination. METHODS: This randomized, blinded and controlled preclinical trial (in line with the ARRIVE guidelines) was conducted in 9 Black Merino sheep to evaluate changes in mastication and rumination after bilateral discectomy and bilateral discopexy, by comparing with a sham surgery control group. The outcomes evaluated were: (1) absolute masticatory time; (2) ruminant time per cycle; (3) ruminant kinematics, and (4) ruminant area. After baseline evaluation and surgical interventions, the outcomes were recorded over 3 successive days, every 30 days, for 6 months. RESULTS: The first month after intervention seemed to be the critical period for significant kinematic changes in the discectomy and discopexy groups. However, 6 months after the bilateral interventions, no significant changes were noticed when compared with the control group. CONCLUSIONS: In this study, bilateral discectomy and discopexy had no significant effect in mastication and ruminatory movement. The introduction of kinematic evaluation presents a new challenge that may contribute to the improvement of future studies on the TMJ domain. PMID- 29277251 TI - [Characterization of the genetic variability of field strains of Brucella canis isolated in Antioquia]. AB - Brucella canis is a facultative intracellular pathogen responsible for canine brucellosis, a zoonotic disease that affects canines, causing abortions and reproductive failure; and the production of non-specific symptoms in humans. In 2005 the presence of B. canis in Antioquia was demonstrated and the strains were identified as type 2. The sequencing of the genome of a field strain denoted Brucella canis str. Oliveri, showed species-specific indel events, which led us to investigate the genomic characteristics of the B. canis strain isolated and to establish the phylogenetic relationships and the divergence time of B. canis str. Oliveri. Conventional PCR sequencing was performed in 30 field strains identifying 5 indel events recognized in B. canis str. Oliveri. ADN from Brucella suis, Brucella melitensis and vaccine strains from Brucella abortus were used as control, and it was determined that all of the studied field strains shared 4 out of the 5 indels of the sequenced Oliveri strain, indicating the presence of more than one strain circulating in the region. Phylogenetic analysis was performed with 24 strains of Brucella using concatenated sequences of genetic markers for species differentiation. The molecular clock hypothesis and Tajima's relative rate test were tested, showing that the Oliveri strain, similarly to other canis species, diverged from B. suis. The molecular clock hypothesis between Brucella species was rejected and an evolution rate and a similar genetic distance between the B. canis were demonstrated. PMID- 29277252 TI - 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. PMID- 29277253 TI - Simultaneous determination of inorganic anions and cations by supercritical fluid chromatography using evaporative light scattering detection. AB - Supercritical fluid chromatography (SFC) is commonly used for the analysis of non polar compounds, but remains poorly explored for the separation of polar and ionized molecules. In this paper, SFC has been investigated for the separation of 14 inorganic ions sampled in aqueous solutions. Four polar stationary phases were first screened using CO2-methanol-based mobile phases containing water or different acidic or basic additives, in order to select the most efficient conditions for the simultaneous retention of inorganic cations and anions and to favor their detection using evaporative light scattering detector (ELSD). Orthogonal selectivity was obtained depending on the stationary phase used: whereas anions are less retained on HILIC stationary phase, 2-ethylpyridine (2 EP) stationary phase exhibits strong interaction for anions. Best results were obtained under gradient elution mode using a 2-EP stationary phase and by adding 0.2% triethylamine in the CO2-methanol-based mobile phase. The composition of the injection solvent was also investigated. The results showed that a methanolic sample containing a percentage of water not exceeding 20% does not affect the analytical performances obtained on 2-EP. Moreover, the presence of triethylamine in the injection solvent contributes to eliminate peaks shoulders. Among the 14 inorganic ions tested, three cations (Li+, Ca2+ and Mg2+) and five anions (Cl-, Br-, NO3-, I-, SCN-) were totally resolved in 15 min. NO3- and NO2- still coeluted in the final optimized conditions. The other investigated ions were either strongly retained on the stationary phase or not detected by the ELSD. PMID- 29277254 TI - A study of the analysis of acidic solutes by hydrophilic interaction chromatography. AB - The analysis of acidic solutes was compared on a cross-linked bonded amino phase and a neutral hybrid inorganic-organic amide phase, previously shown to give reasonable retention of acidic solutes. The amino column gave strong selective retention of acids, which was governed by ionic interactions that mostly increased as the solute became more negatively charged at higher pH. While the relative selectivity of the amide column towards acids, bases and neutrals was completely different to that of the amino column, the selectivity of both columns towards acidic solutes alone was surprisingly similar. It is possible that solute charge also controls retention on the amide column, through increased solute hydrophilicity and increased hydrogen bonding between the ionised form of the acid and neutral polar column groups. On both these silica-based columns there appeared to be a competitive effect between repulsion of acidic solutes from silanols, which become increasingly ionised as the pH is raised. This effect was absent when using a polymer-based amino phase which has no silanols. PMID- 29277255 TI - Validation and application of a multiresidue method based on liquid chromatography-tandem mass spectrometry for evaluating the plant uptake of 74 microcontaminants in crops irrigated with treated municipal wastewater. AB - Reuse of treated wastewater for agricultural purposes can mitigate water stress in some regions where the lack of water is an extended problem. However, the environmental long-term consequences of this practice are still unknown. It is demonstrated that using reclaimed water for irrigation lead to accumulation and translocation of some microcontaminants (MCs) in soil and crops. However, so far, only a small group of contaminants has been investigated. This study aims to develop and validate a simple and efficient multiresidue method based on QuEChERs (Quick, Easy, Cheap, Effective and Rugged) extraction coupled to liquid chromatography tandem mass spectrometry (LC-MS/MS). The novelty of the study relays in the large number of MCs analyzed (74), some of them not previously investigated, in three commodities (lettuce, radish and strawberry). Optimized conditions yielded good results for the three commodities under study. Up to 84% of the compounds were recovered within a 70-120% range, with good repeatability (relative standard deviations below 20% in most cases). Method detection (MDLs) and quantification limits (MQLs) ranged from 0.01 to 2 ng/g. The proposed method was successfully applied to assess the potential uptake of MCs by lettuce and radish crops irrigated with wastewater under controlled conditions for 3 and 1.5 months, respectively. 12 compounds were detected in the crops with concentrations ranging from 0.03 to 57.6 ng/g. N-Formyl-4-aminoantipyrine (4FAA) was the most concentrated compound. The application of this method demonstrated for the first time the accumulation of 5 contaminants of emerging concern (CECs) not previously reported: 4FAA, N-Acetyl-4-aminoantipyrine (4AAA), hydrochlorothiazide, mepivacaine and venlafaxine. PMID- 29277256 TI - Individual Differences in Language Acquisition and Processing. AB - Humans differ in innumerable ways, with considerable variation observable at every level of description, from the molecular to the social. Traditionally, linguistic and psycholinguistic theory has downplayed the possibility of meaningful differences in language across individuals. However, it is becoming increasingly evident that there is significant variation among speakers at any age as well as across the lifespan. Here, we review recent research in psycholinguistics, and argue that a focus on individual differences (IDs) provides a crucial source of evidence that bears strongly upon core issues in theories of the acquisition and processing of language; specifically, the role of experience in language acquisition, processing, and attainment, and the architecture of the language system. PMID- 29277257 TI - Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation. AB - Axonal Charcot-Marie-Tooth disease (CMT) represents an expanding group of inherited motor and sensory neuropathies in clinical practice. SACS-gene related disorders have been associated with complex neurological phenotypes of early onset cerebellar ataxia, spastic-ataxia, spastic paraplegia, demyelinating neuropathy and variable ophthalmological, cognitive and psychiatric disturbances, but never related to pure axonal neuropathy phenotypes. Two unrelated Brazilian men with early-onset axonal CMT-like presentations associated with SACS gene mutations are presented. Both patients presented with pure sensorimotor axonal neuropathy without cerebellar ataxia, spastic paraplegia or other systemic and neurological involvement. Classical neuroimaging findings observed in other sacsinopathies were observed in both cases. Homozygous pathogenic mutations were found in SACS gene in both patients. SACS gene mutations can be associated with pure axonal sensorimotor neuropathy without other neurological features, but with typical neuroimaging features of other sacsinopathies, disclosing the importance of performing neuroimaging studies in patients with suspected axonal CMT. PMID- 29277258 TI - In silico toxicity profiling of natural product compound libraries from African flora with anti-malarial and anti-HIV properties. AB - This paper describes an analysis of the diversity and chemical toxicity assessment of three chemical libraries of compounds from African flora (the p ANAPL, AfroMalariaDb, and Afro-HIV), respectively containing compounds exhibiting activities against diverse diseases, malaria and HIV. The diversity of the three data sets was done by comparison of the three most important principal components computed from standard molecular descriptors. This was also done by a study of the most common substructures (MCSS keys). Meanwhile, the in silico toxicity predictions were done through the identification of chemical structural alerts using Lhasa's knowledge based Derek system. The results show that the libraries occupy different chemical space and that only an insignificant part of the respective libraries could exhibit toxicities beyond acceptable limits. The predicted toxicities end points for compounds which were predicted to "plausible" were further discussed in the light of available experimental data in the literature. Toxicity predictions are in agreement when using a machine learning approach that employs graph-based structural signatures. The current study sheds further light towards the use of the studied chemical libraries for virtual screening purposes. PMID- 29277259 TI - Exciton states and optical properties of the CP26 photosynthetic protein. AB - The photosynthetic complex CP26, one of the minor antennae of the photosystem II, plays an important role in regulation of the excitation energy transfer in the PSII. Due to instability during isolation and purification, it remained poorly studied from the viewpoint of theoretical chemistry because of the absence of X ray crystallography data. In this work, using the recently determined three dimensional structure of the complex we apply the quantum chemical approach to study the properties of exciton states in it. Spectral properties, structure of exciton states and roles of the pigments in the complex and photosystem II are discussed. PMID- 29277260 TI - Reproducibility analysis of upper limbs reachable workspace, and effects of acquisition protocol, sex and hand dominancy. AB - None of the physical testing, nor the goniometers currently used to assess upper limb function have a high validity, sensitivity or reliability. The reachable workspace, i.e. the area covered by the farthest points a subject can reach by hand without moving his/her body, shows promise but has yet to be validated, particularly in terms of reproducibility. Therefore, this study aims to evaluate the reproducibility of the reachable workspace over a period of several weeks, and to assess the effects of two proposed acquisition protocols, as well as those of gender, and hand dominancy. Shoulder movements were recorded using a motion capture system on 10 female and 10 male healthy subjects during a random protocol, i.e. simply asking them to achieve the farthest points they could reach with their hands, and during a standardized protocol, i.e. asking them to perform predefined shoulder elevations while keeping their trunk and elbow straight. The standardized protocol was repeated 7 weeks later. Repeated measures showed no significant difference, good to excellent intraclass correlation coefficients (0.46-0.81) and small bias (0.0-1.2%). The random protocol provided significantly lower and more scattered values for the reachable workspace (80.0 +/- 22.6% vs. 91.0 +/- 8.1%, p = .004), whereas gender and hand-dominancy had no effect. This study showed that the reachable workspace was highly reliable over a period of 7 weeks and that both upper limbs provided similar results. It could be used to monitor various pathologies of the upper limbs and to assess treatment efficiency, using a subject's healthy limb as reference. PMID- 29277261 TI - The contribution of the supraspinatus muscle at sub-maximal contractions. AB - During maximum effort, the supraspinatus muscle contributes approximately 50% of the torque need to elevate the arm, but this has not been examined at sub-maximal levels. The purpose of this study was to determine the contribution of the supraspinatus muscle to shoulder elevation at sub-maximal levels. Seven healthy subjects (four males, three females) performed isometric ramp contractions at the shoulder. Middle deltoid electromyography (EMG) and force applied at the wrist were collected before and after a suprascapular nerve block. For the same level of deltoid EMG, less external force will be measured after the nerve block as the supraspinatus muscle no longer contributes. The difference between the EMG/force curve was the contribution of the supraspinatus muscle. The supraspinatus contributed 40%, 95% CI [32%-48%], to shoulder elevation. The effect of angle (p = .67) and % maximal voluntary contraction (p = .13) on supraspinatus contribution were not significant. The maximum is slightly less than reported in a previous suprascapular nerve block study using maximal contractions. The results from this study can be used to assess supraspinatus contribution in rotator cuff tears, after rehabilitation interventions, and as a restraint in computation modelling. PMID- 29277262 TI - Pancreatectomies for pancreatic neoplasms in pediatric and adolescent age: A single institution experience. AB - BACKGROUND: There are very few data in the current literature regarding the short and long-term outcome of surgery for pediatric pancreatic tumors (PPT). No data are available on the impact of pancreatic surgery on the children's growth. METHODS: This is a retrospective cohort study on a consecutive series of pediatric/adolescent patients who underwent pediatric surgery at Karolinska University Hospital from January 2005 to July 2017. RESULTS: Overall 14 pancreatic operations were performed in 13 patients. The median age was 11.4 years (range 3-15). Six pancreaticoduodenectomies (42.8%), 5 distal pancreatectomies (35.7%), and 3 enucleations (21.5%) were performed. The final histology revealed a solid pseudopapillary tumor in 9 cases (69.2%), neuroblastoma in 1 (7.7%), ganglioneuroma in 1 (7.7%), pancreatoblastoma in 1 (7.7%), and insulinoma in 1 (7.7%). Overall, 3 patients developed post-operative complications (23%). There was no peri-operative mortality. All patients are alive after a median follow-up time of 80 months. Exocrine insufficiency was detected post-operatively in 4 patients (30.7%) Endocrine insufficiency requiring insulin treatment developed in one patient (7.7%). No significant impact on growth was detected in any of the patients after pancreatic resection. CONCLUSIONS: In our series, surgery performed for PPTs seems to be safe and effective. The effect of pancreatic surgery on children's growth does not seem to be significant. PMID- 29277263 TI - Genetics of human epilepsies: Continuing progress. AB - Numerous epilepsy genes have been identified in the last years, mostly in the (rare) monogenic forms and thanks to the increased availability and the decreased cost of next-generation sequencing approaches. Besides the somehow expected group of epilepsy genes encoding various ion channel subunits (e.g. sodium or potassium channel subunits, or GABA receptors, or glutamate-gated NMDA receptors), more diversity has emerged recently, with novel epilepsy genes encoding proteins playing a wide range of physiological roles at the cellular and molecular levels, such as synaptic proteins, members of the mTOR pathway, or proteins involved in chromatin remodeling. The overall picture is somehow complicated: one given epilepsy gene can be associated with more than one epileptic phenotype, and with variable degrees of severity, from the benign to the severe forms (e.g. epileptic encephalopathies), and with various comorbid conditions such as migraine or autism spectrum of disorders. Conversely, one given epileptic syndrome may be associated with different genes, some of which have obvious links with each other (e.g. encoding different subunits of the same receptor) while other ones have no clear relationships. Also genomic copy number variations have been detected, some of which, albeit rare, may confer high risk to epilepsy. Whereas translation from gene identification to targeted medicine still remains challenging, progress in epilepsy genetics is currently revolutionizing genetic-based diagnosis and genetic counseling. Epilepsy gene identification also represents a key entry point to start in deciphering the underlying pathophysiological mechanisms via the design and the study of the most pertinent cellular and animal models - which may in turn provide proofs-of-principle for future applications in human epilepsies. PMID- 29277264 TI - Proteomics and bioinformatics analysis of altered protein expression in the placental villous tissue from early recurrent miscarriage patients. AB - INTRODUCTION: Recurrent miscarriage (RM) affects 5% of women, it has an adverse emotional impact on women. Because of the complexities of early development, the mechanism of recurrent miscarriage is still unclear. We hypothesized that abnormal placenta leads to early recurrent miscarriage (ERM). The aim of this study was to identify ERM associated factors in human placenta villous tissue using proteomics. Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying recurrent miscarriage (RM). METHODS: To gain more insight into mechanisms of recurrent miscarriage (RM), a comparative proteome profile of the human placenta villous tissue in normal and RM pregnancies was analyzed using iTRAQ technology and bioinformatics analysis used by Ingenuity Pathway Analysis (IPA) software. RESULTS: In this study, we employed an iTRAQ based proteomics analysis of four placental villous tissues from patients with early recurrent miscarriage (ERM) and four from normal pregnant women. Finally, we identified 2805 proteins and 79,998 peptides between patients with RM and normal matched group. Further analysis identified 314 differentially expressed proteins in placental villous tissue (>=1.3-fold, Student's t-test, p < 0.05); 209 proteins showed the increased expression while 105 proteins showed decreased expression. These 314 proteins were analyzed by Ingenuity Pathway Analysis (IPA) and were found to play important roles in the growth of embryo. Furthermore, network analysis show that Angiotensinogen (AGT), MAPK14 and Prothrombin (F2) are core factors in early embryonic development. We used another 8 independent samples (4 cases and 4 controls) to cross validation of the proteomic data. DISCUSSION: This study has identified several proteins that are associated with early development, these results may supply new insight into mechanisms behind recurrent miscarriage. PMID- 29277265 TI - Fetal-sex determination of human placental tissues. AB - It is now demonstrated that the sex-specific maternal-placental-fetal interaction plays an important role in placental functions and pathologies. Determination of fetal-sex may therefore be an important consideration in studies using placenta samples. In this present study, we describe a simple, fast, and cheap protocol, which allows the fetal-sex determination of placental tissues from various starting materials (villi or formalin-fixed, paraffin-embedded (FFPE) tissues, isolated cytotrophoblasts or cellular debris from whole cell lysates, and cDNA) by a single duplex PCR reaction followed by agarose gel electrophoresis. PMID- 29277266 TI - Changes in maternal placental growth factor levels during term labour. AB - : Placental growth factor (PlGF) has important angiogenic function that is critical to placental development. Lower levels of PlGF are associated with fetal growth restriction, pre-eclampsia and intrapartum fetal compromise. The aim of this study was to investigate the effect of labour on maternal PlGF levels. METHOD: This was a prospective observational cohort study. Normotensive women with a singleton, normally grown, non-anomalous, fetus between 37 + 0 and 42 + 0 weeks gestation were eligible for inclusion. PlGF was assayed at two time-points in labour. Women undergoing elective caesarean section served as controls. The primary outcome was the intrapartum change in maternal PlGF levels. RESULTS: Fifty-nine labouring and 43 non-labouring participants were included. Median PlGF decreased from 105.5 pg/mL to 80.9 pg/mL during labour (-23.9%, p < 0.001). PlGF levels were significantly lower in the second stage of labour irrespective of onset of labour, parity, mode of birth or gestation >=40 weeks. Compared to multiparous women, nulliparous women had significantly lower PlGF levels at both time-points but had similar overall decline in PlGF. Women who required operative vaginal delivery or emergency caesarean section had lower median PlGF levels at both PlGF time-points and greater drop in PlGF during labour compared to spontaneous vaginal deliveries but these were not statistically significant. No correlation was observed between duration of labour and decline in PlGF levels. CONCLUSION: Overall, median PlGF levels fall by nearly one quarter during labour. This decline may reflect deteriorating placental function during labour. PMID- 29277267 TI - Placental baseline conditions modulate the hyperoxic BOLD-MRI response. AB - OBJECTIVES: Human pregnancies complicated by placental dysfunction may be characterized by a high hyperoxic Blood oxygen level-dependent (BOLD) MRI response. The pathophysiology behind this phenomenon remains to be established. The aim of this study was to evaluate whether it is associated with altered placental baseline conditions, including a lower oxygenation and altered tissue morphology, as estimated by the placental transverse relaxation time (T2*). METHOD: We included 49 normal pregnancies (controls) and 13 pregnancies complicated by placental dysfunction (cases), defined by a birth weight < 10th percentile in combination with placental pathological signs of vascular malperfusion. During maternal oxygen inhalation, we measured the relative DeltaBOLD response ((hyperoxic BOLD - baseline BOLD)/baseline BOLD) from a dynamic single-echo gradient-recalled echo (GRE) MRI sequence and the absolute DeltaT2* (hyperoxic T2*- baseline T2*) from breath-hold multi-echo GRE sequences. RESULTS: In the control group, the relative DeltaBOLD response increased during gestation from 5% in gestational week 20 to 20% in week 40. In the case group, the relative DeltaBOLD response was significantly higher (mean Z-score 4.94; 95% CI 2.41, 7.47). The absolute DeltaT2*, however, did not differ between controls and cases (p = 0.37), whereas the baseline T2* was lower among cases (mean Z score -3.13; 95% CI -3.94, -2.32). Furthermore, we demonstrated a strong negative linear correlation between the Log10 DeltaBOLD response and the baseline T2* (r = -0.88, p < 0.0001). CONCLUSION: The high hyperoxic DeltaBOLD response demonstrated in pregnancies complicated by placental dysfunction may simply reflect altered baseline conditions, as the absolute increase in placental oxygenation (DeltaT2*) does not differ between groups. PMID- 29277268 TI - Dysregulated placental microRNAs in Early and Late onset Preeclampsia. AB - INTRODUCTION: To determine the miRNA expression profile in placentas complicated by Preeclampsia (PE) and compare it to uncomplicated pregnancies. METHODS: Sixteen placentas from women with PE, [11 with early onset PE (EOPE) and 5 with late onset PE (LOPE)], as well as 8 placentas from uncomplicated pregnancies were analyzed using miRNA microarrays. For statistical analyses the MATLAB(r) simulation environment was applied. The over-expression of miR-518a-5p was verified using Quantitative Real-Time Polymerase Chain Reaction. RESULTS: Forty four miRNAs were found dysregulated in PE complicated placentas. Statistical analysis revealed that miR-431, miR-518a-5p and miR-124* were over-expressed in EOPE complicated placentas as compared to controls, whereas miR-544 and miR-3942 were down-regulated in EOPE. When comparing the miRNA expression profile in cases with PE and PE-growth restricted fetuses (FGR), miR-431 and miR-518a-5p were found over-expressed in pregnancies complicated by FGR. DISCUSSION: Since specific miRNAs can differentiate EOPE and LOPE from uncomplicated placentas, they may be considered as putative PE-specific biomarkers. MiR-518a-5p emerged as a potential diagnostic indicator for EOPE cases as well as for PE-FGR complicated placentas, indicating a potential link to the severity of the disease. PMID- 29277270 TI - Human predecidual stromal cells have distinctive characteristics of pericytes: Cell contractility, chemotactic activity, and expression of pericyte markers and angiogenic factors. AB - INTRODUCTION: Human decidual stromal cells (DSCs) play a key role in maternal fetal interactions. Precursors of DSCs (preDSCs) localize around vessels in both the endometrium and decidua. Previous studies suggested a relationship between preDSCs and pericytes because these cells share a perivascular location, alpha smooth muscle actin (alpha-SM actin) expression and the ability to contract under the effects of cytokines. METHODS: To further study this relationship, we established 15 human preDSC lines and 3 preDSC clones. The preDSC lines and clones were tested by flow cytometry with a panel of 29 monoclonal antibodies, 14 of which are pericyte markers. The expression of angiogenic factors was determined by RT-PCR, chemotactic activity was studied with the migration assay, and cell contractility was evaluated with the collagen cell contraction assay. Confocal microscopy was used to study decidual sections. RESULTS: Under the effect of progesterone and cAMP, these lines decidualized in vitro: the cells became rounder and secreted prolactin, a marker of physiological DSC differentiation (decidualization). The antigen phenotype of these preDSC lines and clones was fully compatible with that reported for pericytes. PreDSC lines displayed pericyte characteristics: they expressed angiogenic factors and showed chemotactic and cytokine-induced contractile activity. Confocal microscopic examination of decidual sections revealed the expression of antigens detected in preDSC lines: alpha-SM actin colocalized with CD146, CD140b, MFG-E8, nestin, and STRO-1 (all of which are pericyte markers) in cells located around the vessels, a distinctive location of preDSCs and pericytes. DISCUSSION: Taken together, our results show that preDSCs are pericyte-like cells. PMID- 29277269 TI - Chromosome 19 microRNAs exert antiviral activity independent from type III interferon signaling. AB - INTRODUCTION: Cultured primary human trophoblasts (PHT), derived from term placentas, are relatively resistant to infection by diverse viruses. The resistance can be conferred to non-trophoblastic cells by pre-exposing them to medium that was conditioned by PHT cells. This antiviral effect is mediated, at least in part, by microRNAs (miRNA) expressed from the chromosome 19 microRNA cluster (C19MC). Recently we showed that PHT cells and cells pre-exposed to PHT medium are also resistant to infection by Zika virus (ZIKV), an effect mediated by the constitutive release of the type III interferons (IFN) IFN lambda-1 and IFN lambda-2 in trophoblastic medium. We hypothesized that trophoblastic C19MC miRNA are active against ZIKV, and assessed the interaction of this pathway with IFN lambda-1 - mediated resistance. METHODS: Term PHT cells were cultured using standard techniques. An osteosarcoma cell line (U2OS) was used as non trophoblastic cells, which were infected with either ZIKV or vesicular stomatitis virus (VSV). Trophoblastic extracellular vesicles (EVs) were produced by gradient ultracentrifugation. RT-qPCR was used to determine viral infection, cellular or medium miRNA levels and the expression of interferon-stimulated genes. RESULTS: We showed that C19MC miRNA attenuate infection of U2OS cells by ZIKV, and that C19MC miRNA or exosomes that contain C19MC miRNA did not influence the type III IFN pathway. Similarly, cell exposure to recombinant IFN lambda-1 had no effect on miRNA expression, and these pathways did not exhibit synergistic interaction. DISCUSSION: PHT cells exert antiviral activity by at least two independent mechanisms, mediated by C19MC miRNA and by type III IFNs. PMID- 29277271 TI - Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus? AB - Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with endothelial dysfunction in the foetoplacental vasculature. Foetoplacental endothelial dysfunction is characterized by changes in the l-arginine-adenosine signalling pathway and inflammation. The mechanisms involved in these alterations are suggested to be hyperglycaemia, hyperinsulinemia, and oxidative stress. These conditions increase the release of exosomes, nanovesicles that are generated from diverse cell types, including endothelial cells. Since exosomes can modulate vascular function, they may play an important role in foetoplacental endothelial dysfunction seen in GDM pregnancies. In this review, we summarized current knowledge on the potential role of exosomes in foetoplacental endothelial dysfunction seen in this disease of pregnancy. PMID- 29277272 TI - Classics revisited: Miguel Fernandez on germ layer inversion and specific polyembryony in armadillos. AB - BACKGROUND: Miguel Fernandez was an Argentinian zoologist who published the first account of obligate polyembryony in armadillos. His contribution is here discussed in relation to his contemporaries, Newman and Patterson, and more recent work. FINDINGS: Fernandez worked on the mulita (Dasypus hybridus). He was able to get early stages before twinning occurred and show it was preceded by inversion of the germ layers. By the primitive streak stage there were separate embryonic shields and partition of the amnion. There was, however, a single exocoelom and all embryos were enclosed in a common set of membranes comprising chorion towards the attachment site in the uterine fundus and inverted yolk sac on the opposite face. He showed that monozygotic twinning did not occur in another armadillo, the peludo (Chaetophractus villosus). CONCLUSIONS: Fernandez's work represented a major breakthrough in understanding how twinning occurred in armadillos. His work and that of others is of intrinsic interest to zoologists and has a direct bearing on the origin of monozygotic twins and birth defects in humans. PMID- 29277273 TI - Identification of potential early biomarkers of preeclampsia. AB - INTRODUCTION: It is thought that poor placental perfusion caused by inadequate remodelling of the maternal spiral arteries leads to preeclampsia (PE). To identify novel signalling pathways that contribute to PE pathogenesis and to create prerequisites for the non-invasive diagnosis of PE before clinical manifestations of the disease, this study aimed to evaluate miRNA expression levels in the placenta and blood plasma of pregnant women. METHODS: miRNA deep sequencing followed by real-time quantitative RT-PCR was applied to compare miRNA expression profiles in the placenta and blood plasma from women with early- and late-onset PE relative to the control group. RESULTS: A more than two-fold decrease in miR-532-5p, -423-5p, -127-3p, -539-5p, -519a-3p, and -629-5p and let 7c-5p expression levels was observed in the placenta, while a more than two-fold increase in miR-423-5p, 519a-3p, and -629-5p and let-7c-5p was observed in the blood plasma of pregnant women with PE. The above-listed miRNAs are associated with PE for the first time in this study, except for miR-519a-3p, whose role in PE has already been postulated. Using a logistic regression, plasma samples were classified into the early-onset PE group (probability p = 0.01, 80% specificity, 87.5% sensitivity and 87.5% precision) and showed increased miR-423-5p expression levels that were confirmed by the 9.8-fold up-regulation (r = 0.0002498) of miR 423-5p expression observed in the blood plasma at 11-13 GW by RT-PCR in a group of pregnant women manifesting severe PE clinical signs at 28-33 GW. CONCLUSIONS: miR-423-5p may be considered a potential candidate for the early diagnosis of PE during the targeted management of high-risk pregnancies. PMID- 29277274 TI - Maternal high estradiol exposure alters CDKN1C and IGF2 expression in human placenta. AB - INTRODUCTION: The increased maternal estradiol (E2) concentrations induced by assisted reproductive technology (ART) result in lower birth weight of offspring, which is associated with increased risk of adult diseases. However, the exact mechanism remains unknown. The present study investigated the effect of high E2 exposure on the expression of imprinted genes CDKN1C and IGF2 in human placentas and the DNA methylation status of their differential methylation regions (DMRs). METHODS: The mRNA expression of CDKN1C and IGF2 in human placentas and the human trophoblast cells (HTR8) treated with E2 were investigated by reverse transcription-real time polymerase chain reaction (PCR). The DNA methylation of their DMRs were investigated by sodium bisulfite sequencing. RESULTS: CDKN1C and IGF2 were significantly up-regulated in ART conceived placentas. The mean birth weight of ART singletons was significantly lower than that of naturally conceived (NC) ones, with the increased percentage of small-for-gestational-age (SGA) birth. The DNA methylation was significantly down-regulated in the DMR of CDKN1C (KvDMR1) and up-regulated in the DMR of IGF2 (H19 DMR) in ART placentas. The treatment of E2 altered the expression of the two genes and the DNA methylation of their DMRs in HTR8 to a similar tendency as in vivo. DISCUSSION: The maternal high E2 levels after ART up-regulate the expression of imprinted genes in human placentas through epigenetic modifications, which influences the growth potential of the offspring. Further studies are needed to follow up the growth and development of the ART offspring. PMID- 29277275 TI - Towards standardized criteria for diagnosing chronic intervillositis of unknown etiology: A systematic review. AB - Chronic intervillositis of unknown etiology (CIUE) is a poorly understood, relatively rare condition characterized histologically by the intervillous infiltration of mononuclear cells in the placenta. Clinically, CIUE is associated with poor pregnancy outcome (e.g., impaired fetal growth, preterm birth, fetal death) and high risk of recurrence in subsequent pregnancies. Because CIUE is not defined consistently, it is essential to clearly define this condition. We therefore review the published definitions of CIUE. In addition, we provide an overview of the reviewed histopathological and maternal characteristics, obstetric features, and pregnancy outcomes. Medical publication databases were searched for articles published through February 2017. Eighteen studies were included in our systematic review. The sole inclusion criterion used in all studies was the presence of intervillous infiltrates. Overall, CIUE was characterized by adverse pregnancy outcome. Miscarriage occurred in 24% of cases, with approximately half of these miscarriages defined as late. Impaired growth was commonly observed, 32.4% of pregnancies reached term, and the live birth rate was 54.9%. The high recurrence rate (25.1%) of the intervillous infiltrates in subsequent pregnancies underscores the clinical relevance of CIUE, the need for increased awareness among pathologists and clinicians, and the need for further research. Criteria for the diagnosis of CIUE are proposed and a Delphi study could be used to resolve any controversy regarding these criteria. Future studies should be designed to characterize the full clinical spectrum of CIUE. PMID- 29277276 TI - Preliminary metabolomics analysis of placenta in maternal obesity. AB - INTRODUCTION: Metabolomics identifies phenotypical groups with specific metabolic profiles, being increasingly applied to several pregnancy conditions. This is the first preliminary study analyzing placental metabolomics in normal weight (NW) and obese (OB) pregnancies. METHODS: Twenty NW (18.5 <= BMI< 25 kg/m2) and eighteen OB (BMI>= 30 kg/m2) pregnancies were studied. Placental biopsies were collected at elective caesarean section. Metabolites extraction method was optimized for hydrophilic and lipophilic phases, then analyzed with GC-MS. Univariate and PLS-DA multivariate analysis were applied. RESULTS: Univariate analysis showed increased uracil levels while multivariate PLS-DA analysis revealed lower levels of LC-PUFA derivatives in the lipophilic phase and several metabolites with significantly different levels in the hydrophilic phase of OB vs NW. DISCUSSION: Placental metabolome analysis of obese pregnancies showed differences in metabolites involved in antioxidant defenses, nucleotide production, as well as lipid synthesis and energy production, supporting a shift towards higher placental metabolism. OB placentas also showed a specific fatty acids profile suggesting a disruption of LC-PUFA biomagnification. This study can lay the foundation to further metabolomic placental characterization in maternal obesity. Metabolic signatures in obese placentas may reflect changes occurring in the intrauterine metabolic environment, which may affect the development of adult diseases. PMID- 29277277 TI - New imaging markers for preconceptional and first-trimester utero-placental vascularization. AB - INTRODUCTION: The availability of imaging makers of early placental circulation development is limited. This study aims to develop a feasible and reliable method to assess preconceptional and early first-trimester utero-placental vascular volumes using three-dimensional power Doppler (3D PD) ultrasound on two different Virtual Reality (VR) systems. METHODS: 3D PD ultrasound images of the uterine and placental vasculature were obtained in 35 women, either preconceptionally (n = 5), or during pregnancy at 7 (n = 10), 9 (n = 10) or 11 (n = 10) weeks of gestation. Preconceptional uterine vascular volume (UVV), first-trimester placental vascular volume (PVV) and embryonic vascular volume (EVV) were measured by two observers on two VR systems, i.e., a Barco I-Space and VR desktop. Intra- and inter-observer agreement and intersystem agreement were assessed by intra class correlation coefficients (ICC) and absolute and relative differences. RESULTS: Uterine-, embryonic- and placental vascular volume measurements showed good to excellent intra- and inter-observer agreement and inter-system reproducibility with most ICC above 0.80 and relative differences of less than 20% preconceptionally and almost throughout the entire gestational age range. Inter-observer agreement of PVV at 11 weeks gestation was suboptimal (ICC 0.69, relative difference 50.1%). DISCUSSION: Preconceptional and first-trimester 3D PD ultrasound utero-placental and embryonic vascular volume measurements using VR are feasible and reliable. Longitudinal cohort studies with repeated measurements are needed to further validate this and assess their value as new imaging markers for placental vascular development and ultimately for the prediction of placenta related pregnancy complications. PMID- 29277278 TI - Sustainability of Fishing Is about Abundance: A Response to Bernatchez et al. PMID- 29277279 TI - Reply to the Letter to the Editor: Comments in relation to the CPC case entitled: "Submucosal nodule in buccal mucosa" Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:660-665. PMID- 29277280 TI - Lymphadenopathies in human immunodeficiency virus infection. AB - This article describes the various non-neoplastic lymphadenopathies that occur in patients infected with the human immunodeficiency virus (HIV), before or during the stage of acquired immunodeficiency syndrome (AIDS). The stages that develop during the HIV infection include: primary infection (acute infection, spread of the virus, development of host immune response, and acute retroviral syndrome), chronic infection or clinical latency, and finally, the AIDS stage. Non neoplastic lymphadenopathies can occur at any of these phases of the infection and are due to multiple causes that can be divided into infectious causes (bacterial, fungal, parasitic, viral), and reactive causes (persistent generalized lymphadenopathy and a variety of situations that they also occur in immunocompetent people such as Castleman's disease and Kikuchi-Fujimoto's disease, among others). The general, histological and immunophenotypic characteristics of these pathologies are described. PMID- 29277281 TI - Yield of Computed Tomography (CT) Angiography in Patients with Acute Headache, Normal Neurological Examination, and Normal Non Contrast CT: A Meta-Analysis. AB - BACKGROUND: Patients with acute severe headache, normal neurological examination, and a normal noncontrast head computed tomography (NCCT) may still have subarachnoid hemorrhage, cerebral venous thrombosis (CVT), cervical arterial dissection, or reversible cerebral vasoconstriction syndrome (RCVS). Computed tomography angiography (CTA) is used increasingly in the emergency department for evaluating this, but its added value remains controversial. METHODS: We retrospectively collected data on the diagnostic yield of CTA in patients with acute severe headache, normal neurological examination, and normal NCCT who received additional CTA in the acute phase in 2 secondary referral centers for vascular neurology. We combined data of our patients with those from the literature and performed a meta-analysis. RESULTS: We included 88 patients from our hospital files and 641 patients after literature search. Of 729 patients 54 had a vascular abnormality on CTA (7.4%; 95% confidence interval [CI] 5.5%-9.3%). Abnormalities consisted of aneurysms (n = 42; 5.4%; 95% CI 3.8%-7.0%), CVT (n = 3, .5%), RCVS (n = 4, .5%), Moyamoya syndrome (n = 2, .3%), arterial dissection (n = 2, .3%), and ischemia (n = 1, .1%). Because most of the aneurysms were probably incidental findings, only 12 (1.6%) patients had a clear relation between the headache and CTA findings. The number needed to scan to find an abnormality was 14 overall, and 61 for an abnormality other than an aneurysm. CONCLUSION: Diagnostic yield of CTA in patients with acute headache, normal neurological examination, and normal NCCT is low, but because of the possible therapeutic consequences, its use might be justified in the emergency setting. Prospective studies confirming these results including cost-effectiveness analyses are needed. PMID- 29277283 TI - Correlation between blood alcohol concentration (BAC), breath alcohol concentration (BrAC) and psychomotor evaluation in a clinical monitored study of alcohol intake in Brazil. AB - BACKGROUND: Policies that establish maximum blood alcohol concentrations (BACs) or breath alcohol concentration (BrACs) for drivers while driving can reduce traffic accidents by approximately 20%. In Brazil, the National Transit Council (CONTRAN) considers positive BAC and/or BrAC tests or signs of psychomotor capacity alterations as evaluated by a police authority to be an administrative infraction or even a crime. The observed clinical symptoms of alcohol intoxication based on a subject's appearance may not necessarily reflect the quantified BAC and/or BrAC. This study compared the clinical symptoms identified by a medical authority (M) and a non-medical authority (NM) with BAC and BrAC measurements. METHODS: Brazilian health volunteers (n = 15) drank ethanol (40% v/v) and, at scheduled times, the subjects underwent blood draws for BAC analysis, were tested for BrAC analysis, and underwent psychomotor alteration assessments performed by M and NM. RESULTS: Concentration-time profiles of the BACs and BrACs of the volunteer subjects were generated. The BAC values reached a peak at 60 min and subsequently decreased with time. The average BrAC values decreased with time after ingestion. During the evaluations, M was able to identify a lack of static equilibrium until 240 min and a lack of dynamic equilibrium until 120 min. A lack of upper limb motor coordination was observed until 90 min, and a lack of coordination in the lower limbs was observed only during the first hour. Regarding the tests performed by NM, the signs related to the subjects' appearances were observed more frequently, until 60 min. The other analyzed symptoms were not identified. Naturally, the signs reported by both M and NM disappeared with time. CONCLUSION: The evaluations of psychomotor changes performed by Brazilian M were superior to those performed by NM. However, independent of the examiner, at the alcohol concentrations reached in this study, the psychomotor alteration evaluations were ineffective compared with the BAC and BrAC results. PMID- 29277282 TI - Evaluation of laboratory tests for cirrhosis and for alcohol use, in the context of alcoholic cirrhosis. AB - Laboratory tests can play an important role in assessment of alcoholic patients, including for evaluation of liver damage and as markers of alcohol intake. Evidence on test performance should lead to better selection of appropriate tests and improved interpretation of results. We compared laboratory test results from 1578 patients between cases (with alcoholic cirrhosis; 753 men, 243 women) and controls (with equivalent lifetime alcohol intake but no liver disease; 439 men, 143 women). Comparisons were also made between 631 cases who had reportedly been abstinent from alcohol for over 60 days and 364 who had not. ROC curve analysis was used to estimate and compare tests' ability to distinguish patients with and without cirrhosis, and abstinent and drinking cases. The best tests for presence of cirrhosis were INR and bilirubin, with areas under the ROC curve (AUCs) of 0.91 +/- 0.01 and 0.88 +/- 0.01, respectively. Confining analysis to patients with no current or previous ascites gave AUCs of 0.88 +/- 0.01 for INR and 0.85 +/- 0.01 for bilirubin. GGT and AST showed discrimination between abstinence and recent drinking in patients with cirrhosis, including those without ascites, when appropriate (and for GGT, sex-specific) limits were used. For AST, a cut-off limit of 85 units/L gave 90% specificity and 37% sensitivity. For GGT, cut-off limits of 288 units/L in men and 138 units/L in women gave 90% specificity for both and 40% sensitivity in men, 63% sensitivity in women. INR and bilirubin show the best separation between patients with alcoholic cirrhosis (with or without ascites) and control patients with similar lifetime alcohol exposure. Although AST and GGT are substantially increased by liver disease, they can give useful information on recent alcohol intake in patients with alcoholic cirrhosis when appropriate cut-off limits are used. PMID- 29277284 TI - Alcohol withdrawal upregulates mRNA encoding for CaV2.1-alpha1 subunit in the rat inferior colliculus. AB - We previously reported increased current density through P-type voltage-gated Ca2+ channels in inferior colliculus (IC) neurons during alcohol withdrawal. However, the molecular correlate of this increased P-type channel current is currently unknown. Here, we probe changes in mRNA and protein expression of the pore-forming CaV2.1-alpha1 (P/Q-type) subunits in IC neurons during the course of alcohol withdrawal-induced seizures (AWSs). Rats received three daily doses of ethanol or the vehicle every 8 h for 4 consecutive days. The IC was dissected at various time intervals following alcohol withdrawal, and the mRNA and protein levels of the CaV2.1-alpha1 subunits were measured. In separate experiments, rats were tested for acoustically evoked seizure susceptibility 3, 24, and 48 h after alcohol withdrawal. AWSs were observed 24 h after withdrawal; no seizures were observed at 3 or 48 h or in the control-treated rats. Compared to control-treated rats, the mRNA levels of the CaV2.1-alpha1 subunit were increased 1.9-fold and 2.1-fold at 3 and 24 h, respectively; change in mRNA expression was nonsignificant at 48 h following alcohol withdrawal. Western blot analyses revealed that protein levels of the CaV2.1-alpha1 subunits were not altered in IC neurons following alcohol withdrawal. We conclude that expression of the Cacna1a mRNA increased before the onset of AWS susceptibility, suggesting that altered CaV2.1 channel expression may play a role in AWS pathogenesis. PMID- 29277285 TI - The effects of working memory load and attention refocusing on delay discounting rates in alcohol use disorder with comorbid antisocial personality disorder. AB - Executive working memory capacity (eWMC) is central to adaptive decision-making. Research has revealed reduced eWMC and higher rates of impulsive decision making in individuals with alcohol use disorders (AUDs: DSM-IV Alcohol Dependence of Alcohol Abuse) and antisocial psychopathology (AP). Recent work has shown that placing a load on working memory (WM) further increases impulsive decision making on the delay discounting (DD) task in those with AUDs and AP. The current study examined the effects of an attention refocusing manipulation to offset the effects of this WM-load on DD rates in control subjects, those with AUDs without AP, and AUDs with AP (AUD-AP). Results revealed that 1) the AUD-AP group had higher DD rates (i.e., more impulsive decision-making) than the AUD group, followed by controls, and 2) attention refocusing after a load is placed on WM was associated with lower DD rates compared to the load without refocusing in both AUD groups, but not controls. Results suggest that refocusing attention after a cognitive load may be an effective cognitive strategy for reducing the impulsivity-enhancing effects of cognitive load on decision making in individuals with AUDs and AP. PMID- 29277286 TI - The relationship between the S-wave in lead 1 and recurrence of RVOT PVC ablation. AB - BACKGROUND: Radiofrequency catheter ablation (CA) is a common non-pharmacological treatment option for ventricular premature contractions (PVCs) originating from right ventricular outflow tract (RVOT). In this study, we aimed to investigate the relationship between recurrence after CA for RVOT-PVC and S-wave in lead 1 that was shown to be associated with RVOT depolarization. METHODOLOGY: A total of 104 patients who were referred to our clinic for CA for idiopathic RVOT-PVC between 2012 and 2015years were enrolled. All ECG parameters were measured before and after the ablation procedure. RESULTS: Ablation was successful in 100 patients (96,1%). These patients with successful ablation were followed for a mean duration of 1078days. 13 patients (13%) had recurrence. Univariate logistic regression analysis revealed age (odds ratio: 1.916, p:0,012), presence of post procedural S1 (odds ratio:1.040 p:0,028), post-procedural S1 area (oddsratio:1.023 p:0,041), DeltaS1 area (odds ratio:1.242 p:0,004) as predictors for recurrence. Multivariate logistic regression analysis detected age (odds ratio:1.053 p:0,032) and DeltaS1 area (odds ratio:0.701 p:0,009) as predictors for recurrence. CONCLUSION: Radiofrequency CA for RVOT-PVC can be performed with high procedural success and low complication rates. Age and DeltaS1 area might be helpful for prediction of recurrence after CA. PMID- 29277287 TI - Editorial commentary: Mitochondrial autophagy in cardiac aging is all fluxed up. PMID- 29277288 TI - Early discontinuation of dual antiplatelet therapy in patients treated with the bio-engineered pro-healing sirolimus-eluting (COMBO) stent. AB - BACKGROUND: When the pro-healing COMBO stent is used, a short duration of dual antiplatelet therapy (DAPT) might be safe. However, no cases have been described of patients with short duration of DAPT after COMBO stent placement. METHODS AND RESULTS: We investigate clinical outcomes at 1year after early discontinuation of DAPT in patients participating in the REMEDEE Registry. This is a prospective, multicentre, European, all-comers registry with a 1000 patients treated with COMBO stent. Target lesion failure (TLF), a composite of target vessel-myocardial infarction (tv-MI), cardiac death and target lesion revascularization, and the occurrence of stent thrombosis (ST) in relation with DAPT cessation before 30 and 180days of follow-up is evaluated. At 30days follow-up 48 patients were not on DAPT, at 180days follow-up of 78 patients had no DAPT. Patients with DAPT discontinuation were older, had overall lower left ventricle ejection fraction and more frequent chronic renal failure. No TLF and especially no stent thrombosis were observed in these patients. CONCLUSIONS: Discontinuation of DAPT within 6months after COMBO stent placement did not influence the rate of TLF up to 1-year follow-up. Large randomized trials are needed to confirm the safety of short duration of DAPT after COMBO stent placement. PMID- 29277289 TI - Voice and swallowing outcomes following hypoglossal nerve stimulation for obstructive sleep apnea. AB - OBJECTIVE: Hypoglossal nerve stimulation is an effective treatment for a subset of patients with Obstructive Sleep Apnea (OSA). Although multiple clinical trials demonstrate its efficacy, no previous literature explores the potential impact the stimulator has on swallowing and voice. Our primary objective is to evaluate patient reported post-operative changes in voice or swallowing following hypoglossal nerve stimulator placement. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary care hospital. SUBJECT AND METHODS: Patients scheduled to receive a hypoglossal stimulator were enrolled. Participants completed baseline Voice Handicap Index-10 (VHI-10) and Eating Assessment Tool-10 (EAT-10) questionnaires preoperatively and again at 1week, 3months, and 6months post operatively following placement of a hypoglossal nerve stimulator. RESULTS: 9 males and 5 females completed the study. The mean pre-operative VHI-10 and EAT-10 score was 3 and 0.8 respectively. Using linear mixed models, a clinically and statistically significant increase in the mean EAT-10 score was observed post operatively at 1week (p=0.007), which was not observed at the time points the stimulator was active. A clinically and statistically significant decrease in VHI 10 score was observed following 2months of active stimulator use (p=0.02), which was not observed at any other time point. CONCLUSION: The implantation and use of the hypoglossal nerve stimulator over 5months did not demonstrate any sustained, patient reported changes in voice handicap and swallowing function. While larger studies are warranted, our findings can be used to provide further informed consent for hypoglossal nerve stimulator implantation. PMID- 29277290 TI - Accuracy and reliability of brain natriuretic peptide (BNP) in predicting the prognosis of non-cardiac patients with sepsis. PMID- 29277291 TI - Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease. AB - We recently established a mouse model (288-330+/+) that developed acute respiratory disease resembling human pathology following infection with a high dose (5 * 106 PFU) of mouse-adapted MERS-CoV (icMERSma1). Although this high dose conferred fatal respiratory disease in mice, achieving similar pathology at lower viral doses may more closely reflect naturally acquired infections. Through continued adaptive evolution of icMERSma1 we generated a novel mouse-adapted MERS CoV (maM35c4) capable of achieving severe respiratory disease at doses between 103 and 105 PFU. Novel mutations were identified in the maM35c4 genome that may be responsible for eliciting etiologies of acute respiratory distress syndrome at 10-1000 fold lower viral doses. Importantly, comparative genetics of the two mouse-adapted MERS strains allowed us to identify specific mutations that remained fixed through an additional 20 cycles of adaptive evolution. Our data indicate that the extent of MERS-CoV adaptation determines the minimal infectious dose required to achieve severe respiratory disease. PMID- 29277293 TI - Challenging Diagnosis and Inpatient Rehabilitation of Acute Bilateral Neuralgic Amyotrophy Possibly Attributed to Lyme Disease: A Case Report. AB - : Neuralgic amyotrophy (NA) is a neurologic syndrome of unknown etiology primarily affecting the brachial plexus. We are reporting an unusual case of acute bilateral NA that was possibly secondary to Lyme disease. The patient demonstrated significant functional gains and was discharged home after 2 weeks of inpatient rehabilitation, supporting the role of inpatient rehabilitation in acute NA. In this report, we discuss the diagnosis, electrodiagnostic progression, pain management, goals for inpatient rehabilitation, and overall prognosis of NA. LEVEL OF EVIDENCE: V. PMID- 29277292 TI - Resveratrol attenuates hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats: Role of ROS and ROS-mediated cell signaling. AB - Resveratrol, a natural polyphenolic compound has been reported to attenuate angiotensin II -induced vascular smooth muscle cell (VSMC) hypertrophy; however, whether resveratrol could also inhibit hyperproliferation of VSMC from spontaneously hypertensive rats (SHR) is unexplored. The present study investigates the effect of resveratrol on hyperproliferation of VSMC from SHR and the underlying molecular mechanisms responsible for this response. For these studies, aortic VSMC from SHR and Wistar-Kyoto (WKY) rats were used. The proliferation of VSMC was determined by [3H] thymidine incorporation and the levels of proteins were determined by Western blotting. The enhanced proliferation exhibited by VSMC from SHR was attenuated by resveratrol. In addition, resveratrol attenuated the overexpression of cyclin D1, cyclin E, cyclin dependent kinase 4 (Cdk4), Cdk2, phosphorylated retinoblastoma protein (pRb), Gialpha proteins and enhanced phosphorylation of ERK1/2 and AKT in VSMC from SHR. Furthermore, the overproduction of superoxide anion, increased NADPH oxidase activity, overexpression of Nox2, Nox4 and p47phox proteins, increased phosphorylation of EGFR, IGF-IR, and c-Src were all abrogated by resveratrol. These results suggest that resveratrol attenuates the hyperproliferation of VSMC from SHR through the inhibition of ROS, c-Src, growth factor receptor activation, MAPK/PI3K, Gialpha and cell cycle proteins that are implicated in VSMC hyperproliferation. PMID- 29277294 TI - Structural Basis of Enhanced Crystallizability Induced by a Molecular Chaperone for Antibody Antigen-Binding Fragments. AB - Monoclonal antibodies constitute one of the largest groups of drugs to treat cancers and immune disorders, and are guiding the design of vaccines against infectious diseases. Fragments antigen-binding (Fabs) have been preferred over monoclonal antibodies for the structural characterization of antibody-antigen complexes due to their relatively low flexibility. Nonetheless, Fabs often remain challenging to crystallize because of the surface characteristics of complementary determining regions and the residual flexibility in the hinge region between the variable and constant domains. Here, we used a variable heavy chain (VHH) domain specific for the human kappa light chain to assist in the structure determination of three therapeutic Fabs that were recalcitrant to crystallization on their own. We show that this ligand alters the surface properties of the antibody-ligand complex and lowers its aggregation temperature to favor crystallization. The VHH crystallization chaperone also restricts the flexible hinge of Fabs to a narrow range of angles, and so independently of the variable region. Our findings contribute a valuable approach to antibody structure determination and provide biophysical insight into the principles that govern the crystallization of macromolecules. PMID- 29277295 TI - Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation in Diabetic and Non-Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Diabetic patients account for an increasing number of patients undergoing percutaneous coronary intervention (PCI). However, diabetes mellitus (DM) is associated with increased residual platelet activity during dual antiplatelet treatment (DAPT) and DM patients have worse clinical outcomes after PCI as compared to non-DM. OBJECTIVE: To evaluate efficacy and safety of short duration DAPT (S-DAPT) and long duration DAPT (L-DAPT) after drug eluting stent (DES) implantation in DM and non-DM patients. METHODS: We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the effect of S-DAPT versus L-DAPT after DES implantation in DM and non-DM patients. Efficacy endpoints were all cause mortality, cardiac mortality, myocardial infarction (MI), stent thrombosis (ST), target vessel revascularization (TVR), and composite end point of net adverse clinical events (NACE) (all-cause mortality, cardiac mortality, MI, ST, TVR, stroke, major bleeding). Safety endpoints were major bleeding and stroke. Event rates were compared using a forest plot of relative risk using a random effects model. RESULTS: We included eight RCTs that randomized 28,318 patients to S-DAPT versus L-DAPT (8234 DM and 20,084 non-DM). S-DAPT was associated with an increased rate of ST in non-DM patients [3.67 (2.04, 6.59)]. There was no significant difference in the rate of all-cause mortality, cardiac mortality, ST, MI, TVR, major bleeding, stroke and NACE with S-DAPT and L-DAPT in DM patients [1.19 (0.72-1.95); 1.25 (0.69, 2.25); 1.52 (0.70, 3.29); 1.33 (0.88, 2.01); 1.39 (0.89, 2.17); 0.92 (0.19, 4.42); 0.98 (0.29, 3.28); and 0.94 (0.57, 1.54) respectively]. Further, there was no significant difference in the rate of all cause mortality, cardiac mortality, MI, TVR, major bleeding, stroke and NACE with S-DAPT and L-DAPT in non-DM patients [0.93 (0.58, 1.48); 0.75 (0.42, 1.35); 1.52 (0.81, 2.83); 0.99 (0.71, 1.39); 0.72 (0.28, 1.84); 1.01 (0.40, 2.56); and 1.01 (0.77, 1.32) respectively]. CONCLUSION: Compared to L-DAPT, S-DAPT was associated with significant increase in rate of ST in non-DM patients. Duration of DAPT had no significant impact on rates of all-cause mortality, cardiac mortality, MI, ST and TVR among DM patients. PMID- 29277296 TI - Successful treatment of giant invasive cutaneous squamous cell carcinoma by plum blossom needle assisted photodynamic therapy sequential with imiquimod: Case experience. AB - Giant cutaneous squamous cell carcinoma (cSCC) in elderly people is difficult to treat. Herein, we report a case of 96-year-old male who was diagnosed to have giant facial invasive SCC (4cm*4.5cm*2 cm). He was successfully treated with plum blossom needle assisted photodynamic therapy (PDT) sequential with imiquimod. The patient achieved complete remission after 9 sessions of PDT and 3 months of imiquimod but developed residual vitiligo-like hypopigmentation. There was no recurrence at 18 months of follow-up. This case suggests that plum-blossom needle pretreated PDT sequential by topical imiquimod is a viable treatment option for refractory and giant thick SCC. PMID- 29277297 TI - Effects of Dexmedetomidine-Isoflurane versus Isoflurane Anesthesia on Brain Injury After Cardiac Valve Replacement Surgery. AB - OBJECTIVES: To compare dexmedetomidine combined with isoflurane versus isoflurane anesthesia on brain injury after cardiac surgery. DESIGN: A prospective, randomized, single-blind study. SETTING: University hospital. PARTICIPANTS: Adult patients undergoing elective valve replacement surgery. INTERVENTIONS: Ninety seven patients scheduled for valve replacement surgery were randomly divided into 2 groups: dexmedetomidine and isoflurane (Dex-Iso, n = 50) and isoflurane alone (Iso, n = 47). Dexemedetomidine was infused at 0.6 MUg/kg as a bolus, followed with 0.2 MUg/kg/h until the end of surgery. MEASUREMENTS AND MAIN RESULTS: Jugular blood samples were drawn for analysis of matrix metalloproteinase-9 (MMP 9) and glial fibrillary acidic protein (GFAP) levels on time points of: T1 (before induction); T2 (5 minutes after cardiopulmonary bypass [CPB] onset); T3 (after CPB off); T4 (the first day after operation); T5 (the second day after operation). Plasma lactate levels in arterial and jugular venous blood also were quantified. The difference between arterial and jugular bulb venous blood lactate levels (AVDL) was calculated. An antisaccadic eye movement (ASEM) test was carried out on the day before the operation and the seventh day postoperatively. In both groups, serum MMP-9 and GFAP concentrations increased after CPB, with the peak values occurring after CPB. At time point T5, MMP-9 and GFAP levels were close to those at T1. MMP-9 concentrations in the Dex-Iso group were lower than the Iso group at T3 and T4. GFAP concentrations in the Dex-Iso group were lower at T3 but were higher than the Iso group at T2. No significant differences were found in AVDL between the 2 groups perioperatively except at T2. The ASEM scores decreased significantly postoperatively. There was no significant difference in the ASEM scores between the 2 treatment groups before and after the operation. CONCLUSIONS: The use of dexmedetomidine decreased the biochemical markers of brain injury but did not improve the neuropsychological test result after cardiac surgery. PMID- 29277299 TI - Con: Routine Use of Embolic Filters in Transcatheter Aortic Valve Replacement Is not Indicated. PMID- 29277300 TI - Innovations in Preoperative Planning: Insights into Another Dimension Using 3D Printing for Cardiac Disease. AB - Two-dimensional visualization of complex congenital heart disease has limitations in that there is variation in the interpretation by different individuals. Three dimensional printing technology has been in use for decades but is currently becoming more commonly used in the medical field. Congenital heart disease serves as an ideal pathology to employ this technology because of the variation of anatomy between patients. In this review, the authors aim to discuss basics of applicability of three-dimensional printing, the process involved in creating a model, as well as challenges with establishing utility and quality. PMID- 29277298 TI - A Pilot Analysis of the Association Between Types of Monitored Anesthesia Care Drugs and Outcomes in Transfemoral Aortic Valve Replacement Performed Without General Anesthesia. AB - OBJECTIVE: The types of agents used for monitored anesthesia care (MAC) and their possible differential effects on outcomes have received less study despite increased use over general anesthesia (GA) in transfemoral aortic valve replacements (TAVRs). In this pilot analysis of patients undergoing TAVR using MAC, the authors described the anesthetic agents used and sought to investigate the possible association of anesthetic agent choice with outcomes and the extent to which total weight and time-adjusted doses of anesthetics declined with increasing 10-year age increments. DESIGN: Retrospective observational study. SETTING: Tertiary teaching hospital. PARTICIPANTS: Ninety-three participants scheduled to undergo TAVR, with a primary plan of conscious sedation between November 2014 and June 2016, were included. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Types of MAC were divided into 4 primary groups, but 2 groups were focused: propofol (n = 39) and dexmedetomidine plus propofol (n = 34). Conversion to GA occurred in 6 participants (6.45%) and was not associated with the type of sedation received. The authors also compared patients who received dexmedetomidine with those who did not in accordance with their a priori analytic plan. There were no associations between the use of dexmedetomidine and postoperative delirium or intensive care unit/hospital length of stay. No significant trends in medication dose adjustments were seen across increasing 10 year age increments. CONCLUSIONS: A wide breadth of MAC medications is in use among TAVR patients and does not support differences in outcomes. Despite recommendations to reduce anesthetic drug dosing in the elderly, no significant trends in dose reduction with increasing age were noted. PMID- 29277301 TI - Precipitous Drop in Hemoglobin Oxygen Saturation During Spray Liquid Nitrogen Cryotherapy of Tracheobronchial Lesions. PMID- 29277302 TI - Intracardiac Thrombus Formation During Liver Transplantation: How Do We Prevent This Complication? PMID- 29277303 TI - Modified Tricuspid Annular Plane Systolic Excursion Using Transesophageal Echocardiography and Its Utility to Predict Postoperative Course in Heart Transplantation and Left Ventricular Assist Device Implantation. AB - OBJECTIVES: Perioperative right ventricular (RV) function is important for determining the postoperative course in heart transplantation (HT) and left ventricular assist device (LVAD) implantation. The authors describe a modified tricuspid annular plane systolic excursion (m-TAPSE) using transesophageal echocardiography and assessed its clinical utility in HT and LVAD. DESIGN: Retrospective medical record review. SETTING: A single tertiary-care medical center. PARTICIPANTS: Forty-eight patients who underwent successful HT and 80 patients who underwent successful LVAD placement. MEASUREMENTS AND MAIN RESULTS: Statistically significant correlation between m-TAPSE and RV fractional area change (FAC) was seen for HT and LVAD (r = 0.462, p < 0.01 and r = 0.597, p < 0.01, respectively). For HT, receiver operating characteristics curve analysis yielded that m-TAPSE <0.64 cm provides 100% specificity and 57.1% sensitivity in predicting postoperative nitric oxide (NO) use, whereas RV FAC <24.1% provides 95.1% specificity and 71.4% sensitivity in predicting postoperative NO use (area under the curve 0.798 [95% confidence interval (CI), 0.595-1] v 0.826 [95% CI, 0.581-1], p = 0.397). For LVAD, m-TAPSE <0.71 cm provides 66.7% specificity and 87.5% sensitivity in predicting postoperative NO use, whereas RV FAC <16.3% provides 79.4% specificity and 62.5% sensitivity in predicting postoperative NO use (area under the curve 0.829 [95% CI, 0.732-0.927] v 0.691 [95% CI, 0.54 0.842], p < 0.05). CONCLUSIONS: m-TAPSE validated a good correlation to RV systolic function as reflected by RV FAC for both HT and LVAD. For HT, m-TAPSE was helpful for predicting postoperative NO use; whereas for LVAD, m-TAPSE was helpful for predicting postoperative NO use and RV assist device implantation. m TAPSE should be considered as a useful parameter to decide postoperative management for these cases. PMID- 29277304 TI - The Association Between Pulsatile Portal Flow and Acute Kidney Injury after Cardiac Surgery: A Retrospective Cohort Study. AB - OBJECTIVE: Venous congestion is a possible mechanism leading to acute kidney injury (AKI) following cardiac surgery. Portal vein flow pulsatility is an echographic marker of cardiogenic portal hypertension and might identify clinically significant organ congestion. This exploratory study aims to assess if the presence of portal flow pulsatility measured by transthoracic echography in the postsurgical intensive care unit is associated with AKI after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Specialized care university hospital. PARTICIPANTS: Patients who underwent cardiac surgery between May 2015 and February 2016 and had at least 1 Doppler assessment of portal flow performed by the attending critical care physician during the week following cardiac surgery. INTERVENTIONS: The association between portal flow pulsatility defined as a pulsatility fraction >=50% and the risk of subsequent AKI was assessed using univariate and multivariate logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: The files of 132 consecutive patients were reviewed and 102 patients were included in the analysis. Significant portal flow pulsatility was detected in 38 patients (37.3%) in the week following surgery. During this period, 60.8% developed AKI and 13.7% progressed to severe AKI. The detection of portal flow pulsatility was associated with an increased risk for the development of AKI (odds ration [OR] 4.31, confidence interval [CI] 1.50-12.35, p = 0.007). After adjustment, portal flow pulsatility and AKI were independently associated (OR 4.88, CI 1.54-15.47, p = 0.007). CONCLUSIONS: Assessment of portal flow using Doppler ultrasound at the bedside might be a promising tool to detect patients at risk for AKI due to cardiogenic venous congestion. PMID- 29277305 TI - Stability of Kinesthetic Perception in Efferent-Afferent Spaces: The Concept of Iso-perceptual Manifold. AB - The main goal of this paper is to introduce the concept of iso-perceptual manifold for perception of body configuration and related variables (kinesthetic perception) and to discuss its relation to the equilibrium-point hypothesis and the concepts of reference coordinate and uncontrolled manifold. Hierarchical control of action is postulated with abundant transformations between sets of spatial reference coordinates for salient effectors at different levels. Iso perceptual manifold is defined in the combined space of afferent and efferent variables as the subspace corresponding to a stable percept. Examples of motion along an iso-perceptual manifold (perceptually equivalent motion) are considered during various natural actions. Some combinations of afferent and efferent signals, in particular those implying a violation of body's integrity, give rise to variable percepts by artificial projection onto iso-perceptual manifolds. This framework is used to interpret unusual features of vibration-induced kinesthetic illusions and to predict new illusions not yet reported in the literature. PMID- 29277306 TI - Design, synthesis, and evaluation of polyamine-memantine hybrids as NMDA channel blockers. AB - N-Methyl-d-aspartate (NMDA) receptors have been implicated in learning and memory, and may also play a central role in various conditions leading to neuronal degradation. NMDA receptor antagonists could therefore be of therapeutic benefit for a number of neurological disorders. We have designed hybrid compounds of polyamines and memantine, both of which function as NMDA channel blockers. The triamine derivative with a guanidine moiety showed more potent antagonistic activity than memantine. PMID- 29277307 TI - Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides. AB - A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6 substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5 fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs. PMID- 29277308 TI - Nrf2 as regulator of innate immunity: A molecular Swiss army knife! AB - Organisms are constantly exposed to a broad range of pathological and stress inducing agents, allergens and environmental chemicals that can induce infections, toxicity or other undesirable reactions. Our immune system has evolved over time in order to efficiently respond to these exogenous insults and maintain homeostasis. In particular, the innate immune system acts as primary barrier to prevent the entrance of invasive agents or allergens. This system is comprised of a diversity of cell types that are rapidly activated by recognition of common structures present in many potential pathogens known as pathogen associated molecular patterns (PAMPs). The nuclear factor erythroid 2 related factor 2 (Nrf2) is a relevant basic leucine zipper (bZIP) transcription factor that is essential in the regulation of cell cycle homeostasis, cytoprotection, and innate immunity when cells are under stressful conditions. Although the role of Nrf2 in activating the expression of protective genes - such as antioxidant or anti-inflammatory - is known, its role in innate immunity and immune-related gene expression remains not yet clear. The present review summarizes current knowledge on Nrf2 signaling pathway structure and activity under both physiological state and upon oxidative stress. In addition, the relation between Nrf2 signaling pathway and the innate immune system is discussed, highlighting the potential therapeutic effects of diverse natural and synthetic compounds as Nrf2 regulators. PMID- 29277309 TI - Enhancing the performance of brewing yeasts. AB - Beer production is one of the oldest known traditional biotechnological processes, but is nowadays facing increasing demands not only for enhanced product quality, but also for improved production economics. Targeted genetic modification of a yeast strain is one way to increase beer quality and to improve the economics of beer production. In this review we will present current knowledge on traditional approaches for improving brewing strains and for rational metabolic engineering. These research efforts will, in the near future, lead to the development of a wider range of industrial strains that should increase the diversity of commercial beers. PMID- 29277310 TI - Mechanism of intranasal drug delivery directly to the brain. AB - Neurological diseases are becoming increasingly prominent worldwide due to rapidly aging populations, which greatly contributes to increasing healthcare costs. The development of neuroprotective drugs has so far proven exceptionally difficult due to the blood-brain barrier. One novel approach to address this challenge is to administer drugs intranasally to noninvasively bypass the blood brain barrier. The intranasal route can thus transport drugs directly to the brain from the nasal cavity along the olfactory and trigeminal nerves. The purpose of this review is to describe the details of this mechanism to better direct future research. The intranasal route is composed of two pathways, one being intracellular while the other being extracellular. The intracellular pathway begins with endocytosis by olfactory sensory cells, followed by axonal transport to their synaptic clefts in the olfactory bulb where the drug is exocytosed. This transynaptic process is repeated by olfactory neurons, thereby distributing the drug to other brain regions. In the extracellular mechanism, drugs are transported directly into the cerebral spinal fluid by first passing through the paracellular space across the nasal epithelium, then through the perineural space to the subarachnoid space of the brain. With a growing body of evidence and trials in both rodent and human models, this is an exciting area for research as therapeutics come to market. PMID- 29277311 TI - Targeting gut microbiome: A novel and potential therapy for autism. AB - Autism spectrum disorder (ASD) is a severely neurodevelopmental disorder that impairs a child's ability to communicate and interact with others. Children with neurodevelopmental disorder, including ASD, are regularly affected by gastrointestinal problems and dysbiosis of gut microbiota. On the other hand, humans live in a co-evolutionary association with plenty of microorganisms that resident on the exposed and internal surfaces of our bodies. The microbiome, refers to the collection of microbes and their genetic material, confers a variety of physiologic benefits to the host in many key aspects of life as well as being responsible for some diseases. A large body of preclinical literature indicates that gut microbiome plays an important role in the bidirectional gut brain axis that communicates between the gut and central nervous system. Moreover, accumulating evidences suggest that the gut microbiome is involved in the pathogenesis of ASD. The present review introduces the increasing evidence suggesting the reciprocal interaction network among microbiome, gut and brain. It also discusses the possible mechanisms by which gut microbiome influences the etiology of ASD via altering gut-brain axis. Most importantly, it highlights the new findings of targeting gut microbiome, including probiotic treatment and fecal microbiota transplant, as novel and potential therapeutics for ASD diseases. PMID- 29277312 TI - [Subcostal transversus abdominis plane block can improve analgesia after laparoscopic cholecystectomy]. AB - BACKGROUND AND GOAL OF STUDY: After laparoscopic cholecystectomy, patients have moderate pain in the early postoperative period. Some studies shown beneficial effects of subcostal transversus abdominis plane block on reducing this pain. Our goal was to investigate influence of subcostal transversus abdominis plane block on postoperative pain scores and opioid consumption. MATERIALS AND METHODS: We have randomized 76 patients undergoing laparoscopic cholecystectomy to receive either subcostal transversus abdominis plane block (n=38) or standard postoperative analgesia (n=38). First group received bilateral ultrasound guided subcostal transversus abdominis plane block with 20mL of 0.33% bupivacaine per side before operation and tramadol 1mg.kg-1IV for pain breakthrough (>=6). Second group received after operation tramadol 1mg.kg-1/6h as standard hospital analgesia protocol. Both groups received acetaminophen 1g/8h IV and metamizole 2.5g/12h. Pain at rest was recorded for each patient using NR scale (0-10) in period of 10min, 30min, 2h, 4h, 8h, 12h and 16h after the surgery. RESULTS AND DISCUSSION: We obtained no difference between groups according age, weight, intraoperative fentanyl consumption and duration of surgery. Subcostal transversus abdominis plane block significantly reduced postoperative pain scores compared to standard analgesia in all periods after surgery. Tramadol consumption was significantly lower in the subcostal transversus abdominis plane (24.29+/ 47.54g) than in the standard analgesia group (270.2+/-81.9g) (p=0.000). CONCLUSION: Our results show that subcostal transversus abdominis plane block can provide superior postoperative analgesia and reduction in opioid requirements after laparoscopic cholecystectomy. PMID- 29277313 TI - Quality of life and mood in children with cystic fibrosis: Associations with sleep quality. AB - BACKGROUND: We aimed to investigate the relationship between sleep quality, mood and health-related quality of life (HRQOL) in children with CF and controls. METHODS: Children (7-12years) and adolescents (13-18years) with CF and controls completed sleep evaluation: overnight oximetry and 14days of actigraphy. Age appropriate questionnaires assessed mood (Children's Depression Inventory; CDI or Beck's Depression Inventory), HRQOL (CF Questionnaire-Revised; CFQ-R or PedsQL), and sleepiness (Pediatric Daytime Sleepiness Scale). RESULTS: 87 CF and 55 controls recruited. Children with CF had poorer sleep quality, more sleepiness and lower mood than controls, with a negative correlation between mood score and sleep efficiency. Sleepiness score was predictive of mood score and multiple CFQ R domains. Adolescents with CF also demonstrated poorer sleep and more sleepiness than controls, but no difference in mood. Reduced sleep quality predicted lower CFQ-R scores. No correlation between sleep, mood or HRQOL in controls. CONCLUSIONS: In children and adolescents with CF, impaired sleep quality is associated with lower mood and HRQOL in an age-specific manner. Future research will aid understanding of effective strategies for prevention and treatment of mood disorders and sleep disturbance in children with CF. PMID- 29277314 TI - Molecular dynamics of palmitic acid and lead palmitate in cross-linked linseed oil films: Implications from deuterium magnetic resonance for lead soap formation in traditional oil paintings. AB - Many oil paintings, dating from the 15th century to the present, are affected by the formation of heavy-metal carboxylates (soaps) that alter the structural integrity and appearance of the works. Through transport phenomena not yet understood, free fatty acids formed from oils used as binders migrate through the paint film and react with heavy-metal ions that are constituents of pigments and/or driers, forming metal carboxylates. The local molecular dynamics of fatty acids and metal carboxylates are factors influencing material transport in these systems. We report temperature-dependent 2H NMR spectra of palmitic acid and lead palmitate as pure materials, in cross-linked linseed oil films, and in a lead white linseed oil paint film as part of our broader research into metal soap formation. Local dynamics at the alpha carbon, at the terminal methyl group, and at the middle of the fatty acid chain were observed in specifically deuterated materials. Changes in the dynamic behavior with temperature were observed by the appearance of two species, a solid-like material and a liquid-like material. The relative amounts of the two phases and their deuterium NMR parameters indicate that the amount of liquid-like material and the local dynamics at that site increase with temperature. At the three locations along the chain and at all temperatures, there is a larger percentage of acyl chains of both palmitic acid and lead palmitate that are "mobile" or liquid-like in linseed oil films than there are in the pure materials. However, the percentage of liquid-like species is decreased in a lead white paint film, as compared to a linseed oil matrix. In addition, these experiments indicate that there is a larger percentage of liquid like acyl chains of palmitic acid than of lead palmitate under identical conditions in these model paint systems. PMID- 29277315 TI - Incubation of spermatozoa with Anandamide prior to cryopreservation reduces cryocapacitation and improves post-thaw sperm quality in the water buffalo (Bubalus bubalis). AB - Anandamide (AEA), an endocannabinoid, has been shown to reduce capacitation and acrosomal exocytosis in human spermatozoa. Because buffalo spermatozoa are highly susceptible to cryopreservation induced damage, AEA was assessed as to whether it could protect spermatozoa from cryo-damage. Six ejaculates from six Murrah buffalo bulls (total 36 ejaculates) were utilized for the study. Each ejaculate was divided into four aliquots; spermatozoa in Aliquot 1 were extended in Tris Citrate-Egg Yolk and frozen as per the standard protocol. Spermatozoa in Aliquots 2, 3 and 4 were incubated with AEA at 1 nM, 1 MUM and 10 MUM, respectively in Tris-Citrate extender for 15 min at 37 degrees C before cryopreservation. Cryopreserved spermatozoa were thawed at 37 degrees C for 30 s before assessment of sperm motility, membrane integrity, capacitation, acrosome reaction, mitochondrial membrane potential (MMP) and lipid peroxidation status. The proportion of motile and membrane intact spermatozoa were greater (P < 0.05) with use of 1 MUM AEA incorporated group compared with other groups. The proportion of un-capacitated and acrosome intact spermatozoa was greater (P < 0.05) with use of 1 or 10 MUM of AEA compared with the other groups. When compared to the control group, use of 1 MUM AEA resulted in a greater proportion of spermatozoa with high MMP (P < 0.05). There was no significant difference in the lipid peroxidation status of spermatozoa among any of the four groups. It was inferred that the protective role of AEA during cryopreservation of buffalo spermatozoa was dose dependent and incubation of spermatozoa with AEA at 1 MUM concentration prior to cryopreservation reduced cryo-capacitation and improved post-thaw sperm quality in buffalo. PMID- 29277316 TI - The Flexible Lifestyle Empowering Change (FLEX) intervention for self-management in adolescents with type 1 diabetes: Trial design and baseline characteristics. AB - The Flexible Lifestyle Empowering Change (FLEX) Intervention Study is a multi site randomized controlled trial to test the efficacy of an adaptive behavioral intervention to promote self-management for youth with type 1 diabetes mellitus (T1D). This paper details FLEX design, demographic characteristics of the sample, and outcome variables at baseline. Participants were randomized to either an intervention or control arm after their baseline standardized measurement visit. Baseline data for the primary (glycemic levels) and secondary outcome variables (e.g., motivation and problem-solving, health-related quality of life, risk factors associated with T1D complications) as well as the potential mediator variables (e.g., self-management behavior, family conflict and responsibility) suggest that the study sample was representative of the general population of adolescents with T1D and their parents. The FLEX adaptive intervention is an innovative application of a tailored treatment intervention designed to be readily adopted in real-world practice to meet each adolescent's individualized T1D self-management goals. PMID- 29277317 TI - Early diagnosis of right ventricle-pulmonary artery conduit endocarditis by PET/CT. PMID- 29277318 TI - T2E (TMPRSS2-ERG) fusion transcripts are associated with higher levels of AMACR mRNA and a subsequent prostate cancer diagnosis in patients with atypical small acinar proliferation. AB - Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 (TMPRSS2) and genes from the ETS transcription factor family, most commonly ERG and ETV1, result in alteration that responsible for oncogenic activity in prostate cancer (PC). The aims of the present study were to: 1) investigate the frequency of these fusion transcripts in prostate tissue samples obtained from patients diagnosed with atypical small acinar proliferation (ASAP), 2) determine any clinical significance of T2E expression at the RNA level in predicting PC detection in subsequent biopsies, and 3) evaluate expression of the PC marker, alpha-methylacyl-CoA racemase (AMACR), according to T2E status by real-time quantitative reverse transcription PCR (RT-qPCR). T2E transcripts were detected in 31.7% (n=20) of the patients examined, and this was significantly associated with subsequent detection of PC in ASAP patients with a prostate specific antigen (PSA) level of 4-10ng/ml (p=0.045). AMACR expression was also significantly higher in the patients who were diagnosed with PC in subsequent biopsies than in the patients who were not diagnosed with PC (p=0.034) and in T2E-positive ASAP patients (p=0.002) compared to T2E-negative ASAP patients. Although these results need to be further clinically validated, we suggest that the presence of T2E transcript, in association with higher AMACR expression, is an indicator of PC risk from a T2E-positive focus or an unsampled malignant gland adjacent to a T2E positive site in ASAP lesions. PMID- 29277320 TI - Phenomenology, epidemiology, co-morbidity and treatment of a specific phobia of vomiting: A systematic review of an understudied disorder. AB - Specific Phobia of Vomiting (SPOV) is an under-researched disorder compared to other Specific Phobias. A systematic review was conducted to synthesise existing research across areas of phenomenology, aetiology, epidemiology, co-morbidity, assessment measures and treatment. Online databases (Psychinfo, Embase, Medline, Pubmed and Cochrane Library) were searched using terms related to SPOV and 'emetophobia'. A manual search of reference lists of included papers was also conducted. In total, 385 articles were found and 24 were included in the review. The review was registered on the PROSPERO register (CRD42016046378). The review presents a qualitative synthesis of identified studies exploring the features of SPOV including locus of fear, feared consequences of vomiting, and common safety and avoidance behaviours. It also identified articles describing aetiological factors involved in the development of SPOV, co-morbid disorders and the epidemiology of the disorder. Further studies focused on valid and reliable measures to assess SPOV, and treatments that are effective at reducing symptomatology of SPOV and psychological distress. There are relatively few published research articles on SPOV, and particularly high quality studies exploring effective treatment options for SPOV. Further research should focus on RCTs for comparing different approaches to reducing symptomatology and distress in people with SPOV. PMID- 29277319 TI - Two mulberry phytochelatin synthase genes confer zinc/cadmium tolerance and accumulation in transgenic Arabidopsis and tobacco. AB - Phytochelatin synthase (PCS) is an enzyme involved in the synthesis of phytochelatins, cysteine-rich peptides which play a key role in heavy metal (HM) detoxification of plants. Mulberry (Morus L.), one of the most ecologically and economically important tree genera, has the potential to remediate HM contaminated soils. However, genes involved in HM detoxification in Morus, such as the PCS genes, have not been identified and characterized. In this study, we identified two Morus notabilis PCS genes based on a genome-wide analysis of the Morus genome database. Full-length MnPCS1 and MnPCS2 cDNAs were 1509 and 1491bp long, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that, under 200MUM Zn2+ or either 30 or 100MUM Cd2+ stress, the relative expression of each of the two MaPCSs (from Morus alba) was induced in root, stem and leaf tissues within 24h of exposure to the metals, with Cd2+ inducing expression more strongly than did Zn2+. Based on the analysis of total root length and fresh weight of seedlings, overexpression of MnPCS1 and MnPCS2 in Arabidopsis and tobacco enhanced Zn2+/Cd2+ tolerance in most transgenic individuals. The results of transgenic Arabidopsis lines overexpressing MnPCS1and MnPCS2 suggest that MnPCS1 play a more important role in Cd detoxification than MnPCS2. Zn2+/Cd2+ concentrations in both shoots and roots of the transgenic Arabidopsis seedlings were higher than in wild type (WT) seedlings at two Zn2+/Cd2+ concentrations. In addition, there was a positive correlation between Zn accumulation and the expression level of MnPCS1 or MnPCS2. Our results indicated that the Morus PCS1 and PCS2 genes play important roles in HM stress tolerance and accumulation, providing a useful genetic resource for enhancing tolerance to HMs and for increasing the HM phytoremediation potential of these plants. PMID- 29277321 TI - Network meta-analysis of cardiovascular outcomes in randomized controlled trials of new antidiabetic drugs. AB - BACKGROUND: Randomized controlled trials (RCTs) directly comparing cardiovascular outcomes of new antidiabetic drugs are lacking. We used network meta-analysis to compare new antidiabetic drug classes with respect to major adverse cardiovascular events (MACE) and mortality. METHODS: We searched MEDLINE, EMBASE, the Cochrane database, and ClinicalTrials.gov up to 30 December 2016 for RCTs involving SGLT-2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors in diabetic patients that reported MACE and deaths. Outcomes were compared with frequentist and Bayesian methods using R statistics. RESULTS: Seven RCTs with altogether 62,268 patients were included in the network meta-analysis. The SGLT-2 inhibitor and GLP-1 RAs reduced MACE (OR 0.85, 95%CI 0.73-0.99 and 0.89, 0.82-0.97, respectively) and all cause mortality (0.67, 0.55-0.81 and 0.89, 0.80-0.99, respectively) compared to placebo. Furthermore, the SGLT-2 inhibitor reduced all-cause mortality compared to GLP-1 RAs (0.76, 0.61-0.94). In contrast, DPP-4 inhibitors did not reduce MACE or mortality compared to placebo and were associated with higher all-cause mortality compared to the SGLT-2 inhibitor (1.53, 1.24-1.89) and GLP-1 RAs (1.16, 1.01-1.33). CONCLUSIONS: All-cause mortality and MACE were reduced by the SGLT-2 inhibitor and GLP-1 RAs, but not DPP-4 inhibitors. The SGLT-2 inhibitor had the most beneficial impact on all-cause mortality. DPP-4 inhibitors showed no cardiovascular benefit and were inferior to the other two drug classes in preventing deaths. PMID- 29277322 TI - Meningioma growth dynamics assessed by radiocarbon retrospective birth dating. AB - It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n=6 with meningothelial and n=6 with fibrous subtype, as well as n=2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1+/-6.5years, whereas atypical WHO grade II meningiomas originated 1.5+/-0.1years prior to surgery (p<0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination. PMID- 29277323 TI - Epigenetic Changes in the CRH Gene are Related to Severity of Suicide Attempt and a General Psychiatric Risk Score in Adolescents. AB - The aim of this study, comprising 88 suicide attempters, was to identify hypothalamic-pituitary-adrenal (HPA) -axis coupled CpG-sites showing methylation shifts linked to severity of the suicide attempt. Candidate methylation loci were further investigated as risk loci for a general psychiatric risk score in two cohorts of adolescents (cohort 1 and 2). The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. Subjects were stratified into high-risk and low-risk groups based on the severity of the suicidal behavior. We included CpG sites located within 2000 basepairs away from transcriptional start site of the following HPA-axis coupled genes: corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FK506-binding protein 51 (FKBP5) and the glucocorticoid receptor (NR3C1). The methylation state of two corticotropin releasing hormone (CRH)-associated CpG sites were significantly hypomethylated in the high-risk group of suicide attempters (n=31) (cg19035496 and cg23409074) (p<0.001). Adolescent cohort 1 and 2 consisted of 129 and 93 subjects, respectively, and were stratified by the in silico generated DAWBA measurements of a general psychiatric risk score into high-risk group (>~50% risk) or controls. In adolescent cohort 2, cg19035496 was hypermethylated in subjects with a high general psychiatric risk score. Our results show epigenetic changes in the CRH gene related to severity of suicide attempt in adults and a general psychiatric risk score in adolescents. PMID- 29277325 TI - SIRT1 regulates inflammation response of macrophages in sepsis mediated by long noncoding RNA. AB - Molecular mechanisms for macrophage immune responses modulated by SIRT1 during sepsis remain unclear. Here, we show that SIRT1 expression is down-regulated in macrophages from mouse sepsis model or LPS stimulation. SIRT1 expression in macrophages correlates with low levels of a long noncoding RNA (lncRNA) NONMMUT003701 [named as lncRNA-CCL2]. SIRT1 inhibits lncRNA-CCL2 expression via sustaining a repressive chromatin state in the lncRNA-CCL2 locus. The inflammation cytokines expression is downregulated by knockdown of lncRNA-CCL2. Such inhibition can be reversed partly by decreased SIRT1 activity. Thus, this work uncovers previously unidentified mechanisms in which SIRT1 associates with lncRNA and lncRNA regulates macrophage inflammatory response. PMID- 29277324 TI - Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation. AB - Defective autophagy of monocytes or macrophages might result in NLRP3 inflammasome activation and cause vascular metabolic inflammation. However, the mechanism underlying the initiation of the autophagy response to hyperlipidaemia remains unclear. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is sensitive to the metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated autophagy in regulating NLRP3 inflammasome activation. We determined that the inhibition of autophagy and the activation of the NLRP3 inflammasome were concomitant with reduced SIRT3 levels both in peripheral blood monocytes from obese humans and in palmitate-treated THP 1 cells. Furthermore, we demonstrated that SIRT3 could form a molecular complex with ATG5, while SIRT3 overexpression altered the acetylation of endogenous ATG5. ATG5 acetylation inhibited autophagosome maturation and induced NLRP3 inflammasome activation. In parallel, SIRT3 overexpression in THP-1 cells decreased the palmitate-induced generation of mitochondrial reactive oxygen species, restored autophagy, and attenuated NLRP3 inflammasome activation. The incubation of human aortic endothelial cells (HAECs) with macrophage-conditioned medium (MCM) induced HAEC expression of vascular cell adhesion molecule-1, intercellular adhesion molecule 1, alpha-smooth muscle actin, and collagen-1. The effect of MCM could be reversed by the addition of neutralizing anti-IL-1beta antibody or the overexpression of SIRT3. Consistent with this, en face analyses displayed a marked increase in alpha-SMC-positive endothelial cells in SIRT3-/- mice with acute hyperlipidaemia. Taken together, these findings revealed that SIRT3-deficient macrophages displayed impaired autophagy and accelerated NLRP3 inflammasome activation and endothelial dysfunction. PMID- 29277326 TI - Identification of the functional alteration signatures across different cancer types with support vector machine and feature analysis. AB - Cancers are regarded as malignant proliferations of tumor cells present in many tissues and organs, which can severely curtail the quality of human life. The potential of using plasma DNA for cancer detection has been widely recognized, leading to the need of mapping the tissue-of-origin through the identification of somatic mutations. With cutting-edge technologies, such as next-generation sequencing, numerous somatic mutations have been identified, and the mutation signatures have been uncovered across different cancer types. However, somatic mutations are not independent events in carcinogenesis but exert functional effects. In this study, we applied a pan-cancer analysis to five types of cancers: (I) breast cancer (BRCA), (II) colorectal adenocarcinoma (COADREAD), (III) head and neck squamous cell carcinoma (HNSC), (IV) kidney renal clear cell carcinoma (KIRC), and (V) ovarian cancer (OV). Based on the mutated genes of patients suffering from one of the aforementioned cancer types, patients they were encoded into a large number of numerical values based upon the enrichment theory of gene ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We analyzed these features with the Monte-Carlo Feature Selection (MCFS) method, followed by the incremental feature selection (IFS) method to identify functional alteration features that could be used to build the support vector machine (SVM)-based classifier for distinguishing the five types of cancers. Our results showed that the optimal classifier with the selected 344 features had the highest Matthews correlation coefficient value of 0.523. Sixteen decision rules produced by the MCFS method can yield an overall accuracy of 0.498 for the classification of the five cancer types. Further analysis indicated that some of these features and rules were supported by previous experiments. This study not only presents a new approach to mapping the tissue-of-origin for cancer detection but also unveils the specific functional alterations of each cancer type, providing insight into cancer-specific functional aberrations as potential therapeutic targets. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29277327 TI - Extracellular matrix content and WNT/beta-catenin levels of cartilage determine the chondrocyte response to compressive load. AB - During osteoarthritis (OA)-development extracellular matrix (ECM) molecules are lost from cartilage, thus changing gene-expression, matrix synthesis and biomechanical competence of the tissue. Mechanical loading is important for the maintenance of articular cartilage; however, the influence of an altered ECM content on the response of chondrocytes to loading is not well understood, but may provide important insights into underlying mechanisms as well as supplying new therapies for OA. Objective here was to explore whether a changing ECM content of engineered cartilage affects major signaling pathways and how this alters the chondrocyte response to compressive loading. Activity of canonical WNT , BMP-, TGF-beta- and p38-signaling was determined during maturation of human engineered cartilage and followed after exposure to a single dynamic compression episode. WNT/beta-catenin- and pSmad1/5/9-levels declined with increasing ECM content of cartilage. While loading significantly suppressed proteoglycan synthesis and ACAN-expression at low ECM-content this catabolic response then shifted to an anabolic reaction at high ECM-content. A positive correlation was observed between GAG-content and load-induced alteration of proteoglycan synthesis. Induction of high beta-catenin levels by the WNT-agonist CHIR suppressed load-induced SOX9- and GAG-stimulation in mature constructs. In contrast, the WNT-antagonist IWP-2 was capable of attenuating load-induced GAG suppression in immature constructs. In conclusion, either ECM accumulation associated or pharmacologically induced silencing of WNT-levels allowed for a more anabolic reaction of chondrocytes to physiological loading. This is consistent with the role of proteoglycans in sequestering WNT-ligands in the ECM, thus reducing WNT-activity and also provides a novel explanation of why low WNT activity in cartilage protects from OA-development in mechanically overstressed cartilage. PMID- 29277328 TI - Induction of cytochrome P450 4A14 contributes to angiotensin II-induced renal fibrosis in mice. AB - Angiotensin II (AngII) plays an important role in the pathogenesis of hypertension and associated renal injuries. To elucidate the molecular mechanism by which AngII induces renal damage, we found that AngII infusion significantly induced CYP4A14 expression in renal proximal tubule cells (RPTCs) with marked increases in blood pressure and proteinuria. Renal production of the major CYP4A metabolite, 20-HETE, was also significantly increased in the AngII-treated mice. Compared to wild-type (WT) mice, CYP4A14 knockout (CYP4A14-/-) mice exhibited significantly lower levels of blood pressure, renal 20-HETE production, proteinuria and renal fibrosis following AngII infusion. Furthermore, AngII induced renal expression of profibrotic genes and proinflammatory genes was significantly attenuated in CYP4A14-/- mice. In vitro studies using cultured RPTCs demonstrated that AngII significantly induced CYP4A14 expression and 20 HETE production via the MAPK signaling pathway. AngII treatment increased TGF beta and collagen expression, which was attenuated by the CYP4A inhibitor, TS 011. Moreover, 20-HETE treatment potently induced CYP4A14 expression and TGF-beta and collagen levels. Collectively, these findings suggest that attenuated renal fibrosis in AngII-treated CYP4A14-/- mice may result from both reduced systemic blood pressure and renal 20-HETE production. Therefore, CYP4A14 may represent a useful target for the treatment of AngII-associated renal damage. PMID- 29277329 TI - Human embryonic stem cell-derived cardiomyocytes as an in vitro model to study cardiac insulin resistance. AB - Patients with type 2 diabetes (T2D) and/or insulin resistance (IR) have an increased risk for the development of heart failure (HF). Evidence indicates that this increased risk is linked to an altered cardiac substrate preference of the insulin resistant heart, which shifts from a balanced utilization of glucose and long-chain fatty acids (FAs) towards an almost complete reliance on FAs as main fuel source. This shift leads to a loss of endosomal proton pump activity and increased cardiac fat accumulation, which eventually triggers cardiac dysfunction. In this review, we describe the advantages and disadvantages of currently used in vitro models to study the underlying mechanism of IR-induced HF and provide insight into a human in vitro model: human embryonic stem cell derived cardiomyocytes (hESC-CMs). Using functional metabolic assays we demonstrate that, similar to rodent studies, hESC-CMs subjected to 16h of high palmitate (HP) treatment develop the main features of IR, i.e., decreased insulin stimulated glucose and FA uptake, as well as loss of endosomal acidification and insulin signaling. Taken together, these data propose that HP-treated hESC-CMs are a promising in vitro model of lipid overload-induced IR for further research into the underlying mechanism of cardiac IR and for identifying new pharmacological agents and therapeutic strategies. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. PMID- 29277330 TI - A Hidden Semi-Markov Model based approach for rehabilitation exercise assessment. AB - In this paper, a Hidden Semi-Markov Model (HSMM) based approach is proposed to evaluate and monitor body motion during a rehabilitation training program. The approach extracts clinically relevant motion features from skeleton joint trajectories, acquired by the RGB-D camera, and provides a score for the subject's performance. The approach combines different aspects of rule and template based methods. The features have been defined by clinicians as exercise descriptors and are then assessed by a HSMM, trained upon an exemplar motion sequence. The reliability of the proposed approach is studied by evaluating its correlation with both a clinical assessment and a Dynamic Time Warping (DTW) algorithm, while healthy and neurological disabled people performed physical exercises. With respect to the discrimination between healthy and pathological conditions, the HSMM based method correlates better with the physician's score than DTW. The study supports the use of HSMMs to assess motor performance providing a quantitative feedback to physiotherapist and patients. This result is particularly appropriate and useful for a remote assessment in the home. PMID- 29277331 TI - Predictive value of EEG for febrile seizure recurrence. AB - OBJECTIVE: To define the role of the EEG in predicting recurrence of febrile seizures (FS) in children after a first FS. METHODS: Children with a first simple or complex FS who underwent EEG at our hospital were retrospectively enrolled. EEG recordings were classified in three groups: normal, abnormal (slow activity or epileptiform discharges), and pseudo-petit mal discharge (PPMD) pattern. Children were followed-up for at least three years. RESULTS: A total of 126 patients met the entry criteria, and 113 of them completed the follow-up. Risk of FS recurrence decreased linearly with increasing age (-2% per month). The risk was higher among patients with PPMD pattern (absolute risk 86%, adjusted relative risk 2.00) and abnormal EEG (epileptiform discharges: absolute risk 71%, adjusted relative risk 2.00; slow activity: absolute risk 56%, adjusted relative risk 1.44), compared with those with normal EEG (absolute risk 41%). CONCLUSIONS: PPMD and abnormal EEG should be considered as an independent risk factor for FS recurrence. PMID- 29277332 TI - Cytokine/chemokine elevation during the transition phase from HSV encephalitis to autoimmune anti-NMDA receptor encephalitis. AB - A 3-year-old girl suffered from anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis after resolution of herpes simplex virus encephalitis (HSE). Methylprednisolone pulse and immunoglobulin therapies showed little effect, but the patient completely recovered after six courses of monthly cyclophosphamide pulse therapy and successive maintenance on mycophenolate mofetil for one year. Anti-NMDA receptor antibody in the cerebrospinal fluid (CSF) was minimally detected during the prodromal febrile period and then was seen to be markedly elevated at the onset of second encephalopathy phase. CSF interleukin (IL)-6, and 10, tumor necrosis factor-alpha, interferon gamma, C-X-C motif ligands (CXCL)10 and 13, chemokine ligand 2, and migration inhibitory factor showed a second peak during the prodromal period and were reduced at the onset of anti-NMDA receptor encephalitis. These suggest the presence of cytokine/chemokine phase between the initial HSE and the secondary autoimmune encephalitis phases. Treatment strategy during the early stage of this entity should be further explored. PMID- 29277333 TI - Isolation of Leptospira kmetyi from residential areas of patients with leptospirosis in Kelantan, Malaysia. AB - BACKGROUND: Environmental sampling provides important information that enhances the understanding of the leptospiral human-environment-animal relationship. Several studies have described the distribution of Leptospira in the environment. However, more targeted sites, that is, areas surrounding leptospirosis patients' houses, remain under-explored. Therefore, this study aims to detect the presence of Leptospira spp. in the residential areas of patients with leptospirosis. METHODS: Soil and water samples near leptospirosis patients' residences were collected, processed and cultured into EMJH media. Partial 16S rRNA gene sequencing was performed to confirm the identity of Leptospira. RESULTS: EMJH culture and partial 16S rRNA gene sequencing revealed predominant growth of pathogenic Leptospira kmetyi (17%, n=7/42). All tested locations had at least one Leptospira sp., mostly from the soil samples. CONCLUSION: More than one species of Leptospira may be present in a sampling area. The most common environmental isolates were pathogenic L. kmetyi. PMID- 29277334 TI - Neurological disease may precede lymphadenopathies in Actinomyces europaeus infection. AB - Actinomyces species are part of the commensal flora of the mucous membranes of the oropharynx, gastrointestinal tract and female genital tract. Actinomyces europaeus is a short, nonmotile, facultative anaerobic rod first described in 1997, susceptible in vitro to a wide range of b-lactam antibiotics which are regarded as first choice. In this report we described the case of A. europaeus infection in a young female patient admitted to Intensive Care Unit and the possible damage of vascular endothelium due to a chronic progressive actinomycosis that at first involved neck soft tissue, then cervical lymphnodes, and finally extended to the vascular structure. PMID- 29277335 TI - Unusual Case of Fever and Abdominal Pain. PMID- 29277336 TI - Prognostic value of nocturnal pulse oximetry in patients with heart failure. AB - INTRODUCTION AND OBJECTIVES: To analyze the prognostic value of nocturnal hypoxemia measured with portable nocturnal pulse-oximetry in patients hospitalized due to heart failure and its relation to mortality and hospital readmission. METHODS: We included 38 patients who were admitted consecutively to our unit with the diagnosis of decompensated heart failure. Pulse-oximetry was considered positive for hypoxemia when more than 10 desaturations per hour were recorded during sleep. Follow-up was performed for 30.3 (standard deviation [SD] 14.2) months, the main objective being a combined endpoint of all-cause mortality and hospital readmission due to heart failure. RESULTS: The average age was 70.7 (SD 10.7) years, 63.3% were males. Pulse-oximetry was considered positive for hypoxemia in 27 (71%) patients. Patients with positive pulse-oximetry had the most frequent endpoint (9.1% [1] vs. 61.5% [16], P = 0.003). After multivariate analysis, continuous nocturnal hypoxemia was related to the combined endpoint (HR = 8.37, 1.19-68.4, P = 0.03). DISCUSSION: Patients hospitalized for heart failure and nocturnal hypoxemia measured with portable pulse-oximeter have an increased risk of hospital readmission and death. PMID- 29277337 TI - A brief look at the role of monocyte chemoattractant protein-1 (CCL2) in the pathophysiology of psoriasis. AB - Psoriasis (PsO) is a chronic skin disorder resulting from the imbalanced interactionbetween infiltrating immune cells and keratinocytes. These immune cells, including monocytes, are able to mediate the immune responses in inflamed skin lesions. Chemokines are responsible for the recruitment of leukocytes to sites of inflammation. In patients with PsO, the keratinocytes are the main source of monocyte chemotactic protein 1 (MCP-1/CCL2), which is a CC chemokine. After CCL2 binds to the chemokine receptor CCR2, which mainly is expressed on the surface of monocytes, the monocytes differentiate into macrophages and migrate from the blood stream to sites of inflammation. This process can cause the formation of lesions. Accordingly, it has been hypothesized that CCL2 could be a potential biomarker to monitor the progression of PsO. Thus, evidence suggests that there could be a potential role for CCR2 and CCL2 during treatment of PsO and to prevent its further development. For example, to modify the course of PsO, efforts have been made to inhibit or modulate the CCR2/CCL2 axis. However, before exploring the targeting of the CCR2/CCL2 axis in a clinical setting, better understanding of the different molecular aspects of PsO is required. PMID- 29277338 TI - Hypothalamic abnormalities: Growth failure due to defects of the GHRH receptor. AB - Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model. PMID- 29277339 TI - Koebner Phenomenon In Sweet's Syndrome. PMID- 29277340 TI - Corrigendum to "Osteocalcin is necessary and sufficient to maintain muscle mass in older mice" [Mol Metabol 5 (2017) 1042-1047]. PMID- 29277341 TI - The role of aryl hydrocarbon receptor in bone remodeling. AB - Bone remodeling is a persistent process for maintaining skeletal system homeostasis, and it depends on the dynamic equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts. Aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, plays a pivotal role in regulating skeletal system. In order to better understand the role of Ahr in bone remodeling, we focused on bone remodeling characteristic, and the effects of Ahr on bone formation and differentiation, which suggest that Ahr is a critical control factor in the process of bone remodeling. Moreover, we discussed the impacts of Ahr on several signaling pathways related to bone remodeling, hoping to provide a theoretical basis to improve bone remodeling. PMID- 29277342 TI - Do immune cells lead the way in subchondral bone disturbance in osteoarthritis? AB - Osteoarthritis (OA) is a whole-joint disorder, and non-cartilage articular pathologies, e.g. subchondral bone disturbance, contribute substantially to the onset and progression of the disease. In the early stage of OA, abnormal mechanical loading leads to micro-cracks or micro-fractures that trigger a reparative process with angiogenesis and inflammatory response. With the progression of disease, cystic lesion, sclerosis and osteophytosis occur at tissue level, and osteoblast dysfunction at cellular level. Osteoblasts derived from OA sclerotic bone produce increased amount of type I collagen with aberrant Col1A1/A2 ratio and poor mineralization capability. The coupling mechanism of bone resorption with formation is also impaired with elevated osteoclastic activities. All these suggest a view that OA subchondral bone presents a defective fracture repair process in a chronic course. It has been found that T and B cells, the major effectors in the adaptive immunity, take part in the hard callus formation at fracture site in addition to the initial phase of haematoma and inflammation. Infiltration of lymphocytes could interplay with osteoclasts and osteoblasts via a direct physical cell-to-cell contact. Several lines of evidence have consistently shown the involvement of T and B cells in osteoclastogenesis and bone erosion in arthritic joints. Yet the biological link between immune cells and osteoblastic function remains ambiguous. This review will discuss the current knowledge regarding the role of immune cells in bone remodelling, and address its implications in emerging basic and clinical investigations into the pathogenesis and management of subchondral bone pathologies in OA. PMID- 29277343 TI - The Divergent Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers in Adult Patients With Type 2 Diabetes Mellitus. AB - The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin-converting enzyme inhibitors (ACEi's) suppress angiotensin II (ANG II) concentrations, whereas angiotensin II type 1 (AT1) receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEi's and ARBs are both effective antihypertensive agents and produce similar risk reductions for stroke, a blood pressure-dependent phenomenon. ACEi's also reduce the risk for myocardial infarction (MI) and all cause mortality in high-risk hypertensive patients as well as in people with diabetes, vascular disease and congestive heart failure. ARBs, in contrast, do not reduce the risk for MI or death in randomized clinical trials when assessed vs. placebo. Systematic reviews of ARBs that include meta-analyses or metaregression analyses confirm that ARBs lack the cardiovascular-protective effects of ACEi's. Practice guidelines, especially those for high-risk patients, such as those with diabetes mellitus, should reflect the evidence that ACEi's and ARBs have divergent cardiovascular effects: ACEi's reduce mortality, whereas ARBs do not. ACEi's should remain the preferred RAAS inhibitor for patients at high risk. PMID- 29277344 TI - Responses to the letter titled "No clinically significant effect of new complete denture fabrication and simple dietary advice on nutrient intake and masticatory function of edentulous older people." PMID- 29277345 TI - Implication of the rs670 variant of APOA1 gene with lipid profile, serum adipokine levels and components of metabolic syndrome in adult obese subjects. AB - BACKGROUND & AIMS: A G-to-A transition located 75 base pairs upstream (rs670) from transcription start site of the APOA1 gene is related with metabolic parameters. The aim of the present investigation was to describe the association of rs670 with metabolic syndrome and metabolic parameters. METHODS: The study involved a population of 1000 obese subjects. Measurements of anthropometric parameters, arterial blood pressure, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile, adipokines levels and prevalence of MetS was recorded. Genotype of ApoA1 gene polymorphism (rs670) was evaluated. RESULTS: A sample of 1000 obese subjects with a mean BMI of 36.5 +/- 5.0 kg/m2 was enrolled. In males, weight (delta: 3.3 +/- 1.2 kg; p = 0.01), fat mass (delta: 2.7 +/- 1.1 kg; p = 0.01), waist circumference (delta: 2.8 +/- 1.1 cm; p = 0.02), fasting glucose (delta: 8.9 +/- 2.2 mg/dl; p = 0.01), insulin levels (delta: 3.7 +/- 1.2 UI/L; p = 0.04) and HOMA IR (delta: 1.2 +/- 1.1 units; p = 0.02) were higher in non-A allele carriers than A allele carriers. In males without A allele, an increased risk of hyperglycemia (OR = 1.40, 95% CI = 1.09-2.09, p = 0.04), percentage of central obesity (OR = 4.55, 95% CI = 1.36-15.39, p = 0.01), percentage of low HDL-C (OR = 2.02, 95% CI = 1.02-4.03, p = 0.03) and prevalence of diabetes mellitus (OR = 2.14, 95% CI = 1.03-5.04, p = 0.03) were reported. CONCLUSIONS: rs670 of APOA1 gene has a gender specific influence on serum glucose, insulin, HOMA-IR, fat mass, weight and waist circumference. Males without A allele showed high rates of central obesity, low levels of HDL, hyperglycemia and diabetes mellitus. PMID- 29277346 TI - Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta analysis of prospective cohort studies. AB - BACKGROUND & AIMS: Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer. METHODS: PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer. RESULTS: Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets. CONCLUSIONS: The present meta analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer. PMID- 29277347 TI - Adherence to blood pressure and glucose recommendations in chronic kidney disease hospital inpatients: Clinical inertia and patient adherence. AB - AIMS: To determine the extent to which targets for blood pressure (BP) (<140.90 mmHg) and random blood glucose level (BGL) (<7.7 mmol/L) control in patients with chronic kidney disease (CKD) are achieved; and the extent clinical inertia affects BP and glucose control in CKD and diabetes mellitus (DM). METHODS: Data was collected from the 1st January 2015 until 31st December 2015 on key patient pathology, admission reason, final discharge diagnosis, and information concerning clinical guideline adherence. RESULTS: Eighty-seven (n = 87) CKD patients were included. The average hospital BP for all CKD patients was 134.3/73.4 mmHg, adhering to recommendations of <140/90 mmHg. The average CKD patient pre-admission BP was 134.8/72.2 mmHg compared to the discharge BP of 129.8/72.2 mmHg. At admission, 63.3% and 93.1% of patients adhered to systolic and diastolic BP recommendations, which significantly (p = < .05) increased at discharge to a systolic and diastolic BP adherence of 83.9% and 98.8%, respectively. The average random hospital BGL was 7.7 mmol/L, indicating good control, whereas the pre-hospital HbA1c average was 7.58%, indicating poor control (>7.0% >53 mmol/mol). There were 21 cases of clinical inertia, affecting 18 out of 87 patients (20.7%), with significant adverse hospital discharge differences (p = <.05) between clinical inertia and non- clinical inertia patient systolic BP (144.2 vs. 132.8 mmHg), deranged BGL (66.7% vs. 35.3%), and reduction in kidney function (83.3% vs. 30.9%). CONCLUSION: Adherence appears to be related to inpatient clinical inertia and outpatient patient health literacy and empowerment. PMID- 29277348 TI - Like two peas in a pod: Metabolic syndrome and epicardial obesity. PMID- 29277349 TI - Diabetes mellitus- induction: Effect of different streptozotocin doses on male reproductive parameters. AB - Diabetes mellitus (DM) is reported to be involved in male reproductive impairment, and its impact is evident in the increased prevalence of infertility. Various studies have reported that a single parenteral injection of <40 mg/kg Streptozotocin (STZ) is ineffective in ablating pancreatic beta-cells and creating a rat model to investigate the effect of DM on the male reproductive system. This study therefore aims to validate these claims. Adult male Wistar rats received either a single intraperitoneal injection of STZ (30 mg/kg or 60 mg/kg) or saline (0.9%, Control). Diabetes was confirmed after 72 h if plasma glucose levels were >=14 mmol/L. Body weight, glucose level, fluid and food intake were measured weekly. Animals were sacrificed after 8 weeks of treatment by an overdose of sodium pentobarbital (160 mg/kg body weight). The testis and epididymis were harvested and weighed prior to preparation for histological evaluation. Epididymal sperm morphology was analysed using computer aided sperm analysis (CASA). STZ60 animals presented with significantly lower body weights compared to both control and STZ30 groups. Animals in both STZ30 and STZ60 groups showed decreased normal sperm morphology compared to control. Histological evaluation of the testes showed a decrease in the number of spermatozoa in the seminiferous tubules of animals in the STZ30 and STZ60 groups compared to control. A complete absence of spermiogenesis was observed in the seminiferous tubules of STZ60 animals. These findings prove that an STZ concentration of 30 mg/kg, which is much lower than the reported 40 mg/kg, has adverse effects on the male reproductive system via its diabetogenic effect and can therefore be used to study the impact of DM on male fertility. PMID- 29277350 TI - Clinical Practicability of a Newly Developed Real-time Digital Kymographic System. AB - BACKGROUND: A digital kymogram shows real images of vocal fold vibration. However, DKG is difficult to use in clinical practice because the recorded image cannot be seen instantaneously after examination, as considerable encoding time is required to visualize a digital kymogram. In addition, frame-by frame analysis should be implemented to evaluate high-speed videoendoscopy data, but is time- and labor-intensive. PURPOSE: The purpose of the study was to validate the clinical practicability of a real-time multislice digital kymographic system developed by the authors. We analyzed the promptness and accuracy of the examination before and after intracordal injections in patients with unilateral vocal fold paralysis. METHODS: To assess the clinical applicability of this system, six patients with unilateral vocal fold paralysis were selected. Real time DKG was performed before and immediately after intracordal injection. We observed changes in the digital kymogram after the intracordal injection. RESULTS: Using this system, 10 scanning lines and up to five vertical pixel row could be obtained in real time, and the maximum acquisition time for the DKG image was 10 seconds. A digital kymogram of the patients could be instantaneously acquired, and whether the intracordal injection was appropriate or not. CONCLUSION: This article is the first validation study after the development of the real-time multislice digital kymographic system. Our system may be a promising tool in clinical practice for immediate assessment of the vibratory patterns of the vocal cords. More research is necessary for further clinical validation. PMID- 29277351 TI - Estimation of Source-Filter Interaction Regions Based on Electroglottography. AB - Source-filter interaction is a phenomenon in which acoustic airway pressures influence the glottal airflow at the source (level 1) and the vibration pattern of the vocal folds (level 2). This interaction is most significant when dominant source harmonics are near airway resonances. The influence of acoustic airway pressures on vocal fold vibration (level 2) was studied systematically by changing the supraglottal vocal tract length in human subjects with tube extensions. The subjects were asked to perform fundamental frequency (fo) glides while phonating through tubes of various lengths. An algorithm was developed using the quasi-open quotient extracted from the electroglottograph. Regions of sudden vocal fold vibration pattern change due to source-filter interaction were inferred from contact area changes. The algorithm correctly identified 89% of male and 84.8% of female quantal changes in contact pattern associated with interactions between source harmonics and formants during ascending glides. During the descending glides, the algorithm correctly identified 84% of male and 81.1% of female quantal changes in contact pattern. These results are in comparison with those obtained from the fo-based algorithm (Maxfield et al). PMID- 29277352 TI - Comparative genomic analysis of Lactobacillus mucosae LM1 identifies potential niche-specific genes and pathways for gastrointestinal adaptation. AB - Lactobacillus mucosae is currently of interest as putative probiotics due to their metabolic capabilities and ability to colonize host mucosal niches. L. mucosae LM1 has been studied in its functions in cell adhesion and pathogen inhibition, etc. It demonstrated unique abilities to use energy from carbohydrate and non-carbohydrate sources. Due to these functions, we report the first complete genome sequence of an L. mucosae strain, L. mucosae LM1. Analysis of the pan-genome in comparison with closely-related Lactobacillus species identified a complete glycogen metabolism pathway, as well as folate biosynthesis, complementing previous proteomic data on the LM1 strain. It also revealed common and unique niche-adaptation genes among the various L. mucosae strains. The aim of this study was to derive genomic information that would reveal the probable mechanisms underlying the probiotic effect of L. mucosae LM1, and provide a better understanding of the nature of L. mucosae sp. PMID- 29277354 TI - Launch of the APIC(r) Program of Distinction. PMID- 29277353 TI - Immunologic non-inferiority and safety of the investigational pneumococcal non typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) 4-dose vial presentation compared to the licensed PHiD-CV 1-dose vial presentation in infants: A phase III randomized study. AB - BACKGROUND: To support vaccination programs in developing countries, a 4-dose vial presentation of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was developed. This study assessed immunologic non inferiority and safety of the investigational PHiD-CV 4-dose versus licensed 1 dose vial presentation in infants. METHODS: In this phase III, mono-center, observer-blind study in Bangladesh, 6-10-week-old infants were randomized 1:1 to receive PHiD-CV primary vaccination (at ages 6, 10, 18 weeks) and a booster dose (at age 9 months) with a 4-dose vial (with preservative, 4DV group) or 1-dose vial (preservative-free, 1DV group). DTPw-HBV/Hib was (co)-administered per study protocol and polio, measles and rubella vaccines as part of the national immunization program. Non-inferiority of PHiD-CV 4-dose versus 1-dose vial for each vaccine pneumococcal serotype (VT) and vaccine-related serotype 19A in terms of antibody geometric mean concentration (GMC) was assessed (criterion: upper limit of 2-sided 95% confidence interval of antibody GMC ratios [1DV/4DV] <2 fold). Immune responses were measured. Solicited, unsolicited and serious adverse events (AEs) were evaluated. RESULTS: Of 320 infants (160 per group) vaccinated during the primary vaccination phase, 297 received a booster. Non-inferiority was demonstrated for each VT and 19A. One month post-primary vaccination, for most VT, >=97.9% of infants in each group had antibody concentrations >=0.2 MUg/mL; for 19A >= 80.1% reached this threshold. Pneumococcal antibody responses and opsonophagocytic activity for each VT and 19A were within similar ranges between groups after primary and booster vaccination, as were anti-protein D responses. Booster immune responses were observed in both groups. Reported AEs were within similar ranges for both presentations. CONCLUSION: Immunologic non-inferiority of PHiD-CV 4-dose vial (with preservative) versus PHiD-CV 1-dose vial (preservative free) was demonstrated. Immune responses and reactogenicity following primary/booster vaccination were within similar ranges for both presentations. PHiD-CV 4-dose vial would help improve access and coverage in resource-limited countries. Clinical Trial Registry: NCT02447432. PMID- 29277355 TI - Effect of cetyltrimethyl ammonium bromide on uptake of polycyclic aromatic hydrocarbons by carrots. AB - This is the first study investigating the effect of cationic surfactants on the mobility of polycyclic aromatic hydrocarbons (PAHs) in aged contaminated soils and on PAH bioaccumulation in tuberous vegetables. In an aerobic soil incubation experiment, 150 mg/kg cetyltrimethyl ammonium bromide (CTMAB) decreased the bioavailability of PAHs primarily via immobilization (by 13%). In a carrot pot experiment, the effectiveness of CTMAB to reduce PAH uptake by carrots decreased with time. Accordingly, the bioavailability of PAHs in the soil decreased in the first 90 days and then increased and remained stable until harvest. In the leaching test, the leaching loss of CTMAB (15%) was lower in soils treated with small amounts of CTMAB in several applications than it was in soils (24%) treated once with CTMAB. Therefore, CTMAB, when applied in appropriate doses via addition methods, can effectively reduce the environmental risk of PAH entering humans and livestock through the food chain. PMID- 29277356 TI - Translocation of Epidermal Growth Factor (EGF) to the nucleus has distinct kinetics between adipose tissue-derived mesenchymal stem cells and a mesenchymal cancer cell lineage. AB - Nuclear Epidermal Growth Factor Receptor (EGFR) has been associated with worse prognosis and treatment resistance for several cancer types. After Epidermal Growth Factor (EGF) binding, the ligand-receptor complex can translocate to the nucleus where it functions in oncological processes. By three-dimensional quantification analysis of super-resolution microscopy images, we verified the translocation kinetics of fluorescent conjugated EGF to the nucleus in two mesenchymal cell types: human adipose tissue-derived stem cells (hASC) and SK-HEP 1 tumor cells. The number of EGF clusters in the nucleus does not change after 10 min of stimulation with EGF in both cells. The total volume occupied by EGF clusters in the nucleus of hASC also does not change after 10 min of stimulation with EGF. However, the total volume of EGF clusters increases only after 20 min in SK-HEP-1 cells nuclei. In these cells the nuclear volume occupied by EGF is 3.2 times higher than in hASC after 20 min of stimulation, indicating that translocation kinetics of EGF differs between these two cell types. After stimulation, EGF clusters assemble in larger clusters in the cell nucleus in both cell types, which suggests specific sub-nuclear localizations of the receptor. Super-resolution microscopy images show that EGF clusters are widespread in the nucleoplasm, and can be localized in nuclear envelope invaginations, and in the nucleoli. The quantitative study of EGF-EGFR complex translocation to the nucleus may help to unravel its roles in health and pathological conditions, such as cancer. PMID- 29277357 TI - French guidelines on stereoelectroencephalography (SEEG). AB - Stereoelectroencephalography (SEEG) was designed and developed in the 1960s in France by J. Talairach and J. Bancaud. It is an invasive method of exploration for drug-resistant focal epilepsies, offering the advantage of a tridimensional and temporally precise study of the epileptic discharge. It allows anatomo electrical correlations and tailored surgeries. Whereas this method has been used for decades by experts in a limited number of European centers, the last ten years have seen increasing worldwide spread of its use. Moreover in current practice, SEEG is not only a diagnostic tool but also offers a therapeutic option, i.e., thermocoagulation. In order to propose formal guidelines for best clinical practice in SEEG, a working party was formed, composed of experts from every French centre with a large SEEG experience (those performing more than 10 SEEG per year over at least a 5 year period). This group formulated recommendations, which were graded by all participants according to established methodology. The first part of this article summarizes these within the following topics: indications and limits of SEEG; planning and management of SEEG; surgical technique; electrophysiological technical procedures; interpretation of SEEG recordings; and SEEG-guided radio frequency thermocoagulation. In the second part, those different aspects are discussed in more detail by subgroups of experts, based on existing literature and their own experience. The aim of this work is to present a consensual French approach to SEEG, which could be used as a basic document for centers using this method, particularly those who are beginning SEEG practice. These guidelines are supported by the French Clinical Neurophysiology Society and the French chapter of the International League Against Epilepsy. PMID- 29277358 TI - Protocol of a randomised controlled trial regarding the effectiveness of fluoroscopy-guided manual lymph drainage for the treatment of breast cancer related lymphoedema (EFforT-BCRL trial). AB - OBJECTIVES: Lymphoedema is a dreadful complication following breast cancer therapy. According to the International Society of Lymphology, the consensus treatment for breast cancer-related lymphoedema (BCRL) is the decongestive lymphatic therapy. This is a two-phase treatment and combines different treatment modalities including skin care, manual lymphatic drainage (MLD), compression therapy and exercise. However, the additional effect of MLD is debated since pooled data only demonstrated a limited non-significant additional value. A possible explanation is that in previous studies MLD has been applied blind, without knowledge of patient-specific lymphatic routes of transport. In addition, the MLD hand manoeuvres used by the therapists in previous studies, possibly did not optimally stimulate lymphatic transport. Recently, near-infrared fluorescence imaging has been introduced to visualise the superficial lymphatic network which allows MLD at the most needed location. The aim of the present study is to determine the effectiveness of the fluoroscopy-guided MLD, additional to the other parts of the decongestive lymphatic therapy and compared to the traditional or a placebo MLD, in the treatment of BCRL. STUDY DESIGN: A three-arm double blinded randomised controlled trial will be conducted in different university hospitals in Belgium. Based on a sample size calculation, 201 participants with chronic BCRL stage 1 or 2 of the arm or hand, with at least 5% difference between both sides (corrected for hand dominance) need to be recruited. All participants receive the standard treatment: skin care, compression therapy and exercises. The intervention group additionally receives fluoroscopy-guided MLD. One control group additionally receives the traditional 'blind' MLD and a second control group receives a placebo MLD. All subjects receive 3 weeks of daily intensive treatments and 6 months of maintenance treatment. Follow-up period is 6 months. The primary outcomes are the reduction in lymphoedema volume of the arm/hand and the change in stagnation of lymph fluid at level of the shoulder/trunk. PMID- 29277360 TI - Management of Advanced and Relapsed/Refractory Extranodal Natural Killer T-Cell Lymphoma: An Analysis of Stem Cell Transplantation and Chemotherapy Outcomes. AB - BACKGROUND: Extra-Nodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoma representing approximately 5-10% of T-cell non-Hodgkin lymphomas diagnosed in the United States each year. Patients with advanced stage III/IV ENKL and relapsed refractory ENKL have a poor prognosis even despite aggressive therapy and stem cell transplantation (SCT). We conducted a review of the management of 37 patients with advanced-stage and relapsed/refractory ENKL in a predominantly non Asian cohort evaluating both chemotherapy and SCT outcomes. PATIENTS AND METHODS: We evaluated clinical outcomes in all patients treated for advanced stage III/IV or relapsed/refractory ENKL at MD Anderson cancer center between 2000-2014. Next, we collected stem cell transplant data from four transplant institutions to further evaluate outcomes of both allogeneic (allo-SCT) and autologous (auto-SCT) stem cell transplantation in ENKL. RESULTS: OS and PFS were 73% and 45% at one year, and 30% and 19% at 3-years, respectively. SMILE chemotherapy was more effective in maintaining a CR compared to CHOP (83% vs 17%). Only achievement of CR was prognostic for OS (HR 0.245, p=0.002) and PFS (HR 0.072, p) CONCLUSION: Our results suggest that achievement of a CR is imperative in patients with advanced ENKL, and is desirable for any patient for whom auto-SCT is utilized. SMILE-based chemotherapy appeared effective in attaining a CR, and was also an effective salvage regimen. For patients attaining a first CR, auto-SCT should be strongly considered, but should definitely be utilized in patients attaining CR2. For patients with refractory disease, allo-SCT can be considered in a selected group of patients. PMID- 29277361 TI - ALA-PDT exerts beneficial effects on chronic venous ulcers by inducing changes in inflammatory microenvironment, especially through increased TGF-beta release: A pilot clinical and translational study. AB - A cohort of 19 patients affected by chronic venous ulcers was recruited from our centre. A 4-mm punch biopsy from wound bed was taken before application of ALA 20% gel and repeated one hour after the first PDT irradiation. We observed a significant and progressive reduction of wounds mean volumes right after three ALA-PDT sessions (once per week; 4479.9 +/- 345.5 mm3 vs 34599 +/- 190.3 mm3, p < .01). On immunofluorescence staining from biopsy specimens, we observed a change in all tested stains of post treatment specimens compared to pre-treatment ones. An increase of plasmacytoid dendritic cells (from 699 +/- 22 cells/0.018 mm2 to 1369 +/- 27 cells/0.018 mm2, p < .0001); MHC-II expression (260.39 +/- 99.7 Red, Green, Blue [RGB 0-255] to 370.2 +/- 162.6 RGB (0-255), p < .01), TNF-alpha positive mast cells expression (49 +/- 0.3 cells/0.018 mm2 to 69 +/- 0.4 cells/0.018 mm2, p < .001), TGF-beta expression (59.89 +/- 23.2 RGB (0-255)/cell vs 137.39 +/- 56.6 RGB (0-255)/cell, p < .01) and CD4+/CD25+ Treg cells (39 +/- 1 cells/0.018 mm2 vs 209 +/- 10 cells/0.018 mm2, p < .001) was observed. An increase of TGF-beta was correlated in a statistical significant manner with a reduction of wounds' mean volumes. PMID- 29277362 TI - Rotator cuff tendon-to-bone healing at 12 months after patch grafting of acellular dermal matrix in an animal model. AB - There is no report to investigate the histology and biomechanical strength of remodeled tendon-to-bone junction more than 6 months after patch grafting with acellular dermal matrix (ADM) on rotator cuff defect. We investigated those 12 months after surgery and hypothesized that a new native enthesis is not regenerated and the biomechanical strength is inferior to normal control. Adult male Sprague-Dawley rats underwent ADM patch grafting for the rotator cuff defect. Quantitative histological analysis, immunohistochemical analysis for collagen type I and III, and biomechanical testing were performed 12 months after surgery. The controls were unoperated age-matched rats. In the grafted rats, the collagen arrangement was more irregular and the fibrocartilage layer was smaller at the tendon-bone interface than in the controls although dense collagen fibers in the remodeled tendon were observed; the number of chondrocytes, the percentage of chondrocytes aligned in rows, and the area of the fibrocartilage layer were significantly smaller than in the control group (p = 0.0252, 0.0039, and 0.0252, respectively). Grafted specimens showed significantly lower collagen organization in the midsubstance and tendon-bone interface than the controls (p = 0.0252 and 0.0374, respectively). Immunohistochemical analysis demonstrated that the remodeled tendon fibers were stained more strongly for type III than type I. At 12 months postoperatively, the ultimate load to failure was significantly lower in the graft group than normal control (p = 0.0026); that was 47.8% of normal controls. 12 months after rotator cuff patch grafting with ADM, the formation of a new enthesis grossly resembled the native structure but there was poor cellular organization and the biomechanical strength of remodeled tendon-to-bone was only 48% of normal controls. Advances in tissue engineering and postoperative rehabilitation are needed to promote the healing process after rotator cuff patch grafting. PMID- 29277359 TI - SOHO State-of-the-Art Update and Next Questions: MPN. AB - The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011. The field has continued to advance rapidly since then, and the past 2 years have witnessed important changes to the classification of MPN and diagnostic criteria for polycythemia vera (PV), novel insights into the mechanisms of bone marrow fibrosis in primary myelofibrosis (PMF), increasing appreciation of the biologic differences between essential thrombocythemia (ET), prefibrotic and overt PMF, and between primary and post PV/ET myelofibrosis (MF). Additionally, the mechanisms through which mutant CALR drives JAK-STAT pathway activation and oncogenic transformation are now better understood. Although mastocytosis is no longer included under the broad heading of MPN in the 2016 revision to the World Health Organization classification, an important milestone in mastocytosis research was reached in 2017 with the regulatory approval of midostaurin for patients with advanced systemic mastocytosis (AdvSM). In this article, we review the major recent developments in the areas of PV, ET, and MF, and also briefly summarize the literature on midostaurin and other KIT inhibitors for patients with AdvSM. PMID- 29277363 TI - Anatomic feature of deltoid ligament attachment in posteromedial osteochondral lesion of talar dome. AB - BACKGROUND: Osteochondral lesions of the talus (OLT) are recognized as being commonly associated with trauma. However, the etiology of OLT remains unclear. In the case of a posteromedial lesion of OLT (medial OLT), the deep layer of the deltoid ligament is located close to the medial OLT, and this relationship between a medial lesion and deltoid ligament could be a risk factor for medial OLT. The purpose of this study is to investigate the unique anatomic feature of the deep deltoid attachment to the talus in patients with medial OLT compared with patients with non-medial OLT. METHODS: Forty ankles with medial OLT and 40 ankles without medial OLT were retrospectively reviewed in this study. On the coronal images of MRI, the attachment of deltoid ligament was measured. The continuity of the osteochondral fragment and its bed was evaluated on MRI and arthroscopic findings. RESULTS: Coronal MRI images showed that the attachment of the deep deltoid ligament to the medial OLT was broader and located more proximally than in non-medial OLT. The continuity of fibers from the insertion site of deltoid ligament to the talus to the osteochondral fragment was observed (76.7%). In the arthroscopic findings, the osteochondral fragment was obviously connected to the talus at the medial site in 85.2% of feet. CONCLUSIONS: The location of the deep deltoid ligament attachment to the medial OLT was more proximal and there was the possibility of these anatomic feature might contribute to the pathogenesis of medial OLT. PMID- 29277364 TI - Identification of an interferon-stimulated gene, isg15, involved in host immune defense against viral infections in gilthead seabream (Sparus aurata L.). AB - Interferons (IFNs) play a key role in the innate immunity of vertebrates against viral infections by inducing hundreds of IFN-stimulated genes (ISGs), such as isg15. Isg15 is an ubiquitin-like protein, which can conjugate cellular and viral proteins in a process called ISGylation, although it can also act as a cytokine like protein. Gilthead seabream (Sparus aurata L.) is an important asymptomatic carrier of viral haemorrhagic septicaemia virus (VHSV) and nodavirus, representing a threat to other co-cultivated susceptible species. In order to better understand virus-host interactions in this fish species, this study addresses the identification and molecular characterization of seabream isg15 (sb isg15). In addition, the modulation of transcript levels of sb-isg15 was analysed in SAF-1 cells and seabream acidophilic granulocytes (AGs) stimulated in vitro with different pathogen-associated molecular patterns (PAMPs) or inoculated with VHSV and striped jack nervous necrosis virus (SJNNV). The full-length cDNA of sb isg15 gene, encoding a predicted protein of 155 amino acids, was identified and seen to share the same characteristics as other fish and mammalian isg15 genes. Here we report the clear induction of sb-isg15 transcript levels in SAF-1 cells and AGs stimulated with toll-like receptor (TLR) ligands, such as polyinosinic:polycytidylic acid (poly I:C) or genomic DNA from Vibrio anguillarum (VaDNA), respectively. Furthermore, VHSV and SJNNV inoculation induced a significant degree of sb-isg15 transcription in SAF-1 cells and AGs. However, the relative levels of viral RNA transcription showed that SJNNV replication seems to be more efficient than VHSV in both in vitro systems. Interestingly, sb-isg15 transcript induction elicited by VaDNA was reduced in VHSV- and SJNNV-inoculated AGs, suggesting an interference prompted by the viruses against the type I IFN system. Taken together, these findings support the use of seabream AGs as a valuable experimental system to study virus-host interactions, in which sb-isg15 seems to play an important role. PMID- 29277365 TI - Effect of Agaricus bisporus enriched diet on growth, hematology, and immune protection in Clarias gariepinus against Flavobacterium columnare. AB - The purpose of the present study was to find out the effect of dietary enriched button mushroom, Agaricus bisporus at 1%, 5%, and 10% levels on growth performance, hematology, nonspecific immune responses, and disease resistance in catfish, Clarias gariepinus against Flavobacterium columnare for a period of four weeks. The percentage weight gain and specific growth rate (SGR) were higher in the infected fish fed with 5% A. bisporus enriched diet than with 1% and 10% diets. The red blood cell (RBC), white blood cell (WBC), hematocrit (PCV), and haemoglobin (Hb) values are similar (p > .05) among the experimental groups at the end of fourth week. The phagocytic activity, complement activity, and lysozyme activity were significantly enhanced in the infected fish fed with 5% A. bisporus diet during the experimental period; however, it was significantly enhanced with 10% A. bisporus enriched diet only on weeks 2 and 4. On the other hand, the respiratory burst (RB) activity increased significantly in the infected fish fed with 5% and 10% A. bisporus enriched diets. When fed with 5% A. bisporus diet the cumulative mortality was very low (10%), followed by a high survival rate (89%) in the infected fish; nevertheless, the cumulative mortality was 25% and 20% while it was 74% and 79% when fed with 1% and 10% enriched diets. The present study recommends a dietary supplement of A. bisporus at 5% or 10% level to achieve better growth without side effect, and enhance the nonspecific immune system that prevent mortalities from F. columnare infection in C. gariepinus. PMID- 29277366 TI - Role of Withania somnifera (Ashwagandha) in the management of male infertility. AB - To manage male infertility caused by hormonal imbalance, infections and other predicaments, multifarious treatment strategies are emerging worldwide. Contemporary treatments, such as assisted reproductive techniques, are costly with low success rates of only 10-30%; however, herbal remedies are gaining more attention as an alternative or supplementary therapeutic modality for male infertility. The beneficial effects induced by oral intake of the roots of a small evergreen shrub, Withania sominifera (Ashwagandha) on semen quality of infertile men have previously been studied. Oral intake of Ashwagandha roots has been found to inhibit lipid peroxidation, improve sperm count and motility, and regulate reproductive hormone levels. The molecular mechanisms of these effects, however, are yet to be unveiled. In this review, we will discuss the role of herbal medicines in male infertility; provide a detailed analysis of various human and animal studies involving Withania somnifera; describe a proposed direct oxidative mechanism involving mitigation of oxidative stress as well as an indirect mechanism consisting of a gamma-aminobutyric acid-like-mimetic pathway ameliorating hormonal balance through crosstalk among different endocrine glands to improve male fertility; and how Withania somnifera supplementation mitigates risk factor-induced male infertility as well as ameliorates male fertility. PMID- 29277367 TI - [3D printed medical devices and anatomical models: What kind of distribution and which uses in French hospitals?] AB - 3D printing plays an increasingly important role in the medical sector and particularly in surgery. Nowadays, numerous manufacturers benefit from this technology to produce their medical devices and some hospitals have also purchased 3D printers. In this context, the aim of the present study was to study the distribution and the use of 3D printing in French hospitals in order to its main features in surgery. By conducting a national survey, we targeted hospitals equipped with 3D printers and those using external providers to benefit from this technology. Forty-seven hospitals were identified as using 3D printing including eight equipped with in-house 3D printers. This work gives us a first picture of 3D printing for hospital use in France and it raises questions about hospital pharmacists' involvement in 3D printed medical device production. PMID- 29277368 TI - Re-irradiation is Now a Real Option - But How Do We Take it Forward? PMID- 29277369 TI - Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats. AB - BACKGROUND: Skeletal muscle is adversely affected in type-1 diabetes, and excessively stimulated ubiquitin-proteasome system (UPS) was found to be a leading cause of muscle wasting or atrophy. The role of endoplasmic reticulum (ER) stress in muscle atrophy of type-1 diabetes is not known. Hence, we investigated the role of UPS and ER stress in the muscle atrophy of chronic diabetes rat model. METHODS: Diabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats and were sacrificed 2- and 4-months thereafter to collect gastrocnemius muscle. In another experiment, 2-months post-STZ-injection diabetic rats were treated with MG132, a proteasome inhibitor, for the next 2 months and gastrocnemius muscle was collected. RESULTS: The muscle fiber cross sectional area was diminished in diabetic rats. The expression of UPS components: E1, MURF1, TRIM72, UCHL1, UCHL5, ubiquitinated proteins, and proteasome activity were elevated in the diabetic rats indicating activated UPS. Altered expression of ER-associated degradation (ERAD) components and increased ER stress markers were detected in 4-months diabetic rats. Proteasome inhibition by MG132 alleviated alterations in the UPS and ER stress in diabetic rat muscle. CONCLUSION: Increased UPS activity and ER stress were implicated in the muscle atrophy of diabetic rats and proteasome inhibition exhibited beneficiary outcome. PMID- 29277370 TI - Improved rate of substrate oxidation catalyzed by genetically-engineered myoglobin. AB - This study showcases the potential of unnatural amino acids to enable non-natural functions when incorporated in the protein scaffold of heme metalloproteins. For this purpose, a genetically-engineered myoglobin (Mb) mutant was created by incorporating redox-active 3-amino-l-tyrosine (NH2Tyr) into its active site, replacing the distal histidine (H64) with NH2Tyr. In peroxide-shunt assays, this variant exhibits an increased rate of turnover for thioanisole and benzaldehyde oxidation as compared to the wild-type (WT) Mb. Indeed, in the presence of excess hydrogen peroxide (H2O2), a 9-fold and 81-fold increase in activity was observed over multiple turnovers for thioanisole sulfoxidation and benzoic acid formation, respectively. The increased oxidation activity in the H64NH2Tyr Mb mutant underlined the role of NH2Tyr in the distal active-site scaffold in peroxide activation. Kinetic, electrochemical, and EPR spectroscopic experiments were performed. On the basis of these studies, it is argued that the single NH2Tyr residue within the Mb variant simultaneously serves the role of the conserved His/Arg-pair within the distal pocket of horseradish peroxidase. PMID- 29277371 TI - Repeated fluvoxamine treatment recovers early postnatal stress-induced hypersociability-like behavior in adult rats. AB - Childhood maltreatment is associated with impaired adult brain function, particularly in the hippocampus, and is not only a major risk factor for some psychiatric diseases but also affects early social development and social adaptation in later life. The aims of this study were to determine whether early postnatal stress affects social behavior and whether repeated fluvoxamine treatment reverses these changes. Rat pups were exposed to footshock stress during postnatal days 21-25 (at 3 weeks old: 3wFS). During the post-adolescent period (10-14 weeks postnatal), the social interaction test and Golgi-cox staining of dorsal hippocampal pyramidal neurons were performed. Following exposure to footshock stress, 3wFS rats showed an increase in social interaction time, which might be practically synonymous with hypersociability, and a decrease in spine density in the CA3 hippocampal subregion, but not in CA1. These behavioral and morphological changes were both recovered by repeated oral administration of fluvoxamine at a dose of 10 mg/kg/day for 14 days. These findings suggest that the vulnerability of the hippocampal CA3 region is closely related to social impairments induced by physical stress during the juvenile period and shed some light on therapeutic alternatives for early postnatal stress induced emotional dysfunction. PMID- 29277372 TI - Effects of chlorogenic acid on carbachol-induced contraction of mouse urinary bladder. AB - Chlorogenic acid (CGA) is a polyphenol found in coffee and medicinal herbs such as Lonicera japonica. In this study, the effect of CGA-induced relaxation on carbachol (CCh)-induced contraction of mouse urinary bladder was investigated. CGA (30-300 MUg/ml) inhibited CCh- or U46619-induced contraction in a concentration-dependent manner. SQ22536 (adenylyl cyclase inhibitor) recovered CGA-induced relaxation of CCh-induced contraction; however, ODQ (guanylyl cyclase inhibitor) did not have the same effect. In addition, 3-isobutyl-1-methylxanthine (IBMX) enhanced CGA-induced relaxation; however, forskolin or sodium nitroprusside did not have the same effect. Moreover, Ro 20-1724, a selective phosphodiesterase (PDE) 4 inhibitor, enhanced CGA-induced relaxation, but vardenafil, a selective PDE5 inhibitor, did not have the same effect. In the presence of CCh, CGA increased cyclic adenosine monophosphate (cAMP) level, whereas SQ22536 inhibited the increase of cAMP levels. Moreover, higher cAMP levels were obtained with CGA plus IBMX treatment than the total cAMP levels obtained with separate CGA and IBMX treatments. In conclusion, these results suggest that CGA inhibited CCh-induced contraction of mouse urinary bladder by partly increasing cAMP levels via adenylyl cyclase activation. PMID- 29277373 TI - Exertional Tolerance Assessments After Mild Traumatic Brain Injury: A Systematic Review. AB - OBJECTIVE: To review the literature to identify and summarize strategies for evaluating responses to physical exertion after mild traumatic brain injury (mTBI) for clinical and research purposes. DATA SOURCES: PubMed and EBSCOhost through December 31, 2016. STUDY SELECTION: Two independent reviewers selected studies based on the following criteria: (1) inclusion of participants with mTBI/concussion, (2) use of a measurement of physiological or psychosomatic response to exertion, (3) a repeatable description of the exertion protocol was provided, (4) a sample of at least 10 participants with a mean age between 8 and 65 years, and (5) the article was in English. The search process yielded 2685 articles, of which 14 studies met the eligibility requirements. DATA EXTRACTION: A quality assessment using a checklist was conducted for each study by 2 independent study team members and verified by a third team member. Data were extracted by one team member and verified by a second team member. DATA SYNTHESIS: A qualitative synthesis of the studies revealed that most protocols used a treadmill or cycle ergometer as the exercise modality. Protocol methods varied across studies including differences in initial intensity determination, progression parameters, and exertion duration. Common outcome measures were self reported symptoms, heart rate, and blood pressure. CONCLUSIONS: The strongest evidence indicates that exertional assessments can provide important insight about mTBI recovery and should be administered using symptoms as a guide. Additional studies are needed to verify optimal modes and protocols for post-mTBI exertional assessments. PMID- 29277375 TI - Adherence Measurements in Clinical Trials and Care. PMID- 29277374 TI - Aerobic Exercise as an Adjuvant to Aphasia Therapy: Theory, Preliminary Findings, and Future Directions. AB - PURPOSE: This study investigated whether participation in aerobic exercise enhances the effects of aphasia therapy, and the degree to which basal serum brain-derived neurotropic factor (BDNF) concentrations fluctuate after the beginning of aerobic exercise or stretching activities in individuals with poststroke aphasia. METHODS: The study used a single-subject, multiple-baseline design. Seven individuals with chronic poststroke aphasia participated in 2 Blocks of aphasia therapy: aphasia therapy alone (Block 1), followed by aphasia therapy with the addition of aerobic activity via bicycle ergometer (n = 5) or stretching (n = 2) (Block 2). Serum BDNF concentrations from blood draws were analyzed in 4 participants who exercised and in 1 participant who stretched. FINDINGS: Three of the five exercise participants demonstrated larger Tau-U effects when aphasia therapy was paired with aerobic exercise, whereas 1 of the 2 stretching participants demonstrated a larger effect size when aphasia therapy was paired with stretching. Group-level comparisons revealed a greater overall increase in effect size in the aerobic exercise group, as indicated by differences in Tau-U weighted means. BDNF data showed that all 4 exercise participants demonstrated a decrease in BDNF concentrations during the first 6 weeks of exercise and an increase in BDNF levels near or at baseline during the last 6 weeks of exercise. The stretching participant did not show the same pattern. IMPLICATIONS: Additional research is needed to understand the mechanism of effect and to identify the factors that mediate response to exercise interventions, specifically the optimal dose of exercise and timing of language intervention with exercise. ClinicalTrials.gov identifier: NCT01113879. PMID- 29277376 TI - [Transcultural adaptation into Spanish of the Patient empowerment in long-term conditions questionnaire]. AB - PURPOSE: To describe the process of translation and cultural adaptation of the Patient empowerment in long-term condition to the Spanish language. DESIGN: Translation, cross-cultural adaptation, and pilot testing (cognitive debriefing) LOCATION: Primary and Hospital care. PARTICIPANTS: Ten patients admitted to a cardiology department of a University Hospital MAIN MEASUREMENTS: 1) Direct translation, 2) conciliation and synthesis of the versions by expert panel, 3) back- translation, 4) agreement on the back-translated version with the author of the original version, 5) analysis of comprehensibility through cognitive interviews. RESULTS: There were no differences between the direct-translated versions. The expert panel introduced changes in 23 out of the 47 items of the questionnaire. The author of the original version agreed with the version of the back-translation. In the cognitive interviews, patients reported high difficulty in one item and low difficulty in 4. CONCLUSIONS: The Spanish version of the Patient Empowerment in long-term conditions questionnaire is semantically and conceptually equivalent to the original tool. The assessment of the psychometric properties of the Spanish version of the questionnaire will be carried out at a later stage. PMID- 29277377 TI - Skeletal Muscle Metastasis: An Uncommon Finding in Lung Cancer. PMID- 29277378 TI - Assessment of hypoglycaemia during basal insulin therapy: Temporal distribution and risk of events using a predefined or an expanded definition of nocturnal events. AB - AIM: To describe in type 2 diabetes the 24-hour distribution of hypoglycaemia and compare the frequency of nocturnal events based on a predefined nocturnal window or an expanded interval, using illustrative data for two insulin glargine formulations. METHODS: Temporal distribution of hypoglycaemic events was assessed descriptively and by profile using participant-level data from three randomized trials comparing insulin glargine 300 U/mL (Gla-300) and 100 U/mL (Gla-100). Risk of hypoglycaemia and annualized event rates were compared for the predefined nocturnal interval (00:00 to 05:59h) and an expanded window (22:00h to the pre breakfast glucose measurement). RESULTS: Confirmed (<=3.9mmol/L [<=70 mg/dL]) or severe hypoglycaemic events were reported most frequently between 06:00 and 10:00 h with both insulins. Nearly threefold more events were identified using the expanded nocturnal interval. Risk of >=1 nocturnal event was 25% lower with Gla 300 than Gla-100 with the predefined, and 16% lower with the expanded interval; annualized event rates were 31% and 24% lower with the predefined and expanded window, respectively. The between-insulin difference in number of nocturnal events depended markedly on the chosen nocturnal interval (556 vs. 1145 fewer events with Gla-300 using the predefined vs. expanded interval). CONCLUSIONS: The predefined 00:00-05:59h nocturnal interval excluded many hypoglycaemic events occurring during the actual overnight interval. While Gla-300 reduced hypoglycaemic events versus Gla-100 (regardless of the interval considered), the results obtained using the expanded window better reflect the clinical experience of people treated with basal insulin. PMID- 29277379 TI - Lymph-node metastasis following total laryngectomy and total pharyngolaryngectomy for laryngeal and hypopharyngeal squamous cell carcinoma: Frequency, distribution and risk factors. AB - OBJECTIVES: To evaluate the prevalence and distribution of lymph-node metastasis after total laryngectomy or total pharyngolaryngectomy. MATERIAL AND METHODS: Retrospective single-center series of 136 successive patients undergoing total laryngectomy or total pharyngolaryngectomy with neck dissection for squamous cell carcinoma of the larynx or hypopharynx. RESULTS: The primary site was laryngeal in 110 cases and hypopharyngeal in 26. In 63 patients, surgery was first-line treatment; 73 were operated on for recurrence. The lymph-node metastasis rate, confirmed on histology, was 44.8% regardless of primary site. Hypopharyngeal location was a risk factor for lymph-node metastasis (73.1%, P=0.002) as was the supraglottic subsite (64.3%, P=0.039). Levels IIa and III were invaded in 28.7% and 25.7% of cases, respectively. Level VIb lymph-node involvement was 23.8% in patients who underwent level VIb neck dissection. Lymph-node recurrence rate was 10.3% in levels II to IV and 13.2% in VIb. CONCLUSIONS: Whatever the tumor site, levels IIa and III were most frequently invaded. The high rate of histological involvement of level VIb and of recurrence argues for systematic elective bilateral neck dissection of these territories in some primary sites. PMID- 29277380 TI - Retraction notice to "Ca2+/Calmodulin-dependent protein kinase IIgamma, a critical mediator of the NF-kappaB network, is a novel therapeutic target in non small cell lung cancer" [Cancer Lett. 344(1) (2014) 119-128]. PMID- 29277381 TI - Retraction notice to "Increased Ras GTPase activity is regulated by miRNAs that can be attenuated by CDF treatment in pancreatic cancer cells" [Cancer Lett. 319(2) (2012) 173-181]. PMID- 29277382 TI - Prevalence of chronic comorbidities in chikungunya: A systematic review and meta analysis. AB - BACKGROUND: Epidemiologic evidence suggests that patients with chikungunya virus (CHIKV) infection may be at risk of severe disease complications when they also have comorbidities such as obesity, diabetes, cardiac diseases, and/or asthma. However, the prevalence of these co-existing medical conditions in severe CHIKV cases has not been systematically reported. OBJECTIVE: The aim of the present study is to conduct a systematic review and meta-analysis to describe the prevalence of chronic comorbidities in CHIKV and evaluate their possible contributions to disease severity. METHODS: A search strategy was developed for online databases. Search terms used were "Chikungunya" AND "Diabetes, Hypertension, Stroke, Cardiovascular Diseases, Coronary Artery Diseases, Obesity, OR Asthma". Only 11 articles documenting the frequency of comorbidities in CHIKV were included. Meta-analyses were conducted to evaluate the overall prevalence of comorbidities in the CHIKV infection and stratify the estimates by severity. RESULTS: Among 2,773 CHIKV patients, hypertension was the most prevalent comorbidity (31.3%; 95%CI: 17.9-48.8%) followed by diabetes (20.5%; 95%CI: 12.7 31.3%), cardiac diseases (14.8%; 95%CI: 8.1-25.5%) and asthma (7.9%; 95%CI: 3.3 17.7). There was 4- to 5-fold significant increased prevalence of diabetes, hypertension and cardiac diseases in CHIKV patients over 50 years of age compared to their younger counterparts. Severe CHIKV cases had a significantly higher proportion of diabetes than non-severe cases (p<0.05). CHIKV patients with diabetes had OR of 1.2 (95%CI: 1.05-1.48; p=0.0135) for developing severe infection outcome compared to those with no diabetes. CONCLUSION: Hypertension, diabetes and cardiac diseases may contribute to the severe outcome of CHIKV. Diabetic subjects may be at higher risk of severe infection. These findings may be relevant in developing public health measures and practices targeting CHIKV patients with comorbidities to avert the severe outcome of the infectious disease. PMID- 29277383 TI - Gaze position modulates the effectiveness of forward collision warnings for drowsy drivers. AB - Advanced driver assistance systems (ADAS) have the potential to prevent crashes and reduce their severity. Forward collision warnings (FCW) are quickly becoming standard across vehicle lineups and may prevent frontal crashes by alerting drivers. Previous research has demonstrated the effectiveness of FCW for distracted drivers, but their effectiveness for other types of impairment remains unknown. Like distraction, drowsiness can impair driver response time and lead to crashes. The goal of the present study was to evaluate the effectiveness of FCW for moderately and severely drowsy drivers using a high-fidelity driving simulator. Drowsy drivers were divided into three warning conditions during a revealed stop vehicle forward collision event: An auditory alert, a haptic seat vibration, and a no warning baseline. Results indicate that FCW were effective at speeding drowsy driver response, but only when the drowsy drivers were looking away from the forward roadway at the onset of the event. These results have important implications for ADAS technology and driver state monitoring systems. PMID- 29277384 TI - Effectiveness of visual warnings on young drivers hazard anticipation and hazard mitigation abilities. AB - Previous studies have demonstrated that young drivers fail both to scan for and mitigate latent hazards mostly due to their cluelessness. This study aims to investigate whether these skills could be improved by providing young drivers with alerts in advance of the upcoming threat using a driving simulator experiment. In particular, the warning was presented on the head-up displays (HUD) either 2 s, 3 s or 4 s in advance of a latent threat. The hazard anticipation, hazard mitigation and attention maintenance performance of forty eight young drivers aged 18-25 was evaluated across eight unique scenarios either in the presence or in the absence of latent threat alerts displayed on a HUD. There were four groups overall: one control group (no alert) and three experimental groups (2 s alert, 3 s alert and 4 s alert). The analysis of the hazard anticipation data showed that all three experimental groups with HUD warnings (2 s, 3 s, 4 s) significantly increased the likelihood that drivers would glance towards latent pedestrian and vehicle hazards when compared to the control group. The hazard mitigation analysis showed that in situations involving a pedestrian threat, HUD alerts provided 3 or 4 s in advance of a potential threat led drivers to travel significantly slower than the control group or the 2 s group. No significant effect of a HUD alert on drivers' speed was found when the latent hazard was a vehicle. An analysis of eye behaviors showed that only 7 out of 597 glances at the HUD were longer than 2 s safety-threshold, indicating that the warnings do not seem to distract the driver. PMID- 29277385 TI - Outcomes of resection for solitary <=5 cm intrahepatic cholangiocarcinoma. AB - BACKGROUND: Resection remains the treatment of choice achieving 5-year survival rates of 22% to 40%. The aim of this analysis was to examine the outcomes of patients with solitary <=5 cm intrahepatic cholangiocarcinoma. METHODS: A retrospective chart review was performed on 123 patients undergoing resection for primary intrahepatic cholangiocarcinoma from 1995 to 2013. Group 1 included patients with asymptomatic solitary intrahepatic cholangiocarcinoma measuring <=5 cm. RESULTS: Group 1 (n = 33, 27%) had a greater rate of underlying liver disease, cirrhosis, minor resection, favorable pathologic features including decreased rate of perineural invasion, vascular invasion, lymph node involvement, and satellite nodules (P < .05). Factors associated with overall poor outcome were patients in Group 2 (P=.025), positive margin (P=.04), presence of satellite nodules (P = .008), and multinodularity (P=.058). Factors associated with recurrence in Group 1 were presence of satellite nodules (P=.004), and tumor size >=4 cm (P=.031). Factors associated with decreased survival in Group 1 was transfusion requirement (P = 0.018). The 5-year recurrence and survival rates were (39% vs 67%) and (71% vs 53%) in Group 1 versus Group 2, respectively (P=.111). CONCLUSION: Resection of solitary intrahepatic cholangiocarcinoma <=5 cm can achieve 5-year survival rates up to 71%. Results were comparable to those of patients undergoing transplantation for hepatocellular cancer within the Milan criteria. PMID- 29277386 TI - Outcomes of persistent lymph node involvement after neoadjuvant therapy for stage III rectal cancer. AB - INTRODUCTION: Lymph node involvement is a well-known predictor of recurrent rectal cancer in patient who did not undergo neoadjuvant therapy patients. The role of persistent lymph node disease after neoadjuvant treatment, however, is debatable. This study compares outcomes of patients with clinical, stage III rectal cancer who had nodal disease on surgical pathology after neoadjuvant treatment to patients with negative nodes. METHODS: We reviewed retrospectively a consecutive cohort of all clinical, American Joint Committee on Cancer stage III rectal cancer patients who received neoadjuvant chemoradiotherapy and had an R0 resection at the Massachusetts General Hospital between 2004 and 2015. RESULTS: A total of 166 patients met the inclusion criteria, of whom 53 had persistent nodal disease on pathologic examination. This group had a greater rate of local and distant disease recurrence and a shorter median recurrent disease-free survival than patients with a complete nodal response. In multivariable analyses for disease recurrence, disease free survival was greater for patients without positive results in lymph nodes on pathologic examination. CONCLUSION: Persistent nodal involvement after neoadjuvant therapy is associated with an increased risk of distant metastases and a shorter disease-free survival. Identifying patients with treatment-resistant lymph nodes preoperatively and adjusting neoadjuvant treatment might result in better outcomes. PMID- 29277388 TI - Discussion. PMID- 29277389 TI - Neurophysiology and cognitive reserve: A promising path. PMID- 29277387 TI - Relationship of procedural numbers with meaningful procedural autonomy in general surgery residents. AB - BACKGROUND: Concerns exist regarding the competency of general surgery graduates with performing core general surgery procedures. Current competence assessment incorporates minimal procedural numbers requirements. METHODS: Based on the Zwisch scale we evaluated the level of autonomy achieved by categorical PGY1-5 general surgery residents at 14 U.S. general surgery resident training programs between September 1, 2015 and December 31, 2016. With 5 of the most commonly performed core general surgery procedures, we correlated the level of autonomy achieved by each resident with the number of procedures they had performed before the evaluation period, with the intent of identifying specific target numbers that would correlate with the achievement of meaningful autonomy for each procedure with most residents. RESULTS: Whereas a definitive target number was identified for laparoscopic appendectomy (i.e. 25), for the other 4 procedures studied (i.e. laparoscopic cholecystectomy, 52; open inguinal hernia repair, 42; ventral hernia repair, 35; and partial colectomy, 60), target numbers identified were less definitive and/or were higher than many residents will experience during their surgical residency training. CONCLUSIONS: We conclude that procedural target numbers are generally not effective in predicting procedural competence and should not be used as the basis for determining residents' readiness for independent practice. PMID- 29277390 TI - Guiding the non-bariatric surgeon through complications of bariatric surgery. AB - Complications in bariatric surgery are varied; they are severe at times but infrequent. They may be surgical or non-surgical, and may occur early or late. The goal of this systematic review is to inform and help the attending physician, the emergency physician and the non-bariatric surgeon who may be called upon to manage surgical complications that arise after adjustable gastric band (AGB), sleeve gastrectomy (SG), or gastric bypass (GBP). Data from evidence-based medicine were extracted from the literature by a review of the Medline database and also of the most recent recommendations of the learned societies implicated. The main complications were classified for each intervention, and a distinction was made between early and late complications. Early complications after AGB include prosthetic slippage or perforation; SG can be complicated early by staple line leak or fistula, and BPG by fistula, stenosis and postoperative hemorrhage. Delayed complications of AGB include intragastric migration of the prosthesis, late prosthetic slippage and infection, while SG can be complicated by gastro esophageal reflux, and BPG by anastomotic ulcer and internal hernia. The analysis of available data allowed us to develop decisional algorithms for the management of each of these complications. PMID- 29277391 TI - Distal pancreatectomy with celiac trunk resection without reconstruction (with video). PMID- 29277392 TI - Minimally invasive anterior pelvic internal fixation: An anatomic study comparing Pelvic Bridge to INFIX. AB - OBJECTIVES: Anterior external fixation for pelvic ring fractures has shown to effectively improve stability and reduce mortality. However, these fixators can be associated with substantial morbidity such as pin tract infection, premature loss of fixation, and decreased quality of life in patients. Recently, two new methods of subcutaneous anterior pelvic internal fixation have been developed; the INFIX and the Pelvic Bridge. These methods have the purported advantages of lower wound complications, less surgical site pain, and improved quality of life. We sought to investigate the measured distances to critical anatomic structures, as well as the qualitative and topographic differences notable during implantation of both devices in the same cadaveric specimen. MATERIALS AND METHODS: The Pelvic Bridge and INFIX were implanted in eleven fresh cadavers. Distances were then measured to: the superficial inguinal ring, round ligament, spermatic cord, lateral femoral cutaneous nerve (LFCN), femoral nerve, femoral artery, and femoral vein. Observations regarding implantation and topography were also recorded. RESULTS: The INFIX had greater measured distances from all structures except for the LFCN, in which its proximity placed this structure at risk. Neither device appears to put other critical structures at risk in the supine position. Significant implantation and topographic differences exist between the devices. The INFIX application lacked "safety margins" concerning the LFCN in 10/11 (90.9%) specimens, while Pelvic Bridge placement lacked "safety margins" with regard to the right superficial ring (1/11, 9%) and the right spermatic cord (1/11, 9%). CONCLUSIONS: Both the Pelvic Bridge and INFIX lie at safe distances from most critical pelvic structures in the supine position, though INFIX application places the LFCN at risk. PMID- 29277393 TI - The possible repositioning of an oral anti-arthritic drug, auranofin, for Nrf2 activating therapy: The demonstration of Nrf2-dependent anti-oxidative action using a zebrafish model. AB - The Nrf2 pathway is a biological defense system against oxidative stress. The pharmacological activation of the Nrf2 pathway is a promising therapy for oxidative stress-related diseases, but it has been challenging to find an Nrf2 activator with acceptable toxicity. To circumvent this problem, we focused on an already approved oral anti-arthritic drug, auranofin that has been reported to have the potential to activate Nrf2. We used a zebrafish model to investigate whether auranofin has protective action against oxidative stress in vivo. Auranofin pre-treatment considerably improved the survival of zebrafish larvae that were challenged with a lethal dose of hydrogen peroxide. This protective effect was not observed in an Nrf2 mutant zebrafish strain, suggesting that the activation of the biological defense against oxidative stress was Nrf2-dependent. Auranofin-induced protection was further tested by challenges with redox-active heavy metals. A clear protective effect was observed against arsenite, a highly redox-reactive toxicant. In addition, this effect was also demonstrated to be Nrf2-dependent based on the analysis of an Nrf2 mutant strain. These results clearly demonstrate the anti-oxidative action of auranofin and encourage the repositioning of auranofin as a drug that improves oxidative stress-related pathology. PMID- 29277394 TI - Nitric oxide treatment attenuates muscle atrophy during hind limb suspension in mice. AB - : Debilitating muscle-disuse atrophy in aging or obesity has huge socioeconomic impact. Since nitric oxide (NO) mediates muscle satellite cell activation and induces hypertrophy with exercise in old mice, we tested whether treatment with the NO donor, isosorbide dinitrate (ISDN), during hind limb suspension would reduce atrophy. Mice were suspended 18 days, with or without daily ISDN (66mg/kg). Muscles were examined for atrophy (weight, fiber diameter); regulatory changes in atrogin-1 (a negative regulator of muscle mass), myostatin (inhibits myogenesis), and satellite cell proliferation; and metabolic responses in myosin heavy chains (MyHCs), liver lipid, and hypothalamic gene expression. Suspension decreased muscle weight and weight relative to body weight between 25-55%, and gastrocnemius fiber diameter vs. CONTROLS: In young-adult mice, ISDN attenuated atrophy by half or more. In quadriceps, ISDN completely prevented the suspension induced rise in atrogin-1 and drop in myostatin precursor, and attenuated the changes in MyHCs 1 and 2b observed in unloaded muscles without treatment. Fatty liver in suspended young-adult mice was also reduced by ISDN; suspended young mice had higher hypothalamic expression of the orexigenic agouti-related protein, Agrp than controls. Notably, a suspension-induced drop in muscle satellite cell proliferation by 25-58% was completely prevented (young mice) or attenuated (halved, in young-adult mice) by ISDN. NO-donor treatment has potential to attenuate atrophy and metabolic changes, and prevent regulatory changes during disuse and offset/prevent wasting in age-related sarcopenia or space travel. Increases in precursor proliferation resulting from NO treatment would also amplify benefits of physical therapy and exercise. PMID- 29277396 TI - Botulism in the ICU: Nursing care plan. AB - INTRODUCTION AND CASE EVALUATION: Botulism is a rare disease in Europe, caused by the bacterium Clostridium botulinum, notifiable, non-transmissible person-to person and potentially fatal (between 5 and 10%) if not treated quickly. The favourable opinion of the Clinical Research Ethics Committee was obtained. We present the nursing care plan of a 49-year-old man with a diagnosis of bacterial intoxication caused by Clostridium botulinum, secondary to ingestion of beans in poor condition, who was admitted to the ICU for a total of 35 days. DIAGNOSIS AND PLANNING: Holistic nursing evaluation during the first 24hours, with prioritisation of the systems that were deteriorating fastest: neurological and respiratory. Nine diagnoses were prioritised according to the NANDA taxonomy: Risk for allergy response, Ineffective breathing pattern, impaired oral mucous membrane, Impaired physical mobility, Risk for disuse syndrome, Risk for dysfunctional gastrointestinal motility, Impaired urinary elimination, Risk for acute confusion and Risk for caregiver role strain. DISCUSSION: The nursing care plan, standardised and organised with the NANDA taxonomy and prioritised with the outcome-present state-test (OPT) model, guaranteed the best care based on evidence, as the NOC scores improvement demonstrated. It was impossible to compare the nursing intervention with other case reports. PMID- 29277395 TI - Circadian regulation of metabolism and healthspan in Drosophila. AB - Circadian clocks generate daily rhythms in gene expression, cellular functions, physiological processes and behavior. The core clock mechanism consists of transcriptional-translational negative feedback loops that turn over with an endogenous circa 24h period. Classical genetic experiments in the fly Drosophila melanogaster played an essential role in identification of clock genes that turned out to be largely conserved between flies and mammals. Like in mammals, circadian clocks in flies generate transcriptional rhythms in a variety of metabolic pathways related to feeding and detoxification. Given that rhythms pervade metabolism and the loss of metabolic homeostasis is involved in aging and disease, there is increasing interest in understanding how the clocks and the rhythms they control change during aging. The importance of circadian clocks for healthy aging is supported by studies reporting that genetic or environmental clock disruptions are associated with reduced healthspan and lifespan. For example, arrhythmia caused by mutations in core clock genes lead to symptoms of accelerated aging in both flies and mammals, including neurodegenerative phenotypes. Despite the wealth of descriptive data, the mechanisms by which functional clocks confer healthspan and lifespan benefits are poorly understood. Studies in Drosophila discussed here are beginning to unravel causative relationships between the circadian system and aging. In particular, recent data suggest that clocks may be involved in inducing rhythmic expression of specific genes late in life in response to age-related increase in oxidative stress. This review will summarize insights into links between circadian system and aging in Drosophila, which were obtained using powerful genetics tools available for this model organism and taking advantage of the short adult lifespan in flies that is measured in days rather than years. PMID- 29277397 TI - Corrigendum to "Humanization of JAA-F11, a Highly Specific Anti-Thomsen Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" [Neoplasia 19.9 (2017) 716-733]. PMID- 29277398 TI - Blepharoptosis-Blepharoplasty Bundle Bungle. PMID- 29277399 TI - An Analysis of Medicare Reimbursement to Ophthalmologists: Years 2012 to 2013. PMID- 29277400 TI - The cortical cholinergic system contributes to the top-down control of distraction: Evidence from patients with Parkinson's disease. AB - Past animal and human studies robustly report that the cholinergic system plays an essential role in both top-down and bottom-up attentional control, as well as other aspects of cognition (see Ballinger et al., 2016 for a recent review). However, current understanding of how two major cholinergic pathways in the human brain (the basal forebrain-cortical pathway, and the brainstem pedunculopontine thalamic pathway) contribute to specific cognitive functions remains somewhat limited. To address this issue, we examine how individual variation in the integrity of striatal-dopaminergic, thalamic-cholinergic, and cortical cholinergic pathways (measured using Positron Emission Tomography in patients with Parkinson's disease) was associated with individual variation in the initial goal-directed focus of attention, the ability to sustain attentional performance over time, and the ability to avoid distraction from a highly-salient, but irrelevant, environmental stimulus. Compared to healthy controls, PD patients performed similarly in the precision of attention-dependent judgments of duration, and in sustaining attention over time. However, PD patients' performance was strikingly more impaired by the distractor. More critically, regression analyses indicated that only cortical-cholinergic integrity, not thalamic-cholinergic or striatal-dopaminergic integrity, made a specific contribution to the ability to resist distraction after controlling for the other variables. These results demonstrate that the basal forebrain cortical cholinergic system serves a specific role in executing top-down control to resist external distraction. PMID- 29277401 TI - Mn2+ dynamics in manganese-enhanced MRI (MEMRI): Cav1.2 channel-mediated uptake and preferential accumulation in projection terminals. AB - Manganese-enhanced magnetic resonance imaging (MEMRI) exploits the biophysical similarity of Ca2+ and Mn2+ to map the brain's activity in vivo. However, to what extent different Ca2+ channels contribute to the enhanced signal that MEMRI provides and how Mn2+ dynamics influence Mn2+ brain accumulation after systemic administration of MnCl2 are not yet fully understood. Here, we demonstrate that mice lacking the L-type Ca2+ channel 1.2 (Cav1.2) in the CNS show approximately 50% less increase in MEMRI contrast after repeated systemic MnCl2 injections, as compared to control mice. In contrast, genetic deletion of L-type Ca2+ channel 1.3 (Cav1.3) did not reduce signal. Brain structure- or cell type-specific deletion of Cav1.2 in combination with voxel-wise MEMRI analysis revealed a preferential accumulation of Mn2+ in projection terminals, which was confirmed by local MnCl2 administration to defined brain areas. Taken together, we provide unequivocal evidence that Cav1.2 represents an important channel for neuronal Mn2+ influx after systemic injections. We also show that after neuronal uptake, Mn2+ preferentially accumulates in projection terminals. PMID- 29277402 TI - Early nutrition influences developmental myelination and cognition in infants and young children. AB - Throughout early neurodevelopment, myelination helps provide the foundation for brain connectivity and supports the emergence of cognitive and behavioral functioning. Early life nutrition is an important and modifiable factor that can shape myelination and, consequently, cognitive outcomes. Differences in the nutritional composition between human breast and formula milk may help explain the functional and cognitive disparity often observed between exclusively breast versus formula-fed children. However, past cognitive and brain imaging studies comparing breast and formula feeding are often: cross-sectional; performed in older children and adolescents relying on parental recall of infant feeding; and generally treat formula-fed children as a single group despite the variability between formula compositions. Here we address some of these weakness by examining longitudinal trajectories of brain and neurocognitive development in children who were exclusively breastfed versus formula-fed for at least 3 months. We further examine development between children who received different formula compositions. Results reveal significantly improved overall myelination in breastfed children accompanied by increased general, verbal, and non-verbal cognitive abilities compared to children who were exclusively formula-fed. These differences were found to persist into childhood even with groups matched for important socioeconomic and demographic factors. We also find significant developmental differences depending on formula composition received and that, in particular, long-chain fatty acids, iron, choline, sphingomyelin and folic acid are significantly associated with early myelination trajectories. These results add to the consensus that prolonged and exclusive breastfeeding plays an important role in early neurodevelopment and childhood cognitive outcomes. PMID- 29277403 TI - Probabilistic thresholding of functional connectomes: Application to schizophrenia. AB - Functional connectomes are commonly analysed as sparse graphs, constructed by thresholding cross-correlations between regional neurophysiological signals. Thresholding generally retains the strongest edges (correlations), either by retaining edges surpassing a given absolute weight, or by constraining the edge density. The latter (more widely used) method risks inclusion of false positive edges at high edge densities and exclusion of true positive edges at low edge densities. Here we apply new wavelet-based methods, which enable construction of probabilistically-thresholded graphs controlled for type I error, to a dataset of resting-state fMRI scans of 56 patients with schizophrenia and 71 healthy controls. By thresholding connectomes to fixed edge-specific P value, we found that functional connectomes of patients with schizophrenia were more dysconnected than those of healthy controls, exhibiting a lower edge density and a higher number of (dis)connected components. Furthermore, many participants' connectomes could not be built up to the fixed edge densities commonly studied in the literature (~5-30%), while controlling for type I error. Additionally, we showed that the topological randomisation previously reported in the schizophrenia literature is likely attributable to "non-significant" edges added when thresholding connectomes to fixed density based on correlation. Finally, by explicitly comparing connectomes thresholded by increasing P value and decreasing correlation, we showed that probabilistically thresholded connectomes show decreased randomness and increased consistency across participants. Our results have implications for future analysis of functional connectivity using graph theory, especially within datasets exhibiting heterogenous distributions of edge weights (correlations), between groups or across participants. PMID- 29277404 TI - Multiparametric measurement of cerebral physiology using calibrated fMRI. AB - The ultimate goal of calibrated fMRI is the quantitative imaging of oxygen metabolism (CMRO2), and this has been the focus of numerous methods and approaches. However, one underappreciated aspect of this quest is that in the drive to measure CMRO2, many other physiological parameters of interest are often acquired along the way. This can significantly increase the value of the dataset, providing greater information that is clinically relevant, or detail that can disambiguate the cause of signal variations. This can also be somewhat of a double-edged sword: calibrated fMRI experiments combine multiple parameters into a physiological model that requires multiple steps, thereby providing more opportunity for error propagation and increasing the noise and error of the final derived values. As with all measurements, there is a trade-off between imaging time, spatial resolution, coverage, and accuracy. In this review, we provide a brief overview of the benefits and pitfalls of extracting multiparametric measurements of cerebral physiology through calibrated fMRI experiments. PMID- 29277405 TI - Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. AB - Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two week, randomized, sham-controlled, double-blinded trial the effects of high frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD. PMID- 29277406 TI - A clinical-anatomical signature of Parkinson's disease identified with partial least squares and magnetic resonance imaging. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by a wide array of motor and non-motor symptoms. It remains unclear whether neurodegeneration in discrete loci gives rise to discrete symptoms, or whether network-wide atrophy gives rise to the unique behavioural and clinical profile associated with PD. Here we apply a data-driven strategy to isolate large-scale, multivariate associations between distributed atrophy patterns and clinical phenotypes in PD. In a sample of N = 229 de novo PD patients, we estimate disease related atrophy using deformation based morphometry (DBM) of T1 weighted MR images. Using partial least squares (PLS), we identify a network of subcortical and cortical regions whose collective atrophy is associated with a clinical phenotype encompassing motor and non-motor features. Despite the relatively early stage of the disease in the sample, the atrophy pattern encompassed lower brainstem, substantia nigra, basal ganglia and cortical areas, consistent with the Braak hypothesis. In addition, individual variation in this putative atrophy network predicted longitudinal clinical progression in both motor and non-motor symptoms. Altogether, these results demonstrate a pleiotropic mapping between neurodegeneration and the clinical manifestations of PD, and that this mapping can be detected even in de novo patients. PMID- 29277407 TI - Skin cancer interventions across the cancer control continuum: Review of technology, environment, and theory. AB - The National Cancer Institute's Skin Cancer Intervention across the Cancer Control Continuum model was developed to summarize research and identify gaps concerning skin cancer interventions. We conducted a mapping review to characterize whether behavioral interventions addressing skin cancer prevention and control from 2000 to 2015 included (1) technology, (2) environmental manipulations (policy and/or built environment), and (3) a theoretical basis. We included 86 studies with a randomized controlled or quasi-experimental design that targeted behavioral intervention in skin cancer for children and/or adults; seven of these were dissemination or implementation studies. Of the interventions described in the remaining 79 articles, 57 promoted only prevention behaviors (e.g., ultraviolet radiation protection), five promoted only detection (e.g., skin examinations), 10 promoted both prevention and detection, and seven focused on survivorship. Of the 79 non-dissemination studies, two-thirds used some type of technology (n=52; 65.8%). Technology specific to skin cancer was infrequently used: UVR photography was used in 15.2% of studies (n=12), reflectance spectroscopy was used in 12.7% (n=10), and dermatoscopes (n=1) and dosimeters (n=2) were each used in less than 3%. Ten studies (12.7%) targeted the built environment. Fifty-two (65.8%) of the studies included theory-based interventions. The most common theories were Social Cognitive Theory (n=20; 25.3%), Health Belief Model (n=17; 21.5%), and the Theory of Planned Behavior/Reasoned Action (n=12; 15.2%). Results suggest that skin cancer specific technology and environmental manipulations are underutilized in skin cancer behavioral interventions. We discuss implications of these results for researchers developing skin cancer behavioral interventions. PMID- 29277408 TI - Using path analysis to examine the relationship between sexual abuse in childhood and diabetes in adulthood in a sample of US adults. AB - To understand mechanisms underlying the relationship between adverse childhood experiences (ACE) and diabetes the study evaluated mediators of the relationship between childhood sexual abuse and diabetes in adulthood. This study used cross sectional data from the 2011 Behavioral Risk Factor Surveillance Survey (BRFSS). Participants totaled 48, 526 who completed the ACE module. Based on theoretical relationships, path analysis was used to investigate depression and obesity as pathways between childhood sexual abuse, and diabetes in adulthood. Among adults with diabetes, 11.6% experienced sexual abuse. In the unadjusted model without mediation, sexual abuse was significantly associated with depression (OR=4.48, CI 4.18-4.81), obesity (OR=1.28, CI 1.19-1.38), and diabetes (OR=1.39, CI 1.25 1.53). In the unadjusted model with mediation, depression and obesity were significantly associated with diabetes (OR=1.59, CI 1.48-1.72, and OR=3.77, CI 3.45-4.11, respectively), and sexual abuse and diabetes was no longer significant (OR=1.10, CI 0.98-1.23), suggesting full mediation. After adjusting for covariates in the mediation model, significance remained between sexual abuse and depression (OR=3.04, CI 2.80-3.29); sexual abuse and obesity (OR=1.41, CI 1.29 1.53), depression and diabetes (OR=1.35, CI 1.23-1.47); and obesity and diabetes (OR=3.53, CI 3.20-3.90). The relationship between sexual abuse and diabetes remained insignificant (OR=1.09, CI 0.96-1.24). This study demonstrates that depression and obesity are significant pathways through which childhood sexual abuse may be linked to diabetes in adulthood. These results can guide intervention development, including multifaceted approaches to treat depression and increase physical activity in patients with a history of sexual abuse to prevent diabetes. PMID- 29277409 TI - The geography of crime and violence surrounding tobacco shops, medical marijuana dispensaries, and off-sale alcohol outlets in a large, urban low-income community of color. AB - Tobacco shops, medical marijuana dispensaries (MMD), and off-sale alcohol outlets are legal and prevalent in South Los Angeles, California-a high-crime, low-income urban community of color. This research is the first to explore the geographic associations between these three legal drug outlets with surrounding crime and violence in a large low-income urban community of color. First, spatial buffer analyses were performed using point-location and publically accessible January December 2014 crime data to examine the geography of all felony property and violent crimes occurring within 100, 200, 500, and 1000-foot buffers of these three legal drug outlet types across South Los Angeles. Next, spatial regression analyses explored the geographic associations between density of these outlets and property and violent crimes at the census tract level. Results indicated that mean property and violent crime rates within 100-foot buffers of tobacco shops and alcohol outlets-but not MMDs-substantially exceeded community-wide mean crime rates and rates around grocery/convenience stores (i.e., comparison properties licensed to sell both alcohol and tobacco). Spatial regression analyses confirmed that tobacco shops significantly positively associated with property and violent crimes after controlling for key neighborhood factors (poverty, renters, resident mobility, ethnic/racial heterogeneity). Thus, study findings provide the first empirical evidence that tobacco shops may constitute public health threats that associate with crime and violence in U.S. low-income urban communities of color. Implementing and enforcing control policies that regulate and monitor tobacco shops in these communities may promote community health by improving public safety. PMID- 29277410 TI - HIV-related stigma, racial discrimination, and gender discrimination: Pathways to physical and mental health-related quality of life among a national cohort of women living with HIV. AB - Social inequities compromise health-related quality of life (HR-QoL) among women living with HIV (WLWH). Little is known about health impacts of intersecting stigma based on HIV status, race and gender among WLWH or potential mechanisms to promote HR-QoL. We tested pathways from multiple types of stigma (HIV-related, racial, gender) to physical and mental HR-QoL utilizing baseline survey data from a national cohort of WLWH in Canada (2013-2015). Structural equation modeling was conducted using maximum likelihood estimation methods to test the direct effects of HIV-related stigma, racial discrimination, and gender discrimination on HR-QoL and indirect effects via social support and economic insecurity, adjusting for socio-demographic factors. Among 1425 WLWH (median age: 43years [IQR=35-50]), HIV related stigma and gender discrimination had significant direct effects on mental HR-QoL. Social support mediated the relationship between HIV-related stigma and mental HR-QoL, accounting for 22.7% of the effect. Social support accounted for 41.4% of the effect of gender discrimination on mental HR-QoL. Economic insecurity accounted for 14.3% of the effect of HIV-related stigma, and 42.4% of the effect of racial discrimination, on physical HR-QoL. Fit indices suggest good model fit (chi2[1]=3.319, p=0.069; CFI=0.998; RMSEA=0.042 (90% CI: 0-0.069); SRMR=0.004). Findings reveal complex relationships between intersecting stigma and HR-QoL. Strategies that address intersecting stigma and economic insecurity among WLWH may prevent the harmful impacts of HIV-related stigma and gender discrimination on physical HR-QoL. Increasing social support may mitigate the impacts of stigma on mental health. Findings can inform multi-level interventions to promote health and wellbeing among WLWH. PMID- 29277411 TI - High birth weight modifies association between adolescent physical activity and cardiometabolic health in women and not men. AB - Recent evidence suggests that adverse prenatal development alters physiological response to physical activity, but longitudinal epidemiologic evidence is scant. This study tested the hypothesis that lower physical activity during adolescence and young adulthood is more strongly associated with later cardiovascular disease (CVD) risk and diabetes or prediabetes (DM/PDM) in women and men who were born with high or low birth weight (HBW, LBW), compared to normal birth weight (NBW). We analyzed data from the National Longitudinal Study of Adolescent to Adult Health, a cohort study of US adolescents followed into adulthood (1994-2009). Using sex-stratified multivariable regression, 30-year CVD risk score (calculated using objective measures; n=12,775) and prevalent DM/PDM (n=15,138) at 24-32years of age were each modeled as a function of birth weight category, self-reported moderate-to-vigorous physical activity frequency in adolescence (MVPA1) and young adulthood (MVPA3), and MVPA-birth weight interactions. Greater MVPA1 was associated with lower 30-year CVD risk score and DM/PDM risk in HBW women but not NBW or LBW women. Associations between MVPA1 and 30-year CVD risk or DM/PDM were not modified by HBW in men; or by LBW in women or men. Additionally, birth weight did not modify estimated effects of MVPA3. Findings suggest that frequent MVPA in adolescence may be a particularly important cardiometabolic risk reduction strategy in girls born HBW; however, we found no evidence that birth weight and MVPA interact in cardiometabolic disease risk in men, for MVPA in adulthood, or for LBW. PMID- 29277412 TI - Impact of childhood parent-child relationships on cardiovascular risks in adolescence. AB - This study aims to determine prospective effects of the childhood parent-child relationships on the development of cardiovascular risks in adolescence. Using available 917 parent-child dyads from the Study of Early Child Care and Youth Development (1991 to 2006), we analyzed the prospective effects of childhood parent-child relationships of Conflict and Closeness, as well as their categorized combinations (Harmonic, Dramatic, Hostile, and Indifferent) on the development of subscapular and triceps skinfold thickness (SST/TST), body mass index (BMI), systolic and diastolic blood pressure (SBP/DBP), and heart rate (HR) during adolescence. We found that higher levels of Conflict in the relationship with mothers (slope=0.05, P<0.001) and fathers (slope=0.04, P=0.03) increased the growth rate of TST among girls during adolescence, but not among boys. The maternal-girl dyadic with higher Conflict scores also increased girl's growth rate of BMI percentile (slope=0.10, P=0.02), though the paternal-boy dyadic with higher Conflict scores decreased boy's growth rate of BMI percentile (slope= 0.13, P=0.04). A Hostile maternal-son relationship lowered boy's growth rate of SBP (slope=-3.15, P<0.001) and DBP (slope=-4.42, P<0.001). A Dramatic maternal son relationship increased boy's growth rate of SST (slope=0.89, P<0.001) and TST (slope=0.64, P=0.03). Hostile paternal-daughter relationships were positively associated with the growth rate of TST (slope=0.28, P=0.03). Overall, there was a significant influence of childhood parent-child relationships on the development of cardiovascular risks during adolescence, and the effect was further modified by both parents' and child's gender. PMID- 29277414 TI - Primary HPV testing: U.S. women's awareness and acceptance of an emerging screening modality. AB - BACKGROUND: Primary HPV testing (without the Pap test) has recently been recommended as a cervical cancer screening option in the United States. U.S. women's awareness and acceptance of primary HPV testing were evaluated. METHODS: Data from a 2015 web-based survey of U.S. adults was examined. Analyses were limited to women who were >=18years old, had not undergone a hysterectomy, had not been diagnosed with cervical cancer, and would accept cervical cancer screening (N=1309). Logistic regression was used to identify predictors of acceptance of primary HPV testing every 3years. RESULTS: Primary HPV testing every 3years was the least accepted cervical cancer screening option (13.5%), and annual Pap testing was the most accepted (41.2%). Most women (65.2%) reported that they were unsure how the HPV test is administered. HPV-vaccinated women were more likely to accept primary HPV testing every 3years than unvaccinated women (Adj OR=1.80, 95% CI=1.22-2.63, p=0.003). And, women who had participated in HPV testing at any interval were more likely to accept primary HPV testing every 3years than those who did not have regular HPV tests or were unsure how often they had HPV tests (Adj OR=1.74, 95% CI=1.20-2.52, p=0.003). CONCLUSIONS: Acceptance of primary HPV testing among U.S. women was low and associated with variables which may be indicative of general HPV awareness. Widespread adoption of primary HPV testing may require increasing women's familiarity with the HPV test and screening guidelines. PMID- 29277413 TI - Behavioral and mental health risk factor profiles among diverse primary care patients. AB - Behavioral and mental health risk factors are prevalent among primary care patients and contribute substantially to premature morbidity and mortality and increased health care utilization and costs. Although prior studies have found most adults screen positive for multiple risk factors, limited research has attempted to identify factors that most commonly co-occur, which may guide future interventions. The purpose of this study was to identify subgroups of primary care patients with co-occurring risk factors and to examine sociodemographic characteristics associated with these subgroups. We assessed 12 behavioral health risk factors in a sample of adults (n=1628) receiving care from nine primary care practices across six U.S. states in 2013. Using latent class analysis, we identified four distinct patient subgroups: a 'Mental Health Risk' class (prevalence=14%; low physical activity, high stress, depressive symptoms, anxiety, and sleepiness), a 'Substance Use Risk' class (29%; highest tobacco, drug, alcohol use), a 'Dietary Risk' class (29%; high BMI, poor diet), and a 'Lower Risk' class (27%). Compared to the Lower Risk class, patients in the Mental Health Risk class were younger and less likely to be Latino/Hispanic, married, college educated, or employed. Patients in the Substance Use class tended to be younger, male, African American, unmarried, and less educated. African Americans were over 7 times more likely to be in the Dietary Risk versus Lower Risk class (OR 7.7, 95% CI 4.0-14.8). Given the heavy burden of behavioral health issues in primary care, efficiently addressing co-occurring risk factors in this setting is critical. PMID- 29277416 TI - Is weight cycling associated with adverse health outcomes? A cohort study. AB - Evidence about the health effects of weight cycling is not consistent, with some studies suggesting it is harmful for health. Here we investigated whether weight cycling was associated with weight change and mental health outcomes in 10,428 participants in the mid-age cohort of The Australian Longitudinal Study of Women's Health (ALSWH) over 12years. In 1998 the women were asked how many times they had ever intentionally lost at least 5kg and how many times had they regained this amount. Women were categorised into four weight pattern groups: frequent weight cyclers (FWC, three or more weight cycles), low frequency weight cyclers (LFWC, one or two weight cycles), non-weight cyclers (NWC), and weight loss only (WL). We used generalised linear modelling to investigate relationships between weight pattern group, weight change and mental health outcomes. In 1998, 15% of the women were FWC, 24% LFWC, 46% NWC and 15% were WL. Weight change was similar across weight pattern groups in women with obesity, however healthy weight and overweight FWC gained more weight than women who did not weight cycle. We found no difference in overall mental health scores between groups, but both LFWC and FWC had higher odds of depressive symptoms (adjusted OR 1.5, 95%CI: 1.1 to 1.9 and 1.7, 95%CI: 1.1 to 2.4, respectively) than NWC. Our results suggest that, although weight cycling is not associated with greater weight gain in women with obesity, it may increase depressive symptoms. PMID- 29277415 TI - Socioeconomic position and sedentary behavior in Brazilian adolescents: A life course approach. AB - Socioeconomic position (SEP) is a potential correlate of sedentary behavior in adolescents. The aim of this study was to examine the associations between SEP and self-reported and objective measures of sedentary behavior in adolescents, using a life-course approach. Data from the 1993 Pelotas (Brazil) Birth Cohort Study were analyzed (N=5249). Cross-sectional and longitudinal associations between multiple SEP indicators (maternal education, family income, SEP composite, cumulative family income) at birth, 11, 15 and 18years, and five sedentary behavior outcomes (>=4h/day screen time; >=4h/day TV; >=2h/day computer; >=2h/day video game; >=12.7h/day objectively measured sedentary time) at 11, 15 and 18years, were examined. In cross-sectional analyses, higher SEP was positively associated with more screen time at ages 11 and 15years. There was a consistent and positive association between higher SEP with time spent using a computer, and with sedentary time assessed through accelerometry. SEP at birth had a positive and direct effect on screen, computer and total sedentary time at 18years. Participants in the highest cumulative income group had higher odds of high sedentary behavior in screen (OR: 2.40; 95% CI: 1.50-3.54), computer (OR: 7.35; 95% CI: 4.19-12.89) and total sedentary time (OR: 5.40; 95% CI: 3.53 10.35), respectively, compared with their counterparts with lower cumulative income. Our findings showed that SEP is an early determinant of sedentary behavior in adolescents. PMID- 29277417 TI - Reprint of: Contrasting effects of vortioxetine and paroxetine on pineal gland biochemistry in a tryptophan-depletion model of depression in female rats. AB - We studied the effects of the multi-modal antidepressant, vortioxetine and the SSRI, paroxetine on pineal melatonin and monoamine synthesis in a sub-chronic tryptophan (TRP) depletion model of depression based on a low TRP diet. Female Sprague-Dawley rats were randomised to groups a) control, b) low TRP diet, c) low TRP diet+paroxetine and d) low TRP diet+vortioxetine. Vortioxetine was administered via the diet (0.76mg/kg of food weight) and paroxetine via drinking water (10mg/kg/day) for 14days. Both drugs resulted in SERT occupancies >90%. Vortioxetine significantly reversed TRP depletion-induced reductions of pineal melatonin and serotonin (5-HT) and significantly increased pineal noradrenaline NA. Paroxetine did none of these things. Other studies suggest pineal melatonin synthesis may involve N-methyl-d-aspartate (NMDA) receptors and glutamatergic modulation. Here observed changes may be mediated via vortioxetine's strong 5-HT reuptake blocking action together with possible additional effects on glutamate neurotransmission in the pineal via NMDA receptor-modulation and possibly with added impetus from increased NA output. PMID- 29277419 TI - Systolic Blood Pressure Elevation in Children with Obstructive Sleep Apnea Is Improved with Positive Airway Pressure Use. AB - INTRODUCTION: To evaluate the effect of continuous positive airway pressure (CPAP) treatment on blood pressure (BP) in children with obstructive sleep apnea (OSA). STUDY DESIGN: Retrospective chart review of children aged 7-17 referred to Benioff Children's Hospital Oakland for the evaluation of snoring. Data collected included age, body mass index (BMI), BP, heart rate, apnea-hypopnea index, and oxygen saturation nadir. Children were divided into 3 groups: snorers, untreated OSA, and OSA treated with CPAP. Seventy-five children were identified, 25 in each group. RESULTS: There was no difference in age or apnea-hypopnea index among the groups. The CPAP group had higher BMI than the snorers and untreated OSA groups. Systolic BP was higher in the 2 OSA groups compared with the snorers. After CPAP treatment, systolic BP decreased. The BP decrease was significantly greater in patients with higher BMI at baseline. There was no significant change in diastolic BP in the 3 groups. CONCLUSION: Children with OSA have higher systolic BP than habitual snorers. Treatment with CPAP in children with OSA for 6 months reduced their systolic BP despite a small increase in their BMI. PMID- 29277418 TI - Maternal undernutrition during early pregnancy inhibits postnatal growth of the tibia in the female offspring of rats by alteration of chondrogenesis. AB - Epidemiological research has suggested that birth weights are correlated with adult leg lengths. However, the relationship between prenatal undernutrition (UN) and postnatal leg growth remains controversial. We investigated the effects of UN during early pregnancy on postnatal hindlimb growth and determined whether early embryonic malnutrition affects the functions of postnatal chondrocytes in rats. Undernourished Wistar dams were fed 40% of the daily intake of rats in the control groups from gestational days 5.5-11.5, and femurs, tibias, and trunks or spinal columns were morphologically measured at birth and at 16 weeks of age in control and undernourished offspring of both sexes. We evaluated cell proliferation and differentiation of cultured chondrocytes derived from neonatal tibias of female offspring and determined chondrocyte-related gene expression levels in neonatal epiphysis and embryonic limb buds. Tibial lengths of undernourished female, but not male, offspring were longer at birth and shorter at 16 weeks of age (p < .05) compared with those of control rats. In chondrocyte culture studies, stimulating effects of IGF-1 on cell proliferation (p < .01) were significantly decreased and levels of type II collagen were lower in female undernourished offspring (p < .05). These phenomena were accompanied by decreased expression levels of Col2a1 and Igf1r and increased expression levels of Fgfr3 (p < .05), which might be attributable to the decreased expression of specificity protein 1 (p < .05), a key transactivator of Col2a1 and Igf1r. In conclusion, UN stress during early pregnancy reduces postnatal tibial growth in female offspring by altering the function of chondrocytes, likely reflecting altered expression of gene transactivators. PMID- 29277420 TI - Factors affecting the association of single- and double-stranded RNAs with montmorillonite nanoclays. AB - Montmorillonite (MMT) nanoclays exist as single and stacked sheet-like structures with large surface areas that can form stable associations with many naturally occurring biomolecules, including nucleic acids. They have been utilized successfully as vehicles for delivery of both drugs and genes into cells. Most previous studies have focused on interactions of MMT with DNA. In the current study, we have investigated the binding of small RNAs similar to those used for RNA interference (RNAi) therapy to two major forms of the clay, Na-MMT and Ca MMT. Association of both forms of MMT with several double-stranded RNAs (dsRNAs), including 25mers, 54mers and cloverleaf-shaped transfer RNAs, was weak and increased only slightly after addition of Mg2+ ions to the binding reactions. By contrast, ssRNA 25mers and 54mers bound poorly to Na-MMT but interacted strongly with Ca-MMT. The weak binding of ssRNAs to Na-MMT could be strongly enhanced by addition of Mg2+ ions. The strength of MMT-ssRNA interactions was also examined using inorganic anion competition and displacement assays, as well as electrophoretic mobility shift assays (EMSAs). The aggregate results point to a cation-bridging mechanism for binding of ssRNAs, but not dsRNAs, in the presence of divalent metal cations. PMID- 29277421 TI - Probing the role of ortho-dihydroxy groups on lysozyme fibrillation. AB - Changes in the microenvironment of Trp in lysozyme are one of the key factors in the fibrillation process. Gallic acid through the oxidation of o-dhydroxy moiety into quinone was shown to inhibit lysozyme fibrillation by stabilizing the Trp microregions [Konar et al., Int. J. Biol. Macromol. 103 (2017) 1224-1231]. In this article we compare the inhibitory effects of several gallic acid-based phenolic compounds. The results show that pyrogallol, and 3,4-dihydroxy benzoic acid, each containing the o-dihydroxy moiety exhibited a significant inhibitory effect on lysozyme fibrillation which is further supported by docking studies. Interestingly, the inhibitory effect of pyrogallol is almost similar to that observed for gallic acid. The lower inhibitory effect of 3,5-dihydroxy benzoic acid and 4-hydroxy benzoic acid corroborates this finding as neither of the compounds can be transformed into quinone intermediates. The ineffectiveness of benzoic acid towards fibrillation questions the role of the COOH group in the inhibition. The IC20 values determined show the similar trends. Results of the Thioflavin T binding assay and parameters from the docking studies reveal a strong correlation based on which a relation has been obtained that could be used to identify potential polyphenol based inhibitors by considering docking studies alone. PMID- 29277422 TI - Formulation and in vivo pharmacokinetic evaluation of ethyl cellulose-coated sustained release multiple-unit system of tacrolimus. AB - A novel once-a-day sustained-release (SR) system of tacrolimus (FK506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (EC) polymer as release retardant. Drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. Subsequently, the drug-layered pellets were recoated with EC polymer (0.5-1.5 mg) using a fluid bed granulator. Drug release from the reservoir-type pellets was markedly impeded by the outer EC-based coating layer (EC 1 mg), displaying about 60% of drug release after 8 h, regardless of the acidity of the media. In an in vivo pharmacokinetic study in fasted Cynomolgus monkeys, the drug level in blood was gradually increased over 4.7 h and high drug concentration was maintained until 24 h, with an elimination half-life of 16.6 h. There were no statistical differences between the novel SR pellets and the recently marketed SR capsule (Advagraf(r), Astellas Pharma, Japan) in terms of maximum blood concentration, area under the curve, and half-life values, in both fasted and fed states. Therefore, the novel EC-coated pellets are expected to be bioequivalent to the commercial SR capsule, providing a once-daily dosing regimen in patients with allogenic rejection. PMID- 29277423 TI - Engaging nurses in smoking cessation: Challenges and opportunities in Turkey. AB - This paper discusses the training of nurses in smoking cessation as part of routine patient care in Turkey. Formative research was carried out prior to training to identify challenges faced by smokers when trying to quit. Site visits to government hospitals and cessation clinics were conducted to observe health care provider-patient interactions involving behavior change. Four culturally sensitive cessation training workshops for nurses (n = 54) were conducted in Istanbul. Following training, nurses were debriefed on their experiences delivering cessation advice. Challenges to cessation counseling included lack of time and incentives for nurse involvement; lack of skills to deliver information about the harm of smoking and benefits of quitting; the medicalization of cessation through the use of pharmaceuticals; and hospital policy which devalues time spent on cessation activities. The pay-for-performance model currently adopted in hospitals has de-incentivized doctor participation in cessation clinics. Nurses play an important role in smoking cessation in many countries. In Turkey, hospital policy will require change so that cessation counseling can become a routine part of nursing practice, incentives for providing cessation are put in place, and task sharing between nurses and doctors is clarified. Nurses and doctors need to receive training in both the systemic harms of smoking and cessation counseling skills. Opportunities, challenges and lessons learned are highlighted. PMID- 29277424 TI - Unplanned admissions to inpatient psychiatric treatment and services received prior to admission. AB - BACKGROUND: Inpatient bed numbers are continually being reduced but are not being replaced with adequate alternatives in primary health care. There is a considerable risk that eventually all inpatient treatment will be unplanned, because planned or elective treatments are superseded by urgent needs when capacity is reduced. AIMS OF THE STUDY: To estimate the rate of unplanned admissions to inpatient psychiatric treatment facilities in Norway and analyse the difference between patients with unplanned and planned admissions regarding services received during the three months prior to admission as well as clinical, demographical and socioeconomic characteristics of patients. METHOD: Unplanned admissions were defined as all urgent and involuntary admissions including unplanned readmissions. National mapping of inpatients was conducted in all inpatient treatment psychiatric wards in Norway on a specific date in 2012. Binary logit regressions were performed to compare patients who had unplanned admissions with patients who had planned admissions (i.e., the analyses were conditioned on admission to inpatient psychiatric treatment). RESULTS: Patients with high risk of unplanned admission are suffering from severe mental illness, have low functional level indicated by the need for housing services, high risk for suicide attempt and of being violent, low education and born outside Norway. CONCLUSION: Specialist mental health services should support the local services in their efforts to prevent unplanned admissions by providing counselling, short inpatient stays, outpatient treatment and ambulatory outpatient psychiatry services. IMPLICATIONS FOR HEALTH POLICIES: This paper suggests the rate of unplanned admissions as a quality indicator and considers the introduction of economic incentives in the income models at both service levels. PMID- 29277425 TI - Fetal Outcomes in Intentional Over-the-Counter Medication Overdoses in Pregnancy. PMID- 29277426 TI - Centromere Size and Its Relationship to Haploid Formation in Plants. AB - Wide species crosses often result in uniparental genome elimination and visible failures in centromere function. Crosses involving lines with mutated forms of the CENH3 histone variant that organizes the centromere/kinetochore interface have been shown to have similar effects, inducing haploids at high frequencies. Here, we propose a simple centromere size model that endeavors to explain both observations. It is based on the idea of a quantitative centromere architecture where each centromere in an individual is the same size, and the average size is dictated by a natural equilibrium between bound and unbound CENH3 (and its chaperones or binding proteins). While centromere size is determined by the cellular milieu, centromere positions are heritable and defined by the interactions of a small set of proteins that bind to both DNA and CENH3. Lines with defective or mutated CENH3 have a lower loading capacity and support smaller centromeres. In cases where a line with small or defective centromeres is crossed to a line with larger or normal centromeres, the smaller/defective centromeres are selectively degraded or not maintained, resulting in chromosome loss from the small-centromere parent. The model is testable and generalizable, and helps to explain the counterintuitive observation that inducer lines do not induce haploids when crossed to themselves. PMID- 29277427 TI - Folate Biofortification of Potato by Tuber-Specific Expression of Four Folate Biosynthesis Genes. AB - Insufficient dietary intake of micronutrients, known as "hidden hunger", is a devastating global burden, affecting two billion people. Deficiency of folates (vitamin B9), which are known to play a central role in C1 metabolism, causes birth defects in at least a quarter million people annually. Biofortification to enhance the level of naturally occurring folates in crop plants, proves to be an efficient and cost-effective tool in fighting folate deficiency. Previously, introduction of folate biosynthesis genes GTPCHI and ADCS, proven to be a successful biofortification strategy in rice and tomato, turned out to be insufficient to adequately increase folate levels in potato tubers. Here, we provide a proof of concept that additional introduction of HPPK/DHPS and/or FPGS, downstream genes in mitochondrial folate biosynthesis, enables augmentation of folates to satisfactory levels (12-fold) and ensures folate stability upon long term storage of tubers. In conclusion, this engineering strategy can serve as a model in the creation of folate-accumulating potato cultivars, readily applicable in potato-consuming populations suffering from folate deficiency. PMID- 29277428 TI - Complete Pathway Elucidation and Heterologous Reconstitution of Rhodiola Salidroside Biosynthesis. AB - Salidroside is a bioactive tyrosine-derived phenolic natural product found in medicinal plants under the Rhodiola genus. In addition to their anti-fatigue and anti-anoxia roles in traditional medicine, Rhodiola total extract and salidroside have also displayed medicinal properties as anti-cardiovascular diseases and anti cancer agents. The resulting surge in global demand of Rhodiola plants and salidroside has driven some species close to extinction. Here, we report the full elucidation of the Rhodiola salidroside biosynthetic pathway utilizing the first comprehensive transcriptomics and metabolomics datasets for Rhodiola rosea. Unlike the previously proposed pathway involving separate decarboxylation and deamination enzymatic steps from tyrosine to the key intermediate 4 hydroxyphenylacetaldehyde (4-HPAA), Rhodiola contains a pyridoxal phosphate dependent 4-HPAA synthase that directly converts tyrosine to 4-HPAA. We further identified genes encoding the subsequent 4-HPAA reductase and tyrosol:UDP-glucose 8-O-glucosyltransferase, respectively, to complete salidroside biosynthesis in Rhodiola. We show that heterologous production of salidroside can be achieved in the yeast Saccharomyces cerevisiae as well as the plant Nicotiana benthamiana through transgenic expression of Rhodiola salidroside biosynthetic genes. This study provides new tools for engineering sustainable production of salidroside in heterologous hosts. PMID- 29277429 TI - Characterisation of fluoroquinolone resistance in methicillin-resistant Staphylococcus aureus of human and pig origin. PMID- 29277430 TI - Challenges facing palliative neurology practice: A qualitative analysis. AB - PURPOSE: This study aimed to develop a conceptual understanding of the specific characteristics of palliative care in neurology and the challenges of providing palliative care in the setting of neurological illness. METHOD: The study was conducted at London Health Sciences Centre in Canada using grounded theory methodology. Qualitative thematic analysis was applied to focus group (health care providers physicians, nursing, allied health, trainees) and semi-structured interview (patient-caregiver dyads) data to explore challenges facing the delivery of palliative care in neurology. RESULTS: Specific characteristics of neurological disease that affect palliative care in neurology were identified: 1) timelines of disease progression, 2) barriers to communication arising from neurologic disease, 3) variability across disease progression, and 4) threat to personhood arising from functional and cognitive impairments related to neurologic disease. Moreover, three key challenges that shaped and complicated palliative care in neurology were identified: 1) uncertainty with respect to prognosis, support availability and disease trajectory, 2) inconsistency in information, attitudes and skills among care providers, care teams, caregivers and families, and 3) existential distress specific to neurological disease, including emotional, psychological and spiritual distress resulting from loss of function, autonomy and death. These challenges were experienced across groups, but manifested themselves in different ways for each group. CONCLUSIONS: Further research regarding prognosis, improved identification of patients with palliative care needs, developing an approach to palliative care delivery within neurology and the creation of more robust educational resources for teaching palliative neurology are expected to improve neurologists' comfort with palliative care, thereby enhancing care delivery in neurology. PMID- 29277431 TI - Characterization of distinct ovarian isoform of crustacean female sex hormone in the kuruma prawn Marsupenaeus japonicus. AB - The eyestalk hormone, crustacean female sex hormone (CFSH), regulates the development of female secondary sexual characteristics in the blue crab Callinectes sapidus. After its discovery, several CFSH gene orthologs have been identified in some species of the suborder Pleocyemata as well. Similarly, in species of another suborder (Dendrobranchiata), an ortholog (Maj-CFSH) has been characterized as an eyestalk factor expressed in both females and males of the kuruma prawn, Marsupenaeus japonicus. In this study, another novel CFSH isoform was identified in the same species using cDNA cloning, expression analysis, and recombinant protein production. The isoform has "CFSH-family" structural characteristics but is dominantly expressed in the ovary, and was therefore designated as Maj-CFSH-ov. Its mRNA and protein levels in vitellogenic ovaries are higher than those in non-vitellogenic ovaries. In the vitellogenic ovary, both mRNA and protein expression of Maj-CFSH-ov are localized to oogonia and previtellogenic oocytes that occupy a small portion of vitellogenic ovaries, but not to the major developing oocytes. A vitellogenesis-inhibiting peptide of M. japonicus (Pej-SGP-I) reduced the expression of vitellogenin in incubated ovarian fragments, but not that of Maj-CFSH-ov. These results indicate that M. japonicus possesses two CFSH isoforms that are derived from distinct tissues, the central X organ/sinus gland complex and peripheral ovaries. The expression profile of Maj CFSH-ov suggests its involvement in some reproductive process other than vitellogenesis. PMID- 29277432 TI - Symptoms of anxiety and depression in type 2 diabetes: Associations with clinical diabetes measures and self-management outcomes in the norwegian HUNT study. PMID- 29277433 TI - Thyroid ophthalmopathy of Miguel Hernandez Gilabert. PMID- 29277434 TI - Retinoblastoma and optic nerve enhancement in a brain magnetic resonance scan: is it always a metastasis? AB - CASE REPORT: The case is presented on a girl with a unilateral retinoblastoma that required treatment with intra-arterial chemotherapy. In the nuclear magnetic resonance imaging of the brain performed 1 month after intra-arterial chemotherapy treatment, post-laminar optic nerve (ON) enhancement was observed, leading to the suspicion of an ON tumour infiltration. Additional examinations were requested by which a probable optic neuropathy was diagnosed. DISCUSSION: The ON enhancement in magnetic resonance imaging of the brain in retinoblastoma generally corresponds to tumour invasion of the ON. However, other diagnostic alternatives associated with the use of new treatments, such as intra-arterial chemotherapy, should be considered. PMID- 29277436 TI - [The key role of the pathologist in the diagnosis of syphilis: A case report]. AB - Syphilis is a resurging sexually transmitted infection linked to Treponema Pallidum. Syphilitic lymphadenitis can be present during the 3 stages of the disease. Its histological diagnosis remains challenging for the pathologist given its possible misleading aspect and its ability to mimic as well as reactional as tumoral conditions. We report the case of an HIV-infected young patient referred for suspicion of an aggressive lymphoma. Histological and immunohistochemical analysis of cervical lymphadenopathy revealed secondary syphilis. PMID- 29277435 TI - Assessment of potential heart donors: A statement from the French heart transplant community. AB - Assessment of potential donors is an essential part of heart transplantation. Despite the shortage of donor hearts, donor heart procurement from brain-dead organ donors remains low in France, which may be explained by the increasing proportion of high-risk donors, as well as the mismatch between donor assessment and the transplant team's expectations. Improving donor and donor heart assessment is essential to improve the low utilization rate of available donor hearts without increasing post-transplant recipient mortality. This document provides information to practitioners involved in brain-dead donor management, evaluation and selection, concerning the place of medical history, electrocardiography, cardiac imaging, biomarkers and haemodynamic and arrhythmia assessment in the characterization of potential heart donors. PMID- 29277437 TI - Indoor air quality (IAQ) evaluation of a Novel Tobacco Vapor (NTV) product. AB - The impact of using a Novel Tobacco Vapor (NTV) product on indoor air quality (IAQ) was simulated using an environmentally-controlled chamber. Three environmental simulations were examined; two non-smoking areas (conference room and dining room) and one ventilated smoking area (smoking lounge). IAQ was evaluated by (i) measuring constituents in the mainstream NTV product emissions, (ii) and by determining classical environmental tobacco smoke (ETS) and representative air quality markers. Analysis of the mainstream emissions revealed that vapor from the NTV product is chemically simpler than cigarette smoke. ETS markers (RSP, UVPM, FPM, solanesol, nicotine, 3-ethenylpyridine), volatile organic compound (toluene), carbon monoxide, propylene glycol, glycerol, and triacetin were below the limit of detection or the limit of quantification in both the non-smoking and smoking environments after using the NTV product. The concentrations of ammonia, carbonyls (formaldehyde, acetaldehyde, and acetone), and total volatile organic compounds were the same levels found in the chamber without NTV use. There was no significant increase in the levels of formaldehyde, acetone or ammonia in exhaled breath following NTV use. In summary, under the simulations tested, the NTV product had no measurable effect on the IAQ, in either non-smoking or smoking areas. PMID- 29277438 TI - Hazardous parameters associated with natural radioactivity exposure from black sand. AB - Black sand samples collected from Baltim beaches (Kafr El-Sheikh governorate) in Egypt on the Mediterranean Sea shore were analyzed radiometrically and evaluated using a nondestructive gamma ray spectroscopic techniques. The natural radionuclides of 226Ra, 232Th and 40K in the black sand samples were identified and quantified. It is found that the activity concentrations for 226Ra, 232Th and 40K in different eleven sites (S1S11) were found within the ranges of 28-322, 91 308 and 81-339 Bq/kg, respectively. Moreover, different radiological hazardous parameters (absorbed dose rate, annual effective dose equivalent, radium activity, annual gonadal dose equivalent and excess lifetime cancer risk) were calculated. The results show that these values are greater than the permissible values due to increasing the activity concentrations of the primordial radionuclides 226Ra, 232Th and 40K. The dose rate for radiation emitted at 1 m from the surface of land was measured directly and the results shown that all sites emit radiation doses more than the international permissible value (57 nGy/h) especially at three sites which around 340 nGy/h. These values are important to establish baseline levels of this environmental radioactivity to detect any upcoming change for the local population and resorts people. The relatively high dose rate will be considered as a spa for the physical therapy such as treatment of some skin diseases and rheumatoid. PMID- 29277439 TI - Where do we go from here? Membrane protein research beyond the structure-function horizon. PMID- 29277440 TI - Gene targeting for chylomicronemia syndrome: The brave new world. PMID- 29277441 TI - IgA antibodies to phosphocholine associate with long-term cardiovascular disease risk. AB - BACKGROUND AND AIMS: Antibodies to phosphocholine and oxidized LDL (oxLDL) are proposed to modify progression of atherosclerosis. We investigated the prognostic value of antibodies to phosphocholine (PCho), Streptococcus pneumoniae cell wall polysaccharide (CWPS) and oxLDL in defining long-term CVD survival. METHODS: CVD incidence was followed for 18 years and analyzed with baseline plasma IgM, IgG and IgA antibody levels to PCho, CWPS and oxLDL in 1044 subjects of Oulu Project Elucidating Risk of Atherosclerosis study (OPERA). RESULTS: During the follow-up period, 195 subjects (18.7%) had a CVD event. Cox model with ACC/AHA CVD adjustments (ASCVD) showed that IgA levels to PCho and IgA to CWPS were statistically significant factors predicting CVD risk. IgM and IgG antibodies to PCho, CWPS and oxLDL had no effect on CVD risk after adjusting for other risk factors. Net reclassification improvement (categories: 17-year risk <15%, 15-30%, >30%), was 0.06 (-0.001-0.12, p < 0.054), and IDI was 0.0124 (0.0036-0.0211, p < 0.006) with IgA-PCho added to the ASCVD risk model. Seventeen (9.4%) study subjects with CVD events were correctly reclassified into higher risk category while 9 (5.0%) subjects were classified into lower risk category. Among the non cases, 58 (8.7%) subjects were correctly reclassified into lower risk, and 46 (5.9%) were reclassified into higher risk category. CONCLUSIONS: Plasma IgA antibodies to PCho and Streptococcus pneumoniae CWPS are significant predictors of long-term CVD risk. Additional studies on the role of IgA antibodies in atherogenesis and CVD are warranted. PMID- 29277443 TI - Priming plant resistance by activation of redox-sensitive genes. AB - Priming by natural compounds is an interesting alternative for sustainable agriculture, which also contributes to explore the molecular mechanisms associated with stress tolerance. Although hosts and stress types eventually determine the mode of action of plant-priming agents, it highlights that many of them act on redox signalling. These include vitamins thiamine, riboflavin and quercetin; organic acids like pipecolic, azelaic and hexanoic; volatile organic compounds such as methyl jasmonate; cell wall components like chitosans and oligogalacturonides; H2O2, etc. This review provides data on how priming inducers promote stronger and faster responses to stress by modulating the oxidative environment, and interacting with signalling pathways mediated by salycilic acid, jasmonic acid and ethylene. The histone modifications involved in priming that affect the transcription of defence-related genes are also discussed. Despite the evolutionary distance between plants and animals, and the fact that the plant innate immunity takes place in each plant cell, they show many similarities in the molecular mechanisms that underlie pathogen perception and further signalling to activate defence responses. This review highlights the similarities between priming through redox signalling in plants and in mammalian cells. The strategies used by pathogens to manipulate the host's recognition and the further activation of defences also show similarities in both kingdoms. Moreover, phytochemicals like sulforaphane and 12-oxo-phytodienoic acid prime both plant and mammalian responses by activating redox-sensitive genes. Hence research data into the priming of plant defences can provide additional information and a new viewpoint for priming mammalian defence, and vice versa. PMID- 29277444 TI - Entrainment of the mouse circadian clock: Effects of stress, exercise, and nutrition. AB - The circadian clock system in mammals plays a fundamental role in maintaining homeostasis. Entrainment is an important characteristic of the internal clock, by which appropriate timing is maintained according to external daily stimuli, such as light, stress, exercise, and/or food. Disorganized entrainment or a misaligned clock time, such as jet lag, increases health disturbances. The central clock in the suprachiasmatic nuclei, located in the hypothalamus, receives information about arousal stimuli, such as physical stress or exercise, and changes the clock time by modifying neural activity or the expression of circadian clock genes. Although feeding stimuli cannot entrain the central clock in a normal light-dark cycle, the central clock can partially detect the metabolic status. Local clocks in the peripheral tissues, including liver and kidney, have a strong direct response to the external stimuli of stress, exercise, and/or food that is independent of the central clock. The mechanism underlying entrainment by stress/exercise is mediated by glucocorticoids, sympathetic nerves, oxidative stress, hypoxia, pH, cytokines, and temperature. Food/nutrition-induced entrainment is mediated by fasting-induced hormonal or metabolic changes and re feeding-induced insulin or oxyntomodulin secretion. Chrono-nutrition is a clinical application based on chronobiology research. Future studies are required to elucidate the effects of eating and nutrient composition on the human circadian clock. Here, we focus on the central and peripheral clocks mostly in rodents' studies and review the findings of recent investigations of the effects of stress, exercise, and food on the entrainment system. PMID- 29277445 TI - Biased G protein-coupled receptor agonism mediates Neu1 sialidase and matrix metalloproteinase-9 crosstalk to induce transactivation of insulin receptor signaling. AB - G protein-coupled receptors (GPCR) can participate in a number of signaling pathways, and this property led to the concept of biased GPCR agonism. Agonists, antagonists and allosteric modulators can bind to GPCRs in different ways, creating unique conformations that differentially modulate signaling through one or more G proteins. A unique neuromedin B (NMBR) GPCR-signaling platform controlling mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) crosstalk has been reported in the activation of the insulin receptor (IR) through the modification of the IR glycosylation. Here, we propose that there exists a biased GPCR agonism as small diffusible molecules in the activation of Neu1-mediated insulin receptor signaling. GPCR agonists bombesin, bradykinin, angiotensin I and angiotensin II significantly and dose-dependently induce Neu1 sialidase activity and IR activation in human IR-expressing rat hepatoma cell lines (HTC-IR), in the absence of insulin. Furthermore, the GPCR agonist-induced Neu1 sialidase activity could be specifically blocked by the NMBR inhibitor, BIM 23127. Protein expression analyses showed that these GPCR agonists significantly induced phosphorylation of IRbeta and insulin receptor substrate-1 (IRS1). Among these, angiotensin II was the most potent GPCR agonist capable of promoting IRbeta phosphorylation in HTC-IR cells. Interestingly, treatment with BIM-23127 and Neu1 inhibitor oseltamivir phosphate were able to block GPCR agonist-induced IR activation in HTC cells in vitro. Additionally, we found that angiotensin II receptor (type I) exists in a multimeric receptor complex with Neu1, IRbeta and NMBR in naive (unstimulated) and stimulated HTC-IR cells with insulin, bradykinin, angiotensin I and angiotensin II. This complex suggests a molecular link regulating the interaction and signaling mechanism between these molecules on the cell surface. These findings uncover a biased GPCR agonist-induced IR transactivation signaling axis, mediated by Neu1 sialidase and the modification of insulin receptor glycosylation. PMID- 29277446 TI - Phase I trial of stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary malignancies of the abdomen. AB - PURPOSE/OBJECTIVES: SBRT is used to treat oligometastatic or unresectable primary abdominal malignancies, although ablative dose delivery is limited by proximity of organs-at-risk (OAR). Stereotactic, magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) may improve SBRT's therapeutic ratio. This prospective Phase I trial assessed feasibility and potential advantages of SMART to treat abdominal malignancies. MATERIALS/METHODS: Twenty patients with oligometastatic or unresectable primary liver (n = 10) and non-liver (n = 10) abdominal malignancies underwent SMART. Initial plans prescribed 50 Gy/5 fractions (BED 100 Gy) with goal 95% PTV coverage by 95% of prescription, subject to hard OAR constraints. Daily real-time online-adaptive plans were created as needed, based on daily setup MR-image-set tumor/OAR "anatomy-of-the-day" to preserve hard OAR constraints, escalate PTV dose, or both. Treatment times, patient outcomes, and dosimetric comparisons between initial and adaptive plans were prospectively recorded. RESULTS: Online adaptive plans were created at time of treatment for 81/97 fractions, due to initial plan violation of OAR constraints (61/97) or observed opportunity for PTV dose escalation (20/97). Plan adaptation increased PTV coverage in 64/97 fractions. Zero Grade >= 3 acute (<6 months) treatment-related toxicities were observed. DISCUSSION: SMART is clinically deliverable and safe, allowing PTV dose escalation and/or simultaneous OAR sparing compared to non-adaptive abdominal SBRT. PMID- 29277442 TI - Plasma levels of n-3 fatty acids and risk of coronary heart disease among Japanese: The Japan Public Health Center-based (JPHC) study. AB - BACKGROUND AND AIMS: Higher intake of fish or n-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of coronary heart disease (CHD). However, it is unclear whether increased blood levels of n-3 PUFAs are associated with reduced risk of CHD in the Japanese population. METHODS: The relationship between circulating levels of n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) and risk of CHD was examined in a nested case control study among participants in the Japan Public Health Center (JPHC)-based Study Cohort. Plasma n-3 PUFA phospholipid levels were measured at baseline by gas chromatography in 209 cases with CHD and 418 controls matched for sex, age, date of blood draw, time elapsed since last meal before blood collection, and study location. The CHD cases (n = 209) comprised 168 cases of myocardial infarction and 41 of sudden cardiac death, otherwise classified as 157 non-fatal and 52 fatal coronary events, respectively. Mean duration of follow-up was 13.5 years. RESULTS: Multivariate conditional logistic analysis showed no significant association between n-3 PUFAs and risk of total CHD. The odds ratio (OR) for the highest versus lowest quartiles of plasma n-3 PUFAs was 0.79 (95% confidence interval [95% CI]: 0.41-1.51, p for trend = 0.51). Subtype analysis of CHD revealed that the multivariate ORs for the highest versus lowest quartiles for n 3 PUFAs were 0.91 (95% CI: 0.43-1.89, p for trend = 0.90) for myocardial infarction, 0.08 (95% CI: 0.01-0.88, p for trend = 0.04) for sudden cardiac death, 0.89 (95% CI: 0.42-1.89, p for trend = 0.97) for nonfatal coronary events, and 0.12 (95% CI: 0.02-0.75, p for trend = 0.03) for fatal coronary events. CONCLUSIONS: Plasma n-3 PUFA levels were not associated with risk of total CHD but were inversely associated with risks of sudden cardiac death and fatal coronary events among middle-aged Japanese individuals. PMID- 29277447 TI - Treatment of advanced nasopharyngeal cancer using low- or high-dose concurrent chemoradiotherapy with intensity-modulated radiotherapy: A propensity score matched, nationwide, population-based cohort study. AB - BACKGROUND: No large-scale, head-to-head, phase III, randomized, controlled trial with an adequate sample size has investigated the effect of concurrent low-dose (LD) or high-dose (HD) cisplatin with radiotherapy on nasopharyngeal cancer (NPC). Thus, we conducted a propensity-score-matched, nationwide, population based cohort study in Taiwan to investigate the outcomes of LD-concurrent chemoradiotherapy (CCRT) or HD-CCRT with intensity-modulated radiotherapy (IMRT) in patients with advanced NPC. METHODS: In this study, patients were categorized into 2 groups according to their chemotherapy regimen: HD-CCRT and LD-CCRT groups. RESULTS: We enrolled 1968 patients (328 and 1640 in the LD-CCRT and HD CCRT groups, respectively) who had received CCRT with IMRT. According to both univariate and multivariate Cox regression analyses, a hazard ratio (95% confidence interval) of 0.75 (0.54-1.06, P = .103) was derived for the HD-CCRT group. CONCLUSION: LD-CCRT or HD-CCRT with IMRT can be a standard treatment that can prolong the survival of patients with advanced NPC. PMID- 29277448 TI - J-AIM: Progress, policy and future plans. PMID- 29277449 TI - Symmetric visual response to positive and negative induced spherical defocus under monochromatic light conditions. AB - The purpose of the study was to investigate the sign-dependent response to real and simulated spherical defocus on the visual acuity under monochromatic light conditions. The investigation included 15 myopic participants with a mean spherical equivalent error of -2.98 +/- 2.17 D. Visual acuity (VA) was tested with and without spherical defocus using the source method (simulated defocus) and the observer method (lens-induced defocus) in a range of +/-3.0 D in 1.0 D steps. VA was assessed using Landolt C's, while the threshold was determined with an adaptive staircase procedure. Monochromatic light conditions were achieved using band pass filters with a wavelength of 450 +/- 2 nm, 530 +/- 2 nm and 630 +/- 2 nm. Results showed that the reduction of VA was significantly different under blue lighting conditions, when compared to the green and red light conditions. No significant difference in the reduction of the VA was found between the positive and the negative sign of defocus for all lighting conditions. The agreement for the VA between the source and observer method was significantly dependent on the wavelength as well as on the level of defocus. To conclude, under monochromatic light conditions, myopes show a symmetric sign dependency regarding the influence of spherical defocus on visual acuity. The observed results indicate that the human visual system is capable of integrating the chromatic differences in refraction to distinguish between the signs of defocus. PMID- 29277451 TI - Acoustic Properties of Small Animal Soft Tissue in the Frequency Range 12-32 MHz. AB - Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties of which mimic those of soft tissue. However, the acoustic properties of many soft tissue types have not been measured at ultrasonic frequencies >9 MHz. With the increasing use of high-frequency ultrasound for both clinical and pre-clinical applications, it is of increasing interest to ensure that TMMs accurately reflect the acoustic properties of soft tissue at these higher frequencies. In this study, the acoustic properties of ex vivo brain, liver and kidney samples from 50 mice were assessed in the frequency range 12-32 MHz. Measurements were performed within 6 min of euthanasia in a phosphate buffered saline solution maintained at 37.2 +/- 0.2 degrees C. The measured mean values for the speed of sound for all organs were found to be higher than the International Electrotechnical Commission guideline recommended value for TMMs. The attenuation coefficients measured for brain, liver and kidney samples were compared with the results of previous studies at lower frequencies. Only the measured kidney attenuation coefficient was found to be in good agreement with the International Electrotechnical Commission guideline. The information provided in this study can be used as a baseline on which to manufacture a TMM suitable for high-frequency applications. PMID- 29277450 TI - Perceptual learning while preparing saccades. AB - Traditional perceptual learning protocols rely almost exclusively on long periods of uninterrupted fixation. Taking a first step towards understanding perceptual learning in natural vision, we had observers report the orientation of a briefly flashed stimulus (clockwise or counterclockwise from a reference orientation) presented strictly during saccade preparation at a location offset from the saccade target. For each observer, the saccade direction, stimulus location, and orientation remained the same throughout training. Subsequently, we assessed performance during fixation in three transfer sessions, either at the trained or at an untrained location, and either using an untrained (Experiment 1) or the trained (Experiment 2) stimulus orientation. We modeled the evolution of contrast thresholds (i.e., the stimulus contrast necessary to discriminate its orientation correctly 75% of the time) as an exponential learning curve, and quantified departures from this curve in transfer sessions using two new, complementary measures of transfer costs (i.e., performance decrements after the transition into the Transfer phase). We observed robust perceptual learning and associated transfer costs for untrained locations and orientations. We also assessed if spatial transfer costs were reduced for the remapped location of the pre-saccadic stimulus-the location the stimulus would have had (but never had) after the saccade. Although the pattern of results at that location differed somewhat from that at the control location, we found no clear evidence for perceptual learning at remapped locations. Using novel, model-based ways to assess learning and transfer costs, our results show that location and feature specificity, hallmarks of perceptual learning, subsist if the target stimulus is presented strictly during saccade preparation throughout training. PMID- 29277452 TI - A three year study of metal levels in skin biopsies of whales in the Gulf of Mexico after the Deepwater Horizon oil crisis. AB - In response to the explosion of the Deepwater Horizon and the massive release of oil that followed, we conducted three annual research voyages to investigate how the oil spill would impact the marine offshore environment. Most investigations into the ecological and toxicological impacts of the Deepwater Horizon Oil crisis have mainly focused on the fate of the oil and dispersants, but few have considered the release of metals into the environment. From studies of previous oil spills, other marine oil industries, and analyses of oil compositions, it is evident that metals are frequently encountered. Several metals have been reported in the MC252 oil from the Deepwater Horizon oil spill, including the nonessential metals aluminum, arsenic, chromium, nickel, and lead; genotoxic metals, such as these are able to damage DNA and can bioaccumulate in organisms resulting in persistent exposure. In the Gulf of Mexico, whales are the apex species; hence we collected skin biopsies from sperm whales (Physeter macrocephalus), short-finned pilot whales (Globicephala macrorhynchus), and Bryde's whales (Balaenoptera edeni). The results from our three-year study of monitoring metal levels in whale skin show (1) genotoxic metals at concentrations higher than global averages previously reported and (2) patterns for MC252-relevant metal concentrations decreasing with time from the oil spill. PMID- 29277453 TI - Sarcoidosis post-anti-PD-1 therapy, mimicking relapse of metastatic melanoma in a patient undergoing complete remission. AB - Novel treatments of metastatic melanoma include the usage of checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated antigen (CTLA-4) or anti-programmed death-1 (PD-1) antibodies, which are immunomodulatory antibodies that enhance the immune response against tumors. While they have substantially improved the prognosis for patients, these therapies are associated with a large spectrum of immune-related adverse effects (irAEs). We report a patient developing pulmonary and cutaneous sarcoidosis after pembrolizumab therapy while complete regression of stage IV melanoma was perceived. Coincident development of sarcoidosis and metastatic melanoma as illustrated by this case report poses a diagnostic challenge because, in contrast to other irAEs, both diseases share common features such as pulmonary lesions, hilar adenopathies and skin nodules. Considering sarcoidosis as a potential side-effect of pembrolizumab treatment is crucial to avoid misdiagnosis with malignant lesions, hence careful description and reporting of such cases is primordial for patient care and may also provide us with insightful knowledge on the pathogenesis of immune-related diseases. PMID- 29277454 TI - Entrapped by the uneven central and Middle Eastern terrains: Genetic status of populations of Hirudo orientalis (Annelida, Clitellata, Hirudinida) with a phylogenetic review of the genus Hirudo. AB - Phylogenetic relationships between species of the genus Hirudo plus genetic variation in the entire distribution range of Hirudo orientalis were investigated based on mitochondrial (COI and 12S rDNA) and nuclear (ITS1+5.8S+ITS2) genome regions. The sister relationship of Hirudo orientalis and H. medicinalis was revealed with a high posterior probability. A broad and patchy distribution with minor genetic differences was observed in populations of H. orientalis along the central and Middle Eastern parts of Asia. The known distribution range occurred in topographically heterogeneous landscapes around the Caspian Sea. The demographic analysis suggests the selection of the COI locus under unfavourable respiratory conditions, but population size expansion cannot be fully rejected. The genetic variation trend indicated northward dispersal. Higher haplotype diversity in the South Caspian region potentially suggests the area as a historical refugium for the species. The vast dispersal is assumed to occur after the Pleistocene glaciations via vertebrate hosts. PMID- 29277455 TI - Everybody In! No Bouncers at Tumor Gates. AB - Two recent genomic studies suggest that a large fraction of human tumors evolves in the presence of limited negative selection against somatic mutations. In this context, specific genetic defects enable the establishment of a hypermutant state that may constitute a target for immunotherapeutic interventions. PMID- 29277456 TI - Stress, autonomic imbalance, and the prediction of metabolic risk: A model and a proposal for research. AB - BACKGROUND: Devising novel prevention strategies for metabolic disorders will depend in part on the careful elucidation of the common pathways for developing metabolic risks. The neurovisceral integration model has proposed that autonomic imbalance plays an important role in the pathway from acute and chronic stress to cardiovascular disease. Though generally overlooked by clinicians, autonomic imbalance (sympathetic overactivity and/or parasympathetic underactivity) can be measured and modified by methods that are available in primary care. METHOD: This review applies the neurovisceral integration concept to the clinical setting by proposing that autonomic imbalance plays a primary role in the development of metabolic risks. We present a testable model, a systematic review of the evidence in support of autonomic imbalance as a predictor for metabolic risks, and specific approaches to test this model as a guide to future research on the role of stress in metabolic disorders. CONCLUSIONS: We propose that autonomic imbalance deserves consideration by researchers, clinicians, and policymakers as a target for early interventions to prevent metabolic disorders. PMID- 29277457 TI - Development of fluorescence imaging probes for nicotinic acetylcholine alpha4beta2* receptors. AB - Nicotinic acetylcholine alpha4beta2* receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity alpha4beta2* nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [18F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging alpha4beta2* nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the alpha4beta2* nAChRs in [3H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in alpha4beta2* nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface alpha4beta2* nAChRs, labeled with antibodies specific for a beta2 subunit extracellular epitope indicating that nifrofam labels alpha4beta2* nAChR high affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of alpha4beta2* nAChRs in brain regions. PMID- 29277458 TI - Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors. AB - The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure based drug design to develop a series of potent kinase inhibitors, including 2 arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive. PMID- 29277459 TI - Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase. AB - Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR. PMID- 29277460 TI - Aconitum alkaloids, the major components of Aconitum species, affect expression of multidrug resistance-associated protein 2 and breast cancer resistance protein by activating the Nrf2-mediated signalling pathway. AB - BACKGROUND: Aconitum alkaloids from Aconitum species are often used to treat arthritis and rheumatic diseases but have the drawback of high toxicity. Identifying their pharmacokinetic behaviour is important for the safe clinical application of Aconitum species. Efflux transporters (ETs), including P glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), have important functions in regulating the pharmacokinetic behaviours of drugs and in herb-herb or herb-drug interactions (HDIs). The Aconitum alkaloids regulate P-gp expression and function, but their effects on MRP2 and BCRP expression remain unknown. PURPOSE: To determine the effects of three Aconitum alkaloids, aconitine (AC), benzoylaconine (BAC), and aconine, on MRP2 and BCRP. METHODS: The levels of the protein and mRNA expression of MRP2 and BCRP in vivo and in vitro were measured via Western blotting and real time PCR, respectively. Fluorescence signals of MRP2 and BCRP were detected via confocal fluorescence microscopy. A reporter assay using HepG2-C8 cells, which were generated by transfecting plasmids containing the antioxidant response element (ARE)-luciferin gene into HepG2 cells, was used to examine the ARE luciferin activity. The transport activities of MRP2 and BCRP were tested via flow cytometry using substrate probes. RESULTS: The Aconitum alkaloids significantly up-regulated MRP2 and BCRP expression, accompanied by a marked increase in nuclear factor E2-related factor-2 (Nrf2) expression in the jejunum, ileum, and colon of FVB mice, in the order AC < BAC < aconine. In the in vitro model, the Aconitum alkaloids increased MRP2 and BCRP expression in Caco-2 and LS174T cells, in the order AC < BAC < aconine. Additionally, these alkaloids promoted the translocation of Nrf2 from the cytoplasm to the nucleus and significantly increased ARE-luciferin activity in HepG2-C8 cells. Luteolin, a potent inhibitor of Nrf2, markedly prevented MRP2 and BCRP expression from being induced by the three Aconitum alkaloids. The efflux activity of MRP2 was also significantly increased in cells receiving the same treatment. CONCLUSIONS: The tested Aconitum alkaloids significantly increased the expression of MRP2 and BCRP by activating the Nrf2-mediated signalling pathway and enhanced the efflux activity of MRP2. The potential for herb-herb interactions or HDIs exists when Aconitum species are co-administered with substrate drugs that are transported via MRP2 and BCRP. Therefore, the Aconitum alkaloids may be used as quality indicators for the herbs of Aconitum species. PMID- 29277461 TI - Intra cranial granulomatous disease in common variable immunodeficiency: Case series and review of the literature. AB - BACKGROUND/PURPOSE: Common variable immunodeficiency (CVID) is typically characterized by hypogammaglobulinemia and often but not always recurrent infections. Paradoxically, 8-22% of patients with CVID develop granulomatous disease. Granulomata have been described in many organs including the lungs, skin, liver, spleen, kidneys, eyes, lymph nodes, and intestines. Data about central nervous system (CNS) involvement in CVID are extremely rare. We aim to describe a case series and include an extensive literature review of CNS involvement in CVID to understand the different features and patterns of the disease. METHODS: We searched the English Pubmed database for relevant articles between 1950 and 2014 using the Key Words "common variable immunodeficiency", "granulomatous disease", "brain", "sarcoidosis", and "sarcoid-like syndrome". Data from all case series, surveys, systematic reviews, and individual case reports, as well as retrospective studies were extracted. A total of 15 patients were reported in the literature. We combined our experience with four additional patients from The Cleveland Clinic between 2009 and 2014. Demographics, clinical features, laboratory and imaging findings, treatment and follow-up were extracted for the 19 patients and summarized descriptively. RESULTS: Female sex and Caucasian race represented 63.2% (12/19), and 80% of the patients, respectively. The mean age of CVID diagnosis was 24 years; mean age when the CNS disease was diagnosed was 21.5 years. 68.4% of the patients (13/19) had granulomas involving >=2 organs including the central nervous system, 31.6% (6/19) had CNS granulomas only. Associated granulomatous diseases occurred in lungs (72.7%), lymph nodes (27.2%), spleen (27.2%), eyes (18.1%), liver (18.1%), parotid glands (9%), and skin (9%). Fifty-three percent (10/19) of the patients had documented recurrent infections, all of them being upper respiratory tract infections. CNS manifestations included seizures (31.6%), headaches (21%), vision loss (15.7%), decreased cognition (10.5%), focal weakness (5.2%), nystagmus (5.2%), ataxia (5.2%), coma (5.2%), polyuria, and polydipsia (5.2%). Brain mass was the most common radiologic finding (70%) followed by leptomeningeal enhancement (10%), non specific white matter lesions (10%) and absence of normal signal of the neurohypophysis (10%). Brain pathology was available in 12 patients: findings included granulomatous disease in 83.3%, angiocentric granulomas in 50%, vasculitis without granulomas in 8.3%, and lymphocytic infiltrate of the meninges with diffuse non-caseating granulomas in 8.3%. Cerebrospinal fluid analysis revealed elevated total proteins with/or without lymphocytic pleocytosis in 80%. CONCLUSION: CNS disease is a rare challenging complication of CVID. Patients with brain involvement are generally female, Caucasian, and likely have lung involvement. Although immunoglobulin and steroids remain the first line of treatment, other immunosuppressive agents have shown some promise with regards to recurrent relapsing presentations. PMID- 29277462 TI - Randomized Controlled Trial to Prevent Infant Overweight in a High-Risk Population. AB - OBJECTIVES: Infants are at risk of overweight. Infant overweight predisposes child, adolescent, and adult to obesity. We hypothesized that parent education, initiated prenatally and provided in the home, would reduce the incidence of infant overweight at age 12 months. METHODS: Pregnant obese Latina women were recruited at Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and randomized to intervention versus control. Intervention subjects received home visits by trained Spanish-fluent community health workers who provided counseling on infant growth, breastfeeding, nutrition, child development, sleep, physical activity, and safety. Promotoras did not visit the control subjects. A research assistant collected outcome data on all subjects. RESULTS: Compared to controls, parent education did not reduce infant overweight. Infant overweight developed rapidly and was present in 46% of infants by age 6 months. Infants overweight at 6 months were likely to be overweight at age 12 months (r = 0.60, P < .0001). Overweight was more common in formula-fed infants at ages 6 months (P < .06) and 12 months (P = .005). Breastfeeding was less common in families with employed mothers (P = .02) and unemployed fathers (P < .01), but the father living with the mother at the time of the prenatal visit predicted successful breastfeeding at infant age 2 months (P < .003). Compared to formula feeding, overweight at age 12 months was 2.7 times less likely for infants breastfed for >=2 months (P = .01). CONCLUSIONS: The lack of success of the intervention may be explained in part by a high cesarean section rate in the intervention group, food and employment insecurity, and confounding by WIC breastfeeding promotion, which was available to all mothers. Breastfeeding was the most important mediator of infant overweight. The study supports efforts by WIC to vigorously promote breastfeeding. PMID- 29277463 TI - Impact of Implementation of Electronically Transmitted Referrals on Pediatric Subspecialty Visit Attendance. AB - OBJECTIVE: One barrier to timely access to outpatient pediatric subspecialty care is the complexity of scheduling processes. We evaluated the impact of implementing electronically transmitted referrals on subspecialty visit attendance. METHODS: Through collaboration with stakeholders, an electronically transmitted referral order system was designed, piloted, and implemented in 15 general pediatrics practices, with 24 additional practices serving as controls. We used statistical process control methods and difference-in-differences analysis to examine visits attended, appointments scheduled, appointment nonattendance, and referral volume. Electronically transmitted referrals then were expanded to all 39 practices. We surveyed referring pediatricians at all practices before and after implementation. RESULTS: From April 2015 through September 2016 there were 33,485 referral orders across all practices (7770 before the pilot, 11,776 during the pilot, 13,939 after full implementation). At pilot practices, there was a significant and sustained improvement in subspecialty visits attended within 4 weeks of referral (10.9% to 20.0%; P < .001). Relative to control practices, pilot practices experienced an 8.6% improvement (P = .001). After implementation at control practices, rates of visits attended also improved but to a smaller degree: 11.8% to 14.7% (P < .001). In survey responses, referring pediatricians noted improved scheduling processes but had continued concerns with appointment availability and referral tracking. CONCLUSIONS: While electronically transmitted referrals improved visit attendance after pediatric subspecialty referral, the sizable percentage of children without attended visits, the muted effect at control practices, and pediatrician survey responses indicate that additional work is needed to address barriers to pediatric subspecialty care. PMID- 29277464 TI - Determination of Tedizolid susceptibility interpretive criteria for gram-positive pathogens according to clinical and laboratory standards institute guidelines. AB - For effective antibacterial therapy, physicians require qualitative test results using susceptibility breakpoints provided by clinical microbiology laboratories. This article summarizes the key components used to establish the Clinical Laboratory Standards Institute (CLSI) breakpoints for tedizolid. First, in vitro studies using recent surveillance and clinical trial isolates ascertained minimal inhibitory concentration (MIC) distributions against pertinent organisms, including staphylococci, streptococci, and enterococci. Studies in animal models of infection determined rates of antibacterial efficacy and survival following administration of tedizolid phosphate at doses equivalent to those in humans. Pharmacokinetic and pharmacodynamic analyses examined the relationship between plasma concentrations and MICs against the target organism. Finally, clinical trials assessed clinical and microbiologic outcomes by MIC. All these data were evaluated and combined to obtain the ratified CLSI susceptibility criteria for tedizolid of <=0.5MUg/mL for Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Enterococcus faecalis and <=0.25MUg/mL for Streptococcus anginosus group. PMID- 29277465 TI - Optimal timing of video-assisted thoracoscopic surgery for primary spontaneous pneumothorax in children. AB - PURPOSE: There is no consensus in the pediatric surgical community about when to recommend video-assisted thoracoscopic surgery (VATS) for patients with primary spontaneous pneumothorax (PSP). We aimed to identify factors that predict the likelihood of requiring VATS, and to compare recurrence rates and healthcare utilization among different management approaches to PSP. METHODS: A retrospective chart review and a telephone survey were conducted on all patients 12-21years who were diagnosed with PSP from 2007 to 2015. Data were extracted on patient demographics, initial management, hospital length of stay (LOS), and subsequent admissions, procedures, and recurrences. RESULTS: A total of 46 patients were included with a mean age of 16.1years (+/- 1.2). Most patients were male (41, 89%) and white (16, 44%). Initial management comprised chest tube drainage alone in 28 (61%), no intervention in 8 (17%), and VATS in 10 (22%). Total LOS was 6days (IQR 4-7) and was longer in patients who underwent VATS (p<0.001). Recurrence occurred in 17 patients (37%). However, recurrence and healthcare utilization were not significantly associated with initial management approach. Among those who had initial chest tube drainage, 14 (50%) underwent VATS on that admission, and 8 (28%) had subsequent surgery. Significant predictors of ultimately requiring VATS were presence of an air leak and partial lung expansion. CONCLUSION: Most patients with PSP currently undergo chest tube placement as initial management, although most eventually require VATS. Presence of an air leak and partial lung expansion on chest radiograph within the first 48h of management should prompt earlier surgical intervention. TYPE OF STUDY: Retrospective. LEVEL OF EVIDENCE: III. PMID- 29277466 TI - Determinants of postoperative morbidity and mortality in children managed for typhoid intestinal perforation in Kano Nigeria. AB - BACKGROUND: Intestinal perforation is a serious but poorly understood complication of typhoid fever. This study aims to determine the patient factors associated with postoperative morbidity and mortality. METHODS: We retrospectively reviewed the records of all children presenting to our unit with typhoid intestinal perforation (TIP) between March 2009 and December 2013. The patients were grouped based on postoperative outcome status and were compared with respect to patient related variables, using chi square test. Multivariate analysis was performed using a binary logistic regression model. Significance was assigned to a p-value <0.05. RESULTS: The records of 129 children were analyzed. There were 78 (60.5%) boys and 51 (39.5%) girls. The male/female ratio was 1.53:1. Their ages ranged from 3years to 13years (mean 8.14years; SD 2.61years). A single intestinal perforation was seen in 73.4% (94/128) of them, while 26.6% (34/128) had two or more. Mortality rate was 10.9%. Multivariate analysis showed that multiple intestinal perforations significantly predicted postoperative mortality (p=0.005) and development of postoperative fecal fistula (p=0.013), while serum albumin <32g/L was a predictor of postoperative surgical site infection (p=0.002). CONCLUSION: Multiple intestinal perforations, a postoperative fecal fistula and hypoalbuminemia adversely affected outcome in our patients. LEVEL OF EVIDENCE: III (Retrospective study). Type of study-Prognosis study. PMID- 29277467 TI - Bladder dysfunction in Wolfram syndrome is highly prevalent and progresses to megacystis. AB - AIM: Wolfram syndrome is a rare genetic defect in WFS1 or WSF2(CISD2). It includes diabetes mellitus and insipidis, sensorineural deafness, optic atrophy, but not bladder dysfunction. However, this has appeared a common finding in our national referral clinic, and we sought to quantify this problem. METHODS: Data were collected from a multidisciplinary team managing all Wolfram patients in the UK. The following was analyzed: age, date of non-invasive urodynamics (NIU), symptoms, bladder capacity, voided volume, post-void residual and uroflow pattern. Bladder capacity was given as percentage predicted bladder capacity (PBC). Bladders were divided into normal, overactive (OAB), and underactive (UAB). Symptoms, bladder behavior, and genotyping were correlated. Data were expressed as median (interquartile range). MAIN RESULTS: Forty patients with Wolfram syndrome were identified, and 38 underwent NIU. This showed normal bladder function (n=4), OAB (n=9), UAB (n=25). Symptoms were present in only 11 children. The different patterns of bladder behavior (OAB vs. normal vs. UAB) were significantly associated with different %PBC (36 (29-59)% vs. 105 (93-233)% vs. 100 (77.5-337)%; p<0.001), and percentage emptying (100 (80-100)% vs. 100 (87 100)% vs. 69 (48-93)%; p<0.05). There was no association of genotype, symptoms and bladder behavior. Patients with megacystis were older: [13.4 (9.7-16.1) vs. 15.4 (13.9-18.7) years; p<0.05). CONCLUSION: Bladder dysfunction is very common in Wolfram syndrome (~90%), but most children cope (symptoms ~30%). With time there is a significant progression to megacystis, which may represent an underlying neuropathic myogenic failure and is likely to require intervention in the future. LEVEL OF EVIDENCE: Level II (National cohort study of prognosis). PMID- 29277468 TI - Letter to the editor. PMID- 29277469 TI - The SEISICAT study: a pilot study assessing efficacy and safety of spironolactone in cats with congestive heart failure secondary to cardiomyopathy. AB - INTRODUCTION: The pathophysiology of heart failure involves activation of several neurohormonal systems including the renin-angiotensin-aldosterone system. The mineralocorticoid receptor antagonist spironolactone has been shown to be beneficial in humans and dogs with heart failure. The objective of this pilot study was to investigate the efficacy and safety of spironolactone in cats with heart failure secondary to cardiomyopathy already treated with furosemide and an angiotensin-converting enzyme inhibitor. ANIMALS: Twenty cats with heart failure due to cardiomyopathy. METHODS: The study was a double-blind, randomised, placebo controlled, multicentre clinical study assessing the effect of spironolactone on survival and clinical parameters in cats with heart failure due to cardiomyopathy. The primary end point was mortality, defined as death (spontaneous or by euthanasia) due to cardiac causes. RESULTS: Twenty cats were enrolled: 9 in the spironolactone group and 11 in the placebo group of which 56% (5/9) and 0% (0/11) completed the 15-month period respectively. At inclusion, differences in systemic blood pressure, body condition score, electrocardiographic abnormalities and LA/Ao ratio suggested that disease may be less severe in the spironolactone group. Twenty-two percent (2/9) of cats in the spironolactone group and 82% (9/11) in the control group reached the primary end point (Fisher's exact test, p = 0.0216). No safety issues were identified in either group. CONCLUSIONS: This study suggests that spironolactone is well tolerated, and preliminary results support further investigation to evaluate the efficacy of spironolactone in the treatment of cats with cardiac failure due to cardiomyopathy. PMID- 29277470 TI - Poincare plots as a measure of heart rate variability in healthy dogs. AB - INTRODUCTION: Poincare plots remain largely unused for heart rate variability (HRV) analysis in dogs. The aims of this study were to describe, qualitatively and quantitatively, Poincare plots in healthy dogs, to compare them with other methods of HRV analysis, to assess their day-to-day variability and to investigate the effect of activity on the plots. ANIMALS: Twenty-five healthy dogs. METHODS: Poincare plots, their standard descriptors, and other measures of HRV were generated from 24-hour ambulatory electrocardiographic recordings and 6 hours of rest and activity. RESULTS: The 24-hour Poincare plot demonstrated a 'Y' pattern. The arms of the 'Y' were derived mostly from periods of rest and activity populated the stalk. The quantitative descriptors of the plot had strong correlations in the time-domain, with weaker correlations in the frequency domain. Individuals showed low day-to-day variability of the plot pattern and of the standard deviation of points along the major axis of the plot (SD2), which measures overall HRV. Day-to-day variability was higher for the standard deviation of points perpendicular to the major axis of the plot (SD1), which is a measure of short-term HRV, and for the SD1/SD2 ratio. CONCLUSIONS: Twenty-four hour Poincare plots in healthy dogs show a 'Y' pattern with subtle variations unique to the individual. The amount of activity and rest within the recording has a significant effect on the plot. Quantitative analysis of the plot can be used as a surrogate for time-domain analysis of HRV but visual analysis of the pattern provides additional information. PMID- 29277471 TI - Retrospective evaluation of notched QRS complexes in dogs: 85 cases. AB - INTRODUCTION: Notched QRS complexes on electrocardiography (ECG) have been described in veterinary and human reports, but little is known about this finding in veterinary patients. Therefore, the objectives of this study were to describe the signalment and cardiac disease diagnosis in dogs with notched QRS complexes, as well as to describe the specific leads and number of leads with notched QRS complexes on ECG. ANIMALS: Eighty-five dogs with notched QRS complexes of normal duration in at least one ECG lead. METHODS: Retrospective review of digitally stored ECGs and associated medical records of dogs with a recorded ECG as part of routine clinical evaluation. RESULTS: Age at time of ECG recording was 9.15 +/- 3.38 years for the 85 dogs with notched QRS complexes in at least one ECG lead. The number of ECG leads with notched QRS complexes did not increase with age. Most dogs (69.4%) with notched QRS complexes had cardiac disease. The odds ratio of a dog having cardiac disease if more than one lead was identified with notched QRS complexes was 3.97. The most common cardiac disease identified was chronic atrioventricular valvular degeneration, and the majority of these dogs (80%) had two or less leads with notched QRS complexes. CONCLUSIONS: Dogs with and without cardiac disease can have notched QRS complexes. The likelihood of a dog having cardiac disease that has more than one ECG lead with notched QRS complexes is significant, and this should warrant diagnostic evaluation. PMID- 29277472 TI - A complex of the blood fluke genus Psettarium (Digenea: Aporocotylidae) infecting tetraodontiform fishes of east Queensland waters. AB - Seven species of Psettarium (Digenea: Aporocotylidae), including four new species, are reported from tetraodontiform fishes from off coastal east Queensland. Psettarium pandora n. sp. infects the yellow boxfish, Ostracion cubicus (Ostraciidae), the first known aporocotylid to infect this family of fishes. Three new species are reported from pufferfishes of the genus Arothron (Tetraodontidae): Psettarium yoshidai n. sp. infects the map puffer (Arothron mappa), Psettarium hustoni n. sp. infects the black-spotted puffer (A. nigropunctatus) and Psettarium martini n. sp. infects the starry puffer (A. stellatus). We also report three species of Psettarium from Australian waters for the first time. Paracardicola hawaiensis Martin, 1960, the sole species of Paracardicola, is redescribed based on specimens collected from the type-host, the stars-and-stripes puffer, Arothron hispidus. Paracardicola is synonymised with Psettarium and P. hawaiensis is recombined as Psettarium hawaiiense (Martin, 1960) n. comb. Psettarium pulchellum Yong, Cutmore, Bray, Miller, Semarariana, Palm & Cribb, 2016, described from the narrow-lined puffer (Arothron manilensis) from off Bali, Indonesia, is reported from the same fish species at two locations on the Queensland coast, significantly extending the range of this species. Psettarium nolani (Bray, Cribb & Littlewood, 2013), originally described from French Polynesia, is reported from A. hispidus, A. manilensis and A. stellatus, representing both new host and locality records for this species. Molecular phylogenetic analysis shows these species to all be closely related, such that they cannot be considered to represent separate genera despite their differing morphology. Analysis of 28S sequence data for Psettarium anthicum Bullard & Overstreet, 2006, a non-tetraodontiform-infecting species, shows it to be distantly related to all other species of Psettarium for which sequence data are available. The species is re-assigned to a new genus, Cardallagium n. gen., as Cardallagium anthicum (Bullard & Overstreet, 2006) n. comb. We think it likely that the host range of species of Psettarium is limited to tetraodontiform fishes. We assessed the infection biology of two species, P. nolani and P. hawaiiense n. comb. infecting A. hispidus, using histology to assess the pathways of egg release for these species. Eggs of both species were observed in both circulatory and visceral organs of infected hosts, often in high numbers. Eggs were seen trapped in the mucosal layer of the intestine and, in rare instances, causing lesions in the laminar epithelium, providing the strongest evidence yet that they pass through the gut wall and escape the host via the faeces. Lastly, we discuss the biogeographical implications of our findings, noting that some Psettarium species now show very wide geographical distributions. PMID- 29277473 TI - A Novel Approach to Assessing Head Injury Severity in Pediatric Patient Falls. AB - INTRODUCTION: Pediatric patient falls with head-to-floor impact have the greatest potential for injury. METHODS: An objective measure of head injury severity, the Head Injury Criterion (HIC15), was calculated from anthropometric and biomechanical components of patient falls. A secondary aim was to compare HIC15 levels with the hospital's subjective assignment of level of harm (1-9 scale) used for regulatory reports. RESULTS: Adverse event reports yielded a sample of 49 falls from heights of 72.5 to 1793.0 cm by children ages 11 months through 17 years. Contact velocity from beginning to end was 2.81 to 6.16 ms. Mean acceleration was 19.5 to 95.3g. HIC15 levels of impact ranged from 26.4 to 1,330.0, and mean force upon contact was 2.0 to 9.8 N/kg body mass. Seven (14.3%) children's HIC15 levels exceeded age-specific thresholds, with no follow-up scheduled. Hospital-assigned levels of harm were not correlated with HIC15 levels (r = .23, R2 = .05, p = .12). DISCUSSION: A point-of-care computerized HIC15 algorithm would be useful for diagnostic and follow-up decisions. PMID- 29277474 TI - An evidence of C16 fatty acid methyl esters extracted from microalga for effective antimicrobial and antioxidant property. AB - Fatty acid methyl esters (FAME) derived from lipids of microalgae is known to have wide bio-functional materials including antimicrobials. FAME is an ideal super-curator and superior anti-pathogenic. The present study evaluated the efficiency of FAME extracted from microalgae Scenedesmus intermedius as an antimicrobial agent against Gram positive (Staphylococcus aureus, Streptococcus mutans, and Bacillus cereus) Gram negative (Escherichia coli and Pseudomonas aeruginosa) bacteria and Fungi (Aspergillus parasiticus and Candida albicans). The minimal inhibitory concentration (MIC) for the gram negative bacteria was determined as 12-24 MUg mL-1, whereas MIC for gram positive bacteria was 24-48 MUg mL-1. MIC for the fungi was as high as 60-192 MUg mL-1. The FAME profiles determined by gas chromatography showed 18 methyl esters. Among them, pharmacologically active FAME such as palmitic acid methyl ester (C16:0) was detected at high percentage (23.08%), which accounted for the bioactivity. FAME obtained in this study exhibited a strong antimicrobial activity at the lowest MIC than those of recent reports. This result clearly indicated that FAME of S. intermedius has a strong antimicrobial and antioxidant property and that could be used as an effective resource against microbial diseases. PMID- 29277475 TI - Subtractive genome analysis for in silico identification and characterization of novel drug targets in Streptococcus pneumonia strain JJA. AB - Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium. Humans are the major target for the pneumococcus. The pneumococcus is a common etiological agent of many different diseases such as bacterial meningitis, pneumonia, otitis media (OM), sinusitis, and conjunctivitis. According to the WHO, the pneumococcus is responsible for causing 1 million deaths each year. In 2000, over 14 million children worldwide under the age of 5 years were diagnosed with a pneumococcal disease, with the highest incidence seen in Africa. The human population most susceptible to pneumococcal infections is that of children due to their immature immune system. A sensational increase in antibiotic resistance among S. pneumoniae has been witnessed in different parts of the world since 1980s. The increase of resistance of S. pneumoniae to antibiotics is of major concern throughout the world. Worldwide, there are concerns about rising levels of antibiotic resistance and fears that the efficacy of antimicrobial therapy may be compromised, resulting in treatment failure and reduced utility of older antibiotics, a comparatively novel method has been used to defeat the resistant pathogens since last decade. The computational subtractive genomics approach is one of them, in which the bacterial pathogen complete proteins is gradually rock bottom to a small number of likely drug targets. In this approach the steps which are used to find human non-homologs targets, proteins that are essential to the disease causing agent and participation of the selected proteins in pathogen metabolic pathways which are necessary for the survival of bacteria. We used computational subtractive genomics on consummate proteins of the of S. pneumonia strain JJA in this study and concluded with 2 proteins that can be used as potent drug targets against which new dynamic molecules can be planned to make better the action to treat the disease which is related with pathogen. PMID- 29277476 TI - What is the significance, if any, of the increased incidence of stent thrombosis with dual therapy of dabigatran 110mg twice daily and clopidogrel in the RE-DUAL PCI trial? PMID- 29277477 TI - The communicative role of companion pets in patient-centered critical care. AB - OBJECTIVE: This study examines a personal pet hospital visitation program dedicated to preserving the human-animal bond during chronic, critical, or terminal illness to understand the novel ways companion pets facilitate meaningful communication between patients, providers, and families in hospital settings. METHODS: I thematically analyzed data collected through a variety of qualitative methods, including participant observation, informal and semi structured interviews, and a review of organizational materials. RESULTS: The presence of a patient's personal pet prompted stories and behaviors characterized by (1) compassion, (2) connection, and (3) response between patients, providers, and family members. CONCLUSION: Personal pet hospital visits facilitate storied conversations, foster healing relationships, and offer alternative ways of knowing that can promote greater understandings of the patient's psychosocial context for more personalized care and improved well-being. PRACTICE IMPLICATIONS: Patient-centered critical care requires meaningful consideration of a patient's health, well-being, and comfort. When appropriate, the therapeutic benefits of companion animals and the deep personal bonds between patients and their pets should be acknowledged and provided as part of this care. PMID- 29277478 TI - Hydrogen/deuterium (H/D) exchange of gelatinized starch studied by two dimensional (2D) near-infrared (NIR) correlation spectroscopy. AB - Hydrogen/deuterium (H/D) exchange of gelatinized starch was probed by in-situ near-infrared (NIR) monitoring coupled with two-dimensional (2D) correlation spectroscopy. Gelatinized starch undergoes spontaneous H/D exchange in D2O. During the substitution, the exchange rate essentially becomes different depending on solvent accessibility of various parts of the molecule. Thus, by analyzing the change in the NIR feature observed during the substitution, it becomes possible to sort out local structure and dynamics of the system. 2D correlation analysis of the time-dependent NIR spectra reveals the presence of different local structure of the starch, each having different solvent accessibility. For example, during the H/D exchange, the D2O is first absorbed by starch molecules especially around the surface area between the starch and water, where the water molecules are weakly interacted with the starch molecules. This absorption is quickly followed by the development of HDO species. Further absorption of the D2O results in the penetration of the molecules inside the starch and eventually develops the relatively strong interaction between the HDO and starch molecules because of the presence of dominant starch molecules. PMID- 29277479 TI - Design of tunable ultraviolet (UV) absorbance by controlling the AgAl co sputtering deposition. AB - Changing the structure and composition of a material can alter its properties; hence, the controlled fabrication of metal nanostructures plays a key role in a wide range of applications. In this study, the structure of AgAl ordered arrays fabricated by co-sputtering deposition onto a monolayer colloidal crystal significantly increased its ultraviolet (UV) absorbance owing to a tunable localized surface plasmon resonance (LSPR) effect. By increasing the spacing between two nanospheres and the content of aluminum, absorbance in the UV region could be changed from UVA (320-400nm) to UVC (200-275nm), and the LSPR peak in the visible region gradually shifted to the UV region. This provides the potential for surface-enhanced Raman scattering (SERS) in both the UV and visible regions. PMID- 29277480 TI - Tear evaporation rates: What does the literature tell us? AB - PURPOSE: A previous literature review reported tear evaporation rates (TERs) from studies conducted on rabbits and humans between 1941 and 2003. Closer examination of the presented data revealed inaccuracies in the reporting of some values. This paper presents updated tables of TERs using values from the original papers cited in the review, in addition to incorporating new studies published between 2003 and 2016. METHODS: A copy of each paper cited in the literature review was obtained and checked against the evaporation rate reported in the review. If the expected value could not be found in the cited paper, other papers by the same author were consulted to see if the value had been reported elsewhere. A PubMed and Scopus database search was conducted to find papers published on tear evaporimetry since 2003. RESULTS: Two new tables of TERs were created, based on the values reported by the original author. To aid in interpretation, the majority of results are expressed in units of x 10-7 g/cm2/sec. Where it was not possible to convert these values, some values are expressed as x 10-7 g/sec, x 10 7 g/sec/eye or W/min. CONCLUSIONS: Two new tables of TERs have been compiled to provide an accurate representation of the values reported in the original papers. These tables can be used as a point of reference for other researchers to compare their results. PMID- 29277482 TI - Comparison of narrow-band imaging and confocal laser endomicroscopy for the detection of neoplasia in Barrett's esophagus: A meta-analysis. AB - AIMS: Barrett's esophagus (BE) predisposes to the development of esophageal neoplasia, including high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). A systematic literature review and meta-analysis were performed to assess the accuracy of within-patient comparisons of narrow band imaging (NBI) and confocal laser endomicroscopy (CLE) for diagnosis of HGD/EAC in patients with BE. METHODS: The following databases were examined up to April 2016 without language restriction: PubMed, Embase, Medline, Web of Science and the Cochrane Library. The QUADAS-2 tool for assessing the quality of included studies was used. The meta-analysis included pooled additional detection rate (ADR), diagnostic accuracy, and 95% confidence intervals (CI). The I2 and Q-test were used to determine study heterogeneity. RESULTS: Five studies involving 251 patients, reported within-patient comparisons of NBI and CLE, were eligible for meta analysis. Compared with NBI, pooled ADR of CLE for per-lesion detection of neoplasia in patients with BE was 19.3% (95% CI: 0.05-0.33, I2=74.6%). The pooled sensitivity of NBI was 62.8% (95% CI: 0.56-0.69, I2=94.6%), which was lower (not significantly) than that of CLE (72.3%, 95% CI: 0.66-0.78, I2=89.3%). The pooled specificity of NBI and CLE were similar [85.3% (95% CI: 0.84-0.87, I2=92.1%) vs 83.8% (95% CI: 0.82-0.85, I2=96.8%)]. CONCLUSIONS: When compared with NBI, CLE significantly increased the per-lesion detection rate of esophageal neoplasia, HGD, and EAC in BE patients. Whether CLE is superior to NBI in neoplasia detection at per-patient level needs to be further investigated. PMID- 29277481 TI - Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation. AB - BACKGROUND: Coeliac disease is characterised by an increased mortality mostly due to its complications. AIMS: To study the risk of developing complications according to clinical presentation and age at diagnosis, a combined retrospective prospective longitudinal study was performed in three Italian centres. METHODS: Incidence of complications and mortality rates were calculated using type and age at diagnosis of coeliac disease, sex, and centre of diagnosis as predictors. Patients referred after being found to suffer from coeliac disease elsewhere were excluded. RESULTS: Between 01/1999 and 06/2015, 2225 adult coeliac patients were directly diagnosed in our centres. 17 of them developed a complication and 29 died. In patients older than 60 years at diagnosis of coeliac disease, the risk of complication is 18 times higher than in patients diagnosed at 18-40 years and 9 times higher than in patients diagnosed at 40-60 years. Classical presentation increases the risk of complications by 7 times compared to non-classical presentation; in asymptomatic patients the risk of complication is virtually absent. CONCLUSIONS: The risk of developing complications in coeliac patients is linked to age at diagnosis of coeliac disease and type of clinical presentation. Follow-up methods of coeliac patients should be tailored according to these parameters. PMID- 29277483 TI - Superior Reproducibility of the Leading to Leading Edge and Inner to Inner Edge Methods in the Ultrasound Assessment of Maximum Abdominal Aortic Diameter. AB - OBJECTIVES: Controversy exists regarding optimal caliper placement in ultrasound assessment of maximum abdominal aortic diameter. This study aimed primarily to determine reproducibility of caliper placement in relation to the aortic wall with the three principal methods: leading to leading edge (LTL), inner to inner edge (ITI), and outer to outer edge (OTO). The secondary aim was to assess the mean difference between the OTO, ITI, and LTL diameters and estimate the impact of using either of these methods on abdominal aortic aneurysm (AAA) prevalence in a screening program. METHODS: Radiologists (n=18) assessed the maximum antero posterior abdominal aortic diameter by completing repeated caliper placements with the OTO, LTL, and ITI methods on 50 still abdominal aortic images obtained from an AAA screening program. Inter-observer reproducibility was calculated as the limit of agreement with the mean (LoA), which represents expected deviation of a single observer from the mean of all observers. Intra-observer reproducibility was assessed averaging the LoA for each observer with their repeated measurements. Based on data from an AAA screening trial and the estimated mean differences between the three principal methods, AAA prevalence was estimated using each of the methods. RESULTS: The inter-observer LoA of the OTO, ITI, and LTL was 2.6, 1.9, and 1.9 mm, whereas the intra-observer LoA was 2.0, 1.6, and 1.5 mm, respectively. Mean differences of 5.0 mm were found between OTO and ITI measurements, 2.6 mm between OTO and LTL measurements, and 2.4 mm between LTL and ITI measurements. The prevalence of AAA almost doubled using OTO instead of ITI, while the difference between ITI and LTL was minor (3.3% vs. 4.0% AAA). CONCLUSIONS: The study shows superior reproducibility of LTL and ITI compared with the OTO method of caliper placement in ultrasound determination of maximum abdominal aortic diameter, and the choice of caliper placement method significantly affects the prevalence of AAAs in screening programs. PMID- 29277485 TI - Commentary on "The Safety of Device Registries for Endovascular Abdominal Aortic Aneurysm Repair: Systematic Review and Meta-Regression". PMID- 29277484 TI - Complex Open Surgical Revascularisation for Successful Resolution of Bilateral Lower Limb Ischaemia. PMID- 29277486 TI - Development of a high-throughput bead based assay system to measure HIV-1 specific immune signatures in clinical samples. AB - The monitoring and assessment of a broadly neutralizing antibody (bnAb) based HIV 1 vaccine require detailed measurements of HIV-1 binding antibody responses to support the detection of correlates of protection. Here we describe the development of a flexible, high-throughput microsphere based multiplex assay system that allows monitoring complex binding antibody signatures. Studying a panel of 13 HIV-1 antigens in a parallel assessment of different IgG subclasses (IgG1, IgG2 and IgG3) we demonstrate the potential of our strategy. The technical advances we describe include means to improve antigen reactivity using directed neutravidin-biotin immobilization of antigens and biotin saturation to reduce background. A particular emphasis of our study was to provide tools for the assessment of reproducibility and stability of the assay system and strategies to control for variations allowing the application in high-throughput assays, where reliability of single measurements needs to be guaranteed. PMID- 29277487 TI - Training program for pain assessment in the newborn. AB - AIM: Pain management is correlated with pain assessment in the newborn infant. The aim of this study was to assess the impact of a 2-week training program composed of short (20min), repeated training sessions conducted in the unit. METHODS: Pain assessment was studied by means of audits. Each audit included data recorded from the newborn infant's medical charts on the day the infant was admitted to the unit and 3 days before the audit. An audit was performed before the training program and then repeated every month for 12 months. RESULTS: Eighty eight (53.7%) members of the neonatology staff were trained during the 2-week training program. After the training program, pain assessment "at least once a day" increased by 39.0% and pain assessment "at least once a shift" increased by 21.5% compared to baseline (P<0.05). The effects of the training program were maintained after 12 months (P<0.05). CONCLUSION: A training program with short, repeated sessions conducted in the unit trained 53.7% of the neonatology staff and increased the frequency of pain assessment. PMID- 29277488 TI - Ghrelin mediated neuroprotection - A possible therapy for Parkinson's disease? AB - Parkinson's disease is a common age-related neurodegenerative disorder affecting 10 million people worldwide, but the mechanisms underlying its pathogenesis are still unclear. The disease is characterised by dopamine nerve cell loss in the mid-brain and intra-cellular accumulation of alpha-synuclein that results in motor and non-motor dysfunction. In this review, we discuss the neuroprotective effects of the stomach hormone, ghrelin, in models of Parkinson's disease. Recent findings suggest that it may modulate mitochondrial function and autophagic clearance of impaired organelle in response to changes in cellular energy balance. We consider the putative cellular mechanisms underlying ghrelin-action and the possible role of ghrelin mimetics in slowing or preventing Parkinson's disease progression. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29277490 TI - Gene-environment interactions informing therapeutic approaches to cognitive and affective disorders. AB - Gene-environment interactions drive experience-dependent changes in the brain that alter cognition, emotion and behaviour. Positive engagement with the environment, through novel experience and physical activity, can improve brain function, although the mechanisms mediating such experience-dependent plasticity remain to be fully elucidated. In this article, we discuss the therapeutic value of environmental stimuli, exercise and environmental enrichment (EE), for cognitive and affective disorders, with implications for the understanding and treatment of depression and anxiety disorders. We demonstrate that environmental manipulations are potential therapeutic strategies for improving outcomes in these psychiatric disorders, including beneficial impacts on cognition. We discuss how EE and exercise are therapeutic environmental interventions impacting both affective and cognitive function. Serotonergic (5-HTergic) signaling is strongly implicated in the manifestation of psychiatric disorders and regulates cognitive and emotional processing that can underpin them. Thus, we focus on evidence implicating the serotonergic system in mediating gene-environment interactions to EE and exercise. Finally, we discuss robust gene-environment interactions associated with EE and exercise interventions, and their impacts on specific brain areas, particularly the hippocampus. We focus on potential mediators of this experience-dependent plasticity, including adult neurogenesis and brain-derived neurotrophic factor (BDNF). Furthermore, we explore molecular and cellular mechanisms of experience-dependent plasticity that potentially underlie the restoration of affective and cognitive phenotypes, thus identifying novel therapeutic targets. PMID- 29277489 TI - C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies. AB - C-547, a potent slow-binding inhibitor of acetylcholinesterase (AChE) was intravenously administered to rat (0.05 mg/kg). Pharmacokinetic profiles were determined in blood and different organs: extensor digitorum longus muscle, heart, liver, lungs and kidneys as a function of time. Pharmacokinetics (PK) was studied using non-compartmental and compartmental analyses. A 3-compartment model describes PK in blood. Most of injected C-547 binds to albumin in the bloodstream. The steady-state volume of distribution (3800 ml/kg) is 15 times larger than the distribution volume, indicating a good tissue distribution. C-547 is slowly eliminated (kel = 0.17 h-1; T1/2 = 4 h) from the bloodstream. Effect of C-547 on animal model of myasthenia gravis persists for more than 72 h, even though the drug is not analytically detectable in the blood. A PK/PD model was built to account for such a pharmacodynamical (PD) effect. Long-lasting effect results from micro-PD mechanisms: the slow-binding nature of inhibition, high affinity for AChE and long residence time on target at neuromuscular junction (NMJ). In addition, NMJ spatial constraints i.e. high concentration of AChE in a small volume, and slow diffusion rate of free C-547 out of NMJ, make possible effective rebinding of ligand. Thus, compared to other cholinesterase inhibitors used for palliative treatment of myasthenia gravis, C-547 is the most selective drug, displays a slow pharmacokinetics, and has the longest duration of action. This makes C-547 a promising drug leader for treatment of myasthenia gravis, and a template for development of other drugs against neurological diseases and for neuroprotection. PMID- 29277491 TI - Impact of Community-Based Nutrition Education on Geophagic Behavior and Dietary Knowledge and Practices among Rural Women in Nakuru Town, Kenya: A Pilot Study. AB - OBJECTIVE: Geophagia, the deliberate consumption of rocks, soil, or clay, is prevalent in developing countries, particularly sub-Saharan Africa. Health risks associated with this behavior include parasitosis, heavy metal poisoning, nutrient deficiencies, and poor birth outcomes. This pilot study was designed to reduce geophagic practices and improve nutrition among rural Kenyan women. METHODS: The researchers used snowball sampling to recruit participants (n = 135; aged 15-49 years) from low socioeconomic areas who consumed geophagic materials. Interviews were carried out before and after a nutrition intervention implemented by trained community health volunteers. RESULTS: Nutrition education focusing on geophagia significantly (P < .001) decreased the practice in 77% of participants. Postintervention interviews also demonstrated substantial improvement in understanding the concept of making half the plate vegetables using the healthy plate model. CONCLUSIONS AND IMPLICATIONS: Nutrition education can be useful for reducing geophagia (a largely ignored, unsafe dietary behavior) and enhancing nutritional knowledge in African women. PMID- 29277492 TI - Emergency Department Presentation of Iliopsoas Hematoma in a Severe Hemophiliac. AB - Severe hemophilia A is defined by factor VIII level of <1%. Limited research and case series show that these patients are at the highest risk for bleeding complications, the most common being hemarthrosis and muscle hematoma, respectively.1 While rare, iliopsoas hematoma carries significant morbidity, mortality, and requires prompt intervention in hemophiliac patients. As such, it is essential the emergency providers evaluate for this condition in this unique patient population. We present the case of 21-year-old male with severe hemophilia A who presented with one day of right groin pain after going without his prophylactic factor VIII infusions for one week, with subsequent diagnosis and initial treatment of iliopsoas hematoma made in the ED. PMID- 29277493 TI - Emergency department visits in patients with low acuity conditions: Factors associated with resource utilization. AB - OBJECTIVES: To identify health beliefs of emergency department (ED) patients with low acuity conditions and how these affect ambulance (AMB) utilization. METHODS: We performed a prospective, observational study on a convenience sample of patients 18years or older, who presented to the ED of an urban, academic hospital with an Emergency Severity Index (ESI) triage level of 4 or 5. Demographics, treatment, and disposition data were obtained along with self-administered surveys. Characteristics of patients with low acuity conditions who presented to the ED by AMB were compared to the patients who came to the ED by private transportation (PT). Data were analyzed with the chi-square test, t-test, and Mann-Whitney test. RESULTS: A total of 197 patients (97 AMB and 100 PT) were enrolled. Compared to PT, AMB patients were more likely to: be insured (82% vs. 56%; p=0.000), have a primary care provider (62% vs. 44%; p=0.048), and lack a regular means of transportation (53% vs. 33%; p=0.005). Three surveys were used the SF-8, Short Test of Functional Health Literacy in Adults [STOFHLA], and Health Belief Model [HBM]. Answers to HBM showed patients perceive that their illness required care within one hour of arrival (38% vs. 21%; p=0.04), have used an ambulance in the past year (76% vs. 33%; p=0.001) and to utilize an ambulance in the future for similar concerns (53% vs. 15%; p=0.000). AMB patients were more likely to call an ambulance for any health concern (p=0.035) and felt that there were enough ambulances for all patients in the city (p=0.01). There were no differences in age, employment, level of income and education, nor hospital admission rate between groups. CONCLUSIONS: Ambulance use in low-acuity ED patients is associated with misperceptions regarding severity of illness and resource allocation as well as limited access to private transportation. Understanding patient perceptions of illness and other barriers to receiving care is imperative for the development of interventions aimed at enabling change in health behaviors such as the elective use of limited resources. PMID- 29277494 TI - Accessory occipital suture mimicking fracture in head trauma. AB - The occipital bone is a complex structure due to its anatomy and accessory sutures. Fracture - accessory suture differential diagnosis should be performed carefully in patients with a history of head trauma [4]. In this case report we wanted to emphasize that accessory sutures can be difficult to diagnose in patients with head trauma. We also specified the points to be considered in the suture - fracture differentional diagnosis. A bilateral, symmetrical fissure line was observed in the occipital bone basal part of the patient who was admitted to our emergency department due to head trauma. The patient was followed up with accessory suture and then discharged after paying attention to important points in the differential diagnosis. PMID- 29277495 TI - Clinical pharmacist understanding of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. AB - BACKGROUND: Clinical pharmacists are frequently involved in the management of dyslipidemia, yet clinical pharmacists' knowledge, awareness, and the level of agreement with the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guideline are unknown. OBJECTIVE: The objective of the study was to examine clinical pharmacists' knowledge, awareness, and the level of agreement with the 2013 ACC/AHA cholesterol guideline. METHODS: We administered a validated questionnaire via an online survey that was electronically mailed to clinical pharmacists. We compared responses between those in practice for <= 10 and those in practice for > 10 years, and according to practice specialty. RESULTS: The response rate was 11% (314 of 2845). Most respondents were from the Midwestern and Southeastern US, in practice for <= 10 years, and practiced in family practice/primary care. Nearly all (92%) respondents had read the guideline and 72% were able to identify the 4 statin benefit groups. Notable knowledge gaps included recalling the 4 outcomes of the 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimator (41.4%), understanding differences between the Framingham Risk Score and the ASCVD risk estimator (33.7%), and monitoring lipids after initiating a statin (41.1%). More knowledge gaps were identified in those practicing for > 10 years and who specialized in internal medicine. The use of the ASCVD risk estimator was high; yet nearly half (44.2%) were concerned whether the ASCVD risk estimator would overestimate 10-year ASCVD risk. CONCLUSION: Although most clinical pharmacists had read the 2013 ACC/AHA cholesterol guideline, several knowledge gaps were identified, especially among those with more experience and those practicing in internal medicine. Targeted education efforts are needed to address these gaps. PMID- 29277496 TI - Right Ventricular Pseudoaneurysm After Percutaneous Tricuspid Valve-in-valve Implantation. PMID- 29277497 TI - Superior oblique myokymia treated with levobunolol. AB - Superior oblique myokymia (SOM) is an uncommon condition of unclear etiology that results in episodes of oscillopsia and diplopia. There is no established treatment protocol for SOM. We present 2 cases of SOM successfully managed with topical levobunolol 0.5%; both patients responded to a short course of medication administration and required minimal ongoing therapy. Case 1 was a 69-year-old woman with left SOM who had previously undergone a left Harada-Ito procedure. Her SOM improved immediately on administration of levobunolol and was maintained at follow-up 1 year later. Case 2 was a 49-year-old man with right SOM that affected his ability to work. After 2 days of topical levobunolol 0.5% nightly in the right eye, SOM episodes ceased; he continues to use drops intermittently for occasional recurrences. PMID- 29277498 TI - Retinal astrocytoma regression in tuberous sclerosis patients treated with everolimus. AB - Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) that has been approved by the US Food and Drug Administration for the treatment of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC). Retinal hamartomas, which are one of the major diagnostic features of TSC, tend to remain stable or gradually progress in the natural history of the disease. We report 2 patients with TSC treated with everolimus for SEGA in whom fundus photographs and spectral domain optical coherence tomography demonstrated regression of previously documented multiple retinal hamartomas in all 4 eyes. PMID- 29277499 TI - [Association between the viruses of the acquired immunodeficiency syndrome and the hepatitis C virus among young blood donors in Kinshasa: Retrospective analysis of 10 years]. AB - STUDY OBJECTIVES: The screening of anti-Human Immunodeficiency Virus antibodies is mandatory in every blood donor admitted to the Blood Bank of Kinshasa University Clinics since 1984. However, no compiled data are available to date. The objective of this study was to establish the trend, prevalence, viral co infections, and determinants of Human Immunodeficiency anti-Virus serology in blood donors admitted between 2003-2006 and 2008-2013. PATIENTS AND METHODS: A retrospective analysis was carried out at University Kinshasa Clinics, using blood donors' records during 2003-2006 and 2008-2013. The prevalence of the human immunodeficiency virus per year, age, sex and type of blood donors were estimated. Independent predictors of human immunodeficiency virus seropositivity were also identified. RESULTS: Out of 26,341 blood donors, 2.2% (n=576/26,341) were seropositive for Human Immunodeficiency Virus. Age<25 years (OR=1.7; 95% CI: 1.4-2; P<0.0001) and Hepatitis C virus seropositivity (OR=3; 95% CI; 1.8-4.9; P<0.001) emerged as independent predictors of Human Immunodeficiency Virus seropositivity. CONCLUSION: This study shows a strong association between the Human Immunodeficiency Virus and hepatitis C and younger age respectively. Further studies are needed to ensure safety of Blood donation in Democratic Republic of Congo. PMID- 29277500 TI - Distribution of the internal nasal branch of the infraorbital nerve to the nasal septum: Application to rhinoplasty. AB - BACKGROUND: The course of the nerves along the nasal septum has not been clearly studied, and surgical procedures such as rhinoplasty require a more detailed topography of the nerve supply inside the septum. Therefore, we aimed to investigate the distribution of the internal nasal branch of the infraorbital nerve inside the nasal septum and to define the relationship between it and the nasal cartilages. METHODS: Fourteen sides from eight fresh frozen and embalmed Caucasian cadaveric heads were dissected. The specimens were derived from three males and five females. The ages of the cadavers at death ranged from 65 to 84 years. The course of the internal nasal branch and its relationship between the nasal cartilages were observed using a surgical microscope. RESULTS: On all sides, the internal nasal branch approached the medial crus of the major alar cartilage from behind and traveled anteriorly below the medial crus of the major alar cartilage while giving off anterior inferior septal, middle inferior septal, and posterior inferior septal branches. CONCLUSIONS: Based on the results of this study, we suggest that procedures of the nasal cavity such as rhinoplasty could be modified to avoid injuring the main trunk of the internal nasal branch of the infraorbital nerve inside the nasal septum. PMID- 29277501 TI - The role of angiogenesis, inflammation and estrogen receptors in breast implant capsules development and remodeling. AB - BACKGROUND: Capsular contracture is the most common complication following breast implant placement. The multiple factors unbalancing the physiological response to the foreign body have not been fully elucidated. The aim of this study was to investigate the role of neo-angiogenesis, inflammation and estrogen receptors in peri-prosthetic tissue development and remodeling. METHODS: The study enrolled 31 women who underwent expander substitution with definitive implant. Specimens were stained with hematoxylin/eosin, Masson trichrome, immunohistochemistry and immunofluorescence for alpha-smooth muscle actin, estrogen receptor-alpha (ER alpha), estrogen receptor-beta (ER-beta), Collagen type I and III, CD31 (as a marker of neo-angiogenesis) and vascular endothelial growth factor (VEGF). Inflammatory infiltration was quantified and analyzed. Transmission electron microscopy was performed for ultrastructural evaluation. RESULTS: Myofibroblasts, mainly localized in the middle layer of capsular tissue, expressed VEGF, ER-alpha and ER-beta. ER-beta expression positively correlated with Collagen type I deposition (p= 0.025). Neo-angiogenesis was predominant in the middle layer. CD31 expression positively correlated with Collagen type I expression (p=0.009) and inflammatory infiltration grade (p= 0.004). The degree of inflammatory infiltration negatively correlated with the time from implantation (p = 0.022). DISCUSSION: The middle layer is key in the development and remodeling of capsular tissue. Myofibroblasts produce VEGF, that induces neo-angiogenesis. New vessels formation is also correlated to the inflammatory response. Collagen deposition is associated with ER-beta expression and neo-angiogenesis. These findings may prelude to targeted pharmacologic therapies able to control such interactions, thus hampering the self-sustaining loop promoting the progression of physiologic fibrosis toward pathologic contracture. PMID- 29277502 TI - Tiam1 promotes thyroid carcinoma metastasis by modulating EMT via Wnt/beta catenin signaling. AB - Aberrant expression of the guanine nucleotide exchange factor Tiam1 is implicated in the invasive phenotype of many cancers. However, its involvement in thyroid carcinoma and downstream molecular events remains largely undefined. Here, we examined the effects of Tiam1 on the invasiveness and metastasis of thyroid carcinoma in vitro and in vivo and explored the underlying mechanisms by investigating the regulation of Tiam1 expression and the downstream pathways affected. Our results showed that Tiam1 knockdown inhibited the migratory and invasive capacity of thyroid cancer cells, suppressed epithelial-mesenchymal transition (EMT), and inhibited Wnt/beta-catenin signaling in vitro. Moreover, Tiam1 knockdown suppressed liver metastasis development in vivo. The effects of Tiam1 on metastasis and EMT mediated by the Wnt/beta-catenin pathway were reversed by Rac1 silencing, suggesting that the prometastatic effect of Tiam1 is mediated by the activation of Rac1. These results indicate that Tiam1 may be a prognostic factor and potential therapeutic target for the treatment of thyroid cancers. PMID- 29277503 TI - Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. AB - Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) are both potent immune-modulators. The aberrant proliferation and function of Tregs plays an important role in the development of asthma. Our previous studies have demonstrated the role of MSCs in promoting proliferation and immune-modulating of Tregs, as well as alleviating airway inflammation of asthmatic mice. In the present study, we isolated exosomes secreted by MSCs and investigated their immunomodulation effect on peripheral blood mononuclear cells (PBMCs) of asthmatic patient. We found that MSC exosomes upregulated IL-10 and TGF-beta1 from PBMCs, thus promoting proliferation and immune-suppression capacity of Tregs. Furthermore, antigen presenting cells (APCs) but not CD4+ T cells dependent pathway was shown to be possible mechanism involved in MSC exosome mediated regulation. Our data elucidated the key role of exosomes in immune modulation of MSCs, and suggested the therapeutic potential of MSC exosomes for asthma. PMID- 29277504 TI - SPARC is down-regulated by DNA methylation and functions as a tumor suppressor in T-cell lymphoma. AB - The aim of this study was to assess the functional role of SPARC in T-cell non Hodgkin's lymphoma (T-NHL), as well as the underlying molecular mechanisms. Here, we first identified SPARC expression in T-NHL tissues and cell lines through western blot and real-time PCR (RT-PCR). Overall survival of T-NHL patients with different levels of SPARC was assessed by Kaplan-Meier survival curves. Then cell proliferation, apoptosis, migration and invasion of T-NHL cells with either knockdown or overexpression of SPARC were determined by MTT, flow cytometry, transwell migration and invasion assay, respectively. Finally, the molecular mechanism by which SPARC modulated T-NHL cell progression was assessed. We confirmed that SPARC was significantly down-regulated in T-NHL tissues and cell lines. T-NHL patients with high levels of SPARC demonstrated a favorable clinical outcome. SPARC significantly suppressed cell proliferation, migration and invasion, and EMT process, but facilitated cell apoptosis in T-NHL cells. Further, we found that loss of SPARC expression in T-NHL tissues and cell lines, both in mRNA and protein levels, was associated with the aberrant DNA methylation in SPRAC gene, and the disrupted SPARC expression could be rescued after treatment with the demethylating agent 5-Aza-2'-deoxycitydine (5-Aza-Cdr). Additionally, 5-Aza-Cdr reversed SPARC hypermethylation to restore its biological role as a tumor suppressor in T-NHL cells, including inhibiting cell proliferation, invasion and migration, while promoting cell apoptosis. Our data provided evidence that DNA methylation in SPARC gene may play a role in the progression of T-NHL. PMID- 29277505 TI - Collagen prolyl hydroxylase 3 has a tumor suppressive activity in human lung cancer. AB - Collagen prolyl hydroxylases (P3H) are required for proper collagen biosynthesis. One of the family members P3H3 was downregulated in breast cancer and lymphoma due to DNA methylation. However the role of P3H3 in lung cancer has not yet been elucidated. In this study, we analyzed P3H3 expression in a panel of lung cancer cell lines and primary lung tumors. Epigenetic regulation was explored and the function of P3H3 was investigated by stable transfection and RNA interference. We found that P3H3 was downregulated in 6 out of 10 lung cancer cell lines. A heterogeneous methylation pattern of P3H3 was found in the exon region. In primary lung tumors, immunohistochemistry on tissue microarray (TMA) showed that higher expression of P3H3 was significantly associated with lower tumor N stage and grade (p = 0.035 and p = 0.026, respectively). Ectopic expression of P3H3 inhibited cell proliferation, colony formation, migration as well as invasion, and induced apoptosis together with cell cycle arrest in the G2/M phase. Knockdown of P3H3 led to increased migratory and invasive potential. These Phenomena are accompanied by enhanced p21, decreased cyclin A1 levels and increased caspase 3/7 activities. Taken together, we feel that P3H3 is a novel tumor suppressor and its protein expression is inversely related to lymph node metastasis and tumor differentiation in lung cancer. PMID- 29277506 TI - High-Output Cardiac Failure and Coronary Steal With an Arteriovenous Fistula. AB - Creation of an arteriovenous access for hemodialysis can provoke a sequence of events that significantly affects cardiovascular hemodynamics. We present a 78 year-old man with end-stage renal disease and concomitant coronary artery disease previously requiring coronary artery bypass grafting including a left internal mammary graft to the left anterior descending artery, ischemic cardiomyopathy with left ventricular systolic dysfunction, and severe aortic stenosis who developed hypotension unresponsive to medical therapy after recent angioplasty of his ipsilateral arteriovenous fistula for high-grade outflow stenosis. This case highlights the long-term effects of dialysis access on the cardiovascular system, with special emphasis on complications such as high-output cardiac failure and coronary artery steal syndrome. Banding of the arteriovenous fistula provided symptomatic relief with a decrease in cardiac output. Avoidance of arteriovenous access creation on the ipsilateral upper extremity in patients with a left internal mammary artery bypass graft may prevent coronary artery steal syndrome. PMID- 29277507 TI - Osmotic Demyelination Unrelated to Hyponatremia. AB - Osmotic demyelination unrelated to hyponatremia is rarely reported. We present a case of osmotic demyelination in a patient with hypernatremia in the absence of preceding hyponatremia and review previously reported cases of osmotic demyelination in nonhyponatremic patients. We conclude that a rapid increase in serum sodium concentration and plasma tonicity even in the absence of preceding hyponatremia may surpass the brain's capacity for adaptation to hypertonicity and lead to osmotic demyelination in predisposed individuals. Risk factors for osmotic demyelination in patients with chronic hyponatremia and without hyponatremia are probably similar and are usually associated with states of limited brain osmolyte response, such as alcoholism, liver disease (including those undergoing orthotopic liver transplantation), malnutrition, malignancy, pregnancy/postpartum state, severe illness/sepsis, adrenal insufficiency, and metabolic derangements. Clinicians should be vigilant in identifying individuals who may, even in the absence of hyponatremia, have increased susceptibility to osmotic demyelination and avoid rapid fluctuations in serum sodium concentrations in such patients. PMID- 29277508 TI - Risk Predictors and Causes of Technique Failure Within the First Year of Peritoneal Dialysis: An Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) Study. AB - BACKGROUND: Concern regarding technique failure is a major barrier to increased uptake of peritoneal dialysis (PD), and the first year of therapy is a particularly vulnerable time. STUDY DESIGN: A cohort study using competing-risk regression analyses to identify the key risk factors and risk periods for early transfer to hemodialysis therapy or death in incident PD patients. SETTING & PARTICIPANTS: All adult patients who initiated PD therapy in Australia and New Zealand in 2000 through 2014. PREDICTORS: Patient demographics and comorbid conditions, duration of prior renal replacement therapy, timing of referral, PD modality, dialysis era, and center size. OUTCOMES: Technique failure within the first year, defined as transfer to hemodialysis therapy for more than 30 days or death. RESULTS: Of 16,748 patients included in the study, 4,389 developed early technique failure. Factors associated with increased risk included age older than 70 years, diabetes or vascular disease, prior renal replacement therapy, late referral to a nephrology service, or management in a smaller center. Asian or other race and use of continuous ambulatory PD were associated with reduced risk, as was initiation of PD therapy in 2010 through 2014. Although the risk for technique failure due to death or infection was constant during the first year, mechanical and other causes accounted for a greater number of cases within the initial 9 months of treatment. LIMITATIONS: Potential for residual confounding due to limited data for residual kidney function, dialysis prescription, and socioeconomic factors. CONCLUSIONS: Several modifiable and nonmodifiable factors are associated with early technique failure in PD. Targeted interventions should be considered in high-risk patients to avoid the consequences of an unplanned transfer to hemodialysis therapy or death. PMID- 29277509 TI - Mortality and Allograft Loss Trends Among US Pediatric Kidney Transplant Recipients With and Without Focal Segmental Glomerulosclerosis. AB - BACKGROUND: Pediatric patients with focal segmental glomerulosclerosis (FSGS) have high rates of disease recurrence and allograft failure after kidney transplantation, but there are few data for long-term survival posttransplantation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 12,303 pediatric patients (aged <18 years), including 1,408 (11%) patients with FSGS, who received a first kidney transplant in 1990 through 2009 and were followed up through June 2015 were identified from the US Renal Data System database. PREDICTORS: Primary cause of end-stage renal disease, FSGS or other. OUTCOMES: All-cause patient mortality and allograft loss. RESULTS: All cause mortality significantly improved for patients with FSGS who underwent transplantation in the 2000s versus the 1990s (6.72 vs 12.24 deaths/1,000 patient years; HR, 0.55; 95% CI, 0.39-0.78; P<0.001). Reductions in allograft loss were less dramatic (75.91 vs 89.05 events/1,000 patient-years; HR, 0.85; 95% CI, 0.74 0.98; P=0.02). After adjusting for baseline characteristics at the time of transplantation, patients with FSGS had similar rates of death compared with patients without FSGS (HRs of 0.81 [P=0.6] and 1.06 [P=0.2] among those who underwent transplantation in the 2000s and 1990s, respectively) despite higher rates of allograft loss (HRs of 1.17 [P=0.03] and 1.27 [P<0.001], respectively). Among patients who underwent transplantation in the 2000s, further adjustment for allograft failure as a time-varying covariate demonstrated a lower rate of death among patients with FSGS compared with those without FSGS (HR, 0.70; P=0.02). LIMITATIONS: Lack of information about certain risk factors for mortality, including duration of chronic kidney disease; missing data; and potential primary disease misclassification. CONCLUSIONS: Survival of pediatric kidney transplant recipients with FSGS improved between the 1990s and 2000s and was similar to that of recipients without FSGS. Interestingly, adjustment for allograft failure showed greater survival for pediatric patients with FSGS who underwent transplantation in the 2000s as compared with others, suggesting that effective interventions to decrease allograft loss due to disease recurrence may improve patient survival. PMID- 29277511 TI - Health Insurance and the Use of Peritoneal Dialysis in the United States. AB - BACKGROUND: Many patients in the United States have limited or no health insurance at the time they develop end-stage renal disease (ESRD). We examined whether health insurance limitations affected the likelihood of peritoneal dialysis (PD) use. STUDY DESIGN: Retrospective cohort analysis of patients from the US Renal Data System initiating dialysis therapy in 2006 through 2012. SETTING & PARTICIPANTS: We identified socioeconomically similar groups of patients to examine the association between health insurance and PD use. Patients aged 60 to 64 years with "limited insurance" (defined as having Medicaid or no insurance) at ESRD onset were compared with patients aged 66 to 70 years who were dually eligible for Medicare and Medicaid at ESRD onset. PREDICTOR: Type of insurance coverage at ESRD onset. OUTCOMES: The likelihoods of receiving PD before dialysis month 4, when all patients qualified for Medicare due to ESRD, and of switching to PD therapy following receipt of Medicare. RESULTS: After adjusting for observable patient and geographic differences, patients with limited insurance had an absolute 2.4% (95% CI, 1.1%-3.7%) lower probability of PD use by dialysis month 4 compared with patients with Medicare at ESRD onset. The association between insurance and PD use reversed when patients became Medicare eligible; patients with limited insurance had a 3-fold higher rate of switching to PD therapy between months 4 and 12 of dialysis (HR, 2.9; 95% CI, 1.8 4.6) compared with patients with Medicare at ESRD onset. LIMITATIONS: Because this study was observational, there is a potential for bias from unmeasured patient-level factors. CONCLUSIONS: Despite Medicare's policy of covering patients in the month that they initiate PD therapy, insurance limitations remain a barrier to PD use for many patients. Educating providers about Medicare reimbursement policy and expanding access to pre-ESRD education and training may help overcome these barriers. PMID- 29277510 TI - HLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid Resistant Nephrotic Syndrome. AB - BACKGROUND: Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium. FACTOR: Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles. OUTCOMES: SSNS and SRNS. MEASUREMENTS: Direct sequencing for the HLA DQA1 and APOL1 variants in 115 African American children (65 with SSNS and 50 with SRNS). Imputation of classic HLA alleles and amino acids was done in 363 South Asian children. RESULTS: The 2 HLA-DQA1 variants were significantly associated with SSNS in African American children (C34Y: P=5.7 * 10-11; OR, 3.53; 95% CI, 2.33-5.42; F41S: P=1.2 * 10-13; OR, 4.08; 95% CI, 2.70-6.28), but not with SRNS (C34Y: P=0.6; F41S: P=0.2). APOL1 high-risk variants were not associated with SSNS (P=0.5) but showed significant associations with SRNS (P=1.04 * 10-7; OR, 4.17; 95% CI, 2.23-7.64). HLA-DQA1*0201, HLA-DQB1*0201, and HLA-DRB1*0701 were the classic HLA alleles with the most significant associations with SSNS risk. The most significantly associated amino acid positions were HLA DQalpha1 56 and 76 (both P=2.8 * 10-7). Conditional analysis revealed that these variants most likely account for the observed association. LIMITATIONS: Modest sample size and limited statistical power to detect small to moderate effect sizes. Children studied may not be representative of all African American children in the United States. CONCLUSIONS: HLA-DQA1 is a risk locus for SSNS, but not SRNS, in African American children, consistent with its role in SSNS risk in children of European, Asian, and African ancestries. There is little evidence of a significant role for the APOL1 high-risk alleles in childhood SSNS in African American children. Refinement of the HLA-DQA1 association identified the critical classic HLA antigen types and amino acids of the HLA-DQ alpha1 molecule. PMID- 29277512 TI - Impact of blood manufacturing and donor characteristics on membrane water permeability and in vitro quality parameters during hypothermic storage of red blood cells. AB - Several factors have been proposed to influence the red blood cell storage lesion including storage duration, blood component manufacturing methodology, and donor characteristics [1,18]. The objectives of this study were to determine the impact of manufacturing method and donor characteristics on water permeability and membrane quality parameters. Red blood cell units were obtained from volunteer blood donors and grouped according to the manufacturing method and donor characteristics of sex and age. Membrane water permeability and membrane quality parameters, including deformability, hemolysis, osmotic fragility, hematologic indices, supernatant potassium, and supernatant sodium, were determined on day 5 +/- 2, day 21, and day 42. Regression analysis was applied to evaluate the contribution of storage duration, manufacturing method, and donor characteristics on storage lesion. This study found that units processed using a whole blood filtration manufacturing method exhibited significantly higher membrane water permeability throughout storage compared to units manufactured using red cell filtration. Additionally, significant differences in hemolysis, supernatant potassium, and supernatant sodium were seen between manufacturing methods, however there were no significance differences between donor age and sex groups. Findings of this study suggest that the membrane-related storage lesion is initiated prior to the first day of storage with contributions by both blood manufacturing process and donor variability. The findings of this work highlight the importance of characterizing membrane water permeability during storage as it can be a predictor of the biophysical and chemical changes that affect the quality of stored red blood cells during hypothermic storage. PMID- 29277513 TI - Risk Factors, Treatment, and Immune Dysregulation in Autoimmune Cytopenia after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients. AB - Autoimmune or alloimmune cytopenia (AIC) is a known rare complication of hematopoietic stem cell transplantation (SCT). AIC after SCT is considered difficult to treat and is associated with high morbidity and mortality. In this retrospective study in pediatric patients we evaluated incidence, outcome, potential risk factors, and current treatment strategies. A nested matched case control study was performed to search for biomarkers associated with AIC. Of 531 consecutive SCTs at our center between 2000 and 2016, 26 were complicated by the development of AIC (cumulative incidence, 5.0%) after a median of 5 months post SCT. Autoimmune hemolytic anemia was the most common AIC with 12 patients (46%). We identified nonmalignant disease, alemtuzumab serotherapy pre-SCT, and cytomegalovirus (CMV) reactivation as independently associated risk factors. The cytokine profile of patients at the time of AIC diagnosis appeared to skew toward a more pronounced Th 2 response compared with control subjects at the corresponding time point post-SCT. Corticosteroids and intravenous immunoglobulin as first-line treatment or a wait-and-see approach led to resolution of AIC in 35% of cases. Addition of step-up therapies rituximab (n = 15), bortezomib (n = 7), or sirolimus (n = 3) was associated with AIC resolution in 40%, 57%, and 100% of cases, respectively. In summary, we identified CMV reactivation post-SCT as a new clinical risk factor for the development of AIC in children. The cytokine profile during AIC appears to favor a Th 2 response. Rituximab, bortezomib, and sirolimus are promising step-up treatment modalities. PMID- 29277514 TI - Hip resurfacing before 50years of age: A prospective study of 979 hips with a mean follow-up of 5.1years. AB - BACKGROUND: Hip resurfacing arthroplasty (HRA) is an alternative to total hip arthroplasty (THA) for the treatment of hip osteoarthritis in patients younger than 50 years. Data on revision rates after HRA are conflicting. The National Institute for Health and Care Excellence (NICE) recommends performing only those hip arthroplasty procedures associated with 10-year revision rates no greater than 5% (0.5% per year). Follow-up studies can rapidly determine whether this criterion is met. The uncertainties surrounding revision rates after HRA prompted us to design a study of prospectively enrolled patients aiming (1) to determine the revision rate after HRA performed before 50years of age and (2) to assess the functional, radiological, and biological outcomes of HRA. HYPOTHESIS: The revision rate after HRA performed before 50years of age meets the NICE criterion. MATERIAL AND METHODS: Consecutive patients undergoing HRA before 50years of age were enrolled prospectively. The same implant was used in all patients. Functional outcomes were assessed based on the Harris Hip Score (HHS), Postel Merle d'Aubigne (PMA) score, 12-item Oxford Hip Score (OHS), and UCLA activity score. Radiographic outcomes were assessed, and blood levels of chromium and cobalt were assayed. RESULTS: The study included 936 patients (979 HRAs) with a mean age of 42.7years (16.4-50.0years) at surgery and a mean follow-up of 5.1years (range: 3.1-9.0 years). All four mean functional scores were significantly improved at last follow-up vs. baseline: HHS, 95.9 (39.0-100) vs. 44.3 (18.0-83.0); PMA score, 17.6 (6.0-18.0) vs. 11.7 (3.0-16.0); OHS, 14.3 (12.0 37.0) vs. 40.6 (25.0-60.0); and UCLA activity score, 7.8 (2.0-10.0) vs. 5.6 (1.0 10.0) (p<0.0001). Mean cup inclination in the coronal plane was 42.1 degrees (25.0 degrees -68.0 degrees ). Mean blood cobalt level was significantly higher at last follow-up than at baseline (1.36MUg/L [0.05-8.2MUg/L] vs. 0.61MUg/L [0.01 3.6]) (p<0.001). No patient experienced dislocation. Revision was required for 17 hips and involved changing the implant in 12 (1.2%). The 10-year survival rate with implant change, as the endpoint was 98.7% (95%CI, 97.6%-99.3%), indicating that the NICE criterion was easily met. DISCUSSION: The NICE criterion allows the rapid identification of prostheses with insufficient survival. HRA is theoretically associated with a high risk of aseptic mechanical loosening, as it is performed in young patients who have a high level of physical activity. Nevertheless, our study showed that implant survival after HRA was better than required by the NICE criterion. Thus, HRA is a valid alterative to THA in patients younger than 50years. LEVEL OF EVIDENCE: IV, prospective study with no control group. PMID- 29277515 TI - Complications with cement spacers in 2-stage treatment of periprosthetic joint infection on total hip replacement. AB - INTRODUCTION: The aim of the present study was to assess our management of infected total hip replacement in indications for 2-stage surgical treatment according to current guidelines when a cement spacer has been used. The study hypothesis was that the complications rate related to cement spacers is low. MATERIAL AND METHOD: A single-center retrospective study included 26 patients receiving a spacer between the two stages of total hip replacement, over a 5 year period. We analyzed the spacers used, mechanical complications, infectious complications and the second stage of surgery. RESULTS: During the interval between surgeries, in the 26 patients, there were 19 spacer-related mechanical complications (73% of patients): 11 dislocations (42.3%), 5 spacer fractures (19.2%), 5 femoral bone lyses or fractures (19.2%) and 3 acetabular lyses or fractures (11.5%). In 4 cases, complications were associated. The greater the femoral offset of the spacer, the more frequent were femoral bone lyses or fractures (p=0.05), and the smaller the offset the more frequent were acetabular lyses or fractures (p=0.05). The rates of mechanical complications (p=0.003) and spacer fracture (p=0.02) were significantly greater in older patients. There were 4 cases of reinfection (19%): i.e., an 81% treatment success rate. One reinfection implicated a new bacterium: methicillin-susceptible Staphylococcus aureus. The second surgical stage was significantly longer in complex bipolar revision (p=0.009). CONCLUSION: The present results showed a high risk of spacer related complications, and thus the importance of selection of patients liable to derive real benefit and those for whom a Gilderstone procedure would be preferable. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 29277516 TI - Course of dislocated posterior hip arthroplasty: A continuous 232-patient series at a mean 10 years' follow up (range, 1-22 years). AB - BACKGROUND: Dislocation rates in posterior total hip arthroplasty (THA) range between 2% and 5%, but long-term course (recurrence of dislocation or revision surgery) is not known, most series having short follow-up or small populations. We therefore conducted a retrospective study on a large series, to determine long term rates of recurrence and surgical revision and recurrence risk factors. HYPOTHESIS: Long-term follow-up of a large cohort of THA dislocations enables recurrence rate and factors to be determined. MATERIAL AND METHOD: Five hundred and nine cases of THA dislocation were admitted to our center between 1994 and 2008. A hundred and twenty seven incomplete files and 150 patients who had received their THA elsewhere were excluded, leaving 232 patients: 150 female, 82 male. Mean age at THA (163 primary, 69 revision) was 63 years (range, 15-90 years), and 65 years (range 20-90 years) at first dislocation, with a mean interval to dislocation of 25 months. Minimum follow-up was 8 years up to 2016, or 1 year taking account of deaths (111 deaths). There were 46 anterior, 185 posterior and 1 multidirectional dislocations. The following potential recurrence factors were assessed: gander, age, body-mass index (BMI), etiology, surgical history, bearing diameter and type, component fixation means, dislocation direction, and time to dislocation. RESULTS: A hundred and thirty three of the 232 patients (57%) showed at least 1 recurrence, at a mean 38 months (range, 0.5 252 months); 78 experienced a second and 32 a third recurrence. Ninety-nine (43%) had only 1 dislocation, without recurrence, but 17 of these (17%) underwent reoperation for other causes. The reoperation rate was 17/232 (7%) excluding recurrent instability, and 84/232 (36%) for instability. Fourty-eight months after the first dislocation, 84/133 cases of recurrence (63%) had been reoperated on: 16 complete replacements, 18 bearing replacements, 42 dual mobility cups, one large diameter cup, seven Lefevre retentive cups. The rate of revision surgery for instability was high, at 84/232 (36%), and higher again in relation to recurrence (84/133: 63%). Only posterior dislocation emerged as a factor for recurrence (HR=1.774, 95% CI [1.020-3.083]), the other tested factors showing no correlation.14 of the 84 revision surgeries for instability (16.6%) were followed by recurrence, without identifiable risk factors. CONCLUSION/DISCUSSION: The recurrence rate was 57%, with posterior dislocation as the only risk factor. The rate of revision surgery for recurrence was 84/232 (36%), with 14/84 revision procedures (16.6%) followed by further recurrence. LEVEL OF EVIDENCE: IV, retrospective, without control group. PMID- 29277517 TI - Corrigendum to ""Branched-chain amino acid supplementation and exercise-induced muscle damage in exercise recovery: a meta-analysis of randomized clinical trials"." Nutrition 42(10) (2017) 30-36. PMID- 29277519 TI - How to bridge the intention-behavior gap in food parenting: Automatic constructs and underlying techniques. AB - Although parents often report positive intentions to promote and create a healthy food environment for their children (e.g., setting limits to snacks offered), they also experience difficulties in translating these intentions into actual behaviors. In this position paper, we argue that automatic processes explain an important part of the gap between parents' intentions and their actual food parenting behaviors. We provide a conceptual framework in which we hypothesize that automatic effects on food parenting occur through two key interrelated constructs: habits (key outcome construct) and volitional regulation behaviors (key mediating construct). Moreover, we discuss potentially important impulse focused techniques that may directly change habits (e.g., nudging; inhibitory control training) or indirectly through volitional regulation behaviors (e.g., implementation intentions; mental contrasting). We make use of the literature on the role of intention-behavior discordance in general health behaviors and discuss implications for food parenting practices. Our framework provides a dual process view towards food parenting and may help to explain when and why parents are likely to engage in (un)healthy food parenting behaviors. In addition, this framework may hopefully stimulate research on (combinations of old and) new techniques to promote good food parenting behaviors. PMID- 29277518 TI - Validity of assessing child feeding with virtual reality. AB - Assessment of parents' child feeding behavior is challenging, and there is need for additional methodological approaches. Virtual reality technology allows for the creation of behavioral measures, and its implementation overcomes several limitations of existing methods. This report evaluates the validity and usability of the Virtual Reality (VR) Buffet among a sample of 52 parents of children aged 3-7. Participants served a meal of pasta and apple juice in both a virtual setting and real-world setting (counterbalanced and separated by a distractor task). They then created another meal for their child, this time choosing from the full set of food options in the VR Buffet. Finally, participants completed a food estimation task followed by a questionnaire, which assessed their perceptions of the VR Buffet. Results revealed that the amount of virtual pasta served by parents correlated significantly with the amount of real pasta they served, rs = 0.613, p < .0001, as did served amounts of virtual and real apple juice, rs = 0.822, p < .0001. Furthermore, parents' perception of the calorie content of chosen foods was significantly correlated with observed calorie content (rs = 0.438, p = .002), and parents agreed that they would feed the meal they created to their child (M = 4.43, SD = 0.82 on a 1-5 scale). The data presented here demonstrate that parent behavior in the VR Buffet is highly related to real-world behavior, and that the tool is well-rated by parents. Given the data presented and the potential benefits of the abundant behavioral data the VR Buffet can provide, we conclude that it is a valid and needed addition to the array of tools for assessing feeding behavior. PMID- 29277520 TI - The relevance of anhidrosis in Horner syndrome: Analysis of an image. PMID- 29277521 TI - Chorea/ballism secondary to non-ketotic hyperglycaemia: Report of 4 cases. PMID- 29277522 TI - The premonitory phase: A crucial stage in migraine. AB - INTRODUCTION: The premonitory phase comprises a wide range of symptoms that precede the onset of pain in a migraine episode by up to 48hours. Premonitory symptoms are often not recognised by patients but do have a significant impact on their quality of life. As these symptoms represent the first stage of a migraine attack, they are crucial in improving our understanding of the key points of the origin of migraine. DEVELOPMENT: This paper uses a question-answer format to review the main clinical studies analysing premonitory symptoms, their predictive capacity, the relationship between these symptoms and the biology of migraine, and the role of neuroimaging in the premonitory phase. Finally, we discuss the relevance of these symptoms as potential therapeutic targets in the future. CONCLUSIONS: This study of the premonitory phase has demonstrated that the hypothalamus plays an essential role in the origin of migraine attacks. We should consider the search for new targets in acute migraine treatment in order to act before the onset of the pain. This would imply a radical change in the lives of patients with migraine. PMID- 29277523 TI - Association between self-perceived psychological stress and transitory ischaemic attack and minor stroke: A case-control study. AB - INTRODUCTION: Stroke has a complex aetiopathogenesis influenced by numerous risk factors. There is growing interest in the study of the pathophysiological changes associated with stress and their potential relationship with cerebrovascular disease. The purpose of this paper is to assess the strength of association between exposure to stress and stroke. METHODS: We conducted a case-control study (1:1) to compare exposure to stress in a group of patients with a history of a first transient ischaemic attack (TIA) or minor stroke and in a control group. Participants were asked a subjective question about their perception of stress in the previous months and completed the standardised Effort-Reward Imbalance (ERI) questionnaire. Logistic regression models were used for data analysis. RESULTS: The study included data on 50 cases and 50 controls. There were no significant differences in demographic variables and economic, social, and employment status between cases and controls. Fifty percent of the cases reported moderate to severe stress, compared to 30% of controls (OR: 2.33; 95% CI: 1.02-5.30; P=.041). ERI questionnaire results found that greater effort at work (OR: 1.48; 95% CI: 1.19-1.83) and greater commitment is associated with stroke (OR: 1.34; 95% CI: 1.17-1.54), while higher reward constitutes a protective factor against the disease (OR: 0.71; 95% CI: 0.61-0.82). CONCLUSIONS: There is a strong association between self-perceived psychological stress and TIA. The imbalance between effort and reward at work is also clearly related to TIA. PMID- 29277524 TI - Stroke and cannabis use in patients with no cardiovascular risk factors: a systematic review of case reports. AB - INTRODUCTION: Cannabis and its synthetic analogues are currently the most widely consumed illicit substances worldwide. Multiple alterations have been linked to its use, including cerebrovascular disease (CVD) or stroke, whose association with the substance has been based mainly on the hypothesis of transient vasoconstriction, which explains a large proportion of the cases reported. However, epidemiological studies have not performed an individual analysis of patients without other cardiovascular risk factors, which may limit the estimation of the risk of stroke associated with cannabis use alone. DEVELOPMENT: A systematic literature review was conducted through Medline, EBSCOhost, EMBASE, Lilacs, and Scielo to gather case reports published before 13 May 2016 presenting patients with a diagnosis of CVD or transient ischaemic attack, a history of cannabinoid use, and no other cardiovascular risk factors. Key words such as stroke, cerebrovascular disease, cannabis, and marijuana, among others, were used. A total of 18 case reports were selected from the 566 references found. CONCLUSIONS: There is a wide variety of reports of stroke associated with cannabis use in patients with no other risk factors. Noteworthy findings were presentation at young age and a strong temporal association, which place cannabis use as a potential risk factor for this population in line with the epidemiological and pathophysiological studies in this area. PMID- 29277525 TI - Controlled clinical trials and efficacy: Report of a neurosurgical study. PMID- 29277526 TI - Dalbavancin in-vitro activity obtained against Gram-positive clinical isolates causing bone and joint infections in US and European hospitals (2011-2016). AB - BACKGROUND: Osteomyelitis is a difficult-to-treat infection that regularly involves prolonged use of systemic antibiotics. Dalbavancin has demonstrated activity against Gram-positive isolates, and has been considered as a candidate for the treatment of osteomyelitis in adults and children. This study evaluated the activity of dalbavancin against pathogens isolated from bone and joint infections (BJI). METHODS: Eight hundred and one Staphylococcus aureus, 160 coagulase-negative staphylococci (CoNS), 164 beta-haemolytic streptococci (BHS), 82 Enterococcus faecalis and 45 viridans group streptococci (VGS) causing BJI were collected consecutively (2011-2016) and tested for susceptibility by broth microdilution methods. RESULTS: S. aureus (64.0%) was the most common pathogen associated with BJI, followed by BHS (13.1%) and CoNS (12.8%). All S. aureus (33.3% meticillin-resistant) isolates were susceptible to dalbavancin, linezolid and vancomycin, while daptomycin and clindamycin showed susceptibility rates of 99.5% and 89.0%, respectively. The minimum inhibitory concentration (MIC) results for dalbavancin were at least eight-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS (63.1% meticillin resistant), followed by daptomycin, linezolid and vancomycin. All E. faecalis isolates were inhibited by dalbavancin at <=0.25 mg/L (US Food and Drug Administration susceptibility breakpoint), except for three vancomycin-resistant isolates. High susceptibility rates for ampicillin (98.8%), daptomycin (100.0%), linezolid (100.0%) and vancomycin (95.1%) were obtained against E. faecalis. Dalbavancin was very active against BHS (MIC90 <=0.03 ug/mL), and was the most active agent against VGS (highest MIC <=0.06 mg/L). Ceftriaxone, daptomycin and vancomycin were also active (93.3-100.0% susceptible) against VGS, whereas clindamycin (84.4% susceptible) had marginal activity. CONCLUSION: Dalbavancin appears to be a viable candidate for treating BJI/osteomyelitis caused by Gram positive cocci. PMID- 29277527 TI - High excess costs of infections caused by carbapenem-resistant Gram-negative bacilli in an endemic region. AB - The financial burden of antibiotic resistance is a serious concern worldwide. The aim of this study was to describe the excess costs associated with pneumonia, bacteraemia, surgical site infections and intra-abdominal infections (IAIs) caused by carbapenem-resistant Gram-negative bacilli in Medellin, Colombia, an endemic region for carbapenem resistance. A cohort study was conducted in a third level hospital from 2014-2015. All patients with carbapenem-resistant and carbapenem-susceptible Gram-negative bacterial infections were included. Pharmaceutical, medical and surgical direct costs were described from the health system perspective. Excess costs were estimated from generalised linear models with gamma distribution and adjusted for variables that could affect the cost difference. A total of 218 patients were enrolled, 48 (22.0%) of whom were infected with carbapenem-resistant bacteria. IAIs were the most frequent. The adjusted total excess cost was US$3966 [95% confidence interval (CI) US$1684 6249], with a significantly higher cost for antibiotics, followed by hospital stay, laboratory tests and interconsultation. The highest excess cost was attributed mainly to the use of broad-spectrum antibiotics (US$1827, 95% CI US$1005-2648), followed by length of hospital stay (US$1015, 95% CI US$163-1867). The results of this study highlight the importance of designing antimicrobial stewardship programmes and infection control strategies in endemic regions to reduce the financial threat of antimicrobial resistance to health systems. PMID- 29277528 TI - Determinants of inappropriate empirical antibiotic treatment: systematic review and meta-analysis. AB - This systematic review assessed study-level determinants of non-covering (inappropriate) empirical antibiotic treatment (IEAT), focusing on the influence of study years and the prevalence of multidrug-resistant organisms (MDROs) in the study. Prospective and retrospective observational studies reporting on the association between IEAT and mortality in adult patients with microbiologically documented infections published between 2008-2016 were included. A meta-analysis of IEAT rates was conducted using a random-effects model. Subgroup analyses and mixed-effect single-covariate meta-regression were conducted to identify the association between clinical and methodological study-level covariates and IEAT rates. Heterogeneity was assessed using the I2 measure of inconsistency. Multi covariate meta-regression was conducted including variables with a P-value of <0.1 on single-covariate analysis. A total of 191 studies were included assessing 73 595 patients, most commonly with bacteraemia. The pooled IEAT event rate was 32% [95% confidence interval (CI) 30-35%], with large heterogeneity (I2 = 97.7%). On multi-covariate analyses, the prevalence of any MDRO [odds ratio (OR) per 10% increase in prevalence = 1.11, 95% CI 1.07-1.15], Acinetobacter spp. specifically (OR = 1.99, 95% CI 1.22-3.25) and advancing study years were associated with IEAT rates (OR = 1.03, 95% CI 1.00-1.06 per year). MDRO rates were independently associated with mortality rates in the studies, adjusting to the rate of IEAT. The prevalence of MDROs, mainly multidrug-resistant Gram-negative bacteria, is significantly associated with the probability of prescribing IEAT and mortality rates in recent studies. We show how antibiotic resistance impacts patient management and outcomes. PMID- 29277529 TI - Comparative genomics of rmtB-carrying IncI1 ST136 plasmids in avian escherichia coli isolates from chickens in China. AB - Eight rmtB-carrying avian Escherichia coli strains from a farm in China were characterised in our previous study, but little is known about the backbones and entire multiresistance regions (MRRs) of these plasmids. Here, three rmtB carrying IncI1 ST136 plasmids were analysed by whole-plasmid sequencing and were compared. These plasmids were composed of an 83 470-bp IncI1 backbone carrying genes responsible for plasmid replication, transfer, maintenance and stability functions, as well as a 17 330-bp MRR for pEC006 and pEC007, and a 34 626-bp MRR for pEC008. Plasmid pEC006 was not transferable, thus truncation of the traI gene may explain the inability to conjugate. pEC008 harboured the blaTEM-1, rmtB, aacC2, tetA, floR and strAB genes as well as a class 1 integron cassette array (|dfrA12|orfF|aadA2|), which were interspersed with different mobile elements, including Tn2, Tn1721, Tn1722, Tn5393, ISCfr1, IS5057, ISCR1 and ISCR2, and three copies of IS26. The MRR of pEC008 may have resulted from transposition of Tn1722 into the plasmid backbone. Acquisition and rearrangement of MRRs demonstrated the accumulation of different resistance determinants. PMID- 29277530 TI - Antibacterial activity of high concentrations of carvedilol against Gram-positive and Gram-negative bacteria. AB - Many drugs used to treat non-infectious diseases have also shown excellent antibacterial activity or the ability to enhance the action of antibiotics. The aim of this study was to investigate the antibacterial activity of a popular beta blocker, carvedilol, and its mechanism of antibacterial action. The antibacterial activity of carvedilol was evaluated using the microdilution method and its influence on the viability of bacterial cells was investigated by the alamarBlue(r) test. Changes in phospholipid and fatty acid composition were analysed using LC-MS/MS and GC-MS techniques. The permeability of bacterial cell membranes following exposure to carvedilol was studied using propidium iodide staining and confocal microscopy. The ability of the tested bacteria to degrade carvedilol was examined by LC-MS/MS. In this study, the antibacterial activity of carvedilol is described for the first time, with a decrease in the viability of all assayed bacteria observed following treatment with the beta-blocker. Staphylococcus aureus and Staphylococcus epidermidis were found to be the most sensitive among the tested strains. Significant modifications to fatty acid composition were observed in S. aureus incubated with carvedilol. Moreover, the cell membrane permeability of bacteria incubated with carvedilol was higher for Gram-positive bacteria than for Gram-negative bacteria. Furthermore, Gram negative Escherichia coli and Pseudomonas aeruginosa strains, which were highly resistant to carvedilol, exhibited an ability to eliminate carvedilol from the growth medium. In addition, three carvedilol metabolites were identified in E. coli and P. aeruginosa cultures. The antibacterial activity of carvedilol may suggest its potential usefulness in the synthesis of new antibacterial drugs. PMID- 29277531 TI - Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients. AB - Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration-time data. The mean +/- standard deviation parameter estimates were 8.38 +/- 9.91 L/h for drug clearance and 25.54 +/- 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC <=16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance. PMID- 29277532 TI - Levels of Interleukin-1beta, Interleukin-18, and Tumor Necrosis Factor-alpha in Cerebrospinal Fluid of Aneurysmal Subarachnoid Hemorrhage Patients May Be Predictors of Early Brain Injury and Clinical Prognosis. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe cerebrovascular accident with high morbidity and mortality. The aim of this study is to investigate the relationship between level of inflammatory cytokines in cerebrospinal fluid (CSF) of aSAH patients, the severity of aSAH, and the outcome of aSAH patients. METHODS: aSAH patients were prospectively included and followed up for 6 months. CSF samples were collected at 1-3, 4-6, and 7-9 days after aSAH onset. Levels of interleukin (IL)-1beta, IL-18, and tumor necrosis factor-alpha (TNF-alpha) in the CSF of aSAH patients were measured by enzyme-linked immunosorbent assay. RESULTS: Eighty-one aSAH patients were enrolled. The levels of IL-1beta, IL-18 and TNF-alpha in the CSF were especially higher in the group of aSAH patients with cerebral edema, cerebral vasospasm, and a high grade on Hunt-Hess scale, the high World Federation of Neurological Surgeons grades, and Fisher grade (P < 0.01). Higher levels of plasma C-reactive protein in the blood were correlated with poor outcome. The areas under the receiver operating characteristic curves for the levels of inflammatory cytokines in CSF were 0.85, 0.84, and 0.95, respectively. Clinical features (age, Hunt-Hess grade, etc.) were positively correlated with poor outcomes (P < 0.05). CONCLUSIONS: The levels of IL-1beta, IL-18, and TNF-alpha in CSF were elevated in aSAH patients and were positively associated with cerebral edema and acute hydrocephalus. Our findings suggest that CSF inflammatory cytokines might be biomarkers to assess severity and predict outcomes. PMID- 29277533 TI - Massive Primary Intraventricular Hemorrhage Due to Idiopathic Lateral Posterior Choroidal Artery Aneurysm: Case Illustration. AB - Peripheral aneurysms of the lateral posterior choroidal artery are rare and mostly in association with vascular and occlusive pathologies such as moyamoya disease. To the best of our knowledge, pure lateral posterior choroidal artery aneurysms without association of any other vascular diseases are unique and only 3 cases have been reported in the literature. PMID- 29277534 TI - How to assess physical activity in people with epilepsy? PMID- 29277535 TI - Determination of dolutegravir's unbound fraction in human plasma using validated equilibrium dialysis and LC-MS/MS methods. AB - Assessment of the unbound pharmacologically active fraction (fu; as the ratio of unbound to total concentration) of dolutegravir could improve therapeutic drug monitoring (TDM) in patients that experience virological failure or toxicity, despite receiving adequate total concentrations. This study evaluated (i) dolutegravir's fu through equilibrium dialysis (ED), (ii) the pre-analytical parameters that influence fu, and (iii) fu's inter-individual variability in HIV patients. Validation of the LC-MS/MS method followed FDA guidelines. The results, based on coefficients of variation (results from nominal concentrations <15%), allowed accurate measurement of unbound and total dolutegravir concentrations. Equilibrium during ED was obtained in 4h. Sparse non-specific binding (9%) was observed, allowing results interpretation without interference. Steps before analysis (e.g., conservation at +4 degrees C, freeze/thaw cycles) did not influence fu, allowing easy integration of fu analysis within laboratory routines. Anticoagulants from samples (citrated versus heparinized; p<0.001) and hemolysis (p=0.007) influenced fu and could lead to misinterpretation. Developed was then performed to the HIV-patients' plasma (n=54). Results, expressed as median InterQuartile Range [25%;75%] were 0.45% IQR [0.38; 0.55] for fu, 9.26MUg/L IQR [4.62; 15.14] for unbound, and 2035MUg/L IQR [878.5; 2640] for total concentration. The high inter-individual variability observed in the unbound form from HIV patients was a first step towards integrating dolutegravir TDM. PMID- 29277536 TI - Plasma FGF23 is not elevated in prostate cancer. PMID- 29277537 TI - Transcriptomic Analysis of Two Cdsn-Deficient Mice Shows Gene Signatures Biologically Relevant for Peeling Skin Disease. PMID- 29277538 TI - Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita. AB - Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita is caused by mutations in keratin genes and typified by dystrophic lesions affecting nails, glands, oral mucosa, and palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK) severely impairs mobility in pachyonychia congenita. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in pachyonychia congenita, develop pachyonychia congenita-like PPK. In male Krt16-/- mice, oxidative stress associated with impaired glutathione synthesis and nuclear factor erythroid-derived 2 related factor 2 (NRF2)-dependent gene expression precedes PPK onset, which can be prevented by topical sulforaphane-mediated activation of NRF2. We report here that sulforaphane treatment fails to activate NRF2 and prevent PPK in female Krt16-/- mice despite a similar set of molecular circumstances. Follow-up studies reveal a temporal shift in PPK onset in Krt16-/- females, coinciding with sex specific fluctuations in footpad skin glutathione levels. Dual treatment with sulforaphane and diarylpropionitrile, an estrogen receptor beta selective agonist, results in NRF2 activation, normalization of glutathione levels, and prevention of PPK in female Krt16-/- mice. These findings point to a sex difference in NRF2 responsiveness that needs be considered when exploring NRF2 as a therapeutic target in skin disorders. PMID- 29277539 TI - Skin Wound Healing Is Accelerated by a Lipid Mixture Representing Major Lipid Components of Chamaecyparis obtusa Plant Extract. AB - In chronic nonhealing wounds, the healing process is disrupted and wounds are often infected with bacteria. About 85% of lower extremity amputations in diabetes are attributed to deep infection of foot ulcers. Therefore, infection control is critical for wound care. In this study, we analyzed lipid composition of Chamaecyparis obtusa extract, and we describe the wound-healing properties of its combination of 10 major lipid components. A 10-lipid mixture up-regulated HBD 3 and LL-37 through the olfactory receptor 2AT4 and induced phosphorylation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinases in primary human keratinocytes. In addition, the 10-lipid mixture had direct bactericidal effects against Staphylococcus aureus and Streptococcus pyogenes and protected against staphylococcal alpha-toxin-induced keratinocyte cell death. In an animal model, the 10-lipid mixture accelerated skin wound healing and was also effective in healing wounds superinfected with S. aureus. We suggest that the 10 lipid mixture, because of its wound-healing and antimicrobial properties, can be beneficial for wound treatment. PMID- 29277540 TI - Claudin-3 Loss Causes Leakage of Sweat from the Sweat Gland to Contribute to the Pathogenesis of Atopic Dermatitis. AB - The transfer of sweat to the skin surface without leakage is important for the homeostatic regulation of skin and is impaired in atopic dermatitis. Although the precise composition of the leakage barrier remains obscure, there is a large contribution from claudins, the major components of tight junctions. In humans, claudin-1, -3, and -15 are expressed on sweat ducts, and claudin-3 and -10 are expressed on secretory coils. Although only two claudins are expressed in murine sweat glands, we found that the expression of claudin-3 is conserved. Atopic dermatitis lesional skin had decreased claudin-3 expression in sweat glands, which was accompanied by sweat leakage. This critical role in water barrier function was confirmed in Cldn3-/- and Cldn3+/- mice and those with experimentally decreased claudin-3. Our results show the crucial role of claudin 3 in preventing sweat gland leakage and suggest that the pathogenesis of dermatoses accompanied by hypohidrosis involves abnormally decreased claudin-3. PMID- 29277541 TI - HPV16E7-Induced Hyperplasia Promotes CXCL9/10 Expression and Induces CXCR3+ T Cell Migration to Skin. AB - Chemokines regulate tissue immunity by recruiting specific subsets of immune cells. Mice expressing the E7 protein of human papilloma virus 16 as a transgene from a keratin 14 promoter (K14.E7) show increased epidermal and dermal lymphocytic infiltrates, epidermal hyperplasia, and suppressed local immunity. Here, we show that CXCL9 and CXCL10 are overexpressed in non-hematopoietic cells in skin of K14.E7 mice when compared with non-transgenic animals, and recruit CXCR3+ lymphocytes to the hyperplastic skin. Overexpression of CXCL9 and CXCL10 is not observed in E7 transgenic mice with mutated Rb gene whose protein product cannot interact with E7 (K14.E7xRbDeltaL/DeltaL) and in consequence lack hyperplastic epithelium. CXCR3+ T cells are preferentially recruited by CXCL9 and CXCL10 in supernatants of K14.E7 but not K14.E7xRbDeltaL/DeltaL skin cultures in vitro. CXCR3 signalling promotes infiltration of a subset of effector T lymphocytes that enables donor lymphocyte deficient, E7-expressing skin graft rejection. Taken together, this suggests that recruitment of CXCR3+ T cells can be an important factor in the rejection of precancerous skin epithelium providing they can overcome local immunosuppressive mechanisms driven by skin-resident lymphocytes. PMID- 29277542 TI - Evolution of the MC5R gene in placental mammals with evidence for its inactivation in multiple lineages that lack sebaceous glands. AB - MC5R is one of five melanocortin receptor genes found in placental mammals. MC5R plays an important role in energy homeostasis and is also expressed in the terminal differentiation of sebaceous glands. Among placental mammals there are multiple lineages that either lack or have degenerative sebaceous glands including Cetacea (whales, dolphins, and porpoises), Hippopotamidae (hippopotamuses), Sirenia (manatees and dugongs), Proboscidea (elephants), Rhinocerotidae (rhinos), and Heterocephalus glaber (naked mole rat). Given the loss or diminution of sebaceous glands in these taxa, we procured MC5R sequences from publicly available genomes and transcriptomes, supplemented by a newly generated sequence for Choeropsis liberiensis (pygmy hippopotamus), to determine if this gene remains intact or is inactivated in association with loss/reduction of sebaceous glands. Our data set includes complete MC5R sequences for 114 placental mammal species including two individuals of Mammuthus primigenius (woolly mammoth) from Oimyakon and Wrangel Island. Complete loss or inactivation of the MC5R gene occurs in multiple placental lineages that have lost sebaceous glands (Cetacea, West Indian manatee, African elephant, white rhinoceros) or are characterized by unusual skin (pangolins, aardvarks). Both M. primigenius individuals share inactivating mutations with the African elephant even though sebaceous glands have been reported in the former. MC5R remains intact in hippopotamuses and the naked mole rat, although slightly elevated dN/dS ratios in these lineages allow for the possibility that the accumulation of inactivating mutations in MC5R may lag behind the relaxation of purifying selection. For Cetacea and Hippopotamidae, the absence of shared inactivating mutations in two different skin genes (MC5R, PSORS1C2) is consistent with the hypothesis that semi aquatic lifestyles were acquired independently in these clades following divergence from a common ancestor. PMID- 29277543 TI - Microfluidics for producing poly (lactic-co-glycolic acid)-based pharmaceutical nanoparticles. AB - Microfluidic chips allow the rapid production of a library of nanoparticles (NPs) with distinct properties by changing the precursors and the flow rates, significantly decreasing the time for screening optimal formulation as carriers for drug delivery compared to conventional methods. The batch-to-batch reproducibility which is essential for clinical translation is achieved by precisely controlling the precursors and the flow rate, regardless of operators. Poly (lactic-co-glycolic acid) (PLGA) is the most widely used Food and Drug Administration (FDA)-approved biodegradable polymers. Researchers often combine PLGA with lipids or amphiphilic molecules to assemble into a core/shell structure to exploit the potential of PLGA-based NPs as powerful carriers for cancer related drug delivery. In this review, we discuss the advantages associated with microfluidic chips for producing PLGA-based functional nanocomplexes for drug delivery. These laboratory-based methods can readily scale up to provide sufficient amount of PLGA-based NPs in microfluidic chips for clinical studies and industrial-scale production. PMID- 29277544 TI - Cloning and gene expression analysis of two cDNA of cysteine proteinase genes involved in programmed cell death in the inner integument from developing seeds of Jatropha curcas L. AB - In this paper, two cysteine proteinases were cloned from Jatropha curcas seeds. The full length cDNAs obtained from cloning of Jc-CysEP1 and Jc-CysEP2 genes were 1.516bp and 1500 pb, respectively. The Jc-CysEP1 contained a 1083bp open reading frame (ORF) coding for 360 amino acids. The JcCysEP1 protein sequence had an estimated native molecular weight of 36.89 kDa, with a predicted isoelectric point of 4.55. The average lengths of JcCysEP1 5' UTR and 3' UTR were 269 bp and 167bp, respectively. The Jc-CysEP2 contained a 1077 pb open reading frame (ORF) that encoded 358 amino acids. We also identified UTRs with lengths of 229 pb (5'UTR) and 194 pb (3'UTR). The Jc-CysEP2 sequence had a native molecular weight of 39.94 kDa, with a predicted isoelectric point of 6.19. Real-time PCR analyses of developing seeds (stages I-VII) showed that most cysteine proteinase genes were expressed at stage IV (middle stage) revealing peculiar spatio-temporal differences. JcCysEP2 was the cysteine proteinase gene with the highest expression in inner integument tissue, while JcCysEP1 was expressed in lower levels. Our results suggest that JcCysEP2 could be the major cysteine proteinase gene involved in PCD events in inner integument tissue, playing a critical role in PCD events during seed development, while Jc-CyEP1 and JcCysEP2 genes act cooperatively in stages IV-VII. JcCysEP2 is important to complete their participation in PCD until development of seeds. PMID- 29277545 TI - In vitro reconstitution of translational arrest pathways. AB - Protein translation is tightly regulated to ensure high-fidelity expression of genetic information. Various conditions cause ribosomes to stall while synthesizing new proteins. Different types of translational arrest initiate specific mRNA surveillance, protein quality control, and stress response pathways that directly impact gene expression and protein homeostasis. Our understanding of these pathways is greatly enhanced by reconstituting these processes in cell free systems. The high degree of biochemical manipulability of in vitro systems facilitates the identification of key machineries, mechanistic dissection of their functional roles, and structural analysis of intermediate complexes. Here, we describe principles and methods for reconstituting and analyzing translational arrest pathways in cell-free translation systems using rabbit reticulocyte lysate as an example. These approaches can be exploited to dissect various fundamental, regulatory, and quality control mechanisms of eukaryotic protein translation. PMID- 29277546 TI - Inhibition of Apoptosis Signal-Regulating Kinase 1 Attenuates Myocyte Hypertrophy and Fibroblast Collagen Synthesis. AB - BACKGROUND: Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. METHODS: Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2hours before stimulated with 100nM angiotensin II (AngII), 10MUM indoxyl sulphate (IS) or 10ng/ml transforming growth factor beta1 (TGFbeta1) for 48hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2hours before being stimulated with 100nM AngII for 60hours, 10MUM IS, 10ng/ml interleukin 1beta (IL-1beta) or tumour necrosis factor alpha (TNFalpha) for 48hours. 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. RESULTS: Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1beta- and TNFalpha-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFbeta1-stimulated NCF collagen synthesis and AngII- and TGFbeta1-stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. CONCLUSIONS: Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles. PMID- 29277547 TI - Recurrent Bioprosthetic Valve Thrombosis - Should Long-Term Anticoagulation Be Considered? AB - Bioprosthetic valve thrombosis (BPVT) is an important and potentially reversible cause of valvular dysfunction. This complication can occur many years after surgery and understanding of the precise mechanisms and risk factors is limited. Anticoagulation therapy has been demonstrated to be effective in improving BPVT. However, the optimal duration of therapy and the risk of recurrence are unknown. Herein, we describe two cases-one of late BPVT and one of recurrence of BPVT after cessation of anticoagulation therapy. PMID- 29277548 TI - Outcomes of Video-assisted Minimally Invasive Cardiac Myxoma Resection. AB - BACKGROUND: Myxomas are the most frequent cardiac tumours. Their diagnosis requires prompt removal. In our centre, for valve surgery we use a minimally invasive approach. Here, we report our experience of cardiac myxoma removal through right lateral mini-thoracotomy (RLMT) with particular focus on its feasibility, efficacy and patient safety. METHODS: Between February 2006 and January 2017, 30 consecutive patients (aged 66+/-12.6years, range 35-83 years) underwent atrial myxoma resection through video-assisted RLMT. Percutaneous venous drainage was performed in all patients and direct cannulation of the ascending aorta was performed in 28 out of 30 (93.3%). The diagnosis of atrial myxoma was confirmed by histology. RESULTS: Complete surgical resection was achieved in all patients. The mean cardiopulmonary bypass (CPB) time was 76.5+/ 40.8minutes and average aortic cross-clamping time was 41.5+/-29.8minutes. No patient suffered postoperative complications. Five patients (16.7%) received a blood transfusion. Mechanical ventilation ranged from 3 to 51hours (median 6hours), intensive care unit (ICU) stay ranged from 1 to 5days (median 1day). Total hospital length of stay (HLOS) was 5.6+/-2 days. Home discharge rate was 56.7%. No in-hospital mortality was reported. During follow-up (55.6+/-32.3 months; range 4-132 months), one tumour recurrence was observed. There were three late non-cardiac deaths. Overall survival was 100%, 85.7% and 85.7% at 1, 5 and 10 years, respectively. CONCLUSIONS: The use of video-assisted RLMT is an effective and reproducible strategy in all patients requiring expedited surgery for left atrial myxoma, independently of coexisting morbidity such as systemic embolisation or previous surgery. This technique leads to complete tumour resection, prompt recovery, early home discharge and high freedom from both symptoms and tumour recurrence. PMID- 29277549 TI - The mTOR promotes oxidative stress-induced apoptosis of mesangial cells in diabetic nephropathy. AB - Glomerular mesangial cell (MC) apoptosis is one of the important mechanisms of glomerulosclerosis, which induces an increased severity of albuminuria and promotes the development of diabetic nephropathy (DN). However, the mechanism by which high glucose (HG) induces MCs apoptosis is not fully understood. In the present study, we investigated the effects of mTOR signalling on apoptosis in cultured MCs exposed to HG and in type I diabetes, and tried to clarify the specific mechanisms underlying these effects. In vitro, exposure of MCs to HG stimulated ROS production, decreased the antioxidant enzyme superoxide dismutase (SOD) activity and glutathione (GSH) level, increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, upregulated P53 expression and Bax/Bcl-2 ratio and enhanced cleavage of caspase 3, resulting in an increase in programmed cell death. Pretreatment of the cells with rapamycin ameliorated oxidative stress, reduced the number of apoptotic cells induced by HG and caused the downstream effects of mTOR activation. In vivo, compared with control rats, diabetic rats had more apoptotic cells in glomeruli. Induction of diabetes increased the level of MDA and NADPH oxidase activity, decreased the SOD activity and GSH level, elevated the Bax/Bcl ratio and P53 expression and activated caspase 3. mTOR inhibitor rapamycin treatment prevented these changes further alleviated albuminuria and improved renal function. Taken together, our data suggest that mTOR plays a key role in mediating ROS-induced MC apoptosis in diabetic nephropathy, and these effects have been associated with the promotion of ROS production by upregulating the antioxidant enzyme and downregulating the NADPH oxidase activity. PMID- 29277550 TI - Maternal Zika virus infection and newborn microcephaly-an analysis of the epidemiological evidence. AB - PURPOSE: To evaluate whether existing data and evidence support a causal link between maternal Zika virus (ZIKV) infection and newborn microcephaly. METHODS: I quantified and compared the prevalence of all and severe microcephaly in Brazil, during and before 2015-2016, to assess whether an outbreak has occurred, used time series analysis to evaluate if the presumed outbreak was linked to a previous outbreak of ZIKV infections, and quantitatively synthesized published data from observational studies testing this association. RESULTS: The prevalences of microcephaly in 2015-2016 were similar or lower than background levels (prevalence ratio [PR] for all microcephaly: 0.19; 95% confidence intervals [CI]: 0.17, 0.20). Changes in the number of cases of ZIKV infections at times matching 11-18 weeks of pregnancy were not followed by changes in the number of microcephaly cases (PR for infection at 12 weeks: 1.02; 95% CI: 0.99, 1.05). In observational studies, the prevalence of microcephaly was not significantly increased in newborns of Zika-infected mothers (average PR: 1.30; 95% CI: 0.84, 2.02). CONCLUSIONS: Existing evidence is insufficient to claim maternal ZIKV infection causes microcephaly. Although a public health response seems sensible, it should be consistent with existing knowledge and consider risks, potential benefits and harm, and competing priorities. PMID- 29277551 TI - Diabetes-related factors and abdominal aortic aneurysm events: the Atherosclerotic Risk in Communities Study. AB - PURPOSE: To test the hypothesis that diabetes-related factors (metabolic syndrome [MetS], glucose, insulin, and leptin) are inversely associated with abdominal aortic aneurysm (AAA) risk. METHODS: We followed 13,736 participants, aged 45-64 years, without prior AAA surgery at baseline (1987-1989), for AAA occurrence through 2011. Hazard ratios (HRs) and their 95% confidence intervals (CIs) of AAA were calculated using Cox regression. RESULTS: During 275,054 person-years of follow-up, we identified 518 AAA events. Fasting serum glucose was associated inversely with AAA risk (HR [95% CI] per one unit increment in log2(glucose), 0.54 [0.36-0.80]), but fasting insulin was not associated with AAA. Plasma leptin was also associated inversely with AAA occurrence (HR [95% CI] per one unit increment in log2(leptin), 0.83 [0.71-0.98]). Compared with individuals without MetS, those with MetS had increased risk of AAA (HR [95% CI], 1.24 [1.04-1.48]). Among individuals with or without diabetes, the HRs increased monotonically with a greater number of non-glucose MetS components. CONCLUSIONS: Diabetes, fasting glucose, and plasma leptin were inversely associated with risk of AAA. In contrast, the MetS was associated with increased risk of AAA, due to the influence of the non-glucose MetS components. PMID- 29277552 TI - No impact of surgery on cognitive function: a longitudinal study of middle-aged Danish twins. AB - PURPOSE: To examine the association between exposure to surgery and 10-year change in cognitive functioning. METHODS: Among 2351 middle-aged twins, a 10-year change in composite cognitive scores derived from five cognitive tests was compared between 903 (38%) twins exposed to surgery classified as major, minor, knee and hip replacement, and other, and a reference group of 1448 (62%) twins without surgery, using linear regression models adjusted for socioeconomic factors. Genetic and shared environmental confounding was addressed in intrapair analyses of 48 monozygotic and 74 dizygotic same-sexed twin pairs. RESULTS: In individual-level analyses, twins with major surgery (mean difference, -0.37; 95% CI, -0.76 to 0.02) or knee and hip replacement surgery (mean difference, -0.54; 95% CI, -1.30 to 0.22) had a tendency of a negligibly higher rate of decline in cognitive score than the reference group. In the intrapair analyses, the surgery exposed twin had a higher rate of cognitive decline than the co-twin in 55% (95% CI, 45% to 63%) of the pairs. The mean difference in cognitive decline within pairs was -0.21 (95% CI, -0.81 to 0.39). CONCLUSIONS: No significant associations were found between exposure to surgery and change in cognitive score either in individual-level or in intrapair analyses. PMID- 29277553 TI - Water intake reverses dehydration associated impaired executive function in healthy young women. AB - INTRODUCTION: Healthy women do not always consume Recommended Daily Levels of fluid intake ad libitum. We hypothesized that 1) women lose>=1.0% BW during daily activities, 2) that mild body water loss impairs memory and executive function, 3) water intake to recommended daily levels will improve cognitive function. METHODS: We tested 12 women (26+/-5yr, 22.5+/-2.6kg/m2 BMI). Session 1 was a control (CON) session, during which subjects monitored their food and fluid intake (diary) and activity (Fitbit(r)). The next two sessions were applied in balanced order: dehydration (DEH) session, where subjects minimized drinking, and a euhydration (EUH) session, where subjects drank Recommended Daily Levels of fluid for their age and sex, or 2500ml/24h. We compared emotion, sensory perception and cognition with computer based visual analog tests and computer based cognitive tasks (Cogstate) at 5PM, i.e. baseline (BL) on the evening prior to the session, and at 7AM, 12PM, and 5PM during the session. RESULTS: Urine specific gravity (USG) was similar at BL across conditions (CON 1.013+/-0.002, DEH 1.015+/-0.002, EUH 1.014+/-0.002) and increased with dehydration (CON 1.011+/ 0.003, DEH 1.021+/-0.002, EUH 1.010+/-0.002, P<0.05) by 5PM of the session. Uncontrolled fluid intake and physical activity were similar across sessions. The water challenges did not impact Detection, Identification, One-Card Learning, but EUH improved visual and working memory (Groton Maze Learning Test) errors: CON 40.1+/-11.1, DEH 40.5+/-10.1, EUH 33.9+/-10.9, P<0.05. Executive function [Set Shifting (SETS)] also improved under EUH, errors: BL 22.5+/-12.7 vs. 5PM 17.8+/ 6.2, P<0.05. CONCLUSIONS: Mild dehydration caused deficits in visual and working memory and executive function in healthy young women. These deficits were reversed by drinking water to the European Food Safety Authority and Institute of Medicine requirements of 2.5l/day for adult women. PMID- 29277554 TI - Arrival of carbapenem-hydrolyzing-oxacillinases in Acinetobacter baumannii in Bosnia and Herzegovina. PMID- 29277555 TI - Distribution of bat-borne viruses and environment patterns. AB - Environmental modifications are leading to biodiversity changes, loss and habitat disturbance. This in turn increases contacts between wildlife and hence the risk of transmission and emergence of zoonotic diseases. We analyzed the environment and land use using remote spatial data around the sampling locations of bats positive for coronavirus (21 sites) and astrovirus (11 sites) collected in 43 sites. A clear association between viruses and hosts was observed. Viruses associated to synanthropic bat genera, such as Myotis or Scotophilus were associated to highly transformed habitats with human presence while viruses associated to fruit bat genera were correlated with natural environments with dense forest, grassland areas and regions of high elevation. In particular, group C betacoronavirus were associated with mosaic habitats found in anthropized environments. PMID- 29277556 TI - MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. AB - The mechanisms that lead to neuronal death in neurodegenerative diseases are poorly understood. Prion diseases, like many more common disorders such as Alzheimer's and Parkinson's diseases, are characterized by the progressive accumulation of misfolded disease-specific proteins. The earliest changes observed in brain tissue include a reduction in synaptic number and retraction of dendritic spines, followed by reduced length and branching of neurites. These pathologies are observable during presymptomatic stages of disease and are accompanied by altered expression of transcripts that include miRNAs. Here we report that miR-16 localized within hippocampal CA1 neurons is increased during early prion disease. Modulating miR-16 expression in mature murine hippocampal neurons by expression from a lentivirus, thus mimicking the modest increase seen in vivo, was found to induce neurodegeneration. This was characterized by retraction of neurites and reduced branching. We performed immunoprecipitation of the miR-16 enriched RISC complex, and identified associated transcripts from the co-immunoprecipitated RNA (Ago2 RIP-Chip). These transcripts were enriched with predicted binding sites for miR-16, including the validated miR-16 targets APP and BCL2, as well as numerous novel targets. In particular, genes within the neurotrophin receptor mediated MAPK/ERK pathway were potentially regulated by miR 16; including TrkB (NTRK2), MEK1 (MAP2K1) and c-Raf (RAF). Increased miR-16 expression in neurons during presymptomatic prion disease and reduction in proteins involved in MAPK/ERK signaling represents a possible mechanism by which neurite length and branching are decreased during early stages of disease. PMID- 29277557 TI - Unreported links between trial registrations and published articles were identified using document similarity measures in a cross-sectional analysis of ClinicalTrials.gov. AB - OBJECTIVES: Trial registries can be used to measure reporting biases and support systematic reviews, but 45% of registrations do not provide a link to the article reporting on the trial. We evaluated the use of document similarity methods to identify unreported links between ClinicalTrials.gov and PubMed. STUDY DESIGN AND SETTING: We extracted terms and concepts from a data set of 72,469 ClinicalTrials.gov registrations and 276,307 PubMed articles and tested methods for ranking articles across 16,005 reported links and 90 manually identified unreported links. Performance was measured by the median rank of matching articles and the proportion of unreported links that could be found by screening ranked candidate articles in order. RESULTS: The best-performing concept-based representation produced a median rank of 3 (interquartile range [IQR] 1-21) for reported links and 3 (IQR 1-19) for the manually identified unreported links, and term-based representations produced a median rank of 2 (1-20) for reported links and 2 (IQR 1-12) in unreported links. The matching article was ranked first for 40% of registrations, and screening 50 candidate articles per registration identified 86% of the unreported links. CONCLUSION: Leveraging the growth in the corpus of reported links between ClinicalTrials.gov and PubMed, we found that document similarity methods can assist in the identification of unreported links between trial registrations and corresponding articles. PMID- 29277558 TI - The cohort multiple randomized controlled trial design was found to be highly susceptible to low statistical power and internal validity biases. AB - OBJECTIVES: The "cohort multiple randomized controlled trial" (cmRCT) is a recent innovation by which novel interventions are trialed within large longitudinal cohorts of patients to gain efficiencies and align trials more closely to standard clinical practice. The use of cmRCTs is outpacing its methodological understanding, and more appropriate methods for designing and analyzing such trials are urgently needed. STUDY DESIGN AND SETTING: We established the UK Comprehensive Longitudinal Assessment of Salford Integrated Care cohort of 4,377 patients with long-term conditions within which we are conducting a cmRCT ("Proactive Telephone Coaching and Tailored Support") of telephone-based health coaching. RESULTS: We identify some key methodological challenges to the use of the cmRCT in actual practice. Principal are issues around statistical power, sample size, and treatment effect estimation, for which we provide appropriate methods. Sampling procedures commonly applied in conventional RCTs can result in unintentional selection bias. The fixed data collection points that feature in cmRCTs can also threaten validity. CONCLUSION: The cmRCT may offer advantages over conventional trial designs. However, a cmRCT requires appropriate power calculation, sampling, and analysis procedures; else, studies may be underpowered or subject to validity biases. We offer solutions to some of the key issues, but further methodological investigations are needed. Cohort multiple RCT-specific Consolidated Standards of Reporting Trials guidance may be indicated. PMID- 29277559 TI - Pan-Genotype Hepatitis E Virus Replication in Stem Cell-Derived Hepatocellular Systems. AB - BACKGROUND & AIMS: The 4 genotypes of hepatitis E virus (HEV) that infect humans (genotypes 1-4) vary in geographical distribution, transmission, and pathogenesis. Little is known about the properties of HEV or its hosts that contribute to these variations. Primary isolates grow poorly in cell culture; most studies have relied on variants adapted to cancer cell lines, which likely alter virus biology. We investigated the infection and replication of primary isolates of HEV in hepatocyte-like cells (HLCs) derived from human embryonic and induced pluripotent stem cells. METHODS: Using a cell culture-adapted genotype 3 strain and primary isolates of genotypes 1 to 4, we compared viral replication kinetics, sensitivity to drugs, and ability of HEV to activate the innate immune response. We studied HLCs using quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence assay and enzyme-linked immunosorbent assays. We used an embryonic stem cell line that can be induced to express the CRISPR-Cas9 machinery to disrupt the peptidylprolyl isomerase A gene, encoding cyclophilin A (CYPA), a protein reported to inhibit replication of cell culture adapted HEV. We further modified this line to rescue expression of CYPA before terminal differentiation to HLCs and performed HEV infection studies. RESULTS: HLCs were permissive for infection by nonadapted, primary isolates of HEV genotypes 1 to 4. HEV infection of HLCs induced a replication-dependent type III interferon response. Replication of primary HEV isolates, unlike the cell culture adapted strain, was not affected by disruption of the peptidylprolyl isomerase A gene or exposure to the CYPA inhibitor cyclosporine A. CONCLUSIONS: Cell culture adaptations alter the replicative capacities of HEV. HLCs offer an improved, physiologically relevant, and genetically tractable system for studying the replication of primary HEV isolates. HLCs could provide a model to aid development of HEV drugs and a system to guide personalized regimens, especially for patients with chronic hepatitis E who have developed resistance to ribavirin. PMID- 29277562 TI - Evaluating the expression level of co-stimulatory molecules CD 80 and CD 86 in different types of colon polyps. AB - PURPOSE OF THE STUDY: Co-stimulatory molecules CD80 and CD86 are the members of B7 family, which stimulate the T lymphocytes in response to the malignant colon polyps. However, the expression of these molecules is depressed in cancers. In the present study, the transcription levels of CD80 and CD86 genes in the colon polyps (Precancerous lesions) and its association with the clinical features were examined. PATIENTS AND METHODS: Forty-nine biopsies samples from patients with the colorectal polyps and 10 healthy subjects were collected by the colonoscopy. Questionnaires including clinical and demographic data were filled for all cases. Using Real-time PCR, the mucosal mRNA expression levels of CD80 and CD86 genes were quantified. RESULTS: Adenoma and hyperplastic polyps were reported in 69.3 and 30.7 percent of 49 patients, respectively. Unlike hyperplastic polyps, the expression of CD86 was increased in adenoma polyps compared to controls (RQ=2.75 vs. 0.837, respectively). The data from CD80 showed noticeable reduction about 0.31 and 0.11 in adenoma and hyperplastic polyps, respectively, in response to control group (RQ=0.729). Also, analyzing colon and rectum polyps depicted a marked increment in CD86 level, in contrast to CD80. CONCLUSION: Examining the mRNA expression levels of CD80 and CD86 genes between colon polyps with the rectal polyps shows that the enhanced level of CD86 in adenoma samples could be considered as a valuable biomarker for distinguishing the adenoma from hyperplastic polyps and the masses located in the colon from the rectum. PMID- 29277563 TI - The physiology of Agaricus bisporus in semi-commercial compost cultivation appears to be highly conserved among unrelated isolates. AB - The white button mushroom Agaricus bisporus is one of the most widely produced edible fungus with a great economical value. Its commercial cultivation process is often performed on wheat straw and animal manure based compost that mainly contains lignocellulosic material as a source of carbon and nutrients for the mushroom production. As a large portion of compost carbohydrates are left unused in the current mushroom cultivation process, the aim of this work was to study wild-type A. bisporus strains for their potential to convert the components that are poorly utilized by the commercial strain A15. We therefore focused our analysis on the stages where the fungus is producing fruiting bodies. Growth profiling was used to identify A. bisporus strains with different abilities to use plant biomass derived polysaccharides, as well as to transport and metabolize the corresponding monomeric sugars. Six wild-type isolates with diverse growth profiles were compared for mushroom production to A15 strain in semi-commercial cultivation conditions. Transcriptome and proteome analyses of the three most interesting wild-type strains and A15 indicated that the unrelated A. bisporus strains degrade and convert plant biomass polymers in a highly similar manner. This was also supported by the chemical content of the compost during the mushroom production process. Our study therefore reveals a highly conserved physiology for unrelated strains of this species during growth in compost. PMID- 29277560 TI - Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Therapies for perianal fistulas in patients with Crohn's disease are often ineffective in producing long-term healing. We performed a randomized placebo-controlled trial to determine the long-term efficacy and safety of a single local administration of allogeneic expanded adipose-derived stem cells (Cx601) in patients with Crohn's disease and perianal fistulas. METHODS: We performed a double-blind study at 49 hospitals in Europe and Israel, comprising 212 patients with Crohn's disease and treatment-refractory, draining, complex perianal fistulas. Patients were randomly assigned (1:1) to groups given a single local injection of 120 million Cx601 cells or placebo (control), in addition to the standard of care. Efficacy endpoints evaluated in the modified intention-to-treat population (randomly assigned, treated, and with 1 or more post-baseline efficacy assessment) at week 52 included combined remission (closure of all treated external openings draining at baseline with absence of collections >2 cm, confirmed by magnetic resonance imaging) and clinical remission (absence of draining fistulas). RESULTS: The study's primary endpoint, at week 24, was previously reported (combined remission in 51.5% of patients given Cx601 vs 35.6% of controls, for a difference of 15.8 percentage points; 97.5% confidence interval [CI] 0.5-31.2; P = .021). At week 52, a significantly greater proportion of patients given Cx601 achieved combined remission (56.3%) vs controls (38.6%) (a difference of 17.7 percentage points; 95% CI 4.2-31.2; P = .010), and clinical remission (59.2% vs 41.6% of controls, for a difference of 17.6 percentage points; 95% CI 4.1-31.1; P = .013). Safety was maintained throughout week 52; adverse events occurred in 76.7% of patients in the Cx601 group and 72.5% of patients in the control group. CONCLUSION: In a phase 3 trial of patients with Crohn's disease and treatment-refractory complex perianal fistulas, we found Cx601 to be safe and effective in closing external openings, compared with placebo, after 1 year. ClinicalTrials.gov no: NCT01541579. PMID- 29277564 TI - Feasibility of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Cytology Specimens for Next Generation Sequencing in Non-small-cell Lung Cancer. AB - INTRODUCTION: Next generation sequencing (NGS) testing of lung cancer is recommended by guidelines, and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) often provides the only material available for testing. Previous studies have demonstrated successful NGS testing on cell block samples obtained by EBUS; however, cytology smears provide a more reliable sample with better DNA quality for testing. In this study, we aimed to determine the success rate of OncoScreen (50 gene) and OncoPlus (1213 gene) panel NGS testing of cytology samples obtained by EBUS utilizing 22- and 25-gauge needles. METHODS: Fifty-four patients underwent EBUS-TBNA of lung cancer for which NGS testing was requested. Data was analyzed for needle gauge, cytologic assessment, NGS test success, and sample type (cytology smear or cell block) used for testing. RESULTS: Eighty-five NGS tests were ordered on 54 samples. Overall, 95.3% of samples had successful testing. OncoScreen and OncoPlus panels were successful 98.0% and 91.4% of the time, respectively. Cytology smears provided testing material for 85% of the tests. OncoScreen testing was successful in 97.5% and 100% of the 22- and 25-gauge samples, respectively (P = 1.00). OncoPlus testing was successful in 91.3% and 100% of the 22- and 25-gauge samples, respectively (P = 1.00). CONCLUSIONS: NGS can be reliably performed on cytology smears obtained from EBUS-TBNA. The size of the needle does not seem to affect the success rate of small or large panel NGS tests. PMID- 29277565 TI - Pilot Study of the Safety and Efficacy of Dose Escalation in Stereotactic Body Radiotherapy for Peripheral Lung Tumors. AB - BACKGROUND: This pilot study aimed to evaluate the safety and efficacy of a dose escalation method for the treatment of peripheral lung tumors by administrating steep dose gradients in the target volumes via stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: Patients with peripheral lung tumors were enrolled onto this study and treated with SBRT using a total dose of 70 Gy in 4 fractions at target isocenter, covering the planning target volume surface with 70% of the isodose. The primary end point was the rate of grade 2 or higher radiation pneumonitis (RP) within 1 year. RESULTS: A total of 35 patients were enrolled onto this study between September 2014 and January 2016. Thirty-two patients with primary lung cancers and 3 patients with lung metastases were treated with SBRT. Grade 2 RP was observed in 4 patients within 1 year. No severe RP (grade 3 or higher) was observed within the follow-up period. The median follow-up period was 21.2 months (range, 4.2-31.7 months). Local recurrence was observed in a single patient with lung metastasis. No local recurrence was observed within the follow up period in the 32 patients with primary lung cancer. The local control and overall survival rates at 2 years were 95.7% (95% confidence interval, 72.9-99.4) and 85.2% (95% confidence interval, 67.8-93.6), respectively. CONCLUSION: This dose escalation method with steep dose gradients using SBRT for peripheral lung tumors was safe in the subacute phases. These results also suggest that this method can obtain excellent local control rates. PMID- 29277561 TI - Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice. AB - BACKGROUND & AIMS: The innate immune system responds not only to bacterial signals, but also to non-infectious danger-associated molecular patterns that activate the NLRP3 inflammasome complex after tissue injury. Immune functions vary over the course of the day, but it is not clear whether these changes affect the activity of the NLRP3 inflammasome. We investigated whether the core clock component nuclear receptor subfamily 1 group D member 1 (NR1D1, also called Rev erbalpha) regulates expression, activity of the NLRP3 inflammasome, and its signaling pathway. METHODS: We collected naive peritoneal macrophages and plasma, at multiple times of day, from Nr1d1-/- mice and their Nr1d1+/+ littermates (controls) and analyzed expression NLRP3, interleukin 1beta (IL1B, in plasma), and IL18 (in plasma). We also collected bone marrow-derived primary macrophages from these mice. Levels of NR1D1 were knocked down with small hairpin RNAs in human primary macrophages. Bone marrow-derived primary macrophages from mice and human primary macrophages were incubated with lipopolysaccharide (LPS) to induce expression of NLRP3, IL1B, and IL18; cells were incubated with LPS and adenosine triphosphate to activate the NLRP3 complex. We analyzed caspase 1 activity and cytokine secretion. NR1D1 was activated in primary mouse and human macrophages by incubation with SR9009; some of the cells were also incubated with an NLRP3 inhibitor or inhibitors of caspase 1. Nr1d1-/- mice and control mice were given intraperitoneal injections of LPS to induce peritoneal inflammation; plasma samples were isolated and levels of cytokines were measured. Nr1d1-/- mice, control mice, and control mice given injections of SR9009 were given LPS and D galactosamine to induce fulminant hepatitis and MCC950 to specifically inhibit NLRP3; plasma was collected to measure cytokines and a marker of liver failure (alanine aminotransferase); liver tissues were collected and analyzed by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. RESULTS: In peritoneal macrophages, expression of NLRP3 and activation of its complex varied with time of day (circadian rhythm)-this regulation required NR1D1. Primary macrophages from Nr1d1-/- mice and human macrophages with knockdown of NR1D1 had altered expression patterns of NLRP3, compared to macrophages that expressed NR1D1, and altered patterns of IL1B and 1L18 production. Mice with disruption of Nr1d1 developed more-severe acute peritoneal inflammation and fulminant hepatitis than control mice. Incubation of macrophage with the NR1D1 activator SR9009 reduced expression of NLRP3 and secretion of cytokines. Mice given SR9009 developed less-severe liver failure and had longer survival times than mice given saline (control). CONCLUSIONS: In studies of Nr1d1 /- mice and human macrophages with pharmacologic activation of NR1D1, we found NR1D1 to regulate the timing of NLRP3 expression and production of inflammatory cytokines by macrophages. Activation of NR1D1 reduced the severity of peritoneal inflammation and fulminant hepatitis in mice. PMID- 29277566 TI - Pretransplant serum BAFF levels are associated with pretransplant HLA immunization and renal allograft survival. AB - BACKGROUND: The essential function of B cell-activating factor (BAFF) is regulating the survival and differentiation of B cells. The link between pretransplant BAFF levels and pretransplant alloimmunization and its value to predict subsequent acute antibody-mediated rejection (AMR) and outcome after renal transplantation is not fully understood. METHODS: Objective of our retrospective single-center study was to determine, by ELISA analysis of pretransplant serum BAFF levels in 249 patients undergoing renal transplantation, association between preformed anti-human leukocyte antigen (HLA) antibodies, occurrence of acute antibody mediated rejection (AMR) and renal allograft survival. RESULTS: Pretransplant serum BAFF levels were significantly higher in presensitized recipients with anti-HLA antibodies (3262+/-2796pg/ml) than in recipients without occurrence of anti-HLA antibodies (2252+/-1425pg/ml; p<0.0001). In addition, pretransplant BAFF levels correlated with cumulative MFI values of anti-HLA antibodies (r=0.2966, p=0.0025). Patients with high pretransplant BAFF levels (>=2137pg/ml) experienced significantly lower allograft survival rates compared to low pretransplant BAFF levels (80% vs. 91%; p=0.01). Coexistence of high pretransplant BAFF levels and posttransplant AMR was associated with the worst allograft survival rates (56%). Relative risk (RR) for allograft loss was associated with high serum BAFF levels (RR 2.3; p=0.02), presence of anti-HLA antibodies (RR 2.5; p=0.007) or anti-HLA -donor-specific antibodies (DSAs) (RR 2.6; p=0.003) before transplant and AMR post transplant (RR 2.5; p=0.007). AMR was the strongest independent risk factor for allograft failure (RR 2.6; p=0.03). CONCLUSION: Elevated pretransplant serum BAFF levels negatively affect renal allograft survival and represent a risk factor for allosensitization and subsequent AMR. PMID- 29277569 TI - Membrane permeabilization design of antimicrobial peptides based on chikungunya virus fusion domain scaffold and its antibacterial activity against gram-positive Streptococcus pneumoniae in respiratory infection. AB - The structural dynamics of membrane permeabilization are investigated systematically and compared between viral fusion peptides (VFPs) and antimicrobial peptides (AMPs). It is revealed that the permeabilization process can be divided into two phases: a fast motion phase in water (first phase) and a slow diffusion phase in lipid (second phase). Difference in peptide permeability to neutrally or weakly charged mammalian membrane and to negatively charged bacterial membrane is primarily determined by the first phase, which is dominated by the direct electrostatic interaction between peptide and the hydrophilic surface of membranes. With the harvested knowledge we attempt to rationally design anti-Gram-positive AMPs based on the VFP scaffold of Chikungunya virus fusion domain, which is an 18-mer polypeptide segment (VT18, 84VYPFMWGGAYCFCDAENT101) located in the structural glycoprotein E1 of viral envelope. Our simulations and previous NMR study suggest that the isolated VT18 peptide can be well structured into a double-stranded beta-sheet conformation in water, but would become intrinsically disordering in lipid. Converting the negatively charged VT18 (charge = -2) to two positively charged peptides VT18 KKLV (VYPFMWGGAYCFCKAKLV-NH2) (charge = +3) and VT18-CAKKLV (VYPFCWGGAYAFCKAKLV NH2) (charge = +3) by residue substitution and C-terminal amidation can largely promote peptide approaching to bacterial membrane surface, thus rendering the peptide with a substantially increased antibacterial activity against Gram positive Streptococcus pneumoniae (MIC changes from >200 to 52-105 and 58-90 MUg/ml, respectively). A further cyclization of linear peptide VT18-CAKKLV by adding a disulfide bond across its two strand arms, which results in a cyclic peptide cVT18-CAKKLV () (charge = +3), can effectively stabilize the peptide beta sheet conformation in lipid, thus improving its membrane compatibility in second phase and enhancing its antibacterial potency (MIC = 35-67 MUg/ml). We also demonstrated that the designed AMPs have no or only a moderate cytotoxic effect and hemolytic activity on human normal cells. PMID- 29277568 TI - Effect of dC -> d(m5C) substitutions on the folding of intramolecular triplexes with mixed TAT and C+GC base triplets. AB - Oligonucleotide-directed triple helix formation has been recognized as a potential tool for targeting genes with high specificity. Cystosine methylation in the 5' position is both ubiquitous and a stable regulatory modification, which could potentially stabilize triple helix formation. In this work, we have used a combination of calorimetric and spectroscopic techniques to study the intramolecular unfolding of four triplexes and two duplexes. We used the following triplex control sequence, named Control Tri, d(AGAGAC5TCTCTC5TCTCT), where C5 are loops of five cytosines. From this sequence, we studied three other sequences with dC -> d(m5C) substitutions on the Hoogsteen strand (2MeH), Crick strand (2MeC) and both strands (4MeHC). Calorimetric studies determined that methylation does increase the thermal and enthalpic stability, leading to an overall favorable free energy, and that this increased stability is cumulative, i.e. methylation on both the Hoogsteen and Crick strands yields the largest favorable free energy. The differential uptake of protons, counterions and water was determined. It was found that methylation increases cytosine protonation by shifting the apparent pKa value to a higher pH; this increase in proton uptake coincides with a release of counterions during folding of the triplex, likely due to repulsion from the increased positive charge from the protonated cytosines. The immobilization of water was not affected for triplexes with methylated cytosines on their Hoogsteen or Crick strands, but was seen for the triplex where both strands are methylated. This may be due to the alignment in the major groove of the methyl groups on the cytosines with the methyl groups on the thymines which causes an increase in structural water along the spine of the triplex. PMID- 29277570 TI - Effects of collected road dusts on cell viability, inflammatory response, and oxidative stress in cultured human corneal epithelial cells. AB - Most studies on the adverse effects of air pollution have focused on respiratory and cardiovascular diseases, and there are relatively few studies on eye diseases following exposure of ambient particulate matter (PM). Epidemiological and clinical researches correlating the eye and PMs have recently received attention. PMs are complex mixture of particles that vary in chemical composition and size. This study investigated the influence of collected road dust on cell viability, inflammatory responses, and oxidative stress in human corneal epithelial cells. The collected road dust was classified with respect to aerodynamic diameter and solubility. Exposure concentration was calculated based on the particle deposition rate. We observed a dose-dependent decrease in cell viability at total PM2.5 and PM10. The pellet fractions of total PM2.5 and PM10 mainly contributed to the mitochondrial activity. Although both total PM2.5 and PM10 did not change the membrane integrity, the supernatant fractions significantly affected cell membrane integrity. Both total and fractions induced nitric oxide production and interleukin 8 expression. In addition, total PM2.5 and PM10 increased the oxidative stress; the pellet fractions of total PM2.5 and PM10 also induced higher oxidative stress. However, there was no significant difference between the cellular responses of total PM2.5 and PM10. We observed that the effects of collected road dust on cellular responses were strongly dependent on their concentration and solubility. PMID- 29277571 TI - Less-toxic rearrangement products of NX-toxins are formed during storage and food processing. AB - A new type A trichothecene mycotoxin, NX-2, was previously reported to be produced by North American isolates of the cereal pathogen Fusarium graminearum. Here we describe the isolation and structural characterization of a rearrangement product, called NX2-M1, and related compounds with different acetylation patterns (NX3-M1 and NX4-M1). In the NX-M1 derivatives, the epoxide ring is opened, and a covalent bridge between C-10 and C-12 of the trichothecene backbone is formed. In vitro translation assays showed that NX3-M1 is less toxic for eukaryotic ribosomes than NX-3. NX3-M1 also has a greatly reduced cytotoxic potential on two tested human colon cell lines. Formation of NX3-M1 can therefore be regarded as a detoxification reaction. The related F. graminearum mycotoxin deoxynivalenol (DON), which is frequently occurring worldwide, is very stable during food processing. Testing NX-3 at different pH-values and temperature conditions, as well as under conditions that simulate the storage of infected grains and bread making process, revealed a strongly reduced stability of NX-3 and concurrent formation of NX3-M1. Although the NX-3 formed in planta is as toxic as DON, the extensive formation of the non-toxic rearrangement product should be taken into account for risk assessment of this emerging food contaminant. PMID- 29277572 TI - Glutathione as an antidote for sulfur mustard poisoning: Mass spectrometric investigations of its potency as a chemical scavenger. AB - The banned chemical warfare agent sulfur mustard (SM) still represents a serious threat to civilians and military personnel. Therefore, identification of antidotes and scavengers is of high concern. One promising substance is glutathione (GSH). GSH is known to mitigate symptoms of SM poisoning in vitro and in vivo. However, the mechanism of action remains unclear with respect to physiological impact as well as chemical scavenging by reaction between GSH and SM. Therefore, a novel in vitro method was used to characterize the scavenging potential of GSH. Accordingly, alkylation of human serum albumin (HSA), which represents an established biomarker for SM intoxication, was used as a measure for remaining SM. Coincubation of GSH and SM in human serum was performed, and time-dependent degradation of SM was monitored in the presence and absence of GSH. Protein-derived and small molecular reaction products between GSH, HSA, and SM were analyzed using microbore liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry. Although covalent modification of GSH by SM was observed, measurements clearly documented no significant reduction of SM concentration in the presence of GSH. Accordingly, beneficial therapeutic mechanisms of GSH in the case of SM poisoning would appear to be based on physiological effects than on chemical scavenging. PMID- 29277573 TI - Mass spectrometric analysis of sulfur mustard-induced biomolecular adducts: Are DNA adducts suitable biomarkers of exposure? AB - The bi-functional chemical warfare agent sulfur mustard (SM), whose release in asymmetric conflicts or terrorist attacks represents a realistic threat, induces several kinds of biomolecular adducts, including highly toxic DNA adducts. Isotope dilution liquid chromatographic tandem mass spectrometry (ID-LC-MS/MS) is considered the gold standard for highly accurate, precise, specific and sensitive quantification of DNA adducts in general. Recently, a number of LC-MS/MS approaches have been established to analyze SM-induced protein and DNA adducts in cell culture and rodent animal models. As DNA adducts are mechanism-based biomarkers for SM exposure, results from such studies provide a deeper understanding of the etiology of SM-induced pathologies, especially of long-term effects such as cancer formation. As a result, medical treatment of SM-exposed individuals might be improved. Yet, despite the progress that has been made during the last years, there is still a need for advanced methods of ID-LC-MS/MS for the detection and quantitation of SM adducts. PMID- 29277574 TI - Human cytochrome P450 kinetic studies on six N-2-methoxybenzyl (NBOMe)-derived new psychoactive substances using the substrate depletion approach. AB - A huge number of new chemical derivatives of known drugs of abuse, so-called new psychoactive substances (NPS), are sold and consumed without prior preclinical and clinical testing. For assessing the elimination behaviors, determination of the kinetic constants Km and Vmax of the cytochrome P450 (CYP) isoforms involved in the hepatic metabolism of NPS could help to predict their contributions to hepatic clearance, drug-drug interactions and polymorphisms. Therefore, the aims of the present study were to determine the Km and Vmax values for CYP isoforms using the substrate depletion approach for the six N-2-methoxybenzyl (NBOMe) derived NPS 25B-NBOMe, 25C-NBOMe, 25I-NBOMe, 3,4-DMA-NBOMe, 4-EA-NBOMe, and 4-MMA NBOMe. Furthermore, the contributions of each CYP isozyme to the hepatic net clearance were elucidated using the relative activity factor approach. Several CYPs including CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 were identified to be involved in the metabolism of the investigated compounds. The determined Km values ranged from 0.010 MUM (CYP2D6, 4-MMA-NBOMe) to 13 MUM (CYP2B6, 4-EA NBOMe). All NBOMes were good substrates of CYP2C19 and CYP2D6 resulting in very low Km values in the nanomolar range. The main contributors to hepatic net clearance were CYP2D6 for 25B-NBOMe (69%), 25C-NBOMe (83%), 25I-NBOMe (61%), 3,4 DMA-NBOMe (89%) as well as for 4-EA-NBOMe (62%) and CYP2C19 for 4-MMA-NBOMe (64%). As more than one isoform was involved in the particular steps, the risk of harm associated with drug-drug interactions might be considered low. However, in cases where substances with high contributions from polymorphically expressed CYP2C19 and CYP2D6 are encountered, inter-individual variations in metabolism and excretion cannot be excluded. PMID- 29277576 TI - The release and transmission of amyloid precursor protein via exosomes. AB - Amyloid precursor protein (APP) processing is central in Alzheimer's disease (AD) pathogenesis. The healthy unaffected neurons suffer the transmission of amyloid protein from pathologically affected neurons, which may play an important role in the anatomical spread of the disease. Exosomes are appropriate candidates for transmission of amyloid species, because of their potential role as "intercellular transportation". To address a role of secreted exosomes in neuronal homeostasis in AD, we harvested exosomes from the conditioned medium of HEK293-APP Swe/Ind cells. We have demonstrated that these exosomes contained APP and were capable of efficiently transferring APP to normal primary neurons. Moreover, these exosomes had dose-dependent detrimental effect on cultured neurons. Our results suggest a key mechanism underlying the spread of amyloid protein in the brain and the acceleration of pathology in AD; exosomes secretion serves to amplify and propagate Alzheimer's disease related pathology. PMID- 29277577 TI - Coronaridine congeners modulate mitochondrial alpha3beta4* nicotinic acetylcholine receptors with different potency and through distinct intra mitochondrial pathways. AB - In contrast to plasma membrane-expressed nicotinic acetylcholine receptors (nAChRs), mitochondrial nAChRs function in an ion-independent manner by triggering intra-mitochondrial kinases that regulate the release of cytochrome c (Cyt c), an important step in cellular apoptosis. The aim of this study is to determine the structural requirements for mitochondrial alpha3beta4* nAChR activation by measuring the modulatory effects of two noncompetitive antagonists of these receptors, (+)-catharanthine and (+/-)-18-methoxycoronaridine [(+/-)-18 MC], on Cyt c release from wild-type and alpha7-/- mice mitochondria. The sandwich ELISA results indicated that alpha3beta4* nAChRs are present in liver mitochondria in higher amounts compared to that in brain mitochondria and that these receptors are up-regulated in alpha7-/- mice. Correspondingly, (+/-)-18-MC decreased Cyt c release from liver mitochondria of wild-type mice and from brain and liver mitochondria of alpha7-/- mice. The effect in wild-type mice mitochondria was mediated mainly by the Src-dependent pathway, regulating the apoptogenic activity of reactive oxygen species, while in alpha7-/- mice mitochondria, (+/-)-18-MC strongly affected the calcium-calmodulin kinase II dependent pathway. In contrast, (+)-catharanthine was much less potent than (+/-) 18-MC and triggered several signaling pathways, suggesting the involvement of multiple nAChR subtypes. These results show for the first time that noncompetitive antagonists can induce mitochondrial alpha3beta4* nAChR signaling, giving a more comprehensive understanding on the function of intracellular nAChR subtypes. PMID- 29277578 TI - Perceptions of patients with rheumatic diseases treated with subcutaneous biologicals on their level of information: RHEU-LIFE Survey. AB - OBJECTIVE: To investigate, in Spanish patients with rheumatic diseases treated with subcutaneous biological drugs, their sources of information, which sources they consider most relevant, and their satisfaction with the information received in the hospital. METHODS: Rheumatologists from 50 hospitals handed out an anonymous survey to 20 consecutive patients with rheumatoid arthritis, axial spondyloarthritis or psoriatic arthritis treated with subcutaneous biologicals. The survey was developed ad hoc by 4 rheumatologists and 3 patients, and included questions with closed-ended responses on sources of information and satisfaction. RESULTS: The survey was handed-out to 1,000 patients, 592 of whom completed it (response rate: 59.2%). The rheumatologist was mentioned as the most important source of information (75%), followed by the primary care physician, nurses, and electronic resources; 45.2% received oral and written information about the biological, 46.1% oral only, and 6.0% written only; 8.7% stated that they had not been taught to inject the biological. The percentage of patients satisfied with the information received was high (87.2%), although the satisfaction was lower in relation to safety. If the information came from the rheumatologist, the satisfaction was higher (89.6%) than when coming from other sources (59.6%; P<.001). Satisfaction was also higher if the information was provided orally and written (92.8%) than if provided only orally (86.1%; P=.013); 45.2% reported having sought information from sources outside the hospital. CONCLUSIONS: The rheumatologist is key in transmitting satisfactory information on biological treatment to patients. He or she must also act as a guide, since a high percentage of patients seeks information in other different sources. PMID- 29277579 TI - IgG4-related disease with possible myocardial involvement. AB - IgG4-related disease is characterized by mass lesions, a dense lymphoplasmacytic infiltrate with immunohistochemical positivity for IgG4, storiform fibrosis and, frequently, elevated serum IgG4 levels. It can be multisystemic; however, myocardial involvement, which is objectively determined by imaging tests, has not been described in the medical literature. We report the case of a man with IgG4 related disease with possible myocardial involvement, detected by cardiac magnetic resonance. This raises the question of a differential diagnosis with other diseases such as sarcoidosis and Fabry disease, the differential diagnosis of which is of great importance due to its therapeutic impact. PMID- 29277575 TI - Therapeutic vaccines for high-risk HPV-associated diseases. AB - Cancer is the second leading cause of death worldwide, and it is estimated that Human papillomavirus (HPV) related cancers account for 5% of all human cancers. Current HPV vaccines are extremely effective at preventing infection and neoplastic disease; however, they are prophylactic and do not clear established infections. Therapeutic vaccines which trigger cell-mediated immune responses for the treatment of established infections and malignancies are therefore required. The E6 and E7 early genes are ideal targets for vaccine therapy due to their role in disruption of the cell cycle and their constitutive expression in premalignant and malignant tissues. Several strategies have been investigated for the development of therapeutic vaccines, including live-vector, nucleic acid, peptide, protein-based and cell-based vaccines as well as combinatorial approaches, with several vaccine candidates progressing to clinical trials. With the current understanding of the HPV life cycle, molecular mechanisms of infection, carcinogenesis, tumour biology, the tumour microenvironment and immune response mechanisms, an approved HPV therapeutic vaccine seems to be a goal not far from being achieved. In this article, the status of therapeutic HPV vaccines in clinical trials are reviewed, and the potential for plant-based vaccine production platforms described. PMID- 29277580 TI - In vivo release of peptide-loaded PLGA microspheres assessed through deconvolution coupled with mechanistic approach. AB - In this study, a reevaluation of the in vivo release phases from long-release PLGA-based microspheres is presented, leading to a better characterization of the plasma concentrations/time profile. Microspheres were designed for intramuscular injection releasing a cyclic somatostatin analog over 70 days. Clinical study was performed in 64 healthy subjects receiving a subcutaneous dose of an immediate release solution as reference formulation and an intramuscular injection of microspheres as test formulation. The in vivo input curve was obtained by numerical deconvolution. Results showed that double Weibull function could not fit correctly the tri-phasic (burst, lag, and erosion) in vivo input profile typical for PLGA-based formulations, due to a change in the drug release trend in the terminal phase. Triple Weibull showed a significant improvement in the curve fitting, each term being assigned to one of the following phases: initial (burst/lag), erosion, and terminal phase of drug release. The existence of the additional terminal phase was confirmed by a mechanistic approach as well, which denoted that this phase was, most probably, a consequence of the release mechanism change from erosion to diffusion controlled. The same model demonstrated that the burst release was as well influenced by the polymer swelling, while currently existing theories state that the burst phase is mainly determined by the dissolution of immediately available drug substance and diffusion through surface related pores. PMID- 29277581 TI - Verbal and visuospatial working memory during pregnancy: EEG correlation between the prefrontal and parietal cortices. AB - Pregnancy is a dynamic process during which significant cognitive changes take place. It has been suggested that working memory (WM) is affected during gestation as a result of functional changes among cortical areas, such as the prefrontal and parietal cortices. This study examined cortical electroencephalographic correlations (rEEG) during performance of WM tasks in each trimester of pregnancy. Forty women were divided into 4 groups: first (T1), second (T2), and third (T3) trimester of pregnancy, and a control group of non pregnant women. Electroencephalographic activity (EEG) was recorded from the frontopolar, dorsolateral and parietal cortices during performance of one verbal and one visuospatial working memory task. Only groups T2 and T3 showed increased onset latency in the visuospatial WM. During the verbal WM task, the T1 group showed a higher correlation between dorsolateral areas in the theta and alpha bands, as well as a lower left prefrontal-parietal correlation in the gamma band. During the visuospatial WM task, the T1 and T3 groups showed a higher left EEG correlation in the delta and alpha1 bands, whereas T2 presented a higher right prefrontal-parietal correlation in the gamma band. Although pregnancy had only a subtle effect on the visuospatial WM task, these different patterns of cortical synchronization in each trimester of pregnancy could represent adaptive mechanisms that enabled the pregnant women to focus their attention and use more cognitive resources and so adequately solve the WM tasks. PMID- 29277582 TI - Behavioral tagging: Synaptic event or cellular alteration? AB - Recently a number of studies were published addressing the translation of the synaptic tagging and capture hypothesis (STCH), developed and tested in hippocampal slices, into learning and long-term memory mechanisms in intact animals. Based on behavioral observations, these studies show similar results as in the original STCH experiments. A weak memory, induced by weak training in one hippocampus dependent behavioral task is converted into a long-term memory, by timely related induction of a long-term memory, induced by strong training in a second hippocampus dependent task. The induction of long-term memory should result in the synthesis of plasticity related proteins (PRP), which can be captured by the synapses involved in the weak memory trace and thus be converted into a long-term memory. Here it is outlined, that these results can alternatively be explained by non-synaptic mechanisms like changes in neuronal intrinsic excitability (IE). The plasticity of short and long-term IE show some common features with synaptic plasticity. Thus, behavioral tagging experiments, purely based on behavioral observations, do not necessarily support that synaptic tagging and capture mechanisms are involved in memory formations, unless it has been shown that the weak and strong training protocols result in synaptic early and late potentiation, or the STCH could be extended to short and long-term forms of intrinsic excitability. PMID- 29277583 TI - WISP1 genetic variants as predictors of tumor development with urothelial cell carcinoma. AB - OBJECTIVES: Urothelial cell carcinoma (UCC) of the urinary bladder is a major malignancy of the genitourinary tract. Etiological factors, such as the environment, ethnicity, genetics, and diet, contribute to UCC carcinogenesis. WNT1-inducible signaling pathway protein 1 (WISP1), also known as CCN4, a cysteine-rich protein belonging to the Cyr61, CTGF, Nov (CCN) family of matricellular proteins, has many developmental functions and might be involved in carcinogenesis. This study investigated WISP1 single-nucleotide polymorphisms to evaluate UCC susceptibility and clinicopathological characteristics. MATERIALS AND METHODS: Real-time polymerase chain reaction was used to analyze 4 single nucleotide polymorphisms of WISP1 in 369 patients with UCC and 738 controls without cancer. RESULTS: The results showed that in 128 women with UCC who carried WISP1 rs2929973 (AG + GG) variants had a higher risk of developing an advanced muscle-invasive tumor stage (pT2-pT4, P = 0.007) and a large tumor (T1 T4, P = 0.030). Further analyses revealed that a correlation between the expressions of WISP1 and invasive tumor and large tumor size in urothelial carcinoma was observed in the TCGA (The Cancer Genome Atlas) dataset. CONCLUSIONS: Our results indicated that patients with UCC carrying rs2977530 genetic variants (AG + GG) have a higher risk of developing a more invasive tumor stage and a large tumor. WISP1 polymorphisms may serve as a marker or a therapeutic target in UCC. PMID- 29277584 TI - Comparative effectiveness of robot-assisted vs. open radical cystectomy. AB - OBJECTIVES: Over the past decade, robot-assisted radical cystectomy (RARC) has gained traction as an alternative to the conventional open approach open radical cystectomy (ORC). However, the benefits of RARC over ORC remain unclear. Our objective was to conduct a comparative effectiveness analysis between RARC and ORC using data from the National Cancer Data Base. MATERIALS AND METHODS: Within the National Cancer Data Base, we identified patients with localized muscle invasive bladder cancer who underwent RC between 2010 and 2013. Patients were stratified according to surgical approach: ORC vs. RARC. Intraoperative endpoints included: the presence of positive surgical margins, the performance of a pelvic lymph node dissection, and number of lymph nodes (LN) removed. Postoperative endpoints included: length of stay (LOS), 30- and 90-day postoperative mortality (POM) rates, 30-day readmission rate, and overall survival (OS). To minimize selection bias, observed differences in baseline characteristics between RARC vs. ORC patients were controlled for using weighted propensity scores. Binary endpoints and OS were assessed using propensity score-adjusted logistic and Cox regression analyses, respectively. POM was assessed using propensity score weighted Kaplan-Meier survival estimates at 30 and 90 days after RC. RESULTS: Of 9,561 patients who underwent RC, 2,048 (21.4%) and 7,513 (78.6%) underwent RARC and ORC, respectively. The use of RARC increased over time, from 16.7% in 2010 to 25.3% in 2013. With regard to intraoperative outcomes, RARC was associated with equivalent rates of positive surgical margins (9.3% vs. 10.7%, odds ratio [OR] = 0.86, 95% CI: 0.72-1.03; P = 0.10), higher rates of pelvic lymph node dissection (96.4% vs. 92.0%, OR = 2.30, 95% CI: 1.67-3.16; P<0.001), higher median LN count (17 vs. 12, P<0.001), higher rates of LN count above the median (56.8% vs. 40.4%, OR = 1.94, 95% CI: 1.55-2.42, P<0.001). With regard to postoperative outcomes, receipt of RARC was associated with a shorter median LOS (7 vs. 8, P<0.001), and lower rates of pLOS (45.0% vs. 54.8%, OR = 0.68, 95% CI: 0.58-0.79; P<0.001). The 30- and 90-day POM rates were 2.8%, 6.7% for ORC, and 1.4%, 4.8% for RARC, respectively (hazard ratio [HR] = 0.48, 95% CI: 0.29-0.80, P = 0.005 and HR = 0.71, 95% CI: 0.54-0.93; P = 0.014). Finally, with a mean follow-up of 26.9 months, on IPTW-adjusted Cox regression analysis, RARC vs. ORC was associated with a benefit in OS (HR = 0.79, 95% CI: 0.71-0.88; P<0.001). CONCLUSIONS: Our large contemporary study found an increased adoption of RARC between 2010 and 2013, with more than 1 out of 4 patients undergoing RARC by the end of the study period. We found that RARC was associated with higher LN counts, shorter LOS, and lower POM. Our results allude to potential benefits of RARC while we wait for more definitive answers from randomized trials. PMID- 29277585 TI - A comparison of time taken to return to baseline erectile function following focal and whole gland ablative therapies for localized prostate cancer: A systematic review. AB - OBJECTIVES: To systematically review erectile function (EF) outcomes following primary whole gland (WG) and focal ablative therapies for localized prostate cancer to ascertain whether the treatment modality or intended treatment volume affects the time taken to recover baseline EF. METHOD AND MATERIALS: A systematic review was performed according to the preferred reporting items for systematic review and meta-analysis statement. Inclusion criteria were men with localized prostate cancer treated with primary, ablative therapy. Primary outcome was the return to baseline EF measured with objective, validated symptoms scores. Secondary outcome was use of phosphodiesterase inhibitors or erectile aids. Meta analysis was not performed owing to heterogenous outcome measures. RESULTS: Of 222 articles identified in February 2017, 55 studies which reported EF after ablative therapy were identified but only 17 used validated outcome measures and met inclusion criteria. WG cryotherapy was used in 2 studies, WG high-intensity focused ultrasound (HIFU) in 5, focal cryotherapy in 2, focal HIFU in 3, focal phototherapy or laser therapy in 4, vascular-targeted photodynamic therapy in 3, and irreversible electroporation in 2. WG cryotherapy was associated with a significant decline in EF at 6 months with minimal improvement at 36 months. Baseline IIEF-15 of patients undergoing focal HIFU fell 30 points at 1 month but returned to baseline by 6 months. The remaining focal therapies demonstrated minimal or no effect on EF, but the men in these studies had small foci of disease. The review is limited by lack of randomized studies and heterogenous outcome measures. CONCLUSIONS: Most studies assessing the outcomes of focal therapy on sexual function were not of high quality, used heterogenous outcomes, and had relatively short follow up, highlighting the need for more robustly designed studies using validated patient reported outcome measures for comparison. However, FT in general resulted in less effect on EF than WG ablation. PMID- 29277586 TI - Cortical control of upright stance in elderly. AB - This study examined differences between young and elderly volunteers in cortical involvement to human posture control during quiet stance with normal and altered sensory stimulation (Experiment-1), and biomechanical perturbations (Experiment 2). The primary focus of the first part was to monitor changes in cortical activity when unexpectedly altering the sensory conditions of upright stance, such as switching from stable (eyes open, fixed support surface) to less-stable (eyes closed, sway-referenced support surface) conditions. Our results demonstrate increased cortical activations in delta (0.2-4 Hz) and gamma (30-50 Hz) oscillations, primarily over central-frontal, central, and central parietal cortices during challenging postural conditions. While increased delta rhythms were observed in both groups during challenging sensory conditions, elderly individuals also showed increased gamma band activity over sensorimotor and parietal cortices, when compared to the younger group. To our knowledge, this study is the first to show age differences in balance related cortical activations during continuous postural tasks with challenging sensory conditions. Preliminary correlations also suggest that increased cerebral activity became more relevant to the control of Center of Mass (COM) dynamics when upright stance is threatened. The results of Experiment-2 also showed for the first time that oscillatory rhythms of the cortex are coherent with muscle firing characteristics suggesting increased corticospinal drive from leg motor cortex to lower limb motoneurons following postural perturbations. Finally, perturbation evoked potential (PEP) analyses suggest that, rather than motor system malfunctioning, impairments in perceptual processing of sensory afference forms the basis of prolonged muscle response delays during perturbed balance in the elderly. PMID- 29277587 TI - The Use of Flow Diverter in Ruptured, Dissecting Intracranial Aneurysms of the Posterior Circulation. AB - OBJECTIVE: Acute dissecting aneurysms of the posterior circulation are a rare cause of subarachnoid hemorrhage. Established endovascular treatment options include parent artery occlusion and stent-assisted coiling, but appear to be associated with an increased risk of ischemic stroke. Vessel reconstruction with flow diverters is an alternative treatment option; however, its safety and efficacy in the acute stage remains unclear. METHODS: This is a multicentric retrospective analysis of 15 consecutive acutely ruptured dissecting posterior circulation aneurysms treated with flow diverters. The primary end point was favorable aneurysm occlusion, defined as OKM C1-3 and D (O'Kelly Marotta scale). Secondary end points were procedure-related complications and clinical outcome. RESULTS: Nine of 15 aneurysms (60%) arose from the intradural portion of the vertebral artery, 3 were located on the posterior inferior cerebellar artery and 1 each on the anterior inferior cerebellar artery, posterior cerebral artery, and basilar artery. Flow diverter placement was technically successful in 14 of 15 cases (93%). After endovascular treatment, none of the ruptured aneurysms rebled. Median clinical follow-up was 217 days and median angiographic follow-up was 203 days. Favorable occlusion was observed in 7 of 14 aneurysms (50%) directly after flow diverter placement; of those, 5 were completely occluded (36%). Seven patients (47%) with poor-grade subarachnoid hemorrhage died in the acute phase. Favorable clinical outcome (modified Rankin scale <=2) was observed in 4 of 15 patients (27%) and a moderate outcome (modified Rankin scale 3/4) was observed in 5 of 15 patients (33%). All aneurysms showed complete occlusion at follow-up. CONCLUSIONS: Flow diverters might be a feasible, alternative treatment option for acutely ruptured dissecting posterior circulation aneurysms and may effectively prevent rebleeding. Larger cohort studies are required to validate these results. PMID- 29277589 TI - Transdural Propagation of Glioblastoma Through Foramen Rotundum. AB - BACKGROUND: Glioblastoma, also known as glioblastoma multiforme, is the most common primary malignant cerebral tumor in adults. Although glioblastoma multiforme is one of the most aggressive tumors in the brain, propagation through the dura mater is rare. CASE DESCRIPTION: A 59-year-old man presented with progressive headache and aphasia. Magnetic resonance imaging identified an abnormal mass extending transcranially through the widened foramen rotundum into the infratemporal fossa and cavernous sinus. Emergency surgery was performed because of the patient's disturbed consciousness and uncal herniation. The pathologic diagnosis was glioblastoma with isocitrate dehydrogenase 1 (IDH-1) wild type arising in the left temporal region of the brain, penetrating the dura mater and propagating to the middle fossa with enlargement of the foramen rotundum. The tumor was resected, and radiochemotherapy with temozolomide was administered. CONCLUSION: Although the mechanism of tumor spread is unknown, we hypothesized that originally there may have been spontaneous dural defects or thinning, such as a meningoencephalocele in the middle fossa, and the tumor coincidentally occurred there. PMID- 29277588 TI - Sport-Related Traumatic Brain Injury with and without Helmets in Children. AB - BACKGROUND: Soccer, bicycling, and horseback riding are sports most commonly associated with traumatic brain injury (TBI) in Germany. The latter 2 sports activities are commonly practiced with helmets, and data on helmet use and usefulness vary widely. METHODS: On Ethics Committee approval, a retrospective analysis was performed for patients age 5-17 between January 2009 and August 2014 based on a diagnosis of TBI, using the electronic patient file for 2 university hospital locations. Descriptive data analysis and multivariate and univariate logistic regression were used to calculate odds ratios (ORs). RESULTS: A total of 380 children were identified, including 162 females (42.6%) and 218 males (57.4%), with a mean age of 11.9 +/- 3.8 years. Activities included bicycling (n = 64), horseback riding (n = 19), and soccer (n = 16). Helmet use was documented in 26 patients (14 cyclists, 12 riders), and nonuse was documented in 20 (all cyclists). Compared with not wearing a helmet, wearing a helmet was associated with a trend toward lower odds of loss of consciousness (OR, 0.7; 95% confidence interval [CI], 0.18-2.52). A cohort of 251 patients with non-sports-related TBI (NSTBI) served as a control group for further analyses. Compared with the NSTBI group, the odds of amnesia were 2.9 times greater (95% CI, 1.1-21.6) in the patients with a riding-related TBI and 4.8 times greater (95% CI, 0.3-239) in those with a cycling-related TBI, and the odds of epidural hematoma were 2.2 times greater (95% CI, 0.4-12.3) in those with a cycling-related TBI and 4.9 times greater (95% CI, 0.5-50.4) greater in those with a soccer-related TBI. CONCLUSIONS: We gained important epidemiologic data on pediatric TBI in our region. Despite the descriptive nature of the data, a trend toward reduced odds of loss of consciousness was seen in the helmet wearers. Nevertheless, serious injury can occur despite helmet use. PMID- 29277590 TI - Feasibility of a Modified E-PASS and POSSUM System for Postoperative Risk Assessment in Patients with Spinal Disease. AB - OBJECTIVE: This retrospective case control study aimed to evaluate the feasibility of using Estimation of Physiological Ability and Surgical Stress (E PASS) and Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) systems in patients undergoing spinal surgical procedures. Degenerative spine disease has increased in incidence in aging societies, as has the number of older adult patients undergoing spinal surgery. Many older adults are at a high surgical risk because of comorbidity and poor general health. METHODS: We retrospectively reviewed 217 patients who had undergone spinal surgery at a single tertiary care. We investigated complications within 1 month after surgery. Criteria for both skin incision in E-PASS and operation magnitude in the POSSUM system were modified to fit spine surgery. We calculated the E-PASS and POSSUM scores for enrolled patients, and investigated the relationship between postoperative complications and both surgical risk scoring systems. To reinforce the predictive ability of the E-PASS system, we adjusted equations and developed modified E-PASS systems. RESULTS: The overall complication rate for spinal surgery was 22.6%. Forty-nine patients experienced 58 postoperative complications. Nineteen major complications, including hematoma, deep infection, pleural effusion, progression of weakness, pulmonary edema, esophageal injury, myocardial infarction, pneumonia, reoperation, renal failure, sepsis, and death, occurred in 17 patients. The area under the receiver operating characteristic curve (AUC) for predicted postoperative complications after spine surgery was 0.588 for E-PASS and 0.721 for POSSUM. For predicted major postoperative complications, the AUC increased to 0.619 for E-PASS and 0.842 for POSSUM. The AUC of the E-PASS system increased from 0.588 to 0.694 with the Modified E-PASS equation. CONCLUSIONS: The POSSUM system may be more useful than the E-PASS system for estimating postoperative surgical risk in patients undergoing spine surgery. The preoperative risk scores of E-PASS and POSSUM can be useful for predicting postoperative major complications. To enhance the predictability of the scoring systems, using of modified equations based on spine surgery-specific factors may help ensure surgical outcomes and patient safety. PMID- 29277591 TI - Egg Model Training Protocol for Stereotaxic Neurosurgery and Microelectrode Implantation. AB - BACKGROUND: Neuroscience research uses neurosurgery in animal models for several experimental techniques. To our knowledge, there is no published method for small animal neurosurgery training. Based on the similar thickness of chicken eggshells and mouse, rat, and some small primate skulls, here we propose an egg model training protocol for stereotaxic surgery. MATERIALS AND METHODS: To perform training it was used a boiled egg and the same materials needed to perform stereotaxic neurosurgery in small animals. DISCUSSION: This protocol allows trainees in neuroscience research to become familiar with the microsurgery setting and learn neurosurgery techniques, such as craniotomy drilling, dura mater removal, and electrode implantation. CONCLUSION: Egg model suitably mimics animal neurosurgery for the replacement and sparing of animals intended for training in neurosurgical skills. PMID- 29277592 TI - Colloid Cyst of the Third Ventricle: Long-Term Results of Endoscopic Management in a Series of 112 Cases. AB - OBJECTIVES: The endoscopic approach increasingly is used to treat third ventricular colloid cysts. Our objective was to assess the results of endoscopic resection of colloid cysts of the third ventricle. METHODS: A retrospective study was designed, and a series of 112 consecutive patients (76 male, 36 female) with third ventricular colloid cyst treated by endoscopic surgery was undertaken. RESULTS: We found that the most common clinical presentations in patients with third ventricular colloid cyst were headache, vomiting, and impaired vision. Complete resection was obtained in majority of patients (92%). Meningitis, hemiparesis, and memory deficits occurred most commonly as postoperative complications. CONCLUSIONS: High rates of complete resection of third ventricular colloid cysts, with low morbidity and mortality, are possible with an endoscopic approach. The results of this study support the role of endoscopic resection in the treatment of patients with third ventricular colloid cysts as a safe and effective modality and show how endoscopic resection of third ventricular colloid cysts can produce favorable results. PMID- 29277593 TI - Oculoleptomeningeal Amyloidosis Secondary to the Rare Transthyretin c.381T>G (p.Ile127Met) Mutation. AB - BACKGROUND: Oculoleptomeningeal amyloidosis (OLMA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges along with ocular involvement. Of >100 TTR mutations identified, few have been associated with OLMA. Herein we describe the first report of leptomeningeal amyloidosis associated with the c.381T>G (p.Ile127Met) TTR mutation, linking this variant to the OLMA phenotype. CASE DESCRIPTION: A 53 year-old man presented with a 2-year history of progressive symptoms including upper and lower limb weakness, ataxia, and peripheral and autonomic neuropathy. Neuroimaging, including gadolinium-enhanced magnetic resonance imaging of the brain and spinal axis, identified diffuse leptomeningeal enhancement along the brainstem and spinal cord plus evidence of hemosiderosis. Pathologic and genetic analyses of biopsy material from enhancing intradural extramedullary tissue at the thoracolumbar junction was diagnostic of amyloidosis of a transthyretin type secondary to a TTR c.381T>G (p.Ile127Met) mutation. CONCLUSIONS: OLMA represents a rare subtype of heritable transthyretin amyloidosis that may present with progressive neurological decline secondary to central nervous system leptomeningeal amyloid deposition. This case identifies the c.381T>G (p.Ile127Met) TTR mutation variant as being implicated in the OLMA phenotype. PMID- 29277594 TI - Modified Laminoplasty Preserving the Posterior Deep Extensor Insertion into C2 Improves Clinical and Radiologic Results Compared with Conventional Laminoplasty: A Meta-Analysis. AB - BACKGROUND: Whether modified laminoplasty is better than conventional laminoplasty is unclear. Thus, a meta-analysis comparing the outcomes of preserving or repairing the posterior deep extensor insertion to C2 in laminoplasty was conducted for patients with multilevel cervical spondylotic myelopathy (MCSM). METHODS: Several electronic databases were chosen to search for relevant studies. The primary indices included preoperative and postoperative Japanese Orthopaedic Association (JOA) scores, JOA recovery rate, muscle atrophy rate, preoperative and postoperative range of motion (ROM), ROM decrease rate, and incidence of axial pain. Results are expressed as odds ratios with 95% confidence intervals for the dichotomous outcomes and mean differences for continuous outcomes. RESULTS: Eight studies involving 763 patients were included in this study. The postoperative cervical ROM was significantly higher in the modified group (P = 0.01, MD = 3.0 [0.66, 5.35]), as was the cervical posterior muscle volume (P = 0.02, MD = 28.28 [4.42, 52.3]) and the operation time (MD = 45.04, 95% CI -49.79, -40.29; P < 0.01). The incidence of axial symptoms in the modified group was lower than that in the conventional group (P < 0.01, OR 0.28 [0.17, 0.46]), as was the rate of decrease of cervical ROM (P = 0.004, MD = -6.72 [-11.25, 2.19]). There was no significant difference (P > 0.05) between the groups in blood loss, preoperative and postoperative JOA score, or JOA recovery rate. CONCLUSIONS: Modified laminoplasty had shorter operation times, a lower incidence of axial pain, a higher cervical ROM, and a lower atrophy rate compared with conventional laminoplasty. The clinical and radiologic results of modified laminoplasty have been partly superior to those of conventional laminoplasty to date. PMID- 29277595 TI - Long-Term Follow-Up Comparative Study of Hydroxyapatite and Autologous Cranioplasties: Complications, Cosmetic Results, Osseointegration. AB - OBJECTIVE: A three-dimensional reconstruction technique using the CustomBone (CB) prosthesis allows custom-made cranioplasty (CP) possessing osseointegration properties owing to its porous hydroxyapatite (HA) composition. This reconstruction technique has replaced less expensive techniques such as subcutaneously preserved autologous bone (SP). Our primary objective was to evaluate complications between CB and SP CP techniques. A secondary objective was to assess cosmetic results and osseointegration of CPs. METHODS: This single center study comprised patients undergoing delayed CB or SP CP after craniectomy between 2007 and 2014. A prospective interview was conducted to collect all data, including 2-year follow-up clinical and radiologic data. Cosmetic results were assessed by a qualitative score, and osseointegration was assessed by measuring relative fusion at the CP margins. RESULTS: Of 100 patients undergoing CB or SP CP between 2007 and 2014, 92 (CB, n = 44; SP, n = 48) participated in the prospective interview. No significant difference in complication rates was observed between the 2 groups. The main complication specific to the CB group was fracture of the prosthesis observed in 20.8% patients. A higher rate of good cosmetic results was observed in the CB group (92.5% vs. 74.3%, P = 0.031). In the CB group, 51% of patients demonstrated no signs of bone fusion of the CP. CONCLUSIONS: Although the CB prosthesis is associated with cosmetic advantages, the porous hydroxyapatite composition makes it fragile in the short-term and long term, and effective osseointegration remains uncertain. PMID- 29277596 TI - Smartphone Usage Patterns by Canadian Neurosurgery Residents: A National Cross Sectional Survey. AB - BACKGROUND: Smartphones and their apps are used ubiquitously in medical practice. However, in some cases their use can be at odds with current patient data safety regulations such as Canada's Personal Health Information Protection Act of 2004. To assess current practices and inform mobile application development, we sought to better understand mobile device usage patterns among Canadian neurosurgery residents. METHODS: Through the Canadian Neurosurgery Research Collaborative, an online survey characterizing smartphone ownership and usage patterns was developed and sent to all Canadian neurosurgery resident in April of 2016. Questionnaires were collected and completed surveys analyzed. RESULTS: Of 146 eligible residents, 76 returned completed surveys (52% response rate). Of these 99% of respondents owned a smartphone, with 79% running on Apple's iOS. Four general mobile uses were identified: 1) communication between members of the medical team, 2) decision support, 3) medical reference, and 4) documentation through medical photography. Communication and photography were areas where the most obvious breaches in the Canadian Personal Health Information Protection Act were noted, with 89% of respondents taking pictures of patients' radiologic studies and 75% exchanging them with Short Message System. Hospital policies had no impact on user behaviors. CONCLUSIONS: Smartphones are used daily by most neurosurgery residents. Identified usage patterns are associated with perceived gains in efficacy and challenges in privacy and data reliability. We believe creating and improving workflows that address these usage patterns has a greater potential to improve privacy than changing policies and enforcing regulations. PMID- 29277597 TI - Patient ranking with temporally annotated data. AB - Modern medical information systems enable the collection of massive temporal health data. Albeit these data have great potentials for advancing medical research, the data exploration and extraction of useful knowledge present significant challenges. In this work, we develop a new pattern matching technique which aims to facilitate the discovery of clinically useful knowledge from large temporal datasets. Our approach receives in input a set of temporal patterns modeling specific events of interest (e.g., doctor's knowledge, symptoms of diseases) and it returns data instances matching these patterns (e.g., patients exhibiting the specified symptoms). The resulting instances are ranked according to a significance score based on the p-value. Our experimental evaluations on a real-world dataset demonstrate the efficiency and effectiveness of our approach. PMID- 29277598 TI - Deletion of Rap1 disrupts redox balance and impairs endothelium-dependent relaxations. AB - AIMS: Repressor activator protein 1 (Rap1) is conventionally known as a static structural component of the telomere, but recent evidence indicates that it exerts functions within and outside the nucleus taking part in metabolic regulation and promoting inflammatory responses. The present study investigated whether or not Rap1 deletion affects oxidative stress and nitric oxide (NO) bioavailability in the vascular wall, thus modulating endothelial function. METHODS AND RESULTS: Vascular responsiveness was studied in wire myographs in aortae from Rap1 wildtype and knockout mice. Deletion of Rap1 impaired endothelium-dependent relaxations elicited by acetylcholine. Rap1 deficiency did not affect the activation of endothelial NO synthase or the sensitivity of vascular smooth muscle to NO donors. The blunted acetylcholine-mediated relaxations in Rap1 deficient aortae were restored with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors, apocynin or VAS2870. Rap1 deletion lowered cellular thiol-redox status and diminished activities of thiol redox enzymes, thioredoxin 1 and glutaredoxin 1. CONCLUSIONS: The capacity of thioredoxin 1 and glutaredoxin 1 to reduce intra-protein disulfide bridges is weakened in Rap1 deficient mice, resulting in hyper-activation of NADPH oxidase and greater reactive oxygen species generation. The high oxidative stress in Rap1 deficient mice is implicated with greater oxidative breakdown of NO, explaining the blunted acetylcholine-mediated relaxations in this animal. These findings imply that Rap1 plays an unanticipated role in regulating the fate of NO (a pivotal determinant of vascular homeostasis) and thus identify a new physiological importance of the telomere-associated protein. PMID- 29277599 TI - Evolution of mate-finding Allee effect in prey. AB - The search for mates is often accompanied with conspicuous behaviour or morphology that can be exploited by predators. Here we explore the evolutionary consequences of a trade-off that arises naturally between mate acquisition and risk of predation and study evolution of the rate at which male prey search for mates in a population subject to a mate-finding Allee effect and exposed to either generalist or specialist predators. Since we show that the mate search rate determines the strength of the mate-finding Allee effect, we can alternatively view this as evolution of the mate-finding Allee effect in prey. We contrast two different life histories and find that, predominantly, male prey either evolve towards the maximal mate search rate yielding the weakest possible mate-finding Allee effect (thus showing no adaptive response in mating behaviour to predation risk) or evolutionary bi-stability occurs. In the latter case, males evolve a relatively low mate search rate (hence a relatively strong mate-finding Allee effect, interpreted as an adaptive response of male prey to predation) when initially slow or the maximal mate search rate when initially fast. Disruptive selection does not occur in populations exposed to generalist predators but is possible when predators are specialists. The dimorphic phase, in which fast and conspicuous male prey coexist with slow and cryptic ones, is however but a transient in evolutionary dynamics as one branch goes extinct while the other evolves towards the maximal mate search rate. PMID- 29277600 TI - Morphometric staging of organ development based on cross sectional images. AB - An objective, continuous, and robust method for staging developing embryos or organs is essential for providing a common measure of time when studying quantitative/systems developmental biology. However, classical methods based on factors such as somite number or qualitative visual attributes are discrete and/or ambiguous due to observers' subjectivity. Thus, an alternative staging method based on an explicit and continuous description of developmental states over time, such as anatomy/morphology, is needed. Here, we briefly propose a novel staging method as a natural extension of classical staging based on cross sectional images of organs, which are more accessible than full 3D structures. The contours are represented as 2D closed curves and quantified using elliptic Fourier descriptors. Treating the ambiguity in classical staging as a statistical model, the relationship between the novel morphometric staging and classical staging can be determined. This method was validated by applying it to two different sets of data: chick forebrain and Xenopus hindlimb development. Using this method, it is also possible to reconstruct the time evolution of the average morphology, which would be useful for quantitatively comparing morphologies between embryos or between normal and abnormal conditions. PMID- 29277601 TI - An isotope dilution model for partitioning of phenylalanine and tyrosine uptake by the liver of lactating dairy cows. AB - An isotope dilution model to describe the partitioning of phenylalanine and tyrosine in the bovine liver was developed. The model comprises four intracellular and six extracellular pools and various flows connecting these pools and external blood. Conservation of mass principles were applied to generate the fundamental equations describing the behaviour of the system in the steady state. The model was applied to datasets from multi-catheterised dairy cattle during a constant infusion of [1-13C]phenylalanine and [2,3,5,6 2H]tyrosine tracers. Model solutions described the extraction of phenylalanine and tyrosine from the liver via the portal vein and hepatic artery. In addition, the exchange of free phenylalanine and tyrosine between extracellular and intracellular pools was explained and the hydroxylation of phenylalanine to tyrosine was estimated. The model was effective in providing information about the fates of phenylalanine and tyrosine in the liver and could be used as part of a more complex system describing amino acid metabolism in the whole animal. PMID- 29277602 TI - A circuit-preserving mapping from multilevel to Boolean dynamics. AB - Many discrete models of biological networks rely exclusively on Boolean variables and many tools and theorems are available for analysis of strictly Boolean models. However, multilevel variables are often required to account for threshold effects, in which knowledge of the Boolean case does not generalise straightforwardly. This motivated the development of conversion methods for multilevel to Boolean models. In particular, Van Ham's method has been shown to yield a one-to-one, neighbour and regulation preserving dynamics, making it the de facto standard approach to the problem. However, Van Ham's method has several drawbacks: most notably, it introduces vast regions of "non-admissible" states that have no counterpart in the multilevel, original model. This raises special difficulties for the analysis of interaction between variables and circuit functionality, which is believed to be central to the understanding of dynamic properties of logical models. Here, we propose a new multilevel to Boolean conversion method, with software implementation. Contrary to Van Ham's, our method doesn't yield a one-to-one transposition of multilevel trajectories; however, it maps each and every Boolean state to a specific multilevel state, thus getting rid of the non-admissible regions and, at the expense of (apparently) more complicated, "parallel" trajectories. One of the prominent features of our method is that it preserves dynamics and interaction of variables in a certain manner. As a demonstration of the usability of our method, we apply it to construct a new Boolean counter-example to the well-known conjecture that a local negative circuit is necessary to generate sustained oscillations. This result illustrates the general relevance of our method for the study of multilevel logical models. PMID- 29277603 TI - Comparing evolutionary distances via adaptive distance functions. AB - Distance-based methods for phylogenetic reconstruction are based on a two-step approach: first, pairwise distances are computed from DNA sequences associated with a given set of taxa, and then these distances are used to reconstruct the phylogenetic relationships between taxa. Because the estimated distances are based on finite sequences, they are inherently noisy, and this noise may result in reconstruction errors. Previous attempts to improve reconstruction accuracy focused either on improving the robustness of reconstruction algorithms to this stochastic noise, or on improving the accuracy of the distance estimates. Here, we aim to further improve reconstruction accuracy by utilizing the basic observation that reconstruction algorithms are based on a series of comparisons between distances (or linear combinations of distances). We start by examining the relationship between the stochastic noise in the sequence data and the accuracy of the comparisons between pairwise distance estimates. This examination results in improved methods for distance comparison, which are shown to be as accurate as likelihood-based methods, while being much simpler and more efficient to compute. We then extend these methods to improve reconstruction accuracy of quartet trees, and examine some of the challenges moving forward. PMID- 29277604 TI - Tolerance to hypometabolism and arousal induced by hibernation in the apple snail Pomacea canaliculata (Caenogastropoda, Ampullariidae). AB - Pomacea canaliculata may serve as a model organism for comparative studies of oxidative damage and antioxidant defenses in active, hibernating and arousing snails. Oxidative damage (as TBARS), free radical scavenging capacity (as ABTS+ oxidation), uric acid (UA) and glutathione (GSH) concentrations, activities of superoxide dismutase (SOD) and catalase (CAT), and the protein expression levels of heat shock proteins (Hsp70, Hsc70, Hsp90) were studied in digestive gland, kidney and foot. Tissue TBARS of hibernating snails (45days) was higher than active snails. Hibernation produced an increase of ABTS+ in digestive gland, probably because of the sustained antioxidant defenses (UA and/or GSH and SOD levels). Kidney protection during the activity-hibernation cycle seemed provided by increased UA concentrations. TBARS in the foot remained high 30min after arousal with no changes in ABTS+, but this tissue increased ABTS+ oxidation at 24h to expenses increased UA and decreased GSH levels, and with no changes in SOD and CAT activities. The level of Hsp70 in kidney showed no changes throughout the activity-hibernation cycle but it increased in the foot after hibernation. The tissue levels of Hsp90 in snails hibernating were higher than active snails and returned to baseline 24h after arousal. Results showed that chronic cooling produces a significant oxidative damage in three studied tissues and that these tissue damages are overcome quickly (between 30min to 24h) with fluctuations in different antioxidant defenses (UA, GSH, CAT) and heat shock proteins (Hsp70 and Hsp90). PMID- 29277605 TI - The kinetic properties of hexokinases in African trypanosomes of the subgenus Trypanozoon match the blood glucose levels of mammal hosts. AB - We hypothesize that the hexokinases of trypanosomes of the subgenus Trypanozoon match the blood glucose levels of hosts. We studied the kinetic properties of purified hexokinase in T. equiperdum (specific activity=302U/mg), and compare with other members of Trypanozoon. With ATP (Km=104.7MUM) as phosphate donor, hexokinase catalyzes the phosphorylation of glucose (Km=24.9MUM) and mannose (Km=8.8MUM). With respect to glucose, mannose and inorganic pyrophosphate respectively are a competitive, and a mixed inhibitor of hexokinase. With respect to ATP, both are mixed inhibitors of this enzyme. In T. equiperdum, hexokinase shows a high affinity for glucose. Pleomorphism-transformation of trypanosomes from a multiplicative to a non-multiplicative form-results in a self-limited growth stabilizing glucose consumption. It delays the death of the host, thus prolonging its exposure to tsetse flies. When glucose levels descend, top-down regulation allows trypanosomes to survive through the expression of alternative metabolic pathways. It accelerates the death of the host, but helps trypanosome density to increase enough to ensure transmission without tsetse flies. Pleomorphism, and a hexokinase with a high affinity for glucose, are two main adaptive traits of T. b. brucei. The latter trait, and a strong top-down regulation, are two main adaptive traits of T. equiperdum. For trypanosomes living in glucose-rich blood, a hexokinase with a high affinity for glucose would unnecessarily harm hosts. This may explain why the human parasites, T. b. gambiense and T. b. rhodesiense, possess hexokinases with a low affinity for glucose. PMID- 29277606 TI - Characterization of 2-Cys peroxiredoxin 3 and 4 in common carp and the immune response against bacterial infection. AB - Accumulating evidence suggests that peroxiredoxins (Prxs) eliminate excessive cellular H2O2 and are important factors in redox signaling pathways. In this study, we cloned the full-length cDNAs and genomic sequences of Prx3 and Prx4 from common carp. The common carp Prx3 and Prx4 open reading frames were 753 base pairs (bp) and 783bp in length, respectively, and contained seven exons and six introns. Multiple sequence alignment and phylogenetic analyses revealed that the common carp Prx1-4 proteins share high identities and similar characteristics with other known animal Prxs. Prx3 and Prx4 mRNA were constitutively expressed in all tissues, and the highest Prx3 and Prx4 transcript abundances occurred in head kidney. Although the highest Prx4 protein and mRNA expression were also observed in head kidney, many differences were detected between Prx4 mRNA and protein expression levels in other tissues. Prx3 expression increased significantly in the head kidney 12h after an Aeromonas hydrophila challenge. The A. hydrophila challenge upregulated Prx3 mRNA expression in liver and spleen, increased Prx4 mRNA expression levels in liver and spleen excluding at 36h in spleen, but decreased Prx4 mRNA expression level in the head kidney. The mature Prx4 peptide was recombinantly expressed and purified using Dextrin Beads 6FF and it exhibited thioredoxin (Trx)-dependent peroxidase activity. These data suggest that Prx3 and Prx4 are constitutive and inducible proteins that might play important roles in innate immune function. The Trx-dependent peroxidase activity analysis of recombinant Prx4 further verified the important role of Prxs in the redox system of fish. PMID- 29277607 TI - Effects of mastic oleoresin on wound healing and episiotomy pain: A mixed methods study. AB - INTRODUCTION: Mastic (Pistacia lentiscus) oleoresin (MO is used by traditional Baluch healers to precipitate wound healing and relieve episiotomy pain. OBJECTIVE(S): To investigate the effects of MO on wound healing and episiotomy pain intensity in nulliparous Baluch women. MATERIALS AND METHODS: This study had a mixed methods design. In the qualitative phase, we interviewed 9 traditional healers and 13 women to understand how the indigenous people use MO for wound healing. In the quantitative phase, a randomized controlled trial was performed on primiparous women during July 23-November 22 in 2016. One hundred and forty seven women were randomly assigned to intervention (n=73) and control (n=74) groups. At 48h postpartum, 15g of MO was provided to the women to be administered for three days (through smoking the episiotomy wound). Pain and wound healing were measured at 3, 7, and 10 days postpartum using the visual analogue scale and REEDA scale, respectively. RESULTS: MO had no significant effect on episiotomy pain intensity at 3, 7, and 10 days postpartum (p=0.61, p=0.76, and p=0.45, respectively). In addition, healing rates of the episiotomy wounds treated by MO (mean: 0.11+/-0.45, 0.15+/-0.51, and 0.15+/-0.57, respectively) were higher than those in the control group (mean: 0.21+/-0.70, 0.16+/-0.63, and 0.49+/-0.28, respectively) at 3, 7, and 10 days postpartum; however, the difference between the two groups was not significant (p=0.27, p=0.76, and p=0.23, respectively). CONCLUSION: In the current study, healing rates in the MO group were higher than those in the control group; however, further studies should be undertaken to identify the effects of MO. PMID- 29277608 TI - Triptolide-induced hepatotoxicity can be alleviated when combined with Panax notoginseng saponins and Catapol. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The hepatotoxicity of Tripterygium wilfordii Hook. f. (TW), due to the presence of triptolide (TP), limits its therapeutic potential. Based on the traditional Chinese medicine theory, the theory of "Yi lei xiang zhi" was proposed that Chinese herbs with different efficacy can restrict each other to achieve the least adverse reactions. AIM OF THE STUDY: To observe the effects of Catapol (CAT) and Panax notoginseng saponins (PNS), active ingredients in Rehmannia glutinosa (RG) and Panax notoginseng (PN) respectively, on reducing TP-induced hepatotoxicity, and further to explore the mechanisms. MATERIALS AND METHODS: The human hepatic cell line L-02 was cultured and treated with CAT, PNS or Combinations, and then treated with TP. The cytotoxic assay, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), apoptosis, mitochondrial membrane potential and the expressions of NF-E2-related factor 1 (Nrf1) and its downstream targets were detected. Rats were treated with TP, TP + CAT, TP + PNS, or the combinations for 4 weeks. The levels of ALT, AST and LDH in serum, apoptosis of liver cells, mitochondria injury and the protein expressions of Caspase 3 and Nrf1 were investigated. RESULTS: CAT, PNS or CAT+PNS pre-treatment inhibited TP-induced toxicity in L-02 cells, distinctly decreased the apoptosis, alleviated the reduction of mitochondrial membrane potential, and modulated the expressions of Nrf1 and its downstream target, the mitochondrial transcription factor A (TFAM) and cytochrome C (Cyt-C). CAT, PNS or CAT+PNS inhibited the TP-induced hepatotoxicity in SD rats by reducing the mitochondria injury, decreasing the cells apoptosis and increasing the Nrf1 protein expression. Noticeably, TP + PNS + CAT combinations exhibited more effective than any single ingredient alone. CONCLUSION: PNS and CAT were able to effectively attenuate TP-induced hepatotoxicity. The efficiency benefits from their modulating Nrf1 and its downstream genes TFAM and Cyt-C, and further influencing mitochondrial functions and cells apoptosis. The combination is more effective than single ingredient alone. PMID- 29277609 TI - RA-XII exerts anti-oxidant and anti-inflammatory activities on lipopolysaccharide induced acute renal injury by suppressing NF-kappaB and MAPKs regulated by HO 1/Nrf2 pathway. AB - Acute kidney injury (AKI) is an abrupt loss of kidney function and severe AKI needs renal replacement therapeutic strategy and has high mortality. RA-XII is a natural cyclopeptide, isolated from the traditional Chinese medicine Rubia yunnanensis, exerting anti-inflammatory and anti-tumor activities. The present study aimed to explore the effects of RA-XII on LPS-induced ACI and the underlying molecular mechanism in TCMK-1 cells in vitro. The results indicated that RA-XII delayed the animal death caused by LPS in mice. The kidney histological changes were markedly attenuated by RA-XII. RA-XII also reduced the serum uric acid, creatinine, BUN and renal 8-OHdG. In addition, RA-XII suppressed LPS-induced oxidative stress in kidney, as evidenced by the up-regulation of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels, and the down-regulation of malondialdehyde (MDA) levels. Additionally, RA-XII enhanced heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions in renal tissue sections. Further, RA-XII reduced the release of pro inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6 and IL-18, in renal, which was linked to the inhibition of inhibitor of alpha/nuclear factor kappa B (IkappaBalpha/NF-kappaB) and mitogen-activated protein kinases (MAPKs) pathways. The in vitro study illustrated that the anti-inflammatory effects of RA-XII were partially reversed following Nrf2 and HO-1 inhibition. Together, these findings strongly suggested that RA-XII is a potential agent against acute kidney injury. PMID- 29277610 TI - The transcriptional factor YB-1 positively regulates Hsc70 transcription in Crassostrea hongkongensis. AB - A Y-box binding protein ChYB-1 was discovered as a ChHsc70 promoter-associated protein in Crassostrea hongkongensis by DNA-affinity purification and mass spectrometry analysis. The overexpression of ChYB-1 in heterologous HEK293T cells led to clear enhancement of ChHsc70 promoter expression, while ChYB-1 depletion correlated with significant reduction of ChHsc70 transcription in the hemocytes of C. hongkongensis. Quantitative Real-time PCR analysis revealed that both ChHsc70 and ChYB-1 were transcriptionally responsive to external chemical or physical stressors. This indicates a plausible correlation between ChHsc70 and ChYB-1 in the genetic regulatory pathway triggered by external stresses. This study presents the first evidence of positive regulator for Hsc70 transcription and contributes to a better understanding of the regulatory mechanisms governing Hsc70 expression. PMID- 29277611 TI - Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR 126/SLC7A5 axis in lung cancer. AB - Dysregulated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. The lncRNA plasmacytoma variant translocation 1 (PVT1) is reported to be an oncogene in a variety of cancers. However, the roles of PVT1-5 and its related miRNAs in lung cancer are poorly understood. In this study, we found that PVT1-5 expression was significantly increased in lung cancer tissues and cell lines. By using biotin-labeled lncRNA PVT1-5 probe for miRNA in vivo precipitation (miRIP) in lung cancer cells and dual-luciferase reporterassays, we identified that miR-126 was associated with lncRNA-PVT1-5. Furthermore, knockdown of lncRNA-PVT1-5 in cells could down regulate the expression of SLC7A5, the target of oncogenic miR-126, resulting in the cell proliferation. Conversely, inhibiting the expression of miR-126 markedly increased the expression of SLC7A5 and alleviated cell proliferation inhibition. Thus, our results indicated that lncRNA-PVT1-5 may function as a competing endogenous RNA (ceRNA) for miR-126 to promote cell proliferation by regulating the miR-126/SLC7A5 pathway, suggesting that lncRNA-PVT1-5 plays a crucial role in lung cancer progression and lncRNA-PVT1-5/miR-126/SLC7A5 regulatory network may shed light on tumorigenesis in lung cancer. PMID- 29277612 TI - Conditional constitutive expression system of a drug protein in vivo by positive feedback loop using an inducer-independent artificial transcription factor. AB - Bacterial-mediated drug delivery is a potential and promising strategy for the specific treatment of cancer with therapeutic molecules, especially with genetically encoded proteins. These proteins must be tightly regulated due to cytotoxicity and thus are usually expressed under the control of the PBAD and TetA/TetR promoters in vivo. Since protein expression from these systems is triggered by exogenous inducer, periodic intravenous injection of inducer is necessary. However, these treatments can result in non-homogenous and/or inefficient expression of therapeutic proteins in vivo due to impeded diffusion and dilution of the inducer further from the injection site. To overcome these hurdles, we designed a conditional constitutive expression system equipped with the artificial transcription factor, AraCC, which has two operator-binding domains and simultaneously binds to the I1 and I2 operators of the PBAD promoter for gene expression in an arabinose-independent manner. Using this construct and the wild type protein AraC under the control of the PBAD promoter, we constructed a self-positive feedback system to constitutively express the therapeutic protein when the induction of AraC was triggered once using arabinose. This expression system could be useful in various cancer treatment strategies using bacteria to deliver genetically encoded drugs in vivo. PMID- 29277613 TI - Hypoxia-induced activation of Twist/miR-214/E-cadherin axis promotes renal tubular epithelial cell mesenchymal transition and renal fibrosis. AB - The epithelial-to-mesenchymal transition (EMT) induced by chronic hypoxia is one of the critical causes of renal fibrosis. Previous work reported that the transcription factors Twist plays an important role in hypoxia-induced EMT and renal fibrosis. Recent evidence indicates that miR-214 was regulated by Twist in many fibrotic diseases, but their role in hypoxia-induced EMT and renal fibrosis remains unknown. Here, we found that hypoxia significantly upregulated the expression of miR-214-3p in HK-2 cells, unilateral ureteral obstruction (UUO) nephropathy and patients with chronic kidney disease. Knockdown of miR-214-3p reversed the EMT of renal tubular epithelial cells (TECs) and alleviated fibrosis in the UUO mouse in vivo, while the overexpression of miR-214-3p promoted EMT phenotype and expression of fibrotic factors in TECs under hypoxic condition. In addition, Twist was also observed increased gradually with the prolongation of hypoxia, and it positively correlated with the expression of miR-214-3p in HK-2 cells transfected with Twist-overexpression or Twist-siRNA plasmid. Moreover, miR 214-3p negatively regulated the expression of epithelial cadherin (E-cadherin) by binding the E-cadherin 3' UTR under hypoxic condition. Overall, hypoxia-induced activation of Twist/miR-214/E-cadherin axis is involved in the EMT of TECs, and anti-miR-214 may be an attractive strategy to ameliorate the progression of renal fibrosis. PMID- 29277614 TI - Hepatocellular carcinoma-associated depletion of the netrin-1 receptor Uncoordinated Phenotype-5A (UNC5A) skews the hepatic unfolded protein response towards prosurvival outcomes. AB - In the liver, HBV and HCV infections, exposure to toxics, genetic and metabolic disorders may induce endoplasmic reticulum (ER) stress and the unfolding protein response (UPR). The UPR allows cells to reach ER homeostasis after lumen overload, but also fosters survival of damaged cells and therefore HCC onset. Dependence receptors such as UNC5A trigger apoptosis when unbound to their ligands. We have previously shown that the main dependence receptor ligand, netrin-1, could protect cells against UPR-induced apoptosis through sustained translation. In this study, we show that UNC5A is cumulatively downregulated by the UPR at the transcriptional level in vitro and at the translational level both in vitro and in vivo. We have found that the 5'-untranslated region of the UNC5A mRNA shares a certain homology degree with that of netrin-1, suggesting linked translational regulatory mechanisms, at least during the initial stages of the UPR. RNAi and forced expression studies identified UNC5A as a modulator of cell death in the context of the UPR. UNC5A decrease of association with polysomes and expression oriented cells towards UPR-associated hepatocytic survival. Such data indicate that cooperation between the UPR and UNC5A depletion as previously observed by ourselves in HCC patients samples may foster liver cancer development and growth. PMID- 29277615 TI - Persistent pain accelerates xenograft tumor growth of breast cancer in rat. AB - Pain occurs at all stages of the patients who suffer from cancer. Owing to surgery and bone metastasis, breast cancer patients were usually disturbed by persistent pain. However, the pain-relief-right has not been respected enough in clinical cancer treatment. Whether pain has any adverse effects on cancer development is still unclear. In order to uncover this question, we established two preclinical animal models to explore the effects of pain on the tumor. For the first model, we mimicked neuropathic pain by sciatic nerve ligation on rats with xenograft tumor subcutaneously. For the second model, we mimicked the bone cancer pain by injecting tumor cell suspension into the tibial medullary cavity of rats with xenograft tumor subcutaneously. The rats with persistent pain showed higher tumor volume and tumor weight compared with the group without pain. Interestingly, when the neuropathic pain and bone cancer pain were relieved by drug administration, both the tumor volume and tumor weight were lowered compared with the group without pain relief. In summary, our study indicated that persistent pain acted as a contributing factor to tumor growth. Moreover, the pain relief could weakened the accelerating role of pain in tumor growth. Thus, we should be paid more attention to the cancer patients with persistent pain as well as cancer treatment. PMID- 29277617 TI - Family-led rehabilitation after stroke may not improve patient outcomes compared to usual care [synopsis]. PMID- 29277616 TI - Anosmin-1 is essential for neural crest and cranial placodes formation in Xenopus. AB - During embryogenesis vertebrates develop a complex craniofacial skeleton associated with sensory organs. These structures are primarily derived from two embryonic cell populations the neural crest and cranial placodes, respectively. Neural crest cells and cranial placodes are specified through the integrated action of several families of signaling molecules, and the subsequent activation of a complex network of transcription factors. Here we describe the expression and function of Anosmin-1 (Anos1), an extracellular matrix protein, during neural crest and cranial placodes development in Xenopus laevis. Anos1 was identified as a target of Pax3 and Zic1, two transcription factors necessary and sufficient to generate neural crest and cranial placodes. Anos1 is expressed in cranial neural crest progenitors at early neurula stage and in cranial placode derivatives later in development. We show that Anos1 function is required for neural crest and sensory organs development in Xenopus, consistent with the defects observed in Kallmann syndrome patients carrying a mutation in ANOS1. These findings indicate that anos1 has a conserved function in the development of craniofacial structures, and indicate that anos1-depleted Xenopus embryos represent a useful model to analyze the pathogenesis of Kallmann syndrome. PMID- 29277618 TI - Cost-effectiveness of Future Biomarkers for Colorectal Cancer Screening: Quantified Futility or Call for Innovation? PMID- 29277619 TI - Epithelioid Granulomas Associate With Increased Severity and Progression of Crohn's Disease, Based on 6-Year Follow-Up. AB - BACKGROUND & AIMS: Epithelioid granulomas are characteristics of a subset of patients with Crohn's disease (CD), but their significance, with regard to disease progression and severity, is unclear. We investigated the relationship between granulomas and CD severity over a 6-year time period in a large cohort of patients. METHODS: We performed a retrospective study of patients with CD seen at the Inflammatory Bowel Disease Center at the University of Pittsburgh; data were collected from 2009 through 2014 and patients were assigned to groups with and without histologic evidence of granuloma. Demographic, clinical (including disease activity, quality of life, medication use, and healthcare utilization), and laboratory data were used in association and survival analyses. Differences between groups were evaluated using the Mann-Whitney U-test for continuous variables. RESULTS: Of 1466 patients with CD, granulomas were identified in 187 (12.8%). In the subset of patients who underwent surgery, 21.0% had granulomas. The presence of granuloma was associated with increased serum levels of c reactive protein (odds ratio [OR], 2.9; 95% CI, 2.078-4.208; P < .0001), younger mean age at diagnosis (23.6 +/- 11.3 years in patients with granulomas vs 27.9 +/ 13.3 years in patients without; P = .0005), higher rates of stricturing or penetrating disease phenotype, higher rates of steroid and narcotic use, and higher healthcare utilization. Among patients that underwent surgery, the presence of granulomas was associated with need for repeat surgery during the 6 year observation period (OR, 2.5; 95% CI, 1.54-4.02; P = .0002). Infliximab use was associated with detection of granuloma in a significantly lower proportion of surgical specimens compared to patients who had not been treated with a biologic agent (OR, 0.22; 95 CI, 0.05-0.97; P = .03). CONCLUSIONS: Epithelioid granulomas develop in less than 13% of patients with CD, and are associated with a more aggressive disease phenotype. Patients who have undergone surgery for CD and have granulomas are at increased risk for repeat surgery within 6 years. PMID- 29277620 TI - Re-bleeding and Mortality After Lower Gastrointestinal Bleeding in Patients Taking Anti-platelets or Anti-coagulants. AB - BACKGROUND & AIMS: Patients who develop lower gastrointestinal bleeding (LGIB) while receiving anti-coagulants or anti-platelets have increased severity of bleeding and risk of re-bleeding. We compared outcomes of patients receiving anti platelets, anti-coagulants, or direct oral anti-coagulants (DOACs) who develop LGIB, as well as the effects of withholding these drugs on their course of bleeding. METHODS: We performed a retrospective study of 2528 consecutive adult patients with LGIB at 143 hospitals in the United Kingdom, from September through December 2015; 917 were taking anti-coagulant or anti-platelet drugs and 1218 were taking neither (unexposed). We collected data on demographic features of patients, interventions or medications, outcomes, laboratory test results, and patient readmission until patient death, discharge, or 28 days after admission (whichever came first). Re-bleeding was defined as additional transfusion requirements and/or a decrease in hematocrit >=20% after 24 hrs of clinical stability. Multivariate regression was used to examine the relationship between drug class on presentation with LGIB and re-bleeding, mortality, and cardiovascular events. Rates of re-bleeding and cardiovascular complications in patients who had these drugs withheld were also analyzed. RESULTS: Patients receiving anti-platelets, but not those receiving warfarin (n = 232) or DOACs (n = 102), had a higher risk of in-hospital re-bleeding (monotherapy hazard ratio [HR], 3.57; 95% CI, 1.13-11.28; n = 504 and dual anti-platelet therapy hazard ratio, 5.3; 95% CI, 1.56-18.54; n = 79) compared with the unexposed group. This risk was not lower in patients who received anti-platelets and had the drug withheld for fewer than 5 days, compared to those who continued the drug throughout admission (HR, 0.98; 95% CI, 0.45-2.17) No differences were observed in risk-adjusted mortality or re-admission with further bleeding for patients receiving anti-platelets, DOACs, or warfarin. Cardiovascular events were too few to allow meaningful comparison. CONCLUSIONS: In patients with LGIB, antiplatelet drugs, but not warfarin or DOACs, are associated with an increased risk of re bleeding. Withholding anti-platelets during admission does not lead to reduction in re-bleeding. PMID- 29277621 TI - Increasing Prevalence of Primary Biliary Cholangitis and Reduced Mortality With Treatment. AB - BACKGROUND & AIMS: There are few data from longitudinal studies of trends in primary biliary cholangitis (PBC) among patients under routine clinical care in the United States. We collected data from the Fibrotic Liver Disease consortium to investigate changes in the incidence and prevalence of PBC and the effects of patient demographics, clinical features, and treatment on mortality. METHODS: We collected demographic and clinical data for the general patient population as well as PBC patients receiving care from 11 health systems in different regions of the United States (Northeast, Midwest, Northwest, and South) from January 1, 2003, through December 31, 2014. Annual percentage changes in PBC prevalence and incidence were estimated using join-point Poisson regression. Differences based on race, age, and gender were calculated with rate ratios. All-cause mortality was estimated using Cox regression with adjustment for patient characteristics and treatment with ursodeoxycholic acid (UDCA). Propensity scores were used to adjust for treatment selection bias. Analyses were adjusted by geographic regions. RESULTS: In our racially diverse cohort of 3488 patients with PBC (21% Hispanic, 8% African American, 7% Asian American), 70% had ever received UDCA. From 2006 through 2014, the prevalence of PBC increased from 21.7 to 39.2 per 100,000 persons. Adjusted annual percentage changes in prevalence differed among age groups (<=40 y, 41-50 y, 51-60 y, 61-70 y, and >70 y), ranging from 3.0% to 7.5% (P < .05). Incidence did not change significantly during the study period (4.2 vs 4.3 per 100,000 person-years in 2006 and 2014, respectively; P = .98). Ratios of prevalence for women vs men (3.9:1) and incidence for women vs men (3.2:1) were consistent over the study period. Among African Americans, the prevalence of PBC increased from 16.9 to 30.8 per 100,000 during the study period, and annual incidence ranged from 2.6 to 6.6 per 100,000 person-years. In adjusted analyses, an increased level of alkaline phosphatase at baseline was associated with significantly higher mortality (adjusted hazard ratios [aHR], 1.24; 95% CI, 1.04-1.48 for patients with levels 1-2 times the upper limit of normal and aHR, 2.27; 95% CI, 1.88-2.73 for patients with levels more than 3 times the upper limit of normal). UDCA treatment was associated with significantly reduced mortality (aHR, 0.57; 95% CI, 0.52-0.64). CONCLUSIONS: In an analysis of data from patients receiving routine clinical care in Fibrotic Liver Disease Consortium health systems, we found that the prevalence of PBC increased from 2004 through 2014, despite steady incidence. Patient demographic and clinical characteristics, as well as UDCA treatment, affected mortality. PMID- 29277622 TI - National Early Warning Score Accurately Discriminates the Risk of Serious Adverse Events in Patients With Liver Disease. AB - BACKGROUND & AIMS: The National Early Warning Score (NEWS) is used to identify deteriorating adult hospital inpatients. However, it includes physiological parameters frequently altered in patients with cirrhosis. We aimed to assess the performance of the NEWS in acute and chronic liver diseases. METHODS: We collected vital signs, recorded in real time, from completed consecutive admissions of patients 16 years or older to a large acute-care hospital in Southern England, from January 1, 2010, through October 31, 2014. Using International Classification of Diseases, 10th revision, codes, we categorized patients as having primary liver disease, secondary liver disease, or none. For patients with liver disease, 2 analysis groups were developed: the first was based on clinical group (such as acute or chronic, alcohol-induced, or associated with portal hypertension), and the second was based on a summary of liver related, hospital-level mortality indicator diagnoses. For each, we compared the abilities of the NEWS and 34 other early warning scores to discriminate 24-hour mortality, cardiac arrest, or unanticipated admission to the intensive care unit using the area under the receiver operating characteristic (AUROC) curve and early warning score efficiency curve analyses. RESULTS: The NEWS identified patients with primary, nonprimary, and no diagnoses of liver disease with AUROC values of 0.873 (95% CI, 0.860-0.886), 0.898 (95% CI, 0.891-0.905), and 0.879 (95% CI, 0.877-0.881), respectively. High AUROC values were also obtained for all clinical subgroups; the NEWS identified patients with alcohol-related liver disease with an AUROC value of 0.927 (95% CI, 0.912-0.941). The NEWS identified patients with liver diseases with higher AUROC values than other early warning scoring systems. CONCLUSIONS: The NEWS accurately discriminates patients at risk of death, admission to the intensive care unit, or cardiac arrest within a 24 hour period for a range of liver-related diagnoses. Its widespread use provides a ready-made, easy-to-use option for identifying patients with liver disease who require early assessment and intervention, without the need to modify parameters, weightings, or escalation criteria. PMID- 29277623 TI - Molecular mechanistic pathway of colorectal carcinogenesis associated with intestinal microbiota. AB - The colon rectal portion of gastrointestinal tract (GI) is full of microorganisms with different complex community that plays important role in maintaining homeostasis. But now-a-days different literature indicated that microbiota cause development of colorectal cancer (CRC) with a disease and ultimately aggravates to death. The mechanism inside the colo-rectal portion of GI tract is not fully well-known and bacterial contribution inside it is also fully unclear. Therefore, there is certain evidence trying a target about the unclear mechanism between intestinal microbiota and CRC. Different reports revealed that colo-rectal microorganisms is playing a great role in inducing the onset and progression of CRC with different dynamic mechanisms viz. acceleration of chronic inflammatory state, the biosynthesis of genotoxins that interfere with cell cycle regulation, the production of toxic metabolites, or heterocyclic amine activation of pro-diet carcinogenic compounds. There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. While cancer is largely considered to be a disease of genetic and environmental factors, increasing evidence has demonstrated a role for the microbiota in shaping inflammatory environments and promoting tumor growth and spread. Despite all these advances, different studies depicted the relationship between microbiota and CRC in humans and animal models and aid in developing alternate therapeutic approach based on gut microbiota manipulations. Alteration of the microbiota may be a useful to preventing and altering the trajectory of colorectal cancer. Therefore, the aim of the study is to identify the possible mechanistic mechanism regarding host microbiota interaction in colorectal carcinogenesis. PMID- 29277624 TI - Wider range of allodynia in a rat model of repeated dural nociception compared with infraorbital nerve chronic constriction injury. AB - BACKGROUND: To identify differences in allodynia and grooming behaviours between rat models of either repeated dural nociception with inflammatory soup (IS) or infraorbital nerve chronic constriction injury (IoN-CCI). METHODS: Repeated dural nociception was induced via the application of IS to the dural meninges and IoN CCI was applied to model neuropathic pain. All surgeries were performed on the right side and a sham operation was performed on the control group. Mechanical and thermal withdrawal thresholds were tested on different facial areas and hindpaw during the interictal period and grooming behaviours were recorded. RESULTS: A significant decreases was found in the mechanical withdrawal thresholds of the bilateral vibrissa pad and right periorbital area in both the IS and the IoN-CCI groups, but only in the left periorbital area of the IS group. Hindpaw thermal allodynia was evident only in the IS group. Ipsilateral hindpaw grooming behaviour increased in the IS group and facial grooming behaviour increased in the IoN-CCI group. CONCLUSIONS: Repeated dural nociception induced by IS and IoN-CCI in rats effectively simulated chronic migraine (CM) and trigeminal neuralgia (TN), respectively. The IS group exhibited a wider range of allodynia than the IoN-CCI group, but further studies are necessary to determine underlying mechanisms. PMID- 29277625 TI - Enhanced axonal transport: A novel form of "plasticity" after primate and rodent spinal cord injury. AB - Deficient axonal transport after injury is believed to contribute to the failure of CNS regeneration. To better elucidate neural mechanisms associated with CNS responses to injury, we transected the dominant voluntary motor system, the corticospinal tract (CST), in the dorsolateral T10 spinal cord of rhesus monkeys. Three months later, a 4.5-fold increase in the number of CST axons located in the spared ventral corticospinal tract at both the lesion site and, surprisingly, remotely in the cervical spinal cord was observed. Additional studies of increases in corticospinal axon numbers in rat and primate models demonstrated that increases were transient and attributable to enhanced axonal transport rather than axonal sprouting. Accordingly, increases in axonal transport occur after CNS injury even in the longest projecting pathways of the non-human primate, likely representing an attempted adaptive response to injury as observed in the PNS. PMID- 29277626 TI - Longitudinal study of quantitative changes in pelvic organ support among parous women. AB - BACKGROUND: Pelvic organ prolapse is more common among parous (vs nulliparous) women and also more common after vaginal (vs cesarean) birth. However, very little is known about how childbirth affects the course and progression of the genital hiatus across a woman's life span. OBJECTIVE: The objective of the sttudy was to investigate the longitudinal, quantitative changes in pelvic organ support after childbirth, focusing on the impact of vaginal vs cesarean delivery. STUDY DESIGN: This was a prospective longitudinal cohort study in which parous women were recruited 5-10 years from first delivery and followed up annually. Using data from annual pelvic organ prolapse quantification examinations, we considered changes in vaginal support at the anterior vaginal wall (point Ba), the vaginal apex (point C), and the posterior wall (point Bp). In univariate and multivariable models, we compared pelvic organ support between women who had delivered at least 1 child vaginally vs those delivered exclusively by cesarean. Other covariates considered included race, age at first delivery, and the size of the genital hiatus. For models of support at Ba and Bp, we also considered the independent association with apical support. For women who delivered vaginally, we also considered forceps birth. RESULTS: A total of 1224 women participated for a total of 7055 woman-visits. In multivariable models, vaginal birth was associated with significantly worse support 5 years from first delivery. Also, women with at least 1 vaginal birth had more rapid worsening of support at point C. The width of the genital hiatus was a significant independent predictor of worse support 5 years from delivery as well as the rate of change over time. In models that controlled for the genital hiatus, the strength of the impact of vaginal birth was attenuated. CONCLUSION: Vaginal birth was associated with worse support 5 years from first delivery and with more rapid deterioration in support at the apex. Above and beyond the impact of vaginal birth, the size of the genital hiatus may be an independent marker for those at greatest risk of prolapse progression. PMID- 29277627 TI - An unusually large ciliated cyst of the vulva in an adolescent patient. PMID- 29277628 TI - Mechanical heart valves in pregnancy: the necessity of appropriate and careful anticoagulation. PMID- 29277629 TI - Patterns and correlates of cervical cancer screening initiation in a large integrated health care system. AB - BACKGROUND: The latest 2012 US Preventive Services Task Force cervical cancer screening guidelines recommended screening initiation at age 21 years. Little is known about the cervical cancer screening initiation practices in the community and whether there are critical gaps with respect to adherence to current clinical guidelines. Despite an overall decline in cervical cancer incidence across women of all ages, the incidence rate has not declined among 24-25 year olds between 2000 (2.79 per 100,000) and 2013 (2.93 per 100,000). Thus, it is important to understand cervical cancer screening initiation in young women and how woman- and provider-level factors affect the timing of screening initiation to identify areas for improving cervical cancer prevention. OBJECTIVE: We examined patterns and correlates of cervical cancer screening initiation among women turning age 21 years in a large community-based practice. STUDY DESIGN: Female members of Kaiser Permanente Southern California who turned age 21 years (baseline) during 2013 2015 and had not previously received a Papanicolaou test were included. Cervical cancer screening initiation through October 2016 was captured using electronic health records. Incidence rate and cumulative incidence of screening initiation was calculated. Associations between patient and provider characteristics and screening initiation were evaluated using multivariable Cox models. RESULTS: A total of 38,257 women were included and the Papanicolaou screening initiation rate was 44 per 100 person-years during the study period. Approximately 40% initiated screening within 1 year after turning age 21 years. In multivariable analyses, Asian/Pacific Islanders (hazard ratio, 0.91; confidence interval, 0.86 0.96 compared with non-Hispanic whites); Medicaid enrollees (hazard ratio, 0.90; confidence interval, 0.83, 0.97); those whose primary language is not English (hazard ratio, 0.71; confidence interval, 0.67, 0.75); those who have a historical inpatient visit, primary care physician in pediatrics, internal medicine, or another specialty compared with family practice; and have a male rather than female primary care physician (hazard ratio, 0.46; confidence interval, 0.36, 0.57) less often initiated screening. On the other hand, those who used other preventive services such as getting a human papilloma virus and influenza vaccination and those with a history of pregnancy, contraception use, and sexually transmitted infections more often had timely screening initiation. CONCLUSION: Less than half of the women insured for preventative services initiated screening at age 21 years. Strategies to improve adherence to screening initiation guidelines should consider a tailored approach for at-risk subgroups and addressing initiation challenges associated with male physicians. PMID- 29277630 TI - Vulvar vesicles in an elderly female: cutaneous manifestation of a past malignancy. PMID- 29277631 TI - A proteomic clock of human pregnancy. AB - BACKGROUND: Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable because it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome. OBJECTIVE: The recent availability of a highly multiplexed platform affording the simultaneous measurement of 1310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns caused by fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins and link such attributes to relevant immunological changes. STUDY DESIGN: Pregnant women participated in this longitudinal study. In 2 subsequent sets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 weeks), second (15-20 weeks), and third (24-32 weeks) trimesters and 6 weeks postpartum for analysis with a highly multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piecewise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term. RESULTS: An independently validated model consisting of 74 proteins strongly predicted gestational age (P = 3.8 * 10-14, R = 0.97). The model could be reduced to 8 proteins without losing its predictive power (P = 1.7 * 10-3, R = 0.91). The 3 top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase and signal transducer and activator of transcription pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top-ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with signal transducer and activator of transcription-5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age. CONCLUSION: Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a proteomic clock. Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a clock is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-related pathologies, and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that chrionic somatomammotropin hormone may critically regulate T-cell function during pregnancy. PMID- 29277632 TI - Giant cyst of the Nuck canal: a worrisome trouble for a girl. PMID- 29277633 TI - Which place of pharmacological approaches beyond continuous positive airway pressure to treat vascular disease related to obstructive sleep apnea? AB - Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete upper airway obstruction, occurring during sleep, leading to chronic intermittent hypoxia (IH), which harms the cardiovascular system. OSA is associated with both functional and structural vascular alterations that contribute to an increased prevalence of fatal and non-fatal cardiovascular events. OSA is a heterogeneous disease with respect to the severity of hypoxia, the presence of daytime symptoms, obesity, and cardiovascular comorbidities. Various clusters of OSA phenotypes have been described leading to more highly personalized treatment. The aim of this review is to describe the various therapeutic strategies including continuous positive airway pressure (CPAP), oral appliances, surgery, weight loss, and especially pharmacological interventions that have been evaluated to reduce vascular alterations in both OSA patients and preclinical animal models. Conventional therapies, predominantly CPAP, have a limited impact on vascular alterations in the presence of co-morbidities. A better knowledge of pharmacological therapies targeting IH-induced vascular alterations will facilitate the use of combined therapies and is crucial for designing clinical trials in well-defined OSA phenotypes. PMID- 29277634 TI - A sensitive flow cytometric method for multi-parametric analysis of microRNA, messenger RNA and protein in single cells. AB - Analysis of RNA expression in mixed cell populations often requires laborious and costly cell sorting. Here we describe a flow cytometric assay that combines antibody staining and in situ hybridization for multi-parametric analysis of single cells. This method, referred to as the PrimeFlowTM RNA Assay, enables simultaneous detection of protein markers and RNA targets in mixed cell populations. Both coding and non-coding RNA sequences can be measured with a limit of detection of approximately 10 copies of mRNA and 20 copies of microRNA per cell. In this study, we used mouse bone marrow-derived macrophages to demonstrate that our method allows for analysis of the activation and polarization status of cells using expression patterns of protein and RNA. We then performed analysis of four cell subsets of mouse resident peritoneal cells and showed that the two macrophage populations present in this compartment are relatively heterogeneous in terms of expression of two M2 markers: Arg1, Retnla, and a B-cell attractant chemokine Cxcl13. In addition, we profiled the expression of a panel of microRNA in the four peritoneal cell subsets, showing that the assay can be readily adapted to parallel, high-throughput screening of multiple cell populations. This new method allows for single cell analysis of multiple RNA targets without the need for cell sorting, enables direct correlation between RNA and protein expression, and promises to accelerate biomarker and drug discovery. PMID- 29277635 TI - A Novel and Reliable Method to Detect Microsatellite Instability in Colorectal Cancer by Next-Generation Sequencing. AB - Two types of molecular tests have been established to assess the deficiency of the DNA mismatch repair (MMR) system: microsatellite instability (MSI) and immunohistochemical (IHC) analysis. We have developed a reliable method to analyze the MSI status by next-generation sequencing (NGS) based on read-count distribution. A total of 91 patients with primary colorectal cancer were recruited. These patients included 54 cases with loss of expression of any MMR protein in IHC, suggesting deficient MMR (dMMR), and 37 cases of colorectal cancer with staining of all four MMR proteins in IHC, suggesting proficient MMR in the sample after surgery. DNA was extracted from paired tumor-normal tissue for MSI detection by both the ColonCore NGS panel and PCR. The sequencing data from the NGS panel was processed using various MSI detection pipelines for a comparison with the ColonCore panel. Using the MSI-PCR test as the gold standard, MSI-ColonCore achieved 97.9% sensitivity (47 of 48) and 100% specificity (37 of 37) for the detection of MSI status. MSI-ColonCore also showed more efficient and robust performance compared with other NGS-based MSI detection algorithms. The concordance rate was 92.3% between MSI-ColonCore and IHC testing, and 93.4% between MSI-PCR and IHC testing. These results suggest that MSI-ColonCore is a reliable and robust method for MSI status detection by NGS based on read-count distribution. PMID- 29277636 TI - Evaluation of Diagnostic Utility of a High-Risk Human Papillomavirus PCR Test on Formalin-Fixed, Paraffin-Embedded Head and Neck Tumor Tissues. AB - The increasing prevalence of high-risk human papillomavirus (HR-HPV)-associated head and neck squamous cell carcinoma (HNSCC) has prompted strong clinical demands for detecting HR-HPV directly in the tumor. Although p16 immunohistochemistry (IHC) has been the standard testing method, it has limitations including false positivity, lack of sensitivity in low tumor cell samples such as fine-needle aspirate (FNA), and its subjectivity. We developed a modified method based on a commercial automated HR-HPV PCR assay and evaluated the performance characteristics and the diagnostic utility of this assay for direct HR-HPV detection in the HNSCC samples. HNSCC formalin-fixed, paraffin embedded blocks were retrieved from archives including 44 excisions, 63 biopsies, and 16 FNAs. Tissue slices were trimmed from the blocks, deparaffinized, lysed, and loaded on the commercial automated platform for HR-HPV PCR. All specimens had a concurrent p16 IHC performed. The PCR assay showed high concordance with the p16 IHC (96%; 99/103) and excellent positive agreement (91.5%) and negative agreement (100%). In addition, the PCR assay provided more conclusive results in samples with equivocal p16 IHC results. The modified commercial automated HR-HPV PCR test is a labor-efficient, quick, reliable, sensitive, and specific method for detecting HR-HPV in formalin-fixed, paraffin-embedded samples. This assay also showed excellent diagnostic utility in samples with equivocal p16 IHC results, including FNA cell blocks. PMID- 29277637 TI - Synthesis and characterisation of arsenic nanoparticles and its interaction with DNA and cytotoxic potential on breast cancer cells. AB - Therapeutic applications of arsenic trioxide (ATO) are limited due to their severe adverse effects. However, nanoparticles of ATO might possess inimitable biologic effects based on their structure and size which differ from their parent molecules. Based on this conception, AsNPs were synthesized from ATO and comparatively analysed for their interaction mechanism with DNA using spectroscopic & electrochemical techniques. Finally, anti-proliferative activity was assessed against different breast cancer cells (MDA-MB-231 & MCF-7) and normal non-cancerous cells (HEK-293). The DNA interaction study revealed that AsNPs and ATO exhibit binding constant values in the order of 106 which indicates strong binding interaction. Binding of AsNPs did not disturb the structural integrity of DNA, on the other hand an opposing effect was observed with ATO through biophysical techniques. Further, in vitro study, confirms cytotoxicity of ATO and AsNPs against different cells, however at particular concentration ATO exhibits more cytotoxicity than that of AsNPs. Furthermore, cytotoxicity was confirmed through acridine orange and comet assay. In conclusion, AsNPs are safer than ATO with comparable efficacy and might be a suitable candidate for the development of novel therapeutic agent against breast cancer and other solid tumours. PMID- 29277638 TI - Obituary: Emilio Luciano Ghisalberti (forward to special memorial issue). PMID- 29277639 TI - Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of alpha-Fe2O3 nanoparticles. AB - Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. alpha-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine alpha-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The alpha-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease. PMID- 29277640 TI - Using Image Attributes to Assure Accurate Particle Size and Count Using Nanoparticle Tracking Analysis. AB - Nanoparticle tracking analysis (NTA) obtains particle size by analysis of particle diffusion through a time series of micrographs and particle count by a count of imaged particles. The number of observed particles imaged is controlled by the scattering cross-section of the particles and by camera settings such as sensitivity and shutter speed. Appropriate camera settings are defined as those that image, track, and analyze a sufficient number of particles for statistical repeatability. Here, we test if image attributes, features captured within the image itself, can provide measurable guidelines to assess the accuracy for particle size and count measurements using NTA. The results show that particle sizing is a robust process independent of image attributes for model systems. However, particle count is sensitive to camera settings. Using open-source software analysis, it was found that a median pixel area, 4 pixels2, results in a particle concentration within 20% of the expected value. The distribution of these illuminated pixel areas can also provide clues about the polydispersity of particle solutions prior to using a particle tracking analysis. Using the median pixel area serves as an operator-independent means to assess the quality of the NTA measurement for count. PMID- 29277641 TI - World Health Organization and Essential Medicines. AB - In June 2017, the World Health Organization released 20th Model List of Essential Medicines for adults and sixth Model List of Essential Medicines for children. In our commentary, we describe the changes to the Essential Medicine list, and identify deficits in excluding medicines for management of diseases with a high burden. In using tracer conditions such as cardiovascular and thromboembolic disease, mental health, and diseases of the musculoskeletal system, we highlight the absence of several medicines, which are incorporated into major clinical practice guidelines. We recommend that the World Health Organization review its process with respect to identifying disease conditions as well as evidence-based therapies. PMID- 29277642 TI - Cloning, tissue distribution and nutritional regulation of a fatty acyl Elovl4 like elongase in mud crab, Scylla paramamosain (Estampador, 1949). AB - In this report, the full-length cDNA of fatty acyl Elovl4-like elongase was cloned from the hepatopancreas of Scylla paramamosain by rapid-amplification of cDNA ends (RACE). To the best of our knowledge, this is the first report of Elovl4-like elongase in crustaceans. The full-length cDNA of Elovl4-like was 1119bp, which included a 5'-terminal untranslated region (UTR) of 58bp, a 3' terminal UTR of 44bp and an open reading frame (ORF) of 1017bp encoding a polypeptide of 338 amino acids. Tissue distribution analysis revealed that Elovl4 like transcripts are widely distributed in various organs, with high mRNA levels in the hepatopancreas and cranial ganglia. Further, Elovl4-like transcriptional levels in hepatopancreas were up-regulated in proportion to the replacement of dietary fish oil (FO) with soybean oil (SO). The result showed that Elovl4-like transcripts increased about 0.83 and 1.12-fold respectively when SO constituted 80% and 100% of total oil (P<0.05). These results may contribute to better understanding of the long-chain polyunsaturated fatty acids (LC-PUFA) biosynthetic pathway and regulation mechanism in this species. PMID- 29277643 TI - Revealing critical mechanisms of BR-mediated apple nursery tree growth using iTRAQ-based proteomic analysis. AB - : Brassinosteroid is identified as an important hormone. However, information about brassinosteroid has not been fully elucidated, and few studies concerned its role in apple. The aim of this work was to study the role of brassinosteroid for apple tree growth. In our study, the effect of brassinosteroid on apple nursery tree was analyzed. The biomass, cell size and xylem content of apple nursery tree were obviously evaluated by brassinosteroid treatment; mineral elements contents, photosynthesis indexes, carbohydrate level and hormone contents were significantly high in brassinosteroid treated trees. To explore the molecular mechanisms of these phenotypic differences, iTRAQ-based quantitative proteomics were used to identify the expression profiles of proteins in apple nursery tree shoot tips in response to brassinosteroid at a key period (14days after brassinosteroid treatment). A total of 175 differentially expressed proteins were identified. They were mainly involved in chlorophyII biosynthesis, photosynthesis, carbohydrate metabolism, glycolysis, citric acid cycle, respiratory action, hormone signal, cell growth and ligin metabolism. The findings in this study indicate that brassinosteroid mediating apple nursery tree growth may be mainly through energy metabolism. Important biological processes identified here can be useful theoretical basis and provide new insights into the molecular mechanisms of brassinosteroid. BIOLOGICAL SIGNIFICANCE: Brassinosteroid is very important for plant growth and development. However, the molecular mechanism of brassinosteroid mediating growth process is not perfectly clear in plant, especially in apple nursery tree. We used a combination of physiological and bioinformatics analysis to investigate the effects of brassinosteroid on apple nursery tree growth and development. The data reported here demonstrated that brassinosteroid regulates apple nursery tree growth mainly through energy metabolism. Therefore it can provide a theoretical basis from energy points for developing dwarfed or compact apple trees. This will benefit for low orchard management cost as well as early bearing, and high fruit yield as well as quality. PMID- 29277644 TI - Sex differences in murine myocardium are not exclusively regulated by gonadal hormones. AB - : We investigated sex differences in cardiac protein patterns of intact and castrated mice using proteomics and 1D and 2D immunoblotting. To exclude differences concerning developmental aspects gonadectomy was conducted in mature mice at the age of three months. The main sex-related regulation in the protein pattern of the myocardium occurred for proteins involved in metabolic processes whereas only few proteins involved in other pathways underwent a regulation. Many regulated proteins (2/3) displayed a characteristic V form, which means that these proteins are up- or down-regulated in sexually mature compared to young mice and are back-regulated after castration, emphasizing a direct regulation by gonadal hormones. Several other spots (1/3) showed the same male/female regulation or a drastic increase in male/female spot intensity ratio after castration, suggesting either a regulation independent of sex hormones or a removal of an inhibiting feedback mechanism by gonadectomy. Technically, we found that it cannot be expected that a single spot contains only one protein species and that one protein is present in only one spot. We thus propose for proteomic investigations to identify/quantify all spots of a 2-DE pattern to obtain information about protein speciation and its potential importance for function and pathology. BIOLOGICAL SIGNIFICANCE: Sex related differences in cardiovascular disease, including risk factors, disease manifestation and outcomes, are far from being well understood, and improved biological understanding of these differences in the healthy myocardium is of great importance. We investigated sex related changes of myocardial protein pattern in intact and castrated mice at different ages and found metabolic proteins to be highly regulated, some of which independently from gonadal hormones. PMID- 29277645 TI - Transformation from independent to integrative coding of multi-object arrangements in human visual cortex. AB - To optimize processing, the human visual system utilizes regularities present in naturalistic visual input. One of these regularities is the relative position of objects in a scene (e.g., a sofa in front of a television), with behavioral research showing that regularly positioned objects are easier to perceive and to remember. Here we use fMRI to test how positional regularities are encoded in the visual system. Participants viewed pairs of objects that formed minimalistic two object scenes (e.g., a "living room" consisting of a sofa and television) presented in their regularly experienced spatial arrangement or in an irregular arrangement (with interchanged positions). Additionally, single objects were presented centrally and in isolation. Multi-voxel activity patterns evoked by the object pairs were modeled as the average of the response patterns evoked by the two single objects forming the pair. In two experiments, this approximation in object-selective cortex was significantly less accurate for the regularly than the irregularly positioned pairs, indicating integration of individual object representations. More detailed analysis revealed a transition from independent to integrative coding along the posterior-anterior axis of the visual cortex, with the independent component (but not the integrative component) being almost perfectly predicted by object selectivity across the visual hierarchy. These results reveal a transitional stage between individual object and multi-object coding in visual cortex, providing a possible neural correlate of efficient processing of regularly positioned objects in natural scenes. PMID- 29277647 TI - What can we see with IVIM MRI? AB - Intravoxel Incoherent Motion (IVIM) refers to translational movements which within a given voxel and during the measurement time present a distribution of speeds in orientation and/or amplitude. The IVIM concept has been used to estimate perfusion in tissues as blood flow in randomly oriented capillaries mimics a pseudo-diffusion process. IVIM-based perfusion MRI, which does not require contrast agents, has gained momentum recently, especially in the field oncology. In this introductory review the basic concepts, models, technical requirements and limitations inherent to IVIM-based perfusion MRI are outlined, as well as new, non-perfusion applications of IVIM MRI, such as virtual MR Elastography. PMID- 29277646 TI - Convergence of spoken and written language processing in the superior temporal sulcus. AB - Spoken and written language processing streams converge in the superior temporal sulcus (STS), but the functional and anatomical nature of this convergence is not clear. We used functional MRI to quantify neural responses to spoken and written language, along with unintelligible stimuli in each modality, and employed several strategies to segregate activations on the dorsal and ventral banks of the STS. We found that intelligible and unintelligible inputs in both modalities activated the dorsal bank of the STS. The posterior dorsal bank was able to discriminate between modalities based on distributed patterns of activity, pointing to a role in encoding of phonological and orthographic word forms. The anterior dorsal bank was agnostic to input modality, suggesting that this region represents abstract lexical nodes. In the ventral bank of the STS, responses to unintelligible inputs in both modalities were attenuated, while intelligible inputs continued to drive activation, indicative of higher level semantic and syntactic processing. Our results suggest that the processing of spoken and written language converges on the posterior dorsal bank of the STS, which is the first of a heterogeneous set of language regions within the STS, with distinct functions spanning a broad range of linguistic processes. PMID- 29277648 TI - Susceptibility-induced distortion that varies due to motion: Correction in diffusion MR without acquiring additional data. AB - Because of their low bandwidth in the phase-encode (PE) direction, the susceptibility-induced off-resonance field causes distortions in echo planar imaging (EPI) images. It is therefore crucial to correct for susceptibility induced distortions when performing diffusion studies using EPI. The susceptibility-induced field is caused by the object (head) disrupting the field and it is typically assumed that it remains constant within a framework defined by the object, (i.e. it follows the object as it moves in the scanner). However, this is only approximately true. When a non-spherical object rotates around an axis other than that parallel with the magnetic flux (the z-axis) it changes the way it disrupts the field, leading to different distortions. Hence, if using a single field to correct for distortions there will be residual distortions in the volumes where the object orientation is substantially different to that when the field was measured. In this paper we present a post-processing method for estimating the field as it changes with motion during the course of an experiment. It only requires a single measured field and knowledge of the orientation of the subject when that field was acquired. The volume-to-volume changes of the field as a consequence of subject movement are estimated directly from the diffusion data without the need for any additional or special acquisitions. It uses a generative model that predicts how each volume would look predicated on field change and inverts that model to yield an estimate of the field changes. It has been validated on both simulations and experimental data. The results show that we are able to track the field with high accuracy and that we are able to correct the data for the adverse effects of the changing field. PMID- 29277649 TI - Musical genre-dependent behavioural and EEG signatures of action planning. A comparison between classical and jazz pianists. AB - It is well established that musical training induces sensorimotor plasticity. However, there are remarkable differences in how musicians train for proficient stage performance. The present EEG study outlines for the first time clear-cut neurobiological differences between classical and jazz musicians at high and low levels of action planning, revealing genre-specific cognitive strategies adopted in production. Pianists imitated chord progressions without sound that were manipulated in terms of harmony and context length to assess high-level planning of sequence-structure, and in terms of the manner of playing to assess low-level parameter specification of single acts. Jazz pianists revised incongruent harmonies faster as revealed by an earlier reprogramming negativity and beta power decrease, hence neutralising response costs, albeit at the expense of a higher number of manner errors. Classical pianists in turn experienced more conflict during incongruent harmony, as shown by theta power increase, but were more ready to implement the required manner of playing, as indicated by higher accuracy and beta power decrease. These findings demonstrate that specific demands and action focus of training lead to differential weighting of hierarchical action planning. This suggests different enduring markers impressed in the brain when a musician practices one or the other style. PMID- 29277651 TI - Predictive coding of visual object position ahead of moving objects revealed by time-resolved EEG decoding. AB - Due to the delays inherent in neuronal transmission, our awareness of sensory events necessarily lags behind the occurrence of those events in the world. If the visual system did not compensate for these delays, we would consistently mislocalize moving objects behind their actual position. Anticipatory mechanisms that might compensate for these delays have been reported in animals, and such mechanisms have also been hypothesized to underlie perceptual effects in humans such as the Flash-Lag Effect. However, to date no direct physiological evidence for anticipatory mechanisms has been found in humans. Here, we apply multivariate pattern classification to time-resolved EEG data to investigate anticipatory coding of object position in humans. By comparing the time-course of neural position representation for objects in both random and predictable apparent motion, we isolated anticipatory mechanisms that could compensate for neural delays when motion trajectories were predictable. As well as revealing an early neural position representation (lag 80-90 ms) that was unaffected by the predictability of the object's trajectory, we demonstrate a second neural position representation at 140-150 ms that was distinct from the first, and that was pre-activated ahead of the moving object when it moved on a predictable trajectory. The latency advantage for predictable motion was approximately 16 +/- 2 ms. To our knowledge, this provides the first direct experimental neurophysiological evidence of anticipatory coding in human vision, revealing the time-course of predictive mechanisms without using a spatial proxy for time. The results are numerically consistent with earlier animal work, and suggest that current models of spatial predictive coding in visual cortex can be effectively extended into the temporal domain. PMID- 29277650 TI - Macroscale variation in resting-state neuronal activity and connectivity assessed by simultaneous calcium imaging, hemodynamic imaging and electrophysiology. AB - Functional imaging of spontaneous activity continues to play an important role in the field of connectomics. The most common imaging signal used for these experiments is the blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal, but how this signal relates to spontaneous neuronal activity remains incompletely understood. Genetically encoded calcium indicators represent a promising tool to study this problem, as they can provide brain-wide measurements of neuronal activity compared to point measurements afforded by electrophysiological recordings. However, the relationship between the calcium signal and neurophysiological parameters at the mesoscopic scale requires further systematic characterization. Therefore, we collected simultaneous resting-state measurements of electrophysiology, along with calcium and hemodynamic imaging, in lightly anesthetized mice to investigate two aims. First, we examined the relationship between each imaging signal and the simultaneously recorded electrophysiological signal in a single brain region, finding that both signals are better correlated with multi-unit activity compared to local field potentials, with the calcium signal possessing greater signal-to-noise ratio and regional specificity. Second, we used the resting-state imaging data to model the relationship between the calcium and hemodynamic signals across the brain. We found that this relationship varied across brain regions in a way that is consistent across animals, with delays increasing by600 ms towards posterior cortical regions. Furthermore, while overall functional connectivity (FC) measured by the hemodynamic signal is significantly correlated with FC measured by calcium, the two estimates were found to be significantly different. We hypothesize that these differences arise at least in part from the observed regional variation in the hemodynamic response. In total, this work highlights some of the caveats needed in interpreting hemodynamic-based measurements of FC, as well as the need for improved modeling methods to reduce this potential source of bias. PMID- 29277652 TI - Transient synchronization of hippocampo-striato-thalamo-cortical networks during sleep spindle oscillations induces motor memory consolidation. AB - Sleep benefits motor memory consolidation. This mnemonic process is thought to be mediated by thalamo-cortical spindle activity during NREM-stage2 sleep episodes as well as changes in striatal and hippocampal activity. However, direct experimental evidence supporting the contribution of such sleep-dependent physiological mechanisms to motor memory consolidation in humans is lacking. In the present study, we combined EEG and fMRI sleep recordings following practice of a motor sequence learning (MSL) task to determine whether spindle oscillations support sleep-dependent motor memory consolidation by transiently synchronizing and coordinating specialized cortical and subcortical networks. To that end, we conducted EEG source reconstruction on spindle epochs in both cortical and subcortical regions using novel deep-source localization techniques. Coherence based metrics were adopted to estimate functional connectivity between cortical and subcortical structures over specific frequency bands. Our findings not only confirm the critical and functional role of NREM-stage2 sleep spindles in motor skill consolidation, but provide first-time evidence that spindle oscillations [11-17 Hz] may be involved in sleep-dependent motor memory consolidation by locally reactivating and functionally binding specific task-relevant cortical and subcortical regions within networks including the hippocampus, putamen, thalamus and motor-related cortical regions. PMID- 29277653 TI - MicroRNA-191, regulated by HIF-2alpha, is involved in EMT and acquisition of a stem cell-like phenotype in arsenite-transformed human liver epithelial cells. AB - Inorganic arsenic is widely distributed in the environment, and epidemiologic data show a strong association between arsenic exposure and risk of liver cancer. An understanding of the mechanisms underlying development of liver cancer and metastasis would be useful in reducing the incidence and mortality of liver cancer. MicroRNAs (miRs) act as regulators in liver cancer. Here, we show that acute or chronic exposure of human liver epithelial L-02 cells to arsenite increased expression of miR-191. There were decreased levels of BASP-1 and E cadherin and increased levels of WT-1 and N-cadherin, indicating that arsenite induced epithelial-mesenchymal transition (EMT). Moreover, arsenite increased EpCAM and CD90 mRNA levels, showing the acquisition of stem cell-like properties by these cells. Suppression of miR-191 resulted in repression of EMT and reduced expression of stem-cell markers. Further, a miR-191 inhibitor blocked spheroid formation and production of side population cells. Luciferase reporter assays indicated that miR-191 was a target of HIF-2alpha, and inhibition of miR-191 decreased the neoplastic and metastatic properties of arsenite-transformed L-02 cells. Thus, in arsenite-transformed liver epithelial cells, transcriptional activation of the miR-191 promoter by HIF-2alpha is involved in EMT and in the acquisition of a stem cell-like phenotype. PMID- 29277654 TI - Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: An international workshop report. AB - Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, "Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements", explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches. The importance of using integrated approaches that combine existing data with in vitro and/or computational approaches to generate new data was discussed. Approaches were also proposed to develop a strategy for identifying and overcoming obstacles to replacing animal tests. Attendees noted the importance of dosimetry considerations and of understanding mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Recommendations were made to (1) develop a database of existing acute inhalation toxicity data; (2) prepare a state-of-the-science review of dosimetry determinants, mechanisms of toxicity, and existing approaches to assess acute inhalation toxicity; (3) identify and optimize in silico models; and (4) develop a decision tree/testing strategy, considering physicochemical properties and dosimetry, and conduct proof-of-concept testing. Working groups have been established to implement these recommendations. PMID- 29277656 TI - Unmasking of Urinary-pubic Symphysis Fistula After Implantation of Artificial Urinary Sphincter in Prostate Cancer Survivors-User Beware. AB - OBJECTIVE: To describe the dramatic and rapid unmasking of urinary-pubic symphysis fistula (UPF) and chronic osteomyelitis after artificial urinary sphincter (AUS) implantation. This has never been reported as UPF is usually an insidious sequelae of radiotherapy or energy ablation for prostate cancer. METHODS: We prospectively identified men who underwent rapid clinical decline due to UPF soon after AUS implantation at our institution in the previous 24 months. Chart and imaging was reviewed to assess preoperative and postoperative factors. RESULTS: Three patients were identified. All men had undergone radiation therapy for prostate cancer and all had undergone prior manipulation of the posterior urethra for complications of radiotherapy. Radiation cystitis was present and all had a low cystometric bladder capacity before surgery. All patients declined rapidly after surgery. UPF was diagnosed in 2 men after activation of AUS at 6-7 weeks postoperatively and 1 patient presented before activation at 3 weeks postoperatively. UPF tract was demonstrated with magnetic resonance imaging in the acute phase in all 3 cases. Two patients have undergone cystectomy and loop diversion with resolution of symptoms and one patient is awaiting definitive surgery. CONCLUSION: Unmasking of occult UPF resulted in rapid clinical decline after AUS implantation. Increased intravesical filling pressure from increased urethral resistance likely resulted in opening of occult fistula tracts. UPF should be in the differential diagnosis if there is history of radiotherapy or urethral instrumentation. An underlying and undiagnosed UPF may lead to grave consequences after AUS implantation. PMID- 29277655 TI - Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1). AB - The TMEM16A-mediated Ca2+-activated Cl- current drives several important physiological functions. Membrane lipids regulate ion channels and transporters but their influence on members of the TMEM16 family is poorly understood. Here we have studied the regulation of TMEM16A by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), cholesterol, and fatty acids using patch clamp, biochemistry and fluorescence microscopy. We found that depletion of membrane PI(4,5)P2 causes a decline in TMEM16A current that is independent of cytoskeleton, but is partially prevented by removing intracellular Ca2+. On the other hand, supplying PI(4,5)P2 to inside-out patches attenuated channel rundown and/or partially rescued activity after channel rundown. Also, depletion (with methyl-beta-cyclodextrin M betaCD) or restoration (with M-betaCD+cholesterol) of membrane cholesterol slows down the current decay observed after reduction of PI(4,5)P2. Neither depletion nor restoration of cholesterol change PI(4,5)P2 content. However, M-betaCD alone transiently increases TMEM16A activity and dampens rundown whereas M betaCD+cholesterol increases channel rundown. Thus, PI(4,5)P2 is required for TMEM16A function while cholesterol directly and indirectly via a PI(4,5)P2 independent mechanism regulate channel function. Stearic, arachidonic, oleic, docosahexaenoic, and eicosapentaenoic fatty acids as well as methyl stearate inhibit TMEM16A in a dose- and voltage-dependent manner. Phosphatidylserine, a phospholipid whose hydrocarbon tails contain stearic and oleic acids also inhibits TMEM16A. Finally, we show that TMEM16A remains in the plasma membrane after treatment with M-betaCD, M-betaCD+cholesterol, oleic, or docosahexaenoic acids. Thus, we propose that lipids and fatty acids regulate TMEM16A channels through a membrane-delimited protein-lipid interaction. PMID- 29277657 TI - Effects of Focal vs Total Cryotherapy and Minimum Tumor Temperature on Patient reported Quality of Life Compared With Active Surveillance in Patients With Prostate Cancer. AB - OBJECTIVE: To investigate the effects of focal (hemiablation) or total cryotherapy and minimum tumor temperature on patient-reported quality of life (QoL) in patients with prostate cancer. METHODS: An Institutional Review Board approved database was reviewed for patients who underwent cryotherapy or active surveillance (AS). QoL questionnaire responses were collected and scores were analyzed for differences between focal and total cryotherapy and between very cold (<-76 degrees C) and moderate-cold (>=-76 degrees C) minimum tumor temperatures. RESULTS: A total of 197 patients responded to a total of 547 questionnaires. Focal and total cryotherapy patients had initially lower sexual function scores relative to AS (year 1 mean difference focal: -31.7, P <.001; total: -48.1, P <.001). Focal cryotherapy was associated with a more rapid improvement in sexual function. Both focal and total cryotherapy sexual function scores were not statistically significantly different from the AS cohort by postprocedural year 4. Very cold and moderate-cold temperatures led to initially lower sexual function scores relative to AS (year 1 very cold: -38.1, P <.001; moderate-cold: -30.7, P <.001). Moderate-cold temperature scores improved more rapidly than those of very cold temperature. Neither very cold nor moderate-cold temperatures had a statistically significant difference in sexual function scores relative to AS by postprocedural year 4. Urinary function and bowel habits were not significantly different between focal and total cryotherapy and between very cold and moderate-cold temperature groups. CONCLUSION: Focal cryotherapy and moderate-cold (>=-76 degrees C) temperature were associated with favorable sexual function relative to total cryotherapy and very cold temperature, respectively. No significant differences in urinary function or bowel habits were observed between groups. PMID- 29277658 TI - Agency performance modulates resting-state variation in prefrontal brain regions. AB - Distinguishing the effects of own from others' actions is a prerequisite for effective interpersonal functioning. Individuals differ in their ability to do this. For example, difficulties in self-other attribution have been linked to positive symptoms of schizophrenia such as hallucinations, with causally ambiguous situations proving a universal challenge. The goal of the present study was to examine relationships between individual differences in resting-state functional connectivity and self-other attribution performance. Fifty-five healthy adults completed a resting-state fMRI scan and an attribution task that involved tapping at irregular intervals while listening to a tone sequence. The likelihood that tones in the sequence corresponded to the participant's taps was systematically varied. Using group independent component analysis (ICA) and dual regression, we found that connectivity between prefrontal networks associated with self-referential processing and regions sensitive to externally-generated stimuli was modulated by participants' ability to accurately assess the proportion of tones belonging to self versus other. These findings shed additional light on the neural mechanisms of agency, emphasising that connectivity with prefrontal networks play an important role in self-other differentiation. PMID- 29277659 TI - Quantitative detection method of Enterocytozoon hepatopenaei using TaqMan probe real-time PCR. AB - A TaqMan probe and a pair of specific primers were selected from the small subunit ribosomal DNA (SSU rDNA) sequence of Enterocytozoon hepatopenaei (EHP); this real-time PCR assay was developed and optimized. It showed a good linearity in detecting standards of EHP SSU rDNA fragments from 4 * 102 to 4 * 108 copies/reaction using the established method. The detection limit of the qPCR method was as low as 4 * 101 copies per reaction, which was higher than the conventional PCR and SYBR Green I-based EHP qPCR reported. Using the qPCR assay, EHP was detected in four batches of slow-growing Penaeus vannamei specimens collected from Tianjin and Zhejiang Province in China was detected using qPCR. The results showed that all the hepatopancreas from the slow-growing P. vannamei specimens were detected as EHP-positive. EHP copies of hepatopancreas in some batches had a negative correlation with the body mass index (BMI) of shrimps; however, not all batches of specimens had this negative correlation between EHP copies of hepatopancreas and BMI. This qPCR technique is sensitive, specific and easy to perform (96 tests in <3 h), which provides technical support for the detection and prevention of EHP. PMID- 29277660 TI - Properties and mechanism of d-glucosaminate-6-phosphate ammonia-lyase: An aminotransferase family enzyme with d-amino acid specificity. AB - Salmonella enterica serovar Typhimurium utilizes a wide range of growth substrates, some of which are relatively novel. One of these unusual substrates is d-glucosaminate, which is metabolized by the enzymes encoded in the dga operon. d-Glucosaminate is transported and converted to d-glucosaminate-6 phosphate (G6P) by a phosphotransferase system, composed of DgaABCD. The protein product of dgaE, d-glucosaminate-6-phosphate ammonia lyase (DGL), converts G6P to 2-keto-3-deoxygluconate-6-phosphate, which undergoes a retroaldol reaction catalyzed by the DgaF protein to give d-glyceraldehyde-3-phosphate and pyruvate. We have now developed an improved synthesis of G6P which gives a higher yield. The DGL reaction is of mechanistic interest because it is one of only a few enzymes in the pyridoxal-5'-phosphate (PLP) dependent aminotransferase superfamily known to catalyze reaction of a d-amino acid substrate. The pH dependence of DGL shows an optimum at 7.5-8.5, suggesting a requirement for a catalytic base. alpha-Glycerophosphate and inorganic phosphate are weak competitive inhibitors, with Ki values near 30mM, and d-serine is neither a substrate nor an inhibitor. We have found in rapid-scanning stopped-flow experiments that DGL reacts rapidly with its substrate to form a quinonoid intermediate with lambdamax=480nm, within the dead time (ca. 2msec), which then rapidly decays (k=279s-1) to an intermediate with absorption between 330 and 350nm, probably an aminoacrylate complex. We suggest a mechanism for DGL and propose that the unusual stereochemistry of the DGL reaction requires a catalytic base poised on the opposite face of the PLP-substrate complex from the other members of the aminotransferase superfamily. PMID- 29277661 TI - Crystal structure of d-glycero-alpha-d-manno-heptose-1-phosphate guanylyltransferase from Yersinia pseudotuberculosis. AB - The Gram-negative bacterium Yersinia pseudotuberculosis is the causative agent of yersiniosis. d-glycero-alpha-d-manno-heptose-1-phosphate guanylyltransferase (HddC) is the fourth enzyme of the GDP-d-glycero-alpha-d-manno-heptose biosynthesis pathway which is important for the virulence of the microorganism. Therefore, HddC is a potential target of antibiotics against yersiniosis. In this study, HddC from the synthesized HddC gene of Y. pseudotuberculosis has been expressed, purified, crystallized. Synchrotron X-ray data from a selenomethionine substituted HddC crystal were also collected and its structure was determined at 2.0A resolution. Structure analyses revealed that it belongs to the glycosyltransferase A type superfamily members with the signature motif GXGXR for nucleotide binding. Despite of remarkable structural similarity, HddC uses GTP for catalysis instead of CTP and UTP which are used for other major family members, cytidylyltransferase and uridylyltransferase, respectively. We suggest that EXXPLGTGGA and L(S/A/G)X(S/G) motifs are probably essential to bind with GTP and a FSFE motif with substrate. PMID- 29277662 TI - NF-kappaB in the crosshairs: Rethinking an old riddle. AB - Constitutive NF-kappaB signalling has been implicated in the pathogenesis of most human malignancies and virtually all non-malignant pathologies. Accordingly, the NF-kappaB pathway has been aggressively pursued as an attractive therapeutic target for drug discovery. However, the severe on-target toxicities associated with systemic NF-kappaB inhibition have thus far precluded the development of a clinically useful, NF-kappaB-targeting medicine as a way to treat patients with either oncological or non-oncological diseases. This minireview discusses some of the more promising approaches currently being developed to circumvent the preclusive safety liabilities of global NF-kappaB blockade by selectively targeting pathogenic NF-kappaB signalling in cancer, while preserving the multiple physiological functions of NF-kappaB in host defence responses and tissue homeostasis. PMID- 29277664 TI - The altered platelet mineral ratios in pregnancy complicated with intrauterine growth restriction. AB - Altered function of maternal platelets has been evidenced in intrauterine growth restriction (IUGR) but intraplatelet burden of trace elements, factors known to affect platelet activity, remains unknown in IUGR pregnancy. This study assessed the intraplatelet status of Ca, Cu, Mg, Na, K, P, Zn and their ratios (Ca/P, Ca/Mg, Na/K, Cu/Zn) in IUGR pregnancy (n = 35), uncomplicated pregnancy (n = 25) and in non-pregnant females (n = 25). The IUGR group was characterized by the lowest content of Ca, Mg and Zn, and Ca/P ratio (<1.0), and the highest Ca/Mg and Cu/Zn ratios. The studied parameters in non-pregnant women and in uncomplicated pregnancy were comparable except P content and Ca/Mg ratio which were significantly lower in the former group. No differences in Na and K contents, and Na/K ratio between studied groups were found. This study reports that maternal intraplatelet status of selected minerals may be altered in IUGR. PMID- 29277663 TI - OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam. AB - This study aimed to demonstrate that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between piperacillin and tazobactam. After co administration with piperacillin in rats, the AUC of tazobactam in plasma was significantly increased, and t1/2beta was prolonged with significant reduction in plasma clearance, renal clearance and cumulative urinary excretion. In rat and human kidney slices, probenecid, p-aminohippurate and benzylpenicillin inhibited the uptake of piperacillin and tazobactam. Piperacillin significantly inhibited the uptake of tazobactam. Moreover, the uptakes of piperacillin, tazobactam and sulbactam in hOAT1/3-HEK293 cells were significantly higher compared with mock HEK293 cells, respectively. Piperacillin significantly inhibited the uptake of tazobactam in hOAT1/3-HEK293 cells. The Km values of tazobactam (431 +/- 67 MUM for hOAT1, 377 +/- 63 MUM for hOAT3) were significantly higher than those of piperacillin (37 +/- 5 MUM for hOAT1, 172 +/- 28 MUM for hOAT3). This suggested that piperacillin has a stronger affinity to hOAT1/3 than tazobactam. Meanwhile, the Km values of tazobactam were increased in the presence of piperacillin with unchanged Vmax. This indicated that piperacillin inhibited the uptake of tazobactam in a competitive manner. In conclusion, piperacillin and tazobactam are the substrates of hOAT1/3, and OAT1/3 mediate the DDI between piperacillin and tazobactam. PMID- 29277665 TI - Tacrolimus: An updated review on delivering strategies for multifarious diseases. AB - From the current trends, tacrolimus (TAC) has become an important therapeutic option for the optimal individualization of immunosuppressive therapy especially in case of transplant recipients. TAC is used most frequently in comparison to other immunosuppressants because it offers better safety profile with increased long-term survival in patients especially in children and adolescents. This drug has developed an immense interest in the research field owing to its potential pharmacological scope but due to its poor water solubility, need of concomitant steroids and higher incidences of nephrotoxicity, there comes a need for future research to minimize such limitations and decipher maximum use of the drug. In addition, there are number of formulations attempted to enhance its erratic bioavailability through various techniques namely solid dispersions, inclusion complexes, prodrug approach, SMEDDS etc. The present review aims to acknowledge the TAC pharmacokinetic profile and novel drug delivery systems in multiple diseased conditions by particularly enhancing its poor biopharmaceutical issues as well as dose related toxicity. Collectively, we have updated the data pertaining to the drug delivery prospects of TAC for the period of last 8 10years. PMID- 29277666 TI - Assessment of in vivo anti-tumor activity of human umbilical vein endothelial cell vaccines prepared by various antigen forms. AB - Human umbilical vein endothelial cell (HUVEC) vaccine has been proved as an effective whole-cell vaccine, but the modest therapeutic anti-tumor efficiency limits its clinical use. Various antigen forms, including paraformaldehyde-fixed HUVEC, glutaraldehyde-fixed HUVEC, HUVEC lysate and live HUVEC, have been intensively used in HUVEC vaccine preparation, however, the most effective antigen form has not yet been identified. In the present study, these four commonly used antigen forms were used to prepare vaccines named Para-Fixed-EC, Glu-Fixed-EC, Lysate-EC, and Live-EC respectively, and the anti-tumor efficacy of these four vaccines was investigated. Results showed that Live-EC exhibited the most favorable anti-tumor growth and metastasis effects among the four vaccines in both H22 hepatocellular carcinoma and Lewis lung cancer models. High titer anti-HUVEC antibodies were detected in Live-EC immunized mice sera, and the immune sera of Live-EC group could significantly inhibit HUVEC proliferation and tube formation. Moreover, T cells isolated from Live-EC immunized mice exhibited strong cytotoxicity against HUVEC cells, with an increasing IFN-gamma and decreasing Treg production in Live-EC immunized mice. Finally, CD31 immunohistochemical analysis of the excised tumors verified a significant reduction in vessel density after Live-EC vaccination, which was in accordance with the anti-tumor efficiency. Taken together, all the results proved that live HUVEC was the most effective antigen form to induce robust HUVEC specific antibody and CTL responses, which could lead to the significant inhibition of tumor growth and metastasis. We hope the present findings would provide a rationale for the further optimization of HUVEC vaccine. PMID- 29277667 TI - Triclosan and its derivatives as antimycobacterial active agents. AB - Tuberculosis (TB) represents one of the leading causes of morbidity and mortality worldwide. Development of new potential drugs is essential because of the existence of latent TB and expansion of drug-resistant TB forms (multidrug resistant and extensively drug-resistant tuberculosis). Triclosan is a widely used broad-spectrum biocidal agent. It has been shown to inhibit InhA, an essential enoyl acyl carrier protein reductase, resulting in the lysis of Mycobacterium tuberculosis. Triclosan can be considered as a promising compound for the inhibition of InhA and suppression of mycobacterial growth, because this polychlorinated molecule doesn't require any activation and it is able to affect the function of InhA directly. This approach enables to circumvent resistance to isoniazid. The aim of this review is to describe current knowledge about triclosan and its analogues as potential antimycobacterial agents. PMID- 29277668 TI - Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets. AB - The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16kg/h), mixer speed rpm (500, 850 and 1200rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5s), tablet strength (147N), dissolution in 2.5min (90%) and ejection force (425N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength. Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality. PMID- 29277669 TI - Invited Commentary. PMID- 29277670 TI - Influence of Timing After Thoracic Endovascular Aortic Repair for Acute Type B Aortic Dissection. AB - BACKGROUND: This study aimed to analyze the influence of the timing of intervention from presentation of symptoms to thoracic endovascular aortic repair (TEVAR) and its relation to major complications. Data were collected from the Japan Adult Cardiovascular Surgery Database. METHODS: We retrospectively analyzed the data of 680 patients who underwent TEVAR for acute and subacute type B dissection between January 2008 and January 2013. RESULTS: Thoracic endovascular aortic repair for type B dissection was performed in 680 patients: 295 repairs were performed within 24 hours of presentation of symptoms (hyperacute); 97 between 24 hours and 14 days (acute); and 288 between 14 days and 6 weeks (subacute). Hyperacute patients more frequently had immediate life-threatening complications from type B dissection such as rupture or malperfusion than did acute or subacute patients (41.0% [121 of 295] versus 7.2% [7 of 97] versus 4.2% [12 of 288]; p < 0.001; and 17.3% [51 of 295] versus 8.3% [8 of 97] versus 5.6% [16 of 288]; p < 0.001, respectively). Operative mortality and severe complications including aortic dissection were more common among hyperacute patients (11.9% [35 of 295] versus 0% [0 of 97] versus 1.7% [5 of 288]; p < 0.001; and 32.5% [96 of 295] versus 10.3% [10 of 97] versus 8.3% [24 of 288]; p < 0.001, respectively) and did not differ significantly between acute and subacute patients (p = 0.191 and p = 0.553, respectively). CONCLUSIONS: Although TEVAR performed for aortic dissection within 24 hours of presentation of symptoms was associated with worse outcomes, TEVAR performed between 24 hours and 14 days, as compared with TEVAR between 14 days and 6 weeks, does not appear to increase the risk of perioperative complications. PMID- 29277671 TI - Early and Long-Term Results of Tracheal Sleeve Pneumonectomy for Lung Cancer After Induction Therapy. AB - BACKGROUND: The role of induction therapy (IT) and its effects on morbidity and mortality of patients receiving tracheal sleeve pneumonectomy (TSP) are unclear. We evaluated early and long-term outcomes of patients who underwent TSP after IT. METHODS: From 1998 to 2015, 32 patients (26 men; median age, 63 years) underwent TSP. Twenty-two patients (69%) received IT (cisplatin-based chemotherapy). The TSPs were all right sided and included three completion pneumonectomies. Superior vena cava resection was combined with TSP in 15 cases. Diaphragmatic and vertebral resection was also associated in 1 case each. RESULTS: Operative mortality was nil. Thirty-day mortality was 9% (n = 3). Major complications occurred in 7 patients (21.8%): bronchopleural fistulas in 3; acute respiratory distress syndrome in 2; cardiac hernia in 1; and empyema in 1. The IT had no significant effects on morbidity and mortality. Resection was complete in 31 patients (97%). Pathologic N status was N0 in 2 cases, N1 in 17, and N2 in 13. Nodal downstaging was diagnosed in 13 of 22 patients (59.1%) who received IT (11 passed from N2 to N1, and 2 to N0). Mean survival was 36 months (range, 1 to 181). Overall 5-year survival and disease-free survival were 30.3% and 27.7%, respectively. Patients receiving IT had a poor survival (p = 0.03). At multivariate analysis, nodal downstaging and adjuvant treatment significantly affected survival (p = 0.035 and p = 0.007, respectively). CONCLUSIONS: Tracheal sleeve pneumonectomy is a feasible but technically challenging surgical procedure and provides acceptable results in terms of early and long-term outcomes. Induction therapy did not significantly affect morbidity and mortality. PMID- 29277672 TI - Grading of Emphysema Is Indispensable for Predicting Prolonged Air Leak After Lung Lobectomy. AB - BACKGROUND: The aim of this study was to assess the utility of quantitative computed tomography-based grading of emphysema for predicting prolonged air leak after thoracoscopic lobectomy. METHODS: A consecutive series of 284 patients undergoing thoracoscopic lobectomy for lung cancer was retrospectively reviewed. Prolonged air leak was defined as air leaks lasting 7 days or longer. The grade of emphysema (emphysema index) was defined by the proportion of the emphysematous lung volume (less than -910 HU) to the total lung volume (-600 to -1,024 HU) by a computer-assisted histogram analysis of whole-lung computed tomography scans. RESULTS: The mean length of chest tube drainage was 1.5 days. Fifteen patients (5.3%) presented with prolonged air leak. According to a receiver-operating characteristics curve analysis, the emphysema index was the best predictor of prolonged air leak, with an area under the curve of 0.85 (95% confidence interval: 0.73 to 0.98). An emphysema index of 35% or greater was the best cutoff value for predicting prolonged air leak, with a negative predictive value of 0.99. The emphysema index was the only significant predictor for the length of postoperative chest tube drainage among conventional variables, including the pulmonary function and resected lobe, in both univariate and multivariate analyses. Prolonged air leak resulted in an increased duration of hospitalization (p < 0.001) and was frequently accompanied by pneumonia or empyema (p < 0.001). CONCLUSIONS: The grade of emphysema on computed tomography scan is the best predictor of prolonged air leak that adversely influences early postoperative outcomes. We must take new measures against prolonged air leak in quantitative computed tomography-based high-risk patients. PMID- 29277673 TI - Invited Commentary. PMID- 29277674 TI - Invited Commentary. PMID- 29277675 TI - The inhibitory influence of adipose tissue-derived mesenchymal stem cell environment and Wnt antagonism on breast tumour cell lines. AB - Tumours exhibit a heterogeneous mix of cell types that reciprocally regulate their growth in the tumour stroma, considerably affecting the progression of the disease. Both adipose-derived mesenchymal stem cells and Wnt signalling pathway are vital in driving breast tumour growth. Hence, we examined the effect of secreted factors released by adipose-derived mesenchymal stem cells, and further explored the anti-tumour property of the Wnt antagonist secreted frizzled-related protein 4 (sFRP4) on MCF-7 and MDA-MB-231 breast tumour cells. We observed that conditioned medium and extracellular matrix derived from adipose-derived mesenchymal stem cells inhibited tumour viability. The inhibitory effect of the conditioned medium was retained within its low molecular weight and non-protein component. The conditioned medium also induced apoptosis accompanied by a decrease in the mitochondrial membrane potential in tumour cells, Furthermore, it downregulated the protein expression of active beta-catenin and Cyclin D1, which are major target proteins of the Wnt signalling pathway, and reduced the expression of anti-apoptotic protein Bcl-xL. The combination of conditioned medium and sFRP4 further potentiated the effects, depending on the tumour cell line and experimental assay. We conclude that factors derived from conditioned medium of adipose-derived mesenchymal stem cells and sFRP4 significantly decreased the tumour cell viability and migration rates (MCF-7), accompanied with an enhanced apoptotic activity through inhibition of canonical Wnt signalling. Besides giving an insight to possible paracrine interactions and influence of signalling pathways, reflective of a breast tumour microenvironment, this study emphasises the utilization of cell free-secreted factors and Wnt antagonists to improve conventional anti-cancer strategies. PMID- 29277676 TI - Too much opioid, too much harm. PMID- 29277677 TI - Reply to: Over time, differences in survival and favorable neurologic outcomes between conventional and compression-only cardiopulmonary resuscitation have been gradually reduced in pediatric out-of-hospital cardiac arrest. PMID- 29277678 TI - Desarda versus Lichtenstein technique for the treatment of primary inguinal hernia: A systematic review. AB - BACKGROUND: The aim of this study was to compare the effectiveness between Desarda and Lichtenstein inguinal hernia repair. METHODS: An electronic search for articles about Desarda and Lichtenstein technique published between 2001 and July 2017 was conducted in PubMed, Cochrane Library, Web of Science and EMBASE database. Meta-analysis was performed on surgical time, postoperative recovery, complications and recurrence rate. RESULTS: Eight primary studies identified a total of 1014 patients, of whom 500 and 514 underwent Desarda herniorrhaphy and Lichtenstein herniorrhaphy, respectively. There was no significant difference in terms of operating time, return to normal gait, pain score, wound infection, hematoma, foreinbody sensation, seroma and recurrence rate. CONCLUSIONS: Current evidence suggests that there is no difference between Desarda and Lichtenstein technique in short-term effectiveness. Further high-quality, long follow-up randomized controlled trials are needed to provide more reliable evidence. PMID- 29277679 TI - Intermittent fasting promotes prolonged associative interactions during synaptic tagging/capture by altering the metaplastic properties of the CA1 hippocampal neurons. AB - Metaplasticity is the inherent property of a neuron or neuronal population to undergo activity-dependent changes in neural function that modulate subsequent synaptic plasticity. Here we studied the effect of intermittent fasting (IF) in governing the interactions of associative plasticity mechanisms in the pyramidal neurons of rat hippocampal area CA1. Late long-term potentiation and its associative mechanisms such as synaptic tagging and capture at an interval of 120 min were evaluated in four groups of animals, AL (Ad libitum), IF12 (daily IF for 12 h), IF16 (daily IF for 16 h) and EOD (every other day IF for 24 h). IF had no visible effect on the early or late plasticity but it manifested a critical role in prolonging the associative interactions between weak and strong synapses at an interval of 120 min in IF16 and EOD animals. However, both IF12 and AL did not show associativity at 120 min. Plasticity genes such as Bdnf and Prkcz, which are well known for their expressions in late plasticity and synaptic tagging and capture, were significantly upregulated in IF16 and EOD in comparison to AL. Specific inhibition of brain derived neurotropic factor (BDNF) prevented the prolonged associativity expressed in EOD. Thus, daily IF for 16 h or more can be considered to enhance the metaplastic properties of synapses by improving their associative interactions that might translate into animprovedmemoryformation. PMID- 29277681 TI - Enhanced antitumor and anti-metastasis efficacy against aggressive breast cancer with a fibronectin-targeting liposomal doxorubicin. AB - The chemotherapy of aggressive breast tumor is usually accompanied by a poor prognosis because of the metastasis of tumor cells. Thus, it is important to simultaneously enhance antitumor and anti-metastasis efficacy. Fibronectin and its complexes are expressed on the walls of tumor vessels and in tumor stroma. Moreover, the expression of fibronectin in metastatic sites is even higher than that in primary tumors. Herein, we designed a fibronectin-targeting CREKA modified liposomal doxorubicin (CREKA-Lipo-Dox) for the therapy of metastatic breast tumor. CREKA-Lipo was uniformly formed with high entrapment efficiency. It exhibited longer blood circulation time compared with free Dox, and there was no significant change compared with PEG-Lipo-Dox. Immunofluorescence results revealed that the CREKA-Lipo-Dox could specifically bind to fibronectin in the tumor vessels and tumor stroma. The antitumor and anti-metastasis efficacy of CREKA-loaded liposome was more obvious than that of free Dox or unmodified Dox Lipo. Taken together, binding fibronectin by CREKA could be an attractive therapeutic strategy for metastatic breast cancer in the future. PMID- 29277680 TI - Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate. AB - Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNgamma+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer. PMID- 29277682 TI - Aptamer-guided siRNA-loaded nanomedicines for systemic gene silencing in CD-44 expressing murine triple-negative breast cancer model. AB - In this study, we describe a liposome-based siRNA delivery system with a core composed of siRNA:protamine complex and a shell designed for the active targeting of CD44-expressing cells using for the first time the anti-CD44 aptamer (named Apt1) as targeting ligand. Among all functions, CD44 is the most common cancer stem cell surface biomarker and is found overexpressed in many tumors making this an attractive receptor for therapeutic targeting. This unique non-cationic system was evaluated for the silencing of the reporter gene of luciferase (luc2) in a triple-negative breast cancer model in vitro and in vivo. We show the possibility of conjugating an aptamer to siRNA-containing liposomes for an efficient gene silencing in CD44-expressing tumor cells in vivo, in the perspective of silencing disease-related genes in tumors. PMID- 29277683 TI - New aerosol formulation to control ciprofloxacin pulmonary concentration. AB - Ciprofloxacin (CIP) apparent permeability across a pulmonary epithelium model can be controlled by the affinity of its complex with a metal cation. The higher the complex affinity, the larger is the reduction in CIP apparent permeability. The aim of this study was to evaluate if the control of the CIP apparent permeability observed in vitro could be transposed in vivo to control the CIP lung-to-blood absorption rate and CIP concentrations in the lung epithelial lining fluid (ELF) after intratracheal (IT) administration. Two types of innovative inhalable microparticles loaded with the low-affinity CIP-calcium complex (CIP-Ca) or with the high-affinity CIP-copper complex (CIP-Cu) were formulated and characterized. Then, ELF and plasma pharmacokinetics of CIP were studied in rats after IT administration of these two types of microparticles and of a CIP solution (2.5mg/kg). The presence of Cu2+ had little effect on the microparticle properties and the dry powder had aerodynamic properties which allowed it to reach the lungs. CIP concentrations in ELF were much higher after CIP-Cu microparticles IT administration compared to the other two formulations, with mean AUCELF to AUCu,plasma ratios equal to 1069, 203 and 9.8 after CIP-Cu microparticles, CIP-Ca microparticles and CIP solution pulmonary administration, respectively. No significant modification of lung toxicity markers was found (lactate dehydrogenase and total protein). CIP complexation with Cu2+ seems to be an interesting approach to obtain high CIP concentrations in the ELF of lungs after dry powder IT administration. PMID- 29277684 TI - Commissural axon navigation in the spinal cord: A repertoire of repulsive forces is in command. AB - The navigation of commissural axons in the developing spinal cord has attracted multiple studies over the years. Many important concepts emerged from these studies which have enlighten the general mechanisms of axon guidance. The navigation of commissural axons is regulated by a series of cellular territories which provides the diverse guidance information necessary to ensure the successive steps of their pathfinding towards, across, and away from the ventral midline. In this review, we discuss how repulsive forces, by propelling, channelling, and confining commissural axon navigation, bring key contributions to the formation of this neuronal projection. PMID- 29277685 TI - Cardiac rhythm and pacemaking abnormalities in patients affected by endemic pemphigus in Colombia may be the result of deposition of autoantibodies, complement, fibrinogen, and other molecules. AB - BACKGROUND: We previously showed that one-third of patients affected by endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre-EPF), display autoreactivity to the heart. OBJECTIVE: The purpose of this study was to investigate rhythm disturbances with the presence of autoantibodies and correlate them with ECG changes in these patients. METHODS: We performed a study comparing 30 patients and 30 controls from the endemic area, matched by demographics, including age, sex, weight, work activities, and comorbidities. ECG as well as direct and indirect immunofluorescence, immunohistochemistry, and confocal microscopic studies focusing on cardiac node abnormalities were performed. Autopsies of 7 patients also were reviewed. RESULTS: The main ECG abnormalities seen in the El Bagre-EPF patients were sinus bradycardia (in one-half), followed by left bundle branch block, left posterior fascicular block, and left anterior fascicular block compared with the controls. One-third of the patients displayed polyclonal autoantibodies against the sinoatrial and/or AV nodes and the His bundle correlating with rhythm anomalies and delays in the cardiac conduction system (P <.01). The patient antibodies colocalized with commercial antibodies to desmoplakins I and II, p0071, armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), and myocardium-enriched zonula occludens-1-associated protein (MYZAP; Progen Biotechnik) (P <.01). CONCLUSION: One-third of the patients affected by El Bagre-EPF have rhythm abnormalities that slow the conduction of impulses in cardiac nodes and the cardiac conduction system. These abnormalities likely occur as a result of deposition of autoantibodies, complement, and other inflammatory molecules. We show for the first time that MYZAP is present in cardiac nodes. PMID- 29277686 TI - Accurate localization and catheter ablation of superoparaseptal accessory pathways. AB - BACKGROUND: There remains some confusion delineating the accurate location and the detailed anatomical relationship between atrioventricular accessory pathways (APs) located in the superoparaseptal region. OBJECTIVE: The purpose of this article was to detail the anatomical relationship and accurate location of APs located in the superoparaseptal region. METHODS: Between May 1, 2009 and November 30, 2016, 11 patients with superoparaseptal APs (SPS-APs) were identified in 129 consecutive patients who underwent catheter ablation for APs in our center. RESULTS: A single SPS-AP was detected in all patients (manifest, n = 5; concealed, n = 6). The location of all 11 APs were precisely identified at the region millimeters superior to the His bundle recording site at the tricuspid annulus (S-HB, n = 6; manifest, n = 4); the area millimeters behind the His bundle recording site, adjacent to the right atrial aspect of the noncoronary aortic cusp (B-HB, n = 2; manifest, n = 1); and the true para-His bundle region (P-HB, n = 3). The electrocardiogram of all 5 manifest APs conformed to the typical "anteroseptal AP" pattern: a positive delta wave in leads I, II, avF, and avL; a narrow positive delta wave in lead V1; and a precordial QRS transition at lead V3. All APs were successfully eliminated by catheter ablation. After 54 +/- 26 months of follow-up, all patients were free of arrhythmia. CONCLUSION: Three distinct regions are identified for localization of SPS-APs. Careful mapping and a detailed understanding of the anatomy of this region as well as distinct electrocardiographic characteristics are essential to eliminate such APs safely and effectively. PMID- 29277687 TI - Defibrillator shocks and their effect on objective and subjective patient outcomes: Results of the PainFree SST clinical trial. AB - BACKGROUND: The effect of implantable cardioverter-defibrillator (ICD) shock on device-measured activity and patient-reported outcomes is unknown. OBJECTIVE: The purpose of this study was to analyze the acute and long-term effects of ICD shock on objective behavioral data (ie, device-based physical activity) and subjective patient-reported outcomes (eg, quality of life and shock anxiety). METHODS: The PainFree Smart Shock Technology (SST) clinical trial included 2770 patients with a single- or dual-chamber ICD or cardiac resynchronization therapy - defibrillator device who were followed for 22 +/- 9 months. Participants completed measures of quality of life (EuroQol-5D [EQ-5D] questionnaire) and shock anxiety (Florida Shock Anxiety Scale) at baseline, biannual visits, and monthly for 6 months after an ICD shock. Daily physical activity data were obtained from a built-in device accelerometer. RESULTS: The average daily activity was 185.3 +/- 119.4 min/d. Activity was significantly reduced after an ICD shock (P < .0001) and recovered to a normal level after ~90 days. An ICD shock was also associated with decreased quality of life (EQ5-D health score) and increased EQ-5D anxiety scores, but it did not affect mobility, self-care, activity, or pain. Similarly, shock anxiety (Florida Shock Anxiety Scale) increased in shocked patients and remained significantly elevated at 24 months, regardless of appropriate or inappropriate shock delivery. CONCLUSION: ICD shocks have a long-lasting adverse effect on both objective, device-measured physical activity and subjective patient-reported outcomes of quality of life and shock anxiety. Successful management of patients with an ICD requires attention to clinically relevant behavioral and psychological outcomes to expedite recovery and return to activities of daily living. PMID- 29277688 TI - Ability of using different dry powder inhalers during COPD exacerbations. AB - BACKGROUND: Guidelines suggest that patients hospitalized for acute COPD exacerbations (AECOPD) are treated with short acting bronchodilators. Long acting bronchodilators, offer longer symptom relief but since they are usually administered via Dry Powder Inhalers (DPIs) it is considered that during AECOPD patients would not be able to achieve appropriate inspiratory flow (IF) to receive appropriate drug doses. The aim of the present study was to evaluate whether patients admitted to the hospital for AECOPD, are able to achieve the necessary IF using different DPIs. METHODS: IF was measured daily in patients admitted for AECOPD with a portable IF meter (In-Check Oral inhaler assessment kit), containing a series of adapters that simulate the resistance of 4 DPIs [Turbuhaler (T), Breezhaler/Aerolizer (B/F), Discus (A/A/D) and Handinhaler (HH)]. Dyspnea, spirometry and arterial blood gases were also recorded daily. RESULTS: 44 consecutive patients were included in the study. The majority of patients were able to achieve an IF over 30 L/min with all four device resistances. This minimum required IF was achieved in 90.9%, 100%, 95.5% and 81.8% of patients on admission and in 100%, 100%, 97.7%, and 95.5% of patients on discharge for T, B/F, A/A/D and HH respectively. No functional characteristic was able to predict the achievement of this minimum necessary IF. CONCLUSION: Most patients hospitalized for AECOPD, are able to receive treatment with long acting bronchodilators administered via DPIs. The possible beneficial effects of such an intervention should be tested in further studies. PMID- 29277689 TI - Aerosol delivery during spontaneous breathing with different types of nebulizers- in vitro/ex vivo models evaluation. AB - BACKGROUND: Nebulizers for spontaneous breathing have been evaluated through different study designs. There are limitations in simulated bench models related to patient and nebulizer factors. The aim of this study was to determine the correlation of inhaled drug mass between in vitro and ex vivo studies by testing aerosol deposition of various types of nebulizers. METHODS: Ten healthy subjects were recruited to receive aerosol therapy with five nebulizers in random order: 1) a jet nebulizer (JN); 2) a breath-enhanced nebulizer (BEN); 3) a manually triggered nebulizer (MTN), 4) a breath-actuated nebulizer (BAN), and 5) a vibrating mesh nebulizer (VMN) with valved-adapter. A unit dose of salbutamol containing 5 mg in 2.5 mL was placed into the nebulizer and administered for 10 min. For the ex vivo study, minute ventilation of healthy subjects was recorded for 1 min. For the in vitro study a breathing simulator was utilized with adult breathing patterns. Aerosolized drug from the nebulizers and the accessory tubes was captured using inspiratory and expiratory collecting filters. Captured drug was eluted, measured and expressed as inhaled and exhaled mass using spectrophotometry at a wavelength of 276 nm. RESULTS: 10 healthy subjects were recruited, aged 20.8 +/- 0.7 years old, with a mean height of 166.2 +/- 9.2 cm and weight of 64.7 +/- 12.4 kg. There was no significant difference in the inhaled drug dose between the JN and BEN (15.0 +/- 1.94% and 17.74 +/- 2.65%, respectively, p = .763), yet the inhaled doses were lower than the other three nebulizers (p < .001). The VMN delivered greater inhaled dose than the other four nebulizers (p < .01). The respiratory rate of the cohorts was significantly correlated with the inhaled drug dose. For the in vitro model, the JN delivered a lower inhaled dose (11.6 +/- 1.6, p < .001) than the other nebulizers, whereas the MTN and BAN deposited significantly lower exhaled doses (1.7 +/- 0.4 and 2.7 +/- 0.2, respectively, p < .001). The VMN demonstrated a greater drug dose with the in vitro study than the ex vivo model (44.0 +/- 0.9% and 35.5 +/- 6.3% respectively, p = .003), whereas the JN in the ex vivo model resulted in a greater inhaled drug dose (15.0 +/- 1.9% for ex vivo vs 11.6 +/- 1.6% for in vitro, p = .008). CONCLUSIONS: These in vitro/ex vivo model comparisons of nebulizers performance indicated that breath-related nebulizers can be estimated using an in vitro model; however, the JN and VMN delivered inhaled drug mass differed between models. There was a significant correlation between respiratory rate and inhaled mass, and the inhaled drug dose generated by VMN correlated with minute ventilation. This study demonstrated that the VMN produced greater inhaled drug dose and lowest residual dose, whereas the BEN, BAN, and MTN produced lower exhaled drug dose in both in vitro and ex vivo models. PMID- 29277690 TI - Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: In clinical trials of inhaled bronchodilators, chronic obstructive pulmonary disease (COPD) guidelines recommend that patient-reported outcomes (PROs) are assessed alongside lung function. How these endpoints are related is unclear. METHODS: Pooled longitudinal data from 23 randomised controlled COPD studies were analyzed (N = 23,213). Treatments included long-acting beta2 agonists, long-acting muscarinic antagonists (LABAs or LAMAs) and the LABA/LAMA combination QVA149. Outcome measures were Transition Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) scores, COPD exacerbation frequency and rescue medication use. Relationships between changes in trough forced expiratory volume in one second (DeltaFEV1) and outcomes following treatment were assessed using correlations of data summaries and model-based analysis: generalized linear mixed-effect regression modelling to determine if DeltaFEV1 could predict patient outcomes with different treatments. RESULTS: Mean age was 64 years, 73% were male, and most had moderate (45%) or severe (52%) disease. Statistically significant correlations were observed between DeltaFEV1 and each outcome measure (exacerbations Rs = 0.05; rescue medication, SGRQ, TDI, r = 0.11-0.16; all p < .001). Patients with greater improvements in trough FEV1 had on average better SGRQ and TDI scores, fewer exacerbations, and used less rescue medication. For SGRQ and TDI scores, minimal clinically important differences were observed over the range of pooled DeltaFEV1 values. Model-based predictions confirmed the treatment effect was partly explained by changes in FEV1 from baseline with improvements in PROs observed across all treatments when trough FEV1 improved. Across all endpoints active treatments were better than placebo (p < .0001), and LABA/LAMA treatment resulted in numerically better treatment outcomes than either monocomponent. CONCLUSIONS: These data suggest that FEV1 improvements post bronchodilation correlate with PRO improvements. Further improvements in patient outcomes may be expected by maximizing lung function improvements. TRIAL REGISTRATION: Registration details for the 23 randomised controlled studies used in this pooled analysis are supplied in Additional File 4. PMID- 29277691 TI - Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans. AB - Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzymes in cynomolgus monkey and common marmoset like human P450 enzymes. Information on rhesus monkeys (Macaca mulatta), another macaque species used in drug metabolism studies, is also included for comparison. Among a variety of cynomolgus monkey P450 variants investigated, typical examples include individual pharmacokinetic data for efavirenz and R-warfarin associated with cynomolgus monkey P450 2C9 (formerly 2C43) and 2C19 (2C75) variants, respectively, and for R-omeprazole and S-warfarin associated with marmoset P450 2C19 variants. These findings provide a foundation for understanding the individual pharmacokinetic and toxicological results in non human primates as preclinical models and will help to further support understanding of molecular mechanisms of human P450 function. In addition to these polymorphic P450 enzymes, effects of aging on some drug clearances mediated by cynomolgus monkey and common marmoset P450 enzymes were found in elder animals or animals pretreated with rifampicin. This review describes genetic and acquired individual differences in cynomolgus monkey and common marmoset P450 enzymes involved in drug oxidation associated with pharmacological and/or toxicological effects. PMID- 29277692 TI - Characterization of signalling and regulation of common calcitonin receptor splice variants and polymorphisms. AB - The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget's disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporosis in East Asian populations and, independently, with increased risk of kidney stone disease in a central Asian population. The CTR is pleiotropically coupled, though the relative physiological importance of these pathways is poorly understood. Using both COS-7 and HEK293 cells recombinantly expressing human CTR, we have characterized both splice variant and polymorphism dependent response to CTs from several species in key signalling pathways and competition binding assays. These data indicate that the naturally occurring changes to the intracellular face of CTR alter ligand affinity and signalling, in a pathway and agonist dependent manner. These results further support the potential for these primate-specific CTR variants to engender different physiological responses. In addition, we report that the CTR exhibits constitutive internalization, independent of splice variant and polymorphism and this profile is unaltered by peptide binding. PMID- 29277693 TI - Current mechanistic insights into the CCCP-induced cell survival response. AB - The ring-substituted derivatives of carbonyl cyanide phenylhydrazone, CCCP and FCCP, are routinely used for the analysis of the mitochondrial function in living cells, tissues, and isolated mitochondrial preparations. CCCP and FCCP are now being increasingly used for investigating the mechanisms of autophagy by inducing mitochondrial degradation through the disruption of the mitochondrial membrane potential (DeltaPsim). Sustained perturbation of DeltaPsim, which is normally tightly controlled to ensure cell proliferation and survival, triggers various stress pathways as part of the cellular adaptive response, the main components of which are mitophagy and autophagy. We here review current mechanistic insights into the induction of mitophagy and autophagy by CCCP and FCCP. In particular, we analyze the cellular modifications produced by the activation of two major pathways involving the signaling of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the transcription factor EB (TFEB), and discuss the contribution of these pathways to the integrated cellular stress response. PMID- 29277694 TI - Comparative transcriptomic analysis of shrimp hemocytes in response to acute hepatopancreas necrosis disease (AHPND) causing Vibrio parahemolyticus infection. AB - The recent emergence of acute hepatopancreas necrosis disease (AHPND) in shrimps has posed a major challenge in the shrimp aquaculture industry. The Pir toxin proteins carried by some strains of Vibrio parahaemolyticus are believed to play essential roles in the pathogenesis of AHPND. However, few studies have so far explored how the host immune system responds to these bacteria. In this study, AHPND V. parahaemolyticus (with Pir) and non-AHPND V. parahaemolyticus (without Pir) were injected into two groups of shrimps, and the hemocytes collected for comparative transcriptomic analyses. A total of 1064 differentially expressed genes (DEGs) were identified, of which 910 were up-regulated and 154 were down regulated. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that many DEGs were involved in a number of biological processes such as cellular process, metabolic process and single organism process in the AHPND V. parahaemolyticus injected group than the non AHPND V. parahaemolyticus injected group. Among these, major metabolic processes such as carbohydrate metabolism, lipid metabolism and amino acid metabolism were further identified as the major responsive gene groups. We observed that genes involved in cell growth and anti-apoptosis including src, iap2, cas2, cytochrome P450, gst and cytochromecoxidase were strongly activated in the AHPND V. parahaemolyticus group than in the non-AHPND V. parahaemolyticus group. Collectively, our results unveiled that shrimp hemocytes respond to AHPND related strain of Vibrio parahaemolyticus infection at the transcriptional level, which is useful in furthering our understanding of AHPND. PMID- 29277695 TI - Magnolol protects Ctenopharyngodon idella kidney cells from apoptosis induced by grass carp reovirus. AB - Many natural products from medicinal plants are small molecular weight compounds with enormous structural diversity and show various biological activities. Magnolol is a biphenol compound rich in the stem bark of Magnolia officinalis Rehd et Wils., and is able to suppress viral replication in GCRV-infected grass carp (Ctenopharyngodon idella) kidney (CIK) cells in the previous study. In this study, in vivo studies demonstrated that magnolol was efficient to restrain the replication of GCRV and repair the low level of superoxide dismutase and total antioxidant capacity in serum at the non-toxic concentration in vivo. Furthermore, magnolol inhibited CIK cell apoptosis induced by GCRV and kept the normal cellular morphological structure, reflecting in the protection of CIK cells from cell swelling, the formation of apoptotic bodies, the disappearance of cellular morphology and nuclear fragmentation. Reverse transcript quantitative polymerase chain reaction (RT-qPCR) showed that magnolol facilitated the expression of apoptosis-inhibiting gene bcl-2, while suppressed the expression of apoptosis-promoting gene bax in GCRV-infected cells. Besides, RT-qPCR and enzyme activity assays proved that magnolol suppressed the expression of caspase 3, caspase 8 and caspase 9. Moreover, interactions between magnolol and proteins were predicted by using the STITCH program, which revealed that ten proteins including caspase 3, were involved in the apoptosis pathway, p53 signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway and toll-like receptor signaling pathway. Further assays were performed to test the effect of magnolol on apoptosis pathway, which showed that magnolol dramatically inhibited the activity of caspase 3 rather than those of caspase 8 and caspase 9. Collectively, the present study revealed that magnolol heightened the resistance of grass carp against GCRV infection and refrained GCRV-induced apoptosis, which may be attributed to the direct interaction of magnolol with caspase 3. The present results make a contribution to understanding the mechanisms by which small-molecule drugs possess antiviral activities, and lay a foundation for the development of broad-spectrum antiviral compounds in aquaculture industry. PMID- 29277696 TI - Oxidative burst activity in haemocytes of the freshwater prawn Macrobrachium rosenbergii. AB - Oxidative burst, release of reactive oxygen species/reactive nitrogen species (ROS/RNS) contributed to microorganisms killing, is a vital immune response of crustacean haemocyte. Three morphologic haemocyte types (hyaline cells, HC; semigranular cells, SGC; granular cells, GC) have been defined in crustaceans, and found to play different roles in immune defense. However, oxidative burst activities of different haemocyte subpopulations in crustaceans are currently not documented. In the present study, we investigated the oxidative burst activities of the three haemocyte types in the freshwater prawn Macrobrachium rosenbergii using the common ROS fluorescent probe dichlorofluorescin-diacetate (DCFH-DA). Nitric oxide (NO) donor sodium nitroprusside (SNP) improved the DCF fluorescence in haemocytes, while NO scavenger C-PTIO (2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide) and NO-synthase inhibitor NG-monomethyl-l arginine (L-NMMA) reduced the fluorescence, suggesting that DCF fluorescence intensity could also be modified by intracellular NO level and activity of NO synthase pathway. ROS/RNS was also produced in the untreated haemocytes. GC contained most non-induced ROS/RNS production, while oxidative activity of HC was rather weak. No significant impact of PMA could be observed on ROS/RNS level in all the three cell types. Both zymosan A (ZA) and lipopolysaccharide (LPS) significantly triggered the production of ROS/RNS in SGC and GC, whereas they had no effect on those of HC, suggesting that SGC and GC were the primary cell types involved in pathogens killing by ROS/RNS pathway. Cytochalasin B (Cyt B) inhibited the ZA-induced ROS/RNS production, but could not change the ROS/RNS level stimulated by LPS. For unstimulated haemocytes, ROS/RNS productions decreased 29.6%, 44.1% and 48.6% in SGC, and decreased 44.5%, 28.4% and 57.3% in GC, in the presence of L-NMMA, Fccp and DPI respectively, whereas apocynin could not modulate DCF fluorescence in both SGC and GC, suggesting that mitochondrial oxidative pathway was relatively more dominant in SGC, and NO-synthase (NOS) pathway appeared more active in GC. For LPS-stimulated haemocytes, oxidative activities decreased 22.9%, 42.9%, 29.6% and 60.0% in SGC, and reduced 40.6%, 25.2%, 26.7% and 70.6% in GC with the presence of L-NMMA, apocynin, Fccp and DPI respectively, suggesting that NADPH-oxidase (NOX) pathway in both SGC and GC was activated by LPS, and it became the predominant oxidative pathway in stimulated SGC, while NOS pathway was the relative main source for ROS/RNS production in stimulated GC. PMID- 29277697 TI - Characterization and gene expression analysis of pacu (Piaractus mesopotamicus) inducible nitric oxide synthase (iNOS) following Aeromonas dhakensis infection. AB - Nitric oxide (NO) is an important effector molecule which is involved in a myriad of biological processes, including immune responses against pathogens such as parasites, virus and bacteria. During the inflammatory processes in vertebrates, NO is produced by the inducible nitric oxide synthase (iNOS) enzyme in practically all nucleated cells to suppress or kill intracellular pathogens. The aim of the present study was to characterize the full coding region of the iNOS gene of pacu (Piaractus mesopotamicus), an economically and ecologically important South American fish species, and to analyze mRNA expression levels following intraperitoneal infection with the pathogenic bacterium Aeromonas dhakensis by means of quantitative real time PCR (qPCR). The results showed that the pacu iNOS transcript is 3237 bp in length, encoding a putative protein composed of 1078 amino acid residues. The amino acid sequence showed similarities ranging from 69.03% to 94.34% with other teleost fish and 57.70% with the human iNOS, with all characteristic domains and cofactor binding sites of the enzyme detected. Phylogenetic analysis showed that the iNOS from the red-bellied piranha, another South American characiform, was the closest related sequence to the pacu iNOS. iNOS transcripts were constitutively detected in the liver, spleen and head kidney, and there was a significant upregulation in the liver and spleen at 12, 24 and 48 h after infection with A. dhakensis. No significant variations were observed in the head kidney during the periods analyzed. These results show that iNOS expression was induced by A. dhakensis infection and suggest that this enzyme may be involved in the response to this bacterium in pacu. PMID- 29277698 TI - Interactions between observer and stimuli fertility status: Endocrine and perceptual responses to intrasexual vocal fertility cues. AB - Both men and women find female voices more attractive at higher fertility times in the menstrual cycle, suggesting the voice is a cue to fertility and/or hormonal status. Preference for fertile females' voices provides males with an obvious reproduction advantage, however the advantage for female listeners is less clear. One possibility is that attention to the fertility status of potential rivals may enable women to enhance their own reproductive strategies through intrasexual competition. If so, the response to having high fertility voices should include hormonal changes that promote competitive behavior. Furthermore, attention and response to such cues should vary as a function of the observer's own fertility, which influences her ability to compete for mates. The current study monitored variation in cortisol and testosterone levels in response to evaluating the attractiveness of voices of other women. All 33 participants completed this task once during ovulation then again during the luteal phase. The voice stimuli were recorded from naturally cycling women at both high and low fertility, and from women using hormonal birth control. We found that listeners rated high fertility voices as more attractive compared to low fertility, with the effect being stronger when listeners were ovulating. Testosterone was elevated following voice ratings suggesting threat detection or the anticipation of competition, but no stress response was found. PMID- 29277699 TI - Chronic stress leads to long-lasting deficits in olfactory-guided behaviors, and to neuroplastic changes in the nucleus of the lateral olfactory tract. AB - A recent study reported that the integrity of the nucleus of the lateral olfactory tract (nLOT) is required for normal olfaction and for the display of odor-driven behaviors that are critical for species survival and reproduction. In addition to being bi-directionally connected with a key element of the neural circuitry that mediates stress response, the basolateral nucleus of the amygdala, the nLOT is a potential target for glucocorticoids as its cells express glucocorticoid receptors. Herein, we have addressed this hypothesis by exploring, first, if chronic variable stress (CVS) disrupts odor detection and discrimination, and innate olfactory-driven behaviors, namely predator avoidance, sexual behavior and aggression in male rats. Next, we examined if CVS alters the nLOT structure and if such changes can be ascribed to stress-induced effects on the activity of the main output neurons, which are glutamatergic, and/or of local GABAergic interneurons. Finally, we analyzed if the stress-induced changes are transient or, conversely, persist after cessation of CVS exposure. Our data demonstrate that CVS leads to severe olfactory deficits with inability to detect and discriminate between odors and to innately avoid predator odors. No effects of CVS on sexual and aggressive behaviors were observed. Results also showed that CVS leads to somatic hypertrophy of pyramidal glutamatergic neurons, which likely results from neuronal disinhibition consequent to the loss of inhibitory inputs mediated by GABAergic interneurons. Most of the CVS-induced effects persist beyond a 4-week stress-free period, suggesting long-lasting effects of chronic stress on the structure and function of the olfactory system. PMID- 29277700 TI - Rapid effects of estradiol on aggression depend on genotype in a species with an estrogen receptor polymorphism. AB - The white-throated sparrow (Zonotrichia albicollis) represents a powerful model in behavioral neuroendocrinology because it occurs in two plumage morphs that differ with respect to steroid-dependent social behaviors. Birds of the white striped (WS) morph engage in more territorial aggression than do birds of the tan striped (TS) morph, and the TS birds engage in more parenting behavior. This behavioral polymorphism is caused by a chromosomal inversion that has captured many genes, including estrogen receptor alpha (ERalpha). In this study, we tested the hypothesis that morph differences in aggression might be explained by differential sensitivity to estradiol (E2). We administered E2 non-invasively to non-breeding white-throated sparrows and quantified aggression toward a conspecific 10 min later. E2 administration rapidly increased aggression in WS birds but not TS birds, consistent with our hypothesis that differential sensitivity to E2 may at least partially explain morph differences in aggression. To query the site of E2 action in the brain, we administered E2 and quantified Egr-1 expression in brain regions in which expression of ERalpha is known to differ between the morphs. E2 treatment decreased Egr-1 immunoreactivity in nucleus taeniae of the amygdala, but this effect did not depend on morph. Overall, our results support a role for differential effects of E2 on aggression in the two morphs, but more research will be needed to determine the neuroanatomical site of action. PMID- 29277702 TI - The transcription factors GATA2 and microphthalmia-associated transcription factor regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis. AB - BACKGROUND: Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized by decarboxylating the amino acid histidine, a reaction catalyzed by the histidine decarboxylase (Hdc) gene-encoded enzyme HDC. However, regulation of the Hdc gene in mast cells is poorly understood. OBJECTIVE: We sought to investigate the in vivo regulation of IgE/mast cell-mediated anaphylaxis by the transcription factors GATA2 and microphthalmia-associated transcription factor (MITF) and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells. METHODS: Mice deficient in the transcription factors Gata2, aryl hydrocarbon receptor (Ahr), aryl hydrocarbon receptor repressor (Ahrr), or basic helix-loop helix family member E40 (Bhlhe40) were assessed for anaphylactic reactions. Chromatin immunoprecipitation sequencing analysis identified putative Hdc enhancers. Luciferase reporter transcription assay confirmed enhancer activities of putative enhancers in the Hdc gene. The short hairpin RNA knockdown approach was used to determine the role of MITF in regulating mouse and human HDC gene expression. RESULTS: Connective tissue mast cell-specific Gata2-deficient mice did not have IgE/mast cell-mediated anaphylaxis. GATA2 induced the expression of Mitf, Ahr, Ahrr, and Bhlhe40 in mast cells. MITF, but not AHR, AHRR, or BHLHE40, was required for anaphylaxis. MITF bound to an enhancer located 8.8 kb upstream of the transcription start site of the Hdc gene and directed enhancer activity. MITF overexpression largely restored Hdc gene expression in the Gata2-deficient mast cells. In the human mast cell line LAD2, MITF was required for the HDC gene expression and histamine synthesis. CONCLUSION: The transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis. PMID- 29277701 TI - Oxytocin and the warm outer glow: Thermoregulatory deficits cause huddling abnormalities in oxytocin-deficient mouse pups. AB - Oxytocin is a social and reproductive hormone that also plays critical roles in a range of homeostatic processes, including thermoregulation. Here, we examine the role of oxytocin (OT) as a mediator of brown adipose tissue (BAT) thermogenesis, cold-induced huddling, and thermotaxis in eight-day-old (PD8) OT 'knock out' (OTKO) mouse pups. We tested OTKO and wildtype (WT) pups in single- and mixed genotype groups of six, exposing these to a period of ambient warmth (~35 degrees C) followed by a period of cold (~21.5 degrees C). Whether huddling exclusively with other OTKO or alongside WT pups, OTKO pups showed reduced BAT thermogenesis and were significantly cooler when cold-challenged. Huddles of OTKO pups were also significantly less cohesive than WT huddles during cooling, suggesting that thermoregulatory deficits contribute to contact abnormalities in OTKO pups. To further explore this issue, we examined thermotaxis in individuals and groups of four OTKO or WT pups placed on the cool end of a thermocline and permitted to freely locomote for 2h. When tested individually, male OTKO pups displayed abnormal thermotaxis, taking significantly longer to move up the thermocline and settling upon significantly lower temperatures than WT pups during the 2h test. OTKO mouse pups thus appear to have deficits in both thermogenesis and thermotaxis-the latter deficit being specific to males. Our results add to a growing body of work indicating that OT plays critical roles in thermoregulation and also highlight the entanglement of social and thermoregulatory processes in small mammals such as mice. PMID- 29277703 TI - Nitrosative deamination of 2'-deoxyguanosine and DNA by nitrite, and antinitrosating activity of beta-carboline alkaloids and antioxidants. AB - Endogenous and dietary nitrite produces reactive nitrogen species (RNS) that react with DNA causing mutations. The nitrosation of 2'-deoxyguanosine (dGuo) and DNA with nitrite was studied under different conditions, and the reaction and degradation products identified and analysed by HPLC-DAD-MS. Nitrosative deamination of dGuo produced xanthine along with 2'-deoxyxanthosine whereas DNA afforded xanthine. Formation of xanthine increased with nitrite concentration and in low pH such as that of stomach. Xanthine was measured as a marker of nitrosation of dGuo and DNA, and it was subsequently used to study the antinitrosating activity of beta-carboline alkaloids, and selected antioxidants. Food-occurring tetrahydro-beta-carbolines (THbetaCs) decreased nitrosative deamination of dGuo and DNA under conditions simulating the stomach. Antinitrosating activity was also evidenced for flavonoids (catechin, quercetin) and indole (melatonin) antioxidants. Among THbetaCs the most active antinitrosating compounds were 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acids (THbetaC-3-COOHs) that reacted with nitrite to give N-nitroso derivatives as main products along with 3,4-dihydro-beta-carboline-3-carboxylic acids and aromatic beta-carbolines (norharman and harman). Antinitrosating activity of THbetaCs correlated well with the formation of N-nitroso-THbetaC-3-COOHs. These N nitroso derivatives were stable at pH 7 but degraded in acid conditions affording nitrosating species. PMID- 29277704 TI - Prevention of chronic immobilization stress-induced enhanced expression of glucocorticoid receptors in the prefrontal cortex by inactivation of basolateral amygdala. AB - Repeated exposure to stress precipitates anxiety, depression and cognitive deficits. Stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis is modulated by the prefrontal cortex (PFC) and basolateral amygdala (BLA). It is well established that BLA positively regulates the HPA axis and undergoes hypertrophy following chronic immobilization stress (CIS). However, it is not known whether inactivation of the BLA can modulate the stress-induced changes in the expression of glucocorticoid receptors (GRs) in the PFC. To address this, we stereologically estimated GR+ cell densities in the prelimbic (PrL) and anterior cingulate cortex (ACC). Following ibotenate lesioning of the BLA, rats were subjected to CIS and GR+ cell densities were assessed. CIS increases the GR+ cell densities in PrL and ACC. BLA lesion prior to CIS abolished the CIS-induced increase in GR+ cell densities in both regions. In the second part of experiments, we evaluated whether selective inactivation of BLA during CIS would mimic the effects of BLA lesion. Interestingly, the BLA inactivation specifically during CIS prevented the increase in GR+ cell densities in the PrL and ACC. The findings of our study suggest that BLA regulates the stress-induced increase in prefrontal GR expression, which might be crucial in the emergence of affective and cognitive symptoms following stress. We speculate that modulation of BLA during stress might prevent HPA axis dysfunctions and GR resistance in stress related disorders, and could assist in the development of novel therapeutic strategies to treat stress and associated disorders like depression. Further, molecular studies are warranted for the understanding of stress-induced GR resistance and its prevention via BLA inactivation. PMID- 29277705 TI - Topographic specializations of catecholaminergic cells and ganglion cells and distribution of calcium binding proteins in the crepuscular rock cavy (Kerodon rupestris) retina. AB - The rock cavy (Kerodon rupestris) is a crepuscular Hystricomorpha rodent that has been used in comparative analysis of retinal targets, but its retinal organization remains to be investigated. In order to better characterize its visual system, the present study analyzed neurochemical features related to the topographic organization of catecholaminergic cells and ganglion cells, as well the distribution of calcium-binding proteins in the outer and inner retina. Retinal sections and/or wholemounts were processed using tyrosine hydroxylase (TH), GABA, calbindin, parvalbumin and calretinin immunohistochemistry or Nissl staining. Two types of TH-immunoreactive (TH-IR) cells were found which differ in soma size, dendritic arborization, intensity of TH immunoreactivity and stratification pattern in the inner plexiform layer. The topographic distribution of all TH-IR cells defines a visual streak along the horizontal meridian in the superior retina. The ganglion cells are also distributed in a visual streak and the visual acuity estimated considering their peak density is 4.13 cycles/degree. A subset of TH-IR cells express GABA or calbindin. Calretinin is abundant in most of retinal layers and coexists with calbindin in horizontal cells. Parvalbumin is less abundant and expressed by presumed amacrine cells in the INL and some ganglion cells in the GCL. The topographic distribution of TH-IR cells and ganglion cells in the rock cavy retina indicate a suitable adaptation for using a broad extension of its inferior visual field in aspects that involve resolution, adjustment to ambient light intensity and movement detection without specialized eye movements. PMID- 29277706 TI - Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia. AB - Adrenal androgen excess is the hallmark of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Recently, 11-oxygenated C19 steroids, a class of highly active adrenal-derived androgens, have been described in patients with CAH. The aim of our study was to elucidate the significance of 11-oxygenated androgens in children with CAH. We retrospectively analysed 190 daily urinary excretion rates of glucocorticoid-, 17alpha-hydroxyprogesterone (17OHP)-, and androgen metabolites determined by gas chromatography-mass spectrometry of 99 children aged 3.0-10.9 years with classic CAH on hydrocortisone and fludrocortisone treatment. Daily urinary steroid metabolite excretions were transformed into z-scores using references of healthy children. Androgen metabolite z-scores were separately calculated for androsterone (AN), the major urinary metabolite of androstenedione (A4), testosterone and 5alpha dihydrotestosterone, for urinary metabolites of dehydroepiandrosterone (DHEA), and for 11beta-hydroxyandrosterone (11OHAN), the major urinary metabolite of adrenal-derived 11-oxygenated androgens. Multivariate regression analysis was applied to analyse the precursors of 11OHAN synthesis. 11OHAN, cortisol-, and 17OHP metabolite z-scores were elevated in treated children with CAH, whereas AN- and DHEA metabolite z-scores were normalized or suppressed. Multivariate regression analysis revealed that 11OHAN excretion was strongest associated with 21-deoxycortisol (beta = 0.379; P =.0006), followed by A4 (beta = 0.280; P = .0008)) and 17OHP (beta = 0.243; P = .04) metabolite excretion. Androgen excess in treated children with CAH is solely due to elevated 11-oxygenated androgens that derive in addition to the known conversion from A4 also by direct conversion from 21-deoxycortisol. 11-Oxygenated androgens may represent better biomarkers of adrenal androgen status and treatment response than conventional androgens. PMID- 29277707 TI - The in vitro metabolism of 11beta-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway. AB - Increased circulating 11beta-hydroxyprogesterone (11OHP4), biosynthesised in the human adrenal, is associated with 21-hydroxylase deficiency in congenital adrenal hyperplasia. 17alpha-hydroxyprogesterone levels are also increased, with the steroid's metabolism to dihydrotestosterone in the backdoor pathway contributing to hyperandrogenic clinical conditions. In this study we investigated the in vitro biosynthesis and downstream metabolism of 11OHP4. Both cytochrome P450 11beta-hydroxylase and aldosterone synthase catalyse the biosynthesis of 11OHP4 from progesterone (P4) which is converted to 11-ketoprogesterone (11KP4) by 11beta-hydroxysteroid dehydrogenase type 2, while type 1 readily catalysed the reverse reaction. We showed in HEK-293 cells that these C11-oxy C21 steroids were metabolised by steroidogenic enzymes in the backdoor pathway-5alpha-reductase (SRD5A) and 3alpha-hydroxysteroid type 3 (AKR1C2) converted 11OHP4 to 5alpha pregnan-11beta-ol,3,20-dione and 5alpha-pregnan-3alpha,11beta-diol-20-one, while 11KP4 was converted to 5alpha-pregnan-3,11,20-trione and 5alpha-pregnan-3alpha-ol 11,20-dione (alfaxalone), respectively. Cytochrome P450 17alpha-hydroxylase/17,20 lyase catalysed the hydroxylase and lyase reaction to produce the C11-oxy C19 steroids demonstrated in the conversion of alfaxalone to 11-oxy steroids demonstrated in the conversion of alfaxalone to 11ketoandrosterone. In LNCaP cells, a prostate cancer cell model endogenously expressing the relevant enzymes, 11OHP4 and 11KP4 were metabolised to the potent androgen, 11 ketodihydrotestosterone (11KDHT), thus suggesting the C11-oxy C21 steroids contribute to the pool of validating the in vitro biosynthesis of C11-oxy C19 steroids from C11-oxy C21 steroids. The in vitro reduction of 11KP4 at C3 and C5 by AKR1C2 and SRD5A has confirmed the metabolic route of the urinary metabolite, 3alpha,20alpha-dihydroxy-5beta-pregnan-11-one. Although our assays have demonstrated the conversion of 11OHP4 and 11KP4 by steroidogenic enzymes in the backdoor pathway yielding 11KDHT, thus suggesting the C11-oxy C21 steroids contribute to the pool of potent androgens, the in vivo confirmation of this metabolic route remains challenging. PMID- 29277708 TI - Sex hormone levels and expression of their receptors in lactating and lactating pregnant rats. AB - Parturient rats show a postpartum estrus, a period of sexual receptivity that occurs from 6 to 15 h after the birth of a litter, which allows the mother to gestate a second litter while simultaneously nursing the first one (lactating and pregnant). The present study investigated hormone levels and the expression pattern of estrogen receptor alpha, and beta, progesterone receptor isoforms and SRC1 in the hypothalamus and the preoptic area of lactating as well as in lactating-pregnant rats. In the latter, estradiol levels were 3-fold higher than those observed in lactating rats on day 14, meanwhile progesterone levels did not change in any condition. There were higher levels of prolactin in both lactating and lactating-pregnant rats on day 7 and decreased on the following days. In the hypothalamus of the lactating rat, the content of ERalpha increased during lactation meanwhile that of ERbeta decreased 50% on day 10. The content of both estrogen receptor subtypes in the hypothalamus increased 3-fold on day 21 in lactating-pregnant rats. In the preoptic area, the content of ERalpha was higher in lactating-pregnant rats on days 14 and 21 while the content of progesterone receptor isoforms was lower as compared with those found in lactating animals on days 7 and 10. The content of SRC1 increased 2-fold in the preoptic area only in lactating rats at day 14 and 21. These findings suggest that lactating- pregnant animals should exhibit differential neuroendocrine and molecular characteristics as compared to lactating animals. PMID- 29277709 TI - Granulocyte-colony stimulating factor protects against endoplasmic reticulum stress in an experimental model of stroke. AB - Granulocyte-colony stimulating factor (G-CSF) is an endogenous growth factor that exhibits a diverse range of neuroprotective mechanisms against a variety of neurological disorders including ischemic stroke. We investigated the anti apoptotic mechanisms of G-CSF against endoplasmic reticulum (ER) stress induced apoptosis. Sprague-Dawley rats were subjected to transient occlusion of the middle cerebral artery (MCAO) for 90 min. Rats were injected with G-CSF (n = 15; 50 MUg/kg body weight s.c.) for 4 days, starting 24 h post-MCAO and brains were harvested after 4 days reperfusion (n = 16). Key proteins in ER stress apoptosis were analyzed by immunoblotting. G-CSF reduced infarct volume to 53% and improved neurological deficits. G-CSF treatment significantly (P < .05) attenuated the expression of proteins involved in ER stress apoptosis pathway; ATF4, ATF6, p p38MAPK, pJNK and CHOP. G-CSF treatment also re-established ER homeostasis evident by the reduction of the intraluminal ER stress sensor, GRP78 as well as reducing the overall cellular stress level protein, HSP27. G-CSF also up regulated anti-apoptotic proteins pAKT and Bcl-2 while down-regulated the pro apoptotic protein Bax. G-CSF exerts neuroprotection from cerebral ischemia through the preservation of the ER, resulting in the attenuation of pro-apoptotic proteins and the potentiation of anti-apoptotic proteins. PMID- 29277711 TI - Western Validation of a Novel Gastric Cancer Prognosis Prediction Model in US Gastric Cancer Patients. AB - BACKGROUND: A novel prediction model for accurate determination of 5-year overall survival of gastric cancer patients was developed by an international collaborative group (G6+). This prediction model was created using a single institution's database of 11,851 Korean patients and included readily available and clinically relevant factors. Already validated using external East Asian cohorts, its applicability in the American population was yet to be determined. STUDY DESIGN: Using the Surveillance, Epidemiology, and End Results (SEER) dataset, 2014 release, all patients diagnosed with gastric adenocarcinoma who underwent surgical resection between 2002 and 2012, were selected. Characteristics for analysis included: age, sex, depth of tumor invasion, number of positive lymph nodes, total lymph nodes retrieved, presence of distant metastasis, extent of resection, and histology. Concordance index (C-statistic) was assessed using the novel prediction model and compared with the prognostic index, the seventh edition of the TNM staging system. RESULTS: Of the 26,019 gastric cancer patients identified from the SEER database, 15,483 had complete datasets. Validation of the novel prediction tool revealed a C-statistic of 0.762 (95% CI 0.754 to 0.769) compared with the seventh TNM staging model, C-statistic 0.683 (95% CI 0.677 to 0.689), (p < 0.001). CONCLUSIONS: Our study validates a novel prediction model for gastric cancer in the American patient population. Its superior prediction of the 5-year survival of gastric cancer patients in a large Western cohort strongly supports its global applicability. Importantly, this model allows for accurate prognosis for an increasing number of gastric cancer patients worldwide, including those who received inadequate lymphadenectomy or underwent a noncurative resection. PMID- 29277710 TI - Anxiety, neuroinflammation, cholinergic and GABAergic abnormalities are early markers of Gulf War illness in a mouse model of the disease. AB - Gulf War Illness (GWI) is a chronic disease that affects the 1991 Gulf War (GW) veterans for which treatment is lacking. It has been hypothesized that drugs used to protect military personnel from chemical attacks and insects during the war: pyridostigmine bromide (PB),N, N-diethyl-m-toluamide (DEET), and permethrin (PER) together with stress may have contributed collectively and synergistically to generate GWI. There is a need to find markers of pathology to be used in pre clinical trials. For this purpose we employed a previously validated mouse model of GWI evoked by daily exposure to PB (1.3 mg/kg), DEET (40 mg/kg), PER (0.13 mg/kg), and 5 min of restraint stress for 28 days to analyze behavior, brain pathology and neurochemical outcomes three months later. GWI-model mice were characterized by increased anxiety, decreased hippocampal levels of N-acetyl aspartate, GABA, the GABA-producing enzyme GAD-67 and microglial activation. We also observed that GWI model was sexually dimorphic on some measures: males had increased while females had decreased protein levels of the acetylcholine synthesizing enzyme, choline acetyltransferase, in the septum and hippocampus and decreased levels of the receptor for brain-derived neurotrophic factor, TrkB140, in the hippocampus. Increased hippocampal levels of nerve growth factor were detected in males only. Together the data show behavioral and neuropathological abnormalities detected at 3 months post-exposure and that some of them are sexually dimorphic. Future preclinical studies for GWI may take advantage of this short latency model and should include both males and females as their response to treatment may differ. PMID- 29277712 TI - Economic feasibility and environmental impact of synthetic spider silk production from escherichia coli. AB - Major ampullate spider silk represents a promising protein-based biomaterial with diverse commercial potential ranging from textiles to medical devices due to its excellent physical and thermal properties. Recent advancements in synthetic biology have facilitated the development of recombinant spider silk proteins from Escherichia coli (E. coli). This study specifically investigates the economic feasibility and environmental impact of synthetic spider silk manufacturing. Pilot scale data was used to validate an engineering process model that includes all of the required sub-processing steps for synthetic fiber manufacture: production, harvesting, purification, drying, and spinning. Modeling was constructed modularly to support assessment of alternative downstream processing technologies. The techno-economic analysis indicates a minimum sale price from pioneer and optimized E. coli plants of $761 kg-1 and $23 kg-1 with greenhouse gas emissions of 572 kg CO2-eq. kg-1 and 55 kg CO2-eq. kg-1, respectively. Elevated costs and emissions from the pioneer plant can be directly tied to the high material consumption and low protein yield. Decreased production costs associated with the optimized plant includes improved protein yield, process optimization, and an Nth plant assumption. Discussion focuses on the commercial potential of spider silk, the production performance requirements for commercialization, and the impact of alternative technologies on the system. PMID- 29277713 TI - Clinical hip fracture is accompanied by compression induced failure in the superior cortex of the femoral neck. AB - Hip fractures pose a major health problem throughout the world due to their devastating impact. Current theories for why these injuries are so prevalent in the elderly point to an increased propensity to fall and decreases in bone mass with ageing. However, the fracture mechanisms, particularly the stress and strain conditions leading to bone failure at the hip remain unclear. Here, we directly examined the cortical bone from clinical intra-capsular hip fractures at a microscopic level, and found strong evidence of compression induced failure in the superior cortex. A total of 143 sections obtained from 24 femoral neck samples that were retrieved from 24 fracturing patients at surgery were examined using laser scanning confocal microscopy (LSCM) after fluorescein staining. The stained microcracks showed significantly higher density in the superior cortex than in the inferior cortex, indicating a greater magnitude of strain in the superior femoral neck during the failure-associated deformation and fracture process. The predominant stress state for each section was reconstructed based on the unique correlation between the microcrack pattern and the stress state. Specifically, we found clear evidence of longitudinal compression and buckling as the primary failure mechanisms in the superior cortex. These findings demonstrate the importance of microcrack analysis in studying clinical hip fractures, and point to the central role of the superior cortex failure as an important aspect of the failure initiation in clinical intra-capsular hip fractures. PMID- 29277714 TI - Loop-mediated isothermal amplification assay for the rapid and visual detection of novel porcine circovirus 3. AB - A loop-mediated isothermal amplification (LAMP) assay using hydroxynaphthol blue was developed for the rapid and visual detection of the capsid gene of porcine circovirus 3 (PCV3). The amplification could be completed in 40 min at 62 degrees C, and the results could be visually detected by the naked eye. The assay specifically amplified PCV3 DNA and not other porcine viral nucleic acids. The limit of detection of the assay was 50 PCV3 DNA copies, which was comparable to that of the real-time polymerase chain reaction (qPCR) and lower than that of conventional PCR. In the clinical evaluation, the PCV3 detection rate of the LAMP assay was higher than that of PCR and agreed 100% with that of qPCR. These results indicate that the LAMP assay will be a valuable tool for the rapid, sensitive, and specific detection of PCV3 in clinical samples. PMID- 29277715 TI - Direct modification of the 5-HT3 receptor current by some anticancer drugs. AB - The serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor is an important target in the control of emesis, and 5-HT3 receptor antagonists are effective against the early phase chemotherapy evoked vomiting. We recently reported that the anticancer drugs irinotecan and topotecan directly modulate the 5-HT-mediated 5-HT3 receptor current in vitro. In addition, the drug response depends on the 5 HT3 subunit composition. Here, we explored the effects of 35 anticancer drugs on the 5-HT3 receptor current. We microinjected Xenopus laevis oocytes with human 5 HT3A cRNA or a combination of human 5-HT3A and human 5-HT3B cRNA, and performed two-electrode voltage clamp recordings of 5-HT3A and 5-HT3AB receptor currents in the presence of each of the 35 drugs. Over 25% of the drugs we tested inhibited or potentiated the 5-HT3 receptor current. The drugs that modulated the 5-HT3 receptor current had molecular weights of approximately 500. These results implied that these anticancer drugs could affect 5-HT3 receptor. PMID- 29277716 TI - Further investigation of the effects of 5-hydroxytryptamine, 8-OH-DPAT and DOI to mediate contraction and relaxation responses in the intestine and emesis in Suncus murinus. AB - 5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT1A and 5-HT2 to modify GI motility was investigated in vitro and in vivo. WAY100635 (a 5-HT1A antagonist) inhibited the contraction response to 5-HT in the proximal segments without affecting the maximum response; whilst enhancing the contraction to 5-HT (>30.0nM) in the distal intestine. The selective 5-HT2A and 5-HT2B receptor antagonists MDL-100907 and RS-127445 attenuated 5-HT-induced contractions (<10.0uM) in the distal segments. RS-127445 also attenuated 5-HT induced contractions in the central segments. The selective 5-HT2C receptor antagonist SB-242084, attenuated the responses to 5-HT (> 3.0nM) in the proximal and central but not the distal regions. 8-OH-DPAT-induced relaxation was resistant to the antagonism by 5-HT1A/7 antagonists. DOI in the presence of 5 HT1A/2A/2B/2C antagonists induced greater contraction responses (>1.0uM) in most tissues, whilst RS-127445, or SB-242084, reduced the responses to DOI (< 1.0uM) in some tissues. SB-242084 also suppressed emesis-induced by motion and intragastric CuSO4. In conclusion, within different regions of intestine, 5-HT2 receptors are differently involved in contraction and emetic responses and that 8 OH-DPAT induces relaxation via non-5-HT1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT. PMID- 29277717 TI - Antineoplastic activity of isoliquiritigenin, a chalcone compound, in androgen independent human prostate cancer cells linked to G2/M cell cycle arrest and cell apoptosis. AB - Isoliquiritigenin is a natural chalcone derived from Glycyrrhiza, which has been reported to have anti-tumor activity in recent years. Here, we investigate the anticancer efficacy and associated mechanisms of isoliquiritigenin in human prostate cancer PC-3 and 22RV1 cells. Isoliquiritigenin (25-50MUM) inhibited cell proliferation, induced cell apoptosis, and caused G2/M cell cycle arrest in vitro. This agent also repressed the growth of PC-3 xenograft tumors in vivo with the results of hematoxylin/eosin staining and immunohistochemistry staining showing differences between isoliquiritigenin-treated groups and control group. Next, we used microarray transcriptional profiling to identify isoliquiritigenin regulated genes on PC-3 prostate cancer cells. Multiple genes involved in cell cycle, DNA damage, and apoptosis signaling pathways were changed remarkably with the treatment of isoliquiritigenin. Molecular studies revealed that G2/M arrest was associated with a decrease in cyclin B1, cyclin-dependent kinase 1 (CDK1), and phosphorylated CDK1 (Thr14, Tyr15, and Thr161), whereas the expression of 14 3-3sigma and growth arrest and DNA damage-inducible 45 alpha (GADD45A) was increased. The complexes of cyclin B1-CDK1 were also examined to show a decrease in the binding of CDK1 with cyclin B1. In addition, treatment with relatively high concentrations of isoliquiritigenin induced apoptosis, mainly associated with enhancing apoptosis regulator (Bax/Bcl-2) ratio. Collectively, these findings indicate that isoliquiritigenin modulates cyclin B1-CDK1 for G2/M arrest, together with an alteration of cell cycle regulators and apoptotic factors in human prostate cancer cells. However, we observed pleiotropic effects for isoliquiritigenin in microarray results, suggesting that other biological mechanisms also contribute to its efficacy, which could be of interest for future investigations. PMID- 29277718 TI - Effect of allantoin on experimentally induced gastric ulcers: Pathways of gastroprotection. AB - Gastric ulcer affects people worldwide, and its inefficacy and recurrence have fueled the search for new therapeutic strategies. Despite the well-known use of allantoin in medicines and cosmetic products, its effect has not yet been studied with regard to gastric ulcer. Hence, the aim of the present study was to explore the pharmaco-mechanistic efficacy of allantoin against commonly harmful agents that cause injuries to the stomach. Ethanol, indomethacin, and stress-induced gastric ulcer models were adopted, in addition to pylorus ligature, a quantification of vascular permeability, glutathione (GSH), gastric adhered mucus, prostaglandin (PGE2), pro-inflammatory cytokines levels, myeloperoxidase (MPO), and catalase (CAT) activities. The gastric lesions were examined by gross, histological, and ultrastructural features. The results showed that treatment with allantoin (60mg/kg, per oral) reduced the gastric ulcer formation in all models. Furthermore, allantoin reduced the parameters of gastric acid secretion and attenuated both the vascular permeability and MPO activity. The levels of pro inflammatory cytokines were also reduced, accompanied by a restoration of CAT activity and GSH levels. Notably, allantoin treatment preserved the gastric adhered mucus and PGE2 levels after ethanol administration. Microscopic and ultrastructural analysis revealed that allantoin maintained tissue integrity and prevented morphological changes in cells caused by ethanol. In summary, we demonstrated for the first time that allantoin possesses gastroprotective activity through anti-inflammatory, anti-oxidative, antisecretory, and cytoprotective mechanisms. The antisecretory and cytoprotective mechanisms are probably associated with an increase in PGE2 levels. PMID- 29277720 TI - Extracting information from the shape and spatial distribution of evoked potentials. AB - BACKGROUND: Over 90 years after its first recording, scalp electroencephalography (EEG) remains one of the most widely used techniques in human neuroscience research, in particular for the study of event-related potentials (ERPs). However, because of its low signal-to-noise ratio, extracting useful information from these signals continues to be a hard-technical challenge. Many studies focus on simple properties of the ERPs such as peaks, latencies, and slopes of signal deflections. NEW METHOD: To overcome these limitations, we developed the Wavelet Information method which uses wavelet decomposition, information theory, and a quantification based on single-trial decoding performance to extract information from evoked responses. RESULTS: Using simulations and real data from four experiments, we show that the proposed approach outperforms standard supervised analyses based on peak amplitude estimation. Moreover, the method can extract information using the raw data from all recorded channels using no a priori knowledge or pre-processing steps. COMPARISON WITH EXISTING METHOD(S): We show that traditional approaches often disregard important features of the signal such as the shape of EEG waveforms. Also, other approaches often require some form of a priori knowledge for feature selection and lead to problems of multiple comparisons. CONCLUSIONS: This approach offers a new and complementary framework to design experiments that go beyond the traditional analyses of ERPs. Potentially, it allows a wide usage beyond basic research; such as for clinical diagnosis, brain-machine interfaces, and neurofeedback applications requiring single-trial analyses. PMID- 29277721 TI - Identifying mechanisms of stance control: A single stimulus multiple output model fit approach. AB - BACKGROUND: Posture control models are instrumental to interpret experimental data and test hypotheses. However, as models have increased in complexity to include multi-segmental dynamics, discrepancy has arisen amongst researchers regarding the accuracy and limitations of identifying neural control parameters using a single stimulus. NEW METHOD: The current study examines this topic using simulations with a parameterized model-fit approach. We first determine if the model-fit approach can identify parameters in the theoretical situation with no noise. Then, we measure variability and bias of parameter estimates when realistic noise is included. We also address how the accuracy is influenced by the frequency bandwidth of the stimulus, signal-to-noise of the data, and fitting procedures. RESULTS: We found perfect identification of parameters in the theoretical model without noise. With realistic noise, bias errors were 4.4% and 7.6% for fits that included frequencies 0.02-1.2 Hz and 0.02-0.4 Hz, respectively. Fits between 0.02-1.2 Hz also had the lowest variability in parameter estimates compared to other bandwidths. Parameters with the lowest variability tended to have the largest influence on body sways. Results also demonstrated the importance of closely examining model fits because of limitations in fitting algorithms. COMPARISON WITH EXISTING METHOD: The single input model-fit approach may be a simpler and more practical method for identifying neural control mechanisms compared to a multi-stimulus alternative. CONCLUSIONS: This study provides timely theoretical and practical considerations applicable to the design and analysis of experiments contributing to the identification of mechanisms underlying stance control of a multi-segment body. PMID- 29277719 TI - Miniature pig model of human adolescent brain white matter development. AB - BACKGROUND: Neuroscience research in brain development and disorders can benefit from an in vivo animal model that portrays normal white matter (WM) development trajectories and has a sufficiently large cerebrum for imaging with human MRI scanners and protocols. NEW METHOD: Twelve three-month-old SinclairTM miniature pigs (Sus scrofa domestica) were longitudinally evaluated during adolescent development using advanced diffusion weighted imaging (DWI) focused on cerebral WM. Animals had three MRI scans every 23.95 +/- 3.73 days using a 3-T scanner. The DWI imaging protocol closely modeled advanced human structural protocols and consisted of fifteen b-shells (b = 0-3500 s/mm2) with 32-directions/shell. DWI data were analyzed using diffusion kurtosis and bi-exponential modeling that provided measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axial kurtosis, tortuosity, and permeability diffusivity index (PDI). RESULTS: Significant longitudinal effects of brain development were observed for whole-brain average FA, KA, and PDI (all p < 0.001). There were expected regional differences in trends, with corpus callosum fibers showing the highest rate of change. COMPARISON WITH EXISTING METHOD(S): Pigs have a large, gyrencephalic brain that can be studied using clinical MRI scanners/protocols. Pigs are less complex than non-human primates thus satisfying the "replacement" principle of animal research. CONCLUSIONS: Longitudinal effects were observed for whole-brain and regional diffusion measurements. The changes in diffusion measurements were interepreted as evidence for ongoing myelination and maturation of cerebral WM. Corpus callosum and superficial cortical WM showed the expected higher rates of change, mirroring results in humans. PMID- 29277723 TI - Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond. AB - Mutations in the three canonical collagen VI genes, COL6A1, COL6A2 and COL6A3, cause a spectrum of muscle disease from Bethlem myopathy at the mild end to the severe Ullrich congenital muscular dystrophy. Mutations can be either dominant or recessive and the resulting clinical severity is influenced by the way mutations impact the complex collagen VI assembly process. Most mutations are found towards the N-terminus of the triple helical collagenous domain and compromise extracellular microfibril assembly. Outside the triple helix collagen VI is highly polymorphic and discriminating mutations from rare benign changes remains a major diagnostic challenge. Collagen VI deficiency alters extracellular matrix structure and biomechanical properties and leads to increased apoptosis and oxidative stress, decreased autophagy, and impaired muscle regeneration. Therapies that target these downstream consequences have been tested in a collagen VI null mouse and also in small human trials where they show modest clinical efficacy. An important role for collagen VI in obesity, cancer and diabetes is emerging. A major barrier to developing effective therapies is the paucity of information about how collagen VI deficiency in the extracellular matrix signals the final downstream consequences - the receptors involved and the intracellular messengers await further characterization. PMID- 29277722 TI - The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses. AB - Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins -including bone morphogenetic proteins (BMPs)- via their HS binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors -called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton. Osteochondroma development requires a somatic "second hit" that would complement the germline EXT mutation to further decrease HS production and/levels at perichondrial sites of osteochondroma induction. Cellular studies have shown that the steep decreases in local HS levels: derange the normal homeostatic signaling pathways keeping perichondrium mesenchymal; cause excessive BMP signaling; and provoke ectopic chondrogenesis and osteochondroma formation. Data from HME mouse models have revealed that systemic treatment with a BMP signaling antagonist markedly reduces osteochondroma formation. In sum, recent studies have provided major new insights into the molecular and cellular pathogenesis of HME and the roles played by HS deficiency. These new insights have led to the first ever proof-of-principle demonstration that osteochondroma formation is a druggable process, paving the way toward the creation of a clinically-relevant treatment. PMID- 29277724 TI - Supersaturated silica-lipid hybrids (super-SLH): An improved solid-state lipid based oral drug delivery system with enhanced drug loading. AB - The method of supersaturation for achieving high drug loads in lipid-based formulations is under exploited and relatively unexplored, especially in the case of solid-state lipid-based formulations. Silica-lipid hybrids are solid-state lipid-based formulations designed for improving the oral delivery of poorly water soluble drugs. However, their application to compounds of low potency and requiring large doses is limited by their low drug loading capacity. Here, an innovative technique to fabricate supersaturated silica-lipid hybrid formulations (super-SLH) has been established and the relationship between drug load and performance investigated. Using the model poorly water-soluble drug, ibuprofen, super-SLH was fabricated possessing drug loads ranging from 8 to 44% w/w, i.e. greater than the previously developed standard ibuprofen silica-lipid hybrids (5.6% w/w). Drug crystallinity of the encapsulated ibuprofen ranged from non crystalline to part-crystalline with an increase in drug load. Super-SLH achieved improved rates and extents of dissolution when compared to pure ibuprofen, regardless of the drug load. The percentage increase in dissolution extent at 60 min varied from 200 to 600%. The results of the current study indicate that supersaturation greatly improves drug loading and that 16-25% w/w is the optimum loading level which retains optimal dissolution behaviour for the oral delivery of ibuprofen, which has the potential to be translated to other poorly water soluble drugs. PMID- 29277725 TI - A hybrid approach to predict the relationship between tablet tensile strength and compaction pressure using analytical powder compression. AB - The objective was to present a hybrid approach to predict the strength-pressure relationship (SPR) of tablets using common compression parameters and a single measurement of tablet tensile strength. Experimental SPR were derived for six pharmaceutical powders with brittle and ductile properties and compared to predicted SPR based on a three-stage approach. The prediction was based on the Kawakita b-1 parameter and the in-die Heckel yield stress, an estimate of maximal tensile strength, and a parameter proportionality factor alpha. Three values of alpha were used to investigate the influence of the parameter on the SPR. The experimental SPR could satisfactorily be described by the three stage model, however for sodium bicarbonate the tensile strength plateau could not be observed experimentally. The shape of the predicted SPR was to a minor extent influenced by the Kawakita b-1 but the width of the linear region was highly influenced by alpha. An increased alpha increased the width of the linear region and thus also the maximal predicted tablet tensile strength. Furthermore, the correspondence between experimental and predicted SPR was influenced by the alpha value and satisfactory predictions were in general obtained for alpha = 4.1 indicating the predictive potential of the hybrid approach. PMID- 29277726 TI - Focused empirism: From the case report to the data report. PMID- 29277727 TI - Antimicrobial resistance in urine and skin isolates in Timor-Leste. AB - OBJECTIVES: High rates of antimicrobial resistance (AMR) are seen throughout Southeast Asia. However, limited AMR data exist for Timor-Leste, which is situated on the south-eastern portion of the Malay Archipelago. The purpose of this study was to identify AMR in bacteria isolated from urine and skin swabs from patients in Dili, the capital of Timor-Leste. METHODS: Urine and skin swabs were collected from symptomatic patients in Timor-Leste and were processed for bacterial culture. Isolates were processed in Australia using a VITEK(r)2 system for bacterial identification and to determine antimicrobial susceptibility according to Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: A total of 154 urine isolates and 57 skin isolates were analysed. Of the Enterobacteriaceae, 35% were resistant to ceftriaxone with an extended-spectrum beta-lactamase (ESBL)-producing phenotype. Carbapenem resistance was not observed in any of the Gram-negative isolates. Of the Staphylococcus aureus isolates, 11% were of the community-associated methicillin-resistant S. aureus (CA-MRSA) phenotype. CONCLUSIONS: A moderately high proportion of Gram-negative urine isolates in Timor-Leste demonstrate phenotypic ESBL production, and a relatively low proportion of S. aureus isolates were methicillin-resistant. Improved understanding of AMR rates in Timor-Leste can help guide antimicrobial prescribing and inform antimicrobial stewardship strategies. PMID- 29277728 TI - Draft genome sequence of an extensively drug-resistant Pseudomonas aeruginosa isolate belonging to ST644 isolated from a footpad infection in a Magellanic penguin (Spheniscus magellanicus). AB - OBJECTIVES: The incidence of multidrug-resistant bacteria in wildlife animals has been investigated to improve our knowledge of the spread of clinically relevant antimicrobial resistance genes. The aim of this study was to report the first draft genome sequence of an extensively drug-resistant (XDR) Pseudomonas aeruginosa ST644 isolate recovered from a Magellanic penguin with a footpad infection (bumblefoot) undergoing rehabilitation process. METHODS: The genome was sequenced on an Illumina NextSeq(r) platform using 150-bp paired-end reads. De novo genome assembly was performed using Velvet v.1.2.10, and the whole genome sequence was evaluated using bioinformatics approaches from the Center of Genomic Epidemiology, whereas an in-house method (mapping of raw whole genome sequence reads) was used to identify chromosomal point mutations. RESULTS: The genome size was calculated at 6436450bp, with 6357 protein-coding sequences and the presence of genes conferring resistance to aminoglycosides, beta-lactams, phenicols, sulphonamides, tetracyclines, quinolones and fosfomycin; in addition, mutations in the genes gyrA (Thr83Ile), parC (Ser87Leu), phoQ (Arg61His) and pmrB (Tyr345His), conferring resistance to quinolones and polymyxins, respectively, were confirmed. CONCLUSION: This draft genome sequence can provide useful information for comparative genomic analysis regarding the dissemination of clinically significant antibiotic resistance genes and XDR bacterial species at the human-animal interface. PMID- 29277729 TI - Fractional ablative carbon-dioxide laser treatment improves histologic and clinical aspects of striae gravidarum: A prospective open label paired study. PMID- 29277730 TI - Evaluation of mapping biopsies for extramammary Paget disease: A retrospective study. AB - BACKGROUND: Extramammary Paget disease (EMPD) sometimes shows an ill-defined border and an unexpectedly extended tumor spread beyond the clinical borders. Mapping biopsy is 1 approach for complete surgical removal, but its efficacy has remained controversial. OBJECTIVE: We sought to evaluate mapping biopsies for EMPD. METHODS: We performed a retrospective review of 133 patients with 150 primary EMPD lesions. We histopathologically examined 1182 skin biopsy specimens (975 from mapping biopsy and 207 from lesional biopsy). RESULTS: Only 1.6% of mapping biopsy specimens from well-defined EMPD (13 of 810) were positive. Moreover, 4.6% of mapping biopsy specimens from ill-defined EMPD (8 of 165) were positive, whereas all specimens taken from sites 2 cm or more from the clinical border were negative. For both well-defined and ill-defined EMPD, there was no significant difference in the margin status of surgical resection regardless of mapping biopsy. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Mapping biopsies are unnecessary for well-defined EMPD or when 2-cm margins can be achieved, whereas surgical removal with predetermined margins (1 cm for well defined EMPD and 2 cm for ill-defined EMPD) appears to be safe. Mapping biopsies can be considered when shortening of the safe surgical margin to less than 2 cm is required in ill-defined EMPD. PMID- 29277732 TI - Effects of curettage after shave biopsy of unexpected melanoma: A retrospective review. PMID- 29277731 TI - A real-world, community-based cohort study comparing the effectiveness of topical fluorouracil versus topical imiquimod for the treatment of actinic keratosis. AB - BACKGROUND: The most widely used topical agents for the field-based treatment of multiple actinic keratoses (AKs) are 5-fluorouracil and imiquimod, but their comparative effectiveness has not been assessed in a real-world setting. OBJECTIVE: We compared the effectiveness of 5-fluorouracil and imiquimod in reducing risk for subsequent AKs in a large, integrated health care delivery system in northern California. METHODS: In this cohort study, we identified adult health plan members who had an AK diagnosed in 2007 and who subsequently filled a prescription for 5-fluorouracil or imiquimod (N = 5700). We followed subjects for subsequent AKs identified by the International Classification of Diseases codes and estimated the 2-year (short-term) and 5-year (long-term) differences in cumulative risk while controlling for potential confounding by pretreatment variables. RESULTS: 5-Fluorouracil reduced the short-term incidence of subsequent AKs (cumulative risk difference -4.54% [95% confidence interval, -7.91% to 1.17%]), but there was no statistically significant evidence of a long-term decreased risk (cumulative risk difference -1.43% [95% confidence interval, 3.43% to 0.05%]) compared with that with imiquimod. LIMITATIONS: This is a retrospective study with limited ascertainment of all relevant potential confounding variables. CONCLUSION: We found that 5-fluorouracil appeared to be significantly more effective than imiquimod in the short-term, but not long-term, prevention of subsequent AKs. PMID- 29277733 TI - A simple method to facilitate fat removal from full-thickness skin grafts. PMID- 29277734 TI - Evidence for astrocyte purinergic signaling in cortical sensory adaptation and serotonin-mediated neuromodulation. AB - In the somatosensory cortex, inhibitory networks are involved in low frequency sensory input adaptation/habituation that can be observed as a paired-pulse depression when using a dual stimulus electrophysiological paradigm. Given that astrocytes have been shown to regulate inhibitory interneuron activity, we hypothesized that astrocytes are involved in cortical sensory adaptation/habituation and constitute effectors of the 5HT-mediated increase in frequency transmission. Using extracellular recordings of evoked excitatory postsynaptic potentials (eEPSPs) in layer II/III of somatosensory cortex, we used various pharmacological approaches to assess the recruitment of astrocyte signaling in paired-pulse depression and serotonin-mediated increase in the paired-pulse ratio (pulse 2/pulse 1). In the absence of neuromodulators or pharmacological agents, the first eEPSP is much larger in amplitude than the second due to the recruitment of long-lasting evoked GABAA-dependent inhibitory activity from the first stimulus. Disruption of glycolysis or mGluR5 signaling resulted in a very similar loss of paired-pulse depression in field recordings. Interestingly, paired-pulse depression was similarly sensitive to disruption by ATP P2Y and adenosine A2A receptor antagonists. In addition, we show that pharmacological disruption of paired-pulse depression by mGluR5, P2Y, and glycolysis inhibition precluded serotonin effects on frequency transmission (typically increased the paired-pulse ratio). These data highlight the possibility for astrocyte involvement in cortical inhibitory activity seen in this simple cortical network and that serotonin may act on astrocytes to exert some aspects of its modulatory influence. PMID- 29277735 TI - Low-temperature atomic layer deposition of SiO2/Al2O3 multilayer structures constructed on self-standing films of cellulose nanofibrils. AB - In this paper, we have optimized a low-temperature atomic layer deposition (ALD) of SiO2 using AP-LTO(r) 330 and ozone (O3) as precursors, and demonstrated its suitability to surface-modify temperature-sensitive bio-based films of cellulose nanofibrils (CNFs). The lowest temperature for the thermal ALD process was 80 degrees C when the silicon precursor residence time was increased by the stop flow mode. The SiO2 film deposition rate was dependent on the temperature varying within 1.5-2.2 A cycle-1 in the temperature range of 80-350 degrees C, respectively. The low-temperature SiO2 process that resulted was combined with the conventional trimethyl aluminium + H2O process in order to prepare thin multilayer nanolaminates on self-standing CNF films. One to six stacks of SiO2/Al2O3 were deposited on the CNF films, with individual layer thicknesses of 3.7 nm and 2.6 nm, respectively, combined with a 5 nm protective SiO2 layer as the top layer. The performance of the multilayer hybrid nanolaminate structures was evaluated with respect to the oxygen and water vapour transmission rates. Six stacks of SiO2/Al2O with a total thickness of approximately 35 nm efficiently prevented oxygen and water molecules from interacting with the CNF film. The oxygen transmission rates analysed at 80% RH decreased from the value for plain CNF film of 130 ml m-2 d-1 to 0.15 ml m-2 d-1, whereas the water transmission rates lowered from 630 +/- 50 g m-2 d-1 down to 90 +/- 40 g m-2 d-1This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277736 TI - Order and gelation of cellulose nanocrystal suspensions: an overview of some issues. AB - Cellulose nanocrystals (CNCs) are polydisperse rod-shaped particles of crystalline cellulose I, typically prepared by sulfuric acid hydrolysis of natural cellulose fibres to give aqueous colloidal suspensions stabilized by sulfate half-ester groups. Sufficiently dilute suspensions are isotropic fluids, but as the concentration of CNC in water is increased, a critical concentration is reached where a spontaneously ordered phase is observed. The (equilibrium) phase separation of the ordered chiral nematic phase is in competition with a tendency of the CNC suspension to form a gel. Qualitatively, factors that reduce the stability of the CNC suspension favour the onset of gelation. The chiral nematic structure is preserved, at least partially, when the suspension dries. Solid chiral nematic films of cellulose are of interest for their optical and templating properties, but the preparation of the films requires improvement. The processes that govern the formation of solid chiral nematic films from CNC suspensions include phase separation, gelation and also the effects of shear on CNC orientation during evaporation. Some insight into these processes is provided by polarized light microscopy, which indicates that the relaxation of shear induced orientation to give a chiral nematic structure may occur via an intermediate twist-bend state.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277737 TI - Investigation of the formation mechanisms in high internal phase Pickering emulsions stabilized by cellulose nanocrystals. AB - Medium and high internal phase Pickering emulsions stabilized by cellulose nanocrystals (CNCs) have been prepared and the effects of CNC concentration and type of oil phase on the properties of emulsions were studied. The maximum oil phase volume that can be stabilized by CNCs is 87% when the CNC concentration is 0.6 wt.%; this slightly decreases to 83% when the CNC concentration is increased to 1.2 wt.% or higher. In addition, the oil droplets stabilized with 0.6 wt.% CNC suspensions have a larger size than those stabilized with higher concentration CNC suspensions. As evidenced by the change in oil droplet morphology and size, two different emulsion formation mechanisms are proposed. For a CNC concentration of 0.6 wt.%, the extra oil added into the emulsion is accommodated by the expansion of oil droplet size, whereas for CNC concentrations of 1.2 wt.% and higher, the oil is stabilized mainly by the formation of new oil droplets. PMID- 29277738 TI - Cellulose nanomaterials as green nanoreinforcements for polymer nanocomposites. AB - Unexpected and attractive properties can be observed when decreasing the size of a material down to the nanoscale. Cellulose is no exception to the rule. In addition, the highly reactive surface of cellulose resulting from the high density of hydroxyl groups is exacerbated at this scale. Different forms of cellulose nanomaterials, resulting from a top-down deconstruction strategy (cellulose nanocrystals, cellulose nanofibrils) or bottom-up strategy (bacterial cellulose), are potentially useful for a large number of industrial applications. These include the paper and cardboard industry, use as reinforcing filler in polymer nanocomposites, the basis for low-density foams, additives in adhesives and paints, as well as a wide variety of filtration, electronic, food, hygiene, cosmetic and medical products. This paper focuses on the use of cellulose nanomaterials as a filler for the preparation of polymer nanocomposites. Impressive mechanical properties can be obtained for these materials. They obviously depend on the type of nanomaterial used, but the crucial point is the processing technique. The emphasis is on the melt processing of such nanocomposite materials, which has not yet been properly resolved and remains a challenge.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277739 TI - Optimization of cellulose nanocrystal length and surface charge density through phosphoric acid hydrolysis. AB - Cellulose nanocrystals (CNCs) are emerging nanomaterials with a large range of potential applications. CNCs are typically produced through acid hydrolysis with sulfuric acid; however, phosphoric acid has the advantage of generating CNCs with higher thermal stability. This paper presents a design of experiments approach to optimize the hydrolysis of CNCs from cotton with phosphoric acid. Hydrolysis time, temperature and acid concentration were varied across nine experiments and a linear least-squares regression analysis was applied to understand the effects of these parameters on CNC properties. In all but one case, rod-shaped nanoparticles with a high degree of crystallinity and thermal stability were produced. A statistical model was generated to predict CNC length, and trends in phosphate content and zeta potential were elucidated. The CNC length could be tuned over a relatively large range (238-475 nm) and the polydispersity could be narrowed most effectively by increasing the hydrolysis temperature and acid concentration. The CNC phosphate content was most affected by hydrolysis temperature and time; however, the charge density and colloidal stability were considered low compared with sulfuric acid hydrolysed CNCs. This study provides insight into weak acid hydrolysis and proposes 'design rules' for CNCs with improved size uniformity and charge density.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277740 TI - Liquid crystalline tactoids: ordered structure, defective coalescence and evolution in confined geometries. AB - Tactoids are liquid crystalline microdroplets that spontaneously nucleate from isotropic dispersions, and transform into macroscopic anisotropic phases. These intermediate structures have been found in a range of molecular, polymeric and colloidal liquid crystals. Typically only studied by polarized optical microscopy, these ordered but easily deformable microdroplets are now emerging as interesting components for structural investigations and developing new materials. In this review, we highlight the structure, property and transformation of tactoids in different compositions, but especially cellulose nanocrystals. We have selected references that illustrate the diversity and most exciting developments in tactoid research, while capturing the historical development of this field.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277741 TI - Better together: synergy in nanocellulose blends. AB - Cellulose nanopapers have gained significant attention in recent years as large scale reinforcement for high-loading cellulose nanocomposites, substrates for printed electronics and filter nanopapers for water treatment. The mechanical properties of nanopapers are of fundamental importance for all these applications. Cellulose nanopapers can simply be prepared by filtering a suspension of nanocellulose, followed by heat consolidation. It was already demonstrated that the mechanical properties of cellulose nanopapers can be tailored by the fineness of the fibrils used or by modifying nanocellulose fibrils for instance by polymer adsorption, but nanocellulose blends remain underexplored. In this work, we show that the mechanical and physical properties of cellulose nanopapers can be tuned by creating nanopapers from blends of various grades of nanocellulose, i.e. (mechanically refined) bacterial cellulose or cellulose nanofibrils extracted from never-dried bleached softwood pulp by chemical and mechanical pre-treatments. We found that nanopapers made from blends of two or three nanocellulose grades show synergistic effects resulting in improved stiffness, strength, ductility, toughness and physical properties.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277742 TI - Structure of native cellulose microfibrils, the starting point for nanocellulose manufacture. AB - There is an emerging consensus that higher plants synthesize cellulose microfibrils that initially comprise 18 chains. However, the mean number of chains per microfibril in situ is usually greater than 18, sometimes much greater. Microfibrils from woody tissues of conifers, grasses and dicotyledonous plants, and from organs like cotton hairs, all differ in detailed structure and mean diameter. Diameters increase further when aggregated microfibrils are isolated. Because surface chains differ, the tensile properties of the cellulose may be augmented by increasing microfibril diameter. Association of microfibrils with anionic polysaccharides in primary cell walls and mucilages leads to in vivo mechanisms of disaggregation that may be relevant to the preparation of nanofibrillar cellulose products. For the preparation of nanocrystalline celluloses, the key issue is the nature and axial spacing of disordered domains at which axial scission can be initiated. These disordered domains do not, as has often been suggested, take the form of large blocks occupying much of the length of the microfibril. They are more likely to be located at chain ends or at places where the microfibril has been mechanically damaged, but their structure and the reasons for their sensitivity to acid hydrolysis need better characterization.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277743 TI - Residual wood polymers facilitate compounding of microfibrillated cellulose with poly(lactic acid) for 3D printer filaments. AB - Microfibrillated cellulose (MFC) is a fascinating material with an obvious potential for composite reinforcement due to its excellent mechanics together with high specific surface area. However, in order to use this potential, commercially viable solutions to important technological challenges have to be found. Notably, the distinct hydrophilicity of MFC prevents efficient drying without loss in specific surface area, necessitating storage and processing in wet condition. This greatly hinders compounding with important technical polymers immiscible with water. Differently from cellulose, the chemistry of the major wood polymers lignin and hemicellulose is much more diverse in terms of functional groups. Specifically, the aromatic moieties present in lignin and acetyl groups in hemicellulose provide distinctly less polar surface-chemical functionality compared to hydroxyl groups which dominate the surface-chemical character of cellulose. It is shown that considerable advantages in the production of MFC-filled poly(lactic acid) filaments for three-dimensional printing can be obtained through the use of MFC containing residual lignin and hemicellulose due to their advantageous surface-chemical characteristics. Specifically, considerably reduced agglomerations of MFC in the filaments in combination with improved printability and improved toughness of printed objects are achieved.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277744 TI - Molecular interactions in nanocellulose assembly. AB - The contribution of hydrogen bonds and the London dispersion force in the cohesion of cellulose is discussed in the light of the structure, spectroscopic data, empirical molecular-modelling parameters and thermodynamics data of analogue molecules. The hydrogen bond of cellulose is mainly electrostatic, and the stabilization energy in cellulose for each hydrogen bond is estimated to be between 17 and 30 kJ mol-1 On average, hydroxyl groups of cellulose form hydrogen bonds comparable to those of other simple alcohols. The London dispersion interaction may be estimated from empirical attraction terms in molecular modelling by simple integration over all components. Although this interaction extends to relatively large distances in colloidal systems, the short-range interaction is dominant for the cohesion of cellulose and is equivalent to a compression of 3 GPa. Trends of heat of vaporization of alkyl alcohols and alkanes suggests a stabilization by such hydroxyl group hydrogen bonding to be of the order of 24 kJ mol-1, whereas the London dispersion force contributes about 0.41 kJ mol-1 Da-1 The simple arithmetic sum of the energy is consistent with the experimental enthalpy of sublimation of small sugars, where the main part of the cohesive energy comes from hydrogen bonds. For cellulose, because of the reduced number of hydroxyl groups, the London dispersion force provides the main contribution to intermolecular cohesion.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277745 TI - Cellulose synthase complex organization and cellulose microfibril structure. AB - Cellulose consists of linear chains of beta-1,4-linked glucose units, which are synthesized by the cellulose synthase complex (CSC). In plants, these chains associate in an ordered manner to form the cellulose microfibrils. Both the CSC and the local environment in which the individual chains coalesce to form the cellulose microfibril determine the structure and the unique physical properties of the microfibril. There are several recent reviews that cover many aspects of cellulose biosynthesis, which include trafficking of the complex to the plasma membrane and the relationship between the movement of the CSC and the underlying cortical microtubules (Bringmann et al. 2012 Trends Plant Sci.17, 666-674 (doi:10.1016/j.tplants.2012.06.003); Kumar & Turner 2015 Phytochemistry112, 91-99 (doi:10.1016/j.phytochem.2014.07.009); Schneider et al. 2016 Curr. Opin. Plant Biol.34, 9-16 (doi:10.1016/j.pbi.2016.07.007)). In this review, we will focus on recent advances in cellulose biosynthesis in plants, with an emphasis on our current understanding of the structure of individual catalytic subunits together with the local membrane environment where cellulose synthesis occurs. We will attempt to relate this information to our current knowledge of the structure of the cellulose microfibril and propose a model in which variations in the structure of the CSC have important implications for the structure of the cellulose microfibril produced.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277746 TI - Bioinspired Bouligand cellulose nanocrystal composites: a review of mechanical properties. AB - The twisted plywood, or Bouligand, structure is the most commonly observed microstructural motif in natural materials that possess high mechanical strength and toughness, such as that found in bone and the mantis shrimp dactyl club. These materials are isotropically toughened by a low volume fraction of soft, energy-dissipating polymer and by the Bouligand structure itself, through shear wave filtering and crack twisting, deflection and arrest. Cellulose nanocrystals (CNCs) are excellent candidates for the bottom-up fabrication of these structures, as they naturally self-assemble into 'chiral nematic' films when cast from solutions and possess outstanding mechanical properties. In this article, we present a review of the fabrication techniques and the corresponding mechanical properties of Bouligand biomimetic CNC nanocomposites, while drawing comparison to the performance standards set by tough natural composite materials.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277747 TI - Transparent wood for functional and structural applications. AB - Optically transparent wood combines mechanical performance with optical functionalities is an emerging candidate for applications in smart buildings and structural optics and photonics. The present review summarizes transparent wood preparation methods, optical and mechanical performance, and functionalization routes, and discusses potential applications. The various challenges are discussed for the purpose of improved performance, scaled-up production and realization of advanced applications.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'. PMID- 29277748 TI - New horizons for cellulose nanotechnology. PMID- 29277749 TI - Cancer Progenitor Cells: The Result of an Epigenetic Event? AB - The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells. PMID- 29277750 TI - The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer. AB - BACKGROUND: The use of prophylactic cranial irradiation (PCI) to treat brain metastases (BM) in non-small cell lung cancer (NSCLC) is restricted due to the potential associated toxicity and lack of survival benefit. BM can have a negative impact on neurocognitive function (NF) and quality of life (QOL). The aim of this review was to assess the impact of PCI on disease-specific and NF and QOL outcomes. MATERIALS AND METHODS: An electronic database literature search was completed to identify relevant studies. RESULTS: Fourteen published articles were included. PCI significantly reduced the incidence of BM, but no significant survival advantage was found. NF decline was reported in one trial. No significant difference in QOL with PCI was reported. PCI was well tolerated by the majority of patients with NSCLC and associated with a relatively low toxicity. CONCLUSION: PCI reduces the incidence of BM without any significant survival advantage. PCI has the potential to be beneficial in practice for certain patients with locally advanced NSCLC, based on disease factors and patient preference. PMID- 29277751 TI - Regimens of Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Colorectal Cancer. AB - Although systemic chemotherapy has been improved, peritoneal carcinomatosis remains a factor of poor prognosis in patients with colorectal cancer. In order to achieve a higher drug concentration in the peritoneal cavity, intraperitoneal chemotherapy has been performed. However, the optimal regimen for intraperitoneal chemotherapy has not been determined. In this review of intraperitoneal chemotherapy for colorectal cancer, we summarize regimens of hyperthermic intraperitoneal chemotherapy (HIPEC) and other intraperitoneal chemotherapy modalities, such as early postoperative intraperitoneal chemotherapy (EPIC) and sequential postoperative intraperitoneal chemotherapy (SPIC). Mitomycin C and oxaliplatin are the most common chemotherapeutic agents used for HIPEC. Some combination therapies such as those involving bevacizumab, H2O2, and amifostine have potential to increase HIPEC efficacy. 5-Fluorouracil is used mainly for EPIC and SPIC. Some new agents such as paclitaxel, melphalan, and various nanoparticles have been developed. These novel chemotherapeutic agents may achieve clinical implementation in the future. PMID- 29277752 TI - Should Adjuvant Radiation Therapy Be Systematically Proposed for Male Breast Cancer? A Systematic Review. AB - BACKGROUND: Guidelines for radiotherapy in male breast cancer (MBC) are lacking. Some extrapolate the results from female breast cancer trials, while others advocate systematic adjuvant irradiation. We evaluated clinical practices and outcomes with respect to radiation therapy in MBC treated with locoregional irradiation in the adjuvant setting using a systematic literature review. MATERIAL AND METHODS: We included studies with data about adjuvant radiotherapy published between 1984 and 2017 and including at least 40 patients. RESULTS: We found 29 retrospective series, 10,065 men were diagnosed with breast cancer; 3 100% (mean=54%) received adjuvant radiotherapy. Tumor size and nodal involvement were the strongest prognostic factors. Approximatively half of all cases had nodal metastases. Radiation therapy improved locoregional control in six series, overall survival in three and distant metastasis-free survival in one. CONCLUSION: MBC is diagnosed at a highly advanced stage and may be linked with poorer outcomes. Adjuvant radiation therapy must, at least, be proposed to men with positive nodes. Despite the large number of cases gathered here, arguments for radiotherapy in other prognostic subgroups (especially in pN0) may exist but are not well supported. PMID- 29277753 TI - Managing Focal Nodular Hyperplasia of the Liver: Surgery or Minimally-invasive Approaches? A Review of the Preferable Treatment Options. AB - BACKGROUND/AIM: Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver. As of 2017, many clinical, radiological and surgical features have been largely documented. On the other hand, little is still known about the correlation of FNH with hepatocellular carcinoma, nor the preferable modality of treatment. Our aim was to elucidate the latter topic. MATERIALS AND METHODS: We investigated the pertinent literature available as of 2017 through four popular search engines (PubMed, Science Direct, Scopus and Google Scholar). Four main approaches were selected: conservative treatment, surgery, radiofrequency ablation (RFA) and transarterial embolization (TAE). RESULTS: We found most works to be on conservative and surgical approaches. On the contrary, only one article has been published for RFA to date. Seventeen articles dealt with TAE. CONCLUSION: TAE currently represents the most cogent and successful alternative to surgery. PMID- 29277754 TI - Histone Deacetylase Inhibitors as a Novel Targeted Therapy Against Non-small Cell Lung Cancer: Where Are We Now and What Should We Expect? AB - Non-small cell lung cancer constitutes the most common type of lung cancer, accounting for 85-90% of lung cancer, and is a leading cause of cancer-related death. Despite the progress during the past years, poor prognosis remains a challenge and requires further research and development of novel antitumor treatment. Recently, the role of histone deacetylases in gene expression has emerged showing their regulation of the acetylation of histone proteins and other non-histone protein targets and their role in chromatin organization, while their inhibitors, the histone deacetylase inhibitors, have been proposed to have a potential therapeutic role in diverse malignancies, including non-small cell lung cancer. This review article focuses on the role of histone deacetylase inhibitors in the treatment of non-small cell lung cancer and the major molecular mechanisms underlying their antitumor activity recognized so far. PMID- 29277755 TI - Our ACE in the HOLE: Justifying the Use of Angiotensin-converting Enzyme Inhibitors as Adjuvants to Standard Chemotherapy. AB - Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic. PMID- 29277756 TI - Pacifastin-derived Peptides Target Tumors for Use in In Vivo Imaging. AB - BACKGROUND/AIM: Developments in imaging have improved cancer diagnosis, but identification of malignant cells during surgical resection remains a challenge. The aim of this study was to investigate the pacifastin family of peptides for novel activity targeting tumor cells and the delivery of either imaging or therapeutic agents. MATERIALS AND METHODS: Variants of pacifastin family peptides were generated, chemically modified and tested in human tumor xenografts. RESULTS: A tumor-homing peptide-dye conjugate (THP1) accumulated in tumors in vivo and was internalized into cells. Examination of related peptides revealed residues critical for accumulation and allowed the engineering of improved tumor targeting variants. A THP1-drug conjugate carrying the microtubule inhibitor, MMAE, showed limited activity in vitro and no difference compared to vehicle control in vivo. CONCLUSION: Although there are some obstacles to developing pacifastin-derived peptides for therapeutic activity, these optimized peptides have great promise for cancer imaging. PMID- 29277757 TI - In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer. AB - BACKGROUND: We generated humanized/de-immunized immunotoxins targeting the prostate-specific membrane antigen (PSMA) and tested their cytotoxic activity against prostate cancer cells in vitro. MATERIALS AND METHODS: The humanized/de immunized version of our murine anti-PSMA single-chain antibody fragment (scFv) D7, termed hD7-1(VL-VH), was ligated to the 40-kDa toxin domain of Pseudomonas aeruginosa exotoxin A (PE40), and to the deimmunized 24-kDa toxin domains PE24 or PE24mut. The immunotoxins designated as hD7-1(VL-VH)-PE40, hD7-1(VL-VH)-PE24 and hD7-1(VL-VH)-PE24mut were bacterially expressed and purified by affinity chromatography. Binding and cytotoxicity were examined by flow cytometry and viability assay, respectively. RESULTS: All immunotoxins revealed strong binding to prostate cancer cells expressing PSMA and specific cytotoxicity, with half maximal inhibitory concentration values in the picomolar range. CONCLUSION: We successfully created powerful anti-PSMA immunotoxins with reduced immunogenicity for further clinical development and application against advanced prostate cancer. PMID- 29277758 TI - Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation. AB - BACKGROUND/AIM: Rhabdomyosarcoma is the most common type of pediatric soft-tissue sarcoma. Among the subsets of this disease, alveolar rhabdomyosarcoma (ARMS) expressing paired box 3 (PAX3) and forkhead box O1 (PAX3-FOXO1) fusion oncoprotein has the worst prognosis. The goal of this study was to investigate the chemotherapeutic effects of sphingosine on PAX3-FOXO1-positive ARMS cells [tumor protein p53 (TP53)-mutated RH30 and TP53 wild-type RH18 cells]. MATERIALS AND METHODS: The proliferation, cell death, apoptosis, cell cycle, and MYCN proto oncogene (MYCN) expression of RH30 and RH18 cells were determined. RESULTS: Sphingosine inhibited the growth and caused cell death in a dose-dependent manner in both cell lines. Sphingosine triggered cell death by inducing apoptosis without affecting the cell cycle. MYCN expression was down-regulated within 2 and 4 h of sphingosine treatment in both RH30 and RH18 cells. CONCLUSION: Sphingosine exerts antiproliferative and pro-apoptotic effects via MYCN down-regulation independently of TP53 mutation status in PAX3-FOXO1-positive ARMS cells. PMID- 29277759 TI - The Long Noncoding RNA OIP5-AS1 Is Involved in the Regulation of Cell Proliferation. AB - BACKGROUND/AIM: OPA-interacting protein 5 antisense transcript 1 (OIP5-AS1) is a long noncoding RNA located on human chromosome 15q15.1 and transcribed in the opposite direction to OIP5. Here, we report that OIP5-AS1 is involved in regulating cell proliferation. MATERIALS AND METHODS: HeLa cells were transfected with OIP5-AS1-targeting siRNA oligonucleotides and anti-sense oligonucleotides. The cells were harvested 72 h after transfection and subjected to quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and cell-cycle and apoptosis analysis. RESULTS: OIP5-AS1 was expressed at a lower level in cells harbouring an oncogenic kirsten rat sarcoma viral oncogene homolog (K-RAS) mutation than in cells expressing wild-type K-RAS. Silencing OIP5-AS1 with siRNA oligonucleotides or anti-sense oligonucleotides reduced HeLa cell proliferation. Apoptosis and cell-cycle analysis showed that silencing OIP5-AS1 did not cause apoptosis, but did cause G2/M phase cell-cycle arrest. CONCLUSION: These results suggest that OIP5-AS1 positively regulates cell proliferation by promoting G2/M phase progression. PMID- 29277760 TI - Chemopreventive Potential of In Vitro Fermented Raw and Roasted Hazelnuts in LT97 Colon Adenoma Cells. AB - BACKGROUND/AIM: Due to their unique composition of health-promoting compounds, the consumption of hazelnuts may contribute to the prevention of colon cancer. MATERIALS AND METHODS: Since hazelnuts are often consumed roasted, the impact of different roasting conditions (RC1=140.6 degrees C/25 min, RC2=155.1 degrees C/20 min and RC3=180.4 degrees C/21 min) on chemopreventive effects of in vitro fermented hazelnuts was analyzed in LT97 colon adenoma cells. RESULTS: FS (2.5%) of raw and roasted hazelnuts reduced H2O2-induced DNA damage while 5% FS significantly induced gene expression of SOD2 (3.0-fold) and GSTP1 (2.1-fold). GPx1 mRNA levels were significantly decreased (0.6-fold) by FS (2.5%). The growth of LT97 cells was significantly reduced by hazelnut FS in a time- and dose dependent manner. Hazelnut FS (5%) increased the numbers of early apoptotic cells (9.6% on average) and caspase-3 activities (6.4-fold on average). CONCLUSION: These results indicate a chemopreventive potential of in vitro fermented hazelnuts which is largely unaffected by the roasting process. PMID- 29277761 TI - Antitumor Effects of Lidocaine on Human Breast Cancer Cells: An In Vitro and In Vivo Experimental Trial. AB - AIM: Retrospective studies have suggested a protective effect of regional anesthesia against recurrence after cancer surgery. But confirmation of the in vivo antitumor effects is lacking. We examined the in vitro antitumor effects of lidocaine on various breast cancer cell lines and then assessed these properties in vivo at clinically relevant concentrations. MATERIALS AND METHODS: In vitro experiments: normal breast epithelial cells (NBEC) MCF-10A and three tumor breast epithelial cells (TBEC) lines (MCF-7 luminal A, MDA-MB-231 triple-negative and SKBr3 HER2 positive) were exposed to increasing concentrations of lidocaine. Cell viability, migration and anchorage-independent growth were assessed by MTT, wound healing, and soft-agar growth assays. In vivo experiments: 6-week-old severe combined immunodeficient mice were injected intraperitoneally with MDA-MB-231 cells and were treated with intraperitoneal lidocaine or phosphate-buffered saline. The mice were euthanized when they reached experimental endpoints or sacrificed to determine peritoneal carcinomatosis index and global tumor volumes. RESULTS: Lidocaine reduced the viability of all the cell lines, inhibited migration of TBEC compared to the NBEC, and compromised the anchorage-independent growth of the triple-negative cells. Intraperitoneal lidocaine improved survival of mice with MDA-MB-231 peritoneal carcinomatosis using doses that are consistent with the current clinical settings for analgesia. CONCLUSION: In agreement with the notion that local anesthesia may be beneficial for cancer therapy, lidocaine has a protective effect against breast cancer cells in experimental studies. However, the beneficial impact of local anesthetics on breast cancer needs to be strengthened by additional preclinical and clinical trials. PMID- 29277762 TI - Highly Activated PD-1/PD-L1 Pathway in Gastric Cancer with PD-L1 Expression. AB - BACKGROUND: A recent study demonstrated that immune-checkpoint molecules are associated with tumoral immune evasion. MATERIALS AND METHODS: Programmed cell death protein 1 (PD-1) expression on CD4+ and CD8+ T-cells obtained from gastric cancer tissue was evaluated by multicolor flow cytometry. Immunohistochemical staining was also performed to evaluate programmed cell death ligand-1 (PD-L1) expression on gastric cancer cells. RESULTS: There were statistically significant correlations between PD-L1 expression and age, histology, tumor size, depth of invasion, lymph node metastasis, lymphatic vessel invasion, venous invasion, and disease stage. The 5-year survival rates of patients with and without PD-L1 positive tumors were 48.9% and 80.7%, respectively, and the difference was statistically significant. Multivariate analysis indicated that PD-L1 expression was an independent prognostic indicator. The frequency of PD-1-positive CD4+ and CD8+ T-cells from gastric cancer tissue with PD-L1 expression was significantly more than that from gastric cancer tissue without PD-L1 expression. CONCLUSION: PD-L1 expression was related to a poor prognosis in patients with gastric cancer. Furthermore, PD-1 expression on T-cells was up-regulated in patients with tumors with PD-L1 expression. PMID- 29277763 TI - The Expression of Matrix Metalloproteinases in Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-expressing Cancer of Apocrine Origin. AB - : Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive tumor entity. Since there is no conventional therapy for advanced PCAC, exploratory treatments are sometimes used. As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD). Since EMPD is a skin adenocarcinoma of apocrine gland origin that expresses high levels of RANKL and matrix metalloproteinase (MMP) 7, and EMPD is associated with the presence of RANK+ M2 macrophages, we hypothesized that tumor associated macrophages (TAMs) in adenocarcinomas such as PCAC might also express RANKL and MMP7. MATERIALS AND METHODS: We employed immunohistochemical staining of RANKL and MMP7 in the lesional skin from five patients with PCAC, and microarray analysis of MMPs using human monocyte-derived macrophages. RESULTS: According to DNA microarray analysis, the expression of MMP1 and MMP25 was augmented. The DNA microarray results were verified by using real-time polymerase chain reaction (RT-PCR). Immunohistochemical staining of MMP1 and MMP25 as well as chemokine (C-C motif) ligand (CCL) 5 in the lesional skin from five patients with PCAC showed a substantial number of MMP1-bearing cells and MMP25-bearing cells, as well as CCL5-producing cells, that were distributed in the lesional skin. CONCLUSION: Our study suggests that the RANKL/RANK pathway contributes to the development and maintenance of the immunosuppressive tumor microenvironment and denosumab may be a promising adjuvant therapy targeting TAMs in cancer of apocrine origin. PMID- 29277764 TI - Distribution of Curcumin and THC in Peripheral Blood Mononuclear Cells Isolated from Healthy Individuals and Patients with Chronic Lymphocytic Leukemia. AB - Background/Aim: Curcumin is being widely investigated for its anticancer properties and studies in the literature suggest that curcumin distributes to a higher degree in tumor versus non-tumor cells. In the current study, we report on investigation of the distribution of curcumin and metabolism to THC in PBMC from healthy individuals and chronic lymphocytic leukemia (CLL) patients following exposure to LipocurcTM (liposomal curcumin). Materials and Methods: The time and temperature-dependent distribution of liposomal curcumin and metabolism to tetrahydrocurcumin (THC) were measured in vitro in human peripheral blood mononuclear cells (PBMC) obtained from healthy individuals, PBMC HI (cryopreserved and freshly isolated PBMC) and CLL patients (cryopreserved PBMC) with lymphocyte counts ranging from 17-58*106 cells/ml (PBMCCLL,Grp 1) and >150*106 cells/ml (PBMCCLL,Grp 2). PBMC were incubated in plasma protein supplemented media with LipocurcTM for 2-16 min at 37 degrees C and 4 degrees C and the cell and medium levels of curcumin determined by LC-MS/MS. Results: PBMC from CLL patients displayed a 2.2-2.6-fold higher distribution of curcumin compared to PBMC HI Curcumin distribution into PBMCCLL, Grp 1/Grp 2 ranged from 384.75 - 574.50 ng/g w.w. of cell pellet and was greater compared to PBMC HI that ranged from 122.27-220.59 ng/g w.w. of cell pellet following incubation for up to 15-16 min at 37 degrees C. The distribution of curcumin into PBMCCLL,Grp 2 was time-dependent in comparison to PBMC HI which did not display a time-dependence and there was no temperature-dependence for curcumin distribution in either cell type. Curcumin was metabolized to THC in PBMC. The metabolism of curcumin to THC was not markedly different between PBMC HI (range=23.94-42.04 ng/g w.w. cell pellet) and PBMCCLL,Grp 1/Grp 2 (range=23.08-48.22 ng/g. w.w. cell pellet). However, a significantly greater time and temperature-dependence was noted for THC in PBMCCLL,Grp 2 compared to PBMC HI Conclusion: Curcumin distribution into PBMC from CLL patients was higher compared to PBMC from healthy individuals, while metabolism to THC was similar. The potential for a greater distribution of curcumin into PBMC from CLL patients may be of therapeutic benefit. PMID- 29277765 TI - Traditional Chinese Medicine Curcumin Sensitizes Human Colon Cancer to Radiation by Altering the Expression of DNA Repair-related Genes. AB - BACKGROUND/AIM: The aim of the present study was to investigate the radio sensitizing efficacy of curcumin, a traditional Chinese medicine (TCM) on colon cancer cells in vitro and in vivo. MATERIALS AND METHODS: Human colon cancer HT 29 cells were treated with curcumin (2.5 MUM), irradiation (10 Gy) and the combination of irradiation and curcumin. Cell proliferation was assessed using the MTT assay. Apoptotic cells were detected by Annexin V-PE/7-AAD analysis. PCR was performed to determine differential-expression profiling of 95 DNA-repair genes in irradiated cells and cells treated with both irradiation and curcumin. Differentially-expressed genes were confirmed by Western blotting. In vivo radio sensitizing efficacy of curcumin was assessed in a xenograft mouse model of HT-29 colon cancer. Curcumin was administrated daily by intraperitoneal injection at 20 mg/kg/dose. Mice received irradiation (10 Gy) twice weekly. Apoptosis of the cancer cells following treatment was determined by TUNEL staining. RESULTS: Irradiation induced proliferation inhibition and apoptosis of HT-29 cells in vitro. Concurrent curcumin treatment sensitized the HT-29 tumor to irradiation (p<0.01). DNA repair-related genes CCNH and XRCC5 were upregulated and LIG4 and PNKP downregulated by the combination of curcumin and irradiation compared with irradiation alone (p<0.05). Combined treatment of curcumin and irradiation resulted in a significantly greater tumor-growth inhibition and apoptosis compared to irradiation treatment alone (p<0.01). CONCLUSION: Curcumin sensitizes human colon cancer in vitro and in vivo to radiation. Downregulation of LIG4 and PNKP and upregulation of XRCC5 and CCNH DNA-repair-related genes were involved in the radio-sensitizing efficacy of curcumin in colon cancer. PMID- 29277766 TI - Manganese Inhibits Viability of Prostate Cancer Cells. AB - BACKGROUND/AIM: Androgen deprivation therapy is usually in the initial phase a successful treatment for prostate cancer but eventually most patients develop androgen-independent metastatic disease. This study investigated if manganese (Mn) reduces viability of prostate cancer via induction of apoptosis. MATERIALS AND METHODS: The prostate cancer cell lines PC3, DU145 and LNCaP underwent dose- and time-dependent screening of viability, analyzed by the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Flow cytometry was used for the cell-cycle and apoptosis analyses. Intracellular Mn concentration was measured using inductively coupled plasma-mass spectrometry. RESULTS: At Mn concentrations of 200-1000 MUM, the effect on viability was most pronounced in PC3 followed by LNCaP cells. These cell lines also showed higher intracellular concentration of Mn compared to DU145. In all cell lines, Mn increased the proportion of cells arrested in the G0/G1 phase and induced apoptosis. CONCLUSION: To our knowledge, this is the first report demonstrating Mn as a potential agent in prostate cancer therapy. PMID- 29277767 TI - Antitumor Memory T-Cells Become Functionally Mature from 30 to 100 days in a Mouse Model of Neoplasia. AB - BACKGROUND: Late metastases develop from cancer of the breast, prostate, lung, kidney and malignant melanomas. Memory T-cells have excellent potential to prevent this devastating development in the same way that they routinely prevent emergence of latent viruses. MATERIAL AND METHODS: A peritoneal tumor mouse model of viral oncotherapy was used to generate therapeutic antitumor memory T-cells. Functional in vivo and in vitro assays were used to study the temporal evolution of their anticancer effects. RESULTS: Highly therapeutic antitumor memory was generated by viral oncolytic immunotherapy 30 days after treatment and matured to maximal potency at 100 days. Maturation was not uniform across different measures. CONCLUSION: The results provide guidelines for developing a viral oncolytic vaccine strategy to generate antitumor memory T-cells that can eliminate small nests of metastatic cancer cells in sanctuary sites and prevent emergence of tumors from dormant cancer cell collections. The results are relevant to any immunization strategy designed to generate antitumor memory T cells. PMID- 29277768 TI - Tumor-targeting Salmonella typhimurium A1-R Inhibits Osteosarcoma Angiogenesis in the In Vivo Gelfoam(r) Assay Visualized by Color-coded Imaging. AB - BACKGROUND: We previously developed a color-coded imaging model that can quantify the length of nascent blood vessels using Gelfoam(r) implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice. In this model, nascent blood vessels selectively express GFP. We also previously showed that osteosarcoma cells promote angiogenesis in this assay. We have also previously demonstrated the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R) can inhibit or regress all tested tumor types in mouse models. The aim of the present study was to determine if S. typhimurium A1-R could inhibit osteosarcoma angiogenesis in the in vivo Gelfoam(r) color-coded imaging assay. MATERIALS AND METHODS: Gelfoam(r) was implanted subcutaneously in ND-GFP nude mice. Skin flaps were made 7 days after implantation and 143B-RFP human osteosarcoma cells expressing red fluorescent protein (RFP) were injected into the implanted Gelfoam. After establishment of tumors in the Gelfoam(r), control-group mice were treated with phosphate buffered saline via tail-vein injection (iv) and the experimental group was treated with S. typhimurium A1-R iv Skin flaps were made at day 7, 14, 21, and 28 after implantation of the Gelfoam(r) to allow imaging of vascularization in the Gelfoam(r) using a variable-magnification small-animal imaging system and confocal fluorescence microscopy. RESULTS: Nascent blood vessels expressing ND-GFP extended into the Gelfoam(r) over time in both groups. However, the extent of nascent blood-vessel growth was significantly inhibited by S. typhimurium A1-R treatment by day 28. CONCLUSION: The present results indicate S. typhimurium A1-R has potential for anti-angiogenic targeted therapy of osteosarcoma. PMID- 29277769 TI - alphavbeta6-Fyn Kinase Promotes Epithelial Phenotype in SYF Cells. AB - The 5-year survival rate for patients with oral cancer remains at 50%, in large part due the high rate of post-treatment recurrence. In this study, we transfected epithelial-specific integrin alphavbeta6 and Fyn-kinase, a member of the Src-family kinases, into embryonic murine fibroblasts. In oral cancer, expression of alphavbeta6 is neo-expressed. Using a variety of in vitro assays, including cell migration and multicellular spheroid formation, we determined that these embryonic fibroblasts expressing alphavbeta6 and Fyn-kinase were able to acquire an epithelial phenotype. This is in direct contrast to human oral SCC, where expression of alphavbeta6 with Fyn-kinase promotes epithelial to mesenchymal transition. This demonstrates that signaling pathways can be species specific. PMID- 29277770 TI - Ouabain Induces Apoptotic Cell Death Through Caspase- and Mitochondria-dependent Pathways in Human Osteosarcoma U-2 OS Cells. AB - BACKGROUND/AIM: Ouabain, a plant-derived product/substance with Na+/K+-ATPase inhibiting properties, has been shown to exert anti-cancer activity on human cancer cells. This is the first study to investigate the effect of ouabain on apoptotic cell death of human osteosarcoma-derived U-2 OS cells. MATERIALS AND METHODS: Flow cytometry was used to examine cell viability, cell cycle, and reactive oxygen species (ROS), Ca2+, mitochondrial membrane potential (MMP) and caspase activity. Morphological changes were examined by contrast-phase microscopy, while apoptosis-associated protein levels were analyzed by western blot. RESULTS: Ouabain, at concentrations of 5-60 MUM, significantly decreased the total viable cells and induced cell morphological changes in a time-dependent manner. It also time-dependently decreased G0/G1 phase and increased S and G2/M phase in U-2 OS cells. The production of ROS and the levels of MMPs (DeltaPsim) were inhibited, while Ca2+ production in U-2 OS cells was increased. Regarding cell apoptosis, flow cytometry assay revealed increased caspase-3, -8, and -9 activities in U-2 OS cells. Moreover, western blot results showed that ouabain increased the expression of pro-apoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2 in U-2 OS cells. Furthermore, results also showed that ouabain increased cytochrome c release, apoptosis-inducing factor (AIF) and endonuclease (Endo) G that is associated with apoptosis through caspase-dependent and -independent pathway in U-2 OS cells. CONCLUSION: Our findings provide important insight into the cytotoxic effects of ouabain on U-2 OS cells, in vitro, which are mediated at least partly via cell apoptosis induction. PMID- 29277771 TI - Effects of siRNA Silencing of TUG1 and LCAL6 Long Non-coding RNAs on Patient derived Xenograft of Non-small Cell Lung Cancer. AB - BACKGROUND/AIM: The aim of the present study was to establish a patient-derived xenograft (PDX) mouse model of non-small cell lung cancer (NSCLC) and investigate the anti-tumor efficacy of silencing of TUG1 and LCAL6 long non-coding RNA in the PDX model. MATERIALS AND METHODS: PDXs were established by subcutaneously implanting NSCLC surgical tumor fragments into immunodeficient mice. PDX characterization was performed by histopathological, immunohistochemical and real time polymerase chain reaction (RT-PCR) analyses for NSCLC subtype-specific markers and expression of LCAL6 and TUG1. Anti-tumor efficacy of siRNA silencing of TUG1 and LCAL6 was also investigated in the PDX model. The effect of TUG1 and LCAL6 silencing on protein expression of proliferation marker Ki67 and HOX-gene family HOXB7 in the tumors was assessed by immunohistochemical staining and Western blotting. RESULTS: Establishment of NSCLC PDX models resulted in 9 of 26 cases (34.6%). Lung squamous cell carcinomas (SCC) had a higher engraftment rate (58.3%) than lung adenocarcinomas (ADC) (18.2%) (p<0.05). Comparative analysis indicated these established PDX models of NSCLC closely resembled the original tumors with regard to NSCLC subtype-specific markers TTF-1, napsin A, p63 and expression of LCAL6 and TUG1. The tumor volume and weight were significantly reduced in the TUG1-silenced group as compared to the control group (p<0.05). However, no significant tumor growth inhibition was found in the LCAL6-silenced group (p>0.05). Expression of both TUG1and LCAL6 was reduced by siRNA treatment. Expression of Ki67 and HOXB7 was significantly suppressed in both the TUG1- and LCAL6-silenced groups compared to the control group (p<0.01). The TUG1-silenced group showed more reduced Ki67 expression than the LCAL6-silenced group (p<0.05). CONCLUSION: PDX NSCLC models were established with a high degree of similarity with the original tumor with regard to histological, immunohistochemical features and RNA expression of TUG1 and LCAL6. Silencing of TUG1 inhibited both tumor growth and expression of the proliferation marker Ki67 and HOX-gene family HOXB7 in the PDX model of NSCLC. PMID- 29277772 TI - Deregulation of Nicotinamide N-Methyltransferase and Gap Junction Protein Alpha-1 Causes Metastasis in Adenoid Cystic Carcinoma. AB - BACKGROUND/AIM: Adenoid cystic carcinoma (AdCC) is a malignant tumor that occurs in the salivary glands and frequently metastasizes. The aim of this study was to identify factors mediating AdCC metastasis. MATERIALS AND METHODS: We established three AdCC cell lines by orthotropic transplantation and in vivo selection: parental, highly metastatic (ACCS-M-GFP), and lymph node metastatic (ACCS-LN-GFP) cells. RESULTS: We examined the three cell lines. DNA microarray indicated significantly altered processes in ACCS-LN-GFP cells: particularly, the expression of nicotinamide N-methyltransferase (NNMT) was enhanced the most. NNMT is associated with tumorigenesis and is a potential tumor biomarker. Concomitantly, we found-significant down-regulation of gap junction protein alpha 1. We suggest that ACCS-LN-GFP cells acquire cancer stem cell features involving the up-regulation of NNMT and the loss of gap junction protein alpha-1, leading to epithelial-mesenchymal transition and consequent AdCC metastasis. CONCLUSION: NNMT is a potential biomarker of AdCC. PMID- 29277773 TI - Effects of MERTK Inhibitors UNC569 and UNC1062 on the Growth of Acute Myeloid Leukaemia Cells. AB - BACKGROUND: MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells. MATERIALS AND METHODS: Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated. RESULTS: Treatment with the inhibitors suppressed cell growth and induced apoptosis in all cell lines. OCI/AML5 and TMD7 cells, in which MERTK was constitutively phosphorylated by autocrine mechanisms, were highly susceptible to these inhibitors. The treatment reduced the phosphorylation of MERTK and its down-stream signalling molecules, v-akt murine thymoma viral oncogene homolog 1 (AKT) and extracellular signal-regulated kinase (ERK). Similar effects were observed after MERTK knockdown. The inhibitors and the knockdown caused similar changes in mRNA expression. CONCLUSION: These MERTK inhibitors are potential molecular-targeted drugs for treating AML expressing constitutively phosphorylated MERTK. PMID- 29277774 TI - Combination of Osthole and Cisplatin Against Rhabdomyosarcoma TE671 Cells Yielded Additive Pharmacologic Interaction by Means of Isobolographic Analysis. AB - BACKGROUND/AIM: Osthole is a simple coumarin that has been found to have anticancer, anti-inflammatory, antiviral, anticoagulant, anticonvulsant and antiallergic activities. The aim of this study was to analyze the combined anti proliferative effect of cisplatin (CDDP) and osthole on a rhabdomyosarcoma cell line, and assess the pharmacology of drug-drug interaction between these drugs using isobolographic analysis. MATERIALS AND METHODS: The anticancer actions of osthole in combination with CDDP were evaluated using the tetrazolium dye-based MTT cell proliferation assay. RESULTS: Osthole and CDDP applied together augmented their anti-cancer activities and yielded an additive type of pharmacologic interaction by means of isobolographic analysis. CONCLUSION: Combined therapy using osthole and cisplatin could be suggested as a potential chemotherapy regimen against rhabdomyosarcoma. PMID- 29277775 TI - Novel Metabolically Stable PCA-1/ALKBH3 Inhibitor Has Potent Antiproliferative Effects on DU145 Cells In Vivo. AB - Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA 1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects. This inhibitory activity in vivo was more potent than that of HUHS015 at 32 mg/kg, a known PCA-1/ALKBH3 inhibitor, or docetaxel at 2.5 mg/kg, the drug clinically used for androgen-independent prostate cancer. PMID- 29277776 TI - A Novel Paclitaxel-Loaded Polymeric Micelle System with Favorable Biocompatibility and Superior Antitumor Activity. AB - BACKGROUND/AIM: Polymeric micelles are promising vehicles for paclitaxel delivery. Further improvement in the stability of the micelle formulation is desirable. MATERIALS AND METHODS: Monomethoxy poly(ethylene glycol)-block poly(D,L-lactide)-9-fluorenylmethoxycarbonyl-L-phenylalanine (mPEG-PDLLA Phe(Fmoc)) was synthesized through a classical esterification reaction. Paclitaxel-loaded mPEG-PDLLA-Phe(Fmoc) micelles (PTX-PheMs) were prepared by the self-assembly method. Composition, structure and physicochemical properties were characterized. Pharmacokinetics were evaluated in rats. Therapeutic effect was evaluated in tumor-bearing mice. Safety profile was assessed by a hemolysis assay and an acute-toxicity study. RESULTS: The average size of PTX-PheMs was about 45 nm. The hemolysis and acute-toxicity tests confirmed its biocompatibility and safety. The pharmacokinetics and therapeutic effect experiments demonstrated its long circulation property and superior antitumor effect. CONCLUSION: mPEG-PDLLA Phe(Fmoc) micelle is a biocompatible and effective drug delivery system for hydrophobic drugs such as PTX. PMID- 29277777 TI - Amifostine Protects Mouse Liver Against Radiation-induced Autophagy Blockage. AB - BACKGROUND/AIM: Amifostine is the only selective normal tissue cytoprotector, approved for the protection against platinum toxicities and radiotherapy-induced xerostomia. Free radical scavenger and DNA repair activities have been attributed to the drug. MATERIALS AND METHODS: We investigated the effect of amifostine on autophagy, lysosomal biogenesis and lipophagy of normal mouse liver exposed to clinically relevant doses of radiation. RESULTS: The study provides evidence that ionizing radiation blocks autophagy activity and lysosomal biogenesis in normal mouse liver. Amifostine, protects the liver autophagic machinery and induces lysosomal biogenesis. By suppressing autophagy, ionizing radiation induces lipid droplet accumulation, while pre-treatment with amifostine protects lipophagy and up-regulates the TIP47 protein and mRNA levels, showing a maintenance of lipid metabolism in the liver cells. CONCLUSION: It is concluded that amifostine, aside to DNA protection activity, exerts its cytoprotective function by preventing radiation-induced blockage of autophagy, lysosomal biogenesis and lipophagy. PMID- 29277778 TI - Placental Growth Factor in Bladder Cancer Compared to the Diagnostic Accuracy and Prognostic Performance of Vascular Endothelial Growth Factor A. AB - BACKGROUND/AIM: To evaluate the diagnostic accuracy and prognostic performance of urinary and plasma levels of placental growth factor (PLGF) and provide their comparison with the results of vascular endothelial growth factor A (VEGF-A) in patients with primary and recurrent urinary bladder cancer. MATERIALS AND METHODS: The enzyme-linked immunosorbent assay (ELISA) was used to assess urinary and plasma concentrations of PLGF and VEGF-A in 240 individuals. RESULTS: PLGF levels in urine and plasma were significantly higher in patients with primary bladder cancer than in healthy individuals (p=0.003, p=0.005, respectively). Area under the curve (AUC) of urinary PLGF was 0.68; AUC of plasma PLGF levels was 0.65. Patients with the urine levels of PLGF higher than 82.33 pg/ml had three times higher risk of recurrence. In patients with recurrent bladder cancer, the urinary concentrations of PLGF did not significantly differ from the concentrations in patients without current disease (p=0.61). However, plasma PLGF levels were significantly higher in patients diagnosed with tumor recurrence (p=0.001); AUC of plasma PLGF levels was 0.69. Moreover, patients with plasma levels higher than 10.09 pg/ml had a five-times higher risk of future tumor recurrence. The diagnostic accuracy of PLGF was comparable with VEGF-A. CONCLUSION: From a clinical point of view, PLGF could be considered a valid diagnostic test for the detection of primary and recurrent bladder cancer. In patients with recurrent bladder cancer, plasma PLGF levels can differentiate individuals at risk of tumor recurrence. PMID- 29277779 TI - Angiographic Evaluation of Vascular Damage in Rat Liver After Administration of Epirubicin or Miriplatin. AB - BACKGROUND: Maintaining the function of blood vessels is important for the control of hepatocellular carcinoma (HCC) during treatment with repeated transcatheter arterial chemoembolization (TACE). This study was designed to compare the vascular damage caused by miriplatin (MPT), which has been commonly used for TACE, with the damage caused by epirubicin (EPI). MATERIALS AND METHODS: We used the portal vein of healthy rats for the administration of the drug (MPT or EPI) and/or soybean oil as vehicle. After 2 days, angiography was performed by X-ray computer tomography. RESULTS: The influence of soybean oil on blood vessel function was volume-dependent. EPI showed dose-dependent effects on angiography, and 0.5 mg EPI led to severe (grade 4) blood flow disturbance in all animals. The effect of 1 mg MPT on blood vessels was mild (grade 1) in all animals and not different from that of soybean oil alone. CONCLUSION: Less vascular damage is caused by MPT than by EPI, suggesting that MPT is a useful drug for TACE in HCC. PMID- 29277780 TI - The Contribution of Matrix Metalloproteinase-1 Promoter Genotypes in Taiwan Lung Cancer Risk. AB - BACKGROUND/AIM: Up-regulation of metallo-proteinase (MMP) proteins has been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. The contribution of MMP1 genotype to lung cancer has been investigated in various countries, though, to our knowledge, not in Taiwan. Therefore, in this study, we focused on the contribution of a polymorphism in the promoter region of MMP1 to lung cancer risk in Taiwan population. PATIENTS AND METHODS: Genomic DNA was isolated from peripheral blood of 358 patients with lung cancer and 716 healthy individuals (non-cancer patients). MMP1 rs1799750 polymorphic genotypes of each sample were determined using the typical methodology of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for MMP1 -1607 genotypes were 34.4%, 41.3% and 24.3% in the disease group and 33.9%, 44.0%, and 22.1% in the control group (p trend=0.6298), respectively. The results of carrier comparisons in dominant and recessive models also support the findings that 1G or 2G appears not to be a determinant allelic biomarker for Taiwan lung cancer. CONCLUSION: The MMP1 -1607 1G allele is a non-significant protective biomarker for lung cancer in Taiwan. PMID- 29277781 TI - Expression and Distribution of Galectin-3 in Chromophobe and Papillary Carcinomas. AB - BACKGROUND/AIM: Probably due to their low occurrence, chromophobe and papillary renal cell carcinomas are less well characterized and, currently, there are no reliable prognostic markers for this group of patients. Moreover, the optimal therapy for patients with non-clear renal cell carcinoma (RCC) is unknown yet. Although elevated levels of Galectin-3 (Gal-3) were associated with poor prognosis in conventional RCC, the impact of this protein on carcinogenesis of chromophobe and papillary entities has not been previously described. MATERIALS AND METHODS: Gal-3 expression was investigated in 34 consecutive cases of RCCs, including 19 papillary carcinomas and 15 chromophobe carcinomas. RESULTS: Immunohistochemical analysis of Gal-3 in tumor cells showed 3 patterns of expression: membranous, cytoplasmic and nuclear staining. Most tumors included in our study showed a cytoplasmic expression and it was almost equally distributed between the histologic subtypes. However, only nuclear staining of Gal-3 was associated with both Fuhrman grade and tumor stage (p=0.016 and p=0.032, respectively) in chromophobe subtype. CONCLUSION: Our results indicate that the nuclear expression of Gal-3 has an essential role in the development of chromophobe carcinoma. The association with advanced tumor stage and nuclear grade suggests that this protein is an indicator of aggressiveness in the chromophobe subtype, thus targeting anti-nuclear transport may prove an effective therapy for this particular group of patients. PMID- 29277782 TI - Oncolytic Properties of Ampakines In Vitro. AB - BACKGROUND/AIM: The 5-year survival rate of glioblastoma (GBM) is ~10%, demonstrating that a new therapeutic modality for this cancer is desperately needed. Complicating the search for such a modality is that most large molecules cannot pass through the blood brain barrier, so molecules demonstrating efficacy in vitro may not be useful in vivo because they never reach the brain. Recently, the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) was identified as an effective agent in targeting GBM in vitro and in vivo by agonizing AMPA glutamate receptors (AMPARs), eliciting massive calcium influx and mitochondrial calcium overload and apoptosis. MATERIALS AND METHODS: In the current study, we used a colorimetric cell viability assay to determine if we could enhance the oncolytic effect of FLX in vitro by pre-treating cells with an AMPAR-positive allosteric modulator (Ampakine). RESULTS: Our results demonstrated for the first time that concentrations of the Class I ampakine CX614, which increase AMPAR agonist binding affinity, possess oncolytic activity as a sole agent and synergistically reduce GBM viability when paired with FLX. FLX also demonstrates a dose-dependent induction of apoptosis in cancer cells originating outside the CNS that overexpress calcium-permeable AMPARs. Likewise, CX614 inhibits cancer cell viability in a dose-dependent fashion and its combination with FLX synergistically reduces cell viability. These effects of CX614 were not seen with the Class II ampakines, CX717 and CX1739. CONCLUSION: CX614 inhibits the growth of multiple cancers in vitro and bolsters the oncolytic activity of FLX in several cancers. PMID- 29277783 TI - Up-regulation of UVRAG by HDAC1 Inhibition Attenuates 5FU-induced Cell Death in HCT116 Colorectal Cancer Cells. AB - The ultraviolent irradiation resistance-associated gene (UVRAG), a component of the Beclin 1/autophagy-related 6 complex, regulates the autophagy initiation step and functions in the DNA-damage response. UVRAG is frequently mutated in various cancer types, and mutations of UVRAG increase sensitivity to chemotherapy by impairing DNA-damage repair. In this study, we addressed the epigenetic regulation of UVRAG in colorectal cancer cells. UVRAG expression was increased in cells treated with histone deacetylase (HDAC) inhibitors, such as valproic acid and suberoylanilide hydroxamic acid. Down-regulation of HDAC1 enhanced UVRAG expression in colorectal cancer cells. In addition, both chemical and genetic inhibition of HDAC1 reduced the activation of caspase-3 and cytotoxicity in 5 fluorouracil (5FU)-treated cancer cells. In contrast, UVRAG overexpression inhibited caspase activation and cell death in 5FU-treated cells. Taken together, our findings suggest that up-regulation of UVRAG by HDAC1 inhibition potentiates DNA-damage-mediated cell death in colorectal cancer cells. PMID- 29277784 TI - Carvacrol Targets AXL to Inhibit Cell Proliferation and Migration in Non-small Cell Lung Cancer Cells. AB - BACKGROUND/AIM: AXL has been reported to be overexpressed and highly activated in various cancer types. In this study, we demonstrated the effect of carvacrol on cell proliferation and migration in non-small cell lung cancer (NSCLC) cells by impeding the expression and activation of AXL. MATERIALS AND METHODS: The levels of AXL protein, mRNA and promoter activity were evaluated by western blot, reverse transcription polymerase chain reaction (RT-PCR) and luciferase assay, respectively. AXL-overexpressing cells were established by ectopic expression of AXL cDNA. Cell viability, clonogenicity, and migration were measured in carvacrol treated NSCLC cells. RESULTS: Carvacrol treatment of NSCLC cells caused down regulation of AXL expression at the transcriptional level and also inhibited phosphorylation of AXL upon ligand stimulation. Carvacrol suppressed cell proliferation and migration and its inhibitory effect was attenuated in AXL overexpressing NSCLC cells. CONCLUSION: Our data demonstrate that AXL is a crucial therapeutic target of carvacrol-induced inhibition of NSCLC cell proliferation and migration. PMID- 29277785 TI - Establishment of a Patient-derived Xenograft for Development of Personalized HER2 targeting Therapy in Gastric Cancer. AB - BACKGROUND/AIM: To maximize success rate for development of HER2-targeted therapeutics, patient-derived xenograft (PDX) models reflecting HER2-positive gastric cancer (HER2+ GC) patients were established. MATERIALS AND METHODS: GC tissues obtained from surgery of GC patients were implanted into immune-deficient mice, and tumor tissue of HER2+ PDXs were verified of the patient-mimic HER2 expression by immunohistochemistry and explored for the feasibility by testing with Herceptin, the approved therapeutics and novel HER2 antibody therapeutics being developed. RESULTS: We obtained 5 cases of HER2+ GC PDX models reflecting patient's GC tumor, consisting of 2 cases of HER2 3+ and 2 cases of HER2 2+. Novel HER2 antibody displayed significantly improved anti-cancer efficacy in combination with Herceptin. CONCLUSION: The HER2+ GC PDX models were successfully established to be utilized for preclinical evaluation of HER2-targeting drugs and combined therapies for GC treatment, as an ideal platform of personalized tools for precision therapy. PMID- 29277786 TI - Correlation of Pyruvate Kinase M2 Expression with Clinicopathological Data in Ovarian Cancer. AB - BACKGROUND/AIM: It has been shown in many studies that expression of pyruvate kinase (PK) enzyme plays a key role during cellular metabolism. There is evidence that cancer cells manifesting very dynamic proliferation may control their division in various mechanisms, i.a. by expression of PKM2 isoform. The exact role of PKM2 in ovarian cancer (OC) cells and cancer associated fibroblasts (CAFs) have not been elucidated. MATERIALS AND METHODS: The present study was focused on analysis of PKM2 expression in cancer cells and CAFs in 97 OC cases, mostly of serous histological type. Moreover, relationships between expression of PKM2 and proliferation (Ki-67; MCM-2, -3, -7; cyclin D1), vascular (CD31, D2-40) and mesenchymal (Vim and alphaSMA) markers as well as receptors (ER, PR, HER2, EGFR) were examined. All observations were evaluated in regard to available clinicopathological data. RESULTS: The expression of PKM2 was disclosed only in cytoplasm of OC cells. No statistically significant correlation between PKM2 and tested markers was found. In regard to available clinicopathological data only an increasing trend of PKM2 expression with increasing grade of histological malignancy G was found (p=0.07). CONCLUSION: Due to achieved results concerning expression of PKM2 there is a lack of evidence for its diagnostic and prognostic usage in OC. PMID- 29277787 TI - Phenoxodiol Increases Cisplatin Sensitivity in Ovarian Clear Cancer Cells Through XIAP Down-regulation and Autophagy Inhibition. AB - BACKGROUND/AIM: To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin. MATERIALS AND METHODS: The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting. RESULTS: In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment. CONCLUSION: PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment. PMID- 29277788 TI - A Mouse Model for Oral Mucositis Induced by Cancer Chemotherapy. AB - BACKGROUND: Oral mucositis (OM), one of the side-effects induced by chemotherapy, has 40% incidence and the incidence rate increases to approximately 100% in combination with radiotherapy. We describe OM in ICR mice induced using 5 fluorouracil (5-FU) and 20% acetic acid. MATERIALS AND METHODS: We optimized the dose of 5-FU and 20% acetic acid and validated the efficacy of standard therapies for OM. RESULTS: All mice developed OM after administration of 5-FU and 20% acetic acid. Application of Kenalog(r) reduced maximum ulcer area and the duration of spontaneous recovery in a dose-dependent manner. CONCLUSION: We succeeded in developing a mouse model of OM induced by cancer chemotherapy. New drugs for OM induced by anticancer drugs can be evaluated simply by monitoring the WBC count in this mouse model. This model is expected to contribute to development of new drugs and elucidation of the mechanisms of ameliorating stomatitis as a side-effect of anticancer drugs. PMID- 29277789 TI - The Prognostic Role of Cancer Stem Cell Markers for Long-term Outcome After Resection of Colonic Liver Metastases. AB - BACKGROUND/AIM: To assess the expression of cancer stem cell (CSC) markers CD44, CD133 and CD24 in colon cancer liver metastases and analyse their predictive value for overall survival (OS) and disease-free survival (DFS) after liver resection. MATERIALS AND METHODS: Patients operated on for colon cancer liver metastases were included. CSC marker expression was determined through immunohistochemistry analysis. OS and DFS were compared between marker-positive and marker-negative patients. Multivariate analysis was performed to select predictive variables for OS and DFS. RESULTS: CD133-positive patients had a worse DFS than CD133-negative patients, with a median DFS of 12 and 25 months (p=0.051). Multivariate analysis selected CD133 expression as a significant predictor for DFS. CD44 and CD24 were not found to predict OS or DFS. CONCLUSION: CD133 expression in colonic liver metastases is a negative prognostic factor for DFS after liver resection. In the future, CD133 could be used as a biomarker for risk stratification, and possibly for developing novel targeted therapy. PMID- 29277790 TI - Protein Expression and Genetic Variation of IL32 and Association with Colorectal Cancer in Swedish Patients. AB - BACKGROUND: Interleukin 32 (IL32) is an intracellular pluripotent cytokine produced by epithelial cells, monocytes, T-lymphocytes and natural killer cells and seems to be involved in the pathogenesis of cancer and inflammatory diseases. Our purpose was to assess the role of protein expression and genetic polymorphisms of IL32 in colorectal cancer (CRC) susceptibility. MATERIALS AND METHODS: To gain insight into clinical significance of IL32 in Swedish patients with CRC, using enzyme-linked immunosorbent assay, we determined whether IL32 protein level is altered in CRC tissue (n=75) compared with paired normal tissue and in plasma from patients with CRC (n=94) compared with controls (n=81). The expression of IL32 protein was confirmed by immunohistochemistry (n=73). We used Luminex technology to investigate protein levels of the cytokines IL6, tumor necrosis factor-alpha (TNFalpha) and vascular endothelial growth factor (VEGF) to relate these to IL32 levels in CRC tissue. Three single nucleotide polymorphisms (SNPs) (rs28372698, rs12934561, rs4786370) of the IL32 gene have been proposed as modifiers for different diseases. The present study evaluated the susceptibility of patients possessing these SNPs to CRC. Using TaqMan SNP genotyping assays, these SNPs were screened in Swedish patients with CRC (n=465) and healthy controls (n=331). RESULTS: We found no significant differences in the genotypic frequencies between the patients and healthy controls and no relation to survival for any of the SNPs. However, the SNP rs12934561 was statisticalLY significant associated with older patients. IL32 protein was up-regulated in CRC tissue and related to IL6, TNFalpha, and VEGF, and seems to be modulated by SNP rs28372698. The IL32 protein level in CRC tissue also reflects both disseminated disease and location. CONCLUSION: Our results suggest that altered IL32 protein concentrations in CRC tissue and genotypic variants of IL32 are related to disseminated CRC. PMID- 29277791 TI - Strong Prolyl Hydroxylase Domain 1 Expression Predicts Poor Outcome in Radiotherapy-treated Patients with Classical Hodgkin's Lymphoma. AB - BACKGROUND: Hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain (PHD) proteins control cellular oxygen homeostasis and a wide range of other processes. MATERIALS AND METHODS: We immunohistochemically assessed the expression of HIF1alpha, HIF2alpha, PHD1, PHD2 and PHD3 in 115 cases of classical Hodgkin's lymphoma, all treated in the first line with doxorubicin, bleomycin, vinblastine and darcabazine (ABVD) chemotherapy. RESULTS: In advanced-stage patients treated with involved-field radiotherapy (IFRT), nuclear HIF1alpha expression in reactive cellular infiltrate predicted prolonged relapse-free survival (RFS) (p=0.026). Strong cytoplasmic PHD1 expression in Reed-Sternberg cells was associated with poor RFS among patients treated with IFRT and advanced-stage patients treated with ABVD and IFRT (p=0.0028 and p=0.0058, respectively). In Cox regression analysis, PHD1 was a more significant predictor of relapse (risk ratio=18.383; 95% confidence interval(CI)=1.521-222.246; p=0.022) than the International Prognostic Score. CONCLUSION: HIF and PHD expression appear to be novel prognostic biomarkers in classical Hodgkin's lymphoma. PMID- 29277792 TI - Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-paclitaxel Reduces the Number of Cancer-associated Fibroblasts Through Depletion of Pancreatic Stroma. AB - BACKGROUND: In this study, the effects of neoadjuvant chemotherapy (NAC) on cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma were investigated. MATERIALS AND METHODS: Density of alpha-smooth muscle actin (alphaSMA)-positive fibroblasts in resected surgical specimens from untreated patients, patients receiving conventional gemcitabine plus S-1 (GS), and patients receiving gemcitabine plus nab-paclitaxel (GnP) was determined by hybrid cell counting. 18F-Fluorodeoxyglucose positron-emission tomography (FDG-PET) scans and carbohydrate antigen 19-9 (CA19-9) concentrations were used to assess tumor activity before and after chemotherapy in the GnP group. RESULTS: In this retrospective study of 65 patients, alphaSMA expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of alphaSMA-positive fibroblasts. There were significantly fewer alphaSMA-positive fibroblasts in the GnP than in the untreated and GS groups, but there was no significant difference between the latter two groups. alphaSMA density reflected a decrease in standardized uptake value on FDG-PET, but not CA19-9 concentration, after GnP chemotherapy. CONCLUSION: These data suggest that the GnP regimen induces stromal depletion, resulting in fewer CAFs. PMID- 29277793 TI - Retzius-sparing Robotic-assisted Radical Prostatectomy Associated with Less Bladder Neck Descent and Better Early Continence Outcome. AB - BACKGROUND/AIM: We attempted to evaluate the association of early continence outcome of Retzius-sparing robotic assisted radical prostatectomy (RARP) and bladder neck descent with postoperative cystography. PATIENTS AND METHODS: From November 2014 to December 2015, 30 patients with prostate cancer who received Retzius-sparing LRP/ RARP were compared to 30 patients that received retropubic approach RARP with propensity score matching analysis. Cystogram was used to evaluate the bladder neck descent using the bladder neck to pubic symphysis (BNPS) ratio and the continence state was evaluated. RESULTS: A total 60 patients were included 30 of which had received Retzius-sparing and 30 the retropubic approach, using propensity score matching analysis. There was no difference in age, prostate size, pathology T stage and PSA among groups. BNPS ratio is significantly low in the Retzius-sparing group (0.25+/-0.10 vs. 0.46+/-0.14, p=0.000). Early continence was improved in the Retzius-sparing group and early continence within the first week was 73.3% compared to 26.7% (p=0.000), but no difference was seen at one year (100.0% vs. 93.30%, p=0.150). The independent risk factors affecting post-operative continence were age and approach. The association between less bladder neck descent as BNP ratio and continence was also confirmed (HR=0.048, 95%CI=0.005-0.420, p=0.006). CONCLUSION: With the advantage of more normal pelvic anatomy preserved in Retzius-sparing RARP, it was associated with less bladder neck descent and better early continence outcome. Age was also an independent risk factor for postoperative continence. PMID- 29277794 TI - Clinical Value of 18F-FDOPA PET/CT With Contrast Enhancement and Without Carbidopa Premedication in Patients with Insulinoma. AB - AIM: We evaluated the clinical usefulness of 6-[18F]fluoro-3,4-dihydroxy-L phenylalanine(18F-FDOPA)-positron-emission tomography (PET)/computed tomography (CT) in insulinoma detection with contrast enhancement, early acquisition time, and no carbidopa premedication. PATIENTS AND METHODS: Twenty-six patients diagnosed with hyperinsulinemic hypoglycemia underwent an 18F-FDOPA PET/CT examination. Patients without carbidopa premedication and contrast-enhanced CT were included. Imaging findings were compared to the overall final diagnosis (histological findings). RESULTS: In 10 of 26 patients (eight women, two men; mean age=53 years; age range=30-94 years), a detected lesion was confirmed histologically as an insulinoma. 18F-FDOPA PET detected the tumor in five out of ten patients. Contrast-enhanced CT also detected the tumor in five out of ten. Overall, 18F-FDOPA PET/CT, with contrast enhancement and without carbidopa premedication, was able to detect the insulinoma in seven out of ten patients (70%). CONCLUSION: Based on our data, 18F-DOPA PET/CT, with contrast enhancement and without carbidopa premedication, as a 'one-stop' diagnostic modality is a viable option for insulinoma detection. PMID- 29277795 TI - Prognostic Significance of Pancreatic Metastases from Renal Cell Carcinoma in Patients Treated with Tyrosine Kinase Inhibitors. AB - AIM: The study aimed to define the true impact of pancreatic metastases (PM) from renal cell carcinoma on overall survival (OS) in patients treated with first-line tyrosine kinase inhibitors. PATIENTS AND METHODS: Overall, 321 consecutive patients were analysed. The influence of PM on OS was assessed using the Kaplan Meier estimator and the log-rank test (unadjusted and adjusted) and two multivariabe Cox proportional hazards regressions (CPHR). RESULTS: Thirty-four patients (10%) had PM and 287 (90%) had sites of metastasis other than the pancreas; the median OS was 46.1 and 23.1 months, respectively (unadjusted log rank p=0.020; adjusted log-rank p=0.544). The PM status was an insignificant factor for OS in both CPHR (hazard ratio(HR)=0.84, p=0.603, and HR=0.66, p=0.098). CONCLUSION: The presence of PM was not an independent prognostic factor, but was rather an indicator of an indolent course of the disease. PMID- 29277796 TI - Evaluation of Expression of Human Epidermal Growth Factor Receptor 2 (HER2) in Gastric and Gastroesophageal Junction Adenocarcinoma Using IHC and Dual-ISH. AB - BACKGROUND/AIM: Trastuzumab(r) is used for human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. Our aim was to compare HER2 expression by immunohistochemistry (IHC) and dual in situ hybridization (DISH) in early-stage vs. late-stage gastric and GEJ tumors. MATERIALS AND METHODS: Fifty early-stage and 50 late-stage gastric tumors and a similar number of early-stage and late-stage GEJ tumors were studied. HER2 was analyzed by IHC and dual-ISH using tissue microarray. RESULTS: Of 200 selected cases, 168 had satisfactory results. Among the 110 cases with both tests successfully performed, there were only five cases with discrepancy between assays (4.5%). Seven equivocal (2+) cases by IHC were all found to be amplified by dual-ISH. When compared with IHC, dual-ISH identified 12 additional HER2-positive cases (10.9%). CONCLUSION: The 12.5% overall overexpression/amplification in gastric and GEJ adenocarcinomas is in concordance with previous reports. No correlation was found between tumor stage and HER2 overexpression/amplification. Determination of HER2 in limited tissue samples benefits from combinational IHC and ISH testing. PMID- 29277797 TI - First Clinical Data of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) as Salvage Therapy for Peritoneal Metastatic Biliary Tract Cancer. AB - BACKGROUND: Patients suffering from peritoneal metastasis of biliary tract cancer were treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). PATIENTS AND METHODS: This was a study carried out at a single institution, tertiary referral center certified for therapy of peritoneal disease. Retrospective data analysis was performed of prospective data for PIPAC with intra-peritoneal low-dose doxorubicin (1.5 mg/m2) and cisplatin (7.5 mg/m2) delivered at intervals of 6 weeks. The outcome criteria were microscopic pathological response, survival, and adverse events [Common Terminology Criteria of Adverse Events (v4.0)]. RESULTS: A total of 13 patients (male/female=8/5) with a mean age of 58 (range=37-75) years underwent 17 PIPAC procedures without intraoperative complications. The mean number of PIPAC applications was 1.3 (range=0-3). Due to non-accessibility of the abdominal cavity in two patients (15.4%) and rapid clinical deterioration in six patients (46%), five patients underwent two or more PIPAC applications and were, therefore, eligible for histological analysis to assess carcinoma regression. Overall tumor regression of any degree was determined in 4/5 patients. An overall median survival of 85 days (95% confidence interval(CI)=59.2-110.4 days) after the first PIPAC application was observed. No complications greater than Common Terminology Criteria of Adverse Events (v4.0) level 2 occurred. CONCLUSION: PIPAC can induce objective regression of systemic chemotherapy-resistant peritoneal metastasis of biliary tract cancer. However, due to a rapid clinical deterioration of the patients, almost two-thirds of the patients cannot undergo repetitive PIPAC courses. PMID- 29277798 TI - Safety and Efficacy of Low-dose Nanoparticle Albumin-bound Paclitaxel for HER2 negative Metastatic Breast Cancer. AB - BACKGROUND/AIM: Nab-paclitaxel (nab-PTX) is an albumin-bound paclitaxel formulation. Although nab-PTX has shown superior efficacy compared to conventional paclitaxel (PTX) in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In this study, we aimed to estimate the feasibility of the nab-PTX 175 mg/m2/3weeks regimen. PATIENTS AND METHODS: Patients having metastatic or inoperable HER2 negative breast cancer received 175 mg/m2 of nab-PTX every three weeks. The primary endpoint was safety and the secondary endpoints were response and survival. RESULTS: Seventeen patients were enrolled with a median age of 64 years. Ten patients had estrogen receptor positive disease and seven had triple negative disease. CIPN was observed in seven patients (41%) however, grade 3 CIPN was only seen in one patient (6%). Objective response rate was 41% and progression-free survival was 23 weeks. CONCLUSION: Nab-PTX 175 mg/m2/3wks regimen has a good safety profile and less frequent CIPN. This regimen can contribute to the strategy of MBC treatment. PMID- 29277799 TI - Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image guided Intensity-modulated Radiotherapy. AB - BACKGROUND/AIM: We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring. PATIENTS AND METHODS: We compared 130 patients treated using 2.2 Gy/fraction (Group A) and 144 treated using the 2 Gy/fraction (Group B) with modified PTV (excluding rectal volume) with a median follow-up period of 62 months. Prescribed dose was 72.6-74.8 Gy in 33-34 fractions (Group A) and 72-74 Gy in 36-37 fractions (Group B). RESULTS: Patients in Group B had a reduced rectal and bladder V10-V70 and were irradiated at the maximal dose. Their cumulative incidence of grade <=2 GI toxicity at 5 years improved from 10.1% [95% confidence interval (CI), 4.9-15.3%] to 1.4% (0-3.3%). Grade 2<= urinary toxicity also decreased from 5.5% (1.5-9.4%) in Group A to 1.4% (0-3.3%, p=0.0167) in Group B. The biochemical failure-free 5-year survival rate was 89.1% (95%CI=83.6-95.4%) and 87.5% (82.0-92.9%, p=0.75) in groups A and B, respectively. CONCLUSION: The reduced dose fraction schedule decreased the incidence of late GI toxicity without compromising prostate-specific antigen control. Careful target volume definition and fraction size are important even for IG-IMRT. PMID- 29277800 TI - Utilization of Molecular Testing and Survival Outcomes of Treatment with First- or Second-line Tyrosine Kinase Inhibitors in Advanced Non-small Cell Lung Cancer in a Dutch Population. AB - BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) mutation testing is standard-of-care for advanced non-small cell lung cancer (NSCLC). Outcomes of second-/third-line compared to first-line tyrosine kinase inhibitors (TKIs) have shown conflicting results. We investigated utilization of molecular diagnostics and the outcomes of treatment with first-/second-line TKIs in patients with advanced NSCLC. MATERIALS AND METHODS: Retrospective analysis was carried out of 2,206 patients with stage IIIb/IV NSCLC treated between 2008 and 2014 in four hospitals in the Netherlands. RESULTS: The rate of performing molecular diagnostics increased from 20.8% to 74.4% in the study period. The median overall survival of EGFR mutation-positive patients treated with TKIs was superior compared to EGFR mutation-negative patients treated with chemotherapy (720 vs. 274 days, p<0.0001). No difference in overall survival was found between EGFR mutation-positive patients treated only with TKIs compared to those treated with chemotherapy prior to TKIs, or upon progression under TKIs. CONCLUSION: The rate of EGFR testing has improved, increasing the number of patients eligible for targeted therapy. Chemotherapy, prior or subsequent to TKIs, for the treatment of EGFR mutation-positive patients, did not result in significantly better overall survival compared to that achieved with TKIs alone. PMID- 29277801 TI - Mesenchymal-epithelial Transition and Tumor Vascular Remodeling in Eribulin Chemotherapy for Breast Cancer. AB - BACKGROUND/AIM: Eribulin mesylate (eribulin) is currently used for the treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress the epithelial-mesenchymal transition (EMT) of cancer cells and promote tumor vascular remodeling. In this study, we investigated the expression of markers for EMT and hypoxia in sets of clinical specimens collected before and after eribulin treatment to verify its unique mechanisms. PATIENTS AND METHODS: The expression of markers for EMT and cellular hypoxia [E-cadherin, N-cadherin, vimentin, and carbonic anhydrase 9 (CA9)] was examined immunohistochemically in MBC tissues collected from 20 patients before and after chemotherapy with either eribulin (n=10) or paclitaxel (n=10). RESULTS: An increase of E-cadherin and decrease of CA9 expression were observed in MBC tissues from patients with objective clinical responses to eribulin treatment. Patients with E-cadherin-positive conversion and CA9-negative conversion had significantly higher response rates (p=0.004 and p=0.024, respectively) and prolonged time to treatment failure (p=0.018 and p=0.038, respectively) than patients without changes in marker expression. CONCLUSION: Expression of EMT and hypoxia markers in clinical samples from patients with MBC was suppressed by eribulin treatment. The results provide additional clinical data on improved survival of patients treated with eribulin and the mechanism of response. PMID- 29277803 TI - Computed Tomography Density Change in the Thyroid Gland Before and After Radiation Therapy. AB - BACKGROUND/AIM: Hypothyroidism is an established adverse effect of radiation therapy for head and neck cancer, and computed tomography (CT) density of the thyroid gland is lower in hypothyroid than euthyroid individuals. No previous studies have evaluated changes in CT densities of the thyroid gland caused by radiation therapy. The aim was to investigate the relationship between the change in CT density of the thyroid gland before and after radiation therapy for head and neck cancer and hypothyroidism. MATERIALS AND METHODS: This retrospective study analyzed data of 24 patients treated by radiation therapy for head and neck cancers. After dosimetric analysis of received radiation therapy, a Picture Archiving and Communication System was used to manually contour the thyroid on pre-treatment CT images to enable determination of mean thyroid gland CT densities and received radiation doses. Pre- and post-treatment thyroid function was assessed on the basis of serum TSH concentrations. Multivariate and univariate analyses were used to determine what clinical factors are associated with post-radiation therapy decrease in CT density of the thyroid and Pearson's chi2 test was used to assess correlations between these densities and TSH concentrations. RESULTS: Mean CT densities of the thyroid gland decreased from before to after radiation therapy in 73.9% of our patients (median decrease 16.8 HU). Serum TSH concentrations were significantly higher in patients with greater then median decreases in CT density than in those with lesser or no decreases. CONCLUSION: Post-radiation therapy hypothyroidism may be predicted by significant decreases in CT density of the thyroid gland. PMID- 29277802 TI - Value of Diaphragmatic Surgery During Interval Debulking Surgery. AB - BACKGROUND/AIM: The aim of this study was to assess the value of diaphragmatic surgery to achieve optimal debulking in patients with advanced ovarian cancer treated by neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: This is a retrospective review of the medical records of 182 patients. Diaphragmatic surgery was performed during interval debulking surgery (IDS) in 74 patients between January 2002 and December 2014. The patients were divided in 2 groups: with or without histological residual diaphragmatic disease. The time-course of serum CA125 levels, cytoreductive outcome, overall survival (OS) and relapse-free survival (RFS) were analyzed. Patients without diaphragmatic peritonectomy (DP) during IDS were included in the survival analysis. RESULTS: One hundred thirty two (72.5%) patients had FIGO stage III disease and 43 (23.6%) patients had stage IV disease. Histological examination of DP was positive in 45 patients and negative in 29 patients. CA125 normalization after the 3rd cycle of NAC was significantly associated with negative DP. OS tended to be higher in the DP negative group (37.8 months vs 19 months, p=0.1). Median OS was 40.7 months in the case of IDS without DP and 22 months in the case of IDS with DP (p=0.048). CONCLUSION: Evaluation of residual diaphragmatic disease can be difficult after NAC. The CA125 tumor marker appears to be a useful tool to define the indications for DP. Diaphragmatic surgery after NAC may be of limited value. PMID- 29277804 TI - Debulking Surgery for Pelvic Recurrence After Surgically-treated Tubal Gestational Choriocarcinoma - A Case Report and Literature Review. AB - Gestational choriocarcinomas are very rare malignancies, with only few cases being reported so far. Moreover, the presence of pelvic recurrences after surgically-treated gestational choriocarcinomas is even scarcer situations. We present the case of a 19-year-old patient who was initially submitted to surgery with preoperative diagnosis of ectopic pregnancy. At that moment a left salpingectomy was performed, and the histopathological studies revealed the presence of a left tubal gestational choriocarcinoma. The patient was submitted to adjuvant chemotherapy with methotrexate and dactinomycin. However, six months later she was diagnosed with a pelvic recurrence so she was resubmitted to surgery, debulking to no residual disease being successfully performed. The histopathological studies confirmed the presence of a recurrent tumor with gestational choriocarcinoma structure. PMID- 29277805 TI - Is There a Role for Functional MRI for the Assessment of Extracapsular Extension in Prostate Cancer? AB - BACKGROUND/AIM: Exctracapsular extension (ECE) in prostate cancer has a high impact on treatment decision. MRI might predict presence of ECE non-invasively. PATIENTS AND METHODS: Triplanar T2w-sequences, DWI (diffusion weighted imaging) and DCE (dynamic contrast-enhanced imaging) of 34 patients with PCa were analyzed to prior prostatectomy. Sensitivity (SS) and specificity (SP) of T2w, apparent diffusion coefficient (ADC), plasma flow (PF) and mean transit time (MTT) normalized by PCa/normal tissue ratio for prediction of CI (capsular infiltration)/ECE were determined by area-under-the-receiver-operating characteristics analysis. RESULTS: SS/SP for detecting ECE was 29/85. AUC (area under the curve) of ECE cases was 0.98/0.92/0.69 (cut-off-ratios 3.2/0.51/0.46), SS 93/100/86% and SP 95/80/50% for PF-/MTT-/ADC-ratios, respectively. PF- and MTT ratios between CI and without CI/ECE differed significantly (PF, p<0.0001; MTT, p=0.0134) with SS/SP 84/89% for PF and SS/SP 52/100% for MTT-ratios. No significant differences regarding ADC-ratios were identified. CONCLUSION: ECE/CI can be assessed by quantitative DCE analysis with great diagnostic confidence and higher specificity than ADC. PMID- 29277806 TI - Utility of Nasogastric Tube for Medical and Surgical Oncology of Gastric Cancer: A Prospective Institutional Study on a New and Precious Application of an Old and Economic Device. AB - BACKGROUND/AIM: Concerning gastric cancer (GC), nasogastric tube (NGT) is routinely employed for peri-operative decompression and palliative enteral nutrition. Additionally, we believe to have found a further application. PATIENTS AND METHODS: Between April 2012 and April 2017, 96 GC patients received preoperative nasogastric lavage (GL). All samples were cytologically examined to detect the presence (GL1) or absence (GL0) of malignant cells. Data were analyzed with classificatory, staging and prognostic purpose. RESULTS: GL1 was detected in 46 GC patients: association with tumor depth, lymph node and distant metastasis, lymphovascular and peri-neural invasion, diffuse type and signet-ring cells was significant (respectively p=0.0274, 0.0324, 0.0446, 0.0287, <0.0001, 0.0413, <0.0001). GL1 entailed significantly poorer overall (OS), progression-free, disease-free survival and tumor progression (18 vs. 32 months). At multivariate analysis, GL1 was an independent prognostic factor for worse OS (p=0.0287). CONCLUSION: NGT seems an economic oncologic measure useful for obtaining information on GC staging and prognosis. PMID- 29277807 TI - Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Elderly Patients: Complete Cytoreduction Is Feasible and Crucial for Improved Survival Despite High Carcinomatosis Index. AB - BACKGROUND: We aimed to study the surgical outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in elderly patients, and investigate whether the pursuit of complete cytoreduction implies a survival benefit despite a high peritoneal carcinomatosis index (PCI). PATIENTS AND METHODS: All CRS and HIPEC procedures performed for patients with peritoneal surface malignancy (PSM) >=65 years old between 2005-2017 were included. A control group comprising patients 60-64 years old who underwent CRS and HIPEC over the same period was also selected for comparison of characteristics and outcomes. RESULTS: A total of 54 elderly patients and 27 control patients were included. Increasing age did not result in any difference in demographics, perioperative characteristics, or surgical outcomes. Elderly patients who achieved completeness of cytoreduction (CC) 0/1 were compared to those with CC2/3, and were found to have a higher body mass index, lower peritoneal cancer index, higher rate of inpatient mortality, and a significantly longer median survival (43 vs. 15 months; p=0.020). Cox multivariate regression identified Charlson score >=2, the occurrence of major morbidities, colorectal and sarcoma primary tumor, and CC2/3 as significant predictors of poor survival. CONCLUSION: CRS and HIPEC are feasible in elderly patients without a significant effect of increasing age on the surgical outcomes. CC0/1 carries higher postoperative mortality rate, but yields a longer overall survival. Baseline comorbidities, postoperative complications, certain histologies, and CC2/3 are predictors of poor prognosis in this population. PCI is a predictor of CC, but not of survival when CC0/1 is achieved. PMID- 29277808 TI - Pazopanib for Metastatic Renal Cell Carcinoma: A Registry-based Analysis of 426 Patients. AB - BACKGROUND: Pazopanib is approved for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). The present study was a retrospective registry-based analysis of 426 patients with mRCC treated with pazopanib as first line targeted therapy. PATIENTS AND METHODS: The data were obtained from the Renal Cell Carcinoma Information system registry. Patient baseline parameters, treatment course and outcomes, and toxicity were analysed. RESULTS: Median progression-free and overall survival were 12.9 (95% confidence interval(CI)=11.0 14.8) months and 33.2 (95% CI=29.9-36.4) months, respectively. Overall response rate and disease control rate were 25.1% and 57.4%, respectively. Adverse events led to discontinuation of treatment in 37 (12.1%) patients. CONCLUSION: The results confirm that pazopanib is an effective and safe first-line targeted treatment in patients with mRCC. Both the International mRCC Database Consortium and the Memorial Sloan Kettering models were valid predictors of prognosis and nephrectomy was associated with improved survival. PMID- 29277809 TI - Long-term Outcomes of Carbon-ion Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix. AB - BACKGROUND/AIM: To evaluate the long-term outcomes of carbon-ion radiotherapy (C ion RT) for locally advanced cervical squamous cell carcinoma (LAC-SqCC) in 2 prospective phase I/II studies. PATIENTS AND METHODS: In the first study, 14 patients were treated with 68.8-72.8 Gy (RBE)/24 fractions. In a subsequent study, 22 patients were treated with 64.0-72.0 Gy (RBE)/20 fractions while limiting the dose to the gastro-intestinal (GI) <60 Gy (RBE). RESULTS: The 10 year local control rates were 92% and 61% for the patients administered a total dose of 72.0-72.8 Gy (RBE) and 64.0-68.8 Gy (RBE), respectively. Two patients in the first study developed grade 3/4 rectal or bladder complications; however, no grade 3 or higher complications occurred in the second study. CONCLUSION: C-ion RT with a higher dose was associated with excellent LC in LAC-SqCC. Long-term safety was confirmed based on the establishment of dose constraints for the GI tract. PMID- 29277810 TI - CEA, CA 15-3, and TPS as Prognostic Factors in the Follow-up Monitoring of Patients After Radical Surgery for Breast Cancer. AB - AIM: The aim of this study was to evaluate the ability of tissue polypeptide specific antigen (TPS), carcinoembryonic antigen (CEA), and cancer antigen 15-3 (CA 15-3) to predict relapse in breast cancer patients, when the measurement of biomarkers is performed within 6 months after surgery. PATIENTS AND METHODS: Four hundred and seventy-two patients with breast cancer were evaluated. TPS, CEA, and CA 15-3 were measured in months 1, 3, and 6, after surgery. Disease recurrence was recorded between 7-12 months after surgery. Disease recurrence occurred in 60 patients, while 412 patients remained in recurrence-free status. RESULTS: TPS levels of the recurrence group differed statistically significantly in the first and sixth month after surgery compared to recurrence-free group (p=0.0339, AUC=0.6056; p<0.0001, AUC=0.7196). CEA and CA 15-3 measurements did not achieve a statistically significant difference for any month examined. CONCLUSION: TPS level in the sixth month after surgery is the best candidate biomarker to predict disease recurrence. PMID- 29277811 TI - PTCH1 Germline Mutations and the Basaloid Follicular Hamartoma Values in the Tumor Spectrum of Basal Cell Carcinoma Syndrome (NBCCS). AB - BACKGROUND/AIM: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. MATERIALS AND METHODS: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. RESULTS: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. CONCLUSION: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies. PMID- 29277812 TI - Association Between Laryngopharyngeal Reflux and Radiation-induced Mucositis in Head and Neck Cancer. AB - BACKGROUND/AIM: We investigated whether laryngopharyngeal reflux (LPR) is a risk factor for radiation-induced mucositis. PATIENTS AND METHODS: This was a retrospective cohort study using our departmental database. The study included patients with stage I or II laryngeal and hypopharyngeal cancers treated with radiation therapy alone between April 2009 and March 2014. Based on endoscopic findings, baseline laryngeal signs were evaluated using the reflux finding score (RFS), and the severity of mucositis was assessed during and after radiation therapy. RESULTS: Fifty-eight patients were enrolled. Thirty-one patients were categorized as high RFS (LPR-likely), while 27 patients were categorized as low RFS (LPR-unlikely). Grade 3 mucositis occurred more frequently in the high RFS group (p<0.042). Furthermore, grade 3 mucositis developed earlier in the high RFS group (p<0.001). CONCLUSION: High RFS (i.e., increased likelihood of LPR) appears to be a potential risk factor for developing severe radiation-induced mucositis. PMID- 29277813 TI - Clinical Trial of Radiotherapy After Intravenous Injection of Acridine Orange for Patients with Cancer. AB - AIM: We previously found that low-dose X-ray treatment after systemic administration of acridine orange (AO), which is known to have a low toxicity in animals, inhibited tumor growth in experimental studies using mouse osteosarcoma. In this pilot study, we planned to verify the toxicity of intravenous injection of low-dose AO in humans and investigate the anticancer effect of radiation after systemic AO administration (iAOR) for human cancer. PATIENTS AND METHODS: Eight patients with terminal cancer were treated with iAOR. RESULTS: None of the patients exhibited an adverse effect from AO injection. Three out of the five patients who received a full course of iAOR exhibited clinical or image-based responses, whereas two patients did not. CONCLUSION: The systemic administration of AO was confirmed not to be toxic in humans, and iAOR was suggested to be potentially effective against radioresistant cancer. PMID- 29277814 TI - Low Visceral Fat Content Is a Negative Predictive Marker for Bevacizumab in Metastatic Colorectal Cancer. AB - AIM: This study aimed to clarify the predictive impact of visceral fat on response to bevacizumab in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Pretreatment computed tomography was used to measure visceral fat area (VFA) and patients with mCRC receiving first-line chemotherapy with/without bevacizumab were divided by median VFA value into two groups: high VFA and low VFA. RESULTS: In the bevacizumab-treated group, patients with low VFA had significantly shorter overall survival (OS) than patients with high VFA in univariate (median=21.1 vs. 38.9 months; hazard ratio=1.70, 95% confidence interval=1.06-2.70, p=0.03) and multivariate analysis (hazard ratio=1.85, 95% confidence interval=1.15-3.03, p=0.01). No significant differences were seen in OS between groups treated with chemotherapy alone. The VFA had a marginally significant modifying effect on the relationship between bevacizumab and OS (p for interaction=0.07). CONCLUSION: Our findings provide the first evidence that a low VFA might be a negative predictive marker for response to bevacizumab in patients with mCRC. PMID- 29277815 TI - The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy. AB - BACKGROUND/AIM: We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. PATIENTS AND METHODS: Thirty eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. RESULTS: The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. CONCLUSION: Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective. PMID- 29277816 TI - Paraneoplastic Auto-immune Hemolytic Anemia: An Unusual Sequela of Enteric Duplication Cyst. AB - Enteric duplication (ED) cysts are rare congenital anomalies of the alimentary canal that present in childhood. Although benign in most case, ED cysts have the potential to cause complications including a rare association with secondary carcinomas. Autoimmune hemolytic anemia presenting as a paraneoplastic syndrome secondary to solid tumors is an unusual phenomenon. Here we report a patient case with ED cyst described in association with intestinal adenocarcinoma and warm auto immune hemolytic anemia, with resolution of the hemolysis upon its surgical resection. PMID- 29277817 TI - Evaluation of a Transumbilical Incision as an Approach for Organ Removal in Laparoscopy-assisted Colectomy. AB - AIM: To investigate the risk factors of transumbilical incision for organ removal in laparoscopy-assisted colectomy (LAC). PATIENTS AND METHODS: We enrolled 348 consecutive patients who underwent LAC at our hospital between 2010 and 2013. The occurrence of superficial surgical site infection (SSI) and hernia at the transumbilical port site were recorded. RESULTS: SSI was observed in 15 patients (4.31%); there were no obvious associated risk factors. Hernia occurred in 23 patients (6.61%); multivariate analysis revealed that female sex [odds ratio (OR)=4.736, 95% confidence interval (CI)=1.058 to 24.362; p=0.042] and diabetes mellitus (OR=4.655, 95% CI=1.520 to 13.585; p=0.004) were significantly associated with the risk of hernia. Anastomotic method and the anastomotic site (inside and outside the body) did not contribute to the occurrence of complications. CONCLUSION: Female sex and diabetes mellitus are independent risk factors for hernia formation in patients undergoing transumbilical incision for organ removal in laparoscopy-assisted colectomy. PMID- 29277818 TI - Re-irradiation with 36 Gy (1.5 Gy Twice Daily) Plus Paclitaxel for Advanced Recurrent and Previously Irradiated SCCHN is Feasible. AB - BACKGROUND/AIM: Many patients developing a loco-regional recurrence of squamous cell carcinoma of head and neck (SCCHN) have a poor prognosis. Often, recurrences are unresectable, and patients require a second course of radiotherapy or chemoradiation. We present an approach of chemoradiation including mainly 30 Gy of radiotherapy (1.5 Gy twice daily) plus concurrent paclitaxel. To further improve the prognoses of these patients, we increased the radiation dose from 30 to 36 Gy. PATIENTS AND METHODS: In four patients with recurrent and previously irradiated SCCHN (60-70 Gy) chemoradiation was carried out using 36 Gy (1.5 Gy twice daily) and concurrent paclitaxel (4-5 times 20-25 mg/m2). RESULTS: One-year loco-regional control rates were 75% inside and 67% outside re-irradiated regions. One-year survival was 50%, and median survival time 11 months. Toxicities were mild (grade 0-2). CONCLUSION: Re-irradiation with 36 Gy (1.5 Gy twice daily) plus paclitaxel appears feasible and may lead to promising outcomes. This study is preceding a phase I trial. PMID- 29277819 TI - Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination. AB - BACKGROUND/AIM: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy. PATIENTS AND METHODS: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5 fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up. CONCLUSION: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD. PMID- 29277820 TI - The Severity of Anastomotic Leakage May Negatively Impact the Long-term Prognosis of Colorectal Cancer. AB - BACKGROUND: Anastomotic leakage is a major critical complication in colorectal resection. Although its relevance to oncological outcome has been widely investigated, the correlation between the severity of anastomotic leakage and oncological outcome is not well understood. PATIENTS AND METHODS: The clinical characteristics of 615 patients who underwent curative resection of colorectal cancer with anastomosis and normal healing were compared with 44 similar patients who experienced anastomotic leakage. RESULTS: Of the 44 patients, seven had grade A anastomotic leakage, 21 had grade B and 16 had grade C. Patients with grade A and B anastomotic leakage were treated conservatively (n=28), and those with grade C (n=16) were treated surgically. Those treated surgically had significantly worse recurrence-free survival and worse cancer-specific survival. CONCLUSION: Anastomotic leakage had a negative prognostic impact on cancer specific survival that depended on the severity of anastomotic leakage. PMID- 29277821 TI - Iodine Content Analysis Using Dual-Energy Computed Tomography as a Biomarker of Transitional Cell Carcinoma, an Experience with Separation of the Clotted Blood and Tumorous Tissue. AB - BACKGROUND/AIM: The aim of this study was to evaluate the possibility to discriminate the blood clot from tumorous tissue in the assessment of transitional cell carcinoma (TCC), when CT data are used only from single-phase dual-energy CT (DECT). MATERIALS AND METHODS: A total of 18 patients were included into the retrospective analysis of the prospectively collected data (the average age was 67.3 years, range=62-79 years, 12 males, 6 females). DECT was performed in all patients after intravenous administration of the iodinated contrast material. DECT analysis using three-material decomposition algorithm was used to discriminate blood and enhancing tumorous tissue. In all patients, TCC was detected and subsequently kidney surgery or endoscopy was performed within the next two weeks. The findings were compared with DECT results. RESULTS: In our cohort of patients we found 9 TCC of the renal pelvis or ureter and 7 TCC of the urinary bladder. The accuracy of the TCC detection was 94% (17/18). The presence of coagulated blood within the urinary collecting system together with a tumor was detected in 7 CT examinations. The blood coagulum without a confirmed malignant tumor was found in one case with false positive DECT finding. In other 6 cases bleeding was confirmed during surgery or endoscopy (accuracy 87%). CONCLUSION: The dual-energy data analysis enables discrimination of a blood clot from tumorous tissue. It helps in detection of UCC in cases when the excretion potential of the kidneys is decreased due to fulfillment of the collecting system with blood clots. PMID- 29277822 TI - Bevacizumab Added to Moderate-dose Chemotherapy for Refractory Uterine Cancer. AB - BACKGROUND/AIM: Bevacizumab (bev), when added to a moderate dose combination of previously failed cytotoxins, as a third- and fourth-line therapy for refractory gastric, cholangiocarcinoma, and ovarian cancers, produced high-quality responses. The regimen was based on preclinical models designed in order to simultaneously partner both bev and each of the cytotoxins with 4-5 synergistic drugs. PATIENTS AND METHODS: Eligible patients (n=9) had high-grade endometrial tumors and had failed standard chemotherapy. Bev (10 mg/kg every 2 weeks) and cyclophosphamide (150-250 mg/m2), were added to a combination of gemcitabine, fluorouracil, leucovorin, irinotecan and a platinum analogue -first without and then with docetaxel- each at approximately 1/2 to 1/3 of their standard dosage. Dose modification aimed at a repeated absolute neutrophil count (ANC) of 750 1,500 MUl or platelets of 125,000-75,000 MUl. Safety measures included stop-go use (intermittent, as needed, brief withholding of bev with resumption when again tolerated), of bev, and both prospective and ongoing dose modification in order to protect the bowels. RESULTS: Induction treatment was free of life-threatening complications. Nine consecutive patients, 3 under second- and 6 under multi-line treatment, had 9 objective responses and 8 produced long clinical benefits, 2 of which were complete responses. Seven responses created opportunities for personalized added treatment and research. Absolute median survival was 21.5 months for the 8 patients with platinum-resistant tumors. One patient was unable to tolerate a first standard adjuvant dose of paclitaxel. After rapid peritoneal progression of disease, treatment has produced 52+ months of unmaintained complete remission. CONCLUSION: Bev, in the combination that was used in this study, meets response, survival, and toxicity criteria for further testing against second- or multi-line chemotherapy-resistant tumors and also when a standard treatment is not safe. PMID- 29277823 TI - Clinical Significance of PD-L1 Expression in Brain Metastases from Non-small Cell Lung Cancer. AB - AIM: To investigate the association between positivity for programmed cell death ligand 1 (PD-L1) in brain metastases (BM) and the prognosis or clinical factors in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Thirty-two patients with surgically resected brain-metastatic NSCLC were enrolled. The PD-L1 expression in BM was analyzed using the antibody against human PD-L1 (clone SP142). The PD-L1 positivity was defined as PD-L1 expression on brain-metastatic tumor cells of >=5%. RESULTS: Seven (21.9%) out of 32 patients showed PD-L1 positivity in BM. The PD-L1-positive BM group had a significantly shorter brain-specific disease-free survival than the PD-L1 negative BM group (p<0.05). PD-L1 positivity in BM was significantly associated with a heavy smoking history and the administration of radiotherapy for BM before surgery (p<0.05 and p<0.05, respectively). CONCLUSION: The PD-L1 expression in BM from NSCLC may be associated with local recurrence following surgery, and the smoking- or radiotherapy-derived effects. PMID- 29277824 TI - Carcinoembryonic Antigen as a Predictive Biomarker of Response to Nivolumab in Non-small Cell Lung Cancer. AB - AIM: To find new predictive factors for the efficient use of immune checkpoint inhibitors in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter retrospective cohort study, we evaluated consecutive patients treated with nivolumab between January and October 2016 after second line systemic chemotherapy. The endpoint was progression-free survival (PFS), as defined by Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: A total of 189 patients were included in the study. Sixty-four percent had received two or more prior systemic therapies. In Cox proportional hazard analyses, Eastern Cooperative Oncology Group Performance Status of 2 or more, lactate dehydrogenase (LDH) >=217 mg/dl, and carcinoembryonic antigen >=13.8 ng/ml were independently associated with inferior PFS. LDH was not associated in the sensitivity analysis. CONCLUSION: In patients with NSCLC treated with nivolumab, worse pretreatment performance status, and higher carcinoembryonic antigen were associated with inferior PFS. PMID- 29277825 TI - Stereotactic Radiosurgery Alone for One to Two Brain Metastases from Cancer of Unknown Primary. AB - BACKGROUND/AIM: The use of stereotactic radiosurgery (SRS) alone has become popular for treating patients with a limited number of brain metastases. In very few patients, the primary tumor leading to cerebral spread is unknown. This study investigated the role of SRS for this rare situation. PATIENTS AND METHODS: Eight patients with 1-2 brain metastases from cancer of unknown primary (CUP) received SRS alone (median dose 20 Gy). Five clinical factors were evaluated for association with local control of the irradiated lesions, freedom from new cerebral lesions and survival. RESULTS: Six-month and 12-month survival rates were 63% and 63%, respectively. Improved survival was associated with male gender and only one cerebral lesion. Local control rates at 6 and 12 months were 100%. Six-month rate of freedom from new cerebral lesions was 86%. CONCLUSION: SRS appeared effective and resulted in promising local control and survival rates in patients with 1-2 brain metastases from CUP. PMID- 29277826 TI - Prognostic Significance of Mitochondrial Transcription Factor A Expression in Patients with Right- or Left-sided Colorectal Cancer. AB - BACKGROUND/AIM: Mitochondrial transcription factor A (mtTFA) is necessary for both the transcription and maintenance of mitochondrial DNA (mtDNA). The present study investigated the clinical significance of mtTFA in patients with right- and left-sided colorectal cancer (CRC). PATIENTS AND METHODS: Surgical specimens from 237 CRC patients were immunohistochemically stained with polyclonal anti-mtTFA antibody. The relationships among the mtTFA expression, clinicopathological factors and prognosis were evaluated. RESULTS: Thirty-five (60.3%) of 58 right sided CRC patients and 82 (45.8%) of 179 left-sided CRC patients showed high mtTFA expression. The mtTFA expression significantly correlated with lymph node metastasis, distant metastasis, the TNM stage and lymphatic invasion in left sided CRC patients and did not correlate with any factors in right-sided CRC patients. Univariate and multivariate analyses revealed the mtTFA expression to be a significant prognostic factor in left-sided CRC patients but not in right sided CRC patients. CONCLUSION: These results suggest that a high mtTFA expression is a useful marker for tumor progression and a poor prognosis in left sided CRC patients. PMID- 29277834 TI - Safety and toxicity of axitinib and sorafenib monotherapy for patients with renal cell carcinoma: a meta-analysis. AB - We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma (RCC) patients receiving and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase were searched. Studies enrolled were phase II and III prospective trials, as well as retrospective studies, in which patients diagnosed with RCC were treated with axitinib or sorafenib monotherapy at a starting dose of 5 mg and 400 mg twice daily, respectively. The overall incidence of high grade hypertension, fatigue, gastrointestinal toxicity and hand-foot syndrome, along with their 95% confidence intervals (CI), were calculated using fixed or random effects model according to heterogeneity test results. A total of 26 trials, including 4790 patients, were included in our meta-analysis. Among them, 6 arms were related to axitinib and another 22 were associated with sorafenib. The incidences of hypertension (24.9% vs. 7.9%), fatigue (8.2% vs. 6.6%), gastrointestinal toxicity (17.6% vs. 11.3%) were higher in patients receiving axitinib versus those receiving sorafenib, while the incidence of hand-foot syndrome was lower n patients receiving axitinib versus those receiving sorafenib (9.5% vs. 13.3%). In conclusion, axitinib showed noticeably higher risks of toxicity versus sorafenib. Close monitoring and effective measures for adverse events are recommended during therapy. PMID- 29277827 TI - The Efficacy of Wide Resection for Musculoskeletal Metastatic Lesions of Renal Cell Carcinoma. AB - BACKGROUND/AIM: This study evaluated the outcome of wide resection for metastatic renal cell carcinoma (RCC) to the bone or soft tissue. PATIENTS AND METHODS: Thirty patients who underwent surgery for bone or soft tissue metastatic lesions of RCC were retrospectively evaluated. The surgical procedures were wide resection in 14 patients (group 1) and intralesional resection in 16 (group 2). RESULTS: The 3-, 5-, 10-, and 15-year overall survival (OS) was 76%, 48%, 35%, and 23%, respectively, and OS was significantly favorable in group 1. In addition, recurrence-free survival rate was significantly higher in group 1. In the multivariate analysis, intralesional resection was an independent risk factor for poor prognosis. There was no significant difference in surgical time, though intraoperative hemorrhage was significantly larger in group 2. CONCLUSION: The wide resection of bone and soft tissue metastatic lesions of RCC is a favorable option for controlling local metastasis and improving prognosis. PMID- 29277835 TI - Serum Levels of Visfatin, Omentin and Irisin in Patients with End-Stage Lung Disease Before and After Lung Transplantation. AB - BACKGROUND The aim of this study was to investigate serum concentrations of visfatin, irisin, and omentin in patients with end-stage lung diseases (ESLD) before and after lung transplantation (LTx) and to find relationship between adipokines levels and clinical outcomes. MATERIAL AND METHODS Fourteen consecutive lung transplant recipients (six males and seven females; age 32.0+/ 14.2 years; body mass index (BMI) 21.8+/-5.3 kg/m2) who underwent lung transplantation with initial diagnosis of respiratory failure due to cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) were included. Visfatin, irisin, and omentin serum levels were assayed using commercially available ELISA kits at four time points: the day of LTx (day 0), 72 hours (day 3), one month (day 30) and three months (day 90) after LTx. RESULTS Omentin serum concentration decreased significantly within three days after LTx (350.5+/-302.0 to 200.0+/-0.90 ng/mL; p<0.05), while visfatin serum levels decreased later, 30 days after Ltx (4.81+/-3.78 to 0.78+/-0.35 [0.4 1.1] pg/mL; p<0.05). Downregulated serum levels of both adipokines remained stable for the next two months (256.0 [201.7-642.9] ng/mL and 0.77+/-0.76 pg/mL, respectively; p<0.05). Serum levels of irisin were unchanged before and after Ltx. Immunosuppressive regimen did not affect serum levels of the analyzed adipokines. CONCLUSIONS The study showed for the first time serum omentin and visfatin levels to be decreased after LTx in ESLD patients. Successful LTx contributes to the improvement of impaired lung function parameters and attenuation of ongoing inflammatory process, resulting in altered visfatin and omentin serum levels. Additional influence of immunosuppressive treatment on omentin and visfatin serum concentration cannot be excluded. PMID- 29277836 TI - Kinesio Taping vs. Placebo in Reducing Pregnancy-Related Low Back Pain: A Cross Over Study. AB - BACKGROUND Spinal pain affects approximately 45-56% of pregnant women. Kinesio taping (KT) involves application of flexible water-resistant elastic bands on the patient's body, resulting in painless and non-invasive stimulation. The aim of the study was to determine the influence of KT on reduction of low back pain in pregnant women. MATERIAL AND METHODS Kinesio Tex Gold tapes were applied using the muscular-ligament technique and Polovis Plus textile cladding blinded the sample. The starting position for the KT and placebo with lumbar spine flexion with rotation was in the opposite direction to the application. An "I"-shaped application was used. The material included 106 women in the second and third trimesters of pregnancy, with low back pain. The Visual Analogue Scale (VAS) and the Polish version of the Roland Morris Disability Questionnaire (RMDQ-2004) were used for pain assessment. Participants were randomly divided into 2 groups. KT and placebo were used alternately in 2 groups. RESULTS Mean pain intensity on the 2nd and 7th post-application days was significantly lower in the study group than in the control group. Mean scores for the RMDQ differed significantly before and after KT (p<0.0001), and after KT and placebo (p<0.0057), but there are no differences before and after placebo (p<0.67) and before KT and placebo (p<0.59). CONCLUSIONS Low back pain in pregnant women decreased significantly after KT when compared to placebo. The therapeutic effect appeared on day 2 and continued after removal of the tape. The few side effects did not affect the course of the study. PMID- 29277837 TI - Added sugars and ultra-processed foods in Spanish households (1990-2010). AB - BACKGROUND/OBJECTIVES: To study the association between ultra-processed foods acquisitions and added sugar content of total food purchases in Spanish households in 2010. Changes over time (1990-2000-2010) in ultra-processed food purchases and added sugars content of total food purchases are also compared. SUBJECTS/METHODS: We used data from three nationally representative Household Budget Surveys (HBS) conducted in 1990, 2000 and 2010. Number of studied households was 21,012, 33,730 and 22,116, respectively. Purchased foods and drinks were classified according to NOVA food groups as ultra-processed foods, processed foods, unprocessed or minimally processed foods, or processed culinary ingredients. Linear and Poisson regressions were used to estimate the association between quintiles of energy contribution of ultra-processed foods and added sugars contents of total food purchases in 2010. Changes over time were assessed using tests of linear trend and Student's t test. RESULTS: In 2010, ultra processed foods represented 31.7% of daily energy acquisitions and 80.4% of all added sugars. Added sugars content of food purchases raised from 7.3% in the lowest to 18.2% in the highest quintiles of energy contribution of ultra processed foods. The risk of exceeding 10% energy from added sugars quadrupled between the lowest and highest quintiles. The percentage of ultra-processed foods on all food purchases almost tripled between 1990 and 2010 (from 11.0 to 31.7%), paralleling the increase of added sugars content (from 8.4 to 13.0%). CONCLUSIONS: Cutting down exceeding added sugars availability in Spain may require a reduction in ultra-processed food purchasing. PMID- 29277838 TI - Dietary inflammatory index and inflammatory biomarkers in adolescents from LabMed physical activity study. AB - BACKGROUND/OBJECTIVES: The dietary inflammatory index (DII) is a tool to measure the diet's inflammatory potential and has been used with adults to predict low grade inflammation. The present study aims to assess whether this dietary score predicts low-grade inflammation in adolescents. SUBJECTS/METHODS: The sample comprises 329 adolescents (55.9% girls), aged 12-18 years, from LabMed Physical Activity Study. DII score was calculated based on a food-frequency questionnaire and categorized into tertiles. We collected blood samples to determine the follow inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), complement component 3 (C3), and 4 (C4). In addition we calculated an overall inflammatory biomarker score. Odds ratios (OR) and 95% confidence intervals (95%CI) were computed from binary logistic regression models. RESULTS: DII score, comparing first with third tertile, was positively associated with IL-6 in crude model (OR = 1.88, 95%CI:1.09-3.24, p trend = 0.011) and in fully adjusted (for biological and lifestyle variables) (OR = 3.38, 95%CI:1.24-9.20, p trend = 0.023). Also, DII score was positively associated with C4, when fully adjusted (OR = 3.12, 95%CI:1.21-8.10, p trend = 0.016). DII score was negatively associated with C3 in crude model, comparing first with second but not with third tertile, and no significant associations in fully adjusted model were observed, although a trend was found (OR = 1.71, 95%CI:0.63-4.66, p trend = 0.044). No significant associations were observed between DII score and CRP. However, DII score was positively associated with the overall inflammatory biomarker score, when fully adjusted (OR = 5.61, 95%CI:2.00-15.78, p trend = 0.002). CONCLUSIONS: DII score can be useful to assess the diet's inflammatory potential and its association with low-grade inflammation in adolescents. PMID- 29277839 TI - Effect of synbiotic supplementation in children and adolescents with cystic fibrosis: a randomized controlled clinical trial. AB - BACKGROUND/OBJECTIVES: Cystic fibrosis (CF) is characterized by excessive activation of immune processes. The aim of this study was to evaluate the effect of synbiotic supplementation on the inflammatory response in children/adolescents with CF. SUBJECTS/METHODS: A randomized, placebo-controlled, double-blind, clinical-trial was conducted with control group (CG, n = 17), placebo-CF-group (PCFG, n = 19), synbiotic CF-group (SCFG, n = 22), PCFG negative (n = 8) and positive (n = 11) bacteriology, and SCFG negative (n = 12) and positive (n = 10) bacteriology. Markers of lung function (FEV1), nutritional status [body mass index-for age (BMI/A), height-for-age (H/A), weight-for-age (W/A), upper-arm fat area (UFA), upper-arm muscle area (UMA), body fat (%BF)], and inflammation [interleukin (IL)-12, tumor necrosis factor-alpha (TNF-alpha), IL-10, IL-6, IL 1beta, IL-8, myeloperoxidase (MPO), nitric oxide metabolites (NOx)] were evaluated before and after 90-day of supplementation with a synbiotic. RESULTS: No significance difference was found between the baseline and end evaluations of FEV1 and nutricional status markers. A significant interaction (time vs. group) was found for IL-12 (p = 0.010) and myeloperoxidase (p = 0.036) between PCFG and SCFG, however, the difference was not maintained after assessing the groups individually. NOx diminished significantly after supplementation in the SCFG (p = 0.030). In the SCFG with positive bacteriology, reductions were found in IL-6 (p = 0.033) and IL-8 (p = 0.009) after supplementation. CONCLUSIONS: Synbiotic supplementation shown promise at diminishing the pro-inflammatory markers IL-6, IL-8 in the SCFG with positive bacteriology and NOx in the SCFG in children/adolescents with CF. PMID- 29277840 TI - Investigating comparability of quantitative computed tomography with dual energy x-ray absorptiometry in assessing bone mineral density of patients with chronic spinal cord injury. AB - STUDY DESIGN: Psychometric study using retrospectively collected data. OBJECTIVES: We investigated the comparability of quantitative computed tomography (qCT) in assessing bone mineral density (BMD) with dual energy X-ray absorptiometry (DXA). We evaluated how well previously suggested normal values for spinal Hounsfield units (HU) correlated with routine DXA results in patients with chronic spinal cord injury (SCI). Furthermore, we investigated inter/intra observer reliability of measuring HU in the spine. SETTING: Academic medical center in Tehran, Iran. METHODS: Spinal CT scans of 44 male participants with chronic SCI who had undergone DXA studies on the same day were selected. The main outcome measures were sensitivity, specificity, and area under curve (AUC) of HU at each spinal region against DXA results of areal BMD. The secondary outcome was inter/intra-observer reliability of measuring HU in the spinal column. RESULTS: We found no significant difference between qCT and DXA results (p-value = 0.237, R = 0.188). However, the two methods showed overall unfavorable comparability, with a sensitivity of 0%, 0%, and 80%, specificity of 50%, 90%, and 85%, and area under curve (AUC) of 0.27, 0.53, and 0.83 for cervical, thoracic, and lumbar spine, respectively. The best comparability was achieved at the lumbar region although not statistically significant (p-value = 0.072). Measuring HU was reliable (inter/intra-observer reliability >98%). CONCLUSIONS: This study demonstrates that currently proposed normal values result in unfavorable comparability in the cervical and thoracic regions; however, as the agreement improved at the lumbar spine, it is possible that qCT could become an indicator of bone strength with further research. PMID- 29277841 TI - Using radio astronomical receivers for molecular spectroscopic characterization in astrochemical laboratory simulations: A proof of concept. AB - We present a proof of concept on the coupling of radio astronomical receivers and spectrometers with chemical reactors and the performances of the resulting setup for spectroscopy and chemical simulations in laboratory astrophysics. Several experiments including cold plasma generation and UV photochemistry were performed in a 40 cm long gas cell placed in the beam path of the Aries 40 m radio telescope receivers operating in the 41-49 GHz frequency range interfaced with fast Fourier transform spectrometers providing 2 GHz bandwidth and 38 kHz resolution. The impedance matching of the cell windows has been studied using different materials. The choice of the material and its thickness was critical to obtain a sensitivity identical to that of standard radio astronomical observations. Spectroscopic signals arising from very low partial pressures of CH3OH, CH3CH2OH, HCOOH, OCS, CS, SO2 (<10-3 mbar) were detected in a few seconds. Fast data acquisition was achieved allowing for kinetic measurements in fragmentation experiments using electron impact or UV irradiation. Time evolution of chemical reactions involving OCS, O2 and CS2 was also observed demonstrating that reactive species, such as CS, can be maintained with high abundance in the gas phase during these experiments. PMID- 29277842 TI - Green Synthesis of Halogenated Thiophenes, Selenophenes and Benzo[b]selenophenes Using Sodium Halides as a Source of Electrophilic Halogens. AB - Herein, we report the first synthesis of chlorinated benzo[b]selenophenes via environmentally friendly electrophilic chlorocyclization reaction using "table salt" as a source of "electrophilic chlorine" and ethanol as a solvent. In addition, the synthesis of diverse halogenated heterocycles, including 3-chloro, 3-bromo and 3-iodo thiophenes, selenophenes, and benzo[b]selenophenes was successfully accomplished under the same environmentally benign reaction conditions. This methodology has several advantages over other previously reported reactions as it employs simple starting compounds, an environmentally friendly solvent, ethanol, and non-toxic inorganic reagents under mild reaction conditions, resulting in the high product yields. PMID- 29277843 TI - Accommodating informative dropout and death: a joint modelling approach for longitudinal and semi-competing risks data. AB - Both dropout and death can truncate observation of a longitudinal outcome. Since extrapolation beyond death is often not appropriate, it is desirable to obtain the longitudinal outcome profile of a population given being alive. We propose a new likelihood-based approach to accommodating informative dropout and death by jointly modelling the longitudinal outcome and semi-competing event times of dropout and death, with an important feature that the conditional longitudinal profile of being alive can be conveniently obtained in a closed form. We use proposed methods to estimate different longitudinal profiles of CD4 count for patients from the HIV Epidemiology Research Study. PMID- 29277844 TI - Shared Participatory Research Principles and Methodologies: Perspectives from the USA and Brazil-45 Years after Paulo Freire's "Pedagogy of the Oppressed". AB - The trajectory of participation in health research by community social actors worldwide has been built on a history of community participation from the Ottawa Charter Health Promotion call for community mobilization, to the emancipatory educational philosophy of Paulo Freire, to social movements and organizing for health and social justice. This paper builds on this history to expand our global knowledge about community participation in research through a dialogue between experiences and contexts in two prominent countries in this approach; the United States and Brazil. We first focus on differences in political and scientific contexts, financing, and academic perspectives and then present how, despite these differences, similarities exist in values and collaborative methodologies aimed at engaging community partners in democratizing science and knowledge construction. We present three case studies, one from the U.S. and two from Brazil, which illustrate similar multi-level processes using participatory research tools and Freirian dialogue to contribute to social mobilization, community empowerment, and the transformation of inequitable societal conditions. Despite different processes of evolution, we observed a convergence of participatory health research strategies and values that can transform science in our commitment to reduce health and social inequities and improve community wellbeing. PMID- 29277845 TI - Subacute Right Ventricular Perforation by Pacemaker Lead Causing Left-Sided Hemothorax and Epicardial Hematoma. AB - We report a case of right ventricular wall perforation by a pacemaker lead in a 78-year-old female 18 days after a permanent pacemaker insertion. This injury necessitated explant of the perforating lead and implantation of a new one with surgical backup. We review the literature and discuss the possible risk and protective factors including lead models that were associated with higher incidence of perforation. We review the traditional pacing parameters and their lack of reliability to diagnose perforation and the need for low threshold to utilize imaging in appropriate clinical scenarios. The authors believe this case is of educational value to all health care professionals, especially emergency medicine and internal medicine residents, who routinely see patients with pacemakers complaining of chest pain, shortness of breath, or dizziness. PMID- 29277846 TI - Corrigendum to "Fatal Systemic Vasoconstriction in a Case of Metastatic Small Intestinal NET". AB - [This corrects the article DOI: 10.1155/2017/9810194.]. PMID- 29277847 TI - Organ-specific alterations in circadian genes by vertical sleeve gastrectomy in an obese diabetic mouse model. PMID- 29277848 TI - Low Prevalence of Hepatitis B Vaccination Among Patients Receiving Medical Care for HIV Infection in the United States, 2009 to 2012. AB - Background: Persons with HIV infection are at increased risk for hepatitis B virus infection. In 2016, the World Health Organization resolved to eliminate hepatitis B as a public health threat by 2030. Objective: To estimate the prevalence of hepatitis B vaccination among U.S. patients receiving medical care for HIV infection ("HIV patients"). Design: Nationally representative cross sectional survey. Setting: United States. Participants: 18 089 adults receiving HIV medical care who participated in the Medical Monitoring Project during 2009 to 2012. Measurements: Primary outcomes were prevalence of 1) no documentation of hepatitis B vaccination or laboratory evidence of immunity or infection (candidates to initiate vaccination), and 2) initiation of vaccination among candidates, defined as documentation of at least 1 vaccine dose in a 1-year surveillance period during which patients received ongoing HIV medical care. Results: At the beginning of the surveillance period, 44.2% (95% CI, 42.2% to 46.2%) of U.S. HIV patients were candidates to initiate vaccination. By the end of the surveillance period, 9.6% (CI, 8.4% to 10.8%) of candidates were vaccinated, 7.5% (CI, 6.4% to 8.6%) had no documented vaccination but had documented infection or immunity, and 82.9% (CI, 81.1% to 84.7%) remained candidates. Among patients at facilities funded by the Ryan White HIV/AIDS Program (RWHAP), 12.5% (CI, 11.1% to 13.9%) were vaccinated during the surveillance period versus 3.7% (CI, 2.6% to 4.7%) at facilities not funded by RWHAP. At the end of surveillance, 36.7% (CI, 34.4% to 38.9%) of HIV patients were candidates to initiate vaccination. Limitation: The study was not designed to describe vaccine series completion or actual prevalence of immunity. Conclusion: More than one third of U.S. HIV patients had missed opportunities to initiate hepatitis B vaccination. Meeting goals for hepatitis B elimination will require increased vaccination of HIV patients in all practice settings, particularly at facilities not funded by RWHAP. Primary Funding Source: Centers for Disease Control and Prevention. PMID- 29277849 TI - Evaluating Slow-Release Oral Morphine to Narrow the Treatment Gap for Opioid Use Disorders. PMID- 29277850 TI - Underutilization of Glucagon in the Prehospital Setting. PMID- 29277851 TI - Blood Pressure Control: Missed Opportunity or Potential Holy Grail? PMID- 29277853 TI - Endoscopic endonasal resection of sinonasal/anterior skull base malignancy (Kadish C esthesioneuroblastoma). AB - BACKGROUND: The surgical management of anterior skull base malignancies requires the full complement of open and endoscopic skull base approaches. Due to the evolution of endoscopic techniques, endoscopic approaches are now being employed for complex skull base tumors. METHODS: We present our technique for endoscopic management for an advanced (T4) anterior skull base malignancy that provides a systematic approach to resection, margin assessment, and reconstruction. CONCLUSION: Our surgical strategy provides a systematic approach by which an oncologic resection can be performed within the context of a spectrum of surgical strategies necessary to manage skull base malignancies. PMID- 29277852 TI - Comparative Effectiveness of Implementation Strategies for Blood Pressure Control in Hypertensive Patients: A Systematic Review and Meta-analysis. AB - Background: The prevalence of hypertension is high and is increasing worldwide, whereas the proportion of controlled hypertension is low. Purpose: To assess the comparative effectiveness of 8 implementation strategies for blood pressure (BP) control in adults with hypertension. Data Sources: Systematic searches of MEDLINE and Embase from inception to September 2017 with no language restrictions, supplemented with manual reference searches. Study Selection: Randomized controlled trials lasting at least 6 months comparing the effect of implementation strategies versus usual care on BP reduction in adults with hypertension. Data Extraction: Two investigators independently extracted data and assessed study quality. Data Synthesis: A total of 121 comparisons from 100 articles with 55 920 hypertensive patients were included. Multilevel, multicomponent strategies were most effective for systolic BP reduction, including team-based care with medication titration by a nonphysician (-7.1 mm Hg [95% CI, -8.9 to -5.2 mm Hg]), team-based care with medication titration by a physician (-6.2 mm Hg [CI, -8.1 to -4.2 mm Hg]), and multilevel strategies without team-based care (-5.0 mm Hg [CI, -8.0 to -2.0 mm Hg]). Patient-level strategies resulted in systolic BP changes of -3.9 mm Hg (CI, -5.4 to -2.3 mm Hg) for health coaching and -2.7 mm Hg (CI, -3.6 to -1.7 mm Hg) for home BP monitoring. Similar trends were seen for diastolic BP reduction. Limitation: Sparse data from low- and middle-income countries; few trials of some implementation strategies, such as provider training; and possible publication bias. Conclusion: Multilevel, multicomponent strategies, followed by patient level strategies, are most effective for BP control in patients with hypertension and should be used to improve hypertension control. Primary Funding Source: National Institutes of Health. PMID- 29277854 TI - Update on the effect of exogenous hormone use on glioma risk in women: a meta analysis of case-control and cohort studies. AB - Various studies have confirmed the important roles of endogenous hormones in the development of gliomas, while the roles of exogenous hormones remain controversial. Based on case-control studies and cohort studies, a meta-analysis was exerted to explore the effect of two exogenous hormones use (HRT: hormone replacement therapy; OC: oral contraceptives) on glioma risk. 16 eligible studies, including 11 case-control studies and 5 cohort studies, containing 8055027 women, were included in our study. All included studies have reported the relative risks (RRs) or odds ratios (ORs), and 95% confidence intervals (CIs). We use the fixed-effects model to calculate the estimated overall risk. In case control studies, the risk of glioma was lower in women who had ever been treated with an exogenous hormone than in the control group (HRT: OR 0.91, 95% CI 0.84 0.99; OC: OR 0.99, 95% CI 0.91-1.07). In research of cohort studies, similar results have been obtained (HRT: RR 0.95, 95% CI 0.83-1.08; OC: RR 0.75, 95% CI 0.66-0.84). Our study further confirmed that the use of exogenous hormones has an important impact on the risk of glioma in women. However, more prospective studies are needed to further confirm this conclusion. PMID- 29277855 TI - Bifurcation of brachial artery into a common radial-interosseous trunk and superficial ulnar artery: a rare variation. AB - Variations in the branching pattern of brachial artery and abnormal course of its branches are not uncommon. The present article describes a case of bifurcation of the brachial artery into a common radial-interosseous trunk and superficial ulnar artery. The embryological basis behind the present case report could be, the radial artery establishing a connection with the axis artery just below the level of origin of ulnar artery, the posterior interosseous artery arising from the axis artery distal to the origin of the radial artery. The part of axis artery between origin of ulnar and radial artery must have developed into the common radial-interosseous trunk. The part of axis artery between origin of radial and posterior interosseous arteries develops as the common interosseous artery. The superficial position of ulnar artery could enable the surgeons in raising a free ulnar forearm flap for head and neck reconstructive surgeries. PMID- 29277856 TI - A phase IIa study of HA-irinotecan, formulation of hyaluronic acid and irinotecan targeting CD44 in extensive-stage small cell lung cancer. AB - Preclinical studies in small cell lung cancer (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver chemotherapy and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current study aimed to replicate these findings and obtain data on safety and activity of HA irinotecan (HA-IR). Eligible patients with extensive stage SCLC were consented. A safety cohort (n = 5) was treated with HA-IR and Carboplatin (C). Subsequently, the patients were randomised 1:1 to receive experimental (HA-IR + C) or standard (IR + C) treatment, to a maximum of 6 cycles. The second line patients were added to the study and treated with open label HA-IR + C. Tumour response was measured after every 2 cycles. Baseline tumour specimens were stained for CD44s and CD44v6 expression. Circulating tumour cells (CTCs) were enumerated before each treatment cycle. Out of 39 patients screened, 34 were evaluable for the study. The median age was 66 (range 39-83). The overall response rates were 69% and 75% for experimental and standard arms respectively. Median progression free survival was 42 and 28 weeks, respectively (p = 0.892). The treatments were well tolerated. The incidence of grade III/IV diarrhea was more common in the standard arm, while anaemia was more common in the experimental arm. IHC analysis suggested that the patients with CD44s positive tumours may gain survival benefit from HA-IR. HA-IR is well tolerated and active in ES-SCLC. The effect of HA-IR on CD44s + cancer stem-like cells provide an early hint towards a potential novel target. PMID- 29277857 TI - Percutaneous Mitral Valve Interventions and Heart Failure. AB - Mitral regurgitation (MR) is the most frequent Valvular Heart Disease (VHD) and is an important cause of heart failure. MR can be caused by primary valve abnormality (Degenerative MR/Primary MR) or it can be secondary to cardiomyopathy (Functional MR/Secondary MR). Medical management alleviates symptoms but does not alter the progression of the disease. Current guidelines recommend surgery for moderate-to-severe (Grade > 3) MR in patients with symptoms or evidence of left ventricular dysfunction. Despite current practice guidelines, the majority of patients with severe MR do not undergo surgery. The reasons include high surgical risk from advanced age or multiple comorbidities, and a lack of clear data supporting valve surgery for secondary MR with LV dysfunction. The recent emergence of percutaneous interventional approaches in treating MR has expanded therapeutic options for patients who are at high risk for conventional Mitral Valve (MV) surgery. In this chapter, we will review the novel advancements in the field of percutaneous MV interventions that could potentially become the standard of care for patients with MR and heart failure. PMID- 29277858 TI - Multi-institutional survey on imaging practice patterns in pancreatic ductal adenocarcinoma. AB - PURPOSE: To study the practice patterns for performance and interpretation of CT/MRI imaging studies in patients with pancreatic ductal adenocarcinoma (PDAC) at multiple institutions using a survey-based assessment. METHODS: In this study, abdominal radiologists/body imagers on the Society of Abdominal Radiology disease focused panel for PDAC and from multiple institutions participated in an online survey. The survey was designed to investigate the imaging and reporting practice patterns for PDAC. The survey questionnaire addressed the experience of referring providers, choice of imaging modality for diagnosis and follow-up of PDAC, structured imaging templates utilization for PDAC, and experiences with the use of structured reports. RESULTS: The response rate was 89.6% (43/48), with majority of the respondents working in a teaching hospital or academic research center (95.4%). While 86% of radiologists reported use of structured reporting templates in their practice, only 60.5% used standardized templates specific to PDAC. This lower percentage was despite most of them (77%) being aware of existence of PDAC-specific templates and recognizing their benefits, such as preference by referring providers (83%), improved uniformity (100%), and higher accuracy of reports (76.2%). The common impediments to the use of PDAC-specific templates were interference with efficient workflow (67.5%), lack of interest (52.5%), and complexity of existing templates (47.5%). With regards to imaging practice, 92.7% (n = 40/43) of respondents reported performing dynamic multiphasic pancreatic protocol CT for evaluation of patients with initial suspicion or staging of PDAC. CONCLUSION: Structured reporting templates for PDAC are not universally utilized in subspecialty abdominal/body imaging practices due to concerns of interference with efficient workflow and complexity of templates. Multiphasic pancreatic protocol CT is most frequently performed for evaluation of PDAC. PMID- 29277861 TI - Gene Phylogenies and Orthologous Groups. AB - This chapter covers the theory and practice of ortholog gene set computation. In the theoretical part we give detailed and formal descriptions of the relevant concepts. We also cover the topic of graph-based clustering as a tool to compute ortholog gene sets. In the second part we provide an overview of practical considerations intended for researchers who need to determine orthologous genes from a collection of annotated genomes, briefly describing some of the most popular programs and resources currently available for this task. PMID- 29277860 TI - A Fluorescence Study on Binding Interaction of N-acetylated Dansylamide Conjugates with beta-cyclodextrin, Tween-20 and DPPC Lipid Bilayer Membrane. AB - The present work describes the photophysical behavior of a saturated fatty acid (palmitic acid) containing N-acetylated dansylamide derivative (DAN-PA) into biologically important organized assembly such as beta-cyclodextrin (beta-CD), Tween-20 (T-20) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer membrane. The results were compared by using another N-acetylated dansylamide conjugate having a short hydrophobic tail, DAN-ACYL. Long hydrophobic tail (saturated fatty acid) containing dansylamide conjugate (DAN-PA) shows more efficient binding interactions with the beta-CD as compared to the short tail containing dansylamide derivative (DAN-ACYL). The calculated binding constants values of DAN-PA and DAN-ACYL probes are 1.35 * 102 M -1 and 0.31 * 102 M -1 respectively. The DAP-PA is a sensitive fluorophore for understanding the micellization process in T-20, as compared to the DAN-ACYL because it shows a significant change in fluorescent properties (steady-state and time-resolved both) with changing in T-20 concentrations. The calculated CMC value for T-20 surfactant is 0.07 mM. While the DAN-ACYL does not show any change in the fluorescent properties while changing the T-20 concentrations. Fluorescent parameters like steady-state and time-resolved of DAN-PA are quite sensitive towards the thermo-tropic phase transitional changes into lipid bilayer membrane properties. And the calculated thermo-tropic phase transition temperature by using DAN-PA fluorophore is 42 degrees C. PMID- 29277859 TI - Management of acute heart failure in adult patients with congenital heart disease. AB - Heart failure is an increasing reason for hospitalization and the leading cause of death in patients with adult congenital heart disease (ACHD). Recently, the European Society of Cardiology and the American Heart Association published consensus documents on the management of chronic heart failure in ACHD patients. However, little data and/or guidelines are available for the management of (sub)acute heart failure. The ACHD population is heterogeneous by definition and often has complex underlying anatomy, which could pose a challenge to the physician confronted with the ACHD patient in (sub)acute heart failure. Recognizing the underlying anatomy and awareness of the possible complications related would result in better treatment, avoid unnecessary delays, and improve outcomes of the ACHD patient with (sub)acute heart failure. This review focuses on the management of (sub)acute heart failure in ACHD with specific attention to lesion-specific issues. PMID- 29277862 TI - Pan-Genome Storage and Analysis Techniques. AB - Computational pan-genome analysis has emerged from the rapid increase of available genome sequencing data. Starting from a microbial pan-genome, the concept has spread to a variety of species, such as plants or viruses. Characterizing a pan-genome provides insights into intra-species evolution, functions, and diversity. However, researchers face challenges such as processing and maintaining large datasets while providing accurate and efficient analysis approaches. Comparative genomics methods are required for detecting conserved and unique regions between a set of genomes. This chapter gives an overview of tools available for indexing pan-genomes, identifying the sub-regions of a pan-genome and offering a variety of downstream analysis methods. These tools are categorized into two groups, gene-based and sequence-based, according to the pan genome identification method. We highlight the differences, advantages, and disadvantages between the tools, and provide information about the general workflow, methodology of pan-genome identification, covered functionalities, usability and availability of the tools. PMID- 29277863 TI - Comparative Genomics for Prokaryotes. AB - Bacteria and archaea, collectively known as prokaryotes, have in general genomes that are much smaller than those of eukaryotes. As a result, thousands of these genomes have been sequenced. In prokaryotes, gene architecture lacks the intron exon structure of eukaryotic genes (with an occasional exception). These two facts mean that there is an abundance of data for prokaryotic genomes, and that they are easier to study than the more complex eukaryotic genomes. In this chapter, we provide an overview of genome comparison tools that have been developed primarily (sometimes exclusively) for prokaryotic genomes. We cover methods that use only the DNA sequences, methods that use only the gene content, and methods that use both data types. PMID- 29277864 TI - Assembly, Annotation, and Comparative Genomics in PATRIC, the All Bacterial Bioinformatics Resource Center. AB - In the "big data" era, research biologists are faced with analyzing new types that usually require some level of computational expertise. A number of programs and pipelines exist, but acquiring the expertise to run them, and then understanding the output can be a challenge.The Pathosystems Resource Integration Center (PATRIC, www.patricbrc.org ) has created an end-to-end analysis platform that allows researchers to take their raw reads, assemble a genome, annotate it, and then use a suite of user-friendly tools to compare it to any public data that is available in the repository. With close to 113,000 bacterial and more than 1000 archaeal genomes, PATRIC creates a unique research experience with "virtual integration" of private and public data. PATRIC contains many diverse tools and functionalities to explore both genome-scale and gene expression data, but the main focus of this chapter is on assembly, annotation, and the downstream comparative analysis functionality that is freely available in the resource. PMID- 29277865 TI - Phylogenomics. AB - Phylogenomics aims at reconstructing the evolutionary histories of organisms taking into account whole genomes or large fractions of genomes. The abundance of genomic data for an enormous variety of organisms has enabled phylogenomic inference of many groups, and this has motivated the development of many computer programs implementing the associated methods. This chapter surveys phylogenetic concepts and methods aimed at both gene tree and species tree reconstruction while also addressing common pitfalls, providing references to relevant computer programs. A practical phylogenomic analysis example including bacterial genomes is presented at the end of the chapter. PMID- 29277866 TI - Comparative Genome Annotation. AB - Newly sequenced genomes are being added to the tree of life at an unprecedented fast pace. Increasingly, such new genomes are phylogenetically close to previously sequenced and annotated genomes. In other cases, whole clades of closely related species or strains ought to be annotated simultaneously. Often, in subsequent studies differences between the closely related species or strains are in the focus of research when the shared gene structures prevail. We here review methods for comparative structural genome annotation. The reviewed methods include classical approaches such as the alignment of protein sequences or protein profiles against the genome and comparative gene prediction methods that exploit a genome alignment to annotate a target genome. Newer approaches such as the simultaneous annotation of multiple genomes are also reviewed. We discuss how the methods depend on the phylogenetic placement of genomes, give advice on the choice of methods, and examine the consistency between gene structure annotations in an example. Further, we provide practical advice on genome annotation in general. PMID- 29277867 TI - A Practical Guide for Comparative Genomics of Mobile Genetic Elements in Prokaryotic Genomes. AB - Mobile genetic elements (MGEs) are an important feature of prokaryote genomes but are seldom well annotated and, consequently, are often underestimated. MGEs include transposons (Tn), insertion sequences (ISs), prophages, genomic islands (GEIs), integrons, and integrative and conjugative elements (ICEs). They are intimately involved in genome evolution and promote phenomena such as genomic expansion and rearrangement, emergence of virulence and pathogenicity, and symbiosis. In spite of the annotation bottleneck, there are so far at least 75 different programs and databases dedicated to prokaryotic MGE analysis and annotation, and this number is rapidly growing. Here, we present a practical guide to explore, compare, and visualize prokaryote MGEs using a combination of available software and databases tailored to small scale genome analyses. This protocol can be coupled with expert MGE annotation and exploited for evolutionary and comparative genomic analyses. PMID- 29277868 TI - Comparative Metagenomics. AB - Thanks in large part to newer, better, and cheaper DNA sequencing technologies, an enormous number of metagenomic sequence datasets have been and continue to be generated, covering a huge variety of environmental niches, including several different human body sites. Comparing these metagenomes and identifying their commonalities and differences is a challenging task, due not only to the large amounts of data, but also because there are several methodological considerations that need to be taken into account to ensure an appropriate and sound comparison between datasets. In this chapter, we describe current techniques aimed at comparing metagenomes generated by 16S ribosomal RNA and shotgun DNA sequencing, emphasizing methodological issues that arise in these comparative studies. We provide a detailed case study to illustrate some of these techniques using data from the Human Microbiome Project comparing the microbial communities from ten buccal mucosa samples with ten tongue dorsum samples in terms of alpha diversity, beta diversity, and their taxonomic and functional profiles. PMID- 29277869 TI - Genome Rearrangement Analysis: Cut and Join Genome Rearrangements and Gene Cluster Preserving Approaches. AB - Genome rearrangements are mutations that change the gene content of a genome or the arrangement of the genes on a genome. Several years of research on genome rearrangements have established different algorithmic approaches for solving some fundamental problems in comparative genomics based on gene order information. This review summarizes the literature on genome rearrangement analysis along two lines of research. The first line considers rearrangement models that are particularly well suited for a theoretical analysis. These models use rearrangement operations that cut chromosomes into fragments and then join the fragments into new chromosomes. The second line works with rearrangement models that reflect several biologically motivated constraints, e.g., the constraint that gene clusters have to be preserved. In this chapter, the border between algorithmically "easy" and "hard" rearrangement problems is sketched and a brief review is given on the available software tools for genome rearrangement analysis. PMID- 29277870 TI - Whole Genome Duplication in Plants: Implications for Evolutionary Analysis. AB - The recurrent cycle of whole genome duplication (WGD) followed by massive duplicate gene loss (fractionation) differentiates plant evolutionary history from that of most other phylogenetic domains, where WGD has occurred relatively rarely, even on an evolutionary time scale. We discuss the mechanism of WGD and its biological consequences. We survey the prevalence of WGD in the flowering plants. We outline some of the major kinds of combinatorial optimization problems arising in computational biology for analyzing WGD. Fractionation and its consequences are the subject of mathematical modeling questions and further combinatorial algorithms. A strong connection is made between WGD in phylogenetic context and the theory of gene trees and species trees. We illustrate the analysis of WGD with studies involving a large number of sequenced plant genomes, including grape, the crucifers and other rosids, the asterid tomato, the eudicot Nelumbo nucifera and pineapple, a monocot. PMID- 29277871 TI - Sequence-Based Synteny Analysis of Multiple Large Genomes. AB - Current methods for synteny analysis provide only limited support to study large genomes at the sequence level. In this chapter, we describe a pipeline based on existing tools that, applied in a suitable fashion, enables synteny analysis of large genomic datasets. We give a hands-on description of each step of the pipeline using four avian genomes for data. We also provide integration scripts that simplify the conversion and setup of data between the different tools in the pipeline. PMID- 29277872 TI - Family-Free Genome Comparison. AB - The comparison of genome structures across distinct species offers valuable insights into the species' phylogeny, genome organization, and gene associations. In this chapter, we review the family-free genome comparison tool FFGC which provides several methods for gene order analyses that do not require prior knowledge of evolutionary relationships between the genes across the studied genomes. Moreover, the tool features a complete workflow for genome comparison, requiring nothing but annotated genome sequences as input. PMID- 29277873 TI - Comparative Methods for Reconstructing Ancient Genome Organization. AB - Comparative genomics considers the detection of similarities and differences between extant genomes, and, based on more or less formalized hypotheses regarding the involved evolutionary processes, inferring ancestral states explaining the similarities and an evolutionary history explaining the differences. In this chapter, we focus on the reconstruction of the organization of ancient genomes into chromosomes. We review different methodological approaches and software, applied to a wide range of datasets from different kingdoms of life and at different evolutionary depths. We discuss relations with genome assembly, and potential approaches to validate computational predictions on ancient genomes that are almost always only accessible through these predictions. PMID- 29277874 TI - Comparative RNA Genomics. AB - Over the last two decades it has become clear that RNA is much more than just a boring intermediate in protein expression. Ancient RNAs still appear in the core information metabolism and comprise a surprisingly large component in bacterial gene regulation. A common theme with these types of mostly small RNAs is their reliance of conserved secondary structures. Large scale sequencing projects, on the other hand, have profoundly changed our understanding of eukaryotic genomes. Pervasively transcribed, they give rise to a plethora of large and evolutionarily extremely flexible noncoding RNAs that exert a vastly diverse array of molecule functions. In this chapter we provide a-necessarily incomplete-overview of the current state of comparative analysis of noncoding RNAs, emphasizing computational approaches as a means to gain a global picture of the modern RNA world. PMID- 29277875 TI - Bioinformatic Approaches for Comparative Analysis of Viruses. AB - The field of viral genomic studies has experienced an unprecedented increase in data volume. New strains of known viruses are constantly being added to the GenBank database and so are completely new species with little or no resemblance to our databases of sequences. In addition to this, metagenomic techniques have the potential to further increase the number and rate of sequenced genomes. Besides, it is important to consider that viruses have a set of unique features that often break down molecular biology dogmas, e.g., the flux of information from RNA to DNA in retroviruses and the use of RNA molecules as genomes. As a result, extracting meaningful information from viral genomes remains a challenge and standard methods for comparing the unknown and our databases of characterized sequences may need to be modified. Thus, several bioinformatic approaches and tools have been created to address the challenge of analyzing viral data. In this chapter, we offer descriptions and protocols of some of the most important bioinformatic techniques for comparative analysis of viruses. We also provide comments and discussion on how viruses' unique features can affect standard analyses and how to overcome some of the major sources of problems. Topics include: (1) Clustering of related genomes, (2) Whole genome multiple sequence alignments for small RNA viruses, (3) Protein alignments for marker genes, (4) Analyses based on ortholog groups, and (5) Taxonomic identification and comparisons of viruses from environmental datasets. PMID- 29277876 TI - Comparative Genomics of Gene Loss and Gain in Caenorhabditis and Other Nematodes. AB - Nematodes, such as Caenorhabditis elegans, form one of the most species-rich animal phyla. By now more than 30 nematode genomes have been published allowing for comparative genomic analyses at various different time-scales. The majority of a nematode's gene repertoire is represented by either duplicated or so-called orphan genes of unknown origin. This indicates the importance of mechanisms that generate new genes during the course of evolution. While it is certain that nematodes have acquired genes by horizontal gene transfer from various donors, this process only explains a small portion of the nematode gene content. As evolutionary genomic analyses strongly support that most orphan genes are indeed protein-coding, future studies will have to decide, whether they are result from extreme divergence or evolved de novo from previously noncoding sequences. In this contribution, I summarize several studies investigating gene loss and gain in nematodes and discuss the strengths and weaknesses of individual approaches and datasets. These approaches can be used to ask nematode-specific questions such as associated with the evolution of parasitism or with switches in mating systems, but also can complement studies in other animal phyla like vertebrates and insects to broaden our general view on genome evolution. PMID- 29277877 TI - Comparative Genomics in Drosophila. AB - Since the pioneering studies of Thomas Hunt Morgan and coworkers at the dawn of the twentieth century, Drosophila melanogaster and its sister species have tremendously contributed to unveil the rules underlying animal genetics, development, behavior, evolution, and human disease. Recent advances in DNA sequencing technologies launched Drosophila into the post-genomic era and paved the way for unprecedented comparative genomics investigations. The complete sequencing and systematic comparison of the genomes from 12 Drosophila species represents a milestone achievement in modern biology, which allowed a plethora of different studies ranging from the annotation of known and novel genomic features to the evolution of chromosomes and, ultimately, of entire genomes. Despite the efforts of countless laboratories worldwide, the vast amount of data that were produced over the past 15 years is far from being fully explored.In this chapter, we will review some of the bioinformatic approaches that were developed to interrogate the genomes of the 12 Drosophila species. Setting off from alignments of the entire genomic sequences, the degree of conservation can be separately evaluated for every region of the genome, providing already first hints about elements that are under purifying selection and therefore likely functional. Furthermore, the careful analysis of repeated sequences sheds light on the evolutionary dynamics of transposons, an enigmatic and fascinating class of mobile elements housed in the genomes of animals and plants. Comparative genomics also aids in the computational identification of the transcriptionally active part of the genome, first and foremost of protein-coding loci, but also of transcribed nevertheless apparently noncoding regions, which were once considered "junk" DNA. Eventually, the synergy between functional and comparative genomics also facilitates in silico and in vivo studies on cis-acting regulatory elements, like transcription factor binding sites, that due to the high degree of sequence variability usually impose increased challenges for bioinformatics approaches. PMID- 29277878 TI - Comparative Genomics in Homo sapiens. AB - Genomes can be compared at different levels of divergence, either between species or within species. Within species genomes can be compared between different subpopulations, such as human subpopulations from different continents. Investigating the genomic differences between different human subpopulations is important when studying complex diseases that are affected by many genetic variants, as the variants involved can differ between populations. The 1000 Genomes Project collected genome-scale variation data for 2504 human individuals from 26 different populations, enabling a systematic comparison of variation between human subpopulations. In this chapter, we present step-by-step a basic protocol for the identification of population-specific variants employing the 1000 Genomes data. These variants are subsequently further investigated for those that affect the proteome or RNA splice sites, to investigate potentially biologically relevant differences between the populations. PMID- 29277880 TI - Robot Assisted Radical Prostatectomy in A Patient with Previous Abdominoperineal Resection and Pelvic External Beam Radiation Therapy. AB - Though previous major abdominal surgery and pelvic irradiation may be a significant drawback of subsequent laparoscopic procedure, technological advances such as better visualization and more controlled finer movementsof robotic arms allowing better dissection in robotic-assisted laparoscopic surgery may reduce some of these challenges. However, limited data are available on the effect and safety of robotic surgery in these patients. The aim of this case report is to present efficacy and safety of robot assisted radical prostatectomy in a patient who has rectal and concurrent prostate cancer with the history of abdominoperineal resection, pelvic irradiation and adjuvantchemotherapy. PMID- 29277879 TI - Trigonelline insulates against oxidative stress, proinflammatory cytokines and restores BDNF levels in lipopolysaccharide induced cognitive impairment in adult mice. AB - Neuroinflammation is said to play a pivotal role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). Trigonelline (TRG) is a naturally occurring alkaloid, commonly isolated from fenugreek and coffee beans. In the present study, we investigated whether TRG exerts neuroprotective action against LPS mediated cognitive impairment. Mice pretreated with TRG (50 and 100 mg/kg po) were administered with LPS (250 MUg/kg ip) for 7 days. Memory was assessed in the Morris water maze (MWM) and Y maze. LPS administration caused poor memory retention in MWM and Y maze paradigms, and resulted in marked oxidative stress as evidenced by decrease in superoxide dismutase (SOD), reduced glutathione (GSH) levels and increased lipid peroxidation in the hippocampus and cortex. Cholinergic involvement during neuroinflammation was evaluated by measuring levels of acetylcholinesterase (AChE) enzyme. TRG treatment at both the doses reversed LPS induced behavioral and memory disturbances, significantly decreased the oxidative stress and AChE levels in both the hippocampus and cortex. LPS administration also elevated the tumour necrosis factor (TNF-alpha) and interleukin -6 (IL-6) levels, whereas brain derived neurotrophic factor (BDNF) levels were significantly depleted. TRG pretreatment led to decreased TNF alpha and IL-6 levels and caused a significant upregulation of BDNF levels. In conclusion, present study highlights the promising neuroprotective role of TRG against LPS mediated cognitive impairment which could be attributed to reduced oxidative stress, inhibition of proinflammatory cytokines and restoration of BDNF levels. PMID- 29277881 TI - Quantitative Mineralogical Composition of Calculi and Urine Abnormalities for Calcium Oxalate Stone Formers: A Single-Center Results. AB - PURPOSE: The paper focuses on the relationship of risk factors and metabolic disorders with mineralogical composition of calculi, age and gender of calcium oxalate stone formers. MATERIALS AND METHODS: Stone mineralogical composition, 24 hour biochemistry and pH-profile of urine were examined for sixty four stone formers using powder X-ray diffraction, spectrophotometric and potentiometric techniques. RESULTS: The analysis indicated that 44 % of calculi were composed of pure calcium oxalate monohydrate, whereas other 56 % contained both monohydrate and dihydrate or usually their mixtures with hydroxyl apatite. Hypocitraturia, hypercalciuria and hyperuricosuria were identified as the most frequent disorders. Patients with pure calcium oxalate stones and calcium oxalate mixed with apatite revealed different patterns including age, acid-base balance of urine, calcium, citrate excretion etc.Conclusions: Our results demonstrate that most patients simultaneously reveal several risk factors. The special attention should be paid to normalize the daily citrate, calcium and urate excretion. High risk patients, such as postmenopausal females or stone formers with a high apatite content require a specific metabolic evaluation towards in highlighting abnormalities associated with stone formation. PMID- 29277882 TI - Mesalazine: A Novel Etiology For Drug-Induced Urinary Calculi. AB - We report the case of a 23-year-old woman treated by mesalazine for ulcerative colitis and who subsequently presented recurrent renal colic due to mesalazine urinary stones. This is the second case described in the literature.Mesalazine stones are soft, friable and have an orange-beige color. They are not visible on non-contrast computed tomography (CT). Their diagnosis is based on morpho constitutional analysis and CT-urography. Patients treatedby mesalazine who present renal colic should undergo CT-urography in order to make the diagnosis. PMID- 29277883 TI - Effects of Different Anesthetic Agents on Surgical Site Hemorrhage During Circumcision. AB - PURPOSE: To investigate the effects of ketamine+midazolam and propofol+sevoflurane anesthesia on surgical site hemorrhage during circumcision procedures. MATERIALS AND METHODS: The boys undergoing circumcision surgery were included in the study. The patients were divided into two groups. In Group 1 (n = 50), 0.01 mg/kg midazolam and 2 mg/kg IV ketamine were administered. In Group 2 (n = 50), 1 ?g/kg fentanyl, 1 mg/kg lidocaine 2%, and 2-3 mg/kg IV propofol were administered, and patency of airway was ensured with a laryngeal mask airway. The intraoperative bleeding scale was recorded during the procedure to evaluate surgical site bleeding. Hemorrhage was checked for the first three hours using the postoperative bleeding scale to follow the amount of hemorrhage. RESULTS: Intraoperative bleeding scores were significantly higher in Group 1 as compared to Group 2. However, there was no significant difference between the groups regarding frequency of postoperative hemorrhage. Themean blood pressure values measured at 5th, 10th, 15th minutes and recovery room were significantly higher in Group 1. CONCLUSION: The intraoperative bleeding scores were significantly higher with ketamine+midazolam compared to propofol+sevoflurane. On the other hand this hemorrhage can be controlled easily with appropriate hemostasis, and the amount of blood loss was not clinically significant. We think that our study makes a positive contribution to the literature about the effects of anesthetics on the surgical site bleeding during circumcision. CLINICAL TRIALS REGISTRATION: ACTRN12616000189426. PMID- 29277884 TI - Penile Glans Necrosis Developing after Internal Pudendal Arterial Embolization: A Case Report. AB - Penile glans ischemia or necrosis developing after internal pudendal arterial embolization is very rare; no relevantreport has yet appeared. A 53-year-old male who visited our emergency room because of massive urethral bleedingwas diagnosed with an internal pudendal artery-urethral fistula; he underwent selective embolization of the internalpudendal artery. However, unexpected penile glans ischemic necrosis developed after embolization. We successfullytreated the patients with intravenous infusion of alprostadil, oral pentoxifylline and tadalafil. PMID- 29277885 TI - Different Strains of BK Polyomavirus: VP1 Sequences in a Group of Iranian Prostate Cancer Patients. AB - PURPOSE: BK virus (BKV) has a worldwide seroprevalence in humans. Based on sequences of the major capsid proteins, i.e. viral protein 1 (VP1), there are four BKV genotypes. Each genotype has its own subtypes, and wasshown to be circulating independently in the human population. The aim of this study was to determine BKVgenotypes and subtypes among Iranian patients with prostatic cancer, benign prostatic hyperplasia, and kidney transplantation. MATERIALS AND METHODS: BKV DNA was extracted from prostatic cancers and benign prostatic hyperplasia blocks and also urine of kidney transplantation patients. BKV (VP1) gene was amplified partially (327nt) by homemade polymerase chain reactions and subjected for sequencing and phylogenetic analysis. Bioedit version 7.0 and Mega version 5.0 were used for sequence analysis and for comparing the results with world driven BKV sequences. RESULTS: All of BKV VP1 genes which were derived from Iranian patients were classified with subtype 1b2 strains from Germany and Turkey. Predicted amino acid sequences from the studied region of VP1 showed that all of these nucleotide diversities could change amino acid sequence numbers 60, 68, 72, 73 and 82 among VP1. CONCLUSION: The interesting point was that genetic analysis of derived sequences showed a different feature of genetic diversity among Iranian sequences. This feature has not been reported yet. This characteristic feature of Iranian BKV VP1 gene provides a unique cluster of sequences in phylogenetic tree. PMID- 29277886 TI - The Respiratory Induced Kidney Motion: Does It Really Effect the Shock Wave Lithotripsy? AB - PURPOSE: To investigate the effect of respiratory induced kidney mobility on success of shock wave lithotripsy (SWL) with an electrohydraulic lithotripter. MATERIALS AND METHODS: Between May 2013 and April 2015, 158 patients underwent SWL treatment for kidney stones with an electrohydraulic lithotripter. The exclusion criteria were presence of a known metabolic disease (such as cystinuria), non-opaque stones, need for focusing with ultrasonography, abnormal habitus, urinary tract abnormalities, and inability to tolerate SWL until the end of the procedure. Stones greater than 20 mm, and lower pole stones were also excluded. The movement of the kidneys were measured with fluoroscopy guidance. RESULTS: The procedure was successful in 66.7% of the males, and 56.9% of the females. The mean stone size was 11 +/- 3 mm in the successful group, and it was 14 +/- 4 mm in the unsuccessful group. The mean stone mobility rate was 32 +/- 10 in the successful group and 40 +/- 11 in the unsuccessful group. Multivariate analysis showed that stone size and kidney mobility affected the success rate significantly, however Hounsfield Unit (HU) did not. CONCLUSION: The current study shows the significant effect of kidney motion on the success of SWL. Further studies with different lithotripters are needed to determine the significance of kidney mobility. PMID- 29277887 TI - The Safety and Efficacy of Adjuvant Hemostatic Agents During Laparoscopic Nephron Sparing Surgery: Comparison of Tachosil and Floseal Versus No Hemostatic Agents. AB - PURPOSE: To compare the effectiveness of TachoSil and Floseal during laparoscopic nephron-sparing surgery (LNSS), and to evaluate postoperative complications, especially hemorrhage and urinary leakage. MATERIALS AND METHODS: The medical records of all patients that underwent LNSS for a small renal mass (SRM) performed by the same experienced surgeon were retrospectively analyzed. The patients were divided into the following 3 groups, based on hemostatic agent: group 1: no adjuvant hemostatic agent (no AHA); group 2: TachoSil; group 3: Floseal. RESULTS: The study included 79 patients; no AHA group: n = 18; TachoSil group: n = 25; Floseal group: n = 36. The 3 groups were similar in terms of diameter [29.6 +/- 11.5 mm, 26.4 +/- 13.4 mm and 30.4 +/- 9.6 mm, respectively (P = .218)] and PADUA scores [6.9 +/- 0.9, 6.7 +/- 1 and 6.9 +/- 0.9, respectively (P =.540)]. Mean duration of surgery was significantly shorter in the Floseal group (120.9 +/- 23.1 minutes) than in the no AHA group (156.6 +/- 34.4 minutes). Mean ischemia time was longest in the no AHA group (24.3 +/- 4 minutes) and shortest in the Floseal group(21.3 +/- 4.3 minutes). Intra-abdominal (IA) catheter drainage on postoperative day 1 was significantly higher in the no AHA group thanin the TachoSil and Floseal groups [156.9 +/-78.3 mL vs. 72.6 +/- 64.5 and 60.8 +/- 30.2 mL, respectively (P < .05)]. Mean duration of hospitalization was 3.2 +/- 0.5 days in the no AHA group that was significantly longer than in the Floseal group (2.8 +/- 0.7 days) (P = .043). There were not any differences in intraoperative complications, the transfusion rate, surgical margin positivity, or postoperative complications between the 3 groups (P = .596, P =.403, P = 1.0, P = .876, respectively). However, pseudoaneurism as a late term complication occurred in 27.7% patients in the no AHA group. CONCLUSION: TachoSil and Floseal are safe and effective adjuvant treatments for patients undergoing LNSS. They might be useful especially in preventing pseudo aneurisms, shortening intraoperative ischemia time and hospital stay and decreasing postoperative drainage. Shortened operation and warm ischemia time may also be attributed to long learning curve of LNSS. PMID- 29277888 TI - Survivin is a novel transcription regulator of KIT and is downregulated by miRNA 494 in gastrointestinal stromal tumors. AB - Gain-of-function mutations of KIT are pathognomonic in sporadic gastrointestinal stromal tumors (GISTs). Several microRNAs have been shown to be dysregulated in GISTs and impact KIT expression. Little is known though on KIT-independent targets of KIT-regulating mRNAs. We sought to investigate how miR-494 inhibits GIST proliferation and to identify novel target gene. We used microarray-based gene expression analyses to identify pathways and target genes affected by miR 494. The expressional relationship between survivin and miR-494 was determined in 35 GIST tissues. Cell proliferation assay, FACS analysis, colony formation assay, promoter assays and chromatin immunoprecipitation (ChiP) were performed to clarify the roles of survivin in GIST progression. Gene expression microarray analysis revealed that miR-494 inhibited GISTs by affecting multiple genes in the cell cycle pathway. Survivin (BIRC5) was a key target of miR-494, and its expression showed an inverse correlation with miR-494 expression in 35 GIST tissues (Pearson's correlation coefficient, r = -0.418, p = 0.012). Downregulation of survivin inhibited proliferation and colony formation, and resulted in cell cycle alteration. Induced survivin overexpression relieved miR 494-mediated inhibition of GIST progression. Targeting PI3K effectively suppressed proliferation of GISTs with downregulation of survivin. Survivin also regulated KIT expression at the transcription level. Immunohistochemical analysis using 113 GISTs revealed that survivin expression was significantly correlated with overall survival of GIST patients (p = 0.004). Our findings indicated that miR-494 synergistically suppressed GISTs by concomitantly targeting survivin and KIT. PMID- 29277889 TI - RhoA-stimulated intra-capillary morphology switch facilitates the arrest of individual circulating tumor cells. AB - Metastasis is the primary cause of death for most cancer patients. Hematogenous arrest of circulating tumor cells (CTCs) is an essential prerequisite for metastases formation. Using transparent transgenic zebrafish (kdrl:eGFP; Casper), together with resonant laser scanning confocal microscopy, we tracked the fate of CTCs in vivo in the blood circulation for days. We found the intra-capillary morphology-switch (ICMS) of individual CTCs from strip to sphere was necessary for their intravascular arrests. Further genetic and pharmacological inhibition experiments indicated that the RhoA signaling was necessary for ICMS and the arrest of CTCs. At last, we demonstrated that early treatment by a clinically approved RhoA/ROCK inhibitor, Fasudil, could efficiently inhibit the initial arrest of individual CTCs and reduce the incidence of tumor metastasis in both zebrafish and mouse models. These results together indicate that RhoA-stimulated ICMS represents a mechanism for the arrest of individual CTCs, providing a potential target for future treatments of hematogenous metastatic disease. PMID- 29277890 TI - Rethinking "normal": The role of stochasticity in the phenology of a synchronously breeding seabird. AB - Phenological changes have been observed in a variety of systems over the past century. There is concern that, as a consequence, ecological interactions are becoming increasingly mismatched in time, with negative consequences for ecological function. Significant spatial heterogeneity (inter-site) and temporal variability (inter-annual) can make it difficult to separate intrinsic, extrinsic and stochastic drivers of phenological variability. The goal of this study was to understand the timing and variability in breeding phenology of Adelie penguins under fixed environmental conditions and to use those data to identify a "null model" appropriate for disentangling the sources of variation in wild populations. Data on clutch initiation were collected from both wild and captive populations of Adelie penguins. Clutch initiation in the captive population was modelled as a function of year, individual and age to better understand phenological patterns observed in the wild population. Captive populations displayed as much inter-annual variability in breeding phenology as wild populations, suggesting that variability in breeding phenology is the norm and thus may be an unreliable indicator of environmental forcing. The distribution of clutch initiation dates was found to be moderately asymmetric (right skewed) both in the wild and in captivity, consistent with the pattern expected under social facilitation. The role of stochasticity in phenological processes has heretofore been largely ignored. However, these results suggest that inter-annual variability in breeding phenology can arise independent of any environmental or demographic drivers and that synchronous breeding can enhance inherent stochasticity. This complicates efforts to relate phenological variation to environmental variability in the wild. Accordingly, we must be careful to consider random forcing in phenological processes, lest we fit models to data dominated by random noise. This is particularly true for colonial species where breeding synchrony may outweigh each individual's effort to time breeding with optimal environmental conditions. Our study highlights the importance of identifying appropriate null models for studying phenology. PMID- 29277891 TI - Fluorescence- and multispectral optoacoustic imaging for an optimized detection of deeply located tumors in an orthotopic mouse model of pancreatic carcinoma. AB - A crucial point for the management of pancreatic ductal adenocarcinoma (PDAC) is the decrease of R1 resections. Our aim was to evaluate the combination of multispectral optoacoustic tomography (MSOT) with fluorescence guided surgery (FGS) for diagnosis and perioperative detection of tumor nodules and resection margins in a xenotransplant mouse model of human pancreatic cancer. The peptide cRGD, conjugated with the near infrared fluorescent (NIRF) dye IRDye800CW and with a trans-cyclooctene (TCO) tag for future click chemistry (cRGD-800CW-TCO), was applied to PDAC bearing immunodeficient nude mice; 27 days after orthotopic transplantation of human AsPC-1 cells into the head of the pancreas, mice were injected with cRGD-800CW-TCO and imaged with fluorescence- and optoacoustic devices before and 2, 6 and 24 hr after injection, before they were sacrificed and dissected with a guidance of FGS imaging system. Fluorescence imaging of cRGD 800CW-TCO allowed detection of the tumor area but without information about the depth, whereas MSOT allowed high resolution 3 D identification of the tumor area, in particular of small tumor nodules. Highly sensitive delineation of tumor burden was achieved during FGS in all mice. Imaging of whole-mouse cryosections, histopathological analysis and NIRF microscopy confirmed the localization of cRGD 800CW-TCO within the tumor tissue. In principle, all imaging modalities applied here were able to detect PDAC in vivo. However, the combination of MSOT and FGS provided detailed spatial information of the signal and achieved a complete overview of the distribution and localization of cRGD-800CW-TCO within the tumor before and during surgical intervention. PMID- 29277892 TI - Challenges and Opportunities in the Development of Medical Therapies for Pediatric Populations and the Role of Extrapolation. AB - Extrapolation can be used to address challenges in pediatric drug development. This review describes how these challenges could be addressed by further evolution of quantitative frameworks (i.e., model-based/informed drug discovery and development) and regulatory science in support of pediatric drug development. Included are examples of diseases/indications where extrapolation has been used in different ways as a basis for identifying gaps in the framework and opportunities for continued advancement of pediatric drug development. PMID- 29277893 TI - DCLK1 promotes epithelial-mesenchymal transition via the PI3K/Akt/NF-kappaB pathway in colorectal cancer. AB - Double cortin-like kinase 1 (DCLK1) plays important roles during the epithelial mesenchymal transition (EMT) process in human colorectal cancer (CRC). However, the role of DCLK1 in regulating the EMT of CRC is still poorly understood. In this study, we report evidence that DCLK1 acts as a potent oncogene to drive its extremely malignant character of EMT in an NF-kappaB-dependent manner in CRC cells. Mechanistic investigations showed that DCLK1 induced the NF-kappaBp65 subunit expression through the PI3K/Akt/Sp1 axis and activated NF-kappaBp65 through the PI3K/Akt/IkappaBalpha pathway during the EMT of CRC cells. Moreover, we found that silencing the expression of DCLK1 inhibited the invasion and metastasis of CRC cells in vivo. Collectively, our findings identify DCLK1 as a pivotal regulator of an EMT axis in CRC, thus implicating DCLK1 as a potential therapeutic target for CRC metastasis. PMID- 29277894 TI - The sphingosine kinase 2 inhibitor ABC294640 displays anti-non-small cell lung cancer activities in vitro and in vivo. AB - Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, and is the number one killer among cancers in the United States. The majorities of lung cancer patients do not respond well to conventional chemo- and/or radio-therapeutic regimens, and have a dismal 5-year survival rate of ~15%. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but even with these agents, not all patients respond, and responses are rarely complete. Thus, there is still an urgent need to identify new therapeutic targets in NSCLC and develop novel anti-cancer agents. Sphingosine kinase 2 (SphK2) is one of the key enzymes in sphingolipid metabolism. SphK2 expression predicts poor survival in NSCLC patients, and is associated with Gefitinib-resistance. In this study, the anti-NSCLC activities of ABC294640, the only first-in-class orally available inhibitor of SphK2, were explored. The results obtained indicate that ABC294640 treatment causes significant NSCLC cell apoptosis, cell cycle arrest and suppression of tumor growth in vitro and in vivo. Moreover, lipidomics analyses revealed the complete signature of ceramide and dihydro(dh)-ceramide species in the NSCLC cell-lines with or without ABC294640 treatment. These findings indicate that sphingolipid metabolism targeted therapy may be developed as a promising strategy against NSCLC. PMID- 29277896 TI - C5aR activation in the absence of C5a: A new disease mechanism of autoimmune hemolytic anemia in mice. AB - IgG Fc receptors (FcgammaRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease. Ex-vivo-analyses of liver homogenates from anemic Hc0 mice demonstrate C5a-independent C5aR activation, upregulation of FcgammaR expression and amplification of erythrophagocytosis by macrophages. As assessed by pharmacological inhibition studies, targeting of C5aR, but not of C5, is effective in treating experimental AIHA. Collectively, these results define a previously unrecognized disease mechanism of C5aR activation in AIHA that does not necessarily involve C5 and C5a. PMID- 29277895 TI - Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models. AB - Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4-2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub-G1) in VCaP and C4-2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p-EGFR (Y1068), p-AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133-4 patient-derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 MUm2 ) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control-treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors. PMID- 29277897 TI - Quantitative fecal immunochemical tests for colorectal cancer screening. AB - Fecal immunochemical tests (FITs) for hemoglobin (Hb) are increasingly used for colorectal cancer (CRC) screening. We aimed to review, summarize and compare reported diagnostic performance of various FITs. PubMed and Web of Science were searched from inception to July 24, 2017. Data on diagnostic performance of quantitative FITs, conducted in colonoscopy-controlled average-risk screening populations, were extracted. Summary receiver operating characteristic (ROC) curves were plotted and correlations between thresholds, positivity rates (PRs), sensitivities and specificities were assessed. Seven test brands were investigated across 22 studies. Although reported sensitivities for CRC, advanced adenoma (AA) and any advanced neoplasm (AN) varied widely (ranges: 25-100%, 6-44% and 9-60%, respectively), with specificities for AN ranging from 82% to 99%, the estimates were very close to the respective summary ROC curves whose areas under the curve (95% CI) were 0.905 (0.88-0.94), 0.683 (0.67-0.70) and 0.710 (0.70 0.72) for CRC, AA and AN, respectively. The seemingly large heterogeneity essentially reflected variations in test thresholds (range: 2-82 ug Hb/g feces) and showed moderate correlations with sensitivity (r = -0.49) and specificity (r = 0.60) for AN. By contrast, observed PRs (range: 1-21%) almost perfectly correlated with sensitivity (r = 0.84) and specificity (r = -0.94) for AN. The apparent large heterogeneity in diagnostic performance between various FITs can be almost completely overcome by appropriate threshold adjustments. Instead of simply applying the threshold recommended by the manufacturer, screening programs should adjust the threshold to yield a desired PR which is a very good proxy indicator for the specificity and the subsequent colonoscopy workload. PMID- 29277898 TI - Glucose-6-phosphate dehydrogenase inhibition attenuates acute lung injury through reduction in NADPH oxidase-derived reactive oxygen species. AB - Acute lung injury (ALI) is a heterogeneous disease with the hallmarks of alveolar capillary membrane injury, increased pulmonary oedema and pulmonary inflammation. The most common direct aetiological factor for ALI is usually parenchymal lung infection or haemorrhage. Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) are thought to play an important role in the pathophysiology of ALI. Glucose-6-phosphate dehydrogenase (G6PD) plays an important role both in production of ROS as well as their removal through the supply of NADPH. However, how G6PD modulation affects NOX2-mediated ROS in the airway epithelial cells (AECs) during acute lung injury has not been explored previously. Therefore, we investigated the effect of G6PD inhibitor, 6 aminonicotinamide on G6PD activity, NOX2 expression, ROS production and enzymatic anti-oxidants in AECs in a mouse model of ALI induced by lipopolysaccharide (LPS). ALI led to increased G6PD activity in the AECs with concomitant elevation of NOX2, ROS, SOD1 and nitrotyrosine. G6PD inhibitor led to reduction of LPS induced airway inflammation, bronchoalveolar lavage fluid protein concentration as well as NOX2-derived ROS and subsequent oxidative stress. Conversely, ALI led to decreased glutathione reductase activity in AECs, which was normalized by G6PD inhibitor. These data show that activation of G6PD is associated with enhancement of oxidative inflammation in during ALI. Therefore, inhibition of G6PD might be a beneficial strategy during ALI to limit oxidative damage and ameliorate airway inflammation. PMID- 29277899 TI - Proton-independent activation of acid-sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis. AB - BACKGROUND AND PURPOSE: Acid-sensing ion channels (ASICs) play an important role in synaptic plasticity and learning, as well as in nociception and mechanosensation. ASICs are involved in pain and in neurological and psychiatric diseases, but their therapeutic potential is limited by the lack of ligands activating them at physiological pH. EXPERIMENTAL APPROACH: We extracted, purified and determined the structure of a bisbenzylisoquinoline alkaloid, lindoldhamine, (LIN) from laurel leaves. Its effect on ASIC3 channels were characterized, using two-electrode voltage-clamp electrophysiological recordings from Xenopus laevis oocytes. KEY RESULTS: At pH 7.4 or higher, LIN activated a sustained, proton-independent, current through rat and human ASIC3 channels, but not rat ASIC1a or ASIC2a channels. LIN also potentiated proton-induced transient currents and promoted recovery from desensitization in human, but not rat, ASIC3 channels. CONCLUSIONS AND IMPLICATIONS: We describe a novel ASIC subtype-specific agonist LIN, which induced proton-independent activation of human and rat ASIC3 channels at physiological pH. LIN also acts as a positive allosteric modulator of human, but not rat, ASIC3 channels. This unique, species-selective, ligand of ASIC3, opens new avenues in studies of ASIC structure and function, as well as providing new approaches to drug design. PMID- 29277900 TI - Brain maps 4.0-Structure of the rat brain: An open access atlas with global nervous system nomenclature ontology and flatmaps. AB - The fourth edition (following editions in 1992, 1998, 2004) of Brain maps: structure of the rat brain is presented here as an open access internet resource for the neuroscience community. One new feature is a set of 10 hierarchical nomenclature tables that define and describe all parts of the rat nervous system within the framework of a strictly topographic system devised previously for the human nervous system. These tables constitute a global ontology for knowledge management systems dealing with neural circuitry. A second new feature is an aligned atlas of bilateral flatmaps illustrating rat nervous system development from the neural plate stage to the adult stage, where most gray matter regions, white matter tracts, ganglia, and nerves listed in the nomenclature tables are illustrated schematically. These flatmaps are convenient for future development of online applications analogous to "Google Maps" for systems neuroscience. The third new feature is a completely revised Atlas of the rat brain in spatially aligned transverse sections that can serve as a framework for 3-D modeling. Atlas parcellation is little changed from the preceding edition, but the nomenclature for rat is now aligned with an emerging panmammalian neuroanatomical nomenclature. All figures are presented in Adobe Illustrator vector graphics format that can be manipulated, modified, and resized as desired, and freely used with a Creative Commons license. PMID- 29277902 TI - Divergent responsiveness of two isoforms of the estrogen receptor to mixtures of contaminants of emerging concern in four vertebrates. AB - Contaminants of emerging concern (CECs) are ubiquitous in aquatic environments with well-established endocrine-disrupting effects. A data matrix of 559 water samples was queried to identify two commonly occurring CECs mixtures in Great Lakes tributaries. One mixture consisted of eight agricultural CECs (AG), while another contained 11 urban CECs (UB). The known estrogenic compounds bisphenol A, estrone and nonylphenol were present in both mixtures. According to the EPA Tox21 in ToxCast database, AG and UB mixture at an environmentally relevant concentration were estimated to account for 6.5% and 3.4% estrogenicity of the model endocrine disruptor estradiol-17beta, respectively. Two isoforms of the estrogen receptor (Esr1 and -2, former Eralpha and Erbeta) cloned from fathead minnow, bluegill sunfish, American alligator and human, responded differently to AG and UB mixtures. Human and bluegill Esr1 were the most sensitive to AG and UB mixtures, respectively. Fathead minnow Esr1 and Esr2b were the least sensitive to 10* AG and UB in estrogen dose equivalents, respectively. Even at environmentally documented concentrations, UB significantly activated bluegill Esr1. Moreover, 100* concentrated UB hyperstimulated fathead minnow Esr1 beyond the maximum induction of estradiol-17beta. These results indicate that efficacious receptors and species differ in their response to CEC mixtures. Furthermore, estrogenicity may be present in some CECs not previously considered estrogenic, or, alternatively, estrogenicity of a mixture may be enhanced through chemical interactions. Our study highlights the need for further studies of CECs utilizing a variety of receptors cloned from diverse species. PMID- 29277901 TI - Community partnership for healthy sleep: Research protocol. AB - Beginning early in life, sleep health, including adequate quality, quantity, and consistent sleep routines, is critical to growth and development, behavior, and mental and physical health. Children who live in economically stressed urban environments are at particular risk for sleep deficiency and its negative consequences. Although efficacious sleep health interventions are available, few address the context of economically stressed urban environments. The purpose of this paper is to describe a two-phase protocol for an ongoing NIH/NINR-funded community-engaged study designed to understand the perspectives of parents, community child care and pediatric health care providers about sleep habits, factors that contribute to sleep and sleep habits, sleep difficulty, and potentially useful sleep promotion strategies among children living in economically stressed urban environments. The social-ecological model guides this study. Phase I employs a convergent mixed-methods design, in which we are conducting semi-structured interviews with parents, childcare providers, and primary health care providers. We are collecting 9 days of objective sleep data (wrist actigraphy) from children who are 6-18 months (n = 15) and 19-36 months of age (n = 15) and parent reports of sleep and sleep-related factors using standard questionnaires. In Phase I, we will use a qualitative descriptive approach to analyze the interview data, and descriptive statistics to analyze the survey and actigraph data. In Phase II, we will use the information to develop a contextually relevant program to promote sleep health. Our long-term goal is to improve sleep health and sleep-related outcomes in these children. PMID- 29277903 TI - Impact of food processing and simulated gastrointestinal digestion on gliadin immunoreactivity in rolls. AB - BACKGROUND: The enzymatic modification of wheat proteins during dough fermentation and its digestion as supported by peptidases of microbiological origin can result in the degradation of important peptides in the pathogenesis of coeliac disease. However, baking bread and the high temperature associated with this could change the physicochemical and immunological properties of proteins. Thermal changes in the spatial structure of proteins and their hydrolysis can lead to a masking or degrading of immunoreactive peptides. RESULTS: The addition of prolyl endopeptidase (PEP), comprising peptidases isolated from Lactobacillus acidophilus 5e2 (LA) or transglutaminase (TG) in the course of fermentation, decreases its immunoreactivity by 83.9%, 51.9% and 18.5%, respectively. An analysis of the fractional composition of gliadins revealed that gamma- and omega gliadins are the proteins most susceptible to enzymatic modification. Hydrolysis of wheat storage proteins with PEP and LA reduces the content of alphabeta-, gamma- and omega-gliadins by 13.7%, 60.2% and 41.9% for PEP and by 22.1%, 43.5% and 36.9% for LA, respectively. Cross-linking of proteins with TG or their hydrolysis by PEP and LA peptidases during the process of forming wheat dough, followed by digesting bread samples with PEP and LA peptidases, decreases the immunoreactivity of bread hydrolysates from 2.4% to 0.02%. The content of peptide detected in polypeptide sequences is 263.4 +/- 3.3, 30.9 +/- 1.5 and 7.9 +/- 0.4 mg kg-1 in samples of hydrolysates of bread digested with PEP, as produced from dough modified by TG, PEP and LA, respectively. CONCLUSION: Enzymatic pre modification of proteins during the process of dough fermentation decreases their immunoreactive potential, such that fewer peptides recognised by R5 antibodies are released during the digestion process from the bread matrix. Immunoreactive peptides are degraded more effectively when digestive enzymes are supported by the addition of PEP. (c) 2017 Society of Chemical Industry. PMID- 29277904 TI - Antioxidant therapy for muscular dystrophy: caveat lector! PMID- 29277905 TI - Aryl hydrocarbon receptor-based bioassays for dioxin detection: Thinking outside the box. AB - Despite intensive media coverage and international regulations, man-made persistent organic pollutants such as dioxins represent a serious environmental and health threat. Their detection by sophisticated chromatography technologies is highly complex, impeding the constant monitoring of food or environmental samples. This limitation has fostered the development of generations of bioassays exploiting the molecular function of the aryl hydrocarbon receptor (AhR), which binds toxic compounds and directly activates the transcription of target genes. Here, we review the rich panel of available AhR-dependent bioassays and propose a novel classification based on the source of AhR, which can either be endogenously produced by cell types or tissues naturally responsive to dioxins, or exogenously introduced into a wide range of cellular contexts. In both cases, in vitro and in vivo strategies have been engineered to monitor the formation of molecular complexes, and the activation of direct downstream targets or reporter genes. We evaluate and compare bioassays based on exogenous and endogenous AhR proteins and discuss their specific challenges, strengths and opportunities for futures applications. Undoubtedly, the dynamic field of AhR-dependent bioassays will keep providing new and original strategies to help protect human health and ecosystems from persistent organic pollutants. PMID- 29277906 TI - Individual and interpersonal emotion regulation among adults with substance use disorders and matched controls. AB - OBJECTIVES: Self-report studies show that negative emotional states and ineffective use of emotion regulation strategies are key maintaining factors of substance use disorders (SUD). However, experimental research into emotional processing in adults with SUD is in its infancy. Theoretical conceptualizations of emotion regulation have shifted from a focus on individual (internal) processes to one that encompasses social and interpersonal functions - including the regulation of facial expression of emotion. The purpose of this study was to examine the individual and interpersonal emotion regulation capacity of 35 adults in residential treatment diagnosed with a SUD compared to 35 demographically matched controls (both samples Mage = 25 years; 37% females). DESIGN AND METHODS: Participants completed a facial emotion expression flexibility task while viewing emotive images, as well as the Difficulties of Emotion Regulation Scale (DERS) and the Social (Emotion) Expectancy Scale (SES). RESULTS: Adults in SUD treatment experienced significantly more emotion regulation difficulties on all DERS subscales than controls. They also reported higher levels of negative self-evaluation and social expectancies not to feel negative emotions (anxiety and depression) compared to controls. Moreover, when viewing emotive images, the treatment sample showed significantly less flexibility of their emotional expression compared to the control sample. CONCLUSIONS: These findings demonstrate that the awareness, expression, and regulation of emotions are particularly difficult for people with SUD and this may maintain their substance use and provide an important target for treatment. PRACTITIONER POINTS: Compared to matched controls, adults with substance use disorders self-report significantly more difficulties with emotional awareness and regulation. Compared to matched controls, adults with substance use disorders report significantly greater expectancies not to show depression and anxiety. When viewing positive and negative images, adults with substance use disorders are significantly less flexible in their facial expression of emotion than matched controls in response to regulatory instructions. Emotion regulation should be measured and addressed as part of substance use disorder treatment. PMID- 29277908 TI - Mental rotation and the human body: Children's inflexible use of embodiment mirrors that of adults. AB - Adults' mental rotation performance with body-like stimuli is enhanced if these stimuli are anatomically compatible with a human body, but decreased by anatomically incompatible stimuli. In this study, we investigated these effects for kindergartners and first-graders: When asked to mentally rotate cube configurations attached with human body parts in an anatomically compatible way, allowing for the projection of a human body, children performed better than with pure cube combinations. By contrast, when body parts were attached in an anatomically incompatible way, disallowing the projection of a human body, children performed worse than with pure combinations. This experiment is of specific interest against the background of two different theoretical approaches concerning imagery and the motor system in development: One approach assumes an increasing integration of motor processes and imagery over time that enables older children and adults to requisition motor resources for imagery processes, while the other postulates that imagery stems from early sensorimotor processes in the first place, and is disentangled from it over time. The finding that children of the two age groups tested show exactly the same effects as adults when mentally rotating anatomically compatible and incompatible stimuli is interpreted in favour of the latter approach. Statement of contribution What is already known on this subject? In mental rotation, adults perform better when rotating anatomically possible stimuli as compared to rotating standard cube combinations. Performance is worse when rotating anatomically impossible stimuli. What does this study add? The present study shows that children's mental transformations mirror those of adults in these respects. In case of the anatomically impossible stimuli, this highlights an inflexible use of embodiment in both age groups. This is in line with the Piagetian assumption of imagery being based on sensorimotor processes. PMID- 29277907 TI - A multicentre study investigating vital sign changes occurring in complicated and uncomplicated transfusions. AB - BACKGROUND AND OBJECTIVES: Many hospitals require transfusions to be discontinued when vital signs stray from predetermined ranges, regardless of clinical symptoms. Variations in vital signs may be unrelated to transfusion, however, and needlessly stopping a transfusion may delay medical care while increasing donor exposures and healthcare costs. We hypothesized that a detailed study of vital sign changes associated with transfusion of blood product by component, including those associated with potential reactions (complicated) and those deemed to be uncomplicated, would establish a useful framework of reference for treating clinicians and transfusion services alike. MATERIALS AND METHODS: A retrospective electronic record review of transfusion service and transfusion recipient data was completed on 3852 inpatient transfusion episodes over a 6-month period at four academic tertiary care hospitals across the United States. Vital signs pre- and post-transfusion were recorded by trained clinical research nurses. Serious reactions were adjudicated by a panel of transfusion medicine experts. RESULTS: In both uncomplicated transfusions (n = 3765) and those including an adverse reaction (n = 87), vital sign fluctuations were generally modest. Compared to uncomplicated transfusions, transfusions complicated by febrile reactions were associated with higher pretransfusion temperature and higher pretransfusion pulse rates. Episodes of transfusion circulatory overload were associated with higher pretransfusion respiration rates compared to uncomplicated transfusions. CONCLUSION: Most transfusions are associated with only modest changes in vital signs. Pretransfusion vital signs may be an important yet previously understudied predictor of vital sign changes during transfusion. The optimal role of vital sign assessment during blood transfusion deserves further study. PMID- 29277909 TI - Milk adulteration with acidified rennet whey: a limitation for caseinomacropeptide detection by high-performance liquid chromatography. AB - BACKGROUND: High-performance liquid chromatography (HPLC) is widely employed to determine the caseinomacropeptide (CMP) index and to detect milk tampering with rennet whey. Prior to HPLC analysis, CMP is subject to a trichloracetic acid isolation, causing further soluble proteins in the sample to precipitate. On this basis, we aimed to determine whether rennet whey acidification could adversely affect the HPLC sensitivity with respect to detecting this peptide. RESULTS: As hypothesized, the CMP index from milk with added acidified rennet whey was, on average, half that quantified from milk with added rennet whey. Moreover, the quantum satis of acidified whey added to milk sufficient to demonstrate a HPLC CMP > 30 mg L-1 was 94% greater than that required for this threshold to be reached with rennet whey. CONCLUSION: Milk tampering with acidified rennet whey may limit the analytical sensitivity of the reversed-phase HPLC employed for the screening of CMP and, ultimately, disguise the fraudulent addition of whey to milk. (c) 2017 Society of Chemical Industry. PMID- 29277910 TI - Associated factors of umbilical cord blood collection quality. AB - After 30 years of hematopoietic stem cell use for various indications, umbilical cord blood is considered as an established source of cells with marrow and postmobilization peripheral blood. The limited number of cells still remains a problematic element restricting their use, especially in adults who require to be grafted with a higher cell number. Improving the quality of harvested cord blood, at least in terms of volume and amount of cells, is essential to decrease the number of discarded units. In this review, we examine several variables related to parturient, pregnancy, labor, delivery, collection, the newborn, umbilical cord, and placenta. We aim to understand the biologic mechanisms that can impact cord blood quality. This knowledge will ultimately allow targeting donors, which could provide a rich graft and improve the efficiency of the collection. PMID- 29277911 TI - Role of fetal nutrient restriction and postnatal catch-up growth on structural and mechanical alterations of rat aorta. AB - KEY POINTS: Intrauterine growth restriction (IUGR), induced by maternal undernutrition, leads to impaired aortic development. This is followed by hypertrophic remodelling associated with accelerated growth during lactation. Fetal nutrient restriction is associated with increased aortic compliance at birth and at weaning, but not in adult animals. This mechanical alteration may be related to a decreased perinatal collagen deposition. Aortic elastin scaffolds purified from young male and female IUGR animals also exhibit increased compliance, only maintained in adult IUGR females. These mechanical alterations may be related to differences in elastin deposition and remodelling. Fetal undernutrition induces similar aortic structural and mechanical alterations in young male and female rats. Our data argue against an early mechanical cause for the sex differences in hypertension development induced by maternal undernutrition. However, the larger compliance of elastin in adult IUGR females may contribute to the maintenance of a normal blood pressure level. ABSTRACT: Fetal undernutrition programmes hypertension development, males being more susceptible. Deficient fetal elastogenesis and vascular growth is a possible mechanism. We investigated the role of aortic mechanical alterations in a rat model of hypertension programming, evaluating changes at birth, weaning and adulthood. Dams were fed ad libitum (Control) or 50% of control intake during the second half of gestation (maternal undernutrition, MUN). Offspring aged 3 days, 21 days and 6 months were studied. Blood pressure was evaluated in vivo. In the thoracic aorta we assessed gross structure, mechanical properties (intact and purified elastin), collagen and elastin content and internal elastic lamina (IEL) organization. Only adult MUN males developed hypertension (systolic blood pressure: MUNmales = 176.6 +/- 5.6 mmHg; Controlmales = 136.1 +/- 4.9 mmHg). At birth MUN rats were lighter, with smaller aortic cross-sectional area (MUNmales = (1.51 +/- 0.08) * 105 MUm2 , Controlmales = (2.8 +/- 0.04) * 105 MUm2 ); during lactation MUN males and females exhibited catch-up growth and aortic hypertrophy (MUNmales = (14.5 +/- 0.5) * 105 MUm2 , Controlmales = (10.4 +/- 0.9) * 105 MUm2 ), maintained until adulthood. MUN aortas were more compliant until weaning (functional stiffness: MUNmales = 1.0 +/- 0.04; Controlmales = 1.3 +/- 0.03), containing less collagen with larger IEL fenestrae, returning to normal in adulthood. Purified elastin from young MUN offspring was more compliant in both sexes; only MUN adult females maintained larger elastin compliance (slope: MUNfemales = 24.1 +/- 1.9; Controlfemales = 33.3 +/- 2.8). Fetal undernutrition induces deficient aortic development followed by hypertrophic remodelling and larger aortic compliance in the perinatal period, with similar alterations in collagen and elastin in both sexes. The observed alterations argue against an initial mechanical cause for sex differences in hypertension development. However, the maintenance of high elastin compliance in adult females might protect them against blood pressure rise. PMID- 29277912 TI - A hemorrhagic transformation model of mechanical stroke therapy with acute hyperglycemia in mice. AB - Clinical benefit for mechanical thrombectomy (MT) in stroke was recently demonstrated in multiple large prospective studies. Acute hyperglycemia (HG) is an important risk factor of poor outcome in stroke patients, including those that underwent MT. The aim of this therapy is to achieve a complete reperfusion in a short time, given that reperfusion damage is dependent on the duration of ischemia. Here, we investigated the effects of acute HG in a mouse model of ischemic stroke induced by middle cerebral artery occlusion (MCAO). Hyperglycemic (intraperitoneal [ip] injection of glucose) and control (ip saline injection) 10 week male C57BL6 mice were subjected to MCAO (30, 90, and 180 min) followed by reperfusion obtained by withdrawal of the monofilament. Infarct volume, hemorrhagic transformation (HT), neutrophil infiltration, and neurological scores were assessed at 24 hr by performing vital staining, ELISA immunofluorescence, and behavioral test, respectively. Glucose injection led to transient HG (blood glucose = 250-390 mg/dL) that significantly increased infarct volume, HT, and worsened neurological outcome. In addition, we report that HG promoted blood brain barrier disruption as shown by hemoglobin accumulation in the brain parenchyma and tended to increase neutrophil extravasation within the infarcted area. Acute HG increased neurovascular damage for all MCAO durations tested. HTs were observed as early as 90 min after ischemia under hyperglycemic conditions. This model mimics MT ischemia/reperfusion and allows the exploration of brain injury in hyperglycemic conditions. PMID- 29277913 TI - Unrelated donor choices for allogeneic hematopoietic cell transplantation in Canada: an evaluation of factors influencing donor selection. AB - BACKGROUND: Utilization of unrelated donors and cord blood units (CBUs) for allogeneic hematopoietic cell transplantation continues to increase. Understanding the practices of donor selection by transplant centers is critical for unrelated donor registries and cord blood banks to optimize registry composition and inventory to meet patient need. STUDY DESIGN AND METHODS: Unrelated donor and CBU selection practices of Canadian transplant centers served by Canadian Blood Services' OneMatch Stem Cell & Marrow Network (OM) were reviewed, including HLA match level, locus of disparity, age, sex, and product choice (donor vs. CBU). RESULTS: HLA-matched donors within OM and/or international (INT) registries were preferentially investigated, underscoring the primary importance of HLA matching. In the case of HLA-mismatched donors, HLA-A disparities were most common while DRB1 mismatches were least common. Advanced age, sex, and lack of donor availability were the most frequent reasons that high probability OM donors were overlooked in favor of INT donors. High-probability 10 of 10 HLA-matched female donors from OM were often avoided in favor of INT male donors. Use of female donors, however, increased in cases restricted to more HLA disparate donor options. Caucasian patients were more likely to find 10 of 10 matched donors, whereas use of mismatched donors and CBUs were more prevalent among non-Caucasian patients. CONCLUSIONS: Recruitment and retention of young, male donors from diverse ethnic backgrounds may increase the usage of histocompatible OM donors for patients in need. PMID- 29277914 TI - Synaptic localization of the SUMOylation-regulating protease SENP5 in the adult mouse brain. AB - Covalent conjugation of small ubiquitin-like modifiers (SUMOs) or SUMOylation is a reversible post-translational modification that regulates the stability and function of target proteins. SUMOs are removed from substrate proteins by sentrin/SUMO-specific proteases (SENPs). Numerous studies have implicated SUMOylation in various physiological and pathological processes in neurons. To understand the functional roles of SUMOylation, it is necessary to determine the distribution of enzymes regulating SUMO conjugation and deconjugation; yet, the localization of SENPs has not been described in detail in intact brain tissue. Here, we report the distribution and subcellular localization of SENP3 and 5 in the adult murine brain. Immunohistochemical analyses revealed the ubiquitous distribution of both SENPs across different brain regions. Within individual cells, SENP3 was confined to the nucleus, consistent with the conventional view that SENPs regulate nuclear events. In contrast, SENP5 was detected in the neuropil but not in cell bodies. Moreover, strong SENP5 immunoreactivity was observed in regions with high numbers of synapses such as the cerebellar glomeruli, suggesting that SENP5 localizes to pre- and/or postsynaptic structures. We performed double immunolabeling in cultured neurons and found that SENP5 co-localized with pre- and post-synaptic markers, as well as a mitochondrial marker. Immunoelectron microscopy confirmed this finding and revealed that SENP5 was localized to presynaptic terminals, postsynaptic spines, and mitochondria in axon terminals. These findings advance the current understanding of the functional roles of SUMOylation in neurons, especially in synaptic regulation, and have implications for future therapeutic strategies in neurodegenerative disorders mediated by mitochondrial dysfunction. PMID- 29277915 TI - Diethylstilbestrol regulates mouse gubernaculum testis cell proliferation via PLC Ca2+ -CREB pathway. AB - : Recent evidence suggested a positive correlation between environmental estrogens (EEs) and high incidence of abnormalities in male urogenital system, but the mechanism remains unclear. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernaculum testis cells, but the underlying mechanism is unclear. In this study, mouse gubernaculum testis cells were pretreated with phospholipase C (PLC) inhibitor U 73122 and then treated with DES. The results demonstrated that U-73122 impaired DES-evoked intracellular Ca2+ mobilization in gubernaculum testis cells and inhibited DES-induced proliferation of gubernaculum testis cells. Mechanistically, we found that U-73122 inhibited DES-induced activation of cAMP response element binding protein (CREB) in gubernaculum testis cells. In conclusion, these data suggest that the effects of DES on mouse gubernaculum testis cells are mediated by PLC-Ca2+ -CREB pathway. SIGNIFICANCE OF THE STUDY: Environmental estrogens remain a serious threat to male reproductive health, and it is important to understand the mechanism by which EEs affect the male productive system. Here we explore potential mechanisms how the proliferation and contractility of gubernaculum testis cells are regulated by diethylstilbestrol. Our findings provide the first evidence that PLC-Ca2+ -CREB signalling pathway mediates the nongenomic effects of diethylstilbestrol on gubernaculum testis cells. These findings provide new insight into the role of diethylstilbestrol in the aetiology of male reproductive dysfunction and will help develop better approaches for the prevention and therapy of male reproductive malformation. PMID- 29277916 TI - Do health care reforms in Turkey have a significant effect in equal access to maternal and child health services in Turkey: An evidence from 20 years. AB - This study aimed to investigate whether there was an improvement in the equitable access to maternal and child health care services by examining the effects of socioeconomic and individual factors in Turkey from 1993 to 2013 and determine the effectiveness of health care reforms implemented mainly under the Health Transformation Program since 2003 on equitable access t;o maternal and child health care services in terms of years. The study used nationally representative 5 Turkey Demographic and Health Surveys (1993, 1998, 2003, 2008, and 2013). Prenatal care utilization rate increased from 67.0% in 1993 to 96.2% in 2013 while the rate of women giving birth at health care facilities increased from 63.8% to 98.1% in 2013. Prenatal care utilization and giving birth at health care facilities were higher among women who were under health insurance coverage, first time mothers, those staying in the western region and urban areas, and those with the highest level of wealth. The findings suggest that the issue of equity in the utilization of maternal and child health care services exists in Turkey, and the latest health care reforms under HTP are not effective in diminishing the effect of wealth. PMID- 29277917 TI - Characterization and functional assay of a fatty acyl-CoA reductase gene in the scale insect, Ericerus pela Chavannes (Hemiptera: Coccoidae). AB - Ericerus pela Chavannes (Hemiptera: Coccoidae) is an economically important scale insect because the second instar males secrete a harvestable wax-like substance. In this study, we report the molecular cloning of a fatty acyl-CoA reductase gene (EpFAR) of E. pela. We predicted a 520-aa protein with the FAR family features from the deduced amino acid sequence. The EpFAR mRNA was expressed in five tested tissues, testis, alimentary canal, fat body, Malpighian tubules, and mostly in cuticle. The EpFAR protein was localized by immunofluorescence only in the wax glands and testis. EpFAR expression in High Five insect cells documented the recombinant EpFAR reduced 26-0:(S) CoA and to its corresponding alcohol. The data illuminate the molecular mechanism for fatty alcohol biosynthesis in a beneficial insect, E. pela. PMID- 29277918 TI - Extra virgin olive oil aroma release after interaction with human saliva from individuals with different body mass index. AB - BACKGROUND: The interindividual variability observed in saliva characteristics raises the question of its relationship with variability in fat sensory perception, particularly in aroma compounds. In the present study, which aimed to measure aroma release from different individuals, eleven key aroma compounds of extra virgin olive oil (EVOO) were monitored and quantified in dynamic headspace after an in vitro interaction between EVOO and human saliva. Therefore, 60 individuals were studied from those who were normal weight (NW), overweight (OW) and obese (O). RESULTS: OW and O demonstrate a higher release of C6 compounds compared to NW. By contrast, NW have a higher release of C5 compounds. Pentanal and hexanal also increased after saliva interaction in a refined olive oil that is free from volatiles. Among the saliva samples with a higher release in NW individuals, only pentanal was different. However, the low levels of these lipid oxidation end-products do not appear to be very important with respect to increasing odorous fat sensitivity. CONCLUSION: The results obtained in the present study demonstrate the important role of saliva in the aroma release of EVOO, indicating that humans can perceive it differently in relation to their body mass index. (c) 2017 Society of Chemical Industry. PMID- 29277919 TI - Recessive epidermolytic ichthyosis results from loss of keratin 10 expression, regardless of the mutation location. AB - Epidermolytic ichthyosis (EI) is a rare skin disorder caused by mutations in the genes KRT1 and KRT10, and is usually inherited in an autosomal dominant fashion. Only five recessive mutations causing EI have been described, all of which are located in the central region of the KRT10 gene. In the current study, we aimed to identify the genetic defect underlying EI in a 12-year-old patient. Direct sequencing of the patient's genomic DNA revealed a novel homozygous nonsense mutation residing within the proximal part KRT10 first exon. The mutation was found to co-segregate with the disease phenotype in an autosomal recessive fashion. Using real-time quantitative PCR, we found an almost two-fold decrease in KRT10 expression in the patient's skin compared with the skin of healthy controls. Western blot analysis showed complete absence of keratin 10 protein in the patient's skin, suggesting early protein degradation. PMID- 29277920 TI - Three-dimensional morphological analysis of the human sacroiliac joint: influences on the degenerative changes of the auricular surfaces. AB - The sacroiliac joint (SIJ) is responsible for weight transmission between the spine and lower extremity. However, details of the structure and function of the SIJ remain unclear. In a previous study, we devised a method of quantitatively evaluating the level of degeneration of the SIJ using an age estimation procedure for the auricular surface of the ilium. Our results in that study suggested that the degree of degeneration of the joint surface may be associated with the morphology of the auricular surface of the ilium. In that study, however, the morphology of the auricular surface of the ilium was simplified for analysis, meaning that more detailed investigations were required in future. In the present study, we focused on individual differences in the shape of SIJ and carried out three-dimensional quantitative evaluation of the morphology of the auricular surface of the ilium to ascertain its association with joint degeneration. We produced three-dimensional images of the right auricular surfaces of the ilium of 100 modern Japanese men (age 19-83), and obtained the three-dimensional rectangular coordinates of 11 defined measurement points. We then calculated 16 parameters indicating the morphological characteristics of the auricular surfaces of the ilium from the three-dimensional rectangular coordinates of these measurement points, and used these to perform principal component analysis to investigate trends in the morphology of the auricular surface of the ilium. We found that the morphology of the auricular surface of the ilium could be characterized in terms of (i) size, (ii) concavity of the posterior border and (iii) amount of undulation. An investigation of the correlation between these parameters and age suggested that the amount of undulation of the auricular surface of the ilium tends to diminish with advancing age. In an investigation of the association between morphology of the auricular surface of the ilium and degeneration of the articular surface when the subjects were divided into a high degeneration group (n = 55) and a low-degeneration group (n = 45) and the 16 parameters were compared, there was a significant difference in the amount of undulation of the auricular surface of the ilium. In an investigation limited to older subjects aged >= 60 (n = 47) at the time of death, there were significant differences between the high-degeneration group (n = 27) and low-degeneration group (n = 20) in terms not only of the parameters indicating the amount of undulation of the auricular surface of the ilium but also of those indicating the amount of the concavity of the posterior border. These results suggested that the amount of undulation of the auricular surface of the ilium may affect the degree of degeneration of the articular surface. In addition, in older subjects, the degree of concavity of the posterior border of the SIJ may also affect the degree of degeneration of the articular surface. It is thus likely that differences in the morphology of the auricular surface of the ilium may affect degenerative changes in the SIJ. PMID- 29277921 TI - Clinical factors associated with physician choice of femoral versus radial access: A real-world experience from a single academic center. AB - OBJECTIVES: To analyze clinical factors associated with operator's preference in selection of femoral versus radial access for angiography and percutaneous intervention (PCI) procedures. BACKGROUND: There has been an increase in radial access in cardiac catheterization and PCI in the last few decades. METHODS: Data from 11 226 consecutive cardiac catheterization procedures were collected from Sanford University Medical Center (University of South Dakota, Sanford School of Medicine) from 2011 to 2015. RESULTS: In the overall cases, clinical factors that favored upfront femoral access include patients presenting as ST-elevation myocardial infarction (STEMI) or emergent, coronary artery bypass graft, body mass index (BMI) <30 kg/m2 and age >=70 years, whereas morbidly obese patients (BMI >=35) and age <70 favored upfront radial access. Radial access in the overall group had lower fluoroscopy time (6.5 vs 8.4 min, P < 0.0001) and lower contrast use (68.8 vs 80.6 cc, P < 0.0001). In the PCI group, efficacy of upfront radial access is less evident with radial fluoroscopy time (10.1 vs 11.0 min, P < 0.0028) and contrast use being higher in radial group (113.8 vs 108.2 cc, P < 0.037). Interventional cardiologists were more efficient in diagnostic cases than non-interventional cardiologists. CONCLUSION: STEMI or emergent cases and elderly patients favor upfront femoral access. As BMI increases and age decreases, radial access is progressively favored. In diagnostic cases, radial access appears to be superior to femoral access in efficacy, but the distinction is less obvious in PCI and STEMI or emergent cases. PMID- 29277922 TI - Glutathione levels influence chronological life span of Saccharomyces cerevisiae in a glucose-dependent manner. AB - Diet plays a key role in determining the longevity of the organisms since it has been demonstrated that glucose restriction increases life span whereas a high glucose diet decreases it. However, the molecular basis of how diet leads to the aging process is currently unknown. We propose that the quantity of glucose that fuels respiration influences reactive oxygen species generation and glutathione levels, and both chemical species impact in the aging process. Herein, we provide evidence that mutation of the gene GSH1 in Saccharomyces cerevisiae diminishes glutathione levels. Moreover, glutathione levels were higher with 0.5% than in 10% glucose in the gsh1Delta and wild-type strains. Interestingly, the chronological life span was lowered in the gsh1Delta strain cultured with 10% glucose but not under dietary restriction. The gsh1Delta strain also showed inhibition of the mitochondrial respiration in 0.5 and 10% glucose but only increased the H2 O2 levels under dietary restriction. These results correlate well with the GSH/GSSG ratio, which showed a decrease in gsh1Delta strain cultured with 0.5% glucose. Together, these data indicate that glutathione exhaustion impact negatively both the electron transport chain function and the chronological life span of yeast, the latter occurring when a low threshold level of this antioxidant is reached, independently of the H2 O2 levels. PMID- 29277923 TI - Expression of programmed death ligand-1 on bladder tissues is detected in a clinically and histologically well-defined interstitial cystitis cohort. AB - OBJECTIVE: To investigate the expression of programmed death ligand-1 (PD-L1) in interstitial cystitis (IC). METHODS: We reviewed the data of IC patients underwent hydrodistension plus bladder biopsy. Follow-ups were performed. We assessed the degree of inflammation of the bladder wall on slides stained with hematoxylin and eosin (H&E). We performed immunohistochemistry for PD-L1 expression detection and for counting T lymphocytes and B lymphocytes. RESULTS: The present study included eight men and 32 women. With H&E staining, we detected 13, 15, and 12 patients with mild, moderate, and severe inflammation. The degree of inflammation was negatively correlated with disease course (P = 0.018) and positively correlated with bladder pain (P < 0.001). Hydrodistension was found effective at postoperative 3-month for 19 patients. Overall, 17, 15, 7, and 1 subject had no, mild, moderate, and high PD-L1 expression, that correlated positively with the degree of inflammation. Compared with patients with no and mild PD-L1 expression, patients with moderate and high PD-L1 expression tended to have more effective hydrodistension outcomes (12 of 32 vs 7 of 8; P = 0.017). In the subset of 12 patients with severe inflammation, there were five of six patients (83.3%) with moderate or high PD-L1 expression and one of six patients (16.7%) with no and mild PD-L1 expression with an effective hydrodistension outcome. CONCLUSIONS: Expression of PD-L1 on bladder is detected in a cohort of IC patients presented with diffuse global glomerulation or Hunner ulcer. PD-L1 expression is more common in IC patients with severe bladder inflammation. PMID- 29277924 TI - Identification and characterization of novel promoters for recombinant protein production in yeast Pichia pastoris. AB - Pichia pastoris expression system has been widely used in recombinant protein production. So far the majority of heterologous proteins are expressed by methanol inducible promoter PAOX1 and constitutive promoter PGAP . The use of other promoters is rather limited. Here we selected 16 potentially efficient and regulatory promoter candidates based on the RNA-seq and RNA folding free energy DeltaG data. GFP and recombinant amylase were inserted after these promoters to reveal their strength and efficiency under different carbon sources and culture scales. Two novel promoters were successfully identified and could possibly be applied in recombinant protein expression: the methanol-inducible promoter P0547 and the constitutive promoter P0472 . PMID- 29277925 TI - Morphoea profunda and its relationship to eosinophilic fasciitis. AB - In this small case series, all eight patients were women in their fifth and sixth decades. This is similar to the female predominance in morphoea and less in keeping with eosinophilic fasciitis (EF). All cases had diffuse induration of their limbs with both proximal and distal patterns of distribution, and five of the patients exhibited peau d'orange skin. All patients had diffuse induration of the lower limbs and half had restricted ankle movements. Six patients had concomitant superficial morphoea. This group of patients demonstrated a unique subtype of the morphoea spectrum with some features overlapping with EF. However, there appear to be points of distinction, and we propose that some previously reported cases labelled as EF would be better described as having morphoea profunda (MP). Methotrexate may be a useful treatment for MP, hence it is important to distinguish this from EF, as management may differ. PMID- 29277926 TI - A systematic review and meta-analysis of epidemiologic observational evidence on the effect of periodontitis on diabetes An update of the EFP-AAP review. AB - AIM: To update the available evidence on the impact of periodontitis on diabetes control, incidence and complications. METHODS: Observational studies on the effect of periodontitis on diabetes, published after 2012, were identified through electronic databases and hand-searched journals. Findings were summarized by evidence tables, using PRISMA statement. Quality of the included studies was evaluated through the Newcastle Ottawa scale. RESULTS: Healthy individuals with periodontitis exhibit a poor glycaemic control and a higher risk of developing diabetes. Individuals affected by diabetes show a deterioration of glycaemic control if also affected by periodontitis and significantly higher prevalence of diabetes-related complications. Limited evidence is available on gestational diabetes and type 1 diabetes. CONCLUSIONS: Periodontitis has a significant impact on diabetes control, incidence and complications. Nevertheless, the heterogeneity and quality of the included publications suggest that caution should be exercised when interpreting the data and that there remains an important need for additional evidence. PMID- 29277927 TI - Legionella feeleii: an unusual organism associated with cutaneous infection in an immunocompromised patient. AB - We report a 23-year-old immunocompromised woman who, following cardiac transplantation, presented with an unusual cutaneous eruption. She developed a widespread pustular rash, systemic symptoms and a high temperature with raised inflammatory markers. The diagnosis was reached when a skin biopsy was cultured onto Legionella agar (buffered charcoal yeast extract) and Legionella feeleii was isolated. The patient was treated with 6 weeks of moxifloxacin and her cutaneous lesions gradually resolved. Cutaneous Legionella infections are uncommon and usually affect immunocompromised patients. PMID- 29277928 TI - A proposed framework of key activities and processes in the preparedness and recovery phases of disaster management. AB - This paper proposes an empirically grounded framework for examining the preparedness and recovery phases of disaster management activities and processes pertaining to predictable disasters within a developed country. The two-stage framework provides a single model composed of important preparedness and recovery initiatives, as well as activities and processes derived from empirical data collected for case studies from Australia: the 'Black Saturday' bushfires in the state of Victoria in February 2009; and Cyclone Larry in March 2006. The framework enables a variety of analyses, including the generation of insights into disaster management preparedness and recovery in the context of events in wealthy developed countries. The paper combines two empirical examples, a series of bushfires and a severe tropical cyclone, to enhance understanding of, and to contribute to better, disaster preparedness and recovery in the future. The paper contributes to the growing literature on disasters, preparedness, recovery and associated logistics, and other issues. PMID- 29277929 TI - Recurrent chilblains in a child with neurological impairment. PMID- 29277930 TI - A systematic review and meta-analysis of interventions to increase physical activity in children and adolescents with intellectual disabilities. AB - BACKGROUND: Increasing physical activity (PA) through intervention can promote physical and mental health benefits in children and adolescents. However, children and adolescents with intellectual disabilities (ID) have consistently been shown to engage in low levels of PA, which are insufficient for long-term health. Despite this, little is known about the effectiveness of interventions to increase PA in children and adolescents with ID. The aims of this study were therefore to systematically review how effective interventions are at increasing PA levels in children and adolescents with ID and to further examine what components have been used in these interventions. METHOD: A systematic search of MEDLINE, EMBASE, Education Resources Information Center, Cumulative Index to Nursing and Allied Health Literature, PsychINFO, Cochrane Central Register for Controlled Trials and International Standard Randomised Controlled Trial Number trials registry was conducted (up to July 2016). Articles were included if they met the following eligibility criteria: children and adolescents (<18 years) with ID, measurement of PA at baseline and post-intervention and intervention studies. Effect sizes were calculated as standardised mean difference (d) and meta analysis calculated between intervention and no treatment control intervention. RESULTS: Five studies met the eligibility criteria and were included in the review. Study design, methodological quality and intervention components were varied. Interventions did not support sufficient changes in PA to improve health. The meta-analysis demonstrated that intervention groups were not more effective at increasing PA levels post-intervention (d: 2.20; 95% CI -0.57 to 0.97) compared with control. However, due to a decrease in PA in the control intervention, a moderate significant effect was demonstrated at follow-up (d: 0.49; 95% CI 0.14 to 0.84). CONCLUSIONS: There is a lack of studies which aim to increase PA levels in children and adolescents with ID, with current interventions ineffective. Future studies are required before accurate recommendations for appropriate intervention design and components can be made. PMID- 29277932 TI - Rare case of multicentric reticulohistiocytosis presenting as epidermotropic papular xanthoma and double primary cancers. PMID- 29277931 TI - Percutaneous pulmonary valve implantation in grown-up congenital heart disease patients: Insights from the Zurich experience. AB - OBJECTIVES: The aim of the study was to assess indications, procedural success, complications, echocardiographic, and clinical outcomes of percutaneous pulmonary valve implantation (PPVI) in adult patients with congenital heart disease (CHD). BACKGROUND: PPVI offers a non-surgical treatment option for failing prosthetic conduits in pulmonary position. However, efficacy and clinical outcomes after PPVI are still underreported. METHODS: From January 2008 to March 2016, 25 adult CHD patients with right ventricular outflow tract (RVOT) stenosis and/or pulmonary regurgitation underwent PPVI in our institution. Clinical and echocardiographic data was collected at baseline, at 12 months of follow-up and yearly afterwards. RESULTS: Tetralogy of Fallot and repaired pulmonary atresia were among the most prevalent underlying congenital defects. Twenty-one (84%) received a Medtronic Melody(r) and four (16%) patients an Edwards Sapien valve prosthesis. The PPVI procedure was successful in all 25 patients. Pre-stenting was performed in all but two (8%) patients. PPVI reduced peak-to-peak pulmonary valve gradient from 43 (IQR 28-60) mmHg to 16 (IQR 14-22) mmHg (P < 0.001). Periprocedural complications occurred in two (8%) patients (tricuspid valve damage, pulmonary artery perforation). Over a median follow-up of 43 (IQR 18-58) months all patients were alive. Only two (8%) required re-operation and two (8%) developed stent fractures (one of them had not undergone pre-stenting). NYHA functional class improved significantly, with 20 (80%) patients in NYHA class I on follow-up. CONCLUSIONS: PPVI with Medtronic Melody or Edwards Sapien valve conduits is safe and provides effective relief from right ventricular outflow tract obstruction or pulmonary regurgitation. PMID- 29277933 TI - The arrangement of the coronary artery trunks is subject to inheritance factors: A study in Syrian hamsters. AB - The concept that anatomical variations in the coronary artery tree might be influenced by genes is relatively old. However, empirical evidence on the effect of genotype on the coronary morphology is still scarce. In the Syrian hamster, there is a septal coronary artery which arises from the left or from the right coronary artery and supplies most of the interventricular septum. The aim was to decide whether the anatomical origin of the septal artery is subject to inheritance factors. Overall, 483 internal casts of the heart and coronary arteries were examined. All the hamsters included in this study had normal coronary arteries. The results of 74 crosses were compared statistically to seek for any significant difference between the phenotypes of the offspring and the phenotypes of the parents. The left septal artery was over-represented in the offspring of crosses between parents having both a left septal artery (p < .01), while the right septal artery was over-represented in the offspring of crosses between parents, one with a right and the other with a left septal artery (p < .001), and, more markedly, in the offspring of crosses between parents both with a right septal artery (p < .001). These results are the first to reveal that the coronary artery pattern is influenced by genetic factors, at least in its proximal portion with regard to the aorta. PMID- 29277935 TI - American Journal of Primatology: Goals and priorities of a new editor. PMID- 29277934 TI - FAM20C could be targeted by TET1 to promote odontoblastic differentiation potential of human dental pulp cells. AB - OBJECTIVES: Ten-eleven translocation 1 (TET1) is a DNA methylcytosine (mC) dioxygenase discovered recently that can convert 5-mC into 5 hydroxymethylcytosine (5hmC). We previously reported that TET1 promotes odontoblastic differentiation of human dental pulp cells (hDPCs). The gene encoding the family with sequence similarity 20, member C (FAM20C) protein, is a potential TET1 target and showed demethylation during odontoblastic differentiation of hDPCs in our previous study. This study aimed to explore whether TET1-mediated hydroxymethylation could activate the FAM20C gene, thereby regulating hDPC differentiation. MATERIALS AND METHODS: The expression pattern of FAM20C and its potential changes during odontoblastic induction of hDPCs were assessed by Western blotting. Lentivirus-mediated transduction with short hairpin RNA (shRNA) was used to knock down FAM20C and TET1 expression in hDPCs. The mineralization potential of hDPCs was evaluated with an ALPase activity assay and by observing the mineralized matrix deposition and the expression of odontoblast related markers DSPP and DMP1. Recombinant human FAM20C protein (rhFAM20C) was reintroduced into shTET1 cells in a rescue experiment. The dynamic hydroxymethylation status of the FAM20C gene promoter was examined using hydroxymethylated DNA immunoprecipitation (IP)-PCR. Chromatin IP-PCR and agarose gel electrophoresis were utilized to validate the recruitment of TET1 to its target loci in the FAM20C promoter. RESULTS: FAM20C protein level was upregulated after the odontoblastic induction of hDPCs. shRNA-mediated FAM20C suppression reduced the expression of DSPP and DMP1 after odontoblastic induction for 7 and 14 days. ALPase activity was reduced on day 7, and the formation of mineralized nodules was attenuated on day 14 after odontoblastic induction in FAM20C inhibited hDPCs. Genomic 5hmC levels significantly decreased, and total 5mC levels increased in TET1-deficient hDPCs. In addition, a significant reduction in FAM20C also emerged. The rhFAM20C treatment of shTET1 cells attenuated the mineralization abnormalities caused by TET1 depletion. TET1 depletion prompted a decline in 5hmC levels in several regions on the FAM20C promoter. Enhanced TET1 recruitment was detected at the corresponding loci in the FAM20C promoter during odontoblastic induction. CONCLUSION: TET1 knockdown suppressed odontoblastic differentiation by restraining its direct binding to FAM20C promoter, and hence inhibiting FAM20C hydroxymethylation and subsequent transcription. These results suggest that TET1 potentially promotes the cytodifferentiation potential of hDPCs through its DNA demethylation machinery and upregulation of FAM20C protein expression. PMID- 29277936 TI - RNA Characterization by Solid-State NMR Spectroscopy. AB - The structures of RNAs, which play critical roles in various biological processes, provide important clues and insights into the biological functions of these molecules. However, RNA structure determination remains a challenging topic. In recent years, magic-angle-spinning solid-state NMR (MAS SSNMR) has emerged as an alternative technique for structural and dynamic characterization of RNA. MAS SSNMR has been successfully applied to provide atomic-level structural information about several RNA molecules and RNA-protein complexes. In this Minireview, we give an overview of recent progress in the field of MAS SSNMR based RNA structural characterization, and introduce sample preparation strategies and SSNMR spectroscopic techniques that have been incorporated to identify RNA structural elements. We also highlight a few impressive examples of RNAs that have been investigated extensively by SSNMR. Finally, we briefly discuss future technical trends in the use of MAS SSNMR to facilitate RNA structure determination. PMID- 29277937 TI - Effects of Y361-auto-phosphorylation on structural plasticity of the HIPK2 kinase domain. AB - The dual-specificity activity of the homeodomain interacting protein kinase 2 (HIPK2) is regulated by cis-auto-phosphorylation of tyrosine 361 (Y361) on the activation loop. Inhibition of this process or substitution of Y361 with nonphosphorylatable amino acid residues result in aberrant HIPK2 forms that show altered functionalities, pathological-like cellular relocalization, and accumulation into cytoplasmic aggresomes. Here, we report an in vitro characterization of wild type HIPK2 kinase domain and of two mutants, one at the regulating Y361 (Y361F, mimicking a form of HIPK2 lacking Y361 phosphorylation) and another at the catalytic lysine 228 (K228A, inactivating the enzyme). Gel filtration and thermal denaturation analyzes along with equilibrium binding experiments and kinase assays performed in the presence or absence of ATP competitors were performed. The effects induced by mutations on overall stability, oligomerization and activity support the existence of different conformations of the kinase domain linked to Y361 phosphorylation. In addition, our in vitro data are consistent with both the cross-talk between the catalytic site and the activation loop of HIPK2 and the aberrant activities and accumulation previously reported for the Y361 nonphosphorylated HIPK2 in mammalian cells. PMID- 29277938 TI - Tools of the crook- infection strategies of fungal plant pathogens. AB - Fungi represent an ecologically diverse group of microorganisms that includes plant pathogenic species able to cause considerable yield loses in crop production systems worldwide. In order to establish compatible interactions with their hosts, pathogenic fungi rely on the secretion of molecules of diverse nature during host colonization to modulate host physiology, manipulate other environmental factors or provide self-defence. These molecules, collectively known as effectors, are typically small secreted cysteine-rich proteins, but may also comprise secondary metabolites and sRNAs. Here, we discuss the most common strategies that fungal plant pathogens employ to subvert their host plants in order to successfully complete their life cycle and secure the release of abundant viable progeny. PMID- 29277939 TI - Parallel adaptations and common host cell responses enabling feeding of obligate and facultative plant parasitic nematodes. AB - Parallel adaptations enabling the use of plant cells as the primary food source have occurred multiple times in distinct nematode clades. The hallmark of all extant obligate and facultative plant-feeding nematodes is the presence of an oral stylet, which is required for penetration of plant cell walls, delivery of pharyngeal gland secretions into host cells and selective uptake of plant assimilates. Plant parasites from different clades, and even within a single clade, display a large diversity in feeding behaviours ranging from short feeding cycles on single cells to prolonged feeding on highly sophisticated host cell complexes. Despite these differences, feeding of nematodes frequently (but certainly not always) induces common responses in host cells (e.g. endopolyploidization and cellular hypertrophy). It is thought that these host cell responses are brought about by the interplay of effectors and other biological active compounds in stylet secretions of feeding nematodes, but this has only been studied for the most advanced sedentary plant parasites. In fact, these responses are thought to be fundamental for prolonged feeding of sedentary plant parasites on host cells. However, as we discuss in this review, some of these common plant responses to independent lineages of plant parasitic nematodes might also be generic reactions to cell stress and as such their onset may not require specific inputs from plant parasitic nematodes. Sedentary plant parasitic nematodes may utilize effectors and their ability to synthesize other biologically active compounds to tailor these common responses for prolonged feeding on host cells. PMID- 29277940 TI - Psychophysical well-being profiles in patients before hematopoietic stem cell transplantation. AB - OBJECTIVES: The literature offers very few in-depth reports on the time directly before hematopoietic stem cell transplantation (HSCT). Also, researchers have focused on selected aspects of psychophysical well-being and treated the sample as homogeneous. Thus, we chose to investigate distinct multidimensional well being profiles (including anxiety, depressive symptoms, and health-related quality of life [HRQOL] domains) among patients just before HSCT, as well as profile predictors (generalized self-efficacy) and outcomes (transplant appraisal) on the basis of the transactional stress model. METHODS: Depression (CES-D), anxiety (HADS-A), HRQOL (EORTC QOL-C30), generalized self-efficacy (GSES), and transplant appraisal (single-item scale referred to threat and challenge) were measured in 290 patients (56.9% male; mean age = 47.28, SD = 13.79) after admission for HSCT (67.2% autologous). Unconditional and conditional latent profile analyses were applied. RESULTS: Four latent well-being profiles were identified: well-functioning (51%, highest well-being in all aspects), dysfunctional (10%, weakest functioning in all aspects), and 2 profiles with moderate HRQOL and high (5.6%) or low (33.4%) anxiety and depressive symptoms. Generalized self-efficacy predicted profile membership, controlling for demographic and clinical variables. The highest levels were observed in the well functioning group (P < .01). Appraisal was predicted by latent profile analyses classes: low threat in the well-functioning group (P < .001) and the highest threat and challenge in the dysfunctional group (P < .01). CONCLUSIONS: The findings highlight the diverse nature of well-being in pre-HSCT patients and the manner in which transplant appraisal and generalized self-efficacy are related to different profiles of pre-HSCT multidimensional well-being, thus indicating the practical implications of the study. PMID- 29277941 TI - Nurse workforce scheduling in the emergency department: A sequential decision support system considering multiple objectives. AB - AIM: We propose a nurse scheduling framework based on a set of performance measures that are aligned with multiple outcome measures. A case study for the emergency department is presented. METHODS: A total of 142,564 emergency department attendances over 1 year were included in this study. Operational requirements, constraints and historical workload data were translated into a mixed-integer sequential goal programming model, which considers the following outcome measures: (1) nurse-patient ratios; (2) number of favourable/unfavourable shifts; and (3) dispersion of rest days. Computational studies compared the performance of the mixed-integer sequential goal programming results with manually generated historical nurse schedules. RESULTS: The maximum nurse-patient ratio deviation against the target was approximately 10% compared to 47% generated by the historical rosters (a 10% deviation translates to approximately two nurses). An on-line decision support system, which integrates shift preferences, staff databases and a workload forecasting module, was also developed. CONCLUSION: A decision support system based on the mixed-integer sequential goal programming modelling framework was proposed. The application of the model in a case study for an emergency department demonstrated improvements over existing manual scheduling methods. IMPLICATIONS FOR NURSING MANAGEMENT: This study demonstrates a mathematical, programming-based decision support system, which allows for managerial priorities and nurse preferences to be jointly considered in the automatic generation of nurse rosters. PMID- 29277942 TI - Psychometric analysis of the leadership environment scale (LENS): Outcome from the Oregon research initiative on the organisation of nursing (ORION). AB - AIM: The purpose of this study was to establish the psychometric properties of the new 16-item leadership environment scale. BACKGROUND: The leadership environment scale was based on complexity science concepts relevant to complex adaptive health care systems. METHODS: A workforce survey of direct-care nurses was conducted (n = 1,443) in Oregon. Confirmatory factor analysis, exploratory factor analysis, concordant validity test and reliability tests were conducted to establish the structure and internal consistency of the leadership environment scale. RESULTS: Confirmatory factor analysis indices approached acceptable thresholds of fit with a single factor solution. Exploratory factor analysis showed improved fit with a two-factor model solution; the factors were labelled 'influencing relationships' and 'interdependent system supports'. Moderate to strong convergent validity was observed between the leadership environment scale/subscales and both the nursing workforce index and the safety organising scale. Reliability of the leadership environment scale and subscales was strong, with all alphas >=.85. CONCLUSIONS: The leadership environment scale is structurally sound and reliable. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing management can employ adaptive complexity leadership attributes, measure their influence on the leadership environment, subsequently modify system supports and relationships and improve the quality of health care systems. The leadership environment scale is an innovative fit to complex adaptive systems and how nurses act as leaders within these systems. PMID- 29277943 TI - Trainees' self-evaluation of their development as psychotherapists: An Italian contribution to an international collaborative study on psychotherapy training. AB - This study presents a pilot contribution to the new collaborative, multinational study of psychotherapy trainee development that was undertaken by the Society for Psychotherapy Research Interest Section on Therapist Training and Development (see Orlinsky, Strauss, Ronnestad, et al., ). Although the main project is longitudinal in design, this preliminary study investigated cross-sectional differences between trainees in different years of training and explored the influence of core training experiences-including supervision and personal therapy on their perceived development as therapists. Using the trainee current-progress report that was designed for the Society for Psychotherapy Research Interest Section on Therapist Training and Development project, 90 trainees at 4 different 4-year training programs in Italy provided self-evaluations of their development and of their therapeutic work experiences. Perceived development included overall change, progress, deterioration, overcoming past limitations, and realization of potential as a therapist. Therapeutic work experiences were assessed using scales of healing and stressful involvement (Orlinsky & Ronnestad, ). Year in training and support in supervision predicted perceived development and healing involvement, whereas experiencing criticism in supervision was associated with stressful involvement. Having had personal therapy, and especially ratings of benefit from personal therapy, was also associated with perceived development and healing involvement. Results are discussed with regard of their implications for psychotherapy training. PMID- 29277944 TI - Commitment and a sense of humanity for the adaptation of patients during hospital care. AB - OBJECTIVE: To develop a nursing practice model for the Clinic of the University of the La Sabana that supports the adaptive process of patients during and after their hospital experience. METHODOLOGY: This is a descriptive, methodological study implemented in different phases: (1) characterization of the context, (2) identification of the need for a nursing practice model for strengthening care, (3) literature review, (4) description of the model, and (5) validation. RESULTS: The context of a university hospital and international trends in the development of a professional nursing discipline require theoretical guidance for the ongoing improvement of the practice of nursing. The decision to apply Roy's conceptual model of adaptation clarifies the need for a complementary nursing practice model that brings this macro theory closer to the assistance reality. It is also necessary to make the vocation of service, knowledge and leadership of nursing visible whenever the human adaptive process is a priority. CONCLUSION: The University of La Sabana nursing practice model is a model focused on the commitment and humane treatment for the adaptation of patients during hospital care. It represents a consensus on the essentials of the nursing practice, which seek to support the adaptive process in order to have more comprehensive welfare and consequent improvement of the patient. PMID- 29277945 TI - Community pharmacists' perspectives on shared decision-making in diabetes management. AB - OBJECTIVES: Shared decision-making (SDM) is an approach where patients and clinicians share evidence and patients are supported to deliberate options resulting in preference-based informed decisions. The aim of this study was to describe community pharmacists' perceptions and awareness of SDM within their provision of general diabetes management [including Ontario's MedsCheck for Diabetes (MCD) programme], and potential challenges of implementing SDM within community pharmacy. METHODS: This qualitative study used semistructured interviews with a convenience sample of community pharmacists. Data were analysed using thematic analysis. KEY FINDINGS: We conducted 16 interviews. Six participants were male, and nine were certified diabetes educators. When providing a MCD, participants used aspects of a patient-centred approach focusing on providing education. Variation was evident in participants' description and use of SDM, as well as in their perceived level of training in SDM. Participants also highlighted challenges surrounding implementing a SDM approach in practice. CONCLUSION: Pharmacists are well positioned to apply SDM within community settings; however, implementation barriers exist. Pharmacists will require additional training as well as perceived patient and physician barriers should be addressed to encourage uptake. PMID- 29277946 TI - Discrimination of constructed air samples using multivariate analysis of full scan membrane introduction mass spectrometry (MIMS) data. AB - RATIONALE: Volatile and semi-volatile organic compounds (S/VOCs) are important atmospheric pollutants affecting both human and environmental health. They are directly measured as an unresolved mixture using membrane introduction mass spectrometry (MIMS). We apply chemometric techniques to discriminate, classify, and apportion air samples from a variety of sources. METHODS: Full scan mass spectra of lab-constructed air samples were obtained using a polydimethylsiloxane membrane interface and an electron ionization ion trap mass spectrometer. Normalized full scan spectra were analyzed using principal component analysis (PCA), cluster analysis, and k-nearest neighbours (kNN) for sample discrimination and classification. Multivariate curve resolution (MCR) was used to extract pure component contributions. Similar techniques were applied to VOC mixtures sampled from different woodsmoke emissions and from the headspace above aqueous hydrocarbon solutions. RESULTS: PCA successfully discriminated 32 constructed VOC mixtures from nearly 300 air samples, with cluster analysis showing similar results. Further, kNN classification (k = 1) correctly classified all but one test set sample, and MCR successfully identified the pure compounds used to construct the VOC mixtures. Real-world samples resulting from the combustion of different wood species and those associated with water contaminated with different commercial hydrocarbon products were similarly discriminated by PCA. CONCLUSIONS: Chemometric techniques have been evaluated using full scan MIMS spectra with a series of VOC mixtures of known composition containing known compounds, and successfully applied to samples with known sources, but unknown molecular composition. These techniques have application to source identification and apportionment in real-world environmental samples impacted by atmospheric pollutants. PMID- 29277947 TI - Parental involvement in adolescent depression interventions: A systematic review of randomized clinical trials. AB - Despite the widespread research recommendations for psychiatric nurses and other mental health professionals to include parents in adolescent depression treatment, no systematic reviews have yet synthesized the findings from intervention studies that included parents in the treatment and/or prevention of adolescent depression. Therefore, this systematic review was conducted to (i) identify and describe clinical trials that included parents as an integral component of adolescent depression interventions, (ii) examine the effectiveness of these trials in reducing depressive symptoms, and (iii) evaluate their methodological quality. We systematically searched the databases PubMed and PsycINFO. The search strategy adhered to the PRISMA statement to guide identification and selection of articles. Further, a structured evaluation form was adapted from the CONSORT statement and methodological literature to evaluate the elicited clinical trials. A total of 288 unique articles met criteria for abstract level screening, 45 articles were selected for full-text review, and 16 articles were included in the final analysis. We found that (i) available approaches to include parents in adolescent depression interventions vary in their theoretical stance, purpose, sample characteristics, and measured outcomes, (ii) the health outcomes of these approaches seemed to be contingent upon the nature of parental involvement, and (iii) effective translation of these approaches into practice needs to be considered in the light of their methodological rigour. Our review revealed a variety of promising approaches to utilize the parental and family contexts as a means of preventing or treating adolescent depression. However, more research is needed to determine which interventions, within what contexts, and using what resources will facilitate the best health outcomes for adolescents with depression and their parents. PMID- 29277948 TI - How transformational leadership appears in action with adverse events? A study for Finnish nurse manager. AB - AIM: The aim of this study was to determine whether elements of transformational leadership are present in nursing managers' actions following adverse events. BACKGROUND: Transformational leadership exerts a positive influence on organisational culture and patient safety. METHOD: Eleven nursing managers were interviewed individually using a semi-structured format. Data were analysed using inductive content analysis. RESULTS: Four themes emerged relating to nursing managers' actions following adverse events: patient-centredness as a principle for common action, courage to reform operational models to prevent future adverse events, nursing staff's encouragement of open and blame-free discussion, and challenge to recognize adverse events. CONCLUSION: Nursing managers must understand their responsibilities and the importance of making it clear to staff that patient-centredness should be evident in all health care actions. Nursing managers must also recognize the need to ensure that staff treat patients' interests as the top priority. IMPLICATIONS FOR NURSING MANAGEMENT: If an adverse event occurs, the situation should be discussed with the nursing staff and any unique aspects of the event must be accounted for. Nursing managers must have the skill to motivate and empower staff to find new ways to work, to prevent adverse events and to promote patient safety. PMID- 29277950 TI - Ion Specificity on Electric Energy Generated by Flowing Water Droplets. AB - The development of energy-conversion devices using water movement has actively progressed. Ionovoltaic devices, which are driven by ion dynamics, show ion specificity by which different ions with identical charges show different output performance. However, the ion specificity remains poorly understood because the influence of the ion species on generated electric signals is not elucidated. The ion specificity in electric signals induced by flowing water droplet was investigated in terms of its relationship with the potential profile across the solid-liquid interface. PMID- 29277949 TI - Development and clinical validation of a circulating tumor DNA test for the identification of clinically actionable mutations in nonsmall cell lung cancer. AB - Molecular analysis of potentially actionable mutations has become routine practice in oncological pathology. However, testing a wide range of oncogenes and mutations can be technically challenging because of limitations associated with tumor biopsy. Circulating tumor DNA (ctDNA) is a potential tool for the noninvasive profiling of tumors. In this study, we developed a next-generation sequencing (NGS)-based test for the detection of clinically relevant mutations in ctDNA and evaluated the feasibility of using this ctDNA NGS-based assay as an alternative to tissue genotyping. Tissue and matched blood samples were obtained from 72 patients with advanced nonsmall cell lung cancer (NSCLC). NGS-based testing was performed using plasma cell-free DNA (cfDNA) samples of all 72 patients as well as tumor DNA samples of 46 patients. Of the remaining 26 patients, tDNA was tested by amplification refractory mutation system PCR (ARMS PCR) because of insufficient tissue sample or quality for NGS. Of the 46 patients who had tDNA and cfDNA NGS performed, we found 20 patients were concordant between tDNA and ctDNA alterations and 21 sample pairs were discordant because of additional alterations found in tDNA. Considering all clinically relevant alterations, the concordance rate between tDNA and ctDNA alterations was 54.9% with a sensitivity of 53.2% and a specificity of 75.0%. Our findings demonstrate that targeted NGS using cfDNA is a feasible approach for rapid and accurate identification of actionable mutations in patients with advanced NSCLC, and may provide a safe and robust alternative approach to tissue biopsy. PMID- 29277951 TI - Rationing nurses: Realities, practicalities, and nursing leadership theories. AB - In this paper, we examine the practicalities of nurse managers' work. We expose how managers' commitments to transformational leadership are undermined by the rationing practices and informatics of hospital reform underpinned by the ideas of new public management. Using institutional ethnography, we gathered data in a Canadian hospital. We began by interviewing and observing frontline leaders, nurse managers, and expanded our inquiry to include interviews with other nurses, staffing clerks, and administrators whose work intersected with that of nurse managers. We learned how nurse managers' responsibility for staffing is accomplished within tightening budgets and a burgeoning suite of technologies that direct decisions about whether or not there are enough nurses. Our inquiry explicates how technologies organize nurse managers to put aside their professional knowledge. We describe professionally committed nurse leaders attempting to activate transformational leadership and show how their intentions are subsumed within information systems. Seen in light of our analysis, transformational leadership is an idealized concept within which managers' responsibilities are shaped to conform to institutional purposes. PMID- 29277952 TI - A tale of two cases of pulmonary arteriovenous malformation: How they fared after cardiac transplantation. AB - BACKGROUND: In single ventricle patients, aortopulmonary collaterals (APCs) and pulmonary arteriovenous malformations (PAVMs) following superior cavopulmonary shunt (CPS) can complicate orthotopic heart transplant (OHT) by cyanosis and hemoptysis. Although PAVMs can regress with the restoration of hepatic venous flow to the pulmonary circulation, the effects of hypoxemia on the "unconditioned" allograft are not known. CASES: Two patients with significant PAVMs after CPS were cyanotic following OHT. One patient with predominantly unilateral left PAVMs had arterial saturation levels less than 70% despite pulmonary vasodilators and ventilation. A custom flow restrictor-covered stent was deployed in the pulmonary artery of the affected side, redirecting the blood flow to the contralateral lung, immediately improving cyanosis. When the PAVMs regressed, the flow restrictor stent was dilated to eliminate the constriction. The second patient with PAVMs had cyanosis and severe hemoptysis from APCs post OHT. The APCs required an extensive coil embolization, while the cyanosis responded to oxygen and pulmonary vasodilators. Both recipients did well with gradual resolution of PAVMs within 8 months. CONCLUSIONS: Despite cyanosis from right-to-left intrapulmonary shunting, allograft function recovered. Novel transcatheter interventions can play a role in patients with significant APCs or PAVM following cardiac transplantation. PMID- 29277953 TI - Emergent leadership among tenants with psychiatric disabilities living in supported housing. AB - The overall aim of this study was to explore the experiences of people with psychiatric disabilities living as tenants in independent, supported apartments for the first time. Supported housing provides an alternative to structured, custodial housing models, such as foster homes, or board-and-care homes, for clients in public mental health systems. This article reports findings on how leadership emerged among tenants after making the transition from custodial to supported housing. Semi-structured interviews were conducted with tenants (n = 24) and included questions on their housing history, current living situation, relationships with staff, participation, and understanding or experience of leadership. Interviews were transcribed verbatim, codes generated, and a thematic analysis conducted using a constructivist approach. The findings revealed an understanding and appreciation of leadership among tenants, who identified six pathways to leadership in their housing as a response to unmet tenant needs. Most tenant leaders emerged outside of formal authority or power structures. Supported housing provides a unique social setting and empowering community where the potential of persons with psychiatric disabilities to assume leadership may be realized and further developed. Mental health professionals working in community housing networks are well placed to harness these face-to-face tenant communities, and their natural leaders, as an additional tool in promoting tenant recovery, mutual help, neighbourhood integration, and the broader exercise of citizenship. PMID- 29277954 TI - Cryptosporidiosis in a transplant recipient with severe intractable diarrhea: Detection of Cryptosporidium oocysts by intestinal biopsies. AB - Disseminated Cryptosporidium infection results in manifestations similar to those of graft-versus-host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oocysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppressants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation. PMID- 29277955 TI - Tick-borne illness after transplantation: Case and review. AB - Tick-borne infections in solid organ transplant recipients are an infrequent and difficult diagnostic challenge owing to multiple routes of acquisition and unusual presentations. A 67-year-old male recipient of a combined liver and kidney transplant presented with recurrent fevers following surgery. Standard microbiologic workup was non-diagnostic. Shortness of breath, confusion, lethargy, and hypotension developed along with progressive anemia, requiring multiple blood transfusions. Workup suggested hemolysis and review of the peripheral smear was diagnostic for Babesia microti infection. Tick transmission, transmission via blood products, and/or the transplanted organ were all considered. More extensive questioning revealed a history of intermittent fevers for several months before transplantation. Testing of pre-transplant blood was positive for B. microti antibodies, suggesting infection prior to transplantation. The delayed diagnosis of babesiosis in this patient highlights the need for a detailed exposure history prior to transplantation, as well as considering the potential for atypical presentations of tick-borne infections in immune suppressed solid organ recipients. Furthermore, this case illustrates the importance of early Infectious Disease consultation to meet the challenges exhibited by febrile transplant patients. Infectious Diseases physicians are trained to consider, diagnose, and treat tick-borne infections, contributing to improved clinical outcome. PMID- 29277956 TI - Kidney transplantation and waitlist mortality rates among candidates registered as willing to accept a hepatitis C infected kidney. AB - BACKGROUND: HCV-infected (HCV+) ESRD patients derive significant survival benefit from kidney transplantation (KT) over remaining on dialysis. Given high mortality rates on dialysis and the unique ability to accept HCV+ and HCV- donor kidneys, understanding their access to KT is essential. METHODS: Three thousand nine hundred and sixty-three adult kidney-only candidates reported as willing to accept an HCV+ kidney from 2008 to 2014 were identified and assumed to be HCV+. Time-at-risk began at date of listing. Cumulative incidence of transplant and waitlist mortality were assessed using competing risks, and separate mixed effects Cox proportional hazards models were used to examine waitlist mortality and transplantation rates. All models were adjusted for candidate demographic and clinical characteristics with a random effect for listing organ procurement organization with nested listing center. RESULTS: HCV+ candidates were commonly older (>50 years: 82.6%), African American (52.8%), and male (73.6%). Five years after listing, 35.5% of candidates were transplanted with an HCV+ donor kidney, 9.7% transplanted with an HCV- donor kidney, and 23.6% died on the waitlist. Overall transplant rates exceeded waitlist mortality rates (22.69 vs 11.45 per 100 person-years [PY]), largely driven by transplantation with HCV+ donor kidneys. Utilization of HCV+ donor kidneys was associated with increased transplantation rate (17.72 per 100 PY), while rate of transplant with HCV- donor kidneys was much lower (4.97 per 100 PY) than waitlist mortality (11.45 per 100 PY). CONCLUSION: In light of effective HCV therapies, it may be prudent to institute strategies to decrease waiting time and waitlist mortality for HCV+ candidates by increasing utilization of HCV+ donor kidneys. PMID- 29277957 TI - Early post-transplant diagnosis of cytomegalovirus esophagitis in an ABO incompatible kidney transplant recipients: A case report. AB - Cytomegalovirus (CMV) is a common infectious pathogen in kidney transplant patients. Here, we present a case of CMV esophagitis with antigenemia, that developed within 3 days of kidney transplantation, a timeline generally considered to be too early for development of a CMV infection. Intense immunosuppressive therapy for desensitization in ABO-incompatibility or in the presence of donor-specific antibody can increase the risk for significant opportunistic infection immediately after or even before transplantation. PMID- 29277959 TI - Defining essential processes in plant pathogenesis with Pseudomonas syringae pv. tomato DC3000 disarmed polymutants and a subset of key type III effectors. AB - Pseudomonas syringae pv. tomato DC3000 and its derivatives cause disease in tomato, Arabidopsis and Nicotiana benthamiana. The primary virulence factors include a repertoire of 29 effector proteins injected into plant cells by the type III secretion system and the phytotoxin coronatine. The complete repertoire of effector genes and key coronatine biosynthesis genes have been progressively deleted and minimally reassembled to reconstitute basic pathogenic ability in N. benthamiana, and in Arabidopsis plants that have mutations in target genes that mimic effector actions. This approach and molecular studies of effector activities and plant immune system targets have highlighted a small subset of effectors that contribute to essential processes in pathogenesis. Most notably, HopM1 and AvrE1 redundantly promote an aqueous apoplastic environment, and AvrPtoB and AvrPto redundantly block early immune responses, two conditions that are sufficient for substantial bacterial growth in planta. In addition, disarmed DC3000 polymutants have been used to identify the individual effectors responsible for specific activities of the complete repertoire and to more effectively study effector domains, effector interplay and effector actions on host targets. Such work has revealed that AvrPtoB suppresses cell death elicitation in N. benthamiana that is triggered by another effector in the DC3000 repertoire, highlighting an important aspect of effector interplay in native repertoires. Disarmed DC3000 polymutants support the natural delivery of test effectors and infection readouts that more accurately reveal effector functions in key pathogenesis processes, and enable the identification of effectors with similar activities from a broad range of other pathogens that also defeat plants with cytoplasmic effectors. PMID- 29277958 TI - Effects of Th17 cells and IL-17 in the progression of cervical carcinogenesis with high-risk human papillomavirus infection. AB - The existence of Th17 cells and IL-17 was recently shown in several types of infectious diseases, but their distribution and functions in cervical lesions with high-risk human papillomavirus (HPV) infection have not been fully elucidated. In this study, the frequency of Th17 cells in peripheral blood samples obtained from 28 cervical squamous cell carcinoma patients, 26 CIN1 patients, 30 CIN2 patients, 29 CIN3 patients, 25 high-risk HPV-infected women with normal cervical cytology, and 30 healthy controls was determined by flow cytometry. Besides, the levels of IL-17 in peripheral blood samples as well as in supernatant of cervical tissue homogenate were assessed by enzyme-linked immunosorbent assay (ELISA) simultaneously. We found that during the disease progression of cervical lesions, the proportion of Th17 cells in the total CD4+ cells showed a gradually increased tendency compared with the controls (P < 0.05). Moreover, levels of IL-17 in serum and supernatant of cervical tissue homogenate showed the same tendency as the proportion of Th17 cells (P < 0.05). When compared in pairs, the levels of IL-17 in supernatant differed significantly among the study groups and the control group (P < 0.05), but no significant difference was observed in serum (P > 0.05). In conclusions, the results indicate that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV especially in the cervical microenvironment, which contribute to the disease progression of its associated cervical lesions. PMID- 29277960 TI - Generalized backpropagation algorithm for training second-order neural networks. AB - The artificial neural network is a popular framework in machine learning. To empower individual neurons, we recently suggested that the current type of neurons could be upgraded to second-order counterparts, in which the linear operation between inputs to a neuron and the associated weights is replaced with a nonlinear quadratic operation. A single second-order neurons already have a strong nonlinear modeling ability, such as implementing basic fuzzy logic operations. In this paper, we develop a general backpropagation algorithm to train the network consisting of second-order neurons. The numerical studies are performed to verify the generalized backpropagation algorithm. PMID- 29277961 TI - Liver resection of hepatocellular carcinoma in patients with portal hypertension and multiple tumors. AB - AIM: Liver resection for hepatocellular carcinoma (HCC) has been recommended only for patients with a single tumor without portal hypertension. We aimed to validate this treatment strategy that is based on by the Barcelona Clinic Liver Cancer staging system. METHODS: Patients undergoing liver resection were divided into two groups: patients with single HCC without portal hypertension (Group 1) and those with at least one factors of portal hypertension and multiple tumors, up to three lesions each <=3 cm (Group 2). We compared survival and postoperative complications between the two groups. RESULTS: The median overall and recurrence free survival periods of patients in Group 1 (n = 695) were 8.5 years (95% confidence interval [CI], 6.6-9.0) and 2.4 years (2.2-2.7), respectively, and were significantly longer compared with those of patients in Group 2 (n = 197) (5.6 years [95% CI, 4.8-6.7], P = 0.001, and 1.9 years [1.6-2.1], P < 0.001). On multivariate analysis, the independent factors for overall survival were hepatitis C virus infection (hazard ratio, 1.29 [95% CI, 1.02-1.65], P = 0.032), multiple tumors (1.42 [1.01-1.98], P = 0.040), and vascular invasion (1.66 [1.31 2.10], P < 0.001). Frequency of morbidity (23 [3.3%] patients vs 11 [5.5%] patients, P = 0.143) and mortality (3 [0.4%] patients vs 2 [1.0%] patients, P = 0.305) was not significantly different between the two groups. CONCLUSIONS: Patients with HCC with portal hypertension and/or multiple tumors could be candidates for liver resection due to the safety of the procedure. PMID- 29277963 TI - Comparing the effects of 3 different pressure ulcer prevention support surfaces on the structure and function of heel and sacral skin: An exploratory cross-over trial. AB - Special support surfaces are key in pressure ulcer prevention. The aim of this study was to measure the effects of 3 different types of mattresses (reactive gel, active alternating air, basic foam) on skin properties of the sacral and heel skin after 2 hours loading. Fifteen healthy females (median age 66 years) were included. Transepidermal water loss, skin surface temperature, erythema, stratum corneum hydration, epidermal hydration, skin extensibility, elastic function, and recovery as well as skin roughness parameters were measured under controlled room conditions before loading, immediately after loading, and 20 minutes post-loading in the supine position on the different mattresses. The highest increases in transepidermal water loss, skin temperature, and erythema were observed for the foam mattress after loading, indicating higher deformation and occlusion. Cutaneous stiffness decreased in all 3 groups, indicating structural changes during loading. There was a substantial decrease of mean roughness at the heel skin in the foam group, leading to a flattening of the skin surface. Study results indicate that the type of support surface influences skin structure and function during loading. The gel and air mattress appeared to be more protective compared with the foam mattress, but the differences between the gel and air were minor. PMID- 29277964 TI - Potential characterization of yeasts isolated from Kazak artisanal cheese to produce flavoring compounds. AB - Cheese is a typical handcrafted fermented food in Kazak minority from the Uighur Autonomy Region in China and Central Asia. Among the microbial community that is responsible for Kazak cheese fermentation, yeasts play important role in flavor formation during ripening. To develop ripening cultures, we isolated 123 yeasts from 25 cheese products in Kazak, and identified 87 isolates by the D1/D2 domain of the large subunit rRNA gene sequence. Pichia kudriavzevii was the dominant yeast in Kazak cheese, followed by Kluyveromyces marxianus and Kluyveromyces lactis. Of these, the ability to exhibit enzyme of dominant isolates and contribution to the typical flavor of cheeses was assessed. Enzyme producing yeast strains were inoculated in Hazak cheese-like medium and volatile compounds were identified by head space solid phase micro extraction coupled to gas chromatography and mass spectroscopy. Pichia kudriavzevii N-X displayed the strongest extracellular proteolytic and activity on skim milk agar and produced a range of aroma compounds (ethanol, ethyl acetate, 3-methylbutanol, and acetic acid) for Kazak cheese flavor, could be explored as ripening cultures in commercial production of Kazak cheeses. PMID- 29277966 TI - Role of inflammatory biomarkers in diabetic peripheral neuropathy. AB - Inflammatory pathway from hyperglycemia to diabetic peripheral neuropathy is very important in diagnosis and management. Inflammatory cytokine can be used for prediction and progression of diabetic peripheral neuropathy. PMID- 29277965 TI - Novel insights into the mechanism of SepL-mediated control of effector secretion in enteropathogenic Escherichia coli. AB - Type three secretion systems (T3SSs) are virulence determinants employed by several pathogenic bacteria as molecular syringes to inject effector proteins into host cells. Diarrhea-producing enteropathogenic Escherichia coli (EPEC) uses a T3SS to colonize the intestinal tract. T3S is a highly coordinated process that ensures hierarchical delivery of three classes of substrates: early (inner rod and needle subunits), middle (translocators), and late (effectors). Translocation of effectors is triggered upon host-cell contact in response to different environmental cues, such as calcium levels. The T3S substrate specificity switch from middle to late substrates in EPEC is regulated by the SepL and SepD proteins, which interact with each other and form a trimeric complex with the chaperone CesL. In this study, we investigated the link between calcium concentration and secretion regulation by the gatekeeper SepL. We found that calcium depletion promotes late substrate secretion in a translocon-independent manner. Furthermore, the stability, formation, and subcellular localization of the SepL/SepD/CesL regulatory complex were not affected by the absence of calcium. In addition, we demonstrate that SepL interacts in a calcium-independent manner with the major export gate component EscV, which in turn interacts with both middle and late secretion substrates, providing a docking site for T3S. These results suggest that EscV serves as a binding platform for both the SepL regulatory protein and secreted substrates during the ordered assembly of the T3SS. PMID- 29277967 TI - Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the standard therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-soluble antimalarial drug artemisinin derivative, SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degradation of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Additionally, SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2-AMPK-ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic molecule for the treatment of DLBCL, along with R-CHOP regimen. PMID- 29277968 TI - Efficacy and safety of adding liraglutide to existing insulin regimens in Japanese patients with type 2 diabetes mellitus: A post-hoc analysis of a phase 3 randomized clinical trial. AB - AIMS/INTRODUCTION: To determine the efficacy and safety of adding liraglutide to three different insulin regimens in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In this post-hoc analysis, results from a 36 week, randomized, double-blind, placebo-controlled, parallel-group trial are reported. Individuals with type 2 diabetes mellitus were stratified according to their pre-trial insulin regimen (basal, basal-bolus and premix). The primary objective was to determine whether adding liraglutide (0.9 mg/day) to fixed-dose insulin therapy was superior vs fixed-dose insulin monotherapy, assessed by the effect on glycemic control after 16 weeks of treatment. RESULTS: The treatment effect on glycated hemoglobin reduction was independent of the pre-trial insulin regimen. Comparing liraglutide with a placebo, liraglutide was associated with glycated hemoglobin reduction in all insulin regimens, with placebo-corrected reductions at 16 weeks ranging from -1.45 to -1.17%, and maintained at 36 weeks. Liraglutide resulted in a greater reduction in mean plasma glucose obtained from seven-point self-monitoring, and greater proportions of patients achieved target glycated hemoglobin. With liraglutide, slightly higher proportions of patients receiving basal and basal-bolus insulin reported confirmed hypoglycemia from 0 to 16 weeks. CONCLUSIONS: The efficacy and safety of adding liraglutide to insulin therapy was confirmed, regardless of pre-trial insulin regimen. PMID- 29277969 TI - Predicting delayed healing: The diagnostic accuracy of a venous leg ulcer risk assessment tool. AB - The aim of this study was to validate a newly developed tool that can predict the risk of failure to heal of a venous leg ulcer in 24 weeks. The risk assessment tool was validated, and performance of the tool was assessed using Area Under the Receiver Operating Characteristic Curve (AUC) analysis. Retrospective and prospective validation was conducted through multi-site, longitudinal studies. In the retrospective study (n = 318), 30% of ulcers did not heal within 24 weeks, with the tool demonstrating an AUC of 0.80 (95% CI, 0.68-0.93, P < .001) for the total score. In the prospective study across 10 clinical sites (n = 225), 31% (n = 68) of ulcers did not heal within 24 weeks. Participants were classified with the RAT at enrolment as being at low risk (27%), moderate risk (53%) or high risk (20%) of delayed healing; the proportion of wounds unhealed at 24 weeks was 6%, 29% and 59%, respectively. Validation results of the total score indicated good discrimination and goodness of fit with an AUC of 0.78 (95% CI, 0.71-0.85, P < .001). Validation of this risk assessment tool offers assurance that realistic outcomes can be predicted for patients, and scores can guide early decisions on interventions to address specific risk factors for failing to heal, thus promoting timely healing. PMID- 29277970 TI - Personality and breast cancer screening in women of the GAZEL cohort study. AB - The potential benefit of breast cancer screening is mitigated by the risk of false positives and overdiagnosis, thus advocating for a more personalized approach, based on the individual benefit-harm balance. Since personality might influence the women's appraisal of this balance, this prospective observational cohort study examined whether it could influence mammography use. A total of 2691 postmenopausal women of the GAZEL Cohort Study completed the Bortner Type A Rating Scale and the Buss and Durkee Hostility Inventory in 1993. Associations between personality scores and subsequent mammography use, self-reported through up to five triennial follow-up questionnaires, were estimated with Odds Ratio (OR) and 95% confidence interval (CI) with logistic mixed model regressions, adjusting for age, occupational grade, marital status, family history of breast cancer, age at menarche, age at first delivery, gynecological follow-up, hormone therapy use, and depressive symptoms. Individual propensity scores were used to weight the analyses to control for potential selection biases. More than 90% of the participants completed at least two follow-up questionnaires. Type A personality, but not hostility, was associated with mammography use in both univariate (crude OR [95% CI]: 1.62 [1.24-2.11], P < 0.001) and multivariate analyses (OR [95% CI]: 1.46 [1.13-1.90], P < 0.01). Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among postmenopausal women. While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis. PMID- 29277971 TI - Intake of Fish Oil Specifically Modulates Colonic Muc2 Expression in Middle-Aged Rats by Suppressing the Glycosylation Process. AB - SCOPE: Dietary fats have been shown to affect gut microbiota composition and aging gene expression of middle-aged rats at a normal dose, but little is known about such an effect on gut barrier. In this study, the changes in colonic Muc2 expression are investigated and the underlying mechanism is also proposed. METHODS AND RESULTS: 36 middle-aged Sprague-Dawley rats are assigned to one of the diets containing soybean oil, lard, or fish oil (4%). The rats are fed for 5 weeks and then goblet cells, Muc2 expression, and inflammatory cytokines in the colon are measured. Proteome analysis is performed. Compared with the lard and soybean oil diet groups, intake of fish oil decreases the number of goblet cells, and inhibits Muc2 and TLRs expression in the colon of middle-aged rats, which would impair mucus barrier. Several key enzymes involved in glycosylation process, including Agr2, Gale, Gne, Pmm2, Pdxdc1, Plch1, Pfkp, Cmpk1, and Rexo2, show the lowest abundance in the fish oil diet group. CONCLUSION: Intake of fish oil at a normal dose downregulates colonic Muc2 expression. This negative effect of fish oil may involve the suppression of mucin glycosylation process. PMID- 29277972 TI - Relationship of implant stability and bone density derived from computerized tomography images. AB - BACKGROUND AND PURPOSE: Implant stability is one of the most important factors influencing osseointegration. Using stereolithographical guides for maximizing precision, this study aimed at investigating the relationship between implant stability and bone density derived from computerized tomography analysis. MATERIALS AND METHODS: One hundred ninety-five implants were placed in 48 patients using digitally designed stereolithographical surgical guides. Ninety five implants were placed using a mucosa supported guide and 100 implants were placed using a bone supported guide. Implant stability was measured by means of resonance frequency analysis (RFA) and damping capacity assessment (Periotest, PTV). Bone density (Hounsfield units) was measured at different regions of interest (ROI) and cortex thickness was measured around each implant. RESULTS: Implant stability correlated significantly with the different ROI. The best correlation for RFA was obtained for the spongious bone ROI (r = .64) and PTV best correlated with the coronal cortex density (r = -.41). Shorter implants (9 mm) had a significantly lower primary stability than longer implants (11, 13, 15 mm). Primary stability was also significantly higher in 4 mm diameter implants than in 3.5 mm diameter implants. A formula for the prediction of primary stability based on the different variables investigated was developed. CONCLUSIONS: Bone density and cortex thickness have a significant influence on implant primary stability. Longer and wider implants reached higher primary stability than shorter and narrower implants. These correlations lose their significance after osseointegration has taken place. Implant stability can be predicted based on an preoperative analysis of bone characteristics. PMID- 29277973 TI - Psychodynamic technique early in treatment related to outcome for depressed patients. AB - We examined the relationship between psychodynamic techniques early in treatment with reliable change in depressive symptomatology. Forty-six patients admitted for individual psychodynamic psychotherapy who received a diagnosis representative of a depressive spectrum disorder were assessed pretreatment and posttreatment through self-report of depressive symptoms. Videotapes from two early treatment sessions (3rd and 9th) were independently rated on the Comparative Psychotherapy Process Scale for use of psychodynamic-interpersonal and cognitive-behavioural techniques, with excellent interrater reliability (intraclass correlation coefficient > .75). We found a significant relationship between overall use of psychodynamic technique across early treatment (r = .31, p = .036), as well as specific psychodynamic techniques delivered across early treatment, with change in patient-reported depressive symptoms. Our findings suggest that focusing on affective experiencing and expression, as well as providing interpretations are particularly helpful early in psychodynamic treatment for depression. Clinical implications and future directions are discussed. PMID- 29277974 TI - Registered nurse intent to promote physical activity for hospitalised liver transplant recipients. AB - AIM: To describe how registered nurse work motivation, attitudes, subjective norm and perceived behavioural control influence intention to promote physical activity in hospitalised adult liver transplant recipients. DESIGN: Descriptive study of clinical registered nurses caring for recipients of liver transplant at a tertiary medical centre. METHODS: Intent to Mobilise Liver Transplant Recipient Scale, Work Extrinsic and Intrinsic Motivation Scale, and demographics were used to explore registered nurses' work motivation, attitudes, subjective norms, perceived behavioural control and intention to promote physical activity of hospitalised adult liver transplant recipients during the acute postoperative phase. Data analysis included demographics, comparison between scale items and analysis of factors predicting intent to mobilise. RESULTS: Factors predictive of intention to promote physical activity after liver transplant included appropriate knowledge to mobilise patients (R2 = .40) and identification of physical activity as nursing staff priority (R2 = .15) and responsibility (R2 = .03). DISCUSSION/IMPLICATIONS FOR NURSING MANAGEMENT: When implementing an early mobilisation protocol after the liver transplant, education on effects of physical activity in the immediate postoperative period are essential to promote implementation in practice. Nursing care environment and leadership must be supportive to ensure mobility is a registered nurse priority and responsibility. Nursing managers can leverage results to implement a mobility protocol. PMID- 29277976 TI - A struggle on two fronts: boundary drawing in the lower region of the social space and the symbolic market for 'down-to-earthness'. AB - In this article we use qualitative interviews to examine how Norwegians possessing low volumes of cultural and economic capital demarcate themselves symbolically from the lifestyles of those above and below them in social space. In downward boundary drawing, a range of types of people are regarded as inferior because of perceived moral and aesthetic deficiencies. In upward boundary drawing, anti-elitist sentiments are strong: people practising resource-demanding lifestyles are viewed as harbouring 'snobbish' and 'elitist' attitudes. However, our analysis suggests that contemporary forms of anti-elitism are far from absolute, as symbolic expressions of privilege are markedly less challenged if they are parcelled in a 'down-to-earth' attitude. Previous studies have shown attempts by the privileged to downplay differences in cross-class encounters, accompanied by displays of openness and down-to-earthness. Our findings suggest that there is in fact a symbolic 'market' for such performances in the lower region of social space. This cross-class sympathy, we argue, helps naturalize, and thereby legitimize, class inequalities. The implications of this finding are outlined with reference to current scholarly debates about politics and populism, status and recognition and intersections between class and gender in the structuring of social inequalities. The article also contributes key methodological insights into the mapping of symbolic boundaries. Challenging Lamont's influential framework, we demonstrate that there is a need for a more complex analytical strategy rather than simply measuring the 'relative salience' of various boundaries in terms of their occurrence in qualitative interview data. In distinguishing analytically between usurpationary and exclusionary boundary strategies, we show that moral boundaries in particular can take on qualitatively different forms and that subtypes of boundaries are sometimes so tightly intertwined that separating them to measure their relative salience would neglect the complex ways in which they combine to engender both aversion to and sympathies for others. PMID- 29277975 TI - Perineuronal nets in subcortical auditory nuclei of four rodent species with differing hearing ranges. AB - Perineuronal nets (PNs) are aggregates of extracellular matrix molecules that surround some neurons in the brain. While PNs occur widely across many cortical areas, subcortical PNs are especially associated with motor and auditory systems. The auditory system has recently been suggested as an ideal model system for studying PNs and their functions. However, descriptions of PNs in subcortical auditory areas vary, and it is unclear whether the variation reflects species differences or differences in staining techniques. Here, we used two staining techniques (one lectin stain and one antibody stain) to examine PN distribution in the subcortical auditory system of four different species: guinea pigs (Cavia porcellus), mice (Mus musculus, CBA/CaJ strain), Long-Evans rats (Rattus norvegicus), and naked mole-rats (Heterocephalus glaber). We found that some auditory nuclei exhibit dramatic differences in PN distribution among species while other nuclei have consistent PN distributions. We also found that PNs exhibit molecular heterogeneity, and can stain with either marker individually or with both. PNs within a given nucleus can be heterogeneous or homogenous in their staining patterns. We compared PN staining across the frequency axes of tonotopically organized nuclei and among species with different hearing ranges. PNs were distributed non-uniformly across some nuclei, but only rarely did this appear related to the tonotopic axis. PNs were prominent in all four species; we found no systematic relationship between the hearing range and the number, staining patterns or distribution of PNs in the auditory nuclei. PMID- 29277977 TI - Developmental signature, synaptic connectivity and neurotransmission are conserved between vertebrate hair cells and tunicate coronal cells. AB - In tunicates, the coronal organ represents a sentinel checking particle entrance into the pharynx. The organ differentiates from an anterior embryonic area considered a proto-placode. For their embryonic origin, morphological features and function, coronal sensory cells have been hypothesized to be homologues to vertebrate hair cells. However, vertebrate hair cells derive from a posterior placode. This contradicts one of the principle historical criteria for homology, similarity of position, which could be taken as evidence against coronal cells/hair cells homology. In the tunicates Ciona intestinalis and C. robusta, we found that the coronal organ expresses genes (Atoh, Notch, Delta-like, Hairy-b, and Musashi) characterizing vertebrate neural and hair cell development. Moreover, coronal cells exhibit a complex synaptic connectivity pattern, and express neurotransmitters (Glu, ACh, GABA, 5-HT, and catecholamines), or enzymes for their synthetic machinery, involved in hair cell activity. Lastly, coronal cells express the Trpa gene, which encodes an ion channel expressed in hair cells. These data lead us to hypothesize a model in which competence to make secondary mechanoreceptors was initially broadly distributed through placode territories, but has become confined to different placodes during the evolution of the vertebrate and tunicate lineages. PMID- 29277978 TI - An update of the evidence on the potential impact of periodontal therapy on diabetes outcomes. AB - AIM: To provide an update of the systematic review by Engebretson and Kocher J Clin Periodontol. 2013 Apr;40 Suppl 14:S153 on the effect of periodontal therapy on glycaemic control of people with diabetes. METHODS: PubMed Literature search restricted to meta-analyses published from 2013 to the present was conducted. The search resulted in seven meta-analyses of RCTs. RESULTS: Reduction in HbA1c at 3 4 months was reported in all reviews for the treatment group ranging from -0.27% (95% CI: -0.46, -0.07, p = .007) to -1.03% (95% CI: 0.36, -1.70, p = 0.003). At 6 months post-treatment, an HbA1c reduction ranging from -0.02 (95% CI: -0.20, 0.16, p = .84) to -1.18% (95% CI: 0.72%, 1.64%, p < 0.001) was reported. CLINICAL RELEVANCE: The magnitude of the reduction in HbA1c, which is found to be associated with non-surgical periodontal treatment in patients with diabetes, seems to have clinically significant effects on systemic health, and thus should have a place in the treatment of diabetic patients. CONCLUSIONS: Periodontal treatment (SRP) results in a statistically significant reduction in HbA1C levels at 3 months, with a lower reduction at 6 months. PMID- 29277979 TI - Survival and prognostic factors for patients with melanoma brain metastases in the era of modern systemic therapy. AB - Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4-6 months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan-Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0-8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9 months (95% CI 10.7-19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4 months (95% CI 5.4-7.5), systemic therapy 5.4 months (95% CI 3.1-7.7), systemic therapy and WBRT 5.2 months (95% CI 4.1-6.4), WBRT 4.4 months (95% CI 2.4-6.3), and best supportive care 1.8 months (95% CI 1.2-2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery. PMID- 29277981 TI - A protective role for FADD dominant negative (FADD-DN) mutant in trinitrochlorobenzene (TNCB)-induced murine contact hypersensitivity reactions. AB - BACKGROUND: Fas-associated protein with death domain (FADD) is a classic adaptor protein in apoptosis. Increasing evidence has shown that FADD is also implicated in T-cell development, activation and proliferation. The role of FADD in inflammatory disorders remains largely unexplored. AIM: To assess the role of FADD in inflammatory disorders. METHODS: We established an experimental model of contact hypersensitivity (CHS) by using 2,4,6-trinitrochlorobenzene (TNCB) on transgenic mice expressing a dominant negative mutant of FADD (FADD-DN), RESULTS: CHS responses were clearly attenuated in FADD-DN mice compared with control mice. In the retroauricular lymph nodes, the ratio of CD8+ T cells was also decreased. CONCLUSION: FADD-DN appears to play a protective role in TNCB-induced CHS reactions. PMID- 29277980 TI - Investigating cross-contamination by yeast strains from dental solid waste to waste-handling workers by DNA sequencing. AB - Trying to widen the discussion on the risks associated with dental waste, this study proposed to investigate and genetically compare yeast isolates recovered from dental solid waste and waste workers. Three samples were collected from workers' hands, nasal mucosa, and professional clothing (days 0, 30, and 180), and two from dental waste (days 0 and 180). Slide culture, microscopy, antifungal drug susceptibility, intersimple sequence repeat analysis, and amplification and sequencing of internal transcribed spacer regions were performed. Yeast strains were recovered from all waste workers' sites, including professional clothes, and from waste. Antifungal susceptibility testing demonstrated that some yeast recovered from employees and waste exhibited nonsusceptible profiles. The dendrogram demonstrated the presence of three major clusters based on similarity matrix and UPGMA grouping method. Two branches displayed 100% similarity: three strains of Candida guilliermondii isolated from different employees, working in opposite work shifts, and from diverse sites grouped in one part of branch 1 and cluster 3 that included two samples of Candida albicans recovered from waste and the hand of one waste worker. The results suggested the possibility of cross contamination from dental waste to waste workers and reinforce the need of training programs focused on better waste management routines. PMID- 29277982 TI - Association analysis of novel polymorphisms in 2', 5'-oligoadenylate synthetase gene with reproductive traits in indigenous and cross-bred cattle of Indian Origin. AB - 2', 5'-Oligoadenylate synthetases (OAS) are important components of an interferon mediated antiviral pathway. No polymorphisms in exonic regions of bovine OAS1 gene have been identified and associated with reproduction traits. The objective of the study was to detect and evaluate the effects of mutations in exonic region of bovine OAS1 gene with reproduction traits in cattle. DNA samples collected from 250 individual cows of two Indian dairy breeds (Sahiwal and Frieswal) of cattle were used in the study. The genetic variants of the OAS1 gene were identified with polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequence analysis using seven set of primer pairs. The PCR-SSCP analysis revealed polymorphism in the fragments comprising of exon 2, exon 5 and first fragment of exon 6 while the fragments of exons 1, 3, 4 and second fragment of exon 6 were monomorphic in Sahiwal and Frieswal cattle. The mutations in the amplified region comprising of exon 2 were found to have significant association with age at first breeding and calving, service period, dry period and pregnancy rate. Significant associations were found between SNPs in the exon 5 and service and dry periods of the animal, whereas the genetic variants in the first fragment of the exon 6 showed significant association with age at first breeding and calving. To our knowledge, this study demonstrated for the first time that the polymorphisms in OAS1 gene were associated with reproductive traits and it can be chosen as a candidate gene for improvement of reproductive performance of cattle. PMID- 29277983 TI - Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons. AB - SCOPE: Thymoquinone (TQ) has been used as a potential therapeutic for diseases such as cancer and diabetes. Herein, we aim to investigate the effect of TQ on behavioral and molecular parameters in healthy rat hippocampus. METHODS: TQ (20 mg kg-1 d-1 ) is administered intragastrically for 15 days to adult rats. After behavioral tests, the hippocampal tissues are investigated at the histological and molecular levels. RESULTS: In both dentate gyrus and cornu ammonis 1, TQ significantly increases the number of hippocampal neurons. This increase is supported by a significant increase in the doublecortin expression on both gene and protein levels. In addition, TQ significantly decreases the amount of Caspase 3 expression and the cleavage of poly ADP ribose polymerase, indicating a decrease in apoptosis. Further, ERK, GSK-3, JNK, CREB, and iNOS proteins are found to be positively regulated by TQ. However, the gene expression of synapsin, synaptophysin, NGF, AKT, Bax, NFkB, and p53 and the protein expression of BDNF and nNOS are not affected by TQ. CONCLUSION: These findings suggest that TQ has an enhancing effect on cell survival and neurogenesis in healthy hippocampus, rather inducing apoptosis in damaged neurons. This may proceed via ERK/JNK and CREB signaling pathways as a candidate acting mechanism for TQ. PMID- 29277984 TI - Direct determination of trace phthalate esters in alcoholic spirits by spray inlet microwave plasma torch ionization tandem mass spectrometry. AB - A direct analytical method based on spray-inlet microwave plasma torch tandem mass spectrometry was applied to simultaneously determine 4 phthalate esters (PAEs), namely, benzyl butyl phthalate, diethyl phthalate, dipentyl phthalate, and dodecyl phthalate with extremely high sensitivity in spirits without sample treatment. Among the 4 brands of spirit products, 3 kinds of PAE compounds were directly determined at very low concentrations from 1.30 to 114 ng.g-1 . Compared with other online and off-line methods, the spray-inlet microwave plasma torch tandem mass spectrometry technique is extremely simple, rapid, sensitive, and high efficient, providing an ideal screening tool for PAEs in spirits. PMID- 29277985 TI - Pseudomonas infection following total contact cast application. PMID- 29277986 TI - Trap Depth Engineering of SrSi2O2N2:Ln2+,Ln3+ (Ln2+ = Yb, Eu; Ln3+ = Dy, Ho, Er) Persistent Luminescence Materials for Information Storage Applications. AB - Deep-trap persistent luminescence materials exhibit unique properties of energy storage and controllable photon release under additional stimulation, allowing for both wavelength and intensity multiplexing to realize high-capacity storage in the next-generation information storage system. However, the lack of suitable persistent luminescence materials with deep traps is the bottleneck of such storage technologies. In this study, we successfully developed a series of novel deep-trap persistent luminescence materials in the Ln2+/Ln3+-doped SrSi2O2N2 system (Ln2+ = Yb, Eu; Ln3+ = Dy, Ho, Er) by applying the strategy of trap depth engineering. Interestingly, the trap depth can be tailored by selecting different codopants, and it monotonically increases from 0.90 to 1.18 eV in the order of Er, Ho, and Dy. This is well explained by the energy levels indicated in the host referred binding energy scheme. The orange-red-emitting SrSi2O2N2:Yb,Dy and green emitting SrSi2O2N2:Eu,Dy phosphors are demonstrated to be good candidates of information storage materials, which are attributed to their deep traps, narrow thermoluminescence glow bands, high emission efficiency, and excellent chemical stability. This work not only validates the suitability of deep-trap persistent luminescence materials in the information storage applications, but also broadens the avenue to explore such kinds of new materials for applications in anticounterfeiting and advanced displays. PMID- 29277987 TI - Bioinspired, Manganese-Chelated Alginate-Polydopamine Nanomaterials for Efficient in Vivo T1-Weighted Magnetic Resonance Imaging. AB - Manganese-based nanomaterials are an emerging new class of magnetic resonance imaging (MRI) contrast agents (CAs) that provide impressive contrast abilities. MRI CAs that can respond to pathophysiological parameters such as pH or redox potential are also highly in demand for MRI-guided tumor diagnosis. Until now, synthesizing nanomaterials with good biocompatibility, physiochemical stability, and good contrast effects remains a challenge. This study investigated two new systems of calcium/manganese cations complexed with either alginate-polydopamine or alginate-dopamine nanogels [AlgPDA(Ca/Mn) NG or AlgDA(Ca/Mn) NG]. Under such systems, Ca cations form ionic interactions via carboxylic acids of the Alg backbone to enhance the stability of the synthetic nanogels (NGs). Likewise, complexation of Mn cations also increased the colloidal stability of the synthetic NGs. The magnetic property of the prepared CAs was confirmed with superconducting quantum interference device measurements, proving the potential paramagnetic property. Hence, the T1 relaxivity measurement showed that PDA complexed synthetic NGs reveal a strong positive contrast enhancement with r1 = 12.54 mM-1.s-1 in 7.0 T MRI images, whereas DA-complexed synthetic NGs showed a relatively lower T1 relaxivity effect with r1 = 10.13 mM-1.s-1. In addition, both the synthetic NGs exhibit negligible cytotoxicity with >92% cell viability up to 0.25 mM concentration, when incubated with the mouse macrophage (RAW 264.7) and HeLa cells, and high biocompatibility under in vivo analysis. The in vivo MRI test indicates that the synthetic NG exhibits a high signal-to-noise ratio for longer hours, which provides a longer image acquisition time for tumor and anatomical imaging. Furthermore, T1-weighted MRI results revealed that PEGylated AlgPDA(Ca/Mn) NGs significantly enhanced the signals from liver and tumor tissues. Therefore, owing to the enhanced permeability and retention effect, significantly enhanced in vitro and in vivo imagings, low cost, and one-pot synthesis method, the Mn-based biomimetic approach used in this study provides a promising and competitive alternative for noninvasive tumor detection and comprehensive anatomical diagnosis. PMID- 29277988 TI - Interface Engineering for Controlling Device Properties of Organic Antiambipolar Transistors. AB - The main purpose of this study is to establish a guideline for controlling the device properties of organic antiambipolar transistors. Our key strategy is to use interface engineering to promote carrier injection at channel/electrode interfaces and carrier accumulation at a channel/dielectric interface. The effective use of carrier injection interlayers and an insulator layer with a high dielectric constant (high-k) enabled the fine tuning of device parameters and, in particular, the onset (Von) and offset (Voff) voltages. A well-matched combination of the interlayers and a high-k dielectric layer achieved a low peak voltage (0.25 V) and a narrow on-state bias range (2.2 V), indicating that organic antiambipolar transistors have high potential as negative differential resistance devices for multivalued logic circuits. PMID- 29277989 TI - Control of the Intrinsic Sensor Response to Volatile Organic Compounds with Fringing Electric Fields. AB - The ability to control surface-analyte interaction allows tailoring chemical sensor sensitivity to specific target molecules. By adjusting the bias of the shallow p-n junctions in the electrostatically formed nanowire (EFN) chemical sensor, a multiple gate transistor with an exposed top dielectric layer allows tuning of the fringing electric field strength (from 0.5 * 107 to 2.5 * 107 V/m) above the EFN surface. Herein, we report that the magnitude and distribution of this fringing electric field correlate with the intrinsic sensor response to volatile organic compounds. The local variations of the surface electric field influence the analyte-surface interaction affecting the work function of the sensor surface, assessed by Kelvin probe force microscopy on the nanometer scale. We show that the sensitivity to fixed vapor analyte concentrations can be nullified and even reversed by varying the fringing field strength, and demonstrate selectivity between ethanol and n-butylamine at room temperature using a single transistor without any extrinsic chemical modification of the exposed SiO2 surface. The results imply an electric-field-controlled analyte reaction with a dielectric surface extremely compelling for sensitivity and selectivity enhancement in chemical sensors. PMID- 29277990 TI - Enhanced Light Stability of InGaZnO Thin-Film Transistors by Atomic-Layer Deposited Y2O3 with Ozone. AB - We report the effect of Y2O3 passivation by atomic layer deposition (ALD) using various oxidants, such as H2O, O2 plasma, and O3, on In-Ga-Zn-O thin-film transistors (IGZO TFTs). A large negative shift in the threshold voltage (Vth) was observed in the case of the TFT subjected to the H2O-ALD Y2O3 process; this shift was caused by a donor effect of negatively charged chemisorbed H2O molecules. In addition, degradation of the IGZO TFT device performance after the O2 plasma-ALD Y2O3 process (field-effect mobility (MU) = 8.7 cm2/(V.s), subthreshold swing (SS) = 0.77 V/dec, and Vth = 3.7 V) was observed, which was attributed to plasma damage on the IGZO surface adversely affecting the stability of the TFT under light illumination. In contrast, the O3-ALD Y2O3 process led to enhanced device stability under light illumination (DeltaVth = -1 V after 3 h of illumination) by passivating the subgap defect states in the IGZO surface region. In addition, TFTs with a thicker IGZO film (55 nm, which was the optimum thickness under the current investigation) showed more stable device performance than TFTs with a thinner IGZO film (30 nm) (DeltaVth = -0.4 V after 3 h of light illumination) by triggering the recombination of holes diffusing from the IGZO surface to the insulator-channel interface. Therefore, we envisioned that the O3 ALD Y2O3 passivation layer suggested in this paper can improve the photostability of TFTs under light illumination. PMID- 29277991 TI - Understanding the Origin of the Regioselectivity in Cyclopolymerizations of Diynes and How to Completely Switch It. AB - Grubbs-type olefin metathesis catalysts are known to cyclopolymerize 1,6 heptadiynes to afford conjugated polyenes containing five- or six-membered carbocycles. Although high levels of regioselectivity up to >99:1 were observed previously for the formation of five-membered rings, it was neither possible to deliberately obtain six-membered rings at similar levels of selectivity nor understood why certain catalysts showed this selectively. Combining experimental and computational methods, a novel and general theory for what controls the regiochemistry of these cyclopolymerizations is presented. The electronic demands of the ruthenium-based Fischer carbenes are found to innately prefer to form five membered rings. Reducing the electrophilicity of the carbene by enforcing a trigonal-bipyramidal structure for the ruthenium, where stronger pi-backdonation increases the electron density on the carbene, is predicted to invert the regioselectivity. Subsequent experiments provide strong support for the new concept, and it is possible to completely switch the regioselectivity to a ratio of <1:99. PMID- 29277992 TI - New Class of Type III Porous Liquids: A Promising Platform for Rational Adjustment of Gas Sorption Behavior. AB - Porous materials have already manifested their unique properties in a number of fields. Generally, all porous materials are in a solid state other than liquid, in which molecules are closely packed without porosity. "Porous" and "liquid" seem like antonyms. Herein, we report a new class of Type 3 porous liquids based on rational coupling of microporous framework nanoparticles as porous hosts with a bulky ionic liquid as the fluid media. Positron annihilation lifetime spectroscopy (PALS) and CO2 adsorption measurements confirm the successful engineering of permanent porosity into these liquids. Compared to common porous solid materials, as-synthesized porous liquids exhibited pronounced hysteresis loops in the CO2 sorption isotherms even at ambient conditions (298 K, 1 bar). The unique features of these novel porous liquids could bring new opportunities in many fields including gas separation and storage, air separation and regeneration, gas transport, and permanent gas storage at ambient conditions. PMID- 29277993 TI - Self-Assembled One-Dimensional Porphyrin Nanostructures with Enhanced Photocatalytic Hydrogen Generation. AB - There has been a widespread interest in the preparation of self-assembled porphyrin nanostructures and their ordered arrays, aiming to emulate natural light harvesting processes and energy storage and to develop new nanostructured materials for photocatalytic process. Here, we report controlled synthesis of one dimensional porphyrin nanostructures such as nanorods and nanowires with well defined self-assembled porphyrin networks that enable efficient energy transfer for enhanced photocatalytic activity in hydrogen generation. Preparation of these one-dimensional nanostructures is conducted through noncovalent self-assembly of porphyrins confined within surfactant micelles. X-ray diffraction and transmission electron microscopy results reveal that these one-dimensional nanostructures contain stable single crystalline structures with controlled interplanar separation distance. Optical absorption characterizations show that the self-assembly enables effective optical coupling of porphyrins, resulting in much more enhanced optical absorption in comparison with the original porphyrin monomers, and the absorption bands red shift to more extensive visible light spectrum. The self-assembled porphyrin network facilitates efficient energy transfer among porphyrin molecules and the delocalization of excited state electrons for enhanced photocatalytic hydrogen production under visible light. PMID- 29277994 TI - Choreography of the Reductase and P450BM3 Domains Toward Electron Transfer Is Instigated by the Substrate. AB - The driving force for the electron transfer (ET) step in the catalytic cycle of cytochrome P450BM3 is investigated using three sets of 1 MUs molecular dynamic simulations for the resting state of P450 in complex with the flavin (FMN) in the reductase domain. These sets involve the following: (i) substrate-free (SF), (ii) substrate (N-palmitoyl glycine, i.e., NPG)-bound (SB), and (iii) SB with the semiquinone radical anion (SQ-) of FMN. Starting from the X-ray structure of the SF heme domain, we observe that the alpha1-helix (of the reductase) and the C helix (of the heme) undergo reorientation to a parallel orientation, which is the thermochemically stable form. The reorientation of the helices pushes away the FMN to a distance of 18.4 A from the heme's center. When the substrate binds it causes the I-helix of the heme domain to kink and push the C-helix toward the alpha1-helix, thereby locking the latter two into a stabilized perpendicular conformation, wherein the FMN-heme distance is 12 A. The distance drops further in the SQ- form, and upon QM/MM geometry optimization the two moieties approach 8.8 A, which enhances the ET rate (by 104-106 fold) to the heme's Fe3+ ion. These motions are driven by hydrogen bond strengthening between the C- and the alpha1 helices. Finally, substrate binding leads to formation of an organized water chain connecting the FMN and heme moieties. The water channel assists the ET and couples it to the proton transfer steps that should activate O2 and create the oxo-iron active species. PMID- 29277995 TI - Tilted, Uninterrupted, Monomeric HIV-1 gp41 Transmembrane Helix from Residual Dipolar Couplings. AB - Cryo-electron microscopy and X-ray crystallography have shown that the pre- and postfusion states of the HIV-1 gp41 viral coat protein, although very different from one another, each adopt C3 symmetric structures. A stable homotrimeric structure for the transmembrane domain (TM) also was modeled and supported by experimental data. For a C3 symmetric structure, alignment in an anisotropic medium must be axially symmetric, with the unique axis of the alignment tensor coinciding with the C3 axis. However, NMR residual dipolar couplings (RDCs) measured under three different alignment conditions were found to be incompatible with C3 symmetry. Subsequent measurements by paramagnetic relaxation enhancement, analytical ultracentrifugation, and DEER EPR, indicate that the transmembrane domain is monomeric. 15N NMR relaxation data and RDCs show that TM is highly ordered and uninterrupted for a total length of 32 residues, extending well into the membrane proximal external region. PMID- 29277996 TI - A Structural and Functional Role for Disulfide Bonds in a Class II Hydrophobin. AB - Hydrophobins are multifunctional, highly surface active proteins produced in filamentous fungi and can be identified by eight conserved cysteine residues, which form four disulfide bridges. These proteins can be subdivided into two classes based on their hydropathy profiles, solubility, and structures formed upon interfacial assembly. Here, we probe the structural and functional roles of disulfide bonds for a class II hydrophobin in different interfacial contexts by reducing its disulfides with 1,4-dithiothreitol and blocking the free thiols with iodoacetamide and then examining the protein secondary structure, emulsification capability, hydrophobic surface wetting, and solution self-assembly. Changes in circular dichroism spectra upon reduction and blocking of disulfides are consistent with an increase in the level of random coil secondary structure. Emulsification of octane in water using reduced and unreduced forms of class II hydrophobin showed a substantial loss of emulsification ability without disulfides and stable emulsion formation for hydrophobin with disulfides. Additionally, water contact angle measurements performed on polytetrafluoroethylene treated with solutions of reduced and unreduced hydrophobin showed efficient wetting of the hydrophobic surface for unreduced samples only. Lastly, Forster resonance energy transfer (FRET) was used to assess the role of disulfides in self-assembly in solution, and near complete loss of the FRET signal is consistent with a model in which solution self-assembly does not occur after reduction and blocking of the disulfides. From this, we conclude that, in contrast to class I hydrophobins, the disulfides of this class II hydrophobin are required for protein structural stability, surface activity at both liquid-liquid and solid-liquid interfaces, and solution self-assembly. PMID- 29277997 TI - Oxygen Sensing Based on the Yellowing of Newspaper. AB - Newspaper is known to turn yellow over time. We show here that this yellowing process is sensitive to oxygen when exposed to UV light, leading to oxygen sensing. Oxygen sensing is critical to many applications, including industrial process control and breath analysis, but the existing oxygen sensors have limitations, especially for breath analysis that operates at 100% humidity. The UV irradiation also triggers fluorescence emission from newspaper, and the fluorescence intensity depends on oxygen concentration, providing an additional oxygen sensing method. Newspaper is stable in ambient air, and reactive to oxygen only with UV activation, which overcomes the instability issue of a typical colorimetric sensor in ambient air. The newspaper oxygen sensor works in 100% relative humidity air, containing various interferents. These unique properties of newspaper promise low cost and reliable oxygen sensing applications. PMID- 29277998 TI - High-Performance Stretchable Conductive Composite Fibers from Surface-Modified Silver Nanowires and Thermoplastic Polyurethane by Wet Spinning. AB - Highly stretchable and conductive fibers have attracted great interest as a fundamental building block for the next generation of textile-based electronics. Because of its high conductivity and high aspect ratio, the Ag nanowire (AgNW) has been considered one of the most promising conducting materials for the percolation network-based conductive films and composites. However, the poor dispersibility of AgNWs in hydrophobic polymers has hindered their application to stretchable conductive composite fibers. In this paper, we present a highly stretchable and conductive composite fiber from the co-spinning of surface modified AgNWs and thermoplastic polyurethane (PU). The surface modification of AgNWs with a polyethylene glycol derivative improved the compatibility of PU and AgNWs, which allowed the NWs to disperse homogeneously in the elastomeric matrix, forming effective percolation networks and causing the composite fiber to show enhanced electrical and mechanical performance. The maximum AgNW mass fraction in the composite fiber was 75.9 wt %, and its initial electrical conductivity was as high as 14 205 S/cm. The composite fibers also exhibited superior stretchability: the maximum rupture strain of the composite fiber with 14.6 wt % AgNW was 786%, and the composite fiber was also conductive even when it was stretched up to 200%. In addition, 2-dimensional (2-D) Ag nanoplates were added to the AgNW/PU composite fibers to increase the stability of the conductive network under repeated stretching and releasing. The Ag nanoplates acted as a bridge to effectively prevent the AgNWs from slippage and greatly improved the stability of the conductive network. PMID- 29277999 TI - Nonalcoholic steatohepatitis and hepatic adenomatosis: casual or causal relationship? AB - Hepatic adenomatosis is a benign disease defined as the presence of multiple adenomas in a normal liver. It is an uncommon condition and there are less than a hundred reported cases in the literature. The etiology is unknown, although it has been associated with the use of oral contraceptives, anabolic steroids, certain storage diseases and some genetic mutations linked to maturity onset diabetes of the young. The coexistence of hepatic adenomatosis and nonalcoholic steatohepatitis has been recently described in two patients suffering from metabolic syndrome. This association is particularly interesting due to the growing prevalence of nonalcoholic fatty liver disease in developed countries and the possibility of a common causal pathway. We report the case of a young woman with fructosemia and hepatic steatosis; multiple hepatic adenomas associated to steatohepatitis lesions were also found during clinical follow-up. The possible implications are discussed. PMID- 29278000 TI - Capsule endoscopy with PillCamSB2 versus PillCamSB3: has the improvement in technology resulted in a step forward? AB - AIM: To compare the findings and completion rate of PillCam(r) SB2 and SB3. METHODS: This was a retrospective single-center study that included 357 consecutive small bowel capsule endoscopies (SBCE), 173 SB2 and 184 SB3. The data collected included age, gender, capsule type (PillCam(r) SB2 or SB3), quality of bowel preparation, completion of the examination, gastric and small bowel transit time, small bowel findings, findings in segments other than the small bowel and the detection of specific anatomical markers, such as the Z line and papilla. RESULTS: The mean age of the patients was 48 years and 66.9% were female. The two main indications were suspicion/staging of inflammatory bowel disease (IBD) and obscure gastrointestinal bleeding (OGIB) (43.7% and 40.3%, respectively). Endoscopic findings were reported in 76.2% of examinations and 53.5% were relevant findings. No significant differences were found between SB2 and SB3 with regard to completion rate (93.6% vs 96.2%, p = 0.27), overall endoscopic findings (73.4% vs 78.8%, p = 0.23), relevant findings (54.3% vs 52.7%, p = 0.76), first tertile findings (43.9% vs 48.9%, p = 0.35), extra-SB findings (23.7% vs 17.3%, p = 0.14), Z line and papilla detection rate (35.9% vs 35.7%, p = 0.97 and 27.1% vs 32.6%, p = 0.32, respectively). With regard to the patient subgroups with suspicion/staging of IBD, significant differences were found in relation to the detection of villous edema and the 3rd tertile findings, thus favoring SB3 (26.3% vs 43.8%, p = 0.02 and 47.4% vs 66.3%, p = 0.02, respectively). Mucosal atrophy was significantly more frequently diagnosed with the PillCam(r) SB3 in patients with anemia/OGIB (0% vs 8%, p = 0.03). CONCLUSIONS: Overall, PillCam(r) SB3 did not improve the diagnostic yield compared to SB2, although it improved the detection of villous atrophy and segmental edema. PMID- 29278001 TI - Spontaneous intramural intestinal hemorrhage due to anticoagulation therapy. AB - An 84-years old woman, medicated with acenocumarol, was admitted to the Emergency Room with lower abdominal pain and nauseas and no history of trauma. She was medicated with acenocumarol and had a non-measurable international normalized ratio. The findings of the bowel ultrasound, ileocolonoscopy and biopsies specimens were suggestive of intramural bleeding of the ileum, ileocecal valve and cecum. Spontaneous intramural bleeding of the gastrointestinal wall associated with oral anticoagulation is rare. PMID- 29278002 TI - Cholestasis after TIPS placement in a patient with primary sclerosing cholangitis: an uncommon complication. AB - We present the case of a patient with primary sclerosing cholangitis who presented a rapidly evolving cholestatic syndrome, with severe hyperbilirubinemia after placing a TIPS. It was resolved with a biliary prosthesis inserted by ERCP. To date, no similar cases have been described in the literature, as it is a rare complication and, on the other hand, the experience with TIPS in patients with PSC is limited. The causes of hyperbilirubinemia after TIPS placement are very varied and it is crucial to perform a differential diagnosis to establish an early treatment. PMID- 29278003 TI - Ileocecal endometriosis as an infrequent cause of intussusception. AB - We present a case of ileocecal endometriosis as a cause of infrequent ileocolic intussusception in an adult patient. It is reviewed as published by the authors Sanchez Cifuentes, A et al. 2016, emphasizing the rarity of the location of endometriosis, and its association as a cause of intussusception. PMID- 29278004 TI - Complicated peribiliary cysts in patient without any prior liver disease. AB - Peribiliary cysts involve cystic dilation of the extramural peribiliary glands in the liver hilum and portal tracts. Most peribiliary cysts are asymptomatic. We present the case of a patient without any prior liver disease who developed obstructive jaundice and a liver abscess due to peribiliary cysts. Peribiliary cysts usually appear in patients with severe chronic liver disease and are asymptomatic, although they sometimes appear in patients without prior liver disease and cause serious complications. PMID- 29278005 TI - Chilaiditi syndrome complicated by a sigmoid volvulus and hepatic displacement. AB - Chilaiditi's sign is an anatomical alteration consisting of the transposition of the small intestine or colon between the liver and diaphragm that is asymptomatic and is usually an accidental radiological finding. The onset of Chilaiditi syndrome is accompanied by clinical symptoms and is even rarer. Moreover, the combination of sigmoid volvulus and Chilaiditi syndrome is extremely rare, with only 17 previous published cases, one of which occurred in a female patient. PMID- 29278006 TI - Relationship between disease activity and patient-reported outcomes in rheumatoid arthritis: Post hoc analyses of overall and Japanese results from two phase 3 clinical trials. AB - OBJECTIVE: To examine patient-reported outcomes (PROs) in patients with different rheumatoid arthritis (RA) disease activity levels and identify residual symptoms. METHODS: Post hoc analyses of overall and Japanese data from two randomized controlled trials including RA patients with previous inadequate responses to methotrexate (NCT01710358) or no/minimal previous disease-modifying antirheumatic drug treatment (NCT01711359) (sponsor: Eli Lilly and Company). Week 24 assessments were disease activity (Simplified Disease Activity Index, Disease Activity Score/Disease Activity Score 28 joints-erythrocyte sedimentation rate) and PROs (pain visual analog scale [VAS], morning joint stiffness [MJS], Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue, and Medical Outcomes Study Short Form 36 Health Survey Physical and Mental Component Scores). RESULTS: Patients achieving remission/low disease activity (LDA) at Week 24 had larger/significant improvements from baseline in pain, MJS, disability, fatigue, and physical and emotional quality of life versus patients with high/moderate disease activity. Some patients achieving remission and LDA, reported residual pain (pain VAS >10 mm): 20.8-39.3% and 48.7 70.0% (overall study populations), 16.0-34.5% and 47.1-62.0% (Japanese patients). Residual MJS and fatigue were also reported. CONCLUSION: Remission/LDA were associated with improvements in PROs in overall and Japanese patient populations; however, some patients achieving remission had residual symptoms, including pain. PMID- 29278007 TI - What do polish parents know about dental trauma and its management in children's treatment? A questionnaire study. AB - OBJECTIVES: To evaluate the knowledge of Polish parents concerning traumatic dental injuries (TDIs) and their management in children and to assess the influence of TDI experience on parents' knowledge. METHODS: A questionnaire study conducted from May 2014 to February 2015 involved 741 randomly selected individual parents of children aged 1-17 receiving treatment at the Department of Pediatric Dentistry at the Medical University of Warsaw. The questionnaire consisted of 28 questions concerning TDI management. RESULTS: The study included 600 questionnaires subjected to statistical analysis using a chi2 independence test and Spearman's rank correlation (p < .05). Results show that 68% of parents have never received information about TDI management. As many as 80.5% were unaware of the possibility of immediate replantation of an avulsed tooth; over 60% would not be capable of choosing a suitable transport medium for such a tooth. Over 12% of TDI-experienced parents were unaware of a suitable transport medium for an avulsed tooth. Three times as many inexperienced parents as parents with TDI experience would place an avulsed tooth in saline solution. The independence test presented a strong correlation between parents' education and their knowledge about TDI management. As many as 80% of parents assessed their knowledge about TDI as inadequate. CONCLUSIONS: It appears necessary to introduce programmes for parents to raise their level of awareness concerning this topic. PMID- 29278008 TI - Oral health status of hospitalized amyotrophic lateral sclerosis patients: a single-centre observational study. AB - OBJECTIVE: To assess the intraoral conditions and oral function of patients with amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS: This single-centre, cross-sectional observational study included 50 ALS patients, who were treated with tracheostomy positive-pressure ventilation (TPPV) while hospitalized. The disease duration, TPPV duration, current number of teeth, number of occlusal units, number of decayed/missing/filled teeth, community periodontal index, bleeding on probing, dental calculus, maximum mouth opening, salivation rate, tongue anomalies (atrophy or hypertrophy) and tongue coating were determined for each patient. Differences in intraoral conditions according to disease duration or TPPV duration were statistically analysed. RESULTS: The maximum mouth opening was low in the included patients, with a mean distance of 13.7 +/- 7.4 mm. Furthermore, the maximum mouth opening showed a significant negative correlation with both disease duration and TPPV duration. No statistically significant differences were found between any other intraoral parameters and disease duration or TPPV duration. CONCLUSIONS: Severe dental disease is uncommon among hospitalized ALS patients who receive oral care by nurses; however, mouth opening is very restricted in these patients. Early intervention for restricted mouth opening, directed by a dentist or dental hygienist, is essential in this population. PMID- 29278009 TI - Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult onset Still's disease: A multicenter retrospective study. AB - BACKGROUND: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO 1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria. PMID- 29278010 TI - Pre-liver transplant psychosocial evaluation predicts post-transplantation outcomes. AB - Psychosocial factors greatly impact the course of patients throughout the liver transplantation process. A retrospective chart review was performed of patients who underwent liver transplantation at Hadassah-Hebrew University Medical Center between 2002 and 2012. A composite psychosocial score was computed based on the patient's pre-transplant evaluation. Patients were divided into two groups based on compliance, support and insight: Optimal psychosocial score and Non-optimal psychosocial score. Post-liver transplantation survival and complication rates were evaluated. Out of 100 patients who underwent liver transplantation at the Hadassah-Hebrew University Medical Center between 2002 and 2012, 93% had a complete pre-liver transplant psychosocial evaluation in the medical record performed by professional psychologists and social workers. Post-liver transplantation survival was significantly higher in the Optimal group (85%) as compared to the Non-optimal group (56%, p = .002). Post-liver transplantation rate of renal failure was significantly lower in the Optimal group. No significant differences were observed between the groups in other post-transplant complications. A patient's psychosocial status may impact outcomes following transplantation as inferior psychosocial grades were associated with lower overall survival and increased rates of complications. Pre-liver transplant psychosocial evaluations are an important tool to help predict survival following transplantation. PMID- 29278011 TI - Validation of assistive technology on psychoactive substances for visually impaired people. AB - PURPOSE: To validate the assistive technology "Drugs: reflection for prevention" to be used with visually impaired people. METHOD: Quantitative and quasi experimental study, contrasting knowledge before and after the use of the assistive technology with 140 visually impaired people in institutes and associations for people with visual impairment. A questionnaire with identification data, a pre-test, a post-test and a questionnaire to assess the assistive technology were applied. Data were described through means and standard deviations, and analyses included the McNemar test, the exact binomial distribution test, and the intraclass correlation coefficient. RESULTS: Participants were male (65.7%), 84.3% were blind, aged 37.1 years on average and with schooling of 10.1 years on average. There were more correct answers in the post-test (p <.001). The attributes of the assistive technology were considered adequate: objectives, access, clarity, structure and presentation, relevance and efficacy, and interactivity (p <.001). CONCLUSIONS: The assistive technology "Drugs: reflection for prevention" was considered valid and reliable to inform visually impaired people about psychoactive substance abuse. Implications for rehabilitation Created new tool for prevention substance abuse that can be accessed easily. Improved information about substance psychoactive for users of the assistive technology. Improved quality of life for its users. PMID- 29278012 TI - Pilocytic astrocytoma of the cerebellopontine angle mimicking vestibular schwannoma: report of a rare entity. AB - We present a rare case of a 55-yr old patient of pilocytic astrocytoma of the cerebello-pontine angle mimicking a vestibular schwannoma. The tumor protruded into the porus acusticus causing enlargement of the internal auditory meatus, which is quite an unusual feature of glial tumours. PMID- 29278013 TI - Behind human milk and breastfeeding: not only food. AB - After birth, breastfeeding should not be considered only a normal and physiological event; in fact, it encloses both physical and the psychological aspects. Human milk cannot be compared to any formula milk. Specifically, human milk has immunological and nutritional properties and it is considered the best available option which guarantees an adequate growth and an optimal development of a child. Differences in term of mediators and hormones have been shown between infants who were breastfed and ones who were not. A key point is represented by unmeasurable environmental and psycho-affective factors. So, it may be simplistic to consider human milk only as a nutrient; since it encompasses much more. The aim of our commentary is to review clinical studies about breastfeeding, analysing its consequences on the neuro-developmental achievement, growth and risk of obesity within a holistic view. PMID- 29278014 TI - Healthcare resource utilization among patients with relapsed multiple myeloma in the UK, France, and Italy. AB - AIMS: To assess the real-world healthcare resource utilization (HRU) and costs associated with different treatment regimens used in the management of patients with relapsed multiple myeloma in the UK, France, and Italy. METHODS: Retrospective medical chart review of characteristics, time to progression, level of response, HRU during treatment, and adverse events (AEs). Data collection started on June 1, 2015 and was completed on July 15, 2015. In the 3 months before record abstraction, eligible patients had either disease progression after receiving one of their country's most commonly prescribed regimens or had received the best supportive care and died. Costs were calculated based on HRU and country-specific diagnosis-related group and/or unit reference costs, amongst other standard resources. RESULTS: Physicians provided data for 1,282 patients (387 in the UK, 502 in France, 393 in Italy) who met the inclusion criteria. Mean [median] total healthcare costs associated with a single line of treatment were ?51,717 [35,951] in the UK, ?37,009 [32,538] for France, and ?34,496 [42,342] for Italy, driven largely by anti-myeloma medications costs (contributing 95.0%, 90.0%, and 94.2% of total cost, respectively). During active treatment, the highest costs were associated with lenalidomide- and pomalidomide-based regimens. Mean cost per month was lowest for patients achieving a very good partial response or better. Unscheduled events (i.e. not considered part of routine management, whether or not related to multiple myeloma, such as unscheduled hospitalization, AEs, fractures) accounted for 1-9% of total costs and were highest for bendamustine. LIMITATIONS: The use of retrospective data means that clinical practice (e.g. use of medical procedures, evaluation of treatment response) is not standardized across participating countries/centers, and some data (e.g. low-grade AEs) may be incomplete or differently adjudicated/reported. The centers involved may not be fully representative of national practice. CONCLUSIONS: Drug costs are the main contributor to total HRU costs associated with multiple myeloma. The duration of active treatment may influence the average total costs, as well as response, associated with a single line of therapy. Improved treatment outcomes, and reductions in unscheduled events and concomitant medication use may, therefore, reduce the overall HRU and related costs of care in multiple myeloma. PMID- 29278015 TI - An overview on the current status of cancer nanomedicines. AB - PURPOSE: Cancer remains a significant cause of morbidity and mortality across the globe. A recent report suggests around 14.1 million new cases and 8.2 million cancer-related deaths, which are expected to reach 21.7 million and 13 million by 2030 worldwide, respectively. MATERIALS AND METHODS: Because of highly complex mechanisms of cancer progression, it is important to explore and develop new innovative technologies which are more efficient compared with presently available treatment options. RESULTS: Currently, chemotherapy, radiation and surgery are the most commonly used cancer treatment methods. In the last decade, nanomedicine emerged as an alternative treatment option that uses specific drug delivery systems, improves efficacy of drugs and reduces detrimental side effects to normal tissues. CONCLUSION: In this review, we have summarized cancer nanomedicines (active and passive drug delivery) available in the market. We have also discussed other nanomedicines that are at different stages of clinical trials. PMID- 29278016 TI - Retrospective database analysis of cancer risk in patients with type 2 diabetes mellitus in China. AB - OBJECTIVE: To investigate the association between type 2 diabetes (T2D) and the risk of overall cancer and site-specific cancers in a Chinese population. RESEARCH DESIGN AND METHODS: Tianjin Urban Employee Basic Medical Insurance database (2003-2014) was used to identify patients with newly onset T2D in 2009, patients with prevalent T2D prior to 2009, and general individuals without T2D. Overall and site-specific cancer incidence rates and incidence rate ratios relative to general population were calculated for both incident and prevalent T2D cohorts. Multivariate Cox proportional hazards models adjusting for baseline characteristics and potential bias were conducted. Subgroup analyses based on gender and age were further conducted. RESULTS: For the year 2009, 21,208 patients with onset T2D (mean age 58.8 years; 48.1% female), 28,248 patients with prevalent T2D (mean age 63.7 years; 50.2% female) and 744,339 general individuals (mean age 43.2 years; 47.7% female) were identified. Controlling for confounders, diabetic patients had an overall 56%-59% higher risk of developing cancer, among which the highest risks by site were liver (adjusted hazard ratio [aHR] = 1.80 2.48), colorectal (aHR = 2.41-2.69) and stomach (aHR = 2.02-2.51) cancers (all p < .05). Patients with prevalent T2D had increased cancer risk in the pancreas (aHR = 4.52, p < .001). Female diabetic patients had increased risk in the kidneys (aHR = 3.22-3.31, p < .01). Patients aged between 50 and 59 years had the highest relative risk (90% higher), while the relative risk was the lowest among patients >=70 (45% higher). CONCLUSION: Type 2 diabetes was associated with increased overall cancer risk led by liver, colorectal and stomach cancers. Patients with longer diabetes duration were associated with higher pancreatic cancer risk and female diabetic patients had a higher risk of kidney cancer. PMID- 29278017 TI - In vitro human colonic fermentation of indigestible fraction isolated from lunch menus: impact on the gut metabolites and antioxidant capacity. AB - The indigestible fraction (IF) isolated from three lunch menus: Modified Mexican Lunch (MM-L), Traditional Mexican Lunch (TM-L) and Alternative Mexican Lunch (AM L), was studied in terms of antioxidant capacity (AOX) and metabolites produced through fermentation by human intestinal microbiota. IFs were isolated after withstanding in vitro gastrointestinal digestion and total soluble polyphenols (TSP), condensed tannins (CT), hydrolysable polyphenols (HP) and AOX (DPPH, FRAP) were evaluated. AOX, pH and bacterial metabolites profile changes were also monitored during in vitro colonic fermentation. Lunch menus showed differences in IF, TSP, CT and FRAP values (p<.05). TM-L had the highest TSP and CT contents (0.84 and 1.89 g/100 g DW, respectively). Changes in pH and AOX during fermentation were time-dependent and substrate-dependent (p<.05). Butyric acid production was not significantly modified by the IFs (p>.05). Fifty-seven microbiota-produced volatile compounds were detected by SPME-GC-MS. This study shows the potential effects of food habits on bacterial metabolite production. PMID- 29278018 TI - Underdiagnosis of chronic obstructive pulmonary disease: should smokers be offered routine spirometry tests? PMID- 29278019 TI - A feasibility randomized controlled trial of ReaDySpeech for people with dysarthria after stroke. AB - OBJECTIVE: To evaluate the feasibility of a multicentre randomized controlled trial of ReaDySpeech, an online speech therapy programme for people with dysarthria. DESIGN: Feasibility randomized controlled trial, 2:1 minimization procedure. SETTING: Four UK NHS services across hospital and community. PARTICIPANTS: Forty participants with dysarthria at least one week post-stroke. Interventions/comparator: ReaDySpeech with usual care ( n = 26) versus usual care only ( n = 14). MAIN OUTCOMES: Feasibility measures included the following: recruitment and retention rate, time taken to carry out assessments, success of outcome assessor blinding, fidelity and adherence. Participant baseline and outcome measures collected before and after 8-10 weeks of intervention were the Frenchay Dysarthria Assessment II, Therapy Outcome Measure, Communication Outcomes After Stroke Scale, EQ-5D-5L and Dysarthria Impact Profile. RESULTS: Recruited 40 participants out of 74 eligible people, 1-13 weeks post stroke and mean age 69 years (37-99). Retention was very high (92%). Assessor blinding was not achieved with intervention allocation correctly guessed for 70% of participants (26/37). Time to carry out assessments was acceptable to participants. ReaDySpeech was delivered to 16 of 26 allocated participants, who completed 55% of prescribed activities, but both interventions were delivered at low intensity (mean 6.6 face-to-face sessions of 40-minute duration). CONCLUSION: Recruitment and retention in this randomized controlled trial of computerized therapy for dysarthria is feasible for acute stroke. However, further feasibility work is needed to evaluate whether it is possible to recruit chronic stroke; increase intervention delivery, intensity and adherence; achieve outcome assessor blinding by video-recording and to determine sample size for a larger trial of effectiveness. PMID- 29278020 TI - Diagnosis and management of Lyme neuroborreliosis. AB - INTRODUCTION: The nervous system is involved in 10-15% of patients infected with B. burgdorferi, B. afzelii and B. garinii. This review will address widespread misconceptions about the clinical phenomenology, diagnostic approach and response to treatment of neuroborreliosis. Areas covered: Improvements in diagnostic testing have allowed better definition of the clinical spectrum of neuroborreliosis, with lymphocytic meningitis and uni- or multifocal inflammation of peripheral/cranial nerves predominating. Despite widespread concern that post treatment cognitive/behavioral symptoms might be attributable to persisting infection or aberrant inflammation within the central nervous system a large body of evidence indicates this is extremely improbable. Importantly, recent studies show most neuroborreliosis can be treated with fairly brief courses of oral antibiotics. All high-level evidence confirms that prolonged courses of antibiotics carry harm with no commensurate benefit. Expert commentary: Lyme disease in the US, and corresponding disorders in Europe, are well defined neuro infectious diseases that are highly responsive to antibiotic therapy. Although the nervous system is slow to recover after insults (e.g. persistent facial weakness after appropriately treated facial nerve palsy) there is no evidence that prolonged post-treatment neurocognitive symptoms are related to nervous system infection - either as a triggering event or as a cause of ongoing symptoms. PMID- 29278021 TI - Artful Moments: A framework for successful engagement in an arts-based programme for persons in the middle to late stages of dementia. AB - Art galleries are becoming more inclusive in their activities for those with specific needs. The interdisciplinary team on an inpatient behavioural health unit collaborated with artist-educators at the Art Gallery of Hamilton (Ontario, Canada) to create an arts-based programme. 'Artful Moments' involved using a combination of art appreciation and hands-on art making activities and took place on the unit at the hospital and at the art gallery. A pilot study of eight participants and their care partners who attended the programme is presented. The purpose of the study was to determine if 'Artful Moments' facilitated positive engagement 'in the moment' for persons in the middle-to-late stages of dementia. The perception of the programme's impact from their care partners' perspectives, as well as their satisfaction with the programme is also reported. Extensive education of art gallery staff and clinical staff preceded the programming, with each team sharing expertize with the other. Sessions (n = 27) took place about twice per month. Data were collected through systematic structured observations of patient participants during the activities and through surveys of care partners. Persons with dementia maintained interest, though not necessarily pleasure, during art appreciation and art making, rarely became sad or anxious, and never became angry. Generally the care partners felt that participants enjoyed the experience, and often they were surprised by the very positive response of the participants. Successful engagement was attributed to a dementia friendly environment; supportive communication strategies; and a suitable, well planned activity. PMID- 29278022 TI - Recurrent aphthous ulceration: a review of potential causes and novel treatments. AB - : Purpose of article: This review examines studies published between May 2012 and 2017 with a specific interest in potential recurrent aphthous ulceration (RAU) etiologies and treatment modalities/efficacy, including topical treatments, systemic regimens, vitamin repletion, and laser therapy, among others. MATERIALS AND METHODS: PubMed MEDLINE and Cochrane Database of Systematic Reviews were searched using various combinations of: 'aphthous', 'ulcer', and 'treatment'. The titles and abstracts from the initial literature search were appraised to identify articles for full review and reference sections from each article were searched manually for relevant publications. Both randomized controlled trials and observational reports were included in this review, as some treatment types have not been formally examined in randomized trials. Relevant studies were reviewed, compared, and summarized. RESULTS: RAU can result from systemic disease and trauma, but recent studies have shown a variety of potential etiologies, ranging from vitamin deficiencies, oral microbiota derangements, hematological considerations, stress, genetic polymorphisms to oxidant-antioxidant imbalances, among others. Many modalities of therapy are available and have proven efficacious. CONCLUSIONS: As the exact etiology of RAU is still unknown, therapy is based on symptomatic relief. PMID- 29278023 TI - Effect of alpha-tocopherol megadoses on hematologic parameters and antioxidant capacity of rats in an ultraendurance probe. AB - This study was aimed to analyze the effect of two different megadoses of alpha tocopherol (vit E) in the antioxidant activity and red and white blood series of Wistar rats after a 180-min ultraendurance probe. Three groups of 10 rats were analyzed; VEAG: acute administration of a megadoses of 5,000 IU/kg of vit E the day before the probe; VECG: chronic administration of 1,000 IU/kg/day of vit E for 6 days before the probe; CG: placebo administration. VEAG presented white cells, red blood cells, hematocrit, hemoglobin values significantly higher than CG and VECG (p < 0.05). The mean corpuscular hemoglobin and lymphocytes concentrations were significantly higher in the VECG than in the other two groups (p < 0.05). Similarly, VEAG presented a significantly higher vit E blood concentration than VECG and CG (p < 0.05), and VECG than CG (p < 0.05). Finally, we found a significantly positive correlation between trolox equivalent antioxidant capacity (TEAC) and red blood cells concentration (r = 0.374) and a significantly inverse correlation between TEAC and blood lactate concentration (r = -0.365). Our findings suggest that acute vit E megadoses could protect against transitory sport anemia symptoms and increase the white blood cell count in comparison with the chronic dose and control groups after an ultraendurance probe. PMID- 29278024 TI - Curcumin regulates intracellular calcium release and inhibits oxidative stress parameters, VEGF, and caspase-3/-9 levels in human retinal pigment epithelium cells. AB - In this study, we aimed to observe whether curcumin (cur), a polyphenolic compound derived from the dietary spice turmeric, a yellow substance obtained from the root of the plant Curcuma longa Linn, has any protective effect against blue light irradiation in human retinal pigment epithelium (ARPE-19) cells. For this purpose, we evaluated the intracellular calcium release mechanism, poly ADP ribose polymerase (PARP), procaspase-3/-9 protein expression levels, caspase activation, and reactive oxygen species levels. ARPE-19 cells were divided into four main groups, such as control, cur, blue light, and cur + blue light. Results were evaluated by Kruskal-Wallis and Mann-Whitney U tests as post hoc tests. The cells in cur and cur + blue light samples were incubated with 20 MUM cur. Blue light exposure was performed for 24 h in an incubator. Lipid peroxidation and cytosolic-free Ca2+ [Ca2+]i concentrations were higher in the blue light exposure samples than in the control samples; however, their levels were determined as significantly lower in the cur and cur + blue light exposure samples than in the blue light samples alone. PARP and procaspase-3 levels were significantly higher in blue light samples. Cur administration significantly decreased PARP and procaspase-3 expression levels. Reduced glutathione and glutathione peroxidase values were lower in the blue light exposure samples, although they were higher in the cur and cur + blue light exposure samples. Caspase-3 and -9 activities were lower in the cur samples than in the blue light samples. Moreover, vascular endothelial growth factor (VEGF) levels were significantly higher in the blue light exposure samples. In conclusion, cur strongly induced regulatory effects on oxidative stress, intracellular Ca2+ levels, VEGF levels, PARP expression levels, and caspase-3 and -9 values in an experimental oxidative stress model in ARPE-19 cells. PMID- 29278025 TI - The influence of aging on the effectiveness of heat stress in preventing disuse muscle atrophy. AB - This study examined the aging effect on disuse muscle atrophy prevention using heat stress. Wistar rats aged 7 and 60 weeks were divided into three groups as follows: control, immobilized (Im), and immobilized and heat stressed (ImH). Heat stress was given by immersing the hindlimbs in hot water (42 degrees C) for 60 min, once in every 3 days and the gastrocnemius (GAS) and soleus (SOL) muscles were extracted after 14 days. Muscle-fiber types were classified using ATPase staining. Heat shock protein 70 (HSP70) was assessed through Western blotting. In GAS muscle of both groups and SOL muscle of 7-week-old rats, the fiber diameter of each muscle type in the ImH group significantly increased compared with that in the Im group. However, this could not be observed in the SOL muscle of the 60 week-old rats. The increased percentage of type-I fibers and variability of types I and II muscle-fiber diameter were evident in the SOL muscle of the 60-week rats. HSP70 was significantly elevated in the ImH group compared with in the Im group in both muscle types of both age groups. Thus, effectiveness of heat stress in the prevention of disuse muscle atrophy appears unsatisfactory in aging muscle fibers. PMID- 29278026 TI - The effect of nasal provocation with a single-dose allergen on the physical and cognitive performance of patients with ragweed allergy. AB - Purpose This study aims to compare the impact of active allergic rhinitis on physical and cognitive abilities of trained allergic athletes to untrained allergic patients. Methods Cognitive, respiratory, and fitness functions were assessed before and after allergen exposure. Participants in both groups were provoked intranasally with ragweed allergen. Results The group of athletes revealed significantly higher average values in peak inspiratory flow and fitness index before and after provocation. In neuropsychological assessments, athletes performed significantly better after allergen provocation in complex working memory capacity. Due to single acute allergen exposure, the size of the nasal cavity and nasal inspiratory peak flow significantly decreased in both groups. The physical performance of both groups did not change after provocation. Executive functions and complex working memory capacity of athletes significantly improved resulting from provocation. Conclusions A single-shot allergen in high dose might cause an increase in mental concentration, which was more pronounced in the group of athletes. This study indicates that acute exposure to allergen cannot affect the physical performance and may result in increased mental focus in patients with allergy notwithstanding the declining respiratory functions. PMID- 29278027 TI - Environmental enrichment improved cognitive deficits more in peri-adolescent than in adult rats after postnatal monosodium glutamate treatment. AB - Exposure to enriched environment (EE) is known to promote sensory, cognitive, and motor stimulation with intensified levels of novelty and complexity. In this study, we investigated the positive regulatory effect of short-term exposure to EE on establishing functional recovery in monosodium glutamate (MSG)-induced obese rats. Unless treated, MSG rats exhibited peripheral insulin resistance, cognitive deficits, and a reduction in the total hippocampal volume with decreased neuron count in the DG, CA3, and CA1 subfields. These MSG rats were exposed to short-term EE for 15 days for a period of 6 h/day, beginning either at 45 or at 75 days of age. EE exposure has improved insulin sensitivity, yielded a significant increase in total hippocampal volume along with increase in neuron number in the CA1 subfield of the hippocampus in both age groups. However, as assessed by radial arm maze task, which relies upon the positive reinforcement to test spatial memory, and the Barnes maze task, which utilizes an aversive learning strategy, a complete recovery of cognitive function could be achieved in 2-month-old rats only and not among 3-month-old rats, thus highlighting the importance of critical window period for EE interventions in restoring the memory functions. These results suggest the therapeutic potential of EE paradigm in prevention of cognitive disorders. PMID- 29278028 TI - Post-transplantation morphological and functional changes in kidneys from expanded criteria donors. AB - Introduction Despite an increase in the number of cadaver donors and overall organ transplantations, the dramatic increase in the waiting list makes it necessary to reconsider donor criteria. The authors wanted to examine whether differences could exist in the function and/or morphology of transplanted kidneys originated from expanded criteria donors (ECDs) and ideal donors 1 and 5 years after transplantation. Methods Kidney function and histopathologic findings were analyzed and compared 1 and 5 years after transplantation in 97 patients having ECD kidneys and in 178 patients who received ideal donor kidneys (IDK). Results Serum creatinine level was significantly higher (p = 0.001) and estimated glomerular filtration rate was significantly lower (p = 0.003) in patients having ECD kidneys as compared with those with IDK 5 years after transplantation. Morphological changes in the transplanted kidneys, such as tubulitis (p = 0.025) and interstitial inflammation (p = 0.002), were significantly more frequently present in patients with ECD kidneys than in those with IDK 1 year after transplantation. Conclusion Despite an absence of differences in kidney function 1 year after kidney transplantation between patients having ECD and IDK, morphological differences in the transplanted kidneys can be detected between the two groups of patients. PMID- 29278029 TI - Biochemical status, oxidative and antioxidant responses after 3-month specific training in elite karate athletes. AB - Aim To investigate the effects of 3-month-long specific training program on biochemical status, oxidative and antioxidant responses in elite karatekas. Methods Twenty male karatekas [BMI: 21.9 +/- 2.4 (kg/m2)] participated in this study. They performed a 3-month specific training to prepare for an international competition. We measured selected biochemical parameters, the oxidative and antioxidant responses before (T0) and after 3 months of intense karate training (T1). Results We found significant increases in catalase activity (26.3% +/- 21.3%, p < 0.0005), superoxide dismutase activity (15.9% +/- 28.8%, p < 0.05), and a significant decrease in malondialdehyde levels (17.2% +/- 13.7%, p < 0.0005) after 3 months of karate training. Moreover, the athletes' biochemical status was significantly improved at T1 compared with T0 (for the majority of parameters, p < 0.0005). Conclusions The specific training program improves the prooxidant-antioxidant balance of elite karate athletes. It could be recommended for athletes having similar physical fitness level. PMID- 29278030 TI - scanning sports. PMID- 29278032 TI - brief reports. PMID- 29278033 TI - Mechanisms of the Most Common Ski Injuries. AB - Knee sprains and tibial fractures are two of the most common injuries in skiing. The authors explore their possible causes and discuss ways to prevent them. PMID- 29278034 TI - Getting in Shape to Ski. AB - Every year thousands of unconditioned skiers risk serious injury on the slopes. The authors outline a training program that can enhance both safety and enjoyment. PMID- 29278035 TI - Ski Bindings-Do They Work? AB - Although testing disclosed some limitations in the effectiveness of ski bindings, skiers can take several measures to make sure they get the most out of their equipment. PMID- 29278036 TI - letters. PMID- 29278038 TI - A Look at Alpine Skiing. PMID- 29278037 TI - The Role of Instruction in Preventing Ski Injuries. AB - Even though ski instruction may mean transiently increased risks for the skier, lessons can ultimately mean safer, more enjoyable skiing. PMID- 29278039 TI - Don't Duck Stress-It's Good for You. PMID- 29278041 TI - Medical Aspects of Skiing. PMID- 29278040 TI - Physiological Demands in Downhill Skiing. AB - The aerobic and strength requirements in downhill skiing are high, and the authors outline a conditioning program to help the skier meet them. PMID- 29278042 TI - Exercise in Sickle Cell Disease. PMID- 29278043 TI - Physical Environment Correlates of Physical Activity in Developing Countries: A Review. AB - BACKGROUND: Noncommunicable diseases and obesity are considered problems of wealthy, developed countries. These conditions are rising dramatically in developing countries. Most existing research on the role of the physical environment to support physical activity examines developed countries only. OBJECTIVES: This review identifies physical environment factors that are associated with physical activity in developing countries. METHODS: This review is modeled on a highly cited review by Saelens and Handy in 2008. The current review analyzes findings from 159 empirical studies in the 138 developing countries. RESULTS: Results discuss the association of physical environment features and physical activity for all developing countries and identify the patterns within regions. The review supports the association of traffic safety with physical activity for transportation. Rural (vs urban) residence, distance to nonresidential land uses, and "composite" features of the physical environment are associated with general physical activity. Rural (vs urban) residence is associated with physical activity for work. CONCLUSIONS: More research is needed on associations between the physical environment and physical activity in developing countries. Research should identify specific physical environment features in urban areas that are associated with higher activity levels. PMID- 29278044 TI - Investigating Children's Short-Term Responses to Imposed or Restricted Physical Activity. AB - BACKGROUND: Little is known about whether physical activity compensation occurs. This study experimentally explored the activitystat hypothesis by investigating children's short-term responses to imposed or restricted physical activity. METHODS: A total of 156 children (46 boys; mean age = 11.3 y) from 9 schools wore an ActiGraph accelerometer for 5 days (Monday-Friday) across 2 consecutive weeks. In addition, 145 children (49% boys) simultaneously wore a SenseWear Armband. Schools were randomized to participate in 1 of the 3 experimental conditions that took place on 1 occasion: additional moderate- to vigorous-intensity physical activity (3 schools), additional light-intensity physical activity (3 schools), or restriction of light-intensity physical activity and moderate- to vigorous intensity physical activity (3 schools). Multilevel linear regression models were conducted to examine associations between the day the condition took place and the following day and week (baseline and experiment) for each condition. RESULTS: There was no evidence of a difference between children's activity levels on the day after the experiment condition compared with their usual activity for that day. CONCLUSION: The findings suggest that children do not compensate their sedentary time and/or physical activity levels following imposed or restricted physical activity in the short term. PMID- 29278045 TI - An evaluation of the views of GP Specialty Trainees on their involvement in medical student teaching. AB - Background A recent survey in the North East of England (now Health Education England in the North East) revealed that General Practice Specialty Trainees (GPSTs) wished for more opportunities to teach. The Royal College of General Practitioners (RCGP) states that GPSTs are ideally placed to deliver undergraduate teaching. The aim of this study was to investigate to what extent GPSTs perceived a pilot of teaching medical students to be useful in their development. Methods Ethical approval was granted by Newcastle University. Purposive sampling was used to identify GPSTs to teach fourth year medical students. Semi-structured interviews took place with the GPSTs and data were thematically analysed. Results All five GPSTs involved in the pilot were interviewed. The overall theme was that they felt this to be a valuable opportunity that would inspire them to become involved with education in the future. The study highlighted the need for formal sessions on 'how to teach' for the GPSTs. Discussion An understanding of the benefits of this teaching pilot will allow Newcastle University and local GP Training Programmes to develop opportunities for GPSTs to be involved in education during their training. This may in turn attract GPs into education and inspire medical students to become GPs. PMID- 29278046 TI - Pregnancy affects the pharmacokinetics of sildenafil and its metabolite in the rabbit. AB - 1. There is growing interest in the use of sildenafil during pregnancy for various maternal and fetal conditions. This study aims to investigate the effect of pregnancy on the maternal pharmacokinetics (PK) of sildenafil and its main metabolite desmethylsildenafil in rabbits. Using NONMEM, population PK modeling was performed based on plasma samples from 31 rabbits of whom 15 were pregnant and 16 were not. All received a single subcutaneous sildenafil dose of 10 mg/kg. One sample was obtained per rabbit at either 30, 60, 120, 360, 720 or 1320 min after sildenafil administration. 2. A two- and one-compartment PK-model best described the data for sildenafil and desmethylsildenafil, respectively. Compared to non-pregnant rabbits, the central and peripheral volume of distribution and inter-compartmental clearance of sildenafil were lower in pregnant rabbits [32.1 versus 12.2 L, 110 versus 44.4 L and 25.5 versus 12.1 L/h; all p < 0.05]. The formation clearance from sildenafil to desmethylsildenafil was also reduced during pregnancy [13.3 versus 7.8 L/h; p < 0.05]. 3. In contrast, the elimination clearance of desmethylsildenafil, was higher in pregnancy [73.5 versus 116. 9; p < 0.05]. In rabbits, pregnancy impacts PK parameters of sildenafil and its metabolite, leading to an increased peak concentration and 24 h exposure for sildenafil and a decreased 24 h exposure for desmethylsildenafil. PMID- 29278048 TI - Forum. PMID- 29278049 TI - Detecting Graves' Disease. AB - In brief Graves' disease has a multitude of presentations, and certain symptoms can mimic sports-related concerns such as overtraining. A review of three cases of Graves' disease in young athletes illustrates the spectrum of symptoms and the pathophysiology. Diagnosis involves a detailed patient history, physical exam, and appropriate lab studies, including a thyroid radioactive iodine uptake scan. Treatment consists of symptom management and antithyroid medication, radioactive iodine thyroid ablation, or, rarely, thyroidectomy. PMID- 29278050 TI - Finding Fun in Winter Workouts. PMID- 29278051 TI - Controlling Herpes. PMID- 29278052 TI - CME Self Test. PMID- 29278054 TI - Sports Bras and Briefs. PMID- 29278055 TI - Pearls. PMID- 29278056 TI - Heart Attack Counterattack. PMID- 29278057 TI - When Anxiety Attacks. AB - In brief The athlete who panics or hyperventilates requires immediate stabilization and assessment to rule out more serious diagnoses. Repeated attacks may indicate panic disorder, which can be treated effectively with a combination of psychological and pharmacologic therapy. Drug options include selective serotonin reuptake inhibitors, benzodiazepines, tricyclic antidepressants, and monoamine oxidase inhibitors. PMID- 29278058 TI - Portal Venous Thrombosis in a Backpacker. AB - In brief Effort thrombosis usually afflicts an extremity and is caused by compression. This case report, in contrast, involves superior mesenteric and left portal vein septic thrombosis in a backpacker following prolonged hiking and abdominal straining. The condition may have been caused by localized splanchnic venous ischemia, erosion of the bowel-blood barrier, and release of bacterial endotoxin in this dehydrated and detrained athlete. Diagnosis of this disorder is aided by noting characteristic abdominal pain, fever, nausea, and vomiting, as well as by imaging with MRI, CT, or duplex ultrasonography. Antibiotics and anticoagulants are key to treatment. PMID- 29278059 TI - Electrical Muscle Stimulation During Immobilization. PMID- 29278060 TI - Death in the Ring. PMID- 29278061 TI - NWU's Center: Training Trainers in the Windy City. AB - A dedicated staff with a lean budget and a unique mix of services make Northwestern University's Center for Sports Medicine worth a second look. PMID- 29278062 TI - The Caloric Costs of Rope Skipping and Running. AB - Dr. Getchell has some disappointing news for fitness seekers who believe that jumping rope for ten minutes is equal to 30 minutes of jogging. PMID- 29278063 TI - World-Record Rope Skipping Performance. AB - The authors studied a world-champion rope skipper to see what characteristics contribute to his superior performance and to compare him with other world-class athletes. PMID- 29278065 TI - What's News? PMID- 29278064 TI - Injuries in Junior Ice Hockey. AB - Does the price of a ticket entitle hockey fans to see more injuries? That's the result of excusing paid gate junior hockey players from wearing facial protection. PMID- 29278066 TI - Sportsmedicine Care in Chicago-Area High Schools. AB - Since few high schools have trainers on staff, Ms Porter studied the approach to injury management in 191 schools. PMID- 29278067 TI - letters. PMID- 29278068 TI - scanning sports. PMID- 29278069 TI - Jock Itch. AB - Most inguinal eruptions fall into five categories, and Dr. Brodin describes the diagnosis and treatment, with warnings against the pitfalls of self-medication. PMID- 29278070 TI - brief reports. PMID- 29278071 TI - Athletic Profile of Women College Volleyball Players. AB - Descriptive information about female athletes will help physicians, trainers, and coaches design conditioning programs and determine playing positions. PMID- 29278075 TI - action arena. PMID- 29278073 TI - Lake Placid's Once and Future Sportsmedicine Center. AB - The sophisticated Lake Placid Sports Medicine Center lost its Olympic backing, but still tests and coaches Olympians. PMID- 29278076 TI - a need to know. PMID- 29278077 TI - Evaluation of Running Injuries. AB - The author describes a series of tests he uses to diagnose runners' problems and reports on 589 cases. PMID- 29278078 TI - Body and Soul. PMID- 29278080 TI - User perspectives, preferences and priorities relating to products for managing bladder and bowel dysfunctions. AB - A great many people of all ages around the world cannot fully control their bladder or bowel, or both. Either in the short or long term, they rely upon products and devices to manage the emptying of their bladders and bowels and to collect, absorb and contain leaked urine or faeces. The incontinence product market is large and growing, and ongoing developments in materials and technologies should lead to improvements in these products and devices. Engineers and designers who work in this field - or who plan to do so - need to recognise the breadth of factors that affects the effectiveness and acceptability of products. The primary functions of products for managing bladder and bowel dysfunctions are the collection and containment of urine or faeces - and the associated engineering and design challenges may be considered in terms of flow rates and volumes and methods of acquisition and containment. But products will fail if they do not take into account other factors, some of which relate less directly to these primary functions and some not at all. This article aims to highlight the product characteristics that are most important to the people who use them, and areas where user-centred innovation and development may lead to improvements. PMID- 29278079 TI - Regional and age-dependent residual strains, curvature, and dimensions of the human ureter. AB - The ureters are retroperitoneal structures controlling urine transport from the kidneys to the bladder. Because of the relative scarcity of data on the biomechanical properties of human ureter and the established importance of knowing these properties for understanding its physiology, we initiated biomechanical studies in cadaveric tissue. Herein, we report definite zero stress/no-load geometrical characterization at 15 regions along the ureter of human cadavers aged 23-82 years, estimating the opening angle, circumferential residual strains, axial curvature, and dimensional parameters. Opening angle decreased along the proximal 25% of ureter, increased and reached a maximum near the mid-ureter, and then gradually decreased toward the vesicoureteral junction (young: p < 0.05; middle-aged: p < 0.05; old: p > 0.05; males: p < 0.05; females: p < 0.05). Similar were the regional distributions of residual strain at the interface between epithelium-lamina propria and muscle and of internal but not external residual strain. Wall thickness increased steadily with aging ( p < 0.05 at few regions), while ureteral circumference did not ( p > 0.05 at most regions) and opening angle decreased ( p < 0.05 at several regions). Consistent with Fung's stress-growth law, the muscle layer thickened with age unlike the epithelium-lamina propria that thinned ( p < 0.05 at most regions for both thicknesses). Moderate-to-strong direct correlations of residual strain difference (= external - internal) with opening angle, wall thickness, and curvature were found in most ureters. The presented data will provide insight into the biomechanical response of ureter under zero/low-stress conditions and the relationship between ureteral remodeling and aging. Importantly, they may also be used to inform finite element models and computational studies simulating the ureter. PMID- 29278081 TI - Counting Your Calcium. PMID- 29278082 TI - Detecting Sexually Transmitted Disease. AB - In brief During a routine preparticipation exam, a 17-year-old asymptomatic boy had a 1+ leukocyte esterase reaction on urinalysis. A subsequent urethral smear was positive for Chlamydia trachomatis, a pathogen that can cause urethritis or epididymitis in men and cervicitis and infertility in women. Most authorities do not consider a screening urinalysis a necessary part of the preparticipation exam because the yield of significant renal or metabolic disease is low. However, the newer dipstick strips that incorporate the leukocyte esterase test may prompt a reassessment. PMID- 29278083 TI - Pearls. PMID- 29278084 TI - Laryngeal Trauma. AB - In brief Blunt laryngeal injury is a rare but potentially catastrophic event. If the airway is not totally obstructed, the on-site physician should manage the upper airway following basic airway protocols. If the airway becomes totally obstructed on-site, orotracheal intubation using a small-diameter endotracheal tube is the procedure of choice. Translaryngeal ventilation and surgical cricothyrotomy are relatively contraindicated but may need to be used as a last resort. When the need for advanced airway procedures is likely, the patient should be transported expediently by advanced life support ambulance to the nearest appropriate emergency department. PMID- 29278085 TI - You Deserve Credit. PMID- 29278086 TI - Diagnosing Plantar Fascia Rupture. AB - In brief Though not frequently reported in the literature, plantar fascia tears or ruptures can occur in running and jumping sports. Misdiagnosis as an acute flare of the much more common plantar fasciitis is possible. Though the injury is initially quite disabling, athletes can-as in this case report-return within weeks to competition with proper diagnosis, intervention, and rehabilitation. PMID- 29278091 TI - Forum. PMID- 29278087 TI - Quadriceps Strains and Contusions. AB - In brief Quadriceps injuries can follow direct or indirect trauma. Accurate diagnosis includes differentiating strains from contusions, along with assessing injury severity. Treatment that maximizes recovery and minimizes the risk of complications goes beyond rest, ice, compression, and elevation. Management of strains includes control of pain, swelling, and inflammation, as well as targeted stretching and strengthening exercises. Immediate care of a quadriceps contusion includes immobilization in flexion and is especially important for a quick recovery. After return to play, a thigh pad should be worn to protect the injury site. PMID- 29278092 TI - Sports Medicine Groups 1995. PMID- 29278093 TI - Carpal Tunnel Syndrome. PMID- 29278094 TI - Practical Management of Carpal Tunnel Syndrome. AB - Carpal tunnel syndrome can result from occupational or recreational overuse. Cycling, rowing, and weight lifting are examples of sports that can provoke or exacerbate the syndrome. A detailed sensory examination, motor testing, and provocative tests such as Phalen's maneuver are essential. Nerve conduction studies may also be useful. Conservative treatment is usually attempted first. Modification of technique and equipment, together with use of a splint, often allows patients to continue their desired activities. In selected cases, carpal tunnel release is effective, but complication rates are high. PMID- 29278095 TI - Relieving Winter Skin Discomfort. AB - In brief Dry skin is a concern during winter months among those who are active outdoors. Management focuses on rehydrating the skin and preventing further moisture loss. Practical treatment methods include liberal use of emollients, humidifying home air, showering only once a day, and avoiding soaps and other products that can remove moisture-retaining lipids from the skin. Implementing these measures before the onset of symptoms can help patients prevent xerosis. Severe cases may require topical therapies such as corticosteroids, alpha-hydroxy acids, or antibiotics. PMID- 29278097 TI - Top Contenders. PMID- 29278096 TI - Managing Posterior Shoulder Instability. AB - In brief Posterior shoulder instability, a recently recognized source of pain in throwing, overhand, and contact sports, usually results from repetitive microtrauma or a single traumatic episode. Physical signs often are not obvious, so targeted physical tests, provocative maneuvers, and radiographic studies are needed to identify abnormal humeral head translation. Examination under anesthesia or arthroscopy may be required. The first line of treatment focuses on an intensive physical therapy protocol that strengthens the infraspinatus, teres minor, and posterior deltoid muscles. Surgery may be indicated, but ideal technique is a matter of debate. PMID- 29278098 TI - Scanning Sports. PMID- 29278099 TI - Smart Dressing for Cold Weather Workouts. PMID- 29278100 TI - CME Self Test. PMID- 29278101 TI - Bayesian hidden Markov models for delineating the pathology of Alzheimer's disease. AB - Alzheimer's disease is a firmly incurable and progressive disease. The pathology of Alzheimer's disease usually evolves from cognitive normal, to mild cognitive impairment, to Alzheimer's disease. The aim of this paper is to develop a Bayesian hidden Markov model to characterize disease pathology, identify hidden states corresponding to the diagnosed stages of cognitive decline, and examine the dynamic changes of potential risk factors associated with the cognitive normal-mild cognitive impairment-Alzheimer's disease transition. The hidden Markov model framework consists of two major components. The first one is a state dependent semiparametric regression for delineating the complex associations between clinical outcomes of interest and a set of prognostic biomarkers across neurodegenerative states. The second one is a parametric transition model, while accounting for potential covariate effects on the cross-state transition. The inter-individual and inter-process differences are taken into account via correlated random effects in both components. Based on the Alzheimer's Disease Neuroimaging Initiative data set, we are able to identify four states of Alzheimer's disease pathology, corresponding to common diagnosed cognitive decline stages, including cognitive normal, early mild cognitive impairment, late mild cognitive impairment, and Alzheimer's disease and examine the effects of hippocampus, age, gender, and APOE-[Formula: see text] on degeneration of cognitive function across the four cognitive states. PMID- 29278102 TI - Hepatic veno-occlusive disease during isavuconazole administration. PMID- 29278103 TI - Predicting Athletic Performance. PMID- 29278104 TI - A Challenge to the AMA. PMID- 29278105 TI - Ski Jumping Injuries. PMID- 29278106 TI - Winter Sports Hazards - Covert Considerations. PMID- 29278108 TI - Mike Marshall: Baseball Is His Hobby, Physical Education Is His Life. PMID- 29278107 TI - letters. PMID- 29278109 TI - sportspages. PMID- 29278110 TI - President Ford's Exercise Program: Diversion, not Drudgery. PMID- 29278111 TI - Cross-Country Skiing: An Exercise in Aesthetics and Challenges. PMID- 29278112 TI - a need to know. PMID- 29278113 TI - Artificial Turf: Pros and Cons. PMID- 29278114 TI - Do Long Hair and Football Uniforms Impair Heat Loss? PMID- 29278116 TI - gameplan. PMID- 29278115 TI - trainer's corner. PMID- 29278117 TI - On the Function of Clothes. PMID- 29278118 TI - Choosing a Life Preserver. PMID- 29278119 TI - A Delicate Mix. PMID- 29278120 TI - CME Self Test. PMID- 29278122 TI - Forum. PMID- 29278123 TI - Pearls. PMID- 29278124 TI - Septic Arthritis of the Shoulder. AB - In brief A wrestler developed septic arthritis in his glenohumeral joint. His case is unusual because septic arthritis most commonly affects weight-bearing joints and is usually seen in the very young, the very old, and people who are immunocompromised. Other risk factors include concurrent infection, endocarditis, invasive procedures, and intra-articular corticosteroid injection. Disease onset is usually insidious. Nonspecific findings include restricted motion, mild pain, and joint effusions; systemic signs of toxicity are often mild or absent. Diagnosis is confirmed with joint aspiration and analysis and culture of synovial fluids; definitive treatment often involves arthroscopic debridement followed by 2 to 6 weeks of antibiotics. PMID- 29278125 TI - Breaking Our Own Rules. PMID- 29278127 TI - At-Home Knee Rehabilitation. PMID- 29278128 TI - Keeping Tennis Elbow at Arm's Length. PMID- 29278130 TI - Function Follows Form in Sheehan's World. PMID- 29278129 TI - Corrigendum. PMID- 29278132 TI - Will Sports Survive the Product Liability Suits? PMID- 29278131 TI - brief reports. PMID- 29278133 TI - New Word, New Life-Style. PMID- 29278134 TI - Scuba Divers Answer the Challenge of the Sea. PMID- 29278136 TI - editor's notes. PMID- 29278135 TI - letters. PMID- 29278137 TI - a need to know. PMID- 29278138 TI - Drowning's Deadly Toll: Can More Be Saved? PMID- 29278139 TI - Is It the Product or the User? PMID- 29278140 TI - Evaluation and Treatment of the Stable Ankle Sprain. AB - Simple, prompt treatment for the sprained ankle, combined with a comprehensive rehabilitation program, speed recovery and help prevent reinjury. PMID- 29278141 TI - Ankle Ligament Surgery: Experience over 18 years. AB - Stabilizing the unstable ankle is a difficult and much-debated problem. The author describes a surgical procedure that restores near-normal function. PMID- 29278142 TI - A stratification approach using logit-based models for confounder adjustment in the study of continuous outcomes. AB - The control of confounding is an area of extensive epidemiological research, especially in the field of causal inference for observational studies. Matched cohort and case-control study designs are commonly implemented to control for confounding effects without specifying the functional form of the relationship between the outcome and confounders. This paper extends the commonly used regression models in matched designs for binary and survival outcomes (i.e. conditional logistic and stratified Cox proportional hazards) to studies of continuous outcomes through a novel interpretation and application of logit-based regression models from the econometrics and marketing research literature. We compare the performance of the maximum likelihood estimators using simulated data and propose a heuristic argument for obtaining the residuals for model diagnostics. We illustrate our proposed approach with two real data applications. Our simulation studies demonstrate that our stratification approach is robust to model misspecification and that the distribution of the estimated residuals provides a useful diagnostic when the strata are of moderate size. In our applications to real data, we demonstrate that parity and menopausal status are associated with percent mammographic density, and that the mean level and variability of inpatient blood glucose readings vary between medical and surgical wards within a national tertiary hospital. Our work highlights how the same class of regression models, available in most statistical software, can be used to adjust for confounding in the study of binary, time-to-event and continuous outcomes. PMID- 29278143 TI - Methods for assessing and controlling placebo effects. AB - The placebo serves as an indispensable control in many randomized trials. When analyzing the benefit of a new treatment, researchers are often confronted with large placebo effects that diminish the treatment effect. Various alternative methods have been proposed for analyzing placebo and treatment effects in studies where large placebo effects are expected or have already occurred. This paper presents an overview of methodological work that has been proposed for assessing and/or controlling for placebo effects in randomized trials. Throughout this paper, two main approaches are discussed. The first approach considers designs that represent alternatives to the classical placebo-controlled randomized trial design. Separately, the second approach considers adopting new methods for the statistical analysis of placebo and treatment effects to be implemented after the data have been collected using a classical randomized trial design. PMID- 29278144 TI - A Functional General Stress Response of Bradyrhizobium diazoefficiens Is Required for Early Stages of Host Plant Infection. AB - Phylogenetically diverse bacteria respond to various stress conditions by mounting a general stress response (GSR) resulting in the induction of protection or damage repair functions. In alpha-proteobacteria, the GSR is induced by a regulatory cascade consisting of the extracytoplasmic function (ECF) sigma factor sigmaEcfG, its anti-sigma factor NepR, and the anti-anti-sigma factor PhyR. We have reported previously that sigmaEcfG and PhyR of Bradyrhizobium diazoefficiens (formerly named Bradyrhizobium japonicum), the nitrogen-fixing root nodule symbiont of soybean and related legumes, are required for efficient symbiosis; however, the precise role of the GSR remained undefined. Here, we analyze the symbiotic defects of a B. diazoefficiens mutant lacking sigmaEcfG by comparing distinct infection stages of enzymatically or fluorescently tagged wild-type and mutant bacteria. Although root colonization and root hair curling were indistinguishable, the mutant was not competitive, and showed delayed development of emerging nodules and only a few infection threads. Consequently, many of the mutant-induced nodules were aborted, empty, or partially colonized. Congruent with these results, we found that sigmaEcfG was active in bacteria present in root-hair-entrapped microcolonies and infection threads but not in root associated bacteria and nitrogen-fixing bacteroids. We conclude that GSR controlled functions are crucial for synchronization of infection thread formation, colonization, and nodule development. PMID- 29278145 TI - When Competitive Bodybuilders Collapse. AB - In brief Numerous physiologic derangements can result when body-builders attempt to augment their muscle definition by using diuretics, potassium supplements, and dietary restrictions. A case report describes a 27- year-old male professional bodybuilder who employed these strategies and presented with profound muscle weakness and muscle cramps. He was found to have life-threatening hyperkalemia, ECG changes, mild rhabdomyolysis, and prerenal azotemia. Vigorous volume expansion and potassium-lowering maneuvers reversed the skeletal muscle and cardiac complications. The patient's symptoms resembled those of another professional bodybuilder who died after employing similar drug and diet strategies. PMID- 29278146 TI - Scanning Sports. PMID- 29278147 TI - Healing under pressure. PMID- 29278148 TI - Forum. PMID- 29278149 TI - Managing Groin Pain. AB - In brief The cause of groin pain, common in kicking sports, is obvious when a patient suffers an acute muscle strain. However, a case study involving a 16-year old male high school athlete demonstrates how gradual-onset groin pain can open up a multitude of orthopedic and nonorthopedic diagnostic possibilities including avulsion fracture, osteitis pubis, and inguinal hernia. Muscle strains usually resolve with RICE therapy and a focused rehabilitation program. Conservative treatment is also appropriate in the initial workup of inguinal canal weakness. Surgery may be needed to repair severely torn muscles or to correct an inguinal canal defect. PMID- 29278150 TI - A Close Look at a 'Red Eye'. AB - In brief The "red eye" is one of the most common presentations of eye disease. There are numerous causes of a red eye; fortunately most patients maintain good visual acuity and have an excellent prognosis. By taking a thorough medical and ocular history and performing an ophthalmic examination, physicians can identify the vision-threatening causes, such as cellulitis, corneal ulcer, and acute glaucoma. Once the cause has been determined-and if it is vision threatening physicians should refer patients to an ophthalmologist for definitive treatment. PMID- 29278151 TI - Getting Control of Weight Control. PMID- 29278152 TI - Knee Dislocations. AB - In brief The consequences of a knee dislocation can be devastating. The significant associated risks of severe arterial, venous, or neurologic compromise make this a limb-threatening injury. Therefore, it's essential that the physician make an expedient diagnosis based on physical findings, assess neurovascular status rapidly, splint the knee, and provide immediate transport to an emergency department. A closed reduction is often performed in the emergency room or operating room. Spontaneous reduction makes diagnosis more difficult, and the examiner must suspect knee dislocation in globally unstable knees to definitively diagnose the injury. PMID- 29278153 TI - Cme Self Test. PMID- 29278154 TI - From Anorexia to Obesity. PMID- 29278155 TI - Should This Patient Keep Jogging? PMID- 29278156 TI - Battling the Bulge. PMID- 29278157 TI - Exercising for Overall Fitness. PMID- 29278158 TI - Pearls. PMID- 29278159 TI - Pulmonary and Chest Wall Emergencies. AB - In brief Sports-related chest trauma can Produce a number of injuries that may be medical emergencies: pneumothorax, diaphragmatic paralysis, chest wall trauma, and sternoclavicular dislocation. Severe acute bron- chospasm is another pulmonary condition common in active people. Team physicians must therefore work through the differential diagnosis quickly and initiate on-site treatment as soon as possible. Many of these conditions require definitive treatment at an emergency facility, but on-field clinicians can stabilize the patient and ensure a successful outcome by taking measures such as providing an open airway, resolving a pneumothorax, or reducing a dislocation. PMID- 29278161 TI - Pearls. PMID- 29278162 TI - forum. PMID- 29278163 TI - Tennis Leg. AB - Gastrocnemius strain can be extremely painful and requires immediate medical attention. With proper splinting of the injured leg, nonsteroidal anti inflammatory medications, and an appropriate rehabilitation program, physicians can help tennis leg patients successfully recover. PMID- 29278165 TI - Exercise Excess. AB - A history of multiple overuse injuries is just one of the signs that a patient may have an exercise addiction. After physicians treat the injuries that often accompany this addiction, they face the challenge of helping patients overcome the underlying problem that has transformed them into exercise junkies. PMID- 29278167 TI - HIV and Sports. PMID- 29278166 TI - Shower Your Baby With Good Nutrition. PMID- 29278168 TI - QuikQuiz. PMID- 29278170 TI - scanning sports. PMID- 29278169 TI - Exercising for Two. AB - Clinical experience and recent research challenge the current standards of exercise duration and intensity for pregnant women. By carefully assessing a patient's exercise history and teaching self-monitoring techniques, the physician can work with an active woman to create a safe exercise program during her pregnancy. PMID- 29278171 TI - Outdoors and Active. AB - In brief Summer's onset means physicians will see many skin conditions they don't usually see at other times of the year. Heat, humidity, and exposure to outdoor elements combine to make skin vulnerable to sunburn, parasite contact, infection, insect bites, and allergic reactions to noxious plants. Most conditions are easy to diagnose and treat, but others are less common and require greater effort to determine the etiology. Rapid recognition along with prevention tips can help keep patients active. PMID- 29278172 TI - Managing Heatstroke. PMID- 29278174 TI - Pearls for Your Practice. PMID- 29278173 TI - What Conditions Limit Sports Participation? AB - In brief Over 5 years, 10,540 annual preseason examinations were performed on student-athletes ranging in age from 11 to 19 years. The examining physicians concluded that 9,423 students (89.4%) passed, 1,070 (10.2%) passed with conditions, and 47 (0.4%) failed. The most common reasons cited for those who passed with conditions and those who failed were hypertension, ophthalmologic and genitourinary abnormalities, and musculoskeletal problems. The authors recommend that preparticipation exams follow guidelines based on scientific data and experience rather than tradition or anecdote. PMID- 29278175 TI - Syncope. AB - In brief Syncopal episodes are usually benign, but some causes can be life threatening. The differential diagnosis is extensive and includes vasovagal reaction, decreased intravascular volume, metabolic disorders, cardiac disorders, medication use and abuse, Valsalva maneuver, and intracranial conditions. A detailed account of the event and a medical history direct the workup. Combining a thorough physical examination that emphasizes the cardiovascular and neurologic systems with selective laboratory tests and noninvasive diagnostic studies may reveal why the patient lost consciousness during his or her athletic activities. PMID- 29278176 TI - Stress Fracture of the Distal Radius. AB - In brief A 14-year-old female gymnast reported pain at the dorsum of her right wrist. Physical examination and radiographs suggested a stress fracture of the wrist physis-an injury reported most often in highly competitive, advanced gymnasts. Radiographs revealed marked widening of the growth plate and haziness within the epiphyseal plate. Treatment involved immobilization of the patient's wrist for 7 weeks until radiographic abnormalities reversed, and physical therapy for 2 weeks to increase wrist flexibility and strength. PMID- 29278177 TI - To Combat Hypertension, Increase Activity. AB - In brief Controversy persists over the effects of aerobic exercise on persons with essential hypertension, but most evidence indicates that exercise is beneficial. The higher the blood pressure and less active the patient, the greater the likelihood of blood pressure reduction with exercise. For sedentary patients, moderate activity is usually more beneficial than a strenuous exercise regimen. Exercise usually can be tried before medication, unless the hypertension is severe. PMID- 29278178 TI - A Practical Guide to Prescribing Orthoses. AB - In brief Patients who have pain from such maladies as plantar fasciitis, bunions, ankle sprains, Achilles tendinitis, shin splints, or patel-lofemoral syndrome may benefit from orthotic devices. Orthoses can help alleviate pain that stems from abnormal foot biomechanics, such as overpronation or rigid pes cavus. This guide highlights when orthoses may be appropriate adjuncts for treating active people. PMID- 29278179 TI - Staying Active With COPD. PMID- 29278181 TI - Popliteal Artery Entrapment Syndrome in Athletes. AB - In brief When a young person presents with typical symptoms of claudication that are relieved with rest, physicians should consider a vascular abnormality in the popliteal fossa. The popliteal artery may become entrapped because a cyst or fibrous band compresses the artery or because the artery deviates from its normal course. This article describes the diagnosis and treatment of popliteal artery entrapment syndrome and discusses two case reports. Arteriography is needed to establish the definitive diagnosis. Surgery relieving the entrapment is indicated to alleviate symptoms and to prevent possible future disability from arterial thrombosis and distal embolization or occlusion. This therapy provides excellent results. PMID- 29278183 TI - American College of Sports Medicine: New Growth, New Future? AB - ACSM is experiencing rapid membership growth and an infusion of members representing special disciplines. Some say the growth is too fast and too broad. PMID- 29278184 TI - a need to know. PMID- 29278185 TI - Changes in Fitness Components After a Four-Week Bicycle Tour. AB - In brief Three men and four women, ages 19 to 60, were measured on a battery of laboratory tests before and after a four-week bicycle tour to determine the effects of long-distance bicycling on physical fitness. There was no significant body weight change, although the average total fat weight loss was 1.4 kg. Total skinfold measures showed a significant reduction, and the waist girth reduced 2%. Trunk flexion showed significant improvement, and trunk extension and ankle flexibility showed a slight reduction. Maximal oxygen intake increased significantly (11%). The greatest improvement was the mean bicycle ergometer riding time and resistance to higher work loads (17%). PMID- 29278186 TI - letters. PMID- 29278187 TI - Effects of Diet and Exercise on Peripheral Vascular Disease. AB - In brief A 46-year-old man presented with symptoms of peripheral vascular disease in 1966. In 1976 arteriography revealed 100% occlusion of both femoral arteries at midthigh and some reconstitution of flow via collaterals into the popliteal region. His cholesterol level was initially 407 mg/100 ml, and his walking tolerance was 100 yards. After a 26-day stay at the Pritikin Longevity Center, his cholesterol dropped from 230 mg/100 ml to 130 mg/100 ml, and his walking tolerance increased to 3 miles in one hour with little leg pain. He has run more than 20 road races and completed a marathon. A recent exercise Doppler exam and a second arteriogram indicated a significant increase in blood flow due to dilation of deep femoral arteries and existing collateral vessels. PMID- 29278188 TI - scanning sports. PMID- 29278189 TI - Little Bodies and Healthy Hearts: Life-Style Counseling in the School. AB - Programs such as Feelin' Good are finding that good heart health habits must be learned early-as early as second grade. PMID- 29278190 TI - brief reports. PMID- 29278191 TI - US Golfing Meccas: The Battle of the Bunkers. AB - These famous resorts offer more than the most challenging golf courses in the country: Prepare for tennis, riding, sailing, canoeing, and croquet in case your scores get you down. PMID- 29278192 TI - The Secret in the Sand. PMID- 29278193 TI - Menstrual Irregularity in Athletes: The Unanswered Question. AB - Rose Frisch, PhD, has a simple explanation: It is related to their lean-fat ratio. But she doesn't claim to have all the answers. PMID- 29278195 TI - Clinical Use of Ultrasound. PMID- 29278194 TI - Physiological and Training Profiles of Ultramarathoners. AB - In brief This study describes the physiological profile and training pattern of ultramarathoners and their performance variables during an ultramarathon. The authors studied 17 experienced male ultramarathoners who had completed a 50-mile race. They were arbitrarily divided into two groups for comparison: those who finished in less than six hours (elite) and those who finished in more than six hours (nonelite). The elite ultramarathoners averaged 96 miles per week in training runs with a long single run of 35 miles before a race. They averaged 84% of Vo2 max throughout the 50-mile race. The nonelite runners averaged 60 miles per week with a long run of 27 miles before a race. They averaged 72% of Vo2 max. All subjects expended approximately 6,000 kcal during the race and had low levels of blood lipids. PMID- 29278196 TI - Can an Exercise Program Worsen Heart Disease? AB - In brief This article presents five case reports of patients whose heart disease worsened while they were participating in an exercise program. The purpose is not to imply a relationship between exercise and the deterioration of the subjects' conditions but to illustrate the danger of making broad conclusions from case reports or unusual patients. After considering all the benefits of exercise and the other factors that could explain these patients' deterioration, the authors believe that moderate exercise is a sane prescription. They are currently undertaking a randomized scientific investigation that may provide valid evidence to support this belief. PMID- 29278197 TI - Preparing for a Summer Backpacking Trip. PMID- 29278198 TI - Redshirting the Young Athlete. PMID- 29278199 TI - Tough-Man Fight Prompts New Boxing Legislation. AB - Tough-man fighters generally are unprepared or poorly trained for these contests. Minnesota has new rules that protect tough-man fighters and boxers alike. PMID- 29278200 TI - Physiological Characteristics of Major League Baseball Players. AB - In brief Performance characteristics of professional athletes are of interest to those involved in sports. Major league baseball players were tested for muscular strength, cardiovascular endurance, and body composition. Comparisons were made among positions and with other professional athletes. Results indicated that differences in strength and body composition existed among positions. Cardiovascular endurance of baseball players was comparable to that reported for other professional athletes. These data may be useful as a point of reference for coaching, testing, training, and selecting athletes. PMID- 29278201 TI - Honolulu Marathon Clinics Stress Safety, Not Winning. AB - Cardiologist Jack Scaff's running clinics originally rehabilitated cardiac patients. Now the nine-month sessions prepare runners to race safely. PMID- 29278202 TI - Neuroprotective effects of flavonoid compounds on neuronal death associated to Alzheimer's disease. AB - Alzheimer's disease is an increasing neurodegenerative pathology related to age in many societies. Some aspects of the disease are related to the loss of neuronal cells derived by the formation of extracellular neuritic plaques and the appearance of intracellular neurofibrillary tangles, altogether generate a inflammatory and oxidative status. The accumulation of amyloids in cells induces the activation of the apoptotic cascade which implies capases activation. Alzheimer's disease is treated with acetylcholine esterase inhibitors, although their effects are still far away to reduce or eliminate the problems associated with the pathology. The lack of effective treatment has led to the search for new therapeutic alternatives based on natural products. Flavonoids comprise a group of phenolic compounds that have gained great interest since they present great diversity of biological activities. In the present work, we review the potential uses of flavonoids and the proposed mechanisms of action as a new therapeutic strategy in neurological cell death associated with Alzheimer's disease. PMID- 29278203 TI - Role of Redox Homeostasis and Inflammation in the Pathogenesis of Pulmonary Arterial Hypertension. AB - This review addresses pulmonary arterial hypertension (PAH), an incurable disease, which determines high morbidity and mortality. Definition of the disease, its characteristics, classification, and epidemiology are discussed. A difficulty in the diagnosis of PAH due to the lack of symptoms specificity is highlighted. Echocardiographic analysis and electrocardiogram of patients help in the diagnosis and in the follow up of the disease. Nevertheless, right ventricle (RV) catheterization constitutes the gold standard for diagnosing PAH. Oxidative stress and inflammation, in an interactive manner, play a major role in the development of pulmonary vascular remodeling and consequent increase of pulmonary pressure. The latter results in an increase in RV afterload, culminating with RV hypertrophy, which may progress to failure. Both clinical and experimental studies have shown increased oxidative stress and inflammation, not only in lungs and pulmonary vasculature but also in RV. The use of experimental models, such as the monocrotaline-induced PAH, has helped in the understanding of the pathophysiology of PAH, as well as in the development of new therapeutic strategies. In addition to the traditional therapeutics, the use of therapeutic interventions capable of modulating oxidative stress and inflammation may offer newer strategies in the prevention as well as management of this disease. PMID- 29278204 TI - Looking for new antifungal drugs from flavonoids: impact of the genetic diversity of Candida albicans on the in-vitro response. AB - In an era in which antimicrobial resistance is increasing at an alarming pace, it's very important to find new antimicrobial agents effective against pathogenic microrganisms resistant to traditional treatments. Among the notable breakthroughs in the past years of research in natural-drug discovery there is the identification and testing of flavonoids, a group of plant-derived substances capable of promoting many beneficial effects on humans. These compounds show different biological activities such as inhibition of neuroinflammation and tumor growth as well as antidepressant, antiarthritic, anti-hypercholesterolemic, antidiabetic, antiulcer and antiasthmatic activities. However, one of the most important effects of these phytochemicals is, undoubtedly, their antimicrobial activity against many microbial pathogens. In recent years, hundreds of scientific papers reported the inhibitory effects of flavonoids against pathogenic fungi but none of these has ever considered the inexorable genetic changes occurring within the populations of these microrganisms. Today, we have enough information to estimate genetic diversity within microbial species and recent data revealed that most of fungal pathogens shows a complex population structure in which no a single isolate can be designate as representative of the entire taxon. This is especially true for the highly divergent fungal pathogen Candida albicans, in which the assumption that one or few "standard strains" can represent the whole species is overly unrealistic and should be laid to rest. The goal of this article is to shed light on the extent of genetic variation in C. albicans and how this phenomenon can largely influence the activity of flavonoids against this species. PMID- 29278205 TI - Photodynamic Therapy in Melanoma - Where do we stand? AB - Malignant melanoma is one of the most aggressive malignant tumors with unpredictable evolution. Photodynamic therapy has been successfully used as the first line or palliative therapy for the treatment of lung, esophageal, bladder, non melanoma skin and head and neck cancers. However, classical photodynamic therapy has shown some drawbacks that limit its clinical application in melanoma. The most important challenge is to overcome melanoma resistance, due to melanosomal trapping, presence of melanin, enhanced oxidative stress defense, defects in the apoptotic pathways, immune evasion, neoangiogenesis stimulation. In this review we considered: (1) main signaling molecular pathways deregulated in melanoma as potential targets for personalized therapy, including photodynamic therapy, (2) results of the clinical studies regarding the photodynamic therapy of melanoma, especially advanced metastatic stage, (3) progresses made in the design of anti-melanoma photosensitizers (4) inhibition of tumor neoangiogenesis, as well as (5) advantages of the derived therapies like photothermal therapy, sonodynamic therapy. Moreover, the possibility of combined therapeutical regimens, such as photodynamic therapy and immune stimulation or theranostic approaches may increase the potential beneficial role of photodynamic therapy as an adjuvant in melanoma treatment. PMID- 29278206 TI - A systematic review of evidence-based treatment strategies for obsessive compulsive disorder resistant to first-line pharmacotherapy. AB - BACKGROUND: Serotonin reuptake inhibitors (SRIs) and cognitive-behavioral psychotherapy (CBT) are first-line treatments for obsessive-compulsive disorder (OCD). However, a significant proportion of patients do not respond satisfactorily to first-choice treatments. Several options have been investigated for the management of resistant patients. OBJECTIVE: The aim of the present paper is to systematically review the available literature concerning the strategies for the treatment of resistant adult patients with OCD. METHOD: We first reviewed studies concerning the definition of treatment-resistant OCD; we then analyzed results of studies evaluating several different strategies in resistant patients. We limited our review to double-blind, placebo-controlled studies performed in adult patients with OCD whose resistance to a first adequate (in terms of duration and dosage) SRI trial was documented and where outcome was clearly defined in terms of decrease in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scores and/or response/remission rates (according to the YBOCS). RESULTS: We identified five strategies supported by positive results in placebo-controlled randomized studies: 1) antipsychotic addition to SRIs (16 RCTs, of them 10 positive; 4 head-to-head RCTs); among antipsychotics, available RCTs examined the addition of haloperidol (butyrophenone), pimozide (diphenyl-butylpiperidine), risperidone (SDA: serotonin-dopamine antagonist), paliperidone (SDA), olanzapine (MARTA: multi-acting receptor targeted antipsychotic), quetiapine (MARTA) and aripiprazole (partial dopamine agonist); 2) CBT addition to medication (2 positive RCTs); 3) switch to intravenous clomipramine (SRI) administration (2 positive RCTs); 4) switch to paroxetine (SSRI: selective serotonin reuptake inhibitor) or venlafaxine (SNRI: serotonin-norepinephrine reuptake inhibitor) when the first trial was negative (1 positive RCT); and 5) the addition of medications other than an antipsychotic to SRIs (18 RCTs performed with several different compounds, with only 4 positive studies). CONCLUSION: Treatment resistant OCD remains a significant challenge to psychiatrists. To date, the most effective strategy is the addition of antipsychotics (aripiprazole and risperidone) to SRIs; another effective strategy is CBT addition to medications. Other strategies, such as the switch to another first-line treatment or the switch to intravenous administration are promising but need further confirmation in double-blind studies. The addition of medications other than antipsychotics remains to be studied, as several negative studies exist and positive ones need confirmation (only 1 positive study). PMID- 29278207 TI - Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results. AB - BACKGROUND: Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activators, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human 3 stage. In addition to the promising clinical data published so far, there are new in vitro results indicating that the effect of omecamtiv mecarbil on contractility is rate-dependent. Furthermore, omecamtiv mecarbil was shown to activate cardiac ryanodine receptors, an effect that may carry proarrhythmic risk. METHODS: These new results, together with the controversial effects of the drug on cardiac oxygen consumption, are critically discussed in this review in light of the current literature on omecamtiv mecarbil. RESULTS: In therapeutically relevant concentrations the beneficial inotropic effect of the agent is not likely affected by these new results - in accordance with the good clinical data. At supratherapeutic concentrations, however, activation of cardiac ryanodine receptors may increase arrhythmia propensity, and the stronger effect on diastolic than systolic cell shortening, observed at higher pacing frequencies, may decrease or offset the inotropic effect of omecamtiv mecarbil. CONCLUSION: Further studies with definitely supratherapeutical concentrations of omecamtiv mecarbil should be designed to map the actual risk of these potentially harmful side-effects. PMID- 29278209 TI - Pharmaceutical Cocrystals as an Opportunity to Modify Drug Properties: From the Idea to Application: A Review. AB - The properties of many drugs which have been available on the pharmaceutical market for a long time still need to be improved. Cocrystals are the solid state drug modification which can improve properties such as low solubility, stability and mechanical properties (e.g. compressibility). In this paper, examples of how to use cocrystals to modify properties of API (Active Pharmaceutical Ingredient) will be reported. Additionally, in this review, the way from an idea of the new cocrystal to drug dosage form registration will be shortly described. PMID- 29278208 TI - Identification of the Multifaceted Chemopreventive Activity of Curcumin Against the Carcinogenic Potential of the Food Additive, KBrO3. AB - BACKGROUND: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models. OBJECTIVES: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity. METHOD: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8- OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3. RESULTS: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while upregulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin. CONCLUSION: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3. PMID- 29278210 TI - Biologics in Inflammatory and Immunomediated Arthritis. AB - BACKGROUND: Biologic drugs, introduced in clinical practice almost twenty years ago, represent nowadays a prominent treatment option in patients with chronic inflammatory arthritis, such as Rheumatoid Arthritis, Psoriatic Arthritis and Spondyloarthritis, that include ankylosing spondylitis and non-radiographic axial spondyloarthritis. METHODS: Several compounds targeting different pathways have been marketed and approved for the treatment of inflammatory arthritis, with a significant impact on the clinical outcomes and the natural history of the diseases. RESULTS: There are currently seven classes of biologics that are available for the treatment of inflammatory arthritis, each inhibiting a different aspect of the immune-driven inflammatory pathway. They include: * Tumor Necrosis Factor (TNF) inhibitors (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol); * Interleukin-1 (IL-1) receptor antagonists (anakinra); * Interleukin-6 (IL-6) inhibition (tocilizumab); * Interleukin-12/23 (IL23) inhibition (ustekinumab); * Interleukin-17 (IL-17) inhibition (secukinumab); * B cell inhibition (anti-CD20, rituximab); * T-cell costimulation inhibition (anti CTLA-4, abatacept). CONCLUSION: In this review, we will focus on the role of biologic drugs in the treatment strategies for inflammatory arthritis. PMID- 29278211 TI - Evaluation of the Nutraceutical and Cosmeceutical Potential of Two Cultivars of Rubus fruticosus L. under Different Cultivation Conditions. AB - BACKGROUND: The starting point for the development of new, functional products derived from Rubus fruticosus L. is to determine the optimal cultivation conditions that produce maximal yield of fruits containing desirable bioactive properties. Towards that goal, the effect of soil, soil/peat mixture and light intensity on the nutraceutical and cosmeceutical potential of two cultivars ('Thornfree' and 'Loch Ness') of Rubus fruticosus L. were evaluated. METHODS: The assessment was carried out employing a range of methods for evaluating fruit properties associated with promoting good health such as total antioxidant capacity, secondary metabolites content (vitamin C, polyphenols, flavonoids and anthocyanins) and inhibition analysis of skin-regulating enzymes. RESULTS: 'Thornfree' cultivar produced fruits in all light conditions, while 'Loch Ness' did not produce fruits in low light conditions. The results showed that in Rubus fruticosus L. fruit, the chemical composition and bioactivity are strongly affected by both genetics factors and growing conditions. Extract from 'Thornfree' fruits obtained under low light and soil/peat conditions displayed superior properties such as high antioxidant capacity, high concentrations of phenolics, flavonoids and anthocyanins and high inhibitory potency towards the enzymes tyrosinase and elastase. This extract was used for the development of a topical skin care cream with excellent compatibility and stability. CONCLUSION: Our findings conclude that Rubus fruticosus L. cultivation may be efficiently and effectively manipulated through conventional cultivation techniques to produce promising bioactive ingredients with potential use in commercial cosmetics and pharmaceuticals. PMID- 29278212 TI - Immunomodulatory Effects of Bifidobacterium longum W11 Produced Exopolysaccharide on Cytokine Production. AB - BACKGROUND: Health benefits, including immune modulating capability, exerted by Bifidobacterium strains have been attributed to their exopolysaccharides (EPSs). OBJECTIVE: The effects of the purified EPS from B. longum W11 on cytokine production by peripheral blood mononuclear cells (PBMCs) alone or ConA-stimulated were investigated. METHOD: The production of IFN-gamma, IL-1beta, IL-6 and IL-10 by PBMCs from healthy adult donors was analysed using purified EPS at two different concentrations (100 ug/mL and 200 ug/mL) and ConA, as an immunopotentiating marker. Moreover, the monosaccharide composition of the EPS from B. longum W11 was detected using HPLC analysis. RESULTS: The results demonstrated the ability of purified EPS to increase the production of the tested cytokines, except IL-10, in ConA-stimulated PBMCs. In not-stimulated-PBMCs, EPS increased the production of IL-6 (at 200 ug/mL) and IL-10 (at 100 ug/mL). The HPLC analysis showed the presence of main monomers, galactose and glucose (ratio 1:1 wt/wt), and small amount of rhamnose. CONCLUSION: The results of this study demonstrate the ability of the EPS produced by B. longum W11 to interact in vitro with the human PBMCs, showing an immune-regulatory profile alone and an immune stimulatory profile in ConA-stimulated PBMCs. This suggests putative applications for the EPS from B. longum W11 in different pathological conditions. PMID- 29278213 TI - Biologics in Inflammatory Immune-mediated Systemic Diseases. AB - BACKGROUND: The use of biologic agents in systemic immune-mediated diseases has dramatically increased in recent years, replacing conventional immunosuppressive strategies that are characterized by unspecific mechanisms of action and burdened with serious adverse effects. Biologic drugs have selective action towards specific targets, with considerable steroid-sparing effect. They are used nowadays to induce remission or treat specific organ involvements in systemic autoimmune diseases. CONCLUSION: In this review, we will discuss the scientific evidence supporting the use of biologics in these diseases, with a particular emphasis on their efficacy and safety profile compared to the conventional drugs. PMID- 29278214 TI - Serum Uric Acid is Independently Associated with Diastolic Dysfunction in Apparently Healthy Subjects with Essential Hypertension. AB - OBJECTIVES: Accumulating evidence suggests a direct role of Uric Acid (UA) on Left Ventricular (LV) diastolic function in chronic kidney disease and Heart Failure (HF) patients. Recently, UA has been linked to LV Hypertrophy (LVH) and Diastolic Dysfunction (DD) in women with preserved Ejection Fraction (pEF) but not in corresponding men. We sought to assess if UA could predict indices of DD in hypertensive subjects with pEF independently of gender. METHOD: We consecutively recruited 382 apparently healthy hypertensive subjects (age: 61.7+/ 10.7, women: 61.3%, median EF: 64%). In 318 patients in sinus rhythm, LV mass indexed to body surface area-was calculated (LVMI). LVH was set as an LVMI >116g/m2 or 96 g/m2 in men and women, respectively. The ratio of early transmitral peak velocity (E) to the mitral annular early diastolic velocity (Em) was used as an approximation of mean left atrial pressure (E/Em). RESULTS: UA [median (interquartile range): 5.4(2) mg/dl] independently predicted E/Em (adjusted coefficient: 1.01, p =0.026) while an interaction term between gender and UA was no significant (p=0.684). An ordinal score of DD was calculated taking into account increased E/Em, left atrium dilatation and LVH. Women with increased UA had 254% increased odds (adjusted OR=2.54, p=0.005) to be classified in the upper range of the DD score. CONCLUSION: In hypertensive subjects without HF, UA is independently associated with the presence of DD in both genders and correlates with its severity in women. Further prospective studies are warranted to evaluate the association of UA with adverse cardiovascular outcomes in high risk populations such as HF with pEF. PMID- 29278216 TI - Formulation and Evaluation of Novel Solid Lipid Microparticles for the Sustained Release of Ofloxacin. AB - OBJECTIVE: The aim of this study was to prepare solid lipid microparticles (SLM) with incorporated ofloxacin, suitable for oral delivery. METHODS: Ofloxacin loaded SLM were prepared using stearic acid and chloroform as lipid matrix and Tween-80 as surfactant, by high shear homogenization technique and followed by lyophilization. The physiochemical characterization of SLMs were investigated by scanning electron microscopy, transmission electron microscopy, zeta potential, zone of inhibition, in-vitro study, ex-vivo study and stability study. RESULTS: The result demonstrated that the entrapment efficiency, particle size and zeta potential of microparticles were 86.02%, 203.7nm and -32.68mv, respectively. The in-vitro and ex-vivo studies showed sustained release of drug from formulation. CONCLUSION: These results indicate that SLM might be a promising delivery system to enhance the pharmacological activity of ofloxacin. PMID- 29278215 TI - Percutaneous Coronary Intervention in the Elderly: Are Drug-coated Balloons the Future? AB - BACKGROUND: Balloon angioplasty revolutionised percutaneous treatment for coronary artery disease four decades ago, but vessel-threatening dissections, elastic recoil and restenosis were major drawbacks to an otherwise successful long-lasting intervention. Subsequent advances with bare metal stents and then drug eluting stents followed, aiming to mitigate the risks of acute vessel closure and restenosis. However, stent implantation often necessitates dual antiplatelet therapy for a prolonged period of time, which in itself can lead to adverse outcomes, especially in the frail elderly population at higher risk of bleeding. More recently, bioabsorbable stents have been implemented in clinical practice enabling earlier intimal coverage of the stent and apposition. However, another addition to the armamentarium of percutaneous coronary intervention is the use of drug-coated balloons without the need for deploying any coronary stents or scaffolds. Drugcoated balloons are semi-compliant balloons coated with an antiproliferative agent that is rapidly released on contact with the vessel intima exerting an anti-restenotic effect. The absence of a metallic scaffold means that the need for antiplatelet therapy can potentially be negated in the longer term if required. In this article, we will review the history of percutaneous coronary intervention and the available evidence for the appropriate use of drug-coated balloons especially in the elderly population. CONCLUSION: We will conclude this review by demonstrating the potential use of drug-coated balloon rather percutaneous stenting through case examples. PMID- 29278217 TI - Physicochemical Modifications and Nano Particulate Strategies for Improved Bioavailability of Poorly Water Soluble Drugs. AB - BACKGROUND: Bioavailability is the segment of dose that is bioavailable for its therapeutic effect on the systemic circulation without any change in its characteristics, after administration by either route. It is one of the fundamental pharmacokinetic properties of drugs. It is important because, it defines the amount of drug to be administered for its intended therapeutic effect. If drug is more bioavailable, less amount of it is required to obtain therapeutic effect. However, it is also worth mentioning that most of the newly discovered therapeutic agents have poor solubility and thus low bioavailability. OBJECTIVES: In this article, various methods including conventional and advanced, have been reviewed that could be potentially used for the enhancement of bioavailability. Moreover, the benefits and drawbacks of all the strategies are deliberated to comprehend the probable use of each method supported by latest references. METHODS: Various strategies have been developed to enhance the solubility and thus bioavailability of numerous drugs, some of which are discussed here. All these strategies involve different approaches to improve the bioavailability including physical adaptation, chemical modification and controlling particle size of the engineered particle. RESULTS: These strategies, particularly the nano-particulate systems, not only improve the bioavailability of drugs but at the same time diminish the possible toxicities of the incorporated drugs. CONCLUSION: It can be concluded that this would be a new source of information for the readers. PMID- 29278218 TI - Cracking the Code on Quality and Safety in Healthcare - What Will It Take? AB - Over the next 30 years in Canada, it is estimated that there could be roughly 400,000 average annual cases of patient safety incidents, costing approximately $6,800 per patient and generating an additional $2.75 billion in healthcare treatment costs per year. What will it take to "crack the code" on creating safe environments and practice in healthcare? PMID- 29278219 TI - Five years of Experience using Front-Line Ownership to Improve Healthcare Quality and Safety. AB - Front-line ownership (FLO) is a complexity science-based approach to leading change initiatives that is built upon a foundation of Positive Deviance and the use of Liberating Structures to engage others. In this paper, we outline the use of FLO in four successful patient safety or quality improvement projects in four countries. While the underlying principles guiding the use of FLO were the same for each of these projects, project goals, the types of roles involved and how the projects evolved, spread and were sustained, varied considerably between settings. Allowing for local variability while following consistent overarching simple rules is central to the FLO approach and we believe the key reason why it has met with success. While many parts of healthcare delivery require increased standardization, approaches that allow teams to develop implementation strategies based on their unique local situations, will likely meet with greater success than those that attempt to standardize implementation in addition to practice. PMID- 29278220 TI - Patients as Front-Line Owners and Partners in Improving Quality and Safety. AB - As patient partners, we are pleased by the success of the front-line ownership (FLO) approach in advancing safe care in a variety of initiatives and settings. The FLO underlying principles and approach deeply resonate with us as illustrated in the following quotes from the paper: "Nothing about me without me," "Most passionate change agents are not in roles that typically get invited to participate," "Inviting anybody who is interested in the problem at hand," "FLO creates a way to break down hierarchies, increase positive dialogue between diverse players in organizations, and encourage people who may not have felt empowered previously to come forward and problem-solve." It is not described in the article if and how patients and/or patient partners were involved; therefore, we call on the authors to follow up with that information because it can provide valuable lessons to others who will be looking at implementing FLO in their organizations. Based on our decade-long experience as patient partners at all system levels, on literature and leading practices (key references included) we argue that patients have an important role to play in improvement initiatives and recommend partnering with patients in all improvement efforts. PMID- 29278221 TI - People Powered HealthTM:: Taking Front-Line Ownership to the Next Level. AB - Collaboration is a powerful force of social change. History has shown us time and time again that when people come together with a shared passion for making things better, high impact change can happen. Minds are opened. Voices are heard. Lives are saved. Our experience at Health Standards Organization (HSO) and Accreditation Canada shows that when people feel involved, empowered and engaged in a meaningful way to bring about improvement, then the chances that it will be sustained over time increase as well. This paper builds on the principles of front-line ownership (FLO) initiatives offered by Gardam et al., addresses the tensions between standards and innovation and reminds us that collaboration is all about people, and people power is what converts theory and ideas into reality - especially in healthcare environments. PMID- 29278222 TI - Front-Line Ownership - Necessary but not Sufficient. AB - In their paper, Gardam et al. (2017) set out a series of case studies exemplifying their conceptual construct of front-line ownership (FLO). While the construct of FLO has face validity, in this commentary I urge further consideration of the "conditions" under which FLO will flourish which go beyond the principles set out by the authors. I also challenge the positioning of "standardization" and offer reflections that position "standardization to allow mass customization" to achieve person-centred goals. Finally, I urge greater profile for co-production with users of services in the FLO concept and suggest that shared decision-making offers a natural home for FLO and co-production to come together. PMID- 29278223 TI - Understanding the System You Are in Is Key to Improving It. AB - Front-line ownership (FLO) is an approach to change that is consistent with what we know about complex adaptive systems (CAS), such as a healthcare organization. Traditional change approaches can fail because they are based in the "organization as a machine" metaphor of traditional, scientific management. Both metaphors have their application. It depends on how closely the work naturally resembles a predictable machine. Often, the drive for detailed standardization is a misguided effort to make a human CAS behave more like a machine, so that our traditional approaches to change will work. FLO is a more appropriate tool in a CAS, where shared agreement at the level of a few simple rules (minimum specifications) and allowing flexibility for adaptation within local context is more appropriate than detailed standardization. Because humans in a CAS maintain some control over their discretionary effort, change advocates desiring sustainable change must work with stakeholders to co-create cases for change that resonate with the values of those being asked to change. FLO facilitates the emergence of this level of understanding of shared values. PMID- 29278224 TI - A Matter of Balance: Sharing Front-Line Ownership for Quality and Safety with Patients and Families - Scaling and Spreading Local Improvements for Broader Impact. AB - The approach to front-line ownership proposed by Gardam et al. (2017) consists of many elements integral to most approaches to quality improvement. The mix of these elements may need to be modified in circumstances that have the most impact on patient safety, where a higher level of standardization may be essential and a more directive approach may be needed. The inclusion of patients as partners in quality improvement means that staff do not exclusively own the solutions and power must be shared with others whose views may be quite different. When this lens is applied, the concepts proposed by Gardam et al. do not resonate as strongly and in some cases may appear to promote a provider-centred approach where the experience and wisdom of patients, family and community are undervalued. The need to ensure consistency in quality of care across large systems will also require a balance between local customization and system-wide thinking and delivery, where strategies build on the successes of local teams while enabling timely spread throughout other units and sites. PMID- 29278225 TI - Quality Improvement: Lessons from the English National Health Services. AB - Based on our own experiences leading healthcare improvement in the English National Health Service (NHS), we identify seven themes that connect with the story of front-line ownership (FLO): Create investors not buyers of change - "buy in" is too late in the change process; We need to combine both technical and cultural aspects of change - go slow to go fast and make sure that we pay attention to the human dimensions of change; Build strong ties AND weak ties - reach out to your usual suspects AND find your unusual suspects and unlikely allies; If we want innovation, we need to create psychological safety - the conditions of trust and support that make people feel safe to try new things that might fail; Build energy for change for the long haul, right from the start of your change efforts - go beyond the typical "intellectual" energy and build "social" and "spiritual" energy that create strong foundations for change; Challenge "the myth of the disinterested" - everyone is passionate about something; The leader as coach and team member - be the leadership role model that enables change. PMID- 29278226 TI - Healthcare Quality Improvement Requires Many Approaches. AB - It is a pleasure to respond to the commentaries and we thank the authors for the thought, time and effort they so obviously put into their writing. We are excited that documenting our experience has resulted in such a wide range of opinion. PMID- 29278227 TI - DHEA supplementation improves endometrial HOXA-10 mRNA expression in poor responders. AB - OBJECTIVE: The study was planned to investigate whether DHEA supplementation had an impact on endometrial receptivity in women who were poor responders (POR). MATERIAL AND METHODS: Twenty-eight POR women who were undergoing hysteroscopy and five fertile control subjects were included. The POR women were equally subdivided into two separate groups as patients who were currently using DHEA and those who were not. Endometrial samples of the subjects were obtained during hysteroscopy at the late follicular phase. Expression levels of endometrial HOXA 10, HOXA-11, and LIF mRNA were measured with the using real-time polymerase chain reaction. Spontaneous clinical pregnancy rates were also noted. RESULTS: Compared with POR women who were not given DHEA, upregulated endometrial HOXA-10 (7.33 fold) and HOXA-11 (2.39-fold) mRNA expression were detected in POR women on DHEA. The increase in HOXA-10 mRNA was significant (p<0.03). The fold increase in HOXA 11 mRNA was found as 2.39, which indicated a positive upregulation. However, this fold increment was insignificant (p<0.45). An insignificant increase in spontaneous clinical pregnancy rates in POR women on DHEA (53.3%) was observed compared with POR women who were not given DHEA (43.8%). CONCLUSION: Oral DHEA supplementation in POR upregulates endometrial HOXA-10 mRNA expression, which is known to positively modulate endometrial receptivity. PMID- 29278228 TI - An in vitro study on oocyte and follicles of transplanted ovaries treated with vascular endothelial growth factor. AB - OBJECTIVE: Retrieval of high quality follicles and oocytes from transplanted ovaries is essential for higher fertility preservation efficiency. The effect of vascular endothelial growth factor (VEGF) was evaluated on the survival rate of preantral follicles following ovarian transplantation. MATERIAL AND METHODS: Prepubertal female mice were divided to 6 groups including: control (C), transplanted with no VEGF treatment (T) and transplanted with different dosages of VEGF [0.5 ug/mL (TV1), 1 ug/mL (TV2), 2 ug/mL (TV3), and 4 ug/mL (TV4)]. Twenty-one days later, the left ovaries were removed and transplanted on gluteal muscle. Each dose was injected directly into transplanted ovary. Twenty-one days after transplantation, the ovaries were taken, and follicles and cumulus-oocyte complexes (COCs) were released using 26-gauge needles with a stereo microscope. The number of healthy COCs, matured oocytes, and in vitro developed embryos after fertilization in vitro were evaluated to determine the best dose of VEGF. Follicle number and follicular growth was evaluated relative to the dose of VEGF provided. Transplantation and VEGF treatment with the best dose was performed as mentioned above and in vitro follicle growth in transplanted ovaries was compared with opposite ovaries (OPP). RESULTS: COC retrieval was significantly lower in the transplanted groups compared with the control group (p<0.05). The percentage of metaphase II oocytes was significantly lower in the group treated with 4 ug/mL VEGF compared with the controls (p<0.01). In the TV2 (1 ug/mL) and TV3 (2 ug/mL) groups, the percentages of morula and blastocysts were significantly improved compared with the T group (p<0.01). In the OPP group, the number of follicles was significantly higher compared with the transplanted groups (p<0.01). CONCLUSION: The improving effect of VEGF on in vitro maturation and in vitro development outcome indicates that VEGF administration may increase transplantation efficiency for fertility preservation. PMID- 29278229 TI - Is there any difference between the distances created by towel clamp lifting and towel clamp plus manual lifting of the anterior abdominal wall for direct trocar entry in laparoscopic gynecologic surgery? A prospective interventional study. AB - OBJECTIVE: Most surgeons prefer to perform anterior abdominal wall lifting during abdominal entry to avoid damage to intestines or main vessels. Anterior abdominal wall lifting is assumed to prevent vital organ injuries by creating an adequate distance prior to entry into the peritoneal cavity. In this study, we compared the distance created for trocar entry into the peritoneal cavity with towel clamp lifting and towel clamp plus manual elevation of the anterior abdominal wall. MATERIAL AND METHODS: Forty patients who underwent various laparoscopic procedures were enrolled. The study was performed in two steps: first the anterior abdominal wall was lifted using towel clamps (TC group), next the anterior abdominal wall was lifted via maximal manual elevation from the lower abdomen in addition to towel clamps (TCM group). The insertion distance of a plastic ruler into the abdomen was measured from the parietal peritoneum to the intra-abdominal structure in both groups. RESULTS: There was a statistically significant difference between the two groups (TC group 3.9+/-1.5 cm vs. TCM group 4.5+/-1.5 cm, p<0.001). Correlation analysis of the relationship of distance with BMI in the study groups revealed a strong negative linear correlation [TC group vs. body mass index (BMI); r=-0.719, p<0.001 and TCM group vs. BMI, r=-0.749, p<0.001]. Correlation analysis of the relationship between the study groups and parity number revealed a weak negative linear correlation (TC group vs. parity number, r=-0.071, p=0.76 and the TCM group vs. parity number, p=0.61), which did not reach statistical significance. CONCLUSION: The recruitment of both towel clamps and manual elevation in anterior abdominal wall lifting provides significantly greater distance for trocar entry in laparoscopic surgery. PMID- 29278230 TI - Prevalence of group B Streptococcal colonization among pregnant women and neonates in a tertiary hospital in India. AB - OBJECTIVE: To estimate the prevalence of group B Streptococcus (GBS) carriage among pregnant women attending the antenatal clinic, and the colonization rates among newborn born to colonized mothers. MATERIAL AND METHODS: Women attending the antenatal clinic between 35-37 weeks were screened using rectal and lower vaginal swab. Swabs were initially plated on sheep blood agar and LIM broth. The LIM broth was subcultured after 24 hours onto blood agar and CHROMagar StrepB plates with all plates checked for growth at 24 and 48 hours. All babies born to mothers in the study had surface swabs taken to estimate the vertical transmission rate. RESULTS: Between September 2012 and March 2013, 305 consecutive mothers were screened. Of these, eight mothers were GBS positive in 5% blood agar (2.6%) and 23 mothers showed GBS positivity in enriched media (7.6%). Sixteen of 238 babies (6.7%) were colonized. CONCLUSION: Though lower than rates from most countries, 7.6% of mothers attending an antenatal clinic in south India were colonized with GBS. Use of enrichment media markedly increased the detection rate. Approximately two-thirds of newborn born to colonized mothers were also colonized. There were no instances of invasive GBS disease, indirectly proving the efficacy of intrapartum prophylaxis in preventing neonatal GBS disease. PMID- 29278231 TI - Excisions of severe cervical dysplasia: Are there mandatory diameters of the cone that need to be considered? AB - OBJECTIVE: To achieve optimal depth for negative margin cones after loop electrosurgical excision procedures (LEEP) for cervical dysplasia. MATERIAL AND METHODS: Retrospective cohort analysis of LEEP cones of 201 patients with cervical dysplasia during a four-year period. Analysed cones were divided into two different groups: cones with negative margins without dysplasia, and cones with margins positive for dysplasia. In order to determine the cut-off value of the depth of the resected cones, receiver operating characteristic (ROC) analysis was performed. RESULTS: Negative margins were found in 71.0% (n=49) of all cones, whereas positive margins were reported in 29.0% (n=20). Negative margin cones were achieved in 100% with a cone depth of >=20 mm. A resection depth between 10 19.9 mm led to 73.0% negative margin cones. Calculation of cone volume shows for 2.0 cm3, a sensitivity of 79% and a specificity of 64%. Statistical analysis using an ROC model showed p=0.002. CONCLUSION: Forth greatest safety of patients, cone depths from LEEPs for cervical dysplasia should be >=20 mm to achieve negative margins. PMID- 29278232 TI - Retrospective analysis of episiotomy prevalence. AB - OBJECTIVE: This study was performed to determine the rate of episiotomy. MATERIAL AND METHODS: This retrospective was conducted in 3 state hospitals located in 3 cities in the Central Anatolia region of Turkey. Ethics committee approval was received for this study. Also, institutional permissions from the institutions where the study was conducted were obtained before the study. The sample of the study consisted of 8587 women. The data of the study were collected by analyzing birth records in archive records. RESULTS: The average age of the women was 26.16+/-5.9 years, the average number of deliveries was 2.19+/-1.2, and 52.0% of the women who gave birth via vaginal delivery underwent episiotomy. The rate of episiotomy was found to be 93.3% in primipara women and 30.2% in multipara women. It was determined that neonatal weight did not affect the episiotomy rate, and that neonatal height was higher in deliveries with episiotomy and suture. Also, it was determined that as the age and parity of the women decreased, the rate of episiotomy increased. CONCLUSION: The rate of episiotomy was observed to be high, especially in primipara women. PMID- 29278233 TI - Does size matter? Retrospective analysis of large gynecologic tumors. AB - OBJECTIVE: To evaluate the characteristics of patients who underwent surgery due to the presence of a large pelvic-abdominal mass over a 5-year period in a university clinic. MATERIAL AND METHODS: Among 3476 gynecologic operations, intraoperative findings were evaluated retrospectively. Uterine and/or adnexal masses smaller than 20 cm were excluded to refine "large" tumors and 74 patients with large tumors were enrolled in the study group. Demographic characteristics, intraoperative findings, and results of histopathologic examinations were recorded. Moreover, preoperative and intraoperative findings were compared among tumors with adnexal origin according to their final histopathologic results. RESULTS: The mean age of the patients was 46 years. The most common symptom was abdominal pain, as recorded in 38 (51.4%) patients. Among all patients, 31 (41.9%) had coexisting illness and 13 (17.6%) had a history of surgery. The mean tumor diameter was 25.9+/-8.6 cm (20-60) and 60 (78.9%) tumors were of adnexal origin. The ratios of malignancy for large adnexal and uterine tumors were 34.4% and 12.5%, respectively. When the large adnexal tumors were re-evaluated, the mean cancer antigen (CA) 125 level was significantly higher, and ascites was more frequently detected in malignant tumors (p<0.01) then in benign and borderline tumors. CONCLUSION: Benign and borderline tumors are more common among large abdominopelvic masses, although the presence of ascites and elevated CA 125 may present malignancy in large gynecologic tumors. Further studies with larger sample sizes are needed to define the characteristics of large tumors and their malignant potentials. PMID- 29278234 TI - Diagnostic and treatment guidelines for gastrointestinal and genitourinary endometriosis. AB - Endometriosis is commonly misdiagnosed, even among many experienced gynecologists. Gastrointestinal and genitourinary endometriosis is particularly difficult to diagnose, and is commonly mistaken for other pathologies, such as irritable bowel syndrome, interstitial cystitis, and even psychological disturbances. This leads to delays in diagnosis, mismanagement, and unnecessary testing. In this review, we will discuss the diagnosis and management of genitourinary and gastrointestinal endometriosis. Medical management may be tried first, but often fails in cases of urinary tract endometriosis. This is particularly important in cases of ureteral endometriosis because silent obstruction can lead to eventual kidney failure. Thus, we recommend complete surgical treatment in these cases. Bladder endometriosis may be managed more conservatively, and only if symptomatic, because these rarely lead to significant morbidity. In cases of bowel endometriosis, we recommend medical management first in all cases, and the least invasive surgical management only if medical treatment fails. This is due to the extensive nervous and vasculature supply to the lower rectum. Injury to these nerves and vessels can cause significant complications and postoperative morbidity. PMID- 29278236 TI - What is your diagnosis? PMID- 29278235 TI - Role of hormones in hypoactive sexual desire disorder and current treatment. AB - Over the decades, female sexual dysfunction (FSD) has grown to be an increasingly potential problem that complicates the quality of life among women. In the current review, FSD refers to recurrent and persistent problems with sexual orgasm, desire, or response. One of the most common subtypes of FSD that has evoked increased research interest in the scientific community is hyposexuality. Today, there is a consensus that hyposexuality is a multifactorial condition that manifests with reduced sexual desire resulting in significant interpersonal distress. The objective of the current review was to examine how hormonal profile triggers propagate hypoactive sexual desire disorder (HSDD), and to highlight effective treatment interventions that can be used to manage the condition. The current review describes HSDD as a sexual dysfunction characterized by the absence or lack of sexual desire and fantasies for sexual activities. The review argues that even if the role of sexual hormones is essential in modulating HSDD through therapeutic interventions, an effective comprehension of the biologic mechanisms underlying HSDD is necessary. There is a consensus in the literature that HSDD still poses significant challenges due to the lack of properly formulated treatment regimens and absence of clear clinical guidelines. That is, a better intervention consisting of both psycho-relational and biologic aspects is compulsory if tailored management and accurate diagnosis of HSDD in clinical practice are to be realised. The review concludes that, to date, a reliable clinical intervention to manage hyposexuality is still absent and more interventions, in terms of safety and efficacy, are required. Thus, additional investigation is required to document precise hormonal or non-hormonal pharmacotherapeutic agents for individualised care among patients with HSDD. PMID- 29278237 TI - Hysterectomy A Comprehensive Surgical Approach. AB - This book presents a step-by-step surgical description of vaginal hysterectomy, abdominal hysterectomy, conventional laparoscopic hysterectomy, and robotic assisted hysterectomy. It brings into balance theoretical background, clinical experience, and scientific findings in a readily comprehensible form with numerous illustrations and tables. The book contains a large proportion of interdisciplinary aspects that make a substantial contribution to meeting the growing requirements of interdisciplinary medical treatment. It offers related disciplines the opportunity to describe areas of common overlap and how these can be treated. Verschiedene chirurgische Verfahren einschliebetalich vaginaler Hysterektomie, abdominaler Hysterektomie, konservativer laparoskopischer Hysterektomie und roboterassistierter Hysterektomie werden in diesem englischsprachigen Lehrbuch schrittweise beschrieben. In ausgewogener Art und Weise werden theoretische Hintergrunde, klinische Erfahrungen und wissenschaftliche Erkenntnisse in leicht verstandlicher Form mit zahlreichen Abbildungen und Tabellen dargestellt. Indem es verschiedene interdisziplinare Aspekte behandelt, wird das Buch den wachsenden Anforderungen der interdisziplinaren medizinischen Therapie gerecht. Benachbarte medizinische Fachbereiche kommen zu Wort und haben die Moglichkeit, uberlappende Krankheitsbilder und deren Behandlung zu erlautern. PMID- 29278238 TI - [The user and his use of emergency services and departments]. PMID- 29278239 TI - Communication rights from the margins: politicising young refugees' smartphone pocket archives. AB - Politicising the smartphone pocket archives and experiences of 16 young refugees living in the Netherlands, this explorative study re-conceptualises and empirically grounds communication rights. The focus is on the usage of social media among young refugees, who operate from the margins of society, human rights discourse and technology. I focus on digital performativity as a means to address unjust communicative power relations and human right violations. Methodologically, I draw on empirical data gathered through a mixed-methods, participatory action fieldwork research approach. The empirical section details how digital practices may invoke human right ideals including the human right to self-determination, the right to self-expression, the right to information, the right to family life and the right to cultural identity. The digital performativity of communication rights becomes meaningful when fundamentally situated within hierarchical and intersectional power relations of gender, race, nationality among others, and as inherently related to material conditions and other basic human rights including access to shelter, food, well-being and education. PMID- 29278240 TI - Response: Commentary: The effects of acute stress on core executive functions: A meta-analysis and comparison with cortisol. PMID- 29278241 TI - Improving patient satisfaction in glaucoma care. PMID- 29278242 TI - Missing focus on Human Factors - organizational and cognitive ergonomics - in the safety management for the petroleum industry. AB - More attention has recently been given to Human Factors in petroleum accident investigations. The Human Factors areas examined in this article are organizational, cognitive and physical ergonomics. A key question to be explored is as follows: To what degree are the petroleum industry and safety authorities in Norway focusing on these Human Factors areas from the design phase? To investigate this, we conducted an innovative exploratory study of the development of four control centres in Norwegian oil and gas industry in collaboration between users, management and Human Factors experts. We also performed a literature survey and discussion with the professional Human Factors network in Norway. We investigated the Human Factors focus, reasons for not considering Human Factors and consequences of missing Human Factors in safety management. The results revealed an immature focus and organization of Human Factors. Expertise on organizational ergonomics and cognitive ergonomics are missing from companies and safety authorities and are poorly prioritized during the development. The easy observable part of Human Factors (i.e. physical ergonomics) is often in focus. Poor focus on Human Factors in the design process creates demanding conditions for human operators and impact safety and resilience. There is lack of non-technical skills such as communication and decision-making. New technical equipment such as Closed Circuit Television is implemented without appropriate use of Human Factors standards. Human Factors expertise should be involved as early as possible in the responsible organizations. Verification and validation of Human Factors should be improved and performed from the start, by certified Human Factors experts in collaboration with the workforce. The authorities should check-back that the regulatory framework of Human Factors is communicated, understood and followed. PMID- 29278243 TI - Rethinking balance and impartiality in journalism? How the BBC attempted and failed to change the paradigm. AB - This article reconsiders the concepts of balance and impartiality in journalism, in the context of a quantitative content analysis of sourcing patterns in BBC news programming on radio, television and online in 2007 and 2012. Impartiality is the cornerstone of principles of public service broadcasting at the BBC and other broadcasters modelled on it. However, the article suggests that in the case of the BBC, it is principally put into practice through juxtaposing the positions of the two main political parties - Conservative and Labour. On this basis, the article develops the idea of the 'paradigm of impartiality-as-balance.' This paradigm prevails despite the news organisation's commitment to representing a broader range of opinion. The paradigm of impartiality-as-balance means that only a narrow range of views and voices are heard on the most contentious and important issues. Further, it results in reporting that focuses on party political conflict, to the detriment of a journalism which provides much-needed context. PMID- 29278244 TI - Embassy cinema: what WikiLeaks reveals about US state support for Hollywood. AB - In an article for Foreign Affairs at the outbreak of the World War II, film producer Walter Wanger referred to Hollywood movies as '120,000 American ambassadors'. The preeminence of Hollywood in presenting US ideology to the world has been asserted ever since. Yet the relationship between Hollywood and America's actual ambassadors, employed by the global network of American embassies, has rarely been investigated, despite the key role that this often overlooked aspect of the state apparatus plays in the maintenance of Hollywood's commercial interests and American cultural hegemony. The release by WikiLeaks in November 2010 of over 250,000 diplomatic cables has provided an opportunity to address this gap, by offering researchers an unparalleled insight into the worldwide network of American embassies. This article employs these documents to explain how these embassies have influenced global film policies since early 2003, and the implications they have for conceptions of American power in the wake of the 'War on Terror'. PMID- 29278245 TI - Optimizing preventive maintenance policy: A data-driven application for a light rail braking system. AB - This article presents a case study determining the optimal preventive maintenance policy for a light rail rolling stock system in terms of reliability, availability, and maintenance costs. The maintenance policy defines one of the three predefined preventive maintenance actions at fixed time-based intervals for each of the subsystems of the braking system. Based on work, maintenance, and failure data, we model the reliability degradation of the system and its subsystems under the current maintenance policy by a Weibull distribution. We then analytically determine the relation between reliability, availability, and maintenance costs. We validate the model against recorded reliability and availability and get further insights by a dedicated sensitivity analysis. The model is then used in a sequential optimization framework determining preventive maintenance intervals to improve on the key performance indicators. We show the potential of data-driven modelling to determine optimal maintenance policy: same system availability and reliability can be achieved with 30% maintenance cost reduction, by prolonging the intervals and re-grouping maintenance actions. PMID- 29278246 TI - Twitter and Non-Elites: Interpreting Power Dynamics in the Life Story of the (#)BRCA Twitter Stream. AB - In May 2013 and March 2015, actress Angelina Jolie wrote in the New York Times about her choice to undergo preventive surgery. In her two op-eds, she explained that - as a carrier of the BRCA1 gene mutation - preventive surgery was the best way to lower her heightened risk of developing breast and ovarian cancer. By applying a digital methods approach to BRCA-related tweets from 2013 and 2015, before, during, and after the exposure of Jolie's story, this study maps and interprets Twitter discursive dynamics at two time points of the BRCA Twitter stream. Findings show an evolution in curation and framing dynamics occurring between 2013 and 2015, with individual patient advocates replacing advocacy organizations as top curators of BRCA content and coming to prominence as providers of specialist illness narratives. These results suggest that between 2013 and 2015, Twitter went from functioning primarily as an organization centered news reporting mechanism, to working as a crowdsourced specialist awareness system. This article advances a twofold contribution. First, it points at Twitter's fluid functionality for an issue public and suggests that by looking at the life story-rather than at a single time point-of an issue-based Twitter stream, we can track the evolution of power roles underlying discursive practices and better interpret the emergence of non-elite actors in the public arena. Second, the study provides evidence of the rise of activist cultures that rely on fluid, non-elite, collective, and individual social media engagement. PMID- 29278247 TI - The second life of Kowloon Walled City: Crime, media and cultural memory. AB - Kowloon Walled City (hereafter KWC or Walled City), Hong Kong has been described as 'one of history's great anomalies'. The territory remained under Chinese rule throughout the period of British colonialism, with neither jurisdiction wishing to take active responsibility for its administration. In the postwar period, the area became notorious for vice, drugs and unsanitary living conditions, yet also attracted the attention of artists, photographers and writers, who viewed it as an instance of anarchic urbanism. Despite its demolition in 1993, KWC has continued to capture the imaginations of successive generations across Asia. Drawing on data from an oral and visual history project on the enclave, alongside images, interviews and observations regarding the 'second life' of KWC, this article will trace the unique flow of meanings and reimaginings that KWC has inspired. The article will locate the peculiar collisions of crime and consumerism prompted by KWC within the broader contexts in which they are embedded, seeking out a new interdisciplinary perspective that attends to the internecine spaces of crime, media and culture in contemporary Asian societies. PMID- 29278248 TI - When the spell is broken: gentrification, urban tourism and privileged discontent in the Amsterdam canal district. AB - Expansion of urban tourism in historic districts in European cities is putting increasing pressure on these areas as places to live. In Amsterdam, an ever growing number of tourists visit the famous canal district, which also forms the home of a group of long-term, upper-middle-class residents. While such residents are generally depicted as instigators of urban transformation, in this case, they are on the receiving end. Bringing together the literature on the socio-spatial impact of tourism, belonging and the lived experience of place, this article explores the changing relationship between these established residents and their neighbourhood and provides insight into their growing sense of discontent and even powerlessness in the face of neighbourhood change. PMID- 29278249 TI - Governing the resilience of neoliberalism through biopolitics. AB - Neoliberalism is widely regarded as the main culprit for the 2007/2008 global financial crisis. However, despite this abysmal failure, neoliberalism has not merely survived the crisis, but actually 'thrived'. How is it possible to account for the resilience of neoliberalism? Existing scholarship has answered this question either by focusing on the distinctive qualities of neoliberalism (such as adaptability, internal coherence and capacity to incorporate dissent) or on the biopolitical capacity of neoliberalism to produce resilient subjects. This article adopts a different perspective. Drawing on and partially challenging the perspective of Michel Foucault, I argue that neoliberalism and biopolitics should be considered two complementary governmental rationalities, and that biopolitical rationalities contribute to governing the uncertainties and risks stemming from the neoliberalization of life. Biopolitics, in other words, plays a key role in governing the resilience of neoliberalism. Through this conceptual lens, the article explores how biopolitical rationalities of care have been deployed to govern the neoliberal crisis of the Greek sovereign debt, which threatened the stability of the European banking system and, I shall argue, the neoliberal life, wealth and well-being of the European population. The article discusses how biopolitical racism is an essential component of the biopolitical governance of neoliberalism. Biopolitical racism displaces the sources of risk, dispossession and inequality from the neoliberal regime to 'inferior' populations, whose lack of compliance with neoliberal dictates is converted into a threat to our neoliberal survival. This threat deserves punishment and authorizes further dynamics of neoliberal dispossession. PMID- 29278250 TI - Curses in Acts: Hearing the Apostles' Words of Judgment Alongside 'Magical' Spell Texts. AB - Scholars of Luke-Acts have struggled to define the apostles' proclamations of judgment on those who threatened the early Christian community. Ananias and Sapphira (Acts 4.32-5.11), Simon magus (8.4-25) and Bar-Jesus (13.4-12) all fall victim to the apostles' words of power, yet scholars have typically shied away from categorizing their speeches as curses. Close analysis of the structure, style, phonaesthetic and dramatic aspects of the Greek texts suggests, however, that Luke indeed intends the apostles' speeches to be heard as curses whilst simultaneously presenting them as legitimate acts of power. A comparison with Greek and Coptic 'magical' texts helps to place the curses of Acts in the context of cursing traditions in the wider ancient Mediterranean world. PMID- 29278251 TI - The cultural capitalists: Notes on the ongoing reconfiguration of trafficking culture in Asia. AB - Most analysis of the international flows of the illicit art market has described a global situation in which a postcolonial legacy of acquisition and collection exploits cultural heritage by pulling it westwards towards major international trade nodes in the USA and Europe. As the locus of consumptive global economic power shifts, however, these traditional flows are pulled in other directions: notably for the present commentary, towards and within Asia. PMID- 29278252 TI - Beyond a politics of recrimination: Scandal, ethics and the rehabilitation of violence. AB - The practice of contemporary warfare seems to be plagued by scandal. It is often assumed that the act of bearing witness to these moments of ethical failure, in which the relationship between the martial and the ethical breaks down, plays an important role in holding powerful actors to account for their conduct. Considerable faith has been placed in the role of transparency and truth-telling as foundations for normative engagements with war. This article argues that we must be cautious about this investment. Drawing on the work of Jean Baudrillard, this article offers a method for critically reading scandals as a series of line drawing manoeuvres. Taken together, these manoeuvres demonstrate how scandals function to enable, excuse and obscure the complex landscapes of violence that define the spectacular and mundane sites of contemporary war. Reducing critical engagements with violent practices to a logic of recrimination, scandals often function to revitalise the very principles they appear to contest. Focusing upon the socio-political implications of wartime scandals, this article demonstrates that the performative force of scandals is therefore the reproduction of a violent status quo rather than opening up new spaces for imagining less violent futures. Offering a critical reading of controversies relating to the provision of humanitarian assistance and education in Afghanistan, this article reflects on the ambiguities and anxieties of critiquing violence. PMID- 29278253 TI - News values on social media: News organizations' Facebook use. AB - This study examines the news selection practices followed by news organizations through investigating the news posted on social networking sites and, in particular, the Facebook pages of four foreign Arabic language TV stations: The Iranian Al-Alam TV, Russia Today, Deutsche Welle, and BBC. A total of 15,589 news stories are analyzed in order to examine the prominence of references to countries and political actors. The study reveals that social significance and proximity as well as the news organizations' ideological agenda are the most important elements that dictate the news selection process. PMID- 29278254 TI - Tourist Demand Reactions: Symmetric or Asymmetric across the Business Cycle? AB - Economizing and spending priorities on different types of vacations are investigated during two periods: an economic downturn and returning prosperity. Two nation-wide samples of vacationers are used: one during a downturn, the other one at the start of the recovery period. Through comparing the results, conclusions can be drawn about symmetric or asymmetric tourist demand across the business cycle. The main summer holiday has an asymmetric profile: being fairly crisis-resistant during a recession and showing considerable growth during an expansion. This does not apply to short vacations and day trips, each having a symmetric profile: during a recession they experience substantial reductions and during expansion comparable growth. So when talking about tourist demand in general, one cannot say that it is symmetric or asymmetric across the business cycle: it depends on the type of vacation. Differences in tourist demand are best explained by the role of Quality-of-Life for vacationers. PMID- 29278255 TI - Software Reliability Analysis of NASA Space Flight Software: A Practical Experience. AB - In this paper, we present the software reliability analysis of the flight software of a recently launched space mission. For our analysis, we use the defect reports collected during the flight software development. We find that this software was developed in multiple releases, each release spanning across all software life-cycle phases. We also find that the software releases were developed and tested for four different hardware platforms, spanning from off-the shelf or emulation hardware to actual flight hardware. For releases that exhibit reliability growth or decay, we fit Software Reliability Growth Models (SRGM); otherwise we fit a distribution function. We find that most releases exhibit reliability growth, with Log-Logistic (NHPP) and S-Shaped (NHPP) as the best-fit SRGMs. For the releases that experience reliability decay, we investigate the causes for the same. We find that such releases were the first software releases to be tested on a new hardware platform, and hence they encountered major hardware integration issues. Also such releases seem to have been developed under time pressure in order to start testing on the new hardware platform sooner. Such releases exhibit poor reliability growth, and hence exhibit high predicted failure rate. Other problems include hardware specification changes and delivery delays from vendors. Thus, our analysis provides critical insights and inputs to the management to improve the software development process. As NASA has moved towards a product line engineering for its flight software development, software for future space missions will be developed in a similar manner and hence the analysis results for this mission can be considered as a baseline for future flight software missions. PMID- 29278256 TI - The purpose of United Nations Security Council practice: Contesting competence claims in the normative context created by the Responsibility to Protect. AB - Practice theory provides important insights into the workings of the Security Council. The contribution is currently limited, however, by the conjecture that practice theory operates on 'a different analytical plane' to norm/normative theory. Building on existing critiques, we argue that analysing practices separately from normative positions risks misappropriating competence and reifying practice that is not fit for purpose. This risk is realized in Adler Nissen and Pouliot's practice-based account of the Libya crisis. By returning the normative context created by the Responsibility to Protect to the analytical foreground, and by drawing on a pragmatic conception of 'ethical competence', we find that pre-reflexive practices uncritically accepted as markers of competence for example, 'penholding' - can contribute to the Council's failure to act collectively in the face of mass atrocity. Drawing on extensive interview material, we offer an alternative account of the Libya intervention, finding that the practices of the permanent three (France, the UK and the US) did not cultivate the kind of collective consciousness that is required to implement the Responsibility to Protect. This is further illustrated by an account of the Security Council's failure in Syria, where the permanent three's insistence on regime change instrumentalized the Council at the expense of Responsibility to Protect-appropriate practice. This changed when elected members became 'penholders'. Practice theory can facilitate learning processes that help the Council meet its responsibilities, but only through an approach that combines its insights with those of norm/normative theory. PMID- 29278257 TI - Urban atmospheres. AB - What is an urban atmosphere? How can we differentiate an 'atmosphere' from other facets of urban consciousness and experience? This essay explores some of the wider cultural, political, and philosophical connotations of atmospheres as a focal point for critical reflections on space and subjectivity. The idea of an 'affective atmosphere' as a distinctive kind of mood or shared corporeal phenomenon is considered in relation to recent developments in phenomenology, extended conceptions of agency, and new understandings of materialism. The essay draws in particular on the changing characteristics of air and light to reflect on different forms of sensory experience and their wider cultural and political connotations. The argument highlights some of the tensions and anomalies that permeate contemporary understandings of urban atmospheres. PMID- 29278259 TI - Liveness redux: on media and their claim to be live. AB - Increasingly media are asserting themselves as live. In television, this has been an important strategy and recently it has been employed by new media platforms such as Facebook, Periscope and Snapchat. This commentary explains the revival of live media by exploring the meaning and operations of the concept and argues the continued relevance of the concept for the study of social media. Traditionally, there have been three main approaches to the live in academic writing (i.e. liveness as ontology, as phenomenology and as rhetoric): each has its particular shortcoming. This paper proposes that it is more productive to understand the live as a construction that assists to secure media a central role in everyday life. PMID- 29278258 TI - Multi-class machine classification of suicide-related communication on Twitter. AB - The World Wide Web, and online social networks in particular, have increased connectivity between people such that information can spread to millions of people in a matter of minutes. This form of online collective contagion has provided many benefits to society, such as providing reassurance and emergency management in the immediate aftermath of natural disasters. However, it also poses a potential risk to vulnerable Web users who receive this information and could subsequently come to harm. One example of this would be the spread of suicidal ideation in online social networks, about which concerns have been raised. In this paper we report the results of a number of machine classifiers built with the aim of classifying text relating to suicide on Twitter. The classifier distinguishes between the more worrying content, such as suicidal ideation, and other suicide-related topics such as reporting of a suicide, memorial, campaigning and support. It also aims to identify flippant references to suicide. We built a set of baseline classifiers using lexical, structural, emotive and psychological features extracted from Twitter posts. We then improved on the baseline classifiers by building an ensemble classifier using the Rotation Forest algorithm and a Maximum Probability voting classification decision method, based on the outcome of base classifiers. This achieved an F-measure of 0.728 overall (for 7 classes, including suicidal ideation) and 0.69 for the suicidal ideation class. We summarise the results by reflecting on the most significant predictive principle components of the suicidal ideation class to provide insight into the language used on Twitter to express suicidal ideation. Finally, we perform a 12-month case study of suicide-related posts where we further evaluate the classification approach - showing a sustained classification performance and providing anonymous insights into the trends and demographic profile of Twitter users posting content of this type. PMID- 29278260 TI - Measuring Credibility Perceptions in CSR Communication: A Scale Development to Test Readers' Perceived Credibility of CSR Reports. AB - Credibility is central to communication but often jeopardized by "credibility gaps." This is especially true for communication about corporate social responsibility (CSR). To date, no tool has been available to analyze stakeholders' credibility perceptions of CSR communication. This article presents a series of studies conducted to develop a scale to assess the perceived credibility of CSR reports, one of CSR communication's most important tools. The scale provides a novel operationalization of credibility using validity claims of Habermas's ideal speech situation as subdimensions. The scale development process, carried out in five studies including a literature review, a Delphi study, and three validation studies applying confirmatory factor analysis, resulted in the 16-item Perceived Credibility (PERCRED) scale. The scale shows convergent, discriminant, concurrent, and nomological validity and is the first validated measure for analyzing credibility perceptions of CSR reports. PMID- 29278261 TI - Text World Theory and real world readers: From literature to life in a Belfast prison. AB - Cognitive stylistics offers a range of frameworks for understanding (amongst other things) what producers of literary texts 'do' with language and how they 'do' it. Less prevalent, however, is an understanding of the ways in which these same frameworks offer insights into what readers 'do' (and how they 'do' it). Text World Theory (Werth, 1999; Gavins, 2007; Whiteley, 2011) has proved useful for understanding how and why readers construct mental representations engendered by the act of reading. However, research on readers' responses to literature has largely focused on an 'idealised' reader or an 'experimental' subject-reader often derived from within the academy and conducted using contrived or amended literary fiction. Moreover, the format of traditional book groups (participants read texts privately and discuss them at a later date) as well as online community forums such as Goodreads, means that such studies derive data from post hoc, rather than real-time textual encounters and discussions. The current study is the first of its kind in analysing real-time reading contexts with real readers during a researcher-led literary project ('read.live.learn') in Northern Ireland's only female prison. In doing so, the study is unique in addressing experimental and post hoc bias. Using Text World Theory, the paper considers the personal and social impact of reader engagement in the talk of the participants. As such, it has three interrelated aims: to argue for the social and personal benefits of reading stylistically rich literature in real-time reading groups; to demonstrate the efficacy of stylistics for understanding how those benefits come about, and to demonstrate the inter-disciplinary value of stylistics, particularly its potential for traversing traditional research parameters. PMID- 29278262 TI - Framing narrative journalism as a new genre: A case study of the Netherlands. AB - Although narrative journalism has a long history in the Netherlands, it is in recent years being promoted as a 'new' genre. This study examines the motives underlying this promotional tactic. To that end, we analyze how narrative journalism is framed in (1) public expressions of the initiatives aimed at professionalization of the genre and (2) interviews with journalists and lecturers in journalism programs. Results indicate that in public discourse on narrative journalism, the genre is framed as moving, essential, and as high quality journalism. These frames indicate that the current promotion of narrative journalism as 'new' can be seen as a strategy that journalists apply to withstand the pressures they are facing in the competition with new media. These frames are deepened in the interviews with lecturers and practitioners, who frame narrative journalism as a dangerous game, a paradigm shift, and as the Holy Grail. These frames indicate that narrative journalism is regarded as the highest achievable goal for journalists, but that its practice comes with dangers and risks: it tempts journalists to abandon the traditional principles of objectivity and factuality, which can ultimately cause journalism to lose its credibility and authority. We discuss these findings in terms of boundary work and reflect on implications for narrative journalism's societal function. PMID- 29278263 TI - Disrupting gatekeeping practices: Journalists' source selection in times of crisis. AB - As gatekeepers, journalists have the power to select the sources that get a voice in crisis coverage. The aim of this study is to find out how journalists select sources during a crisis. In a survey, journalists were asked how they assess the following sources during an organizational crisis: news agencies, an organization undergoing a crisis, and the general public. The sample consisted of 214 Dutch experienced journalists who at least once covered a crisis. Using structural equation modeling, sources' likelihood of being included in the news was predicted using five source characteristics: credibility, knowledge, willingness, timeliness, and the relationship with the journalist. Findings indicated that during a crisis, news agencies are most likely to be included in the news, followed by the public, and finally the organization. The significance of the five source characteristics is dependent on source type. For example, to be used in the news, news agencies and organizations should be mainly evaluated as knowledgeable, whereas information from the public should be both credible and timely. In addition, organizations should not be seen as too willing or too eager to communicate. The findings imply that, during a crisis, journalists remain critical gatekeepers; however, they rely mainly on familiar sources. PMID- 29278264 TI - A sprinkling experiment to quantify celerity-velocity differences at the hillslope scale. AB - Few studies have quantified the differences between celerity and velocity of hillslope water flow and explained the processes that control these differences. Here, we asses these differences by combining a 24-day hillslope sprinkling experiment with a spatially explicit hydrologic model analysis. We focused our work on Watershed 10 at the H. J. Andrews Experimental Forest in western Oregon. Celerities estimated from wetting front arrival times were generally much faster than average vertical velocities of delta2H. In the model analysis, this was consistent with an identifiable effective porosity (fraction of total porosity available for mass transfer) parameter, indicating that subsurface mixing was controlled by an immobile soil fraction, resulting in the attenuation of the delta2H input signal in lateral subsurface flow. In addition to the immobile soil fraction, exfiltrating deep groundwater that mixed with lateral subsurface flow captured at the experimental hillslope trench caused further reduction in the delta2H input signal. Finally, our results suggest that soil depth variability played a significant role in the celerity-velocity responses. Deeper upslope soils damped the delta2H input signal, while a shallow soil near the trench controlled the delta2H peak in lateral subsurface flow response. Simulated exit time and residence time distributions with our hillslope hydrologic model showed that water captured at the trench did not represent the entire modeled hillslope domain; the exit time distribution for lateral subsurface flow captured at the trench showed more early time weighting. PMID- 29278265 TI - In Search of Real Circumcision: Ritual Failure and Circumcision in Paul. AB - This article applies the theoretical framework of 'ritual failure', a sub discipline of ritual criticism, to Paul's discussion of circumcision in his letter to the Galatians, Philippians and Romans. It is argued that the application of this theoretical perspective clarifies the dynamics at stake and provides a new way of understanding the development in Paul's position regarding circumcision. There is movement from an attitude of strong propagation, by way of indifference and a subsequent attitude of rejection, to one of modified reintegration into Paul's thinking. At every turn of this development, ritual failure plays a pivotal role and functions as a catalyst for the development of Paul's theology. PMID- 29278266 TI - Regional nerve blockade for early analgesic management of elderly patients with hip fracture - a narrative review. AB - Elderly patients with hip fracture experience high morbidity and mortality, and are often undertreated for pain. Acute pain management in the elderly is challenging, with physiological frailty, medical comorbidities and cognitive impairment commonly compounding pain assessment and treatment. Guidelines outlining current best practice for acute pain management in the elderly now exist, but evidence suggests that practice remains variable and there continues to be scope for improvement. We conducted a narrative review of the literature to examine the challenges of acute pain management in the elderly, and to evaluate evidence for the role of regional nerve blocks for acute pain associated with hip fracture in the elderly. There is consistent evidence that regional nerve blocks can effectively reduce pain associated with hip fracture, providing rapid-onset, site-specific analgesia that is more effective than standard systemic analgesia alone. There is also moderate evidence that nerve blocks may contribute to reduced rates of delirium, and some suggestion of reduced length of inpatient stay, morbidity and mortality, although limited evidence is available. Fascia iliaca blocks are emerging as a block of choice, with evidence they can be safely and rapidly administered under ultrasound guidance in the acute setting, by both trained medical and nursing staff, with good effect. Ideally, comprehensive pain protocols for elderly hip fracture patients are required, that integrate evidence based fascia iliaca block use, timely and repeated pain assessment, and multidisciplinary orthogeriatric patient care. PMID- 29278267 TI - Factors associated with anterior open bite in children with developmental disabilities. AB - AIM: To investigate factors associated with anterior open bite in individuals aged from 2 to 33 years with developmental disabilities. DESIGN: This is a cross sectional study. A total of 271 dental records were examined. The anterior open bite analyzed was determined based on clinic exam. These variables were also analyzed: gender, age, education level of mother, International Code of Diseases (ICD), mouth breathing, use of anticonvulsant drugs, hyperkinesis, pacifier use, thumb sucking, seizure, and involuntary movements. For the purposes of analysis, the individuals were categorized as being with and without anterior open bite. Variables with a p-value of < 0.25 in the bivariate analysis were incorporated into the logistic regression models. RESULTS: Mouth breathers had a 2.60-fold (95% CI: 1.35-5.01) greater chance of exhibiting anterior open bite than nasal breathers. Pacifier users are more likely to have an anterior open bite (3.32 fold, 95% CI: 1.62-6.77). Individuals with reported involuntary movements had a 2.66-fold (95% CI: 1.26-5.63) greater chance of exhibiting anterior open bite. Users of anticonvulsants drugs had a 3.05 (95% CI: 1.57-5.92) greater chance of showing anterior open bite. CONCLUSION: Involuntary movements, mouth breathing, using anticonvulsant drugs, and using pacifier are factors associated with anterior open bite in patients with developmental disabilities. PMID- 29278268 TI - Educational outcomes for children with cerebral palsy: a linked data cohort study. AB - AIM: To identify a cohort of children with cerebral palsy (CP) from hospital data; determine the proportion that participated in standardized educational testing and attained a score within the normal range; and describe the relationship between test results and motor symptoms. METHOD: This population based retrospective cohort study used data from New South Wales, Australia. We linked hospital data for children younger than 16 years of age admitted between 1st July 2000 and 31st March 2014 to education data from 2009 to 2014. Hospital diagnosis codes were used to identify a cohort of children with CP (n=3944) and describe their motor symptoms. Educational outcomes in the CP cohort were compared with those among children without CP. RESULTS: Of those with educational data (n=1770), 46% were exempt from reading assessment because of intellectual or functional disability, 7% were absent or withdrawn from testing and 47% participated in testing. About 30% of all children with educational data had test scores in the normal range. The proportion was greatest among those with hemiplegia (>40%) and lowest among those with tetraplegia (<10%). INTERPRETATION: One-third of children with CP participated in standardized testing and achieved a result in the normal range. The proportions were lower in children with more severe motor symptoms. WHAT THIS PAPER ADDS: From 2009 to 2014, most Australian children with cerebral palsy (CP) attended a mainstream school. The rate of disability-related exemption from standardized educational testing was almost 50%. Thirty per cent of children with CP achieved educational scores in the normal range. PMID- 29278269 TI - Childhood developmental vulnerabilities associated with early life exposure to infectious and noninfectious diseases and maternal mental illness. AB - BACKGROUND: Fetal exposure to infectious and noninfectious diseases may influence early childhood developmental functioning, on the path to later mental illness. Here, we investigated the effects of in utero exposure to maternal infection and noninfectious diseases during pregnancy on offspring developmental vulnerabilities at age 5 years, in the context of estimated effects for early childhood exposures to infectious and noninfectious diseases and maternal mental illness. METHODS: We used population data for 66,045 children from an intergenerational record linkage study (the New South Wales Child Development Study), for whom a cross-sectional assessment of five developmental competencies (physical, social, emotional, cognitive, and communication) was obtained at school entry, using the Australian Early Development Census (AEDC). Child and maternal exposures to infectious or noninfectious diseases were determined from the NSW Ministry of Health Admitted Patients Data Collection (APDC) and maternal mental illness exposure was derived from both APDC and Mental Health Ambulatory Data collections. Multinomial logistic regression analyses were used to examine unadjusted and adjusted associations between these physical and mental health exposures and child developmental vulnerabilities at age 5 years. RESULTS: Among the physical disease exposures, maternal infectious diseases during pregnancy and early childhood infection conferred the largest associations with developmental vulnerabilities at age 5 years; maternal noninfectious illness during pregnancy also retained small but significant associations with developmental vulnerabilities even when adjusted for other physical and mental illness exposures and covariates known to be associated with early childhood development (e.g., child's sex, socioeconomic disadvantage, young maternal age, prenatal smoking). Among all exposures examined, maternal mental illness first diagnosed prior to childbirth conferred the greatest odds of developmental vulnerability at age 5 years. CONCLUSIONS: Prenatal exposure to infectious or noninfectious diseases appear to influence early childhood physical, social, emotional and cognitive developmental vulnerabilities that may represent intermediate phenotypes for subsequent mental disorders. PMID- 29278270 TI - Historical review of the discovery of cadherin, in memory of Tokindo Okada. AB - The cadherin family of cell-cell adhesion molecules plays a pivotal role in animal tissue formation. Discovery of this molecular family can be traced back to some unexpected observations of strange cell behavior that were made around 1970 in the Kyoto University laboratory of Tokindo Okada, and then in the Department of Embryology at the Carnegie Institution of Washington (currently the Carnegie Institution for Science). This article looks back on these discoveries, and recalls how these observations led to the identification of important cell-cell adhesion molecules known as cadherins. PMID- 29278271 TI - Maternal Nanos-Dependent RNA Stabilization in the Primordial Germ Cells of Drosophila Embryos. AB - Nanos (Nos) is an evolutionary conserved protein expressed in the germline of various animal species. In Drosophila, maternal Nos protein is essential for germline development. In the germline progenitors, or the primordial germ cells (PGCs), Nos binds to the 3' UTR of target mRNAs to repress their translation. In contrast to this prevailing role of Nos, here we report that the 3' UTR of CG32425 mRNA mediates Nos-dependent RNA stabilization in PGCs. We found that the level of mRNA expressed from a reporter gene fused to the CG32425 3' UTR was significantly reduced in PGCs lacking maternal Nos (nos PGCs) as compared with normal PGCs. By deleting the CG32425 3' UTR, we identified the region required for mRNA stabilization, which includes Nos-binding sites. In normal embryos, CG32425 mRNA was maternally supplied into PGCs and remained in this cell type during embryogenesis. However, as expected from our reporter assay, the levels of CG32425 mRNA and its protein product expressed in nos PGCs were lower than in normal PGCs. Thus, we propose that Nos protein has dual functions in translational repression and stabilization of specific RNAs to ensure proper germline development. PMID- 29278272 TI - Oral manifestations and dentofacial anomalies in beta-thalassemia major children in Dubai (UAE). AB - AIMS: The purpose of this study was to identify special oral and dentofacial manifestations of beta-thalassemia major (BetaTM) in Emarati children in Dubai (UAE). MATERIALS AND METHODS: A total of 38 (BetaTM) and 76 healthy Emirati children were recruited. An oral examination was conducted to determine dmft/DMFT indices, Simplified Oral Hygiene Index, occlusal anomalies, dentofacial, and soft tissue abnormalities. RESULTS: BetaTM children had significantly higher DMFT compared to the healthy controls (p-value, 0.017). The Met Need Index (MNI) and the Restorative Index (RI) were lower in the BetaTM group but without statistical significance. Calculus Index (CI) was found to be significantly higher in BetaTM children (p-value, 0.002). The proportion of gingivitis was significantly lower in the BetaTM group (p-value, 0.009). BetaTM children had significantly higher proportion of retained primary teeth (p-value, 0.001) and gingival pigmentation compared with healthy controls (p-value, 0.001). BTM children did not have any statistically significant difference in the Angle molar classiication compared to the control. Interestigly, a significantly higher proportion of transverse cross bite was found in the control subjects compared to the BTM group (p-value, 0.004). CONCLUSIONS: Significantly higher DMFT, retained primary teeth, gingival pigmentation, and CI was found in the BTM group compared to the controls while significantly lower gingivitis index and transverse cross bite was seen in the BTM group. PMID- 29278273 TI - Hypoxia-inducible factor-1 (HIF-1) inhibitors from the last decade (2007 to 2016): A "structure-activity relationship" perspective. AB - Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors. PMID- 29278274 TI - The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases. AB - BACKGROUND: Lilly/Avid's AV-1451 is one of the most advanced tau PET tracers in the clinic. Although results obtained in Alzheimer's disease patients are compelling, discrimination of tracer uptake in healthy individuals and patients with supranuclear palsy (PSP) is less clear as there is substantial overlap of signal in multiple brain regions. Moreover, accurate quantification of [18 F]AV 1451 uptake in Alzheimer's disease may not be possible. OBJECTIVES: The aim of the present study was to characterize the in vitro binding of AV-1451 to understand and identify potential off-target binding that could explain the poor discrimination observed in PSP patients. METHODS: [3 H]AV-1451 and AV-1451 were characterized in in vitro binding assays using recombinant and native proteins/tissues from postmortem samples of controls and Alzheimer's disease and PSP patients. RESULTS: [3 H]AV-1451 binds to multiple sites with nanomolar affinities in brain homogenates and to tau fibrils isolated from Alzheimer's disease or PSP patients. [3 H]AV-1451 also binds with similarly high affinities in brain homogenates devoid of tau pathology. This unexpected binding was demonstrated to be because of nanomolar affinities of [3 H]AV-1451 for monoamine oxidase A and B enzymes. CONCLUSIONS: High affinity of AV-1451 for monoamine oxidase proteins may limit its utility as a tau PET tracer in PSP and Alzheimer's disease because of high levels of monoamine oxidase expression in brain regions also affected by tau deposition, especially if monoamine oxidase levels change over time or with a treatment intervention. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29278275 TI - Prevalence of and indications for antipsychotic use in Parkinson's disease. AB - BACKGROUND: The prevalence of patients with PD taking antipsychotics is unknown. OBJECTIVE: To measure the prevalence of patients with PD taking antipsychotics. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to study the use of antipsychotic medication in all persons with Parkinson disease in Olmsted County, Minnesota on 1 January 2006. RESULTS: There were 296 patients with PD in Olmsted County on 1 January 2006. The overall prevalence of antipsychotic use was 9.8% (29 of 296); 95.5% (28 of 29) of the patients had dementia when initiating antipsychotics. The most frequent indication (71.4%; 20 of 28) was psychosis or behavior threatening to the patient or others. CONCLUSIONS: The prevalence of antipsychotic use in patients with PD is lower than expected from previously reported cumulative incidences. Dementia is highly prevalent in those starting antipsychotics. Most of the patients on antipsychotics had a reasonable risk-benefit ratio for taking them. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29278276 TI - Pathological lesions and global DNA methylation in rat prostate under streptozotocin-induced diabetes and melatonin supplementation. AB - Chronic hyperglycemia increases production of reactive oxygen species, which favors carcinogenesis. The association between diabetes and prostate cancer is controversial. Melatonin has antioxidant, anti-inflammatory, and antiproliferative properties. We investigated whether low doses of melatonin prevent the tissue alterations caused by diabetes and alter prostate histology of healthy rats. We also investigated whether experimental diabetes promoted the development of pathological lesions in the ventral prostate of rats. Melatonin was provided in drinking water (10 MUg/kg/day) from age 5 weeks until the end of experiment. Diabetes was induced at 13 weeks by administration of streptozotocin (40 mg/kg, ip). Rats were euthanized at 14 or 21 weeks. Histological and stereological analyses were carried out and the incidence and density of malignant and pre-malignant lesions were assessed. Immunohistochemical assays of alpha-actin, cell proliferation (PCNA), Bcl-2, glutathione S-transferase (GSTPI), and DNA methylation (5-methylcytidine) were performed. Melatonin did not elicit conspicuous changes in the prostate of healthy animals; in diabetic animals there was a higher incidence of atrophy (93%), microinvasive carcinoma (10%), proliferative inflammatory atrophy, PIA (13%), prostatitis (26%), and prostate intraepithelial neoplasia, PIN (20%) associated with an increase of 40% in global DNA methylation. Melatonin attenuated epithelial and smooth muscle cell (smc) atrophy, especially at short-term diabetes-and normalized incidence of PIN (11%), inflammatory cells infiltrates, prostatitis (0%) and PIA (0%) at long-term diabetes. MLT was effective in preventing inflammatory disorders and PIN under diabetic condition. Although MLT has antioxidant action, it did not influence DNA methylation and not avoid carcinogenesis at low doses. PMID- 29278277 TI - Isolation and characterization of an anti-leishmanial disintegrin from Cerastes cerastes venom. AB - Investigating new antimicrobial and antiparasitic components from Viperidae venoms represents an alternative therapeutic strategy. In this study, we report the characterization of a disintegrin isolated from Cerastes cerastes venom, exhibiting antiparasitic activity on Leishmania infantum promastigotes. Indeed, isolated disintegrin, referred to Disintegrin_Cc, induced 84.75% of parasiticidal activity and deep morphological alterations on the parasites. SDS-PAGE analysis indicated that this disintegrin was homogenous. This dimeric disintegrin of 14,193.97 Da contains an RGD domain and four intramolecular disulfide bridges. It presents a high percentage of identity with other related snake disintegrins. Predicted 3D structure indicated that this peptide shares partial homology with well-known active antimicrobial peptides. Disintegrin_Cc inhibited 80% of arachidonic acid-induced platelet aggregation. The obtained results suggest that the isolated molecule plays a dual role as a disintegrin and as an anti leishmanial compound. This component could be useful as a drug in the treatment of leishmaniasis. PMID- 29278278 TI - Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: A phase II randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS-C) was needed. METHODS: This was a randomized, double-blind, placebo-controlled, dose finding trial. Japanese patients with IBS-C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12-week treatment period. The primary endpoint was responder rate of global assessment of relief of IBS symptoms during 12 weeks. The secondary endpoints included responder rates of complete spontaneous bowel movement (CSBM), SBM and abdominal pain/discomfort relief and others. KEY RESULTS: The primary endpoint was 23.2%, 36.2%, 38.7%, 34.8%, and 38.3% in placebo (n = 112), 0.0625 (n = 116), 0.125 (n = 111), 0.25 (n = 112), and 0.5 (n = 107) mg of linaclotide groups with the difference from the placebo group in each linaclotide group (13.0%, 15.5%, 11.6%, 15.1%, P > .05). Monthly responder rate of global assessment of relief of IBS symptoms at month 3 (48.6%), responder rate of CSBM during 12 weeks (45.8%), and responder rate of abdominal pain/discomfort relief during 12 weeks (32.7%) in the 0.5 mg were significantly higher than those in placebo group (29.5%, P < .01; 25.9%, P < .01; and 18.8%, P < .05 respectively). The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES: This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C. PMID- 29278279 TI - A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease. AB - BACKGROUND: Delayed gastric emptying may impair l-dopa absorption, contributing to motor fluctuations. We evaluated the effect of camicinal (GSK962040), a gastroprokinetic, on the absorption of l-dopa and symptoms of PD. METHODS: Phase II, double-blind, placebo-controlled trial. Participants were randomized to receive camicinal 50 mg once-daily (n = 38) or placebo (n = 20) for 7 to 9 days. RESULTS: l-dopa exposure was similar with coadministration of camicinal compared to placebo. Median time to maximum l-dopa concentration was reduced, indicating more rapid absorption of l-dopa. Camicinal resulted in significant reduction in OFF time (-2.31 hours; 95% confidence interval: -3.71, -0.90), significant increase in ON time (+1.88 hours; 95% confidence interval: 0.28, 3.48) per day, and significant decrease in mean total MDS-UPDRS score (-12.5; 95% confidence interval: -19.67, -5.29). Camicinal treatment was generally well tolerated. CONCLUSIONS: PD symptom improvement with camicinal occurred in parallel with more rapid absorption of l-dopa. This study provides evidence of an improvement of the motor response to l-dopa in people with PD treated with camicinal 50 mg once daily compared with placebo, which will require further evaluation. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29278280 TI - Texture-modified diets are associated with decreased muscle mass in older adults admitted to a rehabilitation ward. AB - AIM: Texture-modified diets (TMD) have significantly lower energy and protein content than normal diets. Therefore, TMD can cause malnutrition and loss of muscle mass. However, few studies have reported the relationship between TMD and decreased skeletal muscle mass. The aim of the present study was to clarify the association between TMD and decreased skeletal muscle mass. METHODS: We reviewed data of 188 older adult patients who were admitted to a rehabilitation hospital. TMD were defined based on the Japanese Dysphagia Diet Criteria 2013 proposed by the Japanese Society of Dysphagia Rehabilitation. The Mini Nutritional Assessment Short Form was used to assess nutritional status; dual-energy X-ray absorptiometry was used to measure the skeletal muscle mass index, and the cut off values for decreased skeletal muscle mass index were based on the Asian Working Group for Sarcopenia; the Functional Independence Measure was used to evaluate activities of daily living. RESULTS: The patients' mean age was 80.6 +/- 7.5 years, and 62% were women. A total of 22 patients (11.7%) consumed TMD. A total of 104 patients (55.3%) had decreased skeletal muscle mass, and approximately 90% of them consumed TMD. Decreased skeletal muscle mass index (odds ratio 7.199, 95% confidence interval 1.489-34.805, P <= 0.01) and Functional Independence Measure scores (odds ratio 0.972, 95% confidence interval 0.952-0.992, P <= 0.01) were independently related to TMD in the multivariate analysis. CONCLUSIONS: The TMD group was associated with decreased skeletal muscle mass. Future, prospective studies are necessary to investigate causality. Geriatr Gerontol Int 2018; 18: 698-704. PMID- 29278281 TI - Empiric antibiotics for community-acquired pneumonia: A macrolide and a beta lactam please! PMID- 29278282 TI - Exploring the career choices of White and Black, Asian and Minority Ethnic women pharmacists: a qualitative study. AB - OBJECTIVE: In the UK, a growing number of females entering pharmacy are women from Black, Asian and minority ethnic groups (BAME). Research shows that BAME women are more likely to work in the community sector and be self-employed locums than white women, and Asian women overrepresented in part-time, lower status roles. This study aims to explore the employment choices of white and BAME women pharmacists to see whether their diverse work patterns are the product of individual choices or other organisational factors. METHODS: This study analyses 28 qualitative interviews conducted with 18 BAME and 10 white women pharmacists. The interview schedule was designed to explore early career choices, future career aspirations and key stages in making their career decisions. KEY FINDINGS: The findings show that white and BAME women are influenced by different factors in their early career choices. Cultural preferences for self-employment and business opportunities discourage BAME women from hospital sector jobs early in their careers. Resonating with other studies, the findings show that white and BAME women face similar barriers to career progression if they work part-time. CONCLUSIONS: Women working part-time are more likely to face workforce barriers, irrespective of ethnic origin. Cultural preferences may be preventing BAME women from entering the hospital sector. This research is important in the light of current debates about the future shape of pharmacy practice, as well as wider government policy objectives that seek to improve the working lives of health care professionals and promote racial diversity and equality in the workplace. PMID- 29278283 TI - Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. AB - BACKGROUND: Delirium is the most common neuropsychiatric syndrome encountered by clinicians dealing with older adults and the medically ill and is best characterized by 5 core domains: cognitive deficits, attentional deficits, circadian rhythm dysregulation, emotional dysregulation, and alteration in psychomotor functioning. DESIGN: An extensive literature review and consolidation of published data into a novel interpretation of known pathophysiological causes of delirium. RESULTS: Available data suggest that numerous pathological factors may serve as precipitants for delirium, each having differential effects depending on patient-specific patient physiological characteristics (substrate). On the basis of an extensive literature search, a newly proposed theory, the systems integration failure hypothesis, was developed to bring together the most salient previously described theories, by describing the various contributions from each into a complex web of pathways-highlighting areas of intersection and commonalities and explaining how the variable contribution of these may lead to the development of various cognitive and behavioral dysfunctions characteristic of delirium. The specific cognitive and behavioral manifestations of the specific delirium picture result from a combination of neurotransmitter function and availability, variability in integration and processing of sensory information, motor responses to both external and internal cues, and the degree of breakdown in neuronal network connectivity, hence the term acute brain failure. CONCLUSIONS: The systems integration failure hypothesis attempts to explain how the various proposed delirium pathophysiologic theories interact with each other, causing various clinically observed delirium phenotypes. A better understanding of the underlying pathophysiology of delirium may eventually assist in designing better prevention and management approaches. PMID- 29278284 TI - Co-exposure to fluoride and sulfur dioxide on histological alteration and DNA damage in rat brain. AB - Fluoride (F) and sulfur dioxide (SO2 ) are the two common environmental contaminants that are associated with neurotoxicity. The present study was conducted to explore individual and combined exposure effects of F and SO2 on histological alteration and DNA damage in rat brain. For this, male Wistar albino rats were exposed to sodium fluoride (100 mg/L NaF) and sulfur dioxide (39.3 mg/m3 ) individually and in combination for 8 weeks. Histological alteration in brain is evaluated by hematoxylin-eosin staining, showed shrunken neurons, darkly stained small nucleus and decreased cell numbers in F and SO2 exposed groups. The effect of F and SO2 on DNA damage was assessed by comet assay. The results showed an increase in ratio of tailing and tail length in F or/and SO2 administered rats. In addition, the proportion of grade II and III were also increased in individual and combined exposed groups. Compared with the individual exposure, the proportion the grade III was significantly high in combined exposure, suggesting a synergistic effect of F and SO2 . These results indicate that the brain was more susceptible to the toxic effects of F and SO2 . And combined exposure to these pollutants can lead more pronounced toxic effects on brain. PMID- 29278285 TI - Design and Assembly of a Chiral Metallosalen-Based Octahedral Coordination Cage for Supramolecular Asymmetric Catalysis. AB - Supramolecular containers featuring both high catalytic activity and high enantioselectivity represent a design challenge of practical importance. Herein, it is demonstrated that a chiral octahedral coordination cage can be constructed by using twelve enantiopure Mn(salen)-derived dicarboxylic acids as linear linkers and six Zn4 -p-tert-butylsulfonylcalix[4]arene clusters as tetravalent four-connected vertices. The porous cage features a large hydrophobic cavity (~3944 A3 ) decorated with catalytically active metallosalen species and is shown to be an efficient and recyclable asymmetric catalyst for the oxidative kinetic resolution of racemic secondary alcohols and the epoxidation of olefins with up to >99 % enantiomeric excess. The cage architecture not only prevents intermolecular deactivation and stabilizes the Mn(salen) catalysts but also encapsulates substrates and concentrates reactants in the cavity, resulting in enhanced reactivity and enantioselectivity relative to the free metallosalen catalyst. PMID- 29278286 TI - Autonomic dysfunction in Parkinson's disease: A prospective cohort study. AB - BACKGROUND: Dysautonomia is a frequent and disabling complication of PD, with an estimated prevalence of 30-40% and a significant impact on the quality of life. OBJECTIVES: To evaluate the rate of progression of dysautonomia and, in particular, orthostatic hypotension, in a cohort of unselected PD patients, and assess the extent to which the progression of dysautonomia affects activities of daily living, health-related quality of life, and health care utilization in PD. METHODS: We recruited 131 consecutive patients into a 12-month, prospective, observational cohort study. Clinical measures included the International Parkinson and Movement Disorder Society/UPDRS, the Scale for Outcomes in Parkinson Disease-Autonomic, the Orthostatic Hypotension Symptoms Assessment, and orthostatic blood pressure measurements. Health care utilization was quantified as the number of hospitalizations, emergency room visits, and outpatient clinic evaluations. RESULTS: The overall severity of autonomic symptoms, as measured by the the Orthostatic Hypotension Symptoms Assessment total score, worsened by 20% over 12 months (P < 0.001), with an overall increase in orthostatic hypotension prevalence from 31.1% to 46.7% (P < 0.001). Worsening of autonomic symptoms was independently associated with deterioration in daily living activities (P = 0.021) and health-related quality of life (P = 0.025) adjusting for disease duration, cognitive impairment, and motor severity. Regardless of symptomatic status, orthostatic hypotension was associated with greater deterioration in daily living activities, health care utilization, and falls (P <= 0.009) compared to patients without orthostatic hypotension. CONCLUSIONS: The severity of autonomic symptoms progressed by 20% over 1 year and was independently associated with impairments in daily living activities and health-related quality of life. Symptomatic and asymptomatic orthostatic hypotension were both associated with increased prevalence of falls and health care utilization. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29278287 TI - Balloon pulmonary angioplasty is effective for treating peripheral-type chronic thromboembolic pulmonary hypertension in elderly patients. AB - AIM: Balloon pulmonary angioplasty (BPA) has recently been established as an effective therapy for peripheral-type chronic thromboembolic pulmonary hypertension (CTEPH). However, the safety and effectiveness of BPA in elderly patients with CTEPH have not been clarified. METHODS: A total of 19 patients with CTEPH who underwent BPA were recruited. The patients were assigned to groups by age, <70 years (non-elderly; n = 11) and >=70 years (elderly; n = 8). Hemodynamic parameters, right ventricular function and plasma N-terminal pro-brain natriuretic peptide were assessed before and after BPA, and complications arising after BPA were also evaluated. RESULTS: Hemodynamic parameters and right heart function did not differ significantly between the two groups at baseline. BPA significantly improved pulmonary arterial pressure, pulmonary vascular resistance and fractional area change in both groups (all P < 0.05), although the differences were comparable. No fatal complications developed, but the frequency of minor complications, such as transient hemoptysis, was higher in the elderly group than in the non-elderly group (median 0.45 [interquartile range 0.27-0.63] vs 0 [0-0.33], respectively; P = 0.021). The frequency of such complications was also higher in patients with a psychiatric disorder than in those without (0.50 [0.44-1.00] vs 0.14 [0-0.33], respectively; P = 0.006). Multivariate regression analysis identified higher age, baseline N-terminal pro-brain natriuretic peptide values and an underlying psychiatric disorder as significant predictors of complications of BPA. CONCLUSIONS: BPA is an effective treatment for peripheral type CTEPH regardless of age; however, higher age, N-terminal pro-brain natriuretic peptide values before treatment and an underlying psychiatric disorder might be associated with minor complications. Geriatr Gerontol Int 2018; 18: 678-684. PMID- 29278288 TI - Tics and Tourette syndrome - surplus of actions rather than disorder? PMID- 29278289 TI - Compressed NMR: Combining compressive sampling and pure shift NMR techniques. AB - Historically, the resolution of multidimensional nuclear magnetic resonance (NMR) has been orders of magnitude lower than the intrinsic resolution that NMR spectrometers are capable of producing. The slowness of Nyquist sampling as well as the existence of signals as multiplets instead of singlets have been two of the main reasons for this underperformance. Fortunately, two compressive techniques have appeared that can overcome these limitations. Compressive sensing, also known as compressed sampling (CS), avoids the first limitation by exploiting the compressibility of typical NMR spectra, thus allowing sampling at sub-Nyquist rates, and pure shift techniques eliminate the second issue "compressing" multiplets into singlets. This paper explores the possibilities and challenges presented by this combination (compressed NMR). First, a description of the CS framework is given, followed by a description of the importance of combining it with the right pure shift experiment. Second, examples of compressed NMR spectra and how they can be combined with covariance methods will be shown. PMID- 29278290 TI - Identification of prognostic factors for activities of daily living in elderly patients after hospitalization for acute infectious disease in Japan: A 6-month follow-up study. AB - AIM: We investigated factors that predict the prognosis of activities of daily living (ADL) in elderly patients who had undergone rehabilitation during hospitalization for acute infectious disease. METHODS: The present prospective cohort study included 131 patients who were hospitalized due to acute infectious disease and who had undergone rehabilitation during hospitalization. Patient characteristics collected from medical records included age, sex and comorbidity score. The level of ADL 2 weeks before admission was assessed by interview at the start of rehabilitation. Grip strength testing, Short Physical Performance Battery as an assessment of lower limb function and the Mini-Mental State Examination as an assessment of cognitive status were carried out at the time of hospital discharge. The level of ADL at 6 months after discharge was assessed by telephone interview. Multivariate logistic regression analysis was used to identify factors that independently predict ADL dependence (defined as being dependent in one or more ADL items at 6 months after discharge). RESULTS: The average age of participants was 81.5 years, and 52.7% were women. A total of 22.1% of patients showed dependence in an ADL at 6-month follow-up. Factors that predicted an ADL dependence were comorbidity score (OR 4.19, 95% CI 1.19-14.69) and lower limb function (OR 0.51, 95% CI 0.36-0.72) at discharge. CONCLUSIONS: The present findings have implications for the healthcare planning and well-being of elderly patients during hospitalization and after discharge. Geriatr Gerontol Int 2018; 18: 615-622. PMID- 29278291 TI - Rating scales for cognition in Huntington's disease: Critique and recommendations. AB - Cognitive impairment is one of the main features of Huntington's disease and is present across the disease spectrum. As part of the International Parkinson's Disease and Movement Disorder Society-sponsored project to review all clinical rating scales used in Huntington's disease, a systematic review of the literature was performed to identify cognitive scales used in Huntington's disease and make recommendations for their use. A total of 17 cognitive scales were identified and evaluated. None of the scales met criteria for a "recommended" status. For assessing severity of cognitive dysfunction, the Montreal Cognitive Assessment was "recommended with caveats." The UHDRS Cognitive Assessment, the UHDRS-For Advanced Patients cognitive section, the Alzheimer's Disease Assessment Scale Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini-Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were "suggested" for evaluating severity of cognitive impairment. The MoCA was "suggested" as a screening tool for cognitive impairment. The major challenge in the assessment of cognition in Huntington's disease is the lack of a formal definition of dementia and/or mild cognitive impairment in this disease. The committee concluded that there is a need to further validate currently available cognitive scales in Huntington's disease, but that it is premature to recommend the development of new scales. Recently developed Huntington's disease-specific scales, such as the Huntington's Disease-Cognitive Assessment Battery, hold promise but require the completion of more comprehensive clinimetric development. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29278292 TI - ALDH2 gene G487A polymorphism and coronary artery disease: a meta-analysis including 5644 participants. AB - Several studies indicate the mitochondrial Aldehyde Dehydrogenase-2 (ALDH2) gene G487A polymorphism may be correlated with coronary artery disease (CAD) susceptibility, but a clear consensus has yet to be reached. To elucidate the relationship between the ALDH2 gene G487A polymorphism and CAD within the Chinese population, a meta-analysis of 5644 subjects from nine individual studies was performed. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals were assessed using random or fixed-effect models depending the heterogeneity existence or not. Our meta-analysis found a significant association between ALDH2 gene G487A polymorphism and CAD in the Chinese population under allele (OR: 1.830, 95% CI: 1.560-2.140, P = 1.36 * 10-13 ), recessive (OR: 1.920, 95% CI: 1.530-2.390, P = 1.20 * 10-8 ), dominant (OR: 1.593, 95% CI: 1.336-1.900, P = 2.22 * 10-7 ), homozygous (OR: 2.280, 95% CI: 1.810-2.870, P = 3.17 * 10-12 ) and heterozygous genetic models (OR: 3.330, 95% CI: 2.070-5.370, P = 7.81 * 10-7 ). The positive correlation between the ALDH2 gene G487A polymorphism and CAD makes the mutation a strong candidate as a genetic risk marker for CAD. Through further analysis, we also found that A allele carriers of ALDH2 gene G487A polymorphism may be particularly susceptible to CAD. PMID- 29278293 TI - Green Tea Polyphenol EGCG Alleviates Metabolic Abnormality and Fatty Liver by Decreasing Bile Acid and Lipid Absorption in Mice. AB - SCOPE: The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been shown to ameliorate metabolic abnormalities and fatty liver. The present study investigates the mechanisms of actions of EGCG on bile acid homeostasis and lipid metabolism. METHODS: Male C57BL/6J mice are fed a low-fat diet, a high-fat western-style diet, or a high-fat western-style diet containing 0.32% EGCG. The effects of the treatments on biochemical parameters, gene expression, and lipidomics are analyzed. RESULTS: EGCG treatment significantly reduces body weight gain, mesenteric fat mass, fasting blood glucose, insulin resistance, serum cholesterol, and severity of fatty liver after treatment for 17 weeks, but most of these effects were less apparent at week 33. At week 17, EGCG treatment significantly elevates the mRNA levels of cholesterol 7alpha-hydroxylase, HMG-CoA reductase, low-density lipoprotein receptor, and scavenger receptor B1, and partially normalizes the high-fat diet induced lipidomic profile. The intestinal bile acid content is significantly decreased by EGCG, while fecal excretion of bile acids, cholesterol, and total lipids are increased. CONCLUSION: EGCG decreases bile acid reabsorption, results in lower intestinal bile acid levels, which further decreases the absorption of lipids. These actions contribute to the alleviation of metabolic abnormalities and fatty liver disease caused by the high fat diet. PMID- 29278294 TI - Chemotherapy Immunophenoprofiles in Non-Small-Cell Lung Cancer by Personalized Membrane Proteomics. AB - OBJECTIVES: No study has addressed how the immune status at the molecular level is affected by first-line pemetrexed and cisplatin (PEM-CIS) combination therapy in patients with non-small-cell lung cancer (NSCLC). Thus, we aimed to identify the immune status from membrane proteome alterations in patients with NSCLC upon PEM-CIS treatment. METHODS: The paired peripheral blood mononuclear cells (PBMCs) were collected from four patients with lung adenocarcinoma before and after the first regimen of PEM-CIS treatment and applied quantitative membrane proteomics analysis. RESULT: In the personalized PBMC membrane proteome profiles, 2424 proteins were identified as displaying patient-specific responsive patterns. We discovered an elevated neutrophil activity and a more suppressive T-cell phenotype with the downregulation of cytotoxic T lymphocyte antigen 4 degradation and the upregulation of type 2 T-helper and T-regulatory cells in the patient with the highest progression-free survival (PFS) of 14.5 months. Patients with a PFS of 2 months showed higher expressions of T-cell subsets, MHC class II pathways, and T-cell receptor signaling, which indicated an activated immune status. CONCLUSION AND CLINICAL RELEVANCE: Without the additional isolation of specific immune cell populations, our study demonstrated that PEM-CIS chemotherapy altered patients' immune system in terms of neutrophils, T cells, and antigen presentation pathways. PMID- 29278295 TI - Subjective quality of life in recent onset of psychosis patients and its association with sociodemographic variables, psychotic symptoms and clinical personality traits. AB - AIM: There is lack of research on the study of clinical personality traits in recent onset of psychosis (ROP) patients. The aims of this research were to study the relations among psychosocial, personality and clinical characteristics in ROP patients and also the effect that significant variables had on the different domains of Quality of Life (QoL). METHODS: Data for these analyses were obtained from 81 ROP patients. The Millon Clinical Multiaxial Inventory, the Positive and Negative Syndrome Scale and the World Health Organization Quality of Life Brief Scale were used to assess personality, symptoms and QoL. RESULTS: Correlations between the negative symptoms and the physical, psychological and social domains of QoL, and the disorganized symptoms and physical domain, were found. Furthermore, the physical, psychological and social relationship domains of QoL were lower in patients with schizoid traits and the psychological domain was lower in patients with depressive traits. In contrast, the psychological and social domains were higher in patients with histrionic traits, while the physical domain was higher for patients with narcissistic traits. Multiple linear regressions demonstrated that negative symptoms and narcissistic and depressive traits explained 16.9% of the physical domain. Narcissistic and depressive traits explained 15% of the psychological domain. Finally, the negative symptoms and histrionic traits explained 13.7% of the social domain. CONCLUSIONS: QoL seems to be better explained by negative psychotic symptoms and some clinical personality traits. Our results support the importance of integrated intervention approaches that consider personality. PMID- 29278296 TI - Prediction in mental health research and its limits (or why life can only be understood backwards but must be lived forwards). PMID- 29278297 TI - Association between statin use and physical function among community-dwelling older Japanese adults. AB - AIM: Statin-associated muscle symptoms (SAMS) are the muscle-related side-effects of statins, but the association between statin use and physical function among community-dwelling older adults is unclear. The objective of the present study was to examine the association between statin use and physical function among community-dwelling older Japanese adults by considering the risk factors of statin-associated muscle symptoms. METHODS: The participants were 1022 community dwelling older adults aged 65-88 years, who participated in comprehensive health checkups from 2013 to 2015. Statin use in the participants (381 men and 559 women) was verified by using data from their medicine notebooks. The differences between statin use (users and non-users) and physical functions (grip strength, knee extension torque, normal and maximum gait speed, Timed Up & Go test, one legged stance, quadriceps muscle thickness and echo intensity) were analyzed using the t-test. Multiple regression analyses were also carried out to examine the association between statin use and physical function. RESULTS: A total of 93 men (24.4%) and 154 women (27.5%) were statin users. Grip strength, normal gait speed and one-legged stance declined significantly in statin users compared with the non-users. In multiple regression analysis while controlling for the risk factors of statin-associated muscle symptoms, including age, sex, body mass index and number of medicines, no independent association, between statin use and the reduction of physical functions, was observed. CONCLUSIONS: Statin use was not associated with the decline of physical function in community-dwelling older Japanese adults. Geriatr Gerontol Int 2018; 18: 623-630. PMID- 29278298 TI - Egg White Ovotransferrin-Derived ACE Inhibitory Peptide Ameliorates Angiotensin II-Stimulated Insulin Resistance in Skeletal Muscle Cells. AB - SCOPE: The renin-angiotensin system (RAS) is a major contributor to the development of insulin resistance and its related complications. Egg white ovotransferrin-derived tripeptides, IRW (Ile-Arg-Trp), IQW (Ile-Gln-Trp), or LKP (Leu-Lys-Pro) are previously identified as the inhibitors of angiotensin converting enzyme (ACE), a key enzyme in the RAS. This study aims at determining whether these peptides are effective in improving insulin resistance, and their mechanisms of action, in a rat derived skeletal muscle cell line (L6 cells). METHODS AND RESULTS: Insulin resistance is induced by treating L6 cells with 1 MUm angiotensin II (Ang II) for 24 h. Effects of peptides on glucose uptake are determined using glucose uptake assay, glucose transporter 4 (GLUT4) translocation by immunofluorescence, reactive oxygen species (ROS) by dihydroethidium (DHE) staining, while insulin signaling pathway, Ang II receptor (AT1R or AT2R) levels, and NADPH oxidase activation are measured using Western Blot. Only IRW treatment significantly improves insulin resistance in L6 cells via stimulation of insulin signaling. IRW decreases Ang II-stimulated AT1R expression, ROS formation, and NADPH oxidase activation. CONCLUSIONS: Of three ACE inhibitory peptides studied, only IRW improves insulin resistance in L6 cells, at least partially via reduced AT1R expression and its anti-oxidative activity. PMID- 29278300 TI - Bioavailable Blueberry-Derived Phenolic Acids at Physiological Concentrations Enhance Nrf2-Regulated Antioxidant Responses in Human Vascular Endothelial Cells. AB - SCOPE: Blueberry consumption is believed to confer a cardiovascular health advantage, but the active compounds and effects require characterization. This study aims to identify the polyphenol metabolites in plasma after blueberry juice intake and determine their bioactivity on endothelial cells. METHODS AND RESULTS: Three healthy individuals are recruited to obtain profiles of bioavailable plasma polyphenol metabolites following intake of blueberry juice. Of 33 phenolic compounds screened, 12 aglycone phenolic acids are detected and their maximum plasma concentrations and circulation time determined. Using this information, the effect of three physiologically relevant mixtures of blueberry-derived phenolic acids is investigated for their ability to induce nuclear factor erythroid 2-related factor 2 (Nrf2)-nuclear translocation and downstream gene expression in human endothelial cells. Pretreatment with the phenolic acids for 18 h results in a significant upregulation of the Nrf2-regulated antioxidant response proteins heme oxygenase 1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), following 6 h exposure to 2.5 MUm H2 O2 . CONCLUSION: Physiologically relevant concentrations of blueberry-derived aglycone phenolic acids can induce Nrf2-regulated antioxidant response proteins in vascular endothelial cells in response to low MUm concentrations of H2 O2 . Our results represent an advance over previous studies that have used single compounds or high concentrations in cell-based investigations. PMID- 29278301 TI - Adrenaline reversal may be an unwarranted distraction during emergency cardiovascular care for patients treated with antipsychotics. PMID- 29278299 TI - Molecular mechanisms underlying stress response and adaptation. AB - Environmental stresses are ubiquitous and unavoidable to all living things. Organisms respond and adapt to stresses through defined regulatory mechanisms that drive changes in gene expression, organismal morphology, or physiology. Immune responses illustrate adaptation to bacterial and viral biotic stresses in animals. Dysregulation of the genotoxic stress response system is frequently associated with various types of human cancer. With respect to plants, especially halophytes, complicated systems have been developed to allow for plant growth in high salt environments. In addition, drought, waterlogging, and low temperatures represent other common plant stresses. In this review, we summarize representative examples of organismal response and adaptation to various stresses. We also discuss the molecular mechanisms underlying the above phenomena with a focus on the improvement of organismal tolerance to unfavorable environments. PMID- 29278302 TI - Monophosphoryl Lipid A-Adjuvanted Virosomes with Ni-Chelating Lipids for Attachment of Conserved Viral Proteins as Cross-Protective Influenza Vaccine. AB - Induction of CD8+ cytotoxic T cells (CTLs) to conserved internal influenza antigens, such as nucleoprotein (NP), is a promising strategy for the development of cross-protective influenza vaccines. However, influenza NP protein alone cannot induce CTL immunity due to its low capacity to activate antigen-presenting cells (APCs) and get access to the MHC class I antigen processing pathway. To facilitate the generation of NP-specific CTL immunity the authors develop a novel influenza vaccine consisting of virosomes with the Toll-like receptor 4 (TLR4) ligand monophosphoryl lipid A (MPLA) and the metal-ion-chelating lipid DOGS-NTA Ni incorporated in the membrane. In vitro, virosomes with incorporated MPLA induce stronger activation of APCs than unadjuvanted virosomes. Virosomes modified with DOGS-NTA-Ni show high conjugation efficacy for his-tagged proteins and facilitate efficient uptake of conjugated proteins by APCs. Immunization of mice with MPLA-adjuvanted virosomes with attached NP results in priming of NP specific CTLs while MPLA-adjuvanted virosomes with admixed NP are inefficient in priming CTLs. Both vaccines induce equally high titers of NP-specific antibodies. When challenged with heterosubtypic influenza virus, mice immunized with virosomes with attached or admixed NP are protected from severe weight loss. Yet, unexpectedly, they show more weight loss and more severe disease symptoms than mice immunized with MPLA-virosomes without NP. Taken together, these results indicate that virosomes with conjugated antigen and adjuvant incorporated in the membrane are effective in priming of CTLs and eliciting antigen-specific antibody responses in vivo. However, for protection from influenza infection NP-specific immunity appears not to be advantageous. PMID- 29278303 TI - Virus-Based Nanoparticles of Simian Virus 40 in the Field of Nanobiotechnology. AB - Biomolecular nanostructures derived from living organisms, such as protein cages, fibers, and layers are drawing increasing interests as natural biomaterials. The virus-based nanoparticles (VNPs) of simian virus 40 (SV40), with a cage-like structure assembled from the major capsid protein of SV40, have been developed as a platform for nanobiotechnology in the recent decade. Foreign nanomaterials (e.g., quantum dots (QDs) and gold nanoparticles (AuNPs)) can be positioned in the inner cavity or on the outer surface of SV40 VNPs, through self-assembly by engineering the nanoparticle (NP)-protein interfacial interactions. Construction of these hybrid nanostructures has enabled integration of different functionalities. This review briefly summarizes the applications of SV40 VNPs in this multidisciplinary field, including NP encapsulation, templated assembly of nanoarchitectures, nanophotonics, and fluorescence imaging. PMID- 29278304 TI - Application of micro-solid-phase extraction for the on-site extraction of heterocyclic aromatic amines in seawater. AB - An efficient on-site extraction technique to determine carcinogenic heterocyclic aromatic amines in seawater has been reported. A micro-solid-phase extraction device placed inside a portable battery-operated pump was used for the on-site extraction of seawater samples. Before on-site applications, parameters that influence the extraction efficiency (extraction time, type of sorbent materials, suitable desorption solvent, desorption time, and sample volume) were investigated and optimized in the laboratory. The developed method was then used for the on-site sampling of heterocyclic aromatic amines determination in seawater samples close to distillation plant. Once the on-site extraction completed, the small extraction device with the analytes was brought back to the laboratory for analysis using high-performance liquid chromatography with fluorescence detection. Based on the optimized conditions, the calibration curves were linear over the concentration range of 0.05-20 MUg/L with correlation coefficients up to 0.996. The limits of detection were 0.004-0.026 MUg/L, and the reproducibility values were between 1.3 and 7.5%. To evaluate the extraction efficiency, a comparison was made with conventional solid-phase extraction and it was applied to various fortified real seawater samples. The average relative recoveries obtained from the spiked seawater samples varied in the range 79.9 95.2%. PMID- 29278305 TI - Biological characteristics of human menstrual blood-derived endometrial stem cells. AB - Successful isolation of human endometrial stem cells from menstrual blood, namely menstrual blood-derived endometrial stem cells (MenSCs), has provided enticing alternative seed cells for stem cell-based therapy. MenSCs are enriched in the self-regenerative tissue, endometrium, which shed along the periodic menstrual blood and thus their acquisition involves no physical invasiveness. However, the impact of the storage duration of menstrual blood prior to stem cell isolation, the age of the donor, the number of passages on the self-renewing of MenSCs, the paracrine production of biological factors in MenSCs and expression of adhesion molecules on MenSCs remain elusive. In this study, we confirmed that MenSCs reside in shedding endometrium, and documented that up to 3 days of storage at 4 degrees C has little impact on MenSCs, while the age of the donor and the number of passages are negatively associated with proliferation capacity of MenSCs. Moreover, we found that MenSCs were actually immune-privileged and projected no risk of tumour formation. Also, we documented a lung- and liver-dominated, spleen and kidney-involved organic distribution profile of MenSC 3 days after intravenous transfer into mice. At last, we suggested that MenSCs may have potentially therapeutic effects on diseases through paracrine effect and immunomodulation. PMID- 29278307 TI - Biotransformation of Plant-Derived Phenolic Acids. AB - Phenolic acids are abundant biomass feedstock that can be derived from the processing of lignin or other byproducts from agro-industrial waste. Although phenolic acids such as p-hydroxybenzoic acid, p-coumaric acid, caffeic acid, vanillic acid, cinnamic acid, gallic acid, syringic acid, and ferulic acid can be used directly in various applications, their value can be significantly increased when they are further modified to high value-added compounds. This review summarizes and discusses the new advances in cell-free and whole-cell biocatalysis technologies for reactions important for conversion of phenolic acids including esterification, decarboxylation, amination, halogenation, hydroxylation, and ring-breakage reactions. The products of these reactions are useful for the pharmaceutical, cosmetic, food, fragrance, and polymer industries. Production of phenolic acids is sustainable, and these processes for their biotransformation are clean technologies that do not produce toxic waste and use less energy than conventional physical and chemical methods. Thus, biotransformation of phenolic acids provides an economically viable and sustainable means for producing useful materials for society. PMID- 29278308 TI - Effect of lysyl oxidase (LOX) on corpus cavernous fibrosis caused by ischaemic priapism. AB - Penile fibrosis caused by ischemic priapism (IP) adversely affects patients' erectile function. We explored the role of lysyl oxidase (LOX) in rat and human penes after ischemic priapism (IP) to verify the effects of anti-LOX in relieving penile fibrosis and preventing erectile dysfunction caused by IP in rats. Seventy two rats were randomly divided into six groups: control group, control + beta aminopropionitrile (BAPN) group, 9 hrs group, 9 hrs + BAPN group, 24 hrs group, and 24 hrs + BAPN group. beta-aminopropionitrile (BAPN), a specific inhibitor of LOX, was administered in the drinking water. At 1 week and 4 weeks, half of the rats in each group were randomly selected for the experiment. Compared to the control group, the erectile function of IP rats was significantly decreased while the expression of LOX in the corpus cavernosum was significantly up-regulated in both 9 and 24 hrs group. Proliferated fibroblasts, decreased corpus cavernosum smooth muscle cells/collagen ratios, destroyed endothelial continuity, deposited abnormal collagen and disorganized fibers were observed in IP rats. The relative content of collage I and III was not obviously different among the groups. beta aminopropionitrile (BAPN) could effectively improve the structure and erectile function of the penis, and enhance recovery. The data in this study suggests that LOX may play an important role in the fibrosis of corpus cavernosum after IP and anti-LOX may be a novel target for patients suffering with IP. PMID- 29278306 TI - Haematoma scavenging in intracerebral haemorrhage: from mechanisms to the clinic. AB - The products of erythrocyte lyses, haemoglobin (Hb) and haem, are recognized as neurotoxins and the main contributors to delayed cerebral oedema and tissue damage after intracerebral haemorrhage (ICH). Finding a means to efficiently promote absorption of the haemolytic products (Hb and haem) around the bleeding area in the brain through stimulating the function of the body's own garbage cleaning system is a novel clinical challenge and critical for functional recovery after ICH. In this review, available information of the brain injury mechanisms underlying ICH and endogenous haematoma scavenging system is provided. Meanwhile, potential intervention strategies are discussed. Intracerebral blood itself has 'toxic' effects beyond its volume effect after ICH. Haptoglobin-Hb CD163 as well as haemopexin-haem-LRP1 is believed to be the most important endogenous scavenging pathway which participates in blood components resolution following ICH. PPARgamma-Nrf2 activates the aforementioned clearance pathway and then accelerates haematoma clearance. Meanwhile, the scavenger receptors as novel targets for therapeutic interventions to treat ICH are also highlighted. PMID- 29278310 TI - Erratum. PMID- 29278311 TI - Sleep patterns and their association with depression and behavior problems among Chinese adolescents in different grades. AB - We aimed to examine sleep patterns and their association with depression and behavior problems among Chinese adolescents in different grades. A cross sectional study was conducted in 10 cities of mainland China. A total of 8,998 Chinese adolescents (49.3% males) aged 9-20 years completed a self-administered questionnaire that included questions on sleep patterns, depressive symptoms, behavior problems, and demographic characteristics. The percentage of adolescents who slept less than 7 hr on weekdays increased with grade, while the percentage of adolescents who slept less than 7 hr on weekends remained the same. The gap in sleep length between weekdays and weekends increased from 0.6 hr in grade 5 to 2.3 hr in Grade 12. The regression analysis showed that poor sleep habits were linked to greater emotional and behavioral problems. The associations of sleep length with those problems differed by symptom and grade. Sleeping less related to depression in all grades. More behavior problems were observed in primary school students who had less sleep and in senior high school students who had more sleep than their peers. The preference for going to bed late stably related to both adolescent depression and behavior problems in all grades, although it posed a greater risk for students in higher grades. PMID- 29278309 TI - Monotropein promotes angiogenesis and inhibits oxidative stress-induced autophagy in endothelial progenitor cells to accelerate wound healing. AB - Attenuating oxidative stress-induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries. We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress-induced mitochondrial dysfunction and stimulate bone marrow-derived EPC (BM-EPC) differentiation. Results showed Mtp significantly elevated migration and tube formation of BM-EPCs and prevented tert-butyl hydroperoxide (TBHP)-induced programmed cell death through apoptosis and autophagy by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated viamTOR/p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased macrophage infiltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM-EPCs and protected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that Mtp is a potential therapeutic for endothelial injury-related wounds. PMID- 29278312 TI - Chronobiological research for cognitive science: A multifaceted view. PMID- 29278313 TI - Interactions between psychosocial stress and the circadian endogenous clock. AB - Animals are exposed to regular daily challenges in their environment as well as to unpredictable stressful events, so-called stressors. Both measures require adequate physiological responses that are controlled by the circadian system and the stress system. The two systems are highly linked with each other. The circadian system prepares the animal for the regular daily challenges by upregulating the stress system before the animal's activity phase every day. In addition, unpredicted environmental challenges upregulate the stress system independently of the circadian system. This can happen at any time, even in the middle of the animal's sleeping phase. Although the stress system feeds back on the brain, the circadian master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus is usually not disturbed by stressful events, but instead continues to activate the animal in a regular daily manner. However, the stability of the SCN clock appears to fade away after chronic stress, in particular after chronic psychosocial stress. Chronic psychosocial stress is the major risk factor for major depression and certain anxiety disorders in humans and therefore deserves attention. Here, I review the interactions between the circadian and stress systems after chronic psychosocial stress in an animal model, the social defeat paradigm. PMID- 29278314 TI - Temporal segmentation of cognitive processes in the domain of a few seconds. PMID- 29278315 TI - Retracted: Amelioration of Osteoporosis by Menatetrenone in Elderly Female Parkinson's Disease Patients With Vitamin D Deficiency. PMID- 29278316 TI - Low-Threshold Light Amplification in Bifluorene Single Crystals: Role of the Trap States. AB - Organic single crystals (SCs) expressing long-range periodicity and dense molecular packing are an attractive amplifying medium for the realization of electrically driven organic lasers. However, the amplified spontaneous emission (ASE) threshold (1-10 kW/cm2) of SCs is still significantly higher compared to those of amorphous neat or doped films. The current study addresses this issue by investigating ASE properties of rigid bridging group-containing bifluorene SCs. Introduction of the rigid bridges in bifluorenes enables considerable reduction of nonradiative decay, which, along with enhanced fluorescence quantum yield (72 82%) and short excited state lifetime (1.5-2.5 ns), results in high radiative decay rates (~0.5 * 109 s-1) of the SCs, making them highly attractive for lasing applications. The revealed ASE threshold of 400 W/cm2 in acetylene-bridged bifluorene SCs is found to be among the lowest ever reported for organic crystals. Ultrafast transient absorption spectroscopy enabled one to disclose pronounced differences in the excited state dynamics of the studied SCs, pointing out the essential role of radiative traps in achieving a record low ASE threshold. Although the origin of the trap states was not completely unveiled, the obtained results clearly evidence that the crystal doping approach can be successful in achieving extremely low ASE thresholds required for electrically pumped organic laser. PMID- 29278317 TI - Transferrin-Copper Nanocluster-Doxorubicin Nanoparticles as Targeted Theranostic Cancer Nanodrug. AB - Transferrin (Tf)-templated luminescent blue copper nanoclusters (Tf-Cu NCs) are synthesized. They are further formulated into spherical Tf-Cu NC-doxorubicin nanoparticles (Tf-Cu NC-Dox NPs) based on electrostatic interaction with doxorubicin (Dox). The as-synthesized Tf-Cu NC-Dox NPs are explored for bioimaging and targeted drug delivery to delineate high therapeutic efficacy. Forster resonance energy transfer (FRET) within the Tf-Cu NC-Dox NPs exhibited striking red luminescence, wherein the blue luminescence of Tf-Cu NCs (donor) is quenched due to absorption by Dox (acceptor). Interestingly, blue luminescence of Tf-Cu NCs is restored in the cytoplasm of cancer cells upon internalization of the NPs through overexpressed transferrin receptor (TfR) present on the cell surface. Finally, gradual release of Dox from the NPs leads to the generation of its red luminescence inside the nucleus. The biocompatible Tf-Cu NC-Dox NPs displayed superior targeting efficiency on TfR overexpressed cells (HeLa and MCF 7) as compared to the cells expressing less TfR (HEK-293 and 3T3-L1). Combination index (CI) revealed synergistic activity of Tf-Cu NCs and Dox in Tf-Cu NC-Dox NPs. In vivo assessment of the NPs on TfR positive Daltons lymphoma ascites (DLA) bearing mice revealed significant inhibition of tumor growth rendering prolonged survival of the mice. PMID- 29278318 TI - Phosphorus-Doped Graphitic Carbon Nitride Nanotubes with Amino-rich Surface for Efficient CO2 Capture, Enhanced Photocatalytic Activity, and Product Selectivity. AB - Phosphorus-doped graphitic carbon nitrides (P-g-C3N4) have recently emerged as promising visible-light photocatalysts for both hydrogen generation and clean environment applications because of fast charge carrier transfer and increased light absorption. However, their photocatalytic performances on CO2 reduction have gained little attention. In this work, phosphorus-doped g-C3N4 nanotubes are synthesized through the one-step thermal reaction of melamine and sodium hypophosphite monohydrate (NaH2PO2.H2O). The phosphine gas generated from the thermal decomposition of NaH2PO2.H2O induces the formation of P-g-C3N4 nanotubes from g-C3N4 nanosheets, leads to an enlarged BET surface area and a unique mesoporous structure, and creates an amino-rich surface. The interstitial doping phosphorus also down shifts the conduction and valence band positions and narrows the band gap of g-C3N4. The photocatalytic activities are dramatically enhanced in the reduction both of CO2 to produce CO and CH4 and of water to produce H2 because of the efficient suppression of the recombination of electrons and holes. The CO2 adsorption capacity is improved to 3.14 times, and the production of CO and CH4 from CO2 increases to 3.10 and 13.92 times that on g-C3N4, respectively. The total evolution ratio of CO/CH4 dramatically decreases to 1.30 from 6.02 for g-C3N4, indicating a higher selectivity of CH4 product on P-g-C3N4, which is likely ascribed to the unique nanotubes structure and amino-rich surface. PMID- 29278319 TI - Superior Electro-Oxidation and Corrosion Resistance of Monolayer Transition Metal Disulfides. AB - Physics of monolayer and few-layer transition metal dichalcogenides (TMDs) and chemistry of few-layer TMDs have been well studied in recent years in the context of future electronic, optoelectronic, and energy harvesting applications. However, what has escaped the attention of the scientific community is the unique chemistry of monolayer TMDs. It has been demonstrated that the basal plane of multilayer TMDs is chemically inert, whereas edge sites are chemically active. In this article, we experimentally demonstrate that the edge reactivity of the TMDs can be significantly impeded at the monolayer limit through monolayer/substrate interaction, thus making the monolayers highly resistant to electrooxidation and corrosion. In particular, we found that few-layer flakes of MoS2 and WS2 exfoliated on conductive TiN substrates are readily corroded beyond a certain positive electrode potential, while monolayer remnants are left behind unscathed. The electrooxidation resistance of monolayers was confirmed using a plethora of characterization techniques including atomic force microscope (AFM) imaging, Raman spectroscopy, photoluminescence (PL) mapping, scanning/transmission electron microscope (S/TEM) imaging, and selected area electron diffraction (SAED). It is believed that strong substrate monolayer interaction compared to the relatively weak interlayer van der Waals interaction is responsible for the superior monolayers chemical stability in highly corrosive oxidizing environments. Our findings could pave the way for the implementation of monolayer transition metal disulfides as superior anticorrosion coating which can have a significant socioeconomic impact. PMID- 29278320 TI - Semitransparent Flexible Organic Solar Cells Employing Doped-Graphene Layers as Anode and Cathode Electrodes. AB - Semitransparent flexible photovoltaic cells are advantageous for effective use of solar energy in many areas such as building-integrated solar-power generation and portable photovoltaic chargers. We report semitransparent and flexible organic solar cells (FOSCs) with high aperture, composed of doped graphene layers, ZnO, P3HT:PCBM, and PEDOT:PSS as anode/cathode transparent conductive electrodes (TCEs), electron transport layer, photoactive layer, and hole transport layer, respectively, fabricated based on simple solution processing. The FOSCs do not only harvest solar energy from ultraviolet-visible region but are also less sensitive to near-infrared photons, indicating semitransparency. For the anode/cathode TCEs, graphene is doped with bis(trifluoromethanesulfonyl)-amide or triethylene tetramine, respectively. Power conversion efficiency (PCE) of 3.12% is obtained from the fundamental FOSC structure, and the PCE is further enhanced to 4.23% by adding an Al reflective mirror on the top or bottom side of the FOSCs. The FOSCs also exhibit remarkable mechanical flexibilities through bending tests for various curvature radii. PMID- 29278321 TI - Design and Evaluation of Lyophilized Fibroblast Growth Factor 21 and Its Protection against Ischemia Cerebral Injury. AB - This study investigated the effect of the excipients, including glycine, mannitol, arginine, trehalose, sorbitol, and poloxamer188, on the stability of recombinant human fibroblast growth factor 21(FGF21) during the process of lyophilization and storage. The glass transition temperature (Tg), protein secondary structure, aggregation ratio, and the bioactivity of lyophilized FGF21 were measured. We furthermore investigated the effect of FGF21 against ischemia cerebral injury using the middle cerebral artery occlusion (MCAO) model in rats. The ischemia cerebral injury of MCAO rats was analyzed via 2,3,5 triphenyltetrazolium chloride and Nissl-staining. Endoplasmic reticulum (ER) stress related proteins were detected via Western blot. In this study, we found that aggregation was the primary mode of deterioration of lyophilized FGF21under accelerated storage conditions. Mannitol combined with trehalose and glycine formulations offers the most effective protein protection to reduce the aggregation. Administration of FGF21 protected cerebral ischemia and decreased ER stress related proteins in MCAO rats and PC12 cells. PMID- 29278322 TI - Easy Printing of High Viscous Microdots by Spontaneous Breakup of Thin Fibers. AB - Electrohydrodynamic jetting is emerging as a successful technique for printing inks with resolutions well beyond those offered by conventional inkjet printers. However, the variety of printable inks is still limited to those with relatively low viscosities (typically <20 mPa s) due to nozzle clogging problems. Here, we show the possibility of printing ordered microdots of high viscous inks such as poly(lactic-co-glycolic acid) (PLGA) by exploiting the spontaneous breakup of a thin fiber generated through nozzle-free pyro-electrospinning. The PLGA fiber is deposited onto a partially wetting surface, and the breakup is achieved simply by applying an appropriate thermal stimulation, which is able to induce polymer melting and hence a mechanism of surface area minimization due to the Plateau Rayleigh instability. The results show that this technique is a good candidate for extending the printability at the microscale to high viscous inks, thus extending their applicability to additional applications, such as cell behavior under controlled morphological constraints. PMID- 29278323 TI - In Situ Observation of Carbon Dioxide Capture on Pseudo-Liquid Eutectic Mixture Promoted Magnesium Oxide. AB - Eutectic mixtures of alkali nitrates are known to increase the sorption capacity and kinetics of MgO-based sorbents. Underlying principles and mechanisms for CO2 capture on such sorbents have already been established; however, real-time observation of the system was not yet accomplished. In this work, we present the direct-observation of the CO2 capture phenomenon on a KNO3-LiNO3 eutectic mixture (EM)-promoted MgO sample, denoted as KLM, via in situ transmission electron microscopy (in situ TEM). Results revealed that the pseudoliquid EM undergoes structural rearrangement as MgCO3 evolves from the surface of MgO, resulting in surface roughening and evolution of cloudy structures that stay finely distributed after regeneration. From this, we propose a nucleation and structural rearrangement scheme for MgCO3 and EM, which involves the rearrangement of bulk EM to evenly distributed EM clusters due to MgCO3 saturation as adsorption proceeds. We also conducted studies on the interface between EM over solid MgO and MgCO3 formed during sorption, which further clarifies the interaction between MgO and EM. This study provides better insight into the sorption and regeneration mechanism, as well as the structural rearrangements involved in EM-promoted sorbents by basing not only on intrinsic evolutions but also on real-time observation of the system as a whole. PMID- 29278324 TI - Ternary Iodido Bismuthates and the Special Role of Copper. AB - Two new, isostructural members of the title material class, [PPh4]4[Cu2Bi2I12] (1) and [PPh4]4[Ag2Bi2I12] (2), have been prepared via a facile solution route. The crystal structure of both compounds features a tetranuclear [M2Bi2I12]4- (M = Cu, Ag) anion that displays an unprecedented face-sharing mode of connection between BiI6 octahedra and MI4 tetrahedra, enabling close Bi...M contacts. The two compounds allow for a direct experimental and quantum chemical investigation of the influence of group 11 metal cations on the optical and electronic properties of ternary iodido bismuthate anions, indicating that Cu+ is a better electronic match than Ag+, resulting in a significantly lower optical band gap of the copper compound. PMID- 29278325 TI - An Unusual Triple-Decker Variant of the Tetragonal BaAl4-Structure Type: Synthesis, Structural Characterization, and Chemical Bonding of Sr3Cd8Ge4 and Eu3Cd8Ge4. AB - Reported are the synthesis and the crystal structures of the new ternary phases Sr3Cd8Ge4 and Eu3Cd8Ge4. The structures of both compounds have been established by single-crystal and powder X-ray diffraction methods. They crystallize in the tetragonal space group I4/mmm (No. 139, own structure type, Pearson symbol tI30) with Z = 2, and lattice parameters as follows: a = 4.4941(14) A; c = 35.577(7) A for Sr3Cd8Ge4, and a = 4.4643(12) A; c = 35.537(9) A for Eu3Cd8Ge4, respectively. The most prominent feature of the structure is the complex [Cd2Ge] polyanionic framework, derived by unique ordering of the Cd and Ge atoms in fragments that bear resemblance to the BaAl4 structure type. Temperature dependent DC magnetization measurements indicate that Eu3Cd8Ge4 displays Curie-Weiss paramagnetic behavior with no sign of magnetic ordering in the measured range. Theoretical considerations of the electronic structure on the basis of the tight binding linear muffin-tin orbital (TB-LMTO-ASA) method are also presented and discussed. PMID- 29278327 TI - Efficient Hydrogen Evolution Electrocatalysis at Alkaline pH by Interface Engineering of Ni2P-CeO2. AB - It is of significant importance to develop effective non-noble-metal catalysts for hydrogen evolution electrocatalysis under basic conditions. In this study, we demonstrate the facile construction of a Ni2P-CeO2 interface based on the central point that low-temperature phosphidation of the NiO-CeO2 precursor only converts NiO into Ni2P selectively. The resulting Ni2P-CeO2 nanosheet array on Ti mesh behaves as a durable catalyst for alkaline hydrogen evolution reaction (HER) electrocatalysis, and it can reach 20 mA cm-2 at an overpotential of 84 mV in 1.0 M KOH, outperforming all reported Ni phosphide HER catalysts. Density functional theory calculations reveal that the Ni2P-CeO2 interface can promote water dissociation and optimize hydrogen adsorption free energy. PMID- 29278328 TI - Unpaired Electron Spin Density Distribution across Reduced [2Fe-2S] Cluster Ligands by 13Cbeta-Cysteine Labeling. AB - Iron-sulfur clusters are one of the most versatile and ancient classes of redox mediators in biology. The roles that these metal centers take on are predominantly determined by the number and types of coordinating ligands (typically cysteine and histidine) that modify the electronic structure of the cluster. Here we map the spin density distribution onto the cysteine ligands for the three major classes of the protein-bound, reduced [2Fe-2S](His)n(Cys)4-n (n = 0, 1, 2) cluster by selective cysteine-13Cbeta isotope labeling. The spin distribution is highly asymmetric in all three systems and delocalizes further along the reduced Fe2+ ligands than the nonreducible Fe3+ ligands for all clusters studied. The preferential spin transfer onto the chemically reactive Fe2+ ligands is consistent with the structural concept that the orientation of the cluster in proteins is not arbitrarily decided, but rather is optimized such that it is likely to facilitate better electronic coupling with redox partners. The resolution of all cysteine-13Cbeta hyperfine couplings and their assignments provides a measure of the relative covalencies of the metal-thiolate bonds not readily available to other techniques. PMID- 29278326 TI - Functional Contribution of the Spastic Paraplegia-Related Triglyceride Hydrolase DDHD2 to the Formation and Content of Lipid Droplets. AB - Deleterious mutations in the serine lipase DDHD2 are a causative basis of complex hereditary spastic paraplegia (HSP, subtype SPG54) in humans. We recently found that DDHD2 is a principal triglyceride hydrolase in the central nervous system (CNS) and that genetic deletion of this enzyme in mice leads to ectopic lipid droplet (LD) accumulation in neurons throughout the brain. Nonetheless, how HSP related mutations in DDHD2 relate to triglyceride metabolism and LD formation remains poorly understood. Here, we have characterized a set of HSP-related mutations in DDHD2 and found that they disrupt triglyceride hydrolase activity in vitro and impair the capacity of DDHD2 to protect cells from LD accumulation following exposure to free fatty acid, an outcome that was also observed with a DDHD2-selective inhibitor. We furthermore isolated and characterized LDs from brain tissue of DDHD2-/- mice, revealing that they contain both established LD associated proteins identified previously in other organs and CNS-enriched proteins, including several proteins with genetic links to human neurological disease. These data, taken together, indicate that the genetic inactivation of DDHD2, as caused by HSP-associated mutations, substantially perturbs lipid homeostasis and the formation and content of LDs, underscoring the importance of triglyceride metabolism for normal CNS function and the key role that DDHD2 plays in this process. PMID- 29278329 TI - Insights into Molecular Structures and Optical Properties of Stacked [Au3(RN?CR')3]n Complexes. AB - The molecular structure of stacked cyclic trinuclear gold(I) complexes [Au3(RN?CR')3]n, with n = 1-4, where R = H, methyl (Me), cyclopentyl (cPe), and phenyl (Ph) and R' = OH and methoxy (OMe) were studied computationally at the second-order Moller-Plesset (MP2) and density functional theory (DFT) levels of theory. At the DFT level, the aurophilic and dispersion interactions were accounted for by using the TPSS functional in combination with the semiempirical D3 correction. The structure optimizations yielded the lowest energy for a slided stacked structure of the [Au3(HN?COH)3]2 dimer, where monomers are slightly shifted relative to one another. At the MP2 level, the slided structure is 32 kJ/mol more stable than the staggered dimer structure, which in turn is energetically 11 kJ/mol below the eclipsed structure. The calculations show that aromatic ligands lead to a planar and prismatic structure of [Au3(PhN?COMe)3]4, whereas for [Au3(cPeN?COMe)3]4, a chair conformation is obtained due to steric effects. Excitation energies were calculated for [Au3(RN?CR')3] and [Au3(RN?CR')3]2 with R = H, Me, and cPe and R' = OH and OMe at the time-dependent DFT level using the optimized molecular structures of the singlet ground state. To simulate the luminescence spectra, the lowest triplet excitation energy was also calculated for the molecular structure of the lowest triplet state. The calculated excitation energies of [Au3(HN?COH)3] and [Au3(HN?COH)3]2 are compared with values obtained at the approximate singles and doubles coupled cluster (CC2) and the second-order algebraic diagrammatic construction (ADC(2)) levels of theory. The calculated absorption and emission energies reproduce the experimental trends, with extremely large Stokes shifts. A solvoluminescence mechanism is also proposed. PMID- 29278330 TI - Regiodivergent Iridium(III)-Catalyzed Diamination of Alkenyl Amides with Secondary Amines: Complementary Access to gamma- or delta-Lactams. AB - Alkenyl N-pivaloylhydroxamates undergo an Ir(III)-catalyzed diamination of the alkene with simple exogenous secondary amines under extraordinarily mild reaction conditions. The regioselectivity of the diamination is controlled by the solvent and the electronics of the cyclopentadienyl (Cpx) ligand on Ir. On the basis of a set of mechanistic experiments, we propose that the relative rates of Ir(V) nitrenoid formation versus attack on the amido-Ir-coordinated alkene by the exogenous amine determine the outcome of the reaction. PMID- 29278331 TI - Methodology for the Absolute Configuration Determination of Epoxythymols Using the Constituents of Ageratina glabrata. AB - A methodology to determine the enantiomeric excess and the absolute configuration (AC) of natural epoxythymols was developed and tested using five constituents of Ageratina glabrata. The methodology is based on enantiomeric purity determination employing 1,1'-bi-2-naphthol (BINOL) as a chiral solvating agent combined with vibrational circular dichroism (VCD) measurements and calculations. The conformational searching included an extensive Monte Carlo protocol that considered the rotational barriers to cover the whole conformational spaces. (+) (8S)-10-Benzoyloxy-6-hydroxy-8,9-epoxythymol isobutyrate (1), (+)-(8S)-10-acetoxy 6-methoxy-8,9-epoxythymol isobutyrate (4), and (+)-(8S)-10-benzoyloxy-6-methoxy 8,9-epoxythymol isobutyrate (5) were isolated as enantiomerically pure constituents, while 10-isobutyryloxy-8,9-epoxythymol isobutyrate (2) was obtained as a 75:25 (8S)/(8R) scalemic mixture. In the case of 10-benzoyloxy-8,9 epoxythymol isobutyrate (3), the BINOL methodology revealed a 56:44 scalemic mixture and the VCD measurement was beyond the limit of sensitivity since the enantiomeric excess is only 12%. The racemization process of epoxythymol derivatives was studied using compound 1 and allowed the clarification of some stereochemical aspects of epoxythymol derivatives since their ACs have been scarcely analyzed and a particular behavior in their specific rotations was detected. In more than 30 oxygenated thymol derivatives, including some epoxythymols, the reported specific rotation values fluctuate from -1.6 to +1.4 passing through zero, suggesting the presence of scalemic and close to racemic mixtures, since enantiomerically pure natural constituents showed positive or negative specific rotations greater than 10 units. PMID- 29278332 TI - Synthesis of a Series of Monophthalocyaninato Cyclen Heavy Lanthanide(III) Complexes with Tetragonal Symmetry. AB - A series of the new monophthalocyaninato lanthanide complexes, [Ln(Pc)(cyclen)]Cl (Ln = Y, Tb, Dy, Ho, Er, Tm, and Yb; Pc = phthalocyaninato; cyclen = 1,4,7,10 tetraazacyclododecane) was synthesized and characterized. The crystallographic study of monophthalocyaninato complexes with a capping macrocyclic ligand having no pi-conjugation while keeping the 4-fold symmetry is presented for the first time. All the six complexes were crystallized in a tetragonal structure of the I4mm space group. In addition to this, the Tb complex exhibited a triclinic crystal structure of the P1 space group. All of the complexes are isostructural, where both Pc and cyclen are coordinated to an Ln3+ ion giving an eight coordinate square-antiprismatic geometry. The skew angle between the Pc and cyclen ligands was 45 degrees in the tetragonal crystals and 41.5 degrees in the triclinic crystal. The metal-nitrogen bond lengths were shorter on the Pc ligand side than cyclen side, presumably due to the difference in the charges of the ligands and the steric factor. PMID- 29278333 TI - Iron-Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2-Pyridyl Sulfone. AB - We report the first iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone via selective C-S bond cleavage. This method employs the readily available, bench-stable fluoroalkyl sulfone reagent and inexpensive iron catalyst, allowing facile access to structurally diverse difluoromethylated arenes at low temperatures. The experiment employing a radical clock indicates the involvement of radical species in this iron-catalyzed difluoromethylation process. PMID- 29278334 TI - Coarse-Grained Molecular Dynamics Force-Field for Polyacrylamide in Infinite Dilution Derived from Iterative Boltzmann Inversion and MARTINI Force-Field. AB - We present a mesoscale model of aqueous polyacrylamide in the infinitely dilute concentration regime, by combining an extant coarse-grained (CG) force-field, MARTINI, and the Iterative Boltzmann Inversion protocol (IBI). MARTINI force field was used to retain the thermodynamics of solvation of the polymer in water, whereas the structural properties and intrapolymer interactions were optimized by IBI. Atomistic molecular dynamics simulations of polymer in water were performed to benchmark the mesoscale simulations. Our results from the CG model show excellent agreement in structure with the atomistic system. We also studied the dynamical behavior of our CG system by computing the shear viscosity and compared it with the standard IBI model. The viscosity trends of our model were similar to the atomistic system, whereas the standard IBI model was highly dissimilar as expected. In summary, our hybrid CG model sufficiently mimics an infinitely dilute system, and is superior to both MARTINI and IBI in representing the structure and thermodynamics of the atomistic system, respectively. Our hybrid coarse-graining strategy promises applicability in large-scale simulations of polymeric/biological systems where the structure needs to be replicated accurately while preserving the thermodynamics of a smoother surrounding. PMID- 29278335 TI - Adsorption of Kinetic Hydrate Inhibitors on Growing Surfaces: A Molecular Dynamics Study. AB - We investigate the mechanism of a typical kinetic hydrate inhibitor (KHI), polyvinylcaprolactam (PVCap), which has been applied to prevent hydrate plugs from forming in gas pipe lines, using molecular dynamics simulations of crystal growth of ethylene oxide hydrate. Water-soluble ethylene oxide is chosen as a guest species to avoid problems associated with the presence of the gas phase in the simulation cell such as slow crystal growth. A PVCap dodecamer adsorbs irreversibly on the hydrate surface which grows at supercooling of 3 K when the hydrophobic part of two pendent groups are trapped in open cages at the surface. The amide hydrogen bonds make no contribution to the adsorption. PVCap can adsorb on various crystallographic planes of sI hydrate. This is in contrast to antifreeze proteins, each of which prefers a specific plane of ice. The trapped PVCap gives rise to necessarily the concave surface of the hydrate. The crystal growth rate decreases with increasing surface curvature, indicating that the inhibition by PVCap is explained by the Gibbs-Thomson effect. PMID- 29278336 TI - Evidence of Intermediate Hydrogen States in the Formation of a Complex Hydride. AB - A complex hydride (LaMg2NiH7) composed of La3+, two Mg2+, [NiH4]4- with a covalently bonded hydrogen, and three H- was formed from an intermetallic LaMg2Ni via an intermediate phase (LaMg2NiH4.6) composed of La, Mg, NiH2, NiH3 units, and H atoms at tetrahedral sites. The NiH2 and NiH3 units in LaMg2NiH4.6 were reported as precursors for [NiH4]4- in LaMg2NiH7 [ Miwa et al. J. Phys. Chem. C 2016 , 120 , 5926 - 5931 ]. To further understand the hydrogen states in the precursors (the NiH2 and NiH3 units) and H atoms at the tetrahedral sites in the intermediate phase, LaMg2NiH4.6, we observed the hydrogen vibrations in LaMg2NiH4.6 and LaMg2NiH7 by using inelastic neutron scattering. A comparison of the hydrogen vibrations of the NiH2 and NiH3 units with that of [NiH4]4- shows that the librational modes of the NiH2 and NiH3 units were nonexistent; librational modes are characteristic modes for complex anions, such as [NiH4]4-. Furthermore, the hydrogen vibrations for the H atoms in the tetrahedral sites showed a narrower wavenumber range than that for H- and a wider range than that for typical interstitial hydrogen. The results indicated the presence of intermediate hydrogen states before the formation of [NiH4]4- and H-. PMID- 29278337 TI - Heterogeneous Heterobimetallic Catalysis Enabling Expeditious Access to CF3 Containing vic-Amino Alcohols. AB - A highly anti-selective catalytic asymmetric nitroaldol reaction of trifluoromethyl ketones based on Nd/Na and Pr/Na heterobimetallic catalysts was developed. These catalysts function as heterogeneous catalysts to engage nitroethane and a range of trifluoromethyl ketones in a stereoselective assembly to afford CF3-appended vic-nitroalkanols that could be readily converted to enantioenriched vic-amino alcohols, which are privileged structural motifs in medicinal chemistry. PMID- 29278338 TI - Stereoselective One-Pot Synthesis of Dihydropyrimido[2,1-a]isoindole-6(2H)-ones. AB - A diastereoselective one-pot synthesis of highly substituted dihydropyrimido[2,1 a]isoindole-6(2H)-ones containing three continuous stereocenters is reported. The reaction sequence is based on a hetero-Diels-Alder reaction between an enimide and a N-acylimine followed by an unprecedented Bronsted acid mediated rearrangement of an intermediate 5,6-dihydro-4H-1,3-oxazine to a pyrimido[2,1 a]isoindole. PMID- 29278339 TI - Determinants of Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity in patients with rheumatoid arthritis: A post hoc analysis of overall and Japanese results from phase 3 clinical trials. AB - OBJECTIVES: To assess the determinants of Patient's Global Assessment of Disease Activity (PtGA) and Physician's Global Assessment of Disease Activity (PhGA) in overall and Japanese patients with rheumatoid arthritis (RA) from two large randomized controlled trials. METHODS: Post hoc analysis of overall and Japanese RA patients who had previous inadequate responses to methotrexate or who had no/minimal previous disease-modifying antirheumatic drug treatment. We examined correlations between PtGA/PhGA and tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), inflammatory markers, pain visual analog scale (VAS), and other patient-reported outcomes at baseline, Week 12, and Week 24. Determinants of PtGA/PhGA were identified. RESULTS: In overall populations, pain VAS was the main determinant of PtGA, whereas TJC28 was the main determinant of PhGA in both studies. In Japanese populations, consistent with overall populations, pain VAS was the main determinant of PtGA in both studies; in contrast to overall populations, pain VAS and SJC28/TJC28 played an important role in PhGA. CONCLUSION: Pain was the most important determinant of PtGA, whereas determinants of PhGA varied between populations/studies and were mostly explained by pain/joint counts. Physicians should be aware of patients' perceptions of disease activity when performing assessments/prescribing treatments. PMID- 29278340 TI - Microwave ablation of pancreatic tumors. AB - OBJECTIVES: To evaluate the clinical performance of percutaneous microwave ablation (MWA) for treatment of locally-advanced-pancreatic-cancer (LAPC). MATERIAL AND METHODS: Twenty-two MWA sessions (August 2015-March 2017) in 20 patients with primary pancreatic cancer (13 men, 7 women, mean-age: 59.9 +/- 8.6 years, range: 46-73 years), who had given informed consent, were retrospectively evaluated. All procedures were performed percutaneously under CT-guidance using the same high-frequency (2.45-GHz) MWA device. Tumor location and diameter, ablation diameter and volume, roundness, duration, technical success and efficacy, output energy, complications, and local tumor progression defined as a tumor focus connected to the edge of a previously technically efficient ablation zone were collected. RESULTS: Seventeen pancreatic malignant tumors (77.3%) were located in the pancreatic head and five (22.7%) in the pancreatic tail. Initial Mean Tumor Diameter was 30 +/- 6 mm. Technical success and efficacy were idem (100%). No major complications occurred. Two patients (9.1%) showed minor complications of severe local pain related to MWA. Post-ablation diameter was on average 34.4 +/- 5.8 mm. Mean ablation volume was 7.8 +/- 3.8 cm3. The mean transverse roundness index was 0.74 +/- 0.14. Mean ablation time was 2.6 +/- 0.96 min. The mean applied energy per treatment was 9627 +/- 3953 J. Local tumor progression was documented in one case (10%) of the 10/22 available three-month follow-up imaging studies. CONCLUSION: High-frequency (2.45 GHz) microwave ablation (MWA) for treatment of unresectable and non-metastatic locally-advanced pancreatic-cancer (LAPC) shows promising results regarding feasibility and safety of percutaneous approach after short-term follow-up and should be further evaluated. PMID- 29278341 TI - What Are Risks and Benefits of Not Incorporating Information about Population Growth and Its Impact on Climate Change into Reproductive Care? AB - Fears about the impact of family planning decisions on the environment are not new. Concerns about population growth have often been conflated with concerns about the increasing demographic influence of specific feared or marginalized groups, leading to subsequent unjust treatment of those targeted populations. In clinical encounters such as this case, in which the patient expresses concerns about having another child in light of the effect of population growth on climate change, it is not appropriate for the clinician to impose environmental protection values on a patient's reproductive decision making, as this risks undermining her autonomy as well as perpetuating injustice. When a patient raises such worries, however, the physician's responsibility is to elicit and try to understand the patient's preferences and then to offer treatment choices that align with those values. PMID- 29278342 TI - Are Physicians Obliged to Lead Environmental Sustainability Efforts in Health Care Organizations? AB - Climate change threatens health, health care, and the industries and resources upon which these depend. The growing prevalence and severity of its health consequences and economic costs are alarming health professionals and organizations as their professional obligations, grounded in the core value of health, include protecting against these harms. One means of fulfilling these obligations is to lead or support sustainability initiatives that are built upon current, reliable, accurate, and unbiased evidence and collaboratively tailored to meet specific needs and respond to specific contexts. We consider why and how health professionals and organizations should lead or support such initiatives. PMID- 29278343 TI - How Should Clinicians Weigh the Benefits and Harms of Discussing Politicized Topics that Influence Their Individual Patients' Health? AB - Health implications of politically charged phenomena are particularly difficult for physicians to discuss with their patients and communities. Addressing climate change and its associated health effects involves trade-offs between health and economic prosperity, necessitating that physicians weigh the potential benefits and risks of discussing climate change health effects. We argue that the potential benefits of physician communication and advocacy ultimately outweigh the potential risks. Therefore, physicians should be supported in their efforts to educate their patients and communities about climate change health effects. Furthermore, democratic deliberation could prove helpful in addressing disagreements among physicians within a practice about such politicized health topics. PMID- 29278344 TI - Is Editing the Genome for Climate Change Adaptation Ethically Justifiable? AB - As climate change progresses, we humans might have to inhabit a world for which we are increasingly maladapted. If we were able to identify genes that directly influence our ability to thrive in a changing climate, would it be ethically justifiable to edit the human genome to enhance our ability to adapt to this new environment? Should we use gene editing not only to prevent significant disease but also to enhance our ability to function in the world? Here I suggest a "4-S framework" for analyzing the justifiability of gene editing that includes these considerations: (1) safety, (2) significance of harm to be averted, (3) succeeding generations, and (4) social consequences. PMID- 29278345 TI - The "Buy One, Get One Free" Ethics of Investing Public and Philanthropic Funds in Health and Climate. AB - This article applies various ethical frameworks to inform decision making about investment in two specific goods-strengthening public health and stabilizing the global climate. I begin by outlining how these goods traditionally competed for common and constrained resources. I then discuss how this view of competition has been rendered more problematic by emerging and compelling ethical justifications for investment in both goods based on utilitarian, Rawlsian, and communitarian analyses. I conclude by showing that these goods no longer compete head-to-head in a zero-sum way. Changes in science, technology, and society mean that investment in either good has the potential to advance both goods-that is, the goods have become synergistic. As a result, the case for investing in both is better. PMID- 29278346 TI - Should Health Professionals Speak Up to Reduce the Health Risks of Climate Change? AB - Should physicians take action in the political realm to address climate change? There are many historical examples of physician advocacy in the political sphere, both individually and as a collective, and many have argued that it is important for health professionals to advocate on a variety of issues. But which criteria should be used to determine when and how health professionals should take on particular advocacy issues, and is climate change an appropriate-or even obligatory-arena for physician advocacy? We propose a seven-part deliberative framework for making this determination. PMID- 29278347 TI - Rising Waters and a Smaller Island: What Should Physicians Do for Tuvaluans? AB - Residents of the island nation of Tuvalu will be among the first of the 1.7 million Pacific Islanders to be displaced by the effects of climate change (including rising sea levels, changing distributions of agriculture, and unpredictable weather patterns). Already 3,500 Tuvaluans live in New Zealand (approximately 25 percent of the world's Tuvaluan population), some of whom moved due to climate change. Immigrating to New Zealand presents several challenges for Tuvaluans, including limited job opportunities, health care disparities, and dietary changes. Nevertheless, Tuvaluans in New Zealand continue their culture as they redefine their identity in a new country. Given the growing effects of climate change, physicians around the world will soon care for a new generation of immigrants and will play an important role in advocating for health equity and self-determination among climate-sensitive populations. This article uses personal stories and photographs of Tuvaluans and photographs of Tuvalu and New Zealand to present Tuvaluans' struggles and ethical issues pertaining to health that arise in relocating Tuvaluans. PMID- 29278348 TI - The Importance of Physician Climate Advocacy in the Face of Political Denial. AB - Most physicians accept the general scientific discoveries about anthropogenic global warming and its dangers. Occasional denial by individual physicians of climate change can be readily answered by reference to the scientific consensus. But widespread, organized, political denial of climate change is hazardous to physicians' advocacy for an effective public health and health care response to climate change. This article assumes that physician climate advocacy is ethical and celebrates the many forms of health climate advocacy already under way. It concludes by drawing attention to measures that can scale up and strengthen the health care system's organized response to growing climate health hazards. PMID- 29278349 TI - Characteristics of stent thrombosis in bifurcation lesions analysed by optical coherence tomography. AB - AIMS: This work aimed to investigate a cohort of patients presenting with stent thrombosis (ST) explored by optical coherence tomography (OCT) to identify the underlying mechanical abnormalities in case of bifurcation lesions. METHODS AND RESULTS: The PESTO study was a prospective national registry involving 29 French catheterisation facilities. Patients with acute coronary syndromes were prospectively screened for presence of definite ST and analysed by OCT after culprit lesion reopening. The cohort involved 120 subjects, including 21 patients (17.5% of the global PESTO group; median age: 62.6 yrs; 76% male) with bifurcation lesions. The clinical presentation was acute or subacute ST in 34%, late ST in 5% and very late ST in 62% of the patients. The main underlying mechanisms were strut malapposition in 33%, stent underexpansion in 19% and isolated strut uncoverage in 19% of the cases. The proximal main branch was involved in 71%, distal main branch in 52% and jailed side branch in 5% of the patients. CONCLUSIONS: In this cohort, bifurcation lesions represented a limited number of all ST cases. Different sections of the bifurcation could be involved. Although the underlying mechanisms were various, strut malapposition was the most frequently observed cause. PMID- 29278350 TI - Combined use of coils and Onyx for transcatheter closure of coronary artery fistulae. AB - AIMS: The aim of this study was to evaluate the safety and efficacy of combined endovascular coiling and Onyx embolisation in patients with a coronary artery fistula (CAF). METHODS AND RESULTS: Between September 2014 and September 2016, 26 patients with CAFs were enrolled in our study for attempted combined therapy using coils and Onyx. The mean age of patients was 64.0+/-9.5 years (range, 44-78 years). CAFs were large in 10 and medium in 16 patients. The mean number of coils used was 3.1+/-1.2 (range, two to six), and the average volume of Onyx was 0.4+/ 0.1 ml (range, 0.2-0.6 ml). Immediate post-embolisation angiography demonstrated that complete occlusion was achieved in 23 patients (88.5%) and a small residual fistula was achieved in three patients (11.5%). Follow-up imaging (median, 11.5 months; range, nine to 20) revealed stable occlusion of CAF in 21 cases (80.8%), trivial recanalisation in four cases (15.4%), and large recanalisation in only one case (3.8%). Re-closure was performed in the patient with large recanalisation. During the follow-up period, no deaths, severe procedure-related complications, or new symptoms occurred. CONCLUSIONS: In selected patients with CAF, transcatheter embolisation in combined therapy using coils and Onyx appears to be a valid option, providing a high success rate and low rate of recanalisation. PMID- 29278351 TI - Controversies surrounding authorship of manuscripts by industry employees: academic and industry perspectives. AB - The medical device and pharmaceutical industries play an essential role in the development of cardiovascular devices and drugs, and industry employees are frequently listed as co-authors of clinical trials published in peer-reviewed journals. Potential conflicts of interest in biomedical research have attracted significant attention in recent years, but issues and challenges surrounding authors who are industry employees have not received nearly as much scrutiny. We present a comprehensive discussion of the concerns and challenges regarding the role of industry in the authorship of scientific manuscripts. Academic co authors, industry employees, the editors of medical journals, and, most importantly, readers, need to consider the perception and implications that accompany industry employee authorship. Potential concerns include the effect of industry authors (and industry support) on study design, data analysis, interpretations, conclusions, and, ultimately, scientific content. Meaningful contributions from industry employees must be acknowledged and reported in scientific and clinical publications. Efforts to provide full transparency on industry support and the role of industry contributors are necessary to maintain confidence in the reports of studies with industry involvement. PMID- 29278352 TI - Impact of diagnostic ECG-to-wire delay in STEMI patients treated with primary PCI: a DANAMI-3 substudy. AB - AIMS: We aimed to evaluate the impact of delay from diagnostic pre-hospital electrocardiogram (ECG) to wiring of the infarct-related vessel (ECG-to-wire) >120 minutes on cardiovascular magnetic resonance (CMR) markers of reperfusion success and clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: We included 1,492 patients in the analyses of clinical outcome. CMR was performed in 748 patients to evaluate infarct size and myocardial salvage. In total, 304 patients (20%) had ECG-to-wire >120 minutes, which was associated with larger acute infarct size (18% [interquartile range (IQR), 10-28] vs. 15% [8-24]; p=0.022) and smaller myocardial salvage (0.42 [IQR 0.28-0.57] vs. 0.50 [IQR 0.34-0.70]; p=0.002). However, 33% of the patients with ECG-to-wire >120 minutes still had a substantial myocardial salvage >=0.50. In a multivariable analysis, ECG-to-wire >120 minutes was associated with an increased risk of all-cause mortality and heart failure (hazard ratio 1.61, 95% confidence interval [CI] 1.14-2.26, p=0.007). CONCLUSIONS: ECG-to-wire >120 minutes was associated with larger infarct size, smaller myocardial salvage and a poorer clinical outcome in STEMI patients transferred for primary percutaneous coronary intervention. However, myocardial salvage was still substantial in one third of patients treated beyond 120 minutes of delay. PMID- 29278353 TI - Long-term safety of bioresorbable scaffolds: insights from a network meta analysis including 91 trials. AB - AIMS: The aim of this study was to investigate the long-term safety and efficacy of biodegradable scaffolds and metallic stents. METHODS AND RESULTS: We analysed a total of 91 randomised controlled trials with a mean follow-up of 3.7 years in 105,842 patients which compared two or more coronary metallic stents or biodegradable scaffolds and reported the long-term clinical outcomes (>=2 years). Network meta-analysis showed that patients treated with the Absorb bioresorbable vascular scaffold (BVS) had a significantly higher risk of definite or probable scaffold thrombosis (ScT) compared to those treated with metallic DES. The risk of very late ScT was highest with the Absorb BVS among comparators. Pairwise conventional meta-analysis demonstrated that the elevated risk of ScT with Absorb BVS compared to cobalt-chromium everolimus-eluting stents was consistent across the time points of <=30 days (early), 31 days - 1 year (late) and >1 year (very late) ScT. In addition, target lesion failure rates were significantly higher in the Absorb BVS cohort, driven by both increased risk of target vessel myocardial infarction and ischaemia-driven target lesion revascularisation. CONCLUSIONS: Absorb BVS implantation was associated with increased risk of long-term and very late ScT compared to current-generation metallic DES. The risk of ScT occurred with a rising trend beyond one year. PMID- 29278354 TI - Long-term clinical outcomes of a crystalline sirolimus-eluting coronary stent with a fully bioabsorbable polymer coating: five-year outcomes from the DESSOLVE I and II trials. AB - AIMS: The aim of this study was to evaluate the five-year clinical results of a sirolimus-eluting stent (MiStent SES) with a bioabsorbable coating designed for sustained drug delivery during and after rapid polymer dissolution. METHODS AND RESULTS: The five-year results from the DESSOLVE I and II trials including major adverse cardiac events (MACE), target lesion failure (TLF), target vessel failure (TVF), and stent thrombosis (ST) at five-year follow-up are reported. In DESSOLVE I, 10.3% of patients receiving the MiStent SES (3/29) had a MACE event up to five years without TLF. In DESSOLVE II, 15.1% of patients in the MiStent group (18/119) had a five-year MACE event compared to 22.0% of patients in the Endeavor group (p=0.295). TLF was 9.2% in the MiStent group and 8.5% in the Endeavor group (p=1.00). TVF was 10.1% for MiStent versus 15.3% for Endeavor (p=0.331). Up to five-year follow-up, the MiStent SES has continued to demonstrate low rates of TLR across DESSOLVE I (0.0%) and DESSOLVE II (3.4%). No ST was reported with the MiStent up to five years in the DESSOLVE I trial. In DESSOLVE II, definite or probable ST was 0.0% with MiStent and 1.7% with Endeavor up to five years. CONCLUSIONS: The MiStent SES demonstrated long-term safety and effectiveness with low rates of five-year MACE, TLF, and TVF across these two clinical trials. PMID- 29278355 TI - Novel Magnesium Elektron21-AlN Nanocomposites Produced by Ultrasound-Assisted Casting; Microstructure, Thermal and Electrical Conductivity. AB - In the current work, a novel magnesium alloy Elektron21 reinforced by ceramic AlN nanoparticles were produced by an ultrasound-assisted casting. The fabricated nanocomposites were investigated to evaluate their microstructure, hardness, physical, thermal and electrical conductivity. The microstructural evolutions show that a uniform dispersion of the ceramic particles within the matrix can be achieved by employing the ultrasound-assisted stirring. However, some nanoparticles were found to be pushed by the solidification front. According to the Vickers hardness results, the addition of AlN nanoparticles results in a slight improvement of the mechanical properties of the nanocomposites. What is surprising is that both electrical and thermal conductivity of the nanocomposite were improved significantly as a consequence of AlN addition. This improvement in the conductivity characteristics of the nanocomposite is mainly corresponding to the structural effect of nanoparticles within the matrix. PMID- 29278356 TI - Design, Synthesis and Structure-Activity Relationship of Novel Aphicidal Mezzettiaside-Type Oligorhamnosides and Their Analogues. AB - Oligosaccharides have been used for an environmentally friendly insect control in the agricultural industry. In order to discover novel eco-friendly pesticides, a series of partially acetylated oligorhamnoses mezzettiasides, 2-8, and their analogues, 9-14, with biosurfactant characteristics were designed and synthesized, some of which exhibited comparable to or even stronger aphicidal activity than pymetrozine. Preliminary SAR studies demonstrated that the aphicidal activity of mezzettiasides analogs is highly dependent on their structures, including both the sugar length and the substitutes on the sugar. Among them, trirhamnolipid 9 displayed the strongest aphicidal activity, with an LC50 of 0.019 mmol/L, indicating that the biosurfactant 9 may have potential for use as an environmentally friendly agricultural pesticide. PMID- 29278357 TI - Detection of Singlet Oxygen Formation inside Photoactive Biohybrid Composite Material. AB - Photosynthetic reaction center proteins (RCs) are the most efficient light energy converter systems in nature. The first steps of the primary charge separation in photosynthesis take place in these proteins. Due to their unique properties, combining RCs with nano-structures promising applications can be predicted in optoelectronic systems. In the present work RCs purified from Rhodobacter sphaeroides purple bacteria were immobilized on multiwalled carbon nanotubes (CNTs). Carboxyl-and amine-functionalised CNTs were used, so different binding procedures, physical sorption and chemical sorption as well, could be applied as immobilization techniques. Light-induced singlet oxygen production was measured in the prepared photoactive biocomposites in water-based suspension by histidine mediated chemical trapping. Carbon nanotubes were applied under different conditions in order to understand their role in the equilibration of singlet oxygen concentration in the suspension. CNTs acted as effective quenchers of 1O2 either by physical (resonance) energy transfer or by chemical (oxidation) reaction and their efficiency showed dependence on the diffusion distance of 1O2. PMID- 29278358 TI - Characterisation of L-Type Amino Acid Transporter 1 (LAT1) Expression in Human Skeletal Muscle by Immunofluorescent Microscopy. AB - The branch chain amino acid leucine is a potent stimulator of protein synthesis in skeletal muscle. Leucine rapidly enters the cell via the L-Type Amino Acid Transporter 1 (LAT1); however, little is known regarding the localisation and distribution of this transporter in human skeletal muscle. Therefore, we applied immunofluorescence staining approaches to visualise LAT1 in wild type (WT) and LAT1 muscle-specific knockout (mKO) mice, in addition to basal human skeletal muscle samples. LAT1 positive staining was visually greater in WT muscles compared to mKO muscle. In human skeletal muscle, positive LAT1 staining was noted close to the sarcolemmal membrane (dystrophin positive staining), with a greater staining intensity for LAT1 observed in the sarcoplasmic regions of type II fibres (those not stained positively for myosin heavy-chain 1, Type II-25.07 +/- 5.93, Type I-13.71 +/- 1.98, p < 0.01), suggesting a greater abundance of this protein in these fibres. Finally, we observed association with LAT1 and endothelial nitric oxide synthase (eNOS), suggesting LAT1 association close to the microvasculature. This is the first study to visualise the distribution and localisation of LAT1 in human skeletal muscle. As such, this approach provides a validated experimental platform to study the role and regulation of LAT1 in human skeletal muscle in response to various physiological and pathophysiological models. PMID- 29278359 TI - Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death. AB - Sudden cardiac death is defined as an unexpected decease of cardiac origin. In individuals under 35 years old, most of these deaths are due to familial arrhythmogenic syndromes of genetic origin, also known as channelopathies. These familial cardiac syndromes commonly follow an autosomal dominant pattern of inheritance. Diagnosis, however, can be difficult, mainly due to incomplete penetrance and variable expressivity, which are hallmarks in these syndromes. The clinical manifestation of these diseases can range from asymptomatic to syncope but sudden death can sometimes be the first symptom of disease. Early identification of at-risk individuals is crucial to prevent a lethal episode. In this review, we will focus on the genetic basis of channelopathies and the effect of genetic and non-genetic modifiers on their phenotypes. PMID- 29278360 TI - A Concise Review of the Conflicting Roles of Dopamine-1 versus Dopamine-2 Receptors in Wound Healing. AB - Catecholamines play an important regulatory role in cutaneous wound healing. The exact role of dopamine in human epidermis has yet to be fully elucidated. Current published evidence describes its differential effects on two separate families of G protein coupled receptors: D1-like and D2-like dopamine receptors. Dopamine may enhance angiogenesis and wound healing through its action on dopamine D1 receptors, while impairing wound healing when activating D2 receptors. This review summarizes the evidence for the role of dopamine in wound healing and describes potential mechanisms behind its action on D1 versus D2-like receptors in the skin. PMID- 29278361 TI - Enhanced Infrared Image Processing for Impacted Carbon/Glass Fiber-Reinforced Composite Evaluation. AB - In this paper, an infrared pre-processing modality is presented. Different from a signal smoothing modality which only uses a polynomial fitting as the pre processing method, the presented modality instead takes into account the low order derivatives to pre-process the raw thermal data prior to applying the advanced post-processing techniques such as principal component thermography and pulsed phase thermography. Different cases were studied involving several defects in CFRPs and GFRPs for pulsed thermography and vibrothermography. Ultrasonic testing and signal-to-noise ratio analysis are used for the validation of the thermographic results. Finally, a verification that the presented modality can enhance the thermal image performance effectively is provided. PMID- 29278362 TI - Intra- and Intercellular Quality Control Mechanisms of Mitochondria. AB - Mitochondria function to generate ATP and also play important roles in cellular homeostasis, signaling, apoptosis, autophagy, and metabolism. The loss of mitochondrial function results in cell death and various types of diseases. Therefore, quality control of mitochondria via intra- and intercellular pathways is crucial. Intracellular quality control consists of biogenesis, fusion and fission, and degradation of mitochondria in the cell, whereas intercellular quality control involves tunneling nanotubes and extracellular vesicles. In this review, we outline the current knowledge on the intra- and intercellular quality control mechanisms of mitochondria. PMID- 29278363 TI - Comparison Study on the Estimation of the Spatial Distribution of Regional Soil Metal(loid)s Pollution Based on Kriging Interpolation and BP Neural Network. AB - Soil pollution by metal(loid)s resulting from rapid economic development is a major concern. Accurately estimating the spatial distribution of soil metal(loid) pollution has great significance in preventing and controlling soil pollution. In this study, 126 topsoil samples were collected in Kunshan City and the geo accumulation index was selected as a pollution index. We used Kriging interpolation and BP neural network methods to estimate the spatial distribution of arsenic (As) and cadmium (Cd) pollution in the study area. Additionally, we introduced a cross-validation method to measure the errors of the estimation results by the two interpolation methods and discussed the accuracy of the information contained in the estimation results. The conclusions are as follows: data distribution characteristics, spatial variability, and mean square errors (MSE) of the different methods showed large differences. Estimation results from BP neural network models have a higher accuracy, the MSE of As and Cd are 0.0661 and 0.1743, respectively. However, the interpolation results show significant skewed distribution, and spatial autocorrelation is strong. Using Kriging interpolation, the MSE of As and Cd are 0.0804 and 0.2983, respectively. The estimation results have poorer accuracy. Combining the two methods can improve the accuracy of the Kriging interpolation and more comprehensively represent the spatial distribution characteristics of metal(loid)s in regional soil. The study may provide a scientific basis and technical support for the regulation of soil metal(loid) pollution. PMID- 29278364 TI - TNF-alpha and IFN-gamma Together Up-Regulates Par-4 Expression and Induce Apoptosis in Human Neuroblastomas. AB - The objective of this study was to examine the combined effect of Interferon gamma (IFN-gamma) and Tumor Necrosis factor-alpha (TNF-alpha) on cytotoxicity and expression of prostate apoptosis response-4 (Par-4) and Par-4 interacting proteins B-cell lymphoma (Bcl-2), nuclear factor kappa-light-chain-enhancer of activated B cells/p65 subunit (NF-kappaB/p65), Ak mouse strain thymoma (Akt) in human neuroblastoma (NB) cells. Materials and methods included human neuroblastoma cell lines-SK-N-MC, SK-N-SH, and SH-SY5Y, which were treated with IFN-gamma and TNF-alpha individually, or in combination, and were assessed for viability by tetrazolium (MTT) assay. Apoptosis was monitored by hypodiploid population (by flow cytometry), DNA fragmentation, Poly (ADP-ribose) polymerase (PARP) cleavage, and caspase-8 activity. Transcript level of Par-4 was measured by RT-PCR. Protein levels of Par-4 and suppressor of cytokine signaling 3 (SOCS 3) were assessed by immunoblotting. Cellular localization of Par-4 and p65 was examined by immunofluorescence. Unbiased transcript analysis for IFN-gamma, TNF alpha, and Par-4 were analyzed from three independent clinical datasets from neuroblastoma patients. In terms of results, SK-N-MC cells treated with a combination of, but not individually with, IFN-gamma and TNF-alpha induced apoptosis characterized by hypodiploidy, DNA fragmentation, PARP cleavage, and increased caspase-8 activity. Apoptosis was associated with up-regulation of Par 4 mRNA and protein expression. Immunofluorescence studies revealed that Par-4 was localized exclusively in cytoplasm in SK-N-MC cells cultured for 24 h. but showed nuclear localization at 48 h. Treatment with IFN-gamma and TNF-alpha together enhanced the intensity of nuclear Par-4. In gene expression, data from human neuroblastoma patients, levels of IFN-gamma, and TNF-alpha have strong synergy with Par-4 expression and provide good survival advantage. The findings also demonstrated that apoptosis was associated with reduced level of pro-survival proteins-Bcl-2 and Akt and NF-kappaB/p65. Furthermore, the apoptotic effect induced by IFN-gamma-induced Signal Transducer and Activator of Transcription 1(STAT-1), and could be due to down-regulation of suppressor of cytokine signaling-3 (SOCS3). The study concludes that a combinatorial approach using IFN gamma and TNF-alpha can be explored to maximize the effect in chemotherapy in neuroblastoma, and implies a role for Par-4 in the process. PMID- 29278366 TI - Sliding Spotlight Mode Imaging with GF-3 Spaceborne SAR Sensor. AB - Synthetic aperture radar (SAR) sliding spotlight work mode can achieve high resolutions and wide swath (HRWS) simultaneously by steering the radar antenna beam. This paper aims to obtain well focused images using sliding spotlight mode with the Chinese Gaofen-3 SAR sensor. We proposed an integrated imaging scheme with sliding spotlight echoes. In the imaging scheme, the two-step approach is applied to the spaceborne sliding spotlight SAR imaging algorithm, followed by the Doppler parameter estimation algorithm. The azimuth spectral folding phenomenon is overcome by the two-step approach. The results demonstrate a high Doppler parameter estimation accuracy. The proposed imaging process is accurate and highly efficient for sliding spotlight SAR mode. PMID- 29278365 TI - Sexually Dimorphic Outcomes after Neonatal Stroke and Hypoxia-Ischemia. AB - Cohort studies have demonstrated a higher vulnerability in males towards ischemic and/or hypoxic-ischemic injury in infants born near- or full-term. Male sex was also associated with limited brain repair following neonatal stroke and hypoxia ischemia, leading to increased incidence of long-term cognitive deficits compared to females with similar brain injury. As a result, the design of pre-clinical experiments considering sex as an important variable was supported and investigated because neuroprotective strategies to reduce brain injury demonstrated sexual dimorphism. While the mechanisms underlining these differences between boys and girls remain unclear, several biological processes are recognized to play a key role in long-term neurodevelopmental outcomes: gonadal hormones across developmental stages, vulnerability to oxidative stress, modulation of cell death, and regulation of microglial activation. This review summarizes the current evidence for sex differences in neonatal hypoxic-ischemic and/or ischemic brain injury, considering the major pathways known to be involved in cognitive and behavioral deficits associated with damages of the developing brain. PMID- 29278367 TI - Enhancement of the Laser Transmission Weldability between Polyethylene and Polyoxymethylene by Plasma Surface Treatment. AB - Due to their large compatibility difference, polyethylene (PE) and polyoxymethylene (POM) cannot be welded together by laser transmission welding. In this study, PE and POM are pretreated using plasma that significantly enhances their laser transmission welding strength. To understand the mechanism underlying the laser welding strength enhancement, surface modification is analyzed using contact angle measurements, atomic force microscopy (AFM), optical microscopy, and X-ray photoelectron spectroscopy (XPS). Characterization results show that the plasma surface treatment improves the surface free energy, significantly enhancing the wettability of the materials. The increase in surface roughness and the generation of homogeneous bubbles contribute to the formation of mechanical micro-interlocking. The oxygen-containing groups introduced by the oxygen plasma treatment improve the compatibility of PE and POM, and facilitate the diffusion and entanglement of molecular chains and the formation of van der Waals force. PMID- 29278369 TI - Cellular Entry of Binary and Pore-Forming Bacterial Toxins. PMID- 29278368 TI - Structure and Molecular Dynamics Simulations of Protein Tyrosine Phosphatase Non Receptor 12 Provide Insights into the Catalytic Mechanism of the Enzyme. AB - Protein tyrosine phosphatase non-receptor 12 (PTPN12) is an important protein tyrosine phosphatase involved in regulating cell adhesion and migration as well as tumorigenesis. Here, we solved a crystal structure of the native PTPN12 catalytic domain with the catalytic cysteine (residue 231) in dual conformation (phosphorylated and unphosphorylated). Combined with molecular dynamics simulation data, we concluded that those two conformations represent different states of the protein which are realized during the dephosphorylation reaction. Together with docking and mutagenesis data, our results provide a molecular basis for understanding the catalytic mechanism of PTPN12 and its role in tumorigenesis. PMID- 29278370 TI - A Component-Based Approach for Securing Indoor Home Care Applications. AB - eHealth systems have adopted recent advances on sensing technologies together with advances in information and communication technologies (ICT) in order to provide people-centered services that improve the quality of life of an increasingly elderly population. As these eHealth services are founded on the acquisition and processing of sensitive data (e.g., personal details, diagnosis, treatments and medical history), any security threat would damage the public's confidence in them. This paper proposes a solution for the design and runtime management of indoor eHealth applications with security requirements. The proposal allows applications definition customized to patient particularities, including the early detection of health deterioration and suitable reaction (events) as well as security needs. At runtime, security support is twofold. A secured component-based platform supervises applications execution and provides events management, whilst the security of the communications among application components is also guaranteed. Additionally, the proposed event management scheme adopts the fog computing paradigm to enable local event related data storage and processing, thus saving communication bandwidth when communicating with the cloud. As a proof of concept, this proposal has been validated through the monitoring of the health status in diabetic patients at a nursing home. PMID- 29278372 TI - Influence of Chromium-Cobalt-Molybdenum Alloy (ASTM F75) on Bone Ingrowth in an Experimental Animal Model. AB - Cr-Co-Mo (ASTM F75) alloy has been used in the medical environment, but its use as a rigid barrier membrane for supporting bone augmentation therapies has not been extensively investigated. In the present study, Cr-Co-Mo membranes of different heights were placed in New Zealand white, male rabbit tibiae to assess the quality and volume of new bone formation, without the use of additional factors. Animals were euthanized at 20, 30, 40, and 60 days. Bone formation was observed in all of the cases, although the tibiae implanted with the standard membranes reached an augmentation of bone volume that agreed with the density values over the timecourse. In all cases, plasmatic exudate was found under the membrane and in contact with the new bone. Histological analysis indicated the presence of a large number of chondroblasts adjacent to the inner membrane surface in the first stages, and osteoblasts and osteocytes were observed under them. The bone formation was appositional. The Cr-Co-Mo alloy provides a scaffold with an adequate microenvironment for vertical bone volume augmentation, and the physical dimensions and disposition of the membrane itself influence the new bone formation. PMID- 29278371 TI - Flavonoids and Phenolic Acids from Oregano: Occurrence, Biological Activity and Health Benefits. AB - Several herb species classified as oregano have been widely used in folk medicine to alleviate inflammation-related diseases, respiratory and digestive disorders, headaches, rheumatism, diabetes and others. These potential health benefits are partially attributed to the phytochemical compounds in oregano such as flavonoids (FL) and phenolic acids (PA). Flavonoids and phenolic acids are among the most abundant and most studied phytochemicals in oregano species. Epidemiological, in vitro and in vivo experiments have related long-term consumption of dietary FL and PA with a decreased risk of incidence of chronic diseases. The aim of this manuscript is to summarize the latest studies on the identification and distribution of flavonoids and phenolic compounds from oregano species and their potential antioxidant, anti-inflammatory and anti-cancer health benefits. PMID- 29278374 TI - Nonvolatile Resistive Switching Memory Utilizing Cobalt Embedded in Gelatin. AB - This study investigates the preparation and electrical properties of Al/cobalt embedded gelatin (CoG)/ indium tin oxide (ITO) resistive switching memories. Co. elements can be uniformly distributed in gelatin without a conventional dispersion procedure, as confirmed through energy dispersive X-ray analyzer and X ray photoelectron spectroscopy observations. With an appropriate Co. concentration, Co. ions can assist the formation of an interfacial AlOx layer and improve the memory properties. High ON/OFF ratio, good retention capability, and good endurance switching cycles are demonstrated with 1 M Co. concentration, in contrast to 0.5 M and 2 M memory devices. This result can be attributed to the suitable thickness of the interfacial AlOx layer, which acts as an oxygen reservoir and stores and releases oxygen during switching. The Co. element in a solution-processed gelatin matrix has high potential for bio-electronic applications. PMID- 29278373 TI - Risk Assessment and Implication of Human Exposure to Road Dust Heavy Metals in Jeddah, Saudi Arabia. AB - Data dealing with the assessment of heavy metal pollution in road dusts in Jeddah, Saudi Arabia and its implication to human health risk of human exposure to heavy metals, are scarce. Road dusts were collected from five different functional areas (traffic areas (TA), parking areas (PA), residential areas (RA), mixed residential commercial areas (MCRA) and suburban areas (SA)) in Jeddah and one in a rural area (RUA) in Hada Al Sham. We aimed to measure the pollution levels of heavy metals and estimate their health risk of human exposure applying risk assessment models described by United States Environmental Protection Agency (USEPA). Using geo-accumulation index (Igeo), the pollution level of heavy metals in urban road dusts was in the following order Cd > As > Pb > Zn > Cu > Ni > Cr > V > Mn > Co > Fe. Urban road dust was found to be moderately to heavily contaminated with As, Pb and Zn, and heavily to extremely contaminated with Cd. Calculation of enrichment factor (EF) revealed that heavy metals in TA had the highest values compared to that of the other functional areas. Cd, As, Pb, Zn and Cu were severely enriched, while Mn, V, Co, Ni and Cr were moderately enriched. Fe was considered as a natural element and consequently excluded. The concentrations of heavy metals in road dusts of functional areas were in the following order: TA > PA > MCRA > SA > RA > RUA. The study revealed that both children and adults in all studied areas having health quotient (HQ) < 1 are at negligible non-carcinogenic risk. The only exception was for children exposed to As in TA. They had an ingestion health quotient (HQing) 1.18 and a health index (HI) 1.19. The most prominent exposure route was ingestion. The cancer risk for children and adults from exposure to Pb, Cd, Co, Ni, and Cr was found to be negligible (<=1 * 10-6). PMID- 29278375 TI - Tribochemical Characterization and Tribocorrosive Behavior of CoCrMo Alloys: A Review. AB - Orthopedic implants first started out as an all-metal hip joint replacement. However, poor design and machinability as well as unsatisfactory surface finish subjected the all-metal joint replacement to being superseded by a polyethylene bearing. Continued improvement in manufacturing techniques together with the reality that polyethylene wear debris can cause hazardous reactions in the human body has brought about the revival of metal-on-metal (MOM) hip joints in recent years. This has also led to a relatively new research area that links tribology and corrosion together. This article aims at reviewing the commonly used tribochemical methods adopted in the analysis of tribocorrosion and putting forward some of the models and environmental factors affecting the tribocorrosive behavior of CoCrMo alloys, a widely-used class of biomaterial for orthopedic implants. PMID- 29278376 TI - Doppler Radar Vital Signs Detection Method Based on Higher Order Cyclostationary. AB - Due to the non-contact nature, using Doppler radar sensors to detect vital signs such as heart and respiration rates of a human subject is getting more and more attention. However, the related detection-method research meets lots of challenges due to electromagnetic interferences, clutter and random motion interferences. In this paper, a novel third-order cyclic cummulant (TOCC) detection method, which is insensitive to Gaussian interference and non-cyclic signals, is proposed to investigate the heart and respiration rate based on continuous wave Doppler radars. The k-th order cyclostationary properties of the radar signal with hidden periodicities and random motions are analyzed. The third order cyclostationary detection theory of the heart and respiration rate is studied. Experimental results show that the third-order cyclostationary approach has better estimation accuracy for detecting the vital signs from the received radar signal under low SNR, strong clutter noise and random motion interferences. PMID- 29278377 TI - Media Screening for Obtaining Haematococcus pluvialis Red Motile Macrozooids Rich in Astaxanthin and Fatty Acids. AB - Astaxanthin from Haematococcus pluvialis is commercially produced in a two-stage process, involving green vegetative (macrozooid) and red aplanospore stages. This approach has been scaled up to an industrial process but constraints limit its commercial success and profitability, including: contamination issues, high pigment extraction costs, requirements for high light levels and photo-bleaching in the red stage. However, in addition to the aplanospore stage, this alga can produce astaxanthin in vegetative palmelloid and motile macrozooid cells. In this study, a two-stage process utilising different media in the green stage, with subsequent re-suspension in medium without nitrate was employed to optimise the formation of red motile macrozooids. Optimal growth in the green phase was obtained on cultivation under mixotrophic conditions in EG:JM media followed by re-suspension in medium without nitrate resulting in red motile macrozooids with an astaxanthin content of 2.74% (78.4% of total carotenoids) and a lipid content of 35.3% (rich in unsaturated fatty acids. It is envisaged that the red motile macrozooids could be harvested and fed as a whole-cell product directly in the animal feed and aquaculture sectors, or used as a blend of carotenoids and polyunsaturated fatty acids (PUFAs) in nutraceutical products. PMID- 29278379 TI - A Comparison Study of Quality Attributes of Ground Beef and Veal Patties and Thermal Inactivation of Escherichia coli O157:H7 after Double Pan-Broiling Under Dynamic Conditions. AB - This study compared the quality variation and thermal inactivation of Escherichia coli O157:H7 in non-intact beef and veal. Coarse ground beef and veal patties (2.1 cm thick, 12.4 cm diameter, 180 g) inoculated with E. coli O157:H7, aerobically stored before double pan-broiling for 0-360 s without rest or to 55, 62.5, 71.1, and 76 degrees C (internal temperature) with 0.5- or 3.5-min rest. Microbial population and qualities including color, cooking losses, pH, water activity, fat, and moisture content, were tested. After cooking the beef and veal patties, the weight losses were 17.83-29%, the pH increased from 5.53-5.60 to 5.74-6.09, the moisture content decreased from 70.53-76.02% to 62.60-67.07%, and the fat content increased (p < 0.05) from 2.19-6.46% to 2.92-9.45%. Cooking beef and veal samples with increasing internal temperatures decreased a* and b* values and increased the L* value. Escherichia coli O157:H7 was more sensitive to heat in veal compared to beef with shorter D-value and "shoulder" time. Cooking to 71.1 and 76 degrees C reduced E. coli O157:H7 by >6 log CFU/g regardless of rest time. Cooking to 55 degrees C and 62.5 degrees C with a 3.5-min rest achieved an additional 1-3 log CFU/g reduction compared to the 0.5-min rest. Results should be useful for developing risk assessment of non-intact beef and veal products. PMID- 29278378 TI - Modelling the Transmission Dynamics and Control of Mumps in Mainland China. AB - Mumps is a common childhood viral disease and children have been vaccinated throughout the world since 1967. The incidence of mumps has increased with more than 300,000 young people infected with mumps annually in mainland China since 2005. Therefore, we designed and analyzed long-term mumps surveillance data in an SVEILR (susceptible-vaccinated-exposed-severely infectious-mildly infectious recovered) dynamic transmission model with optimized parameter values to describe the dynamics of mumps infections in China. There were 18.02% of mumps infected young adults seeking medical advice. The vaccine coverage has been insufficient in China. Young adults with frequent contact and mild infection were identified as a major driver of mumps epidemics. The reproduction number of mumps was determined 4.28 in China. Sensitivity analysis of the basic reproduction number and the endemic equilibrium was conducted to evaluate the effectiveness of mumps control measures. We propose to increase the vaccine coverage and make two doses of MMR (Measles, mumps and rubella) vaccines freely available in China. PMID- 29278380 TI - Research on Ship-Radiated Noise Denoising Using Secondary Variational Mode Decomposition and Correlation Coefficient. AB - As the sound signal of ships obtained by sensors contains other many significant characteristics of ships and called ship-radiated noise (SN), research into a denoising algorithm and its application has obtained great significance. Using the advantage of variational mode decomposition (VMD) combined with the correlation coefficient for denoising, a hybrid secondary denoising algorithm is proposed using secondary VMD combined with a correlation coefficient (CC). First, different kinds of simulation signals are decomposed into several bandwidth limited intrinsic mode functions (IMFs) using VMD, where the decomposition number by VMD is equal to the number by empirical mode decomposition (EMD); then, the CCs between the IMFs and the simulation signal are calculated respectively. The noise IMFs are identified by the CC threshold and the rest of the IMFs are reconstructed in order to realize the first denoising process. Finally, secondary denoising of the simulation signal can be accomplished by repeating the above steps of decomposition, screening and reconstruction. The final denoising result is determined according to the CC threshold. The denoising effect is compared under the different signal-to-noise ratio and the time of decomposition by VMD. Experimental results show the validity of the proposed denoising algorithm using secondary VMD (2VMD) combined with CC compared to EMD denoising, ensemble EMD (EEMD) denoising, VMD denoising and cubic VMD (3VMD) denoising, as well as two denoising algorithms presented recently. The proposed denoising algorithm is applied to feature extraction and classification for SN signals, which can effectively improve the recognition rate of different kinds of ships. PMID- 29278381 TI - Colloidal Synthesis and Thermoelectric Properties of CuFeSe2 Nanocrystals. AB - Copper-based chalcogenides that contain abundant, low-cost and environmentally friendly elements, are excellent materials for numerous energy conversion applications, such as photocatalysis, photovoltaics, photoelectricity and thermoelectrics (TE). Here, we present a high-yield and upscalable colloidal synthesis route for the production of monodisperse ternary I-III-VI2 chalcogenides nanocrystals (NCs), particularly stannite CuFeSe2, with uniform shape and narrow size distributions by using selenium powder as the anion precursor and CuCl2.2H2O and FeCl3 as the cationic precursors. The composition, the state of valence, size and morphology of the CuFeSe2 materials were examined by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), transmission electron microscope (TEM) and high resolution transmission electron microscope (HRTEM), respectively. Furthermore, the TE properties characterization of these dense nanomaterials compacted from monodisperse CuFeSe2 NCs by hot press at 623 K were preliminarily studied after ligand removal by means of hydrazine and hexane solution. The TE performances of the sintered CuFeSe2 pellets were characterized in the temperature range from room temperature to 653 K. Finally, the dimensionless TE figure of merit (ZT) of this Earth-abundant and intrinsic p-type CuFeSe2 NCs is significantly increased to 0.22 at 653 K in this work, which is demonstrated to show a promising TE materialand makes it a possible p-type candidate for medium-temperature TE applications. PMID- 29278382 TI - Selecting Feature Subsets Based on SVM-RFE and the Overlapping Ratio with Applications in Bioinformatics. AB - Feature selection is an important topic in bioinformatics. Defining informative features from complex high dimensional biological data is critical in disease study, drug development, etc. Support vector machine-recursive feature elimination (SVM-RFE) is an efficient feature selection technique that has shown its power in many applications. It ranks the features according to the recursive feature deletion sequence based on SVM. In this study, we propose a method, SVM RFE-OA, which combines the classification accuracy rate and the average overlapping ratio of the samples to determine the number of features to be selected from the feature rank of SVM-RFE. Meanwhile, to measure the feature weights more accurately, we propose a modified SVM-RFE-OA (M-SVM-RFE-OA) algorithm that temporally screens out the samples lying in a heavy overlapping area in each iteration. The experiments on the eight public biological datasets show that the discriminative ability of the feature subset could be measured more accurately by combining the classification accuracy rate with the average overlapping degree of the samples compared with using the classification accuracy rate alone, and shielding the samples in the overlapping area made the calculation of the feature weights more stable and accurate. The methods proposed in this study can also be used with other RFE techniques to define potential biomarkers from big biological data. PMID- 29278383 TI - An FT-Raman, FT-IR, and Quantum Chemical Investigation of Stanozolol and Oxandrolone. AB - We have studied the Fourier Transform Infrared (FT-IR) and the Fourier transform Raman (FT-Raman) spectra of stanozolol and oxandrolone, and we have performed quantum chemical calculations based on the density functional theory (DFT) with a B3LYP/6-31G (d, p) level of theory. The FT-IR and FT-Raman spectra were collected in a solid phase. The consistency between the calculated and experimental FT-IR and FT-Raman data indicates that the B3LYP/6-31G (d, p) can generate reliable geometry and related properties of the title compounds. Selected experimental bands were assigned and characterized on the basis of the scaled theoretical wavenumbers by their total energy distribution. The good agreement between the experimental and theoretical spectra allowed positive assignment of the observed vibrational absorption bands. Finally, the calculation results were applied to simulate the Raman and IR spectra of the title compounds, which show agreement with the observed spectra. PMID- 29278384 TI - Marine Cryptophytes Are Great Sources of EPA and DHA. AB - Microalgae have the ability to synthetize many compounds, some of which have been recognized as a source of functional ingredients for nutraceuticals with positive health effects. One well-known example is the long-chain polyunsaturated fatty acids (PUFAs), which are essential for human nutrition. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the two most important long-chain omega 3 (omega-3) PUFAs involved in human physiology, and both industries are almost exclusively based on microalgae. In addition, algae produce phytosterols that reduce serum cholesterol. Here we determined the growth rates, biomass yields, PUFA and sterol content, and daily gain of eight strains of marine cryptophytes. The maximal growth rates of the cryptophytes varied between 0.34-0.70 divisions day-1, which is relatively good in relation to previously screened algal taxa. The studied cryptophytes were extremely rich in omega-3 PUFAs, especially in EPA and DHA (range 5.8-12.5 and 0.8-6.1 ug mg dry weight-1, respectively), but their sterol concentrations were low. Among the studied strains, Storeatula major was superior in PUFA production, and it also produces all PUFAs, i.e., alpha linolenic acid (ALA), stearidonic acid (SDA), EPA, and DHA, which is rare in phytoplankton in general. We conclude that marine cryptophytes are a good alternative for the ecologically sustainable and profitable production of health promoting lipids. PMID- 29278385 TI - A Survey of Naturally-Occurring Steroid Hormones in Raw Milk and the Associated Health Risks in Tangshan City, Hebei Province, China. AB - In recent years, high levels of hormone residue in food, capable of damaging the health of consumers, have been recorded frequently. In this study, 195 raw milk samples were obtained from Tangshan City, China, and the concentrations of 22 steroid hormones were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Cortisol was detected in 12.5% of raw milk samples (mean 0.61 ug/kg; range: = 1 MUg/L . Beyond this, results by antibody-free isoform-differential MS, as described, were in line with those of the World Anti-Doping Agency-approved antibody-based test for 18 native sera and 3 positive controls. In this context, relating 22 kDa-GH to total-GH rather than 22 kDa+20 kDa was considered as an alternative strategy to earlier approaches. However, 20 kDa-GH as an additional measurand, next to 22 kDa- and total-GH, provides useful extra information, as it directly indicates the presence or absence of a non-22 kDa-GH form. PMID- 29278458 TI - Osteologic analysis of ethnic differences in supernumerary ethmoidal foramina: implications for endoscopic sinus and orbit surgery. AB - BACKGROUND: Knowledge of the position of the ethmoidal arteries is critical to enable safe endoscopic sinus and orbital surgery. The presence of a third or "middle" ethmoid variant has recently become more relevant as endoscopic intraconal surgery continues to advance. The purpose of this study was to quantify the presence of supernumerary (ie, over 2) ethmoid foramina in different ethnicities and genders. METHODS: Morphometric osteologic measurements were performed in 273 orbits. Prevalence of supernumerary ethmoid foramina and orbital length data were obtained from human skulls of Asian (n = 54), Caucasian (n = 70), African (n = 39), Hispanic (n = 49), and Middle Eastern (n = 61) derivation. Correlations between gender, ethnicity, symmetry, orbital floor, and lamina papyracea length were assessed by analysis of variance, paired t test, and chi2 test. RESULTS: Supernumerary foramina were identified in 95 of 273 orbits (34.79%). A significantly higher prevalence was seen in Asian (42.59%), African (41.02%), and Hispanic (41.00%) skulls as compared with Caucasian (25.71%) and Middle Eastern (22.95%) skulls (p < 0.05 for all). The length of the orbital floor was significantly shorter in the Asian (3.35 +/- 1.52 cm) specimens (p < 0.01). Asians were found to have the highest risk of ethmoid artery injury compared with the other ethnic groups (ratio of number of supernumerary foramina to orbital floor length = 0.72). CONCLUSION: Supernumerary ethmoidal foramina were common among all orbits studied. Orbits of Asian and African derivation had significantly greater numbers of ethmoidal foramina, both unilaterally and symmetrically and within a shorter orbital length, suggesting a greater proximity between the ethmoidal vessels. Surgeons should be alert to the possible presence of middle ethmoidal vessels during endoscopic sinus and orbital approaches. PMID- 29278457 TI - First evidence of resistance to pyrethroid insecticides in Italian Aedes albopictus populations 26 years after invasion. AB - BACKGROUND: Aedes albopictus has spread during the last few decades all over the world. This has increased significantly the risk of exotic arbovirus transmission (e.g. chikungunya, dengue, and Zika) also in temperate areas, as demonstrated by the Chikungunya 2007 and 2017 outbreaks in northeastern and central Italy. Insecticides are an important tool for limiting the circulation of these mosquito borne viruses. The aim of the present study was to address the gap in current knowledge of pyrethroid insecticide resistance of European Ae. albopictus populations, focusing on populations from Italy, Albania and Greece. RESULTS: Bioassays for resistance to permethrin (0.75%), alpha-cypermethrin (0.05%) or deltamethrin (0.05%) were performed according to World Health Organization (WHO) protocols and showed reduced susceptibility (<90% mortality) of some Italian populations to permethrin and alpha-cypermethrin, but not to deltamethrin. CONCLUSION: This study reports the first evidence of resistance to pyrethroids in adult Italian Ae. albopictus populations. Results refer to the season preceding the Chikungunya 2017 outbreak in central Italy and highlight the need to increase efforts to monitor the spread of insecticide resistance and the need to develop strategies to limit the spread of insecticide resistance, particularly in areas where extensive treatments have been carried out to contain disease outbreaks. (c) 2017 Society of Chemical Industry. PMID- 29278459 TI - Antiviral Activity of Faramea hyacinthina and Faramea truncata Leaves on Dengue Virus Type-2 and Their Major Compounds. AB - The defatted fractions of the Faramea hyacinthina and F. truncata (Rubiaceae) leaf MeOH extracts showed in vitro non-cytotoxic and anti-dengue virus serotype 2 (DENV2) activity in human hepatocarcinoma cell lineage (HepG2). Submitting these fractions to the developed RP-SPE method allowed isolating the antiviral flavanone (2S)-isosakuranetin-7-O-beta-d-apiofuranosyl-(1->6)-beta-d glucopyranoside (1) from both species and yielded less active sub-fractions. The new diastereoisomeric epimer pair (2S) + (2R) of 5,3',5'-trihydroxyflavanone-7-O beta-d-apiofuranosyl-(1->6)-beta-d-glucopyranoside (2a/2b) from F. hyacinthina; the known narigenin-7-O-beta-d-apiofuranosyl-(1->6)-beta-d-glucopyranoside (3) from both species; rutin (4) and quercetin-4'-beta-d-O-glucopyranosyl-3-O rutinoside (5) from F. hyacinthina, and kaempferol-3-O-rutinoside (6), erythroxyloside A (7) and asperuloside (8) from F. truncata have been isolated from these sub-fractions. Compounds 4 - 8 are reported for the first time in Faramea spp. PMID- 29278460 TI - Relationship between treatment persistence and A1C trends among patients with type 2 diabetes newly initiating basal insulin. AB - This study examines the relationship between glycated haemoglobin (A1C) levels and treatment persistence with, or time to discontinuation of, basal insulin in patients with type 2 diabetes (T2D) newly initiating insulin. Claims data were extracted from the Optum Clinformatics database from January 2010 to June 2015. Adult patients with T2D initiating insulin glargine 100 U/mL (Gla-100) or insulin detemir (DET) with >=1 A1C measurement during 12-month baseline and 18-month follow-up periods were included. Patients with a refill gap of >90 days were considered non-persistent; otherwise, patients were considered persistent with insulin. The main outcome was A1C, measured closest to the end of each quarter during the follow-up period. A total of 3993 of 109 934 patients met the inclusion criteria (43.0% persistent; 57.0% non-persistent). Persistent patients were older (54.7 vs 52.7 years; P < .001), were more likely to be male (59.4% vs 54.4%; P = .002), and had significantly lower mean unadjusted A1C values at 18 months (8.26% vs 8.60%; P < .001) and quarterly. Only 43.0% of adults initiating basal insulin persisted with treatment for 18 months, with earlier discontinuation associated with higher A1C. PMID- 29278461 TI - Implementing The Paris System for Reporting Urinary Cytology results in a decrease in the rate of the "atypical" category and an increase in its prediction of subsequent high-grade urothelial carcinoma. AB - BACKGROUND: In the current study, the authors evaluated the impact of implementing The Paris System for Reporting Urinary Cytology (PSRUC) on the prevalence of various cytological categories and their association with a subsequent diagnosis of high-grade urothelial carcinoma (HGUC). METHODS: A comparative study was conducted over the 6-month period before PSRUC implementation (2013), including 1653 patients and 2371 specimens versus a 6 month period after implementation of the PSRUC (2016), including 1478 patients and 2392 specimens. The following cytological categories were correlated with the subsequent biopsy result when available (355 cases): negative for HGUC (NHGUC), atypical urothelial cells (AUC), suspicious for HGUC, and HGUC. RESULTS: Although 18.6% of specimens were diagnosed as AUC in 2013, the percentage was 14.4% in 2016 (P < .0001). Concurrently, the prevalence of the "benign" category increased from 2013 to 2016 (75.4% vs 80%; P < .0001). After implementation of the PSRUC, there was no significant change noted with regard to the association between the categories of NHGUC, suspicious for HGUC, and HGUC and a subsequent HGUC biopsy diagnosis. However, the predictive value of an AUC diagnosis increased from 28.3% to 46.1% (P = .077). Most important, after the implementation of the PSRUC, there was a significant difference noted with regard to the predictive association for HGUC between the NHGUC and AUC groups (13.6% vs 46.1%; P = .003), a difference that was not found to be statistically significant before implementation of the PSRUC (18% vs 28.3%; P = .175). CONCLUSIONS: There was a much higher risk of HGUC conveyed by AUC cytology after implementation of the PSRUC, justifying more aggressive investigations of patients who receive an AUC diagnosis. Cancer Cytopathol 2018;126:207-14. (c) 2017 American Cancer Society. PMID- 29278462 TI - Characterization of two new HLA-B alleles, HLA-B*07:299 and HLA-B*35:350. AB - Two novel HLA-B alleles, B*07:299 and B*35:350, were characterized by genomic full-length sequencing. PMID- 29278463 TI - A novel HLA-B allele: HLA-B*40:241. AB - The HLA-B*40:241 allele differs from B*40:01:01 by 1 nucleotide substitution at position 691. PMID- 29278464 TI - The sinonasal microbiota, neural signaling, and depression in chronic rhinosinusitis. AB - BACKGROUND: The complex relationships between the human microbiota, the immune system, and the brain play important roles in both health and disease, and have been of increasing interest in the study of chronic inflammatory mucosal conditions. We hypothesized that the sinonasal microbiota may act as a modifier of interkingdom neural signaling and, subsequently, mental health, in the upper respiratory inflammatory condition chronic rhinosinusitis (CRS). In this study we investigated associations between the sinonasal microbiota; local concentrations of the neurotransmitters serotonin, dopamine, and gamma-aminobutyric acid (GABA); and depression severity in a cohort of 14 CRS patients and 12 healthy controls. METHODS: Subject demographics, clinical severity scores, depression index scores, and sinonasal swab and mucus samples were collected at the time of surgery. Bacterial communities were characterized from swabs by 16S rRNA gene-targeted sequencing and quantified by quantitative polymerase chain reaction. Mucus concentrations of the neurotransmitters serotonin, dopamine, and GABA were quantified by enzyme-linked immunosorbent assay. RESULTS: Several commonly "health-associated" sinonasal bacterial taxa were positively associated with higher neurotransmitter concentrations and negatively associated with depression severity. In contrast, several taxa commonly associated with an imbalanced sinonasal microbiota negatively associated with neurotransmitters and positively with depression severity. Few significant differences were identified when comparing between control and CRS subject groups, including neurotransmitter concentrations, depression scores, or sinonasal microbiota composition or abundance. CONCLUSION: The findings obtained lend support to the potential for downstream effects of the sinonasal microbiota on neural signaling and, subsequently, brain function and behavior. PMID- 29278465 TI - [Protective effect of Icariin against TGF-beta1-induced injury of rat Leydig cells]. AB - Objective: To study the effect of Icariin on rat Leydig cells with TGF-beta1 induced injury. METHODS: We determined the optimal concentration of Icariin for protecting primarily cultured Leydig cells against TGF-beta1-induced injury by methyl thiazolyl tetrazolium assay. We detected the effects of Icariin on the secretion of estradiol (E2) and activity of aromatase in the injured Leydig cells by radioimmunoassay and Tritium water release experiment and its effect on the gap junctional intercellular communication (GJIC) between the Leydig cells by fluorescence distribution after photobleaching. RESULTS: Different concentrations of Icariin showed different degrees of protective effect on the TGF-beta1-treated Leydig cells, the effect observed at 20 MUg/ml and at its optimum at 160 MUg/ml. After treatment of the injured Leydig cells with Icariin at 160 MUg/ml, significant improvement was observed in the E2 secretion and aromatase activity (P<0.01) as well as in the GJIC between the Leydig cells (P<0.01). CONCLUSIONS: Icariin can effectively protect rat Leydig cells against TGF-beta1-induced injury, which is largely attributed to its effects of increasing E2 synthesis, enhancing aromatase activity, and improving GJIC between Leydig cells. PMID- 29278466 TI - [Sexual satisfaction and its associated factors among individuals with hearing disability]. AB - Objective: To investigate sexual satisfaction (SS) and the factors associated with decreased SS among individuals with hearing disability. METHODS: We conducted an investigation on SS among 439 individuals (268 males and 171 females, aged >=18 yr) with hearing disability using a general information questionnaire, Center for Epidemiologic Studies Depression Scale, Social Support Rating Scale, and a self-report on SS. We identified the factors of decreased SS by multivariate ordinal logistic regression analysis. RESULTS: Totally 76 (17.3%) of the hearing-disability individuals investigated were dissatisfied with their sexual life. SS reduction was significantly correlated with the status of being single (OR=1.72), grade-1 or -2 disability (OR=1.78), physical diseases (OR=2.46), depression (OR=6.61), or inadequate subjective social support (OR=3.28). CONCLUSIONS: SS of hearing-disability persons is relatively low, which can be improved by treating physical diseases, promoting mental health, and providing psycho-social support. PMID- 29278467 TI - [Shang Ring scissor circumcision versus electrotome circumcision for redundant prepuce]. AB - Objective: To compare the clinical effects of Shang Ring scissor circumcision (SC) and electrotome circumcision (EC) in the treatment of redundant prepuce or phimosis.Methods: Results: Conclusion. METHODS: This retrospective study included 524 patients with redundant prepuce or phimosis, 422 treated by SC and 120 by EC. We made comparisons between the two groups of patients in the operation time, intra- and post-operative pain scores, pain scores before, at and after ring removal, wound healing time, and incidence rates of postoperative edema and incision dehiscence. RESULTS: The operation time was longer in the SC than in the EC group ([59.99+/-5.39] vs [39.94+/-4.94] sec, P<0.05), but there were no significant differences between the two groups in the intraoperative pain scores (1.02+/-0.74 vs 1.08+/-0.59, P>0.05) or the pain scores within 24 h after operation (6.74+/-1.01 vs 6.56+/-1.06, P>0.05), 24 h prior to ring removal (1.14+/-0.69 vs 1.10+/-0.64, P>0.05), and after ring removal (2.73+/-0.74 vs 2.85+/-0.75, P>0.05) except at ring removal, which was remarkably lower in the SC than in the EC group (3.56+/-0.47 vs 4.77+/-0.58, P<0.05). The wound healing time was markedly shorter in the former than in the latter ([14.11+/-1.26] vs [39.78+/ 7.55] d, P<0.05), but the incidence rate of incision dehiscence showed no significant difference between the two groups (4.03% [17/422] vs 9.17% [11/120], P>0.05). The rate of postoperative satisfaction with the external penile appearance was 100% in both of the two groups. CONCLUSIONS: Shang Ring scissor circumcision is preferred to electrotome circumcision for its advantages of less pain at ring removal and shorter healing time despite its longer operation time. PMID- 29278468 TI - [Relationship of abnormal sperm DNA methylation with early spontaneous abortion]. AB - Objective: To investigate the relationship between the abnormal sperm DNA methylation level and early spontaneous abortion. METHODS: We randomly selected 98 males who met the inclusion criteria and whose wives suffered from unexplained abortion or embryo abortion, and included another 46 normal healthy men present for pre-pregnancy check-up as controls. We examined the semen quality and sperm morphology, obtained the sperm DNA fragmentation index (DFI) by modified sperm chromatin dispersion, and measured the sperm DNA methylation level using the methylated DNA quantification kit and the colorimetric method. RESULTS: Compared with the normal controls, the men in the unexplained abortion group showed a significantly lower rate of big-halo sperm ([45.50 +/- 26.27] vs [36.49 +/- 23.06]%, P = 0.038), a higher rate of abnormal-head sperm ([77.08+/- 12.21] vs [81.09+/- 10.89]%, P = 0.049), and a lower level of sperm DNA methylation ([0.47 +/- 0.33] vs [0.36 +/- 0.26] ng/MUl, P = 0.035). The sperm DNA methylation level was positively correlated with the percentage of big-halo sperm (OR=0.546, P<0.01). Multivariate regression analysis manifested that sperm head abnormality was an independent risk factor of early spontaneous abortion or embryo abortion (OR=1.032, P = 0.049), while the high methylation level was protective factor against early spontaneous abortion or embryo abortion (OR=0.244, P = 0.03). CONCLUSIONS: The abnormal level of sperm DNA methylation may be one of the important reasons for early spontaneous abortion or embryo abortion. PMID- 29278469 TI - [Embryonal rhabdomyosarcoma in the male reproductive system: A clinicopathological analysis]. AB - Objective: To investigate the pathological characteristics, diagnosis, and differential diagnosis of embryonal rhabdomyosarcoma (ERMS) in the male reproductive system. METHODS: We obtained the clinicopathological features, immunophenotypes, and electron microscopic findings of 11 male patients with ERMS in the reproductive system from 2000 to 2015, analyzed the data, and reviewed relevant literature. RESULTS: ERMS developed in these patients at a median age of 17 (9-58) years, 3 cases in the testis, 4 in the scrotum, 1 in the epididymis, and 3 in the prostate. ERMS presented no clinical specificity, which made it difficult to be differentiated from inflammatory and other benign lesions. Microscopically, the tumor cells were arranged in a diffuse or fascicular distribution and mainly composed of short spindle-like, round, or irregularly shaped cells with nuclear hyperchromatism, the cytoplasm strongly eosinophilic, with differentiation of the striated muscle. Some of the cells were naively differentiated or tennis racket-shaped and some exhibited vacuolar degeneration in the cytoplasm. The nuclei were round or short spindle-shaped with visible nucleoli and mitoses. Immunohistochemically, the tumor cells were positive for Myogenin (5/6), Desmin (11/11), MyoD1 (8/9), and Myosin (1/2). Electron microscopy revealed early myofibrils in the cytoplasm of the tumor cells. CONCLUSIONS: ERMS is a rare and highly malignant tumor characterized by local invasion and early metastasis and apt to develop in the reproductive system of young males. The diagnosis of the malignancy is mainly based on its histopathological and immunohistochemical manifestations, combined with electron microscopy when necessary. Early surgical resection in combination with radio- and chemotherapy is recommended for its treatment, which could reduce the recurrence of the tumor and improve the survival of the patients. PMID- 29278470 TI - [Association of sperm DNA integrity with seminal plasma oxidative stress and its influence on in vitro fertilization in infertile males]. AB - Objective: To investigate the association of sperm DNA integrity with semen routine parameters and seminal plasma oxidative stress and its influence on in vitro fertilization (IVF) in males with infertility. METHODS: Using sperm chromatin dispersion (SCD), we detected sperm DNA damage in 433 infertile men undergoing IVF. Based on the sperm DNA fragmentation index (DFI), we divided the patients into a low DFI (lt;30%) and a high DFI ( >=30%) group and then compared sperm concentration, the percentage of progressively motile sperm (PMS), the contents of malondialdehyde (MDA) and total antioxidant capacity (TAC) in the seminal plasma, and the rates of fertilization, cleavage and high-quality embryos between the two groups of patients. RESULTS: Compared with the low DFI group, the high DFI group showed significantly decreased rates of PMS ([48.6+/-16.7] vs [29.2+/-16.8]%, P<0.01) and fast PMS [19.0+/-9.1] vs [9.4+/-6.6]%, P<0.01), but no statistically significant difference in sperm concentration ([51.4+/-30.9] vs [52.3+/-32.4] *106/ml, P>0.05). The content of MDA in the seminal plasma was markedly higher in the high DFI than in the low DFI group ([2.28+/-0.26] vs [0.95+/-0.18] nmol/L, P<0.01) but that of TAC remarkably lower in the former than in the latter ([10.2+/-3.5] vs [33.2+/-7.9] U/L, P<0.01). The rate of fertilization was significantly lower in the high DFI than in the low DFI group ([58.9+/-30.0] vs [77.2+/-25.0]%, P<0.01), but there were no significant differences between the two groups in the rates of cleavage ([70.7+/-35.6] vs [80.4+/-15.6]%P>0.05) and high-quality embryos ([40.4+/-31.3] vs [41.7+/ 29.4]%,P>0.05). CONCLUSIONS: Sperm DNA damage is associated with seminal oxidative stress and may affect the outcomes of IVF by reducing the rate of fertilization. PMID- 29278471 TI - [Efficacy and safety of Tonglin Powder in the treatment of benign prostatic hyperplasia]. AB - Objective: To investigate the effect and safety of oral Tonglin Powder in the treatment of benign prostatic hyperplasia (BPH). METHODS: We conducted a randomized controlled study on 100 BPH patients, aged 40-85 years, treated with Tonglin Powder (treatment group, n=50) or terazosin (control group, n=50), all for 3 months. Then we obtained the International Prostate Symptom Score (IPSS), quality of life score (QoL), prostate volume, postvoid residual urine volume (PVR), urine routine indexes, and liver and kidney function indexes from the patients and compared them between the two groups before and after treatment. RESULTS: The baseline data of the patients in the treatment and control groups were as follows, IPSS (22.24+/-7.33) vs (21.40+/-8.24), QoL 4 (2-6) vs 4 (2-6), prostate length 45 (30-65) vs 45 (39-65) mm, prostate width 35 (21-54) vs 36 (26 57) mm, and PVR 10 (5-100) vs 10 (10-100) ml, none with statistically significant difference between the two groups (P>0.05). After treatment, the patients of the treatment group, in comparison with those of the control, showed remarkable decreases in IPSS (11.60+/-6.49 vs 15.38+/-7.34, P=0.008) and QoL (2 [0-5] vs 3 [1-6], P=0.01). No statistically significant differences were observed between the treatment and control groups in prostate length (47 [38-67] vs 47.5 [38-67] mm), prostate width (36 [26-57] vs 36.5 [31-57] mm), and PVR (10 [8-100] vs 10 [8 70] ml) (P>0.05). The Nimodipine method of evaluation showed that the excellence rate of therapeutic effectiveness was significantly higher in the treatment than in the control group (40% vs 8%, P<0.001), and so was the total effectiveness rate (82% vs 64%, P=0.043). CONCLUSIONS: Tonglin Powder can effectively improve the symptoms of BPH, such as difficult urination, and hence the patient's quality of life. PMID- 29278472 TI - [Testicular artery-sparing microscopic varicocelectomy combined with Qilin Pills for bilateral varicocele-induced oligoasthenospermia]. AB - Objective: To explore the clinical effect of testicular artery-sparing microscopic varicocelectomy (MV) in combination with Qilin Pills (QL) in the treatment of bilateral varicocele-induced oligoasthenospermia. METHODS: Sixty patients with bilateral varicocele-induced oligoasthenospermia were randomly assigned to receive MV (n=30) or MV+QL (n=30), those in the latter group treated with oral QL for 12 weeks postoperatively. At 4, 8, and 12 weeks after operation, we compared the semen volume, sperm concentration, sperm motility, the levels of serum Inh B, luteinizing hormone (LH) and total testosterone (TT), and the testosterone secretion index (TSI) between the two groups. RESULTS: After surgery, all the patients showed disappearance of varicocele symptoms, remarkably improved semen volume, sperm concentration, sperm motility, serum Inh B and TT levels, TSI, decreased LH and FSH (P<0.01). At 12 weeks after treatment, statistically significant differences were found between the MV and MV+QL groups in Inh B (138.96+/-22.26 vs 129.54+/-22.23) ng/L, LH (3.17+/-0.12 vs 3.59+/-0.11) IU/L, TT (13.98+/-3.02 vs 12.68+/-3.12) nmol/L, and TSI (4.41+/-0.53 vs 3.53+/ 0.51) nmol/ IU (P<0.05). The pregnancy rate was significantly higher in the MV+QL than in the MV group (73.4% vs 36.6%, P<0.05). CONCLUSIONS: Testicular artery sparing microscopic varicocelectomy combined with Qilin Pills is an effective strategy for the treatment of bilateral varicocele-induced oligoasthenospermia by significantly improving the semen quality of the patient. PMID- 29278473 TI - [International focuses in the studies of chronic pelvic pain syndrome: A social network analysis]. AB - Objective: To analyze the internationally published literature relevant to chronic pelvic pain syndrome (CPPS) using bibliometrics and social network analysis, and investigate the current status and focuses of CPPS studies. METHODS: We identified 692 publications on CPPS by searching PubMed up to December 2015, extracted their subject headings, calculated the frequencies of the headings, and constructed a co-occurrence network of the high-frequency (>=10) subject headings. Then we studied the features and structure of the co occurrence network by analyzing its attributes and topological structure. RESULTS: The density of the constructed co-occurrence network was 0.111, with an average distance of 2.886 and a clustering coefficient of 0.685. Its low density, long average distance and high clustering coefficient indicated that it was a sparse network, with a slow speed of information spreading among nodes but a strong potential coherence, which suggested that the current topics in the study of CPPS were scattered and weakly correlated, with a high possibility of being integrated. Based on the topological structure of the co-occurrence network, the topics in the study of CPPS were divided into six aspects: diagnosis and classification, drug therapy, treatment, etiology, microbiology, psychology, and epidemiology, the more important of which were diagnosis and classification, drug therapy, treatment and etiology. CONCLUSIONS: A system has been formed in the studies of CPPS, focusing on the diagnosis, drug therapy, and etiology of the disease. However, the research topics are relatively scattered and frequently repeated. Therefore, more attention should be paid to the macrocosmic guidance and rational coordination of the researches on CPPS. PMID- 29278474 TI - [Safety and effect of transurethral holmium laser enucleation of the prostate versus bipolar transurethral plasmakinetic prostatectomy for benign prostatic hyperplasia: A meta-analysis]. AB - Objective: To evaluate the safety and effect of transurethral holmium laser enucleation of the prostate (HoLEP) in comparison with bipolar transurethral plasmakinetic prostatectomy (TUPKP) in the treatment of benign prostatic hyperplasia (BPH). METHODS: We searched the databases of PubMed, SCI, Ovid, The Cochrane Library, CNKI, CBM, VIP, and Wangfang Data for controlled clinical trials about HoLEP versus TUPKP in the treatment of BPH published up to April 2016. The studies were screened according to the inclusion and exclusion criteria, the data extracted, and their quality evaluated by 2 reviewers independently, followed by a meta-analysis using the RevMan 5.3 software. RESULTS: A total of 7 studies were included, involving 2031 cases. In comparison with TUPKP, HoLEP showed significantly longer operation time (WMD = 24.61, 95% CI 11.88, 37.34, P lt; 0.001), shorter hospital stay (WMD =-1.91, 95% CI -3.74, 0.07, P = 0.04), shorter bladder irrigation time (WMD = -21.50, 95% CI -34.95, 8.06, P = 0.002), shorter catheter-indwelling time (WMD = -27.60, 95% CI -48.17, 7.03, P = 0.009), less hemoglobin loss (WMD = - 0.42, 95% CI -0.78, -0.07, P = 0.02); lower postvoid residual urine (PVR) at 3 months (WMD = -3.35, 95% CI 4.46, -2.23, P<0.001) and 6 months after surgery (WMD =-1.11, 95% CI -2.18, 0.05, P = 0.04); higher maximum urinary flow rate (Qmax) (WMD = 0.42, 95% CI 0.04, 0.80, P = 0.03) and fewer urinary tract irritation symptoms (OR =0.58, 95% CI 0.41, 0.81, P = 0.002) at 12 months after surgery. No statistically significant differences were found between the two groups in the volume of resected tissue, serum sodium reduction, urethral stricture, erectile dysfunction, retrograde ejaculation, or transient urinary incontinence (P>0.05), or in the improvement of the quality of life (QoL) at 1, 3 and 12 months, International Prostate Symptom Score (IPSS) at 1, 3, 6 and 12 months, Qmax at 1, 3 and 6 months, or International Index of Erectile Function-5 (IIEF-5) at 6 months after surgery (P>0.05). CONCLUSIONS: HoLEP is preferred to TUPKP in clinical application for its advantages of higher Qmax at 12 months after surgery, lower PVR at 3 and 6 months, higher peri-operative safety, faster recovery, and fewer urinary tract irritation symptoms. However, for the quantity and quality limitations of the included publications, our findings are to be further supported by large-sample, multi-center, and high-quality prospective controlled clinical studies. PMID- 29278475 TI - [The piRNA pathway and spermatogenesis: Advances in studies]. AB - Piwi-interacting RNAs (piRNAs) are a distinct class of small non-coding RNAs specifically expressed in the germline of many species. Studies show that the piRNA pathway influences spermatogenesis by translation regulation, germline stem cell maintenance, RNA degradation and gene defense in addition to inhibition of transposable elements. This review presents an overview of the piRNA pathway focusing on piRNA, PIWI protein and other related proteins and outlines the latest advances in the studies of the piRNA pathway in spermatogenesis. PMID- 29278476 TI - [Androgen receptor gene polymorphisms and male infertility]. AB - The androgen receptor (AR), as a ligand-dependent transcription protein and a member of the steroid receptor superfamily widely present in the body, is involved in the adjustment of the function of androgens and plays an important role in spermatogenesis. Androgens participate in spermatogenesis by binding AR and initiating the expression of the target gene. The polymorphisms of the AR gene may change the structure of AR and affect its avidity of binding androgens, making their downstream target genes unable to transcribe proteins. With the development of DNA sequencing techniques, studies on the association of the polymorphisms of the AR gene with male infertility have become a hot topic. PMID- 29278477 TI - [Microstructural changes of the corpus cavernosum in hypoxia-induced erectile dysfunction]. AB - Hypoxia is an independent risk factor of erectile dysfunction (ED), and the mechanisms of hypoxia causing ED are varied and complicated. Traditional studies related are concentrated on the changes of the corpus cavernosal endothelium and hormone levels in the body but have failed to achieve notable breakthroughs. Recent researches have demonstrated that such alterations in the corpus cavernosal microstructure as decreased corpus cavernosum smooth muscle cells of the contractile phenotype and fibrillation of the corpus cavernosum may be two important factors of hypoxia-induced ED. This review gives a brief introduction of the management of hypoxia-induced ED with the strategies of intervening in the corpus cavernosal microstructural changes, such as gene therapy, stem cell therapy, and induction of cell autophagy. PMID- 29278478 TI - [Astaxanthin in male reproduction: Advances in studies]. AB - Astaxanthin (AST) is a carotenoid with a strong antioxidant activity and has many biological functions, such as anti-inflammation, immune regulation, anti-tumor, anti-oxidation, anti-aging, and anti-apoptosis. Recent studies show that AST can effectively regulate the dynamic balance between oxidation and antioxidants in the male reproductive system, protect sperm mitochondrial function, ameliorate testicular heat stress and reproductive poison damage, promote the occurrence of sperm capacitation and acrosome reaction, regulate reproductive endocrine hormone balance, and act favorably on primary infertility or metabolic syndrome-related infertility. It also helps the treatment of late-onset hypogonadism and prostate health care. This review updates the studies of AST in male reproductive health and provides some new ideas for the prevention and treatment of male reproductive problems. PMID- 29278480 TI - Retraction: Sun L. et al. Porosity Defect Remodeling and Tensile Analysis of Cast Steel. Materials 2016, 9, 119, doi:10.3390/ma9020119 PMID- 29278481 TI - Notice of Retraction: Interventions That Affect Gastrointestinal Motility in Hospitalized Adult Patients: A Systematic Review and Meta-Analysis of Double Blind Placebo-Controlled Randomized Trials. PMID- 29278479 TI - [Roles of sialic acids in sperm maturation and capacitation and sperm-egg recognition]. AB - Sialic acids are a subset of nine-carbon alpha-keto aldonic acids involved in various biological functions. Sialic acid on the sperm surface is closely related to sperm maturation and capacitation and sperm-egg recognition, which makes sperm negatively charged to avoid accumulation and covers some antigenic determinants there to increase the survival rate of sperm in the female reproductive tract. The loss of sialic acids is an important factor mediating sperm capacitation. Moreover, the sialic acid at the extremity of the protein polymer is involved in signal identification in sperm-egg recognition. Here, we review the current understanding of sialic acids in sperm maturation and capacitation and sperm-egg recognition. PMID- 29278482 TI - Biotemplated Synthesis and Characterization of Mesoporous Nitric Oxide-Releasing Diatomaceous Earth Silica Particles. AB - Diatomaceous earth (DE), a nanoporous silica material composed of fossilized unicellular marine algae, possesses unique mechanical, molecular transport, optical, and photonic properties exploited across an array of biomedical applications. The utility of DE in these applications stands to be enhanced through the incorporation of nitric oxide (NO) technology shown to modulate essential physiological processes. In this work, the preparation and characterization of a biotemplated diatomaceous earth-based nitric oxide delivery scaffold are described for the first time. Three aminosilanes [(3 aminopropyl)triethoxysilane (APTES), N-(6-aminohexyl)aminomethyltriethoxysilane (AHAMTES), and 3-aminopropyldimethylethoxysilane (APDMES)] were evaluated for their ability to maximize NO loading via the covalent attachment of N-acetyl-d penicillamine (NAP) to diatomaceous earth. The use of APTES cross-linker resulted in maximal NAP tethering to the DE surface, and NAP-DE was converted to NO releasing S-nitroso-N-acetyl-penicillamine (SNAP)-DE by nitrosation. The total NO loading of SNAP-DE was determined by chemiluminescence to be 0.0372 +/- 0.00791 MUmol/mg. Retention of diatomaceous earth's unique mesoporous morphology throughout the derivatization was confirmed by scanning electron microscopy. SNAP DE exhibited 92.95% killing efficiency against Gram-positive bacteria Staphylococcus aureus as compared to the control. The WST-8-based cytotoxicity testing showed no negative impact on mouse fibroblast cells, demonstrating the biocompatible potential of SNAP-DE. The development of NO releasing diatomaceous earth presents a unique means of delivering tunable levels of NO to materials across the fields of polymer chemistry, tissue engineering, drug delivery, and wound healing. PMID- 29278483 TI - Semicrystalline Hydrophobically Associated Hydrogels with Integrated High Performances. AB - Hydrophobically associated hydrogels (HA gels) are one of most extensively investigated high strength hydrogels. Semicrystalline HA gels, prepared by micellar copolymerization, show high strength and notable functionalities of self healing and shape-memory. However, the hydrophobic comonomers in these semicrystalline HA gels are usually limited to the long alkyl length monomers (18 alkyl(meth)acrylates). In the present work, N-acryloyl 11-aminoundecanoic acid (A11AUA), consisting of 10 -CH2 groups and a -COOH group at the end of alkyl chain, was used as hydrophobic comonomer to prepare physical A11AUA-based HA gels in the presence of high concentration cetyltrimethylammonium bromide (CTAB) or sodium dodecyl sulfate. Differential scanning calorimetry, wide-angle X-ray scattering, and small-angle X-ray scattering experiments had identified that the A11AUA-based HA gels possessed crystalline domains and clusters of crystalline domains, while lauryl methacrylate (C12M)-based HA gels were amorphous. As a result, A11AUA-based HA gels displayed much better tensile properties than those of C12M-based HA gels. At the optimal condition, the A11AUA-CTAB HA gel demonstrated integrated high performances, including high stiffness (E of 1016 kPa), high strength (sigmaf of 0.75 MPa), high toughness (T of 7540 J/m2), rapid self-recovery (94% recovery after heat treatment at 60 degrees C for 2 min), outstanding shape memory (fully recovered to the permanent shape only 2-14 s), and excellent self-healing properties (as healed at 60 degrees C for 2 h; stress and strain healing efficiency reached to 64% and 85%, respectively). We believe this work provides a new insight for HA gels, which is beneficial to design new hydrogels with integrated high performances, such as high strength, high toughness, large extensibility, and shape-memory and self-healing properties. PMID- 29278484 TI - Flexible and Robust Piezoelectric Polymer Nanocomposites Based Energy Harvesters. AB - Environment friendly, flexible, and robust sensors have attracted considerable research attention due to their potential for a wide range of devices in energy generation and harvesting, sensing, and biomedical applications. In this manuscript, we demonstrate a lead-free, solution processed flexible piezoelectric energy generator based on a nanocomposite film, consisting of MgO nanoparticles of sizes around <50 nm, embedded in poly(vinylidene difluoride) [PVDF] and its copolymer with trifluoroethylene, that is, P(VDF-TrFE) matrix. Piezoelectric, ferroelectric, and leakage current measurements made on samples with various concentrations of MgO nanoparticles revealed a dramatic improvement in these characteristics at 2 wt % MgO with nearly 50% increase in the piezoelectric coefficient as compared to pure P(VDF-TrFE), attributed to the preferred conformation of P(VDF-TrFE) chain, improved crystallinity of the P(VDF-TrFE) matrix, and uniform distribution of nanoparticles. Assessment of the interactions between -OH groups attached to MgO surface and P(VDF-TrFE), carried out using Fourier-transform infrared spectroscopy (FTIR), suggested weak van der Waals forces between -OH groups and P(VDF-TrFE) being responsible for the observed improvement. This flexible nanocomposite device exhibits superior energy harvesting performance with over two-times improvement in the voltage output (2 V) compared to device using P(VDF-TrFE) films alone. Along with superior electrical properties, nanocomposites also exhibit excellent endurance against electrical as well as mechanical fatigue, with piezoelectric coefficient remaining unchanged even after 10 000 bending cycles, supporting their suitability in flexible energy harvesting applications. PMID- 29278485 TI - Unique Features of the Photocatalytic Reduction of H2O and CO2 by New Catalysts Based on the Analogues of CdS, Cd4P2X3 (X = Cl, Br, I). AB - Photochemical reduction of H2O and CO2 has been investigated with a new family of catalysts of the formula Cd4P2X3 (X= Cl, Br, I), obtained by the complete aliovalent substitution of the sulfide ions in CdS by P and X (Cl, Br, I). Unlike CdS, the Cd4P2X3 compounds exhibit hydrogen evolution and CO2 reduction from water even in the absence of a sacrificial agent or a cocatalyst. Use of NixPy as the cocatalyst, enhances hydrogen evolution, reaching 3870 (apparent quantum yield (AQY) = 4.11) and 9258 (AQY = 9.83) MUmol h-1 g-1, respectively, under artificial and natural (sunlight) irradiation, in the case of Cd4P2Br3/NixPy. Electrochemical and spectroscopic studies have been employed to understand the photocatalytic activity of this family of compounds. Unlike most of the semiconductor-based photocatalysts, Cd4P2X3 catalysts reduce CO2 to CO and CH4 in the absence of sacrificial-agent or cocatalyst using water as the electron source. CO, CH4, and H2 have been obtained with these catalysts under artificial as well as sun-light irradiation. First-principles, calculations have been carried out to understand the electronic structure and catalytic features of these new catalysts. PMID- 29278486 TI - Mesh-Embedded Polysulfone/Sulfonated Polysulfone Supported Thin Film Composite Membranes for Forward Osmosis. AB - In this work, mesh-embedded polysulfone (PSU)/sulfonated polysulfone (sPSU) supported thin film composite (TFC) membranes were developed for forward osmosis (FO). The robust mesh integrated in PSU/sPSU sublayer imparts impressive mechanical durability. The blending of hydrophilic sPSU in PSU sublayer affects the hydrophilicity, porosity, pore structure, and pore size of mesh-embedded PSU/sPSU substrates, and the total thickness, cross-linking degree, and roughness of the corresponding TFC-FO membrane active layers. An appropriate incorporation of sPSU not only significantly decreases the structural parameter, S of the mesh embedded substrate to 220 MUm, which is the lowest reported value for fabric backed FO membrane, but also optimizes the permselectivity of the formed active layer. Regarding the osmosis performance, TFC membranes with sPSU modified substrates gain a higher water flux (Jw) while keeping the specific reverse salt flux (Js/Jw) low. The optimal TFC-FO membrane has a Jw of 31.76 LMH with Js/Jw of 0.19 g/L in FO mode when using deionized water feed and 1 M NaCl draw solution. This paper is practical for developing TFC-FO membrane on hydrophilic support membrane materials. PMID- 29278487 TI - Interface Re-Engineering of Li10GeP2S12 Electrolyte and Lithium anode for All Solid-State Lithium Batteries with Ultralong Cycle Life. AB - An ingenious interface re-engineering strategy was applied to in situ prepare a manipulated LiH2PO4 protective layer on the surface of Li anode for circumventing the intrinsic chemical stability issues of Li10GeP2S12 (LGPS) to Li metal, specifically the migration of mixed ionic-electronic reactants to the inner of LGPS, and the kinetically sluggish reactions in the interface. As consequence, the stability of LGPS with Li metal increased substantially and the cycling of symmetric Li/Li cell showed that the polarization voltage could keep relative stable for over 950 h at 0.1 mA cm-2 within +/-0.05 V. The optimized ASSLiB of LiCoO2 (LCO)/LGPS/Li with interface-engineered structure was able to deliver long cycle life and high capacity, i.e., a reversible discharge capacity of 131.1 mAh g-1 at the initial cycle and 113.7 mAh g-1 at the 500th cycle under 0.1 C with a retention of 86.7%. In addition, the factors effected on the interphases formation of the LGPS/Li interface were analyzed, and the mechanism of the stability between LGPS and Li anode with protective layer was further investigated. Moreover, the probable causes of battery degradation were also explored. Above all, this work would give an alternative strategy for the modification of Li anode in high energy density solid-state lithium metal batteries. PMID- 29278488 TI - Self-Reporting Photoluminescent Porous Silicon Microparticles for Drug Delivery. AB - A porous Si (pSi) microparticle-based delivery system is investigated, and the intrinsic luminescence from the particles is employed as a probe to monitor the release of a model protein payload, bovine serum albumin (BSA). The microparticles consist of a core Si skeleton surrounded by a SiO2 shell. Two types of pSi are tested, one with smaller (10 nm) pores and the other with larger (20 nm) pores. The larger pore material yields a higher mass loading of BSA (3 vs 20%). Two different methods are used to load BSA into these nanostructures: the first involves loading by electrostatic physisorption, and the second involves trapping of BSA in the pSi matrix by local precipitation of magnesium silicate. Protein release from the former system is characterized by a burst release, whereas in the latter system, release is controlled by dissolution of the pSi/magnesium silicate matrix. The protein release characteristics are studied under accelerated (0.1 M aqueous KOH, 21 degrees C) and physiologically relevant (phosphate-buffered saline, pH 7.4, 37 degrees C) conditions, and the near infrared photoluminescence signal from the pSi skeleton is monitored as a function of time and correlated with protein release and silicon dissolution. The thickness of the Si core and the SiO2 shell are systematically varied, and it is found that the luminescence signature can be tuned to provide a signal that either scales with protein elution or that changes rapidly near the end of useful life of the delivery system. Although payload release and particle dissolution are not driven by the same mechanism, the correlations between luminescence and payload elution for the various formulations can be used to define design rules for this self-reporting delivery system. PMID- 29278489 TI - Reprogramming the Activatable Peptide Display Function of Adeno-Associated Virus Nanoparticles. AB - We harnessed an intrinsic activatable peptide display behavior shared by several parvoviruses, including the adeno-associated virus (AAV), in order to design protein-based nanodevices that can carry out an exogenous functional output in response to stimulus detection. Specifically, we generated truncated viral capsid subunits that, when combined with native capsid components into mosaic capsids, can perform robust activatable peptide display. By modulating the ratio of subunits in the mosaic capsid, properties of the activatable peptide display function can be optimized. Interestingly, the truncated subunits can form homomeric capsids not observed in nature, but at the price of losing the ability to carry out activatable peptide display. Collectively, our results demonstrate the importance of capsid mosaicism when activatable peptide display is desired and help explain why the wild-type AAV capsid exists as a mosaic of different subunits. This proof-of-concept study illustrates a strategy for reprogramming a particular conformational output behavior of AAV in pursuit of the long-term vision of creating stimulus-responsive nanodevices. PMID- 29278490 TI - Application of a Deep Neural Network to Metabolomics Studies and Its Performance in Determining Important Variables. AB - Deep neural networks (DNNs), which are kinds of the machine learning approaches, are powerful tools for analyzing big sets of data derived from biological and environmental systems. However, DNNs are not applicable to metabolomics studies because they have difficulty in identifying contribution factors, e.g., biomarkers, in constructed classification and regression models. In this paper, we describe an improved DNN-based analytical approach that incorporates an importance estimation for each variable using a mean decrease accuracy (MDA) calculation, which is based on a permutation algorithm; this approach is called DNN-MDA. The performance of the DNN-MDA approach was evaluated using a data set of metabolic profiles derived from yellowfin goby that lived in various rivers throughout Japan. Its performance was compared with that of conventional multivariate and machine learning methods, and the DNN-MDA approach was found to have the best classification accuracy (97.8%) among the examined methods. In addition to this, the DNN-MDA approach facilitated the identification of important variables such as trimethylamine N-oxide, inosinic acid, and glycine, which were characteristic metabolites that contributed to the discrimination of the geographical differences between fish caught in the Kanto region and those caught in other regions. As a result, the DNN-MDA approach is a useful and powerful tool for determining the geographical origins of specimens and identifying their biomarkers in metabolomics studies that are conducted in biological and environmental systems. PMID- 29278491 TI - IMTBX and Grppr: Software for Top-Down Proteomics Utilizing Ion Mobility-Mass Spectrometry. AB - Top-down proteomics has emerged as a transformative method for the analysis of protein sequence and post-translational modifications (PTMs). Top-down experiments have historically been performed primarily on ultrahigh resolution mass spectrometers due to the complexity of spectra resulting from fragmentation of intact proteins, but recent advances in coupling ion mobility separations to faster, lower resolution mass analyzers now offer a viable alternative. However, software capable of interpreting the highly complex two-dimensional spectra that result from coupling ion mobility separation to top-down experiments is currently lacking. In this manuscript we present a software suite consisting of two programs, IMTBX ("IM Toolbox") and Grppr ("Grouper"), that enable fully automated processing of such data. We demonstrate the capabilities of this software suite by examining a series of intact proteins on a Waters Synapt G2 ion-mobility equipped mass spectrometer and compare the results to the manual and semiautomated data analysis procedures we have used previously. PMID- 29278492 TI - Effect of Redox "Non-Innocent" Linker on the Catalytic Activity of Copper Catecholate-Decorated Metal-Organic Frameworks. AB - Two new UiO-68 type of Zr-MOFs featuring redox non-innocent catechol-based linkers of different redox activities have been synthesized through a de novo mixed-linker strategy. Metalation of the MOFs with Cu(II) precursors triggers the reduction of Cu(II) by the phenyl-catechol groups to Cu(I) with the concomitant formation of semiquinone radicals as evidenced by EPR and XPS characterization. The MOF-supported catalysts are selective toward the allylic oxidation of cyclohexene and it is found that the presence of in situ-generated Cu(I) species exhibits enhanced catalytic activity as compared to a similar MOF with Cu(II) metalated naphthalenyl-dihydroxy groups. This work unveils the importance of metal-support redox interactions in the catalytic activity of MOF-supported catalysts which are not easily accessible in traditional metal oxide supports. PMID- 29278493 TI - Crystal Structure Evolution and Notable Thermal Expansion in Hybrid Perovskites Formamidinium Tin Iodide and Formamidinium Lead Bromide. AB - The temperature-dependent structure evolution of the hybrid halide perovskite compounds, formamidinium tin iodide (FASnI3, FA+ = CH[NH2]2+) and formamidinium lead bromide (FAPbBr3), has been monitored using high-resolution synchrotron X ray powder diffraction between 300 and 100 K. The data are consistent with a transition from cubic Pm3m (No. 221) to tetragonal P4/mbm (No. 127) for both materials upon cooling; this occurs for FAPbBr3 between 275 and 250 K, and for FASnI3 between 250 and 225 K. Upon further cooling, between 150 and 125 K, both materials undergo a transition to an orthorhombic Pnma (No. 62) structure. The transitions are confirmed by calorimetry and dielectric measurements. In the tetragonal regime, the coefficients of volumetric thermal expansion of FASnI3 and FAPbBr3 are among the highest recorded for any extended inorganic crystalline solid, reaching 219 ppm K-1 for FASnI3 at 225 K. Atomic displacement parameters of all atoms for both materials suggest dynamic motion is occurring in the inorganic sublattice due to the flexibility of the inorganic network and dynamic lone pair stereochemical activity on the B-site. Unusual pseudocubic behavior is displayed in the tetragonal phase of the FAPbBr3, similar to that previously observed in FAPbI3. PMID- 29278494 TI - Synthesis of Allylic Alcohols via Cu-Catalyzed Hydrocarbonylative Coupling of Alkynes with Alkyl Halides. AB - We have developed a modular procedure to synthesize allylic alcohols from tertiary, secondary, and primary alkyl halides and alkynes via a Cu-catalyzed hydrocarbonylative coupling and 1,2-reduction tandem sequence. The use of tertiary alkyl halides as electrophiles was found to enable the synthesis of various allylic alcohols bearing alpha-quaternary carbon centers in good yield with high 1,2-reduction selectivity. Mechanistic studies that suggested a different pathway was operative with tertiary alkyl halides compared with primary and secondary alkyl halides for generating the key copper(III) oxidative adduct. For tertiary electrophiles, an acyl halide likely forms via radical atom transfer carbonylation. The preference for 1,2-reduction over 1,4-reduction of alpha,beta unsaturated ketones bearing tertiary substituents was rationalized using density functional theory transition state analysis. On the basis of this computational model, the coupling method was extended to primary and secondary alkyl iodide electrophiles by using internal alkynes with aryl substituents, providing trisubstituted allylic alcohols in high yield with good regioselectivity. PMID- 29278495 TI - Comparative Metabolomic Analyses of Ipomoea lacunosa Biotypes with Contrasting Glyphosate Tolerance Captures Herbicide-Induced Differential Perturbations in Cellular Physiology. AB - Glyphosate-tolerant Ipomoea lacunosa is emerging as a problematic weed in the southeastern United States. Metabolomic profiling was conducted to examine the innate physiology and the glyphosate induced perturbations in two biotypes of I. lacunosa (WAS and QUI) that had contrasting glyphosate tolerance. Compared to the less tolerant QUI-biotype, the innate metabolism of the more tolerant WAS-biotype was characterized by a higher abundance of amino acids, and pyruvate; whereas the sugar profile of the QUI biotype was dominated by the transport sugar sucrose. Glyphosate application (80 g ae/ha) caused similar shikimate accumulation in both biotypes. Compared to QUI, in WAS, the content of aromatic amino acids was less affected by glyphosate treatment, and the content of Ala, Val, Ile, and Pro increased. However, the total sugars decreased by ~75% in WAS, compared to ~50% decrease in QUI. The innate, higher proportional abundance, of the transport sugar sucrose in QUI coud partly explain the higher translocation and greater sensitivity of this biotype to glyphosate. The decrease in sugars, accompanied by an increase in amino acids could delay feedback regulation of upstream enzymes of the shikimate acid pathway in WAS, which could contribute to a greater glyphosate tolerance. Our study, through a metabolomics approach, provides complementary data that elucidates the cellular physiology of herbicide tolerance in Ipomoea lacunosa biotypes. PMID- 29278496 TI - Substrate Sorting by a Supercharged Nanoreactor. AB - Compartmentalization of proteases enables spatially and temporally controlled protein degradation in cells. Here we show that an engineered lumazine synthase protein cage, which possesses a negatively supercharged lumen, can exploit electrostatic effects to sort substrates for an encapsulated protease. This proteasome-like nanoreactor preferentially cleaves positively charged polypeptides over both anionic and zwitterionic substrates, inverting the inherent substrate specificity of the guest enzyme approximately 480 fold. Our results suggest that supercharged nanochambers could provide a simple and potentially general means of conferring substrate specificity to diverse encapsulated catalysts. PMID- 29278497 TI - Modular Protein Cages for Size-Selective RNA Packaging in Vivo. AB - Protein cages have recently emerged as an important platform for nanotechnology development. Of the naturally existing protein cages, viruses are among the most efficient nanomachines, overcoming various barriers to achieve component replication and efficient self-assembly in complex biological milieu. We have designed an artificial system that can carry out the most basic steps of viral particle assembly in vivo. Our strategy is based on patchwork capsids formed from Aquifex aeolicus lumazine synthase and a circularly permuted variant with appended cationic peptides. These two-component protein containers self-assemble in vivo, capturing endogenous RNA molecules in a size-selective manner. By varying the number and design of the RNA-binding peptides displayed on the lumenal surface, the length of guest RNA can be further controlled. Using a fluorescent aptamer, we also show that short-lived RNA species are captured by the protein cage. This platform has potential as a model system for investigating virus assembly, as well as developing RNA regulation or sampling tools to augment biotechnology. PMID- 29278498 TI - Charge Disproportionation in Sr0.5Bi0.5FeO3 Containing Unusually High Valence Fe3.5. AB - A Sr analogue of Ca0.5Bi0.5FeO3, Sr0.5Bi0.5FeO3, containing unusually high valence Fe3.5+ ions was synthesized by using a high-pressure technique. It relieves the electronic instability due to the unusually high valence of Fe3.5+ by a single charge disproportionation (CD) transition (Fe3.5+ -> 0.75Fe3+ + 0.25Fe5+) rather than the successive CD and intermetallic charge transfer (CT) transitions seen in Ca0.5Bi0.5FeO3. Conduction-band narrowing due to the significant bend in the Fe-O-Fe bond in the rhombohedral R3c crystal structure stabilized the charge-disproportionated state at low temperatures. Most importantly, Bi3+ ions in Sr0.5Bi0.5FeO3 do not act as countercations accepting oxygen holes as they do in Ca0.5Bi0.5FeO3, resulting in the absence of the intermetallic CT transition. The large cavity of the A-site Sr ions prevents the charge-transferred Bi5+ from being stabilized. In the charge-disproportionated state the nearest-neighbor Fe3+ spins align antiferromagnetically and one-fourth of the Fe3+ spins are randomly replaced by Fe5+ spins coupled ferromagnetically with the neighboring Fe3+ spins. PMID- 29278499 TI - BIM Binding Remotely Regulates BAX Activation: Insights from the Free Energy Landscapes. AB - Activation of the pro-apoptotic BAX protein, a BCL-2 family member, is known to trigger apoptosis by forming pores in the mitochondrial outer membrane (MOM). While in the cytosol, release of its transmembrane C-terminal helix (called alpha9 helix) from a well-characterized binding pocket (BC groove) and subsequent permeabilization of the MOM are understood to be the initiating events of the activation. Concerning what initiates BAX activation, so far one plausible suggestion has been that the transient attachment of BH3-only peptide at a distal site from the BC groove triggers the activation process. Yet how this pivotal step displaces alpha9 from the BC groove has remained poorly understood. Using a combination of standard molecular dynamics and enhanced sampling methods, the energy landscape of BIM (BH3-only peptide) induced BAX activation has been computed, and the molecular origin of those events is hereby reported in atomistic detail. The simulated transition pathway of alpha9 release reveals that BIM subdues the energetic cost of the process by reducing the activation energy barrier to some extent but mostly by minimizing the free energy difference between the active (alpha9-released) and inactive (alpha9-bound) states. Interestingly, the flexibility of the alpha9 helix itself plays a decisive role in this mechanism. The impact of BIM encounter at the distal site is found to propagate to the alpha9 (BC groove bound) mostly through conserved pathways of residue level interactions. Overall, the thermodynamic basis of the "hit-and-run" mechanism for activation of the BCL-2 family is presented reconciling the available biochemical observations. PMID- 29278500 TI - Coordination-Driven Self-Assembly of Ruthenium Polypyridyl Nodes Resulting in Emergent Photophysical and Electrochemical Properties. AB - Ruthenium polypyridyl complexes are among the most studied molecular species for photochemical applications such as light-harvesting and photocatalysis, with [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) serving as an iconic example. We report the use of the [Ru(bpy)2]2+ fragment as a 90 degrees acceptor tecton (M) in coordination-driven self-assembly to synthesize a M4L4 metallacycle (L = 4,4' bipyridine) and a M6L4 truncated tetrahedral cage [L = 2,4,6-tris(4-pyridyl) 1,3,5-triazine]. The M6L4 cage possesses emergent properties attributed to its unique electronic structure, which results in increased visible-light absorption and an emission band that decays biexponentially with times of 3 and 790 ns. The presence of multiple ruthenium centers in the cage results in multiple RuIII/II reduction events, with a cathodic shift of the first reduction relative to that of [Ru(bpy)3]Cl2 (0.56 V vs 1.05 V). The ligand-centered reduction shifts anodically (-1.29 vs -1.64 V) versus the first bpy reduction observed in the parent [Ru(bpy)3]Cl2. The photophysical properties are explained by the existence of two localized charge-transfer states in the cage molecule: one that draws upon the bipyridine pi* orbitals and the other upon the 2,4,6-tris(4-pyridyl)-1,3,5 triazine pi* orbitals. PMID- 29278501 TI - Quaternary Chalcogenide-Based Misfit Nanotubes LnS(Se)-TaS(Se)2 (Ln = La, Ce, Nd, and Ho): Synthesis and Atomic Structural Studies. AB - We have synthesized quaternary chalcogenide-based misfit nanotubes LnS(Se) TaS2(Se) (Ln = La, Ce, Nd, and Ho). None of the compounds described here were reported in the literature as a bulk compound. The characterization of these nanotubes, at the atomic level, has been developed via different transmission electron microscopy techniques, including high-resolution scanning transmission electron microscopy, electron diffraction, and electron energy-loss spectroscopy. In particular, quantification at sub-nanometer scale was achieved by acquiring high-quality electron energy-loss spectra at high energy (~between 1000 and 2500 eV). Remarkably, the sulfur was found to reside primarily in the distorted rocksalt LnS lattice, while the Se is associated with the hexagonal TaSe2 site. Consequently, these quaternary misfit layered compounds in the form of nanostructures possess a double superstructure of La/Ta and S/Se with the same periodicity. In addition, the interlayer spacing between the layers and the interatomic distances within the layer vary systematically in the nanotubes, showing clear reduction when going from the lightest (La atom) to the heaviest (Ho) atom. Amorphous layers, of different nature, were observed at the surface of the nanotubes. For La-based NTs, the thin external amorphous layer (inferior to 10 nm) can be ascribed to a Se deficiency. Contrarily, for Ho-based NTs, the thick amorphous layer (between 10 and 20 nm) is clearly ascribed to oxidation. All of these findings helped us to understand the atomic structure of these new compounds and nanotubes thereof. PMID- 29278502 TI - Interligand Charge Transfer in a Complex of Deprotonated cis-Indigo Dianions and Tin(II) Phthalocyanine Radical Anions with Cp*IrIII. AB - A diamagnetic complex, {(cis-indigo-N,N)2-(Cp*IrIII)} (1), in which deprotonated cis-indigo dianions coordinate an iridium center through two nitrogen atoms was obtained. By employment of the ability of the iridium center in 1 to coordinate an additional ligand, the complex [(Bu4N+)2{[SnII(Pc*3-)](cis-indigo-N,N)2 Cp*IrIII}*-2.0.5(H2Indigo).2.5C6H4Cl2 (2), which has two functional ligands coordinating an IrIII center, was obtained. This complex has a magnetic moment of 1.71 MUB at 300 K, in accordance with an S = 1/2 spin state. The spin density is mainly delocalized over the Pc*3- macrocycle and partially on (cis-indigo-N,N)2-. Due to an effective pi-pi interaction, a thermally activated charge transfer from [SnII(Pc*3-)]*- to (cis-indigo-N,N)2- is observed, with an estimated Gibbs energy (-DeltaG degrees ) of 9.27 +/- 0.18 kJ/mol. The deprotonation of indigo associated with the coordination of IrIII by the indigo releases H+ ions, which protonate noncoordinating indigo molecules to produce leuco cis-indigo (H2Indigo). One H2indigo links two (cis-indigo-N,N)2- dianions in 2 to produce strong N-H...O?C and O-H...O?C hydrogen-bonding interactions. PMID- 29278503 TI - Investigation of Strain-Promoted Azide-Alkyne Cycloadditions in Aqueous Solutions by Capillary Electrophoresis. AB - The Cu-free 1,3-dipolar cycloaddition of cyclooctynes and azides is an up-and coming method in bioorganic chemistry and other disciplines. However, broad application is still hampered by major drawbacks such as poor solubility of the reactants in aqueous media and low reaction rates. It is thus of high demand to devise a fast and user-friendly strategy for the optimization of reaction conditions and reagent design. We describe a capillary electrophoresis (CE) study of reaction kinetics in strain-promoted azide-alkyne cycloadditions (SPAAC) using substrates with acidic or basic functionalities. This study reveals that the pH value has a significant effect on reaction rates as a result of changes in the reactants' charge state via protonation or deprotonation, and the concomitant changes of electronic properties. This novel experimental setup also enables the study of even more challenging conditions such as reactions in micelles and we did indeed observe much faster SPAAC reactions in the presence of surfactants. Careful combination of the above-mentioned parameters resulted in the identification of conditions enabling remarkable rate enhancement by a factor of 80. This electrophoretic method may thus serve as a versatile, fast and reliable tool for screening purposes in all research areas applying SPAAC reactions. PMID- 29278504 TI - Porous Gelatin Membrane Obtained from Pickering Emulsions Stabilized by Graphene Oxide. AB - This article presents a novel procedure for preparing porous membranes from water soluble polymers involving the formation of a Pickering emulsion. Gelatin is a biodegradable biopolymer obtained by the partial hydrolysis of collagen. A biopolymer such as gelatin is capable of adsorbing at an oil/water interface, resulting in decreased interfacial energy. Hence, gelatin is widely employed as an alternate for synthetic surfactants to stabilize emulsions in the food industry. However, high-molecular-weight gelatin leads to large emulsion droplets and poor emulsion stability. The amphoteric nature of graphene oxide (GO) nanosheets was helpful in stabilizing the oil/water interface and allows for the preparation of a stable gelatin/GO emulsion. Membranes fabricated using gelatin/GO have a uniformly distributed porous structure. However, prepared membranes are highly hydrosoluble, so the membranes were cross-linked without affecting their morphology. XRD results evidenced that gelatin effectively exfoliated the graphite oxide which is essential to stabilizing the emulsion. Fabricated gelatin/GO membranes possess uniformly distributed pores and are highly stable in aqueous solution. Pure water filtration tests were conducted on the membranes. The permeability results proved that the membranes fabricated by a Pickering emulsion are promising materials for filtration. PMID- 29278505 TI - Chemical Synthesis of Natural Polyubiquitin Chains through Auxiliary-Mediated Ligation of an Expressed Ubiquitin Isomer. AB - An efficient method for the assembly of polyUb chains using auxiliary-modified Ub isomers is reported. This strategy takes advantages of auxiliary-mediated native chemical ligation between the distal Ub C-terminal hydrazide and the auxiliary of proximal Ub. Using removable protecting groups, Lys48-linked and Lys6-linked tri Ub and even a mixed-linkage Lys6, Lys48-linked triUb in multimilligram quantities was made. These results demonstrate that this strategy yields natural polyubiquitin chains of desired length and linkage by using Ub isomer. PMID- 29278506 TI - Core-Shell-Shell Upconversion Nanoparticles with Enhanced Emission for Wireless Optogenetic Inhibition. AB - Recent advances in upconversion technology have enabled optogenetic neural stimulation using remotely applied optical signals, but limited success has been demonstrated for neural inhibition by using this method, primarily due to the much higher optical power and more red-shifted excitation spectrum that are required to work with the appropriate inhibitory opsin proteins. To overcome these limitations, core-shell-shell upconversion nanoparticles (UCNPs) with a hexagonal phase are synthesized to optimize the doping contents of ytterbium ions (Yb3+) and to mitigate Yb-associated concentration quenching. Such UCNPs' emission contains an almost three-fold enhanced peak around 540-570 nm, matching the excitation spectrum of a commonly used inhibitory opsin protein, halorhodopsin. The enhanced UCNPs are utilized as optical transducers to develop a fully implantable upconversion-based device for in vivo tetherless optogenetic inhibition, which is actuated by near-infrared (NIR) light irradiation without any electronics. When the device is implanted into targeted sites deep in the rat brain, the electrical activity of the neurons is reliably inhibited with NIR irradiation and restores to normal level upon switching off the NIR light. The system is further used to perform tetherless unilateral inhibition of the secondary motor cortex in behaving mice, achieving control of their motor functions. This study provides an important and useful supplement to the upconversion-based optogenetic toolset, which is beneficial for both basic and translational neuroscience investigations. PMID- 29278507 TI - Rh(II)-Catalyzed Chemoselective Oxidative Amination and Nucleophilic Trapping of gem-Dimethyl Alkynyl-Tethered Sulfamates. AB - A Rh(II)-catalyzed chemoselective oxidative amination and nucleophilic trapping of gem-dimethyl sulfamates has been presented. For 2,2-dimethyl-4-arylbut-3-yn-1 yl sulfamates, the reactions underwent a metallonitrene-initiated alkyne oxidation along with nucleophilic trapping of H2O upon oxidation, giving aroyl group containing heterocycles. For 2,2-dimethyl-4-arylpent-3-yn-1-yl sulfamates, the alpha-iminometal carbene intermediate was trapped by aryl group migration, delivering a styryl group containing heterocycles. PMID- 29278508 TI - Are Keggin's POMs Charged Nanocolloids or Multicharged Anions? AB - Owing to their multiple charges and their nanometric size, polyoxometalates (POMs) are at the frontier between ions and charged colloids. We investigated here the effect of POM-POM electrostatics repulsions on their self-diffusion in water by varying POM and supporting salt concentrations. The self-diffusion coefficients of two Keggin's POMs [silicotungstate (SiW12O404-) and phosphotungstate (PW12O403-)] were determined by dynamic light scattering (DLS) and 1H/31P DOSY NMR, whereas POM-POM electrostatic repulsions were investigated by the determination of the static structure factors using small-angle X-ray scattering (SAXS). The self-diffusion coefficients for the two POMs and for different POM/background salt concentrations were collected in a master curve by comparing the averaged POM-POM distance in solution to the Debye length. As for classical charged colloids, we show that the POM's counterions should not be considered in the calculation of the ionic strength that governs POM-POM electrostatic repulsions. This result was confirmed by fitting the POM-POM structure factor by considering a pair potential of spherical charged particles using the well-known Hayter mean spherical approximation (MSA). These Keggin POMs also behave as (super)chaotropic anions (i.e., they have a strong propensity to adsorb on (neutral polar) surfaces, which was also investigated) here on the surface of octyl-beta-glucoside (C8G1) micelles. The variations of (i) the chemical shift of 1H/31P NMR signals and (ii) the self-diffusion coefficients obtained by DOSY 1H/31P NMR of PW3- and of C8G1 were in good agreement, confirming the strong adsorption of POMs on the micelle polar surface from static and dynamic points of view. We concluded that Keggin's POMs behave (i) as anions because they adsorb on surfaces as chaotropic anions and (ii) as colloids because they can be described by a classical colloidal approach by dynamic and static scattering techniques (i.e., by the investigation of their interparticle electrostatic structure factor and self-diffusion without considering the POM's counterions in the ionic strength calculation). This work highlights the dynamic properties of POMs at soft interfaces compared to bulk aqueous solution, which is essential in the understanding of functional properties of POMs, such as (photo)catalysis and the rational design of POM-based hybrid nanomaterials from soft templating routes (i.e., in aqueous solutions at room temperature). PMID- 29278509 TI - Gut microbiota and obesity: implications for fecal microbiota transplantation therapy. AB - Obesity is a major public health issue as it is causally associated with several chronic disorders, including type-2 diabetes, cerebrovascular disease (CVD), and cancer. In the United States and other countries worldwide, the obesity epidemic has drastically impacted the status of health of millions as well as healthcare costs. Aside from poor diet, hygiene, and genetics, there are many other factors thought to play an important role in the emergence of obesity. Nowadays, accumulating evidence is elucidating the relation of dysbiosis of intestinal bacteria with obesity and metabolic disorders. Certain gut microbial strains have been shown to inhibit or attenuate immune responses related to chronic inflammation in experimental models, suggesting that specific species among gut microbiota may play either a protective or a pathogenic role in the progression of obesity. Fecal microbiota transplantation (FMT) can therefore represent a therapeutic approach for obesity treatment. FMT is a relatively straightforward therapy that manipulates the human gastrointestinal (GI) microbiota by transferring healthy donor microbiota into an existing but disturbed microbial ecosystem. However, the relevant scientific work is still in its early stages. In this review, we summarize the cutting-edge research being done into FMT treatment of obesity, current issues in FMT treatment, and the future of FMT and microbial therapeutics. PMID- 29278510 TI - Regulation of basal metabolic rate in uncomplicated pregnancy and in gestational diabetes mellitus. AB - Basal metabolic rate (BMR) is one of the major components of total energy expenditure (TEE). It is affected by various factors, such as body weight, body composition, age, race/ethnicity, gender, biochemical parameters, physical activity, and health status. Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy and it increases the risk for health complications, such as stillbirth, diabetes mellitus, and cardiovascular disease in later life. Both BMR and GDM have been linked with gestational weight gain (GWG), a fact suggesting a possible association between them. However, assessing BMR is a complex procedure, which becomes more complicated when additional parameters, such as pregnancy and GDM, are taken into consideration. The present review summarizes the current knowledge on factors affecting BMR and its regulation in relation to pregnancy and GDM. Future research addressing these associations should thoroughly consider other factors that affect BMI when designing such studies and/or discussing the BMR outcome results. PMID- 29278511 TI - The adrenal gland microenvironment in health, disease and during regeneration. AB - The adrenal gland is a key component of the stress system in the human body. Multiple direct and paracrine interactions between different cell types and their progenitors take place within the adrenal gland microenvironment. These unique interactions are supported by high vascularization and the adrenal cortex extracellular matrix. Alterations in the adrenal gland microenvironment are known to influence the progression of several pathological conditions, such as obesity and sepsis, and to be influenced by these disorders. For example, it has been suggested that activation of immune-adrenal crosstalk during sepsis induces elevated adrenal glucocorticoid levels, whereas crosstalk between adrenocortical cells and sonic hedgehog responsive stem cells was found to contribute to the increased size of the adrenal cortex during obesity. By contrast to sepsis, where activation of adrenal glucocorticoid production has protective effects, chronic exposure to high levels of glucocorticoids induces adverse effects, typically manifested in patients with Cushing syndrome, such as increased body weight, dyslipidemia, glucose intolerance, and hypertension. Therefore, a better understanding of factors involved in the regulation of the adrenal gland microenvironment is crucial. This review highlights bidirectional interactions occurring between the adrenal gland microenvironment and systemic responses during obesity and sepsis. Furthermore, it presents and discusses recent advancements and challenges in attempts to restore or regenerate adrenal gland function, including the use of oxygenated immune-isolating devices. PMID- 29278512 TI - Ketogenic diet and testosterone increase: Is the increased cholesterol intake responsible? To what extent and under what circumstances can there be benefits? PMID- 29278514 TI - Maternal serum placental growth hormone, insulin-like growth factors and their binding proteins at 20 weeks' gestation in pregnancies complicated by gestational diabetes mellitus. AB - OBJECTIVE: To investigate whether maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF binding proteins (IGFBP) 1 and 3 were altered in pregnancies complicated by gestational diabetes mellitus (GDM). METHOD: In a nested case-control study, GDM cases (n=28) and matched controls (n=28) were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Maternal serum hormone concentrations at 20 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no significant difference in maternal serum GH-V concentration in the GDM group compared to the control group (1.64 +/- 0.11 ng/ml vs. 1.38 +/- 0.10 ng/ml, p=0.079). However, GDM cases who delivered large for gestational age (LGA) babies had significantly higher serum GH-V concentrations compared to non-diabetic control cases. Maternal IGF-1 concentrations in GDM pregnancies were significantly higher than in controls (275.7 +/- 11.5 ng/ml vs. 218.5 +/- 11.1 ng/ml, p <0.001). Maternal IGFBP-1 concentrations were significantly lower in GDM pregnancies than in controls (41.04 +/- 3.42 ng/ml vs. 67.58 +/- 6.17 ng/ml, p <0.001). There were no significant differences in serum IGF-2 and IGFBP-3 concentrations between groups. CONCLUSION: Concentrations of IGF-1 and IGFBP-1 in maternal serum were altered in GDM pregnancies compared to controls, suggesting that the IGF axis plays a role in the development of this condition. GH-V may be associated with macrosomia as increased maternal GH-V was observed in GDM cases who delivered LGA babies. PMID- 29278513 TI - Adiponectin levels may help assess the clinical repercussions of obesity irrespective of body mass index. AB - OBJECTIVE: Adiponectin is the major product of adipose tissue. The aim of this study was to associate adiponectin levels with adipose tissue and metabolic indices. DESIGN: Plasma samples of 274 non-diabetic volunteers were collected to evaluate for adiponectin, inflammatory markers, insulin and lipid parameters. Body fat composition was measured by DEXA. RESULTS: As expected, adiponectin levels correlated with body mass index (BMI) and gender but a wide scattering was evident. When the population was divided into two groups per median levels of adiponectin (11.94 MUg/mL), adiponectin was correlated with various metabolic indices. Persons displaying relatively high adiponectin levels [17.7(CI:14.8 21.0]MUg/mL; MEDIAN (25%-75%)] exhibited lower levels of inflammatory markers (hs CRP, plasminogen, erythrocyte sedimentation rate), circulating lipids and markers of insulin sensitivity (fasting blood glucose, insulin, HbA1c and HOMA-IR) compared to those individuals displaying low-adiponectin levels [8.9(CI:6.9 10.6)MUg/mL]. The percentage of high-adiponectin individuals decreased from 69.6% in the normal-BMI group to 36.5% in the obese-BMI group. Average adiponectin levels in the high-adiponectin normal-BMI group were significantly higher compared to the high-adiponectin obese-BMI group (p=0.014). Regarding body fat, only the individuals with high adiponectin levels in either the combined population or within the obese-BMI group displayed low levels of waist-to-hip ratio. Interestingly, high-adiponectin levels within the obese-BMI group were associated with higher legs fat than trunk fat as compared to the low-adiponectin obese-BMI group. CONCLUSIONS: Our data suggest that the distribution of adiponectin above or below a cutoff level may offer additional clinical information over and above that of BMI grouping regarding inflammatory profile, insulin-sensitivity and adiposity. PMID- 29278515 TI - Pegvisomant-primed growth hormone (GH) stimulation test is useful in identifying true GH deficient children. AB - OBJECTIVE: Provocative stimulation tests for growth hormone (GH) assessment have poor reproducibility and can often elicit false positive results in normal children. The aim of our study was to confirm the capability of pegvisomant as an enhancer of GH secretion in unmasking false-positive results in short children (height <-2.0 standard deviation score, SDS) undergoing GH testing. DESIGN: A prospective study was conducted between March and August 2016. Twenty short children (10 males and 10 females), aged 4.6-13.4 years, previously diagnosed as GH deficient (GHD) were included in the study. All subjects received 1 mg/kg of pegvisomant subcutaneously; three days later an insulin tolerance test (ITT) was performed. Insulin-like growth factor-I (IGF-I) was evaluated before and three days after pegvisomant administration. RESULTS: After pegvisomant priming and the ITT stimulation test, 12 out of the 20 children initially classified as GHD showed a GH peak of more than 10 ng/ml and were thus reclassified as short normal. Furthermore, a significant reduction of IGF-I was observed in the GHD group (pre IGF-I: median (IQR) 144.0 (109-248) ng/ml, post IGF-I: 98 (49-165) ng/ml; p<0.001) after pegvisomant administration. CONCLUSIONS: Pegvisomant priming before GH stimulation tests can be used to improve the reliability of the diagnostic work-up in GH deficiency. PMID- 29278517 TI - An insight into familial hypercholesterolemia in Greece: rationale and design of the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). AB - Familial hypercholesterolemia (FH) is the most common metabolic genetic disorder. It is estimated that around 13 million people worldwide have FH. At the same time, only 25% of FH patients have been diagnosed. Moreover, these patients are often undertreated. The true prevalence of FH in Greece is unknown, but it is estimated that there are at least 40,000 FH patients nationwide pointing to a prevalence of 1:250. Patients with FH are at a high risk for cardiovascular events and death at an early age. Therefore, prompt detection of these patients is of pivotal importance in order to implement appropriate preventive measures at a young age. Patient registries are a powerful tool for recording and monitoring a disease and promoting clinical practices, thus contributing to improved outcomes and reduction of healthcare costs. National registries of FH patients have been a success in the Netherlands, Spain and Wales. As Greece did not have a national FH registry, the Hellenic Atherosclerosis Society has organized, established and funded the Hellenic Familial Hypercholesterolemia (HELLAS-FH) national registry in order to promote a better understanding of FH in our country. PMID- 29278516 TI - Serum fetuin-A levels are associated with serum triglycerides before and 6 months after bariatric surgery. AB - OBJECTIVE: The elucidation of the changes of fetuin-A in the context of bariatric surgery. DESIGN: Twenty obese patients (8 males, 12 females; body mass index = 42.5+/-3.4 kg/m2) were studied at baseline and 6 months after bariatric surgery. RESULTS: Serum fetuin-A levels did not differ with regard to the presence of each individual component of the Metabolic Syndrome (MetS) at baseline, except for hypertriglyceridaemia [increased serum fetuin-A levels (p=0.011)]. Circulating fetuin-A was positively correlated with serum triglycerides (TG) (r=0.461, p=0.047) and negatively correlated with serum globulins (r=-0.477, p=0.033) and C reactive protein (CRP) (r=-0.604, p=0.010), while it independently predicted TG at baseline. Circulating fetuin-A did not change during the 6 months either in the whole population or in the subgroups of patients who were positive for each individual component of MetS at baseline and negative for this component at 6 months of follow-up, except for hypertriglyceridaemia [reduction of serum fetuin A levels (p=0.046)]. The subgroup of patients with a decrease in circulating fetuin-A during the 6 months was characterized by a smaller reduction of serum globulins (p=0.003) and CRP (p=0.049). The change in serum fetuin-A levels over the 6 months was positively correlated with the change in TG (r=0.592, p=0.006) and negatively correlated with the change in serum globulins (r=-0.523, p=0.018) and CRP (r=-.494, p=0.037). CONCLUSIONS: Circulating fetuin-A predicted serum triglycerides before as well as 6 months after bariatric surgery. PMID- 29278518 TI - Identification of an AR mutation in Klinefelter syndrome during evaluation for penoscrotal hypospadias. AB - Genital anomalies, ranging from female genitalia to milder degrees of undervirilization, are rarely reported in Klinefelter syndrome, in which a male is classically expected to be born with male external genitalia. Though androgen insensitivity syndrome (AIS) is one of the possible pathogenic mechanisms also in Klinefelter syndrome with genital anomalies, to date the AR gene has not been analyzed in any of the published cases of Klinefelter syndrome of the milder phenotype, except for those patients presenting with a severe phenotype, such as female external genitalia.Lack of interest in considering androgen insensitivity in Klinefelter syndrome with a milder phenotype of genital anomalies may impede its identification through an accurate diagnosis. We present a 14-month-old boy with penoscrotal hypospadias, micropenis, and a ventral penile chordee abnormality who was observed to have both a 47,XXY karyotype and a known missense mutation in the ARgene that was inherited from his mother. Although it is recommended that Klinefelter syndrome be considered in the differential diagnosis of penoscrotal abnormalities, mutations in specific genes involved in androgen synthesis or responsiveness should also be investigated. PMID- 29278519 TI - GnRH-dependent precocious puberty manifested at the age of 14 months in a girl with 47,XXX karyotype. AB - This case report describes a 47,XXX girl who presented very early, at the age of 14 months, with signs of sexual precocity (breast and pubic hair development, menarche) and was finally diagnosed with GnRH dependent precocious puberty with no evidence of underlying central nervous system pathology. Molecular testing did not identify any genetic defect in any of the genes tested (KISS1, KISS1R, DLK1 and the intronless MKRN3). Though previous studies have shown a link between karyotype 47,XXX and precocious puberty, this is the youngest patient reported so far. Treatment with GnRH analog was commenced and proved to be effective, indicating a successful suppression of the hypothalamic-pituitary-ovarian axis. PMID- 29278520 TI - Malignant struma ovarii harboring a unique NRAS mutation: case report and review of the literature. AB - Struma ovarii (SO), a rare tumor containing at least 50% of thyroid tissue, represents approximately 5% of all ovarian teratomas; its malignant transformation rate is reported to occur in up to 10% of cases and metastases occur in about 5-6% of them. We describe a 36-year old woman who underwent laparoscopic left annessectomy two years earlier because of an ovarian cyst. Follow-up imaging revealed a right adnexal mass, ascitis and peritoneal nodes that were diagnosed as comprising a malignant SO with peritoneal secondary localizations at histopathology performed after intervention. Restaging with 18F FDG-PET/CT scan, abdominal CT and ultrasonography showed abnormalities in the perihepatic region and presacral space and left hypochondrium localizations. The patient underwent thyroidectomy, hepatic nodulectomy and cytoreductive peritonectomy: histopathological examination did not show any malignant disease in the thyroid and confirmed the presence of peritoneal localizations due to malignant SO; molecular analysis detected NRAS Q61K mutation in exon 3, whereas no mutations were identified on the BRAF gene. The patient underwent radioiodine treatment: serum Tg was decreased at first follow-up after three months of 131I therapy. We believe that our case raises some interesting considerations. First, pathologists should be aware of this entity and should check for the presence of point mutations suggesting an aggressive disease behavior, which could be beneficial for an optimal therapeutic approach. Second, although most of the knowledge in this field comes from case reports, efforts should be made to standardize the management of patients affected by malignant SO, including use of practice guidelines. PMID- 29278521 TI - The Pineal Gland and its earliest physiological description. PMID- 29278522 TI - A case of idiopathic granulomatous hypophysitis. PMID- 29278523 TI - Menophila: a poetic description of genital ambiguity in Hellenistic literature. PMID- 29278524 TI - Acceptability and feasibility of the standardized direct observation assessment tool in the emergency department in Qatar. PMID- 29278525 TI - Haptic assessment of bone quality in orthopedic surgery: no consensus but perspective for high training potential. PMID- 29278527 TI - Treatment Patterns Among Women Diagnosed With Stage I-III Triple-negative Breast Cancer. AB - OBJECTIVE: To examine contemporary treatment patterns for women diagnosed with stage I-III triple-negative breast cancer (TNBC) in the United States. METHODS: We identified 48,961 patients diagnosed with stage I-III TNBC from 2010 to 2013 in the National Cancer Data Base and created 3 treatment subcohorts (definitive locoregional therapy [appropriate local therapy, including surgery/radiation], adjuvant chemotherapy [stage II-III disease or stage I tumors with tumor size >=1 cm], and adjuvant chemotherapy for small tumors [stage I tumors with tumor size <1 cm and node negative]). We performed descriptive analyses, calculated percentages for treatment receipt, and used multivariable modified Poisson regression models to estimate risk ratios (RRs) with 95% confidence intervals (CIs) predicting receipt of treatments. RESULTS: Older age, larger tumor size, positive nodal status, and Southern/Pacific US regions, but not race/ethnicity, were strongly associated with a lower probability of receiving definitive locoregional therapy. Older age was also strongly associated with lower likelihood of adjuvant chemotherapy receipt, as were grade, negative nodal status, and higher comorbidity. For example, compared with women aged 18 to 39 years, those aged 75 to 90 years were 17% less likely to receive definitive locoregional therapy (RR, 0.83; 95% CI, 0.73-0.88), and 62% less likely to receive adjuvant chemotherapy (RR, 0.38; 95% CI, 0.35-0.41). Age, tumor grade, tumor size, and comorbidity score were also independently associated with receipt of chemotherapy for women with small TNBC. CONCLUSIONS: Advancing age but not race/ethnicity was associated with lower likelihood of recommended treatment receipt among women with TNBC. Although omission of therapy among older patients with breast cancer may be appropriate in the case of smaller and lower risk TNBC, some were likely undertreated. PMID- 29278526 TI - The effects of flipped learning for bystander cardiopulmonary resuscitation on undergraduate medical students. AB - Objectives: To compare bystander cardiopulmonary resuscitation skills retention between conventional learning and flipped learning for first-year medical students. Methods: A post-test only control group design. A total of 108 participants were randomly assigned to either the conventional learning or flipped learning. The primary outcome measures of time to the first chest compression and the number of total chest compressions during a 2-minute test period 6 month after the training were assessed with the Mann-Whitney U test. Results: Fifty participants (92.6%) in the conventional learning group and 45 participants (83.3%) in the flipped learning group completed the study. There were no statistically significant differences 6 months after the training in the time to the first chest compression of 33.0 seconds (interquartile range, 24.0 42.0) for the conventional learning group and 31.0 seconds (interquartile range, 25.0-41.0) for the flipped learning group (U=1171.0, p=0.73) or in the number of total chest compressions of 101.5 (interquartile range, 90.8-124.0) for the conventional learning group and 104.0 (interquartile range, 91.0-121.0) for the flipped learning group (U=1083.0, p=0.75). The 95% confidence interval of the difference between means of the number of total chest compressions 6 months after the training did not exceed a clinically important difference defined a priori. Conclusions: There were no significant differences between the conventional learning group and the flipped learning group in our main outcomes. Flipped learning might be comparable to conventional learning, and seems a promising approach which requires fewer resources and enables student-centered learning without compromising the acquisition of CPR skills. PMID- 29278530 TI - Controversies and clarifications in the classification of disorders of intellectual development, new genetic findings, epilepsy, bullying, and innovative developmental neuropsychiatric treatments (deep-brain stimulation, electroconvulsive therapy, and oxytocin). PMID- 29278528 TI - Treatment of severe skin and soft tissue infections: a review. AB - PURPOSE OF REVIEW: To review the salient features of the management of severe skin and soft tissue infections (SSTIs), including toxic shock syndrome, myonecrosis/gas gangrene, and necrotizing fasciitis. RECENT FINDINGS: For severe SSTIs, intensive care, source control, and broad-spectrum antimicrobials are required for the initial phase of illness. There is an increasing focus on the utility of rapid diagnostic tests to help in selection and de-escalation of antimicrobials for SSTIs. In addition, clinical prediction scores have shown promise in helping predict patients who do not require antimicrobials directed against methicillin-resistant Staphylococcus aureus. Immune status has been shown to be important in clinical outcomes of some, but not all types of SSTIs. The debate for benefits of intravenous immunoglobulin continues to be waged in the recent literature. SUMMARY: Severe SSTIs are common and their management complex due to regional variation in predominant pathogens and antimicrobial resistance patterns, as well variations in host immune responses. Unique aspects of care for severe SSTIs are discussed including the role of surgical consultation and source control. The unique features of SSTIs in immunocompromised hosts are also described. PMID- 29278529 TI - Erythropoietin Does Not Alter Serum Profiles of Neuronal and Axonal Biomarkers After Traumatic Brain Injury: Findings From the Australian EPO-TBI Clinical Trial. AB - OBJECTIVE: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. DESIGN: Single-center, prospective observational study. SETTING: A sub-study of the erythropoietin traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. PATIENTS: Forty-four patients with moderate-to-severe traumatic brain injury. INTERVENTIONS: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. CONCLUSIONS: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection. PMID- 29278531 TI - Nutritional implications of dietary interventions for managing gastrointestinal disorders. AB - PURPOSE OF REVIEW: The aim of this review is to summarize some of the key dietary interventions recommended for common gastrointestinal disorders and to discuss recent evidence regarding their nutritional implications. RECENT FINDINGS: The gluten-free diet has been shown to negatively influence overall diet quality. The gluten-free diet is essential in celiac disease, although it is increasingly used for other perceived health benefits for which an analysis of perceived benefit should be weighed against any nutritional risks. Evidence from short-term controlled trials of a diet low in fermentable oligosaccharides, disaccharides, monosaccharide and polyols in irritable bowel syndrome suggests compromised intake of nutrients such as fiber, iron, and calcium, although findings vary across studies. Meanwhile long-term uncontrolled trials suggest dietary adequacy improves with reintroduction and personalization. Although high-fiber diets may be beneficial in diverticular disease and constipation, it may lead to reductions in energy intake and nutrient absorption in at-risk populations. SUMMARY: The role of therapeutic diets in the management of gastrointestinal disorders is increasingly recognized, but there are limited studies investigating their nutritional implications. The judicious use of dietetic expertise should minimize potential nutritional deficits, however further prospective trials are needed to identify the individuals and nutrients most at risk. PMID- 29278532 TI - Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-analysis of randomized trials. AB - PURPOSE OF REVIEW: Results from nonrandomized cohort studies suggest higher risks of CNS adverse events for dolutegravir, versus other ARVs. There have been two case reports of myocarditis on dolutegravir. Integrase inhibitors have been associated with IRIS in two cohort studies. Meta-analysis of randomized trials can be used to cross-check potential safety signals. This systematic review of drug safety used an EMBASE and MEDLINE search combined with serious adverse event (SAE) reports on the website www.clinicaltrials.gov. Cardiovascular, CNS or IRIS associated adverse events were analysed for dolutegravir versus other ARVs. Relative risks for the comparison between dolutegravir and other antiretrovirals were calculated for each adverse event. Meta-analyses applied Mantel-Haenszel random-effects models. RECENT FINDINGS: There was a higher risk of Grade 1-4 insomnia adverse events for DTG (6.1%) versus other ARVs (4.5%; P = 0.02). There was no significant difference between DTG and other ARVs in the risk of cardiovascular serious adverse events. In the SINGLE and SPRING-1 trials comparing DTG with efavirenz, there were 5/465 patients with reported suicidality SAEs on DTG (1.1%) versus 6/469 (1.3%) on EFV. In other studies, serious adverse events of suicidality were reported for 15/2250 patients on DTG (0.7%) versus 9/2257 patients on other ARVs (0.4%). Risks of IRIS were low, but event rates were low and the main trials excluded CDC stage C disease. SUMMARY: In this meta analysis, there was no significant effect of dolutegravir on the risk of cardiac, IRIS or suicide-related serious adverse events. There was a higher risk of insomnia for DTG. Other completed randomized trials should be included in new evaluations of DTG safety. Continued pharmacovigilance, with regular meta analyses, should be used to monitor safety. PMID- 29278533 TI - Images in Anesthesiology: A Clogged Dialysis Filter Caused by Severe Acutely Induced Hypertriglyceridemia. PMID- 29278534 TI - Cohesin mutations in myeloid malignancies made simple. AB - PURPOSE OF REVIEW: Recurrent loss of function mutations within genes of the cohesin complex have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). STAG2 is the most commonly mutated cohesin member in AML as well as solid tumors. STAG2 is recurrently, mutated in Ewing's Sarcoma, bladder cancer, and glioblastoma, and is one of only ten genes known to be recurrently mutated in over four distinct tissue types of human cancer RECENT FINDINGS: The cohesin complex, a multiprotein ring, is canonically known to align and stabilize replicated chromosomes prior to cell division. Although initially thought to lead to unequal chromosomal separation in dividing cells, data in myeloid malignancies show this is not observed in cohesin mutant MDS/AML, either in large patient cohorts or mouse models. Mounting evidence supports a potential alternate mechanism whereby drivers of cell-type specific gene expression and hematopoietic development are impaired through alteration in three-dimensional nuclear organization and gene structure. SUMMARY: Understanding the functional consequences of cohesin mutations in regulating lineage-specific and signal dependent defects and in myeloid transformation will identify novel pathophysiologic mechanisms of disease and inform the development of novel therapeutic targets. PMID- 29278535 TI - The most novel of the novel agents for acute myeloid leukemia. AB - PURPOSE OF REVIEW: Precious few drugs were successfully developed for acute myeloid leukemia (AML) over the past decades, despite a dramatic expansion of our understanding of its molecular underpinnings during this time. Then in 2017, a wave of new drugs suddenly became approved. This review serves to introduce the newly available drugs, discuss their impact upon therapy, and highlight additional novel agents that are waiting in the wings. RECENT FINDINGS: Newly approved agents in AML include a tyrosine kinase inhibitor for patients with FMS like tyrosine kinase 3 (FLT3) mutations, an inhibitor of mutant isocitrate dehydrogenase (IDH2), and two novel agents using antibody-delivered or liposome delivered cytotoxics. All of these new agents have demonstrable activity in AML and several have improved survival in randomized studies. In addition to these agents, promising data from other inhibitors of FLT3, IDH1, and B-cell lymphoma 2 (BCL2) will be discussed. SUMMARY: Response, survival, and symptom burden of AML therapy are all improving through novel agents. As many of the newly approved drugs benefit-specific genetic subsets, a new priority has emerged to increase the speed of diagnostic genomic studies as a means to guide frontline therapy. This will ensure patients are optimally categorized and treated with to the most rational agents. PMID- 29278536 TI - Ability of Functional Performance Tests to Identify Individuals With Chronic Ankle Instability: A Systematic Review With Meta-Analysis. AB - OBJECTIVE: The purpose of this systematic review with meta-analysis was to determine the effectiveness of functional performance tests (FPTs) in differentiating between individuals with chronic ankle instability (CAI) and healthy controls. DATA SOURCES: The National Library of Medicine Catalog (PubMed), the Cumulative Index for Nursing and Allied Health Literature (CINAHL), and the SPORTDiscus, from inception to June 2017 were searched. Search terms consisted of: "Functional Performance Test*" OR "Dynamic Balance Test*" OR "Postural Stability Test*" OR "Star Excursion Balance Test*" OR "Hop Test*" AND "Ankle Instability" OR "Ankle Sprain." Included articles assessed differences in FPTs in patients with CAI compared with a control group. MAIN RESULTS: Included studies were assessed for methodological quality and level of evidence. Individual and mean effect sizes were also calculated for FPTs from the included articles. Twenty-nine studies met the criteria and were analyzed. The most common FPTs were timed-hop tests, side-hop, multiple-hop test, single-hop for distance, foot-lift test, and the Star Excursion Balance Tests (SEBTs). The side-hop (g = 1.056, P = 0.009, n = 7), timed-hop tests (g = -0.958, P = 0.002, n = 9), multiple-hop test (g = 1.399, P < 0.001, n = 3), and foot-lift tests (g = -0.761, P = 0.020, n = 3) demonstrated the best utility with large mean effect sizes, whereas the SEBT anteromedial (g = 0.326, P = 0.022, n = 7), medial (g = 0.369, P = 0.006, n = 7), and posteromedial (g = 0.374, P < 0.001, n = 13) directions had moderate effects. CONCLUSIONS: The side-hop, timed-hopping, multiple-hop, and foot-lift seem the best FPTs to evaluate individuals with CAI. There was a large degree of heterogeneity and inconsistent reporting, potentially limiting the clinical implementation of these FPTs. These tests are cheap, effective, alternatives compared with instrumented measures. PMID- 29278537 TI - Return to Sport After Arthroscopic Autologous Matrix-Induced Chondrogenesis for Patients With Osteochondral Lesion of the Talus. AB - OBJECTIVE: To determine the rate of return of patients to sport after arthroscopic autologous matrix-induced chondrogenesis (AT-AMIC) for outcomes 2 years after surgery. DESIGN: Retrospective observational cross-sectional study. SETTING: C.A.S.C.O.-Foot and Ankle Unit, Istituto Ortopedico Galeazzi, Milan, Italy. PATIENTS AND INTERVENTION: Twenty-six consecutive patients, 65.4% male (mean +/- SD age: 33.7 +/- 11.0 years), that underwent AT-AMIC procedure between 2012 and 2015 were selected retrospectively. From this population, only sporting patients at amateur's level were included. Arthroscopic autologous matrix-induced chondrogenesis was proposed in patients with pain and persistent disability. MAIN OUTCOME MEASURES: All patients were assessed with the American Orthopaedic Foot and Ankle Score (AOFAS), physical component score of the 12-Item Short Form Health Survey (SF-12), Halasi ankle activity score, and University of California, Los Angeles (UCLA) activity scale preoperatively and at 24 months postoperatively. RESULTS: Overall, 80.8% of the patient group returned to the same preinjury sport. The mean follow-up was 42.6 +/- 10.9 months (range from 25 to 62 months). Significant differences were observed with reference to AOFAS, SF 12, Halasi, and UCLA scores at the last follow-up in patients who had undergone AT-AMIC (all, P < 0.001). CONCLUSIONS: A high percentage of patients return to their preinjury sport after AT-AMIC surgery. PMID- 29278538 TI - A Fire Extinguisher Death: The Macklin Effect. AB - We present the case of an adult white man found dead in a psychiatric institution with fine white powder (monoammonium phosphate) deposited over the entire face after he insufflated the contents of a dry chemical fire extinguisher. Fine white powder was present within the mouth and sinuses and lined the upper airways. On opening the thoracic cavity, approximately 500 g of fine white powder was present within the right thoracic cavity. The esophagus was ruptured. Traumatic emphysema of the posterior sternum wall was present (pneumomediastinum). The ethmoid bones were fractured by the barotrauma. On polarization of the lung tissue, birefringent material was noted deposited along the bronchovascular sheaths and in a subpleural distribution. Death was probably due to a combination of barotrauma and asphyxia.This case study provides strong evidence in support of the etiology and pathophysiology of the Macklin effect. It also provides for the first visual evidence of the phenomenon. PMID- 29278539 TI - A Rare Case of Fatal Bowel Obstruction Secondary to a Colonic Bezoar. AB - A bezoar is a mass of undigested, or partially digested, material forming in the lumen of the gastroenteric tract, causing occlusive or subocclusive events. The most frequent types of bezoars are those composed of vegetable fibers, also called phytobezoars, which, by virtue of their high content in cellulose, hemicellulose, and lignin, remain undigested in the stomach and intestines and, from there, can migrate and occlude the narrowest portions of the bowel. The areas that are most frequently affected by occlusive phenomena related to the presence of bezoars are the stomach and the small intestine, although colic localizations are extremely rare. In this article, we have studied the case of a fatal colic obstruction caused by a phytobezoar in an 84-year-old woman who was found dead at her home. The autopsy revealed that the cause of the obstruction was a large artichoke fragment occluding the central part of the descending colon. Additional histological examinations confirmed that the death was attributable to bowel obstruction resulting in acute peritonitis. PMID- 29278540 TI - A Case of Fatal Cerebral Air Embolism After Blunt Lung Trauma: Postmortem Computed Tomography and Autopsy Findings. AB - Cerebral air embolism is caused by gas bubbles in the vascular system. These bubbles can cause cerebral ischemia by obstructing encephalic blood vessels. It is frequently associated with blunt and penetrating chest trauma as well as iatrogenic interventions. Lung trauma involving laceration of the respiratory tract, lung parenchyma, and blood vessels may result in direct communication of these structures, driving air or gas into the pulmonary venous system. We report a case of a blunt chest trauma that led to massive arterial air embolism that was possible to recognize with the help of postmortem computed tomographic scan examination. PMID- 29278541 TI - The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension. AB - PURPOSE OF REVIEW: For decades, it has been widely accepted that initiation of salt-induced hypertension involves a type of kidney dysfunction (natriuretic handicap), which causes salt-sensitive subjects to initially excrete less of a sodium load than normal subjects and undergo abnormal increases in cardiac output, and therefore blood pressure. Here we discuss emerging views that renal vasodysfunction, not natriuretic dysfunction (subnormal sodium excretion), is usually a critical factor initiating salt-induced hypertension. RECENT FINDINGS: Serious logical issues have been raised with arguments supporting historical views that natriuretic dysfunction initiates hypertension in response to increased salt intake. Most salt-sensitive humans do not have a 'natriuretic handicap' causing them to excrete a sodium load more slowly and retain more of it than salt-resistant normal subjects. Mounting evidence indicates that in most salt-sensitive subjects, renal vasodysfunction, defined as impaired renal vasodilation and abnormally increased renal vascular resistance in response to increased salt intake, in the absence of greater sodium retention than in salt loaded normal subjects, is involved in initiation of salt-induced hypertension. SUMMARY: To advance discovery, prevention, and treatment of primary abnormalities causing salt-induced hypertension, greater research emphasis should be placed on identifying mechanisms mediating subnormal renal vasodilation and abnormally increased renal vascular resistance in response to high-salt diets. PMID- 29278543 TI - Exploring old concepts and new paradigms. PMID- 29278544 TI - Self-management strategies in chronic obstructive pulmonary disease: a first step toward personalized medicine. AB - PURPOSE OF REVIEW: Self-management has gained increased relevance in the management of chronic obstructive pulmonary disease patients. The heterogeneity in self-management interventions has complicated the development of recommendations for clinical practice. In this review, we present the latest findings regarding conceptual definition, effectiveness of self-management interventions and self-management strategies in chronic obstructive pulmonary disease as a first step toward personalized medicine: what, how and to whom? RECENT FINDINGS: Self-management interventions have shown benefits in improving health-related quality of life and reducing hospital admissions. Favorable outcomes can only be achieved if patients have an ultimate goal, that is their desired achievements in their life. In the continuum of care, the components of the self-management program will vary to adapt to the condition of the patient (disease severity, comorbidities) and to factors such as patient motivation, confidence (self-efficacy), access to health care, family and social support. A combination of education, case management and patient-centric action plan has shown the best chance of success. SUMMARY: The individual patient's needs, own preferences and personal goals should inform the design of any intervention with a behavioral component. A continuous loop process has to be implemented to constantly assess what work and does not work, aiming at achieving the desired outcomes for a given patient. PMID- 29278542 TI - Potential kidney toxicity from the antiviral drug tenofovir: new indications, new formulations, and a new prodrug. AB - PURPOSE OF REVIEW: The antiviral agent tenofovir is highly effective for the treatment of HIV and hepatitis B virus infections, and the older prodrug tenofovir disoproxil fumarate (TDF) is also a component of daily preexposure prophylaxis (PrEP) to reduce the risk of HIV infection in high-risk populations. Although TDF is well tolerated, the potential for kidney and bone toxicity has important implications for public health given the large number of individuals exposed to TDF worldwide. This review summarizes the recent literature on kidney and bone health in individuals treated with TDF and the newer prodrug tenofovir alafenamide (TAF). RECENT FINDINGS: Risk factors for TDF toxicity appear to be similar in patients treated for HIV or hepatitis B virus and in HIV-uninfected PrEP users, although drug-drug interactions are a more important concern in HIV positive individuals. The risk of toxicity appears to be lower with TAF, but further studies are needed to confirm the safety of long-term use and to evaluate the efficacy of TAF-based PrEP. SUMMARY: Nephrologists should be aware of the potential kidney and bone toxicity of TDF, as well as unique situations in which the newer prodrug TAF may contribute to kidney injury. PMID- 29278545 TI - Treatment Effect of Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension Quantified by Automatic Comparative Imaging in Computed Tomography Pulmonary Angiography. AB - OBJECTIVES: Balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) can have variable outcomes. To gain more insight into this variation, we designed a method for visualizing and quantifying changes in pulmonary perfusion by automatically comparing computed tomography (CT) pulmonary angiography before and after BPA treatment. We validated these quantifications of perfusion changes against hemodynamic changes measured with right-sided heart catheterization. MATERIALS AND METHODS: We studied 14 consecutive CTEPH patients (12 women; age, 70.5 +/- 24), who underwent CT pulmonary angiography and right-sided heart catheterization, before and after BPA. Posttreatment images were registered to pretreatment CT scans (using the Elastix toolbox) to obtain corresponding locations. Pulmonary vascular trees and their centerlines were detected using a graph cuts method and a distance transform method, respectively. Areas distal from vessels were defined as pulmonary parenchyma. Subsequently, the density changes within the vascular centerlines and parenchymal areas were calculated and corrected for inspiration level differences. For visualization, the densitometric changes were displayed in color-coded overlays. For quantification, the median and interquartile range of the density changes in the vascular and parenchymal areas (DeltaVD and DeltaPD) were calculated. The recorded changes in hemodynamic parameters, including changes in systolic, diastolic, and mean pulmonary artery pressure (DeltasPAP, DeltadPAP, and DeltamPAP, respectively) and vascular resistance (DeltaPVR), were used as reference assessments of the treatment effect. Spearman correlation coefficients were employed to investigate the correlations between changes in perfusion and hemodynamic changes. RESULTS: Comparative imaging maps showed distinct patterns in perfusion changes among patients. Within pulmonary vessels, the interquartile range of DeltaVD correlated significantly with DeltasPAP (R = 0.58, P = 0.03), DeltadPAP (R = -0.71, P = 0.005), DeltamPAP (R = -0.71, P = 0.005), and DeltaPVR (R = -0.77, P = 0.001). In the parenchyma, the median of DeltaPD had significant correlations with DeltadPAP (R = -0.58, P = 0.030) and DeltamPAP (R = -0.59, P = 0.025). CONCLUSIONS: Comparative imaging analysis in CTEPH patients offers insight into differences in BPA treatment effect. Quantification of perfusion changes provides noninvasive measures that reflect hemodynamic changes. PMID- 29278546 TI - Twenty-four hour intraocular pressure measurements and home tonometry. AB - PURPOSE OF REVIEW: IOP is the only treatable risk factor contributing to glaucoma and most management and treatment of glaucoma is based on IOP. However, current IOP measurements are limited to office hours and control of glaucoma in many patients would benefit from the ability to monitor IOP diurnally so as not to miss abnormal pressures, which occur outside of office hours Consequently, to improve patient care, the ability to enable accurate and minimally disruptive diurnal IOP monitoring would improve caring for these patients. RECENT FINDINGS: The studies we selected for this review can be divided into three categories: self-/home-tonometry, continuous invasive intraocular pressure measurements, and continuous noninvasive ocular measurements. SUMMARY: The desire to obtain better insight in our patients' true diurnal IOP has led to the development of home tonometers, in addition to extraocular and intraocular continuous pressure measurement devices. All of the devices have respective advantages and disadvantages, but none to date completely fulfills the goal of providing a true diurnal IOP profile.Video abstracthttp://links.lww.com/COOP/A27. PMID- 29278547 TI - Fenofibrate attenuates cardiac and renal alterations in young salt-loaded spontaneously hypertensive stroke-prone rats through mitochondrial protection. AB - OBJECTIVES: The simultaneous presence of cardiac and renal diseases is a pathological condition that leads to increased morbidity and mortality. Several lines of evidence have suggested that lipid dysmetabolism and mitochondrial dysfunction are pathways involved in the pathological processes affecting the heart and kidney. In the salt-loaded spontaneously hypertensive stroke-prone rat (SHRSP), a model of cardiac hypertrophy and nephropathy that shows mitochondrial alterations in the myocardium, we evaluated the cardiorenal effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist that acts by modulating mitochondrial and peroxisomal fatty acid oxidation. METHODS: Male SHRSPs aged 6-7 weeks were divided in three groups: standard diet (n = 6), Japanese diet with vehicle (n = 6), and Japanese diet with fenofibrate 150 mg/kg/day (n = 6) for 5 weeks. Cardiac and renal functions were assessed in vivo by MRI, ultrasonography, and biochemical assays. Mitochondria were investigated by transmission electron microscopy, succinate dehydrogenase (SDH) activity, and gene expression analysis. RESULTS: Fenofibrate attenuated cardiac hypertrophy, as evidenced by histological and MRI analyses, and protected the kidneys, preventing morphological alterations, changes in arterial blood flow velocity, and increases in 24-h proteinuria. Cardiorenal inflammation, oxidative stress, and cellular senescence were also inhibited by fenofibrate. In salt loaded SHRSPs, we observed severe morphological mitochondrial alterations, reduced SDH activity, and down-regulation of genes regulating mitochondrial fatty acid oxidation (i.e. PPARalpha, SIRT3, and Acadm). These changes were counteracted by fenofibrate. In vitro, a direct protective effect of fenofibrate on mitochondrial membrane potential was observed in albumin-stimulated NRK-52E renal tubular epithelial cells. CONCLUSION: The results suggest that the cardiorenal protective effects of fenofibrate in young male salt-loaded SHRSPs are explained by its capacity to preserve mitochondrial function. PMID- 29278549 TI - New developments in understanding focal cortical malformations. AB - PURPOSE OF REVIEW: Focal cortical dysplasias (FCDs) represent common cortical malformations that are frequently associated with epilepsy. They have so far not been well understood in terms of their molecular pathogenesis, and with respect to mechanisms of seizure emergence. RECENT FINDINGS: Several recent studies have succeeded in making significant advances in understanding the molecular genetics, in particular FCD type II. A second major advance has been the development of novel rodent models of FCDs that replicate a somatic mutation seen in humans, lead to a focal lesion, and recapitulate many phenotypic features of human FCDs. We will discuss these recent advances. SUMMARY: These advances promise significant advances in understanding the heterogeneity of FCDs at the molecular genetic level. They also promise a much better understanding of cell-intrinsic and network mechanisms underlying increased seizure susceptibility and altered cognition. Systematic studies utilizing the approaches summarized here promise to lead to specific strategies regarding when and how to treat specific subgroups of FCDs. PMID- 29278548 TI - The current place of epilepsy surgery. AB - PURPOSE OF REVIEW: Three randomized controlled trials demonstrate that surgical treatment is safe and effective for drug-resistant epilepsy (DRE), yet fewer than 1% of patients are referred for surgery. This is a review of recent trends in surgical referral for DRE, and advances in the field. Reasons for continued underutilization are discussed. RECENT FINDINGS: Recent series indicate no increase in surgical referral for DRE over the past two decades. One study suggests that decreased referrals to major epilepsy centers can be accounted for by increased referrals to low-volume nonacademic hospitals where results are poorer, and complication rates higher. The increasing ability of high-resolution MRI to identify small neocortical lesions and an increase in pediatric surgeries, in part, explain a relative greater decrease in temporal lobe surgeries. Misconceptions continue to restrict referral. Consequently, advocacy for referral of all patients with DRE to epilepsy centers that offer specialized diagnosis and other alternative treatments, as well as psychosocial support, is recommended. Recent advances will continue to improve the safety and efficacy of surgical treatment and expand the types of patients who benefit from surgical intervention. SUMMARY: Surgical treatment for epilepsy remains underutilized, in part because of persistent misconceptions. Rather than promote referral for surgery, it would be more appropriate to advocate that all patients with DRE deserve a consultation at a full-service epilepsy center that offers many options for eliminating or reducing disability. PMID- 29278550 TI - Intelligent use of antiepileptic drugs is beneficial to patients. AB - PURPOSE OF REVIEW: To describe the most important issues a clinician must consider whenever selecting and administering antiepileptic drugs (AEDs). There is no available algorithm that identifies how to individualize selection of AEDs. Proper selection and administration can make an enormous difference in both effectiveness and tolerability. RECENT FINDINGS: Many principles of AED selection remain unchanged. Selection of AEDs must be based on understanding of epilepsy syndrome and seizure type, comorbidities, risk of adverse events, as well as on patient characteristics such as age and sex. Recently personalized medicine through genetics has become a reality for a subset of patients, to select optimal drugs, and avoid side effects. Selection of AEDs for women can be performed to avoid teratogenic agents, as safer AEDs have been identified. There is evidence supporting use of controlled release AED formulations, whenever available. Whenever selecting an optimal dose, physicians should attend to the principle of 'start low, go slow.' 'Intelligent use' includes not only appropriate drug selection, but also optimal and individualized dose adjustment. Drug optimization involves appropriate titration, dose schedule, individualization of therapeutic range and rescue planning SUMMARY: Intelligent drug use, individualized to patient characteristics, can guide management for optimal seizure control. PMID- 29278551 TI - The recurrent pleomorphic adenoma conundrum. AB - PURPOSE OF REVIEW: Recurrent pleomorphic adenoma (RPA) is uncommon. Treatment selection is based on the likely possibility of minimizing the risk of tumour recurrence, avoiding local functional and cosmetic sequelae, and eradicates the possibility of metastatic or malignant transformation. Much has changed since the topic was reviewed in 2001, and this manuscript comments on clinical progress and discusses patient treatment options. RECENT FINDINGS: Surgery is the preferred treatment for head and neck pleomorphic adenoma. Over the recent decade the surgical radicality is favoured for parotid and submandibular gland pleomorphic adenoma, from total gland and tumour removal to endoscopic or minimal open extracapsular tumour excision. Currently molecular pathology and biomarker research has not identified any evidence that separates pleomorphic adenoma from RPA, thus supporting that tumour recurrence is likely associated with surgery. Revision surgery has been reported to be frequently noncurative depending on the extent of the primary surgery, with the added risk of local cosmetic and functional sequelae. Radiotherapy as a nonsurgical modality has advanced and has been shown to be effective in controlling, if not curing, high-risk patients who have identifiable prognostic factors of developing a recurrence and patients with RPA. SUMMARY: Current surgical management of pleomorphic adenoma is associated with improved quality of life and minimal disturbance to cosmetic and functional. The reported incidence of RPA has been reduced by 'expert surgeons' but with limited short-term follow-up following more recent surgical modifications. Patients with RPA should be offered treatment that includes surgery and/or radiotherapy and should be encouraged to partake of this decision making process. PMID- 29278552 TI - Oncologic and functional outcomes of patients treated with transoral CO2 laser microsurgery or radiotherapy for T2 glottic carcinoma: a systematic review of the literature. AB - PURPOSE OF REVIEW: To give an overview of the laryngeal preservation and functional outcomes of patients treated with transoral CO2 laser microsurgery (TLM) or radiotherapy for T2 glottic carcinoma. This information supports physicians and patients in treatment counselling and choices. RECENT FINDINGS: A recent systematic review showed that local control rates at 5-year did not differ between radiotherapy and TLM for T2 glottic tumours. However, there is a lack of comparative data on laryngeal preservation as well as functional outcomes in T2 glottic carcinoma. SUMMARY: Laryngeal preservation for T2 tumours in this review is higher for patients treated primarily with TLM (88.8 vs. 79.0%). It is important to differentiate between tumours with normal and impaired mobility (T2a and T2b) because the latter showed poorer prognosis for both TLM and radiotherapy. Involvement of the anterior commissure does not result in significantly lower oncological results, if adequately staged and treated. More studies are needed to support these data and to compare the functional outcomes between TLM and radiotherapy for T2 glottic carcinoma. PMID- 29278553 TI - Screening for distress in survivorship. AB - PURPOSE OF REVIEW: The current review provides an overview of recent research and other initiatives aimed at increasing and/or systematizing screening for distress in cancer survivors. It is timely given an increasing drive internationally to implement distress screening as part of routine cancer care. RECENT FINDINGS: Screening using brief validated tools is recommended and the single-item distress thermometer continues to be the international screening tool of choice. Although debate continues regarding the most appropriate cut-off distress thermometer score to identify clinically distressed patients, review of checked items from the accompanying problem list can pinpoint sources of distress, to inform targeted intervention. An integrated approach should include screening, and if required, assessment/referral and intervention. However, whilst distress screening is associated with some impact on referral, especially its timeliness, delivery of evidence-based treatments to address identified distress may be limited by patients declining help and a lack of support services. SUMMARY: Although screening for distress in routine care holds promise for reducing costs and enhancing health system efficiency, its implementation across cancer services is variable. Further research is required to evaluate screening implementation and sustainability in routine care, as well as the feasibility of distress screening in long-term cancer survivors who are no longer in regular contact with cancer centres. PMID- 29278554 TI - Matters of the heart: failing better. PMID- 29278555 TI - Lung recruitment prevents collapse during laparoscopy in children: A randomised controlled trial. AB - BACKGROUND: Capnoperitoneum and anaesthesia impair lung aeration during laparoscopy in children. These changes can be detected and monitored at the bedside by lung ultrasound (LUS). OBJECTIVE: The aim of our study was to assess the impact of general anaesthesia and capnoperitoneum on lung collapse and the potential preventive effect of lung recruitment manoeuvres, using LUS in children undergoing laparoscopy. DESIGN: Randomised controlled study. SETTING: Single institution study, community hospital, Mar del Plata, Argentina. PATIENTS: Forty two children American Society of Anesthesiologists I-II aged 6 months to 7 years undergoing laparoscopy. INTERVENTIONS: All patients were studied using LUS before, during and after capnoperitoneum. Children were allocated to a control group (C-group, n=21) receiving standard protective ventilation, or to a lung recruitment manoeuvre group (RM-group) (n=21), in which lung recruitment manoeuvres were performed after recording baseline LUS images before capnoperitoneum. Loss of aeration was scored by summing a progressive grading from 0 to 3 assigned to each of 12 lung areas, based on the detection of four main ultrasound patterns: normal aeration = 0, partial loss-mild = 1, partial loss-severe = 2, total loss-consolidation = 3. MAIN OUTCOME MEASURES: Lung aeration score and atelectasis assessed by ultrasound. RESULTS: Before capnoperitoneum and recruitment manoeuvres in the treated group the two groups presented similar ultrasound scores (5.95 +/- 4.13 vs. 5.19 +/- 3.33, P = 0.5). In the RM-group, lung aeration significantly improved both during (2.71 +/- 2.47) and after capnoperitoneum (2.52 +/- 2.86), compared with the C-group (6.71 +/- 3.54, P < 0.001, and 8.48 +/- 3.22, P < 0.001, respectively). There was no statistically significant difference in the percentage of atelectasis before capnoperitoneum and recruitment manoeuvres in the RM-group (62%) and in the C group (47%, P = 0.750). However, during capnoperitoneum, only 19% of the RM-group had atelectasis compared with 80% in the C-group (P < 0.001). CONCLUSION: The majority of children undergoing laparoscopy have anaesthesia-induced atelectasis. In most cases, lung collapse due to capnoperitoneum could have been prevented by recruitment manoeuvres followed by positive-end expiratory pressure. TRIAL REGISTRY NUMBER: NCT02824146. PMID- 29278556 TI - Discerning the relationship between left ventricular geometry, high-sensitivity troponin T, and nondipper hypertension. AB - INTRODUCTION: Hypertension can cause anatomic changes in the left ventricle, generally leading to abnormal geometry. High-sensitivity cardiac troponin T (hs cTnT) values have been shown to be positively correlated with left ventricular hypertrophy in hypertensive patients. The current study investigated the diagnostic value of hs-cTnT in patient with nondipper hypertension (NDH) as well as determined the correlation between left ventricular geometric patterns and hs cTnT values in hypertensive patients. PATIENTS AND METHODS: A total of 100 consecutive patients (58 women and 42 men) who were referred to our clinic between 1 October 2015 and 1 March 2016 with elevated blood pressure (BP) were included. Of the patients, 63 had dipper hypertension [nocturnal decline in mean BP (>=10%)], whereas the remaining 37 had NDH [nocturnal decline in mean BP (<10%)]. Of note, hs-cTnT levels were measured only once during admission. Echocardiographic examinations were performed at baseline month and repeated at the sixth month. RESULTS: Hs-cTnT was significantly increased in those with NDH (P<0.001). The NDH group experienced significant decreases in concentric hypertrophy pattern over 6 months (P=0.014). Hs-cTnT was significantly related with nondipping status (r=0.747, P<0.001). Hs-cTnT was also an independent predictor of NDH (odds ratio=1.034, 95% confidence interval: 1.018-1049, P<0.001). Hs-cTnT value of more than 0.95 ng/l predicted NDH with a sensitivity of 75% and specificity of 98% (area under the curve: 0.86; 95% confidence interval: 0.782-0.925; P<0.001). CONCLUSION: Our current results indicate that patients with NDH had higher hs-cTnT levels than the patients with dipper hypertension. Hs-cTnT was an independent predictor of NDH and was significantly related with nondipping status. Hence, hs-cTnT may be used as diagnostic biomarker in NDH. PMID- 29278557 TI - Discrepancies Between Alzheimer's Disease Patients' and Caregivers' Ratings About Patients' Quality of Life: A 1-year Observation Study in Brazil. AB - OBJECTIVES: We investigated the factors associated with discrepancies between patients' and caregivers' ratings about patients' general quality of life (QoL) and about the domains of Quality of Life in Alzheimer's disease (QoL-AD) Scale at baseline and 12 months. METHODS: This was a longitudinal study that comprised 114 outpatients with AD and their caregivers. Patients were assessed with the QoL-AD, Mini-mental State Examination, Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia, Cornell Scale for Depression, Functional Activities Questionnaire, and Neuropsychiatric Inventory, and Clinical Dementia Rating Scale. Caregivers answered the QoL-AD, Zarit Burden Interview and Sociodemographic Questionnaire. RESULTS: Linear regression analyses indicated that the factors associated with discrepancies of patients' and caregivers' ratings of patients' QoL-AD were impaired awareness and caregiver burden at baseline and impaired awareness at 12 months. Moreover, the factor associated with discrepancies in the domain memory was impaired awareness and in the domain ability to do chores, impaired awareness and functional deficit. CONCLUSIONS: The discrepancies between patients and caregivers were related to awareness and caregiver burden at baseline and to awareness at 12 months. These results raise questions regarding the subjective nature of QoL and the validity of patients' evaluation of their own QoL. PMID- 29278558 TI - Autopsy of an Elderly Man With Incidentally Diagnosed TDP-43 Proteinopathy. PMID- 29278559 TI - Brain Volumes and Longitudinal Cognitive Change: A Population-based Study. AB - OBJECTIVE: To investigate the association of brain volumes, white matter lesion (WML) volumes, and lacunes, with cognitive decline in a population-based cohort of nondemented persons. METHODS: Within the Rotterdam Study, 3624 participants underwent brain magnetic resonance imaging. Cognition was evaluated at baseline (2005 to 2009) and at the follow-up visit (2011 to 2013). We used a test battery that tapped into domains of executive function, information processing speed, motor speed, and memory. The volumetric measures assessed were total brain volume, lobar (gray matter and white matter) volumes, and hippocampal volumes. We also studied the association of WML volumes and lacunes with cognitive decline using linear regression models. RESULTS: Total brain volume was associated with decline in global cognition, information processing, and motor speed (P<0.001) in analyses controlled for demographic and vascular factors. Specifically, smaller frontal and parietal lobes were associated with decline in information processing and motor speed, and smaller temporal and parietal lobes were associated with decline in general cognition and motor speed (P<0.001 for all tests). Total WML volume was associated with decline in executive function. Lobar WML volume, hippocampal volume, and lacunes were not associated with cognitive decline. CONCLUSIONS: Lower brain volume is associated with subsequent cognitive decline. Although lower total brain volume was significantly associated with decline in global cognition, specific lobar volumes were associated with decline in certain cognitive domains. PMID- 29278560 TI - Are hormonal contraceptives less effective in overweight and obese women? AB - Loss of efficacy of hormonal contraceptives is of particular concern for women who are overweight or obese. Only recently have clinical trials started to include overweight and obese women in their study populations, limiting the data available on which to make the best prescribing decisions for hormonal contraceptives for these patients. Other methods, such as the copper or levonorgestrel-containing intrauterine device, the etonogestrel implant, and depot medroxyprogesterone acetate, are preferred over combined oral contraceptives, the transdermal patch, and the vaginal ring. PMID- 29278562 TI - Disfiguring facial lesions and loss of sensation. AB - Hansen disease (leprosy) continues to be prevalent in some regions of Africa, Asia, and South America, and each year 100 to 300 cases are reported in the United States, especially in immigrants and patients exposed to armadillos. Treatment depends on patient presentation. Hansen disease remains highly stigmatized, though it is now clear that it is not readily transmitted through casual physical contact. PMID- 29278563 TI - Recognizing thyrotoxic hypokalemic periodic paralysis. AB - Thyrotoxic hypokalemic periodic paralysis (THPP) is a rare but potentially serious complication of thyrotoxicosis. The resulting muscle weakness is profound, associated with more severe hypokalemia, yet reversible. However, clinicians must be cautious because patients can develop life-threatening hyperkalemia during treatment. Underlying causes should be investigated as repeated episodes of THPP may occur. PMID- 29278564 TI - Cystic placentomegaly on a second-trimester ultrasound. AB - Placental mesenchymal dysplasia (PMD) is a rare disorder of the placenta characterized by placentomegaly, cystic vesicles, and dilated chorionic blood vessels. Clinically and pathologically, it closely resembles partial molar pregnancy and complete hydatidiform mole with a coexistent healthy fetus, both of which are associated with malignant trophoblastic disease. PMD, however, has no risk of malignant trophoblastic disease and can result in the birth of a normal fetus, highlighting the need for clinician awareness of PMD in order to avoid unnecessary termination of a viable and potentially healthy fetus. PMID- 29278565 TI - Nitrous oxide for labor analgesia. AB - Inhaled nitrous oxide (N2O) has been used worldwide for over 100 years as labor analgesia but has not gained widespread use in the United States. Nitrous oxide provides a noninvasive option for laboring women. This article outlines its efficacy and safety as an analgesic compared with epidural and IV pain medications. PMID- 29278566 TI - Job openings for PAs by specialty. AB - OBJECTIVE: Physician assistants (PAs) have adapted to roles in virtually every practice specialty. One factor that has affected PAs' specialty choices has been the availability of jobs. We describe 2014 job postings for PAs at the national level by practice specialty. METHODS: National data on 2014 job postings for PAs were obtained from a leading labor analytics firm. Each job posting (N = 34,137) was coded with regard to practice specialty and analyzed descriptively. RESULTS: The largest proportions of job postings were in the surgical (28%) and medical subspecialty (23%) categories, followed by primary care (19%), other (18%), and emergency/urgent care (12%). CONCLUSIONS: Job opportunities for PAs are plentiful and are focused in subspecialty practice. Future research should examine trends in job postings for PAs. Trend analyses will be useful for multiple purposes, including informing PAs who are seeking employment and tracking demand for the profession as a whole. PMID- 29278567 TI - Intussusception. PMID- 29278568 TI - Procalcitonin-guided treatment of lower respiratory tract infections. AB - The FDA recently approved a procalcitonin assay for use in hospitals and EDs to help prescribers determine if an antibiotic should be prescribed and for what duration. This article reviews the use of procalcitonin testing and evidence based medical decision-making for patients with sepsis or lower respiratory tract infections. PMID- 29278570 TI - Why is this patient having visual hallucinations? PMID- 29278571 TI - The cost of our care. PMID- 29278572 TI - The truth about PA school. PMID- 29278573 TI - PAs in South Africa. PMID- 29278574 TI - The Author's Reply: Very low-calorie diet, the morbidly obese with liver cirrhosis and bariatric surgery. PMID- 29278575 TI - Very Low-Calorie Diet, the Morbidly Obese With Liver Cirrhosis and Bariatric Surgery. PMID- 29278576 TI - Electrical Stimulation of the Antagonist Muscle during Cycling Exercise Interval Training Improves Oxygen Uptake and Muscle Strength. AB - A hybrid training system (HTS) is a resistance exercise method that combines voluntary concentric muscle contractions and electrically stimulated eccentric muscle contractions. We devised an exercise technique using HTS on cycle ergometer (HCE). The purpose of this study was to compare cardiorespiratory function and muscle strength when cycling exercise is combined with electrical stimulation over an extended period.Twenty-nine healthy young men were divided into an HCE group (n=14) and a VCE group (volitional cycle ergometer alone) (n=15). All subjects performed 30-min cycling exercise interval training sessions three times a week for six weeks.The VO2peak of both groups significantly increased compared to the pre-training period (HCE group: from 31.3+/ 4.4(ml/kg/min) pre-training to 37.6+/-6.7(ml/kg/min) post-training (P=0.0024), and VCE group: from 34.0+/-7.1(ml/kg/min) pre-training to 38.4+/-8.2 (ml/kg/min) (P=0.0057)). After the training, there was no significant difference of changes in VO2peak between the HCE and the VCE groups (P=0.7107). In the VCE group the maximal isokinetic torque of knee extension (60 degrees /sec) post training did not significantly increase compared to the pre-training period (VCE group: from2.4+/-0.5 (Nm/kg) pre-training to 2.5+/-0.4 (Nm/kg) (P=0.4543)). In contrast, in the HCE group the maximal isokinetic torque of knee extension (60 degrees /sec) post training significantly increased compared to pre-training period (HCE group: from 2.5+/-0.3 (Nm/kg) pre-training to 2.8+/-0.3 (Nm/kg) (P<0.0001)). The change in knee extension torque was significantly greater for the HCE group than for the VCE group. In conclusion, cardiopulmonary function and knee extension strength were improved by the use of HCE. PMID- 29278578 TI - Situation-Dependent Medical Device Risk Estimation: Design and Evaluation of an Equipment Management Center For Vendor-Independent Integrated Operating Rooms. AB - OBJECTIVES: The complexity of surgical interventions and the number of technologies involved are constantly rising. Hospital staff has to learn how to handle new medical devices efficiently. However, if medical device-related incidents occur, the patient treatment is delayed. Patient safety could therefore be supported by an optimized assistance system that helps improve the management of technical equipment by nonmedical hospital staff. METHODS: We developed a system for the optimal monitoring of networked medical device activity and maintenance requirements, which works in conjunction with a vendor-independent integrated operating room and an accurate surgical intervention Time And Resource Management System. An integrated situation-dependent risk assessment system gives the medical engineers optimal awareness of the medical devices in the operating room. RESULTS: A qualitative and quantitative survey among ten medical engineers from three different hospitals was performed to evaluate the approach. A series of 25 questions was used to evaluate various aspects of our system as well as the system currently used. Moreover, the respondents were asked to perform five tasks related to system supervision and incident handling. Our system received a very positive feedback. The evaluation studies showed that the integration of information, the structured presentation of information, and the assistance modules provide valuable support to medical engineers. CONCLUSIONS: An automated operating room monitoring system with an integrated risk assessment and Time And Resource Management System module is a new way to assist the staff being outside of a vendor-independent integrated operating room, who are nevertheless involved in processes in the operating room. PMID- 29278577 TI - Evaluation of a Dedicated Tobacco Cessation Support Service for Thoracic Cancer Center Patients. AB - CONTEXT: Cancer patients' continued tobacco use results in poorer therapeutic outcomes including decreased quality of life and survival. OBJECTIVE: To assess reach and impact of a free, opt-out, telephone-based tobacco cessation program for thoracic cancer center patients. DESIGN: Observational study. SETTING: Comprehensive Cancer Center in Western New York. PARTICIPANTS: Current or recent (within past 30 days) tobacco-using thoracic cancer center patients referred to a tobacco cessation support service between October 2010 and October 2012 at a Comprehensive Cancer Center (n = 942/1313 referrals were eligible for cessation support). INTERVENTION: A free, opt-out, telephone-based cessation service that was implemented as standard of care. Cessation specialists had patient-guided conversations that assessed readiness to quit; methods used in the past provided cessation strategies and worked to set up a quit date. There was an average of 35.9 days between referral and first contact. MAIN OUTCOME MEASURES: Program reach (referral and participation rates) and impact (as self-reported cessation outcomes measured twice after referral). RESULTS: Of 942 patients, 730 (77.5%) referred to and called by a tobacco cessation service participated in at least 1 cessation support call, of which 440 of 730 (60.3%) were called for follow-up and 89.5% (394/440) participated. In total, 20.2% (69/342) of current smokers at referral reported at least 7-day abstinence at follow-up. Among current smokers at referral and first contact, being married (odds ratio [OR] = 2.05; 95% confidence interval [CI], 1.01-4.18) and having a lower Eastern Cooperative Oncology Group (ECOG) performance score (OR = 4.05; 95% CI, 1.58-10.39) were associated with quitting at follow-up, after controlling for demographic, clinical, and health behavior characteristics. CONCLUSIONS: Our results demonstrate that 78% of thoracic cancer center patients, if contacted, participated at least once in this cessation support service; for current smokers at referral and first contact, being married and having a lower ECOG performance score were associated with self-reported quitting at follow-up. Other organizations may find our results useful while implementing a systematic way to identify tobacco-using patients as part of routine care and to improve available cessation support services. PMID- 29278579 TI - Sentinel lymph node surgery in prostate cancer using magnetic particles. AB - PURPOSE OF REVIEW: Superparamagnetic iron oxide nanoparticles (SPIONs) are tested to identify sentinel lymph nodes (SLNs) to exploit the advantages of targeted pelvic SLN dissection (sPLND), while circumventing the disadvantages of established radioactive labeling. Here we review recent studies about sPLND in prostate cancer (PCa), including the first results of SLN detection using intraprostatic SPION-injection. RECENT FINDINGS: A recent systematic literature review reveals that the diagnostic accuracy of sPLND is comparable with extended PLND (ePLND). sPLND combined with ePLND achieve better node removal by increasing the number of affected nodes. The first sentinel-based nomogram predicting lymph node invasion is established. A sentinel-nomogram update provides comparative predictions relative to ePLND models. sPLND using a magnetometer and SPIONs as a tracer is successful whenever applied to PCa, and SLN identification using MRI after intraprostatic injection of SPIONs is feasible. SLNs are present in an unexpectedly high number outside the ePLND template. SUMMARY: SLN detection outside the ePLND template and the increased diagnostic value of sPLND compared with ePLND supports the individualized extension of PLND using sPLND in PCa. SPION-MRI, combined with a hand-held magnetometer, provides a nonradioactive technique for preoperative and intraoperative SLN localization. Further studies are required to evaluate the effects of sPLND on oncological outcomes. PMID- 29278580 TI - Retroperitoneal versus transperitoneal robotic-assisted laparoscopic partial nephrectomy: a matched-pair, bicenter analysis with cost comparison using time driven activity-based costing. AB - PURPOSE OF REVIEW: To perform a bicenter, retrospective study of perioperative outcomes of retroperitoneal versus transperitoneal robotic-assisted laparoscopic partial nephrectomy (RALPN) and assess costs using time-driven activity-based costing (TDABC). We identified 355 consecutive patients who underwent RALPN at University of California Los Angeles and the University of Michigan during 2009 2016. We matched according to RENAL nephrometry score, date, and institution for 78 retroperitoneal versus 78 transperitoneal RALPN. Unadjusted analyses were performed using McNemar's Chi-squared or paired t test, and adjusted analyses were performed using multivariable repeated measures regression analysis. From multivariable models, predicted probabilities were derived according to approach. Cost analysis was performed using TDABC. RECENT FINDINGS: Patients treated with retroperitoneal versus transperitoneal RALPN were similar in age (P = 0.490), sex (P = 0.715), BMI (P = 0.273), and comorbidity (P = 0.393). Most tumors were posterior or lateral in both the retroperitoneal (92.3%) and transperitoneal (85.9%) groups. Retroperitoneal RALPN was associated with shorter operative times (167.0 versus 191.1 min, P = 0.001) and length of stay (LOS) (1.8 versus 2.7 days, P < 0.001). There were no differences in renal function preservation or cancer control. In adjusted analyses, retroperitoneal RALPN was 17.6-min shorter (P < 0.001) and had a 76% lower probability of LOS at least 2 days (P < 0.001). Utilizing TDABC, transperitoneal RALPN added $2337 in cost when factoring in disposable equipment, operative time, LOS, and personnel. SUMMARY: In two high volume, tertiary centers, retroperitoneal RALPN is associated with reduced operative times and shortened LOS in posterior and lateral tumors, whereas sharing similar clinicopathologic outcomes, which may translate into lower healthcare costs. Further investigation into anterior tumors is needed. PMID- 29278581 TI - Oncologic outcomes after minimally invasive surgery for cT1 renal masses: a comprehensive review. AB - PURPOSE OF REVIEW: To evaluate current literature reporting oncologic outcomes after robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN). RECENT FINDINGS: Recently, there have been published first mid term results after RAPN (5 years). To date, there are no randomized trials to guide decision-making regarding LPN or robotic partial nephrectomy (RPN), and such trials are unlikely to be forthcoming, given the rapid adoption of RAPN worldwide. We performed a literature search according to Cochrane guidelines up to 1 September 2017, including studies that had more than 40 months of oncologic follow-up. SUMMARY: A total of 2933 patients were included from 14 studies (1498 RAPN, 1525 LPN). RAPN had similar mid-term (5 years) oncologic outcomes as LPN. Large collaborative efforts are still necessary to provide solid long-term oncologic outcomes of open, laparoscopic, and RPN. PMID- 29278582 TI - Computer-assisted surgery: virtual- and augmented-reality displays for navigation during urological interventions. AB - PURPOSE OF REVIEW: To provide an overview of the developments made for virtual- and augmented-reality navigation procedures in urological interventions/surgery. RECENT FINDINGS: Navigation efforts have demonstrated potential in the field of urology by supporting guidance for various disorders. The navigation approaches differ between the individual indications, but seem interchangeable to a certain extent. An increasing number of pre- and intra-operative imaging modalities has been used to create detailed surgical roadmaps, namely: (cone-beam) computed tomography, MRI, ultrasound, and single-photon emission computed tomography. Registration of these surgical roadmaps with the real-life surgical view has occurred in different forms (e.g. electromagnetic, mechanical, vision, or near infrared optical-based), whereby the combination of approaches was suggested to provide superior outcome. Soft-tissue deformations demand the use of confirmatory interventional (imaging) modalities. This has resulted in the introduction of new intraoperative modalities such as drop-in US, transurethral US, (drop-in) gamma probes and fluorescence cameras. These noninvasive modalities provide an alternative to invasive technologies that expose the patients to X-ray doses. Whereas some reports have indicated navigation setups provide equal or better results than conventional approaches, most trials have been performed in relatively small patient groups and clear follow-up data are missing. SUMMARY: The reported computer-assisted surgery research concepts provide a glimpse in to the future application of navigation technologies in the field of urology. PMID- 29278583 TI - Prostate-specific membrane antigen theranostics: therapy with lutetium-177. AB - PURPOSE OF REVIEW: Prostate-specific membrane antigen (PSMA) theranostics offers a new approach for a personalized and targeted treatment for metastatic prostate cancer. Lutetium-177-labelled PSMA-ligands (Lu-PSMA) is a radionuclide therapy that is directed to PSMA expressing prostate cancer. Clinical experience with Lu PSMA in men with advanced prostate cancer is growing. The purpose of this review is to outline the mechanism of action of this therapy, summarize recent efficacy and toxicity data and highlight future direction and challenges in establishing Lu-PSMA treatment as part of routine clinical practice. RECENT FINDINGS: The first reports on safety and efficacy of Lu-PSMA have been retrospective series of men with advanced prostate cancer who previously failed conventional therapies and received Lu-PSMA on compassionate basis. These studies highlight promising efficacy, favourable toxicity profile and quality of life improvements. Limitation stem from the retroospective nature of these data with short follow up. SUMMARY: Several studies suggest that radionuclide therapy with Lu-PSMA has high activity and is well tolerated. Crucial to establishing this treatment in routine clinical management will be the generation of high-level evidence from prospective trials that can confirm the encouraging patient outcomes reported to date. PMID- 29278584 TI - Robot-assisted partial nephrectomy: systematic review of functional results. AB - PURPOSE OF REVIEW: Various ischemia type during partial nephrectomy for renal cell cancer (RCC) resulted in different postoperative functional outcomes. Our objective was to systematically review the contemporary literature on robot assisted partial nephrectomy (RPN) and investigate the association of ischemia type and tumor complexity with postoperative functional outcomes of the operated kidney and overall. RECENT FINDINGS: Forty-five of the 99 reports identified were selected for qualitative analysis. All included studies were observational and nonrandomized. Overall, we found that patients undergoing RPN with zero ischemia and selective artery clamping had a lower decrease in glomerular filtration rates of the operated kidney in comparison to both warm and cold ischemia. This association seems also to play a role in patients with bilateral kidneys harboring complex tumors. SUMMARY: Zero ischemia and selective artery clamping provide the best functional outcomes following robotic partial nephrectomy. This seems to be of particular relevance in patients with single kidney or tumors of high complexity. Whether these changes are statistically or clinically significant cannot be determined within this systematic review. PMID- 29278585 TI - Disparities, Health Inequities, and Vulnerable Populations: Will Academic Medicine Meet the Challenge? PMID- 29278586 TI - Rethinking Postgraduate Training Requirements for Licensure: The Kansas Experience. PMID- 29278587 TI - In Reply to Templeton et al. PMID- 29278588 TI - In Reply to Templeton et al. PMID- 29278589 TI - Transgender Health in an Age of Bathroom Bills. PMID- 29278590 TI - In Reply to Zaidi. PMID- 29278591 TI - Realism Challenges in Documentation Components of Objective Structured Clinical Examinations. PMID- 29278592 TI - The 2017-2018 Standardized Video Interview: An Ethical Concern. PMID- 29278593 TI - Display of Professionalism of the Highest Standard. PMID- 29278595 TI - The Doctor. PMID- 29278594 TI - Artist's Statement: Heart Beat. PMID- 29278596 TI - Commentary on The Doctor. PMID- 29278597 TI - Message in a Bottle. PMID- 29278598 TI - Research Summaries: The 11th Biennial Rivkin Center Ovarian Cancer Research Symposium. AB - In September 2016, the 11th biennial ovarian cancer research symposium was presented by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research. The 2016 symposium focused on 4 broad areas of research: Mechanisms of Initiation and Progression of Ovarian Cancer, Tumor Microenvironment and Models of Ovarian Cancer, Detection and Prevention of Ovarian Cancer, and Novel Therapeutics for Ovarian Cancer. The presentations and abstracts from each of these areas are reviewed in this supplement to the International Journal of Gynecologic Oncology. PMID- 29278599 TI - Meeting Report From the 2016 11th Biennial Ovarian Cancer Research Symposium: Mechanisms of Initiation and Progression of Ovarian Cancers. AB - OBJECTIVE: The aim of this study was to review the latest research advances on the mechanisms of initiation and progression of ovarian cancer. METHODS: At the 11th Biennial Ovarian Cancer Research Symposium, which was held in Seattle, Washington in September 2016, leaders in ovarian cancer research convened to present and discuss current advances and future directions in ovarian cancer research. RESULTS: One session was dedicated to Mechanisms of Initiation and Progression of Ovarian Cancer, and included a keynote presentation from Dr Ronny Drapkin, MD (University of Pennsylvania), and an invited oral presentation from Laising Yen, PhD (Baylor College of Medicine). Nine additional oral presentations were selected from abstract submissions. Thirty-three abstracts were presented in poster format and were grouped into the categories of mechanisms of the genesis of genomic instability, tumor initiation, metastases of ovarian cancers, innate and acquired chemotherapy resistance, tumor progression, tumor-initiating cell and chemotherapy resistance, and immunomodulation. CONCLUSIONS: Eradication of ovarian cancers requires clear understanding of molecular mechanisms of ovarian cancer initiation and progression. These mechanisms will not only drive the precision of early detection, but also discovery of new therapies to target precursor lesions and more advanced stage disease. PMID- 29278600 TI - Ovarian Cancer Prevention, Screening, and Early Detection: Report From the 11th Biennial Ovarian Cancer Research Symposium. AB - OBJECTIVE: The aim of this study is to provide a summary report on recent research advances in ovarian cancer prevention, screening, and early detection that were presented at the 11th Biennial Ovarian Cancer Research Symposium in Seattle, Wash. METHODS: At the symposium, researchers from around the world participated in the poster, invited oral presentation and keynote presentation, and discussed the latest advances in the areas of cancer prevention, screening, and early detection. RESULTS: In the Scientific Session for Prevention, Screening, and Early Detection, Usha Menon, PhD (University of College London), presented exploratory studies from the ongoing UK Collaborative Trial of Ovarian Cancer Screening trial. Karen Lu, MD, presented her studies on BRCA testing and salpingectomies as prevention strategies. Eight speakers were selected from the abstracts for short oral presentations, and the topic ranges from Ovarian Cancer Early Detection Program by Saul Rivkin, MD, to the ultra-deep sequencing of somatic mutations in TP53 in normal and cancer patients by Rosana Risques, PhD. Fourteen additional poster presentations, ranging from the potential role of cancer stem cells in recurrence to retrotransposons in ovarian cancer development, round up the session. CONCLUSIONS: Although progress is being made in the areas of prevention, screening, and early detection, these advances have not yet translated into tangible clinical benefits for patients with ovarian cancer. A wide array of research topics presented in the session provides a glimmer of hope that better understanding of genetic risk factors, refining screening strategies, and developing new methods for early detection will eventually lead to improved outcome for patients with ovarian cancer. PMID- 29278602 TI - Ethnic Differences Identified by Pain Sensitivity Questionnaire Correlate With Clinical Pain Responses. AB - BACKGROUND AND OBJECTIVES: The Pain Sensitivity Questionnaire, English version (PSQ-E), is predictive of pain-related responses to experimental stimuli. Ethnic differences have been noted in experimental measures of pain sensation using quantitative sensory testing. The present study sought to determine if the PSQ-E also identified similar ethnic differences. METHODS: Fifty-seven subjects who self-identified as African Americans (AAs) and who were scheduled to undergo a low-back interventional procedure completed the PSQ-E and other questionnaires. Their data were compared with an age-, sex-, and opioid usage-matched sample of 57 self-identified non-Hispanic white (NHW) subjects. Pain ratings on a visual analog scale (VAS) were obtained following 2 standardized injections of subcutaneous lidocaine (VAS1-infiltration in hand, VAS2-infiltration of procedural site). Correlations between PSQ-E scores, VAS measures, and other inventories were tested. RESULTS: The PSQ-E scores and clinical and experimental pain scores were all significantly elevated in AA compared with NHW patients (P < 0.05 for experimental pain scores, P < 0.001 for PSQ and clinical pain scores). Measures of pain interference, depression, anxiety, and pain catastrophizing were not different between groups. Similar to our previous study, PSQ-E scores significantly correlated with both experimental and clinical pain scores (eg, PSQ E with Brief Pain Inventory pain score: r = 0.39, P < 0.001). CONCLUSIONS: The study demonstrated significantly elevated pain sensitivity in AA compared with NHW patients as measured by the PSQ-E and experimental and clinical pain intensity scores. This shows that the PSQ reflects the known elevation of pain sensitivity in AA subjects and suggests that it may be useful in assessing pain treatment disparities by identifying and standardizing differences in pain sensitivity. PMID- 29278601 TI - Shivering Treatments for Targeted Temperature Management: A Review. AB - BACKGROUND: Shivering is common during targeted temperature management, and control of shivering can be challenging if clinicians are not familiar with the available options and recommended approaches. PURPOSE: The purpose of this review was to summarize the most relevant literature regarding various treatments available for control of shivering and suggest a recommended approach based on latest data. METHODS: The electronic databases PubMed/MEDLINE and Google Scholar were used to identify studies for the literature review using the following keywords alone or in combination: "shivering treatment," "therapeutic hypothermia," "core temperature modulation devices," and "targeted temperature management." RESULTS: Nonpharmacologic methods were found to have a very low adverse effect profile and ease of use but some limitations in complete control of shivering. Pharmacologic methods can effectively control shivering, but some have adverse effects, such that risks and benefits to the patient have to be balanced. CONCLUSION: An approach is provided which suggests that treatment for shivering control in targeted temperature management should be initiated before the onset of therapeutic hypothermia or prior to any attempt at lowering patient core temperature, with medications including acetaminophen, buspirone, and magnesium sulfate, ideally with the addition of skin counterwarming. After that, shivering intervention should be determined with the help of a shivering scale, and stepwise escalation can be implemented that balances shivering treatment with sedation, aiming to provide the most shivering reduction with the least sedating medications and reserving paralytics for the last line of treatment. PMID- 29278603 TI - Interventional Spine and Pain Procedures in Patients on Antiplatelet and Anticoagulant Medications (Second Edition): Guidelines From the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. AB - The American Society of Regional Anesthesia and Pain Medicine (ASRA) 2012 survey of meeting attendees showed that existing ASRA anticoagulation guidelines for regional anesthesia were insufficient for their needs. Those surveyed agreed that procedure-specific and patient-specific factors required separate guidelines for pain and spine procedures. In response, a guidelines committee was formed. After preliminary review of published complications reports and studies, the committee stratified interventional spine and pain procedures according to potential bleeding risk: low-, intermediate-, and high-risk procedures. The ASRA regional anesthesia anticoagulation guidelines were largely deemed appropriate for the low and intermediate-risk categories, but the high-risk category required further investigation. The first guidelines specific to interventional spine and pain procedures were published in 2015. Recent reviews evaluating bleeding complications in patients undergoing specific interventional pain procedures, the development of new regional anesthesia and acute pain guidelines, and the development of new anticoagulants and antiplatelet medications necessitate complementary updated guidelines. The authors desired coordination with the authors of the recently updated regional and acute pain anticoagulation guidelines. The latest evidence was sought through extensive database search strategies and the recommendations were evidence based when available and pharmacology driven otherwise. We could not provide strength and grading of these recommendations because there are not enough well-designed large studies concerning interventional pain procedures to support such grading. Although the guidelines could not always be based on randomized studies or on large numbers of patients from pooled databases, it is hoped that they will provide sound recommendations and the evidentiary basis for such recommendations. This publication is intended as a living document to be updated periodically with consideration of new evidence. PMID- 29278604 TI - Sensory Assessment and Regression Rate of Bilateral Oblique Subcostal Transversus Abdominis Plane Block in Volunteers. AB - BACKGROUND AND OBJECTIVES: The analgesic effect and duration of a transversus abdominis plane (TAP) block remain controversial. Transversus abdominis plane blocks are effective for somatic/incisional pain but do not provide analgesia for visceral pain from intra-abdominal procedures. The purpose of this study was to assess the area and extent of cutaneous sensory blockade and the regression of dermatomal anesthesia after bilateral oblique subcostal TAP block. METHODS: This observational, prospective clinical study consisted of 12 healthy volunteers. All volunteers received a bilateral oblique subcostal TAP block under real-time ultrasound guidance with 20 mL of 0.375% ropivacaine. The anterior abdominal cutaneous area was divided into 3 parts (midabdomen, left-lateral abdomen, right lateral abdomen) using 2 lines drawn in a parasagittal fashion 5 cm lateral to the midline. The area of cutaneous sensory blockade involving the anterior abdomen was assessed 30 minutes after institution of the block using a cold stimulus. This was followed by repeated measurements using a cold stimulus applied along parasagittal lines drawn 3 cm lateral to the midline at 0.5, 6, 10, 14, 18, 22, and 26 hours after blockade. RESULTS: The area of cutaneous sensory blockade of the abdomen was 332 (SD, 73) cm; that of the midabdomen was 253 (SD, 29) cm, which represented an average of 90% of the area of the midabdomen; and that of the lateral abdominal wall (combination of left-lateral abdomen and right lateral abdomen) was 79 (SD, 62) cm, which represented an average of 26% of total lateral abdominal area. Dermatomes T7-T12 of the midabdomen were successfully blocked in all volunteers after using the bilateral oblique subcostal technique. However, T6 and L1 were only variably blocked. The area of cutaneous sensory block of the anterior abdomen regressed over the ensuing 22 hours in the following manner: 90%, 87%, 73%, 50%, 22%, 3%, and 0% at 0.5, 6, 10, 14, 18, 22, and 26 hours, respectively. CONCLUSIONS: Bilateral oblique subcostal TAP block produces a widespread cutaneous sensory blockade with a consistent dermatomal distribution in the midabdomen for a considerable effective duration. PMID- 29278605 TI - Erector Spinae Plane Block for Surgery of the Posterior Thoracic Wall in a Pediatric Patient. AB - OBJECTIVE: Historically, regional anesthesia for surgery on the posterior thoracic wall has been limited to neuraxial and paravertebral nerve blocks. The erector spinae plane (ESP) block is a novel technique that anesthetizes the dorsal rami of the spinal nerves innervating the posterior thoracic wall. We report the use of the ESP block for this clinical application in a pediatric patient. CASE REPORT: A healthy 3-year-old girl was scheduled for resection of a giant paraspinal lipoma extending over the T4-T7 dermatomes. She received a preoperative single-shot ESP block at the level of the T1 transverse process; this level was chosen to avoid the lipoma and cover the planned surgical incision over the T2-T8 dermatomes. Hemodynamic stability and excellent pain control perioperatively were obtained with minimal anesthetic requirements and no systemic analgesics apart from fentanyl administered for induction of anesthesia. Return to normal function (ambulation, feeding, and communication) was achieved within 2 hours after surgery. A pain score of 0 on the FLACC (Face, Legs, Activity, Cry, Consolability) scale was maintained until discharge from the hospital 4 hours after the surgery. First analgesic use was 18 hours after hospital discharge. No complications were reported. CONCLUSIONS: The ESP block is an effective option for surgery on the posterior thoracic wall. The opioid- and anesthetic-sparing effects exhibited in this case facilitated rapid postoperative recovery and early discharge. PMID- 29278606 TI - Local Application of Ultrasound Attenuates Neuropathic Allodynia and Proinflammatory Cytokines in Rats After Thoracotomy. AB - BACKGROUND AND OBJECTIVES: We aimed to investigate the effect of therapeutic ultrasound (TU) on pain sensitivity and the concentration inflammatory cytokines in a thoracotomy rat model. METHODS: Rats were distributed randomly into 4 groups: (1) sham operated, (2) thoracotomy and rib retraction (TRR), (3) TRR rats that received TU (TRR + TU-1), and (4) TRR rats that received TU with the ultrasound turned off (TRR + TU-0). Ultrasound was set at 1-MHz frequency (1.0 W/cm intensity and 100% duty cycle for 5 minutes), began on postoperative day (POD) 10, and then continued once per day, 5 days a week for 3 weeks. RESULTS: The TRR and TRR + TU-0 rats encountered tactile hypersensitivity from PODs 10 to 28. Mechanical withdrawal thresholds were increased (all P < 0.05) following 5 days of TU, but thresholds remained significantly lower than baseline values. Therapeutic ultrasound increased the subcutaneous, but not body temperature. All groups receiving TRR demonstrated an increase in concentration of interleukin 1beta and tumor necrosis factor alpha (TNF-alpha) on POD 14; however, the rise in TNF-alpha concentration was less in the TU-treated group than in the others. The decrease in concentration was greatest in the TRR + TU-1 group and similar between the TRR and TRR + TU-0 groups. CONCLUSIONS: Mechanical allodynia was partially resolved with TU. Tissue temperature increased with ultrasound, while TU restricted the up-regulation of interleukin 1beta and TNF-alpha around the injured intercostal nerve. PMID- 29278607 TI - Biennial Pattern of Rotavirus Gastroenteritis in The Netherlands and a Shifting Age Distribution After a Low Rotavirus Season, 2010-2016. AB - A hyperendemic rotavirus season was expected after a low-endemic 2014 season in the Netherlands. Rotavirus detections were however similar in 2015 and lower in 2016 compared with 2010-2013. Gastroenteritis consultation rates were also similar in 2015, but the age distribution shifted to older children because of an accumulation of noninfected children. Results indicate a possible shift to a biennial rotavirus pattern. PMID- 29278608 TI - Pneumonia Risk Stratification Scores for Children in Low-Resource Settings: A Systematic Literature Review. AB - BACKGROUND: Pneumonia is the leading infectious cause of death among children less than 5 years of age. Predictive tools, commonly referred to as risk scores, can be employed to identify high-risk children early for targeted management to prevent adverse outcomes. This systematic review was conducted to identify pediatric pneumonia risk scores developed, validated and implemented in low resource settings. METHODS: We searched CAB Direct, Cochrane Reviews, Embase, PubMed, Scopus and Web of Science for studies that developed formal risk scores to predict treatment failure or mortality among children less than 5 years of age diagnosed with a respiratory infection or pneumonia in low-resource settings. Data abstracted from articles included location and study design, sample size, age, diagnosis, score features and model discrimination. RESULTS: Three pediatric pneumonia risk scores predicted mortality specifically, and 2 treatment failure. Scores developed using World Health Organization-recommended variables for pneumonia assessment demonstrated better predictive fit than scores developed using alternative features. Scores developed using routinely collected healthcare data performed similarly well as those developed using clinical trial data. No score has been implemented in low-resource settings. CONCLUSIONS: While pediatric pneumonia-specific risk scores have been developed and validated, it is yet unclear if implementation is feasible, what impact, if any, implemented scores may have on child outcomes, or how broadly scores may be generalized. To increase the feasibility of implementation, future research should focus on developing scores based on routinely collected data. PMID- 29278609 TI - Mycoplasma-Induced Rash and Mucositis in a Father and Son: A Case Report. AB - This case report describes a father and son with recurrent Mycoplasma-induced rash and mucositis (MIRM). A father with a remote history of a similar rash in childhood presented to the hospital with a severe rash with mucosal involvement, and elevated Mycoplasma pneumoniae immunoglobulin M titers, consistent with MIRM. Four years later, a similar rash developed in his son with a positive M. pneumoniae polymerase chain reaction assay, which was consistent with MIRM. His course was complicated by recurrence of disease shortly after discharge from the hospital. To our knowledge, this case report is the first to describe recurrent MIRM affecting individuals within the same family. PMID- 29278610 TI - Resource Allocation Strategies to Increase the Efficiency and Sustainability of Gavi's Health System Strengthening Grants. AB - BACKGROUND: Despite the increase in Health System Strengthening (HSS) grants, there is no consensus among global health actors about how to maximize the efficiency and sustainability of HSS programs and their resulting gains. To formally analyze and compare the efficiency and sustainability of Gavi's HSS grants, we investigated the factors, events and root causes that increased the time and effort needed to implement HSS grants, decreased expected outcomes and threatened the continuity of activities and the sustainability of the results gained through these grants in Cameron and Chad. METHODS: We conducted 2 retrospective independent evaluations of Gavi's HSS support in Cameroon and Chad using a mixed methodology. We investigated the chain of events and situations that increased the effort and time required to implement the HSS programs, decreased the value of the funds spent and hindered the sustainability of the implemented activities and gains achieved. RESULTS: Root causes affecting the efficiency and sustainability of HSS grants were common to Cameroon and Chad. Weaknesses in health workforce and leadership/governance of the health system in both countries led to interrupting the HSS grants, reprogramming them, almost doubling their implementation period, shifting their focus during implementation toward procurements and service provision, leaving both countries without solid exit plans to maintain the results gained. CONCLUSIONS: To increase the efficiency and sustainability of Gavi's HSS grants, recipient countries need to consider health workforce and leadership/governance prior, or in parallel to strengthening other building blocks of their health systems. PMID- 29278611 TI - Utility of Point-of-care Ultrasound in Children With Pulmonary Tuberculosis. AB - BACKGROUND: Point-of-care ultrasound (POCUS) detects extrapulmonary tuberculosis (EPTB) in HIV infected adults but has not been evaluated in children despite their higher risk of EPTB. This study's aims were to investigate feasibility of POCUS for EPTB in children, frequency of POCUS findings suggestive of EPTB and time to sonographic resolution of findings with treatment. METHODS: This prospective South African cohort study enrolled children with suspected pulmonary tuberculosis (PTB). POCUS for pleural, pericardial or ascitic effusion, abdominal lymphadenopathy or splenic or hepatic microabscesses was performed and repeated at 1, 3 and 6 months of tuberculosis (TB) treatment. Prevalence of POCUS findings and their association with HIV infection was investigated in children with confirmed PTB (microbiologically proven), unconfirmed PTB (clinically diagnosed) or unlikely TB (respiratory disease that improved during follow-up without TB treatment). RESULTS: Of 232 children [median age 37 months (interquartile range, 18-74)], 39 (17%) were HIV infected. Children with confirmed or unconfirmed PTB had a higher prevalence of POCUS findings than children with unlikely TB [18 of 58 (31%) and 36 of 119 (30%) vs. 8 of 55 (15%); P = 0.04 and P = 0.03, respectively]. Pleural effusion [n = 30 (13%)] or abdominal lymphadenopathy [n = 28 (12%)] were the most common findings; splenic microabscesses [n = 12 (5%)] were strongly associated with confirmed PTB. Children coinfected with HIV and TB were more likely than HIV-uninfected children with TB to have abdominal lymphadenopathy (37% vs. 10%; P < 0.001) or splenic microabscesses (23% vs. 3%; P < 0.001]. Most ultrasound findings were resolved by 3 months with appropriate TB treatment. CONCLUSIONS: POCUS for EPTB in children with PTB is feasible. The high prevalence of findings suggests that POCUS can contribute to timely diagnosis of childhood TB and to monitoring treatment response. PMID- 29278612 TI - Epidemiology of Infectious Complications During Extracorporeal Membrane Oxygenation in Children: A Single-Center Experience in 46 Runs. AB - BACKGROUND: Infections represent a severe complication of extracorporeal membrane oxygenation (ECMO). Aim of the present study was to describe the epidemiology of infections acquired during ECMO in a tertiary care children's hospital. METHODS: Retrospective analysis of clinical records of patients undergoing ECMO between January 2009 and December 2016. For each patient, data were collected on clinical characteristics, modality of ECMO support, site and etiology of documented infections, survival within 1 week after ECMO weaning and/or at pediatric intensive care unit discharge. These data were employed to evaluate overall infection prevalence, infection rate expressed as episodes/1000 days of support and cumulative risk estimates of infections occurring during ECMO. RESULTS: During the study period, a total of 46 ECMO procedures were performed. The overall prevalence of documented infections was 33%, with an infection rate of 27.22 and a cumulative risk of 55%. Bloodstream infection represented the most frequently documented (53%), followed by pneumonia (40%). Coagulase-negative staphylococci and Pseudomonas aeruginosa prevailed as isolated pathogens. Overall survival was 59%, and 46% among those developing infections during ECMO. CONCLUSIONS: ECMO is a procedure at high risk for infections. Our data, limited to 1 center, represent a recent benchmark for further investigations. PMID- 29278613 TI - Immunogenicity and Safety of the Quadrivalent Human Papillomavirus Vaccine in Girls Living With HIV. AB - We evaluated quadrivalent human papillomavirus vaccine seroresponses among 35 girls living with HIV (9-13 years of ages) and compared with data on girls without HIV, as part of a subgroup analysis. The quadrivalent human papillomavirus vaccine was safe and well tolerated. However, antibody response was significantly lower in girls living with HIV relative to girls without HIV. HIV virologic suppression predicted better antibody response. PMID- 29278614 TI - Childhood Infections and Subsequent School Achievement Among 598,553 Danish Children. AB - BACKGROUND: Hospitalizations for infections have been associated with subsequent decreased cognitive ability, but it is uncertain if childhood infections influence subsequent scholastic achievement (SA). We aimed to estimate the association between infections during childhood and SA. METHODS: Nationwide prospective cohort study including 598,553 children born in Denmark between 1987 and 1997 and their parents. Exposures were hospitalization for infections and treatment with anti-infective agents. Outcomes were completion of ninth grade and ninth grade test scores. Data were analyzed with logistic and linear regression analysis techniques and adjusted for any mental disorder, birthweight, Apgar score, malformations at birth, chronic somatic diseases, first-born child, parental educational level and parental mental disorders. RESULTS: Hospitalization with infections was linked to lower completion of ninth grade with an odds ratio of 0.82 (95% confidence interval: 0.79-0.85) compared with children without prior hospitalizations for infections. Dose-response relationships were observed with respect to number of hospital contacts for infections and a shorter time since last hospitalization (all P < 0.001). Among those who completed the ninth grade test score, we found a dose-response and time since relationship between number of prior severe infections and subsequent lower grade scores (P < 0.001). Treatment of nonsevere infections with anti-infective agents did not predict lower completion of ninth grade but was associated with lower grade scores (P < 0.001). CONCLUSIONS: Infections, particularly those requiring hospitalizations, were associated with subsequent affected cognitive ability as indicated by lower SA. These findings might also be explained by missed school days or socioeconomic factors associated with the susceptibility of acquiring infections. PMID- 29278615 TI - Risk for Speech and Language Impairments in Preschool Age HIV-exposed Uninfected Children With In Utero Combination Antiretroviral Exposure. AB - BACKGROUND: Perinatally HIV-exposed but uninfected (HEU) children have elevated risk of late language emergence at 1 year of age, with possible links to in utero antiretroviral (ARV) exposure. We investigated possible risks for speech impairments (SIs) and language impairments (LI) in preschool monolingual HEU children in the United States. METHODS: Speech and language assessments were conducted as part of the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities study at ages 3 (N = 208) and 5 (N = 429) years. Domains of speech, overall language, vocabulary and grammar were assessed. SI and LI were defined by standardized scores <15th percentile and categorized as primary (normal nonverbal IQ >= 85 without hearing loss) and concomitant (low nonverbal IQ and/or presence of hearing loss). Logistic regression models were used to estimate odds of SI and LI for different ARV exposures, adjusted for confounding variables. RESULTS: The risk for language impairments in HEU children was higher than population norms; risk for SIs was not elevated. Risk factors for impairments included male sex, black race and other socioeconomic measures, although these varied by age, primary (P) versus concomitant (C) impairment and by speech or language measure. Adjusted logistic regression models revealed lower and increased risk for specific ARVs. Tenofovir exposure was associated with increased risk for SI at 3 years of age but was associated with decreased risk for concomitant language impairment at 5 years of age. CONCLUSIONS: Further investigation of combination ARV exposure and speech/language impairment among preschool children is needed to confirm associations. PMID- 29278616 TI - Decreased Acute Otitis Media With Treatment Failure After Introduction of the Ten valent Pneumococcal Haemophilus influenzae Protein D Conjugate Vaccine. AB - BACKGROUND: Acute otitis media (AOM) nonresponsive to antibiotics is most commonly caused by antibiotic-resistant Streptococcus pneumoniae and Haemophilus influenzae. A strategy for treating these infections with parenteral ceftriaxone was adopted at the Children's Hospital Iceland. The 10-valent pneumococcal H. influenzae protein D-conjugate vaccine was introduced into the vaccination program in Iceland in 2011. The aim was to study its effect on the incidence of AOM with treatment failure. METHODS: This retrospective observational study included children who visited the Children's Hospital Iceland because of AOM or received ceftriaxone, regardless of indication from 2008-2015. Incidence rate was calculated for prevaccine (2008-2011) and postvaccine (2012-2015) periods using person-years at risk within the hospital's referral region. Incidence rate ratio of ceftriaxone treatment episodes of AOM was calculated using the Mantel-Haenzel method adjusting for age. Incidence risk ratio of ceftriaxone treatment if presenting to the hospital with AOM was calculated to adjust for rate of AOM visits. RESULTS: Visits for AOM decreased from 47.5 to 33.9 visits per 1000 person-years, incidence rate ratio (IRR) 0.86 (95% confidence interval [CI]: 0.81 0.91), P < 0.001. Fewer AOM episodes were treated with ceftriaxone, decreasing from 6.49 to 2.96 treatment episodes per 1000 person-years, with an overall Mantel-Haenzel adjusted IRR 0.45 (95% CI: 0.37-0.54; P < 0.001). This remained significant after adjusting for the decrease in AOM visits, IRR 0.53 (95% CI: 0.44-0.63; P < 0.001). CONCLUSIONS: Visits for AOM and ceftriaxone use decreased significantly after H. influenzae protein D-conjugate vaccine introduction. The observed decrease in ceftriaxone use is presumed to represent a decline in AOM with treatment failure, secondary to a decrease in resistant infections. PMID- 29278618 TI - Team Approach: Osteosarcoma of the Distal Part of the Femur in Adolescents. PMID- 29278619 TI - Simultaneous Treatment of Pelvic and Urological Injuries. PMID- 29278617 TI - Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy associated loci. AB - OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to >=grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE >=grade 3 versus =grade 3 TIPN in 1269 European Americans and 139 African Americans in S0221, was 11.6 and 22.3%, respectively. CALGB 40101 >=grade 3 TOPN was 7.2%. The most significant association with >=grade 3 TIPN was the G allele of rs1858826 in GNGT1 (Pmeta=1.1*10), which showed a decrease in risk of >=grade 3 TIPN (odds ratio=0.29, 95% confidence interval: 0.18-0.46). CONCLUSION: The genetic variants associated with >=grade 3 TIPN are hypothesized to have biochemical functions and reside in and near genes involved in diabetes and diabetic neuropathy. This finding is consistent with results from CALGB 40101 pathway analyses. Larger homogeneous trials with similar dosing and criteria for defining neuropathy are needed to properly assess the relationship of genomics with the neuropathy spectrum. PMID- 29278620 TI - 95th Anniversary of Pathophysiology in Croatia. AB - University level of Pathophysiology research and teaching in Croatia had started with the third year of Medical School of Zagreb in academic year 1919./20. Ever since, despite historical changes of the main university stake holder, the state of Croatia, Department of Pathophysiology development progressed and has made visible academic achievements, with a broader effect in medical community. The first 95 years of academic tradition and major achievements are shortly described in this paper. Professor Miroslav Mikulicic envisioned Pathophysiology in close relations with Pharmacology and made the pioneering steps of establishing the "double" department at Salata. His group was academically very pro-active, with strong international scientific participation and recruitment of professionals. The group published the first voluminous textbook of Pharmacology and Pathophysiology, in Croatian. In fifties, professor Pavao Sokolic established clinical pathophysiology within the Hospital Centre at Rebro. Out of "double" department two new departments were founded, the Pathophysiology one was completed with the clinical ward. That institutional move from Salata hill to the Rebro hill was a necessary gigantic step and a prerequisite for the proper further development. It was in accordance with the concept of the Mikulicic's program of Pathophysiology from 1917. Pavao Sokolic has been remembered for his visions, deep insights into etiopathogenesis, ability to transfer knowledge and friendly relations to students. Sharp intellectual power, emanating charisma, academic erudition and unique clinical competencies made the legendary image of the "Teacher" - as students used to refer to him with admiration. He was second to no one when complex patient issues were to be resolved. Clinical Hospital Centre Zagreb and his Department at Rebro have become a referral point to whom to go to despair. Students recognized in their Teacher the landmark of Croatian medicine, which made a lasting legacy on generations to come. Professor Stjepan Gamulin made molecular medicine the working reality at Rebro. Both in clinical research, and in health system as diagnostic service and tool for all centers in Croatia, molecular measurement in tissue samples came into usage in daily physicians reasoning and therapy prescriptions. Macromolecular aspects of disease have come of age and became clinimetric signs of patients' condition. Professor Gamulin with his group and associated authors wrote the textbook of pathophysiology, which in upcoming 30 years had 7 editions, has become the bestseller in medicine. The textbook was translated and published in English and Albanian. In the most recent book professor Gamulin turned the focus of medical community to clinical epidemiology and a need for retrospective insights into medical efficiency. Medical performance can be improved with the improvement of understanding of underlying etiopathogenetic relations as the foundation of therapy-is the main message. Following the academic legacy and spirit of three charismatic authorities we established two methods of teaching/learning in medicine. The two methods opened up a new avenue, so important for the era of postgenomic plethora of information and demands of precision/personalized medicine. Methodology has been introduced timely. It is student-friendly and usable for advanced types of education. Problem based algorhytmic matrices stimulate analysis and resynthesis of etiopathogenetic pathways. Graphic presentation of the solution integrates horizontal, vertical and longitudinal aspects of the problem. The companion textbook in the form of problem solver has been published in 3 editions, and contains 128 study solved cases. It was published in English, as well. Out of algorhythmic analysis the etiopathogenetic clusters (EPCs) are composed of etiopathogenetic pathway analysis. EPCs are natural units of disease development, the crossing points of processes. They are integrative hubs which tend to make networks of EPCs. Four volume textbook has been published, which elaborates 91 EPCs with 1165 study cases. Unique approach in the first 95 years was defined as Zagreb School of Pathophysiology. It made visible effect outside academia and recognizable image at the international level, in scientific, educational and practical aspects of activities. PMID- 29278621 TI - Integration of Educational and Research Activities of Medical Students (Experience of the Medical Faculty of Saint Petersburg State University). AB - The article is devoted to the role of research activity of the medical students in higher education of physicians. The teaching of physicians in classical universities and specialized medical schools is compared. The history of physicians' training in Russia in imperial, Soviet and post-Soviet periods is reviewed and compared to development of higher medical education in other countries. Article gives the the description of all failed attempts to establish a Medical Faculty within oldest classical university of Russia, crowned by history of last and successful attempt of its establishment. Authors' experience of adjoining education and research in curriculum and extra-curricular life of this Medical Faculty is discussed. The problems of specialization and fundamentalization of medical education are subjected to analysis. Clinical reasoning and reasoning of scholar-experimentalist are compared. The article reviews the role of term and course papers and significance of self-studies and graduation thesis in education of a physician. The paper gives original definition of interactive learning, and discusses the methods and pathways of intermingling the fundamental science and clinical medicine in medical teaching for achievement of admixed competencies of medical doctor and biomedical researcher. PMID- 29278622 TI - Current challenges and problems in teaching pathophysiology in Ukraine - another reaction to Churilov's paper. AB - Pathophysiology in Ukraine has rich traditions and achievements in the scientific areas, as well as in teaching academic discipline. Its history, the main Ukrainian scientific schools and their famous representatives are briefly described. The content of existing study program, the main approaches to teaching, and some methodological and organizational problems needed to be solved are characterized. The necessity and usefulness of developing and implementing the three separate courses of discipline (Essential, Clinical and Advanced Pathophysiology) are substantiated. The place of Pathophysiology in the training of physicians with different kinds of their future activity is discussed. Relation of teaching Pathophysiology to Translational and Personalized Medicine is tried to be shown. PMID- 29278623 TI - Depression and Heart Diseases: Leading Health Problems. AB - Depression is the most common psychiatric disorder in the world population and the most frequent mental disorder in a primary health care. Unrecognized and untreated depression is associated with a poor outcome of treated chronic diseases which co-exist with depression. Depression and cardiovascular diseases are bidirectional related conditions, risks are for each other, and they often co exist. Depression is a common disorder in cardiovascular patients with a prevalence of 20% to 45%, which is much more frequent than in the general population. In cardiac patients with acute myocardial infarction, depression occurs three times more often than in the general population. Depression has a direct effect on the pathophysiological changes of various organ systems, changing the values of blood pressure, heart rate, vasomotor tone, vascular resistance, blood viscosity and plasma volume. The potential mechanism for developing heart disease in depressed patients includes hypothalamic-pituitary adrenal gland dysfunction, increased proinflammatory and prothrombotic factor activity, reduced omega-3 fatty acids, reduced heart rate variability, smoking, physical inactivity, reduced mood, self-esteem and self-efficacy. PMID- 29278624 TI - Allergic reactions and anesthesia. AB - The diagnosis of allergic reactions during anesthesia is difficult. For example, cardio-respiratory symptoms may be due to the accompanying pharmacological effects of anesthetics and poor interpretation of the reaction during anesthesia. It is important to distinguish whether a real allergic reaction has occurred. Accidents with anesthetics and muscle relaxants are observed more often than we expect. Proper anaphylaxis rarely occurs during anesthesia (1: 20000). Muscle relaxants are the most common causes, followed by latex, chlorhexidine, antibiotics and opioids. To confirm the diagnosis it is necessary to perform a larger number of blood and skin tests. Targeted diagnostic approach and therapy allow avoiding more difficult events. Anesthesia should be selected for those medications that have been tested. Additionally, patients should be premedicated with antihistaminics and systemic steroids, as the emergence of intolerance is not completely excluded by negative testing. There is no gold standard for testing, even if every method is precisely performed; there are always false positive and false negative results. When anaphylaxis appears, urgent approach is needed to provide the patient with appropriate treatment. It is necessary to act according to the established algorithms and treatment protocols. Many anesthesiologists will not ever see such a reaction, and very few will see more than one during their work life. Awareness of allergy in anesthesia is still insufficient. PMID- 29278625 TI - The historical use of medicinal plants in traditional and scientific medicine. AB - There is a strong connection between man and nature, ever since his first origins, the man discovered the benefits of the plant kingdom, which he used to feed himself, to heal and to survive. Following the use of eatable, medicinal and poisonous plants takes us into the distant past. The man's first knowledge about plants passed from generation to generation. The ancients Chinese, Egyptians, Indians, Greeks, Romans and the Old Slavs knew a large number of medicinal plants. That knowledge was carried over to other nations as well. Thanks to its geographical location and climate condition, our country is abundant and very rich in variety of species of medicinal plants. In the Middle Ages, there were written many herbal manuals that described the use and procedures in healing with medicinal plants. Many plants were known by the oldest civilizations and they were used by the people for thousands of years. Moreover, today's science has confirmed their effectiveness in the treatment of different diseases. PMID- 29278626 TI - Personality traits and quality of life of mothers who have children with cerebral palsy. AB - BACKGROUND: The quality of life (QOL) of mothers who have children with cerebral palsy (CP) is significantly worse than in mothers with typically developing children. In available literature we have not found an approach which analyzes the correlation of mothers' personality traits with their QOL and health related quality of life (HrQOL). SUBJECTS AND METHODS: The study included 101 mothers of children with CP, aged 4 to 18 years. Mothers' personalities have been assessed by Eysenck EPQ - R questionnaire that determines three personality traits: neuroticism/emotional stability, extroversion/introversion and psychoticism. Maternal HrQOL was assessed by SF-36 questionnaire, Short Form, and their emotional well-being by WHO 5 well-being index. In addition, the influence of mothers' religiosity was also analyzed, using DUREL Religiosity Questionnaire. Motor assessment of children was performed using Gross Motor Function Classification System. The control group consisted of mothers of typically developing children of the same age. RESULTS: Participants with high levels of extraversion had better QOL and HrQOL, as opposed to those with high levels of neuroticism and psychoticism, who had worse physical and mental health. The degree of children's motor impairment and mothers' religiosity did not influence QOL. Regression analysis distinguishes the following predictors for better mothers' QOL: better their mental health, greater level of their vitality, extroversion, living with a partner, a lesser degree of children's motor impairment and better their QOL. CONCLUSIONS: It is vital to identify the factors that affect QOL of a mother and a child with CP. We consider it justified to regularly conduct mothers' professional monitoring and treatment simultaneously with children's treatment and we propose the protocol for the individual and targeted approach. PMID- 29278627 TI - What do pregnant women know about harmful effects of medication and herbal remedies use during pregnancy? AB - BACKGROUND: The objective of this study was assasment of women's knowledge and awareness on medication and herbal remedies use during pregnancy. SUBJECTS AND METHODS: Cross-sectional study was conducted in Department of Obstetrics and Gynaecology University Clinical Hospital Mostar. The study included 230 parturients (primipara) and 20 pharmacists who work in pharmacies of Mostar. Collected and analyzed data was based on a questionnaire of 25 questions. RESULTS: Out of total number of respondents (N =230), 159 of them (69.1%) used some vitamin or mineral product, 44.8% of respondents had problems with morning sickness and vomiting, but they did not use any medication in pregnancy. Higher educated respondents used folic acid more often (p=0.005), they knew the benefits of using folic acid (p<0.001) and magnesium during pregnancy (p=0.002) and they were familiar with harmful effect of alcohol and cigarettes consumption during pregnancy (p=0.005) so as with harmful effect of excessive quantity of vitamin A (p=0.037), they were more familiar with harmful effect of herbal remedies and at least one harmful herb compared to less educated respondents (p<0.001). CONCLUSION: There is lack of knowledge and unawareness on harmful effect of medication use and herbal remedies during pregnancy. PMID- 29278628 TI - Perinatal complications in two cohort groups of preterm newborns in Intensive care unit for Children's Diseases of University Clinical Hospital Mostar. AB - AIM: To determine the frequency and type of complications in two cohort groups of preterm newborns. SUBJECTS AND METHODS: The research involved 100 preterm newborns divided into two groups according to their gestational age: newborns from 24 to 33+6/7 weeks GA and newborns from 34 to 36+6/7 weeks GA. Parameters which were observed with mother were: age, number of births, course and complications in pregnancy. Parameters with infant: gestational age, weight, newborn small for gestational age (IUGR), asphyxia, respiratory distress syndrome, sepsis, hyperbilirubinemia, apnea, anemia, intracranial hemorrhage and metabolic disorder (hypoglycaemia, hypocalcaemia). Research criterion for exclusion was all preterm newborn infants with chromosome anomalies which cause death, fetal death during pregnancy (in utero) and newborns (born after full 37 weeks). RESULTS: After dividing exminees according to their gestational age into two groups, the group with higher gestational age (from 34 to 36+6/7 weeks GA) had 76% and the group with lower gestational age (from 24 to 33+6/7 weeks GA) had 24% of infants. The course of pregnancy was pathological in 68% of pregnancies and normal with 32% of pregnncies, the difference is statistically significant. 97% of pregnant woman had pathological course in the group of preterm newborns with lower GA. The most common perinatal complication was hyperbilirubinemia in 42% of cases, while sepsis was present in 1% of infants. The first group of infants (<33 GA) had mostly combination of 3 or more complications in 46% of infants while the other group mostly had hyperbilirubinemia in 50% and combination of complications in 24% of infants. CONCLUSION: Perinatal complication occurence depends on premature birth and course of pregnancy. Larger number of complications and harder complications which may result with death are more common in patients with lower gestational age (24 to 33+6/7 weeks GA) than in patients with higher gestational age (34 to 36+6/7 weeks GA). PMID- 29278629 TI - Socioeconomics Conditionality of Seroprevalence of Hepatitis a in Three South West Cantons of the Federation of Bosnia and Herzegovina. AB - The prospective study, which was made from Jan 1st 2009. till Dec 31st 2010. in the Clinic for Infectious Diseases within Clinical Hospital Mostar has been implemented in the areas of three southwestern cantons of the Federation of Bosnia and Herzegovina. We wanted to define the seroprevalence of the researched area using seroepidemiological testing of different groups of the population, based on the distribution by sex, age, education, residence and watersupply. The aim of this research was to prove the hypothesis that the decrease of seroprevalency of Hepatitis A has been directly related to the improvement of socio-economic conditions of life that at the end brought the decrease of the total prevalence in patients in younger age groups. The total of 420 examinees from the reasserted sample were analysed and they were classify into age groups. The first group was for the children up to 10 years. Then the group 11-20 follows and etc up to the last group, that complies examinees older than 60. In this way we have got seven groups of 60 examinees, from which the half of them was urban, and the other half was rural inhabitants. In every group analysed the half of examinees were females and the other half were males. The results we acquired with this research did not show any statistically relevant differences of seroprevalence of Hepatitits A between the urban and rural areas, between the sexes, nor between the populations which used different wattersupply objects. A statistically relevant difference was found between populations of different levels of education, but the most important difference was found between seroprevalency in different age groups. Seroprevalence in younger age groups was substantially low and increased in groups rising with age. Comparing this data to results from other similair researches from developed and undeveloped countries we concluded that the researched area, by the level of seroprevalency of Hepatitis A belongs to the category of developed countries. PMID- 29278630 TI - Predictive Value of High Sensitive Troponin I Assay in Acute Coronary Syndrome Compared to Classic Biochemical Markers. AB - The aims of this study were to compare predictive values of hsTroponin I assay with contemporary assays and its usefulness in diagnosis of acute coronary syndrome (ACS). We also aimed to determine reference values of the assay and the possibility of fast ACS diagnosis using hsTnI. The study included 26 patients with ongoing chest pains and suspected ACS. ACS diagnosis was determined using electrocardiographic changes and international guidelines. Biochemical parameters were measured using standard tests which included Troponin I, hsTroponin I, CK, CK-MB and CRP. 10 (38.5 %) patients out of 26 were diagnosed with ACS. Median age was 63.92 years. Comparison of predictive values showed that hsTnI and TnI had an advantage before CK, CK-MB and CRP. hsTnI showed no significant improvements over TnI. With an perfect negative predictive value at admission, hsTnI is recommended for use as a rule-out method for ACS in patients with chest pain and suspected ACS on admission. hsTnI was superior to contemporary TnI assays only as a rule out method for suspected ACS patients at admission. PMID- 29278631 TI - Prevalence of Coronary artery anomalies detected by Coronary CT Angiography in Canton Sarajevo, Bosnia and Herzegovina. AB - BACKGROUND: Coronary artery anomalies (CAAs) are congenital variations of one or more of the coronary arteries and they are an uncommon but important cause of chest pain and, in some cases, sudden cardiac death. Anomalies of coronary arteries may be found incidentally in 0.3-1% of healthy individuals. The three types of coronary artery anomalies are anomalies of origin, anomalies of course and anomalies of termination. The purpose of our study was to estimate the frequency of CAAs in Canton Sarajevo, B&H, and to deteremine the prevalence of origin, course and termination anomalies of coronary arteries. SUBJECT AND METHODS: This was a retrospective analysis of 919 patients who underwent Coronary CT Angiography to determine CAAs in the period from 2013 to 2017. RESULTS: In our study, total number of CAAs have been found among the 130 patients (14.12%) out of which anomalies of origin are found at 14 patients (1.52%), anomalies of course at 115 patients (12.5%) and anomaly of termination in 1 patient (0.1%). Out of 14 cases in total anomalies of origin, anomalies of origin of the left coronary artery are observed among 11 patients (1.2%), and anomalies of origin of the right coronary artery among 3 patients (0.3%). From mentioned 14 cases of the anomalous origin of the coronary arteries, anomalies with clinical significance (interarterial, malignant course) of the coronary arteries are found among 6 patients (0.65%) and anomalies without clinical significance are found among 8 patients (0.87%). Coronary artery anomalies of origin with malignant course are devided in two groups: LMA from right sinus of Valsalva with interarterial course observed in 4 patients (0.43%) and RCA from left sinus of Valsalva, also with interarterial course in 2 patients (0.21%). We found 4 patients (0.43%) with separated origin LAD and LCX, without LMA. The preavlence rates of separate origin of RCA and conus artery, anomaly origin of the LCX from right coronary sinus, anomaly origin of the LMA from posterior coronary sinus and LMA from right coronary sinus without interarterial course were seen in 0.1% of patients. Among 115 cases of anomalies of course 111 cases (12.07%) belongs to bridging (37 cases to LAD; 25 cases to D1 and D2 and 49 to ramus intermedius), and 4 cases (0.43%) belongs to intraatrial course of RCA. Anomaly of termination presented with fistula between LCX and coronary sinus was found only in 1 case. CONCLUSION: Coronary CT angiography is an excellent tool for diagnosis of CAAs regarding origin, course and termination of the coronary arteries. PMID- 29278632 TI - Influence of the Type of Plateletpheresis on the Value of Corpuscular Elements in the Blood Donors. AB - INTRODUCTION: During the plateletpheresis procedure the number of trombocites in the donor's blood significantly decreases, and the levels of the other components of blood as hematocrit, hemoglobin, and leukocyte diminish as well. Influence of the type of procedure DN-CFCS and SN-ICFS it is one of the factors that affects the decrease of the levels of HCT, Hgb and WBC. In this study, our goal was to see the difference in the value of HCT, Hgb, WBC, and platelets after the plateletfphresis process between DN-CFCS and SN-IFCS on the same cell separator - Fenval AMICUS. DONORS AND METHODS: The criteria for participation: men between age of 25-45. Two groups were formed. Group I 112 separation done with the method SN-ICFS and Group II 180 separation done with the method DN-CFCS. STATISTICAL ANALYSIS: To confirm the statistical difference we used Student t-test for independent or dependent samples, as well as Mann-Whitney U test as non parametric alternative. The possibility of errors were accepted for alpha<0.05, and the difference between groups were accepted as statistical relevant for p<0.05. RESULTS: Statistically significant lower values were observed of all researched parameters after separation for the donors on the equipement Amicus DN, and for donors on Amicus SN. A significant higher value of HCT before procedure was found in the AM DN group, in the researches of the other variables there were no significant differences. The resultst for the comparison of variables after procedure procedure for DN and SN procedure. A significant higher value of HCT and a significant higher level of Hgb, as well as a significant lower level of WBV after procedure in the AM DN group, while for the levels of PLT there were no significant differences. CONCLUSION: On the decrease of the value of the observed parameters the type of procedure has an influence that means DN-CFCS or SN-IFCS, continuous or discontinuous flow. PMID- 29278633 TI - Tumor Marker CA 125 in the Diagnosis of Active Pulmonary Tuberculosis - A Study of Adults in Mostar, B&H. AB - BACKGROUND: Tumor marker CA 125 is found in normal mesothelial lung cells and normal bronchial epithelial cells. If destruction of these cells occurs due to inflammation or tumour, CA 125 will be released, and increased in the serum. SUBJECTS AND METHODS: From November 2008 to May 2009 a study analysing CA 125 levels in serum samples from patients who are hospitalized at the Pulmology Department of University Hospital Mostar. Standard laboratory tests, X-ray, sputum examination to BK, and tumour marker CA 125 were performed in all patients. Patients were divided into 5 groups. Comparing clinical and laboratory findings of patients and statistical processing of collected data, conclusions were drown about the role of tumor markers Ca 125 in the diagnosis of pulmonary tuberculosis. RESULTS: This analysis is performed on 220 patients, forty with pulmonary tuberculosis. Of the total number of patients included, there is 60% of the negative findings of tumor marker Ca 125 which is statistically significant (P<0.05). Further analysis of Ca 125 shows that there is 75% of positive findings in active pulmonary tuberculosis, which is a statistically significant difference (P=0.002). Within the group of patients with lung carcinoma, half of the patients showed positive finding of tumor marker CA 125. Statistical analysis showed that sensitivity of CA 125 was 75%, specificity was (68%) and positive predictive value was 12% in patients with active tuberculosis. CONCLUSIONS: The result of this study showed that the increase in serum tumor marker CA 125 is present in active pulmonary tuberculosis as well as in patients with lung cancer. PMID- 29278634 TI - Pain Intensity Scales Comparison in Patient with Abdominal Pain. AB - BACKGROUND: The aim of study was to explore efficiency of the pain rating scales on patients experiencing abdominal pain, determine correlation between the scales and their applicability to general population and determine the minimal clinical important difference in mm on the VAS as discriminatory for difference in pain intensity. SUBJECTS AND METHODS: The study was performed at the Emergency Department of the University Clinical Hospital of Mostar on patients with abdominal pain which started less than 24 hours before, excluding patients under 16 years old, uncooperative patients and those with altered state of consciousness. The sample data were collected from February to May 2010. Hundred patients completed the questionnaire. Two patients, admitted to the Abdominal Surgery Department, were excluded. The patients were asked to sign the informed consent form and assess the level of pain on three scales (VAS, NRS, VRS). RESULTS: The NRS showed a significant difference in assessing the pain intensity in the observed time. By lapse of time, the patients were reporting lower pain intensity (P=0.017). VAS and NRS had high correlation coefficient values, indicating strong correlation and credibility. The NRS showed strong results correlation (r=0.784; P<0.001). Inter-scale correlation was growing over time. Correlation between VAS and NRS was very strong, the strongest in the last measurement (r=0.950; P<0.001). The NRS correlation with VRS (r=0.430; P<0.001) was slightly better than with VAS (r=0.402; P<0.001). The NRS proved to be the most sensitive to changes in pain intensity (SRM=0.305), whereas the VRS showed extremely low responsiveness (SRM=0.185). CONCLUSION: Having proved as the most useful, reliable and efficient pain assessment instrument, the NRS is hereby recommended as method of pain objectification and determining changes in pain intensity. PMID- 29278635 TI - Anxiety sensitivity as a predictor of academic success of medical students at the University of Mostar. AB - Higher education students comprise a particularly vulnerable group for the development of anxiety symptoms and disorders. The aim of our research was to examine the impact of anxiety sensitivity on the success of medical students at the University of Mostar, and to establish the differences between students depending on their sex and the year of study. One hundred students in their first and fifth year of medical school were interviewed using the ASI questionnaire, 7 days prior to their final exams. Here we demonstrate a positive correlation between anxiety sensitivity and academic success. We did not find any significant differences between the first and fifth-year medical students, nor between participants based on their sex. We conclude that anxiety can have a positive impact on the academic achievement of higher education students. PMID- 29278636 TI - Immunohystochemical Expression of Vitamin D Receptor in Development Stages of Colorectal Carcinoma. AB - BACKGROUND: Chemo preventive and antitumor role of vitamin D is manifested through genetic and non genetic ways with a powerful antproliferatory and proapopoptic effect, which is proven by numerous epidemiologic studies. The genetic activity of vitamin D is determined through vitamin D receptors (VDR), a member of stero-thyreoidal family of nuclear receptors, which with vitamin D form a cell nucleus complex responsible for the chemo preventive and antitumor effect. VDR in tissue cells is present in the cytoplasm and the nucleus and manifests its genetic activity after transfer from the cytoplasm to the nucleus. The mechanisms for the transport and genetic control of the transport of VDR from cytoplasm to the nucleus in not yet completely understood. SUBJECTS AND METHODS: By using immunohystochemistry we are evaluating the correlation of cytoplasmic and nuclear expression of VDR during different stages of colorectal carcinoma: normal colorectal mucosa, hyperplasic polyp, low grade adenoma (LGD), high grade adenoma (HGD) and colorectal cancer. RESULTS: Our results confirm that the nuclear VDR expression is strongest in normal colorectal mucosa and in hyper plastic polyps, is gradually weakened in low and high grade adenoma while it is extremely weak or absent in colorectal carcinoma. At the same time the expression of cytoplasm VDR is weakest in normal colorectal mucosa and hyper plastic polyps while it grows during the adenoma stage and is most expressed during colorectal carcinoma. CONCLUSION: We conclude that vitamin D has a strong chemo preventive and antitumor effect in normal colorectal mucosa and hyper plastic polyps, while its antitumor and chemopreventive effect is progressively weakened and ultimately absent in colorectal carcinoma. PMID- 29278637 TI - Medical education changes students' attitudes on psychiatry: survey among medical students in Croatia. AB - In Croatia, psychiatric disorders are the leading group of disorders by days of hospitalization and they are in second place according to the number of hospitalizations in the period of working age. Nevertheless, psychiatry in Croatia, as well as in the world, is one of the least attractive specialties for medical students. In this paper we determined the impact of compulsory education in psychiatry on the attitudes of medical students of the fourth year of the Zagreb school of medicine and Osijek school of medicine. We tested attitudes toward psychiatry, psychiatric treatment and attitudes toward seeking professional psychological help using questionnaires that were filled out twice, at the beginning of psychiatry placement and at the end of psychiatry placement. Questionnaires were completed by 239 students from the Zagreb school of medicine and Faculty of medicine Osijek (response rate 78.4%). After the placement, students had significantly more positive attitudes about psychiatry and psychiatric treatment, as well as the attitudes toward seeking professional psychological help. Attitudes towards psychiatry, seeking psychological help and attitude towards psychiatric medication and psychotherapy correlated with the evaluation of the quality of psychiatric education. Additional forms of education in psychiatry should be offered, in order to maintain and increase the impact of education on students' attitudes. PMID- 29278638 TI - Attitudes of Students of Medicine, University of Mostar According to Induced Abortion. AB - BACKGROUND: Aim of this study was to establish attitudes of medical students on induced abortion and connection of those attitudes with religiousness, length of their studies, sex and various circumstances of pregnancy. SUBJECTS AND METHODS: In total, 148 students of the first, second, fifth and sixth year of medical faculty participated in the research. The study was conducted at the Medical Faculty of the University in Mostar. While collecting the data, we used a survey taken over from literature. The data were tested with adequate statistical methods afterwards. RESULTS: 81.1% of students would perform an abortion under certain circumstances (chi2=57.189; P<0.001). Most students answered that they would perform an abortion in case that a fetus had malformations (chi2=3.892; P=0.49) or if the mother's life were endangered (chi2=47.676; P<0.001). By comparison of students' readiness to perform an abortion under various circumstances of pregnancy depending on length of medical education, statistically significant difference was proved in the following circumstances: rape (chi2=6.097; P=0.014) and if the pregnancy would endanger mother's mental health (chi2=4.488; P=0.034). Students with shorter medical education expressed more liberal attitudes in the above stated circumstances. By comparison of students' readiness to perform an abortion under various circumstances of pregnancy depending on religiousness statistically significant difference was proved in the following circumstances: in case of 'abortion on demand', no matter the reason (chi2=11.908; P=0.012), teenage pregnancy (chi2=33.308; P<0.001) and if the pregnancy would interfere with mother's career chi2=35.897; P<0.001). Unreligious students expressed more liberal attitudes. CONCLUSION: Influence of length of medical education and sex on attitudes on abortion was not proved statistically. Impact of religiousness on that attitude cannot be commented due to very small share of unreligious students in the sample. PMID- 29278639 TI - Pioglitazone Attenuates Atherosclerosis in Diabetic Mice by Inhibition of Receptor for Advanced Glycation End-Product (RAGE) Signaling. AB - BACKGROUND Peroxisome proliferator-activated receptor-g (PPAR-g) exhibits anti inflammatory and anti-diabetic properties, and is protective against cardiovascular diseases. This study aimed to determine the effects of a PPAR-g agonist pioglitazone on atherogenesis in an ApoE knockout mouse (ApoE-/-) diabetic mouse model and in a cultured vascular smooth muscle cells (VSMCs) model. MATERIAL AND METHODS Male ApoE-/- mice were rendered diabetic by 5 daily intraperitoneal injections of streptozotocin. Pioglitazone (20 mg/kg/d) or PPAR gamma inhibitor GW9662 (1 mg/kg/d) were administered for 12 weeks. At the end of treatment, mice were killed and the aortae were isolated. Oil Red O staining was used to evaluate atherosclerotic plaque area. H&E staining was used to evaluate the number of complicated plaques. Western blotting and immunohistochemistry were used to determine the expression of advanced glycation end-products (RAGE) and PPAR-gamma. The effects of pioglitazone and GW9662 on RAGE and PPAR-g expression were examined in cultured primary mouse VSMCs in hyperglycemic conditions. RESULTS Administration of pioglitazone in diabetic ApoE-/- mice successfully reduced atherosclerotic plaque area and the number of complicated plaques. Moreover, pioglitazone inhibited RAGE and stimulated PPAR-gamma protein expression in atherosclerotic plaques of diabetic ApoE-/- mice. In cultured VSMCs upon high-glucose challenge, pioglitazone downregulated RAGE mRNA and protein expression. Blockade of PPAR-gamma activity by GW9662 remarkably attenuated the inhibitory actions of pioglitazone on atherogenesis, both in diabetic ApoE-/- mice and in cultured VSMCs, upon high-glucose challenge. CONCLUSIONS Pioglitazone has a therapeutic effect on atherosclerosis in diabetes, and inhibition of RAGE signaling plays a critical role in mediating the beneficial effects of pioglitazone. PMID- 29278640 TI - Infant cardiopulmonary bypass: CD73 kinetics, association with clinical outcomes, and influence on serum adenosine production capacity. AB - BackgroundExtracellular adenine nucleotides contribute to ischemia-reperfusion injury following infant cardiopulmonary bypass (CPB), whereas conversion to adenosine may be protective. Alkaline phosphatase (AP), a key enzyme responsible for this conversion, decreases after infant CPB. Indirect evidence suggests that soluble CD73 may simultaneously increase and partially offset this loss of AP. We sought to measure CD73 levels in infants undergoing CPB and determine its association with adenosine production capacity and postoperative support requirements.MethodsA prospective cohort study of infants <=120 days of age undergoing CPB. CD73 was measured before CPB and during rewarming. Multivariable modeling evaluated the contributions of CD73/AP to adenosine production capacity and postoperative support requirements.ResultsSerum samples from 85 subjects were analyzed. The median CD73 concentration increased following CPB (95.2 vs. 179.8 ng/ml; P<0.0001). Rewarming CD73 was independently inversely associated with vasoactive inotropic support (P<0.005) and length of intensive care unit stay (P<0.005). Combined AP activity and CD73 concentration predicted adenosine production capacity (P<0.0001).ConclusionsSerum CD73 increases following infant CPB. Low rewarming CD73 is independently associated with increased postoperative support requirements. CD73 and AP together predict serum adenosine production capacity and may represent potential therapeutic targets to clear extracellular adenine nucleotides and improve outcomes following infant CPB. PMID- 29278641 TI - Reduction of brain volumes after neonatal cardiopulmonary bypass surgery in single-ventricle congenital heart disease before Fontan completion. AB - BackgroundLittle is known about the relationship between brain volumes and neurodevelopmental outcome at 2 years of age in children with single-ventricle congenital heart disease (CHD). We hypothesized that reduced brain volumes may be associated with adverse neurodevelopmental outcome.MethodsVolumetric segmentation of cerebral magnetic resonance imaging (MRI) scans was carried out in 44 patients without genetic comorbidities and in 8 controls. Neurodevelopmental outcome was assessed with the Bayley-III scales.ResultsGray matter (GM), deep GM, white matter (WM), and cerebrospinal fluid (CSF) volumes were 611+/-59, 43+/-4.5, 277+/ 30, and 16.4 ml, respectively (interquartile range (IQR) 13.1, 23.3 ml). Children undergoing neonatal cardiopulmonary bypass surgery showed smaller deep GM (P=0.005) and WM (P=0.021) volumes. Brain volumes were smaller in patients compared with controls (GM: P=0.017, deep GM: P=0.012, and WM: P=0.015), whereas CSF volumes were greater (P=0.014). Of all intracranial volumes, only CSF volume was associated with neurodevelopmental outcome, accounting for 21% (P=0.011) of variability in the cognitive composite score when combined with common risk factors in a multivariable analysis.ConclusionIncreased CSF volume represents a significant risk factor for neurodevelopmental impairment in children with single ventricle CHD. Later assessments are warranted to determine the prognostic role of intracranial volumes for long-term outcome. PMID- 29278642 TI - Maternal phenylketonuria syndrome: studies in mice suggest a potential approach to a continuing problem. AB - BackgroundUntreated phenylketonuria (PKU), one of the most common human genetic disorders, usually results in mental retardation. Although a protein-restricted artificial diet can prevent retardation, dietary compliance in adults is often poor. In pregnant PKU women, noncompliance can result in maternal PKU syndrome, where high phenylalanine (Phe) levels cause severe fetal complications. Enzyme substitution therapy using Phe ammonia lyase (PAL) corrects PKU in BTBR Phe hydroxylase (Pahenu2) mutant mice, suggesting a potential for maternal PKU syndrome treatment in humans.MethodsWe reviewed clinical data to assess maternal PKU syndrome incidence in pregnant PKU women. We treated female PKU mice (on normal diet) with PAL, stabilizing Phe at physiological levels, and mated them to assess pregnancy outcomes.ResultsPatient records show that, unfortunately, the efficacy of diet to prevent maternal PKU syndrome has not significantly improved since the problem was first noted 40 years ago. PAL treatment of pregnant PKU mice shows that offspring of PAL-treated dams survive to adulthood, in contrast to the complete lethality seen in untreated mice, or limited survival seen in mice on a PKU diet.ConclusionPAL treatment reduced maternal PKU syndrome severity in mice and may have potential for human PKU therapy. PMID- 29278643 TI - Response biomarkers in neonatal intervention studies. AB - BackgroundUp to 90% of all drugs used in neonatal intensive care units (NICUs) have not been clinically tested for safety and efficacy. To promote drug development for neonates, the pharmaceutical industry is moving toward rigorous testing, necessitating the need to development, and validating biomarkers in neonates to predict their response. The objective of this review is to evaluate the quality of the response biomarker reporting in neonatal clinical trials.MethodsA validated literature search strategy was applied. Prospective neonatal intervention studies reporting response biomarkers published in 2014 were included. The data were extracted independently and in duplicate using a data-extraction form.ResultsFollowing the full-text review, 167 published prospective neonatal trials were included; 35% (59/167) reported the use of response biomarkers. In these 59 trials, we identified 275 biomarkers used to measure the response (pharmacodynamics and safety) reported as primary or secondary outcomes. Heart rate and oxygen saturation were the most commonly reported. Measurement and instrumentation data were often not provided.ConclusionWe identified a huge variability in the selection, measurement, and reporting of neonatal response biomarkers in prospective intervention studies. Reporting initiatives are needed to reduce research waste and improve the reproducibility of biomarker use in neonatal intervention studies. PMID- 29278644 TI - Endothelial cells of extremely premature infants display impaired immune response after proinflammatory stimulation. AB - BackgroundEndothelial cells (ECs) exert immunological functions such as production of proinflammatory cytokines/chemokines as well as facilitation of extravasation of immune cells into infected tissue. Limited data are available on the functionality of ECs from extremely preterm neonates during infection. Accordingly, the aim of our study was to investigate the immune response of premature ECs after proinflammatory stimulation.MethodsCell adhesion receptors' expression and function, nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFkappaB) signaling, and chemokine production were analyzed in umbilical cord ECs from extremely preterm and term neonates after proinflammatory stimulation.ResultsP-selectin and E-selectin surface expression as well as NFkappaB signaling were lower after lipopolysaccharide (LPS) stimulation in premature ECs. Preterm ECs exhibited lower, but significant, cell-adhesive functions after LPS stimulation compared with term ECs. CCL2/CXCL8 chemokine secretion was significantly upregulated after proinflammatory stimulation in both groups. CXCL10 production was significantly increased in term but not in preterm ECs upon stimulation with tumor necrosis factor compared with unstimulated ECs.ConclusionExtremely premature ECs showed partly reduced expression levels and function of cell adhesion molecules. Both NFkappaB signaling and chemokine/cytokine production were reduced in premature ECs. The diminished endothelial proinflammatory immune response might result in impaired infection control of preterm newborns rendering them prone to severe infection. PMID- 29278645 TI - Impact of preterm birth on the developing myocardium of the neonate. AB - BackgroundGlobally, ~10% of infants are born before full term. Preterm birth exposes the heart to the demands of postnatal cardiovascular function before cardiac development is complete. Our aim was to examine, in hearts collected from infants at autopsy, the effects of preterm birth on myocardial structure and on cardiomyocyte development.Methods and resultsHeart tissue was collected at perinatal autopsies of 16 infants who died following preterm birth between 23 and 36 weeks of gestation, and survived for 1-42 days; the hearts of 37 appropriately grown stillborn infants, aged 20-40 weeks of gestation, were used for comparison. Using confocal microscopy and image analysis, cardiomyocyte proliferation, maturation, ploidy, and size were quantified, and interstitial collagen and myocardial capillarization were measured. Preterm birth resulted in a marked reduction in the proliferation of cardiomyocytes relative to age-matched stillborn infant controls (preterm vs. control P<0.0001). In contrast, preterm birth did not affect heart weight, capillarization, interstitial collagen or cardiomyocyte maturation, ploidy, and size.ConclusionsPreterm birth appears to lead to an abrupt reduction in cardiomyocyte cell division. This reduced cardiomyocyte proliferation in preterm infants may adversely impact upon the final number of cardiomyocytes which may reduce cardiac functional reserve, and impair the reparative capacity of the myocardium. PMID- 29278646 TI - Impact of dietary nutrient intake and physical activity on body composition and growth in Indian children. AB - BackgroundTo investigate interrelationships of dietary composition and physical activity (PA) with growth and body composition (BC) in urban Indian school children.MethodsA cross-sectional study was performed in 4,747 Indian school children (2,623 boys) aged 3-18 years. Weight, height, BC by body impedance analyzer, PA and dietary food intakes by questionnaire method were recorded.ResultsMean daily energy and protein intakes as recommended dietary allowance were significantly lower in both boys and girls (P<0.01) above 6 years, with 55% reduction in micronutrient intakes in older children. When compared with World Health Organization references, lower heights in pubertal boys and girls were related to dietary energy and protein intake. Multiple regression analysis showed positive association of height for age z-scores (HAZ) with midparental height z-scores (beta=0.45, P=0.0001) and protein density (beta=0.103, P=0.014). HAZ was negatively associated with inactivity (beta=-0.0001, P=0.049) in boys and girls (R2=0.104, P<0.01). Further, body fat percentage was negatively correlated with moderate or light activity and antioxidant intakes (P<0.01) but not with dietary fat intake. Percentage muscle mass was positively correlated with moderate activity and negatively with inactivity (P<0.05).ConclusionAdequacy of protein and antioxidant intakes, reducing inactivity and increasing moderate activity are essential for optimal growth and body composition in Indian children. PMID- 29278647 TI - Effectiveness of a stunting recovery program for children treated in a specialized center. AB - BackgroundStunting is still very prevalent in many poor and developing regions in the world. This study assessed the effectiveness of a stunting recovery program in children and its associated factors.MethodsThe retrospective study was conducted in a center of stunting recovery. There, children stayed in a day hospital system (9 h per day; 5 days per week), and received five meals per day, providing 80% of their energetic daily needs. The main outcome was the stunting recovery rate (i.e., the child present a height-for-age index (HAZ) >-1.0 at the time of data collection). A total of 75 children treated for at least 24 months, aged between 6 and 48 months and with an HAZ <-2.0 at the time of admission were included.ResultsThe average treatment time was 41 months. About 18 children (24.0%) recovered from stunting. The variable "age at admission >24 months" (prevalence rate (PR)=0.39, 95% confidence interval (CI): 0.15-0.99; P=0.04) and the variable "Household crowding index" (PR=0.65, 95% CI: 0.44-0.95; P=0.03) were associated with the success of the treatment.ConclusionThe environmental conditions in which the children live in their households and late admission to the center negatively influenced the success of stunting recovery, even with an intensive treatment. PMID- 29278648 TI - Clock represses preadipocytes adipogenesis via GILZ. AB - Adiposity is a worldwide health threat that needs to be prevented. Circadian gene Clock (circadian locomotor output cycles kaput) is closely correlated to adiposity; for example, weight gain, adipocytes size expansion, and serum lipid level rise in ClockDelta19 mice compared to C57BL/6J mice. However, the precise role of Clock during adipogenic differentiation is unknown. Herein, the circadian gene Clock is shown to regulate adipogenesis mediated by GILZ. Clock-mediated attenuation and upregulation influenced lipid synthesis and affected the levels of adipogenic transcriptional factors, C/EBP-beta, C/EBP-alpha, PPAR-gamma, and FABP4, both in vivo and in vitro (primary adipose-derived stromal cells and 3T3 L1 cells). Chromatin immunoprecipitation (ChIP) assay, reporter gene assay, and serum shock assay found that Clock transcriptionally regulated the glucocorticoid induced leucine zipper (GILZ). Furthermore, GILZ attenuation could relieve the inhibitory effect of Clock on lipid synthesis and GILZ overexpression also reduced the promotion role of Clock attenuation in adipogenesis suggesting that Clock inhibits adipogenic differentiation of preadipocytes via GILZ. The current results demonstrate how circadian genes are likely to regulate adiposity, affecting the adipogenic differentiation process, as well as, increasing the fat cells number. Therefore, this study may provide novel insights into the underlying mechanism explaining the correlation between Clock mutation and adiposity. PMID- 29278649 TI - Citrate Content of Bone as a Measure of Postmortem Interval: An External Validation Study. AB - The postmortem interval (PMI) of skeletal remains is a crucial piece of information that can help establish the time dimension in criminal cases. Unfortunately, the accurate and reliable determination of PMI from bone continues to evade forensic investigators despite concerted efforts over the past decades to develop suitable qualitative and quantitative methods. A relatively new PMI method based on the analysis of citrate content of bone was developed by Schwarcz et al. The main objective of our research was to determine whether this work could be externally validated. Thirty-one bone samples were obtained from the Forensic Anthropology Center, University of Tennessee, Knoxville, and the Onondaga County Medical Examiner's Office. Results from analyzing samples with PMI greater than 2 years suggest that the hypothetical relationship between the citrate content of bone and PMI is much weaker than reported. It was also observed that the average absolute error between the PMI value estimated using the equation proposed by Schwarcz et al. and the actual ("true") PMI of the sample was negative indicating an underestimation in PMI. These findings are identical to those reported by Kanz et al. Despite these results this method may still serve as a technique to sort ancient from more recent skeletal cases, after further, similar validation studies have been conducted. PMID- 29278650 TI - Synthesis of [15 N]-cholamine bromide hydrobromide. AB - [15 N]-Cholamine is an isotope tag for metabolomics research, because it possesses 2 important properties: an NMR active isotope and a permanent charge for MS sensitivity. Here, we present a scalable synthesis of [15 N]-cholamine. PMID- 29278651 TI - AP1 mediates uPA/uPAR induced FUT4 expression and trophoblast invasion. AB - Trophoblast invasion is crucial for embryo implantation and successful pregnancy. Urokinase-type plasminogen activator (uPA)/urokinase-type plasminogen activator receptor (uPAR) are expressed on trophoblasts and involved in trophoblast invasion. The transcription factor activator protein 1 (AP1) (c-Fos and cJun) and fucosyltransferase IV (FUT4) have been found to be involved in this process. However, the relationship of uPA/uPAR, AP1 and FUT4 is unclear. The current study aimed to investigate the role of AP1 in uPA/uPAR induced FUT4 expression and trophoblast invasion. We found that p-c-Fos and p-c-Jun were decreased in abortion patients compared to that in normal pregnant women. Employing human trophoblastic cells, we then demonstrated that uPA/uPAR induced the expression of p-c-Fos and p-c-Jun. Applying an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP), we further proved that transcription factor AP1 bound to FUT4 promoter that could increase FUT4 transcriptional activity, further promoting trophoblast cell migration and invasion through JNK MAPK signaling pathway. Taken together, these results suggest that uPA/uPAR induces FUT4 expression, and trophoblast cell invasion mediated by AP1 transcription factor (c-Fos and c-Jun). Our findings provide novel insights into the relationship between AP1 and abortion. PMID- 29278652 TI - PARP1 induces cardiac fibrosis by mediating mTOR activity. AB - Cardiac fibrosis is involved in nearly all forms of heart diseases, and is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs). We and others have reported the possibility of poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, as a novel therapeutic target of heart diseases. The cardiac fibrotic induction of mTOR (mammalian target of rapamycin) is mainly due to collagen expression, Smad3 and p53/JNK-mediated apoptosis. However, the possible link between PARP1 and mTOR in the progression of cardiac fibrosis remains unclear. In this study, PARP1 protein expression, and the activity of mTOR and its three target substrates (S6K1, 4E-BP and ULK1) were augmented; meanwhile, the NAD content was significantly reduced in the process of cardiac fibrosis in vivo and in vitro. SD rats were intraperitoneally injected with 3AB (20 mg/kg/d, a well established PARP1 inhibitor) or rapamycin (Rapa, 1 mg/kg/d, used for mTOR inhibition) 7 days after AAC (abdominal aortic constriction) surgery for 6 weeks. Pre-treatment of 3AB or Rapa both relieved AAC-caused cardiac fibrosis and heart dysfunction. Overexpression of PARP1 with adenovirus carrying PARP1 gene (Ad PARP1) specifically transduced into the hearts via intramyocardial multi-point injection caused similar myocardial damage. In CFs, pre-incubation with PARP1 or mTOR inhibitors all blocked TGF-beta1-induced cardiac fibrosis. PARP1 overexpression evoked cardiac fibrosis, which could be antagonized by mTOR inhibitors or NAD supplementation in CFs. These results provide novel and compelling evidence that PARP1 exacerbated cardiac fibrosis, which was partially attributed to NAD-dependent activation of mTOR. This article is protected by copyright. All rights reserved. PMID- 29278653 TI - Physicochemical, Thermal, and Sensory Properties of Blue Corn (Zea Mays L.). AB - : The aim of this study was to investigate some physicochemical and sensory properties of blue corn cultivated in Turkey. The length and width of the cob with kernels, hectoliter, and 1000-kernel weight of blue corn were measured as 7.66, 2.02 mm, 84.40 kg/100 L, and 44.27 g, respectively. The gelatinization onset, peak, and end temperatures were measured as 61.12 degrees C, 64.35 degrees C, and 75.65 degrees C, respectively. The water activity, moisture content, total protein, lipid, and crude fiber contents of the blue corn sample were detected as 0.44, 9.39%, 13.13%, 4.30%, and 2.68%, respectively. Total starch and resistant starch contents of blue corn were determined as 63.94% and 8.89%, respectively. Also, total monomeric anthocyanin content and antioxidant capacity of blue corn were detected as 915.43 mg CGE/kg and 7.99 MUmol TE/g, respectively. Additionally, the major fatty acids detected in blue corn samples were palmitic, stearic, oleic, and linoleic acids. PRACTICAL APPLICATION: Blue corn can be utilized in the production of enjoyable and healthier snacks, such as popcorn and chips, because of its color and high phenolic, anthocyanin, and fiber contents. PMID- 29278654 TI - Up-to-seven criteria as a useful predictor for tumor downstaging to within Milan criteria and Child-Pugh grade deterioration after initial conventional transarterial chemoembolization. AB - AIM: Intermediate-stage hepatocellular carcinoma varies widely in tumor burden and liver function. This study aimed to clarify the importance of subclassification by the up-to-seven criteria in both clinical course and liver function deterioration in such patients. METHODS: We retrospectively analyzed 224 patients with Child-Pugh grade A who underwent initial transarterial chemoembolization (TACE) for hepatocellular carcinoma. Tumor downstaging to within the Milan criteria within 1 year and liver function worsening as Child Pugh grade deterioration from A to B were analyzed. RESULTS: The median survival time was 35.8 months. Forty-five patients had no recurrence within 1 year after initial TACE. Of the 179 patients with at least one recurrence within a year, 44 (25%) achieved tumor downstaging to within the Milan criteria and showed significantly longer survival than non-downstaged ones (P = 0.02). Logistic regression univariate analysis revealed that up-to-seven criteria fulfillment was associated with tumor downstaging to within the Milan criteria (odds ratio 2.6; P = 0.007). The median deterioration time was 26.7 months. Multivariate analysis revealed that beyond the up-to-seven criteria (hazard ratio [HR] 1.9; P = 0.005) was an independent factor associated with Child-Pugh grade deterioration, along with serum albumin (HR 1.54; P = 0.01), serum bilirubin (HR 1.49; P = 0.02), and prothrombin time (HR 1.54; P = 0.04). CONCLUSIONS: The up-to-seven criteria had prognostic value and could predict non-critical recurrence and maintenance of Child-Pugh grade in patients who underwent initial conventional TACE. PMID- 29278655 TI - Eosinophilic esophagitis in Japan: Focus on response to acid suppressive therapy. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by esophageal dysfunction and dense eosinophilic infiltration of esophageal epithelium. According to clinical consensus and guidelines published in 2011, esophageal eosinophilia was classified into two entities based on response to proton pump inhibitor (PPI) administration: EoE and PPI-responsive esophageal eosinophilia (PPI-REE). We have performed a series of investigations to determine whether EoE is actually different from PPI-REE. Consistent with Western reports, more than half of our examined patients with symptomatic esophageal eosinophilia suggestive of EoE achieved histological remission with single PPI therapy. Furthermore, our comparisons of clinical, endoscopic, and histopathological findings between patients with EoE and those with PPI-REE revealed nearly no differences between them. We also compared gene expression profiles in mucosal biopsy specimens between those groups and found that microarray findings obtained from PPI-REE patients substantially overlapped with those from EoE patients, suggesting that both represent the same condition or are variations of a single disease. In addition, we have noted that more than half of EoE patients who show resistance to a PPI therapy respond to vonoprazan, a novel potassium-competitive acid blocker that has been shown to provide more potent and sustained suppression of gastric acid secretion than PPIs. Our results indicate that PPI-REE may constitute a subtype of EoE. Based on novel evidence including results obtained in our studies, the most recently updated guidelines have included responders to PPI therapy within the spectrum of EoE, abandoning the term PPI-REE. PMID- 29278656 TI - Biological Activities of Camelina and Sophia Seeds Phenolics: Inhibition of LDL Oxidation, DNA Damage, and Pancreatic Lipase and alpha-Glucosidase Activities. AB - : The free, esterified and insoluble-bound phenolics of defatted meals of camelina and sophia seeds were extracted using an ultrasonic-assisted procedure and alkaline hydrolysis. The antioxidant activities of the extracts were evaluated using DPPH and hydroxyl radical scavenging assays as well as inhibition of bleaching of beta-carotene in an oil-in-water system. Moreover, inhibition activity against pancreatic lipase, alpha-glucosidase, low density lipoprotein (LDL) oxidation and DNA damage induced by peroxyl and hydroxyl radicals were examined for all seed extracts using in vitro systems. The seed extracts of camelina and sophia not only showed significant antioxidant activity but also inhibited pancreatic lipase and alpha-glucosidase activities effectively. These enzymes in the digestive tract are associated with lipid and carbohydrate digestion, respectively, and control obesity and blood glucose level in the human body. The findings of this work may provide supporting information that camelina and sophia meals may inhibit human LDL oxidation and DNA nicking caused by free radicals and upon consumption may also exert anti-obesity and antidiabetic effects. However, further research is required to confirm these biological activities in vivo. PRACTICAL APPLICATION: The seed phenolic extracts of camelina and sophia not only showed significant antioxidant activity but also effectively inhibited the activities of pancreatic lipase and alpha-glucosidase. Thus, camelina and sophia seed meals may serve as nutritional ingredients with bioactive phenolics that show in vitro antioxidant and biological effects. However, further research is required to confirm these health effects in vivo. PMID- 29278657 TI - Inhibition of autophagy potentiates the anti-metastasis effect of phenethyl isothiocyanate through JAK2/STAT3 pathway in lung cancer cells. AB - Phenethyl isothiocyanate (PEITC) is a natural compound abundant in cruciferous vegetables. PEITC possesses anti-tumor effect in various human malignances. Our previous study has shown that benzyl isothiocyanates (BITC) induce autophagy in lung cancer cells. However, whether autophagy play a role in the inhibitory effect of PEITC on lung cancer metastasis is unclear. In this study, we found that PEITC suppressed migration and invasion of lung cancer cells by regulating MMP2. It also induced autophagy, evidenced by the formation of acidic vesicular organelles (AVOs), the punctate pattern of LC3, the accumulation of LC3-II, and the expression of Beclin-1. Inhibition of autophagy by 3-MA and chloroquine (CQ) or knock down of Beclin-1 enhanced PEITC-caused metastasis inhibition. JAK2/STAT3 pathway was suppressed by PEITC, and further inhibited by 3-MA and CQ or Beclin-1 knock down, as a result of decreased expression of p-JAK2 and p-STAT3. Blocking JAK2/STAT3 pathway by inhibitor AG490 and Stattic suppressed cell migration and decreased the expression of MMP2, MMP9, Twist, and c-Myc. Further in vivo study showed that PEITC inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3 pathway, and inhibitor CQ enhanced this effect. Taken together, our results demonstrate that PEITC inhibits metastasis potential of lung cancer cells, and induces autophagy. The autophagy induced by PEITC preserves metastasis potential of lung cancer cells, via activation of JAK2/STAT3 pathway. Inhibition of autophagy enhanced the inhibitory effect of PEITC on metastasis potential of lung cancer cells. Our finding suggests that targeting autophagy could be a promising strategy for anti-metastasis therapies. PMID- 29278658 TI - Construction of a Dose-Illness Relationship via Modeling Morbidity and Application to Risk Assessment of Wastewater Reuse. AB - A disease burden (DB) evaluation for environmental pathogens is generally performed using disability-adjusted life years with the aim of providing a quantitative assessment of the health hazard caused by pathogens. A critical step in the preparation for this evaluation is the estimation of morbidity between exposure and disease occurrence. In this study, the method of a traditional dose response analysis was first reviewed, and then a combination of the theoretical basis of a "single-hit" and an "infection-illness" model was performed by incorporating two critical factors: the "infective coefficient" and "infection duration." This allowed a dose-morbidity model to be built for direct use in DB calculations. In addition, human experimental data for typical intestinal pathogens were obtained for model validation, and the results indicated that the model was well fitted and could be further used for morbidity estimation. On this basis, a real case of a water reuse project was selected for model application, and the morbidity as well as the DB caused by intestinal pathogens during water reuse was evaluated. The results show that the DB attributed to Enteroviruses was significant, while that for enteric bacteria was negligible. Therefore, water treatment technology should be further improved to reduce the exposure risk of Enteroviruses. Since road flushing was identified as the major exposure route, human contact with reclaimed water through this pathway should be limited. The methodology proposed for model construction not only makes up for missing data of morbidity during risk evaluation, but is also necessary to quantify the maximum possible DB. PMID- 29278659 TI - Decreased levels of serum exosomal miR-638 predict poor prognosis in hepatocellular carcinoma. AB - Currently available studies have implicated that exosome-delivered microRNAs (miRNAs) play crucial roles in human cancer. However, the association of serum exosomal miR-638 and hepatocellular carcinoma (HCC) remains largely unknown. We aim to investigate the expression of exosomal miR-638 in serum of HCC patients and its prognostic role in this deadly disease. Kaplan-Meier and Cox regression analyses were used to determine the survival of patients histologically diagnosed with HCC. Reduced levels of exosomal miR-638 in serum samples from patients with HCC were identified by real-time PCR. Negative association of serum exosomal miR 638 with tumor size, vascular infiltration, and TNM stage was observed in HCC patients. Besides, the proliferation of Huh7 and SMCC7721 HCC cells were significantly inhibited when miR-638 was over-expressed in these cells. In addition, HCC patients with lower levels of serum exosomal miR-638 had poor overall survival than those with higher levels of exosomal miR-638 in serum. Our study strongly suggests that serum exosome-delivered miR-638 may serve as a novel circulating biomarker for HCC. Downregulation of miR-638 predicts poor prognosis for patients with HCC. PMID- 29278660 TI - Breaking Down Silos and Making Use of the Evidence-Based Practice Competencies in Healthcare and Academic Programs: An Urgent Call to Action. PMID- 29278661 TI - Structural and functional responses of periphyton and macroinvertebrate communities to ferric Fe, Cu, and Zn in stream mesocosms. AB - Two mesocosm experiments were conducted to examine effects of ferric iron (Fe) and mixtures of ferric Fe with aqueous metals (Cu, Zn) on stream benthic communities. Naturally colonized benthic communities were exposed to a gradient of ferric Fe (0, 0.4, 1.0, 2.5, 6.2, and 15.6 mg/L) that bracketed the current US Environmental Protection Agency water quality criterion value (1.0 mg/L). After 10 d of exposure to ferric Fe, total macroinvertebrate abundance, number of taxa, and abundance of all major macroinvertebrate groups (Ephemeroptera, Plecoptera, Trichoptera, and Diptera) were significantly reduced. Heptageniid mayflies and chironomids were especially sensitive to Fe oxide deposition and were significantly reduced at 0.4 and 1.0 mg/L total Fe, respectively. In a second mesocosm experiment, periphyton and macroinvertebrate communities were exposed to ferric Fe (0.60 mg/L) with or without aqueous Cu and Zn at 2 treatment levels: low (0.01 mg/L Cu + 0.1 mg/L Zn) and high (0.05 mg/L Cu + 0.5 mg/L Zn). In contrast to previous research, we observed no evidence of a protective effect of Fe on toxicity of metals. Growth rates and protein content of periphyton were significantly reduced by both ferric Fe and aqueous metals, whereas abundance of heptageniid mayflies (Cinygmula) and whole community metabolism were significantly reduced by ferric Fe alone. We hypothesize that Fe oxides inhibited algal growth and enhanced metal accumulation, leading to a reduction in the quantity and quality of food resources for grazers. Mesocosm experiments conducted using natural benthic communities provide a unique opportunity to quantify the relative importance of indirect physical effects and to develop a better understanding of the relationship between basal food resources and consumers in natural stream ecosystems. Environ Toxicol Chem 2018;37:1320-1329. (c) 2017 SETAC. PMID- 29278662 TI - MicroRNA-335-5p suppresses lower extremity deep venous thrombosis by targeted inhibition of PAI-1 via the TLR4 signalingpathway. AB - This study aims to investigate the effects of microRNA-335-5p (miR-335-5p) on lower-extremity deep vein thrombosis (LEDVT) by targeting PAI-1 through the TLR4 signaling pathway in rat models. siRNA, mimic, and inhibitor were used for transfection. The miR-335-5p expression was detected by in situ hybridization. CCK-8 assay and flow cytometry were adopted to detect proliferation, cell cycle, and apoptosis, respectively. Scratch test and Matrigel-based tube formation assay were used to detect the effect of miR-335-5p on cell migration ability and tube formation ability. A miR-335-5p lentivirus plasmid was constructed and injected into LEDVT rats. The length and weight of thrombus were measured, changes of thrombus recanalization were observed by CD34 immunohistochemistry, and levels of PAI-1 and inflammatory factors in femoral vein blood were detected by ELISA. LEDVT rats showed a higher AOD value of PAI-1, higher expression of PAI-1, NF kappaB, Rac1, IL-1beta, and TLR4 and a lower miR-335-5p expression. PAI-1 and miR 335-5p were negatively correlated. Compared to the blank and siRNA-NC groups, the miR-335-5p mimic and siRNA-PAI-1 groups showed declined expression of PAI-1, TLR4, NF-kappaB, Rac1, and IL-1beta, increased proliferation and tube formation abilities, less cells in G0/G1 phase, and decreased apoptosis, decreased length and weight of thrombus, organized thrombus, increased new blood vessels, and decreased levels of PAI-1, IL-1, IL-6, and Tnf-a. miR-335-5p may suppress the occurrence and development of LEDVT in rats by repressing the activation of the TLR4 signaling pathway by targeted inhibition of PAI-1. PMID- 29278663 TI - Do Australian adolescents' and young adults' experiences of cancer care influence their quality of life? AB - OBJECTIVE: To examine the relationship between the cancer care experiences of adolescents and young adults (AYAs) and their quality of life. METHODS: Two hundred and nine AYAs completed a cross-sectional, self-report survey distributed through the population-based cancer registries in 2 Australian states (New South Wales and Victoria). Eligible AYAs were 15 to 24 years old when diagnosed with any cancer (excluding early-stage melanoma) and were 3 to 24 months post diagnosis. Questions examined whether particular care experiences occurred for the patient at different points in the cancer care pathway, including diagnosis, treatment, inpatient care, and at the end of treatment. Quality of life was assessed using the Functional Assessment of Cancer Therapy-General scale. RESULTS: Positive experiences of care at diagnosis, during treatment, during inpatient stays, and when finishing treatment were associated with higher functional, emotional, and social well-being. However, these associations generally became nonsignificant when communication and support experiences were included in the model. Inpatient experiences positively influenced emotional well being over and above the effect of communication and support experiences. CONCLUSIONS: The results suggest that, for most AYAs' quality of life outcomes, positive experiences of age-appropriate communication and emotional support may underpin the effect of positive experiences of care throughout the cancer care pathway. The results support the need for communication and support tailored to an AYA audience, as recognised by recent Australian and international guidelines on the care of AYAs with cancer. PMID- 29278664 TI - The First U.S. Study on Nurses' Evidence-Based Practice Competencies Indicates Major Deficits That Threaten Healthcare Quality, Safety, and Patient Outcomes. AB - BACKGROUND: Tremendous variability in EBP persists throughout the United States even though research supports that implementation of EBP leads to high-quality cost-effective care. Although the first set of EBP competencies for nurses was published in 2014, the state of EBP competency in U.S. nurses is currently unknown. AIMS: The purposes of this study were to: (a) describe the state of EBP competency in nurses across the United States; and (b) determine important factors associated with EBP competency. METHODS: A cross-sectional descriptive study was conducted that gathered data from an anonymous online survey of practicing nurses throughout the U.S. Measures tapped EBP knowledge, beliefs, culture, mentorship, implementation, and reported competency for each of the 13 EBP competencies for practicing nurses and an additional 11 competencies for advanced practice nurses. RESULTS: A total of 2,344 nurses completed the survey from 19 hospitals or healthcare systems. Overall, the nurses reported that they were not yet competent in meeting any of the 24 EBP competencies. Younger nurses and those with higher levels of education reported higher EBP competency (p < .001). The EBP competency scores were not significantly different between nurses in Magnet and non-Magnet designated organizations (p = .28). There were strong positive associations between EBP competency with EBP beliefs (r = .66) and EBP mentorship (r = .69), a moderate positive association between EBP competency and EBP knowledge (r = .43), and a small positive association between EBP competency and culture (r = .29). LINKING EVIDENCE TO ACTION: There is a tremendous need to enhance nurses' skills so that they achieve competency in EBP in order to ensure the highest quality of care and best population health outcomes. Academic programs should ensure competency in EBP in students by the time of graduation and healthcare systems should set it as an expectation and standard for all clinicians. PMID- 29278665 TI - Hyperspectral Imaging in Tandem with R Statistics and Image Processing for Detection and Visualization of pH in Japanese Big Sausages Under Different Storage Conditions. AB - : The potential of hyperspectral imaging with wavelengths of 380 to 1000 nm was used to determine the pH of cooked sausages after different storage conditions (4 degrees C for 1 d, 35 degrees C for 1, 3, and 5 d). The mean spectra of the sausages were extracted from the hyperspectral images and partial least squares regression (PLSR) model was developed to relate spectral profiles with the pH of the cooked sausages. Eleven important wavelengths were selected based on the regression coefficient values. The PLSR model established using the optimal wavelengths showed good precision being the prediction coefficient of determination (Rp2 ) 0.909 and the root mean square error of prediction 0.035. The prediction map for illustrating pH indices in sausages was for the first time developed by R statistics. The overall results suggested that hyperspectral imaging combined with PLSR and R statistics are capable to quantify and visualize the sausages pH evolution under different storage conditions. PRACTICAL APPLICATION: In this paper, hyperspectral imaging is for the first time used to detect pH in cooked sausages using R statistics, which provides another useful information for the researchers who do not have the access to Matlab. Eleven optimal wavelengths were successfully selected, which were used for simplifying the PLSR model established based on the full wavelengths. This simplified model achieved a high Rp2 (0.909) and a low root mean square error of prediction (0.035), which can be useful for the design of multispectral imaging systems. PMID- 29278666 TI - Calorimetric Methods for Measuring Stability and Reusability of Membrane Immobilized Enzymes. AB - : The aim of this work is to develop calorimetric methods for characterizing the activity and stability of membrane immobilized enzymes. Invertase immobilized on a nylon-6 nanofiber membrane is used as a test case. The stability of both immobilized and free invertase activity was measured by spectrophotometry and isothermal titration calorimetry (ITC). Differential scanning calorimetry was used to measure the thermal stability of the structure and areal concentration of invertase on the membrane. This is the 1st demonstration that ITC can be used to determine activity and stability of an enzyme immobilized on a membrane. ITC and spectrophotometry show maximum activity of free and immobilized invertase at pH 4.5 and 45 to 55 degrees C. ITC determination of the activity as a function of temperature over an 8-h period shows a similar decline of activity of both free and immobilized invertase at 55 degrees C. PRACTICAL APPLICATION: Enzyme catalyzed reactions occur in mild and environmentally friendly conditions, but are usually too costly to use in food manufacturing. When free enzymes are used, they are used once and replaced for each reaction, but enzymes immobilized on a solid support can be reused and have the additional advantage of being removed from the product. In this study, new calorimetric methods that are universally applicable to characterizing immobilized enzymes are used to determine the activity, stability, and reusability of invertase immobilized on a nanofiber support. PMID- 29278668 TI - Evaluation of the Influenza Risk Reduction from Antimicrobial Spray Application on Porous Surfaces. AB - Antimicrobial spray products are used by millions of people around the world for cleaning and disinfection of commonly touched surfaces. Influenza A is a pathogen of major concern, leading to up to 49,000 deaths and 114,000 hospitalizations per year in the United States alone. One of the recognized routes of transmission for influenza A is by transfer of viruses from surfaces to hands and subsequently to mucous membranes. Therefore, routine cleaning and disinfection of surfaces is an important part of the environmental management of influenza A. While the emphasis is generally on spraying hard surfaces and laundering cloth and linens with high temperature machine drying, not all surfaces can be treated in this manner. The quantitative microbial risk assessment (QMRA) approach was used to develop a stochastic risk model for estimating the risk of infection from indirect contact with porous fomite with and without surface treatment with an antimicrobial spray. The data collected from laboratory analysis combined with the risk model show that influenza A infection risk can be lowered by four logs after using an antimicrobial spray on a porous surface. Median risk associated with a single touch to a contaminated fabric was estimated to be 1.25 * 10-4 for the untreated surface, and 3.6 * 10-8 for the treated surface as a base case assumption. This single touch scenario was used to develop a generalizable model for estimating risks and comparing scenarios with and without treatment to more realistic multiple touch scenarios over time periods and with contact rates previously reported in the literature. The results of this study and understanding of product efficacy on risk reduction inform and broaden the range of risk management strategies for influenza A by demonstrating effective risk reduction associated with treating nonporous fomites that cannot be laundered at high temperatures. PMID- 29278669 TI - Accelerated Development of Hippocampal Neurons and Limited Adhesion of Astrocytes on Negatively Charged Surfaces. AB - This work examines the development of primary neurons and astrocytes on thoroughly controlled functional groups. Negatively charged surfaces presenting carboxylate (COO-) or sulfonate (SO3-) groups prove beneficial to neuronal behavior, in spite of their supposed repulsive electrostatic interactions with cellular membranes. The adhesion and survival of primary hippocampal neurons on negatively charged surfaces are comparable to or slightly better than those on positively charged (poly-d-lysine-coated) surfaces, and neuritogenesis and neurite outgrowth are accelerated on COO- and SO3- surfaces. Moreover, such favorable influences of the negatively charged surfaces are only seen in neurons but not for astrocytes. Our results indicate that the in vitro developmental behavior of primary hippocampal neurons is sophisticatedly modulated by angstrom sized differences in chemical structure or the charge density of the surface. We believe that this work provides new implications for understanding neuron material interfaces as well as for establishing new ways to fabricate neuro active surfaces. PMID- 29278667 TI - Cancer terminator viruses (CTV): A better solution for viral-based therapy of cancer. AB - In principle, viral gene therapy holds significant potential for the therapy of solid cancers. However, this promise has not been fully realized and systemic administration of viruses has not proven as successful as envisioned in the clinical arena. Our research is focused on developing the next generation of efficacious viruses to specifically treat both primary cancers and a major cause of cancer lethality, metastatic tumors (that have spread from a primary site of origin to other areas in the body and are responsible for an estimated 90% of cancer deaths). We have generated a chimeric tropism-modified type 5 and 3 adenovirus that selectively replicates in cancer cells and simultaneously produces a secreted anti-cancer toxic cytokine, melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24), referred to as a Cancer Terminator Virus (CTV) (Ad.5/3-CTV). In preclinical animal models, injection into a primary tumor causes selective cell death and therapeutic activity is also observed in non-injected distant tumors, that is, "bystander anti-tumor activity." To enhance the impact and therapeutic utility of the CTV, we have pioneered an elegant approach in which viruses are encapsulated in microbubbles allowing "stealth delivery" to tumor cells that when treated with focused ultrasound causes viral release killing tumor cells through viral replication, and producing and secreting MDA-7/IL-24, which stimulates the immune system to attack distant cancers, inhibits tumor angiogenesis and directly promotes apoptosis in distant cancer cells. This strategy is called UTMD (ultrasound targeted microbubble-destruction). This novel CTV and UTMD approach hold significant promise for the effective therapy of primary and disseminated tumors. PMID- 29278670 TI - A novel compound heterozygous mutation in the CYP17A1 gene in a patient with 17alpha-hydroxylase/17,20-lyase deficiency. AB - PURPOSE: 17alpha-hydroxylase/17,20-lyase deficiency is a rare disease caused by mutation of the CYP17A1 gene, resulting in hypertension, hypokalemia, alkalosis, female hypogonadism, and male pseudohermaphroditism. Here we report a case of a 15-year-old girl with 17alpha-hydroxylase/17,20-lyase deficiency, and analyze her clinical and molecular genetic characteristics. PATIENT AND METHODS: A 15-year old Chinese girl had fever, fatigue, high blood pressure, and blood potassium level being significantly lower than normal. Physical examination showed that the patient's breasts were in Tanner stage 1, and she had no armpit hair or pubic hair, but had a normal external genital formation. The hormone concentrations of the patient were measured. Genomic DNA from the patient and her immediate family members was amplified and sequenced. Mutational analysis of the CYP17A1 gene was performed and 17alpha-hydroxylase/17,20-lyase enzymatic activities were assessed in vitro. RESULTS: The patient had clinical features of 17alpha-hydroxylase/17,20 lyase deficiency, including hypokalemia, hypertension, female sexual infantilism, low blood cortisol, estradiol, and plasma renin activity, and increased adrenocorticotropic hormone. DNA sequence analysis revealed compound heterozygous mutations (Ser106Pro/His373Tyr) in CYP17A1. The heterozygous Ser106Pro mutation was detected in the patient's father, whereas the novel heterozygous His373Tyr mutation (c.1117C>T) was detected in her mother. In vitro expression and functional analysis in HEK293 cells showed that this novel mutation His373Tyr resulted in complete loss of 17alpha-hydroxylase and 17,20-lyase activities. CONCLUSION: We identified a novel compound heterozygous CYP17A1 mutation His373Tyr (c.1117C>T) in a patient with 17alpha-hydroxylase/17,20-lyase deficiency. PMID- 29278671 TI - Roles of obesity in the development and progression of breast cancer. AB - Recent preclinical and clinical data accumulate evidence indicating that obesity may worsen the incidence, severity, and mortality of many types of cancer, including breast cancer. In the present review, we discuss the candidate players in this dangerous relationship, namely adipose tissue-related chronic inflammation, immune cell dysregulation, angiogenesis, extracellular matrix stiffness, and genomic instability. Finally, we review some novel therapeutic approaches currently under investigation to prevent and blunt the effects of obesity in breast cancer development and progression, namely caloric restriction, immune checkpoint inhibition, browning of white adipose tissue, and modulation of the microbiota and the immune cell metabolism. PMID- 29278672 TI - The initiation of autoimmunity at epithelial surfaces: a focus on rheumatoid arthritis and systemic lupus erythematosus. AB - It is well established that the autoantibodies that characterize both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are present systemically years before patients develop disease. In both these autoimmune rheumatic diseases, evidence is growing that local autoimmune processes occur at epithelial surfaces potentially initiating localized autoimmunity. For RA, these are mucosal surfaces including the oral mucosa, lung, and gut. At the oral mucosa and lung, risk factors such as periodontal disease and smoking may contribute to autoimmunity by driving the local generation of citrullinated autoantigens. For SLE, the skin may be integral in pathogenesis. It is proposed that defective clearance of apoptotic debris leads to initial innate immune responses preceding autoimmunity. Many tissues may be implicated but the frequency of skin disease, even without autoantibodies, and the role of UV light as a trigger suggest that keratinocytes may be a key site of initiation. In both diseases, a local break in immune tolerance could lead to systemic autoimmunity, and, in the gut, bacterial organisms that colonize the intestine may influence the localized gut immune response through T-cells and promote the development of systemic autoimmunity. In this review, we discuss the evidence for localized epithelial autoimmunity in those at risk of RA and SLE and early disease. Localized autoimmunity at the oral mucosa, lung, gut, and skin will be considered as potential initiating sites of ARD-related autoimmunity. PMID- 29278673 TI - Immunotherapy for glioblastoma: on the sidelines or in the game? AB - The successful eradication of multiple tumor types, often in a durable manner, has recently validated the bona fide potential of an effectively mobilized immune response as a cancer therapy. Critical questions at present, therefore, include deciphering why some patients respond while others do not, as well as why certain cancers respond while others like glioblastoma do not. Glioblastoma remains a major unmet need in medical oncology and is considered incurable with less than 10% of patients surviving five years from diagnosis. Hallmark phenotypic features of glioblastoma including aberrantly activated cell proliferation, survival, invasion, angiogenesis, and treatment resistance are linked with multiple adaptive and supportive mechanisms culminating in formidable heterogeneity across and within individual tumors. Similarly, the complex adaptive abilities of glioblastoma tumors to abrogate anti-tumor immune responses are multifaceted yet integrated. Not unexpectedly, results of recent advanced clinical trials with single-agent immunotherapeutics for glioblastoma have been negative although some early stage studies and anecdotal cases have generated encouraging results. The application of immunotherapies for glioblastoma currently finds itself therefore at a pivotal crossroads. Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma tumors utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma. PMID- 29278674 TI - Antimonial susceptibility and in vivo behaviour of Leishmania major isolates collected in Algeria before and after treatment. AB - The repercussions of cutaneous leishmaniasis therapy on the behaviour and drug susceptibility of Leishmania major parasites is poorly documented. This study explored the link between antimonial susceptibility and in vivo behaviour in Leishmania major isolates collected before and after treatment in Algeria. This study was performed on 3 isolates collected from patients prior to treatment and paired with 3 isolates collected from the same patient after treatment failure. Their in vitro susceptibility towards trivalent (SbIII) and pentavalent (SbV) antimony were ascertained, and their in vivo behaviour was evaluated by determining their capacity to disseminate, proliferate and induce lesions in mice. No relationship was observed between in vitro antimony resistance and parasite fitness in the murine model. PMID- 29278676 TI - Utility of routine surveillance imaging for diffuse large B-cell lymphoma post autologous transplant: A single center experience. AB - Surveillance scans after autologous stem cell transplant (auto-HCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post auto-HCT whose recurrences were detected clinically versus with routine surveillance imaging. Among the 139 patients with RR DLBCL that underwent auto-HCT from 2000 to 2014 at our institution, 37 relapsed: 21 clinical and 16 radiological. The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p = 0.03), and median overall survival (OS) was 587 days and not reached, respectively (p = 0.006). Most patients with relapsed DLBCL after auto-HCT were diagnosed clinically and were likely to be detected earlier and have a shorter OS. Relapse in patients with aggressive disease will likely be detected when clinically apparent, and the outcome of these patients is independent of the way the relapse is diagnosed. Thus, universal scanning after auto-HCT appears to have little benefit. PMID- 29278677 TI - Intimate partner violence victims' acceptance and refusal of on-site counseling in emergency departments: Predictors of help-seeking behavior explored through a 5-year medical chart review. AB - Healthcare services constitute the first formal support that many intimate partner violence (IPV) victims receive and a link to formal welfare and psychological support. The help-seeking behavior for psychosocial support, e.g., Accident and Emergency Departments (AED) onsite counseling, is key to developing effective support for IPV victims. This study aimed to strengthen the health welfare support link to aid IPV prevention in AEDs by investigating the acceptance and refusal of on-site counseling by IPV victims. A retrospective cohort study retrieved and reviewed all records of IPV victims presenting at the AEDs of two Hong Kong hospitals between 2010 and 2014. A total of 157 male and 823 female IPV victims were identified, 295 of whom refused on-site counseling. Bivariate and multivariate analyses were performed to examine the association between help-seeking and demographic and violent injury-related factors. The odds of help-seeking via on-site counseling were significantly lower for victims with mental illness (aOR=0.49; 95% CI=0.27, 0.88). After controlling for all demographic characteristics, mental illness, and drug abuse information, sex remained an independent predictor of help-seeking (aOR=2.62; 95% CI=1.45, 4.74); victims who had experienced >2 abuse incidents were more likely to seek help than those who had experienced <=2 abuse incidents (aOR=1.90; 95% CI=1.11, 3.26). The factors associated with help-seeking from on-site services by IPV victims reflect the need for multidisciplinary collaborative work aimed at IPV prevention. Healthcare professionals require training on how to promote help-seeking behavior targeted specifically for male and female IPV victims according to their needs and preferences. PMID- 29278675 TI - The biology and therapeutic management of melanoma brain metastases. AB - The recent years have seen significant progress in the development of systemic therapies to treat patients with advanced melanoma. Use of these new treatment modalities, which include immune checkpoint inhibitors and small molecule BRAF inhibitors, lead to increased overall survival and better outcomes. Although revolutionary, these therapies are often less effective against melanoma brain metastases, and frequently the CNS is the major site of treatment failure. The development of brain metastases remains a serious complication of advanced melanoma that is associated with significant morbidity and mortality. New approaches to both prevent the development of brain metastases and treat established disease are urgently needed. In this review we will outline the mechanisms underlying the development of melanoma brain metastases and will discuss how new insights into metastasis biology are driving the development of new therapeutic strategies. Finally, we will describe the latest data from the ongoing clinical trials for patients with melanoma brain metastases. PMID- 29278678 TI - Using social media as a tool to predict syphilis. AB - Syphilis rates have been rapidly rising in the United States. New technologies, such as social media, might be used to anticipate and prevent the spread of disease. Because social media data collection is easy and inexpensive, integration of social media data into syphilis surveillance may be a cost effective surveillance strategy, especially in low-resource regions. People are increasingly using social media to discuss health-related issues, such as sexual risk behaviors, allowing social media to be a potential tool for public health and medical research. This study mined Twitter data to assess whether social media could be used to predict syphilis cases in 2013 based on 2012 data. We collected 2012 and 2013 county-level primary and secondary (P&S) and early latent syphilis cases reported to the Center for Disease Control and Prevention, along with >8500 geolocated tweets in the United States that were filtered to include sexual risk-related keywords, including colloquial terms for intercourse. We assessed the relationship between syphilis-related tweets and actual case reports by county, controlling for socioeconomic indicators and prior year syphilis cases. We found a significant positive relationship between tweets and cases of P&S and early latent syphilis. This study shows that social media may be an additional tool to enhance syphilis prediction and surveillance. PMID- 29278679 TI - Cell-specific expression and signal transduction of C-C motif chemokine ligand 2 and atypical chemokine receptors in the porcine endometrium during early pregnancy. AB - Chemokines and atypical chemokine receptors (ACKRs; also known as chemokine decoy receptors) play an important role in reproductive immunology by recruiting leukocytes during early pregnancy. The aim of this study was to determine the expression of C-C motif chemokine ligand 2 (CCL2) and ACKRs in the endometrium during estrous cycle and early pregnancy, and to investigate the functional effects of CCL2 on porcine uterine luminal epithelial (pLE) cells. Our results indicated that CCL2, ACKR1, ACKR3, and ACKR4 were strongly detected in the glandular and luminal epithelium of the endometrium during early pregnancy compared to that in non-pregnant pigs. Recombinant CCL2 improved pLE cell proliferation via activation of the PI3K and MAPK pathways and suppression of endoplasmic reticulum (ER) stress by reducing the expression of ER stress regulatory genes. Collectively, these results provide novel insights into CCL2 mediated signaling mechanisms in the porcine endometrium at the maternal-fetal interface during early pregnancy. PMID- 29278680 TI - Genetic and molecular basis of the immune system in the brachiopod Lingula anatina. AB - The extension of comparative immunology to non-model systems, such as mollusks and annelids, has revealed an unexpected diversity in the complement of immune receptors and effectors among evolutionary lineages. However, several lophotrochozoan phyla remain unexplored mainly due to the lack of genomic resources. The increasing accessibility of high-throughput sequencing technologies offers unique opportunities for extending genome-wide studies to non model systems. As a result, the genome-based study of the immune system in brachiopods allows a better understanding of the alternative survival strategies developed by these immunologically neglected phyla. Here we present a detailed overview of the molecular components of the immune system identified in the genome of the brachiopod Lingula anatina. Our findings reveal conserved intracellular signaling pathways as well as unique strategies for pathogen detection and killing in brachiopods. PMID- 29278681 TI - Asymmetric dispersal in the multi-patch logistic equation. AB - The standard model for the dynamics of a fragmented density-dependent population is built from several local logistic models coupled by migrations. First introduced in the 1970s and used in innumerable articles, this standard model applied to a two-patch situation has never been fully analyzed. Here, we complete this analysis and we delineate the conditions under which fragmentation associated with dispersal is either favorable or unfavorable to total population abundance. We pay special attention to the case of asymmetric dispersal, i.e., the situation in which the dispersal rate from patch 1 to patch 2 is not equal to the dispersal rate from patch 2 to patch 1. We show that this asymmetry can have a crucial quantitative influence on the effect of dispersal. PMID- 29278682 TI - Weight of the evidence of genetic investigations of ancestry informative markers. AB - Ancestry-informative markers (AIMs) are markers that give information about the ancestry of individuals. They are used in forensic genetics for predicting the geographic origin of the investigated individual in crime and identification cases. In the exploration of the genogeographic origin of an AIMs profile, the likelihoods of the AIMs profile in various populations may be calculated. However, there may not be an appropriate reference population in the database. The fact that the likelihood ratio (LR) of one population compared to that of another population is large does not imply that any of the populations is relevant. To handle this phenomena, we derived a likelihood ratio test (LRT) that is a measure of absolute concordance between an AIMs profile and a population rather than a relative measure of the AIMs profile's likelihood in two populations. The LRT is similar to a Fisher's exact test. By aggregating over markers, the central limit theorem suggests that the resulting quantity is approximately normally distributed. If only a few markers are genotyped or if the majority of the markers are fixed in a given population, the approximation may fail. We overcome this using importance sampling and show how exponential tilting results in an efficient proposal distribution. By simulations and published AIMs profiles, we demonstrate the applicability of the derived methodology. For the genotyped AIMs, the LRT approach achieves the nominal levels of rejection when tested on data from five major continental regions. PMID- 29278683 TI - Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing. AB - Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient. In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries. PMID- 29278684 TI - Isolation of human lymphocytes with high yield and viability from the gastrointestinal and female reproductive tract of a humanized DRAG mouse. AB - The mucosal tissues of the gut and female reproductive tract (FRT) are susceptible to pathogen infections including bacteria, viruses, and parasites, and are also the targets for immune disorders such as Crohn's disease, inflammatory bowel disease (IBD), and many types of cancers. However, the role of the mucosal immune cells to control these diseases is largely unknown. The limited availability of human mucosal biopsy tissue and the low number of cells that can be isolated from these tissues hampers the characterization of the phenotype and function of human mucosal immune cell subsets. Therefore, human immune-system humanized mice are surrogate models to investigate the human mucosal immune cell responses during the course of the disease. The current protocols used to harvest the immune cells from the mucosal tissues, however, result in low recovery of cells with poor viability. We have established a novel protocol, which results in a high yield of human lymphocytes with high viability to overcome this issue. The immune cells obtained from a single DRAG mouse by our protocol were sufficient for conducting functional assays and for flow cytometry analyses including phenotypic, exhaustion, and functional panels. PMID- 29278685 TI - Brain plasticity and sleep: Implication for movement disorders. AB - Brain plasticity is a lifelong process and involves both Hebbian and non-Hebbian synaptic plasticity. The latter, such as intrinsic plasticity and homeostatic synaptic plasticity or synaptic scaling, is thought to counteract Hebbian plasticity, in order to maintain a balanced network. Recent studies support the role of sleep in the regulation of homeostatic synaptic plasticity involved in memory and learning processes. Most evidence focus on the dependence of memory and plasticity in sleep mechanisms. Abnormal brain plasticity during sleep might be implicated in the development of movement disorders, particularly Parkinson's disease (PD) and dystonia. From that, the great interest to understand the underlying process of sleep in relation to movement disorders. The first objective of the review is to summarize the latest knowledge about brain plasticity. The second objective is to analyze the association between sleep, memory and brain plasticity. Finally, the review aims to assess the consequence of abnormal plasticity during PD and dystonia with a viewpoint on the underling pathogenesis of these disorders. PMID- 29278686 TI - LQFM030 reduced Ehrlich ascites tumor cell proliferation and VEGF levels. AB - AIMS: This study reports the biological properties of LQFM030 in vivo, a molecular simplification of the compound nutlin-1. MAIN METHODS: Ehrlich ascites tumor (EAT)-bearing mice were treated intraperitoneally with LQFM030 (50, 75 or 150mg/kg) for 10days to determine changes in ascites tumor volume, body weight, cytotoxicity and angiogenesis. Moreover, flow cytometric expression of p53 and p21 proteins and caspase-3/7, -8 and -9 activation were investigated in EAT cells from mice treated. Acute oral systemic toxicity potential of LQFM030 in mice was also investigated using an alternative method. KEY FINDINGS: Treatment of EAT bearing mice with LQFM030 resulted in a marked decline in tumor cell proliferation and the vascular endothelial growth factor (VEGF) levels along with enhanced survival of the mice. Apoptotic tumor cell death was detected through p53 and p21 modulation and increase of caspase-3/7, -8 and -9 activity. LQFM030 also showed orally well tolerated, being classified in the UN GHS category 5 (LD50>2000-5000mg/Kg). SIGNIFICANCE: LQFM030 seems to be a promising antitumor candidate for combinatory therapy with typical cytotoxic compounds, reducing the toxicity burden while allowing a superior anticancer activity. Moreover, these data also open new perspectives for LQFM030 as an antiangiogenic agent for treatment of diseases involving VEGF overexpression. PMID- 29278687 TI - Functional evaluation of natural killer cell cytotoxic activity in NFKB2-mutated patients. PMID- 29278688 TI - Stage-specific metabolic features of differentiating neurons: Implications for toxicant sensitivity. AB - Developmental neurotoxicity (DNT) may be induced when chemicals disturb a key neurodevelopmental process, and many tests focus on this type of toxicity. Alternatively, DNT may occur when chemicals are cytotoxic only during a specific neurodevelopmental stage. The toxicant sensitivity is affected by the expression of toxicant targets and by resilience factors. Although cellular metabolism plays an important role, little is known how it changes during human neurogenesis, and how potential alterations affect toxicant sensitivity of mature vs. immature neurons. We used immature (d0) and mature (d6) LUHMES cells (dopaminergic human neurons) to provide initial answers to these questions. Transcriptome profiling and characterization of energy metabolism suggested a switch from predominantly glycolytic energy generation to a more pronounced contribution of the tricarboxylic acid cycle (TCA) during neuronal maturation. Therefore, we used pulsed stable isotope-resolved metabolomics (pSIRM) to determine intracellular metabolite pool sizes (concentrations), and isotopically non-stationary 13C metabolic flux analysis (INST 13C-MFA) to calculate metabolic fluxes. We found that d0 cells mainly use glutamine to fuel the TCA. Furthermore, they rely on extracellular pyruvate to allow continuous growth. This metabolic situation does not allow for mitochondrial or glycolytic spare capacity, i.e. the ability to adapt energy generation to altered needs. Accordingly, neuronal precursor cells displayed a higher sensitivity to several mitochondrial toxicants than mature neurons differentiated from them. In summary, this study shows that precursor cells lose their glutamine dependency during differentiation while they gain flexibility of energy generation and thereby increase their resistance to low concentrations of mitochondrial toxicants. PMID- 29278689 TI - TRAIL induces apoptosis but not necroptosis in colorectal and pancreatic cancer cells preferentially via the TRAIL-R2/DR5 receptor. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that can trigger apoptosis in many types of human cancer cells via engagement of its two pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). TRAIL can also activate several other signaling pathways such as activation of stress kinases, canonical NF-kappaB signaling and necroptosis. Though both receptors are ubiquitously expressed, their relative participation in TRAIL-induced signaling is still largely unknown. To analyze TRAIL receptor-specific signaling, we prepared Strep-tagged, trimerized variants of recombinant human TRAIL with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, we examined the contribution of individual pro-apoptotic receptors to TRAIL induced signaling pathways. We found that in TRAIL-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeds comparably via both DR4- and DR5-activated signaling. TRAIL-induced apoptosis, enhanced by the inhibitor of the Bcl-2 family ABT-737, or by the translation inhibitor homoharringtonine, proceeded in both cell lines predominantly via the DR5 receptor. ShRNA-mediated downregulation of DR4 or DR5 receptors in HT-29 cells also pointed to a stronger contribution of DR5 in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was activated similarly by both DR4- or DR5-specific ligands. Activation of auxiliary signaling pathways involving NF-kappaB or stress kinases proceeded under apoptotic conditions mainly in a DR5-dependent manner, while these signaling pathways were during necroptosis similarly activated by either of these ligands. Our study provides the first systematic insight into DR4-/DR5-specific signaling in colorectal and pancreatic cancer cells. PMID- 29278690 TI - Occupational exposure to extremely low frequency magnetic fields and risk of Alzheimer disease: A systematic review and meta-analysis. AB - INTRODUCTION: Occupational exposure to extremely low frequency magnetic fields (ELF-MF) occurs in many occupations such as welders, electric utility workers, train drivers and sewing machine operators. There is some evidence suggesting ELF MF exposure to be a risk factor for Alzheimer's disease (AD). The current study aims at systematically reviewing the literature and conducting a meta-analysis to evaluate the risk of AD amongst workers exposed to ELF-MF. METHODS: Bibliographic databases were searched including PubMed, EMBASE, Cochrane Library, and Web of Science in November 2017. Risk of bias was assessed in the all included studies. Pooled estimates were obtained using random-effects meta-analysis. In addition, sources of heterogeneity between studies and publication bias were explored. RESULTS: In total, 20 articles met the inclusion criteria. The pooled results suggest an increased risk of AD (RR: 1.63; 95% CI: 1.35, 1.96). Higher risk estimates were obtained from case-control studies (OR: 1.80; 95% CI: 1.40, 2.32) than from cohort studies (RR: 1.42; 95% CI: 1.08, 1.87). A moderate to high heterogeneity (I2 = 61.0%) and indication for publication bias (Egger test: p < 0.001) were found. CONCLUSION: The results suggested that occupational exposure to ELF-MF might increase the risk of AD. However, this suggestion should be interpreted with caution given the moderate to high heterogeneity and indication for publication bias. PMID- 29278691 TI - ERP components associated with an indirect emotional stop signal task in healthy and depressed participants. AB - Recent research has provided evidence to suggest that emotional stimuli may interfere with response inhibition, due to automatic capture of attention. Whilst previous studies have provided data regarding changes to event-related potentials (ERPs) in emotional Go/NoGo tasks, few studies to-date have utilized an emotional stop signal task (SST). Thirty-five participants were included in the study; 21 healthy controls and 14 depressed. An indirect emotional SST was employed, which consisted of the presentation of neutral, negative or positive visual images. The primary two-choice reaction time task required responding to frame colour (blue or green), whilst in 33% of trials an auditory stop signal was presented, with stop signal delay adjusted according to an adaptive tracking procedure. ERPs associated with both the primary visual task and the auditory SST were analysed using temporal principle components analysis (tPCA). In the primary task, reaction times were found to be slower for negative compared to neutral images. Stop signal reaction time (SSRT) was not found to be affected by image category or depression status. However, the NoGo-N2 component was found to be reduced for positive images, whilst the NoGo-P3 component was reduced for both positive and negative images in comparison to neutral images in the stop signal task. This effect was found to be enhanced for the depressed participants, indicating that inhibitory processing in the presence of positive stimuli may be inhibited to a greater extent in depressed individuals than in healthy controls. These findings provide further evidence for the ability of emotional valence and major depressive disorder to influence inhibitory processing. PMID- 29278692 TI - Cortisol awakening response and emotion at extreme altitudes on Mount Kangchenjunga. AB - The cortisol awakening response (CAR) was examined over a 45days stay at extreme altitudes (above of about 5500m) on Mount Kangchenjunga. The CAR refers to a peak cortisol response during the waking period that is superimposed to the diurnal rhythmicity in cortisol secretion, whose function has been proposed to be the anticipation of demands of the upcoming day (the CAR anticipation hypothesis). According to this hypothesis, we distinguished between resting days on which the expedition team engaged in routine activities in the base camp, and ascent days on which it planned to climb up a very demanding track. We were also interested in examining the association of testosterone with emotional anticipation, given the role of this steroid hormone in reward-related processes in challenge situations. Results showed that the climber group had a bigger CAR on ascent days, relative to the Sherpa group at the same altitude and the non-climber group at sea level. Several methodological issues, however, made it difficult to interpret these group differences in terms of the CAR anticipation hypothesis (e.g. a seemingly influential covariate was awakening time). Although based on tentative results, correlational and regression analyses controlling for awakening time coherently showed that the CAR was associated with anticipation of a hard day and feelings of fear, and testosterone was associated with feelings of energy and positive affect. Whether or not the anticipation of a hard day played a key role in regulation of the CAR, the observation of an intact CAR in the climber group under hypobaric hypoxia conditions would require in-depth reflection from the perspective of human adaptive evolution. PMID- 29278693 TI - Crustacean cardioactive peptides: Expression, localization, structure, and a possible involvement in regulation of egg-laying in the cuttlefish Sepia officinalis. AB - The cuttlefish (Sepia officinalis) is a cephalopod mollusk distributed on the western European coast, in the West African Ocean and in the Mediterranean Sea. On the Normandy coast (France), cuttlefish is a target species of professional fishermen, so its reproduction strategy is of particular interest in the context of stock management. Egg-laying, which is coastal, is controlled by several types of regulators among which neuropeptides. The cuttlefish neuropeptidome was recently identified by Zatylny-Gaudin et al. (2016). Among the 38 neuropeptide families identified, some were significantly overexpressed in egg-laying females as compared to mature males. This study is focused on crustacean cardioactive peptides (CCAPs), a highly expressed neuropeptide family strongly suspected of being involved in the control of egg-laying. We investigated the functional and structural characterization and tissue mapping of CCAPs, as well as the expression patterns of their receptors. CCAPs appeared to be involved in oocyte transport through the oviduct and in mechanical secretion of capsular products. Immunocytochemistry revealed that the neuropeptides were localized throughout the central nervous system (CNS) and in the nerve endings of the glands involved in egg-capsule synthesis and secretion, i.e. the oviduct gland and the main nidamental glands. The CCAP receptor was expressed in these glands and in the subesophageal mass of the CNS. Multiple sequence alignments revealed a high level of conservation of CCAP protein precursors in Sepia officinalis and Loligo pealei, two cephalopod decapods. Primary sequences of CCAPs from the two species were fully conserved, and cryptic peptides detected in the nerve endings were also partially conserved, suggesting biological activity that remains unknown for the time being. PMID- 29278694 TI - Non-clinical assessment of safety and gadolinium deposition after cumulative administration of gadobenate dimeglumine (MultiHance(r)) to neonatal and juvenile rats. AB - To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology. Gadolinium presence in brain, femur, kidneys, liver and skin was determined using inductively coupled plasma-mass spectrometry (ICP-MS). No effects of MultiHance on behavior, cognitive function or any other parameter were noted, even for the highest administered cumulative dose (15 mmol/kg). Gadolinium presence was variable across tissues and decreased during the 60-day treatment-free period. The highest levels were noted in the femur and the lowest levels in the brain. Gadolinium presence in juvenile rat brain following single or repeated MultiHance administrations was minimal and non impactful. PMID- 29278695 TI - Carcinogenicity assessment of the Hedgehog pathway inhibitor, vismodegib in Tg.rasH2 mice and Sprague-Dawley rats. AB - Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of >=0.1-fold and >=0.6-fold, respectively, of the steady-state exposure (AUC0-24h) of the recommended human dose. No malignant tumors were identified in either species. Overall, the totality of pharmacology and nonclinical safety data (lack of genotoxicity, in vitro secondary pharmacological binding, and immunoregulatory effects, and limited effects on the endocrine system) suggests that the development of the benign hair follicle tumors may be related to pharmacologically-mediated disruption of hair follicle morphogenesis, although the exact mechanism of tumorigenesis is unclear. Hair follicle tumors have not been reported in vismodegib-treated patients. The relevance of this finding in rats to patients is uncertain. PMID- 29278696 TI - Individual differences in incentive salience attribution are not related to suboptimal choice in rats. AB - Previous research has shown great variation in the extent to which individual rats attribute incentive salience to stimuli that are predictors of reinforcement. When using the Pavlovian Conditioned Approach procedure, in which a discrete stimulus is presented contingently before the delivery of reinforcement, the attribution of incentive salience is demonstrated by sign tracking behavior (responses directed toward the stimulus predictor of reinforcement), while an absence of this attribution is reflected by goal tracking behavior (responses directed toward the source of reinforcement). It has been reported that sign-tracking subjects have a higher tendency to perform some maladaptive behaviors than goal-tracking subjects, and that in non-classified rats, increasing the incentive salience of the stimuli promotes suboptimal choice in the "suboptimal choice procedure". In this task, subjects are presented with two alternatives, one of them better in terms of the information provided by the discriminative stimuli, but worse in terms of probability of reinforcement (suboptimal alternative). Integrating these ideas, we hypothesized that sign trackers would behave suboptimally, in contrast to goal-trackers. In the present study, 45 rats were classified according to their performance in the Pavlovian Conditioned Approach procedure and subjects with extreme values (sign-trackers, and goal-trackers) were evaluated in the suboptimal choice procedure. Both groups were found to behave optimally, with no differences between them. The difference between groups in capacity of attribution of incentive salience was preserved during the entire experiment, suggesting that this variable is not related to choice performance in the suboptimal choice procedure. PMID- 29278697 TI - Downregulation of 5-hydroxytryptamine7 receptor in the medial prefrontal cortex ameliorates impulsive actions in animal models of schizophrenia. AB - R mRNA in the mPFC was significantly decreased to 5-Hydroxytryptamine7 (5-HT7) receptors in the medial prefrontal cortex (mPFC) play a critical role in complex cognitive impairment in schizophrenia. The mouse model of schizophrenia was established through the neonatal administration of phencyclidine (nPCP). Recombinant adeno-associated virus-mediated gene knockdown was used to investigate the role of mPFC 5-HT7 receptor in the schizophrenia-like symptoms in mice. Under baseline conditions in the 5-choice serial reaction time task (5 CSRTT), nPCP produced a significant attentional impairment that was exacerbated when mice were tested under LITI. Premature and perseverative responding in nPCP mice were both increased, thus suggesting deficits in inhibitory response control. The deficits in attentional performance and premature responding of nPCP mice were improved or fully rescued by 5-HT7 receptor downregulation under heavy perceptual load. Downregulation of the 5-HT7 receptor in the mPFC ameliorated spatial working memory and had no effects on nPCP-induced impairments in recognition memory and MA-induced hyperlocomotion. These results suggest that 5 HT7 receptor is involved in the cognitive outcomes of schizophrenia-like symptoms similar to humans. Downregulation of the 5-HT7 receptor in the mPFC exert complex effects in a mouse model of schizophrenia and may be of benefit in treating schizophrenia-related impulsive actions. PMID- 29278698 TI - GWAS links variants in neuronal development and actin remodeling related loci with pseudoexfoliation syndrome without glaucoma. AB - Pseudoexfoliation syndrome (PEXS) is an age-related elastosis, strongly associated with the development of secondary glaucoma. It is clearly suggested that PEXS has a genetic component, but this has not been extensively studied. Here, a genome-wide association study (GWAS) using a DNA-pooling approach was conducted to explore the potential association of genetic variants with PEXS in a Polish population, including 103 PEXS patients without glaucoma and 106 perfectly (age- and gender-) matched controls. Individual sample TaqMan genotyping was used to validate GWAS-selected single-nucleotide polymorphism (SNP) associations. Multivariate binary logistic regression analysis was applied to develop a prediction model for PEXS. In total, 15 SNPs representing independent PEXS susceptibility loci were selected for further validation in individual samples. For 14 of these variants, significant differences in the allele and genotype frequencies between cases and controls were identified, of which 12 remained significant after Benjamini-Hochberg adjustment. The minor allele of five SNPs was associated with an increased risk of PEXS development, while for nine SNPs, it showed a protective effect. Beyond the known LOXL1 variant rs2165241, nine other SNPs were located within gene regions, including in OR11L1, CD80, TNIK, CADM2, SORBS2, RNF180, FGF14, FMN1, and RBFOX1 genes. None of these associations with PEXS has previously been reported. Selected SNPs were found to explain nearly 69% of the total risk of PEXS development. The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1 rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model. In conclusion, several new susceptibility loci for PEXS without glaucoma suggested that neuronal development and actin remodeling are potentially involved in either PEXS onset or inhibition or delay of its conversion to glaucoma. PMID- 29278699 TI - Postnatal development of bitter taste avoidance behavior in mice is associated with ACTIN-dependent localization of bitter taste receptors to the microvilli of taste cells. AB - Bitter taste avoidance behavior (BAB) plays a fundamental role in the avoidance of toxic substances with a bitter taste. However, the molecular basis underlying the development of BAB is unknown. To study critical developmental events by which taste buds turn into functional organs with BAB, we investigated the early phase development of BAB in postnatal mice in response to bitter-tasting compounds, such as quinine and thiamine. Postnatal mice started to exhibit BAB for thiamine and quinine at postnatal day 5 (PD5) and PD7, respectively. Histological analyses of taste buds revealed the formation of microvilli in the taste pores starting at PD5 and the localization of type 2 taste receptor 119 (TAS2R119) at the microvilli at PD6. Treatment of the tongue epithelium with cytochalasin D (CytD), which disturbs ACTIN polymerization in the microvilli, resulted in the loss of TAS2R119 localization at the microvilli and the loss of BAB for quinine and thiamine. The release of ATP from the circumvallate papillae tissue due to taste stimuli was also declined following CytD treatment. These results suggest that the localization of TAS2R119 at the microvilli of taste pores is critical for the initiation of BAB. PMID- 29278700 TI - PAFR-deficiency alleviates myocardial ischemia/reperfusion injury in mice via suppressing inflammation, oxidative stress and apoptosis. AB - Myocardial ischemia/reperfusion (I/R) still have high morbidity and mortality worldwide. Platelet activating factor (PAF) is a potent phospholipid regulator of inflammation. PAF acts on a single receptor (PAFR), which is expressed on cellular and nuclear membranes of various cell types. The study is aimed to explore if PAFR could modulate myocardial I/R injury in mice. PAFR expressions began to up-regulate at 1 h, and reached peak at 24 h. PAFR deletion markedly attenuated myocardial I/R injury, evidenced by the reduced infarct size and the improved cardiac function. Furthermore, PAFR-knockout inhibited inflammatory response, as demonstrated by down-regulated pro-inflammatory cytokines and chemokine, as well as the inactivation of nuclear factor kappaB (NF-kappaB). Additionally, PAFR-absence ameliorated oxidative stress induced by myocardial I/R, associated with the up-regulation of superoxide dismutase (SOD) and nuclear respiratory factor 2 (Nrf-2) activity. Finally, PAFR-deficiency impeded apoptosis, which was proved by the decreasing in terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL)-positive myocytes, and Caspase-3 cleavage. And the activation of Janus kinase 1-signal transducer and activator of transcription 1 (JAK1/STAT1) pathway was also suppressed by PAFR knockout. The findings above were confirmed in lipopolysaccharide (LPS)-incubated cardiomyocytes with or without PAFR expressions in vitro. In summary, we supposed that inhibiting PAFR reduced inflammation, oxidative stress and apoptosis, and thus might be a promising therapeutic strategy to alleviate myocardial I/R injury. PMID- 29278701 TI - Gentiopicroside ameliorates bleomycin-induced pulmonary fibrosis in mice via inhibiting inflammatory and fibrotic process. AB - Pulmonary fibrosis (PF) is a chronic and ultimately fatal interstitial lung disease of various causes. The advent of nintedanib and pirfenidone provides treatment options for PF patients for the first time. However, the adverse effects of the two drugs such as gastrointestinal disorders and hepatic dysfunction often lead to treatment discontinuation. Gentiopicroside (GPS) is a natural secoiridoid glycoside from gentian species of medicinal plants, and has a variety of pharmacological activities, including hepatoprotective and cholagogic, anti-inflammatory, antinociceptive, and smooth muscle relaxing activities. The present study aimed to investigate the therapeutical effects of GPS on bleomycin (BLM)-induced PF in mice. Severe lung inflammation and fibrosis were observed in BLM-treated mice. GPS significantly ameliorated inflammatory and fibrotic responses in lungs of PF mice which were confirmed by histopathological examinations including light microscopy and transmission electron microscopy. Additionally, GPS significantly decreased the levels of inflammatory cytokines including TNF-alpha and IL-1beta in bronchoalveolar lavage fluid and reduced the content of hydroxyproline in lungs of PF mice. Furthermore, GPS significantly downregulated the expression of TGF-beta1 and CTGF in lungs of PF mice. In vitro, GPS inhibited epithelial-mesenchymal transition of A549 cells stimulated by TGF beta1, in a dose-dependent manner. Our findings suggest that GPS has the potential as an ideal drug candidate for PF, as it has both anti-inflammatory and anti-fibrotic effects. Alveolar epithelial cells and TGF-beta1 may be the main target cells and molecule of GPS on BLM-induced PF, respectively. PMID- 29278702 TI - Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic beta cells. AB - Hypoxia and islet inflammation are involved in beta-cell failure in type 2 diabetes (T2D). Elevated plasma LPS levels have been verified in patients with T2D, and hypoxia occurs in islets of diabetic mice. Activation of inflammasomes in ischemic or hypoxic conditions was identified in various tissues. Here, we investigated whether hypoxia activates the inflammasome in beta cells and the possible mechanisms involved. In mouse insulinoma cell line 6 (MIN6), hypoxia (1% O2) primes the NLRP3 inflammasome along with NF-kappaB signaling activation. Our results demonstrate that hypoxia can activate the NLRP3 inflammasome in LPS primed MIN6 to result in initiating the beta cell inflammatory response and cell death in vitro. Reactive oxygen species (ROS) and the thioredoxin-interacting protein (TXNIP) are up-regulated in response to hypoxia. Finally, the role of the ROS-TXNIP axis in mediating the activation of the NLRP3 inflammasome and cell death was characterized by pretreating with the ROS scavenger N-acetylcysteine (NAC) and performing TXNIP knockdown experiments in MIN6. Our data indicate for the first time that the inflammasome is involved in the inflammatory response and cell death in hypoxia-induced beta cells through the ROS-TXNIP-NLRP3 axis in vitro. This provides new insight into the relationship between hypoxia and inflammation in T2D. PMID- 29278703 TI - Overexpression of Lhx2 suppresses proliferation of human T cell acute lymphoblastic leukemia-derived cells, partly by reducing LMO2 protein levels. AB - T cell acute lymphoblastic leukemia (T-ALL) is a malignant cancer with poor prognosis. The transcriptional co-factor LIM domain only 2 (LMO2) and its target gene HHEX are essential for self-renewal of T cell precursors and T-ALL etiology. LMO2 directly associates with LDB1 in a large DNA-containing nuclear complex and controls the transcription of T-ALL-related genes. Recently, we reported that overexpression of the LIM-homeodomain transcription factor, Lhx2, results in liberation of the Lmo2 protein from the Lmo2-Ldb1 complex, followed by ubiquitin proteasome mediated degradation. Here, we found that proliferation of five human T-ALL-derived cell lines, including CCRF-CEM, was significantly suppressed by retroviral overexpression of Lhx2. The majority of Lhx2-transduced CCRF-CEM cells arrested in G0 phase and subsequently underwent apoptosis. Expression of LMO2 protein as well as HHEX, ERG, HES1 and MYC genes was repressed in CCRF-CEM cells by transduction with Lhx2. Lhx2-mediated growth inhibition was partially rescued by simultaneous overexpression of Lmo2; however, both the C-terminal LIM domain and the homeodomain of Lhx2 were required for its growth-suppressive activity. These data indicate that Lhx2 is capable of blocking proliferation of T-ALL derived cells by both LMO2-dependent and -independent means. We propose Lhx2 as a new molecular tool for anti-T-ALL drug development. PMID- 29278704 TI - HDAC6 interacts with PTPN1 to enhance melanoma cells progression. AB - Histone deacetylase 6 (HDAC6) plays an important role in oncogenic transformation and cancer metastasis. Our previous study has demonstrated that HDAC6 was highly expressed in melanoma cells, and contributed to the proliferation and metastasis of melanoma cells. However, the underlying mechanism of HDAC6 in melanoma metastasis and progression remains largely unclear. In this study, we reported that HDAC6 directly interacted with Tyrosine-protein phosphatase non-receptor type 1 (PTPN1) by performing co-immunoprecipitation (Co-IP) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS). HDAC6 increased the protein level of PTPN1 independent of histone modifying activity. In addition, PTPN1 promoted proliferation, colony formation and migration while decreased apoptosis of melanoma cells through activating extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, we found that matrix metallopeptidase 9 (MMP9) was increased by HDAC6/PTPN1/ERK1/2 axis, which might serve as a mechanism for melanoma invasion and metastasis. In conclusion, HDAC6 might enhance aggressive melanoma cells progression via interacting with PTPN1, which was independent of its histone modifying activity. PMID- 29278705 TI - Evaluation of tryptophan-aspartic acid repeat-containing protein 34 as a novel tumor-suppressor molecule in human oral cancer. AB - Tryptophan-aspartic acid (WD) repeat-containing protein 34 (WDR34), one of the WDR protein superfamilies with five WD40 domains, inhibits a transforming growth factor-beta (TGF-beta) activated kinase 1 (TAK1)-associated NF-kappaB activation pathway. Nevertheless, little is known about the roles of WDR34 in cancer. The current study sought to elucidate the clinical relevance of WDRsfb34 in oral squamous cell carcinoma (OSCC). We found WDR34 down-regulation in OSCCs compared with normal control tissues using real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, and immunohistochemistry. Models of overexpression of WDR34 (oeWDR34) showed depressed cellular growth through cell cycle arrest at the G1 phase. To investigate the inhibitory function of WDR34, we challenged oeWDR34 cells with interleukin (IL)-1, a ligand for activation of the TAK1-NF-kappaB pathway and assessed the expression of a target gene of the pathway. oeWDR34 strongly inhibited IL-6 expression, which is closely related to tumoral growth, compared with control cells, suggesting that WDR34 would be a critical molecule for control of tumoral progression. In addition to the in vitro experiments, WDR34 negativity was correlated with tumoral growth of OSCCs. Our findings suggested that WDR34 inhibits OSCC progression and might be a potential tumor-suppressor molecule in OSCCs. PMID- 29278707 TI - Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition. AB - BACKGROUND: Chronic liver disease is becoming a major cause of morbidity and mortality worldwide. During liver injury, hepatic stellate cells (HSCs) trans differentiate into activated myofibroblasts, which produce extracellular matrix. Succinate and succinate receptor (G-protein coupled receptor91, GPR91) signaling pathway has now emerged as a regulator of metabolic signaling. A previous study showed that succinate and its specific receptor, GPR91, are involved in the activation of HSCs and the overexpression of alpha-smooth muscle actin (alpha SMA). Metformin, a well-known anti-diabetic drug, inhibits hepatic gluconeogenesis in the liver. Many studies have shown that metformin not only prevented, but also reversed, steatosis and inflammation in a nonalcoholic steatohepatitis (NASH) animal model. However, the role of metformin in HSC activation and succinate-GPR91 signaling has not been clarified. METHODS: The immortalized human HSCs, LX-2 cells, were used for the in vitro study. For the in vivo study, male C57BL/J6 mice were randomly divided into 3 groups and were fed with a methionine-choline-deficient diet (MCD diet group) as a nonalcoholic steatohepatitis (NASH) mouse model with or without 0.1% metformin for 12 weeks, or were fed a control methionine-choline-sufficient diet (MCS diet group). RESULTS: In our study, metformin and 5-aminoimidazole-4-carboxamide 1-beta-d ribofuranoside (AICAR), which is an analog of adenosine monophosphate, were shown to suppress alpha-SMA expression via enhanced phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of succinate-GPR91 signaling in activated LX 2 cells induced by palmitate- or succinate. Metformin and AICAR also reduced succinate concentration in the cell lysates when LX-2 cells were treated with palmitate. Moreover, metformin and AICAR reduced interleukin-6 and, transforming growth factor-beta1 production in succinate-treated LX-2 cells. Both metformin and AICAR inhibited succinate-stimulated HSC proliferation and cell migration. Mice fed a MCD diet demonstrated increased steatohepatitis and liver fibrosis compared to that of mice fed control diet. Metformin ameliorated steatohepatitis, liver fibrosis, inflammatory cytokine production and decreased alpha -SMA and GPR91expression in the livers of the MCD diet-fed mice. CONCLUSION: This study shows that metformin can attenuate activation of HSCs by activating the AMPK pathway and inhibiting the succinate-GPR91 pathway. Metformin has therapeutic potential for treating steatohepatitis and liver fibrosis. PMID- 29278706 TI - Endogenous acid ceramidase protects epithelial cells from Porphyromonas gingivalis-induced inflammation in vitro. AB - Ceramidases are a group of enzymes that degrade pro-inflammatory ceramide by cleaving a fatty acid to form anti-inflammatory sphingosine lipid. Thus far, acid, neutral and alkaline ceramidase isozymes have been described. However, the expression patterns of ceramidase isoforms as well as their role in periodontal disease pathogenesis remain unknown. In this study, expression patterns of ceramidase isoforms were quantified by real-time PCR and immunohistochemistry in gingival samples of patients with periodontitis and healthy subjects, as well as in EpiGingivalTM-3D culture and OBA-9 gingival epithelial cells both of which were stimulated with or without the presence of live Porphyromonas gingivalis (ATCC 33277 strain). A significantly lower level of acid ceramidase expression was detected in gingival tissues from periodontal patients compared to those from healthy subjects. In addition, acid-ceramidase expression in EpiGingivalTM 3D culture and OBA-9 cells was suppressed by stimulation with P. gingivalis in vitro. No significant fluctuation was detected for neutral or alkaline ceramidases in either gingival samples or cell cultures. Next, to elucidate the role of acid ceramidase in P. gingivalis-induced inflammation in vitro, OBA-9 cells were transduced with adenoviral vector expressing the human acid ceramidase (Ad-ASAH1) gene or control adenoviral vector (Ad-control). In response to stimulation with P. gingivalis, ASAH1-over-expressing OBA-9 cells showed significantly lower mRNA expressions of caspase-3 as well as the percentage of Annexin V-positive cells, when compared with OBA-9 cells transduced with Ad control vector. Furthermore, in response to stimulation with P. gingivalis, ASAH1 over-expressing OBA-9 cells produced less TNF-alpha, IL-6, and IL1beta pro inflammatory cytokines than observed in OBA-9 cells transduced with Ad-control vector. Collectively, our data show the novel discovery of anti-inflammatory and anti-apoptotic effects of acid ceramidase in host cells exposed to periodontal bacteria, and the attenuation of the expression of host-protective acid ceramidase in periodontal lesions. PMID- 29278708 TI - Genome-wide identification of chromatin-enriched RNA reveals that unspliced dentin matrix protein-1 mRNA regulates cell proliferation in squamous cell carcinoma. AB - Chromatin-enriched noncoding RNAs (ncRNAs) have emerged as key molecules in epigenetic processes by interacting with chromatin-associated proteins. Recently, protein-coding mRNA genes have been reported to be chromatin-tethered, similar with ncRNA. However, very little is known about whether chromatin-enriched mRNA is involved in the chromatin modification process. Here, we comprehensively examined chromatin-enriched RNA in squamous cell carcinoma (SQCC) cells by RNA subcellular localization analysis, which was a combination of RNA fractionation and RNA-seq. We identified 11 mRNAs as highly chromatin-enriched RNAs. Among these, we focused on the dentin matrix protein-1 (DMP-1) gene because its expression in SQCC cells has not been reported. Furthermore, we clarified that DMP-1 mRNA was retained in chromatin in its unspliced form in SQCC in vitro and in vivo. As the inhibition of the unspliced DMP-1 mRNA (unspDMP-1) expression resulted in decreased cellular proliferation in SQCC cells, we performed ChIP qPCR to identify cell cycle-related genes whose expression was epigenetically modified by unspDMP-1, and found that the CDKN1B promoter became active in SQCC cells by inhibiting unspDMP-1 expression. This result was further validated by the increased CDKN1B gene expression in the cells treated with siRNA for unspDMP 1 and by restoration of the decreased cellular proliferation rate by simultaneously inhibiting CDKN1B expression in SQCC cells. Further, to examine whether unspDMP-1 was able to associate with the CDKN1B promoter region, SQCC cells stably expressing PP7-mCherry fusion protein were transiently transfected with the unspDMP-1 fused to 24 repeats of the PP7 RNA stem loop (unspDMP-1 24xPP7) and we found that unspDMP-1-24xPP7 was efficiently precipitated with the antibody against mCherry and was significantly enriched in the CDKN1B promoter region. Thus, unspDMP-1 is a novel chromatin-enriched RNA that epigenetically regulates cellular proliferation of SQCC. PMID- 29278709 TI - Real-world flash glucose monitoring patterns and associations between self monitoring frequency and glycaemic measures: A European analysis of over 60 million glucose tests. AB - AIMS: Randomised controlled trials demonstrate that using flash glucose monitoring improves glycaemic control but it is unclear whether this applies outside trial conditions. We investigated glucose testing patterns in users worldwide under real life settings to establish testing frequency and association with glycaemic parameters. METHODS: Glucose results were de-identified and uploaded onto a dedicated database once readers were connected to an internet ready computer. Data between September 2014 and May 2016, comprising 50,831 readers and 279,446 sensors worldwide, were analysed. Scan rate per reader was determined and each reader was sorted into twenty equally-sized rank-ordered groups, categorised by scan frequency. Glucose parameters were calculated for each group, including estimated HbA1c, time above, below and within range identified as 3.9-10.0 mmol/L. RESULTS: Users performed a mean of 16.3 scans/day [median (IQR): 14 (10-20)] with 86.4 million hours of readings and 63.8 million scans. Estimated HbA1c gradually reduced from 8.0% to 6.7% (64 to 50 mmol/mol) as scan rate increased from lowest to highest scan groups (4.4 and 48.1 scans/day, respectively; p < .001). Simultaneously, time below 3.9, 3.1 and 2.5 mmol/L decreased by 15%, 40% and 49%, respectively (all p < .001). Time above 10.0 mmol/L decreased from 10.4 to 5.7 h/day (44%, p < .001) while time in range increased from 12.0 to 16.8 h/day (40%, p < .001). These patterns were consistent across different countries. CONCLUSIONS: In real-world conditions, flash glucose monitoring allows frequent glucose checks with higher rates of scanning linked to improved glycaemic markers, including increased time in range and reduced time in hyper and hypoglycaemia. PMID- 29278710 TI - Effects of evolving lipid-lowering drugs on carbohydrate metabolism. AB - The understanding that statins reduce but not eliminate the cardiovascular risk associated with disturbed lipid metabolism and the existence of forms of dyslipidemia that are unresponsive or only partially responsive to statins have led to the development of many novel lipid-lowering drugs. Accumulating evidence suggests that the interplay between carbohydrate and lipid metabolism is bidirectional. Thus, any intervention that affects lipid metabolism has the potential to influence the homeostasis of glucose. In this review we summarize the available data on the effects of the evolving lipid-lowering drugs on carbohydrate metabolism. PMID- 29278711 TI - Self-efficacy, self-care and glycemic control in Saudi Arabian patients with type 2 diabetes mellitus: A cross-sectional survey. AB - AIMS: To determine the prevalence of diabetes self-care activities among type 2 diabetes patients and examine the association between socio-demographic and clinical parameters, diabetes self-care activities, and glycemic control among type 2 diabetes patients. METHODS: A cross sectional study was conducted among patients with diabetes (n = 123) at the Sultan Bin Abdulaziz Humanitarian City (SBAHC). A regression model was used to examine the variables that predicted glycemic control. Moreover, a regression analysis examining the effect of each self-efficacy subscale on its respective diabetes self -management (DSM) behavior was carried out. RESULTS: The most frequently reported DSM behaviors were foot care followed by medication taking self-management behavior. The least frequently reported DSM behaviors were exercise self-management behavior and blood sugar testing behavior. Self-efficacy was associated with higher levels of diet, exercise, blood sugar testing, and medication taking self-management behaviors. Diet self-management behaviors and oral hypoglycemic agents (OHA) use were significantly independent predictors of glycemic control HbA1c <7% (53 mmol/mol). CONCLUSIONS: The findings can serve to help clinicians have a better understanding on the extent to which different self-efficacy parameters have an influence on self-management behaviors, which will in turn lead to better glycemic control and thus improved HbA1c levels. PMID- 29278712 TI - A national survey on the efficacy and safety of continuous subcutaneous insulin infusion in patients with type 1 diabetes in Spain. AB - AIMS: To assess safety and benefits of continuous subcutaneous insulin infusion (CSII) therapy in a cohort of type 1 diabetes patients in Spain. METHODS: A web based national registry was created by the Working Group of the Spanish Diabetes Association. All patients on CSII being followed at selected referral centers were included. A cross-sectional analysis was performed. RESULTS: A total of 1275 patients were included. Data completion for patients on CSII was 67 +/- 32%. Indications for treatment were suboptimal glycemic control (32%), high glucose variability (24%), preconception care (14%) and hypoglycemia (11%). In the patients on CSII for >=1 year (n = 843, mean CSII duration of 5 years), HbA1c decreased by 5 mmol/mol (0.5%) in the whole population and by 8 mmol/mol (0.7%) in subjects with suboptimal glycemic control as CSII indication. Percentage of patients achieving HbA1c <= 53 mmol/mol (7%) increased from 20% before CSII to 34% at the end of follow-up. Severe hypoglycemia decreased from 29% to 5%. The rate of discontinuation was 9.5%. HbA1c was lower in patients using bolus advisor and temporary basal rates. CONCLUSIONS: CSII was associated with a sustained improvement in glycemic control and a reduction in severe hypoglycemia. The use of advanced CSII settings was related to better glycemic control. PMID- 29278713 TI - Is metformin beneficial for heart failure in patients with type 2 diabetes? AB - Heart failure is a common and serious cardiovascular complication of type 2 diabetes. Many antihyperglycemic drugs can increase the risk of heart failure. However, it is commonly believed that metformin - the first-line treatment for type 2 diabetes - reduces the risk of and improves the clinical course of heart failure. It is estimated that 20-25% of patients taking metformin have heart failure. Metformin has been shown to have favorable effects on the course of heart failure in experimental models. Furthermore, when compared with other antihyperglycemic medications in nonrandomized epidemiological studies, metformin users had a lower risk of new-onset heart failure and a lower risk of death if they already had heart failure. However, these reports are difficult to interpret, given the potential for prescribing bias and the likelihood that comparator agents caused cardiovascular harm. Meta-analyses of randomized controlled clinical trials have not demonstrated benefits of metformin on the risk of or the clinical course of heart failure. Given metformin's importance in the management of type 2 diabetes and its widespread use in heart failure, the current confidence in its benefits in high-risk patients needs to be re evaluated. PMID- 29278715 TI - Accumulation of beta-synuclein in cortical neurons is associated with autophagy attenuation in the brains of dementia with Lewy body patients. AB - Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia, where an accumulation of aggregated fibrillar alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to visual hallucination, cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances. Beta-synuclein counteracts aggregation of alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human Lewy body dementia (LBD) diseases. Here we examine expression of alpha-, beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age matched controls. We provide evidence for neuronal upregulation of beta-synuclein within the frontal cortex and its decrease in occipital cortex of DLB patients. While beta-synuclein-containing neurons were consistently devoid of oligomeric alpha-synuclein in the frontal cortex, we did not observe an overall correlation between total beta-synuclein and 5G4 levels (marker of oligomeric alpha synuclein). The autophagy markers LC3-II and p62 were increased in the areas of beta-synuclein upregulation in DLB brains, and we show attenuation of autophagy flux when beta-synuclein is overexpressed in vitro. Altogether, this data suggests that beta-synuclein changes in DLB may exacerbate neuronal dysfunction caused by accumulation of alpha-synuclein by influencing protein degradation pathways; this should be taken into consideration when designing therapeutic strategies aimed to decrease alpha-synuclein burden in Lewy body diseases. PMID- 29278714 TI - Does plasticity in thermal tolerance trade off with inherent tolerance? The influence of setal tracheal gills on thermal tolerance and its plasticity in a group of European diving beetles. AB - In the face of global warming, both the absolute thermal tolerance of an ectotherm, and its ability to shift its tolerance level via acclimation, are thought to be fundamentally important. Understanding the links between tolerance and its plasticity is therefore critical to accurately predict vulnerability to warming. Previous studies in a number of ectotherm taxa suggest trade-offs in the evolution of thermal tolerance and its plasticity, something which does not, however, apply to Deronectes diving beetles, where these traits are instead positively correlated. Here we revisit the relationship between thermal tolerance and plasticity in these beetles, paying attention to a recently discovered morphological adaptation supporting under water respiration - setal tracheal gills. Hollow setae on the elytra interconnect with the beetle's tracheal system, providing a gas exchange surface that allows oxygen to be extracted directly from the water. This enables individuals to stay submerged for longer than their subelytral air stores would allow. We show that hypoxia reduced heat tolerance, especially when individuals were denied access to air, forcing them to rely solely on aquatic gas exchange. Species with higher densities of these gas exchanging setae exhibited improved cold tolerance, but reduced heat tolerance and lower plasticity of heat tolerance. Differences in setal tracheal gill density across species were also related to habitat use: species with low gill density were found mainly in intermittent, warmer rivers, where underwater gas exchange is more problematic and risks of surfacing may be smaller. Moreover, when controlling for differences in gill density we no longer found a significant relationship between heat tolerance and its plasticity, suggesting that the previously reported positive relationship between these variables may be driven by differences in gill density. Differences in environmental conditions between the preferred habitats could simultaneously select for characteristic differences in both thermal tolerance and gill density. Such simultaneous selection may have resulted in a non-causal association between cold tolerance and gill density. For heat tolerance, the correlations with gill density could reflect a causal relationship. Species relying strongly on diffusive oxygen uptake via setal tracheal gills may have a reduced oxygen supply capacity and may be left with fewer options for matching oxygen uptake to oxygen demand during acclimation, which could explain their reduced heat tolerance and limited plasticity. Our study helps shed light on the mechanisms that underpin thermal tolerance and plasticity in diving air-breathing ectotherms, and explores how differences in thermal tolerance across species are linked to their selected habitat, morphological adaptations and evolutionary history. PMID- 29278716 TI - 2-O-Carba-oleoyl cyclic phosphatidic acid induces glial proliferation through the activation of lysophosphatidic acid receptor. AB - Lysophosphatidic acid (LPA) and cyclic phosphatidic acid (cPA) are one of the lipid mediators regulating cell proliferation and differentiation through the activation of LPA receptors. An LPA receptor-mediated signal is important for the development of the central nervous system, while it has been demonstrated that LPA caused microglial activation and astroglial dysfunction. Previously, we have reported that cPA and carba analog of cPA, 2-O-carba-cPA (2ccPA), protected neural damage caused by transient ischemia. However, little is known about the target cell of cPA/2ccPA in the central nervous systems. Here, we examined the effect of 2ccPA on glial proliferation and differentiation using the primary astrocytes and oligodendrocyte precursor cells (OPCs) cultures. 2ccPA increased the DNA synthesis of astrocytes and OPCs, but it did not reduce the formazan production in the mitochondria. Further, 2ccPA increased the cell number and cell survival against oxidative stress. The inhibition of LPA receptors by ki16425 abolished 2ccPA-induced DNA synthesis. Extracellular signal-regulated kinase (ERK) was activated by 2ccPA, which contributed to the astroglial DNA synthesis. These results suggest that 2ccPA is a beneficial regulator of glial population through the activation of LPA receptor without reduction of mitochondrial activity. PMID- 29278717 TI - Heart rate variability associated with grey matter volumes in striatal and limbic structures of the central autonomic network. AB - Previous neuroimaging studies have highlighted the functional neural correlates of cardiac vagal activity, providing convergent evidence that the cardiac vagal function is controlled by a number of brain regions in the central autonomic network (CAN). However, it remains largely unknown whether the underlying anatomical basis of those identified regions are associated with individual difference in vagal function. To address the above issue, this study used a large sample of healthy subjects (n = 185) and voxel-based morphometry (VBM) analysis to verify brain morphometry associated with vagal control and the associations varied as a function of gender and age. Our results showed that high frequency component of heart rate variability (HF-HRV) was negatively correlated with grey matter volumes in the right putamen, caudate, amygdala, insula, superior temporal gyrus, temporal pole, and parahippocampal gyrus, demonstrating brain morphological variation in the right-sided striatal and limbic structures of the CAN associated with individual difference in cardiac vagal function. Additionally, gender and age effects on the relationship between cardiac vagal control and brain morphometry were not significant in the current dataset. These findings underscore the importance of striatal and limbic structures in parasympathetic control, and shed light on the underlying anatomical substrates of cardiac vagal activity. PMID- 29278718 TI - A randomised controlled trial of manualized cognitive remediation therapy in adult obesity. AB - OBJECTIVE: Research has indicated that individuals with obesity have neurocognitive deficits, especially in cognitive flexibility that may in turn impact on their weight loss and maintenance. Consequently, we examined the efficacy of a manualised face-to-face cognitive remediation therapy for obesity (CRT-O) within a randomised controlled trial, in terms of improving cognitive flexibility, reducing binge eating behaviour, improving quality of life and helping with weight loss. METHODS: 80 adults with obesity (body mass index >30 kg/m2), 70% binge eaters, received three weekly sessions of group Behavioural Weight Loss (BWL) and then were randomised to 8 sessions of individual CRT-O or to a no-treatment control group. RESULTS: Mixed-effects model analyses revealed that the CRT-O group had a significant improvement in their cognitive flexibility at post-treatment and 3-month follow-up compared to the control group (Cohen's d = 0.96 to 2.1). 68% of those in the CRT-O group achieved a weight loss of 5% or more at follow-up compared to only 15% of the controls (Cohen's d = 1.3). Changes in set-shifting predicted changes in weight (p < .05). Binge eating reduced in the CRT-O group compared to the control (Cohen's d = 0.80). DISCUSSION: This is the first study showing the efficacy of CRT-O for obesity. Future CRT-O studies with longer follow-ups and pairing it with longer BWL programs are needed. TRIALS REGISTRY (ANZCTR): 12613000537752. DATE OF ANZCTR REGISTRATION: 14 May 2013. PMID- 29278719 TI - Expected satiation alone does not predict actual intake of desserts. AB - The degree to which consumers expect foods to satisfy hunger, referred to as expected satiation, has been reported to predict food intake. Yet this relationship has not been established precisely, at a quantitative level. We sought to explore this relationship in detail by determining whether expected satiation predicts the actual intake of semi-solid desserts. Two separate experiments were performed: the first used variations of a given food (eight apple purees), while the second involved a panel of different foods within a given category (eight desserts). Both experiments studied the consumption of two products assigned to volunteers based on their individual liking and expected satiation ratings, given ad libitum at the end of a standardised meal. A linear model was used to find predictors of food intake and included expected satiation scores, palatability scores, BMI, age, sex, TFEQ-R, TFEQ-D, water consumption during the meal, reported frequency of eating desserts, and reported frequency of consuming tested products as explanatory variables. Expected satiation was a significant predictor of actual food intake in both experiments (apple puree: F(1,97) = 18.60, P < .001; desserts: F(1,106) = 9.05, P < .01), along with other parameters such as product palatability and the volunteers' age, sex and food restriction (variation explained by the model/expected satiation in the experiments: 57%/23% and 36%/17%, respectively). However, we found a significant gap between expected and actual consumption of desserts, on group and on individual level. Our results confirm the importance of expected satiation as a predictor of subsequent food intake, but highlight the need to study individual consumption behaviour and preferences in order to fully understand the role of expected satiation. PMID- 29278720 TI - The effects of happiness and sadness on Children's snack consumption. AB - Children appear to engage in emotional eating (i.e., eating in response to negative and positive emotions), but existing research has predominantly relied on parent-report and child-report, which may not necessarily reflect children's actual emotional eating behaviors. This study examined the effects of happiness and sadness on children's observed snack consumption and examined whether child characteristics (i.e., weight, gender, and age) interact with mood to predict snack consumption. To elicit mood, children (N = 91; Mages = 6.8 years; 48 boys) were randomly assigned to one of the three mood induction conditions (happy, sad, or neutral); children's snack consumption was observed and measured after mood induction. Findings showed that children in the sad condition consumed more energy from chocolate, followed by children in the happy condition, and then the neutral condition. However, the reverse pattern was observed for goldfish crackers: children in the neutral condition consumed more energy from this savory snack than children in the happy condition, followed by children in sad condition. Child weight status and gender did not interact with mood to predict snack consumption. Child age did interact with mood: older children consumed more chocolates in the sad condition compared to younger children. Child age was not related to snack consumption in the happy and neutral conditions. This study suggests that emotional eating in response to positive and negative emotions is evident during early childhood, but that this is behavior is developing during this period. PMID- 29278721 TI - The Pax protein Eyegone (Eyg) interacts with the pi-RNA component Aubergine (Aub) and controls egg chamber development in Drosophila. AB - The eyegone (eyg) gene encodes Eyg, a transcription factor of the Pax family with multiple roles during Drosophila development. Eyg has been shown to be nuclear in the cells where it functions. In this report we describe a new functional cytoplasmic distribution of Eyg during egg chamber development in the female ovarioles. The protein is present from the germarium until stage 10 of cyst development. The majority of egg chambers that develop in the absence of Eyg arrest their development before stage 10, show augmented levels of the telomeric retro-transposon TART-A and low levels of heterochromatin marks in the oocyte nucleus. During the maternal to zygotic transition (MTZ) Eyg seems to play a role in destabilizing germ cell less (gcl) and oo 16 RNA binding protein (orb) mRNAs. We were able to show that Eyg interacts with Aubergine (Aub), a component of the pi-RNA pathway during egg chamber development. This interaction could be essential for Eyg to be retained in the cytoplasm and fulfill its functions there. PMID- 29278722 TI - The association of uric acid with the risk of metabolic syndrome, arterial hypertension or diabetes in young subjects- An observational study. AB - BACKGROUND: A growing number of studies are available to shed some light on the association between uric acid (UA) and cardiovascular diseases. However, there have been few studies to support a causal link between UA, metabolic syndrome (MetS), diabetes mellitus (DM) and hypertension (HTN) in young subjects. METHODS: From the Health Examination Registration System of Taiwanese military service during the period 2013-2015, there were 46,561 eligible participants who were 20years old or older in our study. Different analytical steps of analysis were performed to examine the association between UA and cardiometabolic risk using logistic regression, receiver operating characteristic (ROC) curve analysis and Cox regression. RESULTS: For total population, serum UA had significant associations with the presence of MetS (OR=2.08, 95% CI=1.51-2.87), DM (OR=2.59, 95% CI=1.09-6.19) and HTN (OR=1.49, 95% CI=1.07-2.07) in the cross-sectional analysis. According to the cut-off values of UA calculating by the ROC curve analysis in each sex/age subgroup, the association between UA and incident adverse outcomes were analyzed in a longitudinal study. In male, higher UA significantly increased the risks for developing MetS in 30-40years (HR=1.12, 95% CI=1.01-1.25), DM in <30years (HR=2.75, 95% CI=1.38-5.45) and HTN in all subgroups (HR=1.17, 95% CI=1.01-1.37; HR=1.65, 95% CI=1.08-2.53; HR=1.72, 95% CI=1.22-2.43). In females, a higher UA was significantly associated with an increased risk of incident MetS in >40years (HR=2.99, 95% CI=1.34-6.64), HTN in >40years (HR=2.58, 95% CI=1.02-6.55), and no increased risk of DM. CONCLUSIONS: Our study concluded that serum UA is an important predictor for the risk of incident MetS, DM, and HTN in adults, especially in male population. PMID- 29278723 TI - Single nucleotide polymorphisms of microRNA in cardiovascular diseases. AB - Despite the advances in medicine and in science of diagnosis, cardiovascular diseases (CVD) remain the number one cause of morbidity and mortality worldwide. Apart from the modifiable risk factors, genetic factors are believed to also influence the outcome of this umbrella of diseases. Under the genetic factors, miRNA polymorphisms, namely miR-146a (rs2910164), miR-196 (rs11614913) and miR 499 (rs3746444), have become an important tool to study the mechanism that underlie the pathogenesis of this disease. In this review, we analyze the advances made through various research studies and the evidence provided by them in the area of miRNA polymorphisms by comparing the allelic frequencies and genotyping patterns. Interestingly, these studies have contradicting results even those conducted in same set of population. We also highlight the gap in literature search as majority of these studies have been conducted in Chinese population and data gaps are evident in Caucasian population, along with developing countries like, India, where no such data is available. This makes the daunting task of presenting a global picture and of the extent these polymorphisms play a role in CVD progression, even more difficult. Therefore, we suggest that more work needs to be done by taking various geographical domains in to consideration. Also, larger sample size calculated through statistical tools is the key to progress in establishing the genetic co-relation of miRNA polymorphisms and CVDs. PMID- 29278724 TI - Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis. AB - BACKGROUND: Muscular dystrophy is an inherited muscle disease, characterized by progressive muscle wasting and weakness of variable distribution and severity. METHODS: In vitro, high-resolution proton nuclear magnetic resonance (NMR) spectroscopy based analysis was performed on perchloric acid (PCA) extract of muscle specimens of patients suffering from various types of muscular dystrophies to identify alteration in hydrophilic low-molecular weight substances (aqueous metabolites) as compared to muscle of control subjects as well as in between the types of muscular dystrophy. Muscle tissue specimens were obtained from Duchenne muscular dystrophy (DMD) [n=11], Becker muscular dystrophy (BMD) [n=12], facioscapulohumeral dystrophy (FSHD) [n=9] and limb girdle muscular dystrophy (LGMD)-2B [n=22]. Control muscle specimens [n=40] were also taken. RESULTS: Concentration of branched chain amino acids (BCA), glutamine/glutamate (Gln/Glu), acetate (Ace) and fumarate (Fum) was decreased and His was increased in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control subjects. Alanine (Ala) was significantly reduced in BMD, FSHD and LGMD-2B patients as compared to control subjects. Tyrosine (Tyr) was present only in the muscle tissue of control subjects. Propionate (Prop) was present in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients and was absent in muscle tissue of control subjects. Concentration of BCA and Prop is significantly reduced in patients with DMD as compared to BMD, but Glucose is significantly higher in patients with DMD as compared to BMD. Quantity of Glucose, His and Gln/glu are significantly higher in patients with DMD as compared to FSHD, but Prop is significantly reduced in patients with DMD as compared to FSHD. Concentration of Ala and His is significantly higher in patients with DMD as compared to LGMD-2B, but BCA, Glucose and Prop are significantly reduced in patients with DMD as compared to LGMD-2B. Concentration of His is significantly higher in patients with BMD as compared to FSHD. Concentration of His is significantly reduced and Glucose is higher in patients with LGMD-2B as compared to BMD. Glucose concentration is significantly reduced in patients with FSHD as compared to LGMD-2B. ROC curves supported the noticeable discrimination in between the patients with DMD and FSHD for the quantity of Gln/Glu, and patients with LGMD-2B and DMD for the quantity of Ala. Collectively, these findings showed the perturbation of muscle metabolism in muscular dystrophy. CONCLUSIONS: The data of presented study may be used as supporting information for existing methods of the diagnosis for patients with muscular dystrophy. PMID- 29278725 TI - Evaluating the effect of in-process material on the binding mechanisms of surrogate viral particles to a multi-modal anion exchange resin. AB - Bacteriophage binding mechanisms to multi-modal anion exchange resin may include both anion exchange and hydrophobic interactions, or the mechanism can be dominated by a single moiety. However, previous studies have reported binding mechanisms defined for simple solutions containing only buffer and a surrogate viral spike (i.e. bacteriophage PhiX174, PR772, and PP7). We employed phage spiked in-process monoclonal antibody (mAb) pools to model binding under bioprocessing conditions. These experiments allow the individual contributions of the mAb, in-process impurities, and buffer composition on mechanistic removal of phages to be studied. PP7 and PR772 use synergetic binding by the positively charged quaternary amine and the hydrophobic aromatic phenyl group to bind multi modal resin. PhiX174's binding mechanism remains inconclusive due to operating conditions. PMID- 29278726 TI - Assembly of the Lactuca sativa, L. cv. Tizian draft genome sequence reveals differences within major resistance complex 1 as compared to the cv. Salinas reference genome. AB - Lettuce (Lactuca sativa, L.) is an important annual plant of the family Asteraceae (Compositae). The commercial lettuce cultivar Tizian has been used in various scientific studies investigating the interaction of the plant with phytopathogens or biological control agents. Here, we present the de novo draft genome sequencing and gene prediction for this specific cultivar derived from transcriptome sequence data. The assembled scaffolds amount to a size of 2.22 Gb. Based on RNAseq data, 31,112 transcript isoforms were identified. Functional predictions for these transcripts were determined within the GenDBE annotation platform. Comparison with the cv. Salinas reference genome revealed a high degree of sequence similarity on genome and transcriptome levels, with an average amino acid identity of 99%. Furthermore, it was observed that two large regions are either missing or are highly divergent within the cv. Tizian genome compared to cv. Salinas. One of these regions covers the major resistance complex 1 region of cv. Salinas. The cv. Tizian draft genome sequence provides a valuable resource for future functional and transcriptome analyses focused on this lettuce cultivar. PMID- 29278727 TI - Application of CFD in Bioprocessing: Separation of mammalian cells using disc stack centrifuge during production of biotherapeutics. AB - Centrifugation continues to be one of the most commonly used unit operations for achieving efficient harvest of the product from the mammalian cell culture broth during production of therapeutic monoclonal antibodies (mAbs). Since the mammalian cells are known to be shear sensitive, optimal performance of the centrifuge requires a balance between productivity and shear. In this study, Computational Fluid Dynamics (CFD) has been successfully used as a tool to facilitate efficient optimization. Multiphase Eulerian-Eulerian model coupled with Gidaspow drag model along with Eulerian-Eulerian k-epsilon mixture turbulence model have been used to quantify the complex hydrodynamics of the centrifuge and thus evaluate the turbulent stresses generated by the centrifugal forces. An empirical model has been developed by statistical analysis of experimentally observed cell lysis data as a function of turbulent stresses. An operating window that offers the optimal balance between high productivity, high separation efficiency, and low cell damage has been identified by use of CFD modeling. PMID- 29278728 TI - Identification and characterization of a novel B-cell epitope on Aleutian Mink Disease virus capsid protein VP2 using a monoclonal antibody. AB - Aleutian mink disease is caused by a highly contagious parvovirus (Aleutian mink disease virus, AMDV). This disease is one of the most commercially important infectious disease worldwide and causes considerable economic losses to mink farmers. The capsid protein VP2 is the major immunogenic antigenic protein of AMDV, and is involved in viral tropism, pathogenicity, and host selection. However, few reports have described the use of VP2-specific monoclonal antibodies (mAbs) in B-cell epitope identification and immunological detection. In this study, we produced a specific mAb, 1G5, against AMDV VP2 protein (amino acids: 200 ~ 588) and characterized its specificity and relative affinity. Six partially overlapping truncated recombinant proteins and seven synthetized peptides were used to identify the epitopes recognized by 1G5. The results indicate that mAb 1G5 can distinguish AMDV, MEV and CPV2 with high affinity (Ka = 5.37 * 109), and the minimal linear epitope is located in amino acid residues 459EEEGWPAASGTHFED473. Sequence alignments demonstrated that the linear epitope was completely conserved among most Amdoparvoviruses except the bat parvovirus, where three substitutions (463W-463F, 466A-466G and 471F-471Y) were noted. Our results reveal that the identified epitope might be a common B-cell epitope of AMDV antibodies, and the 1G5 mAb can be used to identify the cleavage of the capsid proteins during AMDV infection. This is also the first report of a B-cell epitope on AMDV capsid protein VP2 (VP2: 459-473) using a mAb. These findings have potential applications in the development of new diagnostic tools for AMDV. PMID- 29278729 TI - Stroke promotes survival of nearby transplanted neural stem cells by decreasing their activation of caspase 3 while not affecting their differentiation. AB - Although transplantation of stem cells improves recovery of the nervous tissue, little is known about the influence of different brain regions on transplanted cells. After we confirmed that cells with uniform differentiation potential can be generated in independent experiments, one million of neural stem cells isolated from B6.Cg-Tg(Thy1-YFP)16Jrs/J mouse embryos were transplanted into the brain 24 h after induction of stroke. The lateral ventricles, the corpus callosum and the striatum were tested. Two and four weeks after the transplantation, the cells transplanted in all three regions have been attracted to the ischemic core. The largest number of attracted cells has been observed after transplantation into the striatum. Their differentiation pattern and expression of neuroligin 1, SynCAM 1, postsynaptic density protein 95 and synapsin 1 followed the same pattern observed during in vitro cultivation and it did not differ among the tested regions. Differentiation pattern of the cells transplanted in the stroke affected and healthy animals was the same. On the other hand, neural stem cells transplanted in the striatum of the animals affected by stroke exhibited significantly increased survival rates reaching 260 +/- 19%, when compared to cells transplanted in their wild type controls. Surprisingly, improved survival two and four weeks after transplantation was not due to increased proliferation of the grafted cells and it was accompanied by decreased levels of activity of Casp3 (19.56 +/- 3.1% in the stroke-affected vs. 30.14 +/- 2.4% in healthy animals after four weeks). We assume that the decreased levels of Casp3 in cells transplanted near the ischemic region was linked to increased vasculogenesis, synaptogenesis, astrocytosis and axonogenesis detected in the host tissue affected by ischemia. PMID- 29278730 TI - CM-viewer: Visualizing interaction network of co-mutated and mutually exclusively mutated cancer genes. AB - Cancer genes usually play a crucial role in regulating cell growth. Normal cells transform into malignant tumors by the acquisition of accumulated genetic mutations that enable them to evade normal growth control. It is therefore important to understand the relationships between mutations during cancer development and progression. Although cancer genes with co-occurring and mutually exclusive mutations have already been studied on different scales, there is no timely updated interaction network available for co-mutated and mutually exclusively mutated cancer genes. Therefore, we firstly downloaded 567 cancer genes from COSMIC (catalogue of somatic mutations in cancer) cancer gene census. Secondly, somatic mutations of 71 cancer genomics projects were downloaded from the ICGC (International Cancer Genome Consortium) data portal. Thirdly, mutated cancer genes and affected donors were extracted from the ICGC data to form a mutation matrix where rows are genes, columns are donors, 1 denotes occurrence, and 0 denotes absence of mutation. Afterwards, co-mutated and mutually exclusively mutated cancer gene pairs were identified using DISCOVER (discrete independence statistic controlling for observations with varying event rates). Finally, CM-viewer was developed to visualize the interaction network of cancer genes with co-occurring and mutually exclusive mutations. It is an online visualization tool as well as a biological database. It promises to understand how gene mutations contribute to tumorigenesis and to identify key biomarkers and drug targets for cancer. CM-viewer is freely available at http://www.zhounan.org/comutgene. PMID- 29278731 TI - A test of the adaptive network explanation of functional disorders using a machine learning analysis of symptoms. AB - The classification and etiology of functional disorders is controversial. Evidence supports both psychological and biological (disease) models that show, respectively, that functional disorders should be classified as one (bodily distress syndrome) and many (e.g., irritable bowel syndrome (IBS), fibromyalgia syndrome (FMS), and chronic fatigue syndrome (CFS)). Two network models (symptom network and adaptive network) can explain the specificity and covariation of symptomatology, but only the adaptive network model can explain the covariation of the somatic symptoms of functional disorders. The adaptive network model is based on the premise that a network of biological mechanisms has emergent properties and can exhibit adaptation. The purpose of this study was to test the predictions that symptom similarity increases with pathology and that network connection strengths vary with pathology, as this would be consistent with the notion that functional disorder pathology arises from network adaptation. We conducted a symptom internet survey followed by machine learning analysis. Participants were 1751 people reporting IBS, FMS or CFS diagnosis who completed a 61-item symptom questionnaire. Eleven symptom clusters were identified. Differences in symptom clusters between IBS, FMS and CFS groups decreased as overall symptom frequency increased. The strength of outgoing connections between clusters varied as a function of symptom frequency and single versus multiple diagnoses. The findings suggest that the pathology of functional disorders involves an increase in the activity and causal connections between several symptom causing mechanisms. The data provide support for the proposal that the body is capable of complex adaptation and that functional disorders result when rules that normally improve adaptation create maladaptive change. PMID- 29278732 TI - Loading of polymyxin B onto anionic mesoporous silica nanoparticles retains antibacterial activity and enhances biocompatibility. AB - Polymyxin B is a polycationic antibiotic used as the last line treatment against antibiotic-resistant Gram negative bacteria. However, application of polymyxin B is limited because of its toxicity effects. Herein, we used bare and surface modified mesoporous silica nanoparticles (MSNs) with an average diameter of 72.29 +/- 8.17 nm as adsorbent for polymyxin B to improve its therapeutic properties. The polymyxin B adsorption onto MSN surfaces was explained as a function of pH, type of buffer and surface charge of nanoparticles, according to the zeta potential of silica nanoparticles and adsorption kinetics results. The highest value of the adsorption capacity (about 401 +/- 15.38 mg polymyxin B/ g silica nanoparticles) was obtained for the bare nanoparticles in Tris buffer, pH 9. Release profiles of polymyxin B showed a sustained release pattern, fitting Power law and Hill models. The antibiotic molecules-loaded nanoparticles showed enhanced antibacterial activity compared to free antibiotic against different Gram negative bacteria. Biocompatibility evaluation results revealed that loading of polymyxin B onto MSNs can decrease the cytotoxicity effects of the drug by reducing ROS generation. Our results suggest that formulation of drugs by adsorption onto MSNs may offer a way forward to overcome the adverse effects of some antibiotics such as polymyxin B without compromising their antimicrobial properties. PMID- 29278733 TI - Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process. AB - Poor water solubility and poor bioavailability are problems with many pharmaceuticals. Increasing surface area by micronization is an effective strategy to overcome these problems, but conventional techniques often utilize solvents and harsh processing, which restricts their use. Newer, green technologies, such as supercritical fluid (SCF)-assisted particle formation, can produce solvent-free products under relatively mild conditions, offering many advantages over conventional methods. The antisolvent properties of the SCFs used for microparticle and nanoparticle formation have generated great interest in recent years, because the kinetics of the precipitation process and morphologies of the particles can be accurately controlled. The characteristics of the supercritical antisolvent (SAS) technique make it an ideal tool for enhancing the solubility and bioavailability of poorly water-soluble drugs. This review article focuses on SCFs and their properties, as well as the fundamentals of overcoming poorly water-soluble drug properties by micronization, crystal morphology control, and formation of composite solid dispersion nanoparticles with polymers and/or surfactants. This article also presents an overview of the main aspects of the SAS-assisted particle precipitation process, its mechanism, and parameters, as well as our own experiences, recent advances, and trends in development. PMID- 29278734 TI - Extensive but not Limited Repeated Trials in Passive Avoidance Task Induce Stress like Symptoms and Affect Memory Function in Rats. AB - Stressful and emotionally arousing experiences are remembered, and previous reports show that repeated exposure to stressful condition enhances emotional learning. However, the usefulness of the repeated exposure depends on the intensity and duration. Although repeated training as a strategy to improve memory performance is receiving increased attention from researchers, repeated training may induce stressful effects that have not yet been considered. The present study investigated whether exposure to repetitive learning trials with limited or extensive durations in a passive avoidance task (PAT) would be beneficial or harmful to emotional memory performance in rats. Rats were exposed to repetitive learning trials for two different durations in the limited exposure (exposure to four repetitive trials) and extensive exposure groups (exposure to 16 repetitive trials) in a single day to compare the impact of both conditions on rat emotional memory performance. Alterations in corticosterone content and associated oxidative and neurochemical systems were assessed to explore the underlying mechanism responsible for changes in emotional memory. Following extensive exposure, a negative impact on emotional memory was observed compared with the limited exposure group. A lack of any further improvement in memory function following extensive training exposure was supported by increased corticosterone levels, decreased 5-hydroxytryptamine (5-HT) levels and abnormal oxidative stress levels, which may induce negative effects on memory consolidation. It is suggested that limited exposure to repetitive learning trials is more useful for studying improvement in emotional memory, whereas extensive exposure may produce chronic stress-like condition that can be detrimental and responsible for compromised memory performance. PMID- 29278735 TI - Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia. AB - Fanconi anemia is a rare chromosome instability disorder with a highly variable phenotype. In the antenatal and neonatal periods, the diagnosis is usually suggested by the presence of typical congenital abnormalities such as intrauterine growth retardation, microcephaly and radial ray defects. We report a newborn female with a prenatal diagnosis of Fanconi anemia, complementation group O (FANCO). Antenatal ultrasounds identified symmetrical intrauterine growth retardation, complex heart defect as well as brain anomalies, overlapping fingers and cleft lip and palate. Imperforate anus was detected after birth. Compound heterozygous RAD51C variants c. [571+5G > A]; [c.935G > A] were detected by prenatal whole exome sequencing and cellular hypersensitivity to DNA interstrand crosslinking agents (DEB, MMC) was confirmed after birth. With only one previously described homozygous RAD51C variant to date, our findings expand the phenotypic spectrum of FANCO and suggest it should be part of the antenatal differential diagnosis for trisomy 13 and 18, due to the presence of atypical findings such as cleft lip and palate, holoprosencephaly, growth restriction and overlapping fingers. PMID- 29278736 TI - Identification and characterization of a novel defensin from Asian green mussel Perna viridis. AB - Defensin is one of the most diversified groups of antimicrobial peptides in invertebrate. In the present study, a novel defensin member referred as Pv-Def was identified and characterized from Asian green mussel Perna viridis. Using in silico survey of several EST databases released from diverse tissues of P. viridis, a single peptide referred as Pv-Def was predicted as defensin homologue with Mytilus counterparts. Further analysis on gene structure revealed that Pv Def was 1001 nt in length and consisted of 3 exons and 2 introns. The precursor of Pv-Def was composed of a signal peptide of 19 amino acids and a mature peptide of 45 amino acids. The mature Pv-Def peptide contains 6 cysteines which formed 3 disulfide bonds at 27C1- 54C4, 40C2- 60C5 and 44C3- 62C6. Like most of the defensin family members, mature Pv-Def peptide included an alpha helix and 2 beta strands. Pv-Def showed significantly tissue-specific expression pattern, while highest transcription level was observed in hepatopancreas, which was about 900 folds to that in hemocytes. Moreover, the expression of Pv-Def mRNA in hemocytes was significantly and accurately up-regulated at different time intervals by Vibrio parahaemolyticus challenge. Interestingly, phylogenetic analysis suggested that the Pv-Def possesses closest relationships with arthropods counterparts rather than other mollusk defensins. To our knowledge, this is the first time that a defensin member was reported in Asian green mussel P. viridis. PMID- 29278737 TI - Network science in clinical trials: A patient-centered approach. AB - There has been a paradigm shift in translational oncology with the advent of novel molecular diagnostic tools in the clinic. However, several challenges are associated with the integration of these sophisticated tools into clinical oncology and daily practice. High-throughput profiling at the DNA, RNA and protein levels (omics) generate a massive amount of data. The analysis and interpretation of these is non-trivial but will allow a more thorough understanding of cancer. Linear modelling of the data as it is often used today is likely to limit our understanding of cancer as a complex disease, and at times under-performs to capture a phenotype of interest. Network science and systems biology-based approaches, using machine learning and network science principles, that integrate multiple data sources, can uncover complex changes in a biological system. This approach will integrate a large number of potential biomarkers in preclinical studies to better inform therapeutic decisions and ultimately make substantial progress towards precision medicine. It will however require development of a new generation of clinical trials. Beyond discussing the challenges of high-throughput technologies, this review will develop a framework on how to implement a network science approach in new clinical trial designs in order to advance cancer care. PMID- 29278738 TI - Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin induced microglial activation. AB - There are no effective treatments to slow disease progression in ALS. We previously reported that neuregulin (NRG) receptors are constitutively activated on microglia in the ventral horns in both ALS patients and SOD1 mice and in the corticospinal tracts of ALS patients, and that NRG receptor activation occurs prior to significant clinical disease onset in SOD1 mice. Here, we hypothesize that blocking NRG signaling on microglia would slow disease progression in SOD1 mice using a targeted NRG antagonist (HBD-S-H4). Recombinant HBD-S-H4 directly delivered into the central nervous system (CNS) through implanted intracerebroventricular cannulas showed no signs of toxicity and significantly inhibited NRG receptor activation on microglia resulting in reduced microglial activation and motor neuron loss. The treatment also resulted in a delay in disease onset and an increase in survival. The therapeutic effect was dose dependent that varied as a function of genetic background in two different strains of SOD1 mice. As a complementary drug delivery approach, transgenic mice expressing HBD-S-H4 driven by an astrocytic promoter (GFAP) had slower disease progression in a dose dependent manner, based on the level of HBD-S-H4 expression. These studies provide mechanistic insights into how NRG signaling on microglia may lead to disease progression and demonstrate the utility of a humanized fusion protein that blocks NRG as a novel therapeutic for human ALS. PMID- 29278739 TI - Interaction between p22phox and Nox4 in the endoplasmic reticulum suggests a unique mechanism of NADPH oxidase complex formation. AB - The p22phox protein is an essential component of the phagocytic- and inner ear NADPH oxidases but its relationship to other Nox proteins is less clear. We have studied the role of p22phox in the TGF-beta1-stimulated H2O2 production of primary human and murine fibroblasts. TGF-beta1 induced H2O2 release of the examined cells, and the response was dependent on the expression of both Nox4 and p22phox. Interestingly, the p22phox protein was present in the absence of any detectable Nox/Duox expression, and the p22phox level was unaffected by TGF beta1. On the other hand, Nox4 expression was dependent on the presence of p22phox, establishing an asymmetrical relationship between the two proteins. Nox4 and p22phox proteins localized to the endoplasmic reticulum and their distribution was unaffected by TGF-beta1. We used a chemically induced protein dimerization method to study the orientation of p22phox and Nox4 in the endoplasmic reticulum membrane. This technique is based on the rapamycin-mediated heterodimerization of the mammalian FRB domain with the FK506 binding protein. The results of these experiments suggest that the enzyme complex produces H2O2 into the lumen of the endoplasmic reticulum, indicating that Nox4 contributes to the development of the oxidative milieu within this organelle. PMID- 29278741 TI - A female traveler returning from Peru with an erythematous infraorbital swelling: A diagnostic challenge. PMID- 29278742 TI - Evaluation of the suitability of a Sprague Dawley rat model to assess intravenous iron preparations. AB - The aim of the study was to examine the reproducibility of a rat model to assess the preclinical similarity in safety profiles and tissue accumulation of iron products. Accordingly, the effect of several doses of intravenously administered Venofer(r) and of Ferrlecit(r) on blood parameters, and on kidney and particularly liver toxicity were examined in non-anemic Sprague Dawley rats. The different analysis showed neither a clear treatment nor a dose effect after multiple injections. The parameters measured in this rat strain showed some iron induced adverse effects, but these could not be correlated to treatment specific differences. The findings presented in this paper indicate the difficulty to define a useful preclinical model to evaluate iron-based nano-colloidal preparations. PMID- 29278743 TI - Expression and purification of biologically active bovine Interferon lambda3 (IL28B) in Pichia pastoris. AB - Interferon lambda-3 (IFNlambda3) which is also known as IL28B is a member of type III Interferons which are structurally and genetically different from type I Interferons. These Interferons induce signal transduction pathways similar to type I Interferons which results in the activation of Interferon Stimulated Genes (ISGs). This group of Interferons are tissue specific and reported to have antiviral activity. In the present communication, we report the expression of bovine IFNlambda3 gene (coding for the mature protein) in Pichia pastoris, purification of the expressed protein and evaluation of its biological activity. About 19 kDa protein expressed by the transformed Pichia cells, secreted into the media and the protein was purified by SP-Sepharose ion exchange chromatography with NaCl stepwise gradient elution. Specificity of the protein was confirmed by Western blotting. Pichia expressed IFNlambda3 was found to be biologically active, as it induced ISGs (Mx protein, OAS and PKR genes) in bovine PBMCs. Further it was also found to modulate Th1/Th2 cytokines expression in the stimulated bovine PBMCs. PMID- 29278744 TI - Quantification of surfactant proteins in tears of patients suffering from dry eye disease compared to healthy subjects. AB - PURPOSE: To quantify and compare the amounts of surfactant proteins SP-A, SP-B, SP-C and SP-D in the tear fluid collected from patients with dry eye syndrome and from individuals with a healthy ocular surface. METHODS: Schirmer strips were used to collect tear fluid from both eyes of 241 volunteers (99 men, 142 women; age range: 18-87 years). Dry eye syndrome was diagnosed by ophthalmologists in 125 patients, whereas the healthy control group comprised 116 individuals. The total protein concentration was determined via Bradford assay. The relative concentration of surfactant proteins SP-A through -D was measured by enzyme linked immuno-sorbent assay (ELISA). RESULTS: The mean relative concentrations of SP-A, SP-C and SP-D were significantly higher in the dry eye group as compared to the healthy controls (p<0.05, one-way ANOVA). SP-B was also detected at a higher concentration in the dry eye group, but the difference to the control group was not statistically significant. CONCLUSIONS: The upregulation of SP-A and SP-D in the dry eye group is probably related to these proteins' known antimicrobial and immunomodulatory effects at the ocular surface. It may represent a pathophysiological response to the inflammatory condition of the ocular surface in dry eye. The upregulation of SP-B and SP-C may represent an effort of the lacrimal system to reduce surface tension and thus to counteract the increased tendency of the tear film to tear in dry eye. PMID- 29278740 TI - The A to Z of modulated cell patterning by mammalian thioredoxin reductases. AB - Mammalian thioredoxin reductases (TrxRs) are selenocysteine-containing proteins (selenoproteins) that propel a large number of functions through reduction of several substrates including the active site disulfide of thioredoxins (Trxs). Well-known enzymatic systems that in turn are supported by Trxs and TrxRs include deoxyribonucleotide synthesis through ribonucleotide reductase, antioxidant defense through peroxiredoxins and methionine sulfoxide reductases, and redox modulation of a number of transcription factors. Although these functions may be essential for cells due to crucial roles in maintenance of cell viability and proliferation, findings during the last decade reveal that mammals have major redundancy in their cellular reductive systems. The synthesis of glutathione (GSH) and reductive functions of GSH-dependent pathways typically act in parallel with Trx-dependent pathways, with only one of these systems often being sufficient to support viability. Importantly, this does not imply that a modulation of the Trx system will remain without consequences, even when GSH dependent pathways remain functional. As suggested by several recent findings, the Trx system in general and the TrxRs in particular, function as key regulators of signaling pathways. In this review article we will discuss findings that collectively suggest that modulation in mammalian systems of cytosolic TrxR1 (TXNRD1) or mitochondrial TrxR2 (TXNRD2) influence cell patterning and cellular stress responses. Effects of lower activities include increased adipogenesis, insulin responsiveness, glycogen accumulation, hyperproliferation, and distorted embryonic development, while increased activities correlate with decreased proliferation and extended lifespan, as well as worse cancer prognosis. The molecular mechanisms that underlie these diverse effects, involving regulation of protein phosphorylation cascades and of key transcription factors that guide cellular differentiation pathways, will be discussed. We conclude that the selenium-dependent oxidoreductases TrxR1 and TrxR2 should be considered as key components of signaling pathways that control cell differentiation and cellular stress responses. PMID- 29278745 TI - Strategies towards improving pharmacological management of asthma during pregnancy. AB - Maternal asthma represents a significant burden to individuals and the healthcare system, affecting 1 in 10 pregnancies worldwide. Approximately 50% of asthmatic women experience a deterioration of asthma control at some stage during pregnancy, with a number requiring use of oral corticosteroids for the management of acute exacerbations. The presence of maternal asthma and exacerbations during pregnancy is a noted risk factor for a range of adverse perinatal outcomes including preterm birth, small-for-gestational age, pre-eclampsia, and gestational diabetes. These negative impacts highlight the need for evidence based approaches for improving asthma management during pregnancy and subsequent perinatal outcomes. Despite this, relatively small progress has been made in enhancing the management of maternal asthma in the clinical setting. A major challenge in improving outcomes of asthmatic pregnancies is that there is no single simplified approach for improving outcomes, but rather the requirement to consider the dynamic relationship between a myriad of interrelated factors that ultimately determine an individual's ability to maintain adequate asthma control. Understanding how these factors are impacted by pregnancy and how they can be addressed through various interventions is therefore important in optimising health outcomes. This review summarises key factors involved in influencing outcomes associated with maternal asthma. This includes an overview of the use of asthma medications in pregnancy, while also considering the impacts of interrelated aspects such as medication adherence, health-seeking behaviours, biological and lifestyle factors, co-morbidities, and asthma self-management strategies on asthma control. Addressing such factors through multidisciplinary approaches towards treatment have potential to improve the health of mothers and their offspring. Optimising asthma control should be a high priority within the antenatal setting, with women advised about the importance of good asthma control, managing asthma actively throughout pregnancy by utilising their asthma medications, and managing exacerbations in a timely and effective manner. PMID- 29278747 TI - GABA-containing liposomes: neuroscience applications and translational perspectives for targeting neurological diseases. AB - There are multiple challenges for neuropharmacology in the future. Undoubtedly, one of the greatest challenges is the development of strategies for pharmacological targeting of specific brain regions for treatment of diseases. GABA is the main inhibitory neurotransmitter in the central nervous system, and dysfunction of GABAergic mechanisms is associated with different neurological conditions. Liposomes are lipid vesicles that are able to encapsulate chemical compounds and are used for chronic drug delivery. This short review reports our experience with the development of liposomes for encapsulation and chronic delivery of GABA to sites within the brain. Directions for future research regarding the efficacy and practical use of GABA-containing liposomes for extended periods of time as well as understanding and targeting neurological conditions are discussed. PMID- 29278746 TI - Accuracy of MRI-based finite element assessment of distal tibia compared to mechanical testing. AB - High-resolution MRI-derived finite element analysis (FEA) has been used in translational research to estimate the mechanical competence of human bone. However, this method has yet to be validated adequately under in vivo imaging spatial resolution or signal-to-noise conditions. We therefore compared MRI-based metrics of bone strength to those obtained from direct, mechanical testing. The study was conducted on tibiae from 17 human donors (12 males and five females, aged 33 to 88years) with no medical history of conditions affecting bone mineral homeostasis. A 25mm segment from each distal tibia underwent MR imaging in a clinical 3-Tesla scanner using a fast large-angle spin-echo (FLASE) sequence at 0.137mm*0.137mm*0.410mm voxel size, in accordance with in vivo scanning protocol. The resulting high-resolution MR images were processed and used to generate bone volume fraction maps, which served as input for the micro-level FEA model. Simulated compression was applied to compute stiffness, yield strength, ultimate strength, modulus of resilience, and toughness, which were then compared to metrics obtained from mechanical testing. Moderate to strong positive correlations were found between computationally and experimentally derived values of stiffness (R2=0.77, p<0.0001), yield strength (R2=0.38, p=0.0082), ultimate strength (R2=0.40, p=0.0067), and resilience (R2=0.46, p=0.0026), but only a weak, albeit significant, correlation was found for toughness (R2=0.26, p=0.036). Furthermore, experimentally derived yield strength and ultimate strength were moderately correlated with MRI-derived stiffness (R2=0.48, p=0.0022 and R2=0.58, p=0.0004, respectively). These results suggest that high-resolution MRI-based finite element (FE) models are effective in assessing mechanical parameters of distal skeletal extremities. PMID- 29278748 TI - Protective effect of berberine against cardiac ischemia/reperfusion injury by inhibiting apoptosis through the activation of Smad7. AB - Berberine (BBR) is an isoquinnoline derivative alkaloid extracted from Rhizoma Coptidis that has the potential to protect myocardial tissues from ischemia/reperfusion (I/R) injuries. We attempted to evaluate the effect of BBR on the proliferation and apoptosis of a hypoxia/reoxygenation (H/R) cell model and to reveal the mechanism driving the improving function of BBR myocardial tissues. The H/R cell model was established using H9c2 rat cardiac myoblasts. The cell viability, apoptotic rates, and cell cycle distribution were measured with CCK-8 assay and flow cytometry. The expression of Smad7 and caspase-3 were determined both at mRNA and protein levels. In addition, expression of Smad7 was knocked down with specific siRNA and the effect of the interference was assessed. The proliferation ability of H/R cells was enhanced after the administration of BBR, and the apoptosis and cell cycle arrest due to H/R injury were also alleviated by BBR treatment. Moreover, the treatment of BBR on H/R injury functioned through the Smad7-activation-induced attenuating of apoptosis by activating Smad7 pathway which resulted suppression of caspase 3 expression and activity. The knockdown of Smad7 confirmed our conclusion about the key role of Smad7 in the function of BBR administration. However, our results as well as some previous studies also demonstrated that the effect of BBR was tissue and protocol specific, and the underlying mechanism related to the BBR treatment was so complicated that practical application should be carefully investigated based on certain diseases and patients. PMID- 29278749 TI - Thermodynamic analysis of computed pathways integrated into the metabolic networks of E. coli and Synechocystis reveals contrasting expansion potential. AB - Introducing biosynthetic pathways into an organism is both reliant on and challenged by endogenous biochemistry. Here we compared the expansion potential of the metabolic network in the photoautotroph Synechocystis with that of the heterotroph E. coli using the novel workflow POPPY (Prospecting Optimal Pathways with PYthon). First, E. coli and Synechocystis metabolomic and fluxomic data were combined with metabolic models to identify thermodynamic constraints on metabolite concentrations (NET analysis). Then, thousands of automatically constructed pathways were placed within each network and subjected to a network embedded variant of the max-min driving force analysis (NEM). We found that the networks had different capabilities for imparting thermodynamic driving forces toward certain compounds. Key metabolites were constrained differently in Synechocystis due to opposing flux directions in glycolysis and carbon fixation, the forked tri-carboxylic acid cycle, and photorespiration. Furthermore, the lysine biosynthesis pathway in Synechocystis was identified as thermodynamically constrained, impacting both endogenous and heterologous reactions through low 2 oxoglutarate levels. Our study also identified important yet poorly covered areas in existing metabolomics data and provides a reference for future thermodynamics based engineering in Synechocystis and beyond. The POPPY methodology represents a step in making optimal pathway-host matches, which is likely to become important as the practical range of host organisms is diversified. PMID- 29278751 TI - Correlation between gut microbiota and personality in adults: A cross-sectional study. AB - Personality affects fundamental behavior patterns and has been related with health outcomes and mental disorders. Recent evidence has emerged supporting a relationship between the microbiota and behavior, referred to as brain-gut relationships. Here, we first report correlations between personality traits and gut microbiota. This research was performed using the Revised NEO Personality Inventory and the sequencing data of the 16S rRNA gene in 672 adults. The diversity and the composition of the human gut microbiota exhibited significant difference when stratified by personality traits. We found that personality traits were significantly correlated with diversity of gut microbiota, while their differences were extremely subtle. High neuroticism and low conscientiousness groups were correlated with high abundance of Gammaproteobacteria and Proteobacteria, respectively when covariates, including age, sex, BMI and nutrient intake, were controlled. Additionally, high conscientiousness group also showed increased abundance of some universal butyrate-producing bacteria including Lachnospiraceae. This study was of observational and cross-sectional design and our findings must be further validated through metagenomic or metatranscriptomic methodologies, or metabolomics-based analyses. Our findings will contribute to elucidating potential links between the gut microbiota and personality, and provide useful insights toward developing and testing personality- and microbiota-based interventions for promoting health. PMID- 29278750 TI - Thymic stromal cells: Roles in atrophy and age-associated dysfunction of the thymus. AB - Atrophy of the thymus, the primary site of T lymphocyte generation, is a hallmark of the aging immune system. Age-associated thymic atrophy results in diminished output of new, naive T cells, with immune sequelae that include diminished responses to novel pathogenic challenge and vaccines, as well as diminished tumor surveillance. Although a variety of stimuli are known to regulate transient thymic atrophy, mechanisms governing progressive age-associated atrophy have been difficult to resolve. This has been due in part to the fact that one of the primary targets of age-associated thymic atrophy is a relatively rare population, thymic stromal cells. This review focuses on changes in thymic stromal cells during aging and on the contributions of periodic, stochastic, and progressive causes of thymic atrophy. PMID- 29278752 TI - Cost-effectiveness analysis in papillary thyroid carcinoma patients with different neck dissection strategy: A retrospective cohort study. AB - BACKGROUND: There are two surgical strategies for bilateral neck dissection (BND), simultaneous and two-stage operations. The aim of the study was to compare the cost-effectiveness BND with this two operations in papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: Consecutive PTC patients undergoing BND were studied retrospectively, and were classified into simultaneous group (Group A) and two-stage group (Group B). Demographic, medical costs, complication and surgical variables were recorded. RESULTS: This study included 256 PTC patients, of which 175 (68.4%) underwent simultaneous BND and 81 (31.6%) patients underwent two-stage. Patients in Group B spent almost twice as much on medical costs as patients in Group A ($4145.3 vs. $7352.5). Group A patients also had shorter hospital stays (11.71 +/- 5.12 vs. 23.10 +/- 7.11, P < .0001) and surgery times (203.61 +/- 61.43min vs. 279.58 +/- 71.59min, P < .0001). The average radioactive iodine therapy delay was 67 days in Group B. There was no significant difference in complications (34 vs. 18, P = .605) or disease-free-survival (93.71% vs. 90.12%, P = .243) between the two groups. No difference was found in rates of recurrent laryngeal nerve invasion/resection (12 vs. 11, P = .08; 10 vs. 6, P = .353) or tracheotomy (32 vs. 14, P = .846). However, internal jugular vein invasions were more common in patients with two stage BND (7 vs. 9, P = .029). CONCLUSION: Simultaneous BND is the most cost effective strategy for the management of PTC patients without bilateral internal jugular veins invasion, due to lower treatment cost and the ability to avoid RAI delay. PMID- 29278754 TI - Genotyping of Brucella melitensis and Brucella abortus strains in Kazakhstan using MLVA-15. AB - Currently, although the prevalence of brucellosis in Kazakhstan remains high, there are limited data available on the genetic diversity of circulating Brucella strains. Here, MLVA was employed to genotype a panel of 102 Brucella isolates collected from eight Kazakh regions and neighboring countries (Russia, Kyrgyzstan) during the period 1935-2017. MLVA-11 analysis classified 64 B. abortus strains into genotypes 72, 82, 331, 71, 341 and 69, while one genotype was novel, having no correspondence within the MLVA international database. MLVA 11 analysis of 37 B. melitensis strains showed 100% identity with genotypes 116, 114 and 11. One B. suis strain was classified into genotype 33. Phylogeography based on MLVA-15 demonstrated that all B. abortus and B. melitensis strains belonged to "Abortus C" and "East Mediterranean" lineages, respectively. B. abortus strains from Kazakhstan and Russia resulted genetically related to Portuguese, Brazilian and US isolates, suggesting ancient spread of these lineages from Europe westwards to South America and eastwards to Turkey, Russia and Asia. Most of Kazakh B. melitensis isolates were related to strains circulating in China, likely due to long-term trading partnerships between the two countries. In fine-scale MLVA-15 analysis, 17 B. abortus and 12 B. melitensis genotypes were identified; among them 12 are novel. Interestingly, epidemiological information supporting molecular data were retrieved for two clusters within the B. abortus group, thus proving that MLVA is an appropriate tool for effective traceback analyses. Our findings suggest that molecular genotyping should be applied systematically to support control plans for eradication of brucellosis in Kazakhstan. PMID- 29278753 TI - Intraoperative endoscopy prevents technical defect related leaks in laparoscopic Roux-en-Y gastric bypass: A randomized control trial. AB - BACKGROUND: Postoperative anastomotic leaks, bleeding and stenosis are major causes of morbidity after laparoscopic Roux-en-Y gastric bypass (LRYGB). Retrospective studies suggest that intraoperative endoscopy reduces the incidence of these complications. METHODS: We conducted a prospective randomized controlled trial in a single institution between March 2013 and January 2016. Patients were assigned to one of two groups: LRYGB with Intraoperative Endoscopy (IOE) or LRYGB without IOE. Patient selection criteria were morbidly obese patients, 18 years or older who were candidates to LRYGB. The primary outcome was the frequency of technical defect related anastomotic leaks. Secondary outcomes were operative time, length of hospital stay, anastomotic related complications, reoperations and 30-day mortality. RESULTS: 50 patients were randomly assigned in the IOE group and 50 in the control group. The IOE group had statistically significant lower rate of anastomotic leak (0 vs. 8%, p = .0412), and lower need for reoperation (0 vs. 8%, p = .0412). The IOE group had longer operative time (194.10 vs. 159 min, p < .001), and shorter mean length of hospital stay (2.44 vs. 3.46 days, p = .025). No differences were found in the rate of bleeding of the anastomosis, narrow anastomosis and 30-day mortality. CONCLUSION: This study specifically provides evidence that air leak test performed by intraoperative endoscopy is superior to simple visual inspection in preventing technical defect related leaks after laparoscopic Roux-en-Y gastric bypass. PMID- 29278755 TI - Molecular characterization and phylogenetic analysis of Clostridium perfringens from animals and their environments by cpn60 UT sequencing analysis. AB - Clostridium perfringens an ubiquitous environmental bacterium causes major food borne illnesses, digestive diseases and several soft tissue infections in humans and animals. In the present study, toxin typing of 91 C. perfringens isolates from animals with enteric diseases and their environments revealed the presence of type A and C strains. Enterotoxin gene (cpe), responsible for majority of the food poisoning incidences in humans and enteric infections in animals was present in 60.43 % of the isolates of which 76.3% and 23. 36% were chromosomal and plasmid borne respectively. Neighbour-joining tree inferred from cpn60 UT nucleotide sequences could differentiate the cpe+ve isolates from the cpe-ve isolates, provide clear distinction between the cpe-IS1470 and cpe-IS1151 genotypes and segregate type A and C strains in separate clusters. The present study is the first report on the utilization of cpn60 UT region for C. perfringens phylogeny analysis and demonstrates that cpn60 UT analysis alone, to a greater extent can be a simple, rapid and efficient method for differentiating between cpe+ve and cpe-ve strains or toxin types. The cpb2 gene was observed among 30 isolates of which 16.6% were from porcine sources while the rest were of non-porcine and environmental origin. The cpb2 sequences obtained in the present study though similar among them were diverse both from the consensus and atypical cpb2 sequences reported globally and formed a separate cluster. The study thus reports of novel cpb2 gene variant and warrants its characterization through further studies. PMID- 29278756 TI - Decentralised manufacturing of cell and gene therapy products: Learning from other healthcare sectors. AB - Decentralised or 'redistributed' manufacturing represents an attractive choice for production of some cell and gene therapies (CGTs), in particular personalised therapies. Decentralised manufacturing splits production into various locations or regions and in doing so, imposes organisational changes on the structure of a company. This confers a significant advantage by democratising supply, creating jobs without geographical restriction to the central hub and allowing a more flexible response to external pressures and demands. This comes with challenges that need to be addressed including, a reduction in oversight, decision making and control by central management which can be critical in maintaining quality in healthcare product manufacturing. The unwitting adoption of poor business strategies at an early stage in development has the potential to undermine the market success of otherwise promising products. To maximise the probability of realising the benefits that decentralised manufacturing of CGTs has to offer, it is important to examine alternative operational paradigms to learn from their successes and to avoid their failures. Whilst no other situation is quite the same as CGTs, some illustrative examples of established manufacturing paradigms are described. Each of these shares a unique attribute with CGTs which aids understanding of how decentralised manufacturing might be implemented for CGTs in a similar manner. In this paper we present a collection of paradigms that can be drawn on in formulating a roadmap to success for decentralised production of CGTs. PMID- 29278757 TI - Process and scaling parameters for wet media milling in early phase drug development: A knowledge based approach. AB - Wet media milling is a well-established unit operation for the manufacturing of suspension formulations during early phase pharmaceutical development. However, knowledge about the kinetics of particle breakage is limited, although the impact of hydro-mechanical process parameters on the mean particle size of finished suspensions has been thoroughly investigated. We performed in this work milling trials with two different compounds on two milling devices with different mechanical design and volume scale. We analyzed our data in terms of a kinetic milling model where we included the milling speed as an explicit process parameter in addition to the process duration. We show, that the milling kinetics can be fairly well predicted for a wide range of these operating parameters. The proposed milling model may therefore be useful for rational process planning and scale-up considerations in the industrial setting. PMID- 29278758 TI - Leucine reduces the proliferation of MC3T3-E1 cells through DNA damage and cell senescence. AB - Leucine (Leu) is an essential branched-chain amino acid, present in dairy products, which has been investigated for its important role in cell signaling. The effects of Leu on several kinds of cells have been studied, altough little is known on its action upon bone cells and cell proliferation. Thus, the aim of this study is to investigate the effects of Leu supplementation on the proliferation of pre-osteoblasts from MC3T3-E1 lineage. MC3T3-E1 cells were kept in Alpha medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimitotic. Cells were treated during 48h by adding 50MUM of Leu, which corresponds to a 12.5% increase of the amino acid in the culture medium. The evaluation of viability and proliferation of cultured cells was performed using Trypan Blue dye. In order to identify the mechanisms related to the decreased cellular proliferation, assays were performed to assess cytotoxicity, apotosis, oxidative stress, inflammation, autophagy, senescence and DNA damage. Results showed that Leu supplementation decreased cell proliferation by 40% through mechanisms not related to cell necrosis, apoptosis, oxidative stress, autophagy or inhibition of the mTORC1 pathway. On the other hand, Leu supplementation caused DNA damage. In conclusion, Leu caused a negative impact on bone cell proliferation by inducing cell senescence through DNA damage. PMID- 29278759 TI - Impact of mitochondrial DNA copy number and displacement loop alterations on polycystic ovary syndrome risk in south Indian women. AB - Sequencing of mitochondrial displacement-loop (D-loop) of polycystic ovary syndrome (PCOS) patients and (n=118) and controls (n=114) of south Indian origin showed significant association of D310 (P=0.042) and A189G (P=0.018) SNPs with PCOS. qRT-PCR analysis revealed significantly diminished mtDNA copy number in PCOS patients compared to controls (P=0.038). Furthermore, mtDNA copy number was significantly lower in PCOS cases carrying D310 and 189G alleles when compared to non-carriers (P=0.001 and 0.006 respectively). The D310 carriers also showed significantly elevated LH/FSH ratio (P=0.026). In conclusion, mtDNA D-loop and copy number alterations may constitute an inheritable risk factor for PCOS in south Indian women. PMID- 29278760 TI - Real-time scan speed control of the atomic force microscopy for reducing imaging time based on sample topography. AB - Here, a novel method, real-time scan speed control for raster scan amplitude modulation atomic force microscopes (AM-AFMs), is proposed. In general, the imaging rate is set to a fixed value before the experiment, which is determined by the feedback control calculations on each imaging point. Many efforts have been made to increase the AFM imaging rate, including using the cantilever with high eigenfrequency, employing new scan methods, and optimizing other mechanical components. The proposed real-time control method adjusts the scan speed linearly according to the error of every imaging point, which is mainly determined by the sample topography. Through setting residence time on each imaging point reasonably, the performance of AM-AFMs can be fully exploited while the scanner vibration is avoided when scan speed changes. Experiments and simulations are performed to demonstrate this control algorithm. This method would increase the imaging rate for samples with strongly fluctuant topography up to about 3 times without sacrificing any image quality, especially in large-scale and high resolution imaging, in the meanwhile, it reduces the professional requirements for AM-AFM operators. Since the control strategy employs a linear algorithm to calculate the scanning speed based on the error signal, the proposed method avoids the frequent switching of the scanning speed between the high speed and the low speed. And it is easier to implement because there is no need to modify the original hardware of the AFM for its application. PMID- 29278761 TI - Generation of a SMO homozygous knockout human embryonic stem cell line WAe001-A 16 by CRISPR/Cas9 editing. AB - The human SMO protein encoded by the smoothened (SMO) gene acts as a positive mediator for Hedgehog signaling. This pathway regulates many cellular activities, developmental morphogenesis, and tumorigenesis. Using CRISPR/Cas9 to edit human embryonic stem cell line WA01 (H1), we established a SMO mutant cell line (WAe001 A-16). This cell line has a 40bp homozygous deletion in exon 2 of SMO leading to a shift in the open reading frame and early termination at amino acid position 287. WAe001-A-16 maintains a normal karyotype, parental cell morphology, pluripotency markers, and the capacity to differentiate into all three germline layers. PMID- 29278762 TI - Intravoxel incoherent motion diffusion-weighted MRI for predicting response to neoadjuvant chemotherapy in breast cancer. AB - PURPOSE: To determine the diagnostic performance of intravoxel incoherent motion (IVIM) diffusion-weighted (DW) magnetic resonance imaging (MRI) parameters in predicting response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: Forty-six patients with stage II or III breast cancer underwent MRI including DW imaging with 10 b values before and after 2cycles of NAC. Apparent diffusion coefficient (ADC) and IVIM parameters (D, D*, and f) were obtained using histogram analysis derived from whole-tumor volumes. After surgery, imaging parameters were compared with histopathologic responses using the Miller-Payne grading system. RESULTS: Before NAC, Dmean, D50, and D75 were higher in good responders than in minor responders (P<=0.043). After NAC, ADCmean, ADC50, ADC75, Dmean, D25, D50, and D75 were higher in good responders (P<=0.037). Skewness of ADC and D were lower in good responders after NAC (P<=0.005). Most histogram metrics of posttreatment ADC and D had similar AUC values with reasonable accuracy for prediction of good response (AUC>=0.7, P<0.05). CONCLUSION: D and ADC are useful for the prediction of response to NAC in breast cancer patients. Additional information is obtained by application of the IVIM model in DW imaging analysis and histogram analysis using whole-tumor volume data. PMID- 29278763 TI - Optimal-permittivity Dielectric Liners for a 4.7T Transceiver Array. AB - Placing dielectric pads adjacent to the imaging region is an effective method to increase the signal locally and also increase the radio frequency magnetic field homogeneity in magnetic resonance imaging. The use of local high permittivity pads is becoming more common, and this work focuses on the effect of larger dielectric pads on the transmit/receive performance of an array (e.g., coupling, efficiency and safety) having 8 channels, used to image a cylindrical phantom at 4.7T (200MHz). We investigate the effects of a dielectric liner surrounding the whole volume of interest both with and without an air gap. The simulations reveal that high permittivities are not recommended because they substantially degrade the longitudinal homogeneity, resulting in hot spots of specific absorption rate at the driven end of the array. Furthermore, high permittivities lead to dielectric resonances in the liner at frequencies close to the Larmor frequency, potentially degrading the performance of the array. Indeed, simulations and measurements confirm that a compromise must be made between improvements in field homogeneity and transmit performance, and that an optimal permittivity exists which is much lower than those commonly used in the literature. The optimal permittivity achieves minimal coupling (<-23dB) between array elements, exhibits an intrinsic electromagnetic impedance equal to the geometric mean of those of the coil former and phantom and can be realized with inexpensive materials. For this permittivity the performance with an air gap of thickness equal to that of the liner is equivalent to that without the air gap. PMID- 29278765 TI - Gd-EOB-DTPA-enhanced T1rho imaging vs diffusion metrics for assessment liver inflammation and early stage fibrosis of nonalcoholic steatohepatitis in rabbits. AB - To assess the value of T1rho,T1rho on hepatobiliary phase (HBP) and diffusion metrics in staging of Non-alcoholic fatty liver disease (NAFLD) activity scores, inflammation, fibrosis in NASH rabbits model. Non-alcoholic steatohepatitis (NASH) rabbits model was induced by feeding a varied duration of high-fat, high cholesterol diet. T1rho,T1rho (HBP) 20min after administration of Gd-EOB-DTPA, and Intravoxel incoherent motion imaging (IVIM) diffusion-weighted imaging were performed on a 3.0T magnetic resonance (MR) imaging unit. The diagnostic value of each parameter for NAS, inflammation and fibrosis severity were determined. T1rho (r=0.658) and T1rho (HBP) (r=0.750) have strong association with NASH overall activity, T1rho (HBP) is strongly relevant to inflammation stage (r=0.812). There was negative association between f and inflammation (r=-0.480), whilst no significant relation between other three parameters (apparent diffusion coefficient (ADC), pseudo-diffusion coefficient (D*) and true diffusion coefficient (D)) and inflammation or overall activity. The areas under the receiver operating characteristic curves (AUCs) of f, ADC, T1rho and T1rho-HBP were 0.871, 0.728, 0.849 and 0.949 for differentiating NASH; 0.731, 0.552, 0.925 and 0.922 for G2-3 inflammation; and 0.767, 0.625, 0.816, and 0.882 for S1-2 fibrosis. Comparison of ROC curve showed T1rho (HBP) had an optimal diagnostic performance for NASH [T1rho (HBP) vs ADC, AUC:0.949 vs 0.728, P=0.043], inflammation [T1rho (HBP) vs ADC, AUC:0.922 vs 0.552, P=0.003], fibrosis [T1rho (HBP) vs ADC, AUC:0.882 vs 0.625, P=0.046]. The combination of T1rho (HBP)+perfusion fraction (f) showed highest diagnostic value for NASH (AUC:0.971), inflammation (AUC:0.935). Among T1rho imaging and IVIM diffusion metrics, combination of T1rho (HBP)+f was found to be superior noninvasive imaging biomarker for NASH activity assessment. PMID- 29278764 TI - Robust and efficient pharmacokinetic parameter non-linear least squares estimation for dynamic contrast enhanced MRI of the prostate. AB - PURPOSE: To describe an efficient numerical optimization technique using non linear least squares to estimate perfusion parameters for the Tofts and extended Tofts models from dynamic contrast enhanced (DCE) MRI data and apply the technique to prostate cancer. METHODS: Parameters were estimated by fitting the two Tofts-based perfusion models to the acquired data via non-linear least squares. We apply Variable Projection (VP) to convert the fitting problem from a multi-dimensional to a one-dimensional line search to improve computational efficiency and robustness. Using simulation and DCE-MRI studies in twenty patients with suspected prostate cancer, the VP-based solver was compared against the traditional Levenberg-Marquardt (LM) strategy for accuracy, noise amplification, robustness to converge, and computation time. RESULTS: The simulation demonstrated that VP and LM were both accurate in that the medians closely matched assumed values across typical signal to noise ratio (SNR) levels for both Tofts models. VP and LM showed similar noise sensitivity. Studies using the patient data showed that the VP method reliably converged and matched results from LM with approximate 3* and 2* reductions in computation time for the standard (two-parameter) and extended (three-parameter) Tofts models. While LM failed to converge in 14% of the patient data, VP converged in the ideal 100%. CONCLUSION: The VP-based method for non-linear least squares estimation of perfusion parameters for prostate MRI is equivalent in accuracy and robustness to noise, while being more reliably (100%) convergent and computationally about 3* (TM) and 2* (ETM) faster than the LM-based method. PMID- 29278766 TI - Phase unwinding for dictionary compression with multiple channel transmission in magnetic resonance fingerprinting. AB - PURPOSE: Magnetic Resonance Fingerprinting reconstructions can become computationally intractable with multiple transmit channels, if the B1+ phases are included in the dictionary. We describe a general method that allows to omit the transmit phases. We show that this enables straightforward implementation of dictionary compression to further reduce the problem dimensionality. METHODS: We merged the raw data of each RF source into a single k-space dataset, extracted the transceiver phases from the corresponding reconstructed images and used them to unwind the phase in each time frame. All phase-unwound time frames were combined in a single set before performing SVD-based compression. We conducted synthetic, phantom and in-vivo experiments to demonstrate the feasibility of SVD based compression in the case of two-channel transmission. RESULTS: Unwinding the phases before SVD-based compression yielded artifact-free parameter maps. For fully sampled acquisitions, parameters were accurate with as few as 6 compressed time frames. SVD-based compression performed well in-vivo with highly under sampled acquisitions using 16 compressed time frames, which reduced reconstruction time from 750 to 25min. CONCLUSION: Our method reduces the dimensions of the dictionary atoms and enables to implement any fingerprint compression strategy in the case of multiple transmit channels. PMID- 29278767 TI - MiR-183 regulates milk fat metabolism via MST1 in goat mammary epithelial cells. AB - The nutritional value of goat milk largely depends on its fatty acid content and composition. MicroRNAs (miRNAs) are a class of RNA molecules 18-25nt in length that regulate gene expression and play crucial roles in several biological processes, including fatty acid metabolism. In this study, we analyzed the correlation between differentially expressed miRNAs in goat mammary tissue and the fatty acid composition of goat milk by using Pearson correlations. Results revealed that levels of miR-183 were highly and positively correlated with the fatty acid content in the milk. In addition, we demonstrated that overexpression of miR-183 inhibits milk fat metabolism and inhibition of miR-183 promotes milk fat metabolism. Using Western blot, we demonstrate that MST1, one of the major elements of the Hippo signaling pathway, is a target of miR-183. Immunofluorescence assays revealed that miR-183 targets MST1 in the cytoplasm. In summary, data indicate that miR-183 inhibits the metabolism of milk fat by targeting the MST1 gene in the cytoplasm in goat mammary epithelial cells. PMID- 29278768 TI - Association of polymorphisms in ERAP1 and risk of ankylosing spondylitis in a Chinese population. AB - To explore the association between five polymorphisms in endoplasmic reticulum associated aminopeptidase 1 (ERAP1) gene and risk of ankylosing spondylitis (AS) in a Chinese population. A case-control study enrolled 250 AS patients and 250 healthy controls was carried out. The genotypes of involved polymorphisms (rs27037, rs27038, rs469876, rs27044 and rs27980) in ERAP1 were detected by Sequenom Mass-Array platform. There were significant differences of the level of WBC (white blood cell), Platelets, CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) between AS patients and controls (Pall<0.05). There was statistically association between ERAP1 rs27044 polymorphism and risk of AS, and the carriers with rs27044 CG genotype have an increased the risk for AS (CG versus GG, OR=1.70, 95% CI=1.10-2.62, P=0.015). However, we found no evidence for the association of rs27037, rs469876, and rs27980 polymorphisms in ERAP1 with AS risk. Our findings indicated that ERAP1 rs27044 polymorphism was associated with the susceptibility of AS. PMID- 29278769 TI - MiR-1275 promotes cell migration, invasion and proliferation in squamous cell carcinoma of head and neck via up-regulating IGF-1R and CCR7. AB - PURPOSE: miRNAs can play vital role in migration, invasion and proliferation in Squamous cell carcinoma of head and neck (SCCHN). In our study, we attempted to validate the expression and function of miR-1275 in SCCHN, and we also identified the mechanism by which miR-1275 affects migration, invasion and proliferation of SCCHN. METHODS: Real-time polymerase chain reaction (RT-PCR) was employed to evaluate the expression of miR-1275 in both SCCHN tissues and cell lines. The role of miR-1275 in SCCHN cells was verified by cell function experiments upon transfection with miR-1275 mimics and inhibitor. Western blot analysis was employed to test the target gene expression of miR-1275. Survival analysis was made with the information of SCCHN patients expressed miR-1275 from The Cancer Genome Atlas (TCGA) database. RESULTS: miR-1275 expression was up-regulated in SCCHN tissues and advanced metastatic SCCHN cells. Increasing miR-1275 expression in SCCHN could promote cell migration, invasion and proliferation probably by upregulating Insulin-like growth factor 1 receptor (IGF-1R) and C-C chemokine receptor type 7(CCR7) protein levels, whereas inhibition of miR-1275 could lead the opposite effects, although others have already demonstrated that IGF-1R is a direct target of miR-1275. Survival analysis suggested that patients with lower miR-1275 expression may have a better outcome. CONCLUSIONS: Herein we report for the first time that miR-1275 could act as a tumor-promoter in SCCHN possibly by regulating its target gene via novel miRNA mechanisms. MiR-1275 plays an important role in promoting SCCHN progression. The miR-1275 may be a potential therapeutic target for SCCHN treatment in the future. PMID- 29278770 TI - Identification of the AQP members involved in abiotic stress responses from Arabidopsis. AB - Aquaporins (AQPs) constitute a highly diverse family of water channel proteins that play crucial biological functions in plant growth and development and stress physiology. In Arabidopsis, 35 AQPs are classified into four subfamilies (PIPs, TIPs, NIPs and SIPs). However, knowledge about the roles of different subfamily AQPs remains limited. Here, we explored the chromosomal location, gene structure and expression patterns of all AQPs in different tissues or under different abiotic stresses based on available microarray data. Tissue expression analysis showed that different AQPs had various expression patterns in tissues (root, leaf, flower and seed). Expression profiles under stress conditions revealed that most AQPs were responsive to osmotic, salt and drought stresses. Phenotypic and physiological identification showed that Tip2;2 loss-of-function mutant exhibited less sensitive to abiotic stresses (mannitol, NaCl and PEG) compared with wild type, as evident by analysis of germination rate, root growth, survival rate, ion leakage, malondialdehyde (MDA) and proline contents. Mutant of TIP2;2 modulated the transcript levels of SOS1, SOS2, SOS3, DREB1A, DREB2A and P5CS1, under abiotic stress conditions. This study provides a basis for further functional identification of stress-related candidate AQPs in Arabidopsis. PMID- 29278771 TI - Genome-wide identification and analysis of the evolution and expression patterns of the cellulose synthase gene superfamily in Gossypium species. AB - The cellulose synthase gene superfamily, which includes the cellulose synthase (Ces) and cellulose synthase-like (Csl) families, is involved in the synthesis of cellulose and hemicellulose. This superfamily is critical for cotton fiber development in Gossypium species. Applying a series of bioinformatic methods, we identified 228 Ces/Csl genes from four Gossypium species (G. hirsutum, G. barbadense, G. arboreum, and G. raimondii). These genes were then grouped into 11 subfamilies based on phylogenetic relationships. A subsequent analysis of gene evolution revealed sites in CSLG and CSLJ genes that were under long-term positive selection pressure, with a posterior probability >0.95. Moreover, the dN:dS value for the CSLJ clade was 1.305, suggesting this subfamily was under positive selection pressure. Our data indicated that the dN:dS value ranged from 0.0084 to 0.9693 among the homologous Ces/Csl genes, implying they were under purifying selection pressure. Our transcriptome and qRT-PCR analyses revealed that CesA genes were more highly expressed in tetraploids than in diploids. However, the Csl expression levels exhibited the opposite trend. Furthermore, changes to promoter sequences may have influenced the expression of homologous Ces/Csl genes. Our findings may provide novel insights into the evolutionary relationships and expression patterns of the Ces/Csl genes in Gossypium species. PMID- 29278772 TI - Metric learning with spectral graph convolutions on brain connectivity networks. AB - Graph representations are often used to model structured data at an individual or population level and have numerous applications in pattern recognition problems. In the field of neuroscience, where such representations are commonly used to model structural or functional connectivity between a set of brain regions, graphs have proven to be of great importance. This is mainly due to the capability of revealing patterns related to brain development and disease, which were previously unknown. Evaluating similarity between these brain connectivity networks in a manner that accounts for the graph structure and is tailored for a particular application is, however, non-trivial. Most existing methods fail to accommodate the graph structure, discarding information that could be beneficial for further classification or regression analyses based on these similarities. We propose to learn a graph similarity metric using a siamese graph convolutional neural network (s-GCN) in a supervised setting. The proposed framework takes into consideration the graph structure for the evaluation of similarity between a pair of graphs, by employing spectral graph convolutions that allow the generalisation of traditional convolutions to irregular graphs and operates in the graph spectral domain. We apply the proposed model on two datasets: the challenging ABIDE database, which comprises functional MRI data of 403 patients with autism spectrum disorder (ASD) and 468 healthy controls aggregated from multiple acquisition sites, and a set of 2500 subjects from UK Biobank. We demonstrate the performance of the method for the tasks of classification between matching and non-matching graphs, as well as individual subject classification and manifold learning, showing that it leads to significantly improved results compared to traditional methods. PMID- 29278773 TI - An evaluation of the efficacy, reliability, and sensitivity of motion correction strategies for resting-state functional MRI. AB - Estimates of functional connectivity derived from resting-state functional magnetic resonance imaging (rs-fMRI) are sensitive to artefacts caused by in scanner head motion. This susceptibility has motivated the development of numerous denoising methods designed to mitigate motion-related artefacts. Here, we compare popular retrospective rs-fMRI denoising methods, such as regression of head motion parameters and mean white matter (WM) and cerebrospinal fluid (CSF) (with and without expansion terms), aCompCor, volume censoring (e.g., scrubbing and spike regression), global signal regression and ICA-AROMA, combined into 19 different pipelines. These pipelines were evaluated across five different quality control benchmarks in four independent datasets associated with varying levels of motion. Pipelines were benchmarked by examining the residual relationship between in-scanner movement and functional connectivity after denoising; the effect of distance on this residual relationship; whole-brain differences in functional connectivity between high- and low-motion healthy controls (HC); the temporal degrees of freedom lost during denoising; and the test-retest reliability of functional connectivity estimates. We also compared the sensitivity of each pipeline to clinical differences in functional connectivity in independent samples of people with schizophrenia and obsessive-compulsive disorder. Our results indicate that (1) simple linear regression of regional fMRI time series against head motion parameters and WM/CSF signals (with or without expansion terms) is not sufficient to remove head motion artefacts; (2) aCompCor pipelines may only be viable in low-motion data; (3) volume censoring performs well at minimising motion-related artefact but a major benefit of this approach derives from the exclusion of high-motion individuals; (4) while not as effective as volume censoring, ICA-AROMA performed well across our benchmarks for relatively low cost in terms of data loss; (5) the addition of global signal regression improved the performance of nearly all pipelines on most benchmarks, but exacerbated the distance-dependence of correlations between motion and functional connectivity; and (6) group comparisons in functional connectivity between healthy controls and schizophrenia patients are highly dependent on preprocessing strategy. We offer some recommendations for best practice and outline simple analyses to facilitate transparent reporting of the degree to which a given set of findings may be affected by motion-related artefact. PMID- 29278775 TI - Directed evolution to improve protein folding in vivo. AB - Recently, several innovative approaches have been developed that allow one to directly screen or select for improved protein folding in the cellular context. These methods have the potential of not just leading to a better understanding of the in vivo folding process, they may also allow for improved production of proteins of biotechnological interest. PMID- 29278776 TI - A computerized testing system for primates: Cognition, welfare, and the Rumbaughx. AB - Innovations in apparatus technology come about for a variety of reasons such as the need to use the same methodology with various species, the opportunity to present dynamic and carefully controlled stimuli, the goal of using automation to make data collection more precise or efficient, and the need to control for and/or eliminate the presence of experimenters in the testing context. At the Language Research Center (LRC) of Georgia State University, a computer-based system has been developed and used extensively with nonhuman primate species. This system involves the animal working in an enclosure that provides visual access to a computer screen, access to a joystick to control a cursor on the screen, and access to a food dish where pellets are delivered for correct responses. Here we will describe the history and development of this system as well as some considerations that might be applied to expanding this apparatus to a new environment, including the mobility of test stations, equipment needs, training protocols, and the cost and considerations for initial set up of such a system. A variety of computer based programs have been developed for use with this system. These programs have allowed insight into many nonhuman primate cognitive abilities and we highlight some that have been the focus of study at the LRC such as metacognition, numerical cognition, inhibitory processes, prospective memory, attention, and cognitive control. In addition, this cognitive testing apparatus has been shown to create a stimulating and enriching environment for the animals. We advocate that the computerized testing apparatus is useful for advancing our understanding of nonhuman animal cognition and may be uniquely suited to optimizing animal welfare. This area of research is already rapidly expanding in zoos, and we hope to offer some insight from one journey of designing, implementing and adapting a computerized testing paradigm. PMID- 29278777 TI - Seven myths of memory. AB - In this paper we highlight seven myths about memory, which centre around the fact that memories, as we experience them, are not only about the past, they are also prospective. Although episodic memory provides the template for future scenarios, it can be reassessed each time it is recalled, and in part is dependent on the sequence in which events unfold. We explore seven myths about memory, and the relationship between memory and experience. We refer to 'The Moustachio Quartet', a series of novels, which highlight themes and ideas relevant to our argument, and 'The Creatures in the Night', a picture book of paintings that explore the passage of time. We integrate evidence from science and the arts to explore the subjective nature of memory and mental time travel, arguing that our capacity to juggle multiple perspectives evolved for the act of prospection, as an aid to move time forward to the advantage of our species by imagining future scenarios. PMID- 29278774 TI - Quantitative assessment of structural image quality. AB - Data quality is increasingly recognized as one of the most important confounding factors in brain imaging research. It is particularly important for studies of brain development, where age is systematically related to in-scanner motion and data quality. Prior work has demonstrated that in-scanner head motion biases estimates of structural neuroimaging measures. However, objective measures of data quality are not available for most structural brain images. Here we sought to identify quantitative measures of data quality for T1-weighted volumes, describe how these measures relate to cortical thickness, and delineate how this in turn may bias inference regarding associations with age in youth. Three highly trained raters provided manual ratings of 1840 raw T1-weighted volumes. These images included a training set of 1065 images from Philadelphia Neurodevelopmental Cohort (PNC), a test set of 533 images from the PNC, as well as an external test set of 242 adults acquired on a different scanner. Manual ratings were compared to automated quality measures provided by the Preprocessed Connectomes Project's Quality Assurance Protocol (QAP), as well as FreeSurfer's Euler number, which summarizes the topological complexity of the reconstructed cortical surface. Results revealed that the Euler number was consistently correlated with manual ratings across samples. Furthermore, the Euler number could be used to identify images scored "unusable" by human raters with a high degree of accuracy (AUC: 0.98-0.99), and out-performed proxy measures from functional timeseries acquired in the same scanning session. The Euler number also was significantly related to cortical thickness in a regionally heterogeneous pattern that was consistent across datasets and replicated prior results. Finally, data quality both inflated and obscured associations with age during adolescence. Taken together, these results indicate that reliable measures of data quality can be automatically derived from T1-weighted volumes, and that failing to control for data quality can systematically bias the results of studies of brain maturation. PMID- 29278778 TI - Selection as a domain-general evolutionary process. AB - The behavioral phenotype of an organism results from selective processes acting on variation in behavioral traits during ontogeny (during life span) and phylogeny (across generations). Different adaptive processes can be categorized as environment-phenotype feedback loops. In this cross-disciplinary approach, we discuss the interaction of ontogenetic selective processes, traditionally studied by behavior analysts, and phylogenetic selection processes, traditionally studied by biologists. We elaborate upon the Extended Evolutionary Synthesis by addressing the connection between selection as a domain-general process and phenomena such as classical and operant conditioning, imprinting, adjunctive behavior, and gene-culture coevolution. Selection is in this context understood as a dynamic iterative feedback loop producing a phenotype beyond the strict morphotype. The extended phenotype is related to the concept of niche construction in which the behavior of organisms shapes their environment, which again selects the behavior of the organisms in an iterative process. A discussion of interacting environmental factors selecting human food choice both during phylogeny and ontogeny exemplifies the generality of selection processes acting on behavior. PMID- 29278779 TI - Transaminases for chiral amine synthesis. AB - Amine transaminases are important biocatalysts for the synthesis of chiral primary amines. Unlike many enzymes that have been employed for the synthesis of optically active amines, amine transaminases are capable of asymmetric synthesis and do not rely on costly cofactors that must be regenerated in situ. However, their application as general catalysts for the preparation of amines is hampered by a limited substrate scope, substrate and (co)product inhibition and difficulties associated with displacing challenging reaction equilibrium. There has been important progress made to overcome these challenges, including the development of enzymes with broader substrate scope and the design of methodology to effectively displace the reaction equilibrium. Amine transaminases are also being applied in an increasing range of (chemo)enzymatic cascades and immobilized for applications in flow. PMID- 29278780 TI - Coordination of cell polarity and the patterning of leaf vein networks. AB - During development, the behavior of cells in tissues is coordinated along specific orientations or directions by coordinating the polar localization of components in those cells. The coordination of such cell polarity is perhaps nowhere more spectacular than in developing leaves, where the polarity of hundreds of cells is coordinated in the leaf epidermis and inner tissue to pattern vein networks. Available evidence suggests that the spectacular coordination of cell polarity that patterns vein networks is controlled by auxin transport and levels, and by genes that have been implicated in the polar localization of auxin transporters. PMID- 29278781 TI - Isolation, structure elucidation and anticancer activity from Brevibacillus brevis EGS 9 that combats Multi Drug Resistant actinobacteria. AB - Actinobacteria is the most widely distributed organism in the mangrove environment and produce a large amount of secondary metabolites. A new environmental actinobacterial stain exhibited strong antimicrobial activity against vancomycin and methicillin resistant actinobacteria. The active producer strain was found to be as Brevibacillus brevis EGS9, which was confirmed by its morphological, biochemical characteristics and 16S rRNA gene sequencing. It was deposited in NCBI GeneBank database and received with an accession number of KX388147. Brevibacillus brevis EGS9 was cultivated by submerged fermentation to produce antimicrobial compounds. The anti-proliferative agent was extracted from Brevibacillus brevis EGS9 with ethyl acetate. The bioactive metabolites of mangrove actinobacteria was identified by Liquid chromatography with mass spectrometry analysis. The result of the present investigation revealed that actinobacteria isolated from mangroves are potent source of anticancer activity. The strain of Brevibacillus brevis EGS9 exhibited a potential in vitro anticancer activity. The present research concluded that the actinobacteria isolated from mangrove soil sediment are valuable in discovery of novel species. PMID- 29278782 TI - Correlation and in vitro mechanism of bactericidal activity on E. coli with whey protein isolate during ultrasonic treatment. AB - OBJECTIVE: This study aimed to investigate correlation and in vitro mechanism of bactericidal activity on E. coli with whey protein isolate (WPI) during ultrasonic treatment. METHODS: The structural changes of WPI under ultrasonic field were studied by amino-acid analyzer, circular dichroism, SDS-PAGE, and spectrophotometer. RESULTS: With the increasing of WPI concentration added during ultrasonic treatment, the survival rate of E. coli increased. The influence of WPI on bactericidal activity under ultrasonic treatment might due to the change of tertiary and higher level structures, not by the primary structure, and had little relation with secondary structure. CONCLUSION: The influence of WPI on bactericidal activity during ultrasonic treatment might due to the change of the tertiary structure and higher level structures. PMID- 29278783 TI - Role of dose dependent Escherichia coli as ruminal anti-microflora agent to mitigate biogases production in prickly pear cactus flour based diet. AB - The present investigation was conducted to evaluate the effects of Escherichia coli against the ruminal microflora fermentation activities in the mitigation of CH4 and CO2 production as well as ruminal fermentation kinetics by substituting dietary corn grain with prickly pear cactus (PC) flour. Three total mixed PC rations were prepared (/kg DM): 0 g (Control), 75 g (PC75), and 150 g (PC150). Besides, E. coli was supplemented at four different levels (dose): 0, 10, 20, and 40 mg/g DM of substrates. The in vitro rumen GP, CH4, and CO2 were estimated to be affected due to various doses of E. coli up to 72 h of incubation. Asymptotic GP, fractional rate of GP, and lag time were influenced significantly (P < .05) in the presence of ration. However, E. coli doses showed minor impact on the rate of GP as well as lag time. The asymptotic CH4 production was decreased linearly (P = .005) at the ration PC150. E. coli doses reduced the asymptotic CH4 production at 10 and 20 mg/g DM. The asymptotic CO2 production was linearly (P < .001) decreased by different levels of PC. The cubic (P = .023) effect of E. coli doses as well as significant (P = .002) ration * E. coli doses impact were reported on asymptotic CO2 production. The fractional rate of GP was quadratically (P < .05) influenced by PC and E. coli doses. The rations, dose, and rations * E. coli dose interaction had no influence (P > .05) on lag time. In a nutshell, PC flour inclusion in diet has the potentiality to replace the existing conventional feedstuffs for ruminant. Most importantly, revealing the first report, PC flours along with E. coli supplementation at varied doses mitigated the ruminal biogases production. This was as consequence to the antimicrobial impacts of E. coli against ruminal microflora, and that could certainly be a promising approach in order to improve ruminant's diet constituents. PMID- 29278784 TI - Elucidating the biogeographical variation of the venom of Naja naja (spectacled cobra) from Pakistan through a venom-decomplexing proteomic study. AB - : Naja naja is a medically important species that is distributed widely in South Asia. Its venom lethality and neutralization profile have been reported to vary markedly, but the understanding of this phenomenon has been limited without a comprehensive venom profile for the Pakistani N. naja. This study set to investigate the venom proteome of Pakistani N. naja applying reverse-phase HPLC, SDS-PAGE, mass spectrometry and data-mining approaches. The venom enzymatics and antigen binding activities were also studied. A total of 55 venom proteins comprising 11 toxin families were identified, with three-finger toxins (75.29%) being the predominant component, followed by phospholipase A2 (14.24%) and other proteins (<5%). The enzyme activities of most of the venom components were also detected in this work. The high abundance of long neurotoxins (LNTX, 21.61%) in the Pakistani N. naja venom is varied from that reported for N. naja venoms from other geographical origins. The venom exhibited high immunoreactivity toward Naja kaouthia monovalent antivenom (NKMAV), which was raised against the LNTX predominated heterologous Thai N. kaouthia venom. Together, the findings show that the Pakistani N. naja venom is predominated by LNTX, and this unique property correlates with its high lethality and effective neutralization by the heterologous NKMAV. BIOLOGICAL SIGNIFICANCE: This study reveals the compositional details of the venom proteome of Pakistani spectacled cobra (Naja naja). The protein subtypes, proteoforms, and relative abundances of individual proteins were comprehensively revealed in this study, following a venom decomplexing proteomic approach. The Pakistani cobra venom is unique among the rest of the N. naja venom composition reported thus far, as it contains a high abundance of alpha-neurotoxins (predominated by long neurotoxins); these are highly potent post-synaptic neuromuscular blockers that cause paralysis and are principal toxins that account for the high lethality of the venom (LD50=0.2MUg/g in mice). In contrast, previous reports showed that the N. naja venoms of India and Sri Lanka had a lower content of neurotoxins and a relatively higher value of LD50. The Pakistani cobra venom demonstrated sufficient immunoreactivity toward three antivenom products manufactured outside Pakistan (including the Indian product VINS), however the potency of antigen binding was the highest toward Naja kaouthia monovalent antivenom, a heterologous antivenom raised against a long neurotoxin-predominated venom of the Thai monocled cobra. From the practical standpoint, the findings indicate that the treatment of N. naja envenomation in Pakistan may be improved by the production of a locale-specific antivenom, in which the antivenom produced contains more antibodies that can target and react more specifically with the highly abundant lethal neurotoxins in the Pakistani N. naja venom. PMID- 29278785 TI - Gender-related increase of tropomyosin-1 abundance in platelets of Alzheimer's disease and mild cognitive impairment patients. AB - : The incidence of Alzheimer's disease (AD) is higher in elderly women than in men. The molecular background of this gender-related risk, however, is largely unknown. In a previous proteomics study, we identified significantly elevated levels of monoamine oxidase-B and tropomyosin-1 in AD patients, together with significant changes of the genetic AD risk factors apolipoprotein E4 (APOE4) and glutathione S-transferase omega 1 (GSTO1), in platelets - a promising source for AD blood biomarkers. The present study aimed to investigate the gender specificity as well as the disease-stage dependency of these biomarkers in AD patients and those with mild cognitive impairment (MCI). Tropomyosin-1 and monoamine oxidase-B protein levels were quantified by 2-D DIGE and 1-D Western blotting. Here, for the first time, we revealed a significant increase of 38&39kDa tropomyosin-1 protein levels in female but not male AD (+56%; p=0.008) and MCI patients (+46%; p=0.041) measured by 1-D WB. In contrast, levels of monoamine oxidase-B were, independently of gender, elevated in AD patients (+52%; p=0.009) but unaltered in MCI compared to control subjects. Moreover, we confirmed that APOE4-positive females are at a higher risk (OR=18.7; p=9.7E-09) of developing AD compared to APOE4-positive males (OR=6.5; p=5.9E-04). No gender related effects were observed for GSTO1. SIGNIFICANCE: Platelet tropomyosin-1 constitutes a gender-related and stage-dependent protein in cognitive impairment. In contrast, platelet monoamine oxidase-B, frequently described to be increased in platelets and brains of AD patients, shows a gender-independent but stage related increase since it is unaltered in MCI subjects. A blood biomarker test for this preceding stage of AD that considers gender-specificity is not yet available. The newly described AD-related platelet protein profiles might refine and facilitate routine diagnosis and enable early as well as tailored interventions. PMID- 29278786 TI - High throughput and accurate serum proteome profiling by integrated sample preparation technology and single-run data independent mass spectrometry analysis. AB - : Mass spectrometry (MS)-based serum proteome analysis is extremely challenging due to its high complexity and dynamic range of protein abundances. Developing high throughput and accurate serum proteomic profiling approach capable of analyzing large cohorts is urgently needed for biomarker discovery. Herein, we report a streamlined workflow for fast and accurate proteomic profiling from 1MUL of blood serum. The workflow combined an integrated technique for highly sensitive and reproducible sample preparation and a new data-independent acquisition (DIA)-based MS method. Comparing with standard data dependent acquisition (DDA) approach, the optimized DIA method doubled the number of detected peptides and proteins with better reproducibility. Without protein immunodepletion and prefractionation, the single-run DIA analysis enables quantitative profiling of over 300 proteins with 50min gradient time. The quantified proteins span more than five orders of magnitude of abundance range and contain over 50 FDA-approved disease markers. The workflow allowed us to analyze 20 serum samples per day, with about 358 protein groups per sample being identified. A proof-of-concept study on renal cell carcinoma (RCC) serum samples confirmed the feasibility of the workflow for large scale serum proteomic profiling and disease-related biomarker discovery. BIOLOGICAL SIGNIFICANCE: Blood serum or plasma is the predominant specimen for clinical proteomic studies while the analysis is extremely challenging for its high complexity. Many efforts had been made in the past for serum proteomics for maximizing protein identifications, whereas few have been concerned with throughput and reproducibility. Here, we establish a rapid, robust and high reproducible DIA based workflow for streamlined serum proteomic profiling from 1MUL serum. The workflow doesn't need protein depletion and pre-fractionation, while still being able to detect disease-relevant proteins accurately. The workflow is promising in clinical application, because the usage of small sample amounts makes blood testing much less invasive, the fully integrated sample preparation by the SISPROT technology greatly improve sample preparation throughput and reproducibility, and the scan feature of DIA method provides a way to convert nonrenewable clinical specimens into permanent digital proteome maps which could be easily reanalyzed. PMID- 29278787 TI - Selenite reduction and ammoniacal nitrogen removal in an aerobic granular sludge sequencing batch reactor. AB - Simultaneous removal of selenite and ammonium by aerobic granular sludge was investigated to develop an improved biological treatment process for selenium rich wastewaters. Aerobic granules not previously exposed to selenite were able to remove selenite by converting it to elemental selenium (Se(0)) and simultaneously remove ammonium under different conditions in batch experiments. To achieve sustainable selenite and ammonium removal, an aerobic granular sludge reactor was operated in fill-and-draw mode with a cycle of anaerobic (8 h) and aeration (15 h) phases. Almost complete removal of different initial concentrations of selenite up to 100 MUM was achieved in the anaerobic phase. Ammonium removal was severely inhibited when the granules were initially exposed to 1.27 mg L-1 selenite, but ammonium and total nitrogen removal efficiencies gradually improved to 100 and 98%, respectively, under selenite-reducing conditions. Selenite loading shifted ammonium removal occurring mainly during the anaerobic phase to both the anaerobic and aeration phases. Selenite was removed from the aqueous phase by converting it to nanoparticulate Se(0), which was entrapped in the granular sludge. Scanning electron microscop-energy dispersive X ray spectroscopy and X-ray diffraction analysis confirmed the formation of Se(0) nanospheres and their retention in the granular sludge. The effluent Se ranged from 0.02 to 0.25 mg Se L-1, while treating up to 12.7 mg L-1 selenite, which is lower as compared to previous studies on selenite removal using activated sludge or anaerobic granular sludge. This study shows that aerobic granular sludge reactors are not only capable of removing toxic selenite, but offer improved treatment of Se-rich wastewaters. PMID- 29278788 TI - Reduction in the exchange of coastal dissolved organic matter and microgels by inputs of extra riverine organic matter. AB - Rivers drive large amounts of terrestrial and riverine organic matter into oceans. These organic materials may alter the self-assembly of marine dissolved organic matter (DOM) polymers into microgels and can even affect the behavior of existing natural microgels. We used Suwannee River humic acid, fulvic acid, and natural organic matter as a model of riverine organic matter (ROM) to investigate the impacts of ROM input on DOM polymer and microgel conversion. Our results indicated that the release of extra ROM, even at low concentrations (0.1-10 mg L 1), into the marine organic matter pool decreased the size of self-assembled DOM polymers (from 4-5 MUm to < 1 MUm) and dispersed the existing natural microgels into smaller particles (from 4-5 MUm to 2-3 MUm). The particle size of the microgel phase was also less sensitive than that of the DOM polymers to external changes (addition of ROM). This size reduction in DOM aggregation and existing microgels may be closely tied to the surface chemistry of the organic matter, such as negative surface charge stabilization and Ca2+ cross-linking bridges. These findings reveal that ROM inputs may therefore impede the self-assembly of DOM polymers into particulate organic matter and reduce the sedimentation flux of organic carbon and other elements from surface water to the deep ocean, thereby disturbing the biological pump, the downward transportation of nutrients, and the marine organic carbon cycle. PMID- 29278790 TI - The way out and in: phloem loading and unloading of amino acids. AB - Amino acids represent the major transport form of reduced nitrogen in plants. Long-distance transport of amino acids occurs in the xylem and the phloem. However, the phloem is the main transport route for bulk flow of the organic nitrogen from source leaves to sink tissues. Phloem loading in leaves of most annual plant species follows an apoplasmic transport path and requires the coordinated activity of transport protein mediating cellular export or import of amino acids. Phloem unloading of amino acids is generally a symplasmic process but apoplasmic transport is additionally required for efficient post-phloem nitrogen transport. In this review we summarize the current data on the physiology of amino acid phloem loading and unloading, and the molecular players involved. We discuss the implications of amino acid transporters in nitrogen signaling and highlight the necessity to investigate the coordination of symplasmic and apoplasmic transport processes. PMID- 29278789 TI - Portable platform for rapid in-field identification of human fecal pollution in water. AB - Human fecal contamination of water is a public health risk. However, inadequate testing solutions frustrate timely, actionable monitoring. Bacterial culture based methods are simple but typically cannot distinguish fecal host source. PCR assays can identify host sources but require expertise and infrastructure. To bridge this gap we have developed a field-ready nucleic acid diagnostic platform and rapid sample preparation methods that enable on-site identification of human fecal contamination within 80 min of sampling. Our platform relies on loop mediated isothermal amplification (LAMP) of human-associated Bacteroides HF183 genetic markers from crude samples. Oligonucleotide strand exchange (OSD) probes reduce false positives by sequence specifically transducing LAMP amplicons into visible fluorescence that can be photographed by unmodified smartphones. Our assay can detect as few as 17 copies/ml of human-associated HF183 targets in sewage-contaminated water without cross-reaction with canine or feline feces. It performs robustly with a variety of environmental water sources and with raw sewage. We have also developed lyophilized assays and inexpensive 3D-printed devices to minimize cost and facilitate field application. PMID- 29278791 TI - Phloem function and development-biophysics meets genetics. AB - Evolution of the vascular tissues allowed plants to efficiently settle land, occupy new ecological niches, and thereby crucially shape earth's biosphere. Of the two conducting cell types in the plant vasculature, the tubular network of phloem sieve elements transports phloem sap from source to sink organs. Recent years have witnessed the identification of ever more regulators of sieve element differentiation, as well as a more detailed understanding of phloem physiology and function. From molecular regulators of the commitment to sieve element fate, to enzymatic executors of the differentiation process, the toolbox to investigate sieve element formation has been greatly enlarged. To connect the various players in different genetic layers, and thus to ultimately attain a comprehensive description and understanding of sieve element development at the molecular level, appears to be within reach. PMID- 29278792 TI - Increasing water solubility with decreasing droplet size limits the use of water NMR diffusometry in submicron W/O-emulsion droplet size analysis. AB - HYPOTHESIS: Water droplet size analysis of water-in-oil emulsions using water NMR diffusometry yielded values that were, from a certain shear intensity onwards, independent from the shear which was used during production. It was assumed that the constant water droplet size, obtained for samples prepared at higher shear, were only apparent droplet diameters. Considering the well-known increased solubility of the dispersed phase in the continuous phase at smaller droplet sizes, it is hypothesized that water diffusion in the oil phase was responsible for the fact that apparent rather than real sizes were obtained. EXPERIMENTS: W/O emulsions, prepared with a varying shear intensity, were characterized using dynamic light scattering, light microscopy, T2-relaxometry and PFG-NMR diffusometry. The latter measurements were conducted on both a low- and a high resolution device and was based on either water (LR- and HR-NMR) or a water soluble marker (HR-NMR). FINDINGS: Low-resolution PFG-NMR is incapable of accurately determining the droplet size of W/O-emulsions containing (sub)micron sized droplets. On the other hand, using high-resolution PFG-NMR diffusometry and the addition of an oil insoluble marker to the water phase, the application window could be extended towards smaller droplet sizes. Finally, it was shown that T2-relaxometry was capable of detecting differences in droplet size between (sub)micron sized W/O-emulsions. PMID- 29278793 TI - A novel photocatalytically active mesoporous metal-free PPy grafted MWCNT nanocomposite. AB - A new mesoporous metal-free functionalized multi-walled carbon nanotube (f-MWCNT) covalently grafted polypyrrole (PPy) nanocomposite has been synthesized via chemical oxidative polymerization method keeping different weight ratio of f MWCNT (1-4). Various instrumentation techniques such as UV-DRS, FT-IR, XRD, Raman, TGA, BET and TEM were used to characterize the as-prepared nanocomposite. The successfully constructed photocatalytically active mesoporous metal-free PPy grafted MWCNT nanocomposite was employed for the decontamination of nitrobenzene (NB). Among all the catalysts, f-MWCNT-PPy (3) is found to be efficient due to a large specific surface area and high pore volume by which 99.9% reduction has been achieved within 60 min. The obtained mesoporous, covalently grafted and synergistic f-MWCNT-PPy can be used as an efficient and recyclable photocatalyst for the degradation of organic contaminants from wastewater. Also, study of this kind will undoubtedly expedite new researches on solar-driven water splitting. PMID- 29278794 TI - Sandwich-structured composite fibrous membranes with tunable porous structure for waterproof, breathable, and oil-water separation applications. AB - HYPOTHESIS: In general, microporous membranes with waterproofness, breathability, and oil-water separation performance are prepared from hydrophobic raw materials and demonstrated to exhibit an interconnected porous structure. Hence, constructing porous and gradient-structured composite membranes by integrating robust hydrophobic/lipophilic polyvinylidene fluoride (PVDF) and breathable polyurethane (PU) microporous membranes could help realize a selective separation process. EXPERIMENT: Here, novel polyvinylidene fluoride-carbon nanotube/polyurethane/polyvinylidene fluoride-carbon nanotube (PVDF-CNT/PU/PVDF CNT) sandwich-structured microporous membranes were fabricated by sequential electrospinning. The influence of the thickness ratios of PVDF/PU/PVDF and carbon nanotube (CNT) content on the fibrous construction, porous structure, and wettability of the composite membranes was systematically studied by scanning electron microscopy (SEM), pore size, porosity and contact angle. Significantly, the effect of the fibrous construction, porous structure, and wettability on the waterproofness, breathability, and oil-water separation ability of the composite membranes was investigated. FINDINGS: The novel separation system proved the 'complementary effect' between the PVDF and PU membranes. Further, because of the elaborate gradient construction, superior porous structure, and robust hydrophobicity-oleophilicity, the resultant membranes exhibited moderate waterproofness (38 kPa) and excellent breathability (8.63 kg m-2 d-1), and oil water separation, confirming that they could be promising alternatives for numerous practical applications, such as protective clothing, treatment of oil contaminated water, and membrane distillation. PMID- 29278795 TI - A facile strategy to fabricate hollow cadmium sulfide nanospheres with nanoparticles-textured surface for hexavalent chromium reduction and bacterial inactivation. AB - Exploring morphology and surface structure of semiconductor photocatalyst is crucial for researching their photocatalytic performance. In this paper, hollow CdS nanospheres (CdS-HSs) were successfully fabricated via simple template self removal strategy. The prepared CdS-HSs were characterized by XRD, SEM, HR-TEM, UV vis diffuse reflectance spectra (DRS), XPS, photocurrent response (I-T), photoluminescence (PL) and electrochemistry impedance spectroscopy (EIS). It was found that the prepared CdS-HSs have nanoparticles-textured surface composed of ultra-small CdS nanoparticles (~20 nm) and large surface areas. DRS result demonstrated that the CdS-HSs exhibit strong visible light absorption capacity. The results of photocurrent response, photoluminescence and EIS revealed that hollow structure and nanoparticles-textured surface can effectively increase light reflection effect and decrease recombination rate of electrons and holes. Compared to the traditional CdS, the hollow CdS nanospheres exhibit higher photocatalytic activity on Cr(VI) reduction under visible light irradiation, which are primarily attributed to its rapid separation of electron-hole pairs and improved visible light absorption. Moreover, CdS-HSs was also demonstrated as an effective and potential material on photocatalytic disinfection. The result of mechanism experiments proved that h+, e- and O2- play important roles on the bacteria inactivation. PMID- 29278796 TI - Cell receptor screening for human papillomavirus invasion by using a polyoxometalate-peptide assembly as a probe. AB - The present study constructed a competitive recognition system using cell receptor screening for human papillomavirus (HPV) invasion by using the hybrid assembly of polyoxometalates (POMs) and cationic peptides as a platform. The fine tuning both of the surface charge of POMs and peptide sequence were precisely performed to develop a luminescence switch of POMs, leading to the establishment of a ternary system to identify which types of glycosaminoglycans (GAGs) are potential cell receptors for HPV infection. In addition, the method was successfully applied to construct a hybrid-assembly with the recombined HPV 16 L1 pentamers from Escherichia coli and perform GAGs screening, which validated the system's potential for practical applications. In particular, the intrinsic mechanism for each competitive partner in the system was explained well by using isothermal titration calorimetry (ITC) and time-resolved fluorescence spectra. The present method will be helpful to extend the protocol to other systems by using peptides and POMs with similar properties, and ultimately, we hope it will promote the development of anti-viral agents. PMID- 29278797 TI - Study of graphene dispersions in sodium dodecylsulfate by steady-state fluorescence of pyrene. AB - HYPOTHESIS: Aqueous solutions of ionic surfactants allow the exfoliation of graphene, that can be explained considering the adsorption model of ionic surfactants to hydrophobic surfaces. For many years, pyrene has been used as a fluorescent probe because its sensitivity to the micro-environment. The study of pyrene fluorescence in the presence of different graphene dispersions in an ionic surfactant, would improve the knowledge of the graphene-surfactant interactions. EXPERIMENTS: Different dispersions of graphene in sodium dodecylsulfate were prepared at different weight ratios 0.5, 1 and 2%. The dispersions have been studied by Raman spectroscopy, scanning electron microscopy and transmission electron microscopy. The influence of the dispersions on the pyrene fluorescence has been investigated. FINDINGS: The graphene sheets modified by the surfactant quench the fluorescence of pyrene, which depends on the amount of graphene, the concentration of surfactant and the weight ratio. For surfactant concentrations below the critical micelle concentration, the quenching effect is higher as the weight ratio increases. Once this concentration is reached, the fluorescence increases slightly and then levels off. This behavior has been explained by the adsorption model. For a constant surfactant concentration, two straight lines can be observed in the Stern-Volmer plots whose cut-off point is approximately 20 mg L-1 of graphene. PMID- 29278798 TI - Silsesquioxane stabilized platinum-palladium alloy nanoparticles with morphology evolution and enhanced electrocatalytic oxidation of formic acid. AB - Bimetallic catalysts have attracted enormous attention with their enhanced electrocatalytic properties in fuel cells. Herein a series of silsesquioxane (POSS) stabilized platinum-palladium (PtPd) alloy nanoparticles (NPs) with morphology evolution were facilely synthesized with the co-chemical reduction using formaldehyde as the reductant. By varying the ratio of Pt to Pd, the PtPd alloy NPs evolved from truncated octahedrons to octahedrons, and triangular nanoplates. The mechanism of morphology evolution is that Pt and Pd could self assemble on POSS to form PtxPd1-x intermediates with different Pt/Pd ratios. In addition, formaldehyde could selectively bind to the {1 1 1} facets of Pd to control the growth rates of different facets and help PtxPd1-x intermediates with different Pt/Pd ratio grow into different morphology of PtxPd1-x alloys. The morphology tuning endowed the PtPd alloy NPs superior performance for formic acid electrooxidation. Compared with Pt, Pd NPs, and commercial Pt/C catalyst, the PtPd alloy NPs displayed larger electrochemically active surface area, enhanced electrocatalytic activity and durability toward oxidation of formic acid, and increased CO tolerance. This work suggested that modification of catalytic activity through morphology tuning with composition adjustment might provide some new pathways for the design of promising catalysts with advanced performance. PMID- 29278799 TI - Chitosan-fatty acid interaction mediated growth of Langmuir monolayer and Langmuir-Blodgett films. AB - The interaction of chitosan with bio-membranes, which plays important role in deciding its use in biological applications, is realized by investigating the interaction of chitosan with stearic acid (fatty acid) in Langmuir monolayers (at air-water interface) and Langmuir-Blodgett (LB) films (after transferring it onto solid substrate). It is found from the pressure-area isotherms that the chitosan insertion causes an expansion of chitosan-fatty acid hybrid monolayers, which reduces the elasticity and make the film heterogeneous. It is likely that at low surface pressure chitosan is situated at the interface, interacting with stearic acid molecules via electrostatic and hydrophobic interactions whereas at high pressure chitosan mainly located at subsurface beneath stearic acid molecules. In the latter case the interaction is predominantly electrostatic yielding very small contribution to the surface pressure. The reduction of temperature of the subphase water allows more number of chitosan molecules to reach surface to increase the pressure/interaction. On the other hand, although pure chitosan is found difficult to relocate on the substrate from air-water interface due to its hydrophilic-like nature, it alongside stearic acid (amphiphilic molecules) can be transferred onto substrate using LB technique as evident from infrared spectra. Their out-of-plane and in-plane structures, as extracted from two complementary surface sensitive techniques- X-ray reflectivity and atomic force microscopy, are found strongly dependent on the chitosan mole fraction and the deposition pressure. These analysis of the film-structure will essentially allow one to model the system better and provide better insight into the interaction. PMID- 29278800 TI - Nuclear accident consequence assessment in Hong Kong using JRODOS. AB - The JRODOS (Java-based Real-time Online DecisiOn Support) is a decision support system for off-site emergency management for releases of radioactive material into the environment. This paper documents the application of JRODOS by the Hong Kong Observatory in accident consequence assessment and emergency preparedness studies. For operational considerations, the most computational efficient dispersion model in JRODOS, ATSTEP, is adopted. Verification studies for JRODOS's ATSTEP model have been conducted. Comparison with tracer experiment results showed that under neutral atmospheric conditions and distances up to 50 km, the JRODOS simulation outputs were in general of the same order of magnitude with the tracer data. To further evaluate the capability of JRODOS in short-range simulation, a case study on the Fukushima nuclear power plant accident was also carried out. JRODOS was able to produce realistic simulation results which were comparable to the actual airborne monitoring data of the Cs-137 ground deposition from the Fukushima accident. Furthermore, the results of a comprehensive study to assess the potential consequences of accidents at a nearby nuclear power station are presented. Simulation using the French S3 source term for the Guangdong Nuclear Power Station at Daya Bay showed that the projected effective doses within Hong Kong remain far below the IAEA generic criteria of projected dose for urgent protective actions in sheltering/evacuation, while the projected equivalent dose in thyroid may meet the IAEA generic criteria for use of thyroid blocking agent at some areas in the northeastern part of Hong Kong, at distances of up to about 40 km from Daya Bay depending on the prevailing weather conditions in different seasons. PMID- 29278801 TI - Smart pH-sensitive micelles based on redox degradable polymers as DOX/GNPs carriers for controlled drug release and CT imaging. AB - An amphiphilic copolymer poly(epsilon-caprolactone)-ss-poly(2-(dimethylamino) ethyl methacrylate), PCL-SS-PDMAEMA, was designed and synthesized using ROP and ARGET ATRP methods. Dual stimulus responsive micelles were prepared by the self assembly of PCL-SS-PDMAEMA. PDMAEMA could respond to acid conditions with protonation, followed by enhanced hydrophilicity and swelling of the micellar shell. In addition, the cleavable joint disulfide bond between the core and shell was disrupted when exposed to an abundance of the reductant reductive glutathione GSH, leading to the disassembly of the micellar structure. The smart response behavior can be used for intracellular controlled drug release in tumor cells. In terms of "theranostics" with higher therapy effect, the tool for tumor imaging and diagnose through computed tomography (CT) was considered with the loading of gold nanoparticles (GNPs). GNPs with good distribution were prepared by means of in situ reduction by PDMAEMA block and stabilized by the micelles. Polymeric micelles were used to load the anticancer drug doxorubicin (DOX) in the hydrophobic core and GNPs in the hydrophilic PDMAEMA shell. Subsequently, the micellar theranostics platform combining chemotherapy and CT diagnose was obtained. The pH- or redox-triggered drug release profiles suggesting that the DOX/GNPs-loaded micelles facilitated controlled release in response to different simulated microenvironments. Cellular uptake study was carried out, indicating that the micelles could be fast internalized within several hours. MTT assay showing significant inhibition against HepG2 and MCF-7 cells for the DOX/GNPs loaded micelles. Finally, the in vitro CT imaging assay indicated the good CT diagnosis potential of DOX/GNPs-loaded micelles. The micelle simultaneously loaded with DOX and GNPs represent a promising theranostics platform for efficient cancer chemotherapy and diagnosis. PMID- 29278802 TI - Non-equilibrium atmospheric pressure plasma as innovative method to crosslink and enhance mucoadhesion of econazole-loaded gelatin films for buccal drug delivery. AB - In this paper we developed an innovative, effective and rapid one-step approach to crosslink mucoadhesive gelatin films for buccal drug delivery. The method, which involves the application of non-equilibrium pressure plasma for 3 or 5 minutes/side, was compared with a classical approach based on the use of a chemical crosslinking agent, namely genipin. Econazole nitrate (ECN), an imidazole antifungal agent used for the treatment of skin infections and mucosal candidiasis, was selected as model drug. X-Ray Diffraction characterization performed on the drug-containing gelatin films revealed that ECN undergoes to a topotactic transformation into Econazole (EC) immediately after mixing with gelatin suggesting the occurrence of an acid-base reaction between drug and gelatin during film processing. Plasma treatment, as well as genipin crosslinking, did not provoke any further variation of EC structure. However, plasma exposure significantly improved films adhesiveness and allowed to reach mucoadhesive strength values more than double with respect to those obtained with genipin, ascribable to the presence of polar and hydrophilic groups on the plasma treated film's surface. A residence time of at least 48 h was obtained by properly selecting the plasma exposure times. These results, together with the in vitro data showing retention of antifungal efficacy against a strain of Candida albicans, demonstrated that plasma treatment was a valid and rapid alternative, easy to scale-up, to chemical crosslinking methods for the production of highly mucoadhesive gelatin-based films. PMID- 29278803 TI - Sorption of nucleic acids and proteins on polyaniline and polyaramide nano coatings as studied by spectral-correlation interferometry in a real time mode. AB - Polyaniline (PANI) and polyaramides deposited on the surfaces of glass slides and particulate silica were studied as adsorbents of nucleic acids and proteins by flow-through spectral correlation interferometry and solid-state extraction using spin-cartridges. Double stranded DNA from E. coli as well as pepsin, bovine serum albumin and lysozyme were the analytes studied in contact with the polymer nanolayers in phosphate buffer solution, pH 7.2. None of the coated glass slides could bind the DNA, which passed them practically without adsorption. In contact with polyaramides, the proteins of pI > 4 reversibly formed the 0.2-2.5 nm-thick adsorption layers decomposing on further rinsing with the protein-free eluent. In contact with PANI, the proteins formed stable adsorption layers at pH 7.2, which needed the pH 3.0 to be eluted. Thus, in a neutral aqueous medium optimal for separation of biopolymers, polyaramides, although did not retain DNA, had a weaker affinity to proteins as compared to PANI. Since the recovery of DNA passed through the PANI-coated silica was the maximal among the particulate adsorbents, the PANI-modified composites were preferred as the carriers for the single-step isolation of nucleic acids from complex biological mixtures. PMID- 29278804 TI - Adherence of Pseudomonas aeruginosa onto surfactant-laden contact lenses. AB - There is an immense research interest to utilise contact lens (CLs) as a popular platform for ocular drug delivery. However, CLs are the major predisposing factors of bacterial keratitis which is commonly caused by adhesion of microbes such as Pseudomonas aeruginosa and Staphylococcus epidermidis. The aim of the current study is to explore the effect of surfactants; Poloxamer 188, Polysorbate 80 and Tetronic(r) 90R4 (at 0.25% - 3% v/v) on the characteristics of CLs and on the adhesion abilities of Pseudomonas aeruginosa to the lenses' surfaces. CLs were formulated using a hydrophilic monomer; 2-hydroxyethyl methacrylate (HEMA) together with silicone-based polymer such as Poly dimethyl siloxane (PDMS) or 3,3,3-trifluoropropylsilane (FSA) then lenses were polymerized under UV light. The formulated CLs with surfactants were found to have an increased equilibrium water content (EWC) due to hydrophilic moiety present in surfactants. A relationship was deduced between EWC and surface contact angle of lenses containing surfactants; where an increased EWC was associated with a decrease in contact angle reflecting a more hydrophilic surfaces of CLs. Apart from the 3% Polysorbate 80 (p < .0001) CLs, all other formulations had light transmission values over 80%. Lenses with surfactants were found to have lower bacterial ATP concentration than lenses without surfactants. Poloxamer 188 in FSA lenses reduced bacterial adhesion from 4.22 * 10-4 +/- 1.30 * 10-4 pM to 1.03 * 10-4 +/- 4.86 * 10-5 pM, a reduction by 75.59% when compared to the control lenses (p = .002). Moreover, 1% Tetronic(r) 90R4 in PDMS showed a reduction by 57.17% in ATP concentration. Polysorbate 80 in FSA exhibited the least bacterial adhesion with an average bacterial ATP concentration of 3.85 * 10-5 +/- 2.61 * 10-5 pM; i.e 90.88% less bacterial ATP than control lenses (p = .001). Bioluminescence studies demonstrated a decrease in Pseudomonas aeruginosa adhesion to CLs containing surfactants without impairing the optical and mechanical characteristics of the lenses. PMID- 29278805 TI - Using a foreign language reduces mental imagery. AB - Mental imagery plays a significant role in guiding how we feel, think, and even behave. These mental simulations are often guided by language, making it important to understand what aspects of language contribute to imagery vividness and consequently to the way we think. Here, we focus on the native-ness of language and present evidence that using a foreign language leads to less vivid mental imagery than using a native tongue. In Experiment 1, participants using a foreign language reported less vivid imagery of sensory experiences such as sight and touch than those using their native tongue. Experiment 2 provided an objective behavioral measure, showing that muted imagery reduced accuracy when judging the similarity of shapes of imagined objects. Lastly, Experiment 3 demonstrated that this reduction in mental imagery partly accounted for the previously observed foreign language effects in moral choice. Together, the findings suggest that our mental images change when using a foreign tongue, leading to downstream consequences for how we make decisions. PMID- 29278806 TI - The association of serum nesfatin-1 and ghrelin levels with metabolic syndrome in patients with schizophrenia. AB - Nesfatin-1 and ghrelin are two hormones which has opposite effects and play role in food intake. This study was planned on the idea that both metabolic syndrome and psychiatric disorders are associated with nesfatin-1 and ghrelin. In this study, it was aimed to investigate the levels of ghrelin and nesfatin-1 in patients with schizophrenia, by taking confounding factor as the metabolic syndrome (MS). 55 patients with schizophrenia and 33 healthy controls were included in the study.11 out of the 55 patients (%20) has MS. Serum ghrelin and nesfatin-1 levels of schizophrenia patients with MS have been compared with both healthy controls and schizophrenia patients without MS. Patients with schizophrenia had significantly higher serum nesfatin-1 levels compared to healthy controls. But serum ghrelin levels was not different in both groups. Serum nesfatin-1 concentrations were significantly higher in the schizophrenia patients with MS (10.51-350.8pg/ml) with respect to the healthy control group (4.86-68.91pg/ml). There was no significant statistical difference between the three groups in terms of ghrelin levels. Our findings suggests that, MS presence also contributed to significantly high levels of nesfatin-1 level. Nesfatin-1 may have a part in a novel studies regarding the treatment of schizophrenia and its metabolic effects. PMID- 29278807 TI - Myricetin enhances on apoptosis induced by serum deprivation in PC12 cells mediated by mitochondrial signaling pathway. AB - Polyphenols have many beneficial effects and an effective disease therapeutic auxiliary drug. Previously, myricetin, a polyphenol, had been reported to possess various biological effects on human physiology. However, mechanism of myricetin on apoptosis induced in PC12 cells is still unclear. PC12 cells were treated with myricetin in two concentration levels comprising 0.1 and 1 MUM under serum-free condition. As a result, morphological changes were observed using trypan blue assay. DNA fragmentation was determined by DNA ladder assay to evaluate DNA damage levels. Western blotting results showed that cytosolic cytochrome c which was released from mitochondria. Subsequently, tumor suppressor gene p53, pro apoptotic and anti-apoptotic Bcl-2 family proteins Bax and Bcl-2 were expressed. The caspase cascade reaction was induced through caspase 3 and 9 expression. From these results, it is suggested that myricetin significantly enhanced the apoptosis induced by serum deprivation in a dose-dependent manner in PC12 cells. PMID- 29278808 TI - Acute toxicity, uptake, and elimination of zinc oxide nanoparticles (ZnO NPs) using saltwater microcrustacean, Artemia franciscana. AB - This study aims to evaluate the potential toxic effects of ZnO nanoparticles on Artemia franciscana nauplii. The ZnO NPs suspension was characterized by TEM, EDS and DLS techniques. Acute toxicity was investigated by exposure of nauplii to concentrations of 1, 5, 7.5, 10, 15, 20, 25 and 30 mg/L of ZnO NPs for 48 h and 96 h. The 96-h EC10 and EC50 values of ZnO NPs were found to be 1.39 mg/L and 4.86 mg/L respectively. The ZnO NPs suspensions did not cause any significant acute toxicity after 48 h of exposure, but the immobilization rate increase significantly compare to control group after 96 h (P < 0.05). The results showed that the uptake, accumulation, and elimination of NPs in nauplii depends on the concentration of NPs and time. The elimination rates of 46.66% and 83.85% were recorded at 1 and 10 mg/L of NPs after 24 h of depuration period, respectively. PMID- 29278809 TI - Replication and extension of long-term implicit memory: Perceptual priming but conceptual cessation. AB - We endeavored to replicate Mitchell's (2006) finding of 17-year implicit memory priming. Subjects saw word and picture stimuli in 1999-2000 (M age = 18.9) and were retested after 11-14 years (M = 13.2; M age = 32.1). Via the internet, they completed four implicit memory tasks: picture fragment identification, word fragment completion, word stem completion, and category exemplar generation. Relative to control subjects (matched on stimuli, age, and education), longitudinal subjects revealed priming on picture and word fragment identification (perceptual tasks), but no priming on word stem completion or category exemplar generation (conceptual tasks). Four longitudinal subjects who failed to recall participating in the prior laboratory session had priming similar to the 10 subjects who did remember. Thus, we replicated the longevity of perceptual priming for pictures, and extended this to word fragment priming as well. PMID- 29278810 TI - Asthma prevalence and school-related hazardous air pollutants in the US-Mexico border area. AB - BACKGROUND: Asthma is the most common chronic disease in children and has been linked to high levels of ambient air pollution and certain hazardous air pollutants (HAPs). Outdoor pollutants such as benzene, released by car emissions, and organic chemicals found in diesel exhaust, as well as particles and irritant gases, including nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3), contribute to an increased prevalence of respiratory diseases such as asthma. OBJECTIVES: The objectives of this study were to: 1) conduct a screening survey to identify high risk for asthma among school-age children in Hidalgo County, and, 2) study the potential health impact of school-related exposure to HAPs pertaining to asthma risk. METHODS: We carried out a quantitative cross-sectional study combining a school-based asthma screening survey across 198 schools in Hidalgo County, Texas, with information on school neighborhood environments, including census tract-level information on hazardous air pollutants (HAPs) and socioeconomic status (SES) in the respective school neighborhoods. HAPs levels were assessed based on the EPA 2011 National-Scale Air Toxics Assessment (NATA) while SES information was assessed using data from the 2010-2014 American Community Survey. RESULTS: 2930 students completed the asthma screening survey and results showed an overall asthma prevalence of 9.4%, slightly higher than the national and state prevalence. Participants in the 14-18 years old age group showed a much higher asthma prevalence of 16.7%. When assessing school neighborhood characteristics, our results revealed no significant differences in asthma prevalence across census tracts with different SES levels. For HAPs, in the single-pollutant model, chlorine levels showed a significant linear trend for prevalence of asthma (p=0.03) while hydrochloric acid had a marginally significant linear trend (p=0.08). The association with chlorine remained significant in the multi-pollutant model. CONCLUSIONS: Asthma prevalence among school-age children in Hidalgo County, Texas, is 9.4%, which is slightly higher than the state rate, especially among young adults, ages 14-18 years who had an asthma rate of 16.7%. Results support an association between exposures to school neighborhood HAPs and risk for pediatric asthma, especially as related to chlorine. No significant effects of school-level SES on asthma risk were observed. PMID- 29278811 TI - Enhancing the response rate of strand displacement-based electrochemical aptamer sensors using bivalent binding aptamer-cDNA probes. AB - Electrochemical aptamer (EA) sensors based on aptamer-cDNA duplex probes (cDNA: complementary DNA) and target induced strand displacement (TISD) recognition are sensitive, selective and capable of detecting a wide variety of target analytes. While substantial research efforts have focused on engineering of new signaling mechanisms for the improvement of sensor sensitivity, little attention was paid to the enhancement of sensor response rate. Typically, the previous TISD based EA sensors exhibited relatively long response times larger than 30min, which mainly resulted from the suboptimal aptamer-cDNA probe structure in which most of aptamer bases were paired to the cDNA bases. In an effort to improve the response rate of this type of sensors, we report here the rational engineering of a quickly responsive and sensitive aptamer-cDNA probe by employing the conception of bivalent interaction in supramolecular chemistry. We design a bivalent cDNA strand through linking two short monovalent cDNA sequences, and it is simultaneously hybridized to two electrode-immobilized aptamer probes to form a bivalent binding (BB) aptamer-cDNA probe. This class of BB probe possesses the advantages of less aptamer bases paired to the cDNA bases for quick response rate and good structural stability for high sensor sensitivity. By use of the rationally designed BB aptamer-cDNA probe, a TISD based EA sensor against ATP with significantly enhanced response rate (with a displacement equilibrium time of 4min) and high sensitivity was successfully constructed. We believe that our BB probe conception will help guide future designs and applications of TISD based EA sensors. PMID- 29278812 TI - Optoelectronic fowl adenovirus detection based on local electric field enhancement on graphene quantum dots and gold nanobundle hybrid. AB - An optoelectronic sensor is a rapid diagnostic tool that allows for an accurate, reliable, field-portable, low-cost device for practical applications. In this study, template-free In situ gold nanobundles (Au NBs) were fabricated on an electrode for optoelectronic sensing of fowl adenoviruses (FAdVs). Au NB film was fabricated on carbon electrodes working area using L(+) ascorbic acid, gold chroloauric acid and poly-l-lysine (PLL) through modified layer-by-layer (LbL) method. A scanning electron microscopic (SEM) image of the Au NBs revealed a NB shaped Au structure with many kinks on its surface, which allow local electric field enhancement through light-matter interaction with graphene quantum dots (GQDs). Here, GQDs were synthesized through an autoclave-assisted method. Characterization experiments revealed blue-emissive, well-dispersed GQDs that were 2-3nm in size with the fluorescence emission peak of GQDs located at 405nm. Both Au NBs and GQDs were conjugated with target FAdVs specific antibodies that bring them close to each other with the addition of target FAdVs through antibody antigen interaction. At close proximity, light-matter interaction between Au NBs and QDs produces a local electric signal enhancement under Ultraviolet-visible (UV-visible) light irradiation that allows the detection of very low concentrations of target virus even in complex biological media. A proposed optoelectronic sensor showed a linear relationship between the target FAdVs and the electric signal up to 10 Plaque forming unit (PFU)/mL with a limit of detection (LOD) of 8.75 PFU/mL. The proposed sensing strategy was 100 times more sensitive than conventional ELISA method. PMID- 29278813 TI - A sandwich-type electrochemical immunosensor based on in situ silver deposition for determination of serum level of HER2 in breast cancer patients. AB - The sensitive quantification of Human Epidermal growth factor Receptor 2 (HER2), as a key prognostic tumor marker, plays a critical role in screening, early diagnosis and management of breast cancer. This paper describes a sandwich-type immunoassay with silver signal enhancement strategy for highly sensitive detection of HER2. For this purpose, the target capturing step was designed by functionalization of 3-aminopropyltrimethoxysilane coated magnetite nanoparticles with antibody (antiHER2/APTMS-Fe3O4), as a platform bioconjugate (PB), and immobilized at a bare GCE. Then, in the presence of label-free immunosensor, the PB was covered by magnetic gold nanoparticles self-assembled with thiolated antibodies (antiHER2/Hyd@AuNPs-APTMS-Fe3O4) containing chemically reduced silver ions, as a label bioconjugate (LB). Under optimum conditions, a linear relationship between the differential pulse voltammetric (DPV) stripping signal of silver and the logarithm of HER2 concentrations was obtained in the range of 5.0 * 10-4-50.0ngmL-1 (R2 = 0.9906) with a detection limit of 2.0 * 10-5ngmL-1. The effectiveness of this protocol was evaluated experimentally through employing of designed immunosensor for detection of the serum level of tumor marker. The good consistency of the results with those obtained by the enzyme-linked immunosorbent assay (ELISA) conventional method (p-value of < 0.05) showed that this immunosensor can be applied for the testing of HER2 in clinical samples of breast cancer patients. PMID- 29278814 TI - Electrochemiluminescence evaluation for carbohydrate antigen 15-3 based on the dual-amplification of ferrocene derivative and Pt/BSA core/shell nanospheres. AB - Herein, a novel methodology for ultrasensitive and facile breast cancer biomarker carbohydrate antigen 15-3 (CA15-3) evaluation was proposed by fabricating a sandwiched ECL immunosensor. In the protocol, MOCs-Fc and Pt@BSA-luminol nanohybrids were successfully synthesized and further employed to achieve dual amplification strategy for luminol-H2O2 system. Notably, inherent porous microstructure and large specific surface area from MOCs enabled a high loading of Fc, which succeeded in catalyzing luminol-H2O2 ECL emission and therefore enhancing ECL response. In addition, higher sensitivity could be realized due to the excellent electronic conductivity of MOCs. Furthermore, the as-obtained Pt@BSA- luminol was not only employed as capture probe to recognize CA15-3 after hybridization with Ab2, but also played a crucial role in acting as ECL signal probe due to the presence of massive luminol. It is of vital importance that Pt@BSA core/shell nanospheres showed admirable catalytic effect towards H2O2, which resulted in more excited state luminol and stronger ECL intensity. Therefore, the synergistic amplification strategy of MOCs-Fc and Pt@BSA nanohybrids offered an extremely enhanced ECL signal. The well-established applicable ECL immune- sensing platform displayed favorable analytical performance for CA15-3. In summary, the proposed ECL immunosensor opened a new era for sensitive CA15-3 evaluation and offered a promising platform for clinical breast cancer diagnostics. PMID- 29278815 TI - Magnetic biosensors: Modelling and simulation. AB - In the past few years, magnetoelectronics has emerged as a promising new platform technology in various biosensors for detection, identification, localisation and manipulation of a wide spectrum of biological, physical and chemical agents. The methods are based on the exposure of the magnetic field of a magnetically labelled biomolecule interacting with a complementary biomolecule bound to a magnetic field sensor. This Review presents various schemes of magnetic biosensor techniques from both simulation and modelling as well as analytical and numerical analysis points of view, and the performance variations under magnetic fields at steady and nonstationary states. This is followed by magnetic sensors modelling and simulations using advanced Multiphysics modelling software (e.g. Finite Element Method (FEM) etc.) and home-made developed tools. Furthermore, outlook and future directions of modelling and simulations of magnetic biosensors in different technologies and materials are critically discussed. PMID- 29278816 TI - Ultratrace and robust visual sensor of Cd2+ ions based on the size-dependent optical properties of Au@g-CNQDs nanoparticles in mice models. AB - Visual inspection is expected as an ideal technique, which can directly and conveniently detect heavy metal ions by observing the color change. Insensitivity of detecting weakly colored heavy transition metal ions and low adsorptivity of metal ions on nanoparticle surface are two main factors hindering the application of visual detection in heavy metal ions detection. Herein, we demonstrated an operational colorimetric sensor based on the color dependence of nanoparticles aggregation to selective and facile detect weakly colored transition heavy metal Cd2+ ions that have been considered as the origin of the "Itai-itai" disease. Uniform colloidal 15nm graphite-like nitride doped carbon quantum dots-capped gold nanoparticle (Au@g-CNQDs) was successfully prepared, wherein the existence of numerous heptazine, carboxyl and hydroxyl groups on the nanoparticle's surface strengthened adsorption of the Cd2+ ions on the surface of Au@g-CNQDs through the "cooperative effect". As a consequence, without expensive and intricate exogenous indicators or other special additives, the Cd2+ ions could sensitively and quickly captured to detect at ultra-low concentration within 30s by the naked eye. Under the optimal conditions, the Cd2+ ions sensor possesses good analytical performances with a wide linear range of 0.01-3.0MUM and a detection limit of 10nM (S/N = 3). Moreover, the biodistribution and aggregation of Cd2+ ions were detected effectively in mice organ tissues suggesting its great potential use for real-word applications. PMID- 29278817 TI - Emotional health and coping mechanisms among adolescents in Malaysian residential foster care homes: A comparative study with adolescents living with families. PMID- 29278820 TI - Attachment and psychopathic traits in inpatient female and male adolescents. PMID- 29278819 TI - Quantitative determination of carcinogenic mycotoxins in human and animal biological matrices and animal-derived foods using multi-mycotoxin and analyte specific high performance liquid chromatography-tandem mass spectrometric methods. AB - A sensitive and reliable multi-mycotoxin-based method was developed to identify and quantify several carcinogenic mycotoxins in human blood and urine, as well as edible animal tissues, including muscle and liver tissue from swine and chickens, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the toxicokinetic studies with individual mycotoxins, highly sensitive analyte specific LC-MS/MS methods were developed for rat plasma and urine. Sample purification consisted of a rapid 'dilute and shoot' approach in urine samples, a simple 'dilute, evaporate and shoot' approach in plasma samples and a 'QuEChERS' procedure in edible animal tissues. The multi-mycotoxin and analyte-specific methods were validated in-house: The limits of detection (LOD) for the multi mycotoxin and analyte-specific methods ranged from 0.02 to 0.41 MUg/kg (MUg/L) and 0.01 to 0.19 MUg/L, respectively, and limits of quantification (LOQ) between 0.10 to 1.02 MUg/kg (MUg/L) and 0.09 to 0.47 MUg/L, respectively. Apparent recoveries of the samples spiked with 0.25 to 4 MUg/kg (MUg/L) ranged from 60.1% to 109.8% with relative standard deviations below 15%. The methods were successfully applied to real samples. To the best of our knowledge, this is the first study carried out using a small group of patients from the Chinese population with hepatocellular carcinoma to assess their exposure to carcinogenic mycotoxins using biomarkers. Finally, the multi-mycotoxin method is a useful analytical method for assessing exposure to mycotoxins edible in animal tissues. The analyte-specific methods could be useful during toxicokinetic and toxicological studies. PMID- 29278818 TI - Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control. AB - OBJECTIVES: In this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. METHODS: A total of 48 chronic back pain patients (N = 48) participated in this double blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). RESULTS: We observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (DeltaOOWS = 4.3 +/- 2.4, p < 0.0001; DeltaSOWS = 14.1 +/- 11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. CONCLUSION: We hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT3 receptor antagonists are useful in preventing opioid physical dependence. PMID- 29278821 TI - Optimization analysis in reconstruction of vehicle collision accidents with deficient EDR data. AB - This paper presents an efficient method of estimating preimpact and postimpact speeds of the vehicle without an EDR using only the velocity data obtained from a vehicle with an EDR. Using a large amount of data from vehicle collision experiments conducted in various settings, the limitations of collision models involved in optimization methods utilized in this study were found. The practicality of the proposed velocity estimation method was verified by referencing data from vehicle collision accident cases in Korea and America. Not only was the accuracy of the method verified, but the results also showed that the proposed method was applicable even when the EDR data was partially lost. PMID- 29278822 TI - Slight variations of breech face marks and firing pin impressions over 3070 consecutive firings evaluated by Evofinder(r). AB - To investigate if and how the breech face mark and firing pin impression change over repeated firings, we used an automated ballistic identification system Evofinder(r) to study cartridge cases fired from five Chinese Norinco QSZ-92 9*19mm pistols. Each pistol fired 3070 consecutive shots. The first 20 cartridge cases were all introduced into the system. From the 21st until the 3070th shot, every ten cartridge cases were collected and one random sample of each group was introduced as the 30th, 40th, ..., 3070th round. Thus, we introduced 325 specimens for each pistol and established a database of 1625 specimens. We used the first and every 100th specimen of each firearm to start correlations in the database and analyzed the results, especially the results of specimen 0001, 1000, 2000, 3000. Consequently, specimens fired closer in sequence to the specimen under examination had higher similarity scores. In boxplots, the boxes of known match specimens were much higher than boxes of known non match specimens. The Evofinder(r) ranked nearly all known match specimens in the first position of either firing pin impression list or breech face mark list. In conclusion, the two marks changed over 3070 consecutive shots and cartridge cases of nearer shot numbers were more similar. However, the variations of marks from the same firearm have not exceeded the differences between marks of different firearms and have not hindered the Evofinder(r) to make nearly 100% correct correlations. PMID- 29278823 TI - The relationship between cross-sectional shapes and FTIR profiles in synthetic wig fibers and their discriminating abilities - An evidential value perspective. AB - Wig fragments or fibers may occasionally be recognized as potential physical evidence during criminal investigations. While analytical methods traditionally adopted for the examination of textile fibers are utilized for the characterizations and comparisons of wig specimens, it is essential to understand in deeper detail the valuable contribution of features of these non-routine evidentiary materials as well as the relationship of the gathered analytical data. This study explores the dependence between the microscopic features of cross-sectional shapes and the polymer type gathered by Fourier transform infrared (FTIR) spectroscopy. The discriminating power of the two methods of cross-sectioning and FTIR spectroscopy was also investigated. Forty-one synthetic wigs varying in both quality and price were collected: twenty-three brown, twelve blondes and six black samples. The collected samples were observed using light microscopy methods (bright field illumination and polarized light), before obtaining cross-sections using the Joliff method and analyze them using FTIR spectroscopy. The forty-one samples were divided into ten groups based on one or more of the ten types of cross-sectional shapes that were observed. The majority of encountered cross-sectional shapes were defined as horseshoe, dog bone and lobular. Infrared spectroscopy confirmed modacrylic to be the most prevalent fiber type. Blends of modacrylic and polyvinyl chloride fibers were also observed as well as polypropylene wig samples. The Goodman and Kruskal lambda statistical test was used and showed that the cross-sectional shape and infrared profile were related. From an evidentiary value perspective, this finding has implications when addressing questions about a common source between questioned wig specimens and a wig reference sample. PMID- 29278824 TI - Metabotropic glutamate receptors: the potential for therapeutic applications in Alzheimer's disease. AB - A dysfunction of glutamate signaling is implicated at several levels in the pathogenesis of Alzheimer's disease. Currently, metabotropic glutamate receptors, which have a wide distribution in the central nervous system and activate a multitude of cell signaling pathways, are pursued as targets for therapeutic intervention in Alzheimer's disease. Research is still limited, but results underscore the relevance of ongoing studies. Here we discuss the latest updates regarding metabotropic glutamate receptors and their role in Alzheimer's disease, as well as promising metabotropic glutamate receptor ligands that have been investigated in preclinical models of Alzheimer's disease. PMID- 29278825 TI - Nematode parasites of commercially important fish from the southeast coast of Brazil: Morphological and genetic insight. AB - Studies of nematofauna of teleost fish from the Brazilian coast are relatively scarce and limited to identification based on morphology. The objective of the present study was to determine the diversity and prevalence of nematode parasites in teleost fish from the southeast Atlantic coast of Rio de Janeiro, through morphological, molecular, and ecological approaches. Parasites were collected from sixty specimens each of Genypterus brasiliensis, Micropogonias furnieri, and Mullus argentinae obtained in winters and summers of 2012-2014. Morphological and genetic characterization was conducted using light microscopy and the molecular targets 18S rDNA, ITS1, and mtDNA cox2. Nematodes identified in M. furnieri were Cucculanus genypteri (n = 1575, P = 98.3%) and Hysterothylacium deardorffoverstreetorum (s.l.) (n = 2, P = 3.3%); in G. brasiliensis were Dichelyne (Cucullanellus) sciaenidicola (n = 99, P = 33.3%), Cucculanus pulcherrimus (n = 45, P = 18.3%), Hysterothylacium deardorffoverstreetorum (s.l.) (n = 3, P = 5%), and Anisakis typica (n = 1, P = 1.7%); and, in M. argentinae, were H. deardorffoverstreetorum (s.l.) (n = 146, P = 48.3%), and Procamallanus (Spirocamallanus) halitrophus (n = 4, P = 6.7%). DNA sequence data of C. genypteri, C. pulcherrimus, D. (C.) sciaenidicola, and P. (S.) halitrophus were reported for the first time. New host records are M. argentinae for P. (S.) halitrophus, M. furnieri for A. typica, while H. deardorffoverstreetorum (s.l.) was found in all three fish species. Intestine showed significantly higher intensity than other sites, and no significant seasonal variation in parasitological indices was observed. Hysterothylacium specimens (n = 6) were found in fish muscle, potentially a public health concern. PMID- 29278826 TI - Transitioning from phosphate mining to agriculture: Responses to urea and slow release fertilizers for Sorghum bicolor. AB - Globally, land-use transition from mining to agriculture is becoming increasingly attractive and necessary for many reasons. However, low levels of necessary plant nutrients, and high levels of heavy metals, can hamper plant growth, affecting yield, and potentially, food safety. In post-phosphate mining substrates, for example, nitrogen (N) is a key limiting nutrient, and, although legumes are planted prior to cereals, N supplementation is still necessary. We undertook two field trials on Christmas Island, Australia, to determine whether Sorghum bicolor could be grown successfully in a post-phosphate mining substrate. The first trial investigated N (urea) demand (amount of N required for adequate crop growth) for S. bicolor, and whether N addition could reduce the naturally occurring cadmium (Cd) concentrations in the crop. The second trial examined whether slow release nitrogen fertilizers (SRF) could replace urea to increase biomass and reduce Cd concentrations. Our first trial demonstrated that S. bicolor has a high N demand, with the highest biomass being recorded in the 160kg/ha urea treatment. However, plants treated with 80, 120 and 160kg/ha were not significantly different from one another. After 7weeks of growth, leaf Cd concentrations were significantly lower for all urea treatments compared with the control plants. However, after 23weeks, seed Cd concentrations did not differ across treatments. Our second trial demonstrated that the application of SRF (Macracote(r) and Sulsync(r)) and 160kg/ha urea significantly increased biomass above the control plants. There was, however, no treatment response in terms of Cd or N concentrations in the seed at final harvest. Thus, we have shown that N is currently critical for S. bicolor, even following legume cropping, and that high biomass and a significant reduction in Cd can be attained with appropriate levels of urea. Our work has important implications for cereal growth and food safety in post-mining agriculture. PMID- 29278827 TI - A resistive Q-switch for low-field NMR systems. AB - An NMR Q-switch was designed and constructed specifically for use with low-field NMR apparatus. This featured a comparatively simple resistive damping design. It served to reduce the r.f. probe ring-down time, and hence reduced the signal acquisition delay from 25 ms to 9 ms, on an Earth's magnetic field NMR system. The advantage of this earlier acquisition was demonstrated for both an aqueous suspension of iron oxide particles and using an NMR flow meter. PMID- 29278828 TI - Influence of slosh baffles on thermodynamic performance in liquid hydrogen tank. AB - A calibrated CFD model is built to investigate the influence of slosh baffles on the pressurization performance in liquid hydrogen (LH2) tank. The calibrated CFD model is proven to have great predictive ability by compared against the flight experimental results. The pressure increase, thermal stratification and wall heat transfer coefficient of LH2 tank have been detailedly studied. The results indicate that slosh baffles have a great influence on tank pressure increase, fluid temperature distribution and wall heat transfer. Owning to the existence of baffles, the stratification thickness increases gradually with the distance from tank axis to tank wall. While for the tank without baffles, the stratification thickness decreases firstly and then increases with the increase of the distance from the axis. The "M" type stratified thickness distribution presents in tank without baffles. One modified heat transfer coefficient correlation has been proposed with the change of fluid temperature considered by multiplying a temperature correction factor. It has been proven that the average relative prediction errors of heat transfer coefficient reduced from 19.08% to 4.98% for the wet tank wall of the tank, from 8.93% to 4.27% for the dry tank wall, respectively, calculated by the modified correlation. PMID- 29278829 TI - Efficacy of maternal and biological parameters at the time of diagnosis of gestational diabetes mellitus in predicting neonatal morbidity. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is independently associated with an increased risk of maternal-fetal complications. Improved glycemic control allows reducing perinatal morbidity and mortality and, specifically, the risk of macrosomia and shoulder dystocia which are the most common complications associated with GDM. Nonetheless, a need for early antenatal predictor of neonatal morbidity in women suffering from GDM is required. The objective of the study was to evaluate the efficacy of different maternal, biological, and antenatal parameters at the time of diagnosis of GDM or perinatal variables as predictors of neonatal morbidity. STUDY DESIGN: This was a prospective observational study recruited all pregnant women with diagnosis of GDM at first- or second-trimester in a tertiary care hospital from July 2014 to October 2015. Different antenatal parameters (maternal weight, weight gain during pregnancy, history of GDM, history of macrosomia, serum fructosamine, HbA1c) were obtained at the time of diagnosis of GDM. Mode of delivery was also analyzed. Neonatal morbidity was defined by at least one of the following criteria: preterm birth <37 weeks, macrosomia, shoulder dystocia, respiratory distress syndrome, 5-min Apgar score <7, pH < 7.10 and admission to the NICU (neonatal intensive care unit) for 24 h. Univariate and logistic regression analyses were performed to determine independent antenatal predictors of neonatal morbidity. RESULTS: Two hundred pregnant women with diagnosis of GDM were included. The mean gestational age at the time of diagnosis of GDM was 22 +/- 6 weeks. Insulin was required in 72/200 (36%) women for glycemic control during pregnancy. Neonatal morbidity occurred in 21% (n = 42). In the univariate analysis, neonatal morbidity was associated with nulliparity (50% compared to 32%, p = 0.03), induction of labor (36% compared to 27%, p = 0.03) and cesarean section (36% compared to 12%, p < 0.01). Multivariable logistic regression analysis found a significant association between nulliparity and neonatal morbidity (adjusted odds ratio [OR] 2.3, 95% confidence interval [CI] 1.1-4.7). Cesarean delivery was also significantly associated with neonatal morbidity (aOR 7.6, 95% CI 2.9-20). CONCLUSION: This suggests that nulliparity was an efficient antenatal predictor of neonatal morbidity at the time of diagnosis of GDM. Cesarean section was also associated with neonatal morbidity in women with GDM. PMID- 29278830 TI - Role of recovery residences in criminal justice reform. AB - Over the past decade there has been a clear consensus among drug policy researchers that the practice of incarcerating persons for drug offenses has been counterproductive. As a result, U.S. criminal justice policy is increasingly emphasizing alternative dispositions to incarceration for drug related arrests. In addition, large numbers of persons currently incarcerated for drug related offenses are being released into communities. However, there are serious questions about where these individuals are going to live once released and how they will access needed services. Residential recovery homes in the community are good options for those who wish to pursue abstinence from drugs. They provide a drug- and alcohol-free living environment along with social support for abstinence and successful functioning in the community. This paper reviews recent changes in drug policy the U.S. and describes the variety of recovery home options that are available to persons diverted or released from incarceration. PMID- 29278831 TI - Using drugs in un/safe spaces: Impact of perceived illegality on an underground supervised injecting facility in the United States. AB - BACKGROUND: Supervised injection facilities (SIFs) are spaces where people can consume pre-obtained drugs in hygienic circumstances with trained staff in attendance to provide emergency response in the event of an overdose or other medical emergency, and to provide counselling and referral to other social and health services. Over 100 facilities with formal legal sanction exist in ten countries, and extensive research has shown they reduce overdose deaths, increase drug treatment uptake, and reduce social nuisance. No facility with formal legal sanction currently exists in the United States, however one community-based organization has successfully operated an 'underground' facility since September 2014. METHODS: Twenty three qualitative interviews were conducted with people who used the underground facility, staff, and volunteers to examine the impact of the facility on peoples' lives, including the impact of lack of formal legal sanction on service provision. RESULTS: Participants reported that having a safe space to inject drugs had led to less injections in public spaces, greater ability to practice hygienic injecting practices, and greater protection from fatal overdose. Constructive aspects of being 'underground' included the ability to shape rules and procedures around user need rather than to meet political concerns, and the rapid deployment of the project, based on immediate need. Limitations associated with being underground included restrictions in the size and diversity of the population served by the site, and reduced ability to closely link the service to drug treatment and other health and social services. CONCLUSION: Unsanctioned supervised injection facilities can provide a rapid and user-driven response to urgent public health needs. This work draws attention to the need to ensure such services remain focused on user-defined need rather than external political concerns in jurisdictions where supervised injection facilities acquire local legal sanction. PMID- 29278832 TI - An epidemic surge of influenza A(H3N2) virus at the end of the 2016-2017 season in Taiwan with an increased viral genetic heterogeneity. AB - BACKGROUND: The epidemic of the 2016-2017 influenza season in Taiwan started early with moderate activity and was predominated by the influenza A(H3N2) virus. However, the influenza activity increased dramatically during the late stage of the 2016-2017 season. OBJECTIVES: The genetic and antigenic characteristics of the influenza A(H3N2) virus circulating in Taiwan during the 2016-2017 season were investigated. The relationship between virus clades and the patients' 2016 2017 vaccination histories was determined. STUDY DESIGN: Respiratory samples from patients with influenza-like illness in the community, clustered outbreaks, and inpatients with severe complications were tested for influenza virus. Influenza gene sequencing, phylogenetic analysis and hemagglutination inhibition assay were performed. RESULTS: A total of 1185, 690 and 353 cases of outpatients, inpatients and cluster events were tested positive for the A(H3N2) virus in this report. Multiple clades of the H3N2 virus co-circulated. New genetic variants were detected, including clade 3C.2a.1 with additional N121 K, K92R or T135 K mutations, 3C.2a.3a with T135 K and R150 K mutations and 3C.2a.4. The proportions of N121 K and T135 K mutations were continuously increasing. Most of the viruses (85.4%, 111/130) were antigenically related to the current vaccine strain. Infection by different clade H3N2 viruses did not correlate with immunization with the 2016-2017 vaccine. CONCLUSIONS: The data in this study indicate that antigenic drift is not the primary determinant of the epidemic wave at the end of the 2016-2017 season. The fitness changes in new variants, waning immunity and climatic changes are considered as possible contributors to the resurgence of the influenza A(H3N2) virus. PMID- 29278833 TI - Intermolecular interactions in highly concentrated formulations of recombinant therapeutic proteins. AB - The subcutaneous administration of recombinant therapeutic proteins requires the use of highly concentrated protein formulations to provide the desired dosage in a single injection. These highly concentrated formulations can have very high viscosities, creating challenges in processing (e.g. by ultrafiltration), storage (e.g. enhanced aggregation), and delivery (e.g. injection through small bore needles). Recent work has begun to identify the key intermolecular interactions governing the behavior of these highly concentrated formulations, including the effects of different excipients that have been shown to reduce viscosity and enhance the stability of these formulations. These intermolecular interactions also have a significant effect on the filtrate flux and maximum achievable protein concentration that can be obtained during ultrafiltration used for final concentration and formulation of these therapeutic proteins. PMID- 29278834 TI - Sugar sensing by ChREBP/Mondo-Mlx-new insight into downstream regulatory networks and integration of nutrient-derived signals. AB - Animals regulate their physiology with respect to nutrient status, which requires nutrient sensing pathways. Simple carbohydrates, sugars, are sensed by the basic helix-loop-helix leucine zipper transcription factors ChREBP/Mondo, together with their heterodimerization partner Mlx, which are well-established activators of sugar-induced lipogenesis. Loss of ChREBP/Mondo-Mlx in mouse and Drosophila leads to sugar intolerance, that is, inability to survive on sugar containing diet. Recent evidence has revealed that ChREBP/Mondo-Mlx responds to sugar and fatty acid-derived metabolites through several mechanisms and cross-connects with other nutrient sensing pathways. ChREBP/Mondo-Mlx controls several downstream transcription factors and hormones, which mediate not only readjustment of metabolic pathways, but also control feeding behavior, intestinal digestion, and circadian rhythm. PMID- 29278835 TI - Single stage treatment of diabetic calcaneal osteomyelitis with an absorbable gentamicin-loaded calcium sulphate/hydroxyapatite biocomposite: The Silo technique. AB - BACKGROUND: Chronic osteomyelitis necessities appropriate infected bone and soft tissue excision. The authors describe the Silo surgical technique for the treatment of calcaneal osteomyelitis using a new antibiotic-loaded absorbable calcium sulphate/hydroxyapatite biocomposite. METHODS: The Silo method involves debridement of the dead bone and local delivery of antibiotic in drilled tunnels using the biocomposite. It is combined with multiple sampling and culture specific systemic antibiotic treatment guided by a multidisciplinary team. Twelve consecutive diabetic patients with heel ulcers and calcaneal osteomyelitis were treated with the above method. All had comorbidities (Cierny-Mader (C-M) Class B hosts). The mean age was 68 years (range 50-85). A retrospective review of radiographs and electronic medical records was conducted. RESULTS: Patients were followed up until clinical cure of the ulcer for a mean of 16 weeks (range 12 18). Infection was eradicated in all 12 patients with a single stage procedure following a bone preserving technique. One patient required a subsequent flap operation and six vacuum-assisted closure (V.A.C.). There was also one case of prolonged wound leakage and no calcaneal fractures. CONCLUSIONS: The Silo technique is an effective method of local delivery of antibiotics and can be effectively implemented into the single-stage treatment of calcaneal osteomyelitis offering increased bone preservation and local delivery of antibiotic, decreasing the need for a major amputation. LEVEL OF EVIDENCE: Level IV- case series. PMID- 29278836 TI - The fibularis digiti quinti tendon: A cadaveric study with anthropological and clinical considerations. AB - In addition to the fibularis longus and brevis muscles, a number of anomalous muscles or tendons can arise from the lateral compartment of the leg. The authors describe a bilateral and robust fibularis digiti quinti (FDQ) tendon present in the foot of a 99-year-old female cadaver, present the incidence of this tendon in a cohort of 26 cadavers dissected by podiatric-medical students for a lower extremity anatomy course, and discuss the anthropological and clinical significance of the findings. In these specimen, the FDQ tendon arose from the fibularis brevis tendon proximal to the lateral malleolus, but did not separate completely from the fibularis brevis tendon until passing through the inferior fibular retinaculum. On the lateral dorsum of the foot, the FDQ passed through a third fibular retinaculum formed by the fibularis tertius tendon, and inserted onto the extensor sling of the fifth digit. This case specimen is designated as an example of the fully present category. Of the 52 limbs dissected, 17 limbs (33%) showed a fully present FDQ, while 20 limbs (38%) exhibited an FDQ in a rudimentary form. Thus, 71% of the limbs showed some presence of the FDQ. Because human bipedality requires less dexterity than that of nonhuman primates in the routine use of their hindlimbs, the authors interpret the high variability of the FDQ, including its absence in many feet, as a relaxation of natural selection maintaining this trait since the divergence of humans from African apes. PMID- 29278837 TI - Advances in gap-filling genome-scale metabolic models and model-driven experiments lead to novel metabolic discoveries. AB - With rapid improvements in next-generation sequencing technologies, our knowledge about metabolism of many organisms is rapidly increasing. However, gaps in metabolic networks exist due to incomplete knowledge (e.g., missing reactions, unknown pathways, unannotated and misannotated genes, promiscuous enzymes, and underground metabolic pathways). In this review, we discuss recent advances in gap-filling algorithms based on genome-scale metabolic models and the importance of both high-throughput experiments and detailed biochemical characterization, which work in concert with in silico methods, to allow a more accurate and comprehensive understanding of metabolism. PMID- 29278838 TI - Multiple injections per injection episode: High-risk injection practice among people who injected pills during the 2015 HIV outbreak in Indiana. AB - BACKGROUND: Misuse of prescription opioid analgesics (POA) has increased dramatically in the US, particularly in non-urban areas. We examined injection practices among persons who inject POA in a rural area that experienced a large HIV outbreak in 2015. METHODS: Between August-September 2015, 25 persons who injected drugs within the past 12 months were recruited in Scott County, Indiana for a qualitative study. Data from in-depth, semi-structured interviews were analyzed. RESULTS: All 25 participants were non-Hispanic white and the median age was 33 years (range: 19-57). All had ever injected extended-release oxymorphone (Opana(r) ER) and most (n=20) described preparing Opana(r) ER for multiple injections per injection episode (MIPIE). MIPIE comprised 2-4 injections during an injection episode resulting from needing >1mL water to prepare Opana(r) ER solution using 1mL syringes and the frequent use of "rinse shots." MIPIE occurred up to 10 times/day (totaling 35 injections/day), often in the context of sharing drug and injection equipment. CONCLUSIONS: We describe a high-risk injection practice that may have contributed to the rapid spread of HIV in this community. Efforts to prevent bloodborne infections among people who inject POA need to assess for MIPIE so that provision of sterile injection equipment and safer injection education addresses the MIPIE risk environment. PMID- 29278839 TI - Optimizing expectations and distraction leads to lower cortisol levels after acute stress. AB - BACKGROUND: A new approach of psychological interventions prior to stress aiming to optimize expectations may have beneficial effects on a person's health status by reducing physiological stress. The purpose of this experiment was to determine whether a brief psychological intervention designed to optimize personal control expectations prior to acute stress would affect perceived and biological stress responsiveness in comparison to two more established interventions (fostering gratitude or distraction) in a healthy sample. METHODS: 74 healthy participants were randomized to one of three psychological interventions prior to stress: (i) writing about ways to influence stress to optimize personal control expectations (EXPECTATION), (ii) writing a gratitude-letter (GRATITUDE) (iii) or a distraction writing task (DISTRACTION). After completing the intervention, the Maastricht acute stress test was administered to induce (psychosocial and physiological) stress. Assessments took place at baseline, post-intervention (15 min writing task) and after stress induction (additional salivary assessments: 15 and 30 min after stress). Main outcomes were expectations, emotions, perceived stress, salivary cortisol and alpha-amylase. Personality traits (eg, optimism) were assessed at baseline. RESULTS: EXPECTATION specifically increased personal control expectations (p = .016, d = .72) and GRATITUDE specifically increased gratitude (p = .026, d = .68). EXPECTATION and DISTRACTION led to lower cortisol concentrations after stress induction than GRATITUDE (time x group interaction: p < .001, d = .88). We detected no intervention effects on alpha-amylase or perceived stress. Optimism moderated intervention effects on cortisol (p = .023, d = .74). CONCLUSIONS: Brief psychological interventions aiming to optimize expectations or distraction prior to stress reduce the cortisol response in healthy participants after an acute stressor. PMID- 29278840 TI - Temporal and geospatial trends of pediatric cancer incidence in Nebraska over a 24-year period. AB - BACKGROUND: Data from the Surveillance, Epidemiology, and End Results (SEER) revealed that the incidence of pediatric cancer in Nebraska exceeded the national average during 2009-2013. Further investigation could help understand these patterns. METHODS: This retrospective cohort study investigated pediatric cancer (0-19 years old) age adjusted incidence rates (AAR) in Nebraska using the Nebraska Cancer Registry. SEER AARs were also calculated as a proxy for pediatric cancer incidence in the United States (1990-2013) and compared to the Nebraska data. Geographic Information System (GIS) mapping was also used to display the spatial distribution of cancer in Nebraska at the county level. Finally, location allocation analysis (LAA) was performed to identify a site for the placement of a medical center to best accommodate rural pediatric cancer cases. RESULTS: The AAR of pediatric cancers was 173.3 per 1,000,000 in Nebraska compared to 167.1 per 1,000,000 in SEER. The AAR for lymphoma was significantly higher in Nebraska (28.1 vs. 24.6 per 1,000,000; p = 0.009). For the 15-19 age group, the AAR for the 3 most common pediatric cancers were higher in Nebraska (p < 0.05). Twenty three counties located >2 h driving distance to care facilities showed at least a 10% higher incidence than the overall state AAR. GIS mapping identified a second potential treatment site that would alleviate this geographic burden. CONCLUSIONS: Regional differences within Nebraska present a challenge for rural populations. Novel use of GIS mapping to highlight regional differences and identify solutions for access to care issues could be used by similar states. PMID- 29278841 TI - Patient education-level affects treatment allocation and prognosis in esophageal- and gastroesophageal junctional cancer in Sweden. AB - BACKGROUND: Low socioeconomic status and poor education elevate the risk of developing esophageal- and junctional cancer. High education level also increases survival after curative surgery. The present study aimed to investigate associations, if any, between patient education-level and treatment allocation after diagnosis of esophageal- and junctional cancer and its subsequent impact on survival. METHODS: A nation-wide cohort study was undertaken. Data from a Swedish national quality register for esophageal cancer (NREV) was linked to the National Cancer Register, National Patient Register, Prescribed Drug Register, Cause of Death Register and educational data from Statistics Sweden. The effect of education level (low; <=9 years, intermediate; 10-12 years and high >12 years) on the probability of allocation to curative treatment was analyzed with logistic regression. The Kaplan-Meier-method and Cox proportional hazard models were used to assess the effect of education on survival. RESULTS: A total of 4112 patients were included. In a multivariate logistic regression model, high education level was associated with greater probability of allocation to curative treatment (adjusted OR: 1.48, 95% CI: 1.08-2.03, p = 0,014) as was adherence to a multidisciplinary treatment-conference (adjusted OR: 3.13, 95% CI: 2.40-4.08, p < 0,001). High education level was associated with improved survival in the patients allocated to curative treatment (HR: 0.82, 95% CI: 0.69-0.99, p = 0,036). DISCUSSION: In this nation-wide cohort of esophageal- and junctional cancer patients, including data regarding many confounders, high education level was associated with greater probability of being offered curative treatment and improved survival. PMID- 29278842 TI - Estimating the sensitivity of a prostate cancer screening programme for different PSA cut-off levels: A UK case study. AB - INTRODUCTION: Policy decisions about prostate cancer screening require data on the natural history of histological cancers and the resulting impact of screening. However, the gold standard procedure required to identify true positive histological cancer is a full autopsy of the gland which is not possible in screening studies, leading to verification bias. We aim to estimate the sensitivity of a prostate cancer screening round (PSA result to diagnosis) relative to histological cancer. METHODS: We developed a framework combining data on UK screened and non-screened prostate cancer populations originating from a single round of population-based PSA testing among UK men aged 50-69 years, prostate cancer incidence data, and needle biopsy data from the published literature. RESULTS: Sensitivity of a screening round was highest at age 65-69 years at 33% (95% CI: 30%-37%) and 24% (95% CI: 21%-28%) for PSA cut-off levels of 3 ng/ml and 4 ng/ml, respectively. Sensitivity was lowest at age 50-54 at 15% (95% CI: 12%-17%) and 9% (95% CI: 8%-11%) for PSA cut-off levels of 3 ng/ml and 4 ng/ml, respectively. In contrast, the clinical detection rate in the absence of mass screening, relative to histological cancer, varied between 0.2%-0.7% at age 50-54 and 1.2%-2.7% at age 65-69 from 1995 to 2012. CONCLUSIONS: The framework enabled the sensitivity of a prostate cancer screening round relative to histological cancer diagnosis to be estimated and provides a basis to determine the impact and cost-effectiveness of prostate cancer screening. The approach could be adapted to inform the sensitivity of other biomarkers, cancers and screening programmes. PMID- 29278843 TI - NLGN1 and NLGN2 in the prefrontal cortex: their role in memory consolidation and strengthening. AB - The prefrontal cortex (PFC) is critical for memory formation, but the underlying molecular mechanisms are poorly understood. Clinical and animal model studies have shown that changes in PFC excitation and inhibition are important for cognitive functions as well as related disorders. Here, we discuss recent findings revealing the roles of the excitatory and inhibitory synaptic proteins neuroligin 1 (NLGN1) and NLGN2 in the PFC in memory formation and modulation of memory strength. We propose that shifts in NLGN1 and NLGN2 expression in specific excitatory and inhibitory neuronal subpopulations in response to experience regulate the dynamic processes of memory consolidation and strengthening. Because excitatory/inhibitory imbalances accompany neuropsychiatric disorders in which strength and flexibility of representations play important roles, understanding these mechanisms may suggest novel therapies. PMID- 29278845 TI - Fate of nutrients and heavy metals during two-stage digestion and aerobic post treatment of municipal organic waste. AB - The biogas technology is a promising approach for the recovery of energy and fertilizer from municipal organic waste (MOW). However, only scarce information on the development of initial nutrient and heavy metal loads during processing is available. Therefore, this study investigates properties of source-separated MOW during treatment in a semi-industrial scale two-stage biogas plant and subsequent digestate composting including impurities removal. Data from 15 batch experiments was investigated by material and substance flow analysis. Results of this study have shown that about 40% of nutrients contained in the MOW inflow are mineralized during anaerobic and subsequent aerobic treatment. A higher nutrient release was observed during the anaerobic treatment step. Additionally, impurities removal causes a significant reduction of final nutrient content. Heavy metal analysis confirmed a high heterogeneity of contamination levels. However, digestion and composting do not seem to significantly impact on total heavy metal loads in the substrate flow. PMID- 29278844 TI - The effects of bio-available copper on macrolide antibiotic resistance genes and mobile elements during tylosin fermentation dregs co-composting. AB - In this study, aerobic co-composting of tylosin fermentation dregs (TFDs) and sewage sludge with different adding concentrations of copper (Cu) was investigated to inspect the fate of antibiotic resistance genes (ARGs), metal resistance genes (MRGs) and mobile genetic elements (MGEs). Results showed that two concentrations of Cu did affect not only the abiotic factors but the relative abundances of resistance genes. High concentration of Cu inhibited the metabolic capacity of microbial community and the nitrogen-fixing process while had little effect on the degradation of TYL and TOC. The abundance of ermT, mefA, mphA increased partly attributed to the toxic effects and co-selective pressure from heavy metal reflected by MRGs. There was significant correlation among some environmental factors like pH, bio-Cu, organic matters and ARGs. PMID- 29278846 TI - The contribution of weak CAM to the photosynthetic metabolic activities of a bromeliad species under water deficit. AB - The Crassulacean acid metabolism (CAM) can be a transitory strategy for saving water during unfavourable conditions, like a dry season. In some cases, CAM can also contribute to the maintenance of photosynthetic integrity, even if carbon gain and growth are impaired. CAM occurs in different intensities, being stronger or weaker depending on the degree of nocturnal malic acid accumulation. For example, Guzmania monostachia is an epiphytic tank bromeliad that shows an increase in its nocturnal organic acid accumulation and a variable CAM behaviour when exposed to water deficit. In this context, this study aimed at investigating whether the weak CAM displayed by this species may mitigate the harmful effects of water limitation on its photosynthetic activity. To this, bromeliads were submitted to well-watered and water deficit conditions. Guzmania monostachia plants under water deficiency conditions showed a reduction on atmospheric carbon assimilation without exhibiting changes in PSII integrity and carbohydrate production while showed an increase in nocturnal malic acid accumulation. Additionally, spots with high PSII efficiency in the leaf portion with a greater nocturnal malic acid accumulation were observed in plants exposed to water shortage conditions. These high-efficiency spots might be associated with a greater malate decarboxylation capacity. Also, the malic acid contributed to approximately 50% of the total carbon assimilated under water deficit. These results suggest that weak CAM may participate in photo-protection and it appears to meaningfully contribute to the overall carbon balance, being an important metabolic strategy to maintain plant fitness during water deficit periods. PMID- 29278847 TI - Analysis of the WUSCHEL-RELATED HOMEOBOX gene family in Pinus pinaster: New insights into the gene family evolution. AB - WUSCHEL-RELATED HOMEOBOX (WOX) genes are key players controlling stem cells in plants and can be divided into three clades according to the time of their appearance during plant evolution. Our knowledge of stem cell function in vascular plants other than angiosperms is limited, they separated from gymnosperms ca 300 million years ago and their patterning during embryogenesis differs significantly. For this reason, we have used the model gymnosperm Pinus pinaster to identify WOX genes and perform a thorough analysis of their gene expression patterns. Using transcriptomic data from a comprehensive range of tissues and stages of development we have shown three major outcomes: that the P. pinaster genome encodes at least fourteen members of the WOX family spanning all the major clades, that the genome of gymnosperms contains a WOX gene with no homologues in angiosperms representing a transitional stage between intermediate- and WUS-clade proteins, and that we can detect discrete WUS and WOX5 transcripts for the first time in a gymnosperm. PMID- 29278848 TI - Bisphenol-A antagonizes the rapidly modulating effect of DHT on spinogenesis and long-term potentiation of hippocampal neurons. AB - Bisphenol A (BPA), a common environmental endocrine disruptor, modulates estrogenic, antiestrogenic, and antiandrogenic effects throughout the lifespan. Recent studies found more obvious adverse effect of BPA on some neurobehavior in males than that in females. In this study, BPA at 10-100 nM rapidly increased the densities of the dendrite spine and synapse in cultured hippocampal neurons of rats in vitro within 1 h. Co-treatment of BPA (100 nM) with dihydrotestosterone (DHT, 10 nM) or with 17beta-E2 (10 nM) completely eliminated the promotion of DHT or 17beta-E2 in the densities of the dendritic spine and synapse. Pretreatment of estrogen receptors (ERs) antagonist ICI182,780 but not of androgen receptors (ARs) antagonist flutamide (Flu) for 30min completely blocked BPA-enhanced densities of the dendritic spine and synapse. Pretreatment of flutamide for 30min before BPA and DHT completely rescued BPA-enhanced densities of the dendritic spine and synapse. Furthermore, pretreatment of ERK1/2 inhibitor U0126 or p38 inhibitor SB203580 entirely eliminated BPA-induced increases in the densities of the dendritic spine and synapse. Meanwhile, BPA (100 nM) enhanced long-term potentiation (LTP) induction of dentate gyrus in hippocampal slices of younger male rats, which was not blocked by co-incubation of flutamide but was inhibited by pretreatment of an P38 inhibitor SB203580. Co-application of BPA with DHT inhibited DHT-suppressed LTP. These results are the first demonstrating the antagonism of BPA to the rapid modification of DHT in synaptic plasticity. However, BPA alone rapidly promotes spinogenesis and synaptic activity through ER instead of AR, and both ERKs and p38 signaling pathways are involved in these processes. PMID- 29278849 TI - Distribution and fate modeling of 4-nonylphenol, 4-t-octylphenol, and bisphenol A in the Yong River of China. AB - In this study, the concentrations of 4-nonylphenol (4-NP), 4-tert-octylphenol (4 t-OP), and bisphenol A (BPA) in the water column of the Yong River were investigated and found to be in the range of 140-3948, 6-828, and 15-1415 ng L-1, respectively. A fate and transport model coupled with the Water Quality Analysis Simulation Program (WASP) was developed. After model calibration and validation, the distributions of 4-NP, 4-t-OP, and BPA in the Yong River were modeled for the duration of 2015. The total contaminant loads from the upstream boundary, four tributaries and two wastewater treatment plants were determined to be 2318 kg yr 1 for 4-NP, 506 kg yr-1 for 4-t-OP, and 970 kg yr-1 for BPA. Both measured and modeled results reported higher concentrations of the selected contaminants near river confluences and at the outfalls of the wastewater treatment plants. Peak concentrations were found to always appear in months with relatively reduced precipitation. The influences of adsorption and degradation on the dissolved concentrations of the selected chemicals were also modeled. The combined effects of adsorption and degradation were found to reduce dissolved concentrations of 4 NP, 4-t-OP, and BPA by 17.9%, 30.7%, and 12.1%, respectively. Adsorption was shown to reduce 4-NP concentrations in the Yong River more than degradation. Conversely, adsorption and degradation caused almost equal reductions in the dissolved concentrations of 4-t-OP and degradation caused larger decreases than adsorption in the dissolved concentrations of BPA. PMID- 29278850 TI - Impact of lead tolerant plant growth promoting rhizobacteria on growth, physiology, antioxidant activities, yield and lead content in sunflower in lead contaminated soil. AB - Present study was conducted to evaluate the effect of lead tolerant plant growth promoting rhizobacteria (LTPGPR) on growth, physiology, yield, antioxidant activities and lead uptake in sunflower in soil contaminated with lead under pot conditions. Three pre-characterized LTPGP strains (S2 (Pseudomonas gessardii strain BLP141), S5 (Pseudomonas fluorescens A506) and S10 (Pseudomonas fluorescens strain LMG 2189)) were used to inoculate sunflower growing in soil contaminated with different levels (300, 600 and 900 mg kg-1) of lead by using lead nitrate salt as source of lead. Treatments were arranged according to completely randomized design with factorial arrangements. At harvesting, data regarding growth attributes (root shoot length, root shoot fresh and dry weights), yield per plant, physiological attributes (Chlorophyll 'a', 'b' and carotenoids content), antioxidant activities (Ascorbate peroxidase, catalase, superoxide dismutase and glutathione reductase), proline and malanodialdehyde content, and lead content in root, shoot and achenes of sunflower were recorded. Data were analysed by standard statistical procedures. Results showed that lead contamination reduced the plants growth, physiology and yield at all levels of lead stress. But application of LTPGPR in soil contaminated with lead improved plant growth, physiology, yield, and antioxidant activities, proline, and reduced the malanodialdehyde content (that is reduced by the application of different strains in lead contamination) of sunflower as compared to plants grown in soil without inoculation. Inoculation also promoted the uptake of lead in root, shoots and reduced the uptake of lead in achenes of plants as compared to plants in lead contamination without inoculation. PMID- 29278851 TI - F-box protein 11 promotes the growth and metastasis of gastric cancer via PI3K/AKT pathway-mediated EMT. AB - F-box protein 11 (FBXO11) has both the E3 ubiquitin ligase activity and the methyltrasferase activity, and regulates metastasis, apoptosis and chemosensitivity in human cancer. However, the clinical significance and biological function of FBXO11 in gastric cancer (GC) are rarely known. Here, we demonstrated up-regulated expression of FBXO11 in GC tissues in comparison with that in tumor-adjacent tissues. Clinical analysis based on our specimens and the TCGA database revealed that FBXO11 overexpression was associated with large tumor size, lymph node metastasis and advanced TNM stage. Notably, GC patients with high FBXO11 expression showed a significant shorter overall survival. Cell proliferation and mobility were measured by CCK-8 and Transwell assays. FBXO11 silencing by transfection with two specific shRNAs attenuated proliferation, migration and invasion of MGC-803 cells. In accordance, FBXO11 overexpression promoted these cellular processes in SGC-7901 cells. Mechanistically, FBXO11 obviously facilitated epithelial-mesenchymal transition (EMT) process as suggested by immunoblotting and immunofluorescence data. Moreover, we found that FBXO11 promoted the activation of AKT pathway with increased phosphorylated AKT level in SGC-7901 cells. LY294002 and Wortmannin, phosphotidylinsitol-3-kinase (PI3K) inhibitors, blocked FBXO11 induced EMT, proliferation, migration and invasion of SGC-7901 cells. Phosphatase and tensin homolog (PTEN), which played a crucial role in regulating PI3K/AKT pathway, was negatively modulated by FBXO11 in GC cells. Taken together, our findings contribute to current understanding of the functions of FBXO11 and suggest a mechanism by which FBXO11 plays an oncogenic role in the development of GC possibly by inhibiting PTEN and subsequently promoting PI3K/AKT pathway activation. PMID- 29278852 TI - Adipokines in neurovascular diseases. AB - Adipose tissue is now described as an endocrine organ secreting a number of adipokines contributing to the development of inflammation and metabolic imbalance, but also endothelial dysfunction, vascular remodeling, atherosclerosis, and ischemic stroke. Leptin, adiponectin, and resistin are the most studied adipokines which play important roles in the regulation of cardiovascular homeostasis. Leptin and adiponectin mediate both proatherogenic and antiatherogenic responses. Leptin and adiponectin have been linked to the development of coronary heart disease and may be involved in the underlying biological mechanism of ischemic stroke. Resistin, a pro-inflammatory cytokine, is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. The changes in serum levels of novel adipokines apelin, visfatin are also associated with acute ischemic stroke. These adipokines have been proposed as potential prognostic biomarkers of cardiovascular mortality/morbidity and therapeutic targets in patients with cardiometabolic diseases. In this article, we summarize the biologic role of the adipokines and discuss the link between dysfunctional adipose tissue and metabolic/inflammation imbalance, consequently endothelial damage, progression of atherosclerotic disease, and the occurrence of ischemic stroke. PMID- 29278853 TI - LncRNA HIF1A-AS2 positively affects the progression and EMT formation of colorectal cancer through regulating miR-129-5p and DNMT3A. AB - LncRNAs were a group of RNAs, which can be a regulator or master in biological activities of cancer cells. HIF1A-AS2 belongs to this group, and it has been verified to be able to affect cell activities in several kinds of cancers. In this study, we tried to study the functions of HIF1A-AS2 exerted in colorectal cancer. In order to clearly know about the expression of HIF1A-AS2, miR-129-5p and DNMT3A in CRC tissues and cells, we employed qRT-PCR. The relevance among those three genes was examined by the use of Pearson correlation analysis. With the aid of bioinformatics analysis and dual luciferase reporter assays, the combinations between them were verified one by one MTT, colony formation trans well and western blotting, immunofluorescence, all those assays reflected a fact that as a ceRNA, HIF1A-AS2 could directly bind with miR-129-5p, and could positively affect cell proliferation, invasion and EMT formation by regulation of the expression of miR-129-5p and DNMT3A. Therefore, we obtained a conclusion that HIF1A-AS2 exerted the oncogenic functions in CRC through regulating miR-129 5p/DNMT3A axis, which indicates that HIF1A-AS2 might be a useful therapeutic target in CRC. PMID- 29278854 TI - Overexpression of ALK4 inhibits cell proliferation and migration through the inactivation of JAK/STAT3 signaling pathway in glioma. AB - Aristaless-like homeobox 4 (ALK4) is a member of ALK proteins family and plays an important role in tumorigenesis. However, the expression and function of ALK4 in glioma remain largely unknown. The aim of our study was to elucidate its expression pattern in human glioma tissues and cell lines, as well as its functions in glioma cells. Our results demonstrated that ALK4 was lowly expressed in human glioma tissues and cell lines. Additionally, overexpression of ALK4 significantly suppressed the proliferation, migration and invasion of glioma cells, as well as inhibited the epithelial-mesenchymal transition (EMT) phenotype in glioma cells. Furthermore, overexpression of ALK4 significantly downregulated the phosphorylation levels of JAK2 and STAT3 in U87 cells. STAT3 inhibitor (Niclosamide) obviously enhanced ALK4-inhibted glioma cell proliferation and invasion. In conclusion, we demonstrated that overexpression of ALK4 suppressed glioma cell proliferation, migration and invasion through the inactivation of JAK/STAT3 signaling pathway. Thus, ALK4 may be a potential therapeutic target for the treatment of glioma. PMID- 29278855 TI - Olive oil and leaf extract prevent fluoxetine-induced hepatotoxicity by attenuating oxidative stress, inflammation and apoptosis. AB - Olive oil and leaf extract have several health benefits; however, their beneficial effect against fluoxetine-induced liver injury has not been investigated. The present study aimed to scrutinize the impact of fluoxetine on the liver of rats and to evaluate the protective effects of olive oil and leaf extract. Rats received fluoxetine orally at dose of 10 mg/kg body weight for 7 consecutive days. The fluoxetine-induced rats were concurrently treated with olive oil or leaf extract. At the end of the experiment, blood and liver samples were collected for analysis. Fluoxetine administration significantly increased circulating ALT, AST, ALP and the pro-inflammatory cytokines TNF-alpha and IL 1beta levels in rats. Histological analysis showed several alterations, such as inflammatory cells infiltration, hepatocyte vacuolation and dilated sinusoids in the liver of fluoxetine-induced rats. Concurrent supplementation of olive oil and olive leaf extract significantly reduced circulating liver function marker enzymes and pro-inflammatory cytokines, and prevented fluoxetine-induced histological alterations. Both olive oil and leaf extract significantly decreased liver lipid peroxidation and nitric oxide, and ameliorated liver glutathione, superoxide dismutase, catalase and glutathione peroxidase. In addition, olive oil and leaf extract prevented fluoxetine-induced apoptosis in the liver of rats as evidenced by decreased expression of Bax and caspase-3, and up-regulated expression of Bcl-2. In conclusion, olive oil and leaf extract protect against fluoxetine-induced liver injury in rats through attenuation of oxidative stress, inflammation and apoptosis. PMID- 29278856 TI - Removal of low concentration CH3SH with regenerable Cu-doped mesoporous silica. AB - Mercaptans are highly volatile compounds responsible for disagreeable odors and very low olfactory threshold, especially for CH3SH (0.4 ppvb). To the best knowledge of us, approach for controlling low-concentrated odors (i.e. 1-10 ppm) is scarcely reported. In this research, Cu-doped mesoporous silica was synthesized for removal of low-concentrated CH3SH. The as-prepared samples show considerably thermal and mechanical stability and could be thermal-regenerated. Copper loading ratio and humidity have significant impacts on eliminating odors. According to XRD, TEM, BET, NMR and EPR, we deduce that surface groups on CuO nanoparticles and the SiOCu group are highly possibly transformed into a hydrated complex which is much more effective in capturing CH3SH with its empty Cu-3d orbit. Although CH3SH has to compete with water for absorption sites, it is always the "winner" owing to the strong chelating ability between SH group and Cu (II). PMID- 29278857 TI - Wavelength dependent recovery of UV-mediated damage: Tying up the loose ends of optical based powdery mildew management. AB - Controlled environment chamber experiments at Petri dish level were conducted to examine the wavelength and dose dependent efficacy of ultraviolet (UV) radiation, the recovery action potential of optical radiation applied concomitantly/subsequently to effective UV treatment, and the lapse time between UV treatment and subsequent exposure to recovery wavelength on germination efficiency of Oidium neolycopersici conidia. Conidia of eight- to nine-day-old colonies were dusted on water agar surface in Petri dishes and exposed to UV treatments (without lid). Immediately after UV treatments, Petri dishes were sealed and incubated in darkness or differing optical environments generated using seven different radiation sources (range 290nm to 780nm). Twenty-four hours after UV treatment, fifty conidia from each sample were assessed for germination. Compared to non-UV controls, <10% of the conidia germinated after 30s of exposure to 254nm or 283nm UV and subsequent dark incubation. Conidia germination was almost negligible if the exposure duration increased to 4min. Germination was about 60% with broad spectrum UV after 1min of exposure, and about 35% after 2 to 4min of exposure. There was no reduction of conidia germination with the exposure of <=4min with 310nm. With the tested wavelength and dose ranges, germination recovery was effective in the 350nm to 500nm range. Germination efficiency of conidia treated with effective UV was significantly higher (>73%) if incubated subsequently in the 350nm to 500nm range (germination recovery). Furthermore, germination recovery depends on the characteristics of UV treatment (wavelength, and duration of exposure) and the lapse time between UV treatment and subsequent exposure to optical radiation in the recovery range. The findings of this study provide key criteria for wavelength selection, combination and application time in the optical radiation range, enabling improved design of optical based management strategies against powdery mildews. PMID- 29278858 TI - The Ikaros family in lymphocyte development. AB - The IKZF family of transcription factors are essential regulators of lymphopoiesis. Ikaros, Helios, Aiolos and Eos function as transcriptional repressors and activators during T and B cell differentiation and in mature cell function, depending on the stage of development and/or cell type. Their potential mechanisms of action are varied. Ikaros family proteins partner with multiple complexes, including NuRD, PRC2 and transcription elongation factors, to modulate gene expression and the chromatin state. In humans, mutations in the IKZF genes are associated with B cell deficiency, leukemias and autoimmunity. In this review, we focus on the function of Ikaros family proteins in early T and B lymphocyte development, and discuss the molecular and physiological activities of this family. PMID- 29278859 TI - Acetyl-l-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats. AB - Industrial and agricultural developments in recent years have resulted in the excessive discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity. The main objective of this study was to evaluate acetyl-l carnitine's (ALC) protective ability against the arsenic-induced hepatotoxicity. For this purpose, male Wistar rats were distributed randomly into 5 groups of 8 rats each: control, arsenic (5 mg/kg) and arsenic plus ALC (5 mg/kg; 100, 200, 300 mg/kg). The animals were gavaged for 21 consecutive days. Liver tissue samples were extracted 24 h after the last treatment and were later analyzed for biochemical and histological alterations. The arsenic-induced oxidative damage was confirmed by elevation of malondialdehyde (MDA), a lipid peroxidation byproduct, as well as depletion in physiological antioxidant content such as superoxide dismutase (SOD) and catalase (CAT). Furthermore, alterations in mitochondrial functions including a significant decrease of mitochondrial outer membrane potential and reactive oxygen species (ROS) generation increase, mitochondrial swelling, release of cytochrome c and consequent activation of caspase-3 and caspase-9 and initiation of apoptosis, was observed following arsenic administration. Moreover, the inflammation was confirmed by the overexpression of inflammatory mediators such as NF-KB and IL-1 and IL-6. The present study demonstrated that ALC ameliorates arsenic-induced oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and histological damage. ALC's protective features against arsenic hepatotoxicity may be due to this agent's antioxidant and anti-inflammatory properties as well as its stabilizing effects on mitochondrial function. PMID- 29278860 TI - S-allyl-glutathione, a synthetic analogue of glutathione protected liver against carbon tetrachloride toxicity: Focus towards anti-oxidative efficiency. AB - A simple analogue of well known natural antioxidant glutathione (GSH) called S allyl-glutathione (SAG) was evaluated against carbon tetrachloride (CCl4)-induced oxidative stress liver injury in rat. Pretreatment of SAG attenuated the CCl4 toxicity induced elevation of liver injury markers such as enzymes (AST, ALT, GGT, ALP and LDH) and bilirubin in the blood circulation. Such protective effect of SAG resulted in preservation of liver function observed as normal level of total protein and albumin in plasma as well as inhibition of dyslipidemia in liver. In addition, in silico analysis has proved that SAG has strong affinity with the amino acids present in active site of the human cytochrome P450 2E1 and 3A4. Three important mechanisms provided by SAG such as scavenging of reactive oxidants, replenishing of endogenous antioxidants (SOD, catalase, GPx, GSH and vitamin C) and protection of mitochondrial function (oxidative phosphorylation complex activities) are involved in the optimal function of liver against CCl4 toxicity. PMID- 29278861 TI - Hemitransdomal versus Dome-Binding Suture. AB - The dome-binding suture (DBS) and hemitransdomal suture (HTS) are suture techniques used to narrow and define the nasal tip. The DBS can create a pinched, unnatural appearance, while the HTS puts the lateral crus in a more favorable orientation. This allows a natural contour between the nasal tip and alar lobule while maintaining alar margin support. Objective measurement of the rotational axis of the lateral crus between the DBS and the HTS has not been reported in the literature. To determine whether the DBS or HTS technique results in a more favorable rotational axis of the lateral crus as measured by the alar surface septal angle (ASSA). Open rhinoplasty with cephalic trim and placement of a DBS or HTS was performed in 6 cadaveric heads, for a total of 12 lower lateral cartilages at the VirtuOHSU Simulation and Surgical Training Center at Oregon Health and Science University (OHSU). ASSA measurements were taken at baseline and after placement of either a DBS or HTS. A total of 36 ASSA measurements were obtained. The median baseline ASSA prior to suture placement was 142 degrees (interquartile range [IQR]: 131.5-145 degrees), following DBS placement was 141 degrees (IQR: 33-150.5 degrees), and following HTS placement was 112 degrees (IQR: 108-117 degrees). There was no statistically significant difference of ASSA measurements between baseline and DBS placement (p = 0.24), but there was a statistically significant difference between baseline and HTS (p < 0.0001) and between DBS and HTS (p < 0.0001). The HTS technique creates a more favorable rotational axis of the lateral crus as compared with the DBS, as measured by the ASSA. This study provides objective data to support the use of the HTS for nasal tip contouring. PMID- 29278862 TI - Frontal Fibrosing Alopecia: A Retrospective Analysis of 72 Patients from a German Academic Center. AB - Frontal fibrosing alopecia (FFA) describes the scarring, band-like recession of the frontotemporal hairline. Treatment is difficult, and currently, no evidence based therapy exists. The purpose of this study is to report clinical features and treatment responses in a large cohort of patients with FFA. The authors analyzed a series of 72 patients with a clinical or histologic diagnosis of FFA. A total of 70 patients were female (97.2%), and 2 were male (2.8%). In females, the first onset of FFA was postmenopausal in 81.4% (n = 57). Documented eyebrow loss was present in 61.1% (n = 44), whereas involvement of eyelashes and body hair was reported in only 4.2% (n = 3) and 5.6% (n = 4), respectively. Clinical symptoms were itching (40.3%, n = 29) and trichodynia (4.2%, n = 3) in the alopecic area. Virtually all patients were treated with topical high-potency steroids. Additional treatments were topical tacrolimus, systemic retinoids, and hydroxychloroquine. A total of 48 patients (66.7%) received a combination of high potency steroids with topical pimecrolimus. In this subgroup, subjective improvement or disease stabilization was reported by 64.6% (n = 31), and the hairline was stabilized on average after 9 to 12 months of therapy. The combination therapy of topical high-potency steroids with pimecrolimus may be an effective and steroid-saving treatment for FFA. PMID- 29278863 TI - Otoplasty Online Information: A Comprehensive Analysis of the Websites and Videos that Patients View Regarding Cosmetic Ear Surgery. AB - Physicians should be aware of both websites and videos available online regarding the otoplasty procedure to provide quality care. This study systematically analyzes the authorships, reliability, quality, and readability of the websites, as well as the authorships and primary objectives of the videos regarding otoplasty. Validated instruments were used to analyze the reliability, quality, and readability of websites, and videos were systematically categorized and analyzed. A Google search was conducted, and the first five pages of results were included in this study. After excluding unrelated websites, the remaining 44 websites were categorized by authorship (physician, patient, academic, or unaffiliated) and were analyzed using the validated DISCERN instrument for reliability and quality, as well as various other validated instruments to measure readability. A YouTube search was also conducted, and the first 50 relevant videos were included in the study. These videos were categorized by authorship and their primary objective. Website authorships were physician dominated. Reliability, quality, and overall DISCERN score differ between the four authorship groups by a statistically significant margin (Kruskall-Wallis test, p < 0.05). Unaffiliated websites were the most reliable, and physician websites were the least reliable. Academic websites were of the highest quality, and patient websites were of the lowest quality. Readability did not differ significantly between the groups, though the readability measurements made showed a general lack of material easily readable by the general public. YouTube was likewise dominated by physician-authored videos. While the physician-authored videos sought mainly to inform and to advertise, patient-authored videos sought mainly to provide the patient's perspective. Academic organizations showed very little representation on YouTube, and the YouTube views on otoplasty videos were dominated by the top 20 videos, which represented over 93% of the total views of videos included in this study. PMID- 29278864 TI - Stroke Volume Recruitability during the Third Trimester of Pregnancy. AB - OBJECTIVE: It is unknown whether the heart operates in the ascending or flat portion of the Starling curve during normal pregnancy. Pregnant women do not respond to the passive leg-raising maneuver secondary to mechanical obstruction of the inferior vena cava by the gravid uterus. Our objective was to evaluate if administration of a fluid bolus increases baseline stroke volume (SV) among healthy pregnant patients during the third trimester. STUDY DESIGN: Healthy pregnant women who underwent elective term cesarean sections were included. A noninvasive cardiac output monitor was used to measure hemodynamic variables at baseline and after administration of a 500-mL crystalloid bolus. RESULTS: Forty five women were included in the study. Fluid administration was associated with a statistically significant increase in SV from a baseline value of 71 +/- 11 to 90 +/- 19 mL (95% confidence interval [CI]: 13.67-21.49; p < 0.01) and a significant decrease in maternal heart rate from a baseline of 87 +/- 9 beats per minute to 83 +/- 8 after the fluid bolus (95% CI: -6.81 to -2.78; p = 0.03). No changes in peripheral vascular resistances or any other measured hemodynamic parameters were noted with volume expansion. CONCLUSION: In healthy term pregnancy, the heart operates in the ascending portion of the Starling's curve, rendering it fluid responsive. PMID- 29278866 TI - Is patient exposure preapproval and postapproval a determinant of the timing and frequency of occurrence of safety issues? AB - BACKGROUND: The amount of drug exposure, pre and post approval, is considered to be a direct determinant of knowledge about the safety of a drug. A larger pre approval exposed population is supposed to reduce the risk of unanticipated safety issues post-approval. The amount of use in the postapproval population is also expected to influence the occurrence and timing of safety issues. We investigated how the amount of pre and post approval exposure influences the detection of post-approval safety issues. METHODS: A cohort of innovative drugs approved in Europe was followed for the period of 2012-2016. The main outcome of interest was a new safety issue in the period. Post-approval exposure was collected at 6 month intervals, and pre-approval exposure was collected at the moment of authorisation. Other characteristics collected for the included drugs were anatomical therapeutical chemical (ATC) class, biological status, orphan status and type of approval. We used Cox proportional hazards regression to investigate the association between exposure and the hazard of having a first safety issue. RESULTS: The pre-approval exposure was not associated with the risk of safety issues after adjusting for ATC class, biological status, and treatment duration. Higher post-approval exposure was associated with more new safety issues identified (HR = 2.44 (95% CI = 1.12-5.31)) for drugs with more than 1,000 patient-years of cumulative exposure compared to drugs with less than 1,000 patient years of exposure. CONCLUSION: Our results suggest that postapproval exposure influences the detection of safety issues. PMID- 29278865 TI - Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform. AB - BACKGROUND AND PURPOSE: Statins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. Although effective at preventing cardiovascular disease, statin use is associated with muscle weakness, myopathies and, occasionally, fatal rhabdomyolysis. As simvastatin, a commonly prescribed statin, promotes Ca2+ release from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin directly activates skeletal (RyR1) and cardiac (RyR2) ryanodine receptors. EXPERIMENTAL APPROACH: RyR1 and RyR2 single channel behaviour was investigated after incorporation of sheep cardiac or mouse skeletal SR into planar phospholipid bilayers under voltage-clamp conditions. LC MS was used to monitor the kinetics of interconversion of simvastatin between hydroxy-acid and lactone forms during these experiments. Cardiac and skeletal myocytes were permeabilised to examine simvastatin modulation of SR Ca2+ release. KEY RESULTS: Hydroxy acid simvastatin (active at HMG-CoA reductase) significantly and reversibly increased RyR1 open probability (Po) and shifted the distribution of Ca2+ spark frequency towards higher values in skeletal fibres. In contrast, simvastatin reduced RyR2 Po and shifted the distribution of spark frequency towards lower values in ventricular cardiomyocytes. The lactone pro-drug form of simvastatin (inactive at HMG-CoA reductase) also activated RyR1, suggesting that the HMG-CoA inhibitor pharmacophore was not responsible for RyR1 activation. CONCLUSION AND IMPLICATIONS: Simvastatin interacts with RyR1 to increase SR Ca2+ release and thus may contribute to its reported adverse effects on skeletal muscle. The ability of low concentrations of simvastatin to reduce RyR2 Po may also protect against Ca2+ -dependent arrhythmias and sudden cardiac death. PMID- 29278867 TI - Optical Diagnosis for Colorectal Polyps: A Useful Technique Now or in the Future? AB - In the last few years, interest in the optical diagnosis of colorectal polyps has increased among gastroenterologists. Several studies have shown that the optical diagnosis of small colorectal polyps is safe and feasible in routine clinical practice and is comparable to histopathology. The Narrow-band Imaging International Colorectal Endoscopic Classification provides a validated criterion for the classification of neoplastic and nonneoplastic polyps as well as polyps with deep submucosal invasion using narrow band imaging during real-time colonoscopy. The aim of the present review is to assess the current evidence for and limitations of optical diagnosis and to propose a systematic approach for transferring research findings to patient care. PMID- 29278868 TI - Linear rheology as a potential monitoring tool for sputum in patients with Chronic Obstructive Pulmonary Disease (COPD). AB - BACKGROUND: The rheological properties of sputum may influence lung function and become modified in disease. OBJECTIVE: This study aimed to correlate the viscoelastic properties of sputum with clinical data on the severity of disease in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sputum samples from COPD patients were investigated using rheology, simple mathematical modelling and Scanning Electron Microscopy (SEM). The samples were all collected from patients within two days of their admission to Prince Philip Hospital due to an exacerbation of their COPD. Oscillatory and creep rheological techniques were used to measure changes in viscoelastic properties at different frequencies over time. RESULTS: COPD sputum was observed to behave as a viscoelastic solid at all frequencies studied. Comparing the rheology of exacerbated COPD sputum with healthy sputum (not diagnosed with a respiratory disease) revealed significant differences in response to oscillatory shear and creep-recovery experiments, which highlights the potential clinical benefits of better understanding sputum viscoelasticity. A common power law model G(t)=G0(ttau0)-m was successfully fitted to experimental rheology data over the range of frequencies studied. CONCLUSIONS: A comparison between clinical data and the power law index m obtained from rheology, suggested that an important possible future application of this parameter is as a potential biomarker for COPD severity. PMID- 29278869 TI - Effect of glenohumeral stabilization exercises combined with scapular stabilization on shoulder function in patients with shoulder pain: A randomized controlled experimenter-blinded study. AB - BACKGROUND: Shoulder stabilization exercises consisted of a glenohumeral stabilization and scapular stabilization. No studies have been assessed the superiority of shoulder stabilization until now. OBJECTIVE: To compare the effect of a glenohumeral stabilization exercise (GSE) combined with a scapular stabilization exercise (SSE) on changes in shoulder function in patients with shoulder painMETHODS: Shoulder stability, scapular alignment, pain, muscle power, and range of motion (ROM) were measured before and after the intervention in both groups. RESULTS: Forty subjects with shoulder pain were randomly assigned to an experimental or control group. GSE in the experimental group (n= 20) resulted in significantly better shoulder stability (P= 0.020, from 9.00 +/- 6.90 score to 14.25 +/- 8.58) and pain intensity (P= 0.042, 7.40 +/- 2.44 score to 4.60 +/- 2.06) compared to SSE in the controls (n= 20). However, no significant effects were observed for scapular symmetric alignment including the angles of inferior scapular distance (P= 0.555) and inferior scapular height difference (P= 0.770), muscle power including shoulder flexion (P= 0.942) and shoulder abduction (P= 0.551), or ROM including shoulder flexion (P= 0.852) and shoulder abduction (P= 0.622). CONCLUSION: This study suggests that GSE positively affects shoulder stability and pain control in patients with shoulder pain, probably through a centralization effect on the shoulder mechanism. PMID- 29278870 TI - The effect of stabilization exercises on diaphragm muscle thickness and movement in women with low back pain. AB - BACKGROUND: Diaphragm is an important component of spinal stability. In presence of low back pain, there may be some alterations in this muscle like other muscles that are responsible for lumbal stabilization. OBJECTIVE: This study aims to assess the effects of stabilization exercises on diaphragm muscle thickness and motion along with lumbopelvic stability. METHODS: Twenty-one women with low back pain participated in the study. Stabilization exercises including motor control training were performed on treatment group (n= 11). In control group (n= 10), strentghening exercises were peformed for back muscles, abdominal muscles and hip muscles. The patients underwent a total of 30 sessions of treatment, 3 days in a week for 10 weeks. The diaphragm muscle thickness and motion was evaluated using ultrasound (US), and lumbopelvic stability was evaluated using lumbopelvic stability tests. RESULTS: After the treatment, in the treatment group, increase in diaphragm thickness and improvement in lumbopelvic stability were statically significant (p< 0.05). However, there were no significant changes in diaphragm motion in both groups (p> 0.05). CONCLUSIONS: As a result, stabilization exercises increase diaphragm muscle thickness and improve lumbopelvic stability in women with low back pain. Therefore, stabilization exercises should be considered as a part of the treatment program in low back pain. PMID- 29278871 TI - The effect of surface neuromuscular electrical stimulation on patients with post stroke dysphagia. AB - OBJECTIVE: To assess whether the clinical efficacy of a therapeutic protocol using surface neuromuscular electrical stimulation (sNMES) on patients with post stroke dysphagia (PSD) is superior to that without sNMES, and whether swallowing functional outcome is different with regards to different electrode placement on patients' skin of neck. METHODS: Thirty patients with PSD were randomly allocated into treatment group A (TGA), treatment group B (TGB) and control group according to a random number table. The three groups of patients all received traditional dysphagia therapy (TDT) and other general rehabilitation therapy such as physical therapy and occupational therapy as a basic treatment project. Besides this, sNMES treatment was applied on different sites of patients' neck skin in group A and B separately. All the patients received video-fluoroscopic swallowing study (VFSS) pre-treatment and 2 weeks post-treatment, during which the displacement of the hyolaryngeal complex towards the superior and anterior sides while swallowing semi-liquid diet were measured. Outcome of the VFSS was measured using dysphagia outcome and severity scale (DOSS). RESULTS: Post-treatment evaluation was carried out using water swallow test (WST), repetitive saliva swallowing test (RSST) and dysphagia outcome and severity scale (DOSS) from the three study groups were all improved (P< 0.05). The results of post-treatment evaluation using WST from TGA and TGB were 2.40 +/- 1.26 and 2.10 +/- 0.99 respectively, using RSST from TGA and TGB were 5.30 +/- 1.89 and 5.20 +/- 1.69 respectively, using DOSS from TGA and TGB were 5.20 +/- 1.40 and 5.10 +/- 1.45 respectively. Compared to control group, the results of post-treatment evaluation using the three scales, there were significant improvement between TGA and TGB (P< 0.05), however, the inter group differences of TGA and TGB indicated no statistically significant difference (P> 0.05). The post-treatment evaluation of the moving distance of hyoid bone towards anterior side in swallowing was significantly improved as compared to TGB (-8.40 +/- 7.48, t=-3.552, P= 0.006), and was statistically significant as compared to the control group (P> 0.05). CONCLUSIONS: Swallowing function in the patients with PSD was significantly improved using TDT combined with NMES. Stimulating electrodes placed at the suprahyoid region or on both suprahyoid and infrahyoid regions resulted in no difference of effect. However, NMES on suprahyoid region could further improve the moving distance of hyoid bone anteriorly. PMID- 29278872 TI - Long-term effects of exercise programs among helicopter pilots with flying related LBP. AB - BACKGROUND: Flying related transient Low Back Pain (LBP) among helicopter pilots is considered an occupational distress. OBJECTIVE: To examine if exercise programs can alleviate transient LBP. METHODS: Sixty-five helicopter pilots (92% males), all reporting flying related LBP, responded to an epidemiological survey and a long-term follow-up, 44.8 months later, comprising questions regarding transient LBP and number of sick leaves. Data from 37 pilots participating in two exercise programs, A; general for LBP, B; focused for lumbar trunk (LT), included information from clinical examinations and muscular endurance tests of the LT before and after intervention. Twenty-eight pilots did not participate in any intervention. RESULTS: At long-term follow-up 42% of the pilots still reported flying related transient LBP. Among participants in program B 26% had persistent pain, 70% in program A and 46% among pilots without intervention. Sick-leave reduction was only observed among participants in program B (30% to 4%). Upon re occurrence of LBP symptoms, half of the pilots in program B again performed exercises to improve their pain. CONCLUSION: This study indicates that exercise programs focused towards lumbar trunk muscular endurance reduces flying related transient LBP and sick-leave among helicopter pilots. These findings may have implications for the pilots' working conditions. PMID- 29278873 TI - Increased high-mobility group A2 correlates with lymph node metastasis and prognosis of non-small cell lung cancer. AB - BACKGROUND: High-mobility group A2 (HMGA2) has been investigated to be associated with tumorigenesis; however, the expression pattern and clinical significance of HMGA2 in non-small cell lung cancer (NSCLC) remains poorly understood. The purpose of this study is to examine the expression of HMGA2 and to analyze its relationships with respect to clinico-pathological features and patient survival in NSCLC. METHODS: The expression level of HMGA2 was examined by Western blot and immunohistochemistry in NSCLC cells and tissues. The relationship between HMGA2 expression and survival of NSCLC patients was calculated by a Kaplan-Meier method and the evaluation of risk factor was determined by the multiple regression analysis. RESULTS: NSCLC tissues exhibited a higher expression level of HMGA2 compared to normal tissues (p< 0.05) and the expression level of HMGA2 was significantly associated with poor differentiation of NSCLC (p< 0.05), lymph node metastasis (p< 0.05) and advanced clinical stage (p< 0.05). Besides, HMGA2 was also confirmed to be elevated in NSCLC cells by Western blot. Moreover, increased expression of HMGA2 correlated with decreased survival of NSCLC patients (p< 0.05). CONCLUSIONS: HMGA2 was highly expressed in NSCLC tissues and cells and its overexpression was correlated with low-grade differentiation, lymph node metastasis, advanced clinical stage and poor survival time of NSCLC, which suggested that it could serve as a potential molecular marker and prognostic index for NSCLC. PMID- 29278874 TI - Silencing the autophagy-specific gene Beclin-1 contributes to attenuated hypoxia induced vasculogenic mimicry formation in glioma. AB - OBJECTIVE: To explore the influence of Beclin-1 on vasculogenic mimicry (VM) induced by hypoxia in glioma. METHODS: CD34-PAS staining was carried out to observe VM formation, and immunohistochemistry was used to determine the expression levels of Beclin-1, HIF-1alpha, VEGF and MMP2 in 105 patients with primary glioma. Human glioma U87MG cells were divided into Normoxia, Hypoxia, Hypoxia + NC siRNA and Hypoxia + Beclin-1 siRNA groups. Cobalt chloride (CoCl2) was used to stimulate hypoxic conditions, and a VM tube formation assay was used to detect VM formation. Wound healing and Transwell invasion assays were used to detect the invasive and migratory abilities of U87MG cells, respectively. Fluorescent LC3 puncta analysis was performed to examine the status of autophagic flux. Expression levels of Beclin-1 and VM-related molecules were determined using real-time quantitative-polymerase chain reaction (RT-qPCR) and western blotting. RESULTS: There were 34 VM-positive cases and 71 VM-negative cases among 105 glioma patients, and VM formation was correlated with pathological grade and the expression of Beclin-1, HIF-1alpha, VEGF and MMP2. Positive relations were found between Beclin-1 and the expression of HIF-1alpha, VEGF and MMP2. Under hypoxic conditions, significant increases in the total length of tubes, migration rate, invasion cell number and expression of VM-related molecules were found in U87MG cells. Silencing Beclin-1 markedly decreased hypoxia-induced VM formation and the invasive and migratory abilities, together with the expression of VM related molecules, in U87MG cells and significantly inhibited the autophagic flux. CONCLUSION: Silencing Beclin-1 can attenuate hypoxia-induced VM formation and the metastatic ability of U87MG cells and is a potential target for VM inhibition in glioma. PMID- 29278875 TI - LINC00261 suppresses cell proliferation, invasion and Notch signaling pathway in hepatocellular carcinoma. AB - BACKGROUND: Recent findings have identified thousands of long non-coding RNAs (lncRNAs) and reveal that lncRNAs play crucial roles in the regulation of tumor development and progression. However, the clinical significance and potentially functional value of LINC00261 in hepatocellular carcinoma (HCC) remain unknown. METHODS: Expression of LINC00261 was detected by qRT-PCR in HCC tissues and adjacent normal tissues. Kaplan-Meier analysis was used to assess the relationship between LINC00261 expression and the overall survival (OS) time. Cell proliferation and invasion were evaluated using MTT assay, cell colony formation assay and transwell assay. The protein expression was determined by western blot analysis. RESULTS: In present study, we confirmed that LINC00261 was frequently lower in HCC tissues compared to adjacent normal tissues. Decreased LINC00261 expression associated with lager tumor size, TNM stage (III-IV) and poor overall survival time of HCC patients. The functional assays demonstrated that overexpression of LINC00261 in HCC cells inhibited cell proliferation, cell colony formation, cell invasion and EMT process in vitro. Moreover, we also demonstrated that upregulation of LINC00261 significantly inhibited Notch signaling by downregulating Notch1 and Hes-1 expression in HCC cells. CONCLUSION: These results indicated that LINC00261 may be a potential target of HCC treatment. PMID- 29278876 TI - Elevated levels of serum nidogen-2 in esophageal squamous cell carcinoma. AB - BACKGROUND: Nidogen-2 (NID2), a secretory basement membrane protein, has been implicated as a potential biomarker in ovarian cancer and hepatocellular carcinoma. OBJECTIVE: In this study, we aimed to investigate the utility of detecting serum NID2 levels for identification of esophageal squamous cell carcinoma (ESCC) patients and prediction of poor survival outcome. METHODS: Using an in-house NID2 enzyme-linked immunosorbent assay (ELISA), serum samples from 101 ESCC patients and 50 healthy controls were screened for their NID2 levels. RESULTS: The serum NID2 levels in ESCC patients (median 24.4 MUg/L) are significantly higher (p= 4.3e-09) than that of the healthy controls (median 15.85 MUg/L). The receiver operating characteristic (ROC) curve demonstrated an area under the curve of 0.756. At the threshold of 17.95 MUg/L, the sensitivity and specificity achieved are 0.76 and 0.63, respectively. Kaplan-Meier survival analysis revealed that patients with high serum NID2 levels (? 32.6 MUg/L) have significantly higher risk of death (HR = 1.984, 95% CI: 1.175-3.349; log-rank p value = 0.012) compared to those with low serum NID2 levels (< 20.0 MUg/L). CONCLUSIONS: In conclusion, we show that detecting the elevation of serum NID2 levels has potential diagnostic and prognostic value for ESCC patients. PMID- 29278877 TI - Deregulation of sialidases in human normal and tumor tissues. AB - BACKGROUND: Aberrant sialylation is a characteristic feature associated with cancer. The four types of mammalian sialidases identified to date have been shown to behave in different manners during carcinogenesis. While NEU1, NEU2 and NEU4 have been observed to oppose malignant phenotypes, the membrane-bound sialidase NEU3 was revealed to promote cancer progression. OBJECTIVES: With the aim of improving the knowledge about sialidases deregulation in various cancer types, we investigated the amount of NEU1, NEU3 and NEU4 transcripts in paired normal and tumor tissues from 170 patients with 11 cancer types. METHODS: mRNA was extracted from patients' tissue specimens and retrotranscribed into cDNA, which was quantified by Real-Time PCR. RESULTS: We found NEU1 and NEU3 to be up regulated, while NEU4 was down regulated in most cancer types. In particular, colorectal cancer tissues showed the highest increase in NEU3 expression. Both NEU1 and NEU3 showed a strong up-regulation in ovarian cancer. CONCLUSIONS: Our data show that human sialidases are expressed at different levels in healthy tissues and are strongly deregulated in tumors. Moreover, sialidases expression in our European cohort showed significant differences from Asian populations. Some of these peculiar features open potential applications of sialidases in cancer diagnosis and therapy. PMID- 29278878 TI - Impact of etiology of chronic liver disease on hepatocellular carcinoma biomarkers. AB - BACKGROUND: The role of serum biomarkers in the surveillance of hepatocellular carcinoma (HCC) is controversial. OBJECTIVE: We assessed the diagnostic performances of alpha-fetoprotein (AFP) and protein-induced by vitamin-K absence/antagonist-II (PIVKA-II) in 388 cirrhotic patients with chronic liver disease (CLD). METHODS: Biomarkers were quantified by automated chemiluminescent enzyme-immunoassays (Fujirebio, Tokyo, Japan) at HCC diagnosis in 258 patients (204 males; median age 66.9 years) and in 130 cirrhotics without HCC (104 males; median-age 60.6 years). CLD etiology in HCC/non-HCC was CHB in 48/35, CHC in 126/56 and Non-Viral in 84/39. RESULTS: Overall AUROC values for AFP and PIVKA-II were 0.698 (95%CI = 0.642-0.753, P< 0.001) and 0.780 (95%CI = 0.730-0.831, P< 0.001). AFP/PIVKA-II AUROC (95%CI) were: 0.822 (0.728-0.915)/0.833 (0.739-0.926) in CHB, 0.648 (0.560-0.736)/0.732 (0.650-0.814) in CHC; 0.640 (0.540-0.740)/0.806 (0.722-0.889) in Non-Viral-CLD. AFP/PIVKA-II diagnostic accuracy was 40.5 59.8%/62.7-73.5% and combining both markers 78.2% for CHB, 77% for Non-Viral-CLD and 75% for CHC. AFP correlated with ALT in HCC patients with CHC (rho= 0.463/P< 0.001) and Non-Viral CLD (rho= 0.359/P= 0.047), but not in CHB (treated with antivirals). PIVKA-II correlated with tumour size independently of CLD-etiology (P< 0.001) and AFP in CHB patients only (P= 0.007). CONCLUSION: The diagnostic performance of AFP and PIVKA-II is significantly influenced by the etiology and activity of CLD; their combination provides a better diagnostic accuracy. PMID- 29278879 TI - Overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-beta1/ Smad signaling pathway. AB - Long non-coding RNAs (lncRNAs) were playing critical roles in tumorigenesis. However, in prostate cancer, the roles and mechanisms of lncRNAs especially ANRIL were largely unknown. We investigated the effects of ANRIL on the proliferation and migration of prostate cancer cells using CCK-8 assay and Transwell migration assay. Real-time PCR and western blotting assays were used to analyze the levels of ANRIL, let-7a, TGF-beta1, p-Smad2 and p-Smad7. Our results showed that ANRIL was significantly overexpressed in prostate cancer tissues compared with corresponding normal tissues. Knockdown of ANRIL significantly inhibited the proliferation and migration of prostate cancer LNCap, PC3 and DU145 cells. Knockdown of ANRIL significantly decreased the levels of TGF-beta1 and p-Smad2, and increased the level of p-Smad7 in prostate cancer LNCap cells. We further found that knockdown of ANRIL significantly enhanced the expression of let-7a, and rescue experiment found that let-7a inhibitor recovered the suppressive effects of ANRIL silencing on the proliferation and migration of prostate cancer LNCap, PC3 and DU145 cells. And let-7a inhibitor recovered the suppressive effects of ANRIL silencing on the activity of TGF-beta1/Smad signaling pathway in prostate cancer LNCap cells. Taken together, our findings indicated that overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-beta1/Smad signaling pathway. PMID- 29278880 TI - Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes. AB - BACKGROUND: The option of endocrine therapy in breast cancer remains conventionally promising. OBJECTIVE: We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. METHODS: In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). RESULTS: Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, P< 0.001; sensitivity = 83.0%, specificity = 65.2% and diagnostic odds ratio, DOR = 12.0) and strongly correlated with ER-/PR- conditions (Cramer's V= 0.44, P< 0.001). Methylated PgRb promoter frequently was observed in tumors recognised as ER- or negative ER/PR (77.1%, P< 0.01). Assessment of DNA methylation of ESR1 harbouring methylation at PgRb was a case significantly suggested to be able to detect the lack of ER/PR expressions (55.6%, P< 0.01; sensitivity = 80.6%, specificity = 68.7% and DOR = 8.7). However, methylated PgRb was quite acceptable determinant to contribute with methylated ESR1 to rank tumors as ER-/PR- (64.4%, P< 0.01; sensitivity = 78.0%, specificity = 62.5% and DOR = 6.0). CONCLUSIONS: Despite the methylation status of ESR1 showed preponderant contribution to tumoral phenotypes of ER- and ER-/PR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer. PMID- 29278882 TI - Serine/arginine rich splicing factor 2 expression and clinic pathological features indicating a prognostic factor in human hepatocellular carcinoma patients. AB - BACKGROUND: This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC). METHODS: One hundred and fifty three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed. RESULTS: In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 +/- 2.82), which was significantly higher than that in adjacent normal tissues (2.94 +/- 1.23) (P< 0.05). The expression of SRSF2 in HCC was not associated with gender (chi2= 0.014, P= 0.906), age (chi2= 0.007, P= 0.931), tumor size (chi2= 3.566, P= 0.059) and T stage (chi2= 2.708, P= 0.100), and was significantly correlated with tumor differentiation (chi2= 9.687, P= 0.007), lymph node metastasis (chi2= 4.827, P= 0.028), distal metastasis (chi2= 9.235, P= 0.002), tumor, node, metastasis (TNM) stage (chi2= 3.978, P= 0.046), portal vein invasion and serum alpha-fetoprotein (chi2= 14.919, P= 0.000). The expression of SRSF2 protein in hepatocellular carcinoma was positively correlated (r = 0.704, P< 0.05) with serum alpha fetoprotein through Pearson analysis. The survival rates of SRSF2 overexpressing hepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%). CONCLUSION: SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node metastasis and metastasis of tumor cells, and is positively related to serum alpha fetoprotein content, and affects the postoperative survival time of HCC patients. PMID- 29278881 TI - Effects of exogenous IL-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T cells. AB - BACKGROUND: This study aims to investigate the effects of exogenous interleukin (IL)-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T (Treg) cells. METHODS: After isolating the CD4+ CD25+ Treg cells from the peripheral blood, flow cytometry was used to detect the purity of the Treg cells. A549 cells were divided into blank (no transfection), empty plasmid (transfection with pIRES2-EGFP empty plasmid) or IL 37 group (transfection with pIRES2-EGFP-IL-37 plasmid). RT-PCR was used to detect mRNA expression of IL-37 and ELISA to determine IL-37 and MMP-9 expressions. Western blotting was applied to detect the protein expressions of PCNA, Ki-67, Cyclin D1, CDK4, cleaved caspase-3 and cleaved caspase-9. MTT assay, flow cytometry, scratch test and transwell assay were performed to detect cell proliferation, cycle, apoptosis, migration and invasion. Effect of exogenous IL 37 on the chemotaxis of Treg cells was measured through transwell assay. Xenograft models in nude mice were eastablished to detect the impact of IL-37 on A549 cells. RESULTS: The IL-37 group had a higher IL-37 expression, cell apoptosis in the early stage and percentage of cells in the G0/G1 phase than the blank and empty plasmid groups. The IL-37 group had a lower MMP-9 expression, optical density (OD), percentage of cells in the S and G2/M phases, migration, invasion and chemotaxis of CD4+CD25+ Foxp3+ Treg cells. The xenograft volume and weight of nude mice in the IL-37 group were lower than those in the blank and empty plasmid groups. Compared with the blank and empty plasmid groups, the IL-37 group had significantly reduced expression of PCNA, Ki-67, Cyclin D1 and CDK4 but elevated expression of cleaved caspase-3 and cleaved caspase-9. CONCLUSION: Therefore, exogenous IL-37 inhibits the proliferation, migration and invasion of human lung adenocarcinoma A549 cells as well as the chemotaxis of Treg cells while promoting the apoptosis of A549 cells. PMID- 29278883 TI - MicroRNA-152 inhibits tumor cell growth while inducing apoptosis via the transcriptional repression of cathepsin L in gastrointestinal stromal tumor. AB - OBJECTIVE: MicroRNAs are widely thought to play a regulatory role in gene expression. Although the more unique microRNA expression profiles have been reported in several tumors, there remains a scarcity of knowledge in relation to microRNA expression profiles in GISTs. During this study, through the alteration in the expression of microRNA-152 (miR-152) in gastrointestinal stromal tumor (GIST) cells, we subsequently evaluated its ability to influence the processes associated with cancer, including proliferation, migration, invasion, and apoptosis, as well as the associated mechanisms. METHODS: The expression of miR 152 and cathepsin L (CTSL) in GIST cell lines (GIST882, GIST430, GIST48 and GIST T1) and normal gastric mucosal cell line RGM-1 were determined. A series of miR 152 mimics, miR-152 inhibitors, and siRNA against CTSL were introduced to treat GIST-T1 cells with the lowest miR-152 and the highest CTSL were assessed. Cell viability, cell cycle entry, apoptosis, and cell migration/invasion were all evaluated by means of CCK-8 assay, flow cytometry analyses of Annexin V-FITC/PI staining, and transwell assays. RESULTS: The target prediction program and luciferase reporter gene assay verified CTSL is the target of miR-152. Regarding the biological significance of miR-152, siRNA knockdown and ectopic expression studies revealed that miR-152 mimic or siRNA against CTSL exposure reduced cell viability and migration/invasion, which resulted in more cells arrested at the S stage, and induced apoptosis. MiR-152 inhibitor exposure was observed to have induced effects on CTSL cells as opposed to those induced by that of the miR-152 mimics. In contrast, miR-152 downregulation abrogated the effects induced by siRNA against CTSL treatment. CONCLUSION: The key findings of this study provided evidence suggesting that miR-152 functions by means of binding to CTSL to induce GIST cell apoptosis and inhibit proliferation, migration, and invasion. The anti tumor role of miR-152 makes it an attractive therapeutic target for GIST. PMID- 29278884 TI - Decreased expression of PTH1R is a poor prognosis in hepatocellular carcinoma. AB - BACKGROUND AND AIM: Hypercalcemia is a potentially fatal and not rare complication of hepatocellular carcinoma (HCC), and its underlying mechanism remains unclear. Parathyroid hormone (PTH) is the most important regulator of the concentrations of calcium and phosphate in blood; parathyroid hormone-related protein (PTHrP) was the most frequent cause of humoral hypercalcemia of malignancy; parathyroid hormone 1 receptor (PTH1R) is the common receptor for PTH and PTHrP. The aim of this study is to investigate the expression of PTH, PTHrP, and PTH1R in HCC tissues, and their relationship with clinical pathological characters in HCC. METHODS: First, a meta-analysis based on online Oncomine Expression Array database was conducted to compare the different mRNA expression of PTH1R, PTH and PTHrP between hepatocellular carcinoma and normal tissues. Then, the protein expression level of differentially expressed gene was examined by immunohistochemistry staining in 223 HCC tissues and 102 non-tumorous liver tissues controls. The relationship between the protein expression and clinicopathological parameters was analyzed by chi2 test, and overall survival analysis was performed using Kaplan-Meier survival analysis. RESULTS: PTH1R mRNA expression was significantly lower in HCC tissues compared with normal tissues, while the expression of PTH and PTHrP showed no significant difference between HCC tissues and normal tissues. High PTH1R protein expression was found in 90/102 cases of adjacent non-tumorous liver tissues, and in 91 of 223 cases of HCC tissues. PTH1R expression was significantly related to tumor size, Edmondson Grade, AFP, and overall survival. CONCLUSIONS: PTH1R may be the major cause of hypercalcemia in HCC, and the decreased PTH1R expression was a poor prognosis in HCC. PMID- 29278886 TI - Combination of preoperative D-dimer and mean platelet volume predicts postoperative deep venous thrombosis in breast cancer patients. AB - BACKGROUND: Deep venous thrombosis (DVT) is associated with severe morbidity and mortality in cancer. Mean platelet volume (MPV) is an indicator of activated platelets. OBJECTIVE: We aimed to investigate whether the combination of D-dimer and MPV could have a better performance in predicting deep venous thrombosis (DVT) in patients with breast cancer. MEHTODS: In 342 consecutive breast cancer patients without preoperative DVT, we measured the preoperative D-dimer and MPV levels. Compression ultrasonography was performed in all breast cancer patients before surgery, as well as one month, three months, six months, and twelve months. RESULTS: During a median period of twelve months, 15 of the 234 patients (6.4%) developed DVT. MPV was reduced and D-dimer was increased in patients with DVT events compared to those without DVT. Multivariate Cox analysis revealed that both MPV and D-dimer were independent predictors for DVT events. The area under the ROC curve was 0.619 (95% CI: 0.553 to 0.681) when D-dimer was used alone, whereas it increased to 0.790 (95% CI 0.732 to 0.840, p< 0.001) with the addition of MPV. CONCLUSIONS: The combination of preoperative D-Dimer and MPV improves the predictive power of postoperative DVT risk in breast cancer patients. PMID- 29278885 TI - EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas. AB - PURPOSE: The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho mTOR in resected stage II-III adenocarcinomas. METHODS: Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. RESULTS: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3 year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). CONCLUSIONS: EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers. PMID- 29278887 TI - The Diagnostic and Prognostic Value of a Dual-Tasking Paradigm in a Memory Clinic. AB - BACKGROUND: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI). OBJECTIVE: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer's disease (AD) and to evaluate the association between the dual tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers. METHODS: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly. RESULTS: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p < 0.01). Logistic regression analyses revealed a low prognostic value of the dual tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed. CONCLUSION: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting. PMID- 29278888 TI - Healthy versus Entorhinal Cortical Atrophy Identification in Asymptomatic APOE4 Carriers at Risk for Alzheimer's Disease. AB - Early detection of Alzheimer's disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the E4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE E4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments. Using a virtual navigation task developed in-house, specifically designed to assess spatial versus non-spatial strategies, the current study is the first to differentiate functional and structural differences within APOE E4 allele carriers. APOE E4 allele carriers that predominantly use non-spatial strategies have decreased fMRI activity in the hippocampus and increased atrophy in the hippocampus, entorhinal cortex, and fimbria compared to APOE E4 allele carriers who use spatial strategies. In contrast, APOE E4 allele carriers who use spatial strategies have grey matter levels comparable to non-APOE E4 allele carriers. Furthermore, in a leave-one-out analysis, grey matter in the entorhinal cortex could predict navigational strategy with 92% accuracy. PMID- 29278890 TI - Prevalence of Potentially Inappropriate Medication Use in Older Inpatients with and without Cognitive Impairment: A Systematic Review. AB - BACKGROUND: Older people with cognitive impairment, including dementia and delirium, are high users of acute care services internationally. Potentially inappropriate medication (PIM) use may be associated with adverse outcomes, including hospital re-admission, functional disability, and mortality. OBJECTIVE: This systematic review aimed to quantify and compare the prevalence of PIMs in older inpatients with and without cognitive impairment. METHODS: A systematic search of observational studies was performed independently assessed by two reviewers in Embase, Medline, PsycINFO, International Pharmaceutical Abstracts, Scopus, and Informit. Articles published in English during the period January 2007-June 2017 that reported PIM prevalence in hospital inpatients >= 65 years were included. PIMs were defined as the presence of polypharmacy (multiple medication use) and using implicit or explicit tools, such as the Beers criteria, and 'Screening Tool of Older Person's Prescriptions' (STOPP). RESULTS: 47 articles were included. In studies measuring polypharmacy (n = 15), the prevalence of PIMs ranged from 53.2% to 89.8% and 30.4% to 97.1% for inpatients with and without cognitive impairment, respectively, and 24.0% to 80.0% when cognitive status was unreported. In studies employing explicit and implicit tools (n = 35), the prevalence of PIMs when cognitive impairment was reported ranged from 20.6% to 80.5% using the Beers criteria, and 39.3% to 88.5% using STOPP. When cognitive status was unreported, the prevalence of PIMs ranged from 7.0% to 79.2% using the Beers criteria, and 20.0% to 63.4% using STOPP. CONCLUSION: Our findings suggest a high prevalence of PIMs in older inpatients with and without cognitive impairment. Future studies should investigate the impact of PIM use on patient-centered outcomes, such as functional status and quality of life, to inform enhanced acute care services. PMID- 29278889 TI - Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer's Disease Pathology in Down Syndrome. AB - BACKGROUND: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. OBJECTIVE: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. METHODS: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. RESULTS: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. CONCLUSION: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets. PMID- 29278891 TI - Cerebrospinal Fluid Amyloid-beta Levels are Increased in Patients with Insomnia. AB - Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer's disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-beta (Abeta), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Abeta and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Abeta42 levels were significantly increased in insomnia patients. However, no significant difference was found in Abeta40, total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Abeta40 and Abeta42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Abeta metabolism in the brain, thus increase the risk for developing AD. PMID- 29278892 TI - Tauopathies: Mechanisms and Therapeutic Strategies. AB - Tauopathies are morphologically, biochemically, and clinically heterogeneous neurodegenerative diseases defined by the accumulation of abnormal tau proteins in the brain. There is no effective method to prevent and reverse the tauopathies, but this gloomy picture has been changed by recent research advances. Evidences from genetic studies, experimental animal models, and molecular and cell biology have shed light on the main mechanisms of the diseases. The development of radiology and biochemistry, especially the development of PET imaging, will provide important biomarkers for the clinical diagnosis and treatment. Given the central role of tau in tauopathies, many treatments have constantly emerged, including targeting phosphorylation, targeting aggregation, increasing microtubule stabilization, tau immunization, clearance of tau, anti-inflammatory treatment, and other therapeutics. There is still a long way to go before we obtain drug therapy targeted at multifactor mechanisms. PMID- 29278893 TI - Prediction Model of Conversion to Dementia Risk in Subjects with Amnestic Mild Cognitive Impairment: A Longitudinal, Multi-Center Clinic-Based Study. PMID- 29278894 TI - Asymmetric Ataxia, Depression, Memory Loss, Epilepsy, and Axonal Neuropathy Associated with A Heterozygous DNA Polymerase Gamma Variant of Uncertain Significance, c1370G>a (R457Q). AB - INTRODUCTION: Mutations in the gene encoding DNA polymerase gamma (POLG) impair its ability to proofread mitochondrial DNA (mtDNA) during replication [1]. This results in a high frequency of randomly distributed mtDNA mutations and thus a wide range of phenotypes, including seizures, neuropathy, and cerebellar ataxia [1, 2]. We document a phenotype associated with the rare POLG variant c.1370G>A (p.R457Q). METHODS: Over 10 years, we performed electrodiagnostic and neuropsychologic on a patient who presented with a variety of neurologic symptoms. RESULTS: Testing revealed an axonal sensorimotor polyneuropathy, depression and executive function difficulties, and asymmetric ataxia. Genetic testing revealed a POLG variant of uncertain significance (c.1370G>A, p.R457Q) in a heterozygous state. CONCLUSIONS: We have identified a mutation in POLG that could result in a diverse array of symptoms and signs of our patient. However, interpreting pathogenicity of rare variants such as R457Q is challenging and will likely require identification of patients with similar phenotypes caused by the variant of uncertain significance. PMID- 29278896 TI - Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, X-linked genetic disease that results in progressive muscle loss and premature death, most commonly from respiratory or cardiac failure. DMD is primarily caused by whole exon deletions, resulting in a shift of the dystrophin mRNA reading frame that prevents production of functional dystrophin protein. Eteplirsen, a phosphorodiamidate morpholino oligomer (PMO), is designed to skip exon 51, restore the reading frame, and induce production of internally shortened dystrophin in patients with mutations amenable to such treatment. OBJECTIVE: Describe lung function assessed throughout eteplirsen studies 201/202. METHODS: Studies 201/202 included 12 patients treated with eteplirsen over 5 years. Pulmonary function tests included forced vital capacity (FVC), maximum expiratory pressure (MEP), and maximum inspiratory pressure (MIP). With no long-term placebo control, FVC results were compared with data from the United Dystrophinopathy Project (UDP). MIP and MEP were compared to published natural history. RESULTS: Age-adjusted mixed-model repeated-measures analysis showed decreases of 2.3% and 2.6% annually for FVC% p and MEP% p, and an annual increase of 0.6% for MIP% p for the eteplirsen-treated cohort. Data from the UDP demonstrated a 4.1% decline in FVC% p. The published natural history reports annual declines of at least 2.7% and 3.8% for MEP% p and MIP% p, respectively, in patients with DMD. CONCLUSIONS: With eteplirsen treatment, deterioration of respiratory muscle function based on FVC% p was half of that seen in the UDP; MEP% p and MIP% p compared favorably with natural history. PMID- 29278897 TI - Reliability of the Apathy Evaluation Scale in Myotonic Dystrophy Type 1. AB - BACKGROUND: Apathy is a common debilitating symptom of myotonic dystrophy type 1 (DM1). The Apathy Evaluation Scale (AES) has been identified as a promising measurement instrument to be used in DM1 but its metrological properties must be further documented. OBJECTIVE: To determine the internal consistency of the Self (AES-S), Informant (AES-I), and Clinician (AES-C) versions of the AES and to assess the test-retest reliability, standard error of measurement, and minimal detectable change of the AES-S and AES-I in a sample of DM1 patients and their related informants. RESULTS: All scales showed good internal consistency (Cronbach's alpha: 0.83-0.87) and the AES-S and AES-I showed good test-retest reliability (ICC = 0.79-0.91). Additionally, clinicians and informants had a tendency to overestimate DM1 patients' level of apathy compared to patients' self ratings, suggesting potentially impaired self-awareness in DM1 patients. CONCLUSIONS: The present results advocate the use of the AES-I as a reliable instrument to estimate apathy in DM1 patients for either clinical or research purposes, and support the relevance to pursue the assessment of metrological properties of the AES as a tool of great value for the development of outcomes for clinical trial readiness in DM1. PMID- 29278895 TI - Aberrant Caspase Activation in Laminin-alpha2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity. AB - BACKGROUND: Mutations in the LAMA2 gene encoding laminin-alpha2 cause congenital muscular dystrophy Type 1A (MDC1A), a severe recessive disease with no effective treatment. Previous studies have shown that aberrant activation of caspases and cell death through a pathway regulated by BAX and KU70 is a significant contributor to pathogenesis in laminin-alpha2-deficiency. OBJECTIVES: To identify mechanisms of pathogenesis in MDC1A. METHODS: We used immunocytochemical and molecular studies of human myogenic cells and mouse muscles-comparing laminin alpha2-deficient vs. healthy controls-to identify mechanisms that regulate pathological activation of caspase in laminin-alpha2-deficiency. RESULTS: In cultures of myogenic cells from MDC1A donors, p53 accumulated in a subset of nuclei and aberrant caspase activation was inhibited by the p53 inhibitor pifithrin-alpha. Also, the p53 target BBC3 (PUMA) was upregulated in both MDC1A myogenic cells and Lama2-/- mouse muscles. In addition, studies with sirtuin inhibitors and SIRT1 overexpression showed that caspase activation in MDC1A myotubes was inversely related to sirtuin deacetylase activity. Caspase activation in laminin-alpha2-deficiency was, however, not associated with increased phosphorylation of p38 MAPK. CONCLUSIONS: Aberrant caspase activation in MDC1A cells was mediated both by sirtuin deacetylase activity and by p53. Interventions that inhibit aberrant caspase activation by targeting sirtuin or p53 function could potentially be useful in ameliorating MDC1A. PMID- 29278900 TI - Longitudinal Diffusion-Weighted Whole-Body MRI Demonstrates Dynamic Changes in Muscle Integrity in Motor Neuron Disease. PMID- 29278899 TI - The Utility of the Laboratory Work Up at the Time of Diagnosis of Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Serological testing is routinely performed in the work up for a diagnosis of Amyotrophic Lateral Sclerosis (ALS) to exclude pathologies with similar clinical phenotypes. OBJECTIVE: To determine the proportion of serological workup that changes the primary diagnosis and/or clinical management for patients presenting with signs of ALS. METHODS: A retrospective chart review was conducted on patients from the Calgary Neuromuscular Intake Clinic in which the neurologist working diagnosis post-assessment is ALS. Charts from 2012 to 2016 with completed standard serological workup were reviewed. The proportion of abnormal results per investigation was determined and whether it resulted in a change in diagnosis and/or clinical management. RESULTS: A total of 276 charts were reviewed and 85 met full inclusion criteria. Serum creatine kinase (35%), vitamin B12 (18%), complete blood count with differential (11%), and parathyroid hormone (10%) were the among the investigations that had a proportion of abnormal results greater than 5%. Only 6% of patients had an abnormal result that qualified for a change in their clinical management none of which changed the primary diagnosis of ALS. CONCLUSIONS: Standard serological investigations in the work-up for a patient with ALS may have low utility from a diagnostic and management perspective. PMID- 29278898 TI - Diaphragm: Pathophysiology and Ultrasound Imaging in Neuromuscular Disorders. AB - Respiratory muscles are classically involved in neuromuscular disorders, leading to a restrictive respiratory pattern. The diaphragm is the main respiratory muscle involved during inspiration. Ultrasound imaging is a noninvasive, radiation-free, accurate and safe technique allowing assessment of diaphragm anatomy and function. The authors review the pathophysiology of diaphragm in neuromuscular disorders, the methodology and indications of diaphragm ultrasound imaging as well as possible pitfalls in the interpretation of results. PMID- 29278901 TI - Assessing the use of Radio Frequency Identification technologies as an alternative for insurance costs in hospitals. AB - OBJECTIVES: This research assesses the use of Radio Frequency Identification (RFID) technologies as an alternative for insurance costs in hospitals. METHODS: Despite the advantages of RFID, this technology has not been applied in most hospitals due to implementation costs and amortization of RFID. In this paper, we intend to model the total profit of hospitals in three scenarios namely, application of RFID technology in the hospital, without applying RFID technology in the hospital and insuring patients and equipment in the hospital. RESULTS: We analyzed the aforementioned situations over a period of time to find out how they affect the profit of the hospital. Based on this analysis we concluded that if applying RFID technology is costly, it will be feasible for advanced hospitals with more beds. In the scenario of insuring patients and equipment, if insurance organization takes over a small portion of the cost of the mistakes and oversights, insuring patients and equipment will not be feasible for the hospital, and it is better to apply RFID technology Instead. CONCLUSIONS: RFID is among the technologies applied to reduce mistakes of the personnel in hospitals. Moreover, applying this technology has led to a decrease in the number of personnel required in hospitals. This study models total profit of hospitals in three aforementioned scenarios. Based on analyzing these models we conclude that if applying RFID technology is costly, it will be feasible for advanced hospitals with more beds. PMID- 29278902 TI - Vaccination history in elementary school children enrolled in the varicella epidemic investigations held in Jeju-si, Korea in the first half of 2017. AB - OBJECTIVES: The reported incidence rate of varicella infection in Jeju-do is higher compared with the national average. This study aimed to examine varicella vaccination history and evaluate clinical manifestation of varicella cases in Jeju-do. METHODS: Based on the guideline suggested by the Korea Centers for Disease Control and Prevention (KCDC), two epidemic investigations for varicella infection were conducted in the first half of 2017. The history of varicella vaccination was confirmed using the Integrated Control System for Diseases and Health operated by the KCDC. RESULTS: Out of a total of 60 elementary school children as the study subjects, all had been previously vaccinated against varicella. Twenty cases (33%) showed mild clinical manifestations and no complications. CONCLUSIONS: As the government of Jeju-do has supplied a single labeled vaccine since 2011, there is a need to evaluate the type of vaccination failure such as primary or secondary. PMID- 29278903 TI - The reach of Spanish-language YouTube videos on physical examinations made by undergraduate medical students. AB - This study was conducted to evaluate the performance and reach of YouTube videos on physical examinations made by Spanish university students. We analyzed performance metrics for 4 videos on physical examinations in Spanish that were created by medical students at Miguel Hernandez University (Elche, Spain) and are available on YouTube, on the following topics: the head and neck (7:30), the cardiovascular system (7:38), the respiratory system (13:54), and the abdomen (11:10). We used the Analytics application offered by the YouTube platform to analyze the reach of the videos from the upload date (February 17, 2015) to July 28, 2017 (2 years, 5 months, and 11 days). The total number of views, length of watch-time, and the mean view duration for the 4 videos were, respectively: 164,403 views (mean, 41,101 views; range, 12,389 to 94,573 views), 425,888 minutes (mean, 106,472 minutes; range, 37,889 to 172,840 minutes), and 2:56 minutes (range, 1:49 to 4:03 minutes). Mexico was the most frequent playback location, followed by Spain, Colombia, and Venezuela. Uruguay, Ecuador, Mexico, and Puerto Rico had the most views per 100,000 population. Spanish-language tutorials are an alternative tool for teaching physical examination skills to students whose first language is not English. The videos were especially popular in Uruguay, Ecuador, and Mexico. PMID- 29278904 TI - Usefulness of the DETECT program for assessing the internal structure of dimensionality in simulated data and results of the Korean nursing licensing examination. AB - PURPOSE: The dimensionality of examinations provides empirical evidence of the internal test structure underlying the responses to a set of items. In turn, the internal structure is an important piece of evidence of the validity of an examination. Thus, the aim of this study was to investigate the performance of the DETECT program and to use it to examine the internal structure of the Korean nursing licensing examination. METHODS: Non-parametric methods of dimensional testing, such as the DETECT program, have been proposed as ways of overcoming the limitations of traditional parametric methods. A non-parametric method (the DETECT program) was investigated using simulation data under several conditions and applied to the Korean nursing licensing examination. RESULTS: The DETECT program performed well in terms of determining the number of underlying dimensions under several different conditions in the simulated data. Further, the DETECT program correctly revealed the internal structure of the Korean nursing licensing examination, meaning that it detected the proper number of dimensions and appropriately clustered the items within each dimension. CONCLUSION: The DETECT program performed well in detecting the number of dimensions and in assigning items for each dimension. This result implies that the DETECT method can be useful for examining the internal structure of assessments, such as licensing examinations, that possess relatively many domains and content areas. PMID- 29278905 TI - Clinical empathy in medical students in India measured using the Jefferson Scale of Empathy-Student Version. AB - PURPOSE: The purpose of this study was to assess the clinical empathy of a cohort of medical students spanning 4 years of undergraduate study and to identify factors associated with empathy. METHODS: A cross-sectional study to assess the empathy of undergraduate medical students at the University College of Medical Sciences and GTB Hospital in Delhi, India, was conducted using the Jefferson Scale of Empathy-Student Version. Demographic data were obtained using a pre tested, semi-open-ended questionnaire. RESULTS: Of the 600 students, 418 participated in the survey (69.7%). The mean empathy score was 96.01 (of a maximum of 140), with a standard deviation of 14.56. The empathy scores decreased from the first to the third semester, plateaued at the fifth semester, and rose again in the seventh semester. Empathy was found to be significantly associated with the gender of the participant, with females having higher scores (P<0.001). The age of the participant, place of residence, whose decision it was for the student to enroll in an MBBS (bachelor of medicine and bachelor of surgery) program, and the choice of future specialty were not significantly associated with students' empathy scores. CONCLUSION: The study found significant gender differences in empathy among the participants. The empathy scores tended to decline initially and then rebound over time. The mean empathy levels found in this study are lower than those reported in most similar studies around the world; therefore, further studies are needed to analyze and address the underlying factors associated with this discrepancy. PMID- 29278906 TI - The sights and insights of examiners in objective structured clinical examinations. AB - PURPOSE: The objective structured clinical examination (OSCE) is considered to be one of the most robust methods of clinical assessment. One of its strengths lies in its ability to minimise the effects of examiner bias due to the standardisation of items and tasks for each candidate. However, OSCE examiners' assessment scores are influenced by several factors that may jeopardise the assumed objectivity of OSCEs. To better understand this phenomenon, the current review aims to determine and describe important sources of examiner bias and the factors affecting examiners' assessments. METHODS: We performed a narrative review of the medical literature using Medline. All articles meeting the selection criteria were reviewed, with salient points extracted and synthesised into a clear and comprehensive summary of the knowledge in this area. RESULTS: OSCE examiners' assessment scores are influenced by factors belonging to 4 different domains: examination context, examinee characteristics, examinee examiner interactions, and examiner characteristics. These domains are composed of several factors including halo, hawk/dove and OSCE contrast effects; the examiner's gender and ethnicity; training; lifetime experience in assessing; leadership and familiarity with students; station type; and site effects. CONCLUSION: Several factors may influence the presumed objectivity of examiners' assessments, and these factors need to be addressed to ensure the objectivity of OSCEs. We offer insights into directions for future research to better understand and address the phenomenon of examiner bias. PMID- 29278907 TI - Neutralization efficiency of alcohol based products used for rapid hand disinfection AB - Background: Alcohols are the most commonly used active substances in preparations for quick hand disinfection. They should be bactericidal in very short contact time. PN-EN 13727 + A2: 2015-12 standard, for testing hygienic and surgical handrub disinfection preparations, provides mandatory test conditions of disinfectants in contact times with the range of 30 s to 60 s (hygienic handrub disinfection) and 60 s to 5 min (surgical handrub disinfection). A short contact times for hand hygiene products require a short time of neutralization process. For contact times less than or equal to 10 minutes,the estimated neutralization time is 10 s +/- 1 s. Neutralization is a process that abolishes the action of disinfectants. Correct application of this process allows for proper use of disinfectants in practice and its biocidal effect. Objectives. Verification of the effectiveness of 10-second neutralization time of alcohol based preparations for hygienic handrub disinfection Materials and Method: Neutralization of two products with different ethanol content (89% and 70%) for hygienic handrub disinfection according to PN-EN 13727 + A2: 2015-12 was investigated. The effectiveness of the neutralizer was assessed by determining toxicity of neutralizer, activity of residual effects of the tested products and their derivatives produced during neutralization (10 s) for test organisms (Staphylococcus aureus ATCC 6538; Pseudomonas aeruginosa ATCC 15442; Enterococcus hirae ATCC 10541; Escherichia coli K12 NCTC 10538) Results: The 10-second neutralization time was sufficient to eliminate the residual activity of products for hygienic handrub disinfection with differentiated ethanol concentration. The neutralizer used did not show toxicity to bacteria and did notproduce toxic products with tested preparations after neutralization Conclusions: Conclusions. The use of 10-second neutralization time allows in a precise way designate the contact times for hygienichandrub disinfection products PMID- 29278908 TI - Comprehensive Characterization of Extractable and Nonextractable Phenolic Compounds by High-Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight of a Grape/Pomegranate Pomace Dietary Supplement. AB - Grape and pomegranate are rich sources of phenolic compounds, and their derived products could be used as ingredients for the development of functional foods and dietary supplements. However, the profile of nonextractable or macromolecular phenolic compounds in these samples has not been evaluated. Here, we show a comprehensive characterization of extractable and nonextractable phenolic compounds of a grape/pomegranate pomace dietary supplement using high-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight (HPLC-ESI QTOF) and matrix-assisted laser desorption/ionization (MALDI)-TOF techniques. The main extractable phenolic compounds were several anthocyanins (principally malvidin 3-O-glucoside) as well as gallotannins and gallagyl derivatives; some phenolic compounds were reported in grape or pomegranate for the first time. Additionally, there was a high proportion of nonextractable phenolic compounds, including vanillic acid, and dihydroxybenzoic acid. Unidentified polymeric structures were detected by MALDI-TOF MS analysis. This study shows that mixed grape and pomegranate pomaces are a source of different classes of phenolic compounds including a high proportion of nonextractable phenolic compounds. PMID- 29278909 TI - Neuroprotective Effect of Hydroxytyrosol in Experimental Diabetic Retinopathy: Relationship with Cardiovascular Biomarkers. AB - The aim of the study was to test the neuroprotective effect of hydroxytyrosol (HT) on experimental diabetic retinopathy. Animals were divided in four groups: (1) control nondiabetic rats, (2) streptozotocin-diabetic rats (DR), (3) DR treated with 1 mg/kg/day p.o. HT, and (4) DR treated with 5 mg/kg/day p.o. HT. Treatment with HT was started 7 days before inducing diabetes and was maintained for 2 months. In the DR group, total area occupied by extracellular matrix was increased, area occupied by retinal cells was decreased; both returned to near control values in DR rats treated with HT. The number of retinal ganglion cells in DR was significantly lower (44%) than in the control group, and this decrease was smaller after HT treatment (34% and 9.1%). Linear regression analysis showed that prostacyclin, platelet aggregation, peroxynitrites, and the dose of 5 mg/kg/day HT significantly influenced retinal ganglion cell count. In conclusion, HT exerted a neuroprotective effect on diabetic retinopathy, and this effect correlated significantly with changes in some cardiovascular biomarkers. PMID- 29278910 TI - Novel Method of Constructing Two-Dimensional Correlation Spectroscopy without Subtracting a Reference Spectrum. AB - In this study, we propose a new approach to generate two-dimension spectra to enhance the intensity of cross peaks relevant to intermolecular interaction. We investigate intermolecular interaction between two solutes (denoted as P and Q, where P has a characteristic peak at XP) dissolved in the same solvent via the near diagonal cross peaks around the coordinate (XP, XP) in a two-dimensional (2D) asynchronous spectrum of generalized spectroscopy. Because of physical constrains in many cases, the variation ranges of the initial concentrations of P or Q must be kept very narrow, leading to very weak cross peak intensities. The weak cross peaks vulnerable to noise bring about difficulty in the investigation of subtle intermolecular interaction. Herein, we propose a new of way constructing a 2D asynchronous spectrum without the subtraction of the average spectrum often used as a reference spectrum. Mathematical analysis and computer simulation demonstrate that the near diagonal cross peaks around the coordinate (XP, XP) in the 2D asynchronous spectrum using the new approach possess two characteristics: (1) they can still reflect an intermolecular interaction reliably; 2) the absolute intensities of the cross peaks are significantly stronger than those generated by the conventional method. We incorporate the novel method with the DAOSD (double asynchronous orthogonal sample design scheme) approach and applied the modified DAOSD approach to study hydrogen bonding behavior in diethyl either/methanol/THF system. The new approach made the weak cross peaks, which are not observable in 2D asynchronous spectrum generated using conventional approach, become observable. The appearance of the cross peak demonstrate that When a small amount of THF is introduced into diethyl solution containing low amount of methanol, THF breaks the methanol-diethyl ether complex and forms methanol-THF complex via new hydrogen bond. This process takes place in spite of the fact that the content of diethyl ether is overwhelmingly larger than that of THF. The above result demonstrates that the new approach described in this article is applicable to enhance intensity of cross peaks in real chemical systems. PMID- 29278911 TI - Design, Synthesis, and Biological Evaluation of 68Ga-DOTA-PA1 for Lung Cancer: A Novel PET Tracer for Multiple Somatostatin Receptor Imaging. AB - Most of the radiolabeled somatostatin analogues (SSAs) are specific for subtype somatostatin receptor 2 (SSTR2). Lack of ligands targeting other subtypes of SSTRs, especially SSTR1, SSTR3, and SSTR5, limited their applications in tumors of low SSTR2 expression, including lung tumor. In this study, we aimed to design and synthesize a positron emission tomography (PET) radiotracer targeting multi subtypes of SSTRs for PET imaging. PA1 peptide and its conjugate with 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator or fluorescein isothiocyanate (FITC) at the N-terminal of the lysine position were synthesized. 68Ga was chelated to DOTA-PA1 to obtain 68Ga-DOTA-PA1 radiotracer. The stability, lipophilicity, binding affinity, and binding specificity of 68Ga-DOTA-PA1 and FITC-PA1 were evaluated by various in vitro experiments. Micro-PET imaging of 68Ga-DOTA-PA1 was performed in nude mice bearing A549 lung adenocarcinoma, as compared with 68Ga-DOTA-(Tyr3)-octreotate (68Ga-DOTA-TATE). Histological analysis of SSTR expression in A549 tumor tissues and human tumor tissues was conducted using immunofluorescence staining and immunohistochemical assay. 68Ga-DOTA-PA1 had high radiochemical yield and radiochemical purity of over 95% and 99%, respectively. The radiotracer was stable in vitro in different buffers over a 2 h incubation period. Cell uptake of 68Ga-DOTA-PA1 was 1.31-, 1.33-, and 1.90-fold that of 68Ga-DOTA-TATE, which has high binding affinity only for SSTR2, after 2 h incubation in H520, PG, and A549 lung cancer cell lines, respectively. Micro-PET images of 68Ga-DOTA-PA1 showed that the PET imaging signal correlated with the total expression of SSTRs, instead of SSTR2 only, which was measured by Western blotting and immunofluorescence analysis in mice bearing A549 tumors. In summary, a novel PET radiotracer, 68Ga-DOTA-PA1, targeting multi-subtypes of SSTRs, was successfully synthesized and was confirmed to be useful for PET imaging. It may have potential as a noninvasive PET radiotracer for imaging SSTR-positive tumors. PMID- 29278912 TI - Rotational Dynamics of Solutes with Multiple Single Bond Axes Studied by Infrared Pump-Probe Spectroscopy. AB - To investigate the relationship between the structural degrees of freedom around a vibrational probe and the rotational relaxation process of a solute in solution, we studied the anisotropy decays of three different N3-derivatized amino acids in primary alcohol solutions. By performing polarization-controlled IR pump-probe measurements, we reveal that the anisotropy decays of the vibrational probe molecules in 1-alcohol solutions possess two decay components, at subpicosecond and picosecond time scales. On the basis of results showing that the fast relaxation component is insensitive to the vibrational probe molecule, we suggest that the anisotropy decay of the N3 group on a subpicosecond time scale results from a local, small-amplitude fluctuation of the flexible vibrational probe, which does not depend on the details of its molecular structure. However, the slow relaxation component depends on the solute: with longer alkyl chains attached to the N3 group, the anisotropy decay of the slow component is faster. Consequently, we conclude that the slow relaxation component corresponds to the reorientational motion of the N3 group correlated with other intramolecular rotational motions (e.g., rotational motions of the neighboring alkyl chain). Our experimental results provide important insight into understanding the rotational dynamics of solutes with multiple single bond axes in solution. PMID- 29278913 TI - Imidazole Nitrogens of Two Histidine Residues Participating in N-H...N Hydrogen Bonds in Protein Structures: Structural Bioinformatics Approach Combined with Quantum Chemical Calculations. AB - Protein structures are stabilized by different types of hydrogen bonds. However, unlike the DNA double helical structure, the N-H...N type of hydrogen bonds is relatively rare in proteins. N-H...N hydrogen bonds formed by imidazole groups of two histidine residues have not been investigated. We have systematically analyzed 5333 high-resolution protein structures with resolution 1.8 A or better and identified 285 histidine pairs in which the nitrogen atoms of the imidazole side chains can potentially participate in N-H...N hydrogen bonds. The histidine pairs were further divided into two groups, neutral-neutral and protonated neutral, depending on the protonation state of the donor histidine. Quantum chemical calculations were performed on imidazole groups adopting the same geometry observed in the protein structures. Average interaction energies between the interacting imidazole groups are -6.45 and -22.5 kcal/mol for neutral-neutral and protonated-neutral, respectively. Hydrogen bond interaction between the imidazole moieties is further confirmed by natural bond orbital analyses of the model compounds. Histidine residues involved in N-H...N hydrogen bonds are relatively more buried and have low B-factor values in the protein structures. N H...N hydrogen bond formed by a pair of buried histidine residues can significantly contribute to the structural stability of proteins. PMID- 29278916 TI - Comparison of an InSb Detector and Upconversion Detector for Infrared Polarization Spectroscopy. AB - This paper compares the signal-to-noise ratio obtained using an InSb photodiode for infrared (IR) polarization spectroscopy to that obtained using an upconversion detector, and shows a factor 64 improvement by the change. Upconversion detection is based on using sum frequency generation to move the IR optical signal to near-visible wavelengths to improve the sensitivity. PMID- 29278915 TI - How is cardiac troponin released from injured myocardium? AB - Cardiac troponin I and cardiac troponin T are nowadays the criterion biomarkers for the laboratory diagnosis of acute myocardial infarction due to their very high sensitivities and specificities for myocardial injury. However, still many aspects of their degradation, tissue release and elimination from the human circulation are incompletely understood. Myocardial injury may be caused by a variety of different mechanisms, for example, myocardial ischaemia, inflammatory and immunological processes, trauma, drugs and toxins, and myocardial necrosis is preceded by a substantial reversible prelethal phase. Recent experimental data in a pig model of myocardial ischaemia demonstrated cardiac troponin release into the circulation from apoptotic cardiomyocytes as an alternative explanation for clinical situations with increased cardiac troponin without any other evidence for myocardial necrosis. However, the comparably lower sensitivities of all currently available imaging modalities, including cardiac magnetic resonance imaging for the detection of particularly non-focal myocardial necrosis in patients, has to be considered for cardiac troponin test result interpretation in clinical settings without any other evidence for myocardial necrosis apart from increased cardiac troponin concentrations as well. PMID- 29278917 TI - Experiences with unregulated respite care among family caregivers of children dependent on respiratory technologies. AB - Increasingly, children with respiratory conditions who are dependent on medical technology (e.g. ventilators and tracheostomies) are cared for at home by family caregivers who are at risk for significant health, financial and social burdens. In many jurisdictions, access to quality respite is varied and often the availability of regulated (nursing) providers is insufficient. Rather than go without, some families have secured alternative and unregulated providers to supplement formal home care systems. The purpose of this study was to explore the experiences of family caregivers of children dependent on respiratory technologies who have used unregulated providers for in-home respite care. Through an interpretative description approach, data was gathered from 20 semi structured parent interviews and analysed using constant comparative analysis. Four themes emerged from the data, which were conceptualized as both opportunities and tensions that parents experienced with both unregulated and regulated home care providers: finding the right fit for the child and family; trusting the provider is everything; using unregulated providers offers unique advantages; and accepting that regulated and unregulated care present challenges. Findings signal that unregulated providers play a pivotal role in supporting parents of children who are dependent on respiratory technologies. Implications for practice, policy and future research initiatives are discussed. PMID- 29278918 TI - Does Aging and Disease Increase the Importance of Cognitive Strategies? Social and Temporal Comparisons in Healthy Younger and Older Adults and in Younger and Older Cancer Patients. AB - Social and temporal comparisons may help the individual anchor his or her self image in a social and temporal context. In the Life-Span Theory of Control, comparisons are included in the repertoire of secondary control strategies individuals may apply when primary control strategies are obstructed, for example, by age-related losses or physical decline. The aim of this study was to explore differences in prevalence and effects of social and temporal comparisons in younger and older adults and healthy and diseased individuals ( n = 34). Semistructured interviews were conducted and analyzed using a mixed-methods approach combining qualitative and quantitative data analysis. The results revealed that older adults engaged in more comparisons than younger adults and that the outcomes of comparisons were more positive for older adults, particularly older cancer patients. The results indicate that comparisons may be applied more often by older and diseased individuals in the service of maintaining well-being. PMID- 29278920 TI - Muscle weakness and functional limitations in an ethnically diverse sample of older adults. AB - OBJECTIVES: Muscle weakness is often linked to functional limitations in older adults. However, certain demographic characteristics, such as ethnicity, may differentially impact the association between weakness and functional limitations. This investigation sought to (1) identify sex- and ethnically specific muscle weakness thresholds associated with functional limitations among older adults, and (2) determine the odds of functional limitations for each ethnicity by sex after identifying older adults below the weakness thresholds. DESIGN: Persons aged >=60 years from the 2011-2012 to 2013-2014 waves of the National Health and Nutrition Examination Survey identifying as non-Hispanic white, non-Hispanic black, Hispanic, or non-Hispanic Asian were included. Handgrip strength was normalized to each participant's body weight (normalized grip strength (NGS)). Participants responded to 19-items asking them about their ability to perform certain activities of daily living, instrumental activities of daily living, leisure and social activities, lower extremity mobility functions, and general physical activities. Receiver operating characteristic curves identified the optimal NGS thresholds associated with functional limitations. Covariate-adjusted multiple logistic regression models were performed to determine the odds of functional limitations for weak vs. not-weak participants. RESULTS: Of the 3,027 participants, the highest NGS thresholds for functional limitations were in non-Hispanic Asian males (0.41; p < 0.001) and Hispanic females (0.36; p < 0.001); whereas, the lowest NGS thresholds were in Hispanic males (0.25; p < 0.001) and non-Hispanic black females (0.23; p < 0.001). Weak non-Hispanic Asian males (odds ratio (OR): 10.42; 95% confidence interval (CI): 10.24, 10.61) and females (OR: 11.95; CI: 11.71, 12.19) had the highest odds for functional limitations compared to their non-weak counterparts. CONCLUSION: Preserving muscle strength, especially for certain older adult populations, may help reduce the odds of developing functional limitations. Interventions designed to increase muscle strength to preserve or improve function should consider the role of ethnicity when designing such interventions and identifying at risk populations. PMID- 29278921 TI - Management of hyperuricemia through dietary polyphenols as a natural medicament: A comprehensive review. AB - Hyperuricemia, a condition due to high serum uric acid level and is notorious to health. It is considered to be a potent risk factor for gout and dramatically associated in the development of many chronic diseases such as malignant tumor, cardiovascular disorders and renal failure. Modern innovative medicinal and therapeutic interventions are underlying these days to combat hyperuricemia. Previously reported studies revealed the significant impact of dietary polyphenols (e.g. anthocyanins, phenolic acids, flavonoids etc.) against hyperurecemia disorder. Dietary plant polyphenols, unlike anti- hyperuricemic agents, are not reported to have any side effects in curing hyperuricemia. The current comprehensive review figure outs the use of dietary polyphenols as a natural remedy for the management of hyperuricemia. The sources, affiliated pathways, mode of actions and factors affecting their efficiency to prevent hyperuricemia are deeply discussed in this article. Additionally, limitations and suggestions regarding previously reported studies are also highlighted. PMID- 29278922 TI - The weathering hypothesis and stillbirth: racial disparities across the life span. AB - OBJECTIVE: Given that studies have consistently demonstrated increased risk of stillbirth with increasing maternal age as well as race-ethnic disparities in stillbirth, the primary research question is how stillbirth risks within and between race-ethnic groups change with age. DESIGN: Using fetal death (stillbirth) and live birth data from the National Center for Health Statistics 2007-2014. We calculated crude stillbirth rates (per 1,000 deliveries). Using multivariable logistic regression, we calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for stillbirth across age groups to examine disparities in stillbirth among non-Hispanic blacks (blacks) and non-Hispanic whites (whites). RESULTS: Rates and risks of stillbirth increased as maternal age increased; however, the magnitude of risk varies by race-ethnicity. Compared to women less than 20, black women age 40+ had a risk of almost 3.5 times (aOR = 3.47, 95% CI = 3.24-3.70) whereas among white women age 40+, the risk was more than 2.5 times (aOR = 2.68, 95% CI = 2.55-2.82). The risk of stillbirth among blacks compared to whites increased, peaking at ages 30-34 (aOR = 2.64, 95% CI = 2.56-2.73). At age 35 and beyond, the disparity in risks declined. CONCLUSION: As age increased, the risk of stillbirth increased for both blacks and whites. Because the disparity in risk between blacks and whites did not continue to increase with age, stillbirth does not seem to reflect the weathering hypothesis as other perinatal outcomes do. PMID- 29278923 TI - Environmental Stressors and Their Impact on Health and Disease with Focus on Oxidative Stress. AB - Epidemiological, preclinical and interventional clinical studies have demonstrated that environmental stressors are associated with health problems, namely cardiovascular diseases. According to estimations of the World Health Organization (WHO), environmental risk factors account for an appreciable part of global deaths and life years spent with disability. This Forum addresses the impact of the environmental risk factors such as traffic noise exposure, air pollution by particulate matter (PM), mental stress/loneliness, and the life style risk factor (water-pipe) smoking on health and disease with focus on the cardiovascular system. We will critically discuss the use of observatory/modifiable biomarkers of oxidative stress and inflammation in environmental research on the aforementioned risk factors highlighting the need of exposome studies. Another focus will be on the epigenetic regulation via microRNAs in environmental stress upon exposure to noise and toxins/heavy metals as well as mental stress conditions, providing mechanistic insights into the modulation of microRNA signaling by oxidative stress, and vice versa the contribution of microRNAs to oxidative stress conditions. We will also provide an in-depth overview on the mechanistic pathways that lead to health problems (e.g., cardiovascular diseases) in response to environmental psychosocial stress, air pollution exposure in the form of ambient PM and diesel exhaust, traffic noise exposure, and the life style drug (water-pipe) smoking. Almost all stressors share the activation of the hypothalamic-pituitary-adrenocortical axis and of the sympathetic nervous system with subsequent onset of inflammation and oxidative stress, defining the here proposed therapeutic (antioxidant and exercise) strategies. Antioxid. Redox Signal. 28, 735-740. PMID- 29278924 TI - Depression, anxiety, stress and stigma in informal caregivers of People Living with HIV (PLHIV). AB - Informal caregivers are unpaid individuals who help friends or family members who cannot fully care for themselves. However fulfilling the act of helping debilitated individuals, exposure to another person's traumatic experiences often results in psychological distress. Caregiver's stigma towards HIV worsens this. Hence, this study aims to assess the effect of stigma on the mental health of caregivers so that their needs for support can be determined. A cross sectional hospital based study was carried out in Mangalore, India on 150 informal caregivers of PLHIV. The HIV Stigma Scale was used to assess stigma and DASS-21 was used to assess depression, anxiety and stress. Of the 150 caregivers, 20% marked one or more items on the stigma scale. Frequency of depression, anxiety and stress was 46%, 27% and 8% respectively. Most caregivers who had stigma and anxiety were of those patients diagnosed for a shorter duration of time (<=5 years) n = 20, p = 0.05 and n = 26, p = 0.03 respectively. Spouses of PLHIV (n = 31, p = 0.005), sero-positive caregivers (n = 25, p = 0.03) and those living with patients (n = 39, p = 0.01) suffered most from anxiety. Stress was significantly associated with depression (83%, p = 0.007) and anxiety (66.6%, p = 0.001) in caregivers. In conclusion, more of depression and anxiety was observed among the participants than stress. Stigma was seen in 20% of the participants. Stigma was not significantly associated with depression anxiety and stress. PMID- 29278925 TI - Review of analytical methods for measurement of oat proteins: The need for standardized methods. AB - This review summarizes the analytical methods that have been developed for quantification and characterization of oat proteins. These include sampling, sample preparation, extraction, quantification, separation, detection, and characterization of oat proteins. The review also provides a comparison of different methods for the determination of protein fraction of oat and the efficiency thereof. We conclude that there is a need for further validation of existing data or methods and for a standard methodology to quantify oat proteins. PMID- 29278926 TI - Arecoline ameliorates hyperthyroid condition in mice under cold stress. AB - Betel nut of Areca catechu is chewed by millions of people for increased capacity to work and stress reduction, but it contains arecoline that causes hypothyroidism. The aim is to investigate the role of arecoline on thyroid activity in cold stress in mice. Arecoline treatment (10 mg/kg body wt/day, for 7 d) caused a reduction in thyroid weight and ultrastructural degeneration of thyro follicular cells with depletion of T3 and T4 levels compared with the control mice. Cold stress (4 degrees C for 2 h, twice daily, for 7 d) stimulated thyroid activity ultrastructurally with an elevation of T3 and T4 levels. Arecoline treatment in cold stress suppressed thyroid activity by showing reversed changes to those of cold stress. In contrast, TSH concentrations were consistently increased under all experimental conditions. The findings suggest that cold stress causes hyperthyroidism which arecoline can ameliorate in mice. PMID- 29278927 TI - Time since injury limits but does not prevent improvement and maintenance of gains in balance in chronic stroke. AB - OBJECTIVE: To determine the influence of time since injury on the efficacy and maintenance of gains of rehabilitation of balance after stroke. METHOD: Forty seven participants were assigned to a least (6-12 months), a moderate (12-24 months), or a most chronic (>24 months) group. Participants trained for 20 one hour sessions, administered three to five times a week, combining conventional physical therapy and visual feedback-based exercises that trained the ankle and hip strategies. Participants were assessed before, after the intervention, and one month later with a posturography test (Sway Speed and Limits of Stability) and clinical scales. RESULTS: In contrast to other subjects, the most chronic participants failed to improve their sway and to maintain the benefits detected in the Limits of Stability after the intervention. Although all the participants improved in those clinical tests that better matched the trained skills, time since injury limited the improvement, and over all, the maintenance of gains. CONCLUSION: Time since injury limits but does not prevent improvement in chronic stages post-stroke, and this effect appears to be more pronounced with maintaining gains. These findings support that training duration and intensity as well as type of therapy may need to be adjusted based on time post-stroke. PMID- 29278928 TI - Exploring plant tissue culture in Withania somnifera (L.) Dunal: in vitro propagation and secondary metabolite production. AB - Withania somnifera (L.) Dunal (family: Solanaceae), commonly known as "Indian Ginseng", is a medicinally and industrially important plant of the Indian subcontinent and other warmer parts of the world. The plant has multi-use medicinal potential and has been listed among 36 important cultivated medicinal plants of India that are in high demand for trade due to its pharmaceutical uses. The medicinal importance of this plant is mainly due to the presence of different types of steroidal lactones- withanolides in the roots and leaves. Owing to low seed viability and poor germination, the conventional propagation of W. somnifera falls short to cater its commercial demands particularly for secondary metabolite production. Therefore, there is a great need to develop different biotechnological approaches through tissue and organ culture for seasonal independent production of plants in large scale which will provide sufficient raw materials of uniform quality for pharmaceutical purposes. During past years, a number of in vitro plant regeneration protocols via organogenesis and somatic embryogenesis and in vitro conservation through synthetic seed based encapsulation technology have been developed for W. somnifera. Several attempts have also been made to standardize the protocol of secondary metabolite production via tissue/organ cultures, cell suspension cultures, and Agrobacterium rhizogenes-mediated transformed hairy root cultures. Employment of plant tissue culture based techniques would provide means for rapid propagation and conservation of this plant species and also provide scope for enhanced production of different bioactive secondary metabolites. The present review provides a comprehensive report on research activities conducted in the area of tissue culture and secondary metabolite production in W. somnifera during the past years. It also discusses the unexplored areas which might be taken into consideration for future research so that the medicinal properties and the secondary metabolites produced by this plant can be exploited further for the benefit of human health in a sustainable way. PMID- 29278929 TI - Comparing the Efficacy of Tolterodine and Gabapentin Versus Placebo in Catheter Related Bladder Discomfort After Percutaneous Nephrolithotomy: A Randomized Clinical Trial. AB - PURPOSE: The purpose of this study was to compare the efficacy of tolterodine and gabapentin vs placebo in catheter related bladder discomfort (CRBD) following percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: This study was a double-blind parallel group randomized clinical trial. Patients who were candidates of PCNL were enrolled. Patients were randomized to treatment groups of tolterodine 2 mg orally (PO) (group T, n = 50), gabapentin 600 mg PO (group G, n = 50), and placebo (group P, n = 70) 1 hour before operation using balanced block randomization. The primary endpoint of interest was visual analog pain scale in 1, 3, 12, and 24 hours after the operation. Secondary endpoints included rescue analgesic use (opioid and nonopioid). RESULTS: The frequency of severe CRBD in 1,12, and 24 hours after the operation was 4%, 4%, and 6% in group T vs 4%, 0%, and 2% in group G vs 47%, 14%, and 6% in the P group (p < 0.001). The number of paracetamol injections for CRBD in the T and G groups was significantly lower than the placebo group (1.8 +/- 0.8 vs 1.8 +/- 0.7 vs 3.6 +/- 0.7, p < 0.001). Likewise the number of pethidine injections in the T and G groups was significantly lower than the placebo group (0.42 +/- 0.54 vs 0.68 +/- 0.62 vs 2.4 +/- 0.64, p < 0.001). In patients with history of Double-J insertion, the severity of CRBD was lower in all treatment groups. CONCLUSIONS: Preoperative administration of oral tolterodine or gabapentin reduces postoperative CRBD and the need for rescue analgesics as much as 24 hours after surgery. Patients with history of Double-J insertion experience less CRBD. PMID- 29278930 TI - Radiographic Change of the Distal Tibiofibular Joint Following Removal of Transfixing Screw Fixation. AB - BACKGROUND: Syndesmosis disruptions in the ankle joint are typically treated with anatomic reduction followed by transfixing screw and/or suture button fixation. The purpose of our study was to analyze the effects of the removal of transfixing screws on syndesmosis integrity using plain radiographs and computed tomography (CT) scans. METHODS: Twenty-nine cases (29 patients) who had been treated with transfixing screw fixation for syndesmosis disruptions were studied prospectively. Plain radiographs and CT scans were obtained 1 day before and 3 months after the removal of transfixing screws. The tibiofibular clear space (TCS) and tibiofibular overlap (TFO) were measured on plain radiographs, and the anterior and posterior measurement ratio (A/P ratio) of the syndesmosis was measured on axial CT scans to radiographically analyze the effect of the removal of screws on syndesmosis integrity. RESULTS: On plain radiographs, syndesmosis diastasis was not observed before or after the removal of transfixing screws. No statistically significant difference was found in the TCS and the TFO between measurements at prescrew removal and at postscrew removal ( P = .761 and .628, respectively). However, the syndesmosis was found malreduced on CT scans in 7 cases (24.1%) before screw removal. All 7 cases showed anterior malreduction of the syndesmosis, 5 (71.4%) of which spontaneously reduced after screw removal. The A/P ratio of the 7 cases decreased from a mean of 1.37 (range, 1.26-1.61) at prescrew removal to a mean of 1.12 (range, 0.96-1.25) at postscrew removal ( P = .016). CONCLUSION: Syndesmosis malreduction not observed on plain radiographs after performing transfixing screw fixation was identified with CT scans. Of the cases with a malreduced syndesmosis, 71.4% showed spontaneous reduction after screw removal. Therefore, we believe the removal of transfixing screws is recommended after confirming malreduction on CT scans, although plain radiographs demonstrate anatomic reduction. LEVEL OF EVIDENCE: Level II, prospective prognostic study. PMID- 29278931 TI - CYP1A2*1F Gene Variant, Alkaline Salt Tea Intake and Risk of Esophageal Squamous Cell Carcinoma. AB - Unlike many other cancers, the relationship of CYP1A2*1F (rs762551) polymorphism with esophageal squamous cell carcinoma (ESCC) risk has not been assessed so far. To evaluate its association with ESCC, we conducted a case control study in Kashmir, India, a high risk region. We recruited 404 histopathologically confirmed ESCC cases and 404 controls, individually matched for sex, age and residence to the respective cases. Information was obtained on dietary, lifestyle and environmental factors in face to face interviews using a structured questionnaire from each subject. Genotypes were analyzed by polymerase chain reaction, restriction fragment length polymorphism and sequencing randomly selected samples. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found that mutant genotype (AA) of CYP1A2*1F polymorphism was associated with ESCC risk (OR = 3.11; 95% CI: 1.72-5.36). A very strong ESCC risk was observed in subjects who drank >1250 ml of salt tea daily and harbored mutant genotype of CYP1A2*1F (OR = 14.51; 95% CI: 5.33-39.47). The study indicates that CYP1A2*1F polymorphism is associated with ESCC risk and the risk is modified in salt drinkers. However, more replicative and mechanistic studies are needed to substantiate the findings. PMID- 29278932 TI - Correspondence and cluster analysis of free-drawn clocks in a group of children and adolescents with neurological and psychiatric diseases. AB - The present work addresses the identification and qualitative assessment of errors that appear in a free-drawn clock-drawing test representing the time 8:20 in a sample of 455 children and adolescents with neurological diseases and their controls. The authors sought to verify whether the occurrence of particular errors in the clock drawings significantly differentiates the clinical groups. For statistical evaluation of the results, we applied correspondence analysis and cluster analysis. The results of the study showed that three types of errors played an important role in the differentiation of the groups: spatial neglect, mirror reflection, and phonological depletion. PMID- 29278933 TI - Evaluating the Contribution of the Built Environment on Obesity Among New York State Students. AB - OBJECTIVES: One third of school-aged children in New York State (NYS) are overweight or obese, with large geographic disparities across local regions. We used NYS student obesity surveillance data to assess whether these geographical variations are attributable to the built environment. METHOD: We combined NYS Student Weight Status Category Reporting System 2010-2012 data with other government publicly available data. Ordinary least squares regression models identified key determinants of school district-level student obesity rates for elementary and middle/high schools. Geographical weighted regression models explored spatial variations in local coefficients of the built environment predictors. RESULTS: From ordinary least squares models, higher farmers' market density was only significantly associated with lower obesity rates among elementary school students (b = -0.116; p < .01). Higher fast-food restaurant density was significantly associated with higher obesity rates (b = 0.014; p < .05), and higher land use mix was only significantly associated with lower obesity rates (b = -0.054; p < .01) among middle/high school students. In geographical weighted regression analyses, the inverse association between market density and obesity rates among elementary school students was more pronounced in the eastern portion of the state. The relationship between higher fast-food restaurant density and higher obesity rates among middle/high school students was found in the southeastern portion of the state. CONCLUSIONS: Different patterns of food consumption may explain varying determinants of obesity between younger and older students. Regional variations in local associations between the built environment variables and obesity may suggest differences in how healthy food sources are accessed locally. PMID- 29278934 TI - Impact of Oral and Gastrointestinal Mucositis on Body Weight Alterations during Hematopoietic Stem Cell Transplantation. AB - The aim of this study was to evaluate whether digestive tract mucositis is a predictive factor for body weight (BW) alterations during hematopoietic stem cell transplantation (HSCT). Data about characteristics of transplantation, initial nutritional conditions and gastrointestinal mucositis were collected from adult patients (n = 105) who underwent autologous and allogeneic HSCT. Oral mucositis (OM) was not a predictive factor for BW loss, but it was an independent factor for BW gain in autologous HSCT (beta = 0.329, P = 0.021). Busulfan-fludarabine conditioning regimen (beta = 1.531, P = 0.011) and gender (beta = 1.109, P = 0.038) were significant independent risk factors for BW loss in allogeneic HSCT. Overall survival (OS) was significantly affected by the duration of OM in autologous HSCT (HR = 1.243, P = 0.008). In allogeneic HSCT, BW loss (HR = 1.308, P = 0.049) and diarrhea (HR = 1.139, P = 0.012) interfered significantly with OS. In conclusion, OM was not a risk factor for BW loss, but it influenced BW gain and had a negative impact on OS in autologous HSCT patients. Intestinal mucositis explained partially the BW loss and had a negative impact on OS in allogeneic HSCT. PMID- 29278935 TI - Effect of socioeconomic status on children's psychological well-being in China: The mediating role of family social capital. AB - This study aimed to examine the relationship between socioeconomic status and children's psychological well-being and to investigate the mediating effect of family social capital. A sample of 19,487 school-aged children was collected from 2013-2014 China Education Panel Survey. Structural equation modeling was applied to test the hypothesized model. The results showed that socioeconomic status was not significantly related to the children's psychological well-being. However, two indicators of family social capital, namely, parent involvement and parent child relationship, played a complete mediating role in the direct mechanism. The theoretical and practical contributions were discussed. PMID- 29278936 TI - Third party observer effect: Application to autistic traits in the normal population. AB - This study examined how autistic traits relate to third-party observation during neuropsychological testing. Using a counterbalanced within-subjects design (N = 61), we manipulated the absence and presence of third-party observation when administering alternate forms of the Rey Auditory Verbal Learning Test and Paced Auditory Serial Addition Test to individuals with variable autistic traits. Bayesian linear mixed effects modeling was used to examine the interaction between autistic traits and third-party observation on test performance. With more autistic traits, susceptibility to a third-party observer decreased on the dependent variables. The third-party observer effect may therefore depend on the social awareness exhibited by the examinee. PMID- 29278938 TI - Moving through predeath grief: Psychological support for family caregivers of people with dementia. AB - When caring for a family member with dementia, continuous losses and predeath grief can adversely affect the caregivers' physical and mental health. Interventions for caregivers should therefore also aim at coping with loss and managing predeath grief. It was the objective of the present study to describe sources of grief caregivers report during therapy and to investigate how therapists can support caregivers. Two caregivers who participated in a randomized controlled trial were selected for this case study. Both caregivers received an intervention based on the principles of cognitive-behavioral therapy with grief-focused content that consisted of 12 sessions within six months. Three therapy sessions per participant were transcribed, coded, and analyzed using qualitative content analysis. Results illustrate that both caregivers experienced a loss of companionship with their respective care recipient and ambiguous loss that resulted in intense grief that they found difficult to manage. Therapists responded by supporting the caregivers to acknowledge their losses and identify individual ways to cope with and accept loss and grief. Both caregivers reported higher well-being and an increased ability to manage their grief-related emotions after the therapy ended. The identified intervention strategies fit well into a theoretical framework for grief interventions for dementia caregivers, i.e. the dementia grief model. PMID- 29278937 TI - Unpacking Major Depressive Disorder: From Classification to Treatment Selection. PMID- 29278939 TI - Do mothers affect daughter's behaviors? Diet, physical activity, and sedentary behaviors in Kuwaiti mother-daughter dyads. AB - The objective of the study was to evaluate 169 Kuwaiti mother-daughter dyads and their associations with health behaviors for eating healthy, engaging in physical activity, daughters perceived body weight, time spent with computer/video, and time viewing television. Female students aged 10-14 years were selected from private and public schools in the State of Kuwait. Results demonstrated that daughters exhibited similar behaviors to their mothers in their perceived eating behavior, physical activity, computer/video game use, and TV screen time. Future research is essential to determine the role of mothers in effective health behavior intervention strategies for female Kuwaiti adolescents. PMID- 29278940 TI - Poultry and Fish Consumption in Relation to Total Cancer Mortality: A Meta Analysis of Prospective Studies. AB - Observational studies on the association between fish and poultry intake and the risk of total cancer mortality have been reported with mixed results. Thus, we aimed to assess this association by conducting a meta-analysis of prospective studies. We performed a literature search on PubMed database through February 1, 2017 to identify relative prospective studies. A random-effects model was used to calculate the summary estimates. We identified fourteen prospective studies involving 2,378,204 participants and 96,712 cancer mortality events. Comparing the highest category of consumption with lowest category, pooled relative risk (RR) of total cancer mortality was 0.99 (95% confidence interval [CI], 0.94-1.05) for fish (10 studies) and 0.96 (95% CI, 0.93-1.00) for poultry (8 studies), respectively. However, we failed to identify any dose-response association based on a limited number of eligible studies, with a pooled RR of 0.98 (95% CI, 0.92 1.05) and 0.97 (95% CI, 0.88-1.07) for each 100 g per day increment in fish and poultry consumption, respectively. In summary, this meta-analysis indicates that consumption of either fish or poultry is not substantially associated with lower risk of total cancer mortality. The observed weak inverse association for high poultry consumption needs to be verified in additional large prospective studies. PMID- 29278941 TI - Characteristics of lower airway inflammatory changes in the minimal persistent inflammation of allergic rhinitis in mice. AB - OBJECTIVE: This study aims to establish an experimental mouse model of minimal persistent inflammation (MPI), observe the features of inflammation and hyper responsiveness of the upper/lower airways, and explore the relationship between inflammation and hyper-responsiveness in the upper/lower airways. METHODS: Sixty four female BALB/c mice were randomly divided into four groups: allergic rhinitis (AR) group as positive control, MPI group, negative control group and blank control group. Mice were given high and low-concentrated ovalbumin solution after basic and intensive sensitization to establish AR model and MPI model. Nasal mucosa and lung tissues were stained to observe eosinophil infiltration, goblet cell hyperplasia, and expression of intercellular adhesion molecule 1 (ICAM-1). Airway hyper-responsiveness was assessed. Levels of specific immunoglobulin E (sIgE), interleukin (IL)-4 and IL-5 in peripheral blood, nasal lavage fluid (NLF), and bronchoalveolar lavage fluid (BALF) were detected by Enzyme-linked immunosorbent assay. RESULTS: The eosinophil infiltration and expression of ICAM 1 on nasal mucosa and in lung tissues in the AR and MPI groups were significantly elevated compared to control groups. Goblet cells count increased only in the nasal mucosa and not in lung tissues. Eosinophil and neutrophil count of NLF and BALF in the AR and MPI groups increased significantly compared to control groups. Level of IL-4 did not increase significantly, but sIgE and IL-5 did. CONCLUSIONS: Mice in the MPI status exhibits lower airway inflammation and hyper responsiveness with increase in eosinophil count, goblet cells, ICAM-1, IL-4, and IL-5. These results provide further evidence for the importance of MPI of AR in lower airway diseases. PMID- 29278942 TI - Objective confirmation of asthma diagnosis improves medication adherence. AB - OBJECTIVE: The impact of diagnostic work-up in asthma management on medication redemption and probably also drug adherence is largely unknown, but we hypothesized that a confirmed diagnosis of asthma in a hospital-based out-patient clinic increases the willingness to subsequent medication redemption in a real life setting. METHODS: In a retrospective register-based study, 300 medical records of patients referred with possible asthma during one year were examined, of whom 171 had asthma (57%). One-year data on dispensed medicine was collected using the Danish Registry of Medicinal Product Statistics. Patients who had a positive asthma (e.g. bronchial challenge) were classified as verified asthma, whereas unverified asthma refers to doctor's diagnosis of asthma with negative or no diagnostic tests performed. RESULTS: 111 (65%) had a verified diagnosis and patients with verified asthma were more frequently prescribed new therapy compared to those with unverified asthma (88.9% vs. 65.0%, respectively, p < 0.001). No difference was found in first time redemption of prescriptions (72% vs. 64%, respectively, p = 0.3), whereas the second (52% vs. 27%, p = 0.001) and third or more asthma redeemed prescriptions (37% vs. 17%, p = 0.006) showed increased redemption of prescription and probably adherence in the verified compared with the unverified patients with asthma. Furthermore, the use of inhaled corticosteroid (ICS) was calculated as Percent Days Covered (PDC), which was higher in the verified group compared with the non-verified asthma group (88% vs. 30%, p = 0.004). CONCLUSION: Objective verification of a diagnosis of asthma using asthma tests was associated with an improved redemption of prescription. PMID- 29278943 TI - A retrospective study of ultrasound-guided high intensity focussed ultrasound ablation for multiple uterine fibroids in South Africa. AB - OBJECTIVE: To evaluate the shrinkage rate, symptom relief and improvement of the quality of life following ultrasound-guided high intensity focussed ultrasound (USgHIFU) for multiple uterine fibroids. METHODS: From October 2015 to November 2016, 81 black women with multiple symptomatic fibroids underwent USgHIFU. The number of the fibroids ranged from 3 to 9. The shrinkage rate of fibroids, symptom severity score and quality of life were evaluated following USgHIFU. Magnetic resonance imaging (MRI), the uterine fibroid symptom and quality of life (UFS-QOL) questionnaire were used for evaluation. RESULTS: The mean age of patients was 35.3 +/- 5.9 years. The average weight of these patients was 68.4 +/ 11.4 kg, with the median abdominal subcutaneous fat thickness of 38.0 +/- 11.4 mm. The median fibroid volume was 36.0 (range: 1.8-1220.1) cm3. During HIFU, 60.5% of the patients reported lower abdominal pain, 43.2% sciatic/buttock pain, 60.5% skin "burning" sensation, 6.2% abnormal vaginal discharge and 13.6% transient leg pain. No severe complications were observed. The average volume reduction rate of fibroids in 21 patients who completed the follow-up was 32.5 +/ 24.0, 42.3 +/- 32.2 and 52.5 +/- 36.3% 1, 3 and 6 months after HIFU, respectively. The UFS score decreased and the QOL values significantly increased during the follow-up period. Re-intervention treatment occurred in two of the 21 patients 6 months after HIFU. One patient conceived 3 months after HIFU, and she had a term vaginal delivery without any obstetrical complications. CONCLUSIONS: Based on our results, USgHIFU is safe and effective in treating patients with multiple uterine fibroids. PMID- 29278945 TI - Elastin-like polypeptide incorporated thermally sensitive liposome improve antibiotic therapy against musculoskeletal bacterial pathogens. AB - Musculoskeletal infections caused by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa in children and adults can lead to adverse outcomes including a need for extensive surgical debridement and limb amputation. To enable targeted antimicrobial release in infected tissues, the objective of this study was to design and investigate novel elastin-like polypeptide (ELP)-based thermally sensitive liposomes in vitro. ELP biopolymers can change their phase behaviour at higher temperatures. We hypothesised that ELP-TSL will improve therapeutic efficacy by releasing antimicrobial payloads locally at higher temperatures (>=39 degrees C). ELP-TSL library were formulated by varying cholesterol and phospholipid composition by the thin film and extrusion method. A broad-spectrum antimicrobial (Ciprofloxacin or Cipro) was encapsulated inside the liposomes by the ammonium sulphate gradient method. Cipro release from ELP-TSLs was assessed in physiological buffers containing ~25% serum by fluorescence spectroscopy, and efficacy against Staphylococcus aureus and Pseudomonas aeruginosa was assessed by disc diffusion and planktonic assay. Active loading of Cipro achieved an encapsulation efficiency of 40-70% in the ELP-TSL depending upon composition. ELP-TSL Cipro release was near complete at >=39 degrees C; however, the release rates could be delayed by cholesterol. Triggered release of Cipro from ELP-TSL at ~42 degrees C induced significant killing of S. aureus and P. aeruginosa compared to 37 degrees C. Our in vitro data suggest that ELP-TSL may potentially improve bacterial wound therapy in patients. PMID- 29278946 TI - Experimental assessment of phase aberration correction for breast MRgFUS therapy. AB - PURPOSE: This study validates that phase aberrations in breast magnetic resonance guided focussed ultrasound (MRgFUS) therapies can be corrected in a clinically relevant time frame to generate more intense, smaller and more spatially accurate foci. MATERIALS AND METHODS: Hybrid angular spectrum (HAS) ultrasound calculations in an magnetic resonance imaging (MRI)-based tissue model, were used to compute phase aberration corrections for improved experimental MRgFUS heating in four heterogeneous breast-mimicking phantoms (n = 18 total locations). Magnetic resonance(MR) temperature imaging was used to evaluate the maximum temperature rise, focus volume and focus accuracy for uncorrected and phase aberration-corrected sonications. Thermal simulations assessed the effectiveness of the phase aberration correction implementation. RESULTS: In 13 of 18 locations, the maximum temperature rise increased by an average of 30%, focus volume was reduced by 40% and focus accuracy improved from 4.6 to 3.6 mm. Mixed results were observed in five of the 18 locations, with focus accuracy improving from 6.1 to 2.5 mm and the maximum temperature rise decreasing by 8% and focus volume increasing by 10%. Overall, the study demonstrated significant improvements (p < 0.005) in maximum temperature rise, focus volume and focus accuracy. Simulations predicted greater improvements than observed experimentally, suggesting potential for improvement in implementing the technique. The complete phase aberration correction procedure, including model generation, segmentation and phase aberration computations, required less than 45 min per sonication location. CONCLUSION: The significant improvements demonstrated in this study i.e., focus intensity, size and accuracy from phase aberration correction have the potential to improve the efficacy, time-efficiency and safety of breast MRgFUS therapies. PMID- 29278947 TI - Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. AB - Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid beta-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC50 = 10.2 +/- 1.2, 16.5 +/- 1.7, and 15.3 +/- 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD. PMID- 29278948 TI - Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles. AB - A series of 6-substituted ureido- and thioureido-benzoxaboroles were investigated as inhibitors of carbonic anhydrases from Trypanosoma cruzi (TcCA), and Leishmania donovani chagasi (LdcCA). Both enzymes were inhibited by benzoxaboroles in the micromolar range. Preferential inhibitory potency against the beta-CA LdcCA versus the alpha-CA TcCA was observed with submicromolar inhibitory activities. Some derivatives displayed excellent inhibitory and selectivity profile over the ubiquitous and physiological relevant human off target hCA II. This study provides a convincing opportunity to study benzoxaborole scaffold for the design of antiprotozoan potential drugs targeting the pathogen's carbonic anhydrases. PMID- 29278949 TI - Propagation of free-radical reactions in concentrated protein solutions. AB - The reactions of proteins with biologically relevant oxidants have been widely studied, although most of the work has been performed in diluted homogenous solutions conditions that differ from those in intracellular environments. Cellular compartments represent highly crowded milieu in which high concentrations of biomolecules are present, unspecific intermolecular interactions are promoted, and physicochemical properties of constituents are modified. In this work, we propose that the high concentration at which proteins are present inside cells favours radical oxidative reactions between polypeptides which propagate in an oxygen-dependent process similar to membrane lipid peroxidation. The results presented herein show that highly concentrated solutions of bovine serum albumin (BSA) exposed to peroxynitrite, or metmyoglobin/H2O2, initiate the formation and propagation of protein peroxyl radicals, as evidenced by oxygen consumption, fluorescence spectroscopy, chemiluminescence, and electron paramagnetic resonance studies. Moreover, peroxyl radicals are capable of converting nitrite to nitrogen dioxide, which can oxidise amino acid residues to further assist radical-mediated protein oxidation. In addition, we also show that nitrone spin traps stop these propagation reactions in proteins, in line with the previously reported antioxidant role of these compounds in vivo. In summary, our results suggest that in crowded environments such as cellular compartments radical chain reactions propagate protein oxidative damage, highlighting a previously under recognised mechanism of cellular nitroxidative stress. PMID- 29278950 TI - The effect of different speaker accents on sentence comprehension in children with speech sound disorder. AB - There is substantial evidence that a speaker's accent, specifically an unfamiliar accent, can affect the listener's comprehension. In general, this effect holds true for both adults and children as well as those with typical and impaired language. Previous studies have investigated the effect of different accents on individuals with language disorders, but children with speech sound disorders (SSDs) have received little attention. The current study aims to learn more about the ability of children with SSD to process different speaker accents. Fifteen children with SSD aged between 4;01 and 5;11 years, and 16 typically developing children matched on language ability, age, socioeconomic status, gender and cognitive ability participated in the current study. A sentence comprehension task was carried out with each child, requiring them to follow instructions of increasing length spoken in three different accents - (i) a local Irish (Cork) accent, (ii) a regional North American accent and (iii) a non-native Indian English accent. Results showed no significant group difference and speaker accent did not significantly impact children's performance on the task. The results are discussed in relation to factors that influence accent comprehension, and their implications for children's underlying phonological representations. PMID- 29278951 TI - Calprotectin (S100A8/A9) should preferably be measured in EDTA-plasma; results from a longitudinal study of patients with rheumatoid arthritis. AB - Calprotectin (S100A8/A9), a protein expressed in neutrophils and monocytes/macrophages in circulation and inflamed tissue, is associated with measures of disease activity in rheumatoid arthritis (RA) patients both when measured in ethylenediaminetetraacetic acid (EDTA)-plasma and in serum. We wanted to explore if EDTA-plasma or serum should be preferred for calprotectin as a marker of disease activity. Calprotectin was analysed in EDTA-plasma and serum by enzyme-linked immunosorbent assay (ELISA) at baseline in 141 RA patients, starting biologic disease-modifying anti-rheumatic drugs (bDMARDs), and after three months. Differences between plasma and serum levels of calprotectin were assessed by Wilcoxon signed rank test. Variability was assessed by quartile coefficient of dispersion. Spearman's test explored correlations between calprotectin in plasma and serum and between calprotectin (plasma or serum) and clinical/ultrasound (US) measures of disease activity. Bland Altman plots were used for method comparisons. Conventional inflammatory markers were evaluated for comparison. Calprotectin had similar variability when measured in plasma and serum, but there was a significant difference in concentrations between plasma and serum (p < .001). The correlation coefficients at baseline between calprotectin measured in plasma/serum and measures of disease activity were rs = 0.62/0.46 for sum power Doppler score (PD), rs = 0.60/0.48 for assessor's global visual analogue scale (VAS), rs = 0.59/0.43 for sum grey scale (GS) score and rs = 0.47/0.37 for swollen joint count of 32, all p < .001. Similar differences were found after three months. Calprotectin measured in plasma showed the strongest associations with assessments of disease activity, and EDTA-plasma should preferably be used when evaluating disease activity in RA patients. PMID- 29278952 TI - Seeds of Buchholzia coriacea in Diet Mitigate Ischemic Reperfusion-Induced Gastric Ulceration in Experimental Rats. AB - Buchholzia coriacea (B. coriacea) seeds, in folk medicine, have been documented to prevent gastric ulceration though the mechanism is not fully elucidated. To clarify this, the gastro-healing activities were investigated using graded incorporation of B. coriacea seeds in the diet. Male Wistar rats (150-200 g) were divided into 7 groups (n = 15): unulcerated untreated control, ulcerated untreated control, unulcerated B. coriacea low (10%), ulcerated B. coriacea low (10%), nulcerated B. coriacea high (25%), ulcerated B. coriacea high (25%), and ulcerated omeprazole-treated groups. Rats were fed with B. coriacea diets for 7 weeks; thereafter, ulcer was induced by ischemic reperfusion method. Daily body weight, gastric acid secretion, hematological parameters, stomach ulcer score, and biochemical and histological analyses were evaluated on days 0, 3, and 7 post ulcer induction. Results were subjected to one-way analysis of variance (ANOVA) and presented as mean +/- standard error of the mean (SEM); p <=.05 was considered significant. Significant decreases were observed in mean body weight of B. coriacea-fed compared with control and omeprazole-treated groups from week 7. Ulcerated B. coriacea-fed showed significant decrease in gastric acid secretion by days 3 and 7 compared with ulcerated control groups. Malondialdehyde content was significantly decreased in ulcerated B. coriacea-fed compared with control and omeprazole-treated groups. Significant increases in hematological variables (notably platelet count), superoxide dismutase, catalase, and nitric oxide levels of B. coriacea-fed compared with control and omeprazole-treated groups by days 0 and 3 were observed. Histological evaluations further confirmed these observations. B. coriacea diet enhanced gastric healing activities on ischemic reperfused gastric ulcer. Increased platelet count and nitric oxide levels may play significant roles in this process. PMID- 29278953 TI - Reduction in exhaled nitric oxide tracks improved patient inhaler compliance in difficult asthma-a case study. AB - INTRODUCTION: Exhaled nitric oxide is believed be a useful surrogate for airways inflammation while non-adherence with therapy is known to be associated with worsening of asthma control. CASE: We present the case of a 49-year-old female with steroid-dependent asthma and an exacerbation rate of >20/year. She was enrolled in a 3-month-long prospective study using a validated diagnostic inhaler device that provided objective evidence of inhaler compliance. Fractional exhaled nitric oxide (FeNO), peak expiratory flow rates, asthma control questionnaires were measured throughout the study period. Peripheral eosinophil count was obtained prior to the study, during the study, and immediately afterwards. RESULTS: Improvement in compliance at the end of the study led to significant improvements in lung function peak expiratory flow rate (PEFR), and objective scores of asthma. There was an observed improvement in PEFR after 4 weeks, with an associated decrease in FeNO from 92 to 9 ppb that plateaued over the remainder of the study. Her eosinophil count was 0.79 * 109/litre prior to starting in the study, 0.37 * 109/litre after 2 months, and 0.1 * 109/litre at the end of the study. CONCLUSION: We believe that this is the first case study to objectively prove that improvements in compliance can lead to dramatic reductions in the overall inflammatory airway response and in particular that improvements in patient compliance are mirrored by marked reduction in FeNO levels. These changes occurred in tandem with an observed clinical improvement in our patient. PMID- 29278956 TI - Framework for Infectious Disease Analysis: A comprehensive and integrative multi modeling approach to disease prediction and management. AB - The impact of infectious disease on human populations is a function of many factors including environmental conditions, vector dynamics, transmission mechanics, social and cultural behaviors, and public policy. A comprehensive framework for disease management must fully connect the complete disease lifecycle, including emergence from reservoir populations, zoonotic vector transmission, and impact on human societies. The Framework for Infectious Disease Analysis is a software environment and conceptual architecture for data integration, situational awareness, visualization, prediction, and intervention assessment. Framework for Infectious Disease Analysis automatically collects biosurveillance data using natural language processing, integrates structured and unstructured data from multiple sources, applies advanced machine learning, and uses multi-modeling for analyzing disease dynamics and testing interventions in complex, heterogeneous populations. In the illustrative case studies, natural language processing from social media, news feeds, and websites was used for information extraction, biosurveillance, and situation awareness. Classification machine learning algorithms (support vector machines, random forests, and boosting) were used for disease predictions. PMID- 29278957 TI - Using the Elaboration Likelihood Model to Address Drunkorexia among College Students. AB - BACKGROUND: The many consequences related to alcohol consumption among college students are well documented. Drunkorexia, a relatively new term and area of research, is characterized by skipping meals to reduce caloric intake and/or exercising excessively in attempt to compensate for calories associated with high volume drinking. OBJECTIVE: The objective of this study was to use the Elaboration Likelihood Model to compare the impact of central and peripheral prevention messages on alcohol consumption and drunkorexic behavior. METHODS: Researchers employed a quasi-experimental design, collecting pre- or post-test data from 172 college students living in residence halls at a large Midwestern university, to assess the impact of the prevention messages. Participants in the treatment groups received the message in person (flyer), through email, and via a text message in weekly increments. RESULTS: Results showed that participants exposed to the peripherally framed message decreased the frequency of their alcohol consumption over a 30-day period (p =.003), the number of drinks they consumed the last time they drank (p =.029), the frequency they had more than five drinks over a 30-day period (p =.019), as well as the maximum number of drinks they had on any occasion in the past 30 days (p =.014). Conclusions/Importance: While more research is needed in this area, the findings from this study indicate that researchers and practitioners should design peripheral (short and succinct), rather than central (complex and detailed), messages to prevent drunkorexia and its associated behaviors. PMID- 29278958 TI - Clinical significance of pregnancy in adolescence in Japan. AB - OBJECTIVE: We examined the clinical characteristics and obstetric outcomes in adolescent pregnancies in Japanese women. METHODS: The present study was a retrospective investigation of all primiparous Japanese women with singleton pregnancies who gave birth at >=22 weeks' gestation aged <=18 years old (adolescent pregnancy, n = 325) and aged 28-30 years old (n = 2029) at Japanese Red Cross, Katsushika Maternity Hospital between 2002 and 2016. RESULTS: The frequencies of smoking, economic problems, an unmarried single status at delivery and the start of prenatal care in the first trimester in the adolescent pregnancy group were significantly higher than in the control group (p < .01). The incidences of Chlamydia trachomatis, Condyloma acuminatum, and mental disorders in the adolescent pregnancy group were significantly higher than in the control group (p < .01). Pregnancy in adolescence was not related to adverse obstetric outcomes except preterm delivery (p = .02). CONCLUSIONS: Adolescent pregnancy was not associated with adverse obstetric outcomes; however, adequate social, economic, and mental support is needed for adolescent pregnant women. PMID- 29278959 TI - The influence of maternal life stressors on breastfeeding outcomes: a US population-based study. AB - OBJECTIVE: The purpose of this study was to examine the contribution of maternal financial, emotional, traumatic, and partner-associated stressors on breastfeeding initiation and duration. METHODS: Data (216,756 records) from the Pregnancy Risk Assessment Monitoring System surveys were used in the analysis. Logistic regressions were conducted to estimate the magnitude and direction of associations between maternal stressors occurring in the 12 months prior to infant birth and both breastfeeding initiation and duration up to 4 weeks infant age. RESULTS: A substantial proportion of mothers (42%) reported having experienced one or two major stressors during the 12 months prior to the birth of their infant. Mothers who reported at least one major life stressor in the year before their baby was born were less likely to initiate breastfeeding and more likely to cease by 4 weeks infant age. Emotional and traumatic stressors were found to have the greatest impact on breastfeeding outcomes. CONCLUSIONS: Findings support the design and implementation of screening protocols for major maternal life stressors during regularly scheduled prenatal and newborn visits. Screening for at-risk mothers may lead to more targeted anticipatory guidance and referral with positive effects on breastfeeding outcomes and overall well-being of the mothers and their families. PMID- 29278960 TI - Maternal cytoglobin (CYGB) serum levels in normal and preeclamptic pregnancies. AB - OBJECTIVE: To investigate cytoglobin levels in women with preeclampsia and women with uncomplicated pregnancies. MATERIALS AND METHODS: A cross-sectional study including 26 pregnant women complicated with early-onset preeclampsia (EO-PE) and 26 pregnant women complicated with late-onset preeclampsia (LO-PE) were recruited for the study group. Twenty-seven healthy pregnant women selected randomly were included in the control group. The serum CYGB concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS: Gestational age at delivery and mean birth weight were significantly lower in the preeclampsia groups than in the control group and were found to be the lowest in the EO-PE group (p < .001). Serum CYGB levels were significantly higher in the EO-PE and LO-PE groups as compared with the control group (9.99 (6.08) ng/ml (EOPE), 10.04 (7.04) ng/ml (LOPE) versus 2.84 (0.82) ng/ml), (p < .001). However, a significant difference was not found between the EO-PE and LO-PE groups regarding CYGB levels (p = 1.000). CONCLUSIONS: Serum CYGB levels were significantly higher in patients with EO-PE and LO-PE as compared to healthy pregnant women. PMID- 29278962 TI - Correction to: Farzad Mohajeri et. al., Ultrasound measurement of fetal adrenal gland in fetuses with intrauterine growth restriction, an early predictive method for adverse outcomes. PMID- 29278961 TI - Comparison of the Clinical Efficacy of Abobotulinumtoxin A (ABO) and Onabotulinumtoxin A (ONA) in the Treatment of Crow's Feet Wrinkles: A Split-Face Study. AB - PURPOSE: Comparing the clinical efficacy of Abobotulinumtoxin A (ABO) and Onabotulinumtoxin A(ONA) using a dosing ratio of 2.5U:1.0U in the treatment of crow's feet wrinkles. SUBJECTS AND METHODS: A single-blinded, randomized, split face study, included 40 subjects, with moderate-to-severe crow's feet wrinkles. Patients were subjected to a dose equivalence of (ABO):(ONA); 2.5:1.0 U. Post treatment evaluation was done on 7, 30, and 120 days, comparing: Time, Duration, and Degree of Improvement; Patients Satisfaction. RESULTS: No significant difference was found between ABO & ONA regarding duration and time to improvement on static posture. While on dynamic posture, ABO showed significantly less time and longer duration. Both products produced highly significant improvement of the wrinkles' severity on both static and dynamic posture in comparison to the baseline severity. Satisfaction was more with ABO. CONCLUSION: ABO is a safe, effective alternative to ONA in treating crow's feet wrinkles. PMID- 29278963 TI - A Plasma Cell Myeloma With Post-Therapy Anaplastic Morphology, Osteomyelosclerosis, and Strong Pan-Cytokeratin (AE1/AE3) Expression: A Potential Diagnostic Pitfall. AB - Reactive and neoplastic plasma cells can display considerable morphological anaplasia as well as variable immunoreactivity for epithelial markers including epithelial membrane antigen, pan-cytokeratin (panCK) and high-molecular-weight cytokeratin, potentially creating diagnostic dilemmas. We describe the case of a 51-year-old male, previously treated for IgGlambda plasma cell myeloma, whose bone marrow biopsy showed focal replacement by sheets of pleomorphic malignant cells and grade 3 myelofibrosis, raising the morphological possibility of a carcinomatous infiltration. First-line immunohistochemistry revealed strong panCK as well as CD138 positivity. However, subsequent MUM-1 and CD38 stains were also positive, clinching the diagnosis of relapsed plasma cell myeloma with anaplastic morphology and aberrant strong cytokeratin expression. The case warns of the perils of using limited immunohistochemical panels in poorly differentiated metastatic neoplasms and the importance of providing a complete clinical background to the reporting pathologist. PMID- 29278964 TI - Mild hypothermia protects neurons against oxygen glucose deprivation via poly (ADP-ribose) signaling. AB - OBJECTIVE: Hypothermia is a neuroprotective mechanism that has been validated for use in alleviating neonatal hypoxic-ischemic (HI) brain injury. Nevertheless, it is unclear whether poly (ADP-ribose) (PAR) signaling is involved in hypothermia induced neuroprotection. In this study, we investigated whether mild hypothermia rescues oxygen glucose deprivation (OGD)-induced cell death by modifying PAR relative protein expression, such as AIF, PARP-1, and PAR polymer, in primary cultured hippocampal neurons. METHODS: We analyzed neuronal morphology and related protein expression of PAR signaling after OGD followed by mild hypothermia in primary-cultured newborn hippocampal neurons. RESULTS: Hypothermic treatment resulted in improved neuronal viability and alleviated DNA damage. Results from the protein assay showed that hypothermia attenuated nuclear translocation of apoptosis-inducing factor (AIF), inhibited overactivation of poly(ADP-ribose) polymerase-1 (PARP-1), and decreased production of PAR polymer induced by PARP-1 activation after OGD. CONCLUSIONS: These results showed that mild hypothermia partially protects immature hippocampal neurons against OGD injury in part by interfering with the PAR signaling pathway. PMID- 29278965 TI - Maternal and neonatal outcomes in triplet gestations by trial of labor versus planned cesarean delivery. AB - OBJECTIVE: To determine the rate of vaginal delivery after vaginal trial of labor (TOL) among women with triplet gestations. STUDY DESIGN: This is a retrospective cohort study of all women delivering a viable triplet gestation between 2005 and 2016. The primary outcome was rate of vaginal delivery among all women attempting vaginal delivery. Secondary outcomes included factors associated with undergoing triplet TOL, and maternal and neonatal complications by planned delivery approach. RESULTS: Of the 83 eligible women, 21 (25.3%) underwent TOL. A majority of these (57.1, 95% confidence interval 36.5-75.5%) achieved a vaginal delivery of all three triplets. Women who underwent TOL were more likely to be multiparous or to have spontaneous preterm labor. There were no differences in adverse maternal or neonatal outcomes by planned delivery approach. CONCLUSIONS: The rate of vaginal delivery among women with triplet gestations is higher in this institution than in reported literature, without increased morbidity. PMID- 29278966 TI - Kidney Ultrastructure by Atomic Force Microscopy Imaging Directly From Formalin Fixed-Paraffin Embedded Biopsy: Is This a Dream Come True? PMID- 29278967 TI - Physiotherapy methods to facilitate pelvic floor muscle contraction: A systematic review. AB - AIM: To undertake a systematic review of the literature on physical therapy methods to facilitate voluntary pelvic floor muscles (PFM) contraction. METHODS: The databases consulted were PubMed, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PEDro and CINHAL. The study included randomized controlled trials, quasi-experimental trials and systematic reviews. The GRADE scale was used to assess methodological quality. RESULTS: Six manuscripts were included. The methods investigated included instruction regarding the anatomy and function of the PFM, vaginal palpation, palpation on the central perineal tendon, interruption of urinary flow, biofeedback using a perineometer, vaginal cones, hypopressive exercise, PFM contraction associated with diaphragmatic breathing; and coactivation of abdominal muscles. The studies showed improvement in PFM contraction, but most were of low methodological quality. Only one study was characterized as being of high methodological quality. CONCLUSION: All the studies observed improvement in PFM contraction using various methods, but none were superior over the others. The studies revealed no adverse effects of the interventions used. Patient preferences should be taken into account in clinical decision-making. More studies of high methodological quality on this topic are needed. PMID- 29278968 TI - Clinical improvement, relapse and treatment adherence with paliperidone palmitate 1-month formulation: 1-year treatment in a naturalistic outpatient setting. AB - PURPOSE: To evaluate paliperidone palmitate 1-month formulation (PP1M) effectiveness in a naturalistic outpatient psychiatric setting. MATERIALS AND METHODS: We collected data from 50 outpatients affected by schizophrenia disorders treated with PP1M for 12 months in an Italian Mental Health Department. After analyzing selected demographic, clinical and pharmacological variables, we performed mirror analysis to compare psychiatric hospitalizations and urgent consultations required by the same patient 6 and 12 months before and after PP1M implementation (primary outcome). We analyzed clinical improvement in symptom (Clinical Global Impression-severity and improvement) and functioning (Global Assessment of Functioning) scales and drop-out rate during the 12-month PP1M treatment (secondary outcome). Data were statistically analyzed. RESULTS: The mean PP1M dose was 93.5 mg (+/-27.7 SD) with a mean interval between each injection of 27.1 d (+/-4.5 SD). Twenty-three patients (46%) reported adverse effects (sexual dysfunctions, weight gain and extrapyramidal symptoms).Fifteen patients (30%) dropped out after 137.2 d (+/-103.1 SD) on average: six due to the lack of therapeutic adherence, six due to inefficacy and three due to adverse events. The drop-out patients presented more severe clinical profile in CGI-S and GAF scores at T0 in comparison with others. At mirror analysis, 12-month but not 6-month PP1M treatment statistically significantly reduced psychiatric hospitalizations (t = 2.3, p < .05) and urgent consultations (t = 2.1, p < .05). Both scale scores showed statistically significant improvement at T12 in comparison to T0. CONCLUSIONS: This naturalistic study indicates that long-term PP1M treatment was safe and effective in preventing hospitalizations and urgent consultations as well as in improving clinical course. PMID- 29278969 TI - Emergent primary cesarean delivery and maternal operative morbidity. AB - BACKGROUND: It is unknown how variations in surgical entry time in primary cesarean delivery (CD) may affect operative outcomes and maternal morbidity. OBJECTIVE: Determine whether performing a primary CD in labor emergently ("stat") is associated with adverse maternal outcomes. STUDY DESIGN: Retrospective cohort study of patients who underwent primary CD at The Mount Sinai Hospital during the years of 2011-2016. Women with a singleton pregnancy and without a prior uterine scar attempting a trial of labor were included. An emergent CD was defined as a skin-to-uterine incision (I-U) time of <=3 minutes. Subjects were dichotomized into those with an I-U time of <=3 minutes or >=5 minutes. RESULTS: 1722 patients underwent primary CD and met eligibility criteria. 72 patients with an I-U time of 4 minutes were removed from the analysis. 196 patients (11.9%) had an I-U time <=3 minutes and 1454 patients (88.1%) had an I-U time >=5 minutes. There were no differences in any outcomes between groups. The likelihood of transfusion, hysterectomy, or admission to the intensive care unit (ICU) was 1.5% in the emergent group and 1.0% in the control group (p = .334). Postpartum length of stay was also similar between the groups (3.3 versus 3.2 days, p = .259). When 384 patients with I-U times >10 minutes were excluded, surgical outcomes remained similar between groups. Among the subgroup of patients who reached the second stage of labor, surgical outcomes were also similar between groups. CONCLUSIONS: Emergent primary CD is not associated with increased maternal morbidity. PMID- 29278970 TI - A clinical and microbiological study of puerperal sepsis in a tertiary care hospital in India. AB - OBJECTIVE: This prospective study was carried out to evaluate the clinical profile and bacterial isolates among women with puerperal sepsis in a tertiary hospital in North India. MATERIALS AND METHODS: Women with puerperal sepsis (n = 45) admitted from January 2015 to April 2016 were followed prospectively. Cultures were obtained from cervix, blood, urine, and pyoperitoneum. Initial antibiotics were cefotaxime or piperacillin with tazobactam plus amikacin plus clindamycin or metronidazole and were changed according to sensitivity. RESULTS: Out of 7887 deliveries during this period, 45 (0.2%) women had puerperal sepsis. 16 (35.5%) delivered in the present hospital, 25 (55.5%) at another health care facility, and 4 (8.9%) at home. Delivery was by cesarean section (CS) in 24/45 (53.3%) and vaginal in 21/45 (46.6%). Grade 1 sepsis occurred in 21, grade 2 in two, and grade 3 in 22 women. Majority (29/45 or 64.5%) had no risk factor for puerperal sepsis. There were two (4.4%) deaths and 13/45 (28.8%) had near-miss morbidity. Pathogenic bacteria were isolated in 33/45 (73.3%) in cervical swab (69%), blood, urine, or pus culture with no significant difference in the bacterial yield or species isolated between cotton or polyester swabs (p > .05). Escherichia coli were the commonest isolate and was sensitive to amikacin in all. Five had stillbirths and 4/40 neonates developed sepsis but recovered. CONCLUSIONS: Escherichia coli was the commonest pathogen and was uniformly sensitive to amikacin, which may be included among the initial antibiotics to treat puerperal sepsis in India. PMID- 29278971 TI - Prevention Strategies Against HIV Transmission: A Proactive Approach. AB - Human immunodeficiency virus (HIV) has now transformed into a manageable chronic condition. Highly active antiretroviral therapy (HAART) has proven efficacious at controlling the disease progression. Based on compelling evidence, the Department of Health and Human Services (DHHS) and the Infectious Disease Society of America (IDSA) developed guidelines for the management of persons infected with HIV. However, there are approximately 50 000 new cases of HIV in the United States each year. In this article, we review proactive methods to reduce the transmission of HIV, which include reinforcing patient education, gel-coated condoms that destroy HIV, HIV vaccinations, and adequately utilizing pre-exposure prophylaxis (PrEP), and post-exposure prophylaxis (PEP). Further development and consistent utilization of innovative prevention tools can significantly reduce the incidence of HIV infections regardless of HIV status. PMID- 29278972 TI - Sexual Coercion, Drinking to Cope Motives, and Alcohol-Related Consequences among Self-Identified Bisexual Women. AB - BACKGROUND: Given higher sexual victimization and greater alcohol use among bisexual women, a critical public health challenge is to understand within-group variation that may heighten or explain these associations in bisexual women. OBJECTIVES: The present study tested a moderated-mediation model in which sexual coercion was hypothesized to be associated with alcohol-related consequences via drinking to cope motives in self-identified bisexual women who reported at least occasional binge drinking. Negative affect was hypothesized to moderate the sexual coercion-drinking to cope motives association. METHODS: Participants were a community sample of 107 self-identified bisexual women (age M = 20.97, SD = 2.11) who completed an online survey and reported at least one binge drinking episode as well as engaging in sexual activity in the past 30 days. RESULTS: Of these participants, 57 (53.3%) reported one or more experiences of sexual coercion in the past 30 days. Sexual coercion was associated with negative alcohol-related consequences via drinking to cope motives. Negative affect moderated the association between sexual coercion and drinking to cope motives such that the association was stronger among women with greater negative affect. Conclusions/Importance: Methods of addressing vulnerability to sexual coercion and educating young bisexual women about the association between sexual coercion and potentially problematic affective coping through alcohol use are needed. PMID- 29278973 TI - Changes in Choroidal Thickness after Cataract Surgery. AB - OBJECTIVE: The aim of this study is to compare subfoveal choroidal thickness (SFCT) before and after uneventful phacoemulsification using enhanced depth imaging optical coherence tomography (EDI-OCT). BACKGROUND: Cataract is a major cause of visual impairment in the elderly. Cataract surgery is the most common ophthalmic surgery and is performed simultaneously with glaucoma or vitreous surgery in many cases. However, according to the results in epidemiology studies, cataract surgery is associated with the onset of age-related macular degeneration (AMD) and cataract surgery increases visual acuity in these patients without an increased risk of progression to exudative AMD. METHODS: A prospective study was conducted on 53 eyes of 53 patients who had phacoemulsification. Measurements of SFCT were performed preoperatively, 7 days (D7), 1 month (M1), and 3 months (M3) postoperative using the EDI-OCT technique. Central retinal thickness was also measured at the same time. RESULTS: Twenty-seven male (50.9%) and 26 female (49.1%) with a mean age of 56.43 years +/- 10.34 (SD) were analyzed. The mean choroidal thickness was 199.9 +/- 60.74 um. It significantly increased to 228.42 +/- 59.77 um at D7, then decreased to 210.78 +/- 59.59 um at M1, and then decreased to 200.63 +/- 61 um at M3. The mean retinal thickness was 260.79 +/- 6.12 um. It significantly increased to 294.09 +/- 7.20 um at D7 and then decreased to 274.70 +/- 6.00 um at M1 and 258.92 +/- 5.89 um at M3. CONCLUSION: Mean SFCT increased after cataract surgery. The changes in SFCT return to near the baseline after 3 months. PMID- 29278974 TI - Abdominal Angiostrongyliasis: A Presentation of Eosinophilic Granulomatous Colitis. AB - We present a case of a 4-year-old girl with abdominal angiostrongyliasis who presented with persistent fevers, hepatosplenomegaly, acute abdominal pain, and eosinophilia. Computed tomography scan identified thickening of the ascending colon with a narrowed lumen. Endoscopic evaluation revealed ulcerations and erythema in the ascending colon. The microscopic findings in biopsies included active chronic inflammation with prominent eosinophils and granulomas. A subset of granulomas contained the eggs of Angiostrongylus costaricensis. The definitive method of diagnosing A costaricensis is histology; peripheral blood serology has low specificity and the stool from infected patients does not contain eggs or larvae. Pathologists from endemic regions (Central and South America) are familiar with the typical histologic changes; however, because of increasing global travel, all pathologists should become familiar with A costaricensis, which may mimic common gastrointestinal diseases such as Crohn's disease, appendicitis, and Meckel's diverticulum. PMID- 29278975 TI - Oxidant-Antioxidant Balance in the Aqueous Humor of Patients with Retinal Vein Occlusion. AB - PURPOSE: To analyze oxidative stress parameters in the aqueous humor with retinal vein occlusion. MATERIALS AND METHODS: A total of 56 patients who underwent cataract surgery were enrolled in this study. The eyes with retinal vein occlusion were included in the study group. Aqueous humor was sampled from all patients and analyzed by an automated measurement method. Total oxidant status (TOS), total antioxidant status (TAS), and oxidative stres index (OSI) were calculated. RESULTS: OSI was significantly higher in the study group (p = 0.04). TAS was significantly lower (p = 0.01) and OSI was significantly higher (p = 0.01) in cases with both central retinal vein occlusion and macular edema. Previous laser photocoalugation to the retina and the duration of disease had no significant effect on the levels of oxidative stress parameters. CONCLUSION: OSI was found higher in patients with retinal vein occlusion. This increase is more significant in patients with macular edema and central retinal vein occlusion; in which TAS was also found to decrease. PMID- 29278977 TI - High-sensitivity direct analysis of aflatoxins in peanuts and cereal matrices by ultra-performance liquid chromatography with fluorescence detection involving a large volume flow cell. AB - This paper reports a sensitive and cost effective method of analysis for aflatoxins B1, B2, G1 and G2. The sample preparation method was primarily optimised in peanuts, followed by its validation in a range of peanut-processed products and cereal (rice, corn, millets) matrices. Peanut slurry [12.5 g peanut + 12.5 mL water] was extracted with methanol: water (8:2, 100 mL), cleaned through an immunoaffinity column and thereafter measured directly by ultra performance liquid chromatography-fluorescence (UPLC-FLD) detection, within a chromatographic runtime of 5 minutes. The use of a large volume flow cell in the FLD nullified the requirement of any post-column derivatisation and provided the lowest ever reported limits of quantification of 0.025 for B1 and G1 and 0.01 MUg/kg for B2 and G2. The single laboratory validation of the method provided acceptable selectivity, linearity, recovery and precision for reliable quantifications in all the test matrices as well as demonstrated compliance with the EC 401/2006 guidelines for analytical quality control of aflatoxins in foodstuffs. PMID- 29278978 TI - Statistical optimization of arsenic biosorption by microbial enzyme via Ca alginate beads. AB - Bioremediation of arsenic using green technology via microbial enzymes has attracted scientists due to its simplicity and cost effectiveness. Statistical optimization of arsenate bioremediation was conducted by the enzyme arsenate reductase extracted from arsenic tolerant bacterium Pseudomonas alcaligenes. Response surface methodology based on Box-Behnken design matrix was performed to determine the optimal operational conditions of a multivariable system and their interactive effects on the bioremediation process. The highest biosorptive activity of 96.2 ug gm-1 of beads was achieved under optimized conditions (pH = 7.0; As (V) concentration = 1000 ppb; time = 2 h). SEM analysis showed the morphological changes on the surface of enzyme immobilized gluteraldehyde crosslinked Ca-alginate beads. The immobilized enzyme retained its activity for 8 cycles. ANOVA with a high correlation coefficient (R2 > 0.99) and lower "Prob > F"value (<0.0001) corroborated the second-order polynomial model for the biosorption process. This study on the adsorptive removal of As (V) by enzyme loaded biosorbent revealed a possible way of its application in large scale treatment of As (V)-contaminated water bodies. PMID- 29278979 TI - Impact of a telemedicine eICU cart on sepsis management in a community hospital emergency department. AB - Introduction Intensivist involvement for patients with sepsis is associated with decreased complications and mortality, and lower hospital resource utilization, but few studies have evaluated outcomes for patients exposed to electronic intensive care unit (eICU) telemedicine sepsis management in the emergency department (ED). In this study, we assess whether eICU cart exposure in the ED improved compliance with components of the 2010 Surviving Sepsis Campaign bundles, length of stay (LOS), disposition and hospital costs. Methods An institutional review board-approved, retrospective cohort study was completed on patients with confirmed sepsis who presented to our ED from July 2010 through February 2013. Results Of 711 patient ED encounters, 314 cases met criteria for analysis (95 exposed and 219 non-exposed). Patient cohorts had similar demographics and comorbid International Classification of Diseases, Ninth Edition (ICD-9) diagnoses. The exposed cohort received antibiotics more quickly (122.3 minutes +/-83.3 versus 163.4 minutes +/-204.4, p = 0.043) and were more likely to have lactic acid levels drawn within six hours (98.9% vs. 90%, p = 0.019). The exposed cohort had a shortened ED LOS (in days) 0.08 +/- 0.28 versus 0.16 +/- 0.37, p = 0.036. Hospital LOS, disposition and death were similar in both cohorts. Total hospital costs for the exposed cohort were lower and less variable (US$19,713 +/- 16,550 vs. US$24,364 +/- 25068), but this was not significant ( p = 0.274). Discussion Our findings suggest that in individuals with confirmed sepsis, ED exposure to a telemedicine-based eICU cart impacted adherence to aspects of the Surviving Sepsis Campaign recommended bundle, but did not impact overall survival and medical costs. PMID- 29278980 TI - Clinic-Level Population Health Intervention by PGY2 Ambulatory Care Pharmacy Residents to Optimize Medication Management in a Self-Insured Employer Health Plan Population. AB - BACKGROUND: Postgraduate year 2 ambulatory care pharmacy residents (PGY2 residents) may be able to improve healthcare quality by providing clinical pharmacy services provided to self-insured employer health plan patients. The objectives of this study are to describe this care delivery in a family medicine clinic, and to identify patients most likely to benefit from the service. METHODS: From October 1, 2014 till June 30, 2015, comprehensive medication review was completed by PGY2 residents for patients insured by CU Anthem at the University of Colorado Westminster Family Medicine. For patients with medication related problems (MRPs), a note was sent to the provider before the patient visit. Patient characteristics were compared in those who received a clinical pharmacy note with those who did not. RESULTS: Sixty-eight MRPs were identified in 39 notes; 40 (58.8%) recommendations were implemented. The following Clinical Pharmacy Priority (CP2) score criteria were identified more frequently in patients with MRPs: age >=65 years, diagnosis of diabetes, hypertension, chronic obstructive pulmonary disease, cardiovascular disease, blood pressure >=140/90, hemoglobin A1c >7.9%, and >=6 items on the medication list. CONCLUSION: PGY2 residents identified and resolved numerous clinically relevant MRPs. Patient specific criteria can be utilized to target self-insured employer health plan patients who are likely to have clinically relevant MRPs. PMID- 29278981 TI - Delivering occupational therapy hand assessment and treatment sessions via telehealth. AB - Introduction Telehealth offers a solution to assist delivery of occupational therapy (OT) services for hand therapy in rural and remote locations. However, there is currently no evidence to validate this service model. The aim of this study was to examine the validity of clinical decisions made during hand therapy sessions conducted via telehealth compared to a traditional clinical model (TCM) assessment, and explore patient and clinician satisfaction. Methods Eighteen patients referred for hand therapy to a rural/remote hospital-based outpatient service were assessed simultaneously via telehealth and a TCM assessment. An allied health assistant supported data collection at the patient end. Hand function was assessed using a range of objective measures, subjective scales and patient reported information. Minimal level of percent exact agreement (PEA) between the telehealth OT (T-OT) and the TCM-OT was set at >=80%. Results Level of agreement for all objective measures (dynamometer and pinch gauge reading, goniometer flexion and extension, circumference in millimetres) ranged between 82% and 100% PEA. High agreement (>80% PEA) was also obtained for judgements of scar and general limb function, exercise compliance, pain severity and sensitivity location, activities of daily living and global ratings of change (GROC) scores. There was 100% PEA for overall recommendations. Minimal technical issues were experienced. Patient and clinician satisfaction was high. Discussion Clinical decisions made via telehealth were comparable to the TCM and consumers were satisfied with telehealth as a service option. Telehealth offers the potential to improve access to hand therapy services for rural and remote patients. PMID- 29278982 TI - The Use of Kcentra(r) in the Reversal of Coagulopathy of Chronic Liver Disease. AB - We aim to describe our experience with the four-factor prothrombin complex concentrates (4F-PCC) Kcentra(r) at differing doses in patients with liver cirrhosis requiring emergent hemostasis in the setting of major or life threatening bleeding. An automated query of patients who received Kcentra between January 2014 and March 2016 was performed. Patients who had clinically significant bleeding and received Kcentra for treatment of coagulopathy of chronic liver disease (CCLD) were included in the study. Baseline patient demographics, administration indication, pertinent laboratory values, and other reversal therapies were collected. Four patients met inclusion for analysis. One patient presented with hemopericardium, cardiac tamponade, and shock, and 3 patients presented with intracranial hemorrhage. Each patient experienced an improvement in international normalized ratio (INR) and at least a period of clinical hemostasis after Kcentra administration without complications referable to Kcentra. Kcentra may be a safe, rapid, and effective treatment option for hemorrhagic emergencies associated with CCLD. Further research is needed to determine the ideal monitoring and dosing regimen for use in CCLD. PMID- 29278983 TI - Development, validation and matrix effect of a QuEChERS method for the analysis of organochlorine pesticides in fish tissue. AB - This study aims to develop and validate a method to determine OCPs in fish tissues, minimizing the consumption of sample and reagents, by using a modified QuEChERS along with ultrasound, d-SPE and gas chromatography with an electron capture detector (GC-ECD), refraining the pooling. Different factorial designs were employed to optimize the sample preparation phase. The validation method presented a recovery of around 77.3% and 110.8%, with RSD lower than 13% and the detection limits were between 0.24 and 2.88 MUgkg-1, revealing good sensitiveness and accuracy. The method was satisfactorily applied to the analysis of tissues from different species of fish and OCPs residues were detected. The proposed method was shown effective to determine OCPs low concentrations in fish tissues, using small sample mass (0.5 g), making the sample analyses viable without the need for grouping (pool). PMID- 29278984 TI - Using tele-emergency to avoid patient transfers in rural emergency departments: An assessment of costs and benefits. AB - Introduction Tele-emergency can address several challenges facing emergency departments in rural areas. The purpose of this paper is to (a) examine the rates of avoided transfers in rural emergency departments that adopted tele-emergency applications; and (b) estimate the costs and benefits of using tele-emergency to avoid transfers. Methods Analysis is based on 9048 tele-emergency encounters generated by the Avera eEmergency programme (Sioux Falls, South Dakota) in 85 rural hospitals across seven states between October 2009-February 2014. For each non-transfer patient, physicians indicated whether the transfer was avoided because of tele-emergency activation. The cost-benefit analysis is conducted from the hospital, patient and societal perspectives, and includes technology costs, local hospital revenues and patient-associated savings. All monetary values are expressed in US$. Sensitivity analysis is conducted by examining the worst and best case scenarios of costs, revenues and savings. Results In these analyses, 1175 avoided transfers were attributed to tele-emergency. From a rural hospital perspective, tele-emergency costs around US$1739 to avoid a single transfer. However, tele-emergency saves around US$5563 in avoided transportation and indirect patient costs. Combining these, from a societal perspective, tele emergency has the potential to result in a net savings of US$3823 per avoided transfer while accounting for tele-emergency technology costs, hospital revenues, and patient-associated savings. Conclusion This study highlights various stakeholder perspectives on the financial impact of tele-emergency in avoiding patient transfers in rural emergency departments. Telemedicine has the potential to reduce the number of transfers of emergency department patients and generate some revenue for rural hospitals despite associated technology costs, while incurring substantial patient savings. PMID- 29278986 TI - Reach and effectiveness of the HeartBeat Connections telemedicine pilot program. AB - Introduction Innovative care delivery programs that support primary care providers are needed to reduce the burden of cardiovascular disease (CVD). HeartBeat Connections (HBC) is a primary prevention telemedicine program utilizing registered dietitian nutritionists (RDNs) and registered nurses (RNs) to deliver health coaching and medication therapy protocols for dyslipidaemia and hypertension among patients at high risk for developing CVD. Methods This retrospective cohort study documents the reach and six-month effectiveness of the HBC program for improving CVD risk factors. The sample included 1028 high-risk individuals aged 40-79 (without CVD or diabetes) served between 2010 and 2013 (326 participants, 702 eligible non-participants). Mixed-model analyses of variance were used to compare changes in outcome measures between baseline and six-month follow-up for participants and non-participants. Outcomes were also examined for three groups: non-participants, participants with 1-4 encounters, and participants with > 5 encounters. Results Nearly one-third of all eligible patients participated. There were no significant differences over time between HBC participants and non-participants in blood pressure or body mass. A higher proportion of HBC participants quit using tobacco (7.0 vs. 3.2%, p = 0.004) and achieved the low-density lipoprotein (LDL) program goal of < 100 mg/dL (8.9 vs. 1.1%, p = 0.009). Also, more favourable improvements in total and LDL cholesterol were observed among HBC participants with higher program engagement ( p < 0.05). Discussion The HBC telemedicine program resulted in significant improvement in some, but not all, CVD risk factors over six months. HBC reached many high-CVD risk patients in the target region, which may confer population-level health benefits if this program can be scaled and sustained. Innovative, collaborative care delivery models like HBC can serve as a platform to systematically target and proactively engage at-risk populations, perhaps reducing patients' CVD risk. PMID- 29278985 TI - Structural and functional differences between porcine brain and budding yeast microtubules. AB - The cytoskeleton of eukaryotic cells relies on microtubules to perform many essential functions. We have previously shown that, in spite of the overall conservation in sequence and structure of tubulin subunits across species, there are differences between mammalian and budding yeast microtubules with likely functional consequences for the cell. Here we expand our structural and function comparison of yeast and porcine microtubules to show different distribution of protofilament number in microtubules assembled in vitro from these two species. The different geometry at lateral contacts between protofilaments is likely due to a more polar interface in yeast. We also find that yeast tubulin forms longer and less curved oligomers in solution, suggesting stronger tubulin:tubulin interactions along the protofilament. Finally, we observed species-specific plus end tracking activity for EB proteins: yeast Bim1 tracked yeast but not mammalian MTs, and human EB1 tracked mammalian but not yeast MTs. These findings further demonstrate that subtle sequence differences in tubulin sequence can have significant structural and functional consequences in microtubule structure and behavior. PMID- 29278987 TI - Impact of Pharmacist Intervention on Selection and Timing of Appropriate Antimicrobial Therapy in Septic Shock. AB - BACKGROUND: Current guidelines for septic shock management recommend administration of appropriate, broad-spectrum antimicrobials within 1 hour of recognition. OBJECTIVE: To evaluate the interventions pharmacists make as part of a sepsis response team and to determine if these interventions increase the proportion of patients with appropriate empiric antimicrobial therapy. METHODS: A retrospective cohort study was undertaken reviewing adult patients in a large, academic medical center with confirmed septic shock who had an order for a "sepsis bundle," which includes notification of a pharmacist to assess adequacy of empiric therapy. Pharmacist interventions with regard to selection of empiric antimicrobials were documented. The proportion of patients with initial successful selection of antimicrobial therapy (SSAT) before and after pharmacist intervention was assessed as well as the time to first antimicrobial administration and time to appropriate antimicrobial administration. RESULTS: A total of 76 patients were included. Pharmacist intervention increased the proportion of patients with SSAT from 66% to 80% ( P = .04). Median time to first antimicrobial administration was 43 minutes, and time to appropriate antimicrobial therapy was 1 hour, 34 minutes for the entire cohort, with pharmacist intervention decreasing the latter time significantly in patients without SSAT on initiation of the "sepsis bundle" ( P < .001). CONCLUSION: Pharmacist assessment of patients in septic shock offers the opportunity to improve SSAT. Systems designed to use a pharmacist responder for the care of patients with septic shock maximize the selection of antimicrobials, facilitate rapid administration, and improve surrogate outcomes for mortality in septic shock. PMID- 29278988 TI - Cytotoxic activity of the bioactive principles from Ficus burtt-davyi. AB - Ficus burtt-davyi (Moraceae) is a medicinal plant species indigenous to Southern Africa. In this study, a phytochemical and cytotoxic investigation on F. burtt davyi was conducted to evaluate its ethno-medicinal use. The phytochemical study of the fruits yielded triterpenoids (lupeol and alpha-amyrin). The cytotoxic evaluation was done on the methanolic extracts and selected compounds, lupeol, alpha-amyrin, lupeol acetate and (+)-catechin isolated from F. burtt-davyi stem bark and fruits. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay was carried out against two human cancer cell lines, breast adenocarcinoma (MCF-7) and colorectal adenocarcinoma (Caco-2), and normal human embryonic kidney cells (HEK293). The methanol extract from the stem bark was significantly cytotoxic to MCF-7 and Caco-2 cell lines (p < 0.05) in a concentration-dependent manner with IC50 values of 6.6 and 8.1 ug mL-1, respectively relative to the control. Lupeol and (+)-catechin showed cytotoxic activity against MCF-7 cell lines with IC50 values of 22.6 and 29.8 ug mL-1, respectively and greater cytotoxic activity against Caco-2 cell lines with IC50 values of 10.7 and 9.0 ug mL-1, respectively. Data from this study suggests that F. burtt-davyi exhibits cytotoxicity with no significant inhibitory effects against HEK293. The results also indicate that (+)-catechin and lupeol, the most abundant bioactive principles in the stem bark, are responsible for the synergistic cytotoxic effects against tested human cancer cell lines. This study provides evidence on the pharmaceutical potential of the medicinal plant, F. burtt-davyi, as a chemotherapeutic agent against cancer. PMID- 29278989 TI - Carcinogenic and non-carcinogenic risk assessments of arsenic contamination in drinking water of Ardabil city in the Northwest of Iran. AB - Based on the environmental health assessment framework of the United State Environmental Protection Agency, a quantitative health risk assessment of arsenic in contaminated drinking water in a city in the northwest of Iran has been carried out. In the exposure assessment step, arsenic concentrations in drinking water were determined during four seasons. In addition, the water ingestion rate for different age groups in this region was determined. The concentration of arsenic in 163 collected samples from different locations during four seasons ranged from 0 to 99 MUg L-1. Furthermore, a high percentage of the samples manifested higher levels than the permissible limit of 10 MUg L-1. The total daily water intake rates of four age groups 1 to <2 (group 1), 2 to <6 (group 2), 6 to <16 (group 3), and >=16 years (group 4) were estimated as 0.86, 1.49, 2.00, and 2.33 L day-1, respectively. Calculating the lifetime average daily dose of arsenic indicated that adults (group 4) had the highest and children (group 1) had the lowest daily intake of arsenic in their entire life. The results of risk characteristic showed that the order of excess lifetime cancer risk via arsenic exposure in the four groups was 4 > 3 > 2 > 1. The estimated risks for all age groups were higher than the acceptable range (1E-6 to 1E-4). The hazard quotient values for all of the classified groups were lower than the recommended limit values (<1), but it cannot be concluded that potential non-carcinogenicity risks are non-existent since the possible exposure to arsenic via food and skin may also pose the risk. PMID- 29278990 TI - Clinical Outcomes in Patients With Gram-Negative Infections Treated With Optimized Dosing Cefepime Over Various Minimum Inhibitory Concentrations. AB - BACKGROUND: The Clinical and Laboratory Standards Institute (CLSI) revised cefepime interpretive criteria, introducing the susceptible dose-dependent category for Enterobacteriaceae with a minimum inhibitory concentration (MIC) of 4 to 8 MUg/mL in 2014. Limited clinical data support these new categories. This study compares outcomes of patients treated with standard and high-dose cefepime across various MICs. METHODS: We retrospectively reviewed cases of pneumonia or bacteremia caused by gram-negative organisms treated with adequate doses of cefepime for >=48 hours. Outcomes were compared for MICs of <=2 (low), 4 (medium), and 8 MUg/mL (high). The primary end point was clinical failure, the secondary end point was microbiological failure. RESULTS: Ninety cases met the inclusion criteria: 46, 25, and 19 patients with low, medium, or high MIC, respectively. Multivariate logistic regression revealed that the medium (odds ratio [OR]: 9.13, P < .01) and high (OR: 6.79, P = .01) MIC groups had increased clinical failure. CONCLUSION: Cefepime therapy, even at CLSI-recommended doses, had an increased risk of clinical failure for gram-negative pathogens with MICs of 4 or 8 MUg/mL. This finding suggests that higher dosing regimens (2 g every 8 hours or 1 g every 6 hours) may be necessary to treat serious gram-negative infections with elevated MICs. PMID- 29278991 TI - Managing Nonoperable Intracranial Bleeding Associated With Apixaban: A Series of 2 Cases. AB - OBJECTIVE: To report 2 cases of nonoperable intracranial bleeding associated with apixaban managed by 3-factor prothrombin complex concentrate (PCC3). CASE SUMMARIES: Case 1 presented with a 1.3-cm left parieto-occipital hemorrhage and a thin subdural hematoma (SDH) on the left tentorium of the brain about 6 hours after his last dose of apixaban. Case 2 presented with a 4-mm left parafalcine SDH with time of most recent apixaban dose unknown. The patients received 24.9 to 25.5 U/kg of PCC3 with none to 1 U fresh frozen plasma (FFP) and demonstrated minimal or no progression in lesions measured by repeat computed tomography (CT) after treatment. One patient was discharged to a skilled nursing facility after 8 days; the other patient was discharged to home after 18 days. DISCUSSION: Apixaban has no specific antidote. Current bleeding management strategies are based on expert opinion. The risks and benefits for differing strategies are unclear, and little clinical experience for managing apixaban-associated intracranial bleeding has been reported to date. These cases describe the clinical use of PCC3 to manage parieto-occipital and subdural hemorrhage associated with apixaban in events not requiring surgical intervention. CONCLUSION: In these 2 cases, 25 U/kg PCC3, with none to one unit FFP, ceased apixaban-associated intracranial bleeding without apparent thrombogenic complications. PMID- 29278992 TI - Comorbidity, Polytherapy, and Drug Interactions in a Neurological Context: An Example of a Multidisciplinary Approach to Promote the Rational Use of Drugs. AB - PURPOSE: A high number of adverse drug reactions (ADRs), mainly caused by drug drug interactions (DDIs), occur in neurological wards and few data are available about incidence and prevalence of DDIs in this context. This study investigated (1) the prevalence of drug-drug and drug-disease interactions in patients admitted to a neurological unit in Italy, (2) the risk factors for DDIs, and (3) the diseases and the drug classes mostly involved in drug-drug and drug-disease interactions. METHODS: For 2 months, we performed a retrospective, observational study in the neurological unit of St Bassiano Hospital, enrolling 79 patients who received a drug prescription at discharge. RESULTS: About half of the patients were discharged with 5 or more prescribed drugs, and 72% of patients showed potential, clinically relevant DDIs. Linear correlations were observed between age and number of prescribed drugs ( P < .01) and between age and number of interactions ( P < .01). The number of prescribed drugs was associated with the number of detected DDIs ( P < .01). The application of drug interaction alerts and the use of medication inappropriateness criteria (ie, Beers criteria) were not satisfactory in choosing the best therapy for each patient. Therefore, multidisciplinary discussions of each clinical case was required. CONCLUSION: The study demonstrated that the neurological patient, especially if elderly, has a high risk of DDI and ADRs and that many of these can be avoided by case discussion in multidisciplinary team meetings, in which the presence of a dedicated clinical pharmacist is crucial. PMID- 29278993 TI - Adherence to GOLD Guidelines in the Inpatient COPD Population. AB - PURPOSE: The Global Initiative for Chronic Obstructive Lung Disease guidelines provide recommendations to manage chronic obstructive lung disease (COPD) exacerbations. This study assessed the management of inpatient COPD exacerbations at an urban teaching hospital. METHODS: A retrospective cohort analysis of adults admitted between December 2010 and August 2012 with a COPD exacerbation was conducted. Patient demographics, length of stay (LOS), Charlson comorbidity score, inpatient pulmonary medications, and 30-day readmission were collected. Descriptive statistics characterized guideline adherence and readmission. RESULTS: 94 patients were included with median LOS of 3 days (interquartile range [IQR]: 1-5 days) and median Charlson comorbidity score of 6 (IQR: 5-8). All patients received an inhaled short-acting beta agonist, and 52 (55.3%) also received an inhaled short-acting anticholinergic. Seventy-eight (83%) received systemic corticosteroids, of which 3 received guideline-recommended doses. Sixty four (68.1%) received antibiotics for a pulmonary indication, of which 71.9% received appropriate antibiotics per indication. Of the 94 patients, 2 were managed in complete adherence with GOLD recommendations. A total of 24 (25.5%) patients were readmitted within 30 days of discharge, 9 of these for COPD. CONCLUSION: COPD exacerbation treatment deviated from GOLD recommendations. This provides opportunities for further optimization of treatment of COPD exacerbations. PMID- 29278994 TI - Regulatory Forum Opinion Piece*: Effective Brain Trimming for Regulatory-type Nonclinical Toxicity Studies. AB - Regulatory guidances for nonclinical toxicity testing require brain evaluation but do not require a specific analytical strategy. The Society of Toxicologic Pathology (STP) has produced "best practice" recommendations for brain sampling and processing in general toxicity (GT) studies in adult rodents and nonrodents as well as developmental neurotoxicity (DNT) studies in rodents. This article explains acceptable brain trimming strategies as described in these 2 STP documents. Figures in the DNT and GT "best practices" illustrate coronal brain trimming at specific levels as defined by discrete external and internal anatomic landmarks. However, the text of both "best practice" papers states that institutions may choose different brain trimming levels or other planes (e.g., a longitudinal orientation) as long as key structures are sampled and trimming is consistent among individuals across the study. The STP-recommended number of brain levels to evaluate (7 or 8 coronal sections for GT and DNT studies, respectively) may need to be increased if neurotoxicity is considered possible or likely based on in-life clinical findings or other risk factors (chemical structure, known mode of action, etc.). PMID- 29278995 TI - The BLM Helicase: Keeping recombination honest? PMID- 29278996 TI - A systematic review of prehospital telehealth utilization. AB - Objective There has been moderate evidence of telehealth utilization in the field of emergency medicine, but less is known about telehealth in prehospital emergency medical services (EMS). The objective of this study is to explore the extent, focus, and utilization of telehealth for prehospital emergency care through the analysis of published research. Methods The authors conducted a systematic literature review by extracting data from multiple research databases (including MEDLINE/PubMed, CINAHL Complete, and Google Scholar) published since 2000. We used consistent key search terms to identify clinical interventions and feasibility studies involving telehealth and EMS, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results We identified 68 articles focused specifically on telehealth interventions in prehospital care. The majority (54%) of the studies involved stroke and acute cardiovascular care, while only 7% of these (4) focused on telehealth for primary care. The two most common delivery methods were real-time video-conferencing capabilities (38%) and store and forward (25%); and this variation was based upon the clinical focus. There has been a significant and positive trend towards greater telehealth utilization. European telehealth programs were most common (51% of the studies), while 38% were from the United States. Discussion and Conclusions Despite positive trends, telehealth utilization in prehospital emergency care is fairly limited given the sheer number of EMS agencies worldwide. The results of this study suggest there are significant opportunities for wider diffusion in prehospital care. Future work should examine barriers and incentives for telehealth adoption in EMS. PMID- 29278997 TI - It's Not Just Insurance: The Affordable Care Act and Population Health. PMID- 29278998 TI - Neurocognitive and Fine Motor Deficits in Asymptomatic Adolescents during the Subacute Period after Concussion. AB - Adolescents are at high risk for sustaining concussions. There is considerable controversy regarding the sensitivity of neurocognitive tests to detect and track dysfunction in the aftermath of concussion. Two neurocognitive test batteries were compared during the subacute phase of recovery from concussion to determine sensitivity to concussion. Adolescents (ages 11-17 years) with a concussion diagnosis (eight males, seven females, 9-69 days after injury) were recruited through a concussion clinic and compared with community nonconcussed volunteers (11 males, three females). Adolescents completed the online version of the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) on a desktop computer and the Defense Automated Neurobehavioral Assessment (DANA) on a handheld device, as well as the Grooved Pegboard Test, which assessed manual dexterity and motor speed. There were no differences in self-reported symptoms on the Post-Concussion Symptom Scale comparing concussed and nonconcussed adolescents. No significant between-groups differences were observed in ImPACT performance. Performance deficits were apparent for the DANA assessment, reflecting lower throughput scores for simple reaction time and response inhibition parameters in those with concussion. Concussed adolescents also had slower Grooved Pegboard Test performance when using the nondominant hand. Both the DANA test battery and the Grooved Pegboard Test appear to have promise as tools to detect persistent cognitive and motor dysfunction in the subacute period after concussion. PMID- 29278999 TI - Detection of gelatin adulteration using bio-informatics, proteomics and high resolution mass spectrometry. AB - Following the internationalisation of food production and manufacturing, a significant increase of food fraud was discovered, ranging from false label claims to the use of additives and fillers to increase profitability. The accidental or fraudulent mixing of animal products or by-products from different species is an important preoccupation for consumers with health or ethical concerns. Gelatin is widely used during food processing as well as in cosmetics, nutraceutics and medical formulations. It contains mainly type I, II and III collagen polypeptides. Gelatin speciation was performed using a well-defined proteogenomic annotation, carefully chosen surrogate tryptic peptides and analysis using a hybrid quadrupole-Orbitrap MS. Gelatin samples were dissolved in ammonium bicarbonate buffer and proteins were digested with trypsin. The samples were analysed using high-resolution MS. Chromatography was achieved using a 30 min linear gradient on a Thermo BioBasic C8 100 * 1 mm column at a flow rate of 75 MUL min-1. The MS was operated in full-scan high resolution and accurate mass and using a data-dependent top-10 method. Collagen proteins were methodically analysed in silico in order to generate tryptic peptide mass lists. Following comprehensive MS and MS/MS analyses, we detected and identified several type I collagen peptides and fully characterised the proteotypic peptides [831-846], [847-879], [949-974] and [975-996] (accession number F1SFA7). Additionally, the method was successfully tested with gelatin used in charcuterie meats obtained from grocery stores, fruit-snacks and gelatin capsules. This targeted method allowed comprehensive gelatin speciation and adulteration detection down to 0.1% (w/w) of undesired pork gelatin. PMID- 29279000 TI - Oxygen uptake on-kinetics during six-minute walk test predicts short-term outcomes after off-pump coronary artery bypass surgery. AB - PURPOSE: We aimed to investigate the ability of oxygen uptake kinetics to predict short-term outcomes after off-pump coronary artery bypass grafting. METHODS: Fifty-two patients aged 60.9 +/- 7.8 years waiting for off-pump coronary artery bypass surgery were evaluated. The 6-min walk test distance was performed pre operatively, while simultaneously using a portable cardiopulmonary testing device. The transition of oxygen uptake kinetics from rest to exercise was recorded to calculate oxygen uptake kinetics fitting a monoexponential regression model. Oxygen uptake at steady state, constant time, and mean response time corrected by work rate were analysed. Short-term clinical outcomes were evaluated during the early post-operative of off-pump coronary artery bypass surgery. RESULTS: Multivariate analysis showed body mass index, surgery time, and mean response time corrected by work rate as independent predictors for short-term outcomes. The optimal mean response time corrected by work rate cut-off to estimate short-term clinical outcomes was 1.51 * 10-3 min2/ml. Patients with slower mean response time corrected by work rate demonstrated higher rates of hypertension, diabetes, EuroSCOREII, left ventricular dysfunction, and impaired 6 min walk test parameters. The per cent-predicted distance threshold of 66% in the pre-operative was associated with delayed oxygen uptake kinetics. CONCLUSIONS: Pre-operative oxygen uptake kinetics during 6-min walk test predicts short-term clinical outcomes after off-pump coronary artery bypass surgery. From a clinically applicable perspective, a threshold of 66% of pre-operative predicted 6-min walk test distance indicated slower kinetics, which leads to longer intensive care unit and post-surgery hospital length of stay. Implications for rehabilitation Coronary artery bypass grafting is a treatment aimed to improve expectancy of life and prevent disability due to the disease progression; The use of pre-operative submaximal functional capacity test enabled the identification of patients with high risk of complications, where patients with delayed oxygen uptake kinetics exhibited worse short-term outcomes; Our findings suggest the importance of the rehabilitation in the pre-operative in order to "pre habilitate" the patients to the surgical procedure; Faster oxygen uptake on kinetics could be achieved by improving the oxidative capacity of muscles and cardiovascular conditioning through rehabilitation, adding better results following cardiac surgery. PMID- 29279001 TI - Patulin in fruit juices: occurrence, bioaccessibility, and risk assessment for Serbian population. AB - This paper reports the first study of patulin occurrence in fruit juices and risk assessment related to patulin intake by children, adolescents and adults in Serbia. During 3 consecutive years (2013-2015), 142 fruit (apple or multi-fruit) juices were collected from the market and analysed using HPLC-UV. Patulin was found in 51.4% of juices with 0.7% of the samples in excess of the legal limit of 50 MUg kg-1 (mean 4.3 MUg kg-1). Apple juices showed significantly higher percentage of contaminated samples (74.0% vs 27.5%), as well as higher mean patulin content (6.4 vs 2.1 MUg kg-1) when compared with the multi-fruit ones. Bioaccessibility of patulin in fruit juices was studied using the standardised in vitro digestion method. A mean of 21.6% of the initial patulin amount reached the end of the intestinal phase showing a significant reduction of this toxin during the human digestion process. Risk assessment of patulin intake by Serbian children, adolescents and adults, conducted by deterministic and probabilistic approaches and including the bioaccessibility results, revealed no health concern. Although patulin alone does not represent risk, further research should consider its co-occurrence with other toxic substances in food and potential adverse effects of their mixtures. PMID- 29279002 TI - Paradox of choice and the illusion of autonomy: The construction of ethical subjects in right-to-die activism. AB - The right to die is an issue is predicated on larger cultural understandings of autonomy. Autonomy, in turn, is centered around assumptions of choice, that individuals are able to make health-related decisions based on a rational calculation. In such a way, a medically assisted death is differentiated from suicide. Through an ethnographic study of right-to-die activists in North America and Australia and how they understand ideals of "good deaths," this article will complicate this view by examining the ethical subject constructed by such activism that reveals autonomy to be a useful guiding fiction that mask larger ethical relationships. PMID- 29279003 TI - Exploring attitudes of healthcare professionals towards ICT-based interventions for nursing home residents with dementia: a mixed-methods approach. AB - BACKGROUND: Information and Communication Technologies (ICTs) could be useful for delivering non-pharmacological therapies (NPTs) for dementia in nursing home settings. AIMS: To identify technology-related expectations and inhibitions of healthcare professionals associated with the intention to use ICT-based NPTs. DESIGN: Cross-sectional multi-method survey. METHODS: N = 205 healthcare professionals completed a quantitative survey on usage and attitudes towards ICTs. Additionally, N = 11 semi-structured interviews were conducted. RESULTS: Participants were classified as intenders to use ICTs (53%), non-intenders (14%) or ambivalent (32%). A MANCOVA revealed higher perceived usefulness for intenders compared to non-intenders and ambivalent healthcare professionals (V =.28, F(12, 292)= 3.94, p <.001). Qualitative interviews revealed generally high acceptance of ICTs in the workplace. Furthermore, benefits for residents emerged as a key requirement. CONCLUSION: Staff trainings should stress specific benefits for residents and healthcare professionals to facilitate successful implementation and acceptance of ICTs in nursing home settings. PMID- 29279004 TI - Insights into the role of ribonuclease 4 polymorphisms in amyotrophic lateral sclerosis. AB - Mutations in certain genes of the Ribonuclease (RNASE) superfamily can cause amyotrophic lateral sclerosis (ALS) through altered RNA processing mechanisms. About 30 of these missense mutations in RNASE5/ANG gene have already been reported in ALS patients. In another gene of the ribonuclease superfamily, ribonuclease 4 (RNASE4), missense mutations and single nucleotide polymorphisms have been identified in patients suffering from ALS. However, their plausible molecular mechanisms of association with ALS are not known. Here, we present the molecular mechanisms of RNASE4 polymorphisms with ALS using all-atom molecular dynamics (MD) simulations followed by functional assay experiments. As most ALS causing mutations in RNASE superfamily proteins affect either the ribonucleolytic or nuclear translocation activity, we examined these functional properties of wild-type and known RNASE4 variants, R10W, A98V, E48D and V75I, using MD simulations. Our simulation predicted that these variants would retain nuclear translocation activity and that E48D would exhibit loss of ribonucleolytic activity, which was subsequently validated by ribonucleolytic assay. Our results give a mechanistic insight into the association of RNASE4 polymorphisms with ALS and show that E48D-RNASE4 would probably be deleterious and cause ALS in individuals harbouring this polymorphism. PMID- 29279006 TI - Between living well and dying well: Existential ambivalence and keeping promises alive. AB - I explore the complexities of moral experience during the phase of life after a terminal diagnosis by examining the experiences of one woman living as a hospice patient in St. Croix, US Virgin Islands. Introducing the notion of "existential ambivalence," I show that this can be a period of deep uncertainty, in which what matters to individuals can shift and fluctuate through time, not necessarily lining up with collective ideals of "the good death." I focus on a promise this woman made that continued to pull her toward a version of living well while she was also pulled toward dying. PMID- 29279005 TI - Persistence, dissipation and consumer risk assessment of a combination formulation of flubendiamide and deltamethrin on cucumber. AB - Multi-location supervised field trials were conducted in India at four locations of the All India Network Project (AINP) on Pesticide Residues to study the persistence, dissipation and risk assessment of flubendiamide and deltamethrin on cucumber (Cucumis sativus). Residues of flubendiamide and deltamethrin on cucumber resulting from three spray applications of a combination formulation (flubendiamide 90% + deltamethrin 60%, 150 SC) at recommended (22.5 + 15 g a.i./ha) and double the recommended (45 + 30 g a.i./ha) dose were analysed. On the basis of persistence and dissipation studies, the half- life (T1/2) of flubendiamide on cucumber varied from 1.40 to 2.98 (recommended dose) and 1.55 to 2.76 days (double the recommended dose), while that of deltamethrin ranged from 2.5 to 4.9 (recommended dose) and 2.7 to 3.9 days (double the recommended dose) at the four locations. On the basis of supervised field trial data and using OECD calculator, MRLs in the combination product of 3 mg kg-1 for flubendiamide and 1.5 mg kg-1 for deltamethrin has been proposed for consideration by the Food Safety and Standards Authority of India (FSSAI). Codex, EU and EPA have fixed MRL of 0.2 mg kg-1 for flubendiamide and deltamethrin. PMID- 29279007 TI - The effect of diet enriched with rapeseed meal on endogenous thiouracil contents in urine and milk of cattle. AB - Thyreostatic compounds, such as thiouracil, are orally active drugs that can be used to increase the weight of cattle before slaughter. Due to potentially teratogenic and carcinogenic effects of their residues on public health, the use of thyreostats in animal production has been banned in the European Union since 1981. Systematic detection of low concentrations of thiouracil in the urine of livestock in many countries is believed to be of endogenous origin due to the use of Brassicaceae plants in the animal diet. Therefore, the purpose of the study was to determine the effects of diets rich in rapeseed meal on formation of thiouracil in urine and milk of dairy cows. For two weeks three cows were subjected to a diet supplemented with rapeseed at 30%, compared to the control cattle diet which contained up to 11% rapeseed. During the experiment, samples of urine and milk were collected and analysed by LC-MS/MS. The increase and decrease of thiouracil concentration in urine samples in different animals was individual and cyclic. The highest concentration of natural thiouracil determined in urine was 3.61 MUg l-1. It has been found that endogenous thiouracil exists in two tautomeric forms. A few days of storage of frozen urine samples affected the stability of natural thiouracil, whereas an acidic medium improved the stability of the compound and its isomer, which remained stable even after two months of storage at temperatures below -18 degrees C. Due to the instability of thiouracil, urine samples upon sampling should be delivered to the laboratory as soon as possible or properly preserved. In milk samples, thiouracil was not found above the decision limit of the applied method of 0.63 MUg l-1. Preliminary studies have shown that faecal examination for banned thiouracil can be a complementary test for urine samples, and may be helpful in determining the origin of the compound present in urine. PMID- 29279008 TI - Comparative analysis of thermal unfolding simulations of RNA recognition motifs (RRMs) of TAR DNA-binding protein 43 (TDP-43). AB - TAR DNA-binding protein 43 (TDP-43) inclusions have been found in Amyotrophic lateral sclerosis (ALS) and several other neurodegenerative diseases. Many studies suggest the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy. To elucidate the structural stability and the unfolding dynamics of RRMs, we have carried out atomistic molecular dynamics simulations at two different temperatures (300 and 500 K). The simulations results indicate that there are distinct structural differences in the unfolding pathway between the two domains and RRM1 unfolds faster than RRM2 in accordance with the lower thermal stability found experimentally. The unfolding behaviors of secondary structures showed that the alpha-helix was more stable than beta-sheet and structural rearrangements of beta-sheets results in formation of additional alpha helices. At higher temperature, RRM1 exhibit increased overall flexibility and unfolding than RRM2. The temperature-dependent free energy landscapes consist of multiple metastable states stabilized by non-native contacts and hydrogen bonds in RRM2, thus rendering the RRM2 more prone to misfolding. The structural rearrangements of RRM2 could lead to aberrant protein-protein interactions that may account for enhanced aggregation and toxicity of TDP-43. Our analysis, thus identify the structural and thermodynamic characteristics of the RRMs of TDP-43, which will serve to uncover molecular mechanisms and driving forces in TDP-43 misfolding and aggregation. PMID- 29279009 TI - Fusarium toxins in corn food products: a survey of the Serbian retail market. AB - This paper presents data on the occurrence of Fusarium toxins - zearalenone (ZEA), deoxynivalenol (DON) and fumonisins (FUMs) B1 and B2 - in corn flours and corn flakes marketed in Serbia. A total of 71 samples were collected over 2013 2016 and analysed using HPLC with UV or fluorescence detection. In the case of corn flours, none of the samples taken in 2013 exhibited the presence of ZEA or DON, whereas 90% were positive for FUMs. In 2015, occurrence was very high: ZEA 93%, DON 86% and FUMs 100% (mean 43.3, 322.6 and 323.0 MUg kg-1, respectively), with 21% of the samples exceeding the maximum level for ZEA and 7% for DON and FUMs. In 2016, a lower occurrence was recorded in the case of ZEA (75%) and DON (38%), with drastically lower mean contamination levels (six- and 10-fold, respectively), while FUMs stayed at 97%, with twofold lower mean. The maximum level was exceeded only for ZEA (3%). The frequency of ZEA-DON-FB1 co-occurrence was 86% in 2015 and 25% in 2016. Regarding corn flakes, occurrence summarised for the study period was 87% ZEA, 73% FUMs and 40% DON. One sample (7%) exceeded the maximum levels for both ZEA and DON. Observed occurrence changes were in agreement with the climatic conditions during corn growing seasons preceding the market release of the processed products. PMID- 29279010 TI - Category fluency in schizophrenia: opposing effects of negative and positive symptoms? AB - INTRODUCTION: Category fluency is associated with speed-, executive- and semantic impairments in schizphrenia. It has traditionally been linked to negative symptoms, whereas the relation to positive symptoms is mixed. Associations to the consensus negative, positive and disorganisation factors have not been analysed before. METHODS: Animal fluency was administered to 81 patients with schizophrenia. Measures of overall performance and applied strategies were analysed in relation to the Wallwork five-factor PANSS-model. RESULTS: Negative and disorganisation symptoms were negatively related to overall fluency performance. Positive symptoms were positively related to overall performance when controlling for disorganisation symptoms. Negative symptoms were related to fewer switches, less repetitions, less single animals intrusions, and both less rare and common animals. Positive symptoms were related to more effective retrieval of sub-category exemplars following a sub-category title, whereas there were no relation between symptoms and exemplars when the title was not retrieved. The Beta values of negative and positive symptoms were opposite. CONCLUSION: This is the first study showing that positive symptoms are related to increased fluency performance when disorganisation is controlled for. Like previous studies, negative symptoms were found to depress fluency. Strategy measures indicated that negative symptoms predispose for rigidity, whereas positive symptoms facilitate more efficient associative pathways. PMID- 29279012 TI - Identification of 1',5'-naphthyridinophthalone and its quantification in the color additive D&C Yellow No. 10 (Quinoline Yellow) using high-performance liquid chromatography. AB - The present work reports the identification and characterization of a contaminant, 2-(2'-(1,5-naphthyridinyl))-1,3-indanedione (1',5' naphthyridinophthalone, 1,5NP), in the color additive D&C Yellow No. 10 (U.S. certifiable form of Quinoline Yellow), together with its quantification in batches of the color additive certified by the U.S. Food and Drug Administration (USFDA). The impurity, which is a compound not previously reported in the literature, was synthesised and characterised for use as a reference material. Test portions from 26 certified batches of D&C Yellow No. 10 submitted to USFDA by four domestic and four foreign manufacturers were analyzed for 1,5NP using high-performance liquid chromatography. The results revealed a wide range of 1,5NP levels across batches, with 18 (69.2%) of the test portions containing amounts from 0.32 to 169.94 ug g-1 while the remaining test portions contained no detectable (<0.07 ug g-1) amounts. Samples of the European and Japanese forms of Quinoline Yellow were also analyzed and found to contain a wide range of 1,5NP levels. The varying levels of 1,5NP in all three forms of Quinoline Yellow suggest that contamination can be significantly decreased or eliminated through manufacturing adjustments. Since 1,5NP is closely related to a D&C Yellow No. 10 contaminant (quinophthalone) that has a USFDA-specified limit of 4 ug g-1 and is a known allergen, assessment of the possible allergenicity of 1,5NP is warranted. PMID- 29279011 TI - Recombinant Extracellular Matrix Protein Fragments Support Human Embryonic Stem Cell Chondrogenesis. AB - We previously developed a 14-day culture protocol under potentially GMP, chemically defined conditions, to generate chondroprogenitors from human embryonic stem cells (hESCs). In vivo work has confirmed the cartilage repair capacity of these cells in a nude rat osteochondral defect model. Aiming to enhance hESC-chondrogenesis, we screened a range of extracellular matrix (ECM) molecules for their ability to support differentiation of hESCs toward chondrocytes. We identified two novel ECM protein fragments that supported hESC chondrogenesis: Fibronectin III (fibronectin 7-14 protein fragments, including the RGD domain, syndecan-binding domain, and heparin-binding domain) and fibrillin-1 (FBN1) fragment PF8 (encoded by exons 30-38, residues 1238-1605, which contains the RGD motif but not heparin-binding site). These two protein fragments support hESC-chondrogenesis compared with the substrates routinely used previously (a mixture of fibronectin and gelatin) in our directed chondrogenic protocol. We have identified recombinant fibronectin fragment (FN III) and FBNI fragment (PF8) as alternative coating substrates to promote expression of genes known to regulate chondrocytes and code for chondrocyte ECM components. These recombinant protein fragments are likely to have better batch to batch stability than full-length molecules, especially where extracted from tissue/serum. PMID- 29279013 TI - Novel approaches to diagnosis and treatment of Juvenile Myelomonocytic Leukemia. AB - INTRODUCTION: Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder of infancy/early childhood, resulting from oncogenic mutations in genes involved in the Ras pathway. As JMML often exhibits an aggressive course, the timing of diagnosis and treatment is critical to outcome. Areas covered: This review summarizes current approaches to diagnosis and treatment of JMML, highlighting most recent insights into genetic and epigenetic mechanisms underlying the disease, and providing an overview of novel potential therapeutic strategies. Expert commentary: At present, allogeneic HSCT remains the only potentially effective therapy, being able to cure more than 50% of patients, relapse representing the main cause of treatment failure. Prompt HSCT is recommended for all children with NF1, somatic PTPN11 and KRAS mutations, and for most children with somatic NRAS mutations. Conversely, a 'watch and wait' strategy should be adopted in children with germline CBL mutations, specific somatic NRAS mutation, and in Noonan syndrome patients, since spontaneous resolution has been reported to occur. Novel drugs targeting relevant nodes of JMML leukemogenesis have been explored in pre-HSCT window or at relapse. The use of 5-azacytidine, a DNA-hypomethylating agent reported to induce hematologic and molecular remission in some JMML children, is currently being investigated in clinical trials. PMID- 29279014 TI - Quality indicator survey versus traditional survey in New York State: a comparison of results from annual nursing home surveys. AB - Despite the passage of OBRA'87 for nursing home reform, concerns about care in facilities continue. The Centers for Medicare and Medicaid developed new regulations and the Traditional Survey (TS) process for annual nursing home survey. The survey is conducted by state regional offices to determine facility compliance with federal regulations. Despite the regulations and new survey process, the TS inconsistently identified problems. A computerized process called the Quality Indicator Survey (QIS) was subsequently developed. This study was designed to compare results from TS and QIS on overall deficiencies, select quality indicators, high-severity deficiencies, and severity differences of seven quality indicators in New York State over a 6-year period from 2010 through 2015. Results of t-tests determined a significant difference in the overall mean number of deficiencies (p < .001), and on four indicators: choices (p < .001), nursing staff (p < .001), dental (p < .001), and dignity (p < .05). Facilities using the TS showed a higher mean number of harm level or higher deficiencies (p < .001). Chi-square tests for severity levels showed significantly more higher severity deficiencies on two quality indicators: nutrition (p < 0.001) and hydration (p < 0.05). Thus, the QIS produced a greater mean number of deficiencies, while TS produced more higher severity deficiencies in New York State. PMID- 29279015 TI - Rodent Neural Progenitor Cells Support Functional Recovery after Cervical Spinal Cord Contusion. AB - Previously, we and others have shown that rodent neural progenitor cells (NPCs) can support functional recovery after cervical and thoracic transection injuries. To extend these observations to a more clinically relevant model of spinal cord injury, we performed unilateral midcervical contusion injuries in Fischer 344 rats. Two-weeks later, E14-derived syngeneic spinal cord-derived multi-potent NPCs were implanted into the lesion cavity. Control animals received either no grafts or fibroblast grafts. The NPCs differentiated into all three neural lineages (neurons, astrocytes, oligodendrocytes) and robustly extended axons into the host spinal cord caudal and rostral to the lesion. Graft-derived axons grew into host gray matter and expressed synaptic proteins in juxtaposition with host neurons. Animals that received NPC grafts exhibited significant recovery of forelimb motor function compared with the two control groups (analysis of variance p < 0.05). Thus, NPC grafts improve forelimb motor outcomes after clinically relevant cervical contusion injury. These benefits are observed when grafts are placed two weeks after injury, a time point that is more clinically practical than acute interventions, allowing time for patients to stabilize medically, simplifying enrollment in clinical trials, and enhancing predictability of spontaneous improvement in control groups. PMID- 29279016 TI - Mental health in underground coal miners. AB - As mental health goes beyond the simple absence of mental disorders, this paper characterized mental health components in 89 underground coal miners in southern Brazil. This is a cross-sectional study, that detected a low prevalence of depression; light or moderate anxiety in 13% of the workers; self-perception of good health; life quality and good psychological capacity in most of the participants; poor sleep quality in half of them; reverse correlations between anxiety and life quality, and anxiety and psychological capital; positive correlations between psychological capital and life quality; associations between self-perception of health, time, and sleep quality; associations between anxiety and sleep duration and quality; and between alcohol consumption and location at work (front, rear, or variable). The results suggest vulnerabilities regarding anxiety and sleep quality. However, there is a potential coping of determinants that impact on mental health. PMID- 29279017 TI - Development of an immunochromatographic assay as a screen for detection of total phthalate acid esters in cooking oil. AB - Phthalate acid esters (PAEs) contamination raised concerns as a result of migration from food packaging and environmental exposure. Because of the adverse effects of PAE reported in humans, the aim of this study was to examine the ability to screen for the detection these chemicals as an indicator of potential exposure. Too develop a sensitive screening test to determine PAE, a specific polyclonal antibody against phthalic acid (PA), the hydrolysate of PAEs, was used as a marker of total PAEs. This method involved the use of 4-aminophthalic acid (APA) as an immunizing hapten to generate antibody. Subsequently, this antibody conjugated with labeled gold nanoparticles (GNPs) was then used to develop an immunochromatographic assay (ICA) for visually detecting PA. After establishing optimal assay conditions, the ICA strip detected visually PA at 3 MUg/ml rapidly in less than 5 min. Further, this assay exhibited reliable specificity for PA with no apparent cross-reactivity with structurally related PAEs. A significant correlation between data obtained with the ICA strip and high-performance liquid chromatography (HPLC) analysis was achieved using cooking oils as model spiked samples. The proposed use of ICA offers an effective tool for rapid on-site screening for total PAEs in cooking oils. PMID- 29279019 TI - Ameliorative Activity of Ethanol Extract of Artocarpus heterophyllus Stem Bark on Pancreatic beta-Cell Dysfunction in Alloxan-Induced Diabetic Rats. AB - This study sought to investigate the ameliorative effects of ethanol extract Artocarpus heterophyllus (EAH) in alloxan-induced diabetic rats. The rats were divided into 6 groups, with groups 1 and 2 serving as nondiabetic and diabetic control, respectively; group 3 serving as diabetic rats treated with 5 mg/kg glibenclamide; and groups 4 to 6 were diabetic rats treated with 50, 100, and 150 mg/kg of EAH, respectively. Assays determined were serum insulin, lipid peroxidation, and antioxidant enzyme activities. EAH stem bark reduced fasting blood glucose and lipid peroxidation levels and increased serum insulin levels and activities of antioxidant enzymes. Data obtained demonstrated the ability of EAH stem bark to ameliorate pancreatic beta-cell dysfunction in alloxan-induced diabetic rats. PMID- 29279018 TI - Naturally Available Extracts Inhibiting Cancer Progression: A Systematic Review. AB - AIM: This systematic review is aimed at evaluating the literature on the efficacy of naturally available extracts that inhibit cancer. METHODS: A literature search was performed to strengthening the reporting of observational studies in epidemiology analysis. Approximately 3000 research articles were initially selected. Of these articles, 200 were included, and 2800 were excluded. On further scrutiny, 150 of the 200 studies were reviews, seminars, and presentations, and 50 were original study articles. Among these articles, 20 studies were selected for the systematic review. RESULTS: The predominant molecular pathways followed by natural extracts were nuclear factor kappa B ligand, suppression of the protein kinase B-Akt/P13K pathway (an intracellular signaling pathway important in regulating cell cycle), vascular endothelial growth factor downregulation, and tumor protein-P53 tumor suppressor upregulation. CONCLUSIONS: It is evident that natural extracts have the ability to inhibit cancer progression. Continued research in this field could facilitate the use of natural extracts with currently available anticancer agents. PMID- 29279020 TI - Short-term outcomes comparison between preterm infants with and without acute hypoxic respiratory failure attributable to presumed pulmonary hypoplasia after prolonged preterm premature rupture of membranes before 25 gestational weeks. AB - OBJECTIVE: To determine the updated outcomes of preterm infants with acute hypoxic respiratory failure attributable to presumed pulmonary hypoplasia (PH) following maternal midtrimester prolonged preterm premature rupture of membranes (PPROM). STUDY DESIGN: Among preterm infants with birthweight <1500 g and 23-34 weeks gestational age in a single center, infants exposed to maternal prolonged (>=7 days) PPROM before 25 gestational weeks (PPPROM25, n = 76) were retrospectively reviewed. They were 1:1 matched with infants of matched control group (n = 76) who were unexposed to or exposed to maternal PPROM within 24 hours of delivery by year, gestational age, and weight at birth, sex, and antenatal steroid exposure. The PPPROM25 group was subdivided into infants with and without acute hypoxic respiratory failure attributable to PH (with PH, n = 20, without PH, n = 56, respectively). Clinical characteristics and major outcomes were compared. Risk factors for mortality and morbidity were analyzed using a multivariate logistic regression in the PPPROM25 group. RESULTS: The PH incidence rates were 1.3 and 26.3% and in the matched control and PPPROM25 group, respectively (p < .05). The survival rates were 92.1 and 81.6% in the matched control and PPPROM25 group (p > .05); 87.5 in the PPPROM25 group without PH and 65.0% in group with PH, respectively (p < .05). While there were no significant differences between matched control and PPROM25 group, the PPROM25 with PH group had a significantly higher rate of periventricular leukomalacia (PVL) and composite morbidity, including mortality, bronchopulmonary dysplasia, high-grade intraventricular hemorrhage, and PVL than PPPROM25 without PH group. PH was a significant risk factor for mortality and composite morbidity in the PPPROM25 group. CONCLUSIONS: Despite the improved outcomes in the infants with maternal prolonged PPROM before 25 gestational weeks, presumed PH is still a significant risk factor for their mortality and morbidity. PMID- 29279022 TI - Personality and its Relationship to Depression and Cognition in Older Adults: Implications for Practice. AB - OBJECTIVES: Personality is an important contributor to an individual's mental health and is consistently linked to the two most prevalent mental health conditions among older adults: dementia and depression. This review summarizes the current findings on personality and its association with cognitive decline and depression, as well as treatment outcomes and possible intervention strategies. METHODS: Literature searches were conducted in Web of Science, PubMed, and PsycINFO. Search terms included 'personality traits,' 'depression,' 'treatment,' and 'older adults.' RESULTS: Cognitive decline and depressive disorders are both associated with a common personality profile: high neuroticism, and low conscientiousness, extraversion, openness, and agreeableness. Across studies, the most consistent predictor of late-life depression, its course, and treatment outcomes is higher neuroticism. CONCLUSIONS: Personality traits are associated with cognitive decline, as well as the diagnosis and course of late-life depression in older adults. However, formal personality assessment is not typically incorporated in clients' treatment plans, even though personality traits may influence treatment efficacy and outcomes. CLINICAL IMPLICATIONS: Formal assessment of personality traits may be beneficial in terms of treatment adherence and outcomes for older adults. Tailored interventions that specifically target the client's strengths are likely to be well received by both clients and clinicians. PMID- 29279021 TI - Increased Myo-Inositol in Primary Motor Cortex of Contact Sports Athletes without a History of Concussion. AB - The objective of the study was to determine whether repetitive hits to the head at a subclinical level are associated with structural and functional brain abnormalities and whether these effects are influenced by high levels of fitness associated with intense physical activity. Seventy-two college students were recruited: 24 nonathletic, 24 athletes practicing a varsity contact sport, and 24 athletes practicing a varsity noncontact sport. They were recruited for a neuropsychological evaluation and a magnetic resonance imaging session that included magnetic resonance spectroscopy of primary motor cortex (M1) and prefrontal cortex and susceptibility-weighted imaging. There was no evidence for reduced cognitive performance or presence of micro bleeds in contact sports athletes. Abnormalities in contact sports athletes were found for myo-inositol concentration (mIns) in M1, where levels were significantly higher compared with noncontact sports athletes (p = 0.016) and nonathletes (p = 0.029). In prefrontal cortex, glutamate + glutamine (Glx) was significantly reduced in contact sports athletes compared with noncontact sports athletes (p = 0.016), and a similar reduction was observed for gamma-aminobutyric acid (GABA) levels (p = 0.005). Varsity contact sports are associated with area-specific alterations in mIns concentration in the primary motor cortex. In the prefrontal cortex, high levels of fitness could modulate the effects of head impact exposure on prefrontal metabolite concentration. Indeed, although athletes in contact and noncontact sports show different neurometabolic profiles, they do not differ from sedentary controls. PMID- 29279023 TI - Knobby Eye Syndrome. AB - INTRODUCTION: A spherical globe is traditionally assumed, but this study employed magnetic resonance imaging (MRI) to demonstrate frequent occurrence of non spherical staphylomata in strabismic patients. METHODS: High-resolution, surface coil MRI was obtained in multiple image planes in 21 highly myopic subjects (36 eyes) and compared with 17 normal controls (33 eyes). Images were analyzed for axial length, aspect ratio of eye shape, and deflection of muscle paths. RESULTS: All but two high myopes had strabismus. While myopic globes were generally spherical in 10 myopic eyes including both orthotropic subjects, 15 globes exhibited diffuse posterior staphylomata, 16 equatorial staphylomata, and 4 both posterior and equatorial staphylomata. Equatorial scleral ectasias were positioned to contact and elongate paths of horizontal rectus muscles in some gaze positions. Axial length in myopes averaged 28.8 +/- 3.8 (SD) mm and did not differ significantly between regular vs. irregular staphylomata. Globe aspect ratios in the coronal, axial, and sagittal planes were significantly greater than normal in myopes (P < 0.005), but correlated significantly with axial length only in the axial and sagittal planes (P < 0.03). While myopes with irregular staphylomata were older at 57 +/- 11 years than subjects with spherical globes at 24 +/- 8 years (P < 0.0005), other clinical features were similar. CONCLUSION: Irregular equatorial or posterior staphylomata are common in strabismic axial high myopes, acting, like "cams" affixed to the normally spherical globe so that they may have no mechanical effect until rotating eccentrically against muscles. After rotational contact, staphylomata would nonlinearly increase muscle tension with further duction. Imaging may be clinically informative about this "knobby eye syndrome." PMID- 29279025 TI - Spiritual Diversity and Living with Early-Stage Dementia. AB - Attention to spiritual diversity is necessary for the provision of culturally informed clinical care for people with early-stage dementia and their family members. In this article, an evidence-based theoretical framework for conceptualizing spiritual diversity is described in detail (Pargament, 2011). The framework is then applied to two clinical case studies of people living with early-stage dementia to elucidate the multilayered components of spiritual diversity in this population. The case studies were selected from a larger mixed methods study on spirituality, positive psychological factors, health, and well being in people living with early-stage dementia and their family members. To our knowledge this is the first systematic attempt to apply a theoretical framework for understanding spiritual diversity in this population. Implications for clinical practice are provided. PMID- 29279024 TI - Ultrafine particulate matter exposure impairs vasorelaxant response in superoxide dismutase 2-deficient murine aortic rings. AB - : Studies have linked exposure to ultrafine particulate matter (PM) and adverse cardiovascular events. PM-induced oxidative stress is believed to be a key mechanism underlying observed adverse vascular effects. Advanced age is one factor known to decrease antioxidant defenses and confer susceptibility to the detrimental vascular effects seen following PM exposure. The present study was designed to investigate the vasomotor responses following ultrafine PM exposure in wild type (WT) and superoxide dismutase 2-deficient (SOD2+/-) mice that possess decreased antioxidant defense. Thoracic aortic rings isolated from young and aged WT and SOD2+/- mice were exposed to ultrafine PM in a tissue bath system. Aortic rings were then constricted with increasing concentrations of phenylephrine, followed by relaxation with rising amounts of nitroglycerin (NTG). Data demonstrated that ultrafine PM decreased the relaxation response in both young WT and young SOD2+/- mouse aortas, and relaxation was significantly reduced in young SOD2+/- compared to WT mice. Ultrafine PM significantly diminished the NTG-induced relaxation response in aged compared to young mouse aortas. After ultrafine PM exposure, the relaxation response did not differ markedly between aged WT and aged SOD2+/- mice. Data demonstrated that the greater vascular effect in aortic rings in aged mice ex vivo after ultrafine PM exposure may be attributed to ultrafine PM-induced oxidative stress and loss of antioxidant defenses in aged vascular tissue. Consistent with this conclusion is the attenuation of NTG-induced relaxation response in young SOD2+/- mice. ABBREVIATIONS: H2O2: hydrogen peroxide; NTG: nitroglycerin; PAH: polycyclic aromatic hydrocarbons; PE: l-phenylephrine; PM: particulate matter; ROS: reactive oxygen species; SOD2: superoxide dismutase 2 deficient; WT: wild type. PMID- 29279026 TI - Cortical Visual Connections via the Corpus Callosum are Asymmetrical in Human Infantile Esotropia. AB - PURPOSE: Besides chiasmal hemidecussation, interhemispheric connections are likely important in human binocularity. The corpus callosum (CC) is the major fiber bundle in the mammalian brain which mostly connects homologous cortical areas in the two hemispheres. Visual interhemispheric connections were found abnormal in strabismic cats. No studies have investigated these pathways in humans with infantile strabismus. METHODS: Diffusion tensor imaging was used in four subjects with infantile esotropia (IE) and nine control subjects with normal binocularity, in order to study interhemispheric fibers in the CC connecting the right and left primary visual cortical areas. RESULTS: The number of callosal fibers linking both visual cortical areas between the hemispheres was found to be higher in subjects with IE. Also in IE, the amount of visual callosal fibers found after analysis from the primary visual cortical areas on one side appeared significantly different from the amount starting from the contralateral primary visual areas. The distribution area on one side is wider. CONCLUSION: We show callosal visual fibers to be abnormal in human IE. Subjects with IE showed abnormal numbers of transcallosal fibers connecting the visual cortical areas on both sides which likely results from an abnormal elimination process during development. Pruning of these fibers in IE favors the side of the visual cortex ipsilateral to the dominant eye. This study underlines the likely role of the CC in the development of human binocularity. PMID- 29279027 TI - Harnessing mutual exclusivity between TP53 and ARID1 A mutations. PMID- 29279028 TI - Helping Smokers Quit: The Smoking Cessation Leadership Center Engages Behavioral Health by Challenging Old Myths and Traditions. AB - Smoking is much more common among persons with behavioral health conditions (mental illnesses and/or substance use disorders). Persons with these disorders are more likely to die from smoking-related causes than any other reason. Studies have shown that stopping smoking can improve mental health function, as well as improve outcomes for substance use disorders. Yet, for a variety of reasons, smoking cessation has not been integrated into the treatment of behavioral health conditions, and in many instances tobacco use was not only condoned but encouraged. Beginning in 2007, the Smoking Cessation Leadership Center (SCLC) began engaging relevant agencies in an attempt to stimulate more vigorous smoking cessation activities. Partners included the federal Substance Abuse and Mental Health Services Administration, advocacy organizations such as the National Alliance on Mental Illness and Community Anti-Drug Coalitions of America, and clinical groups such as the American Psychiatric Nurses Association, the American Psychiatric Association, American Psychological Association, National Council on Behavioral Health, and National Association of State Mental Health Program Directors. A signature program featured 16 individual state summits involving agencies and groups from multiple sectors, all aiming to lower smoking rates in behavioral health populations. These activities mark an evolving culture change within behavioral health. PMID- 29279029 TI - Beyond Leisure: The Role of Alcohol in the Lives of Nigerian University Students. AB - BACKGROUND: Alcohol consumption among young people in Nigeria has traditionally been constrained due to the socio-cultural belief that alcohol is for adults. In contemporary Nigeria, media reports indicate that young people drink alcohol regularly in large quantities, but empirical research on what motivates their alcohol use is lacking. OBJECTIVES: To explore the motives for consuming alcohol among male and female students at a Nigerian university. METHODS: Drawing on motivational theories of alcohol use, 31 semi-structured interviews were conducted with students (aged 19-23 years). The data were analyzed to generate themes with the aid of NVivo software. RESULTS: Three themes (drinking to cope; overcoming academic performance anxiety; and drinking to socialize) were identified under coping, enhancement and social motives. First, while both male and female participants used alcohol to attenuate sorrow, anger, and stress, females also drank to ameliorate depression and heartbreak due to relationship problems. Second, men and women perceived that alcohol provided them with "academic courage." Hence, they drank to boost their confidence in delivering class seminars. Relatedly, women used alcohol in a bid to enhance their retentive memory before taking written examinations. Third, men and women engaged in gendered heavy drinking rituals purposefully to get drunk and loosen up. This enables men to discuss what they referred to as "men's affairs" while it enables women to "reveal deep secrets" (to inebriated group members) that they would not ordinarily reveal when they are sober. Women's drink choice was associated with social motives because spirits were used purposefully to quicken their intoxication. CONCLUSIONS: Participants who drank due to coping and social motives consumed larger quantities of alcohol than they consumed on "normal" drinking occasions. We discuss the implications of these findings and offer suggestions for public health interventions that policymakers might consider implementing, to reduce alcohol-related harms in the Nigerian Higher Education system. PMID- 29279030 TI - Case Report of Ipilimumab-Induced Diffuse, Nonnecrotizing Granulomatous Lymphadenitis and Granulomatous Vasculitis. AB - Ipilimumab is indicated for the treatment of melanoma in both the metastatic and adjuvant setting. Ipilimumab inhibits cytotoxic T-lymphocyte antigen 4, leading to the augmentation of T-cell activity and an antitumor immune system response. The side effect profile of ipilimumab consists of autoimmune-like events such as dermatitis, colitis, and thyroiditis. These immune-related adverse events can be serious, often resulting in the need for systemic immunosuppression with corticosteroids. We present a case of diffuse, nonnecrotizing granulomatous lymphadenitis and granulomatous vasculitis in a heavily pretreated patient with metastatic melanoma. After completion of 4 cycles of ipilimumab for the treatment of metastatic melanoma, our patient complained of increasing fatigue, drenching night sweats, and chills. Imaging revealed diffuse adenopathy involving several lymph nodes. Biopsy was positive for nonnecrotizing granulomatous lymphadenitis and granulomatous vasculitis. High-dose prednisone was initiated and tapered gradually over 6 weeks, resulting in complete resolution of the granulomatous disease. PMID- 29279031 TI - The classification of almonds (Prunus dulcis) by country and variety using UHPLC HRMS-based untargeted metabolomics. AB - The aim of this study was to use an untargeted UHPLC-HRMS-based metabolomics approach allowing discrimination between almonds based on their origin and variety. Samples were homogenised, extracted with ACN:H2O (80:20) containing 0.1% HCOOH and injected in a UHPLC-QTOF instrument in both positive and negative ionisation modes. Principal component analysis (PCA) was performed to ensure the absence of outliers. Partial least squares - discriminant analysis (PLS-DA) was employed to create and validate the models for country (with five different compounds) and variety (with 20 features), showing more than 95% accuracy. Additional samples were injected and the model was evaluated with blind samples, with more than 95% of samples being correctly classified using both models. MS/MS experiments were carried out to tentatively elucidate the highlighted marker compounds (pyranosides, peptides or amino acids, among others). This study has shown the potential of high-resolution mass spectrometry to perform and validate classification models, also providing information concerning the identification of the unexpected biomarkers which showed the highest discriminant power. PMID- 29279032 TI - Multiple Myeloma With Multilobated Plasma Cells: An Unusual and Challenging Morphological Variant. PMID- 29279033 TI - Alcohol consumption patterns of older adults: a study in a regional town in Western Australia. AB - AIM: This study aimed to demonstrate that opportunistic health screening at health expos can provide an overall impression of alcohol consumption patterns. DESIGN: A repeated cross-sectional survey design, completed over a four-year period (2011-2014), was used to assess the risk of harmful alcohol consumption, within a community setting of older adults, in the South West region of Western Australia. METHODS: An alcohol screening survey (AUDIT) was used to collect data on alcohol consumption patterns on those aged 65 years and over. A total of 411 surveys were completed. RESULTS: There was a statistically significant difference in mean risk scores across the four years (p < .001). 6.3-22.2% of survey completers presented as 'risky', and a further 3.8-12.3% as 'high risk' in terms of alcohol consumption. CONCLUSIONS: Opportunistic screening for alcohol consumption during health expos can aid the identification of at-risk individuals who may require further education or treatment. PMID- 29279035 TI - Exploring the Most Important Negative Life Events in Older Adults Bereaved of Child, Spouse, or Both. AB - Losing a child or a spouse is described as the worst of experiences. However, it is not known whether older adults bereaved of a child, spouse, or both child and spouse experience these losses as among the most important negative events in their lifetime. The aim of this study was to investigate whether the 1,437 older adults bereaved of a child, spouse, or both included in the southern part of the Swedish National Study of Aging and Care mentioned these losses when asked about their three most important negative life events. Gender differences in their choices of important negative life events were also explored. About 70% of those bereaved of a child or a spouse mentioned these losses as among their three most important negative life experiences. In the child-and-spouse-bereaved group, 48% mentioned both the loss of their child and spouse, while 40% mentioned either the loss of a child or a spouse. Gender differences were only found in the child-and spouse-bereaved group, with a few more women mentioning the loss of the child but not the spouse, and the men showing the opposite pattern. PMID- 29279037 TI - How to Increase the Quality of a Suffering Experience: Lessons Derived From the Diary Narratives of a Dying Adolescent Girl. AB - Personal narratives are assumed to be primary sources of the essential meaning of lived experiences of dying. In this study, I analyzed the personal diary of Mirac Fidan, a terminally ill adolescent with advanced cancer who kept a diary until her death at the age of 15. Mirac's Diary, also published as a book, was subjected to hermeneutic phenomenological narrative analysis. Inferences were drawn regarding the following basic elements: (a) The dynamics in which Mirac lived and (2) her perceptions of herself, her immediate environment, and her experiences. Suffering seems to be the main experience dominating Mirac's life, which I examined with regard to two dimensions: suffering caused by inevitable factors and suffering caused by preventable/changeable factors. The results suggest that if various causes among contextual factors are neutralized, then the quality of the existential experience determined by the inevitable factors would increase. PMID- 29279038 TI - Development of a Bereavement Group in a Geriatric Mental Health Clinic for Veterans. AB - OBJECTIVES: This article describes the development and program evaluation of an 8 session outpatient geriatric mental health clinic bereavement group for United States military veterans who experienced the death of a loved one. METHODS: Group materials were developed based on a review of literature, with a focus on the dual process model of coping with bereavement and complicated grief treatment. Data are presented from 19 veterans who attended at least 4 of the 8 sessions across the five offerings of this group between 2013 and 2015. RESULTS: Self report measures of complicated grief and depressive symptoms decreased significantly from the first to the final session. Veterans indicated that the group met their treatment goals and that they would recommend it to others. Adaptations made to the group over time based on feedback from members and facilitators are discussed. CONCLUSIONS: Preliminary evidence suggests that the group described in this manuscript is effective for bereaved older, male veterans. Future research would be helpful including larger samples and controlled studies. CLINICAL IMPLICATIONS: Most bereaved individuals do not require formal mental health treatment. However, for individuals with distressing symptoms, time-limited group therapy may be an effective treatment. PMID- 29279039 TI - Characterisation and antimicrobial activity of active polypropylene films containing oregano essential oil and Allium extract to be used in packaging for meat products. AB - Cooked ham is more prone to spoilage than other meat products, making preservation a key step in its commercialisation. One of the most promising preservation strategies is the use of active packaging. Oregano essential oil (OEO) and Proallium(r) (an Allium extract) have previously been shown to be useful in polylactic acid (PLA)-active films for ready-to-eat salads. The present work aims to study the suitability of polypropylene (PP) films containing OEO and Proallium(r) in the preservation of cooked ham. Concerning the technological features of the studied material, no significant changes in the mechanical or optical properties of PP films containing the active substances were recorded in comparison to the PP film without extracts. However, films containing both active substances were more flexible than the control film and less strong, highlighting the plasticisation effect of the natural extracts. Moreover, physical properties changed when active substances were added to the film. Incorporation of 4% Proallium(r) affected the transparency of the film to a higher extent compared to 8% OEO, undergoing decreases in transparency of 40% and 45%, respectively. Moreover, only the film containing the highest amount of OEO (8%) significantly decreased the thickness. Both active substances showed antibacterial properties; however, Proallium(r)-active films seemed to be more effective against Brochothrix thermosphacta than PP films containing OEO, with all percentages of Proallium(r) killing the bacterial population present in the ham after 60 days. In addition, materials containing the lowest Proallium(r) content exhibited higher acceptability by consumers in the sensory analyses with 63-100% willing to purchase, better even than the control package (56-89%). In fact, 2% of Proallium(r) obtained the best results in the odour study performed by the panellists. PMID- 29279040 TI - Helping Smokers Quit: New Partners and New Strategies from the University of California, San Francisco Smoking Cessation Leadership Center. AB - The Smoking Cessation Leadership Center (SCLC) was established in 2003 to increase the rate of smoking cessation attempts and the likelihood those efforts would succeed. Although smoking remains the number one cause of preventable death and disability, clinicians underperform in smoking cessation. Furthermore, many clinical organizations, governmental agencies, and advocacy groups put little effort into smoking cessation. Initially targeted at increasing the efforts of primary care physicians, SCLC efforts expanded to include many other medical and non-physician disciplines, ultimately engaging 21 separate specialties. Most clinicians and their organizations are daunted by efforts required to become cessation experts. A compromise solution, Ask, Advise, Refer (to telephone quitlines), was crafted. SCLC also stimulated smoking cessation projects in governmental, not-for-profit, and industry groups, including the Veterans Administration, the Health Resources Services Administration, Los Angeles County, and the Joint Commission. SCLC helped CVS pharmacies to stop selling tobacco products and other pharmacies to increase smoking cessation efforts, provided multiple educational offerings, and distributed $6.4 million in industry supported smoking cessation grants to 55 organizations plus $4 million in direct SCLC grants. Nevertheless, smoking still causes 540,000 annual deaths in the US. SCLC's work in the field of behavioral health is described in a companion article. PMID- 29279041 TI - Exercise through a cardiac rehabilitation program attenuates oxidative stress in patients submitted to coronary artery bypass grafting. AB - BACKGROUND: Cardiovascular disease is the main cause of morbidity and mortality in the world and oxidative stress has been implicated in the pathogenesis. Cardiac rehabilitation in patients with coronary artery disease submitted to coronary artery bypass grafting may prevent cardiovascular events probably through the attenuation of oxidative stress. The aim of this study was to evaluate the benefits of a cardiac rehabilitation program in the control of the systemic oxidative stress. METHODS: The studied population consisted of 40 patients, with chronic stable coronary artery disease submitted to coronary artery bypass grafting, who attended a cardiac rehabilitation program. Biomarkers of oxidative stress were evaluated in the blood of these patients at different moments. RESULTS: After the onset of cardiac rehabilitation, there was a significant and progressive decrease in thiobarbituric acid reactive substances levels and protein carbonyls, an initial increase and subsequent decrease in superoxide dismutase, catalase and glutathione peroxidase activities. Also, a progressive increase of uric acid, while ferric reducing antioxidant power levels increased only at the end of the cardiac rehabilitation and a tendency to increase of glutathione contents. CONCLUSIONS: The results suggest that regular exercise through a cardiac rehabilitation program can attenuate oxidative stress in chronic coronary artery disease patients submitted to coronary artery bypass grafting. PMID- 29279042 TI - Rapid evaporative ionisation mass spectrometry and chemometrics for high throughput screening of growth promoters in meat producing animals. AB - In a proof of concept perspective, Rapid Evaporative Ionisation Mass Spectrometry (REIMS) was explored for the direct analysis of meat samples from beta-agonist treated livestock. In this context, the combination of REIMS with untargeted metabolomics was investigated to identify carcasses from treated animals on the basis of a modification of indirect metabolites profile. The REIMS analysis generated specific lipid profiles which enabled the differentiation of meat samples collected from pigs treated with ractopamine via their feeding regime. Furthermore, the strategy was found successful when tested on different muscle types (loin, shoulder and thigh), which further expands its applicability. Classification performances were greater than 95% accurate which fully answers requirements of a screening strategy. This research indicates that REIMS implemented in an untargeted-metabolomics workflow can be considered as a high throughput and accurate strategy for real-time meat classification in relation to ractopamine (and wider beta-agonists) treatment in pig production. This approach may subsequently be implemented as a rapid screening test, at the slaughterhouse or at border inspection points, to detect such practice. PMID- 29279043 TI - Characterization of pulmonary responses in mice to asbestos/asbestiform fibers using gene expression profiles. AB - Humans exposed to asbestos and/or asbestiform fibers are at high risk of developing many lung diseases including asbestosis, lung cancer, and malignant mesothelioma. However, the disease-causing potential and specific metabolic mechanisms and pathways associated with various asbestos/asbestiform fiber exposures triggering different carcinogenic and non-carcinogenic outcomes are still largely unknown. The aim of this this study was to investigate gene expression profiles and inflammatory responses to different asbestos/asbestiform fibers at the acute/sub-acute phase that may be related to delayed pathological outcomes observed at later time points. Mice were exposed to asbestos (crocidolite, tremolite asbestos), asbestiform fibers (erionite), and a low pathogenicity mineral fiber (wollastonite) using oropharyngeal aspiration. Similarities in inflammatory and tissue damage responses, albeit with quantitative differences, were observed at day 1 and 7 post treatment. Exposure to different fibers induced significant changes in regulation and release of a number of inflammatory cytokines/chemokines. Comparative analysis of changes in gene regulation in the lung on day 7 post exposure were interpretable in the context of differential biological responses that were consistent with histopathological findings at days 7 and 56 post treatment. Our results noted differences in the magnitudes of pulmonary responses and gene regulation consistent with pathological alterations induced by exposures to four asbestos/asbestiform fibers examined. Further comparative mechanistic studies linking early responses with the long-term endpoints may be instrumental to understanding triggering mechanisms underlying pulmonary carcinogenesis, that is lung cancer versus mesothelioma. PMID- 29279044 TI - Evaluation of 16S rRNA qPCR for detection of Mycobacterium leprae DNA in nasal secretion and skin biopsy samples from multibacillary and paucibacillary leprosy cases. AB - Mycobacterium leprae bacilli are mainly transmitted by the dissemination of nasal aerosols from multibacillary (MB) patients to susceptible individuals through inhalation. The upper respiratory tract represents the main entry and exit routes of M. leprae. Therefore, this study aimed to evaluate the sensitivity and specificity of real-time quantitative polymerase chain reaction (qPCR) in detecting M. leprae in nasal secretion (NS) and skin biopsy (SB) samples from MB and paucibacillary (PB) cases. Fifty-four NS samples were obtained from leprosy patients at the Dona Libania National Reference Centre for Sanitary Dermatology in Ceara, Brazil. Among them, 19 MB cases provided both NS and SB samples. Bacilloscopy index assays were conducted and qPCR amplification was performed using specific primers for M. leprae 16S rRNA gene, generating a 124-bp fragment. Primer specificity was verified by determining the amplicon melting temperature (Tm = 79.5 degrees C) and detection limit of qPCR was 20 fg of M. leprae DNA. Results were positive for 89.7 and 73.3% of NS samples from MB and PB cases, respectively. SB samples from MB patients were 100% positive. The number of bacilli detected in NS samples were 1.39 * 103-8.02 * 105, and in SB samples from MB patients were 1.87 * 103-1.50 * 106. Therefore, qPCR assays using SYBR Green targeting M. leprae 16S rRNA region can be employed in detecting M. leprae in nasal swabs from leprosy patients, validating this method for epidemiological studies aiming to identify healthy carriers among household contacts or within populations of an endemic area. PMID- 29279045 TI - Ticagrelor for Neuroendovascular Procedures: A Case Series. AB - BACKGROUND: The development of thromboembolism is one of the most common complications of neuroendovascular procedures. Although several small studies have deemed clopidogrel safe and effective in the prevention of intracranial stent thrombosis, ticagrelor has yet to be assessed in this setting. OBJECTIVE: The objective of this study was to retrospectively evaluate the safety and efficacy of ticagrelor in patients undergoing neuroendovascular procedures. METHODS: A retrospective review of patients receiving ticagrelor following neuroendovascular aneurysm repair. RESULTS: A total of 5 patients undergoing neuroendovascular aneurysm repair received ticagrelor for a median of 5 days while hospitalized. Three patients were treated with stent-assisted coiling, while 2 received pipeline embolization devices. All patients received additional low-dose aspirin therapy. One patient received ticagrelor after experiencing a thrombotic event on clopidogrel, while a second patient was treated with ticagrelor after developing a dermatologic reaction to clopidogrel. Three (60%) patients were successfully treated and discharged on ticagrelor therapy. Two patients experienced cerebrovascular accidents following aneurysm repair while receiving ticagrelor, one of which was potentially due to medication omission. One (20%) patient receiving ticagrelor experienced a small retroperitoneal hematoma; however, ticagrelor therapy was continued without further complication. CONCLUSION: Therapy with ticagrelor may be a safe and effective treatment option for patients undergoing neuroendovascular aneurysm repair. However, future studies are warranted to substantiate these findings. PMID- 29279046 TI - Human Wharton's Jelly Cells Activate Degenerative Nucleus Pulposus Cells In Vitro. AB - To investigate the interaction between human Wharton's jelly cells (WJCs) and degenerative nucleus pulposus cells (NPCs), human WJCs were cocultured with degenerative NPCs with or without direct cell-cell contact. WJCs were isolated from the human umbilical cord and degenerative NPCs were isolated from the surgically obtained degenerative intervertebral disc tissue. The isolated WJCs positively expressed CD73, CD105, CD90, CD29, CD166, and human leukocyte antigen (HLA)-ABC, but negatively expressed CD34, CD45, and HLA-DR. After coculturing with three different WJCs:NPCs ratios for 7 days, the real-time polymerase chain reaction showed that the relative gene expression of nucleus pulposus (NP)-marker genes [aggrecan, type II collagen, and SRY-type HMG box-9 (SOX-9)] was significantly upgraded in all coculture groups (all p < 0.05 compared with control groups). Coculture either with or without cell-cell contact significantly activated the expression of NP-maker genes than controls, but coculture with cell cell contact yielded a higher gene expression than coculture without cell-cell contact. In coculturing with cell-cell contact and WJCs:NPCs of 25:75, the relative gene expression of aggrecan, type II collagen, SOX-9 for WJCs yielded the highest increase by 721-, 1507-, and 1463-folds, respectively (all p < 0.05 compared with WJCs control). In contrast, the highest relative gene expression of aggrecan, type II collagen, SOX-9 for NPCs was 112-, 84-, and 109-folds, respectively, in coculture with cell-cell contact and in WJCs:NPCs of 75:25 (all p < 0.05 compared with NPCs control). In conclusion, the data indicated that coculturing human WJCs with degenerative NPCs induced the NP-like cell differentiation of WJCs and restored the biological status of degenerative NPCs and coculture WJCs and NPCs with direct cell-cell contact yielded more favorable gene expressions. PMID- 29279047 TI - Financial Capability and Sociodemographic Factors among Survivors of Human Trafficking. AB - Improving the economic well-being of the girls and women is a key to reducing re trafficking and in providing stability that survivors can use to rebuild their lives. The study looks at how various sociodemographic traits affected the financial capability of n = 144 women and girls who received intervention at a residential care facility in Ghana, West Africa. Three domain of financial capability are assessed in this, i.e., financial risk, financial planning, and financial saving. A scaled likelihood ratio test (chi-square difference test) was used to evaluate the significance of each direct covariate effect(%). Each of the overall goodness-of-fit indices suggested that the initial CFA model fit the data well, chi2(19, N = 144) = 31.45, p = 0.04, RMSEA = 0.067 (90% CI: 0.017-0.108), TLI = 0.923, CFI = 0.948. Older women reported lower levels of financial savings than younger women. We found that women with secondary school education or higher reported significantly higher financial risk than women with less education. Women with children reported lower levels of financial saving than women without children. Married women indicated significantly more financial saving than single women. There was a significant negative effect of time spent in trafficking conditions on financial saving, indicating the highest average level of financial savings at intervention and decreased thereafter. Programs and policies in resource-scarce contexts that aim to assist trafficking survivors must go beyond providing psychosocial counseling and focus also on economic development opportunities. PMID- 29279048 TI - When Personal Feels Invasive: Foreseeing Challenges in Precision Medicine Communication. AB - Precision medicine (PM) draws upon individual biological and psychosocial factors to create a personalized approach to healthcare. To date, little is known about how healthcare consumers will respond to such highly personalized guidance and treatment. The assumption is that responses will generally be favorable; yet in the media and in online public discussions about PM, concerns have been raised about invasions of privacy and autonomy. Findings from the tailoring literature relevant because PM is, in a sense, "hypertailoring"-similarly suggest a potential for provoking unintended consequences such as personalization reactance, wherein perceived threat to one's privacy or freedom can lead to rejection of the personalized message or its source. Here, we review extant tailoring and other relevant research to identify challenges that could arise in PM communication. We then draw upon a patient-centered communication perspective to highlight elements of the communication process wherein resistance could be mitigated. This review aims to provide preliminary guidance for practitioners when communicating with patients and healthcare consumers about PM, as well as point scholars toward fruitful topics for research in this emerging health communication area. PMID- 29279049 TI - Effect of gaseous ozone treatments on DON, microbial contaminants and technological parameters of wheat and semolina. AB - Deoxynivalenol (DON) is an important mycotoxin produced by several species of Fusarium. It occurs often in wheat grain and is frequently associated with significant levels of its modified form DON-3-glucoside (DON-3-Glc). Ozone (O3) is a powerful disinfectant and oxidant, classified as GRAS (Generally Recognised As Safe), that reacts easily with specific compounds including the mycotoxins aflatoxins, ochratoxin A, trichothecenes and zearalenone. It degrades DON in aqueous solution and can be effective for decontamination of grain. This study reports the efficacy of gaseous ozone treatments in reducing DON, DON-3-Glc, bacteria, fungi and yeasts in naturally contaminated durum wheat. A prototype was used to dispense ozone continuously and homogeneously at different concentrations and exposure time, in 2 kg aliquots of durum wheat. The optimal conditions, which do not affect chemical and rheological parameters of durum wheat, semolina and pasta, were identified (55 g O3 h-1 for 6 h). The measured mean reductions of DON and DON-3-Glc in ozonated wheat were 29% and 44%, respectively. Ozonation also produced a significant (p < 0.05) reduction of total count (CFU/g) of bacteria, fungi and yeasts in wheat grains. PMID- 29279051 TI - EARLY gestational exposure to isoflurane causes persistent cell loss in the dentate gyrus of adult male rats. AB - BACKGROUND: Our previous research showed that 4 h of maternal anesthesia with isoflurane during early gestation in pregnant rats leads to a deficit in spatial memory of adult male offspring. Because spatial memory is predominantly a hippocampally-mediated task, we asked the question if early gestational exposure to isoflurane affects development of the hippocampus in the offspring. FINDINGS: Previously behaviorally characterized adult male rats that were exposed to isoflurane during second trimester were sacrificed at 4 months of age (N = 10 and 13, control and isoflurane groups, respectively) for quantitative histology of hippocampal subregions. Sections were stained with cresyl violet and the total number of cells in the granular layer of the dentate gyrus and the pyramidal cell layer in the CA1 region were determined by a blinded observer using unbiased stereological principles and the optical fractionator method. Data were analyzed using Student's t test; P < 0.05 was accorded statistical significance. Stereological examination revealed 9% fewer cells in the granular layer of the dentate gyrus of isoflurane-exposed adult rats compared to controls (1,002,122 +/ 84,870 vs. 1,091,829 +/- 65,791, respectively; Mean +/- S.D, *P = 0.01). In contrast, there were no changes in the cell number in the CA1 region, nor were there changes in the volumes of both regions. CONCLUSIONS: Our results show that maternal isoflurane anesthesia in rodents causes region-specific cell loss in the hippocampus of adult male offspring. These changes may, in part, account for the behavioral deficits reported in adult rats exposed to isoflurane in utero. PMID- 29279050 TI - Expression regulation and functional analysis of RGS2 and RGS4 in adipogenic and osteogenic differentiation of human mesenchymal stem cells. AB - BACKGROUND: Understanding the molecular basis underlying the formation of bone forming osteocytes and lipid-storing adipocytes will help provide insights into the cause of disorders originating in stem/progenitor cells and develop therapeutic treatments for bone- or adipose-related diseases. In this study, the role of RGS2 and RGS4, two members of the regulators of G protein signaling (RGS) family, was investigated during adipogenenic and osteogenenic differentiation of human mesenchymal stem cells (hMSCs). RESULTS: Expression of RGS2 and RGS4 were found to be inversely regulated during adipogenesis induced by dexamethasone (DEX) and 3-isobutyl-methylxanthine, regardless if insulin was present, with RGS2 up-regulated and RGS4 down-regulated in response to adipogenic induction. RGS2 expression was also up-regulated during osteogenesis at a level similar to that induced by treatment of DEX alone, a shared component of adipogenic and osteogenic differentiation inducing media, but significantly lower than the level induced by adipogenic inducing media. RGS4 expression was down-regulated during the first 48 h of osteogenesis but up-regulated afterwards, in both cases at levels similar to that induced by DEX alone. Expression knock-down using small interfering RNA against RGS2 resulted in decreased differentiation efficiency during both adipogenesis and osteogenesis. On the other hand, expression knock down of RGS4 also resulted in decreased adipogenic differentiation but increased osteogenic differentiation. CONCLUSIONS: RGS2 and RGS4 are differentially regulated during adipogenic and osteogenic differentiation of hMSCs. In addition, both RGS2 and RGS4 play positive roles during adipogenesis but opposing roles during osteogenesis, with RGS2 as a positive regulator and RGS4 as a negative regulator. These results imply that members of RGS proteins may play multifaceted roles during human adipogenesis and osteogenesis to balance or counterbalance each other's function during those processes. PMID- 29279052 TI - Congenital basal meningoceles with different outcomes: a case series. AB - BACKGROUND: Basal meningoceles are rare congenital defects and often clinically occult until they result in life-threatening complications. Therefore, it is important to know the diagnostic clues to early diagnosis. CASE PRESENTATION: We describe three cases of congenital basal meningocele in a 3-year-old Japanese boy, a 1-month-old Japanese baby boy, and a 10-month-old Japanese baby girl. One of our patients died of sepsis due to traumatic rupture of the meningocele during nasal suction. His meningocele remained undiagnosed until it resulted in the fatal complication. The other patients underwent surgical repair without any complications. Their meningoceles were complicated by midfacial anomalies including cleft palate and hypertelorism, or a sign of nasal obstruction such as snoring. CONCLUSIONS: These clinical features may be a clue to the early diagnosis of congenital basal meningocele, which enables its safe preoperative management and provides an opportunity for surgical repair before the condition results in serious complications. PMID- 29279053 TI - Unraveling the conundrum of asthma phenotypes and endotypes. PMID- 29279054 TI - The dilemma of allergy to food additives. AB - OBJECTIVE: To provide a brief summary on food additives and to outline a practical approach for evaluating subjects suspected of having reactions to food additives. DATA SOURCES: Information was derived from selected reviews and original articles published in peer-reviewed journals, supplemented by the clinical experience of the authors. STUDY SELECTION: Priority was given to studies that used blinded, placebo controlled, oral challenges to confirm adverse reactions to food additives. In addition, selected, appropriately evaluated case reports were included. RESULTS: A large number of food additives are widely used in the food industry. Allergic reactions to additives seem to be rare but are very likely underdiagnosed, primarily due to a low index of suspicion. A wide variety of symptoms to food additives have been reported, but a cause-and-effect relationship has not been well documented in the majority of cases. CONCLUSION: Reactions to food additives should be suspected in patients who report symptoms related to multiple foods or to a certain food when commercially prepared but not when home made. It is also prudent to investigate food additives in subjects considered to have "idiopathic" reactions. Except for a limited number of natural additives, there is a small role for skin tests or in vitro testing. Oral challenge, in stages, with commonly used additives is the definitive procedure for detecting the offending agent. Once the specific additive is identified, management is strict avoidance, which can be difficult. PMID- 29279055 TI - Chronic rhinosinusitis with nasal polyps in the elderly: Assessing current evidence. AB - BACKGROUND: The recently reported prevalence of chronic rhinosinusitis (CRS) among people >60 years old was 4.7%, with CRS emerging as the sixth most common chronic condition in the elderly. There is still a dearth of studies that focused on older patients, however, regarding the characteristics of CRS with nasal polyps (CRSwNP). OBJECTIVE: The emerging role of CRSwNP endotyping to enable a tailored medical approach (for elderly patients also) was investigated. METHOD: The present review of data reported predominantly in the past 5 years aimed to critically discuss the pathophysiologic, clinical, and prognostic features of CRSwNP in elderly patients. RESULTS: Although the existing data were not final, they supported the notion that geriatric patients can be managed safely by adopting the same surgical algorithm as for younger adults, including endoscopic sinus surgery (ESS). As for medical therapies, prolonged systemic steroid treatment for CRSwNP should be given with caution to elderly patients because they risk significant adverse effects. There is increasing evidence of a lower CRSwNP recurrence rate after ESS in the elderly than in young adult patients. Contrary to findings in younger patients, recently, analysis of preliminary data showed that histologically eosinophilic CRSwNP or high blood eosinophil counts were not significantly associated with a higher recurrence rate in elderly patients. CONCLUSION: A great challenge in the field of geriatric CRSwNP is to investigate the different endotypes in large series (also by means of biomarker assay in blood and polyp tissue) to identify rational and tailored diagnostic, therapeutic (medical and/or surgical), and follow-up modalities. PMID- 29279056 TI - A review of the efficacy and safety of once-daily tiotropium Respimat 2.5 micrograms in adults and adolescents with asthma. AB - BACKGROUND: Despite current guidelines, many patients with asthma remain symptomatic, particularly those intolerant of, unresponsive to, or uncontrolled by long-acting beta 2-agonists (LABAs). Tiotropium bromide, delivered through the Respimat soft-mist inhaler in 2 puffs of 1.25 micrograms each, is approved for the long-term, maintenance treatment of asthma in patients aged >=6 years. OBJECTIVE: An overview of the use of once-daily tiotropium Respimat 2.5 micrograms in adults and adolescents with varying degrees of asthma severity. The role of the parasympathetic nervous system in the pathophysiology of asthma, the development of tiotropium for respiratory disease, and the value of the Respimat inhaler are also discussed. METHODS: A literature search of all phase II and phase III trials of once-daily tiotropium Respimat 2.5 micrograms. RESULTS: Once daily tiotropium Respimat 2.5 micrograms was studied in five phase III studies: three studies in adults and two in adolescents aged 12-17 years. Tiotropium Respimat 2.5 micrograms demonstrated efficacy in adults and adolescents with mild, moderate, or severe asthma, showing significant improvements in lung function and asthma control in patients with uncontrolled asthma despite inhaled corticosteroids (ICS) or ICS plus LABA use. The adverse event profile of tiotropium was very acceptable, with safety similar to placebo. CONCLUSION: Once daily tiotropium Respimat 2.5 micrograms has positive attributes that include efficacy, a safety profile similar to placebo, once-daily dosing, administration by inhalation, and delivery in the easy-to-use and consistent-dosing Respimat device. However, more data are needed on the effects of tiotropium on clinical outcomes, patients' day-to-day lives, and real-world effectiveness. PMID- 29279057 TI - Characterizing patients with asthma who received Global Initiative for Asthma steps 4-5 therapy and managed in a specialty care setting. AB - BACKGROUND: Severe asthma is recognized in the European Respiratory Society/American Thoracic Society guidelines as a major unmet need in the management of asthma. OBJECTIVE: The study objective was to describe the clinical burden of Global Initiative for Asthma (GINA) steps 4-5 asthma for patients treated by specialists in the U.S. community setting. METHODS: Patients, ages >=12 years, with asthma who received GINA step 4 or 5 treatment and were treated at a large U.S. allergy practice network between January 1, 2010, and April 30, 2016, were retrospectively identified by using electronic health records. Clinical outcomes included lung function (forced expiratory volume in one second of expiration [FEV1] and FEV1% predicted), symptom control (Asthma Control Test [ACT]), the fractional exhaled nitric oxide (FeNO) value (FeNO >=25 ppb indicates airway inflammation), and asthma medication use. The change in outcomes from baseline to 12 and 24 months after the index date was calculated. RESULTS: Of 120,116 patients with asthma, 12,922 (10.8%) had severe asthma, 68% (n = 8751) while on step 4 therapy. The mean baseline prebronchodilation FEV1% predicted was 79.7%, and the mean baseline ACT score was 17.0. With uncontrolled asthma defined as an ACT score of <=19 and/or an FEV1 value of <80% predicted and/or oral corticosteroid use of >=2 bursts, 52.5% and 57.7% of patients on step 4 and step 5 therapy, respectively, had uncontrolled asthma at baseline. Of a subset of patients, 40.9% had an eosinophil count of >=300 cells/mm3 and 44% had an FeNO concentration of >=25 ppb. Small increases in the FEV1 value were observed from baseline to 12 months (n = 4022) and 24 months (n = 2326) postindex (0.07 and 0.04 L, respectively). CONCLUSION: A considerable proportion of patients had uncontrolled asthma while on current GINA steps 4-5 treatment, which indicated that additional therapies may be required to reduce the clinical burden of severe asthma. PMID- 29279058 TI - The effect of omalizumab treatment on the low affinity immunoglobulin E receptor (CD23/fc epsilon RII) in patients with severe allergic asthma. AB - BACKGROUND: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody used in the treatment of severe asthma. Its therapeutic efficacy is primarily attributed to reduction of serum-free IgE and in the expression of high-affinity IgE receptor, fc epsilon RI. However, its effect on the low-affinity IgE receptor fc epsilon RII/CD23 in vivo has not been evaluated. AIM: To determine whether CD23 plays a role in the inflammatory process in severe uncontrolled asthma and whether anti-IgE therapy modulates fc epsilon RII/CD23 expression in these patients. METHODS: We evaluated the expression of IgE receptors fc epsilon RI, fc epsilon RII/CD23, and soluble CD23 (sCD23), and the activation state of peripheral blood monocytes (tumor necrosis factor alpha, interleukin (IL) 1-beta, transforming growth factor (TGF) beta expression) in the patients with severe asthma before and after 24 weeks of omalizumab treatment and in the healthy controls. Cytokine expression of monocytes in response to different stimulation (IL-4, IL-4 plus IgE, IL-4 plus IgE plus anti-IgE, and IL-4 plus IgE plus anti IgE plus anti-CD23 for 72 hours) was determined by enzyme-linked immunosorbent assay. RESULTS: Treatment with omalizumab (for 24 weeks) improved disease control and pulmonary function (forced expiratory volume in the first second of expiration, 64.5 versus 74%; p = 0.021). Mean +/- SE expression of fc epsilon RI on monocytes was higher in the patients with asthma versus the controls (45.7 +/- 12.2% versus 18.6 +/- 5.8%; p = 0.04) and was reduced after omalizumab treatment (45.7 +/- 12.2% versus 15.6 +/- 4.4%; p = 0.027). Mean +/- SE TGF-beta levels in supernatants from monocytes were reduced in the patients treated with omalizumab (211 +/- 6 pg/mL versus 184 +/- 9 pg/mL; p = 0.036). CONCLUSION: Modulation of the low affinity IgE receptor CD23 in severe asthma is complex, and sCD23 may inversely reflect disease activity. Treatment with omalizumab was associated with reduced monocyte activation. PMID- 29279059 TI - Systemic inflammation mediates the detrimental effects of obesity on asthma control. AB - BACKGROUND: Obesity negatively impacts asthma control, but the inflammatory mechanisms are poorly understood. OBJECTIVE: To explore which systemic inflammatory mediators mediate the effects of obesity on asthma control. METHODS: The subjects with stable asthma (n = 108) underwent assessment of clinical characteristics, which included using The Asthma Control Questionnaire (ACQ)-6. Obesity was defined as a body mass index (BMI) of >=30 kg/m2, overweight was defined as BMI between 25 to 29.9 kg/m2, and lean weight was defined as BMI < 25 kg/m2. Body composition, including fat mass (FM), visceral fat area (VFA), and percentage body fat (PBF) was analyzed by bioimpedance. Serum interleukin (IL) 4, IL-5, IL-8, IL-13, IL-17, chemokine (C-C motif) ligand (CCL) 17, CCL22, leptin, adiponectin, C-reactive protein (CRP), and interferon (IFN) gamma were measured by using ELISA. Linear regression models were fitted according to the Baron and Kenny procedures for mediation analysis. RESULTS: FM (12.73 +/- 3.95 versus 18.59 +/- 2.95 versus 27.82 +/- 5.17 kg; p < 0.0001), VFA (65.99 +/- 23.17 versus 93.96 +/- 10.28 versus 123.10 +/- 18.34 cm2; p < 0.0001), PBF (23.86 +/- 7.46 versus 30.74 +/- 5.08 versus 36.21 +/- 6.28 %; p = 0.0003) and ACQ-6 values (0.83 [0, 1.17]) versus 1.15 [0.50, 1.75] versus 1.33 [0.83, 1.83] score; p = 0.002) were different among lean (n = 52), overweight (n = 37), and obese (n = 19) subjects. Serum levels of leptin, IL-5, IL-13, IL-17, CCL17, CRP, and IFN-gamma in the obese group were significantly elevated compared with the subjects who were lean or overweight (all p < 0.05). The mediation analyses found that the effect of obesity, assessed by BMI, on ACQ-6 was significantly mediated through IL-13 and CCL17. Furthermore, IL-13 and CCL17 mediated the effects of body composition (FM, VFA and PBF) on ACQ-6. The effects of obesity assessed by body composition, but not by using BMI, on ACQ-6 were mediated by leptin. CONCLUSION: Our mediation analysis confirmed that systemic inflammation biomarkers, such as leptin, CCL17, IL-4, and IL-13, mediated the effects of obesity on asthma control. This warrants prospective exploration in this distinct asthma phenotype in the future. PMID- 29279061 TI - Characteristics of beef allergy in schoolchildren in Turkey. AB - BACKGROUND: The prevalence of immunoglobulin E (IgE) mediated beef allergy in childhood is unknown. We investigated the prevalence and characteristics of IgE mediated beef allergy in urban schoolchildren. METHODS: This cross-sectional study recruited 6000 randomly selected urban schoolchildren ages 6-17 years from the city center of Giresun in the eastern Black Sea region of Turkey during 2013. Children with suspected IgE-mediated beef allergy, determined by a self administered questionnaire, after providing written consent, were skin-prick tested with commercial beef and cow's milk solutions and prick-prick tested with raw, boiled, and fried beef. Levels of serum-specific IgE to beef specific IgE and serum-specific IgE to cow's milk were determined by using fluorescent enzyme immunoassay. All children with suspected beef allergy were invited for a double blind, placebo controlled food challenge (DBPCFC) to determine the prevalence of IgE-mediated beef allergy. RESULTS: The response rate to the questionnaire was 82.2%. The estimated prevalence of parental-reported IgE-mediated beef allergy was 2.6%. The prevalence of IgE-mediated beef allergy confirmed by DBPCFC was 0.30% (95% confidence interval, 0.18-0.5%). Positive challenge responses were observed in 70.6% (p = 0.027), 76.9% (p = 0.027), and 73.3% (p = 0.028) of the children with a positive family history of beef allergy, positive skin test results, and positive beef specific IgE values, respectively. A beef specific IgE value of >5 kUA/L alone or a combination of a positive family history of beef allergy, positive skin test results, and beef specific IgE values of >3 kUA/L yielded a positive response to DBPCFC. CONCLUSION: The presence of a family history of beef allergy, beef specific IgE value, and skin test result positivity are independently associated with positive DBPCFC results, and combined evaluation of these three parameters increased the positive predictive power of the tests. PMID- 29279060 TI - Heterogeneity of asthma and the risk of celiac disease in children. AB - BACKGROUND: Although human leukocyte antigen (HLA)-DR and HLA-DQ genes and gluten play crucial roles in developing celiac disease (CD), most patients with these risk factors still do not develop CD, which indicates additional unrecognized risk factors. OBJECTIVE: To determine the association between asthma and the risk of CD in children. METHODS: We conducted a population-based retrospective case control study in children who resided in Olmsted County, Minnesota. We identified children with CD (cases) between January 1, 1997, and December 31, 2014, and compared these with children without CD (controls) (1:2 matching). Asthma status was ascertained by using the predetermined asthma criteria (PAC) and the asthma predictive index (API). Data analysis included conditional logistic regression models and an unsupervised network analysis by using an independent phenome-wide association scan (PheWAS) data set. RESULTS: Although asthma status as determined by using PAC was not associated with the risk of CD (odds ratio [OR] 1.4 [95% confidence interval {CI}, 0.8-2.5]; p = 0.2), asthma status by using the API was significantly associated (OR 2.8 [95% CI, 1.3-6.0]; p = 0.008). A subgroup analysis indicated that children with both asthma as determined by using PAC and a family history of asthma had an increased risk of CD compared with those without asthma (OR 2.28 [95% CI, 1.11-4.67]; p = 0.024). PheWAS data showed a cluster of asthma single nucleotide polymorphisms and patients with CD. CONCLUSION: A subgroup of children with asthma who also had a family history of asthma seemed to be at an increased risk of CD, and, thus, the third factor that underlies the risk of CD might be related to genetic factors for asthma. Heterogeneity of asthma plays a role in determining the risk of asthma-related comorbidity. PMID- 29279062 TI - Comparison of the effect of 5-grass pollen sublingual immunotherapy tablets and drops in children with rhinoconjunctivitis. AB - BACKGROUND: One of the most important aspects of sublingual immunotherapy (SLIT) is the regimen of administration. AIM: To find any differences in symptom medication scores between the two groups of SLIT tablets and drops, given pre coseasonally (starting 8 weeks before the pollen season) in children with rhinoconjunctivitis allergy to grass pollen. The secondary outcome were the differences in lung function and induction of T-regulatory forkhead box P3 (FOXP3) positive cells. METHODS: This was a retrospective, secondary analysis of pooled data obtained from our two prospective randomized placebo controlled trials that involved children who underwent SLIT. Forty-one children, ages 6-18 years, with allergic rhinitis (AR), sensitive to grass pollen, participated in the study. RESULTS: Treatment with both tablets and drops significantly reduced all symptoms (nasal, asthma, and ocular) within the groups; there was no significant difference between both groups. When compared with the tablet therapy, there was a trend for drops therapy to be more effective in the reduction of combined symptom-medication score, but the difference was not statistically significant (p = 0.1036); there was no significant difference in asthma and nasal scores. We showed a significant decrease in the fractional exhaled nitric oxide level comparable in both immunotherapy groups. There were no differences between the groups in the induction of CD4+ CD25+ FOXP3+-positive cells in peripheral blood. CONCLUSIONS: Both protocols showed similar decreases in symptom-medication scores; however, when compared with tablet therapy, there was a trend for drops therapy to be more effective in the reduction of combined symptom-medication score. PMID- 29279064 TI - For the Patient. PMID- 29279063 TI - Evaluating satisfaction of patients with hereditary angioedema with their past and present treatments: Implications for future therapies. AB - BACKGROUND: Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration. OBJECTIVE: To understand patients' impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments. METHODS: After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software. RESULTS: Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes. CONCLUSION: Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual's personal goals. PMID- 29279065 TI - Erratum to: Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif. AB - The BMB Reports would like to correct in the ACKNOWLEDGEMENTS of BMB Rep. 49(5), 282-287 titled "Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif." PMID- 29279066 TI - [Physician Involvement in the Activities of the European Medicines Agency]. AB - For more than two decades of activity, the European Medicines Agency has been operating as part of a network with the national medicines agencies in Europe, bringing together - in its various scienti c committees and working groups - European experts on a wide range of topics related to quality assurance, safety and ef cacy of medicines. The work carried out within the European Medicines Agency activities and the conclusions reached at European level affect millions of citizens. The European Medicines Agency considers that it is of great importance to maintain, in a sustainable and consistent manner, the active participation of general practitioners, as well as other medical specialists, in the process of medicines' evaluation and supervision. This article summarizes how the participation of doctors and health professionals in general is promoted in the European Medicines Agency activities. PMID- 29279067 TI - [Breast Cancer: Value-Based Healthcare, Costs and Financing]. AB - INTRODUCTION: Breast cancer is the second most common oncological disease worldwide. To analyse the new disease specific funding programme (breast cancer) implemented at the Francisco Gentil Portuguese Institute of Oncology, Lisbon Center (Instituto Portugues de Oncologia de Lisboa Francisco Gentil), the actual costs of the patients were examined using activity-based costing as a costing methodology. This study addresses the following question: "How much does it cost to treat breast cancer per 'patient-month' compared to the monthly fixed 'funding envelope'?". MATERIALS AND METHODS: The study cohort consisted of 807 patients, corresponding to all the patients eligible for the new disease specific funding programme and who were enrolled during the first year of implementation. Activity based costing was used to calculate the total real costs per stage of disease and per 'patient-month' as well as the deviation from the monthly fixed 'funding envelope'. RESULTS: The total costs were 6.6 M?, whereas the total funding was 5.2 M? for a total of 5648 'patient-months'. In 2014, the balance difference between the funding obtained and the actual costs was -1.4 ?M for the cohort of 807 patients. DISCUSSION: The extreme cases of differences in cost per 'patient month' compared to the monthly fixed 'funding envelope' were (i) stage 0/Tis, with higher funding at 415.23 ? per 'patient-month', and (ii) stage IIIC, with lower funding at 1062.79 ? per 'patient-month'. CONCLUSION: The 'patient-month' cost, regardless of disease stage was 1170.29 ?. The median deviation per 'patient-month' was negative (241.21 ?) compared to the monthly fixed 'funding envelope' of 929.08 ? in the first year. Establishing activity-based costing - funding models will be crucial for the future sustainability of the healthcare sector. PMID- 29279068 TI - [Readmission to an Adolescent Psychiatry Inpatient Unit: Readmission Rates and Risk Factors]. AB - INTRODUCTION: Most mental disorders have a chronic evolution and therefore a certain amount of psychiatric readmissions are inevitable. Several studies indicate that over 25% of child and adolescent inpatients were readmitted within one year of discharge. Several risk factors for psychiatric readmissions have been reported in the literature, but the history of repeated readmissions is the most consistent risk factor. Our aim is to calculate the readmission rates at 30 days and 12 months after discharge and to identify associated risk factors. MATERIAL AND METHODS: The authors consulted the clinical files of patients admitted to the Inpatient Unit between 2010 and 2013, in order to calculate the readmission rates at 30 days and at 12 months. The demographic and clinical characteristics of the readmitted patients were analyzed and compared with a second group of patients with no hospital readmissions, in order to investigate possible predictors of readmission. RESULTS: A total of 445 patients were admitted to our inpatient unit between 2010 and 2013. Six adolescents were readmitted in a 30 days period (1.3%) and 52 were readmitted in a 12 month period after discharge (11.5%). Duration of the hospitalization and the previous number of mental health admissions were significant predictors of future hospital readmissions (p = 0.04 and p = 0.014). DISCUSSION: The low readmission rates may reflect the positive clinical and sociofamilial support being provided after discharge. CONCLUSION: Rehospitalisation is considered a fundamental target for intervention concerning prevention and intervention in mental healthcare. Thus, knowledge regarding their minimisation is crucial. PMID- 29279069 TI - Reconsidering the 'Decline' of Dental Student Empathy within the Course in Latin America. AB - INTRODUCTION: The controversy over the presence of empathic decline within the course in students of medicine, dentistry and health sciences in general, has not fully been studied. This controversy could be partially solved if massive studies of empathy levels are made in similar cultural, social and economic contexts. MATERIAL AND METHODS: Empathy levels within the course were studied in eighteen dental schools from six countries in Latin America (2013). The mean of the empathy levels were used to study the behavior between first and fifth academic years. The values of empathy levels within the course were observed by applying the Jefferson Scale of Physician Empathy, the Spanish version. All these studies were cross-sectional. The value of means observed, were subjected to regression studies and further adjustment curves were obtained and the coefficient of determination were calculated. RESULTS: Six different models of behavior were observed, which found that five of them suffer empathic decline within the course, but with different final results: in some the decline persists until the fifth academic year and in others, this decline 'recovers' persistently until the fifth academic year. The sixth model is characterized by a constant and persistent increase of levels of empathy within the course until the last academic year. DISCUSSION: There are six different models for the behavior of means of levels of empathy within the course evaluated by a common methodology in eighteen dental schools from six countries of Latin America. These findings support the existence of variability of empathic response and a comprehensive approach is needed to find the causes that give rise to this variability. CONCLUSION: In dental students of Latin America, there is variability in the behavior of the distribution in means between the academic years of the dentistry schools examined in this study. PMID- 29279070 TI - Cross-Cultural and Psychometric Properties Assessment of the Exercise Self Efficacy Scale in Individuals with Spinal Cord Injury. AB - INTRODUCTION: The Exercise Self-Efficacy scale (ESES) is a reliable measure, in the English language, of exercise self-efficacy in individuals with spinal cord injury. The aim of this study was to culturally adjust and validate the Exercise Self-Efficacy scale in the Portuguese language. MATERIAL AND METHODS: The Exercise Self-Efficacy scale was applied to 76 subjects, with three-month intervals (three applications in total). The reliability was appraised using the intra-class correlation coefficient and Bland-Altman methods, and the internal consistency was evaluated using Cronbach's alpha. The Exercise Self-Efficacy scale was correlated with the domains of the Quality of life Questionnaire SF-36 and Functional Independence Measure and tested using the Spearman rho coefficient. RESULTS: The Exercise Self-Efficacy scale-Brazil presented good internal consistency (alpha 1 = 0.856; alpha 2 = 0.855; alpha 3 = 0.822) and high reliability in the test-retest (intra-class correlation coefficient = 0.97). There was a strong correlation between the Exercise Self-Efficacy scale-Brazil and the SF-36 only in the functional capacity domain (rho = 0.708). There were no changes in Exercise Self-Efficacy scale-Brazil scores between the three applications (p = 0.796). DISCUSSION: The validation of the Exercise Self Efficacy scale questionnaire permits the assessor to use it reliably in Portuguese speaking countries, since it is the first instrument measuring self efficacy specifically during exercises in individuals with spinal cord injury. Furthermore, the questionnaire can be used as an instrument to verify the effectiveness of interventions that use exercise as an outcome. CONCLUSION: The results of the Brazilian version of the Exercise Self-Efficacy scale support its use as a reliable and valid measurement of exercise self-efficacy for this population. PMID- 29279071 TI - Portuguese Adaptation and Input for the Validation of the Views on Inpatient Care (VOICE) Outcome Measure to Assess Service Users'Perceptions of Inpatient Psychiatric Care. AB - INTRODUCTION: Patient satisfaction is an important measure of health care quality. Patients' views have seldom been considered in the construction of measures addressing satisfaction with inpatient facilities in psychiatry. The Views on Inpatient Care - VOICE - is a first service-user generated outcome measure relying solely on their perceptions of acute care, representing a valuable indicator of service users' perceived quality of care. The present study aimed to contribute to the validation of the Portuguese version of VOICE. MATERIAL AND METHODS: The questionnaire was translated into Portuguese and applied to a sample of eighty-five female inpatients of a psychiatric institution. Data analysis focused on assessing reliability and exploring the impact of demographic and clinical variables on participants' satisfaction. RESULTS: Internal consistency of the questionnaire was high (alpha = 0.87). Participants' age and marital status were associated with differences in scores, with older patients and patients who were married or involved in a close relationship presenting higher satisfaction levels. DISCUSSION: The questionnaire demonstrated good internal consistency and acceptability, as well as construct validity. Further studies should expand the analysis of the psychometric properties of this measure e.g., test-retest reliability. CONCLUSION: The Portuguese version of VOICE is a promising tool to assess service users' perceptions of inpatient psychiatric care in Portugal. PMID- 29279072 TI - [Single Centre Prospective Study of Systematic Pain Evaluation in Portuguese Patients with Metastatic Prostate Cancer]. AB - INTRODUCTION: Pain is one of the most common symptoms reported by cancer patients and is associated with decreased quality of life. Assessment of pain with standardized questionnaires reduces variability in its interpretation and may increase effectiveness of medical interventions. Prostate cancer is the most frequent male neoplasm in Portugal. We designed this study to evaluate the impact of a standardized pain questionnaire on pain management in patients with metastatic prostate cancer. MATERIAL AND METHODS: Single centre prospective observational study of patients with metastatic prostate cancer. The study was designed to evaluate the benefit of systematically evaluating pain with Brief Pain Inventory-Short Form prior to a scheduled medical oncology consult. Patients reporting pain were reassessed one week later by telephone. To assess the benefit two consecutive cohorts were established based on communication of questionnaire results to the treating physician. RESULTS: We recruited 207 patients of which 60% reported pain. Statistically significant decrease in mean pain intensity one week after the scheduled appointment was noted (3.95 vs 3.01; p < 0.001). Patients whose Brief Pain Inventory-Short Form was provided to their oncologist experienced greater reduction in pain, which was non-significant (p = 0.227). Using Brief Pain Inventory-Short Form assessment resulted in a higher probability of pain control (43.5% vs 30.9%; p = 0.193). DISCUSSION: The prevalence of pain founded was higher than described in the literature, probably because our sample was less selected than the published in clinical trials. After the scheduled appointment, there was a statistically significant reduction in mean pain intensity, but the explicit use of this questionnaire was not associated with a statistically significant reduction of pain. CONCLUSION: Patients with metastatic prostate cancer have a high prevalence of pain. Evaluation and treatment by medical oncologists is associated with a reduction of mean pain intensity. The use of Brief Pain Inventory-Short Form was associated with a non-significant increased reduction of pain. PMID- 29279073 TI - Characterization of all Surgical Specimens Provided by a Portuguese Department of Ophthalmology over a 13 Year Period. AB - INTRODUCTION: We intend to evaluate clinically, topographically and morphologically all surgical specimens sent by the Department of Ophthalmology of Hospital de Braga to the Department of Pathology of the same hospital. MATERIAL AND METHODS: Two hundred and fifty eight surgically obtained specimens, from the Department of Ophthalmology of Hospital de Braga, analyzed in the Department of Pathology, from January 2002 to June 2015, were characterized. Data was arranged according to year, age, sex, topography and morphological diagnosis according to the SNOMED(r) coding system. RESULTS: Mean age at time of diagnosis was 54.6 years old; 52.3% were male subjects. The number of specimens was relatively stable until the year 2010, with a significant increase between 2011 and 2013. Most specimens sent corresponded to eyelid (54.7%), followed by conjunctiva (26.7%); the most common pathological diagnosis was malignant epithelial lesions (22.48%), followed by melanocytic tumours (22.09%) and benign epithelial lesions (17.05%). DISCUSSION: The results are distinct from previous publications presumably because of differences between the populations submitted to analysis. CONCLUSION: This is the first indexed publication characterizing surgical specimens from a Department of Ophthalmology in Portugal; moreover, it also includes an extensive review of global epidemiological data about ophthalmic surgical specimens. PMID- 29279074 TI - Metabolic Activity in the Visceral and Subcutaneous Adipose Tissues by FDG-PET/CT in Obese Patients. AB - INTRODUCTION: The emerging role of the 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in the study of the metabolic activity and inflammation in adipose tissue indicates that it might be a reliable tool to complement the risk stratification in obesity. The aims of this study were the evaluation of 18F-fluorodeoxyglucose uptake by visceral adipose tissues and subcutaneous adipose tissues and to determine eventual differences in patients with and without obesity. MATERIAL AND METHODS: Retrospective study of adult patients who underwent whole body 18F-fluorodeoxyglucose-positron emission tomography/ computed tomography scanning between July and August of 2016. STATISTICAL ANALYSIS: SPSSTM software v.20. Statisticalsignificance: p < 0.05. RESULTS: We assessed fluorodeoxyglucose-positron emission tomography/computed tomography scans from 156 patients (58.3% of males) with a mean age of 61.0 +/- 14.1 years. Half of the patients had a body mass index >= 25.0 kg/m2 and 15.4% (n = 24) were obese. In both groups, the mean 18F-fluorodeoxyglucose uptake was higher in visceral adipose tissues. There were no differences in 18F fluorodeoxyglucose uptake in visceral adipose tissues between the groups. Obese patients had lower density of adipose tissue,both in subcutaneous adipose tissues and in visceral adipose tissues. Abdominal circumference and density of visceral adipose tissueshad a positive predictive value in the mean 18F-fluorodeoxyglucose uptake in visceral adipose tissues. Discussion: Through a non-invasive test, this study demonstrated a significant higher metabolic activity in visceral adipose tissues in both obese and non-obese patients. According to our results, abdominal circumference was an important determinant in 18F-fluorodeoxyglucose uptake in visceral adipose tissues. We also demonstrated that obese patients had differences in adipose tissue quality. CONCLUSION: Our findings reinforce the importance of the adipose tissue quality and distribution for metabolic risk stratification. PMID- 29279075 TI - [Pregnancy after Breast Cancer: State of the Art]. AB - Breast cancer survivors have given rise to several issues of major relevance from a clinical and scientific point of view. In fact, breast cancer is the most prevalent malignancy in women of reproductive age. The effect of pregnancy on overall survival and in the recurrence after treatment of breast cancer, as well as the questions related to heredity continue to be matter of the highest timeliness and scientific interest. Most recent studies seem to agree in admitting that pregnancy after breast cancer appears to be potentially safe to both the women and her offspring, although this issue remains complex. Heredity and genetics seem to play an important role in this subject, but the conclusions lack absolute and unequivocal consistency. There is a need for meta-analysis, cohort and case-control studies, translational and prospective studies extended in time, in order to obtain greater safety in the establishment of strategies and guidelines for clinicians and adequate objective information for young breast cancer patients. PMID- 29279076 TI - Symptomatic Hyponatremia after Bowel Preparation: Report of Two Cases and Literature Review. AB - INTRODUCTION: Bowel preparation for colonoscopy and/or colorectal surgery can cause electrolyte imbalances. The risk of electrolyte imbalances seems to be related to the type of bowel cleansing solution, age of patients and comorbidities. CASE REPORT: We report two cases of symptomatic hyponatremia (focal neurological signs and coma) after bowel preparation with sodium picosulfate/magnesium citrate for colonoscopy. In both cases, symptoms related to hyponatremia rapidly disappeared after sodium level correction with intravenous administration of hypertonic saline (3% NaCl). DISCUSSION: Electrolyte imbalances are more common with sodium phosphate-based solutions (NaP) and sodium picosulfate/magnesium citrate, in patients older than 65, in patients treated with thiazide diuretics, angiotensin-converting-enzyme inhibitor, betablockers or antidepressants and in gastrectomized patients. These patients should use macrogol-based solutions (polyethylene glycol). CONCLUSION: In patients at risk (patient > 65 years old, patients taking thiazide diuretics, angiotensin converting-enzyme inhibitors, beta-blockers and antidepressants and with previous gastrectomy) we recommend macrogol-based solutions. PMID- 29279077 TI - Platypnea-Orthodeoxia Syndrome After Complicated Cholecystectomy: An Unsuspected Diagnosis. AB - A 65-year-old woman with no significant prior medical history presented, in the postoperative course of a complicated cholecystectomy, several episodes of arterial desaturation. Pulmonary embolism was repeatedly suspected, but there was no evidence of pulmonary thrombus on the chest computed tomography angiographies obtained. As these episodes were mainly induced by postural changes, a platypnea orthodeoxia syndrome was suspected. A transthoracic echocardiogram was performed and revealed a patent foramen ovale. A transesophageal echocardiography confirmed the presence of a significant right-to-left shunt exacerbated by the Valsalva manouver. The defect was repaired using a percutaneous transcatheter technique with complete resolution of the condition. PMID- 29279078 TI - [Isolated Polycystic Liver Disease]. PMID- 29279079 TI - Pneumatosis Cystoides Intestinalis: An Unexpected Cause of Duodenal Nodules. PMID- 29279080 TI - Corrigendum to "Profiling circulating miRNAs in serum from pigs infected with the porcine whipworm, Trichuris suis" [Vet. Parasitol. 223 (2016) 30-33]. PMID- 29279081 TI - Toxoplasma gondii: A study of oocyst re-shedding in domestic cats. AB - The aim of the present study was to evaluate the re-shedding of T. gondii oocysts in cats fed tissue cysts of homologous and heterologous strains 12, 24 and 36 months after the first infection. Thirteen cats were used in the present study and were divided into four groups: G1 (n=2), G2 (n=3), G3 (n=5), and G4 (n=3). G1, G3 and G4 cats were infected with brain cysts of ME49 and G2 with TgDoveBr8, both genotype II strains of T. gondii. The G1 and G2 cats were re-infected after twelve months with brain cysts of VEG strain (genotype III), and G3 cats were re infected with TgDoveBr1 (genotype II). The G3 cats were re-infected a third time after 24 months from the second infection, and the G4 cats were re-infected 36 months after the initial infection with cysts of the VEG strain. The cats' feces were evaluated using fecal flotation and genotyped with PCR-RFLP. The serological responses for IgM, IgA and IgG were determined by ELISA. All cats shed oocysts after the initial infection. Only one G1 cat shed oocysts when re-infected after twelve months with the VEG strain. No G2 cats excreted oocysts after the second infection with VEG. G3 cats, when re-infected after twelve months with the TgDoveBr1 strain, did not shed oocysts. However, when challenged after a third time with the VEG strain, three out of four cats shed oocysts. In the G4 group, when re-infected after thirty-six months with the VEG strain, two out of three cats shed oocysts. All oocyst samples were genotyped and characterized as the same genotype from the inoculum. Protection against oocyst re-excretion occurred in 90%, 25%, and 33.4% of cats after 12, 24, and 36 months from the initial infection, respectively. Therefore, the environmental contamination by oocysts from re-infected adult cats is only 30% lower than from kittens. In conclusion, the excretion of T. gondii oocysts was higher in experimentally re-infected cats throughout the years, especially when a heterologous strain was used. PMID- 29279082 TI - Spatial multi-criteria decision analysis for modelling suitable habitats of Ornithodoros soft ticks in the Western Palearctic region. AB - Ticks are economically and medically important ectoparasites due to the injuries inflicted through their bite, and their ability to transmit pathogens to humans, livestock, and wildlife. Whereas hard ticks have been intensively studied, little is known about soft ticks, even though they can also transmit pathogens, including African Swine Fever Virus (ASFV) affecting domestic and wild suids or Borrelia bacteria causing tick-borne relapsing fever (TBRF) in humans. We thus developed a regional model to identify suitable spatial areas for a community of nine Ornithodoros tick species (O. erraticus, O. sonrai, O. alactagalis, O. nereensis, O. tholozani, O. papillipes, O. tartakovskyi, O. asperus, O. verrucosus), which may be of medical and veterinary importance in the Western Palearctic region. Multi-Criteria Decision Analysis was used due to the relative scarcity of high-quality occurrence data. After an in-depth literature review on the ecological requirements of the selected tick community, five climate-related factors appeared critical for feeding activity and tick development: (i) a spring temperature exceeding 10 degrees C to induce the end of winter soft tick quiescent period, (ii) a three-months summer temperature above 20 degrees C to allow tick physiological activities, (iii) annual precipitation ranging from 60mm to 750mm and, in very arid areas, (iv) dry seasons interrupted by small rain showers to maintain minimum moisture inside their habitat along the year or (v) residual water provided by perennial rivers near habitats. We deliberately chose not to include biological factors such as host availability or vegetation patterns. A sensitivity analysis was done by performing multiple runs of the model altering the environmental variables, their suitability function, and their attributed weights. To validate the models, we used 355 occurrence data points, complemented by random points within sampled ecoregions. All models indicated suitable areas in the Mediterranean Basin and semi-desert areas in South-West and Central Asia. Most variability between models was observed along northern and southern edges of highly suitable areas. The predictions featured a relatively good accuracy with an average Area Under Curve (AUC) of 0.779. These first models provide a useful tool for estimating the global distribution of Ornithodoros ticks and targeting their surveillance in the Western Palearctic region. PMID- 29279083 TI - Discovery of a recombinant Babesia canis supernatant antigen that protects dogs against virulent challenge infection. AB - : Soluble parasite antigens (SPA) in supernatants of in vitro cultures of Babesia canis can be used to vaccinate dogs against virulent B. canis infection. The moment that immunity becomes apparent coincides with the appearance of antibodies against SPA in the serum of the vaccinated animals. This so-called vaccination challenge serum (VC-serum) was used to precipitate antigens from B. canis culture supernatants in agarose gels. This antigen preparation was then used to analyse the reactivity of sera from vaccinated dogs on western blots. RESULTS: showed that the first appearance of antibody reactivity against a protein that migrated at the 39kDa position in SDS-PAGE gels was associated with the moment vaccinated dogs started to recover from a virulent challenge infection. In addition, pulse chase experiments revealed that a 39-40kDa doublet was released into the supernatant of B. canis cultures starting 15min after the chase. This doublet was specifically precipitated by VC-serum, thus corroborating that the 39-40kDa doublet in SPA preparations was of parasite origin. Partial amino acid sequencing allowed the discovery of the gene that encoded the 39-40kDa doublet (canine Babesia antigen; CBA). The full-length gene was cloned and expressed in E. coli. The recombinant CBA protein (rCBA) was recognized by VC-serum, and antibodies against rCBA precipitated the 39kDa antigen of SPA preparations and of merozoites of B. canis. In addition, anti-rCBA serum reacted with the surface of B. canis merozoites (but not with B. rossi merozoites) in immunofluorescence. Vaccination of dogs with rCBA induced antibodies against rCBA, which recognized B. canis merozoites. Vaccinated dogs were protected against virulent challenge infection by limiting parasite proliferation. As a result, the development of clinical signs was prevented and the animals self-cured. In contrast, six out of seven non vaccinated control dogs developed relatively high parasitaemia and serious clinical signs associated with poor tissue perfusion. This antigen can be used to replace the SPA antigen in the conventional B. canis vaccines, which eliminates the need for dog blood and serum for vaccine production. PMID- 29279084 TI - Spatial-temporal and phylogeographic characterization of Trypanosoma spp. in cattle (Bos taurus) and buffaloes (Bubalus bubalis) reveals transmission dynamics of these parasites in Colombia. AB - Animal Trypanosomiasis (AT) is one of the most important problems in the Colombian livestock industry reducing its production around 30%. Caribbean and Orinoquia regions play a significant role in the development of this industry, having about 6.9 million cattle and 113,000 buffaloes. Considering the paucity in studies to understand the epidemiological features and control of AT in Colombia, the present study reports the seasonal transmission patterns and phylogeographic traits of the causal agents of AT in cattle and buffaloes from these regions. Between 2014 and 2016, a three-point longitudinal survey was designed to evaluate the mentioned characteristics. Molecular analysis in cattle showed an AT prevalence of 39.2% (T. theileri 38.6%, T. evansi 6.7% and T. vivax 0.2%), with higher values during wet and late wet seasons, while in buffaloes the prevalence was 28.2% (T. theileri 28.2% and T. evansi 1.3%), with higher values during the dry season. Additionally, variables such as tabanid abundance, vector control, breeding system, age and anemia signs were significantly associated with AT prevalence (P<0.05). Only T. theileri infection was higher in cattle with anemia signs than those with normal packed cell volume. Finally, phylogeographic analysis revealed that Colombian T. theileri isolates were associated to specific host genotypes IA and IIB, described worldwide; T. vivax isolates were related to the genotype from West Africa; while T. evansi isolates are related to the South American genotypes and to new genotypes. This is the first longitudinal survey that evaluates through molecular methods, the infection of Trypanosoma spp. in two important livestock regions from Colombia, showing that the clinical effects and prevalence of these trypanosomes in cattle and buffaloes are modulated by seasonal variations, host factors, and parasite traits. The results suggest that these factors have to be taken into account to successfully control AT in these regions. PMID- 29279085 TI - Tick-borne infections in dogs and horses in the state of Espirito Santo, Southeast Brazil. AB - This work aims to identify and quantify the percentage of Rickettsia spp., Ehrlichia spp., Babesia spp. and Hepatozoon spp. positive pet dogs, and to identify ticks collected on these animals in the state of Espirito Santo, in the Southeast region of Brazil. The study included 378 dogs, 226 females and 152 males, of various breeds and ages (mean age of 4.1 years). All animals were examined for ticks, and whole blood was collected and processed by conventional PCR protocols for Babesia spp., Anaplasmataceae, Hepatozoon spp. and by real-time PCR for Ehrlichia canis. Of the 378 dogs examined, 157 (41.53%) had ticks at the time of the study, which were identified as R. sanguineus s.l. in 154 animals (98.10%), Amblyomma ovale in one animal (0.63%), and Amblyomma sculptum in 2 animals (1.27%). In the PCR for Babesia spp., 5 animals (1.32%) were positive, producing DNA sequences 100% identical to Babesia vogeli. For Anaplasmataceae, 34 animals (9%) were positive, 10 of which generated DNA sequences 100% similar to Ehrlichia canis. The other 24 samples generated fragments 100% identical to Anaplasma platys. In the PCR for Hepatozoon spp, 39 animals (10.31%) were positive, producing sequences 100% identical to Hepatozoon canis. Finally, in the real-time PCR specific for E. canis, 28 animals (7.40%) were positive. Coinfection with 2 or 3 agents was observed in 20 animals (5.29%). Of the 378 dogs sampled, 312 were analyzed by indirect immunofluorescence assay (IFA) for E. canis and five species of Rickettsia (R. rickettsii, R. parkeri, R. amblyommatis, R. rhipicephali and R. bellii). Among them, 71 dogs (22.75%) had a positive reaction for E. canis and 16 dogs (5.13%) had antibody titers higher than 64 to at least one Rickettsia species, 5 of them (1.60%) to R. rickettsii. Samples of blood were collected from 10 equines in the regions where dogs were found with positive serology for any one of the Rickettsia sp. tested. In the municipality of Vila Velha, two equines were positive for R. bellii with inverse titers of 64 and 128. These results indicate that tick-transmitted agents, such as E. canis, A. platys, B. vogeli, H. canis, and several spotted fever group Rickettsia are circulating in the canine population of the Brazilian state of Espirito Santo. PMID- 29279086 TI - Giardia in a selected population of dogs and cats in Germany - diagnostics, coinfections and assemblages. AB - Infections with the zoonotic endoparasite Giardia duodenalis are widely spread among dogs and cats worldwide. Since the question whether the infection might be transmitted from domestic animals to their owners is still an important topic, a reliable detection of patent Giardia infections and the determination of the associated Giardia assemblages is of major concern. The objectives of the present study were to determine the prevalence of Giardia infections in dogs and cats living in Germany using different diagnostic tests and to identify the Giardia assemblages of infected animals. Furthermore, a possible correlation of coinfections with other endoparasites was analysed. All samples were investigated by enzyme-linked immunosorbent assay (ELISA), merthiolate-iodine-formalin concentration technique (MIFC) and zinc chloride flotation. ELISA-positive samples were additionally screened with a direct immunofluorescence assay (IFA). Faecal DNA was extracted from all Giardia cyst-positive samples and used for multilocus sequence typing with nested PCRs targeting the following gene loci: SSU rRNA (SSU), glutamate dehydrogenase (gdh) and triosephosphate isomerase (tpi). Samples from dogs and cats tested positive for Giardia coproantigen (ELISA) in 30.6% and 17.9%, respectively. The MIFC technique revealed Giardia cysts in 33.9% of canine and in 34.6% of feline ELISA-positive samples, while using IFA, cysts were present in 90.4% of canine and in 76.9% of feline ELISA positive samples. Coinfections with other endoparasites besides Giardia were found in both dogs and cats, yet a statistically significant correlation could solely be drawn for the canine samples. The success rate of the different PCR protocols varied between 23.1% (tpi) and 91.3% (SSU) for dogs and between 25.0% (gdh) and 90.0% (SSU) for cats. Dog-specific Giardia assemblages C and D were detected in 42 and 55 canine isolates, respectively. The cat-specific Giardia assemblage F was detected in 14 feline isolates. Two canine and two feline samples harboured the zoonotic assemblage A. According to the results of the study, Giardia is a common endoparasite in dogs and cats from Germany. The exclusive application of MIFC is insufficient for a reliable identification of patent Giardia infections since the IFA revealed a higher sensitivity for the detection of Giardia cysts in feline and canine faecal samples. Even though the majority of investigated animals harboured the species-specific Giardia assemblages C, D and F, a zoonotic potential arising from assemblage A could not be excluded. PMID- 29279087 TI - Response of drug-susceptible and -resistant Haemonchus contortus larvae to monepantel and abamectin alone or in combination in vitro. AB - There is an increasing interest in the use of combination anthelmintic products for the control of intestinal nematode parasites of livestock. These products are seen as attractive options for parasite control in the face of increasing levels of resistance to the different anthelmintic drug classes, as well as a means to slow the rate at which resistance develops to the individual components of the combination. With the recent introduction of an anthelmintic combination product containing abamectin and monepantel (at 1:12.5), we were interested in measuring the response of drug-susceptible and drug-resistant isolates of Haemonchus contortus to these two drugs alone and in combination, using larval development assays. The GWBII isolate showed resistance to abamectin (12-fold) alongside susceptibility to monepantel. The resistance ratio was reduced from 12- to 3.2 fold when the two drugs were combined. The MPL-R isolate was resistant to both drugs, with resistance factors of 6-fold towards abamectin, and 10.6- and 1008 fold towards monepantel in two sub-populations present in the isolate. This isolate showed 6.4-fold resistance to the drug combination. Hence, for both GWBII and MPL-R, the level of resistance towards the combination was reduced compared to the resistance towards abamectin or monepantel alone, respectively, but was not abolished. However, for GWBII, this in vitro resistance to the drug combination would be expected to have no impact on the in vivo efficacy of the combination drench product as the isolate is resistant to only the abamectin component of the drench, with monepantel remaining effective. On the other hand, the observed in vitro resistance to the combination shown by the MPL-R isolate is derived from significant levels of resistance towards both components separately, and hence may impact on in vivo efficacy of the combination. Isobologram analysis did not find any evidence for a synergistic interaction between the two drugs in larval development assays. We examined the predicted effects of varying the abamectin:monepantel ratio in drug combinations, assuming that the two drugs acted in an additive fashion. For GWBII, resistance to the drug combination was reduced to almost zero as the abamectin:monepantel ratio increased from 1:12.5 to 1:100, reflecting its resistance to only the abamectin component of the combination. For MPL-R, on the other hand, the resistance increased as the relative proportion of monepantel in the combination was increased, reflecting the extreme level of in vitro resistance shown by this isolate to monepantel. PMID- 29279088 TI - Procyanidin A2 in the Australian plant Alectryon oleifolius has anthelmintic activity against equine cyathostomins in vitro. AB - There is a need to investigate new methods of controlling cyathostomins in horses due to increasing anthelmintic resistance amongst these parasites. In a previous study we identified the Australian plant Alectryon oleifolius as having anthelmintic activity towards cyathostomins. This study aimed to isolate and identify the bioactive compound(s) responsible for all or part of this anthelmintic activity and quantify its activity in vitro. The condensed tannin procyanidin A2 was isolated from the plant through a process of bioassay guided fractionation and identified using 1D and 2D nuclear magnetic resonance spectroscopy and high performance liquid chromatography with mass spectrometry. Procyanidin A2 demonstrated significant anthelmintic activity in larval development assays, completely inhibiting development from egg to third larval stage at concentrations as low as 50MUg/mL and having an IC50 value of 12.6MUg/mL. Procyanidin A2 also significantly inhibited larval migration at concentrations of 25MUg/mL. This study indicates that procyanidin A2 is the principal anthelmintic compound in extracts from A. oleifolius, and further highlights the potential for the use of this plant as a component of cyathostomin control programs in the future. PMID- 29279089 TI - Neospora caninum bioassay in gerbils using placental tissues from naturally infected goats. AB - Neospora caninum is one of the main agents that causes abortions in cattle worldwide. However, little is known about the pathogenesis of neosporosis in small ruminants, especially goats. Gerbils (Meriones unguiculatus) have been used as a model for neosporosis, and this species is highly susceptible to infection by bovine N. caninum strains. The present study aimed to evaluate the susceptibility of gerbils to a N. caninum isolate from goats. The placentas were obtained from naturally infected goats, that presented with mild to severe lymphoplasmacytic and histiocytic infiltrate, foci of necrosis, calcification and protozoan-like structures. Immunosuppressed gerbils bioassayed with N. caninum infected placental tissues showed severe neurological signs. Microscopic lesions in these gerbils were characterized by encephalitis, myocarditis, myositis and pancreatitis. These lesions were often associated with a small to moderate number of N. caninum tachyzoites, confirmed by immunohistochemistry and PCR. This is the first report showing that goat N. caninum strains could infect immunocompetent gerbils and cause severe lesions and clinical signs in immunosuppressed gerbils. PMID- 29279090 TI - Evaluation of Saccharum officinarum L. bagasse-derived polysaccharides as native immunomodulatory and anticoccidial agents in broilers. AB - Coccidiosis is one of the most important protozoal diseases of the poultry industry, inflicting heavy economic losses in the form of high mortality and morbidity in affected birds. Under these circumstances, the development of nonchemical consumer-friendly strategies for its effective control is of paramount importance. Therefore, this study was conducted to evaluate the sugarcane (Saccharum officinarum L.) bagasse-derived polysaccharides as native immunomodulatory and anticoccidial agents in commercial broilers. Polysaccharides were recovered from sugarcane bagasse (PSCB) and analyzed by high-performance liquid chromatography (HPLC). Five different sugars including melezitose, maltose, glucose, mannose, and fructose were detected in hydrolyzed solution of PSCB. The isolated PSCB were orally administered to the broilers in three graded doses ranging from 10 to 50mg/kg of body weight/day for 3 consecutive days, i.e., fifth through seventh days of life. Results showed significantly enhanced (p<0.05) lymphoproliferative and humoral responses to T-cell mitogen (PHA-P) and sheep red blood cells (SRBCs) in PSCB-administered chickens. In a challenge experiment, percent protection and daily weight gains were significantly higher (p<0.05), whereas mean oocyst counts and lesion scores were lower (p<0.05) in PSCB-administered chickens as compared to control. ELISA showed that PSCB significantly enhanced (p<0.05) antibody titers against the Eimeria species used for the induction of infection in chickens of PSCB-administered and control groups. In conclusion, PSCB showed the potential to modulate the immune responses in industrial broiler chickens with subsequent protection against coccidial infection. PMID- 29279091 TI - Molecular genotyping of Echinococcus granulosus in the North of Iraq. AB - Cystic echinococcosis/hydatidosis is an important cosmopolitan zoonotic disease that causes large economic losses and human suffering. The larval stages of Echinococcus granulosus are the etiological agents of cystic echinococcosis that showed different genotypes in different regions in the world. The present study was aimed at the detection of E. granulosus strains circulating in two cities from north of Iraq (Kirkuk and Sulaimania). A total of 47 specimens of hydatid cysts were collected from patients and from different domestic intermediate hosts including cattle, sheep, goat and buffalo from slaughterhouses. Molecular characterization was performed by direct sequencing of the mitochondrial DNA (mtDNA) genes coding for the cytochrome c oxidase I (cox1) and the small subunit ribosomal RNA (rrnS). The results showed a high prevalence for the sheep strain (G1), an isolated finding of the buffalo strain (G3) and the presence of seven and three different microvariants for cox1 and rrnS, respectively. This is the first contribution on molecular genotyping of E. granulosus in Iraq with the observation of genotypes other than G1. PMID- 29279092 TI - Weight gain and resistance to gastrointestinal nematode infections in two genetically diverse groups of cattle. AB - Body weight gain (BWG) and gastrointestinal nematode challenge (GIN) were investigated in two genetically diverse groups of cattle. Thirty-two dairy calves (D=Swedish Red/Holstein) and 31 dairy*beef crosses (C=Swedish Red/Holstein*Charolais) pairwise matched by dam breed and birth dates, were monitored for ~20 weeks on a pasture grazed by cattle in the previous year. At turn-out, animals (between 6 and 12 months age) from each genotype were either infected with 5000 third stage (L3) Ostertagia ostertagi (50%) and Cooperia oncophora (50%) larvae (H, high-exposure); or treated monthly with 0.5mg ivermectin (Noromectin(r), Pour-on) per kg bodyweight to remove worms ingested (L, low-exposure). Animals were weighed every fortnight and individual BWG was calculated. Faecal and blood samples were collected every four weeks throughout the experiment for nematode faecal egg counts (FEC) and larvae cultures and serum pepsinogen concentrations (SPC), respectively. Nematode eggs were observed 29 days post turn-out in both H groups. FEC peaked to around 200 eggs per gram (epg) on days 58 and 85 respectively in both H groups. FEC were also observed in the L groups at the same time, but mean epg remained very low (<20epg) and constituted exclusively of C. oncophora. Although, there was no significant difference in SPC values in animals of the different genotypes, ten animals of CH showed a SPC >3.5 IU tyrosine whereas only six DH animals reached similar pepsinogen levels. The level of infection (H and L) significantly affected BWG in both genotypes. Even though there was no statistically significant genotype (C or D)*treatment (H or L) interaction, there was a larger difference in body weight of H and L in C (37kg) compared to D (17kg) genotypes at the end of the experiment. Our data collectively support the view crossbred (C) animals experience the impact of gastrointestinal parasitism more severely compared to pure dairy (D) first season grazers. The mechanisms that underpin this remains speculative. PMID- 29279093 TI - Synergic in vitro combinations of artemisinin, pyrimethamine and methylene blue against Neospora caninum. AB - Neospora caninum is a member of Apicomplexa phylum, the causative agent of neosporosis. The neosporosis combat is not well established and several strategies related to vaccine, chemotherapy and immune modulation are under development. In this work, we evaluated the effects of artemisinin (Art), methylene blue (MB) and pyrimethamine (Pyr) alone or associated, on N. caninum proliferation and elimination using LacZ tagged tachyzoites. The reactive oxygen species (ROS) production after incubation with Art were also performed. Our results indicate that combinations of classical antimalarial drugs improve the parasite control, allowing the use of three drugs in a single dose. Additionally, artemisinin demonstrated distinct ROS production patterns in intra and extracellular N. caninum forms. The drug repurposing appears as a suitable approach, allowing a fast and safe method to evaluate old drugs but novel candidates against neosporosis. PMID- 29279094 TI - Entamoeba histolytica infection in wild lemurs associated with proximity to humans. AB - Amoebiasis, caused by Entamoeba histolytica, affects 50 million people worldwide, and results in 100,000 deaths annually. It is particularly prevalent in developing nations where poverty and poor sanitation contribute to contamination of food and water. E. histolytica is also a zoonotic protozoan parasite with the potential to infect non-human primates. Lemurs, primates endemic to Madagascar, are the most threatened mammalian group in the world due to habitat loss. As forests disappear, humans and lemurs come into more frequent contact, and the potential for E. histolytica to infect lemurs intensifies. Consequently, we screened 176 fecal samples from seven lemur species at eight sites in the rain forests of southeastern Madagascar for E. histolytica to determine if human proximity influenced lemur infection. Of samples examined, 4.0% (from three lemur species) were positive for E. histolytica. Of lemurs infected with E. histolytica, three (43%) exhibited diarrheal feces. Distance to human settlements explained the variation in E. histolytica infection seen in lemurs. These results provide the first evidence of E. histolytica in wild lemurs and highlight the need for additional work to better understand the eco-epidemiology of this potential threat to these species. PMID- 29279095 TI - The predictive value of primary tumor location in patients with metastatic colorectal cancer: A systematic review. AB - Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. It has been reported that left- and right-sided CRC harbor varying disease characteristics, which leads to a difference in prognosis and response to therapy. Recently, there have been retrospective studies about tumor location in metastatic CRC (mCRC) and its potential to predict the effect of anti-vascular endothelial growth factor and anti-epidermal growth factor receptor (anti-EGFR) therapies. In this review, we provide a comprehensive overview of the latest trials studying the predictive value of primary tumor location in mCRC and discuss biomarkers that might be associated with the differences in treatment response. Although data need to be interpreted with caution due to the absence of randomized trials stratified based on tumor location, patients with left-sided CRC seem to benefit more from anti-EGFR therapy than patients with right-sided CRC. Further clinical trials, stratified for tumor location, are warranted. PMID- 29279096 TI - E-cadherin: Its dysregulation in carcinogenesis and clinical implications. AB - E-cadherin is a transmembrane glycoprotein which connects epithelial cells together at adherens junctions. In normal cells, E-cadherin exerts its tumour suppressing role mainly by sequestering beta-catenin from its binding to LEF (Lymphoid enhancer factor)/TCF (T cell factor) which serves the function of transcribing genes of the proliferative Wnt signaling pathway. Despite the ongoing debate on whether the loss of E-cadherin is the cause or effect of epithelial-mesenchymal transition (EMT), E-cadherin functional loss has frequently been associated with poor prognosis and survival in patients of various cancers. The dysregulation of E-cadherin expression that leads to carcinogenesis happens mostly at the epigenetic level but there are cases of genetic alterations as well. E-cadherin expression has been linked to the cellular functions of invasiveness reduction, growth inhibition, apoptosis, cell cycle arrest and differentiation. Studies on various cancers have shown that these different cellular functions are also interdependent. Recent studies have reported a rapid expansion of E-cadherin clinical relevance in various cancers. This review article summarises the multifaceted effect E-cadherin expression has on cellular functions in the context of carcinogenesis as well as its clinical implications in diagnosis, prognosis and therapeutics. PMID- 29279097 TI - Epigenetic regulation of the Hedgehog and Wnt pathways in cancer. AB - The Hedgehog (Hh) and wingless-Int1 (Wnt) pathways are important for tissue patterning in the developing embryo. In adult tissue, both pathways are typically dormant but are activated under certain conditions such as tissue damage. Aberrant activation of these pathways by mutations in key pathway regulators contributes to the genesis and progression of several cancer types. In addition, the impact of epigenetic regulation of the Hh and Wnt pathways on cancer is becoming increasingly clear. In this review, current knowledge on the epigenetic control of Hh and Wnt and the impact on tumor formation will be discussed. First, the role of epigenetic control on ligand production will be discussed, followed by the epigenetic regulation of the extra- and intracellular pathway members. Furthermore, the epigenetic control of pathway target genes will be highlighted. Lastly, an overview of current therapeutic strategies to target aberrant epigenetic control of the Hh and Wnt pathways is provided. PMID- 29279098 TI - Systematic review and survival meta-analysis of real world evidence on first-line pazopanib for metastatic renal cell carcinoma. AB - A systematic review was conducted to identify real world studies reporting outcomes after first-line pazopanib in patients with metastatic renal cell carcinoma. Studies had to be observational and report survival data in terms of progression-free survival and overall survival in order to conduct meta-analysis techniques. These real-world data were compared to those obtained in the phase II and III randomized controlled trials of pazopanib. Real world evidence showed that the clinical and safety outcomes were consistent with those observed in the clinical trials despite the inclusion of unselected patients with a wide spectrum of prognostic features and comorbidities. Similarly to the results of the pivotal studies, good prognosis patients had the most benefit from pazopanib. Further investigation is needed to complement evidence from clinical trials, in particular focused on patient-centered outcomes. PMID- 29279099 TI - A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting. AB - Despite current advances in antiemetic treatments, between 30% to and 60% of oncology patients experience chemotherapy-induced nausea (CIN) and 13% to 33% report chemotherapy-induced vomiting (CIV). Inter-individual differences are observed in the occurrence and severity of chemotherapy-induced nausea and vomiting (CINV). This review summarizes and critiques studies on associations between occurrence and severity of CINV and polymorphisms in serotonin receptor, drug metabolism, and drug transport pathway genes. Sixteen studies evaluated the associations between the occurrence and/or severity of CINV and single nucleotide polymorphisms (SNPs). Across these studies, three SNPs in 5-hydroxytryptamine receptor (5-HT3R) genes, two alleles of the cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene, and three SNPs in ATP binding cassette subfamily B member 1 (ABCB1) gene were associated with the occurrence and severity of CINV. Given the limited number of polymorphisms evaluated, additional research is warranted to identify new mechanisms to develop more targeted therapies. PMID- 29279100 TI - Long-term toxicity of the treatment for germ cell-cancer. A review. AB - Testicular germ-cell cancer (GCC) is a curable disease. Stage I patients are mostly cured by surgery alone. For those with good prognosis advanced disease, radiotherapy in some patients with stage II Seminoma and chemotherapy for all other patients, are responsible for 95% of long-term survivors. Unfortunately, despite this high level of curability, overall survival has been reported lower for those patients receiving either radiotherapy or chemotherapy versus patients treated by surgery alone. Long-term survivors face a higher incidence of second neoplasms, and a higher risk of cardiovascular disease and metabolic syndrome than expected. Other non-life-threatening toxicities such as ototoxicity, neurotoxicity and fertility problems are common. This paper reviews the potential causes of the higher mortality among long-term survivors of testicular tumors, the incidence of them and some recommendations for the diagnoses and prevention of long-term sequelae in patients with GCC. PMID- 29279101 TI - The relationship between body mass index and short term postoperative outcomes in patients undergoing potentially curative surgery for colorectal cancer: A systematic review and meta-analysis. AB - BACKGROUND: The prevalence of obesity has increased worldwide over the last few decades, and is a well-recognized risk factor for colorectal cancer. Surgical site infection is the most frequent complication following surgery for colorectal cancer, and the main cause of postoperative morbidity. The aim of the present systematic review and meta-analysis was to examine the relationship between increasing BMI and postoperative surgical site infection following surgery for colorectal cancer. METHODS: A systemic literature search was conducted using Medline, PubMed, Embase (Ovid) and Web of Science databases from inception to the end of August 2016. Studies examining the relationship between obesity and surgical site infection following surgery for colorectal cancer were included. Analysis of the data was performed using Review Manager version 5.3(The Nordic Cochrane Centre, The Cochrane Collaboration, Copen-hagen, Denmark,) RESULTS: In this meta-analysis, a total of 9535 patients from 16 studies were included. BMI <30 vs >=30kg/m2 was used to examine the association of obesity and surgical site infection in patients from Western countries. The estimated pooled OR demonstrated that obesity increased the risk of surgical site infection by approximately 100% (OR=2.13; 95% CI 1.66-2.72, p<0.001).BMI <25 vs >=25kg/m2 was used to examine the association of obesity and surgical site infection from Asian countries. The estimated pooled OR demonstrated that obesity increased the risk of surgical site infection by approximately 60% (OR=1.63; 95% CI 1.29-2.06, p<0.001). There was little evidence of publication bias in the meta-analysis. CONCLUSION: From this systematic review and meta-analysis there was good evidence that obesity was associated with a significantly higher risk of developing surgical site infection following surgery for colorectal cancer in both ethnic groups. The magnitude of the effect warrants further investigation. PMID- 29279103 TI - Chemical modification of cellulose-rich fibres to clarify the influence of the chemical structure on the physical and mechanical properties of cellulose fibres and thereof made sheets. AB - Despite the different chemical approaches used earlier to increase the ductility of fibre-based materials, it has not been possible to link the chemical modification to their mechanical performance. In this study, cellulose fibres have been modified by periodate oxidation, alone or followed either by borohydride reduction, reductive amination or chlorite oxidation. In addition, TEMPO oxidation, and TEMPO oxidation in combination with periodate oxidation and further reduction with sodium borohydride have also been studied. The objective was to gain understanding of the influence of different functional groups on the mechanical and structural properties of handsheets made from the modified fibres. It was found that the modifications studied improved the tensile strength of the fibres to different extents, but that only periodate oxidation followed by borohydride reduction provided more ductile fibre materials. Changes in density, water-holding capacity and mechanical performance were also quantified and all are dependent on the functional group introduced. PMID- 29279102 TI - A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma. AB - Multiple classes of agent with distinct mechanisms of action are now available for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM), including immunomodulatory agents, proteasome inhibitors, histone deacetylase inhibitors and monoclonal antibodies. Additionally, several different drugs may be available within each agent class, each with their own specific efficacy and safety profile. This expansion of the treatment landscape has dramatically improved outcomes for patients. However, as the treatment options for RRMM become more complex, choosing the class of agent or combination of agents to use in the relapsed setting becomes increasingly challenging. Furthermore, treatment options for specific patient populations such as the elderly, those with high-risk cytogenetic abnormalities and those with refractory disease are yet to be defined in the current treatment landscape. When choosing an appropriate treatment approach, physicians must consider multiple criteria including both patient-related and disease-related factors. The aim should be to provide patient-specific treatment in order to gain a clinical benefit while minimizing toxicity. This review provides an overview of the mechanism of action and efficacy and safety profiles of each class of agent and of treatment regimens that combine different classes of agent, with a special focus on treating specific patient populations. PMID- 29279104 TI - Cross-linked chitosan/beta-cyclodextrin composite for selective removal of methyl orange: Adsorption performance and mechanism. AB - A complex chitosan/beta-cyclodextrin polymer was synthesized by bridging with maleoyl chains followed by cross-linking with glutaraldehyde. The adsorption performance of the synthetic polymer was investigated for selective removal of methyl orange (MO) from aqueous solution. The kinetic behavior was well fitted by the pseudo-second order model, while the adsorption process at equilibrium followed the Langmuir isotherm model. The thermodynamic parameters suggested that the adsorption was exothermic and spontaneous. Under optimal adsorption conditions, the capacity for MO reached 392mg/g with the dosage of 10mg/50mL. Based on the analysis from FTIR, 1H NMR, TGA and zeta potential, the adsorption mechanism could be explained by the synergistic effect of electrostatic attraction of amino groups from chitosan and host-guest interaction from beta cyclodextrin. This adsorbent also demonstrated high selectivity towards MO due to the unique structure of cross-linked chitosan/beta-cyclodextrin polymer that are complementary to that of MO molecule. PMID- 29279105 TI - The starch nanocrystal filled biodegradable poly(epsilon-caprolactone) composite membrane with highly improved properties. AB - The platelet-like starch nanocrystal (SNC) particles were used to prepare composite membrane with biodegradable poly(epsilon-caprolactone) (PCL) for the potential packaging membrane application. The presence of SNC particles improves gas barrier properties, tearing strength, as well as the creep resistance of the PCL membrane evidently at the lower loading levels. This improvement effect can be further enhanced by the surface acetylation of SNC. The presence of acetylated SNC particles (1wt%) can reduce the oxygen transmission rate by about 70% and increase the tearing strength by about 68%, which is due to the improved phase adhesion. The strain failure stage of the membrane is also highly delayed in the presence of acetylated SNC, from hour-time scale to day-time one. Therefore, the biodegradable SNC is a promising candidate to be used as the filler to improve the key properties of biodegradable PCL membrane, but the chemically modified SNC is the better option. PMID- 29279106 TI - Proton NMR relaxometry as probe of gelatinization, plasticization and montmorillonite-loading effects on starch-based materials. AB - The effects of granule disruption, the addition of glycerol and montmorillonite on the granule structure of corn starch were investigated by proton NMR relaxation, through the T2*, T1 and T1rho relaxation times. Films containing 0%, 1%, 5% and 7%(w/w) of clay were prepared by solution casting and the relaxometry data were compared with those gleaned from WAXD, TGA and SEM techniques. Starch gelatinization without glycerol or clay results in an amorphous and rigid film having a dipole coupling higher than that observed for the granule. The plasticization reduces the chains rigid fraction by more than 20% and increases the adsorption of moisture in the region of greater molecular mobility. The addition of 1% of clay reduces the adsorption of moisture and, in concentrations of 5% and 7%, the agglomerates reduce the plasticization effect. These features studied were observed by the Tube-Reptation and Renormalized Rouse models applied at low frequencies. PMID- 29279108 TI - Phosphonium ionic liquid as interfacial agent of layered double hydroxide: Application to a pectin matrix. AB - Phosphonium ionic liquid (IL) combined with 2-ethylhexanoate counter anion has been used as interfacial agent of layered double hydroxide (LDH). First, the intercalation of hexanoate anion between the LDH layers was confirmed by thermogravimetric analysis (TGA) and X-ray diffraction (XRD). Then, this thermally stable organophilic LDH was introduced at different amount (1, 3 and 5wt%) into pectin matrix leading to an increase of the thermal stability of the resulting nanocomposites (+35-40 degrees C). In addition, the good distribution of the modified LDH led to an increase of the mechanical performances through the elastic moduli (+60%) as well as a significant increase of the water barrier properties of two orders of magnitude for the pectin containing 5wt% of LDH-Ionic Liquid. PMID- 29279109 TI - Cellulose-based amorphous solid dispersions enhance rifapentine delivery characteristics in vitro. AB - The efficacy of rifapentine, an oral antibiotic used to treat tuberculosis, may be reduced due to degradation at gastric pH and low solubility at intestinal pH. We hypothesized that delivery properties would be improved in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions (ASDs) with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). ASDs generally reduced rifapentine release at gastric pH, with CASub affording >31-fold decrease in area under the curve (AUC) compared to rifapentine alone. Critically, reduced gastric dissolution was accompanied by reduced degradation to 3-formylrifamycin. Certain ASDs also enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with HPMCAS providing nearly 4-fold increase in total AUC vs. rifapentine alone. These results suggest that rifapentine delivery via ASD with these cellulosic polymers may improve bioavailability in vivo. PMID- 29279107 TI - The role of hydrophobic modification on hyaluronic acid dynamics and self assembly. AB - The advent of nanomedicine has rejuvenated the need for increased understanding of the fundamental physicochemical properties of polymeric amphiphiles. Hyaluronic acid (HA) is a hydrophilic polysaccharide that is frequently conjugated to hydrophobic moieties and then used to entrap dyes and therapeutics. Here, we develop computational models to examine the effects of the hydrophobic modification on supramolecular behavior among three systematically designed HA derivatives substituted with alkyl chains of increasing length. Our simulations coalesce with experimentally obtained results to demonstrate the dependence of supramolecular behavior on intramolecular forces. We show that the formation of clearly defined hydrophobic domains in samples of octadecylamine-modified HA compared to HA conjugates with shorter alkyl chains is a result of more favorable hydrophobic interactions. Trends in hydrodynamic radius and polydispersity are observed in experimental results that coalesce with theoretical calculations, suggesting that supramolecular properties are dependent on the physicochemical characteristics of individual polymer strands. PMID- 29279110 TI - On the origin of sorption hysteresis in cellulosic materials. AB - Moisture sorption and moisture sorption hysteresis of carbohydrates are phenomena which affect the utilisation of products made thereof. Although extensively studied, there is still no consensus regarding the mechanisms behind sorption hysteresis. Attempts have been made to link the behaviour to molecular properties, in particular to softening properties, and the moisture sorption hysteresis has therefore here been investigated by modifying cellulosic fibres to affect their softening properties. The results show that the moisture sorption hysteresis diminishes with decreasing softening temperature, and was even completely absent at the higher degrees of modification. The moisture sorption characteristics also changed from a type II sorption to a more type III sorption behaviour, a feature more prominent the higher the degree of modification and the higher the temperature. For the highest degree of modification studied the sorption characteristics changed from sorbing less water the higher the temperature to sorbing more water with increasing temperature. PMID- 29279111 TI - Chitosan based nano composite adsorbent-Synthesis, characterization and application for adsorption of binary mixtures of Pb(II) and Cd(II) from water. AB - Composite type adsorbent was prepared by integrating chitosan (Cs) with crosslinked polymethacrylic acid (PMA) and nano sized halloysite nanotube (HNT). The structure of the resulting Cs-PMA/HNT adsorbents was characterized by FTIR, NMR, XRD, TGA, SEM/EDX and rheological properties. These functional adsorbents were used for removal of Pb(II) and Cd(II) as single and binary competitive mixtures from water. There was a significant improvement in adsorption properties of crosslinked PMA in the presence of Cs and HNT. The effect of synthesis parameters such as wt.% of Cs and HNT on swelling and process parameters such as solution pH, adsorbent dosage, contact time and feed concentration on adsorption of metal ions from water were studied in batch experiments. For a feed concentration of 100mg/L of metal ion, an adsorbent dose of 0.25g/L and a solution pH of 6, the Cs-PMA/HNT composite adsorbent containing 4wt% Cs and 3wt% HNT showed an adsorption capacity (mg/g)/removal% of 357.4/89.4 and 341.6/85.4 for single Pb(II) and Cd(II), respectively which reduced to 313.7/78.4 and 303.6/77.3 for the same metal ions in their binary mixtures in water. PMID- 29279112 TI - Microencapsulation by pectin for multi-components carriers bearing both hydrophobic and hydrophilic active agents. AB - Oil/water microencapsulation by microfluidic systems has been a prominent delivery method to prepare functional microcapsules in the food, cosmetic, and pharmaceutical industries because it is an easy way to control the shape and size of structures and functionalities. We prepared biocompatible and multi-component microcapsules using the precipitation and ionic crosslinking of pectin in a poor solubility environment and with multivalent cations, respectively. When the aqueous solution (including calcium ions and ethanol) in a sheath flow met the flow of a pectin aqueous solution containing oil droplets, ethanol-gelation and ionic cross-linking occurred, enclosing the inner oil phase droplets by solidified pectin shells. Furthermore, the resulting microcapsules stabilized by pectin shells exhibited functionalities using a hydrophobic agent and nanoparticles of a hydrophilic species that were dissolved and dispersed, respectively, in the oil phase. PMID- 29279113 TI - Novel cationic chitosan derivative bearing 1,2,3-triazolium and pyridinium: Synthesis, characterization, and antifungal property. AB - In this paper, novel cationic chitosan derivative possessing 1,2,3-triazolium and pyridinium groups was synthesized conveniently via cuprous-catalyzed azide-alkyne cycloaddition (CuAAC) and methylation. FTIR, 1H NMR, and elemental analysis examined the structural characteristics of the synthesized derivatives. The antifungal efficiencies of chitosan derivatives against three plant-threatening fungi were assayed by hypha measurement in vitro. The determination showed that chitosan derivative bearing 1,2,3-triazolium and pyridinium displayed tremendously enhanced antifungal activity as compared with chitosan and chitosan derivative bearing 1,2,3-triazole and pyridine. Notably, the inhibitory indices of it against Colletotrichum lagenarium attained 98% above at 1.0mg/mL. The results showed that N-methylation of 1,2,3-triazole and pyridine could effectively enhance antifungal activity of the synthesized chitosan derivatives. Besides, the prepared chitosan derivatives showed non-toxic effect on cucumber seedlings. This synthetic strategy might provide an effective way and notion to prepare novel cationic chitosan antifungal biomaterials. PMID- 29279114 TI - Enhancement of anticancer activity and drug delivery of chitosan-curcumin nanoparticle via molecular docking and simulation analysis. AB - Computational analyses followed by traditional wet-bench experiments have become a method of choice due to successful results. To enhance the solubility and bioavailability of curcumin within chitosan nanoparticle, we have exploited computational methodologies i.e. docking, BBD-RSM and MD simulation for the polymer selection, NPs' formulation, optimization and their stability confirmation in an aqueous medium, respectively. Formulated CSCur NPs were assessed for in-vitro release, which exhibited a sustained release pattern and four-fold higher cytotoxic activity in a nanoparticulated system. Enhanced uptake, apoptotic effect of CSCur NPs were established by morphological changes in cells as observed by fluorescence microscopy and FE-SEM. DNA damage, cell cycle blockage and elevated ROS levels further confirm the anticancer activity of the CSCur NPs following apoptotic pathways. In-vivo study on Danio rerio, for uptake and toxicity reveal the particle's biocompatibility and nontoxicity. Therefore, CSCur NPs could be the potential formulation for a safe chemotherapeutic drug for cancer. PMID- 29279115 TI - A novel voltammetric sensor for the simultaneous detection of Cd2+ and Pb2+ using graphene oxide/kappa-carrageenan/l-cysteine nanocomposite. AB - Simultaneous determination of Cd2+ and Pb2+ was achieved by using graphene oxide/kappa-carrageenan/l-cysteine (GO/kappa-Car/l-Cys) nanocomposite modified glassy carbon electrode (GCE) by Square Wave Anodic Stripping Voltammetry (SWASV). The morphology and functionalization of the prepared nanocomposite were characterized by XRD analysis, Raman spectroscopy, Field emission scanning electron microscopy and FTIR analysis. Under optimum conditions, outstanding linearity was obtained for both Cd2+ and Pb2+ in the range from 5 to 50nM with the detection limits as 0.58nM and 1.08nM respectively. The sensitivity calculated from the slope of calibration curve was 1.39MUA/nM and 1.32MUA/nM for Cd2+ and Pb2+ respectively. We also carried out multiple metal ion detection, interference of anions and surfactants for the detection of Cd2+ and Pb2+ ions. The modified electrode has been applied to the detection of Cd2+ and Pb2+ present in water and milk samples, and the accessed results were satisfactory with that of AAS. PMID- 29279116 TI - Structural characterization and osteogenic bioactivity of a sulfated polysaccharide from pacific abalone (Haliotis discus hannai Ino). AB - Bone morphogenic protein-2 (BMP-2) is known to promote osteogenesis. To find novel adjuvants to enhance the activity of BMP-2, the present study investigated the structure BMP-2-induced osteogenic activity of a water-soluble polysaccharide from the gonad of pacific abalone (Haliotis discus hannai Ino) named AGSP. Through analysis of aldobiouronic acids released from AGSP, monosaccharide composition comparison of AGSP and its reduced product, and methylation analysis and NMR analysis of AGSP and its desulfated derivative, the main structure residue of AGSP was determined as ->3)-GlcA(1->3)-Gal(1-> with sulfated branches comprised of prevelant Gal and minor Glc, and ->4)-beta-GlcA(1->2)-alpha-Man(1-> residue was also found. AGSP possessed a sulfate content of 12.4% with a relative molecular weight of 6.6kDa. AGSP strengthened alkaline phosphatase activity induced by BMP-2 in a dose dependent manner at 10-200MUg/mL with 425% enhancement being observed at 200MUg/mL, indicating AGSP could be an adjuvant candidate to enhance osteogenic activity of BMP-2. PMID- 29279117 TI - Ultrasound-assisted xanthation of cellulose from lignocellulosic biomass optimized by response surface methodology for Pb(II) sorption. AB - Alkali treatment of lignocellulosic biomass is conducted to remove hemi-cellulose and lignin, further increasing the reactivity and accessibility of cellulose. Ultrasound-assisted xanthation of alkali cellulose is optimized by response surface methodology (RSM) with a Box-Behnken design. A predicting mathematical model is obtained by fitting experimental data, and it is verified by analysis of variance. Response surface plots and the contour plots obtained from the model are applied to determine the interactions of experimental variables. The optimum conditions are NaOH concentration 1.3mol/L, ultrasonic time 71.6min and CS2 dosage 1.5mL. FTIR, SEM and XPS characterizations confirm the synthesis and sorption mechanism of cellulose xanthate (CX). Biosorption of Pb (II) onto CX obeys pseudo-second order model and Langmuir model. The sorption mechanism is attributed to surface complexation or ion exchange. CX shows good reusability for Pb (II) sorption. The maximum sorption capacity of Pb(II) is 134.41mg/g, higher than that of other biosorbents. CX has great potential as an efficient and low cost biosorbent for wastewater treatment. PMID- 29279118 TI - In situ controlled release of stromal cell-derived factor-1alpha and antimiR-138 for on-demand cranial bone regeneration. AB - Bone regeneration involves complex physiological processes, which is generally regulated and controlled by multiple bioactive molecules. In situ controlled release of combined bioactive factors in a spatiotemporal sequence for adapting the demand of bone regeneration is a desired strategy. In this study, nanoparticle/hydrogel composite system was constructed by incorporating stromal cell derived factor-1alpha (SDF-1alpha) and chitosan/tripolyphosphate/hyaluronic acid/antimiRNA-138 nanoparticles (CTH/antimiR-138 NPs) in chitosan/beta-sodium glycerol phosphate (CS/GP) hydrogel for rat critical-size calvarial bone regeneration. The fast release of SDF-1alpha promoted the migration of mesenchymal stem cells (MSCs) for 6 d, while the sustained release of antimiR-138 from the nanoparticle/hydrogel compound enhanced the osteogenic differentiation of MSCs over 21 d. 8 weeks after surgery, calvarial specimens were evaluated by microcomputed tomography (MU-CT), histological analysis and immunohistochemistry. Comparing with blank group and hydrogel group, hydrogels incorporated with SDF 1alpha and/or CTH/antimiR-138 NPs significantly enhanced bone regeneration (p<0.05). In addition, the expression of collagen type-1 (COL-1), osteopontin (OPN) and osteocalcin (OCN) proteins were enhanced in the combined drug group (incorporated both SDF-1alpha and CTH/antimiR-138 NPs) in comparison to the hydrogel group. Our research indicated the in situ formation of NPs/hydrogel composite could provide temporal sequence-release of SDF-1alpha and CTH/antimiR 138 NPs for on-demand MSCs homing and cranial bone regeneration. PMID- 29279119 TI - Chitosan oligosaccharide-N-chlorokojic acid mannich base polymer as a potential antibacterial material. AB - Here, a nontoxic antibacterial material based on Chitosan Oligosaccharide-N Chlorokojic acid Mannich base (COS-N-MB) that was synthesized by using the selective partial alkylation reaction displaying excellent activity against bacterial infection. The proposed mechanism of the action of COS-N-MB is that this antibacterial material with positive charge and synergistic antibacterial effects can promote it's adsorption to bacterial cell wall through electrostatic interaction and chelating metal cations. It changed the permeability of the membrane, caused cellular leakage, and destroyed the membrane integrity, leading to complete membrane disruption and eventually death of the bacteria. Besides, COS-N-MB can interact with membrane proteins, causing deformation in the structure and functionality. The good biocompatibility, noncytotoxic, and low hemolysis made this novel material a promising and effective compound for antibacterial applications. PMID- 29279120 TI - Reduction stimuli-responsive unimolecular polymeric prodrug based on amphiphilic dextran-framework for antitumor drug delivery. AB - We report a new reduction-responsive amphiphilic polymeric prodrug based on a linear dextran (DEX) backbone, which was conjugated with an hydrophobic camptothecin (CPT) prodrug block and an hydrophilic poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) block [DEX-PCPT-b-POEGMA (DCO)] by atom transfer radical polymerization (ATRP). This amphiphilic prodrug has a unique molecular structure with prominent features, including strong practicability for methacrylate prodrug monomer, high drug loading rate (up to 23wt%), adjustable proportion of hydrophobic and hydrophobic portions, superior stability in aqueous solution, and easy access to cells. Introduction of a disulfide bond linker between the drug and the carrier can realize the function of reduction-responsive controlled drug-release. The experimental study indicated that the prodrug exhibited notable antitumor activity against HeLa cells and MCF-7 cells in vitro. Compared to similar DCO prodrug based on double carbon bond, the disulfide bond conjugated DCO prodrug induced higher level of tumor cell apoptosis. Considering the drug-loading efficiency, micellar stability, cost of preparation and controlled drug release, the presented prodrug is more advantageous than traditional unimolecular prodrug and represents a promising approach for design of stimuli-responsive polymeric prodrug for effective cancer therapeutics. PMID- 29279121 TI - Fabrication of chitosan-mesoporous silica SBA-15 nanocomposites via functional ionic liquid as the bridging agent for PPL immobilization. AB - A nanocomposite (SBA-CIL-CS) which was combined mesoporous silica SBA-15 material with chitosan via ionic liquid as the bridging agent was successfully fabricated. The morphology and structure of the nanocomposite were characterized in detail with transmission electron microscope, fourier transform infrared spectroscopy, thermogravimetric analysis and nitrogen adsorption-desorption techniques. SBA-CIL CS was investigated as an efficient support for immobilization of porcine pancreas lipase (PPL) and possessed high immobilization efficiency. The properties of immobilized enzyme (SBA-CIL-CS-PPL) such as activity, stability and reusability have been significantly improved, and a preferable pH and temperature tolerance were obtained as well. Results demonstrated the inorganic-organic nanocomposite could be used as an ideal support for enzyme immobilization. PMID- 29279122 TI - Ulvan-chitosan polyelectrolyte complexes as matrices for enzyme induced biomimetic mineralization. AB - Polyelectrolyte complexes (PEC) of chitosan and ulvan were fabricated to study alkaline phosphatase (ALP) mediated formation of apatitic minerals. Scaffolds of the PEC were subjected to ALP and successful mineral formation was studied using SEM, Raman and XRD techniques. Investigation of the morphology via SEM shows globular structures of the deposited minerals, which promoted cell attachment, proliferation and extracellular matrix formation. The PEC and their successful calcium phosphate based mineralization offers a greener route of scaffold fabrication towards developing resorbable materials for tissue engineering. PMID- 29279123 TI - Nanocomposites based on chitosan/silver/clay for durable multi-functional properties of cotton fabrics. AB - The present work addresses an innovative approach for benign development of environmentally synthesis of chitosan-based nanocomposite. The synthesis involves the inclusion via interaction of AgNPs and clay with chitosan (Cs) giving rise to Cs/AgNPs and Cs/AgNPs/clay nanocomposites which when applied independently induce super functionalities. Comparison is made among the two nanocomposites with respect to their intimate association with the in depth cotton fibre-fabric surfaces and the onset of this on the multi-functionalization of cotton fabrics. It is as well to emphasize that Cs/AgNPs/clay nanocomposites prove unequivocally that its use in one-step treatment process for cotton fabrics results in imparting very appreciable good technical properties which, in turn, are reflected on all the gained functionalities of cotton fabrics. Of these functional performance properties, mention is made of cotton fabrics which exhibit high strength, uniform morphology, increased thermal stability, successful deposition of the composite on the surface of cotton fabrics, high water absorption, antimicrobial activity, flame retardant, controlled release of fragrance and UV protection. The obtained data indicate that the treatment for cotton fabrics with these nanocomposite is stable against washing even after 20 washing cycles. Based on encourage data, the environmental benign synthesis of Cs/AgNPs/clay nanocomposites is considered as a promising nanocomposite for the multifunctional finishing textiles. PMID- 29279124 TI - Preparation, characterization and in vivo evaluation of pH sensitive, safe quercetin-succinylated chitosan-alginate core-shell-corona nanoparticle for diabetes treatment. AB - The study aims for development of an efficient polymeric carrier for evaluating pharmaceutical potentialities in modulating the drug profile of quercetin (QUE) in anti-diabetic research. Alginate and succinyl chitosan are focused in this investigation for encapsulating quercetin into core-shell nanoparticles through ionic cross linking. The FT-IR, XRD, NMR, SEM, TEM, drug entrapment and loading efficiency are commenced to examine the efficacy of the prepared nanoparticles in successful quercetin delivery. Obtained results showed the minimum particle size of ~91.58nm and ~95% quercetin encapsulation efficiently of the particles with significant pH sensitivity. Kinetics of drug release suggested self-sustained QUE release following the non-fickian trend. A pronounced hypoglycaemic effect and efficient maintenance of glucose homeostasis was evident in diabetic rat after peroral delivery of these quercetin nanoparticles in comparison to free oral quercetin. This suggests the fabrication of an efficient carrier of oral quercetin for diabetes treatment. PMID- 29279125 TI - Effect of polyethyleneimine modified graphene on the mechanical and water vapor barrier properties of methyl cellulose composite films. AB - A series of novel methyl cellulose (MC) composite films were prepared using polyethyleneimine reduced graphene oxide (PEI-RGO) as an effective filler for water vapor barrier application. The as-prepared PEI-RGO/MC composites were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, tensile test and scanning electron microscopy. The experimental and theoretical results exhibited that PEI-RGO was uniformly dispersed in the MC matrix without aggregation and formed an aligned dispersion. The addition of PEI-RGO resulted in an enhanced surface hydrophobicity and a tortuous diffusion pathway for water molecules. Water vapor permeability of PEI RGO/MC with loading of 3.0% of surface modified graphene was as low as 5.98*10 11gmm-2s-1Pa-1. The synergistic effects of enhanced surface hydrophobicity and tortuous diffusion pathway were accounted for the improved water vapor barrier performance of the PEI-RGO/MC composite films. PMID- 29279126 TI - Gold nanoparticles stabilized by poly(4-vinylpyridine) grafted cellulose nanocrystals as efficient and recyclable catalysts. AB - pH-responsive poly(4-vinylpyridine) (P4VP) grafted cellulose nanocrystals (P4VP-g CNC) were prepared by Surface-Initiated Atom Transfer Radical Polymerization (SI ATRP) and subsequently used to stabilize gold nanoparticles (Au NPs) as efficient and recyclable nanocatalysts for the reduction of 4-nitrophenol (4NP). The presence of P4VP brushes on the CNC surface controlled the growth of Au NPs yielding smaller averaged diameter compared to Au NPs deposited directly on pristine CNC. The catalytic performances of pristine Au NPs, Au@CNC and Au@P4VP-g CNC were compared by measuring the turnover frequency (TOF) for the catalytic reduction of 4NP. Compared to pristine Au NPs, the catalytic activity of Au@CNC and Au@P4VP-g-CNC were 10 and 24 times better. Moreover, the Au@P4VP-g-CNC material could be recovered via flocculation at pH>5, and the recycled nanocatalyst remained highly active. PMID- 29279127 TI - Self-assembly of oleylamine modified nano-fibrillated cellulose from areca husk fibers into giant vesicles. AB - Nanotechnology involving cellulosic substrates has generated a great attention owing to their exceptional physical and chemical properties. Self-assembled nanostructures obtained from carbohydrate polymers are of interest in the biomedical field for the biocompatibility and non-toxic nature. In the present study modification of nano-fibrillated cellulose (NFC) synthesised from the husk fibers of Areca catechu nuts (AHF) was studied by controlled regio-selective amidation with oleylamine (OA) and characterized. The modified system (MNFC) with more than 66% OA content showed self-assembly into unilamellar vesicles of 2-5MUm diameters with a wall thickness of 300-600nm in tetrahydrofuran (THF) at 2.5mgmL 1. This result is attributed to the folding of MNFC into bilayers driven by long cis-unsaturated aliphatic chains in polar aprotic solvents stabilized by hydrogen bonded interactions within the fibrils. These giant vesicles formed can have applications in storage and delivery of drugs in topical applications. PMID- 29279128 TI - High-efficiency production of gamma-cyclodextrin using beta-cyclodextrin as the donor raw material by cyclodextrin opening reactions using recombinant cyclodextrin glycosyltransferase. AB - In comparison with natural alpha- and beta-cyclodextrin (CD), gamma-CD has attracted much attention due to their large hydrophobic cavities, high water solubility, and bioavailability. However, the production of gamma-CD is still rather expensive and time-consuming. To overcome the high cost and long induction time, pUC119 was selected as the gene expression vector, and the recombinant enzyme production time was reduced to 8h from 72h. Furthermore, for the first time, we have successfully produced gamma-CD using beta-CD by cyclodextrin opening reactions through the recombinant CGTase in the presence of maltose. The kinetic mechanism of the coupling reaction was investigated. Moreover, the production of gamma-CD could be affected by several key parameters, such as solvent type, reaction time, pH, and temperature. A maximum gamma-CD yield of 32.9% was achieved by recombinant CGTase in the presence of 5-cyclohexadecen-1 one. This could be a promising method for the industrial production of gamma-CD. PMID- 29279129 TI - Lignocellulose nanofibers prepared by ionic liquid pretreatment and subsequent mechanical nanofibrillation of bagasse powder: Application to esterified bagasse/polypropylene composites. AB - In the present study, we examined the efficacy of choline acetate (ChOAc, a cholinium ionic liquid))-assisted pretreatment of bagasse powder for subsequent mechanical nanofibrillation to produce lignocellulose nanofibers. Bagasse sample with ChOAc pretreatment and subsequent nanofibrillation (ChOAc/NF-bagasse) was prepared and compared to untreated control bagasse sample (control bagasse), bagasse sample with nanofibrillation only (NF-bagasse) and with ChOAc pretreatment only (ChOAc-bagasse). The specific surface area was 0.83m2/g, 3.1m2/g, 6.3m2/g, and 32m2/g for the control bagasse, ChOAc-bagasse, NF-bagasse, and the ChOAc/NF-bagasse, respectively. Esterified bagasse/polypropylene composites were prepared using the bagasse samples. ChOAc/NF-bagasse exhibited the best dispersion in the composites. The tensile toughness of the composites was 0.52J/cm3, 0.73J/cm3, 0.92J/cm3, and 1.29J/cm3 for the composites prepared using control bagasse, ChOAc-bagasse, NF-bagasse, and ChOAc/NF-bagasse, respectively. Therefore, ChOAc pretreatment and subsequent nanofibrillation of bagasse powder resulted in enhanced tensile toughness of esterified bagasse/polypropylene composites. PMID- 29279130 TI - Preparation and characterization of maleoylagarose/PNIPAAm graft copolymers and formation of polyelectrolyte complexes with chitosan. AB - A water soluble derivative in 98% yield with 23.1% incorporation of maleoyl groups was obtained by esterification of agarose with maleic anhydride. Graft copolymers were synthesized through vinyl groups of maleoylagarose with N isopropylacrylamide using ceric ammonium nitrate or ammonium persulfate as initiator, by conventional method or microwave irradiation. High nitrogen content (4.6%) was obtained in the grafting process using ceric ammonium nitrate as initiator without microwave irradiation. Copolymers were characterized by FT-IR and NMR spectroscopies, TGA, DSC and morphological analysis by AFM and SEM microscopy, confirming the grafting of PNIPAAm onto polysaccharide backbone. Hydrogel films were obtained by ionic complexation between opposite charged groups of maleoylagarose-g-poly(N-isopropylacrylamide) and chitosan. The swelling of 1:1w/v maleoylagarose-g-PNIPAAm:chitosan film was higher than 2:1w/v film at 25 and 37 degrees C. 53% release in vitro of diclofenac sodium from 1:1w/v maleoylagarose-g-PNIPAAm:chitosan was obtained at 37 degrees C and pH 6.0 with <0.5 diffusional constant values. PMID- 29279131 TI - Comparative study of ultra-lightweight pulp foams obtained from various fibers and reinforced by MFC. AB - A range of cellulose-based, ultra-lightweight pulp foams with different morphologies were prepared and reinforced with microfibrillated cellulose (MFC). By careful design of the pulp foam forming process, free-standing ultra lightweight pulp foams were obtained through high velocity mixing and air/oven drying from cellulose fiber in the presence of surfactant, MFC, and retention aid. The effects of different types of fibers and surfactants on the air uptake volumes and mechanical properties of the foam were systematically investigated. The structures characterized using an optical microscope and scanning electron microscope (SEM) showed that the foam was composed of wood fibers into two- or three-dimensional microstructures within random orientations surrounding gas bubbles. The results indicated that in spite of the strength of the foam could be manipulated by varying the surfactants and processing parameters, the addition of MFC indeed improved strength of pulp foams further. The process developed in this work provides a cost effective approach to fabricate the strong and ultra lightweight pulp foam, with a density lower than 0.02g/cm3, using a standard handsheet former. PMID- 29279132 TI - Structural features of a new water-soluble polysaccharide from the gum exudates of Amygdalus scoparia Spach (Zedo gum). AB - A new water-soluble polysaccharide (CZGS-1) with molecular weight of 4860kDa and a specific optical rotation of +31.5 degrees (c 1.0, H2O), was extracted from the gum exudate of Amygdalus scoparia Spach by hot water, following by purification with DEAE-cellulose A52 and Sephacryl S-400 HR columns. Monosaccharide composition analysis indicates that CZGS-1 was an arabino galactan including Rha, Ara, Xyl, and Gal with a relative molar ratio of 1.1:20:5.2:17.9. The uronic acid content of CZGS-1 was about 6%. Structural features of CZGS-1 was investigated by a combination of partial acid hydrolysis, methylation and GC-MS analysis, periodic acid oxidation and Smith degradation, FT-IR and NMR spectroscopy. The results indicated that CZGS-1 possesses a backbone of ->3,6) beta-d-Galp-(1->, ->3)-beta-d-Galp-(1->, and ->3)-alpha-l-Araf-(1-> residues with side chains attached to O-3 and O-6 positions of 1,3,6-linked beta-d-Galp. The side chains are consisted of beta-d-Xylp-(1->3)-alpha-l-Araf-(1->3)-alpha-l-Araf (1->), alpha-l-Rhap-(1->6)-beta-d-Galp-(1->), and beta-d-GlcAp-(1->6)-beta-d-Galp (1->). PMID- 29279133 TI - Repetitive transcranial magnetic stimulation in treatment of post polio syndrome. AB - BACKGROUND: Post polio syndrome is a rare disease that occurs decades after polio virus infection. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option with proved effectiveness in drug resistant depression. Possibly it can be helpful in therapy of other neurological diseases including post polio syndrome. OBJECTIVE: To describe a case of patient diagnosed with post polio syndrome who was treated with rTMS stimulation with a good effect. METHODS: Patient had rTMS stimulation of left prefrontal cortex twice a week for an eight weeks. Patient's health status was evaluated before treatment, after last rTMS session and after three months from the end of the treatment. RESULTS: Improvement of fatigue score, mood disturbances and motor functions was observed after treatment. CONCLUSION: rTMS can be an effective method in treatment of post polio syndrome but further studies with larger group need to be done to confirm that data. PMID- 29279134 TI - Mortality after an episode of acute heart failure in a cohort of patients with intermediate ventricular function: Global analysis and relationship with admission department. AB - BACKGROUND AND OBJECTIVE: To compare the outcome of patients with acute heart failure (AHF) with a mid-range left ventricular ejection fraction (HFmrEF) with patients with a reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction. PATIENTS AND METHOD: A prospective observational study included patients diagnosed with AHF in 41 emergency departments. Patients were divided into 3 groups: HFrEF<40%, HFmrEF 40-49% and HFpEF>=50%. We collected 38 independent variables and the adjusted and crude all-cause mortality at one-year in the HFmrEF group was compared with that of the HFrEF and HFpEF groups. The analysis was stratified according to patient destination following ED care. RESULTS: Three thousand nine hundred and fifty-eight patients were included: 580 HFmrEF (14.6%), 929 HFrEF (23.5%) and 2,449 HFpEF (61.9%). Global mortality at one year was 28.5%. The crude mortality of the HFmrEF group was similar to that of the HFpEF group (HR 1.009; 95% CI 0.819-1.243; P=.933) and lower than the HFrEF group (HR 0.800; 95% CI 0.635-1.008; P=.058), but after adjustment for discordant basal characteristics among groups, the mortality of the HFmrEF group did not differ from that of the HFpEF (HRa 1.025; 95% CI 0.825-1.275; P=.821) or HFrEF group (HRa 0.924; 95% CI 0.720-1.186; P=.535). Neither were significant differences found between the HFmrEF group and the other 2 groups in the analysis stratified according to admission or discharge direct from the emergency department. CONCLUSION: Mortality at one-year after an AHF episode in patients with HFmrEF does not differ from that of patients with HFpEF or HfrEF, either globally or based on the main destinations after emergency department care. PMID- 29279135 TI - Pain after ortho-plastic reconstruction of lower limb injuries: A snapshot study. AB - INTRODUCTION: The incidence of pain after flap reconstruction of complex lower limb injury is poorly reported in the literature, and yet represents a significant source of morbidity in these patients. In our centre (Southmead Hospital, Bristol, England) patients who have had flap reconstruction for complex lower limb injury are followed up at a joint ortho-plastics lower limb clinic run weekly. The aim of this study was to report the incidence of pain in such patients at follow-up in the specialist clinic. The impact of the experience of pain upon the quality of life, and the efficacy of analgesia was assessed these cases. PATIENTS AND METHODS: This was a cross sectional snapshot study of a cohort of complex lower limb patients attending our lower limb ortho-plastics outpatient clinic between the dates of: 17/5/16 and 28/6/16. Any patient attending clinic with previous flap reconstruction for lower limb injury was asked to complete the BPI (Brief Pain Index) questionnaire, and details regarding their injury and surgery were collected. RESULTS: There was a 100% response rate, with 33 patients completing the questionnaire. 28 out of the 33 patients (85%) reported ongoing pain. There was no significant relationship between time post operatively and average pain scores (Spearman's Rank R = 0.077), nor was there significant difference by age or gender. Over 25% of the patients with pain were not taking analgesia, however those using simple analgesia (paracetamol, NSAIDS) derived on average over 70% pain relief. CONCLUSIONS: Pain in a common complication following flap reconstruction for complex lower limb injury reported in 85% of our cohort. This pain does not seem to be correlated with time, gender or age, and responds well to simple analgesia in most cases. This emphasises the importance of asking about pain at follow up, and taking simple measures to improve pain outcomes. PMID- 29279136 TI - Magnetic solid-phase extraction of tetracyclines using ferrous oxide coated magnetic silica microspheres from water samples. AB - A novel magnetic solid-phase extraction approach was proposed for extraction of potential residues of tetracyclines (TCs) in tap and river water samples, based on Fe3O4@SiO2@FeO magnetic nanocomposite. Characterized results showed that the received Fe3O4@SiO2@FeO had distinguished magnetism and core-shell structure. Modified FeO nanoparticles with an ~5 nm size distribution were homogeneously dispersed on the surface of the silica shell. Owing to the strong surface affinity of Fe (II) toward TCs, the magnetic nanocomposite could be applied to efficiently extract three TCs antibiotics, namely, oxytetracycline, tetracycline and chlortetracycline from water samples. Several factors, such as sorbent amount, pH condition, adsorption and desorption time, desorption solvent, selectivity and sample volume, influencing the extraction performance of TCs were investigated and optimized. The developed method showed excellent linearity (R > 0.9992) in the range of 0.133-333 MUg L-1, under optimized conditions. The limits of detection were between 0.027 and 0.107 MUg L-1 for oxytetracycline, tetracycline and chlortetracycline, respectively. The feasibility of this method was evaluated by analysis of tap and river water samples. The recoveries at the spiked concentration levels ranged from 91.0% to 104.6% with favorable reproducibility (RSD < 4%). PMID- 29279137 TI - Response surface methodology for the determination of the design space of enantiomeric separations on cinchona-based zwitterionic chiral stationary phases by high performance liquid chromatography. AB - Quality-by-Design approach for enantioselective HPLC method development surpasses Quality-by-Testing in offering the optimal separation conditions with the least number of experiments and in its ability to describe the method's Design Space visually which helps to determine enantiorecognition to a significant extent. Although some schemes exist for enantiomeric separations on Cinchona-based zwitterionic stationary phases, the exact design space and the weights by which each of the chromatographic parameters influences the separation have not yet been statistically studied. In the current work, a screening design followed by a Response Surface Methodology optimization design were adopted for enantioseparation optimization of 3 model drugs namely the acidic Fmoc leucine, the amphoteric tryptophan and the basic salbutamol. The screening design proved that the acid/base additives are of utmost importance for the 3 chiral drugs, and that among 3 different pairs of acids and bases, acetic acid and diethylamine is the couple able to provide acceptable resolution at variable conditions. Visualization of the response surface of the retention factor, separation factor and resolution helped describe accurately the magnitude by which each chromatographic factor (% MeOH, concentration and ratio of acid base modifiers) affects the separation while interacting with other parameters. The global optima compromising highest enantioresolution with the least run time for the 3 chiral model drugs varied extremely, where it was best to set low % methanol with equal ratio of acid-base modifiers for the acidic drug, very high % methanol and 10 fold higher concentration of the acid for the amphoteric drug while 20 folds of the base modifier with moderate %methanol were needed for the basic drug. Considering the selected drugs as models for many series of structurally related compounds, the design space defined and the optimum conditions computed are the key for method development on cinchona-based chiral stationary phases. PMID- 29279140 TI - Letter to the editor: Metacognitive therapy or metacognitive training: What's in a name? PMID- 29279139 TI - Photobacterium carnosum sp. nov., isolated from spoiled modified atmosphere packaged poultry meat. AB - Analysis of spoilage-associated microbiota of modified-atmosphere packaged poultry meat revealed four different bacterial isolates that could not be assigned to known species. They showed a Gram-negative staining behavior, were facultatively aerobic, non-motile with variable cell morphology. Phylogenetic analysis of 16S rDNA and gyrB, rpoD and recA revealed a distinct lineage within the genus Photobacterium with Photobacterium (P.) iliopiscarium DSM 9896T, P. phosphoreum DSM 15556T, P. kishitanii DSM 19954T, P. piscicola LMG 27681T and P. aquimaris DSM 23343T as closest relatives. The designated type strain TMW 2.2021T is non-luminous and grew at 0-20 degrees C (optimum 10-15 degrees C), within pH 5.0-8.5 (optimum 6-8) and in the presence of 0.5-3% (w/v) NaCl (optimum 1%). Major cellular fatty acids of TMW 2.2021T were summed feature 3 (C16:1omega7c/iso C15 3-OH), C16:0, C18:1omega7c and summed feature 2 (C12:0 aldehyde and C10.928 unknown). Quinone analysis revealed Q-8 as sole respiratory ubiquinone. The genome of TMW 2.2021T has a size of 4.56Mb and a G+C content of 38.49mol%. The ANI value between TMW 2.2021T and the type strain of closest relative P. iliopiscarium DSM 9896T was 91.43%. Fingerprinting on the base of M13-RAPD-PCR band pattern and MALDI-TOF MS profiles allowed intraspecies differentiation between our isolates but also supported their distinct lineage to a novel species. Based on phylogenetic, genomic, phenotypic and chemotaxonomic data, strain TMW 2.2021T and further strains represent a novel species of the genus Photobacterium, for which the name Photobacterium carnosum sp. nov. is proposed. The type strain is TMW 2.2021T (=DSM 105454T=CECT 9394T). PMID- 29279138 TI - Viral metagenomics, protein structure, and reverse genetics: Key strategies for investigating coronaviruses. AB - Viral metagenomics, modeling of protein structure, and manipulation of viral genetics are key approaches that have laid the foundations of our understanding of coronavirus biology. In this review, we discuss the major advances each method has provided and discuss how future studies should leverage these strategies synergistically to answer novel questions. PMID- 29279141 TI - Prescribing gardening and conservation activities for health and wellbeing in older people. PMID- 29279142 TI - Multiple successful pregnancies in a woman with biliary atresia and native liver. PMID- 29279143 TI - Reply to: "Chocolate intake in pre-menopausal women". PMID- 29279144 TI - Mild hyperbilirubinaemia as an endogenous mitigator of overweight and obesity: Implications for improved metabolic health. AB - BACKGROUND AND AIMS: Mild endogenous elevation of unconjugated bilirubin (UCB) as seen in Gilbert's syndrome (GS), might mitigate cardiovascular disease (CVD) risk factors including overweight/obesity. This study aimed to determine whether hyperbilirubinaemia is linked to improved anthropometric data and lipid profile. METHODS: Our study considered GS and age-/gender-matched healthy controls (n = 248). Additionally, obese female type 2 diabetic patients (DM2) (n = 26) were included as a "disease control group". RESULTS: BMI, hip circumference (HC), and lipid profile were significantly lower in GS. UCB was inversely correlated with BMI (p <0 .001), HC as well as with fat mass (FM) and lipid variables (p < 0.05). Moreover, DM2 patients had significantly lower UCB compared to GS and healthy controls. Older GS subjects (>=35 years) had significantly reduced anthropometric data and improved lipid profile. CONCLUSIONS: Our results propose that the health promoting potential of mild hyperbilirubinaemia may extend to protection from age related weight gain and dyslipidaemia. PMID- 29279145 TI - Diffusion-weighted magnetic resonance imaging in painful bone metastases: Using quantitative apparent diffusion coefficient as an indicator of effectiveness of single fraction versus multiple fraction radiotherapy. AB - PURPOSE: Bone metastases are a common cause of cancer-related pain. The aim of this study is to determine the optimal radiotherapy schedule for the treatment of painful bone metastases and verify if could cause different biological effects on bone. This has been achieved using functional Magnetic Resonance Imaging (MRI) with diffusion-weighted imaging (DWI). PATIENTS AND METHODS: Fifteen patients received Multiple Fractions Radiation Therapy (MFRT) with a total dose of 30Gy in 10 daily fractions of 3Gy given over 2 weeks and 15 patients received a Single Fraction Radiation Therapy (SFRT) with a dose of 8Gy. Quantitative Apparent Diffusion Coefficient (ADC) values after SFRT or MFRT were compared with response to treatment (pain relief), assessed by Visual Analogue Scale (VAS) before radiotherapy and at 1 and 3 months after the completion of treatment. RESULTS: The two schedules had equal efficacy in terms of pain control, without any difference at 1 and 3 months post radiotherapy. In both treatments, pain reduction was related to an increase in the ADC. However, the median ADC value had an increase of 575 points between the baseline and 3 months (from 1010 to 1585, p=0.02) in the 30Gy group, while it was only 178 points (from 1417 to 1595) in the 8Gy group. CONCLUSIONS: The increase in the ADC values after radiotherapy corresponds to increased cell death. Despite an equal pain control, MFRT treatment seems to be more effective to achieve cancer cells kill. Our preliminary data could also explain the higher retreatment rates in SFRT vs MFRT in long survivors. PMID- 29279146 TI - Pretreatment MR imaging radiomics signatures for response prediction to induction chemotherapy in patients with nasopharyngeal carcinoma. AB - PURPOSE: This study aimed to investigate the capability of magnetic resonance (MR) imaging radiomics signatures for pretreatment prediction of early response to induction chemotherapy in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: This was a retrospective study consisting of 120 patients with biopsy-proven NPC (stage II-IV). Texture features were extracted from the pretreatment morphological MR images for each case. Radiomics signatures were obtained with the least absolute shrinkage and selection operator method (LASSO) logistic regression model. The association between the radiomics signatures and the early response to induction chemotherapy was explored. RESULTS: From the contrast-enhanced T1-weighted MR imaging (CE T1WI), 5 features were selected by the LASSO model. The radiomics signature categorised patients with NPC into response and nonresponse groups (P<0.001). The area under the receiver operating characteristic curve values (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value(NPV) were 0.715(95% CI 0.699-0.731), 0.940, 0.500, 0.568 and 0.897 respectively, where non-responders are true positives. The AUC of 1000 bootstrap internal validation was 0.715. Furthermore, when the features of T1-weighted MR imaging (T1WI), T2-weighted MR imaging (T2WI), T2-weighted fat-suppressed MR imaging (T2WI FS) and CE T1WI were analysed together, 15 features were selected to develop the radiomics signature. The performance of this radiomics signature was better than that developed only from CE T1WI (P<0.05). The AUC value was 0.822(95% CI 0.809-0.835) with sensitivity of 0.980, specificity of 0.529, PPV of 0.593 and NPV of 0.949. The AUC of 1000 bootstrap analysis was 0.821. From T1WI, T2WI, and T2WI FS images separately, no valuable features were selected. CONCLUSIONS: Pretreatment morphological MR imaging radiomics signatures can predict early response to induction chemotherapy in patients with NPC. PMID- 29279147 TI - Seminal vesicle invasion on multi-parametric magnetic resonance imaging: Correlation with histopathology. AB - OBJECTIVES: The pre-treatment risk of seminal vesicle (SV) invasion (SVI) from prostate cancer is currently based on nomograms which include clinical stage (cT), Gleason score (GS) and prostate-specific antigen (PSA). The aim of our study was to evaluate the staging accuracy of 3T (3T) multi-parametric (mp) Magnetic Resonance Imaging (MRI) by comparing the imaging report of SVI with the tissue histopathology. The additional value in the existing prediction models and the role of radiologists' experience were also examined. METHODS: After obtaining institutional review board approval, we retrospectively reviewed clinico pathological data from 527 patients who underwent a robot-assisted radical prostatectomy (RARP) between January 2012 and March 2015. Preoperative prostate imaging with an endorectal 3T-mp-MRI was performed in all patients. Sequences consisted of an axial pre-contrast T1 sequence, three orthogonally-oriented T2 sequences, axial diffusion weighted and dynamic contrast-enhanced sequences. We considered SVI in case of low-signal intensity in the SV on T2-weighted sequences or apparent mass while diffusion-weighted and DCE sequences were used to confirm findings on T2. Whole-mount section pathology was performed in all patients. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MRI (index test) for the prediction of histological SVI (reference standard) were calculated. We developed logistic multivariable regression models including: clinical variables (PSA, cT, percentage of involved cores/total cores, primary GS 4-5) and Partin table estimates. MRI results (negative/positive exam) were then added in the models and the multivariate modeling was reassessed. In order to assess the extent of SVI and the reason for mismatch with pathology an MRI-review from an expert genitourinary radiologist was performed in a subgroup of 379 patients. RESULTS: A total of 54 patients (10%) were found to have SVI on RARP-histopathology. In the overall cohort sensitivity, specificity, PPV and NPV for SVI detection on MRI were 75.9%, 94.7%, 62% and 97% respectively. Based on our sub-analysis, the radiologist's expertise improved the accuracy demonstrating a sensitivity, specificity, PPV and NPV of 85.4%, 95.6%, 70.0% and 98.2%, respectively. In the multivariate analysis PSA (odds ratio [OR] 1.07, p=0.008), primary GS 4 or 5 (OR 3.671, p=0.007) and Partin estimates (OR 1.07, p=0.023) were significant predictors of SVI. When MRI results were added to the analysis, a highly significant prediction of SVI was observed (OR 45.9, p<0.0001). Comparing Partin, MRI and Partin with MRI predictive models, the areas under the curve were 0.837, 0.884 and 0.929, respectively. CONCLUSIONS: MRI had high diagnostic accuracy for SVI on histopathology. It provided added diagnostic value to clinical/Partin based SVI-prediction models alone. A key factor is radiologist's experience, though no inter-observer variability could be examined due to the availability of a single expert radiologist. PMID- 29279148 TI - 3D hybrid profile order technique in a single breath-hold 3D T2-weighted fast spin-echo sequence: Usefulness in diagnosis of small liver lesions. AB - PURPOSE: We compared the efficacy of three-dimensional (3D) isotropic T2-weighted fast spin-echo imaging using a 3D hybrid profile order technique with a single breath-hold (3D-Hybrid BH) with a two-dimensional (2D) T2-weighted fast spin-echo conventional respiratory-gated (2D-Conventional RG) technique for visualising small liver lesions. MATERIALS AND METHODS: This study was approved by our institutional review board. The requirement to obtain written informed consent was waived. Fifty patients with small (<=15mm) hepatocellular carcinomas (HCC) (n=26), or benign cysts (n=24), had undergone hepatic MRI including both 2D Conventional RG and 3D-Hybrid BH. We calculated the signal-to-noise ratio (SNR) and tumour-to-liver contrast (TLC). The diagnostic performance of the two protocols was analysed. RESULTS: The image acquisition time was 89% shorter with the 3D-Hybrid BH than with 2D-Conventional RG. There was no significant difference in the SNR between the two protocols. The area under the curve (AUC) of the TLC was significantly higher on 3D-Hybrid BH than on 2D-Conventional RG. CONCLUSION: The 3D-Hybrid BH sequence significantly improved diagnostic performance for small liver lesions with a shorter image acquisition time without sacrificing accuracy. PMID- 29279149 TI - Noise characteristics of virtual monoenergetic images from a novel detector-based spectral CT scanner. AB - AIM: To evaluate the noise characteristics of virtual monoenergetic images (VMI) obtained from a recently introduced dual-layer detector-based spectral CT (SDCT), both in a phantom and patients. MATERIALS AND METHODS: A cylindrical Catphan(r) 600 phantom (The Phantom Library, Salem NY, USA) was scanned using the SDCT. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured in VMI from 40 to 200keV as well as conventional 120 kVp images. One hundred consecutive patients who had an abdominal CT on the SDCT were then recruited in the study. Noise, SNR and CNR were measured in the liver, pancreas, spleen, kidney, abdominal aorta, portal vein, muscle, bone, and fat, both in VMI (40-200 keV) and conventional 120kVp images. Qualitative image analysis was performed by an independent reader for vascular enhancement and image quality on a 5 point scale (1-worst, 5-best). RESULTS: On phantom studies, noise was low at all energies of VMI. Noise was highest at 40keV (5.3+/-0.2 HU), gradually decreased up to 70keV (3.6+/-0.2 HU), after which it remained constant up to 200keV (3.5+/-0.2 HU). In the patient cohort, noise was low (<25 HU) at all the energy levels of VMI for all the regions, with the exception of bone. For example, noise in the liver was highest at 40keV (13.2+/-4.6 HU), steadily decreased up to 70keV (12.0+/-4.4 HU) and then remained constantly low up to 200keV (11.6+/-4.3HU). For liver, pancreas, portal vein, aorta, muscle and fat, noise at all levels of VMI was lower than of conventional images (p<0.01). For all organs, SNR, and CNR were highest at 40keV (6.8-34.9; 18.3-44.9, respectively) after which they gradually decreased up to 120keV (3.4-6.5; 9.5 13.0) and then remained constant to 200keV (2.6-5.5; 8.5-12.5). Qualitative scores of VMI up to 70keV were significantly higher than the conventional images (p<=0.01), whereas for VMI>=80keV, they were lower than conventional images (p<0.001). CONCLUSION: VMI obtained from the novel SDCT scanner have low noise across the entire spectrum of energies. There are significant SNR and CNR improvements compared to conventional 120 kVp images. PMID- 29279150 TI - Serial magnetic resonance imaging evaluations of irradiated superior cervical sympathetic ganglia: Not every retropharyngeal enlarging mass is a sign of malignancy. AB - INTRODUCTION: To describe serial changes in irradiated superior cervical sympathetic ganglia (SCSGs) on MRI (magnetic resonance imaging) evaluation in patients with head and neck squamous cell carcinoma (HNSCC) and to find the features differentiating them from the metastatic retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study evaluated 52 consecutive patients with definitive radiotherapy with/without chemotherapy for pathologically confirmed HNSCC and pre- and postradiation MRI follow-up evaluations. MR images of SCSGs were analyzed including enhancement pattern, margin, and the presence of intraganglionic hypointensity. RESULTS: MRI evaluations were performed in 36 men and 16 women with HNSCC with an average age of 58 years, range 23-80 years before irradiation (n=52), and at 6 (n=21) and 13-18 (n=52)months follow-up. Mean total radiation dose was 6351+/-483 cGy (range, 5640-7000 cGy). Intraganglionic hypointensity, homogeneous enhancement pattern, and well-defined margins were observed in 96%, 97%, and 97% of ganglia on the last follow-up, which showed no difference between pretreatment and 6-month follow-up (P>0.05). Mixed linear model analysis revealed significant increases in diameter and normalized T2SI of SCSGs after irradiation (P< 0.05). CONCLUSIONS: Despite of the increase in diameter and normalized T2SI of SCSGs, preservation of intraganglionic hypointensity, well-defined margins and homogeneous enhancement might be helpful for radiologists to identify SCSGs during the follow-up of HNSCC patients. PMID- 29279151 TI - Effect of computed tomography window settings and reconstruction plane on 8th edition T-stage classification in patients with lung adenocarcinoma manifesting as a subsolid nodule. AB - PURPOSE: To assess the effect of window settings and reconstruction plane on clinical T-stage determined by solid portion size within subsolid nodules (SSNs), based on 8th-edition TNM standards. MATERIALS AND METHODS: This retrospective study included 247 SSNs from 221 patients who underwent surgery for lung adenocarcinomas between Feb 2012 and Oct 2015. Two radiologists independently measured the diameter of the solid portion on axial, coronal, and sagittal planes using lung- and mediastinal-window. The largest diameter among the measurements on the three planes was referred to as multiplanar measurement. Inter-reader agreement as well as the correlation between the CT and pathologic measurements were calculated using intra-class correlation coefficients (ICCs). The proportions of disagreement in clinical T-stage on different measurement methods were measured. The kappa values for agreement between clinical- and pathological T-stage were measured. RESULTS: Inter-reader agreement was moderate-to-excellent (ICC confidence interval [CI] range, 0.51-0.92) in lung-window, while it was good to-excellent (0.77-0.95) in mediastinal-window. The correlation between the CT and pathologic measurements was good-to-excellent (ICC CI range, 0.63-0.82) in lung-window and fair-to-good (0.25-0.78) in mediastinal-window. The proportions of disagreement between clinical T-stages using mediastinal- and lung-window were 32.0%-41.7% and 33.6%-49.0% with axial and multiplanar measurement, respectively. Multiplanar measurement resulted in upstaging in 12.6%-15.8% and 19.0%-24.3% of cases with mediastinal- and lung-window, respectively, when compared with axial measurement alone. The kappa values for agreement between clinical T-stage and pathological T-stage ranged from 0.53 to 0.69. CONCLUSIONS: Mediastinal-window was a more stable method in the aspect of the inter-reader agreement, but the correlation between the CT and pathologic measurement was better in lung-window. The clinical T-stage varied in up to one-half of the cases according to the window setting, and multiplanar measurement resulted in upstaging in up to one fourth of the cases. PMID- 29279152 TI - MRI features and score for differentiating borderline from malignant epithelial ovarian tumors. AB - PURPOSE: To identify the MRI features of borderline epithelial ovarian tumors (BEOTs) and to differentiate BEOTs from malignant epithelial ovarian tumors (MEOTs). MATERIALS AND METHODS: The clinical and MRI data of 89 patients with a BEOT and 109 patients with a MEOT proven by surgery and histopathology were retrospectively reviewed. MRI features, including bilaterality, size, shape, margin, cystic-solid interface, configuration, papillae or nodules, signal intensity, enhancement, presence of an ipsilateral ovary, peritoneal implants and ascites were analyzed and compared. Based on the odds ratio (OR) values, the significant risk features for BEOTs were scored as 3 (OR~infinity), 2 (5<=OR=40 years who underwent routine clinical chest CT scanning for non-cardiovascular diagnostic indications were followed up until first diagnosis of, or death from, CVD. Using a case-cohort approach, all cases and a random sample of 20% of the participant's CT examinations were visually graded for cardiovascular calcifications and cardiac diameter was measured. The radiological risk score was determined using imaging findings, age, gender, and CT indication. RESULTS: Performance on 5-year CVD risk prediction was assessed. 384 events occurred in 2124 subjects during a mean follow-up of 4.25 years (0-6.4 years). The risk score demonstrated reasonable performance in the studied population. Calibration showed good agreement between actual and 5-year predicted risk of CVD. The c-statistic was 0.71 (95%CI:0.67-0.75). CONCLUSIONS: The radiological CVD risk score performed adequately in the Scottish population offering a potential novel strategy for identifying patients at high risk for developing cardiovascular disease using routine care CT data. PMID- 29279155 TI - Image quality and radiation dose of low-tube-voltage CT with reduced contrast media for right adrenal vein imaging. AB - OBJECTIVES: To compare image quality and radiation dose of right adrenal vein (RAV) imaging computed tomography (CT) among conventional, low kV, and low kV with reduced contrast medium protocols. METHODS: One-hundred-and-twenty patients undergoing adrenal CT were randomly assigned to one of three protocols: contrast dose of 600mgI/kg at 120-kV tube voltage setting (600-120 group), 600mgI/kg at 80kV (600-80 group), and 360mgI/kg at 80kV (360-80 group). Iterative reconstruction was used for 80-kV groups. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the RAV and size-specific dose estimates (SSDE) were measured. Three radiologists evaluated 4-point visualisation scores of RAV by consensus reading. RESULTS: The RAV detectability was 95%, 97.2%, and 97.3% for 600-120, 600-80, and 360-80 groups, respectively (p=1.000). Visualisation scores were not significantly different among the groups (p=0.152). There were no significant differences in CNR or SNR between the 600-120 and 360-80 groups. SSDE of the 360-80 group was significantly lower than that of the 600-120 group (5.86mGy+/-1.44 vs. 7.27mGy+/-1.81, p<0.001). CONCLUSIONS: 80-kV scans with 360 mgI/kg contrast media showed comparable detectability of RAV to conventional scans, while reducing 19% of SSDE. PMID- 29279156 TI - The impact of axillary ultrasound with biopsy in overtreatment of early breast cancer. AB - PURPOSE: (a) To compare the axillary tumor burden detected by fine-needle aspiration cytology (FNAC) versus sentinel lymph node biopsy (SLNB). (b) To evaluate the relationship between axillary tumor burden and the number of suspicious lymph nodes detected by axillary ultrasonography (US). (c) To calculate the false-positive and false-negative rates for FNAC in patients fulfilling ACOSOG Z0011 criteria. METHODS: Retrospective multicenter cross sectional study of 355 pT1 breast cancers. SLNB and axillary lymph node dissection (ALND) were gold standards. Low axillary burden (<=2 positive lymph nodes); high burden (>2 positive lymph nodes). Patients ACOSOG Z0011: false positive (positive FNAC+low burden), false-negative (negative FNAC+high burden). RESULTS: High axillary burden: in entire series 38.5% FNAC+ vs. 5.7% SLNB+ (p<0.0001). In subgroup fulfilling ACOSOG Z0011 criteria: 45.5% vs 6.7%, respectively (p<0.001). 61 positive axillary US. With 1 suspicious node on axillary US: 95.6% had <=2 involved nodes (including pN0); with 2 suspicious nodes: 60% had >2 involved nodes. In ACOSOG Z0011 patients, with 1 suspicious node, 93.7% had <=2 involved nodes. Of the 37 FNAC in ACOSOG Z0011patients: 54.5% false-positives for high burden; 3.8% false-negatives. CONCLUSIONS: FNAC-positive tumors have greater axillary burden, even in patients fulfilling ACOSOG Z0011 criteria. Using axillary US/FNAC to triage patients meeting Z0011 criteria may result in axillary overtreatment. The number of suspicious nodes seen in axillary US is related with the final axillary burden and should be taken into account when deciding to do FNAC in patients fulfilling ACOSOG Z0011 criteria. PMID- 29279157 TI - Pulmonary nodule detection in oncological patients - Value of respiratory triggered, periodically rotated overlapping parallel T2-weighted imaging evaluated with PET/CT-MR. AB - PURPOSE: To prospectively evaluate the detection and conspicuity of pulmonary nodules in an oncological population, using a tri-modality PET/CT-MR protocol including a respiration-gated T2-PROPELLER sequence for possible integration into a simultaneous PET/MR protocol. METHODS: 149 patients referred for staging of malignancy were prospectively enrolled in this single-center study. Imaging was performed on a tri-modality PET/CT-MR setup and was comprised of PET/CT and 3T-MR imaging with 3D dual-echo GRE pulse sequence (Dixon) and an axial respiration gated T2-weighted PROPELLER (T2-P) sequence. Images were assessed for presence, conspicuity, size and interpretation of the pulmonary parenchymal nodules. McNemar's test was used to evaluate paired differences in nodule detection rates between MR and CT from PET/CT. The correlation of pulmonary nodule size in CT and MR imaging was assessed using Pearson correlation coefficient. RESULTS: 299 pulmonary nodules were detected on PET/CT. The detectability was significantly higher on T2-P (60%, p<0.01) compared to T1-weighted Dixon-type sequences (16.1 37.8%). T2-P had a significantly higher detection rate among FDG-positive (92.4%) and among confirmed malignant nodules (75.9%) compared to T1-Dixon. Nodules <10mm were detected less often by MR sequences than by CT (p < 0.01). However, nodules >10mm were detected equally well with T2-P (92.2%) and CT (p >0.05). In a per patient analysis, there was no significant change in the clinical interpretation of the nodules detected with T2-P and CT. CONCLUSION: Despite the overall lower detection rate compared with CT, the free-breathing respiratory gating T2-w sequence showed higher detectability in all evaluated categories compared to breath-hold T1-weighted MR sequences. Specifically, the T2-P was found to be not statistically different from CT in FDG-positive nodules, in detection of nodules >10mm and concerning conspicuity of pulmonary nodules. Overall, the additional time investment into T2-P seems to be justified since clinical relevant assessment of pulmonary lung nodules can mostly be done by T2-P in a whole body PET/MR staging of oncologic patients. PMID- 29279158 TI - Micro-CT in an ectopic pregnancy: New radiological and microscopical perspectives (and level) in the study of the Fallopian tube. PMID- 29279159 TI - Clinical-radiological scoring system for enhanced diagnosis of acute appendicitis. AB - INTRODUCTION: Acute appendicitis is the most common surgical condition in industrialized countries. However, diagnosis in borderline cases is often cumbersome and requires follow-up examinations, and/or a Computed Tomography examination. Therefore, our aim was to develop a combined clinical and sonographic score to enhance prediction of acute appendicitis. PATIENTS AND METHODS: The modified Alvarado score and various established sonographic criteria were investigated in 132 patients with suspected acute appendicitis. Two models were computed accounting for missing values. After analysis of sensitivity and specificity for the modified Alvarado score, logistic regression analysis was performed to identify significantly contributing sonographic features. RESULTS: The threshold of the logistic regression analysis of the two models resulted in the formula: modified Alvarado score+axial Appendix diameter [mm]. When the Appendix diameter is>8mm, 1 point/mm is added, while for a diameter<8mm, 1 point/mm is subtracted. The cut-off value is>=13 for acute appendicitis with a sensitivity 91.4% and a specificity of 100%, compared to a sensitivity of 90% and a specificity of 84.4% for the modified Alvarado score in our cohort. CONCLUSION: The established modified Alvarado score for diagnosis of acute Appendicitis can be improved by adding the axial diameter of the Appendix in a sonographic examination. PMID- 29279160 TI - Preoperative assessment of pleural adhesion by Four-Dimensional Ultra-Low-Dose Computed Tomography (4D-ULDCT) with Adaptive Iterative Dose Reduction using Three Dimensional processing (AIDR-3D). AB - PURPOSE: To assess the feasibility of Four-Dimensional Ultra-Low-Dose Computed Tomography (4D-ULDCT) for distinguishing pleural aspects with localized pleural adhesion (LPA) from those without. METHODS: Twenty-seven patients underwent 4D ULDCT during a single respiration with a 16cm-coverage of the body axis. The presence and severity of LPA was confirmed by their intraoperative thoracoscopic findings. A point on the pleura and a corresponding point on the outer edge of the costal bone were placed in identical axial planes at end-inspiration. The distance of the two points (PCD), traced by automatic tracking functions respectively, was calculated at each respiratory phase. The maximal and average change amounts in PCD (PCDMCA and PCDACA) were compared among 110 measurement points (MPs) without LPA, 16MPs with mild LPA and 10MPs with severe LPA in upper lung field cranial to the bronchial bifurcation (ULF), and 150MPs without LPA, 17MPs with mild LPA and 9MPs with severe LPA in lower lung field caudal to the bronchial bifurcation (LLF) using the Mann-Whitney U test. RESULTS: In the LLF, PCDACA as well as PCDMCA demonstrated a significant difference among non-LPA, mild LPA and severe LPA (18.1+/-9.2, 12.3+/-6.2 and 5.0+/-3.3mm) (p<0.05). Also in the ULF, PCDACA showed a significant difference among three conditions (9.2+/ 5.5, 5.7+/-2.8 and 2.2+/-0.4mm, respectively) (p<0.05), whereas PCDMCA for mild LPA was similar to that for non-LPA (12.3+/-5.9 and 17.5+/-11.0mm). CONCLUSIONS: Four D-ULDCT could be a useful non-invasive preoperative assessment modality for the detection of the presence or severity of LPA. PMID- 29279161 TI - Accuracy of multiparametric MR imaging with PI-RADS V2 assessment in detecting infiltration of the neurovascular bundles prior to prostatectomy. AB - OBJECTIVES: To evaluate the accuracy of assessment of neurovascular bundle (NVB) infiltration using multiparametric magnetic resonance imaging (mpMRI) and PI-RADS V2 prior to prostatectomy. METHODS: The ethics committee approved this retrospective study with waiver of informed consent. N=198 consecutive patients with biopsy proved cancer underwent standardized mpMRI at 3T prior to surgery. NVB infiltration was assessed for each side (a total of 396). Maximum PI-RADS V2 scores were determined for the posterolateral areas adjacent to the NVBs. Imaging results were correlated with postoperative pathology and standard descriptive statistics were calculated. RESULTS: Overall T-staging sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of mpMRI were 64.4%, 89.2%, 82.4%, 76.2% and 78.3%, respectively. In 396 cases NVB infiltration was predicted with 75.3%, 94.0%, 80.2%, 92.1 % and 89.4 % sensitivity, specificity, PPV, NPV and accuracy, respectively. Analyses of 396 NVB and their adjacent PI-RADS V2 scores with pathology revealed significantly more NVB-infiltrations in suspect scores of 5 and 4 vs. uncertain scores of 3-1 (81/264 vs. 16/132, p=0.0001). Considering scores higher than 3 as a criterion of infiltration demonstrated moderate sensitivity and poor specificity (83.5% and 38.8%, respectively). Interobserver agreement of a second reading of a random sample was good (kappa=0.64) for NVB infiltrations and moderate (kappa=0.59) for PI-RADS V2. CONCLUSIONS: Assessment of infiltration of the neurovascular bundles using mpMRI has valuable diagnostic performance, yet PI-RADS V2 Scores demonstrate limited eligibility. Combined findings offer crucial information for the planning of prostatectomy. PMID- 29279162 TI - Do modic changes, disc degeneration, translation and angular motion affect facet osteoarthritis of the lumbar spine. AB - The objective of the study is to identified the correlation between Modic changes (MCs), disc degeneration, motions (translation and angulation) and facet osteoarthritis in lumbar spine. 425 patients who underwent multi-positional lumbar MRI were reviewed. A total of 2250 lumbar spinal segments in neutral position were evaluated for MCs, disc degeneration grading, translation and angulation motion, and facet osteoarthritis. The chi-square test, Kruskal-Wallis, Mann-Whitney U test, Pearson's correlation and linear regression were used to test for statistically significant difference between parameters. MCs type 2 showed the most translational motion. The presence of MCs was significantly correlated with advanced disc degeneration (grade 4-5, Odds ratio 6.29, 95% CI 4.48-8.83) and the presence of facet osteoarthritis (Odds ratio 9.50, 95% CI 6.18 14.62). The presence of facet osteoarthritis had significantly more translation motion than non-osteoarthritis facet (p=0.04). The facet osteoarthritis grade was positively correlated with disc degeneration grade (r=0.309, p-value<0.001). The facet osteoarthritis correlated with the presence of MCs and more translation motion. The severity of facet osteoarthritis was correlated with the advanced disc degeneration. The MCs, translation motion, and disc degeneration were the significant parameters which affected lumbar facet osteoarthritis. PMID- 29279163 TI - Diagnostic properties of the SPIQuestionnaire to detect Posterior Circumflex Humeral Artery Disease in elite volleyball players: a cross-sectional study. AB - OBJECTIVES: Sports related aneurysmal degeneration and thrombosis of the Posterior Circumflex Humeral Artery (PCHA) has been known to cause symptoms of digital ischemia (DI) in elite volleyball players. Studies have reported symptoms of DI in as much as 28% of the elite indoor volleyball players. The purpose of this study was to determine the diagnostic value of the Shoulder PCHA Pathology and digital Ischemia - Questionnaire (SPI-Q) for detection of sports related PCHA disease using ultrasound data as the standard of reference. METHODS: The SPI-Q was completed by elite indoor volleyball players from the highest and single highest Dutch volleyball division and by elite beach volleyball players participating in the 2014 Grand Slam Beach Tournament The Hague (GSBTH). Ultrasound assessment of the dominant shoulder was performed on-site using the SPI-US protocol. The SPI-Q sensitivity, specificity, positive - and negative predictive value and positive - and negative likelihood ratios, and the diagnostic odds ratio were calculated for detection of sports related PCHA disease, using ultrasound as the standard of reference. RESULTS: Two hundred twenty-four elite male indoor volleyball players from the Dutch division were included in this study and 62 elite male and female beach volleyball players participating in the GSBTH: a total of 278 players. Thirty-five percent of the players reported symptoms of DI. The prevalence of PCHA disease was 6.1%. For the SPI-Q we found a sensitivity of 18% (95% CI 4-43), specificity of 64% (95% CI 58 70), positive predictive value of 3% (95% CI 0.7-8.9) and negative predictive value of 92% (95% CI 87-96), positive likelihood ratio of 0.50 (95% CI 0.18 1.40), negative likelihood ratio of 1.28 (95% CI 1.01-1.62) and a diagnostic odds ratio of 0.39 (95% CI 0.11-1.38). CONCLUSION: The diagnostic value of the SPI-Q to detect PCHA disease in elite volleyball players is poor, which makes it unsuitable as a diagnostic instrument for sports related PCHA disease specifically. However, it can be used to assess all-cause symptoms of DI and raise awareness within athletes and sports physicians, which is important for preventing ischemic complications. PMID- 29279164 TI - Clinical application of Half Fourier Acquisition Single Shot Turbo Spin Echo (HASTE) imaging accelerated by simultaneous multi-slice acquisition. AB - PURPOSE: As a single-shot sequence with a long train of refocusing pulses, Half Fourier Acquisition Single-Shot Turbo-Spin-Echo (HASTE) suffers from high power deposition limiting use at high resolutions and high field strengths, particularly if combined with acceleration techniques such as simultaneous multi slice (SMS) imaging. Using a combination of multiband (MB)-excitation and PINS refocusing pulses will effectively accelerate the acquisition time while staying within the SAR limitations. In particular, uncooperative and young patients will profit from the speed of the MB-PINS HASTE sequence, as clinical diagnosis can be possible without sedation. Materials and MethodsMB-excitation and PINS-refocusing pulses were incorporated into a HASTE-sequence with blipped CAIPIRINHA and TRAPS including an internal FLASH reference scan for online reconstruction. Whole brain MB-PINS HASTE data were acquired on a Siemens 3T-Prisma system from 10 individuals and compared to a clinical HASTE protocol. ResultsThe proposed MB PINS HASTE protocol accelerates the acquisition by about a factor 2 compared to the clinical HASTE. The diagnostic image quality proved to be comparable for both sequences for the evaluation of the overall aspect of the brain, the detection of white matter changes and areas of tissue loss, and for the evaluation of the CSF spaces although artifacts were more frequently encountered with MB-PINS HASTE. ConclusionsMB-PINS HASTE enables acquisition of slice accelerated highly T2 weighted images and provides good diagnostic image quality while reducing acquisition time. PMID- 29279165 TI - Computer-aided diagnosis of contrast-enhanced spectral mammography: A feasibility study. AB - OBJECTIVE: To evaluate whether the use of a computer-aided diagnosis-contrast enhanced spectral mammography (CAD-CESM) tool can further increase the diagnostic performance of CESM compared with that of experienced radiologists. MATERIALS AND METHODS: This IRB-approved retrospective study analyzed 50 lesions described on CESM from August 2014 to December 2015. Histopathologic analyses, used as the criterion standard, revealed 24 benign and 26 malignant lesions. An expert breast radiologist manually outlined lesion boundaries on the different views. A set of morphologic and textural features were then extracted from the low-energy and recombined images. Machine-learning algorithms with feature selection were used along with statistical analysis to reduce, select, and combine features. Selected features were then used to construct a predictive model using a support vector machine (SVM) classification method in a leave-one-out-cross-validation approach. The classification performance was compared against the diagnostic predictions of 2 breast radiologists with access to the same CESM cases. RESULTS: Based on the SVM classification, CAD-CESM correctly identified 45 of 50 lesions in the cohort, resulting in an overall accuracy of 90%. The detection rate for the malignant group was 88% (3 false-negative cases) and 92% for the benign group (2 false positive cases). Compared with the model, radiologist 1 had an overall accuracy of 78% and a detection rate of 92% (2 false-negative cases) for the malignant group and 62% (10 false-positive cases) for the benign group. Radiologist 2 had an overall accuracy of 86% and a detection rate of 100% for the malignant group and 71% (8 false-positive cases) for the benign group. CONCLUSIONS: The results of our feasibility study suggest that a CAD-CESM tool can provide complementary information to radiologists, mainly by reducing the number of false-positive findings. PMID- 29279166 TI - Characterization of testicular germ cell tumors: Whole-lesion histogram analysis of the apparent diffusion coefficient at 3T. AB - PURPOSE: To assess the values of parameters derived from whole-lesion histograms of the apparent diffusion coefficient (ADC) at 3T for the characterization of testicular germ cell tumors (TGCTs). MATERIALS AND METHODS: A total of 24 men with TGCTs underwent 3T diffusion-weighted imaging. Fourteen tumors were pathologically confirmed as seminomas, and ten tumors were pathologically confirmed as nonseminomas. Whole-lesion histogram analysis of the ADC values was performed. A Mann-Whitney U test was employed to compare the differences in ADC histogram parameters between seminomas and nonseminomas. Receiver operating characteristic analysis was used to identify the cutoff values for each parameter for differentiating seminomas from nonseminomas; furthermore, the area under the curve (AUC) was calculated to evaluate the diagnostic accuracy. RESULTS: The median of 10th, 25th, 50th, 75th, and 90th percentiles and mean, minimum and maximum ADC values were all significantly reduced for seminomas compared with nonseminomas (p<0.05 for all). In contrast, the median of kurtosis and skewness of ADC values of seminomas were both significantly increased compared with those of nonseminomas (p=0.003 and 0.001, respectively). For differentiating nonseminomas from seminomas, the 10th percentile ADC yielded the highest AUC with a sensitivity and specificity of 100% and 92.86%, respectively. CONCLUSION: Whole lesion histogram analysis of ADCs might be used for preoperative characterization of TGCTs. PMID- 29279167 TI - Comparing sensitivity and specificity of medical imaging tests when verification bias is present: The concept of relative diagnostic accuracy. AB - Medical imaging plays a key role in all stages of cancer management. In evaluating a new imaging modality, the optimal design involves a comparison with standard test results as well as a gold standard, such as a pathological evaluation to determine disease status. However, when both the standard and experimental test results are negative, a gold standard may not always be performed, especially if it involves an invasive and/or costly procedure. In this situation, true disease status cannot be verified, which creates an estimation problem for sensitivity and specificity. The aim of this article is to present the concept of relative accuracy which permits to remove the bias when only patients with at least one positive test receive the gold standard. PMID- 29279168 TI - Value of a radiographic score for the assessment of healing of nailed femoral and tibial shaft fractures: A retrospective preliminary study. AB - OBJECTIVES: To assess the value of a radiographic score for the detection of delayed union in nailed fractures. METHODS: The modified radiographic union score (mRUS) values were determined by three separate radiologists on 259 radiographic sets of 58 nailed tibial or femoral fractures obtained at different timepoints after fracture (mean of 4.5 radiographic sets per fracture). A surgeon determined fracture outcome (normal or delayed union) at a mean of 192days after injury. Mean radiographic scores obtained at different timepoints after fracture were compared between fractures with normal or abnormal healing at follow-up. RESULTS: The mean score values increased significantly over time for fractures with normal healing for all readers (p<0.001). The mean score values determined 11-14 weeks after injury were higher in fractures with normal healing than in fractures with delayed union at follow-up (p<0.05). Scoring of radiographs obtained at about 3 months after injury or later enabled detection of fractures with delayed union with a sensitivity of 0.63-0.77 and a specificity of 1.0 (area under curve: 0.77- 0.88). CONCLUSIONS: The mRUS score can contribute to the detection of delayed union at a delay of about 3 months after injury in nailed shaft fractures. PMID- 29279169 TI - Hepatocellular carcinoma treated with sorafenib: Arterial tumor perfusion in dynamic contrast-enhanced CT as early imaging biomarkers for survival. AB - OBJECTIVES: To investigate whether hepatic perfusion CT yields early imaging biomarkers predictive of the prognosis of hepatocellular carcinoma (HCC) patients treated with sorafenib. METHODS: We evaluated 36 HCC patients who underwent hepatic perfusion CT before- and one week after sorafenib therapy. We measured arterial and portal perfusion in the hepatic tumor and liver parenchyma [(AP)(PP)tumor], [(AP)(PP)liver]. The perfusion ratio was calculated by dividing the post- by the pre-sorafenib value. The effect of each value on the overall survival rate was analyzed with the Cox proportional hazards model; statistically significant parameters were subjected to receiver operating characteristic analysis based on median survival after sorafenib administration to determine the overall survival rate with the Kaplan-Meier method. RESULTS: Pre-APtumor was significantly associated with the overall survival rate (hazard ratio (HR) and 95% confidence interval (CI), 0.16 and 0.02-0.84, p=0.03). The APtumor ratio tended to be associated with the overall survival rate (HR and 95% CI, 2.94 and 0.94-7.88, p=0.06). The overall survival rate was higher in patients with pre APtumor>71.7mL/min/100mL, and with APtumor ratio?1.1 (p<0.01 and 0.03, respectively, in Kaplan-Meier method with log-rank). CONCLUSION: Hepatic perfusion CT yields early imaging biomarkers for predicting overall survival in HCC patients treated with sorafenib. PMID- 29279170 TI - Upper tract urothelial cancer. AB - While urothelial carcinoma is a very common tumor, involvement of the upper tract is relatively uncommon. Consequently, there are no consensus imaging recommendations for upper tract disease. CT urography is the dominant imaging modality for the upper tract, but despite its excellent performance characteristics and being widely accepted as standard of care there is great variability in how CTU exams are performed across practices. MR urography has limited current application, but has the potential to become more mainstream in the future with continued technical advances. Upper tract urothelial carcinoma can manifest as a variety of appearances: a papillary lesion, focal wall thickening, focal enhancement, or as an infiltrative lesion. Pelvicalyceal location is about twice as common as in the ureter. Tumors in the pelvicalyceal location often manifest as an irregular enhancing soft tissue attenuation filling defect, and may be sessile or polypoid in morphology. Within the ureter, 73% are located in the distal segment. PMID- 29279171 TI - Support Vector Machines (SVM) classification of prostate cancer Gleason score in central gland using multiparametric magnetic resonance images: A cross-validated study. AB - PURPOSE: To assess the performance of Support Vector Machines (SVM) classification to stratify the Gleason Score (GS) of prostate cancer (PCa) in the central gland (CG) based on image features across multiparametric magnetic resonance imaging (mpMRI). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. One hundred fifty-two CG cancerous ROIs were identified through radiological pathological correlation. Eleven parameters were derived from the mpMRI and histogram analysis, including mean, median, the 10th percentile, skewness and kurtosis, was performed for each parameter. In total, fifty-five variables were calculated and processed in the SVM classification. The classification model was developed with 10-fold cross-validation and was further validated mutually across two separated datasets. RESULTS: With six variables selected by a feature selection and variation test, the prediction model yielded an area under the receiver operating characteristics curve (AUC) of 0.99 (95% CI: 0.98, 1.00) when trained in dataset A2 and 0.91 (95% CI: 0.85, 0.95) for the validation in dataset B2. When the data sets were reversed, an AUC of 0.99 (95% CI: 0.99, 1.00) was obtained when the model was trained in dataset B2 and 0.90 (95% CI: 0.85, 0.95) for the validation in dataset A2. CONCLUSION: The SVM classification based on mpMRI derived image features obtains consistently accurate classification of the GS of PCa in the CG. PMID- 29279172 TI - Using diagnostic reference levels to evaluate the improvement of patient dose optimisation and the influence of recent technologies in radiography and computed tomography. AB - OBJECTIVES: Twelve years since the implementation of Diagnostic Reference Levels (DRL) process in France, the Nuclear Safety and Radiation Protection French Institute (IRSN) presents its latest analyses performed on the most recent national data. METHODS: Statutorily, each year, medical imaging departments must perform patient exposure evaluation from their clinical practice for at least 2 types of radiographic and computed tomography (CT) examinations freely chosen in the regulatory list. The samples of dosimetric data used for the evaluations must be sent to IRSN for national assessment using a dedicated and secured web portal. The analyses of collected data for radiography and CT allow IRSN to estimate the representativeness of current DRLs in terms of target practices and examinations, dosimetric quantities and numerical values. Technical data are transmitted, such as detector type in radiography or commissioning date of CT, and are included in some complementary analyses in order to evaluate their influence on patient exposure. RESULTS: Since 2004 the involvement of professionals in the DRL process has highly increased in CT (about 80% in 2015) but remains quite weak in radiography (almost 30%). Analyses show some discordance between regulation references and clinical practice leading to clinical doses data which are 40% lower than DRLs in 2015. As a consequence, the list of examinations types and some numerical values should be updated in the regulation. Focused analyses show a significant patient exposure reduction when digital radiography is used and when CT equipment is under five years old. CONCLUSIONS: Based on these findings, IRSN recommends to update DRL regulation with current and relevant examination lists, dosimetric quantities and numerical values. In addition, this study shows that technology and generation of equipment, such as detector type in radiography or image reconstruction algorithm in CT, take an important place in the dose optimisation process, enabling significant patient exposure reduction when it is associated with protocols optimisation. PMID- 29279173 TI - Differentiating between benign and malignant sinonasal lesions using dynamic contrast-enhanced MRI and intravoxel incoherent motion. AB - PURPOSE: To explore the value of dynamic contrast-enhanced MRI (DCE-MRI) and intravoxel incoherent motion (IVIM) for distinguishing between benign and malignant sinonasal lesions and investigate the correlations between the two methods. METHODS AND MATERIALS: Patients with sinonasal lesions (42 benign and 31 malignant) who underwent DCE-MRI and IVIM before confirmation by histopathology were enrolled in this prospective study. Parameters derived from DCE-MRI and IVIM were measured, the optimal cut-off values for differential diagnosis were determined, and the correlations between the two methods were evaluated. Statistical analyses were performed using the Wilcoxon rank sum test, receiver operating characteristic (ROC) curve analysis, and Spearman's rank correlation. RESULTS: Significantly higher Ktrans and Kep values but lower D and f values were found in malignant lesions than in benign lesions (all p<0.001). There were no significant differences in the Ve and D* values between the two groups. The area under the curve (AUC) of Ktrans was significantly higher than those of other parameters. There was no significant difference between the AUCs of DCE-MRI and IVIM with parameters combined (p=0.86). Significant inverse but weak correlations were found between D and Ktrans (r=-0.46, p<0.001), f and Ktrans (r=-0.41, p<0.001), D and Kep (r=-0.37, p=0.008), and f and Kep (r=-0.33, p=0.004). CONCLUSIONS: DCE-MRI and IVIM can effectively differentiate between benign and malignant sinonasal lesions. IVIM findings correlate with DCE-MRI results and may represent an alternative to DCE-MRI. PMID- 29279174 TI - Diagnostic performance of CT signs for predicting adnexal torsion in women presenting with an adnexal mass and abdominal pain: A case-control study. AB - PURPOSE: To determine which CT findings or combinations of CT findings could accurately identify adnexal torsion in a cohort of women admitted for abdominal pain and presenting with an adnexal mass. MATERIALS AND METHODS: The local institutional review board approved this retrospective case-control study involving adults-the informed consent requirement was waived. Enhanced computed tomography (CT) findings of 32 consecutive adnexal torsion and 32 control patients admitted for abdominal pain and presenting with an adnexal mass were independently reviewed by two radiologists, with consensus by a third one, for all CT findings commonly assessed in adnexal torsion. All twisted and untwisted adnexa were confirmed by surgery. Univariate and multivariate analyses were performed for adnexal torsion prediction. RESULTS: The median patient age was 41 years (interquartile range, 30.5-62 years). Only benign masses were encountered in the torsion group. Five CT features were significantly associated with adnexal torsion: a large ovary with a threshold at 80mm (p=0.005), median or contralateral displacement of the adnexa (p=0.00014), asymmetric wall thickening of the mass (p<0.0001), inter-utero-ovarian mass (p<0.0001) and whirlpool sign (p=0.0006). In the multivariate analysis, only the inter-utero-ovarian mass was independently associated with adnexal torsion (odds ratio=130 (CI95%: 15 infinite), p<0.0001) with an excellent overall diagnostic performance (AUC=0.89; CI95%: 0.81-0.97). It was a sensitive (Se=97%, CI95%: 84-100) and specific feature (Sp=81%, CI95%: 64-93). CONCLUSION: An inter-utero-ovarian mass is an accurate and reliable CT finding for diagnosing adnexal torsion in patients with acute abdominal pain and an adnexal mass. PMID- 29279175 TI - MR elastography is effective for the non-invasive evaluation of fibrosis and necroinflammatory activity in patients with nonalcoholic fatty liver disease. AB - OBJECTIVES: To evaluate the performance of magnetic resonance elastography (MRE) in diagnosing and staging hepatic fibrosis in patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and in distinguishing simple steatosis from nonalcoholic steatohepatitis (NASH). METHODS: Ninety subjects (49 NAFLD patients and 41 healthy volunteers) were prospectively enrolled. Liver stiffness measured by MRE was correlated with the grade of fibrosis and/or inflammation determined by liver biopsy. Correlations, ROC (receiver operator characteristic) curves and diagnostic performance were evaluated. The study was approved by the local ethics committee. RESULTS: The area under the ROC curve (AUROC) of MRE in discriminating healthy from NAFLD individuals was 0.964 (P<0.0001), and that for distinguishing advanced (F3-F4) from absent/mild fibrosis (F0-F2) was 0.928 (P<0.0001). The use of a threshold >4.39 kPa resulted in a sensitivity of 90.9% and a specificity of 97.3% for diagnosing advanced fibrosis. For discriminating NASH from simple steatosis, the AUROC was 0.783 (P<0.0001), and the threshold, 3.22 kPa. CONCLUSIONS: MRE is an effective, non invasive method for detecting/staging hepatic fibrosis in NAFLD. This method has good performance in discriminating normal from NAFLD subjects and between the extreme grades of fibrosis. NAFLD patients with inflammation and without fibrosis have higher liver stiffness than those with simple steatosis. PMID- 29279176 TI - Qualitative and semi-quantitative assessment of temporomandibular joint MRI protocols for juvenile idiopathic arthritis at 1.5 and 3.0T. AB - OBJECTIVE: Temporomandibular joints (TMJs) frequently develop silent inflammatory and osteochondral changes in children with juvenile idiopathic arthritis. Data driven recommendations for TMJ imaging protocol are needed to reduce measurement error and scanning time. This study compares the impact of different protocols, imaging coils, and magnet strength on the reliability of image assessment and the subjective quality of images. MATERIALS AND METHODS: Three groups of bilateral TMJ MR studies were retrospectively collected from two institutions, including 24 1.5T and 19 3.0T studies using dedicated TMJ surface coils, and 23 1.5T studies with head coil. Post-contrast sequences were re-compiled from the full protocol to create minimum protocol studies for the three groups. Two radiologists and two non-radiologists first scored the three minimum protocol images according to pre specified definitions, then scored the full protocol images. Minimum-to-full protocol agreement, inter-reader agreement, and subjective item visibility scores were assessed. RESULTS: With dedicated TMJ dual surface coils, minimum-vs-full protocol agreement was moderate to good (0.5-0.8 intraclass correlation coefficients or kappa) for most items, and was not influenced by the magnet strength. Inter-reader reliability was more significantly influenced by the imaging coil and reader's training background than by protocol length or magnet strength differences. Sagittal and coronal planes weighted on PD, T2 Fat Suppressed and T1 Fat Suppressed -postcontrast adequately visualized all the different features, whereas the axial plane was more limited to visualizing synovium. CONCLUSION: Inter-reader reliability and qualitative measure of image quality improved more consistently with the coil offering the higher resolution, rather than increased magnet strength. PMID- 29279177 TI - Using a rubber strip test to classify swollen fingers for ring removal. PMID- 29279178 TI - Radiologic discrepancies in children with special healthcare needs in a pediatric emergency department. AB - BACKGROUND: After-hours radiologic interpretation by nonradiology attendings or resident radiologists introduces the risk of discrepancies. Clinical outcomes following radiologic discrepancies among pediatric emergency department (ED) patients are poorly described. In particular, children with special healthcare needs (CSHCN), have more opportunities for discrepancies and potential consequences than non- CSHCN. Our objective was to determine the rates and types of radiologic discrepancies, and to compare CSHCN to non-CSHCN. METHODS: From July 2014 to February 2015, all children who underwent a diagnostic imaging study at a free-standing children's ED were included. Data collected included radiologic studies - type and location - and clinical details - chief complaint and CSHCN type. Differences between preliminary reads and final pediatric radiology attending reads were defined as discrepancies, and categorized by clinical significance. Descriptive statistics, z-tests, and chi-square were used. RESULTS: Over 8months, 8310 visits (7462 unique patients) had radiologic studies (2620 CSHCN, 5690 non-CSHCN). A total of 198 (2.4%) radiologic discrepancies [56 (28.3%) CSHCN, 142 (71.7%) non-CSHCN] were found. Chief complaints for CSCHN were more often within the cardiac, pulmonary and neurologic systems (p<0.001 for each), whereas non-CSHCN presented with more trauma (p<0.001). The rates of discrepancies (CSHCN 2.1%, non- CSHCN 2.5%, p=0.3) and severity of clinical consequences (p=0.6) were not significantly different between CSHCN and non CSHCN. CONCLUSION: Though the frequency and type of radiologic studies performed between CSHCN and non-CSHCN were different, we found no significant difference in the rate of radiologic discrepancies or the rate of clinically significant radiologic discrepancies. PMID- 29279180 TI - Inequality in self-immolation incidence according to HDI in Iran. PMID- 29279179 TI - [Blood management in geriatric hospitalized population]. AB - INTRODUCTION: In France, nearly 50% of patients transfused in packed red blood cells are 75 or older. The benefit of restrictive transfusion policies is no longer to be demonstrated, but the practices are still far from it. The objective of our study was to show the impact of a decision support tool on transfusion practices, specifically in a hospitalized elderly population. METHOD: A clinical decision support, validated in the improvement of practices, was created, based on the latest transfusion recommendations of 2014. Our study was interventional, monocentric, within the departments of internal medicine and geriatrics of a university hospital from February to July 2016. The clinical decision support was available for any request of transfusion of packed red blood cells for 75 years old or older patient who was hospitalized in one of these two services. RESULTS: There were 134 transfusions out of 173 for which the prescriber used our tool. Comparing 2016 with the previous two years, our tool decreased the rate of packed red blood cells delivered by 11% compared to 2014 (P<0.005), but there was no significant difference compared to 2015. It has also reduced the transfusion rate of multi-unit transfusions by 35% compared with 2014 and by 29% compared with 2015 (P<0.005). CONCLUSION: Our tool, applied specifically to the elderly, is useful to improve transfusion practices and requires to be validated on a larger scale. PMID- 29279181 TI - Embryo culture conditions are significantly improved during uninterrupted incubation: A randomized controlled trial. AB - A parallel group superiority prospective randomised controlled trial was devised to compare the culture characteristics of human pre-implantation stage embryos during uninterrupted culture in a time lapse incubator (TLI) versus the conventional model of interrupted culture in a standard incubator (SI) under low oxygen tension using a single step medium. 221 patients aged 35-and-under, 124 patients aged between 36 and 39 and 86 patients aged 40-and-over years were randomised and cultured either in a SI or in a TLI. Patients in the three age groups were distributed between the TLI and SI in a 1:1 ratio. The development of embryos on days 2, 3 and 5, and the clinical pregnancy and implantation rates were recorded. The fertilisation rate, development of day 2 and clinical pregnancy rates were similar in both treatments but the 8-cell development rate in all age groups combined (p = 0.016), blastocyst development rate (p = 0.0022) and the implantation rate (p = 0.0022) was significantly higher for the uninterrupted culture. These findings demonstrated significant differences between the two incubation groups. It also indicated less efficacious embryonic development with age in both treatments which appeared more pronounced in the conventional incubator. In conclusion uninterrupted culture is superior compared to the interrupted incubation culture system. PMID- 29279182 TI - Elective frozen-thawed embryo transfer (FET) in women at risk for ovarian hyperstimulation syndrome. AB - Elective cryopreservation of cultured embryos has become a treatment option for women at risk for ovarian hyperstimulation syndrome (OHSS). The aim of our study was to investigate the outcome of elective cryopreservation and consecutive frozen-thawed embryo transfer (FET) in a large IVF clinic in Austria. A total of 6104 controlled ovarian hyperstimulation cycles (COH) were performed on 2998 patients including 200 patients (6.7%) who were undergoing elective cryopreservation and FET due to high risk of OHSS. We estimated the cumulative live birth rate using the Kaplan-Meier method and evaluated independent predictors for successful live births with a Cox model. A total of 270 frozen thawed embryo transfers were performed on 200 patients with up to 4 transfers per patient. The first embryo transfer showed a live birth rate of 42.0%, the second transfer showed a cumulative rate of 58.5%. After a total of 4 FETs from the same COH cycle, a cumulative live birth rate of 61.0% per COH cycle could be achieved. Four cases of OHSS occurred amongst these patients (2.0%), all of them of moderate severity. Multivariate analysis identified maternal age, the use of assisted hatching and the number of embryos transferred at the blastocyst stage as independent predictors for cumulative live birth. Our study clearly suggests that elective FET is safe and shows excellent cumulative live birth rates. This concept can, therefore, be used to avoid the severe adverse events caused by COH and the inefficient use of cultured embryos. PMID- 29279184 TI - [Histopathology of cutaneous drug reactions]. AB - There are many different types of cutaneous adverse reactions. The most classical reactions are driven by T lymphocytes that specifically react towards a drug, with an individual genetic susceptibility linked to certain type I major histocompatibility complex alleles. These reactions are characterized by a wide variety of clinical and histopathological presentations, and a wide range of severity. The most frequent entity is the maculopapular rash, while the most aggressive forms are the Steven-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). The histopathological alterations associated to each of these syndromes have been better described in the literature during the past 10 years, encompassing non-specific lesions, as in most drug induced maculopapular rashes, to more specific inflammatory patterns. The finding of confluent apoptotic keratinocytes with epidermal detachment is the prototypical aspect of SJS-TEN. There are however numerous pitfalls, and a similar aspect to those observed in each cutaneous drug reactions entities can be found in other diseases. DRESS syndrome can indeed present with dense and epidermotropic T-cell infiltrate, sometimes with nuclear atypias, and thus can be difficult to distinguish from a primary or secondary cutaneous T-cell lymphoma. The diagnosis of cutaneous adverse reactions relies on a clinical-pathological confrontation and requires an accurate evaluation of drug imputability. PMID- 29279183 TI - Increased fibrosis: A novel means by which GH influences white adipose tissue function. AB - OBJECTIVE: White adipose tissue (WAT) fibrosis - the buildup of extracellular matrix (ECM) proteins, primarily collagen - is now a recognized hallmark of tissue dysfunction and is increased with obesity and lipodystrophy. While growth hormone (GH) is known to increase collagen in several tissues, no previous research has addressed its effect on ECM in WAT. Thus, the purpose of this study is to determine if GH influences WAT fibrosis. DESIGN: This study examined WAT from four distinct strains of GH-altered mice (bGH and GHA transgenic mice as well as two tissue specific GH receptor gene disrupted lines, fat growth hormone receptor knockout or FaGHRKO and liver growth hormone receptor knockout or LiGHRKO mice). Collagen content and adipocyte size were studied in all cohorts and compared to littermate controls. In addition, mRNA expression of fibrosis associated genes was assessed in one cohort (6month old male bovine GH transgenic and WT mice) and cultured 3T3-L1 adipocytes treated with GH. RESULTS: Collagen stained area was increased in WAT from bGH mice, was depot-dependent, and increased with age. Furthermore, increased collagen content was associated with decreased adipocyte size in all depots but more dramatic changes in the subcutaneous fat pad. Notably, the increase in collagen was not associated with an increase in collagen gene expression or other genes known to promote fibrosis in WAT, but collagen gene expression was increased with acute GH administration in 3T3-LI cells. In contrast, evaluation of 6month old GH antagonist (GHA) male mice showed significantly decreased collagen in the subcutaneous depot. Lastly, to assess if GH induced collagen deposition directly or indirectly (via IGF-1), fat (Fa) and liver (Li) specific GHRKO mice were evaluated. Decreased fibrosis in FaGHRKO and increased fibrosis in LiGHRKO mice suggest GH is primarily responsible for the alterations in collagen. CONCLUSIONS: Our results show that GH action is positively associated with an increase in WAT collagen content as well as a decrease in adipocyte size, particularly in the subcutaneous depot. This effect appears to be due to GH and not IGF-1 and reveals a novel means by which GH regulates WAT accumulation. PMID- 29279185 TI - Mechanistic insights into the protective impact of zinc on sepsis. AB - Sepsis, a systemic inflammation as a response to a bacterial infection, is a huge unmet medical need. Data accumulated over the last decade suggest that the nutritional status of patients as well as composition of their gut microbiome, are strongly linked with the risk to develop sepsis, the severity of the disease and prognosis. In particular, the essential micronutrient zinc is essential in the resistance against sepsis and has shown to be protective in animal models as well as in human patients. The potential mechanisms by which zinc protects in sepsis are discussed in this review paper: we will focus on the inflammatory response, chemotaxis, phagocytosis, immune response, oxidative stress and modulation of the microbiome. A full understanding of the mechanism of action of zinc may open new preventive and therapeutic interventions in sepsis. PMID- 29279186 TI - Digital Dermatitis in dairy cattle: The contribution of different disease classes to transmission. AB - Digital Dermatitis (DD) is a claw disease mainly affecting the hind feet of dairy cattle. Digital Dermatitis is an infectious disease, transmitted via the environment, where the infectious "agent" is a combination of bacteria. The standardized classification for DD lesions developed by Dopfer et al. (1997) and extended by Berry et al. (2012) has six distinct classes: healthy (M0), an active granulomatous area of 0-2 cm (M1), an ulcerative lesion of >2 cm (M2), an ulcerative lesion covered by a scab (M3), alteration of the skin (M4), and a combination of M4 and M1 (M4.1). We hypothesize that classes M1, M2, M3, M4, and M4.1 are the potentially infectious classes that can contribute to the basic reproduction ratio (R0), the average number of new infections caused by a typical infected individual. Here, we determine differences in infectivity between the classes, the sojourn time in each of the classes, and the contribution of each class to R0. The analysis is based on data from twelve farms in the Netherlands that were visited every two weeks, eleven times. We found that 93.89% of the transitions from M0 was observed as a transition to class M4, and feet with another class-at-infection rapidly transitioned to class M4. As a consequence, about 70% of the infectious time was spent in class M4. Transmission rate parameters of class-at-infection M1, M2, M3, and M4 were not significantly different from each other, but differed from class-at-infection M4.1. However, due to the relative large amount of time spend in class M4, regardless of the class-at-infection, R0 was almost completely determined by this class. The R0 was 2.36, to which class-at-infection M4 alone contributed 88.5%. Thus, M4 lesions should be prevented to lower R0 to a value below one, while painful M2 lesions should be prevented for animal welfare reasons. PMID- 29279187 TI - The importance of being urgent: The impact of surveillance target and scale on mosquito-borne disease control. AB - With the emergence or re-emergence of numerous mosquito-borne diseases in recent years, effective methods for emergency vector control responses are necessary to reduce human infections. Current vector control practices often vary significantly between different jurisdictions, and are executed independently and at different spatial scales. Various types of surveillance information (e.g. number of human infections or adult mosquitoes) trigger the implementation of control measures, though the target and scale of surveillance vary locally. This patchy implementation of control measures likely alters the efficacy of control. We modeled six different scenarios, with larval mosquito control occurring in response to surveillance data of different types and at different scales (e.g. across the landscape or in each patch). Our results indicate that: earlier application of larvicide after an escalation of disease risk achieves much greater reductions in human infections than later control implementation; uniform control across the landscape provides better outbreak mitigation than patchy control application; and different types of surveillance data require different levels of sensitivity in their collection to effectively inform control measures. Our simulations also demonstrate a potential logical fallacy of reactive, surveillance-driven vector control: measures stop being implemented as soon as they are deemed effective. This false sense of security leads to patchier control efforts that will do little to curb the size of future vector-borne disease outbreaks. More investment should be placed in collecting high quality information that can trigger early and uniform implementation, while researchers work to discover more informative metrics of human risk to trigger more effective control. PMID- 29279189 TI - Hypoparathyroidism: what is the best calcium carbonate supplementation intake form? AB - INTRODUCTION: In hypoparathyroidism, calcium supplementation using calcium carbonate is necessary for the hypocalcemia control. The best calcium carbonate intake form is unknown, be it associated with feeding, juice or in fasting. OBJECTIVE: The objective was to evaluate the calcium, phosphorus and Calcium*Phosphorus product serum levels of hypoparathyroidism women after total thyroidectomy, following calcium carbonate intake in three different forms. METHODS: A crossover study was carried out with patients presenting definitive hypoparathyroidism, assessed in different situations (fasting, with water, orange juice, breakfast with a one-week washout). Through the review of clinical data records of tertiary hospital patients from 1994 to 2010, 12 adult women (18 50 years old) were identified and diagnosed with definitive post-thyroidectomy hypoparathyroidism. The laboratory results of calcium and phosphorus serum levels dosed before and every 30min were assessed, for 5h, after calcium carbonate intake (elementary calcium 500mg). RESULTS: The maximum peak average values for calcium, phosphorus and Calcium*Phosphorus product were 8.63mg/dL (water), 8.77mg/dL (orange juice) and 8.95mg/dL (breakfast); 4.04mg/dL (water), 4.03mg/dL (orange juice) and 4.12mg/dL (breakfast); 34.3mg2/dL2 (water), 35.8mg2/dL2 (orange juice) and 34.5mg2/dL2 (breakfast), respectively, and the area under the curve 2433mg/dLmin (water), 2577mg/dLmin (orange juice) and 2506mg/dLmin (breakfast), 1203mg/dLmin (water), 1052mg/dLmin (orange juice) and 1128mg/dLmin (breakfast), respectively. There was no significant difference among the three different tests (p>0.05). CONCLUSION: The calcium, phosphorus and Calcium*Phosphorus product serum levels evolved in a similar fashion in the three calcium carbonate intake forms. PMID- 29279190 TI - Non-invasive brain stimulation and neuro-enhancement in aging. PMID- 29279188 TI - Clinical correlates of negative health events in a research sample with epilepsy. AB - AIMS: In spite of advances in care, people with epilepsy experience negative health events (NHEs), such as seizures, emergency department (ED) visits, and hospitalizations. Being able to identify characteristics that are associated with NHE risk can help inform care approaches that reduce complications and burden. This analysis using baseline data from a larger randomized epilepsy self management clinical trial assessed the relationship between demographic and clinical variables vs. seizure-related complications among people with epilepsy. METHODS: Data were derived from a baseline sample of a larger prospective study of 120 individuals with epilepsy who experienced an NHE within the last 6months. Demographic characteristics, depression assessed with the 9-item Patient Health Questionnaire (PHQ-9) and the Montgomery-Asberg Depression rating scale (MADRS), quality of life assessed with the 10-item Quality of Life in Epilepsy Inventory (QOLIE-10), self-efficacy assessed the Epilepsy Self-Efficacy Scale (ESES), social support assessed with the Multidimensional Scale of Perceived Social Support (MSPSS), self-management assessed with the Epilepsy Self-Management Scale (ESMS), and stigma assessed with the Epilepsy Stigma Scale (ESS) were all examined in association with past 6-month NHE frequency and 30-day seizure frequency. RESULTS: Except for lower levels of education and lower levels of income being associated with higher 30-day and 6-month seizure frequency, demographic variables were generally not significantly associated with NHEs. Higher 30-day seizure frequency was associated with greater depression severity on PHQ-9 (p<0.01) and MADRS (p<0.01). Higher 6-month seizure frequency was also associated with greater depression severity on PHQ-9 (p<.001) and MADRS (p=0.03). Both 30-day and 6-month seizure frequency were significantly negatively associated with QOLIE-10 (p<0.001). Both 30day (p=0.01) and 6-month (p=0.03) seizure frequency were associated with worse stigma on ESS. Total NHE count was associated with more severe depression on PHQ-9 (p=0.02), and MADRS (p=0.04), worse quality of life on QOLIE-10 (p<0.01), and more stigma on ESS (p=0.03). CONCLUSIONS: Consistent with previous literature, more frequent seizures were associated with worse depression severity and quality of life. A finding that is less established is that higher seizure frequency is also associated with worse epilepsy-related stigma. Epilepsy self-management approaches need to address depression and stigma as well as seizure control. PMID- 29279191 TI - MR findings in the substantia nigra on phase difference enhanced imaging in neurodegenerative parkinsonism. AB - INTRODUCTION: In Parkinson's disease (PD) patients, magnetic resonance (MR) imaging studies using phase difference enhanced imaging (PADRE) and susceptibility-weighted imaging (SWI) showed the obscuration of the boundary between the crural fibers and substantia nigra, and the absence of dorsolateral nigral hyperintensity, respectively. PADRE images have not been evaluated in other types of neurodegenerative parkinsonism, and PADRE and SWI images have not been compared. Here we evaluated PADRE and SWI images in patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or PD and controls, and we compared the diagnostic values. METHODS: PADRE and SWI-like MR images were visually assessed focusing on the substantia nigra in 39 PD patients, eight with PSP, 13 with MSA, and 34 normal controls. RESULTS: The obscuration of the boundary between the crural fibers and substantia nigra on PADRE was observed in: the PD group, 62%; PSP, 100%; MSA, 60%, and controls, 19%. The overall collect classification for neurodegenerative parkinsonism was 74%. The absence of dorsolateral nigral hyperintensity on SWI-like images was present in: PD, 97%; PSP, 100%; MSA, 67%; and controls, 6%, resulting in the overall correct classification of 96%. CONCLUSIONS: The MR feature on PADRE was observed not only in PD but also in other neurodegenerative parkinsonism, especially in PSP with high sensitivity. The finding in substantia nigra on SWI had greater discrimination power than that of PADRE in neurodegenerative parkinsonism, especially in PD. PMID- 29279192 TI - The prevalence of PRKRA mutations in idiopathic dystonia. AB - INTRODUCTION: DYT-PRKRA (DYT16) is considered a rare cause of dystonia parkinsonism. The significance of this gene as a cause of dystonia and its phenotypical characterization must be determined in larger cohorts. We aimed to investigate the role of PRKRA in patients with dystonia. METHODS: We sequenced PRKRA in 153 unrelated Brazilian patients with idiopathic dystonia. The frequency of novel missense variants was investigated in healthy Brazilian controls and in public databases. Homozygosity in the PRKRA region was assessed through polymorphic markers. RESULTS: PRKRA variants were identified in seven probands with isolated dystonia, including a novel c.C795A variant in compound heterozygosity with the previously described c.C665T variant. Heterozygosity in the gene region was observed in two probands who were homozygous for c.C665T, indicating that this mutation originated from independent events, suggesting a hotspot. CONCLUSION: PRKRA is not an unusual cause of idiopathic dystonia. In this cohort, it was responsible for 4.5% of the total of cases (4.9% of the isolated dystonia cases). The most common phenotype was early-onset isolated focal dystonia followed by generalization, parkinsonism was not observed. This is first report of PRKRA causing adulthood-onset dystonia. Screenings of large cohorts are recommended to investigate the role of this gene in isolated dystonia, as well as in dystonia-parkinsonism cases worldwide. PMID- 29279193 TI - Monographic issue of pharmacological research on adult myocardial repair/regeneration. PMID- 29279194 TI - A noninvasive surface wave technique for measuring finger's skin stiffness. AB - The purpose of this work was to develop a compact surface wave elastography (CSWE) device for measuring finger's skin stiffness. The motivation was to develop a noninvasive technique for assessing limited cutaneous systemic sclerosis (lcSSc) in accordance with new ACR/EULAR clarification criteria. Currently, the Modified Rodnan Skin Score (MRSS) is widely used for assessing systemic sclerosis but is challenging for assessing patients with lcSSc. The novelty of CSWE is to develop a noninvasive technique to measure the elastic properties of skin of fingers. In the CSWE device, a local harmonic vibration was generated on the finger's skin. The surface wave speed on the finger's skin was measured without contact using a compact optical probe. The CSWE device was first validated with an ultrasound-based surface wave elastography (USWE) device on a phantom. The CSWE device was then validated with the USWE device on both the dorsal and ventral arms of a volunteer. The CSWE device was evaluated to measure the surface wave speed of four fingers for the volunteer. The CSWE device may be useful for measuring skin stiffness over multiple areas of fingers and hands for assessing lcSSc. PMID- 29279195 TI - Minimizing fiducial localization error using sphere-based registration in jaw tracking. AB - Some of the jaw tracking methods may be limited in terms of their accuracy or clinical applicability. This article introduces the sphere-based registration method to minimize the fiducial (reference landmark) localization error (FLE) in tracking and coregistration of physical and virtual dental models, to enable an effective clinical analysis of the patient's masticatory functions. In this method, spheres (registration fiducials) are placed on the corresponding polygonal concavities of the physical and virtual dental models based on the geometrical principle that establishes a unique spatial position for a sphere inside an infinite trihedron. The experiments in this study were implemented using an optical system which tracked active tracking markers connected to the upper and lower dental casts. The accuracy of the tracking workflow was confirmed in vitro, based on comparing virtually calculated interocclusal regions of close proximity against the physical interocclusal impressions. The target registration error of the tracking was estimated based on the leave-one-sphere-out method to be the sum of the error of the sensors, i.e., the FLE was negligible. Moreover, based on a user study, the FLE of the proposed method was confirmed to be 5 and 10 times smaller than the FLE of conventional fiducial selections on the physical and virtual models, respectively. The proposed tracking method is non-invasive and appears to be sufficiently accurate. To conclude, the proposed registration and tracking principles can be extended to track any biomedical and non biomedical geometries that contain polygonal concavities. PMID- 29279196 TI - Experimental quantification of the fluid dynamics in blood-processing devices through 4D-flow imaging: A pilot study on a real oxygenator/heat-exchanger module. AB - The performance of blood-processing devices largely depends on the associated fluid dynamics, which hence represents a key aspect in their design and optimization. To this aim, two approaches are currently adopted: computational fluid-dynamics, which yields highly resolved three-dimensional data but relies on simplifying assumptions, and in vitro experiments, which typically involve the direct video-acquisition of the flow field and provide 2D data only. We propose a novel method that exploits space- and time-resolved magnetic resonance imaging (4D-flow) to quantify the complex 3D flow field in blood-processing devices and to overcome these limitations. We tested our method on a real device that integrates an oxygenator and a heat exchanger. A dedicated mock loop was implemented, and novel 4D-flow sequences with sub-millimetric spatial resolution and region-dependent velocity encodings were defined. Automated in house software was developed to quantify the complex 3D flow field within the different regions of the device: region-dependent flow rates, pressure drops, paths of the working fluid and wall shear stresses were computed. Our analysis highlighted the effects of fine geometrical features of the device on the local fluid-dynamics, which would be unlikely observed by current in vitro approaches. Also, the effects of non-idealities on the flow field distribution were captured, thanks to the absence of the simplifying assumptions that typically characterize numerical models. To the best of our knowledge, our approach is the first of its kind and could be extended to the analysis of a broad range of clinically relevant devices. PMID- 29279197 TI - Factors affecting staining to discriminate between bull sperm with greater and lesser mitochondrial membrane potential. AB - The sperm mitochondrial membrane potential (MMP) is usually evaluated using the JC-1 dye. This study aimed to verify the effect of incubation temperature (25 degrees C or 38 degrees C), incubation time (10, 30, and 45 min), JC-1 stain concentration (0.2 MUM, 2 MUM, 8 MUM, 12 MUM), and the presence of glycerol (6.6% compared with 0%), on the capacity of the stain to discriminate between sperm with high mitochondrial membrane potential (hMMP) and low mitochondrial membrane potential (lMMP) in fresh and frozen bull sample by both flow cytometry and epifluorescence microscopy. The temperature (38 degrees C for 10 min) and the dye concentration (8 MUM and 12 MUM) resulted in a greater proportion of hMMP (P < .05). The incubation for 45 min at 38 degrees C resulted in a significant reduction of hMMP in samples stained with JC-1 dye at 8 MUM and 12 MUM (P < .01). A longer incubation time (45 min) and greater dye concentration (8 MUM and 12 MUM) resulted in an increased proportion of hMMP sperm in cryopreserved samples. Fresh sperm incubated with glycerol had a hMMP (P < .05). Data for the present study indicate that the optimal incubation temperature was 38 degrees C, with an incubation time differing between fresh (10-30 min) and cryopreserved sperm (at least 45 min). Furthermore, the JC-1 dye concentration used that could reliably detect the proportion of hMMP sperm was 2 MUM in fresh samples, and at least 8 MUM in cryopreserved sperm. PMID- 29279198 TI - Cryopreservation of donkey sperm using non-permeable cryoprotectants. AB - The aim of this study was to evaluate the effect of different concentrations of sucrose combined with bovine serum albumin (BSA), as non-permeable cryoprotectants, on donkey sperm parameters after cryopreservation, in comparison to a control extender containing glycerol. Semen from five Andalusian donkeys (n = 12) were centrifuged and resuspended with a commercial extender for equine sperm (Gent A, Minitube) adding 1% BSA and different concentrations (M, mol/l) of water-diluted sucrose: 0.05, 0.1, 0.25, 0.35 and 0.45. Thereafter, semen (n = 24) were diluted in the same base extender containing 0.25 M sucrose (S25) or glycerol (GLY, Gent B). Sperm were slowly cooled, filled in 0.5 ml straws and frozen in nitrogen vapours. Post-thaw samples were assessed for sperm motility, plasma membrane and DNA integrity and results were compared by ANOVA. In Experiment 1, sperm motility was significantly higher (P < 0.001) for S25 than the remaining treatments, and no differences were found for plasma membrane or DNA integrity. In Experiment 2, no differences were found between S25 or GLY for sperm motility and DNA integrity but plasma membrane integrity was significantly higher (P < 0.05) for S25. In conclusion, the extender with sucrose 0.25 M combined with BSA can be considered as an alternative to conventional extenders with glycerol for donkey sperm cryopreservation. PMID- 29279199 TI - Anti-Mullerian Hormone (AMH), antral follicle count (AFC), external morphometrics and fertility in Tabapua cows. AB - The intense selection of characteristics related to animal performance may affect the reproductive efficiency of beef cows negatively. Selection for fertility along with production traits is, therefore, readily justifiable. The objective of the present study was to evaluate possible relationships among AFC, serum AMH concentrations and external morphometrics with reproductive efficiency in Tabapua (a Brazilian Bos indicus beef breed) females. Antral follicle counts and external morphometrics were measured in nulliparous (n = 162), primiparous (n = 80) and multiparous (n = 351) cows, from four farms. Age at first parturition (AFP), parturition interval (PI), maternal ability (MA), precocity, rusticity and survival (PRS) and overall reproductive efficiency (RE) were evaluated according to the Brazilian Association of Zebu Breeders (ABCZ) data bank indexes. A single blood sample per animal was collected at random stages of the reproductive cycle from a subset of animals (nulliparous = 84, primiparous and multiparous = 136) to determine serum AMH concentrations. The AFC classes were defined as lesser (<28), intermediate (28-50) and greater (>50). Correlations between all variables and the effects of parity and AFC on reproductive traits, AMH and external genitalia size were analyzed by the PROCORR and by the PROCGENMOD procedures of SAS(r) (SAS, Cary, NC, USA), respectively. Antral follicle count did not differ (P = 0.71) among nulliparous (38.6 +/- 23.96) primiparous (47.54 +/- 26.16) and multiparous (41.08 +/- 25) cows and was negatively correlated with pregnancy interval (PI), such that, as PI decreased (r = -0.28; P < 0.005), AFC increased. Vulva width was not affected (P = 0.08) by parity and was larger (P < 0.05) for females in the greater AFC class (8.81 +/- 0.12 cm) compared with the intermediate (8.42 +/- 0.11 cm) and lesser (8.38 +/- 0.13 cm) classes. As vulva width increased, parturition interval decreased (r = -0.15; P < 0.005) and overall reproductive efficiency increased (r = 0.17, p < 0.005). Thoracic depth was associated with greater AFCs (r = 0.10; P < 0.001). Anti-Mullerian hormone concentrations were greater (P < 0.05) for animals in the greater AFC class (1.15 +/- 0.09 ng/mL) compared with the lesser (0.44 +/- 0.02 ng/mL) and intermediate (0.73 +/- 0.05 ng/mL) classes. Vulva width, AFC, external morphometrics and AMH concentrations were moderately associated, considering the low heritability of fertility traits, and should be studied further to be considered in the selection for fertility in Bos indicus cattle. PMID- 29279200 TI - Proteomic analyses of ram (Ovis aries) testis during different developmental stages. AB - Male reproductive capacity is essential for animal breeding and reproduction. In males, the testes produce sperm and secrete androgen, processes which require precise regulation by multiple proteins. The composition of proteins in the ram testes has not yet been studied systematically, thus, the application of proteomics to explore differential protein regulation during ram testes development is of great significance. In the present study, ram testes were studied at five different developmental phases to assess postnatal differences in protein regulation. Two dimensional electrophoresis (2-DE) was used to separate ram testes proteins at each developmental phase, yielding 45 different proteins, 37 of which were identified by Matrix Assisted Laser Desorption Ionization-Time of Flight-Time of Flight-Mass Spectrometry (MALDI-TOF/TOF-MS). Gene Ontology (GO) was used to specifically annotate the biological process, cellular composition, and molecular function of each identified protein. Most of the identified proteins were involved in structural formation, development, reproduction, and apoptosis of the testicular spermatogenic tissue and spermatozoa. Quantitative real time PCR (qRT-PCR), western blot and immunohistochemical methods were used to verify the proteins, and the results were consistent with that of 2-DE. The proteins that were different in abundance that were identified in this study can be used as biomarkers in future studies of ram reproduction. PMID- 29279201 TI - Replication in Imaging Genetics: The Case of Threat-Related Amygdala Reactivity. AB - BACKGROUND: Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk. METHODS: We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 +/- 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available. RESULTS: Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons. CONCLUSIONS: We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings. PMID- 29279203 TI - Response to the Consensus Statement of the PTSD Psychopharmacology Working Group. PMID- 29279204 TI - Ivacaftor restores CFTR-dependent sweat gland fluid secretion in cystic fibrosis subjects with S945L alleles. AB - BACKGROUND: To determine in vivo effects of CFTR modulators on mutation S945L. METHODS: We measured effects of CFTR modulators on CFTR-dependent sweating ('C sweat') in two pancreatic sufficient cystic fibrosis (CF) subjects. S1 (S945L/G542X) took ivacaftor and S2 (S945L/F508del) took ivacaftor+tezacaftor. Sweating was stimulated pharmacologically to produce sequentially both CFTR independent (methacholine stimulated) M-sweat and C-sweat; and the ratio of these was compared. Sweat secretion was measured with two methods: real time secretory rate quantitative recording and by optically measuring the growth of sweat bubbles under oil from multiple identified glands. RESULTS: Using the quantitative recorder, we saw zero C-sweat secretion off-drug, but when on-drug the C-sweat responses for both subjects were comparable to those seen in carriers. The on-drug response was further quantified using the sweat bubble method. Each subject again showed robust C-sweat responses, with C-sweat/M-sweat ratios~half of the ratio determined for a cohort of 40 controls tested under identical conditions. CONCLUSION: These in vivo results, consistent with prior in vitro findings, indicate that the drug treatments restore near-normal function to S945L-CFTR, and support the use of ivacaftor as a treatment for CF patients who carry this allele. PMID- 29279202 TI - The Emerging Relationship Between Interstitial Fluid-Cerebrospinal Fluid Exchange, Amyloid-beta, and Sleep. AB - Amyloid-beta (Abeta) plaques are a key histopathological hallmark of Alzheimer's disease (AD), and soluble Abeta species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrate that Abeta plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although a clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences have shed important new light on how sleep and Abeta homeostasis may be connected in the setting of AD. Abeta, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid along a brain-wide network of perivascular pathways recently termed the glymphatic system. Glymphatic function is primarily a feature of the sleeping brain, rather than the waking brain, and is slowed in the aging and posttraumatic brain. These changes may underlie the diurnal fluctuations in interstitial and cerebrospinal fluid Abeta levels observed in both the rodent and the human. These and other emerging studies suggest that age-related sleep disruption may be one key factor that renders the aging brain vulnerable to Abeta deposition and the development of AD. If this is true, sleep may represent a key modifiable risk factor or therapeutic target in the preclinical phases of AD. PMID- 29279205 TI - The effects of violent media content on aggression. AB - Decades of research have shown that violent media exposure is one risk factor for aggression. This review presents findings from recent cross-sectional, experimental, and longitudinal studies, demonstrating the triangulation of evidence within the field. Importantly, this review also illustrates how media violence research has started to move away from merely establishing the existence of media effects and instead has begun to investigate the mechanisms underlying these effects and their limitations. Such studies range from investigations into cross-cultural differences to neurophysiological effects, and the interplay between media, individual, and contextual factors. Although violent media effects have been well-established for some time, they are not monolithic, and recent findings continue to shed light on the nuances and complexities of such effects. PMID- 29279206 TI - Gun violence. AB - Drawing on the World Health Organization's ecological model, this review explores how contextual and institutional factors shape individual choice and behavior with respect to gun violence. Young men are disproportionately represented among both perpetrators and victims of violence. Although specific characteristics and behaviors present risks, these vary with the specific forms of violence. There is ample international research that suggests the availability of guns increases the risk of lethal violence. When guns are present, suicide attempts are more likely to succeed and assaults are more likely to become homicides. Some research has indicated that stockpiling guns and the fascination with guns is an indicator of antisocial behavior. Broad social, cultural, and political forces both shape and reflect guns violence. PMID- 29279207 TI - Family influences on the development of aggression and violence. AB - Recent research confirms that many of the most salient risk and protective factors for the development of aggression and violence reside in the family system. Family-based risks begin before birth, encompassing genetic and epigenetic processes. Contextual stressors (e.g., poverty, conflict) may impact development directly or indirectly through disrupted parenting behavior, including high negativity, low warmth, harshness, and exposure to violence. The family can also serve as a powerful adaptive system counteracting the risk of aggression and violence. Parents can promote healthy behavioral development through warmth, structure, and prosocial values, as well as by fostering adaptive resources in the child and community. Successful interventions often reduce aggression and violence by supporting parents and families. Recent insights and future directions for research and practice are discussed. PMID- 29279208 TI - Climate, aggression, and violence (CLASH): a cultural-evolutionary approach. AB - The CLimate, Aggression, and Self-control in Humans (CLASH) proposes that aggression and violence increase as climates become hotter and seasonal variation becomes smaller by influencing time-orientation and self-control. Emerging empirical evidence supporting the model is reviewed. Wealth, income inequality, and pathogen stress as powerful influences of these processes are also discussed. We conclude by discussing the theoretical and societal importance of climate change in shaping violence. PMID- 29279209 TI - An integrative theoretical understanding of aggression: a brief exposition. AB - Like other social behaviors, aggressive behavior is always a product of predisposing personal factors and precipitating situational factors. The predisposing factors exert their influence by creating encoded social cognitions including schemas about the world, scripts for social behavior, and normative beliefs about what is appropriate. These social cognitions interact with situational primes to determine behavior. These social cognitions are acquired primarily through observational learning; so youth who are repeatedly exposed to violence will acquire social cognitions promoting aggression that last into adulthood. Thus, violence can be viewed as a contagious disease which can be caught simply through its observation. PMID- 29279210 TI - The I3 Model: a metatheoretical framework for understanding aggression. AB - The I3 Model is a general-purpose metatheory. It posits that three orthogonal processes influence the likelihood and intensity of a given behavior, including aggressive behavior. Instigation encompasses immediate environmental stimuli (e.g., provocation) that normatively afford an aggressive response. Impellance encompasses situational or dispositional qualities (e.g., trait aggressiveness) that influence how strongly the instigator produces a proclivity to enact that response. Inhibition encompasses situational or dispositional qualities (e.g., alcohol intoxication) that influence how strongly the proclivity is overridden rather than manifesting in aggressive behavior. Extant evidence supports Perfect Storm Theory-a theoretical perspective derived from the I3 Model-which posits that aggression is especially likely, and especially intense, to the extent that instigation and impellance are strong and inhibition is weak. PMID- 29279211 TI - The social psychological makings of a terrorist. AB - Social psychological factors pertain to all aspects of terrorism, including how terrorist organizations operate, and the impact of terrorism on everyday people. The present analysis focuses on the aspect of terrorism where social psychology's voice is perhaps most critical: radicalization (i.e., how terrorists are made) and deradicalization (i.e., how terrorists are unmade). In reviewing the literature, we identify three factors critical to radicalization: (1) the individual need that motivates one to engage in political violence, (2) the ideological narrative that justifies political violence, and (3) the social network that influences one's decisions along the pathway to extremism. Theoretical and empirical contributions are discussed. We end with an examination of interviews conducted with former extremists of various ideological leanings to highlight these same three factors as critical to their individual deradicalization experiences. PMID- 29279212 TI - Two pedals drive the bi-cycle of violence: reactive and appetitive aggression. AB - The Good: when you fight to counter threat, your aggression is a reactive defense, and often morally justifiable. The Bad: when you loot and rob, hurt and kill, to obtain social status or material goods, that is an extrinsic reward. This is instrumental aggression. And The Ugly: The intrinsic enjoyment of violence. This 'appetitive aggression' describes a lust for violence, underlying first-person shooter gamers, hunting, and extreme acts of violence, such as murder and massacres. Although violence often results from a combination of these forms of aggression, the differentiation is necessary to understand their interplay, as they drive two interconnected cycles of violence: the reactive cycle, fueled by the motivation to overcome negative feelings, and the hedonically driven appetitive cycle. PMID- 29279213 TI - Some problems with cyberbullying research. AB - Research on cyberbullying is plagued by inconsistent findings and exaggerated claims about prevalence, development over time, and effects. To build a useful and coherent body of knowledge, it essential to achieve some degree of consensus on the definition of the phenomenon as a scientific concept and that efforts to measure cyberbullying are made in a 'bullying context.' This will help to ensure that findings on cyberbullying are not confounded with findings on general cyberaggression or cyberharassment. We tentatively recommend that cyberbullying should be regarded as a subcategory or specific form of bullying, in line with other forms such as verbal, physical, and indirect/relational. PMID- 29279214 TI - Aversive events and aggression. AB - There is perhaps no finding in psychology that is more consistent than the human motivation to avoid negative experiences and seek out positive ones. The current review details some of the aggression-related consequences that result from failures to avoid these negative experiences. Attention is paid to the theoretical processes at work that produce such effects. A review is conducted of the empirical literature detailing animal and human studies, in the lab and field. Lastly, we briefly discuss future directions in research that may advance our understanding of such effects. PMID- 29279215 TI - Testosterone and human behavior: the role of individual and contextual variables. AB - The study of testosterone and aggression originated in experimental studies of animals, showing a direct causal link in some species. Human studies showed an overall weak correlation between testosterone and aggression. A theoretical framework ('the challenge hypothesis') enabled testosterone-behavior interactions in humans to be framed within a theory that emphasized hormonal responses to competition influencing subsequent aggressive behavior. The short-term administrations of testosterone to young women and to young men showed influences on behavioral and neural processes associated with aggression. Other findings are that testosterone influences aggression in high dominance men, and in those with low cortisol levels; and that testosterone can affect both aggressive and prosocial behavior, within the context of an experimental game. PMID- 29279216 TI - Development of aggression. AB - Theories and empirical findings regarding the development of aggression have included advances in four key areas in the last two years. First, studies have increasingly adopted more nuanced operationalization of forms and functions of aggression. Second, mediators and moderators of links between risk factors and the development of aggression have been examined with more precision. Third, advances in neuroscience and studies of gene by environment interactions have led to greater understanding of genetic and neurobiological underpinnings of the development of aggression. Fourth, cross-cultural and international research has tested the generalizability of findings to more diverse samples and has examined culture as a potential moderator of links between risk factors and the development of aggression. PMID- 29279217 TI - The case against physical punishment. AB - We review the literature on parental physical punishment of children, laying out foundations of a case against physical punishment as a form of discipline. We consider the research on physical punishment finding that physical punishment is associated with a number of undesirable outcomes for children and adolescents. We pay special attention to questions of: parent effects versus child effects; whether parental use of physical punishment is moderated by family, neighborhood, or cultural context, and whether physical punishment can be considered to be part of a continuum of family violence. We close with recommendations for positive parenting policies and practices. PMID- 29279218 TI - Rampage shootings: an historical, empirical, and theoretical overview. AB - Rampage shootings is a relatively new term to describe a phenomenon that has a long history. Rampage shootings are mass shootings (generally defined as involving four or more victims), taking place in a public location, with victims chosen randomly or for symbolic purposes. These shootings are isolated events, meaning they are not connected to another criminal act (such as robbery or terrorism). Research suggests that rampage shootings are not a new phenomenon, but have occurred throughout the US since the early 1900s. There is some evidence of an increase in recent years, but definitional differences across studies and data sources make interpreting trends somewhat tenuous. Theories regarding the perpetration of rampage shootings center on masculinity, mental illness, and contagion effects. Policies aimed at preventing rampage shootings remain somewhat controversial and not well-tested in the literature. PMID- 29279219 TI - Hurt people hurt people: ostracism and aggression. AB - Because ostracism hurts, it can trigger aggression. Guided by the theoretical framework of the temporal need-threat model of ostracism, we review the existing research that investigates this ostracism-aggression link over the last two decades. Both correlational and experimental research have provided substantial support for the model's prediction that ostracism may instigate aggression. Recent research continues to investigate why this occurs, and who is most likely to become aggressive when ostracized. A new and exciting body of literature emerges, which seeks to inform interventions for coping with ostracism and for reducing ostracism-related aggression. PMID- 29279220 TI - Gender differences in aggression. AB - Studies on gender differences in aggressive behavior are examined. In proportions of their total aggression scores, boys and girls are verbally about equally aggressive, while boys are more physically and girls more indirectly aggressive. There are genetic determinants of both physical and indirect aggression, suggesting that both types of aggression give evolutionary advantages. Analyses of 2D:4D finger length ratios indicate that the prenatal hormonal environment is crucial for the development of these aggressive strategies. PMID- 29279221 TI - Group Aggression. AB - Group aggression is an important concern for societies around the world. The field of intergroup relations, a sub-field of social-psychology, offers critical insight into the emergence of group conflict and aggression. This review examines the most influential theoretical frameworks from the field of intergroup relations, namely realistic conflict theory, relative deprivation theory, social identity theory, social dominance theory, and deindividuation theory. Associated empirical findings regarding groups synonymous with aggression, such as street gangs, hate groups, rebel and insurgent groups, and terrorist organizations, are explored. This review thus provides a critical overview of the current state of the field. It concludes with implications for the future of intergroup aggression research, drawing on integrated theories that account for both personal and situational factors. PMID- 29279222 TI - Aggression prevention and reduction in diverse cultures and contexts. AB - It is not as difficult to prevent and reduce violence as commonly assumed. The examination of peaceful societies and nonviolent social movements provides insight on how core values and norms like humility, respect for others, love and caring, forgiveness, and patience are fundamental in promoting peace. Additionally, nonviolent attitudes actualized through nonviolent models and non punitive childrearing practices can help socialize children to become nonviolent adults. At the group level, the commitment to nonviolence by individuals using methods of sit-ins, boycotts, strikes, work slow-downs, civil disobedience, marches, and demonstrations in struggles against violence and oppression can bring about positive social change. Thus, the growing number of cases of nonviolent resistance triumphing over injustice and repression as well as the existence of dozens of highly peaceful societies bear witness to the fact that life without violence is possible. PMID- 29279223 TI - The roots of intimate partner violence. AB - Intimate partner violence (IPV) is a paradoxical combination of affection and aggression. So why do people show an all-too-frequent tendency to harm their loved ones? Towards answering this question, we review a broad literature that explicates the ultimate and proximate roots of IPV perpetration. At the ultimate level, IPV perpetration is likely to be the result of evolutionary and socio structural forces. Theories of aggression are then brought to bear in order to articulate the proximal sequence of psychological processes that magnify and constrain IPV. Interpersonal (e.g., rejection), intrapersonal (e.g., self regulation), and biological (e.g., testosterone) factors are discussed in their relation to IPV perpetration. Finally, potentially fruitful avenues for intervention are evaluated, as exemplars of the hope that a robust understanding IPV perpetration will lead to the reduction of this costly behavior. PMID- 29279224 TI - Violence against women. AB - Violence against women causes suffering and misery to victims and their families and places a heavy burden on societies worldwide. It mostly happens within intimate relationships or between people known to each other. Violence against women is a social construction based on a societal consensus about the roles and rights of men and women. Two prevalent forms of violence against women are physical and sexual victimization by an intimate partner, and sexual victimization outside intimate relationships. Explanations of why men engage in aggressive behavior toward women address different levels, including the macro level of society, the micro level of dyadic interactions, and the individual level of perpetrator characteristics. Prevention efforts are needed that address each of these levels. PMID- 29279225 TI - The aggressive brain: insights from neuroscience. AB - Aggression is a complex, multifaceted behavior often caused by numerous factors and expressed in innumerable ways. Like all behaviors, aggression represents the outcome of sets of biological and physiological processes emerging from the brain. Although this may seem obvious, discovering the specific neural circuits and neurophysiological processes responsible for engendering aggressive responses has proven anything but simple. The purpose of this review is to provide a brief overview of discoveries in both human cognitive neuroscience and animal behavioral neuroscience that have begun to shed light-literally in some cases-on the heretofore mysterious neural processes and connections responsible for producing aggressive behavioral responses. PMID- 29279226 TI - Anger and aggression treatments: a review of meta-analyses. AB - In the last several decades, researchers have begun to recognize dysregulated anger as a common and debilitating psychological problem among various psychiatric populations. Accordingly, the treatment of anger and aggression has received increasing attention in the literature. The current article reviews existing meta-analyses of psychosocial intervention for anger and aggression with the aims of (1) synthesizing current research evidence for these interventions, and (2) identifying interventions characteristics associated with effectiveness in specific populations of interest. Results demonstrate that cognitive behavioral treatments are the most commonly disseminated intervention for both anger and aggression. Anger treatments have consistently demonstrated at least moderate effectiveness among both non-clinical and psychiatric populations, whereas aggression treatment results have been less consistent. We discuss the implication of these findings and provide directions for future research in the treatment of anger and aggression. PMID- 29279227 TI - The General Aggression Model. AB - The General Aggression Model (GAM) is a comprehensive, integrative, framework for understanding aggression. It considers the role of social, cognitive, personality, developmental, and biological factors on aggression. Proximate processes of GAM detail how person and situation factors influence cognitions, feelings, and arousal, which in turn affect appraisal and decision processes, which in turn influence aggressive or nonaggressive behavioral outcomes. Each cycle of the proximate processes serves as a learning trial that affects the development and accessibility of aggressive knowledge structures. Distal processes of GAM detail how biological and persistent environmental factors can influence personality through changes in knowledge structures. GAM has been applied to understand aggression in many contexts including media violence effects, domestic violence, intergroup violence, temperature effects, pain effects, and the effects of global climate change. PMID- 29279228 TI - Animal models of excessive aggression: implications for human aggression and violence. AB - Escalated interpersonal aggression and violence are common symptoms of multiple psychiatric disorders and represent a significant global health issue. Current therapeutic strategies are limited due to a lack of understanding about the neural and molecular mechanisms underlying the 'vicious' shift of normal adaptive aggression into violence, and the environmental triggers that cause it. Development of novel animal models that validly capture the salient features of human violent actions combined with newly emerging technologies for mapping, measuring, and manipulating neuronal activity in the brain significantly advance our understanding of the etiology, neuromolecular mechanisms, and potential therapeutic interventions of excessive aggressive behaviors in humans. PMID- 29279229 TI - Aggression as a trait: the Dark Tetrad alternative. AB - Aggression is often construed as a unitary trait fully captured by the Buss-Perry Aggression Questionnaire (BPAQ). Our review of the literature questions that assumption in several respects. Instead of a top-down approach, we argue for a bottom-up conception based on the Dark Tetrad of personality, that is, narcissism, Machiavellianism, psychopathy, and sadism. We highlight research showing that each member of the tetrad responds to different provocations. We conclude that the unitary trait conception of aggression has yielded more confusion than understanding. The term aggression should be reserved for outcomes, with many possible trait*situation predictors. Future research should continue the investigation of moderators as well as cognitive mediators to clarify the triggering of aggression in the individual tetrad members. PMID- 29279230 TI - The weapons effect. AB - In some societies, weapons are plentiful and highly visible. This review examines recent trends in research on the weapons effect, which is the finding that the mere presence of weapons can prime people to behave aggressively. The General Aggression Model provides a theoretical framework to explain why the weapons effect occurs. This model postulates that exposure to weapons increases aggressive thoughts and hostile appraisals, thus explaining why weapons facilitate aggressive behavior. Data from meta-analytic reviews are consistent with the General Aggression Model. These findings have important practical as well as theoretical implications. They suggest that the link between weapons and aggression is very strong in semantic memory, and that merely seeing a weapon can make people more aggressive. PMID- 29279231 TI - The facts on the furious: a brief review of the psychology of trait anger. AB - Some people are more prone to aggression than others. These individual differences are associated with trait anger, a personality dimension that relates to the frequency, intensity, and duration with which people experience angry feelings. Trait anger is an important antecedent of state anger and aggression. People with high trait anger tend to perceive situations as hostile and are less capable of controlling their hostile thoughts and feelings. Moreover, people with high trait anger display heightened approach motivation in threatening situations. This reactive approach motivation may be countered by avoidance states, which may reduce anger among high trait anger people. Insights into the underlying processes of trait anger may be used to combat human aggression. PMID- 29279232 TI - Portal-splenic-mesenteric venous thrombosis in a patient with Klinefelter syndrome. PMID- 29279233 TI - Hepatitis B virus e antigen-negative chronic infection. Treatment based on glutamic pyruvic transaminase and hepatitis B virus deoxyribonucleic acid cut-off values. AB - OBJECTIVES: To identify glutamic pyruvic transaminase (GPT) and hepatitis B virus DNA (HBV-DNA) cut-off values at diagnosis in patients with hepatitis B virus e antigen-negative chronic infection (HBeAg(-)), which may be predictors of clinical course, prognosis and/or the need for antiviral therapy. METHODS: A retrospective and observational cohort study of patients diagnosed with HBeAg(-) chronic infection (2005-2012). A normal GPT cut-off value at diagnosis that predicts abnormal GPT values in the clinical course of the infection, a baseline HBV-DNA cut-off value that predicts an increase in HBV-DNA above 2,000IU/ml, and GPT and HBV-DNA as predictors of the need for treatment were investigated using ROC curves. RESULTS: 126 patients were enrolled (follow-up: 42.1+/-21.5months), 93 of which had normal GPT levels at diagnosis. In the ROC curve analysis, 900IU/ml was found to be the HBV-DNA cut-off value that best predicted this value's increase above 2,000IU/ml (sensitivity: 90%; specificity: 88%; PPV: 79%; NPV: 100%; diagnostic precision: 89%), while 25mU/ml was the normal GPT cut-off value at diagnosis that best predicted subsequently elevated GPT levels (sensitivity: 95.4%; specificity: 81.6%; PPV: 67%; NPV: 96%; diagnostic precision: 80.6%). Patients with GPT 26-40mU/ml at diagnosis presented with more complications or required more treatment than subjects with GPT<=25mU/ml (P<.05). The combined GPT and HBV-DNA values that elicited the highest treatment need were 38mU/ml of GPT and 6,000IU/ml of HBV-DNA (sensitivity: 75%; specificity: 93.4%; PPV: 60%; NPV: 96.6%). CONCLUSION: HBeAg(-) patients with GPT<25mU/ml and HBV DNA<900IU/ml at diagnosis have positive outcomes and may not require such stringent follow-up in the first years after diagnosis. PMID- 29279234 TI - Living without anaemia. PMID- 29279235 TI - Attitudes toward working conditions: are European Union workers satisfied with their working hours and work-life balance? AB - OBJECTIVE: To describe the satisfaction with working hours and satisfaction with work-life balance and their association in the European Union (EU-28). METHOD: This is a cross-sectional study based on data from the Flash Eurobarometer 398 among workers of the EU-28 from 2014 (n=13,683). We calculated percentages and their 95% confidence intervals (95%CI). We also applied a multi-level generalised linear model using the Poisson family, to calculate the adjusted prevalence ratios (aPR) of satisfaction with work-life balance based on working hours. All analyses were stratified by individual, employment and welfare regime country classification. RESULTS: The satisfaction with working hours and work-life balance was 80.62% and 74.48%, respectively, and was significantly higher among women. The highest percentages of satisfaction were found in the Nordic welfare regime countries (90.2% and 85.3%, respectively). There was a statistically significant association between satisfaction with working hours and work-life balance (aPR: 2.63; 95%CI: 2.28-3.04), and the magnitude of the association differed in individual, employment and welfare regime country classifications. The main reasons declared for dissatisfaction were "excessive working hours" (48.7%), "shift work" (27.9%), and "inability to influence the work schedule" (28.3%). Differences were observed according to sex and type of welfare regime. CONCLUSION: The differences found in the association between satisfaction with work-life balance and working hours according to sociodemographic characteristics and welfare regime show that there are inequalities in the working conditions in the EU countries. PMID- 29279236 TI - Patients should now be informed of the benefits of the use of a piezoelectric saw before orthognathic bilateral sagittal split osteotomy. PMID- 29279237 TI - Temperature-driven growth of Legionella in lab-scale activated sludge systems and interaction with protozoa. AB - The occurrence of Legionella pneumophila in activated sludge systems has been reported in the literature. However, the factors triggering its growth are not yet well understood. This knowledge is needed to develop strategies to minimize the risk of the spread of Legionnaires' disease that originates in these systems. In the present study, L. pneumophila multiplied exponentially at 35 degrees C in activated sludge, but lower temperatures (24 degrees C and 15 degrees C) did not favour the growth of the pathogen despite the presence of its protozoan hosts (free-living amoeba and ciliates). L. non-pneumophila species, which are adapted to low temperature, prevailed at 15 degrees C. Legionella was found dispersed in the activated sludge, forming clusters of different sizes and also inside protozoa. This study shows that temperature is a key parameter triggering the growth of L. pneumophila in activated sludge. The detection of infected protozoa suggests that these are important vehicles for the multiplication of Legionella. However, in this study it was not possible to exclude the growth of Legionella directly on the substrate or on the activated sludge matrix. PMID- 29279238 TI - Technification versus humanisation. Artificial intelligence for medical diagnosis. PMID- 29279239 TI - Retinal and optic disc vasculitis in Susac's syndrome. AB - CASE REPORT: The case is presented of 42 year-old woman with no significant medical history, with severe headaches, nausea and vomiting, hearing loss, and alteration of mental status with disorientation and confusion. Ophthalmic examination showed optic disc hyperaemia in right eye, and focal areas of arteriolar occlusion in both eyes. Audiometry demonstrated bilateral neurosensory hypoacusis. Magnetic Resonance Imaging showed multiple small round hyperintense lesions located in the splenium, corpus callosum, basal ganglia, and white matter. DISCUSSION: Besides branch retinal arteriolar occlusion, the angiopathy in Susac's syndrome may affect the optic disc vessels. PMID- 29279240 TI - Proximal obstruction of a XEN gel stent: Diagnosis and treatment. PMID- 29279241 TI - MRI evaluation of sacral chordoma treated with carbon ion radiotherapy alone. AB - BACKGROUND AND PURPOSE: To compare RECIST 1.1 with volume modifications in patients with sacral chordoma not suitable for surgery treated with carbon ions radiotherapy (CIRT) alone. To evaluate patients pain before and after CIRT. To detect if baseline Apparent Diffusion Coefficient values (ADC) from Diffusion Weighted sequences could predict response to treatment. MATERIAL AND METHODS: Patients included had one cycle of CIRT and underwent MRI before and after treatment. For each MRI, lesion maximum diameter and volume were obtained, and ADC values were analyzed within the whole lesion volume. Patients pain was evaluated with Numerical Rating Scale (NRS), considering the upper tumor level at baseline MRIs. RESULTS: 39 patients were studied (mean follow-up 18 months). Considering RECIST 1.1 there was not a significant reduction in tumor diameters (p = 0.19), instead there was a significant reduction in tumor volume (p < 0.001), with a significant reduction in pain (p = 0.021) if the tumors were above vertebrae S2-S3 at baseline MRIs. The assessment of baseline ADC maps demonstrated higher median values and more negative skewness values in progressive disease (PD) patients versus both partial response (PR) and stable disease (SD). CONCLUSIONS: Lesion volume measurement is more accurate than maximum diameter to better stratify the response of sacral chordoma treated with CIRT. Preliminary results suggest that baseline ADC values could be predictive of response to CIRT. PMID- 29279242 TI - Novel fluconazole derivatives with promising antifungal activity. AB - The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action. PMID- 29279244 TI - Succession and diversity of microorganisms and their association with physicochemical properties during green waste thermophilic composting. AB - A comprehensive characterization of the bacterial diversity associated to thermophilic stages of green waste composting was achieved. In this study, eight different treatments (T1-T8) and three replicated lab-scale green waste composting were carried out to compare the effect of the cellulase (i.e. 0, 2%), microbial inoculum (i.e. 0, 2 and 4%) and particle size (i.e. 2 and 5 mm) on bacterial community structure. Physicochemical properties and bacterial communities of T1-T8 composts were observed, and the bacterial structure and diversity were examined by high-throughput sequencing via a MiSeq platform. The results showed that the most abundant phyla among the treatments were the Firmicutes, Chloroflexi and Proteobacteria. The shannon index and non-metric multidimensional scaling (NMDS) showed higher bacterial abundance and diversity at the metaphase of composting. Comparing with 5-mm treatments, particle size of 2-mm had a richer diversity of bacterial communities. The addition of cellulase and a microbial inoculum could promote the fermentation temperature, reduce the compost pH and C/N ratio and result in higher GI index. The humic substance (HS) and humic acid (HA) contents for 2-mm particle size treatments were higher than those of 5-mm treatments. Canonical correspondence analysis suggested that differences in bacterial abundance and diversity significantly correlated with HA, E4/E6 and temperature, and the relationship between bacterial diversity and environmental parameters was affected by composting stages. Based on these results, the application of cellulase to promote green waste composting was feasible, and particle size was identified as a potential control of composting physicochemical properties and bacterial diversity. PMID- 29279243 TI - Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives. AB - Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d Hyp24,Iva25,Pya(4)26,Cha27,36,gammaMeLeu28,Lys30,Aib31]PYY(23-36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism. PMID- 29279245 TI - An optimized low-cost protocol for standardized production of iron-free apoferritin nanocages with high protein recovery and suitable conformation for nanotechnological applications. AB - Ferritin is a globular protein that consists of 24 subunits forming a hollow nanocage structure that naturally stores iron oxyhydroxides. Elimination of iron atoms to obtain the empty protein called apoferritin is the first step to use this organic shell as a nanoreactor for different nanotechnological applications. Different protocols have been reported for apoferritin formation, but some are time consuming, others are difficult to reproduce and protein recovery yields are seldom reported. Here we tested several protocols and performed a complete material characterization of the apoferritin products using size exclusion chromatography, UV-vis spectroscopy, inductively coupled plasma optical emission spectrometry and dynamic light scattering. Our best method removes more than 99% of the iron from loaded holoferritin, recovering 70-80% of the original protein as monomeric apoferritin nanocages. Our work shows that pH conditions of the reduction step and the presence and nature of chelating agents affect the efficiency of iron removal. Furthermore, process conditions also seem to have an influence on the monomer:aggregate proportion present in the product. We also demonstrate that iron contents markedly increase ferritin absorbance at 280nm. The influence of iron contents on absorbance at 280nm precludes using this simple spectrophotometric measure for protein determination in ferritin-iron complexes. Apoferritin produced following our protocol only requires readily-available, cheap and biocompatible reagents, which makes this process standardizable, scalable and applicable to be used for in vivo applications of ferritin derivatives as well as nanotechnological and biotechnological uses. PMID- 29279246 TI - Complement system biomarkers in first episode psychosis. AB - Several lines of evidence implicate immunological/inflammatory factors in development of schizophrenia. Complement is a key driver of inflammation, and complement dysregulation causes pathology in many diseases. Here we explored whether complement dysregulation occurred in first episode psychosis (FEP) and whether this provides a source of biomarkers. Eleven complement analytes (C1q, C3, C4, C5, factor B [FB], terminal complement complex [TCC], factor H [FH], FH related proteins [FHR125], Properdin, C1 inhibitor [C1inh], soluble complement receptor 1 [CR1]) plus C-reactive protein (CRP) were measured in serum from 136 first episode psychosis (FEP) cases and 42 mentally healthy controls using established in-house or commercial ELISA. The relationship between caseness and variables (analytes measured, sex, age, ethnicity, tobacco/cannabis smoking) was tested by multivariate logistic regression. When measured individually, only TCC was significantly different between FEP and controls (p=0.01). Stepwise selection demonstrated interdependence between some variables and revealed other variables that significantly and independently contributed to distinguishing cases and controls. The final model included demographics (sex, ethnicity, age, tobacco smoking) and a subset of analytes (C3, C4, C5, TCC, C1inh, FHR125, CR1). A receiver operating curve analysis combining these variables yielded an area under the curve of 0.79 for differentiating FEP from controls. This model was confirmed by multiple replications using randomly selected sample subsets. The data suggest that complement dysregulation occurs in FEP, supporting an underlying immune/inflammatory component to the disorder. Classification of FEP cases according to biological variables rather than symptoms would help stratify cases to identify those that might most benefit from therapeutic modification of the inflammatory response. PMID- 29279247 TI - Latent class cluster analysis of symptom ratings identifies distinct subgroups within the clinical high risk for psychosis syndrome. AB - The clinical-high-risk for psychosis (CHR-P) syndrome is heterogeneous in terms of clinical presentation and outcomes. Identifying more homogenous subtypes of the syndrome may help clarify its etiology and improve the prediction of psychotic illness. This study applied latent class cluster analysis (LCCA) to symptom ratings from the North American Prodrome Longitudinal Studies 1 and 2 (NAPLS 1 and 2). These analyses produced evidence for three to five subgroups within the CHR-P syndrome. Differences in negative and disorganized symptoms distinguished among the subgroups. Subgroup membership was found to predict conversion to psychosis. The authors contrast the methods employed within this study with previous attempts to identify more homogenous subgroups of CHR-P individuals and discuss how these results could be tested in future samples of CHR-P individuals. PMID- 29279248 TI - Primary surgical management with radial forearm free flap reconstruction in T4 oropharyngeal cancer: Complications and functional outcomes. AB - PURPOSE: Functional outcomes and complication rates after open surgery for advanced-stage oropharyngeal cancers are rarely reported. These measures are critical for choice of treatment modality and patient counseling. We describe the long term functional outcomes and associated complications of primary surgical management of T4 oropharyngeal cancers reconstructed with radial forearm free flaps. MATERIALS AND METHODS: A retrospective review was performed of 40 patients with T4 oropharyngeal cancers treated between 2005 and 2015 at a tertiary care center. RESULTS: Forty patients with T4 oropharyngeal cancers underwent open surgical resection and radial forearm free flap reconstruction at the time of surgery. Mandibulotomy was required in 33 (82.5%) cases. Thirty-five (87.5%) patients received adjuvant radiation or combined chemotherapy and radiation. Tracheostomy was performed in all patients, but every patient was eventually decannulated. Twenty (57.1%) patients required gastrostomy tube placement at some point during treatment; however, 91.4% were on a completely oral diet with a mean FOSS score of 1.6 by 1year after completion of treatment. The addition of adjuvant treatment was the only factor significantly associated with poorer FOSS scores. The overall rates of short and long-term complications were 60.0% and 57.1% respectively. The most common short and long-term complications were infection (30.0%) and velopharyngeal insufficiency (25.7%) respectively. CONCLUSIONS: Traditional open surgical approaches to large tumors of the oropharynx carry higher complication rates than more recent advanced transoral approaches. However, they can still be utilized with excellent long-term functional results in certain cases of advance oropharyngeal cancers not amenable to transoral approaches. With careful reconstruction of oropharyngeal defects, over 90% of patients can achieve a completely oral diet. PMID- 29279249 TI - Reconstruction of a skull base defect after endoscopic endonasal resection of a pituitary adenoma: Sphenoid mucosal flaps. AB - This report describes a bilateral sphenoid sinus mucosal flap for the repair of a sellar floor defect and CSF leak following endoscopic endonasal skull base surgery. The key advantage of this technique is enabling the sphenoid mucosal flaps to remain vascularized, which reduces postoperative complications including CSF leakage, recurrent sinusitis, meningitis, encephalitis and pneumocephalus. The use of this technique is a viable and possibly favorable alternative to free grafts in the reconstruction of small to medium sized sellar defects with low flow or absent CSF leaks base surgery. PMID- 29279250 TI - Pain scores for intravenous cannulation and arterial blood gas test among emergency department patients. AB - OBJECTIVES: To analyse vein catheterisation and blood gas test-related pain among adult patients in the emergency department and to explore pain score-related factors. METHOD: An observational and multicentre research study was performed. Patients undergoing vein catheterisation or arterial puncture for gas test were included consecutively. After each procedure, patients scored the pain experienced using the NRS-11. RESULTS: 780 vein catheterisations and 101 blood gas tests were analysed. Venipuncture was scored with an average score of 2.8 (95% CI: 2.6-3), and arterial puncture with 3.6 (95%CI 3.1-4). Iatrogenic pain scores were associated with moderate - high difficulty procedures (P<.001); with the choice of the humeral rather than the radial artery (P=.02) in the gas test and correlated to baseline pain in venipunctures (P<.001). Pain scores related to other variables such as sex, place of origin or needle gauge did not present statistically significant differences. CONCLUSIONS: Vein catheterisation and blood gas test-related pain can be considered mild to moderately and moderately painful procedures, respectively. The pain score is associated with certain variables such as the difficulty of the procedure, the anatomic area of the puncture or baseline pain. A better understanding of painful effects related to emergency nursing procedures and the factors associated with pain self-perception could help to determine when and how to act to mitigate this undesired effect. PMID- 29279251 TI - Development of ear asymmetry in the American barn owl (Tyto furcata pratincola). AB - Owls are known for their nocturnal hunting capability. Many owl species are able to localize prey in complete darkness just by hearing. Sound localization of strictly nocturnal owls is improved by asymmetrically arranged outer ears. According to Norberg (1977), who worked with adult owls, asymmetrical ears evolved at least four times independently among owls. What is unknown so far is how the ear asymmetry develops in the embryo. Here we examine the embryonic development of ear asymmetry in the American barn owl (Tyto furcata pratincola) in the frame of the 42 stages suggested by Koppl et al. (2005). In this species, the left ear opening in the skin is located higher than its counterpart on the right. Micro-CT scans show that in an anatomically defined coordinate system, the ear openings initially appear symmetrically as does the skull as well as the eyes, the nasal openings, the stapes and the squamosum. The ear openings are initially located ventrally in the skull. Soon after their appearance, the ear openings start to move dorso-occipitally. At the developmental stages 36-39, the left ear opening moves faster than the right one. In this way, an ear asymmetry develops within a few developmental stages. The skull and the other anatomical markers remain symmetrical. Thus, these data show that the soft tissue asymmetry in the barn owl develops already before hatching. It will be interesting to compare the time course described here with the time course of development in owl species with bony ear asymmetries. PMID- 29279252 TI - Automated blood glucose control in type 1 diabetes: A review of progress and challenges. AB - Since the 2000s, research teams worldwide have been working to develop closed loop (CL) systems able to automatically control blood glucose (BG) levels in patients with type 1 diabetes. This emerging technology is known as artificial pancreas (AP), and its first commercial version just arrived in the market. The main objective of this paper is to present an extensive review of the clinical trials conducted since 2011, which tested various implementations of the AP for different durations under varying conditions. A comprehensive table that contains key information from the selected publications is provided, and the main challenges in AP development and the mitigation strategies used are discussed. The development timelines for different AP systems are also included, highlighting the main evolutions over the clinical trials for each system. PMID- 29279253 TI - The rush to risk when interrogating the relationship between methamphetamine use and sexual practice among gay and bisexual men. AB - Much research concerning drug use in the context of sexual activity among gay and bisexual men derives from public health scholarship. In this paper, we critically examine how the relationship between methamphetamine use and sexual risk practice is treated and understood in this body of research. While public health has made important contributions to establishing the link between methamphetamine use and sexual risk-taking, the precise nature of the relationship is not well defined. This creates space for ungrounded assumptions about methamphetamine use to take hold. We outline what appear to be two dominant interpretations of the methamphetamine/sexual practice relationship: the first proposes that methamphetamine has specific pharmacological properties which lead to sexual disinhibition, risky behaviour and poor health outcomes; the second proposes that methamphetamine attracts men who are already inclined toward highly sexualised interactions and risky practice, and that such men are likely to engage in these practices with or without drugs. We suggest that both interpretations are problematic in that they individualise and cast drug and sex practices as inherently risky and biopsychologically determined. We outline a more historically, socially and politically engaged way to understand methamphetamine use in the context of sexual activity by drawing on the concept of sex-based sociality and the ways in which gay and bisexual men may use methamphetamine and sex as social resources around which to build identities, establish relationships, participate in gay communities, and maximise pleasure while protecting themselves and others from harm. PMID- 29279254 TI - Factors related to immediate response to symptoms in patients with stroke or transient ischaemic attack. AB - INTRODUCTION: Despite recent advances in the management of acute stroke, fewer than 10% of patients receive reperfusion therapy. One of the main reasons for such a low rate of administration is the delay on the part of patients and their families in seeking medical attention. This study aimed to analyse this delay. METHODS: A prospective observational study was conducted on consecutive stroke or transient ischaemic attack. Data on sociodemographic and clinical parameters, decision delay, pre-hospital delay, and first medical contact were collected. Descriptive, bivariate, and multivariate logistic regression analyses were performed to determine factors associated with seeking medical attention within the first 15minutes of stroke or TIA occurrence. RESULTS: A total of 382 patients were included, 24.9% of whom had a decision delay of 15minutes or less. Stroke severity (OR 1.08; 95% CI, 1.04-1.13; P<.001), patient's son/daughter witnessing the event (OR 3.44; 95% CI, 1.88-6.27; P<.001), and insulin treatment (OR 2.89; 95% CI, 1.35-6.20; P=.006) were related to an immediate reaction. Lacunar infarcts (OR 0.41; 95% CI, 0.17-0.97; P=.042), partial anterior circulation infarcts (OR 0.43; 95% CI, 0.22-0.85; P=.015), and monosymptomatic events not involving limb paresis or aphasia (OR 0.15; 95% CI, 0.033-0.724; P=.018) favoured delays longer than 15minutes. CONCLUSIONS: Severity of the event and presence of a son/daughter are the factors most frequently associated with an immediate response to stroke. Future interventions should emphasise the need for an immediate response irrespective of severity and include a wider spectrum of symptoms. PMID- 29279255 TI - Reply to the letter to the Editor "Spinal dural arteriovenous fistulas: Early endovascular treatment or surgery?". PMID- 29279256 TI - The popularity of neurology in Spain: An analysis of specialty selection. AB - INTRODUCTION: Neurology is one of the medical specialties offered each year to residency training candidates. This project analyses the data associated with candidates choosing neurology residency programmes in recent years. METHODS: Data related to specialty selection were obtained from official reports by the Spanish Ministry of Health, Social Services, and Equality. Information was collected on several characteristics of teaching centres: availability of stroke units, endovascular intervention, national reference clinics for neurology, specific on call shifts for neurology residents, and links with medical schools or national research networks. RESULTS: The median selection list position of candidates selecting neurology training has been higher year on year; neurology was among the 4 most popular residency programmes in 2016. Potential residents were mainly female, Spanish, and had good academic results. The median number of hospitals with higher numbers of beds, endovascular intervention, stroke units, and national reference clinics for neurology is significantly lower. This is also true when centers are analysed by presence of specific on-call shifts for neurology residents and association with medical schools or national research networks. The centres selected by candidates with the highest median selection list position in 2012-2016 were the Clinico San Carlos, 12 de Octubre, and Vall d'Hebron university hospitals. CONCLUSIONS: Neurology has gradually improved in residency selection choices and is now one of the 4 most popular options. Potential residents prefer larger centres which are more demanding in terms of patient care and which perform more research activity. PMID- 29279257 TI - Epigenetic changes in headache. AB - INTRODUCTION: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target. METHODS: We performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA. RESULTS: A total of 15 English-language publications related to the above terms were obtained. CONCLUSION: There is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets. PMID- 29279258 TI - Serum periostin is not related to asthma predictive index. AB - BACKGROUND: In contrast to adult asthmatic patients, studies on the role of serum periostin levels in schoolchildren with asthma are still conflictive, and very few studies have been performed in pre-schoolers. The aim of this study was to compare serum periostin levels in recurrent wheezer pre-schoolers according to their asthma predictive index (API) condition. METHODS: We performed a case control study enrolling pre-schoolers with recurrent wheezing episodes (>3 episodes confirmed by physician) presented at one paediatric clinic in Santiago, Chile. The population was divided according to stringent API criteria into positive or negative. RESULTS: In a one-year period, 60 pre-schoolers were enrolled. After excluding 12 (due to not fulfilment of inclusion criteria or refusal of blood sample extraction), 48 remaining pre-schoolers (27 males, age range from 24 to 71 months) completed the study; 34 were API positive and 14 were API negative. There were no significant differences in demographics between groups. The level of serum periostin levels for pre-schoolers with positive API and negative API were (median 46.7 [25.5-83.1] and 67.5 [20.5-131.8], p=0.9, respectively). The area under the curve for the serum periostin levels for predict positive API was 0.5, 95% CI [0.29-0.70], p=0.9. No significant correlation between serum periostin levels and peripheral blood eosinophils was found. CONCLUSION: Serum periostin levels were no significantly different between wheezer pre-schoolers with positive and negative API. More studies are needed to confirm this finding. PMID- 29279259 TI - Change in gut microbiota for eczema: Implications for novel therapeutic strategies. AB - Eczema is one of the most common inflammatory diseases, often constituting a lifelong burden for afflicted individuals. The complex interaction of host genetic and multiple environmental factors contribute to its pathogenesis. A relationship between maladjustment of gut microbiota and eczema has been brought into the light of day in most previous studies. In eczema preclinical models, specific intestinal microbial species have been demonstrated to prohibit or dwindle immune responsiveness, indicating that these strains among commensal gut bacteria may exert either a morbific or phylactic function in eczema progression. As such, oral probiotics can serve as a medicinal approach for eczema therapy. Given that relative scientific work is still at the early stage, only limited data are available in the field. New sequencing techniques have been fortunately performed to gain access to an extended research on the relationship between gut bacterial flora and human diseases. In the current review, we identified the role of intestinal microbiota in the development of eczema and how specific bacterial strains adjust the immune responsiveness in the midst of disease progression. Probiotics as an applicable treatment for eczema were evaluated in other threads as well. PMID- 29279260 TI - Scabies, crusted (Norwegian) scabies and the diagnosis of mite sensitisation. AB - Scabies is observed with relatively high frequency in Allergy and Dermatology clinics in developing countries where poor sanitary conditions are prevalent and increasingly in some areas of the world with increased immigrant populations. Since the immunological response to scabies mites includes the production of IgE class antibodies to Sarcoptes scabiei allergens which cross-react with Dermatophagoides major allergens Der p 1 and Der p 2, positive immediate-type skin tests to house dust mite extracts should be interpreted cautiously. Additionally, scabies should be included routinely in the differential diagnosis of itchy rashes in patients living in those areas. PMID- 29279261 TI - Flagellated protozoa detected in Dermatophagoides by light microscopy. AB - House dust mites (HDM) are arthropods of medical importance due to their relationship with allergic diseases. House dust provides a detrital habitat for these organisms, in which human skin scales are a primary food source. For digestion, wall gut cells elaborate potent proteases. Nevertheless, the observation of flagellated protozoa in intestinal extracts of HDM by light microscopy might contribute to digestive processes in mites, opening a new avenue of research regarding the ecological interactions between mites and these microorganisms in the utilisation of such substrates, as well as with regard to allergic diseases. PMID- 29279262 TI - iNKT cells are increased in children with severe therapy-resistant asthma. AB - BACKGROUND: Invariant natural killer T (iNKT) cells play complex functions in the immune system, releasing both Th1 and Th2 cytokines. The role of iNKT cells in human asthma is still controversial and never described in severe therapy resistant asthma in children. The objective of this work was to analyse iNKT frequency in peripheral blood of children with severe therapy-resistant asthma (STRA), compared to children with milder asthma and healthy controls. METHODS: Children with asthma (n=136) (non-severe and STRA) from a referral centre and healthy controls (n=40) were recruited. Peripheral blood mononuclear cells were isolated, stained with anti-CD3 and anti-iNKT (Valpha24Jalpha18), and analysed through flow cytometry. Atopic status was defined by measuring specific IgE in serum. Airway inflammation was assessed by induced sputum. RESULTS: Children with asthma presented an increased frequency of CD3+iNKT+ cells (median 0.38% IQR 0.18 1.9), compared to healthy controls (median 0.26% IQR 0.10-0.43) (p=0.025). Children with STRA also showed an increased frequency of iNKT cells (1.5% IQR 1.05-2.73) compared to healthy controls and non-severe asthmatic children (0.35% IQR 0.15-1.6; p=0.002). The frequency of iNKT cells was not different between atopic and non-atopic children. In addition, iNKT cells were not associated with any inflammatory pattern of induced sputum studied. CONCLUSION: Our data suggests that iNKT cells play a role in paediatric asthma, which is also associated with the severity of disease, but independent of the atopic status. PMID- 29279263 TI - Tear osteopontin level and its relationship with local Th1/Th2/Th17/Treg cytokines in children with allergic conjunctivitis. AB - BACKGROUND: Allergic conjunctivitis (AC) is one of the most common allergic ocular diseases worldwide. Osteopontin (OPN), as a recently described Th2 inflammation related protein, may play a role in the pathogenesis of AC. The aim of this study was to identify the expression of OPN in children with AC. METHODS: Eighty AC children (seasonal and perennial AC) and twenty controls were enrolled in this study. Serum and tears of different time points (during and out of the pollen season) were collected and used for enzyme-linked immunosorbent assay (ELISA) of OPN and T-help cell related cytokines, respectively. The relationship between serum and tears OPN and Th1/2/17Treg related cytokines as well as disease severity were analysed. RESULTS: Our results showed that expression of tear OPN protein by perennial AC patients increased significantly compared with controls or seasonal AC patients out of the pollen season. Tear OPN expression was positively related to local Th2/17 cytokines and negatively related to IL-10 and TGF-beta expression. The tear OPN expression was also significantly related to disease severity. CONCLUSION: Tear OPN reflects the local clinical status of ocular allergy and might play an important pathophysiological role in local Th2/17/Treg inflammation in children with AC. PMID- 29279264 TI - Incidence of mycobacterial disorders in Indian adult male service population followed for over two decades. AB - BACKGROUND: The comprehensive epidemiology of mycobacterial disorders is scarce from our country. The incidence of Tuberculosis (TB) and Leprosy in a cohort of military personnel followed for a long duration was evaluated in this study. METHODS: The data for this descriptive epidemiologic study was derived from the electronic medical records (EMR) data of the service personnel enrolled between 1990 and 2015. They were recruited between the ages of 17 and 18 years in good health and their morbidity data was derived from the medical records. The incidence rate (IR) was calculated as per person-years (py) using appropriate statistical methods. RESULTS: The study population includes 51,217 participants (median age 33 years, range 17-54) with a mean follow up of 12.5 years. Yearly evaluation of the data gave a cumulative follow up duration of 613,925py. A total of 530 patients developed TB, giving an IR of 86.3 per 100,000 person years (95% CI 79.2-93.9). Leprosy was diagnosed in 59 cases giving an IR of 9.6 per 100,000py (95% CI 7.4-12.3). Pulmonary (71%) and pleural (24%) locations were the most common sites of the TB infection. The data about the contribution of the mycobacterial disorders towards the mortality and the subtypes of leprosy was not available in the EMR. CONCLUSION: Low IR of mycobacterial disorders was observed in this study when compared with the previous reports. Healthy lifestyle and good socioeconomic status could explain the low IR of mycobacterial disorders in the military personnel. PMID- 29279265 TI - Adolescent Anorexia: Guiding Principles and Skills for the Dietetic Support of Family-Based Treatment. PMID- 29279266 TI - Academy of Nutrition and Dietetics: Revised 2017 Scope of Practice for the Nutrition and Dietetics Technician, Registered. AB - The Academy of Nutrition and Dietetics (Academy) is the world's largest organization of food and nutrition professionals and the association that represents credentialed nutrition and dietetics practitioners-nutrition and dietetics technicians, registered (NDTRs) and registered dietitian nutritionists (RDNs). An NDTR's scope of practice in nutrition and dietetics has flexible boundaries to capture the depth and breadth of the individual's practice. The NDTR's practice expands with advances in many areas, including nutrition, food production, food safety, food systems management, health care, public health, community health, and information and communication technology. The Revised 2017 Scope of Practice for the NDTR reflects the position of the Academy on the essential role of the NDTR in the management and delivery of food and nutrition services. The scope of practice for the NDTR is composed of education and credentialing, practice resources, Academy Standards of Practice and Standards of Professional Performance, codes of ethics, accreditation standards, state and federal regulations, national guidelines, and organizational policy and procedures. The Revised 2017 Scope of Practice for the NDTR is used in conjunction with the Revised 2017 Standards of Practice in Nutrition Care and the Standards of Professional Performance for NDTRs. The Standards of Practice address activities related to direct patient and client care. The Standards of Professional Performance address behaviors related to the technical role of NDTRs. These standards reflect the minimum competent level of nutrition and dietetics practice and professional performance for NDTRs. A companion document addresses the scope of practice for the RDN. PMID- 29279267 TI - Academy of Nutrition and Dietetics: Revised 2017 Standards of Practice in Nutrition Care and Standards of Professional Performance for Nutrition and Dietetics Technicians, Registered. AB - Nutrition and dietetics technicians, registered (NDTRs) face complex situations every day. Competently addressing the unique needs of each situation and applying standards appropriately are essential to providing safe, timely patient-/client /customer-centered quality nutrition and dietetics care and services. The Academy of Nutrition and Dietetics (Academy) leads the profession by developing standards that can be used by NDTRs (who are credentialed by the Commission on Dietetic Registration) for self-evaluation to assess quality of practice and performance. The Standards of Practice reflect the NDTR's role under the supervision of registered dietitian nutritionists in nutrition screening and the Nutrition Care Process and workflow elements, which includes nutrition screening, nutrition assessment, nutrition diagnosis, nutrition intervention/plan of care, nutrition monitoring and evaluation, and discharge planning and transitions of care. The Standards of Professional Performance consist of six domains of professional performance: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Within each standard, indicators provide measurable action statements that illustrate how the standard can be applied to practice. The Academy's Revised 2017 Standards of Practice and Standards of Professional Performance for NDTRs along with the Academy/Commission on Dietetic Registration Code of Ethics, and the Scope of Practice for the NDTR provide minimum standards and tools for demonstrating competence and safe practice, and are used collectively to gauge and guide an NDTR's performance in nutrition and dietetics practice. PMID- 29279268 TI - Direct-acting antiviral therapy enhances total CD4+ and CD8+ T-cells responses, but does not alter T-cells activation among HCV mono-infected, and HCV/HIV-1 co infected patients. AB - AIM: Chronic immune activation and poor T-cell immune response are strongly associated with disease progression and pathogenesis of both hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-1 infections. Little is known about the impact of anti-HCV Interferon (IFN)-free direct-acting antiviral (DAA) therapy on the systemic T-cells activation and patterns of peripheral T-cells producing pro-inflammatory cytokines. PATIENTS AND METHODS: Forty-five subjects including 18 HCV mono-infected, 17 HCV/HIV-1 co-infected patients under antiretroviral therapy (ART), and 10 healthy controls (HCs) were recruited. Blood samples were collected at baseline (T0) and 12 weeks after the end of DAA therapy (T1). Cell phenotypes (CD3, CD4, CD8), activation markers (CD38 and HLA-DR), and frequency of IFN-gamma, interleukin (IL)-17, and IL-22 producing CD4+ and CD8+ T cells were measured by flow cytometry. Plasma levels of related cytokines were also measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Both HCV, and HCV/HIV-1 patients before and after therapy, showed significant higher percentages of any T-cell subset expressing CD38 and/or HLA-DR compared to HCs. No differences were observed in T-cells activation at T1 compared to T0 in patient groups, and when HCV patients were compared to HCV/HIV-1 group (P>0.05). After therapy, the potential of total circulating T helper (Th) and T cytotoxic (Tc) cells producing IFN-gamma, IL-17, and IL-22 were increased. Plasma level of IFN-gamma at baseline was showed difference compared to HCs, and significantly reduced after therapy (P<0.05). CONCLUSION: Total T-cells immune response enhances after therapy, however, the state of immune activation may remain elevated for a longtime after the end of treatment and contribute to post Sustained Virologic Response (SVR) consequences. PMID- 29279269 TI - Renin angiotensin-aldosterone system (RAAS) blockers usage among type II diabetes mellitus patients-A Retrospective Study. AB - AIMS: Recent data showed an alarming rise of new dialysis cases secondary to diabetic nephropathy despite the growing usage of RAAS blockers. Primary objective of this study is to explore the prevalence of RAAS blockers usage among type II diabetic patients, secondary objectives are to compare the prescribing pattern of RAAS blocker between primary and tertiary care center and to explore if the dose of RAAS blocker prescribed was at optimal dose as suggested by trials. MATERIALS AND METHODS: This is a retrospective study conducted at one public tertiary referral hospital and one public health clinic in Sungai Petani, Kedah, Malaysia. RESULTS: RAAS blockers in T2DM patients was found to be 65%. In primary care, 14.3% of the RAAS blockers prescribed was ARB. Tertiary care had higher utilization of ARB, which was 42.9%. In primary care setting, the most commonly used ACEI were perindopril (92.4%) followed by enalapril (7.6%), meanwhile perindopril was the only ACEI being prescribed in tertiary care. The most prescribed ARB was irbesartan (63.6%) and telmisartan (54.2%) respectively in primary and tertiary care. Overall, 64.9% of RAAS blockers prescribed by both levels of care were found to be achieving the target dose as recommended in landmark trials. Crude odd ratio of prescribing RAAS blocker in primary care versus tertiary care was reported as 2.70 (95% CI: 1.49 to 4.91). CONCLUSION: RAAS blockers usage among T2DM patients was higher in primary care versus tertiary care settings. Majority of the patients did not receive optimal dose of RAAS blockers. PMID- 29279270 TI - Prevalence of thyroid disorders in North Indian Type 2 diabetic subjects: A cross sectional study. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major health burden worldwide with many patients encountering thyroid dysfunction later in their life. Various studies have found that diabetes and thyroid disorders mutually influence each other and both disorders tend to coexists. However, the prevalence of thyroid dysfunction and associated clinical variables in these patients has not been investigated. OBJECTIVES: The study aimed at determining the incidence and prevalence of thyroid dysfunction in patients with T2DM in relation to age, sex, metabolic syndrome and other co-morbid conditions. RESEARCH DESIGNS & METHODS: In this cross-sectional study, 250 Type 2 DM patients were enrolled aged between 40 and 75 years. All the patients were evaluated for thyroid dysfunction by testing thyroid profile (T3, T4 and TSH. These subjects were also investigated for fasting blood sugar (FBS), post prandial glucose (PPG) glycosylated hemoglobin (HbA1c), serum cholesterol, serum triglycerides, high density lipoprotein (HDL), low density lipoprotein(LDL), very low density lipoprotein(VLDL), blood urea, serum creatinine and presence of other co-morbid conditions. The observations and interpretations were recorded and results obtained were statistically analyzed. RESULTS: A high prevalence of thyroid dysfunction (28%) was observed in type 2 diabetic patients with subclinical hypothyroidism (18.8%) as the commonest thyroid disorder. Thyroid dysfunction was more prevalent in females, with presence of dyslipidemia, retinopathy, poor glycemic state (HbA1c >=7) and longer duration of diabetes as significant contributing factors associated. CONCLUSIONS: In addition to glycemic status, screening of thyroid disorder should be routinely done in type 2 diabetic subjects along with other comorbid conditions. PMID- 29279271 TI - Challenges in diagnosing and monitoring diabetes in patients with chronic liver diseases. AB - The prevalence and mortality of diabetes mellitus and liver disease have risen in recent years. The liver plays an important role in glucose homeostasis, and various chronic liver diseases have a negative effect on glucose metabolism with the consequent emergence of diabetes. Some aspects related to chronic liver disease can affect diagnostic tools and the monitoring of diabetes and other glucose metabolism disorders, and clinicians must be aware of these limitations in their daily practice. In cirrhotic patients, fasting glucose may be normal in up until 23% of diabetes cases, and glycated hemoglobin provides falsely low results, especially in advanced cirrhosis. Similarly, the performance of alternative glucose monitoring tests, such as fructosamine, glycated albumin and 1,5-anhydroglucitol, also appears to be suboptimal in chronic liver disease. This review will examine the association between changes in glucose metabolism and various liver diseases as well as the particularities associated with the diagnosis and monitoring of diabetes in liver disease patients. Alternatives to routinely recommended tests will be discussed. PMID- 29279272 TI - The effects of folate supplementation on lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: Although several studies have assessed the effect of folate supplementation on lipid profiles among patients with metabolic diseases, findings are inconsistent. This review of randomized controlled trials (RCTs) was conducted to summarize the evidence on the effects of folate supplementation on lipid profiles among patients with metabolic diseases. METHODS: Randomized controlled trials (RCTs) published in PubMed, EMBASE, Web of Science and Cochrane Library databases up to until 20 August 2017 were searched. Two review authors independently assessed study eligibility, extracted data, and evaluated risk of bias of included studies. Heterogeneity was measured with a Q-test and with I2 statistics. Data were pooled by using the fix or random-effect model based on the heterogeneity test results and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: A total of thirteen randomized controlled trials were included. Folate supplementation did not affect systolic blood pressure (SMD -0.87; 95% CI, -1.83, 0.09) and diastolic blood pressure (SMD -0.59; 95% CI, -1.55, 0.37), and lipid profiles including triglycerides (SMD 0.10; 95% CI, -0.42, 0.63), total- (SMD 0.06; 95% CI, -0.31, 0.43), HDL- (SMD 0.04; 95% CI, -0.36, 0.44), VLDL- (SMD 0.08; 95% CI, -0.24, 0.41), and LDL cholesterol (SMD -0.14; 95% CI, -0.55, 0.28). CONCLUSIONS: Folate supplementation did not affect blood pressures and lipid profiles among patients with metabolic diseases. Additional prospective studies regarding the impact of folate supplementation on blood pressures and lipid profiles in patients with metabolic diseases are necessary. PMID- 29279273 TI - Bistachybotrysins A-C, three phenylspirodrimane dimers with cytotoxicity from Stachybotrys chartarum. AB - Bistachybotrysins A-C (1-3), three phenylspirodrimane dimers representing an unusual [6,6,7,6]-tetracyclic skeleton with a central 2,10 dioxabicyclo[4.3.1]decan-7-ol core fused with two phenyl units, were isolated from a fungal strain, Stachybotrys chartarum CGMCC 3.5365. The structures of 1-3 were elucidated through extensive spectroscopic data analysis, including Mo2(AcO)4-induced and calculated electronic circular dichroism (ECD). 1 and 2 exhibited potent cytotoxicity against four human tumor cell lines with IC50 values in the range of 2.8-7.5 MUM. Furthermore, a possible biogenesis for 1-3 is proposed. PMID- 29279274 TI - Synthesis and biological evaluation of 173-dicarboxylethyl-pyropheophorbide-a amide derivatives for photodynamic therapy. AB - Three novel 173-dicarboxylethyl-pyropheophorbide-a amide derivatives as photosensitizers for photodynamic therapy (PDT) were synthesized from pyropheophorbide-a (Ppa). Their photophysical and photochemical properties, intracellular localization, photocytotoxicity in vitro and in vivo were investigated. All target compounds exhibited low cytotoxicity in the dark and remarkable photocytotoxicity against human esophageal cancer cells. Among them, 1a showed highest singlet oxygen quantum yield. Upon light activation, 1a exhibited significant photocytotoxicity. After PDT treatment, the growth of Eca 109 tumor in nude mice was significantly inhibited. Therefore, 1a is a powerful and promising antitumor photosensitizer for PDT. PMID- 29279275 TI - A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes. AB - A series of AT2R ligands have been synthesized applying a quick, simple, and safe transesterification-type reaction whereby the sulfonyl carbamate alkyl tail of the selective AT2R antagonist C38 was varied. Furthermore, a limited number of compounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acid bioisosteres were synthesized and evaluated. By reducing the size of the alkyl chain of the sulfonyl carbamates, ligands 7a and 7b were identified with significantly improved in vitro metabolic stability in both human and mouse liver microsomes as compared to C38 while retaining the AT2R binding affinity and AT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improved stability in human microsomes as compared to C38. PMID- 29279276 TI - Acquired partial lipodystrophy and C3 glomerulopathy: Dysregulation of the complement system as a common pathogenic mechanism. AB - The activation of the alternative pathway of the complement is involved in the development of several renal diseases, such as atypical haemolytic uremic syndrome and C3 glomerulopathy. In C3 glomerulopathy, a high percentage of patients have circulating levels of the autoantibody called C3NeF, which causes systemic dysregulation of the complement system. In some cases, the presence of this antibody has been related with abnormalities of adipose tissue, causing acquired partial lipodystrophy (Barraquer-Simons syndrome). Acquired partial lipodystrophy is an extremely rare disorder affecting the distribution of subcutaneous adipose tissue and that mainly onsets during childhood. These patients, in addition to possibly presenting with all the metabolic disorders associated with the adipose tissue defect, present with C3 hypocomplementemia and C3NeF and 25% have developed C3 glomerulopathy. Although it has been known for some time how the dysregulation of the complement system affects the kidneys, it remains unknown how it exactly affects adipose tissue; nevertheless, the relationship is quite clear. In this paper, we describe the connection between the complement system with the biology of the adipose tissue and its pathogenesis reflected from acquired partial lipodystrophy. PMID- 29279277 TI - Pulmonary tumour thrombotic microangiopathy due to adenocarcinoma of the lung. A cause of pulmonary hypertension. PMID- 29279278 TI - Identification and assessment of COPD exacerbations. AB - Chronic Obstructive Pulmonary Disease (COPD) exacerbations play a central role in the disease natural history of the disease, affecting its overall severity, decreasing pulmonary function, worsening underlying co-morbidities, impairing quality of life (QoL) and leading to severe morbidity and mortality. Therefore, identification and correct assessment of COPD exacerbations is paramount, given it will strongly influence therapy success. For the identification of exacerbations, several questionnaires exist, with varying degrees of complexity. However, most questionnaires remain of limited clinical utility, and symptom scales seem to be more useful in clinical practice. In the assessment of exacerbations, the type and degree of severity should be ascertained in order to define the management setting and optimize treatment options. Still, a consensual and universal classification system to assess the severity and type of an exacerbation is lacking, and there are no established criteria for less severely ill patients not requiring hospital assessment. This might lead to under reporting of minor to moderate exacerbations, which has an impact on patients' health status. There is a clear unmet need to develop clinically useful questionnaires and a comprehensive system to evaluate the severity of exacerbations that can be used in all settings, from primary health care to general hospitals. PMID- 29279280 TI - The path towards effective antivirals against rabies. AB - Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost. Post-exposure prophylaxis (PEP) is highly effective, however in patients that present with neurological symptoms the case-fatality ratio is extremely high (>99%). During the last decades several attempts to identify potent and effective antivirals were made. Only a few of these demonstrated improvement in clinical signs in animal studies and none of the trials in humans showed significant efficacy. Here we explore novel opportunities to identify more potent anti-rabies molecules. In particular important progress has been made on antivirals against other Mononegavirales (paramyxoviruses, filoviruses) which should be an impetus to test and optimize these molecules towards anti-rabies virus therapies. Effective rabies antivirals for therapeutic use need to be molecules that can be dosed into the cerebrospinal fluid and that rapidly and potently block ongoing virus replication and as such stop the further spread of the virus. Antivirals for prophylactic use can also be envisaged and these should be able to prevent infection of peripheral nerve cells and should have the potential to replace the current anti-rabies immunoglobulins that are used in PEP. PMID- 29279279 TI - Characterization of a novel variant in siblings with Asparagine Synthetase Deficiency. AB - Asparagine Synthetase Deficiency (ASD) is a recently described inborn error of metabolism caused by bi-allelic pathogenic variants in the asparagine synthetase (ASNS) gene. ASD typically presents congenitally with microcephaly and severe, often medically refractory, epilepsy. Development is generally severely affected at birth. Tone is abnormal with axial hypotonia and progressive appendicular spasticity. Hyperekplexia has been reported. Neuroimaging typically demonstrates gyral simplification, abnormal myelination, and progressive cerebral atrophy. The present report describes two siblings from consanguineous parents with a homozygous Arg49Gln variant associated with a milder form of ASD that is characterized by later onset of symptoms. Both siblings had a period of normal development before onset of seizures, and development regression. Primary fibroblast studies of the siblings and their parents document that homozygosity for Arg49Gln blocks cell growth in the absence of extracellular asparagine. Functional studies with these cells suggest no impact of the Arg49Gln variant on basal ASNS mRNA or protein levels, nor on regulation of the gene itself. Molecular modelling of the ASNS protein structure indicates that the Arg49Gln variant lies near the substrate binding site for glutamine. Collectively, the results suggest that the Arg49Gln variant affects the enzymatic function of ASNS. The clinical, cellular, and molecular observations from these siblings expand the known phenotypic spectrum of ASD. PMID- 29279281 TI - Randomized clinical trial of a single versus a double dose of 13-valent pneumococcal conjugate vaccine in adults 55 through 74 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. AB - INTRODUCTION: In older adults, prior administration of 23-valent pneumococcal polysaccharide vaccine (PPSV23) blunts the opsonophagocytic antibody (OPA) response to subsequent administration of 13-valent pneumococcal conjugate vaccine (PCV13). To determine whether a higher dose of PCV13 could mitigate this effect in adults 55 through 74 years of age, we compared OPA responses to a double dose of PCV13 in persons previously vaccinated with PPSV23 with responses to a single dose of PCV13 in previously vaccinated persons, and with a single dose in PPSV23 naive persons. METHODS: Subjects previously vaccinated with PPSV23 were randomly assigned to receive either a single injection or two concurrent injections of 0.5 mL PCV13. Naive subjects received a single injection of 0.5 mL PCV13. Serotype specific OPA responses to 12 of the PCV13 serotypes were assessed on samples collected on Day 29 and Day 181. Comparisons of the OPA titers between study groups were based on the lower bound of the 95% confidence interval of the log geometric mean ratio to define superiority (>1) and non-inferiority (>0.5). RESULTS: At Day 29, the OPA responses to one dose in previously vaccinated (n = 284) versus one dose in naive subjects (n = 311) achieved the threshold for non inferiority for only 3 of the 12 serotypes. In previously vaccinated subjects, responses to a double dose (n = 288) versus a single dose met the threshold for superiority for 7 serotypes. The responses to a double dose in previously vaccinated subjects versus a single dose in naive subjects met the threshold for non-inferiority for 9 serotypes. CONCLUSIONS: There is a dose response to PCV13 in older adults and the higher response to a double dose in previously vaccinated adults is non-inferior to that of a single dose in naive adults for 9 of the 12 PCV13 serotypes evaluated. PMID- 29279282 TI - Parent perceptions of dentists' role in HPV vaccination. AB - INTRODUCTION: Offering HPV vaccine in settings beyond the traditional medical home holds promise for increasing the currently low levels of coverage. As adolescents frequently visit dentists, dental practices may be one such alternative vaccination setting. This study assessed parent attitudes about the roles dental providers could play in HPV prevention, including vaccine provision. METHODS: In September 2016, we conducted an online survey using a national sample (n = 1209) of U.S. parents of adolescent children aged 11-17. Adolescents' mean age was 14; 53% were male and 62% were non-Hispanic white. We identified correlates of parents' comfort with dentists as HPV vaccinators using multivariable logistic regression. RESULTS: Overall, 23% of parents reported that they would feel comfortable with their child receiving HPV vaccine from a dentist. In multivariable analyses, parents had greater odds of being comfortable if they had higher trust in their child's primary care provider (OR = 1.27, 95% CI: 0.96-1.68) and lower odds if their child was female (OR = 0.65, 95% CI: 0.50 0.86). Convenience (20%) and oral health expertise (20%) were the most commonly cited benefits of dentists administering the vaccine. Wanting their child's regular provider to administer and track vaccinations (61% and 58%, respectively), and lack of insurance coverage (30%) were the most commonly cited concerns. Parents expressed somewhat greater comfort with roles dentists might play in promoting HPV vaccination other than vaccine delivery, such as providing education. CONCLUSIONS: Parents in this sample had low comfort with dentists as HPV vaccinators. Findings from this study highlight potential concerns to be addressed before dental practices consider offering HPV vaccination in the future. Further research should assess dentists' perspectives and explore alternative roles for dental providers in HPV prevention efforts. PMID- 29279284 TI - Re-emergence of pneumococcal colonization by vaccine serotype 19F in persons aged >=5 years after 13-valent pneumococcal conjugate vaccine introduction-Alaska, 2008-2013. AB - BACKGROUND: The pneumococcal conjugate vaccine (PCV) was introduced in 2001. Widespread PCV use nearly eradicated pneumococcal colonization by vaccine serotypes. Since 2008, however, colonization by PCV-serotype 19F has increased in Alaska residents. We describe the epidemiology of re-emerging serotype 19F colonization. METHODS: We conducted annual cross-sectional colonization surveys from 2008 to 2013. We recruited children aged <5 years at 2 urban clinics and participants of all ages from Region-A (2 villages), Region-B (4 villages), and Region-C (2 villages). We interviewed participants and reviewed their medical records to obtain demographic information and determine PCV status. We obtained nasopharyngeal swab specimens from participants to identify pneumococci and to determine the pneumococcal serotype, antimicrobial resistance, and multilocus sequence type. We used the Cochran-Armitage test to assess for significant trends in colonization across time periods. RESULTS: Among participants aged <5 years, pneumococcal serotype 19F colonization remained unchanged from 2008-2009 (0.7%) to 2012-2013 (0.5%; P-value [P] = .54). Serotype 19F colonization increased from 2008-2009 to 2012-2013 among participants aged 5-11 years (0.3% to 3.2%; P < .01), participants 12-17 years (0.0% to 2.0%; P < .01), and participants aged >=18 years (0.1% to 0.5%; P < .01). During 2012-2013, 85 (93%) of 91 pneumococcal serotype 19F isolates were identified among participants from Region B; the majority of serotype 19F isolates belonged to an antimicrobial nonsusceptibility pattern corresponding to a novel multilocus sequence type 9074. CONCLUSIONS: PCV continues to protect against serotype 19F colonization in vaccinated children aged <5 years. The direct PCV impact on serotype 19F colonization in persons aged 5-11 years and indirect impact in persons aged >=12 years is waning, possibly because of a newly introduced genotype in Region-B. PMID- 29279283 TI - Evaluating the promise of recombinant transmissible vaccines. AB - Transmissible vaccines have the potential to revolutionize infectious disease control by reducing the vaccination effort required to protect a population against a disease. Recent efforts to develop transmissible vaccines focus on recombinant transmissible vaccine designs (RTVs) because they pose reduced risk if intra-host evolution causes the vaccine to revert to its vector form. However, the shared antigenicity of the vaccine and vector may confer vaccine-immunity to hosts infected with the vector, thwarting the ability of the vaccine to spread through the population. We build a mathematical model to test whether a RTV can facilitate disease management in instances where reversion is likely to introduce the vector into the population or when the vector organism is already established in the host population, and the vector and vaccine share perfect cross-immunity. Our results show that a RTV can autonomously eradicate a pathogen, or protect a population from pathogen invasion, when cross-immunity between vaccine and vector is absent. If cross-immunity between vaccine and vector exists, however, our results show that a RTV can substantially reduce the vaccination effort necessary to control or eradicate a pathogen only when continuously augmented with direct manual vaccination. These results demonstrate that estimating the extent of cross immunity between vector and vaccine is a critical step in RTV design, and that herpesvirus vectors showing facile reinfection and weak cross-immunity are promising. PMID- 29279285 TI - Ubiquitination-proteasome system: A new player in the pathogenesis of psoriasis and clinical implications. AB - Ubiquitination is an important post-translational modification that regulates a myriad of biological processes such as inflammation, immune response, cell differentiation and proliferation. During the last decade, progress in proteomics contributed to the identification of new E3 ligases and their substrates. Hence, deregulated ubiquitination events are found to be involved in several inflammatory disorders, exemplifying by systemic lupus erythematosus (SLE), type 1 diabetes, rheumatoid arthritis (RA) and psoriasis. Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and differentiation. Through regulation of key transcriptional factors or signaling members, ubiquitination is viewed as a key regulator in psoriasis. Thus, targeting ubiquitination pathway holds potential for the treatment of psoriasis. Herein, we summarize the current understanding of ubiquitination in psoriasis, and discuss the prospects for targeting ubiquitination in the treatment of psoriasis. PMID- 29279286 TI - EGFR transactivation is involved in TNF-alpha-induced expression of thymic stromal lymphopoietin in human keratinocyte cell line. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine involved in the pathology of inflammatory skin diseases, such as atopic dermatitis and psoriasis. Tumor necrosis factor (TNF)-alpha, a key cytokine in inflammatory skin diseases, is a known TSLP inducer. TNF-alpha activates NF kappaB and induces transactivation of epidermal growth factor receptor (EGFR) in epithelial cells. However, the detailed mechanism of TSLP induction by TNF-alpha has remained unclear. OBJECTIVE: We investigated the involvement of TNF-alpha induced EGFR transactivation in TSLP expression. METHODS: HaCaT cells were stimulated with TNF-alpha or EGF in the presence or absence of an EGFR kinase inhibitor or other signaling inhibitors. The expression of TSLP mRNA was analyzed by RT-PCR and the phosphorylation level of signal proteins was analyzed by western blot. TSLP promoter and NF-kappaB transcription activities were analyzed by luciferase assay. RESULTS: TNF-alpha-induced TSLP expression was inhibited by the EGFR kinase inhibitor AG1478. While TSLP expression was induced by EGF, it was inhibited by the MEK inhibitor, U0126. Inhibitors of p38 and ADAM proteases suppressed the TNF-alpha-induced TSLP expression and EGFR phosphorylation, but not the EGF-induced expression. CONCLUSION: TNF-alpha-induced EGFR transactivation results in TSLP induction through ERK activation. The activation of p38 and ADAM proteases mediates TNF-alpha-induced EGFR phosphorylation. These findings suggested that the TNF-alpha-induced EGFR transactivation pathway could be a target for the treatment of inflammatory skin diseases. PMID- 29279287 TI - Histone modifiers: Dynamic regulators of the cutaneous transcriptome. AB - By regulating the accessibility of the genome, epigenetic regulators such as histone proteins and the chromatin-modifying enzymes that act upon them control gene expression. Proper regulation of this "histone code" allows for the precise control of transcriptional networks that are essential for establishing and maintaining cell fate and identity, disruption of which may drive carcinogenesis. How these dynamic epigenetic regulators contribute to both skin homeostasis and disease is only beginning to be understood. Here we provide an update of the current understanding of histone modifiers in the skin. Indeed, as one of the most innovative and rapidly expanding areas in all of medicine, it is clear that epigenome-targeting therapies hold great promise for the treatment of dermatological diseases in the coming years. PMID- 29279288 TI - Systemic sclerosis complicated with localized scleroderma-like lesions induced by Kobner phenomenon. AB - BACKGROUND: Scleroderma is a chronic disease of unknown etiology characterized by skin fibrosis and is divided into two clinical entities: systemic sclerosis (SSc) and localized scleroderma (LSc). In general, LSc is rarely complicated with SSc, but a certain portion of SSc patients manifests bilateral symmetric LSc-like lesions on the trunk and extremities. OBJECTIVE: We investigated SSc patients with LSc-like lesions to clarify the underlying pathophysiology. METHODS: Nine SSc cases complicated with LSc-like lesions were clinically and histologically characterized. RESULTS: SSc patients with LSc-like lesions exhibited multiple progressive hyper- and/or hypo-pigmented plaques with mild sclerosis symmetrically distributed on the trunk and extremities, especially abdominal region. In histological assessment, epidermal IL-1alpha expression was elevated in both forearms and LSc-like lesions of these patients to a greater extent than in forearms of control patients (SSc patients without LSc-like lesions). Of note, the infiltration and degranulation of mast cells were evident throughout the dermis of LSc-like lesions, while detectable to a lesser extent in forearms of SSc patients with LSc-like lesions and control patients. CONCLUSION: The epidermis of SSc patients with LSc-like lesions seems to possess an inflammatory phenotype, leading to the activation of mast cells in the dermis of mechanically stressed skin. Kobner phenomenon may be involved in the induction of LSc-like lesions in a certain subset of SSc. PMID- 29279289 TI - ERBB2 mutation: A promising target in non-squamous cervical cancer. AB - OBJECTIVE: ERBB2 mutations have been found in a subset of invasive cervical cancer (ICC). Nevertheless, the prevalence, mutation spectrum, clinicopathological relevance, human papillomavirus (HPV)-genotype association and prognostic significance of ERBB2-mutated ICCs have not been well established. METHODS: In this study, ICC samples (N=1015) were assessed for mutations in ERBB2, KRAS, and PIK3CA by cDNA-based Sanger sequencing. RESULTS: Somatic ERBB2 mutations were detected in 3.15% patients. The ERBB2 mutation rate was significantly higher in adenocarcinoma (4.52%, 7/155), adenosquamous carcinoma (7.59%, 6/79) and neuroendocrine carcinoma (10.34%, 3/29) than that in squamous carcinoma (2.14%, 16/749) (P=0.004, Fisher exact test). In addition, 18.75% of the patients carrying ERBB2 mutations concomitantly harbored PIK3CA or KRAS mutations. Patients with ERBB2-mutated ICCs tended to have a worse prognosis than those with wild-type or PIK3CA-mutated ICCs but a better prognosis than those with KRAS-mutated ICCs. CONCLUSIONS: This study provided a promising rationale for the clinical investigation of tyrosine kinase inhibitors for the treatment of cervical cancer with ERBB2 mutations. Patients with non-squamous cell carcinomas have priority as candidates for ERBB2-targeted therapy. Concurrent PIK3CA/RAS mutations should be considered in the design of clinical trials. PMID- 29279290 TI - Minimizing the effects of oxygen interference on l-lactate sensors by a single amino acid mutation in Aerococcus viridansl-lactate oxidase. AB - l-lactate biosensors employing l-lactate oxidase (LOx) have been developed mainly to measure l-lactate concentration for clinical diagnostics, sports medicine, and the food industry. Some l-lactate biosensors employ artificial electron mediators, but these can negatively impact the detection of l-lactate by competing with the primary electron acceptor: molecular oxygen. In this paper, a strategic approach to engineering an AvLOx that minimizes the effects of oxygen interference on sensor strips was reported. First, we predicted an oxygen access pathway in Aerococcus viridans LOx (AvLOx) based on its crystal structure. This was subsequently blocked by a bulky amino acid substitution. The resulting Ala96Leu mutant showed a drastic reduction in oxidase activity using molecular oxygen as the electron acceptor and a small increase in dehydrogenase activity employing an artificial electron acceptor. Secondly, the Ala96Leu mutant was immobilized on a screen-printed carbon electrode using glutaraldehyde cross linking method. Amperometric analysis was performed with potassium ferricyanide as an electron mediator under argon or atmospheric conditions. Under argon condition, the response current increased linearly from 0.05 to 0.5mM l-lactate for both wild-type and Ala96Leu. However, under atmospheric conditions, the response of wild-type AvLOx electrode was suppressed by 9-12% due to oxygen interference. The Ala96Leu mutant maintained 56-69% of the response current at the same l-lactate level and minimized the relative bias error to -19% from -49% of wild-type. This study provided significant insight into the enzymatic reaction mechanism of AvLOx and presented a novel approach to minimize oxygen interference in sensor applications, which will enable accurate detection of l-lactate concentrations. PMID- 29279291 TI - Initial pathological responses of second-generation everolimus-eluting stents implantation in Japanese coronary arteries: Comparison with first-generation sirolimus-eluting stents. AB - BACKGROUND: The clinical benefit of second-generation drug-eluting stents (2nd DES) has been established, compared to first-generation drug-eluting stents (1st DES). However, pathological response after 2nd DES implantation remains unclear, particularly in the Japanese population. METHODS: Using specimens obtained by autopsy, we compared the histology between 2nd DES (41 sections) and 1st DES (38 sections) lesions within 1 year after stent implantation to evaluate early tissue reaction in Japanese patients. Stent segments were fixed with 10% buffered formalin and embedded in plastic, followed by hematoxylin-eosin and Masson's trichrome staining. Ratio of covered stent struts was calculated, and the area of fibrin deposition was morphometrically evaluated. The degree of inflammation around struts was examined semi-quantitatively (score 0-3). RESULTS: The ratio of covered struts and mean fibrin area of 2nd DES were 0.69+/-0.05 and 658.0+/ 173.4MUm2. Those of 1st DES were 0.44+/-0.12 and 3107.5+/-1405.9MUm2. In the 2nd DES, there was significantly less fibrin deposition and a higher covered struts ratio. The inflammation score was significantly lower in 2nd DESs compared to 1st DESs (1.02+/-0.16 vs. 1.19+/-0.54, p<0.05). CONCLUSIONS: Histopathological analysis showed advanced healing process in 2nd DES compared with 1st DES lesions. These results are consistent with clinical beneficial outcome of 2nd DES implantation. PMID- 29279292 TI - Metrix Matrix: A Cloud-Based System for Tracking Non-Relative Value Unit Value Added Work Metrics. AB - PURPOSE: In the era of value-based medicine, it will become increasingly important for radiologists to provide metrics that demonstrate their value beyond clinical productivity. In this article the authors describe their institution's development of an easy-to-use system for tracking value-added but non-relative value unit (RVU)-based activities. METHODS: Metrix Matrix is an efficient cloud based system for tracking value-added work. A password-protected home page contains links to web-based forms created using Google Forms, with collected data populating Google Sheets spreadsheets. Value-added work metrics selected for tracking included interdisciplinary conferences, hospital committee meetings, consulting on nonbilled outside studies, and practice-based quality improvement. Over a period of 4 months, value-added work data were collected for all clinical attending faculty members in a university-based radiology department (n = 39). Time required for data entry was analyzed for 2 faculty members over the same time period. RESULTS: Thirty-nine faculty members (equivalent to 36.4 full-time equivalents) reported a total of 1,223.5 hours of value-added work time (VAWT). A formula was used to calculate "value-added RVUs" (vRVUs) from VAWT. VAWT amounted to 5,793.6 vRVUs or 6.0% of total work performed (vRVUs plus work RVUs [wRVUs]). Were vRVUs considered equivalent to wRVUs for staffing purposes, this would require an additional 2.3 full-time equivalents, on the basis of average wRVU calculations. Mean data entry time was 56.1 seconds per day per faculty member. CONCLUSIONS: As health care reimbursement evolves with an emphasis on value-based medicine, it is imperative that radiologists demonstrate the value they add to patient care beyond wRVUs. This free and easy-to-use cloud-based system allows the efficient quantification of value-added work activities. PMID- 29279293 TI - A Structured Global Health Training Program for Radiology Residents. PMID- 29279294 TI - Overcoming Health Disparities in the United States: The Value Imperative for Healthier Populations. PMID- 29279295 TI - Financial Implications of Revised ACR Guidelines for Estimated Glomerular Filtration Rate Testing Before Contrast-Enhanced MRI. AB - PURPOSE: To quantify the financial implications of eliminating the need for renal function screening before contrast-enhanced MRI. METHODS: A HIPAA-complaint, institutional review board-exempt retrospective analysis was conducted of all MRI examinations performed at our quaternary care center over a 12-month period (41,336 examinations; 28,970 with contrast). Examination volume-related data, labor costs, and material costs were assessed and applied to a base case model. Univariate sensitivity analyses were conducted to evaluate the impact of individual components on total cost. Bivariate and multivariate sensitivity analyses were then performed. Medicare data were utilized for reimbursement and net cost analysis. RESULTS: The annual base case cost estimate for point-of-care estimated glomerular filtration rate testing before contrast-enhanced MRI was $126,058. Assuming 100% Medicare reimbursement for point-of-care testing, the net departmental cost was still $78,330. In univariate sensitivity analyses, MRI technologist time and i-Stat cartridge (Abbott Laboratories, Lake Bluff, Illinois) pricing were the biggest cost drivers for labor and materials costs, respectively. In multivariate sensitivity analyses, the lowest cost estimate was $6,845 and the highest cost estimate was $787,257. CONCLUSION: Recent changes to screening guidelines for group II gadolinium-based contrast agents by the ACR will likely have major financial implications. PMID- 29279296 TI - Mechanism, Process, and Causation in Ecological Models: A Reply to McGill and Potochnik. PMID- 29279297 TI - Working smarter not harder: Coupling implementation to de-implementation. AB - In this paper, we discuss de-implementation as an implicit part of implementation and organizational change, and consider its underlying processes of unlearning to discontinue or deviate from ineffective practice and learning to applying newer, more effective practices. We describe a typology of de-implementation that represents four types of change: partial reduction, complete reversal, substitution with related replacement and substitution with unrelated replacement of existing practice. We also explicate how learning and unlearning needed for effective change vary in these four types of de-implementation. Last, we propose coupling de-implementation and implementation efforts, which serve conceptual and logistical goals of organizational change. PMID- 29279298 TI - The relevance of history to public health. PMID- 29279299 TI - Characteristics Associated With Decreased or Increased Mortality Risk From Glycemic Therapy Among Patients With Type 2 Diabetes and High Cardiovascular Risk: Machine Learning Analysis of the ACCORD Trial. AB - OBJECTIVE: Identifying patients who may experience decreased or increased mortality risk from intensive glycemic therapy for type 2 diabetes remains an important clinical challenge. We sought to identify characteristics of patients at high cardiovascular risk with decreased or increased mortality risk from glycemic therapy for type 2 diabetes using new methods to identify complex combinations of treatment effect modifiers. RESEARCH DESIGN AND METHODS: The machine learning method of gradient forest analysis was applied to understand the variation in all-cause mortality within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 10,251), whose participants were 40-79 years old with type 2 diabetes, hemoglobin A1c (HbA1c) >=7.5% (58 mmol/mol), cardiovascular disease (CVD) or multiple CVD risk factors, and randomized to target HbA1c <6.0% (42 mmol/mol; intensive) or 7.0-7.9% (53-63 mmol/mol; standard). Covariates included demographics, BMI, hemoglobin glycosylation index (HGI; observed minus expected HbA1c derived from prerandomization fasting plasma glucose), other biomarkers, history, and medications. RESULTS: The analysis identified four groups defined by age, BMI, and HGI with varied risk for mortality under intensive glycemic therapy. The lowest risk group (HGI <0.44, BMI <30 kg/m2, age <61 years) had an absolute mortality risk decrease of 2.3% attributable to intensive therapy (95% CI 0.2 to 4.5, P = 0.038; number needed to treat: 43), whereas the highest risk group (HGI >=0.44) had an absolute mortality risk increase of 3.7% attributable to intensive therapy (95% CI 1.5 to 6.0; P < 0.001; number needed to harm: 27). CONCLUSIONS: Age, BMI, and HGI may help individualize prediction of the benefit and harm from intensive glycemic therapy. PMID- 29279300 TI - No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial. AB - OBJECTIVE: To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER) trial over a 3.5-5-year period. RESEARCH DESIGN AND METHODS: Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels, thyroid and C-cell adverse events, and neoplasms. RESULTS: At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients. CONCLUSIONS: There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C cell malignancies occurred in the liraglutide group. PMID- 29279301 TI - Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1alpha Degradation. AB - RATIONALE: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. OBJECTIVE: We have investigated the role of IPMK in regulating angiogenesis. METHODS AND RESULTS: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1alpha is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1alpha protein and thus VEGF. HIF-1alpha is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1alpha is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1alpha and pVHL. HIF-1alpha prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK deleted cells. IP5 promotes HIF-1alpha prolyl hydroxylation and thus pVHL dependent degradation of HIF-1alpha. Deletion of IPMK in mouse brain increases HIF-1alpha/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. CONCLUSIONS: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1alpha hydroxylation and thus pVHL-dependent degradation of HIF-1alpha. PMID- 29279302 TI - Genetic Evidence for Roles of Yeast Mitotic Cyclins at Single-Stranded Gaps Created by DNA Replication. AB - Paused or stalled replication forks are major threats to genome integrity; unraveling the complex pathways that contribute to fork stability and restart is crucial. Experimentally, fork stalling is induced by growing the cells in presence of hydroxyurea (HU), which depletes the pool of deoxynucleotide triphosphates (dNTPs) and slows down replication progression in yeast. Here, I report an epistasis analysis, based on sensitivity to HU, between CLB2, the principal mitotic cyclin gene in Saccharomyces cerevisiae, and genes involved in fork stability and recombination. clb2Delta cells are not sensitive to HU, but the strong synergistic effect of clb2Delta with most genes tested indicates, unexpectedly, that CLB2 has an important role in DNA replication, in the stability and restart of stalled forks, and in pathways dependent on and independent of homologous recombination. Results indicate that CLB2 functions in parallel with the SGS1 helicase and EXO1 exonuclease to allow proper Rad51 recombination, but also regulates a combined Sgs1-Exo1 activity in a pathway dependent on Mec1 and Rad53 checkpoint protein kinases. The data argue that Mec1 regulates Clb2 to prevent a deleterious Sgs1-Exo1 activity at paused or stalled forks, whereas Rad53 checkpoint activation regulates Clb2 to allow a necessary Sgs1-Exo1 activity at stalled or collapsed forks. Altogether, this study indicates that Clb2 regulates the activity of numerous nucleases at single stranded gaps created by DNA replication. A model is proposed for the function and regulation of Clb2 at stalled forks. These data provide new perspectives on the role of mitotic cyclins at the end of S phase. PMID- 29279303 TI - Fine Mapping of QUICK ROOTING 1 and 2, Quantitative Trait Loci Increasing Root Length in Rice. AB - The volume that the root system can occupy is associated with the efficiency of water and nutrient uptake from soil. Genetic improvement of root length, which is a limiting factor for root distribution, is necessary for increasing crop production. In this report, we describe identification of two quantitative trait loci (QTLs) for maximal root length, QUICK ROOTING 1 (QRO1) on chromosome 2 and QRO2 on chromosome 6, in cultivated rice (Oryza sativa L.). We measured the maximal root length in 26 lines carrying chromosome segments from the long-rooted upland rice cultivar Kinandang Patong in the genetic background of the short rooted lowland cultivar IR64. Five lines had longer roots than IR64. By rough mapping of the target regions in BC4F2 populations, we detected putative QTLs for maximal root length on chromosomes 2, 6, and 8. To fine-map these QTLs, we used BC4F3 recombinant homozygous lines. QRO1 was mapped between markers RM5651 and RM6107, which delimit a 1.7-Mb interval on chromosome 2, and QRO2 was mapped between markers RM20495 and RM3430-1, which delimit an 884-kb interval on chromosome 6. Both QTLs may be promising gene resources for improving root system architecture in rice. PMID- 29279305 TI - Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements. AB - BACKGROUND: Sensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction. METHODS: We evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively. RESULTS: There were 383 patients with Friedreich's ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123+/-0.123 per year vs 0.163+/-0.179, P<0.001; SARA index: 1.5+/-1.2 vs 1.7+/-1.7, P<0.001), indicating slower cerebellar dysfunction indexes for FRDA than for SCA. Patients with SCA2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores. CONCLUSIONS: Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02069509. PMID- 29279304 TI - The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations. AB - Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1-3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis. PMID- 29279306 TI - Structure-function insights into direct lipid transfer between membranes by Mmm1 Mdm12 of ERMES. AB - The endoplasmic reticulum (ER)-mitochondrial encounter structure (ERMES) physically links the membranes of the ER and mitochondria in yeast. Although the ER and mitochondria cooperate to synthesize glycerophospholipids, whether ERMES directly facilitates the lipid exchange between the two organelles remains controversial. Here, we compared the x-ray structures of an ERMES subunit Mdm12 from Kluyveromyces lactis with that of Mdm12 from Saccharomyces cerevisiae and found that both Mdm12 proteins possess a hydrophobic pocket for phospholipid binding. However in vitro lipid transfer assays showed that Mdm12 alone or an Mmm1 (another ERMES subunit) fusion protein exhibited only a weak lipid transfer activity between liposomes. In contrast, Mdm12 in a complex with Mmm1 mediated efficient lipid transfer between liposomes. Mutations in Mmm1 or Mdm12 impaired the lipid transfer activities of the Mdm12-Mmm1 complex and furthermore caused defective phosphatidylserine transport from the ER to mitochondrial membranes via ERMES in vitro. Therefore, the Mmm1-Mdm12 complex functions as a minimal unit that mediates lipid transfer between membranes. PMID- 29279307 TI - Intraneural Injection of ATP Stimulates Regeneration of Primary Sensory Axons in the Spinal Cord. AB - Injury to the peripheral axons of sensory neurons strongly enhances the regeneration of their central axons in the spinal cord. It remains unclear on what molecules that initiate such conditioning effect. Because ATP is released extracellularly by nerve and other tissue injury, we hypothesize that injection of ATP into a peripheral nerve might mimic the stimulatory effect of nerve injury on the regenerative state of the primary sensory neurons. We found that a single injection of 6 MUl of 150 MUm ATP into female rat sciatic nerve quadrupled the number of axons growing into a lesion epicenter in spinal cord after a concomitant dorsal column transection. A second boost ATP injection 1 week after the first one markedly reinforced the stimulatory effect of a single injection. Single ATP injection increased expression of phospho-STAT3 and GAP43, two markers of regenerative activity, in sensory neurons. Double ATP injections sustained the activation of phospho-STAT3 and GAP43, which may account for the marked axonal growth across the lesion epicenter. Similar studies performed on P2X7 or P2Y2 receptor knock-out mice indicate P2Y2 receptors are involved in the activation of STAT3 after ATP injection or conditioning lesion, whereas P2X7 receptors are not. Injection of ATP at 150 MUm caused little Wallerian degeneration and behavioral tests showed no significant long-term adverse effects on sciatic nerve functions. The results in this study reveal possible mechanisms underlying the stimulation of regenerative programs and suggest a practical strategy for stimulating axonal regeneration following spinal cord injury.SIGNIFICANCE STATEMENT Injury of peripheral axons of sensory neurons has been known to strongly enhance the regeneration of their central axons in the spinal cord. In this study, we found that injection of ATP into a peripheral nerve can mimic the effect of peripheral nerve injury and significantly increase the number of sensory axons growing across lesion epicenter in the spinal cord. ATP injection increased expression of several markers for regenerative activity in sensory neurons, including phospho STAT3 and GAP43. ATP injection did not cause significant long-term adverse effects on the functions of the injected nerve. These results may lead to clinically applicable strategies for enhancing neuronal responses that support regeneration of injured axons. PMID- 29279308 TI - Conditional Deletion of Hippocampal CA2/CA3a Oxytocin Receptors Impairs the Persistence of Long-Term Social Recognition Memory in Mice. AB - Oxytocin (OXT) receptors (OXTRs) are prominently expressed in hippocampal CA2 and CA3 pyramidal neurons, but little is known about its physiological function. As the functional necessity of hippocampal CA2 for social memory processing, we tested whether CA2 OXTRs may contribute to long-term social recognition memory (SRM) formation. Here, we found that conditional deletion of Oxtr from forebrain (Oxtr-/-) or CA2/CA3a-restricted excitatory neurons in adult male mice impaired the persistence of long-term SRM but had no effect on sociability and preference for social novelty. Conditional deletion of CA2/CA3a Oxtr showed no changes in anxiety-like behavior assessed using the open-field, elevated plus maze and novelty-suppressed feeding tests. Application of a highly selective OXTR agonist [Thr4,Gly7]-OXT to hippocampal slices resulted in an acute and lasting potentiation of excitatory synaptic responses in CA2 pyramidal neurons that relied on N-methyl-d-aspartate receptor activation and calcium/calmodulin dependent protein kinase II activity. In addition, Oxtr-/- mice displayed a defect in the induction of long-term potentiation, but not long-term depression, at the synapses between the entorhinal cortex and CA2 pyramidal neurons. Furthermore, Oxtr deletion led to a reduced complexity of basal dendritic arbors of CA2 pyramidal neurons, but caused no alteration in the density of apical dendritic spines. Considering that the methodologies we have used to delete Oxtr do not rule out targeting the neighboring CA3a region, these findings suggest that OXTR signaling in the CA2/CA3a is crucial for the persistence of long-term SRM.SIGNIFICANCE STATEMENT Oxytocin receptors (OXTRs) are abundantly expressed in hippocampal CA2 and CA3 regions, but there are little known about their physiological function. Taking advantage of the conditional Oxtr knock-out mice, the present study highlights the importance of OXTR signaling in the induction of long-term potentiation at the synapses between the entorhinal cortex and CA2 pyramidal neurons and the persistence of long-term social recognition memory. Thus, OXTRs in the CA2/CA3a may provide a new target for therapeutic approaches to the treatment of social cognition deficits, which are often observed in patients with neuropsychiatric disorders. PMID- 29279309 TI - Evidence for Long-Timescale Patterns of Synaptic Inputs in CA1 of Awake Behaving Mice. AB - Repeated sequences of neural activity are a pervasive feature of neural networks in vivo and in vitro In the hippocampus, sequential firing of many neurons over periods of 100-300 ms reoccurs during behavior and during periods of quiescence. However, it is not known whether the hippocampus produces longer sequences of activity or whether such sequences are restricted to specific network states. Furthermore, whether long repeated patterns of activity are transmitted to single cells downstream is unclear. To answer these questions, we recorded intracellularly from hippocampal CA1 of awake, behaving male mice to examine both subthreshold activity and spiking output in single neurons. In eight of nine recordings, we discovered long (900 ms) reoccurring subthreshold fluctuations or "repeats." Repeats generally were high-amplitude, nonoscillatory events reoccurring with 10 ms precision. Using statistical controls, we determined that repeats occurred more often than would be expected from unstructured network activity (e.g., by chance). Most spikes occurred during a repeat, and when a repeat contained a spike, the spike reoccurred with precision on the order of <=20 ms, showing that long repeated patterns of subthreshold activity are strongly connected to spike output. Unexpectedly, we found that repeats occurred independently of classic hippocampal network states like theta oscillations or sharp-wave ripples. Together, these results reveal surprisingly long patterns of repeated activity in the hippocampal network that occur nonstochastically, are transmitted to single downstream neurons, and strongly shape their output. This suggests that the timescale of information transmission in the hippocampal network is much longer than previously thought.SIGNIFICANCE STATEMENT We found long (>=900 ms), repeated, subthreshold patterns of activity in CA1 of awake, behaving mice. These repeated patterns ("repeats") occurred more often than expected by chance and with 10 ms precision. Most spikes occurred within repeats and reoccurred with a precision on the order of 20 ms. Surprisingly, there was no correlation between repeat occurrence and classical network states such as theta oscillations and sharp-wave ripples. These results provide strong evidence that long patterns of activity are repeated and transmitted to downstream neurons, suggesting that the hippocampus can generate longer sequences of repeated activity than previously thought. PMID- 29279310 TI - Proliferating NG2-Cell-Dependent Angiogenesis and Scar Formation Alter Axon Growth and Functional Recovery After Spinal Cord Injury in Mice. AB - Spinal cord injury (SCI) induces a centralized fibrotic scar surrounded by a reactive glial scar at the lesion site. The origin of these scars is thought to be perivascular cells entering lesions on ingrowing blood vessels and reactive astrocytes, respectively. However, two NG2-expressing cell populations, pericytes and glia, may also influence scar formation. In the periphery, new blood vessel growth requires proliferating NG2+ pericytes; if this were also true in the CNS, then the fibrotic scar would depend on dividing NG2+ pericytes. NG2+ glial cells (also called oligodendrocyte progenitors or polydendrocytes) also proliferate after SCI and accumulate in large numbers among astrocytes in the glial scar. Their effect there, if any, is unknown. We show that proliferating NG2+ pericytes and glia largely segregate into the fibrotic and glial scars, respectively; therefore, we used a thymidine kinase/ganciclovir paradigm to ablate both dividing NG2+ cell populations to determine whether either scar was altered. Results reveal that loss of proliferating NG2+ pericytes in the lesion prevented intralesion angiogenesis and completely abolished the fibrotic scar. The glial scar was also altered in the absence of acutely dividing NG2+ cells, displaying discontinuous borders and significantly reduced GFAP density. Collectively, these changes enhanced edema, prolonged hemorrhage, and impaired forelimb functional recovery. Interestingly, after halting GCV at 14 d postinjury, scar elements and vessels entered the lesions over the next 7 d, as did large numbers of axons that were not present in controls. Collectively, these data reveal that acutely dividing NG2+ pericytes and glia play fundamental roles in post-SCI tissue remodeling.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) is characterized by formation of astrocytic and fibrotic scars, both of which are necessary for lesion repair. NG2+ cells may influence both scar-forming processes. This study used a novel transgenic mouse paradigm to ablate proliferating NG2+ cells after SCI to better understand their role in repair. For the first time, our data show that dividing NG2+ pericytes are required for post-SCI angiogenesis, which in turn is needed for fibrotic scar formation. Moreover, loss of cycling NG2+ glia and pericytes caused significant multicellular tissue changes, including altered astrocyte responses and impaired functional recovery. This work reveals previously unknown ways in which proliferating NG2+ cells contribute to endogenous repair after SCI. PMID- 29279311 TI - Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease. PMID- 29279313 TI - Correlating Changes in Metabolic Status With Arterial Health: Modest Associations but Any Clinical Implications? PMID- 29279312 TI - Metabolic Predictors of Change in Vascular Function: Prospective Associations From a Community-Based Cohort. AB - Vascular function varies with age because of physiological and pathological factors. We examined relations of longitudinal change in vascular function with change in metabolic traits. Longitudinal changes in vascular function and metabolic traits were examined in 5779 participants (mean age, 49.8+/-14.5 years; 54% women) who attended sequential examinations of the Framingham Offspring, Third Generation, and Omni-1 and Omni-2 cohorts. Multivariable regression analysis related changes in vascular measures (dependent variables), including carotid-femoral pulse wave velocity (CFPWV), forward pressure wave amplitude, characteristic impedance, central pulse pressure, and mean arterial pressure (MAP), with change in body mass index, fasting total:high-density lipoprotein cholesterol ratio, serum triglycerides, and blood glucose. Analyses accounted for baseline value of each vascular and metabolic measure, MAP change, and multiple comparisons. On follow-up (mean, 5.9+/-0.6 years), aortic stiffness (CFPWV, 0.2+/ 1.6 m/s), and pressure pulsatility (forward pressure wave, 1.2+/-12.4 mm Hg; characteristic impedance, 23+/-73 dyne*sec/cm5; central pulse pressure, 2.6+/ 14.7 mm Hg; all P<0.0001) increased, whereas MAP fell (-3+/-10 mm Hg; P<0.0001). Worsening of each metabolic trait was associated with increases in CFPWV and MAP (P<0.0001 for all associations) and an increase in MAP was associated with an increase in CFPWV. Overall, worsening metabolic traits were associated with worsening aortic stiffness and MAP. Opposite net change in aortic stiffness and MAP suggests that factors other than distending pressure contributed to the observed increase in aortic stiffness. Change in metabolic traits explained a greater proportion of the change in CFPWV and MAP than baseline metabolic values. PMID- 29279314 TI - Microtubule Regulation of Kv7 Channels Orchestrates cAMP-Mediated Vasorelaxations in Rat Arterial Smooth Muscle. AB - Microtubules can regulate GPCR (G protein-coupled receptor) signaling in various cell types. In vascular smooth muscle, activation of the beta-adrenoceptor leads to production of cAMP to mediate a vasorelaxation. Little is known about the role of microtubules in smooth muscle, and given the importance of this pathway in vascular smooth muscle cells, we investigated the role of microtubule stability on beta-adrenoceptor signaling in rat renal and mesenteric arteries. In isometric tension experiments, incubation with the microtubule inhibitors colchicine and nocodazole enhanced isoprenaline-mediated relaxations of renal and mesenteric arteries that the microtubule stabilizer, paclitaxel, prevented. Sharp microelectrode experiments showed that colchicine treatment caused increased hyperpolarization of mesenteric artery segments in response to isoprenaline. Application of the Kv7 channel blocker, XE991, attenuated the effect of colchicine on isoprenaline relaxations, whereas iberiotoxin-a BKCa channel blocker-had no effect. In addition, colchicine improved the relaxations to the Kv7.2 to 7.5 activator, S-1, in both renal and mesenteric artery segments compared with dimethyl sulfoxide incubation. We determined that increased mesenteric artery myocytes treated with colchicine showed increased Kv7.4 membrane expression, but Western blot analysis showed no change in total Kv7.4 protein. This study is the first to show microtubule disruption improves the beta adrenoceptor-mediated relaxations of mesenteric and renal arteries and determine this enhancement to be because of increased membrane expression of the Kv7 voltage-gated potassium channels. PMID- 29279315 TI - Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects. AB - We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na+/24 hours, HiNa) and depletion (10 mEq Na+/24 hours+furosemide 40 mg*3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrienoic acids) were considered the total converted 14,15-urine pool. We report ultra-performance liquid chromatography/tandem mass spectrometry plasma EETs, DHETs, and their sum (plasma total pool) for the 3 regioisomers (8,9 , 11,12-, 14,15-) and their sum (08,15-). In salt-resistant subjects, urine total pool was unchanged by HiNa, decreased by LoNa, and correlated with urine sodium excretion, fractional excretion of Na+, and Na+/K+ ratio for the 3 days of the experiment combined (P<0.03). In contrast, plasma total pool increased in LoNa and did not correlate with natriuresis or Na+/K+ ratio but showed correlations between EETs, blood pressures, and catecholamines and between DHETs and aldosterone (P<0.03). Urine total pool of salt-sensitive was lower than that of salt-resistant subjects in certain phases of the experiment, lacked responses to changes in salt balance, and exhibited limited correlations with natriuresis and Na+/K+ ratio during LoNa only. Plasma total pool of salt-sensitive was lower than in salt-resistant subjects and did not correlate with blood pressures or aldosterone but did with catecholamines. We conclude that the urine total pool reflects a renal pool involved in regulation of natriuresis, whereas the plasma total pools are of systemic origin, uninvolved in Na+ excretion, perhaps contributing to regulation of vascular tone. Data suggest that abnormalities in EETs in salt-sensitive subjects participate in their renal or vascular dysfunction, which has potential therapeutic implications. PMID- 29279316 TI - Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma. AB - Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs. PMID- 29279318 TI - Exploration of a Novel Intermediate Response Endpoint in Immunotherapy Clinical Studies. AB - Purpose: Both objective response rate (ORR) and progression-free survival as defined by RECIST are weakly associated with overall survival (OS) in trials evaluating immunotherapy drug products. We proposed a novel intermediate response endpoint (IME) for evaluating immunotherapies.Experimental Design: We defined IME response as having no nontarget lesion progression, no new lesion appearance, and reaching a target lesion response determined by baseline tumor burden, tumor reduction depth, and tumor change dynamics within one year after randomization. Database used consisted of data from randomized active-controlled immunotherapy trials. Criterion for IME was developed on the basis of patient-level data from a training dataset, and further evaluated using an independent testing dataset. A patient-level responder analysis comparing OS between patients with and without an IME response was conducted using combined data. Association between trial level OS hazard ratio (HR) and IME odds ratio (OR) was analyzed using a weighted linear regression model.Results: A total of 5,806 patients from 9 randomized studies were included in the database. At patient level, patients with IME response had improved OS compared with nonresponders (HR = 0.09). At trial level, association between OS and IME was moderate (R2 = 0.68).Conclusions: The IME was moderately associated with OS, and the association appeared to be stronger than the association observed between RECIST-defined ORR and OS. However, the analyses conducted in this research are exploratory and further evaluation is needed before using this endpoint in future studies. Clin Cancer Res; 24(10); 2262-7. (c)2017 AACR. PMID- 29279317 TI - AK098656, a Novel Vascular Smooth Muscle Cell-Dominant Long Noncoding RNA, Promotes Hypertension. AB - Recent studies reported some long noncoding RNAs (lncRNAs)-mediated vascular smooth muscle cells (VSMCs) phenotypic switch, which was a common pathophysiological process of vascular diseases. However, whether human-specific expressed lncRNAs would modulate VSMCs phenotype and participate into the pathogenesis of essential hypertension remains unclear. By comparing the circulating lncRNAs expression profiles between hypertensive patients and healthy controls, we identified a lncRNA-AK098656, strongly upregulated in the plasma of hypertensive patients, and predominantly expressed in VSMCs. AK098656 promoted VSMCs synthetic phenotype evidenced by increasing VSMC proliferation and migration, elevating extracellular matrix proteins, whereas lowering contractile proteins. Furthermore, AK098656 was demonstrated to directly bind with the VSMCs specific contractile protein, myosin heavy chain-11, and an essential component of extracellular matrix, fibronectin-1, and finally lowered these protein levels through protein degradation. AK098656 was also shown to bind with 26S proteasome non-ATPase regulatory subunit 11 and facilitated myosin heavy chain-11 to interact with this protein. In vivo, AK098656 transgenic rats showed spontaneous development of hypertension, with elevated VSMCs synthetic phenotype and narrowed resistant arteries. Transgenic rats also showed slight cardiac hypertrophy without other complications, which was similar with early pathophysiological changes of hypertension. All these data indicated AK098656 as a new human VSMC dominant lncRNA, which could promote hypertension through accelerating contractile protein degradation, increasing VSMC synthetic phenotype, and finally narrowed resistance arteries. PMID- 29279319 TI - Survival of Cancer Stem-Like Cells Under Metabolic Stress via CaMK2alpha-mediated Upregulation of Sarco/Endoplasmic Reticulum Calcium ATPase Expression. AB - Purpose: Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSC) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca2+-dependent apoptosis during glucose deprivation.Experimental Design: We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin dependent protein kinase 2 alpha (CaMK2alpha) gene knockdown, and investigated the role of nuclear factor kappa B (NFkappaB) in CSCs during time-dependent Ca2+ mediated and glucose deprivation-induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-d-glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2alpha via NFkappaB activation. Combined treatment with 2-deoxy-d-glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared with that in untreated control animals or those treated with the metabolic inhibitor alone.Conclusions: The current study provides compelling evidence that CaMK2alpha acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFkappaB. The latter induces expression of SERCA, allowing survival in glucose deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment. Clin Cancer Res; 24(7); 1677-90. (c)2017 AACR. PMID- 29279320 TI - UK Role 4 military infectious diseases and tropical medicine cases in 2005-2013. AB - INTRODUCTION: Infectious diseases are a frequent cause of morbidity among British troops. The aim of this paper is to describe the spectrum of infectious diseases seen when UK service personnel are evacuated for definitive care to the Role 4 Medical Treatment Facility based at Birmingham Heartlands Hospital. METHOD: A retrospective analysis of all military patients presenting with infectious diseases and treated at Birmingham Heartlands Hospital between 14 April 2005 and 31 December 2013 was undertaken. RESULTS: During this period, 502 patients were identified. Infections originated in 49 countries, most commonly Afghanistan (46% cases), the UK (10% cases) and Belize (9% of cases). The most common presentations were dermatological conditions, gastroenterological illnesses and undifferentiated fevers. CONCLUSION: UK service personnel in significant numbers continue to suffer a wide range of infectious diseases, acquired throughout the globe, which often require specialist tertiary infection services to diagnose and manage. Future prospective data collection is recommended to identify trends, which in turn will inform military training needs and future research priorities in the Defence Medical Services (DMS) and allows development of appropriate policies and clinical guidelines for management of DMS personnel with infectious diseases. PMID- 29279321 TI - Power supplies and equipment for military field research: lessons from the British Service Dhaulagiri Research Expedition 2016. AB - INTRODUCTION: The British Service Dhaulagiri Research Expedition (BSDMRE) took place from 27 March to 31 May 2016. The expedition involved 129 personnel, with voluntary participation in nine different study protocols. Studies were conducted in three research camps established at 3600, 4600 and 5140 m and involved taking and storing blood samples, cardiac echocardiography and investigations involving a balance plate. Research in this remote environment requires careful planning in order to provide a robust and resilient power plan. In this paper we aim to report the rationale for the choices we made in terms of power supply, the equipment used and potential military applicability. METHODS: This is a descriptive account from the expedition members involved in planning and conducting the medical research. RESULTS: Power calculations were used to determine estimates of requirement prior to the expedition. The primary sources used to generate power were internal combustion engine (via petrol fuelled electric generators) and solar panels. Having been generated, power was stored using lithium-ion batteries. Special consideration was given to the storage of samples taken in the field, for which electric freezers and dry shippers were used. All equipment used functioned well during the expedition, with the challenges of altitude, temperature and transport all overcome due to extensive prior planning. CONCLUSIONS: Power was successfully generated, stored and delivered during the BSDMRE, allowing extensive medical research to be undertaken. The challenges faced and overcome are directly applicable to delivering military medical care in austere environments, and lessons learnt can help with the planning and delivery of future operations, training exercises or expeditions. PMID- 29279322 TI - Assessment of bullet effectiveness based on a human vulnerability model. AB - INTRODUCTION: Penetrating wounds from explosively propelled fragments and bullets are the most common causes of combat injury. There is a requirement to assess the potential effectiveness of bullets penetrating human tissues in order to optimise preventive measures and wound trauma management. METHODS: An advanced voxel model based on the Chinese Visible Human data was built. A digital human vulnerability model was established in combination with wound reconstruction and vulnerability assessment rules, in which wound penetration profiles were obtained by recreating the penetration of projectiles into ballistic gelatin. An effectiveness evaluation method of bullet penetration using the Abbreviated Injury Scale (AIS) was developed and solved using the Monte Carlo sampling method. RESULTS: The effectiveness of rifle bullets was demonstrated to increase with increasing velocity in the range of 300-700 m/s. When imparting the same energy, the effectiveness of the 5.56 mm bullet was higher than the 7.62 mm bullet in this model. CONCLUSIONS: The superimposition of simulant penetration profiles produced from ballistic gelatin simulant has been used to predict wound tracts in damaged tissues. The authors recognise that determining clinical effectiveness based on the AIS scores alone without verification of outcome by review of clinical hospital records means that this technique should be seen more as a manner of comparing the effectiveness of bullets than an injury prediction model. PMID- 29279324 TI - Age at Menarche, Depression, and Antisocial Behavior in Adulthood. AB - BACKGROUND: Early pubertal timing in girls is one of the best-replicated antecedents of a range of mental health problems during adolescence, but few researchers have examined the duration of these effects. METHODS: We leverage a nationally representative sample (N = 7802 women) managed prospectively from adolescence over a period of ~14 years to examine associations of age at menarche with depressive symptoms and antisocial behaviors in adulthood. RESULTS: Earlier ages at menarche were associated with higher rates of both depressive symptoms and antisocial behaviors in early-middle adulthood largely because difficulties that started in adolescence did not attenuate over time. CONCLUSIONS: These findings indicate that the emotional sequelae of puberty extend further than documented in previous research, and suggest that earlier development may place girls on a life path from which it may be difficult to deviate. The American Academy of Pediatrics already provides guidelines for identifying and working with patients with early pubertal timing. Pediatricians and adolescent health care providers should also be attuned to early maturers' elevated mental health risk and sensitive to the potential duration of changes in mental health that begin at puberty. PMID- 29279323 TI - The Hidden Genomic and Transcriptomic Plasticity of Giant Marker Chromosomes in Cancer. AB - Genome amplification in the form of rings or giant rod-shaped marker chromosomes (RGMs) is a common genetic alteration in soft tissue tumors. The mitotic stability of these structures is often rescued by perfectly functioning analphoid neocentromeres, which therefore significantly contribute to cancer progression. Here, we disentangled the genomic architecture of many neocentromeres stabilizing marker chromosomes in well-differentiated liposarcoma and lung sarcomatoid carcinoma samples. In cells carrying heavily rearranged RGMs, these structures were assembled as patchworks of multiple short amplified sequences, disclosing an extremely high level of complexity and definitely ruling out the existence of regions prone to neocentromere seeding. Moreover, by studying two well differentiated liposarcoma samples derived from the onset and the recurrence of the same tumor, we documented an expansion of the neocentromeric domain that occurred during tumor progression, which reflects a strong selective pressure acting toward the improvement of the neocentromeric functionality in cancer. In lung sarcomatoid carcinoma cells we documented, extensive "centromere sliding" phenomena giving rise to multiple, closely mapping neocentromeric epialleles on separate coexisting markers occur, likely due to the instability of neocentromeres arising in cancer cells. Finally, by investigating the transcriptional activity of neocentromeres, we came across a burst of chimeric transcripts, both by extremely complex genomic rearrangements, and cis/trans splicing events. Post-transcriptional editing events have been reported to expand and variegate the genetic repertoire of higher eukaryotes, so they might have a determining role in cancer. The increased incidence of fusion transcripts, might act as a driving force for the genomic amplification process, together with the increased transcription of oncogenes. PMID- 29279325 TI - When Age-Based Guidance Is Not Enough: The Problem of Early Puberty. PMID- 29279326 TI - Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. AB - CONTEXT: Lactobacillus reuteri DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective. OBJECTIVE: Through an individual participant data meta-analysis, we sought to definitively determine if L reuteri DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type. DATA SOURCES: We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries. STUDY SELECTION: These were double-blind randomized controlled trials (published by June 2017) of L reuteri DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days. DATA EXTRACTION: We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models. RESULTS: Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included. The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] -25.4 [95% confidence interval (CI): -47.3 to -3.5]). The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 1.7 [95% CI: 1.4 to 2.2]). Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 2.6 [95% CI: 2.0 to 3.6]) but were insignificant in formula-fed infants. LIMITATIONS: There were insufficient data to make conclusions for formula-fed infants with colic. CONCLUSIONS: L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research. PMID- 29279327 TI - Is It Time To Recommend Lactobacillus for Colic? Not Necessarily. PMID- 29279328 TI - Hydrogen sulfide inhibits NLRP3 inflammasome activation and reduces cytokine production both in vitro and in a mouse model of inflammation. AB - A variety of stimuli, including monosodium urate (MSU) crystals, activate the NLRP3 inflammasome, and this activation involves several molecular mechanisms including xanthine oxidase (XO) up-regulation and mitochondrial dysfunction. Upon oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 becomes active and cleaves the proinflammatory cytokine IL-1beta into its active secreted form. Hydrogen sulfide (H2S), a gasotransmitter mainly produced by cystathionine gamma-lyase (CSE) in macrophages, could modulate inflammation. Here, we sought to investigate the effects of exogenous and endogenous H2S on NLRP3 inflammasome activation in vitro and in vivo Primed bone marrow-derived macrophages (BMDM) isolated from wildtype (wt) or CSE-deficient mice and human macrophages (THP1 cells and primary macrophages), were stimulated with MSU crystals in the presence or absence of a H2S donor, sodium thiosulfate (STS) or GYY4137 (GYY). In murine and human macrophages in vitro, both STS and GYY inhibited MSU crystal-induced IL-1beta secretion in a dose-dependent manner. Moreover, the H2S donors inhibited MSU crystal-induced XO/caspase-1 activities, mitochondrial reactive oxygen species (ROS) generation, and ASC oligomerization. Accordingly, IL-1beta secretion and XO/caspase-1 activities were higher in CSE deficient BMDMs than in wt BMDMs. For in vivo studies, we experimentally induced peritonitis by intraperitoneal injection of MSU crystals into mice. GYY pretreatment ameliorated inflammation, evidenced by decreased IL-6/monocyte chemoattractant protein-1 (MCP-1) released into peritoneal lavages. Taken together, our results suggest that both exogenous (via H2S donors) and endogenous (via CSE) H2S production may represent approaches for managing, for example, acute gout or other inflammation conditions. PMID- 29279329 TI - Purine nucleotide metabolism regulates expression of the human immune ligand MICA. AB - Expression of the cell-surface glycoprotein MHC class I polypeptide-related sequence A (MICA) is induced in dangerous, abnormal, or "stressed" cells, including cancer cells, virus-infected cells, and rapidly proliferating cells. MICA is recognized by the activating immune cell receptor natural killer group 2D (NKG2D), providing a mechanism by which immune cells can identify and potentially eliminate pathological cells. Immune recognition through NKG2D is implicated in cancer, atherosclerosis, transplant rejection, and inflammatory diseases, such as rheumatoid arthritis. Despite the wide range of potential therapeutic applications of MICA manipulation, the factors that control MICA expression are unclear. Here we use metabolic interventions and metabolomic analyses to show that the transition from quiescent cellular metabolism to a "Warburg" or biosynthetic metabolic state induces MICA expression. Specifically, we show that glucose transport into the cell and active glycolytic metabolism are necessary to up-regulate MICA expression. Active purine synthesis is necessary to support this effect of glucose, and increases in purine nucleotide levels are sufficient to induce MICA expression. Metabolic induction of MICA expression directly influences NKG2D-dependent cytotoxicity by immune cells. These findings support a model of MICA regulation whereby the purine metabolic activity of individual cells is reflected by cell-surface MICA expression and is the subject of surveillance by NKG2D receptor-expressing immune cells. PMID- 29279330 TI - MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2. AB - Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T cell positioning, and limits the spread of inflammation in vivo Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T-cell-driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T-cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3' UTR and reduce expression of ACKR2 transcripts and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further down-regulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 down regulation and concurrent miR-146b up-regulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via down-regulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis. PMID- 29279331 TI - Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). AB - Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PER, ARNT, SIM (PAS) family transcription factor that responds to diverse environmental and cellular ligands. The activity of kynurenine is increased 100 1000-fold by incubation or long-term storage and relies on the hydrophobic ligand binding pocket of AHR, with identical structural signatures for AHR induction before and after activation. We purified trace-active derivatives of kynurenine and identified two novel, closely related condensation products, named trace extended aromatic condensation products (TEACOPs), which are active at low picomolar levels. The synthesized compound for one of the predicted structures matched the purified compound in both chemical structure and AHR pharmacology. Our study provides evidence that kynurenine acts as an AHR pro-ligand, which requires novel chemical conversions to act as a receptor agonist. PMID- 29279333 TI - Circulation Editors and Editorial Board. PMID- 29279334 TI - It's My Heart: Why Not My Data? PMID- 29279332 TI - Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib resistant NF-kappaB activity and increases drug resistance in multiple myeloma. AB - Nuclear factor-kappaB (NF-kappaB) is a family of transcription factors that play a key role in cell survival and proliferation in many hematological malignancies, including multiple myeloma (MM). Bortezomib, a proteasome inhibitor used in the management of MM, can inhibit both canonical and noncanonical activation of NF kappaB in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-kappaB activity. Here, we report that hyaluronan and proteoglycan link protein 1 (HAPLN1) is produced in bone marrow stromal cells from MM patients, is detected in patients' bone marrow plasma, and can activate an atypical bortezomib-resistant NF-kappaB pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-kappaB (IkappaBalpha), despite efficient bortezomib-mediated inhibition of proteasome activity. Moreover, HAPLN1 can also confer bortezomib-resistant survival of MM cells. We propose that HAPLN1 is a novel pathogenic factor in MM that induces an atypical NF-kappaB activation and thereby promotes bortezomib resistance in MM cells. PMID- 29279335 TI - Disrupting the Approach to Sudden Cardiac Death: From Vulnerable Ejection Fraction to Vulnerable Patient. PMID- 29279337 TI - The Truth Is in the Details: The Case for Not Missing the Trees for the Forest. PMID- 29279336 TI - The Future of Low-Density Lipoprotein Cholesterol in an Era of Nonfasting Lipid Testing and Potent Low-Density Lipoprotein Lowering. PMID- 29279338 TI - Rapid Response Teams in Pediatric Patients: Well Intentioned, but Do They Really Help? PMID- 29279339 TI - Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review. AB - Heart transplantation has become a standard therapy option for advanced heart failure. The translation of heart transplantation from innovative experiments to long-term clinical success has married prescient insights with discipline and organization in the domains of surgical techniques, organ preservation, immunosuppression, organ donation and transplantation logistics, infection control, and long-term graft surveillance. This review explores the key milestones of the past 50 years of heart transplantation and discusses current challenges and promising innovations on the clinical horizon. PMID- 29279340 TI - Effect of Basal Insulin Glargine on First and Recurrent Episodes of Heart Failure Hospitalization: The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention). PMID- 29279341 TI - Extended-Duration Betrixaban Reduces the Risk of Rehospitalization Associated With Venous Thromboembolism Among Acutely Ill Hospitalized Medical Patients: Findings From the APEX Trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial). PMID- 29279342 TI - Letter by Ye et al Regarding Article, "Association Between Fetal Congenital Heart Defects and Maternal Risk of Hypertensive Disorders of Pregnancy in the Same Pregnancy and Across Pregnancies". PMID- 29279343 TI - Response by Boyd et al to Letter Regarding Article, "Association Between Fetal Congenital Heart Defects and Maternal Risk of Hypertensive Disorders of Pregnancy in the Same Pregnancy and Across Pregnancies". PMID- 29279344 TI - Letter by Locorotondo et al Regarding Article, "Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients with Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction". PMID- 29279345 TI - Response by Halliday et al to Letter Regarding Article, "Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients with Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction". PMID- 29279346 TI - Correction to: 2017 American Heart Association Focused Update on Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 29279347 TI - Interactions: understanding people and process in prescribing in primary care. PMID- 29279349 TI - The Brief Case: Disseminated Mycobacterium haemophilum Infection in a Kidney Transplant Recipient. PMID- 29279350 TI - Closing the Brief Case: Disseminated Mycobacterium haemophilum Infection in a Kidney Transplant Recipient. PMID- 29279351 TI - Photo Quiz: Fever in an 80-Year-Old Male Carrying Biologic Aortic Prosthesis. PMID- 29279348 TI - International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function. AB - Chemerin, a chemoattractant protein and adipokine, has been identified as the endogenous ligand for a G protein-coupled receptor encoded by the gene CMKLR1 (also known as ChemR23), and as a consequence the receptor protein was renamed the chemerin receptor in 2013. Since then, chemerin has been identified as the endogenous ligand for a second G protein-coupled receptor, encoded by the gene GPR1 Therefore, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name of the receptor protein for chemokine-like receptor 1 (CMKLR1) is chemerin receptor 1, and G protein-coupled receptor 1 is chemerin receptor 2 to follow the convention of naming the receptor protein after the endogenous ligand. Chemerin receptor 1 and chemerin receptor 2 can be abbreviated to Chemerin1 and Chemerin2, respectively. Chemerin requires C-terminal processing for activity, and human chemerin21-157 is reported to be the most active form, with peptide fragments derived from the C terminus biologically active at both receptors. Small-molecule antagonist, CCX832, selectively blocks CMKLR1, and resolvin E1 activation of CMKLR1 is discussed. Activation of both receptors by chemerin is via coupling to Gi/o, causing inhibition of adenylyl cyclase and increased Ca2+ flux. Receptors and ligand are widely expressed in humans, rats, and mice, and both receptors share ~80% identity across these species. CMKLR1 knockout mice highlight the role of this receptor in inflammation and obesity, and similarly, GPR1 knockout mice exhibit glucose intolerance. In addition, the chemerin receptors have been implicated in cardiovascular disease, cancer, steroidogenesis, human immunodeficiency virus replication, and neurogenerative disease. PMID- 29279352 TI - Answer to January 2018 Photo Quiz. PMID- 29279354 TI - Germinal Centers Determine the Prognostic Relevance of Tertiary Lymphoid Structures and Are Impaired by Corticosteroids in Lung Squamous Cell Carcinoma. AB - In solid tumors, the presence of lymph node-like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13+ perivascular and CXCL12+LTB+ and PD-L1+ epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response-related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naive LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment.Significance: Corticosteroid treatment during chemotherapy negatively affects the development of tertiary lymphoid structures and abrogates their prognostic value in patients with lung cancer. Cancer Res; 78(5); 1308-20. (c)2018 AACR. PMID- 29279353 TI - Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia. AB - Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality. Although the etiology is unknown, PE is thought to be caused by defective implantation and decidualization in pregnancy. Pregnant blood pressure high (BPH)/5 mice spontaneously develop placentopathies and maternal features of human PE. We hypothesized that BPH/5 implantation sites have transcriptomic alterations. Next-generation RNA sequencing of implantation sites at peak decidualization, embryonic day (E)7.5, revealed complement gene up-regulation in BPH/5 vs. controls. In BPH/5, expression of complement factor 3 was increased around the decidual vasculature of E7.5 implantation sites and in the trophoblast giant cell layer of E10.5 placentae. Altered expression of VEGF pathway genes in E5.5 BPH/5 implantation sites preceded complement dysregulation, which correlated with abnormal vasculature and increased placental growth factor mRNA and VEGF164 expression at E7.5. By E10.5, proangiogenic genes were down-regulated, whereas antiangiogenic sFlt-1 was up-regulated in BPH/5 placentae. We found that early local misexpression of VEGF genes and abnormal decidual vasculature preceded sFlt-1 overexpression and increased complement deposition in BPH/5 placentae. Our findings suggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant trophoblast invasion and poor placentation that underlie PE.-Sones, J. L., Merriam, A. A., Seffens, A., Brown-Grant, D.-A., Butler, S. D., Zhao, A. M., Xu, X., Shawber, C. J., Grenier, J. K., Douglas, N. C. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia. PMID- 29279355 TI - GADD45beta Loss Ablates Innate Immunosuppression in Cancer. AB - T-cell exclusion from the tumor microenvironment (TME) is a major barrier to overcoming immune escape. Here, we identify a myeloid-intrinsic mechanism governed by the NF-kappaB effector molecule GADD45beta that restricts tumor associated inflammation and T-cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of proinflammatory tumor-associated macrophages (TAM) and intratumoral immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Furthermore, they suggest a therapeutic target in GADD45beta for reprogramming TAM to overcome immunosuppression and T cell exclusion from the TME.Significance: These findings define a myeloid-based immune checkpoint that restricts T-cell trafficking into tumors, with potentially important therapeutic implications to generally improve the efficacy of cancer immunotherapy. Cancer Res; 78(5); 1275-92. (c)2017 AACR. PMID- 29279356 TI - Adaptive and Reversible Resistance to Kras Inhibition in Pancreatic Cancer Cells. AB - Activating mutations in KRAS are the hallmark genetic alterations in pancreatic ductal adenocarcinoma (PDAC) and the key drivers of its initiation and progression. Longstanding efforts to develop novel KRAS inhibitors have been based on the assumption that PDAC cells are addicted to activated KRAS, but this assumption remains controversial. In this study, we analyzed the requirement of endogenous Kras to maintain survival of murine PDAC cells, using an inducible shRNA-based system that enables temporal control of Kras expression. We found that the majority of murine PDAC cells analyzed tolerated acute and sustained Kras silencing by adapting to a reversible cell state characterized by differences in cell morphology, proliferative kinetics, and tumor-initiating capacity. While we observed no significant mutational or transcriptional changes in the Kras-inhibited state, global phosphoproteomic profiling revealed significant alterations in cell signaling, including increased phosphorylation of focal adhesion pathway components. Accordingly, Kras-inhibited cells displayed prominent focal adhesion plaque structures, enhanced adherence properties, and increased dependency on adhesion for viability in vitro Overall, our results call into question the degree to which PDAC cells are addicted to activated KRAS, by illustrating adaptive nongenetic and nontranscriptional mechanisms of resistance to Kras blockade. However, by identifying these mechanisms, our work also provides mechanistic directions to develop combination strategies that can help enforce the efficacy of KRAS inhibitors.Significance: These results call into question the degree to which pancreatic cancers are addicted to KRAS by illustrating adaptive nongenetic and nontranscriptional mechanisms of resistance to Kras blockade, with implications for the development of KRAS inhibitors for PDAC treatment. Cancer Res; 78(4); 985-1002. (c)2017 AACR. PMID- 29279357 TI - Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. AB - The primary immunodeficiencies (PIDs), rare inherited diseases characterized by severe dysfunction of immunity, have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes. Twenty-nine consecutive adult patients, with a mean age at transplant of 24 years (range, 17-50 years), underwent Allo HSCT. Reduced-intensity conditioning (RIC) included fludarabine (Flu)/melphalan/alemtuzumab (n = 20), Flu/busulfan (Bu)/alemtuzumab (n = 8), and Flu/Bu/antithymocyte globulin (n = 1). Stem cell donors were matched unrelated donors or mismatched unrelated donors (n = 18) and matched related donors (n = 11). Overall survival (OS), event-free survival, transplant-related mortality (TRM), acute and chronic graft-versus-host disease incidence and severity, time to engraftment, lineage-specific chimerism, immune reconstitution, and discontinuation of immunoglobulin replacement therapy were recorded. OS at 3 years for the whole cohort was 85.2%. The rarer PID patients without chronic granulomatous disease (CGD) achieved an OS at 3 years of 88.9% (n = 18), compared with 81.8% for CGD patients (n = 11). TRM was low with only 4 deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients, either stable mixed chimerism or full donor chimerism were observed. At last follow-up, 87% of the surviving patients had no evidence of persistent or recurrent infections. Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available. PMID- 29279358 TI - Physical activity for the ageing athlete: the importance of maintaining musculoskeletal health. PMID- 29279359 TI - Infographic: 7 tips for developing and maintaining a high performance sports medicine team. PMID- 29279360 TI - Iodine intake from supplements and diet during pregnancy and child cognitive and motor development: the INMA Mother and Child Cohort Study. AB - BACKGROUND: The effect of mild-to-moderate maternal iodine deficiency on the neuropsychological development of their offspring is uncertain. We aimed to assess the association between iodine status during pregnancy and the cognitive and motor development of children at 4-5 years. METHODS: We conducted a prospective cohort study in four Spanish regions with recruitment of pregnant women between 2003 and 2008 and follow-up of their children up to 4-5 years (mean (SD)=4.8 (0.6)). Cognitive and motor function was assessed in 1803 children using the McCarthy Scales of Children's Abilities. Dietary iodine and supplementation were measured through questionnaires twice during pregnancy. Urinary iodine concentration (UIC) was measured in spot samples. The residuals of a regression of UIC against creatinine were used to define a variable corrected for creatinine (UIC~Cr). RESULTS: Neither iodine supplements nor iodised salt consumption or maternal UIC were associated with cognitive or motor function. After adjusting for creatinine, children of women with UIC~Cr <100 ug/L had 3.93 (95% CI -6.18 to -1.69) general cognitive scores lower than the reference (150-249 ug/L). Dietary iodine was inversely associated with motor scores and milk but not other dairy products or seafood consumption accounted for this association (beta: -1.36; 95% CI -2.12 to -0.61; per one daily milk serving). CONCLUSIONS: We found an association between low maternal urinary iodine and lower cognitive scores in childhood, although only when corrected for creatinine, adding to the evidence that iodine deficiency may have potential harmful effects on neurodevelopment. Iodine supplementation does not appear to improve child's neurodevelopment at 4-5 years. PMID- 29279361 TI - Cystic Fibrosis 2017-The Year in Review. AB - It is always an exciting challenge to write a Year in Review artcicle identifying the best publications in the preceding year; in this case from October 2016 until the AARC meeting in October 2017. This is particularly true for cystic fibrosis (CF), where there has been an explosion of new data, new medications, and new understanding of the pathophysiology of the disease. PubMed lists more than 2,500 papers published during those 12 months, many of them outstanding. I am indebted to many colleagues and friends who are leaders in the CF community, active readers of the pediatric pulmonary listserv, and scientists and clinicians engaged in the care of CF, for offering their suggestions regarding which articles should be included in this review. I believe that you will enjoy reading this curated selection of manuscripts that I have tried to organize by theme. PMID- 29279362 TI - High-Frequency Oscillatory Ventilation Use and Severe Pediatric ARDS in the Pediatric Hematopoietic Cell Transplant Recipient. AB - INTRODUCTION: The effectiveness of high-frequency oscillatory ventilation (HFOV) in the pediatric hematopoietic cell transplant patient has not been established. We sought to identify current practice patterns of HFOV, investigate parameters during HFOV and their association with mortality, and compare the use of HFOV to conventional mechanical ventilation in severe pediatric ARDS. METHODS: This is a retrospective analysis of a multi-center database of pediatric and young adult allogeneic hematopoietic cell transplant subjects requiring invasive mechanical ventilation for critical illness from 2009 through 2014. Twelve United States pediatric centers contributed data. Continuous variables were compared using a Wilcoxon rank-sum test or a Kruskal-Wallis analysis. For categorical variables, univariate analysis with logistic regression was performed. RESULTS: The database contains 222 patients, of which 85 subjects were managed with HFOV. Of this HFOV cohort, the overall pediatric ICU survival was 23.5% (n = 20). HFOV survivors were transitioned to HFOV at a lower oxygenation index than nonsurvivors (25.6, interquartile range 21.1-36.8, vs 37.2, interquartile range 26.5-52.2, P = .046). Survivors were transitioned to HFOV earlier in the course of mechanical ventilation, (day 0 vs day 2, P = .002). No subject survived who was transitioned to HFOV after 1 week of invasive mechanical ventilation. We compared subjects with severe pediatric ARDS treated only with conventional mechanical ventilation versus early HFOV (within 2 d of invasive mechanical ventilation) versus late HFOV. There was a trend toward difference in survival (conventional mechanical ventilation 24%, early HFOV 30%, and late HFOV 9%, P = .08). CONCLUSIONS: In this large database of pediatric allogeneic hematopoietic cell transplant subjects who had acute respiratory failure requiring invasive mechanical ventilation for critical illness with severe pediatric ARDS, early use of HFOV was associated with improved survival compared to late implementation of HFOV, and the subjects had outcomes similar to those treated only with conventional mechanical ventilation. PMID- 29279363 TI - Lack of Benefit of Heliox During Mechanical Ventilation of Subjects With Severe Air-Flow Obstruction. AB - BACKGROUND: The value of heliox (helium-oxygen mixture) for patients with severe air-flow obstruction is uncertain. The purpose of this study was to determine whether heliox could reduce the degree of hyperinflation and hypercapnia in mechanically ventilated patients with severe air-flow obstruction. METHODS: This was a single-center, prospective observational study conducted in a medical ICU of an academic medical center. We assessed the impact of heliox (65-70% helium, 30-35% oxygen) on airway pressures and arterial blood gases of 13 subjects undergoing mechanical ventilation for severe asthma (n = 8) or exacerbation of COPD (n = 5). RESULTS: As compared with ventilation with air-O2, heliox resulted in a reduction in peak airway pressure (54.1 +/- 12.6 cm H2O vs 47.9 +/- 10.8 cm H2O, P < .001) and PaCO2 (64.3 +/- 14.9 mm Hg vs 62.3 + 15.1 mm Hg, P = .01). In contrast, there was no change in plateau pressure (25.3 +/- 5.5 cm H2O vs 25.8 +/ 5.6 cm H2O, P = .14) or total PEEP (13.4 +/- 3.8 cm H2O vs 13.3 +/- 4.1 cm H2O, P = .79) in response to heliox. CONCLUSIONS: In mechanically ventilated subjects with severe air-flow obstruction, administration of heliox had no effect on indices of dynamic hyperinflation (plateau pressure and total PEEP) and resulted in only a small reduction in PaCO2 . PMID- 29279364 TI - Heart Rate and Oxygen Saturation Change Patterns During 6-min Walk Test in Subjects With Chronic Thromboembolic Pulmonary Hypertension. AB - BACKGROUND: The 6-min walk test (6MWT) is commonly performed to assess functional status in patients with chronic thromboembolic pulmonary hypertension. However, changes in heart rate and oxygen saturation (SpO2 ) patterns during 6MWT in patients with chronic thromboembolic pulmonary hypertension remain unclear. METHODS: Thirty-one subjects with chronic thromboembolic pulmonary hypertension were retrospectively evaluated to examine the relationships between the change in heart rate (Deltaheart rate), heart rate acceleration time, slope of heart rate acceleration, heart rate recovery during the first minute after 6MWT (HRR1), change in SpO2 (DeltaSpO2 ), SpO2 reduction time, and SpO2 recovery time during 6MWT, and the severity of pulmonary hemodynamics assessed by right heart catheterization and echocardiography. RESULTS: Subjects with severe chronic thromboembolic pulmonary hypertension had significantly longer heart rate acceleration time (144.9 +/- 63.9 s vs 96.0 +/- 42.5 s, P = .033), lower Deltaheart rate (47.4 +/- 16.9 vs 61.8 +/- 13.6 beats, P = .02), and lower HRR1 (13.3 +/- 9.0 beats vs 27.1 +/- 9.2 beats, P < .001) compared to subjects with mild chronic thromboembolic pulmonary hypertension. Subjects with severe chronic thromboembolic pulmonary hypertension also had significantly longer SpO2 reduction time (178.3 +/- 70.3 s vs 134.3 +/- 58.4 s, P = .03) and SpO2 recovery time (107.6 +/- 35.3 s vs 69.8 +/- 32.7 s, P = .004) than did subjects with mild chronic thromboembolic pulmonary hypertension. Multivariate linear regression analysis showed only mean pulmonary arterial pressure independently was associated with heart rate acceleration time and slope of heart rate acceleration. CONCLUSIONS: Heart rate and SpO2 change patterns during 6MWT are predominantly associated with pulmonary hemodynamics in subjects with chronic thromboembolic pulmonary hypertension. Evaluating heart rate and SpO2 change patterns during 6MWT may serve as a safe and convenient way to follow the change in pulmonary hemodynamics. PMID- 29279365 TI - Clinical Effectiveness of Incentive Spirometry for the Prevention of Postoperative Pulmonary Complications. AB - Incentive spirometry (IS) is commonly prescribed to reduce pulmonary complications, despite limited evidence to support its benefits and a lack of consensus on optimal protocols for its use. Although numerous studies and meta analyses have examined the effects of IS on patient outcomes, there is no clear evidence establishing its benefit to prevent postoperative pulmonary complications. Clinical practice guidelines advise against the routine use of IS in postoperative care. Until evidence of benefit from well-designed clinical trials becomes available, the routine use of IS in postoperative care is not supported by high levels of evidence. PMID- 29279366 TI - Evaluation of Safety and Cost of an Open-Design Oxygen Mask in a Large Community Hospital. AB - BACKGROUND: In our large community hospital, we observed that traditional oxygen masks were sometimes set at an inappropriately low flow. We hoped to eliminate this safety concern through adoption of an open-design oxygen mask. We also hoped that more immediate flow changes would lead to a decrease in medical gas consumption. Finally, by standardizing to one mask, goals were to reduce the cost of oxygen delivery. METHODS: We conducted a retrospective analysis, 12 months before and 12 months after implementation of the open-design oxygen mask. Unusual occurrence reports related to supplemental oxygen delivery were reviewed. Oxygen device use and bulk oxygen consumption were recorded. The total number of patient days was obtained from the electronic medical record. RESULTS: There were no unusual occurrence reports or concerns involving an oxygen device in those areas that converted to the open-design oxygen mask. In fiscal year 2014, bulk oxygen use was 13,036,686 cubic feet, and there were 74,734 patient days. In fiscal year 2016, bulk oxygen use was 12,072,610 cubic feet and there were 99,428 patient days. The reduction in oxygen consumption was $3,670 despite the increase in patient days. In fiscal year 2014, 3,848 oxygen devices were used for a cost of $3,411, and in fiscal year 2016, 5,512 devices were used for a cost of $12,963. The net savings from open-design oxygen mask conversion was $23,487 annual and corrected for increased patient population. Oxygen consumption and supply cost per patient day resulted in $1.19 per patient day pre-implementation and $0.95 after implementation of the open-design oxygen mask (P = .003). CONCLUSIONS: The open-design oxygen mask may be a safe and less costly alternative to traditional oxygen delivery devices. PMID- 29279367 TI - Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. AB - Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases. PMID- 29279368 TI - From in silico hit to long-acting late-stage preclinical candidate to combat HIV 1 infection. AB - The HIV-1 pandemic affecting over 37 million people worldwide continues, with nearly one-half of the infected population on highly active antiretroviral therapy (HAART). Major therapeutic challenges remain because of the emergence of drug-resistant HIV-1 strains, limitations because of safety and toxicity with current HIV-1 drugs, and patient compliance for lifelong, daily treatment regimens. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral polymerase have been a key component of the current HIV-1 combination drug regimens; however, these issues hamper them. Thus, the development of novel more effective NNRTIs as anti-HIV-1 agents with fewer long-term liabilities, efficacy on new drug-resistant HIV-1 strains, and less frequent dosing is crucial. Using a computational and structure-based design strategy to guide lead optimization, a 5 uM virtual screening hit was transformed to a series of very potent nanomolar to picomolar catechol diethers. One representative, compound I, was shown to have nanomolar activity in HIV-1-infected T cells, potency on clinically relevant HIV 1 drug-resistant strains, lack of cytotoxicity and off-target effects, and excellent in vivo pharmacokinetic behavior. In this report, we show the feasibility of compound I as a late-stage preclinical candidate by establishing synergistic antiviral activity with existing HIV-1 drugs and clinical candidates and efficacy in HIV-1-infected humanized [human peripheral blood lymphocyte (Hu PBL)] mice by completely suppressing viral loads and preventing human CD4+ T-cell loss. Moreover, a long-acting nanoformulation of compound I [compound I nanoparticle (compound I-NP)] in poly(lactide-coglycolide) (PLGA) was developed that shows sustained maintenance of plasma drug concentrations and drug efficacy for almost 3 weeks after a single dose. PMID- 29279369 TI - Causes and consequences of decreasing atmospheric organic aerosol in the United States. AB - Exposure to atmospheric particulate matter (PM) exacerbates respiratory and cardiovascular conditions and is a leading source of premature mortality globally. Organic aerosol contributes a significant fraction of PM in the United States. Here, using surface observations between 1990 and 2012, we show that organic carbon has declined dramatically across the entire United States by 25 50%; accounting for more than 30% of the US-wide decline in PM. The decline is in contrast with the increasing organic aerosol due to wildfires and no clear trend in biogenic emissions. By developing a carbonaceous emissions database for the United States, we show that at least two-thirds of the decline in organic aerosol can be explained by changes in anthropogenic emissions, primarily from vehicle emissions and residential fuel burning. We estimate that the decrease in anthropogenic organic aerosol is responsible for averting 180,000 (117,000 389,000) premature deaths between 1990 and 2012. The unexpected decrease in organic aerosol, likely a consequence of the implementation of Clean Air Act Amendments, results in 84,000 (30,000-164,000) more lives saved than anticipated by the EPA between 2000 and 2010. PMID- 29279370 TI - Single-molecule FRET studies on the cotranscriptional folding of a thiamine pyrophosphate riboswitch. AB - Because RNAs fold as they are being synthesized, their transcription rate can affect their folding. Here, we report the results of single-molecule fluorescence studies that characterize the ligand-dependent cotranscriptional folding of the Escherichia coli thiM riboswitch that regulates translation. We found that the riboswitch aptamer folds into the "off" conformation independent of its ligand, but switches to the "on" conformation during transcriptional pausing near the translational start codon. Ligand binding maintains the riboswitch in the off conformation during transcriptional pauses. We expect our assay will permit the controlled study of the two main physical mechanisms that regulate cotranscriptional folding: transcriptional pausing and transcriptional speed. PMID- 29279371 TI - Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia. AB - Ammonia is a potent neurotoxin that is detoxified mainly by the urea cycle in the liver. Hyperammonemia is a common complication of a wide variety of both inherited and acquired liver diseases. If not treated early and thoroughly, it results in encephalopathy and death. Here, we found that hepatic autophagy is critically involved in systemic ammonia homeostasis by providing key urea-cycle intermediates and ATP. Hepatic autophagy is triggered in vivo by hyperammonemia through an alpha-ketoglutarate-dependent inhibition of the mammalian target of rapamycin complex 1, and deficiency of autophagy impairs ammonia detoxification. In contrast, autophagy enhancement by means of hepatic gene transfer of the master regulator of autophagy transcription factor EB or treatments with the autophagy enhancers rapamycin and Tat-Beclin-1 increased ureagenesis and protected against hyperammonemia in a variety of acute and chronic hyperammonemia animal models, including acute liver failure and ornithine transcarbamylase deficiency, the most frequent urea-cycle disorder. In conclusion, hepatic autophagy is an important mechanism for ammonia detoxification because of its support of urea synthesis, and its enhancement has potential for therapy of both primary and secondary causes of hyperammonemia. PMID- 29279372 TI - Body weight homeostat that regulates fat mass independently of leptin in rats and mice. AB - Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass. PMID- 29279373 TI - Low-lying excited states in crystalline perylene. AB - Organic materials are promising candidates for advanced optoelectronics and are used in light-emitting diodes and photovoltaics. However, the underlying mechanisms allowing the formation of excited states responsible for device functionality, such as exciton generation and charge separation, are insufficiently understood. This is partly due to the wide range of existing crystalline polymorphs depending on sample preparation conditions. Here, we determine the linear optical response of thin-film single-crystal perylene samples of distinct polymorphs in transmission and reflection geometries. The sample quality allows for unprecedented high-resolution spectroscopy, which offers an ideal opportunity for judicious comparison between theory and experiment. Excellent agreement with first-principles calculations for the absorption based on the GW plus Bethe-Salpeter equation (GW-BSE) approach of many body perturbation theory (MBPT) is obtained, from which a clear picture of the low-lying excitations in perylene emerges, including evidence of an exciton polariton stopband, as well as an assessment of the commonly used Tamm-Dancoff approximation to the GW-BSE approach. Our findings on this well-controlled system can guide understanding and development of advanced molecular solids and functionalization for applications. PMID- 29279375 TI - Field- and clinically derived estimates of Wolbachia-mediated blocking of dengue virus transmission potential in Aedes aegypti mosquitoes. AB - The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, we report that wMel infected Ae. aegypti (Ho Chi Minh City background), when directly blood-fed on 141 viremic dengue patients, have lower dengue virus (DENV) transmission potential and have a longer extrinsic incubation period than their wild-type counterparts. The wMel-infected mosquitoes that are field-reared have even greater relative resistance to DENV infection when fed on patient-derived viremic blood meals. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. Collectively, these field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti born arboviruses. PMID- 29279376 TI - Genetic variation interacts with experience to determine interindividual differences in learned song. AB - Learning reflects the influence of experience on genetically determined circuitry, but little is known about how experience and genetics interact to determine complex learned phenotypes. Here, we used vocal learning in songbirds to study how experience and genetics contribute to interindividual differences in learned song. Previous work has established that such differences in song within a species depend on learning, but in principle some of these differences could also depend on genetic variation. We focused on song tempo, a learned and quantifiable feature that is controlled by central neural circuitry. To identify genetic contributions to tempo we computer-tutored juvenile Bengalese finches (Lonchura striata domestica) from different genetic backgrounds with synthetic songs in which tempo was systematically varied. Computer-tutored birds exhibited unexpectedly strong heritability for song tempo and comparatively weak influence of experience. We then tested whether heritability was fixed and independent of experience by providing a second group of birds with enriched instruction via live social tutoring. Live tutoring resulted in not only a significant increase in the influence of experience on tempo but also a dramatic decrease in the influence of genetics, indicating that enriched instruction could overcome genetic biases evident under computer tutoring. Our results reveal strong heritable genetic contributions to interindividual variation in song tempo but that the degree of heritability depends profoundly on the quality of instruction. They suggest that for more complex learned phenotypes, where it can be difficult to identify and control relevant experiential variables, heritability may similarly be contingent on the specifics of experience. PMID- 29279378 TI - Q&As with Marsha I. Lester. PMID- 29279374 TI - Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees. AB - A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants. PMID- 29279377 TI - Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis. PMID- 29279379 TI - Two types of aggression in human evolution. AB - Two major types of aggression, proactive and reactive, are associated with contrasting expression, eliciting factors, neural pathways, development, and function. The distinction is useful for understanding the nature and evolution of human aggression. Compared with many primates, humans have a high propensity for proactive aggression, a trait shared with chimpanzees but not bonobos. By contrast, humans have a low propensity for reactive aggression compared with chimpanzees, and in this respect humans are more bonobo-like. The bimodal classification of human aggression helps solve two important puzzles. First, a long-standing debate about the significance of aggression in human nature is misconceived, because both positions are partly correct. The Hobbes-Huxley position rightly recognizes the high potential for proactive violence, while the Rousseau-Kropotkin position correctly notes the low frequency of reactive aggression. Second, the occurrence of two major types of human aggression solves the execution paradox, concerned with the hypothesized effects of capital punishment on self-domestication in the Pleistocene. The puzzle is that the propensity for aggressive behavior was supposedly reduced as a result of being selected against by capital punishment, but capital punishment is itself an aggressive behavior. Since the aggression used by executioners is proactive, the execution paradox is solved to the extent that the aggressive behavior of which victims were accused was frequently reactive, as has been reported. Both types of killing are important in humans, although proactive killing appears to be typically more frequent in war. The biology of proactive aggression is less well known and merits increased attention. PMID- 29279380 TI - ATM and ATR play complementary roles in the behavior of excitatory and inhibitory vesicle populations. AB - ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) are large PI3 kinases whose human mutations result in complex syndromes that include a compromised DNA damage response (DDR) and prominent nervous system phenotypes. Both proteins are nuclear-localized in keeping with their DDR functions, yet both are also found in cytoplasm, including on neuronal synaptic vesicles. In ATM- or ATR-deficient neurons, spontaneous vesicle release is reduced, but a drop in ATM or ATR level also slows FM4-64 dye uptake. In keeping with this, both proteins bind to AP-2 complex components as well as to clathrin, suggesting roles in endocytosis and vesicle recycling. The two proteins play complementary roles in the DDR; ATM is engaged in the repair of double-strand breaks, while ATR deals mainly with single-strand damage. Unexpectedly, this complementarity extends to these proteins' synaptic function as well. Superresolution microscopy and coimmunoprecipitation reveal that ATM associates exclusively with excitatory (VGLUT1+) vesicles, while ATR associates only with inhibitory (VGAT+) vesicles. The levels of ATM and ATR respond to each other; when ATM is deficient, ATR levels rise, and vice versa. Finally, blocking NMDA, but not GABA, receptors causes ATM levels to rise while ATR levels respond to GABA, but not NMDA, receptor blockade. Taken together, our data suggest that ATM and ATR are part of the cellular "infrastructure" that maintains the excitatory/inhibitory balance of the nervous system. This idea has important implications for the human diseases resulting from their genetic deficiency. PMID- 29279381 TI - Global warming leads to more uniform spring phenology across elevations. AB - One hundred years ago, Andrew D. Hopkins estimated the progressive delay in tree leaf-out with increasing latitude, longitude, and elevation, referred to as "Hopkins' bioclimatic law." What if global warming is altering this well-known law? Here, based on ~20,000 observations of the leaf-out date of four common temperate tree species located in 128 sites at various elevations in the European Alps, we found that the elevation-induced phenological shift (EPS) has significantly declined from 34 d?1,000 m-1 conforming to Hopkins' bioclimatic law in 1960, to 22 d?1,000 m-1 in 2016, i.e., -35%. The stronger phenological advance at higher elevations, responsible for the reduction in EPS, is most likely to be connected to stronger warming during late spring as well as to warmer winter temperatures. Indeed, under similar spring temperatures, we found that the EPS was substantially reduced in years when the previous winter was warmer. Our results provide empirical evidence for a declining EPS over the last six decades. Future climate warming may further reduce the EPS with consequences for the structure and function of mountain forest ecosystems, in particular through changes in plant-animal interactions, but the actual impact of such ongoing change is today largely unknown. PMID- 29279383 TI - Impact of an historic underground gas well blowout on the current methane chemistry in a shallow groundwater system. AB - Blowouts present a small but genuine risk when drilling into the deep subsurface and can have an immediate and significant impact on the surrounding environment. Nevertheless, studies that document their long-term impact are scarce. In 1965, a catastrophic underground blowout occurred during the drilling of a gas well in The Netherlands, which led to the uncontrolled release of large amounts of natural gas from the reservoir to the surface. In this study, the remaining impact on methane chemistry in the overlying aquifers was investigated. Methane concentrations higher than 10 mg/L (n = 12) were all found to have delta13C-CH4 values larger than -300/00, typical of a thermogenic origin. Both delta13C-CH4 and deltaD-CH4 correspond to the isotopic composition of the gas reservoir. Based on analysis of local groundwater flow conditions, this methane is not a remnant but most likely the result of ongoing leakage from the reservoir as a result of the blowout. Progressive enrichment of both delta13C-CH4 and deltaD-CH4 is observed with increasing distance and decreasing methane concentrations. The calculated isotopic fractionation factors of epsilonC = 3 and epsilonD = 54 suggest anaerobic methane oxidation is partly responsible for the observed decrease in concentrations. Elevated dissolved iron and manganese concentrations at the fringe of the methane plume show that oxidation is primarily mediated by the reduction of iron and manganese oxides. Combined, the data reveal the long term impact that underground gas well blowouts may have on groundwater chemistry, as well as the important role of anaerobic oxidation in controlling the fate of dissolved methane. PMID- 29279382 TI - Structural basis of the phosphorylation-independent recognition of cyclin D1 by the SCFFBXO31 ubiquitin ligase. AB - Ubiquitin-dependent proteolysis of cyclin D1 is associated with normal and tumor cell proliferation and survival. The SCFFBXO31 (Skp1-Cul1-Rbx1-FBXO31) ubiquitin ligase complex mediates genotoxic stress-induced cyclin D1 degradation. Previous studies have suggested that cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and subsequent proteolysis in the cytoplasm. Here we present the crystal structures of the Skp1-FBXO31 complex alone and bound to a phosphorylated cyclin D1 C-terminal peptide. FBXO31 possesses a unique substrate-binding domain consisting of two beta-barrel motifs, whereas cyclin D1 binds to FBXO31 by tucking its free C-terminal carboxylate tail into an open cavity of the C-terminal FBXO31 beta-barrel. Biophysical and functional studies demonstrate that SCFFBXO31 is capable of recruiting and ubiquitinating cyclin D1 in a phosphorylation-independent manner. Our findings provide a conceptual framework for understanding the substrate specificity of the F-box protein FBXO31 and the mechanism of FBXO31-regulated cyclin D1 protein turnover. PMID- 29279384 TI - Dynamic force spectroscopy of synthetic oligorotaxane foldamers. AB - Wholly synthetic molecules involving both mechanical bonds and a folded secondary structure are one of the most promising architectures for the design of functional molecular machines with unprecedented properties. Here, we report dynamic single-molecule force spectroscopy experiments that explore the energetic details of donor-acceptor oligorotaxane foldamers, a class of molecular switches. The mechanical breaking of the donor-acceptor interactions responsible for the folded structure shows a high constant rupture force over a broad range of loading rates, covering three orders of magnitude. In comparison with dynamic force spectroscopy performed during the past 20 y on various (bio)molecules, the near-equilibrium regime of oligorotaxanes persists at much higher loading rates, at which biomolecules have reached their kinetic regime, illustrating the very fast dynamics and remarkable rebinding capabilities of the intramolecular donor acceptor interactions. We focused on one single interaction at a time and probed the stochastic rupture and rebinding paths. Using the Crooks fluctuation theorem, we measured the mechanical work produced during the breaking and rebinding to determine a free-energy difference, DeltaG, of 6 kcal.mol-1 between the two local conformations around a single bond. PMID- 29279385 TI - High-resolution structure of podovirus tail adaptor suggests repositioning of an octad motif that mediates the sequential tail assembly. AB - The sophisticated tail structures of DNA bacteriophages play essential roles in life cycles. Podoviruses P22 and Sf6 have short tails consisting of multiple proteins, among which is a tail adaptor protein that connects the portal protein to the other tail proteins. Assembly of the tail has been shown to occur in a sequential manner to ensure proper molecular interactions, but the underlying mechanism remains to be understood. Here, we report the high-resolution structure of the tail adaptor protein gp7 from phage Sf6. The structure exhibits distinct distribution of opposite charges on two sides of the molecule. A gp7 dodecameric ring model shows an entirely negatively charged surface, suggesting that the assembly of the dodecamer occurs through head-to-tail interactions of the bipolar monomers. The N-terminal helix-loop structure undergoes rearrangement compared with that of the P22 homolog complexed with the portal, which is achieved by repositioning of two consecutive repeats of a conserved octad sequence motif. We propose that the conformation of the N-terminal helix-loop observed in the Sf6 gp7 and P22 portal:gp4 complex represents the pre- and postassembly state, respectively. Such motif repositioning may serve as a conformational switch that creates the docking site for the tail nozzle only after the assembly of adaptor protein to the portal. In addition, the C-terminal portion of gp7 shows conformational flexibility, indicating an induced fit on binding to the portal. These results provide insight into the mechanistic role of the adaptor protein in mediating the sequential assembly of the phage tail. PMID- 29279387 TI - Retraction for Jayandharan et al., Activation of the NF-kappaB pathway by adeno associated virus (AAV) vectors and its implications in immune response and gene therapy. PMID- 29279386 TI - CO2 reduction to acetate in mixtures of ultrasmall (Cu) n ,(Ag) m bimetallic nanoparticles. AB - Monodispersed mixtures of 6-nm Cu and Ag nanoparticles were prepared by electrochemical reduction on electrochemically polymerized poly-Fe(vbpy)3(PF6)2 film electrodes on glassy carbon. Conversion of the complex to poly Fe(vbpy)2(CN)2 followed by surface binding of salts of the cations and electrochemical reduction gave a mixture of chemically distinct clusters on the surface, (Cu) m ,(Ag) n |polymer|glassy carbon electrode (GCE), as shown by X-ray photoelectron spectroscopy (XPS) measurements. A (Cu)2,(Ag)3|(80-monolayer-poly Fe(vbpy)32+|GCE electrode at -1.33 V vs. reversible hydrogen electrode (RHE) in 0.5 M KHCO3, with 8 ppm added benzotriazole (BTA) at 0 degrees C, gave acetate with a faradaic efficiency of 21.2%. PMID- 29279388 TI - Heat activation is intrinsic to the pore domain of TRPV1. AB - The TRPV1 channel is a sensitive detector of pain-producing stimuli, including noxious heat, acid, inflammatory mediators, and vanilloid compounds. Although binding sites for some activators have been identified, the location of the temperature sensor remains elusive. Using available structures of TRPV1 and voltage-activated potassium channels, we engineered chimeras wherein transmembrane regions of TRPV1 were transplanted into the Shaker Kv channel. Here we show that transplanting the pore domain of TRPV1 into Shaker gives rise to functional channels that can be activated by a TRPV1-selective tarantula toxin that binds to the outer pore of the channel. This pore-domain chimera is permeable to Na+, K+, and Ca2+ ions, and remarkably, is also robustly activated by noxious heat. Our results demonstrate that the pore of TRPV1 is a transportable domain that contains the structural elements sufficient for activation by noxious heat. PMID- 29279389 TI - RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases. AB - Directed migration is essential for cell motility in many processes, including development and cancer cell invasion. RSKs (p90 ribosomal S6 kinases) have emerged as central regulators of cell migration; however, the mechanisms mediating RSK-dependent motility remain incompletely understood. We have identified a unique signaling mechanism by which RSK2 promotes cell motility through leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. RSK2 directly interacts with LARG and nucleotide-bound Rho isoforms, but not Rac1 or Cdc42. We further show that epidermal growth factor or FBS stimulation induces association of endogenous RSK2 with LARG and LARG with RhoA. In response to these stimuli, RSK2 phosphorylates LARG at Ser1288 and thereby activates RhoA. Phosphorylation of RSK2 at threonine 577 is essential for activation of LARG RhoA. Moreover, RSK2-mediated motility signaling depends on RhoA and -B, but not RhoC. These results establish a unique RSK2-dependent LARG-RhoA signaling module as a central organizer of directed cell migration and invasion. PMID- 29279390 TI - Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context. AB - The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the single-trial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus. PMID- 29279391 TI - Inactivation of porcine interleukin-1beta results in failure of rapid conceptus elongation. AB - Conceptus expansion throughout the uterus of mammalian species with a noninvasive epitheliochorial type of placentation is critical establishing an adequate uterine surface area for nutrient support during gestation. Pig conceptuses undergo a unique rapid morphological transformation to elongate into filamentous threads within 1 h, which provides the uterine surface to support development and maintain functional corpora lutea through the production of estrogen. Conceptus production of a unique interleukin 1beta, IL1B2, temporally increases during the period of trophoblast remodeling during elongation. CRISPR/Cas9 gene editing was used to knock out pig conceptus IL1B2 expression and the secretion of IL1B2 during the time of conceptus elongation. Trophoblast elongation occurred on day 14 in wild-type (IL1B2+/+) conceptuses but did not occur in ILB2-null (IL1B2-/-) conceptuses. Although the morphological transition of IL1B2-/- conceptuses was inhibited, expression of a number of conceptus developmental genes was not altered. However, conceptus aromatase expression and estrogen secretion were decreased, indicating that IL1B2 may be involved in the spatiotemporal increase in conceptus estrogen synthesis needed for the establishment of pregnancy in the pig and may serve to regulate the proinflammatory response of endometrium to IL1B2 during conceptus elongation and attachment to the uterine surface. PMID- 29279392 TI - Coordinating carbon and nitrogen metabolic signaling through the cyanobacterial global repressor NdhR. AB - The coordination of carbon and nitrogen metabolism is essential for bacteria to adapt to nutritional variations in the environment, but the underlying mechanism remains poorly understood. In autotrophic cyanobacteria, high CO2 levels favor the carboxylase activity of ribulose 1,5 bisphosphate carboxylase/oxygenase (RuBisCO) to produce 3-phosphoglycerate, whereas low CO2 levels promote the oxygenase activity of RuBisCO, leading to 2-phosphoglycolate (2-PG) production. Thus, the 2-PG level is reversely correlated with that of 2-oxoglutarate (2-OG), which accumulates under a high carbon/nitrogen ratio and acts as a nitrogen starvation signal. The LysR-type transcriptional repressor NAD(P)H dehydrogenase regulator (NdhR) controls the expression of genes related to carbon metabolism. Based on genetic and biochemical studies, we report here that 2-PG is an inducer of NdhR, while 2-OG is a corepressor, as found previously. Furthermore, structural analyses indicate that binding of 2-OG at the interface between the two regulatory domains (RD) allows the NdhR tetramer to adopt a repressor conformation, whereas 2-PG binding to an intradomain cleft of each RD triggers drastic conformational changes leading to the dissociation of NdhR from its target DNA. We further confirmed the effect of 2-PG or 2-OG levels on the transcription of the NdhR regulon. Together with previous findings, we propose that NdhR can sense 2-OG from the Krebs cycle and 2-PG from photorespiration, two key metabolites that function together as indicators of intracellular carbon/nitrogen status, thus representing a fine sensor for the coordination of carbon and nitrogen metabolism in cyanobacteria. PMID- 29279394 TI - Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. AB - In the neurodegenerative disease multiple system atrophy (MSA), alpha-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of alpha-synuclein prions in MSA and Parkinson's disease (PD), we developed nine alpha-synuclein-YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T alpha-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA alpha synuclein prions are conformationally distinct from the misfolded alpha-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases. PMID- 29279393 TI - Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. AB - Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement. Here, we report a simple cell encapsulation design that is readily scalable and conveniently retrievable. The key to this design was to engineer a highly wettable, Ca2+-releasing nanoporous polymer thread that promoted uniform in situ cross-linking and strong adhesion of a thin layer of alginate hydrogel around the thread. The device provided immunoprotection of rat islets in immunocompetent C57BL/6 mice in a short-term (1 mo) study, similar to neat alginate fibers. However, the mechanical property of the device, critical for handling and retrieval, was much more robust than the neat alginate fibers due to the reinforcement of the central thread. It also had facile mass transfer due to the short diffusion distance. We demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 mo as well as in immunodeficient SCID-Beige mice using human islets for 4 mo. We further showed, as a proof of concept, the scalability and retrievability in dogs. After 1 mo of implantation in dogs, the device could be rapidly retrieved through a minimally invasive laparoscopic procedure. This encapsulation device may contribute to a cellular therapy for T1D because of its retrievability and scale-up potential. PMID- 29279396 TI - Protonation state of glutamate 73 regulates the formation of a specific dimeric association of mVDAC1. AB - The voltage-dependent anion channel (VDAC) is the most abundant protein in the outer mitochondrial membrane and constitutes the primary pathway for the exchange of ions and metabolites between the cytosol and the mitochondria. There is accumulating evidence supporting VDAC's role in mitochondrial metabolic regulation and apoptosis, where VDAC oligomerization has been implicated with these processes. Herein, we report a specific pH-dependent dimerization of murine VDAC1 (mVDAC1) identified by double electron-electron resonance and native mass spectrometry. Intermolecular distances on four singly spin-labeled mVDAC1 mutants were used to generate a model of the low-pH dimer, establishing the presence of residue E73 at the interface. This dimer arrangement is different from any oligomeric state previously described, and it forms as a steep function of pH with an apparent pKa of 7.4. Moreover, the monomer-dimer equilibrium affinity constant was determined using native MS, revealing a nearly eightfold enhancement in dimerization affinity at low pH. Mutation of E73 to either alanine or glutamine severely reduces oligomerization, demonstrating the role of protonated E73 in enhancing dimer formation. Based on these results, and the known importance of E73 in VDAC physiology, VDAC dimerization likely plays a significant role in mitochondrial metabolic regulation and apoptosis in response to cytosolic acidification during cellular stress. PMID- 29279397 TI - Profile of David M. Sabatini. PMID- 29279395 TI - Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. AB - Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (~30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3' 5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 A resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold. PMID- 29279398 TI - Hybrid speciation leads to novel male secondary sexual ornamentation of an Amazonian bird. AB - Hybrid speciation is rare in vertebrates, and reproductive isolation arising from hybridization is infrequently demonstrated. Here, we present evidence supporting a hybrid-speciation event involving the genetic admixture of the snow-capped (Lepidothrix nattereri) and opal-crowned (Lepidothrix iris) manakins of the Amazon basin, leading to the formation of the hybrid species, the golden-crowned manakin (Lepidothrix vilasboasi). We used a genome-wide SNP dataset together with analysis of admixture, population structure, and coalescent modeling to demonstrate that the golden-crowned manakin is genetically an admixture of these species and does not represent a hybrid zone but instead formed through ancient genetic admixture. We used spectrophotometry to quantify the coloration of the species-specific male crown patches. Crown patches are highly reflective white (snow-capped manakin) or iridescent whitish-blue to pink (opal-crowned manakin) in parental species but are a much less reflective yellow in the hybrid species. The brilliant coloration of the parental species results from nanostructural organization of the keratin matrix feather barbs of the crown. However, using electron microscopy, we demonstrate that the structural organization of this matrix is different in the two parental species and that the hybrid species is intermediate. The intermediate nature of the crown barbs, resulting from past admixture appears to have rendered a duller structural coloration. To compensate for reduced brightness, selection apparently resulted in extensive thickening of the carotenoid-laden barb cortex, producing the yellow crown coloration. The evolution of this unique crown-color signal likely culminated in premating isolation of the hybrid species from both parental species. PMID- 29279399 TI - Developmental origins of mosaic evolution in the avian cranium. AB - Mosaic evolution, which results from multiple influences shaping morphological traits and can lead to the presence of a mixture of ancestral and derived characteristics, has been frequently invoked in describing evolutionary patterns in birds. Mosaicism implies the hierarchical organization of organismal traits into semiautonomous subsets, or modules, which reflect differential genetic and developmental origins. Here, we analyze mosaic evolution in the avian skull using high-dimensional 3D surface morphometric data across a broad phylogenetic sample encompassing nearly all extant families. We find that the avian cranium is highly modular, consisting of seven independently evolving anatomical regions. The face and cranial vault evolve faster than other regions, showing several bursts of rapid evolution. Other modules evolve more slowly following an early burst. Both the evolutionary rate and disparity of skull modules are associated with their developmental origin, with regions derived from the anterior mandibular-stream cranial neural crest or from multiple embryonic cell populations evolving most quickly and into a greater variety of forms. Strong integration of traits is also associated with low evolutionary rate and low disparity. Individual clades are characterized by disparate evolutionary rates among cranial regions. For example, Psittaciformes (parrots) exhibit high evolutionary rates throughout the skull, but their close relatives, Falconiformes, exhibit rapid evolution in only the rostrum. Our dense sampling of cranial shape variation demonstrates that the bird skull has evolved in a mosaic fashion reflecting the developmental origins of cranial regions, with a semi-independent tempo and mode of evolution across phenotypic modules facilitating this hyperdiverse evolutionary radiation. PMID- 29279400 TI - Ancient polymorphisms and divergence hitchhiking contribute to genomic islands of divergence within a poplar species complex. AB - How genome divergence eventually leads to speciation is a topic of prime evolutionary interest. Genomic islands of elevated divergence are frequently reported between diverging lineages, and their size is expected to increase with time and gene flow under the speciation-with-gene-flow model. However, such islands can also result from divergent sorting of ancient polymorphisms, recent ecological selection regardless of gene flow, and/or recurrent background selection and selective sweeps in low-recombination regions. It is challenging to disentangle these nonexclusive alternatives, but here we attempt to do this in an analysis of what drove genomic divergence between four lineages comprising a species complex of desert poplar trees. Within this complex we found that two morphologically delimited species, Populus euphratica and Populus pruinosa, were paraphyletic while the four lineages exhibited contrasting levels of gene flow and divergence times, providing a good system for testing hypotheses on the origin of divergence islands. We show that the size and number of genomic islands that distinguish lineages are not associated with either rate of recent gene flow or time of divergence. Instead, they are most likely derived from divergent sorting of ancient polymorphisms and divergence hitchhiking. We found that highly diverged genes under lineage-specific selection and putatively involved in ecological and morphological divergence occur both within and outside these islands. Our results highlight the need to incorporate demography, absolute divergence measurement, and gene flow rate to explain the formation of genomic islands and to identify potential genomic regions involved in speciation. PMID- 29279401 TI - Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration. AB - How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration. PMID- 29279403 TI - A mixed-scale dense convolutional neural network for image analysis. AB - Deep convolutional neural networks have been successfully applied to many image processing problems in recent works. Popular network architectures often add additional operations and connections to the standard architecture to enable training deeper networks. To achieve accurate results in practice, a large number of trainable parameters are often required. Here, we introduce a network architecture based on using dilated convolutions to capture features at different image scales and densely connecting all feature maps with each other. The resulting architecture is able to achieve accurate results with relatively few parameters and consists of a single set of operations, making it easier to implement, train, and apply in practice, and automatically adapts to different problems. We compare results of the proposed network architecture with popular existing architectures for several segmentation problems, showing that the proposed architecture is able to achieve accurate results with fewer parameters, with a reduced risk of overfitting the training data. PMID- 29279402 TI - Colorectal cancer specific conditions promote Streptococcus gallolyticus gut colonization. AB - Colonization by Streptococcus gallolyticus subsp. gallolyticus (SGG) is strongly associated with the occurrence of colorectal cancer (CRC). However, the factors leading to its successful colonization are unknown, and whether SGG influences the oncogenic process or benefits from the tumor-prone environment to prevail remains an open question. Here, we elucidate crucial steps that explain how CRC favors SGG colonization. By using mice genetically prone to CRC, we show that SGG colonization is 1,000-fold higher in tumor-bearing mice than in normal mice. This selective advantage occurs at the expense of resident intestinal enterococci. An SGG-specific locus encoding a bacteriocin ("gallocin") is shown to kill enterococci in vitro. Importantly, bile acids strongly enhance this bacteriocin activity in vivo, leading to greater SGG colonization. Constitutive activation of the Wnt pathway, one of the earliest signaling alterations in CRC, and the decreased expression of the bile acid apical transporter gene Slc10A2, as an effect of the Apc founding mutation, may thereby sustain intestinal colonization by SGG. We conclude that CRC-specific conditions promote SGG colonization of the gut by replacing commensal enterococci in their niche. PMID- 29279404 TI - ZmCCT9 enhances maize adaptation to higher latitudes. AB - From its tropical origin in southwestern Mexico, maize spread over a wide latitudinal cline in the Americas. This feat defies the rule that crops are inhibited from spreading easily across latitudes. How the widespread latitudinal adaptation of maize was accomplished is largely unknown. Through positional cloning and association mapping, we resolved a flowering-time quantitative trait locus to a Harbinger-like transposable element positioned 57 kb upstream of a CCT transcription factor (ZmCCT9). The Harbinger-like element acts in cis to repress ZmCCT9 expression to promote flowering under long days. Knockout of ZmCCT9 by CRISPR/Cas9 causes early flowering under long days. ZmCCT9 is diurnally regulated and negatively regulates the expression of the florigen ZCN8, thereby resulting in late flowering under long days. Population genetics analyses revealed that the Harbinger-like transposon insertion at ZmCCT9 and the CACTA-like transposon insertion at another CCT paralog, ZmCCT10, arose sequentially following domestication and were targeted by selection for maize adaptation to higher latitudes. Our findings help explain how the dynamic maize genome with abundant transposon activity enabled maize to adapt over 90 degrees of latitude during the pre-Columbian era. PMID- 29279406 TI - Correction for Isik et al., Perceiving social interactions in the posterior superior temporal sulcus. PMID- 29279405 TI - Interfacial curvature effects on the monolayer morphology and dynamics of a clinical lung surfactant. AB - The morphology of surfactant monolayers is typically studied on the planar surface of a Langmuir trough, even though most physiological interfaces are curved at the micrometer scale. Here, we show that, as the radius of a clinical lung surfactant monolayer-covered bubble decreases to ~100 um, the monolayer morphology changes from dispersed circular liquid-condensed (LC) domains in a continuous liquid-expanded (LE) matrix to a continuous LC linear mesh separating discontinuous LE domains. The curvature-associated morphological transition cannot be readily explained by current liquid crystal theories based on isotropic domains. It is likely due to the anisotropic bending energy of the LC phase of the saturated phospholipids that are common to all natural and clinical lung surfactants. This continuous LC linear mesh morphology is also present on bilayer vesicles in solution. Surfactant adsorption and the dilatational modulus are also strongly influenced by the changes in morphology induced by interfacial curvature. The changes in morphology and dynamics may have physiological consequences for lung stability and function as the morphological transition occurs at alveolar dimensions. PMID- 29279407 TI - Multiple origins of interdependent endosymbiotic complexes in a genus of cicadas. AB - Bacterial endosymbionts that provide nutrients to hosts often have genomes that are extremely stable in structure and gene content. In contrast, the genome of the endosymbiont Hodgkinia cicadicola has fractured into multiple distinct lineages in some species of the cicada genus Tettigades To better understand the frequency, timing, and outcomes of Hodgkinia lineage splitting throughout this cicada genus, we sampled cicadas over three field seasons in Chile and performed genomics and microscopy on representative samples. We found that a single ancestral Hodgkinia lineage has split at least six independent times in Tettigades over the last 4 million years, resulting in complexes of between two and six distinct Hodgkinia lineages per host. Individual genomes in these symbiotic complexes differ dramatically in relative abundance, genome size, organization, and gene content. Each Hodgkinia lineage retains a small set of core genes involved in genetic information processing, but the high level of gene loss experienced by all genomes suggests that extensive sharing of gene products among symbiont cells must occur. In total, Hodgkinia complexes that consist of multiple lineages encode nearly complete sets of genes present on the ancestral single lineage and presumably perform the same functions as symbionts that have not undergone splitting. However, differences in the timing of the splits, along with dissimilar gene loss patterns on the resulting genomes, have led to very different outcomes of lineage splitting in extant cicadas. PMID- 29279408 TI - Control on rate and pathway of anaerobic organic carbon degradation in the seabed. AB - The degradation of organic matter in the anoxic seabed proceeds through a complex microbial network in which the terminal steps are dominated by oxidation with sulfate or conversion into methane and CO2 The controls on pathway and rate of the degradation process in different geochemical zones remain elusive. Radiotracer techniques were used to perform measurements of sulfate reduction, methanogenesis, and acetate oxidation with unprecedented sensitivity throughout Holocene sediment columns from the Baltic Sea. We found that degradation rates transition continuously from the sulfate to the methane zone, thereby demonstrating that terminal steps do not exert feedback control on upstream hydrolytic and fermentative processes, as previously suspected. Acetate was a key intermediate for carbon mineralization in both zones. However, acetate was not directly converted into methane. Instead, an additional subterminal step converted acetate to CO2 and reducing equivalents, such as H2, which then fed autotrophic reduction of CO2 to methane. PMID- 29279409 TI - Listeria monocytogenes triggers noncanonical autophagy upon phagocytosis, but avoids subsequent growth-restricting xenophagy. AB - Xenophagy is a selective macroautophagic process that protects the host cytosol by entrapping and delivering microbes to a degradative compartment. Both noncanonical autophagic pathways and xenophagy are activated by microbes during infection, but the relative importance and function of these distinct processes are not clear. In this study, we used bacterial and host mutants to dissect the contribution of autophagic processes responsible for bacterial growth restriction of Listeria monocytogenesL. monocytogenes is a facultative intracellular pathogen that escapes from phagosomes, grows in the host cytosol, and avoids autophagy by expressing three determinants of pathogenesis: two secreted phospholipases C (PLCs; PlcA and PlcB) and a surface protein (ActA). We found that shortly after phagocytosis, wild-type (WT) L. monocytogenes escaped from a noncanonical autophagic process that targets damaged vacuoles. During this process, the autophagy marker LC3 localized to single-membrane phagosomes independently of the ULK complex, which is required for initiation of macroautophagy. However, growth restriction of bacteria lacking PlcA, PlcB, and ActA required FIP200 and TBK1, both involved in the engulfment of microbes by xenophagy. Time-lapse video microscopy revealed that deposition of LC3 on L. monocytogenes-containing vacuoles via noncanonical autophagy had no apparent role in restricting bacterial growth and that, upon access to the host cytosol, WT L. monocytogenes utilized PLCs and ActA to avoid subsequent xenophagy. In conclusion, although noncanonical autophagy targets phagosomes, xenophagy was required to restrict the growth of L. monocytogenes, an intracellular pathogen that damages the entry vacuole. PMID- 29279411 TI - Removal of perineuronal nets disrupts recall of a remote fear memory. AB - Throughout life animals learn to recognize cues that signal danger and instantaneously initiate an adequate threat response. Memories of such associations may last a lifetime and far outlast the intracellular molecules currently found to be important for memory processing. The memory engram may be supported by other more stable molecular components, such as the extracellular matrix structure of perineuronal nets (PNNs). Here, we show that recall of remote, but not recent, visual fear memories in rats depend on intact PNNs in the secondary visual cortex (V2L). Supporting our behavioral findings, increased synchronized theta oscillations between V2L and basolateral amygdala, a physiological correlate of successful recall, was absent in rats with degraded PNNs in V2L. Together, our findings suggest a role for PNNs in remote memory processing by stabilizing the neural network of the engram. PMID- 29279410 TI - ALKBH5-dependent m6A demethylation controls splicing and stability of long 3'-UTR mRNAs in male germ cells. AB - N6-methyladenosine (m6A) represents one of the most common RNA modifications in eukaryotes. Specific m6A writer, eraser, and reader proteins have been identified. As an m6A eraser, ALKBH5 specifically removes m6A from target mRNAs and inactivation of Alkbh5 leads to male infertility in mice. However, the underlying molecular mechanism remains unknown. Here, we report that ALKBH5 mediated m6A erasure in the nuclei of spermatocytes and round spermatids is essential for correct splicing and the production of longer 3'-UTR mRNAs, and failure to do so leads to aberrant splicing and production of shorter transcripts with elevated levels of m6A that are rapidly degraded. Our study identified reversible m6A modification as a critical mechanism of posttranscriptional control of mRNA fate in late meiotic and haploid spermatogenic cells. PMID- 29279412 TI - Association Between Prompt Defibrillation and Epinephrine Treatment With Long Term Survival After In-Hospital Cardiac Arrest. AB - BACKGROUND: Prior studies have reported higher in-hospital survival with prompt defibrillation and epinephrine treatment in patients with in-hospital cardiac arrest (IHCA). Whether this survival benefit persists after discharge is unknown. METHODS: We linked data from a national IHCA registry with Medicare files and identified 36 961 patients >=65 years of age with an IHCA at 517 hospitals between 2000 and 2011. Patients with IHCA caused by pulseless ventricular tachycardia or ventricular fibrillation were stratified by prompt (<=2 minutes) versus delayed (>2 minutes) defibrillation, whereas patients with IHCA caused by asystole or pulseless electric activity were stratified by prompt (<=5 minutes) versus delayed (>5 minutes) epinephrine treatment. The association between prompt treatment and long-term survival for each rhythm type was assessed with multivariable hierarchical modified Poisson regression models. RESULTS: Of 8119 patients with an IHCA caused by ventricular tachycardia or ventricular fibrillation, the rate of 1-year survival was higher in those treated with prompt defibrillation than with delayed defibrillation (25.7% [1466 of 5714] versus 15.5% [373 of 2405]; adjusted relative risk [RR], 1.49; 95% confidence interval [CI] 1.32-1.69; P<0.0001). This survival advantage persisted at 3 years (19.1% versus 11.0%; adjusted RR, 1.45; 95% CI, 1.23-1.69; P<0.0001) and at 5 years (14.7% versus 7.9%; adjusted RR, 1.50; 95% CI, 1.22-1.83; P<0.0001). Of 28 842 patients with an IHCA caused by asystole/pulseless electric activity, the rate of 1-year survival with prompt epinephrine treatment was higher than with delayed treatment (5.4% [1341 of 24 885] versus 4.3% [168 of 3957]; adjusted RR, 1.20; 95% CI, 1.02-1.41; P=0.02), but this survival benefit was no longer present at 3 years (3.5% versus 2.9%; adjusted RR, 1.17; 95% CI, 0.95-1.45; P=0.15) and at 5 years (2.3% versus 1.9%; adjusted RR, 1.18; 95% CI, 0.88-1.58; P=0.27). CONCLUSIONS: Prompt defibrillation for IHCA caused by ventricular tachycardia or ventricular fibrillation was associated with higher rates of long-term survival throughout 5 years of follow-up, whereas prompt epinephrine treatment for asystole/pulseless electric activity was associated with greater survival at 1 year but not at 3 or 5 years. By quantifying the greater survival associated with timely defibrillation and epinephrine administration, these findings provide important insights into the durability of survival benefits for 2 process-of-care measures in current resuscitation guidelines. PMID- 29279414 TI - T-tubule remodeling and increased heterogeneity of calcium release during the progression to heart failure in intact rat ventricle. AB - A highly organized transverse-tubule (TT) system is essential to normal Ca2+ cycling and cardiac function. We explored the relationship between the progressive disruption of TTs and resulting Ca2+ cycling during the development of heart failure (HF). Confocal imaging was used to measure Ca2+ transients and 2 D z-stack images in left ventricular epicardial myocytes of intact hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats. TT organization was measured as the organizational index (OI) derived from a fast Fourier transform of TT organization. We found little decrease in the synchrony of Ca2+ release with TT loss until TT remodeling was severe, suggesting a TT "reserve" characterized by a wide range of TT remodeling with little effect on synchrony of release but beyond which variability in release shows an accelerating sensitivity to TT loss. To explain this observation, we applied a computational model of spatially distributed Ca2+ signaling units to investigate the relationship between OI and excitation-contraction coupling. Our model showed that release heterogeneity exhibits a nonlinear relationship on both the spatial distribution of release units and the separation between L-type Ca2+ channels and ryanodine receptors. Our results demonstrate a unique relationship between the synchrony of Ca2+ release and TT organization in myocytes of intact rat ventricle that may contribute to both the compensated and decompensated phases of heart failure. PMID- 29279413 TI - Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival. AB - BACKGROUND: On the basis of laboratory cardiopulmonary resuscitation (CPR) investigations and limited adult data demonstrating that survival depends on attaining adequate arterial diastolic blood pressure (DBP) during CPR, the American Heart Association recommends using blood pressure to guide pediatric CPR. However, evidence-based blood pressure targets during pediatric CPR remain an important knowledge gap for CPR guidelines. METHODS: All children >=37 weeks' gestation and <19 years old in Collaborative Pediatric Critical Care Research Network intensive care units with chest compressions for >=1 minute and invasive arterial blood pressure monitoring before and during CPR between July 1, 2013, and June 31, 2016, were included. Mean DBP during CPR and Utstein-style standardized cardiac arrest data were collected. The hypothesis was that DBP >=25 mm Hg during CPR in infants and >=30 mm Hg in children >=1 year old would be associated with survival. Primary outcome was survival to hospital discharge. Secondary outcome was survival to hospital discharge with favorable neurological outcome, defined as Pediatric Cerebral Performance Categories 1 to 3 or no worse than prearrest baseline. Multivariable Poisson regression models with robust error estimates were used to estimate the relative risk of outcomes. RESULTS: Blinded investigators analyzed blood pressure waveforms during CPR from 164 children, including 60% <1 year old, 60% with congenital heart disease, and 54% after cardiac surgery. The immediate cause of arrest was hypotension in 67%, respiratory decompensation in 44%, and arrhythmia in 19%. Median duration of CPR was 8 minutes (quartiles, 3 and 27 minutes). Ninety percent survived the event, 68% with return of spontaneous circulation and 22% by extracorporeal life support. Forty-seven percent survived to hospital discharge, and 43% survived to discharge with favorable neurological outcome. Maintaining mean DBP >=25 mm Hg in infants and >=30 mm Hg in children >=1 year old occurred in 101 of 164 children (62%) and was associated with survival (adjusted relative risk, 1.7; 95% confidence interval, 1.2-2.6; P=0.007) and survival with favorable neurological outcome (adjusted relative risk, 1.6; 95% confidence interval, 1.1-2.5; P=0.02). CONCLUSIONS: These data demonstrate that mean DBP >=25 mm Hg during CPR in infants and >=30 mm Hg in children >=1 year old was associated with greater likelihood of survival to hospital discharge and survival with favorable neurological outcome. PMID- 29279416 TI - The Strength of Physiological Reports and Peer Review. PMID- 29279417 TI - Opinion: Why we need a National Living Soil Repository. PMID- 29279415 TI - Leucine-rich alpha-2 glycoprotein promotes lung fibrosis by modulating TGF-beta signaling in fibroblasts. AB - TGF-beta has an important role in fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Detailed analysis of TGF-beta signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein (LRG) was reported to function as a modulator of TGF-beta signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout (KO) mice with bleomycin-induced lung fibrosis, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild-type (WT) mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, lung fibrosis was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of alpha-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the TGF-beta-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory TGF-beta receptor, is essential for LRG to promote TGF-beta signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes lung fibrosis by modulating TGF-beta-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts. PMID- 29279421 TI - [Bone-derived hormones and their systemic regulation.] AB - Bone has several functions such as supporting our body, protecting internal organs and contributing to hematopoiesis. Recently, it has been revealed that bone also works as an endocrine tissue and systemically regulates functions of other organs. It has been reported that fibroblast growth factor 23(FGF23)regulates phosphate metabolism and osteocalcin affect glucose/energy metabolism. In addition, sclerostin, interleukin-11(IL-11)and lipocalin 2 have been also found to be bone-derived humoral factors. Further investigation concerning the network systems among multiple organs via bone-derived hormones may lead to the development of new drugs. PMID- 29279420 TI - Deregulated profiles of urinary microRNAs may explain podocyte injury and proximal tubule dysfunction in normoalbuminuric patients with type 2 diabetes mellitus. AB - MicroRNAs (miRNAs) are short non-coding RNA species that are important post transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-beta-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM. PMID- 29279422 TI - [Aging-related changes in motor organs and energy metabolism.] AB - Aging causes loss of skeletal muscle mass and strength, which is termed as sarcopenia. Aging of the neurological system may affect motor organs. Reduced muscle mass and increased fat mass induce insulin resistance, which is one of the causes for impaired glucose tolerance in the elderly. PMID- 29279423 TI - [Mechanisms of systemic energy metabolism control through gene regulation in skeletal muscle.] AB - Skeletal muscle is the largest tissue in the human body and plays an important role in the regulation of systemic homeostasis and displays remarkable plasticity in their metabolic responses to caloric availability and physical activity. Skeletal muscle maintains muscle mass suitable for the environment according to its own activity state. Skeletal muscles also affect the energy regulation of the whole body by skeletal muscle itself changing muscle fiber composition due to external and internal factors. This review focuses on the transcriptional regulation mechanism of muscle fiber type, which is responsible for overall energy consumption. PMID- 29279424 TI - [Joint disease and energy metabolism.] AB - Recently, it has been found that systemic metabolic disorders are associated with the onset and progression of various joint diseases. Although osteoarthritis(OA)is mainly a degradative condition of the articular cartilage induced by mechanical stress, there is a growing body of data demonstrating the involvement of metabolic factors including fat metabolism. Recent studies have revealed that adipokines including adiponectin and leptin are associated with inflammation of rheumatoid arthritis. A better understanding of these relationships may lead to new strategies to treat or prevent joint disease such as OA. PMID- 29279425 TI - [Cellular metabolite controls oxidative stress resistance.] AB - Cellular metabolites such as acetylcoenzyme A and nicotinamide adenine dinucleotide control gene transcription via modulating the reader or eraser protein in histone modification. A ketone body, D-beta-hydroxybutyrate is an endogenous metabolite which has been reported as a class I histone deacetylases(HDACs). In this chapter, a molecular basis of the ketone body in transcriptional control and protection against oxidative stress is reviewed and discussed. PMID- 29279426 TI - [Central regulation of appetite and energy metabolism.] AB - Recent advances of neuroscience shed a light in the neural pathway and mechanisms for food intake regulation. The central nervous system(CNS)has also been recognized as a crucial organ to regulate metabolism in peripheral tissues. This includes the increase in glucose and fatty acid utilization in skeletal muscle as well as in brown adipose tissue and the heart, improving type 1 diabetes without change in insulin secretion. CNS regulation for food intake and energy metabolism is important to understand the mechanism for homeostatic regulation in living body. PMID- 29279427 TI - [Exercise and brain function.] AB - Cognitive dysfunction is a public health issue, which is one of the main contributing factors for need-of-care, afflicting patients and their caretakers. It is well accepted that physical activity is in close relationship with brain function. Accumulating data has indicated that exercise training can improve brain functions both directly and indirectly via the alleviation of the diseases underlying, including hypertension and diabetes. Recently, mechanisms bridging brain functions and physical exercises have begun to be clarified. Further studies are required for the understanding of the whole picture of neuropsychiatric diseases and for the development of effective exercise therapy for these diseases. PMID- 29279428 TI - [Thermoregulatory behavior and its central circuit mechanism-What thermosensory pathway drives it?] AB - Thermoregulatory behavior in homeothermic animals is an instinctive behavior to reduce the cost of their homeothermy, such as warm-seeking behavior to reduce metabolic energy for heat production in cold environments. A recent study identified the central neural pathway that transmits cutaneous thermosensory information on environmental temperature to drive thermoregulatory behavior. This study proposed that the brain mechanism that drives thermoregulatory behavior does not require conscious"feeling"(i.e., perception)of skin temperature mediated by the spinothalamocortical pathway, whereas thermosensory information that ascends through the spinal cord and the lateral parabrachial nucleus of the pons generates thermal comfort and discomfort that drive thermoregulatory behavior. PMID- 29279429 TI - [Developing Exercise-mimicking Drugs toward Realization of Preemptive Medicine for Lifestyle-related Diseases.] AB - Modern society is characterized by an explosion of lifestyle-related diseases that have, as their basis, obesity due to lack of exercise, which include the metabolic syndrome, diabetes, cardiovascular disease, cancer, and Alzheimer's disease. While exercise is known to be a definitive preventive or therapeutic measure against these diseases, it is clear that contemporary lifestyles tend to make exercise rather difficult to continue. Thus, there are mounting expectations worldwide for exercise-mimicking drugs that activate exercise-mediated signaling pathways. Therefore, this review discusses the mechanisms through which the adiponectin receptor(AdipoR)likely mimics exercise as a key molecule in lifestyle related diseases, as well as the prospects for emerging small-molecule AdipoR activating compounds that contribute toward realization of preemptive medicine for lifestyle-related diseases. PMID- 29279430 TI - [Sarcopenia and metabolism.] AB - Sarcopenia has been defined as an age-related loss of skeletal muscle mass, strength and function, and its diagnostic criteria is based on usual gait speed, grip strength, and skeletal muscle mass. Whereas underlying pathophysiology and mechanisms of sarcopenia still remains to be established, recent studies have suggested that sarcopenia is a risk factor for metabolic disorders, showing an association with insulin resistance, diabetes, and metabolic syndrome in elderly people. PMID- 29279431 TI - [Anti-osteoporotic drugs and energy metabolism.] AB - Accumulating evidence indicates close and tight relationship between bone tissue and energy expenditure, especially glucose metabolism. In molecular mechanisms, osteocalcin secreted from osteoblasts, as a hormone, is demonstrated in mice to be involved not only in insulin secretion from islet beta-cells but also in insulin resistance in adipose tissue. In addition, since signaling cascades in liver activated by RANK ligand has been shown to participate in augmentation of insulin resistance, pharmacological inhibition of RANK ligand for treatment of osteoporosis is speculated to improve insulin resistance in human. However, data from several clinical trials of ant-osteoporosis drugs have not supported an idea that they were clinically involved in glucose metabolism. Interestingly, some retrospective observational studies demonstrate that long-term administration of bisphosphonates may decrease the incidence of newly onset of type 2 diabetes, although mechanisms by which they do so are totally uncertain. PMID- 29279432 TI - [Impact of estrogen signaling in energy expenditure and metabolism.] AB - There are numerous characteristics of females as a higher organism and maintaining appropriate level of estrogen is possibly the most fundamental and important factor for reproductive aged women. Appropriate secretion of estrogen during the reproductive age is indispensable to keep female in healthy condition. In addition to natural menopause and surgical menopause, aberrant secretion of estrogen in reproductive aged women may predispose to increase risk of osteopenia, dyslipidemia and impaired glucose tolerance, and epidemiological studies and experimental data strongly support that estrogen possesses anti diabetic properties. The function of estrogen in glucose homeostasis can be explained by direct functions of estrogen and by indirect function through estrogen receptors(ERs), although the latter is believed to be mainstream. ERalpha is believed to be the key ER in brain, pancreatic, liver, muscle, adipose tissues, and macrophages. PMID- 29279433 TI - [Topics for basic research(osteoclast and bone resorption)in ASBMR 2017.] AB - This is a brief report summarizing topics in ASBMR 2017 held at Colorado Convention Center in Denver on September 8-11th. In this paper, I report some topics from presentation of basic research(especially osteoclast and bone resorption)in ASBMR 2017. PMID- 29279434 TI - [Topics for basic research regarding osteoclasts and bone-resorption in ASBMR 2017.] AB - This is a brief report regarding the topics about osteoclasts and bone-resorption presented in ASBMR 2017 held in Colorado convention center in Denver, Colorado, in September 8-11, 2017. PMID- 29279435 TI - [Drugs for osteoporosis.] AB - Many important results concerning several drugs for osteoporosis have been presented in ASBMR 2017 meeting. Longer use of denosumab for up to 10 years was shown to induce lower risk of fractures. In addition, antiresorptives were shown to be useful after abaloparatide or romosozumab. Now that several important drugs have been already developed for osteoporosis, research and drug development for other musculoskeletal organs than bone are necessary. PMID- 29279436 TI - [ASBMR topics from clinical to translational research.] AB - Aging and senescence are main topics in this ASBMR Annual Meeting as both the Aurbach lecture and Avioli award lecture focused on the topic. Osteoporosis is one of typical age-related disease and elimination of senescent cells is new strategy of treatment for osteoporosis. Antibody and synthetic antagonist or agonist which modify the action of hormone and growth factor, an inhibitor of ectopic bone formation and a stimulator of muscle mass have been developed as a new drug for metabolic bone diseases and skeletal dysplasias. PMID- 29279437 TI - [The biological role of exosomes in bone remodeling and bone diseases.] AB - Exosomes are about 100nm membrane vesicles, and released from almost all cell types. They carry and transfer a wide variety of molecules, such as mRNAs, microRNAs, proteins, and lipids, as modulators of intercellular communication. Various studies have shown that this exosome-mediated intercellular communication lead to proliferation, invasion and metastasis of cancer cells. In addition to that, emerging data suggest that exosomes are also involved in physiological processes of bone remodeling and bone diseases. Increasing understanding of the working mechanism of exosomes will provide us with new therapeutic and diagnostic opportunities. Here we summarize the current research on exosomes in bone remodeling and bone diseases. PMID- 29279438 TI - [Rotational Isomers of Diphenhydramine]. AB - Diphenhydramine (DP), an antihistaminic agent, may become colored and daker or more fluorescent during storage. Herein, we spectroscopically examined the causes of this phenomenon under various DP storage conditions and durations. The infrared vibration-rotation spectrum shows multiple Gauche (G)-type conformers with different intramolecular n->pi* interaction strengths. The splitting pattern of the dimethylamino group protons in the 1H-NMR spectrum indicates that DP is mainly in the G-type with a small portion in the Trans (T)-type. The correlation between the red-shifted peak intensity in the UV*VIS absorbance spectrum and the coloring progression indicates a decreased intramolecular n->pi* interaction of the G-type under elevated temperature during storage. Enhanced fluorescence detected in the Excitation*Fluorescence spectrum demonstrates G-type (quenching) to T-type (fluorescent) conformation conversion, which is due to activated internal rotation of the dimethylamino group under elevated storage temperature and electronic excitation in the phenyl groups under light irradiation during storage. A signal detected in the ESR spectrum corresponds to the G-type charge transfer (CT) structure wherein part of the nonbonding electron pair on the N atom is intramolecularly redistributed to the phenyl groups. The CT structure presents the G-type quenching characteristics, whereas weak CT bonding corresponds to coloring. The results indicate that the quenching G-type is converted to T-type by heat or light to become color faded and bright with enhanced fluorescence and that T-type is reverted to G-type after storage under cool and dark conditions or by vacuum distillation to lose fluorescence. PMID- 29279439 TI - Unexpected Ventriculitis Complication of Neonatal Meningitis Caused by Streptococcus gallolyticus Subsp. pasteurianus: a Case Report. AB - Streptococcus gallolyticus subsp. pasteurianus, previously recognized as S. bovis biotype II/2, is an uncommon yet important cause of invasive infection in young infants. Here, we report the first case of ventriculitis that was unexpectedly diagnosed in the course of neonatal meningitis due to S. gallolyticus subsp. pasteurianus, and we review the relevant literature. A 28-day-old male infant from Japan presented with fever, lethargy, and irritability. S. bovis was isolated from blood and the cerebrospinal fluid culture and was then identified as S. gallolyticus subsp. pasteurianus. Intravenous antibiotic therapy was initiated, which helped improve the clinical course of the disease; however, the patient presented ventriculitis-related complications diagnosed using follow-up magnetic resonance imaging (MRI) on day 12 of hospitalization. Ampicillin was administered for 21 days and discontinued after the patient showed improvement, according to MRI findings. The patient was discharged without sequelae. Ventriculitis is a rare complication of childhood meningitis due to S. gallolyticus subsp. pasteurianus. However, it may have been underdiagnosed, especially in cases with no specific manifestations similar to the present case. We suggest that MRI should be performed to screen for ventriculitis in the course of meningitis to avoid failure in treatment. PMID- 29279440 TI - Detection of Anisakid Larvae in Marinated Mackerel Sushi in Tokyo, Japan. PMID- 29279441 TI - Data Mining and Machine Learning Algorithms Using IL28B Genotype and Biochemical Markers Best Predicted Advanced Liver Fibrosis in Chronic Hepatitis C. AB - IL28B single nucleotide polymorphism (rs12979860) is an etiology-independent predictor of hepatitis C virus (HCV)-related hepatic fibrosis. Data mining is a method of predictive analysis which can explore tremendous volumes of information from health records to discover hidden patterns and relationships. The current study aims to evaluate and compare the prediction accuracy of scoring system like aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) index versus data mining for the prediction of HCV-related advanced fibrosis. This retrospective study included 427 patients with chronic hepatitis C. We used data mining analysis to construct a decision tree by reduced error (REP) technique, followed by Auto-WEKA tool to select the best classifier out of 39 algorithms to predict advanced fibrosis. APRI and FIB-4 had sensitivity specificity parameters of 0.523-0.831 and 0.415-0.917, respectively. REPTree algorithm was able to predict advanced fibrosis with sensitivity of 0.749, specificity of 0.729, and receiver operating characteristic (ROC) area of 0.796. Out of the 16 attributes, IL28B genotype was selected by the REPTree as the best predictor for advanced fibrosis. Using Auto-WEKA, the multilayer perceptron (MLP) neural model was selected as the best predictive algorithm with sensitivity of 0.825, specificity of 0.811, and ROC area of 0.880. Thus, MLP is better than APRI, FIB-4, and REPTree for predicting advanced fibrosis for patients with chronic hepatitis C. PMID- 29279442 TI - Surveillance of Antibiotic Susceptibility Patterns of Neisseria gonorrhoeae from 2013 to 2015 in Guangxi Province, China. AB - Neisseria gonorrhoeae is a sexually transmitted pathogen highly prevalent worldwide with an increasing trend of resistance to antimicrobial treatment. We conducted this study to trace the susceptibility of N. gonorrhoeae to penicillin (PC), spectinomycin (SPCM), ciprofloxacin (CPFX), azithromycin (AZM), cefixime (CFIX), and ceftriaxone (CTRX) in Guangxi province. In total, 303 N. gonorrhoeae isolates were obtained from patients infected with N. gonorrhoeae in 6 cities in Guangxi during 2013-2015, and the antibiotic susceptibility patterns were analyzed by an agar dilution assay. The results showed that N. gonorrhoeae was susceptible to treatment with cephalosporins, including CTRX (99.7% of isolates), CFIX (99%), SPCM (100%), and AZM (96.4%), and this is the first report of antibiotic susceptibility for AZM surveillance of N. gonorrhoeae in Guangxi. Penicillinase-producing N. gonorrhoeae (PPNG) isolates increased in prevalence from 37% in 2013 to 64% in 2015 (P = 0.068), and tetracycline-resistant N. gonorrhoeae (TRNG) prevalence increased from 23% in 2013 to 44% in 2015 (P = 0.071). High resistance of N. gonorrhoeae to PC was associated with infection in patients at ages 25 to 30 years (P < 0.05), whereas PPNG positivity (P < 0.01), and TRNG positivity were risk factors for CPFX resistance (P = 0.0407). Our study provides plausible evidence for therapeutic strategies and N. gonorrhoeae infection control and prevention in Guangxi, China. PMID- 29279443 TI - Epidemiology and Antibiogram Profile of Vibrio cholerae Isolates between 2004 2013 from Odisha, India. AB - Cholera is an acute diarrheal disease caused by Vibrio cholerae serogroups O1 and O139, which are known to cause epidemics of cholera in Odisha. The present study was intended to document the antibiotic resistance pattern among clinical isolates of both serogroups of V. cholerae (O1 and O139) isolated during 2004 2013. Nine-hundred nine isolates of V. cholerae were included in this study and were identified by standard procedures. An antibiotic sensitivity test was performed by the disc diffusion method. The seasonality of cholera in this region indicated that there was one peak in the rainy season only. The number of cholera cases started increasing from July and declined starting from the month of October onward. The adult age group of patients was the worst affected among all age groups of patients. The 2 different serogroups of V. cholerae (O1 and O139) showed different prevalence rates (%) of resistance to all the antibiotics in each year. Serogroup O1 showed uniformly high resistance to co-trimoxazole, furazolidone, and nalidixic acid throughout the study. Chloramphenicol encountered resistance only during 2009, but the strains were sensitive in the other years. The emergence of multiple drug-resistant V. cholerae strains may significantly influence the control of future outbreaks and epidemics of cholera in this region. PMID- 29279444 TI - Detection of Escherichia coli Producing CTX-M-1-Group Extended-Spectrum beta Lactamases from Pigs in Aichi Prefecture, Japan, between 2015 and 2016. AB - We investigated the prevalence and characteristics of extended-spectrum beta lactamase (ESBL)-producing Escherichia coli isolates from Japanese pigs. A total of 345 pig fecal specimens were collected from 30 farms in the Aichi prefecture of Japan between June 2015 and April 2016, and 22 unique ESBL-producing E. coli were isolated from 16 samples spanning 8 farms. The ESBL types included CTX-M-15 (54.5%), CTX-M-55 (27.2%), CTX-M-3 (0.9%), and CTX-M-14 (0.9%). The predominant plasmid replicon type was IncN, and the isolates carried blaCTX-M-55. Nine sequence type (ST)s, including ST117, ST1706, ST38, and ST10, were detected in the ESBL-producers, but no B2-O25-ST131 was found. ESBL producers were highly resistant to cefotaxime, ceftiofur, and tetracycline, but were susceptible to imipenem, amikacin, and fosfomycin (FOM), although 2 ST354 isolates showed resistance to ciprofloxacin. All 11 chloramphenicol-resistant isolates, including ST117 (n = 6) and ST38 (n = 3) isolates, harbored floR, and the 2 FOM-resistant ST38 isolates harbored fosA3. Our results suggest that pigs do not act as direct reservoirs in the transmission of ESBL genes to E. coli in humans. However, ST117 E. coli carrying IncN-type plasmids mediating blaCTX-M-55 were isolated from several different farms, suggesting the potential for future spread in Japan. Therefore, plasmid sequence analyses and continuous surveillance are necessary from an epidemiological point of view and are required to better protect against ESBL-producer transmission. PMID- 29279445 TI - Prevalence and Phylogenetic Analysis of Hepatitis E Virus among Pigs in Japan. AB - The number of reported cases of human hepatitis E virus (HEV) infection has increased since 2012. Pigs are considered an important source of viruses causing human HEV infection. It is possible that the prevalence of HEV among pigs at slaughter age (approximately 6 months old) has increased in the last decade. Therefore, we investigated the current prevalence of HEV among pigs in Japan. Although HEV RNA was detected in rectal content samples from pigs aged from one to 5 months, no HEV RNA was detected in any samples from 6-month-old pigs. The highest viral shedding prevalence (33%) was detected among 3-month-old pigs. This study shows that there has been no change in the prevalence of HEV among pigs at the slaughter age, in the prevalence of HEV by age group on pig farms, or in the phylogenetic classification of HEV isolates in the last decade. Therefore, factors downstream of the pork production stage may be contributing to the increased number of human HEV infection cases. PMID- 29279446 TI - The Status of Susceptibility of Japanese Encephalitis Vectors to Insecticides in Endemic Areas of Northern Districts of West Bengal, India. AB - Emergence and spread of resistance among vectors toward different insecticides is a serious problem for the Japanese encephalitis (JE) control program. Regularly monitoring the status of susceptibility of vector species to insecticides is important for formulating proper vector control measures. In this study, we studied the susceptibility status of major JE vectors from northern West Bengal, toward 4% DDT, 0.05% deltamethrin, and 5% malathion. Two- to three-day-old unfed female mosquitoes were subjected to a susceptibility bioassay using a World Health Organization kit. Corrected mortality (CM) and knockdown times were estimated. Culex tritaeniorhynchus, Cx. vishnui, Cx. pseudovishnui, and Cx. gelidus were the major JE vectors present in the study areas. All 4 vector species were highly tolerant to DDT with CM < 90%. Cx. tritaeniorhynchus, Cx. vishnui, Cx. pseudovishnui, and Cx. gelidus were tolerant to deltamethrin with CM < 90%, except for Cx. gelidus of Darjeeling and Malbazar. At most of the study sites, malathion was effective against Cx. vishnui, Cx. pseudovishnui, and Cx. gelidus with CM >= 98%. In contrast, Cx. tritaeniorhynchus was tolerant to malathion in all study areas. Predominant JE vector populations were highly tolerant to all 3 analyzed insecticides, except deltamethrin for Cx. gelidus and malathion for Cx. vishnui, Cx. pseudovishnui, and Cx. gelidus. The results of this study may be useful for better planning and implementing a JE control strategy. PMID- 29279447 TI - Isolation and Complete Genome Sequencing of Zika Virus Imported from the Dominican Republic to Japan. AB - Zika virus (ZIKV) infection has been documented within Central and South America, Asia, and Africa. Here we report the isolation of virus from a patient infected with ZIKV returning to Japan from the Dominican Republic. The ZIKV strain was imaged by electron microscopy and its complete genome sequence was analyzed. Phylogenetic analysis and molecular characterization revealed that the strain was of Asian lineage, and carried 2 unique mutations in its NS5 region. These mutations are characteristic of strains that originated in the Dominican Republic and the USA in 2016. PMID- 29279448 TI - Comparison of Three Molecular Subtyping Methods among O157 and Non-O157 Shiga Toxin-Producing Escherichia coli Isolates from Japanese Cattle. AB - To determine the infection source, route, and extent of an outbreak, it is important to subtype Shiga toxin-producing Escherichia coli (STEC) isolates belonging to the same serotype for clustering into clonally related groups. In this study, we compared 3 molecular subtyping methods-multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and multiple-locus variable number of tandem repeat analysis (MLVA)-using O157 and non-O157 STEC isolates from Japanese beef cattle. A total of 73 STEC isolates belonging to 9 O serogroups were analyzed. By means of 3 molecular subtyping methods, the strains were subdivided into 9 MLST sequence types (STs), 23 PFGE types, and 26 MLVA types. The STEC classification by O-serogrouping and MLST was almost identical. Furthermore, PFGE and MLVA could systematically classify STEC isolates of the same serotypes and STs. MLVA and PFGE were found to be highly efficient subtyping methods after O-serogrouping for the classification of not only O157 but also non O157 STEC isolates in an outbreak investigation. PMID- 29279449 TI - Simulation Study of the Effects of Host Availability on Bite Rate of Aedes albopictus (Skuse) (Diptera: Culicidae) and Risk of Dengue Outbreaks in Non Endemic Areas. AB - Aedes albopictus is an important vector of dengue fever and tends to live in specific area, where it may ambush blood host that it encounters. Thus, host contact frequency may affect the bite rate and risk of disease outbreak, although no studies have examined these parameters. The present study used a simple model to clarify the fundamental relationship between host availability, bite rate, and risk of dengue outbreaks in non-endemic areas. A hypothetical isolated mosquito population was divided into "ambush" and "resting" subpopulations, and human hosts were modeled as visiting the mosquito population at constant intervals. A single infectious human who visited the mosquito population only on a single occasion was responsible for mosquito infections and consequently, secondary infections among humans who subsequently visit the area after the incubation period. The results confirmed that the bite rate per host increased with decreasing host availability. The number of secondary infections among hosts exhibited a unimodal relationship with the frequency of host visits, with a maximum value at host visits every 24 h. Furthermore, when host availability was not very low, the bite rate was a good indicator of the potential risk of dengue outbreaks. Therefore, human-bait-sweep collection data may be useful for monitoring the risk of dengue outbreaks. PMID- 29279450 TI - Ten-Year Surveillance of Measles Virus from 2007-2016 in Osaka City, Japan. AB - Measles is a highly contagious infection caused by the measles virus (MV). This study performed long-term surveillance in order to survey the prevalence of MV. A total of 417 patients diagnosed with or suspected of having measles were tested for MV between January 2007 and December 2016 in Osaka City, Japan. Reverse transcription-polymerase chain reaction-based testing of clinical specimens showed that 54 patients (12.9%) were MV-positive. An MV epidemic occurred in 2007, in which all detected MV strains were genotype D5, an epidemic strain in Japan at that time. The detected wild-type MV strains in sporadic or outbreak associated cases since 2011 included genotypes D4, D8, B3, and H1. Three vaccine strains (all genotype A) were also detected. Children <10 years of age accounted for 90.0% of the MV-positive patients in 2007. In contrast, adults (>= 20 years of age) accounted for the majority of MV-positive cases since 2011, as follows: 100%, 50%, 71.4%, 100%, and 87.5% of cases in 2011, 2013, 2014, 2015, and 2016, respectively. The recent high rate of two-dose MV vaccination coverage among children in Japan may have contributed to the reduced risk of MV infection and onset of measles in young persons. PMID- 29279451 TI - Epidemiology of Respiratory Pathogens in Children with Lower Respiratory Tract Infections in Shanghai, China, from 2013 to 2015. AB - This study aimed to explore the epidemiology of pathogens in children who were hospitalized with lower respiratory tract infections (LRTIs) at the Children's Hospital of Fudan University, Shanghai, China. Children aged less than 18 years who were hospitalized with LRTIs were enrolled from January 2013 to December 2015. Respiratory specimens were collected for the detection of common respiratory viruses, atypical bacteria, and other bacteria using current laboratory diagnostic tests. The epidemiological characteristics of the respiratory pathogens were analyzed. Of the 10,123 specimens obtained from the patients, 5,966 (58.7%) were positive for at least 1 pathogen. Mycoplasma pneumoniae (M.pneumoniae) was the most commonly detected pathogen (15.7%), followed by respiratory syncytial virus (RSV) (13.9%). Co-infections were found in 11.4% of patients. Of these co-infections, viral-bacterial co-infections were the most common. The detection rates for the respiratory pathogens varied considerably by age. RSV was the most common pathogen in children aged less than 24 months. Clear seasonal peaks were observed for RSV, M. pneumoniae, parainfluenza virus, human metapneumovirus, Moraxella catarrhalis, and Haemophilus influenza infections. Our findings demonstrate specific epidemiological patterns in children with LRTIs in Shanghai, China. PMID- 29279452 TI - Prevalence and Genotype Distribution of Chlamydia trachomatis in Urine among Men Attending Sexually Transmitted Disease Clinics in Guangdong Province, China, in 2016. AB - Studies have rarely assessed the genotype distribution of Chlamydia trachomatis (CT) in urine among men attending sexually transmitted disease clinics (MSCs) in China. This study was aimed at investigating the prevalence and molecular epidemiology of CT infection by examining urine samples among MSCs from different geographic areas of Guangdong Province, China. A cross-sectional study was conducted among MSCs from 10 human immunodeficiency virus sentinel surveillance sites in Guangdong Province. CT DNA was extracted from male urine samples and analyzed using a Roche cobas 4800 CT/NG. The ompA genes were amplified by nested PCR and sequenced. The leukocyte esterase test was performed by routine urine analysis at local clinics. Of the 1,903 samples, 163 (8.6%, 95% confidence interval [CI] 3.8-16.3%) tested positive for CT. The highest prevalence (10.5%) of CT infection was observed among participants aged between 21 and 30 years. A total of 130 CT-positive samples (79.8%, 130/163) were successfully genotyped by nested PCR, resulting in 8 genotypes. The most prevalent genotypes were D, E, F, and J, with proportions of 20.8%, 20.0%, 17.7%, and 16.9%, respectively. There were no significant correlations between the geographical areas, leukocyte esterase test results and genotype distribution. Promotion of detection and molecular epidemiology research is needed for effective and comprehensive prevention and control programs. PMID- 29279453 TI - Evaluation of the FilmArray Blood Culture Identification Panel on Detection of Pathogenic Microorganisms in Positive Blood Cultures: the First Clinical Report in Japan. AB - FilmArray (FA) is a multiplex PCR-based desktop microbial detection system. The blood culture identification (BCID) panel is an adaptable panel for FA, which diagnoses sepsis and/or systemic infections by detecting 14 bacterial species, 4 bacterial genera, 1 bacterial family, 5 yeast species, and 3 antimicrobial resistance genes (mecA, Klebsiella pneumoniae carbapenemase [KPC], and vanA/B) in positive blood cultures within 1 h. We retrospectively evaluated the FA-BCID panel using 54 positive blood cultures, in which 57 bacterial and 3 yeast strains were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The FA-BCID panel revealed 59 microorganisms in 53 samples; this performance was similar to that of MALDI-TOF MS analysis; however, 1 bacterium in 1 sample was not detected. In addition, mecA genes were detected in 12 Staphylococcus species, which all manifested methicillin resistance in susceptibility testing, whereas genes KPC and vanA/B were not detected, in agreement with the results of antimicrobial susceptibility testing. Although more information on antimicrobial resistance, including activity of IMP metallo-beta-lactamases, is required in Japan, the FA-BCID panel can detect pathogenic microorganisms in positive blood cultures rapidly, and this method could be beneficial for proper treatment of sepsis and/or systemic infections, especially in small hospitals. PMID- 29279454 TI - Human Parainfluenza Virus Type 3 Infections in Patients with Hematopoietic Stem Cell Transplants: the Mode of Nosocomial Infections and Prognosis. AB - There have been a few prospective and comprehensive surveillance studies on the respiratory viral infections (RVIs) among patients undergoing hematopoietic stem cell transplantation (HSCT). A 2-year prospective cohort surveillance study of symptomatic and asymptomatic RVIs was performed in hospitalized HSCT patients. Oropharyngeal (OP) swab samples were serially collected each week from 1 week before and up to 100 days after HSCT and were tested for virus isolation with cell culture-based viral isolation (CC-based VI) and a multiplex PCR (MPCR). A total of 2,747 OP swab samples were collected from 250 HSCT patients (268 HSCT procedures). Among these patients, 79 had RVIs (CC-based VI, n = 63; MPCR, n = 17). The parainfluenza virus type 3 (PIV3) accounted for 71% (57/80) of the cases of RVIs. Some PIV3 infections were asymptomatic and involved a longer virus shedding period. The PIV3 was often cultured from samples taken before the onset of a respiratory disease. The PIV3 infections were attributed to the transmission of nosocomial infections. PIV3 infections before engraftment will more likely result in the development of lower respiratory tract infections and worse outcomes. A real-time monitoring of respiratory viral infections in the HSCT ward among patients with or without respiratory symptoms is required for the prevention of nosocomial RVIs, especially of PIV3 infections. PMID- 29279455 TI - Exogenous BMP-7 Facilitates the Recovery of Cardiac Function after Acute Myocardial Infarction through Counteracting TGF-beta1 Signaling Pathway. AB - Myocardial fibrosis after acute myocardial infarction (AMI) is one of the main causes of myocardial remodeling and heart function abnormalities. Bone morphogenetic protein-7 (BMP-7) has been reported to play essential roles in anti fibrosis. In this study, we demonstrated the role of exogenous BMP-7 on myocardial fibrosis and heart function recovery after AMI. A rat model of AMI was established via ligation of the left anterior descending coronary artery (LAD). Twenty rats were grouped into sham group which underwent chest open operation, but did not receive LAD ligation. Another 40 rats underwent LAD ligation were randomly grouped into saline-treated group (n = 20) and BMP-7-treated group (n = 20) which received saline treatment or exogenous BMP-7 treatment for 14 days, respectively. Two weeks after LAD ligation, the survival rate of BMP-7-treated AMI group was significantly improved compared to the saline group. Moreover, the cardiac function was preserved as shown by echocardiography examination, and the infarcted size was limited upon BMP-7 treatment. In addition, we investigated the role of TGF-beta1 signaling pathway in BMP-7-mediated cardioprotective effects by analyzing the expression levels of TGF-beta1, Smad 2 and Smad 3 in the infarct zone, border zone, and non-infarct zone. Western blot and quantitative PCR results suggested that BMP-7 attenuated myocardial fibrosis through counteracting TGF-beta1 signaling pathway, thereby exerting cardioprotective effects. In conclusion, our data provide a potential therapeutic direction for preserving cardiac function and improving prognosis of AMI patients. PMID- 29279456 TI - Exploring Attractiveness of the Basic Sciences for Female Physicians. AB - In Japan, traditional gender roles of women, especially the role of motherhood, may cause early career resignations in female physicians and a shortage of female researchers. Besides this gender issue, a general physician shortage is affecting basic science fields. Our previous study suggested that female physicians could be good candidates for the basic sciences because such work offers good work-life balance. However, the attractiveness for female physicians of working in the basic sciences, including work-life balance, is not known. In a 2012 nationwide cross-sectional questionnaire survey, female physicians holding tenured positions in the basic sciences at Japan's medical schools were asked an open-ended question about positive aspects of basic sciences that clinical medicine lacks, and we analyzed 58 respondents' comments. Qualitative analysis using the Kawakita Jiro method revealed four positive aspects: research attractiveness, priority on research productivity, a healthy work-life balance, and exemption from clinical duties. The most consistent positive aspect was research attractiveness, which was heightened by medical knowledge and clinical experience. The other aspects were double-edged swords; for example, while the priority on research productivity resulted in less gender segregation, it sometimes created tough competition, and while exemption from clinical duties contributed to a healthy work-life balance, it sometimes lowered motivation as a physician and provided unstable income. Overall, if female physicians lack an intrinsic interest in research and seek good work-life balance, they may drop out of research fields. Respecting and cultivating students' research interest is critical to alleviating the physician shortage in the basic sciences. PMID- 29279457 TI - Broad clinical spectrum and diverse outcomes of prolactinoma with pediatric onset: medication-resistant and recurrent cases. AB - Prolactinoma is a benign tumor of the pituitary gland that rarely occurs in children and adolescents; thus, the clinical spectrum and long-term prognosis in these patients remain unknown. This study was performed to investigate the long term outcomes of medical treatment and the prognostic factors for remission and relapse in children and adolescents with prolactinoma. Three male subjects and four female subjects between the ages of 7- and 17-years-old were included in this study. The mean initial serum prolactin level was 443 +/- 251.8 ng/mL (range, 152-946 ng/mL). During the follow-up period (range, 0.6-20 years), a dopamine agonist was administered, and surgery or radiotherapy was performed in cases of resistance to medical treatment or relapse. Unlike female subjects with macroadenoma who often exhibit a good clinical course, two male subjects with early onset macroadenoma presented with visual disturbances. These subjects showed resistance to medical therapy and relapsed, eventually requiring surgical removal and radiotherapy; one of the subjects manifested a metastatic thrombus in the internal jugular vein. In conclusion, pediatric prolactinoma exhibits a broad clinical spectrum, a relatively high incidence of macroadenoma, resistance to medical therapy, and frequent tumor relapses. In addition, a poor prognosis appears to be correlated with male sex, age at disease onset, and histopathological characteristics. PMID- 29279458 TI - Whole-genome sequencing revealed armadillo repeat containing 5 (ARMC5) mutation in a Chinese family with ACTH-independent macronodular adrenal hyperplasia. AB - Primary macronodular adrenal hyperplasia (PMAH), also known in the past as bilateral macronodular adrenalhyperplasia or adrenocorticotropin (ACTH) independent macronodular adrenal hyperplasia, is a rare type of Cushing's syndrome (CS) and is associated with bilateralenlargement of the adrenal glands. It accounts for <1% of all endogenous cases of CS. In order toidentify the pathogenic mutations in the causative gene of (AIMAH pedigrees, Whole-genome sequencing of three patients in family I was used to retrieve candidate causative genes. Meanwhile, the causative gene was identified by Sanger sequencing from the two pedigrees. Sequencing of ARMC5 exons of three patients was carried out to identify somatic mutations. Moreover, haploid clone of one tumor DNA sample was conducted. ARMC5 was the causative gene of two pedigrees confirmed by whole genome sequencing (WGA) and Sanger sequencing. The variant sites of the two families were c.C943T (p.R315W) and c.C1960T (p.R654X), respectively. Autosomal dominant inheritance of AIMAH was confirmed by genotypes of one family member. Several somatic mutations were discovered in tumor DNA samples. In addition, haploid clone of tumor DNA was confirmed by germline mutation and somaticmutation, which suggested the pathogenic mechanism of "two-hit-model." ARMC5 was the causative gene of AIMAH pedigrees. This AIMAH in this study presented autosomal dominant inheritance, fitting to Mendelian inheritance law. However, the pathogenic mode of this disease showed as compound heterozygote. PMID- 29279459 TI - Does Size Matter? Cryoballoon-Based Pulmonary Vein Isolation Using a Novel 25-mm Circular Mapping Catheter. AB - BACKGROUND: Real-time recording of pulmonary vein isolation (PVI) using a circular mapping catheter has become a key aspect of cryoballoon (CB) ablation. The aim of this study was to investigate the procedural safety, efficacy and rate of real-time pulmonary vein (PV) recording using a novel circular mapping catheter with a 25-mm loop size for CB-based PVI.Methods and Results:A total of 40 patients with symptomatic atrial fibrillation (AF) underwent PVI using a second-generation CB and a novel 25-mm circular mapping catheter. A total of 159 PV were identified and successfully isolated. Real-time PV recording was achieved in 80% of the PV. In 3 right inferior PV the circular mapping catheter had to be exchanged for a stiff guidewire due to insufficient mechanical support. Therefore, acute PVI using exclusively the circular mapping catheter was achieved in 156/159 PV (98%). Mean procedure and fluoroscopy times were 66+/-21 min and 15+/-6 min, respectively. Transient phrenic nerve palsy occurred in 1 patient as the only procedural complication. CONCLUSIONS: The exclusive use of a novel 25-mm circular mapping catheter for CB ablation of AF results in a real-time PV recording rate of 80% and isolation of 98% of targeted PV. PMID- 29279460 TI - Silent Cerebral Infarction in East Asian vs. Non-Asian Atrial Fibrillation Patients - Meta-Analysis. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in the ageing population in East Asia. Silent cerebral infarction (SCI) is defined as cerebral infarction in the absence of corresponding clinical symptoms, and is a highly prevalent and morbid condition in AF. SCI is increasingly being recognized as a risk factor for future stroke, which can lead to cognitive decline or dementia. The latter is an increasingly common health problem in East Asia.Methods and Results:We conducted a meta-analysis to compare the association of AF and SCI between East Asian and non-Asian patients. AF was associated with SCI in patients with no symptomatic stroke history (relative risk [RR], 2.24; 95% CI: 1.26-3.99, I2=83%; P=0.006) although the prevalence varied widely between studies (P for heterogeneity<0.001). In non-Asian patients, the prevalence of SCI in AF is higher than that in controls (RR, 1.85; 95% CI: 1.65-2.08, I2=17%; P<0.001). There was no significant racial difference between Asian and non-Asian studies (P=0.53). CONCLUSIONS: In East Asia, AF was significantly associated with SCI and no racial difference was seen between East Asian and non-Asian patients. The present findings offer clinicians new insights into the association between AF and SCI. PMID- 29279461 TI - Immunoglobulin G Subclass 4-Related Lymphoplasmacytic Thoracic Aortitis in a Patient with Acute Type A Aortic Dissection. AB - Immunoglobulin G subclass 4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disease characterized by an elevated serum IgG4 level and an IgG4-positive lymphocyte infiltrate mainly in exocrine tissues. Previous reports documented IgG4-RD in several cardiovascular disorders. We present a case of type A aortic dissection associated with IgG4-RD. A 52-year-old man diagnosed with a type A aortic dissection was referred for surgical treatment. He underwent emergency hemiarch reconstruction with a prosthetic graft. His postoperative recovery was uncomplicated. Histopathologic examination of his aortic tissue showed marked adventitial thickening with fibrosis and an IgG4-positive plasma cell infiltrate. He was diagnosed with type A aortic dissection incidentally complicated by IgG4-RD. The relationship between IgG4-RD and the pathogenesis of aortic dissection remains unknown and requires further investigation. PMID- 29279462 TI - Recurrence of Spontaneous Pneumothorax Is Not Associated with Allegedly Risk Prone Lifestyle Conduct. AB - PURPOSE: Spontaneous pneumothorax (PNTX) is a common disease frequently operated at specialized thoracic surgery units. Videothoracoscopic surgery (VATS) has become the standard for treatment and recurrence prevention. While there is broad consensus regarding indications and techniques of PNTX surgery, postoperative risks and consecutive patient behavioral advice have not been sufficiently elucidated. METHODS: Single-center cohort analysis of 641 patients operated for primary PNTX by VATS over 10 years. Putatively recurrence-prone lifestyle activities (smoking status, flying habits, and scuba diving) and actual occurrence of recurrences were correlated. RESULTS: Follow-up rate was 46% (279/607 patients). Mean time interval between primary operation and follow-up was 61 (range: 5-177) months. In 10 patients (3.6%), a PNTX recurrence was observed. Regarding postoperative risk behavior reported at follow-up, 28% of patients were active smokers (15 +/- 7 cigarettes/day), 59% traveled by plane repeatedly, and only two patients did scuba diving (0.7%). Low body-mass-index was associated with an increase in PNTX recurrence, whereas smoking, flying, and scuba diving could not be identified as risk factors. CONCLUSION: In our study, none of the supposed "classic" lifestyle-associated risk factors for PNTX recurrence after VATS proved to be a significant threat. Postoperative patient behavior might not be constrained by overcautious medical advice. PMID- 29279463 TI - Sex and site differences in urinary excretion of conjugated pyrene metabolites in the West African Shorthorn cattle. AB - Industrialization, economic and population growth rates in Ghana have increased the release of contaminants including polycyclic aromatic hydrocarbons (PAHs) into the environment through which humans and animals are exposed. Cattle is reported to be exposed to high levels of PAHs through feed and inhalation. Once exposed, PAHs are metabolized and excreted in urine, feces or bile. In a previous study, cattle in Ghana was reported to excrete high levels of 1-hydroxypyrene (1 OHPyr) due to high exposure to the parent compound, pyrene. 1-OHPyr is further metabolized to glucuronide and sulfate conjugates. Thus, the aim of this study was to investigate the sex and site differences in urinary excretion of conjugated pyrene metabolites using cattle urine collected from rural and urban sites of the Ashanti region, Ghana. From the results, geometric mean concentration adjusted by specific gravity indicated that 1-OHPyreneGlucuronide (PyG) was the most abundant conjugate followed by PyrenediolSulfate (M3). The sum of conjugated pyrene metabolites and sum of both conjugated and deconjugated pyrene metabolites correlated significantly with PyG, PydiolSulfate (M2) and PydiolSulfate (M3). The study revealed no significant difference in urinary excretion of conjugated pyrene metabolites between rural and urban sites. This indicated that similar to urban sites, cattle in rural sites were exposed to high levels of pyrene. There was no significant difference in urinary concentrations of conjugated pyrene metabolites between sexes. PMID- 29279464 TI - Decreased expression of the immediate early protein, ICP4, by deletion of the tegument protein VP22 of equine herpesvirus type 1. AB - VP22 is a major tegument protein of equine herpesvirus type 1 (EHV-1). In the present study, we examined functions of VP22 in EHV-1 replication by viral protein expression analyses in cells infected with the VP22-deficient virus. The expressions of several viral proteins in the cells infected with the VP22 deficient virus were lower than those in the cells infected with the parent virus. One of the weakly expressed proteins was identified as ICP4, which is a major regulatory protein encoded by an immediate early gene of EHV-1. A real-time PCR analysis showed that the mRNA expression of ICP4 was the same in cells infected with the parent and VP22-deficient viruses. Hence, VP22 appears to promote synthesis of ICP4 post-transcriptionally. PMID- 29279465 TI - Inhibition of actin polymerization by marine toxin pectenotoxin-2. AB - Pectenotoxin-2 (PCTX-2) is one of the polyether macrolide toxins isolated from scallops involved in diarrheic shellfish poisoning via actin depolymerization. In the present study, we examined the bioactive mechanism of PCTX-2 in smooth muscle cells and clarify mode of action of the PCTX-2-induced actin depolymerization using purified skeletal actin. PCTX-2 (300 nM-3 uM) non-selectively inhibited vascular smooth muscle contractions elicited by high K+ or phenylephrine in a dose-dependent manner. However, elevated cytosolic Ca2+ and myosin light chain phosphorylation stimulated by high K+ were only slightly inhibited by PCTX-2. By monitoring the fluorescent intensity of pyrenyl-actin, PCTX-2 was found to inhibit both the velocity and degree of actin polymerization. The critical concentration of G-actin was linearly increased in accordance with the concentration of PCTX-2, indicating sequestration of G-actin with 1 to 1 ratio. The kinetics of F-actin depolymerization by dilution assay indicated that PCTX-2 does not sever F-actin. Transmission electron microscopic and confocal microscopic observations demonstrated that PCTX-2 selectively depolymerized filamentous actin without affecting tublin. In conclusion, PCTX-2 is a potent natural actin depolymerizer which sequesters G-actin without severing F-actin. PMID- 29279466 TI - Prolonged Dry Cough without Pulmonary Changes on Radiological Imaging. AB - A 16-year-old boy who was a non-smoker presented with a prolonged severe dry cough and malaise of 3 months in duration. Despite an increase in the patient's inflammatory marker levels, no respiratory lesions were radiologically or serologically detected. We suspected that the cough reflex pathway had been stimulated by large vessel vasculitis (LVV, a non-respiratory inflammatory condition) and diagnosed the patient with Takayasu arteritis. While inflammation of either the ascending pharyngeal or pulmonary artery have been reported to cause cough in patients with LVV, the present case shows that intense inflammation of the aortic arch and the starting portion of its main branches may stimulate a vagus nerve branch as a novel mechanism causing cough. PMID- 29279467 TI - Racemose Hemangioma of the Bronchial Artery. PMID- 29279468 TI - Extending Carotid Artery Thrombus Associated with Thrombocytosis. PMID- 29279469 TI - A Giant Gastrointestinal Stromal Tumor with Cystic Morphology. PMID- 29279470 TI - Glycogen Hepatopathy: An Under-recognized Hepatic Complication of Uncontrolled Type 1 Diabetes Mellitus. PMID- 29279471 TI - Extracardiac Tumor from Duodenal Primary Gastrointestinal Stromal Tumor. PMID- 29279472 TI - Infective Endarteritis due to Staphylococcus capitis. PMID- 29279473 TI - False Elevation of the Blood Tacrolimus Concentration, as Assessed by an Affinity Column-mediated Immunoassay (ACMIA), Led to Acute T Cell-mediated Rejection after Kidney Transplantation. AB - Tacrolimus is the most commonly used immunosuppressant. Because of its narrow therapeutic range, it is necessary to frequently monitor its concentration. We report the case of a 25-year-old man who underwent kidney transplantation whose tacrolimus concentrations, as measured by an affinity column-mediated immunoassay, were falsely elevated. As we reduced the dose of tacrolimus, the recipient developed T cell-mediated rejection. Using the same blood samples, an enzyme-multiplied immunoassay technique showed that the patient's levels of tacrolimus were extremely low. A further examination indicated that the false increase in the tacrolimus concentration was likely due to an unknown interfering substance. We administered methylprednisolone and antithymocyte-globulin. The patient's serum creatinine level decreased and remained stable after these treatments. PMID- 29279474 TI - Invasive Candida Infection with Ureteral Obstruction. PMID- 29279475 TI - Anti-mitochondrial M2 Antibodies and Myopathy: Author's Reply. PMID- 29279476 TI - Unilateral Exophthalmos due to Lymphomatous Involvement. PMID- 29279477 TI - Decreased Serum Adiponectin Level during Catecholamine Crisis in an Obese Patient with Pheochromocytoma. AB - We herein report the case of a 37-year-old man with both pheochromocytoma and visceral fat accumulation and describe the sequential changes in his adiponectin levels throughout the clinical course from catecholamine crisis until the follow up for adrenalectomy. His adiponectin level decreased during catecholamine crisis and increased after adrenalectomy. However, his adiponectin level decreased again at two years postoperatively when his visceral fat area greatly increased. This case suggests that catecholamines and visceral fat volume may affect adiponectin metabolism in subjects with pheochromocytoma, which may precipitate cardiovascular complications in this endocrine disease. PMID- 29279478 TI - EBV-positive Reactive Hyperplasia Progressed into EBV-positive Diffuse Large B cell Lymphoma of the Elderly over a 6-year Period. AB - A 70-year-old woman with lymphadenopathy was admitted to hospital in 2008. Lymph node biopsy showed reactive lymphoid hyperplasia (RH) with monoclonal proliferation of Epstein-Barr virus (EBV). Her lymphadenopathy regressed without treatment. In 2014, the patient presented with nasal obstruction because of a left nasal mass. She was diagnosed with EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly based on the examination of a biopsy specimen of the mass. The IgH rearrangement in the specimens from the 2008 and the 2014 revealed that they were genetically identical. This is the first report of RH progressing to DLBCL, and suggests that EBV-positive B-cells in RH lymph nodes predict the evolution to DLBCL. PMID- 29279479 TI - Fatal Disseminated Tuberculosis during Treatment with Ruxolitinib Plus Prednisolone in a Patient with Primary Myelofibrosis: A Case Report and Review of the Literature. AB - A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib. PMID- 29279480 TI - Salmonella houtenae-induced Empyema Complicated with Chronic Tuberculous Empyema. AB - Salmonella spp. are food-borne pathogens that usually cause gastroenteritis, although bacteremia and subsequent focal metastatic infection can also occasionally occur. Of the known Salmonella spp., Salmonella houtenae is a rare subspecies, comprising less than 1% of all Salmonella strains. We herein report the first case of S. houtenae-induced empyema complicated with chronic tuberculous empyema, which was successfully treated by antibacterial agents alone. We wish to highlight the importance of being aware that Salmonella spp. can cause empyema in cases suffering from chronic tuberculous empyema; moreover, despite the successful completion of treatment with antibacterial agents, periodical follow-up is mandatory in such cases. PMID- 29279481 TI - Lupus Pleuritis with Silicotic Nodules in the Parietal Pleura. AB - A 63-year-old man with occupational exposure to silica presented with cutaneous ulcer, pleuritic pain, and a fever. Laboratory data showed lymphopenia and positive serum antinuclear and anti-DNA antibodies. Computed tomography of the chest showed egg shell-like calcification of the hilar and mediastinal lymph nodes without pulmonary parenchymal involvement of silicosis. A surgical biopsy showed silicotic nodules with surrounding infiltration of lymphocytes and plasma cells in the parietal pleura. With a diagnosis of systemic lupus erythematosus (SLE), systemic corticosteroid therapy was given, which led to the resolution of symptoms and laboratory abnormalities. We discuss the relationship between silica exposure and the development of SLE. PMID- 29279482 TI - Immune-related Colitis Induced by the Long-term Use of Nivolumab in a Patient with Non-small Cell Lung Cancer. AB - We herein report a case of immune-related colitis induced by the long-term use of nivolumab. A 62-year-old Japanese man was treated with nivolumab at 3 mg/kg every 2 weeks for advanced lung adenocarcinoma. The patient was admitted to our hospital due to non-bloody watery diarrhea after the 70th dose of nivolumab. A biopsy specimen of the colon mucosa revealed evidence of colitis with cryptitis and crypt microabscesses. He was diagnosed with immune-related colitis and started on predonisolone 60 mg/day. Subsequently, his symptoms remarkably resolved. Consideration of immune-related adverse events up to several years after the initiation of nivolumab is important. PMID- 29279483 TI - Radiation Pneumonitis with Eosinophilic Alveolitis in a Lung Cancer Patient. AB - A 59-year-old woman suffering from dry cough and dyspnea was admitted to our hospital. She had undergone concurrent chemo-radiotherapy five months earlier. Chest computed tomography revealed bilateral ground-glass opacities extending outside the irradiated lung field. Her eosinophil numbers were increased in both the peripheral blood and the bronchoalveolar lavage fluid; therefore, she was diagnosed with radiation pneumonitis accompanied by eosinophilic alveolitis. Steroid therapy promptly improved the pneumonitis. Radiation pneumonitis accompanied by eosinophilic alveolitis extending outside the irradiated field is rare. Bronchoalveolar lavage is useful for a diagnosis, and steroid therapy is effective for treatment. PMID- 29279484 TI - Typhoid Vaccination among Japanese Travelers to South Asia and the Factors Associated with Compliance. AB - Objective In 2010, candid advice concerning the low rate of typhoid vaccination among Japanese travelers was received from Nepal. Recently, progressive Japanese travel clinics have encouraged Japanese travelers to be vaccinated against typhoid fever in conjunction with officially approved vaccines, such as hepatitis A vaccine. We herein report the status of typhoid vaccinations for Japanese travelers to the most endemic area (South Asia) and describe the factors associated with compliance. Methods In the travel clinic at Kurume University Hospital, we used the following criteria to retrospectively extract the records of new pre-travel Japanese clients between January 2011 and March 2015: hepatitis A vaccine administered, traveling to South Asian countries, and >=2 years of age. We first summarized the participants and then divided them into typhoid vaccinated and typhoid non-vaccinated groups for a comparative analysis. Results This study included 160 clients. A majority (70.0%) of these clients traveled for business. The duration of trips was long (>=1 month) (75.0%), and India was a popular destination (90.6%). A comparative study between the vaccinated group (n=122) and the non-vaccinated group (n=38) revealed that the two factors most positively associated with typhoid vaccination were business trips [adjusted odds ratio (aOR) 3.59, 95% confidence interval (CI) 1.42-9.06] and coverage by a company/organization payment plan (aOR 7.14, 95% CI 2.67-20.3). Conclusion The trend toward typhoid vaccination among Japanese travelers to South Asia with pre travel consultation is correlated with business trips and coverage by a company/organization payment plan. If problems concerning the cost of vaccines were resolved, more travelers would request typhoid vaccination. PMID- 29279485 TI - Clinical Condition and Management of 114 Mamushi (Gloydius blomhoffii) Bites in a General Hospital in Japan. AB - Objective Mamushi (Gloydius blomhoffii) snakebite is the most common type of snake injury in Japan and is also seen in China and Korea. Although the components of Mamushi venom have been investigated, epidemiological and clinical descriptions still remain limited in the English literature. The aim of this study was to review the clinical features and management of patients with injuries related to Mamushi snakebites. Methods We conducted a retrospective examination of 114 Mamushi snakebite cases encountered at a general hospital in Japan from January 2004 to November 2016. Data were collected from the medical records. Results We found that Mamushi snakebites commonly occurred during summer and the daytime, with elderly men typically being affected. The symptom grade at initial consultation was significantly worse in the walk-in group than in the ambulance admission group, probably due to treatment delay. The number of fangs that pierced the skin was not related to the severity of the symptoms. The group treated with a tourniquet more frequently exhibited exacerbation of symptoms than those that received other treatments (p<0.001). Conclusion The delay between patients being bitten and arriving at hospital as well as the number of fangs that pierced the skin did not affect the duration of hospitalization; however, proximal tourniquation should be avoided in such cases, as significant exacerbation of local symptoms was observed when this procedure was applied. PMID- 29279486 TI - Differences in the Serum 4beta-hydroxycholesterol Levels of Patients with Chronic Hepatitis C Virus (HCV) Infection: A Possible Impact on the Efficacy and Safety of Interferon (IFN)-free Treatment. AB - Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4beta-hydroxycholesterol (4betaHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4betaHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4betaHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4betaHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4betaHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV. PMID- 29279487 TI - Changes in Antidiabetic Drug Prescription and Glycemic Control Trends in Elderly Patients with Type 2 Diabetes Mellitus from 2005-2013: An Analysis of the National Center Diabetes Database (NCDD-03). AB - Objective To analyze the changes in the pharmacotherapy and glycemic control trends in elderly patients with type 2 diabetes mellitus (T2DM) in Japan. Methods We extracted the data of 7,590 patients (5,396 men and 2,194 women; median year of birth: 1945) with T2DM registered in the National Center Diabetes Database for the years 2005 to 2013, and conducted age-stratified (<65, 65-74, and >=75 years of age) analyses. Results The hemoglobin A1c (HbA1c) levels declined from 2005 to 2013, and for those who received antihyperglycemic drug prescription, the HbA1c levels were lower in the older age group than in the younger age group. In the >=75 age group, dipeptidyl peptidase-4 inhibitors (DPP4i) became the most frequently prescribed drug (49.1%) in 2013, and sulfonylureas remained the second most frequently prescribed drug (37.8%) with decreased prescribed doses. The prescription ratio of oral drugs associated with a risk of hypoglycemia was higher in patients >=75 years of age than in those <75 years of age (40.5% and 26.4%, respectively in 2013), although it showed a downward trend. The prescription rates of insulin for patients >=75 years of age increased during the study period. Conclusion The pharmacotherapy trends for elderly patients with T2DM changed dramatically in Japan with the launch of DPP4i in 2009. Glycemic control in a considerable portion of the >=75 age group in Japan was maintained at the expense of potential hypoglycemia by the frequent, although cautious, use of sulfonylureas, glinides and insulin. PMID- 29279488 TI - TAFRO Syndrome with Disseminated Intravascular Coagulation Successfully Treated with Tocilizumab and Recombinant Thrombomodulin. AB - TAFRO syndrome is a systemic inflammatory disorder that is characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. Although thrombocytopenia is one of the major features of TAFRO syndrome, complications of disseminated intravascular coagulation (DIC) are not common. The therapeutic strategy for TAFRO syndrome complicated by DIC has not been established. We herein describe a case of TAFRO syndrome with DIC that was successfully treated with tocilizumab (an anti-IL-6 receptor antibody) and recombinant thrombomodulin (rTM). This case suggests a possible therapeutic benefit of rTM in patients with TAFRO syndrome complicated by DIC. PMID- 29279489 TI - Glycogenic Hepatopathy in Type 1 Diabetes Mellitus. AB - Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM), and is characterized by elevated liver enzymes, hepatomegaly, and glycogen accumulation. We herein present the case of a 23-year old man with poorly controlled T1DM who had liver dysfunction. Imaging studies showed severe hepatomegaly and fatty liver. The examination of a liver biopsy specimen revealed fatty droplets, ballooning, inflammation, and mild fibrosis. Subsequent periodic acid-Schiff (PAS) staining after diastase digestion confirmed GH. In this case, the improvement of hyperglycemia, not HbA1c, resulted in the improvement of the patient's liver function. This is the first report on the use of continuous glucose monitoring in patients with GH to show that continuous hyperglycemia may worsen GH. PMID- 29279490 TI - Renal Mucinous Tubular and Spindle Cell Carcinoma Shows a High Uptake on 18F-FDG PET/CT. AB - We herein report a rare case of mucinous tubular and spindle cell carcinoma (MTSCC) in an 80-year-old woman. A well circumscribed tumor located on the right kidney was discovered incidentally as a result of screening non-contrast CT. Fluorodeoxyglucose positron emission tomography (FDG PET)/CT showed the increased tracer accumulation in the tumor. The histological diagnosis was MTSCC, which is a rare and only recently established subtype of the malignant renal cell carcinoma (RCC). The present case suggests the clinical benefit of a high uptake of FDG combined with enhanced contrast CT in the differentiation of MTSCCs and other RCCs. PMID- 29279492 TI - CyberKnife Stereotactic Radiosurgery for Cholangiocarcinoma. AB - Cholangiocarcinoma is a devastating cancer with a poor prognosis. Patients are often diagnosed at the advanced stage, and curative surgery is impossible. Radiation therapy is used for cases of advanced cancer. A 50-year-old woman with stage IVb intrahepatic cholangiocarcinoma was diagnosed with unresectable cancer, and had chemotherapy; however, the disease progressed. CyberKnife radiosurgery was performed, which was able to control the symptoms of liver failure and prolong her life. Her symptoms, which included jaundice, ascites, and edema disappeared and her tumor markers became normal. Even though she relapsed and was not able to survive, she was able to stay home with her family until the last days of her life. CyberKnife radiosurgery was useful as a non-invasive palliative treatment and successfully alleviated the symptoms of a patient with advanced cancer. PMID- 29279491 TI - IgG4-related Disease - A Systemic Disease that Deserves Attention Regardless of One's Subspecialty. AB - IgG4-related disease (IgG4-RD) is an inflammatory condition characterized by a high serum IgG4 concentration and the abundant infiltration of lymphocytes and IgG4-positive plasma cells in the tissue, as well as spatial (diverse clinical manifestations) and temporal (the possibility of recurrence) multiplicities. Since the initial documentation of IgG4-related disease in patients with autoimmune pancreatitis in 2001, a growing body of evidence has been accumulating to suggest that various-virtually all-organs can be affected by IgG4-RD. In general, steroid therapy is effective and is considered to be the first-line treatment for IgG4-RD. The precise mechanism underlying this systemic disorder has remained unknown. Considering that IgG4-RD was specified as being an intractable disease in 2015, further studies are needed to clarify whether IgG4 RD is indeed a distinct disease entity or a complex of disorders of different etiologies and clinical conditions. PMID- 29279493 TI - Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder, Hodgkin Type, following Epstein-Barr Viral Hepatitis in a Patient with Rheumatoid Arthritis. AB - A 59-year-old man with an 18-year history of rheumatoid arthritis who had been treated with steroids, methotrexate, and infliximab presented with a high-grade fever, cervical lymphadenopathy, and hepatosplenomegaly. Epstein-Barr virus (EBV) hepatitis was diagnosed based on the liver histology and EBV antibody titer. The symptoms improved temporarily, but five months later, the fever, skin rash, jaundice, and thrombocytopenia relapsed. Bone marrow and liver biopsies demonstrated infiltration with Reed-Sternberg cells. Based on these findings, the patient was diagnosed with other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD), Hodgkin lymphoma type. This case followed a rare clinical course, in that acute hepatitis preceded the diagnosis of OIIA-LPD. PMID- 29279494 TI - Raoultella planticola Bacteremia in a Patient with Early Gastric Cancer. AB - The patient was an 81-year-old man who was found to have bacteremia due to Raoultella planticola, which might have entered the circulation through the bile duct during the passing of a gallbladder stone. In the present case, we screened for malignancies because most cases of R. planticola bacteremia occur after trauma, invasive procedures, or in patients with malignancy (70.6%). Early gastric cancer was detected. Although the association between R. planticola bacteremia and malignancy remains speculative in the present case, it may be useful to scrutinize similar cases involving low-virulence bacteremia for possible malignancies or immune conditions. PMID- 29279495 TI - Thyrotoxicosis in Graves' Disease with Invasive Laryngeal Cancer. PMID- 29279496 TI - Paraneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma. AB - A 50-year-old man with lung adenocarcinoma (c-T1aN2M1b) experienced reddish purpura mainly on the lower legs after receiving 12 cycles of second-line chemotherapy with docetaxel. There was tumor enlargement on computed tomography performed to assess the therapeutic response, so paraneoplastic IgA vasculitis was considered. IgA vasculitis was diagnosed based on a biopsy of the skin lesion and histology of an upper gastrointestinal hemorrhagic mucosal erosion. As IgA vasculitis can lead to serious gastrointestinal or systemic complications, IgA vasculitis should be considered as a differential diagnosis for rashes in patients with malignancy. PMID- 29279497 TI - Isolated Finger Palsy Following a Spectacular Shrinking Deficit. PMID- 29279498 TI - Granulomatosis with Polyangiitis Complicated by Hypertrophic Pachymeningitis Presenting with Simultaneous Multiple Intracerebral Hemorrhages. AB - Central nervous system (CNS) involvement in granulomatosis with polyangiitis (GPA), including pachymeningitis and CNS vasculitis, is uncommon. Although intracerebral hemorrhage (ICH) has been reported in GPA, simultaneous multiple ICH (SMICH) is rare. We describe the case of a 50-year-old woman with a history of a limited form of GPA with chronic pachymeningitis who presented with acute onset headache accompanied by nausea and vomiting, and who developed consciousness impairment. Computed tomography revealed bilateral subcortical ICH. Sinus thrombosis was not apparent on angiography. The patient was treated with high-dose corticosteroid therapy. The cause of the steroid-responsive SMICH in this case was unknown, but it might have been CNS vasculitis. Patients with GPA may present with SMICH, which is considered an indication for immunosuppressive therapy. PMID- 29279499 TI - Anthracosis with a Mosaic Attenuation Pattern. PMID- 29279500 TI - Hepatic Angiomyolipoma Staining in the Post-vascular Phase of Contrast-enhanced Ultrasound Due to the Presence of Macrophages. AB - A 47-year-old Japanese man was referred to hospital after the detection of a liver tumor. Dynamic computed tomography and gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging were consistent with a diagnosis of hepatocellular carcinoma (HCC). No perfusion defect was observed in the post-vascular phase of contrast-enhanced ultrasound (CEUS). Histopathological staining of the tumor cells was positive for antibodies against HMB-45 and cluster of differentiation (CD) 68, confirming the diagnosis of hepatic angiomyolipoma (HAML). These findings indicated the presence of macrophages in HAML. We herein report a case of HAML explain how macrophages that are present within the tumor affect the staining characteristics in the post vascular phase of CEUS. PMID- 29279501 TI - Drug-induced Pressure Ulcers in a Middle-aged Patient with Early-stage Parkinson's Disease. AB - Drug-induced pressure ulcer (DIPU), which is a newly recognized adverse drug reaction, is associated with the administration of psychiatric drugs in geriatric patients with dementia. The notification of the causative drugs is crucial to the treatment of DIPU. We herein report the case of a 56-year-old woman with early stage Parkinson's disease who developed DIPUs after starting olanzapine treatment for depressive symptoms. Our findings illustrate that if an akinetic patient with pressure ulcers is encountered, the patient's medication should be reviewed by a multidisciplinary team, to evaluate whether the development of the pressure ulcer is drug-related, regardless of the patient's age. PMID- 29279502 TI - Giant Cavernous Hemangioma of the Adrenal Gland in an Elderly Patient. AB - Cavernous hemangioma is a rare, non-functional, benign adrenal tumor. Adrenal cavernous hemangioma is often diagnosed after surgery with a histologic examination. A 70-year-old man complaining of appetite loss was admitted to our hospital. An incidental large left adrenal mass was found by computed tomography (CT). There were no clinical signs of adrenogenital syndrome, Cushing's syndrome or primary aldosteronism. Total resection was carried out. The pathological diagnosis was cavernous hemangioma. The differentiation of adrenal tumor is necessary in cases of large tumors, and resection is desirable given the risks of hemorrhaging and rupture. PMID- 29279503 TI - Lung Metastases from Bile Duct Adenocarcinoma Mimicking Chronic Airway Infection and Causing Diagnostic Difficulty. AB - We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma. PMID- 29279504 TI - Unique Cellulitis: Helicobacter cinaedi. PMID- 29279505 TI - Current Status and Issues Regarding Transitional Health Care for Adults and Young Adults with Special Health Care Needs in Japan. AB - With the progress of medical care in recent years, the prognosis of intractable diseases of childhood onset has markedly improved. Young adults with special health care needs require continuous medical support throughout their lifetimes. To provide them with optimal health care services, a smooth transition from the pediatric medical system to the adult one is essential. However, in Japan many adult health providers are not sufficiently prepared to care for these patients, due both to limited opportunities to gain up-to-date medical knowledge on transitional health care and a lack of familiarity with the medical treatment of childhood-onset chronic diseases. In this review, we discuss current issues in transitional health care in Japan from an internist's viewpoint. PMID- 29279506 TI - Severe Steroid-responsive Skin Disorders Related to Ledipasvir and Sofosbuvir for HCV. AB - Combination therapy with ledipasvir and sofosbuvir (LDV/SOF), direct-acting antiviral agents, is highly effective against hepatitis C virus genotype 1 infection. Although LDV/SOF is safer than conventional treatment, reports have indicated that LDV/SOF was discontinued in certain cases due to severe skin disorders. A 68-year-old woman presented with a rash after starting LDV/SOF treatment. We interrupted LDV/SOF and began the oral administration of prednisolone (PSL). After the rash improved, we re-started LDV/SOF with PSL. After treatment, the rash clearly improved; we checked for a sustained virologic response 12 weeks after treatment. Steroids may therefore be an effective treatment option for controlling the side effects of LDV/SOF. PMID- 29279507 TI - Paget's Disease of Bone Presenting with Peripheral Neuropathy. PMID- 29279508 TI - Bazex Syndrome. PMID- 29279509 TI - Candida albicans Myocarditis and Renal Abscess. PMID- 29279510 TI - Prevalence of Multiple White and Flat Elevated Lesions in Individuals Undergoing a Medical Checkup. AB - Objective The pathogenesis of multiple white and flat elevated lesions in the stomach has not been elucidated. We investigated the prevalence of such lesions and their characteristics in affected individuals. Methods The subjects were 1,995 individuals (1,320 men, 675 women; mean age 54.2+/-9.5 years) who visited our medical center for a comprehensive annual medical checkup and in whom the status of Helicobacter pylori infection could be determined. The presence of multiple white and flat elevated lesions in the stomach and the degree of gastric mucosal atrophy were evaluated using endoscopic findings. Results Multiple white and elevated lesions in the stomach were observed in 60 subjects (3.0%), who were predominantly women and older in comparison to those without such lesions. The prevalence rates of these lesions in H. pylori-positive and H. pylori-negative and in post-eradicated subjects were 0.5%, 1.3%, and 4.6%, respectively. A multiple logistic regression analysis demonstrated that post-eradication status, female gender, older age, and a higher grade of gastric mucosal atrophy were significant risk factors for the occurrence of multiple white and elevated lesions. Conclusion Multiple white and elevated lesions were frequently observed in subjects with successful H. pylori eradication. PMID- 29279511 TI - IgA Nephropathy after Nivolumab Therapy for Postoperative Recurrence of Lung Squamous Cell Carcinoma. AB - Immune checkpoint inhibitors (ICIs) are becoming a common and important cancer therapy. ICIs are associated with a unique category of side effects, termed immune-related adverse events (irAEs). We herein report the case of a 72-year-old man with postoperative recurrence of lung squamous cell carcinoma who was treated with nivolumab and who developed proteinuria and a worsening kidney function. A kidney biopsy revealed IgA nephropathy. After drug withdrawal, the proteinuria improved and the deterioration of the patient's renal function was halted. Although renal irAEs are considered to be rare and glomerulonephritis is not typical presentation, physicians need to pay more attention to renal irAEs and glomerular injury. PMID- 29279512 TI - Bilateral Adrenal Hemorrhage in a Patient with Antiphospholipid Syndrome during Chronic Graft-versus-host Disease. AB - We present the case of a 56-year-old man with an upper respiratory infection followed by fatigue, hypotension, and hyponatremia. Bilateral adrenal hemorrhage was confirmed, based on T2-weighted magnetic resonance imaging. The patient had previously undergone allogeneic hematopoietic stem cell transplantation and had been diagnosed with antiphospholipid syndrome (APS) during the development of chronic graft-versus-host disease. A prompt diagnosis and steroid replacement, in addition to anticoagulant therapy, resulted in a favorable outcome. Once the diagnosis of APS has been confirmed, which might be the sign of bilateral adrenal hemorrhage, the initial manifestations of adrenal insufficiency should never be overlooked. PMID- 29279514 TI - An Evaluation of Clinical Economics and Cases of Cost-effectiveness. AB - In order to maintain and develop a universal health insurance system, it is crucial to utilize limited medical resources effectively. In this context, considerations are underway to introduce health technology assessments (HTAs), such as cost-effectiveness analyses (CEAs), into the medical treatment fee system. CEAs, which is the general term for these methods, are classified into four categories, such as cost-effectiveness analyses based on performance indicators, and in the comparison of health technologies, the incremental cost effectiveness ratio (ICER) is also applied. When I comprehensively consider several Japanese studies based on these concepts, I find that, in the results of the analysis of the economic performance of healthcare systems, Japan shows the most promising trend in the world. In addition, there is research indicating the superior cost-effectiveness of Rituximab against refractory nephrotic syndrome, and it is expected that health economics will be actively applied to the valuation of technical innovations such as drug discovery. PMID- 29279513 TI - The Safety and Efficacy of Combination Therapy of Sorafenib and Radiotherapy for Advanced Hepatocellular Carcinoma: A Retrospective Study. AB - Objective Sorafenib is a standard therapy for advanced hepatocellular carcinoma (HCC), whereas radiotherapy is effective for local control of extrahepatic spread (EHS) or macrovascular invasion (MVI). This study investigated the safety and efficacy of this combined therapy to treat advanced HCC. Methods This retrospective study reviewed 62 patients with advanced-stage HCC with EHS or MVI who received sorafenib therapy, excluding the patients with only lung metastases. Results Of the 62 patients, 15 were treated using the combined therapy of sorafenib and radiotherapy (group RS), and 47 were treated with sorafenib monotherapy (group S). In group RS, patients were treated using three-dimensional conformal radiotherapy with a total irradiation dose of 30-60 Gy (median, 50 Gy). Irradiation was targeted at the bone, lymph nodes, adrenal gland, and MVI in 6, 5, 1, and 4 patients, respectively. The overall incidence of adverse events was 93.3% in group RS and 91.5% in group S (p=N.S.). Incidences of thrombocytopenia, leukopenia, and skin reaction were significantly higher in group RS (73.3%, 40.0%, and 66.7%, respectively) than in group S (36.2%, 10.6%, and 27.7%, respectively, p=0.02, 0.02, and <0.01, respectively). The incidence of severe adverse events, however, was comparable in the 2 groups: 20% in group RS and 19.2% in group S. The median progression-free survival (PFS) of EHS or MVI, PFS of whole lesions, and overall survival were longer in group RS (13.5, 10.6, and 31.2 months, respectively) than in group S (3.3, 3.5, and 12.1 months, respectively) (p<0.01 for all). Conclusion Sorafenib in combination with radiotherapy is a feasible and tolerable treatment option for advanced HCC. PMID- 29279515 TI - Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis (AAV) Restricted to the Limbs. AB - A previously healthy 58-year-old man was admitted for muscle pain and weakness [manual muscle testing (MMT) of 4/4 for upper and lower limbs]. We detected elevated levels of inflammatory makers and PR3-anti-neutrophil cytoplasmic antibody (ANCA). Subsequently, the muscle weakness rapidly progressed to an MMT of 2 for all limbs. Magnetic resonance imaging indicated muscle edema, and the creatine kinase (CK) level increased to 29,998 U/L. Methylprednisolone (mPSL) and cyclophosphamide pulse therapy improved the patient symptoms. MMT recovered to 4 for all limbs. A muscle biopsy showed degenerated muscle fibers surrounded by neutrophil-predominant infiltration. In addition, lamina elastic breakdown and fibrinoid necrosis of arterioles were observed. A final diagnosis of microscopic polyangiitis (MPA) limited to the muscles was made. PMID- 29279516 TI - Spontaneous Development of Acute Obstructive Suppurative Pancreatic Ductitis Associated with Pancreatic Carcinoma: A First Case Report. AB - A 68-year-old man with a history of diabetes mellitus was admitted to our hospital with a diagnosis of acute pancreatitis. Abdominal computed tomography revealed a suspicious tumor in the body of the pancreas, along with a dilated main pancreatic duct and edema of the pancreatic tail. Endoscopic retrograde pancreatography was performed after treating the patient's pancreatitis. When a cannula tip was advanced beyond the stenosis, deep into the distal pancreatic duct, thick white pus was evacuated. A bacteriological examination of the aspirated pancreatic juice revealed Enterobacter cloacae, and a cytological examination revealed adenocarcinoma. The diagnosis was acute obstructive suppurative pancreatic ductitis associated with pancreatic carcinoma. PMID- 29279517 TI - The Role of Double-balloon Enteroscopy in the Diagnosis and Surgical Treatment of Metastatic Small Bowel Tumors. AB - Objective The aim of the present study is to investigate the role of double balloon enteroscopy in the diagnosis and surgical treatment of metastatic small bowel tumors. Patients We retrospectively reviewed the records of 13 patients with metastatic small bowel tumors among 376 patients who underwent double balloon enteroscopy from June 2005 to March 2017 in our hospital. Results The primary lesion sites were the lung (n=9), kidney (n=2), stomach (n=1) and duodenum (n=1). The clinical presentations were anemia requiring blood transfusion (n=10), obstructive symptoms (n=2), and no symptoms (n=1). The locations of the metastatic small bowel tumors were the jejunum (n=7), ileum (n=1), and both sites (n=5). The histological diagnosis of the metastatic tumor was made from biopsy specimens taken with double-balloon enteroscopy from all 11 patients whose condition permitted a biopsy. In seven patients, the findings on double-balloon endoscopy were determinants of the kind and extent of surgical treatment performed. Four patients had multiple metastatic small bowel tumors, and all were able to be removed surgically with guidance from preoperative tattooing at double-balloon endoscopy. After operation, blood transfusions were no longer needed in four of six patients who had required preoperative transfusions for the treatment of anemia, and one patient with intestinal obstructive symptoms was able to resume oral intake. Conclusion Double-balloon endoscopy was useful for making a histological diagnosis and directing surgical treatment in patients with metastatic small bowel tumors. Surgical treatment afforded palliation of symptoms in five patients. PMID- 29279518 TI - Anti-mitochondrial M2 Antibodies and Myopathy. PMID- 29279519 TI - Burkitt Lymphoma of the Duodenum. PMID- 29279520 TI - Taurine Protects Primary Neonatal Cardiomyocytes Against Apoptosis Induced by Hydrogen Peroxide. AB - The aim of this study was to investigate the effects of taurine (Tau) on primary cultured neonatal myocardial cells treated with hydrogen peroxide (H2O2) and the underlying mechanism. Primary cardiac myocytes from neonatal Wistar rats were pre incubated with Tau, and its effects on cell viability and expression of CaM, CaMKII, p53, Bcl-2, and Bax were examined. Tau enhanced the viability of myocardial cells, decreased apoptosis, and alleviated the intracellular calcium overload, especially at dosages of 40 or 80 mM (P < 0.01 or P < 0.001, respectively). Moreover, Tau could inhibit the H2O2-induced decrease in CamKII and CaM expression at both the mRNA and protein levels. The pattern of CaMKII expression was consistent with that of the anti-apoptotic protein Bcl-2, but contrasted the pattern of the pro-apoptotic proteins p53 and Bax. Thus, our results show that Tau protects myocardial cells against damage caused by H2O2 exposure, suggesting that it might play a role in the mitochondrial apoptotic pathway by upregulating the expression of CaMKII to rescue myocardial cells. However, the underlying mechanism still needs to be investigated. In addition, we tested the protective effect of taurine on cardiac myocytes, and the effect of taurine on another model, specifically an animal model. PMID- 29279521 TI - Influence of Renal Sympathetic Denervation in Patients with Early-Stage Heart Failure Versus Late-Stage Heart Failure. AB - Renal sympathetic denervation (RDN) is currently being investigated in multiple studies of heart failure (HF). Our aim was to assess the safety and effectiveness of RDN in patients with HF, and determine which patients could achieve more beneficial effects of RDN. A total of 17 consecutive patients with HF were enrolled in the study. Clinical symptoms, office blood pressure, and laboratory results were obtained and echocardiography was performed before and 12 months after RDN. Changes from baseline to 12 months were analyzed for all patients and for two subgroups based on HF duration (group 1: HF duration <= 3 years, n = 9; group 2: HF duration > 3 years, n = 8). The RDN procedure was successful in all patients and no procedure-related complications were documented. In comparison to baseline, there was a significant increase in left ventricular ejection fraction (LVEF) in all patients and group 1 (P < 0.05 for both), which did not happen in group 2. LAD, LVDs, and RVD also showed a significant reduction in group 1 (P < 0.05 for both). At 12 months, the reductions in TNF-alpha and CRP were significant for all patients and for patients in group 1 separately. No obvious changes in echocardiographic parameters, 6-minute walking distance, TNF-alpha, or CRP were recorded in group 2. No changes in BNP in either group were observed at the 12th month of follow-up. RDN could improve cardiac function and led to a significant drop in inflammatory markers in patients with HF. We also found that patients in early-stage HF could benefit more from RDN. PMID- 29279522 TI - Comparison of Direct Oral Anticoagulants and Warfarin in the Treatment of Deep Venous Thrombosis in the Chronic Phase. AB - We assessed the efficacy and safety of direct oral anticoagulants (DOACs) for the treatment of deep venous thrombosis (DVT) in the chronic phase through comparison with conventional warfarin therapy.A total of 807 consecutive patients who were diagnosed with having DVT in the chronic phase were included (484 patients to warfarin therapy and 323 patients to DOAC therapy). The condition of leg veins was assessed 3 to 6 months after starting the therapies by ultrasound examination. Major bleeding and mortality during the therapies were followed up.There was no significant difference between the two groups in the thrombosis improvement rate (DOAC group: 91.2% versus warfarin group: 88.9%). There was no significant difference between the two groups in major bleeding (DOAC group: 1.8% versus warfarin group: 1.8%). In patients with active cancer, the DOAC group had a borderline higher thrombosis improvement rate than the warfarin group (92.1% versus 80.0%, P = 0.05). The proportion of major bleeding in the patients with active cancer was slightly higher in the warfarin group than in the DOAC group (4.3% versus 2.8%; P = 0.71). Active cancer was not an independent risk factor for major bleeding and recurrence in the DOAC group (OR 2.68, 95% CI 0.51-14.1; P = 0.24 and OR 0.65, 95% CI 0.20-2.07; P = 0.47).In treatment using oral anticoagulants for DVT in the chronic phase, DOACs exhibited equal efficacy and safety as warfarin did. Particularly DOACs appear to be an attractive therapeutic option for cancer-associated DVT in chronic phase, with relatively low anticipated rates of recurrence and major bleeding. PMID- 29279523 TI - Soluble ST2 in Patients with Nonvalvular Atrial Fibrillation and Prediction of Heart Failure. AB - Atrial fibrillation (AF) is the most common clinically relevant arrhythmia. AF is a strong independent risk factor for the subsequent development of heart failure (HF). HF and AF can interact to perpetuate and exacerbate each other. Soluble ST2 (sST2) is a biomarker of cardiomyocyte stretch that is useful in the diagnosis and prognosis of HF. Its role in the field of AF has not yet been well investigated. We studied the concentration of sST2 in a cohort of 174 subjects (62.1% men; mean age, 65.6 +/- 10.3 years [+/- standard deviation (SD) ]) with nonvalvular AF and 116 age-matched patients with sinus rhythm (SR). Subjects were subdivided into 3 groups: paroxysmal AF, persistent AF, and SR. Plasma sST2 concentrations were measured using an electrochemiluminescence-based immunoassay. The sST2 level was higher in persistent AF patients (P < 0.05) and paroxysmal AF patients (P < 0.05) than in SR patients. No significant difference was found between persistent AF and paroxysmal AF. sST2 was correlated with left atrial diameter (LAD) (r = 0.21; P < 0.01). During a median follow-up time of 6 months, 43 subjects with non-valvular AF in the study had HF. Cox proportional hazard analysis revealed both sST2 and LAD were independent predictors of HF. sST2 concentrations are higher in AF than SR. Plasma sST2 may be a useful biomarker in predicting HF in patients with AF. PMID- 29279524 TI - Transcriptional Analysis of Endothelial Cell Alternation Induced by Atrial Natriuretic Polypeptide in Human Umbilical Vein Endothelial Cells. AB - The aim of this study was to explore how atrial natriuretic polypeptide (ANP) affects the properties and function of endothelial cells. Gene expression data GSE56976 generated at 0, 1, and 6 hours after ANP incubation in human umbilical vein endothelial cells (HUVEC) was used. Microarray data were preprocessed for differentially expressed genes (DEGs) in each time-dependent group. Next, gene ontology (GO), pathway analysis, and transcriptional regulation were performed. Co-expression clustering analysis of DEGs and functional enrichment analysis of co-expression modules were processed. RT-PCR analysis was performed to validate gene expression. DEGs were obtained and their counts were increased from 0 hours to 6 hours. No overlapping DEGs were obtained among the 3 groups. The DEGs of ANP_6hours, including TGFB2 (transforming growth factor, beta 2), LTF (lactotransferrin/lactoferrin), and ETV7 (Ets variant 7) were mainly related with cell apoptosis and immune responses. The DEGs in the network of ANP_0hour were mainly associated with epithelial ion transport processes. In addition, 3 co expressed modules were detected. CSF2 (colony stimulating factor 2) and PF4 (platelet factor 4) of the blue module were related with cytolysis, while FXYD1 (FXYD domain containing ion transport regulator 1) and TGFB2 of the yellow module were mainly enriched in ion transport and the ovulation cycle. The expression of TGFB2 obtained by microarray analysis was consistent with that of RT-PCR. Ion transport could be affected promptly after ANP treatment, and subsequently, the cytolysis of vein endothelial cells may be promoted and endothelial permeability would be enhanced, followed by activated immune responses. PMID- 29279525 TI - Planimetry of the Orifice Area in Aortic Valve Stenosis Using Phase-Contrast Cardiac Magnetic Resonance Imaging. AB - Manual planimetry is a well-established method using transesophageal echocardiography (TEE) to assess the severity of aortic stenosis (AS). TEE, however, is a less than optimal approach in patients with calcified valves. Even when using cine-cardiac magnetic resonance (CMR), it is often difficult to evaluate the true border of the aortic orifice because of jet turbulence. With phase-contrast sequences of CMR, high flow signals at the aortic orifice can be clearly visualized, even in cases with severe calcification and jet turbulence. Therefore, the aims of the present study were to compare the utility of CMR using phase-contrast imaging with TEE and cine-CMR for the performance of planimetry of the aortic valve. The study cohort consisted of 30 consecutive patients with moderate or severe aortic valve stenosis documented by TEE who had undergone phase-contrast and cine-CMR for the evaluation of AS. Manual planimetry of the area of high flow signal was traced over the phase-contrast images at systolic peak, when the aortic valve is maximally opened. The results showed that the aortic valvular area (AVA) value derived from TEE correlated better with phase contrast planimetry (r2 = 0.84, P < 0.05) than cine-mode planimetry (r2 = 0.57, P < 0.05). Bland-Altman plots indicated that the variation of measuring AVA was greater using the cine-mode method than the phase-contrast method. In conclusion, phase-contrast CMR offers a tool for evaluating the severity of aortic valve stenosis noninvasively. Phase-contrast CMR has the potential to become a routine clinical option as an alternative to TEE, at least in selected cases. PMID- 29279526 TI - In Situ Skeletonized Right Internal Mammary Artery Bypass Grafting to Left Anterior Descending Artery. AB - This study aimed to evaluate the feasibility and the mid-term efficacy of an in situ skeletonized right internal mammary artery (IMA) bypass grafting to a left anterior descending artery (LAD), and to determine risk factors for IMA graft failure in a single-center study.From January 2012 to December 2015, 189 patients (173 males, 50.6 +/- 6.0 years old) undergoing first isolated coronary artery bypass grafting surgery with the in situ skeletonized right IMA grafting to the LAD were included in this study. Baseline characteristics, peroperative data, and follow-up outcomes were investigated and analyzed.The length of the in situ skeletonized right IMA grafts was 18.6 +/- 1.2 cm (17.0-22.0 cm). Intraoperative graft flow of the in situ skeletonized right IMA grafting to LAD was 42 +/- 9 mL/minute (18-72 mL/minute) associated with measured pulsatility index of 0.8 4.3. In-hospital mortality was 0.5%. Postoperative morbidity included acute myocardial infarction (0.5%), stroke (0.5%), and deep sternal wound infections (1.1%). The mid-term survival was 97.2% and the incidence of repeat revascularization was 0.6%. The patency rate of the in situ skeletonized right IMA grafting to the LAD was 97.1% by computed tomography angiography examination during the follow-up period of 23.2 +/- 9.7 months. Additionally, logistic regression analysis showed that intraoperative graft flow had an independent influence on the risk of the mid-term right IMA graft failure.The strategy of the in situ skeletonized right IMA grafting to the LAD is feasible and effective. Intraoperative graft flow was an independent risk factor for the mid-term right IMA graft failure. PMID- 29279528 TI - Long Period and High Level of D-Dimer after Coronary Artery Bypass Grafting Surgery. AB - Hyper-coagulation after off-pump coronary artery bypass grafting (OPCAB) is one of the main reasons for graft thrombosis. D-dimer is closely linked to the activation of coagulation. Few studies have reported the variation range and long term abnormal coagulation after OPCAB in the Chinese population. Our study aimed to determine the characteristics and value of D-dimer after OPCAB.In this prospective study, 265 patients who underwent OPCAB for the first time were recruited from 2011 to 2012. The D-dimer level of the patients was tested before surgery and on the 1st, 4th, and 14th day, and 1st, 2nd, and 3rd month after surgery. Clinical data in the perioperative period and during the one-year follow up period were recorded.D-dimer level increased from day 4 after OPCAB ([1321.9 +/- 36.4] MUg/L), peaked at 1 month ([2839.7 +/- 101.4] MUg/L), and decreased to the baseline ([370.3 +/- 260.2] MUg/L) 3 months after surgery. No death occurred, but 25 (10%) patients suffered recurrent angina in the one-year follow-up. They had significantly higher D-dimer level at one month after OPCAB than those of patients who did not suffer from angina. Preoperative ejection fraction <50% and D-dimer level >2915 MUg/L at one month after surgery were significantly associated the recurrent angina.After OPCAB, patients have a higher level of D dimer. And this lasts for a long period (about 3 months). It may reflect a certain degree of hypercoagulable and hyperfibrinolytic state after OPCAB. PMID- 29279527 TI - Impact of Water- and Lipid-Soluble Statins on Nonculprit Lesions in Patients with Acute Coronary Syndrome. AB - Statins can be differentiated into two types, based on their solubility, which have potentially differing effects on the coronary artery wall. However, suspected differences in statins' effects on plaque composition have not been systemically investigated.Sixty-seven patients with acute coronary syndrome (ACS) were randomly assigned to either atorvastatin (10 mg/day) or rosuvastatin (2.5 mg/day). Intravascular ultrasound (IVUS) and integrated backscatter (IB)-IVUS, an established tool to quantify each plaque's components, were performed immediately after emergent percutaneous coronary intervention (PCI). Follow-up IVUS was performed between 6 and 12 months after PCI. Serial changes in serum lipid profiles and plaque composition volumes were compared between the two groups.Thirty-five patients were eligible for serial IB-IVUS analyses. The mean low-density lipoprotein-cholesterol level significantly decreased in the atorvastatin and rosuvastatin groups (P < 0.001); plaque volumes were also significantly reduced from 82.0 +/- 46.2 to 74.9 +/- 41.3 mm3 (P = 0.01) and from 74.7 +/- 35.3 to 67.7 +/- 27.0 mm3 (P = 0.02), respectively. IB-IVUS revealed a significant reduction in fibrous volume from 33.8 +/- 20.0 to 27.5 +/- 14.9 mm3 (P < 0.01) and from 29.6 +/- 13.6 to 24.8 +/- 7.6 mm3 (P < 0.05), respectively; however, significant changes were not noted in the volume of the lipid pool for the atorvastatin group and the rosuvastatin group, respectively.Water- and lipid soluble statins may be similarly effective in reducing coronary plaques in patients with ACS as judged qualitatively and quantitatively. Further study is needed to determine whether differences between water- and lipid-soluble statins affect plaque components. PMID- 29279529 TI - Optical Frequency Domain Imaging of Very Late Stent Thrombosis Following Bare Metal Stent Implantation for Acute Myocardial Infarction. AB - A 43-year-old man was admitted to our hospital with ST-segment elevation acute coronary syndrome. He had experienced myocardial infarction 19 months previously, and a bare-metal stent (BMS) had been implanted in the culprit distal right coronary artery at another hospital. Emergency coronary angiography showed thrombotic in-stent occlusion of the BMS. Intravascular ultrasound revealed an undersized stent compared with the size of the vessel and late stent malapposition (LSM) with abundant thrombi. The lesion was successfully recanalized via thrombectomy and plain old balloon angioplasty. Optical frequency domain imaging performed at follow-up coronary angiography confirmed the improvement of the LSM and incomplete neointimal stent coverage. This report illustrates the importance of imaging modalities in elucidating the mechanism of BMS-related very late stent thrombosis. PMID- 29279530 TI - Deeper S Wave in Lead V5 and Broader Extent of T Wave Inversions in the Precordial Leads are Clinically Useful Electrocardiographic Parameters for Predicting Pulmonary Hypertension. AB - Electrocardiography (ECG) is used to screen for pulmonary hypertension (PH). However, it is unclear which parameters of ECG are the most useful for screening.ECG parameters related to right ventricular hypertrophy criteria were examined in 145 ECGs of subjects who were suspected to have PH and underwent right heart catheterization (RHC) (age 58.4 +/- 17.5 years, 112 women, mean pulmonary arterial pressure [MPAP] 35.4 +/- 13.3 mmHg). Based on the results of RHC, 108 subjects had PH (56 pulmonary arterial hypertension [PAH] and 52 chronic thromboembolic pulmonary hypertension [CTEPH]).Fourteen of 17 ECG parameters in the present study were significantly associated with PH on univariate analysis. On multivariable logistic regression analysis, S wave depth in lead V5 (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.10-1.47) and depth of T wave inversion in lead V4 (OR 1.21, 95% CI 1.03-1.46) were independent predictors of MPAP >= 25 mmHg, and the cut-off values determined by receiver operating characteristic curve analyses were 0.42 mV and -0.28 mV, respectively.In conclusion, a deeper S wave in lead V5 and the presence of a wider extent of negative T waves in the precordial leads may be clinically simple and useful ECG parameters for screening for PH. PMID- 29279531 TI - Dual Antiplatelet Therapy Guided by CYP2C19 Polymorphisms after Implantation of Second-Generation Drug-Eluting Stents for Management of Acute Coronary Syndrome. AB - Prasugrel, a novel P2Y12 receptor inhibitor, is administered to patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI), but it can increase the risk of bleeding. The Japanese exhibit weaker responses to clopidogrel than other races because of CYP2C19 polymorphisms; thus, it is unclear whether these patients should continue dual antiplatelet therapy (DAPT) using prasugrel or switch to clopidogrel in the chronic phase. Here we evaluated the clinical outcomes of DAPT guided by CYP2C19 polymorphisms after implantation of second-generation drug-eluting stents (DESs) for ACS management. Patients with ACS receiving PCI via DES from November 2011 to March 2015 were divided into two groups: conventional DAPT with clopidogrel (n = 41) and gene-guided DAPT (n = 24). In the gene-guided DAPT group, all patients with ACS were given DAPT using prasugrel as soon as possible; extensive and intermediate metabolizers receiving PCI for the first time were switched to clopidogrel at least 2 weeks after discharge, and intermediate metabolizers with repeated ACS and poor metabolizers continued on DAPT using prasugrel. Notably, gene-guided DAPT significantly reduced major adverse cardiovascular/cerebrovascular events (MACCEs; 22.0% versus 4.2%, hazard ratio [HR]: 0.15, 95% confidence interval [CI]: 0.01-0.81; P = 0.0247). Hemorrhagic complications were observed in 3.1% of patients receiving conventional DAPT and absent in the gene-guided group. Moreover, multivariate analysis showed that gene-guided DAPT significantly decreased MACCE incidence (HR: 0.15, 95% CI: 0.01-0.81; P = 0.033). Collectively, these data suggest that CYP2C19 polymorphism analysis may improve treatment decisions in patients with ACS receiving DES-PCI. PMID- 29279532 TI - Acute Type A Aortic Dissection with Iliac Malperfusion in a Patient with Scimitar Syndrome. AB - We encountered a 35-year-old male patient with scimitar syndrome, acute type A aortic dissection, and severe iliac malperfusion. He presented with pain and weakness of the left lower extremity and underwent ascending aorta replacement through sternotomy and right anterior thoracotomy. Left iliac artery flow was recovered after the operation and the patient was discharged on the tenth day without any complication. The purpose of this report is to discuss the considerations in aortic surgery in patients with scimitar syndrome, and the surgical principles for treatment of aortic dissection with critical limb ischemia. PMID- 29279533 TI - The Incidence, Risk Factors, and Outcomes of Hyperlactatemia after Heart Transplantation. AB - Hyperlactatemia (HL) is associated with tissue hypoperfusion during cardiac surgery, which results in postoperative morbidity and mortality among patients undergoing cardiopulmonary bypass surgery. The aim of this study was to determine the incidence, risk factors, and outcome of HL after heart transplantation (HTx) in one of the largest Japanese single-center cohorts. We retrospectively studied the lactate levels in 49 patients who underwent HTx at the University of Tokyo Hospital from August 1, 2010 to November 30, 2015. All of the patients were over 20 years of age. Arterial blood samples were analyzed during the operation and until 24 hours after surgery. Twenty-nine patients (59.2%) had HL after intensive care unit admission. At 24 hours after surgery, the lactate levels of all patients had recovered to the normal range. A multivariate analysis showed that the total ischemic time of the donor heart (odds ratio [OR], 1.0176; 95% confidence interval [CI], 1.0004-1.0375; P = 0.0444) and the duration of preoperative left ventricular assist device (LVAD) support (OR, 0.9977; 95% CI, 0.9952-0.9997; P = 0.0218) were risk factors for HL. Pulmonary complications were noted in 24.1% of the patients with high lactate values but in none of the patients without HL (P = 0.0182); however, there were no cases of hospital death, and the length of hospital stay did not differ to a statistically significant degree between HL groups (P = 0.719). Although HL after HTx was common, it appeared to be transient and benign. Donor heart ischemia and the duration of preoperative LVAD support were associated with HL after transplantation. PMID- 29279534 TI - Transcatheter Retrieval of Embolized Atrial Septal Defect Occluder Device by Waist Capture Technique. AB - This case study describes the successful percutaneous transcatheter retrieval of an embolized Amplatzer occluder device using the "waist capture technique" in a patient with an atrial septal defect. This technique allowed for stability of the Amplatzer device, compression of the atrial discs for easier removal, prevention of further embolization, and minimal injury to vasculature during device retrieval. This novel and effective technique can be used safely for the retrieval of Amplatzer devices in the venous system. PMID- 29279541 TI - In vitro evaluation of electrospun PLGA/PLLA/PDLLA blend fibers loaded with naringin for guided bone regeneration. AB - The present study was to evaluate fiber mesh loaded with naringin via electrospinning to guide bone regeneration in vitro. The naringin-loaded fiber mesh was prepared via elctrospinning of PLGA, PLLA, PDLLA blending solution with naringin. SEM showed that naringin decreased the fiber's diameter according to the concentration of naringin. After 20 days' degradation in PBS, the drug-loaded fiber meshes still kept their stability with about 10% decrease in tensile strength. In vitro release experiments showed a sustained and steady naringin releasing profile with little initial burst releasing. Compared to the mats without naringin, the fiber mats loaded with naringin showed the most pronounced enhancement of cell growth when MC3T3-E1 cells were cultured on the fiber mats. The blend fiber loaded with naringin has optimized physical properties and sustained release profile in vitro. The study presents a promising fibrous mesh material for guided bone regeneration therapy. PMID- 29279542 TI - Customized surgical template fabrication under biomechanical consideration by integrating CBCT image, CAD system and finite element analysis. AB - This study developed a customized surgical template under mechanical consideration for molar intrusion. Two finite element (FE) models were analyzed for the primary stability under 100 gf traction forces with one mini-screw inserted at the buccal side in horizontal and another in palatal side with two optional positions at 60 degrees (P60) or 15 degrees (P15) angles with inclination toward the molar occlusal surface. The surgical template was generated using rapid prototyping (RP) printing for the clinical application based on improved primarily stability model. The surrounding bone strains for models P15 and P60 were far lower than the bone remodeling critical value. Model P60 presented much lower micro-motion in the screw/bone interface and the screw head displacement than those values in model P15. Using FE analysis for biomechanical evaluation and combining with CT image, image superimposed method and CAD technique can fabricate accuracy/security customized surgical template for mini-screws with better primary stability. PMID- 29279543 TI - Osteoblasts preferentially adhere to peaks on micro-structured titanium. AB - The aim of the study was to investigate cell adhesion to micro-structured titanium. Osteoblastic MC3T3 cells were cultured on smooth (P) or sand blasted/acid-etched (SLA) titanium discs and were observed at scanning electron microscope/focused ion beam (SEM/FIB). Myosin II and actin microfilaments were labelled for epifluorescence microscopy. FIB revealed that cell adhesion initiated centrally and expanded to the cell periphery and that cells attached on the substrate by bridging over the titanium irregularities and adhering mostly on surface peaks. Gaps were visible between concave areas and cytoplasm and areas around ridges represented preferred attachment points for cells. A different myosin distribution was observed between samples and myosin inhibition affected cell responses. Taken together our data indicate that cells attach on micro-rough titanium by bridging over its irregularities. This is likely mediated by myosin II, whose distribution is altered in cells on SLA discs. PMID- 29279544 TI - Use of grape seed extract for improving the shear bond strength of total-etching adhesive to bleached enamel. AB - This study was to ascertain if grape seed extract (GSE) can restore the shear bond strength (SBS) of total-etching adhesive to enamel immediately after bleaching. Immediately after bleaching with Beyond gel, different concentrations of GSE were applied to the surface of bovine enamel for 1 min before bonding of resin composite with Adper single bond 2 or All-Bond 3 adhesive. SBS values and debonding modes were recorded. Structure of the bonding interface and elements on enamel surface were analyzed by scanning electron microscopy and X-ray photoelectron spectroscopy (XPS). SBS was found to be compromised significantly in 0 and 2.5% GSE groups. GSE (>=5%) could restore the SBS to the level of control. Failure in the adhesive joint was always the major debonding mode. No significant difference was found by XPS. Thus, GSE can restore the SBS compromised after bleaching in 1 min if the concentration is >=5%. PMID- 29279545 TI - Shear bond strength and microleakage of a new self-etch adhesive pit and fissure sealant. AB - This study aimed to evaluate the shear bond strength (SBS) and microleakage of a new self-etch adhesive-based fissure sealant (EG) on aprismatic enamel in comparison to conventional fissure sealing with 30 s acid etching (CG). The fissures were sealed according to the manufacturer's instructions. Each group was divided into 3 subgroups: 1-day water storage, 3-month water storage, and 5,000* thermocycling. After measuring SBS using the Ultradent method, failure mode was analyzed. In additional 16 teeth, microleakage was tested using dye penetration method. Pairwise comparisons were analyzed using Mann-Whitney U-Test. Multiple linear regression was performed to assess the factors influencing on SBS. EG had significantly lower mean SBS (4.1 MPa+/-2.1) than the CG (17.6 MPa+/-6.4). CG (1.1%) performed significantly better than the EG (12.8%) in microleakage analysis. The tested EG yielded significantly inferior results and its clinical use should be decided after weighing its pros and cons. PMID- 29279546 TI - Application of fluoridated hydroxyapatite thin film coatings using KrF pulsed laser deposition. AB - Fluoridated hydroxyapatite (FHA) was investigated for application as an implant coating for titanium bone substitute materials in dental implants. A KrF pulsed excimer deposition technique was used for film preparation on a titanium plate. The compacts were ablated by laser irradiation at an energy density of 1 J/cm2 on an area 1*1 mm2 with the substrate at room temparature. Energydispersive spectrometric analysis of the FHA film revealed peaks of fluorine in addition to calcium and phosphorus. X-ray diffraction revealed the presence of crystalline FHA on the FHA film after a 10 h post annealing treatment at 450 degrees C. The FHA film coating exhibited significant dissolution resistance to sodium phosphate buffer for up to 21 days, and favorable cell attachment of human mesenchymal stem cells compared with HA film. The results of this study suggest that FHA coatings are suitable for real-world implantation applications. PMID- 29279547 TI - Characterization of fluoride releasing restorative dental materials. AB - This study aimed to evaluate and compare certain mechanical properties, Vickers hardness, water sorption, fluoride-release, shrinkage-stress and wear of five commercial fluoride-releasing restorative materials (Dyract, CompGlass, BEAUTIFIL II, ACTIVA-Restorative, and GC Fuji II LC), in relation to their microstructural characteristics. Mechanical properties were determined for each material following ISO standards. A wear test was conducted with 15,000 chewing cycles using a dual-axis chewing simulator. Daily fluoride-release was measured during the first 10 days by using a fluoride ion selective electrode. Scanning electron microscopy (SEM) was used to evaluate the microstructure of each material. Results were statistically analysed using ANOVA followed by post hoc Tukey's test. ACTIVA-Restorative exhibited the highest fracture toughness (1.1 MPa m1/2) among the materials tested. BEAUTIFIL II presented the highest flexural strength (145 MPa) which was not significantly different (p>0.05) from CompGlass and Dyract. Highest fluoride-release measurement was located for GC Fuji II LC among other tested materials. PMID- 29279548 TI - Concept and clinical application of the resin-coating technique for indirect restorations. AB - The resin-coating technique is one of the successful bonding techniques used for the indirect restorations. The dentin surfaces exposed after cavity preparation are coated with a thin film of a coating material or a dentin bonding system combined with a flowable composite resin. Resin coating can minimize pulp irritation and improve the bond strength between a resin cement and tooth structures. The technique can also be applied to endodontically treated teeth, resulting in prevention of coronal leakage of the restorations. Application of a resin coating to root surface provides the additional benefit of preventing root caries in elderly patients. Therefore, the coating materials have the potential to reinforce sound tooth ("Super Tooth" formation), leading to preservation of maximum tooth structures. PMID- 29279549 TI - Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4 CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future. Notably, premalignant mutations, tumor-specific mutations, and mutations specific to tumor-infiltrating B cells were identified in AITL. Thus, multi-step and multi-lineage genetic events may lead to the development of AITL. PMID- 29279550 TI - Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects. AB - Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a large-cell neoplasm with anaplastic morphology immunostained by the Ki-1 antibody, which recognizes CD30. In 1994, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion receptor tyrosine kinase was identified in a subset of patients, leading to subdivision of this disease into ALK-positive and -negative ALCL in the present World Health Organization classification. Due to variations in morphology and immunophenotype, which may sometimes be atypical for lymphoma, many differential diagnoses should be considered, including solid cancers, lymphomas, and reactive processes. CD30 and ALK are key molecules involved in the pathogenesis, diagnosis, and treatment of ALCL. In addition, signal transducer and activator of transcription 3 (STAT3)-mediated mechanisms are relevant in both types of ALCL, and fusion/mutated receptor tyrosine kinases other than ALK have been reported in ALK-negative ALCL. ALK-positive ALCL has a better prognosis than ALK-negative ALCL or other peripheral T-cell lymphomas. Patients with ALK positive ALCL are usually treated with anthracycline-based regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOEP (CHOP plus etoposide), which provide a favorable prognosis, except in patients with multiple International Prognostic Index factors. For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings. PMID- 29279552 TI - Nephrotic syndrome during the tapering of oral steroids after pathological diagnosis of Kimura disease from a lacrimal gland mass: case report and review of 10 Japanese patients. AB - A 42-year-old man with eosinophilia and high serum immunoglobulin E (IgE) developed a lacrimal gland mass on the left side. Excisional biopsy revealed hyperplasia of lymphoid follicles, and infiltration with lymphocytes and eosinophils around lacrimal gland acini, leading to the pathological diagnosis of Kimura disease. IgE-positive cells were mainly found along follicular dendritic cells, and a small number of IgG4-positive cells was present. One month after oral prednisolone was started at 40 mg daily and tapered to 10 mg daily, he developed lower leg edema on both sides and marked proteinuria (10.8 g/day). Renal biopsy showed no glomerular abnormalities, no immunoglobulin deposition, and no tubulointerstitial infiltration with eosinophils, leading to the diagnosis of minimal change nephrotic syndrome. Proteinuria subsided in response to an increased dose of prednisolone to 30 mg daily. Proteinuria relapsed three times in the following 5 years when oral prednisolone was tapered. In conclusion, Kimura disease manifested as an orbital mass and did not relapse. However, nephrotic syndrome relapsed frequently with background eosinophilia and high serum IgE. This study reviewed the clinical features of 10 Japanese patients with Kimura disease associated with proteinuria. PMID- 29279551 TI - Unilateral conjunctival infiltration of Adult T-cell leukemia/lymphoma. Case report and literature review. AB - Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia virus type 1 infection. Although conjunctival lymphoma is commonly reported with B-cell lymphoma, it rarely occurs in cases of ATLL. A 73 year-old Japanese female patient was admitted to our institution with evidence of abnormal lymphocytes, lymphadenopathy, and lung nodular lesions. Acute type ATLL was diagnosed, and therapy following the mLSG15 protocol was initiated. At the end of the second course, new bone lesions were detected. A modified treatment regimen was scheduled, but was postponed due to the appearance of gastrointestinal symptoms. Close observation resulted in a diagnosis of cytomegalovirus enteritis. One month after the diagnosis, the patient developed pain and discomfort in her left eye, which was determined to be due to a bulbar conjunctival tumor. Pathological findings revealed conjunctival infiltration of ATLL. Mogamulizumab treatment was initiated and was successful in eradicating the conjunctival lesions after the first course. However, at the end of the third course of therapy, pancytopenia was noted. Therefore, mogamulizumab therapy was discontinued, and the patient was on follow-up observation. Although there was no relapse of the conjunctival lesions, the patient died 1 year after the initial diagnosis, following therapy resistance. PMID- 29279553 TI - Low grade B-cell leukemia/lymphoma with macrogloburinemia. PMID- 29279554 TI - Topics on the molecular pathogenesis and therapeutic approaches for T/NK-cell lymphoma. PMID- 29279555 TI - Pharmacotherapy for Neuropathic Pain in Japan. AB - Neuropathic pain (NeP) results from injury to, or disease of, the peripheral or central components of the neural systems involved in pain. In contrast to inflammatory pain, NeP can persist after healing from the initial injury has resolved. Antipyretic agents, such as non-steroidal anti-inflammatory drugs, steroids, and acetaminophen are ineffective, while specific agents such as gabapentinoids, antidepressants, antiepileptics, and opioids are effective in treating NeP. In this review, we address the definition of NeP, pharmacotherapy for NeP in Japan, pain classification, setting goals for successful NeP medication, and the Japanese algorithm for the pharmacotherapy of NeP with specific prescription guidance. PMID- 29279556 TI - Lymphangiography Was Useful in Postoperative Intractable Chylothorax after Surgery for Esophageal Cancer: A Case Report. AB - Postoperative chylothorax after surgery for esophageal cancer is a rare but serious complication. Treatment initially consists of conservative therapy and, if it fails to provide improvement, it is important to perform surgical treatment without delay. We report on a recent case of intractable chylothorax. This report describes a 72-year-old man with Stage III esophageal squamous cell carcinoma. Subtotal esophagectomy, through a right thoracoabdominal approach with two-field lymphadenectomy, and cervical esophagogastric anastomosis via the retrosternal route, were performed. On the 12th postoperative day, a diagnosis of chylothorax was made. Conservative treatment was initiated, but it proved to be ineffective. Therefore, ligation of the thoracic duct via a thoracotomy was performed, but this was not effective, either. Lymphangiography undertaken to identify the site of the leak in the thoracic duct enabled a diagnosis of an extremely rare double thoracic duct and identification of the site of the leak in the thoracic duct, thereby allowing curative direct ligation of the site. This case underscores the remarkable usefulness of lymphangiography in dealing with intractable postoperative chylothorax. PMID- 29279557 TI - Effectiveness of Measuring Genetic Polymorphisms in Metabolizing Enzymes of Tacrolimus within One Medical Facility. AB - OBJECTIVES: Because genetic polymorphisms cause diverse activity in drug metabolizing enzymes, drug concentrations in the blood may be variable among patients. We analyzed the genotypes of CYP3A5 and MDR1, and investigated their relationship with whole blood drug concentrations. METHODS: Eight patients were administered an oral dose of tacrolimus for one week or longer prior to enrollment in this study. Whole blood concentrations for tacrolimus were measured 12 hours post oral administration, on the same day as genotyping, within our hospital using a fully automated gene analyzer. The procedures became so rapid that collection of blood samples could be completed within the same day (approximately one hour). RESULTS: The genotype frequency of CYP3A5 was *3/*3 in five patients, *1/*3 in two patients, and *1/*1 in one patient. All five patients with *3/*3 showed favorable increases in tacrolimus blood concentrations. In the two patients with *1/*3, an increase in tacrolimus blood concentration was not readily achieved in one patient, but increased favorably in the other patient. In the patient with *1/*1, tacrolimus was not detectable in the patient's blood. A favorable treatment effect was obtained by changing tacrolimus to cyclosporine. It is notable that genotypes in patients where tacrolimus was not detected in the blood were wild types: 2677G/G and 3435C/C in MDR1. CONCLUSIONS: The measurement of genetic polymorphisms in metabolizing enzymes of tacrolimus, within one medical facility, is applicable for the selection of immunosuppressants and individual dosing for the treatment of autoimmune disease. PMID- 29279558 TI - Consecutive Bilateral Hip Arthroscopy for Symptomatic Bilateral Femoroacetabular Impingement in an Elite Rugby player: A Case Report. AB - We report a case of concurrent bilateral hip arthroscopy for symptomatic bilateral femoroacetabular impingement (FAI) performed under the single anesthesia on an elite rugby player. A 27-year-old rugby player who played for a top league had bilateral hip joint pain. Physical examination revealed bilateral tenderness in the anterior area of the hips, with positive impingement signs. Based on the findings of hip radiography and magnetic resonance imaging, the patient's symptoms were diagnosed as bilateral FAI with hip labral tears. Bilateral hip arthroscopy under the single anesthesia was performed due to refractory symptoms. He returned to regular rugby games without any symptoms in either hip. Bilateral hip arthroscopic surgery under the single anesthesia should be an effective treatment for typical and symptomatic FAI, even in elite athletes. PMID- 29279559 TI - A Case of Metastatic Basal Cell Carcinoma Treated with Cisplatin and Adriamycin. AB - A 72-year-old man was referred to our hospital for treatment of an ulcer that had been growing on his back for 10 years. Physical examination showed an ulcerated tumor from the neck to the back and swollen cervical lymph nodes. The tumor size was 12*9 cm. Histology of the biopsy showed a nodular and morpheic basal cell carcinoma (BCC). A chest computed tomography (CT) scan showed multiple lung tumors. CT-guided biopsy of the lung and the cervical lymph node revealed metastatic basal cell carcinoma (MBCC). The primary skin tumor was resected and a total of 10 courses of cisplatin (25 mg/m2/day*75%) and adriamycin (50 mg/m2*75%) were administered for metastatic basal cell carcinoma (MBCC). The patient died 5 years and 3 months after his first visit. Autopsy revealed MBCC in the lung, kidney, pancreas, several lymph nodes, liver and bone. A portion of the tumor cells were composed of squamoid cells with eosinophilic cytoplasm, large nuclei, lack of the characteristic peripheral palisading and retraction artifacts, and variable cytoplasmic keratinization. These pathological findings were compatible with basosquamous cell carcinoma. Chemotherapy was effective for MBCC in this patient. PMID- 29279560 TI - A Drug Interaction between Crizotinib and Warfarin in Non-Small-Cell Lung Cancer: A Case Report. AB - We report a case of increased prothrombin time-international normalized ratio (PT INR) when crizotinib and warfarin were co-administered. A 74-year-old Japanese woman presented to the hospital with dyspnea, and was diagnosed with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Three years after surgical resection of the tumor, the patient started crizotinib because of the recurrence of NSCLC. She received 2 mg/day warfarin due to a medical history of cerebral infarction and chronic atrial fibrillation. Before crizotinib initiation, the patient's PT-INR was 2.60. After 7 days of daily doses of crizotinib, the patient's PT-INR increased to 3.65. This case report provides the first evidence of a drug interaction between crizotinib and warfarin. PMID- 29279561 TI - Prompt Procedures Have a Great Impact on the Consequences of Asiatic Black Bear Mauling. AB - INTRODUCTION: Although bear-inflicted human injuries are rare and the mortality rate of the injuries is usually not high, the chances of bear-human interactions have been increasing, with fatal cases being reported in Japan every year. The aim of this study was to report a series of bear-inflicted injuries and discuss their management and severity. MATERIALS AND METHODS: A retrospective study was performed at the emergency and critical care center of Aizu Chuo Hospital, a tertiary care center in Japan, from May 2013 to September 2015. During this period, we encountered 14 black bear injury patients (12 men and 2 women). RESULTS: Six victims were attacked in dense forests while collecting wild vegetables; 4 victims were attacked near their houses. Lacerations of the scalp and face were the most frequent injuries, affecting 13 patients. Three patients developed hemorrhagic shock. Injury severity scores ranged from 2 to 12 (median value, 6). None of the injuries was fatal. Thirteen patients were transported by the local fire department's ambulances, 9 of whom were transferred to doctor ambulances. CONCLUSIONS: Although the severity and mortality rate following bear inflicted injuries are not high, these encounters usually take place in remote rural areas, so a delay in rescue and proper care can lead to the incident becoming fatal. Hence, early decisions and arrangements for patient transportation to a tertiary care center and prompt measures to save lives will have a positive impact on the consequences of such incidents. PMID- 29279562 TI - Midterm Result of Arthroscopic Bicruciate Ligament Sutures for Multiligament Knee Injury in an Adolescent Patient. AB - BACKGROUND: Treatment of multiligament knee injuries, especially in adolescent patients, is challenging for orthopedic surgeons. Repair of collateral ligaments and reconstruction of cruciate ligaments are usually performed, however, ligament reconstruction with transphyseal or physeal-sparing techniques may lead to physeal damage and growth disturbances in skeletally immature patients. We present a case report on performing bicruciate ligament sutures arthroscopically in an adolescent patient. PATIENT AND METHODS: The patient was a 14-year-old boy, who was diagnosed with injuries to the anterior cruciate ligament, posterior cruciate ligament, and medial collateral ligament. Single-stage arthroscopic primary suturing of the anterior and posterior cruciate ligaments and open medial collateral ligament suturing were performed 7 days after the injury. RESULTS AND DISCUSSION: The patient returned to routine activities, including high-level competitive sports, at 8 months post-surgery, and currently, 8.5 years after surgery, remains without complications. Suture repair was able to minimize the size of the bone tunnels and to re-establish knee stability with native tissues. Therefore, the application of sutures may be a useful option for repairing multiligament knee injuries, particularly in adolescent patients. PMID- 29279563 TI - A Case of Anomalous Congenital Band that Was Difficult to Differentiate from Omphalomesenteric Duct Anomaly. AB - Anomalous congenital band (ACB) is rare and difficult to identify preoperatively. Here we report a pediatric ACB case that was preoperatively suspected using computed tomography and was difficult to differentiate from omphalomesenteric duct anomaly. ACB should be considered in the differential diagnosis of acute abdomen. PMID- 29279564 TI - A Case of a Giant Cell Tumor of the Tendon Sheath of the Middle Phalanx of the Fourth Toe. AB - Giant cell tumors of the tendon sheath (GCT-TS) are one of the most common tumors of the hand, along with ganglions. However, occurrence in the toes is far less common. Here we present a rare case of GCT-TS at the middle phalanx level of the flexor digitorum longus tendon sheath. Magnetic resonance imaging showed low intensity both on T1 and T2 weighted images. To the best of our knowledge, our case is the first report of a GCT-TS arising at the middle phalanx level of the flexor digitorum longus tendon sheath of the fourth toe. Although GCT-TS are rare in the toe, they must be included in the differential diagnoses of soft tissue tumors arising in the toes. PMID- 29279565 TI - The effects of marsupialization on bone regeneration adjacent to keratocystic odontogenic tumors, and the mechanisms involved. AB - Bone resorption in the jaws is one of the most severe complications of keratocystic odontogenic tumors (KCOTs), and can be treated by either enucleation or marsupialization. However, the effects of marsupialization on bone regeneration adjacent to KCOTs, and the mechanisms involved, are still unclear. In this study, samples of 27 KCOTs were collected (20 before marsupialization and 7 after marsupialization) to detect the expression of bone regeneration-related molecules adjacent to KCOTs by immunohistochemistry and real-time quantitative polymerase chain reaction (qPCR). The results showed that bone formation was significantly enhanced in the KCOT capsule wall adjacent to bone after marsupialization, as demonstrated by alkaline phosphatase activity assay and immunostaining for bone morphogenetic protein. Moreover, immunohistochemistry revealed that osteoprotegerin (OPG) was up-regulated in the KCOT capsule wall adjacent to bone after marsupialization, while receptor activator of nuclear factor-kappaB ligand (RANKL) was down-regulated. Real-time qPCR also demonstrated increased expression of OPG after marsupialization, accompanied by a decrease in the expression of osteoclastogenesis-related molecules such as cathepsin K, matrix metalloproteinase-9, NFATc1, RANK and RANKL. This study provides further evidence that marsupialization may promote bone regeneration adjacent to KCOTs partially through regulation of the OPG/RANK/RANKL signaling pathway. PMID- 29279566 TI - Trace of organic sulfur compounds detected from debonded interface between transparent acrylic resin and gold alloy. AB - The purpose of the current study was to evaluate the bonding performance of two single-liquid primers, which contained 6-(4-vinylbenzyl-n-propyl) amino-1,3,5 triazine-2,4-dithione (VTD) or 6-methacryloyloxyhexyl 2-thiouracil 5-carboxylate (MTU-6), used for bonding between metals and an acrylic resin. A gold alloy and high-purity titanium were used as adherend materials, and a transparent acrylic resin initiated with tri-n-butylborane derivative was selected as the luting material. Both adherends were treated with one of the primers and bonded with the luting material, after which shear bond strength was determined. Fourier transform infrared spectroscopy was used to analyze debonded resin specimens. Shear bond strength to gold alloy was significantly greater than that to titanium for both the VTD and MTU-6 primers. A trace of thiol structure, probably derived from VTD and MTU-6, was detected on resin surfaces debonded from gold alloy. These results indicate that the two organic sulfur compounds, which are stable in an atmospheric environment, are tautomerized into a thiol structure, thus allowing adsorption onto noble metals. In addition, the adsorbed thiol compounds contribute to chemical bonding between the acrylic resin and noble metal alloy, as polymerizable adhesive functional monomers. PMID- 29279567 TI - Effects of cleaning methods for custom abutment surfaces on gene expression of human gingival fibroblasts. AB - The aim of this study was to develop an effective method for cleaning implant abutments made by computer-aided design and computer-aided manufacturing techniques and to investigate the effect of decontamination in vitro. Briefly, a newly developed reagent (PK) and/or vacuum plasma (Plasma) were used to clean the surfaces of zirconia disks, and the effects of this decontamination were evaluated by X-ray photoelectron spectroscopy. Human gingival fibroblasts (HGFs) were cultured on sample disks for 6, 24, and 48 h. We evaluated cell attachment and gene expression of the acute inflammatory cytokines interleukin-6 and vascular endothelial growth factor A, and type 1 collagen. In the PK and PK+Plasma groups, surface contaminants were reduced by washing. In addition, HGF attachments was increased in the PK and PK+Plasma groups. Gene expressions of interleukin-6 and vascular endothelial growth factor A were lower at 6 h. Gene expression of type 1 collagen was increased at all time points after seeding. These results suggest that decontamination of implant abutment surfaces is important in initial HGF attachment and may improve the biological seal of peri implant soft tissue. PMID- 29279568 TI - Rapid detection of Candida albicans in oral exfoliative cytology samples by loop mediated isothermal amplification. AB - Loop-mediated isothermal amplification (LAMP) rapidly amplifies DNA under isothermal conditions. The aim of this study was to detect Candida albicans and compare the positivity rate in the LAMP reaction with that of conventional methods for oral exfoliative cytology (EC) samples. Sixty-eight EC samples from 53 patients were subjected to LAMP analysis. These patients had been clinically diagnosed with leukoplakia, squamous cell carcinoma, oral lichen planus (OLP), stomatitis, oral candidiasis, and other malignancies. LAMP reactions were defined as positive when the sample turbidity exceeded 0.1 (arbitrary unit). Periodic acid-Schiff (PAS) staining and microbial culture were also performed to detect Candida species in EC samples. The LAMP reaction detected C. albicans in 42.6% of EC samples. Candida species were detected in 32.4% of the same samples by culturing and in 29.4% of samples by PAS staining. C. albicans DNA was detected most frequently in samples from OLP patients. We conclude that, in comparison to conventional methods for detection of C. albicans, the LAMP method is highly sensitive and time-saving, and does not require expensive equipment or diagnostic technology. It may therefore be useful for on-site screening of C. albicans at dental clinics. PMID- 29279569 TI - Bond strength of universal adhesives to air-abraded zirconia ceramics. AB - The bond strength of universal adhesives to air-abraded zirconia ceramic was evaluated. Overall, 40 zirconia ceramic blocks with dimensions of 6 * 6 * 4 mm were cut from pre-sintered blanks. The sintered blocks were embedded in self cured acrylic resin. The zirconia blocks were then randomly allocated to four groups (n = 10) in which different universal adhesives were used, except for the control group in which no universal adhesive was used. A silicon mold was used to build the resin cement. All specimens were stored in distilled water for 24 h at 37 degrees C and mounted on a universal testing machine. They were then subjected to shear bond strength testing at a cross-speed of 0.5 mm/min until failure occurred. The failure modes were analyzed using a digital microscope at 50* magnification. Univariate one-way analysis of variance and Tukey's post-hoc test were used for statistical analysis. Compared with the control group, the groups with universal adhesives showed statistically significant differences (P < 0.05). In addition, there was no statistically significant difference in the bond strengths of the groups with universal adhesives (P > 0.05) . After 24 h of storage, the cementation bond to air-abraded zirconia ceramic was improved by the application of a universal adhesive. PMID- 29279570 TI - Continuous combined intake of polydextrose and lactitol stimulates cecal fermentation and salivary IgA secretion in rats. AB - Immunoglobulin A (IgA), which plays an important role in infection defense, is upregulated in the large intestine and oral cavity through dietary fiber intake. However, the mechanism underlying salivary IgA increase through dietary fiber intake remains unknown. This study investigated time-dependent effects of non absorbable polydextrose (PDX) and lactitol intake on salivary IgA secretion and cecal fermentation. Five-week-old rats were fed a fiber-free diet with or without 25 g/kg PDX and 25 g/kg lactitol for 1, 4, and 8 weeks. Compared to control, those who ingested PDX and lactitol had higher salivary IgA flow rates per weight of submandibular gland tissue at 4 and 8 weeks (P < 0.05), greater cecal weight and digesta at 1, 4, and 8 weeks (P < 0.05), and lower concentrations of short chain fatty acids (SCFAs) in cecal digesta (P = 0.0003). These findings suggest that the consumption of PDX and lactitol may upregulate salivary IgA secretion possibly by stimulating absorption of SCFAs produced by cecal fermentation. Thus, continuous ingestion of PDX and lactitol for up to 4 weeks could increase salivary IgA and promote immune defense against pathogen invasion through the oral route. PMID- 29279571 TI - Transplantation of mature adipocyte-derived dedifferentiated fat cells into three wall defects in the rat periodontium induces tissue regeneration. AB - The transplantation of dedifferentiated fat (DFAT) cells in combination with poly(d,l-lactic-co-glycolic acid) (PLGA) scaffolds has previously been proven as an effective approach in promoting periodontal tissue regeneration in a rat fenestration defect model. The aim of this study was to assess the regenerative potential of DFAT cells in a rat model of three-wall periodontal bone defect. Three-wall bone defects were created bilaterally on the mesial side of rat maxillary first molars and were either left untreated or treated by implantation of PLGA scaffolds with DFAT cells or PLGA alone. Four weeks after surgery, the tissues were processed for micro-computed tomography (micro-CT) and histomorphometric examination. Micro-CT revealed that the PLGA/DFAT group had significantly higher rates of bone regeneration than the other groups, while histomorphometric analysis showed that the PLGA/DFAT group had significantly higher densities of collagen fiber bundles in acellular and cellular cementum than the PLGA group. Moreover, the results indicate that the placement of the PLGA scaffold prevented the downgrowth of the junctional epithelium. These findings suggest that DFAT cells contribute to tissue regeneration in three-wall periodontal defects, while PLGA provides space necessary for periodontal tissue restoration. PMID- 29279572 TI - Reactions of human dental pulp cells to capping agents in the presence or absence of bacterial exposure. AB - An ideal pulp-capping agent needs to have good biocompatibility and promote reparative dentinogenesis. Although the effects of capping agents on healthy pulp are known, limited data regarding their effects on bacterial contaminated pulp are available. This study aimed to evaluate the reaction of contaminated pulps to various capping agents to assist clinicians in making informed decisions. Human dental pulp (HDP) cell cultures were developed from extracted human molars. The cells were exposed to a bacterial cocktail comprising Porphyromonas gingivalis, Prevotella intermedia, and Streptococcus gordonii before being cocultured with capping agents such as mineral trioxide aggregate (MTA) Portland cement (PC), and Dycal. HDP cell proliferation was assayed by MTS colorimetric cell proliferation assay, and its differentiation was evaluated by real-time PCR for detecting alkaline phosphatase, dentin sialophosphoprotein, and osteocalcin expressions. MTA and PC had no apparent effect, whereas Dycal inhibited HDP cell proliferation. PC stimulated HDP cell differentiation, particularly when they were exposed to bacteria. MTA and Dycal inhibited differentiation, regardless of bacterial infection. In conclusion, PC was the most favorable agent, followed by MTA, and Dycal was the least favorable agent for supporting the functions of bacterial compromised pulp cells. PMID- 29279573 TI - Effect of local bone marrow stromal cell administration on ligature-induced periodontitis in mice. AB - Bone marrow-derived multipotent stromal cells (BMSCs) have potent antiinflammatory effects. This study aimed to investigate the antiinflammatory potential of BMSCs using a mouse model of ligature-induced periodontitis. BMSCs were isolated from the femurs and tibiae of mice. Periodontitis was induced by placing a ligature around the right maxillary second molar. After 3 days, the mice were administered BMSC in the gingiva of the mesial interdental papilla around the ligatured molar. The ligatured and non-ligatured mice that were not administered BMSC served as controls. Differences in inflammatory infiltration and bone resorption around the roots of the second molar were assessed and were subsequently quantified using microcomputed tomography (micro-CT), histological analysis, and tartrate-resistant acid phosphatase (TRAP) staining. Micro-CT revealed that alveolar bone loss around the ligatured molars increased in a time dependent manner; however, the effect was significantly less in BMSC-treated mice compared with ligatured control mice. Tissue histopathology revealed that BMSC administration mitigated inflammatory infiltration in ligatured BMSC mice. In addition, the number of TRAP-positive osteoclasts was markedly elevated in ligatured control mice compared with those in BMSC-treated mice. These findings indicate that local BMSC administration can mitigate inflammation and alveolar bone resorption, suggesting that administering BMSC leads to new therapeutics for periodontitis. PMID- 29279574 TI - Sports drink consumption and dental erosion among amateur runners. AB - This cross-sectional study assessed the prevalence and potential risk factors for dental erosion in amateur athletes at running events. After a sample calculation, 108 runners from the state of Rio de Janeiro, Brazil, were selected and examined for dental wear by a single trained and calibrated evaluator (kappa = 1.00). To identify risk factors, the runners were interviewed by using a standardized, semi structured questionnaire. The average (SD) age of the runners was 34.2 (11.45), and the prevalence of dental erosion was 19.4%. Gastroesophageal reflux, running frequency per week, and time expended during competition were associated with dental erosion (P < 0.05). The association between use of isotonic drinks and dental erosion was not significant (P > 0.05). In conclusion, dental erosion was not associated with use of isotonic drinks. However, frequency of exercise per week and gastroesophageal reflux were risk factors for dental erosion. PMID- 29279575 TI - Topic of Influence, Methane and Microbes. PMID- 29279576 TI - Hydrocarbon Degradation and Bacterial Community Responses During Remediation of Sediment Artificially Contaminated with Heavy Oil. AB - Natural biodegradation of heavy oil in the marine environment can be accelerated by the addition of nutrients or seeding of pre-selected microorganisms. In this study, a microcosm experiment was conducted to investigate the effects of inorganic nutrient supplementation (biostimulation) and bacterial consortium amendment (bioaugmentation) on the natural degradative processes of artificially contaminated sediment. Our results revealed that the addition of nutrients had greater effect on remediation than the addition of bacterial cells. Supplementation of inorganic nutrients promoted and sustained the growth of oil degrading and heterotrophic bacteria throughout the experimental period. Highest reduction in the total petroleum hydrocarbons, and of their components, n alkanes, polycylic aromatic hydrocarbons (PAHs) and alkyl PAHs, were obtained in the biostimulated microcosms. Changes in the bacterial community were monitored by the PCR-DGGE (polymerase chain reaction-denaturing gradient gel electrophoresis) method targeting the 16S rDNA gene. Results revealed different responses of the bacterial community to the addition of heavy oil and remediation agents. Shifts in the bacterial communities in the seawater were more dynamic than in the sediment. Results of this study showed that addition of remediation agents significantly enhanced the natural biodegradation of heavy oil in a sediment-seawater microcosm trial. PMID- 29279577 TI - Characterization of Anti-Ice Nucleation Activity of the Extract from Coffee Refuse. AB - The supercooling-facilitating (SCF) activities, that is, the anti-ice nucleation activity of the hot water extracts from five types of processed food refuse was examined. The extract with the highest activity among five hot water extracts was coffee refuse, showing 1.50C of SCF activity at a final concentration of 0.1 mg/ml. From the hot water extract of coffee refuse, the coffee refuse extract containing various polyphenols was prepared by the ultrafiltration (less than MWCO 10,000), a solvent fractionation of ethyl acetate. The yield of coffee refuse extract was 0.9% (w/w) from dried coffee refuse. The SCF activity of the coffee refuse extract at a final concentration of 1.0 mg/ml was 4.2C. HPLC analysis of the coffee refuse extract showed that caffeine and chlorogenic acid, which are major components of coffee, could be found at 173 and 62.3 ug/ml, respectively. However, the SCF activities of both compounds (0.70 and 1.06C) at a final concentration of 0.1 mg/ml were lower than those of ferulic acid and coumaric acid, respectively at 3.40 and 2.35C. This is the first report to our knowledge on the SCF activity of caffeine. The SCF activity of caffeine at a final concentration of 1.0 mg/ml was 2.3C. The specificity of caffeine against various ice nuclei containing calcium oxalate, 9-fluorenon, and ice nucleating bacteria was examined. Caffeine at a final concentration of 1.0 mg/ml could inhibit the ice nucleation activity of calcium oxalate, and Pseudomonas fluorescens KUIN-1 at the same level that of as silver iodide. From these results, it was suggested that the extract could be able to be applied to the field to control the frost damage of the vegetables and that the harvested vegetables might be stored unfrozen even at 0C or less. PMID- 29279578 TI - Characterization and Application of Lytic Bacteriophages against Campylobacter jejuni Isolated from Poultry in Japan. AB - The aim was to isolate Campylobacter jejuni-specific lytic phages from meats on the market in Japan. These phages were effectively isolated from 13 of 15 (86.7%) retail chicken meat samples (skin and liver) by the enrichment method using Preston Campylobacter Selective Enrichment Broth and 10 host Campylobacter strains. Among the 26 phage isolates, 14 were extracted by means of C. jejuni L26 as a host strain. Phage PHC10 showed the broadest lytic spectrum: active against 67.4% of the 46 C. jejuni strains tested. The other phage isolates showed different lytic spectra. Because phages PHC5, PHC10, PHC19, PHC22, and PHC25 possess an icosahedral head and a contracted tail, they seem to be members of the Myoviridae family. Effects of 19 phage isolates on viability of C. jejuni were investigated. These phages reduced viable counts of C. jejuni by 1-3 log after 6 12 h of incubation at 42C as compared to the initial counts. The C. jejuni L26 was found to be suitable as a host because of the wide hosting range. The phages isolated in this study seem to be promising biocontrol agents against C. jejuni in food. PMID- 29279579 TI - Stability of Weakly Acidic Hypochlorous Acid Solution with Microbicidal Activity. AB - Hypochlorous acid (HOCl) solution (200 ppm, pH 6) was prepared and evaluated for their stabilities and microbicidal activities. We demonstrated that HOCl is unstable against ultraviolet (UV) light, sunshine, contact with air, and elevated temperature (?25C). Furthermore, in the HOCl solution, the presence of excess NH2 or CHO-containing organic compounds such as proteins and carbohydrates, or of inorganic ions such as NO2-, SO3-, PO3-, Fe2+, Cu2+, and CuS, resulted in the rapid consumption of HOCl by oxidation reactions, and significantly decreased the microbicidal activity of the HOCl solution against coliform bacteria and total viable cell count. Thus, production of stable HOCl solution requires formulation in pure water harboring concentrations as low as possible of various compounds and ions, as well as storage in dark and cool conditions (<10C) to maintain the concentration of HOCl molecules and microbicidal activity. PMID- 29279580 TI - Antibacterial Activities of Surfactants in the Laundry Detergents and Isolation of the Surfactant Resistant Aquatic Bacteria. AB - Linear alkylbenzene sulfonate (LAS) and polyoxyethylene lauryl ether (POLE) are major surfactants contained in the laundry detergents. In the present study, the antibacterial activities of the surfactants to aquatic microorganisms were compared. When freshwater samples from a small river in Okayama city were treated with each of the surfactants, only LAS showed the significant antibacterial activity. Several strains, which survived after the treatment with 2.0% LAS, were isolated and identified by sequencing of 16S rDNA. All strains were classified into the family Enterobacteriaceae. However, this family was not a major member of the aquatic microflora, suggesting that the bacteria in Enterobacteriaceae have a common property of LAS-resistance in the river water. PMID- 29279581 TI - Anti-Ice Nucleation Activities of Adenine and Poly-A Nucleotides. AB - Most of the ice nucleation activity inhibitor reported so far are compounds processing the hydroxyl group such as the polyphenolic derivative. After examining the anti-ice nucleation activity of the purine base, the highest compound is theophylline, and the activity showed 3.80+/-0.32C at a final concentration of 0.1 mg/ml. We found that the activity of the adenine which was essential to genome information DNA was higher than that of guanine. After examining effect of adenine concentration, high activity showed 9.1+/-1.2C and became approximately constant above 0.1 mg/ml. This active rise is a result of effect of concentration under alkaline condition. Therefore after examining effect of pH on the activity of adenine, this activity rose under an alkaline condition. The active rise predicts that an electric charge of adenine is a factor. Among four kinds of nucleotide of 6 bases, poly-A nucleotide was higher and showed 1.33+/-0.42C at a final concentration of 0.1 mg/ml. This activity of poly-A were proportional to the number of the base. From these results, it was suggested that the poly-A and adenine could be able to be applied to the field to preserve the blood and tissue which differentiated in the generative medicine. PMID- 29279582 TI - Histopathological diagnoses in soft tissue tumours: an experience from a tertiary centre in Malaysia. AB - Soft tissue tumours are a group of remarkably diverse neoplasms that frequently pose significant diagnostic challenges to general pathologists. This study aimed to compare the agreement of histopathological diagnoses between general pathologists from various referral institutes and the referred soft tissue pathologist in a tertiary centre. The common discrepancies and their causes are also presented here. A retrospective study was conducted on 243 cases of potential soft tissue tumours referred to Hospital Kuala Lumpur, Malaysia over a period of 5 years. Reports by the referring pathologists and the soft tissue pathologist were compared based on tumour classification and tumour behaviour. Overall, there was moderate agreement in soft tissue tumour diagnoses in both tumour classification (weighted kappa = 0.423) and tumour behavior (weighted kappa = 0.548). The highest agreement of tumour classification was seen in the adipocytic tumours (21/28 cases), Ewing sarcoma (5/7 cases) and smooth-muscle tumours (3/5 cases). The highest rates of discrepancies were the so-called fibrohistiocytic tumours (7/11 cases), vascular tumours (9/15 cases) and undifferentiated/ unclassified sarcomas (19/32 cases). Full agreement for tumour behaviour was seen in 178 cases and there were 21 cases of zero agreement. Liposarcoma, alveolar soft part sarcoma and benign fibrous histiocytoma were the most frequent benign/malignant diagnostic discrepancies. The most common causes of discrepancy were wrong morphological interpretation followed by insufficient immunohistochemical stains performed. In conclusion, review of diagnosis by a pathologist specialized in soft tissue improves the quality of diagnosis in these heterogenous and rare tumours. A good panel of immunohistochemical stains with additional molecular study is crucial in the general hospital laboratories practice. PMID- 29279583 TI - Psychological markers underlying murder weapon profile: a quantitative study. AB - The horrific nature of murder using different types of weapons has been an important focal point of many criminological studies. Weapons that are used in murders seem to play dominant roles in murder investigations as they may provide information leading to arrest. The established factors for weapon usage include environmental context, demography and availability of weapons. However, there is insufficient research attention on the psychological functioning of murderers for particular weapon usage. In light of this, the current study seeks to narrow this gap of information by identifying the influences of psychological traits on weapon usage among a sample of male murderers. The present cross-sectional study was conducted among 71 male murderers incarcerated in 11 prisons within Peninsular Malaysia. The selection of the sample was based on predetermined selection criteria using a purposive sampling method. A guided self-administered questionnaire comprising sociodemography variables and four Malay validated psychometric instruments: Zuckerman-Kuhlman Personality Questionnaire-40-Cross Culture, Self-control Scale, "How I Think" Questionnaire and Aggression Questionnaire; was used. Independent sample t-test was performed to establish the mean score differences of psychological traits between the murderers who used single and multiple weapons while Kruskal-Wallis tests were carried out to ascertain the differences between the specific types of weapons used among the murderers. Following this, one-way ANOVA was carried out to ascertain the psychological trait differences among the murderers according to the different sources of weapon. Results indicated specific psychological traits influenced the number(s), source(s) and type(s) of weapon used in committing murder. The findings have implications for the psychological profiling of unknown murderers within the Malaysian context. PMID- 29279584 TI - Immunohistochemical expression of NANOG in urothelial carcinoma of the bladder. AB - Urothelial carcinoma is a common malignant neoplasm that has a poor prognosis and a high frequency of recurrence and metastasis. Constant disease surveillance with periodic and long term cystoscopy examination is necessary for management of the disease. However, the monitoring and therapy regimen is expensive, incurring a massive burden to patients and the government. Therefore, the development of specific biomarkers for urothelial carcinoma at an early stage and recurrence detection becomes a priority. Homeobox genes are a family of genes that are involved in tumourigenesis. They might be potential prognostic markers for urothelial carcinoma. The study investigated the expression pattern of NANOG which is one of a homeobox gene in different stages and grades of urothelial carcinoma. NANOG expressions were also correlated with patient demographic factors and clinicopathological parameters. The expression of NANOG in 100 formalin-fixed paraffin-embedded urothelial carcinoma tissues was determined by immunohistochemistry. Immunohistochemistry showed positive expression of NANOG in all specimens with detection in the cytoplasm, nuclei and the nuclear membrane of the cancer cells. The immunohistochemical expression of NANOG increased across stages and grades of the tumour. The expression of NANOG was not significantly associated with demographic factors; gender (p = 0.376), race (p = 0.718) and age (p = 0.058) as well as with most of the clinicopathological parameters; pathological stage (p = 0.144), grade (p = 0.625), lymph node involvement (p = 0.174) and distant metastasis (p = 0.228). However, NANOG expression showed significant correlation with tumour invasion (p = 0.019). We concluded that NANOG might be a potential biomarker for early diagnosis of urothelial carcinoma of the bladder. PMID- 29279585 TI - Distribution of gastric adenocarcinoma subtypes in different ethnicities in Kuala Lumpur, Malaysia. AB - The multiracial population in Malaysia has lived together for almost a century, however, the risk of gastric cancer among them varies. This study aimed to determine the distribution of different gastric adenocarcinoma subtypes and Helicobacter pylori infection status among gastric adenocarcinoma patients. Patients with gastric adenocarcinoma were enrolled from November 2013 to June 2015. Blood samples were collected for detection of H. pylori using ELISA method. Gastric adenocarcinoma cases were more prevalent in the Chinese (52.8%), followed by the Malays (41.7%) and least prevalent in the Indians (5.6%). Gastric adenocarcinoma located in the cardia was significantly more prevalent in the Malays (66.7%) compared to the Chinese (26.3%), whereas non-cardia cancer was diagnosed more in the Chinese (73.7%) compared to the Malays (33.3%) [P = 0.019; OR = 5.6, 95 CI: 1.27 to 24.64]. The Malays also had significantly higher prevalence of gastric tumour located at the cardia or fundus than other gastric sites compared to the Chinese (P = 0.002; OR: 11.2, 95% CI: 2.2 to 56.9). Among the cardia gastric cancer patients, 55.6% of the Malays showed intestinal histological subtype, whereas all the Chinese had the diffuse subtype. More than half of the patients (55.3%) with gastric adenocarcinoma were positive for H. pylori infection and among them, 66.7% were Chinese patients. The risk of gastric adenocarcinoma in our population is different among ethnicities. Further studies on host factors are needed as it might play an important role in gastric cancer susceptibility in our population. PMID- 29279586 TI - Expression of clusterin in colorectal carcinoma in relation to clinicopathological criteria. AB - BACKGROUND/AIM: Colorectal carcinoma (CRC) carries a high incidence of morbidity and mortality. Prognosis is related to nodal metastasis and stage. Clusterin is a widely distributed glycoprotein with not yet fully understood functions. Clusterin may be overexpressed in some tumours or under expressed in other tumours. The aim behind this study is to examine the relation of clusterin cytoplasmic immunostaining to tumour characteristics, disease relapse, and survival in CRC. MATERIALS AND METHODS: Paraffin blocks of 133 CRCs were retrieved from the Department of Pathology, King Abdulaziz University, Jeddah, Saudi Arabia. Immunostaining was done using antibody to clusterin. Staining expression in 10% of malignant cells was used as a cut-off to determine low immunostaining and high immunostaining. Statistical tests were used to evaluate the association of clusterin immunostaining with clinicopathological parameters. RESULTS: Immunohistochemical results showed clusterin low immunostaining in CRC and nodal metastases. No association was found between clusterin immunostaining and tumour grade, age, tumour invasiveness, distant metastases, vascular invasion, nodal metastases, relapse, and survival. CONCLUSION: Our study showed low clusterin immunostaining in CRC with lack of association with prognostic indicators in CRC. These results raise the controversy of understanding the role of clusterin in CRC. Further molecular studies are required to explore more about possible mechanisms of clusterin association with tumorigenicity, apoptosis, tumour growth progression, local and vascular invasion, and metastasis of CRC. PMID- 29279587 TI - Cyclooxygenase-2 (COX2) expression in adenocarcinoma surpasses that of squamous cell carcinoma in the uterine cervix. AB - Over the years, adenocarcinoma (ADC), which has a worse prognosis than squamous cell carcinoma (SCC) of the cervix, has shown an increasing trend. Cyclooxygenase 2 (COX2) expression which has been associated with worse prognosis in several solid cancers was studied for its association with SCC and ADC of the cervix. 35 histologically re-confirmed SCC and 35 ADC were immunohistochemically stained for COX2 using a mouse monoclonal antibody to COX2 (1:100; Dako: Clone CX-294) on a Ventana Benchmark XT. The histoscore was computed as intensity of staining, semi quantitated on a scale of 0-3 with 0 = negative, 1 = weak, 2 = moderate and 3 = strong staining intensity; multiplied by percentage of immunopositivity on a scale of 0-4 with 0 = <1%, 1 = 1-25%, 2 = 26-50%, 3 = 51-75% and 4 = >=75% of immunopositive tumour cells. Histoscore 1-3/12 was considered as low and >=4/12 as high COX2 expression. SCC affected Chinese more than Malays, while Malays had more ADC (p = 0.032). Mean age at presentation of SCC (57.5 years) was about a decade later than ADC at 47.9 years (p = 0.002). 30/35 (85.7%) of SCC and 34/35 (97.1%) of ADC expressed COX2. Histoscores of ADC (median = 4.0, IQR = 3.0-6.0) was significantly higher (p = 0.014) than those of SCC (median = 3.0, IQR = 2.0 3.0). High histoscores (>=4/12) were more frequent in ADC (55.9%) compared with SCC (26.7%) (p = 0.018), implicating COX2, either directly or indirectly, as a possible player in influencing the poorer outcome of ADC compared with SCC. PMID- 29279588 TI - Comparison of the sensitivity and specificity of p16/Ki-67 dual staining and HPV DNA testing of abnormal cervical cytology in the detection of histology proven cervical intraepithelial neoplasia grade 2 and above (CIN 2+). AB - INTRODUCTION: Human papillomavirus (HPV) testing is used as a means of triaging cervico-vaginal smears with low grade squamous abnormalities or as part of co testing with cytology. While HPV testing has a high sensitivity, it has a low specificity in detecting cervical intraepithelial neoplasia grade 2 and above (CIN 2+) leading to unnecessary colposcopy referrals. We investigate the accuracy of the p16/Ki-67 dual immunocytochemical stain in determining the presence of CIN 2+ lesions on histology and its potential as a superior biomarker for triage. METHODS: Liquid based cervico-vaginal cytology specimens with squamous abnormalities and corresponding histology from 97 women with subsequent colposcopy and biopsy were included. The specimens were then subjected to the dual stain and Roche Cobas 4800 multiplex real time PCR HPV DNA testing. The sensitivity and specificity of the dual stain and HPV testing were calculated using CIN 2+ on histology as a reference standard. RESULTS: The sensitivity and specificity of the dual stain in detecting histology proven CIN 2+ was 93.7% and 76.5% while HPV testing was 85.7% and 14.7% respectively. Of the 44 women with ASCUS or LSIL on cytology, the dual stain also reduced the number of unnecessary colposcopy referrals from 27 to 7 when used as a triage marker compared to HPV testing. CONCLUSION: p16/Ki-67 dual stain was more sensitive and specific than HPV testing in determining the presence of CIN 2+ on histology. It could triage low grade cervico-vaginal specimens more effectively and potentially help women avoid unnecessary colposcopies. Future studies are needed to further evaluate its role in cervical cancer screening programmes. PMID- 29279589 TI - DNA vaccination with a plasmid encoding LACK-TSA fusion against Leishmania major infection in BALB/c mice. AB - Vaccination would be the most important strategy for the prevention and elimination of leishmaniasis. The aim of the present study was to compare the immune responses induced following DNA vaccination with LACK (Leishmania analogue of the receptor kinase C), TSA (Thiol-specific-antioxidant) genes alone or LACK TSA fusion against cutaneous leishmaniasis (CL). Cellular and humoral immune responses were evaluated before and after challenge with Leishmania major (L. major). In addition, the mean lesion size was also measured from 3th week post infection. All immunized mice showed a partial immunity characterized by higher interferon (IFN)-gamma and Immunoglobulin G (IgG2a) levels compared to control groups (p<0.05). IFN-gamma/ Interleukin (IL)-4 and IgG2a/IgG1 ratios demonstrated the highest IFN-gamma and IgG2a levels in the group receiving LACK-TSA fusion. Mean lesion sizes reduced significantly in all immunized mice compared with control groups at 7th week post-infection (p<0.05). In addition, there was a significant reduction in mean lesion size of LACK-TSA and TSA groups than LACK group after challenge (p<0.05). In the present study, DNA immunization promoted Th1 immune response and confirmed the previous observations on immunogenicity of LACK and TSA antigens against CL. Furthermore, this study demonstrated that a bivalent vaccine can induce stronger immune responses and protection against infectious challenge with L. major. PMID- 29279590 TI - Distribution of adeB and NDM-1 genes in multidrug resistant Acinetobacter baumannii isolated from infected wound of patients admitted in a tertiary care hospital in Bangladesh. AB - BACKGROUND: The adeB gene in Acinetobacter baumannii regulates the bacterial internal drug efflux pump that plays a significant role in drug resistance. The aim of our study was to determine the occurrence of adeB gene in multidrug resistant and New Delhi metallo-beta-lactamase-1 (NDM- 1) gene in imipenem resistant Acinetobacter baumannii isolated from wound swab samples in a tertiary care hospital of Bangladesh. METHODS: A total of 345 wound swab samples were tested for bacterial pathogens. Acinetobacter baumannii was identified by culture and biochemical tests. Antimicrobial susceptibility pattern was determined by the disc diffusion method according to CLSI standards. Extended spectrum beta lactamases were screened using the double disc synergy technique. Gene encoding AdeB efflux pump and NDM-1 were detected by Polymerase Chain Reaction (PCR). RESULTS: A total 22 (6.37%) Acinetobacter baumannii were identified from 345 wound swab samples and 20 (91%) of them were multidrug resistant. High resistance rates to some antibiotics were seen namely, cefotaxime (95%), amoxyclavulanic acid (90%) and ceftriaxone (82%). All the identified Acinetobacter baumannii were sensitive to colistin and 82% to imipenem. Two (9%) ESBL producing Acinetobacter baumannii strains were detected. adeB gene was detected in 16 (80%) out of 20 multidrug resistant Acinetobacter baumannii. 4 (18%) of 22 Acinetobacter baumannii were imipenem resistant. NDM-1 gene was detected in 2 (50%) of the imipenem resistant strains of Acinetobacter baumannii. CONCLUSION: The results of this study provide insight into the role of adeB gene as a potential regulator of drug resistance in Acinetobacter baumanni in Bangladesh. NDM-1 gene also contributes in developing such resistance for Acinetobacter baumannii. PMID- 29279591 TI - Transperineal template-guided prostate saturation biopsies in men with suspicion of prostate cancer: a pilot study from Pakistan. AB - Traditionally, transrectal ultrasound (TRUS)-guided biopsies are done for the diagnosis of prostate cancer (PCa) in Pakistan. The transperineal template-guided saturation biopsy (TTSB) approach has been recently introduced in Pakistan and we share diagnostic yields and pathological findings of specimens taken for PCa diagnosis in men with elevated serum total prostate specific antigen (PSA) and negative TRUS-guided prostate biopsies. In all, 16 patients investigated at the Department of Urology, Sindh Institute of Urology and Transplantation (SIUT), underwent TTSB. The mean age of patients was 67.8 +/- 8.8 (range: 55 - 84) years. The median PSA was 9.5 (IQR: 7.9 - 19.8) ng/ ml. The duration of symptoms before biopsy ranged from 1 month to 144 months. The prostate was enlarged with mean weight of 73.5 +/- 55.5 g. Histopathology revealed PCa in 5 of 16 (31.2%) cases. The Gleason score was 6 (3+3), 7 (3+4) and 8 (4+4) in 1 case each (6.3%) and 10 (5+5) in 2 cases (12.5%). At least two cores were positive in all positive cases. None of the patients required antibiotics post-procedure. In conclusion, the TTSB technique is a promising option for patients with elevated PSA level and negative transrectal prostate biopsies for the detection of PCa in our setting. PMID- 29279592 TI - Rapidly increasing liver progenitor cell numbers in human regenerating liver after portal vein ligation and liver partition. AB - BACKGROUND: Liver regeneration is dependent on the proliferation of hepatocytes. Hepatic progenitor cells are intra-hepatic precursor cells capable of differentiating into hepatocytes or biliary cells. Although liver progenitor cell proliferation during the regenerative process has been observed in animal models of severe liver injury, it has never been observed in vivo in humans because it is unethical to take multiple biopsy specimens for the purpose of studying the proliferation of liver progenitor cells and the roles they play in liver regeneration. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a staged procedure for inducing remnant liver hypertrophy so that major hepatectomy can be performed safely. This staged procedure allows for liver biopsy specimens to be taken before and after the liver begins to regenerate. CASE PRESENTATION: The liver progenitor cell proliferation is observed in a patient undergoing ALPPS for a metastatic hepatic tumour. Liver biopsy is acquired before and after ALPPS for the calculation of average number of liver progenitor cell under high magnification examination by stain of immunomarkers. This is the first in vivo evidence of growing liver progenitor cells demonstrated in a regenerating human liver. PMID- 29279593 TI - Diagnostic conundrum of a perineal tumour: a rectal gastrointestinal stromal tumour mimic. AB - Gastrointestinal stromal tumour (GIST) is a common mesenchymal tumour arising in the gastrointestinal tract, but not frequently encountered in the rectum. Herein, we describe a case of a rectal GIST which mimicked histomorphological features of a schwannoma; thus, making intraoperative frozen section evaluation challenging. Although subsequent immunohistochemistry and molecular findings readily confirmed the diagnosis of a GIST, we wish to draw attention to three clues that will help the pathologist steer clear of this potential diagnostic pitfall. One, GISTs are relatively more common than schwannomas in the rectum. Two, schwannomas usually have very little mitoses. Three, rectal GISTs commonly exhibit nuclear palisades. We also discuss the diagnostic, prognostic and therapeutic functions of immunohistochemical and molecular investigations. As the surgical intent for rectal GISTs is for en-bloc excision with wide margins, we surmise that the intraoperative consult should include GIST as a possible differential diagnosis for rectal mesenchymal tumours. In view of the potential for neoadjuvant treatment with imatinib before surgical excision to preserve sphincter function, a multidisciplinary approach is recommended for establishing most effective treatment strategy in these rare complex cases. PMID- 29279594 TI - POEMS syndrome. AB - POEMS syndrome is the syndrome of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and typical Skin changes. A 65-year-old lady presented with the 2-day-history of inability to walk, 4-month-history of progressive worsening of muscle weakness of both lower limbs and 1-year-history of progressive worsening of bilateral numbness of lower limbs. Nerve conduction study revealed generalized sensorimotor demyelinating polyneuropathy. She was initially treated as chronic inflammatory demyelinating polyradiculoneuropathy with intravenous immunoglobulin (IVIG) and high-dose prednisolone. However, she had no significant neurological improvement despite getting standard therapy. In addition to peripheral neuropathy, the presence of hepatosplenomegaly, skin changes, polycythaemia and thrombocytosis prompted for further investigations. She was diagnosed as POEMS syndrome based on the presence of two mandatory major criteria [polyneuropathy, monoclonal plasma cell proliferative disorder (lambda)], one major criterion (sclerotic bone lesions) and three minor criteria (organomegaly, skin changes and thrombocytosis/polycythaemia). She received treatment with melphalan and prednisolone. She achieved clinical improvement and partial response (haematologic and radiological) after six cycles of therapy. We highlight the awareness of this rare syndrome, for patients presenting with peripheral neuropathy and not responding to its standard therapy, by recognizing other associated clinical manifestations and proceeding further diagnostic work up. PMID- 29279595 TI - Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma - a rare vascular neoplasm with deceptive morphology and distinctive immunophenotype. AB - Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma is a rare, low grade vascular (endothelial) neoplasm typically presenting as multicentric, superficial to deep nodules in extremities with a slight tendency of affecting young adult males. We report a case of pseudomyogenic hemangioendothelioma in a 15-year-old boy presenting initially with a 1 cm right thigh painless cutaneous lump. The lump was excised with the clinical impression of a sebaceous cyst. On microscopy, a poorly circumscribed, mild to moderately atypical spindle cell lesion in fascicular and storiform patterns with strikingly myoid-like eosinophilic cytoplasm was identified. The spindle cells were highlighted by pancytokeratin AE1/AE3, CD31, and ERG with retained INI-1, while being negative for MNF116, S100, CD34, EMA, desmin, SMA, caldesmon, myogenin, MyoD1, HHV-8 and CD163. Following the first diagnostic report, a positron emission tomography computed tomography (PET-CT) scan revealed another 4 cm ill-defined nodule accompanied by a smaller adjacent 0.7 cm ipsilateral satellite nodule within the right psoas muscle that displayed similar morphology and immunophenotype as the cutaneous lump, supporting the multicentric feature of this unique entity. It is an uncommon yet increasingly recognised neoplasm of endothelial origin possessing a misleading myoid morphology and distinctive immunophenotype worth notifying. PMID- 29279596 TI - Light chain multiple myeloma: an evaluation of its biochemical investigations. AB - Multiple myeloma is a type of plasma cell dyscrasia, characterised by presence of paraprotein or monoclonal (M)-protein in serum or urine. The M-protein may consist of an intact immunoglobulin, the heavy chain only or the light chain only. The latter, designated as light chain multiple myeloma (LCMM) makes up almost 20% of myelomas. Clinical manifestation is often heralded by hypercalcaemia, renal impairment, normocytic normochromic anaemia and bone lesions, reflecting end-organ damage, collectively known as the acronym CRAB. In particular, free light chain nephrotoxicity accounts for the high prevalence of renal impairment seen in LCMM. This case illustrates a typical presentation of LCMM with focal discussion on its initial and diagnostic, as well as prognostic biochemical investigations. PMID- 29279597 TI - Severe asymptomatic hypophosphataemia in a child with T-acute lymphoblastic leukaemia. AB - Hypophosphataemia is a metabolic disorder that is commonly encountered in critically ill patients. Phosphate has many roles in physiological functions, thus the depletion of serum phosphate could lead to impairment in multiple organ systems, which include the respiratory, cardiovascular, neurological and muscular systems and haematological and metabolic functions. Hypophosphataemia is defined as plasma phosphate level below 0.80 mmol per litre (mmol/L) and can be further divided into subgroups of mild (plasma phosphate of 0.66 to 0.79 mmol/L), moderate (plasma phosphate of 0.32 to 0.65 mmol/L) and severe (plasma phosphate of less than 0.32 mmol/L). The causes of hypophosphataemia include inadequate phosphate intake, decreased intestinal absorption, gastrointestinal or renal phosphate loss, and redistribution of phosphate into cells. Symptomatic hypophosphataemia associated with haematological malignancies has been reported infrequently. We report here a case of asymptomatic severe hypophosphataemia in a child with acute T-cell lymphoblastic leukaemia. A 14-year-old Chinese boy was diagnosed to have acute T cell lymphoblastic leukaemia (ALL). His serum biochemistry results were normal except inorganic phosphate and lactate dehydrogenase levels. The serum inorganic phosphate level was 0.1mmol/L and the level was low on repeated analysis. The child had no symptoms related to low phosphate levels. The possible causes of low phosphate were ruled out and urine Tmp/GFR was normal. Chemotherapy regime was started and the serum phosphate levels started to increase. Hypophosphataemia in leukaemia was attributed to shift of phosphorus into leukemic cells and excessive cellular phosphate consumption by rapidly proliferating cells. Several reports of symptomatic hypophosphataemia in myelogenous and lymphoblastic leukaemia in adults have been reported. To our knowledge this is the first case of severe asymptomatic hypophosphataemia in a child with ALL. PMID- 29279598 TI - Secondary polycythaemia in a Malay girl with homozygous Hb Tak. AB - Hb Tak is one of more than 200 high affinity haemoglobin variants reported worldwide. It results from the insertion of two nucleotides (AC) at the termination codon, between codon 146 and codon 147 of the beta-globin gene [Beta 147 (+AC)]. Polycythaemia is the main clinical feature although affected carriers are usually asymptomatic and do not require intervention. Several case studies in this region have reported the co-inheritance of Hb Tak with Hb E, delta beta and beta thalassaemia with one case of homozygous Hb Tak in a Thai boy. In this case report, a cluster of haemoglobin Tak was found in a family of Malay ethnic origin. Cascade family screening was conducted while investigating a 4-year old girl who presented with symptomatic polycythaemia. She had 2 previous Hb analysis done, at 7-month and 2-year-old with the diagnosis of possible Hb Q Thailand and Homozygous Hb D, respectively. Both diagnosis did not fit her clinical presentations. She was plethoric, had reduced exercise tolerance as well as cardiomyopathy. Her parents were consanguineously married and later diagnosed as asymptomatic carriers of Hb Tak. Consequently, re-analysis of the girl's blood sample revealed a homozygous state of Hb Tak. In conclusion, high oxygen affinity haemoglobin like Hb Tak should be considered in the investigation of polycythaemic patients with abnormal Hb analyses. In this case, DNA analysis was crucial in determining the correct diagnosis. PMID- 29279600 TI - Abstracts of the 2017 4th Annual Scientific Meeting of the Malaysian Division of the International Academy of Pathology. PMID- 29279599 TI - Solid pseudopapillary neoplasm of the pancreas with liver metastasis initially misinterpreted as benign haemorrhagic cyst. AB - Solid pseudopapillary neoplasm (SPN) of the pancreas is considered a low malignant neoplasm with a good prognosis. However, 5% to 15% of patients with SPNs develop metastatic disease, most commonly in the liver. Metastatic hepatic malignancies that show pseudocystic features are rare. Here we describe the case of a middle-aged female with a cystic liver metastasis from SPN. To the best of our knowledge, SPN with a single cystic liver metastasis has not been described, although these tumours frequently undergo haemorrhagic-cystic degeneration. Thus, in these patients the marked cystic change could be misinterpreted as a benign lesion. PMID- 29279601 TI - Isolation and Culture of Primary Mouse Retinal Pigment Epithelial (RPE) Cells with Rho-Kinase and TGFbetaR-1/ALK5 Inhibitor. AB - BACKGROUND Primary RPE cells could be a reliable model for representing in vivo status of RPE compared with cell lines. We present a protocol for in vitro isolation and culture of primary RPE cells from C57BL mice. MATERIAL AND METHODS We used C57BL mice ages 7 days to 4 months. The RPE layer was separated from the neural retina layer by digestion with 2% Dispase for 45 min and scraped off from the choroid after 25-min incubation in 37 degrees C. Collected RPE sheets were gently pipetted up into smaller sheets. RPE sheets were transferred into well plates and cultured in vitro for 2 weeks. To inhibit epithelial-mesenchymal transition (EMT) of RPE cells, we used Y27632 and Repsox to treat cultured primary RPE cells. RESULTS RPE cells isolated from C57BL mice maintained pigmented and hexagonal morphology in culture. However, long-term in vitro culture lead to the periphery cells of a RPE sheet becoming mesenchymal-like cells. In contrast to the control group, Y27632 and Repsox, which are inhibitors of Rho-kinase or TGFbetaR-1/ALK5, promoted primary RPE cells to maintain epithelial-like morphology and eventually become confluent. CONCLUSIONS RPE cells isolated from C57BL mice could be a powerful cell model to study the biological function of RPE. Especially, C57BL mice with different defective genetic background resulting in ocular diseases, would expand the genome type of RPE cells. The method presented here could be an efficient and applicable technique to obtain large numbers of primary RPE cells that maintain some characteristics of in vivo RPE. PMID- 29279603 TI - History of the fragmentation of the African rain forest in the Dahomey Gap: insight from the demographic history of Terminalia superba. AB - Paleo-environmental reconstructions show that the distribution of tropical African rain forests was affected by Quaternary climate changes. They suggest that the Dahomey Gap (DG)-the savanna corridor that currently separates Upper Guinean (UG, West Africa) and Lower Guinean (LG, western Central Africa) rain forest blocks-was forested during the African Humid Holocene period (from at least 9 ka till 4.5 ka), and possibly during other interglacial periods, while an open vegetation developed in the DG under drier conditions, notably during glacial maxima. Nowadays, relics of semi-deciduous forests containing UG and LG forest species are still present within the DG. We used one of these species, the pioneer tree Terminalia superba (Combretaceae), to study past forest fragmentation in the DG and its impact on infraspecific biodiversity. A Bayesian clustering analysis of 299 individuals genotyped at 14 nuclear microsatellites revealed five parapatric genetic clusters (UG, DG, and three in LG) with low to moderate genetic differentiation (Fst from 0.02 to 0.24). Approximate Bayesian Computation analyses inferred a demographic bottleneck around the penultimate glacial period in all populations. They also supported an origin of the DG population by admixture of UG and LG populations around 54,000 (27,600-161,000) years BP, thus before the Last Glacial Maximum. These results contrast with those obtained on Distemonanthus benthamianus where the DG population seems to originate from the Humid Holocene period. We discuss these differences in light of the ecology of each species. Our results challenge the simplistic view linking population fragmentation/expansion with glacial/interglacial periods in African forest species. PMID- 29279602 TI - New Therapeutic Perceptions in a Patient with Complicated Herpes Simplex Virus 1 Keratitis: A Case Report and Review of the Literature. AB - BACKGROUND Keratitis caused by herpes simplex virus (HSV) can have detrimental effects on the cornea leading to loss of vision. Modern therapies can contribute to the prevention of anatomical and functional damage. CASE REPORT An 80-year-old male with complicated HSV-1 keratitis of the left eye (confirmed diagnosis after microbiological investigation) presented three months after antiviral treatment with corneal blurring, severe epitheliopathy, thinning of the stroma, and neovascularization. At the time he was referred, the visual acuity of his left eye was very low, as he could only count fingers at a one-foot distance. He was initially started on oral acyclovir (800 mg once daily) and topical poly carboxymethyl glucose sulfate; afterwards he underwent amniotic membrane (AM) transplantation and localized treatment with anti-VEGF factors. One month after the AM transplantation there was an obvious improvement of the corneal surface. Ophthalmic suspension of cyclosporine-A 1% was also added to his treatment. After three months, a transplantation of stem cells (deriving from the sclerocorneal junction of his right eye) was carried out at the sclerocorneal junction, as the corneal damage and neovascularization was more severe at this anatomical area. Four months after the last surgery, his visual acuity was 1/10 (note, he had a history of an old vascular episode) and the cornea was sufficiently clear with no signs of epitheliopathy and almost complete subsidence of the neovascularization. CONCLUSIONS Transplantation of AM and stem cells in combination with anti-VEGF factors and topical administration of cyclosporine-A 1% and poly-carboxymethyl glucose sulfate (a regenerative factor of corneal matrix) contributed substantially in the management of herpetic keratitis complications. PMID- 29279604 TI - Geographical isolation and environmental heterogeneity contribute to the spatial genetic patterns of Quercus kerrii (Fagaceae). AB - Southwest China is one of the major global biodiversity hotspots. The Tanaka line, extending within southwestern China from its northwest to its southeast, is an important biogeographical boundary between the Sino-Japanese and Sino Himalayan floristic regions. Understanding the evolutionary history of the regional keystone species would assist with both reconstructing historical vegetation dynamics and ongoing biodiversity management. In this research, we combined phylogeographic methodologies and species distribution models (SDMs) to investigate the spatial genetic patterns and distribution dynamics of Quercus kerrii, a dominant evergreen oak inhabiting southwest China lowland evergreen broadleaved forests (EBLFs). A total of 403 individuals were sampled from 44 populations throughout southwest China. SDMs and mismatch distribution analysis indicated that Q. kerrii has undergone northward expansion since the Last Glacial Maximum (LGM). Quantitative analysis revealed that the range expansion of Q. kerrii since the LGM exceeded that of the sympatric mid-elevation species Quercus schottkyana, likely owing to their contrasting distribution elevations and habitat availabilities. The historical climate change since the LGM and the latitude gradient of the region played an important role in shaping the genetic diversity of Q. kerrii. The genetic differentiation index and genetic distance surface of Q. kerrii populations east of the Tanaka line exceeded those to its west. The long-term geographic isolation and environmental heterogeneity between the two sides of the Tanaka line might increase species divergence patterns and local adaptation. This study provides new insights into the historical dynamics of subtropical EBLFs and the changing biota of southwest China. PMID- 29279607 TI - Technique: Single-cell transcriptomes in space. PMID- 29279608 TI - Detection of de novo single nucleotide variants in offspring of atomic-bomb survivors close to the hypocenter by whole-genome sequencing. AB - Ionizing radiation released by the atomic bombs at Hiroshima and Nagasaki, Japan, in 1945 caused many long-term illnesses, including increased risks of malignancies such as leukemia and solid tumours. Radiation has demonstrated genetic effects in animal models, leading to concerns over the potential hereditary effects of atomic bomb-related radiation. However, no direct analyses of whole DNA have yet been reported. We therefore investigated de novo variants in offspring of atomic-bomb survivors by whole-genome sequencing (WGS). We collected peripheral blood from three trios, each comprising a father (atomic bomb survivor with acute radiation symptoms), a non-exposed mother, and their child, none of whom had any past history of haematological disorders. One trio of non-exposed individuals was included as a control. DNA was extracted and the numbers of de novo single nucleotide variants in the children were counted by WGS with sequencing confirmation. Gross structural variants were also analysed. Written informed consent was obtained from all participants prior to the study. There were 62, 81, and 42 de novo single nucleotide variants in the children of atomic-bomb survivors, compared with 48 in the control trio. There were no gross structural variants in any trio. These findings are in accord with previously published results that also showed no significant genetic effects of atomic-bomb radiation on second-generation survivors. PMID- 29279610 TI - Neuroimmunology in 2017: The central nervous system: privileged by immune connections. PMID- 29279611 TI - Immunotherapy: HLA genotype: good to be different. PMID- 29279609 TI - Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome. AB - Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features. PMID- 29279612 TI - Are histones real pathogenic agents in sepsis? PMID- 29279605 TI - Cancer transcriptome profiling at the juncture of clinical translation. AB - Methodological breakthroughs over the past four decades have repeatedly revolutionized transcriptome profiling. Using RNA sequencing (RNA-seq), it has now become possible to sequence and quantify the transcriptional outputs of individual cells or thousands of samples. These transcriptomes provide a link between cellular phenotypes and their molecular underpinnings, such as mutations. In the context of cancer, this link represents an opportunity to dissect the complexity and heterogeneity of tumours and to discover new biomarkers or therapeutic strategies. Here, we review the rationale, methodology and translational impact of transcriptome profiling in cancer. PMID- 29279606 TI - Nuclear receptors in cancer - uncovering new and evolving roles through genomic analysis. AB - Nuclear receptors (NRs) have historically been at the forefront of cancer research, where they are known to act as critical regulators of disease. They also serve as biomarkers for tumour subclassification and targets for hormone therapy. However, most tumour types express extensive repertoires of NRs, whose interactions provide multiple paths for disease progression and offer potentially untapped mechanisms for therapeutic interventions. Recently, next-generation sequencing technologies have provided genome-wide insights into the complex interplay of NR transcriptional networks and their contribution to the development and progression of cancer. These findings have altered the traditional understanding of NR activities in oncogenesis. PMID- 29279614 TI - Are histones real pathogenic agents in sepsis? PMID- 29279613 TI - The dawn of vaccines for cancer prevention. AB - An important role of the immune system is in the surveillance for abnormal or transformed cells, which is known as cancer immunosurveillance. Through this process, the first changes to normal tissue homeostasis caused by infectious or other inflammatory insults can be detected by the immune system through the recognition of antigenic molecules (including tumour antigens) expressed by abnormal cells. However, as they develop, tumour cells can acquire antigenic and other changes that allow them to escape elimination by the immune system. To bias this process towards elimination, immunosurveillance can be improved by the administration of vaccines based on tumour antigens. Therapeutic cancer vaccines have been extensively tested in patients with advanced cancer but have had little clinical success, which has been attributed to the immunosuppressive tumour microenvironment. Thus, the administration of preventive vaccines at pre malignant stages of the disease holds promise, as they function before tumour associated immune suppression is established. Accordingly, immunological and clinical studies are yielding impressive results. PMID- 29279615 TI - Antimicrobial activity of root canal irrigants against biofilm forming pathogens- An in vitro study. AB - Aims: The aim of the study was to check the antimicrobial activity of the 5% Sodium hypochlorite, 2% Chlorhexidine, 0.10% Octenidine (OCT), and 2% Silver Zeolite (SZ) at different time intervals against a single species biofilm of Enterococcus faecalis, Staphylococcus aureus, and Candida albicans model prepared on a nitrocellulose membrane. Settings and Design: In vitro nitrocellulose biofilm model was used to check antibacterial efficacy of root canal irrigants. Materials and Methods: The in vitro nitrocellulose biofilm model was used to check the antibacterial activity of root canal irrigants. Single species biofilms were suspended into 96-well microtiter plate and treated with root canal irrigants for 1, 5, 10, 15, 30, and 60 s, respectively. The remaining microbial load in the form of colony-forming unit/ml after antimicrobial treatment was tabulated and data were statistically analyzed. Statistical Analysis: SPSS version 17, Kruskal-Wallis ANOVA, Mann-Whitney U-test, and Wilcoxon matched pair test (P < 0.05) were used. Results: All tested microorganisms were eliminated within 30 s by all the antimicrobial substances tested except normal saline. 2% chlorhexidine and 0.10% OCT were equally effective against C. albicans at 30 s. Conclusion: The newly tested irrigants have shown considerable antibacterial activity against selected single species biofilm. OCT (0.10%) can be used as an alternative endodontic irrigant. PMID- 29279616 TI - Cytocompatibility of a self-adhesive gutta-percha root-filling material. AB - Context: A novel root-filling material based on the incorporation of ultrafine alkaline bioactive glass particles (bioactive gutta-percha, [BGP]) was developed to work without sealer. Aim: In the present study, the objective was to verify the in vitro biological response to this material by assessing its cytocompatibility. Materials and Methods: Prototypes of BGP were compared to conventional gutta-percha (GP), dense polystyrene beads as a negative control and fragments of latex as a positive control. Extracts of each material were prepared according to ISO 10993-5:2009, and human osteoblast-like cells in primary culture were exposed to all extracts for 24 h. Cell viability was assayed sequentially for three different parameters: mitochondrial activity, membrane integrity, and cell density. Statistical Analysis Used: Nonparametric analysis (using Kruskal Wallis test combined with post hoc Dunn's test) was performed for comparison among groups, with significance established at 5%. Results: BGP reduced mitochondrial activity to 62% of control, but presented no toxicity on membrane integrity and proliferation assays. BGP effect on metabolism was dose-dependent and reduced to acceptable levels with dilution. Conclusion: The novel GP material presented slight dose-dependent effects on cell metabolism but did not affect cell survival. PMID- 29279617 TI - Effect of saliva and blood contamination on the shear bond strength of fifth-, seventh-, and eighth-generation bonding agents: An in vitro study. AB - Aim: To evaluate the bond strength of different adhesives after contamination with saliva and blood at various steps of application. Materials and Methods: Buccal surfaces of 180 human premolars were sliced to expose dentin. The specimens were randomly divided into six groups (n = 30), in which saliva and blood were used as contaminants in three groups each. The groups were further divided according to the generation (fifth - OptiBond Solo Plus Kerr, USA; seventh - OptiBond All-In-One Kerr, USA; eighth - Futurabond DC, Voco, Germany) of the adhesive used. Effect of contaminant application both before and after polymerization of the adhesive was evaluated. Composite cylinders were fabricated on exposed dentinal surfaces and were subjected to shear bond strength test. The results were subjected to one-way analysis of variance and t-test. Results: The eighth-generation adhesive showed the highest mean shear bond strength, followed by fifth- and seventh-generation adhesive. Salivary contamination resulted in greater decrease of bond strength when contaminated before polymerization. However, the results were vice versa when blood contamination was done, except in the case of fifth-generation adhesive. Blood contamination produced the lowest shear bond strength in all conditions. Conclusion: The eighth-generation adhesives showed the highest and blood contamination the lowest bond strength in all conditions. PMID- 29279618 TI - Comparison of canal transportation and centering ability of Twisted Files, HyFlex controlled memory, and Wave One using computed tomography scan: An in vitro study. AB - Aim: The aim of the present study was to compare the canal transportation and centering ability of three rotary nickel-titanium (NiTi) systems (Twisted Files [TF], HyFlex controlled memory [CM], and Wave One [WO]) in curved root canals using computed tomography (CT). Materials and Methods: Sixty freshly extracted single-rooted teeth having curved root canals with at least 25-35 degrees of curvature were selected. The teeth were randomly divided into three experimental groups of twenty each. After preparation with TF, HyFlex CM, and WO, all teeth were scanned using CT to determine the root canal shape. Pre- and post instrumentation images were obtained at three levels, 3 mm apical, 9 mm middle, and 15 mm coronal above the apical foramen were compared using CT software. Amount of transportation and centering ability were assessed. The three groups were statistically compared with analysis of variance and post hoc Tukey's honestly significant difference test. Results: Least apical transportation and higher centering ability were seen in HyFlex CM file system in all the three sections followed by TF. WO file system showed maximum transportation. Conclusions: The canal preparation with HyFlex CM file system showed lesser transportation and better centering ability than TF, WO file system. PMID- 29279619 TI - Comparative evaluation of the bond strength of posterior composite with different cavity configurations and different liners using a two-step etch and rinse adhesive system: In vitro study. AB - Introduction: Conventional Class II cavity preparations used for restoring small lesions with amalgam may be inappropriate for composite resin restorations due to the extensive cavity form, large occlusal contact area, and thin or missing margins of the tooth. Cavity preparation in the proximal areas as per the precepts of Clark is a conservative method of caries excavation and tooth preparation. Materials and Methods: Conventional Class II and Clark's Class II cavities were prepared on the mesial surfaces of 60 molars. All cavities were given a standard buccolingual width of 2 mm, an occlusogingival height of approximately 3.5 mm and an axial depth of 1.5 mm. These were then restored using flowable composites or resin-modified glass-ionomer cement liners and nanohybrid composites. The compressive bond strength was tested with a universal testing machine. Results: The compressive bond strength was the highest for Clarks Class II cavity preparation with a lining of flowable composites. Conventional Box only Class II cavities restored with flowable liners showed the next best result. Conclusion: Clark's class II cavity preparation can be used as efficiently as the conventional Class II box preparation with the advantage of preserving more tooth structure, more precise tooth preparation, good bond strength and better esthetics. PMID- 29279621 TI - Calotropis gigantea extract as a potential anticariogenic agents against Streptococcus mutans: An in vivo comparative evaluation. AB - Objective: The current study was intended to evaluate and compare the in vivo efficacy of Calotropis gigantea mouth rinse as anticariogenic agents with 0.2% chlorhexidine and Listerine mouth rinse. Materials and Methods: An experimental crossover study was conducted on sixty school children aged 14-15 years. Participants were divided into three Groups A, B, and C. In all children, baseline unstimulated saliva samples were collected and assessed for Streptococcus mutans counts. The study was conducted in three phases; each phase lasted for 8 days separated by a washout period of 15 days in between them. Groups A, B, and C were treated with 0.2% chlorhexidine, Listerine and C. gigantea extract mouth rinses, respectively, in the Phase I and assessed for salivary S. mutans counts. Subsequently, mouth rinses were crossed over as dictated by the Latin square design in Phase II and III. Results and Conclusion: All the three mouth rinses have individually shown a statistically significant reduction in the salivary S. mutans counts. PMID- 29279620 TI - Can active signals of cellphone interfere with electronic working length determination of a root canal in a dental clinic? An in vivo study. AB - Objective: To evaluate the interference of active cellphones during electronic working length (EWL) determination of a root canal. Materials and Methods: Thirty patients requiring root canal treatment in the anterior teeth or premolars having single canal and mature apices were selected for this study. Working length determination was done using no. 15 K-file. Electronic apex locators ProPex Pixi and Root ZX mini were used for working length determination. Cellphones iPhone 6s and Xolo Q3000 were evaluated for their interference. The experiment was conducted in a closed room (9 feet * 9 feet). Working length was measured with no cellphone in the room, iPhone 6s in a calling mode, Xolo Q3000 in a calling mode, and Xolo Q3000 and iPhone 6s simultaneously in a calling mode. Stability of the readings was also determined for every condition. Statistical Analysis: The data were statistically analyzed using one-way ANOVA and paired t-test at 0.05 level of significance. Results: Results were not statistically significant. Conclusion: Within the limitations of the present study, cellphones do not interfere with the EWL determination. PMID- 29279622 TI - Evaluation of effect of different disposable infection control barriers on light intensity of light-curing unit and microhardness of composite - An in vitro study. AB - Aims: This study evaluated effect of infection control barriers on light intensity (LI) of light-curing unit (LCU) and microhardness of composite. Materials and Methods: Four different disposable barriers (n = 30) were tested against the control. LI for each barrier was measured with Lux meter. One hundred and fifty Teflon molds were equally divided into five groups of thirty each. Composite was filled in bulk in these molds and cured without and with barrier. Microhardness was evaluated on top and bottom surface of composite specimen with microhardness testing machine and hardness ratio (HR) was derived. Statistical Analysis Used: One-way analysis of variance, Tukey's honestly significant difference test, and paired t-test using SPSS version 18 software. Results: All barriers had significantly reduced the baseline LI of LCU (P < 0.0001), but only Cure Elastic Steri-Shield and latex cut glove pieces (LCGP) significantly reduced the microhardness of the composite (P < 0.05). However, HR determined inadequate curing only with LCGP. Conclusions: Although entire tested barrier significantly reduced the LI; none, except LCGP markedly affected the degree of cure of the composite. PMID- 29279623 TI - Concentration and time-dependent effect of initial sodium hypochlorite on the ability of QMix and ethylenediaminetetraacetic acid to remove smear layer. AB - Aims: The aim of this study was to compare the ability of 17% ethylenediaminetetraacetic acid (EDTA) and QMix with different concentrations and time exposures of initial sodium hypochlorite (NaOCl) to remove the smear layer from the root canals. Materials and Methods: Eighty maxillary central incisors were used. After instrumentation, the teeth were divided into eight experimental groups according to the initial and final rinse. About 2.5% and 5% NaOCl were used during instrumentation and for 1 or 3 min was used as postinstrumentation initial irrigants, and 17% EDTA and QMix used as final irrigants. The apical and middle parts of the specimens were observed by scanning electron microscope. Statistical Analysis Used: Data were analyzed using the Kruskal-Wallis, Mann Whitney, and Friedman's test. Results: Regardless of the type of final irrigant, QMix allowed more smear layer removal than EDTA after using 5% initial NaOCl for 3 min. In the apical part of the root canal walls, the smear layer was not completely removed. Conclusion: QMix and EDTA were similarly effective in smear layer removal at the middle parts of the root canal regardless of the concentration and time exposure of initial NaOCl, while none of the irrigation protocols was able to remove smear layer at the apical parts. PMID- 29279624 TI - An in vitro study to find the incidence of mesiobuccal 2 canal in permanent maxillary first molars using three different methods. AB - Aim: In-vitro study was done to evaluate the incidence of MB2 canals using three different methods (CBCT, CLINICAL ANALYSIS AND DENTAL LOUPES) and to compare the efficacy of the three methods in identifying the incidence of MB2 canals in maxillary permanent first molars. Materials and Methods: The study sample consisted of 120 extracted intact permanent maxillary molars. These extracted teeth were subjected to CBCT. Later the teeth were access opened with naked eye to find the incidence of MB2 canal, and then the teeth were visualised under dental loupe to locate MB2 canal if they were missed under naked eye. Results was statistically analysed by Mc Nemar's tests with Bonferroni correction, Chi square test and Cochran's Q test. Result: CBCT showed high incidence (68.3%) of MB2 canal in maxillary first molars and it showed to be a reliable method in detecting MB2 canal. When compared to dental loupe (52.5%) and naked eye (25%), the dental loupe improved the detection of MB2 canal. Conclusion: Within the parameter of this study in detecting the incidence of MB2 canal, using CBCT dental loupes and naked eye, detection of MB2 canal was significantly higher with CBCT followed by dental loupe and least with naked eye. PMID- 29279625 TI - An analysis of cyclic fatigue resistance of reciprocating instruments in different canal curvatures after immersion in sodium hypochlorite and autoclaving: An in vitro study. AB - Aim: The aim of this study is to assess the effect of sodium hypochlorite and sterilization on the cyclic fatigue resistance of two reciprocating nickel titanium files using a rotary and a reciprocating motor. Materials and Methods: Totally, 160 Reciproc and Wave One files were tested. The eighty files of the same brand were assigned into four groups (n = 20). These four groups were further divided into two subgroups, 1a and 1b, 2a and 2b, 3a and 3b, 4a and 4b consisting of ten files in each group. 2.5% NaOCl for 5 min, 2.5% NaOCl for 5 min + 1 cycle of autoclave sterilization, 2.5% NaOCl for 5 min + 5 cycles of autoclave sterilization, no sterilization (control). Groups 1a, 2a, 3a, and 4a were subjected to 30 degrees and Groups 1b, 2b, 3b, and 4b were subjected to 60 degrees canal curvature. Results: Intergroup comparison reveals that there is an increase in cyclic fatigue resistance from the first cycle to the fifth cycle of autoclave which is statistically significant. Conclusion: Reciproc and Wave One showed reduced cyclic fatigue resistance on immersion in NaOCl for 5 min. Multiple autoclaving cycles significantly increased the cyclic fatigue resistance of Reciproc file system in both the curvatures. There was a decrease in cyclic fatigue resistance for Wave One after multiple autoclaving at 60 degrees curvature which was statistically significant. PMID- 29279626 TI - Effect of recasting on element release from base metal dental casting alloys in artificial saliva and saline solution. AB - Aim: The aim of this study was to quantitatively estimate the concentration of ion release from recasted base metal alloys in various pH conditions using atomic absorption spectroscopy (AAS). Materials and Methods: Specimens of commercially available dental casting alloys (cobalt [Co]-chromium [Cr] and nickel [Ni]- chromium [Cr]) were prepared using lost-wax casting techniques and were stored in the test solution for 1 week and 4 weeks, and ions released during chemical corrosion were detected using AAS. Results: An increase in the quantity of ion release was observed with recasting. These changes were higher after twice recasting in Ni-Cr alloy. PMID- 29279628 TI - Providing a harmonious smile with laminate veneers for a patient with peg-shaped lateral incisors. AB - The most common discrepancy concerning tooth size is the presence of peg-shaped lateral incisors, which can cause teeth with reduced size, anterior diastema, and consequently an unpleasant smile. The development of the adhesive dentistry and ceramic veneers allowed all ceramic-bonded restorations to become an esthetic and functional approach to reestablish the smile harmony. The purpose of this clinical report is to describe a conservative treatment approach to recover an esthetic disharmony caused by bilateral peg-shaped lateral incisors. A 30-year old female patient was seeking treatment to solve an esthetic disharmony of her smile. Lithium disilicate veneers were planned and build-up with the help of diagnostic models, wax-up, mock-up, and silicone guides, to restore the morphology, size, function, and esthetic of upper lateral incisors and smile. The lithium disilicate veneers were able to provide the harmonization of the patient's smile, recovering the teeth size, shape, and anatomic characteristics. PMID- 29279627 TI - One-year comparative evaluation of Ketac Nano with resin-modified glass ionomer cement and Giomer in noncarious cervical lesions: A randomized clinical trial. AB - Aim: The purpose of this study was to evaluate the clinical performance of Ketac Nano (KetacTM N100), RMGIC (Fuji FillingTM LC), and Giomer (Beautifil(r) II) in noncarious cervical lesions (NCCLs). Materials and Methods: One operator restored 120 NCCLs in 20 subjects, with at least two lesions restored with one of the restorative materials: RMGIC (control group), Giomer and Ketac Nano (experimental groups). Two observers evaluated retention, marginal discoloration, marginal adaptation, color match, surface roughness, and postoperative sensitivity using modified USPHS criteria at baseline, 6, and 12 months. Study Design: Double blinded randomized clinical trial (RCT). Statistical Analysis: Kruskal-Wallis test, Mann-Whitney U-test, Wilcoxon matched-pairs test. Results: There was statistically significant difference observed between Giomer, Ketac Nano and RMGIC after 12 months (P < 0.05). There was a significant decrease in retention rates for Giomer (P = 0.0050), increased marginal discoloration and color mismatch for Ketac Nano (P = 0.0025, P = 0.0053), increased surface roughness and color mismatch with RMGIC (P = 0.0022, P = 0.0077) from baseline to 12 months. Conclusion: Within the limitations of this RCT of 12 months, Ketac Nano and RMGIC restorations were better retained in NCCLs while superior color match and surface finish were observed with Giomer restorations. PMID- 29279629 TI - Management of invasive cervical resorption using a surgical approach followed by an internal approach after 2 months due to pulpal involvement. AB - Invasive cervical resorption (ICR) is an aggressive and invasive form of external tooth resorption that commences in the cervical region which can be managed using either a nonsurgical, surgical or a combination of nonsurgical and surgical approach. The restoration of resorptive defects having a coronal and radicular extent can be challenging as a single material cannot be used to restore the entire defect. This case presented with Heithersay's Class 3 ICR lesion in tooth #12, which was managed initially using a surgical approach and restoration of ICR defect with a combination of resin modified glass ionomer cement, composite resin and mineral trioxide aggregate (MTA). However, the patient presented with pulpal symptoms 2 months later which warranted a root canal therapy. An internal approach was then used to debride and remove remnant fibro-osseous tissue. The defect was then repaired with MTA. A 1 year follow-up demonstrated adequate periapical healing and no pathologic changes around the restored resorptive defect. PMID- 29279630 TI - Erratum: Root canal treatment of a fused mandibular incisor using cone-beam computed tomography as a diagnostic aid. AB - [This corrects the article on p. 58 in vol. 20, PMID: 28761256.]. PMID- 29279631 TI - A Clinical Study on the Initial Assessment of Arterial Lactate and Base Deficit as Predictors of Outcome in Trauma Patients. AB - Background: Trauma is a leading cause of mortality in India. Outcomes can be improved by early recognition of hemorrhagic shock and expedited management. At present, we rely on traditional vital signs, which are not sensitive measures. Point of care biochemical markers have been emerging as prognostic markers in trauma, but have not been studied in Indian setting. Aims: This study aims to study the association between arterial lactate and base deficit (BD) at emergency department (ED) admission and 24 h outcome in trauma patients at risk of hemodynamic compromise. Materials and Methods: This was a prospective observational study on 100 trauma patients at risk of hemodynamic compromise in tertiary care center ED. Arterial blood gas analysis at admission and 24 h outcomes were noted and statistically analyzed. Results: Arterial lactate >=4 mmol/L (sensitivity 100% and specificity 85.9%), BD >=12 mEq/L (sensitivity 87.5% and specificity 82.6%) had more sensitivity than vital signs for predicting 24 h mortality. Higher lactate and BD were associated with increased blood transfusion requirement. Best cutoff values for predicting transfusion were lactate >=2.9 mmol/L (sensitivity 65.2% and specificity 90.7%), BD >=8 mEq/L (sensitivity 78.3% and specificity 75.9%). BD-based classification was comparable to ATLS classification in predicting mortality and determining transfusion requirements. Patients with higher arterial lactate and BD were found to have higher 24 h Intensive Care Unit (ICU) admission. Conclusion: Emergency admission arterial lactate and Base Deficit are useful predictors of mortality, need for blood transfusion and ICU admission at 24 h. It can be used to triage, identify shock early, assess transfusion requirement, and prognosticate trauma patients. PMID- 29279632 TI - The PCQP Score for Volume Status of Acutely Ill Patients: Integrating Vascular Pedicle Width, Caval Index, Respiratory Variability of the QRS Complex and R Wave Amplitude. AB - Introduction: Techniques for measuring volume status of critically ill patients include invasive, less invasive, or noninvasive ones. The present study aims to assess the accuracy of noninvasive techniques for measuring volume status of critically ill patients. Patients and Methods: A total of 111 critically ill patients admitted to the emergency department and undergoing central venous catheterization were included in the study. Five parameters were measured including vascular pedicle width (VPW), diameter of inferior vena cava, caval index, respiratory changes in QRS, and P wave amplitude. Patients with risk factors which could decrease the accuracy of central venous pressure (CVP) value were excluded from study. We compared these parameters with static CVP parameter. Finally, based on the afore-mentioned parameters, PCQP role in criteria was designed. Results: In detecting loss of circulating blood volume, area under the curve of VPW was 0.92 (90%, confidence interval [CI]: 0.85-0.99), diameter of inferior vena cava was 0.82 (90%, CI: 0.72-0.91), caval index was 0.9 (90%, CI: 0.82-0.98), and changes in QRS and P waves were 0.88 (95%, CI: 0.81-0.95) and 0.73 (95%, CI: 0.63-0.82), respectively. PCQP role in criteria was designed according to these parameters, and at its best cutoff point (score 6), VPW had a sensitivity of 97.4% (95%, CI: 84.57-99.99) and specificity of 83.6% (95%, CI: 72.65-90.86) for the detection of loss of circulating blood volume (<8 cmH2O). Conclusion: PCQP score could be a reliable and noninvasive technique for the assessment of volume status in critically ill patients. PMID- 29279633 TI - Critical Care Junior Doctors' Profile in a Lower Middle-income Country: A National Cross-sectional Survey. AB - Background and Aims: Retention of junior doctors in specialties such as critical care is difficult, especially in resource-limited settings. This study describes the profile of junior doctors in adult state intensive care units in Sri Lanka, a lower middle-income country. Materials and Methods: This was a national cross sectional survey using an anonymous self-administered electronic questionnaire. Results: Five hundred and thirty-nine doctors in 93 Intensive Care Units (ICUs) were contacted, generating 207 responses. Just under half of the respondents (93, 47%) work exclusively in ICUs. Most junior doctors (150, 75.8%) had no previous exposure to anesthesia and 134 (67.7%) had no previous ICU experience while 116 (60.7%) ICU doctors wished to specialize in critical care. However, only a few (12, 6.3%) doctors had completed a critical care diploma course. There was a statistically significant difference (P < 0.05) between the self-assessed confidence of anesthetic background junior doctors and non-anesthetists. The overall median competency for doctors improves with the length of ICU experience and is statistically significant (P < 0.05). ICU postings were less happy and more stressful compared to the last non-ICU posting (P < 0.05 for both). The vast majority, i.e., 173 (88.2%) of doctors felt the care provided for patients in their ICUs was good, very good, or excellent while 71 doctors (36.2%) would be happy to recommend the ICU where they work to a relative with the highest possible score of 10. Conclusion: Measures to improve training opportunities for these doctors and strategies to improve their retention in ICUs need to be addressed. PMID- 29279634 TI - Role of Urinary Neutrophil Gelatinase-associated Lipocalin as a Biomarker of Acute Kidney Injury in Patients with Circulatory Shock. AB - Background: The early prediction of acute kidney injury (AKI) by the current clinical and laboratory methods remains inadequate. Neutrophil gelatinase associated lipocalin (NGAL) has emerged as a promising noninvasive biomarker of kidney injury in shock. The aim of this study was to assess the ability of urinary NGAL (uNGAL) to predict AKI in adult Intensive Care Unit (ICU) patients. Materials and Methods: We prospectively studied 70 patients with circulatory shock admitted to the ICU over a period of 1 year. uNGAL was analyzed at ICU admission and after 24 h. Risk, injury, failure, loss, and end-stage kidney criteria were calculated at admission and for consecutive 4 days. The primary outcome was AKI defined as an increase in creatinine of at least 50% from baseline or a reduction in urine output to <0.5 ml/kg/h for 6 h. Results: uNGAL was a good diagnostic marker for AKI development; at day 1, the cutoff value 48.54 ng/mL had a sensitivity and specificity of 79.49 and 73.14, respectively, and the area under the curve (AUC) of 0.82 (95% confidence interval [CI], 0.75 0.87) for predicting AKI. At day 2, the cutoff value 190.92 ng/mL had a sensitivity and specificity of 90.0 and 64.66, respectively, and the AUC of 0.76 (95% CI, 0.70-0.88) for predicting AKI. Conclusion: uNGAL could be a good early predictor biomarker of AKI following circulatory shock. PMID- 29279635 TI - Reliability and Validity of the Checklist for Early Recognition and Treatment of Acute Illness and Injury as a Charting Tool in the Medical Intensive Care Unit. AB - Background: Resuscitation of critically ill patients is complex and potentially prone to diagnostic errors and therapeutic harm. The Checklist for early recognition and treatment of acute illness and injury (CERTAIN) is an electronic tool that aims to provide decision-support, charting, and prompting for standardization. This study sought to evaluate the validity and reliability of CERTAIN in a real-time Intensive Care Unit (ICU). Materials and Methods: This was a prospective pilot study in the medical ICU of a tertiary care medical center. A total of thirty patient encounters over 2 months period were charted independently by two CERTAIN investigators. The inter-observer recordings and comparison to the electronic medical records (EMR) were used to evaluate reliability and validity, respectively. The primary outcome was reliability and validity measured using Cohen's Kappa statistic. Secondary outcomes included time to completion, user satisfaction, and learning curve. Results: A total of 30 patients with a median age of 59 (42-78) years and median acute physiology and chronic health evaluation III score of 38 (23-50) were included in this study. Inter-observer agreement was very good (kappa = 0.79) in this study and agreement between CERTAIN and the EMR was good (kappa = 0.5). CERTAIN charting was completed in real-time that was 121 (92-150) min before completion of EMR charting. The subjective learning curve was 3.5 patients without differences in providers with different levels of training. Conclusions: CERTAIN provides a reliable and valid method to evaluate resuscitation events in real time. CERTAIN provided the ability to complete data in real-time. PMID- 29279636 TI - Treatment of Acute Kidney Injury Complicating Septic Shock with EMiC2 High-cutoff Hemofilter: Case Series. AB - Introduction: Extracorporeal blood purification therapies have been proposed to improve outcomes of patients with severe sepsis, with or without accompanying acute kidney injury (AKI), by removal of excessive inflammatory mediators. Materials and Methods: We report our experience with EMiC2 high-cutoff continuous venovenous hemofiltration/hemodialysis (HCO-CVVH/HD) in seven patients with AKI complicating septic shock. Results: The median treatment duration was 71 h, and the procedure was well tolerated. Trough serum albumin level of 20 g/L was observed after 2 h of treatment and none of the patients required albumin supplement. The hospital mortality rate was 29%, which appeared more favorable than the predicted mortality of 60%-78% based on disease severity scores. Circulating levels of interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha improved over time. Conclusion: This case series shows that HCO-CVVH/CVVHD using EMiC2 hemofilter may provide good cytokine modulation, when used along with good quality standard sepsis therapy. A further large-scale prospective randomized controlled trial is recommended. PMID- 29279638 TI - Prophylaxis and Incidence of Symptomatic Deep Vein Thrombosis in Indian Patients with Sepsis: DETECT-Deep Vein Thrombosis Registry. AB - Purpose: To assess thromboprophylaxis rate and incidence of symptomatic deep vein thrombosis (DVT) in Indian patients with acute sepsis. Materials and Methods: Adult patients with sepsis, within 48 h of sepsis onset/hospital admission were included. DVT was assessed using Doppler ultrasonography if clinical signs were present. Data were collected at inclusion, discharge, and 30 +/- 7 days (if discharged before 30 days). Results: The study included 278 patients (men: 69.4%; mean age: 56.3 +/- 17.99 years). Out of 275 patients (data missing for 3 patients), 188 (68.4%; 95% confidence interval: 62.5-73.8) received DVT prophylaxis (185 at admission and 3 at discharge; pharmacological prophylaxis: n = 88, mechanical prophylaxis: n = 65, pharmacological + mechanical prophylaxis: n = 35) and 87 received no prophylaxis. In line with American College of Chest Physicians 2008 recommendations, among patients who received pharmacological prophylaxis (n = 123), low-molecular-weight heparin was given to 85.4% (n = 105) patients (duration: 9.1 +/- 6.36 days), unfractionated heparin to 12.2% (n = 15) patients (duration: 9.2 +/- 9.18 days), and fondaparinux to 5.7% (n = 7) patients (duration: 6.8 +/- 3.30 days); 27/63 patients at high-risk of bleeding received mechanical prophylaxis; no patient received aspirin. Of 9 patients who developed DVT, 7 received no thromboprophylaxis (data missing for 2 patients). In total, 186/274 (67.9%) patients recovered from sepsis. Conclusions: Two-third patients received thromboprophylaxis. The substantial role of thromboprophylaxis in DVT prevention mandates monitoring and control of thromboprophylaxis through internal audits in hospitals. PMID- 29279637 TI - An Interventional Quality Improvement Study to Assess the Compliance to Cardiopulmonary Resuscitation Documentation in an Indian Teaching Hospital. AB - Background: Cardiopulmonary resuscitation (CPR) should be performed as per the international guidelines; however, compliance to these guidelines is difficult to assess. This study was conducted to determine the compliance to American Heart Association (2010) guideline on CPR documentation by among resident physicians before and after resident training (two arms). Methods: This pre postinterventional quality improvement study was conducted in a referral center, North India. Data of hospitalized in-hospital CPR patients were collected in the form of quality indicators (checklists) as defined by the guideline and compared between two arms of before-after resident training. Residents were given appropriate training in CPR technique as per the guideline. The compliance of CPR documentation was assessed pre- and post-intervention. Results: The baseline arm compliance of various components of CPR documentation was low. The postintervention arm compliances of all components significantly increased (baseline, 2.5% to postintervention, 15.11%, P = 0.03). Individual components assessed were documentation of assessment of responsiveness (65% to 77.9%, P = 0.19), assessment of breathing (37.5% to 58.1%, P = 0.03), assessment of carotid pulse (62.5% to 79%, P = 0.05), rate of chest compressions (20% to 39.5%, P = 0.04), airway management (62.5% to 82.5%, P = 0.02), and compressions to breaths ratio (12.5% to 31.4%, P = 0.02). Documentation of chest compression rate compared to nondocumentation (12 of 42 vs. 11 of 84, P = 0.04) was independently associated with a higher rate of return of spontaneous circulation. The study however did not show any survival benefits. Conclusions: This study establishes that the compliance to CPR documentation is poor as assessed by CPR documentation content and quality, which improves after physician training, but not up to the mark level (100%) that may be due to busy Indian hospital settings and human behavioral factors. Due to ethical constraints of live CPR assessment, this document checklist approach may be considered as an internal quality assessment method for CPR compliance. Furthermore, correct instruction in CPR technique along with proper documentation of the procedure is required, followed up with periodic re-education during the residency period and beyond. PMID- 29279639 TI - Posterior Reversible Leukoencephalopathy Syndrome (PRES) in Intensive Care Unit - Case series. AB - Introduction: Posterior reversible encephalopathy syndrome (PRES) is characterized by a range of clinico neuro radiological manifestation along with hypertension due to varied etiology. Contrary to its name, a small number of patients have residual neurological deficits. Patients with severe manifestation of PRES may get admitted to the Intensive Care Unit (ICU) due to coma or status epilepticus. Small case series and large multicenter studies have been reported. Materials and Methods: We report a single center series of ten cases admitted to ICU over a 5 year period in a tertiary care centre. We retrospectively analyzed patients, admitted to adult ICU with different etiologies, and diagnosed to have PRES. Outcome at discharge and at 90 days after ICU admission was noted. Result: The most common etiologies were medications. ICU admissions were mainly for uncontrolled hypertension, seizures, and low level of consciousness. All except one patient were ventilated. Four patients had residual neurological damage. Conclusion: Irrespective of the etiology, early control of blood pressure, and removal of precipitating factors is of paramount importance to prevent morbidity and mortality. Awareness about PRES among the intensivist is necessary to ensure early recognition and treatment. PMID- 29279640 TI - Effect of Intensive Education and Training of Nurses on Ventilator-associated Pneumonia and Central Line-associated Bloodstream Infection Incidence in Intensive Care Unit at a Tertiary Care Center in North India. AB - Objective: The aim was to analyze the impact of education and training of nurses on the incidence of ventilator-associated pneumonia (VAP) and central line associated bloodstream infection (CLABSI). Patients and Methods: A prospective observational study at a tertiary care hospital included adult patients with Intensive Care Unit stay >48 h. The study was done in three phases: in Phase 1, baseline VAP and CLABSI incidence was calculated; in Phase 2, education and training of nurses; and in Phase 3, data were recollected for the incidence of VAP and CLABSI. Results: The baseline incidence of VAP in Phase 1 was 28.86/1000 ventilator days and that of CLABSI was 7.89/1000 central-line days. In Phase 3, the incidence of VAP increased to 35.06 and that of CLABSI decreased significantly, 1.73. Conclusion: Intensive education and training sessions with feedback from nurses over a period of 6 months led to significant reduction in the incidence of CLABSI; however, the incidence of VAP increased. PMID- 29279641 TI - Cerebral Air Embolism Secondary to Lung Laceration. AB - Cerebral air embolism is a rare clinical entity in day-to-day practice. The introduction of air into the venous or the arterial system can cause cerebral air embolism leading to severe neurological deficits. The common causes reported in the literature are iatrogenic; it can be caused by positive pressure maneuvers performed during cardiac resuscitation, lung biopsy, and the placement of venous catheters in the presence of a patent foramen ovale. We report a case of cerebral air embolism which has occurred secondary to lung laceration. The patient underwent intercostal drainage for hydro-pneumothorax and developed forceful cough and suddenly changed in consciousness. Air embolism was diagnosed by computed tomography brain and was managed by high-concentration oxygen therapy and other supportive measures and is being discharged in satisfactory condition. PMID- 29279642 TI - Imidacloprid Poisoning: An Emerging Cause of Potentially Fatal Poisoning. AB - There are a variety of pesticides that are used to control the pests in agricultural lands and other places. Newer pesticides, developed as an alternative to highly toxic organophosphates such as imidacloprid including other neonicotinoid compounds, are being increasingly used considering their less harmful effects in case of human exposures. Though it is considered relatively safer to human beings, it can lead to potentially life-threatening complications and acute poisoning with these compounds may be fatal in large ingestion. We report a case of poisoning with imidacloprid compound presenting with a variety of systemic features including respiratory failure and patient's improvement with conservative management. PMID- 29279643 TI - Meckel's Diverticulitis Masquerading as Acute Pancreatitis: A Diagnostic Dilemma. AB - Meckel's diverticulum is a remnant of the proximal part of the vitellointestinal duct and is the most common congenital anomaly of the gastrointestinal tract. It may either remain asymptomatic or present with myriad of clinical presentations. Gastrointestinal bleeding is the most common presentation in children whereas it is intestinal obstruction in the case of adults. We report a 9-year-old boy who presented with acute onset of periumbilical pain and nonbilious vomiting. His clinical and laboratory parameters were unremarkable, except for serum amylase levels. He was conservatively managed initially as acute pancreatitis with paralytic ileus. However, the child deteriorated in a course of 2 days with bilious vomiting, abdominal distension, and dehydration. Imaging was suggestive of an ileoileal intussusception, and exploratory laparotomy identified Meckel's diverticulum as the lead point for the intussusception. The histopathological examination revealed inflamed heterotopic pancreatic tissue at the apex of the diverticulum thus explaining the elevated amylase levels. This case is reported to highlight the atypical presentation of Meckel's diverticulum and the high clinical suspicion warranted in diagnosing such concomitant intussusception. PMID- 29279644 TI - Canagliflozin-associated Diabetic Ketoacidosis with Lower-than-anticipated Glucose Levels. AB - The Food and Drug Administration has approved the use of sodium-glucose co transporter 2 (SGLT-2) inhibitors for use in Type II diabetics. These are a relatively new addition to the armamentaria of diabetes management. Postmarketing surveillance is a witness to several side effects, a morbid one being ketoacidosis. Herein is discussed a scenario of a Type II diabetic who presented with substantial ketoacidosis without significant hyperglycemia. The absence of the customary precipitating factors and the presence of a recent introduction of canagliflozin, a SGLT-2 inhibitor to the diabetes prescription, hinted at the causal relationship. Of note, she had never experienced diabetic ketoacidosis in the past prior to commencement of SGLT-2 inhibitor therapy. As clinicians, we need to be aware of the treatment-emergent adverse effect of this relatively new class of diabetic treatment. PMID- 29279645 TI - Methadone Gastrobezoar in a Psychiatric Patient Presented in Coma. AB - A 43-year-old psychiatric patient was transferred in coma and hypercapnic respiratory failure at the emergency department. He was intubated for airway protection and transferred to the Intensive Care Unit (ICU). Abdominal X-ray revealed a radiopaque mass; a pharmacobezoar was suspected and confirmed by gastroscopy; one large in the stomach fundus and a smaller one in the pylorus. Gastric lavage through the gastroscope and administration of gastro-kinetic drugs and laxatives were able to dilute the bezoars. Tablets retrieved from the stomach identified as methadone and toxicological tests of the gastric fluid confirmed the presence of methadone as the only organic chemical compound. The patient was extubated on the 7th day and released from the ICU on the 10th day under psychiatric consultation having normal vital signs. Methadone gastric bezoar may lead to persistent intoxication, respiratory failure, and coma requiring ICU care. Diagnosis may be difficult and a high index of suspicion is needed. PMID- 29279646 TI - Malpositioning of Central Venous Catheter from Right to Left Subclavian Vein: A Rare Complication. AB - Invasive monitoring with central venous catheter (CVC) is a valuable tool now a day in Intensive Care Units and in postoperative hemodynamically unstable patients. It is often employed for administering medications and parenteral nutrition. In most of the instances, these catheters are inserted using proper topographical landmarks and ultrasonography-guided methods. Central venous cannulation is associated now and then with unexpected complications despite the use of all precautions and help of imaging techniques. There is a wide variety of complications related to the central venous cannulation including malpositioning. Malpositioning of the catheter into contralateral subclavian is an extremely unusual event. Here, we report a rare case of malpositioning of CVC from the right to the left subclavian vein also we outline how the misplacement was identified and effectively managed. PMID- 29279647 TI - Influenza B Virus Triggering Macrophage Activation Syndrome in an Infant. AB - Macrophage activation syndrome (MAS) is a potentially fatal complication caused by excessive activation and expansion of macrophages and T lymphocytes. It can be triggered by various infections and is characterized by the development of cytopenias, hyperferritinemia, liver dysfunction, and coagulopathy. We report a 10-month-old female infant with fever, convulsions, and hepatosplenomegaly. Laboratory data of bicytopenia, low erythrocyte sedimentation rate, and elevated liver enzymes suggested MAS. This was supported by the presence of hyperferritinemia with hypertriglyceridemia. MAS was triggered by influenza B virus. She responded to treatment with immunoglobulin and steroid. PMID- 29279648 TI - Accidental Ingestion of Traces of Cyanide: A Clinical Experience. PMID- 29279649 TI - Integrative Weaning Index: A Few Observations. PMID- 29279650 TI - The Value of an Appreciation of Clinical Profiles in Communities as Aide-memoire When Faced with Difficult Ophthalmic Diagnoses. PMID- 29279651 TI - Mesopic Quality of Vision after Accelerated 18 mW/cm2 Corneal Cross-linking: Mid term Results. AB - PURPOSE: The purpose of the study was to determine 2-year changes in mesopic higher-order aberrations (HOAs) and contrast sensitivity (CS) after accelerated corneal cross-linking (CXL) in keratoconus patients. MATERIALS AND METHODS: In this before-after interventional case series, patients with progressive keratoconus were subjected to accelerated CXL (18 mW/cm2, 5 min). Patients were examined with the OPD-Scan III and CVS-1000 grating charts under mesopic conditions at baseline and at 12 and 24 months after CXL. RESULTS: At 24 months after CXL, compared to baseline, mesopic CS in spatial frequencies of 3, 6, 12, and 18 cycle per degree reduced respectively to 0.09 +/- 0.27, 0.09 +/- 0.32, 0.11 +/- 0.19, and 0.02 +/- 0.10; these changes were not statistically significant (all P > 0.05). The reduction in ocular HOAs was 0.11 +/- 0.43; ocular coma, trefoil, and spherical aberration (SA) decreased by 0.09 +/- 0.36, 0.05 +/- 0.35, and 0.00 +/- 0.13 microns, respectively (all P > 0.05). Reductions in corneal HOAs (0.89 +/- 7.08) including coma (0.99 +/- 3.55), SA (1.14 +/- 3.92), and trefoil (1.28 +/- 5.53) were not statistically significant (all P > 0.05). Coma had the highest share of corneal HOAs before and 24 months after CXL and the largest 24-month decrease was seen in corneal SA. CONCLUSION: At 2 years after accelerated CXL, despite reduced keratometry and corneal flattening, mesopic CS as well as ocular and corneal HOA remained unchanged, and the procedure did not cause a reduction in patients' vision quality. PMID- 29279652 TI - Evaluation of Topical Lignocaine Jelly 2% for Recurrent Pterygium Surgery with Glue-free Autologous Conjunctival Graft. AB - AIM: This study aims to evaluate the efficacy of lignocaine 2% jelly as a topical anesthesia in recurrent pterygium surgery with glue-free conjunctival limbal autograft. MATERIALS AND METHODS: A prospective, nonrandomized, observational study, comprising of 51 patients (51 eyes) having recurrent pterygium, was conducted at a tertiary eye care center in central India. Pterygium excision with glue-free autologous conjunctival grafting was done under 2% lignocaine jelly. The visual analog scale was utilized to record the intra- and post-operative pain score. Patient comfort, intraoperative painful sensations perceived by the patient, supplemental anesthesia, complications, and surgeon discomfort were noted. Anesthetist also noted vital parameters and any intravenous drugs required. RESULTS: No difference in intra- and post-operative pain score (P = 0.24) was observed in the patients. Zero score, i.e. no pain was noticed in 30 patients (58.8%) patients. The average surgical time was 29.20 min (+1.11). The average surgeon discomfort score was 0.18 + 0.51. Inadvertent eye movement was seen in 3 patients (5.9%). Lid squeeze was noted in 45 patients (88.2%) during placement of lid speculum. Forty-eight patients (94.1%) gave preference to the topical anesthesia of 2% lignocaine jelly compared to the previous mode of anesthesia. CONCLUSION: Pterygium surgery with glue-free autogenous conjunctival grafting can be performed successfully by preoperative local application of 2% lignocaine jelly. The ease of application, lack of toxicity and sufficient effect to complete the surgery make it an efficient alternative to injectable anesthetics. PMID- 29279653 TI - Clinical Profile and Outcomes of Optic Neuritis in an HIV Prevalent Urban Community in South Africa. AB - PURPOSE: To determine the clinical profile, causes and response to corticosteroid therapy in patients admitted and treated for optic neuritis at a tertiary hospital in Cape Town, South Africa. METHODS: A retrospective case review of 117 patients with optic neuritis between January 2002 and December 2012. Demographic information, clinical presentation, course of illness, investigations performed and visual outcomes at discharge and at three month follow up were collected for analysis. RESULTS: 60 of 117 patients (51%) had an identifiable secondary cause for optic neuritis. Of the 57 patients with idiopathic optic neuritis, 14 had features associated with demyelinating disease. HIV and syphilis accounted for 62% of secondary causes of optic neuritis. Presenting visual acuity of hand movements (HM) or worse and absence of pain with extra ocular movement were associated with poorer final visual outcomes in the idiopathic optic neuritis group. CONCLUSION: Optic neuritis in our patients, as elsewhere in Africa, tends to be atypical in presentation. A high proportion of patients have an identifiable secondary cause. These patients thus require more extensive investigation in order to identify causes which may influence management. Secondary optic neuritis and idiopathic atypical optic neuritis carry a poorer prognosis than typical demyelinating optic neuritis. PMID- 29279654 TI - Intravitreal Bevacizumab for Choroidal Neovascularization Associated with Angioid Streaks: Long-term Results. AB - PURPOSE: The purpose of the study was to evaluate the long-term efficacy and safety of intravitreal bevacizumab (IVB) in the treatment of choroidal neovascularization (CNV) secondary to angioid streaks (AS). MATERIALS AND METHODS: Noncomparative, interventional retrospective case series involving ten patients (15 eyes) with a minimum follow-up of 25 months following IVB for AS associated CNV. Demographic and clinical details at baseline and during follow-up were collected from patient records. Detailed clinical examination was followed by fundus fluorescein angiography and optical coherence tomography to confirm CNV. Both primary and recurrent CNVs were treated with monthly injections of IVB till the lesion stabilized. Primary outcome measures were the percentage of patients with stable or improved visual acuity (VA) and with stable or decreased central retinal thickness (CRT) at the last visit. Secondary outcome measure was the incidence of ocular and systemic complications. RESULTS: Recurrence was observed in 11 eyes (73.33%) over a mean follow-up of 57.33 months (range: 25 100). A mean number of injections administered was 5.60. VA improved or stabilized in 73.33% and deteriorated in 26.67% of eyes at the final visit. Mean CRT improved from 324.40 MUm at baseline to 265.53 MUm at final visit, which was statistically significant. Complications observed were ocular hypertension in one patient and thromboembolic event in another patient. CONCLUSIONS: IVB appears to be a safe and effective option to treat CNV and to preserve vision over a prolonged period. It cannot eliminate the risk of recurrent CNV indicating the need for more effective treatments to arrest this visually debilitating condition. PMID- 29279655 TI - Outcomes of Pneumatic Retinopexy for the Management of Rhegmatogenous Retinal Detachment at a Tertiary Care Center. AB - PURPOSE: The purpose of the study was to report the outcomes of pneumatic retinopexy (PR) for rhegmatogenous retinal detachment (RRD). METHODS: A retrospective chart review of all patients with RRD who were managed with PR at the King Khaled Eye Specialist Hospital between 2000 and 2014. Data were collected on preoperative ocular history, characteristics of the RRD, postoperative anatomical and visual outcomes, and secondary surgeries. RESULTS: Sixty-five eyes comprised the study sample with mean a follow-up of 42 months. Eighteen (27%) eyes had a history of ocular surgery and 5 (7.6%) had previous ocular trauma. Thirty-nine (60%) eyes had macula on RRD. Retinal detachment (RD) was caused by a single break in fifty (76.9%) eyes. Superior breaks were found in 56 (86.1%) eyes. Twelve (18%) eyes had posterior vitreous detachment. Fifty-one (78.5%) eyes underwent PR under local anesthesia and 9 (13.8%) underwent conjunctival peritomy. Octafluoropropane gas was used in 49 (75.4%) eyes and sulfur hexafluoride in 16 (24.6%) eyes. Cryotherapy was performed in 48 (73.8%) eyes and only laser photocoagulation in 8 (12.3%) eyes. Nine (13.8%) eyes underwent both cryotherapy and laser photocoagulation. Primary anatomical healing was achieved in 45 (69.2%) eyes, of which 20 (30.8%) required a second intervention. The final anatomical outcome was achieved in 100% of the eyes. At final visit, vision improved in 72% of eyes, was maintained in14.5%, and decreased in 9.7% (6). CONCLUSION: PR is a safe procedure for RRD repair. The final anatomical outcome was excellent in all cases including the recurrent RD after primary failure. PMID- 29279656 TI - Prevalence and Major Causes of Visual Impairment in Iranian Adults: A Systematic Review. AB - PURPOSE: The purpose of this study is to provide a pooled estimate of moderate-to severe visual impairment (MSVI) and blindness in Iran for people 50 years and over and to identify the major causes through systematic review. MATERIALS AND METHODS: International (PubMed, ISI Web of Science, and Scopus) and national databases (Scientific Information Database, Barakat Knowledge Network System, Iran Databank of Ophthalmology Research, and Magiran) databases were searched. Following relevance assessment and critical appraisal, eight studies were included. A funnel plot was drawn to explore the stability for estimation. Single variable meta-regression analysis was applied for heterogeneity assessment, and a random effect model was used (but no significant source for the observed heterogeneity was found). RESULTS: Age-standardized pooled estimate of MSVI was 4.24% (95% confidence interval [CI]: 2.92-5.56); 3.98% (95% CI: 2.37-5.59) for men, and 4.08% (95% CI: 2.95-5.21) for women. Blindness (visual acuity <3/60) prevalence was 1.31% (95% CI: 1.23-1.39); 0.96% (95% CI: 0.89-1.03) for men, and 1.13% (95% CI: 1.06-1.20) for women. Causes of visual impairment (VI) were cataract (40.23%), amblyopia (12.03%), corneal opacity (9.63%), age-related macular degeneration (9.31%), diabetic retinopathy (4.94%), and glaucoma (3.67%). CONCLUSION: VI prevalence in the 50 years and older population in Iran seems significantly better than the corresponding global estimates. A rough 60% rate of treatable VI was estimated, mostly attributable to unoperated cataract. PMID- 29279657 TI - Real-time Optical Coherence Tomography Incorporated in the Operating Microscope during Cataract Surgery. AB - A 55-year-old male presented with reduced vision due to senile cataract. The patient consented to undergo real-time intraoperative anterior segment-optical coherence tomography (AS-OCT) during phacoemulsification with intraocular lens (IOL) implantation. Images were captured at various points during the surgery. The use of AS-OCT incorporated into the surgical microscope was evaluated as an adjunct to cataract surgery. We were able to successfully evaluate, in real-time, wound architecture, the attachment of Descemet's membrane, the posterior capsule, and IOL position. Real-time AS-OCT can be used to proactively address potential complications and verify IOL placement intraoperatively. PMID- 29279658 TI - Macular Hole Secondary to Polypoidal Choroidal Vasculopathy. AB - We report a case of polypoidal choroidal vasculopathy (PCV) presented with massive submacular hemorrhage (SMH) and macular hole (MH). Spectral domain optical coherence tomography confirmed the presence of MH along with SMH and also revealed an extrafoveal-notched pigment epithelium detachment (PED) suggestive of PCV. Urgent pneumatic displacement with perfluoropropane (C3F8) was done. Indocyanine green angiography done 3 weeks later showed polyps in the superonasal macula corresponding to PED. Extrafoveal polyps were treated with laser photocoagulation. Inverted flap MH surgery was planned but the patient was lost to follow-up. PMID- 29279659 TI - Superior Oblique Myokymia: Some Novel Observations. AB - Superior oblique myokymia is a rare condition, characterized by spontaneous rhythmic contractions of the superior oblique muscle and was first described by Duane in 1906. However, the pathophysiology of this condition remains poorly understood even today. A number of medical and surgical treatment modalities have been tried, with variable results. We report a case of superior oblique myokymia in a pregnant female, which could be triggered with flashlight stimulation, and the result of treatment with timolol maleate 0.5% ophthalmic solution. PMID- 29279660 TI - Occult Optic Disc Pit Maculopathy in a Glaucomatous Disc. AB - Optic pits are congenital defects of the optic disc. Diagnosis of optic pit maculopathy is quite challenging in the absence of a clinically visible or optical coherence tomography (OCT) proven pit. One such scenario is when there is advanced glaucomatous cupping. We present a case in which OCT helped detect optic disc pit maculopathy in a 60-year-old female. PMID- 29279661 TI - Setting Benchmarks for the New User: Training on the Robotic Simulator. AB - Background and Objectives: Data showing the impact of the robotic simulator on fellowship training are limited. This study was conducted to determine whether simulator scores reflect the experience of the robotic gynecologic surgeon and to develop a simulator curriculum for trainees in gynecologic oncology. Methods: All faculty and fellows in the Department of Gynecologic Oncology and Reproductive Medicine were asked to participate. For phase 1, all participants were divided into 2 groups based on robotic surgical experience: beginner (0-50 cases) and experienced (>50 cases). Each participant completed 9 modules 3 times each to establish baseline data. Median module scores for the experienced group defined the benchmarks scores. In phase 2, all trainees who did not meet the benchmark score on a module were asked to repeat the module until they reached the score twice. Results: Twenty-four participants were included: 18 beginners and 6 experienced surgeons. For all modules, experienced surgeons received higher median scores than beginners. There was a significant difference between the scores of the 2 groups in the Energy Switching 1 (87.5 vs 92.5; P = .002) and Suture Sponge 2 (75.0 vs 87.3; P = .011) modules. Thirteen trainees participated in phase 2. For 8 of 9 of the modules, >75% of trainees met proficiency, with a median of 3 to 6 attempts (range, 2-24). Conclusion: Based on the findings, scores reflected each surgeon's experience. With repetition, most of the trainees were able to reach the benchmark scores. Further study is needed to determine the impact of surgical simulation on true intraoperative performance. PMID- 29279662 TI - CT Scan Reliability in Detecting Internal Hernia after Gastric Bypass. AB - Background and Objectives: Internal hernia (IH) after gastric bypass can be a life-threatening complication. Obstruction presents acutely or as chronic relapses, with symptoms of abdominal pain, nausea, and vomiting. Early detection and exploration of IH as the cause of small bowel obstruction (SBO) is critical in this surgical emergency and can reduce morbidity and mortality. We conducted a retrospective review of laparoscopic Roux-en-Y bypass (LRYGB) records to determine the specificity and sensitivity of computed tomography (CT) in identifying postoperative IH. Methods: Records of 550 patients who underwent antecolic antegastric laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery over a 5-year period (2010-2014) were retrospectively reviewed for complications. Our study population comprised patients who returned with signs and symptoms of obstruction who underwent CT imaging followed by laparoscopic exploration. Results: Thirty-four patients were found to have obstruction on CT scan at >=6 weeks after LRYGB. Six (17.7%) were found to have IH by preoperative CT imaging before laparoscopic exploration. Of the 6 patients identified to have IH before exploration, 4 (28%) had consistent findings at operation, yielding a sensitivity of 28.6% and specificity of 90.0%. Operative findings identified other causes of SBO: adhesions (n = 17), IH (n = 14), jejunojejunostomy stenosis (n = 2), and phytobezoar (n = 1). Conclusions: IH after LRYGB is difficult to detect. Our study found CT to have a low sensitivity but a high specificity in detecting IH. Therefore, laparoscopic exploration continues to be the best diagnostic and therapeutic intervention for this complication. PMID- 29279663 TI - Nerve Bundle Hydrodissection and Sexual Function after Robot Prostatectomy. AB - Background and Objectives: Loss of erectile function is common after prostatectomy, and surgeons have long sought techniques that reduce this adverse outcome. This study was conducted to assess erectile function after robot assisted laparoscopic prostatectomy, with and without hydrodissection (HD) of the neurovascular bundles (NVBs). Methods: Using a database of 335 consecutive RALP procedures conducted by 2 surgeons, we identified all nerve-sparing surgeries performed by HD or standard dissection (SD). The primary and secondary endpoints were Sexual Health Inventory for Men (SHIM) scores and surgical margin positivity, respectively. Subset analyses were performed on men with preoperative SHIM scores >=17. Determinants of the postoperative SHIM score were evaluated by multivariate linear regression. Results: Among men with preoperative SHIM scores >=17 who underwent bilateral complete nerve sparing (n = 73), mean preoperative SHIM scores were similar in the HD and SD groups, but were significantly higher in the HD group at 6 months (16.1 +/- 8.6 vs 8.3 +/- 8.1; P = .024) and >1 year after surgery (16.9 +/- 7.1 vs 9.1 +/- 6.4; P = .004). According to multivariate linear regression analysis including all patients, HD at RALP (odds ratio [OR] 6.9; 95% confidence interval (CI) 2.8-11.0; P = .001) and preoperative SHIM score were independent predictors of erectile function at >1 year after surgery. There was no significant difference in surgical margin positivity between groups (P = .36). Conclusion: HD of the NVB appears to improve erectile function after RALP. PMID- 29279664 TI - Evaluation of intracanal acetazolamide in late reimplanted rat teeth. AB - Objective: The aim of this study was to evaluate the use of acetazolamide combined with different agents as intracanal medication in late reimplanted rat teeth. Materials and Methods: In 100 Wistar rats, divided into 5 groups of 20, one of the following medications was used: Acetazolamide liquid (AL); AL with calcium hydroxide powder (ALHC); acetazolamide powder with AL; acetazolamide powder with physiological solution; and calcium hydroxide with physiological solution (control). At 30 and 60 days after reimplantation, the animals were sacrificed, tissues were processed, and cuts were stained with hematoxylin and eosin. An optical microscope was used to determine the following: percentage of inflammatory root resorption (RRI); percentage of substitute root resorption (RRS); and presence of ankylosis. The data obtained was submitted for statistical analysis. Results: Group ALHC had a significantly higher RRS than the control group at 60 days (P = 0.01). Group AL showed significantly less ankylosis than the other groups, including the control, at 30 days. AL showed results similar to those of the control group with respect to RRS. Conclusion: Acetazolamide has the potential to be an effective intracanal medication. PMID- 29279665 TI - Modulating toll-like receptor-mediated inflammatory responses following exposure of whole cell and lipopolysaccharide component from Porphyromonas gingivalis in wistar rat models. AB - Objective: To explore host innate inflammatory response and the signal pathway induced by Porphyromonas gingivalis by measuring level of toll-like receptor 2 (TLR2) and TLR4 activity. Materials and Methods: Animal experimental study with pretest-posttest controlled group design were done between January 1 and December 10, 2016.. Total of 28 wistar rats had been used, randomized into 7 groups, each were given various dose of intra-sulcural injection of Porphyromonas gingivalis lipopolysaccharide. Statistical Analysis: Normality were measured by Shapiro-Wilk test, while statistical analysis made by ANOVA, t test, Pearson, and linear regression model.. Results: At day 0, no significant difference TLR2 and TLR4 level were measured. At day 4, there is a slight difference between TLR2 and TLR4 level in each group. At day 11, there is a significant difference between TLR2 and TLR4 level in each group. Group with exposure of whole cell will develop greater TLR2 but lower TLR4 level. In the contrary, group with exposure of LPS will develop greater TLR4 but lower TLR2 level. Conclusion: Our data supported that P. gingivalis played a vital role in the pathogenesis of pathogen-induced inflammatory responses in which TLR2 and TLR4 have different molecular mechanisms following recognition of pathogens and inflammatory response. PMID- 29279666 TI - The effect of toothpastes with bleaching agents on the force decay of elastomeric orthodontic chains. AB - Objective: The aim of this study was to evaluate the effect of agents available in whitening toothpastes (Crest(r) and Sensodyne(r)) in vitro on the force decay of elastomeric chains used in orthodontics. Materials and Methods: A total of 300 specimens of elastomeric chains were divided into five groups (n = 60) and were evaluated. These groups included (1) the regular Crest(r) toothpaste and distilled water solution, (2) whitening Crest(r) toothpaste and distilled water solution, (3) regular Sensodyne(r) toothpaste and distilled water solution, (4) whitening Sensodyne(r) toothpaste and distilled water solution, and (5) distilled water as a control group. The samples' force was measured using Instron at intervals of 0, 1, 7, 14, 21, and 28 days. Data were analyzed by SPSS software. Results: At the initial time point, the difference in the force values of elastomeric chain between any of the groups was not significant (P > 0.05). On the 1st day, there was a significant difference (P < 0.05) between all groups except the groups of whitening Crest(r), regular, and whitening Sensodyne(r) (P > 0.05). On days 7, 14, and 28, the rate of decline for all groups was statistically significant (P < 0.05). Conclusions: According to the results obtained in the present study, it seems that toothpastes without whitening agents have less effect on force decay of elastomeric chain over time. PMID- 29279667 TI - Shade changing effectiveness of plasdone and blue covarine-based whitening toothpaste on teeth stained with chlorhexidine and black tea. AB - Objective: This study evaluated the effectiveness of toothbrushing with whitening toothpaste in altering the shade of stained human enamel. Materials and Methods: Thirty fragments of human enamel, stained with chlorhexidine/black tea underwent 1000 and 5000 brushing cycles (BC) with (n = 10): PLS (Gel Dental Day, Bitufo), Close Up White Now, Unilever (COVB) and regular (Gel Dental Night, Bitufo) toothpaste. Images were taken before staining (baseline), after staining (STN) and following 1000 and 5000 BC and were analyzed using the CIELAB parameters (DeltaE, Deltab and DeltaL). Statistical Analysis Used: Data were submitted to two-way ANOVA (alpha = 0.05). Results: DeltaE was higher from STN to baseline; 1000 BC to STN and 5000 BC to STN (P < 0.001). Significant differences in Deltab values were found from 1000 BC to STN and 5000 BC to STN. For COVB, greater DeltaL was observed from 1000 BC to STN, what differed statistically from the regular toothpaste (P < 0.05). There was no difference between toothpaste when DeltaL was calculated from 5000 CB to STN. Conclusions: Toothpaste containing COVB or PLS in association with 5000 BCs showed similar effectiveness in changing enamel shade; but after the first 1000 toothbrushing cycles, the use of COVB toothpaste promoted higher lightness in stained enamel. PMID- 29279668 TI - X-ray diffraction analysis of hydroxyapatite-coated in different plasma gas atmosphere on Ti and Ti-6Al-4V. AB - Objective: The aim is to study the effect of plasma working gas on composition, crystallinity, and microstructure of hydroxyapatite (HA) coated on Ti and Ti-6Al 4V metal substrates. Materials and Methods: Ti and Ti-6Al-4V metal substrates were coated with HA by plasma spray using four plasma gas atmospheres of argon, argon/hydrogen, nitrogen, and nitrogen/hydrogen. The degree of crystallinity, the phases present, and microstructure of HA coating were characterized using X-ray diffraction and scanning electron microscopy. Results: Variation in crystallinity and the microstructure of HA coating on plasma gas atmosphere was observed. Micro cracks due to thermal stresses and shift in the 2theta angle of HA compared to feedstock was seen. Conclusion: Plasma gas atmosphere has a significant influence on composition, crystallinity, and micro-cracks of HA-coated dental implants. PMID- 29279669 TI - The clinical evaluation of platelet-rich plasma on free gingival graft's donor site wound healing. AB - Objective: It has been proved that platelet-rich plasma (PRP) can promote wound healing. In this way, PRP can be advantageous in periodontal plastic surgeries, free gingival graft (FGG) being one such surgery. Materials and Methods: In this randomized split-mouth controlled trial, 10 patients who needed bilateral FGG were selected, and two donor sites were randomly assigned to experience either natural healing or healing-assisted with PRP. The outcome was assessed based on the comparison of the extent of wound closure, Manchester scale, Landry healing scale, visual analog scale, and tissue thickness between the study groups at different time intervals. Statistical Analysis Used: Repeated measurements of analysis of variance and paired t-test were used. Statistical significance was P <= 0.05. Results: Significant differences between the study groups and also across different time intervals were seen in all parameters except for the changes in tissue thickness. Conclusion: PRP accelerates the healing process of wounds and reduces the healing time. PMID- 29279670 TI - A survey of fissure sealants and dental caries prevalence in the first permanent molars among primary school girls in Riyadh, Saudi Arabia. AB - Objectives: To investigate the prevalence of caries and fissure sealants on the first permanent molars (FPMs) among 6-9-year-old girls in Riyadh, Saudi Arabia. Materials and Methods: The FPMs of 17,891 school girls from 120 randomly selected public primary schools were evaluated by visual and tactile examination for the carious status and the presence of fissure sealants. Chi-square test was used to analyze the data at level of 5%. Results: A total of 58,140 FPMs were assessed in the 17,891 children. Nearly 64.6% of the children were caries free. Only 1.3% of the children had at least one fissure sealant applied. At tooth level, the decayed FPMs counted for 24.6%. There was obvious underutilization of fissure sealants on the FPMs; 0.8% (n = 478). The caries prevalence in the mandibular FPMs (33%) was significantly higher than in the maxillary FPMs, 18.2% (P < 0.01). The proportion of carious FPMs increased with age of the children significantly (P < 0.01). There was no significant difference in the proportion of the presence of fissure sealants among the three different grade/age groups (P > 0.05). Conclusions: Caries prevalence in the FPMs was high and serious among this cohort of young students. This was contrasting the very low prevalence of fissure sealants. PMID- 29279671 TI - Dental students' knowledge of medication-related osteonecrosis of the jaw. AB - Objectives: The aim of this study was to evaluate and assess knowledge and attitude of dental students about medication-related osteonecrosis of the jaw (MRONJ), to optimize future training programs in this field. Materials and Methods: A cross-sectional study was administrated. Ninety-eight participants agreed to complete an anonymous questionnaire. It was divided into two sections: the first section was about general information such as interviewer's gender and date of birth; the second section included questions about bisphosphonates (BPs), others medication associated to osteonecrosis of the jaw (ONJ), risk factors, and prevention of osteonecrosis. Descriptive statistics were computed and the odds ratio was used to compare the odds for the groups. Results: Ninety-nine percent of participants declared to know BPs, but only 26.9% of 4th year and 34.8% of 6th year students knew the correct definition of MRONJ. Almost all of students identified the importance to report, in anamnesis, the use of BPs, as well as to check-up patients before the beginning of treatment; on the other hand, the knowledge about how invasive dental treatment might be carried out in patients under therapy was not adequate. In addition, half of the students did not recognize any active principle or commercial name of BPs. The situation was even worse regarding alternative drugs involved in ONJ. Conclusions: These findings are alarming and the lack of knowledge about MRONJ suggests that greater educational efforts should be performed about this pathology at undergraduate level. PMID- 29279672 TI - Smartphone application as an aid in determination of caries risk and prevention: A pilot study. AB - Objective: To assess the dietary and oral hygiene pattern before and after the usage of cariometer app. Materials and Methods: Dietary score recorded by cariometer was assessed for 7 days for preschool children in the age group of 2-6 years. The frequency of brushing and mouth rinsing was assessed before and after the usage of app. Paired t-test was conducted to compare the dietary score, brushing frequency, and rinsing frequency pre and post the use of the app. Results: There was a significant improvement in the dietary pattern followed by the patients at the day 7 as compared to day 1. About 90% of children brushed twice at day 7 of the use of cariometer. There was a significant increase in the frequency of rinsing after meals at day 7 as compared to day 1 of the use of cariometer. Conclusion: There was a significant improvement in the dietary pattern and the oral hygiene habit after the use of app. PMID- 29279673 TI - Impact of preventive care orientation on caries status among preschool children. AB - Objective: This study aims to study the impact of preventive care orientation given to caregivers of child daycare centers on their knowledge and on the prevalence of early childhood caries (ECC) among preschool children. Materials and Methods: Caregivers of twenty child daycare centers in Emirate of Sharjah were interviewed and 435 children attending these centers were surveyed for decayed missing filled teeth (dmft). The sample data were analyzed using t-tests and one-way ANOVA to assess the statistical significance of the differences in dmft score found between groups. Results: No significant correlation was found between dmft scores and family income of urban or rural centers, mothers' level of education, mothers' employment status in public centers, and frequency of dental visits. There was a significant correlation between dmft scores and mothers' employment status in private centers with the lowest scores among children of working mothers. High caries rates were observed in children attending private daycare centers where sweetened milk, juices, and snacks were served more frequently. There was a significant difference between private and public centers in caregivers' level of knowledge regarding oral health in favor of the latter. Low dmft scores were found to be associated with high level of knowledge of caregivers in public centers. Conclusions: Children are more likely to develop ECC if their caregivers are lacking knowledge or regular provision of preventive care orientation. This makes caregivers and school teachers better candidates for oral health education programs than parents. PMID- 29279674 TI - The prevalence of halitosis (oral malodor) and associated factors among dental students and interns, Lahore, Pakistan. AB - Objective: To evaluate the prevalence of halitosis and the factors associated with it among dental students and interns in Lahore, Pakistan. Methods: A cross sectional study design was chosen, and a sample of dental students and interns was collected from seven dental colleges in Lahore, Pakistan. A total of 833 participants were approached in person as convenient sample population. A self reported questionnaire was administered and informed consent was obtained. The associations between oral malodor and different variables of the study were explored using analytical statistics (Chi-square test and logistic regression analysis). Statistical significance was determined using a 95% confidence interval (CI). Results: Six hundred and fifteen participants (aged 19-27 years) completed the survey with a response rate of 73.8%. The prevalence of self reported halitosis was 75.1%. More female (51.4%) than male students (23.7%) reported oral malodor, and most participants (61%) reported early morning halitosis. Thirteen percent of respondents had examination for oral malodor by a dentist and 37.6% treated the condition with self-medication. Binary logistic regression model showed that male gender (odds ratio [OR] =0.44, CI = 0.22-0.87), daily use of dental floss (OR = 0.28, CI = 0.13-0.58), and drinking tea with mint (OR = 0.44, CI = 0.22-0.89) were significantly associated with oral malodor. The participants with tongue coating had higher odds (OR = 2.75, CI = 1.13-6.69) of having oral malodor than those without tongue coating, and the association was statistically significant. Conclusions: The study identified high prevalence of oral malodor among dental students and interns. They should receive appropriate diagnosis and management of the condition from dentist. The regular use of dental floss and removal of tongue coating can significantly reduce halitosis. PMID- 29279675 TI - The effect of two cross-linking agents on dentin bond strength of resin-modified glass ionomer. AB - Objectives: The hybrid layer at the interface of resin-modified glass ionomer cements and dentin is prone to degradation by endogenous matrix metalloproteinases. We aimed to investigate the effect of two types of collagen crosslinkers, carbodiimide and proanthocyanidin (PA), on immediate and medium term bond strength of a resin-modified glass ionomer to dentin. Materials and Methods: Seventy-two molars were flattened on the occlusal surface to expose dentin. The specimens were divided into control, 1-ethyl-3-(3-dimethylaminopropy) carbodiimide hydrochloride (EDC), and PA groups (n = 24). In the EDC and PA groups, carbodiimide and PA solutions were applied for 1 min, respectively. Resin modified glass ionomer was bonded. Half of the specimens in each group were tested for shear bond strength after 24 h and the other half were tested after 6 months. Statistical Analysis: Data were analyzed with SPSS version 16 (SPSS Inc, Chicago, IL, USA), using two-way ANOVA, and subgroup analysis was performed using one-way ANOVA, Tukey's test, and t-test. Results: Two-way ANOVA showed that treatment and time affected the bond strength. Carbodiimide and PA did not affect the immediate bond strength (P = 0.51). After 6 months, the bond strength of the EDC group was significantly lower than that of the control and PA groups. Bond strength of the control and PA groups increased after 6 months (P <= 0.002). Conclusion: PA did not interfere with maturation of RMGIC unlike carbodiimide. Therefore, it can be suggested as an matrix metalloproteinase inhibitor before bonding of resin-modified glass ionomer to dentin. PMID- 29279676 TI - Comparative evaluation of calcium phosphate-based varnish and resin-modified glass ionomer-based varnish in reducing dentinal hypersensitivity: A randomized controlled clinical trial. AB - Objective: The aim of this study was to evaluate the efficacy of MI varnish and Clinpro XT varnish in reducing dentinal hypersensitivity. Materials and Methods: Patients with cervical dentinal hypersensitivity were selected for the study. The teeth to be tested were isolated. Then, a blast of air and ice cold water was applied on the tooth surface, and the score was measured by visual analog scale. The patients were randomly assigned to one of the treatment groups (Group 1: MI varnish; Group 2; Clinpro XT varnish). The manufacturer's instructions were followed. The sensitivity scores were recorded immediately and after 1 week of therapy. Statistical Analysis: Mann-Whitney U-test and Wilcoxon-matched pairs test were used for the analysis. Results and Conclusion: Although both varnishes were shown to reduce the dentinal hypersensitivity in patients, according to statistics, MI Varnish was a better agent to reduce dentinal hypersensitivity than Clinpro XT varnish. PMID- 29279677 TI - On the synthesis and characterization of beta-tricalcium phosphate scaffolds coated with collagen or poly (D, L-lactic acid) for alveolar bone augmentation. AB - Objectives: After tooth loss, dimensional alterations on the alveolar bone ridge can occur that can negatively affect the placement of dental implants. The purpose of this study was to evaluate the synthesis, and mechanical properties of beta-tricalcium phosphate (beta-TCP) scaffolds coated with bioabsorbable polymers, namely, collagen and poly (D, L-lactic acid) (PDLLA). Materials and Methods: beta-TCP powder was obtained by reactive milling and then characterized by X-ray diffraction and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS). beta-TCP scaffolds were obtained by replica method, in which polyurethane foams are immersed in beta-TCP suspension and thereafter submitted to a thermal treatment to remove the polyurethane and sinter the ceramic. Type-I collagen or PDLLA were used to coat the beta-TCP scaffolds by dip coating method. Scaffolds were separated in four groups depending on the coating material: noncoated (Group A), double immersion in collagen (Group B), double immersion in PDLLA (Group C), and ten immersions in PDLLA (Group D). Samples were characterized by compressive tests and SEM/EDS. Data were statistically analyzed through two-way ANOVA (p = 0.05). Results: Chemical and microscopic analyses revealed proper morphology and chemical composition of powder particles and scaffolds with or without polymeric coatings. Scaffolds coated with PDLLA showed higher compressive strength (0.11 +/- 0.054 MPa) than those of collagen (0.022 +/ 0.012 MPa) or noncoated groups (0.024 +/- 0.012 MPa). Conclusions: The coating method of beta-TCP with PDLLA revealed a potential strategy to increase the mechanical strength of porous ceramic materials while collagen can enhance cell migration. PMID- 29279678 TI - Cytotoxic and the proliferative effect of cuttlefish bone on MC3T3-E1 osteoblast cell line. AB - Objective: To evaluate the cytotoxic and the proliferative effect of cuttlefish bone on MC3T3-E1 osteoblast cell line. Materials and Methods: MC3T3-E1 cells were treated with 0.5, 1, 5, 25, 50, 100, or 200 MUg/ml cuttlefish bone powder (CBP). Cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. This assay was also used to determine cell proliferation over 16 days of treatment with 0.5, 25, or 100 MUg/ml CBP. Results: CBP was not cytotoxic to MC3T3-E1 cells at any concentration. The percentage of cell viability in the 0.5-200 MUg/ml CBP groups dose dependently decreased from 107.52 +/- 11.03 to 92.48 +/- 5.60%; however, the differences between the groups or the negative control group were not significant. At 16 days, 0.5, 25, and 100 MUg/ml CBP groups showed 123.19 +/- 10.07%, 126.02 +/- 15.69%, and 133.33 +/- 11.74% proliferation, respectively, that were significantly higher than that of the control group. Conclusion: These results indicate that CBP promotes osteoblast proliferation and may be a potential material to increase the number of osteoblasts in a bone defect in the oral cavity. PMID- 29279679 TI - Effectiveness of platelet-rich fibrin in the management of pain and delayed wound healing associated with established alveolar osteitis (dry socket). AB - Objective: To assess the efficacy of platelet-rich fibrin (PRF) on the pain and healing of the extraction socket related with established alveolar osteitis (dry socket, AO) after the removal of maxillary and mandibular molars. Materials and Methods: One hundred consecutive adult patients with age group ranging from 18 to 40 years along with established dry socket after maxillary and mandibular molar extractions who have not received any treatment for the same were included in this single-arm clinical trial. PRF was placed in the maxillary and mandibular molar extraction sockets after adequate irrigation of the socket. All the patients evaluated for the various study variables which include pain, degree of inflammation, and healthy granulation tissue formation (wound healing) at the 1st, 3rd, 7th, and 14th post-PRF placement day in the alveolar socket. Data were analyzed using Shapiro-Wilk's test, Chi-square test and/or Student's t-test, Friedman's test, Wilcoxon signed-rank test, and Bonferroni test, with the significance level set at P < 0.05. Results: There was significant reduction in pain associated with AO at the 3rd and 7th post-PRF placement day in the extraction socket along with mark decrease in the degree of inflammation at the 3rd post-PRF placement day, and there was better wound healing by the end of the 2nd week. Conclusion: The use of PRF in this clinical trial illustrates the promising results in terms of reduced pain and better healing in the patients with sustained AO. PMID- 29279680 TI - Smile esthetics: Impact of variations in the vertical and horizontal dimensions of the maxillary lateral incisors. AB - Objective: The purpose of this study was to determine the perception of trained dental professionals and laypersons toward the esthetic impact of variations in the vertical position, width, and gingival height of the maxillary lateral incisor. Materials and Methods: The present study analyzed the perspective of smile photographs by dental professionals such as "fifty orthodontics and fifty general dental practitioners (GDPs)" as well as fifty laypersons, consisting of an equal number of male and female participants. Photographs edited to depict alteration of golden proportion, incisal length, and gingival height of lateral incisor. SPSS software was used to analyze the data and determine the significant difference within all the participants, at 0.05% level (95% confidence interval). Results: There was no significant difference in ranking between the genders. Golden proportion of 62%-67% were ranked the highest by orthodontists, whereas GDPs and laypersons preferred 67%. Regarding gingival display, corrected height of -0.5 and -1 mm received highest ranking from all the three groups. In case of lateral incisal length, -0.5 mm was ranked highest by laypersons, in contrast to 1 mm by orthodontists and GDPs. Conclusion: Specific differences were observed in the ranking of smile esthetics by health-care professionals and laypersons. Golden proportion of 62% and 67% were ranked the highest by orthodontists, whereas GDPs and laypersons preferred 67%. Corrected gingival height of -0.5 and 1 mm received highest ranking from all the three groups. In case of lateral incisal length, -0.5 mm was ranked highest by laypersons, in contrast to -1 mm by orthodontists and GDPs. PMID- 29279681 TI - Awareness of basic life support among Saudi dental students and interns. AB - Objective: Fatal medical emergencies may occur at any time in the dental clinic. The present study assessed the level of awareness and attitudes toward basic life support (BLS) among Saudi dental students and interns. Materials and Methods: A self-administered questionnaire comprising 23 closed-ended questions was used in this survey. The first part of the questionnaire assessed the demographical profile of the students such as age, gender, and educational level. The second part investigated their knowledge and awareness about BLS. Data from 203 respondents were analyzed using Statistical Package for the Social Studies version 22.0. Results: The response rate was 81.2%. Overall, the respondents showed a low level of knowledge with significant differences between males and females (<0.001). Surprisingly, final-year dental students showed relatively better knowledge than interns though the differences were not statistically significant. Conclusion: The present study demonstrates poor knowledge among dental students regarding BLS and showed the urgent need for continuous refreshing courses for this critical topic. PMID- 29279682 TI - Dental prosthetic status and prosthetic needs of geriatric patients attending the College of Dentistry, Al Jouf University, Kingdom of Saudi Arabia. AB - Objective: To evaluate the dental prosthetic status and prosthetic needs of geriatric patients attending the College of Dentistry, Al Jouf University, Kingdom of Saudi Arabia. Materials and Methods: Patients aged 60 years and above were included in this study. The World Health Organization oral health assessment pro forma was employed to record the data pertaining to the prosthetic status and prosthetic treatment needs of participants. Data obtained were analyzed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) Version 20.0. Differences in proportions were compared using the Chi-square test. Results: Out of 286 edentulous patients, 69.06% needed some form of prosthetic treatment, 73.77% did not have any prosthesis in upper arch, and 80.06% did not have any prosthesis in lower arch. Out of 162 males, 32.09% and 26.54% had prosthesis in upper and lower arch, respectively. Among 124 females, 18.54% and 19.35% had prosthesis in upper and lower arch, respectively. In males, the need for any type of prosthesis in upper and lower arch was 68.51% and 75.92%, respectively. In females, the need for prosthesis in upper and lower arch was 57.25% and 72.58%, respectively. The need for multiunit prosthesis was more in both arches in both genders. The need for complete denture and combination of single- or multiunit prosthesis was more among the males as compared to females in maxilla and vice versa for mandible. Conclusion: The observations of this study propose that the greater part of the prosthetic needs were insufficient among the geriatric people. PMID- 29279683 TI - Evaluation of child preference for dentist attire and usage of camouflage syringe in reduction of anxiety. AB - Objectives: The aim of this study is to evaluate the child preference for dentist attire and camouflage versus conventional syringe in reduction of anxiety. Materials and Methods: A total of 600 children aged 6-14 years were made to look at a set of six photos of an individual dressed with different colored apron of pink, green, blue, white colors, formal dress, and cartoon character along with conventional syringe and camouflage syringe with a toy-like appearance to permit injection of local anesthesia. Children's anxiety level during injections and with colored coat was assessed and recorded using the Modified Child Dental Anxiety Scale faces version. Statistical Analysis Used: SPSS statistical software version 21 and using Chi-square test. Results: Among age group of 6-8 years, 65.33% selected colorful apron, while other age groups 9-10, 11-12 years, and 13 14 years selected 47.34%, 57.34%, and 50.67% white coat, respectively (P < 0.05). For syringe, 78% of younger age group (6-10 years) preferred camouflage syringe, whereas 71% of older age group (11-14 years) preferred conventional syringe. Anxiety level of all children for syringe was more compared to that of white coat. Conclusion: Younger children prefer colorful attire of dentist and camouflage syringe over conventional compared to older one. PMID- 29279684 TI - Self-ligating versus conventional metallic brackets on Streptococcus mutans retention: A systematic review. AB - Objective: The present study aimed to review the literature systematically and assess comparatively whether self-ligating metallic brackets accumulate less Streptococcus mutans biofilm than conventional metallic brackets. Material and methods: The systematic search was performed following PRISMA guidelines and registration in PROSPERO. Seven electronic databases (Google Scholar, LILACS, Open Grey, PubMed, SciELO, ScienceDirect, and Scopus) were consulted until April 2016, with no restriction of language and time of publication. Only randomized clinical studies verifying S. mutans colonization in metallic brackets (self ligating and conventional) were included. All steps were performed independently by two operators. Results: The search resulted in 546 records obtained from the electronic databases. Additionally, 216 references obtained from the manual search of eligible articles were assessed. Finally, a total of 5 studies were included in the qualitative synthesis. In 1 study, the total bacterial count was not different among self-ligating and conventional brackets, whereas in 2 studies the amount was lower for self-ligating brackets. Regarding the specific count of S. mutans, 2 studies showed less accumulation in self-ligating than in conventional brackets. Conclusion: Based on the limited evidence, self-ligating metallic brackets accumulate less S. mutans than conventional ones. However, these findings must be interpreted in conjunction with particularities individual for each patient - such as hygiene and dietary habits, which are components of the multifactorial environment that enables S. Mutans to proliferate and keep retained in the oral cavity. PMID- 29279685 TI - Psychological factors in oral mucosal and orofacial pain conditions. AB - The psychological aspects of chronic pain conditions represent a key component of the pain experience, and orofacial pain conditions are not an exception. In this review, we highlight how psychological factors affect some common oral mucosal and orofacial pain conditions (namely, oral lichen planus, recurrent aphthous stomatitis, burning mouth syndrome, and temporomandibular disorders) with emphasis on the significance of supplementing classical biomedical treatment modalities with appropriate psychological counseling to improve treatment outcomes in targeted patients. A literature search restricted to reports with highest relevance to the selected mucosal and orofacial pain conditions was carried out to retrieve data. PMID- 29279686 TI - Abutment misfit in implant-supported prostheses manufactured by casting technique: An integrative review. AB - The aim of this study was to perform an integrative review of the literature on the clinically usual prosthesis-abutment misfit over implant-supported structures manufactured by conventional casting technique. The present integrative review used the PRISMA methodology. A bibliographical search was conducted on the following electronic databases: MEDLINE/PubMed (National Library of Medicine), Scopus (Elsevier), ScienceDirect (Elsevier), Web of Science (Thomson Reuters Scientific), Latin American and Caribbean Center on Health Sciences Information (BIREME), and Virtual Health Library (BVS). A total of 11 relevant studies were selected for qualitative analysis. The prosthetic-abutment vertical misfit considered clinically usual ranged from 50 to 160 MUm. The vertical misfit depends on several steps during technical manufacturing techniques, which includes the materials and technical procedures. Lower values in misfit are recorded when precious metal or titanium alloys are utilized. Although a vertical misfit mean value of 100 MUm has been considered clinically usual, most of the previous studies included in this revision showed lower mean values. PMID- 29279688 TI - Dental amalgam fillings and the use of technological devices as an environmental factor: Updating the cumulative mercury exposure-based hypothesis of autism. PMID- 29279687 TI - Prosthodontic maintenance and peri-implant tissue conditions for telescopic attachment-retained mandibular implant overdenture: Systematic review and meta analysis of randomized clinical trials. AB - The mandibular implant-retained overdentures (MIRO) are a highly successful prosthetic treatment option. However, an argument still present regarding its design and type of attachment system. This systematic review and meta-analysis aimed to perform a qualitative and quantitative analysis of the scientific literature regarding the telescopic attachments versus other attachment systems retaining mandibular implant overdentures. Manual and electronic database (PubMed and Cochrane) searches were performed to identify randomized controlled trials (RCTs) comparing telescopic versus other attachment systems. Independently, two investigators extracted the trials' data. The Cochrane tool was used for assessing the quality of included studies. Meta-analyses were performed for the included RCTs and reported the same outcome measures. Nine RCTs were identified. Three RCTs (corresponding to four publications) were included in the study. The other five trials were excluded from the study. The meta-analysis revealed no difference between telescopic crowns and ball attachment retaining mandibular implant overdenture as regards prosthodontic maintenance. Regarding peri-implant conditions, ball-retained mandibular overdenture showed statistically significant more probing depth around implants records in ball-retained overdenture when compared to the telescopic group. However, there are no statistically significant differences between two interventions in regard to marginal bone loss, bleeding index, gingival index, and plaque index. In conclusions, no significant differences in prosthodontic maintenance and peri-implant condition between telescopic attachments and ball attachments retaining MIRO. However, this should be considered with caution because of a limited number of included studies. PMID- 29279689 TI - A Solitary Intestinal Myofibroma: A Rare Cause of Neonatal Anemia. AB - Solitary infantile myofibroma with visceral involvement is very rare. We present an unusual case of a solitary myofibroma with abdominal localization in a 1-day old female neonate who presented with severe anemia and rectal bleeding. A bleeding myofibroma was found, located in the wall of the jejunum, and totally resected. In case of a solitary lesion, treatment is relatively easy and effective, with excellent prognosis after total resection. The multiple form (myofibromatosis) has a poor prognosis with low survival rates. We therefore recommend total body MRI for all patients diagnosed with myofibroma to rule out other lesions. PMID- 29279690 TI - Immune Checkpoint Inhibitor-Associated Type 1 Diabetes Mellitus: Case Series, Review of the Literature, and Optimal Management. AB - With the introduction of immune checkpoint inhibitors into clinical practice, various autoimmune toxicities have been described. Antibodies targeting the receptor:ligand pairing of programmed death receptor-1 (PD-1) and its cognate ligand programmed death-ligand 1 (PD-L1) in rare reports have been associated with autoimmune diabetes mellitus. We report 2 cases of rapid-onset, insulin dependent, type 1 diabetes mellitus in the setting of administration of nivolumab, a fully human monoclonal antibody to PD-1, and atezolizumab, a humanized monoclonal antibody to PD-L1. This appears to be the first report of autoimmune diabetes mellitus associated with atezolizumab. In addition, we provide a brief review of similar cases reported in the literature and a discussion of potential mechanisms for this phenomenon and propose a diagnostic and treatment algorithm. PMID- 29279691 TI - Recurrent Masses after Testicular Cancer: Growing Teratoma Syndrome. A Case Report and Review of the Literature. AB - Background: Growing teratoma syndrome is a rare syndrome that affects patients with nonseminomatous germ-cell tumors (NSGCTs). It is characterized by recurrent growing masses that appear during or after chemotherapy in the presence of normal levels of tumor markers. Histological examination is the only way to confirm the diagnosis. Case Presentation: We present the case of a 36-year-old man who developed recurrent masses after curative treatment for NSGCT of the testicle. His tumor markers were normal. The patient was cured after multiple surgical procedures. Conclusions: Close follow-up after treatment for NSGCT is very important for early detection of this syndrome, which can occur even many years after tumor onset. Normal blood makers can be misleading, and surgery remains the only curative treatment. PMID- 29279692 TI - Long-Term Survival of a Patient with Adenocarcinoma of the Esophagogastric Junction with a Portal Vein Tumor Thrombosis Who Underwent Palliative Total Gastrectomy: A Case Report. AB - Portal vein tumor thrombosis (PVTT) with advanced gastric cancer is very rare; when it occurs, it exhibits aggressive growth and carries a poor prognosis. In addition, definitive treatment has not been established due to insufficient data. Herein, we report a case of PVTT associated with an adenocarcinoma of the esophagogastric junction that was successfully controlled by means of a palliative total gastrectomy without surgical resection of the PVTT and administration of palliative continuous doxifluridine. PMID- 29279693 TI - A Rare Case of Classical Hodgkin Lymphoma Diagnosed 10 Years after Liver Transplant. AB - Posttransplant lymphoproliferative disorders (PTLD) represent a rare and potentially life-threatening complication after liver transplantation. Classical Hodgkin lymphoma (cHL), with an incidence of approximately 1.8-3.4% of all PTLD cases, represents a minority of PTLD, mainly presenting as a late transplant complication. The main risk factors for the development of PTLD are Epstein-Barr virus (EBV) infection and intensive immunosuppression. However, other risk factors like hepatitis C virus may, together with EBV infection, contribute to the development of PTLD. Here we present a case of late-onset EBV-positive cHL that occurred 10 years after an unrelated donor liver transplantation. To our knowledge, this is the first report of cHL occurring with such a long interval after liver transplantation. Given the low incidence of cHL PTLD, there is little information regarding pathology, clinical characteristics, and management of this disease. The development of individual, risk-adapted treatments may improve the long-term outcome of cHL PTLD. PMID- 29279694 TI - A Case of Thyroid Papillary Carcinoma: Remarkable Decrease in Multiple Lung Metastases within 40 Years after a Single Administration of Radioiodine without Thyroidectomy and with Later Anaplastic Transformation. AB - Differentiated thyroid carcinoma is an uncommon malignancy of childhood and adolescence that is unique because it has an overall favorable prognosis despite its relatively high rate of nodal and distant metastases. Total thyroidectomy and positive 131I therapy are recommended for cases with pulmonary metastases. In contrast, anaplastic thyroid cancer is one of the most aggressive malignancies that have an unfavorable and miserable prognosis. We report a case with an impressively long history. The patient had multiple pulmonary metastases that had been diagnosed by 131I administration when he was 14 years old, about 45 years before he underwent thyroidectomy. He had been kept unaware of his disease by his family and received no treatment for most of his life. Pulmonary nodules were noted at several medical checkups and showed a remarkable decrease in size during the untreated 44-year period after the 131I administration. At age 58, his thyroid cancer was first detected and total thyroidectomy was performed, with subsequent radioiodine therapy for pulmonary metastases. Unfortunately, anaplastic carcinoma developed and he died of disseminated tumors later. PMID- 29279695 TI - Undiagnosed Esophageal Adenocarcinoma Presenting as Multiple Brain Metastases. AB - Brain metastases from gastrointestinal malignancies are exceedingly rare occurrences that carry a very poor prognosis. This holds especially true in cases where brain metastases from esophageal primaries are the initial presentation of a previously unidentified gastrointestinal malignancy. Our patient, a 60-year-old male with a past history of a right temporal teratoma, family history of breast cancer, and no smoking history, presented with a chief complaint of recurrent headaches. His history of present illness and physical examination included a two month history of frontal headache, progressive fatigue, and unintentional weight loss. He underwent an extensive initial workup including CT-head, CT abdomen/pelvis, CT-chest, bone scan, tumor marker analysis, and MRI-brain. The initial head CT revealed multiple intracranial lesions suspicious for malignancy. A PET scan later revealed his primary to be a malignancy of the distal esophagus. His treatment course thus far has been aggressive, consisting of surgical resection, systemic chemotherapy with capcetibine-oxaliplatin as well as paclitaxel-carboplatin, and radiation therapy. He has had several recurrences since starting treatment, but has continued to maintain a good performance status with only minor symptoms. Currently, the patient has survived for 17 months after his diagnosis of stage IV (T3, N2, M1) moderately differentiated adenocarcinoma and is undergoing treatment with trastuzumab and stereotactic radiosurgery. This report demonstrates that although cases of esophageal adenocarcinoma that present as brain metastases typically carry a poor prognosis, with early and aggressive treatment patients can survive well past one year after diagnosis. PMID- 29279696 TI - Immune Thrombocytopenia as a Consequence of Rocky Mountain Spotted Fever. AB - Primary immune thrombocytopenia (ITP) - also called idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura - is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults. Rocky Mountain spotted fever (RMSF) is a potentially lethal, but curable, tick-borne disease. We present a case of ITP that was triggered by RMSF. PMID- 29279697 TI - Misdiagnosed Refractory Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type, Successfully Treated: A Case Report. AB - Extranodal natural killer/T-cell lymphoma (ENKL), nasal type, is a rare, aggressive non-Hodgkin lymphoma for which no clear standard of care has been established, particularly in the relapsed/refractory disease setting. Because of its rarity, randomized trials are not conducted specifically on ENKL, nasal type; however, case reports and small case series can provide important insights into potential new treatments. We present a case report of a patient with ENKL, nasal type (previously misdiagnosed as relapsing chronic sinusitis), whose disease progressed during multi-agent chemotherapy but responded to second-line treatment with single-agent pralatrexate. We discuss treatment options for relapsed/refractory ENKL, nasal type, and suggest that pralatrexate be further evaluated in this clinical setting. PMID- 29279698 TI - Pazopanib and Statin-Induced Rhabdomyolysis. AB - Background: The VEGF inhibitor pazopanib is a widely used first-line therapy for the treatment of advanced renal cell carcinoma. Potential drug-drug interactions and toxicities may be underrecognized. Case Presentation: A 73-year-old woman with metastatic renal cell carcinoma on treatment with pazopanib presented with progressive inability to ambulate. The initial concern was for metastasis to the spine. However, MRI of the spine revealed diffuse muscle edema with no metastatic deposits or lytic lesions. Upon further evaluation, creatine kinase was significantly elevated and the diagnosis of rhabdomyolysis was made. With aggressive hydration and discontinuation of both pazopanib and rosuvastatin, the patient made a full recovery. Conclusion: This case of drug-induced rhabdomyolysis demonstrates an unexpected toxicity resulting from concomitant pazopanib and rosuvastatin therapy. This combination is predicted to be safe due to different, nonoverlapping effects on the cytochrome p450 enzymes. Discontinuation of statin therapy in patients with metastatic cancer should be considered when the risk of cancer-related death exceeds the risk of cardiovascular-related death. PMID- 29279699 TI - Endocrine Health Problems Detected in 764 Patients Evaluated in a Late Effects Clinic. AB - Background: Many pediatric cancer survivors have endocrine conditions. After treatment with alkylating agents, steroids, methotrexate, and radiation, several endocrine dysfunctions may appear. Surveillance for late effects is recommended by guidelines worldwide. Objective: The objective of this study was to describe the endocrine outcomes of 764 patients followed during a 20 years' period in our out-patient clinic. Design: We retrospectively reviewed the medical records. Patients: The study included 764 patients whose oncological or hematological dangerous diseases appeared before they were 18 years old. Larger groups were constituted by leukemias, central nervous tumors, and lymphomas. Outcome Measures: The frequency and types of endocrine conditions were analyzed. Results: 1,091 endocrine conditions were observed in all groups. The most common types of endocrine conditions were problems with growth and the thyroid. We found puberty abnormalities and bone problems in third and fourth places of frequency. ACTH insufficiency was found in seventh place. Conclusion: Endocrine dysfunctions are very common in survivor populations. Endocrinologists should be aware of international guidelines and make an effort to optimize screening and treatment of endocrine effects of cancer therapy. The crucial period is the puberty with growth spurt failure and accelerated maturity both of which can bring future social and professional difficulties. PMID- 29279700 TI - Minimal Change Disease as Initial Presentation of ALK-Positive Anaplastic Large Cell Lymphoma in a Pediatric Patient. AB - The association between nephrotic syndrome (NS), hemophagocytic lymphohistiocytosis (HLH), and certain paraneoplastic syndromes has been documented in the literature. However, nephrotic changes as part of paraneoplastic syndromes are rare in lymphoid malignancies, particularly in non Hodgkin lymphoma. We report the sudden onset of acute renal failure and NS in a 14-year-old male who initially presented with HLH and was subsequently diagnosed with ALK-positive anaplastic large-cell lymphoma (ALCL). The treatment of ALCL reversed both the HLH and NS findings. This case demonstrates the importance of considering lymphoma in pediatric patients presenting with NS and HLH. PMID- 29279701 TI - A Rare Case of Docetaxel-Induced Hydrocephalus Presenting with Gait Disturbances Mimicking and Coexisting with Taxane-Associated Polyneuropathy: The Relevance of Differential Diagnosis, Clinical Assessment, and Response to Ventriculoperitoneal Shunt. AB - Docetaxel constitutes a widely used chemotherapeutic agent as a first-line treatment for several neoplastic diseases. One of the most common side effects induced by this drug is polyneuropathy, which among other symptoms can cause gait disbalance. However, in exceptional cases gait disturbances could be related to docetaxel-induced hydrocephalus, a rare event that up to the present has been overseen throughout the medical literature and should be meticulously differentiated from polyneuropathy, since its clinical features, treatment, and prognosis differ drastically. We present the case of a woman with a progressive gait disturbance that started immediately after having been treated with docetaxel for breast cancer resembling the same clinical characteristics as seen in patients affected by normal pressure hydrocephalus. The symptoms had been observed for about 2 years as having been caused only by polyneuropathy, given the high incidence of this side effect and the accompanying numbness of distal extremities. However, brain MRI evidenced a marked enlargement of the ventricular system. Brain metastases as well as carcinomatous meningitis were ruled out. After having placed a ventriculoperitoneal shunt, the patient showed a rapid, long-lasting and outstanding improvement of gait performance. We discuss the coexistence, in this case, of taxane-associated hydrocephalus and polyneuropathy and describe the clinical features, assessment and surgical outcome of docetaxel induced hydrocephalus, since its early recognition and differentiation from the highly frequent taxane-associated polyneuropathy has relevant consequences for the management and treatment of these patients. PMID- 29279702 TI - A Rare Differential Diagnosis of an Adrenal Mass: A Case Report. AB - Ten years after his last treatment for diffuse large B-cell lymphoma, a seemingly healthy, 64-year-old man presented for his lymphoma-related follow-up. Ultrasound revealed an impressive tumor in the right adrenal gland. Due to recurrent cancer therapies in the past, this seemed highly suspicious of a second malignancy, such as primary adrenal carcinoma. Surprisingly, histology disclosed a very different but rare cause for this pseudotumorous lesion. PMID- 29279703 TI - A 48-Year-Old Male with Cutaneous Metastases of NUT Midline Carcinoma Misdiagnosed as Herpes Zoster. AB - NUT (nuclear protein of the testis) midline carcinoma (NMC) is a rare, poorly differentiated neoplasm with dismal prognosis. Though NMC are often metastatic by the time of presentation, cutaneous metastases have not been well described in the literature. We report a case of NMC in a patient who presented with grouped well-demarcated tender non-ulcerated erythematous nodules on the right mid-back. The lesions were initially diagnosed and treated as herpes zoster. Following failure to improve with antiviral therapy, imaging and skin biopsy revealed that the lesions were in fact cutaneous NUT carcinoma. Although NMC is an uncommon diagnosis, clinicians should be aware that affected patients can develop skin involvement to avoid unnecessary and harmful treatments. PMID- 29279704 TI - Occult Breast Carcinoma Presenting as Scalp Metastasis. AB - Breast cancer is the most common tumor among women, and approximately 6% of the patients have de novo metastatic breast cancer. Occult breast cancer accounts for only 0.1-0.8% of the cases and most commonly presents with axillary lymphadenopathy. Scalp metastases are rare and have been described as a sign of progression or widespread metastatic disease. Here, we describe a rare case of de novo metastatic breast cancer to the scalp as the single site of spread and without an identifiable primary breast tumor. PMID- 29279705 TI - Durable Near-Complete Response to Anti-PD-1 Checkpoint Immunotherapy in a Refractory Malignant Solitary Fibrous Tumor of the Pleura. AB - Solitary fibrous tumor of the pleura is a rare and usually benign primary neoplasm arising from mesenchymal cells of the submesothelial tissue. We present here the case of a patient diagnosed with CD34-positive advanced malignant solitary fibrous tumor of the pleura whose disease failed to respond to combination cytotoxic chemotherapy agents, but demonstrated a prompt near complete response to checkpoint blockade treatment using the anti-programmed death (PD)-1 monoclonal antibody pembrolizumab, based on tumor molecular profiling revealing tumoral expression positivity for both programmed death ligand 1 (PD-L1) and PD-1. The patient experienced minimal adverse effects from the treatment with durable favorable response lasting up to cycle 26. PMID- 29279706 TI - Metachronous and Synchronous Occurrence of 5 Primary Malignancies in a Female Patient between 1997 and 2013: A Case Report with Germline and Somatic Genetic Analysis. AB - The number of patients with multiple primary malignancies has been increasing steadily in recent years. In the present study, we describe a unique case of an 81-year-old woman with 5 metachronous and synchronous primary malignant neoplasms. The patient was first diagnosed with an endometrium adenocarcinoma in 1997 and a colon adenocarcinoma in 2002. Eleven years after her colon surgery, in 2013, the patient presented with 3 other primary malignancies within a 4-month time span: an invasive malignant melanoma on the lower leg, an invasive mucinous breast carcinoma in the right breast, and a pleomorphic spindle cell sarcoma on the left upper arm. Subsequent routine medical checkups in 2013-2017 revealed no metastases of the primary malignancies. The patient mentioned a familial aggregation of malignant tumors, including 2 sisters with breast cancer and a brother with lung cancer. Interestingly, next-generation sequencing analysis of the patient's blood sample detected no mutations in the BRCA1, BRCA2, TP53, PTEN, CDH1, PALB2, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, STK11, BMPR1A, SMAD4, PTEN, POLE, POLD1, GREM1, and GALNT12 genes. Therefore, whole genome sequencing is warranted to identify cancer-related genetic alterations in this patient with quintuple primary malignancies. PMID- 29279707 TI - A Case of Diffuse Large B-Cell Lymphoma Mimicking Primary Effusion Lymphoma-Like Lymphoma. AB - A 93-year-old female was transferred to the emergency ward of our hospital due to disturbance of consciousness and hypotension. Computed tomography showed bilateral pleural and pericardial effusion without evidence of tumor masses or lymphadenopathy. Cytodiagnosis of pleural effusion revealed proliferation of atypical lymphoid-like cells with pan-B surface markers. We suspected primary effusion lymphoma-like lymphoma; however, the monoclonality of these cells was not confirmed. Cytodiagnosis of bone marrow revealed lymphoma cells with monoclonal B-cell markers. These findings prompted a diagnosis of diffuse large B cell lymphoma with bone marrow invasion. In the case of pericardial or pleural effusion, clinicians should consider carefully both hematological malignancy and its classification. PMID- 29279709 TI - Long-Term Survival with Regorafenib in KRAS-Mutated Metastatic Rectal Cancer. AB - Regorafenib, an oral multikinase inhibitor, was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer progressing on standard therapies. Here, we describe the clinical history of a 63-year-old male patient who was treated with regorafenib in the pivotal CORRECT trial. The patient was initially diagnosed in November 2008 with nonmetastatic KRAS-mutated (exon 2, codon 12) rectal cancer. He underwent successful surgery and was treated with 5 cycles of adjuvant chemotherapy. In 2010, lung metastases (KRAS-mutated) were detected and the patient received 6 cycles of FOLFIRI plus bevacizumab. By January 2011, the metastases had progressed. The patient, who was asymptomatic with an Eastern Cooperative Oncology Group performance status of 0, was enrolled onto the CORRECT trial and received best supportive care plus regorafenib (160 mg once daily for 3 weeks of a 4-week cycle) over a period of 2 years, during which time the disease remained stable and the patient remained asymptomatic. Grade 1 anemia and thrombocytopenia were the only treatment-emergent adverse events reported. After receiving 26 cycles of regorafenib, a majority of the lung lesions progressed, and third-line palliative 5-fluorouracil, leucovorin, and oxaliplatin chemotherapy was administered. The patient died in May 2016. PMID- 29279708 TI - Metachronous Development of Meningothelial Meningioma, Basal Cell Carcinoma, and Glioblastoma Multiforme in a Patient with Pancreatic Incidentaloma. AB - We report the unique case of a 61-year-old male patient with known pancreatic incidentaloma who additionally developed 3 other histologically different tumors: left sphenoid wing meningothelial meningioma, basal cell carcinoma of the occiput, and right occipital lobe glioblastoma multiforme. The latter were totally removed with a favorable clinical outcome. The patient's family history was unremarkable, and no data on any previous head and neck irradiation were found. PMID- 29279710 TI - Stroke in a Young Man Secondary to Paroxysmal Atrial Fibrillation and Thyrotoxicosis: A Case Report. AB - We report a case of a male patient with stroke caused by atrial fibrillation (AF) due to thyrotoxicosis. At hospital admission, he presented hypertension and AF. Magnetic resonance imaging confirmed a right-side ischemic area. The thyrotoxicosis was confirmed by thyroid function and thyroid scintigraphy that showed goiter with diffuse hypercaptation. The patient was treated with tapazole and total thyroidectomy, and pathological findings suggested Graves' disease. Hyperthyroidism is associated with increased supraventricular ectopic activity in patients with a normal heart, and may be an important causal link between hyperthyroidism and AF. The patient experienced significant clinical improvement, but presented long-term neuropsychiatric disorders. PMID- 29279711 TI - A Case of Recurrent Ischemic Stroke due to Intravascular Lymphomatosis, Undiagnosed by Random Skin Biopsy and Brain Imaging. AB - Intravascular lymphoma (IVL) is a rare disease characterized by the proliferation of lymphoma cells in the lumen of the small blood vessels. Although early diagnosis of IVL is important to prolong survival of the patients, its atypical symptoms and clinical course often delay its diagnosis. More than half of the patients are diagnosed at autopsy. We report a 68-year-old man who presented with transient ideomotor apraxia and mildly elevated soluble interleukin-2 receptor levels. He was initially diagnosed with aortogenic embolic stroke. He developed rapidly progressive neurological manifestations with enlargement of brain lesions on brain computed tomography and magnetic resonance imaging and died 3 months after symptom onset. The diagnosis of IVL could not be made by random skin biopsy, but was finally made at autopsy. For the early diagnosis, sufficient random skin biopsy or brain biopsy should be planned when suspected. PMID- 29279712 TI - Case Report: Migrainous Infarct without Aura. AB - Background: Stroke in a migraine with aura has been documented in several cases, even deserving the merit of a classification as complicated migraine. Herein, we present a rare case of migrainous infarct without aura. The diagnosis was challenging due to lack of risk factors. The patient was unique in not having any other comorbidities. Case Presentation: The case is of a 21-year-old female presenting with right-sided hemiplegia and facial drooping. She had had an index presentation of throbbing headaches for the past 2 years, typical of a migraine but not preceded by any aura symptoms. However, in the current episode, the pain became excessively severe and accompanied by right-sided hemiplegia and facial drooping. A full investigation workup using MRI revealed evidence of infarct in the left temporoparietal and basal ganglion region. Conclusion: Our case highlights the need to evaluate silent ischemic stroke in case of prolonged headache with a history of migraine as well as the need for precaution to avoid the use of triptans or opioids in such a case. It also highlights the conditions that need to be excluded before labeling it as a migrainous infarct. PMID- 29279713 TI - Tramadol Induced Adrenal Insufficiency: Histological, Immunohistochemical, Ultrastructural, and Biochemical Genetic Experimental Study. AB - Tramadol is a synthetic, centrally acting analgesic. It is the most consumed narcotic drug that is prescribed in the world. Tramadol abuse has dramatically increased in Egypt. Long term use of tramadol can induce endocrinopathy. So, the aim of this study was to analyze the adrenal insufficiency induced by long term use of tramadol in experimental animals and also to assess its withdrawal effects through histopathological and biochemical genetic study. Forty male albino rats were used in this study. The rats were divided into 4 groups (control group, tramadol-treated group, and withdrawal groups). Tramadol was given to albino rats at a dose of 80 mg/kg body weight for 3 months and after withdrawal periods (7-15 days) rats were sacrificed. Long term use of tramadol induced severe histopathological changes in adrenal glands. Tramadol decreased the levels of serum cortisol and DHEAS hormones. In addition, it increased the level of adrenal MDA and decreased the genetic expression of glutathione peroxidase and thioredoxin reductase in adrenal gland tissues. All these changes started to return to normal after withdrawal of tramadol. Thus, it was confirmed that long term use of tramadol can induce severe adrenal insufficiency. PMID- 29279714 TI - Metastatic Basal Cell Carcinoma: A Rare Manifestation of a Common Disease. AB - Introduction: Basal cell carcinoma (BCC) is considered the most common malignancy in Caucasians. It constituted about 80% of all nonmelanoma skin tumors and, despite its high prevalence, is an extremely rare occurrence of metastases, with incidence rates varying from 0.0028% to 0.55%. Case Report: A 58-year-old male patient with BCC on the left nasolabial sulcus for 17 years, reporting 3 previous excisions, evolved with local recurrence. A new procedure was performed, and anatomopathological study confirmed sclerosing BCC. Seven months later, he presented with a mass in the left submandibular region. Combined positron emission tomography and computed tomography (PET-CT) showed cervical hypercaptation in the left cervical level I and vertebral body of L5. Excision of the cervical lesion was performed with diagnosis of sclerosing BCC compromising the submandibular gland. Biopsy of the lumbar lesion was found to be compatible with bone metastasis. Conclusion: BCC represents a very common entity, and the presence of metastasis, although infrequent, must be proposed because of the greater morbidity and mortality of this complication. This case shows the importance of early diagnosis and intervention in BCC as a way to avoid unfavorable outcomes. PMID- 29279715 TI - Racial/Ethnic Differences in the Modifying Effect of Community Violence on the Association between Paternity Status and Preterm Birth. AB - Preterm birth (PTB) is a major public health concern in the US. Lack of established paternity has been linked with increased risk of PTB. Community violence (CV) may modify the association, and racial/ethnic differences may exist. Using a geographically defined cohort of women in Richmond, Virginia (N = 27,518), we examined racial/ethnic differences in the modifying effect of CV on the association between paternity status and PTB. Results showed that lack of established paternity was associated with incremental greater odds of PTB across CV quartiles in NH-Whites (quartile-1: AOR = 1.42, 95% CI = 0.95-2.12; quartile 2: AOR = 1.45, 95% CI = 0.57-3.71; quartile-3: AOR = 3.12, 95% CI = 2.67-6.32), NH-Blacks (quartile-1: AOR = 1.16, 95% CI = 0.85-1.58; quartile-2: AOR = 1.32, 95% CI = 0.82-2.12; quartile-3: AOR = 1.64, 95% CI = 1.24-2.16), and Hispanics (quartile-1: AOR = 1.29, 95% CI = 0.65-2.55; quartile-2: AOR = 1.34, 95% CI = 0.67-2.69). Odds of PTB were highest among NH-White women. Public health practitioners should be aware of the negative effect of lack of paternal presence on PTB in women resident in high violence rate communities and racial/ethnic differences that exist. PMID- 29279717 TI - The Evaluation of Toxicity Induced by Psoraleae Fructus in Rats Using Untargeted Metabonomic Method Based on UPLC-Q-TOF/MS. AB - Psoraleae Fructus is the dry and mature fruit of leguminous plant Psoralea corylifolia L., with the activity of warming kidney and enhancing yang, warming spleen, and other effects. However, large doses can cause liver and kidney toxicity. Therefore, it is necessary to evaluate the toxicity of Psoraleae Fructus systematically. Although traditional biochemical indicators and pathological tests have been used to evaluate the safety of drug, these methods lack sensitivity and specificity, so a fast and sensitive analytical method is urgently needed. In this study, an ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method was used to analyze the metabolic profiles of rat plasma. The changes of metabolites in plasma samples were detected by partial least squares-discriminant analysis (PLS DA). Compared with the control group, after 7 days of administration, the pathological sections showed liver and kidney toxicity, and the metabolic trend was changed. Finally, 13 potential biomarkers related to the toxicity of Psoraleae Fructus were screened. The metabolic pathways involved were glycerol phospholipids metabolism, amino acid metabolism, energy metabolism, and so forth. The discovery of these biomarkers laid a foundation for better explaining the hepatotoxicity and nephrotoxicity of Psoraleae Fructus and provided a guarantee for its safety evaluation. PMID- 29279718 TI - Lannea acida A. Rich. (Anacardiaceae) Ethanol Extract Exhibits Estrogenic Effects and Prevents Bone Loss in an Ovariectomized Rat Model of Osteoporosis. AB - Phytoestrogens have been shown to prevent postmenopausal osteoporosis. Lannea acida is a medicinal plant traditionally used in Cameroon to treat infertility, gynaecological complaints, and rheumatism. These uses prompted us to evaluate estrogenic activity of Lannea acida bark ethanolic extract and its antiosteoporotic potential in ovariectomized Wistar rats. In vitro, the E-screen assay was used to assess the ability of L. acida extract to induce MCF-7 cells proliferation. In vivo, a 3-day uterotrophic assay and a 12-week oral treatment in ovariectomized adult rats were carried out to evaluate the ability of L. acida extract to prevent bone mass loss. L. acida extract induced MCF-7 cell proliferation. In vivo, it significantly increased the uterine wet weight, uterine and vaginal epithelial heights, and mammary glands differentiation. At 200 mg/kg, a long-term treatment with the extract prevented body weight gain (p < 0.05) and loss of bone mass and/or density (p < 0.05) induced by ovariectomy. Also, a significant (p < 0.001) decrease of alkaline phosphatase activity was observed with 50 mg/kg. L. acida extract improved bone microarchitecture and could restore normal bone mineralization by increasing the inorganic phosphorus and calcium level in bone. These findings provide evidence that Lannea acida is a potential alternative for the prevention of postmenopausal osteoporosis. PMID- 29279716 TI - Fraxinus: A Plant with Versatile Pharmacological and Biological Activities. AB - Fraxinus, a member of the Oleaceae family, commonly known as ash tree is found in northeast Asia, north America, east and western France, China, northern areas of Pakistan, India, and Afghanistan. Chemical constituents of Fraxinus plant include various secoiridoids, phenylethanoids, flavonoids, coumarins, and lignans; therefore, it is considered as a plant with versatile biological and pharmacological activities. Its tremendous range of pharmacotherapeutic properties has been well documented including anticancer, anti-inflammatory, antioxidant, antimicrobial, and neuroprotective. In addition, its bioactive phytochemicals and secondary metabolites can be effectively used in cosmetic industry and as a competent antiaging agent. Fraxinus presents pharmacological effectiveness by targeting the novel targets in several pathological conditions, which provide a spacious therapeutic time window. Our aim is to update the scientific research community with recent endeavors with specifically highlighting the mechanism of action in different diseases. This potentially efficacious pharmacological drug candidate should be used for new drug discovery in future. This review suggests that this plant has extremely important medicinal utilization but further supporting studies and scientific experimentations are mandatory to determine its specific intracellular targets and site of action to completely figure out its pharmacological applications. PMID- 29279719 TI - Modulation of Acupuncture on Cell Apoptosis and Autophagy. AB - Acupuncture has been historically practiced to treat medical disorders by mechanically stimulating specific acupoints. Despite its well-documented efficacy, its biological basis largely remains elusive. Recent studies suggested that cell apoptosis and autophagy might play key roles in acupuncture therapy. Therefore, we searched PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI), aiming to find the potential relationship between acupuncture and cell apoptosis and autophagy. To provide readers with objective evidence, some problems regarding the design method, acupoints selection, acupuncture intervention measure, and related diseases existing in 40 related researches were shown in this review. These findings demonstrated that acupuncture has a potential role in modulating cell apoptosis and autophagy in animal models, suggesting it as a candidate mechanism in acupuncture therapy to maintain physiologic homeostasis. PMID- 29279720 TI - A Variational Level Set Approach Based on Local Entropy for Image Segmentation and Bias Field Correction. AB - Image segmentation has always been a considerable challenge in image analysis and understanding due to the intensity inhomogeneity, which is also commonly known as bias field. In this paper, we present a novel region-based approach based on local entropy for segmenting images and estimating the bias field simultaneously. Firstly, a local Gaussian distribution fitting (LGDF) energy function is defined as a weighted energy integral, where the weight is local entropy derived from a grey level distribution of local image. The means of this objective function have a multiplicative factor that estimates the bias field in the transformed domain. Then, the bias field prior is fully used. Therefore, our model can estimate the bias field more accurately. Finally, minimization of this energy function with a level set regularization term, image segmentation, and bias field estimation can be achieved. Experiments on images of various modalities demonstrated the superior performance of the proposed method when compared with other state-of-the art approaches. PMID- 29279722 TI - Current diagnostic procedures for diagnosing vertigo and dizziness. AB - Vertigo is a multisensory syndrome that otolaryngologists are confronted with every day. With regard to the complex functions of the sense of orientation, vertigo is considered today as a disorder of the sense of direction, a disturbed spatial perception of the body. Beside the frequent classical syndromes for which vertigo is the leading symptom (e.g. positional vertigo, vestibular neuritis, Meniere's disease), vertigo may occur as main or accompanying symptom of a multitude of ENT-related diseases involving the inner ear. It also concerns for example acute and chronic viral or bacterial infections of the ear with serous or bacterial labyrinthitis, disorders due to injury (e.g. barotrauma, fracture of the oto-base, contusion of the labyrinth), chronic-inflammatory bone processes as well as inner ear affections in the perioperative course. In the last years, diagnostics of vertigo have experienced a paradigm shift due to new diagnostic possibilities. In the diagnostics of emergency cases, peripheral and central disorders of vertigo (acute vestibular syndrome) may be differentiated with simple algorithms. The introduction of modern vestibular test procedures (video head impulse test, vestibular evoked myogenic potentials) in the clinical practice led to new diagnostic options that for the first time allow a complex objective assessment of all components of the vestibular organ with relatively low effort. Combined with established methods, a frequency-specific assessment of the function of vestibular reflexes is possible. New classifications allow a clinically better differentiation of vertigo syndromes. Modern radiological procedures such as for example intratympanic gadolinium application for Meniere's disease with visualization of an endolymphatic hydrops also influence current medical standards. Recent methodical developments significantly contributed to the possibilities that nowadays vertigo can be better and more quickly clarified in particular in otolaryngology. PMID- 29279723 TI - Diagnostics and therapy of vestibular schwannomas - an interdisciplinary challenge. AB - Vestibular schwannomas (VS) expand slowly in the internal auditory canal, in the cerebellopontine angle, inside the cochlear and the labyrinth. Larger tumors can displace and compress the brainstem. With an annual incidence of 1:100,000 vestibular schwannoma represent 6-7% of all intracranial tumors. In the cerebellopontine angle they are by far the most neoplasm with 90% of all lesions located in this region. Magnetic resonance imaging (MRI), audiometry, and vestibular diagnostics are the mainstays of the clinical workup for patients harboring tumors. The first part of this paper delivers an overview of tumor stages, the most common grading scales for facial nerve function and hearing as well as a short introduction to the examination of vestibular function. Upholding or improving quality of life is the central concern in counseling and treating a patient with vestibular schwannoma. Preservation of neuronal function is essential and the management options - watchful waiting, microsurgery and stereotactic radiation - should be custom-tailored to the individual situation of the patient. Continuing interdisciplinary exchange is important to monitor treatment quality and to improve treatment results. Recently, several articles and reviews have been published on the topic of vestibular schwannoma. On the occasion of the 88th annual meeting of the German Society of Oto-Rhino Laryngology, Head and Neck surgery a special volume of the journal "HNO" will be printed. Hence this presentation has been designed to deviate from the traditional standard which commonly consists of a pure literature review. The current paper was conceptually woven around a series of interdisciplinary cases that outline examples for every stage of the disease that show characteristic results for management options to date. Systematic clinical decision pathways have been deduced from our experience and from results reported in the literature. These pathways are graphically outlined after the case presentations. Important criteria for decision making are size and growth rate of the tumor, hearing of the patient and the probability of total tumor resection with preservation of hearing and facial nerve function, age and comorbidity of the patient, best possible control of vertigo and tinnitus and last but not least the patient's preference and choice. In addition to this, the experience and the results of a given center with each treatment modality will figure in the decision making process. We will discuss findings that are reported in the literature regarding facial nerve function, hearing, vertigo, tinnitus, and headache and reflect on recent studies on their influence on the patient's quality of life. Vertigo plays an essential role in this framework since it is an independent predictor of quality of life and a patient's dependence on social welfare. Pathognomonic bilateral vestibular schwannomas that occur in patients suffering from neurofibromatosis typ-2 (NF2) differ from spontaneous unilateral tumors in their biologic behavior. Treatment of neurofibromatosis type-2 patients requires a multidisciplinary team, especially because of the multitude of separate intracranial and spinal lesions. Off-label chemotherapy with Bevacizumab can stabilize tumor size of vestibular schwannomas and even improve hearing over longer periods of time. Hearing rehabilitation in NF2 patients can be achieved with cochlear and auditory brainstem implants. PMID- 29279721 TI - Recent surgical options for vestibular vertigo. AB - Vertigo is not a well-defined disease but a symptom that can occur in heterogeneous entities diagnosed and treated mainly by otolaryngologists, neurologists, internal medicine, and primary care physicians. Most vertigo syndromes have a good prognosis and management is predominantly conservative, whereas the need for surgical therapy is rare, but for a subset of patients often the only remaining option. In this paper, we describe and discuss different surgical therapy options for hydropic inner ear diseases, Meniere's disease, dehiscence syndromes, perilymph fistulas, and benign paroxysmal positional vertigo. At the end, we shortly introduce the most recent developments in regard to vestibular implants. Surgical therapy is still indicated for vestibular disease in selected patients nowadays when conservative options did not reduce symptoms and patients are still suffering. Success depends on the correct diagnosis and choosing among different procedures the ones going along with an adequate patient selection. With regard to the invasiveness and the possible risks due to surgery, in depth individual counseling is absolutely necessary. Ablative and destructive surgical procedures usually achieve a successful vertigo control, but are associated with a high risk for hearing loss. Therefore, residual hearing has to be included in the decision making process for surgical therapy. PMID- 29279724 TI - Implantable hearing devices. AB - Combined hearing loss is an essential indication for implantable hearing systems. Depending on the bone conduction threshold, various options are available. Patients with mild sensorineural deafness usually benefit from transcutaneous bone conduction implants (BCI), while percutaneous BCI systems are recommended also for moderate hearing loss. For combined hearing losses with moderate and high-grade cochlear hearing loss, active middle ear implants are recommended. For patients with incompatibilities or middle ear surgery, implants are a valuable and proven addition to the therapeutic options. PMID- 29279725 TI - Tympanoplasty - news and new perspectives. AB - Techniques and biomaterials for reconstructive middle ear surgery are continuously and steadily developing. At the same time, clinical post-surgery results are evaluated to determine success or failure of the therapy. Routine quality assessment and assurance is of growing importance in the medical field, and therefore also in middle ear surgery. The exact definition and acquisition of outcome parameters is essential for both a comprehensive and detailed quality assurance. These parameters are not the audiological results alone, but also additional individual parameters, which influence the postoperative outcome after tympanoplasty. Selection of patients and the preoperative clinical situation, the extent of the ossicular chain destruction, the chosen reconstruction technique and material, the audiometric frequency selection and the observational interval are only some of them. If these parameters are not well documented, the value of comparative analyses between different studies is very limited. The present overview aims at describing, comparing, and evaluating some of the existing assessment and scoring systems for middle ear surgery. Additionally, new methods for an intraoperative quality assessment in ossiculoplasty and the postoperative evaluation of suboptimal hearing results with imaging techniques are available. In the area of implant development, functional elements were integrated in prostheses to enable not only good sound transmission but also compensation of occurring atmospheric pressure changes. In combination with other components for ossicular repair, they can be used in a modular manner, which so far show experimentally and clinically promising results. PMID- 29279726 TI - Hearing aids: indications, technology, adaptation, and quality control. AB - Hearing loss can be caused by a number of different pathological conditions. Some of them can be successfully treated, mainly by surgery, depending on the individual's disease process. However, the treatment of chronic sensorineural hearing loss with damaged cochlear structures usually needs hearing rehabilitation by means of technical amplification. During the last two decades tremendous improvements in hearing aid technology led to a higher quality of the hearing rehabilitation process. For example, due to sophisticated signal processing acoustic feedback could be reduced and hence open fitting options are available even for more subjects with higher degrees of hearing loss. In particular for high-frequency hearing loss, the use of open fitting is an option. Both the users' acceptance and the perceived sound quality were significantly increased by open fittings. However, we are still faced with a low level of readiness in many hearing impaired subjects to accept acoustic amplification. Since ENT specialists play a key-role in hearing aid provision, they should promote early hearing aid rehabilitation and include this in the counselling even in subjects with mild and moderate hearing loss. Recent investigations demonstrated the benefit of early hearing aid use in this group of patients since this may help to reduce subsequent damages as auditory deprivation, social isolation, development of dementia, and cognitive decline. For subjects with tinnitus, hearing aids may also support masking by environmental sounds and enhance cortical inhibition. The present paper describes the latest developments of hearing aid technology and the current state of the art for amplification modalities. Implications for both hearing aid indication and provision are discussed. PMID- 29279729 TI - Developments of Nonacupoint Needling in Japan. PMID- 29279728 TI - A Comparison of Er:YAG Laser with Photon-Initiated Photoacoustic Streaming, Nd:YAG Laser, and Conventional Irrigation on the Eradication of Root Dentinal Tubule Infection by Enterococcus faecalis Biofilms: A Scanning Electron Microscopy Study. AB - This study evaluated the antimicrobial efficacy of Er:YAG laser activation with photon-initiated photoacoustic streaming (PIPS), Nd:YAG laser disinfection, and conventional irrigation on Enterococcus faecalis biofilms using scanning electron microscopy (SEM). Biofilms were grown on 110 root halves and divided into the following: Groups 1 and 2 (saline and 1% NaOCl with apical position of PIPS, resp.), Groups 3 and 4 (saline and 1% NaOCl with coronal position of PIPS, resp.), Groups 5 and 6 (Nd:YAG laser after saline and 1% NaOCl irrigation, resp.) and Groups 7, 8, and 9 (conventional irrigation with 1% NaOCl, 6% NaOCl, and saline, resp.). SEM images of the apical, middle, and coronal levels were examined using a scoring system. Score differences between Groups 1 and 2 were insignificant at all levels in the remaining biofilm. Group 4 had significantly greater bacterial elimination than Group 3 at all levels. Differences in Nd:YAG laser irradiation between Groups 5 and 6 were insignificant. Groups 7 and 8 were insignificantly different, except at the middle level. Saline group had a higher percentage of biofilms than the others. In this study, PIPS activation with NaOCl eliminates more E. faecalis biofilms in all root canals regardless of the position of the fiber tip. PMID- 29279730 TI - Introducing a Standardized Acupuncture Protocol for Peripheral Neuropathy: A Case Series. AB - Background: Peripheral neuropathy (PN) is defined as damage to the peripheral nervous system caused by a primary lesion or dysfunction. Multiple recent trials have suggested that acupuncture is beneficial for treating neuropathic pain. One challenge in acupuncture research is the lack of standardization of point selection, number of needles used, needle-retention time, needling depth, amount of needle manipulation, and use of moxibustion and electroacupuncture (EA). Objectives: This article presents a standardized acupuncture protocol for the treatment of PN that incorporates structural acupuncture principles based on proximity to peripheral nerves and on traditional approaches to the treatment of neuropathic pain. Materials and Methods: Ten consecutive patients diagnosed with large- or small-fiber neuropathy of various etiologies were treated with a standardized protocol, based on anatomical correlations of peripheral nerves and acupuncture points. Manual acupuncture was applied to left LR 4, LU 5; bilateral LI 11, KI 27, ST 36, GB 34, SP 6, SP 9, LI 4, TE 5, and BaFeng (except for the space between the first and second digits of the toes; LR 3 was used for that space). EA was applied to bilateral KI 3-1 and bilateral ST 41-LR 3. Patients underwent at least six acupuncture sessions, although the total number of sessions varied. Outcomes were measured using a visual analogue scale (VAS) and clinical signs and symptoms. Results: All 10 patients indicated improvement on the VAS and in clinical presentation. Conclusions: This standardized protocol appears to be effective for the treatment of neuropathy of various causes, including large- and small-fiber involvement. Further studies with larger sample sizes and randomized comparisons against sham acupuncture and other acupuncture regimens will be helpful to determine if this protocol could be established as a guideline for approaching peripheral neuropathy. PMID- 29279731 TI - Acupuncture-Associated Vasovagal Response: Revised Terminology and Hospital Experience. AB - Background: Vasovagal responses associated with acupuncture therapy are relatively uncommon adverse events, occurring in ~0.02%-7% of treatments. The complex neurocardiovascular reflexes involved in vasovagal responses can induce a range of symptoms such as dizziness, nausea, sweating, bradycardia, hypotension, and, in some cases, syncope or convulsions. Although patients typically recover quickly with proper support, these events may be of concern and anxiety-producing for both patient and provider. Providers need to be well-versed in methods for prevention and treatment of acupuncture-associated vasovagal responses to promote safe practice environments, patient satisfaction and comfort, and cost effectiveness. Objectives: To examine the biomedical and Traditional Chinese Medicine mechanisms of vasovagal responses, propose updated terminology, and outline steps for prevention and treatment. Methods: During an 18-month period, 281 community-style acupuncture treatments were performed on family members of admitted patients and hospital staff members at the University of Minnesota Masonic Children's Hospital. Five (1.8%) treatments resulted in documented acupuncture-associated vasovagal response (AAVR) symptoms. Results: All 5 patients recovered from their AAVR symptoms after treatment interventions. After recovery, 3 patients reported reductions in their main complaint symptoms; main complaint symptom outcomes were not recorded for the other 2 patients. Conclusions: As integrative practices become more prevalent in academic institutions and primary care environments, clear communication about, as well as prevention treatment, documentation and reporting of acupuncture-associated adverse events will become increasingly valuable. The authors recommend that clinicians in integrative practice clinical environments consider developing formal AAVR response plans as well as training students, supervising and attending providers, and ancillary staff members to ensure rapid, prepared handling and documentation of AAVR incidents. PMID- 29279732 TI - Electroacupuncture Could Reduce Motion Sickness Susceptibility in Healthy Male Adults: A Double-Blinded Study. AB - Objective: Motion sickness is the main cause of nausea-related symptoms during passive motion in transportation. The aim of this study was to evaluate the effects of electroacupuncture (EA) for the reduction of motion sickness symptoms. Materials and Methods: Study participants were randomly assigned into three groups: Group A, therapeutic EA; Group B, sham EA; and group C, a control group. After an EA session, participants were exposed to a motion stimulus, using a rotating chair. Their symptoms were measured using the Greek version of the Gianaros Motion Sickness Assessment Questionnaire (MSAQ). Results: In this study 20 volunteers participated. All 3 groups of subjects showed increases in their motion sickness symptoms after exposure to the motion stimulus. The mean total symptom score for Group A was 59,375, for Group B it was 74,333, and in Group C was it 93,166. This difference is partially statistically significant when comparing Group A with Group C, especially in a peripheral group of symptoms, as measured by the Gianaros MSAQ. Conclusions: The results of the present study suggest that participants who received therapeutic EA prior to motion stimulation tended to have fewer motion sickness symptoms in comparison with their counterparts, who were not given any therapy. PMID- 29279727 TI - Current audiological diagnostics. AB - Today's audiological functional diagnostics is based on a variety of hearing tests, whose large number takes account of the variety of malfunctions of a complex sensory organ system and the necessity to examine it in a differentiated manner and at any age of life. The objective is to identify nature and origin of the hearing loss and to quantify its extent as far as necessary to dispose of the information needed to initiate the adequate medical (conservative or operational) treatment or the provision with technical hearing aids or prostheses. Moreover, audiometry provides the basis for the assessment of impairment and handicap as well as for the calculation of the degree of disability. In the present overview, the current state of the method inventory available for practical use is described, starting from basic diagnostics over to complex special techniques. The presentation is systematically grouped in subjective procedures, based on psychoacoustic exploration, and objective methods, based on physical measurements: preliminary hearing tests, pure tone threshold, suprathreshold processing of sound intensity, directional hearing, speech understanding in quiet and in noise, dichotic hearing, tympanogram, acoustic reflex, otoacoustic emissions and auditory evoked potentials. Apart from a few still existing gaps, this method inventory covers the whole spectrum of all clinically relevant functional deficits of the auditory system. PMID- 29279734 TI - Usefulness of Organ Electrodermal Diagnostics in Detection of Breast Pathology: A Multicenter, Randomized, Double-Blinded Clinical Study. AB - Objective: Pathology of an internal organ/body part causes corresponding skin areas-organ projection areas/acupuncture points-to rectify applied electrical currents (a diode phenomenon) once the resistance "breakthrough effect" has been induced in these specific, and sometimes remote, skin zones. The aim of this study was to estimate the diagnostic accuracy-as well as the scope of utilization for detection of breast pathology of organ electrodermal diagnostics (OED), which utilizes this electrophysiologic phenomenon. Materials and Methods: A multicenter randomized, double-blinded comparative study of OED results and clinical diagnoses, as the criteria standards, was done on 400 female volunteers, with a mean age of 39 (standard deviation: 9 years), at three academic breast clinics. Participants were divided into 7 groups: (1) a control group; (2) a cancer survivor group; (3) a breast-fibroadenoma group; (4) a mastitis group; (5) a breast-abscess group; (6) a preinvasive breast-cancer group; and (7) an invasive breast-cancer group. Results: The OED overall detection rate was 88.8%, the sensitivity rate was 92.7%, and the specificity rate was 76.5%. The predictive value for positive OED results equaled 92.4% and, for negative OED results, equaled 77.3%. However, both sensitivity and specificity rates varied among specific groups. The highest sensitivity rates were shown by OED in groups with serious pathologies, such as invasive cancer (94.2%), preinvasive cancer (90.0%), breast abscess (94.4%), and mastitis (95.9%). The OED results correlated with the intensity of the pathologic process within breasts but were not affected by either the type or the etiology of the disease. Conclusions: OED appears to be a reliable method for detecting breast pathology; this method might also estimate the intensity of a breast pathologic process but cannot explain the cause of the disease directly. PMID- 29279733 TI - Efficacy of Parietal Acupoint Therapy: Scalp Acupuncture for Neck/Shoulder Stiffness with Related Mood Disturbance. AB - Objectives: Yamamoto New Scalp Acupuncture is a quick and effective microsystem of acupuncture used for treating various symptoms for which the somatotopic area is the scalp. This article describes Parietal Acupoint Therapy (PAPT), which is another approach, using a different scalp somatotopy, and to evaluate PAPT's effect on neck/shoulder stiffness and related mood disturbances. Materials and Methods:Subjects: Forty-six volunteers suffering from chronic neck/shoulder stiffness with various symptoms (headache, dizziness, and related mood disturbance) participated in this study and were randomly divided into 2 groups: treatment (26 subjects) and control (20 subjects). Interventions: PAPT, PC points, and PL points were used. Outcome Measures: Immediately before and after treatment, to evaluate the patients' psychobiologic and mood states, salivary alpha amylase (sAA) levels were determined and the Profile of Mood States Second Edition (POMS 2)-Short Form scale was administered. Neck/shoulder stiffness was evaluated using a visual analogue scale (VAS) score immediately before and after, and at 3 and 7 days post-therapy. Results: sAA levels were not significantly different in either group after versus before the intervention. There were significant decreases in mean scores in the POMS 2 subscales Anger/Hostility (P < 0.001), Confusion/Bewilderment (P < 0.001), Depression/Dejection (P < 0.01), Fatigue/Inertia (P < 0.001), Tension/Anxiety (P < 0.001), and Total Mood Disturbance (P < 0.001) post-therapy in the treatment group, but not in the control group. The mean VAS score significantly improved in the treatment group post-therapy, which persisted during the observation period. Conclusions: PAPT treatment on PC points ameliorated neck/shoulder stiffness and related mood disturbance. PAPT has the potential to be as effective as other scalp acupuncture types. PMID- 29279736 TI - Treatment of Facial Pain with I Ching Balance Acupuncture. AB - Background: Trigeminal neuralgia (TN) is the most common cranial neuralgia in adults, with a slightly higher incidence in women than in men. This chronic pain condition affects the trigeminal nerve, also known as the 5th cranial nerve. It is one of the most deeply distributed nerves in the head. Antiseizure drugs are the main biomedical treatment of TN. However, TN is not the only source of facial pain. Background persistent idiopathic facial pain (PIFP) is also a chronic disorder, recurring daily for more than 2 hours per day over more than 3 months. PIFP occurs in the absence of a neurologic deficit. The underlying pathophysiologies of TN and PIFP are still unknown, and treatment options have not been sufficiently evaluated. Nevertheless, neuropathic mechanisms could be relevant in both TN and PIFP. Cases: A 65-year-old Caucasian female with left facial pain was diagnosed by a neurologist with TN ~2.5 years prior to seeking acupuncture treatment. A 42-year-old Caucasian female with left and right facial pain was diagnosed by a neurologist with PIFP ~3 years prior to commencing acupuncture treatment. The cause of facial pain was treated with 60-minute sessions of I Ching Balance Acupuncture (ICBA) twice per week. Prior to each session, the effect of the previous session was recorded carefully in the patients' files. Results: A complete dissipation of pain was achieved after 29 and 60 ICBA sessions in the TN and the PIFP patient, respectively. Conclusions: The present article is the one of the first to demonstrate the efficacy of ICBA treatment for refractory facial pain. As the present article shows, ICBA treatment affects facial pain of different types successfully. However, additional larger-scale studies are necessary to validate the efficacy of ICBA in TN and PIFP treatment. PMID- 29279735 TI - Effect of Acupuncture on Chronic Pelvic Pain Secondary to Abdominal Myofascial Syndrome Not Responsive to Local Anesthetic Block: A Pilot Study. AB - Objective: Strong evidence shows that 85% of women with chronic pelvic pain (CPP) have musculoskeletal disorders, such as abdominal myofascial pain syndrome (AMPS). The aim of this research was to assess the efficacy of local acupuncture treatment for women with CPP secondary to AMPS unresponsive to treatment with trigger-point injection. Materials and Methods: This pilot study involved 17 women with moderate-to-severe AMPS-related CPP. Acupuncture treatments were given at abdominal-wall trigger points once per week for 10 consecutive weeks. Pain relief was assessed with a visual analogue scale (VAS), the McGill questionnaire, and pressure dynamometer. Quality of life and psychosocial function (risk for anxiety and depression) were evaluated using the Short-Form-36 questionnaire and the Hospital Anxiety and Depression scale. Assessments were performed at baseline and after 1, 3, and 6 months of treatment. Results: Both the VAS and McGill pain questionnaire showed significantly decreased pain intensity (VAS, P < 0.001; and McGill, P 0.049), and the effects were sustained even at 6 months after treatment. Conclusions: Acupuncture treatment was effective for the women who participated in this study, and the current authors believe that these preliminary results suffice to recommend performing randomized controlled trials. PMID- 29279738 TI - Computed Tomography-Based Occipital Condyle Morphometry in an Indian Population to Assess the Feasibility of Condylar Screws for Occipitocervical Fusion. AB - Study Design: A retrospective computed tomography (CT)-based morphometric study of 82 occipital condyles in the Indian population, focusing on critical morphometric dimensions with relation to placing condylar screws. Purpose: This study focused on determining the feasibility of placing occipital condylar screws in an Indian population using CT anatomical morphometric data. Overview of Literature: The occipital condylar screw is a novel technique being explored as one of the options in occipitocervical stabilization. Sex and ethnic variations in anatomical structures may restrict the feasibility of this technique in some populations. To the best of our knowledge, there are no CT-based data on an Indian population that assess the feasibility of occipital condylar screws. Methods: We measured the dimensions of 82 occipital condyles in 41 adults on coronal, sagittal, and axial reconstructed CT images. The differences were noted between the right and left sides and also between males and females. Statistical analysis was performed using the t-test, with a p-value of <0.05 considered significant. Results: Mean sagittal length and height were 17.2+/-1.7 mm and 9.1+/-1.5 mm, respectively. Mean condylar angle/screw angle was 38.0 degrees +/ 5.5 degrees from midline, with mean condylar length and width of 19.6+/-2.6 mm and 9.5+/-1.0 mm, respectively. Average coronal height on the anterior and posterior hypoglossal canal was 10.8+/-1.4 mm and 9.0+/-1.4 mm, respectively. The values in females were significantly lower than those in males, except for screw angle and condylar width. Based on Lin et al.'s proposed criteria, eight of 82 condyles were not suitable for condylar screws. Conclusions: Preliminary CT morphometry data of the occipital condyle shows that condylar screws are anatomically feasible in a large portion of the Indian population. However, because a small number of population may not be suitable for this technique, meticulous study of preoperative anatomy using detailed CT data is advised. PMID- 29279739 TI - Evaluation of Two Novel Integrated Stand-Alone Spacer Designs Compared with Anterior and Anterior-Posterior Single-Level Lumbar Fusion Techniques: An In Vitro Biomechanical Investigation. AB - Study Design: In vitro biomechanical investigation. Purpose: To compare the biomechanics of integrated three-screw and four-screw anterior interbody spacer devices and traditional techniques for treatment of degenerative disc disease. Overview of Literature: Biomechanical literature describes investigations of operative techniques and integrated devices with four dual-stacked, diverging interbody screws; four alternating, converging screws through a polyether-ether ketone (PEEK) spacer; and four converging screws threaded within the PEEK spacer. Conflicting reports on the stability of stand-alone devices and the influence of device design on biomechanics warrant investigation. Methods: Fourteen cadaveric lumbar spines were divided randomly into two equal groups (n=7). Each spine was tested intact, after discectomy (injured), and with PEEK interbody spacer alone (S), anterior lumbar plate and spacer (AP+S), bilateral pedicle screws and spacer (BPS+S), circumferential fixation with spacer and anterior lumbar plate supplemented with BPS, and three-screw (SA3s) or four-screw (SA4s) integrated spacers. Constructs were tested in flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Researchers performed one-way analysis of variance and independent t-testing (p<=0.05). Results: Instrumented constructs showed significantly decreased motion compared with intact except the spacer-alone construct in FE and AR (p<=0.05). SA3s showed significantly decreased range of motion (ROM) compared with AP+S in LB (p<=0.05) and comparable ROM in FE and AR. The three-screw design increased stability in FE and LB with no significant differences between integrated spacers or between integrated spacers and BPS+S in all loading modes. Conclusions: Integrated spacers provided fixation statistically equivalent to traditional techniques. Comparison of three-screw and four-screw integrated anterior lumbar interbody fusion spacers revealed no significant differences, but the longer, larger-diameter interbody spacer with three-screw design increased stabilization in FE and LB; the diverging four-screw design showed marginal improvement during AR. PMID- 29279737 TI - Apoptotic Protease Activating Factor-1 Inhibitor Mitigates Myocardial Ischemia Injury via Disturbing Procaspase-9 Recruitment by Apaf-1. AB - (2S,3S,4S,5R,6R)-6-(4-((4-guanidinobutoxy)carbonyl)-2,6-dihydroxyphenoxy)-3,4,5 trihydroxytetrahydro-2H-pyran-2-carboxylic acid (ZYZ-488) was discovered as a novel inhibitor of apoptotic protease activating factor-1 (Apaf-1). In present work, a surface plasmon resonance (SPR) assay confirms the direct binding between ZYZ-488 and Apaf-1 and this interaction was found to be able to block the recruitment of procaspase-9 by Apaf-1. This study also shows that the treatment of MI (myocardial infarction) mice with this novel Apaf-1 inhibitor remarkably reduces the infarct size, improves cardiac functions, and attenuates the histopathology changes caused by MI. Meanwhile, here it is shown that ZYZ-488 decreases myocardial enzyme release, inhibits cardiomyocyte apoptosis, and suppresses the activation of the downstream cascade of caspases. Moreover, in silico prediction validated the drug-like properties of ZYZ-488. In conclusion, our findings present the first piece of evidence indicating the interaction between Apaf-1 and procaspase-9 as a novel therapeutic target in myocardial infarction and suggesting ZYZ-488 as a promising therapeutic option for myocardial infarction disease. PMID- 29279740 TI - Detection of O-Linked-N-Acetylglucosamine Modification and Its Associated Enzymes in Human Degenerated Intervertebral Discs. AB - Study Design: Human herniated discs were obtained from discectomy specimens for the immunohistochemical detection of O-GlcNAc and O-GlcNAcase (OGA)/O-GlcNAc transferase (OGT). Purpose: This study aimed to quantify the extent of O GlcNAcylation and its associated enzymes (OGT/OGA) in human degenerated intervertebral discs. Overview of Literature: The O-GlcNAcylation of nuclear, cytoplasmic, and mitochondrial proteins as well as the effects of such post translational modifications are currently the focus of extensive research. O GlcNAcylation is believed to contribute to the etiology of chronic illnesses by acting as a nutrient and stress sensor in the cellular environment. Mature intervertebral disc cells are chondrocyte-like cells, and O-GlcNAc has been shown to promote chondrocyte apoptosis in vitro. We believe that O-GlcNAcylation is a key regulator of disc degeneration. Methods: Fifty-six specimens were fixed for 24 hours in a 10% solution of neutral-buffered formaldehyde, dehydrated, and embedded in paraffin. Tissue slices (4-um-thick) were used for hematoxylin-eosin staining and immunohistochemistry. Results: We found that O-GlcNAcylation of cytoplasmic proteins was less than that of nuclear proteins in both single cells and cell clusters. Cytoplasmic O-GlcNAcylation occurs subsequent to nuclear O GlcNAcylation and is directly proportional to disc degeneration. OGT and O-GlcNAc expression levels were identical in all specimens examined. Conclusions: O-GlcNAc and OGA/OGT expression is shown to correlate for the first time with intervertebral disc cell degeneration. Increasing disc degeneration is associated with increasing O-GlcNAcylation in both nuclear and cytoplasmic proteins in human disc cells. PMID- 29279741 TI - Generation of Induced Pluripotent Stem Cells and Neural Stem/Progenitor Cells from Newborns with Spina Bifida Aperta. AB - Study Design: We established induced pluripotent stem cells (iPSCs) and neural stem/progenitor cells (NSPCs) from three newborns with spina bifida aperta (SBa) using clinically practical methods. Purpose: We aimed to develop stem cell lines derived from newborns with SBa for future therapeutic use. Overview of Literature: SBa is a common congenital spinal cord abnormality that causes defects in neurological and urological functions. Stem cell transplantation therapies are predicted to provide beneficial effects for patients with SBa. However, the availability of appropriate cell sources is inadequate for clinical use because of their limited accessibility and expandability, as well as ethical issues. Methods: Fibroblast cultures were established from small fragments of skin obtained from newborns with SBa during SBa repair surgery. The cultured cells were transfected with episomal plasmid vectors encoding reprogramming factors necessary for generating iPSCs. These cells were then differentiated into NSPCs by chemical compound treatment, and NSPCs were expanded using neurosphere technology. Results: We successfully generated iPSC lines from the neonatal dermal fibroblasts of three newborns with SBa. We confirmed that these lines exhibited the characteristics of human pluripotent stem cells. We successfully generated NSPCs from all SBa newborn-derived iPSCs with a combination of neural induction and neurosphere technology. Conclusions: We successfully generated iPSCs and iPSC-NSPCs from surgical samples obtained from newborns with SBa with the goal of future clinical use in patients with SBa. PMID- 29279742 TI - Prevalence and Complications of Postoperative Transfusion for Cervical Fusion Procedures in Spine Surgery: An Analysis of 11,588 Patients from the American College of Surgeons National Surgical Quality Improvement Program Database. AB - Study Design: Retrospective cohort study. Purpose: The purpose of this study was to assess the rate of blood transfusion after cervical fusion surgery, and its effect on complication rates. Overview of Literature: Cervical spine fusions have gained interest in the literature since these procedures are now ever more frequently being performed in an outpatient setting with few complications. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients that underwent cervical fusion from 2010 to 2013. Multivariate regression analysis was used to determine postoperative complications associated with transfusion and cervical fusion. Results: We identified 11,588 patients who had cervical fusion between 2010 and 2013. The rate of blood transfusion following cervical fusion found to be 1.47%. All transfused patients were found to have increased risk of venous thromboembolism (TBE) (odds ratio [OR], 3.19; 95% confidence interval [95% CI], 1.16-8.77), myocardial infarction (MI) (OR, 9.12; 95% CI, 2.53-32.8), increased length of stay (LOS) (OR, 28.03; 95% CI, 14.28-55.01) and mortality (OR, 4.14; 95% CI, 1.44-11.93). Single level fusion had increased risk of TBE (OR, 3.37; 95% CI, 1.01-11.33), MI (OR, 10.5; 95% CI, 1.88-59.89), and LOS (OR, 14.79; 95% CI, 8.2-26.67). Multilevel fusion had increased risk of TBE (OR, 5.64; 95% CI, 1.15 27.6), surgical site infection (OR, 16.29; 95% CI, 3.34-79.49), MI (OR, 10.84; 95% CI, 2.01-58.55), LOS (OR, 26.56; 95% CI, 11.8-59.78), and mortality (OR, 10.24; 95% CI, 2.45-42.71). Patients who had anterior cervical discectomy and fusion surgery and received a transfusion had an increased risk of TBE (OR, 4.87; 95% CI, 1.04-22.82), surgical site infection (OR, 9.73; 95% CI, 2.14-44.1), MI (OR, 9.88; 95% CI, 1.87-52.2), increased LOS of more than 2 days (OR, 28.34; 95% CI, 13.79-58.21) and increase in mortality (OR, 6.3; 95% CI, 1.76-22.48). While, transfused patients who had posterior fusion surgery had increased risk of MI (OR, 10.45; 95% CI, 1.42-77.12) and increased LOS of more than 6 days (OR, 4.42; 95% CI, 2.68-7.29). Conclusions: Our results demonstrate that although cervical fusions can be done as outpatient procedures special precautions and investigations should be done for patients who receive transfusion after cervical fusion. These patients are demonstrated to have higher rate of MI, TBE, wound infection and mortality when compared to those who do not receive transfusion. PMID- 29279743 TI - Prevalence of Lumbosacral Transitional Vertebra in Individuals with Low Back Pain: Evaluation Using Plain Radiography and Magnetic Resonance Imaging. AB - Study Design: Descriptive cross-sectional study. Purpose: To determine the frequency of lumbosacral transitional vertebrae (LSTV) in patients with low back pain (LBP) and the role of iliolumbar ligament (ILL) origin from L5 in LSTV cases. Overview of Literature: Transitional vertebrae are developmental variants of the spine. LSTV is a common congenital abnormality, and failure to recognize this anomaly may result in serious consequences during surgery. Methods: All patients aged 11-90 years of either gender with LBP for any duration, who presented for X-ray and magnetic resonance imaging (MRI) of the lumbosacral spine, were included. X-rays of the lumbosacral spine in anteroposterior and lateral views were acquired. In addition, T1- and T2-weighted sagittal and axial MRI was performed. Images were evaluated on a workstation. Results: Of 504 patients, transitional vertebrae were observed in 75 patients (15%). Among them, 39 (52%) patients had Castellvi type III and 36 (48%) patients had Castellvi type II. However, on MRI, 42 (56%) patients had O'Driscoll type II, 18 (24%) patients had O'Driscoll type IV, and 15 patients (20%) had O'Driscoll type III. ILL origin from L5 was significantly higher (n=429, 100%) among patients with a normal lumbosacral junction than among patients with a transitional lumbosacral junction (n=22, 29.3%) (p<0.001). Conclusions: LSTV occurs at a high frequency in patients with LBP. Furthermore, in the presence of LSTV, the ILL is not a reliable marker for the identification of L5. PMID- 29279745 TI - Effects of Atorvastatin in Patients with Acute Spinal Cord Injury. AB - Study Design: Clinical trial study. Purpose: The aim of this study was to evaluate the effect of atorvastatin on sensory and motor function in patients with acute spinal cord injury. Overview of Literature: The prevalence and incidence of traumatic spinal cord injury are increasing. Statins are well established for use in hypercholesterolemia as well as during anti-inflammatory events. Methods: This clinical trial study included 60 patients with acute spinal cord injury. These were randomly divided into two groups: the case group which received atorvastatin and also underwent surgical therapy and the control group which only underwent surgical therapy. Results: The severity of spinal cord lesions was evaluated based on the Frankel grade at three periods; this showed no significant difference between the two groups. Comparisons of the levels of pain between the groups based on a Visual Analog Scale system showed no significant difference at the three periods. Conclusions: We observed no improvement at the 3 and 6-month follow-up in patients who were administered atorvastatin. However, a comparison of the two groups based on pain severity demonstrated a significant difference, suggesting that atorvastatin had a positive effect on patients with spinal cord injury. PMID- 29279744 TI - Postoperative Spinal Epidural Hematoma: The Danger Caused by the Misuse of Thrombin-Containing Local Hemostatics. AB - Study Design: Retrospective case-control study. Purpose: To examine the hypothesis that the misuse of thrombin-containing local hemostatics (TCLH) increases the risk of postoperative spinal epidural hematoma (POSEH). Overview of Literature: Many studies have focused on hypocoagulability as a risk factor for POSEH. However, there are no prior reports on the increased risk of POSEH in hypercoagulable states. Methods: Posterior instrumented lumbar spine surgery cases over 2 consecutive years were divided into two groups: a study group (98 patients in whom TCLH was used) and a control group (176 patients in whom TCLH was not used). The excess TCLH matrix that was not associated with blood clot was not removed from the patients in the study group. The senior author decided whether to use TCLH or not. Suction drains were used in all patients. The demographics, coagulation-related factors, and intraoperative factors of the patients in the two groups were analyzed. The development of POSEH was compared between the two groups. Results: The two groups were homogenous in demographics (age and sex), coagulation-related factors (platelet count, prothrombin time, activated partial thromboplastin time, and platelet function analysis), and surgical factors (total blood loss, operation time, blood loss/10 minutes, number of fusion segments, posterolateral fusion/posterior lumbar interbody fusion, and virgin or revision surgery). POSEH developed more frequently in the patients in the study group than in those in the control group (14/98 patients, 14.3% vs. 3/176 patients, 1.7%, respectively; p=0.001; odds ratio, 17.1). Conclusions: TCLH causes blood clot not only at the edge of damaged vessels but also at the site of extravascular blood. Excess TCLH matrix not associated with blood clot at the epidural space can enhance POSEH development because early clotted hematomas do not drain through suction drains. PMID- 29279746 TI - Epidemiology and Clinical Management of Traumatic Spine Injuries at a Major Government Hospital in Cambodia. AB - Study Design: Cross sectional study. Purpose: To characterize the pattern of injury, describe the current clinical management, and determine the outcomes in traumatic spine injury (TSI) patients presenting to a major government hospital in Phnom Penh, Cambodia. Overview of Literature: There is a paucity of literature on epidemiology or current clinical practices for TSIs in Cambodia. The findings from this study can thus serve as a valuable resource for future progress in treating TSIs in low-income countries. Methods: This study was a cross-sectional study of TSI patients admitted to Preah Kossamak Hospital in Phnom Penh, Cambodia. Demographics, cause of spinal injury, spinal level of injury, surgical procedures and techniques, complications, and American Spinal Injury Association (ASIA) grades were recorded and analyzed. Results: Eighty patients were admitted with TSI between October 2013 and June 2014. Falls from heights were the most common cause of TSI, followed by road traffic accidents. 78% of the admitted patients underwent at least one surgical procedure. Without intraoperative imaging, 4 patients (6%) had wrong level surgery, and 1 patient (2%) had misplacement of pedicle screws. Sacral decubitus ulcers were the most common non surgically related complication. Antibiotics were administered to >90% of patients. There were no in-hospital mortalities. Of the 60 spinal cord injury (SCI) patients, 32% (19/60) showed improvement in their ASIA grade at the time of discharge, and 52% (31/60) showed no change. At follow-up, 32% (19/60) of SCI patients reported improvement, and 8% (5/60) reported no change. However, 36 SCI patients (60%) were lost to follow-up. Conclusions: Despite technological limitations, outcomes of TSI patients in Cambodia appear favorable with evidence of clinical improvement and low mortality. PMID- 29279747 TI - Prevalence of Neuropathic Pain and Patient-Reported Outcomes in Korean Adults with Chronic Low Back Pain Resulting from Neuropathic Low Back Pain. AB - Study Design: A noninterventional, multicenter, cross-sectional study. Purpose: We investigated the prevalence of neuropathic pain (NP) and patient-reported outcomes (PROs) of the quality of life (QoL) and functional disability in Korean adults with chronic low back pain (CLBP). Overview of Literature: Among patients with CLBP, 20%-55% had NP. Methods: Patients older than 20 years with CLBP lasting for longer than three months, with a visual analog scale (VAS) pain score higher than four, and with pain medications being used for at least four weeks before enrollment were recruited from 27 general hospitals between December 2014 and May 2015. Medical chart reviews were performed to collect demographic/clinical features and diagnosis of NP (douleur neuropathique 4, DN4). The QoL (EuroQoL 5-dimension, EQ-5D; EQ-VAS) and functional disability (Quebec Back Pain Disability Scale, QBPDS) were determined through patient surveys. Multiple linear regression analyses were performed to compare PROs between the NP (DN4>=4) and non-NP (DN4<4) groups. Results: A total of 1,200 patients (females: 65.7%; mean age: 63.4+/-13.0 years) were enrolled. The mean scores of EQ-5D, EQ VAS, and QBPDS were 0.5+/-0.3, 55.7+/-19.4, and 40.4+/-21.1, respectively. Among all patients, 492 (41.0%; 95% confidence interval, 38.2%-43.8%) suffered from NP. The prevalence of NP was higher in male patients (46.8%; p<0.01), in patients who had pain based on radiological and neurological findings (59.0%; p<0.01), and in patients who had severe pain (49.0%; p<0.01). There were significant mean differences in EQ-5D (NP group vs. non-NP group: 0.4+/-0.3 vs. 0.5+/-0.3; p<0.01) and QBPDS (NP group vs. non-NP group: 45.8+/-21.2 vs. 36.3+/-20.2; p<0.01) scores. In the multiple linear regression, patients with NP showed lower EQ-5D (beta=-0.1; p<0.01) and higher QBPDS (beta=7.0; p<0.01) scores than those without NP. Conclusions: NP was highly prevalent in Korean patients with CLBP. Patients with CLBP having NP had a lower QoL and more severe dysfunction than those without NP. To enhance the QoL and functional status of patients with CLBP, this study highlights the importance of appropriately diagnosing and treating NP. PMID- 29279748 TI - Surgical Outcomes of Cervical Myelopathy in Patients with Athetoid Cerebral Palsy: A 5-Year Follow-Up. AB - Study Design: Observational cohort study. Purpose: To assess the surgical outcomes of posterior decompression and fusion for cervical myelopathy in patients with athetoid cerebral palsy. Overview of Literature: Patients with athetoid cerebral palsy demonstrate involuntary movements and develop severe cervical spondylosis with kyphosis. In these patients, surgery is often performed at an early age because of myelopathy. A few studies have reported about the long term outcomes of surgical treatment; however, they contain insufficient information. Methods: From 2003 to 2008, 13 patients with cervical myelopathy due to athetoid cerebral palsy underwent posterior fusion surgery and were included in this study. The Japanese Orthopaedic Association (JOA) score, neck disability index (NDI), C2-7 angle on radiography, and need for additional surgical treatment were examined at 1 and 5 years postoperatively. Results: The mean C2-7 angle was -10.5 degrees +/-21.1 degrees preoperatively and was corrected to -2.9 degrees +/-13.5 degrees immediately postoperatively. This improvement was maintained for 5 years. The JOA score was 9.5+/-2.5 preoperatively and 12.2+/-1.7 at the 5-year follow-up. NDI was 17+/-6.9 preoperatively and 16+/-7.5 at the 5 year follow-up. Patient satisfaction with surgery on a 100-point scale was 62.2+/ 22.5 at the 5-year follow-up. Three patients needed additional surgery for loosening of screws. These results demonstrate good surgical outcomes for posterior fusion at 5 years. Conclusions: Posterior decompression and fusion should be considered a viable option for cervical myelopathy in patients with athetoid cerebral palsy. PMID- 29279749 TI - A Safe Surgical Procedure for Old Distractive Flexion Injuries of the Subaxial Cervical Spine. AB - Study Design: Retrospective review. Purpose: To describe a safe and effective surgical procedure for old distractive flexion (DF) injuries of the subaxial cervical spine. Overview of Literature: Surgical treatment is required in old cases when a progression of the kyphotic deformity and/or persistent neck pain and/or the appearance of new neurological symptoms are observed. Since surgical treatment is more complicated and dangerous in old cases than in acute distractive-flexion cases, the indications for surgery and the selection of the surgical procedure must be carefully conducted. Methods: To identify a safe and effective surgical procedure, the procedure selected, reason(s) for its selection, and associated neurological complications were investigated in 13 patients with old cervical DF injuries. Results: No neurological complications were observed in nine patients (DF stage 2 or 3) who underwent the anterior posterior-anterior (A-P-A) method and two patients (DF stage 1) who underwent the posterior method. It was initially planned that two patients (DF stage 2) who underwent the P-A method would be treated using the Posterior method alone; however, anterior discectomy was added to the procedure after the development of a severe spinal cord disorder. Conclusions: The A-P-A method (anterior discectomy, posterior release and/or partial facetectomy, reduction and instrumentation, anterior bone grafting) is considered to be a suitable surgical procedure for old cervical DF injuries. PMID- 29279750 TI - Anterior Longitudinal Ligament Reconstruction to Reduce Hypermobility of Cervical and Lumbar Disc Arthroplasty. AB - Study Design: Retrospective case series. Purpose: This study aims to present the early clinical and radiological outcomes of anterior longitudinal ligament (ALL) reconstruction following disc arthroplasty. Overview of Literature: Although cervical and lumbar disc arthroplasty have entered the clinical setting, there are still concerns regarding the short and long term complications arising from hypermobility of current prosthesis designs. Reconstruction of the ALL is a potential solution to disc arthroplasty hypermobility. Methods: ALL reconstruction following disc arthroplasty have been performed by the senior author over a 24 month period. Ligament replacements used include allograft and synthetic, ligament advanced reinforcement system (LARS) ligaments. Methods of fixation used include titanium staples, bone anchors and suture fixation. Radiological follow-up pre- and postoperative Oswestry disability index, Neck Disability Index, Patient Satisfaction index scores were recorded on all patients. Results: A total of 18 ALL reconstructions were performed. There have been no cases of early complications, revision surgery for recurrent symptoms or implant failure. Of the 6 patients receiving a minimum of 15 months follow-up, 4 patients received an allograft, 2 patients received the LARS ligament. Favourable, postoperative clinical and radiographic outcomes have been demonstrated. Conclusions: ALL reconstruction following cervical and lumbar disc arthroplasty is a promising solution to addressing non-physiological kinematics of current disc arthroplasty devices. Randomized, controlled studies with larger study samples and long-term follow-up are required to establish these conclusions. PMID- 29279751 TI - Thoracolumbar Vertebral Injuries with Neurological Deficit Treated with Posterior Decompression, Short Segment Pedicle Screw Fixation, and Interlaminar Fusion. AB - Study Design: Prospective clinical study. Purpose: The purpose of this study was to evaluate the effect of interlaminar fusion and short segment pedicle screw fixation on thoracolumbar vertebral injuries for preventing pain and post traumatic kyphosis. Overview of Literature: The treatment of thoracolumbar injuries continues to be one of the most controversial areas in spine care. The main aim of surgical treatment is to decompress the spinal cord or nerve roots, realign the spine, and correct or prevent post-traumatic kyphosis. We evaluated the outcome of interlaminar fusion along with posterior decompression and short segment pedicle screw fixation in patients with thoracolumbar fractures with neurological deficit. Methods: Twenty-two patients with traumatic thoracolumbar vertebral injuries and neurological deficit underwent short segment pedicle screw fixation above and below the fractured vertebrae, posterior decompression, and interlaminar fusion using a bone graft. Results: All patients were followed up for 12 months postoperatively. The average operative time and blood loss was 142 minutes and 214 mL, respectively. Of the 22 patients, 14 recovered completely. Of the nine patients with American Spinal Injury Association (ASIA) grade A disease, two improved by 1 grade, whereas one each improved by grades 2, 3, and 4, and four did not recover. Radiologically, vertebral kyphosis angle improved from 20.91 preoperatively to 15.73 postoperatively, sagittal index improved from 24.77 to 18.73, the sagittal plane kyphosis angle improved from 17.45 to 11.41, regional angle kyphosis improved from 14.73 to 10.14, the superior inferior end plate angle from 16.14 to 13.00, and mean anterior body compression improved from 36.26 to 27.64 postoperatively. No implant failed and no patient had neurological deterioration. Conclusions: Short segment pedicle screw fixation with posterior decompression and interlaminar fusion provided considerable reduction in kyphosis, restored the vertebral height of patients with thoracolumbar vertebral injuries and neurological deficit, and prevented development of delayed kyphotic deformity. PMID- 29279752 TI - Difference in Spinal Sagittal Alignment and Health-Related Quality of Life between Males and Females with Cervical Deformity. AB - Study Design: Large cohort study. Purpose: To clarify spinal sagittal alignment and health-related quality of life (HRQOL) according to sex in volunteers aged >50 years with cervical deformity (CD). Overview of Literature: Adult spinal deformities, especially those associated with lumbosacral lesions, are more frequent in females; however, CD is observed to a greater extent in males. Methods: We divided 656 volunteers (263 males, 393 females; age, 50-89 years [mean, 73 years]) as follows: males with CD (CDM; 82 patients); males without CD (NCDM, 181); females with CD (CDF, 36); and females without CD (NCDF, 357). CD was defined as C2-7 sagittal vertical axis (SVA) >=40 mm. We measured pelvic tilt (PT), pelvic incidence minus lumbar lordosis (PI-LL), thoracic kyphosis, T1 slope, cervical lordosis, C7 SVA, and C2-7 SVA. HRQOL was evaluated using EuroQOL five dimensions questionnaire (EQ-5D). Results: In CDM, NCDM, CDF, and NCDF groups, the respective parameters were as follows: PT: 15 degrees , 14 degrees , 26 degrees , and 21 degrees ; PI-LL: 7 degrees , 5 degrees , 16 degrees , and 10 degrees ; C2-7 SVA: 49, 24, 46, and 20 mm; C7 SVA: 61, 40, 75, and 47 mm; and EQ 5D: 0.82, 0.88, 0.78, and 0.81. PT and PI-LL were significantly greater in the CDF group than in the NCDF group (p<0.05) but were not significantly different between CDM and NCDM groups. The CDF group already showed deterioration of spinopelvic alignment, although it was maintained in the CDM group. EQ-5D in showed significantly greater deterioration the CDM group than in the NCDM group; deterioration of lumbopelvic parameters had less influence in males (p<0.05). Conclusions: Sagittal spinal deformity may have different mechanisms in males and females. The deterioration of spinal sagittal alignment in males may originate from the cervical spine, and CD may be associated with HRQOL. PMID- 29279753 TI - Area of Ostectomy in Posterior Percutaneous Endoscopic Cervical Foraminotomy: Images and Mid-term Outcomes. AB - Study Design: Retrospective. Purpose: To analyze whether the cross-sectional area of the intervertebral foramen at the outermost edge of the resection site is associated with postoperative outcomes and whether our fluoroscopic method for determining the resection area is appropriate. Overview of Literature: There is no consensus on the criteria for determining an optimal resection area to obtain sufficient decompression while maintaining intervertebral stability in posterior percutaneous endoscopic cervical foraminotomy. Previous reports have recommended a facet resection rate (FRR) of <=50%. Intervertebral foramen stenosis often extends to the exit zone. The cross-sectional area of the intervertebral foramen is occasionally small at the outermost edge of the resection site. No report has analyzed whether these aspects are associated with postoperative outcomes. Methods: Lateral margins of the resection area were set at lateral borders of the vertebral body on frontal fluoroscopic view. Because the percutaneous endoscope has a small diameter, surrounding structures can easily be identified using frontal view fluoroscopy to determine the resection area. FRRs were calculated from postoperative computed tomography images. The smallest cross-sectional area of the intervertebral foramen around the lateral edge of the resection area (SALE) was measured and compared wit clinical outcomes. Results: The mean FRR was 41.7% at C5-C6 and 48.9% at C6-C7. SALE was not correlated with clinical outcomes. Conclusions: Residual stenosis in the lateral portion of the intervertebral foramen is weakly associated with postoperative outcomes. Our process achieved adequate FRRs and favorable postoperative outcomes, suggesting that our criteria for determining the resection area are appropriate. PMID- 29279754 TI - Assessment of the Relationship between Pelvic Tilt and the Sacro-Femoral-Pubic Angle in Middle-Aged and Elderly Asian Individuals. AB - Study Design: Cross-sectional study. Purpose: The purpose of this study was to evaluate the correlation between pelvic tilt (PT) and the sacro-femoral-pubic (SFP) angle, which is easier to identify than PT, in middle-aged and elderly Asian subjects from the general population. Overview of Literature: Measuring PT is important in the diagnosis and treatment of adult spinal deformity. However, identifying femoral heads, which are necessary to determine PT, using sagittal radiographs is often difficult. Methods: Standing coronal and sagittal pelvic radiographs of individuals aged more than 50 years were taken during a local medical examination. The subjects were divided into female, male, and total groups at the time of evaluation. Linear regression analysis was performed to investigate the relationship between PT and the SFP angle, which were obtained from the X-rays. Results: The present study included 291 subjects. There were no statistically significant differences between the left and right SFP angles, and there was gender difference regarding the SFP angle. However, a gender difference was observed regarding PT. The correlation between PT and the SFP angle was substantiated in each group. Pearson's correlation coefficients between PT and the SFP angle in the total, female, and male groups were 0.696, 0.853, and 0.619, respectively. In the linear regression analysis, PT was calculated as follows: PT=60.1-0.77*(SFP angle) in the total group, PT=62.8-0.80*(SFP angle) in the female group, and PT=51.5-0.64*(SFP angle) in the male group. Conclusions: A significant correlation between PT and the SFP angle was observed in middle-aged and elderly Asian subjects from the general population. PMID- 29279755 TI - Delayed Neurological Deficits after Osteoporotic Vertebral Fractures: Clinical Outcomes after Surgery. AB - Study Design: Retrospective cohort. Purpose: To review the clinical presentation of operated patients with delayed neurological deficits after osteoporotic vertebral fractures (OVFs). Overview of Literature: Delayed neurological deficits can occur from 1 week to 5.7 months after OVFs. Baba has reported 78% good-to excellent improvement (i.e., >=50%) after 20 posterior (Cotrel-Dubousset) and 7 anterior (Kaneda in 4, Zielke ventral derotational spondylodesis in 2, and un instrumented anterior fusion in 1) fusions. Predictive factors for neurological deficits include burst type, vacuum sign, kyphosis, angular instability, and retropulsion. Methods: Patients with neurological deficits after OVF who received spinal operations between 2000 and 2016 were included. Results: Totally, 28 patients with a mean age of 77 years underwent surgery. Neurological deficits occurred at an average of 5.4 weeks after the onset of back pain. The most common site was L1. Burst fracture was present in 14 patients and vacuum sign in seven. Surgery was performed within an average of 3.9 days of the onset of neurological deficit. Baba's score improved significantly from 5.96 to 9.81, with good-to excellent improvement in 18 (64%) patients. Better outcomes based on Baba's scores (improvement>60% [median]) were associated with compression fractures, preoperative retropulsion of <41%, and correction of >16%. Poor improvement in Baba's scores (<25%) was associated with surgical complications and burst fracture type. Twenty-two patients (79%) regained walking ability, and seven of 15 (47%) patients demonstrated improved sphincter control at the latest follow up. Six Frankel grade B patients did not achieve neurological recovery, four of whom exhibited postoperative surgical complications and died at 2 years because of medical problems. Implant migration occurred in six patients, albeit this was of no clinical significance. Conclusions: Although OVFs are commonly considered benign, delayed neurological deficits can occur. The significant improvement in clinical function after surgery for neurological deficits is associated with compression (and not burst) fractures, lack of surgical complications, and optimal restoration of retropulsion. PMID- 29279756 TI - Prevalence of Chronic Nonspecific Low Back Pain and Its Associated Factors among Middle-Aged and Elderly People: An Analysis Based on Data from a Musculoskeletal Examination in Japan. AB - Study Design: A cross-sectional study. Purpose: To clarify the prevalence of chronic nonspecific low back pain (CNSLBP) and its associated factors among middle-aged and elderly Japanese individuals using data from a musculoskeletal examination conducted in general Japanese populations. Overview of Literature: Most studies evaluating low back pain-associated factors have been conducted in Western countries, but they have not always evaluated CNSLBP. Methods: We obtained data on 213 subjects aged >50 years who responded to a survey regarding age, gender, body mass index, lifestyle-related diseases (diabetes mellitus, hypertension, and hyperlipidemia), glucocorticoid use, smoking and alcohol drinking habits, labor intensity, and chronic low back pain (CLBP) and underwent screening for lumbar spinal stenosis, evaluation for quality of life (QOL), and evaluation for specific spinal pathology via thoracolumbar spine X-rays. We investigated the prevalence of CNSLBP and association between CNSLBP and measured variables. Results: The prevalence of CNSLBP and chronic specific low back pain (CSLBP) was 15.4% and 9.3%, respectively. Among the subjects with CLBP, 62.2% had CNSLBP. In age-adjusted logistic models, smoking habits (p=0.049, odds ratio [OR]=2.594), low back pain (p<0.001, OR=0.974), lumbar function (p=0.001, OR=0.967), and social function (p=0.023, OR=0.976) in the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were significantly associated with CNSLBP, whereas EQ-5D utility score (p=0.024, OR=0.068), low back pain (p=0.007, OR=0.981), lumbar function (p=0.001, OR=0.963), walking ability (p=0.001, OR=0.968), and social function (p=0.002, OR=0.966) in JOABPEQ were significantly associated with CSLBP. Conclusions: CNSLBP among middle-aged and elderly individuals was associated with smoking habits and decreased QOL; however, CSLBP was considered to be more multilaterally associated decreased QOL. PMID- 29279757 TI - Safety of Pedicle Screws in Adolescent Idiopathic Scoliosis Surgery. AB - To review existing publications on the safety of pedicle screw insertions in adolescent idiopathic scoliosis (AIS). Despite having increased risk for neurological and visceral injuries, the use of pedicle screws have led to increased correction rates in scoliosis surgery. A review was performed on topics pertinent to pedicle screw insertion in AIS, which included pedicle morphometry in AIS, structures at risk during pedicle screw insertion, and accuracy and safety of various pedicle screw insertion techniques. The importance of computer navigation and future research regarding pedicle screw placement in AIS were also briefly reviewed. Many authors have reported abnormal pedicle anatomy in AIS. Injury to the neural structures was highest over the apical region, whereas aortic injury was the highest at T5 and T10. In the proximal thoracic spine, the esophagus could be injured even with screws as short as 25 mm. Overall pedicle perforation rates for perforations >0 and >2 mm (assessed by computed tomography) ranged from 6.4% to 65.0% and 3.7% to 29.9%, respectively. The critical pedicle perforation (>2 mm excluding lateral thoracic) and anterior perforation (>0 mm) rates was reported to range from 1.5% to 14.5% and 0.0% to 16.1%, respectively. Pedicle perforation rates were lower with the use of computer navigation. The incidence of neurological adverse events after scoliosis surgery was 0.06%-1.9%. Aortic injury has only been observed in case reports. According to the available literature, pedicle screw insertion in AIS is considered safe with low rates of clinical adverse events. Moreover, the use of navigation technology has been shown to reduce pedicle perforation rates. PMID- 29279758 TI - The Role of Dynamic Magnetic Resonance Imaging in Cervical Spondylotic Myelopathy. AB - Dynamic spinal cord compression has been investigated for several years, but until the advent of open MRI, the use of dynamic MRI (dMRI) did not gain popularity. Several publications have shown that cervical cord compression is both static and dynamic. On many occasions the evaluation of cervical spondylotic myelopathy (CSM) is straightforward, but patients are frequently encountered with a significantly worse clinical examination than would be suggested by radiological images. In this paper, we present an extensive review of the literature in order to describe the importance of dMRI in various settings and applications. A detailed literature review was performed in the Medline and Pubmed databases using the terms "cervical spondylotic myelopathy", "dynamic MRI", "kinetic MRI", and "myelomalalcia" for the period of 1980-2016. The study was limited to English language, human subjects, case series, retrospective studies, prospective reports, and clinical trials. Reviews, case reports, cadaveric studies, editorials, and commentaries were excluded. The literature search yielded 180 papers, 19 of which met inclusion criteria. However, each paper had evaluated results and outcomes in different ways. It was not possible to compile them for meta-analysis or pooled data evaluation. Instead, we evaluated individual studies and present them for discussion. We describe a number of parameters evaluated in 2661 total patients, including dynamic changes to spinal cord and canal dimensions, transient compression of the cord with changes in position, and the effects of position on the intervertebral disc. dMRI is a useful tool for understanding the development of CSM. It has found several applications in the diagnosis and preoperative evaluation of many patients, as well as certain congenital dysplasias and Hirayama disease. It is useful in correlating symptoms with the dynamic changes only noted on dMRI, and has reduced the incidence of misdiagnosis of myelopathy. PMID- 29279759 TI - A standardization model based on image recognition for performance evaluation of an oral scanner. AB - PURPOSE: Accurate information is essential in dentistry. The image information of missing teeth is used in optically based medical equipment in prosthodontic treatment. To evaluate oral scanners, the standardized model was examined from cases of image recognition errors of linear discriminant analysis (LDA), and a model that combines the variables with reference to ISO 12836:2015 was designed. MATERIALS AND METHODS: The basic model was fabricated by applying 4 factors to the tooth profile (chamfer, groove, curve, and square) and the bottom surface. Photo-type and video-type scanners were used to analyze 3D images after image capture. The scans were performed several times according to the prescribed sequence to distinguish the model from the one that did not form, and the results confirmed it to be the best. RESULTS: In the case of the initial basic model, a 3D shape could not be obtained by scanning even if several shots were taken. Subsequently, the recognition rate of the image was improved with every variable factor, and the difference depends on the tooth profile and the pattern of the floor surface. CONCLUSION: Based on the recognition error of the LDA, the recognition rate decreases when the model has a similar pattern. Therefore, to obtain the accurate 3D data, the difference of each class needs to be provided when developing a standardized model. PMID- 29279760 TI - Fracture load and survival of anatomically representative monolithic lithium disilicate crowns with reduced tooth preparation and ceramic thickness. AB - PURPOSE: To investigate the effect of reducing tooth preparation and ceramic thickness on fracture resistance of lithium disilicate crowns. MATERIALS AND METHODS: Specimen preparation included a standard complete crown preparation of a typodont mandibular left first molar with an occlusal reduction of 2 mm, proximal/axial wall reduction of 1.5 mm, and 1.0 mm deep chamfer (Group A). Another typodont mandibular first molar was prepared with less tooth reduction: 1 mm occlusal and proximal/axial wall reduction and 0.8 mm chamfer (Group B). Twenty crowns were milled from each preparation corresponding to control group (n=5) and conditioned group of simultaneous thermal and mechanical loading in aqueous environment (n=15). All crowns were then loaded until fracture to determine the fracture load. RESULTS: The mean (SD) fracture load values (in Newton) for Group A were 2340 (83) and 2149 (649), and for Group B, 1752 (134) and 1054 (249) without and with fatigue, respectively. Reducing tooth preparation thickness significantly decreased fracture load of the crowns at baseline and after fatigue application. After fatigue, the mean fracture load statistically significantly decreased (P<.001) in Group B; however, it was not affected (P>.05) in Group A. CONCLUSION: Reducing the amount of tooth preparation by 0.5 mm on the occlusal and proximal/axial wall with a 0.8 mm chamfer significantly reduced fracture load of the restoration. Tooth reduction required for lithium disilicate crowns is a crucial factor for a long-term successful application of this all ceramic system. PMID- 29279761 TI - Load-bearing capacity of various CAD/CAM monolithic molar crowns under recommended occlusal thickness and reduced occlusal thickness conditions. AB - PURPOSE: The goal of this study was to evaluate the fracture resistances of various monolithic crowns fabricated by computer-aided design and computer-aided manufacturing (CAD/CAM) with different thickness. MATERIALS AND METHODS: Test dies were fabricated as mandibular molar forms with occlusal reductions using CAD/CAM. With different occlusal thickness (1.0 or 1.5 mm), a polymer-infiltrated ceramic network (Enamic, EN), and zirconia-reinforced lithium silicate (Suprinity, SU and Celtra-Duo, CD) were used to fabricate molar crowns. Lithium disilicate (e.max CAD, EM) crowns (occlusal: 1.5 mm) were fabricated as control. Seventy crowns (n=10 per group) were bonded to abutments and stored in water for 24 hours. A universal testing machine was used to apply load to crown until fracture. The fractured specimens were examined with a scanning electron microscopy. RESULTS: The type of ceramics and the occlusal thickness showed a significant interaction. With a recommended thickness (1.5 mm), the SU revealed the mean load similar to the EM, higher compared with those of the EN and CD. The fracture loads in a reduced thickness (1.0 mm) were similar among the SU, CD, and EN. The mean fracture load of the SU and CD enhanced significantly when the occlusal thickness increased, whereas that of the EN did not. CONCLUSION: The fracture loads of monolithic crowns were differently influenced by the changes in occlusal thickness, depending on the type of ceramics. Within the limitations of this study, all the tested crowns withstood the physiological masticatory loads both at the recommended and reduced occlusal thickness. PMID- 29279762 TI - Detection of proximal caries using quantitative light-induced fluorescence digital and laser fluorescence: a comparative study. AB - PURPOSE: The purpose of this study was to evaluate the in vitro validity of quantitative light-induced fluorescence-digital (QLF-D) and laser fluorescence (DIAGNOdent) for assessing proximal caries in extracted premolars, using digital radiography as reference method. MATERIALS AND METHODS: A total of 102 extracted premolars with similar lengths and shapes were used. A single operator conducted all the examinations using three different detection methods (bitewing radiography, QLF-D, and DIAGNOdent). The bitewing x-ray scale, QLF-D fluorescence loss (DeltaF), and DIAGNOdent peak readings were compared and statistically analyzed. RESULTS: Each method showed an excellent reliability. The correlation coefficient between bitewing radiography and QLF-D, DIAGNOdent were -0.644 and 0.448, respectively, while the value between QLF-D and DIAGNOdent was -0.382. The kappa statistics for bitewing radiography and QLF-D had a higher diagnosis consensus than those for bitewing radiography and DIAGNOdent. The QLF-D was moderately to highly accurate (AUC = 0.753 - 0.908), while DIAGNOdent was moderately to less accurate (AUC = 0.622 - 0.784). All detection methods showed statistically significant correlation and high correlation between the bitewing radiography and QLF-D. CONCLUSION: QLF-D was found to be a valid and reliable alternative diagnostic method to digital bitewing radiography for in vitro detection of proximal caries. PMID- 29279763 TI - Influence of different surface treatments on bond strength of novel CAD/CAM restorative materials to resin cement. AB - PURPOSE: To evaluate the effects of different surface treatments on the bond strength of novel CAD/CAM restorative materials to resin cement by four point bending test. MATERIALS AND METHODS: The CAD/CAM materials under investigation were e.max CAD, Mark II, Lava Ultimate, and Enamic. A total of 400 bar specimens (4*1.2*12 mm) (n=10) milled from the CAD/CAM blocks underwent various pretreatments (no pretreatment (C), hydrofluoric acid (A), hydrofluoric acid + universal adhesive (Scotchbond) (AS), sandblasting (Sb), and sandblasting + universal adhesive (SbS)). The bars were luted end-to-end on the prepared surfaces with a dual curing adhesive resin cement (Variolink N, Ivoclar Vivadent) on the custom-made stainless steel mold. Ten test specimens for each treatment and material combination were performed with four point bending test method. Data were analyzed using ANOVA and Tukey's test. RESULTS: The surface treatment and type of CAD/CAM restorative material showed a significant effect on the four point bending strength (FPBS) (P<.001). For LDC, AS surface treatment showed the highest FPBS results (100.31 +/- 10.7 MPa) and the lowest values were obtained in RNC (23.63 +/- 9.0 MPa) for control group. SEM analyses showed that the surface topography of CAD/CAM restorative materials was modified after treatments. CONCLUSION: The surface treatment of sandblasting or HF acid etching in combination with a universal adhesive containing MDP can be suggested for the adhesive cementation of the novel CAD/CAM restorative materials. PMID- 29279764 TI - Effects of Hybrid Coat on shear bond strength of five cements: an in vitro study. AB - PURPOSE: To evaluate the sealing performance of Hybrid Coat and its influence on the shear bond strength of five dentin surface cements. MATERIALS AND METHODS: Six premolars were pretreated to expose the dentin surface prior to the application of Hybrid Coat. The microscopic characteristics of the dentinal surfaces were examined with scanning electron microscopy (SEM). Then, 40 premolars were sectioned longitudinally, and 80 semi-sections were divided into a control group (untreated) and a study group (treated by Hybrid Coat). Alloy restoration was bonded to the teeth specimen using five different cements. Shear bond strength was measured by the universal testing machine. The fracture patterns and the adhesive interface were observed using astereomicroscope. RESULTS: SEM revealed that the lumens of dentinal tubules were completely occluded by Hybrid Coat. The Hybrid Coat significantly improved the shear bond strength of resin-modified glass ionomer cement (RMGIC) and resin cement (RC) but weakened the performance of zinc phosphate cement (ZPC), zinc polycarboxylate cement (ZPCC) and glass ionomer cement (GIC). CONCLUSION: Hybrid Coat is an effective dentinal tubule sealant, and therefore its combined use with resin or resin-modified glass ionomer cements can be applied for the prostheses attachment purpose. PMID- 29279765 TI - Investigation of the cytotoxicity of thermoplastic denture base resins. AB - PURPOSE: The purpose of this study was to investigate the in vitro cytotoxicity of thermoplastic denture base resins and to identify the possible adverse effects of these resins on oral keratinocytes in response to hot water/food intake. MATERIALS AND METHODS: Six dental thermoplastic resin materials were evaluated: three polyamide materials (Smile tone, ST; Valplast, VP; and Luciton FRS, LF), two acrylic materials (Acrytone, AT; and Acryshot, AS), and one polypropylene resin material (Unigum, UG). One heat-polymerized acrylic resin (Vertex RS, RS) was chosen for comparison. After obtaining extracts from specimens of the denture resin materials (Phi=10 mm and d=2 mm) under different extraction conditions (37C for 24 hours, 70C for 24 hours, and 121C for 1 hour), the extracts (50%) or serial dilutions (25%, 12.5%, and 6.25%) in distilled water were co-cultured for 24 hours with immortalized human oral keratinocytes (IHOKs) or mouse fibroblasts (L929s) for the cytotoxicity assay described in ISO 10993. RESULTS: Greater than 70% viability was detected under all test conditions. Significantly lower IHOK and L929 viability was detected in the 50% extract from the VP (70C) and AT (121C) samples (P<.05), but only L929 showed reduced viability in the 50% and 25% extract from LF (37C) (P<.05). CONCLUSION: Extracts obtained from six materials under different extraction conditions (37C, 70C, and 121C) did not exhibit severe cytotoxicity (less than 70% viability), although their potential risk to oral mucosa at high temperatures should not be ignored. PMID- 29279766 TI - Evaluation of marginal and internal gap of three-unit metal framework according to subtractive manufacturing and additive manufacturing of CAD/CAM systems. AB - PURPOSE: To evaluate the fit of a three-unit metal framework of fixed dental prostheses made by subtractive and additive manufacturing. MATERIALS AND METHODS: One master model of metal was fabricated. Twenty silicone impressions were made on the master die, working die of 10 poured with Type 4 stone, and working die of 10 made of scannable stone. Ten three-unit wax frameworks were fabricated by wax up from Type IV working die. Stereolithography files of 10 three-unit frameworks were obtained using a model scanner and three-dimensional design software on a scannable working die. The three-unit wax framework was fabricated using subtractive manufacturing (SM) by applying the prepared stereolithography file, and the resin framework was fabricated by additive manufacturing (AM); both used metal alloy castings for metal frameworks. Marginal and internal gap were measured using silicone replica technique and digital microscope. Measurement data were analyzed by Kruskal-Wallis H test and Mann-Whitney U-test (alpha=.05). RESULTS: The lowest and highest gaps between premolar and molar margins were in the SM group and the AM group, respectively. There was a statistically significant difference in the marginal gap among the 3 groups (P<.001). In the marginal area where pontic was present, the largest gap was 149.39 +/- 42.30 um in the AM group, and the lowest gap was 24.40 +/- 11.92 um in the SM group. CONCLUSION: Three-unit metal frameworks made by subtractive manufacturing are clinically applicable. However, additive manufacturing requires more research to be applied clinically. PMID- 29279767 TI - 3-dimensional reconstruction of mandibular canal at the interforaminal region using micro-computed tomography in Korean. AB - PURPOSE: The purpose of this study was to identify the complex course of the mandibular canal using 3D reconstruction of microCT images and to provide the diagram for clinicians to help them understand at the interforaminal region in Korean. MATERIALS AND METHODS: Twenty-six hemimandibles obtained from cadavers were examined using microCT, and the images were reconstructed. At both the midpoint of mental foramen and the tip of anterior loop, the bucco-lingual position, the height from the mandibular inferior border, the horizontal distance between two points, and position relative to tooth site on the mandibular canal were measured. The angle that the mental canal diverges from the mandibular canal was measured in posteriorsuperior and lateral-superior direction. RESULTS: The buccal distance from the mandibular canal was significantly much shorter than lingual distance at both the mental foramen and the tip of anterior loop. The mandibular canal at the tip of anterior loop was significantly located closer to buccal side and higher than at the mental foramen. And the mental canal most commonly diverged from the mandibular canal below the first premolar by approximately 50 degrees posterior-superior and 41 degrees lateral-superior direction, which had with a mean length of 5.19 mm in front of the mental foramen, and exited to the mental foramen below the second premolar. CONCLUSION: These results suggest that it could form a hazardous tetrahedron space at the interforaminal region, thus, the clinician need to pay attention to the width of a premolar tooth from the mental foramen during dental implant placement. PMID- 29279768 TI - Oral health-related quality of life in patients with implant treatment. AB - PURPOSE: Patient-reported outcomes are increasingly commonly used as a method of evaluating treatments. This cross-sectional study aimed to evaluate implant treatment from the perspective of patient-reported outcomes. MATERIALS AND METHODS: Subjects were 804 patients who visited the Department of Oral Implantology at Osaka Dental University. The participants were categorized into a pre-implant group and a post-implant group. They were further categorized into five subgroups based on the number of occlusal supports provided by the remaining teeth according to the Eichner classification. The participants answered a basic questionnaire and the General Oral Health Assessment Index (GOHAI) questionnaire, an oral health-related quality of life (QOL) scale. GOHAI scores were compared according to the number of occlusal supports within each group and between the two groups. RESULTS: The results revealed a significant difference in terms of the number of occlusal supports within the pre-implant group; GOHAI scores decreased as the number of occlusal supports decreased (P<.001). However, no significant difference was observed in GOHAI scores in terms of the number of occlusal supports in the post-implant group (P>.05). GOHAI scores significantly improved in both pre- and post-implant groups in all occlusal support subgroups (P<.001). CONCLUSION: GOHAI scores decrease as occlusal support is lost. However, implant treatment performed in areas of loss improves the GOHAI score when occlusal support is restored. PMID- 29279769 TI - Biofilm formation on denture base resin including ZnO, CaO, and TiO2 nanoparticles. AB - PURPOSE: This laboratory study aimed to investigate the effect of doping an acrylic denture base resin material with nanoparticles of ZnO, CaO, and TiO2 on biofilm formation. MATERIALS AND METHODS: Standardized specimens of a commercially available cold-curing acrylic denture base resin material were doped with 0.1, 0.2, 0.4, or 0.8 wt% commercially available ZnO, CaO, and TiO2 nanopowder. Energy dispersive X-ray spectroscopy (EDX) was used to identify the availability of the nanoparticles on the surface of the modified specimens. Surface roughness was determined by employing a profilometric approach; biofilm formation was simulated using a monospecies Candida albicans biofilm model and a multispecies biofilm model including C. albicans, Actinomyces naeslundii, and Streptococcus gordonii. Relative viable biomass was determined after 20 hours and 44 hours using a MTT-based approach. RESULTS: No statistically significant disparities were identified among the various materials regarding surface roughness and relative viable biomass. CONCLUSION: The results indicate that doping denture base resin materials with commercially available ZnO, CaO, or TiO2 nanopowders do not inhibit biofilm formation on their surface. Further studies might address the impact of varying particle sizes as well as increasing the fraction of nanoparticles mixed into the acrylic resin matrix. PMID- 29279771 TI - Erratum: Comparison of retention forces with various fabrication methods and materials in double crowns. AB - [This corrects the article on p. 308 in vol. 9, PMID: 28874999.]. PMID- 29279770 TI - Dental biomaterials for chairside CAD/CAM: State of the art. AB - The wide use of chairside CAD/CAM restorations has increased the diversity of the restorative material. For the practitioner, the selection of the appropriate material is difficult amongst the variety offered by the market. Information on the characteristics of the products can be difficult to assess due to the lack of up-to-date classification and the lack of reliability of manufacturer's advertising. The purpose of this article is to structure the data on restorative materials provided by various sources in order for the practitioner to choose the product most suited to the clinical situation. The objective is to classify chairside CAD/CAM materials and to define their characteristics and indications. PMID- 29279772 TI - Combination of negative pressure wound therapy and systemic steroid therapy in postsurgical pyoderma gangrenosum after reduction mammoplasty; a case of proven efficacy and safety. PMID- 29279773 TI - Automatic CDR Estimation for Early Glaucoma Diagnosis. AB - Glaucoma is a degenerative disease that constitutes the second cause of blindness in developed countries. Although it cannot be cured, its progression can be prevented through early diagnosis. In this paper, we propose a new algorithm for automatic glaucoma diagnosis based on retinal colour images. We focus on capturing the inherent colour changes of optic disc (OD) and cup borders by computing several colour derivatives in CIE L*a*b* colour space with CIE94 colour distance. In addition, we consider spatial information retaining these colour derivatives and the original CIE L*a*b* values of the pixel and adding other characteristics such as its distance to the OD centre. The proposed strategy is robust due to a simple structure that does not need neither initial segmentation nor removal of the vascular tree or detection of vessel bends. The method has been extensively validated with two datasets (one public and one private), each one comprising 60 images of high variability of appearances. Achieved class-wise averaged accuracy of 95.02% and 81.19% demonstrates that this automated approach could support physicians in the diagnosis of glaucoma in its early stage, and therefore, it could be seen as an opportunity for developing low-cost solutions for mass screening programs. PMID- 29279774 TI - A novel white blood cells segmentation algorithm based on adaptive neutrosophic similarity score. AB - Background: White blood cells (WBCs) play a crucial role in the diagnosis of many diseases according to their numbers or morphology. The recent digital pathology equipments investigate and analyze the blood smear images automatically. The previous automated segmentation algorithms worked on healthy and non-healthy WBCs separately. Also, such algorithms had employed certain color components which leak adaptively with different datasets. Methods: In this paper, a novel segmentation algorithm for WBCs in the blood smear images is proposed using multi scale similarity measure based on the neutrosophic domain. We employ neutrosophic similarity score to measure the similarity between different color components of the blood smear image. Since we utilize different color components from different color spaces, we modify the neutrosphic score algorithm to be adaptive. Two different segmentation frameworks are proposed: one for the segmentation of nucleus, and the other for the cytoplasm of WBCs. Moreover, our proposed algorithm is applied to both healthy and non-healthy WBCs. in some cases, the single blood smear image gather between healthy and non-healthy WBCs which is considered in our proposed algorithm. Also, our segmentation algorithm is performed without any external morphological binary enhancement methods which may effect on the original shape of the WBC. Results: Different public datasets with different resolutions were used in our experiments. We evaluate the system performance based on both qualitative and quantitative measurements. The quantitative results indicates high precision rates of the segmentation performance measurement A1 = 96.5% and A2 = 97.2% of the proposed method. The average segmentation performance results for different WBCs types reach to 97.6%. Conclusion: In this paper, a method based on adaptive neutrosphic sets similarity score is proposed in order to detect WBCs from a blood smear microscopic image and segment its components (nucleus and the cytoplasm). The proposed segmentation algorithm can be utilized for fully-automated classification systems, such systems can be either for the healthy WBCs or even for non-healthy WBCs specially the leukemia cells. PMID- 29279775 TI - Functional characterization of a novel somatic oncogenic mutation of PIK3CB. AB - Class I phosphoinositide 3-kinase (PI3K) enzymes have attracted considerable attention as drug targets in cancer therapy over the last 20 years. The signaling pathway triggered by class I PI3Ks is dysregulated in a range of tumor types, impacting cell proliferation, survival and apoptosis. Frequent oncogenic mutations of PIK3CA have previously been discovered. In contrast, reports of PIK3CB mutations have been limited; however, in most cases, those that have been identified have been shown to be activating and oncogenic. The functional characterization of a PIK3CB catalytic domain mutant, p110betaE1051K, first discovered by others in castrate-resistant prostate cancer (mCRPC), is outlined in this report; our data suggest that p110betaE1051K is a gain-of-function mutation, driving PI3K signaling, tumorigenic cell growth and migration. Tumor cells expressing p110betaE1051K are sensitive to p110beta inhibition; its characterization as an oncogenic driver adds to the rationale for targeting p110beta and indicates a continuing need to further develop specific PI3K inhibitors for clinical development in cancer therapy. PMID- 29279776 TI - Adolescent Trajectories of Aerobic Fitness and Adiposity as Markers of Cardiometabolic Risk in Adulthood. AB - Purpose: The aim of this study was to investigate whether adolescent growth trajectories of aerobic fitness and adiposity were associated with mid-adulthood cardiometabolic risk (CMR). Methods: Participants were drawn from the Saskatchewan Growth and Development Study (1963-1973). Adolescent growth trajectories for maximal aerobic capacity (absolute VO2 (AbsVO2)), skinfolds (SF), representing total body (Sum6SF) and central adiposity (TrunkSF), and body mass index (BMI) were determined from 7 to 17 years of age. In mid-adulthood (40 to 50 years of age), 61 individuals (23 females) returned for follow-ups. A CMR score was calculated to group participants as displaying either high or a low CMR. Multilevel hierarchical models were constructed, comparing the adolescent growth trajectories of AbsVO2, Sum6SF, TrunkSF, and BMI between CMR groupings. Results: There were no significant differences in the adolescent development of AbsVO2, Sum6SF, TrunkSF, and BMI between adult CMR groupings (p > 0.05). Individuals with high CMR accrued 62% greater adjusted total body fat percentage from adolescence to adulthood (p=0.03). Conclusions: Growth trajectories of adolescent aerobic fitness and adiposity do not appear to be associated with mid adulthood CMR. Individuals should be encouraged to participate in behaviours that promote healthy aerobic fitness and adiposity levels throughout life to reduce lifelong CMR. PMID- 29279777 TI - Ornithine Transcarbamylase Deficiency: If at First You Do Not Diagnose, Try and Try Again. AB - Ornithine transcarbamylase (OTC) deficiency is well known for its diagnosis in the neonatal period. Presentation often occurs after protein feeding and manifests as poor oral intake, vomiting, lethargy progressing to seizure, respiratory difficulty, and eventually coma. Presentation at adulthood is rare (and likely underdiagnosed); however, OTC deficiency can be life-threatening and requires prompt investigation and treatment. Reports and guidelines are scarce due to its rarity. Here, we present a 59-year-old woman with a past history of irritable bowel syndrome who underwent a reparative operation for rectal prolapse and enterocele. Her postoperative course was complicated by a bowel perforation (which was repaired), prolonged mechanical ventilation, tracheostomy, critical illness myopathy, protein-caloric malnutrition, and altered mental status. After standard therapy for delirium failed, further investigation showed hyperammonemia and increased urine orotic acid, ultimately leading to the diagnosis of OTC deficiency. This case highlights the importance of considering OTC deficiency in hospitalized adults, especially during the diagnostic evaluation for altered mental status. PMID- 29279778 TI - Intraoperative Use of CBCT for Identification and Localization of Calcified Canals: A Clinical Technique. AB - Localization of calcified canals has always been a challenge in the field of endodontics. The following report of three cases describes a technique for the identification and negotiation of obliterated canals by use of cone beam computed tomography (CBCT) intraoperatively. Canal orifices could not be found clinically in all three cases. Gutta-percha points were placed and compacted at the position where the canal orifices were estimated to be. Intraoperative CBCT was taken, and the distance between the gutta-percha points and the canal orifices was calculated at all planes of space in the first two cases. In the third case, only one canal orifice could be identified due to obliteration of the other canals. PMID- 29279779 TI - Preeruptive Intracoronal Radiolucencies: Detection and Nine Years Monitoring with a Series of Dental Radiographs. AB - Preeruptive intracoronal radiolucencies (PEIRs) are mostly incidentally found by routine radiographic examination of unerupted teeth. PEIRs are classified into two types according to the nature of the lesion: progressive and nonprogressive. A case report of a 17-year-old boy with a nonprogressive PEIR on the permanent mandibular left second molar is presented. The lesion was initially detected on an unerupted tooth at age eight years, eight months. It was clinically and radiographically assessed yearly. Cone beam computed tomography (CBCT) was used to evaluate the lesion's size and location when the patient was 11 and 14 years old. The assessments confirmed that the lesion was nonprogressive and had no connection to the pulp or oral cavity. Due to the static nature of the detected PEIR during the nine-year follow-up period, the patient's low caries-risk status, and high patient and parental cooperation in periodic dental care, it was decided to place resin sealant on the affected tooth and monitor the lesion without any operative treatment. PMID- 29279780 TI - Locked Central Fracture Dislocation of the Hip in a Child after Low-Energy Trauma. AB - We present the case of a 13-year-old boy who sustained a locked central fracture dislocation of the right acetabulum following a bicycle fall. Immediate external reduction maneuvers under general anesthesia were unsuccessful due to intrapelvic entrapment of the femoral head. Open reduction internal fixation was achieved 48 hours later. After an initial satisfactory postoperative course, the patient ended up developing severe hip osteoarthritis 16 months after the procedure. The rarity of this injury in children is discussed, with its possible implications on joint congruity and potential growth injury. PMID- 29279781 TI - Thyroid Carcinoma on the Side of the Absent Lobe in a Patient with Thyroid Hemiagenesis. AB - Background: Thyroid carcinoma complicated by hemiagenesis is very rare, and previous reports have not described this cancer on the side of the absent lobe. Methods and Results: We report the case of a 64-year-old woman in whom left thyroid hemiagenesis was discovered incidentally during investigations of abnormal sensation during swallowing. A tumorous 1.4 cm lesion was also found on the side of the absent lobe, left of the isthmus. Fine-needle aspiration biopsy revealed class V papillary carcinoma, but no lymph node metastases. Total thyroidectomy was performed for stage cT1bN0M0 carcinoma. Histopathology revealed normal thyroid tissues in the right lobe and isthmus, while the left lobe was absent. The mostly papillary carcinoma was adjacent to the truncated thyroid tissue, with a portion histologically consistent with poorly differentiated carcinoma. Conclusions: All previously reported cases of thyroid cancer complicated by hemiagenesis have represented carcinoma occurring within the present lobe. This case is extremely rare. PMID- 29279782 TI - A Singleton Infant with Bilateral Renal Agenesis and Normal Pulmonary Function. AB - Bilateral renal agenesis leads to anhydramnios and other sequelae including pulmonary hypoplasia. There have been rare case reports of normal pulmonary function in the presence of bilateral renal agenesis in monoamniotic discordant twins, but this has never been reported in a singleton pregnancy. The few reported cases in twins have all been fatal in the neonatal period with no reported cases of survival beyond 2 months. We describe the first case of a singleton infant with bilateral renal agenesis who had normal pulmonary function and did well on peritoneal dialysis for 4 years while awaiting a renal transplant. PMID- 29279783 TI - Coprophagia in an 8-Year-Old Hospitalized Patient: A Case Report and Review of the Literature. AB - Consult-liaison psychiatrists often encounter difficult clinical scenarios. We present a pediatric case of presumptive coprophagia. After a negative medical work-up, the pediatrics team asked psychiatry to assist them in managing this relatively rare disorder in the hospital setting. Little is known about the etiology and treatment of coprophagia in the pediatric population. Using the case as a catalyst, we discuss what is known about this disorder as well as treatment strategies in the hospital setting. PMID- 29279784 TI - Endovascular Repair of Aortobronchial Fistula due to Saccular Aneurysm of Thoracic Aorta. AB - Aortobronchial fistula (ABF) is a rare condition which can be lethal if left untreated. Open surgical treatment carries high morbidity and mortality. Recent advances in endovascular technology have made thoracic endovascular aortic repair (TEVAR) the treatment of choice. We present a successful endovascular repair of aortobronchial fistula due to a saccular aneurysm of descending thoracic aorta. PMID- 29279785 TI - Leptospira Seroprevalence in Domestic Dogs and Cats on the Caribbean Island of Saint Kitts. AB - Leptospirosis is an important bacterial zoonotic disease that affects humans and many animal species. Knowledge of prevalence of Leptospira in a given geographic region supports the implementation of effective control/prevention programmes and thus reduces the transmission risks. This study provides Leptospira seroprevalence and serovar distribution in dogs and cats on the Caribbean island of Saint Kitts. Convenient serum samples from domestic dogs (n = 101) and cats (n = 50) were tested by the microscopic agglutination test (MAT) using 21 Leptospira serovars belonging to 17 serogroups. Seroprevalence was recorded at 73.2% in dogs (95% confidence interval CI: 62.5-80.1%). Agglutinating antibodies to Leptospira were present against 13 of the 21 serovars tested by MAT. The highest seroprevalence was observed for serovar Autumnalis (56.4%) followed by Icterohaemorrhagiae (27.7%), Canicola (17.8%), Djasiman (14.9%), Bratislava (11.9%), Pyrogenes (11.9%), and Pomona (7.9%). A very low seroprevalence (4%, 95% CI: 0.5-14%) was observed in cats. This data confirms that dogs in Saint Kitts have a high-level exposure to a diverse set of Leptospira serovars. PMID- 29279786 TI - Studies on Chemical Composition and Antioxidant Activity of Rudbeckia triloba. AB - The paper describes the physicochemical studies made on the decorative plant, Rudbeckia triloba (Asteraceae). For this purpose, essential oil, infusion, decoction, and hydroalcoholic macerate obtained from different aerial parts of Rudbeckia triloba were analyzed. The main phytochemical constituents identified by GC-MS analysis were found to be alpha-pinene (in dried leaves (46.0%) and flowers (40.1%)) and beta-phellandrene (in essential oil of dried inflorescences (26.09%)). The Folin-Ciocalteu and quercetin assays revealed different values of total phenolic and flavonoid contents of petals, leaves, and seeds as a function of the solvent used and extraction procedure. The hydroalcoholic macerate of petals was found to present the maximum phenolic and flavonoid contents (130.29 +/- 5.58 mg gallic acid equivalent/g dry vegetable material and 30.72 +/- 1.35 mg quercetin equivalent/g dry vegetable material, resp.) and also exhibits the lower value of EC50 (0.32% (v/v)), obtained by applying the DPPH. assay. Comparing the extraction methods applied, the maceration was found to be the most effective for phenolic compounds, most likely due to the solvent (70% ethanol). The use of water-alcohol mixture leads to an improvement of the extraction yield of phenolic compounds (including those with higher molecular weights) than by using water as extractive solvent, in the case of infusions and decocts. PMID- 29279788 TI - Diet, Lung Function, and Asthma Exacerbations in Puerto Rican Children. AB - Changes in dietary patterns may partly explain the epidemic of asthma in industrialized countries. The objective of this study was to examine the relationship between dietary patterns and lung function and asthma exacerbations in Puerto Rican children. This is a case-control study of 678 Puerto Rican children (ages 6-14 years) in San Juan (Puerto Rico). All participants completed a respiratory health questionnaire and a 75-item food frequency questionnaire. Food items were aggregated into 7 groups: fruits, vegetables, grains, protein, dairy, fats, and sweets. Logistic regression was used to evaluate consumption frequency of each group and asthma. Based on the results, a dietary score was created [range from -2 (unhealthy diet: high consumption of dairy and sweets, low consumption of vegetables and grains) to 2 (healthy diet: high consumption of vegetables and grains and low consumption of dairy and sweet)]. Multivariable linear or logistic regression was used to assess the relationship between dietary score and lung function or asthma exacerbations. After adjustment for covariates, a healthier diet (each 1-point increment in dietary score) was associated with significantly higher %predicted forced expiratory volume in the first second (FEV1) and %predicted forced vital capacity (FVC) in control subjects. Dietary pattern alone was not associated with asthma exacerbations, but children with an unhealthy diet and vitamin D insufficiency (plasma 25(OH)D <30 ng/mL) had higher odds of >=1 severe asthma exacerbation [odds ratio (OR) = 3.4, 95% confidence interval (CI) = 1.5-7.5] or >=1 hospitalization due to asthma (OR = 3.9, 95% CI = 1.6-9.8, OR = 3.4, 95% CI = 1.5-7.5) than children who ate a healthy diet and were vitamin D sufficient. A healthy diet, with frequent consumption of vegetables and grains and low consumption of dairy products and sweets, was associated with higher lung function (as measured by FEV1 and FVC). Vitamin D insufficiency, together with an unhealthy diet, may have detrimental effects on asthma exacerbations in children. PMID- 29279787 TI - Acute Chest Syndrome in Children with Sickle Cell Disease. AB - Acute chest syndrome (ACS) is a frequent cause of acute lung disease in children with sickle cell disease (SCD). Patients may present with ACS or may develop this complication during the course of a hospitalization for acute vaso-occlusive crises (VOC). ACS is associated with prolonged hospitalization, increased risk of respiratory failure, and the potential for developing chronic lung disease. ACS in SCD is defined as the presence of fever and/or new respiratory symptoms accompanied by the presence of a new pulmonary infiltrate on chest X-ray. The spectrum of clinical manifestations can range from mild respiratory illness to acute respiratory distress syndrome. The presence of severe hypoxemia is a useful predictor of severity and outcome. The etiology of ACS is often multifactorial. One of the proposed mechanisms involves increased adhesion of sickle red cells to pulmonary microvasculature in the presence of hypoxia. Other commonly associated etiologies include infection, pulmonary fat embolism, and infarction. Infection is a common cause in children, whereas adults usually present with pain crises. Several risk factors have been identified in children to be associated with increased incidence of ACS. These include younger age, severe SCD genotypes (SS or Sbeta0 thalassemia), lower fetal hemoglobin concentrations, higher steady state hemoglobin levels, higher steady-state white blood cell counts, history of asthma, and tobacco smoke exposure. Opiate overdose and resulting hypoventilation can also trigger ACS. Prompt diagnosis and management with intravenous fluids, analgesics, aggressive incentive spirometry, supplemental oxygen or respiratory support, antibiotics, and transfusion therapy, are key to the prevention of clinical deterioration. Bronchodilators should be considered if there is history of asthma or in the presence of acute bronchospasm. Treatment with hydroxyurea should be considered for prevention of recurrent episodes. This review evaluates the etiology, pathophysiology, risk factors, clinical presentation of ACS, and preventive and treatment strategies for effective management of ACS. PMID- 29279789 TI - Asthma Screening in Pediatric Sickle Cell Disease: A Clinic-Based Program Using Questionnaires and Spirometry. AB - A clinician diagnosis of asthma is associated with increased morbidity and mortality in people with sickle cell disease (SCD). We hypothesized that a screening program would help identify children with asthma needing referral to pulmonary clinic. We conducted a single-center project to screen patients with SCD for asthma using a previously validated questionnaire (Breathmobile) and for pulmonary function abnormalities with portable spirometry. Participants with a positive questionnaire and/or abnormal spirometry were referred to pediatric pulmonary clinic. We evaluated clinical associations with abnormal spirometry and questionnaire responses. Of the 157 participants, 58 (37%) had a positive asthma screening questionnaire. Interpretable spirometry was available for 105 (83% of those eligible) and of these, 35 (34%) had abnormal results. The asthma questionnaire was 87.5% sensitive [95% confidence interval (CI) 74.8-95.3] and 85.3% specific (95% CI 77.3-91.4) to detect a clinician diagnosis of asthma. Participants with positive questionnaires were older (mean age 12.2 vs. 9.9 years, P = 0.012). Spirometry identified 16 additional participants who had normal asthma questionnaires. Seventy-four participants (47%) were referred to pediatric pulmonary clinic and 25 (34%) of these participants scheduled clinic appointments; however, only 13 (52%) were evaluated in pulmonary clinic. Clinic based asthma screening and spirometry frequently identified individuals with asthma and pulmonary function abnormalities. Only 22% of those referred were eventually seen in pulmonary clinic. The impact of improved screening and treatment on the pulmonary morbidity in SCD needs to be defined and is an area for future investigation. In addition, case management or multidisciplinary clinics may enhance future screening programs. PMID- 29279790 TI - Developing a Mobile Health Intervention for Low-Income, Urban Caregivers of Children with Asthma: A Pilot Study. AB - Objective: This pilot study explored the initial feasibility and efficacy of providing feedback to low-income, urban caregivers of children with persistent asthma about their daily experiences reported via ecological momentary assessment (EMA) on caregiver emotional health (quality of life, perceived stress, and positive affect). Methods: Data were collected from 28 caregivers and their children (7-12 years). Caregivers completed a baseline session, 14 days of EMA surveys via smartphone, and were randomized to intervention or control groups. The intervention group received individualized EMA feedback regarding areas of daily life that may be making it harder to manage child asthma. The control group received information on general child health. Caregivers completed assessments 4 weeks and 4 months postintervention. Results: In the EMA group, caregivers experienced an increase in perceived stress from baseline to postintervention, but a decrease in perceived stress from postintervention to follow-up. There were no significant changes in outcome measures for the control group. Conclusion: Preliminary findings suggest that providing caregivers with feedback from daily assessments may reduce stress, which could be targeted in future mobile health interventions for low-income, urban families of children with asthma. PMID- 29279791 TI - Pulmonary Mycobacterium Avium-Intracellulare Complex Infection in an Infant: A Silent and Coincidental Finding. AB - An 11-month-old healthy infant girl was noted to have left lower lobe (LLL) opacities on chest X-ray (CXR) after developing desaturations during an elective cochlear implant surgery. Repeat CXR 10 days later revealed hyperexpansion of the left lung and persistent LLL opacity. Chest computerized tomography revealed enlarged mediastinal lymph nodes, left mainstem bronchial obstruction, and nodular opacities. Bronchoscopic biopsy of the endobronchial tissue revealed multiple necrotizing granulomas and grew Mycobacterium avium-intracellulare, Streptococcus viridans, and Actinomyces odontolyticus. This case illustrates the potential for significant mediastinal lymphadenopathy, and endobronchial and parenchymal lesions caused by nontuberculous mycobacteria, which can present insidiously and without respiratory symptoms in otherwise healthy infants, despite advanced pulmonary disease. PMID- 29279792 TI - Personalized Medicine in Preschool Children with Asthma. AB - A growing body of literature has investigated optimizing asthma management by identifying phenotypes and biomarkers to guide the treatment. In particular, management of asthma in preschool children remains challenging due to different phenotype presentation in early life. The focus of this review is to summarize the recent data on personalized medicine in management of preschool children with wheezing. PMID- 29279793 TI - First cephalosomatic anastomosis in a human model. AB - Background: Cephalosomatic anastomosis (CSA) has never been attempted before in man as the transected spinal cords of the body donor and body recipient could not be "fused" back together. Recent advances made this possible. Here, we report on the surgical steps necessary to reconnect a head to a body at the cervical level. Methods: Full rehearsal of a CSA on two recently deceased human cadavers was performed at Harbin Medical University, Harbin, China. Results: The surgery took 18 hours to complete within the time frame planned for this surgery. Several advances resulted from this rehearsal, including optimization of the surgical steps, sparing of the main nerves (phrenics, recurrent laryngeal nerves), and assessment of vertebral stabilization. Conclusion: Several specialties are involved in a full-scale CSA, including neck surgery, vascular surgery, orthopedic surgery, plastic surgery, gastrointestinal surgery, and neurosurgery, as well as the operating staff. This rehearsal confirmed the surgical feasibility of a human CSA and further validated the surgical plan. Education and coordination of all the operating teams and coordination of the operative staff was achieved in preparation for the live human CSA. PMID- 29279794 TI - Surgical nuances of partial sacrectomy for chordoma. AB - Background: Sacral chordomas are rare, slow growing, locally aggressive tumors. Unfortunately, aggressive surgical resection is often associated with increased neurological morbidity. Methods: This technical note focuses on the utilization of partial sacrectomy for the resection of complex spinal chordomas. Results: The case presented documents the potential range of postoperative morbidity seen in patients undergoing partial sacrectomy for chordomas. Despite iatrogenic morbidity and tumor recurrence, with the cooperation of medical and surgical spine specialists, majority of patients can achieve good long-term outcomes. Conclusions: Sacral chordomas are rare lesions and pose a therapeutic challenge for spinal surgeons and oncologists. En-bloc surgical resection (e.g., partial sacrectomy) is the treatment of choice for these lesions, and the cooperation between subspecialists can lead to good neurologic outcomes, particularly if gross total resection is achieved. PMID- 29279795 TI - Primary intracranial leiomyosarcoma presenting with massive peritumoral edema and mass effect: Case report and literature review. AB - Background: Primary intracranial leiomyosarcomas (LMSs) are unusual tumors of the central nervous system (CNS) affecting all age groups, and are recently, becoming more prevalent in immunosuppressive conditions such as in patients with human immunodeficiency virus (HIV) infection. However, only a few CNS LMS case reports exist in the English literature, on the occurrence of this rare entity in immunocompetent adults. Even, rarer is a purely intraparenchymal occurrence without any dural attachment in afflicted individuals. To the best of our knowledge, only four such cases have been reported in the literature until now. None of these cases were associated with marked peritumoral brain edema (PTBE) and mass effect as seen in our case and falsely suggesting an underlying glioma. Case Description: A 45-year-old male patient, presented with headache, right sided weakness and difficulties with speech over 4 months along with a single generalized tonic clonic seizure. Physical examination revealed mild to moderate papilledema, motor aphasia, and right-sided hemiparesis. Radiographic evaluation showed a large left temporo-parietal mass extending into the basal ganglia with intense heterogeneous contrast enhancement. There was marked perilesional edema and mass effect with midline shift. The patient underwent a left temporo-parietal craniotomy for subtotal resection of the tumor. The post-operative period was uneventful. Histopathology revealed a spindle cell tumor, which stained immunopositive for smooth muscle actin, vimentin, and S-100, yielding the diagnosis of LMS. Conclusion: Primary intracranial LMS can rarely occur in immuno competent adult patients and should be considered in the differential diagnosis of intraparenchymal lesions presenting with significant PTBE. PMID- 29279796 TI - Calcification in original plaque and restenosis following carotid artery stenting. AB - Background: The relationship between calcification in primary plaque and recurrent stenosis after carotid artery stenting (CAS) is not established, but an inverse association with restenosis following carotid endarterectomy (CEA) has been suggested. Methods: We retrospectively analyzed 75 plaques of 109 consecutive CAS with regard to calcification, using the calcium score and shape, location, and other characteristics of original plaques together with stenting related factors. CAS was performed in a standard fashion with an embolic protection device. Greater-than-moderate restenosis (>=50%) was assessed by peak systolic velocity (PSV) with duplex ultrasonography (>=130 cm/s, internal/common carotid or distal/proximal PSV ratio >=2.0). Results: Univariate analysis revealed percentages of dyslipidemia treated with statins (P = 0.03), calcification in distal ICA (P = 0.02), and immediate residual stenosis (P = 0.02) were significantly higher in patients with greater-than-moderate restenosis, whereas calcification in carotid bulb and usage of open-cell stent were rather less frequent (P < 0.001 and P = 0.02, respectively). Multivariate logistic regression analysis showed that rarity of calcification in carotid bulb was a sole independent predictor for greater-than-moderate recurrent carotid stenosis 1 year after CAS (OR = 0.21, CI = 0.06-0.77, P = 0.02). Conclusions: Calcium score was not significantly related to restenosis at 1 year after CAS, as was previously found following CEA, though scarcity of calcification in carotid bulb was suggested as a predictor of in-stent restenosis. Compared to post-CEA restenosis, carotid plaque calcification may be inversely but tenuously associated with recurrent stenosis 1 year post-CAS. No other stenting factors (e.g., stent design, pre-/post-dilation, or protection devices) showed a significant association with recurrent stenosis post-CAS. PMID- 29279797 TI - Dual floor burr hole technique in deep brain stimulation: A retrospective study on 209 patients. AB - Background: Skin erosion/infections due to deep brain stimulation hardware are highly worrisome complications. They can lead to the removal of the entire deep brain stimulation device, and consequently hold the whole treatment in otherwise pharmacologically refractory patients. Several techniques have been used such as C-shape skin incision and dual floor burr hole or single passage of connecting cables to reduce the incidence of skin complications. Methods: In this paper, we describe our experience in 209 patients using a dual-floor burr hole technique to reduce skin adverse effects. Conclusion: The dual floor burr hole technique is a safe technique with a low incidence of skin erosions and complications. PMID- 29279798 TI - A giant pseudoaneurysm of the occipital artery. AB - Background: Pseudoaneurysms of the occipital artery (OA) are extremely rare and can occur following head trauma or iatrogenic injury; OA anatomy seems to play a crucial role in their pathogenesis. Case Description: This report describes the case of a 76-year-old patient with a giant OA pseudoaneurysm secondary to a head injury the patient had sustained 1 month earlier. After radiological confirmation via ultrasonography (US) and computed tomography angiography (CTA), the patient underwent surgery for resection of the lesion. An uneventful postoperative course with no recurrence was confirmed at 1 and 2-month follow-up visits. Conclusions: Despite their rarity, pseudoaneurysms of the OA should be considered in the differential diagnosis of patients presenting with an occipital pulsatile mass. Prompt management reduces the risk of a serious hemorrhage. In our case, considering the size of the lesion, surgical resection seemed to be the only reasonable option. PMID- 29279799 TI - Prediction of 30-day mortality in spontaneous cerebellar hemorrhage. AB - Background: Cerebellar hemorrhage is a potentially life-threatening condition and an understanding of the factors influencing outcome is essential for sound clinical decision-making. Methods: We retrospectively evaluated data from 50 consecutive patients who suffered a first spontaneous cerebellar hemorrhage (SCH) from 2005 to 2014, analysing their short-term outcomes and identifying possible clinical, radiological and therapeutic risk factors for poor prognosis and death within 30 days. Results: Among 50 patients with first SCH, the mean age was 72 +/ 10 years. Median Glasgow Coma Scale (GCS) score on admission was 11 [interquartile range (IQR) = 7-11]. Among 50 patients, 19 patients (38%) underwent surgical hemorrhage evacuation with placement of an external ventricular drain (EVD), 12 patients (24%) received an EVD only and 19 patients (38%) were treated conservatively. The 30-day mortality rate was 36%. In multivariate analysis only the GCS score on admission was a significant predictor of 30-day mortality [odds ratio (OR) = 0.598; 95% confidence interval (CI) = 0.406-0.879; P = 0.009]. For prediction of 30-day mortality, receiver operating characteristic curve analysis confirmed that the best cut-off point was a GCS score of 10 on admission [area under the curve: 0.882, 95% CI = 0.717-1, P < 0.001]. Conclusion: Lower GCS score on admission was associated with increased 30 day mortality and poorer short-term outcome in patients with SCH. For patients with a GCS score <10 on admission, it is important to balance the possibility of survival afforded by further therapy against the formidable risk of significant functional disability and poor quality of life. PMID- 29279800 TI - Closed therapy of thoracic and lumbar vertebral body fractures in trauma patients. AB - Background: The failure rate for the closed/non-surgical treatment of thoracic and lumbar vertebral body fractures (TLVBF) in trauma patients has not been adequately evaluated utilizing computed tomography (CT) studies. Methods: From 2007 to 2008, consecutive trauma patients, who met inclusion criteria, with a CT diagnosis of acute TLVBF undergoing closed treatment were assessed. The failure rates for closed therapy, at 3 months post-trauma, were defined by progressive deformity, vertebral body collapse, or symptomatic/asymptomatic pseudarthrosis. The Arbeitsgemeinschaft fur Osteosynthesefragen (AO) classification was utilized to classify the fractures (groups A1 and non-A1 fractures) and were successively followed with CT studies. Results: There were 54 patients with 91 fractures included in the study; 66 were A1 fractures, and 25 were non-A1 fractures. All had rigid bracing applied with flat and upright X-ray films performed to rule out instability. None had sustained spinal cord injuries. Thirteen patients (24%) failed closed therapy [e.g. 13 failed fractures (14%) out of 91 total fractures]. Five failed radiographically only (asymptomatic), and eight failed radiographically and clinically (symptomatic). A1 fractures had a 4.5% failure rate, while non-A1 fractures failed at a rate of 40%. Conclusion: Failure of closed therapy for TLVBF in the trauma population is not insignificant. Non-A1 fractures had a much higher failure rate when compared to A1 fractures. We recommend close follow-up particularly of non-A1 fractures treated in closed fashion using successive CT studies. PMID- 29279802 TI - Reconstructing the severed spinal cord. PMID- 29279801 TI - Technical factors affecting outcomes following endovascular treatment of posterior circulation atherosclerotic lesions. AB - Background: Atherosclerotic disease of the vertebrobasilar system causes significant morbidity and mortality. All lesions require aggressive medical management, but the role of endovascular interventions remains unsettled. This study examines such endovascular interventions for vertebrobasilar atherosclerosis. Methods: Retrospective review was performed of prospectively maintained procedure logs at three hospitals with comprehensive neurointerventional services. Patients with angiographically-proven stenosis undergoing elective stent placement were selected for analysis of demographic factors, lesion characteristics, and treatment details. Multivariate analysis was performed to evaluate for associations with ischemic stroke, death, and functional status as measured by modified Rankin scale at multiple intervals. Results: One hundred and twenty-three lesions were treated in 110 patients. A total of 43 (58.1%) lesions caused stroke, while 66 (89.2%) caused transient ischemic attacks (TIAs). Forty lesions (32.5%) were at the vertebral origin; 97 (60.2%) were intracranial. A total of 112 (91.1%) were treated successfully. 4 (3.3%) of 10 (8.1%) procedural complications were symptomatic. Intracranial lesions were associated with death at 1 and 2 years (OR 24.91, P < 0.001) and mRS >2 at last contact (OR 12.83, P < 0.001). Stenting treatment with conjunctive angioplasty had lower rates of death (OR 0.303, P = 0.046) and mRS >2 at last contact (OR 0.234, P = 0.018) when angioplasty was performed with a device other than that packaged with the stent. Conclusion: Endovascular treatment of vertebrobasilar atherosclerosis can be performed safely, particularly for vertebral origin lesions. Higher rates of technical failure and complication may be acceptable for certain intracranial lesions due to their refractory nature and the morbidity caused by such lesions. Treatment should be tailored to features of each individual lesion. PMID- 29279803 TI - Wound-Healing Potential of Oil of Hypercium perforatum in Excision Wounds of Male Sprague Dawley Rats. AB - Objective: To evaluate the wound-healing activity of oil of Hypercium perforatum (St. John's wort), in excision wounds of male white rats. Approach: The current methods of wound management involve the use of antibiotic creams. The search for more natural materials for the purpose of healing of wounds has led to the discoveries of potential agents prepared from plant extracts. Hyperforin and Hypericin are important phytochemical constituents found in H. perforatum, which have been highlighted for their antimicrobial, antiviral, and anti-inflammatory properties in recent times. Therefore, we have attempted to explore the wound healing activity of oil obtained from H. perforatum.Results:H. perforatum oil emulsion has been demonstrated to have significant wound-healing potential as compared with mupirocin ointment and petroleum jelly (Vaseline). Animals treated with H. perforatum showed a 97% (18.9 mm2/day) reduction in wound area as compared with animals treated with mupirocin (68%) (12.8 mm2/day) and animals treated with Vaseline (69%) (13.7 mm2/day). X-ray analysis of skin of animals treated with H. perforatum showed a significant increase in angiogenesis as compared with other groups in the study. Innovation: This study identified the wound-healing activity of oil of H. perforatum.Conclusion: The findings of this study support the wound-healing potential of H. perforatum along with other therapeutic uses. PMID- 29279804 TI - A Comparison of the Effects of Topical Prolavacid Solution (a Polyhexamethylene Biguanide-Based Wound Cleanser) and Medihoney Ointment in a Rat Model of Cutaneous Wound. AB - Objective: This experimental work examined the healing effect and probable adverse impact of topical Prolavacid(r) solution (a polyhexamethylene biguanide based wound cleanser) and topical Medihoney ointment in an animal model of cutaneous wound. Approach: We randomly divided 22 adult Sprague-Dawley rats (all were male) in two groups (n = 11): (1) those for which Prolavacid solution was poured on the skin wound surface; and (2) those animals for which Medihoney(r) ointment was applied to the wounds. These two agents were applied daily throughout the study period (21 days). We photographically followed the wounds' contraction with imaging performed on days 0, 7, and 21 postwounding. The histopathologic features of the healing wounds were evaluated using skin biopsies taken on days 7 and 21 postwounding. Results: The difference in mean wound surface area between two groups was not statistically significant on the examined days. Histopathological assessment indicated no statistically significant difference between the Prolavacid- and Medihoney-treated groups on days 7 and 21. We did not detect tissue necrosis following the topical application of Prolavacid solution. Innovation: This was the first study to examine the efficacy and probable adverse consequences of topical Prolavacid on cutaneous wound healing process. Conclusion: Our work showed no statistically significant difference between the efficacy of daily topical application of Prolavacid and Medihoney products on the healing process of fresh cutaneous wounds in our rat model. PMID- 29279805 TI - A Low-Cost Technique for Intraoperative Imaging of Cell Delivery and Retention in a Model of Delayed Wound Healing. AB - Objective: Techniques to validate successful delivery of cell products are expensive, time-consuming, and require transport of the animal to imaging facilities, preventing their widespread use as documentation tools. The goal of this study was to determine if a low-cost portable microscope could provide sufficient performance to be used to document delivery of cell products and track retention over time. Approach: A Dino-Lite fluorescence microscope and an Odyssey CLx whole-animal scanner were compared on the basis of resolution, sensitivity, and linearity. The impact of different injection profiles on image quality was also compared and the system was used to track cells, injected freely or on scaffolds, in a model of diabetic wound healing. Results: Both systems were able to detect 50 fluorescently labeled cells and there was a linear relationship between the fluorescence signal and cell number in vitro. In vivo, both systems were found to be nonlinear, but highly correlated with one another. The Dino-Lite system was able to distinguish between depth of injection, diffuse injections, subcutaneous injections, and failed injections. Innovation: In contrast to traditional imaging systems, the technique presented here is affordable, rapid enough that it can be used to validate every injection, and can be brought to the animal, reducing handling and stress that may interfere with wound healing processes. Conclusion: Collectively, we found that the speed, affordability, and portability of handheld microscopes combined with their technical capabilities make them a valuable and accessible tool for routine validation, documentation, and tracking of cell products delivered to wounds. PMID- 29279806 TI - Incisional Negative-Pressure Wound Therapy for Perineal Wounds After Abdominoperineal Resection for Rectal Cancer, a Pilot Study. AB - Objective: Abdominoperineal resection (APR) is associated with high incidence of surgical wound infections. The use of incisional negative-pressure wound therapy (iNPWT) is known to reduce wound infections for several surgical indications. The aim of this pilot study was to investigate the potential of a new portable negative-pressure therapy device on perineal wound healing in patients undergoing APR. Approach: A new single-use incisional negative-pressure therapy device was applied in 10 patients. A negative pressure of -80 mmHg was continued for 7 days postsurgery. Incidence of wound complications and time to wound healing were compared with a historical control group of 10 patients undergoing APR in 2014, treated with conventional wound care. Results: Patient characteristics were comparable in both groups. Mean 1.6 dressings were used per patient. A wound complication was diagnosed in seven patients versus six in the control group. Wound infections were diagnosed median 11.5 days after surgery, compared with 10.5 days in the control group. Duration of wound healing was shorter in the study group (median 8.5 weeks vs. 13 weeks). Innovation: This is the first study to report on the use of this iNPWT device for patients who underwent APR for rectal cancer. Conclusion: In this study, iNPWT did not reduce wound complications. Wound infections occurred slightly later and seemed to have a less severe clinical course. After treatment with iNPWT, the duration of wound healing was shorter. PMID- 29279807 TI - An Autologous Anti-Inflammatory Protein Solution Yielded a Favorable Safety Profile and Significant Pain Relief in an Open-Label Pilot Study of Patients with Osteoarthritis. AB - Osteoarthritis (OA) is a progressive and degenerative disease, which may result in significant pain and decreased quality of life. Recent updates in our understanding of OA have demonstrated that it is a whole joint disease that has many similarities to an unhealed wound containing inflammatory cytokines. The nSTRIDE Autologous Protein Solution (APS) Kit is a medical device under development for the treatment of OA. The APS Kit processes a patient's own blood at the point of care to contain high concentrations of anti-inflammatory cytokines and anabolic growth factors. This study assessed the safety and treatment effects of a single intra-articular injection of APS. Eleven patients were enrolled in this study. Sufficient blood could not be drawn from one patient who was subsequently withdrawn, leaving 10 patients treated. Minor adverse events (AEs) were experienced by seven subjects (63.6%). There was one serious AE (diverticulitis) unrelated to the device or procedure. One subject experienced AEs that were judged "likely" to be procedure related (arthralgia/musculoskeletal discomfort) and all resolved within 6 days of injection. All other AEs were unrelated to the device or procedure. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores improved significantly over time (ANOVA, p < 0.0001, 12.0 +/- 1.2 preinjection, 3.3 +/- 2.9 one year postinjection, and 72.5% WOMAC pain improvement). There was significant positive correlation between white blood cell concentration in APS and improvement in WOMAC pain scores. PMID- 29279808 TI - Anaplastic Carcinoma of the Pancreas: A Rare Clinical Entity. AB - Anaplastic carcinoma of the pancreas (ACP) is a very rare histologic subtype of pancreatic cancer and associated with more aggressive and poor prognosis than pancreatic ductal adenocarcinoma. We aimed to review this rare entity and discuss its clinical features, diagnosis and therapy. We presented a case of a 63-year old male patient that diagnosed as ACP with cyst formation at a tertiary medical center with a detailed review of the current medical literature. We performed pancreaticoduodenectomy operation with lymph node dissection after diagnosis. Any complication after surgery was not observed. Anaplastic pancreas carcinomas are associated with poor survival when compared to invasive ductal adenocarcinomas. Clinical, radiological, laboratory and histological features may be helpful in making differential diagnosis and should be kept in mind in the diagnosis of this rare pancreatic malignancy. PMID- 29279809 TI - Duplication of the Sphenomandibular Ligament. AB - The normal origin of attachment of the sphenomandibular ligament is from the spine of the sphenoid bone and derailment of its course might interfere with mandibular nerve anesthetic blockade. During routine dissection of the skull base and mandibular region, a case of an anatomical variation of the sphenomandibular ligament was observed. The ligament was found to be composed of two parts; an anterior part with a wide origin from the spine of the sphenoid bone and a posterior part arising from the mandibular fossa of the temporal bone. This case and related literature were reviewed. To our knowledge, a split sphenomandibular ligament has not been previously reported. Such a variation should be kept in mind by oral surgeons and dentists during procedures in this area such as inferior alveolar nerve anesthetic blockade. PMID- 29279810 TI - Role of Concurrent Systemic Therapy with Adjuvant Radiation Therapy for Locally Advanced Cutaneous Head and Neck Squamous Cell Carcinoma. AB - Objective To evaluate the role of concurrent systemic therapy to postoperative radiation therapy (RT) for locally advanced cutaneous head and neck squamous cell carcinoma (LA-cHNSCC). Materials and methods A retrospective study of 32 patients with LA-cHNSCC receiving postoperative RT with and without systemic therapy was conducted. Patients with LA-cHNSCC after surgical resection with one or more high risk features were evaluated. Local regional control (LRC), distant control (DC), and acute and late toxicities were evaluated with Fisher exact tests. Progression free survival (PFS) and overall survival (OS) were evaluated utilizing Kaplan Meier and log-rank analyses. Univariate Cox proportional hazard analyses were used to examine patient, disease, and treatment-related factors with OS and PFS. Results While comparing patients receiving RT with systemic therapy (n = 14) vs RT alone (n = 18), LRC was 92.9% vs 72.2% (p = 0.20), DC 92.9% vs 94.4% (p = 1.0), median PFS 17.7 months vs 34.4 months (p = 0.48), and median OS 20.9 months vs 34.4 months (p = 0.03), respectively. On univariate analyses, use of concurrent systemic therapy was associated with an increased risk of death with an HR of 3.5 [95% confidence interval (CI): 1.04 - 11.6] (p = 0.04), while patients treated for recurrent disease who had previously treated superficial primaries had improved OS with an HR of 0.10 [95% CI: 0.01-0.80] (p = 0.03). There were no significant differences in acute or chronic toxicities between groups. Conclusions Patients receiving postoperative RT alone for LA-cHNSCC had better OS than patients receiving concurrent systemic therapy. There were no differences in any other endpoints evaluated. PMID- 29279811 TI - Radiation Necrosis Following Proton Beam Therapy in the Pediatric Population: a Case Series. AB - Radiation necrosis after proton beam radiotherapy in the pediatric population is a finding that should be evaluated. We present two cases of radiation necrosis in pediatric patients who underwent proton beam radiation therapy following gross total resection of tumors. As seen in both our cases, patients often present with radiographic changes found on surveillance imaging. While the progression of disease should certainly be considered in any patient with radiographic changes, understanding the radiographic findings and the clinical course of radiation necrosis is paramount in order to prevent unnecessary surgical intervention. PMID- 29279812 TI - First Metatarsophalangeal Joint Arthrodesis in Hallux Valgus Versus Hallux Rigidus Using Cup and Cone Preparation Compression Screw and Dorsal Plate Fixation. AB - Various techniques have been described for first metatarsophalangeal (MTP) joint arthrodesis. The purpose of this study was to determine if cup and cone preparation by a single surgeon with an interfragmentary screw and dorsal plate fixation provides a comparable union rate in hallux valgus versus hallux rigidus. Our study included all patients who underwent first MTP joint fusions using cup and cone preparation with an interfragmentary compression screw and dorsal plate fixation from 2010 to 2015. We compared union rates in 65 patients with hallux rigidus with 47 who had hallux valgus. One of 65 hallux rigidus cases developed non-union and underwent revision surgery. One of 47 patients in the hallux valgus group developed a painless non-union. All other patients achieved union based on post operative radiographs. Our rate of painful non-union was 1.5% for hallux rigidus and 0% for hallux valgus, which is lower than recent published literature of 7% for hallux valgus and 3.7% for hallux rigidus. We found no difference between the two groups suggesting this method may provide stronger fixation and may be preferable when dealing with hallux valgus. First metatarsophalangeal joint fusion in patients with severe hallux valgus and hallux rigidus, using spherical reamers, compression screw and dorsal plate fixation is equally successful at achieving clinical and radiographic fusion in both hallux valgus and hallux rigidus. PMID- 29279813 TI - The Assessment of Fusion Following Sacroiliac Joint Fusion Surgery. AB - Sacroiliac joint fusions (SIJF) have been the subject of many research studies. The technical success of an SIJF is in part determined by whether osseous bridging occurs across the sacroiliac joint (SIJ). However, no validated SIJF assessment method has been described. Our objective was to document previously described SIJF assessment methods and define and validate a detailed assessment system for SIJF. Our results are only intended to establish computed tomography (CT)-based guidelines for SIJF to be used in a subsequent large clinical study to correlate them with clinical outcomes. The SIJF literature was reviewed to document previous descriptions of SIJF assessments. A detailed system was then developed for assessing SIJF from CT exams. To provide data that can be used to address a range of research questions, the system included assessing bridging bone relative to the SIJ anatomy, bridging bone immediately adjacent to the threaded implants crossing the joint, as well as bridging bone close to but not immediately adjacent to the implants. The system was applied to assessing SIJF from thin-slice CT exams in 19 patients 12 months following surgery. Two experienced radiologists implemented the assessment system, and in the event of a disagreement, an adjudicator was used. Most prior studies provide very little detail about how SIJF was assessed. Using the new assessment system, the agreement between the primary readers was substantial (0.67 using Gwet's AC1 statistic). Bridging bone representing a fusion of the SIJ was identified in most patients both immediately adjacent to the threaded implants crossing the joint, as well as distant to the implants. A detailed radiographic assessment system proved to be applicable to SIJF. The assessment system includes explicit language describing the location and extent of bridging bone across the SIJ. Standardization of the assessment of the SIJFs may allow for a more meaningful comparison of data between studies. PMID- 29279814 TI - An Uncommon Cause of Dysuria in a Female Patient: Huge Urinary Bladder Stones. AB - The urinary bladder stones are formed due to urinary retention, obstruction to the flow of urine commonly caused by enlargement of the prostate in males, urinary tract infections, and foreign body. The urinary bladder stones are usually found in males, and its presentation in females is a rare entity. Recurrence of urinary tract stones is commonly due to either repeated urinary tract infections or any metabolic condition. We present a case of a 75-year-old female patient who had a history of urinary tract infection and bladder stone formation and was operated for the 16th time recently for removal of her bladder stones. PMID- 29279815 TI - Correlation of Histopathology and Clinical Symptoms in Meralgia Paresthetica. AB - Meralgia paresthetica is a neuropathic pain disorder resulting from an entrapment neuropathy of the lateral femoral cutaneous nerve. This condition results in pain, paresthesias and numbness over the anterolateral aspect of the thigh. We present a case of meralgia paresthetica and discuss both the clinical and histopathological findings as they relate to one another. We report a case of meralgia paresthetica refractory to conservative treatment who underwent neurectomy with successful treatment of symptoms. Histopathological examination revealed moderate loss of myelinated axons with some axonal atrophy. The distinct pathologic findings were axonal regeneration clusters and thinly myelinated axons as well as moderate perineurial thickening. These findings corresponded well to the patient's preoperative symptoms of paresthesias and pain. This case serves to shed light on the pathophysiology of meralgia paresthetica and its clinical presentation. It also shows the role of surgical treatment in cases refractory to conservative management in order to alleviate painful symptoms. PMID- 29279816 TI - When Ablation Is Not the Answer: Acute Left Main Thrombosis Causing Incessant Ventricular Tachycardia Following Left Ventricular Assist Device Implant. AB - Ventricular arrhythmia from aortic cusp thrombosis and coronary embolization is a rare complication of left ventricular assist device (LVAD) implantation. In this report, we present a case of acute left main and left anterior descending artery occlusion from embolic aortic cusp thrombi after LVAD implant. The patient presented with chest pain and incessant ventricular tachycardia post-LVAD implant. This was successfully treated by intracoronary thrombolysis, aspiration thrombectomy, and rheolytic thrombectomy. We present a rare case of successful percutaneous coronary intervention performed for incessant ventricular tachycardia in the setting of acute coronary thrombosis following LVAD implant. PMID- 29279817 TI - Multi level statistical optimization of l-asparaginase from Bacillus subtilis VUVD001. AB - Physical and chemical factors influencing the anti-leukemic l-asparaginase enzyme production by Bacillus subtilis VUVD001 were optimized using multi-stage optimization on the basis of preliminary experimental outcomes obtained by conventional one-factor-at-a-time approach using shake flasks. Process variables namely carbon, nitrogen sources, pH and temperature were taken into consideration during response surface methodology (RSM) optimization. The finest enzyme activity of 0.51 IUml-1 obtained by OFAT method was enhanced by 3.2 folds using RSM optimization. Artificial neural network (ANN) modelling and genetic algorithm (GA) based optimizations were further carried out to improve the enzyme drug yield. Results were also validated by conducting experiments at optimum conditions determined by RSM and GA optimization methods. The novel bacterium yielded in 2.88 IUml-1 of enzyme activity at optimum process variables determined by GA optimization, i.e., 0.5% glucose, 8.0% beef extract, 8.3 pH and 49.9 degrees C temperature. The study explored the optimized culture conditions for better yielding of anti-leukemic enzyme drug from a new bacterial source namely Bacillus subtilis VUVD001. PMID- 29279818 TI - Differential levels of metabolites and enzymes related to aroma formation in aromatic indica rice varieties: comparison with non-aromatic varieties. AB - Accounting for aroma production in different aromatic indica rice varieties based on variations in the levels of concerned metabolites and enzymes is poorly explored. The present investigation was, therefore, focused on unraveling the differential levels of metabolites and activities of enzymes related to aroma formation in eleven indigenous aromatic rice varieties, as compared with four non aromatic varieties. The levels of metabolites such as proline (Pro) and Delta1 pyrroline-5-carboxylate (P5C), and the activity of related enzymes such as proline dehydrogenase (PDH), Delta1-pyrroline-5-carboxylate synthetase (P5CS), and ornithine aminotransferase (OAT) were comparatively higher in the aromatic varieties, with Kalonunia and Tulaipanji registering the highest Pro, Kalonunia the highest P5C content, Gobindobhog with the highest PDH activity, Gobindobhog and Tulaipanji with the highest P5CS, and Pusa Basmati-1 with the highest OAT activity. The levels of putrescine (Put) and gamma-aminobutyric acid (GABA) were comparatively lower in aromatic varieties, with concomitant higher diamine oxidase (DAO) activity, especially in the varieties Gobindobhog and Tulaipanji. The betaine-aldehyde dehydrogenase 2 (BADH2) enzyme activity was remarkably lesser in aromatic varieties, especially Radhunipagal and Gobindobhog. Though the metabolites such as glycine-betaine and higher polyamines such as spermidine and spermine showed no specific trend with respect to their quantitative level in either aromatic or non-aromatic varieties, they were notably lower in the aromatic varieties such as Gobindobhog, Kalonunia, and Tulaipanji, indicating a possibility of their involvement in aroma formation. Therefore, the levels of metabolites such as Pro, P5C and methylglyoxal (MG), and the activity of enzymes such as PDH, P5CS, OAT, and DAO were comparatively higher in the aromatic rice varieties than the non-aromatic ones, whereas the levels of Put, GABA, and BADH2 were lower. Overall, the present study showed that there exist variations in the accumulations of such metabolites as well as differential activity of enzymes controlling their production, which altogether regulate generation of aroma in aromatic varieties. PMID- 29279819 TI - Improvement in xylooligosaccharides production by knockout of the beta-xyl1 gene in Trichoderma orientalis EU7-22. AB - The goal of this study was to enhance the production of xylooligosaccharides (XOs) and reduce the production of xylose. We investigated beta-xylosidases, which were key enzymes in the hydrolysis of xylan into xylose, in Trichoderma orientalis EU7-22. The binary vector pUR5750G/bxl::hph was constructed to knock out the beta-xyl1 gene (encoding beta-xylosidases) in T. orientalis EU7-22 by homologous integration, producing the mutant strain T. orientalis Bxyl-1. Xylanase activity for strain Bxyl-1 was 452.42 IU/mL, which increased by only 0.07% compared to that of parental strain EU7-22, whereas beta-xylosidase activity was 0.06 IU/mL, representing a 91.89% decrease. When xylanase (200 IU/g xylan), produced by T. orientalis EU7-22 and T. orientalis Bxyl-1, was used to hydrolyze beechwood xylan, in contrast to the parental strain, the XOs were enhanced by 83.27%, whereas xylose decreased by 45.80% after 36 h in T. orientalis Bxyl-1. Based on these results, T. orientalis Bxyl-1 has great potential for application in the production of XOs from lignocellulosic biomass. PMID- 29279821 TI - Submandibular sialolithiasis with CT and scintigraphy: CT values and salivary gland excretion in the submandibular glands. AB - Purpose: Sialolithiasis is one of the most prevalent large obstructive disorders of the submandibular glands. The aim of this study was to investigate submandibular sialolithiasis with computed tomography (CT) and scintigraphy, with a particular focus on the relationship between CT values of the submandibular glands and their excretion rate. Materials and Methods: Fifteen patients with submandibular sialolithiasis who underwent CT and salivary gland scintigraphy were included in this study. The relationship between the CT values of submandibular glands with and without sialoliths and salivary gland excretion measured using salivary gland scintigraphy was statistically analyzed. Dynamic images were recorded on the computer at 1 frame per 20 seconds. The salivary gland excretion fraction was defined as A (before stimulation test [counts/frame]) / B(after stimulation test [counts/frame]) using time-activity curves. Results: The CT values in the submandibular glands with and without sialoliths was 9.9+/-44.9 Hounsfield units (HU) and 34.2+/-21.8 HU, respectively (P=.233). Regarding the salivary gland excretion fraction using scintigraphy, the A/B value in the submandibular glands with sialoliths (1.09+/-0.23) was significantly lower than in the submandibular glands without sialoliths (1.99+/ 0.57, P=.000). Conclusion: Assessments of the CT values and the salivary gland excretion fraction using scintigraphy in the submandibular glands seem to be useful tools evaluating submandibular sialolithiasis. PMID- 29279820 TI - Internal derangement as a predictor of provoked pain on mouth opening: A magnetic resonance imaging study. AB - Purpose: This study investigated the relationship between pain and internal derangement in temporomandibular disorder (TMD) patients using magnetic resonance imaging (MRI). Materials and Methods: This study analyzed 356 TMD patients (712 temporomandibular joints [TMJs]). The inclusion criteria were the presence of spontaneous or provoked pain on one or both TMJs and having undergone MRI. The patients with provoked pain were divided into 3 groups: pain on palpation, pain on mouth opening, and pain on mastication. MRI was performed using a 1.5-T scanner. T1- and T2-weighted parasagittal and paracoronal images were obtained. According to the findings on the T1-weighted images, another 3 groups were created based on internal derangement: normal, disc displacement with reduction, and disc displacement without reduction. The MRI findings were independently interpreted by 2 experienced oral and maxillofacial radiologists at 2 different times. Statistical analysis was performed by the chi-square test using SPSS (version 12.0; SPSS Inc., Chicago, IL, USA). Results: Provoked pain on mouth opening was found to be correlated with internal derangement in TMD patients (P<.05). However, spontaneous pain and provoked pain on palpation or mastication were not associated with internal derangement (P>.05). Conclusion: These results suggest that internal derangement was a significant predictor of provoked pain on mouth opening. PMID- 29279822 TI - Repeat analysis of intraoral digital imaging performed by undergraduate students using a complementary metal oxide semiconductor sensor: An institutional case study. AB - Purpose: This study was performed to quantify the repeat rate of imaging acquisitions based on different clinical examinations, and to assess the prevalence of error types in intraoral bitewing and periapical imaging using a digital complementary metal-oxide-semiconductor (CMOS) intraoral sensor. Materials and Methods: A total of 8,030 intraoral images were retrospectively collected from 3 groups of undergraduate clinical dental students. The type of examination, stage of the procedure, and reasons for repetition were analysed and recorded. The repeat rate was calculated as the total number of repeated images divided by the total number of examinations. The weighted Cohen's kappa for inter and intra-observer agreement was used after calibration and prior to image analysis. Results: The overall repeat rate on intraoral periapical images was 34.4%. A total of 1,978 repeated periapical images were from endodontic assessment, which included working length estimation (WLE), trial gutta-percha (tGP), obturation, and removal of gutta-percha (rGP). In the endodontic imaging, the highest repeat rate was from WLE (51.9%) followed by tGP (48.5%), obturation (42.2%), and rGP (35.6%). In bitewing images, the repeat rate was 15.1% and poor angulation was identified as the most common cause of error. A substantial level of intra- and interobserver agreement was achieved. Conclusion: The repeat rates in this study were relatively high, especially for certain clinical procedures, warranting training in optimization techniques and radiation protection. Repeat analysis should be performed from time to time to enhance quality assurance and hence deliver high-quality health services to patients. PMID- 29279823 TI - Root surface areas of maxillary permanent teeth in anterior normal overbite and anterior open bite assessed using cone-beam computed tomography. AB - Purpose: The aim of this study was to compare the root surface areas of the maxillary permanent teeth in Thai patients exhibiting anterior normal overbite and in those exhibiting anterior open bite, using cone-beam computed tomography (CBCT). Materials and Methods: CBCT images of maxillary permanent teeth from 15 patients with anterior normal overbite and 18 patients with anterior open bite were selected. Three-dimensional tooth models were constructed using Mimics Research version 17.0. The cementoenamel junction was marked manually. The root surface area was calculated automatically by 3-Matic Research version 9.0. The root surface areas of each tooth type from both types of bite were compared using the independent t-test (P<.05). The intraclass correlation coefficient was used to assess intraobserver reliability. Results: The mean root surface areas of the maxillary central and lateral incisors in individuals with anterior open bite were significantly less than those in those with normal bite. The mean root surface area of the maxillary second premolar in individuals with anterior open bite was significantly greater than in those with normal bite. Conclusion: Anterior open-bite malocclusion might affect the root surface area, so orthodontic force magnitudes should be carefully determined. PMID- 29279824 TI - Multispectral X-ray imaging to distinguish among dental materials. AB - Purpose: Dual-energy X-ray imaging is widely used today in various areas of medicine and in other applications. However, no similar technique exists for dental applications. In this study, we propose a dual-energy technique for dental diagnoses based on voltage-switching. Materials and Methods: The method presented in this study allowed different groups of materials to be classified based on atomic number, thereby enabling two-dimensional images to be colorized. Computer simulations showed the feasibility of this approach. Using a number of different samples with typical biologic and synthetic dental materials, the technique was applied to radiographs acquired with a commercially available dental X-ray unit. Results: This technique provided a novel visual representation of the intraoral environment in three colors, and is of diagnostic value when compared to state-of the-art grayscale images, since the oral cavity often contains multiple permanent foreign materials. Conclusion: This work developed a technique for two dimensional dual-energy imaging in the context of dental applications and showed its feasibility with a commercial dental X-ray unit in simulation and experimental studies. PMID- 29279825 TI - CT evaluation of underlying bone sclerosis in patients with oral squamous cell carcinoma: A preliminary retrospective study. AB - Purpose: Underlying bone sclerosis is frequently observed in clinical settings when oral squamous cell carcinoma (OSCC) invades the jaw bone. The aim of this study was to assess the prevalence and characteristics of underlying bone sclerosis in patients with OSCC. Materials and Methods: We retrospectively reviewed the computed tomographic (CT) images of 131 patients who underwent mandibulectomy between January 2012 and December 2015 to treat OSCC. The presence, degree, and extent of underlying bone sclerosis were assessed on CT images and correlated with the following imaging patterns of bone invasion: cortical invasion, medullary invasion with a smooth margin, and medullary invasion with an irregular margin. The chi-square test was used to determine the relationships between the variables. Results: The prevalence of underlying bone sclerosis on CT images was 70.1% (47 of 67). The prevalence was 85.7% (42 of 49) in patients with medullary invasion, but it was 27.8% (5 of 18) in patients with only cortical invasion, indicating a significant increase in the prevalence of underlying bone sclerosis in patients with medullary invasion (P<.05). Aggressive patterns of bone invasion were associated with increases in the degree and extent of the underlying bone sclerosis (P<.05). Conclusion: More than two-thirds of OSCC cases with bone invasion showed underlying bone sclerosis. On CT images, reactive sclerosis in the remaining margin of the alveolar bone should not be used as the primary means to differentiate periodontal inflammatory lesions from those resulting from OSCC. PMID- 29279826 TI - Frequency of different maxillary sinus septal patterns found on cone-beam computed tomography and predicting the associated risk of sinus membrane perforation during sinus lifting. AB - Purpose: Analyzing different patterns of maxillary sinus septa in cone-beam computed tomography (CBCT) images and predicting maxillary sinus membrane perforations. Materials and Methods: In this cross-sectional study, CBCT images of 222 patients ranging from 20 to 81 years old were evaluated. One hundred fifty two patients (93 females and 59 males) who had maxillary sinus septa in axial views were included in this study. Cross-sectional images were used to determine classifications of sinus septa and the risk of membrane perforation using a method modified from Al-Faraje et al. Variables of sex, age, and dental status were considered. Chi-squared and Kruskal-Wallis tests were used for data analysis (P<.05). Results: In this study, 265 maxillary sinus septal patterns were found. The mean age of the patients was 44.1+/-14.7 years old. The Class I and VII-div II patterns had the greatest and least prevalence, respectively. Furthermore, there was a significant relationship between the location of septa and the frequency of membrane perforation risk (P<.05). In this study, the relationship of different patterns of septa with dental status did not differ significantly (P>0.05). Conclusion: A higher prevalence of moderate risk of membrane perforation in the molar region relative to the premolar region was observed. Furthermore, maxillary sinus septa occur most frequently in the molar region, demonstrating the importance of paying attention to this region during sinus lift surgery. This study did not show any relationship between tooth loss and the presence of septa. PMID- 29279827 TI - Parotid mandibular bone defect: A case report emphasizing imaging features in plain radiographs and magnetic resonance imaging. AB - Mandibular bone depression, also known as Stafne bone cavity, is defined as a bone depression filled mainly with salivary gland tissue. Parotid gland bone defects are infrequently observed. We report the case of a 52-year-old male patient who underwent radiographic examinations due to temporomandibular joint dysfunction, and a radiolucent area was detected in the mandibular ramus, with a provisional diagnosis of traumatic bone cyst or parotid mandibular bone defect. The patient was then referred for magnetic resonance imaging, which demonstrated a hyperintense area eroding the mandibular ramus, which corresponded to glandular tissue. Although the defect was a benign lesion, radiolucencies in the mandibular ramus lead to concerns among professionals, because their radiographic features can resemble various intrabony neoplastic lesions, such as giant cell tumors or benign tumors of the parotid gland. PMID- 29279828 TI - Rare finding of Eustachian tube calcifications with cone-beam computed tomography. AB - Soft tissue calcification is a pathological condition in which calcium and phosphate salts are deposited in the soft tissue organic matrix. This study presents an unusual calcification noted in the cartilaginous portion of the Eustachian tube. A 67-year-old woman presented for dental treatment, specifically for implant placement, and cone-beam computed tomography (CBCT) was performed. The CBCT scan was reviewed by a board-certified oral and maxillofacial radiologist and revealed incidental findings of 2 distinct calcifications in the cartilaginous portion of the Eustachian tube. To the authors' knowledge, no previous study has reported the diagnosis of Eustachian tube calcification using CBCT. This report describes an uncommon variant of Eustachian tube calcification, which has a significant didactic value because such cases are seldom illustrated either in textbooks or in the literature. This case once again underscores the importance of having CBCT scans evaluated by a board-certified oral and maxillofacial radiologist. PMID- 29279829 TI - Magnetic resonance imaging appearance of foreign-body granulomatous reactions to dermal cosmetic fillers. AB - Foreign body granulomas can develop after the injection of various cosmetic filling materials into the facial area to flatten wrinkles. Clinically, reactive lesions are easily mistaken for soft-tissue neoplasms or cysts. This report presents a case of foreign body granuloma in a 52-year-old female patient complaining of a painless swelling in the nasolabial region. Both clinical and histological features are described, underscoring the diagnostic role of magnetic resonance imaging findings. PMID- 29279830 TI - Homocystinuria with Stroke and Positive Familial History. AB - Homocystinuria is the second most common treatable aminoacidopathy. Clinically, affected patients present with eye, skeleton, central nervous system, and most importantly, vascular system abnormalities. This autosomal recessive disorder leads to accumulation of homocysteine and its metabolites in the blood and urine. In this report, we present a case with clinical and biochemical findings of homocystinuria with stroke and a positive familial history of the disease in her brother. A 4-year-old girl was admitted to pediatric emergency ward because of acute onset of right hemiparesis and subsequent generalized tonic-clonic seizures. Cranial magnetic resonance imaging revealed acute infarct areas in the left cerebral hemisphere. Metabolic screening revealed elevated concentrations of serum homocysteine and methionine and a normal serum concentration of vitamin B12. These findings, along with a positive familial history led to the diagnosis of homocystinuria. In any child who presents with stroke, some rare condition such as homocystinuria should be considered in diagnosis. PMID- 29279831 TI - Optimal DNA Isolation Method for Detection of Nontuberculous Mycobacteria by Polymerase Chain Reaction. AB - Background: Nontuberculous mycobacteria (NTM) are a group of opportunistic pathogens and these are widely dispersed in water and soil resources. Identification of mycobacteria isolates by conventional methods including biochemical tests, growth rates, colony pigmentation, and presence of acid-fast bacilli is widely used, but these methods are time-consuming, labor-intensive, and may sometimes remain inconclusive. Materials and Methods: The DNA was extracted from NTM cultures using CTAB, Chelex, Chelex + Nonidet P-40, FTA(r) Elute card, and boiling The quantity and quality of the DNA extracted via these methods were determined using UV-photometer at 260 and 280 nm, and polymerase chain reaction (PCR) amplification of the heat-shock protein 65 gene with serially diluted DNA samples. Results: The CTAB method showed more positive results at 1:10-1:100,000 at which the DNA amount was substantial. With the Chelex method of DNA extraction, PCR amplification was detected at 1:10 and 1:1000 dilutions. Conclusions: According to the electrophoresis results, the CTAB and Chelex DNA extraction methods were more successful in comparison with the others as regard producing suitable concentrations of DNA with the minimum use of PCR inhibitor. PMID- 29279832 TI - The Comparison of Preventive Analgesic Effects of Ketamine, Paracetamol and Magnesium Sulfate on Postoperative Pain Control in Patients Undergoing Lower Limb Surgery: A Randomized Clinical Trial. AB - Background: In considering the importance of postoperative pain management and its consequences on its related secondary outcomes including nausea, vomiting, and operation-related complications, we aimed to compare the effectiveness of the three analgesic agents including ketamine, paracetamol, and magnesium sulfate for postoperative pain relief and associated consequences in this trial. Materials and Methods: In this double-blinded randomized control clinical trial, patients scheduled for elective lower extremity orthopedic surgery under general anesthesia were enrolled and randomized into four groups for receiving intravenous ketamine (0.25 mg/kg), paracetamol (15 mg/kg), magnesium sulfate (7.5 mg/kg), and placebo (normal saline), immediately after the induction of anesthesia. Postoperative pain scores, analgesic, and metoclopramide use, and frequency of vomiting and satisfaction score of studied patients in the four studied groups during the 6 h, 6-12 h, and 12-24 h after recovery were recorded and compared. Results: In this trial, thirty patients randomized in each studied groups. Mean of postoperative pain score was significantly lower in ketamine group than others during 24 h after recovery (P < 0.001). Mean of additive analgesic use was significantly lower in ketamine group during 12 h after recovery (P < 0.001), but it was not significantly different during 12-24 h after recovery (P = 0.12). Mean of vomiting frequency and metoclopramide use was not different between groups (P > 0.05). Excellent and good satisfaction score were significantly higher in ketamine group than other groups (P = 0.04). Conclusions: Ketamine has more superior effect for during recovery and postoperative pain controlling and analgesic use than paracetamol and magnesium sulfate. PMID- 29279834 TI - Comparative Study after Hamstring Anterior Cruciate Ligament Reconstruction with Endobutton and Rigidfix: A Clinical Trial Study. AB - Background: One of the most common orthopedic clinic visits involves direct and indirect knee trauma leading to rupture of anterior cruciate ligament (ACL). Endobutton and Rigidfix are most frequent treating methods that used by orthopedic surgeons. Thus the aim of this study was compare the clinical results of reconstructing arthroscopic ACL of the knee through two methods namely Rigidfix and Endobutton. Materials and Methods: In a clinical trial study, a total of 40 patients with rupture of ACL were selected and randomly divided into two groups. The groups were treated through fixation procedures either Endobutton or Rigidfix. Prior to surgery and then at least 2 years after surgery, the patients were under physical examination in terms of knee range of motion, knee stability, knee pain, ability to perform daily activities and exercises and compared between the two groups. Results: The knee range of motion in Endobutton and Rigidfix were 135.73 +/- 2.63 and 129.87 +/- 7.14 degrees resprectively (P = 0.06). comparing two groups, during last month in Endobutton and Rigidfix the frequency of knee pain were 2.5 +/- 1.4 and 3.4 +/- 1.4 respectively (P = 0.08). Moreover, the pain intensity score were 2.9 +/- 1.5 and 2.6 +/- 1.1 (P = 0.49). But there was a significant difference observed in patients' satisfaction and ability to perform sports activities. Conclusions: The two fixation methods namely Endobutton and Rigidfix are not preferred over one another. But patients' satisfaction and ability to perform sports activities in Endobutton was better than the Rigidfix. PMID- 29279833 TI - Preventive Effect of Maternal Forced Exercise on Offspring Pain Perception and Intensity: The Role of 5-HT2 and D2 Receptors. AB - Background: Many previous studies showed that maternal forced exercise can reduce some central disorders in offsprings, but its clear mechanism remains unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise in offspring neurodevelopment and effect on some behaviors were evaluated. Materials and Methods: Forty-eight pregnant rats were trained by forced exercise, and some behavioral assays in their offspring were performed in the presence and absence of 5-HT2 and D2 receptor antagonists in various experimental groups. Results: Our data showed that maternal forced exercise caused increase in latency of pain perception in offsprings in hot plate test, writhing test (WT), and tail flick test. Furthermore, a decrease in intensity was shown by WT. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists could inhibit these effects of forced exercise and cause disturbances in pain perception and intensity. Conclusion: Our data suggested that maternal forced exercise causes protective effects on offspring pain perception and intensity, and in this effect, 5-HT2 and D2 receptors are probably involved. PMID- 29279835 TI - An Evaluation on Iran International Public Health Summer School in Relation to its Efficacy Based on Participants' Experience and Opinions. AB - Background: A serious challenge to educate health staff for public health is to appear encouraging enough to persuade them for learning issues on this field and implementing new educational methods and innovative ways. Iran International Public Health Summer School (IPHS) made an effort to provide medical sciences students with a fortune to get familiar with and involved in public health. This study intended to evaluate the efficacy of this event. Materials and Methods: This cross-sectional study was performed in March-April 2015 by the help of an electronic self-administered questionnaire filled out by 49 Iranian participants 6 months after IPHS2014. The questionnaire assessed the main goals in seven main domains: Interest, activities, and general knowledge in the field of public health, general skills, educational methods, educational and executive schedules, and general satisfaction. Results: Average scores of all domains were >3 (the mean), and all were statistically significant. The highest average score belonged to educational methods (3.92) and the lowest was calculated for the item regarding participants' activities on public health (3.5). No significant difference was found between positive answers of individuals who were interested or active in public health prior to the event and those who had no background. Conclusions: We believe IPHS was a unique instance in Public Health Education in Iran. Considering the level of success of this program to reach its goals for both students' with or without any previous background on public health, it is recommended as a general model to be simulated in other developing countries. PMID- 29279836 TI - Evaluation of Endometrial Angiogenesis in Mice Uterus Before Implantation in Natural Cycles Followed by Use of Human Menopausal Gonadotropin - Human Chorionic Gonadotropin Drugs and Epigallocatechin Gallate. AB - Background: Angiogenesis plays a major role in endometrial receptivity and thickening of the endometrium immediately before implantation. The aim of the present work was to evaluate the antiangiogenic properties of epigallocatechin-3 gallate (EGCG) from green tea in angiogenesis of endometrium. Materials and Methods: In this study, forty adult female NMARI mice randomly divided into four groups. Control group received vehicle; human menopausal gonadotropin/human chorionic gonadotropin (HMG/HCG) group received 7.5 IU HMG intraperitoneal (IP) and 48 h later 7.5 IU HCG was injected (IP) for ovarian stimulation; HMG/HCG + EGCG group received HMG and HCG in the same manner as the previous group and also received 5 mg/kg EGCG at 0, 24, 48, and 72 h after injection of HMG; and the group EGCG received 5 mg/kg EGCG. A male mouse was kept with two female animals in the same cage for mating. Mice were dissected 96 h after administration of HMG (immediately before implantation) and tissue processing was carried out for the uterine specimens. CD31-positive cells were counted by use of histological and immunohistochemical methods. Results: Angiogenesis in EGCG-treated group was less than that of control and gonadotropin group (P < 0.05). The number of endothelial cells was counted by CD31 marker under a light microscope and showed significant differences between all groups (P < 0.05). Conclusion: EGCG significantly inhibited the angiogenesis in endometrium (in natural cycles) through antiangiogenic effects. PMID- 29279837 TI - Effects of Taping on Pain and Functional Outcome of Patients with Knee Osteoarthritis: A Pilot Randomized Single-blind Clinical Trial. AB - Background: To determine the effects of knee taping in combination with exercise and medical treatment on functional outcome and pain of patients with knee osteoarthritis (OA). Materials and Methods: In a randomized single-blinded clinical trial, 36 patients with knee OA were randomly assigned to two study groups. Both groups received exercise and medical therapy for 6 weeks. In addition, the first group (20 patients) received taping in the first 3 weeks. Pain severity (assessed by visual analog scaling), weekly amount of analgesics consumption, timed get up and go test (TUG), and step tests were recorded at baseline, 3 and 6 weeks after the treatment and were further compared between two study groups. Results: There was no significant difference between two groups in pain severity score (P = 0.228), step test score (P = 0.771), TUG test score (P = 0.821) and weekly amount of analgesics consumption (P = 0.873) at baseline. After 3 weeks, weekly amount of analgesics consumption (P = 0.006), pain severity (P < 0.001) was significantly lower in taping group whereas step test score (P = 0.006) was significantly higher in the taping group. After 6 weeks, patients in taping group had significantly lower pain severity (P = 0.011) and higher step test score (P = 0.042). However, there was no significant difference in TUG test score (P = 0.443) and weekly amount of analgesics consumption (P = 0.270) between two groups. Conclusion: Therapeutic knee taping may be an effective method for short-term management of pain and disability in patients with knee OA. PMID- 29279838 TI - Level of High Sensitive C-reactive Protein and Procalcitonin in Pregnant Women with Mild and Severe Preeclampsia. AB - Background: In this study, we compare the level of two inflammatory markers, high sensitive C-reactive protein (hs-CRP) and procalcitonin (PCT), in pregnant women with mild and severe preeclampsia (PE) and women with normal pregnancy. Materials and Methods: In this case-control study, normal pregnant women and pregnant women with PE were enrolled. Pregnant women with diagnosed PE were selected as case group and classified into two groups with mild and severe PE. Serum samples for measurement of hs-CRP and PCT were obtained and compared in studied groups. Results: In this study, 50 normal pregnant women and 59 pregnant women with PE, 26 (44.1%) mild, and 33 (55.9%) severe were studied. Mean of hs-CRP and PCT was higher in pregnant women with PE than normal pregnant women (7.71 +/- 6.19 vs. 5.44 +/- 3.94, P = 0.02 for hs-CRP and 0.05 +/- 0.03 vs. 0.04 +/- 0.01, P = 0.001 for PCT). Area under curve for hs-CRP and PCT was 0.611 and 0.646, respectively. The optimal cut-off point for hs-CRP was 5.24 with a sensitivity of 62.7% and a specificity of 56%. The optimal cut-off point for PCT was 0.042 with a sensitivity of 71% and a specificity of 54%. Conclusion: The findings of this study indicated that higher level of hs-CRP and PCT in pregnant women with PE than those with normal pregnancy could potentially explain the exaggerated inflammation in PE. Regarding significantly increased level of hs-CRP in severe PE than mild PE, we could suggest that hs-CRP is more appropriate marker for investigating pregnant women with severe PE, and its clinical usefulness is superior to PCT in this regard. PMID- 29279839 TI - Limited Approach in Endoscopic Dacryocystorhinostomy of Pediatrics. AB - Background: Limited spatial nasal cavity in children, make pediatric dacryocystorhinostomy (DCR) a difficult surgical procedure. We apply a limited approach to pediatric DCR and follow them for their consequences. Materials and Methods: An experimental study was done in pediatric DCR with limited approach (age < 14-year-old). After written consent, with general anesthesia, with nasal endoscopic surgery, lacrimal bone is exposed and extruded. In contrast with routine procedure, ascending process of maxillary sinus reserve; and marsupialization and wide exposure to lacrimal sac was done only by lacrimal bone defect; and cannulation preserve with temporary silicone tube. Results: Between 2006 and 2012, 16 pediatric DCR was done by a unique surgeon in 2 otorhinolaryngologic centers. Before surgery 14 (87.5%) had epiphora, 3 (18.8%) had eye discharge, and 3 (18.8%) had eye sticky eye. Two (12.5%) had history of facial trauma, and 10 (62.5%) had congenital nasolacrimal duct insufficiency. Five (31.3%) had history of dacryocystitis. Patients were followed for 17 +/- 9 months. Silicone tube stayed for 4 +/- 2.5 months. We could follow 7 patients and minimal improvement or need to revision surgery considered as technical failure. After surgery, 3 patients had no epiphora with complete improvement; 2 had very good improvement with confidence of the patients and parents; 2 cases had unsuccessful surgery in our patients, who needs to another surgery. One of them had several probing and surgery before our endoscopic DCR. Conclusions: Limited approach in endoscopic DCR of pediatrics can be done in noncomplicated patients, with minimal manipulation, more confidence, and acceptable results. PMID- 29279841 TI - Erratum: Pro-inflammatory Cytokine Response and Genetic Diversity in Merozoite Surface Protein 2 of Plasmodium falciparum Isolates from Nigeria. AB - [This corrects the article on p. 142 in vol. 6.]. PMID- 29279840 TI - Pro-inflammatory Cytokine Response and Genetic Diversity in Merozoite Surface Protein 2 of Plasmodium falciparum Isolates from Nigeria. AB - Background: Polymorphisms in Plasmodium falciparum merozoite surface protein-2 (msp-2) and associated parasite genetic diversity which varies between malaria endemic regions remain a limitation in malaria vaccine development. Pro inflammatory cytokines are important in immunity against malaria, understanding the influence of genetic diversity on cytokine response is important for effective vaccine design. Methods: P. falciparum isolates obtained from 300 Nigerians with uncomplicated falciparum malaria at Ijede General Hospital, Ijede (IJE), General Hospital Ajeromi, Ajeromi (AJE) and Saint Kizito Mission Hospital, Lekki, were genotyped by nested polymerase chain reaction of msp-2 block 3 while ELISA was used to determine the pro-inflammatory cytokine response to describe the genetic diversity of P. falciparum. Results: Eighteen alleles were observed for msp-2 loci. Of the 195 isolates, 61 (31.0%) had only FC27-type alleles, 38 (19.7%) had only 3D7-type alleles, and 49.3% had multiple parasite lines with both alleles. Band sizes were 275-625 bp for FC27 and 150-425 bp for 3D7. Four alleles were observed from LEK, 2 (375-425 bp) and 2 (275-325 bp) of FC27-and 3D7 types, respectively; 12 alleles from AJE, 9 (275-625 bp) and 3 (325-425 bp) of FC27-types and 3D7-types, respectively; while IJE had a total of 12 alleles, 9 (275-625 bp) and 3 (325-425 bp) of FC27-types and 3D7-types, respectively. Mean multiplicity of infection (MOI) was 1.54. Heterozygosity (HE) ranged from 0.77 to 0.87 and was highest for IJE (0.87). Cytokine response was higher among <5 years and was significantly associated with MOI (P > 0.05) but with neither parasite density nor infection type. Conclusion: P. falciparum genetic diversity is extensive in Nigeria, protection via pro-inflammatory cytokines have little or no interplay with infection multiplicity. PMID- 29279842 TI - Characterization and Identification of Cryptic Biopeptides in Carya illinoinensis (Wangenh K. Koch) Storage Proteins. AB - The objective of this research was to identify and characterize the encoded peptides present in nut storage proteins of Carya illinoinensis. It was found, through in silico prediction, proteomic analysis, and MS spectrometry, that bioactive peptides were mainly found in albumin and glutelin fractions. Glutelin was the major fraction with ~53% of the nut storage proteins containing at least 21 peptides with different putative biological activities, including antihypertensives, antioxidants, immunomodulators, protease inhibitors, and inhibitors of cell cycle progression in cancer cells. Data showed that using 50 MUg/mL tryptic digests of enriched peptides obtained from nut glutelins is able to induce up to 19% of apoptosis in both HeLa and CasKi cervical cancer cells. To our knowledge, this is the first report that shows the potential value of the nut encoded peptides to be considered as adjuvants in cancer therapies. PMID- 29279843 TI - Image Restoration for Fluorescence Planar Imaging with Diffusion Model. AB - Fluorescence planar imaging (FPI) is failure to capture high resolution images of deep fluorochromes due to photon diffusion. This paper presents an image restoration method to deal with this kind of blurring. The scheme of this method is conceived based on a reconstruction method in fluorescence molecular tomography (FMT) with diffusion model. A new unknown parameter is defined through introducing the first mean value theorem for definite integrals. System matrix converting this unknown parameter to the blurry image is constructed with the elements of depth conversion matrices related to a chosen plane named focal plane. Results of phantom and mouse experiments show that the proposed method is capable of reducing the blurring of FPI image caused by photon diffusion when the depth of focal plane is chosen within a proper interval around the true depth of fluorochrome. This method will be helpful to the estimation of the size of deep fluorochrome. PMID- 29279844 TI - Effectiveness of Fibrin Sealant Patch in Reducing Drain Volume after Pelvic Lymph Node Dissection in Women with Gynecologic Malignancy. AB - Background: The goal of this study was to evaluate the effectiveness of fibrin sealant in decreasing postoperative lymphatic drainage in women after pelvic lymphadenectomy and/or para-aortic lymphadenectomy during gynecologic cancer surgery. Methods: This study is a retrospective case-control study. Forty-five patients who underwent staging surgery were enrolled. Twenty-seven patients were in the fibrin sealant group (group A) and 18 in the control group (group B). The two groups were compared for the total volume of drain, hospital stay, harvested lymph node, and incidence of asymptomatic lymphocele. Lymphocele formation was evaluated by computed tomography (CT) on 3 months after surgery. Results: There were no significant differences in patient demographics between group A and B with respect to age, BMI, and harvested lymph nodes. Patients who received fibrin sealants had reduced total volume of drainage from postoperative days 2 to 5 compared to the control group (group A versus group B: 994.819 +/- 745.85 ml versus 1847.89 +/- 1241.41 ml; P = 0.015). However no differences were observed in hospital stay (P = 0.282), duration of drain (P = 0.207), and incidence of asymptomatic lymphocele at 3 months (P = 0.126). Conclusion: The results of this study indicate that the application of fibrin sealants after pelvic and/or para aortic lymphadenectomy may reduce lymphatic drainage in gynecologic malignancy. PMID- 29279845 TI - Affective Synchrony and Autonomic Coupling during Cooperation: A Hyperscanning Study. AB - Previous research highlighted that during social interactions people shape each other's emotional states by resonance mechanisms and synchronized autonomic patterns. Starting from the idea that joint actions create shared emotional experiences, in the present study a social bond was experimentally induced by making subjects cooperate with each other. Participants' autonomic system activity (electrodermal: skin conductance level and response: SCL, SCR; cardiovascular indices: heart rate: HR) was continuously monitored during an attentional couple game. The cooperative motivation was induced by presenting feedback which reinforced the positive outcomes of the intersubjective exchange. 24 participants coupled in 12 dyads were recruited. Intrasubject analyses revealed higher HR in the first part of the task, connoted by increased cognitive demand and arousing social dynamic, while intersubject analysis showed increased synchrony in electrodermal activity after the feedback. Such results encourage the use of hyperscanning techniques to assess emotional coupling in ecological and real-time paradigms. PMID- 29279846 TI - Autoantibodies against CYP-2C19: A Novel Serum Marker in Pediatric De Novo Autoimmune Hepatitis? AB - Diagnosis of de novo autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLT) is challenging especially in the absence of hyper-gamma globulinemia. Circulating autoantibodies are not sensitive nor specific in de novo AIH but when positive increase the diagnostic probability. We report the discovery of novel liver microsomal (LM) autoantibodies against CYP-2C19 in a 9 year-old boy with "de novo" AIH developed 7 years after OLT. Graft dysfunction presented with hypertransaminasemia (up to 400 IU/L), while serum gamma-globulins remained within the normal range for age. Liver histology and response to high dose prednisone (2 mg/kg/day) with the addition of azathioprine therapy further supported the diagnosis of de novo AIH. Autoantibodies investigation by indirect immunofluorescence (IF) on rodent tissues showed a novel staining pattern involving the pericentral liver zone and sparing the renal tissue. Human but not rat liver proteins immunoblotting allowed us to characterize the novel LM antibodies and to identify CYP-2C19 as human antigen. The finding offers insights into the controversial discussion about autoimmunity versus alloreactivity with regard to the pathogenesis of de novo AIH. Correct information on human versus rat tissue antigens tested by methods other than IF for antibodies detection may have significant implications for the correct diagnosis and management of patients followed up after OLT. PMID- 29279847 TI - Bacterial Diversity in Feline Conjunctiva Based on 16S rRNA Gene Sequence Analysis: A Pilot Study. AB - Changes in the microbial populations in the conjunctival sacs of animals have traditionally been evaluated using conventional microbiology techniques. The goal of this study was to examine the suitability of a methodology which may reveal a previously unknown microbiome inhabiting feline conjunctival membranes. In the present study, we determined the microbial diversity in feline conjunctivas based on 16S rRNA gene sequence analysis. Five taxa not described earlier in veterinary ophthalmology (i.e., Staphylococcus caprae, Staphylococcus succinus, Propionibacterium acnes, Psychrobacter faecalis, and Bacillus subtilis) were identified in feline conjunctivas with a high similarity (99-100%). The study demonstrates that the feline conjunctival sacs are inhabited by much more rich and diverse microbial communities than previously thought using culture-based methods. From the clinical perspective, this could suggest that other laboratory procedures (e.g., extended incubation time in the case of Actinobacteria, formerly order Actinomycetales) or a new tool like culture-independent approaches (next-generation DNA sequencing) should be taken into account. PMID- 29279848 TI - Connexin43 and AMPK Have Essential Role in Resistance to Oxidative Stress Induced Necrosis. AB - Reactive oxygen species (ROS) induced oxidative stress leads to cell damage and neurological disorders in astrocytes. The gap junction protein connexin43 (Cx43) could form intercellular channels in astrocytes and the expression of Cx43 plays an important role in protecting the cells from damage. In the present study, we investigated the contribution of Cx43 to astrocytic necrosis induced by the ROS hydrogen peroxide (H2O2) and the mechanism by which AMPK was involved in this process. Fluorescence microscopy, flow cytometry, and western blot were used quantitatively and qualitatively to determine the cell apoptosis, necrosis, and protein expression. Lack of Cx43 expression or blockage of Cx43 channels resulted in increased H2O2-induced astrocytic necrosis, supporting a cell protective effect of functional Cx43 channels. Our data suggest that AMPK is important for Cx43-mediated ROS resistance. Inhibition of AMPK activation results in reduction of necrosis and ROS production. Taken together, our findings suggest that the role of Cx43 in response to H2O2 stress is dependent on the activation of AMPK signaling pathways and regulates ROS production and cell necrosis. PMID- 29279849 TI - Comparison between Peritoneal Macrophage Activation by Bougainvillea xbuttiana Extract and LPS and/or Interleukins. AB - Activation of macrophages may be one of the possible approaches in modulating inflammation. We previously reported that Bougainvillea xbuttiana extract showed an immunomodulatory activity. Here we compare the activation of macrophages exposed to B. xbuttiana extract and compare it with the other treatments such as LPS, IL-4, and IL-10. The cytotoxic effect of extract on peritoneal macrophages was determined by the technique of violet crystal staining. To verify the activation of macrophages we used the tests of vacuolization, hydrogen peroxide production, and percentages of cellular expansion and phagocytosis. The levels of interleukins secreted by macrophages treated with the extract, LPS, and cytokines were determined by the biological assay for the determination of TNF levels and by ELISA for all other interleukins. NO levels were evaluated by colorimetric reactions using Griess reagent. Our results showed that B. xbuttiana extract induced (a) low cytotoxicity percentages, (b) increased vacuolization, hydrogen peroxide production and cell expansion and phagocytosis percentages, and (c) decreased production of TNF-alpha, IFN-gamma, IL-1beta, and IL-6 and potentiated production of IL-4, IL-10 and TGF-beta. These results suggest that B. xbuttiana extract was able to activate the murine macrophages in a manner similar to those macrophages exposed to IL-4 and IL-10. PMID- 29279850 TI - An Improved Binary Differential Evolution Algorithm to Infer Tumor Phylogenetic Trees. AB - Tumourigenesis is a mutation accumulation process, which is likely to start with a mutated founder cell. The evolutionary nature of tumor development makes phylogenetic models suitable for inferring tumor evolution through genetic variation data. Copy number variation (CNV) is the major genetic marker of the genome with more genes, disease loci, and functional elements involved. Fluorescence in situ hybridization (FISH) accurately measures multiple gene copy number of hundreds of single cells. We propose an improved binary differential evolution algorithm, BDEP, to infer tumor phylogenetic tree based on FISH platform. The topology analysis of tumor progression tree shows that the pathway of tumor subcell expansion varies greatly during different stages of tumor formation. And the classification experiment shows that tree-based features are better than data-based features in distinguishing tumor. The constructed phylogenetic trees have great performance in characterizing tumor development process, which outperforms other similar algorithms. PMID- 29279851 TI - Aberrant Long Noncoding RNAs Expression Profiles Affect Cisplatin Resistance in Lung Adenocarcinoma. AB - Background: Long noncoding RNAs (lncRNAs) have been shown to be involved in the mechanism of cisplatin resistance in lung adenocarcinoma (LAD). However, the roles of lncRNAs in cisplatin resistance in LAD are not well understood. Methods: We used a high-throughput microarray to compare the lncRNA and mRNA expression profiles in cisplatin resistance cell A549/DDP and cisplatin sensitive cell A549. Several candidate cisplatin resistance-associated lncRNAs were verified by real time quantitative reverse transcription polymerase chain reaction (PCR) analysis. Results: We found that 1,543 lncRNAs and 1,713 mRNAs were differentially expressed in A549/DDP cell and A549 cell, hinting that many lncRNAs were irregular from cisplatin resistance in LAD. We also obtain the fact that 12 lncRNAs were aberrantly expressed in A549/DDP cell compared with A549 cell by quantitative PCR. Among these, UCA1 was the aberrantly expressed lncRNA and can significantly reduce the IC50 of cisplatin in A549/DDP cell after knockdown, while it can increase the IC50 of cisplatin after UCA1 was overexpressed in NCI H1299. Conclusions: We obtained patterns of irregular lncRNAs and they may play a key role in cisplatin resistance of LAD. PMID- 29279852 TI - The Expression of AQP5 and UTs in the Sweat Glands of Uremic Patients. AB - Purpose: To research the distribution and quantitative changes of UT-A1, UT-B1, and AQP5 in uremic skin tissue. Methods: 34 cases of uremic patients (UP) and 11 controls were recruited. Immunohistochemistry, immunofluorescence, RT-PCR, and Western Blot were used to identify the proteins in sweat glands. Results: AQP5, UT-A1, and UT-B1 were expressed and localized in human skin basal lines, skin sweat glands, and sweat ducts, both in UP and controls. Compared to controls, AQP5 mRNA abundance was significantly decreased in UP (P < 0.01), and, with the decrease of eGFR, the AQP5 expression was significantly decreased (P < 0.05). By contrast, UT-A1 and UT-B1 mRNA abundance was significantly increased in the skin of UP compared with the control (P < 0.01), and, with the decrease of eGFR, the AQP5 expression was significantly increased (P < 0.05). We found that the gene changes were coincident with the corresponding target proteins. The urea transporter subtypes, UT-A1 and UT-B1, were expressed in the skin basal cell layer and exocrine sweat glands. The abundance of UT-A1 and UT-B1 in uremic sweat glands was significantly increased in UP, while the expression of AQP5 was decreased. Conclusion: Elimination of urea through the skin by producing sweat is a potential therapeutic strategy for renal failure patients. PMID- 29279853 TI - Insulin Resistance, Type 1 and Type 2 Diabetes, and Related Complications 2017. PMID- 29279854 TI - Victimization and Human Immunodeficiency Virus-Related Risk Among Transgender Women in India: A Latent Profile Analysis. AB - Globally, transgender women (TGW) experience multiple forms of victimization such as violence and discrimination that can place them at risk for poor sexual health. To date, research overlooks the heterogeneity in experiences of victimization among TGW. Furthermore, few studies have examined the association between victimization and sexual risk among TGW in India, despite the high burden of HIV and victimization in this community. Latent profile analysis was performed to identify patterns of victimization in a convenience sample of 299 TGW recruited from nongovernmental organizations across four states in India. Analysis of covariance was performed to examine differences in sexual risk (i.e., alcohol use before sex; inconsistent condom use with a male regular partner, a male causal partner, and a male paying partner; and having multiple sexual partners) between latent profiles. Five distinct profiles of Indian TGW were identified based on the type and severity of victimization: (1) Low victimization, (2) High verbal police victimization, (3) High verbal and physical police victimization, (4) Moderate victimization, and (5) High victimization. While controlling for age, education, income, HIV status, and marital status, results revealed that TGW in the moderate victimization and high victimization profiles had higher sexual risk than TGW in the low victimization and high verbal police victimization profiles. In addition, TGW in high verbal and physical police victimization profile had higher sexual risk than TGW in low victimization profile. These findings underscore the importance of tailoring sexual risk reduction interventions to the specific needs of TGW based on patterns of victimization. PMID- 29279855 TI - Child Abuse and Neglect, and Psychiatric Disorders in Nonviolent and Violent Female Offenders. AB - Although the percentage of crimes committed by females has increased over the last 20 years in the United States, most research focuses on crimes by males. This article describes an examination of the extent to which childhood maltreatment predicts violent and nonviolent offending in females and the role of psychiatric disorders. Using data from a prospective cohort design study, girls with substantiated cases of physical and sexual abuse and neglect were matched with nonmaltreated girls (controls) on the basis of age, race, and approximate family socioeconomic class, and followed into adulthood (N = 582). Information was obtained from official arrest records and participant responses to a standardized structured psychiatric interview. Women with a history of any childhood maltreatment, physical abuse, sexual abuse, and neglect were at significantly increased risk for having an arrest for violence, compared to control women. Except for those with a history of physical abuse, abused and neglected women were also at increased risk for arrest for a nonviolent crime, compared to controls. In bivariate chi-square comparisons, the three groups of women (violent offenders, nonviolent offenders, and nonoffenders) differed significantly in the diagnoses of posttraumatic stress disorder (PTSD), alcohol abuse, drug abuse, and dysthymia, but not major depressive disorder, and violent female offenders had significantly higher rates of these disorders compared to nonoffenders. However, with controls for age and race, PTSD was the only psychiatric disorder to distinguish women arrested for a violent crime compared to a nonviolent crime (adjusted odds ratio [AOR] = 6.32, confidence interval [95% CI] = 1.84-21.68, p < 0.01), and PTSD moderated the relationship between childhood maltreatment and violent offending (AOR = 5.55, 95% CI = 1.49-20.71): women with histories of childhood maltreatment were equally likely to have an arrest for violence, regardless of PTSD diagnosis, whereas having a diagnosis of PTSD increased the risk of violence for women without maltreatment histories. Together, these findings suggest two pathways to violent offending among females one through childhood maltreatment and a second through PTSD. Implications of these findings are discussed. PMID- 29279856 TI - Corrigendum to "Rheumatological Findings in Candidates for Valvular Heart Surgery". AB - [This corrects the article DOI: 10.5402/2012/927923.]. PMID- 29279857 TI - Corrigendum to "Comparison between Fluconazole with Oral Protexin Combination and Fluconazole in the Treatment of Vulvovaginal Candidiasis". AB - [This corrects the article DOI: 10.5402/2012/375806.]. PMID- 29279858 TI - Unsupervised Network Analysis of the Plastic Supraoptic Nucleus Transcriptome Predicts Caprin2 Regulatory Interactions. AB - The supraoptic nucleus (SON) is a group of neurons in the hypothalamus responsible for the synthesis and secretion of the peptide hormones vasopressin and oxytocin. Following physiological cues, such as dehydration, salt-loading and lactation, the SON undergoes a function related plasticity that we have previously described in the rat at the transcriptome level. Using the unsupervised graphical lasso (Glasso) algorithm, we reconstructed a putative network from 500 plastic SON genes in which genes are the nodes and the edges are the inferred interactions. The most active nodal gene identified within the network was Caprin2. Caprin2 encodes an RNA-binding protein that we have previously shown to be vital for the functioning of osmoregulatory neuroendocrine neurons in the SON of the rat hypothalamus. To test the validity of the Glasso network, we either overexpressed or knocked down Caprin2 transcripts in differentiated rat pheochromocytoma PC12 cells and showed that these manipulations had significant opposite effects on the levels of putative target mRNAs. These studies suggest that the predicative power of the Glasso algorithm within an in vivo system is accurate, and identifies biological targets that may be important to the functional plasticity of the SON. PMID- 29279859 TI - Boosting of Thalamic D2 Dopaminergic Transmission: A Potential Strategy for Drug Seeking Attenuation. AB - This commentary focuses on novel findings by Clark et al. (2017) published in eNeuro, which show that dopamine D2 receptors (D2Rs) in the paraventricular nucleus of the thalamus (PVT) are involved in cocaine sensitization. We extend the discussion on how their findings contribute to our understanding of the role of the PVT in drug seeking by providing new insight on the role of the PVT in the regulation of food-seeking and fear responses. We also consider the significance of the neuroanatomical findings reported by Clark et al., that the PVT is reciprocally connected with areas of the brain involved in addiction and discuss the implications associated with the source and type of dopaminergic fibers innervating this area of the thalamus. PMID- 29279860 TI - Cortical Neuroprosthesis Merges Visible and Invisible Light Without Impairing Native Sensory Function. AB - Adult rats equipped with a sensory prosthesis, which transduced infrared (IR) signals into electrical signals delivered to somatosensory cortex (S1), took approximately 4 d to learn a four-choice IR discrimination task. Here, we show that when such IR signals are projected to the primary visual cortex (V1), rats that are pretrained in a visual-discrimination task typically learn the same IR discrimination task on their first day of training. However, without prior training on a visual discrimination task, the learning rates for S1- and V1 implanted animals converged, suggesting there is no intrinsic difference in learning rate between the two areas. We also discovered that animals were able to integrate IR information into the ongoing visual processing stream in V1, performing a visual-IR integration task in which they had to combine IR and visual information. Furthermore, when the IR prosthesis was implanted in S1, rats showed no impairment in their ability to use their whiskers to perform a tactile discrimination task. Instead, in some rats, this ability was actually enhanced. Cumulatively, these findings suggest that cortical sensory neuroprostheses can rapidly augment the representational scope of primary sensory areas, integrating novel sources of information into ongoing processing while incurring minimal loss of native function. PMID- 29279862 TI - Editorial: Experimental Bias in Electrophysiological Studies. PMID- 29279861 TI - The Magnitude of Trial-By-Trial Neural Variability Is Reproducible over Time and across Tasks in Humans. AB - Numerous studies have shown that neural activity in sensory cortices is remarkably variable over time and across trials even when subjects are presented with an identical repeating stimulus or task. This trial-by-trial neural variability is relatively large in the prestimulus period and considerably smaller (quenched) following stimulus presentation. Previous studies have suggested that the magnitude of neural variability affects behavior such that perceptual performance is better on trials and in individuals where variability quenching is larger. To what degree are neural variability magnitudes of individual subjects flexible or static? Here, we used EEG recordings from adult humans to demonstrate that neural variability magnitudes in visual cortex are remarkably consistent across different tasks and recording sessions. While magnitudes of neural variability differed dramatically across individual subjects, they were surprisingly stable across four tasks with different stimuli, temporal structures, and attentional/cognitive demands as well as across experimental sessions separated by one year. These experiments reveal that, in adults, neural variability magnitudes are mostly solidified individual characteristics that change little with task or time, and are likely to predispose individual subjects to exhibit distinct behavioral capabilities. PMID- 29279863 TI - Combinatorial Inputs to the Ventral Striatum from the Temporal Cortex, Frontal Cortex, and Amygdala: Implications for Segmenting the Striatum. AB - The canonical striatal map, based predominantly on frontal corticostriatal projections, divides the striatum into ventromedial-limbic, central-association, and dorsolateral-motor territories. While this has been a useful heuristic, recent studies indicate that the striatum has a more complex topography when considering converging frontal and nonfrontal inputs from distributed cortical networks. The ventral striatum (VS) in particular is often ascribed a "limbic" role, but it receives diverse information, including motivation and emotion from deep brain structures, cognition from frontal cortex, and polysensory and mnemonic signals from temporal cortex. Using anatomical tract-tracing in 17 male adult monkeys (Macaca nemestrina, Macaca fascicularis, Macaca mulatta), we build upon this striatal map by systematically mapping inputs from frontal cortex, amygdala, temporal pole, and medial temporal cortex. We find that the VS contains heterogeneous subregions that become apparent when considering both the identities and strengths of inputs. We parcellated the VS into a ventromedial sector receiving motivation and emotion-related information from regions including area TG, ventromedial PFC, ACC, and amygdala; and a more functionally diverse dorsolateral sector that receives this information coupled to cognitive and sensorimotor information from dorsolateral PFC, ventrolateral PFC, premotor cortex, area TAr, and area TEr. Each sector was further parcellated into smaller regions that had different proportions of these inputs. Together, the striatum contains complex, selective input combinations, providing substrates for myriad associations. This VS parcellation provides a map that can guide and interpret functional interactions in healthy individuals and those with psychiatric disorders, and may be useful in targeting treatments for specific psychiatric conditions. PMID- 29279864 TI - Skin-like biosensor system via electrochemical channels for noninvasive blood glucose monitoring. AB - Currently, noninvasive glucose monitoring is not widely appreciated because of its uncertain measurement accuracy, weak blood glucose correlation, and inability to detect hyperglycemia/hypoglycemia during sleep. We present a strategy to design and fabricate a skin-like biosensor system for noninvasive, in situ, and highly accurate intravascular blood glucose monitoring. The system integrates an ultrathin skin-like biosensor with paper battery-powered electrochemical twin channels (ETCs). The designed subcutaneous ETCs drive intravascular blood glucose out of the vessel and transport it to the skin surface. The ultrathin (~3 MUm) nanostructured biosensor, with high sensitivity (130.4 MUA/mM), fully absorbs and measures the glucose, owing to its extreme conformability. We conducted in vivo human clinical trials. The noninvasive measurement results for intravascular blood glucose showed a high correlation (>0.9) with clinically measured blood glucose levels. The system opens up new prospects for clinical-grade noninvasive continuous glucose monitoring. PMID- 29279865 TI - Rain-fed agriculture thrived despite climate degradation in the pre-Hispanic arid Andes. AB - Archaeological research suggests significant human occupation in the arid Andean highlands during the 13th to 15th centuries, whereas paleoclimatic studies reveal prolonged drier and colder conditions during that period. Which subsistence strategy supported local societies in this harsh environment? Our field and aerial surveys of archaeological dwelling sites, granaries, and croplands provide the first evidence of extended pre-Hispanic agriculture supporting dense human populations in the arid Andes of Bolivia. This unique agricultural system associated with quinoa cultivation was unirrigated, consisting of simple yet extensive landscape modifications. It relied on highly specific environmental knowledge and a set of water-saving practices, including microterracing and biennial fallowing. This intense agricultural activity developed during a period of unfavorable climatic change on a regional and global scale, illustrative of efficient adaptive strategies to cope with this climatic change. PMID- 29279866 TI - Penetration mechanics of a beetle intromittent organ with bending stiffness gradient and a soft tip. AB - Hyper-elongated structures and their penetration are widespread among insects, for example, intromittent organs, ovipositors, and piercing-sucking mouthparts. The penetration of thin structures with high aspect ratio without buckling and rupturing is mechanically very challenging. However, this problem is economically solved in nature, and the solutions might be helpful for, for example, in the development of harmless catheters. We focus on the penetration process of a hyper elongated structure of a cassidine beetle intromittent organ, termed a flagellum. We applied a three-point bending test for the flagellum to measure its bending stiffness along the entire flagellum. We demonstrated the bending stiffness gradient, in which the basal half is relatively stiff and the apical half is softer, whose good performance during copulation had been previously numerically demonstrated. The stiffness gradient is the result of the flagellum shape, which is cylindrical and tapered toward the tip. Moreover, the curved tip comprises a harder outer curve and a softer inner curve. Considering the findings of preceding studies, the flagellum works in the following way: (i) the bending stiffness gradient supports the flagellum, easily fitting to a shape of a highly coiled spermathecal duct, (ii) the stiffness property of the very tip may make the tip tougher, and (iii) the curled tip and homogeneously cylindrical shape of the organ help the very tip to fit the shape of the spermathecal duct of the female. Our study shows that the apparently simple flagellum penetration is achieved with numerous elaborate mechanical adaptations. PMID- 29279868 TI - Uretero-Arterio-Enteric Fistula Formation and Stent Thrombosis After Endovascular Treatment of Ureteroarterial Fistula: A Case Report and Review of Literature. AB - Background: Ureteroarterial fistulas (UAFs) are rare life-threatening complications of indwelling ureteral stents. Endovascular repair of these fistulas is now commonly used but the long-term outcomes are unknown. Case Presentation: We present a 51-year-old African American female with history of cervical cancer status after a hysterectomy and radiation. She has bilateral ureteral strictures that were managed with chronic, indwelling ureteral stents. She subsequently developed a right UAF and was treated with an endovascular stent to the external iliac artery. After 2 years, she subsequently developed hematuria and hematochezia and was found to have a uretero-arterial-enteric fistula. We performed an exploratory laparotomy and repair of the fistula. The patient was subsequently managed with indwelling nephrostomy tubes and had no further episodes of bleeding. Conclusion: To our knowledge, this is the first reported case of uretero-arterial-enteric fistula after endovascular treatment of UAF. Our experience demonstrates the need for a high index of suspicion and close surveillance after treatment for patients with UAF. PMID- 29279867 TI - In vivo genome editing improves motor function and extends survival in a mouse model of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord and brain. In particular, autosomal dominant mutations in the superoxide dismutase 1 (SOD1) gene are responsible for ~20% of all familial ALS cases. The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated (Cas9) genome editing system holds the potential to treat autosomal dominant disorders by facilitating the introduction of frameshift-induced mutations that can disable mutant gene function. We demonstrate that CRISPR-Cas9 can be harnessed to disrupt mutant SOD1 expression in the G93A-SOD1 mouse model of ALS following in vivo delivery using an adeno-associated virus vector. Genome editing reduced mutant SOD1 protein by >2.5-fold in the lumbar and thoracic spinal cord, resulting in improved motor function and reduced muscle atrophy. Crucially, ALS mice treated by CRISPR-mediated genome editing had ~50% more motor neurons at end stage and displayed a ~37% delay in disease onset and a ~25% increase in survival compared to control animals. Thus, this study illustrates the potential for CRISPR-Cas9 to treat SOD1-linked forms of ALS and other central nervous system disorders caused by autosomal dominant mutations. PMID- 29279869 TI - Bilateral Renal Anastomosing Hemangiomas: A Tale of Two Kidneys. AB - Background: Renal anastomosing hemangioma (RAH) is an extremely rare benign vascular tumor first described in 2009. Making this diagnosis is fraught with challenges. Radiologically they share features consistent with renal cell carcinomas (RCCs). Their vascular nature poses risks if considering preoperative biopsy and histologically they share characteristics akin to angiosarcomas. The few reports published in the literature suggest presentation with hematuria, flank pain, and polycythemia although the majority are diagnosed at postnephrectomy histologic examination. This case represents the first metachronous RAH in the literature, and is the first RAH presenting with severe hemorrhage. Case Presentation: A 62-year-old woman of Albanian heritage presented to urology with visible hematuria and positive urine cytology. Three years before this presentation, she had undergone an elective radical right-sided nephrectomy for a suspected RCC detected on magnetic resonance imaging, which proved to be an RAH after postoperative histologic examination of the specimen. The patient was investigated with cystoscopy and ureteroscopy for this new hematuria presentation, both of which were unremarkable. Fourteen hours post ureteroscopy, the patient became severely hypotensive and developed acute kidney injury. A CT scan indicated a large left-sided renal subcapsular and retroperitoneal hematoma that was actively bleeding. The patient was hemodynamically unstable and, therefore, required an emergency open left-sided nephrectomy, rendering her anephric and dialysis dependent. Postoperative histologic examination proved that the left kidney also contained an RAH. Conclusion: The anastomosing hemangioma is an important subtype to differentiate from angiosarcoma before and after a nephrectomy. Urologists should carefully consider invasive tests in patients with previously diagnosed vascular lesions as there may be an increased risk of bleeding. Patients with a previously diagnosed anastomosing hemangioma may require surveillance of the contralateral kidney. PMID- 29279870 TI - Percutaneous Stone Removal in an Adult with a Continent Cutaneous Reservoir: Case Report and Review of the Literature. AB - Stone formation is a known long-term complications of continent urinary reservoirs. We present a rare case of a large stone in a continent cutaneous reservoir in a 56-year-old male managed with percutaneous cystolithotomy. The patient presented with recurrent urinary tract infections and stomal incontinence. CT revealed an 8-cm stone occupying the entire lumen of his reservoir. Rather than removing this large stone through an open approach, the pouch was accessed percutaneously and lithotripsy was performed. In this report, we demonstrate our operative technique and that percutaneous cystolithalopaxy may be a safe and effective alternative for the management of large stones within continent cutaneous reservoirs. PMID- 29279871 TI - Primary Vaginal Calculus in a Woman with Disability: Case Report and Literature Review. AB - Background: Vaginal stones are rare and often unknown entities. Most urologists may never see a case in their careers. Case Presentation: We present the case of a 34-year-old bedridden Caucasian woman with mental and physical disabilities who presented with a large primary vaginal calculus, which, surprisingly, had remained undiagnosed until the patient suffered a right renal colic caused by a ureteral stone. The vagina was completely filled and a digital examination was not possible. For this reason, the stone was removed using surgical pliers with some maneuvering. A vesicovaginal fistula was excluded, as well as foreign bodies or other nidi of infection. After, urethral lithotripsy was performed as planned. The postoperative course and follow-up were uneventful. Conclusion: Although vaginal calculi are extremely rare in literature, their differential diagnosis should be considered in women with incontinence and associated disabilities, paraplegia, or prolonged immobilization in recumbent position. PMID- 29279872 TI - Massive Dilation of the Ureter: An Endoscopic Management of Persistent Urinary Leak After Partial Nephrectomy. AB - Introduction: The incidence of urinary leakage is increased as nephron sparing surgery becomes more used for the management of small renal masses. We present an endourologic approach in a patient with a persistent urinary leak after partial nephrectomy by placing two synchronous ureteral stents to improve drainage and avoid further potential surgery. Patients and Method: A 39-year-old patient presented with a urine leak on the fifth postoperative day after an open partial nephrectomy. Initially, the leakage was managed with a placement of a 6F Double-J stent. However, due to persistence of leakage after a month, two ureteral stents (a 6F Double-J stent and a 14F endopyelotomy stent) were placed. With this maneuver, the ureter was dilated to 20F and a bladder catheter was placed to complete the drainage. Results: At 3 weeks, a CT urography was performed, which showed complete resolution of the urinary leakage compared with previous examination. The stents were removed the following day and the patient required no further intervention. The follow-up examination was continued for 24 months without any symptom of the patient and any sign of leak recurrence. Conclusion: Endoscopic approach to urinary leak after partial nephrectomy obtaining high ureteral gauge can be a good alternative, avoiding more aggressive surgical approaches. PMID- 29279873 TI - Wandering Double-J Stent in the Retroperitoneum: A Case Report. AB - Background: Double-J (DJ) stent is an integral part of urologic practice. DJ stents can have numerous complications such as persistent irritative symptoms, encrustations, and up and down migrations within the pelvicaliceal system (PCS), but displacement outside the urinary tract is rare. We are presenting a unique case of DJ stent lying outside the PCS for more than a decade. Case Presentation: A 46-year-old female presented with left flank pain and dysuria. She had undergone percutaneous nephrolithotomy in the left side 11 years ago. Imaging studies revealed a forgotten DJ stent with proximal part lying in the PCS with dense encrustations and the distal coil in the retroperitoneum at the level of the contralateral sacroiliac joint with the shaft crossing the midline at fourth lumbar vertebral level. The malpositioned forgotten stent was removed intact using the multimodal endourologic technique. During follow-up, the patient had prompt relief of symptoms and a preserved renal unit. Conclusion: To the best of our knowledge, this is the first report of malpositioned and forgotten DJ stent for more than a decade with lower end lying near the opposite lower ureter managed effectively by an endourologic method. PMID- 29279874 TI - Calcium Tartrate Tetrahydrate, Case Report of a Novel Human Kidney Stone. AB - Background: Calcium tartrate tetrahydrate has been reported as the main mineral in urinary stones in rats that have significant tartrate in their diet, but in humans, there has been only one mention of calcium tartrate stones in the form of bladder stone, and that case was in Africa. Case Presentation: Patient is a 34 year-old Caucasian male who presented with typical symptoms of nephrolithiasis. CT abd/pelvis (renal stone protocol) revealed a 2 cm nonobstructing stone of the right renal pelvis. Patient underwent an uncomplicated right percutaneous nephrolithotomy and was noted to be stone free after surgery. Stone analysis was difficult with regard to determining composition, but was finally identified as calcium tartrate tetrahydrate. Conclusion: This was an unusual case, as this is the first recorded case of a calcium tartrate tetrahydrate outside of Africa. This type of stone had only been mainly described in rat models with dl bitartrate in their diet. Our patient was an otherwise healthy, relatively muscular individual with no obvious source for this stone other than a vitamin and amino acid supplement that he takes regularly that contains l-carnitine (as tartrate) and choline (as bitartrate and citrate). The prevalence of this stone type is presently unknown, as stone analysis laboratories have not had the ability to recognize it. Although a connection between the supplement and stone formation is conjecture at this time, we believe this necessitates further investigation. PMID- 29279875 TI - Enacted Stigma, Mental Health, and Protective Factors Among Transgender Youth in Canada. AB - Purpose: We aimed to assess the Minority Stress Model which proposes that the stress of experiencing stigma leads to adverse mental health outcomes, but social supports (e.g., school and family connectedness) will reduce this negative effect. Methods: We measured stigma-related experiences, social supports, and mental health (self-injury, suicide, depression, and anxiety) among a sample of 923 Canadian transgender 14- to 25-year-old adolescents and young adults using a bilingual online survey. Logistic regression models were conducted to analyze the relationship between these risk and protective factors and dichotomous mental health outcomes among two separate age groups, 14- to 18-year-old and 19- to 25 year-old participants. Results: Experiences of discrimination, harassment, and violence (enacted stigma) were positively related to mental health problems and social support was negatively associated with mental health problems in all models among both age groups. Among 14-18 year olds, we examined school connectedness, family connectedness, and perception of friends caring separately, and family connectedness was always the strongest protective predictor in multivariate models. In all the mental health outcomes we examined, transgender youth reporting low levels of enacted stigma experiences and high levels of protective factors tended to report favorable mental health outcomes. Conversely, the majority of participants reporting high levels of enacted stigma and low levels of protective factors reported adverse mental health outcomes. Conclusion: While these findings are limited by nonprobability sampling procedures and potential additional unmeasured risk and protective factors, the results provide positive evidence for the Minority Stress Model in this population and affirm the need for policies and programs to support schools and families to support transgender youth. PMID- 29279876 TI - Underactive bladder. PMID- 29279877 TI - Definition and symptoms of underactive bladder. AB - Underactive bladder (UAB) is a symptom syndrome reflecting the urodynamic observation of detrusor underactivity (DU), a voiding contraction of reduced strength and/or duration, leading to prolonged or incomplete bladder emptying. An International Continence Society Working Group has described UAB as characterised by a slow urinary stream, hesitancy and straining to void, with or without a feeling of incomplete bladder emptying and dribbling, often with storage symptoms. Since DU often coexists with bladder outlet obstruction, or storage dysfunction (detrusor overactivity or incontinence), the exact contribution of the DU to the presenting complaints can be difficult to establish. The presence of voiding and post voiding lower urinary tract symptoms (LUTS) is implicitly expected in UAB, but a reduced sensation of fullness is reported by some patients, and storage LUTS are also an important factor in many affected patients. These may result from a postvoid residual, but often they do not. The storage LUTS are often the key driver in leading the patient to seek healthcare input. Nocturia is particularly common and bothersome, but what the role of DU is in all the range of influences on nocturia has not been established. Qualitative research has established a broad impact on everyday life as a result of these symptoms. In general, people appear to manage the voiding LUTS relatively well, but the storage LUTS may be problematic. PMID- 29279878 TI - Epidemiology of underactive bladder: Common but underresearched. AB - Detrusor underactivity (DU) or underactive bladder is a common cause of lower urinary tract symptoms (LUTS), but it is still poorly understood and underresearched. Although there has been a proposed definition by International Continence Society in 2002, no widely accepted diagnostic criteria have been established for this entity in clinical practice. Therefore, it has been rare to identify community-based researches on the epidemiology of DU until now. Only certain studies have reported the prevalence of DU in community-dwelling cohorts with significant LUTS using arbitrary urodynamic criteria for DU and these investigations have indicated that DU accounts for 25%-48% and 12%-24% of elderly men and women, respectively. However, these prevalence data based on the urodynamic definition apparently are limited in their extrapolation to the general population. Despite the clinical ambiguity of DU, its clinical effects on quality of life are quite significant, especially in the elderly population. An overall and proper comprehension of epidemiologic studies of DU may be crucial for better insight into DU, relevant decision making, and a more reasonable allocation of health resources. Therefore, researchers should find clues to the solution for the clinical diagnosis of this specific condition of LUTS from contemporary epidemiologic studies and try to develop a possible definition of 'clinical' DU from further studies. PMID- 29279879 TI - Clinical implications of underactive bladder. AB - Underactive bladder (UAB) is a common urologic condition but a complex disease that causes troublesome lower urinary tract symptoms. Currently, management of UAB remains unsatisfactory. Also, many urological diseases can be combined with UAB. In these combined cases, the treatment results may be affected by UAB component. This review focuses on the clinical implications of UAB in patients with common urologic conditions, including bladder outlet obstruction, overactive bladder syndrome and stress urinary incontinence. PMID- 29279880 TI - Pathophysiology of the underactive bladder. AB - Underactive bladder (UAB), which has been described as a symptom complex suggestive of detrusor underactivity, is usually characterized by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and slow stream often with storage symptoms. Several causes such as aging, bladder outlet obstruction, diabetes mellitus, neurologic disorders, and nervous injury to the spinal cord, cauda equine, and peripheral pelvic nerve have been assumed to be responsible for the development of UAB. Several contributing factors have been suggested in the pathophysiology of UAB, including myogenic failure, efferent and/or afferent dysfunctions, and central nervous system dysfunction. In this review article, we have described relationships between individual contributing factors and the pathophysiology of UAB based on previous reports. However, many pathophysiological uncertainties still remain, which require more investigations using appropriate animal models. PMID- 29279881 TI - Current pharmacological and surgical treatment of underactive bladder. AB - Generally accepted guidelines are not yet available on the management of underactive bladder (UAB). Although the natural history of UAB is still not fully understood, observation may be an acceptable management option in patients with tolerable lower urinary tract symptoms and little risk of upper urinary tract damage. If needed, scheduled and double voiding may be recommended as an effective and safe add-on therapy. Parasympathomimetics have been widely used for the management of UAB, but the evidence does not support clinical benefit. The efficacy of alpha-blockers has also not yet been clearly demonstrated. However, selective alpha-blockers may help to enhance voiding efficiency and to decrease possible upper tract damage. Sacral neuromodulation is a surgical option for nonobstructive UAB approved by the Food and Drug Administration. However, the response rate of test stimulation is not high and the efficacy of permanent implants does not always coincide with that of test stimulation. Although surgery to reduce outlet resistance may be a viable option in UAB with presumed obstruction, surgery seems to have little role in those without obstruction. Latissimus dorsi detrusor myoplasty has shown promising results in restoring voluntary voiding in selected patients. The procedure requires a multidisciplinary team approach of urologists and plastic reconstructive experts. In summary, current treatments of UAB remain unsatisfactory. The multifactorial nature of UAB pathogenesis complicates the appropriate management for each patient. Future research to establish a more clinically relevant definition of UAB will be required to open new era of UAB management. PMID- 29279883 TI - Periconceptional Folate Supplementation and the Risk of Autism Following Antiepileptic Drug Exposure. PMID- 29279882 TI - New therapeutic directions to treat underactive bladder. AB - Underactive bladder (UAB) is a term used to describe a constellation of symptoms that is perceived by patients suggesting bladder hypocontractility. Urodynamic measurement that suggest decreased contractility of the bladder is termed detrusor underactivity (DUA). Regulatory approved specific management options with clinically proven ability to increase bladder contractility do not currently exist. While DUA specific treatments presumably will focus on methods to increase efficiency of bladder emptying capability relying on augmenting the motor pathway in the micturition reflex, other approaches include methods to augment the sensory (afferent) contribution to the micturition reflex which could result in increased detrusor contractility. Another method to induce more efficient bladder emptying could be to induce relaxation of the bladder outlet. Using cellular regenerative techniques, the detrusor smooth muscle can be targeted so the result is to increase detrusor smooth muscle function. In this review, we will cover areas of potential new therapies for DUA including: drug therapy, stem cells and regenerative therapies, neuromodulation, and urethral flow assist device. Paralleling development of new therapies, there also needs to be clinical studies performed that address how DUA relates to UAB. PMID- 29279884 TI - Use of Advanced Imaging Tests and the Not-So-Incidental Harms of Incidental Findings. PMID- 29279885 TI - Questioning the Effectiveness of Newer Antiseizure Medications. PMID- 29279886 TI - Association of Hospitalist Years of Experience With Mortality in the Hospitalized Medicare Population. AB - Importance: Substantial numbers of hospitalists are fresh graduates of residency training programs. Current data about the effect of hospitalist years of experience on patient outcomes are lacking. Objective: To describe the association of hospitalist years of experience with 30-day mortality and hospital mortality of their patients. Design, Setting, and Participants: We used a 5% sample of national Medicare data of patient and hospital characteristics to build a multilevel logistic regression model to predict mortality as a function of years of experience of the hospitalists. We created 2 cohorts. The first was a cross-sectional cohort of 21 612 hospitalists working between July 1, 2013, and June 30, 2014, with a 5-year look-back period to assess their years of prior experience as a hospitalist, and the second was a longitudinal cohort of 3860 hospitalists in their first year of practice between July 1, 2008, and June 30, 2011, who continued practicing hospital medicine for at least 4 years. Main Outcomes and Measures: Thirty-day postadmission mortality adjusted for patient and hospital characteristics in a 3-level logistic regression model. Hospital mortality was a secondary outcome. Results: Among 21 612 hospitalists caring for Medicare inpatients from July 1, 2013, to June 30, 2014, 5445 (25%) had 1 year of experience or less, while 11 596 (54%) had 4 years of experience or more. We then identified 3860 physicians in their first year as hospitalists who continued to practice as hospitalists for 4 years. There was a significant association between hospitalist experience and mortality. Observed 30-day mortality was 10.50% for patients of first-year hospitalists vs 9.97% for patients of hospitalists in their second year. The mortality odds for patients of second-year hospitalists were 0.90 (95% CI, 0.84-0.96) compared with patients of first-year hospitalists. Observed hospital mortality was 3.33% for patients cared for by first-year hospitalists vs 2.96% for second-year hospitalists. (odds ratio, 0.84; 95% CI, 0.75-0.95). For both 30-day and hospital mortality, there was little change in odds of mortality between the second year and subsequent years of experience. Conclusions and Relevance: Patients cared for by hospitalists in their first year of practice experience higher mortality. Early-career hospitalists may require additional support to ensure optimal outcomes for their patients. PMID- 29279887 TI - Regional Variation of Computed Tomographic Imaging in the United States and the Risk of Nephrectomy. AB - Importance: While computed tomography (CT) represents a tremendous advance in diagnostic imaging, it also creates the problem of incidental detection-the identification of tumors unrelated to the clinical symptoms that initiate the test. Objective: To determine the geographic variation in the United States in CT imaging and the corresponding association with one of the most consequential sequelae of incidental detection: nephrectomy. Design, Setting, and Participants: This study is a cross-sectional analysis of age-, sex-, and race-adjusted Medicare data (January 2010-December 2014) from 306 hospital referral regions (HRRs) in the United States and includes information from 15 million fee-for service Medicare beneficiaries age 65 to 85 years. Exposures: Regional CT risk (ie, the proportion of the population receiving either a chest or abdominal CT over 5 years). Main Outcomes and Measures: Five-year risk of nephrectomy (partial or total). Results: Data from 15 million fee-for-service Medicare beneficiaries age 65 to 85 years were gathered and illustrate that 43% of Medicare beneficiaries age 65 to 85 years received either a chest or abdominal CT from January 2010 to December 2014. This risk varied across the HRRs, ranging from 31% in Santa Cruz, California, to 52% in Sun City, Arizona. Increased regional CT risk was associated with a higher nephrectomy risk (r = 0.38; 95% CI, 0.28-0.47), particularly among HRRs with more than 50 000 beneficiaries (r = 0.47; 95% CI, 0.31-0.61). After controlling for HRR adult smoking rates, imaging an additional 1000 beneficiaries was associated with 4 additional nephrectomies (95% CI, 3-5). Case-fatality rates for those who underwent nephrectomy were 2.1% at 30 days and 4.3% at 90 days. Conclusions and Relevance: Fee-for-service Medicare beneficiaries are commonly exposed to CT imaging. Those residing in high-scanning regions face a higher risk of nephrectomy, presumably reflecting the incidental detection of renal masses. Additional surgery should be considered one of the risks of excessive CT imaging. PMID- 29279889 TI - Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. AB - Importance: Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important. Objective: To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure. Design, Setting, and Participants: The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163 844 of 277 702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n = 104 946) were included in the analysis from March 1, 2016, through June 13, 2017. Exposures: Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19. Main Outcomes and Measures: Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits. Results: The overall mean (SD) age of the 104 946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2 1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (beta = -0.3; P = .03) and folic acid doses (beta = 0.5; P < .001). Concentrations of AEDs were not associated with the degree of autistic traits. Conclusions and Relevance: Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously. PMID- 29279888 TI - Prevalence of Systemic Atherosclerosis Burdens and Overlapping Stroke Etiologies and Their Associations With Long-term Vascular Prognosis in Stroke With Intracranial Atherosclerotic Disease. AB - Importance: Patients who have experienced stroke with intracranial atherosclerotic disease (ICAD) may also have concomitant atherosclerosis in different arterial beds and other possible causes for ischemic stroke. However, little is known about the frequency and prognostic effect of such overlapping diseases. Objectives: To describe the prevalence of systemic atherosclerotic burdens and overlapping stroke etiologies and their contributions to long-term prognoses among patients who have experienced stroke with ICAD. Design, Setting, and Participants: The Asymptomatic Myocardial Ischemia in Stroke and Atherosclerotic Disease study is a single-center prospective study in which 405 patients with acute ischemic stroke within 10 days of onset were consecutively enrolled between June 2005 and December 2008 and followed up for 4 years. After excluding 2 patients because of incomplete investigations, 403 were included in this analysis. Main Outcomes and Measures: Significant ICAD was defined as having 50% or greater stenosis/occlusion by contrast-enhanced/time-of-flight magnetic resonance angiography, computed tomography angiography, and/or transcranial Doppler ultrasonography. Systemic vascular investigations on atherosclerotic disease were performed with ultrasonography in carotid arteries, aorta and femoral arteries, and by angiography in coronary arteries. Coexistent stroke etiologies were assessed using the atherosclerosis, small-vessel disease, cardiac pathology, other cause, and dissection (ASCOD) grading system. We estimated the 4 year risk of major adverse cardiovascular events (MACE), including vascular death, nonfatal cardiac events, nonfatal stroke, and major peripheral arterial events. Results: Of 403 participants, 298 (74%) were men and the mean (SD) age was 62.6 (13.1) years. Significant ICAD was found in 146 (36.2%). Patients with significant ICAD more often had aortic arch (70 [60.9%] vs 99 [49.0%]; P = .04) and coronary artery (103 [76.9%] vs 153 [63.2%]; P = .007) atherosclerosis than those without. Among patients with ICAD, concurrent stenosis in the extracranial carotid artery (24 [23.4%] vs 3 [9.0%]; P = .08; adjusted hazard ratio[aHR] = 2.12) and the coronary artery (19 [29.9%] vs 8 [12.8%]; P = .01; aHR = 1.90) increased the MACE risk. Furthermore, patients with ICAD who also had any cardiac pathology (ASCOD grade C1-3) were at a higher MACE risk than others (grade C0) (20 [28.2%] vs 7 [11.4%]; P = .01; aHR = 2.24). By contrast, patients with ICAD with any form of small vessel disease (grade S1-3) had a lower MACE risk than those without (grade S0) (20 [17.3%] vs 6 [34.6%]; P = .05; aHR = 0.23). Conclusions and Relevance: Patients with ICAD often have coexisting systemic atherosclerosis and multiple potential stroke mechanisms that affect their prognosis, suggesting that extensive evaluations of overlapping diseases may allow better risk stratification. PMID- 29279890 TI - Atypical Cause of "Typical" Hypertensive Intracranial Bleeding. PMID- 29279891 TI - Hypoglycemia in Hospice Patients With Type 2 Diabetes in a National Sample of Nursing Homes. PMID- 29279893 TI - Are Structural Magnetic Resonance Imaging and General Movements Assessment Sufficient for Early, Accurate Diagnosis of Cerebral Palsy? PMID- 29279892 TI - Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study. AB - Importance: A study published in 2000 showed that more than one-third of adults with epilepsy have inadequate control of seizures with antiepileptic drugs (AEDs). This study evaluates overall treatment outcomes in light of the introduction of more than 1 dozen new AEDs in the past 2 decades. Objective: To assess long-term treatment outcome in patients with newly diagnosed and treated epilepsy. Design, Setting, and Participants: This longitudinal observational cohort study was conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. A total of 1795 individuals who were newly treated for epilepsy with AEDs between July 1, 1982, and October 31, 2012, were included in this analysis. All patients were followed up for a minimum of 2 years (until October 31, 2014) or until death, whichever came sooner. Data analysis was completed between March 2015 and May 2016. Exposures: Treatment with antiepileptic drugs for patients newly diagnosed with epilepsy. Main Outcomes and Measures: Seizure control was assessed at the end of the study period. Probability of achieving 1-year seizure freedom was estimated for each AED regimen prescribed. Multivariable models assessed the associations between risk factors and AED treatment outcome after adjustments were made for demographic and clinical characteristics. Results: Of the 1795 included patients, 964 (53.7%) were male; the median age was 33 years (range, 9-93 years). At the end of the study period, 1144 patients (63.7%) had been seizure free for the previous year or longer. Among those achieving 1-year seizure freedom, 993 (86.8%) were taking monotherapy and 1028 (89.9%) had achieved seizure control with the first or second AED regimens. Of the total patient pool, 906 (50.5%) remained seizure free for 1 year or longer with the initial AED. If this AED failed, the second and third regimens provided an additional 11.6% and 4.4% likelihoods of seizure freedom, respectively. Only 2.12% of patients attained optimal seizure control with subsequent AEDs. Epilepsy that was not successfully controlled with the first AED had 1.73 times greater odds of not responding to treatment for each subsequent medication regimen (odds ratio, 1.73; 95% CI, 1.56-1.91; P < .001). Conclusions and Relevance: Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved. Most patients who attain control do so with the first or second AED. The probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried. More than one-third of patients experience epilepsy that remains uncontrolled. PMID- 29279894 TI - Binaural Speech Understanding With Bilateral Cochlear Implants in Reverberation. AB - Purpose: The purpose of this study was to investigate whether bilateral cochlear implant (CI) listeners who are fitted with clinical processors are able to benefit from binaural advantages under reverberant conditions. Another aim of this contribution was to determine whether the magnitude of each binaural advantage observed inside a highly reverberant environment differs significantly from the magnitude measured in a near-anechoic environment. Method: Ten adults with postlingual deafness who are bilateral CI users fitted with either Nucleus 5 or Nucleus 6 clinical sound processors (Cochlear Corporation) participated in this study. Speech reception thresholds were measured in sound field and 2 different reverberation conditions (0.06 and 0.6 s) as a function of the listening condition (left, right, both) and the noise spatial location (left, front, right). Results: The presence of the binaural effects of head-shadow, squelch, summation, and spatial release from masking in the 2 different reverberation conditions tested was determined using nonparametric statistical analysis. In the bilateral population tested, when the ambient reverberation time was equal to 0.6 s, results indicated strong positive effects of head-shadow and a weaker spatial release from masking advantage, whereas binaural squelch and summation contributed no statistically significant benefit to bilateral performance under this acoustic condition. These findings are consistent with those of previous studies, which have demonstrated that head-shadow yields the most pronounced advantage in noise. The finding that spatial release from masking produced little to almost no benefit in bilateral listeners is consistent with the hypothesis that additive reverberation degrades spatial cues and negatively affects binaural performance. Conclusions: The magnitude of 4 different binaural advantages was measured on the same group of bilateral CI subjects fitted with clinical processors in 2 different reverberation conditions. The results of this work demonstrate the impeding properties of reverberation on binaural speech understanding. In addition, results indicate that CI recipients who struggle in everyday listening environments are also more likely to benefit less in highly reverberant environments from their bilateral processors. PMID- 29279895 TI - Characterizing Kaiser Permanente Southern California's Experience With the California End of Life Option Act in the First Year of Implementation. PMID- 29279897 TI - Are Structural Magnetic Resonance Imaging and General Movements Assessment Sufficient for Early, Accurate Diagnosis of Cerebral Palsy?-Reply. PMID- 29279896 TI - Association of Childhood Blood Lead Levels With Criminal Offending. AB - Importance: Lead is a neurotoxin with well-documented effects on health. Research suggests that lead may be associated with criminal behavior. This association is difficult to disentangle from low socioeconomic status, a factor in both lead exposure and criminal offending. Objective: To test the hypothesis that a higher childhood blood lead level (BLL) is associated with greater risk of criminal conviction, recidivism (repeat conviction), conviction for violent offenses, and variety of self-reported criminal offending in a setting where BLL was not associated with low socioeconomic status. Design, Setting, and Participants: A total of 553 individuals participated in a prospective study based on a population-representative cohort born between April 1, 1972, and March 31, 1973, from New Zealand; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38 years (December 2012). Statistical analysis was performed from November 10, 2016, to September 5, 2017. Exposures: Blood lead level measured at age 11 years. Main Outcomes and Measures: Official criminal conviction cumulative to age 38 years (data collected in 2013), single conviction or recidivism, conviction for nonviolent or violent crime, and self-reported variety of crime types at ages 15, 18, 21, 26, 32, and 38 years. Results: Participants included 553 individuals (255 female and 298 male participants) who had their blood tested for lead at age 11 years. The mean (SD) BLL at age 11 years was 11.01 (4.62) MUg/dL. A total of 154 participants (27.8%) had a criminal conviction, 86 (15.6%) had recidivated, and 53 (9.6%) had a violent offense conviction. Variety scores for self-reported offending ranged from 0 to 10 offense types at each assessment; higher numbers indicated greater crime involvement. Self-reported offending followed the well-established age-crime curve (ie, the mean [SD] variety of self-reported offending increased from 1.99 [2.82] at age 15 years to its peak of 4.24 [3.15] at age 18 years and 4.22 [3.02] at age 21 years and declined thereafter to 1.10 [1.59] at age 38 years). Blood lead level was a poor discriminator between no conviction and conviction (area under the curve, 0.58). Overall, associations between BLL and conviction outcomes were weak. The estimated effect of BLL was lower for recidivism than for single convictions and lower for violent offending than for nonviolent offending. Sex adjusted associations between BLL reached statistical significance for only 1 of the 6 self-reported offending outcomes at age 15 years (r = 0.10; 95% CI, 0.01 0.18; P = .02). Conclusions and Relevance: This study overcomes past limitations of studies of BLL and crime by studying the association in a place and time where the correlation was not confounded by childhood socioeconomic status. Findings failed to support a dose-response association between BLL and consequential criminal offending. PMID- 29279898 TI - The Roles of Vowel Fronting, Lengthening, and Listener Variables in the Perception of Vocal Femininity. AB - Purpose: The goal of this study was to test whether fronting and lengthening of lax vowels influence the perception of femininity in listeners whose dialect is characterized as already having relatively fronted and long lax vowels in male and female speech. Method: Sixteen English words containing the /i E upsilon alpha/ vowels were produced by a male speaker with 2 degrees of vowel fronting. Then, the vowel duration was manipulated in 3 steps. Thirty-nine listeners from the Southern United States judged how feminine each word sounded to them on an interval scale. Results: The results of mixed-effects modeling showed that the words with more fronted and longer variants of the vowels were perceived as more feminine than the same words with less fronted and shorter variants of the vowels. These effects, however, were modulated by the vowel type, listener's area of upbringing, and gender. Conclusions: Fronting (except for /upsilon/) and lengthening of lax vowels make words sound more feminine for Southern listeners, which has implications for clients who wish to modify the perception of femininity invoked by their speech. The relative strength of the gender and regional associations of these vowel characteristics should be further examined across dialects. PMID- 29279899 TI - What Parents Need to Know About the Risks of Lead Exposure for Children. PMID- 29279900 TI - The Need to Include Biological Variables in Prospective Longitudinal Studies of the Development of Criminal Behavior. PMID- 29279901 TI - Treatment of Immune Thrombocytopenia: A Teachable Moment. PMID- 29279902 TI - Small Steps to Address Medical Resident Burnout. PMID- 29279904 TI - Reflecting on the Bicentennial of Mary Shelley's Frankenstein: From Novel to Film and the 2 Brains. PMID- 29279903 TI - Association of Timing of Weight Gain in Pregnancy With Infant Birth Weight. AB - Importance: Gestational weight gain is a determinant of infant birth weight, but it is unclear whether its timing in pregnancy may hold implications in this regard. Previous studies have yielded conflicting findings on the association of maternal weight gain in early pregnancy with birth weight. However, as these studies have typically recruited women during the first trimester, they are inherently limited by a reliance on self-reported pregravid weight. Objective: To evaluate the associations of directly measured maternal pregravid weight and the timing of subsequent weight gain across pregnancy with infant birth weight. Design, Setting, and Participants: In this prospective, preconception, observational cohort study, 1164 newly married women in Liuyang, China, underwent pregravid evaluation at a median of 19.9 weeks before a singleton pregnancy during which they underwent serial weight measurements. The study was conducted from February 1, 2009, to November 4, 2015. Data analysis was performed between September 1, 2016, and May 6, 2017. Exposure: Maternal weight gain was calculated for the following 10 gestational intervals: from pregravid to less than 14, 14 to 18, 19 to 23, 24 to 28, 29 to 30, 31 to 32, 33 to 34, 35 to 36, 37 to 38, and 39 to 40 weeks. Main Outcomes and Measures: Associations of pregravid weight and weight gain within each of the 10 gestational intervals with the outcome of infant birth weight. Results: The mean (SD) age of the 1164 women included in the study was 25.3 (3.1) years. Pregravid weight was consistently associated with infant birth weight. However, among the 10 gestational intervals, only weight gain from pregravid to 14 weeks and from 14 to 18 weeks was associated with birth weight. Birth weight increased by 13.6 g/kg (95% CI, 3.2-24.1 g/kg) of maternal weight gain from pregravid to 14 weeks and by 26.1 g/kg (95% CI, 3.8-48.4 g/kg) of maternal weight gain from 14 to 18 weeks. Conclusion and Relevance: Maternal weight only in the first half of gestation is a determinant of infant birth weight. Before pregnancy and early gestation may be a critical window for intervention to affect subsequent birth weight. PMID- 29279905 TI - Evidence-Based Management of Patent Foramen Ovale in Patients With Ischemic Stroke. PMID- 29279906 TI - Movie Review of The Immortal Life of Henrietta Lacks. PMID- 29279907 TI - Error in Figure Title. PMID- 29279908 TI - Low-Level Air Pollution Associated With Death: Policy and Clinical Implications. PMID- 29279909 TI - Authorship and Team Science. PMID- 29279910 TI - Sports-Related Eye Injuries. PMID- 29279911 TI - Opioid Emergency Declared. PMID- 29279912 TI - NIH Strategy to Combat Opioid Crisis. PMID- 29279913 TI - Crowdsourcing Pregnancy Data. PMID- 29279914 TI - CMS Vows to Overhaul Medicaid. PMID- 29279916 TI - Charcot's Opinion and Criticism of German Medicine. PMID- 29279917 TI - Trends in Self-reported and Biochemically Tested Marijuana Use Among Pregnant Females in California From 2009-2016. PMID- 29279918 TI - Spiritual Care in Medicine. PMID- 29279919 TI - Evidence Required for Drugs Granted Accelerated Approval. PMID- 29279920 TI - Azithromycin and Survival After Hematopoietic Stem Cell Transplant. PMID- 29279921 TI - Intensive Lifestyle Intervention for Type 2 Diabetes. PMID- 29279922 TI - Spiritual Care in Medicine-Reply. PMID- 29279923 TI - Evidence Required for Drugs Granted Accelerated Approval-Reply. PMID- 29279924 TI - Azithromycin and Survival After Hematopoietic Stem Cell Transplant-Reply. PMID- 29279926 TI - Guselkumab (Tremfya) for Psoriasis. PMID- 29279925 TI - Intensive Lifestyle Intervention for Type 2 Diabetes-Reply. PMID- 29279927 TI - Stenting Does Not Relieve Stable Angina Symptoms. PMID- 29279929 TI - Gamification Shows Promise in Motivating Physical Activity. PMID- 29279928 TI - Recumbent Delivery With Epidural and Spontaneous Vaginal Births. PMID- 29279930 TI - Prochlorperazine Superior to Hydromorphone for Migraine. PMID- 29279931 TI - Surgery Improves Seizures in Children With Drug-Resistant Epilepsy. PMID- 29279932 TI - Association of Short-term Exposure to Air Pollution With Mortality in Older Adults. AB - Importance: The US Environmental Protection Agency is required to reexamine its National Ambient Air Quality Standards (NAAQS) every 5 years, but evidence of mortality risk is lacking at air pollution levels below the current daily NAAQS in unmonitored areas and for sensitive subgroups. Objective: To estimate the association between short-term exposures to ambient fine particulate matter (PM2.5) and ozone, and at levels below the current daily NAAQS, and mortality in the continental United States. Design, Setting, and Participants: Case-crossover design and conditional logistic regression to estimate the association between short-term exposures to PM2.5 and ozone (mean of daily exposure on the same day of death and 1 day prior) and mortality in 2-pollutant models. The study included the entire Medicare population from January 1, 2000, to December 31, 2012, residing in 39 182 zip codes. Exposures: Daily PM2.5 and ozone levels in a 1-km * 1-km grid were estimated using published and validated air pollution prediction models based on land use, chemical transport modeling, and satellite remote sensing data. From these gridded exposures, daily exposures were calculated for every zip code in the United States. Warm-season ozone was defined as ozone levels for the months April to September of each year. Main Outcomes and Measures: All-cause mortality in the entire Medicare population from 2000 to 2012. Results: During the study period, there were 22 433 862 million case days and 76 143 209 control days. Of all case and control days, 93.6% had PM2.5 levels below 25 MUg/m3, during which 95.2% of deaths occurred (21 353 817 of 22 433 862), and 91.1% of days had ozone levels below 60 parts per billion, during which 93.4% of deaths occurred (20 955 387 of 22 433 862). The baseline daily mortality rates were 137.33 and 129.44 (per 1 million persons at risk per day) for the entire year and for the warm season, respectively. Each short-term increase of 10 MUg/m3 in PM2.5 (adjusted by ozone) and 10 parts per billion (10-9) in warm season ozone (adjusted by PM2.5) were statistically significantly associated with a relative increase of 1.05% (95% CI, 0.95%-1.15%) and 0.51% (95% CI, 0.41% 0.61%) in daily mortality rate, respectively. Absolute risk differences in daily mortality rate were 1.42 (95% CI, 1.29-1.56) and 0.66 (95% CI, 0.53-0.78) per 1 million persons at risk per day. There was no evidence of a threshold in the exposure-response relationship. Conclusions and Relevance: In the US Medicare population from 2000 to 2012, short-term exposures to PM2.5 and warm-season ozone were significantly associated with increased risk of mortality. This risk occurred at levels below current national air quality standards, suggesting that these standards may need to be reevaluated. PMID- 29279933 TI - Effect of Antibiotic Prophylaxis on Surgical Site Infections Following Removal of Orthopedic Implants Used for Treatment of Foot, Ankle, and Lower Leg Fractures: A Randomized Clinical Trial. AB - Importance: Following clean (class I, not contaminated) surgical procedures, the rate of surgical site infection (SSI) should be less than approximately 2%. However, an infection rate of 12.2% has been reported following removal of orthopedic implants used for treatment of fractures below the knee. Objective: To evaluate the effect of a single dose of preoperative antibiotic prophylaxis on the incidence of SSIs following removal of orthopedic implants used for treatment of fractures below the knee. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial including 500 patients aged 18 to 75 years with previous surgical treatment for fractures below the knee who were undergoing removal of orthopedic implants from 19 hospitals (17 teaching and 2 academic) in the Netherlands (November 2014-September 2016), with a follow-up of 6 months (final follow-up, March 28, 2017). Exclusion criteria were an active infection or fistula, antibiotic treatment, reimplantation of osteosynthesis material in the same session, allergy for cephalosporins, known kidney disease, immunosuppressant use, or pregnancy. Interventions: A single preoperative intravenous dose of 1000 mg of cefazolin (cefazolin group, n = 228) or sodium chloride (0.9%; saline group, n = 242). Main Outcomes and Measures: Primary outcome was SSI within 30 days as measured by the criteria from the US Centers for Disease Control and Prevention. Secondary outcome measures were functional outcome, health-related quality of life, and patient satisfaction. Results: Among 477 randomized patients (mean age, 44 years [SD, 15]; women, 274 [57%]; median time from orthopedic implant placement, 11 months [interquartile range, 7-16]), 470 patients completed the study. Sixty-six patients developed an SSI (14.0%): 30 patients (13.2%) in the cefazolin group vs 36 in the saline group (14.9%) (absolute risk difference, -1.7 [95% CI, -8.0 to 4.6], P = .60). Conclusions and Relevance: Among patients undergoing surgery for removal of orthopedic implants used for treatment of fractures below the knee, a single preoperative dose of intravenous cefazolin compared with saline did not reduce the risk of surgical site infection within 30 days following implant removal. Trial Registration: clinicaltrials.gov Identifier: NCT02225821. PMID- 29279934 TI - Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. AB - Importance: The increased social and economic burdens for osteoporosis-related fractures worldwide make the prevention of such injuries a major public health goal. Previous studies have reached mixed conclusions regarding the association between calcium, vitamin D, or combined calcium and vitamin D supplements and fracture incidence in older adults. Objective: To investigate whether calcium, vitamin D, or combined calcium and vitamin D supplements are associated with a lower fracture incidence in community-dwelling older adults. Data Sources: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to December 24, 2016, using the keywords calcium, vitamin D, and fracture to identify systematic reviews or meta-analyses. The primary randomized clinical trials included in systematic reviews or meta-analyses were identified, and an additional search for recently published randomized trials was performed from July 16, 2012, to July 16, 2017. Study Selection: Randomized clinical trials comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment for fracture incidence in community dwelling adults older than 50 years. Data Extraction and Synthesis: Two independent reviewers performed the data extraction and assessed study quality. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs), and 95% CIs using random-effects models. Main Outcomes and Measures: Hip fracture was defined as the primary outcome. Secondary outcomes were nonvertebral fracture, vertebral fracture, and total fracture. Results: A total of 33 randomized trials involving 51 145 participants fulfilled the inclusion criteria. There was no significant association of calcium or vitamin D with risk of hip fracture compared with placebo or no treatment (calcium: RR, 1.53 [95% CI, 0.97 to 2.42]; ARD, 0.01 [95% CI, 0.00 to 0.01]; vitamin D: RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, -0.00 to 0.01]. There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, -0.00 to 0.00]). No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, and baseline serum 25 hydroxyvitamin D concentration. Conclusions and Relevance: In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people. PMID- 29279936 TI - Heat Stroke. PMID- 29279935 TI - Association of Modifiable Risk Factors in Young Adulthood With Racial Disparity in Incident Type 2 Diabetes During Middle Adulthood. AB - Importance: In the United States, black individuals are twice as likely to develop type 2 diabetes compared with white individuals, and these disparities are particularly pronounced in young and middle age. Prior studies have identified differences in traditional risk factors that may be associated with racial disparities in diabetes incidence but have not simultaneously adjusted for risk factors measured across multiple domains (eg, the individual and the environment) and updated over time. Objective: To determine the relative associations of modifiable biological, neighborhood, psychosocial, socioeconomic, and behavioral factors in young adulthood with the observed racial disparity in diabetes incidence between middle-aged black and white individuals. Design, Setting, and Participants: Black and white men and women from the observational Coronary Artery Risk Development in Young Adults study, aged 18 to 30 years, without diabetes at baseline (1985-1986; N = 4251) were observed through 2015 2016. Sex-stratified multivariable-adjusted Cox proportional hazards modeling, with adjustment for time-updated covariates, was used to estimate risk for incident diabetes. Percent reduction in the beta coefficient (the logarithm used to calculate the hazard ratio [HR]) was calculated to compare black to white participants. Exposures: Self-identified race and factors including biological (eg, fasting glucose, body mass index), neighborhood (racial segregation and tract-level poverty), psychosocial (depressive symptoms), socioeconomic (eg, personal and parental educational attainment, current employment), and behavioral (eg, regular alcohol consumption, smoking) domains. Main Outcomes and Measures: Incident type 2 diabetes mellitus. Results: The mean (SD) age at baseline was 25 (3.6) years, 49% (n = 2066) of the sample was black, and 54% (n = 2304) were women. Over a mean follow-up of 24.5 years, 504 cases of incident diabetes were identified. Using sex-stratified multivariable-adjusted Cox proportional hazards models, black women and men were more likely to develop diabetes than white men and women (black women: HR, 2.86 [95% CI, 2.19-3.72] and risk difference [RD], 89 cases/1000 people [95% CI, 61-117]; black men: HR, 1.67 [95% CI, 1.28-2.17] and RD, 47 cases/1000 people [95% CI, 15-78]) after adjustment for age and center. Biological factors were most strongly associated with the disparity in diabetes risk between black and white individuals for women (percent reduction in beta, 112%) and men (percent reduction in beta, 86%). There was no longer disparity in diabetes risk between black and white middle-aged adults after adjustment for biological, neighborhood, psychosocial, socioeconomic, and behavioral factors measured over time (HR for women, 0.79 [95% CI, 0.55-1.14]; HR for men, 0.92 [95% CI, 0.62-1.38]). Conclusions and Relevance: In this cohort study comparing black and white participants, there was a statistically significant increased risk of incident type 2 diabetes among black women and men. However, after adjustment for modifiable risk factors during young adulthood, the disparity was no longer statistically significant. PMID- 29279937 TI - Insulin Dosing Error in a Patient With Severe Hyperkalemia. PMID- 29279941 TI - Lyme Disease Spreading Beyond States With Historically High Incidence. PMID- 29279939 TI - Negative Capability and the Art of Medicine. PMID- 29279942 TI - Most Drinking Water-Associated Disease Outbreaks Linked to Legionella. PMID- 29279943 TI - Assessment of alteration in liver 18F-FDG uptake due to steatosis in lymphoma patients and its impact on the Deauville score. AB - AIM: Our aim was (1) to evaluate the prevalence of steatosis in lymphoma patients and its evolution during treatment; (2) to evaluate the impact of hepatic steatosis on 18F-FDG liver uptake; and (3) to study how hepatic steatosis affects the Deauville score (DS) for discriminating between responders and non responders. METHODS: Over a 1-year period, 358 PET scans from 227 patients [122 diffuse large B cell lymphoma (DLBCL), 57 Hodgkin lymphoma (HL) and 48 Follicular lymphoma (FL)] referred for baseline (n = 143), interim (n = 79) and end-of treatment (EoT, n = 136) PET scans were reviewed. Steatosis was diagnosed on the unenhanced CT part of PET/CT examinations using a cut-off value of 42 Hounsfield units (HU). EARL-compliant SULmax were recorded on the liver and the tumour target lesion. DS were then computed. RESULTS: Prevalence of steatosis at baseline, interim and EoT PET was 15/143 (10.5%), 6/79 (7.6%) and 16/136 (11.8%), respectively (p = 0.62).Ten out of 27 steatotic patients (37.0%) displayed a steatotic liver on all examinations. Six patients (22.2%) had a disappearance of hepatic steatosis during their time-course of treatment. Only one patient developed steatosis during his course of treatment. Liver SULmax values were significantly lower in the steatosis versus non-steatotic groups of patients for interim (1.66 +/- 0.36 versus 2.15 +/- 0.27) and EoT (1.67 +/- 0.29 versus 2.17 +/- 0.30) PET. CT density was found to be an independent factor that correlated with liver SULmax, while BMI, blood glucose level and the type of chemotherapy regimen were not. Using a method based on this correlation to correct liver SULmax, all DS4 steatotic patients on interim (n = 1) and EoT (n = 2) PET moved to DS3. CONCLUSIONS: Steatosis is actually a theoretical but not practical issue in most patients but should be recognised and corrected in appropriate cases, namely, for those patients scored DS4 with a percentage difference between the target lesion and the liver background lower than 30%. PMID- 29279944 TI - Is the whole larger than the sum of the parts? Integrated PET/MRI as a tool for response prediction. PMID- 29279946 TI - Adaptive statistical iterative reconstruction use for radiation dose reduction in pediatric lower-extremity CT: impact on diagnostic image quality. AB - BACKGROUND: For the past several years, increased levels of imaging radiation and cumulative radiation to children has been a significant concern. Although several measures have been taken to reduce radiation dose during computed tomography (CT) scan, the newer dose reduction software adaptive statistical iterative reconstruction (ASIR) has been an effective technique in reducing radiation dose. To our knowledge, no studies are published that assess the effect of ASIR on extremity CT scans in children. OBJECTIVE: To compare radiation dose, image noise, and subjective image quality in pediatric lower extremity CT scans acquired with and without ASIR. MATERIALS AND METHODS: The study group consisted of 53 patients imaged on a CT scanner equipped with ASIR software. The control group consisted of 37 patients whose CT images were acquired without ASIR. Image noise, Computed Tomography Dose Index (CTDI) and dose length product (DLP) were measured. Two pediatric radiologists rated the studies in subjective categories: image sharpness, noise, diagnostic acceptability, and artifacts. RESULTS: The CTDI (p value = 0.0184) and DLP (p value <0.0002) were significantly decreased with the use of ASIR compared with non-ASIR studies. However, the subjective ratings for sharpness (p < 0.0001) and diagnostic acceptability of the ASIR images (p < 0.0128) were decreased compared with standard, non-ASIR CT studies. CONCLUSION: Adaptive statistical iterative reconstruction reduces radiation dose for lower extremity CTs in children, but at the expense of diagnostic imaging quality. Further studies are warranted to determine the specific utility of ASIR for pediatric musculoskeletal CT imaging. PMID- 29279945 TI - Dysplasia and overgrowth: magnetic resonance imaging of pediatric brain abnormalities secondary to alterations in the mechanistic target of rapamycin pathway. AB - The current classification of malformations of cortical development is based on the type of disrupted embryological process (cell proliferation, migration, or cortical organization/post-migrational development) and the resulting morphological anomalous pattern of findings. An ideal classification would include knowledge of biological pathways. It has recently been demonstrated that alterations affecting the mechanistic target of rapamycin (mTOR) signaling pathway result in diverse abnormalities such as dysplastic megalencephaly, hemimegalencephaly, ganglioglioma, dysplastic cerebellar gangliocytoma, focal cortical dysplasia type IIb, and brain lesions associated with tuberous sclerosis. We review the neuroimaging findings in brain abnormalities related to alterations in the mTOR pathway, following the emerging trend from morphology towards genetics in the classification of malformations of cortical development. This approach improves the understanding of anomalous brain development and allows precise diagnosis and potentially targeted therapies that may regulate mTOR pathway function. PMID- 29279947 TI - The Dynamics of Trust in the Shanghai Water Supply Regime. AB - Trust in natural resource managers and planners is recognized as a crucial component of the public's perception of environmental risks, including the risk of consuming water in cities. Although China is famous for its dubious water quality, public perception of the performance of water suppliers in China has scarcely been considered. Yet this is important, not least because improvements in urban water quality are most likely if the public perceives that there is a risk, which is a function of their levels of trust. We, therefore, examine the Shanghai public's trust in urban water authorities through analysis of the results from a face-to-face questionnaire that 5007 residents responded to. We find that although respondents show a moderate level of overall trust in water suppliers, they have less trust in the honesty and fairness of these organizations. In addition, we find that hukou status and education help explain the differences in people's trust in Shanghai's water authorities, and that these are more influential than factors such as gender and age. For water managers in Shanghai, this implies trust can be improved through a greater effort at public relations and increased transparency about decision making and levels of pollution. PMID- 29279948 TI - Developmental patterns of fetal fat and corresponding signal on T1-weighted magnetic resonance imaging. AB - BACKGROUND: Evaluation of subcutaneous fetal fat layer thickness on T1-weighted sequences can be used to predict birth weight. Little is known about normal MR signal patterns of subcutaneous tissue throughout pregnancy. OBJECTIVE: To establish developmental patterns of subcutaneous fetal fat signal on T1-weighted sequences during the 2nd and 3rd trimesters. MATERIALS AND METHODS: We retrospectively examined T1-weighted images of 110 fetal MRI scans. We measured signal intensity of subcutaneous fat on thighs, buttocks, trunk, nuchal region, chin and scalp. We then calculated the ratios of the obtained values with fetal muscle, amnios and maternal fat signal, and compared the results with those of immunohistochemical examination of adipose tissue extracted from the abdominal wall of fetuses as part of standard autopsy protocol. RESULTS: We included 60 MRI scans in fetuses without intra-uterine growth restriction or macrosomia of non diabetic mothers (range 23-37 weeks of gestation). Fat T1 intensity of all anatomical regions was low in all fetuses before 26 weeks of gestation. It became more hyperintense with increasing gestational age, in the following order: chin and nuchal region, then buttocks, thighs and trunk, and eventually the scalp at 33 weeks of gestation. After 33 weeks of gestation, all fetal subcutaneous tissues demonstrated overall hyperintense signal. This progression followed the conversion at immunohistochemistry of fetal adipose tissue composition from predominant brown to white adipose cells in 19 fetuses (19-41 weeks of gestation). CONCLUSION: Between 26 weeks and 33 weeks of gestation, subcutaneous fetal fat signal changed in an orderly pattern from chin to buttocks and scalp. This may reflect the conversion from predominant brown to white adipose tissues in subcutaneous fetal fat. PMID- 29279950 TI - Four-quadrant/column classification of tibial plateau fractures. PMID- 29279949 TI - Re-irradiation with curative intent in patients with squamous cell carcinoma of the head and neck: a national survey of usual practice on behalf of the Italian Association of Radiation Oncology (AIRO). AB - OBJECTIVE: To report the results of a national survey investigating the pattern of practice of curative re-irradiation (ReRT) for recurrent squamous cell carcinoma of the head and neck. METHODS: In March 2016, a 22-item, 4-section questionnaire was sent to all Italian Radiation Oncology centers. Sections were focused on assessing the expertise level of each center and collecting specific information on reRT prescription modalities in the adjuvant and definitive settings. RESULTS: Overall, 77 centers completed the survey. The majority (50/77, 64.9%) of participating radiation oncologists were senior consultants (> 10 years of experience). Of the responding centers, 63 (81.8%) performed curative ReRT, while 14 (18.1%) did not, mainly (5/14, 35.7%) due to the avoidance of severe toxicity. The use of adjuvant ReRT was reported by less than half of the interviewed radiation oncologists (36/77, 46.7%). In case of unresectable local recurrence, definitive ReRT was claimed to be adopted in 55/77 (71.4%) for non nasopharyngeal and 47/77 (61%) for nasopharyngeal cancer. The preferred treatment technique was Intensity Modulated Radiation Therapy (IMRT) followed by Stereotactic Body Radiation Therapy (SBRT). When IMRT was applied, the most common (19/55 responders, 34.5%) selection of treatment volume consisted of the Gross Tumor Volume (GTV) + 0.5 cm margin to account for microscopic disease. CONCLUSION: Despite the absence of definitive evidence-based recommendations, a possible consideration for ReRT in case of unresectable recurrent head and neck cancer was reported by over 80% of radiation oncologists taking part in the national survey. PMID- 29279951 TI - Hip osteonecrosis and pregnancy in healthy women. AB - PURPOSE: Osteonecrosis has been reported to be associated with pregnancy in the absence of other known risk factors for the disease. Few population-based data exist to support an association since the association is rare. We investigated the association of the femoral head and pregnancy to define if pregnancy was a risk factor and to define the risk period. METHODS: Using a case-crossover method design among 652 patients who were healthy (without any known cause of osteonecrosis) during or after pregnancy, we defined the periods of risk based on the timing of reported osteonecrosis and pregnancy. We compared each patient's likelihood of osteonecrosis during a ten years period including five years antepartum, pregnancy and five years postpartum with nine month intervals for the ten year and three month intervals for the two years after gestation. RESULTS: For the 436 women who had only one child and one hip osteonecrosis, the incidence of osteonecrosis was 71.8% during pregnancy and the postpartum period, compared with 28.2% during the equivalent antepartum period for this population. Nine months after delivery, the risk of osteonecrosis declined progressively over time, from an odds ratio of 14.5 (95% confidence interval, 8.2-18.3) in last trimester of pregnancy. After the 27th month following onset of pregnancy, the relative risk was no more significantly different from the baseline risk observed in the antepartum period of women who had osteonecrosis before gestation. For women with several children, a subsequent pregnancy was not associated with osteonecrosis. CONCLUSIONS: A risk of hip osteonecrosis is present during the end of pregnancy and after delivery, and appears to decrease quickly. PMID- 29279952 TI - Hidebound bowel sign. PMID- 29279953 TI - Chemical Peeling with a Modified Phenol Formula for the Treatment of Facial Freckles on Asian Skin. AB - BACKGROUND: Chemical peeling is an efficient method for the treatment of pigment disorders. For freckles, medium-depth to deep peeling using a phenol solution is one of the most effective chemical peels, and modifications of facial skin can be observed up to 20 years after peeling. However, applying phenol to the skin may cause serious side effects. Phenol peeling has been rarely used in Asia due to its tendency to cause permanent pigmentary changes and hypertrophic scars. METHODS: In total, 896 Chinese inpatients with facial freckles were enrolled in this study. The phenol formula was modified with crystalline phenol, dyclonine, camphor, anhydrous alcohol and glycerin and adjusted to a concentration of 73.6 90.0%. The entire peeling treatment was divided into two procedures performed separately on 2 days. RESULTS: All patients exhibited 26% or greater improvement, and 99.66% of patients exhibited 51% or greater improvement (good and excellent). Scarring and systemic complications were not observed in any patient. CONCLUSIONS: The modified phenol formula is very effective and safe for the treatment of facial freckles in Asian patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29279954 TI - A breath of information: the volatilome. AB - Volatile organic compounds (VOCs) are small molecular mass substances, which exhibit low boiling points and high-vapour pressures. They are ubiquitous in nature and produced by almost any organism of all kingdoms of life. VOCs are involved in many inter- and intraspecies interactions ranging from antimicrobial or fungal effects to plant growth promotion and human taste perception of fermentation products. VOC profiles further reflect the metabolic or phenotypic state of the living organism that produces them. Hence, they can be exploited for non-invasive medicinal diagnoses or industrial fermentation control. Here, we introduce the reader to these diverse applications associated with the monitoring and analysis of VOC emissions. We also present our vision of real-time VOC analysis enabled by newly developed analytical techniques, which will further broaden the use of VOCs in even wider applications. Hence, we foresee a bright future for VOC research and its associated fields of applications. PMID- 29279955 TI - Duplication and Deletion of 22q11 Associated with Anomalous Pulmonary Venous Connection. AB - Anomalous pulmonary venous connection (APVC) is an uncommon congenital anomaly in which pulmonary venous blood flows directly into the right side of the heart or into the systemic veins. To identify whether there is any association between 22q11 CNVs and APVC, we analyzed the clinical data of 86 APVC patients and then studied the CNVs of 22q11 in 86 sporadic APVC patients by multiplex ligation dependent probe amplification. The results showed that two patients carried the CNVs of 22q11, one patient had the deletion of 22q11 and the other had the duplication of 22q11. The incidence was significantly higher than that in the normal population (P < 0.01) that suggests a possible etiologic association between the duplication or deletion of 22q11 and the APVC in our patients. PMID- 29279956 TI - Strain improvement by combined UV mutagenesis and ribosome engineering and subsequent fermentation optimization for enhanced 6'-deoxy-bleomycin Z production. AB - The bleomycins (BLMs) are important clinical drugs extensively used in combination chemotherapy for the treatment of various cancers. Dose-dependent lung toxicity and the development of drug resistance have restricted their wide applications. 6'-Deoxy-BLM Z, a recently engineered BLM analogue with improved antitumor activity, has the potential to be developed into the next-generation BLM anticancer drug. However, its low titer in the recombinant strain Streptomyces flavoviridis SB9026 has hampered current efforts, which require sufficient compound, to pursue preclinical studies and subsequent clinical development. Here, we report the strain improvement by combined UV mutagenesis and ribosome engineering, as well as the fermentation optimization, for enhanced 6'-deoxy-BLM production. A high producer, named S. flavoviridis G-4F12, was successfully isolated, producing 6'-deoxy-BLM at above 70 mg/L under the optimized fermentation conditions, representing a sevenfold increase in comparison with that of the original producer. These findings demonstrated the effectiveness of combined empirical breeding methods in strain improvement and set the stage for sustainable production of 6'-deoxy-BLM via pilot-scale microbial fermentation. PMID- 29279958 TI - Chromium removal from solution by five photosynthetic bacteria isolates. AB - Biological method has been recognized as a low-cost and ecofriendly approach for removing heavy metals from aqueous wastes. In this study, the ability of five photosynthetic bacteria isolates (strains labeled SC01, HN02, SC05, JS01, and YN01) was examined for their ability to remove Cr from Cr-containing solutions. Furthermore, the possible removal mechanisms were elucidated by comparing chromium removal rates, antioxidant reaction, and accumulation of reactive oxygen species (ROS). Among the five bacteria, strains SC01 and SC05 presented the highest removal rates of chromium ions and the activity of cysteine desulfhydrase under Cr stress. They also showed lower levels of ROS and cell death than the other three bacteria strains under Cr stress. In addition, total bacteriochlorophyll content and activities of six antioxidant enzymes in SC01 were highest among these selected strains. On the contrary, strain HN02 presented the lowest level of Cr removal and the lowest activities of antioxidant enzymes. It also exhibited the highest level of ROS under Cr(VI) stress. Overall, these results show that the strains SC01 and SC05 have good Cr removal ability and could be used for removal of Cr in industrial effluents. PMID- 29279957 TI - Production of 5-ketofructose from fructose or sucrose using genetically modified Gluconobacter oxydans strains. AB - The growing consumer demand for low-calorie, sugar-free foodstuff motivated us to search for alternative non-nutritive sweeteners. A promising sweet-tasting compound is 5-keto-D-fructose (5-KF), which is formed by membrane-bound fructose dehydrogenases (Fdh) in some Gluconobacter strains. The plasmid-based expression of the fdh genes in Gluconobacter (G.) oxydans resulted in a much higher Fdh activity in comparison to the native host G. japonicus. Growth experiments with G. oxydans fdh in fructose-containing media indicated that 5-KF was rapidly formed with a conversion efficiency of 90%. 5-KF production from fructose was also observed using resting cells with a yield of about 100%. In addition, a new approach was tested for the production of the sweetener 5-KF by using sucrose as a substrate. To this end, a two-strain system composed of the fdh-expressing strain and a G. oxydans strain that produced the sucrose hydrolyzing SacC was developed. The strains were co-cultured in sucrose medium and converted 92.5% of the available fructose units into 5-KF. The glucose moiety of sucrose was converted to 2-ketogluconate and acetate. With regard to the development of a sustainable and resource-saving process for the production of 5-KF, sugar beet extract was used as substrate for the two-strain system. Fructose as product from sucrose cleavage was mainly oxidized to 5-KF which was detected in a concentration of over 200 mM at the end of the fermentation process. In summary, the two-strain system was able to convert fructose units of sugar beet extract to 5-KF with an efficiency of 82 +/- 5%. PMID- 29279959 TI - Correction to: Increased heterologous production of the antitumoral polyketide mithramycin a by engineered Streptomyces lividans TK24 strains. AB - The original publication contains error error in the Materials and Methods section and in the acknowledgement section. PMID- 29279960 TI - Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size. AB - Heart size is an important factor in cardiac health and disease. In particular, increased heart weight is predictive of adverse cardiovascular outcomes in multiple large community-based studies. We use two cohorts of Diversity Outbred (DO) mice to investigate the role of genetics, sex, age, and diet on heart size. DO mice (n = 289) of both sexes from generation 10 were fed a standard chow diet, and analyzed at 12-15 weeks of age. Another cohort of female DO mice (n = 258) from generation 11 were fed either a high-fat, cholesterol-containing (HFC) diet or a low-fat, high-protein diet, and analyzed at 24-25 weeks. We did not observe an effect of diet on body or heart weight in generation 11 mice, although we previously reported an effect on other cardiovascular risk factors, including cholesterol, triglycerides, and insulin. We do observe a significant genetic effect on heart weight in this population. We identified two quantitative trait loci for heart weight, one (Hwtf1) at a genome-wide significance level of p <= 0.05 on MMU15 and one (Hwtf2) at a genome-wide suggestive level of p <= 0.1 on MMU10, that together explain 13.3% of the phenotypic variance. Hwtf1 contained collagen type XXII alpha 1 chain (Col22a1), and the NZO/HlLtJ and WSB/EiJ haplotypes were associated with larger hearts. This is consistent with heart tissue Col22a1 expression in DO founders and SNP patterns within Hwtf1 for Col22a1. Col22a1 has been previously associated with cardiac fibrosis in mice, suggesting that Col22a1 may be involved in pathological cardiac hypertrophy. PMID- 29279961 TI - Assessment of mitochondrial DNA heteroplasmy detected on commercial panel using MPS system with artificial mixture samples. AB - Mitochondrial DNA (mtDNA) heteroplasmy is a potential genetic marker for forensic mtDNA analysis as well as phylogenic studies. Frequency of mtDNA heteroplasmy has been investigated in different populations through massively parallel sequencing (MPS) analysis, revealing various levels of frequency based on different MPS systems. For accurate heteroplasmy identification, it is essential to explore reliable detection threshold on various MPS systems. In addition, software solutions and pipelines need to be evaluated to analyze data effectively. In this study, heteroplasmy analysis was conducted on a commercially available mtDNA analysis system developed for forensic caseworks with artificially mixed DNA samples known for ratios and variant positions for assessment. mtDNA heteroplasmy > 10% was detectable with Torrent Variant Caller (TVC) while lower levels were identified using GeneMarker(r) HTS specialized software for minor variant detection. This study implies that analytical parameters and tools need to be optimized and evaluated for low-level heteroplasmy identification. Automated system with simple and efficient workflow is needed for forensic caseworks. PMID- 29279962 TI - Double dermal sinus tracts of the cervical and thoracic regions: a case in a 3 year-old child and review of the literature. AB - INTRODUCTION: Dermal sinus tracts are rare congenital abnormalities characterized by an epithelium-lined tract that extends from the subcutaneous tissue to the underlying thecal sac or neural tube. These developmental anomalies can present asymptomatically with a cutaneous dimple or with devastating complications including recurrent episodes of meningitis, or neurological complications including paralysis. Dermal sinus tracts generally occur as single lesions, and the presentation of midline double dermal sinus tracts of the cervical and thoracic regions has not been previously described. METHODS: Here, we present the case of a 3-year-old girl suffering from recurrent episodes of myelitis, paraparesis, and intramedullary intradural masses, who was diagnosed with double dermal sinus tracts of the cervical and thoracic regions. We also present a summary of all previous reported cases of multiple dermal sinus tracts. RESULTS: Our patient was successfully treated surgically and is now 2 years status post her last procedure with a significant improvement in her neurologic function and normal muscle strength and tone for her age, and there was no recurrence of her symptoms. CONCLUSIONS: Early treatment with prophylactic surgery should be performed when possible, but removal of these lesions once symptoms have arisen can also lead to success, as in the case presented here. Complete excision and intradural exploration is required to excise the complete tract. PMID- 29279963 TI - Malignant triton tumor of trigeminal nerve-case report. AB - INTRODUCTION: Here we are presenting a unique case of malignant triton tumor of the trigeminal nerve in a 4-year-old boy who presented with diplopia and ptosis. INTERVENTION: Near total excision of the tumor was performed, and adjuvant chemotherapy and radiotherapy were administered. RESULTS: The patient is in good health and has no evidence of clinical and radiological tumor recurrence for 22 months. PMID- 29279964 TI - Hypertrophic olivary degeneration in children after posterior fossa surgery. An underdiagnosed condition. AB - BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare transsynaptic form of degeneration occurring after injury to the dentato-rubro-olivary pathway ("Guillain-Mollaret triangle"). The majority of studies have described HOD resulting from posterior fossa (PF) hemorrhage or infarction. HOD in patients undergoing PF surgery has not been well characterized. These lesions are rare and symptomatic children with HOD are even more uncommon. The purpose of this study was to evaluate HOD that develops after PF operations in children. MATERIALS AND METHODS: A literature review was carried out describing 37 pediatric cases of HOD in 13 articles. In addition, two new cases of our own experience were included. CONCLUSIONS: HOD is a rare complication related after PF tumors surgery and symptoms may be misdiagnosed with pediatric cerebellar mutism syndrome. Children with HOD usually do not develop palatal tremor but ataxia is common. PMID- 29279965 TI - Mesorhizobium zhangyense sp. nov., isolated from wild Thermopsis lanceolate in northwestern China. AB - A Gram-stain-negative strain, 23-3-2T, was isolated from a nodule of Thermopsis lanceolate grown in Northwest China. Phylogenetic analysis of 16S rRNA gene sequence showed that the strain was closely related to Mesorhizobium camelthorni CCNWXJ 40-4T and M. alhagi CCNWXJ 12-2T having 98.0 and 97.9% similarities, respectively. Phylogenetic analysis based on the protein-coding genes atpD and glnA showed lower similarity with the same closely related species (94.5 and 89.9%, respectively), which suggest that 23-3-2T strain represents a distinctly delineated genospecies of the genus Mesorhizobium. The 23-3-2T strain grew at 20 37 degrees C temperature (optimum 28 degrees C) and 5.0-9.0 pH range (optimum pH 7.0). The cells contained Q-10 as the sole respiratory quinone and 18:1omega7c (24.56%) as the major cellular fatty acid. The DNA relatedness between the strain 23-3-2T and the two reference strains was 39-44%. Based on the phenotypic, chemotaxonomic and phylogenetic properties, strain 23-3-2T represents a novel species of the genus Mesorhizobium, for which the name Mesorhizobium zhangyense sp. nov. is proposed. The type strain is 23-3-2T (= CGMCC 1.15528T = NBRC 112337T). The respective DPD Taxon Number is TA00147. PMID- 29279966 TI - Betulinic acid alleviates dextran sulfate sodium-induced colitis and visceral pain in mice. AB - Betulinic acid (BA) exhibits many biological effects including anti-inflammatory and anti-oxidant activities. Free radicals and pro-inflammatory mediators play an important role in the pathology of inflammatory bowel disease (IBD) and associated pain. We, therefore, examined the anti-oxidant, anti-inflammatory, and anti-nociceptive potential of BA in colitis. Colitis was induced with 3% (w/v) dextran sulfate sodium (DSS) in drinking water in mice for 1to7 days. BA (3, 10 and 30 mg/kg) was given orally for 0 to 7 days. BA was also tested for its efficacy in acetic acid and mustard oil-induced visceral nociception in mice at same doses. BA significantly prevented diarrhea; bleeding and colonic pathological changes induced by DSS. Further, BA reduced the colon nitrite, malondialdehyde, myeloperoxidase, and lipid hydroperoxide levels and restored the superoxide dismutase, catalase and reduced glutathione levels to normalize the redox balance in DSS-exposed mice. Inflammatory mediators like matrix metalloproteinase-9 and prostaglandin E2 levels were also significantly attenuated by BA in colitis mice. Additionally, BA reduced acetic acid and mustard oil-induced visceral pain in mice. In conclusion, the results of the present study suggest that BA possesses good anti-nociceptive activity and the anti-IBD effects of BA are due to its anti-oxidant and anti-inflammatory potential. PMID- 29279967 TI - NK2 and NK1 receptor-mediated effects of NKA and analogs on colon, bladder, and arterial pressure in anesthetized dogs. AB - Tachykinin NK2 receptor (NK2R) agonists have potential to alleviate clinical conditions associated with bladder and gastrointestinal under activity. The effects of agonists with differing selectivity for NK2R over NK1Rs on colorectal, bladder, and cardiovascular function were examined in anesthetized dogs. Intravenous (IV) administration of NKA, LMN-NKA ([Lys5,MeLeu9,Nle10]-NKA(4-10)), and [beta-Ala8]-NKA(4-10) caused a dose-related increase in colorectal pressure (up to 98 mmHg) that was blocked by pretreatment with the NK2R antagonist GR 159897 (1 mg/kg), and hypotension (decrease in mean arterial pressure of ~40 mmHg) that was blocked by the NK1R antagonist CP-99,994 (1 mg/kg). Despite the greater in vitro selectivity of LMN-NKA and [beta-Ala8]-NKA(4-10) for NK2R over NK1Rs compared with NKA, all 3 agonists increased colorectal pressure and caused hypotension within a similar dose range when administered as a bolus (0.1-300 MUg/kg IV), or even as a slow IV infusion over 5 min (NKA; 0.02-0.6 MUg/kg/min). In contrast, subcutaneous (SC) administration of LMN-NKA (3-10 MUg/kg) increased colorectal pressure (up to 50 mmHg) and elicited micturition (? 85% voiding efficiency) without causing hypotension. NK2R agonists can produce rapid-onset, short-duration, colorectal contractions, and efficient voiding of urine without hypotension after SC administration, indicating that routes of administration that avoid the high plasma concentrations associated with IV dosing improve the separation between desired and unwanted pharmacodynamic effects. The potent hypotensive effect of NKA in dogs was unexpected based on published studies in humans in which IV infusion of NKA did not affect blood pressure at doses that increased gastrointestinal motility. PMID- 29279968 TI - Urine trouble: should we think differently about UTI? AB - Urinary tract infection (UTI) is clinically important, given that it is one of the most common bacterial infections in adult women. However, the current understanding of UTI remains based on a now disproven concept that the urinary bladder is sterile. Thus, current standards for UTI diagnosis have significant limitations that may reduce the opportunity to improve patient care. Using data from our work and numerous other peer-reviewed studies, we identified four major limitations to the contemporary UTI description: the language of UTI, UTI diagnostic testing, the Escherichia coli-centric view of UTI, and the colony forming units (CFU) threshold-based diagnosis. Contemporary methods and technology, combined with continued rigorous clinical research can be used to correct these limitations. PMID- 29279969 TI - LeFort colpocleisis: a step-by-step simulation video for Female Pelvic Surgeons. AB - INTRODUCTION AND HYPOTHESIS: LeFort colpocleisis is a minimally invasive surgical option for patients with pelvic organ prolapse who no longer desire sexual activity. Pelvic surgeons have limited exposure to this procedure during their training, and are therefore less likely to offer this procedure to their patients. METHODS: We use a split screen live action surgery, side by side with a low cost 3D model of a prolapse to describe a LeFort colpocleisis step by step. RESULTS: This video is an easily reproducible guide to the steps and surgical techniques necessary to successfully perform a LeFort colpocleisis. The simulation model can be used to educate and train those performing female pelvic surgery. CONCLUSION: Pelvic surgeons should be able to offer LeFort colpocleisis to their patients. This video may be used to facilitate the understanding and reproducibility of the procedure. PMID- 29279970 TI - What's new in ICU in 2050: big data and machine learning. PMID- 29279971 TI - The CVC and CRBSI: don't use it and lose it! PMID- 29279972 TI - Are nurses ready to help to improve cost-effectiveness? A multicentric national survey on knowledge of costs among ICU paramedical staff. PMID- 29279973 TI - Psychiatric symptoms after acute respiratory distress syndrome: a 5-year longitudinal study. AB - PURPOSE: We aimed to characterize anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms over 5-year follow-up after acute respiratory distress syndrome (ARDS) and determine risk factors for prolonged psychiatric morbidity. METHODS: This prospective cohort study enrolled patients from 13 medical and surgical intensive care units in four hospitals, with follow-up at 3, 6, 12, 24, 36, 48, and 60 months post-ARDS. Trained research staff administered the Hospital Anxiety and Depression Scale (HADS) (scores >= 8 on anxiety and depression subscales indicating substantial symptoms) and the Impact of Event Scale-Revised (IES-R, scores >= 1.6 indicating substantial PTSD symptoms) at each follow-up visit. RESULTS: Of 196 consenting survivors, 186 (95%) completed HADS and IES-R assessments; 96 (52%) had any continuous or recurring (prolonged) symptoms, and 71 (38%), 59 (32%), and 43 (23%) had prolonged anxiety, depression, and PTSD symptoms, respectively (median total durations 33-39 months, 71-100% of observed follow-up time). Prolonged psychiatric symptoms tended to co-occur across domains; the most common morbidity pattern involved substantial symptoms in all three domains. Worse pre-ARDS mental health, including prior depression and psychological distress in the period immediately preceding ARDS, was strongly associated with prolonged post-ARDS psychiatric morbidity across symptom domains. CONCLUSIONS: Clinically significant and long-lasting symptoms of anxiety, depression, and PTSD are common in the first 5 years after ARDS. In-hospital screening of psychiatric history, including recent anxiety and depression symptoms, may be useful for long-term mental health treatment planning after ARDS. PMID- 29279974 TI - Real-time three-dimensional transesophageal echocardiography fails to discriminate between infectious vegetation and artifact. PMID- 29279975 TI - Determining the Optimal Number of Core Needle Biopsy Passes for Molecular Diagnostics. AB - PURPOSE: The number of core biopsy passes required for adequate next-generation sequencing is impacted by needle cut, needle gauge, and the type of tissue involved. This study evaluates diagnostic adequacy of core needle lung biopsies based on number of passes and provides guidelines for other tissues based on simulated biopsies in ex vivo porcine organ tissues. METHODS: The rate of diagnostic adequacy for pathology and molecular testing from lung biopsy procedures was measured for eight operators pre-implementation (September 2012 October 2013) and post-implementation (December 2013-April 2014) of a standard protocol using 20-gauge side-cut needles for ten core biopsy passes at a single academic hospital. Biopsy pass volume was then estimated in ex vivo porcine muscle, liver, and kidney using side-cut devices at 16, 18, and 20 gauge and end cut devices at 16 and 18 gauge to estimate minimum number of passes required for adequate molecular testing. RESULTS: Molecular diagnostic adequacy increased from 69% (pre-implementation period) to 92% (post-implementation period) (p < 0.001) for lung biopsies. In porcine models, both 16-gauge end-cut and side-cut devices require one pass to reach the validated volume threshold to ensure 99% adequacy for molecular characterization, while 18- and 20-gauge devices require 2-5 passes depending on needle cut and tissue type. CONCLUSION: Use of 20-gauge side-cut core biopsy needles requires a significant number of passes to ensure diagnostic adequacy for molecular testing across all tissue types. To ensure diagnostic adequacy for molecular testing, 16- and 18-gauge needles require markedly fewer passes. PMID- 29279976 TI - Clinical Outcomes of Endovascular Aneurysm Repair with the Kilt Technique for Abdominal Aortic Aneurysms with Hostile Aneurysm Neck Anatomy: A Korean Multicenter Retrospective Study. AB - PURPOSE: We aimed to evaluate the clinical efficacy and short-term clinical outcomes of Kilt technique-based endovascular aneurysm repair (EVAR) with Seal(r) stent-grafts for abdominal aortic aneurysms (AAAs) with hostile neck anatomy (angle > 60 degrees ). MATERIALS AND METHODS: We retrospectively evaluated the pre-EVAR and follow-up computed tomography angiography findings of 24 patients (mean age 71 +/- 11 years; age range 32-87 years; mean follow-up 50 +/- 12 months) with hostile neck AAAs treated between 2010 and 2015. Serial change in aneurysmal neck angle was calculated using a standardized protocol. Relationships between clinical variables and outcomes were evaluated using univariate and multivariate Cox analyses and mixed-model regression. In addition, the Kaplan Meier method was used to assess the cumulative rates of survival, endoleak, and reintervention. RESULTS: The primary technical success rate (success within 24 h after EVAR) was 100% (24/24). The survival rate was 96 +/- 8% at 1 month, 6 months, 1 year, and 3 years, and 87 +/- 18% at 5 years. Endoleaks occurred in three patients. Four reinterventions were performed in three patients; no surgical revisions were required. Causes of post-EVAR mortality included intracerebral hemorrhage at 14 days and rhabdomyolysis at 32 months. The most remarkable change after Kilt-based EVAR was an acute decrease in the neck angle, which was observed between the pre-EVAR and first follow-up visits (at 1 month) (P = 0.001). CONCLUSION: Kilt-based EVAR with Seal(r) stent-grafts for AAAs with a severely angulated neck (angle > 60 degrees ) provided high technical success, low mortality, and low complication rates during short-term follow-up. PMID- 29279977 TI - A model predicting operative mortality in the UK has only limited value in Denmark. AB - PURPOSE: Postoperative mortality from colorectal cancer varies between surgical departments. Several models have been developed to predict the operative risk. This study aims to investigate whether the original and the revised Association of Coloproctology of Great Britain and Ireland (ACPGBI) model can predict 30-day mortality after colorectal cancer surgery in Denmark. METHODS: Data were collected from the Danish Colorectal Cancer Group database which has > 95% completeness. All patients operated on from January 2007 to December 2013 were included. The individual estimated operative risk was calculated with the original and revised ACPGBI models. Discrimination and calibration were evaluated with a Receiver Operating Characteristic (ROC) curve analysis and a Hosmer Lemeshow test, respectively. RESULTS: In total, 22,807 patients underwent open or laparoscopic colorectal cancer surgery. After excluding 1437 patients because of missing data, 21,370 patients were left for the analyses. The observed 30-day mortality was 5.0%. The original and revised ACPGBI models estimated an operative risk of 7.0 and 4.0%, respectively, with a significant difference in observed and estimated mortality in both models. However, in patients with an estimated risk of at least 26%, i.e., high-risk, good calibration was found with the original ACPGBI model. Discrimination was good with an AUC of 0.83 (95% CI 0.82-0.84) in both models. CONCLUSION: The original and revised ACPGBI models are not suitable prediction models for postoperative mortality in the Danish colorectal cancer population. However, the original model might be applicable in predicting mortality in high-risk patients. PMID- 29279978 TI - The Draft Genome Sequence of Thermophilic Thermoanaerobacterium thermosaccharolyticum M5 Capable of Directly Producing Butanol from Hemicellulose. AB - A novel thermophilic and butanogenic Thermoanaerobacterium thermosaccharolyticum M5 was successfully isolated and characterized, which could produce butanol from hemicellulose via a unique ethanol-butanol (EB) pathway through consolidated bioprocessing (CBP). This represents the first wild-type bacterium which could produce butanol from hemicellulose via CBP under thermophilic conditions. The assembled draft genome of strain M5 is 2.64 Mp, which contains 2638 genes and 2465 protein-coding sequences with 33.90% G + C content. Among these annotated proteins, xylanases, xylosidases, and bifunctional alcohol/aldehyde dehydrogenase (AdhE) play key roles in the achievement of EB production from hemicellulose through CBP. PMID- 29279979 TI - Correction to: Common findings of bla CTX-M-55-encoding 104-139 kbp plasmids harbored by extended-spectrum beta-lactamase-producing Escherichia coli in pork meat, wholesale market workers, and patients with urinary tract infection in Vietnam. AB - The original version of this article unfortunately contained a mistake. The legends of Tables 2 and 3, Fig. 1 are incorrect. The corrected legends are given below. PMID- 29279981 TI - Fall risk during opposing stance perturbations among healthy adults and chronic stroke survivors. AB - Studies examining recovery from SLIPS and TRIPS indicate higher incidence of falls during SLIPS than TRIPS however, differences in the recovery mechanisms during these opposing perturbations have not been examined. We therefore aimed to compare the reactive balance responses contributing to fall risk during SLIPS and TRIPS at comparable perturbation intensity among community-dwelling healthy adults and chronic stroke survivors. Younger adults (N = 11), age-matched adults (N = 11) and chronic stroke survivors (N = 12) were exposed to a single SLIP and TRIP through a motorized treadmill (16 m/s2, 0.20 m). Center of mass (COM) state stability was measured by recording COM position and velocity relative to base of support, i.e., D COM/BOS and X COM/BOS, respectively. Trunk and compensatory step kinematics were also recorded. During SLIPS, the incidence of falls among stroke survivors was greater than healthy adults (53.83% vs. 0%), however not for TRIPS. All groups showed higher change in postural stability from liftoff to touchdown during TRIPS than SLIPS. Among healthy adults higher change in D COM/BOS during TRIPS was accompanied by the ability to control trunk flexion at step touchdown and lower peak trunk velocity as compared with SLIPS, with no significant differences in compensatory step length between the perturbations (p > 0.05). Chronic stroke survivors increased compensatory step length during TRIPS versus SLIPS (p < 0.05) contributing to greater stability change. They were unable to control trunk excursion and peak trunk velocity as compared with the healthy adults leading to lower stability than healthy younger and age-matched adults during SLIPS and lower stability than younger adults during TRIPS. Difficulty in trunk control during SLIPS among all individuals and compensatory step length among stroke survivors emphasizes higher fall risk for SLIPS than TRIPS among these populations. PMID- 29279982 TI - Mapping of non-numerical domains on space: a systematic review and meta-analysis. AB - The spatial numerical association of response code (SNARC) effect is characterized by low numbers mapped to the left side of space and high numbers mapped to the right side of space. In addition to numbers, SNARC-like effects have been found in non-numerical magnitude domains such as time, size, letters, luminance, and more, whereby the smaller/earlier and larger/later magnitudes are typically mapped to the left and right of space, respectively. The purpose of this systematic and meta-analytic review was to identify and summarise all empirical papers that have investigated horizontal (left-right) SNARC-like mappings using non-numerical stimuli. A systematic search was conducted using EMBASE, Medline, and PsycINFO, where 2216 publications were identified, with 57 papers meeting the inclusion criteria (representing 112 experiments). Ninety-five of these experiments were included in a meta-analysis, resulting in an overall effect size of d = .488 for a SNARC-like effect. Additional analyses revealed a significant effect size advantage for explicit instruction tasks compared with implicit instructions, yet yielded no difference for the role of expertise on SNARC-like effects. There was clear evidence for a publication bias in the field, but the impact of this bias is likely to be modest, and it is unlikely that the SNARC-like effect is a pure artefact of this bias. The similarities in the response properties for the spatial mappings of numerical and non-numerical domains support the concept of a general higher order magnitude system. Yet, further research will need to be conducted to identify all the factors modulating the strength of the spatial associations. PMID- 29279984 TI - An ion quencher operated lamp for multiplexed fluorescent bioassays. AB - A novel and adjustable lamp based on competitive interaction among dsDNA-SYBR Green I (SGI), ion quencher, and analyte was designed for bioanalysis. The "filament" and switch of the lamp could be customized by employing different dsDNA and ion quencher. The poly(AT/TA) dsDNA was successfully screened as the most effective filament of the lamp. Two common ions, Hg2+ and Fe3+, were selected as the model switch, and the corresponding ligand molecules cysteine (Cys) and pyrophosphate ions (PPi) were selected as the targets. When the fluorescence-quenched dsDNA/SGI-ion complex was introduced into a target containing system, ions could be bound by competitive molecules and separate from the complex, thereby lighting the lamp. However, no light was observed if the biomolecule could not snatch the metal ions from the complex. Under the optimal conditions, sensitive and selective detection of Cys and PPi was achieved by the lamp, with practical applications in fetal bovine serum and human urine. This ion quencher regulated lamp for fluorescent bioassays is simple in design, fast in operation, and is more convenient than other methods. Significantly, as many molecules could form stable complexes with metal ions selectively, this ion quencher operated lamp has potential for the detection of a wide spectrum of analytes. Graphical abstract A novel and adjustable lamp on the basis of competitive interaction among dsDNA-SYBR Green I, ions quencher and analyte was designed for bioanalysis. The filament and switch of lamp could be customized by employing different dsDNA and ions quencher. PMID- 29279983 TI - Surgical anatomy of neurovascular structures related to ventral C1-2 complex: an anatomical study. AB - OBJECTIVE: Transoral odontoidectomy and ventral C1-2 stabilization are important surgical procedures, performed to decompress ventral spinal cord, and to stabilize craniovertebral junction. These procedures require knowledge regarding surgical anatomy of neurovascular structures ventral to the C1-2 complex. The aim of this study is to evaluate the relationships between neurovascular structures and bony landmarks in ventral atlantoaxial complex. MATERIALS AND METHODS: This study was performed on six formaldehyde fixed cadaveric head and neck specimens. Relevant anatomical parameters, including distances from the midsagittal line to internal carotid arteries (ICA), vertebral arteries (VA), and hypoglossal nerves (HN), were measured using electronic calipers. RESULTS: The mean distance between ICA and midsagittal line was observed as 26.13 mm at the level of axis and 24.67 mm at the level of the atlas. The mean distance between VA and midsagittal line was observed as 15.38 mm at the level of axis and 26.54 mm at the level of the atlas. The mean distance between HN and midsagittal line was observed as 33.27 and 33.58 mm at the level of the atlas and axis, respectively. CONCLUSION: This study confirmed that ICA and HN proceeded ventrally or laterally along the lateral aspect of the C1 lateral mass; therefore, the area located ventrally along the medial components of the C1 lateral mass was the safe zone for anterior surgical approach. PMID- 29279985 TI - Label-free screening of foodborne Salmonella using surface plasmon resonance imaging. AB - It is estimated that 95% of the foodborne infections are caused by 15 major pathogens. Therefore, rapid and effective multiplex screening techniques for these pathogens with improved efficiencies could benefit public health at lower costs. Surface plasmon resonance imaging (SPRi) provides a label-free, multiplex analytical platform for pathogen screening. In this study, we have developed a singleplex immunoassay for Salmonella to evaluate the potential of SPRi in pathogen detection. Anti-Salmonella and control ligands were arrayed onto the SPRi sensor chip in a microarray format. The influences of ligand immobilization pH and concentration were optimized, and a pause flow protocol was adopted to improve assay rapidity and sensitivity. The method shows good specificity against 6 non-Salmonella species and was able to detect 5 of 6 Salmonella serotypes, including 3 serotypes most frequently associated with outbreaks. Limits of detection were found to be 2.1 * 106 CFU/mL in phosphate-buffered saline and 7.6 * 106 CFU/mL in the presence of chicken rinse matrix with 8.9 * 107 CFU/mL of indigenous microflora. The condition of antibody array regeneration was optimized for sequential sample injections. Finally, the SPRi immunoassay was used to detect Salmonella directly from artificially spiked chicken carcass rinse samples. As low as 6.8 CFU/mL of Salmonella could be detected after overnight enrichment in buffered peptone water, demonstrating the potential in streamlined pathogen screening with minimal sample preparation and without detection labels. Graphical abstract ?. PMID- 29279986 TI - A strategy of utilizing Zn(II) as metallic pivot in room temperature ionic liquid to prepare molecularly imprinted polymers for compound with intramolecular hydrogen bonds. AB - A method of preparing molecularly imprinted polymers (MIPs) with Zn(II) as a metallic pivot was adopted to solve the problem of imprinting compound with intramolecular hydrogen bonds by forming stronger coordination binding interaction among the template-functional monomer-Zn2+ complex. A ternary porogenic system including dimethyl sulfoxide, dimethylformamide, and room temperature ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate was employed to fabricate imprinted monolith with high porosity and good flow-through properties, in which chicoric acid (CA), zinc acetate, 4-vinylpyridine (4-VP), and ethylene glycol dimethacrylate (EDMA) was the template, metallic ion, functional monomer, as well as crosslinker, respectively. The influence of polymerization factors including the 4-VP-CA ratio, monomer-crosslinker ratio, template-Zn2+ ratio on imprinting factors was systematically investigated. When the ratio of 4-VP to CA was 24:1, the greatest IF value (24.81) was achieved on the CA-MIP prepared with zinc acetate. In addition, off-line SPE with the optimal MIPs monolith led to high purity of CA (98.0% +/- 0.5%) from extraction of Cichorium intybus L. roots with the recovery of 77.5% +/- 2.5% (n = 6). As a conclusion, the strategy of introducing metal ions as metal pivot to prepare MIPs was a powerful method for the MIPs synthesis to the template molecules with intramolecular hydrogen bonds. PMID- 29279987 TI - Metabolism of a sea lamprey pesticide by fish liver enzymes part B: method development and application in quantification of TFM metabolites formed in vivo. AB - The sea lamprey (Petromyzon marinus) is a destructive invasive species in the Great Lakes. Since the 1960s, tons of the lampricide 3-trifluoromethyl-4 nitrophenol (TFM) has been applied to selected tributaries each year to eliminate or reduce sea lamprey larval populations. Therefore, the environmental impact of TFM needs to be evaluated. However, the metabolism of TFM and its mechanism of selective toxicity in sea lamprey is not yet fully understood. Based upon our previous report on the identification, synthesis, and characterization of TFM metabolites observed in liver incubates from sea lamprey and non-target fishes, we now provide a robust assay for quantifying TFM and its metabolites in fish liver tissue. This method is important for assessing bioaccumulation of TFM in the ecosystems. The compounds purified in our previous report were used to develop and validate a quantitative ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay for TFM and TFM metabolites formed in vivo. Several sample preparation techniques were compared, and a protein precipitation method was selected. The unavailability of stable isotopic internal standards was overcome by using a matrix matching method. After a thorough validation, this method was applied to determine the concentrations of TFM and its metabolites in fish liver tissues from animals exposed to TFM, and in the comparison between dead animals and survivors. Seven of eight expected metabolites were observed, some for the first time in vivo. Our results indicate that in vivo nitroreduction, glucuronidation, sulfation, and glutathione conjugation are involved in TFM metabolism in sea lamprey. PMID- 29279988 TI - Electron spin resonance spectroscopy for immunoassay using iron oxide nanoparticles as probe. AB - With the help of iron oxide nanoparticles, electron spin resonance spectroscopy (ESR) was applied to immunoassay. Iron oxide nanoparticles were used as the ESR probe in order to achieve an amplification of the signal resulting from the large amount of Fe3+ ion enclosed in each nanoparticle. Rabbit IgG was used as antigen to test this method. Polyclonal antibody of rabbit IgG was used as antibody to detect the antigen. Iron oxide nanoparticle with a diameter of either 10 or 30 nm was labeled to the antibody, and Fe3+ in the nanoparticle was probed for ESR signal. The sepharose beads were used as solid phase to which rabbit IgG was conjugated. The nanoparticle-labeled antibody was first added in the sample containing antigen, and the antigen-conjugated sepharose beads were then added into the sample. The nanoparticle-labeled antibody bound to the antigen on sepharose beads was separated from the sample by centrifugation and measured. We found that the detection ranges of the antigen obtained with nanoparticles of different sizes were different because the amount of antibody on nanoparticles of 10 nm was about one order of magnitude higher than that on nanoparticles of 30 nm. When 10 nm nanoparticle was used as probe, the upper limit of detection was 40.00 MUg mL-1, and the analytical sensitivity was 1.81 MUg mL-1. When 30 nm nanoparticle was used, the upper limit of detection was 3.00 MUg mL-1, and the sensitivity was 0.014 and 0.13 MUg mL-1 depending on the ratio of nanoparticle to antibody. Graphical abstract Schematic diagram of procedure and ESR spectra. PMID- 29279989 TI - Demonstration of hydrazide tagging for O-glycans and a central composite design of experiments optimization using the INLIGHTTM reagent. AB - The INLIGHTTM strategy for N-linked glycan derivatization has been shown to overcome many of the challenges associated with glycan analysis. The hydrazide tag reacts efficiently with the glycans, increasing their non-polar surface area, allowing for reversed-phase separations and increased ionization efficiency. We have taken the INLIGHTTM strategy and adopted it for use with O-linked glycans. A central composite design was utilized to find optimized tagging conditions (45% acetic acid, 0.1 MUg/MUL tag concentration, 37 C, 1.75 h). Derivatization at optimized conditions was much quicker than any hydrazide derivatization strategy used previously. Human immunoglobulin A (IgA) and bovine submaxillary mucin (BSM) were then deglycosylated through hydrazinolysis and the removed glycans were tagged under optimum conditions. XIC of tagged glycans and MS2 data show successful hydrazide tagging of O-linked glycans for the first time. Graphical abstract The INLIGHTTM hydrazide tag was optimized using a central composite design for derivatization of O-linked glycans. Two glycoprotein standards were deglycosylated through hydrazinolysis and tagged at the optimized conditions. MS/MS data shows INLIGHTTM derivatization of glycans demonstrating successful hydrazide tagging of O-glycans for the first time. PMID- 29279990 TI - Meet the contributors. PMID- 29279991 TI - Counting the number of enzymes immobilized onto a nanoparticle-coated electrode. AB - To immobilize enzymes at the surface of a nanoparticle-based electrochemical sensor is a common method to construct biosensors for non-electroactive analytes. Studying the interactions between the enzymes and nanoparticle support is of great importance in optimizing the conditions for biosensor design. This can be achieved by using a combination of analytical methods to carefully characterize the enzyme nanoparticle coating at the sensor surface while studying the optimal conditions for enzyme immobilization. From this analytical approach, it was found that controlling the enzyme coverage to a monolayer was a key factor to significantly improve the temporal resolution of biosensors. However, these characterization methods involve both tedious methodologies and working with toxic cyanide solutions. Here we introduce a new analytical method that allows direct quantification of the number of immobilized enzymes (glucose oxidase) at the surface of a gold nanoparticle coated glassy carbon electrode. This was achieved by exploiting an electrochemical stripping method for the direct quantification of the density and size of gold nanoparticles coating the electrode surface and combining this information with quantification of fluorophore-labeled enzymes bound to the sensor surface after stripping off their nanoparticle support. This method is both significantly much faster compared to previously reported methods and with the advantage that this method presented is non-toxic. Graphical abstract A new analytical method for direct quantification of the number of enzymes immobilized at the surface of gold nanoparticles covering a glassy carbon electrode using anodic stripping and fluorimetry. PMID- 29279992 TI - Optimization of Solvent Terminated Dispersive Liquid-Liquid Microextraction of Copper Ions in Water and Food Samples Using Artificial Neural Networks Coupled Bees Algorithm. AB - A multivariate method based on solvent terminated dispersive liquid-liquid microextraction was developed for the determination of Cu2+ ions in aqueous samples. In the proposed approach, di-2-ethylhexylphosphoric acid, xylene and acetone were used as chelating agent, dispersive and extraction solvents, respectively. The effects of various factors on the extraction efficiency such as extraction and dispersive solvent volumes, salt addition and pH were studied using central composite design (CCD) and artificial neural networks coupled bees algorithm (ANN-BA). Upon comparison of these techniques, ANN-BA model was considered to be better optimization method due to its higher percentage relative recovery (about 5%) as compared to the CCD approach. The linear range and the limits of detection (S/N = 3) and quantitation (S/N = 10) were 0.22-140, 0.08 and 0.22 ug L-1, respectively. Under the optimal conditions, the recoveries for real samples spiked with 0.1 and 0.3 mg L-1 were in the range of 85-98%. PMID- 29279993 TI - Influence of Varying Water Quality Parameters on the Acute Toxicity of Silver to the Freshwater Cladoceran, Ceriodaphnia dubia. AB - The acute toxicity of silver to Ceriodaphnia dubia was investigated in laboratory reconstituted waters as well as in natural waters and reconstituted waters with natural organic matter. The water quality characteristics of the laboratory reconstituted waters were systematically varied. The parameters that demonstrated an ability to mitigate the acute toxic effects of silver were chloride, sodium, organic carbon, and chromium reducible sulfide. Factors that did not have a consistent effect on the acute toxicity of silver to C. dubia, at least over the range of conditions tested, included hardness, alkalinity, and pH. The biotic ligand model was calibrated to the observed test results and found to be of use in quantifying the effect of changing water quality characteristics on silver bioavailability and toxicity. The model generally predicted silver toxicity within a factor of two and should be useful in modifying water quality criteria. PMID- 29279994 TI - Short-term fluctuation of lens corneal distance and clinical correlation with phacodonesis. AB - BACKGROUND: To analyze the role of short-term lens-corneal distance (LCD) fluctuation in quantifying preoperative phacodonesis and predicting intraoperative zonular weakness. METHODS: Patients were divided into control (lens without clinical phacodonesis) and study (lens with suspicious and clinical phacodonesis) groups for evaluation. Slit-lamp examination followed by IOLMaster (Carl Zeiss) for LCD assessment was performed. Five readings were taken at five time points (0 s, 15 s, 30 s, 45 s & 60 s) continuously over a minute (short term) for the LCD fluctuation calculation. RESULTS: A total of 135 eyes (82 controls and 53 study) were assessed. Study group included 32 (60.3%) suspicious and 21 (39.6%) moderate to severe phacodonesis. There was difference between the control and study eyes (p = 0.000) in short-term LCD fluctuation. Twenty-one study eyes (39.6%) showed LCD difference > 1 mm, including 11 eyes (52.3%) with > 2 mm. There was a difference in LCD with respect to severity of phacodonesis (p = 0.000). In the study eyes, 13 eyes underwent glued IOL implantation (clinical phacodonesis - ten, suspicious phacodonesis - three), and two eyes (suspicious phacodonesis) had glued capsular hook. Thirteen eyes (clinical phacodonesis - ten, suspicious phacodonesis - three) required intraoperative vitrectomy due to vitreous ingress. Intraoperative zonular weakness in 62.5% of eyes with suspicious donesis and association (Chi-square = 0.000) of weakness with preoperative LCD fluctuation was noted. CONCLUSIONS: Short-term lens-corneal distance fluctuation can be used as a parameter for quantifying lens stability and as an aid in assessing the intraoperative risk. PMID- 29279996 TI - Postoperative mortality and morbidity following non-cardiac surgery in a healthy patient population. AB - PURPOSE: Perioperative mortality ranges from 0.4% to as high as nearly 12%. Currently, there are no large-scale studies looking specifically at the healthy surgical population alone. The primary objective of this study was to report 30 day mortality and morbidity in healthy patients and define any risk factors. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) dataset, all patients assigned an American Society of Anesthesiologists physical status (ASA PS) classification score of 1 or 2 were included. Further patients were excluded if they had a comorbidity or underwent a procedure not likely to classify them as ASA PS 1 or 2. Multivariable logistic regression was performed to identify predictors of the outcomes, in which odds ratios (OR) and 95% confidence intervals (95% CI) were reported. RESULTS: There were 687,552 healthy patients included in the final analysis. Following surgery, 0.7, 7.0, and 0.7 per 1000 persons experienced 30-day mortality, sepsis, and stroke or myocardial infarction, respectively. Healthy patients greater than 80 years of age had the highest odds for mortality (OR 17.7, 95% CI 12.4-25.1, p < 0.001). Case duration was associated with increased mortality, especially in cases greater than or equal to 6 h (OR 3.0, 95% CI 2.0-4.5, p < 0.001). CONCLUSIONS: Thirty-day mortality and morbidity is, as expected, lower in the healthy surgical population. Age may be an indication to further risk stratify patients that are ASA PS 1 or 2 to better reflect perioperative risk. PMID- 29279995 TI - Type A and B monoamine oxidases distinctly modulate signal transduction pathway and gene expression to regulate brain function and survival of neurons. AB - Type A and B monoamine oxidases (MAO-A, -B) mediate and modulate intracellular signal pathways for survival or death of neuronal cells. MAO-A is associated with development of neuronal architecture, synaptic activity, and onset of psychiatric disorders, including depression, and antisocial aggressive impulsive behaviors. MAO-B produces hydrogen peroxide and plays a vital role in neuronal loss of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. This review presents a novel role of MAO-A and B, their substrates and inhibitors, and hydrogen peroxide in brain function and neuronal survival and death. MAO-A activity is regulated not only by genetic factor, but also by environmental factors, including stress, hormonal deregulation, and food factors. MAO-A activity fluctuates by genetic-environmental factors, modulates the neuronal response to the stimuli, and affects behavior and emotional activities. MAO-B inhibitors selegiline and rasagiline protect neurons via increase expression of anti-apoptotic Bcl-2 and pro-survival neurotrophic factors in human neuroblastoma SH-SY5Y and glioblastoma U118MG cell lines. MAO-A knockdown suppressed the rasagiline-induced gene expression in SH-SY5Y cells, whereas MAO-B silencing enhanced the basal- and selegiline-induced gene expression in U118MG cells. MAO-A and B were shown to function as a mediator or repressor of gene expression, respectively. Further study on cellular mechanism underlying regulation of signal pathways by MAO-A and B may bring us a new insight on the role of MAOs in decision of neuronal fate and the development of novel therapeutic strategy may be expected for neuropsychiatric disorders. PMID- 29279997 TI - Outcomes of surgery for hepatocellular carcinoma with tumor thrombus in the inferior vena cava or right atrium. AB - The prognosis of hepatocellular carcinoma (HCC) patients with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is extremely poor. We reviewed the recent surgical treatments and outcomes of this form of advanced HCC. TT is classified into three types according to its anatomic location relative to the heart: the inferior hepatic type (type I), where the TT is in the IVC below the diaphragm; the superior hepatic type (type II), where the TT is in the IVC above the diaphragm, but still outside the RA; and the intracardiac type (type III), where the TT is above the diaphragm and has entered the RA. Type I can be treated relatively easily by standard radical hepatectomy. For type II, the intrathoracic IVC is approached via the abdominal cavity and an incision in the diaphragm with total hepatic vascular exclusion (THVE). For type III, hepatectomy plus thrombectomy is generally performed under cardiopulmonary bypass. If the TT is only just inside the RA, THVE can be performed by mobilizing the liver caudally. The median overall survival of HCC patients with TT in the IVC or RA, who undergo curative resection, is 19.0-30.8 months. As postoperative recurrence is likely to develop, even after curative surgery, effective postoperative adjuvant chemotherapy is required. PMID- 29279998 TI - Modified anterior-only reduction and fixation for traumatic cervical facet dislocation (AO type C injuries). AB - PURPOSE: Surgical reduction of uni and bi-facetal dislocations of the cervical spine (AO type C injuries) can be performed by posterior, anterior or combined approaches. Ease of access, low infection rates and less risks of neurological worsening has popularized anterior approach. However, the reduction of locked cervical facets can be intricate through anterior approach. We analyzed the safety, efficacy and outcomes at a minimum 1 year, of a novel anterior reduction technique for consecutively treated cervical facet dislocations. MATERIALS AND METHODS: Patients with single level traumatic sub-axial cervical dislocation (n = 39) treated by this modified anterior technique were studied. The technique involved standard Smith-Robinson approach, discectomy beyond PLL, use of inter laminar distracter to distract while Caspar pins were used as "joysticks" (either flexion-extension or lateral rotation moments are provided), to reduce the sub luxed facets. Among 51 patients with cervical type C injury treated during the study period, 4 patients who had spontaneous reduction and 8 treated by planned global fusion were excluded. RESULTS: 39 patients of mean age 49.9 years were studied. The levels of injury included (C3-4 = 2, C4-5 = 5, C5-6 = 20, C6-7 = 12). 18 were bi-facetal and 21 were uni-facetal dislocation. One facet was fractured in 17 and both in 5 patients. 30% (n = 13) had a concomitant disc prolapse. The neurological status was as follows: 9 ASIA A, 9 ASIA C, 13 ASIA D and 8 ASIA E. All the patients were successfully reduced by this technique and fixed with anterior locking cervical locking plates. No supplemental posterior surgery was performed. 22 patients with incomplete deficit showed recovery. The mean follow-up was 14.3 months and there was no implant failure except one patient who had partial loss of the reduction. CONCLUSION: Patients with traumatic sub-axial cervical dislocation (AO type C injuries) can be safely and effectively reduced by this technique. Other advantages include minimal blood loss, less risks of infection, shorted fusion zone, good fusion rate and neurological recovery. PMID- 29279999 TI - Biodegradation of alkali lignin by a newly isolated Rhodococcus pyridinivorans CCZU-B16. AB - Based on the Prussian blue spectrophotometric method, one high-throughput screening strategy for screening lignin-degrading microorganisms was built on 24 well plate at room temperature. One high activity of alkali lignin-degrading strain Rhodococcus pyridinivorans CCZU-B16 was isolated from soil. After the optimization of biodegradation, 30.2% of alkali lignin (4 g/L) was degraded under the nitrogen-limited condition (30/1 of C/N ratio; g/g) at 30 degrees C for 72 h. It was found that syringyl (S) units and guaiacyl (G) in lignin decreased after biodegradation. Moreover, the accumulated lipid in cells had a fatty acid profile rich in C16 and C18 with four major constituent fatty acids including palmitic acid (C16:0; 22.4%), palmitoleic acid (C16:1; 21.1%), stearic acid (C18:0; 16.2%), and oleic acid (C18:1; 23.1%). In conclusion, Rhodococcus pyridinivorans CCZU-B16 showed high potential application in future. PMID- 29280001 TI - Gene-based SNP identification and validation in soybean using next-generation transcriptome sequencing. AB - Gene-based molecular markers are increasingly used in crop breeding programs for marker-assisted selection. However, identification of genetic variants associated with important agronomic traits has remained a difficult task in soybean. RNA-Seq provides an efficient way, other than assessing global expression variations of coding genes, to discover gene-based SNPs at the whole genome level. In this study, RNA isolated from four soybean accessions each with three replications was subjected to high-throughput sequencing and a range of 44.2-65.9 million paired end reads were generated for each library. A total of 75,209 SNPs were identified among different genotypes after combination of replications, 89.1% of which were located in expressed regions and 27.0% resulted in amino acid changes. GO enrichment analysis revealed that most significant enriched genes with nonsynonymous SNPs were involved in ribonucleotide binding or catalytic activity. Of 22 SNPs subjected to PCR amplification and Sanger sequencing, all of them were validated. To test the utility of identified SNPs, these validated SNPs were also assessed by genotyping a relative large population with 393 wild and cultivated soybean accessions. These SNPs identified by RNA-Seq provide a useful resource for genetic and genomic studies of soybean. Moreover, the collection of nonsynonymous SNPs annotated with their predicted functional effects also provides a valuable asset for further discovery of genes, identification of gene variants, and development of functional markers. PMID- 29280002 TI - Iron-sulfur clusters biogenesis by the SUF machinery: close to the molecular mechanism understanding. AB - Iron-sulfur clusters (Fe-S) are amongst the most ancient and versatile inorganic cofactors in nature which are used by proteins for fundamental biological processes. Multiprotein machineries (NIF, ISC, SUF) exist for Fe-S cluster biogenesis which are mainly conserved from bacteria to human. SUF system (sufABCDSE operon) plays a general role in many bacteria under conditions of iron limitation or oxidative stress. In this mini-review, we will summarize the current understanding of the molecular mechanism of Fe-S biogenesis by SUF. The advances in our understanding of the molecular aspects of SUF originate from biochemical, biophysical and recent structural studies. Combined with recent in vivo experiments, the understanding of the Fe-S biogenesis mechanism considerably moved forward. PMID- 29280003 TI - Octocoral co-infection as a balance between host immunity and host environment. AB - Co-infection is the reality in natural populations, but few studies incorporate the players that matter in the wild. We integrate the environment, host demography, two parasites, and host immunity in a study of co-infection to determine the drivers of parasite interactions. Here, we use an ecologically important Caribbean sea fan octocoral, Gorgonia ventalina, that is co-infected by a copepod and a labyrinthulid protist. We first expanded upon laboratory studies by showing that immune suppression is associated with the labyrinthulid in a natural setting. Histological analyses revealed that immune cells (amoebocytes) were significantly suppressed in both labyrinthulid infections and co-infections relative to healthy sea fans, but remained unchanged in copepod infections. However, surveys of natural coral populations demonstrated a critical role for the environment and host demography in this co-infection: the prevalence of copepod infections increased with sea fan size while labyrinthulid prevalence increased with water depth. Although we predicted that immune suppression by the labyrinthulid would facilitate copepod infection, the two parasites did not co occur in the sea fans more often than expected by chance. These results suggest that the distinct ecological drivers for each parasite overwhelm the role of host immune suppression in determining the distribution of parasites among hosts. This interplay of the environment and parasite-mediated immune suppression in sea fan co-infection provides insights into the factors underlying co-occurrence patterns in wild co-infections. Moving forward, simultaneous consideration of co-occurring parasites, host traits, and the environmental context will improve the understanding of host - parasite interactions and their consequences. PMID- 29280004 TI - The Drug of Abuse Gamma-Hydroxybutyric Acid Exhibits Tissue-Specific Nonlinear Distribution. AB - The drug of abuse gamma-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus L lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose. K p values for GHB varied in both a tissue- and dose-dependent manner and were less than 0.5 (except in the kidney). Nonlinear partitioning was observed in the liver (0.06 at 400 mg/kg to 0.30 at 800 mg/kg), kidney (0.62 at 400 mg/kg to 0.98 at 800 mg/kg), and heart (0.15 at 400 mg/kg to 0.29 at 800 mg/kg), with K p values increasing with dose consistent with saturation of transporter-mediated efflux. In contrast, lung partitioning decreased in a dose-dependent manner (0.43 at 400 mg/kg to 0.25 at 800 mg/kg) suggesting saturation of active uptake. L-lactate administration decreased K p values in liver, striatum, and hippocampus and increased K p values in lung and spleen. GHB demonstrates tissue-specific nonlinear distribution consistent with the involvement of monocarboxylate transporters. These observed complexities are likely due to the involvement of MCT1 and 4 with different affinities and directionality for GHB transport. PMID- 29280005 TI - Goshajinkigan for prevention of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. AB - PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) limits the dose of chemotherapy and reduces patients' quality of life. Goshajinkigan is a Japanese herbal medicine used to alleviate neuropathy and general pain. A clinical guideline for prevention and management of CIPN stated that the prophylactic efficacy of goshajinkigan against CIPN was inconclusive. We conducted a systematic review to examine whether goshajinkigan prevents CIPN in patients receiving neurotoxic chemotherapy. METHODS: We searched PubMed, EMBASE, Ichushi, and the Cochrane Central Register of Controlled Trials for eligible trials. Randomized controlled trials that examined the efficacy and safety of goshajinkigan for prevention of CIPN were included. Our primary outcomes were incidence of CIPN, response to chemotherapy, and adverse effects. We pooled data using a random effects model. RESULTS: We analyzed five trials involving a total of 397 patients. When evaluated with Neurotoxicity Criteria of Debiopharm, goshajinkigan was associated with reduced incidence of CIPN of grade >= 1 (risk ratio [RR] 0.43; 95% CI, 0.27 to 0.66) and grade 3 (RR 0.42; 95% CI, 0.25 to 0.71), but this beneficial association was not found for grade >= 2 of CIPN. Goshajinkigan was not associated with reduced incidence of CIPN when assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events, or improved response to chemotherapy. Goshajinkigan was well tolerated based on one trial. CONCLUSIONS: Goshajinkigan is unlikely to prevent CIPN in patients undergoing neurotoxic chemotherapy. Given the low quality and insufficient amount of the evidence, use of goshajinkigan as standard of care is not currently recommended. PMID- 29280006 TI - Minimally invasive unicompartmental knee arthroplasty. AB - The exact indication for a unicompartmental knee arthroplasty (UKA) remains debated. Minimally invasive techniques have been developed to decrease the surgical trauma related to the prosthesis implantation, and this technique is well fitted to UKA. However, there are concerns about loss of accuracy with minimally invasive techniques. Furthermore, rapid recovery techniques have been developed in order to reduce the length of hospital stay. Again, UKA is well fitted to these new developments of postoperative care. We combine routinely a minimal invasive operative technique with navigation assistance to ensure proper positioning of the implants as well as an optimal ligamentous balance. Instruments have been adapted for use with a typical 6-cm skin incision with little change from the conventional navigated operating technique. A multimodal pain treatment is implemented immediately after the implantation, with special attention to a routine saphenous nerve blockade. Patients are instructed to stand up on the day of surgery with full weight bearing and to mobilize the knee joint without restriction. They may be discharged at least on the day following surgery, and the most favorable patients may be operated in our day-case surgery unit. These conclusions should be confirmed on a larger scale. PMID- 29280007 TI - Key Performance Indicators to Measure Improvement After Implementation of Total Laboratory Automation Abbott Accelerator a3600. AB - The aim of the study was to estimate improvement of work efficiency in the laboratory after implementation of total laboratory automation (TLA) by Abbott Accelerator a3600 in the laboratory with measuring different key performance indicators (KPIs) before and after TLA implementation. The objective was also to recommend steps for defining KPIs in other laboratories. For evaluation of improvement 10 organizational and/or technical KPIs were defined for all phases of laboratory work and measured before (November 2013) and after (from 2015 to 2017) TLA implementation. Out of 10 defined KPIs, 9 were successfully measured and significantly improved. Waiting time for registration of samples in the LIS was significantly reduced from 16 (9-28) to 9 (6-16) minutes after TLA (P < 0.001). After TLA all tests were performed at core biochemistry analyzers which significantly reduced walking distance for sample management (for more than 800 m per worker) and number of tube touches (for almost 50%). Analyzers downtime and engagement time for analyzers maintenance was reduced for 50 h and 28 h per month, respectively. TLA eliminated manual dilution of samples with extreme results with sigma values increment from 3.4 to >6 after TLA. Although median turnaround time TAT for potassium and troponin was higher (for approximately 20 min), number of outliers with TAT >60 min expressed as sigma values were satisfying (>3). Implementation of the TLA improved the most of the processes in our laboratory with 9 out of 10 properly defined and measured KPIs. With proper planning and defining of KPIs, every laboratory could measure changes in daily workflow. PMID- 29280008 TI - Probing structure, thermochemistry, electron affinity, and magnetic moment of thulium-doped silicon clusters TmSi n (n = 3-10) and their anions with density functional theory. AB - The most stable structures and electronic properties of TmSi n (n = 3-10) clusters and their anions have been probed by using the ABCluster global search technique combined with the PBE, TPSSh, and B3LYP density functional methods. The results revealed that the most stable structures of neutral TmSi n and their anions can be regarded as substituting a Si atom of the ground state structure of Si n + 1 with a Tm atom. The reliable AEAs, VDEs and simulated PES of TmSi n (n = 3-10) are presented. Calculations of HOMO-LUMO gap revealed that introducing Tm atom to Si cluster can improve photochemical reactivity of the cluster. The NPA analyses indicated that the 4f electron of Tm atom in TmSi n (n = 3-10) and their anions do not participate in bonding. The total magnetic moments of TmSi n are mainly provided by the 4f electrons of Tm atom. The dissociation energy of Tm atom from the most stable structure of TmSi n and their anions has been calculated to examine relative stability. PMID- 29280009 TI - Intramedullary ependymoma: long-term outcome after surgery. AB - BACKGROUND: Overall (OS) and progression-free survival (PFS) of patients undergoing spinal ependymoma resection has been frequently reported. Contrarily, OS and PFS of purely intramedullary ependymomas have not been clearly determined yet. METHODS: The data of 37 patients undergoing resection of an intramedullary ependymoma (IE) from January 2000 to December 2016 were analysed retrospectively. RESULTS: The mean age was 46 years. The male:female ratio was 24:13. The median duration of symptoms was 12 months. Sixty-two per cent of ependymomas were in the cervical, 24% in the thoracic, and 14% in the conus region in our series. The median volume was 1.3 ml. A syrinx was found in 49% and a cyst in 32%. GTR was achieved in 89%, STR in three (8%), and PR in one patient (3%). Median follow-up was 114 months. PFS was 87%, 82%, and 82% at 5, 10, and 15 years, respectively. OS was 97%, 88%, and 63% at 5, 10, and 15 years, respectively. There was a significant difference in PFS depending on the extent of resection and in OS depending on the pre-operative clinical status. There was no significant difference in OS and PFS regarding the other examined influencing factors. CONCLUSION: GTR resection was the most important factor influencing PFS. According to our results OS of IEs is much worse than that of spinal ependymomas. Our analysis confirms that patients with good pre-operative (McCormick grade 1 and 2) clinical status have significantly better OS than patients with McCormick grade 3 and higher. PMID- 29280010 TI - Role of vitamin D deficiency in systemic lupus erythematosus incidence and aggravation. AB - Vitamin D is one of the main groups of sterols; playing an important role in phospho-calcic metabolism. The conversion of 7-dehydrocholesterol to pre- vitamin D3 in the skin, through solar ultraviolet B radiation, is the main source of vitamin D. Since lupus patients are usually photosensitive, the risk of developing vitamin D deficiency in is high in this population. Although evidences showed the connotation between systemic lupus erythematosus (SLE) and vitamin D through which SLE can lead to lower vitamin D levels, it is also important to consider the possibility that vitamin D deficiency may have a causative role in SLE etiology. This paper analyzes existing data from various studies to highlight the role of vitamin D deficiency in SLE occurrence and aggravation and the probable efficacy of vitamin D supplementation on SLE patients. We searched "Science Direct" and "Pub Med" using "Vitamin D" and "SLE" for finding the studies focusing on the association between vitamin D deficiency and SLE incidence and consequences. Evidences show that vitamin D plays an important role in the pathogenesis and progression of SLE and vitamin D supplementation seems to ameliorate inflammatory and hemostatic markers; so, can improve clinical subsequent. PMID- 29280011 TI - High burden of adverse events is associated with reduced remission rates in early rheumatoid arthritis. AB - Adverse events (AEs) are common during disease-modifying antirheumatic drug (DMARD) treatment, but their influence on treatment results is unclear. We studied AEs in relation to disease activity in early rheumatoid arthritis (RA). Ninety-nine patients started intensive treatment with three conventional synthetic DMARDs (csDMARDs) and oral prednisolone, and were randomized to a 6 month induction treatment with infliximab or placebo. All AEs during the first 12 months of treatment were recorded. We scored each AE based on severity (scale 1 4) and defined the burden of AEs as the sum of these scores. Patients were divided into tertiles according to the burden of AEs. As outcomes, we assessed 28 joint disease activity score (DAS28) levels and remission rates at 12 and 24 months. Three hundred thirty-one AEs in 99 patients were reported, and 27 (8%) were categorized as severe or serious. Mean burden of AEs per patient was 5.4 +/- 4.3. Seventy-nine AEs (24%) led to temporary (n = 52) or permanent (n = 27) csDMARD discontinuation. Of discontinuations, 1, 21, and 57 were detected in the first, second, and third tertiles, respectively. DAS28 remission rates decreased across tertiles at 12 months (94, 94, and 76%; p for linearity 0.029) and at 24 months (90, 86, and 70%; p for linearity 0.021). Mean DAS28 levels increased across tertiles at 12 months (1.5 +/- 1.0, 1.7 +/- 0.9, and 1.9 +/- 1.2; p for linearity 0.021) and at 24 months (1.4 +/- 0.8, 1.6 +/- 1.0, and 1.9 +/- 1.1; p for linearity 0.007). High burden of AEs is associated with higher disease activity and lower likelihood of remission in early RA. PMID- 29280013 TI - Preoperative predictors of beyond endoscopic submucosal dissection indication or lymphovascular invasion in endoscopic resection for early gastric cancer. AB - BACKGROUND: To successfully resect early gastric cancer (EGC), prediction of lymph node metastasis is essential. Beyond endoscopic submucosal dissection (ESD) indication or lymphovascular invasion (LVI) are known risk factors associated with lymph node metastasis. However, accurate prediction of tumor invasion depth or LVI is impossible before endoscopic resection even when endoscopic ultrasound is used. The aim of this study was to identify the predictive factors associated with beyond ESD indication or LVI after ESD for EGC. METHODS: Between Jan 2011 and Feb 2015, 532 lesions from 506 patients who received ESD for EGCs were included. We reviewed the data of patients diagnosed as EGCs without ulceration or those smaller than 3 cm with ulceration. RESULTS: The incidence of EGCs found to be beyond expanded ESD indications or present of LVI after ESD was 11.1% (59/532). On multivariable analysis, endoscopic features of SM invasion, surface color changes, and elevated lesions were associated with beyond ESD indication or LVI. In particular, submucosal (SM) invasive features such as SM tumor-like marginal elevation [odds ratio (OR) 17.2; 95% confidence interval (CI) 2.0 146.7], fusion of convergent folds (OR 12.9; 95% CI 3.9-42.1), irregular surface (OR 17.8; 95% CI 5.6-56.8), and discoloration of the tumor surface (OR 16.1; 95% CI 2.4-105.9) were significant risk factors for beyond ESD indication or LVI. CONCLUSIONS: The decision to proceed with endoscopic resection for EGCs with endoscopic features of SM invasion, surface color changes, or elevated forms must be made cautiously. PMID- 29280012 TI - SUOX is negatively associated with multistep carcinogenesis and proliferation in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck region. The aim of this study was to identify the key molecules and to elucidate the molecular mechanisms of OSCC carcinogenesis through a microarray analysis of RNA extracted from normal epithelium, dysplasia, and squamous cell carcinoma components. Out of molecules that showed changes in gene expression in the microarray analysis, we focused on Sulfite oxidase (SUOX), which correlated significantly with carcinogenic process and exhibited a stepwise decrease in expression. The expression of SUOX was evaluated in detail at the protein level using samples from 58 patients with cancer of the tongue, and correlating clinicopathological factors were also comprehensively examined. SUOX expression declined significantly from normal epithelium to dysplasia to squamous cell carcinoma components in line with carcinogenic process. With regard to squamous cell carcinoma, SUOX expression was significantly lower when T classification was high. Our findings indicated that SUOX is negatively associated with the progression and proliferation of tongue cancer, and suggest that SUOX may be a key molecule in tongue tumors. PMID- 29280014 TI - Robotic-assisted versus laparoscopic pancreaticoduodenectomy: oncological outcomes. AB - BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) is being performed with increasing frequency for pancreatic cancer, but the most oncologically efficacious surgical platform, whether robotic or laparoscopic, is yet to be determined. Currently, there are no national studies comparing the oncological outcomes between robotic (RPD) and laparoscopic (LPD) pancreaticoduodenectomy. METHODS: This was a retrospective study using the National Cancer Database between 2010 and 2013. We compared the perioperative, pathological, and mid-term oncological outcomes between RPD and LPD. RESULTS: There were 1623 MIPD cases, of which 90% were LPD and 10% were RPD. Most LPD (63%) and RPD (51%) cases were performed at institutions with a volume of <= 5 MIPDs per year. There were no differences in patient- and tumor-related factors between the groups. The majority of treated tumors were adenocarcinoma (90.1% for RPD and 89.1% for LPD). RPDs were more likely to be performed at academic centers (89.1%) compared to LPDs (68.1%, P < 0.001) and at higher-volume centers (median MIPD/year of 4.7 for RPD vs 3.6 for LPD, P < 0.001). There was no difference in the median number of examined lymph nodes, margin status, median length of stay, 90-day mortality, or 30-day readmission between groups. There was no difference in median overall survival for pancreatic adenocarcinoma between LPD (20.7 months) and RPD (22.7 months; log-rank P = 0.445). The 1- and 3-year overall survival rates were 74 and 31% for LPD and 71 and 33% for RPD. CONCLUSION: In this national cohort of patients, LPD and RPD were associated with equivalent perioperative, pathological, and mid-term oncological outcomes. PMID- 29280015 TI - The Mendelsohn Maneuver and its Effects on Swallowing: Kinematic Analysis in Three Dimensions Using Dynamic Area Detector CT. AB - This study investigated the effects of Mendelsohn maneuver with three-dimensional kinematic analysis. Nine female speech-language pathologists (nine females, mean +/- SD 27.1 +/- 3.5 years old) underwent 320-row area detector scan during swallows of 4-ml nectar-thick liquid using with no maneuvers (control) and with Mendelsohn maneuver (MM). Critical event timing (hyoid, soft palate, epiglottis, laryngeal vestibule, true vocal cords (TVC), UES), hyoid and laryngeal excursion, cross-sectional area of UES, and volume of pharyngeal cavity and bolus were measured and compared between two swallows. In MM, all the events were significantly prolonged with delayed termination time (p < 0.05) except UES opening. The onset, termination, and duration of UES opening were not significantly affected by MM nor was timing of bolus transport. The hyoid bone was positioned significantly higher at maximum displacement (p = 0.011). Pharyngeal constriction ratio was 95.1% in control and 100% of all subjects in MM. Duration of minimum pharyngeal volume was significantly longer in MM than in control (p = 0.007). The MM produces several distinct changes in the kinematics of swallowing in healthy subjects with no dysphagia. The changes in the timing and magnitude of hyoid displacements and prolonged closure of the pharynx during swallowing suggest the utility of MM for improving the safety and efficiency of swallowing in selected cases. PMID- 29280016 TI - Virome analysis of lily plants reveals a new potyvirus. AB - Lily plants exhibiting virus-like symptoms of leaf yellowing, twisting and brownish necrotic spots were collected, and next-generation sequencing of small RNAs was conducted to identify the associated viruses. Cucumber mosaic virus, lily symptomless virus and a hitherto unrecorded potyvirus, tentatively named "lily yellow mosaic virus" (LYMV), were detected. The genomic RNA of LYMV was 9811 nt in length, encoding a large polyprotein of 3,124 amino acids with a predicted Mr of 353.3 kDa. BLAST analysis showed that LYMV shared a high degree of amino acid sequence identity with Thunberg fritillary mosaic virus (55%), bean yellow mosaic virus (52%), clover yellow vein virus (51%), leek yellow stripe virus (51%), and lily mottle virus (52%), and these viruses clustered together in a phylogenetic tree. PMID- 29280017 TI - Molecular dynamics simulations of asymmetric heterodimers of HER1/HER2 complexes. AB - The family of human epidermal growth factor receptors (HER) is involved in tumor cell growth. Homodimerization and heterodimerization of the HER family are important for activation of these receptors. The structures of homodimer conformation are well characterized, while the structures of heterodimer conformations, especially between HER1 and HER2, are not completely understood. In this study, two models of possible asymmetric HER1/HER2 kinase domains were built. Molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) methods were applied to examine the possibility of these two-heterodimer interactions. From our results, it could be concluded that the HER2 kinase domain prefers to serve as the receiver rather than the activator. Key binding residues of this dimer complex at N lobe of HER2 is ALA683 and at C lobe of HER1 are GLU914, GLU917, and ASP930. This study will be useful in allowing us to predict and be able to control activity of this enzyme in disease in the future. Graphical abstract A model of the asymmetric dimer of HER1-HER2 heterodimer with key intereaction residues in (a) HER1A and (b) HER2R by molecular dynamic simulation. PMID- 29280018 TI - Correction to: Management of pregnancy-related issues in multiple sclerosis patients: the need for an interdisciplinary approach. AB - The original version contained a mistake. The authors have specified only in a few paragraphs that all the contents of the paper are meant for Copaxone but not for unbranded glatiramer acetate, Authors ask to add the specification of Copaxone or branded glatiramer acetate everytime. PMID- 29280020 TI - Role of trabeculectomy in advanced glaucoma: Whether we stand to consider it a bane or a boon today? AB - PURPOSE: To elucidate the role of trabeculectomy in advanced glaucoma. MATERIALS AND METHODS: Only patients with primary open-angle glaucoma were selected. All patients who had cup-disc ratio of 0.9 or a near-total cupping were given a trial of aggressive maximum medical therapy for IOP control for at least 4 weeks. Target IOP was defined as <= 12 mm Hg. Patients who showed progression were included in the study. A total of 10 patients were selected. Trabeculectomy was performed using limbal-based conjunctival flap. Patients were followed up for a period of 2 years for visual acuity, intraocular pressure, visual fields, slit lamp biomicroscopy and bleb morphology. RESULTS: Mean preoperative intraocular pressure on five drugs was 21.7 +/- 3.8 mm Hg (range 18-27 mm Hg) on maximum medical therapy. Mean post-operative intraocular pressure was 11 +/- 1.78 mm Hg (range 9-13 mm Hg) and 11 +/- 1.92 mm Hg (range 9-14 mm Hg) at 1 month and 6 months post-operatively, respectively. Post-operatively, the visual acuity remained stable in 17 patients. It dropped by 1 Snellen line in 2 patients and 2 Snellen lines in 1 patient, respectively, over a period of 6 months and later improved to 6/6P following cataract surgery. There was no defined visual field progression in any of the 20 patients. CONCLUSION: Besides being a cost-effective alternative to medical management, trabeculectomy not only provides a better IOP control but also has a high safety profile when performed by an experienced surgeon. PMID- 29280019 TI - Impact of short-term cycle ergometer training on quality of life, cognition and depressive symptomatology in multiple sclerosis patients: a pilot study. AB - In this pilot study, we investigate whether a routine cycle ergometry training programme has therapeutic potential in individuals with multiple sclerosis (MS) by improving quality of life (QOL) and depressive symptomatology, while ameliorating cognitive disturbances. Healthy volunteers and MS patients cycled for 30 min at 65-75% age-predicted maximal heart rate on a recumbent ergometer, with this session repeated twice a week for 8 weeks. QOL, depressive symptomatology and cognitive function were assessed pre- and post-exercise using the MS Quality of Life-54 (MSQOL-54) questionnaire, 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) questionnaire and the Cambridge Neuropsychological Test Automated Battery (CANTAB), respectively. We determined that QOL was lower in MS patients, compared to healthy subjects, with a reduction in physical and mental health summary scores observed. Exercise improved both physical and mental health scores in MS patients. In support of this, exercise was shown to reduce depressive symptomatology in MS patients. Exercise was also associated with an improvement in visual sustained attention, executive function/cognitive flexibility and hippocampal-dependent visuospatial memory in patients. Overall, this study identifies a short-term exercise programme that improves physical and mental health, while reducing depressive symptomatology and cognitive dysfunction in MS. PMID- 29280021 TI - Clinical features and neurosurgical treatment of trigonal cavernous malformations. AB - The goals of this study were to analyze the incidence, clinical manifestations, neuroimaging findings, surgical treatments, and neurological outcomes of trigonal cavernous malformations (TCMs). Among 1395 cases of intracranial and intraspinal cavernous malformations (CMs) surgically treated between 2003 and 2016 at Beijing Tiantan Hospital, a series of 12 patients with TCM was chosen for analysis and their records were reviewed. We also performed an exhaustive literature search using PubMed to identify all previously reported cases in the literatures. TCMs accounted for 0.86% of the entire series of the central nervous system (CNS) CMs. The case series consisted of five male and seven female patients (ratio 1:1.4), with an average age at presentation of 32.9 years (7-53 years). In all the cases, headache was the most common initial symptom (66.7%). Complete resection without surgical mortality was achieved in all the cases. Postoperative complications included fever, lower limb weakness, sensory aphasia, and calculational capacity declination. Follow-up period after diagnosis was 15 to 74 months (mean 48.3 months); no patient was lost to follow-up. All the patients were considered to be in excellent clinical condition. TCMs are rare lesions; they can reach large size, and their symptoms and signs commonly resulted from mass effect. Surgical intervention is the treatment of choice for TCMs; patients can obtain favorable neurological outcomes after complete resection. PMID- 29280023 TI - Body signals used during social play in captive immature western lowland gorillas. AB - The play face is a well-established play signal in nonhuman primates that functions to invite play and convey a playful intent. However, recent evidence indicates that some species display repertoires of play signals that may have more specific meanings related to particular aspects of play. Furthermore, previous studies have inconsistently categorized gorilla behaviors as play signals versus actual play. Here we aim to identify behaviors displayed by two immature captive western lowland gorillas (Gorilla gorilla gorilla) at the Buffalo Zoo that meet three necessary criteria to be considered play signals. Specifically, we (1) investigate whether 21 candidate signals are significantly different from actual play behaviors, (2) and from similar signals used in non play contexts, and (3) determine whether they predict the occurrence of social play. The results indicate that at least 18 of the 21 candidate signals have strong support for classification as play signals. These findings represent first steps in determining the function of multiple play signals in gorillas. PMID- 29280022 TI - Molecular characterization and expression analysis of the Na+/H+ exchanger gene family in Medicago truncatula. AB - One important mechanism plants use to cope with salinity is keeping the cytosolic Na+ concentration low by sequestering Na+ in vacuoles, a process facilitated by Na+/H+ exchangers (NHX). There are eight NHX genes (NHX1 through NHX8) identified and characterized in Arabidopsis thaliana. Bioinformatics analyses of the known Arabidopsis genes enabled us to identify six Medicago truncatula NHX genes (MtNHX1, MtNHX2, MtNHX3, MtNHX4, MtNHX6, and MtNHX7). Twelve transmembrane domains and an amiloride binding site were conserved in five out of six MtNHX proteins. Phylogenetic analysis involving A. thaliana, Glycine max, Phaseolus vulgaris, and M. truncatula revealed that each individual MtNHX class (class I: MtNHX1 through 4; class II: MtNHX6; class III: MtNHX7) falls under a separate clade. In a salinity-stress experiment, M. truncatula exhibited ~ 20% reduction in biomass. In the salinity treatment, sodium contents increased by 178 and 75% in leaves and roots, respectively, and Cl- contents increased by 152 and 162%, respectively. Na+ exclusion may be responsible for the relatively smaller increase in Na+ concentration in roots under salt stress as compared to Cl-. Decline in tissue K+ concentration under salinity was not surprising as some antiporters play an important role in transporting both Na+ and K + . MtNHX1, MtNHX6, and MtNHX7 display high expression in roots and leaves. MtNHX3, MtNHX6, and MtNHX7 were induced in roots under salinity stress. Expression analysis results indicate that sequestering Na+ into vacuoles may not be the principal component trait of the salt tolerance mechanism in M. truncatula and other component traits may be pivotal. PMID- 29280024 TI - Left ventricular cardiac hemangioma in a patient with chronic heart failure. AB - Cardiac hemangiomas are rare benign tumors. Here, we report the case of a man in his 30s who had a cardiac hemangioma with no symptoms. He was being treated with beta-blockers for chronic heart failure with hypertensive heart disease at Osaka Minato Central Hospital. Routine echocardiography revealed a mobile spherical mass in the left ventricle that had not been detected on echocardiography performed 4 months previously. Subsequently, the tumor was excised to prevent potential embolic events and was pathologically diagnosed as a cardiac hemangioma. This case demonstrates the relatively rapid progress of a cardiac hemangioma regardless of beta-blocker administration, which is occasionally used for the treatment of hemangiomas. The efficacy of beta-blockers in treating cardiac hemangiomas may vary according to the type of beta-blocker. Echocardiography is useful in screening and follow-up of cardiac hemangiomas; however, additional imaging modalities are needed for differential diagnosis. PMID- 29280025 TI - Management of nonfunctioning pituitary adenomas (NFAs): observation. AB - Clinically nonfunctioning pituitary adenomas (NFAs) range from those causing significant hypothalamic/pituitary dysfunction and visual field compromise due to their large size to those being completely asymptomatic. In the absence of hypersecretion, hypopituitarism or visual field defects, patients with NFAs may be followed by periodic surveillance using MRI to detect tumor enlargement. In some cases, endocrine tests are also needed during observation to discover new pituitary dysfunction. Enlargement of NFAs without treatment occurs in about 10% of microadenomas and 23% of macroadenomas. Growth of a pituitary incidentaloma, the development of visual field defects or the development of hypopituitarism are potential indications for surgery during follow up. PMID- 29280026 TI - Management of non-functioning pituitary adenomas: surgery. AB - Non-functional pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that do not over-secrete hormonal products, therefore, they are generally detected through symptoms of mass effect, including headache, vision loss, or hypopituitarism. There are multiple pathological subtypes of NFPAs, such as null cell adenomas, silent gonadotrophs, silent somatotrophs, silent corticotrophs, and silent subtype 3, all of which can be classified based on immunohistochemical studies and electron microscopy. Despite these numerous pathological subtypes, surgical resection remains the first-line treatment for NFPAs. Diagnosis is best made using high resolution MRI brain with and without gadolinium contrast, which is also helpful in determining the extent of invasion of the tumor and recognizing necessary sinonasal anatomy prior to surgery. Additional pre operative work-up should include full laboratory endocrine evaluation with replacement of hormone deficiencies, and ideally, full neuro-ophthalmologic exam. Although transcranial surgical approaches to the pituitary gland can be performed, the most common approach used is the transnasal transsphenoidal approach with endoscopic or microscopic visualization. This approach avoids retraction of the brain and cranial nerves during tumor removal. Surgery for symptoms caused by mass effect, including headaches and visual loss, are successfully treated with surgical resection, resulting in improvement in pre operative symptoms as high as 90% in some reports. Although the risk of complications is low, major and minor events, such as permanent hypopituitarism, persistent CSF leak, and carotid artery injury can occur at rates ranging from zero to about 9%. PMID- 29280027 TI - Gay and Bisexual Adolescent Boys' Perspectives on Parent-Adolescent Relationships and Parenting Practices Related to Teen Sex and Dating. AB - Close parent-adolescent relationships and specific parenting practices (e.g., communication about sex, monitoring) are associated with reduced sexual risk behavior among heterosexual youth. Despite gay/bisexual male youth being at increased risk of HIV, little is known about parental influences on their sexual behavior. As such, the goal of the current study was to examine parent-adolescent relationships and parenting practices related to teen sex and dating from the perspective of gay/bisexual adolescent boys. Online focus groups were conducted with 52 gay/bisexual male youth ages 14-17 years. Most gay/bisexual adolescent boys felt that their sexual orientation had an influence on their relationships with their parents and discussions about sex/dating. Although some felt that their relationships improved after coming out, a larger percentage reported that it put strain on their relationships. Discussions about sex/dating generally decreased after coming out, but some youth described positive conversations with their parents. Many reported that their parents struggled with whether or not to adapt parenting practices (e.g., rules about dating) after they came out. Youth consistently noted that parent-adolescent relationships and parenting practices depended on the adolescent's level of outness. Findings have important implications for refining HIV prevention programs for gay/bisexual adolescent boys, especially interventions that include parents. PMID- 29280028 TI - Influences of climatic parameters on piglet preweaning mortality in Thailand. AB - The objective of the present study was to determine the influences of temperature, humidity, and temperature-humidity index (THI) on piglet preweaning mortality in a conventional open-housing system commercial swine herd in Thailand. The analyzed data included 11,157 litters from 3574 Landrace * Yorkshire crossbred sows. The daily temperature, humidity, and THI data were collected from a meteorological station near the herd. The associations between temperature, humidity, and THI for periods before and after farrowings and piglet preweaning mortality were analyzed. Piglet preweaning mortality (log transformation) and the proportion of litters with piglet preweaning mortality greater than 20% were analyzed by using general linear mixed models and generalized linear mixed models (GLIMMIX), respectively. On average, the piglet preweaning mortality and the proportion of litters with piglet preweaning mortality greater than 20% were 14.5% (14.2 to 14.8% CI) and 26.4% (25.5 to 27.2% CI), respectively. Piglet preweaning mortality was positively correlated with the mean temperature (r = 0.028, P = 0.003), humidity (r = 0.038, P < 0.001), and THI (r = 0.036, P < 0.001) during 0-7 days postpartum. In primiparous sows, piglet preweaning mortality increased from 12.1 to 18.5% (+ 6.4%, P < 0.001) when the mean temperature during 0-7 days postpartum increased from < 25.0 to >= 29 degrees C. However, the influence of the temperature during 0-7 days postpartum was insignificant in multiparous sows (P = 0.569, P = 0.593, and P = 0.539 in sows parity numbers 2, 3-5, and 6-9, respectively). Likewise, piglet preweaning mortality increased from 10.7 to 16.7% (+ 6.0%, P = 0.012) when humidity during 0 7 days postpartum increased from < 60 to >= 80% in primiparous sows but it was insignificant in sows parity numbers 3-5 (P = 0.095) and 6-9 (P = 0.219). Moreover, the proportion of the litters with piglet preweaning mortality greater than 20% in primiparous sows increased from 18.3 to 32.4% (+ 14.1%, P = 0.017) when the THI during 0-7 days postpartum increased from < 73 to >= 81. In conclusion, the negative influences of temperature, humidity, and THI on piglet preweaning mortality were more evident in primiparous than multiparous sows. These findings implied that strategies to reduce temperature for postpartum sows in the open-housing system in Thailand are inadequate, and the proper management of postpartum primiparous sows should be emphasized. PMID- 29280029 TI - Prevalence of gastrointestinal nematode infections in goat flocks on semi-arid rangelands of northeastern Mexico. AB - The objective of this study was to determine the prevalence of gastrointestinal nematode (GIN) infection in goat flocks on semi-arid rangelands of northeastern Mexico (25 degrees N, 350-400 mm annual precipitation). The study included 668 pluriparous goats from 18 herds in five municipalities of Coahuila and Nuevo Leon, Mexico. Five genetic groups were considered (predominance of Boer, Nubian, Alpine, Saanen, and Toggenburg). Fecal samples were taken from the rectum of each animal to determine the number of eggs per gram (EPG) of GIN. The prevalence of flocks with GIN infections was 88.9%. Similar results were observed for the number of goats infected in the flocks. The Alpine breed presented the highest prevalence and highest EPG loads of GIN, whereas Boer and Nubian were the genetic groups with the lowest (P < 0.05) EPG. There was a negative effect of GIN infection on the live weight of goats (P < 0.05). The GIN genera found were Trichostrongylus spp. and Haemonchus spp. It was concluded that in the goat flocks of the semi-arid zones of Mexico was found a high prevalence of infections with gastrointestinal nematodes. The municipality and the breed of the animals were factors that showed influence on this prevalence and the level of infection of the goats. PMID- 29280030 TI - Effect of retirement on cognitive function: the Whitehall II cohort study. AB - According to the 'use it or lose it' hypothesis, a lack of mentally challenging activities might exacerbate the loss of cognitive function. On this basis, retirement has been suggested to increase the risk of cognitive decline, but evidence from studies with long follow-up is lacking. We tested this hypothesis in a cohort of 3433 civil servants who participated in the Whitehall II Study, including repeated measurements of cognitive functioning up to 14 years before and 14 years after retirement. Piecewise models, centred at the year of retirement, were used to compare trajectories of verbal memory, abstract reasoning, phonemic verbal fluency, and semantic verbal fluency before and after retirement. We found that all domains of cognition declined over time. Declines in verbal memory were 38% faster after retirement compared to before, after taking account of age-related decline. In analyses stratified by employment grade, higher employment grade was protective against verbal memory decline while people were still working, but this 'protective effect' was lost when individuals retired, resulting in a similar rate of decline post-retirement across employment grades. We did not find a significant impact of retirement on the other cognitive domains. In conclusion, these findings are consistent with the hypothesis that retirement accelerates the decline in verbal memory function. This study points to the benefits of cognitively stimulating activities associated with employment that could benefit older people's memory. PMID- 29280032 TI - Semantic Ambiguity: Do Multiple Meanings Inhibit or Facilitate Word Recognition? AB - It is not clear whether multiple unrelated meanings inhibit or facilitate word recognition. Some studies have found a disadvantage for words having multiple meanings with respect to unambiguous words in lexical decision tasks (LDT), whereas several others have shown a facilitation for such words. In the present study, we argue that these inconsistent findings may be due to the approach employed to select ambiguous words across studies. To address this issue, we conducted three LDT experiments in which we varied the measure used to classify ambiguous and unambiguous words. The results suggest that multiple unrelated meanings facilitate word recognition. In addition, we observed that the approach employed to select ambiguous words may affect the pattern of experimental results. This evidence has relevant implications for theoretical accounts of ambiguous words processing and representation. PMID- 29280031 TI - Estimation of the Effect of Body Weight on the Development of Osteoarthritis Based on Cumulative Stresses in Cartilage: Data from the Osteoarthritis Initiative. AB - Evaluation of the subject-specific biomechanical effects of obesity on the progression of OA is challenging. The aim of this study was to create 3D MRI based finite element models of the knee joints of seven obese subjects, who had developed OA at 4-year follow-up, and of seven normal weight subjects, who had not developed OA at 4-year follow-up, to test the sensitivity of cumulative maximum principal stresses in cartilage in quantitative risk evaluation of the initiation and progression of knee OA. Volumes of elements with cumulative stresses over 5 MPa in tibial cartilage were significantly (p < 0.05) larger in obese subjects as compared to normal weight subjects. Locations of high peak cumulative stresses at the baseline in most of the obese subjects showed a good agreement with the locations of the cartilage loss and MRI scoring at follow-up. Simulated weight loss (to body mass index 24 kg/m2) in obese subjects led to significant reduction of the highest cumulative stresses in tibial and femoral cartilages. The modeling results suggest that an analysis of cumulative stresses could be used to evaluate subject-specific effects of obesity and weight loss on cartilage responses and potential risks for the progression of knee OA. PMID- 29280033 TI - A combined Fisher and Laplacian score for feature selection in QSAR based drug design using compounds with known and unknown activities. AB - Quantitative structure-activity relationship (QSAR) is an effective computational technique for drug design that relates the chemical structures of compounds to their biological activities. Feature selection is an important step in QSAR based drug design to select the most relevant descriptors. One of the most popular feature selection methods for classification problems is Fisher score which aim is to minimize the within-class distance and maximize the between-class distance. In this study, the properties of Fisher criterion were extended for QSAR models to define the new distance metrics based on the continuous activity values of compounds with known activities. Then, a semi-supervised feature selection method was proposed based on the combination of Fisher and Laplacian criteria which exploits both compounds with known and unknown activities to select the relevant descriptors. To demonstrate the efficiency of the proposed semi-supervised feature selection method in selecting the relevant descriptors, we applied the method and other feature selection methods on three QSAR data sets such as serine/threonine-protein kinase PLK3 inhibitors, ROCK inhibitors and phenol compounds. The results demonstrated that the QSAR models built on the selected descriptors by the proposed semi-supervised method have better performance than other models. This indicates the efficiency of the proposed method in selecting the relevant descriptors using the compounds with known and unknown activities. The results of this study showed that the compounds with known and unknown activities can be helpful to improve the performance of the combined Fisher and Laplacian based feature selection methods. PMID- 29280034 TI - Correction to: Chronic Administration of S-Allylcysteine Activates Nrf2 Factor and Enhances the Activity of Antioxidant Enzymes in the Striatum, Frontal Cortex and Hippocampus. AB - The original version of this article unfortunately contained a mistake. PMID- 29280035 TI - Lymphovascular invasion and lymph node metastasis rates in papillary adenocarcinoma of the stomach: implications for endoscopic resection. AB - BACKGROUND: Current Japanese gastric cancer treatment guidelines recommend the same endoscopic resection criteria for papillary early gastric cancer (EGC) and well-differentiated (WD) or moderately differentiated (MD) EGC. To evaluate the appropriateness of this recommendation, we compared the clinicopathological characteristics of papillary EGC with those of WD, MD, poorly differentiated (PD), and signet ring cell (SRC) EGC. METHODS: A total of 6710 patients who underwent radical gastrectomy for EGC were included. Clinicopathological characteristics of papillary EGC were retrospectively reviewed and compared with those in other EGC subtypes. RESULTS: Papillary EGC accounted for 1.9% (130/6710) of total cases. Patients with papillary EGC were older and showed a male predominance compared to patients with PD or SRC EGC. Papillary EGCs showed significantly higher submucosal and lymphovascular invasion rates than WD or MD EGC or PD or SRC EGC. However, the LN metastasis rate of papillary EGC was comparable to or lower than that in other EGC subtypes. LN metastasis rates in mucosal cancers were 1.5%, 1.1%, and 4.0%, and those in submucosal cancers were 9.4%, 11.9%, and 17.6% for papillary EGC, WD or MD EGC, and PD or SRC EGC, respectively. In multivariate analysis, lymphatic invasion and PD or SRC histology were the strongest risk factors for LN metastasis. Among 63 papillary EGC that met the curative endoscopic resection criteria, no case showed LN metastasis. CONCLUSIONS: Endoscopic resection can be indicated for papillary EGC according to current guidelines. Given a considerable lymphovascular invasion rate, careful histological evaluation is required after endoscopic resection for papillary EGC. PMID- 29280036 TI - Seronegative autoimmune autonomic neuropathy: a distinct clinical entity. AB - PURPOSE: Autoimmune autonomic ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with autoimmune autonomic failure lacking this antibody. METHODS: Retrospective chart review. RESULTS: Six patients presented with subacute autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids. CONCLUSION: In these cases of autoimmune autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative autoimmune autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG. PMID- 29280037 TI - Prenatal and Postpartum Care Disparities in a Large Medicaid Program. AB - Objectives Pennsylvania's maternal mortality, infant mortality, and preterm birth rates rank 24th, 35th, and 25th in the country, and are higher among racial and ethnic minorities. Provision of prenatal and postpartum care represents one way to improve these outcomes. We assessed the extent of disparities in the provision and timeliness of prenatal and postpartum care for women enrolled in Pennsylvania Medicaid. Methods We performed a cross-sectional evaluation of representative samples of women who delivered live births from November 2011 to 2015. Our outcomes were three binary effectiveness-of-care measures: prenatal care timeliness, frequency of prenatal care, and postpartum care timeliness. Pennsylvania's Managed Care Organizations (MCOs) were required to submit these outcomes to the state after reviewing administrative and medical records through a standardized, validated sampling process. We assessed for differences in outcomes by race, ethnicity, region, year, and MCO using logistic regression. Results We analyzed data for 12,228 women who were 49% White, 31% Black/African American, 4% Asian, and 15% Hispanic/Latina. Compared to Black/African American women, white and Asian women had higher odds of prenatal and postpartum care. Hispanic/Latina women had higher frequency of prenatal care than non-Hispanic women. Pennsylvania's Southeast had lower prenatal care and Northwest had lower postpartum care than other regions. Prenatal care significantly decreased in 2014 and increased in 2015. We observed differences between MCOs, and as MCO performance diminished, racial disparities within each plan widened. We explored hypotheses for observed disparities in secondary analyses. Conclusions for Practice Our data demonstrate that interventions should address disparities by race, region, and MCO in equity-promoting measures. PMID- 29280038 TI - Physicians' Awareness and Utilization of Genetic Services in Texas. AB - The number of disorders for which genetic testing is available has increased nearly 500% in the past 15 years. Access to genetic tests and services often hinges on physicians' ability to identify patients at risk for genetic disease and provide appropriate testing and counseling or refer to genetic specialists. Recent research demonstrates the need for referrals to genetic specialists by showing that many physicians lack skills required to perform appropriate genetic services, such as making proper risk assessments, providing genetic counseling, ordering genetic testing and interpreting results. However, little research exists on physicians' awareness and utilization of genetic services. In this study, an electronic survey evaluating practicing physicians' awareness of, utilization of and perceived barriers to genetic services in Texas, and interest in learning more about genetics and genetic services was distributed via state physician organizations. Of the 157 participants, approximately half reported they were moderately or very aware of genetic testing and services in their area. Very few reported awareness of telemedicine services. Over two-thirds reported never or rarely referring to genetic counselors or other genetic specialists, despite 75% reporting they had noticed an increased impact of genetics on their field and 61% reporting they had discussed genetics more in their day-to-day practice in the last 5-10 years. Only 20% reported genetics was very integral to their specialty. Over three-fourths of all participants indicated interest in learning more about genetics, genetic testing, and genetic services. Among the most frequently chosen barriers to genetic counselors were awareness-related barriers such as not knowing how to refer to a genetic counselor. Responses to many items varied significantly by medical specialty. The results identify a need to increase awareness of genetic services and referral logistics. Specific findings can help direct outreach efforts to educate clinicians, such as developing clinically meaningful, specialty-specific educational objectives. PMID- 29280039 TI - Left ventricular outflow tract arrhythmias with divergent QRS morphology: mapping of different exits and ablation strategy. AB - BACKGROUND: Ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) can have multiple exits exhibiting divergent ECG features. METHODS: In a series of 131 patients with VAs with LVOT origin, 10 patients presented with divergent QRS morphologies. Multisite endo- and epicardial mapping of different exit sites was performed. RESULTS: The earliest ventricular activity of 23 LVOT VAs in 10 patients was detected in the endocardium of the LV in 7 patients, the aortic sinuses of Valsalva (SoV) in 3 patients, the distal coronary sinus in 6 patients, the anterior interventricular vein in 3 patients, and the posterior right ventricular outflow tract (RVOT) in 4 patients. Simultaneous elimination of two divergent QRS morphologies of LVOT VAs by ablation from a single site was achieved in 5 patients (aorto-mitral continuity in 3 patients, SoV and RVOT in each 1 patient) using a mean maximum ablation energy of 46 +/- 5 W. Sequential ablation from two or three different sites, including trans-pericardial and distal coronary sinus ablation in each 2 patients, led to elimination of the divergent VA QRS morphologies in the other 5 patients. During the follow-up of 28 +/- 29 months, 4 of the 10 patients had recurrence of at least one LVOT VA. A 43 year-old patient with muscular dystrophy Curschmann-Steinert had recurrence of sustained LVOT VTs and died of sudden cardiac death. CONCLUSIONS: Multisite mapping of different exit sites of LVOT VAs can guide ablation of intramural foci but the recurrence rate after initially successful ablation was high. PMID- 29280040 TI - The relationships between timing of first childbirth, parity, and health-related quality of life. AB - PURPOSE: A few studies have investigated the relationship between age at first childbirth and health-related quality of life (HRQoL). This study examined the relationship between age at first childbirth and HRQoL and whether parity mediates this timing of the first childbirth-HRQoL relationship in women aged 50 years or above. METHODS: The study population included 5146 parous women >= 50 years in the cross-sectional survey, the Korea National Health and Nutrition Examination Survey 2010-2012. HRQoL was evaluated by the EuroQol five-dimensional descriptive system. Participants were grouped according to quartiles of age at first childbirth (ranges: 13-21, 22-23, 24-25, and 26-44 years). This study used linear regression analysis to examine the relationship between age at first childbirth and HRQoL and on each dimension. Mediation analysis was used to examine the contribution of age at first childbirth to HRQoL and to each dimension. RESULTS: This study found the increasing pattern of HRQoL across quartiles of age at first childbirth (P for trend = 0.030). Odds of problems in self-care and anxiety/depression dimensions significantly increased across the quartiles. Women with later age at first childbirth tended to have better HRQoL (B = 0.352, P = 0.003); parity significantly contributed to this relationship. Decreasing parity accounted for 33.5% of the relationship between late first childbirth and increased HRQoL. Early age at first childbirth significantly increased odds of the mobility problem through increasing parity. CONCLUSIONS: Women of an early age at first childbirth tended to have lower HRQoL through giving more deliveries. Our findings suggest that more attention needs to be given to women with early pregnancy and more delivery to prevent impaired HRQoL. PMID- 29280041 TI - Threshold analysis in the presence of both the diagnostic and the therapeutic risk. AB - The well-established a priori probability of illness threshold in medical decision making, introduced by Pauker and Kassirer (N Engl J Med 293:229-234, 1975; N Engl J Med 302:1109-1117, 1980), involves the diagnostic risk only. We generalize the threshold analysis by adding the therapeutic risk, i.e., in accounting for the risk that a treatment might sometimes fail. We derive a priori probability of illness threshold as a function of the probability of successful treatment, as well as the inverted function, where the successful treatment probability threshold is a function of the a priori probability of illness. The thresholds in the general model are higher than those in the special cases where one of the two risks is absent. Applications show that the changes in the thresholds can be substantial. Our general model might explain empirical findings of much higher thresholds than the Pauker-Kassirer model suggests. PMID- 29280042 TI - Long-term use of basal insulin and the risk of breast cancer. PMID- 29280044 TI - Hydrogels Containing Antibiofilm and Antimicrobial Agents Beneficial for Biofilm Associated Wound Infection: Formulation Characterizations and In vitro Study. AB - Bacterial biofilm which adheres onto wound surface is shown to be impervious to antibiotics and this in turn delays wound healing. Previous studies showed that antibiofilm agents such as xylitol and ethylenediaminetetraacetic acid (EDTA) prevent bacterial adherence onto surfaces. Formulation of a wound dressing containing antibiofilm agents may be a plausible strategy in breaking the biofilm on wound surfaces and at the same time increase the efficacy of the antibiotic. The purpose of this study was to develop hydrogel formulations containing antibiofilm agents along with antibiotic (gentamicin) for bacterial biofilm associated wound infection. Sodium carboxymethyl cellulose (NaCMC) hydrogels loaded with antibiofilm agents and antibiotic were prepared. The hydrogels were characterized for their physical properties, rheology, Fourier transform infrared spectroscopy (FTIR), drug content uniformity, differential scanning calorimetry (DSC) and in vitro drug release study. The antibiofilm (Crystal Violet staining and XTT assay) and antibacterial performances of the hydrogels against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli were assessed in vitro. The formulated hydrogels showed adequate release of both antibiofilm agents (xylitol and EDTA). Both antimicrobial and antibiofilm tests showed promising results and demonstrated that the combination of xylitol, EDTA, and gentamicin had an additive effect against both Gram-positive and Gram negative bacteria. In summary, NaCMC (sodium carboxymethyl cellulose) hydrogels containing the combination of antimicrobial and antibiofilm agents were successfully developed and this can be a new strategy in combating biofilm in wound infection which in turn accelerate wound healing. PMID- 29280043 TI - Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06). AB - BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel. RESULTS: 173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2. CONCLUSION: These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naive patients receiving trastuzumab and/or lapatinib. PMID- 29280045 TI - Binding of pigments to the cyanobacterial high-light-inducible protein HliC. AB - Cyanobacteria possess a family of one-helix high-light-inducible proteins (HLIPs) that are widely viewed as ancestors of the light-harvesting antenna of plants and algae. HLIPs are essential for viability under various stress conditions, although their exact role is not fully understood. The unicellular cyanobacterium Synechocystis sp. PCC 6803 contains four HLIPs named HliA-D, and HliD has recently been isolated in a small protein complex and shown to bind chlorophyll and beta-carotene. However, no HLIP has been isolated and characterized in a pure form up to now. We have developed a protocol to purify large quantities of His tagged HliC from an engineered Synechocystis strain. Purified His-HliC is a pigmented homo-oligomer and is associated with chlorophyll and beta-carotene with a 2:1 ratio. This differs from the 3:1 ratio reported for HliD. Comparison of these two HLIPs by resonance Raman spectroscopy revealed a similar conformation for their bound beta-carotenes, but clear differences in their chlorophylls. We present and discuss a structural model of HliC, in which a dimeric protein binds four chlorophyll molecules and two beta-carotenes. PMID- 29280046 TI - High-normal albuminuria and incident chronic kidney disease in a male nondiabetic population. AB - BACKGROUND: High-normal albuminuria is an important risk factor for incident chronic kidney disease in diabetic populations, in contrast to an uncertain association in nondiabetic populations. This study aimed to reveal the relationship between high-normal albuminuria and incident chronic kidney disease in a Japanese nondiabetic population. METHODS: A 10-year follow-up retrospective cohort study was performed involving 1378 Japanese men (mean age 44 +/- 5.3 years) without chronic kidney disease and diabetes mellitus. Chronic kidney disease was diagnosed as either estimated glomerular filtration rate < 60 mL/min/1.73 m2 or a urine albumin-to-creatinine ratio >= 30 mg/g. RESULTS: At baseline, age, estimated glomerular filtration rate, and the presence of hematuria, hypertension, and dyslipidemia were independently associated with the albumin-to-creatinine ratio. Among the 1378 participants, 185 (13.4%) fulfilled diagnostic criteria for chronic kidney disease over the 10-year follow-up period. Median annual estimated glomerular filtration rate decline showed a deterioration with increasing quartiles of baseline albumin-to-creatinine ratio (P = 0.004). Participants who had a baseline albumin-to-creatinine ratio in the highest quartile (5.9-28.9 mg/g) were more likely to develop micro- or macroalbuminuria (odds ratio: 16.23, 95% confidence interval 6.56-54.03), chronic kidney disease (odds ratio: 2.48, 95% confidence interval 1.64-3.82), and hypertension (odds ratio 2.06, 95% confidence interval 1.30-3.31), but not diabetes mellitus compared with those who had an albumin-to-creatinine ratio in the lowest quartile (1.3-3.6 mg/g) after adjustment for potential confounders. CONCLUSIONS: High normal albuminuria was associated with incident chronic kidney disease in this Japanese nondiabetic male population. PMID- 29280048 TI - Sequence effects of the involuntary and the voluntary components of symbolic cueing. AB - The orienting of attention has been found to be influenced by the previous cueing status in a spatial-cueing paradigm. The explanation for this sequence effect remains uncertain. This study separated the involuntary and the voluntary components of arrow cueing by manipulating the predicted target locations. For example, a left arrow cue may have indicated that the target was more likely to appear at the up location. Therefore, three trial types were repeated or switched between trials: cued (targets appeared along the direction of the arrows), predicted (targets appeared at the locations predicted by the arrows), and unrelated (targets appeared at the other two locations, neither cued nor predicted). RTs of cued trials were found to be significantly facilitated after a previous cued trial; however, the same effect was not observed for predicted trials. The results suggest that significant sequence effects are induced only in the involuntary component of arrow cueing. The findings support the feature integration hypothesis for the sequence effect of symbolic cueing. PMID- 29280047 TI - An evaluation of the protective effect of esomeprazole in an experimental model of renal ischemia-reperfusion. AB - PURPOSE: The ischemia and subsequent reperfusion (IR) which occurs in partial nephrectomy used in the treatment of renal tumors causes loss of parenchyma in the damaged kidney. The aim of this study is to evaluate, both biochemically and histologically, the efficacy of esomeprazole in an ischemia-reperfusion model in rat kidneys. METHODS: The rats were randomized into three groups of seven animals each, referred to as the sham, control, and PPI groups. In the sham group, only a laparotomy was performed. In the control group, following laparotomy the left renal artery was dissected and tied for 30-min ischemia. In the PPI group, a vascular route to the tail vein was opened, and 10 mg/kg esomeprazole was administered. After 1 h, the same procedures described for the control group were performed. All the animals were killed 24 h after the procedure. Biochemical analyses were applied for evaluation of oxidant and antioxidant agents in the blood and left kidney of each subject (oxidative markers: malondialdehyde, myeloperoxidase; antioxidant marker: superoxide dismutase). In the histological examination of the kidney tissues stained with hematoxylin-eosin, the TUNEL method was applied in the evaluation of apoptosis. RESULTS: No statistically significant biochemical difference was determined in the blood and tissue samples. In the histological and apoptosis evaluations, a statistically significant difference was determined between the sham, control, and PPI groups. The median (IQR) values of the TUNEL-positive cells were counted as 1.50 (4) in the sham group, 11.50 (12) in the control group, and 6.00 (9) in the PPI group (p < 0.001). CONCLUSIONS: A protective effect of esomeprazole was confirmed in renal ischemia-reperfusion damage created in an experimental rat model. PMID- 29280049 TI - Attention without awareness: Attentional modulation of perceptual grouping without awareness. AB - Perceptual grouping is the process through which the perceptual system combines local stimuli into a more global perceptual unit. Previous studies have shown attention to be a modulatory factor for perceptual grouping. However, these studies mainly used explicit measurements, and, thus, whether attention can modulate perceptual grouping without awareness is still relatively unexplored. To clarify the relationship between attention and perceptual grouping, the present study aims to explore how attention interacts with perceptual grouping without awareness. The task was to judge the relative lengths of two centrally presented horizontal bars while a railway-shaped pattern defined by color similarity was presented in the background. Although the observers were unaware of the railway shaped pattern, their line-length judgment was biased by that pattern, which induced a Ponzo illusion, indicating grouping without awareness. More importantly, an attentional modulatory effect without awareness was manifested as evident by the observer's performance being more often biased when the railway shaped pattern was formed by an attended color than when it was formed by an unattended one. Also, the attentional modulation effect was shown to be dynamic, being more pronounced with a short presentation time than a longer one. The results of the present study not only clarify the relationship between attention and perceptual grouping but also further contribute to our understanding of attention and awareness by corroborating the dissociation between attention and awareness. PMID- 29280050 TI - NiftyPET: a High-throughput Software Platform for High Quantitative Accuracy and Precision PET Imaging and Analysis. AB - We present a standalone, scalable and high-throughput software platform for PET image reconstruction and analysis. We focus on high fidelity modelling of the acquisition processes to provide high accuracy and precision quantitative imaging, especially for large axial field of view scanners. All the core routines are implemented using parallel computing available from within the Python package NiftyPET, enabling easy access, manipulation and visualisation of data at any processing stage. The pipeline of the platform starts from MR and raw PET input data and is divided into the following processing stages: (1) list-mode data processing; (2) accurate attenuation coefficient map generation; (3) detector normalisation; (4) exact forward and back projection between sinogram and image space; (5) estimation of reduced-variance random events; (6) high accuracy fully 3D estimation of scatter events; (7) voxel-based partial volume correction; (8) region- and voxel-level image analysis. We demonstrate the advantages of this platform using an amyloid brain scan where all the processing is executed from a single and uniform computational environment in Python. The high accuracy acquisition modelling is achieved through span-1 (no axial compression) ray tracing for true, random and scatter events. Furthermore, the platform offers uncertainty estimation of any image derived statistic to facilitate robust tracking of subtle physiological changes in longitudinal studies. The platform also supports the development of new reconstruction and analysis algorithms through restricting the axial field of view to any set of rings covering a region of interest and thus performing fully 3D reconstruction and corrections using real data significantly faster. All the software is available as open source with the accompanying wiki-page and test data. PMID- 29280051 TI - Long Non-coding RNA Linc-ROR Is Upregulated in Papillary Thyroid Carcinoma. AB - Long non-coding RNAs (lncRNAs) may contribute to carcinogenesis and tumor progression by regulating transcription and gene expression. The role of lncRNAs in the regulation of thyroid cancer progression is being extensively examined. Here, we analyzed three lncRNAs that were overexpressed in papillary thyroid carcinomas, long intergenic non-protein coding RNA, regulator of reprogramming (Linc-ROR, ROR) PVT1 oncogene (PVT1), and HOX transcript antisense intergenic RNA (HOTAIR) to determine their roles in thyroid tumor development and progression. ROR expression has not been previously examined in thyroid carcinomas. Tissue microarrays (TMAs) of formalin-fixed paraffin-embedded tissue sections from 129 thyroid cases of benign and malignant tissues were analyzed by in situ hybridization (ISH), automated image analysis, and real-time PCR. All three lncRNAs were most highly expressed in the nuclei of PTCs. SiRNA experiments with a PTC cell line, TPC1, showed inhibition of proliferation with siRNAs for all three lncRNAs while invasion was inhibited with siRNAs for ROR and HOTAIR. SiRNA experiments with ROR also led to increased expression of miR-145, supporting the role of ROR as an endogenous miR-145 sponge. After treatment with TGF-beta, there was increased expression of ROR, PVT1, and HOTAIR in the PTC1 cell line compared to control groups, indicating an induction of their expression during epithelial to mesenchymal transition (EMT). These results indicate that ROR, PVT1, and HOTAIR have important regulatory roles during the development of PTCs. PMID- 29280052 TI - Patient and provider perspectives on the development of personalized medicine: a mixed-methods approach. AB - While genetic testing gains adoption in specialty services such as oncology, neurology, and cardiology, use of genetic and genomic testing has yet to be adopted as widely in primary care. The purpose of this study is to identify and compare patient and primary care provider (PCP) expectations of genetics services in primary care. Patient and PCP perspectives were assessed through a mixed method approach combining an online survey and semi-structured interviews in a primary care department of a large academic medical institution. A convenience sample of 100 adult primary care patients and 26 PCPs was gathered. The survey and interview questions focused on perceptions of genetic testing, experience with genetic testing, and expectations of genetic services in primary care. Patients felt that their PCP was knowledgeable about genetic testing and expected their PCP to be the first to recognize a need for genetic testing based on family history. Nonetheless, patients reported that PCPs rarely used family history information to discuss genetic risks or order testing. In contrast, PCPs felt uncertain about the clinical utility and scientific value of genetic testing. PCPs were concerned that genetic testing could cause anxiety, frustration, discrimination, and reduced insurability, and that there was unequal access to testing. PCPs described themselves as being "gatekeepers" to genetic testing but did not feel confident or have the desire to become experts in genetic testing. However, PCPs were open to increasing their working knowledge of genetic testing. Within this academic medical center, there is a gap between what patients expect and what primary care providers feel they are adequately prepared to provide in terms of genetic testing services. PMID- 29280053 TI - CD200Fc Attenuates Retinal Glial Responses and RGCs Apoptosis After Optic Nerve Crush by Modulating CD200/CD200R1 Interaction. AB - To explore the hypothesis that CD200Fc, a CD200R1 agonist with anti-inflammatory properties, will inhibit retinal glial cells hyperactivation and retinal ganglion cells (RGCs) apoptosis after optic nerve injury. CD200Fc was immediately administered after optic nerve crush (ONC) once by intravitreal injection. Rats were euthanized at 5 days after ONC. The density of RGCs was counted by immunostaining of retina flat mounts for Brn3a. TUNEL assay, immunoblotting analysis of ionized calcium-binding adapter molecule 1(iba1) (microglia marker) and glial fibrillary acidic protein (GFAP) (astrocytes and Muller cells marker), RT-PCR analysis of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-8 and IL-10, ELISA measure protein levels of inflammatory cytokines and western blot analysis of CD200 and CD200R1 were evaluated. CD200Fc treatment suppressed ONC-induced RGCs loss through inhibition of RGCs apoptosis. Additionally, expression of glial cells activation markers GFAP and iba1 and production of pro-inflammatory cytokines (COX-2, iNOS, MCP-1, TNF-alpha, IL-8) were decreased in CD200Fc treated animals after ONC. Meanwhile, anti-inflammatory cytokine IL-10 was increased by CD200Fc treatment in ONC induced rat retina. Finally, we found that CD200Fc significantly inhibited ONC induced increased in expression of CD200 and raised the already high basal CD200R1 expression in the rat retina after ONC. Our results demonstrated that the anti-inflammatory effects of CD200Fc in ONC rats model through inhibited the activation of retinal glial cells via the interaction between CD200 and CD200R1, and the neuroprotective effects of CD200Fc on RGCs thought inhibited its apoptosis. PMID- 29280054 TI - Recent advances in the study of hepatitis B virus covalently closed circular DNA. AB - Chronic hepatitis B infection is caused by hepatitis B virus (HBV) and a total cure is yet to be achieved. The viral covalently closed circular DNA (cccDNA) is the key to establish a persistent infection within hepatocytes. Current antiviral strategies have no effect on the pre-existing cccDNA reservoir. Therefore, the study of the molecular mechanism of cccDNA formation is becoming a major focus of HBV research. This review summarizes the current advances in cccDNA molecular biology and the latest studies on the elimination or inactivation of cccDNA, including three major areas: (1) epigenetic regulation of cccDNA by HBV X protein, (2) immune-mediated degradation, and (3) genome-editing nucleases. All these aspects provide clues on how to finally attain a cure for chronic hepatitis B infection. PMID- 29280056 TI - Assignment of 1H, 13C and 15N resonances and secondary structure of the Rgd1 RhoGAP domain. AB - The protein Rgd1 is involved in the regulation of cytoskeleton formation and in signalling pathways that control cell polarity and growth in Saccharomyces cerevisiae. Rgd1p is composed of a F-BAR domain required for membrane binding and a RhoGAP domain responsible for activating Rho3p and Rho4p, two GTPases respectively involved in bud growth and cytokinesis. Rgd1p is recruited to the membrane through interactions with phosphoinositide lipids, which bind the two isolated domains and stimulate the RhoGAP activity on Rho4p. As previously shown by crystallography, the membrane-binding F-BAR domain contains a conserved inositol phosphate binding site, which explains the preferential binding of phosphoinositides. In contrast, RhoGAP domains are not expected to bind lipids. In order to unravel this puzzling feature, we solved the three-dimensional structure of the isolated protein and found a cryptic phosphoinositide binding site involving non conserved residues (Martinez et al. 2017). The assignment of the resonances and secondary structure of Rgd1-RhoGAP (aa 450-666) is presented here. PMID- 29280055 TI - Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. AB - Microglia and macrophages are the main non-neuronal subsets of myeloid origin in the brain, and are critical regulators in neurodegenerative disorders, where inflammation is a key factor. Since HIV infection results in neurological perturbations that are similar to those in aging, we examined microglial and infiltrating myeloid subsets in the search for changes that might resemble the ones in aging. For that, we used the SIV infection in rhesus macaques to model neuroAIDS. We found that Sirt-1, a molecule that impacts survival and health in many models, was decreased in cell preparations containing a majority of microglia and myeloid cells from the brain of infected macaques. The role of Sirt 1 in neuroAIDS is unknown. We hypothesized that Sirt-1 silencing functions are affected by SIV. Mapping of Sirt-1 binding patterns to chromatin revealed that the number of Sirt-1-bound genes was 29.6% increased in myeloid cells from infected animals with mild or no detectable neuropathology, but 51% was decreased in severe neuropathology, compared to controls. Importantly, Sirt-1-bound genes in controls largely participate in neuroinflammation. Promoters of type I IFN pathway genes IRF7, IRF1, IFIT1, and AIF1, showed Sirt-1 binding in controls, which was consistently lost after infection, together with higher transcription. Loss of Sirt-1 binding was also found in brains from old uninfected animals, suggesting a common regulation. The role of Sirt-1 in regulating these inflammatory markers was confirmed in two different in vitro models, where Sirt-1 blockage modulated IRF7, IRF1 and AIF1 levels both in human macrophage cell lines and in human blood-derived monocytes from various normal donors, stimulated with a TLR9 agonist. Our data suggests that Sirt-1-inflammatory gene silencing is disturbed by SIV infection, resembling aging in brains. These findings may impact our knowledge on the contribution of myeloid subsets to the neurological consequences of HIV infection, aggravated and overlapping with the aging process. PMID- 29280057 TI - Effects of Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease in an Obese Rat Model. AB - BACKGROUND/AIM: Laparoscopic sleeve gastrectomy (SG) is an increasingly used bariatric surgery, which is reported to be effective for nonalcoholic fatty liver disease (NAFLD). Recently, activation of farnesoid X receptor (FXR), which is a nuclear receptor of bile acid (BA), was reported to contribute to the resolution of NAFLD. However, it is unclear whether SG has an effect on expression of FXR in the liver. We aimed to investigate the expression of FXR and its related factors in the liver after SG and to clarify the relationship between changes in FXR expression and NAFLD in an obese rat model. METHODS: Thirty male Zucker fatty rats were divided into three groups: sham-operated (SO) control, pair-fed (PF) control, and SG. Eight weeks after the surgery, metabolic parameters, plasma levels of total BA and liver enzymes, liver triglyceride (TG) content, and mRNA expression of FXR and its related factors, such as small heterodimer partner (SHP) and peroxisome proliferator-activated receptor alpha (PPARalpha), were measured. RESULTS: Metabolic parameters in the SG group were significantly improved compared with the SO group. Liver enzymes and TG were significantly lower in the SG group than in the SO group. Plasma levels of BA were significantly higher in the SG group than in the SO and PF groups. mRNA expression of FXR, SHP, and PPARalpha in the liver was significantly higher in the SG group than in the SO group. CONCLUSIONS: These results suggest that the effects of SG on NAFLD should be associated with the expression of the FXR pathway in the liver in a Zucker fatty rat model. PMID- 29280058 TI - Ethnicity Does Not Influence Glycemic Outcomes or Diabetes Remission After Sleeve Gastrectomy or Gastric Bypass in a Multiethnic Asian Cohort. AB - BACKGROUND: In Asia, metabolic-bariatric surgery (MBS) rates have grown rapidly in parallel with rising prevalence of obesity and type 2 diabetes (T2D). OBJECTIVE: The objective of this study was to identify factors that influence glycemic outcomes and diabetes remission 12 months after sleeve gastrectomy (SG) or gastric bypass (GB) in a multiethnic Asian cohort. SETTING: The study's setting was in a tertiary hospital in Singapore. METHODS: Data from 145 T2D patients who had SG (37%) or GB (63%) and at least 1-year follow-up were analyzed. Diabetes remission was defined as hemoglobin A1c <= 6.0% without diabetes medications. Analysis involved binary logistic regression to identify predictors and general linear regression for variables associated with glycemic improvement after surgery. RESULTS: Baseline parameters are as follows: BMI 40.0 +/- 7.6 kg/m2, A1c 8.4 +/- 1.6%, diabetes duration 9.3 years, ethnic composition: Chinese (51.7%), Malay (23.4%), Indian (20.7%), Others (4.1%). 55.9% achieved diabetes remission at 1 year. Baseline A1c, baseline BMI, and diabetes duration were significant pre-operative factors for remission (cumulative R 2 = 0.334). At 12 months, percentage weight loss was similar after SG (24.1 +/- 7.4%) and GB (25.4 +/- 7.4%, p = 0.31). Greater A1c decrease was seen with GB compared to SG (2.7 +/- 1.6 vs 2.0 +/- 1.5%, p = 0.006), significant even after adjustment for weight loss, age, BMI, baseline A1c, and diabetes duration (p = 0.033). Weight loss at 12 months also correlated independently with A1c reduction. Ethnicity did not influence weight loss, diabetes remission, or glycemic control after MBS. CONCLUSION: Baseline A1c, baseline BMI, and diabetes duration independently predict diabetes remission after MBS. GB is more effective in controlling T2D compared to SG despite similar weight loss, whereas ethnicity does not play a significant role in the multiethnic Asian cohort. PMID- 29280059 TI - Team-Based Learning Module for Undergraduate Medical Education: a Module Focused on the Human Papilloma Virus to Increase Willingness to Vaccinate. AB - Human papilloma virus (HPV) vaccination rates lag behind other vaccines, primarily because of weak provider recommendations, and are associated with nearly 30,000 new cancer diagnoses a year. Educating medical students about HPV using active, team-centered learning may increase assimilation of information and may increase vaccination rates. A team-based learning (TBL) module focused on HPV for first-year medical students about HPV will better increase knowledge and likeliness to vaccinate than traditional education methods. Baseline HPV knowledge in medical students across Texas was assessed by surveying all 4-year undergraduate medical schools. Students at one medical school then participated in a week-long TBL focused on basic and clinical concepts relating to HPV, and then were re-surveyed upon completion of the course module. At baseline assessment, first-year student at the intervention site performed at the same level as first-year medical students across the state of Texas on knowledge and satisfaction with their HPV-related medical school education. After the TBL implementation, students performed significantly better than similar-year students and equal to graduating seniors, on knowledge of HPV- and HPV-related cancers, and report significantly higher satisfaction with education measures. Students at the intervention site were significantly more likely to recommend the HPV vaccination in future practice. Short-term knowledge and willingness to recommend vaccination are improved with a targeted HPV TBL early in medical education, which may provide a basis of knowledge that could translate into improved vaccination rates. PMID- 29280060 TI - Minimally invasive approach (robotic and laparoscopic) to biliary-enteric fistula secondary to cholecystectomy bile duct injury. AB - Spontaneous biliary-enteric fistula after laparoscopic cholecystectomy bile duct injury is an extremely rare entity. Y-en-Roux hepaticojejunostomy has been demonstrated to be an effective surgical technique to repair iatrogenic bile duct injuries. Seven consecutive patients underwent robotic-assisted (n = 5) and laparoscopic (n = 2) biliary-enteric fistula resection and bile duct repair at our hospital from January 2012 to May 2017. We reported our technique and described post-procedural outcomes. The mean age was 52.4 years, mostly females (n = 5). The mean operative time was 240 min for laparoscopic cases and 322 min for robotic surgery, and the mean estimated blood loss was 300 mL for laparoscopic and 204 mL for robotic cases. In both groups, oral feeding was resumed between day 2 or 3 and hospital length of stay was 4-8 days. Immediate postoperative outcomes were uneventful in all patients. With a median of 9 months of follow-up (3-52 months), no patients developed anastomosis-related complications. We observed in this series an adequate identification and dissection of the fistulous biliary-enteric tract, a safe closure of the fistulous orifice in the gastrointestinal tract and a successful bile duct repair, providing the benefits of minimally invasive surgery. PMID- 29280062 TI - Correction to: Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma. AB - Page 1205, the author names and affiliations which previously read. PMID- 29280063 TI - Editorial for issue #1 2018. PMID- 29280061 TI - Antifungal activity of oral (Tragacanth/acrylic acid) Amphotericin B carrier for systemic candidiasis: in vitro and in vivo study. AB - In an effort to increase the oral bioavailability of Amphotericin B (AmB), a pH sensitive drug carrier composed of Tragacanth (Trag) and acrylic acid (AAc) was prepared using gamma-irradiation. The swelling behavior of (Trag/AAc) hydrogels was characterized as a function of pH and ionic strength of the swelling medium. The obtained swelling indices revealed the ability of the prepared hydrogel to protect a loaded drug in stomach-simulated medium (Fickian behavior) and to release such drug in intestinal-simulated medium (non-Fickian behavior). In vitro release studies of the antifungal (AmB) were performed to evaluate the hydrogel potential as a drug carrier. The antifungal activity of the prepared oral formulation was investigated in a mouse model of systemic candidiasis. Data revealed that (Trag/AAc)-AmB has a potent antifungal efficacy as demonstrated by prolonging the survival time and reducing the tissue fungal burden, serum antibody titers, as well as inflammatory cytokines in kidney and liver tissues. Furthermore, in vivo toxicity of (Trag/AAc)-AmB was assessed via measuring kidney and liver functions, and results displayed the safety of this novel AmB formulation which was confirmed by histopathological examination. Overall, results indicated that the prepared (Trag/AAc)-AmB is an effective oral delivery system for AmB with better bioavailability and minimal toxicity and could represent a promising approach for improving the therapeutic index of the drug. PMID- 29280064 TI - Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial. AB - : SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0.62; 95% confidence level [CL] 0.43-0.89; p = 0.009). Furthermore, patients receiving macitentan and background therapy had a 37% reduction in the risk of being hospitalized for PAH (HR 0.63; 95% CL 0.41-0.96) compared with patients receiving background therapy only (placebo arm). Macitentan treatment in combination with background therapy was also associated with improvements in exercise capacity, functional class, cardiopulmonary hemodynamics, and health related quality of life compared with background therapy alone. The safety profile of macitentan as part of a combination therapy regimen was consistent with that of macitentan in the overall SERAPHIN population. The SERAPHIN study has provided evidence that combination therapy with macitentan and a PDE-5i is effective and well tolerated in the management of PAH. Based on these data, and those from subsequent long-term trials, combination therapy is increasingly recognized as an important treatment option for improving long-term outcomes in PAH. CLINICAL TRIAL REGISTRATION NUMBER: NCT00660179. PMID- 29280065 TI - Workers not Paid for Sick Leave after Implementation of the New York City Paid Sick Leave Law. AB - This study examined factors associated with being paid for sick leave after implementation of the New York City (NYC) paid sick leave law. A random sample of NYC residents was surveyed by telephone multiple times over a 2-year period. Participants (n = 1195) reported socio-demographics, awareness of the law, income, work hours per week, and payment for sick time off work. In the year after implementation of the law, part-time workers were significantly more likely to attend work while sick than full-time workers (relative risk = 1.25, 95% CI = 1.1, 1.4). Seventy percent of workers who missed work due to illness (n = 249) were paid for sick leave. Part-time workers, respondents not aware of the benefit (30% of workers), and workers without a college degree were the least likely to be paid for sick days. More than one third (37%) of persons not paid for sick leave worked in retail, food service, or health care. Although 70% of respondents were paid for sick leave after implementation of the law, part-time workers and workers with low education were least likely to access the benefit and more likely to work while sick. The disparity in paid sick leave may have public health consequences as many persons not paid for sick leave had occupations that carry a high risk of disease transmission to others. PMID- 29280066 TI - Diagnostic accuracy of 11C-methionine PET in detecting neuropathologically confirmed recurrent brain tumor after radiation therapy. AB - OBJECTIVE: This study aims to determine the diagnostic test accuracy (DTA) of 11C methionine (MET) PET in the discrimination between recurrent tumor and radiation induced injury in neuropathologically confirmed cases. METHODS: A retrospective cohort of 30 patients with previously irradiated intracranial tumors (23 gliomas, 6 metastases, and 1 meningioma) was included. All patients underwent a preoperative MET PET and postoperative neuropathological analysis. Maximum and mean standardized uptake values (SUV) were obtained in the lesion, in the contralateral mirror region, and in the contralateral frontal cortex. Lesion-to background SUV ratios (SUR mirror and SUR cortex) were then calculated. The Mann Whitney U test was used to evaluate differences in SUV ratios between confirmed recurrent tumor and radiation injury. DTA was determined through receiver operating characteristic (ROC) analysis. RESULTS: Twenty-one patients had recurrent tumor and nine had radiation injury. The area under the ROC curve (AUC) was 0.89 for SURmaxmirror and 0.88 for SURmaxcortex. The mean (SD) of SURmaxmirror was 2.37 (0.58) in tumor recurrence and 1.57 (0.40) in radiation necrosis (P <= 0.001). The corresponding values for SURmaxcortex were 2.13 (0.50) and 1.45 (0.37) (P = 0.001). Clinically relevant cutoffs were SURmaxmirror >= 1.99 giving a specificity of 100% for tumor recurrence with a sensitivity of 76% and SURmaxcortex >= 1.58 giving a sensitivity and specificity of 90 and 78%, respectively. CONCLUSIONS: Based on neuropathologically confirmed cases, the DTA of SURmaxmirror and SURmaxcortex from 11C-methionine PET was high when discriminating recurrent tumor from radiation injury. PMID- 29280067 TI - Examining alterations in GABA concentrations in the basal ganglia of patients with Parkinson's disease using MEGA-PRESS MRS. AB - PURPOSE: The aim of this study was to compare the gamma-amino butyric acid (GABA) levels in the left basal ganglia (BG) of patients with Parkinson's disease (PD) to those of healthy control (HC) volunteers using proton magnetic resonance spectroscopy (1H MRS). MATERIALS AND METHODS: The GABA+ signal-the composite signal from GABA, macromolecules (MMs), and homocarnosine-was detected. GABA+ levels were examined in 21 PD patients and 15 age- and sex-matched HCs. 3T-1H-MRS using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence was performed in order to detect GABA+ levels in the left BG, and the spectra were processed using the Gannet software. Differences in GABA+ levels between the two groups were analyzed using independent t-test analysis. RESULTS: The GABA+ levels were significantly lower (P < 0.001) in the left BG of the patients with PD (1.31 +/- 0.21 i.u.) than in the left BG of the HCs (1.62 +/- 0.26 i.u.). CONCLUSION: The lower GABA+ levels in the left BG of the PD patients suggest that GABA plays an important role in the pathogenesis of PD. The reduced GABA+ levels in the PD patients may be associated with GABAergic dysfunction. PMID- 29280068 TI - Clinical significance of patterns of increased [18F]-FDG uptake in the thyroid gland: a pictorial review. AB - In the diagnosis and staging of oncologic patients, [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is well recognized as an important functional imaging modality. FDG-PET also has been used for cancer screening in healthy individuals. In general, the normal thyroid gland shows absent or low uptake on FDG-PET, which is often identified as an incidental finding on PET. Today, thyroid FDG uptake can be seen in three patterns: diffuse; focal; and diffuse-plus-focal. Diffuse thyroid uptake is mainly considered an indicator of chronic thyroiditis. Focal thyroid uptake has been associated with malignancy (range 25-50%). Diffuse-plus-focal uptake is not well recognized and might also indicate a risk of malignancy. Understanding the patterns of thyroid FDG uptake is thus important for nuclear medicine physicians or radiologists when giving recommendations to the referring physician. In this pictorial review, we show the clinical significance of different patterns of thyroid uptake on FDG-PET [PET/computed tomography (CT)], including ultrasonography (US) findings. PMID- 29280069 TI - Correction to: Mild Depression in Low Back Pain: the Interaction of Thought Suppression and Stress Plays a Role, Especially in Female Patients. AB - This article was updated to correct the author names. Family and given names are in the correct order. PMID- 29280071 TI - Distribution and reproductive plasticity of Gyrinicola batrachiensis (Oxyuroidea: Pharyngodonidae) in tadpoles of five anuran species. AB - Previous studies on Gyrinicola batrachiensis indicate that these pinworms have distinct reproductive strategies dependent on the development time to metamorphosis of their anuran tadpole hosts. In tadpoles of amphibian species with short developmental periods (a few weeks), female nematodes reproduce parthenogenetically, and only produce thick-shelled eggs used as transmission agents from tadpole to tadpole. In contrast, nematodes in tadpoles with longer larval developmental periods (months to years) reproduce by haplodiploidy, and females produce thick-shelled as well as autoinfective thin-shelled eggs. However, recent investigations on the haplodiploidy strain of G. batrachiensis indicate that plasticity exists in the ability of these nematodes to produce thin shelled autoinfective eggs when these nematodes infect tadpoles of co-occurring amphibian species. Yet, little information is available on the potential mechanism for this reproductive plasticity because few co-occurring amphibian species have been examined for the reproductive strategies of these nematodes. Therefore, our goals were to document field host specificity and reproductive strategies of nematode populations in tadpoles of five co-occurring amphibian species that varied in their larval developmental periods. Additionally, we evaluated adult worm morphology from each infected amphibian species to assess any differences in worm development and reproductive strategy of pinworm populations in different amphibian species. Of the five amphibian species examined, four were infected with the haplodiploid strain of G. batrachiensis. Prevalence of G. batrachiensis ranged from a high of 83% in Acris blandchardi to a low of 15% in Pseudacris clarkii; whereas mean intensity was highest for Rana sphenocephala (10 +/- 10.36) and lowest for Hyla chrysoscelis (3.23 +/- 3.35). Prevalence appeared to be controlled by tadpole ecology and life history, while mean intensity appeared to be controlled by tadpole physiology and worm reproductive strategy, but not necessarily the developmental period of each anuran species. G. batrachiensis observed in long developing tadpoles of R. sphenocephala had high mean intensities and conformed to the haplodiploidy reproductive strategy with both male and female worms being present, and females produced thick-shelled and thin-shelled eggs. In contrast, tadpoles of A. blanchardi, H. chrysoscelis, and P. clarkii, which varied in their developmental times from long to short, had relatively low mean intensities and contained both male and female G. batrachiensis. However, female worms only produced thick shelled eggs in these hosts. Importantly, morphological differences existed among female worms recovered from R. sphenocephala and female worms recovered from A. blanchardi tadpoles with long developmental periods. These data strongly suggest that when the haplodiploidy strain of G. batrachiensis is shared by tadpoles of different amphibian species, species-specific differences in interactions between these nematodes and their development in different amphibian host species have a strong influence on the reproductive plasticity of these nematodes. PMID- 29280070 TI - Safety of Human Papillomavirus Vaccines: An Updated Review. AB - Human papillomavirus (HPV) vaccines are now included in immunisation programmes in 71 countries. Unfortunately, uptake has been impacted in some countries by reduced confidence in the safety of the HPV vaccine. In 2013, we published an extensive review demonstrating a reassuring safety profile for bivalent (2vHPV) and quadrivalent (4vHPV) vaccines. A nonavalent (9vHPV) vaccine is now available and HPV immunisation programmes have been extended to males in 11 countries. The aim of this updated narrative review was to examine the evidence on HPV vaccine safety, focusing on the 9vHPV vaccine, special populations and adverse events of special interest (AESI). The previous searches were replicated to identify studies to August 2016, including additional search terms for AESI. We identified 109 studies, including 15 population-based studies in over 2.5 million vaccinated individuals across six countries. All vaccines demonstrated an acceptable safety profile; injection-site reactions were slightly more common for 9vHPV vaccine than for 4vHPV vaccine. There was no consistent evidence of an increased risk of any AESI, including demyelinating syndromes or neurological conditions such as complex regional pain or postural orthostatic tachycardia syndromes. The risk benefit profile for HPV vaccines remains highly favourable. PMID- 29280072 TI - New primers for the detection Leishmania species by multiplex polymerase chain reaction. AB - Leishmaniasis is caused by protozoa of the Leishmania genus, which is divided into subgenus Viannia and Leishmania. In humans, the course of infection largely depends on the host-parasite relationship and primarily of the infective species. The objective of the present study was to design specific primers to the identification of Leishmania species using multiplex PCR. Four primers were designed, based on the GenBank sequences of the kDNA minicircle, amplifying 127 bp for subgenus Viannia, 100 bp for L. amazonensis, and 60 bp for Leishmania donovani complex and L. major. None of the primers amplified Trypanosoma cruzi or L. mexicana. The limit of detection of multiplex PCR was 2 * 10-5 parasites for L. braziliensis, 2 x 10-3 parasites for L. amazonensis, and 1.4 * 10-3 parasites for L. infantum. The high sensitivity of multiplex PCR was confirmed by the detection of parasites in different biological samples, including lesion scrapings, spleen imprinting of a hamster, sandflies, and blood. The multiplex PCR that was developed herein presented good performance with regard to detecting and identifying the parasite in different biological samples and may thus be useful for diagnosis, decision making with regard to the proper therapeutic approach, and determining the geographic distribution of Leishmania species. PMID- 29280073 TI - First detection of Echinococcus multilocularis in Croatia. AB - Echinococcus multilocularis has been spreading through Europe but has not yet been reported in Croatia. We report the results of a surveillance programme to detect E. multilocularis in red foxes (Vulpes vulpes) in different parts of Croatia. PCR-based screening of faecal samples from 238 red foxes in 2015 and 150 in 2016 indicate prevalences of 7.5% in 2015 and 6.6% in 2016 (overall 7.2%, CI 4.9 to 10.3). Positive samples were confirmed by sequencing parts of the nad1 gene and the gene encoding mitochondrial 12S rRNA. Geographic locations of all examined and positive cases were mapped to provide data on the distribution of E. multilocularis. Our results provide the first detection of E. multilocularis in Croatia and extend the southern boundary of this parasite's endemic area. PMID- 29280074 TI - Correction to: Cyclic fatigue and torsional strength of three different thermally treated reciprocating nickel-titanium instruments. AB - The original version of this article contained a mistake. The name Jader Carvalho Pinto should have been Jader Camilo Pinto. PMID- 29280075 TI - Effect of flapless ridge preservation with two different alloplastic materials in sockets with buccal dehiscence defects-volumetric and linear changes. AB - OBJECTIVE: To test whether or not one out of two alloplastic materials used for ridge preservation (RP) is superior to the other in terms of volumetric and linear ridge changes over time. MATERIALS AND METHODS: In 16 adult beagle dogs, the distal roots of P3 and P4 were extracted and 50% of the buccal bone plate removed. Ridge preservation was performed randomly using two different alloplastic bone grafting substitutes (poly lactic-co-glycolic acid (PLGA) coated biphasic calcium phosphate particles consisting of 60% hydroxyapatite (HA) and 40% beta-tricalcium phosphate (beta-TCP=test 1), (a biphasic calcium phosphate consisting 60% HA and 40% beta-TCP=test 2) and a resorbable collagen membrane or a control group (sham). Sacrifice was performed at three time-points (4, 8, 16 weeks later). Impressions were taken before extraction, after RP, and at sacrifice, allowing for assessment of volumetric changes. A multi-way ANOVA was computed, and partial Type-II F tests were performed. RESULTS: Both ridge preservation procedures minimized the volume loss compared to spontaneous healing. The median buccal volume changes between pre-extraction and sacrifice were - 1.76 mm (Q1 = - 2.56; Q3 = - 1.42) for test 1, - 1.62 mm (Q1 = - 2.06; Q3 = - 1.38) for test 2, and - 2.42 mm (Q1 = - 2.63; Q3 = - 2.03) for control. The mean ridge width measurements did not show statistically significant differences between test 1 (- 2.51 mm; Q1 = - 3.25; Q3 = - 1.70) and test 2 (- 2.04 mm; Q1 = 3.82; Q3 = - 1.81) (p = 0.813), but between test and control (- 3.85 mm; Q1 = - 5.02; Q3 = - 3.27) (p = 0.003). CONCLUSIONS: Both RP techniques were successful in maintaining the buccal contour from pre-extraction to sacrifice to a similar extent and more favorable compared to spontaneous healing. CLINICAL RELEVANCE: Alloplastic materials can successfully be used for RP procedures. PMID- 29280076 TI - Clinical and laboratory evaluation of the effects of different treatment modalities on titanium healing caps: a randomized, controlled clinical trial. AB - OBJECTIVES: The objective of this study is to evaluate the effects of treatment modalities on titanium surface characteristics and surrounding tissues. MATERIALS AND METHODS: Eighteen participants each had four titanium healing caps (HC) attached to four newly inserted implants. After healing, each HC was randomly assigned to either (1) titanium curettes (TC), (2) stainless steel ultrasonic tip (PS), (3) erythritol air-polishing powder (EP), or (4) only rubber cup polishing (CON). Probing depths (PD), bleeding on probing (BOP), matrix metalloproteinase 8 (MMP-8), and periopathogens were recorded before and 3 months following instrumentation. After final assessments, HCs were removed, cleaned, and subjected to (a) bacterial colonization (Streptococcus gordonii, 24 h; mixed culture, 24 h) and (b) gingival fibroblasts (5 days). HC surfaces were analyzed with a scanning electron microscope (SEM). RESULTS: No significant differences between the groups were evident before or after instrumentation for PD and BOP (except TC showed a significant decrease in PD; p = 0.049). MMP-8 levels and bacterial loads were always very low. MMP-8 decreased further after instrumentation, while bacteria levels showed no change. No significant differences (p > 0.05) were evident in bacterial colonization or fibroblast attachment. A comparison of the overall mean SEM surface roughness scores showed a significant difference between all groups (p < 0.0001) with the lowest roughness after EP. CONCLUSIONS: All treatments performed yielded comparable outcomes and may be implemented safely. CLINICAL RELEVANCE: Clinicians may fear implant surface damage, but all instrumentation types are safe and non-damaging. They can be implemented as needed upon considering the presence of staining and soft and hard deposits. PMID- 29280077 TI - Effects of combined human parathyroid hormone (1-34) and menaquinone-4 treatment on the interface of hydroxyapatite-coated titanium implants in the femur of osteoporotic rats. AB - The objective of this study was to investigate the effects of human parathyroid hormone (1-34) (PTH1-34; PTH) plus menaquinone-4 (vitamin K2; MK) on the osseous integration of hydroxyapatite (HA)-coated implants in osteoporotic rats. Ovariectomized female Sprague-Dawley rats were used for the study. Twelve weeks after bilateral ovariectomy, HA-coated titanium implants were inserted bilaterally in the femoral medullary canal of the remaining 40 ovariectomized rats. All animals were then randomly assigned to four groups: Control, MK, PTH and PTH + MK. The rats from groups MK, PTH and PTH + MK received vitamin K2 (30 mg/kg/day), PTH1-34 (60 MUg/kg, three times a week), or both for 12 weeks. Thereafter, serum levels of gamma-carboxylated osteocalcin (Gla-OC) were quantitated by ELISA and the bilateral femurs of rats were harvested for evaluation. The combination of PTH and MK clearly increased the serum levels of Gla-OC (a specific marker for bone formation) compared to PTH or MK alone. The results of our study indicated that all treated groups had increased new bone formation around the surface of implants and increased push-out force compared to Control. In addition, PTH + MK treatment showed the strongest effects in histological, micro-computed tomography and biomechanical tests. In summary, our results confirm that treatment with PTH1-34 and MK together may have a therapeutic advantage over PTH or MK monotherapy on bone healing around HA-coated implants in osteoporotic rats. PMID- 29280078 TI - Increased risk of fractures in patients with polycystic ovary syndrome: a nationwide population-based retrospective cohort study. AB - Polycystic ovary syndrome (PCOS) is a complex disorder; various features of this disorder may influence bone metabolism and skeletal mass. The contribution of PCOS to lower bone mineral density has been recognized. However, the impact of PCOS on the long-term risks for fractures remains inconclusive. The aim of this study was to determine the risk of overall fracture and fractures at different anatomic sites in patients with PCOS. Using a nationwide health insurance claims database, we included 11,106 subjects, aged 15-80 years, with newly diagnosed PCOS (ICD-9-CM: 254.4X) during 2000-2012. Patients with PCOS and respective age matched (1:4) controls without PCOS were enrolled. The occurrence of fracture was monitored until the end of 2013. Cox regression and computed hazard ratios (HR) with 95% confidence intervals (95% CI) were used to determine the risk of PCOS among women with fractures. The PCOS and non-PCOS groups were comprised of 11,106 patients with PCOS and 44,424 participants without PCOS, respectively. Patients with PCOS had a higher incidence of any fractures compared with non-PCOS group (10.16 versus 8.07 per 1000 person-years) and a greater risk of any fractures [adjusted hazard ratio (aHR) = 1.23, 95% CI = 1.13-1.33], osteoporotic fractures (aHR = 1.33, 95% CI = 1.15-1.54), spine fractures (aHR = 1.36, 95% CI = 1.11 1.66) and forearm fractures (aHR = 1.39, 95% CI = 1.07-1.80), but the risk for femur or hip fracture, humerus, wrist and non-osteoporotic fractures were not increased. In conclusion, the PCOS group had a higher occurrence rate of fractures than the non-PCOS group. These results provide evidence for the adverse effects of PCOS on the risk of fractures. PMID- 29280080 TI - Correction to: Ki67 labeling index: assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms. AB - The authors of the above article have correct the caption for Figure 3 - namely the second sentence - clarifying the information depicted within the picture correcting the Ki67 index percentage. Figure 3 and the corrected caption can be found below. PMID- 29280079 TI - Photobiomodulation increases mitochondrial citrate synthase activity in rats submitted to aerobic training. AB - This study investigated the effects of photobiomodulation by low-laser laser therapy (LLLT) on the activities of citrate synthase (CS) and lactate dehydrogenase (LDH) and the anaerobic threshold (AT) in rats submitted to treadmill exercise. Fifty-four rats were allocated into four groups: rest control (RCG), rest laser (RLG), exercise control (ECG), and exercise laser (ELG). The infrared LLLT was applied daily on the quadriceps, gluteus maximum, soleus, and tibialis anterior muscles. Muscle samples (soleus, tibialis anterior, and cardiac muscles) were removed 48 h after the last exercise session for spectrophotometric analysis of the CS and LDH. The CS activity (MUmol/protein) in ELG (16.02 and 0.49) was significantly greater (P < 0.05) than RCG (2.34 and 0.24), RLG (6.25 and 0.17), and ECG (6.76 and 0.26) in the cardiac and soleus muscles, respectively. The LDH activity (in 1 Mm/protein) in soleus muscle was smaller (P < 0.05) for ELG (0.33) compared to ECG (0.97), RLG (0.79), and RCG (1.07). For cardiac muscle, the LDH activity was smaller (P < 0.05) in ELG (1.38) compared to ECG (1.91) and RCG (2.55). The ECG and ELG showed increases in the maximum speed and a shift of the AT to higher effort levels after the training period, but no differences occurred between the exercised groups. In conclusion, the aerobic treadmill training combined with LLLT promotes an increase of oxidative capacity in this rat model, mainly in muscles with greater aerobic capacity. PMID- 29280081 TI - How to Adapt Chemical Risk Assessment for Unconventional Hydrocarbon Extraction Related to the Water System. AB - We identify uncertainties and knowledge gaps of chemical risk assessment related to unconventional drillings and propose adaptations. We discuss how chemical risk assessment in the context of unconventional oil and gas (UO&G) activities differs from conventional chemical risk assessment and the implications for existing legislation. A UO&G suspect list of 1,386 chemicals that might be expected in the UO&G water samples was prepared which can be used for LC-HRMS suspect screening. We actualize information on reported concentrations in UO&G-related water. Most information relates to shale gas operations, followed by coal-bed methane, while only little is available for tight gas and conventional gas. The limited research on conventional oil and gas recovery hampers comparison whether risks related to unconventional activities are in fact higher than those related to conventional activities. No study analyzed the whole cycle from fracturing fluid, flowback and produced water, and surface water and groundwater. Generally target screening has been used, probably missing contaminants of concern. Almost half of the organic compounds analyzed in surface water and groundwater exceed TTC values, so further risk assessment is needed, and risks cannot be waived. No specific exposure scenarios toward groundwater aquifers exist for UO&G-related activities. Human errors in various stages of the life cycle of UO&G production play an important role in the exposure. Neither at the international level nor at the US federal and the EU levels, specific regulations for UO&G-related activities are in place to protect environmental and human health. UO&G activities are mostly regulated through general environmental, spatial planning, and mining legislation. PMID- 29280082 TI - Indexing method for assessment of pollution potential of leachate from non engineered landfill sites and its effect on ground water quality. AB - Dumping of solid waste in a non-engineered landfill site often leads to contamination of ground water due to leachate percolation into ground water. The present paper assesses the pollution potential of leachate generated from three non-engineered landfill sites located in the Tricity region (one each in cities of Chandigarh, Mohali and Panchkula) of Northern India and its possible effects of contamination of groundwater. Analysis of physico-chemical properties of leachate from all the three landfill sites and the surrounding groundwater samples from five different downwind distances from each of the landfill sites were collected and tested to determine the leachate pollution index (LPI) and the water quality index (WQI). The Leachate Pollution Index values of 26.1, 27 and 27.8 respectively for landfill sites of Chandigarh (CHD), Mohali (MOH) and Panchkula (PKL) cities showed that the leachate generated are contaminated. The average pH values of the leachate samples over the sampling period (9.2 for CHD, 8.97 for MOH and 8.9 for PKL) show an alkaline nature indicating that all the three landfill sites could be classified as mature to old stage. The WQI calculated over the different downwind distances from the contamination sites showed that the quality of the groundwater improved with an increase in the downwind distance. Principal component analysis (PCA) carried out established major components mainly from natural and anthropogenic sources with cumulative variance of 88% for Chandigarh, 87.1% for Mohali and 87.8% for Panchkula. Hierarchical cluster analysis (HCA) identifies three distinct cluster types for the groundwater samples. These clusters corresponds to a relatively low pollution, moderate pollution and high pollution regions. It is suggested that all the three non-engineered landfill sites be converted to engineered landfill sites to prevent groundwater contamination and also new sites be considered for construction of these engineered landfill sites as the present dumpsites are nearing the end of their lifespan capacity. PMID- 29280083 TI - Synthesis and Photochemical Properties of 2,3;5,6-bis(cyclohexano)-BODIPY. AB - The boron-dipyrromethene (BODIPY) dye containing an annelated cyclohexyl rings at the 2,3 and 5,6-positions of pyrroles has been synthesized and characterized. Photochemical properties of the obtained compound have been investigated in different individual solvents. 2,3;5,6-Bis(cyclohexano)-BODIPY exhibits intense chromophore properties with maximum of S o -> S 1 band in the 543-549 nm (A from 66000 to 96000 L/mol.cm). The complex is a fluorophore with a quantum yield up to ~ 100%. The influence of solvent polarity on the spectral properties was evaluated. To better understand the spectroscopic results, quantum chemical calculations were carried out. Photostability of dye was studied.Graphical Abstract. PMID- 29280084 TI - The effect of Nesfatin-1 on food intake in neonatal chicks: role of CRF1 /CRF2 and H1/ H3 receptors. AB - The present study was designed to determine the effect of central injection of Nesfatin-1 and corticotropin and histaminergic systems on food intake in neonatal meat-type chicks. In this study, 7 experiments were designed, each with 4 treatment groups. In experiment 1, four groups of chicks received the ICV injection of (A) phosphate-buffered saline (PBS), (B) Nesfatin-1 (10 ng), (C) Nesfatin-1 (20 ng) and (D) Nesfatin-1 (40 ng). In experiment 2, (A) PBS, (B) Astressin-B (CRF1/CRF2 receptors antagonist; 30 ug), (C) Nesfatin-1 (40 ng) and (D) Nesfatin-1 + Astressin-B were injected. In experiments 3-6, chicken received ICV injection of the Astressin2-B (CRF2 receptor antagonist; 30 ug), alpha-FMH (alpha fluoromethyl histidine; as inhibitor of histidine decarboxylase, 250 nmol), Chlorpheniramine (histamine H1 receptors antagonist, 300 nmol), Famotidine (histamine H2 receptors antagonist, 82 nmol) and Thioperamide (histamine H3 receptors antagonist, 300 nmol) instead of the Astressin-B. Then the cumulative food intake measured until 120 min post-injection. According to the results, ICV injection of Nesfatin-1 dose dependently decreased food intake in neonatal chicks (P < 0.05). Co-injection of the Nesfatin-1 and Astressin-B (CRF1/CRF2) inhibited Nesfatin-1 induced hypophagia (P < 0.05). ICV inejction of the Nesfatin-1 + Astressin-B significantly inhibited the effect of Nesfatin-1 on food intake (P < 0.05). In addition, alpha-FMH and chlorpheniramine attenuated Nesfatin-1-induced hypophagia in chicks (P < 0.05); while thioperamide significantly amplified the effect of Nesfatin-1 on food intake in chicks (P < 0.05). These results suggested Nesfatin-1 has an anorectic effect in 3-hour food deprived neonatal meat-type chicks and this effect was mediated by corticotropin CRF1/CRF2 as well as histamine H1 and H3 receptors. PMID- 29280085 TI - Usefulness of a single-assay chemiluminescence test (Tularaemia VIRCLIA IgG + IgM monotest) for the diagnosis of human tularemia. Comparison of five serological tests. AB - The aim of this work was to ascertain the usefulness of a new commercially available single-assay chemiluminescence test (CHT) for the diagnosis of human tularemia (Tularaemia VIRCLIA IgG + IgM monotest, Vircell, Santa Fe, Granada, Spain). A total of 773 sera from 773 patients including 364 initial sera from patients with diagnosed tularemia, patients with suspected tularemia not confirmed (100), healthy people (152), patients with serology positive to Brucella (97), patients diagnosed with other infectious diseases (30), and patients diagnosed with autoimmune diseases (30) were included. All sera were tested by CHT, "in-house" microagglutination test (MAT), immunochromatographic test (ICT) (Virapid Tularaemia, Vircell, Santa Fe Granada, Spain), and "in-house" ELISA IgG, and ELISA IgM. Of the total initial sera, 334 (sensitivity 91.8%) were positive in the CHT, 332 (sensitivity 91.2%) in the MAT, 330 (sensitivity 90.7%) in the ICT, and 328 (sensitivity 90.1%) in the ELISA IgG and ELISA IgM tests. The specificity of the CHT was 96.7%; of the MAT, 100%; of the ICT, 98.7%; and of the ELISA IgG and ELISA IgM, 97.4%. In the group of patients with serology positive to Brucella, at least 12.4% of sera were positive in tularemia tests (12.4% in ELISA IgM, 13.4% in MAT, 14.4% in ICT, and 15.5% in CHT and ELISA IgG). In conclusion, CHT presents a sensitivity and specificity in early diagnosis of human tularemia, similar to MAT, ICT, and ELISA IgG and ELISA IgM. Its single assay design allows lower costs, especially in areas of low endemicity or inter epidemic periods. PMID- 29280086 TI - Negative regulation of MAVS-mediated innate immune response by ASC. AB - Stringent control of the type I interferon signaling pathways is critical to effective host immune responses, however, the molecular mechanisms that negatively regulate these pathways are still poorly understood. Here, we show that apoptosis speck-like protein (ASC), an adaptor protein of inflammasome complex, can inhibit IFN-beta signaling response by interacting with mitochondrial antiviral signaling protein (MAVS). Importantly, ASC-specific siRNA knockdown enhanced virus-induced type I interferon production, with consequent reduction of virus replication. Taken together, these results suggest that ASC, as a negative regulator of the MAVS-mediated innate immunity, may play an important role in host protection upon virus infection. PMID- 29280087 TI - Depression and Help-Seeking Among Native Hawaiian Women. AB - The purpose of this mixed-methods study was to gain insight about Native Hawaiian (NH) women's experiences with, and viewpoints of, depression and help-seeking behaviors (N = 30: 10 from the university and 20 from the community). More women reported depression in the interviews than through their Center for Epidemiologic Studies Depression Scale (CES-D) responses. Quantitative data revealed 57% of the women had ever received mental health help (80% of university vs. 45% of community sample). There was a range of satisfaction reported for various types of mental health care, with satisfaction being the highest for spiritual/religious advisor/folk healer. During the interviews, one woman reported that she is currently receiving professional care and five women are seeking help from their family/social network. Future research should explore reasons for the differences in the quantitative and qualitative findings regarding depression and associated help-seeking as well as in the satisfaction levels by type of help-seeking. PMID- 29280088 TI - visnormsc: A Graphical User Interface to Normalize Single-cell RNA Sequencing Data. AB - Single-cell RNA sequencing (RNA-seq) allows the analysis of gene expression with high resolution. The intrinsic defects of this promising technology imports technical noise into the single-cell RNA-seq data, increasing the difficulty of accurate downstream inference. Normalization is a crucial step in single-cell RNA seq data pre-processing. SCnorm is an accurate and efficient method that can be used for this purpose. An R implementation of this method is currently available. On one hand, the R package possesses many excellent features from R. On the other hand, R programming ability is required, which prevents the biologists who lack the skills from learning to use it quickly. To make this method more user friendly, we developed a graphical user interface, visnormsc, for normalization of single-cell RNA-seq data. It is implemented in Python and is freely available at https://github.com/solo7773/visnormsc . Although visnormsc is based on the existing method, it contributes to this field by offering a user-friendly alternative. The out-of-the-box and cross-platform features make visnormsc easy to learn and to use. It is expected to serve biologists by simplifying single cell RNA-seq normalization. PMID- 29280089 TI - Developing a Mass Media Campaign to Promote Mammography Awareness in African American Women in the Nation's Capital. AB - This study developed and examined the reach and impact of a culturally appropriate mass media campaign pilot, designed to increase awareness about the importance of mammography screening and the available community mammography services for low-income African American women ages 40 and above. We conducted formative research using focus groups to inform campaign development, resulting in five emergent themes-good breast health, holistic views of healthiness, cancer fatalism, fear of mammogram machines, and mammogram affordability. The campaign targeted specific low-income African American communities in the District of Columbia via print ads in Metro stations and on buses, print ads in the Washington Informer, and online ads on a local TV network website. Data were collected before, during, and after campaign implementation to assess reach and impact. Reach was measured by number of impressions (number of people exposed to the campaign), while impact was assessed via online ad click-through rates, website use and referrals, and mammography center calls. The campaign was successful in reaching the target audience, with a total combined reach from all media of 9,479,386 impressions. In addition, the mammography center received significant increases in new website visitors (1482 during the campaign, compared to 24 during the preceding period) as well as 97 calls to the dedicated phone line. Further research involving a more long-term investment in terms of funding and campaign run time, coupled with a more robust evaluation, is needed to assess if culturally appropriate mass media campaigns can generate increased mammography screening rates and decrease breast-cancer-related mortality. PMID- 29280090 TI - When You Go. PMID- 29280091 TI - The Gut Microbiome in Neuromyelitis Optica. AB - Neuromyelitis optica (NMO) is a rare, disabling, sometimes fatal central nervous system inflammatory demyelinating disease that is associated with antibodies ("NMO IgG") that target the water channel protein aquaporin-4 (AQP4) expressed on astrocytes. There is considerable interest in identifying environmental triggers that may elicit production of NMO IgG by AQP4-reactive B cells. Although NMO is considered principally a humoral autoimmune disease, antibodies of NMO IgG are IgG1, a T-cell-dependent immunoglobulin subclass, indicating that AQP4-reactive T cells have a pivotal role in NMO pathogenesis. When AQP4-specific proliferative T cells were first identified in patients with NMO it was discovered that T cells recognizing the dominant AQP4 T-cell epitope exhibited a T helper 17 (Th17) phenotype and displayed cross-reactivity to a homologous peptide sequence within a protein of Clostridium perfringens, a commensal bacterium found in human gut flora. The initial analysis of gut microbiota in NMO demonstrated that, in comparison to healthy controls (HC) and patients with multiple sclerosis, the microbiome of NMO is distinct. Remarkably, C. perfringens was the second most significantly enriched taxon in NMO, and among bacteria identified at the species level, C. perfringens was the one most highly associated with NMO. Those discoveries, along with evidence that certain Clostridia in the gut can regulate the balance between regulatory T cells and Th17 cells, indicate that gut microbiota, and possibly C. perfringens itself, could participate in NMO pathogenesis. Collectively, the evidence linking microbiota to humoral and cellular immunity in NMO underscores the importance for further investigating this relationship. PMID- 29280092 TI - Classifying clinical notes with pain assessment using machine learning. AB - Pain is a significant public health problem, affecting millions of people in the USA. Evidence has highlighted that patients with chronic pain often suffer from deficits in pain care quality (PCQ) including pain assessment, treatment, and reassessment. Currently, there is no intelligent and reliable approach to identify PCQ indicators inelectronic health records (EHR). Hereby, we used unstructured text narratives in the EHR to derive pain assessment in clinical notes for patients with chronic pain. Our dataset includes patients with documented pain intensity rating ratings > = 4 and initial musculoskeletal diagnoses (MSD) captured by (ICD-9-CM codes) in fiscal year 2011 and a minimal 1 year of follow-up (follow-up period is 3-yr maximum); with complete data on key demographic variables. A total of 92 patients with 1058 notes was used. First, we manually annotated qualifiers and descriptors of pain assessment using the annotation schema that we previously developed. Second, we developed a reliable classifier for indicators of pain assessment in clinical note. Based on our annotation schema, we found variations in documenting the subclasses of pain assessment. In positive notes, providers mostly documented assessment of pain site (67%) and intensity of pain (57%), followed by persistence (32%). In only 27% of positive notes, did providers document a presumed etiology for the pain complaint or diagnosis. Documentation of patients' reports of factors that aggravate pain was only present in 11% of positive notes. Random forest classifier achieved the best performance labeling clinical notes with pain assessment information, compared to other classifiers; 94, 95, 94, and 94% was observed in terms of accuracy, PPV, F1-score, and AUC, respectively. Despite the wide spectrum of research that utilizes machine learning in many clinical applications, none explored using these methods for pain assessment research. In addition, previous studies using large datasets to detect and analyze characteristics of patients with various types of pain have relied exclusively on billing and coded data as the main source of information. This study, in contrast, harnessed unstructured narrative text data from the EHR to detect pain assessment clinical notes. We developed a Random forest classifier to identify clinical notes with pain assessment information. Compared to other classifiers, ours achieved the best results in most of the reported metrics. Graphical abstract Framework for detecting pain assessment in clinical notes. PMID- 29280093 TI - Towards estimation of respiratory muscle effort with respiratory inductance plethysmography signals and complementary ensemble empirical mode decomposition. AB - Respiratory inductance plethysmography (RIP) sensor is an inexpensive, non invasive, easy-to-use transducer for collecting respiratory movement data. Studies have reported that the RIP signal's amplitude and frequency can be used to discriminate respiratory diseases. However, with the conventional approach of RIP data analysis, respiratory muscle effort cannot be estimated. In this paper, the estimation of the respiratory muscle effort through RIP signal was proposed. A complementary ensemble empirical mode decomposition method was used, to extract hidden signals from the RIP signals based on the frequency bands of the activities of different respiratory muscles. To validate the proposed method, an experiment to collect subjects' RIP signal under thoracic breathing (TB) and abdominal breathing (AB) was conducted. The experimental results for both the TB and AB indicate that the proposed method can be used to loosely estimate the activities of thoracic muscles, abdominal muscles, and diaphragm. Graphical abstract ?. PMID- 29280094 TI - The numerical study on the effects of cardiac function on the aortic oxygen distribution. AB - Although venoarterial extracorporeal membrane oxygenation (VA-ECMO) was widely used in clinical practice, the effects of cardiac output on the aortic oxygen distribution were still unclear. Hence, the present study aims to evaluate the effect of cardiac function on the aortic oxygen distribution under VA-ECMO support. A novel model, combining computational fluid dynamics, multiphase fluid approach, and oxygen transport theory together, was established. According to the clinical practice, four cardiac output conditions, including 0, 1, 2, and 2.5 L/min, were designed. The results demonstrated that the proposed method could accurately calculate the distribution of oxygen in the aorta. Moreover, the aortic oxygen distribution was significantly regulated by the local blood flow pattern. The deoxygenated blood flow and oxygenated blood flow met at the aortic arch and formed the so-called oxygenshed phenomenon. Along with the cardiac output increase, the oxygenshed was moved from the proximal of the aortic arch to the descending aorta. Meanwhile, the oxygen contents in the brachiocephalic artery and left common carotid artery were reduced along with the increase of cardiac output. The study could provide much useful information on the oxygen distribution in the aorta to surgeons and operators of VA-ECMO. Graphical abstract The results showed the deoxygenated blood and oxygenated blood met at the aortic arch and formed the so-called "oxygenshed" phenomenon. This phenomenon is consistent with the phenomenon called "watershed". PMID- 29280095 TI - The Efficacy of Tetrasodium EDTA on Biofilms. AB - The aetiology of delayed wound healing characteristic of a chronic wound is relatively unknown but is thought to be due to a combination of the patient's underlying pathophysiology and external factors including infection and biofilm formation. The invasion of the wound by the hosts' resident microbiome and exogenous microorganisms can lead to biofilm formation. Biofilms have increased tolerance to antimicrobial interventions and constitute a concern to chronic wound healing. Consequently, anti-biofilm technologies with proven efficacy in areas outside of wound care need evaluation to determine whether their efficacy could be relevant to the control of biofilms in wounds. The aim of this study was to assess the anti-biofilm capabilities of tetrasodium EDTA (t-EDTA) as a stand alone liquid and when incorporated in low concentrations into wound dressing prototypes. Results demonstrated that a low concentration of t-EDTA (4%) solution was able to kill Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), S. epidermidis, Pseudomonas aeruginosa and Enterococcus faecalis within in vitro biofilms after a 24-h contact time. The incorporation of low levels of t-EDTA into prototype fibrous wound dressings resulted in a 3-log reduction of bacteria demonstrating its microbicidal ability. Furthermore, hydrogels incorporating only a 0.2% concentration of t-EDTA (at preservative levels) caused a small reduction in biofilm. In conclusion, these studies show that t-EDTA as a stand-alone agent is an effective anti-biofilm agent in vitro. We have demonstrated that t-EDTA is compatible with numerous wound dressing platforms. EDTA could provide an essential tool to manage biofilm-related infections and should be considered as an anti-biofilm agent alone or in combination with other antimicrobials or technologies for increased antimicrobial performance in recalcitrant wounds. PMID- 29280096 TI - Management of Bradyarrhythmias in Heart Failure: A Tailored Approach. AB - Patients with heart failure (HF) may develop a range of bradyarrhythmias including sinus node dysfunction, various degrees of atrioventricular block, and ventricular conduction delay. Device implantation has been recommended in these patients, but the specific etiology should be sought as it may influence the choice of the type of device required (pacemaker vs. implantable cardiac defibrillator). Also, pacing mode must be carefully set in patients with heart failure (HF) and left ventricular systolic dysfunction.In this chapter, we summarize the knowledge required for a tailored approach to bradyarrhythmias in patients with heart failure. PMID- 29280097 TI - Current treatment paradigms in pediatric short bowel syndrome. AB - Pediatric short bowel syndrome (SBS) is a serious condition which occurs in children with congenital or acquired reduction in length of the small intestine. SBS results in excessive fluid loss, nutrient malabsorption, electrolyte abnormalities, increased susceptibility to infections, parenteral nutrition associated complications and affects weight gain and growth. In children, SBS is debilitating and uniformly fatal without treatment. The primary goal of treatment is to restore enteral autonomy and reduce long-term dependence on parenteral support by increasing the absorptive potential of the remnant intestine. In this review, the medical and surgical management of SBS including pharmacologic agents, parenteral nutrition, dietary strategies, surgical lengthening procedures, and small bowel transplant will be discussed. PMID- 29280098 TI - Dual slag filters for enhanced phosphorus removal from domestic waste water: performance and mechanisms. AB - The phosphorus (P) removal of five combinations of dual filters consisting of blast furnace slag (BFS), argon oxygen decarburisation slag (AOD) and electric arc furnace slag (EAF) was evaluated in column experiments with domestic waste water. The columns were fed with waste water for 24 days. The column with only EAF had the best P removal performance (above 93% throughout the experiment). The speciation of the bound P was evaluated by P K-edge X-ray absorption near-edge structure (XANES) spectroscopy. In all five columns, the main P species of the slag packed in the outlet chamber was amorphous calcium phosphate (ACP). In samples from the inlet chambers, the contributions from crystalline Ca phosphates, P adsorbed on gibbsite and P adsorbed on ferrihydrite were usually much greater, suggesting a shift of P removal mechanism as the waste water travelled from the inlet to the outlet. The results provide strong evidence that P was predominantly removed by the slags through the formation of ACP. However, as the pH decreased with time due to the progressively lower dissolution of alkaline silicate minerals from the slag, the ACP was rendered unstable and hence redissolved, changing the P speciation. It is suggested that this process strongly affected the lifespan of the slag filters. Of the slags examined, EAF slag had the best P removal characteristics and BFS the worst, which probably reflected different dissolution rates of alkaline silicates in the slags. PMID- 29280099 TI - Exploitation of olive oil mill wastewaters and molasses for ethanol production using immobilized cells of Saccharomyces cerevisiae. AB - An alcoholic fermentation process is described, involving molasses, the main by product of the sugar industry, blended with crude olive oil mill wastewaters (OOMWs) and immobilized Saccharomyces cerevisiae cells on delignified cellulosic material (DCM). For comparison, fermentations with free cells were also carried out. Initially, the optimum blending mixture for molasses dilution was sought after, while at a second step repeated batch fermentations at a temperature range 5-30 degrees C were performed to monitor the operational stability of the system. A 1/1 ratio of OOMWs/tap water blending mixture and cell immobilization resulted in higher fermentation parameters. Ethanol concentration and daily productivity values recorded at temperatures >= 20 degrees C (up to 67.8 g L-1 and 67.6 g L-1 d-1, respectively) could be adopted by the industrial sector, although the decline in fermentation efficiency observed, probably due to the toxicity effects of OOMWs. Finally, the potential of OOMWs treatment for ethanol production is highlighted and assessed. PMID- 29280100 TI - Toxic and essential elements in seafood from Mausund, Norway. AB - In annual surveys conducted during the period 2012-2015, concentrations of the toxic or essential elements B, Se, Cd, Sn, Cs, Hg, Pb, Al, Cr, Mn, Fe, Ni, Cu, Zn, and As were analyzed in brown meat of edible crab (Cancer pagurus), and filets of cod (Gadus morhua) and halibut (Hippoglossus hippoglossus) in one of the most important commercial crab fishing areas in Norway, at Mausund in Froya municipality in Sor-Trondelag, Norway. Concentrations of the elements were analyzed in sediments in 2015. Several salmon farms are located in this area. Samples were extracted by HNO3 and analyzed using inductively coupled plasma mass spectroscopy (ICP-MS). Crab, cod, and halibut were caught in a total of five locations. One of these locations was in the proximity of a salmon farm. In edible crabs, the mean ranks were significantly different between two locations only for Sn (p = 0.034). When all data were pooled, the mean ranks statistics showed significant difference between all years for the elements Se (p = < 0.001), Cs (p = 0.005), Mn (p = 0.002), Zn (p = 0.006), and As (p = 0.001) in edible crab. The study showed elevated levels of Cd in edible crabs in 2012, 2013, 2014, and 2015, with the highest levels in 2015. In cod, there were significant differences between locations for the elements B (p = 0.003), and Pb (p = 0.04), as well as between the years for the elements B, Sn, Cs, Hg, Cr, and As (p = < 0.01). The study showed elevated level of Pb in cod in 2013. Halibut showed no significant differences between years or locations for any elements. The Cd, Hg, and Pb values of the sediments in this study indicate that local geogenic sources cannot be considered a major cause of high values in local biota. PMID- 29280101 TI - Effect of Cd stress on the bioavailability of Cd and other mineral nutrition elements in broad bean grown in a loess subsoil amended with municipal sludge compost. AB - Municipal sludge compost (MSC) is commonly used as fertilizer or an amendment in barren soils. However, MSC-borne Cd is of great concern in food safety because of its toxicity. Loess subsoil (LS) is barren and lacks nutrients, but it has a strong ability to absorb and stabilize heavy metals. Hence, LS may be amended with MSC and may reduce the bioavailability of Cd. To simulate the dose effect of the accumulated MSC-borne Cd in amended LS, pot experiments were conducted to study the bioavailability of Cd and other mineral nutrition elements in broad bean (Vicia faba L.) under Cd stress. Plant height and dry biomass remarkably increased as the physicochemical properties of LS were significantly improved; however, they were not significantly influenced by the added Cd. The Cd in the plants grown in MSC amended-LS (P2) mainly accumulated in roots (32.12 mg kg-1) and then in stems and leaves (6.00 mg kg-1). Less Cd (0.74 mg kg-1) accumulated in the edible parts, where the Cd concentration was 53% lower than that in the edible parts of plants grown in LS (P1). The decreased Cd concentrations in the P2 beans may be due to the biomass dilution effect. Notably, the Cd concentrations in the beans exceeded the national safety limit value (0.2 mg kg 1) when the Cd treatment levels exceeded 2 mg kg-1 in LS and 6 mg kg-1 in amended LS. The MgCl2 extraction procedures can be used to assess Cd bioavailability in amended soil-plant systems. The potential antagonism of Zn and Cu against Cd toxicity in the soil-plant system may explain why this plant can tolerate higher Cd concentrations after MSC application. PMID- 29280102 TI - The properties and dynamic changes of DOM subfractions during food waste and sugarcane leaves co-composting. AB - The purpose of this research was to evaluate the properties and dynamic changes of humic acids (HA), fulvic acids (FA), hydrophobic neutrals (HoN), and hydrophilic (Hi) fractions of dissolved organic matter (DOM) during food waste and sugarcane leaves co-composting process. The pools of HA, FA, HoN, and Hi were separated from DOM by fractionation method, and characterized using spectroscopic (UV-vis, FTIR) and pyrolysis-GC/MS analyses. The least peaks in the HA pool were found in FTIR spectra with the simple structure in HA. The highest value of SUV254 was observed in HA, indicating that the HA pool played a dominant role in aromaticity of DOM. Hydrophobic compounds (HA, FA, HoN) had higher percentages of alkanes and cyclo-alkanes at the end of composting, while lower contents in the Hi pool. Both DOM and its subfractions increased the Chinese flowering cabbage (Brassica campestris L.) seed germination rate (SGR), whereas HA had a significant effect on promoting the root growth. PMID- 29280103 TI - Distribution of perfluorinated compounds in drinking water treatment plant and reductive degradation by UV/SO32- process. AB - Perfluorinated compounds (PFCs), which are widely used in industrial and residential areas, have a large negative impact on the environment. This study investigated the removal efficiency of five PFCs in a drinking water treatment plant. The results indicate that the total PFC concentration in raw water is 261.51 ng L-1 and that perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the predominant pollutants. Among all of the treatment processes, coagulation sedimentation process had the highest removal ratio of PFCs (36.12%), and removal ratio was the least in the sand filtration process. The ozonation/activated carbon and disinfection processes increased the concentration of PFCs. Therefore, developing an effective treatment to degrade PFCs is feasible. In this study, we proposed a method using UV irradiation of SO32- at 365 nm to degrade PFCs. The SO32- concentration, pH, and initial concentration had profound impacts on the degradation of PFCs. When the PFC initial concentration was 20 mg L-1, the SO32- concentration was 2.4 g L-1, and in the presence of buffer, the degradation of PFCs was the most efficient, with the degradation ratio close to 100% after 60 min of reaction. During the degradation of PFCs, short-chain PFCs and hydrofluorinated carboxylic acid were generated. From the above, we proposed a detailed mechanism of degradation and its possible pathways. PMID- 29280104 TI - A study of the influence of regional environmental expenditure on air quality in China: the effectiveness of environmental policy. AB - Based on the panel data model, data on environmental expenditures, the air quality index, economic aggregates, industrial structures, etc., of seven seriously polluted cities in China, from the period 2007-2015, were collected, and this paper estimates the general relationship between environmental expenditures and the air quality index. Besides, the impact of the fuel tax policy on air quality as well as on the relationship between environmental expenditure and the air quality index is tested using the method of regression discontinuity. We find that there is a long-term equilibrium relationship between environmental expenditure and air quality index as well as a 0.0507% positive effect of the former on the latter. Second, for Beijing, Taiyuan, Chongqing, and Lanzhou, a 1% increase in environmental expenditure leads to 0.0773, 0.0125, 0.0965, and 0.0912% decreases in the air quality index, respectively; however, for Shijiazhuang, Ji'nan, and Urumqi, effect of environmental expenditure on air quality is insignificant. Third, both economic growth and optimization of the industrial structure can lead to an improvement of air quality. Fourth, since the implementation of the fuel tax policy in 2009, the air quality of the sample cities has improved, and the pulling effect of environmental expenditure on the air quality index has decreased from 0.0507 to 0.0048%. Our findings cannot only clarify the effect of environmental expenditures on air quality but can also objectively judge the effectiveness of environmental policies of China to a certain extent. It may benefit Chinese government to effectively govern air pollution with fiscal tools in conjunction with economic and environmental characteristics. PMID- 29280105 TI - The impact of olive mill wastewater spreading on soils using integrated approach of proximal soil survey, spatial, and multivariate analyses. AB - Olive oil production generates a large amount of olive mill wastewater (OMW), the most difficult to treat of agro-industrial effluents. Spreading of OMW across the soilscape has become the most frequently used practice in several Mediterranean basin countries but is hotly debated because of its potential to impair soil environs. The research hypothesis states that soil deterioration is correlated strongly with the spatiotemporal rate of OMW application; thus, the spatial pattern of the soil attributes should be established in conjunction with the rate of OMW spreading. The spatial pattern was ascertained using proximal soil sensing that measures the apparent electrical conductance (ECa). Eight representative locations were identified using grouping analysis of the ECa data. The soils were analyzed for selected physical and chemical attributes known to be affected by OMW spreading as well as ancillary parameters needed for the calibration of the ECa. Discriminant analysis successfully categorized 76% of the ECa groups, selecting CEC, sand, pH, and ESP as the most powerful discriminatory variables in the grouping analysis. The correlation coefficients between the measured ECa, and the calculated ECa, and soil moisture were very high (r > 0.77, P < 0.05), suggesting that the proximal soil survey results are well calibrated. The spreading of untreated OMW over more than 7 years did not impair the soils under study. No significant changes in soil chemo-physical properties such as pH (< 7.66), electrical conductivity in saturated paste (< 3.58 dS m-1), sodium adsorption ratio (< 2.3), potassium adsorption ratio (< 0.33), exchangeable sodium percentage (< 3.85%), and unsaturated hydraulic conductivity (< 0.3 cm h 1) were found in comparison with untreated soils. The results support the premise that moderate quantities of OMW (50-70 m3 ha-1 year-1) equally spread over the soilscape will have little impact on soil health. PMID- 29280106 TI - Impact of Race Versus Education and Race Versus Income on Patients' Motivation to Participate in Clinical Trials. AB - Our study investigates whether levels of motivation and barriers to participation in clinical trials vary with patients' education and income. A self-administered survey asked outpatients to rank potential influential factors on a "0" to "4" significance scale for their motivation to participate in clinical trials. Principal component analysis (PCA), analysis of variance (ANOVA), Kruskal-Wallis, and Mann-Whitney U tests analyzed the impact of race, education, and income on their motivation to participate. Analysis included 1841 surveys; most respondents had a high school education or some college, and listed annual income < $30,000. There was a significant interaction between race and income on our motivation scale 1 scores (p = .0261). Compared with their counterparts, subjects with less education/lower income ranked monetary compensation (p = .0420 and p < .0001, respectively) as a higher motivator. Minorities and patients with less education and lower income appear to be more influenced by their desire to please the doctor, the race and sex of the doctor, and the language spoken by the doctor being the same as theirs. For all races, education appeared to have a direct relationship with motivation to participate, except for African-Americans, whose motivation appeared to decline with more education. Income appeared to have an inverse relationship with motivation to participate for all races. PMID- 29280109 TI - [Interpretation of Chinese guidelines for the diagnosis and treatment of constipation surgery (2017)]. AB - The Chinese Society of Coloproctology (CSCP) released the updated "guidelines for the diagnosis and treatment of constipation surgery" in 2017. The major amendments include the following aspects: (1) According to defecation reflex involving parts of the classification, the cause of constipation is divided into three parts, including colorectal factors, internal and external colorectal factors. The new division is more rational, easy to make clear the location and the possible pathogenesis. (2) Constipation is divided into slow transit constipation, outlet obstructive constipation and mixed constipation. The main consideration of this division is the name of the surgery for the outlet obstructive constipation, such as the rectal prolapse and the rectocele. (3) The 6-hour observation time point is added in the colonic transit test and to make clear whether the stomach and the small intestine has slow transit. (4) Micro ecological preparations, promoting dynamic drugs and promoting secretion drugs as well as psychological treatment and acupuncture treatment are added in non surgical treatment of constipation (5) The antegrade colonic enema is removed from surgical treatment of slow transit constipation; in the surgical treatment of internal rectal prolapse, STARR surgery is added and Delorme surgery is deleted; transrectal and transperineal approach are added in the surgical treatment of rectocele. In this paper, we compare the domestic and international constipation-related guidelines, and summarize the main revisions in the 2017 edition of "guidelines for the diagnosis and treatment of constipation surgery". PMID- 29280107 TI - Neural response to working memory demand predicts neurocognitive deficits in HIV. AB - Human immunodeficiency virus (HIV) continues to have adverse effects on cognition and the brain in many infected people, despite a reduced incidence of HIV associated dementia with combined antiretroviral therapy (cART). Working memory is often affected, along with attention, executive control, and cognitive processing speed. Verbal working memory (VWM) requires the interaction of each of the cognitive component processes along with a phonological loop for verbal repetition and rehearsal. HIV-related functional brain response abnormalities during VWM are evident in functional MRI (fMRI), though the neural substrate underlying these neurocognitive deficits is not well understood. The current study addressed this by comparing 24 HIV+ to 27 demographically matched HIV seronegative (HIV-) adults with respect to fMRI activation on a VWM paradigm (n back) relative to performance on two standardized tests of executive control, attention and processing speed (Stroop and Trail Making A-B). As expected, the HIV+ group had deficits on these neurocognitive tests compared to HIV- controls, and also differed in neural response on fMRI relative to neuropsychological performance. Reduced activation in VWM task-related brain regions on the 2-back was associated with Stroop interference deficits in HIV+ but not with either Trail Making A or B performance. Activation of the posterior cingulate cortex (PCC) of the default mode network during rest was associated with Hopkins Verbal Learning Test-2 (HVLT-2) learning in HIV+. These effects were not observed in the HIV- controls. Reduced dynamic range of neural response was also evident in HIV+ adults when activation on the 2-back condition was compared to the extent of activation of the default mode network during periods of rest. Neural dynamic range was associated with both Stroop and HVLT-2 performance. These findings provide evidence that HIV-associated alterations in neural activation induced by VWM demands and during rest differentially predict executive-attention and verbal learning deficits. That the Stroop, but not Trail Making was associated with VWM activation suggests that attentional regulation difficulties in suppressing interference and/or conflict regulation are a component of working memory deficits in HIV+ adults. Alterations in neural dynamic range may be a useful index of the impact of HIV on functional brain response and as a fMRI metric in predicting cognitive outcomes. PMID- 29280108 TI - CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study. AB - CINAMMON is a phase IV, open-label, single-arm, pilot study assessing maraviroc (MVC) in the central nervous system (CNS) when added to darunavir/ritonavir monotherapy (DRV/r) in virologically suppressed HIV-infected subjects. CCR5 tropic participants on DRV/r were recruited. Participants remained on DRV/r for 12 week (w) (control phase). MVC 150 mg qd was added w12-w36 (intervention phase). Lumbar puncture (LP) and neurocognitive function (Cogstate) examinations scheduled at baseline, w12 and w36; MRI before w12, again at w36. Primary endpoint was CSF inflammatory marker changes during intervention phase. Secondary endpoints included changes in NC function and MRI parameters. CSF/plasma DRV/r concentrations measured at w12 and w36, MVC at w36. Nineteen patients recruited, 15 completed (17M, 2F). Dropouts: headache (2), knee problem (could not attend, 1), personal reasons (1). Mean age (range) 45.4 years (27.2-65.1), 13/19 white, 10/19 MSM. No changes in selected CSF markers were seen w12-w36. Overall NC function did not improve w12-w36: total age adjusted z score improved by 0.27 (weighted paired t test; p = 0.11); for executive function only, age adjusted z score improved by 0.54 (p = 0.03). MRI brain parameters unchanged. DRV plasma:CSF concentration ratio unchanged between w12 (132) and w36 (112; p = 0.577, Wilcoxon signed-rank). MVC plasma:CSF concentration ratio was 35 at w36. No changes in neuroinflammatory markers seen. In this small study, addition of 24w MVC 150 mg qd to stable DRV/r monotherapy showed possible improvement in executive function with no global NC effect. Learning effect cannot be excluded. This effect should be further evaluated. PMID- 29280110 TI - [Update of the Rome IIII( criteria for functional constipation]. AB - The Rome IIII( criteria were released in May 2016. Based on the development of brain-intestinal axis theory, intestinal microecology, pharmacogenomics and social psychology, the Rome IIII( criteria revise the definition, diagnostic criteria, clinical evaluation process, and treatments of functional constipation (FC). The revisions are as follows: (1) Definition: FC and constipation predominant irritable bowel syndrome are considered to be on a continuum rather than as independent entities. (2) Diagnostic criteria: the Bristol stool scale type 1, type 2 and spontaneous bowel movements are added in the diagnostic criteria, respectively, refining the criteria for stool consistency and frequency. (3) Clinical evaluation process: the Rome IIII( criteria specifies the clinical assessment procedure for FC. The aim is to exclude organic disease, to detect the structural changes of the combination, to determine the type of guidance therapy, and to reduce unnecessary checks to improve diagnostic efficiency. (4) Pathophysiologic mechanism: much more newly investigated mechanisms are added, including the risk factors, genetics, inadequate colonic propulsion and defecation disorder. (5) Treatment: the treatment regimen summarizes the evidence-based medical evidence of new drugs, such as secretagogues and bile acid transport inhibitors, and evaluates the safety of all the new and old drugs. Compared to the Rome III( standard, the diagnosis of FC will be more stringent and efficient, and the treatment options will be more standardized and reasonable with the Rome IIII(. PMID- 29280111 TI - [Choice of surgical procedures and control of surgical risks in chronic constipation]. AB - Surgery, as one of the methods for the treatment of chronic constipation, is the final choice after the failure of non-surgical treatment with its specific particularity. The history of surgical treatment of chronic constipation is complex and tortuous. How to select operation among many kinds of surgery, and control risk is difficult for clinician. The choice of surgical procedure depends mainly on the patient's conditions, the objective examination basis and the experience of physician teams. Based on the previous reports and the team's experience, this paper discusses the choice of surgical treatment for the following types of chronic constipation: (1) Slow transit constipation: subtotal colorectal resection plus ileorectal anastomosis or ascending colon rectum anastomosis is widely used at present in the domestic, and its efficacy is quite good. (2) Outlet obstructive constipation: surgical treatment needs to be cautious with no consensus, and surgeons must follow the advice of "minimally invasive first" principle. (3) Mixed constipation: there is no clear and unified surgical treatment, while Jinling surgery is a promising way of operation. (4) Adult Hirschsprung's disease: surgery is the only treatment, and removing the stenosis segment, transitional segment and obvious expansion segment is the basic principle, and preventive ileostomy at the same time is also recommended. (5) Adult idiopathic megacolon: subtotal colectomy with ileorectal anastomosis or ascending colon rectum anastomosis is highly recommended. (6) Hypoganglionosis: it is rare, and no consensus has been reached in surgical treatment. How to select the proper timing and mode of operation, and how to control the operation risk are the contents that clinicians must master. With the development of laparoscopic surgical technology, minimally invasive surgery is becoming the main direction of constipation treatment. PMID- 29280112 TI - [Multidisciplinary-team approach in diagnosis and treatment of patients with chronic constipation]. AB - Chronic constipation is one of the common diseases in clinic. For the complicated causes and pathophysiology, the overall efficacy is not satisfactory in the traditional medical model. Multidisciplinary-team (MDT) approach is a new team medical model, which is also an important systematic and modular medical approach. Treating patients with chronic constipation by multidisciplinary-team approach is an effective way to improve the overall efficacy. In diagnosis, MDT approach can get more accurate and explicit diagnosis and type of the constipation by gathering patients' detailed medical history, complete physical examination, laboratory and image test, patients' mental and nutritional condition. In treatment, MDT members can cooperate in various fields, such as basic research, medicine, physics, psychology, surgery and conversion therapy, and that may provides more thoughts and methods for the treatment of chronic constipation. PMID- 29280113 TI - [Relationship between functional constipation and brain-gut-microbiota axis]. AB - Although with the higher prevalence, the overall treatment result of functional constipation is still not satisfied at home and abroad. The diagnosis and treatment of functional constipation are still to focus on colon itself. Functional constipation has complex interactions among intestinal flora, intestinal autonomic nerve and central nervous system. Patients with functional constipation have different degrees of mental and psychological dysfunction, and abnormal brain function can result in disorders of colon dynamics, secretion and immune function. At the same time, there is a significant imbalance of intestinal flora in patients with functional constipation. Intestinal flora plays an important role in the release of neurotransmitter and the activity of hypothalamic-pituitary-adrenal axis (HPA axis). Intestinal flora is an important regulator of development, maturity and activity of central nervous system. Therefore, the interaction in the brain-gut-microbiota axis may provide a broader strategy for the diagnosis and treatment of functional constipation and neuropsychiatric disorder. PMID- 29280114 TI - [Promotion of basic research in efficacy enhancement of chronic constipation]. AB - The incidence of chronic constipation increases year by year, but it is underestimated in affecting the health of patients. Clinical diagnosis and treatment of chronic intractable constipation is difficult, owing to the diversity of clinical manifestations and the unclear pathogenesis. The basic research is expected to identify the pathophysiological mechanism of chronic intractable constipation in the future, which can find out a ultimate solution approach and improve clinical efficacy. At present there are several basic research ways attracting our attention, including enteric nervous system (such as nerve cells, intestinal neurotransmitters, intestinal sensory nerve regulation mechanism), intestinal smooth muscle cells, Cajal interstitial cells and sacral neuromodulation and intestinal microecology. Although current basic researches are still very preliminary, but they have laid foundations of clinical drug development and application of new technology. PMID- 29280115 TI - [Pelvic floor biofeedback therapy in pelvic floor diseases]. AB - Pelvic floor biofeedback therapy is safe and effective in chronic constipation, urinary incontinence, fecal incontinence and pelvic floor pain whereas the heterogeneous indication affects the efficacy evaluation and technical communication. The best indications are as follows: (1) Pelvic floor myogenic dysfunction without severe pelvic organ prolapse and severe neurogenic defect; (2) Patients have good mental cognition and treatment adherence who fulfill the training with the therapist. The training protocol is conducted at hospital or at home, and is as follows: (1) To help patients to target the pelvic floor muscles; (2) To improve the type I( muscle tonic contraction variability; (3) To improve the pelvic floor type I( and type II( muscles activity coordination; (4) To enhance the pelvic floor muscle strength and rectum defecation awareness. The biofeedback efficacy is evaluated with different symptoms, questionnaire score, patient satisfaction recognition and long-term outcomes. Pelvic floor biofeedback therapy will be highlighted and extended to the primary care in near future following the pragmatic randomized controlled clinical trials, collection and analysis of big data. PMID- 29280116 TI - [Efficacy observation of periodic fecal microbiota transplantation in the treatment of refractory constipation]. AB - OBJECTIVE: To evaluate the efficacy of periodic fecal microbiota transplantation (FMT) for refractory constipation. METHODS: Clinical data of 49 patients with refractory constipation undergoing FMT through standard transplantation path of nasojejunal tube between April 2015 and April 2016 in Intestinal Microenvironment Treatment Centre of Nanjing General Hospital were analyzed retrospectively. Of 49 patients, 25 received single FMT for only 6 days (single group), and 24 received periodic FMT with another 6 days FMT 1 month after the first 6 days FMT (periodic group). The follow up was at 12 weeks after treatment. Autonomous defecation frequency, Wexner constipation score, gastrointestinal quality of life index and related adverse reaction were evaluated and compared at 4-, 8- and 12-week after treatment. Statistical analysis was performed on the difference after treatment at each time point, and the greater difference indicated the better improvement. RESULTS: There were no statistically significant differences in general characteristics between the two groups (all P<0.05). Before treatment, Wexner constipation score was 17.32+/-2.66 and 16.25+/-2.47, gastrointestinal quality of life index was 81.84+/-8.73 and 83.25+/-7.87, autonomous defecation frequency was (1.64+/-0.57) time/week and (1.42+/-0.65) time/week in single group and periodic group respectively, whose differences were not significant (all P>0.05). Compared with before FMT treatment, the autonomous defecation frequency, Wexner constipation score, gastrointestinal quality of life index were obviously improved at the 4-, 8-, 12-week (all P=0.000). At the 4-week after FMT treatment, the improvement degree of autonomous defecation frequency, Wexner constipation score, gastrointestinal quality of life index was compared between two groups, and no statistically significant differences were found (all P>0.05). While at 8 week and 12-week after FMT treatment, as compared to single group, periodic group had greater Wexner constipation score (at 8-week: 7.29+/-2.05 vs. 5.96+/-2.30, t=2.135, P=0.038; at 12-week: 7.21+/-1.98 vs. 5.80+/-2.43, t=2.218, P=0.031), greater gastrointestinal quality of life index (at 8-week: 25.71+/-8.91 vs. 20.20+/-8.53, t=2.211, P=0.032; at 12-week: 24.16+/-8.99 vs. 18.92+/-8.28, t=2.127, P=0.039) and better autonomous defecation frequency [at 8-week: (2.42+/ 0.93) time/week vs. (1.72+/-0.61) time/week, t=3.110, P=0.003; at 12-week: (1.37+/-0.88) time/week vs. (0.84+/-0.62) time/week, t=2.454, P=0.018]. CONCLUSION: Periodic FMT has better efficacy than single FMT in the treatment of refractory constipation. PMID- 29280117 TI - [Long-term efficacy of stapled transanal rectal resection for obstructed defecation syndrome]. AB - OBJECTIVE: To evaluate the long-term efficacy of stapled transanal rectal resection (STARR) in treating obstructed defecation syndrome(ODS). METHODS: Clinical data of 95 female patients with ODS undergoing STARR at Department of Colorectal Surgery, Rocket Army General Hospital from February 2010 to August 2012 were analyzed retrospectively. The Cleveland constipation scoring system (CSS), Longo ODS scoring system and severe symptoms score(SSS) were used to evaluate the degree and intensity of clinical symptoms. Patient satisfaction was assessed by visual analogue scale (VAS). Clinical symptoms at postoperative 12 month were defined as short-term efficacy, and at the end of follow up (>=48 months) were defined as long-term efficacy. RESULTS: The mean age was 54.5 (29 to 79) years and the median follow-up was 65 (48 to 78) months. Eighty (84.2%) and 44 (46.3%) patients completed the short-term and long-term efficacy evaluation respectively. At the end of follow up, compared with the baseline levels before operation, the CSS score (14.69 vs. 6.02), ODS score (16.51 vs. 5.73) and SSS score (14.64 vs. 5.14) were significantly decreased (all P<0.01), but the VAS score (3.96 vs. 7.20, P<0.01) was significantly increased. A total of 10 patients (22.7%) developed symptomatic recurrence. The self-reported definitive satisfaction was excellent in 10 (22.7%) patients, fairly good in 17(38.6%), good in 9(20.5%), and poor in 8(18.2%). The total effective rate was 81.8%(36/44). CONCLUSION: Long-term efficacy of STARR in the treatment of ODS is good, but the rate of symptomatic recurrence is relatively high. PMID- 29280118 TI - [Effects of perioperative intestinal microecological treatment on postoperative complications and gastrointestinal function in patients with refractory functional constipation]. AB - OBJECTIVE: To investigate the effects of perioperative intestinal microecological treatment on postoperative complications and gastrointestinal function in patients with refractory functional constipation by nonrandomized controlled trial. METHODS: A total of 198 patients with refractory functional constipation who underwent Jinling procedure in our department from 2014 to 2015 were prospectively enrolled, and were divided into conventional treatment group (n=100, routine intestinal preparation was used before operation; probiotics and prebiotics were applied if diarrhea or abdominal distention occurred after operation) and microecological treatment group (n=98, routine perioperative management was applied; probiotics, prebiotics and enteral nutrition were administered since 2 weeks before operation; probiotics and prebiotics were given again when exhaust and defecation recovered after operation). The general clinical data, postoperative complications, gastrointestinal quality of life index (GIQLI), Wexner constipation score, the incidence of abdominal distension and diarrhea during follow-up were collected. RESULTS: The baseline information was not significantly different between two groups (all P>0.05) as well as the morbidity of postoperative complication [27.6% (27/98) vs 37.0% (37/100), P=0.155]. Compared with conventional treatment group, microecological treatment group had obviously lower incidence of enteritis [2.0%(2/98) vs. 9.0% (9/100), P=0.034] and shorter postoperative hospital stay [(7.2+/-3.1) d vs. (9.8+/-3.6) d, P=0.040]. The incidences of diarrhea and abdominal distension in microecological treatment group were obviously lower than those in conventional treatment group [30.9% (29/94) vs. 46.9% (45/96), P=0.024; 44.7%(42/94) vs. 60.4%(58/96), P=0.030] at postoperative 1-month. Compared with conventional treatment group, microecological treatment group had obviously higher GIQLI (52.36 vs. 43.55, P=0.026) at postoperative 1-month. At postoperative 12-month, the incidences of diarrhea and abdominal distension decreased obviously in both two groups but without significant differences [diarrhea: 3.4% (3/89) vs. 3.3%(3/90), P=0.989; abdominal distention: 6.7% (6/89) vs. 5.6% (5/90), P=0.742]. GIQLI and Wexner score were improved but without significant differences as well (all P>0.05). CONCLUSION: Perioperative intestinal microecological treatment can obviously reduce the incidences of postoperative enteritis, early abdominal distension and early diarrhea, improve the postoperative early GIQLI, and shorten postoperative hospital stay. PMID- 29280119 TI - [Efficacy of Altemeier procedure in the treatment of rectal prolapse]. AB - OBJECTIVE: To evaluate the safety and efficacy of the perineal rectosigmoidectomy (Altemeier procedure) in the treatment of full thickness rectal prolapse. METHODS: Clinical and follow-up data of 52 patients with full thickness rectal prolapse undergoing Altemeier procedure in 9 hospitals from September 2010 to July 2016 were analyzed retrospectively. Of which 38 cases were from Zhongnan Hospital of Wuhan University, 1 case from Suizhou Central Hospital of Hubei province, 1 case from Jingzhou Second People's Hospital of Hubei province, 3 cases from Wuxue First People's Hospital of Hubei province, 1 case from Jingmen First People's Hospital of Hubei province, 1 case from Tuanfeng County Hospital of Hubei province, 4 cases from Jingzhou Central Hospital of Hubei province, 2 from PLA Rocket Army General Hospital, 1 case from the Affiliated Hospital of Xuzhou Medical University in Jiangsu province. Altemeier operation steps: The line shaped teeth, the prolapsed rectum is first exposed to the anus. In the dentate line proximal 1-3 cm with ultrasonic knife or Ligasure ring outer rectal incision, using electric knife to mark pre resection line in rectal mucosa. Open down in front of the pelvic peritoneum. Incision of the outer intestine and the reduction of the internal rectum and part of sigmoid colon. To free and remove excess pelvic retroperitoneal, pelvic peritoneum and be at the top of the colon or rectum anterior pelvic reconstruction suture. The rear of the levator ani muscle forming rectum. Pull gently to the anus and rectum and sigmoid, in the absence of tension, 2-3 cm outside the anus was selected as the proximal inner bowel pre resection line, along the line of pre transection of proximal bowel resection, again the broken end of intestine full-thickness end-to-end anastomosis. Postoperative complication and recurrence were summarized. Gastrointestinal quality of life index (GIQLI), Wexner constipation score and Wexner fecal incontinence score were used to evaluate the efficacy. RESULTS: All the 52 patients were beyond moderate full thickness rectal prolapse. Thirty-one were male and 21 were female with age ranging from 22 to 83 (average 53) years. The length of prolapsed rectum was 6 to 20 (average 9) cm and course of disease was 0.5 to 46(average 19.5) years. No perioperative death. Five patients (9.6%) had postoperative complications, including 2 anastomotic bleeding, 1 wall portion dehiscence of anastomosis, 1 anastomotic stenosis, and 1 malnutrition. Recurrence rate was 9.6%(5/52) within the long-term follow-up of 5 to 71 (median 40) years. Compared with the preoperative results, Wexner constipation score and Wexner fecal incontinence score decreased obviously (2.1+/-1.4 vs. 4.6+/-3.4, 4.8+/-4.1 vs. 6.8+/-4.1), and GIQLI significantly increased from 99.6+/-8.0 to 103.0+/-9.1 (all P<0.05) at 6-month after operation. Above 3 scores were sustained and continuously improved at 12-, 24-, and 36-month during the follow-up (all P<0.05). CONCLUSION: Altemeier procedure possesses good efficacy with low morbidity of complication and recurrence in the treatment of full thickness rectal prolapse. PMID- 29280120 TI - [Clinical application of compound anastomotic device in protective terminal ileostomy during rectal cancer operation]. AB - OBJECTIVE: To investigate the clinical effect of the application of "compound anastomotic device" on the high-risk colorectal anastomosis in rectal cancer patients undergoing protective ileostomy. METHODS: A total of 116 rectal cancer patients undergoing surgical procedure and prophylactic ileostomy in Tongji Hospital (90 cases) and The Third People's Hospital of Jingdezhen City (26 cases) from May 2011 to October 2016 were prospectively enrolled in the study. Paralleled control study and random digital table were applied. Fifty-eight cases received the compound anastomotic device for protective ileostomy (anastomosis ring group) and 58 cases underwent traditional terminal ileostomy (traditional group). The compound device was mainly composed of Valtrac biodegradable anastomosis ring, drainage tube and condom. Operational procedure was as follows: Ileocecum was freed through incision following laparoscopic total mesorectal excision; Two intestinal ring-shape purses were made; Intestinal wall between purse string was cut and the compound anastomotic device was put into; The purse was tightened and anastomosis ring was closed; The compound device was embed and pull out through the Trocar hole in the right lower abdomen; Then the drainage tube was fixed to the abdominal wall and connected with a drainage bag or an outer pocket. Incidence of anastomotic leak, stoma-related complications, hospital stay and total cost of two groups were compared. RESULTS: The general clinical data between two groups were not significantly different(all P>0.05). Stoma operation was performed successfully in all the patients of two groups. The stoma operation time was (34.6+/-13.8) min in anastomosis ring group and (25.8+/ 14.0) min in traditional group with significant difference (t=2.123, P=0.035). Postoperative anastomotic leak occurred in 7 cases, including 3 cases with small fistula in traditional group and 4 cases in anastomosis ring group, of whom 1 case underwent left-low abdominal colonic stoma after necrotic intestine resection. All the patients were discharged within postoperative 7 to 37 days. In traditional group, 35 cases (60.3%) occurred stoma-related complications, the total hospitalization expenses was (65+/-28) thousand yuan, and the average hospital stay (including stoma reversion) was (23.6+/-11.8) days. In anastomosis ring group, 17 cases (29.3%) occurred stoma-related complications, the total hospitalization expense was (52+/-11) thousand Yuan, and the average hospital stay was (21.0+/-16.8) days. The incidence of anastomotic fistula and the hospital stay had no significant difference between two groups (all P>0.05). The stoma-related complication morbidity (chi2=3.216, P=0.002) and the total hospitalization expenses (t=2.683, P=0.027) in anastomosis ring group were significantly lower than those in traditional group. CONCLUSION: Compared with traditional ileostomy, the application of compound anastomotic device for protective ileostomy would be better to benefit the recovery of patients. PMID- 29280121 TI - [Effect of adjuvant chemotherapy on the prognosis of stage II( colon cancer patients with high risk factors]. AB - OBJECTIVE: To investigate the effect of adjuvant chemotherapy on the prognosis of stage II( colon cancer patients with high risk factors. METHODS: Clinicopathological and follow-up data of stage II( colon cancer patients undergoing radical surgery from January 2001 to March 2012 at Gastrointestinal Cancer Center of Peking University Cancer Hospital were retrospectively analyzed. The effect of adjuvant chemotherapy (within postoperative 2 month, fluorine uracil as main drugs) on the prognosis of high-risk patients was analyzed. High risk factors were defined as having at least one of the following factors: (1) tumor stage T4; (2) poor differentiation; (3) with vascular cancer embolus; (4) number of harvested lymph node less than 12; (5) complicated with obstruction or perforation. RESULTS: A total of 497 patients with stage II( colon cancer were included in this study, of whom 258 cases(51.9%) had high risk factors, including stage T4 tumor in 80 cases(16.1%), poor differentiation in 80 cases (16.1%), cancer embolus in 37 cases (7.4%), lymph node harvested number less than 12 in 88 cases (17.7%), and obstruction or perforation in 85 cases (17.1%). Among 497 patients, number of cases with 1 to 4 high risk factors was 170 (34.2%), 68 (13.7%), 16 (3.2%) and 4 (0.8%), respectively. The last follow-up time was December 2016. The 5-year overall survival rate of all the 497 patients was 81.7%. The 5-year overall survival rate of 239 patients without high risk factors was 87.0%. The 5-year survival rate in patients with 1 to 4 risk factors was 81.9%, 73.7%, 66.7% and 25.0%, respectively (P=0.001). There was no significant difference in 5-year survival rate between 103 patients with adjuvant chemotherapy and 394 patients without adjuvant chemotherapy (79.6% vs. 82.8%, P=0.814). In patients with high risk factors, 80(31.0%) received adjuvant chemotherapy. There was no significant difference of 5-year survival rate between 80 patients with adjuvant chemotherapy and 178 patients without adjuvant chemotherapy (81.4% vs. 74.7%, P=0.147). Multivariate analysis showed that preoperative CEA level, T4 stage, lymph node harvested number, and tumor differentiation were the independent prognostic factors of patients with stage II( colon cancer (all P<0.05). CONCLUSIONS: The proportion of patients with at least one risk factor is quite high in stage II( colon cancer cases. Adjuvant chemotherapy can not prolong the overall survival time of high risk patients. PMID- 29280122 TI - [Establishment of nomogram model to predict peritoneal metastasis in colon cancer patients without distant metastasis by preoperative imaging examination]. AB - OBJECTIVE: To establish a nomogram model to predict the peritoneal metastasis in colon cancer patients without distant metastasis by preoperative imaging examination. METHODS: Clinicopathological data of colon cancer patients without distant metastasis by preoperative imaging examination who underwent surgery in our department between January 2000 and December 2014 were retrospectively analyzed. Predictors of peritoneal carcinomatosis were analyzed by univariate and Logistic multivariate analyses. Base on the independent predictors by multivariable analysis results, a nomogram model was formulated with further use of R software. The total score was calculated by the addition of each predictor score, indicating the corresponding risk of peritoneal metastasis. The score was greater in the nomogram, and the risk was higher in peritoneal implantation metastasis. A receiver operating characteristic(ROC) curve was then constructed to evaluate the predictive abilities of the various preoperative factors and nomogram. RESULTS: A total of 1 417 patients were defined as above and enrolled in the study. The median age was (60.5+/-13.3) years, 835 cases (58.9%) were male, and 132 cases (9.3%, 132/1417) were diagnosed with synchronous peritoneal carcinomatosis during operation. Univariate analysis showed that peritoneal metastasis was associated with age, incidence of abdominal pain, incidence of mucous bloody stool, CEA level, traversible rate, tumor diameter, ratio of infiltrating type cancer, differentiation, histological type, cT staging and cN staging (all P<0.05). Logistic multivariate analysis revealed that younger age (OR:0.974, 95%CI: 0.958 to 0.990, P=0.001), later clinical T stage (OR: 2.949, 95%CI: 1.588 to 5.476, P=0.001), lesion not traversible(OR: 0.519, 95%CI: 0.314 to 0.858, P=0.011), infiltrative gross type (OR: 1.812, 95%CI: 1.099 to 2.987, P=0.020), larger tumor (OR: 1.044, 95%CI: 0.998 to 1.093, P=0.061), higher preoperative serum CEA level(OR:1.004,95%CI: 1.001 to 1.007, P=0.007) and histopathologic type of mucinous or signet ring cell adenocarcinoma (OR:1.642, 95%CI: 1.009 to 2.673, P=0.046) were independent risk factors. The nomogram model was further established based on above 7 independent risk factors, whose total score was 350 and area under the ROC curve was 0.753(P=0.000). CONCLUSION: The nomogram model can be helpful to screen the colon cancer patients with high risk of peritoneal metastasis and to avoid unnecessary laparotomy for colon cancer patients without distant metastasis by preoperative imaging examination. PMID- 29280123 TI - [Complications analysis of subcutaneous venous access port for chemotherapy in patients with gastrointestinal malignancy]. AB - OBJECTIVE: To describe and analyze the complications of subcutaneous venous access port for patients with gastrointestinal malignancy. METHODS: Data of 1 912 patients with gastrointestinal malignancy who accepted chemotherapy in our department via subcutaneous venous access ports, including 127 cases in upper arm, 865 cases in subclavicular vein and 920 cases in internal jugular vein, from June 2007 to April 2016 were analyzed retrospectively. Associated complications and risk factors were emphatically investigated. RESULTS: Postoperative complications were confirmed in 233 patients(12.2%), and complication morbidity was 37.0%(47/127), 15.5%(134/865), 6.7%(62/920) in upper arm group, subclavicular vein group, internal jugular vein group respectively, whose difference was statistically significant (chi2=71.060, P=0.000). Sixty-one(3.2%) patients developed early complications (in the day of insertion, including catheter dislocation, pneumothorax, arterial damage). Early complication morbidity of upper arm group (14.2%, 18/127) was higher as compared to subclavicular vein group (3.4%, 29/865) and internal jugular vein group(1.5%, 14/920) with significant difference (chi2=57.867, P=0.000). Postoperative long-term complications (catheter dislocation, thrombosis, pinch-off syndrome, infusion base exposure, catheter detachment) were found in 182(9.5%) patients. Morbidity of long-term complication was 5.2%(48/920) in internal jugular vein group, which was significantly lower than 22.8% (29/127) in upper arm group and 12.1% (105/865) in subclavicular vein group with statistically significant difference (chi2=50.828, P=0.000). Multivariate analysis indicated that subclavicular vein intubation (OR=0.536, 95%CI: 0.341 to 0.843; P=0.007 OR=0.156, 95%CI: 0.096 to 0.253, P=0.000), internal jugular vein intubation (OR=0.156, 95%CI: 0.096 to 0.253, P=0.000), operation time <40 minutes (OR=0.458, 95%CI: 0.342 to 0.613, P=0.000) and standardized training (OR=0.233,95%CI: 0.171 to 0.318, P=0.000) were protective factors of postoperative complication; besides, subclavicular vein intubation (OR=0.458, 95%CI: 0.342 to 0.613, P=0.000), internal jugular vein intubation (OR=0.233, 95%CI: 0.171 to 0.318, P=0.000) and standardized training (OR=0.313, 95%CI: 0.173 to 0.568, P=0.000) were protective factors of thrombosis. CONCLUSIONS: Subcutaneous venous access port implantation is a preferable access to central vein. Appropriate intubation approach and standardized training may reduce postoperative complications effectively. Internal jugular vein approach is safer and more reliable than upper arm vein and subclavian vein approach. PMID- 29280124 TI - [Efficacy analysis of endoscopic therapy for early colorectal carcinoma: a retrospective study of 113 cases]. AB - OBJECTIVE: To analyze the clinical efficacy of endoscopic therapy for early colorectal cancer. METHODS: Clinical data of 113 early colorectal mucosal carcinoma or submucosal carcinoma receiving endoscopic therapy were retrospectively analyzed and compared with 39 early colorectal cancer cases receiving surgery during the same time. RESULTS: All the cases were well moderately differentiated adenocarcinoma. Size of tumors in endoscopic group was (26.2+/-21.5) mm, and that was (30.9+/-24.3) mm in surgery group (P=0.257). Baseline data between the two groups were not significantly different (all P>0.05). Significantly shorter median operating time [15.0 minutes vs. 203.0 minutes, chi2=69.322, P=0.000] and median hospital stay [3.0 days vs. 17.0 days, chi2=76.180, P=0.000] were observed in endoscopic group compared with surgery group. The en bloc resection rate, curative resection rate, lymph node metastatic rate and complication rate were not significantly different between two groups (all P>0.05). Ten patients in endoscopic group were referred to additional surgery for deep invasion and/or incomplete resection, of whom 7 received radical surgery, and the other 3 cases without radical surgery did not develop recurrence during follow-up of (20.5+/-0.9) months. After follow-up for (17.5+/-15.8) months, the local recurrence rate was 5.3% (6/113) in endoscopic group and 0 (0/39) in surgery group without significant difference (chi2=0.983, P=0.321). There was no significant difference in 5-year tumor-free survival rate between two groups (91.8% vs. 97.0%, chi2=1.533, P=0.216). CONCLUSION: Endoscopic therapy possesses shorter operating time, shorter hospital stay and similar efficacy as compared to surgery in the treatment of early colorectal cancer. PMID- 29280125 TI - [Pediatric colonoscopy in South China: a single-center experience from 229 cases]. AB - OBJECTIVE: To investigate the safety, feasibility, clinical value, indication, and distribution of diagnostic diseases in different age groups of colonoscopy in pediatric patients. METHODS: A retrospective analysis was performed on the data of pediatric patients receiving colonoscopy from April 2013 to June 2016 at The Sixth Affiliated Hospital of Sun Yat-sen University. Pediatric patients were divided into 0-6 years group (n=57) and 7-14 years group (n=172). Indication for colonoscopy, detective events and diagnostic diseases distribution were compared between two groups. RESULTS: A total of 229 pediatric patients (male 157 and female 72) were divided into 0-6 years group (57/229, 24.9%) and 7-14 years group(172/229, 75.1%). The main Indications for colonoscopy included abdominal pain (81/229, 35.4%), hematochezia (64/229, 27.9%), crissum abscess or fistula (40/229, 17.5%). Hematochezia was the most common complaint in 0-6 years group (40/57, 70.2%), while abdominal pain in 7-14 years group (74/172, 43.0%). Completion rate between 0-6 years group and 7-14 years group was not significantly different (87.72% vs. 85.47%, chi2=0.181, P=0.671). Only one pediatric patient (1/229, 0.4%) developed transient oxygen desaturation and recovered quickly after oxygen supply and aspiration of sputum. No serious complications such as bleeding, perforation or death occurred. Including 45 pediatric patients in 0-6 years group and 102 pediatric patients in 7-14 years group, a total of 147 pediatric patients (147/229, 64.2%) were found to have colorectal lesions. Inflammatory bowel disease (57/147, 38.8%), colonic polyps (40/147, 27.2%) and other intestinal inflammation (39/147, 26.5%) were the main findings. The most frequent diagnosis in 0-6 years group was colonic polyps (28/57, 49.1%), among them, 25 pediatric patients (25/28, 89.3%) were with the complaint of hematochezia. The most frequent diagnosis in 7-14 years group was Inflammatory bowel disease (54/172, 31.4%), among them, 29 pediatric patients (29/54, 53.7%) were with the complaint of abdominal pain. CONCLUSIONS: Pediatric colonoscopy is safe and effective. Hematochezia and abdominal pain are the most common complaints in 0-6 years group and 7-14 years group respectively. Colonic polyps and inflammatory bowel disease are the most frequent diagnosis in 0-6 years group and 7-14 years group respectively. PMID- 29280126 TI - [Association of serum miRNA6086 expression with postoperative anal fistula recurrence]. AB - OBJECTIVE: To investigate the association between serum miRNA-6086 expression level and anal fistula recurrence. METHODS: Clinical data and serum samples of 60 patients with anal fistula and mix hemorrhoid identified by pathology undergoing resection in our department from August 2015 to August 2016 were collected. In addition, serum samples of 20 patients matching with fistula group in age, gender and body weight and receiving only hemorroidectomy were collected as control during the same period. Serum miRNA6086 expression level was detected by real time quantitative RT-PCR method, and the association of serum miRNA6086 expression level with clinicopathologic features was analyzed. Univariate ANOVA test and multivariate logistic regression analysis were performed to analyze the association between serum miRNA6086 expression level and anal fistula recurrence. RESULTS: The relative expression of serum miRNA6086 in fistula group was 65.85+/ 15.57, which was significantly up-regulated for 4.87 folds of 13.52+/-7.32 in control group(P<0.05). In fistula group, 24 cases(40%) developed anal fistula recurrence, whose serum miRNA6086 expression was significantly higher compared to 36 cases without recurrence (74.06+/-12.92 vs. 60.38+/-14.90, P<0.05). No associations of serum miRNA6086 expression with age, gender, BMI, drug history, acute phase were observed (P>0.05), while association of serum miRNA6086 expression level with the type, number and position of anal fistula was significant (all P<0.05). Univariated analysis indicated that anal fistula type (chi2=6.890, P=0.009), anal fistula number (chi2=0.554, P<0.001) and serum miRNA6086 expression (chi2=11.390, P=0.001) were significantly associated with anal fistula recurrence. Multivariate logistic regression analysis showed that complex anal fistula (OR=4.75, 95%CI: 1.84 to 12.01, P=0.001) and high expression of serum miRNA6086 (OR=3.22, 95%CI:1.31 to 8.22, P=0.011) were independent risk factors of anal fistula recurrence. CONCLUSION: Up-regulated expression of serum miRNA6086 is associated to the anal fistula type and may be valuable in predicting the prognosis. PMID- 29280127 TI - [Three methods for controlling presacral massive bleeding during pelvic operations]. AB - OBJECTIVE: To evaluate three different methods for controlling presacral massive bleeding during pelvic operations. METHODS: Clinical data of 11 patients with presacral massive bleeding during pelvic operation at The Sixth Affiliated Hospital of Sun Yat-sen University and 157 Branch Hospital of Guangzhou General Hospital of Guangzhou Military Command from January 2001 to January 2016 were analyzed retrospectively. Hemostasis methods for presacral massive bleeding during operation included gauze packing (whole pressure), drawing pin (local pressure) and absorbable gauze (absorbable gauze was adhered to bleeding position with medical glue after local pressure). Efficacy of these 3 methods for controlling bleeding was evaluated and compared. RESULTS: Ten patients were male and 1 was female with average age of 65.2 (40 to 79) years old. Eight cases were rectal cancer, 2 were presacral malignancies and 1 was rectal benign lesion. Bleeding volume during operation was 300 to 2 500 (median 800) ml. From 2001 to 2012, 4 cases received gauze packing, of whom, 3 cases were scheduled Dixon resection before operation and then had to be referred to Hartman resection; 3 cases died of systemic failure due to postoperative chronic errhysis and infection, and 1 underwent re-operation. At the same time from 2001 to 2012, 5 cases received drawing pin, of whom, bleeding of 3 cases was successfully controlled and Dixon resection was completed. In other 2 cases with hemostasis failure, 1 case underwent re-operation following the use of gauze packing, and another 1 case received absorbable gauze hemostasis. All the 5 patients were healing. From 2013 to 2016, 2 cases completed scheduled anterior resection of rectum after successful hemostasis with absorbable gauze and were healing and discharged. CONCLUSIONS: Gauze packing hemostasis is a basic method for controlling presacral massive bleeding. Drawing pin and absorbable gauze hemostasis are more precise and may avoid the change of surgical procedure. But drawing pin has the possibility of hemostasis failure. Absorbable gauze hemostasis with medical adhesive is effective, simple and fast. PMID- 29280128 TI - [Meta-analysis of sacral nerve stimulation for fecal incontinence]. AB - OBJECTIVE: To evaluate the efficacy of sacral nerve stimulation (SNS) therapy for fecal incontinence. METHODS: Clinical researches which evaluated the efficacy of SNS and were published between 1946 and 2016 were systematically searched from electronic databases, including PubMed, Ovid Medline, Web of Science, Wanfang database and Chinese Journal Full-text Database. Grey area literatures were also searched. Influence of SNS therapy on fecal incontinence episodes (FIE) or Wexner incontinence score (WIS) was systematically evaluated. The statistical analysis was performed by RevMan5.2. RESULTS: A total of 6 studies including 270 patients (147 patients in SNS group and 123 patients in control group) with fecal incontinence were enrolled in this systematic review. SNS therapy was associated with a significant reduction in FIE (SMD=-0.69, 95%CI: -0.97 to -0.41, P<0.001) and a significant reduction in WIS (SMD=-5.05, 95%CI: -8.73 to -1.36, P=0.007). Sensitivity analysis showed that the results of this study were stable and the direction and significance of results were not changed (P=0.000 for both). Publication bias was not found by funnel picture in this study. CONCLUSION: SNS significantly improves the outcome of patients with fecal incontinence. PMID- 29280129 TI - [Preliminary discussion of therapeutic strategies in persistent inflammation immunosuppression catabolism syndrome]. AB - So far, there is still lack of effective treatment to control persistent inflammation immunosuppression catabolism syndrome (PICS) appeared generally in those chronic critical illnesses (CCI) patients, restricted by the development of medicine and scientific research nowadays. Because the uncontrolled PICS aggravates continuously, ICU stay of the CCI patients has been obviously prolonging and the late mortality elevates greatly. So exploring effective therapeutic strategies is obviously pressing. With the characteristics in PICS such as that elderly with sepsis or severe trauma tops the list of morbidity, progressing illness is difficult to intervent and various pathology changes occur simultaneously, the fundamental principle of treatment, "Focal screening, early control, joint intervention" must be followed. As for the specific intervention, lessoning from some diseases with immune and metabolic disorders to take "anabolic nutrition support", is a research focus presently as well as a considerably potential breakthrough at the treatment research in the future. This review retrospects a series of therapeutic strategies of PICS, such as immunity, metabolism regulation, nutrition support, glucose control and physiotherapy, in the purpose of laying the foundation of the development of joint intervention strategy for PICS. PMID- 29280130 TI - [Impact of postoperative pathological features of esophageal squamous cell carcinoma on the prognosis]. AB - Esophageal cancer is located in the 8th position of the incidence of malignant tumors and the 6th most common cause of cancer-related mortality in the world, while China has the highest incidence and mortality of esophageal cancer. Esophageal squamous cell carcinoma (ESCC), the predominant histologic type of esophageal cancer in China, accounts for about 90%. Despite recent improvement of surgical techniques and philosophy, however, the prognosis of ESCC patients treated with surgery is still poor, and 5-year survival remains unsatisfactorily low. So far, the pathogenesis of esophageal squamous cell carcinoma is still unclear, and effective prevention is also out of the question. To find the main factors affecting the prognosis of esophageal squamous cell carcinoma, and to improve the survival of patients, are the main directions of all scholars. Postoperative pathology of esophageal squamous cell carcinoma is considered to be one of the most important predictors of prognosis. Currently, the evaluation of postoperative esophageal prognosis mainly depends on TNM staging, but some criteria of its specific content and staging remains controversial. In this paper recent domestic and foreign related researches and clinical trials reports are collected, and the postoperative pathological features affecting esophageal squamous cell carcinoma prognosis were reviewed. PMID- 29280131 TI - Exploring performance of, and attitudes to, Stop- and Mock-Before-You-Block in preventing wrong-side blocks. AB - We conducted an online survey to assess the career experiences of wrong side blocks, the practice of Stop-Before-You-Block, the recently described method of Mock-Before-You-Block and attitudes to these. Respondents were 208 anaesthetists across nine hospitals (173 consultants or Staff and Associate Specialist doctors'), representing 3623 years of collective anaesthetic practice. There had been a total of 62 wrong side blocks (by 51 anaesthetists and one current trainee). Predisposing factors for this were commonly ascribed to distractions (35 (69%), for example due to rushing or teaching), patient positioning (9 (18%)) or miscommunication (6 (12%)). Two (4%) respondents felt they had performed Stop Before-You-Block too early; 62 (41%) of all respondents stated they performed Stop-Before-You-Block as early as preparing the skin or on arrival of the patient in the anaesthetic room, and not any later. Twenty (10%) respondents admitted to not performing Stop-Before-You-Block at all or only occasionally (including 5 (2%) who had performed a wrong side block). Mock-Before-You-Block was easily understood (by 169 out of 197 (86%)) and 14 out of 61 (23%) respondents felt it would have prevented the wrong side error in their case. However, free-text comments indicated that many anaesthetists were reluctant to use a method that interrupted their performance of the block. We conclude that considerable work is needed to achieve full compliance with Stop-Before-You-Block at the correct time. PMID- 29280132 TI - Segmentation of clustered cells in negative phase contrast images with integrated light intensity and cell shape information. AB - Automated cell segmentation plays a key role in characterisations of cell behaviours for both biology research and clinical practices. Currently, the segmentation of clustered cells still remains as a challenge and is the main reason for false segmentation. In this study, the emphasis was put on the segmentation of clustered cells in negative phase contrast images. A new method was proposed to combine both light intensity and cell shape information through the construction of grey-weighted distance transform (GWDT) within preliminarily segmented areas. With the constructed GWDT, the clustered cells can be detected and then separated with a modified region skeleton-based method. Moreover, a contour expansion operation was applied to get optimised detection of cell boundaries. In this paper, the working principle and detailed procedure of the proposed method are described, followed by the evaluation of the method on clustered cell segmentation. Results show that the proposed method achieves an improved performance in clustered cell segmentation compared with other methods, with 85.8% and 97.16% accuracy rate for clustered cells and all cells, respectively. PMID- 29280133 TI - Itching for answers: Prevalence and severity of pruritus in psoriasis. AB - BACKGROUND/OBJECTIVES: Pruritus is the most frequently reported complaint or symptom for psoriasis patients. Despite the morbidity associated with pruritus in psoriasis few studies have evaluated the prevalence of itch in psoriasis with the current use of biological agents. METHOD: This was a multi-site cross-sectional observational study conducted in New South Wales, Australia. Psoriasis patients were approached during their outpatient clinic, phototherapy or private consultations. Data on psoriasis characteristics, severity and treatment were collected. The patients were then asked to complete a survey regarding the frequency, severity and aggravators of their psoriasis. RESULTS: Data were collected from 179 patients with a mean age of 52.3 years, of whom 55% were male. Altogether 63 (35%) had a psoriasis area severity index (PASI) > 10, 42 (24%) were on biological agents and 84 (47%) were receiving phototherapy. The number of patients who reported itch all the time was 40 (22%), most of the time 48 (27%), and never 19 (11%). Patients with nail psoriasis were significantly less likely to have itch all or most of the time (P = 0.01). Itch all or most of the time was significantly more likely in patients with PASI > 10 (P = 0.013). No treatment was associated with reduced itch. Itch was reported to be most frequent in the winter season. CONCLUSION: Few patients with psoriasis do not suffer from pruritus. Despite their promise, biological agents are not associated with reduced itch. PMID- 29280134 TI - A retrospective pilot study to determine whether the reproductive tract microbiota differs between women with a history of infertility and fertile women. AB - BACKGROUND: We know very little about the microbiota inhabiting the upper female reproductive tract and how it impacts on fertility. AIMS: This pilot study aimed to examine the vaginal, cervical and endometrial microbiota for women with a history of infertility compared to women with a history of fertility. MATERIALS AND METHODS: Using a retrospective case-control study design, women were recruited for collection of vaginal, cervical and endometrial samples. The microbiota composition was analysed by 16S ribosomal RNA (rRNA) gene amplification and endometrial expression of selected human genes by quantitative reverse transcription polymerase chain reaction. RESULTS: Sixty-five specimens from the reproductive tract of 31 women were successfully analysed using 16S rRNA gene amplicon sequencing (16 controls and 15 cases). The dominant microbial community members were consistent in the vagina and cervix, and generally consistent with the endometrium although the relative proportions varied. We detected three major microbiota clusters that did not group by tissue location or case-control status. There was a trend that infertile women more often had Ureaplasma in the vagina and Gardnerella in the cervix. Testing for the expression of selected genes in the endometrium did not show evidence of correlation with case-control status, or with microbial community composition, although Tenascin-C expression correlated with a history of miscarriage. CONCLUSIONS: There is a need for further exploration of the endometrial microbiota, and how the microbiota members or profile interplays with fertility or assisted reproductive technologies. PMID- 29280135 TI - Feasibility of the salivary transcriptome as a novel biomarker in determining disease susceptibility. AB - BACKGROUND AND OBJECTIVE: The salivary transcriptome may present as a readily available and non-invasive source of potential biomarkers. The development of chronic periodontitis is determined by individual patient susceptibility; hence, the aim of this study was to determine the potential of the salivary transcriptome as a biomarker of disease susceptibility using chronic periodontitis as an example. MATERIAL AND METHODS: Using an Oragene(r) RNA kit, the total RNA was purified from the saliva of 10 patients with chronic periodontitis and 10 patients without chronic periodontitis. The quantity and quality of the total RNA was determined, and a measure of gene expression via cDNA was undertaken using the Affymetrix microarray system. The microarray profiling result was further validated by real-time quantitative polymerase chain reaction. RESULTS: Spectrophotometric analysis showed the total RNA purified from each participant ranged from 0.92 MUg/500 MUL to 62.85 MUg/500 MUL. There was great variability in the quantity of total RNA obtained from the 2 groups in the study with a mean of 10.21 +/- 12.71 MUg/500 MUL for the periodontitis group and 15.97 +/- 23.47 MUg/500 MUL for the control group. Further the RNA purity (based on the A260 /A280 ratio) for the majority of participants (9 periodontitis and 6 controls) were within the acceptable limits for downstream analysis (2.0 +/- 0.1). The study samples, showed 2 distinct bands at 23S (3800 bp) and 16S (1500 bp) characteristic of bacterial rRNA. Preliminary microarray analysis was performed for 4 samples (P2, P6, H5 and H9). The percentage of genes present in each of the 4 samples was not consistent with about 1.8%-18.7% of genes being detected. Quantitative real-time polymerase chain reaction confirmed that the total RNA purified from each sample was mainly bacterial RNA (Uni 16S) with minimal human mRNA. CONCLUSION: This study showed that minimal amounts of human RNA were able to be isolated from the saliva of patients with periodontitis as well as controls. Further work is required to enhance the extraction process of human mRNA from saliva if the salivary transcriptome is to be used in determining individual patient susceptibility. PMID- 29280136 TI - The influence of tongue strength on oral viscosity discrimination acuity. AB - : The ability to generate tongue pressures is widely considered to be critical for liquid bolus propulsion in swallowing. It has been proposed that the application of tongue pressure may also serve the function of collecting sensory information regarding bolus viscosity (resistance to flow). In this study, we explored the impact of age-related reductions in tongue strength on oral viscosity discrimination acuity. The experiment employed a triangle test discrimination protocol with an array of xanthan-gum thickened liquids in the mildly to moderately thick consistency range. A sample of 346 healthy volunteers was recruited, with age ranging from 12 to 86 (164 men, 182 women). On average, participants were able to detect a 0.29-fold increase in xanthan-gum concentration, corresponding to a 0.5-fold increase in viscosity at 50/s. Despite having significantly reduced tongue strength on maximum isometric tongue-palate pressure tasks, and regardless of sex, older participants in this study showed no reductions in viscosity discrimination acuity. PRACTICAL APPLICATIONS: In this article, the relationship between tongue strength and the ability to discriminate small differences in liquid viscosity during oral processing is explored. Given that tongue strength declines with age in healthy adults and is also reduced in individuals with dysphagia, it is interesting to determine whether reduced tongue strength might contribute to difficulties in evaluating liquid viscosity during the oral stage of swallowing. Using an array of mildly to moderately thick xanthan-gum thickened liquids, this experiment failed to find any evidence that reductions in tongue strength influence oral viscosity discrimination acuity. PMID- 29280138 TI - Vaccination protects against invasive HPV-associated cancers. PMID- 29280139 TI - Mycosis fungoides occurring at the site of previous herpes zoster eruption. AB - Numerous clinicopathological variants of mycosis fungoides have been described in the literature. Dermatomal or zosteriform mycosis fungoides is one reported variant but a clear aetiology has never been documented. We report a case of mycosis fungoides proved by biopsy and immunohistochemistry that developed in a 55-year-old man at the site of previous herpes zoster eruption. We also present a review of the relevant literature to add to the understanding of rare variants of mycosis fungoides and aid in the clinical recognition of zosteriform mycosis fungoides. PMID- 29280137 TI - Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype Guided Antiplatelet Therapy. AB - CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. PMID- 29280140 TI - PKCepsilon promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis. AB - PKCepsilon is implicated in T cell activation and proliferation and is overexpressed in CD4+ -T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCepsilon takes part in autoimmunity, its role in the molecular pathophysiology of immune-mediated disorders is still largely unknown. We studied PKCepsilon expression in circulating CD4+ -T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4+ subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCepsilon is overexpressed in CD4+ -T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCepsilon interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCepsilon is forcibly downregulated, CD4+ -T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17-lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCepsilon as a potential target in Th17-mediated diseases. PMID- 29280141 TI - Out Drinking the Joneses: Neighborhood Factors Moderating the Effects of Drinking on Relationship Quality over the First Four Years of Marriage. AB - Neighborhood quality has been cross-sectionally linked to both relationship behaviors and relationship well-being. Consistent with the Vulnerability Stress Adaptation model of relationship functioning (Karney & Bradbury, 1995), we hypothesized that associations between social behaviors (e.g., drinking) and relationship quality could be moderated by neighborhood factors. Specifically, we characterized neighborhoods along multiple dimensions using multiple methods (self-report, census) to investigate how neighborhood factors might clarify ambiguous effects of alcohol use on marital functioning. A nationally recruited sample of 303 newlywed couples completed a baseline assessment around the time of marriage and was then assessed yearly across the first 4 years of marriage (94% retention). Three level HLM slope-intercept models were used to model changes in relationship satisfaction across the first 4 years of marriage. Results suggested that, for couples living in highly disordered neighborhoods, positive shifts in overall levels of drinking within specific waves of assessment were associated with corresponding negative shifts in satisfaction whereas in neighborhoods without perceived disorder, this effect was reversed. For couples living in neighborhoods with low levels of domestic structures (high census rates of single renters without children), within-couple discrepancies favoring higher rates of husband drinking in specific waves predicted poorer relationship quality for both partners in those same waves whereas those same discrepancies predicted higher satisfaction in high domesticity neighborhoods (high census rates of married homeowners with children). The findings provide insight into the different roles of alcohol use in relationship maintenance and highlight the importance of using external context to understand intradyadic processes. PMID- 29280142 TI - Definitions of anaesthetic technique and the implications for clinical research. PMID- 29280144 TI - Working out wrong-side blocks. PMID- 29280143 TI - Immunostimulatory effect of pepsin enzymatic extract from Porphyra yezoensis on murine splenocytes. AB - BACKGROUND: Porphyra yezoensis is a red alga consumed mainly in Korea, Japan, and China for food. This study researches the immunological effect of pepsin extract of P. yezoensis (PPEE) on murine splenocytes. RESULTS: PPEE was not toxic on murine splenocytes and dramatically increased the proliferation of splenocytes compared with untreated control. Flow cytometry assay performed to sum up the effect of PPEE (31.3 and 62.5 ug mL-1 ) on major immune cells revealed that PPEE had no effect on the function of CD3e+ CD4+ T-helper cells, CD3e+ CD8+ T cytotoxic cells, or CD44+ CD62L- effector T cells in splenocytes compared with untreated control. More importantly, CD45+ CD11b+ macrophage and dendritic cell populations and Ly-6C+ Ly-6G+ macrophages/monocytes in splenocytes were activated by PPEE treatment compared with untreated control. Further experiments showed that PPEE treatment increased the secretion of macrophage-derived cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and interleukin-12, and macrophage-activating cytokines interferon-gamma and interleukin-10 compared with untreated control. CONCLUSION: Taken together, these results suggest that PPEE has an immune stimulatory effect on macrophages, dendritic cells, and memory T cells. This property signifies the potential medicinal value of PPEE in clinical implications for immune-compromised diseases. (c) 2017 Society of Chemical Industry. PMID- 29280145 TI - Comparative analysis of volatile compound profiles of propolis from different provenances. AB - BACKGROUND: Propolis is a complex mixture that honey bees produce from the exudates of various plants and presents many medicinal properties. Its chemical composition varies according to the phytogeography characteristics of each region, among others. The aim of this study was to identify and characterize the volatile organic compounds (VOCs) present in Venezuelan propolis and compare with reference samples such as Brazilian and Argentinian propolis. RESULTS: A total of 90 VOCs were identified in a series of propolis samples using both solid-phase microextraction and dynamic headspace (DHS), both coupled to a gas chromatograph electron ionization mass spectrometer. In the case of Venezuelan propolis, sesquiterpenes, esters, aromatic compounds, and aliphatic hydrocarbons were identified. Limonene was found only in Venezuelan samples, this being the first time it has been identified in samples from this country. In the case of green propolis, beta-caryophyllene and nerolidol were the major compounds. As for the Argentinian samples, prenyl acetate, benzyl acetate, and 2-phenylethyl acetate were detected only in these samples. CONCLUSIONS: Possible chemical markers of natural sources such as limonene were detected using DHS extraction. Several compounds have also been identified for the first time in Venezuelan propolis. Cluster analysis allowed the relating of the propolis VOCs profile to their provenance. (c) 2017 Society of Chemical Industry. PMID- 29280147 TI - The origins of the circumventricular organs. AB - The circumventricular organs (CVOs) are specialised neuroepithelial structures found in the midline of the brain, grouped around the third and fourth ventricles. They mediate the communication between the brain and the periphery by performing sensory and secretory roles, facilitated by increased vascularisation and the absence of a blood-brain barrier. Surprisingly little is known about the origins of the CVOs (both developmental and evolutionary), but their functional and organisational similarities raise the question of the extent of their relationship. Here, I review our current knowledge of the embryonic development of the seven major CVOs (area postrema, median eminence, neurohypophysis, organum vasculosum of the lamina terminalis, pineal organ, subcommissural organ, subfornical organ) in embryos of different vertebrate species. Although there are conspicuous similarities between subsets of CVOs, no unifying feature characteristic of their development has been identified. Cross-species comparisons suggest that CVOs also display a high degree of evolutionary flexibility. Thus, the term 'CVO' is merely a functional definition, and features shared by multiple CVOs may be the result of homoplasy rather than ontogenetic or phylogenetic relationships. PMID- 29280146 TI - Volatile changes in Hawaiian noni fruit, Morinda citrifolia L., during ripening and fermentation. AB - BACKGROUND: Noni fruit (Morinda citrifolia L., Rubiaceae) has been used in traditional medicine throughout the tropics and subtropics and is now attracting interest in western medicine. Fermented noni juice is of particular interest for its promising antitumor activity. The present study collected and analyzed volatiles released at nine time intervals by noni fruit during ripening and fermentation using headspace autosampling coupled to gas chromatography-mass spectrometry. RESULTS: Twenty-three noni volatiles were identified and relatively quantified. In addition to volatiles previously identified in noni, four novel volatile 3-methyl-2/3-butenyl esters were identified via the synthesis of reference compounds. Principle component analysis (PCA) and canonical discriminant analysis (CDA) were used to facilitate multidimensional pattern recognition. PCA showed that ripening noni fruit cluster into three groups, pre ripe, fully ripe (translucent) and fermented, based on released volatiles. CDA could 83.8% correctly classify noni samples when all ripeness stages were analyzed and 100% when samples were classified into the three PCA groupings. CONCLUSION: The results of the present study confirm the identities of 3-methyl 2/3-butenyl esters, both novel and previously identified, through the synthesis of reference compounds. These esters constitute a large percentage of the volatiles released by fully ripe and fermented noni and likely produced from the decomposition of noniosides, a group of unique glucosides present in the fruit. (c) 2017 Society of Chemical Industry. PMID- 29280148 TI - Bioactive hydrolysates from casein: generation, identification, and in silico toxicity and allergenicity prediction of peptides. AB - BACKGROUND: Bioactive casein peptides have attracted considerable attention for their applications in industry. However, there is little clarity regarding mass spectrometric profiles for peptides in enzymatic hydrolysates of casein produced under varying conditions. In this study, the compositions of the peptides from casein hydrolysates were compared for different enzyme/substrate ratio (E/S) and hydrolysis times. The toxicity, allergenicity and bioactivity of the identified peptides were assessed in silico. RESULTS: A total of 70 unique peptides were identified, and there were 28, 21, 13 and 8 peptides from alphas1 -casein, alphas2 -casein, beta-casein and kappa-casein respectively. The peptide number decreased with the increase in E/S and hydrolysis time. Moreover, peptides with relative molecular mass Mr ranging from 1000 to 1500 Da occupied the highest proportion of 31.43%, and almost all of the peptides showed Mr less than 5000 Da. In silico analysis showed that all of the peptides were non-toxic and non allergenic, and several of them were assessed by PeptideRanker as having a relatively high likelihood of being bioactive peptides. CONCLUSIONS: Composition of the peptides in the casein hydrolysates varied with the enzymolysis conditions. This study's results may facilitate the production of target bioactive peptides by controlling E/S and hydrolysis time, which is beneficial for the application of casein peptides in the functional food industry. (c) 2017 Society of Chemical Industry. PMID- 29280149 TI - A phylogenetic comparative method for evaluating trait coevolution across two phylogenies for sets of interacting species. AB - Evaluating trait correlations across species within a lineage via phylogenetic regression is fundamental to comparative evolutionary biology, but when traits of interest are derived from two sets of lineages that coevolve with one another, methods for evaluating such patterns in a dual-phylogenetic context remain underdeveloped. Here, we extend multivariate permutation-based phylogenetic regression to evaluate trait correlations in two sets of interacting species while accounting for their respective phylogenies. This extension is appropriate for both univariate and multivariate response data, and may use one or more independent variables, including environmental covariates. Imperfect correspondence between species in the interacting lineages can also be accommodated, such as when species in one lineage associate with multiple species in the other, or when there are unmatched taxa in one or both lineages. For both univariate and multivariate data, the method displays appropriate type I error, and statistical power increases with the strength of the trait covariation and the number of species in the phylogeny. These properties are retained even when there is not a 1:1 correspondence between lineages. Finally, we demonstrate the approach by evaluating the evolutionary correlation between traits in fig species and traits in their agaonid wasp pollinators. R computer code is provided. PMID- 29280150 TI - Shelf-life dating of shelf-stable strawberry juice based on survival analysis of consumer acceptance information. AB - BACKGROUND: Accurate shelf-life dating of food products is crucial for consumers and industries. Therefore, in this study we applied a science-based approach for shelf-life assessment, including accelerated shelf-life testing (ASLT), acceptability testing and the screening of analytical attributes for fast shelf life predictions. Shelf-stable strawberry juice was selected as a case study. RESULTS: Ambient storage (20 degrees C) had no effect on the aroma-based acceptance of strawberry juice. The colour-based acceptability decreased during storage under ambient and accelerated (28-42 degrees C) conditions. The application of survival analysis showed that the colour-based shelf-life was reached in the early stages of storage (<=11 weeks) and that the shelf-life was shortened at higher temperatures. None of the selected attributes (a* and DeltaE* value, anthocyanin and ascorbic acid content) is an ideal analytical marker for shelf-life predictions in the investigated temperature range (20-42 degrees C). Nevertheless, an overall analytical cut-off value over the whole temperature range can be selected. CONCLUSIONS: Colour changes of strawberry juice during storage are shelf-life limiting. Combining ASLT with acceptability testing allowed to gain faster insight into the change in colour-based acceptability and to perform shelf-life predictions relying on scientific data. An analytical marker is a convenient tool for shelf-life predictions in the context of ASLT. (c) 2017 Society of Chemical Industry. PMID- 29280151 TI - Review of pentosidine and pyrraline in food and chemical models: formation, potential risks and determination. AB - Pyrraline and pentosidine are advanced Maillard reaction products derived from the reaction of glucose with the lysine amino group on proteins. They have been implicated in uremia, diabetes, and related complications, including inflammation, retinopathy, and nephropathy. This review focuses on the formation mechanism, human potential risks, and detections of pentosidine and pyrraline and lays the foundation for further study of pentosidine and pyrraline. (c) 2017 Society of Chemical Industry. PMID- 29280152 TI - Silent KEL alleles identified from Japanese individuals with the Ko phenotype. AB - BACKGROUND AND OBJECTIVE: The rare Ko phenotype lacks all 36 antigens in the Kell blood system. The molecular basis of the Ko phenotype has been investigated, and more than 40 silent KEL alleles are reported by many investigators. The majority of silent alleles are the KEL*02 background. Here, we report molecular genetic analysis of the KEL gene in Japanese individuals with the Ko phenotype. MATERIALS AND METHODS: The Ko phenotype was screened from Japanese blood donors for several years using monoclonal anti-Ku or anti-K14 by an automated blood grouping system PK7300. Kell-related antigens were typed by standard tube tests. Genomic DNA was extracted from the blood samples, and KEL gene was analysed by polymerase chain reaction (PCR) and Sanger sequencing. RESULTS: We collected 35 Ko blood samples with K-k-, Kp(a-b-), Js(a-b-) and K14-. PCR and sequence analysis revealed that 11 individuals were homozygous for a mutant KEL allele with a c.299G>C (p.Cys100Ser) mutation (rs. 200268316). Three individuals were homozygous for the KEL*02N.24 allele that is c.715G>T (p.Glu239*), and one individual was homozygous for the KEL*02N.40 allele that is c.1474C>T (p.Arg492*). Five individuals were homozygous for novel KEL alleles with single-nucleotide mutations, four individuals had a c.2175delC (p.Pro725 fs*43), and one individual had a c.328delA (p.Arg110 fs*79). The remaining 15 individuals were compound heterozygous, and eight new alleles were identified from them. CONCLUSIONS: We identified three known and ten new silent KEL alleles from Japanese individuals with the Ko phenotype. The KEL allele with the c.299G>C (p.Cys100Ser) mutation was the most frequent. PMID- 29280153 TI - Methods for identification and differentiation of different Shewanella spp. isolates for diagnostic use. AB - Shewanella spp. are Gram-negative, rod-shaped, motile bacteria that are widely distributed in marine and freshwater environments. The bacteria are present in the physiological microflora of fish from temperate waters and are known as fish spoilage species. From clinically healthy fish and from fish with skin ulcerations, Shewanella spp. is regularly isolated, indicating a possible role as fish pathogen. In this study, 74 isolates of Shewanella spp. were analysed. For species identification, biochemical techniques, 16S rRNA sequencing, MALDI-TOF MS and the Sherlock Microbial Identification System (MIS) based on the composition of fatty acid ethyl esters were compared. The phylogenetic relationship, cytotoxicity in vitro and resistance against antibiotics were tested. The most reliable method for species identification was 16S rRNA sequencing. From diseased fish, clinically healthy fish and the aquatic environment, different Shewanella species were isolated. This indicates that Shewanella spp. is widespread in the aquatic milieu and acts as a secondary pathogen. The virulence of Shewanella spp. is probably not depending on the species but on the isolate itself. Many isolates of Shewanella spp. were showing multiresistances against antibiotic substances, especially in samples derived from retailers and in routine diagnostics, all Shewanella spp. should therefore be tested for resistances against antibiotic agents. PMID- 29280154 TI - Performance of range-separated hybrid exchange-correlation functionals for the calculation of magnetic exchange coupling constants of organic diradicals. AB - The prediction of magnetic behavior is important for the design of new magnetic materials. Kohn-Sham density functional theory is popular for this purpose, although one should be careful about choosing the right exchange-correlation functional. Here, we perform a statistical analysis to test different range separated hybrid density functionals for the calculation of magnetic exchange coupling constants J of fourteen organic diradicals. Our analysis suggests that in absolute terms the MN12SX functional performs best among the series of twelve functionals studied here (including the popular B3LYP), followed by N12SX functionals along with Scuseria's HSE series of functionals. LC- omegaPBE was found to be the least accurate, which is in contrast with its good performance for calculating J for transition metal complexes. The HSE family of functionals and B3LYP are the only functionals to reproduce the qualitative trends of the coupling constants correctly for the ferromagnetically coupled diradicals under study. (c) 2017 Wiley Periodicals, Inc. PMID- 29280155 TI - Nanosecond pulsed electric field incorporation technique to predict molecular mechanisms of teratogenicity and developmental toxicity of estradiol-17beta on medaka embryos. AB - Herein, we propose using a nanosecond pulsed electric field (nsPEF) technique to assess teratogenicity and embryonic developmental toxicity of estradiol-17beta (E2 ) and predict the molecular mechanisms of teratogenicity and embryonic developmental defects caused by E2 on medaka (Oryzias latipes). The 5 hour post fertilization embryos were exposed to co-treatment with 10 MUm E2 and nsPEF for 2 hours and then continuously cultured under non-E2 and nsPEF conditions until hatching. Results documented that the time to hatching of embryos was significantly delayed in comparison to the control group and that typical abnormal embryo development, such as the delay of blood vessel formation, was observed. For DNA microarray analysis, 6 day post-fertilization embryos that had been continuously cultured under the non-E2 and nsPEF condition after 2 hour co treatments were used. DNA microarray analysis identified 542 upregulated genes and one downregulated gene in the 6 day post-fertilization embryos. Furthermore, bioinformatic analyses using differentially expressed genes revealed that E2 exposure affected various gene ontology terms, such as response to hormone stimulus. The network analysis also documented that the estrogen receptor alpha in the mitogen-activated protein kinase signaling pathway may be involved in regulating several transcription factors, such as FOX, AKT1 and epidermal growth factor receptor. These results suggest that our nsPEF technique is a powerful tool for assessing teratogenicity and embryonic developmental toxicity of E2 and predict their molecular mechanisms in medaka embryos. PMID- 29280156 TI - The Many Roles of Type II Phosphatidylinositol 4-Kinases in Membrane Trafficking: New Tricks for Old Dogs. AB - The type II phosphatidylinositol 4-kinases (PI4KIIs) produce the lipid phosphatidylinositol 4-phosphate (PtdIns4P) and participate in a confusing variety of membrane trafficking and signaling roles. This review argues that both historical and contemporary evidence supports the function of the PI4KIIs in numerous trafficking pathways, and that the key to understanding the enzymatic regulation is through membrane interaction and the intrinsic membrane environment. By summarizing new research and examining the trafficking roles of the PI4KIIs in the context of recently solved molecular structures, I highlight how mechanisms of PI4KII function and regulation are providing insights into the development of cancer and in neurological disease. I present an integrated view connecting the cell biology, molecular regulation, and roles in whole animal systems of these increasingly important proteins. PMID- 29280157 TI - Native Bovine and Porcine Pericardia Respond to Load With Additive Recruitment of Collagen Fibers. AB - Bovine and porcine pericardia are currently used for manufacturing prosthetic heart valves: their design has become an increasingly important area of investigation in parallel with progressively expanding indications for the transcutaneous approach to heart valves replacement. Before being cut and shaped, pericardial tissues are expected to be properly characterized. Actually, the mechanical assessment of these biomaterials lacks standardized protocols. In particular, the role of preconditioning for achieving a constant mechanical response of tissue samples is still controversial. In the present work, the mechanical response to uniaxial load of native bovine and porcine pericardia, with and without preconditioning was assessed; moreover, the mechanical behavior of pericardia was investigated and explained. It was demonstrated that: (i) pericardial tissue samples hold memory of the loading history but just within the extent of the deformation applied; (ii) the behavior of native bovine and porcine pericardia in response to load is explained by a mechanism based on the additive recruitment of collagen fibers; (iii) the current concept that plasticity is absent in pericardium has to be at least in part reconsidered. PMID- 29280158 TI - pyEFP: Automatic decomposition of the complex molecular systems into rigid polarizable fragments. AB - We present an open source tool able to describe intermolecular electrostatic interactions within the framework of the effective fragment potential (EFP) method. Complex molecular structure is subdivided into compact rigid fragments and parameters of their interactions are obtained from ab initio calculations. Automatic procedure allows for searching of these parameters into the existing database and merge new fragments into it. A set of standard fragments useful for the studies of organic semiconductors is also provided. Input files both for purely EFP and hybrid QM/MM calculations can be generated. The program is written in python and freely available on GitHub: https://github.com/ale-odinokov/pyEFP (c) 2017 Wiley Periodicals, Inc. PMID- 29280159 TI - A profile of morbidity and mortality rounds within resident training programs of the American College of Veterinary Surgeons. AB - OBJECTIVE: To describe the structure and role of morbidity and mortality rounds (MMR) in resident training programs of the American College of Veterinary Surgeons (ACVS). STUDY DESIGN: Cross-sectional analysis: survey. SAMPLE POPULATION: ACVS surgical resident program directors. METHODS: Electronic surveys consisting of 27 questions were sent to the directors of 142 ACVS resident programs. RESULTS: Forty-five (31.6%) programs completed the survey, including 24 (53.3%) from small animal programs and 21 (46.7%) from large animal programs. Thirty-two (71.1%) programs incorporated regular MMR in their training. The primary goal of these rounds was improvement of patient care (63%) and education (31%). Selection of cases was based on unexpected mortality (80%), unexpected morbidity (77.4%), teaching value (65.7%), and review of medical errors (63%). Twenty-six percent of programs reported conducting formal follow-up for topics discussed during MMR. Ninety-five percent of programs believed that MMR were valuable. CONCLUSION: MMR are commonly incorporated in surgical resident training programs. The primary objectives of these rounds are to educate residents, refine hospital medical and operational policies, and to improve patient care. The majority of residency programs view MMR as worthwhile. However, the majority of veterinary residency programs fail to follow up MMR with formal initiatives for improvement and objective outcome assessments for issues identified during MMR. PMID- 29280161 TI - Modification of Aortic Cannula With an Inlet Chamber to Induce Spiral Flow and Improve Outlet Flow. AB - Physiologically, blood ejected from the left ventricle in systole exhibited spiral flow characteristics. This spiral flow has been proven to have several advantages such as lateral reduction of directed forces and thrombus formation, while it also appears to be clinically beneficial in suppressing neurological complications. In order to deliver spiral flow characteristics during cardiopulmonary bypass operation, several modifications have been made on an aortic cannula either at the internal or at the outflow tip; these modifications have proven to yield better hemodynamic performances compared to standard cannula. However, there is no modification done at the inlet part of the aortic cannula for inducing spiral flow so far. This study was carried out by attaching a spiral inducer at the inlet of an aortic cannula. Then, the hemodynamic performances of the new cannula were compared with the standard straight tip end hole cannula. This is achieved by modeling the cannula and attaching the cannula at a patient-specific aorta model. Numerical approach was utilized to evaluate the hemodynamic performance, and a water jet impact experiment was used to demonstrate the jet force generated by the cannula. The new spiral flow aortic cannula has shown some improvements by reducing approximately 21% of impinging velocity near to the aortic wall, and more than 58% reduction on total force generated as compared to standard cannula. PMID- 29280160 TI - When MicroRNAs Meet RNA Editing in Cancer: A Nucleotide Change Can Make a Difference. AB - RNA editing is a major post-transcriptional mechanism that changes specific nucleotides at the RNA level. The most common RNA editing type in humans is adenosine (A) to inosine (I) editing, which is mediated by ADAR enzymes. RNA editing events can not only change amino acids in proteins, but also affect the functions of non-coding RNAs such as miRNAs. Recent studies have characterized thousands of miRNA RNA editing events across different cancer types. Importantly, individual cases of miRNA editing have been reported to play a role in cancer development. In this review, we summarize the current knowledge of miRNA editing in cancer, and discuss the mechanisms on how miRNA-related editing events modulate the initiation and progression of human cancer. Finally, we discuss the challenges and future directions of studying miRNA editing in cancer. PMID- 29280162 TI - Managing Traps and Pitfalls During Initial Steps of an ECMO Retrieval Program Using a Miniaturized Portable System: What Have We Learned From the First Two Years? AB - The aim of this study was to provide early and mid-term results of the newly established extracorporeal membrane oxygenation (ECMO) retrieval service in a tertiary cardiothoracic center using the miniaturized portable Cardiohelp System (Maquet, Rastatt, Germany). A particular attention was paid to organizational and logistic specifics as well as challenges and pitfalls associated with initial phase of the program. From January 2015 until January 2017 a heterogenic group of 28 consecutive patients underwent ECMO implantation in distant hospitals for acute cardiac, pulmonary or combined failure as a bridge-to-decision and were subsequently transported to our institution. Each cannulation was performed bedside on intensive care units (ICU) using the Seldinger's technique. Early outcomes and mid-term overall survival with up to two-year follow-up along with the impact of ongoing cardiopulmonary resuscitation (CPR) on outcome were presented. Also, changes in hemodynamics and tissue perfusion factors 24 h after ECMO implantation were evaluated. ECMO implantations were performed in 15 distant departments with the median distance of 23(10;40) (maximum 60) km. A total of 15 patients (54%) were cannulated under CPR with the median duration of 30(20;110) (maximum 180) min. After 24 h of support there were significant improvements in SvO2 (P = 0.021), mean arterial pressure (P = 0.027), FiO2 (P = 0.001), lactate (P = 0.001), and pH (P < 0.001). The mean ECMO support duration was 96 +/- 100 (maximum 384) hours, whereas 11 patients (40%) were weaned off support and discharged from hospital. Overall cumulative survival in patients without the need for CPR was 61.5% at one week and 38.5% at 1 month, 6 month, and 1 year, whereas patients requiring CPR survived in 40% at one week, and 33.3% at 1 month, 6 month, and 1 year (Log-Rank (Mantel-Cox) P = 0.374, Breslow (Generalized Wilcoxon) P = 0.162). Our initial experience shows that launching new ECMO retrieval programs in centers with sufficient ICU capacities and local ECMO experience can be feasible and associated with acceptable "real world" results despite the initial learning curve. Rapid logistical organization and team flexibility are the key points to ensure comparable survival of patients requiring prolonged CPR. PMID- 29280163 TI - Theoretical insights into the 1D-charge transport properties in a series of hexaazatrinaphthylene-based discotic molecules. AB - Discotic liquid crystal (DLC) materials have attracted considerable attention mainly due to their high charge carrier mobilities in quasi-one-dimensional columns. In this article, five hexaazatrinaphthylene-based DLC molecules were investigated theoretically, and their frontier molecular orbital energy levels, crystal structures, and electron/hole drift mobilities were calculated by combination of density functional theory (DFT) and semiclassical Marcus charge transfer theory. The systems studied in this work include three experimentally reported molecules (1, 2, and 3) and two theoretically designed molecules (4 and 5). Compared with the 1-3 compounds, 4 and 5 have three more extended benzene rings in the pi-conjugated core. The present results show that the orders of the frontier molecular orbital energy levels and electron drift mobilities agree very well with the experiment. For 4 and 5, the electron/hole reorganization energies are lower than those of compounds 1-3. Furthermore, the calculated electron/hole transfer integral of 5 is the largest among all the five systems, leading to the highest electron and hole mobilities. In addition, the hydrophobicity and solubility were also evaluated by DFT, indicating that compound 5 has good hydrophobicity and good solubility in trichloromethane. As a result, it is expected that compound 5 can be a potential charge transport material in electronic and optoelectronic devices. (c) 2017 Wiley Periodicals, Inc. PMID- 29280164 TI - The epistemic costs of compromise in bioethics. AB - Bioethicists sometimes defend compromise positions, particularly when they enter debates on applied topics that have traditionally been highly polarised, such as those regarding abortion, euthanasia and embryonic stem cell research. However, defending compromise positions is often regarded with a degree of disdain. Many are intuitively attracted to the view that it is almost always problematic to defend compromise positions, in the sense that we have a significant moral reason not to do so. In this paper, we consider whether this common sense view can be given a principled basis. We first show how existing explanations for the problematic nature of compromise fall short of vindicating the common sense view, before offering our own explanation, which, we claim, comes closer to vindicating that view. We argue that defending a compromise will typically have two epistemic costs: it will corrupt attempts to use the claims of ethicists as testimonial evidence, and it will undermine standards that are important to making epistemic progress in ethics. We end by suggesting that the epistemic costs of compromise could be reduced by introducing a stronger separation between ethical debate aimed at fulfilling the epistemic role of ethics, and ethical debate that aims to directly produce good policy or practice. PMID- 29280165 TI - Computer monitor pixellation and Sloan letter visual acuity measurement. AB - PURPOSE: To assess the effects of changing computer monitor pixel density on visual acuity measurements made using Sloan optotypes. METHODS: Acuity was measured on 10 participants aged 19 to 38 years (mean 27.9 +/- 7.0) measured binocularly wearing their best spectacle correction. Stimuli were eight lines of five Sloan letter optotypes in logarithmic progression, ranging in size from -0.4 to 0.3 logMAR. Test distance was varied so that pixels on the monitor ranged in size from 0.125 mins of arc to 1.97 mins of arc. Two sampling approaches were used: (1) unfiltered sampling, with each pixel rendered either black or white; and (2) filtered sampling with pixel luminance averaged across a pixel aperture, giving grey-scale smoothing of letter edges. RESULTS: A broken line fit was made to each data set, with acuity being stable at an asymptotic threshold VAas for small pixels sizes, with thresholds increasing linearly when pixel sizes exceeded a critical pixel size Pcrit . For unfiltered stimuli, Pcrit averaged 1.1 mins of arc and for unfiltered stimuli averaged 0.69 mins of arc. For filtered stimuli, Pcrit was 1.79xVAas , and for unfiltered Pcrit was 1.05xVAas . CONCLUSION: The results show that grey-scale filtering makes acuity measurement more resistant to the effects of pixellation. Based on a conservative interpretation of these findings, we make the recommendation that charts be constructed with, for filtered optotypes, a maximum pixel size of 0.6 x of the smallest MAR used and, for unfiltered optotypes, 0.35 x the smallest MAR used. PMID- 29280166 TI - Pyrite: A blender plugin for visualizing molecular dynamics simulations using industry-standard rendering techniques. AB - Molecular dynamics (MD) simulations provide critical insights into many biological mechanisms. Programs such as VMD, Chimera, and PyMOL can produce impressive simulation visualizations, but they lack many advanced rendering algorithms common in the film and video-game industries. In contrast, the modeling program Blender includes such algorithms but cannot import MD-simulation data. MD trajectories often require many gigabytes of memory/disk space, complicating Blender import. We present Pyrite, a Blender plugin that overcomes these limitations. Pyrite allows researchers to visualize MD simulations within Blender, with full access to Blender's cutting-edge rendering techniques. We expect Pyrite-generated images to appeal to students and non-specialists alike. A copy of the plugin is available at http://durrantlab.com/pyrite/, released under the terms of the GNU General Public License Version 3. (c) 2017 Wiley Periodicals, Inc. PMID- 29280167 TI - From applied ethics to empirical ethics to contextual ethics. AB - Bioethics became applied ethics when it was assimilated to moral philosophy. Because deduction is the rationality of moral philosophy, subsuming facts under moral principles to deduce conclusions about what ought to be done became the prescribed reasoning of bioethics, and bioethics became a theory comprised of moral principles. Bioethicists now realize that applied ethics is too abstract and spare to apprehend the specificity, particularity, complexity and contingency of real moral issues. Empirical ethics and contextual ethics are needed to incorporate these features into morality, not just bioethics. The relevant facts and features of problems have to be identified, investigated and framed coherently, and potential resolutions have to be constructed and assessed. Moreover, these tasks are pursued and melded within manifold contexts, for example, families, work and health care systems, as well as societal, economic, legal and political backgrounds and encompassing worldviews. This naturalist orientation and both empirical ethics and contextual ethics require judgment, but how can judgment be rational? Rationality, fortunately, is more expansive than deductive reasoning. Judgment is rational when it emanates from a rational process of deliberation, and a process of deliberation is rational when it uses the resources of non-formal reason: observation, creative construction, formal and informal reasoning methods and systematic critical assessment. Empirical ethics and contextual ethics recognize that finite, fallible human beings live in complex, dynamic, contingent worlds, and they foster creative, critical deliberation and employ non-formal reason to make rational moral judgments. PMID- 29280168 TI - Resident Accuracy of Musculoskeletal Palpation With Ultrasound Verification. AB - OBJECTIVES: The purpose of this observational study was to determine the accuracy of musculoskeletal palpation of the medial joint line of the knee, medial patellar tendon, and posterior tibialis tendon verified by ultrasound imaging among physical medicine and rehabilitation residents. METHODS: Eighteen physical medicine and rehabilitation resident physicians at a single specialized institution were asked to identify the medial joint line of the knee, medial patellar tendon, and posterior tibialis tendon on 2 separate standardized patient models during a single data collection. They were asked to place a paper clip flat on the surface of the skin parallel to the specified anatomic structure. A high-frequency linear array transducer was used to identify whether the paper clip was correctly placed over the structures and to measure the distance from the intended structure. RESULTS: The accuracy rates for palpation of the medial joint line, medial patellar tendon, and posterior tibialis tendon in both models were 14%, 36%, and 28%, respectively, for all levels of residents. Accuracy rates for all of the structures by level of education were 19%, 29%, and 31% for postgraduate years 2, 3, and 4. Median confidence scores were 3.75, 3.5, and 2 for the medial joint line, medial patellar tendon, and posterior tibialis tendon. CONCLUSIONS: This study highlights the level of inaccuracy of musculoskeletal palpation skills and draws further attention to an area of much-needed improvement in our musculoskeletal residency training programs. Ultrasound imaging is an effective noninvasive method for providing swift feedback to medical students and residents and thereby reduce the instances of inaccurate musculoskeletal palpation. PMID- 29280169 TI - Comparative analysis of the effect of antihypertensive drugs on the survival of perforator flaps in a rat model. AB - BACKGROUND: First-line antihypertensive drugs include calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. In this study, we compared the effects of antihypertensive drugs on the survival of perforator flaps in a rat model. MATERIALS AND METHODS: Fifty normotensive rats were randomly divided into five groups, with 10 rats in each group. Four different antihypertensive drugs were given via oral gavage for 7 days: group I: 1.5 mg/kg amlodipine; group II: 15 mg/kg captopril; group III: 15 mg/kg losartan; group IV: 7 mg/kg dichlozid; and group V: saline. An 8 * 10-cm sized extended dorsal island skin flap based on the unilateral deep circumflex iliac artery perforator was elevated and fixed in place. At postoperative day 7, evaluation of viable flap area, edema measurement, and histological analysis were conducted. RESULTS: No significant difference in systolic blood pressure was observed preoperatively between any of the groups. The mean flap survival area was 81.54 +/- 6.71, 55.76 +/- 21.01, 48.45 +/- 13.72, 58.14 +/- 16.96, and 67.99 +/- 10.68% in groups I, II, III, IV, and V, respectively. It was significantly increased in group I (P = .007) and decreased in group III (P = .011) compared with the control group. The mean full-thickness necrosis area was significantly increased in group III (P = .024) compared to the control group. CONCLUSIONS: Angiotensin receptor blockers adversely affected the survival of perforator flaps, while calcium channel blockers increased it. These results suggest that the regimen of antihypertensive drugs may need to be carefully selected for patients undergoing perforator flap reconstruction. PMID- 29280170 TI - A boundary-optimized rejection region test for the two-sample binomial problem. AB - Testing the equality of 2 proportions for a control group versus a treatment group is a well-researched statistical problem. In some settings, there may be strong historical data that allow one to reliably expect that the control proportion is one, or nearly so. While one-sample tests or comparisons to historical controls could be used, neither can rigorously control the type I error rate in the event the true control rate changes. In this work, we propose an unconditional exact test that exploits the historical information while controlling the type I error rate. We sequentially construct a rejection region by first maximizing the rejection region in the space where all controls have an event, subject to the constraint that our type I error rate does not exceed alpha for any true event rate; then with any remaining alpha we maximize the additional rejection region in the space where one control avoids the event, and so on. When the true control event rate is one, our test is the most powerful nonrandomized test for all points in the alternative space. When the true control event rate is nearly one, we demonstrate that our test has equal or higher mean power, averaging over the alternative space, than a variety of well-known tests. For the comparison of 4 controls and 4 treated subjects, our proposed test has higher power than all comparator tests. We demonstrate the properties of our proposed test by simulation and use our method to design a malaria vaccine trial. PMID- 29280171 TI - Placenta Increta After Cervical Conization. PMID- 29280172 TI - Modeling the pH-ammonia toxicity relationship for Hydra viridissima in soft waters with low ionic concentrations. AB - There are limited data concerning the toxicity of ammonia in fresh soft waters. Ammonia toxicity is largely dependent on pH and temperature. The US Environmental Protection Agency (USEPA) has derived equations to adjust species toxicity estimates based on changes in pH and temperature. It has been reported that the pH-ammonia toxicity relationship, derived by the USEPA, may differ in waters with low ionic concentrations because of the absence of potentially ameliorative ionic constituents. The present study aimed to assess the pH-ammonia toxicity relationship for the tropical green hydra, Hydra viridissima, across a range of pH values in a natural water with low ionic content. Ammonia toxicity to H. viridissima was assessed at a pH range between 6.0 and 8.5 and temperature 27.5 +/- 1 degrees C. Test solution pH was maintained using a pH buffer. The resulting median effect concentrations ranged from 9.62 (7.95-11.65) mg L-1 total ammonia nitrogen at pH 6.0 to 0.64 (0.50-0.81) mg L-1 total ammonia nitrogen at pH 7.9. The results indicated that increasing pH increased the sensitivity of H. viridissima to ammonia. The pH dependence equation derived by the USEPA accurately described the relationship between pH and ammonia toxicity for H. viridissima. However, when the model parameters for the generic pooled relationship were used, the fit was less accurate (r2 = 0.66), indicating that the generic pooled pH-dependence equations may not be appropriate for use with this species. Environ Toxicol Chem 2018;37:1189-1196. (c) 2017 SETAC. PMID- 29280173 TI - 7-hydroxy-staurosporine, UCN-01, induces DNA damage response, and autophagy in human osteosarcoma U2-OS cells. AB - Human osteosarcoma (bone cancer) is a highly malignant and the most prevalent bone tumor affecting children. Despite recent advances in the understanding of the molecular mechanism by which anticancer drugs kill osteosarcoma or block its growth, however, the mortality rate has declined only modestly. Thus, a new therapeutic approach is needed to be established. 7-hydroxystaurosporine, UCN-01, abrogates the G2 checkpoint thus enhancing the cytotoxicity of chemotherapeutic agents. In addition, it has been evaluated in clinical trials as a single antineoplastic agent in treating several cancers. However, the effects of UCN-01 on treating bone cancer has never been tested. In this study, we found that UCN 01 induced cell cycle arrest and apoptosis in the human osteosarcoma, U2-OS cells. In addition, the migration ability was also reduced, suggesting UCN-01 inhibited cell growth and migration. When U2-OS cells were treated with UCN-01, DNA damage response was triggered. The ataxia telangiectasia mutated (ATM) and the non-canonical downstream effector, ERK, was activated by UCN-01. In addition, depletion of ATM or inhibition of ERK deteriorated the cell viability in UCN-01 treated U2-OS cells. Furthermore, UCN-01 induced autophagy activation for protecting cells from apoptosis. Thus, UCN-01 might function as a single antineoplastic agent in treating human osteosarcoma. PMID- 29280174 TI - Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. AB - BACKGROUND: Diabetes and periodontitis are chronic non-communicable diseases independently associated with mortality and have a bidirectional relationship. AIMS: To update the evidence for their epidemiological and mechanistic associations and re-examine the impact of effective periodontal therapy upon metabolic control (glycated haemoglobin, HbA1C). EPIDEMIOLOGY: There is strong evidence that people with periodontitis have elevated risk for dysglycaemia and insulin resistance. Cohort studies among people with diabetes demonstrate significantly higher HbA1C levels in patients with periodontitis (versus periodontally healthy patients), but there are insufficient data among people with type 1 diabetes. Periodontitis is also associated with an increased risk of incident type 2 diabetes. MECHANISMS: Mechanistic links between periodontitis and diabetes involve elevations in interleukin (IL)-1-beta, tumour necrosis factor alpha, IL-6, receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio, oxidative stress and Toll-like receptor (TLR) 2/4 expression. INTERVENTIONS: Periodontal therapy is safe and effective in people with diabetes, and it is associated with reductions in HbA1C of 0.27-0.48% after 3 months, although studies involving longer-term follow-up are inconclusive. CONCLUSIONS: The European Federation of Periodontology (EFP) and the International Diabetes Federation (IDF) report consensus guidelines for physicians, oral healthcare professionals and patients to improve early diagnosis, prevention and comanagement of diabetes and periodontitis. PMID- 29280175 TI - Complications and Radiologic Features of Breast Augmentation via Injection of Aquafilling Gel. AB - Many attempts have been made to augment breasts using injectable materials; however, various complications are associated with these materials. Aquafilling gel (Aquafilling, Podebrady, Czech Republic) is a new soft tissue filler that has been used as an implant material for the face and lip and recently for breast augmentation. This article describes 3 cases of augmentation mammoplasty using Aquafilling gel, focusing on their complications and radiologic features. PMID- 29280176 TI - "Y Sign" at the Level of the 3-Vessel and Trachea View: An Effective Fetal Marker of Aortic Dextroposition Anomalies in the First Trimester. AB - OBJECTIVES: The "Y sign" at the level of the 3-vessel and trachea view corresponds to thinning of main pulmonary artery and arterial duct and a dilated transverse aortic arch. The purpose of this study was to evaluate the Y sign for the diagnosis of aortic dextroposition anomalies at the time of the first trimester scan and to assess the screening performance of only the Y sign, only abnormal left axis deviation (axis sign), and their combination for the diagnosis of aortic dextroposition anomalies. METHODS: A prospective evaluation of 6025 pregnant women undergoing first-trimester ultrasonography was conducted. The cardiac axis was measured in all examined patients and considered abnormal (positive axis sign) at greater than 57 degrees . The frequency of the Y sign and the axis sign was assessed for this population, and their screening performance for the diagnosis of aortic dextroposition anomalies was calculated. RESULTS: A total of 5775 patients fulfilled the inclusion criteria. Aortic dextroposition anomalies were diagnosed in 17 cases (tetralogy of Fallot in 8 and Fallot-like double-outlet right ventricle in 9). The Y sign was found in 18 of 5775 (0.3%) fetuses examined, of which 7 of 18 were confirmed with tetralogy of Fallot, 9 of 18 with a Fallot-like double-outlet right ventricle, and 2 of 18 with pulmonary stenosis. A positive axis sign of greater than 57 degrees was found in 20 fetuses, including 4 with normal heart anatomy. The sensitivity values of the Y sign, the axis sign, and their combination were 94%, 76%, and 94%, respectively. CONCLUSIONS: Visualization of the Y sign should increase the suspicion of aortic dextroposition anomalies in the late first trimester. The screening performance of the Y sign alone and in combination with an abnormal cardiac axis was high and may aid in the early diagnosis of aortic dextroposition anomalies in the fetus. PMID- 29280177 TI - Questions on "Serial two-year follow-up after lymphaticovenular anastomosis for the treatment of lymphedema". PMID- 29280178 TI - Relationship Between Cavum Septi Pellucidi Measurements and Fetal Hypoplastic Left Heart Syndrome or Dextro-Transposition of the Great Arteries. AB - OBJECTIVES: The aim of this study was to compare the size and position of the cavum septi pellucidi (CSP) in fetuses with hypoplastic left heart syndrome (HLHS) or dextro-transposition of the great arteries (d-TGA) with healthy fetuses. METHODS: The CSP length, CSP width, and frontal lobe length were measured in 185 healthy fetuses (404 scans), 11 fetuses with HLHS (16 scans), and 11 fetuses with d-TGA (12 scans) between January 2005 and April 2016. Each measurement was compared between healthy fetuses and those with HLHS or d-TGA, controlling for the biparietal diameter. RESULTS: Positive correlations were noted between biparietal diameter and CSP length, CSP width, and frontal lobe length (adjusted R2 = 0.811, 0.821, and 0.878, respectively). An increased CSP length was found in both fetuses with HLHS and those with d-TGA (P < .0001). The CSP width was only increased in fetuses with d-TGA (P = .0466). No difference in the frontal lobe length was noted. CONCLUSIONS: In fetuses with HLHS, the CSP is increased in length. In fetuses with d-TGA, the CSP is increased in both length and width. PMID- 29280179 TI - Multiple-rater kappas for binary data: Models and interpretation. AB - Interrater agreement on binary measurements with more than two raters is often assessed using Fleiss' kappa, which is known to be difficult to interpret. In situations where the same raters rate all items, however, the far less known kappa suggested by Conger, Hubert, and Schouten is more appropriate. We try to support the interpretation of these characteristics by investigating various models or scenarios of rating. Our analysis, which is restricted to binary data, shows that conclusions concerning interrater agreement by kappa heavily depend on the population of items or subjects considered, even if the raters have identical behavior. The standard scale proposed by Landis and Koch, which verbally interprets numerical values of kappa, appears to be rather subjective. On the basis of one of the models for rater behavior, we suggest an alternative verbal interpretation for kappa. Finally, we reconsider a classical example from pathology to illustrate the application of our methods and models. We also look for subgroups of raters with similar rating behavior using hierarchical clustering. PMID- 29280181 TI - Modeling time-varying exposure using inverse probability of treatment weights. AB - For estimating the causal effect of treatment exposure on the occurrence of adverse events, inverse probability weights (IPW) can be used in marginal structural models to correct for time-dependent confounding. The R package ipw allows IPW estimation by modeling the relationship between the exposure and confounders via several regression models, among which is the Cox model. For right-censored data and time-dependent exposures such as treatment switches, the ipw package allows a single switch, assuming that patients are treated once and for all. However, to accommodate multiple switches, we extend this package by implementing a function that allows for multiple and intermittent exposure status in the estimation of IPW using a survival model. This extension allows for the whole exposure treatment trajectory in the estimation of IPW. The impact of the estimated weights on the estimated causal effect, with both methods, is assessed in a simulation study. Then, the function is illustrated on a real dataset from a nationwide prospective observational cohort including patients with inflammatory bowel disease. In this study, patients received one or multiple medications (thiopurines, methotrexate, and anti-TNF) over time. We used a Cox marginal structural model to assess the effect of thiopurines exposure on the cause specific hazard for cancer incidence considering other treatments as confounding factors. To this end, we used our extended function which is available online in the Supporting Information. PMID- 29280180 TI - Comparison of the outcomes of dynamic/static tests and palpation tests in TMD pain patients. AB - : In addition to palpation tests, dynamic/static tests have been proposed to complement temporomandibular disorders (TMD) patients' evaluation in the clinical setting. The aim of this study was to assess the intra- and inter-observer reliability of the palpation tests and of the dynamic/static tests, and to determine whether those tests would yield comparable outcomes in terms of pain diagnoses. Ninety-eight (N = 98) consecutive adult patients were examined during 2 clinical sessions by 2 independent examiners, based on muscle and joint palpation techniques described in the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). They also underwent dynamic/static tests. The intra-observer reliability of palpation tests was generally poor, with fair to-good to excellent ICC values only for the superior masseter and intra-oral sites. The inter-observer reliability of palpation was fair-to-good for muscles, but it was poor for the TMJ lateral pole. Both intra- and inter-observer reliability for the dynamic/static tests varied from fair-to-good to excellent. The intra-observer reliability for muscle pain diagnoses based on palpation tests was between poor and fair-to-good, whereas the inter-observer reliability was excellent. The intra-observer reliability for pain diagnoses based on dynamic/static tests was fair-to-good, and the inter-observer reliability varied from fair-to-good to excellent. CONCLUSIONS: Some features of the dynamic/static tests make them potentially more useful than palpation tests for selected clinical purposes, such as discriminating between joint and muscle pain as well as monitoring symptoms course. Thus, findings from this investigation suggest that both tests should be included in the TMD diagnostic algorithms. PMID- 29280182 TI - Systematic review and meta-analysis found higher levels of behavioural problems in male left-behind children aged 6-11 years. AB - AIM: Left-behind children (LBC) now account for more than 1 in 5 Chinese children, and they often suffer from behavioural problems when their parents leave their rural homes to seek work in urban areas. The primary aim of this meta analysis was to compare the incidence rates and factor scores of behavioural problems in LBC, who now account for more than one-fifth of Chinese children, and non-LBC. METHODS: This systematic review and meta-analysis explored the children's characteristic behavioural problems using the Achenbach Child Behaviour Check List. A subgroup analysis was conducted to compare the different behavioural problems of LBC with different characteristics. The meta-analysis assessed 1405 papers and analysed 13 papers from 2007 to 2015, covering 10 264 LBC and 8909 non-LBC from 2 to 19 years of age. RESULTS: The incidence rates of behavioural problems were higher in LBC than non-LBC. The highest risks were noted in boys aged between 6 and 11 years of age, who were more likely to be withdrawn and be affected by somatic complaints, schizophreniform disorder, compulsive behaviour and depression. CONCLUSION: Interventions and policies are urgently needed to tackle behavioural issues among LBC, especially high-risk males aged 6-11 years. PMID- 29280183 TI - Semiparametric Bayesian models for evaluating time-variant driving risk factors using naturalistic driving data and case-crossover approach. AB - Driver behavior is a major contributing factor for traffic crashes, a leading cause of death and injury in the United States. The naturalistic driving study (NDS) revolutionizes driver behavior research by using sophisticated nonintrusive in-vehicle instrumentation to continuously record driving data. This paper uses a case-crossover approach to evaluate driver-behavior risk. To properly model the unbalanced and clustered binary outcomes, we propose a semiparametric hierarchical mixed-effect model to accommodate both among-strata and within stratum variations. This approach overcomes several major limitations of the standard models, eg, constant stratum effect assumption for conditional logistic model. We develop 2 methods to calculate the marginal conditional probability. We show the consistency of parameter estimation and asymptotic equivalence of alternative estimation methods. A simulation study indicates that the proposed model is more efficient and robust than alternatives. We applied the model to the 100-Car NDS data, a large-scale NDS with 102 participants and 12-month data collection. The results indicate that cell phone dialing increased the crash/near crash risk by 2.37 times (odds ratio: 2.37, 95% CI, 1.30-4.30) and drowsiness increased the risk 33.56 times (odds ratio: 33.56, 95% CI, 21.82-52.19). This paper provides new insight into driver behavior risk and novel analysis strategies for NDS studies. PMID- 29280184 TI - An update on the evidence for pathogenic mechanisms that may link periodontitis and diabetes. AB - AIM: To provide an update of the review by Taylor (Journal of Clinical Periodontology, 2013, 40, S113) regarding the scientific evidence of the biological association between periodontitis and diabetes. METHODS: Literature searches were performed using MeSH terms, keywords and title words and were published between 2012 and November 2016. All publications were screened for their relevance. The data from the articles were extracted and summarized in tables and a narrative review. RESULTS: Small-scale molecular periodontal microbiome studies indicate a possible association between altered glucose metabolism in pre-diabetes and diabetes and changes in the periodontal microbiome, with no evidence for casual relationships. Clinical and animal studies found elevated gingival levels of IL1-beta, TNF-alpha, IL-6, RANKL/OPG and oxygen metabolites in poorly controlled diabetes. In addition, individuals with diabetes and periodontitis exhibit high levels of circulating TNF-alpha, CRP and mediators of oxidative stress, and successful periodontal treatment reduces their levels. CONCLUSIONS: The elevated pro-inflammatory factors in the gingiva of patients with poorly controlled diabetes suggest a biological pathway that may aggravate periodontitis. Some evidence suggests that the systemic inflammatory burden in periodontitis has the potential to affect diabetes control, but no studies addressed the impact of successful periodontal therapy on the pathophysiological mechanisms involved in systemic complications of diabetes. PMID- 29280185 TI - Neural perspectives on cognitive control development during childhood and adolescence should take into account how obesity affects brain development. PMID- 29280186 TI - Ibrutinib discontinuation in Waldenstrom macroglobulinemia: Etiologies, outcomes, and IgM rebound. AB - Ibrutinib is the first approved therapy for symptomatic patients with Waldenstrom macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count <=100 K/uL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (>=25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control. PMID- 29280187 TI - Ultrasound-based scoring system for differential diagnosis of polypoid lesions of the gallbladder. AB - BACKGROUND AND AIM: Polypoid lesions of the gallbladder may be neoplastic or non neoplastic. Correct diagnosis would help reduce unnecessary cholecystectomies. This study aimed to determine the predictive value of individual ultrasound characteristics for diagnosis of neoplastic polyps and to build a scoring system based on these characteristics. METHODS: A total of 109 patients with gallbladder polyps >= 6 mm underwent conventional ultrasound examination and received finally diagnosis by pathological examination. All images were analyzed to determine characteristics of the lesions. Univariate and multivariate analyses were used to identify the predictors of neoplastic polyps, and a scoring system was built based on multivariate analysis. RESULTS: Maximum diameter, height/width ratio, base width, presence of hyper-echoic spots, and intralesional blood flow were statistically significant (P = 0.011, P = 0.016, P = 0.003, P = 0.031, and P = 0.022, respectively) predictors of neoplastic lesions. The total score = (Maximum diameter, >= 13.9 mm = 1, < 13.9 = 0) + (Base width, >= 3.5 mm = 1, < 3.4 = 0) + (Height/width ratio, <= 1.05 = 1, > 1.05 = 0) + (Hyper-echoic spots, presence = 0, absence = 1) + (Blood flow, presence = 1, absence = 0). Receiver operating characteristic curve showed that the sensitivity, specificity, and accuracy for the risk of neoplastic polyps with scores of 3 or higher were 81.6%, 86.7%, and 84.4%, respectively. CONCLUSION: This ultrasound-based scoring system could be a useful means for differentiating between neoplastic and non-neoplastic gallbladder polyps in the clinic. PMID- 29280189 TI - Adiponectin concentration data improve the estimation of atherosclerotic risk in normal and in overweight subjects. AB - BACKGROUND: The combinations of adipokines and body mass parameters to estimate carotid atherosclerotic disease have not been completely delineated. OBJECTIVE: To test the combinations of well-established, easily accessible body mass indices and circulating biomarkers to identify increased carotid intima-media thickness (cIMT) in a primary prevention setting. DESIGN AND PATIENTS: In a cross-sectional analysis of 339 asymptomatic individuals with no history of cardiovascular events, inflammatory and insulin sensitivity biomarkers as well as adipokine levels were measured and combined with body mass parameters to evaluate the best marker for increased cIMT. RESULTS: As isolated parameters, body mass index (BMI) and adiponectin best identified abnormal cIMT (P = .04). Adiponectin levels were also linked to the relationship between BMI and cIMT (beta = 0.0371; P = .01). Twenty-nine individuals with increased cIMT were missed by BMI alone but detected by combining BMI and adiponectin measurements. When compared with BMI alone, the combination of adiponectin plus BMI improved the c-statistic (0.549-0.567) and the integrated discrimination improvement index (0.01725; P = .021). Segregation of individuals by the combined use of BMI + adiponectin is associated with significant differences in insulin sensitivity, glomerular filtration rate, systemic inflammatory activity, dyslipidaemia and cIMT. CONCLUSIONS: Combining plasma adiponectin measurements and BMI improves estimation of cIMT as compared to anthropometric parameters. PMID- 29280188 TI - On the substructure controls in rare variant analysis: Principal components or variance components? AB - Recent studies showed that population substructure (PS) can have more complex impact on rare variant tests and that similarity-based collapsing tests (e.g., SKAT) may suffer more severely by PS than burden-based tests. In this work, we evaluate the performance of SKAT coupling with principal components (PC) or variance components (VC) based PS correction methods. We consider confounding effects caused by PS including stratified populations, admixed populations, and spatially distributed nongenetic risk; we investigate which types of variants (e.g., common, less frequent, rare, or all variants) should be used to effectively control for confounding effects. We found that (i) PC-based methods can account for confounding effects in most scenarios except for admixture, although the number of sufficient PCs depends on the PS complexity and the type of variants used. (ii) PCs based on all variants (i.e., common + less frequent + rare) tend to require equal or fewer sufficient PCs and often achieve higher power than PCs based on other variant types. (iii) VC-based methods can effectively adjust for confounding in all scenarios (even for admixture), though the type of variants should be used to construct VC may vary. (iv) VC based on all variants works consistently in all scenarios, though its power may be sometimes lower than VC based on other variant types. Given that the best performed method and which variants to use depend on the underlying unknown confounding mechanisms, a robust strategy is to perform SKAT analyses using VC based methods based on all variants. PMID- 29280190 TI - Paediatricians' expectations and perspectives regarding genetic testing for children with developmental disorders. AB - AIM: To investigate paediatricians' expectations and perspectives of genetic testing for children with developmental disorders. METHODS: Paediatricians working in a developmental clinic were surveyed each time they ordered a chromosomal microarray (CMA) for a child with developmental disorders. Clinical charts were reviewed. Results were analysed using mixed methodology. RESULTS: Ninety-seven % (73/76) of surveys were completed. Paediatricians reported that 36% of parents had difficulties understanding genetic testing and that 40% seemed anxious. The majority expected testing to have positive impacts on children/families. The themes raised were (i) clarifying the diagnosis (56%), (ii) understanding the aetiology of the condition (55%), (iii) enabling prenatal diagnosis/counselling (43%), (iv) improving medical care for the child (15%) and (v) decreasing parental guilt/anxiety (8%). Less than half anticipated negative impacts; 74% expected that the most helpful result for their patient would be an abnormal result explaining the disorder. Among the 73 children for whom CMA was ordered, 81% got tested: 66% of the results were normal, 19% were abnormal and contributed to explain the condition and 12% were abnormal but of unknown significance. CONCLUSION: Paediatricians generally expect many positive and less negative impacts of genetic testing for children with developmental disorders. Parental perspectives are needed. PMID- 29280191 TI - Randomised study found that improved nutritional intake was associated with better sleep patterns in prepubertal children who were both short and lean. AB - AIMS: Nutrition and sleep are prerequisites for linear growth and we addressed the under-researched role of sleep in this equation. METHODS: This was a prospective randomised, double-blinded, placebo-controlled study of nutritional supplements in 164 healthy lean, short, prepubertal children with 83 in the supplement group and 81 in the placebo group. From November 2010 to November 2013, we focussed on children aged three to nine years referred for specialist growth assessments to the Schneider Children's Medical Center, Israel. Progress was assessed using anthropometric measurements, sleep questionnaires and three day food diaries at baseline and after the six-month intervention. RESULTS: Children in the supplement group who took at least 50% of the recommended dose had shorter sleep latency than those who did not (p = 0.046). Children who fell asleep in less than 15 minutes had significantly improved standard deviation scores for weight (0.25 +/- 0.34 versus 0.07 +/- 0.36, p = 0.044) and height (0.09 +/- 0.13 versus 0.03 +/- 0.13, p = 0.057) than those who took longer to fall asleep. Positive correlations were found between mean sleep duration and caloric and macronutrient intake per kilogram. CONCLUSION: Adequate nutritional intake was associated with better sleep patterns and may enhance linear growth. PMID- 29280192 TI - IGFBP-7 inhibits the differentiation of oligodendrocyte precursor cells via regulation of Wnt/beta-Catenin signaling. AB - Oligodendrocytes (OLs) are glial cells that form myelin sheaths in the central nervous system. Myelin sheath plays important role in nervous system and loss of it in neurodegenerative diseases can lead to impairment of movement. Understanding the signals and factors that regulate OL differentiation can help to address novel strategies for improving myelin repair in neurodegenerative diseases. The aim of this study was to investigate the role of insulin-like growth factor-binding proteins 7 (IGFBP-7) in differentiating OL precursor cells (OPCs). It was found that oligodendrocyte precursors undergoing differentiation were accompanied by selective expression of IGFBP-7. In addition, knockdown of IGFBP-7 promoted differentiation of oligodendrocytes and increased formation of myelin in cultured cells. In contrast, excessive expression of IGFBP-7 inhibited differentiation of oligodendrocytes. Furthermore, overexpression of IGFBP-7 in oligodendrocyte precursor cells increased transcription of Wnt target genes and promoted beta-Catenin nuclear translocation. These findings suggest that IGFBP-7 negatively regulates differentiation of oligodendrocyte precursor cells via regulation of Wnt/beta-Catenin signaling. PMID- 29280193 TI - Sonographic Evaluation of Liver Hemodynamic Indices in Overweight and Obese Dogs. AB - BACKGROUND: Hepatic circulatory disturbances have been associated with obesity and fatty liver in humans. In the veterinary literature, however, there is limited information regarding the effects of different body condition scores (BCS) on liver hemodynamic indices in dogs. OBJECTIVES: To investigate the influence of BCS on liver hemodynamic indices. ANIMALS: Fifty-three client-owned dogs of various breeds were included. METHODS: Prospective observational study. Dogs were divided into 3 BCS groups using a 5-point scale: G1 - 12 ideal dogs, G2 - 21 overweight dogs, G3 - 20 obese dogs. Mean portal velocity (MPV), portal blood flow volume (PBFV), portal congestion index (PCI), hepatic artery resistivity index (HARI), and hepatic vein (HV) spectral wave were obtained by pulsed Doppler sonography. Alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT) activities were determined. Liver enzymes activities and liver hemodynamic indices were compared among groups. RESULTS: Obese dogs had lower MPV, higher percentage of abnormal hepatic vein spectral wave and higher median ALP activity than did ideal dogs (P < 0.05). Overweight and obese dogs had lower PBFV than ideal dogs (P < 0.01). Overweight dogs had higher median GGT activity than ideal dogs (P < 0.05). No difference was observed for PCI, HARI and median ALT activity among the groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Obesity was associated with changes in portal vein indices and in HV spectral wave. These changes were accompanied by significant differences in some liver enzymes activities and could be a sign of early liver disease. PMID- 29280194 TI - Effect of Prophylactic Calcitriol Administration on Serum Ionized Calcium Concentrations after Parathyroidectomy: 78 Cases (2005-2015). AB - BACKGROUND: Prophylactic administration of calcitriol has been suggested to mitigate the risk of hypocalcemia after parathyroidectomy. The effect of calcitriol on postoperative serum ionized calcium concentrations has not been evaluated in dogs after parathyroidectomy. HYPOTHESIS/OBJECTIVES: To determine the effect of prophylactic calcitriol administration on postoperative serum ionized calcium (iCa) concentrations in dogs with primary hyperthyroidism (PHPTH) treated by parathyroidectomy. ANIMALS: Seventy-eight dogs with primary hyperparathyroidism treated surgically. METHODS: Multi-institutional retrospective case study. Medical records from 2005 to 2015 were evaluated. Dogs were included if they had a diagnosis of PHPTH and had surgery to remove parathyroid tissue. Serum iCa concentrations were monitored for a minimum of 2 days postoperatively. Two study groups were evaluated: calcitriol administration and no calcitriol administration. RESULTS: Serial postoperative iCa concentrations measured at 12-hour time intervals for 2 days postoperatively were positively associated with preoperative iCa concentrations. This association was evident at each time interval, and the effect of preoperative iCa concentrations on postoperative iCa concentrations decreased as time elapsed (12 hours, P < 0.0001; 24 hours, P < 0.0001; 36 hours, P < 0.04; and 48 hours, P = 0.01). Prophylactic calcitriol administration was not found to be significantly associated with postoperative iCa concentrations or its rate of decrease after parathyroidectomy. CONCLUSION AND CLINICAL IMPORTANCE: We found no protective value in administering calcitriol prophylactically to prevent hypocalcemia in the immediate postoperative period (48 hours) after parathyroidectomy. Preoperative iCa concentrations had a significant positive association with postoperative iCa concentrations throughout the monitoring period. PMID- 29280195 TI - Empirically derived dimensional syndromes of self-reported psychopathology: Cross cultural comparisons of Portuguese and US elders. AB - OBJECTIVE: As the world population ages, mental health professionals increasingly need empirically supported assessment instruments for older adult psychopathology. This study tested the degree to which syndromes derived from self-ratings of psychopathology by elders in the US would fit self-ratings by elders in Portugal. METHODS: The Older Adult Self-Report (OASR) was completed by 352 60- to 102-year-olds in Portuguese community and residential settings. RESULTS: Confirmatory factor analyses tested the fit of the 7-syndrome OASR model to self-ratings by Portuguese elders. The primary fit index (Root Mean Square Error of Approximation) showed good fit, while secondary fit indices (the Comparative Fit Index and the Tucker-Lewis Index) showed acceptable fit. Loadings of 95 of the 97 items on their expected syndromes were statistically significant (mean = .63), indicating that the items measured the syndromes well. Correlations between latent factors, ie, between the hypothesized syndrome constructs measured by the items, averaged .66. The correlations between syndromes reflect varying degrees of comorbidity between problems comprising particular pairs of syndromes. CONCLUSIONS: The results support the syndrome structure of the OASR for Portuguese elders, offering Portuguese clinicians and researchers a useful instrument for assessing a broad spectrum of psychopathology. The results also offer a core of empirically supported taxonomic constructs of later life psychopathology as a basis for advancing clinical practice, training, and cross cultural research. PMID- 29280196 TI - Effect of Heat-treatment on Accuracy of Infrared Spectroscopy and Digital and Optical Brix Refractometers for Measuring Immunoglobulin G Concentration in Bovine Colostrum. AB - BACKGROUND: Heat-treatment of colostrum is a method developed to reduce calf exposure to pathogens. Infrared (IR) spectroscopy and Brix refractometers can be used for measuring colostral IgG concentration and assessing colostrum quality. OBJECTIVES: To determine the impact of heat-treatment on accuracy of IR spectroscopy and Brix refractometers for measuring colostral IgG concentration and assessing colostrum quality before and after heat-treatment. ANIMALS: A total of 60 Holstein dairy cows on 8 commercial dairy farms. METHODS: A cross-sectional study was designed to determine the effect of heat-treatment at 60 degrees C and 63 degrees C each for 30 and 60 minutes duration on colostral IgG concentration measured by the reference radial immunodiffusion (RID) assay, IR spectroscopy, and digital and optical refractometers. RESULTS: Colostrum IgG concentration significantly decreased after heat-treatment at 63 degrees C for 30 or 60 minutes as measured by RID, but the IgG values remained unchanged when measured by IR spectroscopy and refractometers. The lowest correlation coefficient found between IR spectroscopy (r = 0.70) and RID results was in colostrum heat-treated at 63 degrees C for 60 minutes. For digital (r = 0.48) and optical (r = 0.50) refractometers, the lowest correlation coefficient was at 63 degrees C for 30 minutes when compared to RID. The accuracy of the IR spectroscopy, digital and optical Brix refractometers was decreased from 91.7 to 80%, 81.7 to 45%, and 80 to 45%, respectively, when colostrum heat-treated at 63 degrees C for 60 minutes. CONCLUSIONS AND CLINICAL IMPORTANCE: Radial immunodiffusion, IR spectroscopy, and Brix refractometers exhibit utility for measuring IgG concentration when colostrum heat-treated at 60 degrees C but does not detect decrease IgG concentrations when heat-treated at 63 degrees C. PMID- 29280197 TI - Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: Case report and review of fungal pericarditis. AB - Cryptococcus neoformans is a saprophytic fungal pathogen that can cause serious illness in immune-compromised hosts and it presents with a wide variety of clinical symptoms. We present a fatal case of fulminant C. neoformans infection presenting as pericardial tamponade in a 71-year-old male with chronic myelomonocytic leukaemia undergoing chemotherapy with the JAK-STAT inhibitor ruxolitinib. We also review the published cases of fungal pericarditis/tamponade. In addition to illustrating an atypical presentation of C. neoformans, this case highlights the risk for opportunistic fungal infections in patients with haematological malignancies, especially the ones treated with small molecule kinase inhibitors. PMID- 29280198 TI - Candiduria in kidney transplant recipients: Is antifungal therapy useful? AB - A French single-centre retrospective study between 2010 and 2014 was undertaken to assess candiduria's incidence in kidney transplant recipients (KTR), and the use and impact of antifungal treatment on outcome. Candiduria was defined as a urine culture with >=103 cfu/mL of Candida species. Candiduria clearance, severe complications and death rates were estimated by Kaplan-Meier methods and the effect of treatment by Cox models. 52/1223 (4.3%) KTR had >=1 episode of candiduria, 42 (81%) were females, 18 (35%) had diabetes, with an incidence of 2.3/100 person-year of follow-up. Candiduria was asymptomatic in 51 (98%) patients. Candida glabrata was the most frequent pathogen identified. Overall fungal clearance rate was 89%. Antifungal therapy was initiated in only 14 episodes (12%), according to guidelines. Three patients (6%) developed severe complications in the first 2 weeks after transplantation, and 8 (15%) died. Antifungal treatment had no impact on candiduria clearance (HR, 0.6; 95% CI, 0.3 1.1; P = .10), on recurrence rate (HR, 0.5; 95% CI, 0.1-2.3; P = .41) and on the risk of severe complications or death (HR, 1.1; 95% CI, 0.3-4.8; P = .89). Candiduria is rare and usually asymptomatic among KTR. Candiduria management in the immediate post-transplant period deserves careful attention. PMID- 29280199 TI - Human neonatal Fc receptor as a new potential antibody binding protein for antibody immobilization. AB - A critical challenge in producing an antibody-based assay with the highest reproducibility and sensitivity is the strategy to immobilize antibodies to solid phase. To date, numerous methods of antibody immobilization were reported but each was subjected to its advantages and limitations. The current study proposes a new potential antibody binding protein, the human neonatal fragment crystallizable (Fc) receptor. This protein has shown its high affinity to the Fc of antibody either in vivo or in vitro. Human neonatal Fc receptor is a heterodimer constructed by p51 alpha-heavy chain and beta2-microglobulin light chain; however, the binding sites toward the antibody are located in the p51 alpha-heavy chain. Hence, vector cloning and recombinant protein expression were carried out to express the p51 alpha-heavy chain of the human neonatal Fc receptor (hFcRn-alpha). The recombinant protein expressed, hFcRn-alpha, was adopted to pin rabbit IgG against hepatitis B virus surface antigen to a solid phase. A sandwich enzyme-linked immunosorbent assay was further developed to evaluate the efficiency of hFcRn-alpha-directed immobilization in antigen detection. The result was compared with the conventional physical adsorption method. The findings demonstrated that human neonatal Fc receptor was efficient in pinning antibodies and generating higher signals compared with the physical adsorption of antibody. PMID- 29280200 TI - A study of human neutrophil antigen genotype frequencies in Hong Kong. AB - BACKGROUND: Alloantibodies against human neutrophil antigens (HNA) are associated with a variety of clinical conditions. Over the past decade, the allelic and genotypic frequencies of the five HNA systems have been evaluated. Although the HNA system is less polymorphic than human leukocyte antigens (HLA), significant differences in the genotypic and allele frequencies still exist in different populations, even those living in close proximity. OBJECTIVES: To delineate HNA genotypic and allele frequencies to provide vital information on estimating the risk of HNA-associated diseases for our local population. METHODS: Using a validated, in-house-developed assay, genotyping for HNA-1, HNA-3, HLA-4 and HNA-5 was performed on 300 samples from Chinese blood donors from Hong Kong. In addition, the frequency of the HNA-2 c.843A > T allele was also determined. RESULTS: The allele frequencies of HNA-1a, -1b and -1c alleles were 67.8, 31.5 and 0%, respectively, whereas the frequencies of HNA-3a and HNA-3b were 71.0 and 29.0%, respectively. The frequencies of HNA-4a and -4b alleles were 99.5 and 0.5%, respectively, and for HNA-5a and -5b, alleles were 85.2 and 14.8%, respectively. Homozygotes for the HNA-2 c.843 TT variant were absent in our population, whereas only <4% of the population were c.843AT heterozygote carriers. CONCLUSIONS: This is the first study to define HNA genotype and allele frequencies using a validated modified in-house PCR-SSP method in the Hong Kong Chinese blood donor population. Our approach provides a cost-effective assay for conducting routine HNA typing and facilitates the incorporation of these assays into routine clinical service. Our results are comparable with those reported in the Guangzhou Chinese population, but the allele frequencies in our Hong Kong Chinese population are significantly different from the reported European frequencies, confirming that a geographical difference exists for HNA allele frequencies. PMID- 29280201 TI - Yolk-Shell Nanostructures: Design, Synthesis, and Biomedical Applications. AB - Yolk-shell nanostructures (YSNs) composed of a core within a hollow cavity surrounded by a porous outer shell have received tremendous research interest owing to their unique structural features, fascinating physicochemical properties, and widespread potential applications. Here, a comprehensive overview of the design, synthesis, and biomedical applications of YSNs is presented. The synthetic strategies toward YSNs are divided into four categories, including hard templating, soft-templating, self-templating, and multimethod combination synthesis. For the hard- or soft-templating strategies, different types of rigid or vesicle templates are used for making YSNs. For the self-templating strategy, a number of unconventional synthetic methods without additional templates are introduced. For the multimethod combination strategy, various methods are applied together to produce YSNs that cannot be obtained directly by only a single method. The biomedical applications of YSNs including biosensing, bioimaging, drug/gene delivery, and cancer therapy are discussed in detail. Moreover, the potential superiority of YSNs for these applications is also highlighted. Finally, some perspectives on the future research and development of YSNs are provided. PMID- 29280202 TI - Environmental distribution of Cryptococcus species and some other yeast-like fungi in India. AB - A study of environmental distribution revealed the occurrence of Cryptococcus neoformans and C. gattii in 9% and 3%, respectively, of 611 samples investigated. C. neoformans showed the highest isolation frequency from tree trunk hollows in Delhi (31%), whereas C. gattii occurred in 12% of the samples in Delhi and 5% in Rajasthan. In addition, Cryptococcus laurentii (=Papiliotrema laurentii), C. rajasthanensis (=Papiliotrema rajasthanensis), C. podzolicus (=Saitozyma podzolica) and C. flavescens (=Papiliotrema flavescens) occurred in 0.5% each. The recovery of C. flavescens and C. podzolicus was new findings for India. One more noteworthy finding was isolation of a new yeast, recently classified as Saitozyma cassiae sp. Novo. The previous strain of this yeast came from tree bark debris in South India. Our isolates came from decayed wood inside a trunk hollow of an Acacia tree in, Bharatpur Bird Sanctuary, Rajasthan. The isolations of novel strains of Cutaneotrichosporon moniliiforme from decayed wood of a Pinus tree was another significant finding. Phenotypically, they differed from T. moniliforme by being encapsulated cells, had melanin-like pigment production and were unable to assimilate d-manitol and d-melezitose. AFLP analysis showed a distinctive banding profile vis-a-vis the reference strains of T. moniliiforme and Cryptotrichosporon anacardii. PMID- 29280203 TI - Improving the cytological diagnosis of high-grade serous carcinoma in ascites with a panel of complementary biomarkers in cell blocks. AB - INTRODUCTION: Precise cytological diagnosis of pelvic high-grade serous carcinoma (HGSC) in ascites is important for tumour staging, therapeutic decision-making and prognostic evaluation. However, it can often be difficult to distinguish metastatic HGSC cells from reactive mesothelial cells based on morphology alone. Immunocytochemical analysis of ascites cell blocks has been used to obtain accurate diagnosis and provide a reliable basis for treatment decisions in the clinic. This study was performed to determine whether a panel of antibodies is necessary to achieve high specificity and sensitivity for the identification of HGSC cells. METHODS: Ascites samples from 70 cases (70/253, 27.7%) of histologically confirmed HGSC were postoperatively collected from 2012 to 2015 and were immunocytochemically analysed. RESULTS: The sensitivity and specificity of Ber-EP4 (a marker of HGSC) for detecting HGSC was 85.7% and 82.1%, respectively, whereas the sensitivity and specificity of HBME-1 for identifying mesothelial cells was 100% and 68.3%, respectively. To improve the rate of detection further of HGSC, 29 cases of ascites were also stained for E-cadherin (a marker of HGSC) and calretinin (a marker of mesothelial cells). The combination of Ber-EP4 and E-cadherin as markers of adenocarcinoma cells increased the sensitivity and specificity for HGSC detection to 100% and 88.9%, respectively. Meanwhile, the sensitivity and specificity for mesothelial cell identification increased to 100% and 90%, respectively, when HBME-1 and calretinin were combined. CONCLUSION: This panel of complementary biomarkers is valuable and ideal for the differential diagnosis of HGSC based on ascites cytology. PMID- 29280204 TI - An eight-channel sodium/proton coil for brain MRI at 3 T. AB - The purpose of this work is to illustrate a new coil decoupling strategy and its application to a transmit/receive sodium/proton phased array for magnetic resonance imaging (MRI) of the human brain. We implemented an array of eight triangular coils that encircled the head. The ensemble of coils was arranged to form a modified degenerate mode birdcage whose eight shared rungs were offset from the z-axis at interleaved angles of +/-30 degrees . This key geometric modification resulted in triangular elements whose vertices were shared between next-nearest neighbors, which provided a convenient location for counter-wound decoupling inductors, whilst nearest-neighbor decoupling was addressed with shared capacitors along the rungs. This decoupling strategy alleviated the strong interaction that is characteristic of array coils at low frequency (32.6 MHz in this case) and allowed the coil to operate efficiently in transceive mode. The sodium array provided a 1.6-fold signal-to-noise ratio advantage over a dual nuclei birdcage coil in the center of the head and up to 2.3-fold gain in the periphery. The array enabled sodium MRI of the brain with 5-mm isotropic resolution in approximately 13 min, thus helping to overcome low sodium MR sensitivity and improving quantification in neurological studies. An eight channel proton array was integrated into the sodium array to enable anatomical imaging. PMID- 29280205 TI - Interstitial P-Doped CdS with Long-Lived Photogenerated Electrons for Photocatalytic Water Splitting without Sacrificial Agents. AB - Photocatalytic hydrogen evolution from pure water is successfully realized by using interstitial P-doped CdS with rich S vacancies (CdS-P) as the photocatalyst in the absence of any electron sacrificial agents. Through interstitial P doping, the impurity level of S vacancies is located near the Fermi level and becomes an effective electron trap level in CdS-P, which can change dynamic properties of photogenerated electrons and thus prolong their lifetimes. The long-lived photogenerated electrons are able to reach the surface active sites to initiate an efficient photocatalytic redox reaction. Moreover, the photocatalytic activity of CdS-P can be further improved through the loading of CoP as a cocatalyst. PMID- 29280206 TI - Utilization of Peroxide Reduction Reaction at Air-Liquid-Solid Joint Interfaces for Reliable Sensing System Construction. AB - The utilization of hydrogen peroxide (H2 O2 ) cathodic reaction is an ideal approach to develop reliable biosensors that are immune to interferences arising from oxidizable endogenous/exogenous species in biological solutions. However, practical application of such a detection scheme is limited due to the significantly fluctuating oxygen levels in solutions, as oxygen can be reduced at similar potentials. Herein, this limitation is addressed by developing a novel electrode system with superhydrophobicity-mediated air-liquid-solid joint interfaces, which allows the rapid and continuous transport of oxygen from the air phase to the electrode surface and provides a fixed interfacial oxygen concentration. Using cathodic measurement of the enzymatic product H2 O2 , the sensing platform is applied to detect glucose, a model analyte, achieving a remarkably high selectivity (~2% signal modulation due to common biologic interferents), sensitivity (18.56 uA cm-2 mm-1 ), and a dynamic linear range up to 80 * 10-3 m. The utility of H2 O2 reduction reaction at triphase interface to achieve reliable sensing platforms is general, and hence has broad potential in the fields of medical research, clinical diagnosis, and environmental analysis. PMID- 29280207 TI - Blocking Energy-Loss Pathways for Ideal Fluorescent Organic Light-Emitting Diodes with Thermally Activated Delayed Fluorescent Sensitizers. AB - Organic light-emitting diodes (OLEDs) based on thermally activated delayed fluorescence-sensitized fluorescence (TSF) offer the possibility of attaining an ultimate high efficiency with low roll-off utilizing noble-metal free, easy-to synthesize, pure organic fluorescent emitters. However, the performances of TSF OLEDs are still unsatisfactory. Here, TSF-OLEDs with breakthrough efficiencies even at high brightnesses by suppressing the competitive deactivation processes, including direct charge recombination on conventional fluorescent dopants (CFDs) and Dexter energy transfer from the host to the CFDs, are demonstrated. On the one hand, electronically inert terminal-substituents are introduced to protect the electronically active core of the CFDs; on the other hand, delicate device structures are designed to provide multiple energy-funneling paths. As a result, unprecedentedly high maximum external quantum efficiency/power efficiency of 24%/71.4 lm W-1 in a green TSF-OLED are demonstrated, which remain at 22.6%/52.3 lm W-1 even at a high luminance of 5000 cd m-2 . The work unlocks the potential of TSF-OLEDs, paving the way toward practical applications. PMID- 29280208 TI - Medial gastrocnemius muscle stiffness cannot explain the increased ankle joint range of motion following passive stretching in children with cerebral palsy. AB - NEW FINDINGS: What is the central question of this study? Can the increased range of motion seen acutely after stretching in children with cerebral palsy be explained by changes in the stiffness of the medial gastrocnemius fascicles? What is the main finding and its importance? We show, for the first time, that passive muscle and tendon properties are not changed acutely after a single bout of stretching in children with cerebral palsy and, therefore, do not contribute to the increase in range of motion. This contradicts common belief and what happens in healthy adults. ABSTRACT: Stretching is often used to increase or maintain the joint range of motion (ROM) in children with cerebral palsy (CP), but the effectiveness of these interventions is limited. Therefore, our aim was to determine the acute changes in muscle-tendon lengthening properties that contribute to increased ROM after a bout of stretching in children with CP. Eleven children with spastic CP [age 12.1 (3 SD) years, 5/6 hemiplegia/diplegia, 7/4 gross motor function classification system level I/II] participated. Each child received three sets of five * 20 s passive, manual static dorsiflexion stretches separated by 30 s rest, with 60 s rest between sets. Before and immediately after stretching, ultrasound was used to measure medial gastrocnemius fascicle lengthening continuously over the full ROM and an individual common ROM pre- to post-stretching. Simultaneously, three-dimensional motion of two marker clusters on the shank and the foot was captured to calculate ankle angle, and ankle joint torque was calculated from manually applied torques and forces on a six degrees-of-freedom load cell. After stretching, the ROM was increased [by 9.9 (12.0) deg, P = 0.005]. Over a ROM common to both pre- and post-measurements, there were no changes in fascicle lengthening or torque. The maximal ankle joint torque tolerated by the participants increased [by 2.9 (2.4) N m, P = 0.003], and at this highest passive torque the maximal fascicle length was 2.8 (2.4) mm greater (P = 0.009) when compared with before stretching. These results indicate that the stiffness of the muscle fascicles in children with CP remains unaltered by an acute bout of stretching. PMID- 29280209 TI - Sleep spindles and slow waves in schizophrenia and related disorders: main findings, challenges and future perspectives. AB - Sleep abnormalities have recently gained renewed attention in patients diagnosed with schizophrenia. Disrupted thalamocortical brain oscillations hold promise as putative biomarkers or endophenotypes of the disorder. Despite an increase in studies related to sleep spindle and slow-wave activity, findings remain in part contradictory. Although sleep spindle deficits have been confirmed in several groups of patients with chronic, medicated schizophrenia, data on the early stages of the disorder and in unmedicated subjects are still insufficient. Findings on slow-wave abnormalities are largely inconclusive, possibly due to the different criteria employed to define the phenomenon and to the influence of atypical antipsychotics. In this review, we aim to address the methodological and practical issues that may have limited the consistency of findings across research groups and different patient populations. Given the neurobiological relevance of these oscillations, which reflect the integrity of thalamocortical and cortico-cortical function, research in this domain should be encouraged. To promote widespread consensus over the scientific and clinical implications of these sleep-related phenomena, we advocate uniform and sound methodological approaches. These should encompass electroencephalographic recording and analysis techniques but also selection criteria and characterization of clinical populations. PMID- 29280210 TI - Genetically Engineered Liposome-like Nanovesicles as Active Targeted Transport Platform. AB - Ligand-targeted delivery of drug molecules to various types of tumor cells remains a major challenge in precision medicine. Inspired by the secretion process and natural cargo delivery functions of natural exosomes, biomimetic synthetic strategies are exploited to prepare biofunctionalized liposome-like nanovesicles (BLNs) that can artificially display a wide variety of targeting protein/peptide ligands and directly encapsulate medical agents for enhanced drug delivery. Here, as a proof of concept, genetically engineered BLNs, which display human epidermal growth factor (hEGF) or anti-HER2 Affibody as targeting moieties, are developed to, respectively, target two types of tumor cells. Notably, in comparison to synthetic liposomes covalently coupled with hEGF, it is demonstrated in this work that biosynthetically displayed hEGF ligands on BLNs possess higher biological activities and targeting capabilities. Additionally, treatments with doxorubicin-loaded BLNs displaying Affibody ligands exhibit much better antitumor therapeutic outcomes than clinically approved liposomal doxorubicin (Doxil) in HER2-overexpressing BT474 tumor xenograft models. These data suggest that BLN is suitable as a potent surrogate for conventional proteoliposomes or immunoliposomes as a result of excellent targeting capacities and facile production of BLNs. PMID- 29280211 TI - Radial magnetic resonance imaging (MRI) using a rotating radiofrequency (RF) coil at 9.4 T. AB - The rotating radiofrequency coil (RRFC) has been developed recently as an alternative approach to multi-channel phased-array coils. The single-element RRFC avoids inter-channel coupling and allows a larger coil element with better B1 field penetration when compared with an array counterpart. However, dedicated image reconstruction algorithms require accurate estimation of temporally varying coil sensitivities to remove artefacts caused by coil rotation. Various methods have been developed to estimate unknown sensitivity profiles from a few experimentally measured sensitivity maps, but these methods become problematic when the RRFC is used as a transceiver coil. In this work, a novel and practical radial encoding method is introduced for the RRFC to facilitate image reconstruction without the measurement or estimation of rotation-dependent sensitivity profiles. Theoretical analyses suggest that the rotation-dependent sensitivities of the RRFC can be used to create a uniform profile with careful choice of sampling positions and imaging parameters. To test this new imaging method, dedicated electronics were designed and built to control the RRFC speed and hence positions in synchrony with imaging parameters. High-quality phantom and animal images acquired on a 9.4 T pre-clinical scanner demonstrate the feasibility and potential of this new RRFC method. PMID- 29280212 TI - Lack of evidence for the transmission of hepatitis E virus by coagulation factor concentrates based on seroprevalence data. AB - BACKGROUND: Whether hepatitis E virus (HEV) infection can be transmitted by coagulation factor concentrates remains unclear. OBJECTIVES: The HEV seroprevalence in blood donors and recipients of coagulation factor concentrates was compared to obtain evidence of whether a transmission of HEV by coagulation factor concentrates could occur. METHODS: Archived samples from whole blood donors and patients who had received coagulation factor concentrates were investigated for the presence of anti-HEV IgG by ELISA. Western blotting was used to confirm the positive samples that showed reactivity in the ELISA. RESULTS: Of 357 blood donors, 68 (19%) presented IgG antibodies against HEV. Two of 92 patients who had received coagulation factor concentrates (2.2%) and 1 of the 69 patients who had received plasma-derived products (1.5%) tested positive for anti HEV IgG. The seroprevalence of HEV in the patient group was significantly lower (P = 0.038) than that in the donor group. The two positive patients were a 72 year-old man treated with plasma-derived products and a 5-year-old girl treated with a recombinant coagulation factor concentrate. CONCLUSION: HEV seroprevalence was significantly higher in the blood donors than in the patients with a history of coagulation factor concentrate administration. In one of two patients with detectable anti-HEV IgG antibodies, the coagulation factor concentrate was not the probable source of infection. Our data suggest that HEV is efficiently inactivated during the manufacturing process of coagulation factor concentrates. Thus, testing for the presence of HEV RNA in plasma donated for the preparation of coagulation factor concentrates may not be necessary. PMID- 29280213 TI - Metabolism of bisphenol S in mice after oral administration. AB - RATIONAL: As an important substitute of bisphenol A (BPA), bisphenol S (BPS) shows comparable estrogenic effects. BPS is now widely used in consumer products with widespread human exposures. In order to evaluate the health risk of BPS, it is essential to develop a rapid method for the determination of BPS and its metabolites as well as its biotransformation capacity in vivo. METHODS: Two major BPS phase II metabolites, BPS glucuronide (BPS-G) and BPS sulfate (BPS-S), were synthesized and used as standards for the development of UPLC-ESI-MS/MS method. Phase II metabolism of BPS in imprinting control region (ICR) female mice after the oral administration with different dosages (10, 100, 1000 MUg/kg body weight) was investigated. RESULTS: Urinary elimination was the main excretion route for BPS, with the total recovery ranging from 52.8% to 78.1%. In urine, BPS-G was identified as the predominant metabolite, and the maximum concentrations of BPS-G and BPS-S were obtained at 6 h after the oral administration upon the adjustment by creatinine. BPS was the major compound existed in feces. Only trace amounts of BPS and its metabolites were detected in digestive and excretory related tissues (<1%). CONCLUSIONS: The distribution and metabolic pathway of BPS in mice were assessed. More than 50% of BPS was excreted through phase II metabolism. Due to the biological inactivity of BPS-G and BPS-S, rapid metabolism of BPS to BPS-G and BPS-S may result in reduced toxicity of BPS in vivo. PMID- 29280214 TI - Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11. AB - For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies. PMID- 29280215 TI - Cardiolipin synthase A colocalizes with cardiolipin and osmosensing transporter ProP at the poles of Escherichia coli cells. AB - Osmosensing by transporter ProP is modulated by its cardiolipin (CL)-dependent concentration at the poles of Escherichia coli cells. Other contributors to this phenomenon were sought with the BACterial Two-Hybrid System (BACTH). The BACTH tagged variants T18-ProP and T25-ProP retained ProP function and localization. Their interaction confirmed the ProP homo-dimerization previously established by protein crosslinking. YdhP, YjbJ and ClsA were prominent among the putative ProP interactors identified by the BACTH system. The functions of YdhP and YjbJ are unknown, although YjbJ is an abundant, osmotically induced, soluble protein. ClsA (CL Synthase A) had been shown to determine ProP localization by mediating CL synthesis. Unlike a deletion of clsA, deletion of ydhP or yjbJ had no effect on ProP localization or function. All three proteins were concentrated at the cell poles, but only ClsA localization was CL-dependent. ClsA was shown to be N terminally processed and membrane-anchored, with dual, cytoplasmic, catalytic domains. Active site amino acid replacements (H224A plus H404A) inactivated ClsA and compromised ProP localization. YdhP and YjbJ may be ClsA effectors, and interactions of YdhP, YjbJ and ClsA with ProP may reflect their colocalization at the cell poles. Targeted CL synthesis may contribute to the polar localization of CL, ClsA and ProP. PMID- 29280217 TI - Award Winners and Abstracts of the 31st Annual Symposium of The Protein Society, Montreal, Canada, July 24-27, 2017. PMID- 29280216 TI - Contribution of cervical cytology in the diagnostic work-up of patients with endometrial cancer. AB - INTRODUCTION: Abnormal cervical cytology in patients with endometrial cancer (EC) has been associated with poor outcome. The aim of this study was to evaluate whether cervical cytology could contribute to an improved preoperative identification of high-grade EC (serous, clear cell, carcinosarcoma, high-grade endometrioid EC) in final histology. METHODS: A retrospective cohort study was performed in five hospitals in the Netherlands. A total of 554 patients with EC that underwent primary surgical treatment between 2002 and 2010 were included. Primary outcome was defined as the contribution of abnormal cervical cytology in the preoperative identification of high-grade EC. As secondary outcome, recurrence-free survival (RFS) and disease-specific survival were determined based on preoperative cervical cytology, and compared to the currently established risk factors: myometrial invasion, high-grade and lymph vascular space invasion. RESULTS: Abnormal cervical cytology was present in 45.1%. For patients with preoperative inconclusive and high-grade histology, the presence of abnormal cervical cytology contributed to an improved identification of high grade EC in final histology (odds ratio [OR] 6.40 [95% confidence interval {CI}: 1.92-21.26]; OR 2.86 [95% CI: 1.14-7.14]), respectively. Patients with abnormal cervical cytology had a significant worse 5-year median RFS. Abnormal cervical cytology was independently related to RFS (hazard ratio 1.67 [95% CI: 1.04-2.68]) and disease-specific survival (hazard ratio 3.15 [95% CI: 1.74-5.71]). CONCLUSIONS: Abnormal cytology contributes to the preoperative identification of patients with high-grade EC, and is associated with compromised outcome. Future studies are warranted to determine whether cervical cytology could be incorporated into preoperative prediction models for lymph node metastasis. PMID- 29280218 TI - Rapid Monitoring of Pharmacological Volatiles of Night-Flowering Evening-Primrose According to Flower Opening or Closing by Fast Gas Chromatography/Surface Acoustic Wave Sensor (Electronic zNose). AB - INTRODUCTION: Aroma is important in night-flowering species, as visually they can not be observed well. Thus, the analysis of the volatiles of evening-primrose is of great interest in biological fields and therapy. Furthermore, the analysis of volatiles demands rapid and simple procedure, because volatiles decompose. OBJECTIVE: The aim of this study is to show the rapid monitoring of the volatiles of evening-primrose according to the flowering or closing by fast gas chromatography/surface acoustic wave GC/SAW. Moreover, calibration according to the sensor temperature of the GC/SAW was performed, achieving a high reproducibility and excellent sensitivity. METHODOLOGY: GC/SAW is an effective analytical method that provides on-line measurements without pretreatment of sample. Headspace solid-phase micro-extraction coupled to gas chromatography mass spectrometry (HS-SPME-GC-MS) and dynamic headspace trapping and extraction with GC-MS were employed to confirm the identification of the volatiles of evening primrose compared to GC/SAW. RESULTS: Linalool was found to be the dominant component, comprising 96.4-25.2% of the total amount, according to the opening or closing. Interestingly, the amount of indole also varied according to the opening or closing (3.0-0.0%) such as linalool. Also, while the sensitivity increased with the reduction in the sensor temperature of the GC/SAW, the reproducibility showed a tendency to decrease. CONCLUSION: The results showed that flower opening is related to the volatiles emission, which is pharmacological and plant defensive. GC/SAW can be a useful analytical method for the rapid monitoring of volatiles of evening-primrose according to the opening or closing as it provides second unit analysis, as well as simple, and aroma pattern recognition. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29280219 TI - 3D-Printed Biomimetic Super-Hydrophobic Structure for Microdroplet Manipulation and Oil/Water Separation. AB - Biomimetic functional surfaces are attracting increasing attention for various technological applications, especially the superhydrophobic surfaces inspired by plant leaves. However, the replication of the complex hierarchical microstructures is limited by the traditional fabrication techniques. In this paper, superhydrophobic micro-scale artificial hairs with eggbeater heads inspired by Salvinia molesta leaf was fabricated by the Immersed surface accumulation three dimensional (3D) printing process. Multi-walled carbon nanotubes were added to the photocurable resins to enhance the surface roughness and mechanical strength of the microstructures. The 3D printed eggbeater surface reveals interesting properties in terms of superhydrophobilicity and petal effect. The results show that a hydrophilic material can macroscopically behave as hydrophobic if a surface has proper microstructured features. The controllable adhesive force (from 23 MUN to 55 MUN) can be easily tuned with different number of eggbeater arms for potential applications such as micro hand for droplet manipulation. Furthermore, a new energy-efficient oil/water separation solution based on our biomimetic structures was demonstrated. The results show that the 3D printed eggbeater structure could have numerous applications, including water droplet manipulation, 3D cell culture, micro reactor, oil spill clean-up, and oil/water separation. PMID- 29280221 TI - What is adolescent polycystic ovary syndrome? AB - The diagnostic criteria for adolescent polycystic ovary syndrome (PCOS) has been derived from adult criteria, which makes diagnosis challenging as criteria include normal physiological events that occur during puberty such as acne, hirsutism, menstrual irregularities, high androgen levels and polycystic ovarian morphology on pelvic ultrasound. The only criteria that applies from the adult criteria is exclusion of other conditions that mimic PCOS. Clinical findings consistent with hyperandrogenaemia during adolescence include inflammatory acne, hirsutism, alopecia and/or menstrual irregularities, which are severe and present 2 years after menarche. The measurement of androgen levels during adolescence should take into account age, puberty, type of androgen measured, assay used and diurnal rhythm. Multiple measurements are useful to demonstrate hyperandrogenaemia. The combination, severity and persistence of the hyperandrogenic symptoms and hyperandrogenaemia in girls 2 years or more post menarche support the diagnosis of adolescent PCOS. Adolescent girls with these findings should be followed up into adulthood. PMID- 29280222 TI - The eyes have it: Using eye tracking to inform information processing strategies in multi-attributes choices. AB - Although choice experiments (CEs) are widely applied in economics to study choice behaviour, understanding of how individuals process attribute information remains limited. We show how eye-tracking methods can provide insight into how decisions are made. Participants completed a CE, while their eye movements were recorded. Results show that although the information presented guided participants' decisions, there were also several processing biases at work. Evidence was found of (a) top-to-bottom, (b) left-to-right, and (c) first-to-last order biases. Experimental factors-whether attributes are defined as "best" or "worst," choice task complexity, and attribute ordering-also influence information processing. How individuals visually process attribute information was shown to be related to their choices. Implications for the design and analysis of CEs and future research are discussed. PMID- 29280220 TI - FtsA reshapes membrane architecture and remodels the Z-ring in Escherichia coli. AB - Cell division in prokaryotes initiates with assembly of the Z-ring at midcell, which, in Escherichia coli, is tethered to the inner leaflet of the cytoplasmic membrane through a direct interaction with FtsA, a widely conserved actin homolog. The Z-ring is comprised of polymers of tubulin-like FtsZ and has been suggested to provide the force for constriction. Here, we demonstrate that FtsA exerts force on membranes causing redistribution of membrane architecture, robustly hydrolyzes ATP and directly engages FtsZ polymers in a reconstituted system. Phospholipid reorganization by FtsA occurs rapidly and is mediated by insertion of a C-terminal membrane targeting sequence (MTS) into the bilayer and further promoted by a nucleotide-dependent conformational change relayed to the MTS. FtsA also recruits FtsZ to phospholipid vesicles via a direct interaction with the FtsZ C-terminus and regulates FtsZ assembly kinetics. These results implicate the actin homolog FtsA in establishment of a Z-ring scaffold, while directly remodeling the membrane and provide mechanistic insight into localized cell wall remodeling, invagination and constriction at the onset of division. PMID- 29280223 TI - Psychiatric comorbidities among ovarian cancer survivors in South Korea: A nationwide population-based, longitudinal study. AB - PURPOSE: The aim of this time-dependent study was to analyze the prevalence of mental disorders in ovarian cancer survivors using claims data in South Korea. MATERIALS AND METHODS: We confirmed mental disorders in a nationwide cohort of 9763 patients who were diagnosed with ovarian cancer between January 1, 2010 and December 31, 2014. We categorized the prevalence of mental disorders based on the age and the time of diagnosis. RESULTS: A total of 821 ovarian cancer patients were diagnosed with a mental disorder, 1 year prior to the cancer diagnosis. Of those patients, 311 were diagnosed with depression (37.9%) and 245 with anxiety (29.8%) during their first visit. The overall frequency of mental disorders peaked within 2 months after the cancer diagnosis. The highest rate of increase after diagnosis was noted in stress reaction/adjustment disorders. While depression was relatively high (40.4%) in the younger age group under 60 years, anxiety was higher (39.4%) in the elderly group over 60 years old. Age was a significant predictive factor for mental disorders (P = 0.002), and patients over 50 years were at a higher risk for mental disorders (hazard ratio: 1.29, P = 0.002). CONCLUSION: Mental disorders in ovarian cancer survivors showed different patterns of prevalence depending on age at the time of diagnosis and the nature of disease. Timely diagnosis and intervention for psychological distress could increase the quality of life for ovarian cancer survivors. PMID- 29280224 TI - Trends in opioid utilisation in Australia, 2006-2015: Insights from multiple metrics. AB - PURPOSE: Population-based observational studies have documented global increases in opioid analgesic use. Many studies have used a single population-adjusted metric (number of dispensings, defined daily doses [DDDs], or oral morphine equivalents [OMEs]). We combine these volume-based metrics with a measure of the number of persons dispensed opioids to gain insights into Australian trends in prescribed opioid use. METHODS: We obtained records of prescribed opioid dispensings (2006-2015) subsidised under Australia's Pharmaceutical Benefits Scheme. We used dispensing claims to quantify annual changes in use according to 3 volume-based metrics: DDD/1000 pop/day, OME/1000 pop/day, and dispensings/1000 pop. We estimated the number of persons dispensed at least one opioid in a given year (persons)/1000 pop using data from a 10% random sample of Pharmaceutical Benefits Scheme-eligible Australians. RESULTS: Total opioid use increased according to all metrics, especially OME/1000 pop/day (51% increase) and dispensings/1000 pop (44%). Weaker opioid use remained stable or declined; strong opioid use increased. The rate of persons accessing weaker opioids only decreased 31%, and there was a 238% increase in persons dispensed only strong opioids. Strong opioid use also increased according to dispensings/1000 pop (140%), OME/1000 pop/day (80%), and DDD/1000 pop/day (71% increase). CONCLUSIONS: Our results suggest that the increases in total opioid use between 2006 and 2015 were predominantly driven by a growing number of people treated with strong opioids at lower medicine strengths/doses. This method can be used with or without person level data to provide insights into factors driving changes in medicine use over time. PMID- 29280225 TI - Response to Kypri's commentary on Moore: red tape, the limitations of policy and a science of prevention. PMID- 29280226 TI - Gambling and physical intimate partner violence: Results from the national epidemiologic survey on alcohol and related conditions (NESARC). AB - BACKGROUND AND OBJECTIVES: Links between intimate partner violence (IPV) and gambling problems are under researched in general population samples. Understanding these relationships will allow for improved identification and intervention. We investigated these relationships and sought to determine whether links were attenuated by axis I and II disorders. METHODS: This study examined data from waves 1 and 2 (N = 25,631) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC); a nationally representative survey of U.S. adults. Gambling symptoms and other psychiatric disorders were measured at wave 1 by the Alcohol Use Disorder and Associated Disability Interview Schedule DSM-IV Version (AUDADIS-IV). Physical IPV victimization and perpetration in the last 12 months were assessed 3 years later at wave 2 using items from the Conflict Tactics Scale-R. Binary logistic regression models were used to examine associations separately for males and females. RESULTS: Problem gambling was associated with increased odds of both IPV perpetration for males (OR = 2.62, 95%CI = 1.22-5.60) and females (OR = 2.87, 95%CI = 1.29-6.42), and with IPV victimization for females only (OR = 2.97, 95%CI = 1.31-6.74). Results were attenuated with inclusion of axis I and axis II disorders; links between gambling and IPV were weaker than those involving other mental health conditions. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: There are prospective associations with gambling problems and physical IPV which have implications for identification, spontaneous disclosure, and treatment seeking. The links between gambling problems and violence are complex and should not be considered independently of co-occurring mental health and substance use disorders. (Am J Addict 2018;27:7 14). PMID- 29280227 TI - Neuroimaging of Dilated Perivascular Spaces: From Benign and Pathologic Causes to Mimics. AB - Perivascular spaces (PVSs), also known as Virchow-Robin spaces, are pial-lined, fluid-filled structures found in characteristic locations throughout the brain. They can become abnormally enlarged or dilated and in rare cases can cause hydrocephalus. Dilated PVSs can pose a diagnostic dilemma for radiologists because of their varied appearance, sometimes mimicking more serious entities such as cystic neoplasms, including dysembryoplastic neuroepithelial tumor and multinodular and vacuolating neuronal tumor, or cystic infections including toxoplasmosis and neurocysticercosis. In addition, various pathologic processes, including cryptococcosis and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, can spread into the brain via PVSs, resulting in characteristic magnetic resonance imaging appearances. This review aims to describe the key imaging characteristics of normal and dilated PVSs, as well as cystic mimics and pathologic processes that directly involve PVSs. PMID- 29280228 TI - An update on medication guides. PMID- 29280229 TI - Subjective sleep-related variables in those who have and have not experienced sleep paralysis. AB - Research suggests that poor sleep quality is related to the occurrence of sleep paralysis, although the precise relationship between these two variables is unknown. This association has generated interest due to the related possibility that improving sleep quality could help to combat episodes of sleep paralysis. To date, studies examining the association between sleep quality and sleep paralysis have typically measured sleep quality using general measures such as the global score of the Pittsburgh Sleep Quality Index (PSQI). The aim of this study was to increase the precision of our understanding of the relationship between sleep paralysis and other aspects of sleep by investigating associations between different sleep-related variables and sleep paralysis. Using data from the G1219 twin/sibling study, analyses were performed on 860 individuals aged 22-32 years (66% female). Results showed that two components of the PSQI, sleep latency and daytime dysfunction, were predictors of sleep paralysis. In addition, a number of other sleep-related variables were related significantly to sleep paralysis. These were: insomnia symptoms, sleep problems commonly related to traumatic experiences, presleep arousal, cognitions about sleep and excessive daytime sleepiness. There was no relationship with sleep-disordered breathing, diurnal preference or sleeping arrangements. Potential mechanisms underlying these results and suggestions for future research are discussed. PMID- 29280230 TI - High prevalence of diabetes mellitus, hypertension and obesity among persons with a recorded diagnosis of intellectual disability or autism spectrum disorder. AB - BACKGROUND: Obesity and lack of physical activity are frequently reported in persons with intellectual disability (ID) or autism spectrum disorder (ASD). We hypothesised a higher prevalence of diabetes and hypertension in this population. METHOD: We used administrative data for all primary and specialist outpatient and inpatient healthcare consultations for people with at least one recorded diagnosis of diabetes mellitus, hypertension or obesity from 1998 to 2015. Data were drawn from the central administrative database for Stockholm County, Sweden. It was not possible to separate data for type 1 and type 2 diabetes. We stratified 26 988 individuals with IDs or ASD into three groups, with Down syndrome treated separately, and compared these groups with 1 996 140 people from the general population. RESULTS: Compared with the general population, men and women with ID/ASD had 1.6-3.4-fold higher age-adjusted odds of having a registered diagnosis of obesity or diabetes mellitus, with the exception of diabetes among men with Down syndrome. A registered diagnosis of hypertension was only more common among men with ID/ASD than in the general population. CONCLUSIONS: Diabetes and blood pressure health screening, along with efforts to prevent development of obesity already in childhood, are necessary for individuals with IDs and ASD. We believe that there is a need for adapted community-based health promotion programmes to ensure more equitable health for these populations. PMID- 29280231 TI - A biopsychosocial understanding of lower back pain: Content analysis of online information. AB - OBJECTIVES: (1) To develop a checklist to assess the representation of biopsychosocial lower back pain (LBP) online information; (2) to analyse publicly accessed online LBP information from a Google search for the degree that psychosocial contributors are described alongside the traditional biomedical approach to explaining LBP; (3) whether websites use information on pain biology to educate on LBP; (4) any inaccurate or false information regarding the mechanisms of LBP and; (5) the amount of websites certified by established benchmarks for quality health information. MATERIALS AND METHODS: An online search was conducted using the Google search engines of six major English speaking countries. Website content was analysed using three checklists developed for the purpose of this study - Biopsychosocial information categorisation checklist and scoring criteria; pain biology information checklist; and the inaccurate information checklist. Website quality was identified by the presence of an Health on the Net certification (HONcode). RESULTS: Of the fifteen websites analysed, the content of 26.7% of websites was classified as 'biomedical', 60% 'limited psychosocial' and 13.3% 'reasonable psychosocial'; 20% included information on pain biology; 46.7% inaccurately implied pain to be equal to tissue damage and 46.7% implied pathways specific to pain transmission; 40% were HONcode certified. CONCLUSION: Online LBP information retrieved through a Google search has limited to no integration of psychosocial or pain biology information. The focus on tissue pathology is further supported by the inaccurate descriptions of pain as equal to tissue damage and as an input to the central nervous system (CNS). Online LBP information needs to be guided by criteria more sensitive to the psychosocial contributors to pain. SIGNIFICANCE: The online LBP information retrieved from a Google search needs to be guided by information more sensitive to the psychosocial contributors to pain and disability. This study also highlights the presence of inaccurate information that implied pain as a measure of tissue damage or as an input to the nervous system. PMID- 29280232 TI - Intraspecific variation in seed morphology of tribe vicieae (Papilionoidae) using scanning electron microscopy techniques. AB - Seed micromorphology of 12 species of tribe Vicieae (Papilionoidae) representing five genera were examined using Scanning Electron Microscope (SEM). The different seed types were described, illustrated, compared, and their taxonomic importance is discussed. Seeds exhibit great diversity in ultrastructure and a variety of novel morphological features have been determined among and within genera of the tribe. Seeds were characterized by oval to round shape, ovate to oblong outline and striate to papillate ornamentation. Radiate and wavy cell pattern has been observed as a characteristic exomorphological feature. In Vicia sativa, testa cells superficially seem to form peltate hairs. As a result, seed micromorphology with few exceptions showed variation and its taxonomic value was significant in distinguishing taxa at species level. The disparity in shape and density of papillae or protuberances and alignment of testa cells, may possibly give further insight at intraspecific level within tribe. The findings also illustrated that the use of SEM in seed morphology can reveal hidden morphological affinities among species and showed potential in delimitation of Vicieae members generally at tribe, genus, and particularly at species level. PMID- 29280233 TI - Operant self-administration of pregabalin in a mouse model of neuropathic pain. AB - BACKGROUND: Pregabalin is a first-line agent for neuropathic pain treatment whose abuse liability remains controversial. Surprisingly, studies exploring the reinforcing properties of pregabalin in operant mouse models are missing. METHODS: We evaluated the acquisition of operant pregabalin self-administration in mice exposed to a partial sciatic nerve ligation (PSNL) or a sham operation. After surgery, mice were trained in operant boxes to intravenously self administer pregabalin at 1.5 or 3 mg/kg/inf or saline during 10 days. Thermal and mechanical sensitivity were assessed before and after self-medication, and depressive-like behaviour was evaluated after discontinuation of the treatment. RESULTS: Partial sciatic nerve ligation and sham-operated mice exposed to pregabalin at 3 mg/kg/inf showed higher active responding compared to mice exposed to saline. The differences in active responding were more robust in nerve injured than in sham-operated mice. Self-medication at either dose of pregabalin partially inhibited thermal hypersensitivity, whereas only self-medication at 3 mg/kg/inf reduced mechanical sensitivity. Finally, a depressive-like behaviour was revealed after saline treatment in nerve-injured mice, and this emotional manifestation was abolished after pregabalin treatment at the high dose. CONCLUSIONS: Pregabalin showed reinforcing effects both in PSNL and sham-operated mice and attenuated the nociceptive and emotional manifestations of neuropathic pain in mice self-administering this drug. Therefore, pregabalin self administration was related to neuropathic pain relief, but also to reinforcing properties related to psychotropic drug effects. This study reveals the improvement in nociceptive and emotional manifestations of neuropathic pain after operant pregabalin self-medication in mice and suggests the reinforcing effects of this drug in an operant paradigm. SIGNIFICANCE: This study shows that mice with a nerve injury self-administer pregabalin at doses effective reducing nociceptive hypersensitivity and depressive-like behaviour associated with the neuropathic pain model. Interestingly, mice without neuropathy also develop operant self-administration behaviour, suggesting potential abuse liability of this first-line drug for neuropathic pain treatment. PMID- 29280234 TI - Clinical and biochemical features at diagnosis of type 1 diabetes in patients between 0 and 18 years of age from Jordan. AB - OBJECTIVE: Data regarding type 1 diabetes mellitus (T1D) in Jordan are extremely scarce. We aim to evaluate the clinical and laboratory characteristics at diagnosis of T1D in a group of children from Jordan. METHODS: The records of 437 (boys/girls: 224/213) children with type 1 diabetes followed in the years 2012 to 2016 were evaluated retrospectively. The data were assessed by sex and age subgroups (<5, 6-10, and 11-18 years). RESULTS: Mean age of children at diagnosis was 7.3 +/- 3.6 years. The first peak in the number of T1D cases in terms of age at diagnosis was observed in the age group between 6 and 8 years (n = 116 [26.5%], 95% confidence interval [CI]: 22.3%-30.6%). This was followed by the age group of 3 to 5 years (n = 108 [24.7%], 95% CI: 20.6%-28.7%). Although the patients mostly presented in winter (30.0%, 95% CI: 25.6%-34.3%), no season related significant differences were found. The frequency of ketoacidosis at diagnosis was 40.7% (95% CI: 36%-45.3%). At presentation, 22.8% (95% CI: 18.9% 26.7) of our patients had a positive history of T1D in their extended families. In addition, 61.1% (95% CI: 56.5%-65.7%) of the patients were started on premixed insulin at diagnosis. CONCLUSION: The findings possibly indicate a decreasing age of T1D onset in Jordanian patients. The high frequency of ketoacidosis at presentation is noteworthy. In addition, the initial insulin protocols are not in accordance with the recommended insulin therapy for children and adolescents with T1D. PMID- 29280235 TI - First signs of macroinvertebrate recovery following enhanced restoration of boreal streams used for timber floating. AB - Although ecological restoration generally succeeds in increasing physical heterogeneity, many projects fail to enhance biota. Researchers have suggested several possible explanations, including insufficient restoration intensity, or time-lags in ecological responses that prevent detection of significant changes in short-term monitoring programs. This study aims to evaluate whether benthic macroinvertebrate communities responded to an expanded set of stream restoration measures within a study period of one to five years after completion of the restoration project. We studied 10 forest streams in northern Sweden that were channelized in the past for timber floating. Managers subjected six of these streams to habitat restoration, on each of these we selected two reaches, located in close proximity but differing in restoration intensity. In "basic" restored reaches, the restoration managers broke up the channelized banks and returned cobbles and small boulders to the main channel. In "enhanced" restoration reaches, they added additional large wood and boulders to reaches previously subjected to basic restoration, and rehabilitated gravel beds. The remaining four streams were not restored, and thus represent the baseline impacted (channelized) condition. We surveyed stream benthic assemblages before the enhanced restoration (year 2010) and three times afterward between 2011 and 2015. Five years after restoration, macroinvertebrate assemblages at the enhanced restored reaches were more differentiated from channelized conditions than those at basic-restored reaches. This reflected increased relative abundances of the insect orders Ephemeroptera and Trichoptera and the bivalve molluscs Sphaeriidae and decreased relative abundances of Chironomidae (Diptera). Analysis of functional traits provided further insights on the mechanistic explanations driving the recovery, e.g., indicating that the augmented channel retention capacity at enhanced restored reaches favored taxa adapted to slow flow conditions and more effectively retained passive aquatic dispersers. The increased restoration intensity in enhanced restored reaches has resulted in shifts in the composition of benthic macroinvertebrate assemblages, including increases in more sensitive taxa. These shifts became fully apparent five years after the enhanced restoration. Our results emphasize the value of longer-term monitoring to assess ecological responses following restoration, and of undertaking additional restoration as a valuable management option for previously restored sites that failed to achieve biotic recovery. PMID- 29280236 TI - Advanced Pediatric Neurosonography Techniques: Contrast-Enhanced Ultrasonography, Elastography, and Beyond. AB - Recent technical advances in neurosonography continue broadening the diagnostic utility, sensitivity, and specificity of ultrasound for detecting intracranial abnormalities bed side. The clinical and functional applications of neurosonography have significantly expanded since the 1980s when transcranial Doppler sonography first allowed anatomic and hemodynamic delineation of the intracranial vessels through the thin temporal skull. In the past few years, contrast-enhanced ultrasonography, elastography, 3D/4D reconstruction tools, and high-resolution microvessel imaging techniques have further enhanced the diagnostic significance of neurosonography. Given these advances, a thorough familiarity with these new techniques and devices is crucial for a successful clinical application allowing improved patient care. It is essential that future neurosonography studies compare these advanced techniques against the current "gold standard" computed tomography and magnetic resonance imaging to assure the accuracy of their diagnostic potential. This review will provide a comprehensive update on currently available advanced neurosonography techniques. PMID- 29280237 TI - Direct and indirect effects of false safety behaviors on cannabis use and related problems. AB - BACKGROUND AND OBJECTIVES: In light of increasing rates of cannabis use and use related problems, efforts to understand malleable psychological vulnerability factors related to use and related problems remain important as they can inform prevention and treatment efforts. Recent data indicate that false safety behaviors (FSB; ie, behaviors that may be effective in decreasing anxiety in the short-term, but can maintain and even exacerbate anxiety in the long-term) are related to cannabis problem severity. Thus, an important next step is to identify factors implicated in the relation between FSB and cannabis use behavior. The current study tested whether FSB were uniquely related to cannabis use problems and high-risk cannabis use motives. We also tested whether FSB were indirectly related to cannabis outcomes via high-risk motives. METHOD: The sample consisted of 349 current (69.6% female) cannabis-using undergraduates who completed an online survey. RESULTS: FSB was robustly related to cannabis-related problems and cannabis use motives (ie, coping and availability) after controlling for anxiety and cannabis use frequency. FSB was indirectly related to cannabis problems via coping and availability motives and to cannabis use frequency via coping motives. DISCUSSION AND CONCLUSIONS: Results add to a growing literature indicating that FSB are related to cannabis problem severity and extend this work by identifying mechanisms underlying this relationship. SCIENTIFIC SIGNIFICANCE: Data indicate that FSB may be an under recognized, yet clinically important, vulnerability factor related to cannabis use problems. (Am J Addict 2018;27:29-34). PMID- 29280238 TI - Grazing alters net ecosystem C fluxes and the global warming potential of a subtropical pasture. AB - The impact of grazing on C fluxes from pastures in subtropical and tropical regions and on the environment is uncertain, although these systems account for a substantial portion of global C storage. We investigated how cattle grazing influences net ecosystem CO2 and CH4 exchange in subtropical pastures using the eddy covariance technique. Measurements were made over several wet-dry seasonal cycles in a grazed pasture, and in an adjacent pasture during the first three years of grazer exclusion. Grazing increased soil wetness but did not affect soil temperature. By removing aboveground biomass, grazing decreased ecosystem respiration (Reco ) and gross primary productivity (GPP). As the decrease in Reco was larger than the reduction in GPP, grazing consistently increased the net CO2 sink strength of subtropical pastures (55, 219 and 187 more C/m2 in 2013, 2014, and 2015). Enteric ruminant fermentation and increased soil wetness due to grazers, increased total net ecosystem CH4 emissions in grazed relative to ungrazed pasture (27-80%). Unlike temperate, arid, and semiarid pastures, where differences in CH4 emissions between grazed and ungrazed pastures are mainly driven by enteric ruminant fermentation, our results showed that the effect of grazing on soil CH4 emissions can be greater than CH4 produced by cattle. Thus, our results suggest that the interactions between grazers and soil hydrology affecting soil CH4 emissions play an important role in determining the environmental impacts of this management practice in a subtropical pasture. Although grazing increased total net ecosystem CH4 emissions and removed aboveground biomass, it increased the net storage of C and decreased the global warming potential associated with C fluxes of pasture by increasing its net CO2 sink strength. PMID- 29280239 TI - On-line preparatory information for children and their families undergoing dental extractions under general anesthesia: A phase III randomized controlled trial. AB - BACKGROUND: Family-centered interactive on-line games are increasingly popular in healthcare, but their effectiveness for preoperative preparation needs further research. www.scottga.org is the new on-line version of a proven nonweb-based game for children and parents/caregivers. AIMS: The aim of this study was to evaluate if www.scottga.org improved children's anxiety and families' satisfaction compared with controls. METHODS: In this phase III double-blind randomized controlled trial, children/parents/caregivers received (i) www.scottga.org, (ii) standard care, or (iii) a placebo hand-washing game. The intervention and placebo games were available online for home usage and provided again on the ward before surgery. All children were accompanied by parent/caregivers at induction and observed and scored using validated measures. Stratified randomization and generalized linear models were used. An intention-to treat approach was adopted. RESULTS: Overall, 52/176 children had baseline "psychological disturbance." Children's anxiety increased preinduction, but there were no differences between groups (Facial Image Scale: video-standard OR = 1.08, P = .82, 95% CI [0.56, 2.1]; video-placebo OR = 0.9, P = .77 95% CI [0.46, 1.8]). There were no differences in induction behavior (visual analog scale: video mean = 3.5; standard care mean = 3.5; placebo mean = 3.7: video-standard OR = 2.0, P = .42, 95% CI [-0.6, 1.3]; video-placebo OR = 1.53, P = .65, 95% CI [-0.8, 1.1]) or induction anxiety (modified Yale Preoperative Anxiety Scale: video-standard OR 1.02, P = .97, 95% CI [0.61, 2.6]; video-placebo OR 1.38, P = .49, 95% CI [0.87, 3.81]). Families favored the intervention regarding the "child handling the visit better" (Treatment Evaluation Inventory: video-standard OR = 12; 95% CI 4.7-32; P < .001; video-placebo OR = 8.2; 95% CI 3-22; P < .001) and "improving the child's ability to cope" (Treatment Evaluation Inventory: video-standard OR = 21; 95% CI 8-56; P < .001 and video-placebo OR = 13; 95% CI 5-34; P < .001). CONCLUSION: Families believed that a video-game preparation helped their child's perioperative anxiety, but there were no objective measures of behavioral improvement associated with this intervention. PMID- 29280241 TI - Parental cancer: Characteristics of users of child-centred counselling versus individual psycho-oncological treatment. AB - OBJECTIVE: The aims of this study were to investigate the characteristics of users of a specific child-centred counselling service (COSIP) and to compare those to parents using an individual psycho-oncological treatment (PO). METHODS: We conducted a retrospective analysis on data of users of COSIP and users of PO. Database was the routine assessment (demographic and disease-related characteristics, GAD-7, PHQ-9, EORTC QLQ-C30, and current concerns) of an outpatient psycho-oncological clinic with additional child-centred counselling. A total of 151 patients and 49 partners with children <=21 years were included. We conducted descriptive analyses and group comparisons. RESULTS: Fifty-nine patients and partners used COSIP only or additionally to individual psycho oncological service. PO users were more depressed and were more anxious than COSIP users. Patients using PO reported worse emotional functioning than patients using COSIP. Partners using PO reported worse global quality of life and more symptoms of fatigue than partners using COSIP. With regard to current concerns, patients using COSIP reported child-related issues more frequently than PO users. PO users reported symptoms of anxiety, depressive symptoms, or exhaustion more frequently than COSIP users. CONCLUSIONS: The findings demonstrate that patients and partners self-referring to PO or COSIP are highly burdened. COSIP users experience different psychosocial burden than PO users. As poor mental state of parents is a risk factor for the development of mental problems in children, parents using only PO may benefit from additional child-centred support. Accordingly, the need for COSIP should be assessed continuously during PO of patients with children <=21 years. PMID- 29280242 TI - Pain patterns during adolescence can be grouped into four pain classes with distinct profiles: A study on a population based cohort of 2953 adolescents. AB - INTRODUCTION: Although multi-site pain is common in adolescents, pain conditions are frequently diagnosed and treated in isolation. Little is known about whether there are specific sites in which pain commonly co-occurs. This study examines the patterns of pain in adolescents, and whether these are associated with sports participation, health-related quality of life (HRQoL), and sex. METHODS: In previously collected cohort data ('Adolescent Pain in Aalborg-2011'), adolescents (aged 12-19) completed an online questionnaire, including demographic data, current pain sites, sports participation and HRQoL (assessed by Euro-QoL 5D-3L). Latent class analysis was used to classify spatial pain patterns, based on the pain sites. The analysis included 2953 adolescents. RESULTS: Four classes were identified as follows: (1) little or no pain (63% of adolescents), (2) majority lower extremity pain (10%), (3) multi-site bodily pain (22%) and (4) head and stomach pain (3%). The lower extremity multi-site pain group reported highest weekly sports participation (p < 0.001; mean: 2.9 days/week; 95% CI 2.7 to 3.2), while the multi-site bodily pain and the multi-site head and stomach pain groups had lowest EQ-5D scores (p < 0.001). Males were more likely to belong to the little or no pain class, whereas females were more likely to belong to the multi site bodily pain class. CONCLUSIONS: Latent class analysis identified distinct classes of pain patterns in adolescents, characterized by sex, differences in HRQoL and sports participation. The class with multi-site bodily pain and reduced quality of life was the largest among adolescents reporting pain, and future research on treatment strategies should consider targeting this group. PMID- 29280243 TI - Patient experience in clinical trials: results of a survey. PMID- 29280244 TI - Complex systems thinking in emergency medicine: A novel paradigm for a rapidly changing and interconnected health care landscape. AB - INTRODUCTION: The specialty of emergency medicine is experiencing the convergence of a number of transformational forces in the United States, including health care reform, technological advancements, and societal shifts. These bring both opportunity and uncertainty. 21ST CENTURY CHALLENGES: Persistent challenges such as the opioid epidemic, rising health care costs, misaligned incentives, patients with multiple chronic diseases, and emergency department crowding continue to plague the acute, unscheduled care system. REDUCTIONISM AND COMPLEX SYSTEMS THINKING: The traditional approach to health care practice and improvement reductionism-is not adequate for the complexity of the twenty-first century. Reductionist thinking will likely continue to produce unintended consequences and suboptimal outcomes. Complex systems thinking provides a perspective and set of tools better suited for the challenges and opportunities facing public health in general, and emergency medicine more specifically. IMPLICATIONS FOR EMERGENCY MEDICINE: This article introduces complex systems thinking and argues for its application in the context of emergency medicine by drawing on the history of the circumstances surrounding the formation of the specialty and by providing examples of its application to several practice challenges. PMID- 29280245 TI - Systematic genetic analyses of genome-wide association study data reveal an association between the key nucleosome remodeling and deacetylase complex and bipolar disorder development. AB - BACKGROUND: Genome-wide association studies (GWASs) are used to identify genetic variants for association with bipolar disorder (BD) risk; however, each GWAS can only reveal a small fraction of this association. This study systematically analyzed multiple GWAS data sets to provide further insights into potential causal BD processes by integrating the results of Psychiatric Genomics Consortium Phase I (PGC-I) for BD with core human pathways and functional networks. METHODS: The i-Gsea4GwasV2 program was used to analyze data from the PGC-I GWAS for BD (the pathways came from Reactome), as well as the nominally significant pathways. We established a gene network of the significant pathways and performed a gene set analysis for each gene cluster of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) GWAS data for the volumes of the intracranial region and seven subcortical regions. RESULTS: A total of 30 of 1816 Reactome pathways were identified and showed associations with BD risk. We further revealed 22 interconnected functional and topologically interacting clusters (Clusters 0-21) that were associated with BD risk. Moreover, we obtained brain transcriptome data from BrainSpan and found significant associations between common variants of the genes in Cluster 1 with the hippocampus (HIP; P = .026; family-wise error [FWE] correction) and amygdala (AMY; P = .016; FEW correction) in Cluster 8 with HIP (P = .022; FWE correction). The genes in Cluster 1 were enriched for the transcriptional co-expression profile in the prenatal AMY, and core genes (CDH4, MTA2, RBBP4, and HDAC2) were identified to be involved in regulating early brain development. CONCLUSION: This study demonstrated that the HIP and AMY play a central role in neurodevelopment and BD risk. PMID- 29280246 TI - Rich club and reward network connectivity as endophenotypes for alcohol dependence: a diffusion tensor imaging study. AB - We aimed to examine the whole-brain white matter connectivity and local topology of reward system nodes in patients with alcohol use disorder (AUD) and unaffected siblings, relative to healthy comparison individuals. Diffusion-weighted magnetic resonance imaging scans were acquired from 18 patients with AUD, 15 unaffected siblings of AUD patients and 15 healthy controls. Structural networks were examined using network-based statistic and connectomic analysis. Connectomic analysis showed a significant ordered difference in normalized rich club organization (AUD < Siblings < Controls). We also found rank ordered differences (Control > Sibling > AUD) for both nodal clustering coefficient and nodal local efficiency in reward system nodes, particularly left caudate, right putamen and left hippocampus. Network-based statistic analyses showed that AUD group had significantly weaker connectivity than controls in the right hemisphere, mostly in the edges connecting putamen and hippocampus with other brain regions. Our results suggest that reward system network abnormalities, especially in subcortical structures, and impairments in rich-club organization might be related to the familial predisposition for AUD. PMID- 29280247 TI - Learning by observation and learning by doing in Down and Williams syndromes. AB - New skills may be learned by active experience (experiential learning or learning by doing) or by observation of others' experience (learning by observation). In general, learning by observation reduces the time and the attempts needed to learn complex actions and behaviors. The present research aimed to compare learning by observation and learning by doing in two clinical populations with different etiology of intellectual disability (ID), as individuals with Down syndrome (DS) and individuals with Williams syndrome (WS), with the hypothesis that specific profiles of learning may be found in each syndrome. To this end, we used a mixture of new and existing data to compare the performances of 24 individuals with DS, 24 individuals with WS and 24 typically developing children on computerized tasks of learning by observation or learning by doing. The main result was that the two groups with ID exhibited distinct patterns of learning by observation. Thus, individuals with DS were impaired in reproducing the previously observed visuo-motor sequence, while they were as efficient as TD children in the experiential learning task. On the other hand, individuals with WS benefited from the observational training while they were severely impaired in detecting the visuo-motor sequence in the experiential learning task (when presented first). The present findings reinforce the syndrome-specific hypothesis and the view of ID as a variety of conditions in which some cognitive functions are more disrupted than others because of the differences in genetic profile and brain morphology and functionality. These findings have important implications for clinicians, who should take into account the genetic etiology of ID in developing learning programs for treatment and education. PMID- 29280248 TI - Fine-scale spatial climate variation and drought mediate the likelihood of reburning. AB - In many forested ecosystems, it is increasingly recognized that the probability of burning is substantially reduced within the footprint of previously burned areas. This self-limiting effect of wildland fire is considered a fundamental emergent property of ecosystems and is partly responsible for structuring landscape heterogeneity (i.e., mosaics of different age classes), thereby reducing the likelihood of uncharacteristically large fires in regions with active fire regimes. However, the strength and longevity of this self-limiting phenomenon is not well understood in most fire-prone ecosystems. In this study, we quantify the self-limiting effect in terms of its strength and longevity for five fire-prone study areas in western North America and investigate how each measure varies along a spatial climatic gradient and according to temporal (i.e., annual) climatic variation. Results indicate that the longevity (i.e., number of years) of the self-limiting effect ranges between 15 yr in the warm and dry study area in the southwestern United States to 33 yr in the cold, northern study areas in located in northwestern Montana and the boreal forest of Canada. We also found that spatial climatic variation has a strong influence on wildland fire's self limiting capacity. Specifically, the self-limiting effect within each study area was stronger and lasted longer in areas with low mean moisture deficit (i.e., wetter and cooler settings) compared to areas with high mean moisture deficit (warmer and drier settings). Last, our findings show that annual climatic variation influences wildland fire's self-limiting effect: drought conditions weakened the strength and longevity of the self-limiting effect in all study areas, albeit at varying magnitudes. Overall, our study provides support for the idea that wildland fire contributes to spatial heterogeneity in fuel ages that subsequently mediate future fire sizes and effects. However, our findings show that the strength and longevity of the self-limiting effect varies considerably according to spatial and temporal climatic variation, providing land and fire managers relevant information for effective planning and management of fire and highlighting that fire itself is an important factor contributing to fire-free intervals. PMID- 29280250 TI - A Quintuple [6]Helicene with a Corannulene Core as a C5 -Symmetric Propeller Shaped pi-System. AB - The synthesis and structural analysis of a quintuple [6]helicene with a corannulene core is reported. The compound was synthesized from corannulene in three steps including a five-fold intramolecular direct arylation. X-ray crystallographic analysis revealed a C5 -symmetric propeller-shaped structure and one-dimensional alignment in the solid state. The enantiomers of the quintuple [6]helicene were successfully separated by HPLC, and the chirality of the two fractions was identified by CD spectroscopy. A kinetic study yielded a racemization barrier of 34.2 kcal mol-1 , which is slightly lower than that of pristine [6]helicene. DFT calculations indicate a rapid bowl-to-bowl inversion of the corannulene moiety and a step-by-step chiral inversion pathway for the five [6]helicene moieties. PMID- 29280249 TI - 'It's when you're not doing too much you feel tired': A qualitative exploration of fatigue in end-stage kidney disease. AB - BACKGROUND: Fatigue is commonly experienced in end-stage kidney disease (ESKD) patients. In order to develop patient-centred psychosocial interventions to help patients manage fatigue symptoms, a more in-depth understanding regarding the experience of fatigue is needed. OBJECTIVE: The objective of this study was to explore renal patients' experiences of fatigue, across renal replacement therapy (RRT) modalities. METHODS: Twenty-five in-depth semi-structured interviews were conducted. Interviews were audio-taped, transcribed, and analysed using inductive thematic analysis. RESULTS: Main themes included the strong role of the illness and treatment in the aetiology of fatigue. Two contrasting streams of illness fatigue interpretations emerged: catastrophizing versus normalizing. Participants emphasized the importance of having a sense of purpose in facilitating active management of fatigue. Many participants described the consequences of fatigue on their functioning. Low mood, frustration, and anger were common emotional consequences of fatigue. Three dominant fatigue management strategies emerged: one related to accommodation of activities around fatigue, another on increasing activities to counteract fatigue, and the third one revolved around self compassion. Social support emerged as an important aspect of the fatigue experience, serving as a source of motivation, yet participants were wary of becoming a burden to others. CONCLUSION: Findings identify casual attributions, behavioural and emotional reactions, management strategies, and facilitators of active management of fatigue in ESKD. Untying fatigue from the illness and treatment may help patients to develop alternative less catastrophic perceptions of fatigue, increase their perception of control over fatigue, and facilitate active fatigue management. Statement of contribution What is already known on this subject? Fatigue is persistent and debilitating in end-stage kidney disease (ESKD), with no consistent treatment model. Promising evidence is available for psychological fatigue interventions in other chronic conditions. There is a gap in studies looking at the fatigue experiences of patients with ESKD across renal replacement therapies. What does this study add? Fatigue is not inherently negative, but shaped by patients' beliefs and behaviours. Findings provide novel insights, for example, on the important role social support seems to play in fatigue. An in-depth understanding of fatigue may help to inform a future patient centred intervention in ESKD. PMID- 29280251 TI - Carbon-Supported Nickel Selenide Hollow Nanowires as Advanced Anode Materials for Sodium-Ion Batteries. AB - Carbon-supported nickel selenide (Ni0.85 Se/C) hollow nanowires are prepared from carbon-coated selenium nanowires via a self-templating hydrothermal method, by first dissolving selenium in the Se/C nanowires in hydrazine, allowing it to diffuse out of the carbon layer, and then reacting with nickel ions into Ni0.85 Se nanoplates on the outer surface of the carbon. Ni0.85 Se/C hollow nanowires are employed as anode materials for sodium-ion batteries, and their electrochemical performance is evaluated via the cyclic voltammetry and electrochemical impedance spectroscopy combined with ex situ X-ray photoelectron spectroscopy and X-ray diffraction measurements. It is found that Ni0.85 Se/C hollow nanowires exhibit greatly enhanced cycle stability and rate capability as compared to Ni0.85 Se nanoparticles, with a reversible capacity around 390 mA h g 1 (the theoretical capacity is 416 mA h g-1 ) at the rate of 0.2 C and 97% capacity retention after 100 cycles. When the current rate is raised to 5 C, they still deliver capacity of 219 mA h g-1 . The synthetic methodology introduced here is general and can easily be applied to building similar structures for other metal selenides in the future. PMID- 29280252 TI - Sex hormones in alcohol consumption: a systematic review of evidence. AB - Sex hormones play an important role in establishing sex-distinctive brain structural and functional variations that could contribute to the sex differences in alcohol consumption behavior. Here, we systematically reviewed articles that studied sex hormone impacts on alcohol consumption and alcohol use disorder (AUD). An extensive literature search conducted in MEDLINE, PubMed, Scopus and CINAHL databases identified 776 articles, which were then evaluated for pre specified criteria for relevance and quality assurance. A total of 50 articles, including 19 human studies and 31 animal studies, were selected for this review. Existing evidence supports the association of increased testosterone level and increased risk for alcohol use and AUD in males but results are inconclusive in females. In contrast, the evidence supports the association of increased estrogen level and increased alcohol use in females, with mixed findings reported in males. Much less is known about the impact of progestins on alcohol use and misuse in human subjects. Future observational and experimental studies conducted in both sexes with a comprehensive hormone panel are needed to elucidate the impact of the interplay between various sex hormone levels during various developmental stages on alcohol use-related phenotypes and AUD. PMID- 29280253 TI - Association between dietary pattern scores and the prevalence of colorectal adenoma considering population subgroups. AB - AIM: The purpose of the current study is to examine the dietary patterns in a diverse cohort of individuals and to see if the identified dietary patterns predict the prevalence of adenoma in a cross-sectional study. METHODS: Factor analysis was used to derive both sex- and population subgroup-specific dietary patterns among participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Logistic regression was used to assess associations between identified factor scores and colorectal adenoma (CRA) in sex-specific subgroups. RESULTS: Three diet patterns were observed in this cohort: 'Fruits and vegetables', 'Western' and 'Sweet and salty'. Foods that loaded on each factor were similar between the racial subgroups. In men, being in the highest quintile of 'Western' dietary scores was associated with higher odds of any (adjusted odds ratio (aOR) = 1.21; 95% confidence interval (CI) = 1.03 1.42), advanced (aOR = 1.32; 95% CI = 1.07-1.63) or multiple (>1; aOR = 1.51; 95% CI = 1.17-1.94) adenoma, compared to those in the lowest quintile. These results were most notably seen in Caucasian men. In women, having a 'Fruits and vegetable' score in the highest quintile was associated with lower odds of multiple adenoma (>1; aOR = 0.53; 95% CI = 0.28-1.00). CONCLUSIONS: Of the three dietary factors, the 'Western' diet pattern was most strongly associated with prevalent CRA in Caucasian men. Further research is needed to examine the association between dietary factor scores and adenomas in the proximal colon, where there are larger racial disparities in prevalence. PMID- 29280254 TI - Characterization of the functional near-infrared spectroscopy response to nociception in a pediatric population. AB - BACKGROUND: Near-infrared spectroscopy can interrogate functional optical signal changes in regional brain oxygenation and blood volume to nociception analogous to functional magnetic resonance imaging. AIMS: This exploratory study aimed to characterize the near-infrared spectroscopy signals for oxy-, deoxy-, and total hemoglobin from the brain in response to nociceptive stimulation of varying intensity and duration, and after analgesic and neuromuscular paralytic in a pediatric population. METHODS: We enrolled children 6 months-21 years during propofol sedation before surgery. The near-infrared spectroscopy sensor was placed on the forehead and nociception was produced from an electrical current applied to the wrist. We determined the near-infrared spectroscopy signal response to increasing current intensity and duration, and after fentanyl, sevoflurane, and neuromuscular paralytic. Heart rate and arm movement during electrical stimulation was also recorded. The near-infrared spectroscopy signals for oxy-, deoxy-, and total hemoglobin were calculated as optical density*time (area under curve). RESULTS: During electrical stimulation, nociception was evident: tachycardia and arm withdrawal was observed that disappeared after fentanyl and sevoflurane, whereas after paralytic, tachycardia persisted while arm withdrawal disappeared. The near-infrared spectroscopy signals for oxy-, deoxy-, and total hemoglobin increased during stimulation and decreased after stimulation; the areas under the curves were greater for stimulations 30 mA vs 15 mA (13.9 [5.6-22.2], P = .0021; 5.6 [0.8-10.5], P = .0254, and 19.8 [10.5-29.1], P = .0002 for HbO2 , Hb, and HbT , respectively), 50 Hz vs 1 Hz (17.2 [5.8-28.6], P = .0046; 7.5 [0.7-14.3], P = .0314, and 21.9 [4.2-39.6], P = .0177 for HbO2 , Hb, and HbT , respectively) and 45 seconds vs 15 seconds (16.3 [3.4-29.2], P = .0188 and 22.0 [7.5-36.5], P = .0075 for HbO2 and HbT , respectively); the areas under the curves were attenuated by analgesics but not by paralytic. CONCLUSION: Near-infrared spectroscopy detected functional activation to nociception in a broad pediatric population. The near-infrared spectroscopy response appears to represent nociceptive processing because the signals increased with noxious stimulus intensity and duration, and were blocked by analgesics but not paralytics. PMID- 29280255 TI - Incidence and prevalence trends of youth-onset type 2 diabetes in a cohort of Canadian youth: 2002-2013. AB - OBJECTIVE: Youth-onset type 2 diabetes is an emerging disease. We estimated incidence and prevalence trends of youth-onset type 2 diabetes between 2002 and 2013 in the Canadian province of British Columbia. METHODS: This population-based cohort study used a validated diabetes case-finding definition and algorithm to differentiate type 2 from type 1 diabetes to identify youth <20 years with type 2 diabetes within linked population-based administrative data. Age-standardized incidence and prevalence were calculated. JoinPoint regression and double exponential smooth modeling were used. RESULTS: From 2002/2003 to 2012/2013, the incidence of youth-onset type 2 diabetes increased from 3.45 (95% confidence interval, CI: 2.43, 4.80) to 5.16 (95% CI: 3.86, 6.78)/100 000. The annual percent change (APC) in incidence was 3.74 (95% CI: 1.61, 5.92; P = 0.003) overall, while it was 5.94 (95% CI: 1.84, 10.20; P = 0.009) and 0.53 (95% CI: 5.04, 6.43; P = 0.837) in females and males, respectively. The prevalence increased from 0.009% (95% CI: 0.007, 0.011) in 2002/2003 to 0.021% (95% CI: 0.018, 0.024) in 2012/2013 with an APC of 7.89 (95% CI: 6.41, 9.40; P < 0.0001). In females, it increased from 0.012% (95% CI: 0.009, 0.015) to 0.027% (95% CI: 0.023, 0.032) and in males from 0.007% (95% CI: 0.005, 0.009) to 0.015% (95% CI: 0.012, 0.019). By 2030, we forecast a prevalence of 0.046% (95% CI: 0.043, 0.048). CONCLUSIONS: Youth-onset type 2 diabetes is increasing with higher rates in females vs males. If these rates continue, in 2030, the number of cases will increase by 5-fold. These data are needed to set priorities for diabetes prevention in youth. PMID- 29280256 TI - Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association. AB - Heart failure (HF) is a complex clinical syndrome with multiple interactions between the failing myocardium and cerebral (dys-)functions. Bi-directional feedback interactions between the heart and the brain are inherent in the pathophysiology of HF: (i) the impaired cardiac function affects cerebral structure and functional capacity, and (ii) neuronal signals impact on the cardiovascular continuum. These interactions contribute to the symptomatic presentation of HF patients and affect many co-morbidities of HF. Moreover, neuro cardiac feedback signals significantly promote aggravation and further progression of HF and are causal in the poor prognosis of HF. The diversity and complexity of heart and brain interactions make it difficult to develop a comprehensive overview. In this paper a systematic approach is proposed to develop a comprehensive atlas of related conditions, signals and disease mechanisms of the interactions between the heart and the brain in HF. The proposed taxonomy is based on pathophysiological principles. Impaired perfusion of the brain may represent one major category, with acute (cardio-embolic) or chronic (haemodynamic failure) low perfusion being sub-categories with mostly different consequences (i.e. ischaemic stroke or cognitive impairment, respectively). Further categories include impairment of higher cortical function (mood, cognition), of brain stem function (sympathetic over-activation, neuro cardiac reflexes). Treatment-related interactions could be categorized as medical, interventional and device-related interactions. Also interactions due to specific diseases are categorized. A methodical approach to categorize the interdependency of heart and brain may help to integrate individual research areas into an overall picture. PMID- 29280257 TI - Experiences of mental health nursing staff working with voice hearers in an acute setting: An interpretive phenomenological approach. AB - : WHAT IS KNOWN ON THE SUBJECT?: Community mental health staff and their service users have reported mixed views on the importance of talking about the content of voices. Community staff have reported feeling that they do not have the skills to explore voice content and worry about making things worse. Voice hearers experiencing extreme distress due to the content of their voices can access support through acute inpatient mental health services. No previous studies have focused on the experiences of staff who nurse voice hearers at a time of acute distress. WHAT DOES THIS STUDY ADD TO EXISTING KNOWLEDGE?: MHNs and HSWs working with voice hearers in acute distress report feeling powerless and helpless, as they feel that they cannot lessen the distress experienced by the voice hearer. Despite these difficult feelings, staff report finding ways of coping, including using structured tools to help make sense of their service users' voice-hearing experiences and accessing reflective practice forums. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Due to the current context of increased acuity and limited resources in acute services, there may be a need to further protect time for staff to access reflective practice groups and supervision forums to help them manage the difficult feelings arising from their work with voice hearers. ABSTRACT: Introduction Mental health nursing (MHN) staff in acute settings work with voice hearers at times of crises when they experience high levels of distress. Previous research has focused on community mental health staff's experiences and their service users views on exploring the content of voices. No studies have explored this from an acute mental health service perspective. Aim This study therefore sought to explore the experiences of staff working with voice hearers in an acute mental health service. Method Due to the exploratory nature of the research, a qualitative design was chosen. Three MHNs and five healthcare support workers (HSWs) were interviewed. The data were analysed using Interpretative Phenomenological Analysis. Results A group analysis elicited three master themes: "It's quite scary really, not unlike a horror movie;" "I can only influence what's in front of me;" and "Just chipping away". Discussion Staff working with voice hearers in acute settings experience feelings of powerlessness and helplessness, as they feel unable to reduce the distress experienced by voice hearers in their care. Staff employ coping strategies to help manage these difficult feelings, including using structured tools in their work with voice hearers and attending reflective practice forums. Implications for Practice Acute mental health services may need to protect time for staff to access regular reflective practice and other supervision forums to help manage their feelings of powerlessness and helplessness arising from their work with voice hearers. PMID- 29280259 TI - Therapeutic relationships, risk, and mental health practice. AB - Despite significant changes to mental health services, nurses remain the professional group most likely to be in close contact with people who experience mental health problems. A core part of the contemporary identity of the mental health nurse is one who is able to provide acceptance and support for an individual's recovery through the therapeutic relationship. Yet there have always been some tensions with the mental health nursing role that can appear to challenge this relational focus. An increasing prominence of risk management in mental health care can position mental health nurses as responsible for enacting restrictions and has reignited interest in the role of mental health professionals in social control. This paper reports on one part of a multiple case study, which aimed to explore mental health professionals' experiences of such tensions in the context of decision-making. Interviews and observations were undertaken in acute ward and assertive outreach settings. Findings suggested that risk dominated decision-making to such an extent it defined the way service users were understood and treated. A distant relationship between professionals and service users helped to create and maintain this situation. There needs to be a greater focus on service users' subjective experiences in the decision-making process to challenge the definition of people with mental health problems as risky. PMID- 29280260 TI - Control of Target Molecular Recognition in a Small Pore Space with Biomolecule Recognition Gating Membrane. AB - A biomolecule-recognition gating membrane, which introduces thermosensitive graft polymer including molecular recognition receptor into porous membrane substrate, can close its pores by recognizing target biomolecule. The present study reports strategies for improving both versatility and sensitivity of the gating membrane. First, the membrane is fabricated by introducing the receptor via a selectively reactive click reaction improving the versatility. Second, the sensitivity of the membrane is enhanced via an active delivering method of the target molecules into the pores. In the method, the tiny signal of the target biomolecule is amplified as obvious pressure change. Furthermore, this offers 15 times higher sensitivity compared to the previously reported passive delivering method (membrane immersion to sample solution) with significantly shorter recognition time. The improvement will aid in applying the gating membrane to membrane sensors in medical fields. PMID- 29280261 TI - Deproteinized bovine bone matrix induces osteoblast differentiation via macrophage polarization. AB - Bone grafts are widely used in bone regeneration to increase the speed and quality of new bone formation. While they are routinely characterized based on their biocompatible and bioactive properties, they also exert a profound impact on host immune responses, which in turn can display a significant effect on the healing and repair process. In this study, we investigated the role of macrophage behavior on deproteinized bovine bone matrix (DBBM, BioOss) to investigate their impact on creating either a pro- or anti-inflammatory microenvironment for tissue integration. RT-PCR and immunofluorescence staining results demonstrated the ability for RAW 264.7 cells to polarize toward M2 wound-healing macrophages in response to DBBM and positive control (IL-4). Interestingly, significantly higher expression of interleukin-10 and higher number of multinucleated giant cells (MNGCs) was observed in the DBBM group. Thereafter, conditioned media (CM) from macrophages cultured with DBBM seeded with MC3T3-E1 cells demonstrated a marked increase in osteoblast differentiation. Noteworthy, this effect was reversed by blocking IL10 with addition of IL10 antibody to CM from the DBBM macrophages. Furthermore, the use of dendritic cell specific transmembrane protein (DC-STAMP) knockout to inhibit MNGC formation in the DBBM group resulted in a significant reduction in osteoblast differentiation, indication a pivotal role for MNGCs in biomaterials-induced osteogenesis. The results from this study indicate convincingly that the immune response of macrophages towards DBBM has a potent effect on osteoblast differentiation. Furthermore, DBBM promoted macrophage fusion and polarization towards an M2 wound-healing phenotype, further created a microenvironment favoring biomaterial-induced osteogenesis. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1236-1246, 2018. PMID- 29280262 TI - Prognostic factors in the early phase of acute encephalopathy. AB - BACKGROUND: Neurological sequelae occur in 40% of patients with acute encephalopathy (AE). The early prediction of poor outcomes is critical to the initiation of appropriate treatment. The aim of the present study was therefore to elucidate prognostic factors that can be quickly and feasibly evaluated on hospital admission in patients with AE. METHODS: We analyzed data from 51 AE patients admitted to Hirakata City Hospital between January 2005 and December 2014. Age at onset, sex, underlying disease, status epilepticus (SE), presence of benzodiazepine-resistant SE (BZD-resistant SE), and basic blood serum parameters on admission were evaluated in relation to each patient's outcome. RESULTS: On univariate analysis age at onset, BZD-resistant SE, and serum aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, and platelet count varied significantly according to outcome. On multivariate analysis age at onset (<=21 months), presence of BZD-resistant SE, and AST (>=46 IU/L) were identified as independent variables associated with poor outcome. CONCLUSION: Age at onset, presence of BZD-resistant SE, and AST are associated with a poor prognosis in AE. PMID- 29280263 TI - Superior Self-Powered Room-Temperature Chemical Sensing with Light-Activated Inorganic Halides Perovskites. AB - Hybrid halide perovskite is one of the promising light absorber and is intensively investigated for many optoelectronic applications. Here, the first prototype of a self-powered inorganic halides perovskite for chemical gas sensing at room temperature under visible-light irradiation is presented. These devices consist of porous network of CsPbBr3 (CPB) and can generate an open-circuit voltage of 0.87 V under visible-light irradiation, which can be used to detect various concentrations of O2 and parts per million concentrations of medically relevant volatile organic compounds such as acetone and ethanol with very quick response and recovery time. It is observed that O2 gas can passivate the surface trap sites in CPB and the ambipolar charge transport in the perovskite layer results in a distinct sensing mechanism compared with established semiconductors with symmetric electrical response to both oxidizing and reducing gases. The platform of CPB-based gas sensor provides new insights for the emerging area of wearable sensors for personalized and preventive medicine. PMID- 29280264 TI - Anti-Shiga toxin 2 antibodies in enterohemorrhagic Escherichia coli O104:H4 infected patients may predict hemolytic uremic syndrome. AB - BACKGROUND AND AIM: An outbreak of Shiga toxin 2 (Stx2) producing enterohemorrhagic and enteroaggregative Escherichia coli O104:H4 infection in May 2011 in Germany caused enterocolitis and an unprecedented high 22% rate of hemolytic uremic syndrome (HUS). We hypothesized that anti-Stx2 IgM or IgG titers might predict HUS development. METHODS: Thirty-two patients infected with enterohemorrhagic Escherichia coli O104:H4 (HUS: n = 23; non-HUS: n = 9) were retrospectively screened for anti-Stx2 IgM/IgG and matched with clinical data regarding HUS development, fever, superinfection, dialysis, neurological symptoms, intensive care, antibiotic treatment, and plasmapheresis. RESULTS: Only HUS patients showed a prominent Stx2-specific humoral response in the early acute phase. Despite a strong trend towards prediction of HUS development, statistical analysis revealed no significant correlation between high IgM/IgG titers and further key clinical parameters such as fever, superinfection, neurological symptoms, antibiotic treatment, and plasmapheresis. CONCLUSIONS: Anti-Stx2 antibodies seem to accompany or even precede HUS development. PMID- 29280265 TI - Three-dimensional cultured tissue constructs that imitate human living tissue organization for analysis of tumor cell invasion. AB - Preventing cancer metastasis requires a thorough understanding of cancer cell invasion. These phenomena occur in human 3-D living tissues. To this end, we developed a human cell-based three-dimensional (3-D) cultured tissue constructs that imitate in vivo human tissue organization. We investigated whether our 3-D cell culture system can be used to analyze the invasion of human oral squamous cell carcinoma (OSCC) cells. The 3-D tissue structure consisted of five layers of normal human dermal fibroblasts along with human dermal lymphatic endothelial cell tubes and was generated by the cell accumulation technique and layer-by layer assembly using fibronectin and gelatin. OSCC cells with different lymph metastatic capacity were inoculated on the 3-D tissues and their invasion through the 3-D tissue structure was observed. Conventional methods of analyzing cell migration and invasion, that is, 2-D culture-based transwell and Matrigel assays were also used for comparison. The results using the 3-D cultured tissue constructs were comparable to those obtained using conventional assays; moreover, use of the 3-D system enabled visualization of differential invasion capacities of cancer cells. These results indicate that our 3-D cultured tissue constructs can be a useful tool for analysis of cancer cell invasion in a setting that reflects the in vivo tissue organization. (c) 2018 The Authors. journal Of Biomedical Materials Research Part A Published By Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part A: 00A: 000-000, 2018. PMID- 29280266 TI - Senescence promotes in vivo reprogramming through p16INK4a and IL-6. AB - Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin-6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c-Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity. In this system, Ink4a/Arf-null tissues cannot undergo senescence, fail to produce IL6, and cannot reprogram efficiently; whereas p53-null tissues undergo extensive damage and senescence, produce high levels of IL6, and reprogram efficiently. Here, we have further explored the genetic determinants of in vivo reprogramming. We report that Ink4a, but not Arf, is necessary for OSKM induced senescence and, thereby, for the paracrine stimulation of reprogramming. However, in the absence of p53, IL6 production and reprogramming become independent of Ink4a, as revealed by the analysis of Ink4a/Arf/p53 deficient mice. In the case of the cell cycle inhibitor p21, its protein levels are highly elevated upon OSKM activation in a p53-independent manner, and we show that p21 null tissues present increased levels of senescence, IL6, and reprogramming. We also report that Il6-mutant tissues are impaired in undergoing reprogramming, thus reinforcing the critical role of IL6 in reprogramming. Finally, young female mice present lower efficiency of in vivo reprogramming compared to male mice, and this gender difference disappears with aging, both observations being consistent with the known anti-inflammatory effect of estrogens. The current findings regarding the interplay between senescence and reprogramming may conceivably apply to other contexts of tissue damage. PMID- 29280267 TI - Multifunctional Interlayer Based on Molybdenum Diphosphide Catalyst and Carbon Nanotube Film for Lithium-Sulfur Batteries. AB - A multifunctional interlayer, composed of molybdenum diphosphide (MoP2 ) nanoparticles and a carbon nanotube (CNT) film, is introduced into a lithium sulfur (Li-S) battery system to suppress polysulfide migration. Molybdenum diphosphide acts as the catalyst and can capture polysulfides and improve the polysulfide conversion activity during the discharge/charge processes. The CNT film acts as a conductive skeleton to support the MoP2 nanoparticles and to ensure their uniform distribution. The CNT film physically hinders polysulfide migration, acts as a current collector, and provides abundant electron pathways. The Li-S battery containing the multifunctional MoP2 /CNT interlayer exhibits excellent electrochemical performance. It delivers a reversible specific capacity of 905 mA h g-1 over 100 cycles at 0.2 C, with a capacity decay of 0.152% per cycle. These results suggest the introduction of the multifunctional CNT/MoP2 interlayer as an effective and practical method for producing high-performance Li S batteries. PMID- 29280268 TI - Obstetricians' awareness associated with better outcomes. PMID- 29280269 TI - Synergistic Interlayer and Defect Engineering in VS2 Nanosheets toward Efficient Electrocatalytic Hydrogen Evolution Reaction. AB - A simple one-pot solvothermal method is reported to synthesize VS2 nanosheets featuring rich defects and an expanded (001) interlayer spacing as large as 1.00 nm, which is a ~74% expansion as relative to that (0.575 nm) of the pristine counterpart. The interlayer-expanded VS2 nanosheets show extraordinary kinetic metrics for electrocatalytic hydrogen evolution reaction (HER), exhibiting a low overpotential of 43 mV at a geometric current density of 10 mA cm-2 , a small Tafel slope of 36 mV dec-1 , and long-term stability of 60 h without any current fading. The performance is much better than that of the pristine VS2 with a normal interlayer spacing, and even comparable to that of the commercial Pt/C electrocatalyst. The outstanding electrocatalytic activity is attributed to the expanded interlayer distance and the generated rich defects. Increased numbers of exposed active sites and modified electronic structures are achieved, resulting in an optimal free energy of hydrogen adsorption (?GH ) from density functional theory calculations. This work opens up a new door for developing transition metal dichalcogenide nanosheets as high active HER electrocatalysts by interlayer and defect engineering. PMID- 29280270 TI - Cell ingression: Relevance to limb development and for adaptive evolution. AB - Cell ingression is an out-of-plane type of cell intercalation that is essential for the formation of multiple embryonic structures including the limbs. In particular, cell ingression underlies epithelial-to-mesenchymal transition of lateral plate cells to initiate limb bud growth, delamination of neural crest cells to generate peripheral nerve sheaths, and emigration of myoblasts from somites to assemble muscles. Individual cells that ingress undergo apical constriction to generate bottle shaped cells, diminish adhesion to their epithelial cell neighbors, and generate protrusive blebs that likely facilitate their ingression into a subepithelial tissue layer. How signaling pathways regulate the progression of delamination is important for understanding numerous developmental events. In this review, we focus on cellular and molecular mechanisms that drive cell ingression and draw comparisons between different morphogenetic contexts in various model organisms. We speculate that cell behaviors that facilitated tissue invagination among diploblasts subsequently drove individual cell ingression and epithelial-to-mesenchymal transition. Future insights that link signalling pathways to biophysical mechanisms will likely advance our comprehension of this phenomenon. PMID- 29280271 TI - Nursing as concrete philosophy, Part I: Risjord on nursing knowledge. AB - This essay addresses the problem of the essentiality of nursing knowledge and what kind of theory, if any, is essential to nursing practice. The overarching aim of the essay was to argue for the thesis that nursing may be described as a kind of philosophical activity, and, consequently, that philosophy is the kind of "theory" that is essential to nursing practice and to the nursing discipline at large. The essay consists of two papers. The present paper, Part I, is a critical examination of Mark Risjord's discussion of the problem of the theory-practice gap in his Nursing Knowledge: Practice, Science, Philosophy, from 2010. According to Risjord, the cause of the theory-practice gap originates in an erroneous conception of science (logical positivism) which had a decisive influence upon the way nursing scholars appropriated theoretical frameworks for the nursing discipline. This philosophical influence is considered in effect to have generated the theory-practice gap. In order to bridge the gap, Risjord suggests, the nursing discipline needs to adopt a standpoint epistemology conjoined with a postpositivist conception of scientific theory. In this way, a legitimate brand of nursing science may be developed and the theory-practice gap overcome. I will argue that neither Risjord's diagnosis of the problem, nor his recommended cure, may succeed in rescuing the nursing discipline from the theory-practice gap. Rather, the real cause of the theory-practice gap, I will claim, derives from an erroneous conception of nursing (not of science), namely the conception of nursing as a kind of science (roughly speaking). On my view, to overcome the gap, the nursing discipline needs to make salient the inherently philosophical character of nursing. In the second paper (Part II), I will continue the discussion of nursing knowledge and delineate the thesis of nursing as a kind of concrete philosophy. PMID- 29280272 TI - Lip service: Public mental health services and the care of Aboriginal and Torres Strait Islander peoples. AB - The failure of public mental services in Australia to provide care deemed culturally safe for Aboriginal and Torres Strait Islander people has persisted despite several national reports and policies that have attempted to promote positive service change. Nurses represent the largest professional group practising within these services. This article reports on a multisited ethnography of mental health nursing practice as it relates to this group of mental health service users. It explores the beliefs and ideas that nurses identified about public mental health services and the services they provided to Aboriginal and Torres Strait Islander people. During the fieldwork, mental health nurses described the constricting effect of the biomedical paradigm of mental illness on their abilities to provide authentic holistic care focused on social and emotional well-being. Despite being the most numerous professional group in mental health services, the speciality of mental health nursing appears unable to change this situation and in many cases maintain this status quo to the potential detriment of their Aboriginal and Torres Strait Islander service users. PMID- 29280274 TI - A High Aspect Ratio Serpentine Structure for Use As a Strain-Insensitive, Stretchable Transparent Conductor. AB - The development of strain-insensitive stretchable transparent conductors (TCs) is essential for manufacturing stretchable electronics. Despite recent progress, achieving a high optoelectronic performance under applied strain of 50% continues to present a significant challenge in this research field. Herein, an ultratall and ultrathin high aspect ratio serpentine metal structure is described that exhibits a remarkable stretching ability (the resistance remains constant under applied strain of 100%) and simultaneously provides an excellent transparent conducting performance (with a sheet resistance of 7.6 Omega ?-1 and a transmittance of 90.5%). It is demonstrated that the highly stretchable transparent conducting properties can be attributed to the high aspect ratio feature. A high aspect ratio (aspect ratio of 17-367) structure permits facile deformation of the serpentine structure with in-plane motion, leading to a high stretching ability. In addition, this structural feature avoids the classic tradeoff between optical transmittance and electrical conductance, providing a high electrical conductance without decreasing the optical transmittance. The practical utility of these devices is tested by using these TCs as stretchable interconnectors among LEDs or in wearable VOC gas sensors. PMID- 29280273 TI - Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). RESULTS: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. CONCLUSION: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease. PMID- 29280275 TI - Solution-Processed Metal Coating to Nonwoven Fabrics for Wearable Rechargeable Batteries. AB - Wearable rechargeable batteries require electrode platforms that can withstand various physical motions, such as bending, folding, and twisting. To this end, conductive textiles and paper have been highlighted, as their porous structures can accommodate the stress built during various physical motions. However, fabrics with plain weaves or knit structures have been mostly adopted without exploration of nonwoven counterparts. Also, the integration of conductive materials, such as carbon or metal nanomaterials, to achieve sufficient conductivity as current collectors is not well-aligned with large-scale processing in terms of cost and quality control. Here, the superiority of nonwoven fabrics is reported in electrochemical performance and bending capability compared to currently dominant woven counterparts, due to smooth morphology near the fiber intersections and the homogeneous distribution of fibers. Moreover, solution-processed electroless deposition of aluminum and nickel-copper composite is adopted for cathodes and anodes, respectively, demonstrating the large-scale feasibility of conductive nonwoven platforms for wearable rechargeable batteries. PMID- 29280276 TI - Ultrathin Porous NiFeV Ternary Layer Hydroxide Nanosheets as a Highly Efficient Bifunctional Electrocatalyst for Overall Water Splitting. AB - Herein, the hydrothermal synthesis of porous ultrathin ternary NiFeV layer double hydroxides (LDHs) nanosheets grown on Nickel foam (NF) substrate as a highly efficient electrode toward overall water splitting in alkaline media is reported. The lateral size of the nanosheets is about a few hundreds of nanometers with the thickness of ~10 nm. Among all molar ratios investigated, the Ni0.75 Fe0.125 V0.125 -LDHs/NF electrode depicts the optimized performance. It displays an excellent catalytic activity with a modest overpotential of 231 mV for the oxygen evolution reaction (OER) and 125 mV for the hydrogen evolution reaction (HER) in 1.0 m KOH electrolyte. Its exceptional activity is further shown in its small Tafel slope of 39.4 and 62.0 mV dec-1 for OER and HER, respectively. More importantly, remarkable durability and stability are also observed. When used for overall water splitting, the Ni0.75 Fe0.125 V0.125 -LDHs/NF electrodes require a voltage of only 1.591 V to reach 10 mA cm-2 in alkaline solution. These outstanding performances are mainly attributed to the synergistic effect of the ternary metal system that boosts the intrinsic catalytic activity and active surface area. This work explores a promising way to achieve the optimal inexpensive Ni-based hydroxide electrocatalyst for overall water splitting. PMID- 29280277 TI - Nanostructural Uniformity of Ordered Mesoporous Materials: Governing Lithium Storage Behaviors. AB - Nanostructured materials make a considerable impact on the performance of lithium storage characteristics in terms of the energy density, power density, and cycle life. Direct experimental observation, by a comparison of controlled nanostructural uniformity of electrode materials, reveals that the lithium storage behaviors of mesoporous MoO2 and CuO electrodes are linearly correlated with their nanostructural uniformity. Reversible capacities of mesoporous MoO2 and CuO electrodes with well-developed nanostructures (1569 mA h g-1 for MoO2 and 1029 mA h g-1 for CuO) exceed their theoretical capacity based on the conversion reaction (838 mA h g-1 for MoO2 and 674 mA h g-1 for CuO). Given that exact understanding of the origin of the additional capacity is essential in maximizing the energy density of electrode material, this work may help to gain some insights into the development of high energy-density lithium-storage materials for next-generation lithium rechargeable batteries. PMID- 29280278 TI - Bioadhesive Polymersome for Localized and Sustained Drug Delivery at Pathological Sites with Harsh Enzymatic and Fluidic Environment via Supramolecular Host-Guest Complexation. AB - Targeted and sustained delivery of drugs to diseased tissues/organs, where body fluid exchange and catabolic activity are substantial, is challenging due to the fast cleansing and degradation of the drugs by these harsh environmental factors. Herein, a multifunctional and bioadhesive polycaprolactone-beta-cyclodextrin (PCL CD) polymersome is developed for localized and sustained co-delivery of hydrophilic and hydrophobic drug molecules. This PCL-CD polymersome affords multivalent crosslinking action via surface CD-mediated host-guest interactions to generate a supramolecular hydrogel that exhibits evident shear thinning and efficient self-healing behavior. The co-delivery of small molecule and proteinaceous agents by the encapsulated PCL-CD polymersomes enhances the differentiation of stem cells seeded in the hydrogel. Furthermore, the PCL-CD polymersomes are capable of in situ grafting to biological tissues via host-guest complexation between surface CD and native guest groups in the tissue matrix both in vitro and in vivo, thereby effectively extending the retention of loaded cargo in the grafted tissue. It is further demonstrated that the co-delivery of small molecule and proteinaceous drugs via PCL-CD polymersomes averts cartilage degeneration in animal osteoarthritic (OA) knee joints, which are known for their biochemically harsh and fluidically dynamic environment. PMID- 29280279 TI - Issues and Challenges Facing Flexible Lithium-Ion Batteries for Practical Application. AB - With the advent of flexible electronics, lithium-ion batteries have become a key component of high performance energy storage systems. Thus, considerable effort is made to keep up with the development of flexible lithium-ion batteries. To date, many researchers have studied newly designed batteries with flexibility, however, there are several significant challenges that need to be overcome, such as degradation of electrodes under external load, poor battery performance, and complicated cell preparation procedures. In addition, an in-depth understanding of the current challenges for flexible batteries is rarely addressed in a systematical and practical way. Herein, recent progress and current issues of flexible lithium-ion batteries in terms of battery materials and cell designs are reviewed. A critical overview of important issues and challenges for the practical application of flexible lithium-ion batteries is also provided. Finally, the strategies are discussed to overcome current limitations of the practical use of flexible lithium-based batteries, providing a direction for future research. PMID- 29280280 TI - 3D Graphene Encapsulated Hollow CoSnO3 Nanoboxes as a High Initial Coulombic Efficiency and Lithium Storage Capacity Anode. AB - 3D Graphene sheets encapsulated amorphous hollow CoSnO3 nanoboxes (H-CoSnO3 @reduced graphene oxide [RGO]) are successfully fabricated by first preparing 3D graphene oxides encapsulated solid CoSn(OH)6 nanocubes, followed by an alkaline etching process and subsequent heating treatment in Ar. The hollow CoSnO3 nanoboxes with average particle size of 230 nm are uniformly and tightly encapsulated by RGO sheets. As an anode material for Li-ion batteries, H-CoSnO3 @RGO displays high initial Coulombic efficiency of 87.1% and large reversible capacity of 1919 mA h g-1 after 500 cycles at the current density of 500 mA g-1 . Moreover, excellent rate capability (1250, 1188, 1141, 1115, 1086, 952, 736, and 528 mA h g-1 at 100, 200, 300, 400, 500, 1000, 2000, and 5000 mA g-1 , respectively) is acquired. The reasons for excellent lithium storage properties of H-CoSnO3 @RGO are discussed in detail. PMID- 29280281 TI - The impact of exercise frequency upon microvascular endothelium function and oxidative stress among patients with coronary artery disease. AB - PURPOSE: This study compared the effects of low and high weekly exercise frequencies on microvascular endothelium function and oxidative stress among patients with coronary artery disease. METHODS: Thirty-four male patients completed a 6-month cardiac rehabilitation programme, from which 23 performed exercise with a high frequency (HF) and 11 with a low frequency (LF). Systemic microvascular blood flow, maximal aerobic capacity, blood lipids, oxidative stress and anthropometric data were assessed prior to and after the cardiac rehabilitation programme. Microvascular blood flow was assessed in the skin of the forearm using laser speckle contrast imaging coupled with iontophoresis of acetylcholine. RESULTS: Maximal aerobic capacity, biochemical analysis and anthropometric data were similar between groups prior to and after the cardiac rehabilitation programme (P>0.05). However, after 6 months of cardiac rehabilitation performed with HF, there was an increase in the peak response to acetylcholine compared with LF (83.5 +/- 58.5 versus 21.8 +/- 22.4%; P<0.05). Changes in lipid peroxidation (HF: -5.5 +/- 9.4 versus LF: 2.2 +/- 12.0 pmol MDA mg-1 ; P = 0.19), catalase activity (HF: 0.07 +/- 0.17 versus LF: 0.04 +/- 0.08 U mg-1 ; P = 0.74) and nitric oxide levels (HF: 1.8 +/- 15.3 versus LF: -3.2 +/- 12.3 MUM; P = 0.36) were similar between groups after cardiac rehabilitation. CONCLUSION: Six months of aerobic exercise training performed with high frequency is preferable to low frequency aiming endothelium microvascular function increases in patients with coronary artery disease. The mechanisms involved in this response are unclear and warrant additional research. PMID- 29280282 TI - Integrating community assembly and biodiversity to better understand ecosystem function: the Community Assembly and the Functioning of Ecosystems (CAFE) approach. AB - The research of a generation of ecologists was catalysed by the recognition that the number and identity of species in communities influences the functioning of ecosystems. The relationship between biodiversity and ecosystem functioning (BEF) is most often examined by controlling species richness and randomising community composition. In natural systems, biodiversity changes are often part of a bigger community assembly dynamic. Therefore, focusing on community assembly and the functioning of ecosystems (CAFE), by integrating both species richness and composition through species gains, losses and changes in abundance, will better reveal how community changes affect ecosystem function. We synthesise the BEF and CAFE perspectives using an ecological application of the Price equation, which partitions the contributions of richness and composition to function. Using empirical examples, we show how the CAFE approach reveals important contributions of composition to function. These examples show how changes in species richness and composition driven by environmental perturbations can work in concert or antagonistically to influence ecosystem function. Considering how communities change in an integrative fashion, rather than focusing on one axis of community structure at a time, will improve our ability to anticipate and predict changes in ecosystem function. PMID- 29280284 TI - Combined Effect of the Microstructure and Underlying Surface Curvature on the Performance of Biomimetic Adhesives. AB - The importance of the geometry of the micro-/nanosized attachment elements for adhesive characteristics of gecko-inspired microstructured surfaces has been comprehensively discussed in recent years. Due to the complex hierarchical structure of these systems, they possess a broad range of adhesion control capabilities by either passive or active adaptability of their underlying structures to the specific substrate and/or behavioral situation. Here, the influence of macroscopic geometry of backing layers hosting biomimetic microstructured surfaces is examined. The flat, convex, and concave macroscopic configurations of the bioinspired microstructured adhesive surfaces are examined on their adhesive performance under varying degrees of curvature and preloads. Microstructured surfaces demonstrated an adhesion range differing by up to a factor of 2 alone through varying backing layer configuration. The results can aid in understanding the influence of curvature geometry on hierarchically structured adhesive systems and the implementation of biomimetic structured surfaces in applications such as robots and grippers optimized for different sized objects. PMID- 29280283 TI - PET/CT to detect adverse reactions to metal debris in patients with metal-on metal hip arthroplasty: an exploratory prospective study. AB - Metal-on-metal (MoM) bearings in total hip arthroplasties and hip resurfacing arthroplasties have recently shown a new type of complication: adverse reactions to metal debris (ARMD). ARMD is characterized by local severe inflammation and tissue necrosis leading to implant failures. The gluteal muscle region is important for the patient outcome after revision surgery. This prospective positron emission tomography/computed tomography (PET/CT) study was undertaken to evaluate the characteristics of 2-deoxy-2-[18 F]fluoro-d-glucose ([18 F]FDG) and [68 Ga]Gallium citrate ([68 Ga]Citrate) PET/CT in ARMD patients. [18 F]FDG and [68 Ga]Citrate PET/CT were performed in 18 hip arthroplasty patients: 12 ARMD patients (with 16 MoM hips) and six arthroplasty controls without ARMD. Tracer uptake was evaluated visually, and maximum standardized uptake (SUVmax ) was measured in the gluteal muscle region. ARMD severity was graded by metal artefact reduction sequence-magnetic resonance imaging (MARS-MRI). Periprosthetic [18 F]FDG uptake was observed in 15 of 16 hips, [68 Ga]Citrate uptake in three of 16 hips, respectively. The distribution of tracer uptake resembled infection in three hips. In the gluteal muscle region, the SUVmax of [18 F]FDG was significantly greater in hips with moderate and severe ARMD compared with the controls (P = 0.009 for [18 F]FDG and P = 0.217 for [68 Ga]Citrate). In patients who needed revision surgery, an intraoperative finding of gluteal muscle necrosis was associated with increased local SUVmax as detected by preoperative [18 F]FDG (P = 0.039), but not by [68 Ga]Citrate (P = 0.301). In conclusion, the inflammatory reaction to metal debris in hip arthroplasty patients is best visualized with [18 F]FDG. PMID- 29280286 TI - Fluid Mixing for Low-Power 'Digital Microfluidics' Using Electroactive Molecular Monolayers. AB - A switchable electrode, which relies on an indium-tin oxide conductive substrate coated with a self-assembled monolayer terminated with an anthraquinone group (AQ), is reported as an electrowetting system. AQ electrochemical features confer the capability of yielding a significant modulation of surface wettability as high as 26 degrees when its redox state is switched. Hence, an array of planar electrodes for droplets actuation is fabricated and integrated in a microfluidic device to perform mixing and dispensing on sub-nanoliter scale. Vehiculation of cells across microfluidic compartments is made possible by taking full advantage of surface electrowetting in culture medium. PMID- 29280285 TI - Treatment-related changes after short-term exposure of SD rats to Aloe vera whole leaf freeze-dried powder. AB - Aloe vera is a widely used natural herb from which many sorts of commercial products have been derived using different preparation technologies. Aloe whole leaf powder is one of the most popular subtypes. The long-term impact of aloe products has already been reported; however, there have been few studies about short-term exposure, and especially about the relative impact of Aloe vera whole leaf freeze-dried powder (AWFP). To provide more toxicological data and to document the early changes induced by AWFP, in this study 120 SD rats were divided into four groups (control and 400/1200/2000 mg/kg treatment groups) and were administered AWFP once daily by oral gavage for 28 consecutive days, followed by a two week recovery phase. The results showed that AWFP could induce soft/loose changes in faeces. Significantly decreased white blood cell (WBC) counts, associated with reduced lymphocyte counts were also noted. The relative organ weight, including both organ-to-body weight ratio and organ-to-brain weight ratio of kidneys, was significantly increased in 2000 mg/kg compared with that in controls. Histopathologically, pigmentation in the kidneys and increased mucosal thickness in colon were also noted in a dose response groups. Other changes observed in the study were not considered to be treatment related, and 400 mg/kg was considered as the no-observed-adverse-effect level. The study provided clear evidence of treatment-related changes with a short-term exposure to AWFP. This is also the first report of the early colon morphologic changes associated with stool changes noted previously in-life phase, providing additional toxicity data which will contribute to our understanding about the short-term usage of AWFP as a remedy. PMID- 29280287 TI - Determination and dissipation of afidopyropen and its metabolite in wheat and soil using QuEChERS-UHPLC-MS/MS. AB - The dissipations of afidopyropen and its metabolite in wheat plant and soil were determined using a quick, easy, cheap, effective, rugged, and safe method with ultra-high performance liquid chromatography and tandem mass spectrometry under a field ecosystem. The limits of quantification were estimated for both target compounds as 0.001 mg/kg. The recoveries of afidopyropen and its metabolite ranged from 94 to 114% (soil), 90 to 109% (wheat seed) and 81 to 91% (wheat straw) at levels of 0.001, 0.01, 0.1, and 2.0 mg/kg with relative standard deviations <=7%. The results of the residual dynamics experiments showed that afidopyropen dissipated rapidly in wheat plant and soil. Its metabolite initially showed a tendency of rapid increase followed by a decrease in wheat plant but could not be detected in soil. The data showed that the first + first-order model was more suitable for describing the decline of afidopyropen in wheat and soil. The half-lives of afidopyropen in wheat plant and soil were 1.65 and 1.21 days, respectively. PMID- 29280288 TI - Morphological and Compositional Design of Pd-Cu Bimetallic Nanocatalysts with Controllable Product Selectivity toward CO2 Electroreduction. AB - Electrochemical conversion of carbon dioxide (electrochemical reduction of carbon dioxide) to value-added products is a promising way to solve CO2 emission problems. This paper describes a facile one-pot approach to synthesize palladium copper (Pd-Cu) bimetallic catalysts with different structures. Highly efficient performance and tunable product distributions are achieved due to a coordinative function of both enriched low-coordinated sites and composition effects. The concave rhombic dodecahedral Cu3 Pd (CRD-Cu3 Pd) decreases the onset potential for methane (CH4 ) by 200 mV and shows a sevenfold CH4 current density at -1.2 V (vs reversible hydrogen electrode) compared to Cu foil. The flower-like Pd3 Cu (FL-Pd3 Cu) exhibits high faradaic efficiency toward CO in a wide potential range from -0.7 to -1.3 V, and reaches a fourfold CO current density at -1.3 V compared to commercial Pd black. Tafel plots and density functional theory calculations suggest that both the introduction of high-index facets and alloying contribute to the enhanced CH4 current of CRD-Cu3 Pd, while the alloy effect is responsible for high CO selectivity of FL-Pd3 Cu. PMID- 29280289 TI - Design Principles of Functional Polymer Separators for High-Energy, Metal-Based Batteries. AB - Next-generation rechargeable batteries that offer high energy density, efficiency, and reversibility rely on cell configurations that enable synergistic operations of individual components. They must also address multiple emerging challenges,which include electrochemical stability, transport efficiency, safety, and active material loss. The perspective of this Review is that rational design of the polymeric separator, which is used widely in rechargeable batteries, provides a rich set of opportunities for new innovations that should enable batteries to meet many of these needs. This perspective is different from the conventional view of the polymer separator as an inert/passive unit in a battery, which has the sole function to prevent direct contact between electrically conductivecomponents that form the battery anode and cathode. Polymer separators, which serve as the core component in a battery, bridge the electrodes and the electrolyte with a large surface contact that can be utilized to apply desirable functions. This Review focuses specifically on recent advances in polymer separator systems, with a detailed analysis of several embedded functional agents that are incorporated to improve mechanical robustness, regulate ion and mass transport, and retard flammability. The discussion is also extended to new composite separator concepts that are designated traditionally as polymer/gel electrolytes. PMID- 29280290 TI - Sports involvement, injury history, and non-medical use of prescription opioids among college students: An analysis with a national sample. AB - BACKGROUND AND OBJECTIVES: The United States is in the midst of a prescription drug epidemic, particularly related to opioids. To more effectively deal with the devastating outcomes associated with non-medical use of prescription opioids (NUPO), research is needed to identify populations at increased risk. The current research builds on a small number of studies that have shown that adolescents involved in competitive sports are more likely to report NUPO. Specifically, we examine the relationship between athlete status, injury history, and NUPO among college students. METHODS: Using data from the National College Health Assessment (NCHA II from 2008 to 2011), we estimated several logistic regression models to examine the individual, and combined, effects of sex, athlete status, and injury history on NUPO. RESULTS: In the NCHA II 8.3% of students reported NUPO, 8.0% identified as a varsity athlete, and 17.4% reported an injury. Looking at factors individually, having an injury, being a varsity athlete, and being male were all significantly associated with NUPO. By combining these factors together we were able to determine that male athletes, athletes with injuries, and male athletes with injuries were at the greatest risk for NUPO, after controlling for relevant covariates. DISCUSSION AND CONCLUSIONS: To create effective prevention and intervention programs that target the health and wellness of college students, it is important to understand which groups of students are most likely to report NUPO. SCIENTIFIC SIGNIFICANCE: This study advances our understanding of the relationship between sports involvement and NUPO. (Am J Addict 2018;27:15-22). PMID- 29280291 TI - Separation of enantiomers of new psychoactive substances by high-performance liquid chromatography. AB - New psychoactive substances are defined as compounds with consciousness-changing effects and have been developed simultaneously with classical drugs. They arise through structural modifications of illegal substances and are mainly produced to circumvent laws. Availability is simple, since new psychoactive substances can be purchased from the Internet. Among them many chemical drug compound classes are chiral and thus the two resulting enantiomers can differ in their effects. The aim of this study is to develop a suitable chiral high-performance liquid chromatography separation method for a broad spectrum of new psychoactive substances using cellulose tris(3,5-dichlorophenylcarbamate) as a chiral selector. Experiments were performed by high-performance liquid chromatography in normal-phase mode under isocratic conditions using ultraviolet detection. Direct separation was carried out on a high-performance liquid chromatography column (Lux(r) i-Cellulose-5, 3.5 MUm, Phenomenex(r)), available since 2016. Excellent separation results were obtained for cathinones. After further optimization, even 47 instead of 39 out of 52 cathinones showed baseline separation. For amphetamine derivatives, satisfactory results were not achieved. Further, new psychoactive substances from other compound classes such as benzofuranes, thiophenes, phenidines, phenidates, morpholines, and ketamines were partially resolved, depending on the polarity and degree of substitution. All analytes, which were mainly purchased from the Internet, were proven to be traded as racemates. PMID- 29280292 TI - Hypopharyngeal evaluation in obstructive sleep apnea with awake flexible laryngoscopy: Validation and updates to Cormack-Lehane and Modified Cormack Lehane scoring systems. AB - OBJECTIVE: To validate the use of Cormack-Lehane and Modified Cormack-Lehane scoring systems to classify patterns of hypopharyngeal airway visualization seen during awake flexible laryngoscopy among patients with obstructive sleep apnoea. STUDY DESIGN: Validation study using samples collected from a prospective database. SETTING: University Medical Center. PARTICIPANTS: Data were obtained from a retrospective review of a prospective database of flexible fiberoptic examination recordings in 274 consecutive OSA subjects (Stanford Sleep Medicine/Surgery Clinic). MAIN OUTCOME MEASURES: Single still images from awake fiberoptic laryngoscopy examinations of the vocal cords from 90 different patients were presented to 2 experts and 4 novice raters. Raters used two grading systems (Cormack-Lehane scale and Modified Cormack-Lehane) to rate vocal cord visualization. Percent agreement and Cohen's kappa statistical analysis were used to evaluate inter-rater reliability and intrarater reliability for each grading system. Feedback from the participants was then used to propose updates to further improve upon the existing grading scales for their applicability to awake flexible endoscopy. RESULTS: The Cormack-Lehane and Modified Cormack-Lehane scale both communicate unobstructed and restricted views of the vocal cords reliably. Compared to the 4-grade scale, however, a modified 5-grade Vocal Cord Grading System allows for better objective communication of common variations in hypopharyngeal airway visualization. CONCLUSION: We propose a 5-Grade Vocal Cord Grading System that builds upon existing grading systems to allow for efficient and reliable communication of hypopharyngeal airway examination during awake fiberoptic laryngoscopy. PMID- 29280293 TI - Subclinical hypothyroidism: A common finding in adult patients with cyanotic congenital heart disease. AB - OBJECTIVE: Cyanotic congenital heart disease is a systemic disease, with effects on multiple organ systems. A high prevalence of subclinical hypothyroidism (SCH) has been reported in a small cohort of cyanotic congenital heart disease patients. Subclinical hypothyroidism has been associated with various adverse cardiovascular effects, as well as an increased risk of progression to overt hypothyroidism. The aim of this study was to examine the prevalence of SCH in cyanotic congenital heart disease patients, consider possible etiologies, and evaluate thyroid function over time. METHODS: First, 90 clinically stable cyanotic congenital heart disease patients were examined with blood samples (thyroid-stimulating hormone, C-reactive protein, hemoglobin, hematocrit, and N terminal pro-brain-natriuretic peptide) in a cross-sectional descriptive study. Second, a longitudinal follow-up study of 43 patients originating from the first study part, was carried out. These patients had thyroid function parameters (thyroid-stimulating hormone, thyroid hormones, and thyroid peroxidase antibodies) evaluated biannually. RESULTS: Elevated thyroid-stimulating hormone was present in 24% of the 90 screened patients. During follow-up (6.5 +/- 1.0 years), SCH (defined as >=2 consecutive elevated thyroid-stimulating hormone values) was present in 26%. Three patients progressed to overt hypothyroidism. Patients with SCH were younger (34 +/- 12 vs 42 +/- 16 years; P = .01) and had a lower oxygen saturation (80 +/- 5 vs 84 +/- 6%; P = .03). CONCLUSION: Subclinical hypothyroidism is a very common finding in cyanotic congenital heart disease. This is not associated with increased levels of C-reactive protein, heart failure, or autoimmunity but appears to be associated with cyanosis and age. Since the clinical impact of SCH is uncertain, further studies are needed to determine this. Regular thyroid evaluation is recommended in cyanotic congenital heart disease patients since SCH can develop to overt hypothyroidism. PMID- 29280294 TI - Urban rural disparity in female breast cancer incidence rate in China and the increasing trend in parallel with socioeconomic development and urbanization in a rural setting. AB - BACKGROUND: Worldwide breast cancer incidence correlates with socioeconomic status and increases in parallel with westernization, however urban-rural disparity and trends have not been adequately investigated in China. METHODS: The age standardized rate (ASR) of female breast cancer by population-based cancer registration was compared between urban Shijiazhuang city and rural Shexian County in relation to socioeconomic status. The increasing trend of breast cancer in Shexian County from 2000-2015 was examined using Joinpoint analysis and the correlation with gross domestic product (GDP) per capita was analyzed. RESULTS: In 2012, the ASR of female breast cancer in Shijiazhuang was more than three times higher than in Shexian County (45.5/1 00 000 vs.13.8/1 00 000; P < 0.01) when the GDP per capita was 2.6 times higher (US$6964.80 vs. US$2700). In parallel with rapid socioeconomic development and urbanization, the biennial ASR of female breast cancer in Shexian county has increased significantly from 2.8/1 00 000 in 2000-2001 to 17.3/1 00 000 in 2014-2015, with an average biennial percent change of +10.2% (P < 0.01). The Pearson correlation between ASR and GDP was significantly positive (r = 0.94, P < 0.01). CONCLUSION: The incidence of breast cancer in women in China is increasing along with lifestyle westernization and changing reproductive patterns associated with socioeconomic development and urbanization. Urgent prevention measures, including the development of a healthy diet, giving birth at a younger age, an increase in breastfeeding, limiting menopause estrogen therapy, and control of alcohol consumption, are required. PMID- 29280296 TI - Lock and chop: A novel method for the generation of a PICK1 PDZ domain and piperidine-based inhibitor co-crystal structure. AB - The membrane protein interacting with kinase C1 (PICK1) plays a trafficking role in the internalization of neuron receptors such as the amino-3-hydroxyl-5-methyl 4-isoxazole-propionate (AMPA) receptor. Reduction of surface AMPA type receptors on neurons reduces synaptic communication leading to cognitive impairment in progressive neurodegenerative diseases such as Alzheimer disease. The internalization of AMPA receptors is mediated by the PDZ domain of PICK1 which binds to the GluA2 subunit of AMPA receptors and targets the receptor for internalization through endocytosis, reducing synaptic communication. We planned to block the PICK1-GluA2 protein-protein interaction with a small molecule inhibitor to stabilize surface AMPA receptors as a therapeutic possibility for neurodegenerative diseases. Using a fluorescence polarization assay, we identified compound BIO124 as a modest inhibitor of the PICK1-GluA2 interaction. We further tried to improve the binding affinity of BIO124 using structure-aided drug design but were unsuccessful in producing a co-crystal structure using previously reported crystallography methods for PICK1. Here, we present a novel method through which we generated a co-crystal structure of the PDZ domain of PICK1 bound to BIO124. PMID- 29280297 TI - Hypercrosslinked particles for the extraction of sweeteners using dispersive solid-phase extraction from environmental samples. AB - This work presents a new extraction material, namely, Q-100, based on hypercrosslinked magnetic particles, which was tested in dispersive solid-phase extraction for a group of sweeteners from environmental samples. The hypercrosslinked Q-100 magnetic particles had the advantage of suitable pore size distribution and high surface area, and showed good retention behavior toward sweeteners. Different dispersive solid-phase extraction parameters such as amount of magnetic particles or extraction time were optimized. Under optimum conditions, Q-100 showed suitable apparent recovery, ranging in the case of river water sample from 21 to 88% for all the sweeteners, except for alitame (12%). The validated method based on dispersive solid-phase extraction using Q-100 followed by liquid chromatography with tandem mass spectrometry provided good linearity and limits of quantification between 0.01 and 0.1 MUg/L. The method was applied to analyze samples from river water and effluent wastewater, and four sweeteners (acesulfame, saccharin, cyclamate, and sucralose) were found in both types of sample. PMID- 29280298 TI - Emotions as student feedback. AB - BACKGROUND: Student feedback is often sought by educators in order to inform future developments in teaching or curriculum development. A lack of engagement with current feedback tools is thought, partly, to result from students perceiving no gain from the activity. The emotional adjective feedback tool (EAFT) is designed around the concept of emotional intelligence, where students feed back to tutors, after clinical teaching, by selecting and elaborating on emotional adjectives that describe their learning experiences. With a need to enhance and drive compassionate care, this emotional engagement might make the process of feedback more meaningful for students and may provide more useful feedback for staff. METHODS: Year-1 medical students (n = 115) completed the EAFT and a traditional feedback tool (TFT) after two clinical skills sessions. Using a questionnaire, they demonstrated their preference and explained their reasoning. After the collection of student feedback using both tools, staff members (n = 12) in two focus groups reviewed the feedback and discussed their preferred tool if they were the tutor of that lesson. RESULTS: Thematic analysis of both student and staff data demonstrated that EAFT provided staff with information relating to teaching qualities and the learning experience of students. TFT delivered information regarding the organisational aspects of lessons. Reflection using the EAFT granted more personal and thought-provoking feedback, emphasising its student-centred structure. Emotional engagement might make the process of feedback more meaningful for students DISCUSSION: Completing the EAFT encouraged students to reflect upon their learning, providing feedback for staff that was more student-centred; however, it remains clear that various tools work for different feedback objectives, environments and students. PMID- 29280299 TI - A Freestanding and Long-Life Sodium-Selenium Cathode by Encapsulation of Selenium into Microporous Multichannel Carbon Nanofibers. AB - Selenium cathode has attracted more and more attention because of its comparable volumetric capacity but much higher electrical conductivity than sulfur cathode. Compared to Li-Se batteries, Na-Se batteries show many advantages, including the low cost of sodium resources and high volumetric capacity. However, Na-Se batteries still suffer from the shuttle effect of polyselenides and high volumetric expansion, resulting in the poor electrochemical performance. Herein, Se is impregnated into microporous multichannel carbon nanofibers (Se@MCNFs) thin film with high flexibility as a binder-free cathode material for Na-Se batteries. The fibrous unique structure of the Se@MCNFs is beneficial to alleviate the volume change of Se during cycling, improve the utilization of active material, and suppress the dissolution of polyselenides into electrolyte. The freestanding Se@MCNF thin-film electrode exhibits high discharge capacity (596 mA h g-1 at the 100th cycle at 0.1 A g-1 ) and excellent rate capability (379 mA h g-1 at 2 A g-1 ) for Na-Se batteries. In addition, it also shows long cycle life with a negligible capacity decay of 0.067% per cycle over 300 cycles at 0.5 A g-1 . This work demonstrates the possibility to develop high performance Na-Se batteries and flexible energy storage devices. PMID- 29280295 TI - Emerging roles of RNA-binding proteins in diabetes and their therapeutic potential in diabetic complications. AB - Diabetes is a debilitating health care problem affecting 422 million people around the world. Diabetic patients suffer from multisystemic complications that can cause mortality and morbidity. Recent advancements in high-throughput next generation RNA-sequencing and computational algorithms led to the discovery of aberrant posttranscriptional gene regulatory programs in diabetes. However, very little is known about how these regulatory programs are mis-regulated in diabetes. RNA-binding proteins (RBPs) are important regulators of posttranscriptional RNA networks, which are also dysregulated in diabetes. Human genetic studies provide new evidence that polymorphisms and mutations in RBPs are linked to diabetes. Therefore, we will discuss the emerging roles of RBPs in abnormal posttranscriptional gene expression in diabetes. Questions that will be addressed are: Which posttranscriptional mechanisms are disrupted in diabetes? Which RBPs are responsible for such changes under diabetic conditions? How are RBPs altered in diabetes? How does dysregulation of RBPs contribute to diabetes? Can we target RBPs using RNA-based methods to restore gene expression profiles in diabetic patients? Studying the evolving roles of RBPs in diabetes is critical not only for a comprehensive understanding of diabetes pathogenesis but also to design RNA-based therapeutic approaches for diabetic complications. WIREs RNA 2018, 9:e1459. doi: 10.1002/wrna.1459 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing Translation > Translation Regulation. PMID- 29280300 TI - Situation analysis of procurement and production of multiple micronutrient supplements in 12 lower and upper middle-income countries. AB - Globally, there are few vitamin and mineral ingredient manufacturers. To support local, in-country or regional procurement and production of multiple micronutrient supplements (MMS), the following production scenarios are possible: (a) straight ingredients of vitamins and minerals forms imported or locally produced that are mixed, tableted, or encapsulated and packaged by a local manufacturer; (b) import or local production of a vitamin and minerals premix that is tableted or encapsulated and packaged locally; (c) import of a bulk, finished product (tablets or capsules) that is packaged and branded; and (d) or import of a branded packaged product. This paper is a situation analysis of the market, manufacturing, and policy factors that are driving the production of MMS in 12 lower and upper middle-income countries. Key informants completed a self administered structured questionnaire, which examined the local context of products available in the market and their cost, regulations and policies, in Brazil, Colombia, Guatemala, Mexico, Peru, Bangladesh, India, Vietnam, Ghana, Kenya, Nigeria, and South Africa. Our study found that although most countries have the capacity to produce locally MMS, the major barriers observed for sustainable and affordable production include (a) poor technical capacity and policies for ensuring quality along the value chain and (b) lack of policy coherence to incentivize local production and lower the manufacture and retail price of MMS. Also, better guidelines and government oversight will be required because not one country had an MMS formulation that matched the globally recommended formulation of the United Nations Multiple Micronutrient Preparation (UNIMMAP). PMID- 29280301 TI - A Fluorescent Biofunctional DNA Hydrogel Prepared by Enzymatic Polymerization. AB - DNA has arisen as a promising building material for the construction of hydrogels owing to its unique properties such as designability and biocompatibility. All DNA hydrogels with only DNA molecules may have limited applications; hence a composite DNA hydrogel with multifunctional moieties is highly desired to cater for specific applications. Herein, a multifunctional DNA hydrogel is created by incorporating DNA with silver nanoclusters (AgNCs), in which AgNCs render the hydrogel simultaneously with fluorescent and antibacterial functions. A circular DNA is rationally designed, which allows for the elongation of DNA chain via an enzymatic polymerization as well as the formation of AgNCs onto DNA scaffolds. The resultant hybrid DNA hydrogel not only shows distinctive morphology and mechanical properties, but also exhibits fluorescent and antibacterial functions. These characteristics, along with its biocompatibility, will allow the hydrogel to be suitable for a variety of potential biomedical applications such as tissue engineering, wound dressing, biosensing, and bioimaging. PMID- 29280302 TI - Combining Phosphoproteomics Datasets and Literature Information to Reveal the Functional Connections in a Cell Phosphorylation Network. AB - Protein phosphorylation modulates many biological processes. However, the characterization of the complex regulatory circuits underlying cell response to external and internal stimuli is still limited by our inability to describe the phosphorylation network on a global scale. Modern MS-based phosphoproteomics allows monitoring tens of thousands of phosphorylation sites in multiple conditions, making the approach ideal to explore signaling pathways mediated by phosphorylation. Here, we review recent advances in phosphoproteomics and discuss some of the computational approaches developed to facilitate extraction of signaling information from these datasets. Finally, this review focuses on approaches that integrate prior literature information with unbiased phosphoproteomics experiments. PMID- 29280303 TI - Dual CCR2/5 Antagonist Attenuates Obesity-Induced Insulin Resistance by Regulating Macrophage Recruitment and M1/M2 Status. AB - OBJECTIVE: Adipose tissue inflammation induced by macrophage infiltration through the C-C motif chemokine receptor (CCR) 2 or CCR5 pathway has a pivotal role in obesity-related disease and insulin resistance. Here, the effect of PF4178903, a dual CCR2/CCR5 antagonist, on obesity and insulin resistance was evaluated. METHODS: Forty male C57BL/6J mice were divided into four groups as follows: (1) regular diet (RD), (2) RD with PF4178903, (3) high-fat diet (HFD), and (4) HFD with PF4178903. All mice were sacrificed 12 weeks after the beginning of the experiment. Biochemical analyses and adipose tissue examinations were performed. RESULTS: After treatment with PF4178903, both body weight and adipocyte size in white adipose tissue were decreased in HFD-fed mice. Furthermore, PF4178903 treatment reduced adipose tissue macrophages (ATMs) and lowered serum proinflammatory cytokines in HFD-fed mice. PF4178903 treatment significantly improved HFD-induced insulin resistance and glucose intolerance. Fluorescence activated cell sorter analysis revealed that PF4178903 treatment reduced the CD8 + T cell fraction in white adipose tissue of HFD-fed mice. PF4178903 treatment reduced M1-polarized macrophages while inducing an M2-dominant shift in macrophages within white adipose tissue in HFD-fed mice. CONCLUSIONS: Dual CCR2/CCR5 antagonism ameliorates insulin resistance and inflammation in obesity by regulating ATM recruitment and polarization in white adipose tissue. PMID- 29280304 TI - Evaluating the Association of Tooth Form of Maxillary Central Incisors with Face Shape Using AutoCAD Software: A Descriptive Study. AB - PURPOSE: To assess the different forms of maxillary central incisors (MCI) and determine their association with the shape of the face for men and women. MATERIALS AND METHODS: A total of 200 subjects (100 women, 100 men) aged between 18 and 30 years with healthy dentition were randomly selected from K.L.E. V.K Institute of Dental Sciences, Belagavi, India. Two standardized photographs (portrait and shape of the MCI) were taken for each subject and opened in AutoCAD 2009 software that was used to prepare technical drawings of face and tooth forms. The dental ratios (extent of line TA: extent of line TB) obtained after the tracings, were classified as tapered (<=0.61), ovoid (>0.61 and <0.69), or square (>=0.70). This classification was used to relate tooth form to the shape of the face and compare the form of MCI between men and women. Association between the shape of the MCI and the face was determined by Chi-square test using R 3.3.1 software. RESULTS: The most prevalent tooth form among the subjects was ovoid (women, 32%; men, 31%) followed by tapered (women, 13%; men, 16%). The least prevalent shape was square (women, 5%; men, 3%). The most prevalent face shape was tapered (women, 34%; men, 25%) followed by ovoid (women, 15%; men, 22%) and the least prevalent was square (women, 1%; men, 3%). An association between face shape and tooth form was statistically not significant. CONCLUSION: The most prevalent tooth form in both men and women was ovoid, and the least prevalent was square. The association between face shape and tooth form was not significant and did not abide by William's "Law of Harmony." However, there was an association between face shape and gender. PMID- 29280305 TI - Iron deficiency and red cell indices in patients with heart failure: reply. PMID- 29280307 TI - Ultra-performance convergence chromatography method for the determination of four chromones and quality control of Saposhnikovia divaricata (Turcz.) Schischk. AB - Ultra-performance convergence chromatography is an environmentally friendly analytical technique that employs dramatically reduced amounts of organic solvents compared to conventional chromatographic methods. In this study, a rapid, sensitive, and environmentally friendly method based on ultra-performance convergence chromatography was developed for the quantification of four major chromones present in the roots of Saposhnikovia divaricata (Turcz.) Schischk. Using this method, the analysis time was significantly shortened compared to conventional high-performance liquid chromatography techniques. In addition, the influence of cosolvent type, cosolvent ratio, column temperature, system pressure, and flow rate on the peak resolution was investigated. The proposed method was validated in terms of its limits of detection, limits of quantitation, linearity, precision, and accuracy. More specifically, the limits of detection of the four chromones ranged from 0.006 to 0.033 MUg/mL, while the limits of quantitation ranged from 0.019 to 0.101 MUg/mL. Our method also exhibited a good regression (r2 > 0.999), excellent precision (RSD < 0.60%), and acceptable recoveries (99.48-102.89%). Finally, the quantities of these four chromones present in 20 commercial samples from Korea and China were successfully evaluated using the developed method, indicating that the proposed method is suitable for the rapid and accurate quality control of Saposhnikovia divaricata. PMID- 29280306 TI - Sex Commonalities and Differences in Obesity-Related Alterations in Intrinsic Brain Activity and Connectivity. AB - OBJECTIVE: This study aimed to characterize obesity-related sex differences in the intrinsic activity and connectivity of the brain's reward networks. METHODS: Eighty-six women (n = 43) and men (n = 43) completed a 10-minute resting functional magnetic resonance imaging scan. Sex differences and commonalities in BMI-related frequency power distribution and reward seed-based connectivity were investigated by using partial least squares analysis. RESULTS: For whole-brain activity in both men and women, increased BMI was associated with increased slow 5 activity in the left globus pallidus (GP) and substantia nigra. In women only, increased BMI was associated with increased slow-4 activity in the right GP and bilateral putamen. For seed-based connectivity in women, increased BMI was associated with reduced slow-5 connectivity between the left GP and putamen and the emotion and cortical regulation regions, but in men, increased BMI was associated with increased connectivity with the medial frontal cortex. In both men and women, increased BMI was associated with increased slow-4 connectivity between the right GP and bilateral putamen and the emotion regulation and sensorimotor-related regions. CONCLUSIONS: The stronger relationship between increased BMI and decreased connectivity of core reward network components with cortical and emotion regulation regions in women may be related to the greater prevalence of emotional eating. The present findings suggest the importance of personalized treatments for obesity that consider the sex of the affected individual. PMID- 29280308 TI - Examining Two Prevailing Models of Loss of Control Eating Among Community-Based Girls. AB - OBJECTIVE: Cognitive-behavioral and interpersonal models of loss of control (LOC) eating have been underexplored in adolescents. METHODS: By using data from community-based adolescent girls assessed annually over 4 years, the cognitive behavioral (n = 416) and interpersonal (n = 418) models were examined by using a regression-based bootstrapping approach. RESULTS: Body dissatisfaction at 14 years prospectively predicted LOC eating at 18 years, both directly (direct effect = -0.039; SE = 0.017; P = 0.02) and indirectly via dieting (indirect effect = -0.010; 95% CI: -0.022 to -0.003). Interpersonal functioning at 14 years was negatively associated with negative emotionality at 17 years, which, in turn, was prospectively associated with LOC eating at 18 years (indirect effect = 0.001; 95% CI: -0.001 to -0.0003); however, the direct association between age 14 interpersonal functioning and age 18 LOC eating was not significant (direct effect = -0.001; SE = 0.001; P = 0.47). CONCLUSIONS: These findings support the cognitive-behavioral model, and partially support the interpersonal model, with the latter findings implying that over time, negative emotionality may promote LOC eating independent of the effects of prior social functioning. Prevention and early intervention efforts for LOC eating may benefit from integrating these theoretical frameworks. PMID- 29280309 TI - Plasma Amino Acids During 8 Weeks of Overfeeding: Relation to Diet Body Composition and Fat Cell Size in the PROOF Study. AB - OBJECTIVE: Different amounts of dietary protein during overfeeding produced similar fat gain but different amounts of gain in fat-free body mass. Protein and energy intake may have differential effects on amino acids during overfeeding. METHODS: Twenty-three healthy adult men and women were overfed by 40% for 8 weeks with 5%, 15%, or 25% protein diets. Plasma amino acids were measured by gas chromatography and mass spectrometry at baseline and week 8. Body composition was measured by dual-energy x-ray absorptiometry, fat cell size (FCS) from subcutaneous fat biopsies, and insulin resistance by euglycemic-hyperinsulinemic clamp. RESULTS: The following three amino acid patterns were seen: increasing concentration of five essential and three nonessential amino acids with increasing protein intake, higher levels of six nonessential amino acids with the low-protein diet, and a pattern that was flat or "V" shaped. Dietary fat and protein were both correlated with changes in valine, leucine/isoleucine/norleucine, phenylalanine, and tyrosine, but energy intake was not. The change in fat mass and weight was related to the change in several amino acids. Baseline FCS and the interaction between glucose disposal and FCS were associated with changes in several amino acids during overfeeding. CONCLUSIONS: Overfeeding dietary protein affects the levels of both essential and nonessential amino acids. PMID- 29280311 TI - Fluorination Enhances Serum Stability of Bioreducible Poly(amido amine) Polyplexes and Enables Efficient Intravenous siRNA Delivery. AB - The use of small interfering RNA (siRNA) in cancer treatment has been limited by the lack of effective systemic delivery methods. Although synthetic polycations have been widely explored in siRNA delivery, polycation/siRNA polyplexes often suffer from insufficient stability in vivo. Here, rationally designed siRNA delivery systems that meet the requirements for systemic siRNA delivery to distant tumors are reported. The hypothesis that modular design of delivery systems based on poly(amido amine)s that combine fluorination for systemic stability with bioreducibility for easy intracellular siRNA release, and PEGylation for improved safety and colloidal stability will overcome problems with contradicting siRNA delivery demands is tested. PEGylated, fluorinated, and bioreducible copolymers (PEG-PCD-F) with different degree of fluorination are thus synthesized. The fluorinated copolymers readily formed polyplexes with siRNA and achieved greatly improved gene silencing efficacy in multiple cell lines in vitro when compared with nonfluorinated controls. The results show fluorination induced enhancement of stability, cellular uptake, and endosomal escape of the polyplexes, while exhibiting efficient siRNA release in reducing intracellular environment. PEG-PCD-F polyplexes with siRNA against Bcl2 inhibit breast tumor growth following systemic intravenous administration. The results provide strong evidence of successful combination of bioreducibility with fluorination and PEGylation to achieve systemic siRNA polyplex delivery. PMID- 29280310 TI - Osteogenic Stimulation of Human Adipose-Derived Mesenchymal Stem Cells Using a Fungal Metabolite That Suppresses the Polycomb Group Protein EZH2. AB - Strategies for musculoskeletal tissue regeneration apply adult mesenchymal stem/stromal cells (MSCs) that can be sourced from bone marrow- and lipo aspirates. Adipose tissue-derived MSCs are more easily harvested in the large quantities required for skeletal tissue-engineering approaches, but are generally considered to be less osteogenic than bone marrow MSCs. Therefore, we tested a new molecular strategy to improve their osteogenic lineage-differentiation potential using the fungal metabolite cytochalasin D (CytoD). We show that CytoD, which may function by redistributing the intracellular location of beta-actin (ACTB), is a potent osteogenic stimulant as reflected by significant increases in alkaline phosphatase activity, extracellular matrix mineralization, and osteoblast-related gene expression (e.g., RUNX2, ALPL, SPARC, and TGFB3). RNA sequencing analyses of MSCs revealed that acute CytoD treatment (24 hours) stimulates a broad program of osteogenic biomarkers and epigenetic regulators. CytoD decreases mRNA and protein levels of the Polycomb chromatin regulator Enhancer of Zeste Homolog 2 (EZH2), which controls heterochromatin formation by mediating trimethylation of histone 3 lysine 27 (H3K27me3). Reduced EZH2 expression decreases cellular H3K27me3 marks indicating a global reduction in heterochromatin. We conclude that CytoD is an effective osteogenic stimulant that mechanistically functions by blocking both cytoplasmic actin polymerization and gene-suppressive epigenetic mechanisms required for the acquisition of the osteogenic phenotype in adipose tissue-derived MSCs. This finding supports the use of CytoD in advancing the osteogenic potential of MSCs in skeletal regenerative strategies. Stem Cells Translational Medicine 2018;7:197-209. PMID- 29280312 TI - Dysbiosis Signatures of Gut Microbiota Along the Sequence from Healthy, Young Patients to Those with Overweight and Obesity. AB - OBJECTIVE: To investigate the gut microbiota in healthy volunteers (HVs), patients with overweight (OW), and patients with obesity (OB), including those with acanthosis nigricans (AN) or without AN (N-AN). METHODS: Microbial 16S rRNA genes were examined by using pyrosequencing technology and analyzed by using bioinformatics methods. RESULTS: Subjects in the OW and OB groups showed severe disturbances in glycemic control, lipid profile, and inflammatory markers (all P < 0.05); patients with AN had worse metabolic status (P < 0.001) and a lower diversity of microbiota (P < 0.05). The OB and HV groups showed totally different gut microbiota composition. In the OB group, beneficial microbiotas including Bifidobacterium (0.01% vs. 0.05%, false discovery rate [FDR] = 4.27*10-5 ), anti inflammatory Faecalibacterium (6.70% vs. 13.82%, FDR = 0.010), and butyrate producing Ruminococcaceae were significantly decreased, whereas Bacillus (0.58% vs. 0.04%, FDR = 0.013) and potential opportunistic pathogens such as Fusobacterium (1.44% vs. 0.11%, FDR < 0.01) and Escherichia-Shigella (6.01% vs. 0.76%, FDR = 0.041) had outgrown dramatically. Function prediction revealed a significant increase in lipopolysaccharide biosynthesis proteins and bacterial invasion of epithelial cell-associated genes and a significant decrease in glucose and essential amino acid-related genes. CONCLUSIONS: Gut microbiotas and their functions were significantly changed in obesity. More prospective studies on association and causality between microbiota and obesity are imperative and might contribute to the prevention, diagnosis, and treatment of obesity. PMID- 29280313 TI - Efficacy and safety of oxycodone/naloxone as add-on therapy to gabapentin or pregabalin for the management of chemotherapy-induced peripheral neuropathy in Korea. AB - AIMS: To investigate the efficacy and safety of oxycodone/naloxone in patients with chemotherapy-induced peripheral neuropathy (CIPN) inadequately controlled with pregabalin or gabapentin. METHODS: This 4-week, multicenter, interventional, single-arm phase IV study included 72 Korean patients with CIPN inadequately controlled with pregabalin or gabapentin (Numeric Rating Scale 0-10; NRS >=4 at baseline). In addition to pregabalin or gabapentin at existing doses, patients received 20/10 mg/day oxycodone/naloxone (up-titrated to 80/40 mg/day as needed). The primary endpoint was change in NRS score after 4 weeks. Secondary endpoints included Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-NTX) scores and safety assessments. RESULTS: The mean +/- standard deviation (SD) dose of oxycodone/naloxone was 23.3 +/- 7.5 mg/day. At week 4, NRS score reduction was 1.29 +/- 1.84 points (21.4% reduction; P < 0.0001). Patients on taxane-based chemotherapy experienced a significantly smaller mean change in NRS score at week 4 compared to patients on other chemotherapy (-0.63 +/- 1.54 [n = 30] vs. -1.83 +/- 1.00 [n = 36]; P = 0.0072). Although there were no significant changes in FACT/GOG-NTX total scores, improvements were observed in the neurotoxicity subscale measuring numbness/tingling of hands (mean +/- SD change: -0.27 +/- 1.04; P = 0.0427) and feet (-0.60 +/- 1.09; P < 0.0001). Forty-two (58.3%) patients reported adverse events. There were no clinically significant changes in laboratory tests or vital signs. CONCLUSION: Oxycodone/naloxone added to pregabalin or gabapentin provided additional pain relief and symptom control in Korean patients with CIPN, without clinically significant safety concerns. PMID- 29280314 TI - Advances in Magnetic Nanoparticles for Biomedical Applications. AB - Magnetic nanoparticles (NPs) are emerging as an important class of biomedical functional nanomaterials in areas such as hyperthermia, drug release, tissue engineering, theranostic, and lab-on-a-chip, due to their exclusive chemical and physical properties. Although some works can be found reviewing the main application of magnetic NPs in the area of biomedical engineering, recent and intense progress on magnetic nanoparticle research, from synthesis to surface functionalization strategies, demands for a work that includes, summarizes, and debates current directions and ongoing advancements in this research field. Thus, the present work addresses the structure, synthesis, properties, and the incorporation of magnetic NPs in nanocomposites, highlighting the most relevant effects of the synthesis on the magnetic and structural properties of the magnetic NPs and how these effects limit their utilization in the biomedical area. Furthermore, this review next focuses on the application of magnetic NPs on the biomedical field. Finally, a discussion of the main challenges and an outlook of the future developments in the use of magnetic NPs for advanced biomedical applications are critically provided. PMID- 29280315 TI - A Photoinduced Reversible Phase Transition in a Dipeptide Supramolecular Assembly. AB - Tunable supramolecular assembly has found various applications in biomedicine, molecular catalysis, optoelectronics, and nanofabrication. Unlike traditional covalent conjugation, non-covalent introduction of a photoswitchable moiety enables reversible photomodulation of non-photosensitive dipeptide supramolecular assembly. Under light illumination, a long-lived photoacid generator releases a proton and mediates the dissociation of dipeptide-based organogel, thereby resulting in sol formation. Under darkness, the photoswitchable moiety entraps a proton, resulting in gel regeneration. Furthermore, accompanying the isothermal recycled gel-sol transition in a spatially controlled manner, renewable patterns are spontaneously fabricated. This new concept of light-controlled phase transition of amino acid-based supramolecular assemblies will open up the possibility of wide applications. PMID- 29280316 TI - Early-stage idiopathic mesenteric phlebosclerosis incidentally combined with adenocarcinoma of the ascending colon: A report of two cases. PMID- 29280317 TI - Selective Cell Penetrating Peptide-Functionalized Polymersomes Mediate Efficient and Targeted Delivery of Methotrexate Disodium to Human Lung Cancer In Vivo. AB - It is a long challenge to develop nanomedicines that simultaneously possess tumor cell selectivity and penetration functions. Here, it is reported that selective cell penetrating peptide (RLWMRWYSPRTRAYGC)-functionalized polymersomes (SCPP-PS) mediate efficient and targeted delivery of methotrexate disodium (MTX) to human lung cancer in vivo. SCPP-PS with an SCPP density of 18.7% is self-crosslinked, has a small size (63-65 nm), and high MTX loading (up to 19.4 wt%), shows selective uptake and fast penetration into A549 lung cancer cells, and efficiently releases MTX intracellularly. Interestingly, MTX-loaded SCPP-PS (MTX SCPP-PS) displays much lower IC50 than those of MTX-PS and free MTX. Installing SCPP to polymersomes has no detrimental effect to their long blood circulation time but significantly increases drug accumulation in A549 tumor (5.3% injected dose per gram at 8 h post injection). Remarkably, SCPP-PS exhibits deep penetration in to A549 tumors. MTX-SCPP-PS completely inhibits tumor progression and significantly improves survival rates in mice bearing A549 lung tumor xenografts as compared to MTX-PS and free MTX groups (median survival time: 75 vs 45 and 38 d, respectively), without causing noticeable adverse effects. These results highlight that functionalization of nanomedicines with SCPP is a feasible strategy to achieve efficient and targeted tumor therapy. PMID- 29280318 TI - Navigating Market Authorization: The Path Holoclar Took to Become the First Stem Cell Product Approved in the European Union. AB - Gene therapy, cell therapy, and tissue engineering have the potential to revolutionize the treatment of disease and injury. Attaining marketing authorization for such advanced therapy medicinal products (ATMPs) requires a rigorous scientific evaluation by the European Medicines Agency-authorization is only granted if the product can fulfil stringent requirements for quality, safety, and efficacy. However, many ATMPs are being provided to patients under alternative means, such as "hospital exemption" schemes. Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells), a novel treatment for eye burns, is one of the few ATMPs to have been granted marketing authorization and is the first containing stem cells. This review highlights the differences in standards between an authorized and unauthorized medicinal product, and specifically discusses how the manufacture of Holoclar had to be updated to achieve authorization. The result is that patients will have access to a therapy that is manufactured to high commercial standards, and is supported by robust clinical safety and efficacy data. Stem Cells Translational Medicine 2018;7:146-154. PMID- 29280319 TI - Importance of the RpoE Regulon in Maintaining the Lipid Bilayer during Antimicrobial Treatment with the Polycationic Agent, Chlorhexidine. AB - The emergence of multidrug resistance in bacteria has reached alarming levels. To solve this growing problem, discovery of novel cellular targets or pathways important for antimicrobial resistance is urgently needed. In this study, we explored how the alternative sigma factor, RpoE, protects Escherichia coli O157 against the toxic effects of the polycationic antimicrobial agent, chlorhexidine (CHX). Susceptibility of this organism to CHX was found to directly correlate to the growth rate, with the faster replicating wild-type being more susceptible to CHX than its more slowly replicating DeltarpoE O157 mutant. Once the wild-type and rpoE mutant strains had undergone growth arrest (entered the stationary growth phase), their resistance to CHX became entirely dependent on the functionality of RpoE. The RpoE regulon plays a critical role in maintaining the integrity of the asymmetric lipid bilayer of E. coli, thereby preventing the intracellular accumulation of CHX. Finally, using a single-cell, high-resolution, synchrotron-based approach, we discovered a subpopulation of the rpoE mutant strain with no detectable intracellular CHX, a predominant characteristic of the wild-type CHX-resistant population. This finding reveals a role of phenotypic heterogeneity in antimicrobial resistance. PMID- 29280320 TI - Convenient Monitoring System of Intracellular microRNA Expression during Adipogenesis via Mechanical Stimulus-Induced Exocytosis of Lipovesicular miRNA Beacon. AB - Noninvasive investigation of microRNAs (miRNAs) expression, which is deeply related to biological phenomena such as stem cell differentiation, in culture soup is particularly useful for monitoring of stem cell differentiation without phototoxicity of living cells, especially when cell morphologies remain unchanged during differentiation. However, real-time detection of miRNA in culture soup is not recommended because of insufficient miRNA amounts in culture soup. In this study, a convenient method is introduced for real-time assessing intracellular miRNA in culture soup by using lipovesicular miRNA beacon (Lipo-mB) and mechanical stimulus-mediated exocytosis. Pipetting-harvest of culture soup induces exocytosis-secretion of fluorescence signal of Lipo-mB from cytoplasm into culture soup. To demonstrate this method, Lipo-mB is applied for monitoring of adipogenesis by analyzing the expression levels of various intracellular miRNAs, which are related to adipogenesis regulators. The fluorescence intensity profile of the culture soup is correlated with the quantitative reverse transcription-polymerase chain reaction data and absorbance of Oil Red O staining. These results demonstrate that Lipo-mB can successfully monitor stem cell differentiation by sensing changes in miRNA expression from culture soup of living cells. Lipo-mB can be further developed as an accurate sensing system for analyzing subtle differences in genotype, even when changes in phenotype cannot be observed. PMID- 29280321 TI - Current Approaches to Bone Tissue Engineering: The Interface between Biology and Engineering. AB - The successful regeneration of bone tissue to replace areas of bone loss in large defects or at load-bearing sites remains a significant clinical challenge. Over the past few decades, major progress is achieved in the field of bone tissue engineering to provide alternative therapies, particularly through approaches that are at the interface of biology and engineering. To satisfy the diverse regenerative requirements of bone tissue, the field moves toward highly integrated approaches incorporating the knowledge and techniques from multiple disciplines, and typically involves the use of biomaterials as an essential element for supporting or inducing bone regeneration. This review summarizes the types of approaches currently used in bone tissue engineering, beginning with those primarily based on biology or engineering, and moving into integrated approaches in the areas of biomaterial developments, biomimetic design, and scalable methods for treating large or load-bearing bone defects, while highlighting potential areas for collaboration and providing an outlook on future developments. PMID- 29280323 TI - Biomimetic Tissue-Engineered Bone Substitutes for Maxillofacial and Craniofacial Repair: The Potential of Cell Sheet Technologies. AB - Maxillofacial defects are complex lesions stemming from various etiologies: accidental, congenital, pathological, or surgical. A bone graft may be required when the normal regenerative capacity of the bone is exceeded or insufficient. Surgeons have many options available for bone grafting including the "gold standard" autologous bone graft. However, this approach is not without drawbacks such as the morbidity associated with harvesting bone from a donor site, pain, infection, or a poor quantity and quality of bone in some patient populations. This review discusses the various bone graft substitutes used for maxillofacial and craniofacial repair: allografts, xenografts, synthetic biomaterials, and tissue-engineered substitutes. A brief overview of bone tissue engineering evolution including the use of mesenchymal stem cells is exposed, highlighting the first clinical applications of adipose-derived stem/stromal cells in craniofacial reconstruction. The importance of prevascularization strategies for bone tissue engineering is also discussed, with an emphasis on recent work describing substitutes produced using cell sheet-based technologies, including the use of thermo-responsive plates and the self-assembly approach of tissue engineering. Indeed, considering their entirely cell-based design, these natural bone-like substitutes have the potential to closely mimic the osteogenicity, osteoconductivity, osteoinduction, and osseointegration properties of autogenous bone for maxillofacial and craniofacial reconstruction. PMID- 29280322 TI - Tissue Sodium Content is Elevated in the Skin and Subcutaneous Adipose Tissue in Women with Lipedema. AB - OBJECTIVE: To test the hypothesis that tissue sodium and adipose content are elevated in patients with lipedema; if confirmed, this could establish precedence for tissue sodium and adipose content representing a discriminatory biomarker for lipedema. METHODS: Participants with lipedema (n = 10) and control (n = 11) volunteers matched for biological sex, age, BMI, and calf circumference were scanned with 3.0-T sodium and conventional proton magnetic resonance imaging (MRI). Standardized tissue sodium content was quantified in the calf skin, subcutaneous adipose tissue (SAT), and muscle. Dixon MRI was employed to quantify tissue fat and water volumes of the calf. Nonparametric statistical tests were applied to compare regional sodium content and fat-to-water volume between groups (significance: two-sided P <= 0.05). RESULTS: Skin (P = 0.01) and SAT (P = 0.04) sodium content were elevated in lipedema (skin: 14.9 +/- 2.9 mmol/L; SAT: 11.9 +/ 3.1 mmol/L) relative to control participants (skin: 11.9 +/- 2.0 mmol/L; SAT: 9.4 +/- 1.6 mmol/L). Relative fat-to-water volume in the calf was elevated in lipedema (1.2 +/- 0.48 ratio) relative to control participants (0.63 +/- 0.26 ratio; P < 0.001). Skin sodium content was directly correlated with fat-to-water volume (Spearman's rho = 0.54; P = 0.01). CONCLUSIONS: Internal metrics of tissue sodium and adipose content are elevated in patients with lipedema, potentially providing objective imaging-based biomarkers for differentially diagnosing the under-recognized condition of lipedema from obesity. PMID- 29280324 TI - Tension-Activated Delivery of Small Molecules and Proteins from Superhydrophobic Composites. AB - The fabrication and performance of mechanically responsive multilayer superhydrophobic composites are reported. The application of tensile strain triggers the release of small molecules and proteins from these composites, with different tensile strain magnitudes and coating thickness influencing agent release. These mechanoresponsive composites consist of an absorbent drug core surrounded by an electrosprayed superhydrophobic protective coating that limits drug release in the absence of tensile strain. Coating thickness and applied tensile strain control release of chemotherapeutic cisplatin and enzyme beta galactosidase, as measured by atomic absorption and UV-vis spectrophotometry, respectively, with preserved in vitro activity. Such mechanically responsive drug delivery devices, when coupled to existing dynamic mechanical forces in the body or integrated with mechanical medical devices, such as stents, will provide local controlled dosing. PMID- 29280325 TI - Design and Structure-Function Characterization of 3D Printed Synthetic Porous Biomaterials for Tissue Engineering. AB - 3D printing is now adopted for use in a variety of industries and functions. In biomedical engineering, 3D printing has prevailed over more traditional manufacturing methods in tissue engineering due to its high degree of control over both macro- and microarchitecture of porous tissue scaffolds. However, with the improved flexibility in design come new challenges in characterizing the structure-function relationships between various architectures and both mechanical and biological properties in an assortment of clinical applications. Presently, the field of tissue engineering lacks a comprehensive body of literature that is capable of drawing meaningful relationships between the designed structure and resulting function of 3D printed porous biomaterial scaffolds. This work first discusses the role of design on 3D printed porous scaffold function and then reviews characterization of these structure-function relationships for 3D printed synthetic metallic, polymeric, and ceramic biomaterials. PMID- 29280326 TI - Cross-linkable graphene oxide embedded nanocomposite hydrogel with enhanced mechanics and cytocompatibility for tissue engineering. AB - Graphene oxide (GO) is an attractive material that can be utilized to enhance the modulus and conductivities of substrates and hydrogels. To covalently cross-link graphene oxide sheets into hydrogels, abundant cross-linkable double bonds were introduced to synthesize the graphene-oxide-tris-acrylate sheet (GO-TrisA). Polyacrylamide (PAM) nanocomposite hydrogels were then fabricated with inherent covalently and permanently cross-linked GO-TrisA sheets. Results showed that the covalently cross-linked GO-TrisA/PAM nanocomposite hydrogel had enhanced mechanical strength, thermo stability compared with GO/PAM hydrogel maintained mainly by hydrogen bonding between PAM chains and GO sheets. In vitro cell study showed that the covalently cross-linked rGO-TrisA/PAM nanocomposite hydrogel had excellent cytocompatibility after in situ reduction. These results suggest that rGO-TrisA/PAM nanocomposite hydrogel holds great potential for tissue engineering applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1247-1257, 2018. PMID- 29280327 TI - Effect of hay supplementation timing on rumen microbiota in suckling calves. AB - An animal feeding trial was conducted on 18 seven-day-old Holstein dairy bull calves weighing 42 +/- 3 kg each. Calves were randomly assigned into three groups (n = 6 each). The dietary treatments were as follows: (1) milk and starter for the control group (MS), (2) supplementation of oat hay from week 2 on the basis of milk and starter (MSO2), and (3) supplementation of oat hay from week 6 on the basis of milk and starter (MSO6). All animals were fed starter and oat hay ad libitum. The major phyla in the different groups of rumen fluid included Firmicutes, Actinobacteria, Bacteroidetes, Proteobacteria, and Euryarchaeota. The major genera were identified, and major genera proportions in the three groups were as follows: Methanobrevibacter (Euryarchaeota), 2.1%, 1.7%, and 2.1%; Olsenella (Actinobacteria), 23.9%, 17.7%, and 12.8%; Prevotella (Bacteroidetes), 10.5%, 16.5%, and 19.2%; Dialister (Firmicutes), 3.3%, 4.1%, and 2.8%; Succiniclasticum (Firmicutes), 3.8%, 4.7%, and 9.2%; and Sharpea (Firmicutes), 0.4%, 2.5%, and 0.2%, respectively. There were no significant differences in the various phyla among the three groups (p > .05). The results showed that calves hay supplementation time did not affect the diversity of the rumen microbiota in the suckling calves. However, the hay supplementation altered the proportion of the various microbial populations, supplementation of oat hay from week 2 on the basis of milk and starter could improve calves rumen pH. PMID- 29280328 TI - Recent Progress in Developing Injectable Matrices for Enhancing Cell Delivery and Tissue Regeneration. AB - Biomaterials are key factors in regenerative medicine. Matrices used for cell delivery are especially important, as they provide support to transplanted cells that is essential for promoting cell survival, retention, and desirable phenotypes. Injectable matrices have become promising and attractive due to their minimum invasiveness and ease of use. Conventional injectable matrices mostly use hydrogel precursor solutions that form solid, cell-laden hydrogel scaffolds in situ. However, these materials are associated with challenges in biocompatibility, shear-induced cell death, lack of control over cellular phenotype, lack of macroporosity and remodeling, and relatively weak mechanical strength. This Progress Report provides a brief overview of recent progress in developing injectable matrices to overcome the limitations of conventional in situ hydrogels. Biocompatible chemistry and shear-thinning hydrogels have been introduced to promote cell survival and retention. Emerging investigations of the effects of matrix properties on cellular function in 3D provide important guidelines for promoting desirable cellular phenotypes. Moreover, several novel approaches are combining injectability with macroporosity to achieve macroporous, injectable matrices for cell delivery. PMID- 29280329 TI - Endoscopic ultrasound guided fine-needle aspiration: What variables influence diagnostic yield? AB - BACKGROUND: Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) plays an important role in the diagnosis of various lesions. We sought to determine factors that influence the diagnostic yield of EUS-FNA, specifically, the presence of a cytopathologist, FNA site, and the endoscopist's skill. METHODS: The data on cytopathologist's availability, duration of procedure, number of passes made, and diagnostic material for cell block (CB) preparation was collected over an 18 months period. RESULTS: 230 specimens (218 patients) were obtained from pancreas (114), lymph node (64), submucosal lesions of the gastrointestinal tract (27), liver (8), and miscellaneous (17) sites. The results were classified as informative (77.8%) and non-informative (NI) (22.2%). The NI rate was significantly high, when a cytopathologist was absent (P = .0008). As the likelihood of cytopathologist's presence increased from 35.8% to 82.9%, the CB quality increased (P < .0001). In the absence of a cytopathologist, the likelihood of NI result increased more than 2-fold (P = .03) and of an inadequate CB increased 3-fold (P < .0001). The more experienced endoscopist "C" (compared to the less experienced "A + B") was less likely to get inadequate material (40.5% vs. 66.3%) (P = .0001). CONCLUSION: The diagnostic yield of EUS-FNA is significantly related to the presence of an on-site cytopathologist and endoscopist's skill in procuring diagnostic material. PMID- 29280330 TI - Aminolated and Thiolated PEG-Covered Gold Nanoparticles with High Stability and Antiaggregation for Lateral Flow Detection of Bisphenol A. AB - The few lateral flow assays (LFAs) established for detecting the endocrine disrupting chemical bisphenol A (BPA) have employed citrate-stabilized gold nanoparticles (GNPs), which have inevitable limitations and instability issues. To address these limitations, a more stable and more sensitive biosensor is developed by designing strategies for modifying the surfaces of GNPs with polyethylene glycol and then testing their effectiveness and sensitivity toward BPA in an LFA. Without the application of any enhancement strategy, this modified BPA LFA can achieve a naked-eye limit of detection (LOD) of 0.8 ng mL-1 , which is 12.5 times better than the LOD of regular BPA LFAs, and a quantitative LOD of 0.472 ng mL-1 . This modified LFA has the potential to be applied to the detection of various antigens. PMID- 29280331 TI - Cytological features in eight patients with ALK-rearranged lung cancer. AB - BACKGROUND: ALK-rearranged lung cancer has been recently identified. Although signet-ring cell morphology and mucinous cribriform pattern are considered to be characteristic of ALK-rearranged lung cancer. Some studies have also suggested cytological features. METHODS: This study investigated cytological features of ALK-rearranged lung cancer in eight patients. RESULTS: Cytologically, the tumor cell group varied from isolated to large clusters. Small nucleoli, fine granular to vesicular chromatin, and nuclear groove were observed in all patients. Furthermore, extracellular and intracellular mucin and signet-ring cells were identified in five patients. CONCLUSION: This study demonstrated that the presence of extracellular and intracellular mucin, signet-ring cells, small nucleoli, fine granular to vesicular chromatin, and nuclear groove in cytological samples may be a diagnostic clue for ALK-rearranged lung cancer. PMID- 29280332 TI - Making ecological models adequate. AB - Critical evaluation of the adequacy of ecological models is urgently needed to enhance their utility in developing theory and enabling environmental managers and policymakers to make informed decisions. Poorly supported management can have detrimental, costly or irreversible impacts on the environment and society. Here, we examine common issues in ecological modelling and suggest criteria for improving modelling frameworks. An appropriate level of process description is crucial to constructing the best possible model, given the available data and understanding of ecological structures. Model details unsupported by data typically lead to over parameterisation and poor model performance. Conversely, a lack of mechanistic details may limit a model's ability to predict ecological systems' responses to management. Ecological studies that employ models should follow a set of model adequacy assessment protocols that include: asking a series of critical questions regarding state and control variable selection, the determinacy of data, and the sensitivity and validity of analyses. We also need to improve model elaboration, refinement and coarse graining procedures to better understand the relevancy and adequacy of our models and the role they play in advancing theory, improving hind and forecasting, and enabling problem solving and management. PMID- 29280333 TI - Assessment of resting energy expenditure and body composition in Japanese pregnant women with diabetes. AB - AIMS/INTRODUCTION: To measure longitudinal changes in resting energy expenditure and body composition of Japanese pregnant women with or without diabetes. MATERIALS AND METHODS: The study population consisted of women who had delivered a live singleton neonate after 22 weeks' gestation at Okayama University Hospital from July 2013 to June 2017. Resting energy expenditure and body composition were measured in the first trimester, second trimester, third trimester and postpartum. RESULTS: A total of 144 women participated in this study: 103 with normal glucose tolerance and 41 with diabetes. The resting energy expenditure (kcal/day) of pregnant women with normal glucose tolerance was significantly higher in the third trimester (1,644 +/- 234) than in the first (1,461 +/- 215) and second trimesters (1,491 +/- 219), and postpartum (1,419 +/- 254), whereas that of pregnant women with diabetes did not significantly change during all periods (1,568 +/- 404, 1,710 +/- 332, 1,716 +/- 251, 1,567 +/- 249). The resting energy expenditure of women with good glycemic control was lower than that of women with poor control. Fat-free mass was closely correlated with resting energy expenditure. CONCLUSIONS: The resting energy expenditure of Japanese pregnant women with normal glucose tolerance was significantly increased in the third trimester. The resting energy expenditure of women with good glycemic control was lower than that of women with poor control. Resting energy expenditure and fat free mass are potential indexes for medical nutrition therapy in pregnant women with diabetes. PMID- 29280334 TI - Retroperitoneal ectopic brain: Case report and literature review. AB - Heterotopic neural tissue (HNT) has been identified in many sites. In our literature review, we have found only two cases of HNT located in the retroperitoneum. As far as we know, cytological features of HNT have not been described. We here report a case of retroperitoneal HNT diagnosed by fine-needle aspiration (FNA) cytology and subsequent resection. Our patient was a male infant born at 26 weeks' gestation. A retroperitoneal solid-cystic lesion measuring 3.8 cm was identified by abdominal ultrasound. FNA was performed and cytology showed highly cellular smears with single cells and masses of fibrillary material. Cells were small with rounded irregular nuclei and variable cytoplasm. Multinucleated cells, cells with neuronal morphology, calcifications, and hemosiderophages could also be seen. The lesion was excised and histology showed fibrillary areas, glial cells, neurons, and ependymal cells. Synaptophysin, GFAP, and EMA were expressed in distinct areas and cell types. No recurrences were observed. PMID- 29280335 TI - Amyloidosis diagnosed in cytology specimen of pleural effusion: A case report. AB - Amyloidosis is a rare condition resulting from extracellular deposition of amyloid, a fibrillary material derived from various precursor proteins. Involvement of the pleura by amyloidosis is a rare but serious complication. Pleural amyloidosis is primarily diagnosed by identifying amyloid deposition by histology on pleural biopsy specimens. Hereby, we report a case of systemic amyloidosis where we were able to identify amyloid in a pleural effusion specimen sent for cytopathology evaluation. A 59-year-old male with newly diagnosed multiple myeloma and systemic amyloidosis underwent therapeutic thoracentesis. The H&E stained cell block sections revealed a single, less than one millimeter focus of waxy material surrounded by a rim of reactive mesothelial cells suspicious for amyloid deposit in a background of fibrin, lymphocytes, and reactive mesothelial cells. The focus stained salmon pink with Congo-red special stain and showed apple-green birefringence under polarized light. Our finding suggests that pleural involvement in patients with systemic amyloidosis can be identified on effusion specimens and avert the need for more invasive procedures like pleural or pulmonary parenchymal biopsies. PMID- 29280336 TI - Assessing the current and future biological control potential of Trichogramma ostriniae on its hosts Ostrinia furnacalis and Ostrinia nubilalis. AB - BACKGROUND: Understanding interactions between biocontrol agents and their pest hosts under climate change should assist implementation of biocontrol strategies, by identifying appropriate biocontrol agents for release or determining the optimal timing of releases. Species distribution models (SDMs) were applied to evaluate the distributions of Trichogramma ostriniae and its native host, Ostrinia furnacalis, in southeastern Asia, and a non-native host, Ostrinia nubilalis, in a novel range, North America, using MAXENT and CLIMEX modelling approaches. RESULTS: The models led to similar predictions about the expected distribution of the two species in Asia, and emphasized likely mismatches between host and natural enemy. Trichogramma ostriniae was predicted to occur in the summer corn region of China, with distribution limits linked to its sensitivity to cold, seasonality of radiation and precipitation. The modelled Ostrinia nubilalis distribution overlapped with the main corn production areas of the northeastern USA and Canada; temporary/seasonal suitable habitat was also predicted across the southeastern USA. Climate change scenarios are predicted to favour T. ostriniae over its hosts in northeastern China and North America. CONCLUSION: The modelling approaches used here proved useful for assessing environmental factors linked to an egg parasitoid and its lepidopteran hosts and identifying areas potentially suitable for inundative releases. (c) 2017 Society of Chemical Industry. PMID- 29280337 TI - Analysis of bioactive components and multi-component pharmacokinetics of saponins from the leaves of Panax notoginseng in rat plasma after oral administration by LC-MS/MS. AB - In this study, simple ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass tandem mass spectrometry is used to characterize the absorbed components in rat plasma after the oral administration of saponins from the leaves of Panax notoginseng. Seventeen prototype compounds are structurally characterized. Furthermore, a simple and sensitive liquid chromatography with tandem mass spectrometry method is also used for the simultaneous determination of notoginsenoside Fc, ginsenoside Rb1, ginsenoside Rc, ginsenoside Rb3, ginsenoside Rd, and notoginsenoside Fe in rat plasma within 5 min. After n-butanol mediated liquid-liquid extraction, all analytes were separated on a C18 column and monitored in negative ion mode. Linearity, sensitivity, intra- and inter-assay precision, accuracy, recovery, matrix effect, and stability were all within acceptable ranges. The validated liquid chromatography with tandem mass spectrometry method is successfully applied to the pharmacokinetic study of saponins from the leaves of Panax notoginseng in rats after oral administration. The results suggest that notoginsenoside Fc and ginsenoside Rb3 showed relatively higher exposure compared with other saponins. All saponins showed a long duration in plasma with a t1/2 longer than 15 h, except notoginsenoside Fe (t1/2 = 2.78 h). This study provides important information about the metabolism of saponins from the leaves of Panax notoginseng, which is useful for completely understanding its mechanism of action. PMID- 29280338 TI - Rodlike Supramolecular Nanoassemblies of Degradable Poly(Aspartic Acid) Derivatives and Hydroxyl-Rich Polycations for Effective Delivery of Versatile Tumor-Suppressive ncRNAs. AB - The delivery of tumor-suppressive noncoding RNAs (ncRNAs) including short ncRNAs (i.e., miRNAs) and long ncRNAs (lncRNAs) is put forward to treat tumors. In this work, novel rodlike supramolecular nanoassemblies (CNC @CB[8] @ PGEA) of degradable poly(aspartic acid) (PAsp) derivatives-grafted cellulose nanocrystals (CNCs) and hydroxyl-rich polycations (ethanolamine-functionalized poly(glycidyl methacrylate), PGEA) are proposed via typical cucurbit[8]uril (CB[8])-based host guest interactions for delivery of different ncRNAs to treat hepatocellular carcinoma (HCC). Spindly CNCs, one kind of natural polysaccharide nanoparticles, possess good biocompatibility and unique physico-chemical properties. PGEA with abundant hydroxyl groups is one promising gene carrier with low cytotoxicity. PAsp can benefit the disassembly and degradability of nanoassemblies within cells. CNC @ CB[8]@PGEA combines the different unique properties of CNC, PGEA, and PAsp. CNC @ CB[8] @ PGEA effectively complexes the expression constructs of miR-101 (plasmid pc3.0-miR-101) and lncRNA MEG3 (plasmid pc3.0-MEG3). CNC @ CB[8] @ PGEA produces much better transfection performances than PGEA-containing assembly units. In addition, the codelivery system of CNC @ CB[8] @ PGEA/(pc3.0 MEG3+pc3.0-miR-101) nanocomplexes demonstrates better efficacy in suppressing HCC than CNC @ CB[8] @ PGEA/pc3.0-MEG3 or CNC @ CB[8] @ PGEA/pc3.0-miR-101 nanocomplexes alone. Such rodlike supramolecular nanoassemblies will provide a promising means to produce efficient delivery vectors of versatile tumor suppressive nucleic acids. PMID- 29280339 TI - Letter to the editor: Uncommon cells in cerebrospinal fluid cytology. PMID- 29280340 TI - 2D MoS2 Nanostructures for Biomedical Applications. AB - MoS2 nanosheets, a typical kind of layered transition metal dichalcogenides with the 2D structure and many unique physical and chemical properties, have attracted a lot of research interests in various fields. Typically, MoS2 nanosheets present similarities to graphene in terms of their large surface area and strong absorbance in near-infrared region, which in combination with their easily functionalized surface make them promising nanoplatforms in biomedical applications. Herein, the progress of MoS2 nanosheets and their composites in the area of nanomedicine, with the emphasis on their synthesis and modification strategies, their biomedical applications in biosensing, imaging and therapy, as well as evaluations of their in vivo behaviors and toxicology profiles are summarized. Finally, the challenges and opportunities of applying MoS2 -based nanomaterials in the biomedicine areas will be discussed. PMID- 29280342 TI - Targeted On-line SPE-LC-MS/MS Assay for the Quantitation of 12 Apolipoproteins from Human Blood. AB - Laborious sample pretreatment of biological samples represents the most limiting factor for the translation of targeted proteomics assays from research to clinical routine. An optimized method for the simultaneous quantitation of 12 major apolipoproteins (apos) combining on-line SPE and fast LC-MS/MS analysis in 6.5 min total run time was developed, reducing the manual sample pretreatment time of 3 MUL serum or plasma by 60%. Within-run and between-day imprecisions below 10 and 15% (n = 10) and high recovery rates (94-131%) were obtained applying the high-throughput setup. High-quality porcine trypsin was used, which outperformed cost-effective bovine trypsin regarding digestion efficiency. Comparisons with immunoassays and another LC-MS/MS assay demonstrated good correlation (Pearson's R: 0.81-0.98). Further, requirements on sample quality concerning sampling, processing, and long-term storage up to 1 year were investigated revealing significant influences of the applied sampling material and coagulant on quantitation results. Apo profiles of 1339 subjects of the LIFE Adult-Study were associated with lifestyle and physiological parameters as well as establish parameters of lipid metabolism (e.g., triglycerides, cholesterol). Besides gender effects, most significant impact was seen regarding lipid-lowering medication. In conclusion, this novel highly standardized, high-throughput targeted proteomics assay utilizes a fast, simultaneous analysis of 12 apos from least sample amounts. PMID- 29280341 TI - Body Mass Index and Subjective Social Status: The Coronary Artery Risk Development in Young Adults Study. AB - OBJECTIVE: Subjective social status (SSS), or perceived social status, may explain, in part, the relationship between socioeconomic status (SES) and obesity. The objective of this study was to test whether SSS mediates the relationship between two indicators of SES (income and education) and body mass index (BMI). METHODS: A cross-sectional, structural equation path analysis was applied to the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 2,624). The analysis tested whether SSS (MacArthur scale), education, and income were associated with BMI at the year 20 examination (adjusting for sex, age, and race), and it was hypothesized that the associations of education and income with BMI would be at least partly mediated by SSS. RESULTS: SSS had a significant direct effect on BMI (-0.21, P = 0.018). Education had a significant direct relationship with SSS (0.11, P < 0.001) and a small but significant indirect relationship with BMI through SSS (-0.02, P = 0.022). Although income did not have a significant direct relationship with BMI, it did have a significant indirect relationship through SSS (b = -0.05, P = 0.019). CONCLUSIONS: Results are consistent with the hypothesized model in which SSS partially mediates the relationship between SES indicators and BMI. PMID- 29280344 TI - Crash simulation: an immersive learning model. AB - BACKGROUND: Far West New South Wales Local Emergency Management Committee runs an annual crash simulation exercise to assess the operational readiness of all local emergency services to coordinate and manage a multi-casualty exercise. CONTEXT: Since 2009, the Broken Hill University Department of Rural Health (BHUDRH) has collaborated with the committee, enabling the inclusion of health students in this exercise. It is an immersive interprofessional learning experience that evaluates teamwork, communication and safe effective clinical trauma management outside the hospital setting. INNOVATION: After 7 years of modifying and developing the exercise, we set out to evaluate its impact on the students' learning, and sought ethics approval from the University of Sydney for this study. At the start of this year's crash simulation, students were given information sheets and consent forms with regards to the research. Once formal debriefing had finished, the researchers conducted a semi-structured focus-group interview with the health students to gain insight into their experience and their perceived value of the training. Students also completed short-answer questionnaires, and the anonymised responses were analysed. Crash simulation ... evaluates teamwork, communication and safe effective clinical trauma management IMPLICATIONS: Participants identified that this multidisciplinary learning opportunity in a pre-hospital mass casualty situation was of value to them. It has taken them outside of their usually protected hospital or primary care setting and tested their critical thinking and communication skills. We recommend this learning concept to other educational institutions. Further research will assess the learning value of the simulated event to the other agencies involved. PMID- 29280343 TI - The ropAe gene encodes a porin-like protein involved in copper transit in Rhizobium etli CFN42. AB - Copper (Cu) is an essential micronutrient for all aerobic forms of life. Its oxidation states (Cu+ /Cu2+ ) make this metal an important cofactor of enzymes catalyzing redox reactions in essential biological processes. In gram-negative bacteria, Cu uptake is an unexplored component of a finely regulated trafficking network, mediated by protein-protein interactions that deliver Cu to target proteins and efflux surplus metal to avoid toxicity. Rhizobium etliCFN42 is a facultative symbiotic diazotroph that must ensure its appropriate Cu supply for living either free in the soil or as an intracellular symbiont of leguminous plants. In crop fields, rhizobia have to contend with copper-based fungicides. A detailed deletion analysis of the pRet42e (505 kb) plasmid from an R. etli mutant with enhanced CuCl2 tolerance led us to the identification of the ropAe gene, predicted to encode an outer membrane protein (OMP) with a beta-barrel channel structure that may be involved in Cu transport. In support of this hypothesis, the functional characterization of ropAe revealed that: (I) gene disruption increased copper tolerance of the mutant, and its complementation with the wild type gene restored its wild-type copper sensitivity; (II) the ropAe gene maintains a low basal transcription level in copper overload, but is upregulated when copper is scarce; (III) disruption of ropAe in an actP (copA) mutant background, defective in copper efflux, partially reduced its copper sensitivity phenotype. Finally, BLASTP comparisons and a maximum likelihood phylogenetic analysis highlight the diversification of four RopA paralogs in members of the Rhizobiaceae family. Orthologs of RopAe are highly conserved in the Rhizobiales order, poorly conserved in other alpha proteobacteria and phylogenetically unrelated to characterized porins involved in Cu or Mn uptake. PMID- 29280346 TI - Microbial acid fermentation products: An annotated selection of World Wide Web sites relevant to the topics in microbial biotechnology. PMID- 29280345 TI - Microbial electrochemical technologies: maturing but not mature. PMID- 29280347 TI - Microbiome Yarns: human biome reproduction, evolution and visual acuity,,. PMID- 29280349 TI - Translational model to predict pulmonary pharmacokinetics and efficacy in man for inhaled bronchodilators. AB - Translational pharmacokinetic (PK) models are needed to describe and predict drug concentration-time profiles in lung tissue at the site of action to enable animal to-man translation and prediction of efficacy in humans for inhaled medicines. Current pulmonary PK models are generally descriptive rather than predictive, drug/compound specific, and fail to show successful cross-species translation. The objective of this work was to develop a robust compartmental modeling approach that captures key features of lung and systemic PK after pulmonary administration of a set of 12 soluble drugs containing single basic, dibasic, or cationic functional groups. The model is shown to allow translation between animal species and predicts drug concentrations in human lungs that correlate with the forced expiratory volume for different classes of bronchodilators. Thus, the pulmonary modeling approach has potential to be a key component in the prediction of human PK, efficacy, and safety for future inhaled medicines. PMID- 29280350 TI - Emerging Biotechnology Applications of Aqueous Two-Phase Systems. AB - Liquid-liquid phase separation between aqueous solutions containing two incompatible polymers, a polymer and a salt, or a polymer and a surfactant, has been exploited for a wide variety of biotechnology applications throughout the years. While many applications for aqueous two-phase systems fall within the realm of separation science, the ability to partition many different materials within these systems, coupled with recent advances in materials science and liquid handling, has allowed bioengineers to imagine new applications. This progress report provides an overview of the history and key properties of aqueous two-phase systems to lend context to how these materials have progressed to modern applications such as cellular micropatterning and bioprinting, high throughput 3D tissue assembly, microscale biomolecular assay development, facilitation of cell separation and microcapsule production using microfluidic devices, and synthetic biology. Future directions and present limitations and design considerations of this adaptable and promising toolkit for biomolecule and cellular manipulation are further evaluated. PMID- 29280348 TI - Bacillus subtilis, the model Gram-positive bacterium: 20 years of annotation refinement. AB - Genome annotation is, nowadays, performed via automatic pipelines that cannot discriminate between right and wrong annotations. Given their importance in increasing the accuracy of the genome annotations of other organisms, it is critical that the annotations of model organisms reflect the current annotation gold standard. The genome of Bacillus subtilis strain 168 was sequenced twenty years ago. Using a combination of inductive, deductive and abductive reasoning, we present a unique, manually curated annotation, essentially based on experimental data. This reveals how this bacterium lives in a plant niche, while carrying a paleome operating system common to Firmicutes and Tenericutes. Dozens of new genomic objects and an extensive literature survey have been included for the sequence available at the INSDC (AccNum AL009126.3). We also propose an extension to Demerec's nomenclature rules that will help investigators connect to this type of curated annotation via the use of common gene names. PMID- 29280351 TI - MiR-27b-3p Regulation in Browning of Human Visceral Adipose Related to Central Obesity. AB - OBJECTIVE: Given the rising prevalence of central obesity and the discovery that beige cells appear within white adipose tissue, strategies to enhance these energy-expending adipocytes or "browning" within white adipose depots have become of therapeutic interest to combat obesity and its associated disorders. This study focused on, the role of microRNA (miRNA)-27b-3p in human visceral adipose tissue (VAT) browning. METHODS: Expression of miR-27b-3p and UCP1 in VAT and serum of humans was measured. MiR-27b-3p was overexpressed or suppressed in human visceral stromal fraction cells to analyze the potential role of miR-27b-3p. RESULTS: UCP1 expression in human VAT decreased with elevated BMI and waist-hip ratio, whereas expression of miR-27b-3p was found to correlate positively with BMI and waist-hip ratio. High expression of miR-27b-3p was associated with reduced browning ability of human visceral adipocytes. Antagonism of miR-27b-3p led to the enhancement of browning ability in human visceral adipocytes. CONCLUSIONS: These findings highlight the decreased browning ability of VAT from humans with obesity and the role of miR-27b-3p in regulating browning of human visceral adipocytes. They suggest that miR-27b-3p should be further explored as a potential target for the treatment of central obesity. PMID- 29280352 TI - Mg-Al and Zn-Al Layered Double Hydroxides Promote Dynamic Expression of Marker Genes in Osteogenic Differentiation by Modulating Mitogen-Activated Protein Kinases. AB - The effect of LDH samples comprised of chloride anions intercalated between positive layers of magnesium/aluminum (Mg-Al LDH) or zinc/aluminum (Zn-Al LDH) chemical composition on pre-osteoblast performance is investigated. Non-cytotoxic concentrations of both LDHs modulated pre-osteoblast adhesion by triggering cytoskeleton rearrangement dependent on recruiting of Cofilin, which is modulated by the inhibition of the Protein Phosphatase 2A (PP2A), culminating in osteoblast differentiation with a significant increase of osteogenic marker genes. The alkaline phosphatase (ALP) and bone sialoprotein (BSP) are significantly up modulated by both LDHs; however, Mg-Al LDH nanomaterial promoted even more significance than both experimental controls, while the phosphorylations of mitogen-activated protein kinase (MAPKs)- extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) significantly increased. MAPK signaling is necessary to activate Runt-related transcription factor 2 (RUNX2) gene. Concomitantly, it is also investigated whether challenged osteoblasts are able to modulate osteoclastogenesis by investigating both osteoprotegerin (OPG) and Receptor activator of nuclear factor kappa-ligand (RANKL) in this model; a dynamic reprogramming of both these genes is found, suggesting LDHs in modulating osteoclastogenesis. These results suggest that LDHs interfere in bone remodeling, and they can be considered as nanomaterials in graft-based bone healing or drug delivery materials for bone disorders. PMID- 29280353 TI - Exposures of male rats to environmental chemicals [bisphenol A and di (2 ethylhexyl) phthalate] affected expression of several proteins in the developing epididymis. AB - Hormonally active agents are released into the environment from industrial and manufacturing activity. Evidence in the literature indicates that impaired reproductive capacity in wildlife and laboratory species is associated with chemical exposures. In particular, bisphenol A (BPA) and di (2-ethylhexyl) phthalate (DEHP) have generated public interest due to their presence in several consumer products. In this study, we determined that expression of steroid hormone receptors (estrogen and androgen receptors), Wnt4, and beta-catenin was greater (p < 0.05) in the rat epididymis at 35 days of age compared to 21 and 90 days. Second, timed-pregnant Long-Evans dams were exposed to the chemicals BPA and DEHP by gavage from gestational days 12-21. The caput epididymis was collected from cohorts of male offspring at 35 and 90 days of age and processed for Western blot analysis. Results showed that prenatal BPA and DEHP exposures affected (p < 0.05) expression of estrogen and androgen receptor, Wnt4, beta catenin, MAPK, and HOXD4 protein in the epididymis. Data have implications for morphological development of the epididymis, a possibility that would be explored in future studies. PMID- 29280355 TI - Muscles of the trunk and pelvis are responsive to testosterone administration: data from testosterone dose-response study in young healthy men. AB - Testosterone dose-dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose-response trial. Participants were young healthy men aged 18-50 years participating in the 5alpha-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone production and weekly injections of 50, 125, 300, or 600 mg of testosterone enanthate and were randomized to receive either 2.5 mg dutasteride (5aR inhibitor) or placebo daily for 20 weeks. Muscles of the trunk and the pelvis were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose effect of testosterone on changes in the psoas major muscle area was the primary outcome; secondary outcomes included changes in paraspinal, abdominal, pelvic floor, ischiocavernosus, and obturator internus muscles. The association between changes in testosterone levels and muscle area was also assessed. Testosterone dose-dependently increased areas of all truncal and pelvic muscles. The estimated change (95% confidence interval) of muscle area increase per 100 mg of testosterone enanthate dosage increase was 0.622 cm2 (0.394, 0.850) for psoas; 1.789 cm2 (1.317, 2.261) for paraspinal muscles, 2.530 cm2 (1.627, 3.434) for total abdominal muscles, 0.455 cm2 (0.233, 0.678) for obturator internus, and 0.082 cm2 (0.003, 0.045) for ischiocavernosus; the increase in these volumes was significantly associated with the changes in on-treatment total and free serum testosterone concentrations. In conclusion, core muscles of the trunk and pelvis are responsive to testosterone administration. Future trials should evaluate the potential role of testosterone administration in frail men who are predisposed to falls and men with pelvic floor dysfunction. PMID- 29280357 TI - Errata. PMID- 29280356 TI - 'Easier ways to get a publication': the problem of low quality scientific publications. PMID- 29280359 TI - AANP News. PMID- 29280358 TI - Thermoresponsive Supramolecular Chemotherapy by "V"-Shaped Armed beta Cyclodextrin Star Polymer to Overcome Drug Resistance. AB - Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer beta-CD-v-(PEG-beta-PNIPAAm)7 consisting of a beta-CD core, grafted with thermo-responsive poly(N isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple "V"-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between beta-cyclodextrin and anti-cancer drug via inclusion complex (IC). Furthermore, the temperature induced chain association of PNIPAAm segments facilitated the IC to form supramolecular nanoparticles at 37 degrees C, whereas the presence of PEG impart great stability to the self-assemblies. When incubated with MDR-1 membrane pump regulated drug resistant tumor cells, much higher and faster cellular uptake of the supramolecular nanoparticles were detected, and the enhanced intracellular retention of drugs could lead to significant inhibition of cell growth. Further in vivo evaluation showed high therapeutic efficacy in suppressing drug resistant tumor growth without a significant impact on the normal functions of main organs. This work signifies thermo-responsive supramolecular chemotherapy is promising in combating pump mediated drug resistance in both in vitro and in vivo models, which may be encouraging for the advanced drug delivery platform design to overcome drug resistant cancer. PMID- 29280360 TI - It takes a Village.... PMID- 29280361 TI - Cardiovascular disease and omega-3s: Prescription products and fish oil dietary supplements are not the same. AB - BACKGROUND AND PURPOSE: Despite achievement of optimal low-density lipoprotein cholesterol (LDL-C) control with statin therapy, patients with elevated triglycerides (TGs) and residual cardiovascular risk are commonly encountered in clinical practice. METHODS: We present information from completed and ongoing clinical trials examining Rx omega-3s for TG-lowering and omega-3 dietary supplements to highlight important differences affecting patient management for nurse practitioners. CONCLUSIONS: Rx omega-3s demonstrate robust reductions in TGs and may have a role in reducing residual cardiovascular risk. Products containing docosahexaenoic acid (DHA) may raise LDL-C and should not be substituted for Rx eicosapentaenoic acid (EPA)-only icosapent ethyl, which does not raise LDL-C. Omega-3 dietary supplements (e.g., fish oils containing EPA and DHA) may be used for general health promotion; however, they are not regulated as medications and concerns regarding quality, purity, safety, and variability of content exist. It is important to advise patients that omega-3 dietary supplements are not medications and should not be substituted for Rx omega-3s. Large-scale cardiovascular outcomes studies are underway for Rx omega-3s in statin-treated patients. IMPLICATIONS FOR PRACTICE: Nurse practitioners can take an active role in reducing residual cardiovascular risk and educating patients about important differences between Rx omega-3s and fish oil supplements. PMID- 29280362 TI - Overview of the improvement of the ring-stage survival assay-a novel phenotypic assay for the detection of artemisinin-resistant Plasmodium falciparum. AB - Artemisinin resistance in Plasmodium falciparum threatens the remarkable efficacy of artemisinin-based combination therapies worldwide. Thus, greater insight into the resistance mechanism using monitoring tools is essential. The ring-stage survival assay is used for phenotyping artemisinin-resistance or decreased artemisinin sensitivity. Here, we review the progress of this measurement assay and explore its limitations and potential applications. PMID- 29280363 TI - Integrative taxonomy of Leptonetela spiders (Araneae, Leptonetidae), with descriptions of 46 new species. AB - Extreme environments, such as subterranean habitats, are suspected to be responsible for morphologically inseparable cryptic or sibling species and can bias biodiversity assessment. A DNA barcode is a short, standardized DNA sequence used for taxonomic purposes and has the potential to lessen the challenges presented by a biotic inventory. Here, we investigate the diversity of the genus Leptonetela Kratochvil, 1978 that is endemic to karst systems in Eurasia using DNA barcoding. We analyzed 624 specimens using one mitochondrial gene fragment (COI). The results show that DNA barcoding is an efficient and rapid species identification method in this genus. DNA barcoding gap and automatic barcode gap discovery (ABGD) analyses indicated the existence of 90 species, a result consistent with previous taxonomic hypotheses, and supported the existence of extreme male pedipalpal tibial spine and median apophysis polymorphism in Leptonetela species, with direct implications for the taxonomy of the group and its diversity. Based on the molecular and morphological evidence, we delimit and diagnose 90 Leptonetela species, including the type species Leptonetela kanellisi (Deeleman-Reinhold, 1971). Forty-six of them are previously undescribed. The female of Leptonetela zhai Wang & Li, 2011 is reported for the first time. Leptonetela tianxinensis (Tong & Li, 2008) comb. nov. is transferred from the genus Leptoneta Simon, 1872; the genus Guineta Lin & Li, 2010 syn. nov. is a junior synonym of Leptonetela; Leptonetela gigachela (Lin & Li, 2010) comb. nov. is transferred from Guineta. The genus Sinoneta Lin & Li, 2010 syn. nov. is a junior synonym of Leptonetela; Leptonetela notabilis (Lin & Li, 2010) comb. nov. and Leptonetela sexdigiti (Lin & Li, 2010) comb. nov. are transferred from Sinoneta; Leptonetela sanchahe Wang & Li nom. nov. is proposed as a replacement name for Sinoneta palmata (Chen et al., 2010) because Leptonetela palmata is preoccupied. PMID- 29280364 TI - Genome size of 14 species of fireflies (Insecta, Coleoptera, Lampyridae). AB - Eukaryotic genome size data are important both as the basis for comparative research into genome evolution and as estimators of the cost and difficulty of genome sequencing programs for non-model organisms. In this study, the genome size of 14 species of fireflies (Lampyridae) (two genera in Lampyrinae, three genera in Luciolinae, and one genus in subfamily incertae sedis) were estimated by propidium iodide (PI)-based flow cytometry. The haploid genome sizes of Lampyridae ranged from 0. 42 to 1. 31 pg, a 3. 1-fold span. Genome sizes of the fireflies varied within the tested subfamilies and genera. Lamprigera and Pyrocoelia species had large and small genome sizes, respectively. No correlation was found between genome size and morphological traits such as body length, body width, eye width, and antennal length. Our data provide additional information on genome size estimation of the firefly family Lampyridae. Furthermore, this study will help clarify the cost and difficulty of genome sequencing programs for non model organisms and will help promote studies on firefly genome evolution. PMID- 29280365 TI - More Antisepsis, Less Antibiotics Whenever Possible. AB - Increasing bacterial resistance to antibiotics has recently become an important medical challenge. In ophthalmology antibiotics are widely used for treatment and prophylaxis of ocular infections. In many cases antiseptics may be a valuable adjunct and sometimes even an alternative to antibiotics for the prevention and treatment of infections, reducing the overuse of antibiotics. This review aims to highlight the available literature on the subject of antibiotic resistance in ophthalmology. Full understanding of this growing problem is necessary for tailoring effective pre-, intra-, and postoperative management to improve antibiotic stewardship programs. PMID- 29280366 TI - Outcomes of Infantile-Onset Glaucoma Associated With Port Wine Birthmarks and Other Periocular Cutaneous Vascular Malformation. AB - PURPOSE: The incidence of infantile-onset secondary glaucoma associated with periocular cutaneous vascular malformations is high and the outcomes of these glaucomatous eyes have anecdotally been poor. The purpose of this study was to determine the anatomic and visual outcomes of affected eyes. DESIGN: Retrospective case series. METHODS: Consecutive patients with early-onset (younger than 36 months of age) glaucoma associated with cutaneous vascular malformations from 1995-2015 were included. RESULTS: Seventeen eyes of 13 patients with Sturge-Weber syndrome (SW, n = 10), Klippel-Trenaunay-Weber syndrome (KTW, n = 1), cutis marmorata telangiectatica congenita (CMTC, n = 1), and phakomatosis pigmentovascularis (PPV, n = 1) were included. Three SW and 1 KTW patient had bilateral glaucoma. At presentation, mean age was 6.5 +/- 9.1 months and mean intraocular pressure was 27.2 +/- 6.13 mm Hg. The average number of surgical procedures per eye increased from 1.0 +/- 0.5 (range, 0-2) at less than 5 years' follow-up (9 eyes) to 3.5 +/- 2.3 (range, 1-7) with at least 5 years' follow-up (8 eyes). Visual acuity was better than or equal to 20/70 in 2 of 6 eyes (33%) with less than 5 years' follow-up and in 3 of 7 eyes (43%) with at least 5 years' follow-up. Additionally, a higher number of baseline risk factors correlated with poorer visual outcome. CONCLUSIONS: After a mean follow up of 6.6 years, visual outcome in infantile-onset secondary glaucoma associated with cutaneous periocular vascular malformation is guarded. Increased numbers of baseline risk factors and procedures are associated with poorer vision. PMID- 29280367 TI - Intravitreal Bevacizumab in Diabetic Retinopathy. Recommendations from the Pan American Collaborative Retina Study Group (PACORES): The 2016 Knobloch Lecture. AB - The advent of intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications has revolutionized the treatment of diabetic eye diseases. Herein, we report the outcomes of clinical studies carried out by the Pan-American Collaborative Retina Study Group (PACORES), with a specific focus on the efficacy of intravitreal bevacizumab in the management of diabetic macular edema and proliferative diabetic retinopathy. We will also discuss the use of intravitreal bevacizumab as a preoperative, adjuvant therapy before vitrectomy for proliferative diabetic retinopathy. PMID- 29280368 TI - Retinal Vein Occlusion Review. AB - Retinal vein occlusions are a very common condition with great importance in ophthalmology clinical practice. This article reviews the salient epidemiology, risk factors, clinical features, and treatments related to retinal vein occlusions. PMID- 29280369 TI - Characteristics of the regional human milk bank in Poland - donors, recipients and nutritional value of human milk AB - Background: In case of shortage of breast milk despite proper lactation care or the poor state of the mother's health, breast milk from human milk bank is recommended for feeding preterm infants Objective: This study retrospectively evaluated the first year of the operation of the Regional Human Milk Bank Material and methods: Data concerning donors was collected in the human milk bank during the cooperation. The clinical characteristics of the recipients was made on the basis of medical documentation from the Holy Family Hospital in Warsaw, Poland. Analysis of nutritional value was performed with the human milk analyzer (MIRIS AB) Results: In the first year of activity, 45 voluntary donors established cooperation, donating from 650 to 32030 ml of human milk. The content of nutrients in milk provided by donors was variable - protein 0.4-1.5 g / 100 ml, fat 1.1-7.4 g / 100 ml, carbohydrates 6.3-7.9 g / 100 ml. The average length of using donated human milk was 4 days and the average volume of milk for one infant was 282 ml Conclusions: The donor profiles have a significant impact on the milk composition form HMB. The nutritional value can be improved by recruitment donors from mothers that gave birth prematurely and by beginning donation at earlier stages of lactation as soon as lactation is stabilized. In case of shortage of mothers own milk the immediate implementation of donors milk as a short-term support can significantly reduce the food intolerance incidence in the group of prematurely born infants PMID- 29280370 TI - Adherence to nutrition guidelines in patients with cardiovascular diseases (CVD) as a secondary prevention AB - Background: The appropriate nutrition is an important component of the secondary prevention of cardiovascular diseases (CVD) Objectives: The aim of the study was to investigate if the patients with cardiovascular disease were informed of the role of appropriate nutrition in prevention or received nutrition guidelines and to assess the dietary intake compared to recommendations for patients with cardiovascular disease who received or not nutrition guidelines Material and Methods: The study was conducted among patients with cardiovascular disease (n = 127) of cardiological hospital clinic, aged 62 +/- 11. The questionnaire was used to obtain personal and anthropometric details, information if patients had received nutrition guidelines. The method of 3-day food records was used for dietary assessment Results: 20% of subjects had not received nutrition guidelines and almost 40% of subjects did not recognize the nutrition effect on cardiovascular disease development. Compared to the diets of the subjects who had not received nutrition guidelines, the diets of those who had received them were of significantly lower intake of: energy from saturated fatty acids (15%, p = 0.006), cholesterol (21%, p = 0.012) and higher intake (14-26%) of potassium (p = 0,003), sodium (p = 0.013), phosphorus (p = 0.044), magnesium (p = 0.003), iron (p = 0.005), copper (p = 0.001), zinc (p = 0.046). Among the patients who had received nutrition guidelines, percentage of the subjects whose intake of nutrients was consistent with recommendations was higher Conclusions: Not all subjects had received nutrition guidelines. Diets of those who had received them were more balanced, but in neither group nutrition guidelines were complied with PMID- 29280371 TI - Improvement in anthropometric parameters after rational dietary intervention in women with Polycystic Ovary Syndrom as the best method to support treatment AB - Background: Polycystic ovary syndrome (PCOS) is a disorder often occurring in women at reproductive age. An important factor in PCOS pathogenesis is insulin resistance, which pronounces hyperandrogenism and leads to the development of various metabolic disorders Objectives: The aim of this study is to determine the effect of reduction diet with low glycemic index (GI) on anthropometric parameters of women with PCOS and the assessment of the effectiveness of the diet on body mass and adipose tissue reduction Material and methods: The study was performed on 24 women with PCOS diagnosed with Rotterdam's criteria. Anthropometric measurements and bioelectrical impedance were performed. All participants received 7-day diet and recommendations relating to the change in lifestyle. After three months of using the dietary recommendations the measurements were repeated Results: Statistical significance was observed for body mass (?on average by 5.93 kg+/-2.95), BMI (?2.14 kg/m2+/-1.2), circumference of: waist (?7.7 cm+/-5.9), hip (?4.8 cm+/-5.4), arm (?1.9 cm+/-3.7) and measurements of skin fold under the shoulder blade (?4.8 mm+/-4,6), above iliac crest (?6.76 mm+/-5.7) and above triceps brachii muscle (?5.25 mm+/-7.4). Considering body composition measurements, statistically significant were differences in the measurements of BCMI (?18.042+/-8.8), TBW expressed in percentage (?2.729+/-2.75) and in litres (?0.071+/-5.15), FM in percentage (?3.291+/-5.6) and in kg (3.354 kg+/-4.9) Conclusions: Body mass reduction using a rational diet with low GI is an effective method to support of PCOS treatment. Using reduction diet for three months together with increased physical activity enables to reduce body weight by on average 5.93 kg, which increases the chances to treat infertility in women. This should be the suggested type of diet in PCOS treatment PMID- 29280372 TI - The International Health Regulations (IHR) - 10 years of global public health security. PMID- 29280373 TI - Index, Volume 92, 2017, Nos. 1-52. PMID- 29280374 TI - Inverse Resistance Change Cr2Ge2Te6-Based PCRAM Enabling Ultralow-Energy Amorphization. AB - Phase-change random access memory (PCRAM) has attracted much attention for next generation nonvolatile memory that can replace flash memory and can be used for storage-class memory. Generally, PCRAM relies on the change in the electrical resistance of a phase-change material between high-resistance amorphous (reset) and low-resistance crystalline (set) states. Herein, we present an inverse resistance change PCRAM with Cr2Ge2Te6 (CrGT) that shows a high-resistance crystalline reset state and a low-resistance amorphous set state. The inverse resistance change was found to be due to a drastic decrease in the carrier density upon crystallization, which causes a large increase in contact resistivity between CrGT and the electrode. The CrGT memory cell was demonstrated to show fast reversible resistance switching with a much lower operating energy for amorphization than a Ge2Sb2Te5 memory cell. This low operating energy in CrGT should be due to a small programmed amorphous volume, which can be realized by a high-resistance crystalline matrix and a dominant contact resistance. Simultaneously, CrGT can break the trade-off relationship between the crystallization temperature and operating speed. PMID- 29280375 TI - Synthesis of 9,9-Disubstituted Fluorenes from 2-Iodobiphenyls and alpha Diazoesters under Palladium Catalysis. AB - 9,9-Disubstituted fluorenes are widely employed in materials science. We have developed a straightforward approach for the synthesis of 9,9-disubstituted fluorenes from 2-iodobiphenyls and alpha-diazoesters. The reaction proceeds via a tandem palladium-catalyzed C(sp2)-H activation/carbenoid insertion sequence. PMID- 29280376 TI - Toward GW Calculations on Thousands of Atoms. AB - The GW approximation of many-body perturbation theory is an accurate method for computing electron addition and removal energies of molecules and solids. In a canonical implementation, however, its computational cost is [Formula: see text] in the system size N, which prohibits its application to many systems of interest. We present a full-frequency GW algorithm in a Gaussian-type basis, whose computational cost scales with N2 to N3. The implementation is optimized for massively parallel execution on state-of-the-art supercomputers and is suitable for nanostructures and molecules in the gas, liquid or condensed phase, using either pseudopotentials or all electrons. We validate the accuracy of the algorithm on the GW100 molecular test set, finding mean absolute deviations of 35 meV for ionization potentials and 27 meV for electron affinities. Furthermore, we study the length-dependence of quasiparticle energies in armchair graphene nanoribbons of up to 1734 atoms in size, and compute the local density of states across a nanoscale heterojunction. PMID- 29280377 TI - Roles of Pseudo-Closed s2 Orbitals for Different Intrinsic Hole Generation between Tl-Bi and In-Bi Bromide Double Perovskites. AB - Although metal halide double perovskites A2B(I)B(III)X6 are expected as nontoxic alternatives for lead halide perovskites, recent studies have shown that only Tl(I)-Bi(III) and In(I)-Bi(III) bromides are thermodynamically stable and possess optoelectronic properties suitable for photovoltaic absorbers. Here, we show, through density functional theory calculations, that Tl-Bi and In-Bi bromide double perovskites exhibit significantly different semiconducting behaviors due to the different energy levels of the highest-occupied pseudoclosed s2 orbitals of Tl(I) and In(I). While Tl-Bi double perovskites can exhibit semiconducting p type properties, In-Bi bromide double perovskites exhibit metallic p-type ones regardless of the synthesis condition due to the extremely low formation energy of In vacancy. Such difference makes Tl-Bi bromide double perovskites suitable for optoelectronic applications, but not In-Bi bromide double perovskites. Furthermore, there is a high probability for In to substitute a Bi site, forming a local In-In bromide double perovskite structure with a lower local conduction band minimum, detrimentally affecting the open circuit voltage of In-Bi bromide double perovskite-based thin film solar cells. PMID- 29280378 TI - Photothermally Activated Nanocrystalline Oxynitride with Superior Performance in Flexible Field-Effect Transistors. AB - Photochemical reactions in inorganic films, which can be promoted by the addition of thermal energy, enable significant changes in the properties of films. Metaphase films depend significantly on introducing external energy, even at low temperatures. We performed thermal-induced, deep ultraviolet-based, thermal photochemical activation of metaphase ZnOxNy films at low temperature, and we observed peculiar variations in the nanostructures with phase transformation and densification. The separated Zn3N2 and ZnO nanocrystalline lattice in amorphous ZnOxNy was stabilized remarkably by the reduction of oxygen defects and by the interfacial atomic rearrangement without breaking the N-bonding. On the basis of these approaches, we successfully demonstrated highly flexible, nanocrystalline ZnOxNy thin-film transistors on polyethylene naphthalate films, and the saturation mobility showed more than 60 cm2 V-1 s-1. PMID- 29280379 TI - Large-Area Self-Assembly of Silica Microspheres/Nanospheres by Temperature Assisted Dip-Coating. AB - This work reports a temperature-assisted dip-coating method for self-assembly of silica (SiO2) microspheres/nanospheres (SPs) as monolayers over large areas (~cm2). The area over which self-assembled monolayers (SAMs) are formed can be controlled by tuning the suspension temperature (Ts), which allows precise control over the meniscus shape. Furthermore, the formation of periodic stripes of SAMs, with excellent dimensional control (stripe width and stripe-to-stripe spacing), is demonstrated using a suitable set of dip-coating parameters. These findings establish the role of Ts, and other parameters such as withdrawal speed (Vw), withdrawal angle (thetaw), and withdrawal step length (Lw). For Ts ranged between 25 and 80 degrees C, the morphological analysis of dip-coatings shows layered structures comprising of defective layers (25-60 degrees C), single layers (70 degrees C), and multilayers (>70 degrees C) owing to the variation of SP flux at the meniscus/substrate assembling interface. At Ts = 70 degrees C, there is an optimum Vw, approximately equal to the downshift speed of the meniscus (Vm = 1.3 MUm/s), which allows the SAM formation over areas (2.25 cm2) roughly 10 times larger than reported in the literature using nanospheres. Finally, the large-area SAM is used to demonstrate the enhanced performance of antireflective coatings for photovoltaic cells and to create metal nanomesh for Si nanowire synthesis. PMID- 29280380 TI - High-Performance Transparent Conducting Metal Network Electrodes for Perovksite Photodetectors. AB - Transparent conducting electrodes with high transparency and conductivity are necessary components for optoelectronic devices. In this work, a facile wet chemical lift-off process is first introduced to fabricate Au network flexible transparent electrodes with electrospun polymer fiber network as mask. Low resistance (5.18 Omega sq-1) of the transparent electrode was obtained when the transparency was around 90%, which was comparable to the state-of-the-art transparent electrodes. Low root-mean-square roughness of 23 nm was obtained when the Au nanowire thickness was 30 nm. The perovskite CH3NH3PbI3 photodetector based on the 30 nm thick Au network electrode shows a large linear dynamic range of 138 dB, a high detectivity over 1012 Jones, and better flexibility than that based on the commercial indium tin oxide electrode, which demonstrates that the Au network electrode is a promising flexible transparent conducting electrode for optoelectronic devices. PMID- 29280381 TI - High-Mobility and Hysteresis-Free Flexible Oxide Thin-Film Transistors and Circuits by Using Bilayer Sol-Gel Gate Dielectrics. AB - In this paper, we demonstrate high-performance and hysteresis-free solution processed indium-gallium-zinc oxide (IGZO) thin-film transistors (TFTs) and high frequency-operating seven-stage ring oscillators using a low-temperature photochemically activated Al2O3/ZrO2 bilayer gate dielectric. It was found that the IGZO TFTs with single-layer gate dielectrics such as Al2O3, ZrO2, or sodium doped Al2O3 exhibited large hysteresis, low field-effect mobility, or unstable device operation owing to the interfacial/bulk trap states, insufficient band offset, or a substantial number of mobile ions present in the gate dielectric layer, respectively. To resolve these issues and to explain the underlying physical mechanisms, a series of electrical analyses for various single- and bilayer gate dielectrics was carried out. It is shown that compared to single layer gate dielectrics, the Al2O3/ZrO2 gate dielectric exhibited a high dielectric constant of 8.53, low leakage current density (~10-9 A cm-2 at 1 MV cm 1), and stable operation at high frequencies. Using the photochemically activated Al2O3/ZrO2 gate dielectric, the seven-stage ring oscillators operating at an oscillation frequency of ~334 kHz with a propagation delay of <216 ns per stage were successfully demonstrated on a polymeric substrate. PMID- 29280382 TI - Boosting Two-Dimensional MoS2/CsPbBr3 Photodetectors via Enhanced Light Absorbance and Interfacial Carrier Separation. AB - Transition metal dichalcogenides (TMDs) are promising candidates for flexible optoelectronic devices because of their special structures and excellent properties, but the low optical absorption of the ultrathin layers greatly limits the generation of photocarriers and restricts the performance. Here, we integrate all-inorganic perovskite CsPbBr3 nanosheets with MoS2 atomic layers and take the advantage of the large absorption coefficient and high quantum efficiency of the perovskites, to achieve excellent performance of the TMD-based photodetectors. Significantly, the interfacial charge transfer from the CsPbBr3 to the MoS2 layer has been evidenced by the observed photoluminescence quenching and shortened decay time of the hybrid MoS2/CsPbBr3. Resultantly, such a hybrid MoS2/CsPbBr3 photodetector exhibits a high photoresponsivity of 4.4 A/W, an external quantum efficiency of 302%, and a detectivity of 2.5 * 1010 Jones because of the high efficient photoexcited carrier separation at the interface of MoS2 and CsPbBr3. The photoresponsivity of this hybrid device presents an improvement of 3 orders of magnitude compared with that of a MoS2 device without CsPbBr3. The response time of the device is also shortened from 65.2 to 0.72 ms after coupling with MoS2 layers. The combination of the all-inorganic perovskite layer with high photon absorption and the carrier transport TMD layer may pave the way for novel high-performance optoelectronic devices. PMID- 29280383 TI - Engineering of beta-Hydroxyl Esters into Elastomer-Nanoparticle Interface toward Malleable, Robust, and Reprocessable Vitrimer Composites. AB - Rubbers are strategically important due to their indispensable applications in the daily life and high-tech fields. For their real-world applications, the covalent cross-linking, reinforcement, and malleability of rubbers are three important issues because they are closely related to the elasticity, mechanical properties, and recycling of the rubber materials. Herein, we demonstrate a simple way to prepare covalently cross-linked yet recyclable and robust elastomeric vitrimer composites by incorporating exchangeable beta-hydroxyl ester bonds into the elastomer-nanoparticle interface using epoxy group-functionalized silica (Esilica) as both cross-linker and reinforcement in carboxyl group-grafted styrene-butadiene rubber (CSBR). The Esilica-cross-linked CSBR composites exhibit promising mechanical properties due to the covalent linkages in the interface and fine silica dispersion in the matrix. In addition, the interface can undergo dynamic reshuffling via transesterification reactions to alter network topology at high temperatures, conferring the resulting composites the ability to be reshaped and recycled. PMID- 29280384 TI - Phenolic glycosides from Lavandual angustifolia. AB - Four new phenolic glycosides (1-4), together with 12 known ones (5-16), were isolated from the essential oil extraction waste of Lavandula angustifolia. Their structures were unequivocally determined by extensive spectroscopic analysis (1D and 2D NMR, HR-ESI-MS, UV, and optical rotation), chemical method, and comparison with data reported in the literature. The antioxidant activities of all compounds and new compounds' influence on melanin content in B16 melanoma cells were examined, which indicated that compounds 1, 8, 13 had a certain degree of DPPH free radical scavenging activities, while only compound 2 could increase the melanin content with a dose-dependent manner. PMID- 29280385 TI - Formulation and statistical optimization of intravenous temozolomide-loaded PEGylated liposomes to treat glioblastoma multiforme by three-level factorial design. AB - The aim of the presented study was to develop PEGylated liposomes of Temozolomide (TMZ) that provide optimum drug concentration at tumor site. Reverse phase evaporation (REV) method was used to prepare TMZ-loaded PEGylated liposomes. Formulation was optimized by using design expert software by 32 factorial design. The physicochemical properties including size, morphology, entrapment efficiency, drug loading, etc. of formulated liposomes were evaluated. Finally, the optimized formulation was selected for in vitro drug release and stability study. In vivo pharmacokinetic study in rats showed that TMZ-loaded PEGylated liposomes leads to 1.6-fold increase in AUCTotal in blood and 4.2-fold increase in brain as compared to free drug solution. This formulated PEGylated liposomes offers a promising approach for treatment of Glioblastoma Multiforme. PMID- 29280386 TI - The association between biopsychosocial factors and disability in a national health survey in South Africa. AB - The association between psychosocial factors and disability is less clear. This study investigated the biological and psychosocial (employment and psychological distress) factors associated with level of disability in an adult sample in South Africa. Data were analysed from a cross-sectional survey among adults aged 18-64 (n = 4974). Multiple linear regression was used to investigate the associations of the selected variables with disability. The mean percentage score on the WHODAS scale of disability was 5.31% (95% CI: 4.74-5.88). Age (p < 0.001) and race (p = 0.0002) were significantly associated with disability, and history of stroke (beta = 7.19, 95% CI: 3.19-11.20) and heart-related conditions (beta = 2.08, 95% CI: [0.23-3.93) showed positive associations. Of the psychosocial variables, psychological distress (beta = 10.49 [8.63-12.35]) showed a strong positive association while employment (-1.62 [-2.36 to -0.88]) showed a negative association with disability. The association between demographic factors, medical conditions and increased disability confirms the findings in the literature. The finding that psychological distress is associated with increased disability has not been frequently reported. This study highlights specific psychosocial targets that may be usefully addressed by health policies and interventions in order to improve disability management. PMID- 29280387 TI - Serotonin transporter 5-HTTLPR genotype is associated with intrusion and avoidance symptoms of DSM-5 posttraumatic stress disorder (PTSD) in Chinese earthquake survivors. AB - BACKGROUND AND OBJECTIVES: Prior studies have found that the serotonin transporter gene-linked polymorphic region (5-HTTLPR) interacts with trauma exposure to increase general risk for Posttraumatic Stress Disorder (PTSD). However, there is little knowledge about the effects of the interaction on distinct symptom clusters of PTSD. This study aimed to investigate the relation between the interaction of 5-HTTLPR and earthquake-related exposures and a contemporary phenotypic model of DSM-5 PTSD symptoms in a traumatised adult sample from China. DESIGN: A cross-sectional design with gene-environment interaction (G * E) approach was adopted. METHODS: Participants were 1131 survivors who experienced 2008 Wenchuan earthquake. PTSD symptoms were assessed with the PTSD Checklist for DSM-5 (PCL-5). The 5-HTTLPR polymorphism was genotyped with capillary electrophoresis (CE) in ABI 3730xl genetic Analyzer. RESULTS: Although there was no significant interaction between 5-HTTLPR and traumatic exposure on total PTSD symptoms, respondents with the LL genotype of 5 HTTLPR who were highly exposed to the earthquake experienced lower intrusion and avoidance symptoms than those with the S-allele carriers. CONCLUSIONS: The findings suggest that the 5-HTTLPR may have an important impact on the development of PTSD and add to the extant knowledge on understanding and treating of posttraumatic psychopathology. PMID- 29280388 TI - Methotrexate-conjugated L-lysine coated iron oxide magnetic nanoparticles for inhibition of MCF-7 breast cancer cells. AB - Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase enzyme, is a chemotherapeutic agent for treating a diversity of neoplasms. In this study, we design and developed a new formulation of MTX that serves as drug carrier and examined its cytotoxic effect in vitro. This target drug delivery system is dependent on the release of the MTX within the lysosomal compartment. The iron oxide magnetic nanoparticles (IONPs) were first surface-coated with L-lysine and subsequently conjugated with MTX through amidation between the carboxylic acid end groups on MTX and the amine groups on the IONPs surface. MTX-conjugated L lysine coated IONPs (F-Lys-MTX NPs) was characterized by X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, vibrating sample magnetometer, and transmission electron microscopy techniques. The cytotoxicity of the void of MTX and F-Lys-MTX NPs were compared to each other by MTT assay of the treated MCF-7 cell lines. The results showed that the zeta-potential of F-Lys-MTX NPs was about -5.49 mV and the average size was 43.72 +/- 4.73 nm. Model studies exhibited the release of MTX via peptide bond cleavage in the presence of proteinase K and at low pH. These studies specify that F-Lys-MTX NPs have a very remarkable anticancer effect, for breast cancer cell lines. PMID- 29280389 TI - The effects of black garlic on the working memory and pyramidal cell number of medial prefrontal cortex of rats exposed to monosodium glutamate. AB - Monosodium glutamate-induced exitotoxicity causes oxidative stress in many brain areas, including the medial prefrontal cortex. The ethanolic garlic (Allium sativum) extract is considered as a neuroprotective substance. The present study aimed at investigating the effects of the ethanolic fermented garlic extract on the working memory and the pyramidal cell number of the medial prefrontal cortex of adolescent male Wistar rats exposed to monosodium glutamate (MSG). Twenty-five rats were randomly divided into five groups. The C- group was given 0.9% NaCl solution. The C + group was given 2 mg/g bw of MSG. The T1, T2, and T3 groups were given MSG and garlic extract (0.0125, 0.025, and 0.05 mg/g bw, respectively). All treatments were conducted for 10 days. The working memory capability of the rats was measured using Y-maze test. The total number of pyramidal cells of the medial prefrontal cortex was estimated using physical fractionator method. The working memory performances of the T1, T2, and T3 groups were significantly better than that of the C + group. There were no significant differences between groups in the estimated total number of pyramidal cell of medial prefrontal cortex. The MSG may not cause the death of neurons, but it may modify neuronal architectures that are sufficient to disrupt memory functions. Black garlic may play a role as an antioxidant agent that prevents the prefrontal cortex from glutamate-induced oxidative stress. It is concluded that the ethanolic fermented garlic extract prevented the working memory impairment following MSG administration. PMID- 29280390 TI - Reliability and validity of the Korean version of the 15-item Dispositional Resilience Scale. AB - This study assessed the reliability and validity of the Korean version of the 15 item Dispositional Resilience Scale (DRS-15) in a sample of Korean adults. In a baseline study conducted in June 2015, the DRS-15, Center for Epidemiologic Studies-Depression Scale (CES-D), and Korean Resilience Questionnaire-53 (KRQ-53) were administered to 409 Korean adults aged 20-79 years. A 1-year follow-up study was conducted in June 2016, and the CES-D was administered to assess predictive validity. Confirmatory factor analysis identified three dimensions for the DRS 15: commitment, control, and challenge (chi2/df = 2.32, GFI = .90, AGFI = .88, RMR = .04, TLI = .91, NFI = .89, and RMSEA = .05), and concurrent and predictive validity were demonstrated via the CES-D and KRQ-53. Furthermore, the DRS-15 established known-group validity. Cronbach's alpha coefficients for internal consistency reliability of the three subscales ranged from .75 to .83. Three-week test-retest reliability coefficients ranged from .80 to .81. The KDRS-15 showed satisfactory construct and criterion validity and internal consistency. PMID- 29280391 TI - Development of a new esomeprazole delayed release gastro-resistant pellet formulation with improved storage stability. AB - This study describes the development of a new esomeprazole (ESO) delayed release gastro-resistant formulation with improved storage stability. A three-step (drug , sub(seal)- and enteric-) coating process was employed with the aid of a fluid bed coater. Several formulation factors (namely, size and quantity of starting non-pareil sugar spheres, binder quantity during drug-layering, sub(seal)-coating polymer type, and quantity and enteric coating quantity) were evaluated and the whole process was modeled with the aid of feed-forward back-propagation artificial neural networks (ANNs). Results showed that the selection of small sized starting spheres (45/60 mesh size) leads to pellet agglomeration, while as sub(seal)-coating weight gain increases a reduction in ESO dissolution rate is observed. The enteric-coating applied (Eudragit L30D-55) showed good gastro resistant performance in both 0.1 N HCl and pH 4.5 media, while immediate release profiles with more than 85% of ESO being released in less than 30 min were obtained. The effect of cellulose-based sub(seal)-coating polymers, (namely, hydroxypropyl cellulose and hydroxypropylmethyl cellulose) on formulation's storage stability at 40 +/- 2 degrees C/75 +/- 5%RH indicated that only hydroxypropylmethyl cellulose was able to stabilize ESO delayed-release formulations in terms of assay, dissolution, impurities, and gastro-resistance performance. Finally, scanning electron microscopy (SEM) analysis revealed smooth and homogeneous external surface/coating layers in all three levels (drug-, sub(seal)-, and enteric- coating), while x-ray diffraction showed no polymorphic transformations. PMID- 29280392 TI - Comorbidity of Internet use disorder and attention deficit hyperactivity disorder: Two adult case-control studies. AB - Objectives There is good scientific evidence that attention deficit hyperactivity disorder (ADHD) is both a predictor and a comorbidity of addictive disorders in adulthood. These associations not only focus on substance-related addictions but also on behavioral addictions like gambling disorder and Internet use disorder (IUD). For IUD, systematic reviews have identified ADHD as one of the most prevalent comorbidities besides depressive and anxiety disorders. Yet, there is a need to further understand the connections between both disorders to derive implications for specific treatment and prevention. This is especially the case in adult clinical populations where little is known about these relations so far. This study was meant to further investigate this issue in more detail based on the general hypothesis that there is a decisive intersection of psychopathology and etiology between IUD and ADHD. Methods Two case-control samples were examined at a university hospital. Adult ADHD and IUD patients ran through a comprehensive clinical and psychometrical workup. Results We found support for the hypothesis that ADHD and IUD share psychopathological features. Among patients of each group, we found substantial prevalence rates of a comorbid ADHD in IUD and vice versa. Furthermore, ADHD symptoms were positively associated with media use times and symptoms of Internet addiction in both samples. Discussion Clinical practitioners should be aware of the close relationships between the two disorders both diagnostically and therapeutically. When it comes to regain control over one's Internet use throughout treatment and rehabilitation, a potential shift of addiction must be kept in mind on side of practitioners and patients. PMID- 29280393 TI - Internet gaming disorder and online gambling disorder: Clinical and personality correlates. AB - Background and aims The recent growth of Internet use has led to an increase of potentially problematic behaviors that can be engaged online, such as online gambling or Internet gaming. The aim of this study is to better conceptualize Internet gaming disorder (IGD) by comparing it with gambling disorder (GD) patients who only gamble online (online GD). Methods A total of 288 adult patients (261 online GD and 27 IGD) completed self-reported questionnaires for exploring psychopathological symptoms, food addiction (FA), and personality traits. Results Both clinical groups presented higher psychopathological scores and less functional personality traits when compared with a normative Spanish population. However, when comparing IGD to online GD, some singularities emerged. First, patients with IGD were younger, more likely single and unemployed, and they also presented lower age of disorder onset. In addition, they displayed lower somatization and depressive scores together with lower prevalence of tobacco use but higher FA scores and higher mean body mass index. Finally, they presented lower novelty seeking and persistence traits. Discussion GD is fully recognized as a behavioral addiction, but IGD has been included in the Appendix of DSM-5 as a behavioral addiction that needs further study. Our findings suggest that IGD and online GD patients share some emotional distress and personality traits, but patients with IGD also display some differential characteristics, namely younger age, lower novelty seeking scores and higher BMI, and FA scores. Conclusions IGD presents some characteristics that are not extensive to online GD. These specificities have potential clinical implications and they need to be further studied. PMID- 29280394 TI - Insomnia partially mediated the association between problematic Internet use and depression among secondary school students in China. AB - Background and aims This study aims to examine the mediating effects of insomnia on the associations between problematic Internet use, including Internet addiction (IA) and online social networking addiction (OSNA), and depression among adolescents. Methods A total of 1,015 secondary school students from Guangzhou in China participated in a cross-sectional survey. Levels of depression, insomnia, IA, and OSNA were assessed using the Center for Epidemiological Studies-Depression Scale, Pittsburgh Sleep Quality Index, Young's Diagnostic Questionnaire, and Online Social Networking Addiction Scale, respectively. Logistic regression models were fit to test the associations between IA, OSNA, insomnia, and depression. The mediation effects of insomnia were tested using Baron and Kenny's strategy. Results The prevalence of depression at moderate level or above (CES-D >= 21), insomnia, IA, and OSNA were 23.5%, 37.2%, 8.1%, and 25.5%, respectively. IA and OSNA were significantly associated with depression (IA: AOR = 2.79, 95% CI: 1.71, 4.55; OSNA: AOR = 3.27, 95% CI: 2.33, 4.59) and insomnia (IA: AOR = 2.83, 95% CI: 1.72, 4.65; OSNA: AOR = 2.19, 95% CI: 1.61, 2.96), after adjusting for significant background factors. Furthermore, insomnia partially mediated 60.6% of the effect of IA on depression (Sobel Z = 3.562, p < .002) and 44.8% of the effect of OSNA on depression (Sobel Z = 3.919, p < .001), respectively. Discussion The high prevalence of IA and OSNA may be associated with increased risk of developing depression among adolescents, both through direct and indirect effects (via insomnia). Findings from this study indicated that it may be effective to develop and implement interventions that jointly consider the problematic Internet use, insomnia, and depression. PMID- 29280396 TI - Connected to TV series: Quantifying series watching engagement. AB - Background and aims Television series watching stepped into a new golden age with the appearance of online series. Being highly involved in series could potentially lead to negative outcomes, but the distinction between highly engaged and problematic viewers should be distinguished. As no appropriate measure is available for identifying such differences, a short and valid measure was constructed in a multistudy investigation: the Series Watching Engagement Scale (SWES). Methods In Study 1 (NSample1 = 740 and NSample2 = 740), exploratory structural equation modeling and confirmatory factor analysis were used to identify the most important facets of series watching engagement. In Study 2 (N = 944), measurement invariance of the SWES was investigated between males and females. In Study 3 (N = 1,520), latent profile analysis (LPA) was conducted to identify subgroups of viewers. Results Five factors of engagement were identified in Study 1 that are of major relevance: persistence, identification, social interaction, overuse, and self-development. Study 2 supported the high levels of equivalence between males and females. In Study 3, three groups of viewers (low-, medium-, and high-engagement viewers) were identified. The highly engaged at-risk group can be differentiated from the other two along key variables of watching time and personality. Discussion The present findings support the overall validity, reliability, and usefulness of the SWES and the results of the LPA showed that it might be useful to identify at-risk viewers before the development of problematic use. PMID- 29280395 TI - Attachment and emotion regulation in substance addictions and behavioral addictions. AB - Background Risky behaviors have been related to emotional regulation and attachment, which may constitute risk factors for developing an addictive behavior. However, there may also be differences between substance and non substance-related addictions. Aims This study aimed to examine the relationship of emotional regulation and attachment, with substance (alcohol and drug abuse), and non-substance-related addictions (gambling disorder, video game addiction, and problematic Internet use) in adolescents and emerging adults. The study also aimed to examine gender differences for such predictors. Methods The sample comprised 472 students aged 13-21 years recruited from high schools and vocational education centers. Results Findings demonstrated that emotion regulation was predictive of all addictive behaviors assessed in this study (alcohol and drug abuse, gambling disorder, video game addiction, and problematic Internet use), whereas attachment predicted non-substance-related addictions (gambling disorder, video game addiction, and problematic Internet use). In addition, gender differences were found, with females scoring significantly higher in maternal and peer attachment, whereas males scored significantly higher in gambling disorder and video game addiction. Conclusion The findings may be useful for preventive and clinical interventions conducted with youth regarding addictive behaviors. PMID- 29280397 TI - Measures of behavioral function predict duration of video game play: Utilization of the Video Game Functional Assessment - Revised. AB - Background Internet gaming disorder (IGD) was introduced in the DSM-5 as a way of identifying and diagnosing problematic video game play. However, the use of the diagnosis is constrained, as it shares criteria with other addictive orders (e.g., pathological gambling). Aims Further work is required to better understand IGD. One potential avenue of investigation is IGD's relationship to the primary reinforcing behavioral functions. This study explores the relationship between duration of video game play and the reinforcing behavioral functions that may motivate or maintain video gaming. Methods A total of 499 video game players began the online survey, with complete data from 453 participants (85% white and 28% female), were analyzed. Individuals were placed into five groups based on self-reported hours of video gaming per week, and completed the Video Game Functional Assessment - Revised (VGFA-R). Results The results demonstrated the escape and social attention function were significant in predicting duration of video game play, whereas sensory and tangible were not significant. Conclusion Future implications of the VGFA-R and behaviorally based research are discussed. PMID- 29280398 TI - Association between Internet gaming disorder and generalized anxiety disorder. AB - Introduction This study evaluates the association between generalized anxiety disorder (GAD) and Internet gaming disorder (IGD) and the role of behavior inhibition in young adults. Methods We recruited 87 people with IGD and a control group of 87 people without a history of IGD. All participants underwent a diagnostic interview based on the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, IGD and GAD criteria, and completed a questionnaire on behavior inhibition, depression, and anxiety. Results Logistic regression revealed that adults with GAD were more likely (odds ratio = 8.11, 95% CI = 1.78 37.09) to have IGD than those without it. The OR decreased when controlling for behavior inhibition. IGD subjects with GAD had higher depressive and anxiety score than those without GAD. Conclusions GAD was associated with IGD. Comorbid GAD can contribute to higher emotional difficulty. GAD should be well-assessed and interventions planned when treating young adults with IGD. Behavioral inhibition confounds the association between GAD and IGD. Further study is necessary to evaluate how to intervene in behavioral inhibitions to attenuate the risk of GAD and IGD comorbidity. PMID- 29280399 TI - Gambling and family: A two-way relationship. AB - Background and aims Families play an important role in the evolution of gambling and are also adversely affected by the disordered gambling of any one of their members. The aims of this study were to explore both the role families play in gambling initiation, maintenance, and help-seeking, and the harm caused to families by the gambling behavior using a qualitative approach. Methods Regular older adult gamblers were included in the study. In-depth interviews were conducted with 25 older adults to gain an understanding of gambling from their perspective. Older adult gamblers described their lived experience of gambling ranging from initiation to harm and attempts to cut down or limit gambling. Data were analyzed using thematic network analysis. Results The mean age of the 25 participants was 66.2 years. The majority were male (n = 18), of Chinese ethnicity (n = 16), had secondary education (n = 9), were married (n = 20), and currently employed (n = 15). Four organizing themes related to the role of families in initiation and maintenance of gambling, harm caused to family members, and their role in help-seeking were identified. Discussion and conclusions The study emphasizes the role of Asian families in both initiation and maintenance of gambling. Hence, families must be involved in prevention and outreach programs. Family members must be educated, so that they can encourage help-seeking to ensure early treatment and recovery. There is a need for interventional studies for reducing stress and improving coping among family members. PMID- 29280400 TI - A risk assessment study on accidents at French level crossings using Bayesian belief networks. AB - Level crossing (LX) safety continues to be one of the most critical issues for railways despite an ever increasing focus on improving design and practices. In the present paper, a framework of probabilistic risk assessment and improvement decision based on Bayesian belief networks (PRAID-BBN) is proposed. The developed framework aims to analyse various impacting factors which may cause LX accidents, and quantify the contribution of these factors so as to identify the crucial factors which contribute most to the LX accidents. A detailed statistical analysis is first carried out based on the accident/incident data. A BBN risk model is established according to the statistical results. Then, we apply the PRAID-BBN framework on the basis of the accident/incident data provided by SNCF, the French national railway operator. The main outputs of our study are conducive to efficiently focusing on the effort/budget to make LXs safer. PMID- 29280401 TI - Spectral Coefficient Analyses of Word-Initial Stop Consonant Productions Suggest Similar Anticipatory Coarticulation for Stuttering and Nonstuttering Adults. AB - A longstanding hypothesis about the sensorimotor mechanisms underlying stuttering suggests that stuttered speech dysfluencies result from a lack of coarticulation. Formant-based measures of either the stuttered or fluent speech of children and adults who stutter have generally failed to obtain compelling evidence in support of the hypothesis that these individuals differ in the timing or degree of coarticulation. Here, we used a sensitive acoustic technique-spectral coefficient analyses-that allowed us to compare stuttering and nonstuttering speakers with regard to vowel-dependent anticipatory influences as early as the onset burst of a preceding voiceless stop consonant. Eight adults who stutter and eight matched adults who do not stutter produced C1VC2 words, and the first four spectral coefficients were calculated for one analysis window centered on the burst of C1 and two subsequent windows covering the beginning of the aspiration phase. Findings confirmed that the combined use of four spectral coefficients is an effective method for detecting the anticipatory influence of a vowel on the initial burst of a preceding voiceless stop consonant. However, the observed patterns of anticipatory coarticulation showed no statistically significant differences, or trends toward such differences, between the stuttering and nonstuttering groups. Combining the present results for fluent speech in one given phonetic context with prior findings from both stuttered and fluent speech in a variety of other contexts, we conclude that there is currently no support for the hypothesis that the fluent speech of individuals who stutter is characterized by limited coarticulation. PMID- 29280402 TI - Computer users' ergonomics and quality of life - evidence from a developing country. AB - This study is aimed at investigating the quality of workplace ergonomics at various Pakistani organizations and quality of life of computer users working in these organizations. Two hundred and thirty-five computer users (only those employees who have to do most of their job tasks on computer or laptop, and at their office) responded by filling the questionnaire covering questions on workplace ergonomics and quality of life. Findings of the study revealed the ergonomics at those organizations was poor and unfavourable. The quality of life (both physical and mental health of the employees) of respondents was poor for employees who had unfavourable ergonomic environment. The findings thus highlight an important issue prevalent at Pakistani work settings. PMID- 29280403 TI - Ticagrelor in modern cardiology - an up-to-date review of most important aspects of ticagrelor pharmacotherapy. AB - INTRODUCTION: Ticagrelor is a first drug of a new chemical class cyclopentyltriazolopyrimidines. It is an antiplatelet agent with a unique mechanism of action, allowing a direct and reversible competitive inhibition of P2Y12 receptor. According to newest guidelines, it is recommended for prevention of thrombotic events in patients with acute coronary syndromes. Moreover, it is preferred over clopidogrel, an older generation antiplatelet drug, and therefore gains more interest in modern cardiology and vascular medicine. Areas covered: This review is a comprehensive and thorough summary of the most important findings on ticagrelor. Pharmacokinetics, pharmacogenetics, drug-drug interactions, adverse effects, efficacy in specific patient populations and off label properties of ticagrelor are discussed in this paper. Moreover, the results from pivotal clinical trials are presented. Expert opinion: Introduction of ticagrelor, a first directly-acting and reversible P2Y12 inhibitor, gave some new possibilities as the efficacy of older drugs was often insufficient. Despite some drawbacks, such as a risk of bleeding events or dyspnea, a rapid onset of action, consistency in the antiplatelet effect and reports on pleiotropic properties make this drug a promising candidate for a first-choice antiplatelet agent in patients with acute coronary events. PMID- 29280404 TI - Delineating closely related species of Tylostega Meyrick (Lepidoptera: Crambidae: Spilomelinae) from mainland China using DNA barcodes. AB - Integrative taxonomic study of three species of the genus Tylostega revealed that the genetic distances of the COI gene among the tested species was relatively large (3.27-7.60%). The Automatic Barcode Gap Discovery (ABGD) system performed better than the Barcode Index Number (BIN) in discriminating closely related species. This work provides a molecular baseline for future integrative taxonomic study of Crambidae. PMID- 29280405 TI - Lexical Segmentation in Artificial Word Learning: The Effects of Converging Sublexical Cues. AB - This study examines how French listeners segment and learn new words of artificial languages varying in the presence of different combinations of sublexical segmentation cues. The first experiment investigated the contribution of three different types of sublexical cues (acoustic-phonetic, phonological and prosodic cues) to word learning. The second experiment explored how participants specifically exploited sublexical prosodic cues. Whereas complementary cues signaling word-initial and word-final boundaries had synergistic effects on word learning in the first experiment, the two manipulated prosodic cues redundantly signaling word-final boundaries in the second experiment were rank-ordered with final pitch variations being more weighted than final lengthening. These results are discussed in light of the notions of cue type, cue position and cue efficiency. PMID- 29280406 TI - The Role of Perception in the Typology of Geminate Consonants: Effects of Manner of Articulation, Segmental Environment, Position, and Stress. AB - The present study seeks to answer the question of whether consonant duration is perceived differently across consonants of different manners of articulation and in different contextual environments and whether such differences may be related to the typology of geminates. The results of the cross-linguistic identification experiment suggest higher perceptual acuity in labeling short and long consonants in sonorants than in obstruents. Duration categories were also more consistently and clearly labeled in the intervocalic than in the preconsonantal environment, in the word-initial than in the word-final position, and after stressed vowels than between unstressed vowels. These perceptual asymmetries are in line with some typological tendencies, such as the cross-linguistic preference for intervocalic and post-stress geminates, but contradict other proposed cross linguistic patterns, such as the preference for obstruent geminates and the abundance of word-final geminates. PMID- 29280407 TI - Investigation of piperazines as human carbonic anhydrase I, II, IV and VII activators. AB - Four human (h) carbonic anhydrase isoforms (CA, EC 4.2.1.1), hCA I, II, IV, and VII, were investigated for their activation profile with piperazines belonging to various classes, such as N-aryl-, N-alkyl-, N-acyl-piperazines as well as 2,4 disubstituted derivatives. As the activation mechanism involves participation of the activator in the proton shuttling between the zinc-coordinated water molecule and the external milieu, these derivatives possessing diverse basicity and different scaffolds were appropriate for being investigated as CA activators (CAAs). Most of these derivatives showed CA activating properties against hCA I, II, and VII (cytosolic isoforms) but were devoid of activity against the membrane associated hCA IV. For hCA I, the KAs were in the range of 32.6-131 uM; for hCA II of 16.2-116 uM, and for hCA VII of 17.1-131 uM. The structure-activity relationship was intricate and not easy to rationalize, but the most effective activators were 1-(2-piperidinyl)-piperazine (KA of 16.2 uM for hCA II), 2-benzyl piperazine (KA of 17.1 uM for hCA VII), and 1-(3-benzylpiperazin-1-yl)propan-1 one (KA of 32.6 uM for hCA I). As CAAs may have interesting pharmacologic applications in cognition and for artificial tissue engineering, investigation of new classes of activators may be crucial for this relatively new research field. PMID- 29280408 TI - Optimizing the long-term management of chronic migraine with onabotulinumtoxinA in real life. AB - INTRODUCTION: Management of chronic migraine is challenging. OnabotulinumtoxinA (OBT-A) is the only medication licensed for prevention of chronic migraine, and has been widely adopted in clinical practice. Limited data is available on its long-term use. Areas covered: Data from controlled trials are combined with available data on the long-term use of OBT-A in real-life studies, with information obtained in a recent survey among Italian headache centers, and the clinical experience of the authors. Six areas were identified as relevant to patients with chronic migraine: 1) definition of responders to OBT-A; 2) management of responders to OBT-A; 3) optimal timing of prophylaxis with OBT-A; 4) position of OBT-A in prevention of chronic migraine; 5) management of medication overuse, and 6) patient education. Expert commentary: This review provides an update on the latest evidence regarding the long-term use of OBT-A in chronic migraine and analyzes the critical issues in the decision-making process that emerge from the analysis of the literature and routine practice. A treatment algorithm is proposed for the adoption in the daily practice. PMID- 29280409 TI - Challenges of using new and repurposed drugs for the treatment of multidrug resistant tuberculosis in children. AB - INTRODUCTION: New and repurposed antituberculosis drugs are urgently needed to more safely and effectively treat multidrug-resistant (MDR) tuberculosis (TB) in children. Multiple challenges limit timely access to new MDR-TB treatments in children. Areas covered: Diagnosis of MDR-TB in children remains a barrier, with few children with MDR-TB diagnosed and treated. Other barriers to timely access to new and repurposed drugs are discussed, and include delayed initiation of paediatric trials, limited funding for paediatric drug development, fragmented regulatory systems and operational challenges. The status of access to current repurposed and novel drugs is presented. Expert commentary: More timely initiation of paediatric trials is needed and paediatric work should happen and be funded in parallel with each phase of adult trials. Better quality data, increased regulator resources and expertise, harmonization of regulatory requirements across borders/organisations and registration fee waivers would improve registration timelines. Improved diagnosis, recording and reporting will establish better demand. Improved systems for procurement and supply chain management would reduce in-country operational barriers to getting medications to children. The challenges must be addressed to ensure timely and equitable access to new drugs and regimens that are urgently needed for effective, safe and shorter treatment of children with MDR-TB. PMID- 29280410 TI - Iron balance and iron supplementation for the female athlete: A practical approach. AB - Maintaining a positive iron balance is essential for female athletes to avoid the effects of iron deficiency and anaemia and to maintain or improve performance. A major function of iron is in the production of the oxygen and carbon dioxide carrying molecule, haemoglobin, via erythropoiesis. Iron balance is under the control of a number of factors including the peptide hormone hepcidin, dietary iron intake and absorption, environmental stressors (e.g. altitude), exercise, menstrual blood loss and genetics. Menstruating females, particularly those with heavy menstrual bleeding are at an elevated risk of iron deficiency. Haemoglobin concentration [Hb] and serum ferritin (sFer) are traditionally used to identify iron deficiency, however, in isolation these may have limited value in athletes due to: (1) the effects of fluctuations in plasma volume in response to training or the environment on [Hb], (2) the influence of inflammation on sFer and (3) the absence of sport, gender and individually specific normative data. A more detailed and longitudinal examination of haematology, menstrual cycle pattern, biochemistry, exercise physiology, environmental factors and training load can offer a superior characterisation of iron status and help to direct appropriate interventions that will avoid iron deficiency or iron overload. Supplementation is often required in iron deficiency; however, nutritional strategies to increase iron intake, rest and descent from altitude can also be effective and will help to prevent future iron deficient episodes. In severe cases or where there is a time-critical need, such as major championships, iron injections may be appropriate. PMID- 29280411 TI - The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients. AB - INTRODUCTION: Synovial Sarcoma (SS) and Myxoid Round Cell Liposarcoma (MRCL) are devastating sarcoma subtypes with few treatment options and poor outcomes in the advanced setting. However, both these diseases may be ideal for novel immunotherapies targeting the cancer-testis antigen, NY-ESO-1. Areas covered: In this review, we discuss the novel NY-ESO-1 targeted vaccine regimen, CMB305. This regimen uses a unique integration-deficient, dendritic-cell targeting lentiviral vector from the ZVex(r) platform, LV305, in order to prime NY-ESO-1 specific T cells. LV305 has single agent activity, and, in one case, caused a durable partial response in a refractory SS patient. CMB305 also includes a boost from a NY-ESO-1 protein vaccine given along with a potent toll-like-4 receptor agonist, glycopyranosyl lipid A. CMB305 induces NY-ESO-1 specific T cell responses in both SS and MRC patients and these patients had excellent overall survival (OS) outcomes in the initial phase I study. Expert commentary: CMB305 is a therapeutic vaccine regimen targeting NY-ESO-1 based on the lentiviral vaccine vector, LV305. Phase I studies have proven this vaccine is active immunologically. Data suggesting this vaccine may improve OS for SS and MRCL patients is exciting but early, and on-going work is testing the impact of CMB305 on patient outcomes. PMID- 29280412 TI - Tooth root and alveolar bone grey values derived from cone-beam CT imaging in maxillary incisor teeth with and without apical root resorption. AB - INTRODUCTION: In orthodontic treatment, an increased bone mineral density of the alveolar bone is considered as a risk factor for apical root resorption (ARR), whereas the mineral density of cementum has been associated with root protection against resorption. METHODS: This study aimed at evaluating the grey values (GVs) of the apical third of the root and of the alveolar bone adjacent to maxillary incisors with and without ARR in orthodontic patients. Twenty-one patients under treatment who presented one incisor with ARR and its corresponding contralateral without ARR were selected and submitted to cone-beam computed tomography. GVs were evaluated on the images obtained of four areas of the apical third of the root and of four areas of the adjacent alveolar bone. RESULTS AND CONCLUSIONS: The radicular tissue of the apical third of the incisors with ARR showed greater root GV (p < .05) than that of the incisors without ARR. Supra-apical alveolar bone exhibited greater GV in the incisors without ARR than incisors with ARR (p < .05). Root GV was not associated with root protection, but rather seemed to have facilitated the process of resorption. The GV of the lingual bone was associated with a higher progression of ARR in the incisors. PMID- 29280413 TI - Integrated system of occupational safety and health and fire protection of the fire rescue brigades members. AB - The objective of the conducted research is the identification and determination of requirements of members of fire rescue brigades during operations in the conditions of high risk in order to minimize the possibilities for injury incidence during the intervention. The research is focused on examination, determination and identification of factors affecting the increasing number of occupational injuries of members of fire rescue brigades during interventions. Hypothetical framework of the research problem consists of general hypothesis and six special hypotheses. Results suggest that almost all respondents believe that their skills and abilities are applicable in the intervention phase, but less than a half believe that their skills are applicable in prevention phase. Two thirds of respondents stated that in their organization they have support for further education and upgrading while a half of respondents stated that they need education concerning identification, assessment and management of risks that can lead to emergency situations. PMID- 29280414 TI - The relationship between dietary quality, serum brain-derived neurotrophic factor (BDNF) level, and the Val66met polymorphism in predicting depression. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of depression, may be influenced by dietary quality. Both dietary quality and serum BDNF have been researched independently in regard to their effect on depression; however, there is limited research investigating the relationship between the two factors and how they interact in depression. Additionally, a single-nucleotide polymorphism (SNP) (Val66Met) in the BDNF gene, which has been implicated in BDNF levels and depression, may contribute to the complex relationship between depression, dietary quality, and BDNF level. METHODS: One hundred and eighty-seven participants with major depressive disorder and 55 non-depressed healthy controls were recruited for this case-control analysis. The relationship between dietary quality and depression was assessed via a novel dietary quality score (the Australian Dietary Quality Score). Serum BDNF levels were measured and the Val66Met SNP was genotyped. RESULTS: Healthy controls had a significantly higher diet quality than depressed participants (t = 2.435, P = 0.016). A logistic regression model investigating age, sex, serum BDNF levels, dietary quality and depression, as well as any interactions, found that lower dietary quality, and surprisingly, higher BDNF levels, were associated with increased depression risk, P = 0.037 and P < 0.001, respectively. Neither seasonality (at the time of recruitment) nor the Val66Met polymorphism was associated with BDNF levels in this sample. Furthermore, there was no evidence of interaction between the Val66Met polymorphism, BDNF levels, dietary quality, and depression. CONCLUSION: Higher dietary quality was associated with both decreased depression incidence and severity in this cross sectional analysis. The Val66Met polymorphism did not appear to predict BDNF levels, depression incidence, or modify the relationship between dietary quality and BDNF. Further studies utilizing a larger sample size are needed to confirm this finding. PMID- 29280415 TI - Dynamic processes in emotion regulation choice. AB - Because emotion regulation (ER) processes operate over time, they potentially change the context in which subsequent ER processes occur. To test this proposal, fifty-two healthy participants completed the ER choice task. Thirty standardized low- and high-intensity negative images were used to generate different emotional contexts in which participants selected between distraction or reappraisal strategies to decrease the intensity of their negative emotion. Participants then implemented their selected strategy and rated their negative emotion. Using a dynamic perspective, we examined as predictors of ER strategy choice, in addition to current stimulus intensity, several contextual factors from the immediately preceding trial: preceding stimulus intensity and strategy choice, and the intensity of negative affect following the previous strategy implementation and thus preceding the current trial. Results replicated earlier findings that participants are more likely to choose distraction for high-intensity images. Extending earlier findings, selecting reappraisal in the preceding trial and greater negative affect preceding the current trial were associated with lower odds of choosing distraction. The lack of significant interactions among the current and preceding trial factors suggests that these effects on ER choice were direct and not through moderating the effect of current stimulus intensity. These findings support dynamic theories of ER. PMID- 29280416 TI - Quantitative Trait Loci Mapping of Multiple Independent Loci for Resistance to Fusarium oxysporum f. sp. vasinfectum Races 1 and 4 in an Interspecific Cotton Population. AB - Fusarium wilt, caused by the soilborne fungal pathogen Fusarium oxysporum f. sp. vasinfectum, is a vascular disease of cotton (Gossypium spp.). F. oxysporum f. sp. vasinfectum race 1 (FOV1) causes major plant injury and yield loss in G. hirsutum cultivars with coinfection with root-knot nematode (Meloidogyne incognita), while F. oxysporum f. sp. vasinfectum race 4 (FOV4) causes plant damage without nematode coinfection in G. hirsutum and in G. barbadense cultivars. Quantitative trait loci (QTL) analysis of the interspecific cross G. barbadense Pima S-7 * G. hirsutum Acala NemX revealed separate multiple loci determining resistance to FOV1 and FOV4, confirming that race specificity occurs in F. oxysporum f. sp. vasinfectum. Based on the area under the disease progress stairs, six major QTLs on chromosomes (Chrs) 1, 2, 12, 15 (2), and 21 contributing 7 to 15% to FOV1 resistance and two major QTLs on Chrs 14 and 17 contributing 12 to 33% to FOV4 resistance were identified. Minor-effect QTLs contributing to resistance to both FOV1 and FOV4 were also identified. These results define and establish a pathosystem of race-specific resistance under polygenic control. This research also validates the importance of previously reported markers and chromosome regions and adds new information for the location of F. oxysporum f. sp. vasinfectum resistance genes. Some F8 recombinant inbred lines have resistance to both FOV1 and FOV4 and also to root-knot nematode, providing multiple resistance sources for breeding. PMID- 29280417 TI - Different answers to different audiences: effects of social context on the accuracy-informativeness trade-off. AB - Research on conversational exchanges shows that people attempt to optimise their responses' relevance when they definitely know the correct answer (e.g., "What time is it?"). However, such certainty is often unavailable while speakers may still be under social pressure to provide an answer. We investigated how social context influences the informativeness level when answering questions under uncertainty. In three experiments, participants answered difficult general knowledge questions placed in different social contexts (formal vs. informal). Participants generated their answers, then they were presented with a given context, and decided on the number of alternative responses they wanted to provide (single, with one alternative vs. plural, with several alternatives) and whether the answer should be reported or withheld (report option). Participants reported more answers in the informal context. In the formal context, single answers were preferred, and they were more frequently reported. We conclude that social context influences the level of informativeness in a conversation, affecting achievable accuracy. Our results also show the joint influence of the confidence and the social context on willingness to share information. PMID- 29280418 TI - Comparative effect of Camellia sinensis teas on object recognition test deficit and metabolic changes induced by cafeteria diet. AB - OBJECTIVES: Consumption of high-fat and high-sugar diets in Western countries has increased significantly causing major global health problems including metabolic syndrome and obesity. In addition, studies have suggested that obesity can lead to learning and memory deficits. In this context, the use of natural compounds with low costs, minor side effects and increased antioxidant activity, such as teas, could reduce the damages induced by obesity. We investigated the effect of white, green, red, and black teas (Camellia sinensis) and their possible neuroprotective mechanisms in an experimental obesity model induced by a cafeteria diet (CD). METHODS: Female Swiss mice (20-30 g) were used; they received a normal diet or a hypercaloric diet (CD) during 8 weeks. Concomitantly, some mice received orally white, green, red, or black teas (1% dose) or water. RESULTS: The mice subjected to CD showed weight gain, body fat accumulation, increased glucose, cholesterol, and triglycerides, associated to recognition memory deficits and increased reactive species (RS) levels and acetylcholinesterase (AChE) activity in the hippocampus. All teas significantly reduced AChE activity and partially reduced fat accumulation. Green and red teas reduced memory deficit. White, green, and black teas reduced RS levels, while only green and black tea reduced plasma triglyceride levels. DISCUSSION: According to the results obtained it is possible to conclude that green tea was better than other teas in reducing effects of the CD model, being able to protect a greater number of parameters. PMID- 29280419 TI - A preliminary analysis of incident investigation reports of an integrated steel plant: some reflection. AB - Large integrated steel plants employ an effective safety management system and gather a significant amount of safety-related data. This research intends to explore and visualize the rich database to find out the key factors responsible for the occurrences of incidents. The study was carried out on the data in the form of investigation reports collected from a steel plant in India. The data were processed and analysed using some of the quality management tools like Pareto chart, control chart, Ishikawa diagram, etc. Analyses showed that causes of incidents differ depending on the activities performed in a department. For example, fire/explosion and process-related incidents are more common in the departments associated with coke-making and blast furnace. Similar kind of factors were obtained, and recommendations were provided for their mitigation. Finally, the limitations of the study were discussed, and the scope of the research works was identified. PMID- 29280421 TI - Theory and Metrics of Community Resilience: A Systematic Literature Review Based on Public Health Guidelines. AB - A systematic literature review on quantitative methods to assess community resilience was conducted following Institute of Medicine and Patient-Centered Outcomes Research Institute standards. Community resilience is the ability of a community to bounce back or return to normal after a disaster strikes, yet there is no agreement on what this actually means. All studies reviewed addressed natural disasters, but the methodological approaches can be applied to technological disasters, epidemics, and terrorist attacks. Theoretical frameworks consider the association between vulnerability, resilience, and preparedness, yet these associations vary across frameworks. Because of this complexity, indexes based on composite indicators are the predominant methodological tool used to assess community resilience. Indexes identify similar dimensions but observe resilience at both the individual and geographical levels, reflecting a lack of agreement on what constitutes a community. A consistent, cross-disciplinary metric for community resilience would allow for identifying areas to apply short term versus long-term interventions. A comparable metric for assessing geographic units in multiple levels and dimensions is an opportunity to identify regional strengths and weaknesses, develop timely targeted policy interventions, improve policy evaluation instruments, and grant allocation formulas design. (Disaster Med Public Health Preparedness. 2017;11:756-763). PMID- 29280422 TI - Health Care Coalitions as Response Organizations: Houston After Hurricane Harvey. AB - Health care coalitions play an increasingly important role in both preparedness for, response to, and recovery from large scale disaster events occurring across the United States. The actions taken by the South East Texas Regional Advisory Council (SETRAC) in response to the landfall of Hurricane Harvey, and the consequential flooding that ensued, serve as an excellent example of how health care coalitions are increasingly needed to play a unifying role in response. This paper highlights a number of the strategic planning, operational planning and response, information sharing, and resource coordination and management activities that were undertaken for the response to Hurricane Harvey. The successful response to this devastating storm in the Houston, Texas area serves as an example to other regions across the country as they work to implement the 2017-2022 health care capabilities articulated by the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response. (Disaster Med Public Health Preparedness. 2017;11:637-639). PMID- 29280423 TI - Anemia was an Uncommon Complication of Severe Malaria in a High-Transmission Rural Area of Western Uganda. AB - The clinical epidemiology of severe malaria among patients presenting to peripheral health centers has not been well described. We conducted a prospective, observational cohort study to describe the epidemiology and clinical manifestations of severe malaria in a highland area of declining transmission intensity in Western Uganda. Individuals presenting with a history of fever were screened with a malaria rapid diagnostic test (RDT). We prepared blood smears and conducted clinical and laboratory testing for those with a positive RDT. We defined severe malaria in accordance with World Health Organization guidelines for research and epidemiological studies. A total of 6,641 individuals underwent testing for malaria. Ninety-six of 1,462 (6.6%) participants with confirmed parasitemia satisfied the criteria for severe malaria. The incidence of severe malaria peaked between 2 and 3 years of age (incidence rate ratio = 17.1, 95% confidence interval = 8.4-34.9, P < 0.001) and then declined steadily until age 10. However, we also found a second peak among those >= 50 years of age. Severe anemia was uncommon, detected in only 5.3% of cases. Instead, shock (22.2%) and lactic acidosis (19.4%) were most frequently encountered. Our results suggest that the clinical characteristics of severe malaria presenting to rural, peripheral health centers may be different than previously observed in referral centers. These findings merit further investigation into the optimal methods for identification and management of severe malaria in rural health centers in the region. PMID- 29280424 TI - Treatment-Seeking Behavior after the Implementation of a Unified Policy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Malaria in Papua, Indonesia. AB - Artemisinin combination therapy is recommended for the treatment of multidrug resistant Plasmodium falciparum and Plasmodium vivax. In March 2006, antimalarial policy in Indonesia was changed to a unified treatment with dihydroartemisinin piperaquine for all species of malaria because of the low efficacy of previous drug treatments. In 2013, a randomized cross-sectional household survey in Papua was used to collect data on demographics, parasite positivity, treatment-seeking behavior, diagnosis and treatment of malaria, and household costs. Results were compared with a similar survey undertaken in 2005. A total of 800 households with 4,010 individuals were included in the 2013 survey. The prevalence of malaria parasitemia was 12% (348/2,795). Of the individuals who sought treatment of fever, 67% (66/98) reported attending a public provider at least once compared with 46% (349/764) before policy change (P < 0.001). During the 100 visits to healthcare providers, 95% (95) included a blood test for malaria and 74% (64/86) resulted in the recommended antimalarial for the diagnosed species, the corresponding figures before policy change were 48% (433/894) and 23% (78/336). The proportion of individuals seeking treatment more than once fell from 14% (107/764) before policy change to 2% (2/98) after policy change (P = 0.005). The mean indirect cost per fever episode requiring treatment seeking decreased from US$44.2 in 2005 to US$33.8 in 2013 (P = 0.006). The implementation of a highly effective antimalarial treatment was associated with better adherence of healthcare providers in both the public and private sectors and a reduction in clinical malaria and household costs. PMID- 29280425 TI - Characterization of Invasive Salmonella Serogroup C1 Infections in Mali. AB - Nontyphoidal Salmonella (NTS) are the leading cause of foodborne infections worldwide and a major cause of bloodstream infections in infants and HIV-infected adults in sub-Saharan Africa (SSA). Salmonella Typhimurium (serogroup B) and Salmonella Enteritidis (serogroup D) are the most common serovars in this region. However, data describing rarer invasive NTS serovars, particularly those belonging to serogroups C1 and C2, circulating in SSA are lacking. We previously conducted systematic blood culture surveillance on pediatric patients in Bamako, Mali, from 2002 to 2014, and the results showed that serovars Typhimurium and Enteritidis accounted for 32% and 36% of isolates, respectively. Here, we present data on 27 Salmonella serogroup C1 strains that were isolated during this previous study. The strains were typed by serum agglutination and multilocus sequence typing (MLST). Sixteen strains were Salmonella Paratyphi C, four were Salmonella Colindale, and two were Salmonella Virchow. Interestingly, five strains were identified as the very rare Salmonella Brazzaville using a combination of serum agglutination and flagellin gene typing. Phenotypic characterization showed that Salmonella Brazzaville produced biofilm and exhibited catalase activity, which were not statistically different from the gastroenteritis-associated Salmonella Typhimurium sequence type (ST) 19. All tested Salmonella Paratyphi C strains were poor biofilm producers and showed significantly less catalase activity than Salmonella Typhimurium ST19. Overall, our study provides insight into the Salmonella serogroup C1 serovars that cause invasive disease in infants in Mali. In addition, we show that MLST and flagellin gene sequencing, in association with traditional serum agglutination, are invaluable tools to help identify rare Salmonella serovars. PMID- 29280426 TI - Assessing Knowledge, Attitudes, and Preventive Practices Related to Kala-A: A Study of Rural Madhepura, Bihar, India. AB - To assess the knowledge, attitude, and preventive practices related to kala-azar in Madhepura district of Bihar, a community-based cross-sectional study was carried out in November 2014. A total of 353 households were interviewed from 24 villages of four blocks of Madhepura district. Data were collected using structured interview schedule. For knowledge, attitude, and preventive practice indexes, scores were assigned to individual questions based on the accuracy of responses. Univariate and binary logistic regressions were applied for the analysis. Eighty-four percent households had heard of kala-azar disease, but only 15.9% could recognize that sand flies were responsible for transmitting the disease. Overall, only 43.9% had fair knowledge on kala-azar disease (e.g., mode of transmission, signs and symptoms, and the outcome if left untreated) and the vector (breeding place, season, and biting time). Almost 48.6% had a favorable attitude toward treatability and management of kala-azar and 37.7% practiced proper mechanism to prevent and control kala-azar. Occupation emerged as a significant predictor for all three indexes. Other important predictors for the attitude index were literacy, household type, households ever had a kala-azar case, and knowledge index. Despite 61.8% of the households ever reported to have a member diagnosed with kala-azar, the overall knowledge of the disease and vector, attitude, and practices about prevention and control of kala-azar was found to be lagging. Therefore, our investigation suggests that further strengthening of comprehensive knowledge about kala-azar and preventive practices is needed. PMID- 29280427 TI - Evaluating the Recombinant T24H Enzyme-Linked Immunoelectrotransfer Blot Assay for the Diagnosis of Neurocysticercosis in a Panel of Samples from a Large Community-Based Randomized Control Trial in 60 Villages in Burkina Faso. AB - Current guidelines for the diagnosis of neurocysticercosis (NCC) recommend the use of the lentil lectin-bound glycoprotein enzyme-linked immunoelectrotransfer blot assay (LLGP-EITB) as the reference standard for serological testing. In response to the drawbacks involved with the use of the LLGP-EITB, a recombinant T24H antigen (rT24H) EITB assay was developed, with promising results. However, the test has yet to be evaluated among individuals from sub-Saharan Africa (SSA). The aim of the present study was to investigate the performance of the rT24H EITB assay for the detection of NCC cases in a panel of serum samples (N = 366, of which 173 patients presented with epileptic seizures and/or severe chronic headaches, and 193 matched manifestation-free participants) collected as part of a large community-based trial in Burkina Faso. A perfect agreement between the rT24H EITB and the native gp24 (and its homodimer, gp42) LLGP-EITB was found (kappa value of 1.0). Furthermore, among patients with the neurological manifestations of interest who underwent a computed tomography scan, the rT24H EITB and native antigen LLGP-EITB had a comparable ability to correctly identify NCC cases with multiple viable (rT24H: sensitivity: 80.0%), single viable (66.7%), and calcified/degenerating cysts only (25.0%), albeit for multiple viable and calcified cysts, the rT24H estimated sensitivity seemed lower, but more uncertain, than previously reported. The rT24H EITB specificity was high (98.2%) and in line with previous studies. This study confirms the value of the recombinant rT24H EITB as an alternative to the native antigen LLGP-EITB for the diagnosis of NCC in a SSA community setting. PMID- 29280429 TI - Case Report: Carbapenemase-Producing Enterobacteriaceae in an Asylum Seeker with Multidrug-Resistant Tuberculosis. AB - A Syrian asylum seeker with multidrug-resistant tuberculosis (TB) developed a bronchopleural fistula after pneumonectomy. Although screening tests were negative on admission, carbapenemase-producing Enterobacteriaceae were cultured after a few months of TB treatment. Prevalence of multidrug-resistant organisms is reported to be increased in asylum seekers compared with the general Dutch population. Arduous conditions during transit and interrupted health care delivery in our patient led to multiple-resistant microorganisms that complicated treatment. PMID- 29280430 TI - Funduscopy in Cerebral Malaria Diagnosis: An International Survey of Practice Patterns. AB - Cerebral malaria (CM) is a significant cause of mortality and morbidity in sub Saharan Africa, particularly among young children. Malarial retinopathy is the most specific clinical finding in CM, and fundus examination could help clinicians distinguish CM from other causes of encephalopathy in resource-poor areas. To assess clinician knowledge, practice patterns, and barriers to the use of funduscopy in the diagnosis of CM, we designed a descriptive multinational survey of clinicians in malaria endemic areas. Results of this survey showed that 19% of respondents were not aware of the utility of eye examinations for malarial retinopathy, and almost half (49%) never or almost never examine the eyes in cases of suspected CM. Educating clinicians about malarial retinopathy could be important in improving diagnostic specificity for CM. PMID- 29280428 TI - African and Asian Zika Virus Isolates Display Phenotypic Differences Both In Vitro and In Vivo. AB - Zika virus (ZIKV) is a mosquito-borne member of the genus Flavivirus that has emerged since 2007 to cause outbreaks in Africa, Asia, Oceania, and most recently, in the Americas. Here, we used an isolate history as well as genetic and phylogenetic analyses to characterize three low-passage isolates representing African (ArD 41525) and Asian (CPC-0740, SV0127-14) lineages to investigate the potential phenotypic differences in vitro and in vivo. The African isolate displayed a large plaque phenotype (~3-4 mm) on Vero and HEK-293 cells, whereas the Asian isolates either exhibited a small plaque phenotype (~1-2 mm) or did not produce any plaques. In multistep replication kinetics in nine different vertebrate and insect cell lines, the African isolate consistently displayed faster replication kinetics and yielded ~10- to 10,000-fold higher peak virus titers (infectious or RNA copies) compared with the Asian isolates. Oral exposure of Aedes aegypti mosquitoes with the African isolate yielded higher infection and dissemination rates compared with the Asian isolates. Infection of Ifnar1-/- mice with the African isolate produced a uniformly fatal disease, whereas infection with the Asian isolates produced either a delay in time-to-death or a significantly lower mortality rate. Last, the African isolate was > 10,000-fold more virulent than the Asian isolates in an interferon type I antibody blockade mouse model. These data demonstrate substantial phenotypic differences between low-passage African and Asian isolates both in vitro and in vivo and warrant further investigation. They also highlight the need for basic characterization of ZIKV isolates, as the utilization of the uncharacterized isolates could have consequences for animal model and therapeutic/vaccine development. PMID- 29280431 TI - Identification and Functional Validation of a Biomarker for the Diagnosis of Miltefosine Relapse during Visceral Leishmaniasis. AB - Miltefosine is the only orally administrable drug for the treatment of leishmaniasis. But in recent years, a decline in its efficacy points toward the emergence of resistance to this drug. Knowledge of biomarkers for miltefosine resistance may be beneficial for proper selection of treatment regimen. Splenic aspirates were collected and parasites cultured from patients relapsed after initial cure (N = 15) and successfully treated (N = 15) with miltefosine. Differential expression of genes in miltefosine-resistant strains was examined by DNA microarray and validated by real-time reverse transcription polymerase chain reaction and Western blotting. Of 669 upregulated genes, the cysteine protease like protein of calpain family (GenBank: CBZ34784) was found to be significantly overexpressed in resistant parasite strains and only anti-calpain antibodies showed its presence in the sera of relapse patients through Western blotting. Calpain family cysteine protease-like protein can be useful as a potential biomarker of miltefosine unresponsiveness. PMID- 29280432 TI - A Combined Syndromic Approach to Examine Viral, Bacterial, and Parasitic Agents among Febrile Patients: A Pilot Study in Kilombero, Tanzania. AB - The use of fever syndromic surveillance in sub-Saharan Africa is an effective approach to determine the prevalence of both malarial and nonmalarial infectious agents. We collected both blood and naso/oro-pharyngeal (NP/OP) swabs from consecutive consenting patients >= 1 year of age, with an axillary temperature >= 37.5 degrees C, and symptom onset of <= 5 days. Specimens were analyzed using both acute febrile illness (AFI) and respiratory TaqMan array cards (Resp TAC) for multiagent detection of 56 different bloodstream and respiratory agents. In addition, we collected epidemiologic data to further characterize our patient population. We enrolled 205 febrile patients, including 70 children (1 < 15 years of age; 34%) and 135 adults (>= 15 years of age; 66%). AFI TAC and Resp TAC were performed on 191 whole blood specimens and 115 NP/OP specimens, respectively. We detected nucleic acid for Plasmodium (57%), Leptospira (2%), and dengue virus (1%) among blood specimens. In addition, we detected 17 different respiratory agents, most notably, Haemophilus influenzae (64%), Streptococcus pneumonia (56%), Moraxella catarrhalis (39%), and respiratory syncytial virus (11%) among NP/OP specimens. Overall median cycle threshold was measured at 26.5. This study provides a proof-of-concept for the use of a multiagent diagnostic approach for exploratory research on febrile illness and underscores the utility of quantitative molecular diagnostics in complex epidemiologic settings of sub Saharan Africa. PMID- 29280433 TI - CD45RO+ T Cells and T Cell Activation in the Long-Lasting Immunity after Leishmania infantum Infection. AB - Manifestations of Leishmania infantum infection range from asymptomatic to symptomatic visceral leishmaniasis (VL). People with symptomatic VL (sVL) have suppressed immune responses against Leishmania antigens that are reversed after clinical cure. The intradermal leishmanin skin test (LST) is negative during sVL, but it becomes positive after treatment. The aim of this study was to compare T cell responses in individuals with sVL, recovered VL (RecVL), and endemic controls. Endemic controls were household contacts of a VL case and they were grouped by their LST results, either positive (LST+) or negative (LST-). Mononuclear cells were studied ex vivo or after stimulation with soluble Leishmania antigens (SLA); cell surface markers and cytokines were determined. T cells, ex vivo, from individuals with sVL and from LST+ individuals presented a higher activation for CD4+ and CD8+ cells expressing CD69. However, lymphocytes from sVL stimulated with SLA had lower percentages of CD4+ and CD8+ cells expressing CD69 and CD8+ cells expressing CD25, with no release of interferon gamma or tumor necrosis factor. sVL subjects had lower percentage of memory cells (CD4+ CD45RO+), ex vivo, without SLA stimulation than RecVL, LST+, or LST- (P = 0.0022). However, individuals with sVL had fewer regulatory cells after SLA stimulation (CD4+ CD25HIGH, P = 0.04 and CD4+ FOXP3+, P = 0.02) than RecVL. The decrease in specific memory and activated CD4+ and CD8+ cells, as in response to Leishmania antigens, could explain, in part, the immune impairment during sVL. Finally, protective T cell responses are long lasting because both RecVL or LST+ individuals maintain a specific protective response to Leishmania years after the primary infection. PMID- 29280434 TI - Surveillance versus ablation for incidentally diagnosed small renal tumours: the SURAB feasibility RCT. AB - BACKGROUND: There is uncertainty around the appropriate management of small renal tumours. Treatments include partial nephrectomy, ablation and active surveillance. OBJECTIVES: To explore the feasibility of a randomised trial of ablation versus active surveillance. DESIGN: Two-stage feasibility study: stage 1 - clinician survey and co-design work; and stage 2 - randomised feasibility study with qualitative and economic components. METHODS: Stage 1 - survey of radiologists and urologists, and development of patient information materials. Stage 2 - patients identified across eight UK centres with small renal tumours (< 4 cm) were randomised (1 : 1 ratio) to ablation or active surveillance in an unblinded manner. Randomisation was carried out by a central computer system. The primary objective was to determine willingness to participate and to randomise a target of 60 patients. The qualitative and economic data were collected separately. RESULTS: The trial was conducted across eight centres, with a site specific period of recruitment ranging from 3 to 11 months. Of the 154 patients screened, 36 were eligible and were provided with study details. Seven agreed to be randomised and one patient was found ineligible following biopsy results. Six patients (17% of those eligible) were randomised: three patients received ablation and no serious adverse events were recorded. The 3- and 6-month data were collected for four (67%) and three (50%) out of the six patients, respectively. The qualitative substudy identified factors directly impacting on the recruitment of this trial. These included patient and clinician preferences, organisational factors (variation in clinical pathway) and standard treatment not included. The health economic questionnaire was designed and piloted; however, the sample size of recruited patients was insufficient to draw a conclusion on the feasibility of the health economics. CONCLUSIONS: The trial did not meet the criteria for progression and the recruitment rate was lower than hypothesised, demonstrating that a full trial is presently not possible. The qualitative study identified factors that led to variation in recruitment across the sites. Implementation of organisational and operational measures can increase recruitment in any future trial. There was insufficient information to conduct a full economic analysis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31161700. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 81. See the NIHR Journals Library website for further project information. PMID- 29280436 TI - Heterodimers reign in the embryo. AB - Experiments by three independent groups on zebrafish have clarified the role of two signaling factors, Nodal and Gdf3, during the early stages of development. PMID- 29280435 TI - Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm. AB - The noncoding genome is pervasively transcribed. Noncoding RNAs (ncRNAs) generated from enhancers have been proposed as a general facet of enhancer function and some have been shown to be required for enhancer activity. Here we examine the transcription-factor-(TF)-dependence of ncRNA expression to define enhancers and enhancer-associated ncRNAs that are involved in a TF-dependent regulatory network. TBX5, a cardiac TF, regulates a network of cardiac channel genes to maintain cardiac rhythm. We deep sequenced wildtype and Tbx5-mutant mouse atria, identifying ~2600 novel Tbx5-dependent ncRNAs. Tbx5-dependent ncRNAs were enriched for tissue-specific marks of active enhancers genome-wide. Tbx5 dependent ncRNAs emanated from regions that are enriched for TBX5-binding and that demonstrated Tbx5-dependent enhancer activity. Tbx5-dependent ncRNA transcription provided a quantitative metric of Tbx5-dependent enhancer activity, correlating with target gene expression. We identified RACER, a novel Tbx5 dependent long noncoding RNA (lncRNA) required for the expression of the calcium handling gene Ryr2. We illustrate that TF-dependent enhancer transcription can illuminate components of TF-dependent gene regulatory networks. PMID- 29280437 TI - Genomics and 3-Dimensional Brachytherapy for Cervical Cancer: Significant Steps Forward. PMID- 29280438 TI - Salvage Treatment Options for Recurrent Seminoma? PMID- 29280439 TI - Chemotherapy Is the Preferred Treatment for Seminomas Relapsing After First-line Chemotherapy. PMID- 29280440 TI - Regional Therapy Might Have a Role. PMID- 29280441 TI - A House Divided: The Irradiation Versus Prostatectomy Debate Continues. PMID- 29280442 TI - ProtecTing Low-Risk Prostate Cancer. PMID- 29280443 TI - PRADO: A Palliative Care Model for Every Radiation Oncology Practice. PMID- 29280444 TI - Addressing the Challenges of Narrow Network Plans in Oncology. PMID- 29280445 TI - The Influence of Health Insurance Policy on Radiation Oncology Physician SBRT/SABR Use Practices: A North American Survey. AB - PURPOSE: European data suggest that 8-fraction stereotactic body radiation therapy (SBRT) regimens may be similar in efficacy with less toxicity than <=5 fraction SBRT for central lung lesions. However, under current Centers for Medicare and Medicaid Services guidelines, SBRT in the United States (US) is reimbursed for only <=5 fractions, whereas there are no such restrictions for reimbursement in Canada. We hypothesize that US-specific SBRT reimbursement policies influence the use of >=5-fraction SBRT in US academic centers in comparison with comparable Canadian centers. METHODS AND MATERIALS: A 15-question electronic survey was distributed to radiation oncologists at National Cancer Institute-designated cancer centers in the US and the 10 highest research-funded cancer centers in Canada. Fisher exact test or exact logistic regression if applicable was used, where P<.05 was considered statistically different from neutral. RESULTS: Of the 143 radiation oncologists from 60 US cancer centers and 6 Canadian cancer centers who completed the survey (17.6% response rate), 125 routinely prescribe SBRT. Fifty percent of US physicians versus 0% of Canadian physicians indicated that there are instances when they would like to prescribe >5-fraction SBRT but prescribe <=5 fractions because of insurance reimbursement (P=.076 and P=.001, respectively). Seventy percent (P=.006) of US radiation oncologists versus 0% (P=.001) of Canadian radiation oncologists report that SBRT clinical investigation is constrained by the insurance reimbursement. The most common reported deterrent to prescribing >5-fraction SBRT in the US was insurance reimbursement (49.5%). CONCLUSIONS: US radiation oncologists are more likely than those in Canada to report that SBRT clinical investigation and >5-fraction SBRT use may be negatively influenced by health insurance reimbursement; this perception was not held by physicians in Canada. Health care environment may significantly affect radiation therapy decision making and practice patterns. PMID- 29280446 TI - Burnout Evaluation of Radiation Residents Nationwide: Results of a Survey of United States Residents. AB - PURPOSE: To assess rates of burnout among US radiation oncology residents and evaluate program/resident factors associated with burnout. METHODS AND MATERIALS: A nationwide survey was distributed to residents in all US radiation oncology programs. The survey included the Maslach Burnout Index-Human Services Survey (MBI-HSS) as well as demographic and program-specific questions tailored to radiation oncology residents. Primary endpoints included rates of emotional exhaustion, depersonalization, and personal accomplishment from MBI-HSS subscale scores. Binomial logistic models determined associations between various residency/resident characteristics and high burnout levels. RESULTS: Overall, 232 of 733 residents (31.2%) responded, with 205 of 733 (27.9%) completing the MBI HSS. High levels of emotional exhaustion and depersonalization were reported in 28.3% and 17.1%, respectively; 33.1% experienced a high burnout level on at least 1 of these 2 MBI-HSS subscales. Low rates of personal accomplishment occurred in 12% of residents. Twelve residents (5.9%) reported feeling "at the end of my rope" on a weekly basis or more. On multivariable analysis there was a statistically significant inverse association between perceived adequacy of work life balance (odds ratio 0.37; 95% confidence interval 0.17-0.83) and burnout. CONCLUSIONS: Approximately one-third of radiation oncology residents have high levels of burnout symptoms, consistent with previous oncology literature, but lower levels than those among physicians and residents of other specialties. Particularly concerning was that more than 1 in 20 felt "at the end of my rope" on a weekly basis or more. Targeted interventions to identify symptoms of burnout among radiation oncology residents may help to prevent the negative downstream consequences of this syndrome. PMID- 29280447 TI - Recent Trends in Radiation Oncology Fellowship Training in the United States. PMID- 29280448 TI - Effect of Breast Irradiation on Cardiac Disease in Women Enrolled in BCIRG-001 at 10-Year Follow-Up. AB - PURPOSE: To investigate cardiac toxicity associated with breast radiation therapy (RT) at 10-year follow-up in BCIRG-001, a phase 3 trial comparing adjuvant anthracycline chemotherapy (fluorouracil, doxorubicin, and cyclophosphamide) with anthracycline-taxane chemotherapy (docetaxel, doxorubicin, and cyclophosphamide) in women with lymph node-positive early breast cancer. METHODS AND MATERIALS: Prospective data from all 746 patients in the control arm (fluorouracil, doxorubicin, and cyclophosphamide) of BCIRG-001 at 10-year follow-up were obtained from Project Data Sphere. Cardiac toxicities examined included myocardial infarction (MI), heart failure (HF), arrhythmias, and relative and absolute left ventricular ejection fraction decrease of >20% from baseline. Toxicities were compared between patients who received RT versus no RT, left sided RT versus no RT, and internal mammary nodal RT versus no RT. RESULTS: Of the 746 patients, 559 (75%) received RT to a median dose of 50 Gy. Myocardial infarction occurred in 3 RT patients (0.5%) versus 6 no-RT patients (3%) (P=.01). Heart failure was seen in 15 RT patients (2.7%) versus 3 no-RT patients (1.6%) (P=.6). Among these, 35 RT patients (18%) had a left ventricular ejection fraction relative decrease of >20% baseline versus 7 (10%) who did not receive RT (P=.1). Arrhythmias were more common in RT patients (3.2%) versus no-RT patients (0%) (P=.01). On univariable and multivariable analysis HF was not significantly associated with RT, and MI was negatively associated with RT. CONCLUSIONS: In this retrospective analysis of prospective toxicity outcomes, there is an increased risk of arrhythmias but no clear evidence of significantly increased risk of MI or HF at 10 years in lymph node-positive women treated with breast RT and uniform adjuvant doxorubicin-based chemotherapy. Given the low incidence of these outcomes, studies with larger numbers are needed to confirm our findings. PMID- 29280450 TI - Perspectives on Postmastectomy Radiation Therapy for Persistent Nodal Disease After Neoadjuvant Chemotherapy: Is Hindsight 20/20? PMID- 29280449 TI - Postmastectomy Radiation in Breast Cancer Patients With Pathologically Positive Lymph Nodes After Neoadjuvant Chemotherapy: Usage Rates and Survival Trends. AB - PURPOSE: To analyze postmastectomy radiation therapy (PMRT) usage and its association with overall survival (OS) in breast cancer patients with pathologically positive lymph nodes after neoadjuvant chemotherapy (NAC). METHODS AND MATERIALS: Using the National Cancer Database, we identified women with nonmetastatic breast cancer diagnosed from 2004 to 2013 who had received NAC and undergone mastectomy with macroscopic pathologically positive lymph nodes. Joinpoint regression models were used to assess temporal trends in annual PMRT usage. Multivariable regression models were used to identify factors associated with PMRT use. A time-dependent Cox model was used to evaluate the predictors of mortality. RESULTS: The study included 29,270 patients, of whom 62.5% received PMRT. PMRT was markedly underused among all nodal subgroups, in particular, among ypN2 (68.4%) and ypN3 (67.0%) patients. Hispanic patients and those with Medicaid or Medicare insurance were less likely to receive PMRT than were non-Hispanics and patients with other insurance carriers. The adjusted 5-year OS rates were similar in ypN1 and ypN2 patients with or without PMRT but were significantly greater in ypN3 patients receiving PMRT (66% vs 63%; P=.042). On multivariable analysis, PMRT was associated with improved survival only among ypN3 patients after adjusting for patient, facility, and tumor variables (multivariable hazard ratio 0.85; 95% confidence interval 0.74-0.97). CONCLUSIONS: A considerable portion of breast cancer patients with advanced residual nodal disease after NAC did not receive appropriate adjuvant radiation. We also found socioeconomic disparities in national PMRT practice patterns. Patients with ypN3 disease might derive a survival benefit from PMRT. PMID- 29280451 TI - The Problem of Establishing Standards of Care in an Uncommon Malignancy: Brachytherapy for Invasive Penile Carcinoma. PMID- 29280452 TI - Conventional Versus Hypofractionated Radiation Therapy for Localized or Locally Advanced Prostate Cancer: A Systematic Review and Meta-analysis along with Therapeutic Implications. AB - PURPOSE: A systematic review and meta-analysis were conducted to evaluate the therapeutic outcomes of conventional radiation therapy (CRT) and hypofractionated radiation therapy (HRT) for localized or locally advanced prostate cancer (LLPCa). METHODS AND MATERIALS: A total of 599 abstracts were extracted from 5 databases and screened in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Only phase III trials randomized between CRT and HRT in LLPCa with a minimum of 5 years of follow-up data were considered. The evaluated endpoints were biochemical failure, biochemical and/or clinical failure, overall mortality, prostate cancer-specific mortality, and both acute and late gastrointestinal (GI) and genitourinary (GU) (grade >=2) toxicity. RESULTS: Ten trials from 9 studies, with a total of 8146 patients (CRT, 3520; HRT, 4626; 1 study compared 2 HRT schedules with a common CRT regimen), were included in the evaluation. No significant differences were found in the patient characteristics between the 2 arms. However, the RT parameters differed significantly between CRT and HRT (P<.001 for all). The use of androgen deprivation therapy varied from 0% to 100% in both groups (mean +/- standard deviation 43.3% +/- 43.6% for CRT vs HRT; P=NS). The odds ratio, risk ratio, and risk difference (RD) between CRT and HRT for biochemical failure, biochemical and/or clinical failure, overall mortality, prostate cancer-specific mortality, acute GU toxicity, and late GU and GI toxicities were all nonsignificant. Nevertheless, the incidence of acute GI toxicity was 9.1% less with CRT (RD 0.091; odds ratio 1.687; risk ratio 1.470; P<.001 for all). On subgroup analysis, the patient groups with <=66.8% versus >66.8% androgen deprivation therapy (RD 0.052 vs 0.136; P=.008) and <76% versus >=76% full seminal vesicles in the clinical target volume (RD 0.034 vs 0.108; P<.001) were found to significantly influence the incidence of acute GI toxicity with HRT. CONCLUSIONS: HRT provides similar therapeutic outcomes to CRT in LLPCa, except for a significantly greater risk of acute GI toxicity. HRT enables a reduction in the overall treatment time and offers patient convenience. However, the variables contributing to an increased risk of acute GI toxicity require careful consideration. PMID- 29280454 TI - Doing the Right Thing for the Wrong Reason. PMID- 29280453 TI - Multicenter Randomized Double-Blind, Placebo-Controlled Trial GORTEC (Groupe Oncologie Radiotherapie Tete et Cou) 2009-01 Evaluating the Effect of the Regenerating Agent on Radiodermatitis of Head and Neck Cancer Patients. AB - PURPOSE: Concomitant cetuximab and radiation therapy (RT) can induce severe radiodermatitis in patients with head and neck cancer (HNC). OTD70DERM, a regenerating agent (RGTA), is a structural and functional analogue of glycosaminoglycans. Preclinical studies have shown that topical RGTA can markedly reduce radiation-induced mucosal and cutaneous toxicities without tumor protection. The present study aimed to evaluate the effect of topical RGTA on radiodermatitis in patients with HNC undergoing RT and cetuximab, for whom RT induced skin reactions are frequent and/or severe. The primary endpoint was the incidence of grade >=2 radiodermatitis. METHODS AND MATERIALS: We performed a multicenter, randomized, double-blind, placebo-controlled trial of patients with newly diagnosed HNC undergoing conventionally fractionated RT (70 Gy in 35 fractions) and weekly cetuximab. Patients were randomized 1:1 to receive topical OTD70DERM or placebo on irradiated skin once daily. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to evaluate radiodermatitis (photographs of radiation zone). The Dermatology Life Quality Index score was also evaluated. All the skin reactions seen on the photographs were scored independently by 2 outside experts. RESULTS: Of the 76 randomized patients (38 in each arm), 72 were available for the final radiodermatitis evaluation (37 in the RGTA arm and 35 in the placebo arm). No significant difference was observed concerning the incidence or duration of grade >=2 radiodermatitis between the 2 arms (81% for RGTA vs 80% for placebo; P=.9). Also, no significant difference was found between the 2 arms regarding grade >=2 radiodermatitis evaluated by the 2 experts using the photographs of 68 patients (76% vs 74%; P=.78). Finally, no significant difference was found in the Dermatology Life Quality Index score (score >10, 15% vs 20%; P=.45). CONCLUSIONS: Despite the good preclinical rationale, RGTA did not reduce the incidence and severity of radiodermatitis in patients with HNC. PMID- 29280455 TI - A Detailed Dosimetric Analysis of Spinal Cord Tolerance in High-Dose Spine Radiosurgery. AB - OBJECTIVE: Dose-volume tolerance of the spinal cord (SC) in spinal stereotactic radiosurgery (SRS) is difficult to define because radiation myelitis rates are low, and published reports document cases of myelopathy but do not account for the total number of patients treated at given dose-volume combinations who do not have myelitis. This study reports SC toxicity from single-fraction spinal SRS and presents a comprehensive atlas of the incidence of adverse events to examine dose volume predictors. METHODS AND MATERIALS: A prospective database of all patients undergoing single-fraction spinal SRS at our institution between 2004 and 2011 was reviewed. SC toxicity was defined by clinical myelitis with accompanying magnetic resonance imaging (MRI) signal changes that were not attributable to tumor progression. Dose-volume histogram (DVH) atlases were created for these endpoints. Rates of adverse events with 95% confidence limits and probabilities that rates of adverse events were <2% and <5% for myelitis were determined as functions of dose and absolute volume. RESULTS: Information about DVH and myelitis was available for 228 patients treated at 259 sites. The median follow up time was 14.6 months (range, 0.1-138.3 months). The median prescribed dose to the planning treatment volume was 24 Gy (range, 18-24 Gy). There were 2 cases of radiation myelitis (rate r=0.7%) with accompanying MRI signal changes. Myelitis occurred in 2 patients, with Dmax >13.33 Gy, and minimum doses to the hottest 0.1, 0.2, 0.5, and 1 cc were >10.66, 10.9, and 8 Gy, respectively; however, both myelitis cases occurred below the 34th percentile for Dmax and there were 194 DVHs in total with Dmax >13.33 Gy. CONCLUSIONS: A median SC Dmax of 13.85 Gy is safe and supports that a Dmax limit of 14 Gy carries a low <1% rate of myelopathy. No dose-volume thresholds or relationships between SC dose and myelitis were apparent. This is the largest study examining dosimetric data and radiation-induced myelitis in de novo spine SRS. PMID- 29280456 TI - Magnetic Resonance Image Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: An Experience From a Tertiary Cancer Center in a Low and Middle Income Countries Setting. AB - PURPOSE: To determine the clinical impact of magnetic resonance image guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC) (stages II and III) in a tertiary care cancer hospital in a low and middle income countries setting. METHODS AND MATERIALS: Ninety-four LACC patients enrolled in a prospective EMBRACE (An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer) protocol treated with external radiation therapy (45 Gy in 25 fractions) with or without weekly cisplatin, followed by magnetic resonance IGABT (4 fractions of 7 Gy), were analyzed in detail for dosimetric and clinical outcomes including late toxicities. RESULTS: The mean (+/ standard deviation) high-risk clinical target volume (HR-CTV) at the first session of brachytherapy and at the second session of brachytherapy for the current study cohort was 46.94 +/- 24.6 cm3 and 42.7 +/- 22.5 cm3, respectively, with mean minimum dose received by 90% volume (D90) of 88.3 +/- 4.4 equivalent 2 Gy fractionation (GyEQD2). At median follow-up (39 months), the local control rate (LCR) and overall progression-free survival rate were 90.1% +/- 3.4% and 72.1% +/- 4.8%, respectively, with grade 3 bladder toxicity in 3% of patients and rectum toxicity in 9%. The LCR at 39 months was significantly better in patients with stage IIB and IVA disease versus stage IIIB disease (100% vs 85%, P=.013). Local failures were limited to stage IIIB only and were associated with significantly larger HR-CTVs at brachytherapy (70 +/- 25.7 cm3 vs 44.3 +/- 21.9 cm3, P=.01) but not with HR-CTV D90 doses (which were similar for patients who had local failures vs those who did not: 86.3 +/- 3.9 alpha/beta equal to 10 Gy (Gy10) vs 88.5 +/- 5 alpha/beta equal to 10 Gy, P=.987). CONCLUSIONS: IGABT leads to a significant improvement in LCR and overall progression-free survival in LACC and should be considered for wider implementation in developing countries to improve outcomes. PMID- 29280457 TI - Reirradiation for Recurrent Pediatric Central Nervous System Malignancies: A Multi-institutional Review. AB - PURPOSE: Reirradiation has been proposed as an effective modality for recurrent central nervous system (CNS) malignancies in adults. We evaluated the toxicity and outcomes of CNS reirradiation in pediatric patients. METHODS AND MATERIALS: The data from pediatric patients <21 years of age at the initial diagnosis who developed a recurrent CNS malignancy that received repeat radiation therapy (RT) across 5 facilities in an international pediatric research consortium were retrospectively reviewed. RESULTS: Sixty-seven pediatric patients underwent CNS reirradiation. The primary diagnoses included medulloblastoma/primitive neuroectodermal tumor (n=20; 30%), ependymoma (n=19; 28%), germ cell tumor (n=8; 12%), high-grade glioma (n=9; 13%), low-grade glioma (n=5; 7%), and other (n=6; 9%). The median age at the first course of RT was 8.5 years (range 0.5-19.5) and was 12.3 years (range 3.3-30.2) at reirradiation. The median interval between RT courses was 2.0 years (range 0.3-16.5). The median radiation dose and fractionation in equivalent 2-Gy fractions was 63.7 Gy (range 27.6-74.8) for initial RT and 53.1 Gy (range 18.6-70.1) for repeat RT. The relapse location was infield in 52 patients (78%) and surrounding the initial RT field in 15 patients (22%). Thirty-seven patients (58%) underwent gross or subtotal resection at recurrence. The techniques used for reirradiation were intensity modulated RT (n=46), 3-dimensional conformal RT (n=9), stereotactic radiosurgery (n=4; 12-13 Gy * 1 or 5 Gy * 5), protons (n=4), combined modality (n=3), 2-dimensional RT (n=1), and brachytherapy (n=1). Radiation necrosis was detected in 2 patients after the first RT course and 1 additional patient after reirradiation. Six patients (9%) developed secondary neoplasms after initial RT (1 hematologic, 5 intracranial). One patient developed a secondary neoplasm identified shortly after repeat RT. The median overall survival after completion of repeat RT was 12.8 months for the entire cohort and 20.5 and 8.4 months for patients with recurrent ependymoma and medulloblastoma after reirradiation, respectively. CONCLUSIONS: CNS reirradiation in pediatric patients could be a reasonable treatment option, with moderate survival noted after repeat RT. However, prospective data characterizing the rates of local control and toxicity are needed. PMID- 29280458 TI - Radiation Therapy for Optic Pathway and Hypothalamic Low-Grade Gliomas in Children. AB - PURPOSE: The long-term survival of pediatric patients with optic pathway or hypothalamic low-grade glioma (LGG) who receive radiation therapy (RT) has not been previously assessed. METHODS AND MATERIALS: A retrospective study was performed of all patients with optic-hypothalamic pediatric LGG treated with RT at a single institution. Eligible patients were aged <=21 years at the time of RT and had localized LGG diagnosed by neuroimaging or histology. The median RT dose was 54 Gy, delivered in 30 fractions. Event-free survival (EFS) was defined as survival without progression or secondary high-grade glioma. Days were counted from the first day of RT. RESULTS: Eighty-nine patients were included in the study, with a median follow-up period of 12.5 years. Of the patients, 14 had neurofibromatosis type 1 (NF-1). The 10-year EFS rate was 61.9% (95% confidence interval [CI], 31.2%-82.1%) for patients with NF-1 and 67.5% (95% CI, 54.8% 77.3%) for those without NF-1. The 10-year overall survival rate was 92.3% (95% CI, 56.6%-98.9%) for patients with NF-1 and 98.4% (95% CI, 89.1%-99.8%) for those without NF-1. Pre-RT chemotherapy (which was more commonly given to younger patients) was associated with reduced EFS, whereas younger age was associated with reduced overall survival. Possible RT-induced neoplasms developed in 8 patients, including 4 with NF-1. The 10-year cumulative incidence of clinically significant vasculopathy was 7.1% (95% CI, 2.9%-13.9%); vasculopathy did not develop in any child aged >10 years at the commencement of RT. CONCLUSIONS: RT is an effective treatment for optic-hypothalamic LGG. Older children without NF-1 have a low risk of late toxicity. RT can be considered for selected younger patients or individuals with NF-1 as a salvage treatment after progression. PMID- 29280459 TI - Update of a Prospective Study of Stereotactic Body Radiation Therapy for Post Chemoradiation Residual Disease in Stage II/III Non-Small Cell Lung Cancer. AB - PURPOSE: To report long-term outcomes (risk of late toxicities, local control, and survival) of dose escalation by stereotactic radiation therapy boost to residual fluorodeoxyglucose positron emission tomography-positive residual disease after chemoradiation (CRT) in stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with stage IIB/III NSCLC underwent computed tomography or positron emission tomography-computed tomography screening approximately 1 month after completion of CRT. Limited residual disease (<=5 cm) within the site of the primary tumor received a stereotactic radiation therapy boost of either 10 Gy * 2 fractions or 6.5 Gy * 3 fractions to the primary tumor, to achieve a total Biologically Equivalent Dose >100 Gy. RESULTS: Thirty-seven patients received protocol therapy. With a median follow-up of 25.2 months, the crude local control rate for the entire group was 78% (n=29), but 10 patients (29%) and 24 patients (65%) developed regional and metastatic disease, respectively. At last follow-up, 5 patients (13.5%) remain alive, all with no evidence of disease, whereas 27 (73%) died of disease and the remaining 5 (13.5%) died of other causes. Median overall survival (OS) for the entire group was 25.2 months. Predictors for grade 3 pneumonitis included age and mean lung dose. Poorer median OS was associated with histology: median OS 15.6 months for squamous cell versus 34.8 months for other histologies (large cell neuroendocrine tumors excluded) (P=.04). The median progression-free survival was 6 months, with IIIB disease having significantly worse median progression-free survival (stages IIB/IIA being 9.4 months, vs 4.7 months for stage IIIB [P=.03]). CONCLUSIONS: Stereotactic radiation therapy boost after CRT is a safe treatment resulting in improvements in local control for locally advanced NSCLC. No additional late toxicities were seen. Possible improvement in OS was found, but further study in a larger prospective trial is needed. PMID- 29280460 TI - Preoperative Chemoradiation Therapy Does Not Increase Risk of Anastomotic Leak in Patients With Gastric Cancer. AB - INTRODUCTION: We sought to determine whether preoperative chemoradiation therapy or chemotherapy increases the risk of anastomotic leak after gastrectomy in gastric cancer patients without gastroesophageal junction involvement. METHODS: We reviewed data from a prospectively maintained database of patients who underwent gastrectomy at our institution between 2001 and 2016. The incidence of anastomotic leak and symptomatic intra-abdominal fluid collection was determined and tested for associations with the type of preoperative therapy. Risk factors for these adverse events were identified by univariate and multivariable logistic regression models. RESULTS: Of 346 included patients, 35% had upfront surgery, 44% had preoperative chemoradiation therapy, and 21% had preoperative chemotherapy. Anastomotic leak and intra-abdominal fluid collection were diagnosed in 3.5% and 7.5% of patients, respectively. Multivariable analysis revealed that concomitant organ resection was the only significant risk factor for anastomotic leak or intra-abdominal fluid collection (P=.014). The type of preoperative therapy was not a risk factor for anastomotic leak or intra abdominal fluid collection. CONCLUSIONS: Anastomotic leak and intra-abdominal fluid collection were rare after gastrectomy, and neither type of preoperative therapy increased the risk of these adverse events. Our results add to the existing literature that preoperative therapy, including preoperative chemoradiation therapy, is safe for patients with gastric cancer. PMID- 29280461 TI - Comparative Outcomes After Definitive Chemoradiotherapy Using Proton Beam Therapy Versus Intensity Modulated Radiation Therapy for Esophageal Cancer: A Retrospective, Single-Institutional Analysis. AB - PURPOSE: To compare clinical outcomes between proton beam therapy (PBT) and intensity modulated radiation therapy (IMRT) in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT). METHODS AND MATERIALS: From 2007 through 2014, 343 EC patients who received definitive CRT with either PBT (n=132) or IMRT (n=211) were retrospectively analyzed. Survival, recurrence, and treatment toxicity were compared between groups. A Cox proportional hazards regression model was performed to test the association between patient/treatment variables and survival. RESULTS: Patient/treatment variables were overall well balanced, except for age and race. Compared with IMRT, PBT had significantly better overall survival (OS; P=.011), progression-free survival (PFS; P=.001), distant metastasis-free survival (DMFS; P=.031), as well as marginally better locoregional failure-free survival (LRFFS; P=.075). No significant differences in rates of treatment-related toxicities were observed between groups. On multivariate analysis, IMRT had worse OS (hazard ratio [HR] 1.454; P=.01), PFS (HR 1.562; P=.001), and LRFFS (HR 1.461; P=.041) than PBT. Subgroup analysis by clinical stage revealed considerably higher 5-year OS (34.6% vs 25.0%, P=.038) and PFS rates (33.5% vs 13.2%, P=.005) in the PBT group for patients with stage III disease. However, no significant intergroup differences in survival were identified for stage I/II patients. CONCLUSIONS: Compared with IMRT, PBT might be associated with improved OS, PFS, and LRFFS, especially in EC patients with locally advanced disease. These results need confirmation by prospective studies. PMID- 29280462 TI - Optimizing Dose Per Fraction: A New Chapter in the Story of the Abscopal Effect? PMID- 29280463 TI - Cavernous Nerve Injury by Radiation Therapy May Potentiate Erectile Dysfunction in Rats. AB - PURPOSE/OBJECTIVES: Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiation therapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients experience RiED within 3 to 5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED; however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are postganglionic parasympathetic nerves located beside the prostate gland that assist in penile erection. This study was designed to investigate the role of CN injury, tissue damage, and altered signaling pathways in an RiED rat model. METHODS AND MATERIALS: Male rats were exposed to a single dose of 25 Gy prostate-confined RT. Erectile function was evaluated by intracavernous pressure (ICP) measurements conducted both 9 and 14 weeks after RT. Neuronal injury was evaluated in the CN using quantitative polymerase chain reaction, conduction studies, transmission electron microscopy, and immunoblotting. Masson trichrome staining was performed to elucidate fibrosis level in penile tissues. RESULTS: There were significant alterations in the ICP (P<.0001) of RT rats versus non-RT rats. TEM analysis showed decreased myelination, increased microvascular damage, and progressive axonal atrophy of the CN fibers after RT. Electrophysiologic analysis showed significant impairment of the CN conduction velocity after RT. RT also significantly increased RhoA/Rho associated protein kinase 1 (ROCK1) mRNA and protein expression. In addition, penile tissue showed increased apoptosis and fibrosis 14 weeks after RT. CONCLUSIONS: RT-induced CN injury may contribute to RiED; this is therefore a rationale for developing novel therapeutic strategies to mitigate CN and tissue damage. Moreover, further investigation of the RhoA/ROCK pathway's role in mitigating RiED is necessary. PMID- 29280464 TI - Adaptive Radiation Therapy: Off-Line, On-Line, and In-Line? PMID- 29280465 TI - Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography for Prostate Cancer: Distribution of Disease and Implications for Radiation Therapy Planning. AB - PURPOSE: To explore the prostate-specific membrane antigen (PSMA)-avid distribution of prostate cancer (PC) on positron emission tomography (PET), both at the time of initial diagnosis and at the time of relapse after definitive local treatment. METHODS AND MATERIALS: A total of 179 PSMA PET scans in patients with nil or <=3 lesions on conventional imaging were retrospectively categorized into 3 subgroups: group A, high-risk PC with no prior definitive therapy (n=34); group B, prior prostatectomy (n=75); and group C, prior radiation therapy (n=70). The numbers and locations of the PSMA-avid lesions were mapped. The PSMA-positive lesions were identified subjectively by a nuclear medicine physician on the basis of clinical experience and taking into account the recent literature and artefacts. RESULTS: A total of 893 PSMA-avid lesions were identified; at least 1 lesion was detected in 80% of all scans. A high detection rate was present even at very low serum PSA levels (eg, at PSA <=0.20 ng/mL in group B, the detection rate was 46%). Thirty-eight percent of studies revealed extrapelvic disease (41%, 31%, and 46% in groups A, B, and C, respectively). Almost one-third of all studies showed only oligometastases (24%, 36%, and 31% in groups A, B, and C, respectively). A large proportion of these (40%) were a solitary lesion. CONCLUSIONS: Prostate-specific membrane antigen PET demonstrated a large number of otherwise unknown metastatic lesions. Therefore we recommend PSMA PET for more accurate assessment of disease burden in initial staging of high-risk PC, as well as for restaging in patients with prostate-specific antigen relapse after primary therapies. Furthermore, a high proportion of oligometastases on PSMA PET provides a prime opportunity to investigate the role of targeted local therapies for oligometastatic PCs. PMID- 29280466 TI - Image Distortions on a Plastic Interstitial Computed Tomography/Magnetic Resonance Brachytherapy Applicator at 3 Tesla Magnetic Resonance Imaging and Their Dosimetric Impact. AB - PURPOSE: To quantify magnetic resonance imaging (MRI) distortions on a plastic intracavitary/interstitial applicator with plastic needles at a field strength of 3 T and to determine the dosimetric impact, using patient data. METHODS AND MATERIALS: For 11 cervical cancer patients, our clinical MRI protocol was extended with 3 scans. From the first scan, a multi-echo acquisition, a map of the magnetic field (B0) was calculated and used to quantify the field inhomogeneity. The expected displacements of the applicator were quantified for the clinical sequence using the measured field inhomogeneity and the clinical sequence's bandwidth. The second and third scan were our routine clinical sequence (duration: <5 minutes each), acquired consecutively using opposing readout directions. The displacement of the applicator between these scans is approximately twice the displacement due to B0 inhomogeneity. The impact of the displacement on the dose was determined by reconstructing the applicator on both scans. The applicator was then shifted and rotated the same distance as the observed displacement to create a worst-case scenario (ie, twice the actual displacement due to B0 inhomogeneity). Next, the dose to 98%/90% (D98/D90) of the clinical target volume at high risk, as well as the dose to the most irradiated 2 cm3 for bladder and rectum, were calculated for the original plan as well as the shifted plan. RESULTS: For a volume of interest containing the intrauterine device and the ovoids the 95th percentile of the absolute displacement ranged between 0.2 and 0.75 mm, over all patients. For all patients, the difference in D98/D90 in the opposing readout scans with the original plan was at most 4.7%/4.3%. For the dose to the most irradiated 2 cm3 of bladder/rectum, the difference was at most 6.0%/6.3%. CONCLUSIONS: The dosimetric impact of distortions on this plastic applicator with plastic needles is limited. Applicator reconstruction for brachytherapy planning purposes is feasible at 3 T MRI. PMID- 29280467 TI - Potential of Proton Therapy to Reduce Acute Hematologic Toxicity in Concurrent Chemoradiation Therapy for Esophageal Cancer. AB - PURPOSE: Radiation therapy dose escalation using a simultaneous integrated boost (SIB) is predicted to improve local tumor control in esophageal cancer; however, any increase in acute hematologic toxicity (HT) could limit the predicted improvement in patient outcomes. Proton therapy has been shown to significantly reduce HT in lung cancer patients receiving concurrent chemotherapy. Therefore, we investigated the potential of bone marrow sparing with protons for esophageal tumors. METHODS AND MATERIALS: Twenty-one patients with mid-esophageal cancer who had undergone conformal radiation therapy (3D50) were selected. Two surrogates for bone marrow were created by outlining the thoracic bones (bone) and only the body of the thoracic vertebrae (TV) in Eclipse. The percentage of overlap of the TV with the planning treatment volume was recorded for each patient. Additional plans were created retrospectively, including a volumetric modulated arc therapy (VMAT) plan with the same dose as for 3D50; a VMAT SIB plan with a dose prescription of 62.5 Gy to the high-risk subregion within the planning treatment volume; a reoptimized TV-sparing VMAT plan; and a proton therapy plan with the same SIB dose prescription. The bone and TV dose metrics were recorded and compared across all plans and variations with respect to PTV and percentage of overlap for each patient. RESULTS: The 3D50 plans showed the highest bone mean dose and TV percentage of volume receiving >=30 Gy (V30Gy) for each patient. The VMAT plans irradiated a larger bone V10Gy than did the 3D50 plans. The reoptimized VMAT62.5 VT plans showed improved sparing of the TV volume, but only the proton plans showed significant sparing for bone V10Gy and bone mean dose, especially for patients with a larger PTV. CONCLUSIONS: The results of the present study have shown that proton therapy can reduced bone marrow toxicity. PMID- 29280468 TI - Superiority in Robustness of Multifield Optimization Over Single-Field Optimization for Pencil-Beam Proton Therapy for Oropharynx Carcinoma: An Enhanced Robustness Analysis. AB - PURPOSE: To compare the difference in robustness of single-field optimized (SFO) and robust multifield optimized (rMFO) proton plans for oropharynx carcinoma patients by an improved robustness analysis. METHODS AND MATERIALS: We generated rMFO proton plans for 11 patients with oropharynx carcinoma treated with SFO intensity modulated proton therapy with simultaneous integrated boost prescription. Doses from both planning approaches were compared for the initial plans and the worst cases from 20 optimization scenarios of setup errors and range uncertainties. Expected average dose distributions per range uncertainty were obtained by weighting the contributions from the respective scenarios with their expected setup error probability, and the spread of dose parameters for different range uncertainties were quantified. Using boundary dose distributions created from 56 combined setup error and range uncertainty scenarios and considering the vanishing influence of setup errors after 30 fractions, we approximated realistic worst-case values for the total treatment course. Error bar metrics derived from these boundary doses are reported for the clinical target volumes (CTVs) and organs at risk (OARs). RESULTS: The rMFO plans showed improved CTV coverage and homogeneity while simultaneously reducing the average mean dose to the constrictor muscles, larynx, and ipsilateral middle ear by 5.6 Gy, 2.0 Gy, and 3.9 Gy, respectively. We observed slightly larger differences during robustness evaluation, as well as a significantly higher average brainstem maximum and ipsilateral parotid mean dose for SFO plans. For rMFO plans, the range uncertainty-related spread in OAR dose parameters and many error bar metrics were found to be superior. The SFO plans showed a lower global maximum dose for single-scenario worst cases and a slightly lower mean oral cavity dose throughout. CONCLUSIONS: An enhanced robustness analysis has been proposed and implemented into clinical systems. The benefit of better CTV coverage and OAR dose sparing in oropharynx carcinoma patients by rMFO compared with SFO proton plans is preserved in a robustness analysis with consideration of setup error and range uncertainty. PMID- 29280469 TI - In Regard to Vashistha et al. PMID- 29280470 TI - In Reply to van der Steen-Banasik et al. PMID- 29280474 TI - Anemia in Pregnancy: A Pragmatic Approach. AB - Importance: Anemia is common in pregnancy, ranging from 5.4% in developed countries to more than 80% in developing countries. Anemia in pregnancy has been associated with prematurity, low birth weight, and adverse pregnancy outcomes. Objective: This review uses clinical vignettes to illustrate the clinical presentations, approach to diagnosis, maternal and fetal implications, and treatment for the common etiologies of anemia in pregnancy. Evidence Acquisition: Literature review. Results: Normal physiological changes in pregnancy result in alterations of hematological parameters particularly in a reduction of hemoglobin (Hb) concentration. Consequently, the Hb used to define anemia in pregnancy is lower than in nonpregnant patients. As there is an increased requirement of iron in pregnancy, it is not unexpected that iron deficiency remains the most common cause of anemia and warrants a preemptive approach to prevent a further reduction in Hb. The syndromes associated with microangiopathic hemolytic anemia may pose a diagnostic challenge, as there are several potential etiologies that may be difficult to differentiate, and microangiopathic hemolytic anemia can be associated with significant maternal and fetal morbidity andmortality. Anemia secondary to sickle cell disease and autoimmune hemolytic anemiamerit special attention because there are risks secondary to red blood cell transfusion and risks to withholding transfusion. Conclusions: Anemia in pregnancy is potentially associated with maternal and fetal adverse outcomes. Providing evidence-based care is essential to achieving the best pregnancy outcomes. PMID- 29280473 TI - The Safety of Low-Molecular-Weight Heparin During and After Pregnancy. AB - Importance: In industrialized countries, venous thromboembolism remains a leading cause of mortality in pregnant women. Low-molecular-weight heparin (LMWH) is the most commonly recommended anticoagulant in pregnancy, having been proven effective and safe in multiple prospective clinical trials. Objective: The aim of this article is to outline existing recommendations for proper use of LMWH in pregnancy and data on risks of LMWH. Evidence Acquisition: Wereviewed guidelines froma number of professional societies.We also examined the current literature behind the various risks associated with LMWH use. Results: Our review outlines the current data that guide the use of LMWH in pregnancy. With prophylactic dosing, LMWH comes with a 0.5% risk of antepartum bleeding and a 1% risk of postpartum hemorrhage that is not different from clinical trial controls. With treatment dosing, there is a 1.5% risk of antepartum bleeding and a 2% risk of postpartum hemorrhage. Overall, current evidence behind these risks is limited, and this review suggests areas of further study moving forward. PMID- 29280475 TI - The comparative efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. A Cochrane systematic review with meta-analysis and trial sequential analysis. AB - We compared the efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. Our outcomes were: recovery time from second twitch to train-of-four ratio > 0.9; recovery time from post-tetanic count 1-5 to train-of-four ratio > 0.9; and risk of composite adverse and serious adverse events. We searched for randomised clinical trials irrespective of publication status and date, blinding status, outcomes reported or language. We included 41 studies with 4206 participants. Time to reversal of neuromuscular blockade from second twitch to a train-of-four ratio > 0.9 was 2.0 min with sugammadex 2 mg.kg 1 and 12.9 min with neostigmine 0.05 mg.kg-1 , with a mean difference (MD) (95%CI)) of 10.2 (8.5-12.0) (I2 = 84%, 10 studies, n = 835, Grades of Recommendation, Assessment, Development and Evaluation (GRADE): moderate quality). Time to reversal of neuromuscular blockade from a post-tetanic count of 1-5 to a train-of-four ratio > 0.9 was 2.9 min with sugammadex 4 mg.kg-1 and 48.8 min with neostigmine 0.07 mg.kg-1 , with a MD (95%CI) of 45.8 (39.4-52.2) (I2 = 0%, 2 studies, n = 114, GRADE: low quality). There were significantly fewer composite adverse events in the sugammadex group compared with neostigmine, with a risk ratio (95%CI) of 0.60 (0.49-0.74) (I2 = 40%, 28 studies, n = 2298, number needed to treat (NNT): 8, GRADE: moderate quality). Specifically, the risk of bradycardia (RR (95%CI) 0.16 (0.07-0.34), n = 1218, NNT: 14, GRADE: moderate quality), postoperative nausea and vomiting (RR (95%CI) 0.52 (0.28-0.97), n = 389, NNT: 16, GRADE: low quality) and overall signs of postoperative residual paralysis (RR (95%CI) 0.40 (0.28-0.57), n = 1474, NNT: 13, GRADE: moderate quality) were all reduced. There was no significant difference regarding the risk of serious adverse events (RR 0.54, 95%CI 0.13-2.25, I2 = 0%, n = 959, GRADE: low quality). Sugammadex reverses neuromuscular blockade more rapidly than neostigmine and is associated with fewer adverse events. PMID- 29280476 TI - Protein-engineering of chitosanase from Bacillus sp. MN to alter its substrate specificity. AB - Partially acetylated chitosan oligosaccharides (paCOS) have various potential applications in agriculture, biomedicine, and pharmaceutics due to their suitable bioactivities. One method to produce paCOS is partial chemical hydrolysis of chitosan polymers, but that leads to poorly defined mixtures of oligosaccharides. However, the effective production of defined paCOS is crucial for fundamental research and for developing applications. A more promising approach is enzymatic depolymerization of chitosan using chitinases or chitosanases, as the substrate specificity of the enzyme determines the composition of the oligomeric products. Protein-engineering of these enzymes to alter their substrate specificity can overcome the limitations associated with naturally occurring enzymes and expand the spectrum of specific paCOS that can be produced. Here, engineering the substrate specificity of Bacillus sp. MN chitosanase is described for the first time. Two muteins with active site substitutions can accept N-acetyl-D glucosamine units at their subsite (-2), which is impossible for the wildtype enzyme. PMID- 29280477 TI - Mood disorders and prospective suicidality in young adults: a population-based cohort study. AB - OBJECTIVE: To assess the prospective associations of mood disorders and suicidality in a community sample of young adults from south Brazil. METHOD: Prospective population-based cohort study. Young adults (18-24 years old) were recruited and followed up on 5 years later; people were interviewed at their homes. Suicidality, as well as mood and anxiety disorders, was assessed using the Mini-International Neuropsychiatric Interview. The impact of mood episodes on suicidality was both evaluated when they occurred in the same wave (a current episode) and when suicidality occurred prospectively, with suicidality measured at follow-up (a past episode). RESULTS: The sample included 1560 young adults at baseline, with 1244 reassessed at follow-up (80.6%). Depressive episodes, both current and past, had a significant impact on suicidality in the final multivariable model. Manic episodes, however, were less consistently associated with suicidality. CONCLUSION: Depressive episodes have a strong, independent, and robust association with prospective suicidality. The association between manic episodes and suicidality, on the other hand, was dependent on the analysis and deserves further exploration. PMID- 29280478 TI - Convergent evolution of floral shape tied to pollinator shifts in Iochrominae (Solanaceae). AB - Flower form is one of many floral features thought to be shaped by pollinator mediated selection. Although the drivers of variation in flower shape have often been examined in microevolutionary studies, relatively few have tested the relationship between shape evolution and shifts in pollination system across clades. In the present study, we use morphometric approaches to quantify shape variation across the Andean clade Iochrominae and estimate the relationship between changes in shape and shifts in pollination system using phylogenetic comparative methods. We infer multiple shifts from an ancestral state of narrow, tubular flowers toward open, bowl-shaped, or campanulate flowers as well as one reversal to the tubular form. These transitions in flower shape are significantly correlated with changes in pollination system. Specifically, tubular forms tend to be hummingbird-pollinated and the open forms tend to be insect-pollinated, a pattern consistent with experimental work as well as classical floral syndromes. Nonetheless, our study provides one of the few empirical demonstrations of the relationship between flower shape and pollination system at a macroevolutionary scale. PMID- 29280480 TI - Identification of process conditions influencing protein aggregation in Chinese hamster ovary cell culture. AB - Protein aggregation of monoclonal antibodies (mAbs) is a common phenomenon associated with the production of these biopharmaceuticals. These aggregates can lead to adverse side effects in patients upon administration, thus expensive downstream processing steps to remove the higher molecular weight species are inevitable. A preferable approach is to reduce the level of aggregation during bioprocessing by a careful adjustment of critical process parameters. Recently, new analytical methods enabled characterization of mAb aggregation during bioprocessing of mammalian cells. Furthermore, rapid and efficient bioprocess optimization has been performed using design of experiments (DoE) strategies. In this work, we describe a DoE-based approach for the analysis of process parameters and cell culture additives influencing protein aggregation in Chinese hamster ovary (CHO) cell cultures. Important bioprocess variables influencing the aggregation of mAb and host cell proteins were identified in initial screening experiments. Response surface modeling was further applied in order to find optimal conditions for the reduction of protein aggregation during cell culture. It turned out that a temperature-shift to 31 degrees C, osmolality above 420 mOsm/kg, agitation at 100 rpm and 0.04% (w/v) antifoam significantly reduced the level of aggregates without substantial detrimental effects on cell culture performance in our model system. Finally, the aggregation reducing conditions were verified and applied to another production system using a different bioprocess medium and another CHO cell line producing another mAb. Our results show that protein aggregation can be controlled during cell culture and helps to improve bioprocessing of mAbs, by giving insights into the protein aggregation at its origin in mammalian cell culture. PMID- 29280479 TI - Assisted reproductive technology (ART) cumulative live birth rates following preimplantation genetic diagnosis for aneuploidy (PGD-A) or morphological assessment of embryos: A cohort analysis. AB - BACKGROUND: Preimplantation genetic diagnosis for aneuploidy (PGD-A) for all 24 chromosomes improves implantation and clinical pregnancy rates per single assisted reproductive technology (ART) cycle. However, there is limited data on the live-birth rate of PGD-A over repeated cycles. AIM: To assess the cumulative live-birth rates (CLBR) of PGD-A compared with morphological assessment of embryos of up to three 'complete ART cycles' (fresh plus frozen/thaw cycles) in women aged 37 years or older. MATERIALS AND METHODS: A retrospective cohort study of ART treatments undertaken by ART-naive women at a large Australian fertility clinic between 2011 and 2014. Cohorts were assigned based on the embryo selection method used in their first fresh cycle [PGD-A, n = 110 women (PGD-A group); morphological assessment of embryos, n = 1983 women (control group)]. CLBR, time to clinical pregnancy and cycles needed to achieve a live birth were measured over multiple cycles. RESULTS: Compared to the control group, the PGD-A group achieved a higher per cycle live-birth rate (14.47% vs 9.12%, P < 0.01), took a shorter mean time to reach a clinical pregnancy leading to a live-birth (104.8 days vs 140.6 days, P < 0.05) and required fewer cycles to achieve a live-birth (6.91 cycles vs 10.96 cycles, P < 0.01). However, after three 'complete ART cycles', the CLBR was comparable for the two groups (30.90% vs 26.77%, P = 0.34). CONCLUSION: This is the first study to assess the effectiveness of PGD-A over multiple ART cycles. These real-world findings suggest that PGD-A leads to better outcomes than using morphological assessment alone in women of advanced maternal age. PMID- 29280481 TI - Methanol independent induction in Pichia pastoris by simple derepressed overexpression of single transcription factors. AB - Carbon source regulated promoters are well-studied standard tools for controlling gene expression. Acquiring control over the natural regulation of promoters is important for metabolic engineering and synthetic biology applications. In the commonly used protein production host Komagataella phaffii (Pichia pastoris), methanol-inducible promoters are used because of their tight regulation and exceptional strength. Yet, induction with toxic and flammable methanol can be a considerable safety risk and cannot be applied in many existing fermentation plants. Here we studied new regulatory circuits based on the most frequently used alcohol oxidase 1 promoter (PAOX1 ), which is tightly repressed in presence of repressing carbon sources and strongly induced by methanol. We compared different overexpression strategies for putative carbon source dependent regulators identified by a homology search in related yeasts and previously published literature in order to convert existing methanol dependent expression strains into methanol free systems. While constitutive overexpression showed only marginal or detrimental effects, derepressed expression (activated when the repressing carbon source is depleted) showed that three transcription factors (TFs) are single handedly suitable to strongly activate PAOX1 in P. pastoris without relying on any specifically engineered host strains. Transcriptome analyses demonstrated that Mxr1, Mit1, and Prm1 regulate partly overlapping and unique sets of genes. Derepressed overexpression of a single TF was sufficient to retrofit existing PAOX1 based expression strains into glucose/glycerol regulated, methanol-free systems. Given the wide applicability of carbon source regulated promoters, the simplicity and low cost of controlling carbon source feed rates in large scale bioreactors, similar approaches as in P. pastoris may also be useful in other organisms. PMID- 29280482 TI - National trends in primary tracheoesophageal puncture after total laryngectomy. AB - OBJECTIVES/HYPOTHESIS: Tracheoesophageal puncture (TEP) can be performed at the time of laryngectomy (primary) or postoperatively (secondary). Prior studies demonstrate safe and earlier voice acquisition and rehabilitation with primary TEP. The objectives of this study were to assess national trends in primary TEP and identify factors associated with its use. STUDY DESIGN: Retrospective review. METHODS: Retrospective analysis of the Nationwide Inpatient Sample (NIS) from 2010 to 2014 was performed. The NIS was queried for patients who underwent total laryngectomy (TL) (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 30.3-30.4) and primary TEP (ICD-9-CM 31.95). Patient demographics, comorbidities, and factors known to influence the decision to perform TEP were characterized. Factors associated with primary TEP were identified by multivariable regression. RESULTS: A total of 15,410 patients underwent TL during the study period. Of this cohort, 1,124 patients (7.3%) underwent primary TEP. Among patients who underwent primary TEP, 80.9% had laryngeal cancer, 16.4% had pedicled or free-flap reconstruction at the time of TL, 4.2% underwent partial pharyngectomy, and 48.0% underwent cricopharyngeal myotomy (CPM). The majority of primary TEPs were performed at urban teaching hospitals (90.6%). In multivariable regression, patients who underwent CPM were at significantly increased odds of primary TEP (odds ratio: 3.79, P < .0001). Flap reconstruction, partial pharyngectomy, age, gender, history of laryngeal cancer, hospital region, and teaching status were not associated. CONCLUSIONS: Primary TEP is associated with earlier voice restoration after TL but is infrequently performed. The majority of primary TEPs are performed in teaching hospitals, and primary TEP is associated with concurrent cricopharyngeal myotomy. Future studies should investigate practice patterns associated with primary TEP. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2320-2325, 2018. PMID- 29280483 TI - 3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia. AB - INTRODUCTION: 3,4-diaminopyridine has been used to treat Lambert-Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. METHODS: We conducted a randomized double-blind placebo-controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for >= 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up-and-go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM-related weakness (W-SAS). RESULTS: Thirty-two participants were randomized to continuous 3,4-DAP or placebo groups. None of the 14 participants who received continuous 3,4-DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. DISCUSSION: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM. Muscle Nerve 57: 561 568, 2018. PMID- 29280484 TI - Intranasal tissue necrosis associated with opioid abuse: Case report and systematic review. AB - OBJECTIVE: Opioid abuse is a common disorder affecting over 2 million Americans. Intranasal tissue necrosis is a previously described sequela of nasal opioid inhalation, with a similar presentation to invasive fungal rhinosinusitis (IFRS). The goal of this case report and systematic review is to evaluate the evidence supporting this uncommon disease, with qualitative analysis of the presentation, management and treatment outcomes. DATA SOURCES: MEDLINE, EMBASE, Google Scholar, Scopus, and Web of Science. REVIEW METHODS: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English language studies reporting intranasal mucosal injury associated with prescription opioid abuse. Primary outcomes included clinical presentation, treatment strategies, and outcomes. RESULTS: Systematic review identified 61 patients for qualitative analysis. Common clinical features include facial pain without a history of chronic sinusitis or known immunodeficiency. Diagnostic nasal endoscopy revealed superficial debris with underlying tissue necrosis, consistent with a preliminary diagnosis of IFRS. Characteristic pathologic findings include mucosal ulceration with an overlying acellular substrate, often with polarizable material. Fungal colonization is often reported, with several accounts of angiocentric invasion in immunocompetent patients. Complete symptom resolution is expected following surgical debridement with cessation of intranasal opioid inhalation, with 89% of identified patients experiencing a complete resolution of disease. CONCLUSION: Intranasal opioid abuse is a prevalent condition associated with chronic pain and tissue necrosis that is clinically concerning for invasive fungal disease. Whereas IFRS must be excluded, even in patients without known immunodeficiency, complete resolution of symptoms can be expected following surgical debridement with cessation of opioid abuse. Laryngoscope, 1767-1771, 2018. PMID- 29280486 TI - Online Early. PMID- 29280487 TI - NEXT MONTH IN Epilepsia. PMID- 29280488 TI - Tongue motion variability with changes of upper airway stimulation electrode configuration and effects on treatment outcomes. AB - OBJECTIVES/HYPOTHESIS: Upper airway stimulation (UAS) is an effective treatment for obstructive sleep apnea (OSA). Previous data have demonstrated a correlation between the phenotype of tongue motion and therapy response. Closed loop hypoglossal nerve stimulation implant offers five different electrode configuration settings which may result in different tongue motion. STUDY DESIGN: Two-center, prospective consecutive trial in a university hospital setting. METHODS: Clinical outcomes of 35 patients were analyzed after at least 12 months of device use. Tongue motion was assessed at various electrode configuration settings. Correlation between the tongue motion and treatment response was evaluated. RESULTS: OSA severity was significantly reduced with the use of UAS therapy (P < .001). Changes in tongue motion patterns were frequently observed (58.8%) with different electrode configuration settings. Most of the patients alternated between right and bilateral protrusion (73.5%), which are considered to be the optimal phenotypes for selective UAS responses. Different voltage settings were required to achieve functional stimulation levels when changing between the electrode settings. CONCLUSIONS: UAS is highly effective for OSA treatment in selected patients with an apnea-hypopnea index between 15 and 65 events per hour and higher body mass index. Attention should be given to patients with shifting tongue movement in response to change of electrode configuration. The intraoperative cuff placement should be reassessed when tongue movement shifting is observed. LEVEL OF EVIDENCE: 4 Laryngoscope, 1970-1976, 2018. PMID- 29280489 TI - Down syndrome and pediatric obstructive sleep apnea surgery: A national cohort. AB - OBJECTIVES/HYPOTHESIS: To analyze the trend of sleep surgeries in pediatric patients with Down syndrome (DS) and obstructive sleep apnea (OSA), and to compare this to nonsyndromic (NS) children with OSA. STUDY DESIGN: Retrospective cohort database analysis. METHODS: Analysis of the 1997 to 2012 editions of the Kid's Inpatient Database was conducted. Using International Classification of Diseases, Ninth Revision codes, all patients with OSA were identified, and subsequently, subgroups of NS children and children with DS were identified. Trends of the number and types of sleep surgeries were analyzed. RESULTS: A total of 48,301 and 2,991 sleep surgeries were identified in the NS and DS groups, respectively, during the study period. Tonsillectomy with adenoidectomy was the most common procedure in both groups, but the proportion of tonsillectomy with adenoidectomy decreased over time (P < .01). The proportion of palatal surgery and tracheostomy also decreased significantly, whereas there was an increase in the proportion of lingual tonsillectomies, tongue-base reduction procedures, and supraglottoplasties performed in both groups over time. The relative rates of change in these procedures were higher in the DS population. CONCLUSIONS: Tonsillectomy with adenoidectomy remains the most commonly performed procedure, although there was a significant increase in other sleep surgeries performed (lingual tonsillectomy, tongue-base reduction, and supraglottoplasty) between the two study periods, especially in children with DS. LEVEL OF EVIDENCE: 2c. Laryngoscope, 1963-1969, 2018. PMID- 29280490 TI - Doxycycline treatment efficacy in dogs with naturally occurring Anaplasma phagocytophilum infection. AB - OBJECTIVES: To evaluate doxycycline treatment efficacy and post-treatment pathogen persistence in dogs naturally infected with Anaplasma phagocytophilum in endemic regions of the USA. MATERIALS AND METHODS: Symptomatic dogs in four US states (MN, WI, CT and CA) were evaluated before treatment with doxycycline and approximately 30 and 60 days post-treatment. Clinicopathological parameters, co exposures and A. phagocytophilum DNA in whole blood and lymph node samples were compared between A. phagocytophilum infected and uninfected dogs. RESULTS: In total, 42 dogs fulfilled the inclusion criteria, with 16 dogs (38%) blood PCR positive and 26 dogs (62%) blood PCR-negative for A. phagocytophilum. At initial evaluation, the proportion of clinicopathological abnormalities was similar between A. phagocytophilum infected and uninfected dogs, although thrombocytopenia and lymphopenia were statistically more prevalent among A. phagocytophilum infected dogs. Treatment with doxycycline resulted in resolution of all clinical abnormalities in infected dogs; four dogs had persistent haematological abnormalities, including mild leukopenia, eosinopenia and lymphopenia. All 16 infected dogs became blood PCR-negative approximately 30 and 60 days after treatment onset. Additionally, 13/13 (100%) lymph node specimens tested post-treatment were PCR-negative. Select clinicopathological abnormalities persisted in uninfected dogs after treatment. CLINICAL SIGNIFICANCE: The results of this study support the efficacy of doxycycline therapy for clinical treatment of dogs naturally infected with A. phagocytophilum in the USA. This study did not find clinical, haematological or microbiological indicators that supported the persistence of A. phagocytophilum infection in naturally infected dogs following treatment with doxycycline for 28 days. PMID- 29280491 TI - Is deep plane rhytidectomy superior to superficial musculoaponeurotic system plication facelift? PMID- 29280492 TI - Unexpected prominent tension pneumosella five years after endoscopic endonasal transsphenoidal surgery. AB - Tension pneumosella (TP) is a rare entity reported as the invagination of the sphenoid sinus mucosa into the skull base after endonasal transsphenoidal surgery. Few studies have reported on TP, and in these studies, invagination is confined to either the intrasellar or suprasellar area. We encountered a case of unexpected prominent TP toward the intracranial space 5 years after endoscopic endonasal transsphenoidal surgery (EETS) for a nonfunctioning pituitary adenoma. In addition, we present a hypothesis of the underlying mechanism by a pressure gradient change between the extracranial and intracranial space in TP formation. For repair, a pedicled nasal septal flap was fabricated from the remaining part of the septal mucosa, and a pedicled inferior turbinate flap was created. Moreover, the nasal septal cartilage was used as a rigid support for reconstruction, which was useful for preventing TP recurrence. This is the first report of an unexpected prominent TP after EETS. It is important for otorhinolaryngologists and neurosurgeons to be aware of the possibility of TP following EETS. Laryngoscope, 1798-1801, 2018. PMID- 29280493 TI - The effects of concurrent chemoradiation therapy to the base of tongue in a preclinical model. AB - OBJECTIVES/HYPOTHESIS: To develop a clinically relevant model of oropharyngeal concurrent chemoradiation therapy (CCRT) in order to quantify the effects of CCRT on tongue function and structure. CCRT for advanced oropharyngeal cancer commonly leads to tongue base dysfunction and dysphagia. However, no preclinical models currently exist to study the pathophysiology of CCRT-related morbidity, thereby inhibiting the development of targeted therapeutics. STUDY DESIGN: Animal model. METHODS: Twenty-one male Sprague-Dawley rats were randomized into three groups: 2 week (2W), 5 month (5M), and control (C). The 2W and 5M animals received cisplatin, 5-fluorouracil, and five fractions of 7 Gy to the tongue base; the C animals received no intervention. In vivo tongue strength and displacement, as well as hyoglossus muscle collagen content, were assessed. Analyses were conducted 2 weeks or 5 months following completion of CCRT in the 2W and 5M groups, respectively. RESULTS: Peak tetanic and twitch tongue forces were significantly reduced in both 2W and 5M animals compared to controls (tetanic: P = .0041, P = .0089, respectively; twitch: P = .0201, P = .0020, respectively). Twitch half-decay time was prolonged in 2W animals compared to controls (P = .0247). Tongue displacement was significantly reduced across all testing parameters in 5M animals compared to both the C and 2W groups. No differences in collagen content were observed between experimental groups. CONCLUSIONS: The current study is the first to describe a preclinical model of CCRT to the head and neck with an emphasis on clinical relevance. Tongue strength decreased at 2 weeks and 5 months post-CCRT. Tongue displacement increased only at 5 months post CCRT. Fibrosis was not detected, implicating alternative causative factors for these findings. LEVEL OF EVIDENCE: NA Laryngoscope, 1783-1790, 2018. PMID- 29280495 TI - TSR2 Induces laryngeal cancer cell apoptosis through inhibiting NF-kappaB signaling pathway. AB - OBJECTIVES/HYPOTHESIS: Human laryngeal squamous cell carcinoma (LSCC) is a malignancy that was discovered originally in the epithelial tissue of laryngeal mucosa. However, the underlying molecular mechanism is still not clear. In this study, we aimed to investigate the potential molecular mechanisms of TSR2 in the LSCC cell apoptosis. STUDY DESIGN: The expression of TSR2 was first analyzed in LSCC tissues. Then functional effects of TSR2 on Hep-2 and AMC-HN-8 cell lines were performed by overexpression pcDNA3.1-TSR2. METHODS: We investigated the expression level of TSR2 in LSCC tissues and cells by performing quantitative real-time polymerase chain reaction (qRT-PCR). The pcDNA3.1-TSR2 was constructed to explore the effect of overexpressing TSR2 in Hep-2 cells and AMC-HN-8 cells. We further investigated the effect of overexpressing TSR2 on cell apoptosis related protein and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) p65 nuclear translocation through Western blot and terminal dUTP nick end-labeling assays. RESULTS: We found that TSR2 was downregulated in LSSC tissues and cells compared with the controls, and the overexpression of TSR2 in Hep-2 and AMC-HN-8 cells could promote cell apoptosis and related apoptosis proteins. The Western blot/qRT-PCR data further indicated that overexpression of TSR2 in Hep-2 and AMC-HN-8 cells could lead to a block of NF-kappaB signaling pathway via decreasing nuclear NF-kappaB p65 and increasing cytoplasm NF-kappaB p65. Moreover, overexpression of TSR2 significantly inhibited the phosphorylation of IkappaBalpha and IKKalpha/beta. CONCLUSIONS: The results indicated that TSR2 induced apoptosis was mediated by inhibiting the NF-kappaB signaling pathway, which may provide an effective target in gene therapy for LSCC. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E130-E134, 2018. PMID- 29280494 TI - Bidirectional modulation of glutamatergic synaptic transmission by metabotropic glutamate type 7 receptors at Schaffer collateral-CA1 hippocampal synapses. AB - KEY POINTS: Neurotransmitter release is inhibited by metabotropic glutamate type 7 (mGlu7 ) receptors that reduce Ca2+ influx, yet synapses lacking this receptor also produce weaker release, suggesting that mGlu7 receptors may also prime synaptic vesicles for release. Prolonged activation of mGlu7 receptors with the agonist l-AP4 first reduces and then enhances the amplitude of EPSCs through a presynaptic effect. The inhibitory response is blocked by pertussis toxin, while the potentiating response is prevented by a phospholipase C inhibitor (U73122) and an inhibitor of diacylglycerol (DAG) binding (calphostin C), suggesting that this receptor also couples to pathways that generate DAG. Release potentiation is associated with an increase in the number of synaptic vesicles close to the plasma membrane, which was dependent on the Munc13-2 and RIM1alpha proteins. The Glu7 receptors activated by the glutamate released following high frequency stimulation provoke a bidirectional modulation of synaptic transmission. ABSTRACT: Neurotransmitter release is driven by Ca2+ influx at synaptic boutons that acts on synaptic vesicles ready to undergo exocytosis. Neurotransmitter release is inhibited when metabotropic glutamate type 7 (mGlu7 ) receptors provoke a reduction in Ca2+ influx, although the reduced release from synapses lacking this receptor suggests that they may also prime synaptic vesicles for release. These mGlu7 receptors activate phospholipase C (PLC) and generate inositol trisphosphate, which in turn releases Ca2+ from intracellular stores and produces diacylglycerol (DAG), an activator of proteins containing DAG-binding domains such as Munc13 and protein kinase C (PKC). However, the full effects of mGlu7 receptor signalling on synaptic transmission are unclear. We found that prolonged activation of mGlu7 receptors with the agonist l-AP4 first reduces and then enhances the amplitude of EPSCs, a presynaptic effect that changes the frequency but not the amplitude of the mEPSCs and the paired pulse ratio. Pertussis toxin blocks the inhibitory response, while the PLC inhibitor U73122, and the inhibitor of DAG binding calphostin C, prevent receptor mediated potentiation. Moreover, this DAG-dependent potentiation of the release machinery brings more synaptic vesicles closer to the active zone plasma membrane in a Munc13-2- and RIM1alpha-dependent manner. Electrically evoked release of glutamate that activates mGlu7 receptors also bidirectionally modulates synaptic transmission. In these conditions, potentiation now occurs rapidly and it overcomes any inhibition, such that potentiation prevails unless it is suppressed with the PLC inhibitor U73122. PMID- 29280496 TI - Silent aspiration: Who is at risk? AB - OBJECTIVE: To determine the prevalence of silent aspiration in pediatric patients and identify which diagnoses may be associated with this finding. METHODS: An institutional review board-approved retrospective review was conducted for all patients under the age of 18 who underwent modified barium swallow (MBS) studies at a tertiary children's hospital in 2015. Speech-language pathologists reviewed MBS studies to identify aspiration/silent aspiration on each fluid consistency tested. Charts were reviewed to collect demographic information and the otolaryngologic, neurologic, genetic, and syndromic diagnoses of each patient. RESULTS: Among 1,286 patients who underwent MBS, 440 (34%) demonstrated aspiration. Within the aspiration group, 393 (89%) specifically demonstrated silent aspiration. Thin fluids were silently aspirated in 81% of these patients. Of children aged <6 months, 41% were found to aspirate and, of those, 95% silently aspirated. Median age at which patients demonstrated silent aspiration was 1.1 years. Silent aspiration was documented in 41% of patients with laryngeal cleft, 41% of patients with laryngomalacia, and 54% of patients with unilateral vocal fold paralysis. Laryngeal cleft, laryngomalacia, unilateral vocal fold paralysis, developmental delay, epilepsy/seizures, syndrome, and congenital heart disease were all associated with silent aspiration. CONCLUSION: Silent aspiration may be associated with a number of underlying conditions and is more common than previously described. Caregivers and clinicians should be aware that the absence of cough does not eliminate the possibility of aspiration. Modified barium swallow studies can reveal silent aspiration, which is difficult to detect on clinical feeding evaluation. Modified barium swallow findings can guide feeding therapy and the overall management of aspiration. LEVEL OF EVIDENCE: 4. Laryngoscope, 1952-1957, 2018. PMID- 29280497 TI - Aggregating the symptoms of superior semicircular canal dehiscence syndrome. AB - OBJECTIVES/HYPOTHESIS: To aggregate symptoms reported by patients with superior canal dehiscence syndrome (SCDS) and to develop an evidence-based symptom set by performing a systematic review of the literature. STUDY DESIGN: Database search and critical assessment of research studies. METHODS: Medline and PubMed databases were searched for articles that reported the preoperative symptoms of adult and pediatric patients with unilateral and bilateral SCDS. Articles were excluded if they reported on associated diseases or did not report symptoms. RESULTS: Of the 397 articles retrieved, 66 were retained for quantitative analysis. Among 431 patients with SCDS, 91 symptom terms were reported. After combining synonymous terms, 22 symptoms were derived by consensus. Of the raw total number of reported symptoms, 92.5% can be attributed to five common symptoms: spontaneous dizziness (51%), autophony (42.5%), pressure-induced vertigo (37.4%), hearing loss (39.9%), and sound-induced vertigo (42.7%). CONCLUSIONS: This systematic review of symptoms reported by patients with SCDS identified a 22-item common symptom set. These items can be used to create an evidence-based patient-reported outcome measure to evaluate health-related quality of life in SCDS. Laryngoscope, 1932-1938, 2018. PMID- 29280499 TI - G5G2.5 core-shell tecto-dendrimer specifically targets reactive glia in brain ischemia. AB - Secondary neuronal death is a serious stroke complication. This process is facilitated by the conversion of glial cells to the reactive pro-inflammatory phenotype that induces neurodegeneration. Therefore, regulation of glial activation is a compelling strategy to reduce brain damage after stroke. However, drugs have difficulties to access the CNS, and to specifically target glial cells. In the present work, we explored the use core-shell polyamidoamine tecto dendrimer (G5G2.5 PAMAM) and studied its ability to target distinct populations of stroke-activated glial cells. We found that G5G2.5 tecto-dendrimer is actively engulfed by primary glial cells in a time- and dose-dependent manner showing high cellular selectivity and lysosomal localization. In addition, oxygen-glucose deprivation or lipopolysaccharides exposure in vitro and brain ischemia in vivo increase glial G5G2.5 uptake; not being incorporated by neurons or other cell types. We conclude that G5G2.5 tecto-dendrimer is a highly suitable carrier for targeted drug delivery to reactive glial cells in vitro and in vivo after brain ischemia. PMID- 29280498 TI - Precision-porous templated scaffolds of varying pore size drive dendritic cell activation. AB - Scaffold based systems have shown significant potential in modulating immune responses in vivo. While there has been much attention on macrophage interactions with tissue engineered scaffolds for tissue regeneration, fewer studies have looked at the effects of scaffold design on the response of immune cells-that is, dendritic cells (DCs). Here, we present the effects of varying pore size of poly (2-hydroxyethyl methacrylate) (pHEMA) and poly(dimethylsiloxane) (PDMS, silicone) scaffolds on the maturation and in vivo enrichment of DCs. We employ a precision templating method to make 3-D porous polymer scaffolds with uniformly defined and adjustable architecture. Hydrophilic pHEMA and hydrophobic PDMS scaffolds were fabricated in three pore sizes (20, 40, 90 MUm) to quantify scaffold pore size effects on DCs activation/maturation in vitro and in vivo. In vitro results showed that both pHEMA and PDMS scaffolds could promote maturation in the DC cell line, JAWSII, that resembled lipopolysaccharide (LPS)-activated/matured DCs (mDCs). Scaffolds with smaller pore sizes correlate with higher DC maturation, regardless of the polymer used. In vivo, when implanted subcutaneously in C57BL/6J mice, scaffolds with smaller pore sizes also demonstrated more DCs recruitment and more sustained activation. Without the use of DC chemo attractants or chemical adjuvants, our results suggested that DC maturation and scaffold infiltration profile can be modulated by simply altering the pore size of the scaffolds. PMID- 29280500 TI - Early improvement in PANSS-30, PANSS-8, and PANSS-6 scores predicts ultimate response and remission during acute treatment of schizophrenia. AB - OBJECTIVE: PANSS-8 and PANSS-6 are derived from the 30-item Positive and Negative Syndrome Scale (PANSS-30). We investigate whether PANSS-8 or PANSS-6 is a reliable, valid, sensitive to change measure, and scalable, and whether early improvement using them can predict response/remission. METHOD: Data were from 3 trials for 270 schizophrenia inpatients receiving antipsychotics. Internal consistency, validity, sensitivity to change, and scalability using PANSS-30, PANSS-8, and PANSS-6 at each assessment were examined. Early improvement was defined as at least 20% reduction of PANSS-30, PANSS-8, or PANSS-6 scores at week 2. Response was defined as at least 40% reduction of PANSS-30 and remission as a score of PANSS-8 <= 3 on each item at endpoint. Receiver operating characteristic analysis was used to determine which rating scale had better discriminative capacity. RESULTS: PANSS-8 and PANSS-6 showed acceptable internal consistency, were highly correlated with PANSS-30, and had sensitivity to change. PANSS-8 and PANSS-6 were scalable at each assessment, except for PANSS-6 at baseline. Early improvement using PANSS-8 or PANSS-6 had comparable predictive values with that of PANSS-30 for response/remission. CONCLUSION: PANSS-8 and PANSS-6 are clinically useful measures. Early improvement, regardless of whether PANSS-30, PANSS-8, or PANSS-6 is used, is a statistically significant predictor of response/remission. PMID- 29280501 TI - 'Just because a doctor says something, doesn't mean that [it] will happen': self perception as having a Fertility Problem among Infertility Patients. AB - Only some individuals who have the medically defined condition 'infertility' adopt a self-definition as having a fertility problem, which has implications for social and behavioural responses, yet there is no clear consensus on why some people and not others adopt a medical label. We use interview data from 28 women and men who sought medical infertility treatment to understand variations in self identification. Results highlight the importance of identity disruption for understanding the dialectical relationship between medical contact and self identification, as well as how diagnosis acts both as a category and a process. Simultaneously integrating new medical knowledge from testing and treatment with previous fertility self-perceptions created difficulty for settling on an infertility self-perception. Four response categories emerged for adopting a self perception of having a fertility problem: (i) the non-adopters - never adopting the self-perception pre- or post-medical contact; (ii) uncertain - not being fully committed to the self-perception pre- or post-medical contact; (iii) assuming the label - not having prior fertility concerns but adopting the self perception post-medical contact; and (iv) solidifying a tentative identity - not being fully committed to a self-perception pre-medical contact, but fully committed post-medical contact. (A virtual abstract of this paper can be viewed at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA). PMID- 29280502 TI - Transmembrane Signal Transduction in Two-Component Systems: Piston, Scissoring, or Helical Rotation? AB - Allosteric and transmembrane (TM) signaling are among the major questions of structural biology. Here, we review and discuss signal transduction in four helical TM bundles, focusing on histidine kinases and chemoreceptors found in two component systems. Previously, piston, scissors, and helical rotation have been proposed as the mechanisms of TM signaling. We discuss theoretically possible conformational changes and examine the available experimental data, including the recent crystallographic structures of nitrate/nitrite sensor histidine kinase NarQ and phototaxis system NpSRII:NpHtrII. We show that TM helices can flex at multiple points and argue that the various conformational changes are not mutually exclusive, and often are observed concomitantly, throughout the TM domain or in its part. The piston and scissoring motions are the most prominent motions in the structures, but more research is needed for definitive conclusions. PMID- 29280503 TI - Once a French Speaker, Always a French Speaker? Bilingual Children's Thinking About the Stability of Language. AB - Despite early emerging and impressive linguistic abilities, young children demonstrate ostensibly puzzling beliefs about the nature of language. In some circumstances monolingual children even express the belief that an individual's language is more stable than her race. The present research investigated bilingual children's thinking about the relative stability of language and race (Kinzler & Dautel, 2012). Five-to six-year-old bilingual children were asked to judge whether a target child who varied in race (White or Black) and language (English or French) would grow up to be an adult who maintained the target child's race or her language. Similar to many monolingual children, a heterogeneous group of bilingual children on average chose the language-match. Yet French-English bilingual children were relatively more likely to choose the race-match, especially when tested in their non-dominant language. Specific experience with relevant languages, and communicating in a non-dominant language, may contribute to children's developing metalinguistic success and their thinking about social categorization. PMID- 29280504 TI - Cartilage quantitative T2 relaxation time 2-4 years following isolated anterior cruciate ligament reconstruction. AB - Cartilage T2 relaxation time in isolated anterior cruciate ligament reconstruction (ACLR) without concomitant meniscal pathology and their changes over time remain unclear. The purpose of this exploratory study was to: (i) compare cartilage T2 relaxation time (T2 values) in people with isolated ACLR at 2-3 years post-surgery (baseline) and matched healthy controls and; (ii) evaluate the subsequent 2-year change in T2 values in people with ACLR. Twenty-eight participants with isolated ACLR and nine healthy volunteers underwent knee magnetic resonance imaging (MRI) at baseline; 16 ACLR participants were re-imaged 2 years later. Cartilage T2 values in full thickness, superficial layers, and deep layers were quantified in the tibia, femur, trochlear, and patella. Between group comparisons at baseline were performed using analysis of covariance adjusting for age, sex, and body mass index. Changes over time in the ACLR group were evaluated using paired sample t-tests. ACLR participants showed significantly higher (p = 0.03) T2 values in the deep layer of medial femoral condyle at baseline compared to controls (mean difference 4.4 ms [13%], 95%CI 0.4, 8.3 ms). Over 2 years, ACLR participants showed a significant reduction (p = 0.04) in T2 value in the deep layer of lateral tibia (mean change 1.4 ms [-7%], 95%CI 0.04, 2.8 ms). The decrease in T2 values suggests improvement in cartilage composition in the lateral tibia (deep layer) of ACLR participants. Further research with larger ACLR cohorts divided according to meniscal status and matched healthy cohorts are needed to further understand cartilage changes post ACLR. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2022-2029, 2018. PMID- 29280505 TI - Representing, Running, and Revising Mental Models: A Computational Model. AB - People use commonsense science knowledge to flexibly explain, predict, and manipulate the world around them, yet we lack computational models of how this commonsense science knowledge is represented, acquired, utilized, and revised. This is an important challenge for cognitive science: Building higher order computational models in this area will help characterize one of the hallmarks of human reasoning, and it will allow us to build more robust reasoning systems. This paper presents a novel assembled coherence (AC) theory of human conceptual change, whereby people revise beliefs and mental models by constructing and evaluating explanations using fragmentary, globally inconsistent knowledge. We implement AC theory with Timber, a computational model of conceptual change that revises its beliefs and generates human-like explanations in commonsense science. Timber represents domain knowledge using predicate calculus and qualitative model fragments, and uses an abductive model formulation algorithm to construct competing explanations for phenomena. Timber then (a) scores competing explanations with respect to previously accepted beliefs, using a cost function based on simplicity and credibility, (b) identifies a low-cost, preferred explanation and accepts its constituent beliefs, and then (c) greedily alters previous explanation preferences to reduce global cost and thereby revise beliefs. Consistency is a soft constraint in Timber; it is biased to select explanations that share consistent beliefs, assumptions, and causal structure with its other, preferred explanations. In this paper, we use Timber to simulate the belief changes of students during clinical interviews about how the seasons change. We show that Timber produces and revises a sequence of explanations similar to those of the students, which supports the psychological plausibility of AC theory. PMID- 29280506 TI - Immunoglobulin replacement therapy for yellow nail syndrome. PMID- 29280508 TI - Does freeze-all policy affect IVF outcome in poor ovarian responders? AB - OBJECTIVE: To evaluate whether the freeze-all strategy affects in-vitro fertilization (IVF) outcome in poor ovarian responders (POR) defined according to the Bologna criteria. METHOD: This was a retrospective cohort study of patients undergoing IVF treatment between January 2012 and December 2016 at a single center. A total of 433 POR (as defined by the Bologna criteria) fulfilled criteria and were included in the study; of these, 277 patients underwent fresh embryo transfer (ET) and 156 followed the freeze-all policy. All patients underwent controlled ovarian stimulation (COS) following a gonadotropin-releasing hormone antagonist protocol, and cleavage-stage ET. Main outcome measure was ongoing pregnancy rate. Secondary outcomes included implantation and clinical pregnancy rates. The freeze-all strategy was implemented when the progesterone serum level was > 1.5 ng/mL or the endometrium was < 7 mm on the trigger day, or as per patient preference. Patients with previous failed fresh ET also underwent fresh ET or freeze-all strategy considering the indications mentioned above. RESULTS: Mean maternal age in the freeze-all group was 39.5 +/- 3.6 years and in the fresh ET group was 39.7 +/- 3.8 years (P = 0.54). Mean number of embryos transferred (nET) was 1.53 +/- 0.6 and 1.60 +/- 0.6 (P = 0.12) in the freeze-all and fresh ET groups, respectively. Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh ET groups (9.6% vs 10.1%, respectively; relative risk (RR), 0.95; 95% CI, 0.52-1.73), nor did the clinical pregnancy rate (14.1% vs 13.7%, respectively; RR, 1.03; 95% CI, 0.63-1.67). Implantation rate was 9.6% and 9.8% (P = 0.82) in the freeze-all and fresh ET groups, respectively. Logistic regression analysis (including maternal age, antral follicle count, number of retrieved and mature oocytes, nET, and fresh ET vs freeze-all strategy) indicated that maternal age (P < 0.001) and nET (P = 0.039) were the only independent variables associated with ongoing pregnancy rate. CONCLUSIONS: The freeze-all strategy, compared with fresh ET, had no impact on IVF outcomes in POR patients as defined according to the Bologna criteria. Multicenter studies including large numbers of patients should be carried out to confirm the results of this study and reach conclusions about the potential benefits of the freeze-all policy for poor responders. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29280507 TI - Soybean oil containing ginseng saponins as adjuvants promotes production of cytokines and enhances immune responses to foot-and-mouth disease vaccine. AB - In the present study, the adjuvant effect of soybean oil containing ginseng root saponins (SO-GS-R) on the immune response to foot-and-mouth disease vaccine (FMDV) in mice was investigated. When immunized with FMDV antigen emulsified in an SO-GS-R formulation, mice generated remarkably higher serum antibody and cytokine responses than mice immunized with FMDV antigen alone. To elucidate the mechanisms underlying the adjuvant effect of SO-GS-R, we measured cytokines in serum and muscle tissue after intramuscular injection of SO-GS-R. The results showed that injection of SO-GS-R significantly increased the levels of IL-1beta, IL-5, IL-6, G-CSF, KC, MCP-1, MIP-1alpha, and MIP-1beta in both serum and muscle. These results suggested that SO-GS-R recruits neutrophils, eosinophils, T cells and macrophages, causing immune cell recruitment at the injection site, driving antigen-presenting cells to actively participate in the onset of immunity, and amplifying the immune responses. Considering its adjuvant activity and plant derived properties, SO-GS-R should be further studied for its adjuvant effect on vaccines used in food animals. PMID- 29280509 TI - Screening for mental health needs of New Zealand youth in secure care facilities using the MAYSI-2. AB - BACKGROUND: Young people admitted to secure facilities generally have particularly high rates of mental, emotional and behavioural problems, but little is known about the mental health needs of this group in New Zealand. AIMS: To describe prevalence of probable mental health disorder and related needs among young people in secure facilities in New Zealand. METHODS: Massachusetts youth screening instrument - second version (MAYSI-2) data were obtained from the records of young people admitted to one secure care facility (n = 204) within a 12 month period. We used descriptive statistics to determine prevalence of problems overall and multivariate analysis of variance to compare MAYSI-2 scores between gender and ethnic groups. RESULTS: Nearly 80% of these young people scored above the 'caution' or 'warning' cut-off on the MAYSI-2, a substantially higher proportion than reported in studies in other countries. There was a tendency for girls and for Maori and Pacific Islander subgroups to have a higher rate of probable psychopathology. CONCLUSIONS: Young people in secure facilities in New Zealand have substantial service needs. Early intervention that engages them in services upon first contact with the youth justice system might help reduce this burden. Further validation of the MAYSI-2 in New Zealand may be warranted because of the unique ethnic make-up of these young offenders. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29280510 TI - The challenges of promoting osteogenesis in segmental bone defects and osteoporosis. AB - Conventional clinical management of complex bone healing scenarios continues to result in 5-10% of fractures forming non-unions. Additionally, the aging population and prevalence of osteoporosis-related fractures necessitate the further exploration of novel ways to augment osteogenesis in this special population. This review focuses on the current clinical modalities available, and the ongoing clinical and pre-clinical research to promote osteogenesis in segmental bone defects, delayed unions, and osteoporosis. In summary, animal models of fracture repair are often small animals as historically significant large animal models, like the dog, continue to gain favor as companion animals. Small rodents have well-documented limitations in comparing to fracture repair in humans, and few similarities exist. Study design, number of studies, and availability of funding continue to limit large animal studies. Osteoinduction with rhBMP-2 results in robust bone formation, although long-term quality is scrutinized due to poor bone mineral quality. PTH 1-34 is the only FDA approved osteo-anabolic treatment to prevent osteoporotic fractures. Limited to 2 years of clinical use, PTH 1-34 has further been plagued by dose-related ambiguities and inconsistent results when applied to pathologic fractures in systematic human clinical studies. There is limited animal data of PTH 1-34 applied locally to bone defects. Gene therapy continues to gain popularity among researchers to augment bone healing. Non-integrating viral vectors and targeted apoptosis of genetically modified therapeutic cells is an ongoing area of research. Finally, progenitor cell therapies and the content variation of patient-side treatments (e.g., PRP and BMAC) are being studied. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1559-1572, 2018. PMID- 29280511 TI - Modeling the resiliency of energy-efficient retrofits in low-income multifamily housing. AB - Residential energy efficiency and ventilation retrofits (eg, building weatherization, local exhaust ventilation, HVAC filtration) can influence indoor air quality (IAQ) and occupant health, but these measures' impact varies by occupant activity. In this study, we used the multizone airflow and IAQ analysis program CONTAM to simulate the impacts of energy retrofits on indoor concentrations of PM2.5 and NO2 in a low-income multifamily housing complex in Boston, Massachusetts (USA). We evaluated the differential impact of residential activities, such as low- and high-emission cooking, cigarette smoking, and window opening, on IAQ across two seasons. We found that a comprehensive package of energy and ventilation retrofits was resilient to a range of occupant activities, while less holistic approaches without ventilation improvements led to increases in indoor PM2.5 or NO2 for some populations. In general, homes with simulated concentration increases included those with heavy cooking and no local exhaust ventilation, and smoking homes without HVAC filtration. Our analytical framework can be used to identify energy-efficient home interventions with indoor retrofit resiliency (ie, those that provide IAQ benefits regardless of occupant activity), as well as less resilient retrofits that can be coupled with behavioral interventions (eg, smoking cessation) to provide cost-effective, widespread benefits. PMID- 29280512 TI - The evolutionary characteristics and structural biology of Gallus toll-like receptor 21. AB - Toll-like receptors (TLRs) are an important part of the innate immune system, acting as a first line of defense against many invading pathogens. The ligand known to bind Gallus toll-like receptor 21 (gTLR21) is the unmethylated cytosine phosphate guanine dideoxy nucleotide motif; however, the evolutionary characteristics and structural biology of gTLR21 are poorly elaborated. Our results suggest that gTLR21 is phylogenetically and evolutionarily related to the TLR11 family and is perhaps a close ortholog of the Mus TLR13. Structural biology of homology modeling of the gTLR21 ectodomain structure suggests that it has no Z loop like that seen in Mus TLR9. The cytosolic toll-IL-1 receptor region of gTLR21 contains a central 4-stranded parallel beta-sheet (betaA-betaD) surrounded by 5 alpha-helices (alphaA-alphaE) on both sides, a highly conserved structure also seen in other TLRs. Molecular docking analysis reveals that the gTLR21 ectodomain has the potential to distinguish between different ligands. Homodimer analysis results also suggest that Phe842 and Pro844 of the BB loop and Cys876 of the alphaC helix in gTLR21 are conserved in other cytosolic toll-IL-1 receptor domains of other TLRs and may contribute to the docking of homodimers. Our study on the evolutionary characteristics and structural biology of gTLR21 reveals that the molecule may have a broader role to play in innate immune system; however, further experimental validation is required to confirm our findings. PMID- 29280513 TI - Clinical pharmacists in general practice: an initial evaluation of activity in one English primary care organisation. AB - OBJECTIVES: This aim of this research was to characterise the breadth and volume of activity conducted by clinical pharmacists in general practice in Dudley Clinical Commissioning Group (CCG), and to provide quantitative estimates of both the savings in general practitioner (GP) time and the financial savings attributable to such activity. METHODS: This descriptive observational study retrospectively analysed quantitative data collected by Dudley CCG concerning the activity of clinical pharmacists in GP practices during 2015. KEY FINDINGS: Over the 9-month period for which data were available, the 5.4 whole time equivalent clinical pharmacists operating in GP practices within Dudley CCG identified 23 172 interventions. Ninety-five per cent of the interventions identified were completed within the study period saving the CCG in excess of L1 000 000. During the 4 months for which resource allocation data were available, the clinical pharmacists saved 628 GP appointments plus an additional 647 h that GPs currently devote to medication review and the management of repeat prescribing. CONCLUSIONS: This research suggests that clinical pharmacists in general practice in Dudley CCG are able to deliver clinical interventions efficiently and in high volume. In doing so, clinical pharmacists were able to generate considerable financial returns on investment. Further work is recommended to examine the effectiveness and cost-effectiveness of clinical pharmacists in general practice in improving outcomes for patients. PMID- 29280514 TI - Left dorsolateral prefrontal cortex atrophy is associated with frontal lobe function in Alzheimer's disease and contributes to caregiver burden. AB - OBJECTIVE: Caregivers of patients with dementia experience physical and mental deterioration. We have previously reported a correlation between caregiver burden and the Frontal Assessment Battery (FAB) total scores of patients with Alzheimer's disease (AD), especially regarding the dependency factor from the Zarit Burden Interview. The present study aimed to identify an objective biomarker for predicting caregiver burden. METHODS: The participants were 26 pairs of caregivers and patients with AD and mild-to-moderate dementia. Correlations between regional gray matter volumes in the patients with AD and the FAB total scores were explored by using whole-brain voxel-based morphometric analysis. Path analysis was used to estimate the relationships between regional gray matter volumes, FAB total scores, and caregiver burden based on the Zarit Burden Interview. RESULTS: The voxel-based morphometric revealed a significant positive correlation between the FAB total scores and the volume of the left dorsolateral prefrontal cortex. This positive correlation persisted after controlling for the effect of general cognitive dysfunction, which was assessed by using the Mini-Mental State Examination. Path analysis revealed that decreases in FAB scores, caused by reduced frontal lobe volumes, negatively affected caregiver burden. CONCLUSIONS: The present study revealed that frontal lobe function, based on FAB scores, was affected by the volume of the left dorsolateral prefrontal cortex. Decreased scores were associated with greater caregiver burden, especially for the dependency factor. These findings may facilitate the development of an objective biomarker for predicting caregiver burden. PMID- 29280515 TI - Subdural haemorrhage in infants: abuse or natural causes? The importance of thorough child death review. PMID- 29280517 TI - UVA1 impairs the repair of UVB-induced DNA damage in normal human melanocytes. AB - The exact correlation between melanoma and sun-light is still a controversially debated issue. Although natural sunlight contains various ratios of UVA and UVB, most investigators so far focused on the effects of single solar wavebands and neglected possible interactions. Therefore, in this study primary human melanocytes of three donors were simultaneously exposed to physiologic doses of UVA1 and UVB. Effects on apoptosis were analysed using annexin V assays and cell death ELISAs, and effects on DNA damage were investigated using southwestern slot blots. While UVA1 did not influence UVB-induced apoptosis, UVA1 impaired the repair of UVB-induced cyclobutane pyrimidine dimers (CPD) as the amount of CPD was 1.8 times higher in UVA1 + UVB than in UVB only exposed melanocytes six hours after irradiation. We conclude that UVA1 might contribute to melanomagenesis as it partially inhibits the repair of UVB-induced CPD in human melanocytes while it does not affect UVB-mediated apoptosis. PMID- 29280516 TI - Suppression of STAT3 NH2 -terminal domain chemosensitizes medulloblastoma cells by activation of protein inhibitor of activated STAT3 via de-repression by microRNA-21. AB - Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription-3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional role of activated STAT3 in MB, by using a cell permeable STAT3-NH2 terminal domain inhibitor (S3-NTDi) that specifically perturbs the structure/function of STAT3. We have implemented several biochemical experiments using human MB tumor microarray (TMA) and pediatric MB cell lines, derived from high-risk SHH-TP53 mutated and MYC-amplified Non-WNT/SHH tumors. Treatment of MB cells with S3-NTDi leads to growth inhibition, cell cycle arrest, and apoptosis. S3-NTDi downregulated expression of STAT3 target genes, delayed migration of MB cells, attenuated epithelial-mesenchymal transition (EMT) marker expressions and reduced cancer stem-cell associated protein expressions in MB-spheres. To elucidate mechanisms, we showed that S3-NTDi induce expression of pro-apoptotic gene, C/EBP homologous protein (CHOP), and decrease association of STAT3 to the proximal promoter of CCND1 and BCL2. Of note, S3-NTDi downregulated microRNA-21, which in turn, de-repressed Protein Inhibitor of Activated STAT3 (PIAS3), a negative regulator of STAT3 signaling pathway. Furthermore, combination therapy with S3 NTDi and cisplatin significantly decreased highly aggressive MYC-amplified MB cell growth and induced apoptosis by downregulating STAT3 regulated proliferation and anti-apoptotic gene expression. Together, our results revealed an important role of STAT3 in regulating MB pathogenesis. Disruption of this pathway with S3 NTDi, therefore, may serves as a promising candidate for targeted MB therapy by enhancing chemosensitivity of MB cells and potentially improving outcomes in high risk patients. PMID- 29280518 TI - A new tool to test active ingredient using lactic acid in vitro, a help to understand cellular mechanism involved in stinging test: An example using a bacterial polysaccharide (Fucogel(r) ). AB - The stinging test is an in vivo protocol that evaluates sensitive skin using lactic acid (LA). A soothing sensation of cosmetics or ingredients can be also appreciated through a decrease in stinging score. To predict the soothing sensation of a product before in vivo testing, we developed a model based on an LA test and substance P (SP) release using a co-culture of human keratinocytes and NGF-differentiated PC12 cells. A bacterial fucose-rich polysaccharide present in Fucogel(r) was evaluated as the soothing molecule in the in vivo stinging test and our in vitro model. Excluding toxic concentrations, the release of SP was significant from 0.2% of lactic acid for the PC12 cells and from 0.1% of lactic acid for the keratinocytes. When the pH was adjusted to approximately 7.4, LA did not provoke SP release. At these concentrations of LA, 0.1% of polysaccharide showed a significant decrease in SP release from the two cellular types and in co cultures without modifying the pH of the medium. In vivo, a stinging test using the polysaccharide showed a 30% decrease in prickling intensity vs the placebo in 19 women between the ages of 21 and 69. Our in vitro model is ethically interesting and is adapted for cosmetic ingredients screening because it does not use animal experimentation and limits human volunteers. Moreover, Fucogel(r) reduced prickling sensation as revealed by the in vivo stinging test and inhibits the neurogenic inflammation as showed by our new in vitro stinging test based on SP release. PMID- 29280519 TI - Subcutaneous immunoglobulin for the treatment of deep morphoea in a child. AB - Morphoea, also known as localized scleroderma, is a disorder characterized by excessive collagen deposition leading to thickening of the dermis and/or subcutaneous tissues. Intravenous IgG therapy has induced improvement in some fibrotic conditions. The primary indication for subcutaneous IgG (SCIG) is in primary immunodeficiency disorders as replacement therapy; however, recently there has been considerable interest in SCIG as an immunomodulatory agent. We report an 11-year-old girl with deep morphoea who was successfully treated with SCIG. PMID- 29280520 TI - Significance of isolated papillary muscle hypertrophy: A comparison of left ventricular hypertrophy diagnosed using electrocardiography vs echocardiography. AB - AIMS: The clinical significance of papillary muscle hypertrophy and its electrocardiography (ECG) findings has not been fully elucidated. This study aimed to investigate the relationship between ECG findings and papillary muscle hypertrophy and to confirm the importance of papillary muscle measurements on transthoracic echocardiography (TTE). METHODS AND RESULTS: Of the 237 consecutive patients who showed left ventricular hypertrophy (LVH) pattern on a 12-lead ECG, TTE data were available for 101 patients. The patients were divided into the two groups according to the presence (ECG-LVH [strain pos] group, n = 60) or absence (ECG-LVH [strain neg] group, n = 41) of LV strain pattern (study 1). The prevalence of papillary muscle hypertrophy using TTE was significantly higher in the ECG-LVH (strain neg) group than in the ECG-LVH (strain pos) group (P = .0002). Of the 42 cases with papillary muscle hypertrophy, 5 cases (12%) showed isolated papillary muscle hypertrophy with normal geometry. ECG data were prospectively analyzed for 36 patients who were diagnosed with papillary muscle hypertrophy by TTE (study 2). The prevalence of LV strain pattern was significantly higher in patients with LV wall hypertrophy than in those without LV wall hypertrophy (P = .04). Of the 25 cases with papillary muscle hypertrophy, 6 cases (24%) showed normal geometry and 4 cases (16%) showed ECG abnormality. CONCLUSIONS: Isolated papillary muscle hypertrophy can cause ECG abnormalities such as LV high voltage and LV strain pattern. Particular attention must be paid to the papillary muscle during echocardiographic examinations. PMID- 29280522 TI - Psoriasis and multiple sclerosis - hidden link? PMID- 29280521 TI - Left atrial appendage myxofibrosarcoma: A rare masquerader of myxoma and thrombus "all that glitters is not gold". AB - Left atrial appendage mass can occasionally pose a serious challenge to physicians to identify the nature of the mass with the aid of imaging techniques. We present a case of 67-year-old man, who was evaluated for suspected left atria myxoma. Transesophageal echocardiography revealed a heterogeneous density originating from left atrial appendage, thought to be most consistent with a myxoma. Cardiac magnetic resonance imaging, uncharacteristically, gave an equivocal picture, suggesting the mass to be a myxoma on initial imaging and a thrombus with evidence of liquefaction necrosis following postcontrast enhancement. Surprisingly, histopathology of the mass following its surgical excision yielded a rare diagnosis of myxofibrosarcoma. PMID- 29280523 TI - Depression and suicidality in psoriasis patients: emotional needs to discover. PMID- 29280524 TI - Public perception of dermatology and dermatologists: a very relevant but untapped issue. PMID- 29280525 TI - JEADV on the rise. PMID- 29280528 TI - Transplant International in a nutshell. PMID- 29280527 TI - The effects of superovulation and reproductive aging on the epigenome of the oocyte and embryo. AB - A societal preference of delaying maternal age at first childbirth has increased reliance on assisted reproductive technologies/therapies (ART) to conceive a child. Oocytes that have undergone physiologic aging (>=35 years for humans) are now commonly used for ART, yet evidence is building that suboptimal reproductive environments associated with aging negatively affect oocyte competence and embryo development-although the mechanisms underlying these relationship are not yet well understood. Epigenetic programming of the oocyte occurs during its growth within a follicle, so the ovarian stimulation protocols that administer exogenous hormones, as part of the first step for all ART procedures, may prevent the gamete from establishing an appropriate epigenetic state. Therefore, understanding how oocyte. Therefore, understanding how hormone stimulation and oocyte physiologic age independently and synergistically physiologic age independently and synergistically affect the epigenetic programming of these gametes, and how this may affect their developmental competence, are crucial to improved ART outcomes. Here, we review studies that measured the developmental outcomes affected by superovulation and aging, focusing on how the epigenome (i.e., global and imprinted DNA methylation, histone modifications, and epigenetic modifiers) of gametes and embryos acquired from females undergoing physiologic aging and exogenous ovarian stimulation is affected. PMID- 29280530 TI - Relationship between QRS measurements and left ventricular morphology and function in asymptomatic individuals. AB - BACKGROUND AND AIM: QRS amplitude and duration are associated with increased left ventricular (LV) volume, mass and dysfunction. However, the diagnostic concordance between QRS measurements and LV morphology and function, as shown by Doppler echocardiography, is not well established. We investigated the relationships of QRS duration and amplitude with echocardiographic measurements of LV morphology and systolic and diastolic function in normal individuals. METHODS: Individuals without signs or symptoms of coronary artery disease or heart failure, who underwent clinical examination as a part of a cross-sectional survey for the prevalence of coronary risk factors, randomly selected from the population list in Caltanissetta, Italy, were included in the study. QRS duration and amplitude were automatically measured using inbuilt software. LV ejection and filling patterns were studied using Doppler echocardiography. RESULTS: We studied 184 individuals (96 men and 88 women), mean age 55.9 (11.3). QRS duration increased by 5.4 ms for every 100 g increase in LV mass, and by 4.6 ms for each 10 mm increase in LV end-diastolic diameter. The amplitude increased by 0.8 mm for every 100 g increase in LV mass. There was no relationship with LV dimensions. A nonlinear correlation was found between QRS amplitude and indexes of global dyssynchrony. The time-voltage QRS area correlated with LV mass, dimensions and indexes of dyssynchrony. There was no relationship between QRS measurements and ejection fraction. CONCLUSIONS: QRS prolongation and increase in amplitude are strongly influenced by LV increased mass and volume, as well as by dyssynchrony, independently of ejection fraction. PMID- 29280531 TI - Dissociative identity disorder: Restoration of executive functions after switch from alter to host personality. PMID- 29280529 TI - Protective effects of melatonin on the in vitro developmental competence of bovine oocytes. AB - The present study investigated the effects of melatonin on bovine oocyte maturation and subsequent embryonic development in vitro. Results showed that the nuclear and cytoplasmic maturation, characterized by first polar body extrusion, normal distribution of cortical granules and mitochondria, as well as increased mitochondrial membrane potential, were significantly improved in 10-9 mol/L melatonin-treated oocytes. Melatonin supplementation reduced intracellular reactive oxygen species level and enhanced glutathione production. Meanwhile, the presence of melatonin (10-9 mol/L) during oocyte maturation resulted in a decreased early apoptotic rate in oocytes. After in vitro fertilization, oocytes receiving melatonin supplementation exhibited a significantly higher blastocyst formation rate and yielded a markedly lower number of apoptotic cells. Mechanistic explorations showed that addition of 10-9 mol/L melatonin to in vitro maturation media significantly attenuated the transcript level of caspase 3, while the expressions of BCL-2, XIAP, CAT and HSP70 were significantly reinforced in the resultant embryos. Taken together, melatonin ameliorates bovine oocyte maturation potential, and the beneficial effects can affect subsequent embryonic development. The protective role of melatonin may be due to its anti apoptotic and anti-oxidative activities. PMID- 29280532 TI - Sludge reflects intra-amniotic inflammation with or without microorganisms. AB - PROBLEM: To investigate whether amniotic fluid (AF) "sludge" in patients with preterm labor (PTL) with intact membranes is related to intra-amniotic infection or inflammation. METHOD OF STUDY: 105 PTL patients before 29 weeks' gestation were enrolled. AF "sludge" was evaluated by transvaginal sonography. Microorganisms were identified in AF by our newly established PCR method using a eukaryote-made thermostable DNA polymerase. RESULTS: AF "sludge" was present in 18.1% (19/105) of patients. The results obtained in the AF "sludge" group vs the no "sludge" group were as follows: (i) a similar positive rate of microorganisms in AF by PCR, 31.6% (6/19) vs 38.4% (33/86); (ii) a higher level of AF interleukin-8, 15.2 (0.2-381.5) ng/mL vs 5.8 (0.1-413.7) ng/mL; P = .005); and (3) a higher frequency of histological chorioamnionitis, 52.6% (10/19) vs 23.3% (20/86); P = .010. CONCLUSION: The presence of AF "sludge" is related to intra amniotic inflammation with or without microorganisms. PMID- 29280534 TI - Association of acute stent strut malapposition on long-term outcomes. PMID- 29280533 TI - Comparative effects of aripiprazole and selected antipsychotic drugs on lipid peroxidation in plasma. AB - AIM: The aim of the present study was to evaluate and compare the effects of a new antipsychotic, aripiprazole (unique due to its mechanism of action), with the effects of selected antipsychotic drugs, such as quetiapine, olanzapine, clozapine, risperidone, and ziprasidone (at the final concentrations corresponding to clinically effective doses used for the treatment of acute episodes of schizophrenia) on lipid peroxidation in human plasma measured by the level of thiobarbituric acid reactive substances (TBARS), which is a marker of oxidative stress. METHODS: The levels of TBARS were measured spectrophotometrically, according to the modification of the Rice-Evans method. RESULTS: Our results indicate that antipsychotics at doses recommended for the treatment of acute episodes of schizophrenia may induce distinct changes in the levels of lipid peroxidation products (TBARS) in plasma. Aripiprazole had no effect on the level of a lipid peroxidation marker in plasma, although used at lower doses it showed insignificant prooxidative properties similar to clozapine. Quetiapine had the strongest antioxidant properties, contrary to prooxidative action of risperidone, ziprasidone or haloperidol, and clozapine at lower doses. Olanzapine reduced the level of TBARS in plasma only at a lower dose. CONCLUSION: Antipsychotics at doses recommended for the treatment of acute episode in schizophrenia may induce the distinct changes in plasma lipid peroxidation. Aripiprazole did not induce significant changes in plasma lipid peroxidation. In further studies, the role of oxidative stress in schizophrenic patients together with their clinical symptomatology and use of antipsychotics should be taken into account. PMID- 29280535 TI - Repeat MitraClip for early recurrent mitral regurgitation. AB - Treatment for recurrent mitral regurgitation (MR) after MitraClip therapy remains a challenging issue. This study reports the efficacy of repeat MitraClip therapy for recurrent MR during the early phase after the index MitraClip procedure. We present a case series of four consecutive patients who underwent repeat MitraClip procedures for severe recurrent MR during the early phase. Partial clip detachment (PCD) was the suspected cause of recurrent MR in these cases. All patients received additional clip(s). PCD could be stabilized and MR grade improved in all cases compared with that before the second procedure. Repeat MitraClip procedures for recurrent MR due to PCD are feasible during the early phase. However, patients having PCD with paracommissural MR may not be good candidates for repeat MitraClip. PMID- 29280536 TI - Screening of genes involved in epithelial-mesenchymal transition and differential expression of complement-related genes induced by PAX2 in renal tubules. AB - AIM: The aim of the present study was to screen and verify downstream genes involved in the epithelial mesenchymal transition (EMT) induced by paired box 2 (PAX2) in NRK-52E cells. METHODS: NRK-52E cells were transfected with lentivirus carrying PAX2 gene or no-load virus respectively. Total RNA was isolated 72 h after transfection from PAX2-overexpressing cells and control cells. Isolated RNA was then hybridized with the Rat OneArray Plus expression profile chip. The chips were examined by Agilent 0.1 XDR to screen for differentially expressed genes, which were further analyzed to investigate complement-related genes as genes of interest. RESULTS: In NRK-52E cells, PAX2 overexpression promoted EMT followed by upregulation of 298 genes and downregulation of 293 genes. KEGG analysis indicated the differential expression of genes related to cytokines and their receptors, extracellular matrix (ECM), MAPKs, local adhesion, cancer, the complement cascade, and coagulation. Gene oncology analysis screened out genes related to molecular functions (e.g., hydrolase activity, phospholipase activity, components of the ECM) and biological processes (e.g., cell development, signal transduction, phylogeny), and cell components (e.g., cytoplasm, cell membrane, and ECM). Analysis of the complement system revealed upregulation of C3 and downregulation of CD55 and complement regulator factor H (CFH). CONCLUSION: PAX2 overexpression upregulates EMT in vitro and may regulate C3, CD55, and CFH. PMID- 29280537 TI - Pembrolizumab induced acute corneal toxicity after allogeneic stem cell transplantation. PMID- 29280538 TI - 'You're there because you are unprofessional': patient and public involvement as liminal knowledge spaces. AB - Patient and public involvement in health research and care has been repeatedly theorised using the metaphor of spaces, knowledge spaces and participatory citizenship spaces. Drawing on data from a three year qualitative study of people involved in health research with organisations across England, this article explores where these spaces fit in a wider social, political and historical landscape. It outlines a theme recurring frequently in the study data: a unified public/patient/service-user perspective in opposition to a professional/clinical/academic view. This is discussed in relation to Habermas's division between the lifeworld and system. Patient and public involvement is mapped as spaces between these spheres, therefore between the social norms pertaining to them. In this way, involvement spaces are seen as liminal, in between or threshold spaces; this concept provides us with new insights on both the opportunities and the conflicts that are integral in the ambiguous, complex interactions which take place in these spaces. PMID- 29280540 TI - Contact killing and antimicrobial properties of copper. AB - With the emergence of antibiotic resistance, the interest for antimicrobial agents has recently increased again in public health. Copper was recognized in 2008 by the United States Environmental Protection Agency (EPA) as the first metallic antimicrobial agent. This led to many investigations of the various properties of copper as an antibacterial, antifungal and antiviral agent. This review summarizes the latest findings about 'contact killing', the mechanism of action of copper nanoparticles and the different ways micro-organisms develop resistance to copper. PMID- 29280539 TI - Bacteriological evaluation of composted manure solids prepared from anaerobic digested slurry for hygienic recycled bedding materials for dairy cows. AB - Changes in mastitis-causing pathogens, pH and water content in composted manure solids (CMS) prepared from digested slurry were evaluated during turning at 2-day intervals for 8 days (C1-C4). The numbers of streptococci, coagulase-negative staphylococci and coliforms were 2.6 * 101 , 1.7 * 102 and 1.0 * 101 colony forming units (cfu)/g in CMS (C4) (summer), and these counts were markedly lower (P < 0.05) than those in CMS (C0 and C1). The bacterial counts ranged from 101 to 1.7 * 102 cfu/g in CMS (C4) (summer) and were within approved levels, <1 * 106 cfu/g, indicating a minimal mastitis risk. The temperatures in CMS (C1-C4) increased to 63 degrees C-74 degrees C in summer and 67 degrees C-70 degrees C in winter. The mean pH values in CMS (C0-C4) were 9.2 in summer and 8.7 in winter, and water contents ranged from 61.7% to 69.6% in summer and 73.2% to 66.2% in winter. The significant decrease of pathogenic bacteria in CMS appears to be closely related to temperature >63 degrees C for 8 days, pH 8.7-9.2, and water content 62% to 73%. This study demonstrates that prepared CMS has value as a recycled material with the potential to alleviate udder health issues in dairy cows. PMID- 29280542 TI - Evolution of optic nerve photography for glaucoma screening: a review. AB - Visual evaluation of the optic nerve has been one of the earliest and most widely used methods to evaluate patients for glaucoma. Photography has proven very useful for documentation of the nerve's appearance at a given time, allowing more detailed scrutiny then, and later comparison for change. Photography serves as the basis for real-time or non-simultaneous review in telemedicine and screening events allowing fundus and optic nerve evaluation by experts elsewhere. Expert evaluation of disc photographs has shown diagnostic performance similar to other methods of optic nerve evaluation for glaucoma. Newer technology has made optic nerve photography simpler, cheaper and more portable creating opportunities for broader utilization in screening in underserved populations by non-physicians. Recent investigations suggest that non-physicians or software algorithms for disc photograph evaluation have promise to allow more screening to be done with fewer experts. PMID- 29280541 TI - Ventricular arrhythmias immediately following transcatheter pulmonary valve implantation: A cause for concern? AB - BACKGROUND: Transcatheter pulmonary valve implantation (TPVI) has revolutionized the care of patients with congenital disorders of the right ventricular outflow tract (RVOT) and is increasingly being used in patients with native outflow tracts. This is the first study to specifically report the occurrence of ventricular arrhythmias in the immediate post-TPVI period. METHODS AND RESULTS: Medical records of all adult and pediatric patients who underwent TPVI at our institution between May 1, 2011 and March 1, 2016, were reviewed for the presence of clinically significant ventricular arrhythmias occurring within 30 days of TPVI. We defined a clinically significant arrhythmia as any ventricular arrhythmia that led to hemodynamic instability, resulted in a change of dose or addition of a new anti-arrhythmic medication, caused a delay in discharge, or was the primary reason for readmission. Seventy-five patients, with a median age of 19 years (range 4-65 years), underwent TPVI. In total, 12 (16%) patients had a clinically significant ventricular arrhythmia within 30 days following TPVI. Patients with native outflow tracts were at higher risk of post-TPVI arrhythmias than non-native outflow tract (29% vs. 9%, P = 0.02, adjusted OR 4.8, 95%CI 1.2 20.2). There were no cases of hemodynamic compromise or sudden cardiac death. The arrhythmias were well controlled with beta-blocker therapy. CONCLUSION: In this single center study, ventricular arrhythmias were common following TPVI, particularly in native outflow tract patients. However, the arrhythmias were generally benign and responded well to medical therapy when indicated. Long term therapy was often not needed. PMID- 29280543 TI - Associations between Escherichia coli O157 shedding and the faecal microbiota of dairy cows. AB - AIMS: Dairy cattle shed pathogenic Escherichia coli O157 (O157) in faeces, playing a role in human exposure. We aimed to measure faecal microbial communities in early lactation dairy cattle, and model outcomes with O157 shedding metrics. METHODS AND RESULTS: Daily faecal samples were collected from 40 cattle on two Colorado dairies for five consecutive days, and characterized for O157. 16S rRNA gene sequencing was used to measure sample-level microbial communities. Alpha-diversity metrics were associated with O157 outcomes via regression modelling, adjusting for confounders. Differential abundance of taxa were identified between O157(+) and O157(-) samples and between shedding days of individuals, using matched Wilcoxon rank-sum tests, zero-inflated Gaussian (ZIG) regression and negative binomial regression. After removing an outlier, multi-day and intermittently shedding cows had lower average richness compared to those that never shed. ZIG modelling revealed Bacillus coagulans to be more abundant in O157(-) samples, while Moryella were more abundant in O157(+) samples. Negative binomial models and Wilcoxon tests revealed no differentially abundant taxa between O157(+) vs O157(-) samples, or between shedding days of individuals. CONCLUSIONS: Microbial diversity and some taxa may be influenced by or affect O157 shedding by dairy cattle. SIGNIFICANCE AND IMPACT OF THE STUDY: If future work corroborates these findings, dairy cow microbial community changes may be used to guide on-farm strategies that mitigate O157 dissemination, protecting the human food chain. PMID- 29280544 TI - Low prevalence of the 'gang of seven' and absence of the O80:H2 serotypes among Shigatoxigenic and enteropathogenic Escherichia coli (STEC and EPEC) in intestinal contents of healthy cattle at two slaughterhouses in Belgium in 2014. AB - AIMS: The purpose of this survey was to estimate the respective prevalence of the 'gang of seven' and 'non-gang of seven' serotypes of Shigatoxigenic and enteropathogenic Escherichia coli and to identify the O80:H2 serotype in 245 intestinal contents collected at two slaughterhouses in Belgium in 2014. METHODS AND RESULTS: After overnight enrichment growth, the 69 intestinal contents testing positive with PCR targeting the eae, stx1 and stx2 genes were inoculated onto four agar media. Of the 2542 colonies picked up, 677 from 59 samples were PCR confirmed. The most frequent virulotypes were eae+ in 47 (80%) samples, stx2+ in 20 (34%) samples and eae+ stx1+ in 16 (27%) samples. PCR-positive colonies belonged to different virulotypes in 36 samples. No colony was O80-positive, whereas two eae+ colonies from two samples were O26:H11, 50 eae+ stx1+ and eae+ from eight samples were O103:H2 and two eae+ stx1+ stx2+ colonies from one sample were O157:H7. CONCLUSIONS: The 'non-gang of seven' serotypes are more frequent than the 'gang of seven' serotypes and the O80:H2 serotype was not detected among Shigatoxigenic and enteropathogenic Escherichia coli in the intestines of cattle at these two slaughterhouses. SIGNIFICANCE AND IMPACT OF THE STUDY: Although the identification protocols of Shigatoxigenic Escherichia coli focus on the 'gang of seven' serotypes, several other serotypes can be present with possible importance in public health. Innovative selective identification procedures should be designed. PMID- 29280545 TI - Perforated balloon technique: A simple and handy technique to combat no-reflow phenomenon in coronary system. AB - OBJECTIVE: Examining the efficacy and outcomes of intracoronary (IC) instillation of adenosine using a novel perforated balloon technique (PBT) to combat no-reflow phenomenon during percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). BACKGROUND: Occurrence of no-reflow during PCI is a serious adverse prognostic event and inability to re-establish better flow is associated with poor outcomes. Several pharmacological and non-pharmacological interventions have been used to treat this situation. This series describes the use of PBT for IC adenosine administration and its effects on outcomes during real world interventional practice. METHODS: Subjects comprised of 24 patients with ACS (out of a total of 1,634 patients undergoing PCI between January 2016 and June 2017) in whom we used PBT for IC administration of adenosine to treat coronary no reflow. RESULTS: PBT for IC adenosine instillation was used in 24 (1.5%) of 1,634 patients undergoing PCI. TIMI grade III flow was established in 21 patients (87.5%). In two patients (8.3%) TIMI grade II flow was established and in one patient (4.2%) we were unsuccessful. CONCLUSION: We demonstrate the safety and efficacy of a novel strategy for adenosine instillation in the distal coronary bed, the PBT. This technique enables rapid and cost-effective treatment of no reflow phenomenon during PCI for ACS. PMID- 29280546 TI - Age and Hydration dependence of jowl and forearm skin firmness in young and mature women. AB - BACKGROUND: Quantitative assessment of possible linkages between skin's firmness and water content is useful for cosmetic and clinical purposes and to better understand features of advancing age. OBJECTIVES: Our goals were to characterize age-related differential features in skin firmness in women and determine the relationship between skin firmness and indices of skin water. METHODS: Skin firmness was quantified using handheld devices that measure the force to indent skin 0.3 and 1.3 mm (F0.3 and F1.3). Skin hydration was quantified using handheld devices that measured tissue dielectric constant (TDC) at 300 MHz to skin depths of 0.5 and 2.0-2.5 mm. All parameters were measured bilaterally in the jowl area and volar forearm of 60 women grouped by age <45 years (YOUNG) and >=45 years old (MATURE). RESULTS: All measured parameters were bilaterally symmetrical at jowl and forearm. Forearm and jowl indentation forces were greater in YOUNG with statistically significant declines with advancing age with regression relations most evident at shallower indentation depths (P < .001). Quantitative relations for arm and jowl were F0.3 = 0.256 * AGE + 32.7 mN and F0.3 = -0.07 * AGE + 17.7 mN. Firmness was related to TDC values only when indentation force and TDC were assessed on the arm at the shallowest skin depths, as weakly related to firmness and was observed to change with age only when measured to a depth of 0.5 mm represented by TDC5 = 0.096 * AGE + 32.7. CONCLUSIONS: Experimental finding show clear differences in skin firmness between age-groups with skin hydration playing a minor role. Possible explanations and suggestions for further studies are provided. PMID- 29280547 TI - The relative validity of a food record using the smartphone application MyFitnessPal. AB - AIM: The present study aimed to validate food records on the application MyFitnessPal (MFP), comparing them with paper-based food records (P-FR). METHODS: Thirty university students, including males and females, volunteered and recorded dietary intakes on P-FR and MFP food records (MFP-FR). The values of energy, macronutrients and fibre from MFP-FR were compared with data from P-FR, calculated using Brazilian food composition tables. Adjustments for in-person variability and energy intake were performed, and comparisons were made between each data set, using the Wilcoxon signed-rank test, Spearman's correlation and Bland-Altman agreement plots. RESULTS: Positive moderate correlations between P FR and MFP-FR for all variables, and non-significant associations for energy and fibre were found. The Bland-Altman plots showed tendency to underestimation and relatively narrow limits of agreement. Carbohydrate and lipids show trends of increasing the degree of overestimation with increased intake, even after data normalisation. CONCLUSIONS: MFP tends to underestimate ingestion of nutrients probably due to inadequacies in the MFP database. However, MFP showed good relative validity, especially for energy and fibre. Its use, as well as other similar applications, should be encouraged, due to ease of assessing dietary information, although careful usage is recommended because of database gaps. PMID- 29280548 TI - Retrobulbar axonal degeneration due to optic disc drusen. PMID- 29280549 TI - New insights on the baker's yeast-mediated hydration of oleic acid: the bacterial contaminants of yeast are responsible for the stereoselective formation of (R)-10 hydroxystearic acid. AB - AIMS: The preparation of the high-value flavour gamma-dodecalactone is based on the biotransformation of natural 10-HSA, which is in turn obtained by microbial hydration of oleic acid. We want to establish a reliable baker's yeast-mediated procedure for 10-HSA preparation. METHODS AND RESULTS: The previously reported yeast-mediated hydration procedures are unreliable because bacteria-free baker's yeast is not able to hydrate oleic acid. The actual responsible for performing this reaction are the bacterial contaminants present in baker's yeast. Moreover, we demonstrated that the enantioselectivity in the production of (R)-10-HSA is affected mainly by the temperature used in the biotransformation. CONCLUSIONS: We demonstrated that Saccharomyces cerevisiae is not able to hydrate oleic acid, whereas different bacterial strains present in baker's yeast transform oleic acid into (R)-10-HSA. We reported a general procedure for the preparation of (R)-10 HSA starting from oleic acid and using commercially available baker's yeast. SIGNIFICANCE AND IMPACT OF THE STUDY: This study holds both scientific and industrial interest. It unambiguously establishes that the eukaryote micro organisms present in baker's yeast are not able to hydrate oleic acid. The isolation of oleic acid hydrating bacterial strains from commercial baker's yeast points to their prospective use for the industrial synthesis of 10-HSA. PMID- 29280550 TI - Determination of macrolide antibiotics residues in pork using molecularly imprinted dispersive solid-phase extraction coupled with LC-MS/MS. AB - A class-specific macrolide molecularly imprinted polymer was synthesized by precipitation polymerization using tulathromycin as the template and methacrylic acid as the functional monomer. The polymers revealed different specific adsorption and imprinting factor for macrolides with different spatial arrangement of side chains as well as lactonic ring size. And the molecularly imprinted polymer possessed maximum adsorption capacity (54.1 mg/g) and highest imprinting factor (2.4) toward 15-membered ring azithromycin. On the basis of molecularly imprinted polymer dispersive solid-phase extraction, a rapid, selective, and reproducible method for simultaneous determination of seven macrolide antibiotics residues in pork was established by using liquid chromatography with tandem mass spectrometry. At spiking levels of 5, 10, 25, and 100 MUg/kg, average recoveries of seven macrolides ranged from 68.6 to 95.5% with intraday and interday relative standard deviations below 8%. The limits of detection and limits of quantification were 0.2-0.5 and 0.5-2.0 MUg/kg, respectively. PMID- 29280551 TI - Predictors of patient radiation exposure during transcatheter aortic valve replacement. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) exposes patients to radiation. OBJECTIVES: We sought to identify factors associated with higher radiation exposure and to quantify their relative influence, which may inform reduction of this hazard. METHODS: All TAVR procedures at Rhode Island Hospital between March 20, 2012 and February 12, 2017 were included. Procedures were performed by two co-primary operators using a Siemens Artis Zeego system. Radiation metrics were generated by the imaging system. The primary metric was dose-area product (DAP, Gy*cm2 ), and secondary metrics were reference point air kerma (mGy) and fluoroscopy time (minutes). Data collected for the STS/ACC TVT Registry were utilized to develop a multivariable linear regression model predicting DAP. RESULTS: In 294 TAVRs, median DAP was 169 Gy*cm2 [interquartile range (IQR) 106-238]. The r2 values for the full 27-variable DAP model and reduced eight-variable model were 0.457 and 0.420, respectively. Valve area, aortic insufficiency, and procedure year (suggesting absence of a learning curve) were non-significant predictors in the full model, while increasing weight, cutdown transfemoral access, higher pre-procedure creatinine and hemoglobin, and vascular complications predicted higher DAP in both models. Results were unchanged when DAP was log-transformed. Secondary models for air kerma and fluoroscopy time revealed similar predictors. CONCLUSION: Factors associated with increased procedural complexity and duration as well as radiation attenuation and scatter predict increased patient radiation exposure during TAVR. Modification of procedural technique, especially using percutaneous femoral vascular access, may facilitate reduction in exposure. PMID- 29280552 TI - Left ventricular perforation after Impella placement. PMID- 29280553 TI - Dapsone for topical use in extemporaneous preparations. AB - BACKGROUND: The sulfone dapsone has an established role in systemic therapy. Its pharmacological and toxicological properties are well known. Topically, dapsone is used in a gel formulation for the treatment of acne vulgaris. In addition, there have been individual case reports on the efficacy of topical dapsone preparations in the treatment of various neutrophilic dermatoses. To date, no finished medicinal product for topical use has been available in Germany. MATERIAL AND METHODS: Against this background, we set out to develop extemporaneous preparations containing dapsone (5 %) that meet the quality requirements of the European Pharmacopoeia as well as the manufacturing requirements of the German Ordinance on the Operation of Pharmacies (ApBetrO). These formulations included the incorporation of dapsone in a hydrophobic cream base ("hydrophobe Basiscreme DAC") as well as in methylprednisolone aceponate 0.1 % ointment (alternatively, in the latter's cream base without active ingredient). RESULTS: Tests aimed at investigating the physical, chemical, and microbiological stability of these formulations showed them to meet the aforementioned quality requirements. CONCLUSION: The extemporaneous formulations presented herein broaden the therapeutic options for topical treatment, in particular for patients with chronic inflammatory dermatoses associated with a neutrophilic pathogenesis. PMID- 29280554 TI - Paraneoplastic pyoderma gangrenosum-like ulceration in T-cell large granular lymphocytic leukemia. PMID- 29280555 TI - Rhizosphere-associated Alcaligenes and Bacillus strains that induce resistance against blast and sheath blight diseases, enhance plant growth and improve mineral content in rice. AB - AIMS: To examine the biocontrol activities of five rhizobacterial strains (i.e. Alcaligenes faecalis strains Bk1 and P1, Bacillus amyloliquefaciens strain Bk7 and Brevibacillus laterosporus stains B4 and S5), to control the rice blast and sheath blight diseases in greenhouse and to study their possible modes of action. METHODS AND RESULTS: Five potential plant growth-promoting rhizobacterial (PGPR) strains isolated from rice rhizospheres were tested for in vitro antifungal activities against Magnaporthe oryzae, Rhizoctonia solani, Botrytis cinerea and Fusarium graminearum. In vitro trials showed that three strains, Bk1, P1 and Bk7, were able to unanimously suppress the mycelial growth of the target pathogens. In greenhouse, the application of these three PGPR strains significantly suppressed the incidences of rice blast and sheath blight diseases. At 2 weeks after pathogen inoculation, the highest percentages of disease suppression were noted for Alc. faecalis strain Bk1 (72%) for rice blast, Alc. faecalis strain P1 (71%) for sheath blight, followed by B. amyloliquefaciens strain Bk7. Moreover, these strains significantly improved the plant growth, enriched the content of mineral nutrients in seedlings and increased the expression of major defence-related rice genes. All three strains were marked positive for phosphate solubilization, the production of indoleacetic acid, ammonia and siderophores and catalase activity. In addition, these strains were able to form biofilms and carried multiple lipopeptide biosynthetic genes as revealed by multiplex PCR. CONCLUSION: This study reports new potential biocontrol agents for blast and sheath blight diseases of rice. SIGNIFICANCE AND IMPACT OF THE STUDY: This study contributes to better understanding of the mechanisms involved in interaction between beneficial rhizobacteria, fungal pathogens and host plants. PMID- 29280556 TI - Report on the 6th Congress of the Association for Health Information and Libraries in Africa (AHILA 6), Lusaka, Zambia, 14-18 September 1998. PMID- 29280557 TI - Innovations on the Internet. PMID- 29280558 TI - Rural information deprivation? PMID- 29280559 TI - Characterization and application of a lanthanide-based metal-organic framework in the development and validation of a matrix solid-phase dispersion procedure for pesticide extraction on peppers (Capsicum annuum L.) with gas chromatography-mass spectrometry. AB - The metal-organic framework [(La0.9 Sm0.1 )2 (DPA)3 (H2 O)3 ]infinity was synthetized and characterized by X-ray diffractometry, differential thermogravimetric analysis, and infrared spectroscopy. The material was tested for the development and validation of a matrix solid-phase dispersion procedure for extraction of atrazine, bifenthrin, bromuconazole, clofentezine, fenbuconazole, flumetralin, procymidone, and pirimicarb, from peppers, with analysis using gas chromatography with mass spectrometry in the selected ion monitoring mode. The method developed was linear over the range tested (50.0 1000.0 MUg/kg for procymidone and 200.0-1000.0 MUg/kg for all other pesticides), with correlation coefficients ranging from 0.9930 to 0.9992. Experiments were carried out at 250.0, 500.0, and 1000.0 MUg/kg fortification levels, and resulted in recoveries in the range of 52.7-135.0%, with coefficient of variation values between 5.2 and 5.4%, respectively, for [(La0.9 Sm0.1 )2 (DPA)3 (H2 O)3 ]infinity sorbent. Detection and quantification limits ranged from 16.0 to 67.0 MUg/kg and from 50.0 to 200.0 MUg/kg, respectively, for the different pesticides studied. The results were compared with literature data. The developed and validated method was applied to real samples. The analysis detected the presence of residues of pesticides procymidone, fenbuconazole, flumetralin, clofentezine, atrazine, and bifenthrin. PMID- 29280560 TI - Alloying in an Intercalation Host: Metal Titanium Niobates as Anodes for Rechargeable Alkali-Ion Batteries. AB - We discuss here a unique flexible non-carbonaceous layered host, namely, metal titanium niobates (M-Ti-niobate, M: Al3+ , Pb2+ , Sb3+ , Ba2+ , Mg2+ ), which can synergistically store both lithium ions and sodium ions via a simultaneous intercalation and alloying mechanisms. M-Ti-niobate is formed by ion exchange of the K+ ions, which are specifically located inside galleries between the layers formed by edge and corner sharing TiO6 and NbO6 octahedral units in the sol-gel synthesized potassium titanium niobate (KTiNbO5 ). Drastic volume changes (approximately 300-400 %) typically associated with an alloying mechanism of storage are completely tackled chemically by the unique chemical composition and structure of the M-Ti-niobates. The free space between the adjustable Ti/Nb octahedral layers easily accommodates the volume changes. Due to the presence of an optimum amount of multivalent alloying metal ions (50-75 % of total K+ ) in the M-Ti-niobate, an efficient alloying reaction takes place directly with ions and completely eliminates any form of mechanical degradation of the electroactive particles. The M-Ti-niobate can be cycled over a wide voltage range (as low as 0.01 V) and displays remarkably stable Li+ and Na+ ion cyclability (>2 Li+ /Na+ per formula unit) for widely varying current densities over few hundreds to thousands of successive cycles. The simultaneous intercalation and alloying storage mechanisms is also studied within the density functional theory (DFT) framework. DFT expectedly shows a very small variation in the volume of Al titanium niobate following lithium alloying. Moreover, the theoretical investigations also conclusively support the occurrence of the alloying process of Li ions with the Al ions along with the intercalation process during discharge. The M-Ti-niobates studied here demonstrate a paradigm shift in chemical design of electrodes and will pave the way for the development of a multitude of improved electrodes for different battery chemistries. PMID- 29280561 TI - Detailed Analysis of Pancreatic Tumor Cell Attachment on Gradient PDEGMA Brushes. AB - Poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) brushes show interesting thermoresponsive behavior that can be applied for cell release surfaces. Here it is shown that PDEGMA thickness gradients, which are synthesized by surface-initiated atom transfer radical polymerization, allow the systematic and precise analysis of the attachment of PaTu 8988 cells. By pumping the polymerization solution into the reactor with vertically fixed initiator samples, PDEGMA gradients with linearly increasing dry ellipsometric thickness with typical slopes of 2.5 nm cm-1 are obtained. A very narrow transition of PaTu 8988t cell attachment is observed that starts for a thickness larger than 7.1 +/- 0.2 nm. For PDEGMA layers thicker than 8.7 +/- 0.2 nm no attached cells are found. This very narrow transition in brush properties within a thickness difference of <2 nm from cell-adherent to cell-nonadherent can be determined in much greater detail than before owing to the thickness gradients with shallow slope. PMID- 29280562 TI - Mandenka from Senegal: Next Generation Sequencing typings reveal very high frequencies of particular HLA class II alleles and haplotypes. PMID- 29280563 TI - Characterization of the Proteome of Theobroma cacao Beans by Nano-UHPLC-ESI MS/MS. AB - Cocoa seed storage proteins play an important role in flavour development as aroma precursors are formed from their degradation during fermentation. Major proteins in the beans of Theobroma cacao are the storage proteins belonging to the vicilin and albumin classes. Although both these classes of proteins have been extensively characterized, there is still limited information on the expression and abundance of other proteins present in cocoa beans. This work is the first attempt to characterize the whole cocoa bean proteome by nano-UHPLC-ESI MS/MS analysis using tryptic digests of cocoa bean protein extracts. The results of this analysis show that >1000 proteins could be identified using a species specific Theobroma cacao database. The majority of the identified proteins were involved with metabolism and energy. Additionally, a significant number of the identified proteins were linked to protein synthesis and processing. Several proteins were also involved with plant response to stress conditions and defence. Albumin and vicilin storage proteins showed the highest intensity values among all detected proteins, although only seven entries were identified as storage proteins. A comparison of MS/MS data searches carried out against larger non specific databases confirmed that using a species-specific database can increase the number of identified proteins, and at the same time reduce the number of false positives. The results of this work will be useful in developing tools that can allow the comparison of the proteomic profile of cocoa beans from different genotypes and geographic origins. Data are available via ProteomeXchange with identifier PXD005586. PMID- 29280565 TI - Quantitative Proteomic Analysis of Changes Related to Age and Calorie Restriction in Rat Liver Tissue. AB - Calorie restriction (CR) is the most frequently studied mechanism for increasing longevity, protecting against stress, and delaying age-associated diseases. Most studies have initiated CR in young animals to determine the protective effects against aging. Although aging phenomena are well-documented, the molecular mechanisms of aging and CR remain unclear. In this study, we observe changes in hepatic proteins upon age-related and diet-restricted changes in the rat liver using quantitative proteomics. Quantitative proteomes are measured using tandem mass tag labeling followed by LC-MS/MS. We compare protein levels in livers from young (6 months old) and old (25 months old) rats with 40% calorie-restricted (YCR and OCR, respectively) or ad libitum diets. In total, 44 279 peptides and 3134 proteins are identified and 260 differentially expressed proteins are found. Functional enrichment analysis show that these proteins are mainly involved in glucose and fatty acid metabolism-related processes, consistent with the theory that energy metabolism regulation is dependent on age-related and calorie restricted changes in liver tissue. In addition, proteins mediating inflammation and gluconeogenesis are increased in OCR livers, but not YCR livers. These results show that CR in old rats might not have antiaging benefits because liver inflammation is increased. PMID- 29280564 TI - beta-Cyclodextrin polymer@Fe3 O4 based magnetic solid-phase extraction coupled with HPLC for the determination of benzoylurea insecticides from honey, tomato, and environmental water samples. AB - In this work, a magnetic beta-cyclodextrin polymer was successfully prepared and used as an adsorbent for the magnetic solid-phase extraction of six benzoylurea insecticides (diflubenzuron, triflumuron, hexaflumuron, teflubenzuron, flufenoxuron, and chlorfluazuron) from honey, tomato, and environmental water samples. The influence of the main experimental conditions on the extraction was studied. Under the optimized conditions, the beta-cyclodextrin polymer@Fe3 O4 showed an excellent extraction performance for the benzoylurea insecticides. A good linearity was obtained for the analytes in the range of 3.0-800 ng/g for honey samples, 0.3-160 ng/g for tomato samples, and 0.1-80.0 ng/mL for water samples, with the correlation coefficients above 0.9998. Satisfactory repeatabilities were achieved, with the relative standard deviations less than 5.7%. The limits of detection (S/N = 3) of the method for the benzoylurea insecticides were 0.2-0.8 ng/g for honey samples, 0.04-0.10 ng/g for tomato samples, and 0.02-0.05 ng /mL for water samples. The method was successfully used for the determination of the six benzoylurea insecticides residues in honey, tomato, and environmental water samples with a satisfactory result. PMID- 29280566 TI - gamma-Secretase Inhibition Induces Muscle Hypertrophy in a Notch-Independent Mechanism. AB - A wide variety of cellular processes and signaling events are regulated by the proteolytic enzyme gamma-secretase. Notch-1 is one of the substrates of gamma secretase and its role in the regulation of muscle differentiation has been well described. Importantly, besides Notch-1, a number of proteins have been identified to undergo proteolysis by gamma-secretase. To date, the specific role of gamma-secretase during embryonic skeletal muscle differentiation has not been studied. Therefore, we address this question through the analysis of in vitro grown chick myogenic cells during the formation of multinucleated myotubes. The gamma-secretase inhibitor DAPT (N-N[-(3,5-Difluorophenacetyl-l-alanyl)]-S-328 phenylglycine-t-butyl-ester) induces muscle hypertrophy. Knockdown of Notch-1 using siRNA specific to chick shows no significant effect in myotube size, suggesting that gamma-secretase-dependent effects on muscle hypertrophy in chick myogenic cells are Notch-1-independent. We also investigate the effects of gamma secretase inhibition in the whole proteomic profile of chick myogenic cells. We identified 276 differentially expressed proteins from Label-free proteomic approach. Data overview of interaction network obtained from STRING show that after gamma-secretase inhibition cells exhibited imbalance in protein metabolism, cytoskeleton/adhesion, and Sonic Hedgehog signaling. The collection of these results provides new insights into the role of gamma-secretase in skeletal muscle hypertrophy. PMID- 29280567 TI - Type 1 diabetes mellitus associated with activated phosphatidylinositol 3-kinase delta syndrome, type 2. PMID- 29280569 TI - Sol-gel niobia sorbent with a positively charged octadecyl ligand providing enhanced enrichment of nucleotides and organophosphorus pesticides in capillary microextraction for online HPLC analysis. AB - A niobia-based sol-gel organic-inorganic hybrid sorbent carrying a positively charged C18 ligand (Nb2 O5 -C18 (+ve)) was synthesized to achieve enhanced enrichment capability in capillary microextraction of organophosphorus compounds (which include organophosphorus pesticides and nucleotides) before their online analysis by high-performance liquid chromatography. The sorbent was designed to simultaneously provide three different types of molecular level interactions: electrostatic, Lewis acid-base, and van der Waals interactions. To understand relative contributions of various molecular level analyte-sorbent interactions in the extraction process, two other sol-gel niobia sorbents were also created: (a) a purely inorganic sol-gel niobia sorbent (Nb2 O5 ) and (b) an organic-inorganic hybrid sol-gel niobia sorbent carrying an electrically neutral-bonded octadecyl ligand (Nb2 O5 -C18 ). The extraction efficiency of the created sol-gel niobia sorbent (Nb2 O5 -C18 (+ve)) was compared with that of analogously designed and synthesized titania-based sol-gel sorbent (TiO2 -C18 (+ve)), taking into consideration that titania-based sorbents present state-of-the-art extraction media for organophosphorus compounds. In capillary microextraction with high performance liquid chromatography analysis, Nb2 O5 -C18 (+ve) had shown 40-50% higher specific extraction values (a measure of extraction efficiency) over that of TiO2 -C18 (+ve). Compared to TiO2 -C18 (+ve), Nb2 O5 -C18 (+ve) also provided superior analyte desorption efficiency (96 vs. 90%) during the online release of the extracted organophosphorus pesticides from the sorbent coating in the capillary microextraction capillary to the chromatographic column using reversed phase high-performance liquid chromatography mobile phase. PMID- 29280570 TI - Reconciling gene trees with organism history: the mtDNA phylogeography of three Nesotes species (Coleoptera: Tenebrionidae) on the western Canary Islands. AB - The processes of island colonization and speciation are investigated through mtDNA studies on Canary Island beetles. The genus Nesotes (Coleoptera: Tenebrionidae) is represented by 19 endemic species on the Canary Islands, the majority of which are single island endemics. Nesotes conformis is the most widespread, occurring on Gran Canaria, Tenerife, La Palma and El Hierro. Nesotes conformis forms a paraphyletic assemblage, with a split between Gran Canaria and the other three islands. Nesotes conformis of the western Canary Islands cluster with Nesotes altivagans and Nesotes elliptipennis from Tenerife. Fifty-two individuals from this western islands species complex have been sequenced for 675 base pairs of the mtDNA cytochrome oxidase II gene, representing Tenerife, La Palma and El Hierro. A neighbour joining analysis of maximum likelihood distances resulted in three distinct mtDNA lineages for N. conformis, two of which also include mitotypes of N. altivagans and N. elliptipennis. Through application of parametric bootstrap tests, we are able to reject hypotheses of monophyly for both N. conformis and N. altivagans. Nesotes altivagans and N. elliptipennis are poorly separated morphologically and mtDNA sequence data adds support to this being one species with a highly variable morphology. We propose that N. altivagans/N. elliptipennis is recently derived from two ancestral mtDNA lineages within N. conformis from the Teno region of Tenerife. We further propose colonization of the younger islands of La Palma and El Hierro by N. conformis from a mitochondrial lineage within the Teno massif (colonization; diversification; mitochondrial DNA; Canary Islands; Coleoptera). PMID- 29280571 TI - Phylogeography of Caribbean lizard malaria: tracing the history of vector-borne parasites. AB - The Anolis lizards of the eastern Caribbean islands are parasitized by several species of malaria parasites (Plasmodium). Here I focus on two species of Plasmodium, using molecular data (mitochondrial cytochrome b sequences) to recover the phylogeography of the parasites throughout the Lesser Antilles and Puerto Rico. The two parasites were originally described as a single species, P. azurophilum, which infects both red and white blood cells. Here the two species are termed P. azurophilum Red and P. azurophilum White based on their host cell type. Six haplotypes were found in 100 infections sequenced of P. azurophilum Red and six in 45 infections of P. azurophilum White. Nested clade analysis revealed a significant association of geographical location and clades as well as a pattern of past fragmentation of parasite populations. This is consistent with the hypothesis that vector-borne parasites such as malaria may be subject to frequent local extinctions and recolonizations. Comparison of the phylogeography of the lizard and parasites shows only weak concordance; that is, the parasites colonized the lizards in the islands, but dispersal events between islands via vectors or failed lizard colonizations were present. The two parasites had different histories, P. azurophilum Red colonized the islands from both the north and south, and P. azurophilum White originated in the central Lesser Antilles, probably from P. azurophilum Red, then moved to both north and south. This is the first study to examine the biogeography of a pair of sibling species of vector borne parasites within an island archipelago system. PMID- 29280572 TI - Diversity of age-specific reproductive rates may result from ageing and optimal resource allocation. AB - This paper reports the results of a dynamic programming model which optimizes resource allocation to growth, reproduction and repair of somatic damage, based on the disposable soma theory of ageing. Here it is shown that different age dependent patterns of reproductive rates are products of optimal lifetime strategies of resource partitioning. The array of different reproductive patterns generated by the model includes those in which reproduction begins at the maximum rate at maturity and then declines to the end of life, or increases up to a certain age and then drops. The observed patterns reflect optimal resource allocation shaped by the level of extrinsic mortality. A continuous decline in the reproductive rate from the start of reproduction is associated with high extrinsic mortality, and an early increase in the reproductive rate occurs under low extrinsic mortality. A long-lived organism shows a low reproductive rate early in life, and short-lived organisms start reproduction at the maximum rate. PMID- 29280573 TI - Genetic variation and asexual reproduction in the facultatively parthenogenetic cockroach Nauphoeta cinerea: implications for the evolution of sex. AB - Asexual reproduction could offer up to a two-fold fitness advantage over sexual reproduction, yet higher organisms usually reproduce sexually. Even in facultatively parthenogenetic species, where both sexual and asexual reproduction is sometimes possible, asexual reproduction is rare. Thus, the debate over the evolution of sex has focused on ecological and mutation-elimination advantages of sex. An alternative explanation for the predominance of sex is that it is difficult for an organism to accomplish asexual reproduction once sexual reproduction has evolved. Difficulty in returning to asexuality could reflect developmental or genetic constraints. Here, we investigate the role of genetic factors in limiting asexual reproduction in Nauphoeta cinerea, an African cockroach with facultative parthenogenesis that nearly always reproduces sexually. We show that when N. cinerea females do reproduce asexually, offspring are genetically identical to their mothers. However, asexual reproduction is limited to a nonrandom subset of the genotypes in the population. Only females that have a high level of heterozygosity are capable of parthenogenetic reproduction and there is a strong familial influence on the ability to reproduce parthenogenetically. Although the mechanism by which genetic variation facilitates asexual reproduction is unknown, we suggest that heterosis may facilitate the switch from producing haploid meiotic eggs to diploid, essentially mitotic, eggs. PMID- 29280568 TI - Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. AB - Fibroblasts have exceptional phenotypic plasticity and capability to secrete vast amount of soluble factors, extracellular matrix components and extracellular vesicles. While in physiological conditions this makes fibroblasts master regulators of tissue homeostasis and healing of injured tissues, in solid tumors cancer associated fibroblasts (CAFs) co-evolve with the disease, and alter the biochemical and physical structure of the tumor microenvironment, as well as the behavior of the surrounding stromal and cancer cells. Thus CAFs are fundamental regulators of tumor progression and influence response to therapeutic treatments. Increasing efforts are devoted to better understand the biology of CAFs to bring insights to develop complementary strategies to target this cell type in cancer. Here we highlight components of the tumor microenvironment that play key roles in cancer progression and invasion, and provide an extensive overview of past and emerging understanding of CAF biology as well as the contribution that MS-based proteomics has made to this field. PMID- 29280574 TI - Female polyandry affects their sons' reproductive success in the red flour beetle Tribolium castaneum. AB - A potential benefit to females mating with multiple males is the increased probability that their sons will inherit traits enhancing their pre- or post mating ability to obtain fertilizations. We allowed red flour beetle (Tribolium castaneum) females to mate on three consecutive days either repeatedly to the same male or to three different males. This procedure was carried out in 20 replicate lines, 10 established with wild-type, and 10 with the Chicago black morph, a partially dominant phenotypic marker. The paternity achieved by the sons of females from polyandrous vs. monandrous lines of contrasting morph was assessed in the F1, F2 and F3 generation by mating wild-type stock females to two experimental males and assigning the progeny to either sire based on phenotype. The sons of polyandrous wild-type females achieved significantly higher paternity when mating in the second male role than the sons of monandrous wild-type females. By contrast, when mating in the first male role, males produced by females from polyandrous lines tended to have lower paternity than males from monandrous lines. Both effects were independent of the number of mates of the black competitor's mother, and interacted significantly with the number of progeny laid by the female. These results provide the first evidence that manipulating the number of mates of a female can influence her sons' mating success and suggest a potential trade-off between offence and defence in this species. PMID- 29280575 TI - An analysis of G matrix variation in two closely related cricket species, Gryllus firmus and G. pennsylvanicus. AB - An important issue in evolutionary biology is understanding the pattern of G matrix variation in natural populations. We estimated four G matrices based on the morphological traits of two cricket species, Gryllus firmus and G. pennsylvanicus, each reared in two environments. We used three matrix comparison approaches, including the Flury hierarchy, to improve our ability to perceive all aspects of matrix variation. Our results demonstrate that different methods perceive different aspects of the matrices, which suggests that, until more is known about these methods, future studies should use several different statistical approaches. We also found that the differences in G matrices within a species can be larger than the differences between species. We conclude that the expression of the genetic architecture can vary with the environment and that future studies should compare G matrices across several environments. We also conclude that G matrices can be conserved at the level of closely related species. PMID- 29280576 TI - Evolutionary trade-offs in locomotor capacities in lacertid lizards: are splendid sprinters clumsy climbers? AB - We tested the hypothesis that an evolutionary trade-off exists between the capacity to run on level terrain and the ability to climb inclined structures in lacertid lizards. Biomechanical and physiological models of lizard locomotor performance suggest that the morphological design requirements of a ground dwelling vs. scansorial life style are difficult to reconcile. This conflict is thought to preclude simultaneous evolution of maximal locomotor performance on level and inclined terrain. This notion has been corroborated by comparative studies on lizard species from other groups (Anolis, Chamaeleo, Sceloporus), but is not supported by our data on 13 species from the family Lacertidae. We found no indication of a negative association between maximal sprint speed of lizards over a level racetrack (indicative of ground-dwelling locomotor performance), on an inclined stony surface (indicative of climbing performance over rock faces) and inclined mesh surface (indicative of clambering performance among vegetation). Moreover, morphological characteristics associated with fast sprinting capacities (e.g. long hind limbs) apparently enhance, rather than hinder climbing and clambering performance. We conclude that in our sample of lacertid lizards, the evolution of fast sprinting capacity on level terrain has not inflicted major restrictions on climbing and clambering performance. PMID- 29280577 TI - Fitness-consequences of geitonogamous selfing in a clonal marine angiosperm (Zostera marina). AB - Plant mating systems have received considerable attention because the proportion of selfed vs. outcrossed progeny is an important evolutionary factor. In clonally reproducing plants, geitonogamous selfing between distant ramets belonging to the same genet is expected to be widespread, yet empirical data are sparse. Nothing is known about between-ramet selfing in aquatic flowering plants with subaqueous pollen transfer, most of which display pronounced clonal reproduction. From two locations in the western Baltic Sea, I present data on the effects of patch isolation and clonal diversity on the outcrossing rate of eelgrass, Zostera marina L., based on the genotypes of maternal plants and recently fertilized ovules scored at eight microsatellite loci. There were no differences in outcrossing rates between vegetation patches and continuous meadow although patches were nearly always composed of single genets. Quantitative effects of clonal diversity were present in the continuous vegetation where a significant positive correlation between genet diversity and the proportion of outcrossed offspring was detected (Kendall's tau=0.82, P=0.0017). On a population-scale as well, the genotypic diversity was positively correlated with outcrossing. The relative fitness of selfed offspring was low (omega +/- 95% confidence interval=0.56 +/- 0.032 and 0.322 +/- 0.15) indicating that geitonogamy incurred substantial fitness costs. Selfing rates in Z. marina may not be in evolutionary equilibrium because of spatial and temporal heterogeneity of clonal size and diversity. The high prevalence of dioecy in seagrasses may have evolved to avoid the fitness costs associated with geitonogamy. PMID- 29280578 TI - Immunoglobulin plasma concentration in relation to egg laying and mate ornamentation of female barn swallows (Hirundo rustica). AB - In vertebrates, offspring have a relatively inefficient immune system soon after birth. Female birds transmit immunoglobulins to the egg, which can confer protection against parasites to their offspring after hatching, but allocation of immune factors can depend on the reproductive value of the offspring as affected, for example, by the quality of their father. We analyse the variation in immunoglobulin levels of female barn swallows (Hirundo rustica) during the breeding cycle in relation to the expression of a secondary sexual character of their mates. Circulating immunoglobulins peaked on approximately the day before that of laying of their first egg, but postlaying concentration was similar to the concentration well before laying. Immunoglobulin levels per unit volume of plasma were lower for females breeding late compared with those breeding early. Haematocrit of females reached an absolute minimum on the day of laying of the third egg. In males, concentration of immunoglobulins relative to other plasma proteins did not change in relation to the breeding stage. Smaller relative concentrations of immunoglobulins and haematocrit were observed in males breeding late in the season. Immunoglobulin concentration of females was positively correlated with the level of ornamentation of their mates. These results suggest that females alter their immune profile to transmit humoral factors providing immune defence against pathogens to their offspring after hatching. This enhancement of immune protection is larger when the offsprings are of relatively large reproductive value as when sired by high quality males. Alternatively, females with relatively large immunoglobulin concentration preferentially mate with the most ornamented males. PMID- 29280579 TI - Size-dependent sex allocation in a simultaneous hermaphrodite parasite. AB - Most models of sex allocation distinguish between sequential and simultaneous hermaphrodites, although an intermediate sexual pattern, size-dependent sex allocation, is widespread in plants. Here we investigated sex allocation in a simultaneous hermaphrodite animal, the tapeworm Schistocephalus solidus, in which adult size is highly variable. Sex allocation was determined using stereological techniques, which allow measuring somatic and reproductive tissues in a common currency, namely volume. We investigated the relationships between individual volume and allocation to different reproductive tissues using an allometric model. One measure of female allocation, yolk gland volume, increased more than proportionally with individual volume. This is in contrast to the measure of male allocation, testis volume, which showed a strong tendency to increase less than proportionally with individual volume. Together these patterns led to sex allocation being strongly related to individual volume, with large individuals being more biased towards female allocation. We discuss these findings in the light of current ideas about size-dependent sex allocation in, primarily, plants and try to extend them to simultaneous hermaphrodite animals. PMID- 29280580 TI - Ploidy evolution in the yeast Saccharomyces cerevisiae: a test of the nutrient limitation hypothesis. AB - The nutrient limitation hypothesis provides a nongenetic explanation for the evolution of life cycles that retain both haploid and diploid phases: differences in nutrient requirements and uptake allow haploids to override the potential genetic advantages provided by diploidy under certain nutrient limiting conditions. The relative fitness of an isogenic series of haploid, diploid and tetraploid yeast cells (Saccharomyces cerevisiae), which were also equivalent at the mating type locus, was measured. Fitness was measured both by growth rate against a common competitor and by intrinsic growth rate in isolated cultures, under four environmental conditions: (1) rich medium (YPD) at the preferred growth temperature (30 degrees C); (2) nutrient poor medium (MM) at 30 degrees C; (3) YPD at a nonpreferred temperature (37 degrees C); and (4) MM at 37 degrees C. In contrast to the predictions of the nutrient limitation hypothesis, haploids grew significantly faster than diploids under nutrient rich conditions, but there were no apparent differences between them when fitness was determined by relative competitive ability. In addition, temperature affected the relative growth of haploids and diploids, with haploids growing proportionately faster at higher temperatures. Tetraploids performed very poorly under all conditions compared. Cell geometric parameters were not consistent predictors of fitness under the conditions measured. PMID- 29280581 TI - Changes in thermotolerance and Hsp70 expression with domestication in Drosophila melanogaster. AB - To examine how the duration of laboratory domestication may affect Drosophila stocks used in studies of thermotolerance, we measured expression of the inducible heat-shock protein Hsp70 and survival after heat shock in D. melanogaster strains recently collected from nature and maintained in laboratory culture for up to 50 or more generations. After an initial increase in both Hsp70 expression and thermotolerance immediately after transfer to laboratory medium, both traits remained fairly constant over time and variation among strains persisted through laboratory domestication. Furthermore, variation in heat tolerance and Hsp70 expression did not correlate with the length of time populations evolved in the laboratory. Therefore, while environmental variation likely contributed most to early shifts in strain tolerance and Hsp70 expression, other population parameters, for example genetic drift, inbreeding, and selection likely affected these traits little. As long as populations are maintained with large numbers of individuals, the culture of insects in the laboratory may have little effect on the tolerance of different strains to thermal stress. PMID- 29280582 TI - Parthenogenetic flatworms have more symbionts than their coexisting, sexual conspecifics, but does this support the Red Queen? AB - The Red Queen hypothesis predicts that sexuality is favoured when virulent parasites adapt quickly to host genotypes. We studied a population of the flatworm Schmidtea polychroa in which obligate sexual and parthenogenetic individuals coexist. Infection rates by an amoeboid protozoan were consistently higher in parthenogens than in sexuals. Allozyme analysis showed that infection was genotype specific, with the second most common clone most infected. A laboratory measurement of fitness components failed to reveal high infection costs as required for the Red Queen. Although fertility was lower in more infected parthenogens, this effect can also be explained by the accumulation of mutations. We discuss these and other characteristics of our model system that may explain how a parasite with low virulence can show this pattern. PMID- 29280583 TI - Relative fitness of two hermaphroditic mating types in the androdioecious clam shrimp, Eulimnadia texana. AB - Androdioecy (populations of males and hermaphrodites) is a rare reproductive form, being described from only a handful of plants and animals. One of these is the shrimp Eulimnadia texana, which has populations comprised of three mating types: two hermaphroditic types (monogenics and amphigenics) and males. In a recent study, the amphigenic hermaphrodites were found to be in greater abundance than that predicted from a model of this mating system. Herein, we compare the relative fitness of offspring from amphigenic and monogenic siblings, attempting to understand the greater relative abundance of the former. Populations started with offspring from selfed monogenic hermaphrodites had a net reproductive rate (R) 87% that of offspring from their amphigenic siblings. Additionally, within populations of amphigenic offspring (which included males, monogenics and amphigenics), amphigenics survived longer than monogenics. These differences help to explain the increased relative abundance of amphigenics in natural populations, but amphigenics continue to be more abundant than expected. PMID- 29280584 TI - Cultural niche construction and human evolution. AB - Organisms frequently choose, regulate, construct and destroy important components of their environments, in the process changing the selection pressures to which they and other organisms are exposed. We refer to these processes as niche construction. In humans, culture has greatly amplified our capacity for niche construction and our ability to modify selection pressures. We use gene-culture coevolutionary models to explore the evolutionary consequences of culturally generated niche construction through human evolution. Our analysis suggests that where cultural traits are transmitted in an unbiased fashion from parent to offspring, cultural niche construction will have a similar effect to gene-based niche construction. However, cultural transmission biases favouring particular cultural traits may either increase or reduce the range of parameter space over which niche construction has an impact, which means that niche construction with biased transmission will either have a much smaller or a much bigger effect than gene-based niche construction. The analysis also reveals circumstances under which cultural transmission can overwhelm natural selection, accelerate the rate at which a favoured gene spreads, initiate novel evolutionary events and trigger hominid speciation. Because cultural processes typically operate faster than natural selection, cultural niche construction probably has more profound consequences than gene-based niche construction, and is likely to have played an important role in human evolution. PMID- 29280585 TI - Sponge paraphyly and the origin of Metazoa. AB - In order to allow critical evaluation of the interrelationships between the three sponge classes, and to resolve the question of mono- or paraphyly of sponges (Porifera), we used the polymerase chain reaction (PCR) to amplify almost the entire nucleic acid sequence of the 18S rDNA from several hexactinellid, demosponge and calcareous sponge species. The amplification products were cloned, sequenced and then aligned with previously reported sequences from other sponges and nonsponge metazoans and variously distant outgroups, and trees were constructed using both neighbour-joining and maximum parsimony methods. Our results suggest that sponges are paraphyletic, the Calcarea being more related to monophyletic Eumetazoa than to the siliceous sponges (Demospongiae, Hexactinellida). These results have important implications for our understanding of metazoan origins, because they suggest that the common ancestor of Metazoa was a sponge. They also have consequences for basal metazoan classification, implying that the phylum Porifera should be abandoned. Our results support the upgrading of the calcareous sponge class to the phylum level. PMID- 29280586 TI - Facultative sex allocation in snow skink lizards (Niveoscincus microlepidotus). AB - Mathematical models suggest that reproducing females may benefit by facultatively adjusting their relative investment into sons vs. daughters, in response to population-wide shifts in operational sex ratio (OSR). Our field studies on viviparous alpine skinks (Niveoscincus microlepidotus) document such a case, whereby among- and within-year shifts in OSR were followed by shifts in sex allocation. When adult males were relatively scarce, females produced male-biased litters and larger sons than daughters. The reverse was true when adult males were relatively more common. That is, females that were courted and mated by few males produced mainly sons (and these were larger than daughters), whereas females that were courted and mated by many males produced mainly daughters (and these were larger than sons). Maternal body size and condition also covaried with sex allocation, and the shifting pattern of sexual size dimorphism at birth may reflect these correlated effects rather than a discrete component of an evolved sex-allocation strategy. PMID- 29280587 TI - Effective population size, reproductive success and sperm precedence in the butterfly, Bicyclus anynana, in captivity. AB - A pedigree approach is used to estimate the effective population size yn two population cages of the butterfly, Bicyclus anynana. Each cage was founded with 54 individually marked adults of each sex. Matings were recorded over a 3-day period. Eggs were then collected from each female over a similar period before the numbers of hatching larvae were counted to assess progeny number. The males showed a higher variance in reproductive success than the females. Since about one-quarter of all females mated more than once, we also examined the pattern of sperm precedence using molecular markers or, in separate crossing experiments, wing pattern mutants. Both instances of complete first and last male sperm precedence, as well as of sperm mixing, were found. In some crosses a 'leakiness' was found in which some of the early eggs laid by a female were fertilized by a male partner which was subsequently completely unsuccessful. However, the estimates of effective population size were largely unaffected by the pattern of sperm precedence. Estimates for Ne : N in each cage were close to 0.60. The possibility of obtaining comparable estimates in selected natural populations of butterflies is discussed. PMID- 29280588 TI - Temperature and clinal variation in larval growth efficiency in Drosophila melanogaster. AB - Geographic clines in ectotherm species including Drosophila melanogaster have been found throughout the world, with genetically larger body size and shorter development time occurring at high latitudes. Temperature is thought to play a major role in the evolution of this clinal variation. Laboratory thermal selection has effects similar to those seen in geographical clines. Evolution at low temperatures results in more rapid development to larger adult flies. This study investigated the effects of geographical origin and experimental temperature on larval growth efficiency in D. melanogaster. Larvae from populations that had evolved at high latitudes were found to use limited food more efficiently, so that the overall adult body size achieved was larger. Larvae reared at a lower experimental temperature (18 degrees C) used food more efficiently than those reared at a higher temperature (25 degrees C). The increases in growth efficiency found in populations from high latitudes could explain their increased body size and more rapid development. PMID- 29280589 TI - Basal cell carcinoma of the nipple-areola complex with multiple lesions: Possible causative role of radiation. PMID- 29280590 TI - Editorial Board and International Advisory Board: Angew. Chem. Int. Ed. 1/2018. PMID- 29280591 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 1/2018. PMID- 29280592 TI - Diversity and Collaboration-Essential Ingredients for Success. PMID- 29280593 TI - Quantitative Proteomic Analysis in Candida albicans Using SILAC-Based Mass Spectrometry. AB - Stable isotope labelling by amino acids in cell culture (SILAC) in conjunction with MS analysis is a sensitive and reliable technique for quantifying relative differences in protein abundance and posttranslational modifications between cell populations. We develop and utilise SILAC-MS workflows for quantitative proteomics in the fungal pathogen Candida albicans. Arginine metabolism provides important cues for escaping host defences during pathogenesis, which limits the use of auxotrophs in Candida research. Our strategy eliminates the need for engineering arginine auxotrophs for SILAC experiments and allows the use of ARG4 as selectable marker during strain construction. Cells that are auxotrophic for lysine are successfully labelled with both lysine and arginine stable isotopes. We find that prototrophic C. albicans preferentially uses exogenous arginine and down-regulates internal production, which allow it to achieve high incorporation rates. However, similar to other yeast, C. albicans is able to metabolise heavy arginine to heavy proline, which compromised the accuracy of protein quantification. A computational method is developed to correct for the incorporation of heavy proline. In addition, we utilise the developed SILAC labelling in C. albicans for the global quantitative proteomic analysis of a strain expressing a phosphatase-dead mutant Cdc14PD . PMID- 29280594 TI - Predicting Analgesic Use after Spinal Surgery. PMID- 29280597 TI - THE PLIGHT OF THE PERIOPERATIVE NURSE PRACTITIONER IN AUSTRALIA. AB - "A nurse practitioner is a registered nurse educated to a post graduate Masters level and authorised to function autonomously and collaboratively in an advanced and extended clinical role' (Queensland Government 2011). PMID- 29280595 TI - S2k Guidelines - Cutaneous Lymphomas Update 2016 - Part 2: Treatment and Follow up (ICD10 C82 - C86). PMID- 29280596 TI - The HLA-G 14 bp insertion/deletion polymorphism and its association with soluble HLA-G levels in women with recurrent miscarriages. AB - HLA-G, a nonclassical class-Ib gene is mainly expressed on extravillous trophoblasts at the fetal-maternal interface. HLA-G molecule is considered to play an important role in maternal immune suppression during pregnancy. The 14 bp insertion/deletion polymorphism (rs66554220) in exon eight of the HLA-G gene influences HLA-G mRNA stability and isoform splicing patterns. In this study, 202 recurrent miscarriage (RM) women with two or more than two consecutive miscarriages, their 202 partners and 204 fertile control women with at least one live birth and no miscarriages were analyzed for 14 bp insertion/deletion polymorphism. Soluble HLA-G (sHLA-G) levels were also determined and compared between randomly selected 111 RM women and 111 control women using QAYEE-Bio ELISA kits. Student's t test and chi2 test were used to depict the statistical differences. The results showed no significant differences for 14 bp allele and genotype frequencies between the study groups. However, our study showed a significant difference (P = .0107) for sHLA-G levels in RM women and control women. Furthermore, a significant difference (P = .0135) for sHLA-G levels in relation to +/-14 bp heterozygous genotype was seen between the two groups. The 14 bp allele sharing between the partners did not show any significant association with the number of miscarriages in RM couples. The association of 14 bp polymorphism and recurrent miscarriages was not significant in our study. PMID- 29280598 TI - SITUATION AWARENESS AND PATIENT SAFETY IN THE PERIOPERATIVE ENVIRONMENT. AB - In 2014-15 there were 10.2 million hospitalisations in Australia, and approximately 2.5 million of those admissions required surgery. As such, perioperative safety is crucial to patient outcomes (AIHW 2016). PMID- 29280599 TI - SURGICAL COUNTING: A PERIOPERATIVE NURSE'S PERSPECTIVE. AB - The Australian College of Perioperative Nurses (ACORN) have developed a set of standards to guide clinical practice within the perioperative setting. The ACORN standard 'Management of accountable items used during surgery and procedures' (ACORN 2016) details a process for perioperative nurses to follow when undertaking a surgical count. PMID- 29280600 TI - PARENTAL PRESENCE DURING INDUCTION OF ANAESTHESIA -- AN EVIDENCE BASED PRACTICE REVIEW. AB - Parental presence during the induction of anaesthesia remains a controversial issue related to family centered care which is highlighted through discrepancies in observational studies, beliefs and current practices. PMID- 29280601 TI - GUIDANCE FOR PERIOPERATIVE NURSES TO PREVENT PERIOPERATIVE HYPOTHERMIA IN OBSTETRICS. AB - The prevention of perioperative hypothermia is a responsibility of all members of the perioperative team. Nurses are well placed to have a central role in implementing strategies to reduce perioperative heat loss, which is associated with a host of adverse outcomes (National Collaborating Centre for Nursing and Supportive Care 2008). PMID- 29280602 TI - COLOURED PATIENT FOLDERS: THE LITTLE THINGS MAKING A DIFFERENCE FOR THE BEDSIDE NURSE. AB - Jointly initiated by Monash Children's and The Royal Children's Hospital (RCH), The Victorian Children's Tool for Observation and Response project known as VICTOR (www.victor.org.au) is a sector-led project funded by the Victorian Paediatric Clinical Network. PMID- 29280603 TI - A2K: A COMPREHENSIVE AND SYSTEMATIC APPROACH TO THE PHYSICAL ASSESSMENT OF POSTOPERATIVE PATIENT. AB - The physical assessment of postoperative patients is a crucial and potentially lifesaving skill that may be improved with the use of a mnemonic to guide assessment structure. PMID- 29280604 TI - IMPLEMENTING A MENTORING PROGRAM IN THE OPERATING SUITE. AB - Due to the rapidly increasing demand for healthcare, driven by an ageing population and the rising cost of technology, Australia is facing the challenge of sustaining a health workforce to meet this demand. In the most recent Health Workforce Australia (HWA) Report (2014) a predicted shortfall in the supply and demand of critical care and emergency nurses was reported. PMID- 29280605 TI - PHYSICAL RESTRAINTS IN INTENSIVE CARE: EXPERIENCES OF PATIENTS, FAMILIES AND NURSES. AB - Critically ill patients admitted to an intensive care unit (ICU) often require many invasive procedures and medical devices (Martin and Mathisen 2005). While these interventions are a necessity, they can potentially cause patients a great amount of pain and discomfort, often leading to restlessness and agitation (Langley et al. 2011). PMID- 29280606 TI - Patient Opinion on the Affordable Care Act in an Otolaryngology Practice: the Ideological Divide. AB - OBJECTIVE: To assess patient opinion on the Patient Protection and Affordable Care Act (PPACA) in an Otolaryngology practice and the factors that influence those opinions. STUDY DESIGN: Observational study. METHODS: An anonymous survey assessing patient opinion on the PPACA, demographic information, political affiliation, medical diagnosis, and insurance status was distributed to patients in three separate Otolaryngology clinics (General, cancer, and Low income/Indigent) from April to June 2014. A total of 300 surveys were distributed and 207 were used for final analysis. The primary study outcome measures were patient opinion of the PPACA and statistically significant variables affecting that opinion. The association of Support for the PPACA and variables were tested using the Chi-square test. RESULTS: The only variables that showed a significant association with support for the PPACA were Political Party (p<0.0001) and Ethnicity (p=0.0050). Specifically, a higher proportion of Democrats support the PPACA than Republicans and a higher proportion of African Americans and Hispanic/Latinos support the PPACA than Whites and Native Americans. CONCLUSION: Our survey of current Otolaryngology patients mirrors national findings of the division between Republicans and Democrats in their attitudes towards the Affordable Care Act. Political party appears to be the most significant factor in shaping patient opinion on this controversial subject regardless of insurance status or cancer diagnosis and a higher proportion of African Americans and Hispanic/Latinos support the PPACA than Whites and Native Americans. LEVEL OF EVIDENCE: IV. PMID- 29280607 TI - Correction to Thrombin Ultrasensitive Detection Based on Chiral Supramolecular Assembly Signal-Amplified Strategy Induced by Thrombin-Binding Aptamer. PMID- 29280608 TI - Phase Transformations in the CeO2-Sm2O3 System: A Multiscale Powder Diffraction Investigation. AB - The structure evolution in the CeO2-Sm2O3 system is revisited by combining high resolution synchrotron powder diffraction with pair distribution function (PDF) to inquire about local, mesoscopic, and average structure. The CeO2 fluorite structure undergoes two phase transformations by Sm doping, first to a cubic (C type) and then to a monoclinic (B-type) phase. Whereas the C to B-phase separation occurs completely and on a long-range scale, no miscibility gap is detected between fluorite and C-type phases. The transformation rather occurs by growth of C-type nanodomains embedded in the fluorite matrix, without any long range phase separation. A side effect of this mechanism is the ordering of the oxygen vacancies, which is detrimental for the application of doped ceria as an electrolyte in fuel cells. The results are discussed in the framework of other Y and Gd dopants, and the relationship between nanostructuring and the above equilibria is also investigated. PMID- 29280609 TI - New Perspectives in Biofilm Eradication. AB - Microbial biofilms, which are elaborate and highly resistant microbial aggregates formed on surfaces or medical devices, cause two-thirds of infections and constitute a serious threat to public health. Immunocompromised patients, individuals who require implanted devices, artificial limbs, organ transplants, or external life support and those with major injuries or burns, are particularly prone to become infected. Antibiotics, the mainstay treatments of bacterial infections, have often proven ineffective in the fight against microbes when growing as biofilms, and to date, no antibiotic has been developed for use against biofilm infections. Antibiotic resistance is rising, but biofilm-mediated multidrug resistance transcends this in being adaptive and broad spectrum and dependent on the biofilm growth state of organisms. Therefore, the treatment of biofilms requires drug developers to start thinking outside the constricted "antibiotics" box and to find alternative ways to target biofilm infections. Here, we highlight recent approaches for combating biofilms focusing on the eradication of preformed biofilms, including electrochemical methods, promising antibiofilm compounds and the recent progress in drug delivery strategies to enhance the bioavailability and potency of antibiofilm agents. PMID- 29280610 TI - Immunomodulatory ECM-like Microspheres for Accelerated Bone Regeneration in Diabetes Mellitus. AB - Bone repair and regeneration process is markedly impaired in diabetes mellitus (DM) that affects hundreds of millions of people worldwide. As a chronic inflammatory disease, DM creates a proinflammatory microenvironment in defective sites. Most of the studies on DM-associated bone regeneration, however, neglect the importance of immunomodulation under the DM condition and adopt the same approaches to normal bone healing, leading to limited bone healing. In this study, we developed a unique bioinspired injectable microsphere as an osteoimmunomodulatory biomaterial that modulates macrophages to create a prohealing microenvironment under the DM condition. The microsphere was self assembled with heparin-modified gelatin nanofibers, and interleukin 4 (IL4) was incorporated into the nanofibrous heparin-modified gelatin microsphere (NHG-MS). IL4 has binding domains with heparin, and the binding of IL4 to heparin stabilizes this cytokine, protects it from denaturation and degradation, and subsequently prolongs its sustained release to modulate macrophage polarization. The IL4-loaded NHG-MS switched the proinflammatory M1 macrophage into a prohealing M2 phenotype, recovered the M2/M1 ratio to a normal level, efficiently resolved the inflammation, and ultimately enhanced osteoblastic differentiation and bone regeneration. The development of osteoimmunomodulatory biomaterials that harness the power of macrophages for immunomodulation, therefore, is a novel and promising strategy to enhance bone regeneration under DM condition. PMID- 29280611 TI - Facile Strategy to Generate Aligned Polymer Nanofibers: Effects on Cell Adhesion. AB - Structure of polymer fiber membranes plays a vital role in controlling cell responses as applied to immobilize targets for specific cell interactions. Electrospinning is a simple and powerful method to prepare polymer fiber membranes with scales from nano- to micrometers. In this report, a facile yet versatile strategy has been developed for fabricating polymer nanofiber membranes with well-aligned structures using a glass sheet between the needle and a static drum as the collector. Effects of solution concentration, polymer molecular weight, applied voltage, and collection distance on the morphologies of the formed fibers were systematically studied. Adhesion of cells (e.g., mouse melanoma cells B16-F10 and fibroblast cells NIH-3T3) on the fiber membrane has been further investigated. Our results show that cell morphologies varied from elongated to spherical on the random fiber membrane when the pore area of membrane decreased. In contrast, on the membrane with aligned morphology, when decreasing the gap width of fiber membrane, cell is found to keep elongated state and spread along the alignment direction. This work provides a facile yet effective strategy to engineer surface structures of the fiber membranes for controlling cell adhesion. PMID- 29280612 TI - Light-Guided Nanomotor Systems for Autonomous Photothermal Cancer Therapy. AB - Machines have greatly contributed to the human civilization, enabling tasks beyond our capacities for improved quality of life. Recently, the progress in nanotechnology has triggered to build a miniaturized machine of nanoscale. In this context, synthetic nanomotors have gained considerable interest because of their great promise for diverse applications. Currently, the movement control of these nanomotors has been widely investigated using various stimuli. Here, we demonstrate near-infrared (NIR) light controlled on/off motion of stomatocyte nanomotors powered by the conversion of hydrogen peroxide. The nanomotors encapsulating naphthalocyanine (NC) are aggregated or separated (collective motion) with or without near-IR light illumination, resulting in the well controlled movement. Remarkably, the nanomotors can move directionally toward hydrogen peroxide released from cancer cells and photothermally ablate the cancer cells. Taken together, our stomatocyte nanomotor systems can be effectively harnessed for autonomous photothermal cancer therapy. PMID- 29280613 TI - Multiphoton-Polymerized 3D Protein Assay. AB - Multiphoton polymerization (MPP) enables 3D fabrication of micro- and nanoscale devices with complex geometries. Using MPP, we create a 3D platform for protein assays. Elevating the protein-binding sites above the substrate surface allows an optically sectioned readout, minimizing the inevitable background signal from nonspecific protein adsorption at the substrate surface. Two fluorescence-linked immunosorbent assays are demonstrated, the first one relying on streptavidin biotin recognition and the second one on antibody recognition of apolipoprotein A1, a major constituent of high-density lipoprotein particles. Signal-to-noise ratios exceeding 1000 were achieved. The platform has high potential for 3D multiplexed recognition assays with an increased binding surface for on-chip flow cells. PMID- 29280614 TI - Illumination of Nanoliter-NMR Spectroscopy Chips for Real-Time Photochemical Reaction Monitoring. AB - We report the use of a small-volume nuclear-magnetic-resonance (NMR)-spectroscopy device with integrated fiber-optics for the real-time detection of UV-vis-light assisted chemical reactions. An optical fiber is used to guide the light from LEDs or a laser diode positioned safely outside the magnet toward the 25 nL detection volume and placed right above the microfluidic channel, irradiating the transparent back of the NMR chip. The setup presented here overcomes the limitations of conventional NMR systems for in situ UV-vis illumination, with the microchannel permitting efficient light penetration even in highly concentrated solutions, requiring lower-power light intensities, and enabling high photon flux. The efficacy of the setup is illustrated with two model reactions activated at different wavelengths. PMID- 29280615 TI - Elusive Scorpionates: C3-Symmetric, Formally Dianionic, Facially Tridentate Ligands. AB - The reaction of AlCl3 with [(2-HO-3,5-tBu2C6H2)3P] (H3[O3P]) results in AlCl[O3PH] ([O3PH]2- = [(2-O-3,5-tBu2C6H2)3PH]2-), which is a zwitterionic molecule containing an unprecedented C3-symmetric but formally dianionic chelate. Derivatization of [O3PH]2- gives [O3PR]2- (R = hydrocarbon), demonstrating the development of a novel class of long elusive scorpionates. PMID- 29280616 TI - Recombinant Peptidomimetic-Nano Luciferase Tracers for Sensitive Single-Step Immunodetection of Small Molecules. AB - Phage borne peptides isolated from phage libraries have proven to be valuable reagents for the development of small-molecule immunoassays. However, the large size, low diffusion rate, and biological nature of the phage particles create some limitations to their use and require secondary reagents for its detection. In this work, we explore the use of the Nano luciferase (NanoLuc) as a fusion partner to generate recombinant tracers for immunoassay development. The imidaclothiz peptidomimetic C2-15 that specifically binds to the anti imidaclothiz monoclonal antibody (mAb) 1E7 was fused to NanoLuc, both at the N terminus (C2-15-NanoLuc) and C terminus (NanoLuc-C2-15). NanoLuc-C2-15 showed better performance than C2-15-NanoLuc and was adopted to develop a bioluminescent enzyme immunoassay (BLEIA) and a bioluminescence lateral flow immunoassay (BLLFIA) for imidaclothiz. The luminescence signal of NanoLuc-C2-15 rapidly reaches high intensity with slow attenuation, which enabled one to capture the BLLFIA readout by using a smartphone without an external light source. The IC50 of the BLEIA and BLLFIA were 3.3 +/- 0.2 and 6.4 +/- 0.4 ng mL-1, respectively. Both immunoassays exhibited good accuracy for the detection of imidaclothiz in environmental and agricultural samples. PMID- 29280617 TI - Synaptic Plasticity in the Nucleus Accumbens: Lessons Learned from Experience. AB - Synaptic plasticity contributes to behavioral adaptations. As a key node in the reward pathway, the nucleus accumbens (NAc) is important for determining motivation-to-action outcomes. Across animal models of motivation including addiction, depression, anxiety, and hedonic feeding, selective recruitment of neuromodulatory signals and plasticity mechanisms have been a focus of physiologists and behaviorists alike. Experience-dependent plasticity mechanisms within the NAc vary depending on the distinct afferents and cell-types over time. A greater understanding of molecular mechanisms determining how these changes in synaptic strength track with behavioral adaptations will provide insight into the process of learning and memory along with identifying maladaptations underlying pathological behavior. Here, we summarize recent findings detailing how changes in NAc synaptic strength and mechanisms of plasticity manifest in various models of motivational disorders. PMID- 29280618 TI - Electrically Conductive Coordination Polymer for Highly Selective Chemiresistive Sensing of Volatile Amines. AB - A new electrically conductive coordination polymer is synthesized using anthracene-incorporated organic ligand. The compound exhibits a band-like structure and long-range pi-pi stacking of ligand. Interestingly, the fabricated chemiresisitor using this coordination polymer shows selective sensing behavior for volatile amine detection with characteristics of quick response, good reproducibility, and room-temperature operation. This study not only presents a rare example of electrically conductive coordination polymer but also illustrates the useful application of coordination polymer for chemiresistor. PMID- 29280619 TI - Dual Role of a Fluorescent Peptidyl Probe Based on Self-Assembly for the Detection of Heparin and for the Inhibition of the Heparin-Digestive Enzyme Reaction. AB - The detection of fluorescent probes for biomolecules and control of the function of a complex through a recognition process have not been investigated intensively. A fluorescent peptidyl probe (1) based on the self-assembly stimulated by heparin was synthesized. The fluorescent probe with an aggregation induced emission fluorophore formed a self-assembling complex with heparin, resulting in a sensitive and selective turn-on response to heparin compared to its biological competitors. The detection limits for heparin were measured to be 138.0 pM (R2 = 0.976) in aqueous solution and 2.6 nM (R2 = 0.996) in aqueous solution containing human serum. Nanosized aggregates formed through the self assembly of the complex showed potent resistance against the heparin-digestive enzyme. The dual role of the probe for the detection of heparin and the inhibition of heparinase-mediated digestion through the recognition process was used for the real-time monitoring of the enzyme activity of heparinase for the digestion of heparin. Furthermore, the dual role of the probe was applied for the detection of the oversulfated chondroitin sulfate contaminant in heparin. PMID- 29280620 TI - Electrochemiluminescence Peptide-Based Biosensor with Hetero-Nanostructures as Coreaction Accelerator for the Ultrasensitive Determination of Tryptase. AB - In this work, a luminol-centric biosensor was constructed for the ultrasensitive detection of tryptase (TPS) combining dissolved O2 as the endogenous coreactant and Au-Ag-Pt heteronanostructures (AAPHNs) as coreaction accelerator. Dissolved O2 could rapidly generate superoxide anion radical (O2*-) with the catalysis of AAPHNs to in situ react with luminol anion radical (L*-) to generate excited state species 3-aminophthalate (AP2-*) for emitting ECL signal, resulting in a remarkable "single on" state. In order to further improve the sensitivity of the sensor, we employed self-assembled DNA nanotubes (DNANTs) as a carrier to immobilize the luminophore of doxorubicin-luminol (Dox-Lu) complex. In this assay system, target tryptase could directly induce the cleavage of vasoactive intestinal peptide (VIP), which caused the ECL probe of DNANTs-Dox-Lu releasing from the electrode surface to obtain a significant "signal off" state. By changing the signal from "on" to "off", the proposed ECL peptide-based biosensor for TPS detection achieved a dynamic concentration range (2.5 pg/mL-200 ng/mL) with an extremely low detection limit of 0.81 pg/mL. This work presented a new signal amplification method for the construction of the sensor based on the luminol-dissolved O2 ECL system. PMID- 29280622 TI - Pulverization Control by Confining Fe3O4 Nanoparticles Individually into Macropores of Hollow Carbon Spheres for High-Performance Li-Ion Batteries. AB - In this article, double carbon shell hollow spheres which provide macropores (mC) for ultrasmall Fe3O4 nanoparticle (10-20 nm) encapsulation individually were first prepared (Fe3O4@mC). The well-constructed Fe3O4@mC electrode materials offer the feasibility to study the volume change, aggregation, and pulverization process of the active Fe3O4 nanoparticles for Li-ion storage in a confined space. Fe3O4@mC exhibits excellent electrochemical performances and delivers a high capacity of 645 mA h g-1 at 2 A g-1 after 1000 cycles. Even at 10 A g-1 or after 1000 cycles at 2 A g-1, the porous carbon structure was well maintained and no obvious aggregation and pulverization of the Fe3O4 nanoparticles was observed, although the volume of the active Fe3O4 particles was expanded to 40-60 nm compared to that of the original particles (10-20 nm). This can be due to the in situ embedment of one Fe3O4 nanoparticle into one macropore individually. The uniform dispersion and confinement of the Fe3O4 nanoparticles in the macropores of the carbon shell could effectively accommodate severe volume variations upon cycling and prevent self-aggregation and spreading out from the carbon shell during the expansion process of the nanoscale Fe3O4 particles, leading to improved capacity retention. Our work confirms the effectiveness for pulverization control by confining Fe3O4 nanoparticles individually into macropores to improve its Li-ion storage properties, providing a novel strategy for the design of new-structured anode materials for Li-ion batteries. PMID- 29280621 TI - Study of Forster Resonance Energy Transfer to Lipid Domain Markers Ascertains Partitioning of Semisynthetic Lipidated N-Ras in Lipid Raft Nanodomains. AB - Cellular membranes are heterogeneous planar lipid bilayers displaying lateral phase separation with the nanometer-scale liquid-ordered phase (also known as "lipid rafts") surrounded by the liquid-disordered phase. Many membrane associated proteins were found to permanently integrate into the lipid rafts, which is critical for their biological function. Isoforms H and N of Ras GTPase possess a unique ability to switch their lipid domain preference depending on the type of bound guanine nucleotide (GDP or GTP). This behavior, however, has never been demonstrated in vitro in model bilayers with recombinant proteins and therefore has been attributed to the action of binding of Ras to other proteins at the membrane surface. In this paper, we report the observation of the nucleotide-dependent switch of lipid domain preferences of the semisynthetic lipidated N-Ras in lipid raft vesicles in the absence of additional proteins. To detect segregation of Ras molecules in raft and disordered lipid domains, we measured Forster resonance energy transfer between the donor fluorophore, mant, attached to the protein-bound guanine nucleotides, and the acceptor, rhodamine conjugated lipid, localized into the liquid-disordered domains. Herein, we established that N-Ras preferentially populated raft domains when bound to mant GDP, while losing its preference for rafts when it was associated with a GTP mimic, mant-GppNHp. At the same time, the isolated lipidated C-terminal peptide of N-Ras was found to be localized outside of the liquid-ordered rafts, most likely in the bulk-disordered lipid. Substitution of the N-terminal G domain of N Ras with a homologous G domain of H-Ras disrupted the nucleotide-dependent lipid domain switch. PMID- 29280623 TI - Metabolism of a Phenylarsenical in Human Hepatic Cells and Identification of a New Arsenic Metabolite. AB - Environmental contamination and human consumption of chickens could result in potential exposure to Roxarsone (3-nitro-4-hydroxyphenylarsonic acid), an organic arsenical that has been used as a chicken feed additive in many countries. However, little is known about the metabolism of Roxarsone in humans. The objective of this research was to investigate the metabolism of Roxarsone in human liver cells and to identify new arsenic metabolites of toxicological significance. Human primary hepatocytes and hepatocellular carcinoma HepG2 cells were treated with 20 or 100 MUM Roxarsone. Arsenic species were characterized using a strategy of complementary chromatography and mass spectrometry. The results showed that Roxarsone was metabolized to more than 10 arsenic species in human hepatic cells. A new metabolite was identified as a thiolated Roxarsone. The 24 h IC50 values of thiolated Roxarsone for A549 lung cancer cells and T24 bladder cancer cells were 380 +/- 80 and 42 +/- 10 MUM, respectively, more toxic than Roxarsone, whose 24 h IC50 values for A549 and T24 were 9300 +/- 1600 and 6800 +/- 740 MUM, respectively. The identification and toxicological studies of the new arsenic metabolite are useful for understanding the fate of arsenic species and assessing the potential impact of human exposure to Roxarsone. PMID- 29280624 TI - Near-Infrared Light Induced Phase Transition of Biodegradable Composites for On Demand Healing and Drug Release. AB - Light responsive materials play an important role in many biomedical applications. Despite the great potential, commonly available systems are limited by their toxicity and lack of biodegradability. Here, an efficient light triggered system from safe, biodegradable star-poly(ethylene glycol) (star-PEG) and poly(epsilon-caprolactone) (PCL) with varying melting points controlled by the length of the CL segments is described. When incorporated with gold nanoshells (GNS) and exposed to near-infrared (NIR) irradiation, matrices temporarily disengage, thus allowing efficient on-demand healing and drug release. The responsiveness of this system to light, with its tailorable physical and healing properties, biocompatibility, biodegradability, and the capability to incorporate drugs and on-demand drug release are all desirable traits for numerous clinical applications. PMID- 29280625 TI - Water-Resistant Polymeric Acid Membrane Catalyst for Acetone Detection in the Exhaled Breath of Diabetics. AB - Endogenous volatile organic compounds (VOCs) such as acetone in exhaled human breath are associated with metabolic conditions in the bloodstream. Development of compact, rapid detectors of exhaled breath chemical composition in clinical settings is challenging due to the small sample size that can be collected during a single exhalation as well as spectroscopic interference by the abundance of water. In this paper, we show that the activity of a catalytic polymer membrane (Nafion 117) toward the heterogeneous condensation reaction of immobilized resorcinol reagent with gas-phase acetone can be preserved even at 100% ambient relative humidity through the incorporation of organic acids such as vanillic or tiglic. The reaction produces a colored flavan product that permits highly selective and sensitive correlation to acetone concentration in exhaled breath. Such behavior suggests solvent displacement, analogous to homogeneous liquid phase systems. However, unlike classic acid-base equilibria, the extent of optode water resistance is shown to increase with the pKa of the imbibed organic acid while peak signal intensity of the imbibed acid undergoes a bathochromic shift to longer wavelengths. These observations are consistent with competition between organic acid deprotonation by water in a mixed solvent system on the one hand and immobilization on the other. Finally, we demonstrate how when applied to the direct chemical analysis of acetone in exhaled human breath, the approach yields excellent correlation to blood glucose in diabetics. PMID- 29280626 TI - Multifunctional Microwell Arrays for Single Cell Level Functional Analysis of Lymphocytes. AB - Functional analysis of lymphocytes is important for development of vaccines and diagnosis/treatment of various immune-related diseases. In this review, we describe multifunctional microwell arrays that enable functional analysis of lymphocytes at the single cell level. We first discuss key parameters for microwell array design. Then, we describe how different types of multifunctional microwell arrays were developed for various applications, including live cell imaging of lymphocyte activation, proliferation, and differentiation, and analyses of effector functions such as cytokine secretion and target cell lysis. Incorporation of novel surface chemistries and functional materials into microwell arrays for enhancing sensing capabilities will widen applications of this technology. Multifunctional microwell arrays will be a powerful tool for the development of novel therapeutics against immune-related diseases, in particular, for cancer immunotherapy. PMID- 29280627 TI - Composition Formulas of Inorganic Compounds in Terms of Cluster Plus Glue Atom Model. AB - The present paper attempts to identify the molecule-like structural units in inorganic compounds, by applying the so-called "cluster plus glue atom model". This model, originating from metallic glasses and quasi-crystals, describes any structure in terms of a nearest-neighbor cluster and a few outer-shell glue atoms, expressed in the cluster formula [cluster](glue atoms). Similar to the case for normal molecules where the charge transfer occurs within the molecule to meet the commonly known octet electron rule, the octet state is reached after matching the nearest-neighbor cluster with certain outer-shell glue atoms. These kinds of structural units contain information on local atomic configuration, chemical composition, and electron numbers, just as for normal molecules. It is shown that the formulas of typical inorganic compounds, such as fluorides, oxides, and nitrides, satisfy a similar octet electron rule, with the total number of valence electrons per unit formula being multiples of eight. PMID- 29280628 TI - Structural Effects on the Spin Dynamics of Potential Molecular Qubits. AB - Control of spin-lattice magnetic relaxation is crucial to observe long quantum coherence in spin systems at reasonable temperatures. Such a control is most often extremely difficult to achieve, because of the coexistence of several relaxation mechanisms, that is direct, Raman, and Orbach. These are not always easy to relate to the energy states of the investigated system, because of the contribution to the relaxation of additional spin-phonon coupling phenomena mediated by intramolecular vibrations. In this work, we have investigated the effect of slight changes on the molecular structure of four vanadium(IV)-based potential spin qubits on their spin dynamics, studied by alternate current (AC) susceptometry. The analysis of the magnetic field dependence of the relaxation time correlates well with the low-energy vibrational modes experimentally detected by time-domain THz spectroscopy. This confirms and extends our preliminary observations on the role played by spin-vibration coupling in determining the fine structure of the spin-lattice relaxation time as a function of the magnetic field, for S = 1/2 potential spin qubits. This study represents a step forward in the use of low-energy vibrational spectroscopy as a prediction tool for the design of molecular spin qubits with long-lived quantum coherence. Indeed, quantum coherence times of ca. 4.0-6.0 MUs in the 4-100 K range are observed for the best performing vanadyl derivatives identified through this multitechnique approach. PMID- 29280629 TI - Correction to "Highly Active and Selective Hydrogenation of CO2 to Ethanol by Ordered Pd-Cu Nanoparticles". PMID- 29280630 TI - Phenanthrenes: A Promising Group of Plant Secondary Metabolites. AB - Although phenanthrenes are considered to constitute a relatively small group of natural products, discovering new phenanthrene derivatives and evaluating their prospective biological activities have become of great interest to many research groups worldwide. Based on 160 references, this review covers the phytochemistry and pharmacology of 213 naturally occurring phenanthrenes that have been isolated between 2008 and 2016. More than 40% of the 450 currently known naturally occurring phenanthrenes were identified during this period. The family Orchidaceae is the most abundant source of these compounds, although several new plant families and genera have been involved in the search for phenanthrenes. The presence of certain substituent patterns may be restricted to specific families; vinyl-substituted phenanthrenes were reported only from Juncaceae plants, and prenylated derivatives occur mainly in Euphorbiaceae species. Therefore, these compounds also can serve as chemotaxonomic markers. Almost all of the newly isolated compounds have been studied for their biological activities (e.g., potential cytotoxic, antimicrobial, anti-inflammatory, and antioxidant effects), and many of them showed multiple activities. According to the accumulated data, denbinobin, with a novel mechanism of action, has great potential as a lead compound for the development of a new anticancer agent. PMID- 29280631 TI - Liquid Chromatography High-Resolution Mass Spectrometry Identifies the Glycation Sites of Bovine Serum Albumin Induced by d-Ribose with Ultrasonic Treatment. AB - Ultrasonication is an emerging technology applied in food processing and biological experimental pretreatments. Cavitation phenomena induced during ultrasonic treatment can generate localized high temperature and pressure, which can result in glycation reaction between protein and reducing sugars. In this study, the mixture of bovine serum albumin (BSA) and d-ribose was treated under 600 W for different times. Interestingly, a large amount of carbonized black materials appeared after ultrasonication, while the UV absorbance and intrinsic fluorescence spectra reflecting conformational changes were not obvious. Only 12 sites (11 lysines and 1 arginine) of the BSA with ribose under ultrasonic treatment for 35 min were identified through liquid chromatography high resolution mass spectrometry (LCHR-MS). K547, K548, R359/R360, and K587 were the most reactive glycated sites, with the average degree of substitution per peptide molecule (DSP) value ranging from 15 to 35%. The glycated modification was distributed not only in domain III, but also in domains I and II. The glycated modification could occur during ultrasonic treatment, thereby influencing the properties of biomacromolecule after extraction. PMID- 29280632 TI - Germacrane-Type Sesquiterpenoids with Antiproliferative Activities from Eupatorium chinense. AB - Ten new germacrane-type sesquiterpenoids (1-10) were isolated from a whole plant extract of Eupatorium chinense. The structures were elucidated by analysis of their NMR and MS data as well as by comparison with literature values. The absolute configuration of eupachinsin A (1) was determined by single-crystal X ray diffraction analysis. Compounds 3 and 4 exhibited cytotoxicity against a human breast cancer cell line (MDA-MB-231), with IC50 values of 0.8 and 3.4 MUM, respectively. In addition, compounds 3-5 showed cytotoxicity against the human hepatocellular carcinoma cell line (HepG2), with IC50 values ranging from 3.6 to 7.6 MUM. PMID- 29280633 TI - Superconductivity on Hole-Doping Side of (La0.5-xNa0.5+x)Fe2As2. AB - (La0.5-xNa0.5+x)Fe2As2 ((La,Na)122) is an interesting system in the sense that either electrons (x < 0) or holes (x > 0) can be doped into the Fe2As2 layers, simply by changing the composition value x. However, only nonbulk superconducting samples (single crystals) with x = 0.1 have been synthesized to date. Here, we successfully synthesize polycrystalline samples with a wide hole-doping composition range of 0 <= x <= 0.35 via a conventional solid-state reaction, by tuning the reaction temperature according to x. The parent compound, (La0.5Na0.5)Fe2As2 (x = 0), is a nonsuperconductor with a resistivity anomaly at 130 K due to structural and antiferromagnetic transitions. We find that the temperature of the resistivity anomaly decreases with increasing x and that bulk superconductivity emerges for 0.15 <= x <= 0.35. The maximum transition temperature is 27.0 K, for x = 0.3. An electronic phase diagram for the hole doping side is constructed. However, electron-doped samples (x < 0) cannot be synthesized; thus, the other half of the electronic phase diagram of (La,Na)122 requires resolution to study the electron-hole symmetry in Fe-based superconductors. PMID- 29280634 TI - Investigation of Nascent Base Pair and Polymerase Behavior in the Presence of Mismatches in DNA Polymerase I Using Molecular Dynamics. AB - Optimizing DNA polymerases for a broad range of tasks requires an understanding of the factors influencing polymerase fidelity, but many details of polymerase behavior remain unknown, especially in the presence of mismatched nascent base pairs. Using molecular dynamics, the large fragment of Bacillus stearothermophilus DNA polymerase I is simulated in the presence of all 16 possible standard nucleoside triphosphate-template (dNTP-dN) pairs, including four Watson-Crick pairs and 12 mismatches. The precatalytic steps of nucleotide addition from nucleotide insertion to immediately preceding catalysis are explored using three starting structures representing different stages of nucleotide addition. From these simulations, interactions between dNTPs and the DNA-protein complex formed by the polymerase are elucidated. Patterns of large scale conformational shifts, classification of nucleotide pairs based on composition, and investigation of the roles of residues interacting with dNTPs are completed on 50+ MUs of simulation. The role of molecular dynamics in studies of polymerase behavior is discussed. PMID- 29280635 TI - Rhodium-Catalyzed Regio- and Enantioselective Addition of N-Hydroxyphthalimide to Allenes: A Strategy To Synthesize Chiral Allylic Alcohols. AB - We achieved the first Rh-catalyzed regio- and enantioselective additions of N hydroxyphthalimide to allenes. This transformation is accomplished via mild reaction conditions, leveraging on Josiphos SL-J003-2 as a chiral ligand to furnish branched O-allyl compounds in good yields with moderate to excellent enantioselectivities. The substrate scope is broad, and various functional groups are tolerated. The utility of this methodology is elaborated by transformation to allylic alcohols with different functional groups as well as to chiral O-allyl hydroxylamines. PMID- 29280636 TI - Oxy-Difluoroalkylation of Allylamines with CO2 via Visible-Light Photoredox Catalysis. AB - A selective oxy-difluoroalkylation of allylamines with carbon dioxide (CO2) via visible-light photoredox catalysis is reported. These multicomponent reactions are efficient and environmentally friendly to generate a series of important 2 oxazolidinones with functionalized difluoroalkyl groups. The good functional group tolerance, broad substrate scope, easy scalability, mild reaction conditions, and facile functionalization of products provide great potential for application in organic synthesis and pharmaceutical chemistry. PMID- 29280637 TI - [Impact of nutritional assessment in patients with heart failure]. PMID- 29280638 TI - The effects of a high-protein, high-calorie, fiber- and fructo-oligosaccharide enriched enteral formula on nutritional status, bowel habits and tolerance: Safety and Effectiveness of Enteral Nutrition in elderly Spanish patients (SENS Study). AB - BACKGROUND: Enteral nutrition (EN) is an effective nutritional intervention for patients at risk of malnutrition or malnourished. However, complications such as gastrointestinal intolerance, hyperglycemia or refeeding syndrome can be triggered by EN. AIM: To investigate the effects of a tube feeding formula (TFF) on patients' nutritional status, biochemical status, bowel habits and safety. METHODOLOGY: Observational, prospective and multicenter study. Patients >= 18 years, undernourished or at nutritional risk, who were prescribed a high-calorie, high-protein, fiber-fortified TFF were included. Patients were evaluated over a period of eight weeks (baseline [V1], four weeks [V2] and eight weeks [V3]). RESULTS: A statistically significant increase in weight (1.5 kg), body mass index (0.6 kg/m2) and nutritional intake (59.7 kcal/day) was observed between V1 and V2. Between V1 and V3, there was a statistically significant decrease in the percentage of individuals with abnormal biochemical markers for glucose, potassium, total protein and albumin. The number of patients' bowel movements remained stable throughout the study with a mean of 1.1 daily bowel movements. CONCLUSION: The TFF was safe and well tolerated, improving patients' nutritional status without altering patients' bowel habits. PMID- 29280639 TI - Clinical use of metal and plastic calipers for nutritional assessment of patients under long-term enteral feeding through endoscopic gastrostomy. AB - BACKGROUND: Endoscopic gastrostomy (PEG) fed patients, including those with neurologic disorders (ND) or head and neck cancer (HNC) present high malnutrition risk and speech difficulties. Teams taking care of these patients need to rely on anthropometric data. Skinfold thickness (TSF) is used to assess nutritional status, but the use of heavy, large and expensive metal calipers may become a limitation. This study aimed to compare and correlate TSF measurements using a metal caliper and a plastic caliper in PEG fed patients. METHODS: Prospective observational study on adult PEG fed patients. TSF was measured using plastic Ross and Lange metal calipers. Paired measurements were compared and correlated. RESULTS: Fifty-one patients, 37 men (72.5%), 14 women (27.5%): 28 (54.9%) ND patients; 23 (45.1%) with HNC. In total, 94 TSF measurements were performed using both plastic and metal calipers. Significant association was found between TSF measurements with the two equipments (rs = 0.94; p < 0.001). High correlation was observed between TSF measurements using both calipers for both genders (men: rs = 0.93; p < 0.001; women: rs = 0.96; p < 0.001), age (< 65 years: rs = 0.98; p < 0.001; >= 65 years: rs = 0.88; p < 0.001), underlying condition (ND: rs = 0.91; p < 0.001; HNC: rs = 0.95; p < 0.001) and time of TSF evaluation (before PEG: rs = 0.95; p < 0,001; after PEG: rs = 0.92; p < 0.001). CONCLUSIONS: TSF measurements obtained with small, light and cheap plastic Ross caliper were equivalent to those obtained with larger, heavier and more expensive metal caliper. For everyday clinical practice, plastic calipers may be suitable for teams taking care of PEG fed patients in hospital wards, outpatient clinic and home visits. PMID- 29280640 TI - Homemade diet versusdiet industrialized for patients using alternative feeding tube at home - An integrative review. AB - BACKGROUND: Enteral nutrition therapy can be provided using comercialized products (chemically defined formulas) or blenderized home-made preparations. OBJECTIVE: To perform an integrative review of the literature comparing the use of both type of formulation. METHODS: In this descriptive study papers published in English, Spanish or Portuguese Brazil, in journals indexed in the databases PubMed, EMBASE, Scopus, Web of Science and Bireme without the period 2010 to 2015 were reviewed The terms "enteral nutrition, foods, formulated, diet, homemade diet industrial and artisanal diet" according to the MeSH were used for the search. RESULTS: Twelve articles were selected. Most studies showed a level 4 of evidence and were published in journal in the higher Qualis index. Four aspects were evaluated: comparison between groups studying the clinical effects; comparison of the chemical composition of home-made products; physical-chemical and microbiological analysis of the enteral diets comes; articles on epidemiological Data on home enteral nutrition. CONCLUSION: Industrialized diet is more suitable for patients using alternative feeding supply at home. But it has a higher cost. PMID- 29280641 TI - [Assessment of the clinical quality indicator "early enteral nutrition" in intensive care units]. AB - BACKGROUND: Early enteral nutrition (EN) offers multiple benefits on critically ill patients and its monitoring was established as a clinical quality indicator (CQI) for intensive care units (ICU) by the Spanish Society of Critical Care (SEMICYUC). However, no results have been published on the systematized monitoring of this CQI. OBJECTIVE: To assess the compliance of the CQI "Early EN" at ICU. METHODS: A retrospective longitudinal study was conducted on 386 consecutive ICU patients receiving EN. Data were collected including time from admission until EN was started, as well as clinical results. SPSS statistics software was used for analysis and the CQI was assessed according to SEMYCIUC criteria. RESULTS AND CONCLUSION: CQI's compliance was 70.2%, not reaching the settled standard of 100%. Barriers preventing CQI compliance ought to be analyzed and its standard of 100% reconsidered. PMID- 29280642 TI - [Physical activity, physical fitness and quality of diet in schoolchildren from 8 to 12 years]. AB - BACKGROUND: The assessment of physical activity, physical fitness, and dietary quality in early ages is a physiological and public health need to contribute to the consolidation of a healthy lifestyle during adulthood. Hypotheses and objectives: Schoolchildren with a better level of physical activity have a better physical condition; schoolchildren with a higher level of physical activity have a better quality of diet; schoolchildren with a better level of physical condition have a better quality of the diet. The objective was to analyze the relationship between physical activity, physical condition and diet quality. METHODS: A cross-sectional descriptive study with 298 schoolchildren aged 8-12 years. Fitness was assessed using the ALPHA-Fitness battery and physical activity and diet quality was assessed by means of questionnaires. RESULTS: Schoolchildren with a better level of physical activity had a better level of physical fitness. The schoolchildren with a better level of physical condition showed a higher level of physical activity. Schoolchildren with a high level of physical activity and an average level of physical fitness, as well as schoolchildren with a high level of physical fitness (regardless of their level of physical activity), presented a better quality of the diet. CONCLUSION: The relationship between physical activity and physical condition is positive and bidirectional. Physical activity, fitness, and quality of diet are positively related. PMID- 29280643 TI - Estimation of body fat among 2-to-7-year-old Spanish children by different skinfolds equations and waist-to-height ratio. AB - INTRODUCTION: It seems relevant to analyze the body composition in the early childhood. However, there is not an agreement in the protocol to assess body composition in this age range/group. OBJECTIVE: To determine the most useful equation to estimate the body fat percentage that preschool children contain and the utility of the waist-to-height ratio to determine abdominal obesity. METHODS: We measured (weight, height, waist circumference and skinfolds) in 285 children aged 2 to 7 years old. BMI Z-Score, waist-to-height ratio and body fat percentage were estimated by Brook and Lukaski, Siri, Goran, Slaughter, Deurenberg, Huang, Dezenberg and Hoffman equations. RESULTS: It was found 26% combined overweight and obesity, with similar distribution in both sexes. The body fat obtained with the Hoffman equation (15.6-31.9%) showed the highest correlation with children BMI Z-Score. Waist-to-height ratio also presented a good relationship with children weight status. There were not significant differences between gender and body fat percentage or waist-to-height ratio. CONCLUSIONS: Hoffman equation and waist-to-height ratio could be adequate to estimate body fat percentage and abdominal obesity respectively in Spanish preschool children from medium-low socioeconomic status. PMID- 29280644 TI - Does the presence of pressure ulcers entail "high risk of negative outcomes" in geriatric rehabilitation? Results from a retrospective cohort study. AB - AIM: A retrospective cohort study was performed in order to evaluate the prevalence of pressure ulcers (PrUs) in older patients admitted to a geriatric rehabilitation unit of a postacute care hospital and to investigate the impact of the presence of PrUs on clinical outcomes of the rehabilitation process. METHODS: We studied 668 post-acute patients consecutively attended, from January 2010 to December 2011. The effect of having PrUs at admission was evaluated based on its impact on outcomes: final destination, functional status, mortality and length of stay in the rehabilitation unit. RESULTS: PrUs prevalence at admission was 16%. Patients with PrUs were older, more disabled and had more complex conditions, including malnutrition and cognitive impairment. In the bivariate analysis, we found patients with PrUs at admission had worst final outcome (%): discharge home (69.2 vs.82.5), discharge long term care setting (14 vs.6.4), discharge acute care (8.4 vs.6.2) and death (8.4 vs.4.8); p < 0.001, and worst Barthel Index score at discharge 57 (SD 34.1) vs.83 (SD 33.6); p < 0.001, with longer length of stay in the unit 61 (SD 42.3) vs.53 (SD 37.1); p 0.004. In the multivariate analysis, PrUs presence was found as one of the variables with significant association to no return to home. Finally, a negative association between PrUs at admission and functional gain at discharge of the postacute unit was identified. CONCLUSIONS: PrUs were prevalent and had negative impact on clinical outcomes of our geriatric unit, as discharge destination, functional gain and Length of Stay, in vulnerable patients. PMID- 29280645 TI - [Content validity of Food Quality Survey of Elderly (FQSE)]. AB - BACKGROUND: There are few instruments that evaluate the quality of food of elderly (ED) in the community. OBJECTIVE: To carry out the content validity of the survey designed to determine the Food Quality Survey of Elderly (FQSE). MATERIAL AND METHODS: Based on the existing literature, a questionnaire was designed to evaluate the FQSE. Content validity was performed using the Content Validity Index through the calculation of the Content Validity Ratio of Lawshe. Twenty-eight experts participated in the validation process. Subsequently, the validated survey was applied to ED. RESULTS: Twenty-three questions were validated in content, distributed in the 2 subscales of the instrument. The first 15 questions subscale Healthy eating habits and 8 questions subscale Unhealthy eating habits. The Content Validity Index was 0.85. Four hundred and fifty-eight ED were surveyed. In the subscale of Healthy eating habits, 11.2% of men and 11.4% of women presented healthy eating habits; 54.4% of men and 42.9% of women presented unhealthy eating habits. Finally, in the sum of both scales, only 16.6% of men and 17.6% of women categorize within Good Food Quality. CONCLUSION: The FQSE survey is a valid instrument in content and easy to apply to EL and allows evaluating and characterizing the quality of the diet of this age group. PMID- 29280646 TI - [Anthropometric characteristics and functional fitness of Chilean community dwelling older adults]. AB - INTRODUCTION: Anthropometry and functional fitness (FF) are fundamental aspects for functional independence conservation of older adults (OA). However, little has been investigated in chilean OA. OBJECTIVE: To analyze anthropometric and FF characteristics of non-disabled OA. METHODS: One hundred and sixteen subjects participated in the study. It was determined the prevalence of weight categories (Body Mass Index [BMI]) and cardiometabolic risk (CMR) (Waist Circumference [WC], Waist-Hip Ratio [WHR] and Waist-to-Height ratio [WHtR]). Additionally, "under the norm" physical performance and performance standards (Senior Fitness Test Battery [SFT]). Anthropometric and FF differences were analyzed according sex and age categories. RESULTS: A total of 63.8% and 73.5% of men and women respectively were overweight. The highest prevalence of CMR was obtained through WHtR and the tests with the highest prevalence of low performance were 2-minute step Test and Back scratch Test. The performance standard was reached in 29.7% and 17.3%, in men and women respectively. Men presented greater height, WHR, strength and aerobic capacity. Women had greater hip circumference, BMI, WHtR and flexibility. These results tends to be maintained in the analyzes according age categories. CONCLUSIONS: The studied sample presented a high prevalence of overweight, CMR and low physical performance especially in women. Due its low cost and complexity, it is proposed that integral evaluation of anthropometric and FF parameters should be implemented in primary care programs aimed to preserving functionality of OA. PMID- 29280647 TI - [Relation of variant rs180077 of gen cholesterol ester transfer protein variant, with fat mass, HDL-cholesterol in obese subjects with diabetes mellitus type 2]. AB - BACKGROUND: There is few evidence of cholesterol ester transfer protein (CETP) in subjects with obesity and diabetes mellitus. OBJECTIVES: We examined the association of the polymorphism (rs1800777) of CETP gene on anthropometric parameters, lipid profile and adipokines in subjects with obesity and diabetes mellitus type 2. MATERIAL AND METHODS: A population of 229 obese subjects with diabetes mellitus type 2 was enrolled. An electrical bioimpedance, blood pressure, dietary intake, exercise and biochemical analyses were recorded. RESULTS: Two hundred and seventeen subjects (94.8%) had genotype GG and 12 GA (5.2%) (genotype AA was not detected). Weight (delta: 14.4 +/- 2.1 kg, p = 0.01), body mass index (delta: 2.2 +/- 1.1 kg/m2, p = 0.01), fat mass (delta: 11.2 +/- 3.1 kg, p = 0.02), waist circumference (delta: 3.9 +/- 2.0 cm, p = 0.02), waist to hip ratio (delta: 0.04 +/- 0.02 cm; p = 0.01), tryglicerides (delta: 48.6 +/- 9.1 mg / dl, p = 0.03) and leptin levels (delta: 58.6 +/- 15.9 mg/dl, p = 0.02) were higher in A allele carriers than non A allele carriers. Levels of HDL cholesterol were lower in A allele carriers than non-carriers (delta: 5.6 +/- 1.1 mg/dl, p = 0.03). In regression analysis, HDl cholesterol, weight and fat mass remained in the model with the SNP. CONCLUSION: Our results show an association of this CETP variant at position +82 on HDL cholesterol, levels and adiposity parameters in obese subjects with diabetes mellitus type 2. PMID- 29280648 TI - Resistin in morbidly obese patients before and after gastric bypass surgery. AB - BACKGROUND AND OBJECTIVES: Resistin was originally suggested to be a potential mediator of obesity-related insulin resistance in rodents. However, in humans, the role of resistin in obesity and insulin resistance has not yet been demonstrated. The present study investigates whether there are differences in resistin levels between patients with morbid obesity and lean subjects, and analyzes changes in resistin levels after significant weight loss secondary to bariatric surgery. METHODS: Sixty-eight patients with morbid obesity (body mass index [BMI] >= 40 kg/m2) and 31 lean subjects (BMI < 25 kg/m2) were selected. The study variables were: weight, height, BMI, waist-hip ratio (WHR), fat mass, family history of cardiovascular disease (CVD), type 2 diabetes mellitus (DM), hypertension, dyslipidemia, smoking, glucose, glycated hemoglobin (HbA1c), insulin, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), adiponectin and resistin. Homoeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) were calculated. The obese patients underwent gastric bypass surgery, and the above mentioned variables were reassessed after 12 months and major weight loss. RESULTS: There were no significant differences in resistin levels between morbidly obese patients and healthy subjects of normal weight, or between obese patients before and after weight loss. Resistin levels in morbidly obese patients were not correlated to adiposity anthropometric measures, insulin, glucose, HOMA, QUICKI, hsCRP, IL-6 or adiponectin. In the morbid obesity group, after one year of weight loss, the only study parameter correlated to resistin levels was IL-6. CONCLUSION: Our results do not support a relationship among resistin levels, obesity and insulin resistance in humans. PMID- 29280649 TI - Waist-to-height ratio and its relation with cardiometabolic risk factors in children from Bucaramanga, Colombia. AB - BACKGROUND: Currently, the waist-to-height ratio (WHtR) has emerged as a practical and useful indicator for identifying cardiometabolic risk in child and adolescent population. OBJECTIVE: To evaluate the association between the WHtR and cardiometabolic risk factors (CMRFs) in a cohort of children in Bucaramanga, Colombia. METHODS: Analytical cross-sectional study. Child population between 6 10 years old from Bucaramanga (n = 1,282). Dependent variables: hypertension, pre hypertension, overweight/obesity, impaired glucose, insulin resistance and dyslipidemia. Main independent variable: waist-toheight ratio. The association between dependent and independent variables was evaluated using binomial regression models. RESULTS: 9.77% of the children presented a WHtR of risk (95% CI: 8.19% to 11.52%). After adjustment for age, sex, socioeconomic status and physical activity, the WHtR of risk was significantly associated with lower HDL levels and higher levels of triglycerides, insulin resistance, hypertension and pre-hypertension (PR = 2.46 95% CI :1.70 to 3.55, p = 0.000, PR = 2.24 95% CI: 1.50 to 3.35, p = 0.000, PR = 9.39 95% CI: 5.40 to 16.30, p = 0.000, PR = 8.03 95% CI: 2.01 to 32.07, p = 0.003 y PR = 2.67 95% CI: 1.60 to 4.47, p = 0.000, respectively). CONCLUSION: Children with WHtR of risk were more likely to develop high levels of blood pressure and triglycerides, insulin resistance and lower levels of HDL. PMID- 29280650 TI - [Association between cardiometabolic risk factors, physical activity and sedentariness in Chilean university students]. AB - INTRODUCTION: There is a huge evidence in adults, that a high level of physical activity and a low level of sedentariness are associated independently with a reduction of cardiometabolic risk factors (CMRF). This association has been poor evaluated in young people and the results are not conclusive. OBJECTIVE: To estimate the association between CMRF, physical activity and sedentariness in Chilean university students. METHODS: Cross-sectional study. Sample of 326 students who enrolled at University of La Frontera, Temuco, Chile, in 2014. They were selected randomly and stratified according to faculty, career and gender. We measured anthropometry, blood pressure, lipidic profile, glycemia, insulin resistance, tobacco and alcohol consumption. These variables were associated with physical activity level (PAL) and sedentariness using the IPAQ questionnaire. RESULTS: The students with a low PAL had a higher probability of abdominal obesity (OR: 4.68; IC 95% 1.86-11.73), metabolic syndrome (OR: 3.80; IC 95% 1.23 11.73) and triglycerides elevated (OR: 2.61 IC 95%; 1.18-5.75), compared with students with moderate and vigorous PAL (p < 0.05). There were no association between CMRF and sedentariness, even after fit by physical activity. CONCLUSIONS: We found an association between CMRF and PAL which was independent of sedentatiness. We believe it is very important to implement effective physical activity programs at universities. It is necesary to encourage students in order to increase the physical activity level to a moderate and vigorous range with the purpose of decreasing their cardiovascular risk. We consider it is recommendable to keep studying the association between sedentariness and CMRF. PMID- 29280651 TI - [Nutritional status and the relationship regarding functional status after stroke]. AB - OBJECTIVE: To assess the nutritional status (NS) of patients at three months of suffering a stroke, and to establish the relationship between functional recovery and complications in this period. MATERIAL AND METHODS: A cross-sectional observational study evaluating the NS of patients older than 65 years at three months of having a stroke. The NS was assessed using the Mini Nutritional Assessment (MNA). Sociodemographic and anthropometric data, cardiovascular risk factors, as well as functional status (through the Barthel index and the modified Rankin scale) and the presented complications were collected. RESULTS: One hundred and three patients were included, with a medium age of 75.81 (+/- 6.73). The MNA score was 23.13 points (+/- 4.47); 8.2% had malnutrition and 38.1% had risk of malnutrition. There were no differences in the NS between women and men (p = 0.076) neither relation of the NS with age. NS deficiency was associated with poorer function (r = 0.608; p < 0.001), the development of complications (urinary tract infection and fever) (p = 0.044) and dysphagia (p = 0.014). In addition, those patients with better nutritional status had a better quality of life (r = 0.506; p < 0.001). It was also associated with poorer socioeconomic status (p = 0.020) and institutionalization (p = 0.004). CONCLUSIONS: The risk of malnutrition is common in stroke survivors at the short-term. This NS is associated with a worse functional situation and self-perceived quality of life and with a higher rate of complications. Early detection of the risk of malnutrition is essential in patients who have suffered a stroke. PMID- 29280652 TI - Dietary intake and zinc status in amyotrophic lateral sclerosis patients. AB - BACKGROUND: There is considerable evidence that abnormal zinc homeostasis is related to amyotrophic lateral sclerosis (ALS) pathogenesis, and malnutrition is an independent prognostic factor for worsened survival of ALS patients. OBJECTIVE: To evaluate the dietary intake and zinc status in patients with ALS, treated in a specialized outpatient facility in Natal, Brazil. METHODS: Twenty patients with ALS (case group) and 37 healthy subjects (control group) were included. Clinical and anthropometric assessments were carried out and dietary intake was obtained from two 24-hour recalls. Plasma and urinary zinc concentrations were determined by atomic absorption spectrophotometry. RESULTS: Most of the participants were eutrophic. Mean energy, protein, carbohydrate and fat intake was significantly lower for the case group. There was greater prevalence of inadequate zinc intake in the case group (35%) compared to controls (27%). Mean plasma zinc was significantly lower in the case group than in controls (77.13 +/- 22.21 vs 87.84 +/- 17.44 ugZn/dl). Urinary zinc did not differ significantly between cases and controls. In the case group, plasma and urinary zinc concentrations were below reference values in 50.0% and 52.6% of patients, respectively. CONCLUSION: A large portion of patients with ALS exhibited poor dietary intake and changes in body zinc status. The zinc deficiency found in half of the ALS patients may contribute to a worsened prognosis and should be the target of nutritional intervention that aims to correct this deficiency. PMID- 29280653 TI - Validation of a Food Frequency Questionnaire for the indigenous Epera-Siapidara people in Ecuador. AB - BACKGROUND: A Food Frequency Questionnaire (FFQ) must be designed and validated in the local environment to ensure that the method is adapted to the objectives of the study and the population. OBJECTIVE: The aim of this study was to validate an FFQ to evaluate the food consumption pattern of the Epera-Siapidara population of Ecuador. One hundred and fourindividuals (54% men and 46% women), aged between 2 and 84, took part in the study. METHODS: The validity of this tool was assessed by comparing the relationship between the average daily nutrient intake estimated by the FFQ and the intake estimated in the three non-consecutive 24 h dietary recalls (24hR). The existing correlations were evaluated by Pearson's or Spearman's correlation, the inter-class correlation coefficient, Lin's concordance correlation coefficient and a Bland-Altman plot. RESULTS: The values estimated by the FFQ were significantly higher for minerals and vitamins. The relative correlation coefficients ranged from 0.71 to 0.23 for Na and Ca, respectively, while the inter-class correlation coefficient ranged from 0.84 to 0.33 for Na and cholesterol, respectively. Lin's concordance correlation coefficient was higher for macronutrients, with values ranging from between 0.35 for lipids to 0.51 for energy. Only 6% of the participants were wrongly classified. The Bland-Altman plots showed an overestimation of macronutrient and calcium intake by the FFQ compared with the 24hR, and an underestimation of fiber intake. CONCLUSION: The FFQ demonstrated a good external consistency, which makes it a suitable instrument for correctly identifying the food and nutrient intake of the Epera-Siapidara population. PMID- 29280654 TI - Food intake, plate waste and its association with malnutrition in hospitalized patients. AB - BACKGROUND: Hospital malnutrition is a worldwide dilemma and challenge. High levels of plate waste contribute to malnutrition-related complications in hospital. We investigated the association between the levels of plate waste, food intake and patient satisfaction with nutritional risk and malnutrition prevalence in three hospital settings. METHODS: The sample population of 120 patients, aged 18-65 year, admitted consecutively over a 12 month period to 3 different educational university hospitals was included. For all the patients, diet history, anthropometric measurements, body mass index and patient satisfaction with the hospital food service was evaluated. Weight plate waste for all daily meals was done and actual intakes computed individually for each day. Nutrition risk screening (NRS)-2002 (>= 3) tool was used for estimating the nutritionally at-risk population. Results: From one hundred twenty non-critically ill patients with a mean 8.9 +/- 3.5 day length of hospital stay, 40.8% (49) were men and 59.2% (71) were female. Mean energy and protein requirements were 2,030.3 +/- 409.03 kcal/day and 76.13 +/- 15.33 g/day respectively. Mean intakes were 1,326 +/- 681.44 kcal/day and 66.81 +/- 31.66 g/day respectively. The mean percent of plate waste for lunch and dinner were 37.7 +/- 29.88 and 30.4 +/- 23.61 respectively. In the total population, 25% of patients were satisfied and 75% patients were unsatisfied with hospital foods. Based on BMI (< 20), unintentional weight loss (> 10%), malnutrition prevalence was 12.5% and 14.2% respectively during hospitalization. The prevalence of nutritionally at-risk population was 30% at admission time and reached 33.3% at discharge. CONCLUSION: Plate waste and hospital malnutrition were highly prevalent in accompanying with increasing nutritionally risk progression. So it should be addressed as an important health issue and appropriate strategies for stimulating governmental policies should be adopted. PMID- 29280655 TI - [Impact of malnutrition on long-term mortality in outpatients with chronic heart failure]. AB - BACKGROUND: Undernutrition is common among acute heart failure patients and its prognosis impact has been established. The prognosis role of undernutrition among chronic heart failure patients is not known. Objetive:The aim of this study were to evaluate the influence of nutritional status on long-term mortality in patients with chronic hear failure. METHODS: 304 consecutively patients attended in our Heart failure Unit from November 2011 to November 2016 were prospectively analysed. A global nutritional assessment was performed and the states of undernutrition and at risk of malnutrition were assessment by the Mini Nutritional Assessment test. Their possible independent association with mortality was analyzed by Cox multivariate analysis. RESULTS: The mean age was 74.6 +/- 10.1 years, 41.1% were female and the most frequent aetiology was ischemic heart disease (39.1%). 11.5% of the patients were classified as undernourished and 38.2% were classified as at risk of malnutrition. The remaining 50.3% were classified by the MNA as adequate nutritional status. After 28 months (median of follow-up), mortality was 68.9%, 33.3% and 15.2%, respectively (Log-rank, p < 0.001). When Cox multivariate analysis was performed, the state of undernutrition was an independent predictor of mortality (Hazard ratio 2.73; 95% confidence interval, 1.55-4.81; p < 0.001). CONCLUSIONS: The prevalence of undernutrition and risk of malnutrition reaches high levels in chronic heart failure patients. Moreover, the state of undernutrition by Mini Nutritional Assessment score is an independent predictor of mortality in these patients. PMID- 29280656 TI - [Prevalence of malnutrition to income in a basic general hospital]. AB - OBJECTIVE: The main objective has been to evaluate and quantify the prevalence of malnutrition at admission, the degree of severity and the correlation with the nutritional parameters in a basic general hospital of the first level. METHODS: Observational, transverse, and randomized study of 244 patients (59.8% male and 40.2% female) performed during the first 24 hours of hospital admission and with a nutritional assessment including nutritional screening (CONUT(r)), anthropometric parameters, other analytical parameters and a quantification of hospital stay. RESULTS: In this study, 60.7% of the sample has at least one criterion of malnutrition (anthropometric and/or analytical). When considering at least two altered nutritional parameters (one of them analytical type), the prevalence was 29.1%. Prealbumin and transferrin have been shown to be particularly sensitive to moderate to severe and mild malnutrition, respectively. CONUT(r) has detected nutritional risk of a mild nature in 39.8%. Malnourished patients have a longer stay, and are statistically significant in oncological versusnon-oncological patients. CONCLUSIONS: Anthropometric parameters, on their own, can generate some degree of controversy over the prevalence of malnutrition, so it is considered as appropriate to use two parameters, at least one of an analytical type. Prealbumin is the most sensitive and specific indicator, and CONUT(r) is an easy, quick and economical tool for nutritional screening. In order to greatly alleviate malnutrition at hospital admission, the objective of the study, it would be wise to strengthen its screening and treatment from Primary Health Care. PMID- 29280657 TI - [Assessment of diet in patients with chronic kidney diseases without dialysis and relationship with the nutritional status]. AB - BACKGROUND: Diet is one of the pillars of the treatment for patients with chronic kidney disease without dialysis (NDD-CKD). Despite this, very few studies have evaluated the diet in Spanish population. OBJECTIVE: To evaluate the diet of a group of patients with advanced CKD, comparing it with the recommendations, and its relation with nutritional status. MATERIAL AND METHODS: A cross-sectional study of 74 patients (39 men), with a mean age of 70.9 +/- 13.6 years and creatinine clearance of 15.3 +/- 2.1 mL/min. Biochemical, anthropometric and intake variables (3-day dietary record) were collected, comparing them with the recommendations for patients with CKD and, if they did not exist, with nutritional recommendations and objectives for the Spanish population. The nutritional status was assessed by modified criteria of protein-energy wasting (PEW). RESULTS: The mean energy intake was 23.2 +/- 6.5 kcal/kg body weight/day, and the protein intake was 0.93 +/- 0.2 g/kg body weight/day. Men had a higher intake of alcohol and vitamin D whereas women presented a higher intake of trans fatty acids and vitamin B1. In addition, 91.4% of patients had high intake of phosphorus and 73% of potassium. Only 2.7% showed an adequate intake of vitamin D and 21.6% of folates; 18.9% of patients presented PEW. A positive correlation was found between albumin, body mass index (BMI) and creatinine clearance. CONCLUSION: Most patients with non-dialysis CKD do not meet dietary recommendations or nutritional goals, regardless of gender and PEW status, considering renal function as a limiting factor. PMID- 29280658 TI - ["Consumption of restricted foods" in Mexican hypertensive patients]. AB - BACKGROUND: Strict adherence to personal health recommendations is necessary to improve the clinical control of arterial hypertension. OBJECTIVE: To identify predictors of the behavior to avoid the "consumption of restricted foods" in a sample of hypertensive patients from Tamaulipas, Mexico. METHOD: Participants were 183 patients with arterial hypertension diagnosis, who completed two self administered questionnaires and different questions regarding adherence and self care behaviors. A trajectory analysis was used for the interpretation of data. RESULTS: Less tolerance to frustration, a major affective social support and a lower body mass index were behavior predictors to avoid the consumption of restricted foods (pBS= 0.294, chi2/gl= 1.417, GFI = 0.993, AGFI = 0.965, NFI = 0.934, IFI = 0.980 y SRMR = 0.040), explaining approximately 20% of the variance in the study behavior. CONCLUSION: The study of adherence and self-care behaviors demands to identify what and how some personal and interpersonal variables are influencing in their daily practice, which can contribute to improve the interdisciplinary interventions programs in clinical and communitarian settings for attending patients living with arterial hypertension. PMID- 29280659 TI - Prevalence of hypovitaminosis D and associated factors in adolescent students of a capital of northeastern Brazil. AB - BACKGROUND: Hypovitaminosis D is a frequent problem in the world and can be influenced by several factors. OBJECTIVE: To estimate the prevalence of hypovitaminosis D and associated factors in adolescent students of a capital city of northeastern Brazil. METHODS: Cross-sectional epidemiological study assessing 220 school adolescents of both sexes aged 15 to 19 years. A questionnaire was applied to assess sociodemographic (skin color, mother's education and receiving social benefits) and behavioral data (number of hours of sleep per day, sun exposure, physical activity and dietary vitamin D intake). Anthropometric nutritional status was assessed by BMI (body mass index) for age. Serum 25 (OH) D concentrations, PTH and serum calcium were measured by blood samples. We identified individuals with hypovitaminosis D as those with 25 (OH) D < 30 ng/dL. The analysis of factors associated with hypovitaminosis D was performed by simple and multivariate Poisson Regression. RESULTS: The prevalence of hypovitaminosis D was 57.3%. The female population had a significantly higher prevalence than the male. In the final adjusted model, the variable independently associated with hypovitaminosis D in females was the lowest serum calcium concentrations, and for males it was BMI, in which adolescents who had overweight/obesity were 2.4 times more likely to have hypovitaminosis D than the eutrophic ones. CONCLUSIONS: The present study found a high prevalence of hypovitaminosis D in the analyzed population, especially in female adolescents. In addition, the factors independently associated with hypovitaminosis D were found to be overweight/obese in boys and low calcium concentrations in girls. PMID- 29280660 TI - [Food consumption patterns among university students in Zamora]. AB - AIMS: To assess, using a posterioritechniques, prevailing food consumption patterns of university students in Zamora and their association with food groups, in order to know how far can be away from a healthy diet, such as the Mediterranean diet. METHODS: Cross-sectional, descriptive and observational study of a representative sample of university students in the province of Zamora (n = 213, 18-29 years). Food consumption was assessed using a validated semi quantitative consumer frequency questionnaire, which included 64 foods, grouped into 13 food groups. Consumption patterns were determined by factor analysis. RESULTS: University students in Zamora show two consumption patterns: "Mediterranean", which accounts for 19.4% of the total variance and is characterized by consumption of dairy products, fish and seafood, meats and vegetables, sausages, cereals and tubers, fruit and vegetables and olive oil, and "Western", which accounts for 22.2% of the total variance and is characterized by consumption of dairy products, eggs, meats and vegetables, sausages, nuts, other fats other than olive oil, pastries and sweets, prepared foods and sugar sweetened beverages, with low consumption of fruit and vegetables. The factor analysis shows a sample adequacy measure (KMO) of 0.615. CONCLUSIONS: The university students of Zamora are in nutritional transition, with a diet that moves away from the recommendations of the Mediterranean Diet. PMID- 29280661 TI - Classical and emergent cardiovascular disease risk factors in type 2 diabetics from the Vallecas area (DICARIVA study). AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major independent risk factor for cardiovascular disease (CVD) and a highly prevalent disease with a wide variety of associated metabolic disorders. OBJECTIVES: To describe features and prevalence of altered CVD risk factors in a T2DM population: DIabetes CArdiovascular RIsk of VAllecas (DICARIVA) study. PATIENTS AND METHODS: 735 adult Spanish patients of the Vallecas area with T2DM from the Infanta Leonor Hospital (Madrid, Spain) were included in the study. Age, disease time-evolution, anthropometric measurements, glycemia, glucated haemoglobin A1c (HbA1c), lipid/lipoprotein profile, total cholesterol/high density lipoprotein cholesterol (HDL-cholesterol), low density lipoprotein cholesterol (LDL-cholesterol)/HDL cholesterol and triglycerides/HDL-cholesterol ratios, triglycerides-glucose index (TyG), fibrinogen, high sensitivity-c reactive protein (hs-CRP) and microalbuminuria were assessed. RESULTS: Mean, standard deviations, and percentile distributions were obtained in males, females and the whole T2DM population for classical and emergent CVD risk markers. Obesity was found in 45% of patients, while 60% had high cardiovascular risk according to waist circumference and conicity index. Total and LDL-cholesterol were at desirable and optimum levels, respectively, in 60% of patients. One third showed the conjoint presence of low HDL-cholesterol, high triglycerides and small and dense LDL. Increased levels of hs-CRP, hyperfibrinogenia and microalbuminuria were detected in 40%, 50% and 30% of patients, respectively. Age, body mass index, total cholesterol, hs-CRP and fibrinogen were higher while weight, conicity index, total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol and triglycerides/HDL-cholesterol ratios, and microalbuminuria lower in women. According to TyG values 62% of patients suffered metabolic syndrome. CONCLUSIONS: Altered anthropometric and metabolic CVD risk factors were highly prevalent in the DICARIVA study. The CVD marker cut-off points obtained in some emergent markers seems relevant and would be employed for future early T2DM diagnoses strategy in order to reduce its high morbidity and mortality impact. PMID- 29280662 TI - [Influence of the dance discipline on body image distortion and dissatisfaction in preadolescents, adolescents and young women dancers]. AB - BACKGROUND: Dance discipline could modulate the presence of alterations in body image, which is a factor relationship with eating disorders. OBJECTIVE: To analyze the body image distortion and dissatisfaction in student dancers based on dance discipline. METHODS: Two hundred and ninety-eight preadolescents, adolescents and young classical, contemporary and Spanish dancers took part in the study. Participants self-fulfilled the "silhouette scale for adolescents" in order to determine the perceived and ideal image. The real body image was calculated with the body mass index data (BMI). After that, distortion index, dissatisfaction index and the relation between real and ideal image were calculated. RESULTS: About distortion index, classical and contemporary dancers perceived themselves with a higher BMI than they had, whereas Spanish dance showed the opposite tendency. Significant differences among classical dancers and the other modalities were found (p < 0.017). Based on distortion index results, ten dancers showed a high risk for developing an eating disorder. In the dissatisfaction index, all disciplines selected as ideal to be thinner as they perceived themselves, without significant differences. About the real/ideal index, contemporary and Spanish dancers considered as ideal silhouettes with a lower BMI than they had. Classical dancers showed the opposite tendency, with significant differences among this group and the others (p < 0.017). CONCLUSIONS: Most dancers have a self-image which is not related with the reality. This could act as a factor which induce eating disorders. PMID- 29280663 TI - Nutritional and neuropsychological profile of the executive functions on binge eating disorder in obese adults. AB - OBJECTIVE: To examine the relationships between obese patients with and without binge eating disorder (BED) and the neuropsychological profiles of their executive functions. METHODS: Data from 36 obese individuals (BMI >= 30 kg/m2) were divided into two groups, where one group was found to be positive for signs of BED according to the Binge Eating Scale. Two neuropsychological tests of executive function were carried out: the Go/No-go Task and the Iowa Gambling Task (IGT). Nutritional status was evaluated by measures of body weight, height and abdominal circumference, and from these, body mass indexes (BMI) were calculated. RESULTS: Both groups presented similar nutritional characteristics; there were no differences when it came to the health status of individuals with or without BED. Participants found positive for signs of BED had the lowest IGT scores (p = 0.004), and Go/No-go omission scores (p = 0.015) and commission scores (p = 0.04). Further statistically significant differences were also observed here between the two groups. Statistical differences in the IGT results correlated with BED, and were associated categorically (p = 0.005). CONCLUSION: Obese individuals frequently present deficits in selective attention, inhibitory control, decision-making and planning that can be directly related to binge eating and which is linked to BED. Nutritional status did not differ between the two groups studied, and did not show any connection with the disorder. PMID- 29280664 TI - [Role of the stevia and L-carnitine of a nutritional supplement on glycemic impact in adults]. AB - Currently the food industry has generated interest in non-nutritive sweeteners, for example Stevia and in special components such as L-carnitine, used in formulations of nutritional supplements for glycemic control specific for diabetics. The present study evaluated the effect of stevia and L-carnitine on the glycemic index (GI) and glycemic load (CG) of a nutritional supplement in 19 healthy subjects (9 men and 10 women), who randomly completed 3 consumption tests, 1 for the supplement and 1 for each reference product: Glucose solution (SG) and white bread (PB), obtaining blood samples at the 0, 15, 30, 45, 60, 90 and 120 min times; for measurement of blood glucose, basal and postprandial insulin. The increase area under the glucose curve (IAUC) was lower for supplement 11,778.73 than for reference products (SG) 13,724.06; (PB) 13,153.56 alpha= p 0.005. IG = (62) and CG = (16) were intermediate and lower than white bread IG = (69) and CG = (18), with no difference in postprandial insulin. This demonstrates that this nutritional supplement formulated with stevia and L carnitine is able to prolong the glycemic response without increasing the insulin requirements in healthy subjects. Specific studies are required in diabetics to validate whether the glycemic impact is lower than the standard product. The presence of other nutrients in the formula, influential in these indicators, does not allow to infer that the results are due only to the type of sweetener used and the L-carnitine. PMID- 29280665 TI - Use of nutritional supplements and ergogenic aids in professional tennis players. AB - INTRODUCTION: Nutritional supplements and ergogenic aids (NS&EA) are used between training/matches with the goal of enhancing tennis performance. Scientific literature about prevalence and use of NS&EA in professional tennis players is scarce. OBJECTIVE: The aim of the study was to describe the NS&EA used by professional tennis players during a season. METHODS: Using a validated self administered questionnaire, 62 professional male and 9 professional female tennis players (11% in their gender specific top 100 tennis world ranking (i.e.,ATP/WTA)) registered all the used NS&EA. RESULTS: Eighty-one percent of the participants declared taking at least one NS&EA. Strength and conditioning trainers (S&C) and tennis coaches were the professionals who recommended most of the NS&EA in the players outside the TOP-100 (OT100; 50.7% and 39.1%, respectively). However, sports nutritionist were the principal advisors in the top-100 tennis players (T100; 62.5%). Sports drinks were the NS&EA most commonly used by all participants (81.7%). T100 participants used caffeine (p = 0.042), creatine (p = 0.001), iron (p = 0.013) and CHO-protein mix (p = 0.033) significantly more frequently that OT100 players. CONCLUSIONS: There is a high prevalence of NS&EA use among professional tennis players independently of their tennis ranking position. However, T100 tennis player have an increased use of certain substances such us caffeine, creatine, iron and CHO-Protein mix. For the rest of the studied NS&EA the use was similar between T100 and OT100 players. It is possible that the differences in NS&EA use between groups could be related to the different professionals on charge of nutritional advice in T100 vs OT100. PMID- 29280666 TI - [Bone metabolism in child and adolescent athletes: a systematic review]. AB - BACKGROUND: Physical exercise is beneficial for the prevention of osteoporosis. Bone metabolism markers are the main indicators of metabolic balance and may indicate early risk in bone tissue. AIM: This systematic review aims to summarize and update present knowledge about bone metabolism markers in child and adolescent athletes. METHOD: Literature search was conducted up to March 2017 in PubMed and Sport Discus. A total of 19 studies (case-control, longitudinal and randomized control trials) met the inclusion criteria and were included in the review. RESULTS: In females, bone remodeling decreases with age independently of sport practiced. Athletes with amenorrhea had lower levels of both markers of bone turnover than control subjects. High-impact sports present higher biomarkers in females. A brief period of training have positive effects in bone formation markers in adolescent males. CONCLUSIONS: The age, sex type of exercise and sport, and performance level of the subjects can deeply affect bone metabolism markers during adolescence. More studies are needed to establish common criteria for metabolic response to physical exercise in these stages. PMID- 29280667 TI - [Intragastric injection of botulinum toxin. A real alternative for obesity treatment? A systematic review]. AB - BACKGROUND: Obesity is a prevalent disease in our environment, which comorbidities suppose a great challenge to public health. Intragastric injection of botulinum toxin has been used as treatment for obesity, both in humans and animals. It acts by inhibiting gastric emptying and inducing early satiety, consequently reducing intake and finally achieving weight loss. MATERIALS AND METHODS: A bibliographic search in PubMed, Scopus and EMBASE databases between 2000 and 2016 was carried out. Articles regarding the physiological basis of the treatment with intragastric injection of botulinum toxin in human were included, as well as interventional studies, randomised or not. RESULTS: A total of 105 articles were found and 10 were chosen according to our inclusion criteria. Of those, only 4 were randomised and 8 lasted between 8 and 24 weeks. In four of the studies, one randomised, a statistically significant weight loss was found which varied between 3.5 and 11.8 kg. Most of the studies found slowing of gastric emptying. None of them notified any significant side-effects. CONCLUSION: Intragastric injection of botulinum toxin could be useful and safe in the treatment of obesity but better designed, placebo-controlled, long term and with an adequate sample size studies are needed. PMID- 29280668 TI - [The dynamic gastrointestinal simulator (simgi(r)): a useful tool for clinical nutrition]. AB - The human gastrointestinal tract harbours the most complex and abundant community of the human body, the colon being where the highest microbial concentration is found (1012 cell/g). The intestinal microbiota exerts metabolic, trophic and protective functions which are important in the maintenance of the host health. Over recent decades, numerous studies have attempted to provide scientific evidence about the environmental factors that can impact on human health through the modulation of the intestinal microbiota composition. However, this approach is changing, and a new focus on assessing changes at functional level is being developed. If we apply this dual approach to the role played by the diet, it is obvious the need of dynamic gastrointestinal simulation models such as simgi(r) that allow to evaluate the transformations undergone by food and/or food ingredients during their transit through the gastrointestinal tract, as well as to determine potential changes in the composition and functionality of the intestinal microbiota after food ingestion. So far the studies using the simgi(r) have confirmed its potential applications in the area of food as a prior step to its application in clinical nutrition to prevent and/or treat diseases associated with intestinal dysbiosis and metabolic disorders. Likewise, this review includes feasible perspectives of the use of simgi(r) in clinical research concerning to diseases related to the intestinal microbiota. PMID- 29280670 TI - [Reply: "Importance of selection criteria for the determination of sugar sweetened beverage consumption in children and adolescents"]. PMID- 29280671 TI - [Reply: "The antioxidants in the process of ocular pathology]. PMID- 29280672 TI - [Logistic regression and clinical decisions]. PMID- 29280669 TI - [Home and Ambulatory Artificial Nutrition (NADYA) Group Report - Home parenteral nutrition in Spain, 2016]. AB - OBJECTIVE: To communicate HPN data obtained from the HPN registry of the NADYA SENPE group (www.nadya-senpe.com) for the year 2016. MATERIAL AND METHODS: Descriptive analysis of the data collected from adult and pediatric patients with HPN in the NADYA-SENPE group registry from January 1st, 2016 to December 31st, 2016. RESULTS: There were 286 patients from 42 Spanish hospitals (54.2% women), 34 children and 252 adults, with 294 episodes, which represent a prevalence rate of 6.16 patients / million inhabitants / year 2016. The most frequent diagnosis in adults was "palliative cancer" (25.8%), followed by "others". In children it was "motility alterations" with 6 cases (17.6%), Hirschsprung's disease and necrotising enterocolitis, both with 5 children (14.7%). The first indication was short bowel syndrome in both children (64.7%) and adults (37.3%), followed by intestinal obstruction in 28.6% adults and 14.7% in children. The most frequently used type of catheter was tunnelled in both children (70.6%) and adults (37.9%). The most frequent complication in adults was infection related to the catheter, which presented a rate of 0.48 infections / 1,000 days of NPD. During this period, 71 episodes ended in adults and the main cause was death (57.7%) followed by resuming the oral route (31%). CONCLUSIONS: There is a progressive increase of centers and professional collaborators in the registry who report patients receiving parenteral nutrition at home. The main indications of HPN and the motive for ending have remained stable. PMID- 29280673 TI - [Reply: "Logistic regression and clinical decisions"]. PMID- 29280674 TI - Solar drying of wastewater sludge: a case study in Marrakesh, Morocco. AB - This paper presents a site-specific study of solar drying of wastewater sludge in the region of Marrakesh in Morocco. During the course of the experiments, drying pans (DP) and solar greenhouse drying processes were studied in summer and winter seasons. To simulate the DP process, representative samples were dried in plastic cylindrical plates in ambient conditions, near an Open Greenhouse Sludge Dryer (OGSD) designed and constructed as a tunnel plant. Results showed that the dry solids' (DS) concentration of 80% was reached in only 32 h in summer and 57 h in winter by DP process. The OGSD reached the same concentration in 45 and 65 h in summer and winter, respectively. The important influence of wind speed had a greater effect than the temperature on drying rate. The sludge water evaporation caused a large volume reduction during DP and OGSD processes in both seasons. The removal of total and fecal coliforms during summer experiment was noticeably better in the OGSD, even for Clostridium perfringens. Based on the obtained results, the solar greenhouse drying was practical and beneficial to wastewater sludge management and can be recommended as an alternative to DP in arid climate zones generally, and in Marrakesh particularly. PMID- 29280675 TI - The political biography of an earthquake - aftermath and Amnesia in Gujarat, India. PMID- 29280676 TI - Testing for Human Norovirus and Recovery of Process Control in Outbreak Associated Produce Items. AB - The development of rapid and sensitive detection methods for human noroviruses (HuNoV) in produce items is critical, especially with the recent rise in outbreaks associated with this food commodity. In this study, 50-g portions of various produce items linked to a norovirus outbreak (celery, cucumber, lettuce, grapes, and radish) were artificially inoculated with murine norovirus (MNV-1) and concentrated either by ultracentrifugation or polyethylene glycol (PEG) precipitation after elution with an alkaline Tris-glycine-beef extract buffer supplemented with pectinase. As a viral concentration step following virus elution and clarification, ultracentrifugation yielded a faster method (<8 h, including reverse transcription quantitative PCR), with MNV-1 recoveries similar to or better, than those obtained with PEG precipitation. The addition of polyvinylpyrrolidone to the elution buffer, to remove polyphenolic inhibitors, improved MNV-1 recoveries by over two- and fivefold for cucumber and grapes, respectively. However, despite MNV-1 recoveries ranging from 10 to 38% as calculated with 10-fold diluted RNA, contaminating HuNoV was not detected in any of the outbreak-associated samples tested. For store-bought produce samples, the limit of detection for artificially seeded HuNoV GII.4 was determined to be 103 copies per 50 g, with reproducible detection achieved in grapes, radish, and celery. The results support the use of ultracentrifugation as an alternative approach to PEG precipitation to concentrate norovirus from a variety of produce items. PMID- 29280677 TI - Response to Questions Posed by the Department of Defense Regarding Microbiological Criteria as Indicators of Process Control or Insanitary Conditions?. PMID- 29280679 TI - Do online health communities enhance patient-physician relationship? An assessment of the impact of social support and patient empowerment. AB - The diffusion of the Web 2.0 has made it possible for patients to exchange on online health communities, defined as computer-mediated communities dedicated to health topics, wherein members can build relationships with other members. It is now acknowledged that online health communities provide users not only with medical information but also with social support with no time or geographical boundaries. However, in spite of their considerable interest, there is still a paucity of research as to how online health communities alter the patient physician relationship. This research aims at filling this gap and examines how online health communities, while providing users with computer-mediated social support and empowerment, impact the patient-physician relationship. Six hypotheses are proposed and tested. A survey was developed and 328 responses were collected from online patient groups in Canada in 2016. The data were analysed using structural equation modelling. All but one hypothesis are validated. The results show that user computer-mediated social support positively influences user empowerment and participation during the consultation, which in turn determines user commitment to the relationship with the physician. Importantly and contrary to our expectations, user empowerment is found to be significantly but negatively related to user commitment with the physician. PMID- 29280681 TI - Terror, love and brainwashing: attachment in cults and totalitarian systems. PMID- 29280680 TI - SMARCB1-deficient Tumors of Childhood: A Practical Guide. AB - The SMARCB1 gene ( INI1, BAF47) is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, involved in the epigenetic regulation of gene transcription. SMARCB1 acts as a tumor suppressor gene, and loss of function of both alleles gives rise to SMARCB1-deficient tumors. The prototypical SMARCB1 deficient tumor is the malignant rhabdoid tumor (MRT) which was first described in the kidney but also occurs in soft tissue, viscera, and the brain (where it is referred to as atypical teratoid rhabdoid tumor or AT/RT). These are overwhelmingly tumors of the very young, and most follow an aggressive and ultimately lethal course. Morphologically, most but not all contain a population of "rhabdoid" cells, which are large cells with abundant cytoplasm, perinuclear spherical inclusions, and eccentric vesicular nuclei with large inclusion-like nucleoli. MRT immunohistochemistry reveals complete loss of SMARCB1 nuclear expression, and molecular analysis confirms biallelic SMARCB1 inactivation in the vast majority. Rare AT/RTs have loss of SMARCA4, another SWI/SNF member, rather than SMARCB1. With the widespread adoption of SMARCB1 immunohistochemistry, an increasing number of SMARCB1-deficient tumors outside of the MRT-AT/RT spectrum have been described. In addition to MRT and AT/RT, pediatric tumors with complete loss of SMARCB1 expression include cribriform neuroepithelial tumor, renal medullary carcinoma, and epithelioid sarcoma. Tumors with variable loss of SMARCB1 expression include subsets of epithelioid malignant peripheral nerve sheath tumor, schwannomas arising in schwannomatosis, subsets of chordomas, myoepithelial carcinomas, and sinonasal carcinomas. Variable and reduced expression of SMARCB1 is characteristic of synovial sarcoma. In this review, the historical background, clinical characteristics, morphology, immunohistochemical features, and molecular genetics most germane to these tumors are summarized. In addition, familial occurrence of these tumors (the rhabdoid tumor predisposition syndrome) is discussed. It is hoped that this review may provide practical guidance to pathologists encountering tumors that have altered expression of SMARCB1. PMID- 29280683 TI - ZrO2-toughened Al2O3 composites with better fracture and wear resistance properties. AB - In view of the importance of the fracture resistance and wear properties on the performance and durability in a number of engineering applications, we have analysed such properties of sintered zirconia toughened alumina with varying zirconia content of 5 and 15 wt.%. Using micro-computed tomography, homogenous particulate distribution of zirconia is established through 3D volume rendering of the sintered pellet and by 2D orthoslice view. Depending on zirconia content and MgO addition (sintering additive), an interesting combination of strength and toughness properties was recorded with the investigated materials. While explaining the origin of cracking on worn surfaces of optimized zirconia toughened alumina, theoretical calculations revealed that the maximum tensile stress at the trailing edge of sliding contact is higher than critical damage stress. Such analysis incorporates the effect of factors such as the internal stresses due to thermal expansion anisotropy of non-cubic Al2O3 matrix, mismatch in elastic modulus/thermal expansion and athermal ZrO2 phase transformation. PMID- 29280684 TI - Sport-related concussive convulsions: a systematic review. AB - OBJECTIVES: The incidence of sport-related concussion (SRC) continues to rise. Presentations of concussed athletes vary from subtle symptoms to notable signs. Between the 4th and 5th iterations of the Concussion in Sport Group (CISG) guidelines, concussive convulsions were removed as a modifying factor, but little evidence or discussion supported this change. While considerable research exists regarding post-traumatic epilepsy in moderate to severe traumatic brain injury, convulsions following SRC are relatively understudied. There is no clear consensus on the prevalence of convulsions, seizures, or the management of these entities following SRC. The aim of this review was to assess the state of the literature, describe the management trends of concussive convulsions and post traumatic epilepsy in the SRC population, and provide evidence and guidance for the management of these athletes. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adapted for a review of heterogeneous literature. English-language titles and abstracts published prior to June 2017 were searched systematically across four electronic databases. Primary peer-reviewed journal articles were included if they reported individuals of any age or gender who suffered a concussion or mild traumatic brain injury that was associated with seizure activity during a sports/recreational event. RESULTS: Of 852 records screened for review, 58 full text articles were assessed for eligibility. Eight studies with 130 athletes total met the inclusion criteria. Of these individuals suffering a SRC convulsion or a post-concussive seizure, 0.8% received antiepileptic medications, 24.6% underwent electroencephalography, and 30.8% underwent brain imaging. The mean time until the participant returned to play was 14.8 days. Only 6.9% developed long-term sequelae over a mean follow-up time of 3.3 years. CONCLUSIONS: The current literature describing concussive convulsions and post-concussion seizure in sports is limited. A void of primary literature concerning the management of patients with concussive convulsions or seizures and the long-term sequelae among this population remains. However, the evidence available suggests that concussive convulsions do not need to be a primary modifying factor in the management of SRC. PMID- 29280686 TI - State-dependent alterations of lipid profiles in patients with bipolar disorder. AB - Objective Serum lipid levels may be associated with the affective severity of bipolar disorder, but data on lipid profiles in Asian patients with bipolar disorder and the lipid alterations in different states of opposite polarities are scant. We investigated the lipid profiles of patients in the acute affective, partial, and full remission state in bipolar mania and depression. Methods The physically healthy patients aged between 18 and 45 years with bipolar I disorder, as well as age-matched healthy normal controls were enrolled. We compared the fasting blood levels of glucose, cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein of manic or depressed patients in the acute phase and subsequent partial and full remission with those of their normal controls. Results A total of 32 bipolar manic patients (12 women and 20 men), 32 bipolar depressed participants (18 women and 14 men), and 64 healthy control participants took part in this study. The mean cholesterol level in acute mania was significantly lower than that in acute depression (p < 0.025). The lowest rate of dyslipidemia (hypertriglyceridemia or low high-density lipoprotein cholesterol) was observed in acute bipolar mania. Conclusion Circulating lipid profiles may be easily affected by affective states. The acute manic state may be accompanied by state-dependent lower cholesterol and triglyceride levels relative to that in other mood states. PMID- 29280687 TI - Evaluation of the value of team-based psychiatric consultation in a general hospital setting. AB - Background With the increase use of pay for performance in healthcare, 30-day readmissions after discharges are critically important. Objective A team-based psychiatric consultation approach was tested in an inpatient hospital setting. This is the first study that examines 30-day readmission rate with this approach. Methods In this quality improvement study, 164 patients received a team-based psychiatric consultation that included daily meetings during the weekdays between psychiatrists and hospitalists and 436 received care of treatment-as-usual or traditional consultation-liaison services. Results Overall 30-day readmission rate was not significantly different between intervention and nonintervention groups. However, in subgroups with high risk of mortality or severe illness, the intervention group had a 0% 30-day readmission rate for both high risk of mortality and severe illness subgroups, while the nonintervention group's readmission rate was 5% for high risk of mortality group and 3% for severely ill patients. Annual hospital cost saving is estimated between a quarter million and 1.5 million dollars for these subgroups. Conclusion The team-based psychiatric consultation approach demonstrated the potential for substantial cost savings in providing care for patients with high risk of mortality and severe illness. Thus, this intervention may be very useful in caring for patients with complex chronic conditions. PMID- 29280685 TI - Associations among comorbid anxiety, psychiatric symptomatology, and diabetic control in a population with serious mental illness and diabetes: Findings from an interventional randomized controlled trial. AB - Objective Serious mental illness and type II diabetes mellitus have a high comorbidity, and both have a higher prevalence of anxiety disorders compared to the general population. Targeted Training in Illness Management is a group-based self-management training approach which targets serious mental illness and type II diabetes mellitus concurrently. This analysis examines data from a randomized controlled trial of Targeted Training in Illness Management intervention to examine the impact of comorbid anxiety on baseline psychiatric symptomatology and diabetic control, and on longitudinal treatment outcomes. Methods We conducted secondary analyses on data from a prospective, 60-week, randomized controlled trial testing Targeted Training in Illness Management versus treatment as usual in 200 individuals with serious mental illness and diabetes. Primary outcomes included measures related to serious mental illness symptoms, functional status, general health status, and diabetes control. Measures were compared between those participants with anxiety disorders versus those without anxiety at baseline as well as over time using linear mixed effects analyses. Results Forty seven percent of the participants had one or more anxiety disorders. At baseline, those with an anxiety diagnosis had higher illness severity, depressive, and other psychiatric symptomatology and disability. Diabetic control (HbA1c) was not significantly different at baseline. In the longitudinal analyses, no significant mean slope differences over time (group-by-time interaction effect) between those with anxiety diagnoses and those without in treatment as usual group were found for primary outcomes. Within the Targeted Training in Illness Management arm, those with anxiety disorders had significantly greater improvement in mental health functioning. Those with anxiety comorbidity in the Targeted Training in Illness Management group demonstrated significantly lower HbA1c levels compared to no anxiety comorbidity and also demonstrated a greater improvement in HbA1c over the first 30 weeks compared to those without anxiety comorbidity. Conclusion Comorbid anxiety in serious mental illness and type II diabetes mellitus population is associated with increased psychiatric symptomatology and greater disability. Individuals from this population appear to experience greater improvement in functioning from baseline with the Targeted Training in Illness Management intervention. Anxiety comorbidity in the serious mental illness and type II diabetes mellitus population does not appear to have a negative impact on diabetic control. These complex relationships need further study. Clinical Trials Registration ClinicalTrials.gov: Improving outcomes for individuals with serious mental illness and diabetes (NCT01410357). PMID- 29280688 TI - Psychological assessment of acute schizophrenia patients who experienced seclusion either alone or in combination with restraint. AB - Objective Numerous studies on the effects of seclusion and/or restraint in acute psychiatric treatment have reported both positive and negative effects. However, no studies to date have evaluated the effects of seclusion and/or restraint on schizophrenia patients using a rating scale. Thus, to examine the effects of seclusion and/or restraint on schizophrenia patients, we used the Brief Psychiatric Rating Scale and assessed the psychological condition of patients. Methods Factor analysis was conducted to create subscales of Brief Psychiatric Rating Scale, and psychiatric changes were assessed with respect to each subscale using multiple logistic regression analyses. Analyses were performed on three groups (i.e. entire, higher functioning, and lower functioning groups) involving a total of 1559 schizophrenia patients aged 18 to 65 years. Results In the entire and lower functioning groups, seclusion was a significant predictor of improvements related to the "hostility/suspiciousness" subscale. Seclusion combined with restraint was associated with improvements related to the "psychosis/thinking disorder" subscale. In the higher functioning group, there were no significant predictors. Conclusions It is implied that seclusion and/or restraint is related to improved psychiatric symptoms only among patients whose functioning is impaired. To verify the present findings, further studies involving multiple sites and additional psychiatric measures are necessary. PMID- 29280689 TI - Irritable bowel syndrome and quality of life in a community-dwelling population in Japan. AB - Objective Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and is characterized by recurrent abdominal pain or abnormal defecation. This investigation evaluated the relationship between IBS and self-reported quality of life in a community-dwelling population in Japan. Methods For this cross-sectional survey, we enrolled 1002 volunteers who participated in the Iwaki Health Promotion Project in 2013. IBS symptoms were evaluated using the criteria from the Japanese version of the Rome III Questionnaire. The assessments included an interview to obtain sociodemographic data, the second version of the Short-Form Health Survey (SF-36), and the Center for Epidemiologic Studies Depression Scale. Multiple regression analysis was used to assess the relationship between IBS symptoms and scores on the SF-36. Results A total of 59 subjects (5.9%) were classified as having IBS. Scores for all eight domains of the SF-36, the physical component summary, and the mental component summary were significantly and negatively associated with the Center for Epidemiologic Studies Depression scores. Physical functioning, role physical, vitality, mental health, and physical component summary scores were significantly and negatively associated with IBS. Conclusions The burden of IBS symptoms affects both physical and mental wellbeing, even after adjusting for confounders. Our findings suggest that screening for IBS symptoms and evaluating the need for medical care is important for community health workers. PMID- 29280690 TI - Implementation of a "Flipped Classroom" for Neurosurgery Resident Education. AB - INTRODUCTION: Engaging residents across a multiyear training spectrum is challenging given the heterogeneity of experience and limited time available for educational activities. A "flipped classroom" model, in which residents prepare ahead of time for mentored topic discussions, has potential advantages. METHODS: We implemented a curriculum consisting of topics distributed across the specialty. Weekly, each resident was randomly assigned to research a specific aspect of an assigned topic appropriate to his or her level of experience: junior residents about what characterizes each clinical entity, midlevel residents about when to intervene, and chief residents about how to administer treatment. Residents completed an anonymous survey 6 months after implementation. Board examination performance was assessed before and after implementation. RESULTS: A total of 12 residents participated in the program. Weekly, 1.75+/-0.40 hours were spent in preparation, with senior residents reporting less time than junior residents. All residents indicated that the accumulation of experience across 7 years of residency was a major advantage of this program, and all preferred it to lectures. Performance on the board examination significantly increased after implementation (from 316+/-36 to 468+/-45, p<0.05). CONCLUSIONS: The flipped classroom is a viable approach to resident education and is associated with increased engagement and improved performance using validated knowledge assessment tools. PMID- 29280691 TI - The British Rhinological Society multidisciplinary consensus recommendations on the hospital management of epistaxis. AB - OBJECTIVE: Epistaxis is a common ENT emergency in the UK; however, despite the high incidence, there are currently no nationally accepted guidelines for its management. This paper seeks to recommend evidence-based best practice for the hospital management of epistaxis in adults. METHODS: Recommendations were developed using an Appraisal of Guidelines for Research and Evaluation ('AGREE II') framework. A multifaceted systematic review of the relevant literature was performed and a multidisciplinary consensus event held. Management recommendations were generated that linked the level of supporting evidence and a Grading of Recommendations Assessment, Development and Evaluation ('GRADE') score explaining the strength of recommendation. RECOMMENDATIONS: Despite a paucity of high-level evidence, management recommendations were formed across five management domains (initial assessment, cautery, intranasal agents, haematological factors, and surgery and radiological intervention). CONCLUSION: These consensus recommendations combine a wide-ranging review of the relevant literature with established and rigorous methods of guideline generation. Given the lack of high-level evidence supporting the recommendations, an element of caution should be used when implementing these findings. PMID- 29280692 TI - Intranasal cautery for the management of adult epistaxis: systematic review. AB - BACKGROUND: Cauterisation techniques are commonly used and widely accepted for the management of epistaxis. This review assesses which methods of intranasal cautery should be endorsed as optimum treatment on the basis of benefits, risks, patient tolerance and economic assessment. METHOD: A systematic review of the literature was performed using a standardised methodology and search strategy. RESULTS: Eight studies were identified: seven prospective controlled trials and one randomised controlled trial. Pooling of data was possible from 3 studies, yielding a total of 830 patients. Significantly lower re-bleed rates were identified (p < 0.01) using electrocautery (14.5 per cent) when compared to chemical cautery (35.1 per cent). No evidence suggested that electrocautery was associated with more adverse events or discomfort. Limited evidence supported the use of a vasoconstrictor agent and operating microscope during the procedure. The included studies had considerable heterogeneity in terms of design and outcome measures. CONCLUSION: Consistent evidence suggests that electrocautery has higher success rates than chemical cautery, and is not associated with increased complications or patient discomfort. Lower quality evidence suggests that electrocautery reduces costs and duration of hospital stay. PMID- 29280694 TI - Initial assessment in the management of adult epistaxis: systematic review. AB - BACKGROUND: The initial assessment of epistaxis patients commonly includes: first aid measures, observations, focused history taking, and clinical examinations and investigations. This systematic review aimed to identify evidence that informs how the initial assessment of these patients should be conducted. METHOD: A systematic review of the literature was performed using a standardised methodology and search strategy. RESULTS: Seventeen articles were included. Factors identified were: co-morbidity, intrinsic patient factors, coagulation screening and ice pack use. Hypertension and anticoagulant use were demonstrated to adversely affect outcomes. Coagulation screening is useful in patients on anticoagulant medication. Four studies could not be accessed. Retrospective methodology and insufficient statistical analysis limit several studies. CONCLUSION: Sustained ambulatory hypertension, anticoagulant therapy and posterior bleeding may be associated with recurrent epistaxis, and should be recorded. Oral ice pack use may decrease severity and can be considered as first aid. Coagulation studies are appropriate for patients with a history of anticoagulant use or bleeding diatheses. PMID- 29280697 TI - National audit of epistaxis management. PMID- 29280693 TI - Epistaxis 2016: national audit of management. AB - BACKGROUND: Epistaxis is a common condition that can be associated with significant morbidity, and it places a considerable burden on our healthcare system. This national audit of management sought to assess current practice against newly created consensus recommendations and to expand our current evidence base. METHODS: The management of epistaxis patients who met the inclusion criteria, at 113 registered sites across the UK, was compared with audit standards during a 30-day window. Data were further utilised for explorative analysis. RESULTS: Data for 1826 cases were uploaded to the database, representing 94 per cent of all cases that met the inclusion criteria at participating sites. Sixty-two per cent of patients were successfully treated by ENT clinicians within 24 hours. The 30-day recurrent presentation rate across the dataset was 13.9 per cent. Significant event analysis revealed an all-cause 30 day mortality rate of 3.4 per cent. CONCLUSION: Audit findings demonstrate a varying alignment with consensus guidance, with explorative analysis countering some previously well-established tenets of management. PMID- 29280695 TI - Intranasal packs and haemostatic agents for the management of adult epistaxis: systematic review. AB - BACKGROUND: The mainstay of management of epistaxis refractory to first aid and cautery is intranasal packing. This review aimed to identify evidence surrounding nasal pack use. METHOD: A systematic review of the literature was performed using standardised methodology. RESULTS: Twenty-seven eligible articles were identified relating to non-dissolvable packs and nine to dissolvable packs. Nasal packing appears to be more effective when applied by trained professionals. For non dissolvable packs, the re-bleed rates for Rapid Rhino and Merocel were similar, but were higher with bismuth iodoform paraffin paste packing. Rapid Rhino packs were the most tolerated non-dissolvable packs. Evidence indicates that 96 per cent of re-bleeding occurs within the first 4 hours after nasal pack removal. Limited evidence suggests that dissolvable packs are effective and well tolerated by patients. There was a lack of evidence relating to: the duration of pack use, the economic effects of pack choice and the appropriate care setting for non dissolvable packs. CONCLUSION: Rapid Rhino packs are the best tolerated, with efficacy equivalent to nasal tampons. FloSeal is easy to use, causes less discomfort and may be superior to Merocel in anterior epistaxis cases. There is no strong evidence to support prophylactic antibiotic use. PMID- 29280696 TI - Surgical and interventional radiological management of adult epistaxis: systematic review. AB - BACKGROUND: There is variation regarding the use of surgery and interventional radiological techniques in the management of epistaxis. This review evaluates the effectiveness of surgical artery ligation compared to direct treatments (nasal packing, cautery), and that of embolisation compared to direct treatments and surgery. METHOD: A systematic review of the literature was performed using a standardised published methodology and custom database search strategy. RESULTS: Thirty-seven studies were identified relating to surgery, and 34 articles relating to interventional radiology. For patients with refractory epistaxis, endoscopic sphenopalatine artery ligation had the most favourable adverse effect profile and success rate compared to other forms of surgical artery ligation. Endoscopic sphenopalatine artery ligation and embolisation had similar success rates (73-100 per cent and 75-92 per cent, respectively), although embolisation was associated with more serious adverse effects (risk of stroke, 1.1-1.5 per cent). No articles directly compared the two techniques. CONCLUSION: Trials comparing endoscopic sphenopalatine artery ligation to embolisation are required to better evaluate the clinical and economic effects of intervention in epistaxis. PMID- 29280698 TI - Haematological factors in the management of adult epistaxis: systematic review. AB - BACKGROUND: The management of epistaxis requires an understanding of haematological factors that may complicate its treatment. This systematic review includes six distinct reviews examining the evidence supporting epistaxis specific management strategies relating to warfarin, direct oral anticoagulants, heparin, antiplatelet agents, tranexamic acid and transfusion. METHOD: A systematic review of the literature was performed using a standardised methodology and search strategy. RESULTS: Limited numbers of articles were identified in each systematic review, with level 1 evidence only regarding the use of tranexamic acid. No studies met the inclusion criteria within the heparin, direct oral anticoagulants or transfusion systematic reviews. Many studies were limited by small sample sizes and significant risk of bias. CONCLUSION: The management of major bleeding and transfusion practice is well documented in national guidance from multiple sources. The guidelines include advice on anticoagulants, antiplatelet agents and tranexamic acid. In the absence of more specific evidence, these guidelines should be applied in the management of epistaxis. PMID- 29280699 TI - Study of the role of telomerase in colorectal cancer: preliminary report and literature review. AB - AIM: The aim of our study is to focus on hTERT (human Telomerase Reverse Transcriptase) expression to identify tumoral tissue after a comparison to TP53 and KRAS. More than 85% of cancer cells contain genetic aberrations and also overexpression of hTERT, and, in fact, the promoter of hTERT characterizes all malignant cells. PATIENTS AND METHODS: Our sample is composed of 18 patients, including 10 with CRC that underwent surgical procedure and 8 patients without CRC, which represent the control group. The hTERT gene expression, KRAS and p53 were evaluated by methodical Real Time - PCR on RNA extracted from tumor tissues, peritumoral tissue and control cases. RESULTS: Within the CRC group the evaluation of the tumor tissue showed an increase of hTERT expression with a statistical significance (> 0.1) in 5 of these, also associated with substantial increase of KRAS (> 0.2). The peritumoral tissue assessment showed important increase in KRAS in 4 patients (> 0.2), while hTERT is not found to be particularly increased. The value of p53 did not show any particular significance (<0.1). DISCUSSION: The analysis of our data leads us to consider that the increase of hTERT is evident in patients suffering from CRC and that some of them will become significant in relation to the increase of KRAS and independent of p53. In peritumoral tissues, however, KRAS increases considerably, instead hTERT maintains a low concentration and this is compatible with the cellular evolution of the neoplastic tissue adjacent to the tumor. CONCLUSIONS: hTERT could be used for diagnosis and prognosis in the future, to be able to identify the risk of tumor progression and to set up an adequate therapy. PMID- 29280700 TI - Open and endovascular treatment by covered and multilayer stents in the therapy of renal artery aneurysms: mid and long term outcomes in a single center experience. AB - AIM: The purpose of this paper is to evaluate the mid and long terms outcomes of open and endovascular surgical treatment, as well as multilayer stent, in patients affected by Renal Artery Aneurysm (RAA). PATIENTS AND METHODS: Twenty five patients with RAA (24 monolateral and 1 bilateral aneurysm, 26 aneurysms) were observed between 2000 and 2015: 4 were not treated due to the small size of the aneurysm (< 2.5 cm); out of the remaining, 16 underwent endovascular treatment, 2 were treated by open surgery consisting in aneurysmectomy and graft reconstruction and 5 (in 1 patient bilateral) were treated by ex vivo repair and autotransplantation. RESULTS: Out of the 22 patients treated for RAA, one patient operated upon open surgery presented an early thrombosis of a PTFE graft, followed by nephrectomy (4.7%); one patient underwent autotransplantation showed an ureteral kinking without functional consequences. In a follow-up ranging from 1 and 11 years (mean 5 years), no deaths were observed; all the renal arteries repaired were patents and 16 out of 21 patients had a significative reduction of systemic blood pressure. DISCUSSION: The choice of the best treatment is based on aneurysm's morphology according to Rundback's classification. The type I, involving the main renal artery, is always treated by endovascular approach; type II, involving renal artery bifurcations may be treated by open surgery or multilayer stents; type III (hilar or intraparenchymal aneurysms) needs only an open surgical treatment as autotransplantation. CONCLUSION: Based on our experience it seems that most of RAAs may be treated by endovascular technique. The ex vivo autotransplantation represents the first-line treatment in hilar and intraparenchymal aneurysms. Multilayer stents seem to have good outcome in the treatment of aneurysms involving arterial bifurcations. Mid and long term results, related to kidney preservation and to normalization of blood pressure, seems satisfying. PMID- 29280701 TI - Laparoscopic adjustable gastric banding migration: an early approach for a late complication. AB - AIM: Laparoscopic adjustable gastric banding (LAGB) migration is an uncommon late complication after bariatric surgery. It usually presents with an unexplained weight increase or without any symptom. Current guidelines do not establish the timing of a clear endoscopic follow-up to prevent and/or to treat this kind of complication. PATIENTS AND METHODS: Long-term follow-up was performed in 217 patients with LAGB (37 underwent surgery in other bariatric centers). At the endoscopic check, 3 patients presented banding erosion respectively 7, 9 and 11 years after surgery. In all three cases the patients, lost at the follow-up in their bariatric centers, had weight gain. During the endoscopy was treated just one patient because of the advanced migration. For the other patients, with a minimal migration, the choice was to perform an endoscopic surveillance every 4 months. DISCUSSION: Removal of eroded gastric banding with common endoscopic devices is feasible, safe, and effective. CONCLUSION: With our experience we suggest to perform planned endoscopy at least within 2 years in order to guarantee the early diagnosis and managing of gastric banding erosion. PMID- 29280702 TI - Effective management of extensive tissue loss after abdominoperineal resection for Buschke-Loewenstein tumor. AB - The giant condyloma acuminatum or Buschke-Loewenstein tumor is a rare, sexually transmitted disease. It is an epithelial tumor characterized by its high potential of malignancy towards developing into a highly invasive squamous cell carcinoma. The present case concerns a drug addicted 40-year-old man who smuggled drugs using his rectum. He had a partially ulcerated mass in the perianal area of about 20 x 10 cm. He reported a progressive growth of this neoplasm during the last 3 years associated with perianal pain, obstructed defecation, bad sitting posture, no fever and weight loss. Our first approach was a left laparoscopic loop colostomy for a fecal diversion and antalgic purpose, and biopsy of the perineal mass. Then, he underwent a complete excision of the perianal neoplasm. The pathologist's positive diagnosis of a well differentiated squamous cell carcinoma, evidently necessitated the radicalization of the surgical procedure of abdominal perineal resection. In consideration of the surgical wound depth and size, a VAC Therapy with Negative Pressure Wound Therapy was applied. The BLT incidence rate has been steadily increasing over the last decade especially among male patients. An aggressive surgical approach is usually to get the best oncologic outcome but the difficult management of the perianal wound is challenging. In our experience VAC therapy has been shown to be an effective tool in promoting the healing of the perineal wound after abdominoperineal resection. PMID- 29280703 TI - Cervical ultrasound assessment of thyroid nodules at risk of malignancy: single center experience. AB - AIM: The increasing diagnosis of thyroid nodules makes proper assessment of their nature and course of treatment essential, considering that thyroidectomy may be unnecessary and only contribute to higher healthcare system costs. Although criteria have been proposed for the stratification of these patients according to risk by use of cervical ultrasound and fine needle aspiration biopsy (FNAB), not all medical units may be equipped or have access to trained medical professionals to perform FNAB. The aim of this study was to show that cervical ultrasound may be sufficient for the evaluation of thyroid nodules in the treatment decision making process. PATIENTS AND METHODS: 206 patients with single thyroid nodules and nodular goiter were assessed through cervical ultrasound and FNAB for the correlation between pretreatment classification and final diagnosis on histological examination. RESULTS: 26.5% of single nodes proved malignant on paraffin studies, as compared to only 14% of nodular goiters. FNAB recorded a sensibility of 33.3%, specificity of 93.3%, false-negative rate of 50% and false positive rate of 12.5%, whereas cervical ultrasound recorded a sensibility of 92.3%, specificity of 75.3%, false-negative rate of 2.8% and false-positive rate of 48.9%. CONCLUSION: Cervical ultrasound evaluation is a reliable method in the preoperative diagnosis of thyroid cancer patients. PMID- 29280704 TI - Reversible pneumatosis cystoides intestinalis after liver transplantation. AB - Pneumatosis cystoides intestinalis (PCI) is a rare disease characterized by the presence of multiple gas-filled cysts within the submucosa or subserosa of the intestinal wall. We report a case of PCI in a 54-yearold man 4 weeks after liver transplantation due to hepatitis B virus (HBV)-associated liver cirrhosis presenting with illness, diarrhea and abdominal pain. CT scans revealed normal shape of the abdominal parenchymal organs and no intra-hepatic complication due to liver transplantation. Main abdominal venous and arterial vessels resulted patent. Colic loops appeared diffusely thickened for the presence of variable diameter air-filled cysts located within the bowel wall. The patient underwent conservative treatment and the CT control after 4 weeks showed a complete PCI resolution. PCI after adult liver transplantation is probably due to the pre transplantation chemotherapy, immunosuppressive therapy and opportunistic enteric infections. Abdominal CT represents the gold standard technique for diagnosing PCI and for evaluating its extension and complications providing data on other abdominal pathologies. It appears as variable diameter gas-filled cysts located within the bowel wall and it is often associated with pneumo-peritoneum probably due to the rupture of subserosal cysts. PCI has a favorable outcome and requires conservative treatment. Major differential diagnosis includes intestinal pneumatosis due to bowel ischemia. PCI after liver transplantation represents an uncommon bowel disease with a favorable prognosis. CT represents the reference imaging technique for diagnosing the disease and evaluating the response to therapy which is usually conservative rather than surgical. PMID- 29280705 TI - Non-functioning parathyroid cystic tumour: malignant or not? Report of a case. AB - Parathyroid carcinoma (PC) is a very rare endocrine tumour, usually characterized by symptoms such as a neck mass, dysphonia, severe hypercalcemia exceeding 140 mg/L and elevated serum parathyroid hormone levels, even more than 5 times the upper limit of normal. Non-functioning parathyroid cancer is extremely rare and, in this case, its pre-operative diagnosis is often difficult. A 54-year old female patient, referring dysphagia and dysphonia, underwent neck ultrasound and neck CT. A left thyroid nodule, probably cystic, was found. It presented caudal extent on anterior mediastinum causing compression of the left lateral wall of the trachea. The preoperative calcemia was into the normal range. The patient underwent left thyroid lobectomy. Histological exam showed a cystic lesion, immunohistochemically originating from parathyroid that oriented for carcinoma. The 18 months follow-up did not show a residual-recurrent disease. The parathyroid origin of a neck lesion could not be suspected before surgery when specific laboratory tests are not available and clinical effects of hyperparathyroidism syndrome are not present. Histological features are not always sufficient for the differential diagnosis between the parathyroid adenoma and carcinoma. The immunohistochemistry is an useful tool that can aid to reach the definite diagnosis. PMID- 29280707 TI - Successful conservative treatment of enterocutaneous fistula with cyanoacrylate surgical sealant: case report. AB - AIM: Enterocutaneous (EC) fistula is an abnormal communication between the gastrointestinal tract and the skin. The majority of EC fistulas result from surgery. Only 15-25% of EC fistulas are spontaneous and they often result from underlying diseases such as Crohn's disease, radiation and chemotherapy. CASE REPORT: A 62-year old woman who, in 2012, underwent Pylorus-preserving cephalic pancreaticoduodenectomy (PPPD sec. Traverso-Longmire), due to an advanced pancreatic ductal adenocarcinoma (pT3N1M1). After surgery, the patient underwent chemotherapy with folfirinox regimen. In December 2016, as a result of the appearance of metastatic liver lesions and perianastomotic recurrence, the patient underwent second line treatment with Gemcitabine and pab-paclitaxel. After five months from the beginning of this new second line therapy she presented an EC fistula. The fistula of the patient was successfully treated with total parenteral nutrition and with percutaneous injection of cyanoacrylic sealant. RESULTS: The result suggests the advisability of percutaneous injection of sealant devices, such as cyanoacrylate glue; in order to successfully control stable Enterocutaneous fistulas with acceptable morbidity and mortality especially in particular situations, such as, with low output EC fistulas without signs of complications or on patients considered not suitable for surgery, a conservative approach could ensure the control of the fistula. CONCLUSION: This approach is easy and safe, viable and useful for future trials on the efficacy in conservative treatment of EC fistula. PMID- 29280706 TI - Renal endometriosis mimicking complicated cysts of kidney: report of two cases. AB - Endometriosis is a common gynecologic disorder characterized by ectopic endometrial tissue growth outside the uterine cavity. Although usually occurring in pelvic organs, endometrial lesions may involve urinary tract. Renal endometriosis is extremely rare and it has only occasionally been reported in the past. We report two cases of patients with renal cystic lesions, incidentally found at imaging techniques during oncologic follow-up for gastric sarcoma and melanoma, initially misinterpreted as complicated haemorrhagic cysts and then histologically characterized as renal localizations of extragenital endometriosis. PMID- 29280708 TI - Justifying Rehabilitation Intensity Through Functional Performance Measures in Postacute Care. AB - The Centers for Medicare and Medicaid Services (CMS) has scrutinized the provision of rehabilitation services in skilled nursing facilities (SNFs) for some time. Little research guidance exists on appropriate dosage or rehabilitation intensity (RI) among SNF patients or patients in other postacute care (PAC) settings. CMS developed a PAC assessment, the Continuity Assessment Record and Evaluation (CARE) Tool, in response to questions about what issues drive placement in various PAC settings under Medicare. The ability to adequately assess functional outcomes and correlate them to the RI provided by using the CARE Tool is promising. However, further research, policy advocacy, and practice analysis must be undertaken to promote and protect adequate access to occupational therapy and physical therapy in SNFs and other PAC settings. Individual practitioners must participate in data gathering to ensure that the data for analysis are fully informed by the occupational therapy perspective. PMID- 29280709 TI - Errata. AB - [This corrects the article DOI: 10.5014/ajot.2017.023358.] and [This corrects the article DOI: 10.5014/ajot.2017.712001.]. PMID- 29280710 TI - State of the Science of Sensory Integration Research With Children and Youth. AB - Many children and youth with and without disabilities are affected by challenges in processing and integrating sensations. Occupational therapy practitioners serve a pivotal role in the evaluation and treatment of this population. This special section of the American Journal of Occupational Therapy includes articles that elucidate the relationship between sensory processing and participation in valued occupations as well as articles that guide best practice, including systematic reviews on common occupational therapy interventions for children and youth with challenges in processing and integrating sensation. This editorial elaborates on key issues for future research. PMID- 29280711 TI - Efficacy of Occupational Therapy Using Ayres Sensory Integration(r): A Systematic Review. AB - This systematic review addresses the question "What is the efficacy of occupational therapy using Ayres Sensory Integration(r) (ASI) to support functioning and participation as defined by the International Classification of Functioning, Disability and Health for persons with challenges in processing and integrating sensory information that interfere with everyday life participation?" Three randomized controlled trials, 1 retroactive analysis, and 1 single-subject ABA design published from 2007 to 2015, all of which happened to study children with autism, met inclusion criteria. The evidence is strong that ASI intervention demonstrates positive outcomes for improving individually generated goals of functioning and participation as measured by Goal Attainment Scaling for children with autism. Moderate evidence supported improvements in impairment-level outcomes of improvement in autistic behaviors and skills-based outcomes of reduction in caregiver assistance with self-care activities. Child outcomes in play, sensory-motor, and language skills and reduced caregiver assistance with social skills had emerging but insufficient evidence. PMID- 29280712 TI - Effectiveness of Cognitive and Occupation-Based Interventions for Children With Challenges in Sensory Processing and Integration: A Systematic Review. AB - This systematic review examines the evidence for the effectiveness of cognitive and occupation-based interventions to improve self-regulation in children and youth who have challenges in processing and integrating sensory information. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guided the methodology. Five studies identified through a comprehensive database search met the inclusion criteria and were separated into categories of cognitive and occupation-based interventions. Articles that did not specifically measure sensory integration (SI) or processing challenges were omitted. Synthesis of the articles suggests that self-regulation (e.g., sensory processing, emotional regulation, executive functioning, social function) improved with cognitive and occupation-based interventions. Because the number of studies that measured sensory processing or SI challenges was limited, researchers are encouraged to include these measures in future research to understand the impact of a broader range of cognitive and occupation-based interventions. PMID- 29280713 TI - Parental or Teacher Education and Coaching to Support Function and Participation of Children and Youth With Sensory Processing and Sensory Integration Challenges: A Systematic Review. AB - This systematic review examines the literature published from January 2007 through May 2015 related to the effectiveness of occupational therapy interventions using parental or teacher education and coaching with children with challenges in sensory processing and sensory integration (SP-SI). Of more than 11,000 abstracts and 86 articles that were considered, only 4 met the criteria and were included in this review. Studies of parental training and coaching for children with challenges in SP-SI and comorbid autism spectrum disorder have suggested that educational or coaching programs could result in positive outcomes for both parents and children, often in a relatively short time period. Recommendations include a greater focus on providing educational interventions for parents and teachers and including specific assessment of SP-SI before implementing interventions meant to address those issues. Specific recommendations for future research are provided. PMID- 29280714 TI - Specific Sensory Techniques and Sensory Environmental Modifications for Children and Youth With Sensory Integration Difficulties: A Systematic Review. AB - This systematic review examined the effectiveness of specific sensory techniques and sensory environmental modifications to improve participation of children with sensory integration (SI) difficulties. Abstracts of 11,436 articles published between January 2007 and May 2015 were examined. Studies were included if designs reflected high levels of evidence, participants demonstrated SI difficulties, and outcome measures addressed function or participation. Eight studies met inclusion criteria. Seven studies evaluated effects of specific sensory techniques for children with autism spectrum disorder (ASD) or attention deficit hyperactivity disorder: Qigong massage, weighted vests, slow swinging, and incorporation of multisensory activities into preschool routines. One study of sensory environmental modifications examined adaptations to a dental clinic for children with ASD. Strong evidence supported Qigong massage, moderate evidence supported sensory modifications to the dental care environment, and limited evidence supported weighted vests. The evidence is insufficient to draw conclusions regarding slow linear swinging and incorporation of multisensory activities into preschool settings. PMID- 29280715 TI - Comparison of Two Tools to Assess Sensory Features in Children With Autism Spectrum Disorder. AB - OBJECTIVE: This article documents the convergent validity of the Sensory Profile (SP) and the Sensory Processing Measure (SPM)-Home Form for children with autism spectrum disorder (ASD). METHO: . Parents of 34 children with ASD between ages 5 and 8 yr filled out both measures. Through correlations, chi2 tests, and levels of agreement between classifications, the results for the SP and the SPM-Home Form were compared. RESULTS: The raw scores were correlated for some sensory domains (hearing, vision, touch, and proprioception) and for social functioning. The classifications showed a significant level of agreement for most scales (kappas = .247-.589, p <= .05) and for the total scores (kappa = .324, p <= .01). CONCLUSION: This study provides further evidence of convergent validity between both tools. The SPM-Home Form identifies more children with ASD who present with sensory features for every domain measured by both tools. PMID- 29280716 TI - Investigation of the Relationship Between Sensory Processing and Motor Development in Preterm Infants. AB - OBJECTIVE: The aim of this study was to analyze the correlation between sensory processing and motor development in preterm infants. METHOD: We included 30 preterm and 30 term infants with corrected and chronological ages between 10 and 12 mo. We used the Test of Sensory Functions in Infants to evaluate sensory processing and the Alberta Infant Motor Scale to evaluate motor development. RESULTS: The Spearman correlation test indicated a strong positive relationship between sensory processing and motor development in preterm infants (r = .63, p < .001). CONCLUSION: Given the relationship between sensory processing and motor development in the preterm group, the evaluation of sensory processing and motor development in preterm infants was considered necessary for the effective implementation of physiotherapy assessment and interventions. PMID- 29280717 TI - Introduction to the Evaluation in Ayres Sensory Integration(r) (EASI). AB - Comprehensive, reliable, and valid assessment is essential for individually tailored, appropriate, and effective intervention planning and implementation. Research, education, and practice using an Ayres Sensory Integration(r) (ASI) approach have a long history of prioritizing comprehensive assessment. To meet the need for a set of tests that will fully evaluate the constructs of ASI with psychometrically strong, internationally appropriate, and easily accessible measurement tools, the development of the Evaluation in Ayres Sensory Integration(r) (EASI) has been initiated. This article introduces the EASI, describes the overarching plan for its development, and reports the results of promising preliminary analyses of discriminative validity data. PMID- 29280718 TI - Relationship Between Sensory Processing and Sleep in Typically Developing Children. AB - OBJECTIVE: The relationship between sensory processing factors and the sleep habits and patterns of typically developing children ages 8-12 yr was investigated. METHOD: Forty-five typically developing children and their parents or caregivers took part. Parents completed the Sensory Processing Measure-Home Form, Children's Sleep Hygiene Scale, and Children's Sleep Habits Questionnaire, and the children completed the Children's Report of Sleep Patterns. Spearman rho correlation and linear regression analyses were completed with the children's sleep habits and patterns as the dependent variables and the sensory processing factors as the independent variables. RESULTS: Sensory processing factors were significantly associated with the children's sleep habits and patterns, as reported by parents and children. Predictive relationships were established between the children's sensory processing factors and sleep habits and patterns. CONCLUSION: Occupational therapy practitioners should consider sensory processing factors when working with children who present with suspected sleep problems. PMID- 29280720 TI - Sensory Processing in the General Population: Adaptability, Resiliency, and Challenging Behavior. AB - : Sensory processing is a personal trait that can contribute to challenging behavior. Protective factors, such as resiliency, can support children in managing their behavior, yet little research has addressed the contribution of sensory processing to protective factors. Therefore, in this cross-sectional study we aimed to determine the contribution of sensory processing (using the Sensory Profile-2) to challenging behavior and protective factors (using the Behavior Assessment System for Children, 2nd ed., Parent Rating Scales) in a sample of 51 children ages 6-11 yr from the general U.S. POPULATION: The results indicated that sensory avoiding predicts externalizing behaviors, depression, resiliency, and adaptability. In addition, sensory seeking is related to depression and resiliency, whereas sensory sensitivity is related to externalizing behaviors. Implications for occupational therapy research and practice are discussed. PMID- 29280719 TI - Relationship Between Sensory Processing and Pretend Play in Typically Developing Children. AB - OBJECTIVE: We sought to investigate the relationship between sensory processing and pretend play in typically developing children. METHOD: Forty-two typically developing children ages 5-7 yr were assessed with the Child Initiated Pretend Play Assessment and the Home and Main Classroom forms of the Sensory Processing Measure (SPM). RESULTS: There were significant relationships between elaborate pretend play and body awareness (r = .62, p < .01), balance (r = .42, p < .01), and touch (r = .47, p < .01). Object substitution was associated with social participation (r = .42, p < .05). CONCLUSIONS: The sensory processing factors (from the SPM)-namely, Body Awareness, Balance, Touch, and Social Participation were predictive of the quality of children's engagement in pretend play in the home environment. The results indicated that, to engage and participate in play, children are involving sensory processing abilities, especially body awareness, balance, and touch. PMID- 29280721 TI - Criterion Validity of the Child's Challenging Behavior Scale, Version 2 (CCBS-2). AB - OBJECTIVE: The Child's Challenging Behavior Scale, Version 2 (CCBS-2), measures maternal rating of a child's challenging behaviors that compromise maternal mental health. The CCBS-2, the Child Behavior Checklist (CBCL), and the Strengths and Difficulties Questionnaire (SDQ) were compared in a sample of typically developing young Australian children. METHOD: Criterion validity was investigated by correlating the CCBS-2 with "gold standard" measures (CBCL and SDQ subscales). Data were collected in a cross-sectional survey of mothers (N = 336) of children ages 3-9 yr. RESULTS: Correlations with the CBCL externalizing subscales demonstrated moderate (rho = .46) to strong (rho = .66) correlations. Correlations with the SDQ externalizing behaviors subscales were moderate (rho = .35) to strong (rho = .60). CONCLUSION: The criterion validity established in this study strengthens the psychometric properties that support ongoing development of the CCBS-2 as an efficient tool that may identify children in need of further evaluation. PMID- 29280723 TI - Adjusting Challenge-Skill Balance to Improve Quality of Life in Older Adults: A Randomized Controlled Trial. AB - OBJECTIVE: We sought to investigate whether occupational therapy that includes adjusting the challenge-skill balance improves health-related quality of life (HRQOL) for older adults in comparison with standard occupational therapy. METHOD: In this single-blind, randomized controlled trial, 56 older adults were assigned to two groups that received 10 sessions of occupational therapy with and without adjustment of challenge-skill balance. The primary outcome was change in HRQOL after 10 sessions of occupational therapy. RESULTS: Significant differences were observed in HRQOL using the EuroQol-5 Dimension score (p = .022, d = 0.76) and the eight-item Short-Form Health Survey scores for general health (p = .001, d = 0.99) and in flow experience using the Flow State Scale for Occupational Tasks (p = .008, d = 0.82). CONCLUSION: Assessment and adjustment of the challenge-skill balance of activities may effectively improve older adults' HRQOL. PMID- 29280722 TI - Feasibility Trial of Tailored Home Modifications: Process Outcomes. AB - OBJECTIVE: The aim of this study was to conduct a process evaluation to examine the implementation of a randomized controlled trial of home modifications designed to reduce the risk of falls and improve daily activity performance among community-dwelling older adults. METHOD: A process evaluation was conducted alongside a blinded, randomized sham-controlled trial (n = 92). Participants were followed for 1 yr after intervention. The process evaluation was framed using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. RESULTS: The treatment group improved daily activity performance over 12 mo compared with the sham control group (F = 4.13; p = .024). The intervention elements and dose were delivered with greater than 90% accuracy. Participants reported a 91% adherence rate at 12 mo. CONCLUSION: The complex intervention of home modifications examined in this study is acceptable to older adults, is feasible, and can be delivered with high fidelity for frail, community-dwelling older adults. PMID- 29280724 TI - Curriculum-Level Strategies That U.S. Occupational Therapy Programs Use to Address Occupation: A Qualitative Study. AB - OBJECTIVE: This study's objective was to describe curriculum-level strategies used to convey occupation to occupational therapy students. METHOD: The study used a descriptive qualitative research design. Fifteen occupational therapy and 10 occupational therapy assistant programs participated in interviews, submitted curriculum artifacts such as syllabi and assignments, and recorded teaching sessions. Data were coded both inductively and deductively and then categorized into themes. RESULTS: Occupational therapy programs designed strategies on two levels of the curriculum, infrastructure and implementation, to convey knowledge of occupation to students. The degree to which strategies explicitly highlighted occupation and steered instruction fluctuated depending on how differentiated occupation was from other concepts and skills. CONCLUSION: Two arguments are presented about the degree to which occupation needs to be infused in all curricular elements. To guide curriculum design, it is critical for educators to discuss beliefs about how ubiquitous occupation is in a curriculum and whether curricular elements portray occupation to the extent preferred. PMID- 29280725 TI - Men in Occupational Therapy: Issues, Factors, and Perceptions. AB - OBJECTIVE: Relatively few men are occupational therapy practitioners in the United States. Little research has examined issues germane to men working in the profession. The objective of this study was to investigate perceptions, issues, and factors surrounding male occupational therapy practitioners. METHOD: A survey link was emailed to 9,467 licensed occupational therapy practitioners in Ohio; 699 participants responded, yielding a response rate of 7.66%. RESULTS: Male and female participants provided both similar and significantly different responses to the survey questions. Differences generally involved responses to questions on personal finances and client education. Themes were identified from the open ended questions regarding gender stereotypes. CONCLUSION: Although male and female practitioners differed in opinion on several issues and perceptions related to the profession, in general they were happy with their career choice. Specifically, participants expressed that they enjoyed their job, contributed to society, and had a sense of job security, regardless of gender. PMID- 29280726 TI - Self-Awareness and Recovery of Independence With Strategy Training. AB - OBJECTIVE: Poor self-awareness co-occurs with cognitive impairments after stroke and may influence independence in daily activities. Strategy training promotes independence after stroke, but poor awareness may attenuate treatment response. We examined the degree to which awareness status affected changes in independence attributed to strategy training. METHOD: We conducted a secondary analysis of 30 participants with cognitive impairments after acute stroke randomized to strategy training or attention control in addition to typical inpatient rehabilitation. We measured awareness with the Self-Awareness of Deficits Interview and independence with the FIMTM. Data were analyzed using general linear models. RESULTS: Poor awareness attenuated improvements in independence over time, F(3, 55) = 3.04, p = .038. Strategy training promoted greater improvements in independence over time relative to attention control, F(3, 55) = 5.93, p = .002. However, the interaction between awareness and intervention was not significant, F(1, 19) = 0.025, p = .877. CONCLUSION: Awareness status may not affect the response to strategy training, indicating that strategy training may benefit people with poor awareness. PMID- 29280727 TI - Redesigning the Peer Audit Process to Enhance Clinical Dialogue. AB - This case report describes the process used to engage clinicians in redesigning the peer audit system and the outcome of this effort at the Rehabilitation Therapies department of the University of Vermont Medical Center in Burlington. A wide variety of peer audit processes, tools, and requirements have been used across disciplines and clinical sites. Rehabilitation therapy staff participated in a group project using a project charter to design the new approach to the peer audit. A single peer audit tool and unified audit process were developed for use across therapy disciplines and care settings. A survey was used to collect pre- and postrevision data. Responses to all survey questions indicated favorable change. Broad engagement of clinical staff in the redesign resulted in a peer audit process that was completed more consistently and was more likely to be perceived as resulting in meaningful discussion, encouraging critical thinking, and improving clinical skills. PMID- 29280728 TI - Sleep as an Occupational Need. AB - In the same way the human body requires food, hydration, and oxygen, it also requires sleep. Even among healthy people, the amount and quality of sleep substantially influence health and quality of life because sleep helps regulate physiological functioning. Given the impact of sleep on participation, the American Occupational Therapy Association reclassified sleep from an activity of daily living to an occupational domain. Poor sleep is a frequent medical complaint, especially among populations with neurological impairment. Occupational therapy practitioners should consider routinely screening for factors affecting their clients' sleep. By addressing such factors, as well as related routines and habits, practitioners can enhance the effectiveness of rehabilitation, promote health and well-being, and increase engagement and life quality. Practitioners should acknowledge the importance of sleep in practice, and the study of sleep should be prioritized by researchers in the field to meet client needs and establish evidence for interventions. PMID- 29280729 TI - Occupational Therapy Interventions for People With Alzheimer's Disease. AB - Evidence Connection articles provide a clinical application of systematic reviews developed in conjunction with the American Occupational Therapy Association's (AOTA's) Evidence-Based Practice Project. In this Evidence Connection article, we describe a case report of a person with Alzheimer's disease. The occupational therapy assessment and intervention process in the home setting is described. Findings from the systematic reviews on this topic were published in the November/December 2017 issue of the American Journal of Occupational Therapy and in AOTA's Occupational Therapy Practice Guidelines for Adults With Alzheimer's Disease and Related Major Neurocognitive Disorders. Each article in this series summarizes the evidence from the published reviews on a given topic and presents an application of the evidence to a related clinical case. Evidence Connection articles illustrate how the research evidence from the reviews can be used to inform and guide clinical reasoning. PMID- 29280730 TI - Phenotype inference in an Escherichia coli strain panel. AB - Understanding how genetic variation contributes to phenotypic differences is a fundamental question in biology. Combining high-throughput gene function assays with mechanistic models of the impact of genetic variants is a promising alternative to genome-wide association studies. Here we have assembled a large panel of 696 Escherichia coli strains, which we have genotyped and measured their phenotypic profile across 214 growth conditions. We integrated variant effect predictors to derive gene-level probabilities of loss of function for every gene across all strains. Finally, we combined these probabilities with information on conditional gene essentiality in the reference K-12 strain to compute the growth defects of each strain. Not only could we reliably predict these defects in up to 38% of tested conditions, but we could also directly identify the causal variants that were validated through complementation assays. Our work demonstrates the power of forward predictive models and the possibility of precision genetic interventions. PMID- 29280731 TI - Cryo-EM structure of the bifunctional secretin complex of Thermus thermophilus. AB - Secretins form multimeric channels across the outer membrane of Gram-negative bacteria that mediate the import or export of substrates and/or extrusion of type IV pili. The secretin complex of Thermus thermophilus is an oligomer of the 757 residue PilQ protein, essential for DNA uptake and pilus extrusion. Here, we present the cryo-EM structure of this bifunctional complex at a resolution of ~7 A using a new reconstruction protocol. Thirteen protomers form a large periplasmic domain of six stacked rings and a secretin domain in the outer membrane. A homology model of the PilQ protein was fitted into the cryo-EM map. A crown-like structure outside the outer membrane capping the secretin was found not to be part of PilQ. Mutations in the secretin domain disrupted the crown and abolished DNA uptake, suggesting a central role of the crown in natural transformation. PMID- 29280732 TI - Combining robotic training and inactivation of the healthy hemisphere restores pre-stroke motor patterns in mice. AB - Focal cortical stroke often leads to persistent motor deficits, prompting the need for more effective interventions. The efficacy of rehabilitation can be increased by 'plasticity-stimulating' treatments that enhance experience dependent modifications in spared areas. Transcallosal pathways represent a promising therapeutic target, but their role in post-stroke recovery remains controversial. Here, we demonstrate that the contralesional cortex exerts an enhanced interhemispheric inhibition over the perilesional tissue after focal cortical stroke in mouse forelimb motor cortex. Accordingly, we designed a rehabilitation protocol combining intensive, repeatable exercises on a robotic platform with reversible inactivation of the contralesional cortex. This treatment promoted recovery in general motor tests and in manual dexterity with remarkable restoration of pre-lesion movement patterns, evaluated by kinematic analysis. Recovery was accompanied by a reduction of transcallosal inhibition and 'plasticity brakes' over the perilesional tissue. Our data support the use of combinatorial clinical therapies exploiting robotic devices and modulation of interhemispheric connectivity. PMID- 29280733 TI - Stochastic resonance mediates the state-dependent effect of periodic stimulation on cortical alpha oscillations. AB - Brain stimulation can be used to engage and modulate rhythmic activity in brain networks. However, the outcomes of brain stimulation are shaped by behavioral states and endogenous fluctuations in brain activity. To better understand how this intrinsic oscillatory activity controls the susceptibility of the brain to stimulation, we analyzed a computational model of the thalamo-cortical system in two distinct states (rest and task-engaged) to identify the mechanisms by which endogenous alpha oscillations (8Hz-12Hz) are modulated by periodic stimulation. Our analysis shows that the different responses to stimulation observed experimentally in these brain states can be explained by a passage through a bifurcation combined with stochastic resonance - a mechanism by which irregular fluctuations amplify the response of a nonlinear system to weak periodic signals. Indeed, our findings suggest that modulation of brain oscillations is best achieved in states of low endogenous rhythmic activity, and that irregular state dependent fluctuations in thalamic inputs shape the susceptibility of cortical population to periodic stimulation. PMID- 29280734 TI - Interactions between stimulus and response types are more strongly represented in the entorhinal cortex than in its upstream regions in rats. AB - Previously we reported results which suggested that response types are critical in dissociating the lateral entorhinal cortex (LEC) from the medial entorhinal cortex (MEC) in a scene memory task (Yoo and Lee, 2017). Here, we investigated whether the perirhinal cortex (PER) and postrhinal cortex (POR), the upstream regions of the LEC and MEC, respectively, could be dissociated similarly. We conducted four tasks by combining different stimulus and response types. Our results suggest that the PER is important whenever object recognition is required and, together with prior findings, imply that PER-LEC networks are essential in goal-directed interactions with objects. The POR appears critical for recognizing visual scenes and may play key roles in scene-based navigation together with the MEC. The relative lack of functional dissociation between stimulus and response types at the PER-POR level suggests that actions conditioned on the recognition of external stimuli may be uniquely represented from the EC. PMID- 29280735 TI - Decoding the centromeric nucleosome through CENP-N. AB - Centromere protein (CENP) A, a histone H3 variant, is a key epigenetic determinant of chromosome domains known as centromeres. Centromeres nucleate kinetochores, multi-subunit complexes that capture spindle microtubules to promote chromosome segregation during mitosis. Two kinetochore proteins, CENP-C and CENP-N, recognize CENP-A in the context of a rare CENP-A nucleosome. Here, we reveal the structural basis for the exquisite selectivity of CENP-N for centromeres. CENP-N uses charge and space complementarity to decode the L1 loop that is unique to CENP-A. It also engages in extensive interactions with a 15 base pair segment of the distorted nucleosomal DNA double helix, in a position predicted to exclude chromatin remodelling enzymes. Besides CENP-A, stable centromere recruitment of CENP-N requires a coincident interaction with a newly identified binding motif on nucleosome-bound CENP-C. Collectively, our studies clarify how CENP-N and CENP-C decode and stabilize the non-canonical CENP-A nucleosome to enforce epigenetic centromere specification and kinetochore assembly. PMID- 29280736 TI - The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture. AB - Production of most eukaryotic mRNAs requires splicing of introns from pre-mRNA. The splicing reaction requires definition of splice sites, which are initially recognized in either intron-spanning ('intron definition') or exon-spanning ('exon definition') pairs. To understand how exon and intron length and splice site recognition mode impact splicing, we measured splicing rates genome-wide in Drosophila, using metabolic labeling/RNA sequencing and new mathematical models to estimate rates. We found that the modal intron length range of 60-70 nt represents a local maximum of splicing rates, but that much longer exon-defined introns are spliced even faster and more accurately. We observed unexpectedly low variation in splicing rates across introns in the same gene, suggesting the presence of gene-level influences, and we identified multiple gene level variables associated with splicing rate. Together our data suggest that developmental and stress response genes may have preferentially evolved exon definition in order to enhance the rate or accuracy of splicing. PMID- 29280737 TI - A Critical Appraisal of the Effect of Gonadotropin-Releasing Hormon Analog Treatment on Adult Height of Girls with Central Precocious Puberty. AB - Central precocious puberty (CPP) is a diagnosis that pediatric endocrinologists worldwide increasingly make in girls of age 6-8 years and is mostly idiopathic. Part of the reason for increasing referral and diagnosis is the perception among the doctors as well as the patients that treatment of CPP with long-acting gonadotropin-releasing hormon analogues (GnRHa) promote height of the child. Although, the timing and the tempo of puberty does influence statural growth and achieved adult height, the extent of this effect is variable depending on several factors and is modest in most cases. Studies investigating GnRHa treatment in girls with idiopathic CPP demonstrate that treatment is able to restore adult height compromised by precocious puberty. However, reports on untreated girls with precocious puberty demonstrate that some of these girls achieve their target height without treatment as well, thus, blurring the net effect of GnRHa treatment on height in girls with CPP. Clinical studies on treatment of girls with idiopathic CPP on adult stature suffers from the solid evidence-base due mainly to the lack of well-designed randomized controlled studies and our insufficiencies of predicting adult height of a child with narrow precision. This is particularly true for girls in whom age of pubertal onset is close to physiological age of puberty, which are the majority of cases treated with GnRHa nowadays. Heterogeneous nature of pubertal tempo (progressive vs. nonprogressive) leading to different height outcomes also complicates the interpretation of the results in both treated and untreated cases. This review will attemp to summarize and critically appraise available data in the field. PMID- 29280738 TI - Genetic Causes of Rickets. AB - Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches. PMID- 29280739 TI - Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2. AB - Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease. PMID- 29280740 TI - Latest Insights on the Etiology and Management of Primary Adrenal Insufficiency in Children. AB - Primary adrenal insufficiency (PAI) is a heterogeneous group of disorders characterized by an impaired production of cortisol and other steroid hormones by the adrenal cortex. Most of the causes of PAI in childhood are inherited and monogenic in origin and are associated with significant morbidity and mortality whenever the diagnosis and treatment is delayed. Therefore, early and accurate diagnosis would allow appropriate management for the patients and genetic counselling for the family. Congenital adrenal hyperplasia accounts for most cases of PAI in childhood, followed by abnormalities in the development of the adrenal gland, resistance to adrenocorticotropin hormone action and adrenal destruction. In recent years, the use of genome-wide, next-generation sequencing approaches opened new avenues for identifying novel genetic causes in the PAI spectrum. Understanding the genetic basis of adrenal disorders is key to develop innovative therapies for patients with PAI. The promising progress made in congenital adrenal hyperplasia treatment brings new perspectives for personalized treatment in children with PAI. The aim of this review is to characterize recent advances in the genetics and management of PAI in children. PMID- 29280741 TI - Insulin Resistance, Prediabetes, Metabolic Syndrome: What Should Every Pediatrician Know? AB - The Metabolic syndrome describes a clustering of typical cardiovascular risk factors. The syndrome is also known as "Insulin Resistance syndrome" as a substantial part of the pathophysiology is driven by resistance to the metabolic effects of insulin. The major cause of insulin resistance in childhood is a typical lipid partitioning pattern characterized by increased deposition of lipids within insulin responsive tissues, such as the liver and skeletal muscle and within the viscera. This lipid deposition pattern is also associated with infiltration of intra-abdominal tissues with cells of the immune system, inducing systemic, low-grade inflammation typically observed in insulin resistant obese children and adolescents. Several clues derived from a careful history and physical examination, along with a basic laboratory workup, provide clues in regards to risk stratification in obese children. PMID- 29280742 TI - The Rationale for Growth Hormone Therapy in Children with Short Stature. AB - Growth hormone (GH) was first isolated from cadaver pituitary glands, requiring laborious and expensive collection of glands, followed by extraction and purification of the hormone. This limited supply restricted its use to children with severe GH deficiency who were treated with low dosages and suboptimal schedules. The development of recombinant DNA-derived GH, allowed the production of virtually unlimited amounts of GH, leading to the approval for therapy for a large number of childhood conditions characterized by non-GH deficient short stature. The aim of this review is to provide a critical overview on the daily use of GH in two paradigmatic conditions of non-GH deficient short stature which are children born small for gestational age and with idiopathic short stature, highlighting the available strength of evidence for efficacy and safety. PMID- 29280743 TI - Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder. AB - Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsalpha protein activity in peripheral erythrocyte membranes in vitro. However, PHP classification fails to differentiate all patients with different clinical and molecular findings for PHP subtypes and classification become more complicated with more recent molecular characterization and new forms having been identified. So far, new classifications have been established by the EuroPHP network to cover all disorders of the PTH receptor and its signaling pathway. Inactivating PTH/PTH related protein signaling disorder (iPPSD) is the new name proposed for a group of these disorders and which can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsalpha mutations (PHP-Ia, PHP Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described. With these new classifications, the aim is to clarify the borders of each different subtype of disease and make the classification according to molecular pathology. The iPPSD group is designed to be expandable and new classifications will readily fit into it as necessary. PMID- 29280745 TI - Sex Assignment in Conditions Affecting Sex Development. AB - The newborn infant with atypical genitalia presents a challenging clinical scenario and requires expert input. There have been appreciable advances in our knowledge of the underlying causes that may lead to a mere difference or a more serious disorder of sex development (DSD), the natural history of conditions, as well as the short and long-term complications of these conditions themselves, together with the clinical interventions that are associated with these conditions. With this information, the DSD expert can be more confident when discussing options with the parents of the newborn infant. By working within a multidisciplinary team, the expert should be able to support the family whilst individualising the management plan so that it is also cognizant of the shifts in societal attitudes and expectations around concepts of diversity and openness. It is, therefore, likely that the practice of assigning sex, especially in those cases where sex assignment is unclear on expert assessment, will continue to show temporal, social and geographical variations. It is imperative that clinical data for rare conditions such as these are collected in a standardized format and shared through a common registry so that any evidence that is used for future shifts in practice has a stronger foundation than that which is currently available. PMID- 29280744 TI - Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. AB - Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases. It is now well established that about 10-20% of IHH cases recover from IHH either spontaneously or after receiving some sex steroid replacement therapy. Moreover, there may be an overlap or transition between constitutional delay in growth and puberty (CDGP) and IHH. It has been increasingly observed that oligogenic inheritance and clinical recovery complicates the phenotype/genotype relationship in IHH, thus making it challenging to find new IHH-associated genes. In a clinical sense, recognizing those IHH genes and associated phenotypes may improve our diagnostic capabilities by enabling us to prioritize the screening of particular gene(s) such as synkinesia (ANOS1), dental agenesis (FGF8/FGFR1) and hearing loss (CHD7). Also, IHH-associated gene studies may be translated into new therapies such as for polycystic ovary syndrome. In a scientific sense, the most significant contribution of IHH-associated gene studies has been the characterization of the long-sought gonadotropin releasing hormone pulse generator. It appears that genetic studies of IHH will continue to advance our knowledge in both the biological and clinical domains. PMID- 29280747 TI - The change of motor cortical excitability between eyes open and closed conditions. AB - The effect of the eyes closed and eyes open states on transcranial magnetic stimulation (TMS)-induced motor cortex response remains unclear. This study evaluated the difference in TMS-induced motor cortical responses between the eyes open and eyes closed states. Ten healthy right-handed participants participated in three experiments. The stimulation-response curve of motor-evoked potential, short-interval intracortical inhibition, intracortical facilitation, and cortical silent period were determined in both the eyes open and eyes closed states, in random order. The order of performance of the eyes open and eyes closed states was also random. The stimulation-response curve obtained in the eyes open state was steeper than that obtained in the eyes closed state. The resting and active motor thresholds, cortical silent period, short-interval intracortical inhibition, and intracortical facilitation were similar in the eyes open and eyes closed states. These data demonstrate that the eyes closed state may affect the recruitment of cortical circuits and thus diminish the TMS-evoked motor output. PMID- 29280748 TI - Self-protection of type III fibrocytes against severe 3-nitropropionic-acid induced cochlear damage in mice. AB - After intense sound exposure, the lack of obvious degeneration in type III fibrocytes suggests that they might protect themselves against acoustic trauma. However, it is unknown whether and how type III fibrocytes play this role in other cochlear damage models. In this study, we investigated the self-protection of type III fibrocytes against severe cochlear energy failure induced by local administration of 3-nitropropionic acid to the inner ear. We detected that the type III fibrocytes did not degenerate significantly after 500 mM 3 nitropropionic acid application, and showed increased expression of proliferation marker Ki67. Moreover, low immunoreactivity for inducible nitric oxide synthase and cleaved caspase-3 was observed in type III fibrocytes 2 days after damage. These results indicate that after severe cochlear energy failure type III fibrocytes possess obvious proliferation activity, as well as strong antioxidant and antiapoptotic capacity, which can protect them from degeneration. PMID- 29280749 TI - The Nicotine Content of a Sample of E-cigarette Liquid Manufactured in the United States. AB - OBJECTIVES: Use of electronic cigarettes has dramatically increased in the United States since 2010, with a forecasted growth of 37% between 2014 and 2019. There is little research on e-liquid nicotine concentration from domestic manufacturers. However, limited research outside of the United States found wide inconsistencies between the labeled concentration of nicotine in e-liquids and the actual nicotine concentration. METHODS: The 7 most popular online manufacturers or distributors were identified. E-liquid samples of the 5 most popular flavors from each manufacturer were purchased in nicotine concentrations of 0 and 18 mg/mL. Of the samples purchased (n = 70), all were labeled as produced in the United States of America. The researchers anonymized the samples before sending them to an independent university laboratory for testing. RESULTS: The 35 e-liquid samples labeled 18 mg/mL nicotine measured between 11.6 and 27.4 mg/mL (M = 18.7, SD = 3.3) nicotine. The labeled 18 mg/mL samples measured as little as 35% less nicotine and as much as 52% greater nicotine. In the 35 samples labeled 0 mg/mL, nicotine was detected (>0.01 mg/mL) in 91.4% of the samples (range 0-23.9 mg/mL; M = 2.9, SD = 7.2). Six samples from 2 manufacturers labeled as 0 mg/mL were found to contain nicotine in amounts ranging from 5.7 to 23.9 mg/mL. CONCLUSION: This study demonstrates the nicotine labeling inaccuracies present in current e-liquid solutions produced in the United States. Incorrect labeling poses a significant risk to consumers and supports the recent regulation changes enacted by the US Food and Drug Administration. Additional routine testing of nicotine concentrations should be conducted to evaluate the effectiveness of the regulations on future e-liquid production. PMID- 29280750 TI - Long-Term Topical Diquafosol Tetrasodium Treatment of Dry Eye Disease Caused by Chronic Graft-Versus-Host Disease: A Retrospective Study. AB - OBJECTIVES: The aim of this study was to assess the safety and efficacy of long term use of 3% diquafosol ophthalmic solution (DQS), an eye drop for mucin production and water secretion, for treating dry eye disease (DED) caused by chronic graft-versus-host disease (cGVHD). METHODS: We retrospectively evaluated the safety and efficacy of DQS in 10 patients with mild to moderate cGVHD-induced DED. The efficacy was assessed by (1) degree of symptoms, (2) Schirmer I test value, (3) tear film breakup time (TFBUT), and (4) fluorescein and rose bengal scores. RESULTS: The median duration of DQS treatment was 12.0 months (range 6-17 months). DQS was effective for relieving severe pain caused by cGVHD-related DED. Although the Schirmer I test value was enhanced only marginally, the long-term application of DQS significantly improved the corneal/conjunctival epitheliopathy and tear film stability: the fluorescein score improved from 5.9+/-0.6 to 1.3+/ 1.1 points (P=1.771*10); rose bengal staining from 4.7+/-1.6 to 2.0+/-1.5 points (P=0.008); and TFBUT from 2.6+/-0.9 to 4.6+/-1.6 mm (P=0.009). Furthermore, the long-term DQS treatment caused no major adverse events. CONCLUSIONS: This study suggested that long-term DQS treatment is a safe and robust approach for alleviating cGVHD-related DED. PMID- 29280746 TI - Congenital Hyperinsulinism: Diagnosis and Treatment Update. AB - Pancreatic beta-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic beta-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH. PMID- 29280751 TI - Different Genotypes of Adhesion Operon Genes in Staphylococcus epidermidis Isolates From Various Ocular Infections. AB - BACKGROUND: Staphylococcus epidermidis is one of the common causes of bacterial keratitis and post-operation infections. One of the most important virulence factors of S. epidermidis is biofilm formation. Poly-N-acetylglucosamine (PNAG) production is critical for biofilm formation in S. epidermidis. The intercellular adhesion (ica) operon is formed by icaA, icaD, icaB, and icaC genes, which participate in the biosynthesis of PNAG. Strains of S. epidermidis from different infections show different genotypes in relation to adhesion operon genes. Therefore, regarding the fact that the pathogenic strain in each community has unique genotypes, this study investigated the relation between ica operon genotypes and various ocular infections. However, the correlation between the ica operon genes and the mecA gene was analyzed in the isolates. METHODS: For this study, samples of the conjunctiva, cornea, and intraocular fluid of patients with ocular infection were collected. After culture and incubation, detection of S. epidermidis was performed using biochemical and coagulase tests. The antibiotic susceptibility of the bacteria was evaluated by the disk diffusion method. After this, DNA was extracted from the bacteria and the presence of icaA, icaD, is256, and mecA genes was analyzed using polymerase chain reaction. RESULTS: All 50 coagulase-negative Staphylococcus samples isolated from different eye infections were characterized as S. epidermidis. Most of the samples (36%) were isolated from the cornea and the others were, respectively, from the conjunctiva (24%), vitreous (20%), anterior chamber (8%), eyelid (6%), and nasolacrimal duct (6%). The icaA, icaD, and is256 genes were detected with different genotypes in isolates from keratitis and endophthalmities compared with conjunctivitis. Overall, the most isolated genotype from ocular infections was icaA+. icaD+. is256+. (46%). Most of the isolates (82.60%) had mecA, icaA, and icaD genes simultaneously, which indicates a strong relationship between the adhesion genes and the antibiotic resistance gene. CONCLUSIONS: The adhesion operon genes were observed with different genotypes in S. epidermidis samples isolated from various ocular infections. PMID- 29280752 TI - Medical Graduates, Truthful and Useful Analytics With Big Data, and the Art of Persuasion. AB - The authors propose that the provision of state-of-the-art, effective, safe, and affordable health care requires medical school graduates not only to be competent practitioners and scientists but also to be policy makers and professional leaders. To meet this challenge in the era of big data and cloud computing, these graduates must be able to understand and critically interpret analyses of large, observational datasets from electronic health records, third-party claims files, surveys, and epidemiologic health datasets.The authors contend that medical students need to be exposed to three components. First, students should be familiar with outcome metrics that not only are scientifically valid but also are robust, useful for the medical community, understandable to patients and relevant to their preferences and health goals, and persuasive to health administrators and policy decision makers. Next, students must interact with an inclusive set of analysts including biostatisticians, mathematical and computational statisticians, econometrists, psychometricians, epidemiologists, informaticians, and qualitative researchers. Last, students should learn in environments in which data analyses are not static with a "one-size-fits-all" solution but, rather, where mathematical and computer scientists provide new, innovative, and effective ways of solving predictable and commonplace data limitations such as missing data; make causal inferences from nonrandomized studies and/or those with selection biases; and estimate effect size when patient outcomes are heterogeneous and surveys have low response rates. PMID- 29280753 TI - Postexamination Analysis: The Item Characteristic Curve. PMID- 29280754 TI - Fake It 'Til You Make It: Pressures to Measure Up in Surgical Training. AB - PURPOSE: Expectations of certainty and confidence in surgical culture are a source of internal conflict for surgeons and learners, with surgeons describing a pressure to project an image that is, at times, inconsistent with how they feel internally. The authors explored surgical residents' perceptions of "impression management" and its effects on surgical judgment and decision making. METHOD: The authors used a constructivist grounded theory approach to conduct and analyze 15 semistructured interviews with general surgery trainees at an urban Canadian academic health center between 2012 and 2014. Interviews explored impression management in the context of resident learning and performance. Analysis was inductive, whereby emergent themes contributed to a developing conceptual framework, and deductive, using an existing theory of impression management. RESULTS: Residents described sensing an "expectation" to portray an image aligned with the ideal surgical stereotype of confidence and certainty, and shared strategies used to mirror this image. Impression management strategies were used to portray an image of competence, with the aim to improve access to teaching and evaluations. Unintended consequences of impression management on decision making, patient safety, and resident wellness were identified. CONCLUSIONS: These findings contribute to a deeper understanding of the potential impact of the sociocultural context on residency training, and provide a language allowing for more explicit discussions about the impact of surgical culture on trainee behaviors. Translation includes formal instruction of these concepts in the curriculum so that trainees better recognize, reflect on, and cope with the pressures to perform in front of others. PMID- 29280755 TI - Using Relational Reasoning Strategies to Help Improve Clinical Reasoning Practice. AB - Clinical reasoning-the steps up to and including establishing a diagnosis and/or therapy-is a fundamentally important mental process for physicians. Unfortunately, mounting evidence suggests that errors in clinical reasoning lead to substantial problems for medical professionals and patients alike, including suboptimal care, malpractice claims, and rising health care costs. For this reason, cognitive strategies by which clinical reasoning may be improved-and that many expert clinicians are already using-are highly relevant for all medical professionals, educators, and learners.In this Perspective, the authors introduce one group of cognitive strategies-termed relational reasoning strategies-that have been empirically shown, through limited educational and psychological research, to improve the accuracy of learners' reasoning both within and outside of the medical disciplines. The authors contend that relational reasoning strategies may help clinicians to be metacognitive about their own clinical reasoning; such strategies may also be particularly well suited for explicitly organizing clinical reasoning instruction for learners. Because the particular curricular efforts that may improve the relational reasoning of medical students are not known at this point, the authors describe the nature of previous research on relational reasoning strategies to encourage the future design, implementation, and evaluation of instructional interventions for relational reasoning within the medical education literature. The authors also call for continued research on using relational reasoning strategies and their role in clinical practice and medical education, with the long-term goal of improving diagnostic accuracy. PMID- 29280756 TI - Creating Structured Opportunities for Social Engagement to Promote Well-Being and Avoid Burnout in Medical Students and Residents. AB - Increasing attention is being paid to medical student and resident well-being, as well as to enhancing resilience and avoiding burnout in medical trainees. Medical schools and residency programs are implementing wellness initiatives that often include meditation and other mindfulness activities, self-reflection, journaling, and lectures or workshops on resilience tools such as metacognition and cognitive restructuring. These interventions have in common the creation of opportunities for trainees to become more aware of their experiences, to better recognize stressors, and to regulate their thoughts and feelings so that stressors are less likely to have harmful effects. They often enable trainees to temporarily distance themselves mentally and emotionally from a stressful environment. In this Invited Commentary, the author suggests that medical school leaders and residency program directors should also create structured opportunities for trainees to establish meaningful connections with each other to provide greater social support and thereby reduce the harmful effects of stress. Social connection and engagement, as well as group identification, have potential to promote well-being and reduce burnout during training. PMID- 29280757 TI - KIR3DL1 alleles and their epistatic interactions with human leukocyte antigen class I influence resistance and susceptibility to HIV-1 acquisition in the Pumwani sex worker cohort. AB - OBJECTIVE: To determine the associations of KIR3DL1/S1(3DL1/S1) and its epistatic interactions with human leukocyte antigen class I (HLA-I) alleles with resistance and susceptibility to HIV-1. DESIGN: Despite repeated exposure to HIV-1, a subset of women enrolled in the Pumwani sex worker cohort remain HIV uninfected. Previous studies have shown that specific HLA class I and II alleles were associated with this natural immunity. In this study, we investigated the association of 3DL1/S1 and its epistatic interactions with HLA-I, with resistance or susceptibility to HIV-1 acquisition. METHODS: We used a sequence-based typing method to genotype 3DL1/S1 of 641 women in this cohort. The association of 3DL1/S1 and its epistatic interactions with HLA-I were analyzed using SPSS statistics software. RESULTS: 3DL1041 is enriched in the HIV-1-resistant women [P = 0.009, Pc = 0.0468, odds ratio (OR): 3.359, 95% confidence interval (CI): 1.39 8.32], whereas, 3DL1020 was associated with susceptibility to HIV-1 infection before correction for multiple comparisons (P = 0.029, Pc = 0.0858, OR: 0.316, 95%CI: 0.10-1.04). Epistatic interactions between several 3DL1 alleles and specific HLA-I alleles were observed. Among them the cocarriage of 3DL1041 with Bw4 (P = 1E - 05, Pc = 0.0015, OR: 13.33, 95%CI: 3.43-51.9), or Bw6 (P = 0.008, Pc = 0.272, OR: 3.92, 95%CI: 1.51-10.17), increased the odds of remaining HIV-1 uninfected. Further, 3DL1041+/Bw4+ women who entered the cohort HIV negative remained uninfected (P = 0.032, Pc = 0.0858). Cocarriage of 3DL101501 with C02 : 10 (P = 2.73E - 07, Pc = 7.0954E - 06), B15 : 03 (P = 3.21E - 04, Pc = 0.0042), A24 supertype (P = 8.89E - 04, Pc = 0.0077), or A23 : 01 (P = 0.0036, Pc = 0.0236) was associated with increased susceptibility to seroconversion. CONCLUSION: The effects of interactions between 3DL1 and HLA-I alleles on resistance/susceptibility to HIV-1 infection suggest that innate immunity plays an important role in HIV-1 acquisition and should be studied and explored for HIV prevention. PMID- 29280759 TI - Phylogenetic analysis as a forensic tool in HIV transmission investigations. AB - : Because HIV is a fast-evolving virus, HIV genomic sequences of several individuals can be used to investigate whether they belong to a transmission network. Since the infamous 'Florida dentist case' in the beginning of the 1990s, phylogenetic analyses has been recurrently used in court settings as a forensic tool in HIV transmission investigations, for example cases where one or more complainants allege that a defendant has unlawfully infected them with HIV. Such cases can arise both in the context of HIV-specific criminal laws - in countries where transmission of HIV infection is specifically criminalized - or in the context of general laws, for example, by applying physical or sexual assault laws to HIV-related cases. Although phylogenetic analysis as a forensic technique for HIV transmission investigations has become common in several countries, the methodologies have not yet been standardized, sometimes giving rise to unwarranted conclusions. In this literature review, we revisit HIV court case investigations published in the scientific literature, as well as the methodological aspects important for the application and standardization of phylogenetic analyses methods as a forensic tool. Phylogenetic methodologies are improving quickly, such that more recently, phylogenetic relatedness, directionality of transmission and timing of nodes in the tree are used to assess whether the phylogenetic transmission analysis is consistent with or contradicting the charges. We find that there has been a lack of consistency between methods used in court case investigations and that it is essential to define guidelines to be used by phylogenetic forensic experts in HIV transmission cases in court. PMID- 29280758 TI - Changes in insulin sensitivity over time and associated factors in HIV-infected adolescents. AB - OBJECTIVE: To compare prevalence of insulin resistance between perinatally HIV infected (PHIV+) and perinatally HIV-exposed, but uninfected adolescents (PHEU), determine incidence of and contributory factors to new and resolved cases of insulin resistance in PHIV+, and evaluate glucose metabolism. DESIGN: Cross sectional design for comparison of prevalence among PHIV+ and PHEU. Longitudinal design for incidence and resolution of insulin resistance among PHIV+ at risk for these outcomes. METHODS: The source population was adolescents from pediatric HIV clinics in the United States and Puerto Rico participating in the Pediatric HIV/AIDS Cohort Study, an ongoing prospective cohort study designed to evaluate impact of HIV infection and its treatment on multiple domains in preadolescents and adolescents. Insulin resistance was assessed by homeostatic model assessment of insulin resistance. Those with incident insulin resistance underwent 2-h oral glucose tolerance test and HbA1c. Baseline demographic, metabolic, and HIV specific variables were evaluated for association with incident or resolved insulin resistance. RESULTS: Unadjusted prevalence of insulin resistance in PHIV+ was 27.3 versus 34.1% in PHEU. After adjustment for Tanner stage, age, sex, and race/ethnicity, there was no significant difference between groups. Factors positively associated with developing insulin resistance included female sex, higher BMI z score, and higher waist circumference; those associated with resolving insulin resistance included male sex and lower BMI z score. CONCLUSION: Prevalence of insulin resistance in PHIV+ and PHEU was substantially higher than that reported in HIV-uninfected nonoverweight youth, but similar to that in HIV uninfected obese youth. Factors associated with incident or resolved insulin resistance among PHIV+ were similar to those reported in HIV-negative obese youth. However, a contributory role of HIV infection and/or its treatment to the incident risk of insulin resistance cannot be excluded. PMID- 29280760 TI - The HIV-1 Tat protein affects human CD4+ T-cell programing and activation, and favors the differentiation of naive CD4+ T cells. AB - OBJECTIVE: HIV infection is characterized by several immune dysfunctions, such as chronic activation of the immune system, premature aging and loss of CD4 T cells, in particular within the naive compartment. The Tat protein of HIV is released extracellularly and enters neighboring cells affecting their functionality, for instance impacting on CD8 T-cell programs and activity. As the presence and/or induction of anti-Tat immune responses is associated with reduced T-cell dysfunction and CD4 T-cell loss, we investigated whether Tat impacts human resting or activated CD4 T cells. METHODS: Purified CD4 T cells were activated by T cell receptor engagement in the presence or absence of Tat. Cytokine production, surface phenotype and expression of transcription factors important for T-cell programing were measured. Purified naive CD4 T cells were cultured in nonpolarizing conditions in the presence or absence of Tat and their proliferation and differentiation was evaluated. RESULTS: Tat favors the secretion of IL2, IFNgamma and TNFalpha in CD4 T cells, as well as the upregulation of T-bet and Eomes expression. Naive CD4 T cells cultured in the presence of Tat showed enhanced expansion and differentiation toward memory phenotype, showing in particular recruitment into the effector memory T-cell pool. CONCLUSION: Tat affects the programing and functionality of CD4 T lymphocytes favoring the differentiation of naive CD4 T cells. PMID- 29280761 TI - A baseline metabolomic signature is associated with immunological CD4+ T-cell recovery after 36 months of antiretroviral therapy in HIV-infected patients. AB - OBJECTIVES: Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after antiretroviral therapy (ART) to envisage the underlying mechanistic pathways that influence the treatment response. DESIGN: This was a multicentre, prospective cohort study in ART-naive and a pre-ART low nadir (<200 cells/MUl) HIV-infected patients (n = 64). METHODS: We obtained clinical data and metabolomic profiles for each individual, in which low molecular weight metabolites, lipids and lipoproteins (including particle concentrations and sizes) were measured by NMR spectroscopy. Immunological recovery was defined as reaching CD4 T-cell count at least 250 cells/MUl after 36 months of virologically successful ART. We used univariate comparisons, Random Forest test and receiver operating characteristic curves to identify and evaluate the predictive factors of immunological recovery after treatment. RESULTS: HIV-infected patients with a baseline metabolic pattern characterized by high levels of large high density lipoprotein (HDL) particles, HDL cholesterol and larger sizes of low density lipoprotein particles had a better immunological recovery after treatment. Conversely, patients with high ratios of non-HDL lipoprotein particles did not experience this full recovery. Medium very-low-density lipoprotein particles and glucose increased the classification power of the multivariate model despite not showing any significant differences between the two groups. CONCLUSION: In HIV infected patients, a baseline healthier metabolomic profile is related to a better response to ART where the lipoprotein profile, mainly large HDL particles, may play a key role. PMID- 29280762 TI - Brentuximab vedotin with AVD shows safety, in the absence of strong CYP3A4 inhibitors, in newly diagnosed HIV-associated Hodgkin lymphoma. AB - OBJECTIVE: Brentuximab vedotin is a Food and Drug Administration approved anti CD30 antibody drug conjugate potently active in Hodgkin lymphoma. Trials of brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (AVD-BV) excluded patients with HIV. We studied the safety of AVD-BV in newly diagnosed HIV-associated classical Hodgkin lymphoma . DESIGN AND METHODS: Patients diagnosed with stage II-IV HIV-associated classical Hodgkin lymphoma received AVD BV on days 1 and 15 every 28 days for six cycles. Anti-HIV medications with strong CYP3A4 inhibition were excluded. This phase 1 trial followed a 3+3 dose de escalation design started with brentuximab vedotin at 1.2 mg/kg with standard dosing of AVD. Dose-limiting toxicities were defined in cycle one. RESULTS: Seven patients were enrolled with six being evaluable: five of six stage III/IV, three with an international prognostic score at least 4. With no dose-limiting toxicities identified, all six were treated at the 1.2 mg/kg dose. Only five grade (G) three nonhematological adverse events were noted in three patients: pulmonary infection, diarrhea, and peripheral neuropathy. No G4/5 adverse events occurred. PET/computer tomography was negative in five of six after cycle 2 and six of six post therapy. Progression-free survival was 100% at 25 months with all patients in remission. One patient was deemed ineligible for taking ritonavir, a strong CYP3A4 inhibitor, but developed G3/4 adverse events including febrile neutropenia, and pancreatitis and though consented was excluded from all evaluation. CONCLUSION: AVD-BV was well tolerated at recommended phase 2 dose of 1.2 mg/kg. Concurrent strong CYP3A4 inhibitors should be avoided. A phase 2 study of AVD-BV is currently enrolling (NCT01771107). PMID- 29280763 TI - Intravaginal Diazepam for the Treatment of Pelvic Floor Hypertonic Disorder: A Double-Blind, Randomized, Placebo-Controlled Trial. AB - OBJECTIVES: Pelvic floor hypertonic disorder is characterized by an involuntary spasm of the levator ani muscles and is associated with several clinical syndromes. Several treatment options have been described; however, treatment efficacy data are limited. The objective of this study was to determine the efficacy of intravaginal diazepam for the treatment of pelvic pain secondary to levator ani muscle spasm in comparison to placebo. METHODS: Adult women with complaints of pelvic pain, who were noted to have levator ani muscle spasm on physical examination, were approached for enrollment in a double-blind, placebo controlled, randomized clinical trial. Eligible participants were randomized to receive 10-mg diazepam capsules or identical-appearing placebo capsules. The primary outcome was the change in pain scores measured by a 100-mm visual analog scale at 4 weeks. Several validated questionnaires were similarly assessed as secondary outcomes. RESULTS: In total, 49 women were randomized (25 in the diazepam arm and 24 in the placebo arm). At 4 weeks, 35 women returned for follow up and had complete data available analysis. There was no difference in visual analog scale scores between the treatment groups after 4 weeks (50 vs 39 mm, for diazepam and placebo, respectively; P = 0.36). There were also no differences noted in the questionnaire scores. CONCLUSIONS: It is unlikely that self administered intravaginal diazepam suppositories promote an improvement in the 100-mm visual analog scale of 20 mm or more or other substantial symptom improvement in women with pelvic floor hypertonic disorder. PMID- 29280764 TI - Primary Central Nervous System Lymphoma With Light Chain Deposition Disease (Aggregoma). PMID- 29280765 TI - Vigabatrin: Lessons Learned From the United States Experience. AB - Vigabatrin was introduced as an antiseizure medication in the United Kingdom in 1989 and was extensively used until 1997 when concerns arose regarding peripheral visual field loss. When the drug was approved in the United States in 2009, it carried a black box warning for the risk of permanent visual loss, and the pharmaceutical company was mandated to create a drug registry to assess for visual deficits. The vigabatrin drug registry has documented a relatively large percentage (37%) of preexisting, baseline visual deficits and a paucity (2%) of potential new visual findings. The vigabatrin vision study, a prospective, longitudinal, single-arm, open-label study, confirmed that adult patients with refractory complex partial seizures had a large number of visual deficits at baseline. An unexpected finding during the first year of therapy with vigabatrin was an increase in retinal thickness on optical coherence tomography. The experience from vigabatrin in the United States emphasizes the importance of baseline eye findings when considering the potential of drug toxicity involving the visual pathways. PMID- 29280766 TI - Optic Nerve Avulsion After Finger-Poke Injury. AB - We present a case of optic nerve avulsion as a result of finger-poke injury to the eye. Spectral domain optical coherence tomography demonstrated a plunging cup indicative of the avulsion, a finding not previously described. Optic nerve avulsion is a form of anterior indirect traumatic optic neuropathy evoked by a sudden severe rotation at the junction of the optic nerve and globe induced, in this case, by penetration of the finger into the nasal orbit. PMID- 29280768 TI - HIV Pre-exposure Prophylaxis Prescribing Through Telehealth. PMID- 29280767 TI - Sexual Networks of Racially Diverse Young MSM Differ in Racial Homophily But Not Concurrency. AB - BACKGROUND: Substantial racial disparities exist in HIV infection among young men who have sex with men (YMSM). However, evidence suggests black YMSM do not engage in greater levels of risk behavior. Sexual networks may help explain this paradox. This study used egocentric exponential random graph models to examine variation in concurrency (ie, 2 or more simultaneous partners) and homophily (ie, same race/ethnicity partners) across race/ethnicity groups in a diverse sample of YMSM. METHODS: Data for this study come from a longitudinal cohort study of YMSM. Participants (n = 1012) provided data regarding their sexual contacts during the 6 months before their first study visit. A series of egocentric exponential random graph models examined how providing separate estimates for homophily and concurrency parameters across race/ethnicity improved the fit of these models. Networks were simulated using these parameters to examine how local network characteristics impact risk at the whole network level. RESULTS: Results indicated that homophily, but not concurrency, varied across race/ethnicity. Black participants witnessed significantly higher race/ethnicity homophily compared with white and Latino peers. Extrapolating from these models, black individuals were more likely to be in a connected component with an HIV-positive individual and closer to HIV-positive individuals. However, white individuals were more likely to be in large connected components. CONCLUSIONS: These findings suggest that high racial homophily combined with existing disparities in HIV help perpetuate the spread of HIV among black YMSM. Nonetheless, additional work is required to understand these disparities given that homophily alone cannot sustain them indefinitely. PMID- 29280769 TI - Brief Report: Disclosure, Consent, Opportunity Costs, and Inaccurate Risk Assessment Deter Pediatric HIV Testing: A Mixed-Methods Study. AB - BACKGROUND: Prompt child HIV testing and treatment is critical; however, children are often not diagnosed until symptomatic. Understanding factors that influence pediatric HIV testing can inform strategies to increase testing. METHODS: A mixed methods study was conducted at a tertiary hospital in Nairobi, Kenya. Three focus group discussions with health care workers (HCWs) and 18 in-depth interviews with HIV-infected adults with children of unknown status were analyzed using thematic analysis. A structured questionnaire was administered to 116 HIV-infected caregivers of children of unknown status to triangulate qualitative findings. RESULTS: Analysis revealed 3 key periods of the pediatric HIV testing process: decision to test, test visit, and posttest. Key issues included: decision to test: inaccurate HIV risk perception for children, challenges with paternal consent, lack of caregiver HIV status disclosure to partners or older children; test experience: poor understanding of child consent/assent and disclosure guidelines, perceived costs of testing and care, school schedules, HCW discomfort with pediatric HIV testing; and posttest: pessimism regarding HIV-infected children's prognosis, caregiver concerns about their own emotional health if their child is positive, and challenges communicating about HIV with children. Concerns about all 3 periods influenced child testing decisions. In addition, 3 challenges were unique to pediatric HIV: inaccurate HIV risk perception for children; disclosure, consent, and permission; and costs and scheduling. CONCLUSIONS: Pediatric HIV testing barriers are distinct from adult barriers. Uptake of pediatric HIV testing may be enhanced by interventions to address misconceptions, disclosure services, psychosocial support addressing concerns unique to pediatric testing, child-focused HCW training, and alternative clinic hours. PMID- 29280770 TI - Using Longitudinal Survey Data to Estimate Mental Health Related Transitions to a Disability Pension: Analysis of an Australian Household Panel Study. AB - OBJECTIVE: This study examined the association between mental ill-health and subsequent receipt of a disability pension in Australia, and assessed how the strength of the association varied in relation to the duration between mental health measurement and reported disability pension receipt. METHODS: Eight thousand four hundred seventy-four working-age adults not receiving a disability pension at baseline were followed for up to 11 years; 349 transitioned onto a disability pension. Discrete-time survival analysis considered baseline and time varying (12-month lagged) measures of mental ill-health. RESULTS: Proximal measures of mental ill-health were more strongly associated with subsequent pension receipt than baseline measures (odds ratio: 6.6 vs 3.9) and accounted for a significantly greater proportion of pension transitions (35% vs 21%). CONCLUSION: Mental ill-health is an independent risk factor for disability pension receipt, and proximal circumstances better capture this association than mental health measured earlier. PMID- 29280771 TI - Effects of the New York State Workers Compensation Board Medical Treatment Guidelines on Return to Work. AB - OBJECTIVE: Examine the association between New York State Workers' Compensation Medical Treatment Guidelines (Guidelines) adherence and return-to-work after occupational low back injuries. Assess adherence to Guidelines by examining diagnostic and treatment utilization. METHOD: Retrospective chart review of cases. Outcomes of interest were lost time duration and diagnostic/treatment utilization rates. Time to event analyses performed using Kaplan-Meier plots and Cox proportional hazard model. RESULTS: Care received after implementation of Guidelines resulted in decreased lost time. Treatment rates were consistent, while diagnostic imaging use was inconsistent with Guidelines recommendations. CONCLUSIONS: Guidelines use positively influenced return-to-work after acute occupational low back injuries. Inconsistencies in following Guidelines were observed for diagnostic tests, having a potential paradoxical effect on lost time. Further studies are necessary to test for additional hypotheses. PMID- 29280772 TI - MiRNA-Regulated Changes in Extracellular Matrix Protein Levels Associated With a Severe Decline in Lung Function Induced by Silica Dust. AB - OBJECTIVE: The aim of this study was to explore the potential role of extracellular matrix (ECM) regulated by miRNAs in lung function decline. METHODS: We convened 270 silica dust exposed subjects and divided them into three groups according to lung function data. MiRNAs were measured by real-time quantitative polymerase chain reaction detecting system and ECM-related proteins were detected by enzyme linked immunosorbent assay. Data were analyzed by t test, Chi-squared tests, nonparametric Mann-Whitney U test, and Spearman rank correlation coefficient. RESULTS: Lower miR-200c and miR-29c were observed in subjects with severe lung function decline and higher ECM proteins were observed in subjects with mild or severe lung function decline. MiRNA and ECM were significantly correlated with FVC%, FEV1%, MMF%, and PEF% (r: 0.204 to 0.458, P < 0.01) and that miRNA were significantly correlated with ECM (r: 0.309 to 0.687, P < 0.01). CONCLUSION: The abnormal ECM regulated by miRNAs may play an important role in lung function decline associated with silica dust exposure. PMID- 29280773 TI - Work Engagement, Productivity, and Self-Reported Work-Related Sedentary Behavior Among Japanese Adults: A Cross-Sectional Study. AB - OBJECTIVE: The aim of this study was to examine the relationships between work engagement, productivity, and self-reported work-related sedentary behavior in Japanese adults. METHODS: The present study recruited 2572 Japanese individuals (20-59 years old) via an internet survey and assessed their demographic characteristics, work-related characteristics, and sedentary behavior. Data were analyzed with logistic regression. RESULTS: The mean proportion of work days involving work-related sedentary behavior was approximately 70% and the mean number of weekly working hours was approximately 43 hours. Among those aged 40 to 59 years, work-related sedentary behavior was associated with low work vigor (odds ratio: 1.43), dedication (1.61), absorption (1.39), and total score of work engagement (1.49). Among those aged 20 to 39 years, work-related sedentary behavior was associated with low efficiency (1.38). CONCLUSION: Reducing work related sedentary behavior may improve workers' engagement and productivity. PMID- 29280774 TI - Physical Exposures, Work Tasks, and OSHA-10 Training Among Temporary and Payroll Construction Workers. AB - OBJECTIVE: We characterize and compare the self-reported physical exposures, work tasks, and OSHA-10 training in a non-probabilistic sample of temporary and payroll construction workers. METHODS: In June 2016, a total of 250 payroll and temporary general laborers employed at Florida construction sites completed a survey at the job site as part of the falls reported among minority employees (FRAME) study. RESULTS: Workers employed through temp agencies (57.1%) were significantly more likely to report moving or lifting materials more than 100 pounds than payroll workers (38.5%; P < 0.01). Temporary construction workers with 10-hour OSHA training (22.2%) spent significantly less time with intense hand use/awkward hand posture than temporary workers without 10-hour OSHA training (46.9%; P = 0.048). CONCLUSIONS: Temp construction workers with OSHA 10 hour training reported less hazardous physical postures than workers without the same training. PMID- 29280775 TI - Mental Health in the Workplace: A Call to Action Proceedings From the Mental Health in the Workplace-Public Health Summit. AB - OBJECTIVE: The aim of the study was to declare a call to action to improve mental health in the workplace. METHODS: We convened a public health summit and assembled an Advisory Council consisting of experts in the field of occupational health and safety, workplace wellness, and public policy to offer recommendations for action steps to improve health and well-being of workers. RESULTS: The Advisory Council narrowed the list of ideas to four priority projects. CONCLUSIONS: The recommendations for action include developing a mental health in the workplace (1) "how to" guide, (2) scorecard, (3) recognition program, and (4) executive training. PMID- 29280776 TI - Fitness-for-Duty Assessments of Industrial Firefighters: Guidance for Occupational Medicine Physicians. AB - : Industrial firefighters share many characteristics with municipal firefighters; however, employers frequently have not addressed or characterized the unique job duties, hazards, and specific physical/mental demands associated with industrial firefighting. In addition, gaps exist in the medical literature with regard to industrial firefighter demographics, behavioral risk factors, and chronic diseases. Finally, the proper methodologies for fitness-for-duty assessment of employees acting in this capacity are lacking. To address these gaps, the American College of Occupational and Environmental Medicine (ACOEM) convened a Task Force in 2014, to develop fitness-for-duty guidance for industrial firefighters. This document highlights these gaps and suggests research opportunities to enhance the health and safety of this population. While an extensive literature review found a lack of studies for this population-thus excluding the development of an evidence-based document-sufficient materials were available from which to draw preliminary conclusions, considerations for best practices, and recommendations for future studies. PMID- 29280778 TI - Perceptions of Integration of the Clinical Pharmacist into the Patient Care Medical Home Model. AB - INTRODUCTION: The patient-centered medical home (PCMH) model is a multidisciplinary, team-based approach to healthcare that focuses on actively involving the patient in clinical decision making. The Veterans Health Administration (VA), while desiring to be a national leader in the delivery of primary care services, used the principles of the PCMH model to design the patient-aligned care team (PACT). The purpose of this study, was to explore the perception of the PACT members after integration of a clinical pharmacist to the PACT. METHODS: This was a single-center cross-sectional study conducted at an integrated Veterans Health Administration system. We electronically surveyed PACT staff practicing within VA-Tennessee Valley Health Care System as of October 1, 2016 using a modified version of the Medicine Medication Use Processes Matrix (MUPM) containing 19 items on five theoretical grouping of processes (evaluation and management, monitoring, medication review, documentation, and education) and two groupings(clinician satisfaction and access). RESULTS: Ninety-one complete responses were received. Perceptions were positive, with 79% rated as either 4 ("moderate contribution") or 5 ("major contribution"). Individual responses based on discipline, with the exception of the medical support assistant were rated positive, specifically job satisfaction. CONCLUSIONS: This study evaluated the perceptions of clinical pharmacist integration into the PACT model. Respondents perceived clinical pharmacist beneficial. PMID- 29280777 TI - Secure Provider-to-Provider Communication With Electronic Health Record Messaging: An Educational Outreach Study. AB - INTRODUCTION: With increasing electronic health record (EHR) use, providers are talking less with one another. Now, many rely on EHRs, informal emails, or texts, introducing fragmentation and new data security challenges with new communication strategies. We aimed to examine the impact of a physician champion educational outreach intervention to promote electronic provider-to-provider communication in a large academic multispecialty group. METHODS: Physician champions provided educational outreach to 16 academic departments, using 10-minute case-based presentations. Online surveys assessed communication preferences and practices. Electronic health record queries counted EHR messaging use before and after intervention. Descriptive statistics compared responses by specialty (z-test). Paired responses with pre-post data were compared using chi-square tests. Time series analysis assessed EHR messaging rates before intervention versus after intervention. RESULTS: Five hundred seventeen providers responded to the postoutreach survey. Eighty-six percent were familiar with EHR messaging tool and 78% knew how to use it after intervention. Among practitioner groups, Family Medicine preferred EHR messaging the most (62%). Groups who declined outreach least preferred it (26%). Among 88 respondents with paired pre-post intervention surveys, familiarity rose (79-96%), and self-reported use increased (66-88%). CONCLUSIONS: Physician champion educational outreach increased the use of the secure provider-to-provider EHR messaging tool. PMID- 29280779 TI - Breast Cancer: Does Type of Hospital Where You Get Surgery Affect Survival? AB - Under the Affordable Care Act (ACA), more women are insured with Medicaid, which should improve healthcare access. We sought to determine whether there are survival differences among patients with breast cancer undergoing surgery at facilities with varying proportions of Medicaid patients. We used New York State (NYS) Vital Statistics death records data linked with NYS discharge inpatient and ambulatory surgery databases to examine 90-day survival after surgery from 2008 to 2013. We used all Medicaid discharges to calculate and create quintiles of facilities based on Medicaid volume. We calculated survival hazard ratios using a marginal Cox model controlling for clustering of patients within hospitals, age, race, insurance, year of surgery, and comorbidities. Women who received surgery in facilities with the highest quintile of Medicaid volume had higher 90-day mortality (2.1% vs. 0.07%, p < .001) compared with those treated in facilities with lowest Medicaid volume, even after adjusting for multiple confounders. Consequently, although the ACA may improve access, healthcare quality remains questionable because patients treated at facilities with high proportions of Medicaid volume appear to have worse 90-day survival, likely due to quality of surgical and postsurgical care. Policymakers must ensure that quality of care is not negatively impacted by programs to reduce costs. PMID- 29280780 TI - New Editorial Board Talent. PMID- 29280781 TI - Scleral Lens Clearance Assessment with Biomicroscopy and Anterior Segment Optical Coherence Tomography. AB - SIGNIFICANCE: It is important to be able to accurately estimate the central corneal clearance when fitting scleral contact lenses. Tools available have intrinsic biases due to the angle of viewing, and therefore an idea of the amount of error in estimation will benefit the fitter. PURPOSE: To compare the accuracy of observers' ability to estimate scleral contact lens central corneal clearance (CCC) with biomicroscopy to measurements using slit-lamp imaging and anterior segment optical coherence tomography (AS-OCT). METHODS: In a Web-based survey with images of four scleral lens fits obtained with a slit-lamp video imaging system, participants were asked to estimate the CCC. Responses were compared with known values of CCC of these images determined with an image-processing program (digital CCC) and using the AS-OCT (AS-OCT CCC). Bland-Altman plots and concordance correlation coefficients were used to assess the agreement of CCC measured by the various methods. RESULTS: Sixty-six participants were categorized for analysis based on the amount of experience with scleral lens fitting into novice, intermediate, or advanced fitters. Comparing the estimated CCC to the digital CCC, all three groups overestimated by an average of +27.3 +/- 67.3 MUm. The estimated CCC was highly correlated to the digital CCC (0.79, 0.92, and 0.94 for each group, respectively). Compared with the CCC measurements using AS-OCT, the three groups of participants overestimated by +103.3 MUm and had high correlations (0.79, 0.93, and 0.94 for each group). DISCUSSION: Results from this study validate the ability of contact lens practitioners to observe and estimate the CCC in scleral lens fittings through the use of biomicroscopic viewing. Increasing experience with scleral lens fitting does not improve the correlation with measured CCC from digital or the AS-OCT. However, the intermediate and advanced groups display significantly less inter-observer variability compared with the novice group. PMID- 29280783 TI - Isoniazid for the Prevention of Tuberculosis in HIV-Infected Children: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Isoniazid is recommended for prevention of tuberculosis (TB) in HIV infected adults, but its efficacy in children living with HIV (CLHIV) is not known. We performed a systematic review to assess the efficacy of isoniazid for the prevention of TB in CLHIV. METHODS: We searched PubMed, Cochrane Clinical Trial Registry and Google Scholar from inception to December 2016. Any randomized controlled trial assessing the role of isoniazid for the prevention of TB in CLHIV was eligible for inclusion. The primary endpoint was TB incidence; secondary end points were mortality, overall survival and severe adverse events. Dual independent extraction of all data was performed. Data were pooled under a random effects model and summarized either as risk ratio (RR) or hazard ratio along with 95% confidence intervals (CIs). RESULTS: Of 931 references, 3 randomized controlled trials enrolling 977 patients met the inclusion criteria. Pooled results showed a statistically nonsignificant reduction in TB incidence (RR: 0.70; 95% CI: 0.47-1.04; P = 0.07) and mortality (RR: 0.94; 95% CI: 0.39 2.23; P = 0.88) with the use of isoniazid compared with placebo. One study was stopped early because of excess deaths in the placebo arm. However, results from subgroup analysis restricted to only completed trials did not change the overall findings. CONCLUSIONS: Isoniazid did not reduce the incidence of TB in CLHIV. All included studies were performed in regions with high prevalence of TB making the overall generalizability limited. PMID- 29280784 TI - Visceral Leishmaniasis-Optimum Treatment Options in Children. AB - Visceral leishmaniasis affects 200-400 thousands people annually worldwide. For last few decades, there has been a steady decline in the response to pentavalent antimonial (Sb), the drug that has been used for treating visceral leishmaniasis for almost a century. Oral miltefosine and amphotericin B are alternative drugs being been used in the treatment of leishmaniasis in children. Liposomal amphotericin B has the advantage over conventional amphotericin B is that higher doses can be given with fewer adverse effects. Liposomal amphotericin B in combination with other drugs is the preferred treatment option globally especially in Indian subcontinent. Combination therapy with multiple drugs should undergo larger clinical trials in children as these will shorten the duration of therapy, improve compliance and decrease both toxicity and drug resistance. PMID- 29280785 TI - The Epidemiology of Healthcare-associated Infections in Pediatric Cardiac Intensive Care Units. AB - BACKGROUND: Healthcare-associated infections (HAIs) represent serious complications for patients within pediatric cardiac intensive care units (CICU). HAIs are associated with increased morbidity, mortality and resource utilization. There are few studies describing the epidemiology of HAIs across the entire spectrum of patients (surgical and nonsurgical) receiving care in dedicated pediatric CICUs. METHODS: Retrospective analyses of 22,839 CICU encounters from October 2013 to September 2016 across 22 North American CICUs contributing data to the Pediatric Cardiac Critical Care Consortium clinical registry. RESULTS: HAIs occurred in 2.4% of CICU encounters at a rate of 3.3 HAIs/1000 CICU days, with 73% of HAIs occurring in children <1 year. Eighty encounters (14%) had >=2 HAIs. Aggregate rates for the 4 primary HAIs are as follows: central line associated blood stream infection, 1.1/1000 line days; catheter-associated urinary tract infections, 1.5/1000 catheter days; ventilator-associated pneumonia, 1.9/1000 ventilator days; surgical site infections, 0.81/100 operations. Surgical and nonsurgical patients had similar HAIs rates/1000 CICU days. Incidence was twice as high in surgical encounters and increased with surgical complexity; postoperative infection occurred in 2.8% of encounters. Prematurity, younger age, presence of congenital anomaly, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Categories (STAT) 4-5 surgery, admission with an active medical condition, open sternum and extracorporeal membrane oxygenation were independently associated with HAIs. In univariable analysis, HAI was associated with longer hospital length of stay and durations of urinary catheter, central venous catheter and ventilation. Mortality was 24.4% in patients with HAIs versus 3.4% in those without, P < 0.0001. CONCLUSIONS: We provide comprehensive multicenter benchmark data regarding rates of HAIs within dedicated pediatric CICUs. We confirm that although rare, HAIs of all types are associated with significant resource utilization and mortality. PMID- 29280786 TI - Nephrotoxicity With Vancomycin in the Pediatric Population: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Vancomycin is frequently used to treat methicillin-resistant Staphylococcus aureus infections in pediatric patients. Vancomycin exposure may lead to an increase in frequency of nephrotoxicity. Our aim was to conduct a systematic review to describe predictors of nephrotoxicity associated with vancomycin, including documented trough concentrations >=15 mg/L. We also aimed to use a meta-analysis to assess the impact of a vancomycin trough >=15 mg/L on nephrotoxicity. METHODS: A literature search was performed using PubMed, Cochrane Library, Embase and Web of Sciences database. We included randomized clinical trials and observational studies evaluating the relationship between vancomycin troughs and nephrotoxicity in pediatric-age patients. Studies not measuring troughs or defining a different cut-off point than 15 mg/L were excluded. Data on age, exclusion criteria, nephrotoxicity definition, risk factors for nephrotoxicity and vancomycin trough levels were extracted from selected papers. RESULTS: Ten studies were identified for meta-analysis. All subjects had comparatively normal baseline serum creatinine values. Common risk factors identified included elevated (>=15 mg/L) trough levels, renal impairment, hypovolemia and concurrent use of nephrotoxic medications. Troughs >=15 mg/L increased nephrotoxicity by 2.7-fold (odds ratio (OR), 2.71; 95% confidence interval: 1.82-4.05; I = 40%; Q = 0.09). These odds were further increased among patients in the pediatric intensive care unit (OR, 3.61; 95% confidence interval: 1.21-10.74; I = 45%; Q = 0.18). CONCLUSIONS: Though the rate of vancomycin induced nephrotoxicity is increased in pediatric patients with higher vancomycin troughs, other factors such as intensive care unit admission, hypovolemia and concurrent nephrotoxic drug use appear to contribute to the development of nephrotoxicity. PMID- 29280782 TI - Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee. AB - BACKGROUND: Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed. METHODS: The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas committee performed a MEDLINE review using several preselected key terms relating to management considerations in adult and pediatric AP. The literature was summarized, quality of evidence reviewed, and statements of recommendations developed. The authorship met to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation. RESULTS: The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values >=3 times upper limits of normal, (3) imaging findings consistent with AP). Adequate fluid resuscitation with crystalloid appears key especially within the first 24 hours. Analgesia may include opioid medications when opioid-sparing measures are inadequate. Pulmonary, cardiovascular, and renal status should be closely monitored particularly within the first 48 hours. Enteral nutrition should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and management. Children should be carefully followed for development of early or late complications and recurrent attacks of AP. CONCLUSIONS: This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP. PMID- 29280787 TI - 2017: A Year of Uncertainty, Upheaval, and Undoing. AB - Major changes in policy, attitudes, and events leave many reeling. PMID- 29280788 TI - Improving our Emotional Intelligence. PMID- 29280789 TI - The Ethical Dimensions of Hospital Administration. PMID- 29280790 TI - Missed Opportunities for Military Medics in the Nursing Profession. PMID- 29280791 TI - RNs' Role in Enhancing Primary Care-Deja Vu? AB - The work of nurses in community health has always been transformative. PMID- 29280792 TI - The Top Health Care News Story of 2017: American Instabilities: Health Care Reform, Opioid Overdoses. AB - When you can't agree what the problem is, you can't begin to solve it. PMID- 29280793 TI - The Top Nursing News Stories of 2017. PMID- 29280794 TI - The Top Social Justice News Stories of 2017. PMID- 29280795 TI - 2017 Win-Loss Scoreboard. AB - AJN takes a look back at some of the health care achievements (and disappointments) of 2017. PMID- 29280796 TI - Stories to Watch in 2018. PMID- 29280797 TI - A Missed Opportunity in HIV Prevention? AB - PrEP is effective in at-risk individuals, but barriers to widespread use remain. PMID- 29280800 TI - The FDA's Latest Response to Opioid Abuse and Overdose. PMID- 29280805 TI - Worked at Home During the Blizzard? Not Nurses. AB - : Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to draw the attention of AJN readers to posts we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com. PMID- 29280806 TI - Increasing the Connectivity and Autonomy of RNs with Low-Risk Obstetric Patients. AB - : : Objective: RNs are adopting an ever-larger role in health care models designed to reduce costs, increase patient satisfaction, and improve patient outcomes. Most research exploring such models has focused on those involving physicians or advanced practice nurses rather than RNs. This study explored the perspectives of patients, RNs, and other providers regarding a new prenatal connected care model for low-risk patients aimed at reducing in-office visits and creating virtual patient-RN connections. METHODS: This qualitative evaluation was performed as part of a larger randomized controlled trial of the new care model. Individual interviews and asynchronous online focus groups were conducted with a total of 41 patients, up to 10 unit and connected care RNs, and up to 17 other providers (up to eight physicians and nine certified nurse midwives [CNMs]). RESULTS: Thematic analysis indicated that patients in the new care model valued connectedness and relationships with the connected care RNs, including the ability to contact them as needed outside the office setting. Patients also valued their relationships with physicians and CNMs. Physicians appreciated having more time to care for higher-risk patients, and the connected care RNs appreciated being able to work to a fuller scope of practice, although participants in all provider groups suggested the increased use of protocols and other systems to ensure patient safety and improve communication among providers. CONCLUSIONS: A prenatal connected care model for low-risk women allowed patients to decrease the number of scheduled in-person clinic visits with physicians or CNMs while building stronger nurse-patient relationships through virtual connected care visits with an RN. The results included increased patient satisfaction and greater autonomy for RNs, allowing them to work to a fuller scope of practice. Although the new model gave physicians more time in which to see higher-risk patients, CNM-patient relationships may have been limited. PMID- 29280807 TI - Gastric Bypass Surgery has Long-Term Health Benefits. PMID- 29280808 TI - Improved Patient Hand Hygiene Reduces C. Difficile Infections in Hospitals. PMID- 29280809 TI - Missed Nursing Care Increases the Risk of Death After Surgery. PMID- 29280810 TI - New Guideline for the Evaluation of a Neck Mass in Adults. PMID- 29280811 TI - Preventing Falls and Fall-Related Injuries at Home. AB - : This article is part of a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Public Policy Institute. Results of focus groups, conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project, supported evidence that family caregivers aren't given the information they need to manage the complex care regimens of family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's health care at home.The articles in this new installment of the series explain principles for promoting safe mobility that nurses should reinforce with family caregivers. Each article also includes an informational tear sheet-Information for Family Caregivers-that contains links to instructional videos. To use this series, nurses should read the article first, so they understand how best to help family caregivers, and then encourage the caregivers to watch the videos and ask questions. For additional information, see Resources for Nurses. PMID- 29280812 TI - Predatory Journals: Alerting Nurses to Potentially Unreliable Content. AB - Exploitative publications are degrading scholarly publishing. PMID- 29280813 TI - The Effects of Lateral Positioning in Critically Ill Adults. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org. PMID- 29280814 TI - A Dream of Horses. AB - A psychiatric nurse bears witness to an aging veteran's hidden possibilities. PMID- 29280815 TI - Use of Scribes for Documentation Assistance in Rheumatology and Endocrinology Clinics: Impact on Clinic Workflow and Patient and Physician Satisfaction. AB - BACKGROUND/OBJECTIVE: The aim of this study was to examine the impact of utilizing medical scribes on clinic workflow, physician professional satisfaction, and patient satisfaction in rheumatology and endocrinology clinics. METHODS: We conducted a within-practice pilot study of medical scribes that included a 6-week intervention phase (documentation assistance by medical scribes) followed by a control phase (usual documentation with no assistance) in outpatient rheumatology and endocrinology clinics at an academic medical center. We evaluated the following outcomes: physician professional satisfaction (range, 5-25, with higher values denoting higher satisfaction), autonomy (range, 4-16, with higher values denoting higher autonomy), perception of clinic workflow (range, 1 = calm, 5 = chaotic), and patient satisfaction (5-point Likert item, anchors: strongly agree, strongly disagree). RESULTS: Six physicians, including 3 rheumatologists and 3 endocrinologists, and 496 patients nested within their practices participated. The use of a medical scribe was not associated with physician professional satisfaction (18.17 [SD, 2.9] vs. 17.83 [SD, 1.94], not statistically significant), perception of clinic workflow (2.50 [SD, 0.84] vs. 3.17 [SD, 0.75], not statistically significant), or autonomy (8.67 [SD, 3.44] vs. 8.83 [SD, 3.06], not statistically significant). Physicians had an overall favorable view of the medical scribes program and perceived that documentation support provided by scribes was useful and easy to use and had a positive impact on their clinic workflow. Patient satisfaction was high during the intervention phase (99.4% strongly agree/agree) but not significantly different than in the control phase. CONCLUSIONS: Rheumatologists, endocrinologists, and their patients had consistently positive views regarding the use of a medical scribe without an observed negative effect on clinic workflow in outpatient clinics. PMID- 29280816 TI - Genetic Analysis for rs2241880(T > C) in ATG16L1 Polymorphism for the Susceptibility of Gout. PMID- 29280817 TI - Newly Diagnosed Systemic Lupus Erythematosus: Atypical Presentation With Focal Seizures and Long-standing Lymphadenopathy. AB - BACKGROUND: Systemic lupus erythematosus (SLE) may present with involvement of multiple organ systems, usually with a constellation of nonspecific constitutional symptoms and signs. Seizures and thrombosis are uncommon at presentation. CASE PRESENTATION: We present the case of a 17-year-old boy of African descent with an 11-year history of persistent lymphadenopathy with negative outpatient workup for lymphoma and immunodeficiency who was admitted to our tertiary care hospital for new-onset seizure activity. Over the course of the initial hospital stay, the patient was found to have evidence of thrombosis in multiple organ systems with negative antiphospholipid antibody. Complications included brain hemorrhage secondary to sagittal and cortical vein thrombosis and focal neurological findings of left side weakness and seizures. Following the initiation of steroids and immunosuppressant agents, symptoms resolved, but there followed several readmissions for aggression and psychosis-like symptoms. CONCLUSIONS: In this case, we convey the unique mosaic presentation of SLE and highlight how treatment can cloud the clinical picture, making it difficult to diagnose some SLE manifestations, such as neuropsychiatric lupus that could resemble steroid-induced psychosis. PMID- 29280818 TI - Attitudes Toward and Management of Fibromyalgia: A National Survey of Canadian Rheumatologists and Critical Appraisal of Guidelines. AB - BACKGROUND: Canadian rheumatologists' attitudes toward and management of fibromyalgia remain uncertain. OBJECTIVE: The aim of this study was to explore management strategies and attitudes of Canadian rheumatologists toward fibromyalgia and concordance with guideline recommendations. METHODS: We administered a 17-item cross-sectional survey to Canadian rheumatologists and explored the concordance between respondents' management practices with the 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia. RESULTS: Among 331 Canadian rheumatologists who were approached, 140 returned the survey for a 42% response rate. The majority felt that fibromyalgia was a useful clinical diagnosis (110/138 [80%]) but was divided as to whether fibromyalgia was objectively defined (75/138 [54%]) or a psychosocial condition (42/138 [30%]) or could result in an inability to work (37/138 [27%]). Contrary to guideline recommendations, most (82/134 [61%]) endorsed that tender points were useful for diagnosis. Half endorsed potentially refusing consultations with fibromyalgia patients, and only 42% (59/139) agreed that there were effective therapies for this syndrome. Consistent with the guideline, most respondents managed fibromyalgia with education, exercise therapy, antidepressants, and nonnarcotic analgesics (>=89% for all); however, fewer than half agreed that any of these modalities were effective (endorsement ranged from 9% to 47%). Assessment of the 2012 guideline revealed a number of important limitations. CONCLUSIONS: Canadian rheumatologists largely do not provide primary care for fibromyalgia. Most adhere to guideline recommendations for management of fibromyalgia, but few endorse these interventions as effective. Further research, including updating of the 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia, is required to inform this disconnect. PMID- 29280819 TI - Gangrene of All Digits and Toes Attributable to Systemic Lupus Erythematosus With Negative Antiphospholipid Antibodies. PMID- 29280821 TI - Geyser Sign. PMID- 29280820 TI - Gastroduodenal Artery Aneurysm in a Patient With Granulomatosis With Polyangiitis. PMID- 29280822 TI - Distal Hand Metastases: Clinical and Ultrasonographic Appearance. PMID- 29280823 TI - Retinal Vasculitis Is Principally a Single-Organ Vasculitis of the Eye. PMID- 29280824 TI - A Case of Relapsing Polychondritis Mimicking Hemophagocytic Lymphohistiocytosis After Propionibacterium acnes Infection. AB - We describe a 69-year-old man who presented with a right sternocleidomastoid intramuscular abscess that grew Propionibacterium acnes. Despite initial improvement with antibiotics, he subsequently developed signs and symptoms fulfilling diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) fevers, cytopenias, hyperferritinemia, splenomegaly, and low natural killer cell activity. The patient improved spontaneously but at outpatient follow-up complained of erythema over the bridge of his nose as well as bilateral ear redness sparing the earlobes at which point relapsing polychondritis (RP) was diagnosed. Treatment with steroids and methotrexate resulted in complete symptom resolution. This is the first reported case of RP presenting after this particular infection and as a mimic of HLH. Diagnosis of RP is often delayed because of the heterogeneous and relapsing nature of symptoms. This case illustrates the importance of outpatient follow-up; RP criteria were not fulfilled for more than 2 months after initial presentation. PMID- 29280825 TI - Tuberculosis Infection Despite Isoniazid Prophylaxis in a Patient With Psoriatic Arthritis Treated With Etanercept. PMID- 29280826 TI - An Unusual Cause of Dysphagia. PMID- 29280827 TI - Nature of Perceived Bone Defects in Apparently Otherwise Healthy Individuals: Source of the Erosive Perspective. PMID- 29280828 TI - Syphilitic Interstitial Keratitis in a Patient Diagnosed With Sjogren's Syndrome. PMID- 29280829 TI - A Case Series on Patients on Tofacitinib in Combination With a Biologic. PMID- 29280830 TI - Isolated Bicipito-radial Bursitis in a Patient With Rheumatoid Arthritis. PMID- 29280831 TI - Own your nursing career. PMID- 29280832 TI - Letters. PMID- 29280834 TI - What to consider when choosing a graduate nursing program. PMID- 29280836 TI - Nursing2018(r) salary and benefits survey report. PMID- 29280837 TI - Treating Barrett esophagus with radiofrequency ablation. PMID- 29280839 TI - A closer look at lower extremity peripheral arterial disease. PMID- 29280841 TI - Five steps to your next writing retreat. PMID- 29280842 TI - What cowboys taught me. PMID- 29280843 TI - Closing the gap for patients with rectus abdominis diastasis. PMID- 29280844 TI - Near-miss medication errors provide a wake-up call. PMID- 29280845 TI - Nurse perceptions of the family violence screening process and education program in a rural healthcare system. PMID- 29280846 TI - Pain management for long-term-care residents. PMID- 29280847 TI - Shouldering a patient's pain. PMID- 29280848 TI - Could melatonin be the cure for sleepless nights? PMID- 29280849 TI - Online resources for COPD. PMID- 29280850 TI - Anti-infective drugs. PMID- 29280853 TI - Longitudinal Associations of Neighborhood-level Racial Residential Segregation with Obesity Among Blacks. AB - BACKGROUND: Despite 50 years since the passage of the Fair Housing Act of 1968, the majority of black Americans continue to live in highly segregated communities. Differing exposure to obesogenic environments in segregated neighborhoods may contribute to racial disparities in obesity prevalence. METHODS: We used prospective data from the Coronary Artery Risk Development in Young Adults (CARDIA) study to examine associations between levels of neighborhood-level racial residential segregation and incident obesity in black men and women. Obesity, determined by measured anthropometry, and residential segregation, measured using the local Gi*statistic, were recorded at baseline and follow-up at years 7, 10, 15, 20, and 25. We used marginal structural survival models to account for time-dependent confounding and for loss to follow-up. RESULTS: Black women living in highly segregated neighborhoods at the prior exam were 30% more likely to become obese during the follow-up period as compared with women living in neighborhoods with low levels of segregation after adjustment for sociodemographic and cardiovascular risk covariates (hazard ratio = 1.3 [95% confidence interval = 1.0, 1.7]). Cumulatively high exposure to segregation averaged across time points was associated with 50% higher hazard of obesity (hazard ratio = 1.5 [95% confidence interval = 1.0, 2.3]) among women. We observed few differences in obesity incidence among men by segregation levels. CONCLUSIONS: Fewer health-promoting resources, stressful neighborhood context, and social norms that are less stigmatizing of obesity may contribute to these findings, but more research on specific pathways leading from segregation to obesity is needed to understand differing patterns between men and women. PMID- 29280854 TI - Spermatocytic Seminoma: A Report of 85 Cases Emphasizing its Morphologic Spectrum Including Some Aspects not Widely Known. AB - Spermatocytic seminoma (or, alternatively, spermatocytic tumor) of the testis is rare and errors in pathologic diagnosis are still made. As it has a good prognosis, except when it, rarely, undergoes sarcomatous transformation, accurate diagnosis and differentiating it from usual seminoma and other malignant neoplasms such as lymphoma are crucial. To potentially contribute information of diagnostic aid we reviewed the largest series of cases reported to date to characterize in detail their histologic spectrum. The patients ranged from 30 to 81 years (average, 52 y); 30% were in the fourth decade. The neoplasms ranged from 1.4 to 15 cm (average, 5.7 cm). Most were fleshy, soft, and often lobulated and 11 were edematous or mucoid. Low-power microscopic examination either showed a predominant multinodular (43/85) or diffuse (42/85) pattern. All tumors had the classic "tripartite" cellular population. Five tumors showed a relatively monomorphic population of the intermediate cell type with vesicular chromatin and very prominent nucleoli, at least focally. Two tumors underwent sarcomatous transformation, with 1 having a focus of atypical cartilage. Additional findings, some not previously reported or emphasized, included: (1) frequent edema fluid (87%) often causing spaces, both follicle-like (24%) and irregular (39%), a finding seen in some usual seminomas (but less frequently) and rarely seen in lymphomas; (2) tumor nodules showing partial rims of fibrin (20%); (3) a distinctive arrangement of connecting tumor islands (19%); (4) prominent lymphocytic infiltrates (8%); (5) granulomatous inflammation (1%); (6) striking mitotic activity and apoptosis; (7) intratubular spread (64%); and (8) vessel invasion (11%) and necrosis (8%). Awareness of these aspects may be of importance either at the time of intraoperative evaluation or on final pathologic analysis and help avoid significant errors in diagnosis. PMID- 29280852 TI - Bivariate Genome-Wide Association Study of Depressive Symptoms With Type 2 Diabetes and Quantitative Glycemic Traits. AB - OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type 2 diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits. METHODS: We estimated single-nucleotide polymorphism (SNP)-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the linkage disequilibrium score regression by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by DIAGRAM consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, and homeostatic model assessment of beta-cell function and insulin resistance by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate genome-wide association study approach with summary statistics from genome-wide association study meta-analyses and reported loci with genome-wide significant bivariate association p value (p < 5 * 10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases. RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the linkage disequilibrium score regression analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). However, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes). CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D, or glycemic traits suggesting major differences in underlying biology of these traits. However, several potential pleiotropic loci were identified between depressive symptoms, T2D, and fasting glucose, suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci. PMID- 29280855 TI - Discussion: The Expanded Use of Autoaugmentation Techniques in Oncoplastic Breast Surgery. PMID- 29280856 TI - Bovine Acellular Dermal Matrix in Immediate Breast Reconstruction: A Retrospective, Observational Study with SurgiMend. AB - BACKGROUND: Acellular dermal matrices can be combined with implant-based breast reconstruction to help optimize outcomes. SurgiMend PRS is a fetal bovine dermis derived acellular dermal matrix composed of type I collagen and approximately 30 percent type III collagen, sharing many of the properties of human cadaveric acellular dermal matrix. METHODS: This was a retrospective, single-center analysis of 111 adult patients (147 breasts) undergoing one-stage (83.7 percent) or two-stage (16.3 percent) immediate breast reconstruction after mastectomy. The aims were to characterize the safety profile of SurgiMend and investigate associations between risk factors and complications. RESULTS: The mean age of the patients was 47.9 years and the mean body mass index was 24.7 kg/m. After a median follow-up of 24.3 months, the overall rates of minor and major complications were 25.2 percent (n = 37 of 147) and 12.9 percent (n = 19 of 147), respectively. The most common major complications were seroma [n = 12 (8.2 percent)] and necrosis [n = 9 (6.1 percent)]. All occurred within 3 months after surgery. The rate of capsular contracture was 2.7 percent (n = 4). A total of 2.7 percent of implanted breasts (n = 4) required explantation. In a univariate analysis, smokers had a greater risk of major complications (p = 0.013), and postoperative radiation therapy and obesity were associated with an increased risk of capsular contracture (p = 0.006) and explantation (p = 0.006), respectively. In a multivariate analysis, several factors were associated with complications or explantation, including obesity (p < 0.05), preoperative chemotherapy (p < 0.001), and mastectomy weight (p < 0.05). These associations align with other studies of implant-based reconstruction and do not appear to be specific to this acellular dermal matrix. CONCLUSION: The results are consistent with previous analyses of SurgiMend, and support its value in implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29280857 TI - Microbial Evaluation in Capsular Contracture of Breast Implants. AB - BACKGROUND: Capsular contracture around breast implants is a severe and unpredictable complication experienced by up to 50 percent of patients after breast augmentation and reconstruction, and represents a major cause leading to reoperation. Several lines of evidence point to the involvement of subclinical infections and of bacterial biofilm formation. METHODS: To reduce the incidence of capsular contracture following mammaplasty, the authors studied the correlation between contamination by exogenous and endogenous bacterial flora and the capacity to develop bacterial biofilm in mammary implants. The authors performed a microbiological study assessing microbial growth of swabs from breast skin, nipple-areola complex, and mammary gland biopsy specimens. Furthermore, the authors compared the results with the data resulting from cultural experiments from biopsy specimens of periprosthetic capsule, contracted or not, and from the surfaces of the relative prosthesis. RESULTS: Between July of 2012 and July of 2013, a series of 65 female patients from the area of Naples, Italy, and its province, who underwent breast plastic surgery with the use of implants for aesthetic or reconstructive reasons, were included in the study. The authors noticed that there is a greater tendency for capsular contracture to form in oncologic patients who received radiotherapy, patients with precedent capsular contracture, and patients with cutaneous contamination by biofilm-producing microbes. CONCLUSIONS: Although all of the new technical procedures tend to reduce the amount of bacterial charge that comes into contact with the prosthesis at the time of its introduction, a minimal amount must always be taken for granted. This is the rationale for a preventative personalized antibiotic therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29280858 TI - 22 Cases of Breast Implant-Associated ALCL: Awareness and Outcome Tracking from the Italian Ministry of Health. AB - BACKGROUND: To date, 359 cases of anaplastic large cell lymphoma (ALCL) in women with breast implants (breast implant-associated ALCL [BIA-ALCL]) worldwide have been reported among more than 10 million patients who have received implants, but health care authorities suspect this is a possible underestimation, and the limited number of cases makes it difficult to clarify its cause. The General Directorate of Medical Devices and Pharmaceutical Services of the Italian Ministry of Health has examined and studied the Italian BIA-ALCL cases. METHODS: An official document has been diffused to all medical associations, aiming at encouraging all physicians to notify each BIA-ALCL case. A retrospective study has been performed on the notified BIA-ALCL cases collected in the database named Dispovigilance. RESULTS: Research on Dispovigilance returns a list of 22 BIA-ALCL cases. The mean patient age was 49.6 years (range, 30 to 71 years). The average time to the onset of the symptoms was 6.8 years (range, 1 to 22 years). The average time to diagnosis was 7.8 years (range, 4 to 22 years). The estimated incidence of the Italian BIA-ALCL cases related to 2015 is 2.8 per 100,000 patients. CONCLUSIONS: The pathogenesis of BIA-ALCL remains unknown. The establishment of a national breast implant registry is needed to better understand some aspects of this disease. Future genetic studies on the population affected could clarify why only some patients with implants develop this disease. PMID- 29280859 TI - Outcome Analysis of Free Flap Salvage in Outpatients Presenting with Microvascular Compromise. AB - BACKGROUND: Extensive flap salvage attempts are routinely performed in patients with late-onset flap vascular crisis despite low flap survival rates. A knowledge gap exists in management of compromised free flaps in patients who present with perfusion-related complications after hospital discharge. METHODS: A retrospective review of 7443 free flaps used in 7128 cancer patients at a single institution from January of 2001 to March of 2015 was performed. RESULTS: Of 7443 free flap reconstructions, 856 patients (12 percent) were taken back to the operating room. Also, 261 patients (4 percent) suffered from microvascular compromise, of whom 110 (1 percent) experienced total flap loss. The authors identified 17 patients (10 breast cancer patients and seven head and neck cancer patients) who had vascular flap compromise and underwent reoperation after hospital discharge (median, 10 days; range, 4 to 107 days) after free flap reconstruction. Of these 17 patients, nine breast cancer patients and two head and neck cancer patients underwent flap salvage attempts. Salvage procedures included thrombectomy, thrombolytic and heparin injections, and reanastomoses (11 patients); vein grafting (four patients); vein supercharging with cephalic turndown (two patients); and change of recipient vessels (two patients). Sixteen of the 17 patients (94 percent) experienced total flap loss, and one patient (6 percent) had partial flap loss requiring long-lasting wound treatment. CONCLUSIONS: Outpatient free flap salvage has a low success rate regardless of flap type, recipient site, or patient population. The authors' study suggests that immediate second-line reconstruction is more effective for late-onset flap vascular crisis than extensive flap salvage procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 29280860 TI - MBN 2016 Aesthetic Breast Meeting BIA-ALCL Consensus Conference Report. AB - Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon neoplasia occurring in women with either cosmetic or reconstructive breast implants. The actual knowledge about BIA-ALCL deriving from the literature presents several limits, and it remains difficult to make inferences about BIA ALCL epidemiology, cause, and pathogenesis. This is the reason why the authors decided to organize an evidence-based consensus conference during the Maurizio Bruno Nava (MBN 2016) Aesthetic Breast Meeting held in Milan in December of 2016. Twenty key opinion leaders in the field of plastic surgery from all over the world have been invited to express and discuss their opinion about some key questions on BIA-ALCL, trying to reach a consensus about BIA-ALCL cause, pathogenesis, diagnosis, and treatment in light of the actual best evidence. PMID- 29280861 TI - Discussion: Septum-Based Nasal Tip Plasty: A Comparative Study between Septal Extension Graft and Double-Layered Conchal Cartilage Extension Graft. PMID- 29280862 TI - Adverse Event Incidences following Facial Plastic Surgery Procedures: Incorporating FACE-Q Data to Improve Patient Preparation. AB - BACKGROUND: Before creation and validation of the FACE-Q by Pusic et al., adverse event types and incidences following facial cosmetic procedures were objectively measured and reported by physicians, potentially leading to misrepresentation of the true patient experience. This article analyzes and compares adverse event data from both FACE-Q and recent review articles, incorporating patient-reported adverse event data to improve patient preparation for facial cosmetic procedures. METHODS: FACE-Q adverse event data were extracted from peer-reviewed validation articles for face lift, rhinoplasty, and blepharoplasty, and these data were compared against adverse effect risk data published in recent Continuing Medical Education/Maintenance of Certification and other articles regarding the same procedures. RESULTS: The patient-reported adverse event data sets and the physician-reported adverse event data sets do contain overlapping elements, but each data set also contains unique elements. The data sets represent differing viewpoints. Furthermore, patient-reported outcomes from the FACE-Q provided incidence data that were otherwise previously not reported. CONCLUSIONS: In the growing facial cosmetic surgery industry, patient perspective is critical as a determinant of success; therefore, incorporation of evidence-based patient reported outcome data will not only improve patient expectations and overall experience, but will also reveal adverse event incidences that were previously unknown. Given that there is incomplete overlap between patient-reported and physician-reported adverse events, presentation of both data sets in the consultation setting will improve patient preparation. Furthermore, use of validated tools such as the FACE-Q will allow surgeons to audit themselves critically. PMID- 29280863 TI - Corset Trunkplasty: Recommended with Abdominal Skin Laxity and Open Cholecystectomy Scar. AB - BACKGROUND: Patients undergoing abdominoplasty with previous upper abdominal wall scars are at an increased risk for postoperative complications. The corset trunkplasty is a newer technique to treat abdominal wall laxity of the entire anterolateral abdomen while incorporating any previous open cholecystectomy scar. The authors performed a comparative outcomes study to determine whether the corset procedure would decrease the incidence of postoperative complications in patients with abdominal wall laxity and an open cholecystectomy scar when compared with traditional abdominoplasty. METHODS: A retrospective study was performed on patients who underwent traditional and corset abdominoplasty. Patients were divided into four groups: traditional with scar, corset with scar, traditional no scar, and corset no scar. Evaluated metrics included procedure time, postoperative length of stay, complications, reoperations, and readmission rates. RESULTS: Fifty-eight subjects were included in the study (traditional with scar, n = 15; corset with scar, n = 13; traditional no scar, n = 15; and corset no scar, n = 15). Demographics were similar among groups: body mass index, 33.7 kg/m; age, 44.3 years; and American Society of Anesthesiologists status, 2.5. The corset procedure took longer than the traditional method, regardless of whether a scar was present (146.1 minutes versus 125.7 minutes). However, the traditional with scar group had the greatest length of stay and higher complication, readmission, and reoperation rates. The corset with scar group had comparable outcomes to the corset no scar and traditional no scar groups. CONCLUSIONS: The corset trunkplasty procedure resulted in fewer adverse outcomes compared with traditional abdominoplasty in patients with previous open cholecystectomy scar. Its use should be considered in patients with significant abdominal wall laxity and existing upper abdominal surgical scars. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29280864 TI - Discussion: Corset Trunkplasty: Recommended with Abdominal Skin Laxity and Open Cholecystectomy Scar. PMID- 29280865 TI - Development and Internal Validation of the Abdominoplasty Risk Calculator. AB - BACKGROUND: Risk calculators are an emerging tool that provide granular, individualized risk estimation. Presently, there is a paucity of risk calculators specific to plastic surgery. Abdominoplasty is a popular plastic surgery procedure associated with moderate risks of complications, such as surgical-site infection and dehiscence, and would benefit from the ability to provide patients with accurate, personalized risk assessment. METHODS: Abdominoplasties from the National Surgical Quality Improvement Program 2005 to 2014 database were identified by Current Procedural Terminology code. Relevant perioperative variables included age, body mass index, sex, smoking history, diabetes, American Society of Anesthesiologists class, pulmonary comorbidities, hypertension, bleeding disorders, and operative duration. Multiple logistic regressions were used to generate 30-day risk models for medical complications, surgical-site infection, wound dehiscence, and reoperation. Internal validation of model performance was conducted using C-statistics, Hosmer-Lemeshow tests, and Brier scores. RESULTS: Among the 2499 cases identified, complication rates were as follows: medical complications, 3.8 percent; superficial surgical-site infection, 2.4 percent; deep or organ-space surgical-site infection, 1.6 percent; wound dehiscence, 1.0 percent; and reoperation, 2.0 percent. Risk prediction models were constructed and all demonstrated good predictive performance, with mean predicted risks closely matching observed complication rates. The distributions of predicted risk were wide and contained outliers with very high risk. A user friendly, open-access online interface for these models is published at AbdominoplastyRisk.org. CONCLUSIONS: The authors developed an internally valid risk calculator for which individual patient characteristics can be input to predict 30-day complications after abdominoplasty. Given that estimated risk can vary widely, individualized risk assessment is a way to enhance shared decision making between surgeon and patient. PMID- 29280866 TI - The Impact of Botulinum Toxin on Brow Height and Morphology: A Randomized Controlled Trial. AB - BACKGROUND: Previous reports have objectively demonstrated the efficacy of botulinum toxin for brow elevation. No clinical trial has compared the variation of the eyebrow shape and height when the lateral eyebrow depressors are injected alone or in combination with the medial eyebrow depressors. METHODS: A prospective, randomized, controlled study was designed to evaluate and compare the effect of two different botulinum toxin injection techniques on brow shape and position. Patients were divided into two groups. AbobotulinumtoxinA was injected in the lateral eyebrow depressors alone (group 1) or in both the lateral and medial eyebrow depressors (group 2). Objective eyebrow measurements were performed using standardized preinjection and postinjection photographs. Patient satisfaction was also evaluated. RESULTS: Fifteen patients (30 eyebrows) were included in each group. The brow elevated by 0.6 to 2.1 mm at all positions in group 1. In group 2, the brow elevated from the medial limbus to the lateral edge of the brow (1 to 1.7 mm), with no changes at the level of the medial brow and canthus. When comparing the two injection techniques, the authors found a statistically significant difference in the change of eyebrow height at the level of the medial brow, medial canthus, and lateral brow edge. Ninety-seven percent of patients were satisfied with their results. CONCLUSION: Different eyebrow injection techniques yield different elevation patterns. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29280867 TI - Staying Safe during Gluteal Fat Transplantation. AB - Gluteal augmentation with fat transplantation is increasing in demand but has been associated with a concerning number of fatality reports. Despite these reports, various surgeons have safely performed gluteal fat transplantation on a large number of patients with no reported mortality. The important aspects of safely performing gluteal fat transplantation are reviewed. Proper patient selection, favorable instrumentation, patient positioning, proper technique, and knowledge of anatomy are critical to improving the safety of this procedure. Adherence to these key principles should allow a reduction in mortality from this procedure, which would safely allow its continued offering in the setting of increasingly high demand. PMID- 29280868 TI - The Impact of Labiaplasty on Sexuality. AB - BACKGROUND: Labiaplasty is one of the aesthetic procedures that has shown the greatest increase in the number of operations in recent years, although the absolute number of these procedures is still very low. Labia minora hypertrophy causes not only functional discomfort and sexual difficulties, but also embarrassment and aesthetic concern. The aim of this study was to assess the impact of labiaplasty on the patient's quality of life, self-esteem, and sexual function. METHODS: Twenty-four consecutive sexually active patients, who expressed the desire to undergo labiaplasty, were divided into two groups of 12 patients each: the intervention group that underwent labiaplasty immediately after responding the first questionnaires, and the control group that received no intervention during the study period. All patients were assessed for health related quality of life, self-esteem, and sexual function using the Brazilian Portuguese versions of the Medical Outcomes Study 36-Item Short Form Health Survey, the Brazilian version of the Rosenberg Self-Esteem scale, and the Female Sexual Function Questionnaire, respectively. The questionnaires were administered at inclusion and at 3 and 6 months later in both groups. Comparisons within and between groups were performed. Statistical analysis was performed at a significance level of p < 0.05. RESULTS: No significant differences in Rosenberg Self-Esteem scale or Medical Outcomes Study 36-Item Short Form Health Survey score were found in either group during the study period. However, a significant improvement was found in the Female Sexual Function Questionnaire total score in the pain and enjoyment domains. CONCLUSION: Labiaplasty had a positive impact on sexual functioning of the study population. PMID- 29280869 TI - Discussion: The Impact of Labiaplasty on Sexuality. PMID- 29280870 TI - Components of the Hanging Columella: Strategies for Refinement. AB - The columella is a significant factor in the aesthetic balance of the nose, particularly the lower one-third of the nose. Its position is dependent on the anatomical constituents of the columella, and neighboring anatomical structures. Six components of the hanging columella have been identified: the caudal septum, medial crura, columellar skin, membranous septum, anterior nasal spine, and depressor septi nasi muscle. Columellar refinement begins with a careful analysis and diagnosis of the contributing components, followed by surgical techniques to address these components individually. The cumulative effect of correction of individual components appropriately positions the columella and contributes significantly to the enhancement of nasal aesthetics. Refinement of the columella can be achieved through appropriately trimming the caudal septum; repositioning and reshaping the medial crura; excising redundant columellar skin, membranous septum, and nasal mucosa; appropriately contouring the anterior nasal spine; and dividing the depressor nasi septi nasi. PMID- 29280871 TI - Discussion: Biological Properties and Therapeutic Value of Cryopreserved Fat Tissue. PMID- 29280872 TI - PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing. AB - BACKGROUND: Cell therapy with mesenchymal stromal cells is a promising strategy for tissue repair. Restoration of blood flow to ischemic tissues is a key step in wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) superfamily, consisting of transcription factors targeted for degradation by prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the proangiogenic capability of mesenchymal stromal cells and to use these modified cells to promote wound healing. METHODS: Mesenchymal stromal cells harvested from mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; control cells were transduced with scrambled shRNA (shScramble) construct. Gene expression quantification, human umbilical vein endothelial cell tube formation assays, and wound healing assays were used to assess the effect of PHD knockdown mesenchymal stromal cells on wound healing dynamics. RESULTS: PHD-2 knockdown mesenchymal stromal cells overexpressed HIF-1alpha and multiple angiogenic factors compared to control (p < 0.05). Human umbilical vein endothelial cells treated with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited increased formation of capillary-like structures and enhanced migration compared with human umbilical vein endothelial cells treated with conditioned medium from shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 0.05). Histologic studies revealed increased blood vessel density and increased cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells (p < 0.05). CONCLUSIONS: Silencing PHD-2 in mesenchymal stromal cells augments their proangiogenic potential in wound healing therapy. This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors. PMID- 29280873 TI - Comparison of Surgical Strategies between Proximal Nerve Graft and/or Nerve Transfer and Distal Nerve Transfer Based on Functional Restoration of Elbow Flexion: A Retrospective Review of 147 Patients. AB - BACKGROUND: Surgical strategy to treat incomplete brachial plexus injury with palsies of the shoulder and elbow by using proximal nerve graft/transfer or distal nerve transfer is still debated. The aim of this study was to compare both strategies with respect to the recovery of elbow flexion. METHODS: One hundred forty-seven patients were enrolled: 76 patients underwent reconstruction using proximal nerve graft/transfer, and 71 patients underwent reconstruction using distal nerve transfer. All patients were evaluated preoperatively and postoperatively to assess the recovery rate and muscle strength of elbow flexion. Shoulder abduction and hand grip power were also recorded to assess any concomitant postoperative changes between the two methods. RESULTS: The best recovery rate for functional elbow flexion (p = 0.006) and the fastest recovery to M3 strength (p < 0.001) were found in the double fascicular transfer group. However, recovery of shoulder abduction with proximal nerve graft/transfer was significantly better than with distal nerve transfer (80.3 percent versus 66.2 percent in shoulder abduction >=60 degrees; and 56.6 percent versus 38.0 percent in shoulder abduction >=90 degrees). A significant decrease in grip strength between the operative and nonoperative hands was also found in patients undergoing distal nerve transfer (p = 0.001). CONCLUSIONS: Proximal nerve graft/transfer offers more accurate diagnosis and proper treatment to restore shoulder and elbow function simultaneously. Distal nerve transfer can offer more efficient elbow flexion. Combined, both strategies in primary nerve reconstruction are especially recommended when there is no healthy or not enough donor nerve available. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29280874 TI - Thenar Dysplasia in Radial Polydactyly Depends on the Level of Bifurcation. AB - BACKGROUND: Little is known about thenar dysplasia in radial polydactyly, other than that thenar hypoplasia occasionally occurs in radial polydactyly with triphalangism. In particular, the phenotype and level of duplication associated with thenar dysplasia remain unclear. METHODS: The abductor pollicis brevis and flexor pollicis brevis muscles were visualized using three-dimensional ultrasound, and their horizontal geometry was assessed using a biaxial level classification system. Subjects were categorized into three phenotypes according to the developmental condition of the radial thumb. The relationship between the level of distribution of the muscles and the level of the bifurcation of the radial thumb was investigated. RESULTS: Nineteen patients with radial polydactyly without triphalangism were included. There were 10 patients with the nonfloating type, three with the floating type, and six with the rudimentary type. All patients with bifurcation at or more distal to the metacarpophalangeal joint had normal thenar muscle distribution, but the muscles in patients with bifurcation at or more proximal to the level of the metacarpals were confined, regardless of phenotype. The level of muscle distribution was strongly correlated with the level of the bifurcation of the radial thumb. CONCLUSIONS: These findings suggest that formation of the thenar muscles in the longitudinal direction in radial polydactyly might depend on the level of bifurcation of the radial thumb. The presence of thenar dysplasia even in floating-type or rudimentary-type duplications is of clinical and etiologic importance. PMID- 29280875 TI - Teaching Palatoplasty Using a High-Fidelity Cleft Palate Simulator. AB - BACKGROUND: Cleft palate repair is a challenging procedure for cleft surgeons to teach. A novel high-fidelity cleft palate simulator has been described for surgeon training. This study evaluates the simulator's effect on surgeon procedural confidence and palatoplasty knowledge among learners. METHODS: Plastic surgery trainees attended a palatoplasty workshop consisting of a didactic session on cleft palate anatomy and repair followed by a simulation session. Participants completed a procedural confidence questionnaire and palatoplasty knowledge test immediately before and after the workshop. RESULTS: All participants reported significantly higher procedural confidence following the workshop (p < 0.05). Those with cleft palate surgery experience had higher procedural confidence before (p < 0.001) and after (p < 0.001) the session. Palatoplasty knowledge test scores increased in 90 percent of participants. The mean baseline test score was 28 +/- 10.89 percent and 43 +/- 18.86 percent following the workshop. Those with prior cleft palate experience did not have higher mean baseline test scores than those with no experience (30 percent versus 28 percent; p > 0.05), but did have significantly higher scores after the workshop (61 percent versus 35 percent; p < 0.05). All trainees strongly agreed or agreed that the simulator should be integrated into training and they would use it again. CONCLUSIONS: This study demonstrates the effective use of a novel cleft palate simulator as a training tool to teach palatoplasty. Improved procedural confidence and knowledge were observed after a single session, with benefits seen among trainees both with and without previous cleft experience. PMID- 29280876 TI - Strategic Considerations for Effective Sagittal Resection of the Mandible to Achieve a Slim and Attractive Jawline. AB - BACKGROUND: Sagittal resection of the mandible has been widely used to reduce the width of the lower face and is usually carried out in combination with a mandibular contouring procedure. However, the surgical outcomes of this procedure are unclear because sagittal resection is rarely performed as a single procedure. The authors clarify misunderstandings regarding this procedure and introduce an improved strategic approach for sagittal resection of the mandible. METHODS: Under general anesthesia, mandible contouring was performed first with a curved osteotomy, followed by sagittal resection of the outer cortex of mandible. The amount and extent of each procedure was determined in accordance with preoperative analysis. RESULTS: From 2012 to 2014, a consecutive series of 212 patients who underwent mandible contouring surgery without concomitant chin surgery were included in the study. A total of 189 patients underwent both mandibular contouring surgery and sagittal resection, whereas 13 underwent only sagittal resection and 10 underwent only mandibular contouring surgery. All operations were carried out successfully without any severe complications, and most patients had satisfactory aesthetic outcomes. CONCLUSIONS: The authors found that the sagittal resection of the mandible should be performed in accordance with the shape of the mandible to effectively reduce facial width and achieve better aesthetic outcomes for both profile and frontal views. In an outcurved type mandible, conventional mandibular contouring may be effective alone, whereas sagittal resection focusing on removing the mandible body region is essential for incurved-type mandibles. In straight line-type mandibles, both procedures are necessary. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29280878 TI - Ability to Cope with Pain Puts Migraine Surgery Patients in Perspective. AB - BACKGROUND: Candidates for migraine surgery are chronic pain patients with significant disability. Currently, migraine-specific questionnaires are used to evaluate these patients. Analysis tools widely used in evaluation of better understood pain conditions are not typically applied. This is the first study to include a commonly used pain questionnaire, the Pain Self-Efficacy Questionnaire (PSEQ) that is used to determine patients' pain coping abilities and function. It is an important predictor of pain intensity/disability in patients with musculoskeletal pain, as low scores have been associated with poor outcome. METHODS: Ninety patients were enrolled prospectively and completed the Migraine Headache Index and PSEQ preoperatively and at 12 months postoperatively. Scores were evaluated using paired t tests and Pearson correlation. Representative PSEQ scores for other pain conditions were chosen for score comparison. RESULTS: All scores improved significantly from baseline (p < 0.01). Mean preoperative pain coping score (PSEQ) was 18.2 +/- 11.7, which is extremely poor compared with scores reported for other pain conditions. Improvement of PSEQ score after migraine surgery was higher than seen in other pain conditions after treatment (112 percent). Preoperative PSEQ scores did not influence postoperative outcome. CONCLUSIONS: The PSEQ successfully demonstrates the extent of debility in migraine surgery patients by putting migraine pain in perspective with other known pain conditions. It further evaluates functional status, rather than improvement in migraine characteristics, which significantly adds to our understanding of outcome. Poor preoperative PSEQ scores do not influence outcome and should not be used to determine eligibility for migraine surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29280879 TI - The Public Face of Transplantation: The Potential of Education to Expand the Face Donor Pool. AB - BACKGROUND: Despite the growing success of facial transplantation, organ donor shortages remain challenging. Educational health campaigns can effectively inform the general public and institute behavioral modifications. A brief educational introduction to facial transplantation may positively influence the public's position on facial donation. METHODS: The authors anonymously surveyed 300 participants, gathering basic demographic information, donor registration status, awareness of facial transplantation, and willingness to donate solid organs and facial allografts. Two-hundred of these participants were presented an educational video and subsequently resurveyed on facial donation. Factorial parametric analyses were performed to compare exposure responses before and after watching video exposure. RESULTS: Among participants completing the survey alone (control group), 49 percent were registered donors, 78 percent reported willingness to donate solid organs, and 52 percent reported willingness to donate facial allograft. Of participants who watched the video (video group) 52 percent were registered; 69 and 51 percent were willing to donate solid organs and face, respectively. Following educational intervention, 69 percent of participants in the video group reported willingness to donate facial tissue, an 18 percent increase (p < 0.05), that equated to those willing to donate solid organs. The greatest increase was observed among younger participants (23 percent); women (22 percent); Jewish (22 percent), Catholic (22 percent), and black/African American (25 percent) participants; and respondents holding a higher degree. No significant differences according to gender or ethnicity were observed. CONCLUSION: Educational interventions hold much promise for increasing the general public's awareness of facial transplantation and willingness to participate in donation of facial allografts. PMID- 29280877 TI - Choanal Atresia and Craniosynostosis: Development and Disease. AB - A number of textbooks, review articles, and case reports highlight the potential comorbidity of choanal atresia in craniosynostosis patients. However, the lack of a precise definition of choanal atresia within the current craniosynostosis literature and widely varying methods of detection and diagnosis have produced uncertainty regarding the true coincidence of these conditions. The authors review the anatomy and embryologic basis of the human choanae, provide an overview of choanal atresia, and analyze the available literature that links choanal atresia and craniosynostosis. Review of over 50 case reports that describe patients diagnosed with both conditions reveals inconsistent descriptions of choanal atresia and limited use of definitive diagnostic methodologies. The authors further present preliminary analysis of three dimensional medical head computed tomographic scans of children diagnosed with craniosynostosis syndromes (e.g., Apert, Pfeiffer, Muenke, and Crouzon) and typically developing children and, although finding no evidence of choanal atresia, report the potentially reduced nasal airway volumes in children diagnosed with Apert and Pfeiffer syndromes. A recent study of the Fgfr2c Crouzon/Pfeiffer syndrome mouse model similarly found a significant reduction in nasal airway volumes in littermates carrying this FGFR2 mutation relative to unaffected littermates, without detection of choanal atresia. The significant correlation between specific craniosynostosis syndromes and reduced nasal airway volume in mouse models for craniosynostosis and human pediatric patients indicates comorbidity of choanal and nasopharyngeal dysmorphologies and craniosynostosis conditions. Genetic, developmental, and epidemiologic sources of these interactions are areas particularly worthy of further research. PMID- 29280880 TI - Umbilicus Reconstruction with Bilateral Square "Pumpkin-Teeth" Advancement Flaps. AB - The creation of a neoumbilicus is a common challenge for plastic surgeons. The authors present their technique of umbilical reconstruction with bilateral square "pumpkin-teeth" advancement flaps. The technique described is applicable in both the setting of a vertical midline incision and when no midline incision is present (e.g., an abdominoplasty). The reconstruction has been performed in over 50 patients with a vertical midline incision and five patients without a midline incision. The only complications noted were persistent serous drainage in several patients with vertical incision and inadequate depth in one patient without a midline incision. This technique is quickly performed, and avoids small flaps, external incisions, and healing by secondary intention. PMID- 29280881 TI - Discussion: Reconstruction of the Heel, Middle Foot Sole, and Plantar Forefoot with the Medial Plantar Artery Perforator Flap: Clinical Experience with 28 Cases. PMID- 29280882 TI - The Best of Abdominal Wall Reconstruction. AB - LEARNING OBJECTIVES: After reviewing this article, the participant should be able to: 1. List major risk factors for hernia formation and for failure of primary repair. 2. Outline an algorithmic approach to anterior abdominal wall reconstruction based on the degree of contamination, components involved in the deficit, and width of the hernia defect. 3. Describe appropriate indications for synthetic and biological mesh products. 4. List common flaps used in anterior abdominal wall reconstruction, including functional restoration strategies. 5. Describe the current state of the art of vascularized composite tissue allotransplantation strategies for abdominal wall reconstruction. SUMMARY: Plastic surgeons have an increasingly important role in abdominal wall reconstruction-from recalcitrant, large incisional hernias to complete loss of abdominal wall domain. A review of current algorithms is warranted to match evolving surgical techniques and a growing number of available implant materials. The purpose of this article is to provide an updated review of treatment strategies to provide an approach to the full spectrum of abdominal wall deficits encountered in the modern plastic surgery practice. PMID- 29280883 TI - Evidence-Based Medicine: Current Practices in Rhinoplasty. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Perform aesthetic and functional nasal analysis to guide septorhinoplasty. 2. Recognize common complications associated with rhinoplasty. 3. Select appropriate septorhinoplasty techniques to refine nasal aesthetics and treat nasal airway obstruction. 4. Identify factors leading to poor patient satisfaction following rhinoplasty. SUMMARY: Septorhinoplasty is among the most technically challenging procedures in the realm of plastic and reconstructive surgery. Moreover, it is a constantly evolving topic with extensive background literature. Surgeons must be comfortable with the traditional knowledge base and the current practices in the field. This article reviews the latest thinking on patient selection, functional indications, aesthetic analysis, and operative techniques in septorhinoplasty, with an emphasis on key cartilage grafting and tip suture techniques. PMID- 29280884 TI - Postoperative Nausea and Vomiting with Plastic Surgery: A Practical Advisory to Etiology, Impact, and Treatment. AB - Ambulatory surgery is common in plastic surgery, where many aesthetic and reconstructive procedures can be performed in hospitals, ambulatory surgery centers, or office-based surgery facilities. Outpatient surgery offers advantages to both the patient and the surgeon by increasing accessibility, flexibility, and convenience; lowering cost; and maintaining high-quality care. To optimize a patient's experience and comfort, postoperative nausea and vomiting (PONV) should be prevented. However, in those patients who develop PONV, it must be appropriately managed and treated. The incidence of PONV is variable. It is often difficult to accurately predict those patients who will develop PONV or how they will manifest symptoms. There are a variety of recommended "cocktails" for PONV prophylaxis and treatments that are potentially effective. The decision regarding the type of treatment given is often more related to provider preference and determination of side-effect profile, rather than targeted to specific patient characteristics, because of the absence of large volumes of reliable data to support specific practices over others. Fortunately, there are several tenets for the successful prevention and treatment of PONV we have extracted from the literature and summarize here. The following is a summary for the practicing plastic surgeon of the current state of the literature regarding PONV cause, risk factors, prophylaxis, and treatment that may serve as a guide for further study and practice management. PMID- 29280885 TI - Discussion: Postoperative Nausea and Vomiting with Plastic Surgery: A Practical Advisory to Etiology, Impact, and Treatment. PMID- 29280886 TI - Discussion: Why the p Value Alone Is Not Enough: The Need for Confidence Intervals in Plastic Surgery Research. PMID- 29280887 TI - Smoking as an Independent Risk Factor for Postoperative Complications in Plastic Surgical Procedures: A Propensity Score-Matched Analysis of 36,454 Patients from the NSQIP Database from 2005 to 2014. AB - BACKGROUND: Smoking has been associated with wound healing complications and overall morbidity in multiple specialties, including plastic surgery. From 2005 to 2014, smoking prevalence among U.S. adults decreased from 20.9 percent to 16.8 percent. This study aims to investigate whether smoking prevalence among plastic surgery patients paralleled the national trend and whether smoking was an independent risk factor for postoperative complications. METHODS: The 2005 to 2014 American College of Surgeons National Surgical Quality Improvement Program database was used to examine smoking prevalence and 30-day postoperative complications in 36,454 patients who underwent common plastic surgical procedures with extensive planes of dissection. Patients were propensity score-matched for demographics and comorbidities. Smokers were stratified by pack-years. RESULTS: Compared to the national trend, a significantly smaller percentage of plastic surgical patients were smokers (p = 0.01), with a less dramatic decline in prevalence. Smokers had significantly increased deep incisional surgical-site infections, incisional dehiscence, and reoperation (p < 0.01 for all). However, superficial surgical-site infection rates were not significantly different (p = 0.18). Smokers with 11 or more pack-years had significantly increased deep surgical-site infection (p < 0.01) and reoperations (p < 0.01). There were no significant differences in graft/prosthesis/flap loss (p = 0.07), bleeding (p = 0.40), sepsis (p = 0.87), or venous thromboembolism (p = 0.16) rates between smokers and nonsmokers. CONCLUSIONS: This is the first large-scale propensity score-matched database analysis isolating smoking as a risk factor for postoperative complications in plastic surgical procedures. Smoking was an independent risk factor for deep incisional surgical-site infection, incisional dehiscence, and reoperation. Interestingly, superficial surgical-site infection rates were not significantly different. The authors recommend continued judicious patient selection and preoperative smoking counseling to optimize postoperative outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 29280888 TI - Work-Related Musculoskeletal Injuries in Plastic Surgeons in the United States, Canada, and Norway. AB - BACKGROUND: Musculoskeletal injuries are more common among surgeons than among the general population. However, little is known about these types of injuries among plastic surgeons specifically. The authors' goals were to evaluate the prevalence, nature, causes, and potential solutions of these musculoskeletal injuries among plastic surgeons in three different countries: the United States, Canada, and Norway. METHODS: A survey was e-mailed to plastic surgeons in the United States, Canada, and Norway, soliciting their demographics, practice description, history of musculoskeletal issues, potential causes of these symptoms, and proposed suggestions to address these injuries. The prevalence of various musculoskeletal symptoms was calculated, and predictors of these symptoms were evaluated using multivariate logistic regression. RESULTS: The survey was sent to 3314 plastic surgeons, with 865 responses (response rate, 26.1 percent); 78.3 percent of plastic surgeons had musculoskeletal symptoms, most commonly in the neck, shoulders, and lower back. U.S. surgeons were significantly more likely to have musculoskeletal symptoms than Norwegian surgeons (79.5 percent versus 69.3 percent; p < 0.05); 6.7 percent of all respondents required surgical intervention for their symptoms. The most common causative factors were long surgery duration, tissue retraction, and prolonged neck flexion. The most common solutions cited were core-strengthening exercises, stretching exercises, and frequent adjustment of table height during surgery. CONCLUSIONS: Plastic surgeons are at high risk for work-related musculoskeletal injuries. Ergonomic principles can be applied in the operating room to decrease the incidence and severity of those injuries, and to avoid downstream sequelae, including the need for surgery. PMID- 29280889 TI - Defining Outcomes Articles for the Journal. PMID- 29280890 TI - Facial Contouring by Targeted Restoration of Facial Fat Compartment Volume: The Midface. PMID- 29280891 TI - Reply: Facial Contouring by Targeted Restoration of Facial Fat Compartment Volume: The Midface. PMID- 29280892 TI - Public Perception of Cosmetic Surgeons versus Plastic Surgeons: Increasing Transparency to Educate Patients. PMID- 29280893 TI - Reply: Public Perception of Cosmetic Surgeons versus Plastic Surgeons: Increasing Transparency to Educate Patients. PMID- 29280894 TI - Reply: The Split Pectoralis Flap: Combining the Benefits of Pectoralis Major Advancement and Turnover Techniques in One Flap. PMID- 29280895 TI - Three-Dimensional, Computer-Assisted, Three-Layer Models of the Face. PMID- 29280896 TI - Complications of Regional Anesthesia. PMID- 29280897 TI - Brugada Syndrome Induced by an Interscalene Block: A Case Report. AB - CASE: A 57-year-old woman with no noteworthy medical or surgical history underwent an interscalene block with bupivacaine in preparation for an arthroscopic rotator cuff repair. Following administration of the bupivacaine, the patient sustained a ventricular fibrillation arrest. After successful cardiopulmonary resuscitation, she was diagnosed with Brugada syndrome. An implantable cardioverter-defibrillator was placed, and the rotator cuff repair was performed 1 month later. CONCLUSION: Brugada syndrome is an abnormality of the cardiac conduction system that leads to cardiac arrhythmias. Several anesthetic agents trigger Brugada-like electrocardiographic abnormalities. To our knowledge, this is the first report of an interscalene block inducing Brugada syndrome. PMID- 29280898 TI - Knee Arthrodesis in a Patient with Charcot Neuroarthropathy Secondary to Familial Amyloid Polyneuropathy: A Case Report. AB - CASE: We report a rare case of severe Charcot neuroarthropathy of the knee secondary to familial amyloid polyneuropathy, which was treated surgically with a knee arthrodesis. This treatment allowed an early symptomatic and functional improvement and a short consolidation time without any major complications. CONCLUSION: Neuropathy is the earliest and most major burden in patients with familial amyloid polyneuropathy; it requires careful evaluation and adequate treatment aimed at preventing or slowing the progression of secondary damage, involving Charcot neuroarthropathy, that may occur. Surgical arthrodesis with antegrade intramedullary nailing may be appropriate in a patient with severe Charcot neuroarthropathy of the knee. PMID- 29280899 TI - Surgical Correction of Severe Kyphoscoliosis Associated with Crouzon Syndrome with Serious Postoperative Respiratory Problems: A Case Report. AB - CASE: A 12-year-old girl with Crouzon syndrome presented to our hospital with scoliosis (114 degrees ) and kyphosis from T8 to T12 (138 degrees ). After she had been in halo-gravity traction for 2 weeks, we performed posterior correction and fusion surgery from T3 to L3, with a posterior vertebral column resection of T10. She experienced postoperative respiratory failure and remained on a ventilator for 4 weeks. With rehabilitation, the respiratory function had recovered by postoperative week 8. At the 2-year follow-up, there was no loss of correction or any other complication. CONCLUSION: Serious perioperative respiratory complications may occur when a patient with Crouzon syndrome is treated surgically. PMID- 29280900 TI - Factors associated with the true location of ingested fishbones. AB - OBJECTIVES: Fishbone ingestion is a common problem worldwide, and the first step for managing this condition is to locate the fishbone precisely. However, until now, no study has analysed the true location of fishbone and its associated factors. Thus, this study identified the factors predicting the true location of fishbone and subsequently attempted to provide a management algorithm for fishbone ingestion. PATIENTS AND METHODS: This retrospective study was carried out at St Martin De Porres Hospital, Taiwan, between January 2015 and January 2016. All patients were diagnosed as having fishbone ingestion within the pharynx and underwent fishbone removal. RESULTS: This study included 198 consecutive patients with a mean age of 43.1 years (range: 1-84 years). The sensitivity of lateral neck radiography in the diagnosis of fishbone in the pharynx was only 22%. The fishbone locations were as follows: the tonsil in 72 (36.4%) patients, the tongue base/vallecula in 112 (56.6%) and the hypopharynx in 14 (7.0%). Multiple logistic regression analysis showed that patient age and fishbone length were significant independent risk factors associated with the true location of fishbone ingestion. Among all patients, fishbone was removed transorally under direct vision in 73 (36.9%) patients and using flexible nasopharyngoscopy in 125 (63.1%) patients. CONCLUSION: Patient age and fishbone length are important independent factors associated with the location of ingested fishbone. Lateral neck radiography is not beneficial for diagnosing fishbone ingestion within the pharynx. Flexible nasopharyngoscopy, by contrast, is an important method for the diagnosis and treatment of fishbone ingestion within this location. PMID- 29280901 TI - Measuring Organizational Capacity to Accelerate Health Care Innovation in Academic Health Centers. AB - In an era of rising clinical costs and shrinking federal research dollars, the survival of the academic health center may depend on its capacity to cultivate high-impact innovations in care delivery on an accelerated basis. Yet, the health sciences literature offers little guidance regarding the key organizational determinants most likely to facilitate such innovation. We report on the conceptualization, development, and preliminary testing of a new 21-item Accelerated Healthcare Innovation Capacity scale for addressing that knowledge gap. Instrument development followed a standardized process, including expert panel testing of the new scale's content relevance validity. A sample (N = 53) of academic health center administrators, clinicians, and faculty affiliated with a single organization volunteered to complete the Accelerated Healthcare Innovation Capacity scale in survey form. Data were analyzed to evaluate scale reliability, internal consistency, and construct validity. High-expert agreement (overall S CVI of 0.91) was obtained on content relevance validity. Cronbach alpha for the scale was 0.941. Exploratory factor analysis confirmed the theoretical soundness of the scale's conceptual framework, which showed high-impact health care innovation support to be a complex, multidimensional concept involving key facilitating factors across 3 major constructs-that is, Culture, Structure, and Policy-with implications for future research and managerial practice, particularly for staff development educators engaged in evaluating quality management and organizational change strategies. PMID- 29280902 TI - Assessing the Organizational Characteristics Influencing Quality Improvement Implementation in Saudi Hospitals. AB - BACKGROUND: The health care system in Saudi Arabia has serious problems with quality and safety that can be reduced through systematic quality improvement (QI) activities. Despite the use of different QI models to improve health care in Saudi hospitals during the last 2 decades, consistent improvements have not yet been achieved and the results are still far below expectations. This may reflect a problem in introducing and implementing the QI models in the local contexts. The objective of this study is to assess the extent of QI implementation in Saudi hospitals and to identify the organizational characteristics that make Saudi hospitals particularly challenging for QI. Understanding these characteristics can inform efforts to improve them and may lead to more successful implementation. METHODS: A mixed-methods approach was conducted using 2 data collection tools: questionnaires and interviews. The quantitative phase (questionnaires) aimed to uncover the current level of QI implementation in Saudi hospital as measured by 7 critical dimensions adapted from the literature. The qualitative phase (interviews) aimed to understand the organizational characteristics that impede or underpin QI in Saudi hospitals. RESULTS AND DISCUSSION: The QI implementation was found to be significantly poor across the 7 dimensions with average score ranging between 22.80 +/- 0.57 and 2.11 +/- 0.69 on a 5-point Likert scale and with P value of less than .05. We also found that the current level of QI implementation helped Saudi hospitals neither to improve "customer satisfaction" nor to achieve measurable improvements in "quality results" scoring significantly low at 2.11 +/- 0.69 with P value of .000 and 2.47 +/- 0.57 with P value of .000, respectively. Our study confirms the presence of a multitude of organizational barriers that impede QI in Saudi hospitals. These are related to organizational culture, human resources management, processes and systems, and structure. These 4 were found to have the strongest impact on QI in Saudi hospitals. CONCLUSION: It appears that the most important contributing factors to the successful implementation of QI in Saudi hospitals are proper human resources utilization and effective quality management. Through careful planning, change management, proper utilization of human resources, supportive quality information systems, focus on processes and systems, structural support, and an organizational culture that is compatible with QI philosophy, Saudi hospitals will be more capable in achieving sustained measureable improvements in the quality and safety of patient care. PMID- 29280903 TI - Framework for Research on Implementation of Process Redesigns. AB - BACKGROUND: Complex system interventions benefit from close attention to factors affecting implementation and resultant outcomes. This article describes a framework for examining these factors in process redesign (PR) and for assessing PR outcomes. METHODS: Using literature scans and expert comment on draft frameworks based on the Consolidated Framework for Implementation Research, a team of researchers developed the PR framework for the Agency for Healthcare Research and Quality. As a case study, an independent team of researchers in a large care system subsequently applied the PR framework to implementation of Lean based primary care redesigns. RESULTS: The PR framework adds 2 domains to the Consolidated Framework for Implementation Research, focused on relevant measures of implementation and outcomes, as well as some new constructs to the Consolidated Framework for Implementation Research. Using the PR framework to guide a study of primary care PR, researchers found that the health care reform environment encouraged staff recognition of need for redesign, but physicians worried about key redesign issues, including colocation with care team partners and the competencies of the individuals assigned to manage new workflows. Team member acceptance of the redesign was also influenced by other features of the implementation process and contextual features, including the decision style of the local clinic. CONCLUSIONS: The PR framework helped guide the qualitative study and aided researchers in informing their leadership about critical issues affecting PR implementation. PMID- 29280904 TI - Rapid Patient Discharge Contribution to Bed Surge Capacity During a Mass Casualty Incident: Findings From an Exercise With New York City Hospitals. AB - BACKGROUND: Mass casualty incidents may increase patient volume suddenly and dramatically, requiring hospitals to expeditiously manage bed inventories to release acute care beds for disaster victims. Electronic patient tracking systems combined with unit walk-throughs can identify patients for rapid discharge. The New York City (NYC) Department of Health and Mental Hygiene's 2013 Rapid Patient Discharge Assessment (RPDA) aimed to determine the maximum number of beds NYC hospitals could make available through rapid patient discharge and to characterize discharge barriers. METHODS: Unit representatives identified discharge candidates within normal operations in round 1 and additional discharge candidates during a disaster scenario in round 2. Descriptive statistics were performed. RESULTS: Fifty-five NYC hospitals participated in the RPDA exercise; 45 provided discharge candidate counts in both rounds. Representatives identified 4225 patients through the RPDA: among these, 1138 (26.9%) were already confirmed for discharge; 1854 (43.9%) were round 1 discharge candidates; and 1233 (29.2%) were round 2 discharge candidates. These 4225 patients represented 21.4% of total bed capacity. Frequently reported barriers included missing prescriptions for aftercare or discharge orders. CONCLUSION: The NYC hospitals could implement rapid patient discharge to clear one-fifth of occupied inpatient beds for disaster victims, given they address barriers affecting patients' safe and efficient discharge. PMID- 29280905 TI - Ultrasound-Guided Peripheral Intravenous Catheters to Reduce Central Venous Catheter Use on the Inpatient Medical Ward. AB - PURPOSE: The traditional technique of placing a peripheral intravenous (IV) catheter is successful in most cases on inpatient wards. However, when the traditional method fails, a central venous catheter may be placed to maintain IV access. These catheters are associated with risks including central line associated bloodstream infection. METHODS: We evaluated the effectiveness and acceptability of an ultrasound-guided peripheral IV service to reduce the number of newly placed central venous catheters on an inpatient ward. Central venous catheters were counted daily on intervention and control wards using a standard protocol, and rates of newly placed catheters were compared using a Poisson regression model. Nurses were surveyed to assess acceptability and perceived benefit. RESULTS: We found a reduction in the rate of newly placed central venous catheters on the intervention unit compared with the control unit at 90 days: mean 0.47 versus 0.67 newly placed central venous catheters/day, but the difference was not significant (P = .08). Nurses were in favor of the ultrasound guided IV service, with perceived benefit to their patients. CONCLUSION: Ultrasound-guided peripheral IV might reduce unnecessary central venous catheters on general inpatient wards. A portable ultrasound used for this purpose was found to be acceptable by nursing staff. PMID- 29280906 TI - Evaluating and Improving the Efficiency of Patient Flow in the Bronchoscopy Suite in a Tertiary Care Center: A QI Project! AB - PURPOSE: The bronchoscopy suite is where pulmonologists perform the majority of their procedures like bronchoscopy, endobronchial ultrasound, and navigational bronchoscopy among others. Faculty and fellows in our division have reported multiple delays in the procedure start time in our bronchoscopy. OBJECTIVES: Objectives of the study were (1) to identify the areas of delays in procedure start time, (2) to identify potential high-yield areas of interventions to reduce delays, (3) to assess the impact of interventions on efficacy of bronchoscopy suit. METHODS: We have conducted a quality improvement project aiming at identifying areas of delays and implemented an intervention aiming at minimizing those delays. We retrospectively collected the data about the patient flow from arrival to hospital to discharge between June and August 2016. We used fishbone technique to identify the potential reasons for delay in procedures and to identify low-effort high-yield areas. Our intervention was raising awareness and education among the personnel and designing the process to reduce time delays and improve efficacy. We collected the data about the patient flow prospectively after the invention was implemented. RESULTS: The study showed that 76.4% of our preintervention procedures had a late start time. The postintervention results revealed a statistically significant reduction in the procedure late start times by 24.4% (P = .02). Signing the procedure H and P was also identified as a major area of delay, which has improved postintervention (65.5 % vs 33.3%, P = 0.017). CONCLUSION: The faculty and fellows' perceptions were translated into objective data, which serves as a first step in our division to improve the patient flow process in the bronchoscopy suite. Areas of delays were identified and our intervention resulted in significant improvement, but more work needs to be done to achieve a more efficient patient flow in the bronchoscopy suite while maintaining a safe patient care. PMID- 29280907 TI - A Quality Improvement Initiative to Reduce "Out-of-ICU" Cardiopulmonary Arrests in a Tertiary Care Hospital in India: A 2-Year Learning Experience. AB - QUALITY PROBLEM OR ISSUE: To assess impact of medical emergency team (MET) in reducing "out-of-ICU" cardiopulmonary arrests and identify barriers to its optimal utilization. INITIAL ASSESSMENT: Frequently observed critical clinical signs and laboratory values of "out-of-ICU" crashes were used to develop Amrita Early Warning Criteria. CHOICE OF SOLUTION: A physician-led MET was established to respond to code MET, activated by a primary nurse. IMPLEMENTATION: Rates of "out-of-ICU" cardiopulmonary arrests per 1000 admissions were compared in pre-MET (2013-2014) and post-MET periods (2014-2016) along with disposition following MET and mortality. Descriptive statistics and logistic regression were used for comparative analysis. EVALUATION: For continued quality improvement, a Likert agreement scale questionnaire collated the nurse's feedback on MET. 386 Code MET were recorded with an activation rate of 18.8 per 1000 inpatients for 2014-2016. Common MET triggers were desaturation (53%), seizure (10%), and syncope (9%). Seventy-one percent of activations were attended within 5 minutes, with 45% reported during nurse's night shift hours. Medical emergency team interventions resulted in 59% being shifted to ICU. In the "post-MET" period, "Cold Blue" dose reduced from 6.9 in 2013-2014 to 2.6 (P = .0002) in 2014-2015 and 3.2 (P = .01) in 2015-2016. Ninety-three percent of the Code Blues with prior MET calls were "delayed MET" and 28% of the Code Blues without prior MET activation were "missed MET." Nurse's feedback revealed that 46% lacked knowledge of correct MET activation process while 31% expressed a fear of reprisal for inappropriate activation. LESSONS LEARNED: Although MET intervention was successful in significantly reducing "out-of-ICU" Code Blues, focused training of nurses is required for continued quality improvement. PMID- 29280908 TI - Expanding the Presence of Primary Services at Rapid Response Team Activations: A Quality Improvement Project. AB - Rapid response teams (RRTs) were implemented to provide critical care services for deteriorating patients outside of intensive care units. To date, research on RRT has been conflicting, with some studies showing significant mortality benefit and reduction in cardiac arrest events and others showing no benefit. However, studies have consistently showed improved outcomes when RRTs work closely with primary services. Baseline data analysis at our institution found that primary services were present only on 50% of RRT activations. This quality improvement project aimed to improve the presence of primary services during RRT activations by 25%. With a survey, the main barrier that prevented primary services to be present was identified as the primary services' failure to recognize them as a crucial part of the RRT. Education tools and in-person sessions were implemented reinforcing the importance of primary services presence during RRT activations. The intervention leads to increasing presence of primary services at RRT activations, transfers to higher level of care, and changes in code status. However, there was no difference in hospital or intensive care unit length of stay or in survival. PMID- 29280909 TI - Establishing an Ambulatory Quality and Safety Oversight Structure. PMID- 29280910 TI - Addressing Social Determinants to Improve Community Health. PMID- 29280914 TI - Anemia and coronary artery disease: pathophysiology, prognosis, and treatment. AB - The mechanisms, pathophysiology, and treatment of anemia in coronary artery disease (CAD) are complex. The hemodynamic changes found in the acute anemic state may contribute to progressive arterial wall and left ventricular hypertrophy if the anemic state persists chronically. We will examine the evidence for anemia as an independent risk factor for CAD events and cardiovascular mortality after percutaneous coronary intervention. We will also investigate the thresholds for appropriate blood transfusion in patients with CAD, as well as the cardiovascular outcomes associated with the utilization of a liberal versus conservative blood transfusion strategy. Although there is evidence supporting the use of intravenous iron replacement in patients with congestive heart failure, we will demonstrate the lack of evidence for iron replacement in patients with CAD. Finally, we will examine the evidence for increased cardiovascular mortality and venous thromboembolic events with the use of erythropoietin-stimulating agents in patients with CAD. PMID- 29280915 TI - Bladder cancer risk in users of selected drugs for cardiovascular disease prevention. AB - The aim of this study was to investigate the relation between bladder cancer risk and the use of selected drugs for cardiovascular disease (CVD) prevention, such as aspirin, statins, and calcium channel blockers (CCBs). We analyzed data from a multicentric case-control study carried out in Italy between 2003 and 2014, including 690 bladder cancer cases and 665 hospital controls. Odds ratios (ORs) of bladder cancer and corresponding 95% confidence intervals (CIs) were estimated using unconditional multiple logistic regression models. The ORs for bladder cancer were 1.21 (95% CI: 0.87-1.68) for regular use of aspirin, 0.72 (95% CI: 0.54-0.97) for use of any CCBs, and 1.32 (95% CI: 0.87-1.99) for use of any statins. A slight inverse association was found with duration of use of CCBs, whereas no consistent association was found with duration of use, age at first use, and frequency for aspirin and statin use, or with indication of use for aspirin (as an analgesic or, for CVD prevention). No significant association was found for various combinations of drugs or for all drugs combined (OR=1.23, 95% CI: 0.31-4.85). Our data indicate the lack of a relevant association between the use of selected drugs for CVD prevention and bladder cancer risk, although suggest a potential favorable role for CCBs. PMID- 29280916 TI - Erlotinib for coexisting typical bronchial carcinoid and advanced lung adenocarcinoma: does the epidermal growth factor receptor mutation status matter? AB - Adenocarcinoma (AC) is the most common type of primary pulmonary malignancy. Lung carcinoid, however, is a rare neuroendocrine tumor. Their coexistence is extremely uncommon. We report the unique case of synchronous advanced lung AC of the right upper lobe (stage IIIB) and typical endobronchial carcinoid tumor in the contralateral lower lobe in a 49-year-old white female who had never smoked. PET-computed tomography scan revealed a fluorine-18-fluorodeoxyglucose-avid AC lesion, whereas the carcinoid tumor was fluorine-18-fluorodeoxyglucose occult. After two lines of platinum-based combination chemotherapies and radiotherapy, the AC progressed, and oral tyrosine kinase inhibitor therapy with erlotinib was initiated in third line. On erlotinib, the AC remained stable for 50 months until disease progression, whereas the carcinoid completely regressed. Molecular testing of the rebronchoscopied AC revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene, whereas the carcinoid was retrospectively EGFR mutation negative. The patient eventually succumbed to ileus caused by intra-abdominal spread of disease, surviving a remarkable 80 months with good performance status throughout most of the follow-up period. To the best of our knowledge, this is the first reported case of synchronous primary lung cancers with different EGFR mutation status, describing an unexpected response of an EGFR-wild-type carcinoid to third-line erlotinib. PMID- 29280917 TI - Long-Term Variability of Distortion-Product Otoacoustic Emissions in Infants and Children and Its Relation to Pediatric Ototoxicity Monitoring. AB - OBJECTIVE: Distortion-product otoacoustic emissions (DPOAEs) provide a rapid, noninvasive measure of outer hair cell damage associated with chemotherapy and are a key component of pediatric ototoxicity monitoring. Serial monitoring of DPOAE levels in reference to baseline measures is one method for detecting ototoxic damage. Interpreting DPOAE findings in this context requires that test retest differences be considered in relation to normal variability, data which are lacking in children. This study sought to (1) characterize normal test-retest variability in DPOAE level over the long time periods reflective of pediatric chemotherapy regimens for a variety of childhood ages and f2 primary frequencies using common clinical instrumentation and stimulus parameters; (2) develop level shift reference intervals; and (3) account for any age-related change in DPOAE level or measurement error that may occur as the auditory system undergoes maturational change early in life. DESIGN: Serial DPOAE measurements were obtained in 38 healthy children (25 females and 13 males) with normal hearing and ranging in age from one month to 10 years at the initial (baseline) visit. On average, children were tested 5.2 times over an observation period of 6.5 months. Data were collected in the form of DP grams, in which DPOAE level was measured for f2 ranging from 1.4 to 10 kHz, using a fixed f2/f1 ratio of 1.22 and stimulus level of 65/55 dB SPL for L1/L2. Age effects on DPOAE level and measurement error were estimated using Bayesian regression of the longitudinal data. The raw and model-based distribution of DPOAE test-retest differences were characterized using means and standard error of the measurement for several ages and f2's. RESULTS: DPOAE test-retest differences for the children in this study are at the high end of those previously observed in adults, as reflected in the associated shift reference intervals. Further, although we observe substantial child specific variation in DPOAE level, the pattern of age-related changes is highly consistent across children. Across a wide range of f2's, DPOAE level decreases by 3 to 4 dB from 1 to 13 months of age followed by a more gradual decline of <1 dB/year. An f2 of 6 kHz shows the smallest decrease during the early rapid maturation period. DPOAE measurement error is fairly constant with age. It is 3 to 4 dB at most f2's and is greater (indicating poorer reliability) at 1.5, 8, and 10 kHz. CONCLUSIONS: DPOAE level decreases with childhood age, with the greatest changes observed in the first year of life. Maturational effects during infancy and greater measurement error at very low and high f2's affect test retest variability in children. An f2 of 6 kHz shows minimal maturation and measurement error, suggesting it may be an optimal sentinel frequency for ototoxicity monitoring in pediatric patients. Once validated with locally developed normative data, reference intervals provided herein could be used to determine screen fail criteria for serial monitoring using DPOAEs. Employing state-of-the-art calibration techniques might reduce variability, allowing for more sensitive screen fail criteria. PMID- 29280918 TI - Association between celiac disease and schizophrenia: a meta-analysis. AB - BACKGROUND/OBJECTIVE: Recent epidemiologic studies have suggested that patients with celiac disease might be at an increased risk of schizophrenia. However, the data on this risk remain inconclusive. This meta-analysis was conducted with the aim to summarize all available evidence. METHODS: A literature search was carried out using MEDLINE and Embase database from inception to June 2017. Studies that compared the risk of schizophrenia among patients with celiac disease versus individuals without celiac disease were included. Pooled odds ratio and 95% confidence interval were calculated using a random-effect, generic inverse variance method. RESULTS: Of the 284 retrieved studies, four met our eligibility criteria and were included in the analysis. We found a higher risk of schizophrenia among patients with celiac disease compared with individuals without celiac disease with the pooled odds ratio of 2.03 (95% confidence interval: 1.45-2.86). The statistical heterogeneity of this study was insignificant (I=0%). CONCLUSION: This systematic review and meta-analysis found a significantly higher risk of schizophrenia among patients with celiac disease. PMID- 29280919 TI - Short article: Presence, extent and location of pancreatic necrosis are independent of aetiology in acute pancreatitis. AB - OBJECTIVE: The most common aetiologies of acute pancreatitis (AP) are gallstones, alcohol and idiopathic. The impact of the aetiology of AP on the extent and morphology of pancreatic and extrapancreatic necrosis (EXPN) has not been clearly established. The aim of the present study was to assess the influence of aetiology on the presence and location of pancreatic necrosis in patients with AP. PATIENTS AND METHODS: We carried out a post-hoc analysis of a previously established multicentre cohort of patients with AP in whom a computed tomography was available for review. Clinical data were obtained from the medical records. All computed tomographies were revised by the same expert radiologist. The impact of aetiology on pancreatic and EXPN was calculated. RESULTS: In total, 159 patients with necrotizing pancreatitis were identified from a cohort of 285 patients. The most frequent aetiologies were biliary (105 patients, 37%), followed by alcohol (102 patients, 36%) and other aetiologies including idiopathic (78 patients, 27%). No relationship was found between the aetiology and the presence of pancreatic necrosis, EXPN, location of pancreatic necrosis or presence of collections. CONCLUSION: We found no association between the aetiology of AP and the presence, extent and anatomical location of pancreatic necrosis. PMID- 29280920 TI - Liver transplantation for hepatocellular carcinoma within the Milan criteria versus the University of California San Francisco criteria: a comparative study. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Currently, liver transplantation (LT) for HCC is the only hope for cure from the tumor and from end-stage liver disease (ESLD). The organ pool shortage in deceased donor LT and the donor-related ethical concerns in living donor LT necessitate the use of rigorous criteria for LT for HCC. In this respect, two main criteria for LT for HCC were implemented with good outcome, namely, the Milan and the University of California San Francisco criteria. Comparison of the outcome of LT for HCC using either of the two criteria has seldom been reported in the literature. PATIENTS AND METHODS: Eighty-eight patients underwent LT between August 2003 and end of July 2013 for the presence of pathologically proven pure HCC lesions at our institution. Cases of pediatric LT or liver retransplantation were excluded from this study. Cases with mixed HCC and cholangiocarcinoma were excluded from this study. RESULTS: Eighty-eight patients underwent LT between August 2003 and July 2013 for the presence of pathologically proven pure HCC lesions at our institution. The mean follow-up duration was 45+/-30.9 months. HCC recurrence was related significantly to the presence of vascular invasion and degree of differentiation of HCC lesion (P value of 0.0001 and 0.001, respectively). CONCLUSION: Patient and tumor free survival did not differ significantly between patients within Milan or University of California San Francisco criteria or beyond both criteria. Vascular invasion and poor differentiation are still the most influential factors for post transplant long-term outcomes in HCC patients. PMID- 29280921 TI - Impact of steatosis and inflammation definitions on the performance of NASH tests. AB - BACKGROUND AND AIM: One of the unmet needs in subjects with metabolic risks is the prediction of metabolic liver disease by noninvasive tests. The construction of performant tests is dependent on the appropriateness of the histological reference definition. The aim of this study was to analyze the limitations of similar European (Fatty Liver Inhibition of Progression) and USA (Clinical Research-Network) standard definitions and their impact on the construction of tests. METHODS: We hypothesized that a simpler histological definition of non alcoholo steato-hepatitis (NASH), which does not require the presence of steatosis and the presence of both lobular inflammation and ballooning, should improve the concordance rates with previously validated blood tests. We reviewed the landmark studies in metabolic liver disease, sources of the standard definitions, and we compared the adequacy of these standards to other possible definitions in 1081 subjects with biopsies, by concordance and accuracy rates. RESULTS: The limitations of standard definitions included the presence of appropriate controls in only 6.6% of landmark studies, an arbitrary definition of steatosis and NASH covering only four (15%) out of 27 possible combinations of features, compared with 18 (67%) for a simplified NASH definition, which did not require steatosis. A total of 39/1081 (3.6%) cases were not identified by standard definition, but were identified by the simplified definition as significant active disease, including 15 cases with significant fibrosis. The simplified definition increased the kappa concordance (P<0.0001) between test prediction and histological reference. CONCLUSION: A simplified definition of NASH could help in the construction of biomarkers with higher performances. PMID- 29280922 TI - Effects of liver cirrhosis and patient condition on clinical outcomes in intrahepatic cholangiocarcinoma: a retrospective analysis of 156 cases in a single center. AB - OBJECTIVE: The incidence of intrahepatic cholangiocarcinoma (iCCA) has been increasing over the past few decades. Liver cirrhosis is an independent risk factor for the development of iCCA. This study aimed to examine the prognostic impact of liver cirrhosis and patient condition on the treatment of iCCA. PATIENTS AND METHODS: We retrospectively analyzed the cases of 156 patients diagnosed with iCCA between 1990 and 2014 in our center. Patients were divided into subgroups depending on the presence and severity of liver cirrhosis and the type of treatment. Clinical data, patient characteristics, and overall survival were compared between these groups. RESULTS: Forty-seven (30%) of 156 patients had liver cirrhosis, predominantly with Child-Pugh scores A (n=27) and B (n=12). The median survival differed between patients receiving tumor resection (34 months), chemotherapy (10 months), and best supportive care (2 months). An Eastern Cooperative Oncology Group Performance Status score more than 1 was a predictor of poor survival in all patients (P<0.001), independent of the presence of cirrhosis. Resection could be performed less frequently in cirrhotic patients (6 vs. 31 patients; P=0.04). If resection was performed, the presence of cirrhosis A/B did not influence survival. Cirrhosis A/B did not influence the outcome in patients receiving chemotherapy either. In cirrhotic patients receiving chemotherapy, cancer antigen 19-9 levels above 129 U/ml were associated with a significantly shorter survival (22.5 vs. 3 months, P=0.0003). CONCLUSION: The presence of liver cirrhosis in iCCA has been underestimated. There was no difference in survival between noncirrhotic patients and patients with compensated cirrhosis. Patients' general condition seems to be of more prognostic value in the treatment of iCCA than the presence of cirrhosis. Therefore, the presence of cirrhosis A/B should not prevent patients with a good Eastern Cooperative Oncology Group Performance Status score from receiving tumor resection or chemotherapy. PMID- 29280923 TI - Local Anesthetic Systemic Toxicity in Total Joint Arthroplasty: Incidence and Risk Factors in the United States From the National Inpatient Sample 1998-2013. AB - BACKGROUND: Local anesthetic systemic toxicity (LAST) is a rare and potentially devastating complication of regional anesthesia. Single-institution registries have reported a decreasing incidence, but these results have limited broad applicability. A recent study using a US database found a relatively high incidence of LAST. We used the National Inpatient Sample, a US database of inpatient admissions, to identify the national incidence and associated risk factors for LAST in total joint arthroplasties. METHODS: In this retrospective study, we studied patients undergoing hip, knee, or shoulder arthroplasty, from 1998 to 2013, with an adjunct peripheral nerve blockade. We used a multivariable logistic regression to identify patient conditions, hospital level variables, and procedure sites associated with LAST. RESULTS: A total of 710,327 discharges met inclusion criteria. The average adjusted incidence was 1.04 per 1000 peripheral nerve blocks, with decreasing trend over the 15-year study period (odds ratio [OR], 0.90; P = 0.002). Shoulder arthroplasty (OR, 4.35; P = 0.0001) compared with knee or hip arthroplasty and medium-size (OR, 3.34; P = 0.003) and large size (OR, 2.40; P = 0.025) hospitals as compared with small hospitals were associated with increased odds of LAST. CONCLUSIONS: The incidence of LAST nationally in total joint arthroplasty with adjunct nerve blocks is similar to recent estimates from academic centers, with a small decreasing trend through the study period. Despite an overall low incidence rate, practitioners should continue to maintain vigilance for manifestations of LAST, especially as the use of regional anesthesia continues to increase. PMID- 29280925 TI - Contemporary Utilization of Resuscitative Thoracotomy: Results From the AAST Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) Multicenter Registry. AB - INTRODUCTION: Several reviews of resuscitative thoracotomy (RT) use over the last five decades have been conducted, most recently the evidence-based practice management guideline (PMG) of the Eastern Association for the Surgery of Trauma (EAST). The present study was designed to examine contemporary RT utilization and outcomes compared with historical data (n = 10,238) from the EAST PMG review from published series 1974 to 2013. METHODS: The American Association for the Surgery of Trauma Aortic Occlusion for Trauma and Acute Care Surgery (AORTA) registry was utilized to identify patients undergoing RT in the emergency department (ED) from November 2013 to December 2016. Demographics, injury data, physiologic presentation, and outcomes were reviewed and compared with those of the EAST PMG review. RESULTS: Three-hundred ten RT patients from 16 contributing AORTA centers were identified. The majority were injured by penetrating mechanisms (197/310, 64% [gunshot (163/197, 83%)]). Signs of life (SOL) (organized electrical activity, pupillary response, spontaneous movement, or appreciable pulse/blood pressure) were present on arrival in 47% (147/310). When compared with the EAST PMG results, there was no difference in either hospital survival (5% vs. 8%) or neurologically intact survival between historical controls or AORTA registry patients in any category combination of mechanism/anatomic location/presenting signs of life. Blunt injuries W/O SOL on admission continue to constitute 14% (45/310) of RTs in the ED, without documented survivors. CONCLUSION: Comparison of historical RT controls to more contemporary patients from the AORTA registry suggests that practices and outcomes following RT have not changed. Despite a wealth of accumulated data over several decades, RT continues to be performed for patients after blunt mechanisms of injury who present W/O SOL despite lack of demonstrated hope for survival benefit. PMID- 29280926 TI - Critical Illness-Related Corticosteroid Insufficiency in Cardiogenic Shock Patients: Prevalence and Prognostic Role. AB - BACKGROUND: Cardiogenic shock shares with septic shock common hemodynamic features, inflammatory patterns, and most likely similar complications such as critical illness-related corticosteroid insufficiency. The aim of this study was to evaluate the prevalence of critical illness-related corticosteroid insufficiency in cardiogenic shock patients and to secondarily assess its prognostic value on 90-day mortality. METHODS: A single-center prospective observational study conducted over a 3-year period and including all patients with cardiogenic shock. Main exclusion criteria were patients with prior cardiac arrest, sepsis, ongoing corticosteroid therapy, and etomidate administration. A short corticotropin test was performed in the first 24 h following admission. Serum cortisol levels were measured before (T0) and 60 min (T60) after administration of 250 MUg of cosyntropin. Critical illness-related corticosteroid insufficiency was defined according to the 2017 consensus definition (basal total cortisol<10 MUg.dL or a delta cortisol T60-T0<9 MUg.dL) as well as the thresholds published in 2016 in cardiogenic shock patients associated with worst prognosis (basal total cortisol>29 MUg.dL and delta cortisol T60-T0<17 MUg.dL). RESULTS: Seventy-nine consecutive patients hospitalized in intensive care for cardiogenic shock met the inclusion criteria. Overall mortality was 43% at day 90. Forty-two percent had critical illness-related corticosteroid insufficiency using the 2017 consensus definition and 32% using the 2016 cardiogenic shock thresholds. Presence of critical illness-related corticosteroid insufficiency was not an independent factor associated with 90-day mortality irrespective of the thresholds used. CONCLUSION: Critical illness-related corticosteroid insufficiency is a frequent occurrence in medical cardiogenic shock. However, in this study, such insufficiency was not associated with prognosis. PMID- 29280927 TI - Hydrogen Inhalation is Superior to Mild Hypothermia for Improving Neurological Outcome and Survival in a Cardiac Arrest Model of Spontaneously Hypertensive Rat. AB - BACKGROUND: Postcardiac arrest syndrome is the consequence of whole-body ischemia reperfusion events that lead to multiple organ failure and eventually to death. Recent animal studies demonstrated that inhalation of hydrogen greatly mitigates postresuscitation myocardial dysfunction and brain injury. However, the influence of underlying heart disease on the efficacy of hydrogen is still unknown. In the present study, we investigated the effects of hydrogen inhalation on neurological outcome and survival in a cardiac arrest model of spontaneously hypertensive rat (SHR). METHODS: Cardiopulmonary resuscitation was initiated after 4 min of untreated ventricular fibrillation in 40 SHRs. Immediately after successful resuscitation, animals were randomized to be ventilated with 98% oxygen and 2% nitrogen under normothermia (Ctrl), 2% nitrogen under hypothermia (TH), 2% hydrogen under normothermia (H2), or 2% hydrogen under hypothermia (H2+TH) for 2 h. Hypothermia was maintained at 33 degrees C for 2 h. Animals were observed up to 96 h for assessment of survival and neurologic recovery. RESULTS: No statistical differences in baseline measurements were observed among groups and all the animals were successfully resuscitated. Compared with Ctrl, serum cardiac troponin T measured at 5 h and myocardial damage score measured at 96 h after resuscitation were markedly reduced in H2, TH, and H2+TH groups. Compared with Ctrl and TH, astroglial protein S100 beta measured during the earlier postresuscitation period, and neurological deficit score and neuronal damage score measured at 96 h were considerably lower in both H2 and H2+TH groups. Ninety-six hours survival rates were significantly higher in the H2 (80.0%) and H2+TH (90.0%) groups than TH (30.0%) and to Ctrl (30.0%). CONCLUSIONS: Hydrogen inhaling was superior to mild hypothermia for improving neurological outcome and survival in cardiac arrest and resuscitation model of systemic hypertension rats. PMID- 29280924 TI - Metabolomics and Precision Medicine in Trauma: The State of the Field. AB - Trauma is a major problem in the United States. Mortality from trauma is the number one cause of death under the age of 45 in the United States and is the third leading cause of death for all age groups. There are approximately 200,000 deaths per year due to trauma in the United States at a cost of over $671 billion in combined healthcare costs and lost productivity. Unsurprisingly, trauma accounts for approximately 30% of all life-years lost in the United States. Due to immense development of trauma systems, a large majority of trauma patients survive the injury, but then go on to die from complications arising from the injury. These complications are marked by early and significant metabolic changes accompanied by inflammatory responses that lead to progressive organ failure and, ultimately, death. Early resuscitative and surgical interventions followed by close monitoring to identify and rescue treatment failures are key to successful outcomes. Currently, the adequacy of resuscitation is measured using vital signs, noninvasive methods such as bedside echocardiography or stroke volume variation, and other laboratory endpoints of resuscitation, such as lactate and base deficit. However, these methods may be too crude to understand cellular and subcellular changes that may be occurring in trauma patients. Better diagnostic and therapeutic markers are needed to assess the adequacy of interventions and monitor responses at a cellular and subcellular level and inform clinical decision-making before complications are clinically apparent. The developing field of metabolomics holds great promise in the identification and application of biochemical markers toward the clinical decision-making process. PMID- 29280928 TI - Thrombin Provokes Degranulation of Platelet alpha-Granules Leading to the Release of Active Plasminogen Activator Inhibitor-1 (PAI-1). AB - BACKGROUND: The balance of fibrinolytic mediators is crucial to the survival of the critically ill patient, with tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) playing significant roles. While elevated levels of PAI-1 are associated with increased morbidity and mortality, the source of this PAI-1 remains elusive. Platelets contain 90% of circulating plasma PAI-1, however, their ability to release active PAI-1 is controversial. We hypothesize platelets contain active PAI-1 in alpha-granules capable of immediate degranulation when exposed to high concentrations of thrombin. METHODS: In vitro apheresis platelets were stimulated with thrombin (1 IU/mL, 5 IU/mL) followed by the collection of supernatant (5-120 min). Supernatant and lysate PAI-1 was measured by ELISA. The experiment was repeated in the presence of t-PA followed by measurement of t-PA:PAI-1 complex measurement by ELISA. Finally, healthy whole blood underwent dilution with control and thrombin-treated platelet lysate followed by thrombelastography (TEG) in a t-PA-stimulated TEG. RESULTS: Thrombin provoked immediate near-complete degranulation of PAI-1 from alpha-granules (median 5m 5 IU/mL thrombin 125.1 ng/mL, 1 IU/mL thrombin 114.9 ng/mL, control 9.9 ng/mL). The released PAI-1 rapidly complexed with t-PA, with a 4-fold increase in complex formation in the thrombin-treated supernatant. Conversely, PAI-1 in the control lysate demonstrated a 6-fold increase in complex formation compared with thrombin lysate. Last, control platelet lysate inhibited t-PA induced fibrinolysis by TEG (median LY30 control 15m 7.9%), while thrombin treated platelet lysates, after PAI-1 degranulation, were unable to affect the fibrinolysis profile (median LY30 5 IU/mL 28.5%, 1 IU/mL 12.4%). CONCLUSION: Thrombin provokes rapid alpha-degranulation of active PAI-1, capable of complexing with t-PA and neutralizing t-PA-induced fibrinolysis by TEG. PMID- 29280929 TI - Lumbar Interbody Fusion: A Historical Overview and a Future Perspective. AB - : : In this historical study we present an overview of lumbar interbody fusion surgery, which is one of the most commonly performed instrumented spinal fusion surgeries. The present article focuses on the history of lumbar interbody fusion surgery, starting from the foundation which was laid in the 19th and 20th century until today. The development of material and techniques evolved from simple wiring to the combination of transforaminal interbody fusion with polyether ether ketone cages and pedicle screw fixation with poly axial screws. The possibilities of instrumented spinal fusion grew during the past 100 years, and a considerable increase in instrumented spinal surgery was seen over the past decades. Today, gain lies in perfection of techniques and deliberate indication and development of guidelines. Therefore, more standardized studies on instrumented spinal surgery are needed to be done and techniques should be personalized on the patients' specific needs. LEVEL OF EVIDENCE: N/A. PMID- 29280930 TI - Diagnostic Benefits of Axial-Loaded MRI Over Recumbent MRI in Obese LBP Patients. AB - STUDY DESIGN: Single center before-after case series study. OBJECTIVES: To determine when and in which kind of lower back pathologies, axial-loaded MRI provides additional benefit over recumbent MRI SUMMARY AND BACKGROUND DATA.: Systems simulating physiological axial loading of the spine in patients examined in the supine position have recently been introduced in clinical practice. However, indications for examinations with axial loading have yet to be clearly specified. METHODS: Ninety patients (46 males, 44 females, aged 20-90 years) with LBP underwent lumbar spine magnetic resonance imaging (MRI) with and without axial loading. MRI was performed in a supine position on a 1.5 T system using a compression device. A high-resolution 3D T2-weighted sequence was used for image acquisition. Clinical characteristics of patients were established using questionnaire surveys and demographic data. MR images were assessed for the appearance of changes after axial loading. After determining which patients showed significant changes, logistic regression analysis was performed with 15 independent variables (clinical, demographic, and imaging-related). RESULTS: After axial loading, 48.9% of patients showed additional changes. Multivariate analysis revealed that only obesity was a statistically significant predictor of the occurrence of changes (p < 0.05). After axial loading, 11 potentially clinically relevant changes appeared in 7 patients, the most common being absolute spinal stenosis (n = 7). CONCLUSIONS: Axial loading may increase the diagnostic value of lumbar spine MRI in patients with obesity and/or those with suspected spinal canal stenosis. LEVEL OF EVIDENCE: 4. PMID- 29280931 TI - Preinjury Patient Characteristics and Postinjury Neurological Status Are Associated With Mortality Following Spinal Cord Injury. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: This study investigates the association between spinal cord injuries (SCI) and post-injury mortality. SUMMARY OF BACKGROUND DATA: SCIs) are severe conditions treated in the acute trauma setting. Owing to neurological deficits, unstable spinal columns, and associated injuries, these patients often have complex inpatient hospitalizations with significant morbidity and mortality. It is assumed that a high rate of postinjury mortality would follow such severe injuries; however, the effect of SCI and its treatment on predictors of longevity remain largely unknown. METHODS: Patients seen at a regional referral center for SCI were reviewed from a prospectively maintained database. Four hundred and twenty-six patients with SCI and varying degrees of injury between 2004 and 2009 were collected. Injury characteristics, including injury severity score, level of SCI, and type of SCI were retrieved. To determine independent predictors of 5-year mortality, a logistic regression using patient and injury characteristics at the time of presentation was performed. RESULTS: Average age was 47.4 years (range: 14-95), and 74.5% (318/426) were male. Half of the cohort sustained low-energy mechanisms of injury (220/426; 52.4%). The 30-day, 90-day, 1-year, 2-year, and 5-year mortality rates in the SCI cohort were 6.6% (28/426), 9.2% (39/426), 12.0% (51/426), 15.0% (64/426), and 17.8%, respectively (76/426). Logistic regression demonstrated that increasing age (B = 1.06, P < 0.001), increasing ICU length-of-stay (B = 1.06; P = 0.002), decreased motor score at presentation (B = 0.98; P = 0.004), and lack of surgical intervention (B = 0.38; P < 0.001) were independent predictors of mortality at 5 years. CONCLUSION: There is substantial mortality associated with SCI. A significant proportion of the mortalities occurred acutely after injury. Mortality was associated with neurological deficit and severity of injury, as well as with preinjury patient characteristics. To combat this high rate of death, efforts are needed to address the concomitant disease processes associated with neurological deficits. LEVEL OF EVIDENCE: 3. PMID- 29280932 TI - Comparing Lumbar Disc Space Preparation With Fluoroscopy Versus Cone Beam Computed Tomography and Navigation: A Cadaveric Study. AB - STUDY DESIGN: Cadaveric study. OBJECTIVE: This cadaveric study sought to evaluate the efficacy of disc space preparation with cone beam-computed tomography with navigation (CBCT+N) for instrument placement compared with instrument placement with conventional fluoroscopy. SUMMARY OF BACKGROUND DATA: Disc space preparation from a transforaminal lumbar approach is challenging with respect to visualization, and surgeons currently rely on tactile feel and two-dimensional imaging in the operating room to assess instrument positioning. METHODS: Two orthopedic spine surgeons performed 40 disc space preparations after eight cadavers were randomly assigned to fluoroscopy versus CBCT+N. Digital images of each vertebral endplate were captured and the percent disc removed by area for the total disc and by quadrants was determined using digital imaging software. RESULTS: There were 20 lumbar disc levels prepared in the fluoroscopy group. There were 3 thoracolumbar, and 17 lumbar disc levels prepared in the experimental group. Percent disc removed relative to the total area of the disc, as determined by the digital imaging software, was higher in the CBCT+N group (P <= 0.0001). More disc was removed in both the anterior contralateral and posterior contralateral quadrants in the CBCT+N group (P = 0.0006 and P <= 0.0001 respectively). The intraclass correlation coefficient among blinded reviewers for percent disc removed was 0.759 (95% confidence interval, 0.587-0.866)]. There was no difference in time to complete disc space preparation, number of instrument passes, or number of endplate violations between the two groups (P = 0.28, P = 0.92, and P = 0.34 respectively). CONCLUSION: The results of this cadaveric investigation reveal that CBCT+N guidance may be used to assess instrument placement for interbody disc space preparation in a similar length of time, with no difference in instrument passes or endplate violations, in comparison with fluoroscopy. LEVEL OF EVIDENCE: 5. PMID- 29280933 TI - Percutaneous Kyphoplasty: Is Bilateral Approach Necessary? AB - STUDY DESIGN: A multicenter retrospective study of patients who underwent unilateral and bilateral balloon kyphoplasty. OBJECTIVE: The aim of this study was to compare the radiographic and clinical results of unilateral and bilateral balloon kyphoplasty to treat osteoporotic vertebral compression fractures. SUMMARY OF BACKGROUND DATA: Percutaneous kyphoplasty has long been used as a successful method in the treatment of osteoporotic vertebral compression fractures. Although the bilateral approach is considered to be the mainstay application of percutaneous kyphoplasty, the unilateral approach has also been shown to be sufficient and even more effective in some cases. METHODS: A total of 87 patients who underwent percutaneous kyphoplasty due to osteoporotic vertebral compression fractures between 2009 and 2016 were retrospectively evaluated and divided into two groups as patients who underwent unilateral or bilateral percutaneous kyphoplasty. Unilateral percutaneous kyphoplasty was performed in 36 and bilateral percutaneous kyphoplasty in 51 patients. The groups were compared in terms of clinical outcomes, radiological findings, and complications. Clinical outcomes were evaluated using Visual Analogue Scale and Oswestry Disability Index and the radiological findings were evaluated by comparing the preoperative and postoperative day 1 and year 1 values of anterior, middle, and posterior vertebral heights and kyphosis angle. RESULTS: Clinical improvement occurred in both groups but no significant difference was observed. In radiological workup, no significant difference was found between the groups in terms of improvements in vertebral heights and kyphosis angle. Operative time and the amount of cement used for the surgery were significantly lower in the patients that underwent unilateral kyphoplasty. CONCLUSION: Unilateral percutaneous kyphoplasty is as effective as bilateral percutaneous kyphoplasty both radiologically and clinically. Operative time and the amount of cement used for the surgery are significantly lower in unilateral kyphoplasty, which may play a role in decreasing complication rates. LEVEL OF EVIDENCE: 3. PMID- 29280935 TI - Letter to Indications for CT-Angiography of the Vertebral Arteries after Trauma. PMID- 29280934 TI - Causes and Timing of Unplanned 90-day Readmissions Following Spine Surgery. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of this study was to evaluate the causes, timing, and factors associated with unplanned 90-day readmissions following elective spine surgery. SUMMARY OF BACKGROUND DATA: Unplanned readmissions after spine surgery are costly and an important determinant of the value of care. Several studies using database information have reported on rates and causes of readmission. However, these often lack the clinical detail and actionable data necessary to guide early postdischarge interventions. METHODS: Patients undergoing elective spine surgery for degenerative disease at a major medical center were enrolled in a prospective longitudinal registry. Patient and surgery-specific characteristics, baseline, and 3-month patient-reported outcomes were prospectively recorded. Readmissions were reviewed retrospectively to establish the reason and time to readmission. A multivariable Cox proportional hazard model was created to analyze the independent effects of several factors on readmission. RESULTS: Of 2761 patients with complete 3-month follow-up, 156 had unplanned 90-day readmissions (5.6%). The most common reason was surgery-related (52%), followed by medical complications (38%) and pain (10%). Pain readmissions presented with a median time of 6 days. Medical readmissions presented at 12 days. Surgical complications presented at various times with wound complications at 6 days, cerebrospinal fluid leaks at 12 days, surgical site infections at 23 days, and surgical failure at 38 days. A history of myocardial infarction, osteoporosis, higher baseline leg and arm pain scores, longer operative duration, and lumbar surgery were associated with readmission. CONCLUSION: Nearly half of all unplanned 90-day readmissions were because of pain and medical complications and occurred with a median time of 6 and 12 days, respectively. The remaining 52% of readmissions were directly related to surgery and occurred at various times depending on the specific reason. This timeline for pain and medical readmissions represents an opportunity for targeted postdischarge interventions to prevent unplanned readmissions following spine surgery. LEVEL OF EVIDENCE: 3. PMID- 29280936 TI - THE ROLE OF INTRAOCULAR GAS TAMPONADE IN RHEGMATOGENOUS RETINAL DETACHMENT: A Synthesis of the Literature. AB - PURPOSE: To review the literature regarding intraocular gas tamponade after vitrectomy for rhegmatogenous retinal detachment. METHODS: The history and evolution of the use of gas is described. The theories explaining gas tamponade are discussed, and efficacy and safety studies in human and animal models are covered. RESULTS: A total of 61 articles relating to gas tamponade were cited in this review. CONCLUSION: Gas tamponade is a frequently used procedure in vitreoretinal surgery. An understanding of its mechanism of action is crucial for its safe use when determining which gas is to be used and at what concentration. PMID- 29280937 TI - EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT AND RANIBIZUMAB IN ASIAN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Subgroup Analyses From the View Trials. AB - PURPOSE: To assess the treatment effect of intravitreal aflibercept and ranibizumab in Asian patients with neovascular age-related macular degeneration. METHODS: We evaluated data from VIEW 1 and VIEW 2, comparing functional and morphologic outcomes at Week 96 between intravitreal aflibercept 2 mg monthly (2q4) or 2 mg bimonthly after 3 initial monthly doses (2q8) versus ranibizumab 0.5 mg monthly among Asian patients (n = 269) and between Asian and white patients (n = 2044). RESULTS: In Asian patients, there were no significant differences between intravitreal aflibercept 2q4 and 2q8 compared with ranibizumab in mean gain in best-corrected visual acuity (10.23 and 8.35 vs. 8.51 letters). Reduction in central retinal thickness was greater for intravitreal aflibercept 2q4 (150.43 MUm, P = 0.0075) and 2q8 (148.15 MUm, P = 0.0126) than ranibizumab (119.46 MUm). The proportion of dry retinas was greater for intravitreal aflibercept 2q4 (65.7%, P < 0.01) than ranibizumab (41.7%). There were no differences in outcomes between Asian and white patients. Serious treatment-emergent ocular adverse events occurred in <8% of treated eyes, evenly distributed across subgroups. CONCLUSION: In Asian patients with neovascular age related macular degeneration, functional and morphologic outcomes were largely similar between intravitreal aflibercept and ranibizumab groups, and to results seen in white patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29280938 TI - CHOROIDAL TUMOR BIOPSY: A Review of the Current State and a Glance Into Future Techniques. AB - PURPOSE: To review the indications for and the methods of obtaining biopsies in eyes with uveal melanoma. In addition, this review provides recommendations for avoiding biopsy-related complications and discusses the future directions of biopsy techniques for uveal melanoma. METHODS: This review is based on a presentation by the authors (PM and MM) at the 2017 Duke Advanced Vitreoretinal Surgery Course and an extensive literature review using PubMed. RESULTS: Transscleral and transvitreal fine-needle aspiration biopsy, and transvitreal vitrectomy-assisted biopsy techniques are described. The use of 25- and 27-gauge needles and vitreous cutters through a transvitreal approach are most commonly used. Complications are uncommon but may include vitreous hemorrhage, retinal detachment, and rarely, extraocular extension. Proper technique and precautions will minimize the occurrence of these rare complications. CONCLUSION: Biopsy of uveal melanoma either using a needle or vitrectomy-assisted procedures is safe and these techniques continue to improve with new vitreoretinal surgical advances. PMID- 29280939 TI - OUTCOMES OF VITRECTOMY WITH SILICONE OIL TAMPONADE FOR MANAGEMENT OF RETINAL DETACHMENT IN EYES WITH CHORIORETINAL COLOBOMA. AB - PURPOSE: To estimate the outcomes of retinal detachment in eyes with chorioretinal coloboma managed by pars plana vitrectomy and silicone oil tamponade. METHODS: A retrospective chart review of 10 eyes (10 patients) who underwent pars plana vitrectomy for retinal detachment with chorioretinal coloboma. RESULTS: The average age at the time of the surgery was 29.8 +/- 19.7 years. The mean follow-up period was 28.8 +/- 28.4 months. The mean silicone oil tamponade duration was 9.8 +/- 3.5 weeks. Of 10 eyes, 4 (40%) had retinal breaks outside the coloboma, 4 (40%) had breaks inside the coloboma, 1 (10%) had breaks inside and outside the coloboma, and in 1 eye (10%); the causative retinal break was not localized. Preoperatively, the mean visual acuity was 20/2,500 (n = 9), and 1 (10%) was recorded as "Not CSM." At the final examination, the mean visual acuity for the patients with measurable visual acuity was 20/200 (P = 0.06), and in the remaining eye was recorded as light perception. The retina was finally reattached in nine eyes (90%). Postoperative complications included cataract in three (30%), persistent elevated intraocular pressure in one (10%), band keratopathy in one (10%), and proliferative vitreoretinopathy in one (10%). CONCLUSION: Complete pars plana vitrectomy with or without lensectomy, laser photocoagulation around the peripheral retina, around all the peripheral breaks and around the colobomatous area, and silicone oil tamponade is effective for retinal detachment in eyes with chorioretinal coloboma. Silicone oil removal as early as possible did not increase the risk of redetachment and seems to reduce the incidence of oil-related complications in such cases. PMID- 29280942 TI - The Occurrence of Flavonoids and Related Compounds in Cedrus brevifolia A. Henry ex Elwes & A. Henry Needles. Inhibitory Potencies on Lipoxygenase, Linoleic Acid Lipid Peroxidation and Antioxidant Activity. AB - The phytochemical analysis of the polar extracts of Cedrus brevifolia needles yielded 20 compounds, namely from the methanol extract we isolated three flavonoids (1-3), one hydrolysable tannin (4), eleven phenolic derivatives (5-15) and one apocarotenoid (16), while from the methanol: water (5:1) extract we isolated four flavonoids (17-20). Chemical structures of all isolated compounds were determined by 1D, 2D-NMR (1 Dimension, 2 Dimensions Nuclear Magnetic Resonance) and UV-Vis (Ultraviolet-Visible) spectroscopy. Furthermore, the antioxidant potentials and the anti-inflammatory activities of both crude extracts and isolates were evaluated through DPPH radical scavenging capability, linoleic acid lipid peroxidation inhibition, and soybean LOX inhibition assays. This is the first report on the chemical profile of C. brevifolia needles. Catechin was the main compound derived from the methanol extract. According to our results, 4-O-beta-d-glucopyranyl trans-p-coumaric acid and taxifolin were the most active ingredients. PMID- 29280940 TI - CHANGES IN PLASMA VASCULAR ENDOTHELIAL GROWTH FACTOR LEVEL AFTER INTRAVITREAL INJECTION OF BEVACIZUMAB, AFLIBERCEPT, OR RANIBIZUMAB FOR DIABETIC MACULAR EDEMA. AB - PURPOSE: The aim of this study was to investigate the changes in plasma vascular endothelial growth factor (VEGF) level depending on the severity of diabetic retinopathy (DR) or diabetic macular edema (DME) and after intravitreal injection of bevacizumab, aflibercept, or ranibizumab for treatment of DME. METHODS: Plasma VEGF level was evaluated in 72 patients with DR and changes were measured in 42 patients with DME receiving intravitreal injections of bevacizumab, aflibercept, or ranibizumab at the initial injection. RESULTS: There were no correlations between plasma VEGF level and the severity of DME or DR. Baseline plasma VEGF level (51.9 pg/mL) was significantly reduced using bevacizumab to 11.9 pg/mL after 1 week and 24.1 pg/mL after 4 weeks (P = 0.0130 and 0.0201, respectively). In aflibercept-treated eyes, plasma VEGF decreased from 52.2 pg/mL to 7.8 pg/mL and 12.6 pg/mL, respectively, at the same time points (both P < 0.001). No such reductions were observed in patients receiving ranibizumab. CONCLUSION: Baseline plasma VEGF level showed no correlations with DR or DME severity, whereas intravitreal injection of bevacizumab or aflibercept significantly reduced plasma VEGF for up to 4 weeks and ranibizumab produced no such effects. Changes in plasma VEGF level seemed not to be critical in progression or treatment of DME and DR. PMID- 29280941 TI - Superoxide Anions and NO in the Paraventricular Nucleus Modulate the Cardiac Sympathetic Afferent Reflex in Obese Rats. AB - This study was conducted to explore the hypothesis that the endogenous superoxide anions (O2-) and nitric oxide (NO) system of the paraventricular nucleus (PVN) regulates the cardiac sympathetic afferent reflex (CSAR) contributing to sympathoexcitation in obese rats induced by a high-fat diet (42% kcal as fat) for 12 weeks. CSAR was evaluated by monitoring the changes of renal sympathetic nerve activity (RSNA) and the mean arterial pressure (MAP) responses to the epicardial application of capsaicin (CAP) in anaesthetized rats. In obese rats with hypertension (OH group) or without hypertension (OB group), the levels of PVN O2 , angiotensinII (Ang II), Ang II type 1 receptor (AT1R), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were elevated, whereas neural NO synthase (nNOS) and NO were significantly reduced. Moreover, CSAR was markedly enhanced, which promoted the elevation of plasma norepinephrine levels. The enhanced CSAR was attenuated by PVN application of the superoxide scavenger polyethylene glycol superoxide dismutase (PEG-SOD) and the NO donor sodium nitroprusside (SNP), and was strengthened by the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC) and the nNOS inhibitor N(omega)-propyl-l-arginine hydrochloride (PLA); conversely, there was a smaller CSAR response to PLA or SNP in rats that received a low-fat (12% kcal) diet. Furthermore, PVN pretreatment with the AT1R antagonist losartan or with PEG-SOD, but not SNP, abolished Ang II-induced CSAR enhancement. These findings suggest that obesity alters the PVN O2- and NO system that modulates CSAR and promotes sympathoexcitation. PMID- 29280943 TI - Characterization of a Long-Lived Alginate Lyase Derived from Shewanella Species YH1. AB - Polysaccharides from seaweeds are widely used in various fields, including the food, biomedical material, cosmetic, and biofuel industries. Alginate, which is a major polysaccharide in brown algae, and the products of its degradation (oligosaccharides) have been used in stabilizers, thickeners, and gelling agents, especially in the food industry. Discovering novel alginate lyases with unique characteristics for the efficient production of oligosaccharides may be relevant for the food and pharmaceutical fields. In this study, we identified a unique alginate lyase derived from an alginate-utilizing bacterium, Shewanella species YH1. The recombinant enzyme (rAlgSV1-PL7) was produced in an Escherichia coli system and it was classified in the Polysaccharide Lyase family 7. The optimal temperature and pH for rAlgSV1-PL7 activity were around 45 degrees C and 8, respectively. Interestingly, we observed that rAlgSV1-PL7 retained over 80% of its enzyme activity after incubation at 30 degrees C for at least 20 days, indicating that rAlgSV1-PL7 is a long-lived enzyme. Moreover, the degradation of alginate by rAlgSV1-PL7 produced one to four sugars because of the broad substrate specificity of this enzyme. Our findings suggest that rAlgSV1-PL7 may represent a new commercially useful enzyme. PMID- 29280944 TI - NGS Reveals Molecular Pathways Affected by Obesity and Weight Loss-Related Changes in miRNA Levels in Adipose Tissue. AB - Both obesity and weight loss may cause molecular changes in adipose tissue. This study aimed to characterize changes in adipose tissue miRNome in order to identify molecular pathways affected by obesity and weight changes. Next generation sequencing (NGS) was applied to identify microRNAs (miRNAs) differentially expressed in 47 samples of visceral (VAT) and subcutaneous (SAT) adipose tissues from normal-weight (N), obese (O) and obese after surgery-induced weight loss (PO) individuals. Subsequently miRNA expression was validated by real time PCR in 197 adipose tissues and bioinformatics analysis performed to identify molecular pathways affected by obesity-related changes in miRNA expression. NGS identified 344 miRNAs expressed in adipose tissues with >=5 reads per million. Using >2 and <-2 fold change as cut-offs we showed that the expression of 54 miRNAs differed significantly between VAT-O and SAT-O. Equally, between SAT-O and SAT-N, the expression of 20 miRNAs differed significantly, between SAT-PO and SAT N the expression of 79 miRNAs differed significantly, and between SAT-PO and SAT O, the expression of 61 miRNAs differed significantly. Ontological analyses disclosed several molecular pathways regulated by these miRNAs in adipose tissue. NGS-based miRNome analysis characterized changes of the miRNA profile of adipose tissue, which are associated with changes of weight possibly responsible for a differential regulation of molecular pathways in adipose tissue when the individual is obese and after the individual has lost weight. PMID- 29280945 TI - Modulation of Intestinal Epithelial Permeability in Differentiated Caco-2 Cells Exposed to Aflatoxin M1 and Ochratoxin A Individually or Collectively. AB - Aflatoxin M1 (AFM1) and ochratoxin A (OTA) are mycotoxins commonly found in milk; however, their effects on intestinal epithelial cells have not been reported. In the present study, we show that AFM1 (0.12 and 12 MUM) and OTA (0.2 and 20 MUM) individually or collectively increased the paracellular flux of lucifer yellow and fluorescein isothiocyanate (FITC)-dextrans (4 and 40 kDa) and decreased transepithelial electrical resistance values in differentiated Caco-2 cells after 48 h of exposure, indicating increased epithelial permeability. Immunoblotting and immunofluorescent analysis revealed that AFM1, OTA, and their combination decreased the expression levels of tight junction (TJ) proteins and disrupted their structures, namely, claudin-3, claudin-4, occludin, and zonula occludens-1 (ZO-1), and p44/42 mitogen-activated protein kinase (MAPK) partially involved in the mycotoxins-induced disruption of intestinal barrier. The effects of a combination of AFM1 and OTA on intestinal barrier function were more significant (p < 0.05) than those of AFM1 and OTA alone, yielding additive or synergistic effects. The additive or synergistic effects of AFM1 and OTA on intestinal barrier function might affect human health, especially in children, and toxin risks should be considered. PMID- 29280947 TI - Graphene Oxide in Lossy Mode Resonance-Based Optical Fiber Sensors for Ethanol Detection. AB - The influence of graphene oxide (GO) over the features of an optical fiber ethanol sensor based on lossy mode resonances (LMR) has been studied in this work. Four different sensors were built with this aim, each comprising a multimode optical fiber core fragment coated with a SnO2 thin film. Layer by layer (LbL) coatings made of 1, 2 and 4 bilayers of polyethyleneimine (PEI) and graphene oxide were deposited onto three of these devices and their behavior as aqueous ethanol sensors was characterized and compared with the sensor without GO. The sensors with GO showed much better performance with a maximum sensitivity enhancement of 176% with respect to the sensor without GO. To our knowledge, this is the first time that GO has been used to make an optical fiber sensor based on LMR. PMID- 29280946 TI - Secondary Metabolite Profiling of Species of the Genus Usnea by UHPLC-ESI-OT-MS MS. AB - Lichens are symbiotic associations of fungi with microalgae and/or cyanobacteria, which are considered among the slowest growing organisms, with strong tolerance to adverse environmental conditions. There are about 400 genera and 1600 species of lichens and those belonging to the Usnea genus comprise about 360 of these species. Usnea lichens have been used since ancient times as dyes, cosmetics, preservatives, deodorants and folk medicines. The phytochemistry of the Usnea genus includes more than 60 compounds which belong to the following classes: depsides, depsidones, depsones, lactones, quinones, phenolics, polysaccharides, fatty acids and dibenzofurans. Due to scarce knowledge of metabolomic profiles of Usnea species (U. barbata, U. antarctica, U. rubicunda and U. subfloridana), a study based on UHPLC-ESI-OT-MS-MS was performed for a comprehensive characterization of their secondary metabolites. From the methanolic extracts of these species a total of 73 metabolites were identified for the first time using this hyphenated technique, including 34 compounds in U. barbata, 21 in U. antarctica, 38 in U. rubicunda and 37 in U. subfloridana. Besides, a total of 13 metabolites were not identified and reported so far, and could be new according to our data analysis. This study showed that this hyphenated technique is rapid, effective and accurate for phytochemical identification of lichen metabolites and the data collected could be useful for chemotaxonomic studies. PMID- 29280948 TI - Enantiomeric Effect of d-Amino Acid Substitution on the Mechanism of Action of alpha-Helical Membrane-Active Peptides. AB - V13K, a 26-residue peptide, has been shown to have strong antimicrobial activity, negligible hemolytic activity, and significant anticancer activity. In the present work, V13K was used as the framework to investigate the influence of helicity, as influenced by d-amino acid substitutions in the center of the peptide polar and non-polar faces of the amphipathic helix, on biological activity. The antibacterial and anticancer activities of the peptides were investigated. Atomic force microscopy and other biophysical methods were used to investigate the effect of peptide helicity on biological activity. The results showed the importance of suitable and rational modification of membrane-active peptides, based on helicity, in optimizing potential biological activity. PMID- 29280950 TI - Mixed H2/Hinfinity-Based Fusion Estimation for Energy-Limited Multi-Sensors in Wearable Body Networks. AB - In wireless sensor networks, sensor nodes collect plenty of data for each time period. If all of data are transmitted to a Fusion Center (FC), the power of sensor node would run out rapidly. On the other hand, the data also needs a filter to remove the noise. Therefore, an efficient fusion estimation model, which can save the energy of the sensor nodes while maintaining higher accuracy, is needed. This paper proposes a novel mixed H2/Hinfinity-based energy-efficient fusion estimation model (MHEEFE) for energy-limited Wearable Body Networks. In the proposed model, the communication cost is firstly reduced efficiently while keeping the estimation accuracy. Then, the parameters in quantization method are discussed, and we confirm them by an optimization method with some prior knowledge. Besides, some calculation methods of important parameters are researched which make the final estimates more stable. Finally, an iteration based weight calculation algorithm is presented, which can improve the fault tolerance of the final estimate. In the simulation, the impacts of some pivotal parameters are discussed. Meanwhile, compared with the other related models, the MHEEFE shows a better performance in accuracy, energy-efficiency and fault tolerance. PMID- 29280949 TI - Peripheral 5-HT3 Receptors Are Involved in the Antinociceptive Effect of Bunodosine 391. AB - Bunodosine 391 (BDS 391), a low molecular weight compound isolated from the sea anemone Bunodosoma cangicum, increases the nociceptive threshold and inhibits inflammatory hyperalgesia. Serotonin receptors are involved in those effects. In this study, we have expanded the characterization of the antinociceptive effect of BDS 391 demonstrating that, in rats: (a) the compound inhibits (1.2-12 ng/paw) overt pain, in the formalin test, and mechanical hyperalgesia (0.6-6.0 ng/paw) detected in a model of neuropathic pain; (b) intraplantar administration of ondansetron, a selective 5-HT3 receptor antagonist, blocks the effect of BDS 391, whereas ketanserin, a 5-HT2 receptor antagonist, partially reversed this effect, indicating the involvement of peripheral 5-HT2 and 5-HT3 receptors in BDS 391 antinociception; and (c) in binding assay studies, BDS 391 was not able to displace the selective 5-HT receptor antagonists, suggesting that this compound does not directly bind to these receptors. The effect of biguanide, a selective 5 HT3 receptor agonist, was also evaluated. The agonist inhibited the formalin's nociceptive response, supporting an antinociceptive role for 5-HT3 receptors. Our study is the first one to show that a non-peptidic low molecular weight compound obtained from a sea anemone is able to induce antinociception and that activation of peripheral 5-HT3 receptors contributes to this effect. PMID- 29280951 TI - Cytotoxic Terpenoids from the Roots of Dracocephalum taliense. AB - A chemical investigation of methanol extract from the roots of Dracocephalum taliense led to the isolation of a new aromatic abietane diterpenoid, 12-methoxy 18-hydroxy-sugiol (1), and one highly-oxygenated ursane triterpenoid, 2alpha,3alpha-dihydroxy-11alpha,12alpha-epoxy-urs-28,13beta-olide (2), together with 15 known natural products (3-17). Among these, compounds 1-13 and 15-17 were detected for the first time in the genus of Dracocephalum. The structures of all of these isolates were determined by extensively spectroscopic analyses. In the anti-inflammatory assay, compounds 1 and 2 had no obvious inhibitory activity on the release of cytokine IL-2 in lipopolysaccharide-induced RAW 264.7 macrophages. However, compound 2 exhibited significant cytotoxic activity against cell lines HepG2 (IC50 = 6.58 +/- 0.14 MUM) and NCI-H1975 (IC50 = 7.17 +/- 0.26 MUM). PMID- 29280952 TI - Effects of Cadmium Exposure on Age of Menarche and Menopause. AB - Cadmium exposure can cause several adverse health effects. Animal studies have also shown that cadmium exposure can affect menarche or menopause. However, data is limited in humans. We conducted a retrospective study to assess whether cadmium exposure was associated with different ages of menarche and menopause in a Chinese population. A total of 429 women living in control (n = 137) and two cadmium-polluted areas (n = 292) were included in this study. A total of 223 and 206 subjects were included in the analysis for menarche and menopause, respectively. The median menarche age of population living in the heavily cadmium polluted area was significantly younger than those in the control area (14.0 vs. 15.0, p < 0.01). Logistic regression showed that the odds ratio (OR) of early occurrence of menarche (<13 years) in the population living in the heavily polluted area and moderately polluted area was 3.7 (95% confidence interval (CI): 1.5-9.7) and 1.3 (95% CI: 0.7-2.6) compared with control, respectively. No significant difference was observed in the age of menopause in the population of these three areas. In conclusion, our data indicated that cadmium exposure may cause early menarche. PMID- 29280954 TI - Human Scalp Hair as an Indicator of Exposure to the Environmental Toxin beta-N Methylamino-l-alanine. AB - Dietary or aerosol exposure to the environmental neurotoxin beta-N-methylamino-l alanine (BMAA) is a putative risk factor for the development of sporadic neurodegenerative disease. There are many potential sources of BMAA in the environment, but BMAA presence and quantities are highly variable. It has been suggested that BMAA in human hair may serve as an indicator of exposure. We sought to evaluate the use of the BMAA content of human scalp hair as an indicator of exposure, as well as the correlation between specific lifestyle or dietary habits, reported as hypothesised exposure risk factors, and BMAA in hair. Scalp hair samples and questionnaires were collected from participants in a small residential village surrounding a freshwater impoundment renowned for toxic cyanobacterial blooms. Data suggested a positive correlation between hair BMAA content and consumption of shellfish, and possibly pork. No statistically significant correlations were observed between hair BMAA content and residential proximity to the water or any other variable. Hair BMAA content was highly variable, and in terms of exposure, probably reflects primarily dietary exposure. However, the BMAA content of human hair may be affected to a great extent by several other factors, and as such, should be used with caution when evaluating human BMAA exposure, or correlating exposure to neurodegenerative disease incidence. PMID- 29280953 TI - Risk Factors for Internet Gaming Disorder: Psychological Factors and Internet Gaming Characteristics. AB - Background: Understanding the risk factors associated with Internet gaming disorder (IGD) is important to predict and diagnose the condition. The purpose of this study is to identify risk factors that predict IGD based on psychological factors and Internet gaming characteristics; Methods: Online surveys were conducted between 26 November and 26 December 2014. There were 3568 Korean Internet game users among a total of 5003 respondents. We identified 481 IGD gamers and 3087 normal Internet gamers, based on Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria. Logistic regression analysis was applied to identify significant risk factors for IGD; Results: The following eight risk factors were found to be significantly associated with IGD: functional and dysfunctional impulsivity (odds ratio: 1.138), belief self-control (1.034), anxiety (1.086), pursuit of desired appetitive goals (1.105), money spent on gaming (1.005), weekday game time (1.081), offline community meeting attendance (2.060), and game community membership (1.393; p < 0.05 for all eight risk factors); Conclusions: These risk factors allow for the prediction and diagnosis of IGD. In the future, these risk factors could also be used to inform clinical services for IGD diagnosis and treatment. PMID- 29280955 TI - Immune Modulation of NYVAC-Based HIV Vaccines by Combined Deletion of Viral Genes that Act on Several Signalling Pathways. AB - An HIV-1 vaccine continues to be a major target to halt the AIDS pandemic. The limited efficacy of the RV144 phase III clinical trial with the canarypox virus based vector ALVAC and a gp120 protein component led to the conclusion that improved immune responses to HIV antigens are needed for a more effective vaccine. In non-human primates, the New York vaccinia virus (NYVAC) poxvirus vector has a broader immunogenicity profile than ALVAC and has been tested in clinical trials. We therefore analysed the HIV immune advantage of NYVAC after removing viral genes that act on several signalling pathways (Toll-like receptors TLR-interferon, cytokines/chemokines), as well as genes of unknown immune function. We generated a series of NYVAC deletion mutants and studied immune behaviour (T and B cell) to HIV antigens and to the NYVAC vector in mice. Our results showed that combined deletion of selected vaccinia virus (VACV) genes is a valuable strategy for improving the immunogenicity of NYVAC-based vaccine candidates. These immune responses were differentially modulated, positive or negative, depending on the combination of gene deletions. The deletions also led to enhanced antigen- or vector-specific cellular and humoral responses. These findings will facilitate the development of optimal NYVAC-based vaccines for HIV and other diseases. PMID- 29280956 TI - Electrochemical Corrosion and In Vitro Bioactivity of Nano-Grained Biomedical Ti 20Nb-13Zr Alloy in a Simulated Body Fluid. AB - The bioactivity and the corrosion protection for a novel nano-grained Ti-20Nb 13Zr at % alloy were examined in a simulated body fluid (SBF). The effect of the SPS's temperature on the corrosion performance was investigated. The phases and microstructural details of the developed alloy were analyzed by XRD (X-ray Diffraction), SEM (Scanning Electron Microscopy), and TEM (Transmission Electron Microscope). The electrochemical study was investigated using linear potentiodynamic polarization and electrochemical impedance spectroscopy in a SBF, and the bioactivity was examined by immersing the developed alloy in a SBF for 3, 7, and 14 days. The morphology of the depositions after immersion was examined using SEM. Alloy surface analysis after immersion in the SBF was characterized by XPS (X-ray Photoelectron Spectroscopy). The results of the bioactivity test in SBF revealed the growth of a hydroxyapatite layer on the surface of the alloy. The analysis of XPS showed the formation of protective oxides of TiO2, Ti2O3, ZrO2, Nb2O5, and a Ca3(PO4)2 compound (precursor of hydroxyapatite) deposited on the alloy surface, indicating that the presented alloy can stimulate bone formation. The corrosion resistance increased by increasing the sintering temperature and the highest corrosion resistance was obtained at 1200 degrees C. The improved corrosion protection was found to be related to the alloy densification. The bioactivity and the corrosion resistance of the developed nanostructured alloy in a SBF renders the nanostructured Ti-20Nb-13Zr alloy a promising candidate as an implant material. PMID- 29280957 TI - Emotional Encoding Context Leads to Memory Bias in Individuals with High Anxiety. AB - We investigated whether anxious individuals, who adopt an inherently negative mindset, demonstrate a particularly salient memory bias for words tainted by negative contexts. To this end, sequentially presented target words, overlayed onto negative or neutral pictures, were studied in separate blocks (within subjects) using a deep or shallow encoding instruction (between-subjects). Following study, in Test 1, participants completed separate recognition test blocks for the words overlayed onto the negative and the neutral contexts. Following this, in Test 2, participants completed a recognition test for the foils from each Test 1 block. We found a significant three-way interaction on Test 2, such that individuals with high anxiety who initially studied target words using a shallow encoding instruction, demonstrated significantly elevated memory for foils that were contained within the negative Test 1 block. Results show that during retrieval (Test 1), participants re-entered the mode of processing (negative or neutral) engaged at encoding, tainting the encoding of foils with that same mode of processing. The findings suggest that individuals with high relative to low anxiety, adopt a particularly salient negative retrieval mode, and this creates a downstream bias in encoding and subsequent retrieval of otherwise neutral information. PMID- 29280959 TI - Pain-Causing Venom Peptides: Insights into Sensory Neuron Pharmacology. AB - Venoms are produced by a wide variety of species including spiders, scorpions, reptiles, cnidarians, and fish for the purpose of harming or incapacitating predators or prey. While some venoms are of relatively simple composition, many contain hundreds to thousands of individual components with distinct pharmacological activity. Pain-inducing or "algesic" venom compounds have proven invaluable to our understanding of how physiological nociceptive neural networks operate. In this review, we present an overview of some of the diverse nociceptive pathways that can be modulated by specific venom components to evoke pain. PMID- 29280960 TI - MetaGOmics: A Web-Based Tool for Peptide-Centric Functional and Taxonomic Analysis of Metaproteomics Data. AB - Metaproteomics is the characterization of all proteins being expressed by a community of organisms in a complex biological sample at a single point in time. Applications of metaproteomics range from the comparative analysis of environmental samples (such as ocean water and soil) to microbiome data from multicellular organisms (such as the human gut). Metaproteomics research is often focused on the quantitative functional makeup of the metaproteome and which organisms are making those proteins. That is: What are the functions of the currently expressed proteins? How much of the metaproteome is associated with those functions? And, which microorganisms are expressing the proteins that perform those functions? However, traditional protein-centric functional analysis is greatly complicated by the large size, redundancy, and lack of biological annotations for the protein sequences in the database used to search the data. To help address these issues, we have developed an algorithm and web application (dubbed "MetaGOmics") that automates the quantitative functional (using Gene Ontology) and taxonomic analysis of metaproteomics data and subsequent visualization of the results. MetaGOmics is designed to overcome the shortcomings of traditional proteomics analysis when used with metaproteomics data. It is easy to use, requires minimal input, and fully automates most steps of the analysis including comparing the functional makeup between samples. MetaGOmics is freely available at https://www.yeastrc.org/metagomics/. PMID- 29280958 TI - Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs. AB - MicroRNAs (miRs, miRNAs) are regulatory small noncoding RNAs, with their roles already confirmed to be important for post-transcriptional regulation of gene expression affecting cell physiology and disease development. Upregulation of a cancer-causing miRNA, known as oncogenic miRNA, has been found in many types of cancers and, therefore, represents a potential new class of targets for therapeutic inhibition. Several strategies have been developed in recent years to inhibit oncogenic miRNAs. Among them is a direct approach that targets mature oncogenic miRNA with an antisense sequence known as antimiR, which could be an oligonucleotide or miRNA sponge. In contrast, an indirect approach is to block the biogenesis of miRNA by genome editing using the CRISPR/Cas9 system or a small molecule inhibitor. The development of these inhibitors is straightforward but involves significant scientific and therapeutic challenges that need to be resolved. In this review, we summarize recent relevant studies on the development of miRNA inhibitors against cancer. PMID- 29280962 TI - Selection of a Very Active Microbial Community for the Coupled Treatment of Tetramethylammonium Hydroxide and Photoresist in Aqueous Solutions. AB - Aerobic treatment of wastewater containing Tetramethylammonium hydroxide (TMAH) and photoresist was investigated using a lab scale reactor inoculated with activated sludge coming from urban wastewater treatment that never received TMAH before. The consumption of TMAH was monitored by liquid ion chromatography. Biodiversity indices were calculated from Denaturing Gradient Gel Electrophoresis (DGGE) bands distribution and used to estimate changes in community composition related to adaptation to the new feeding compound. The first week of adaptation was crucial, and it was analyzed in detail: many organisms died, and the microbial community suffered a great shock. TMAH levels remained constant through the first four days, and then suddenly dropped to undetectable, and at the same time NH4+ increased. When the community showed complete adaptation, predominant groups of bacteria were obtained by the Illumina sequencing of 16s rDNA amplicons, to provide insights on ecology of the adapted community, focusing on the main actors of TMAH abatement. Richness of species (Rr) peaks suggest that the development of TMAH-consuming bacteria leads to persistent consortia that maintain toxicity resistance over time. This showed adaptation and changes of the population to the different feeding conditions, and it opens new perspectives in the in situ treatment of these important residues of industrial processes without relying on external processing plants. PMID- 29280963 TI - NH4OH Treatment for an Optimum Morphological Trade-off to Hydrothermal Ga-Doped n ZnO/p-Si Heterostructure Characteristics. AB - Previous studies on Ga-doped ZnO nanorods (GZRs) have failed to address the change in GZR morphology with increased doping concentration. The morphology change affects the GZR surface-to-volume ratio and the real essence of doping is not exploited for heterostructure optoelectronic characteristics. We present NH4OH treatment to provide an optimum morphological trade-off to n-GZR/p-Si heterostructure characteristics. The GZRs were grown via one of the most eminent and facile hydrothermal method with an increase in Ga concentration from 1% to 5%. The supplementary OH- ion concentration was effectively controlled by the addition of an optimum amount of NH4OH to synchronize GZR aspect and surface-to volume ratio. Hence, the probed results show only the effects of Ga-doping, rather than the changed morphology, on the optoelectronic characteristics of n GZR/p-Si heterostructures. The doped nanostructures were characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, photoluminescence, Hall-effect measurement, and Keithley 2410 measurement systems. GZRs had identical morphology and dimensions with a typical wurtzite phase. As the GZR carrier concentration increased, the PL response showed a blue shift because of Burstein-Moss effect. Also, the heterostructure current levels increased linearly with doping concentration. We believe that the presented GZRs with optimized morphology have great potential for field-effect transistors, light-emitting diodes, ultraviolet sensors, and laser diodes. PMID- 29280961 TI - RNA Interference Therapies for an HIV-1 Functional Cure. AB - HIV-1 drug therapies can prevent disease progression but cannot eliminate HIV-1 viruses from an infected individual. While there is hope that elimination of HIV 1 can be achieved, several approaches to reach a functional cure (control of HIV 1 replication in the absence of drug therapy) are also under investigation. One of these approaches is the transplant of HIV-1 resistant cells expressing anti HIV-1 RNAs, proteins or peptides. Small RNAs that use RNA interference pathways to target HIV-1 replication have emerged as competitive candidates for cell transplant therapy and have been included in all gene combinations that have so far entered clinical trials. Here, we review RNA interference pathways in mammalian cells and the design of therapeutic small RNAs that use these pathways to target pathogenic RNA sequences. Studies that have been performed to identify anti-HIV-1 RNA interference therapeutics are also reviewed and perspectives on their use in combination gene therapy to functionally cure HIV-1 infection are provided. PMID- 29280964 TI - The Impact of Graphene on the Fabrication of Thin Film Solar Cells: Current Status and Future Prospects. AB - Commercial solar cells have a power conversion efficiency (PCE) in the range of 10-22% with different light absorbers. Graphene, with demonstrated unique structural, physical, and electrical properties, is expected to bring the positive effects on the development of thin film solar cells. Investigations have been carried out to understand whether graphene can be used as a front and back contacts and active interfacial layer in solar cell fabrication. In this review, the current progress of this research is analyzed, starting from the graphene and graphene-based Schottky diode. Also, the discussion was focused on the progress of graphene-incorporated thin film solar cells that were fabricated with different light absorbers, in particular, the synthesis, fabrication, and characterization of devices. The effect of doping and layer thickness of graphene on PCE was also included. Currently, the PCE of graphene-incorporated bulk heterojunction devices have enhanced in the range of 0.5-3%. However, device durability and cost-effectiveness are also the challenging factors for commercial production of graphene-incorporated solar cells. In addition to the application of graphene, graphene oxides have been also used in perovskite solar cells. The current needs and likely future investigations for graphene-incorporated solar cells are also discussed. PMID- 29280966 TI - Vanishing Point Extraction and Refinement for Robust Camera Calibration. AB - This paper describes a flexible camera calibration method using refined vanishing points without prior information. Vanishing points are estimated from human-made features like parallel lines and repeated patterns. With the vanishing points extracted from the three mutually orthogonal directions, the interior and exterior orientation parameters can be further calculated using collinearity condition equations. A vanishing point refinement process is proposed to reduce the uncertainty caused by vanishing point localization errors. The fine-tuning algorithm is based on the divergence of grouped feature points projected onto the reference plane, minimizing the standard deviation of each of the grouped collinear points with an O(1) computational complexity. This paper also presents an automated vanishing point estimation approach based on the cascade Hough transform. The experiment results indicate that the vanishing point refinement process can significantly improve camera calibration parameters and the root mean square error (RMSE) of the constructed 3D model can be reduced by about 30%. PMID- 29280965 TI - The Glutamatergic System in Primary Somatosensory Neurons and Its Involvement in Sensory Input-Dependent Plasticity. AB - Glutamate is the most common neurotransmitter in both the central and the peripheral nervous system. Glutamate is present in all types of neurons in sensory ganglia, and is released not only from their peripheral and central axon terminals but also from their cell bodies. Consistently, these neurons express ionotropic and metabotropic receptors, as well as other molecules involved in the synthesis, transport and release of the neurotransmitter. Primary sensory neurons are the first neurons in the sensory channels, which receive information from the periphery, and are thus key players in the sensory transduction and in the transmission of this information to higher centers in the pathway. These neurons are tightly enclosed by satellite glial cells, which also express several ionotropic and metabotropic glutamate receptors, and display increases in intracellular calcium accompanying the release of glutamate. One of the main interests in our group has been the study of the implication of the peripheral nervous system in sensory-dependent plasticity. Recently, we have provided novel evidence in favor of morphological changes in first- and second-order neurons of the trigeminal system after sustained alterations of the sensory input. Moreover, these anatomical changes are paralleled by several molecular changes, among which those related to glutamatergic neurotransmission are particularly relevant. In this review, we will describe the state of the art of the glutamatergic system in sensory ganglia and its involvement in input-dependent plasticity, a fundamental ground for advancing our knowledge of the neural mechanisms of learning and adaptation, reaction to injury, and chronic pain. PMID- 29280967 TI - Biomarkers for Pulmonary Inflammation and Fibrosis and Lung Ventilation Function in Chinese Occupational Refractory Ceramic Fibers-Exposed Workers. AB - Refractory ceramic fibers (RCFs) can cause adverse health effects on workers' respiratory system, yet no proper biomarkers have been used to detect early pulmonary injury of RCFs-exposed workers. This study assessed the levels of two biomarkers that are related to respiratory injury in RCFs-exposed workers, and explored their relations with lung function. The exposure levels of total dust and respirable fibers were measured simultaneously in RCFs factories. The levels of TGF-beta1 and ceruloplasmin (CP) increased with the RCFs exposure level (p < 0.05), and significantly increased in workers with high exposure level (1.21 +/- 0.49 ng/mL, 115.25 +/- 32.44 U/L) when compared with the control group (0.99 +/- 0.29 ng/mL, 97.90 +/- 35.01 U/L) (p < 0.05). The levels of FVC and FEV1 were significantly decreased in RCFs exposure group (p < 0.05). Negative relations were found between the concentrations of CP and FVC (B = -0.423, p = 0.025), or FEV1 (B = -0.494, p = 0.014). The concentration of TGF-beta1 (B = 0.103, p = 0.001) and CP (B = 8.027, p = 0.007) were associated with respirable fiber exposure level. Occupational exposure to RCFs can impair lung ventilation function and may have the potential to cause pulmonary inflammation and fibrosis. TGF-beta1 and CP might be used as sensitive and noninvasive biomarkers to detect lung injury in occupational RCFs-exposed workers. Respirable fiber concentration can better reflect occupational RCFs exposure and related respiratory injuries. PMID- 29280968 TI - Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]-quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects. AB - A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a-k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b-c, and 7e-g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 uM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a-c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 uM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets. PMID- 29280970 TI - Background Registration-Based Adaptive Noise Filtering of LWIR/MWIR Imaging Sensors for UAV Applications. AB - Unmanned aerial vehicles (UAVs) are equipped with optical systems including an infrared (IR) camera such as electro-optical IR (EO/IR), target acquisition and designation sights (TADS), or forward looking IR (FLIR). However, images obtained from IR cameras are subject to noise such as dead pixels, lines, and fixed pattern noise. Nonuniformity correction (NUC) is a widely employed method to reduce noise in IR images, but it has limitations in removing noise that occurs during operation. Methods have been proposed to overcome the limitations of the NUC method, such as two-point correction (TPC) and scene-based NUC (SBNUC). However, these methods still suffer from unfixed pattern noise. In this paper, a background registration-based adaptive noise filtering (BRANF) method is proposed to overcome the limitations of conventional methods. The proposed BRANF method utilizes background registration processing and robust principle component analysis (RPCA). In addition, image quality verification methods are proposed that can measure the noise filtering performance quantitatively without ground truth images. Experiments were performed for performance verification with middle wave infrared (MWIR) and long wave infrared (LWIR) images obtained from practical military optical systems. As a result, it is found that the image quality improvement rate of BRANF is 30% higher than that of conventional NUC. PMID- 29280969 TI - Psychological Predictors of Sexual Intimate Partner Violence against Black and Hispanic Women. AB - Background: Although various types of intimate partner violence (IPV) tend to co occur, risk factors of each type of IPV may differ. At the same time, most of the existing literature on risk factors of IPV among minorities has used a cross sectional design and has focused on physical rather than sexual IPV. We conducted the current study to compare Black and Hispanic women for psychological predators of change in sexual IPV over time. Methods: Using data from the Fragile Families and Child Wellbeing Study (FFCWS), this study followed 561 Black and 475 Hispanic women with their male partners for four years. Independent variables included male partners' depression, anxiety, problem alcohol use, and male-to-female physical and psychological IPV perpetration. The dependent variable was sexual IPV reported by female partners, measured at baseline, two years, and four years later. Covariates included age, income, marital status and educational level. We used a multi-group latent growth curve model (LGCM) to explain intercept, linear, and quadratic slopes, which represent the baseline, and linear and curvilinear trajectories of male-to-female sexual IPV, where groups were defined based on ethnicity. Results: Psychological IPV was associated with sexual IPV at baseline among both ethnic groups. The male partner's depression was a risk factor for an increase in sexual IPV over time among Black but not Hispanic women. Anxiety, problem alcohol use and physical IPV did not have an effect on the baseline or change in sexual IPV over time. Psychological IPV was not associated with an increase in sexual IPV over time in either ethnic groups. Conclusions: There is a need for screening of sexual IPV in the presence of psychological IPV among minority women. There is also a need for screening and treatment of male partners' depression as a strategy to reduce sexual IPV among Black women. PMID- 29280971 TI - Estimating the Causal Impact of Proximity to Gold and Copper Mines on Respiratory Diseases in Chilean Children: An Application of Targeted Maximum Likelihood Estimation. AB - In a town located in a desert area of Northern Chile, gold and copper open-pit mining is carried out involving explosive processes. These processes are associated with increased dust exposure, which might affect children's respiratory health. Therefore, we aimed to quantify the causal attributable risk of living close to the mines on asthma or allergic rhinoconjunctivitis risk burden in children. Data on the prevalence of respiratory diseases and potential confounders were available from a cross-sectional survey carried out in 2009 among 288 (response: 69 % ) children living in the community. The proximity of the children's home addresses to the local gold and copper mine was calculated using geographical positioning systems. We applied targeted maximum likelihood estimation to obtain the causal attributable risk (CAR) for asthma, rhinoconjunctivitis and both outcomes combined. Children living more than the first quartile away from the mines were used as the unexposed group. Based on the estimated CAR, a hypothetical intervention in which all children lived at least one quartile away from the copper mine would decrease the risk of rhinoconjunctivitis by 4.7 percentage points (CAR: - 4.7 ; 95 % confidence interval ( 95 % CI): - 8.4 ; - 0.11 ); and 4.2 percentage points (CAR: - 4.2 ; 95 % CI: - 7.9 ; - 0.05 ) for both outcomes combined. Overall, our results suggest that a hypothetical intervention intended to increase the distance between the place of residence of the highest exposed children would reduce the prevalence of respiratory disease in the community by around four percentage points. This approach could help local policymakers in the development of efficient public health strategies. PMID- 29280972 TI - Investigation on Synthesis, Stability, and Thermal Conductivity Properties of Water-Based SnO2/Reduced Graphene Oxide Nanofluids. AB - With the rapid development of industry, heat removal and management is a major concern for any technology. Heat transfer plays a critically important role in many sectors of engineering; nowadays utilizing nanofluids is one of the relatively optimized techniques to enhance heat transfer. In the present work, a facile low-temperature solvothermal method was employed to fabricate the SnO2/reduced graphene oxide (rGO) nanocomposite. X-ray diffraction (XRD), thermogravimetric analysis (TGA), X-ray photoelectron spectroscope (XPS), Raman spectroscopy, and transmission electron microscopy (TEM) have been performed to characterize the SnO2/rGO nanocomposite. Numerous ultrasmall SnO2 nanoparticles with average diameters of 3-5 nm were anchored on the surface of rGO, which contain partial hydrophilic functional groups. Water-based SnO2/rGO nanofluids were prepared with various weight concentrations by using an ultrasonic probe without adding any surfactants. The zeta potential was measured to investigate the stability of the as-prepared nanofluid which exhibited great dispersion stability after quiescence for 60 days. A thermal properties analyzer was employed to measure thermal conductivity of water-based SnO2/rGO nanofluids, and the results showed that the enhancement of thermal conductivity could reach up to 31% at 60 degrees C under the mass fraction of 0.1 wt %, compared to deionized water. PMID- 29280973 TI - Transcriptome-Wide Identification and Characterization of Potato Circular RNAs in Response to Pectobacterium carotovorum Subspecies brasiliense Infection. AB - Little information about the roles of circular RNAs (circRNAs) during potato Pectobacterium carotovorum subsp. brasiliense (Pcb) interaction is currently available. In this study, we conducted the systematic identification of circRNAs from time series samples of potato cultivars Valor (susceptible) and BP1 (disease tolerant) infected by Pcb. A total of 2098 circRNAs were detected and about half (931, 44.38%) were intergenic circRNAs. And differential expression analysis detected 429 significantly regulated circRNAs. circRNAs play roles by regulating parental genes and sponging miRNAs. Gene Ontology (GO) enrichment of parental genes and miRNAs targeted mRNAs revealed that these differentially expressed (DE) circRNAs were involved in defense response (GO:0006952), cell wall (GO:0005199), ADP binding (GO:0043531), phosphorylation (GO:0016310), and kinase activity (GO:0016301), suggesting the roles of circRNAs in regulating potato immune response. Furthermore, weighted gene co-expression network analysis (WGCNA) found that circRNAs were closely related with coding-genes and long intergenic noncoding RNAs (lincRNAs). And together they were cultivar-specifically regulated to strengthen immune response of potato to Pcb infection, implying the roles of circRNAs in reprogramming disease responsive transcriptome. Our results will provide new insights into the potato-Pcb interaction and may lead to novel disease control strategy in the future. PMID- 29280975 TI - Design and Practical Evaluation of a Family of Lightweight Protocols for Heterogeneous Sensing through BLE Beacons in IoT Telemetry Applications. AB - The Internet of Things (IoT) involves a wide variety of heterogeneous technologies and resource-constrained devices that interact with each other. Due to such constraints, IoT devices usually require lightweight protocols that optimize the use of resources and energy consumption. Among the different commercial IoT devices, Bluetooth and Bluetooth Low Energy (BLE)-based beacons, which broadcast periodically certain data packets to notify their presence, have experienced a remarkable growth, specially due to their application in indoor positioning systems. This article proposes a family of protocols named Lightweight Protocol for Sensors (LP4S) that provides fast responses and enables plug-and-play mechanisms that allow IoT telemetry systems to discover new nodes and to describe and auto-register the sensors and actuators connected to a beacon. Thus, three protocols are defined depending on the beacon hardware characteristics: LP4S-6 (for resource-constraint beacons), LP4S-X (for more powerful beacons) and LP4S-J (for beacons able to run complex firmware). In order to demonstrate the capabilities of the designed protocols, the most restrictive (LP4S-6) is tested after implementing it for a telemetry application in a beacon based on Eddystone (Google's open beacon format). Thus, the beacon specification is extended in order to increase its ability to manage unlimited sensors in a telemetry system without interfering in its normal operation with Eddystone frames. The performed experiments show the feasibility of the proposed solution and its superiority, in terms of latency and energy consumption, with respect to approaches based on Generic Attribute Profile (GATT) when multiple users connect to a mote or in scenarios where latency is not a restriction, but where low energy consumption is essential. PMID- 29280974 TI - Harnessing Invariant NKT Cells to Improve Influenza Vaccines: A Pig Perspective. AB - Invariant natural killer T (iNKT) cells are an "innate-like" T cell lineage that recognize glycolipid rather than peptide antigens by their semi-invariant T cell receptors. Because iNKT cells can stimulate an extensive array of immune responses, there is considerable interest in targeting these cells to enhance human vaccines against a wide range of microbial pathogens. However, long overlooked is the potential to harness iNKT cell antigens as vaccine adjuvants for domestic animal species that express the iNKT cell-CD1d system. In this review, we discuss the prospect of targeting porcine iNKT cells as a strategy to enhance the efficiency of swine influenza vaccines. In addition, we compare the phenotype and tissue distribution of porcine iNKT cells. Finally, we discuss the challenges that must be overcome before iNKT cell agonists can be contemplated for veterinary use in livestock. PMID- 29280976 TI - A Novel Multi-Approach Protocol for the Characterization of Occupational Exposure to Organic Dust-Swine Production Case Study. AB - Swine production has been associated with health risks and workers' symptoms. In Portugal, as in other countries, large-scale swine production involves several activities in the swine environment that require direct intervention, increasing workers' exposure to organic dust. This study describes an updated protocol for the assessment of occupational exposure to organic dust, to unveil an accurate scenario regarding occupational and environmental risks for workers' health. The particle size distribution was characterized regarding mass concentration in five different size ranges (PM0.5, PM1, PM2.5, PM5, PM10). Bioburden was assessed, by both active and passive sampling methods, in air, on surfaces, floor covering and feed samples, and analyzed through culture based-methods and qPCR. Smaller size range particles exhibited the highest counts, with indoor particles showing higher particle counts and mass concentration than outdoor particles. The limit values suggested for total bacteria load were surpassed in 35.7% (10 out of 28) of samples and for fungi in 65.5% (19 out of 29) of samples. Among Aspergillus genera, section Circumdati was the most prevalent (55%) on malt extract agar (MEA) and Versicolores the most identified (50%) on dichloran glycerol (DG18). The results document a wide characterization of occupational exposure to organic dust on swine farms, being useful for policies and stakeholders to act to improve workers' safety. The methods of sampling and analysis employed were the most suitable considering the purpose of the study and should be adopted as a protocol to be followed in future exposure assessments in this occupational environment. PMID- 29280977 TI - Flaccidoxide-13-Acetate Extracted from the Soft Coral Cladiella kashmani Reduces Human Bladder Cancer Cell Migration and Invasion through Reducing Activation of the FAK/PI3K/AKT/mTOR Signaling Pathway. AB - Metastasis of cancer is the cause of the majority of cancer deaths. Active compound flaccidoxide-13-acetate, isolated from the soft coral Cladiella kashmani, has been found to exhibit anti-tumor activity. In this study, Boyden chamber analysis, Western blotting and gelatin zymography assays indicated that flaccidoxide-13-acetate exerted inhibitory effects on the migration and invasion of RT4 and T24 human bladder cancer cells. The results demonstrated that flaccidoxide-13-acetate, in a concentration-dependent manner, reduced the levels of matrix metalloproteinase-2 (MMP-2), MMP-9, urokinase-type plasminogen activator receptor (uPAR), focal adhesion kinase (FAK), phosphatidylinositide-3 kinases (PI3K), p-PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, Ras homolog gene family, member A (Rho A), Ras, mitogen-activated protein kinase kinase 7 (MKK7) and mitogen-activated protein kinase kinase kinase 3 (MEKK3), and increased the expressions of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in RT4 and T24 cells. This study revealed that flaccidoxide-13-acetate suppressed cell migration and invasion by reducing the expressions of MMP-2 and MMP-9, regulated by the FAK/PI3K/AKT/mTOR pathway. In conclusion, our study was the first to demonstrate that flaccidoxide-13-acetate could be a potent medical agent for use in controlling the migration and invasion of bladder cancer. PMID- 29280978 TI - Effects of Fusarium Head Blight on Wheat Grain and Malt Infected by Fusarium culmorum. AB - Fusarium head blight is a destructive disease of cereals worldwide. The aim of this research was to study the effect of heavy Fusarium infection with Fusarium culmorum and biosynthesis of mycotoxins on different wheat varieties during malting by setting up field trials with control and Fusarium-inoculated treatments at the Agricultural Institute Osijek. The highest occurrence of Fusarium mycotoxins was expectedly recorded in susceptible variety in grain and malt (3247 and 1484 ug kg-1 for deoxynivalenol (DON), 735 and 1116 ug kg-1 for 3 acetyl deoxynivalenol (3-ADON), 37 and 233 ug kg-1 for zearalenone (ZEN), respectively). Based on published information, complemented by our own results, the following conclusions can be drawn: The presence of 3-ADON in different wheat varieties might be the result of its conversion into DON by deacetylation during the malting process. The detection of the mycotoxin ZEN indicated that this mycotoxin is only specific for wheat malt. PMID- 29280979 TI - Perturbation Theory for Scattering from Multilayers with Randomly Rough Fractal Interfaces: Remote Sensing Applications. AB - A general, approximate perturbation method, able to provide closed-form expressions of scattering from a layered structure with an arbitrary number of rough interfaces, has been recently developed. Such a method provides a unique tool for the characterization of radar response patterns of natural rough multilayers. In order to show that, here, for the first time in a journal paper, we describe the application of the developed perturbation theory to fractal interfaces; we then employ the perturbative method solution to analyze the scattering from real-world layered structures of practical interest in remote sensing applications. We focus on the dependence of normalized radar cross section on geometrical and physical properties of the considered scenarios, and we choose two classes of natural stratifications: wet paleosoil covered by a low loss dry sand layer and a sea-ice layer above water with dry snow cover. Results are in accordance with the experimental evidence available in the literature for the low-loss dry sand layer, and they may provide useful indications about the actual ability of remote sensing instruments to perform sub-surface sensing for different sensor and scene parameters. PMID- 29280980 TI - Hydrophobic and Hydrophilic Au and Ag Nanoparticles. Breakthroughs and Perspectives. AB - This review provides a broad look on the recent investigations on the synthesis, characterization and physico-chemical properties of noble metal nanoparticles, mainly gold and silver nanoparticles, stabilized with ligands of different chemical nature. A comprehensive review of the available literature in this field may be far too large and only some selected representative examples will be reported here, together with some recent achievements from our group, that will be discussed in more detail. Many efforts in finding synthetic routes have been performed so far to achieve metal nanoparticles with well-defined size, morphology and stability in different environments, to match the large variety of applications that can be foreseen for these materials. In particular, the synthesis and stabilization of gold and silver nanoparticles together with their properties in different emerging fields of nanomedicine, optics and sensors are reviewed and briefly commented. PMID- 29280981 TI - Beta-N-Methylamino-L-Alanine (BMAA) Toxicity Is Gender and Exposure-Age Dependent in Rats. AB - Cyanobacterial beta-N-methylamino-L-alanine (BMAA) has been suggested as a causative or contributory factor in the development of several neurodegenerative diseases. However, no BMAA animal model has adequately shown clinical or behavioral symptoms that correspond to those seen in either Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD). We present here the first data that show that when neonatal rats were exposed to BMAA on postnatal days 3, 4 and 5, but not on gestational day 14 or postnatally on days 7 or 10, several AD and/or PD-related behavioral, locomotor and cognitive deficits developed. Male rats exhibited severe unilateral hindlimb splay while whole body tremors could be observed in exposed female rats. BMAA-exposed rats failed to identify and discriminate a learned odor, an early non-motor symptom of PD, and exhibited decreased locomotor activity, decreased exploration and increased anxiety in the open field test. Alterations were also observed in the rats' natural passive defense mechanism, and potential memory deficits and changes to the rat's natural height avoidance behavior could be observed as early as PND 30. Spatial learning, short-term working, reference and long-term memory were also impaired in 90-day-old rats that had been exposed to a single dose of BMAA on PND 3-7. These data suggest that BMAA is a developmental neurotoxin, with specific target areas in the brain and spinal cord. PMID- 29280982 TI - Ex Vivo Evaluation of Cementless Acetabular Cup Stability Using Impact Analyses with a Hammer Instrumented with Strain Sensors. AB - The acetabular cup (AC) implant stability is determinant for the success of cementless hip arthroplasty. A method based on the analysis of the impact force applied during the press-fit insertion of the AC implant using a hammer instrumented with a force sensor was developed to assess the AC implant stability. The aim of the present study was to investigate the performance of a method using a hammer equipped with strain sensors to retrieve the AC implant stability. Different AC implants were inserted in five bovine samples with different stability conditions leading to 57 configurations. The AC implant was impacted 16 times by the two hammers consecutively. For each impact; an indicator IS (respectively IF) determined by analyzing the time variation of the signal corresponding to the averaged strain (respectively force) obtained with the stress (respectively strain) hammer was calculated. The pull-out force F was measured for each configuration. F was significantly correlated with IS (R2 = 0.79) and IF (R2 = 0.80). The present method has the advantage of not modifying the shape of the hammer that can be sterilized easily. This study opens new paths towards the development of a decision support system to assess the AC implant stability. PMID- 29280983 TI - A New Zenith Tropospheric Delay Grid Product for Real-Time PPP Applications over China. AB - Tropospheric delay is one of the major factors affecting the accuracy of electromagnetic distance measurements. To provide wide-area real-time high precision zenith tropospheric delay (ZTD), the temporal and spatial variations of ZTD with altitude were analyzed on the bases of the latest meteorological reanalysis product (ERA-Interim) provided by the European Center for Medium-Range Weather Forecasts (ECMWF). An inverse scale height model at given locations taking latitude, longitude and day of year as inputs was then developed and used to convert real-time ZTD at GPS stations in Crustal Movement Observation Network of China (CMONOC) from station height to mean sea level (MSL). The real-time ZTD grid product (RtZTD) over China was then generated with a time interval of 5 min. Compared with ZTD estimated in post-processing mode, the bias and error RMS of ZTD at test GPS stations derived from RtZTD are 0.39 and 1.56 cm, which is significantly more accurate than commonly used empirical models. In addition, simulated real-time kinematic Precise Point Positioning (PPP) tests show that using RtZTD could accelerate the BDS-PPP convergence time by up to 32% and 65% in the horizontal and vertical components (set coordinate error thresholds to 0.4 m), respectively. For GPS-PPP, the convergence time using RtZTD can be accelerated by up to 29% in the vertical component (0.2 m). PMID- 29280984 TI - Towards the Use of Unmanned Aerial Systems for Providing Sustainable Services in Smart Cities. AB - Sustainability is at the heart of many application fields where the use of Unmanned Aerial Systems (UAS) is becoming more and more important (e.g., agriculture, fire detection and prediction, environmental surveillance, mapping, etc.). However, their usage and evolution are highly conditioned by the specific application field they are designed for, and thus, they cannot be easily reused among different application fields. From this point of view, being that they are not multipurpose, we can say that they are not fully sustainable. Bearing this in mind, the objective of this paper is two-fold: on the one hand, to identify the whole set of features that must be provided by a UAS to be considered sustainable and to show that there is no UAS satisfying all these features; on the other hand, to present an open and sustainable UAS architecture that may be used to build UAS on demand to provide the features needed in each application field. Since this architecture is mainly based on software and hardware adaptability, it contributes to the technical sustainability of cities. PMID- 29280985 TI - Pediatric Hypothermic Submersion Injury and Protective Factors Associated with Optimal Outcome: A Case Report and Literature Review. AB - Drowning is the 3rd leading cause of unintentional injury death worldwide, with the highest rates of fatality among young children. Submersion injuries with cardiac arrest can lead to long-term neurologic morbidity. Severe hypothermic submersion injuries have complex treatment courses and survivors have variable neurocognitive outcomes. We describe the course of a hypothermic submersion injury in a 6-year-old previously healthy boy. The description includes premorbid and post-injury neurocognitive functioning. A review of the literature of pediatric cold-water submersion injury was performed. Despite prolonged cardiopulmonary resuscitation (>100 min) and water temperature well above freezing, our patient had an optimal neurocognitive outcome following hypothermic submersion injury. Available literature is limited but suggests that increased submersion time, increased duration of resuscitation, and higher water temperatures are associated with worse outcomes. Care guidelines have been created, but outcomes related to these guidelines have not been studied. Our case highlights potential important determinants of outcome after drowning. Incident specific characteristics and therapeutic interventions should be considered when evaluating this population. Treatment guidelines based on currently available literature may fail to incorporate all potential variables, and consideration should be given to prolonged resuscitative efforts based on individual case characteristics until further data is available. PMID- 29280986 TI - Disparities in Non-Fatal Health Outcomes in Pediatric General Trauma Studies. AB - When prevention efforts fail, injured children require high-quality health services to support their recovery. Disparities in non-fatal injury outcomes, an indicator of health-care quality, have received minimal attention. We evaluated the extent to which general trauma follow-up studies published in the peer reviewed scientific literature provide evidence of socially patterned inequities in health, functional or disability outcomes >=4 weeks after childhood injuries. Using a systematic search, we identified 27 eligible cohort studies from 13 high income countries. We examined the extent to which the reported health outcomes varied across the PROGRESS criteria: place of residence, race/ethnicity, occupation, gender/sex, religion, socio-economic status, and social capital. The available evidence on differential outcomes is limited as many studies were compromised by selection or retention biases that reduced the participation of children from demographic groups at increased risk of adverse outcomes, or the analyses mainly focused on variations in outcomes by sex. Given the limited research evidence, we recommend greater attention to systematic collection and reporting of non-fatal injury outcomes disaggregated by socio-demographic indicators in order to identify disparities where these exist and inform equity focused interventions promoting the recovery of injured children. PMID- 29280988 TI - Induced Pluripotent Stem Cell-Derived Red Blood Cells and Platelet Concentrates: From Bench to Bedside. AB - Red blood cells and platelets are anucleate blood components indispensable for oxygen delivery and hemostasis, respectively. Derivation of these blood elements from induced pluripotent stem (iPS) cells has the potential to develop blood donor-independent and genetic manipulation-prone products to complement or replace current transfusion banking, also minimizing the risk of alloimmunization. While the production of erythrocytes from iPS cells has challenges to overcome, such as differentiation into adult-type phenotype that functions properly after transfusion, platelet products are qualitatively and quantitatively approaching a clinically-applicable level owing to advances in expandable megakaryocyte (MK) lines, platelet-producing bioreactors, and novel reagents. Guidelines that assure the quality of iPS cells-derived blood products for clinical application represent a novel challenge for regulatory agencies. Considering the minimal risk of tumorigenicity and the expected significant demand of such products, ex vivo production of iPS-derived blood components can pave the way for iPS translation into the clinic. PMID- 29280987 TI - Anti-Inflammatory and Skin Barrier Repair Effects of Topical Application of Some Plant Oils. AB - Plant oils have been utilized for a variety of purposes throughout history, with their integration into foods, cosmetics, and pharmaceutical products. They are now being increasingly recognized for their effects on both skin diseases and the restoration of cutaneous homeostasis. This article briefly reviews the available data on biological influences of topical skin applications of some plant oils (olive oil, olive pomace oil, sunflower seed oil, coconut oil, safflower seed oil, argan oil, soybean oil, peanut oil, sesame oil, avocado oil, borage oil, jojoba oil, oat oil, pomegranate seed oil, almond oil, bitter apricot oil, rose hip oil, German chamomile oil, and shea butter). Thus, it focuses on the therapeutic benefits of these plant oils according to their anti-inflammatory and antioxidant effects on the skin, promotion of wound healing and repair of skin barrier. PMID- 29280990 TI - DPMIND: degradome-based plant miRNA-target interaction and network database. AB - Motivation: MicroRNAs (miRNAs) play essential roles in plant growth, development and stress responses through post-transcriptionally regulating the expression levels of their target mRNAs. Although some tools and databases were developed for predicting the relationships between miRNAs and their targets (miR-Tar), most of them were dependent on computational methods without experimental validations. With the development of degradome sequencing techniques, researchers can identify potential interactions based on degradome sequencing data. The validations with specific degradome data are useful to identify the miR-Tar interactions (MTIs) occurring in/under some specific tissues or treatments. Degradome-based plant miRNA-target interaction and network database (DPMIND) collected almost all available plant degradome data and built a retrieval and analysis platform of miRNA-target interactions and miRNA regulatory networks (MRNs). Results: DPMIND contains the recently updated 3794 miRNAs and 28 666 verified MTIs with 69 degradomes from 10 plant species. Not only the verified MTIs but also the degradome-based MRNs can be retrieved from DPMIND. Users can search for the verified MTIs and build degradome-based MRNs for the specific miRNAs or targets. DPMIND can build the MRNs based on all degradomes or specific degradomes, which helps to identify all possible connections among specific miR-Tar and compare the miRNA-mediated networks among various tissues or treatments. It can also build the networks mediated by all known miRNAs based on specific degradomes. Furthermore, DPMIND can be used to study the conservation and specificity of MTIs and sub-networks across different plant tissues or species. Availability and implementation: http://202.195.246.60/DPMIND/. Contact: huangji@njau.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29280991 TI - R2DGC: threshold-free peak alignment and identification for 2D gas chromatography mass spectrometry in R. AB - Summary: Comprehensive 2D gas chromatography-mass spectrometry is a powerful method for analyzing complex mixtures of volatile compounds, but produces a large amount of raw data that requires downstream processing to align signals of interest (peaks) across multiple samples and match peak characteristics to reference standard libraries prior to downstream statistical analysis. Very few existing tools address this aspect of analysis and those that do have shortfalls in usability or performance. We have developed an R package that implements retention time and mass spectra similarity threshold-free alignments, seamlessly integrates retention time standards for universally reproducible alignments, performs common ion filtering and provides compatibility with multiple peak quantification methods. We demonstrate that our package's performance compares favorably to existing tools on a controlled mix of metabolite standards separated under variable chromatography conditions and data generated from cell lines. Availability and implementation: R2DGC can be downloaded at https://github.com/rramaker/R2DGC or installed via the Comprehensive R Archive Network (CRAN). Contact: sjcooper@hudsonalpha.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29280989 TI - Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazole Derivatives as Potential Antitumor Agents against Chronic Myelogenous Leukemia: Striking Effect of Nitrothiazole Moiety. AB - In an attempt to develop potent antitumor agents, new 1,3,4-thiadiazole derivatives were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the K562 chronic myelogenous leukemia cell line that expresses the Bcr-Abl tyrosine kinase. N-(5-Nitrothiazol-2-yl)-2 ((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (2) inhibited the Abl protein kinase with an IC50 value of 7.4 uM and showed selective activity against the Bcr-Abl positive K562 cell line. Furthermore, a Bcr-Abl-compound 2 molecular modelling simulation highlighted the anchoring role of the nitrothiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. These results provide promising starting points for further development of novel kinase inhibitors. PMID- 29280993 TI - Response to "Comments on 'Double-Blind Comparison of Ultrasonic and Conventional Osteotomy in Terms of Early Postoperative Edema and Ecchymosis'". PMID- 29280992 TI - Subtle variation in shade avoidance responses may have profound consequences for plant competitiveness. AB - Background and Aims: Although phenotypic plasticity has been shown to be beneficial for plant competitiveness for light, there is limited knowledge on how variation in these plastic responses plays a role in determining competitiveness. Methods: A combination of detailed plant experiments and functional-structural plant (FSP) modelling was used that captures the complex dynamic feedback between the changing plant phenotype and the within-canopy light environment in time and 3-D space. Leaf angle increase (hyponasty) and changes in petiole elongation rates in response to changes in the ratio between red and far-red light, two important shade avoidance responses in Arabidopsis thaliana growing in dense population stands, were chosen as a case study for plant plasticity. Measuring and implementing these responses into an FSP model allowed simulation of plant phenotype as an emergent property of the underlying growth and response mechanisms. Key Results: Both the experimental and model results showed that substantial differences in competitiveness may arise between genotypes with only marginally different hyponasty or petiole elongation responses, due to the amplification of plant growth differences by small changes in plant phenotype. In addition, this study illustrated that strong competitive responses do not necessarily have to result in a tragedy of the commons; success in competition at the expense of community performance. Conclusions: Together, these findings indicate that selection pressure could probably have played a role in fine-tuning the sensitive shade avoidance responses found in plants. The model approach presented here provides a novel tool to analyse further how natural selection could have acted on the evolution of plastic responses. PMID- 29280994 TI - PRAPI: post-transcriptional regulation analysis pipeline for Iso-Seq. AB - Summary: The single-molecule real-time (SMRT) isoform sequencing (Iso-Seq) based on Pacific Bioscience (PacBio) platform has received increasing attention for its ability to explore full-length isoforms. Thus, comprehensive tools for Iso-Seq bioinformatics analysis are extremely useful. Here, we present a one-stop solution for Iso-Seq analysis, called PRAPI to analyze alternative transcription initiation (ATI), alternative splicing (AS), alternative cleavage and polyadenylation (APA), natural antisense transcripts (NAT), and circular RNAs (circRNAs) comprehensively. PRAPI is capable of combining Iso-Seq full-length isoforms with short read data, such as RNA-Seq or polyadenylation site sequencing (PAS-seq) for differential expression analysis of NAT, AS, APA and circRNAs. Furthermore, PRAPI can annotate new genes and correct mis-annotated genes when gene annotation is available. Finally, PRAPI generates high-quality vector graphics to visualize and highlight the Iso-Seq results. Availability and implementation: The Dockerfile of PRAPI is available at http://www.bioinfor.org/tool/PRAPI. Contact: lfgu@fafu.edu.cn. PMID- 29280995 TI - The autonomous flowering-time pathway pleiotropically regulates seed germination in Arabidopsis thaliana. AB - Background and Aims: Two critical developmental transitions in plants are seed germination and flowering, and the timing of these transitions has strong fitness consequences. How genetically independent the regulation of these transitions is can influence the expression of life cycles. Method: This study tested whether genes in the autonomous flowering-time pathway pleiotropically regulate flowering time and seed germination in the genetic model Arabidopsis thaliana, and tested whether the interactions among those genes are concordant between flowering and germination stages. Key Results: Several autonomous-pathway genes promote flowering and impede germination. Moreover, the interactions among those genes were highly concordant between the regulation of flowering and germination. Conclusions: Despite some degree of functional divergence between the regulation of flowering and germination by autonomous-pathway genes, the autonomous pathway is highly functionally conserved across life stages. Therefore, genes in the autonomous flowering-time pathway are likely to contribute to genetic correlations between flowering and seed germination, possibly contributing to the winter-annual life history. PMID- 29280996 TI - CRNET: an efficient sampling approach to infer functional regulatory networks by integrating large-scale ChIP-seq and time-course RNA-seq data. AB - Motivation: NGS techniques have been widely applied in genetic and epigenetic studies. Multiple ChIP-seq and RNA-seq profiles can now be jointly used to infer functional regulatory networks (FRNs). However, existing methods suffer from either oversimplified assumption on transcription factor (TF) regulation or slow convergence of sampling for FRN inference from large-scale ChIP-seq and time course RNA-seq data. Results: We developed an efficient Bayesian integration method (CRNET) for FRN inference using a two-stage Gibbs sampler to estimate iteratively hidden TF activities and the posterior probabilities of binding events. A novel statistic measure that jointly considers regulation strength and regression error enables the sampling process of CRNET to converge quickly, thus making CRNET very efficient for large-scale FRN inference. Experiments on synthetic and benchmark data showed a significantly improved performance of CRNET when compared with existing methods. CRNET was applied to breast cancer data to identify FRNs functional at promoter or enhancer regions in breast cancer MCF-7 cells. Transcription factor MYC is predicted as a key functional factor in both promoter and enhancer FRNs. We experimentally validated the regulation effects of MYC on CRNET-predicted target genes using appropriate RNAi approaches in MCF-7 cells. Availability and implementation: R scripts of CRNET are available at http://www.cbil.ece.vt.edu/software.htm. Contact: xuan@vt.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29280997 TI - DeepSig: deep learning improves signal peptide detection in proteins. AB - Motivation: The identification of signal peptides in protein sequences is an important step toward protein localization and function characterization. Results: Here, we present DeepSig, an improved approach for signal peptide detection and cleavage-site prediction based on deep learning methods. Comparative benchmarks performed on an updated independent dataset of proteins show that DeepSig is the current best performing method, scoring better than other available state-of-the-art approaches on both signal peptide detection and precise cleavage-site identification. Availability and implementation: DeepSig is available as both standalone program and web server at https://deepsig.biocomp.unibo.it. All datasets used in this study can be obtained from the same website. Contact: pierluigi.martelli@unibo.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29280998 TI - Incidence and developmental timing of endosperm failure in post-zygotic isolation between wild tomato lineages. AB - Background and Aims: Defective hybrid seed development in angiosperms might mediate the rapid establishment of intrinsic post-zygotic isolation between closely related species. Extensive crosses within and among three lineages of wild tomatoes (Solanum section Lycopersicon) were performed to address the incidence, developmental timing and histological manifestations of hybrid seed failure. These lineages encompass different, yet fairly recent, divergence times and both allopatric and partially sympatric pairs. Methods: Mature seeds were scored visually 2 months after hand pollinations, and viable-looking seeds were assessed for germination success. Using histological sections from early developing seeds from a sub-set of crosses, the growth of three major seed compartments (endosperm, embryo and seed coat) was measured at critical developmental stages up to 21 d after pollination, with a focus on the timing and histological manifestations of endosperm misdevelopment in abortive hybrid seeds. Key Results: For two of three interspecific combinations including the most closely related pair that was also studied histologically, almost all mature seeds appeared 'flat' and proved inviable; histological analyses revealed impaired endosperm proliferation at early globular embryo stages, concomitant with embryo arrest and seed abortion in both cross directions. The third interspecific combination yielded a mixture of flat, inviable and plump, viable seeds; many of the latter germinated and exhibited near-normal juvenile phenotypes or, in some instances, hybrid necrosis and impaired growth. Conclusions: The overall results suggest that near-complete hybrid seed failure can evolve fairly rapidly and without apparent divergence in reproductive phenology/biology. While the evidence accrued here is largely circumstantial, early-acting disruptions of normal endosperm development are most probably the common cause of seed failure regardless of the type of endosperm (nuclear or cellular). PMID- 29280999 TI - Multiple hot-deck imputation for network inference from RNA sequencing data. AB - Motivation: Network inference provides a global view of the relations existing between gene expression in a given transcriptomic experiment (often only for a restricted list of chosen genes). However, it is still a challenging problem: even if the cost of sequencing techniques has decreased over the last years, the number of samples in a given experiment is still (very) small compared to the number of genes. Results: We propose a method to increase the reliability of the inference when RNA-seq expression data have been measured together with an auxiliary dataset that can provide external information on gene expression similarity between samples. Our statistical approach, hd-MI, is based on imputation for samples without available RNA-seq data that are considered as missing data but are observed on the secondary dataset. hd-MI can improve the reliability of the inference for missing rates up to 30% and provides more stable networks with a smaller number of false positive edges. On a biological point of view, hd-MI was also found relevant to infer networks from RNA-seq data acquired in adipose tissue during a nutritional intervention in obese individuals. In these networks, novel links between genes were highlighted, as well as an improved comparability between the two steps of the nutritional intervention. Availability and implementation: Software and sample data are available as an R package, RNAseqNet, that can be downloaded from the Comprehensive R Archive Network (CRAN). Contact: alyssa.imbert@inra.fr or nathalie.villa vialaneix@inra.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281000 TI - A high-resolution map of the human small non-coding transcriptome. AB - Motivation: Although the amount of small non-coding RNA-sequencing data is continuously increasing, it is still unclear to which extent small RNAs are represented in the human genome. Results: In this study we analyzed 303 billion sequencing reads from nearly 25 000 datasets to answer this question. We determined that 0.8% of the human genome are reliably covered by 874 123 regions with an average length of 31 nt. On the basis of these regions, we found that among the known small non-coding RNA classes, microRNAs were the most prevalent. In subsequent steps, we characterized variations of miRNAs and performed a staged validation of 11 877 candidate miRNAs. Of these, many were actually expressed and significantly dysregulated in lung cancer. Selected candidates were finally validated by northern blots. Although isolated miRNAs could still be present in the human genome, our presented set likely contains the largest fraction of human miRNAs. Contact: c.backes@mx.uni-saarland.de or andreas.keller@ccb.uni saarland.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281001 TI - Genome U-Plot: a whole genome visualization. AB - Motivation: The ability to produce and analyze whole genome sequencing (WGS) data from samples with structural variations (SV) generated the need to visualize such abnormalities in simplified plots. Conventional two-dimensional representations of WGS data frequently use either circular or linear layouts. There are several diverse advantages regarding both these representations, but their major disadvantage is that they do not use the two-dimensional space very efficiently. We propose a layout, termed the Genome U-Plot, which spreads the chromosomes on a two-dimensional surface and essentially quadruples the spatial resolution. We present the Genome U-Plot for producing clear and intuitive graphs that allows researchers to generate novel insights and hypotheses by visualizing SVs such as deletions, amplifications, and chromoanagenesis events. The main features of the Genome U-Plot are its layered layout, its high spatial resolution and its improved aesthetic qualities. We compare conventional visualization schemas with the Genome U-Plot using visualization metrics such as number of line crossings and crossing angle resolution measures. Based on our metrics, we improve the readability of the resulting graph by at least 2-fold, making apparent important features and making it easy to identify important genomic changes. Results: A whole genome visualization tool with high spatial resolution and improved aesthetic qualities. Availability and implementation: An implementation and documentation of the Genome U-Plot is publicly available at https://github.com/gaitat/GenomeUPlot. Contact: vasmatzis.george@mayo.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281002 TI - An automated benchmarking platform for MHC class II binding prediction methods. AB - Motivation: Computational methods for the prediction of peptide-MHC binding have become an integral and essential component for candidate selection in experimental T cell epitope discovery studies. The sheer amount of published prediction methods-and often discordant reports on their performance-poses a considerable quandary to the experimentalist who needs to choose the best tool for their research. Results: With the goal to provide an unbiased, transparent evaluation of the state-of-the-art in the field, we created an automated platform to benchmark peptide-MHC class II binding prediction tools. The platform evaluates the absolute and relative predictive performance of all participating tools on data newly entered into the Immune Epitope Database (IEDB) before they are made public, thereby providing a frequent, unbiased assessment of available prediction tools. The benchmark runs on a weekly basis, is fully automated, and displays up-to-date results on a publicly accessible website. The initial benchmark described here included six commonly used prediction servers, but other tools are encouraged to join with a simple sign-up procedure. Performance evaluation on 59 data sets composed of over 10 000 binding affinity measurements suggested that NetMHCIIpan is currently the most accurate tool, followed by NN align and the IEDB consensus method. Availability and implementation: Weekly reports on the participating methods can be found online at: http://tools.iedb.org/auto_bench/mhcii/weekly/. Contact: mniel@bioinformatics.dtu.dk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281003 TI - Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth. AB - With half a million babies born preterm each year in the USA and about 15 million worldwide, preterm birth (PTB) remains a global health issue. Preterm birth is a primary cause of infant morbidity and mortality and can impact lives long past infancy. The fact that there are numerous, and many currently unidentified, etiologies of PTB has hindered development of tools for risk evaluation and preventative therapies. Infection is estimated to be involved in nearly 40% of PTBs of known etiology; therefore, understanding how infection-mediated inflammation alters the cervical milieu and leads to preterm tissue biomechanical changes are questions of interest. Using RNA-seq, we identified enrichment of components involved in inflammasome activation and unique proteases in the mouse cervix during lipopolysaccharide (LPS)-mediated PTB and not physiologically at term before labor. Despite transcriptional induction of inflammasome components, there was no evidence of functional activation based on assessment of mature IL1B and IL18 proteins. The increased transcription of proteases that target both elastic fibers and collagen and concentration of myeloid-derived cells capable of protease synthesis in the cervical stroma support the structural disruption of elastic fibers as a functional output of protease activity. The recent demonstration that elastic fibers contribute to the biomechanical function of the pregnant cervix suggests their protease-induced disruption in the infection model of LPS-mediated PTB and may contribute to premature loss of mechanical competency and preterm delivery. Collectively, the transcriptomics and ultrastructural data provide new insights into the distinct mechanisms of premature cervical remodeling in response to infection. PMID- 29281004 TI - Computational identification of binding energy hot spots in protein-RNA complexes using an ensemble approach. AB - Motivation: Identifying RNA-binding residues, especially energetically favored hot spots, can provide valuable clues for understanding the mechanisms and functional importance of protein-RNA interactions. Yet, limited availability of experimentally recognized energy hot spots in protein-RNA crystal structures leads to the difficulties in developing empirical identification approaches. Computational prediction of RNA-binding hot spot residues is still in its infant stage. Results: Here, we describe a computational method, PrabHot (Prediction of protein-RNA binding hot spots), that can effectively detect hot spot residues on protein-RNA binding interfaces using an ensemble of conceptually different machine learning classifiers. Residue interaction network features and new solvent exposure characteristics are combined together and selected for classification with the Boruta algorithm. In particular, two new reference datasets (benchmark and independent) have been generated containing 107 hot spots from 47 known protein-RNA complex structures. In 10-fold cross-validation on the training dataset, PrabHot achieves promising performances with an AUC score of 0.86 and a sensitivity of 0.78, which are significantly better than that of the pioneer RNA-binding hot spot prediction method HotSPRing. We also demonstrate the capability of our proposed method on the independent test dataset and gain a competitive advantage as a result. Availability and implementation: The PrabHot webserver is freely available at http://denglab.org/PrabHot/. Contact: leideng@csu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281005 TI - Comments on "Double-Blind Comparison of Ultrasonic and Conventional Osteotomy in Terms of Early Postoperative Edema and Ecchymosis". PMID- 29281006 TI - PINE-SPARKY.2 for automated NMR-based protein structure research. AB - Summary: Nuclear magnetic resonance (NMR) spectroscopy, along with X-ray crystallography and cryoelectron microscopy, is one of the three major tools that enable the determination of atomic-level structural models of biological macromolecules. Of these, NMR has the unique ability to follow important processes in solution, including conformational changes, internal dynamics and protein-ligand interactions. As a means for facilitating the handling and analysis of spectra involved in these types of NMR studies, we have developed PINE-SPARKY.2, a software package that integrates and automates discrete tasks that previously required interaction with separate software packages. The graphical user interface of PINE-SPARKY.2 simplifies chemical shift assignment and verification, automated detection of secondary structural elements, predictions of flexibility and hydrophobic cores, and calculation of three dimensional structural models. Availability and implementation: PINE-SPARKY.2 is available in the latest version of NMRFAM-SPARKY from the National Magnetic Resonance Facility at Madison (http://pine.nmrfam.wisc.edu/download_packages.html), the NMRbox Project (https://nmrbox.org) and to subscribers to the SBGrid (https://sbgrid.org). For a detailed description of the program, see http://www.nmrfam.wisc.edu/pine sparky2.htm. Contact: whlee@nmrfam.wisc.edu or markley@nmrfam.wisc.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281007 TI - Safety of ovarian tissue transplantation in patients with borderline ovarian tumors. AB - STUDY QUESTION: Is transplantation of cryopreserved ovarian tissue from patients with borderline ovarian tumors (BOTs) a safe procedure? SUMMARY ANSWER: BOT cells were found in frozen-thawed and xenografted ovarian tissue in 1 of 11 BOT patients. WHAT IS KNOWN ALREADY: The risk of reintroducing malignant cells upon ovarian tissue transplantation has been subject of debate for many years. Reimplantation of cryopreserved ovarian tissue from leukemia patients is unsafe, while results from studies of cryopreserved ovarian tissue from other forms of cancer, such as Hodgkin's lymphoma, are reassuring. STUDY DESIGN, SIZE, DURATION: Prospective experimental study conducted in an academic research unit using ovarian tissue from 11 patients undergoing cryopreservation for BOTs. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histology, immunohistochemistry (IHC) for mucin 1 (MUC1) and cytokeratin 7 (CK7) and molecular analysis by reverse transcription quantitative polymerase chain reaction (RT-qPCR) for CK7 and MUC1 were performed on frozen-thawed ovarian tissue from 11 patients. Long-term (5 months) xenografting of ovarian tissue in immunodeficient mice was performed. The xenografts were analyzed by histology, IHC and RT-qPCR, furthermore IHC for CD10, a marker of endometriosis, was performed on a selected sample. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis by histology, IHC and RT-qPCR indicated 10 of the ovarian tissue samples were negative. Analysis of the xenograft samples indicated nine were negative for malignant cells but in two xenografts glandular lesions were detected by histology. In these two xenografts, CK7 and MUC1 markers were demonstrated by IHC and CK7 expression also by RT-qPCR. A BOT was confirmed in the xenograft in which the original ovarian tissue was positive, while in the other case IHC demonstrated expression of endometriosis marker CD10. LIMITATIONS, REASONS FOR CAUTION: Cryopreserved ovarian fragments cannot be tested before transplantation, therefore the preimplantation analysis cannot guarantee that all cryopreserved fragments will be free of BOT cells. WIDER IMPLICATIONS OF THE FINDINGS: BOT cells can be found in cryopreserved ovarian tissue from BOT patients, therefore preimplantation analysis is an absolute prerequisite. Endometriosis can also be detected in cryopreserved ovarian tissue and caution should also be exercised in this scenario. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (FNRS-PDR Convention T.0077.14, Televie Grant 7.4590.16 awarded to Rossella Masciangelo, and Grant 5/4/150/5 awarded to Marie-Madeleine Dolmans), the Fonds Speciaux de Recherche, and the Foundation Against Cancer. None of the authors have any conflicting interests to declare. PMID- 29281008 TI - Testicular organoids: a new model to study the testicular microenvironment in vitro? AB - BACKGROUND: In recent decades, a broad range of strategies have been applied to model the testicular microenvironment in vitro. These models have been utilized to study testicular physiology and development. However, a system that allows investigations into testicular organogenesis and its impact in the spermatogonial stem-cell (SSC) niche in vitro has not been developed yet. Recently, the creation of tissue-specific organ-like structures called organoids has resurged, helping researchers to answer scientific questions that previous in vitro models could not help to elucidate. So far, a small number of publications have concerned the generation of testicular organoids and their application in the field of reproductive medicine and biology. OBJECTIVE AND RATIONALE: Here, we aim to elucidate whether testicular organoids might be useful in answering current scientific questions about the regulation and function of the SSC niche as well as germ cell proliferation and differentiation, and whether or not the existing in vitro models are already sufficient to address them. Moreover, we would like to discuss how an organoid system can be a better solution to address these prominent scientific problems in our field, by the creation of a rationale parallel to those in other areas where organoid systems have been successfully utilized. SEARCH METHODS: We comprehensively reviewed publications regarding testicular organoids and the methods that most closely led to the formation of these organ-like structures in vitro by searching for the following terms in both PubMed and the Web of Science database: testicular organoid, seminiferous tubule 3D culture, Sertoli cell 3D culture, testicular cord formation in vitro, testicular morphogenesis in vitro, germ cell 3D culture, in vitro spermatogenesis, testicular de novo morphogenesis, seminiferous tubule de novo morphogenesis, seminiferous tubule-like structures, testicular in vitro model and male germ cell niche in vitro, with no restrictions to any publishing year. The inclusion criteria were based on the relation with the main topic (i.e. testicular organoids, testicular- and seminiferous-like structures as in vitro models), methodology applied (i.e. in vitro culture, culture dimensions (2D, 3D), testicular cell suspension or fragments) and outcome of interest (i.e. organization in vitro). Publications about grafting of testicular tissue, germ cell transplantation and female germ-cell culture were excluded. OUTCOMES: The application of organoid systems is making its first steps in the field of reproductive medicine and biology. A restricted number of publications have reported and characterized testicular organoids and even fewer have denominated such structures by this method. However, we detected that a clear improvement in testicular cell reorganization is recognized when 3D culture conditions are utilized instead of 2D conditions. Depending on the scientific question, testicular organoids might offer a more appropriate in vitro model to investigate testicular development and physiology because of the easy manipulation of cell suspensions (inclusion or exclusion of a specific cell population), the fast reorganization of these structures and the controlled in vitro conditions, to the same extent as with other organoid strategies reported in other fields. WIDER IMPLICATIONS: By way of appropriate research questions, we might use testicular organoids to deepen our basic understanding of testicular development and the SSC niche, leading to new methodologies for male infertility treatment. PMID- 29281009 TI - mTM-align: an algorithm for fast and accurate multiple protein structure alignment. AB - Motivation: As protein structure is more conserved than sequence during evolution, multiple structure alignment can be more informative than multiple sequence alignment, especially for distantly related proteins. With the rapid increase of the number of protein structures in the Protein Data Bank, it becomes urgent to develop efficient algorithms for multiple structure alignment. Results: A new multiple structure alignment algorithm (mTM-align) was proposed, which is an extension of the highly efficient pairwise structure alignment program TM align. The algorithm was benchmarked on four widely used datasets, HOMSTRAD, SABmark_sup, SABmark_twi and SISY-multiple, showing that mTM-align consistently outperforms other algorithms. In addition, the comparison with the manually curated alignments in the HOMSTRAD database shows that the automated alignments built by mTM-align are in general more accurate. Therefore, mTM-align may be used as a reliable complement to construct multiple structure alignments for real world applications. Availability and implementation: http://yanglab.nankai.edu.cn/mTM-align. Contact: zhng@umich.edu or yangjy@nankai.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29281010 TI - A pro-inflammatory role of Fcalpha/MUR on marginal zone B cells in sepsis. AB - Fc receptors play important roles for a wide array of immune responses. In contrast to the well-defined Fcgamma and Fcepsilon receptors, the molecular and functional characteristics of Fc receptors for IgA and IgM have remained incompletely understood for years. Recent progress has unveiled the characteristics of Fc receptors for IgA and IgM, including Fcalpha/MU receptor (Fcalpha/MUR) (CD351), polymeric immunoglobulin receptor (poly-IgR), Fcalpha receptor (FcalphaRI) (CD89) and FcMU receptor (FcMUR). In this review, we summarize the molecular and functional characteristics of Fcalpha/MUR in comparison with poly-IgR, FcMUR and FcalphaRI, and focus particularly on the pro inflammatory function of Fcalpha/MUR expressed on marginal zone B cells in sepsis. PMID- 29281011 TI - Extracorporeal membrane oxygenation for cardiogenic shock due to alcoholic cardiomyopathy: a long-term follow-up of 4 cases. AB - Even though alcoholism is a major health concern, alcoholic cardiomyopathy is a little-known pathology. The exact prevalence remains elusive (20-40% of dilated cardiomyopathy). However, it can lead to dilated cardiomyopathy, heart failure and refractory cardiogenic shock. The literature on cardiogenic shock in alcoholic cardiomyopathy is limited. We report 4 cases of patients with refractory cardiogenic shock due to heavy alcohol consumption, who were treated with venoarterial extracorporeal membrane oxygenation. The evolution was favourable with recovery in 3 patients and the need for heart transplantation in 1 patient. After 3-5 years, all patients are alive, 2 of 4 are sober, all of them are on cardiac follow-up and none of them have presented with a cardiac relapse. PMID- 29281012 TI - Induction of human tolerogenic dendritic cells by 3'-sialyllactose via TLR4 is explained by LPS contamination. AB - The human milk oligosaccharide 3'-sialyllactose (3'SL) has previously been shown to activate murine dendritic cells (DC) in a Toll-like receptor (TLR) 4-mediated manner ex vivo. In this study we aimed to investigate whether 3'SL has similar immunomodulatory properties on human DC. 3'SL was shown to induce NF-kappaB activation via human TLR4. However, LPS was detected in the commercially obtained 3'SL from different suppliers. After the removal of LPS from 3'SL, we studied its ability to modify DC differentiation in vitro. In contrast to LPS and 3'SL, LPS free 3'SL did not induce functional and phenotypical changes on immature DC (iDC). iDC that were differentiated in the presence of LPS or 3'SL showed a semi mature phenotype (i.e., fewer CD83+CD86+ DC), produced IL-10 and abrogated IL 12p70 and tumor necrosis factor-alpha levels upon stimulation with several TLR ligands. Differentiation into these tolerogenic DC was completely abrogated by LPS removal from 3'SL. In contrast to previous reports in mice, we found that LPS free 3'SL does not activate NF-kappaB via human TLR4. In conclusion, removing LPS from (oligo)saccharide preparations is necessary to study their potential immunomodulatory function. PMID- 29281013 TI - Characterization of a novel MIIA domain-containing protein (MdcE) in Bradyrhizobium spp. AB - Several genes coding for proteins with metal ion-inducible autocleavage (MIIA) domains were identified in type III secretion system tts gene clusters from draft genomes of recently isolated Bradyrhizobium spp. MIIA domains have been first described in the effectors NopE1 and NopE2 of Bradyrhizobium diazoefficiens USDA 110. All identified genes are preceded by tts box promoter motifs. The identified proteins contain one or two MIIA domains. A phylogenetic analysis of 35 MIIA domain sequences from 16 Bradyrhizobium strains revealed four groups. The protein from Bradyrhizobium sp. LmjC strain contains a single MIIA domain and was designated MdcE (MdcELmjC). It was expressed as a fusion to maltose-binding protein (MalE) in Escherichia coli and subsequently purified by affinity chromatography. Recombinant MalE-MdcELmjC-Strep protein exhibited autocleavage in the presence of Ca2+, Cu2+, Cd2+ and Mn2+, but not in the presence of Mg2+, Ni2+ or Co2+. Site-directed mutagenesis at the predicted cleavage site abolished autocleavage activity of MdcELmjC. An LmjC mdcE- mutant was impaired in the ability to nodulate Lupinus angustifolius and Macroptilium atropurpureum. PMID- 29281016 TI - Virtual and real septal myectomy using 3-dimensional printed models. AB - We present 2 cases of extended septal myectomy using low-cost 3-dimensional (3D) printed models of the interventricular septum with its fragment cut out mechanically or by initial 'virtual' myectomy. 3D prints exhibited excellent cardiac imaging and planning of the 'optimal' volume and shape of the resection, as well as intraoperative quality control of septal myectomy by filling a trough in the 3D-printed interventricular septum with excised myocardium. PMID- 29281014 TI - Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease. AB - Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition. PMID- 29281017 TI - LUMA in cardiac development and function. PMID- 29281015 TI - Recent Activity in Expanding Populations and Purifying Selection Have Shaped Transposable Element Landscapes across Natural Accessions of the Mediterranean Grass Brachypodium distachyon. AB - Transposable element (TE) activity has emerged as a major cause of variation in genome size and structure among species. To what extent TEs contribute to genetic variation and divergence within species, however, is much less clear, mainly because population genomic data have so far only been available for the classical model organisms. In this study, we use the annual Mediterranean grass Brachypodium distachyon to investigate TE dynamics in natural populations. Using whole-genome sequencing data for 53 natural accessions, we identified more than 5,400 TE polymorphisms across the studied genomes. We found, first, that while population bottlenecks and expansions have shaped genetic diversity in B. distachyon, these events did not lead to lineage-specific activations of TE families, as observed in other species. Instead, the same families have been active across the species range and TE activity is homogeneous across populations, indicating the presence of conserved regulatory mechanisms. Second, almost half of the TE insertion polymorphisms are accession-specific, most likely because of recent activity in expanding populations and the action of purifying selection. And finally, although TE insertion polymorphisms are underrepresented in and around genes, more than 1,000 of them occur in genic regions and could thus contribute to functional divergence. Our study shows that while TEs in B. distachyon are "well-behaved" compared with TEs in other species with larger genomes, they are an abundant source of lineage-specific genetic variation and may play an important role in population divergence and adaptation. PMID- 29281019 TI - Canakinumab for Residual Inflammatory Risk. PMID- 29281020 TI - Paul Ridker MD. PMID- 29281018 TI - Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model. AB - In humans, a copy of the DUX4 retrogene is located in each unit of the D4Z4 macrosatellite repeat that normally comprises 8-100 units. The D4Z4 repeat has heterochromatic features and does not express DUX4 in somatic cells. Individuals with facioscapulohumeral muscular dystrophy (FSHD) have a partial failure of somatic DUX4 repression resulting in the presence of DUX4 protein in sporadic muscle nuclei. Somatic DUX4 derepression is caused by contraction of the D4Z4 repeat to 1-10 units (FSHD1) or by heterozygous mutations in genes responsible for maintaining the D4Z4 chromatin structure in a repressive state (FSHD2). One of the FSHD2 genes is the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. SMCHD1 mutations have also been identified in FSHD1; patients carrying a contracted D4Z4 repeat and a SMCHD1 mutation are more severely affected than relatives with only a contracted repeat or a SMCHD1 mutation. To evaluate the modifier role of SMCHD1, we crossbred mice carrying a contracted D4Z4 repeat (D4Z4-2.5 mice) with mice that are haploinsufficient for Smchd1 (Smchd1MommeD1 mice). D4Z4-2.5/Smchd1MommeD1 mice presented with a significantly reduced body weight and developed skin lesions. The same skin lesions, albeit in a milder form, were also observed in D4Z4-2.5 mice, suggesting that reduced Smchd1 levels aggravate disease in the D4Z4-2.5 mouse model. Our study emphasizes the evolutionary conservation of the SMCHD1-dependent epigenetic regulation of the D4Z4 repeat array and further suggests that the D4Z4-2.5/Smchd1MommeD1 mouse model may be used to unravel the function of DUX4 in non-muscle tissues like the skin. PMID- 29281021 TI - The prestigious TCT 2017 Award. PMID- 29281022 TI - Karin Sipido MD PhD. PMID- 29281023 TI - Cardiovascular Research. PMID- 29281024 TI - Christmas 2017 and New Year Greetings. PMID- 29281025 TI - Frontiers of lipid research: cholesterol variability, HDL biogenesis, genetics of myalgia, and lipoprotein(a). PMID- 29281026 TI - Can you recommend me a good GP? Describing social differences in patient satisfaction within 31 countries. AB - Objective: This study aims to explore social differences in patient satisfaction of their general practitioner (GP) according to patient's gender, education, household income and ethnicity in Europe. Design: By using multilevel logistic modelling the impact of socioeconomic indicators (i.e. gender, education, household income and ethnicity) on patient satisfaction is estimated. In each model the authors controlled for indicators of person-focused care and strength of the primary care system. Setting: Primary care in 31 European countries. Participants: Patients who were sitting in the waiting room of the GP were asked to participate. They filled in the questionnaire after the consultation with the GP. Intervention: Describing social differences in patient satisfaction among European primary care patients. Main Outcome Measure(s): Patient satisfaction. Results: This study confirms previous research and reveals high levels of satisfaction with primary care in Europe. On average, 92.1% of the respondents would recommend their GP to their family or relatives. Variance in patient satisfaction is mostly explained at patient level, ~75% of the variance can be assigned to patient characteristics. Likewise, women, low-income groups and first generation migrants are less satisfied with their GP. Lastly, all indicators of person-focused care are positively associated with patient satisfaction, showing that the more person-focused the care, the higher the satisfaction among the patients. Conclusions: Notwithstanding the high satisfaction rates in Europe, patient satisfaction is still determined by patients' socioeconomic status (gender and household income), migration background and the degree of person centred care. Therefore, policymakers and health professionals should target these population groups in order to improve the satisfaction rates in their country. PMID- 29281027 TI - Cas9/sgRNA selective targeting of the P23H Rhodopsin mutant allele for treating retinitis pigmentosa by intravitreal AAV9.PHP.B-based delivery. AB - P23H is the most common mutation in the RHODOPSIN (RHO) gene leading to a dominant form of retinitis pigmentosa (RP), a rod photoreceptor degeneration that invariably causes vision loss. Specific disruption of the disease P23H RHO mutant while preserving the wild-type (WT) functional allele would be an invaluable therapy for this disease. However, various technologies tested in the past failed to achieve effective changes and consequently therapeutic benefits. We validated a CRISPR/Cas9 strategy to specifically inactivate the P23H RHO mutant, while preserving the WT allele in vitro. We, then, translated this approach in vivo by delivering the CRISPR/Cas9 components in murine Rho+/P23H mutant retinae. Targeted retinae presented a high rate of cleavage in the P23H but not WT Rho allele. This gene manipulation was sufficient to slow photoreceptor degeneration and improve retinal functions. To improve the translational potential of our approach, we tested intravitreal delivery of this system by means of adeno associated viruses (AAVs). To this purpose, the employment of the AAV9-PHP.B resulted the most effective in disrupting the P23H Rho mutant. Finally, this approach was translated successfully in human cells engineered with the homozygous P23H RHO gene mutation. Overall, this is a significant proof-of concept that gene allele specific targeting by CRISPR/Cas9 technology is specific and efficient and represents an unprecedented tool for treating RP and more broadly dominant genetic human disorders affecting the eye, as well as other tissues. PMID- 29281029 TI - Investigation of the non-thermal effects of exposing cells to 70-300 GHz irradiation using a widely tunable source. AB - This study investigated the effects of millimeter wave (MMW) irradiation with a wide range of frequencies on the proliferation and activity of normal human skin fibroblast (NB1RBG) and human glioblastoma (A172) cells. Very few studies have focused on low-power, long-term irradiation of cells with a widely tunable source. Our research examined non-thermal effects on cells exposed to radiation at low power with tunable frequencies from 70 GHz to 300 GHz. A widely tunable MMW source was set within a cell culture incubator. To avoid the effect of heat generation due to irradiation, the intensity was maintained below 10 MUW and the device was arranged such that the irradiation came from underneath the cells. Irradiation was performed by sweeping from 70 GHz to 300 GHz in 1.0 GHz steps. The MMW source was positioned 100 mm away from the container in which the cells were cultured. Cells were exposed to MMWs for either 3, 70 or 94 h. Measurements of cell proliferation were made using the alternating current measurement method. We found no difference in proliferation between cells exposed to MMWs and unexposed cells. A colorimetric method using novel tetrazolium compound: MTS [3 (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt] was used for cell activity and cytotoxicity assays. We found no difference in cellular activity or toxicity between MMW-exposed cells and sham cells. Our study thus found no non-thermal effect as a result of exposure of cells to 70 GHz to 300 GHz of radiation. PMID- 29281030 TI - Motor learning and metaplasticity in striatal neurons: relevance for Parkinson's disease. AB - Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human alpha-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human alpha-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse. PMID- 29281028 TI - Please do not recycle! Translation reinitiation in microbes and higher eukaryotes. AB - Protein production must be strictly controlled at its beginning and end to synthesize a polypeptide that faithfully copies genetic information carried in the encoding mRNA. In contrast to viruses and prokaryotes, the majority of mRNAs in eukaryotes contain only one coding sequence, resulting in production of a single protein. There are, however, many exceptional mRNAs that either carry short open reading frames upstream of the main coding sequence (uORFs) or even contain multiple long ORFs. A wide variety of mechanisms have evolved in microbes and higher eukaryotes to prevent recycling of some or all translational components upon termination of the first translated ORF in such mRNAs and thereby enable subsequent translation of the next uORF or downstream coding sequence. These specialized reinitiation mechanisms are often regulated to couple translation of the downstream ORF to various stimuli. Here we review all known instances of both short uORF-mediated and long ORF-mediated reinitiation and present our current understanding of the underlying molecular mechanisms of these intriguing modes of translational control. PMID- 29281031 TI - Effect of long fasting on myocardial accumulation in 18F-fluorodeoxyglucose positron emission tomography after chemoradiotherapy for esophageal carcinoma. AB - This study sought to evaluate the effect of fasting time prior to 18F fluorodeoxyglucose positron emission tomography (FDG-PET) on myocardial accumulation of FDG in patients receiving radiotherapy for esophageal carcinoma, and the spatial relationship between the irradiated dose and myocardial accumulation of FDG. Forty-one patients with thoracic esophageal carcinoma received FDG-PET with <18-h (24 patients) or >=18-h (17 patients) fasting status. Their myocardial accumulation patterns of FDG were categorized using the maximal standardized uptake value (SUVmax) into three types: physiological, focal and no pathological accumulation. The incidence rates of each pattern were then compared using the Fisher's exact test between two types of fasting, >=18-h and <18-h, prior to FDG-PET. Additionally, the left ventricle was defined using four subsites depending on the irradiated doses, and the SUVmax values were compared among the subsites using the Kruskal-Wallis test. The incidence of the physiological accumulation pattern decreased significantly more in the >=18-h fasting status group than in the <18-h fasting group (18% versus 71%, P = 0.002), and the focal accumulation of FDG was detected at a significantly higher rate (65% versus 13%, P = 0.001). The left ventricular subsites receiving the higher doses showed significantly higher SUVmax values than did the subsites receiving the lower doses (P < 0.001). In conclusion, radiotherapy was associated with abnormal myocardial accumulation of FDG. Long fasting for 18 h or more prior to FDG-PET would be useful in detecting subsequent myocardial damage from chemoradiotherapy compared with <18-h fasting prior to FDG-PET. PMID- 29281032 TI - ZmWRKY79 positively regulates maize phytoalexin biosynthetic gene expression and is involved in stress response. AB - Maize (Zea mays) accumulates maize terpenoid phytoalexins (MTPs), kauralexins and zealexins in response to various elicitations. Although the key biosynthetic genes for these have been characterized, the regulatory mechanism remains unclear. Through co-correlation analysis, a transcription factor (TF), ZmWRKY79, was identified as highly correlated with expression of MTP biosynthetic genes. Gene expression analysis indicated that ZmWRKY79 was induced by Fusarium graminearum infection, phytohormone treatment, and multiple stresses. Overexpression of ZmWRKY79 in maize protoplasts increased expression of genes involved in MTP biosynthesis, jasmonic acid and ethylene pathways, and scavenging of reactive oxygen species (ROS). Subsequent transient RNAi in maize protoplast compromised the induction of MTP biosynthetic genes by jasmonic acid and ethylene combined treatment. Such regulation was further demonstrated to be dependent on a W-box or WLE cis-element. Transient overexpression of ZmWRKY79 in tobacco conferred resistance against Rhizoctonia solani infection through reducing ROS production. Our results indicate that MTP biosynthesis is regulated by the common transcription factor ZmWRKY79, which plays a broad role as a potential master regulator in stress response through involvement in phytohormone metabolism or signaling and ROS scavenging. PMID- 29281034 TI - Concomitant surgical treatment of coronary artery disease and coarctation of the aorta in a patient with dextrocardia. AB - We report the case of a 43-year-old woman with severe coronary artery disease, coarctation of the aorta and dextrocardia. Concomitant repair was achieved by coronary artery bypass grafting and ascending-descending bypass of the proximal descending thoracic aorta. PMID- 29281033 TI - Comparing and Combining Topiramate and Aripiprazole on Alcohol-Related Outcomes in a Human Laboratory Study. AB - Aims: The goal of this study was to evaluate the efficacy of topiramate up to 200 mg/day and of aripiprazole up to 15 mg/day, alone and combined, in reducing alcohol-related outcomes in a human laboratory study. Method: This was a 5 week, between-subject, double-blind, placebo-controlled human laboratory study with topiramate [0 mg/day (placebo), 100 mg/day, 200 mg/day] and aripiprazole [0 mg/day (placebo), 7.5 mg/day, 15 mg/day] in 90 non-treatment seeking, heavy drinking, alcohol-dependent individuals. Main outcomes were the efficacy of 200 mg/day topiramate and 15 mg/day aripiprazole, alone and combined, in reducing drinks consumed during an alcohol self-administration procedure (human laboratory phase) and while receiving the study medications prior to the laboratory session (naturalistic drinking phase). Other outcomes in the laboratory phase included alcohol craving, and alcohol biphasic effects. Results: In the human laboratory phase, topiramate 200 mg/day reduced alcohol craving [**P < 0.01] and amplified alcohol-induced stimulation [*P < 0.05], but did not reduce the number of drinks consumed. Topiramate 200 mg/day was also effective in reducing drinking days [*P < 0.05], and alcohol craving [*P < 0.05], in the naturalistic drinking phase. No significant findings were found for aripiprazole for any of the outcomes analyzed. Conclusion: Participants receiving 200 mg/day topiramate reported reduced alcohol drinking and craving, and increased alcohol-related stimulation. These findings provide further support for the role of topiramate as a pharmacological treatment for AUD. ClinicalTrial.gov Identifier: NCT00884884. Short Summary: This study tested topiramate and aripiprazole alone and in combination. The results replicate past findings and suggest that topiramate may be an effective treatment for alcohol use disorder. The present results suggest that the combination of topiramate and aripiprazole do not warrant further evaluation. PMID- 29281035 TI - Cellular responses and gene expression profiles of colonic Lgr5+ stem cells after low-dose/low-dose-rate radiation exposure. AB - We previously found that high-dose-rate radiation induced a replenishment of the colonic Lgr5+ stem cell pool, whereas low-dose-rate radiation did not. To identify key molecules that determine the dose-rate effects on this stem cell pool, we harvested colonic Lgr5+ stem cells by cell sorting at 2 weeks after exposure to 1 Gy of high-dose-rate (30 Gy/h) or low-dose-rate (0.003 Gy/h) radiation and analyzed their gene expression profiles using RNA-Seq. We found that pathways related to DNA damage response, cell growth, cell differentiation and cell death were upregulated in Lgr5+ stem cells irradiated with high dose rates, whereas pathways related to apical junctions and extracellular signaling were upregulated in low-dose-rate-irradiated colonic Lgr5+ stem cells. Interestingly, biological events involving apical junctions are known to play an important role in the exclusion of transformed cells that are surrounded by normal epithelial cells through 'cell competition'. We speculated that cell competition, through apical junctions and extracellular ligands, might contribute to the dose-rate effect on Lgr5+ cell replenishment. To understand this mechanism, we focused on 69 genes that were significantly upregulated in low-dose rate-irradiated cells, which we named DREDGE (Dose-Rate Effect Determining GEnes). Based on these findings, we propose a possible mechanism underlying the dose-rate effect observed in the colonic stem cell pool. PMID- 29281036 TI - A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-1. AB - Background: Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods: REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5-14 days. The primary endpoint of this study was a >=20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population. Results: ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, -0.13%; 95% confidence interval, -6.42%-6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild. Conclusions: Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens. Clinical Trials Registration: NCT02600611. PMID- 29281038 TI - Smoking Cessation Pharmacotherapy, Even Without Counseling, Remains a Cornerstone of Treatment. PMID- 29281037 TI - Central Administration of Cyclosporine A Decreases Ethanol Drinking. AB - Aims: Abstinence among alcohol dependent liver graft recipients is remarkably high. The routine use of anti-immune agents in these patients led to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing alcohol consumption. It remained unclear, however, whether the decreased alcohol consumption in rodent models is mediated through peripheral suppression of immune response or centrally through direct inhibition of cyclophilin-CLN in the brain. We tested the hypothesis that direct brain inhibition of CLN with intracerebroventricular (ICV) injections of the immunosuppressant cyclosporine A (CsA) is sufficient to decrease ethanol consumption in a rodent model of binge-like drinking. Methods: Male C57BL/6NHsd mice were put through a modified 'drinking in the dark' (DID) paradigm. Effects of both peripheral (IP) and central (ICV) injections of CsA on ethanol consumption were assessed. Results: Here, as in earlier work, IP CsA administration significantly decreased alcohol consumption. Supporting our hypothesis, central administration of CsA was sufficient to decrease alcohol consumption in a dose-dependent manner. There was no significant effect of CsA on water or sucrose consumption. Conclusions: These results clearly implicate a CLN mediated mechanism in brain in the inhibitory effects of CsA on ethanol consumption and provide novel targets for investigation of treatment for Alcohol Use Disorders (AUD). These results also add to the growing body of literature implicating neuroimmune mechanisms in the etiology, pathophysiology and behaviors driving AUD. Short Summary: The unusually high abstinence rate and routine use of immunosuppressants in AUD liver graft recipients led us to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing drinking. Here we demonstrate that this effect is mediated by brain rather than peripheral immune mechanisms. PMID- 29281039 TI - Assessing individual-level needle and syringe coverage parameters and the measurement of coverage in Melbourne, Australia: methods and impacts. AB - Background: To assess the structure of individual-level needle and syringe coverage measurement formula, and to estimate the impact of coverage-related behaviours/parameters (instances of syringe acquisition, total syringes acquired, peer-to-peer syringe distribution, injecting frequency) on overall coverage. Methods: Data are drawn from the Melbourne (Australia) injecting drug user cohort study, 2010-16. Data from 518 participants were analysed. We used correlations to explore the relationships between coverage parameters; pooled multiple-linear regression to estimate the effect of each parameter on coverage over time; and exploratory factor analysis to assess the relevance of each parameter within the coverage formula. Results: A 1-unit increase in injecting frequency over time reduced coverage by 10.93 percentage points, almost twice as much as other coverage parameters. Factor analysis results indicated potential improvements to coverage formula structure. Conclusions: Our results suggest that reducing injecting frequency amongst people who inject drugs has the largest improvement in coverage levels, indicating harm reduction services should prioritize it. We also demonstrate that coverage measurement has been inconsistent to date. We sought to refine the method to assist in generating comparable research. PMID- 29281040 TI - Effectiveness of Pharmaceutical Smoking Cessation Aids in a Nationally Representative Cohort of American Smokers. AB - Background: Despite strong efficacy in randomized trials, the population effectiveness of pharmaceutical aids in long-term smoking cessation is lacking, possibly because of confounding (factors that are associated with both pharmaceutical aid use and difficulty quitting). Matching techniques in longitudinal studies can remove this confounding bias. Methods: Using the nationally representative Tobacco Use Supplement to the Current Population Survey (TUS-CPS), we assessed the effectiveness of medications to aid quitting among baseline adult smokers who attempted to quit prior to one year of follow-up in two longitudinal studies: 2002-2003 and 2010-2011. Pharmaceutical aid users and nonusers with complete data (n = 2129) were matched using propensity score models with 12 potential confounders (age, sex, race-ethnicity, education, smoking intensity, nicotine dependence, previous quit history, self-efficacy to quit, smoke-free homes, survey year, and cessation aid use). Using matched data sets, logistic regression models were fit to assess whether use of any individual pharmaceutical aid increased the proportion of patients who were abstinent for 30 days or more at follow-up. Results: Propensity score matching markedly improved balance on the potential confounders between the pharmaceutical aid use groups. Using matched samples to provide a balanced comparison, there was no evidence that use of varenicline (adjusted risk difference [aRD] = 0.01, 95% confidence interval [CI] = -0.07 to 0.11), bupropion (aRD = 0.02, 95% CI = -0.04 to 0.09), or nicotine replacement (aRD = 0.01, 95% CI = -0.03 to 0.06) increased the probability of 30 days or more smoking abstinence at one-year follow-up. Conclusions: The lack of effectiveness of pharmaceutical aids in increasing long term cessation in population samples is not an artifact caused by confounded analyses. A possible explanation is that counseling and support interventions provided in efficacy trials are rarely delivered in the general population. PMID- 29281041 TI - Patterns of multi-morbidity and prediction of hospitalisation and all-cause mortality in advanced age. AB - Background: multi-morbidity is associated with poor outcomes and increased healthcare utilisation. We aim to identify multi-morbidity patterns and associations with potentially inappropriate prescribing (PIP), subsequent hospitalisation and mortality in octogenarians. Methods: life and Living in Advanced Age; a Cohort Study in New Zealand (LiLACS NZ) examined health outcomes of 421 Maori (indigenous to New Zealand), aged 80-90 and 516 non-Maori, aged 85 years in 2010. Presence of 14 chronic conditions was ascertained from self report, general practice and hospitalisation records and physical assessments. Agglomerative hierarchical cluster analysis identified clusters of participants with co-existing conditions. Multivariate regression models examined the associations between clusters and PIP, 48-month hospitalisations and mortality. Results: six clusters were identified for Maori and non-Maori, respectively. The associations between clusters and outcomes differed between Maori and non-Maori. In Maori, those in the complex multi-morbidity cluster had the highest prevalence of inappropriately prescribed medications and in cluster 'diabetes' (20% of sample) had higher risk of hospitalisation and mortality at 48-month follow-up. In non-Maori, those in the 'depression-arthritis' (17% of the sample) cluster had both highest prevalence of inappropriate medications and risk of hospitalisation and mortality. Conclusions: in octogenarians, hospitalisation and mortality are better predicted by profiles of clusters of conditions rather than the presence or absence of a specific condition. Further research is required to determine if the cluster approach can be used to target patients to optimise resource allocation and improve outcomes. PMID- 29281042 TI - Seed germination in parasitic plants: what insights can we expect from strigolactone research? AB - Obligate root-parasitic plants belonging to the Orobanchaceae family are deadly pests for major crops all over the world. Because these heterotrophic plants severely damage their hosts even before emerging from the soil, there is an unequivocal need to design early and efficient methods for their control. The germination process of these species has probably undergone numerous selective pressure events in the course of evolution, in that the perception of host derived molecules is a necessary condition for seeds to germinate. Although most of these molecules belong to the strigolactones, structurally different molecules have been identified. Since strigolactones are also classified as novel plant hormones that regulate several physiological processes other than germination, the use of autotrophic model plant species has allowed the identification of many actors involved in the strigolactone biosynthesis, perception, and signal transduction pathways. Nevertheless, many questions remain to be answered regarding the germination process of parasitic plants. For instance, how did parasitic plants evolve to germinate in response to a wide variety of molecules, while autotrophic plants do not? What particular features are associated with their lack of spontaneous germination? In this review, we attempt to illustrate to what extent conclusions from research into strigolactones could be applied to better understand the biology of parasitic plants. PMID- 29281043 TI - Density Dependence and Growth Rate: Evolutionary Effects on Resistance Development to Bt (Bacillus thuringiensis). AB - It has long been recognized that pest population dynamics can affect the durability of a pesticide, but dose remains the primary component of insect resistance management (IRM). For transgenic pesticidal traits such as Bt (Bacillus thuringiensis Berliner (Bacillales: Bacillaceae)), dose (measured as the mortality of susceptibles caused by a toxin) is a relatively fixed characteristic and often falls below the standard definition of high dose. Hence, it is important to understand how pest population dynamics modify durability and what targets they present for IRM. We used a deterministic model of a generic arthropod pest to examine how timing and strength of density dependence interacted with population growth rate and Bt mortality to affect time to resistance. As in previous studies, durability typically reached a minimum at intermediate doses. However, high population growth rates could eliminate benefits of high dose. The timing of density dependence had a more subtle effect. If density dependence operated simultaneously with Bt mortality, durability was insensitive to its strengths. However, if density dependence was driven by postselection densities, decreasing its strength could increase durability. The strength of density dependence could affect durability of both single traits and pyramids, but its influence depended on the timing of density dependence and size of the refuge. Our findings suggest the utility of a broader definition of high dose, one that incorporates population-dynamic context. That maximum growth rates and timing and strength of interactions causing density dependent mortality can all affect durability, also highlights the need for ecologically integrated approaches to IRM research. PMID- 29281044 TI - Radiobiological response of U251MG, CHO-K1 and V79 cell lines to accelerator based boron neutron capture therapy. AB - In the current article, we provide in vitro efficacy evaluation of a unique accelerator-based neutron source, constructed at the Budker Institute of Nuclear Physics (Novosibirsk, Russian Federation), for boron neutron capture therapy (BNCT), which is particularly effective in the case of invasive cancers. U251MG, CHO-K1 and V79 cells were incubated and irradiated in various concentrations of boric acid with epithermal neutrons for 2-3 h in a plexiglass phantom, using 2.0 MeV proton energy and 1.5-3.0 mA proton current, resulting in a neutron fluence of 2.16 * 1012 cm-2. The survival curves of cells loaded with boron were normalized to those irradiated without boron (to exclude the influence of the fast neutron and gamma dose components) and fit to the linear-quadratic (LQ) model. Colony formation assays showed the following cell survival rates (means +/ SDs): CHO-K1: 0.348 +/- 0.069 (10 ppm), 0.058 +/- 0.017 (20 ppm), 0.018 +/- 0.005 (40 ppm); V79: 0.476 +/- 0.160 (10 ppm), 0.346 +/- 0.053 (20 ppm), 0.078 +/ 0.015 (40 ppm); and U251MG: 0.311 +/- 0.061 (10 ppm), 0.131 +/- 0.022 (20 ppm), 0.020 +/- 0.010 (40 ppm). The difference between treated cells and controls was significant in all cases (P < 0.01) and confirmed that the neutron source and irradiation regimen were sufficient for control over cell colony formation. We believe our study will serve as a model for ongoing in vitro experiments on neutron capture therapy to advance in this area for further development of accelerator-based BNCT into the clinical phase. PMID- 29281045 TI - Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease. AB - Hyperphosphorylated tau aggregates are characteristic of tauopathies including progressive supranuclear palsy (PSP) and Alzheimer disease (AD), but factors contributing to pathologic tau phosphorylation are not well understood. Here, we studied the regulation of the major tau phosphatase, the heterotrimeric AB55alphaC protein phosphatase 2 A (PP2A), in PSP and AD. The assembly and activity of this PP2A isoform are regulated by reversible carboxyl methylation of its catalytic C subunit, while the B subunit confers substrate specificity. We sought to address whether the decreases in PP2A methylation and its methylating enzyme, leucine carboxyl methyltransferase (LCMT-1), which are reported in AD, relate to tau pathology or to concomitant amyloid pathology by comparing them in the relatively pure tauopathy PSP. Immunohistochemical analysis of frontal cortices showed that methyl-PP2A is reduced while demethyl-PP2A is increased, with no changes in total PP2A or B55alpha subunit, resulting in a reduction in the methyl/demethyl PP2A ratio of 63% in PSP and 75% in AD compared to controls. Similarly, Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains. This was associated with a decrease in LCMT-1 and an increase in the demethylating enzyme, protein phosphatase methylesterase (PME-1), in both diseases. These findings suggest that PP2A dysregulation in tauopathies may contribute to the accumulation of hyperphosphorylated tau and to neurodegeneration. PMID- 29281047 TI - Symptom-Triggered Detoxification Using the Alcohol-Withdrawal-Scale Reduces Risks and Healthcare Costs. AB - Aims: As there are only a few existing experimental studies on symptom-triggered therapy for patients with alcohol withdrawal, we investigated the effectiveness of symptom-triggered detoxification regarding the use and dosage of benzodiazepine and withdrawal complications in a naturalistic clinical setting of a specialized treatment center for alcohol use disorder. Methods: In total, 301 charts of patients who entered residential treatment for alcohol withdrawal were included in the retrospective analysis. Charts of 176 patients treated with the Alcohol Withdrawal-Scale (AWS) were compared to the charts of 125 patients treated with treatment as usual (TAU) before the implementation of AWS. Sociodemographical and clinical variables, previous detoxifications and complications, duration of treatment, use and dose of benzodiazepine and other withdrawal medication, complications and premature discontinuation of treatment were abstracted from the patients' medical records. Results: The two groups did not differ in any demographical or clinical variables measured upon treatment admission. The total percentage of patients being treated with benzodiazepines during detoxification decreased from 78.4 to 38.6% after the implementation of the AWS. The implementation of the AWS significantly reduced the duration of the acute detoxification from 136 to 66 h, and the use, duration and dose of benzodiazepine by nearly two-thirds while complications and treatment discontinuation remained unvaryingly. Healthcare costs for detoxification were reduced by half per patient. Conclusions: The findings indicate that symptom triggered treatment for alcohol withdrawal is safe and effective in a naturalistic clinical setting and significantly reduces healthcare costs and the risk for overmedicating patients. PMID- 29281046 TI - Cross-Cultural Adaptation and Psychometric Properties of the AUDIT and CAGE Questionnaires in Tanzanian Swahili for a Traumatic Brain Injury Population. AB - Aims: To develop Swahili versions of the Alcohol Use Disorders Identification Test (AUDIT) and CAGE questionnaires and evaluate their psychometric properties in a traumatic brain injury (TBI) population in Tanzania. Methods: Swahili versions of the AUDIT and CAGE were developed through translation and back translation by a panel of native speakers of both English and Swahili. The translated instruments were administered to a sample of Tanzanian adults from a TBI registry. The validity and reliability were analyzed using standard statistical methods. Results: The translated versions of both the AUDIT and CAGE questionnaires were found to have excellent language clarity and domain coherence. Reliability was acceptable (>0.85) for all tested versions. Confirmatory factor analysis of one, two and three factor solution for the AUDIT and one factor solution for the CAGE showed adequate results. AUDIT and CAGE scores were strongly correlated to each other (R > 0.80), and AUDIT scores were significantly lower in non-drinkers compared to drinkers. Conclusions: This article presents the first Swahili and Tanzanian adaptations of the AUDIT and CAGE instruments as well as the first validation of these questionnaires with TBI patients. Both instruments were found to have acceptable psychometric properties, resulting in two new useful tools for medical and social research in this setting. PMID- 29281048 TI - Communicating Messages About Drinking. PMID- 29281049 TI - The Influence of Alcohol Use on Outcomes in Patients Transplanted for Non alcoholic Liver Disease. AB - : Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) is a common event that has been extensively studied. In contrast, alcohol consumption has usually been neglected in patients transplanted for other liver diseases. First off, patients can be mislabeled as 'non-ALD' when they suffer from another chronic liver disease. Then, alcohol consumption is not systematically tracked after LT in recipients having a primary indication other than ALD, although there are increasing data incriminating alcohol as responsible for graft damage and impaired survival. This review discusses the potential consequences of alcohol after liver transplantation, focusing on patients transplanted for non-alcoholic liver disease, as well as the legitimate role of an addiction specialist, before and after LT. Short Summary: Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) is a common event that has been extensively studied. In contrast, alcohol consumption has usually been neglected in patients transplanted for other liver diseases. There are increasing data showing that alcohol consumption and its consequences should be tracked in every transplant candidate and recipient. PMID- 29281050 TI - Estimation of the occupational exposure dose for medical diagnostic X-ray workers in Jiangsu, China, using a retrospective dosimetry method. AB - Medical diagnostic X-ray workers are one occupational group that has exposure to continuous low doses of external radiation over their working lifetimes. Current ICRP recommendations [ICRP. Recommendations of the International Commission on Radiological Protection. ICRP Publication 60. Ann ICRP 1991;21 (1-3)] state that there is no threshold of stochastic effects induced by radiation exposure such as carcinogenicity or genetic defects, and that the frequency of the effects is proportional to the amount of exposure to low levels of radiation, which is measured by radiation dose. In order to determine the dose information for this special occupational group over their working lifetimes (focusing particularly on workers exposed before 1985, when there was no personal dose monitoring), a sampling survey of the occupational history for these workers was conducted and an occupational history database was established. Using the database and retrospective dosimetry method of Zhang et al. (A retrospective dosimetry method for occupational dose for Chinese medical diagnostic X-ray workers. Radiat Prot Dosimetry 1998;77:69-72), the annual occupational exposure dose for medical diagnostic X-ray personnel working between 1950 and 2011 was computerized. Some annual dose results estimated using the proposed method were numerically in good agreement with the monitoring results. The average of the annual dose for these medical workers peaked during the mid-1950s and then declined, reaching very low levels by the 1990s and remaining at those levels thereafter. The trend in the annual dose is similar to that reported by earlier studies by Zielinski et al. (Health outcomes of low-dose ionizing radiation exposure among medical workers: a cohort study of the Canadian national dose registry of radiation workers. Int J Occup Med Environ Health 2009;22:149-56). The dose calculated by the retrospective dosimetry method can truly indicate the degree of the workers' exposure in their medical X-ray diagnostic work. PMID- 29281051 TI - Evaluation of a Novel Global Immunity Assay to Predict Infection in Organ Transplant Recipients. AB - Background: Solid organ transplant recipients (SOTRs) are predisposed to infection due to the need for lifelong immunosuppression, although tools to measure the overall degree of immunosuppression are limited. In this study, we used a novel global cell-mediated immunity (CMI) assay to quantify the degree of immunosuppression and predict subsequent infections. Methods: Consecutive SOTRs were enrolled and provided whole blood to conduct the global CMI assay (QuantiFERON Monitor) at 1, 3, and 6 months posttransplant. The assay measures plasma interferon gamma (IFN-gamma) levels after stimulation of whole blood with antigens that stimulate both innate and adaptive immunity. Bacterial, viral, and fungal infections were prospectively recorded. Results: We enrolled 137 patients who provided CMI measurements on at least 1 study timepoint. Median age was 58 years; transplant types were kidney (32.1%), liver (30.7%), and lung (36.5%). At least 1 episode of infection occurred in 32 of 137 (23.4%) patients between 1 and 3 months, 34 of 135 (25.1%) between 3 and 6 months, and 39 of 132 (29.5%) between 6 and 12 months. IFN-gamma levels were significantly lower in those with at least 1 episode of infection vs no infection at month 1 (P = .04), month 3 (P = .05), and month 6 (P = .006). Patients who developed opportunistic infections (OIs) also showed a significantly lower CMI than those without OI at months 3 and 6. Using a cutoff value of <=10 IU/mL of IFN-gamma, there was a 2- to 3-fold greater likelihood of subsequent infection in those with lower CMI. Conclusions: We show that a novel global immunity assay is able to quantify the level of immunosuppression and predict the risk of subsequent infection episodes in organ transplant recipients. PMID- 29281052 TI - Mite Fauna Assessment in Houses of Two distinct Socioeconomic Groups From Southern Brazil. AB - House dust mites (HDM) are the main source of aeroallergens worldwide, yet epidemiological differences between socioeconomic factors in association with this medical condition have not been studied in the south region of Brazil. To assess the prevalence of HDM in two socioeconomically distinct populations of patients with allergic asthma or rhinitis, the differences between samples from houses of high-income families and low-income families were analyzed. Mite samples were collected between July and December 2015, in Porto Alegre, Brazil. The HDM were Dermatophagoides pteronyssinus and Dermatophagoides farinae (Hughes; Acari: Pyroglyphidae). Also, other non-pyroglyphid house mites were identified in dust samples: Tyrophagus putrescentiae (Schrank; Acari: Acaridae), Chortoglyphus arcuatus, and Cheyletus malaccensis. Identification of species was performed through morphological keys with a stereomicroscope and a phase optical microscope. A total of 104 homes was evaluated (low-income group: n = 53; high income group, n = 51). We found a total of 721 mites, representing 11 species, in 93 (89%) houses. In the remaining houses, no mites were found. We observed no significant differences of species composition between the groups studied. However, the number of mites was significantly higher in the low-income group (P < 0.001). D. pteronyssinus was the predominant species detected, with 286 mites (39.6%). D. farinae was not detected in any sample. Our results show that living rooms from low-income families present higher numbers of HDM. PMID- 29281053 TI - Reported Incidence and Survival of Fallopian Tube Carcinomas: A Population-Based Analysis From the North American Association of Central Cancer Registries. AB - Background: Recognition that serous tubal intraepithelial carcinoma (STIC) may represent the first manifestation of many high-grade cancers that were once considered ovarian primary tumors has led to changes in diagnostic practices that could dramatically increase the reporting of tubal carcinomas in US population based cancer registries. Further, increased detection of early-stage tubal carcinomas through increased recognition coupled with meticulous pathology processing protocols raises important unanswered questions about the clinical behavior of such lesions, which can only be answered using large data sets. However, rates of tubal carcinomas have not been recently analyzed. Accordingly, we analyzed population-based incidence and survival data for fallopian tube carcinoma in situ (CIS; an imperfect surrogate of STIC), tubal carcinomas, and for comparison, ovarian carcinomas, in the North American Association of Central Cancer Registries (NAACCR) registries. Methods: Total counts, standardized incidence rates, and stage-specific survival were computed using 30 NAACCR registries (1999-2012). Temporal incidence rate patterns were analyzed by joinpoint regression with estimates of annual percentage change (APC). All statistical tests were two-sided. Results: Fallopian tube CIS incidence rates were stable from 1999 to 2002, then increased from 2002 to 2012 (APC = 16.2%, 95% confidence interval [CI] = 10.9% to 21.7%, P < .001). Rates of early- and late stage tubal carcinomas showed similar patterns, whereas high-grade serous ovarian carcinoma rates were relatively stable. Five-year cause-specific survival was 97.9% (95% CI = 93.7% to 99.3%) for tubal CIS and 83.2% (95% CI = 77.3% to 87.7%) for early-stage high-grade serous tubal carcinoma. Conclusions: Reporting of tubal CIS and tubal carcinoma have increased in recent years, likely reflecting changes in pathology processing of specimens and diagnosis. Developing standardized reporting for tubal neoplasms is needed to enable analysis of outcomes for these comparatively uncommon but increasingly recognized tumors. PMID- 29281055 TI - Resection of a Midbrain Cavernous Malformation Via Far Posterior Subtemporal Approach to the Dorsolateral Brainstem: 2-Dimensional Operative Video. PMID- 29281054 TI - Radiation-induced unrepairable DSBs: their role in the late effects of radiation and possible applications to biodosimetry. AB - Although the vast majority of DNA damage induced by radiation exposure disappears rapidly, some lesions remain in the cell nucleus in very small quantities for days to months. These lesions may cause a considerable threat to an organism and include certain types of DNA double-strand breaks (DSBs) called 'unrepairable DSBs'. Unrepairable DSBs are thought to cause persistent malfunctioning of cells and tissues or cause late effects of radiation, especially the induction of delayed cell death, mutation, senescence, or carcinogenesis. Moreover, the measurement of unrepairable DSBs could potentially be used for retrospective biodosimetry or for identifying individuals at greater risk for developing the adverse effects associated with radiotherapy or chemotherapy. This review summarizes the concept of unrepairable DSBs in the context of persistent repair foci formed at DSBs. PMID- 29281056 TI - Phytomelatonin: a universal abiotic stress regulator. AB - Melatonin, a derivative of tryptophan, was first detected in plant species in 1995 and it has been shown to be a diverse regulator during plant growth and development, and in stress responses. Recently, great progress has been made towards determining the detailed functions of melatonin in plant responses to abiotic stress. Melatonin priming improves plant tolerance to cold, heat, salt, and drought stresses through regulation of genes involved in the DREB/CBF, HSF, SOS, and ABA pathways, respectively. As a scavenger of free radicals, melatonin also directly detoxifies reactive oxygen species, thus alleviating membrane oxidation. Abiotic stress-inhibited photosynthesis is partially recovered and metabolites accumulate in the presence of melatonin, leading to improved plant growth, delayed leaf senescence, and increased stress tolerance. In this review, we summarize the interactions of melatonin with phytohormones to regulate downstream gene expression, protein stabilization, and epigenetic modification in plants. Finally, we consider the need for, and approaches to, the identification of melatonin receptors and components during signaling transduction pathways. PMID- 29281057 TI - Detection of Leishmania DNA and Blood Meal Identification in Sand Flies (Diptera: Psychodidae) From Lencois Maranhenses National Park Region, Brazil. AB - To elucidate portions of the transmission cycles of American tegumentary leishmaniasis (TL) and visceral leishmaniasis (VL) occurring in the region surrounding the Lencois Maranhenses National Park, an important tourist center in Brazil, the present study objectives were to determine the rate of natural infection by Leishmania spp. and the blood meal in caught sand flies species in the region. Sand flies were captured over 36 mo in 62 locations of the municipality of Barreirinhas, Maranhao with notifications of disease incidence. Species identification of parasites was performed with internal transcribed spacer 1 (ITS1) PCR-RFLP using HaeIII enzyme. Blood meal identification was performed with cytochrome b (cytb) gene PCR-RFLP using HaeIII and MboI enzyme. The species Lutzomyia longipalpis (Lutz and Neiva 1912) presented a positivity rate of 3.7% for Leishmania infantum. Species not considered vectors of this parasite such as Lu. lenti (Mangabeira 1938) and Lu. whitmani (Antunes & Coutinho 1939) showed infection rates of 0.6% and 0.9%, respectively. Among the vectors of Leishmania spp. was Lu. whitmani with detection rate of 0.3% for Le. braziliensis and Lu. flaviscutellata (Mangabeira 1942) with a detection rate of 8% for Le. amazonensis. After restriction of amplification product encoding a 359bp sequence of the cytb recognized in as follows: pigs (37.9%); dogs (27.4%); chickens (20.9%); horses (9%), rodents (3.3%), and humans (1.4%). The presence of Leishmania DNA in sand flies fed with human blood and domestic animals in villages with transmission of VL and TL suggests that transmission could be occurring in the locations of the infected patients. PMID- 29281060 TI - Measuring Wisdom: Existing Approaches, Continuing Challenges, and New Developments. AB - The question how wisdom can best be measured is still open to debate. Currently, there are two groups of wisdom measures: open-ended performance measures and self report measures. This overview article describes the most popular current measures of wisdom: the Berlin Wisdom Paradigm, the Bremen Wisdom Paradigm, Grossmann's wise-reasoning approach, the Three-Dimensional Wisdom Scale, the Self Assessed Wisdom Scale, and the Adult Self-Transcendence Inventory. It discusses the specific challenges of both open-ended and self-report approaches with respect to content validity, convergent and divergent validity, concurrent and discriminant validity, and ecological validity. Finally, promising new developments are outlined that may bridge the gap between wisdom as a competence and wisdom as an attitude and increase ecological validity by being more similar to real-life manifestations of wisdom. These new developments include autobiographical approaches and advice-giving paradigms. PMID- 29281058 TI - Transcriptomic and Metabolomic Reprogramming from Roots to Haustoria in the Parasitic Plant, Thesium chinense. AB - Most plants show remarkable developmental plasticity in the generation of diverse types of new organs upon external stimuli, allowing them to adapt to their environment. Haustorial formation in parasitic plants is an example of such developmental reprogramming, but its molecular mechanism is largely unknown. In this study, we performed field-omics using transcriptomics and metabolomics to profile the molecular switch occurring in haustorial formation of the root parasitic plant, Thesium chinense, collected from its natural habitat. RNA sequencing with de novo assembly revealed that the transcripts of very long chain fatty acid (VLCFA) biosynthesis genes, auxin biosynthesis/signaling-related genes and lateral root developmental genes are highly abundant in the haustoria. Gene co-expression network analysis identified a network module linking VLCFAs and the auxin-responsive lateral root development pathway. GC-TOF-MS analysis consistently revealed a unique metabolome profile with many types of fatty acids in the T. chinense root system, including the accumulation of a 25-carbon long chain saturated fatty acid in the haustoria. Our field-omics data provide evidence supporting the hypothesis that the molecular developmental machinery used for lateral root formation in non-parasitic plants has been co-opted into the developmental reprogramming of haustorial formation in the linage of parasitic plants. PMID- 29281059 TI - Identification of C-terminal Regions in Arabidopsis thaliana Phytochelatin Synthase 1 Specifically Involved in Activation by Arsenite. AB - Phytochelatins (PCs) are major chelators of toxic elements including inorganic arsenic (As) in plant cells. Their synthesis confers tolerance and influences within-plant mobility. Previous studies had shown that various metal/metalloid ions differentially activate PC synthesis. Here we identified C-terminal parts involved in arsenite- [As(III)] dependent activation of AtPCS1, the primary Arabidopsis PC synthase. The T-DNA insertion in the AtPCS1 mutant cad1-6 causes a truncation in the C-terminal regulatory domain that differentially affects activation by cadmium (Cd) and zinc (Zn). Comparisons of cad1-6 with the AtPCS1 null mutant cad1-3 and the double mutant of tonoplast PC transporters abcc1/2 revealed As(III) hypersensitivity of cad1-6 equal to that of cad1-3. Both cad1-6 and cad1-3 showed increased As distribution to shoots compared with Col-0, whereas Zn accumulation in shoots was equally lower in cad1-6 and cad1-3. Supporting these phenotypes of cad1-6, PC accumulation in the As(III)-exposed plants were at trace level in both cad1-6 and cad1-3, suggesting that the truncated AtPCS1 of cad1-6 is defective in PCS activity in response to As(III). Analysis of a C-terminal deletion series of AtPCS1 using the PCS-deficient mutant of fission yeast suggested important regions within the C-terminal domain for As(III)-dependent PC synthesis, which were different from the regions previously suggested for Cd- or Zn-dependent activation. Interestingly, we identified a truncated variant more strongly activated than the wild-type protein. This variant could potentially be used as a tool to better restrict As mobility in plants. PMID- 29281061 TI - Electronic Medication Regimen Complexity Index at admission and complications during hospitalization in medical wards: a tool to improve quality of care? AB - Objective: Adverse events during hospitalization are a major worry considering their frequency and their burden. Many could be avoided by immediate identification of at-risk patients at admission and adapted prevention. The complexity of a patient's medication regimen immediately available at admission is a good indicator of the complexity of the patient's condition. This study aims to determine whether the electronic Medication Regimen Complexity Index (MRCI) at admission is associated with complications during hospitalization. Design: We performed a multilevel logistic regression model, adjusted for age and sex. Setting: Premier PerspectiveTM database, a clinical and financial information system from 417 US hospitals. Participants: Adults hospitalized for more than 3 days in a medical ward and included in Premier's PerspectiveTM database for 2006. Intervention(s): Multilevel logistic regression. Main Outcome Measure: Association of the MRCI and complications during hospitalization, defined as in hospital death, hospital-acquired infection, pressure ulcers; and need for highly technical healthcare, identified as the secondary introduction of catecholamines. Results: In total, 1 592 383 admissions were included. The median MRCI at admission was 13 [interquartile range: 9-19]. The higher the MRCI, the higher the adjusted odds ratio of the following: in-hospital mortality, hospital-acquired infections, pressure ulcers and the secondary introduction of catecholamines. Conclusions: Our results suggested that the MRCI at admission was correlated with patient complexity, independent of age. Considering that patients with complex conditions pose a heavier workload for staff, measuring MRCI at admission could be used to allocate resources in medical wards at an institutional level. The MRCI might be a useful tool to assess the management of care. PMID- 29281062 TI - Cardiac MR imaging genotoxicity? PMID- 29281063 TI - Linking Demography and Consumption of Henosepilachna vigintioctopunctata (Coleoptera: Coccinellidae) Fed on Solanum photeinocarpum (Solanales: Solanaceae): With a New Method to Project the Uncertainty of Population Growth and Consumption. AB - Because life tables are capable of providing the most comprehensive description on the survival, stage differentiation, and the reproduction of animal populations, they can be considered as the bases of population ecology and pest management. Researchers concerned with studies involving life tables inevitably face the problem of describing the variabilities that occur in the survival, stage differentiation, and fecundity data. Finding a means to include these variabilities in population projections concerning pest management may be problematic. Henosepilachna vigintioctopunctata (F.) (Coleoptera: Coccinellidae) is a pest of many plant species in Asia, including cultivated crops, ornamentals, and wild plants. The raw life history data (survival, stage differentiation, and fecundity) and consumption rate of both sexes of H. vigintioctopunctata reared on Solanum photeinocarpum Nakamura et Odashima (Solanales: Solanaceae) were collected in the laboratory and analyzed based on the age-stage, two-sex life table theory. The intrinsic rate of increase (r), finite rate of increase (lambda), net reproductive rate (R0), mean generation time (T), and net consumption rate (C0) of H. vigintioctopunctata were 0.1312 d-1, 1.1402 d-1, 603.5 offspring, 48.8 d, and 77.8 cm2, respectively. By using the bootstrap technique with 100,000 samples, we demonstrated that the life tables constructed based on the 2.5th and 97.5th percentiles of R0 and lambda can be used to describe the variabilities found in the survival and fecundity curves and to project the uncertainty of population growth. PMID- 29281064 TI - Maize leaf PPDK regulatory protein isoform-2 is specific to bundle sheath chloroplasts and paradoxically lacks a Pi-dependent PPDK activation activity. AB - In C4 plants, the pyruvate phosphate dikinase regulatory protein (PDRP) regulates the C4 pathway enzyme pyruvate phosphate dikinase (PPDK) in response to changes in incident light intensity. In maize (Zea mays) leaves, two distinct isoforms of PDRP are expressed, ZmPDRP1 and ZmPDRP2. The properties and C4 function of the ZmPDRP1 isoform are well understood. However, the PDRP2 isoform has only recently been identified and its properties and function(s) in maize leaves are unknown. We therefore initiated an investigation into the maize PDRP2 isoform by performing a side by side comparison of its enzyme properties and cell-specific distribution with PDRP1. In terms of enzyme functionality, PDRP2 was found to possess the same protein kinase-specific activity as PDRP1. However, the PDRP2 isoform was found to lack the phosphotransferase activity of the bifunctional PDRP1 isoform except when PDRP2 in the assays is elevated 5- to 10-fold. A primarily immuno-based approach was used to show that PDRP1 is strictly expressed in mesophyll cells and PDRP2 is strictly expressed in bundle sheath strand cells (BSCs). Additionally, using in situ immunolocalization, we establish a regulatory target for PDRP2 by showing a significant presence of C4 PPDK in BSC chloroplasts. However, a metabolic role for PPDK in this compartment is obscure, assuming PPDK accumulating in this compartment would be irreversibly inactivated each dark cycle by a monofunctional PDRP2. PMID- 29281065 TI - Usefulness of Sealants for Dural Closure: Evaluation in an In Vitro Model. AB - BACKGROUND: Cerebrospinal fluid (CSF) leakage occurs in 4% to 32% of cranial surgeries and is associated with significant patient burden and expense. The use of sealant as an adjunct to primary dural closure is assumed to help prevent CSF leakage. OBJECTIVE: To examine the utility of different sealants for dural closure using an in Vitro model. METHODS: We evaluated 9 commonly used dural sealants, including Tachosil (Takeda Inc, Osaka, Japan), Adherus (Hyperbranch Inc, Durham, North Carolina), Duraform (Codman, Raynham, Massachusetts), Tissudura (Baxter, Deerfield, Illinois), Hemopatch (Baxter), TissuePatchDural (Tissuemed, Leeds, United Kingdom), Tisseel (Baxter), Duragen Secure (Integra, Plainsboro, New Jersey), and Duraseal, (Integra). Sealants were tested in 2 novel in Vitro setups using fresh porcine dura: the first tested the acute burst pressure of a sealed 3-mm gap, while the second examined resistance to a pressure wave mimicking intracranial pressure for 72 h. RESULTS: Adherus showed the highest mean burst pressure (87 +/- 47 mmHg) followed by Tachosil (71 +/- 16 mmHg) and Duraseal (51 +/- 42 mmHg); these were the only 3 sealants showing burst pressures above normal physiological intracranial pressure. In the 72-h setup, only Adherus and Duraseal maintained appropriate sealing for the duration of the experiment. Tachosil released from the dura after 1.4 h (95% confidence interval, -1.8-4.7). CONCLUSION: Given the high cost of sealants and the results of this study, we advocate a critical attitude toward sealant application as an adjunct to classic dural closure. PMID- 29281066 TI - Serum dehydroepiandrosterone sulphate, psychosocial factors and musculoskeletal pain in workers. AB - Background: The serum level of dehydroepiandrosterone sulphate (DHEA-S) has been suggested as a biological marker of stress. Aims: To assess the association between serum DHEA-S, psychosocial factors and musculoskeletal (MS) pain in university workers. Methods: The study population included voluntary workers at the scientific departments of the University of Trieste (Italy) who underwent periodical health surveillance from January 2011 to June 2012. DHEA-S level was analysed in serum. The assessment tools included the General Health Questionnaire (GHQ) and a modified Nordic musculoskeletal symptoms questionnaire. The relation between DHEA-S, individual characteristics, pain perception and psychological factors was assessed by means of multivariable linear regression analysis. Results: There were 189 study participants. The study population was characterized by high reward and low effort. Pain perception in the neck, shoulder, upper limbs, upper back and lower back was reported by 42, 32, 19, 29 and 43% of people, respectively. In multivariable regression analysis, gender, age and pain perception in the shoulder and upper limbs were significantly related to serum DHEA-S. Effort and overcommitment were related to shoulder and neck pain but not to DHEA-S. The GHQ score was associated with pain perception in different body sites and inversely to DHEA-S but significance was lost in multivariable regression analysis. Conclusions: DHEA-S was associated with age, gender and perception of MS pain, while effort-reward imbalance dimensions and GHQ score failed to reach the statistical significance in multivariable regression analysis. PMID- 29281067 TI - Exaggerated exercise-induced sytolic blood pressure response: arterial baroreceptor sensitivity or carotid stiffness? PMID- 29281068 TI - Effects of excess DL- and L-methionine on growth performance of starter Pekin ducks. AB - A dose-response experiment was conducted to investigate the effects of excess DL methionine (DLM) and L-methionine (LM) on growth response of starter Pekin ducks from 7 to 21 days of age. A total of 462 seven-day-old male Pekin ducklings were allotted to 77 wire-floor pens with 6 birds per pen. There were 11 treatments including a methionine-adequate control diet (containing 0.49% methionine) and control diets supplemented with 5 levels of crystal DLM or LM (0.25, 0.50, 0.75, 1.0, and 1.25%) based on equal product weight. At 21 d of age, weight gain, feed intake, and feed/gain of ducks from each pen were measured. In our study, the weight gain and feed intake did not change markedly and kept a plateau when supplemental DLM or LM was below 0.50%, but the weight gain and feed intake decreased further as supplemental DLM or LM increased from 0.50 to 1.25%. When the maximum safe level (MSL) of supplemental methionine sources and methionine content of the control diets were combined, the total tolerable upper limits of methionine for weight gain and feed intake were 0.91 and 0.85% when DLM was used, respectively, and the corresponding values were 0.89 and 0.84% when LM was used, respectively. On the other hand, both excess DLM and LM reduced weight gain and feed intake (P < 0.05) but there were no significant differences (P > 0.05) in weight gain and feed intake between the ducks fed DLM- and LM-supplemented diets. Furthermore, linear slope-ratio assay was also used to evaluate the relative toxicity of excess DLM and LM. According to this assay, the efficiencies of DLM relative to LM for depression of weight gain and feed intake were 97 and 95%, respectively. In summary, excess DL- and L-methionine were toxic for starter Pekin ducks and both methionine sources were equally growth depressing. PMID- 29281069 TI - Effectiveness of behavioral interventions to reduce the intake of sugar-sweetened beverages in children and adolescents: a systematic review and meta-analysis. AB - Context: Consumption of sugar-sweetened beverages (SSBs) among children has been associated with adverse health outcomes. Numerous behavioral interventions aimed at reducing the intake of SSBs among children have been reported, yet evidence of their effectiveness is lacking. Objective: This systematic review explored the effectiveness of educational and behavioral interventions to reduce SSB intake and to influence health outcomes among children aged 4 to 16 years. Data Sources: Seven databases were searched for randomized controlled trials published prior to September 2016. Studies identified were screened for eligibility. Study Selection: Trials were included in the review if they met the PICOS (Population, Intervention, Comparison, Outcome, and Study design) criteria for inclusion of studies. Data Extraction: Data were extracted by 2 reviewers following Cochrane guidelines and using Review Manager software. Results: Of the 16 trials included, 12 were school based and 4 were community or home based. Only 3 trials provided data that could be pooled into a meta-analysis for evaluating change in SSB intake. Subgroup analyses showed a trend toward a significant reduction in SSB intake in participants in school-based interventions compared with control groups. Change in body mass index z scores was not statistically significant between groups. Conclusions: The quality of evidence from included trials was considered moderate, and the effectiveness of educational and behavioral interventions in reducing SSB intake was modest. Systematic Review Registration: PROSPERO registration number CRD42014004432. PMID- 29281070 TI - Radiation-Induced Cavernous Malformations After Single-Fraction Meningioma Radiosurgery. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is a commonly performed procedure for patients with intracranial meningiomas. OBJECTIVE: To describe the clinical features of patients with radiation-induced cavernous malformations (RICM) after single-fraction meningioma SRS. METHODS: Retrospective study of patients having single-fraction SRS for intracranial meningioma at our center from 1990 through 2009, and 1 patient who had single-fraction SRS elsewhere. Patients were excluded if they refused research authorization (n = 7), had a World Health Organization Grade II or III meningioma (n = 65), had a genetic predisposition for tumor development (n = 52), had prior or concurrent radiation therapy (n = 49), or had less than 2 yr of magnetic resonance imaging follow-up after SRS (n = 77). The median follow-up of the remaining 426 patients was 7.9 yr (range, 2-24.9). RESULTS: Three RICM (0.7%) were identified at 2, 10, and 21 yr after SRS. Two patients were asymptomatic, whereas 1 patient had a brainstem hemorrhage causing facial weakness and numbness. The risk of developing an RICM after SRS was 0.2% at 5 yr and 0.9% at 15 yr. All patients were observed and remained stable without additional bleeding in follow-up of 7, 12.8, and 2 yr, respectively. A fourth patient developed progressive neurological dysfunction starting 7 yr after SRS at another center and was treated for several years with bevacizumab without improvement. Surgical resection was performed 11.5 yr after SRS and histologic examination was consistent with an RICM. CONCLUSION: The risk of RICM after single-fraction SRS for intracranial meningiomas is very low, but the latency period noted until their detection emphasizes the need for extended imaging follow-up after SRS of benign lesions. PMID- 29281072 TI - Retrosigmoid Craniotomy and Petrosal Fissure Dissection for Transpeduncular Resection of a Deep Pontine Arteriovenous Malformation: 2-Dimensional Operative Video. PMID- 29281071 TI - The role of retrograde signals during plant stress responses. AB - Chloroplast and mitochondria not only provide the energy to the plant cell but due to the sensitivity of organellar processes to perturbations caused by abiotic stress, they are also key cellular sensors of environmental fluctuations. Abiotic stresses result in reduced photosynthetic efficiency and thereby reduced energy supply for cellular processes. Thus, in order to acclimate to stress, plants must re-program gene expression and cellular metabolism to divert energy from growth and developmental processes to stress responses. To restore cellular energy homeostasis following exposure to stress, the activities of the organelles must be tightly co-ordinated with the transcriptional re-programming in the nucleus. Thus, communication between the organelles and the nucleus, so-called retrograde signalling, is essential to direct the energy use correctly during stress exposure. Stress-triggered retrograde signals are mediated by reactive oxygen species and metabolites including beta-cyclocitral, MEcPP (2-C-methyl-d erythritol 2,4-cyclodiphosphate), PAP (3'-phosphoadenosine 5'-phosphate), and intermediates of the tetrapyrrole biosynthesis pathway. However, for the plant cell to respond optimally to environmental stress, these stress-triggered retrograde signalling pathways must be integrated with the cytosolic stress signalling network. We hypothesize that the Mediator transcriptional co-activator complex may play a key role as a regulatory hub in the nucleus, integrating the complex stress signalling networks originating in different cellular compartments. PMID- 29281073 TI - Comprehensive Anatomic Assessment of the Pterional, Orbitopterional, and Orbitozygomatic Approaches for Basilar Apex Aneurysm Clipping. AB - BACKGROUND: The pterional approach, along with its orbitopterional and orbitozygomatic extensions, is among the most common surgical approaches for tackling challenging aneurysms of the basilar artery apex (BAX). There is general consensus that the orbitozygomatic approach provides the best exposure for these lesions. However, there is little objective evidence to support approach selection for surgical treatment of BAX aneurysms. OBJECTIVE: To compare different features regarding surgical treatment of BAX aneurysms between the pterional, orbitopterional, and orbitozygomatic approaches. METHODS: The pterional, orbitopterional, and orbitozygomatic approaches were sequentially completed on 10 cadaveric specimens. The visibility of perforators, lengths of exposure, and safe clipping for major BAX branches, surgical area of exposure, and the surgical freedom for the BAX target were assessed. RESULTS: The orbitopterional approach provided significantly greater values than the pterional approach in all variables, except for exposure of the bilateral P1 posterior cerebral artery (PCA) perforators. When compared to the orbitopterional approach, the orbitozygomatic approach did not provide a statistically significant increase in (1) surgical freedom through the carotid-oculomotor triangle, (2) area of exposure, (3) ipsilateral, and (4) contralateral P1 PCA perforator visibility, and (5) ipsilateral PCA exposure and (6) clipping lengths. CONCLUSION: The orbitopterional approach provides significantly greater surgical exposure to BAX than the pterional approach. The orbitopterional approach is less invasive while providing similar surgical access to the BAX compared to the orbitozygomatic. The results of this study show that the orbitopterional approach may be optimal for the treatment of most BAX aneurysms, particularly to reduce morbidity resulting from the full orbitozygomatic approach. PMID- 29281074 TI - Deep Brain Stimulation for Essential Tremor: Aligning Thalamic and Posterior Subthalamic Targets in 1 Surgical Trajectory. AB - BACKGROUND: Ventral intermediate nucleus (VIM) deep brain stimulation (DBS) and posterior subthalamic area (PSA) DBS suppress tremor in essential tremor (ET) patients, but it is not clear which target is optimal. Aligning both targets in 1 surgical trajectory would facilitate exploring stimulation of either target in a single patient. OBJECTIVE: To evaluate aligning VIM and PSA in 1 surgical trajectory for DBS in ET. METHODS: Technical aspects of trajectories, intraoperative stimulation findings, final electrode placement, target used for chronic stimulation, and adverse and beneficial effects were evaluated. RESULTS: In 17 patients representing 33 trajectories, we successfully aligned VIM and PSA targets in 26 trajectories. Trajectory distance between targets averaged 7.2 (range 6-10) mm. In all but 4 aligned trajectories, optimal intraoperative tremor suppression was obtained in the PSA. During follow-up, active electrode contacts were located in PSA in the majority of cases. Overall, successful tremor control was achieved in 69% of patients. Stimulation-induced dysarthria or gait ataxia occurred in, respectively, 56% and 44% of patients. Neither difference in tremor suppression or side effects was noted between aligned and nonaligned leads nor between the different locations of chronic stimulation. CONCLUSION: Alignment of VIM and PSA for DBS in ET is feasible and enables intraoperative exploration of both targets in 1 trajectory. This facilitates positioning of electrode contacts in both areas, where multiple effective points of stimulation can be found. In the majority of aligned leads, optimal intraoperative and chronic stimulation were located in the PSA. PMID- 29281075 TI - Transvenous Curative Embolization of Cerebral Arteriovenous Malformations: A Prospective Cohort Study. AB - BACKGROUND: Curative transvenous embolization is an emerging strategy for treatment of cerebral arteriovenous malformations (AVMs). OBJECTIVE: To assess contemporary outcomes of transvenous embolization as a stand-alone therapy for cerebral AVMs. METHODS: We prospectively followed 40 patients with 41 AVMs who underwent transvenous endovascular therapy between January 2008 and January 2015. Patient demographics, AVM characteristics, endovascular techniques used, angiographic results, clinical outcomes, and complications were assessed independently. RESULTS: Thirty-eight of 41 (92.6%) AVMs were anatomically cured. The mean patient age was 37.7 yr (range, 18-69 yr) and 55% were female. Twenty seven (67.5%) patients presented with hemorrhage. The mean size of the AVM nidus was 2.8 +/- 1.2 cm, and low Spetzler-Martin grade AVMs comprised 41.5% of lesions. The majority of patients were treated in 1 session (56%; n = 23). The mean follow-up period was 28.4 (range, 6-106 mo). There was 1 (2.5%) hemorrhagic complication related to microcatheter navigation and 1 (2.5%) venous infarction was observed without clinical consequences. At 6-mo follow-up, 1 (2.5%) patient had significant disability. There were no recurrences during the follow-up period. Overall mortality was 2.5% and procedure-related mortality was 0%. CONCLUSION: This prospective contemporary series demonstrates a high rate of complete AVM obliteration and excellent functional outcomes in patients with both ruptured and unruptured AVMs treated with transvenous embolization. This approach is promising and warrants further investigation as a treatment for select AVMs. PMID- 29281076 TI - Impaired baroreflex sensitivity, carotid stiffness, and exaggerated exercise blood pressure: a community-based analysis from the Paris Prospective Study III. AB - Aims: People with exaggerated exercise blood pressure (BP) have adverse cardiovascular outcomes. Mechanisms are unknown but could be explained through impaired neural baroreflex sensitivity (BRS) and/or large artery stiffness. This study aimed to determine the associations of carotid BRS and carotid stiffness with exaggerated exercise BP. Methods and results: Blood pressure was recorded at rest and following an exercise step-test among 8976 adults aged 50 to 75 years from the Paris Prospective Study III. Resting carotid BRS (low frequency gain, from carotid distension rate, and heart rate) and stiffness were measured by high precision echotracking. A systolic BP threshold of >= 150 mmHg defined exaggerated exercise BP and >=140/90 mmHg defined resting hypertension (+/ antihypertensive treatment). Participants with exaggerated exercise BP had significantly lower BRS [median (Q1; Q3) 0.10 (0.06; 0.16) vs. 0.12 (0.08; 0.19) (ms2/mm) 2*108; P < 0.001] but higher stiffness [mean +/- standard deviation (SD); 7.34 +/- 1.37 vs. 6.76 +/- 1.25 m/s; P < 0.001) compared to those with non exaggerated exercise BP. However, only lower BRS (per 1SD decrement) was associated with exaggerated exercise BP among people without hypertension at rest {specifically among those with optimal BP; odds ratio (OR) 1.16 [95% confidence intervals (95% CI) 1.01; 1.33], P = 0.04 and high-normal BP; OR, 1.19 (95% CI 1.07; 1.32), P = 0.001} after adjustment for age, sex, body mass index, smoking, alcohol, total cholesterol, high-density lipoprotein cholesterol, resting heart rate, and antihypertensive medications. Conclusion: Impaired BRS, but not carotid stiffness, is independently associated with exaggerated exercise BP even among those with well controlled resting BP. This indicates a potential pathway from depressed neural baroreflex function to abnormal exercise BP and clinical outcomes. PMID- 29281078 TI - Robotically-Operated Video Optical Telescopic-microscopy Resection of an Arteriovenous Malformation With Port-Assisted Intraoperative Surgical Devascularization: 2-Dimensional Operative Video. PMID- 29281077 TI - Value of Neonicotinoid Insecticide Seed Treatments in Mid-South Cotton (Gossypium hirsutum [Malvales: Malvaceae]) Production Systems. AB - Neonicotinoid insecticides are currently one of two classes of chemicals available as a seed treatment for growers to manage early season insect pests of cotton, Gossypium hirsutum L. (Malvales: Malvaceae), and they are used on nearly 100% of cotton hectares in the midsouthern states. An analysis was performed on 100 seed-treatment trials from Arkansas, Louisiana, Mississippi, and Tennessee to determine the value of neonicotinoid seed treatments in cotton production systems. The analysis compared seed treated with neonicotinoid insecticides seed treatments plus a fungicide with seed only treated with fungicide. When analyzed by state, cotton yields were significantly greater when neonicotinoid seed treatments were used compared with fungicide-only treatments. Cotton treated with neonicotinoid seed treatments yielded 123, 142, 95, and 104 kg ha-1, higher than fungicide only treatments for Arkansas, Louisiana, Mississippi, and Tennessee, respectively. Across all states, neonicotinoid seed treatments provided an additional 115 kg lint ha-1 comparedwith fungicide only treated seed. Average net returns from cotton with a neonicotinoid seed treatment were $1,801 per ha-1 compared with $1,660 per ha-1 for cottonseed treated with fungicide only. Economic returns for cotton with neonicotinoid seed treatments were significantly greater than cottonseed treated with fungicide only in 8 out of 15 yr representing every state. These data show that neonicotinoid seed treatments provide significant yield and economic benefits in Mid-South cotton compared with fungicide only treated seed. PMID- 29281079 TI - Lanthanum deposition in the gastric mucosa in a patient undergoing hemodialysis. PMID- 29281080 TI - Precancerous Lesions of Ovarian Cancer-A US Perspective. PMID- 29281081 TI - HISP: a hybrid intelligent approach for identifying directed signaling pathways. AB - Signal transduction plays important roles in biological systems. Unfortunately, our knowledge about signaling pathways is far from complete. Specifically, the direction of signaling flows is less known even though the signaling molecules of some signaling pathways have been determined. In this paper, we propose a novel hybrid intelligent method, namely HISP (Hybrid Intelligent approach for identifying directed Signaling Pathways), to determine both the topologies of signaling pathways and the direction of signaling flows within a pathway based on integer linear programming and genetic algorithm. By integrating the protein protein interaction, gene expression, and gene knockout data, our HISP approach is able to determine the optimal topologies of signaling pathways in an accurate way. Benchmark results on yeast MAPK signaling pathways demonstrate the efficiency of our proposed approach. When applied to the EGFR/ErbB signaling pathway in human hepatocytes, HISP unveils a high-resolution signaling pathway, where many signaling interactions were missing by existing computational approaches. PMID- 29281083 TI - Smokeless tobacco use is 'replacing' the smoking epidemic in the South East Asia Region. AB - Background: The sustained anti-tobacco campaign initiated in response to the mounting evidence against tobacco smoking has driven tobacco companies and smokers to look for alternative choices, such as smokeless tobacco (SLT) products. If this strategy advances it could undermine several gains made by the campaign over the years. Our objective was to examine the trends in the prevalence of different tobacco types in three countries (Bangladesh, India and Nepal) of South-East Asia. Methods: Data from national surveys was used to estimate the trends of weighted and age standardized prevalence (along with 95% CI) of different tobacco products. The share of each tobacco type was then calculated as a percentage of total tobacco use for each time point and country. Results: In all the three countries, smoking prevalence declined (by 6% in Bangladesh, 3% in India and 7% in Nepal) but SLT use increased (by 3% in Bangladesh, 6% in India and 4% in Nepal) over the study period. SLT use increased irrespective of whether the total tobacco use increased or decreased. The share of SLT as a percentage of total tobacco use increased from 15% to 19% among Bangladeshi men, from 46% to 61% in India and from 29% to 41% in Nepal. Conclusions: In South-East Asia, a clear shift in the product preference from smoking to SLT was noted. Misleading advertising by tobacco companies may be responsible for the increase in the SLT prevalence, which is as harmful as smoking. Countries should strengthen policies to restrict SLT usage and prevent the rise of its use. Implications: It has been documented that the smoking prevalence has been declining in most countries of the South-East Asia region where effective anti-tobacco laws have been implemented. But due to a number of factors, the prevalence of smokeless tobacco has been increasing steadily, making the entire anti-tobacco movement less effective in terms of reducing the tobacco attributable disease burden. In this context, this study has provided a detailed comparative analysis of the prevalence of smokeless tobacco use and smoking in three countries of the SEAR where such data was available. It can be clearly seen that the preference for smoking has shifted towards the smokeless tobacco in all the three study countries. This study recommends that tobacco control interventions should be aligned with the changing dynamics of the tobacco epidemic, and the need of the hour is placing restrictions of smokeless tobacco use so as to drive forward the gains of the anti-tobacco movement. PMID- 29281082 TI - Improved chloroplast energy balance during water deficit enhances plant growth: more crop per drop. AB - The non-energy-conserving alternative oxidase (AOX) respiration of plant mitochondria is known to interact with chloroplast photosynthesis. This may have consequences for growth, particularly under sub-optimal conditions when energy imbalances can impede photosynthesis. This hypothesis was tested by comparing the metabolism and growth of wild-type Nicotiana tabacum with that of AOX knockdown and overexpression lines during a prolonged steady-state mild to moderate water deficit. Under moderate water deficit, the AOX amount was an important determinant of the rate of both mitochondrial respiration in the light and net photosynthetic CO2 assimilation (A) at the growth irradiance. In particular, AOX respiration was necessary to maintain optimal proton and electron fluxes at the chloroplast thylakoid membrane, which in turn prevented a water-deficit-induced biochemical limitation of photosynthesis. As a result of differences in A, AOX overexpressors gained more biomass and knockdowns gained less biomass than wild type during moderate water deficit. Biomass partitioning also differed, with the overexpressors having a higher percentage, and the knockdowns having a lower percentage, of total above-ground biomass in reproductive tissue than wild-type. The results establish that improving chloroplast energy balance by using a non energy-conserving respiratory electron sink can increase photosynthesis and growth during prolonged water deficit. PMID- 29281084 TI - Comparison of Attraction and Trapping Capabilities of Bucket- and Delta-Style Traps With Different Pheromone Emission Rates for Gypsy Moths (Lepidoptera: Erebidae): Implications for Understanding Range of Attraction and Utility in Surveillance. AB - Delta- and bucket-style (Universal or Unitrap) traps baited with 1 standard survey lure and 1/3 and 3 lures were compared for their attractiveness and trapping efficiencies for gypsy moth, Lymantria dispar L. (Lepidoptera: Erebidae), males. With bucket traps, the numbers of males attracted to within 2 m of traps and the proportion of these actually captured were identical among the three doses although the percentage of attracted males actually captured in bucket traps was low, less than 15%. A three-lure delta trap attracted about 70% more males than traps with the two lower doses. Capture efficiencies were above 80% for 1/3- and one-lure traps and about 60% for traps baited with three lures. The number of males captured in delta traps was equivalent for the three doses although our observations also suggest that a delta trap baited with three lures drew males from a wider range than lower dose lures and therefore would be a more sensitive trap for detecting incipient populations. We also noted that males tended to arrive in clusters, suggesting that attraction over moderate distances requires periods when the wind direction is fairly constant. This observation coupled with the great variability in the direction of male arrival to the traps also suggests that important changes in the area of influence of the plume are driven in such forested areas by slower but greater changes in wind direction compared with open habitats. PMID- 29281085 TI - Increases in activity of proteasome and papain-like cysteine protease in Arabidopsis autophagy mutants: back-up compensatory effect or cell-death promoting effect? AB - Autophagy is essential for protein degradation, nutrient recycling, and nitrogen remobilization. Autophagy is induced during leaf ageing and in response to nitrogen starvation, and is known to play a fundamental role in nutrient recycling for remobilization and seed filling. Accordingly, ageing leaves of Arabidopsis autophagy mutants (atg) have been shown to over-accumulate proteins and peptides, possibly because of a reduced protein degradation capacity. Surprisingly, atg leaves also displayed higher protease activities. The work reported here aimed at identifying the nature of the proteases and protease activities that accumulated differentially (higher or lower) in the atg mutants. Protease identification was performed using shotgun LC-MS/MS proteome analyses and activity-based protein profiling (ABPP). The results showed that the chloroplast FTSH (FILAMENTATION TEMPERATURE SENSITIVE H) and DEG (DEGRADATION OF PERIPLASMIC PROTEINS) proteases and several extracellular serine proteases [subtilases (SBTs) and serine carboxypeptidase-like (SCPL) proteases] were less abundant in atg5 mutants. By contrast, proteasome-related proteins and cytosolic or vacuole cysteine proteases were more abundant in atg5 mutants. Rubisco degradation assays and ABPP showed that the activities of proteasome and papain like cysteine protease were increased in atg5 mutants. Whether these proteases play a back-up role in nutrient recycling and remobilization in atg mutants or act to promote cell death is discussed in relation to their accumulation patterns in the atg5 mutant compared with the salicylic acid-depleted atg5/sid2 double mutant, and in low nitrate compared with high nitrate conditions. Several of the proteins identified are indeed known as senescence- and stress-related proteases or as spontaneous cell-death triggering factors. PMID- 29281086 TI - Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry. AB - Aims: Current atrial fibrillation (AF) guidelines discourage antiplatelet (AP) monotherapy as alternative to anticoagulants (ACs). Why AP only is still used is largely unknown. Methods and results: Factors associated with AP monotherapy prescription were analysed in GARFIELD-AF, a registry of patients with newly diagnosed (<=6 weeks) AF and >=1 investigator-determined stroke risk factor. We analysed 51 270 patients from 35 countries enrolled into five sequential cohorts between 2010 and 2016. Overall, 20.7% of patients received AP monotherapy, 52.1% AC monotherapy, and 14.1% AP + AC. Most AP monotherapy (82.5%) and AC monotherapy (86.8%) patients were CHA2DS2-VASc >=2. Compared with patients on AC monotherapy, AP monotherapy patients were frequently Chinese (vs. Caucasian, odds ratio 2.73) and more likely to have persistent AF (1.32), history of coronary artery disease (2.41) or other vascular disease (1.67), bleeding (2.11), or dementia (1.81). The odds for AP monotherapy increased with 5 years of age increments for patients >=75 years (1.24) but decreased with age increments for patients 55-75 years (0.86). Antiplatelet monotherapy patients were less likely to have paroxysmal (0.67) or permanent AF (0.57), history of embolism (0.56), or alcohol use (0.90). With each cohort, AP monotherapy declined (P<0.0001), especially non-indicated use. AP + AC and no antithrombotic therapy were unchanged. However, even in 2015 and 2016, about 50% of AP-treated patients had no indication except AF (71% were CHA2DS2-VASc >=2). Conclusion: Prescribing AP monotherapy in newly diagnosed AF has declined, but even nowadays a substantial proportion of AP-treated patients with AF have no indication for AP. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362. PMID- 29281087 TI - Prediction of Infection After Solid Organ Transplantation: Is Measuring Cell Mediated Immunity the Answer? PMID- 29281088 TI - Prediction of acute gastrointestinal and genitourinary radiation toxicity in prostate cancer patients using lymphocyte microRNA. AB - Background: To search for novel biomarkers that can predict acute radiation toxicity, we conducted microRNA expression analysis of peripheral blood lymphocytes (PBLs). Methods: The discovery cohort was 69 patients with localized adenocarcinoma of the prostate who received intensity-modulated radiation therapy between October 2007 and October 2010. The validation cohort was 72 patients treated with low-dose-rate brachytherapy between May 2008 and March 2014. After13 microRNAs were selected by TaqMan(r) Array analysis in a preliminary experiment, expression of these microRNAs in all samples was analyzed by RT-PCR. Results: In the discovery cohort, the average prostate volume, the rectal volume receiving 70 Gy, and expression of miR-410 and miR-221 were significant risk factors for Grade 1-2 gastrointestinal toxicity. Receiver operating characteristic analysis showed that the area under the curve (AUC) was 0.807. The maximum dose to the urinary bladder, prostate volume, pretreatment urinary function score, and miR-99a and miR-221 expression were risk factors for Grade 2 genitourinary toxicity. The corresponding AUC was 0.796. In the validation cohort, reproducibility of these markers was confirmed for gastrointestinal toxicity, but not for genitourinary toxicity. Conclusion: Combining radiation dose parameters with microRNA expression in PBLs may be useful for predicting acute gastrointestinal toxicity of radiation therapy, thus contributing to personalized treatment of prostate cancer. PMID- 29281090 TI - Novel reagents for human prolactin research: large-scale preparation and characterization of prolactin receptor extracellular domain, non-pegylated and pegylated prolactin and prolactin receptor antagonist. AB - To provide new tools for in vitro and in vivo prolactin (PRL) research, novel protocols for large-scale preparation of untagged human PRL (hPRL), a hPRL antagonist (del 1-9-G129R hPRL) that acts as a pure antagonist of hPRL in binding to hPRL receptor extracellular domain (hPRLR-ECD), and hPRLR-ECD are demonstrated. The interaction of del 1-9-G129R hPRL with hPRLR-ECD was demonstrated by competitive non-radioactive binding assay using biotinylated hPRL as the ligand and hPRLR-ECD as the receptor, by formation of stable 1:1 complexes with hPRLR-ECD under non-denaturing conditions using size-exclusion chromatography, and by surface plasmon resonance methodology. In all three types of experiments, the interaction of del 1-9-G129R hPRL was equal to that of unmodified hPRL. Del 1-9-G129R hPRL inhibited the hPRL-induced proliferation of Baf/LP cells stably expressing hPRLR. Overall, the biological properties of del 1 9-G129R hPRL prepared by the protocol described herein were similar to those of the antagonist prepared using the protocol reported in the original study; however, the newly described protocol improved yields by >6-fold. To provide long lasting hPRL as a new reagent needed for in vivo experiments, we prepared its mono-pegylated analogue and found that pegylation lowers its biological activity in a homologous in vitro assay. As its future use will require the development of a PRL antagonist with highly elevated affinity, del 1-9-G129R hPRL was expressed on the surface of yeast cells. It retained its binding capacity for hPRLR-ECD, and this methodology was shown to be suitable for future development of high affinity hPRL antagonists using a library of randomly mutated open reading frame of del 1-9-G129R hPRL and selecting high-affinity mutants by yeast surface display methodology. PMID- 29281089 TI - Seasonal Reproductive Biology of Drosophila suzukii (Diptera: Drosophilidae) in Temperate Climates. AB - Drosophila suzukii (Matsumura; Diptera: Drosophilidae) is a key pest of sweet cherry and small fruits worldwide. The present studies were designed to describe the reproductive physiology in both sexes, through dissections of their reproductive organs. We extensively dissected female D. suzukii throughout the season from 2013 to 2016 and classified the reproductive status flies based on five recognizable ovarian maturation stages: 1) no ovaries; 2) unripe ovaries 3) ripening eggs in ovarioles; 4) mature eggs in ovarioles; and 5) mature eggs in the abdomen. Development was examined as a function of calendar days as well as degree-days (DD). Results obtained from winter collections revealed that females collected from November to March contained a lower percentage of mature eggs than females collected from April to September. These data suggest that environmental conditions during the dormant period induce reproductive diapause. Oogenesis likely increased with an increase in mean monthly temperatures and DD. The first overwintered females with mature eggs were dissected as early as 21 February 2014 in Trento (7 DD). Additionally, we found that a low proportion of males (less than 50%) had sperm in their testes between January and March, yet during the same period females already have sperm stored in their spermathecal. Ivy berries was an alternative but unfavorable non-crop host during the late dormant period, as evidenced by emergence of smaller adults when compared to individuals emerging from cherry fruits. This study showed that D. suzukii females have great potential for oviposition early in the season, posing a risk to early season maturing crop hosts. PMID- 29281091 TI - Self-reported drowsiness and safety outcomes while driving after an extended duration work shift in trainee physicians. AB - Objectives : Extended duration (>=24 h) work shifts (EDWS) are associated with increased risk of motor vehicle crashes, and awareness of any impairment has important implications on legal accountability for any adverse driving outcome. The extent to which adverse driving events were preceded by pre-drive self reported sleepiness was evaluated in medical residents after EDWS. Methods: Sixteen resident physicians (10F;29.2+/-2.0y) working EDWS were monitored when driving on their commute to and from the hospital (438 drives). Sleep and work hours were obtained from daily logs, and adverse driving outcomes were captured from a driving log completed at the end of each drive. Subjective sleepiness (Karolinska Sleepiness Scale; KSS) and objective drowsiness were captured using a time-stamped, hand held device and infra-red reflectance oculography. Results: Subjective sleepiness and objective indices of drowsiness were positively correlated, and both were elevated following EDWS. Compared to the commute to work, EDWS were associated with more than double the self-reported adverse outcomes when driving home; significantly higher than drives to or from the day shift at comparable times of day. EDWS more than tripled the odds of reporting sleep-related, inattentive, hazardous or violation driving events. The number and type of adverse event was predicted by the pre-drive KSS level, and in a dose dependent manner. Conclusions: Driving after EDWS puts resident physicians/drivers and other road users at avoidable and unnecessary risk. Demonstrating self-reported sleepiness at the beginning of the drive is associated with adverse outcomes has serious implications on the legal accountability for driving when drowsy. PMID- 29281093 TI - Large-scale determination and characterization of cell type-specific regulatory elements in the human genome. AB - Histone modifications have been widely elucidated to play vital roles in gene regulation and cell identity. The Roadmap Epigenomics Consortium generated a reference catalog of several key histone modifications across >100s of human cell types and tissues. Decoding these epigenomes into functional regulatory elements is a challenging task in computational biology. To this end, we adopted a differential chromatin modification analysis framework to comprehensively determine and characterize cell type-specific regulatory elements (CSREs) and their histone modification codes in the human epigenomes of five histone modifications across 127 tissues or cell types. The CSREs show significant relevance with cell type-specific biological functions and diseases and cell identity. Clustering of CSREs with their specificity signals reveals distinct histone codes, demonstrating the diversity of functional roles of CSREs within the same cell or tissue. Last but not least, dynamics of CSREs from close cell types or tissues can give a detailed view of developmental processes such as normal tissue development and cancer occurrence. PMID- 29281092 TI - Biosynthesis of quebrachitol, a transportable photosynthate, in Litchi chinensis. AB - Although methylated cyclitols constitute a major proportion of the carbohydrates in many plant species, their physiological roles and biosynthetic pathway are largely unknown. Quebrachitol (2-O-methyl-chiro-inositol) is one of the major methylated cyclitols in some plant species. In litchi, quebrachitol represents approximately 50% of soluble sugars in mature leaves and 40% of the total sugars in phloem exudate. In the present study, we identified bornesitol as a transient methylated intermediate of quebrachitol and measured the concentrations of methyl inositols in different tissues and in tissues subjected to different treatments. 14CO2 feeding and phloem exudate experiments demonstrated that quebrachitol is one of the transportable photosynthates. In contrast to other plant species, the biosynthesis of quebrachitol in litchi is not associated with osmotic stress. High quebrachitol concentrations in tissues of the woody plant litchi might represent a unique carbon metabolic strategy that maintains osmolality under reduced-sucrose conditions. The presence of bornesitol but not ononitol in the leaves indicates a different biosynthetic pathway with pinitol. The biosynthesis of quebrachitol involves the methylation of myo-inositol and the subsequent epimerization of bornesitol. An inositol methyltransferase gene (LcIMT1) responsible for bornesitol biosynthesis was isolated and characterized for the first time, and the biosynthesis pathways of methyl-inositols are discussed. PMID- 29281095 TI - Proximal and Distal Occlusion of Complex Cerebral Aneurysms-Implications of Flow Modeling by Fluid-Structure Interaction Analysis. AB - BACKGROUND: In complex cerebral aneurysms, adequate treatment by complete occlusion is not always possible. Partial occlusion by either proximal or distal occlusion is an alternative. However, the hemodynamic consequences of these partial occlusion options are often not easily predictable. OBJECTIVE: To assess the feasibility of fluid-structure interaction (FSI) analysis to investigate the hemodynamic changes after partial occlusion in cerebral aneurysms. METHODS: Two patients were analyzed. One was treated by proximal occlusion and 1 by distal occlusion. In both, flow replacement bypass surgery was performed. Three dimensional models were constructed from magnetic resonance angiography (MRA) scans and used for FSI analysis. A comparative study was done for pre- and postoperative conditions. Postoperative thrombosis was modeled and analyzed for the distal occlusion. FSI results were compared to postoperative angiograms and computed tomography (CT)-scans. RESULTS: Proximal occlusion resulted in reduction of velocity, wall shear stresses, and disappearance of helical flow patterns in the complete aneurysm. Distal occlusion showed a decrease of velocity and wall shear stress in the dome of the aneurysm. Results were validated against postoperative CT-scans and angiograms at 1-, 7-, and 9-mo follow-up. Addition of thrombus to the distal occlusion model showed no change in velocities and luminal pressure but resulted in decrease in wall tension. CONCLUSION: This pilot study showed hemodynamic changes in 2 patients with proximal and distal occlusion of complex cerebral aneurysms. The FSI results were in line with the follow-up CT scans and angiograms and indicate the potential of FSI as a tool in patient specific surgical interventions. PMID- 29281094 TI - Impaired Processing of Prohormones in Secretogranin III-Null Mice Causes Maladaptation to an Inadequate Diet and Stress. AB - Secretogranin III (SgIII), a member of the granin family, binds both to another granin, chromogranin A (CgA), and to a cholesterol-rich membrane that is destined for secretory granules (SGs). The knockdown of SgIII in adrenocorticotropic hormone (ACTH)-producing AtT-20 cells largely impairs the regulated secretion of CgA and ACTH. To clarify the physiological roles of SgIII in vivo, we analyzed hormone secretion and SG biogenesis in newly established SgIII-knockout (KO) mice. Although the SgIII-KO mice were viable and fertile and exhibited no overt abnormalities under ordinary rearing conditions, a high-fat/high-sucrose diet caused pronounced obesity in the mice. Furthermore, in the SgIII-KO mice compared with wild-type (WT) mice, the stimulated secretion of active insulin decreased substantially, whereas the storage of proinsulin increased in the islets. The plasma ACTH was also less elevated in the SgIII-KO mice than in the WT mice after chronic restraint stress, whereas the storage level of the precursor proopiomelanocortin in the pituitary gland was somewhat increased. These findings suggest that the lack of SgIII causes maladaptation of endocrine cells to an inadequate diet and stress by impairing the proteolytic conversion of prohormones in SGs, whereas SG biogenesis and the basal secretion of peptide hormones under ordinary conditions are ensured by the compensatory upregulation of other residual granins or factors. PMID- 29281096 TI - Relating experimentally-induced fear to pre-existing phobic fear in the human brain. AB - While prior work has demonstrated that fear-conditioning changes the neural representation of previously neutral stimuli, it remains unknown to what extent this new representation abstracts away from specific fears and which brain areas are involved therein. To investigate this question, we sought commonalities between experimentally-induced fear via electric shocks and pre-existing phobia. Using functional MRI, we tested the effect of fear-conditioning pictures of dogs in 21 spider-fearful participants across three phases: baseline, post conditioning, and extinction. Considering phobic stimuli as a reference point for the state of fear allowed us to examine whether fear-conditioning renders information patterns of previously neutral stimuli more similar to those of phobic stimuli. We trained a classification algorithm to discriminate information patterns of neutral stimuli (rats) and phobic stimuli and then tested the algorithm on information patterns from the conditioned stimuli (dogs). Performing this cross-decoding analysis at each experimental phase revealed brain regions in which dogs were classified as rats during baseline, as spiders following conditioning, and again as rats after extinction. A follow-up analysis showed that changes in visual perception information cannot explain the changing classification performance. These results demonstrate a common neural representation for processing fear-eliciting information, either pre-existing or acquired by classical conditioning. PMID- 29281097 TI - Decision Making in the Wait-and-Scan Approach for Vestibular Schwannomas: Is There a Price to Pay in Terms of Hearing, Facial Nerve, and Overall Outcomes? AB - BACKGROUND: The wait-and-scan modality has emerged as an important strategy in the management of vestibular schwannoma (VS) as it has been demonstrated that many tumors grow slowly or do not show any growth over long periods. OBJECTIVE: To analyze long-term outcomes of wait-and-scan in the treatment of patients with VS, discuss the factors contributing to the decision making, determine the inherent risks of the policy, and compare our results with literature. METHODS: In total, 576 patients with sporadic unilateral VS who were managed with wait-and scan were reviewed retrospectively. Of these, a subset of 154 patients with 5-yr follow-up was separately analyzed. The tumor characteristics including patterns of growth, rate of growth, hearing outcomes, and likely factors affecting the above parameters were analyzed. RESULTS: The mean period of follow-up was 36.9 +/ 30.2 mo. The mean age was 59.2 +/- 11.6 yr. Thirteen different patterns of tumor growth were observed. Eighty-four (54.5%) of 154 tumors with 5-yr follow-up showed no growth throughout 5 yr. Fifty-six (36.4%) tumors showed mixed growth rates. Only 57 (37%) patients had serviceable hearing at the start of follow-up, but 32 (56.1%) maintained it at the end of follow-up. One hundred fifty (26%) of the 576 patients who failed wait-and-scan had to be taken up for surgery. CONCLUSION: While there may be no price to pay in wait-and-scan as far as hearing is concerned, this may not be the case for facial nerve outcomes, wherein the results may be better if the patients are taken earlier for surgery. PMID- 29281098 TI - Origin of new genes after zygotic genome activation in vertebrate. AB - New genes are drivers of evolutionary innovation and phenotypic evolution. Expression of new genes in early development raises the possibility that new genes could originate and be recruited for functions in embryonic development, but this remains undocumented. Here, based on temporal gene expression at different developmental stages in Xenopus tropicalis, we found that young protein coding genes were significantly enriched for expression in developmental stages occurring after the midblastula transition (MBT), and displayed a decreasing trend in abundance in the subsequent stages after MBT. To complement the finding, we demonstrate essential functional attributes of a young orphan gene, named as Fog2, in morphological development. Our data indicate that new genes could originate after MBT and be recruited for functions in embryonic development, and thus provide insights for better understanding of the origin, evolution, and function of new genes. PMID- 29281099 TI - Pretty Good or Pretty Bad? The Ovary and Chemicals in Personal Care Products. AB - Personal care products (PCP) contain a myriad of chemicals generally formulated to provide a safe and beneficial use. Nonetheless, an increasing amount of laboratory animal and human studies indicate that some chemicals in PCP are associated with decreased hormone production, diminished ovarian reserve, ovarian cancer, and early pregnancy loss. The ovary is key to female fertility by providing the eggs and sex steroid hormones for fertilization and maintenance of reproductive function, respectively. Thus, understanding how chemicals in PCP affect the ovary will shed some light on their potential effects on female fertility. In this review, we provide an overview of: (1) ovarian function as a determinant of fertility in females, (2) the status of knowledge regarding the effects of seven common chemicals in PCP on the ovary, and (3) significant gaps in the literature along with opportunities to eliminate some of the gaps. Findings from the limited existing data suggest that chemicals in PCP such as dibutyl phthalate can reach the ovary in humans and impact its function in animal models. Unfortunately, it is still difficult to assess how relevant findings of experimental studies are to women because of lack of human exposure data for most of these chemicals and the lack of studies that mimic real-life exposures. In contrast to chemicals such as bisphenol A and dioxin, the investigation of the effects of chemicals in PCP on reproductive function is still limited and warrants further investigation to fill existing data gaps. PMID- 29281102 TI - Cervical Spine Deformity-Part 3: Posterior Techniques, Clinical Outcome, and Complications. PMID- 29281100 TI - Antiviral Response in the Nasopharynx Identifies Patients With Respiratory Virus Infection. AB - Background: Despite the high burden of respiratory infection and the importance of early and accurate diagnosis, there is no simple diagnostic test to rule in viral infection as a cause of respiratory symptoms. Methods: We performed RNA sequencing on human nasal epithelial cells following stimulation of the intracellular viral recognition receptor RIG-I. Next, we evaluated whether measuring identified host mRNAs and proteins from patient nasopharyngeal swabs could predict the presence of a respiratory virus in the sample. Results: Our first study showed that a signature of 3 mRNAs, CXCL10, IFIT2, and OASL, predicted respiratory virus detection with an accuracy of 97% (95% confidence interval [CI], 0.9-1.0), and identified proteins correlating with virus detection. In a second study, elevated CXCL11 or CXCL10 protein levels identified samples containing respiratory viruses, including viruses not on the initial test panel. Overall area under the curve (AUC) values were: CXCL11 AUC = 0.901 (95% CI, 0.86-0.94); CXCL10 AUC = 0.85 (95% CI, 0.80-0.91). Conclusions: Host antiviral mRNAs and single host proteins detectable using nasopharyngeal swabs accurately predict the presence of viral infection. This approach holds promise for developing rapid, cost-effective tests to improve management of patients with respiratory illnesses. PMID- 29281103 TI - Incidence and Predictive Factors of Sepsis Following Adult Spinal Deformity Surgery. AB - BACKGROUND: Surgery for adult spinal deformity (ASD) improves quality of life, yet morbidity is high. Sepsis is a challenging postoperative complication that can result in death and drive inpatient resources. OBJECTIVE: To identify the incidence and risk factors for development of sepsis within 30 days following ASD surgery. METHODS: Adult patients who underwent thoracolumbar spinal deformity correction between 2008 and 2014 were identified in the National Surgical Quality Improvement Program database. Demographic and operative variables were extracted. The primary outcome was development of postoperative sepsis. Multivariable logistic regression modeling was used to identify independent risk factors for sepsis. RESULTS: A total of 6158 patients underwent ASD surgery. Of these, 156 (2.5%) developed sepsis postoperatively. Independent risk factors included operative time (odds ratio [OR]: 1.004, 95% confidence interval [CI]: 1.003 1.005, P < .001), male sex (OR: 1.47, 95% CI: 1.05-2.05, P = .023), diabetes (OR: 1.59, 95% CI: 1.05-2.40, P = .027), functional dependency (OR: 1.82, 95% CI: 1.12 2.95, P = .015), weight loss (OR: 2.45, 95% CI: 1.04-5.78, P = .040), bleeding disorder (OR: 2.58, 95% CI: 1.34-4.93, P = .004), and ascites (OR: 56.11, 95% CI: 5.01-628.50, P = .001). This model demonstrated strong predictive capacity, with an area under the curve of 0.80. Patients who developed sepsis were significantly more likely to have a prolonged hospital stay (P < .001), be readmitted (P < .001), and die (P < .001). The median (range) time to sepsis was 9 d (0-30). CONCLUSION: In patients undergoing ASD surgery, male sex, diabetes, ascites, bleeding disorder, functional dependency, excessive weight loss and increased operative time independently predicted sepsis. This perioperative patient profile can be used for preoperative risk assessment, patient counseling, and postoperative management for patients undergoing ASD surgery. PMID- 29281104 TI - Antigenic Characterization of a Novel Recombinant GII.P16-GII.4 Sydney Norovirus Strain With Minor Sequence Variation Leading to Antibody Escape. AB - Background: Human noroviruses are the leading cause of acute gastroenteritis. Strains of the GII.4 genotype cause pandemic waves associated with viral evolution and subsequent antigenic drift and ligand-binding modulation. In November 2015, a novel GII.4 Sydney recombinant variant (GII.P16-GII.4 Sydney) emerged and replaced GII.Pe-GII.4 Sydney as the predominant cause of acute gastroenteritis in the 2016-2017 season in the United States. Methods: Virus-like particles of GII.4 2012 and GII.4 2015 were compared for ligand binding and antibody reactivity, using a surrogate neutralization assay. Results: Residue changes in the capsid between GII.4 2012 and GII.4 2015 decreased the potency of human polyclonal sera and monoclonal antibodies. A change in epitope A resulted in the complete loss of reactivity of a class of blockade antibodies and reduced levels of a second antibody class. Epitope D changes modulated monoclonal antibody potency and ligand-binding patterns. Conclusions: Substitutions in blockade antibody epitopes between GII.4 2012 and GII.4 2015 influenced antigenicity and ligand-binding properties. Although the impact of polymerases on fitness remains uncertain, antigenic variation resulting in decreased potency of antibodies to epitope A, coupled with altered ligand binding, likely contributed significantly to the spread of GII.4 2015 and its replacement of GII.4 2012 as the predominant norovirus outbreak strain. PMID- 29281101 TI - Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial. AB - Aims: We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD). Methods and results: The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure >= 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22-0.67; P < 0.001]. The Kaplan-Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0-4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler derived systolic pulmonary pressure were similar in both groups. Conclusion: Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided. The trial is registered with ClinicalTrials.gov, number NCT00862043. PMID- 29281105 TI - A major trade-off between structural and photosynthetic investments operative across plant and needle ages in three Mediterranean pines. AB - Pine (Pinus) species exhibit extensive variation in needle shape and size between juvenile (primary) and adult (secondary) needles (heteroblasty), but few studies have quantified the changes in needle morphological, anatomical and chemical traits upon juvenile-to-adult transition. Mediterranean pines keep juvenile needles longer than most other pines, implying that juvenile needles play a particularly significant role in seedling and sapling establishment in this environment. We studied needle anatomical, morphological and chemical characteristics in juvenile and different-aged adult needles in Mediterranean pines Pinus halepensis Mill., Pinus pinea L. and Pinus nigra J. F. Arnold subsp. salzmannii (Dunal) Franco hypothesizing that needle anatomical modifications upon juvenile-to-adult transition lead to a trade-off between investments in support and photosynthetic tissues, and that analogous changes occur with needle aging albeit to a lower degree. Compared with adult needles, juvenile needles of all species were narrower with 1.6- to 2.4-fold lower leaf dry mass per unit area, and had ~1.4-fold thinner cell walls, but needle nitrogen content per dry mass was similar among plant ages. Juvenile needles also had ~1.5-fold greater mesophyll volume fraction, ~3-fold greater chloroplast volume fraction and ~1.7 fold greater chloroplast exposed to mesophyll exposed surface area ratio, suggesting overall greater photosynthetic activity. Changes in needle traits were similar in aging adult needles, but the magnitude was generally less than the changes upon juvenile to adult transition. In adult needles, the fraction in support tissues scaled positively with known ranking of species tolerance of drought (P. halepensis > P. pinea > P. nigra). Across all species, and needle and plant ages, a negative correlation between volume fractions of mesophyll and structural tissues was observed, manifesting a trade-off between biomass investments in different needle functions. These results demonstrate that within the broad trade-off, juvenile and adult needle morphophysiotypes are separated by varying investments in support and photosynthetic functions. We suggest that the ecological advantage of the juvenile morphophysiotype is maximization of carbon gain of establishing saplings, while adult needle physiognomy enhances environmental stress tolerance of established plants. PMID- 29281106 TI - Delayed Interferon Type 1-Induced Antiviral State Is a Potential Factor for Hemorrhagic Fever With Renal Syndrome Severity. AB - Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. Interferon (IFN) responses play an important role in HFRS pathogenesis and early IFN-beta response is delayed by pathogenic hantaviruses. The severity of HFRS caused by Dobrava virus (DOBV) and Puumala virus (PUUV) varies. Our aim was to determine whether differences in early activation of IFN type 1-induced antiviral state influence HFRS severity. Peripheral blood mononuclear cells (PBMCs) from healthy donors and HFRS patients were stimulated with DOBV or PUUV and expression of selected genes was measured. PUUV, but not DOBV, activated IFN type 1-induced antiviral state in stimulated PBMCs, and IFNbeta, STAT-1, and MxA were highly upregulated. Upregulation of MxA was earlier in acute-phase PBMCs and higher in convalescent-phase PBMCs from patients with mild compared with severe PUUV infection. Our study showed that delayed IFN type 1-induced antiviral state could contribute to HFRS severity, particularly in PUUV infection. PMID- 29281107 TI - Outcomes of Operative Treatment for Adult Cervical Deformity: A Prospective Multicenter Assessment With 1-Year Follow-up. AB - BACKGROUND: Despite the potential for profound impact of adult cervical deformity (ACD) on function and health-related quality of life (HRQOL), there are few high quality studies that assess outcomes of surgical treatment for these patients. OBJECTIVE: To determine the impact of surgical treatment for ACD on HRQOL. METHODS: We conducted a prospective cohort study of surgically treated ACD patients eligible for 1-yr follow-up. Baseline deformity characteristics, surgical parameters, and 1-yr HRQOL outcomes were assessed. RESULTS: Of 77 ACD patients, 55 (71%) had 1-yr follow-up (64% women, mean age of 62 yr, mean Charlson Comorbidity Index of 0.6, previous cervical surgery in 47%). Diagnoses included cervical sagittal imbalance (56%), cervical kyphosis (55%), proximal junctional kyphosis (7%) and coronal deformity (9%). Posterior fusion was performed in 85% (mean levels = 10), and anterior fusion was performed in 53% (mean levels = 5). Three-column osteotomy was performed in 24% of patients. One year following surgery, ACD patients had significant improvement in Neck Disability Index (50.5 to 38.0, P < .001), neck pain numeric rating scale score (6.9 to 4.3, P < .001), EuroQol 5 dimension (EQ-5D) index (0.51 to 0.66, P < .001), and EQ-5D subscores: mobility (1.9 to 1.7, P = .019), usual activities (2.2 to 1.9, P = .007), pain/discomfort (2.4 to 2.1, P < .001), anxiety/depression (1.8 to 1.5, P = .014). CONCLUSION: Based on a prospective multicenter series of ACD patients, surgical treatment provided significant improvement in multiple measures of pain and function, including Neck Disability Index, neck pain numeric rating scale score, and EQ-5D. Further follow-up will be necessary to assess the long-term durability of these improved outcomes. PMID- 29281108 TI - Green magic: regulation of the chloroplast stress response by (p)ppGpp in plants and algae. AB - The hyperphosphorylated nucleotides guanosine pentaphosphate and tetraphosphate [together referred to as (p)ppGpp, or 'magic spot'] orchestrate a signalling cascade in bacteria that controls growth under optimal conditions and in response to environmental stress. (p)ppGpp is also found in the chloroplasts of plants and algae where it has also been shown to accumulate in response to abiotic stress. Recent studies suggest that (p)ppGpp is a potent inhibitor of chloroplast gene expression in vivo, and is a significant regulator of chloroplast function that can influence both the growth and the development of plants. However, little is currently known about how (p)ppGpp is wired into eukaryotic signalling pathways, or how it may act to enhance fitness when plants or algae are exposed to environmental stress. This review discusses our current understanding of (p)ppGpp metabolism and its extent in plants and algae, and how (p)ppGpp signalling may be an important factor that is capable of influencing growth and stress acclimation in this major group of organisms. PMID- 29281110 TI - Surgical Treatment vs Nonsurgical Treatment for Brain Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia: A Retrospective Multicenter Consortium Study. PMID- 29281109 TI - Egg and Larval Morphology of Culicoides sonorensis (Diptera: Ceratopogonidae). AB - The egg and larval instars (L1-L4) of Culicoides sonorensis Wirth and Jones are described. Average (range) of body lengths of a laboratory colony (Van Ryn) were 0.45 (0.43-0.48) mm for eggs, 0.72 (0.39-0.92) mm for L1, 1.8 (1.3-2.2) mm for L2, 3.6 (2.2-5.0) mm for L3, and 5.9 (5.0-6.9) mm for L4. Head capsule lengths were 0.067 (0.064-0.070) mm for L1, 0.100 (0.094-0.110) for L2, 0.157 (0.144 0.168) for L3, and 0.316 (0.300-0.324) mm for L4. Wild and colony L4 larvae differed in many standard metrics such as head length or width, but head ratios and pharyngeal armature measurements were comparable. Standard external and internal features of the head capsule are described. Scanning electron microscope photos revealed pharyngeal armature structure was similar for L2-L4. The pharyngeal armature and piercing mandibles suggest a generalist feeder and opportunistic predator. Egg ansullae were randomly distributed (as opposed to rows in most other Culicoides spp.) and averaged 1.98 ansullae per 25 um2 of egg surface. Ansullae were widened and porous apically, averaging 1.29 microns long, 0.65 um at the base, and 1.06 um at the apex. Only the L1 had a proleg, structurally complex, and featuring five rows of posteriorily directed, shorter spines (1-3 um long) and 8-10 setae 18 um long with hooked tips. On terrestrial mud, this proleg was used for surface crawling, and the L1 navigated dry conditions better than the more aquatic L2-L4 stages. Eggs are laid above waterline, and the L1 proleg is probably an advantage in terrestrial surface movement. PMID- 29281111 TI - A leu-rich repeat receptor-like protein kinase, FaRIPK1, interacts with the ABA receptor, FaABAR, to regulate fruit ripening in strawberry. AB - Strawberry (Fragaria*ananassa) is a model plant for studying non-climacteric fruit ripening regulated by abscisic acid (ABA); however, its exact molecular mechanisms are yet not fully understood. In this study, a predicted leu-rich repeat (LRR) receptor-like kinase in strawberry, red-initial protein kinase 1 (FaRIPK1), was screened and, using a yeast two-hybrid assay, was shown to interact with a putative ABA receptor, FaABAR. This association was confirmed by bimolecular fluorescence complementation and co-immunoprecipitation assays, and shown to occur in the nucleus. Expression analysis by real-time PCR showed that FaRIPK1 is expressed in roots, stems, leaves, flowers, and fruit, with a particularly high expression in white fruit at the onset of coloration. Down regulation of FaRIPK1 expression in strawberry fruit, using Tobacco rattle virus induced gene silencing, inhibited ripening, as evidenced by suppression of ripening-related physiological changes and reduced expression of several genes involved in softening, sugar content, pigmentation, and ABA biosynthesis and signaling. The yeast-expressed LRR and STK (serine/threonine protein kinase) domains of FaRIPK1 bound ABA and showed kinase activity, respectively. A fruit disc-incubation test revealed that FaRIPK1 expression was induced by ABA and ethylene. The synergistic action of FaRIPK1 with FaABAR in regulation of strawberry fruit ripening is discussed. PMID- 29281112 TI - Modified mRNA-Based Vaccines Elicit Robust Immune Responses and Protect Guinea Pigs From Ebola Virus Disease. AB - Most current Ebola virus (EBOV) vaccine candidates are based on viral vectors, some of which cause side effects or require complex manufacturing. Modified mRNA vaccines are easily produced, safe, and are highly immunogenic. We developed 2 mRNA vaccines based on the EBOV envelope glycoprotein, which differed by the nature of signal peptide for improved glycoprotein post-translational translocation. The mRNAs were formulated with lipid nanoparticles to facilitate delivery. Vaccination of guinea pigs induced EBOV-specific IgG and neutralizing antibody responses and 100% survival after EBOV infection. The efficacy of our mRNA vaccine combined with preclinical safety data supports testing in clinical studies. PMID- 29281113 TI - Complication Rates and Maintenance of Correction After 3-Column Osteotomy in the Elderly: Report of 55 Patients With 2-Year Follow-up. AB - BACKGROUND: Three-column osteotomies (3CO) provide substantial correction for adult spinal deformity (ASD), but carry risks of complications and revisions. The risk-benefit balance of 3CO in the elderly remains unclear. OBJECTIVE: To evaluate sagittal alignment and complications after 3CO in a population over 70 yr old. METHODS: Radiographic retrospective review of consecutive patients over 70 yr ("Elderly") undergoing 3CO for ASD. Demographic, operative, and outcomes data were collected. Full-spine radiographs were analyzed at baseline and 2-yr postoperatively. Results were compared to a group of young controls ("Young") matched by global sagittal alignment. RESULTS: Elderly (n = 55) and Young (n = 52) were similar in operating room time, blood loss, levels fused, and revision surgeries. Elderly and Young groups had similar baseline radiographic malalignment for pelvic tilt, pelvic incidence-lumbar lordosis (PI-LL), and sagittal vertical axis (P > .5 for all). At 2-yr postoperatively, both groups underwent significant improvement in the setting of sagittal alignment parameters (Elderly: sagittal vertical axis 150 mm to 59 mm, P < .001; pelvic tilt 33 degrees to 25 degrees , P < .001; PI-LL 35 degrees to PI-LL 6 degrees , P < .001). However, the Elderly group underwent significantly greater correction in PI-LL than the Young group (-29 degrees vs -20 degrees , P = .024). There were no differences in total, intraoperative or postoperative complications or revisions between groups, though the Elderly group had more intraoperative complications when major blood loss was included. The Elderly group had more severe proximal junctional kyphosis (22.1 degrees vs 9.6 degrees in Young; P < .001). CONCLUSION: Compared to young patients, elderly patients may achieve the same, or even better, correction in radiographic spinopelvic parameters. In addition, not only the total intraoperative and postoperative complication rates but also revision rates were comparable between both groups. PMID- 29281114 TI - Serum albumin concentration and risk of end-stage renal disease: the REGARDS study. AB - Background: Serum albumin concentration is a commonly available biomarker with prognostic value in many disease states. It is uncertain whether serum albumin concentrations are associated with incident end-stage renal disease (ESRD) independently of urine albumin-to-creatinine ratio (ACR). Methods: A longitudinal evaluation was performed of a population-based community-living cohort from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Participants were >=45 years of age at study entry and had serum albumin, creatinine, cystatin C and spot urine ACR measured at the baseline visit (n = 19 633). Estimated glomerular filtration rate (eGFR) was from the Chronic Kidney Disease Epidemiology Collaboration combined creatinine-cystatin C equation. Baseline serum albumin concentration was the predictor variable, and hazard ratios (HRs) for incident ESRD (from US Renal Data System linkage) were calculated in sequentially adjusted models. Results: Age at study entry was 63.9 +/- 9.7 years, 62% of the participants were female and 40% were black. Mean eGFR at baseline was 83.3 +/- 20.8 mL/min/1.73 m2. Over a median 8-year follow-up, 1.2% (n = 236) developed ESRD. In models adjusted for baseline eGFR, ACR and other ESRD risk factors, the HR for incident ESRD was 1.16 [95% confidence interval (CI) 1.01-1.33] for each standard deviation (0.33 g/dL) lower serum albumin concentration. The HR comparing the lowest (<4 g/dL) and highest quartiles (>=4.4 g/dL) of serum albumin was 1.61 (95% CI 0.98-2.63). Results were qualitatively similar among participants with eGFR <60 and >=60 mL/min/1.73 m2, and those with and without diabetes. Conclusions: In community-dwelling US adults, lower serum albumin concentration is associated with higher risk of incident ESRD independently of baseline urine ACR, eGFR and other ESRD risk factors. PMID- 29281115 TI - SmJAZ8 acts as a core repressor regulating JA-induced biosynthesis of salvianolic acids and tanshinones in Salvia miltiorrhiza hairy roots. AB - Jasmonates (JAs) are important plant hormones that regulate a variety of plant development and defense processes, including biosynthesis of secondary metabolites. The JASMONATE ZIM DOMAIN (JAZ) proteins act as negative regulators in the JA signaling pathways of plants. We first verified that methyl jasmonate (MeJA) enhanced the accumulation of both salvianolic acids and tanshinones in Salvia miltiorrhiza (Danshen) hairy roots by inducing the expression of their biosynthetic pathway genes. Nine JAZ genes were cloned from Danshen and their expression levels in hairy roots were all increased by treatment with MeJA. When analyzed in detail, however, SmJAZ8 showed the strongest expression in the induced hairy roots. Overexpression or RNAi of SmJAZ8 deregulated or up-regulated the yields of salvianolic acids and tanshinones in the MeJA-induced transgenic hairy roots, respectively, and transcription factors and biosynthetic pathway genes showed an expression pattern that mirrored the production of the compounds. Genetic transformation of SmJAZ8 altered the expression of other SmJAZ genes, suggesting evidence of crosstalk occurring in JAZ-regulated secondary metabolism. Furthermore, the transcriptome analysis revealed a primary-secondary metabolism balance regulated by SmJAZ8. Altogether, we propose a novel role for SmJAZ8 as a negative feedback loop controller in the JA-induced biosynthesis of salvianolic acids and tanshinones. PMID- 29281116 TI - Characterization of two TERMINAL FLOWER1 homologs PgTFL1 and PgCENa from pomegranate (Punica granatum L.). AB - FLOWERING LOCUS T (FT) and TERMINAL FLOWER1/CENTRORADIALIS (TFL1/CEN) are the key regulators of flowering time in plants with FT promoting flowering and TFL1 repressing flowering. TFL1 also controls floral meristem identity and its maintenance. In this study we have characterized two pomegranate (Punica granatum L.) TFL1/CEN-like genes designated as PgTFL1 and PgCENa. The expression of PgTFL1 and PgCENa fluctuated through alternate pruning and flowering cycles, being highly expressed during the vegetative phase (immediately after pruning) and decreasing gradually in the months thereafter such that their lowest levels, especially for PgCENa coincided with the flowering phase. Both the genes are able to functionally suppress the Arabidopsis tfl1-14 mutant flowering defect. Their expression in Arabidopsis resulted in delayed flowering time, increased plant height and leaf number, branches and shoot buds as compared with wild type, suggesting that PgTFL1 and PgCENa are bonafide homologs of TFL1. However, both the genes show distinct expression patterns, being expressed differentially in vegetative shoot apex and floral bud samples. While PgTFL1 expression was low in vegetative shoot apex and high in flower bud, PgCENa expression showed the opposite trend. These results suggest that the two TFL1s in pomegranate may be utilized to control distinct developmental processes, namely repression of flowering by PgCENa and development and growth of the reproductive tissues by PgTFL1 via distinct temporal and developmental regulation of their expression. PMID- 29281117 TI - An update on equine post-operative ileus: Definitions, pathophysiology and management. AB - Post-operative ileus (POI) is a serious condition which any horse undergoing abdominal surgery is at risk of developing, leading to increased hospitalisation time and resulting costs. Advances in the understanding of the development of equine POI are mainly based on human and rodent literature, where manipulation induced inflammation has been identified as a trigger, with activation of resident muscularis externa macrophages playing a crucial role in the pathophysiology. Despite many pharmacological trials in all species, there is no single completely successful treatment for POI, highlighting that the condition is multifactorial in cause and requires a multimodal approach to minimise its incidence. PMID- 29281118 TI - Estrogen Deficiency-Mediated M2 Macrophage Osteoclastogenesis Contributes to M1/M2 Ratio Alteration in Ovariectomized Osteoporotic Mice. AB - In this study, for the first time we discovered that the M1/M2 macrophage phenotype ratio is increased in bone marrow of ovariectomized (OVX) osteoporotic C57BL/6 mice. Considering estrogen is the main variable, we assumed that estrogen participated in this alteration. To determine whether and how estrogen contributes to the change of the M1/M2 ratio, we first isolated bone marrow macrophages (BMMs) from mice femur and stimulated the cells with lipopolysaccharide (LPS)/interferon gamma (IFN-gamma) for M1 polarization and interleukin 4 (IL-4)/IL-13 for M2 polarization. M1 and M2 macrophages were then exposed to RANKL stimulation, we found that M2 macrophage but not M1 macrophage differentiated into functional osteoclast leading to increased M1/M2 ratio. Intriguingly, 17beta-estradiol (E2) pretreatment prevented osteoclastogenesis from M2 macrophages. By constructing shRNA lentivirus interfering the expression of different estrogen receptors in M2 macrophages, we found that estrogen protects M2 macrophage from receptor activator of nuclear factor kappaB ligand (RANKL) stimulation selectively through estrogen receptor alpha (ERalpha) and the downstream blockage of NF-kappaB p65 nuclear translocation. Animal studies showed that ERalpha selective agonist 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) was able to replicate the therapeutic effects of E2 in treating osteoporotic OVX mice. Together, our findings reveal that estrogen deficiency mediated M2 macrophage osteoclastogenesis leads to increased M1/M2 ratio in OVX mice. Reducing the M1/M2 ratio is a potential therapeutic target in treating postmenopausal osteoporosis. (c) 2017 American Society for Bone and Mineral Research. PMID- 29281119 TI - Gestational Weight Gain-for-Gestational Age Z-Score Charts Applied across U.S. Populations. AB - BACKGROUND: Gestational weight gain may be a modifiable contributor to infant health outcomes, but the effect of gestational duration on gestational weight gain has limited the identification of optimal weight gain ranges. Recently developed z-score and percentile charts can be used to classify gestational weight gain independent of gestational duration. However, racial/ethnic variation in gestational weight gain and the possibility that optimal weight gain differs among racial/ethnic groups could affect generalizability of the z-score charts. The objectives of this study were (1) to apply the weight gain z-score charts in two different U.S. populations as an assessment of generalisability and (2) to determine whether race/ethnicity modifies the weight gain range associated with minimal risk of preterm birth. METHODS: The study sample included over 4 million live, singleton births in California (2007-2012) and Pennsylvania (2003-2013). We implemented a noninferiority margin approach in stratified subgroups to determine weight gain ranges for which the adjusted predicted marginal risk of preterm birth (gestation <37 weeks) was within 1 or 2 percentage points of the lowest observed risk. RESULTS: There were minimal differences in the optimal ranges of gestational weight gain between California and Pennsylvania births, and among several racial/ethnic groups in California. The optimal ranges decreased as severity of prepregnancy obesity increased in all groups. CONCLUSIONS: The findings support the use of weight gain z-score charts for studying gestational age-dependent outcomes in diverse U.S. populations and do not support weight gain recommendations tailored to race/ethnicity. PMID- 29281120 TI - Iron Supplementation-Induced Phosphaturic Osteomalacia: FGF23 is the Culprit. PMID- 29281121 TI - The Associations of Breast Feeding with Infant Growth and Body Mass Index to 16 years: 'Children of 1997'. AB - BACKGROUND: Controversial findings concerning associations of breast feeding with growth have been reported. This study examined whether the associations of breast feeding with early growth trajectories and body mass index to 16 years differed by sex or age. METHODS: In Hong Kong's 'Children of 1997' population representative birth cohort, contemporaneously reported breast-feeding status in the first 3 months was classified as exclusive breast feeding (BF) (n = 470), mixed feeding (MF) (n = 2693), and formula feeding (FF) (n = 4204). Adjusted sex- and age-specific associations of breast feeding with infant growth (gains in weight-for-age z scores (WAZ), length/height-for-age z scores (LAZ), and body mass-index-for-age z score (BAZ) based on the World Health Organization standards/references from birth to 36 months) were assessed using linear regression and mixed modelling, respectively. Adjusted sex-specific associations of breast feeding with average BAZ from 3 months to 16 years were assessed using generalized estimating equation. Potential confounders were maternal and infant characteristics, and household income. RESULTS: Among 7367 children, associations of breast feeding with infant growth did not vary by sex, but WAZ gains varied by age. Greater WAZ gains were observed in BF than FF infants from 0 to 3 months but in FF than BF infants from 3 to 9 months. Breast feeding was not associated with overall BAZ from 3 months to 16 years, with no differences by sex. CONCLUSIONS: Our findings suggest that breast feeding may only have short-term effects on growth. Further studies of the role of breast feeding in other metabolic diseases may be needed. PMID- 29281122 TI - Occupational exposure to textile dust and lung cancer risk: Results from the ICARE Study. AB - BACKGROUND: To investigate the association of lung cancer with occupational exposure to textile dust and specifically to cotton dust in the population-based case-control study ICARE. METHODS: Lifelong occupational history of 2926 cases and 3555 controls was collected using standardized questionnaires, with specific questions for textile dust exposure. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models controlling for confounding factors including smoking and asbestos exposure. RESULTS: An inverse association between textile dust exposure and lung cancer was found among workers exposed >=5% of their work time (OR = 0.80, 95%CI = 0.58 1.09), more pronounced for distant exposures (40+ years; up to a 56% reduced risk, statistically significant). The OR of lung cancer was significantly decreased among workers exposed to cotton fibers (OR = 0.70, 95%CI = 0.48-0.97). CONCLUSIONS: Our results provide some evidence of a decreased risk of lung cancer associated with exposure to textile dust, particularly cotton. PMID- 29281123 TI - Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. AB - Mitochondria are essential organelles within the cell where most ATP is produced through oxidative phosphorylation (OXPHOS). A subset of the genes needed for this process are encoded by the mitochondrial DNA (mtDNA). One consequence of OXPHOS is the production of mitochondrial reactive oxygen species (ROS), whose role in mediating cellular damage, particularly in damaging mtDNA during ageing, has been controversial. There are subsets of neurons that appear to be more sensitive to ROS-induced damage, and mitochondrial dysfunction has been associated with several neurodegenerative disorders. In this review, we will discuss the current knowledge in the field of mtDNA and neurodegeneration, the debate about ROS as a pathological or beneficial contributor to neuronal function, bona fide mtDNA diseases, and insights from mouse models of mtDNA defects affecting the central nervous system. PMID- 29281124 TI - Letter to the Editor: Do we have to redefine lameness in the era of quantitative gait analysis? PMID- 29281125 TI - Resident intestinal eosinophils constitutively express antigen presentation markers and include two phenotypically distinct subsets of eosinophils. AB - Intestinal eosinophils are implicated in homeostatic and disease-associated processes, yet the phenotype of intestinal tissue-dwelling eosinophils is poorly defined and their roles in intestinal health or disease remain enigmatic. Here we probed the phenotype and localization of eosinophils constitutively homed to the small intestine of naive mice at baseline, and of antigen-sensitized mice following intestinal challenge. Eosinophils homed to the intestinal lamina propria of naive mice were phenotypically distinguished from autologous blood eosinophils, and constitutively expressed antigen-presenting cell markers, suggesting that intestinal eosinophils, unlike blood eosinophils, may be primed for antigen presentation. We further identified a previously unrecognized resident population of CD11chi eosinophils that are recovered with intraepithelial leucocytes, and that are phenotypically distinct from both lamina propria and blood eosinophils. To better visualize intestinal eosinophils in situ, we generated eosinophil reporter mice wherein green fluorescent protein expression is targeted to both granule-delimiting and plasma membranes. Analyses of deconvolved fluorescent z-section image stacks of intestinal tissue sections from eosinophil reporter mice revealed eosinophils within intestinal villi exhibited dendritic morphologies with cellular extensions that often contacted the basement membrane. Using an in vivo model of antigen acquisition in antigen sensitized mice, we demonstrate that both lamina propria-associated and intraepithelium-associated eosinophils encounter, and are competent to acquire, lumen-derived antigen. Taken together these data provide new foundational insights into the organization and functional potential of intestinal tissue dwelling eosinophils, including the recognition of different subsets of resident intestinal eosinophils, and constitutive expression of antigen-presenting cell markers. PMID- 29281128 TI - Re: Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report. PMID- 29281127 TI - Bone Tissue Collagen Maturity and Mineral Content Increase With Sustained Hyperglycemia in the KK-Ay Murine Model of Type 2 Diabetes. AB - Type 2 diabetes mellitus (T2DM) increases fracture risk for a given bone mineral density (BMD), which suggests that T2DM changes bone tissue properties independently of bone mass. In this study, we assessed the effects of hyperglycemia on bone tissue compositional properties, enzymatic collagen crosslinks, and advanced glycation end-products (AGEs) in the KK-Ay murine model of T2DM using Fourier transform infrared (FTIR) imaging and high-performance liquid chromatography (HPLC). Compared to KK-aa littermate controls (n = 8), proximal femoral bone tissue of KK-Ay mice (n = 14) exhibited increased collagen maturity, increased mineral content, and less heterogeneous mineral properties. AGE accumulation assessed by the concentration of pentosidine, as well as the concentrations of the nonenzymatic crosslinks hydroxylysylpyridinoline (HP) and lysyl pyridinoline (LP), did not differ in the proximal femurs of KK-Ay mice compared to controls. The observed differences in tissue-level compositional properties in the KK-Ay mice are consistent with bone that is older and echo observations of reduced remodeling in T2DM. (c) 2017 American Society for Bone and Mineral Research. PMID- 29281126 TI - Effects of Gastric Bypass Surgery on Bone Mass and Microarchitecture Occur Early and Particularly Impact Postmenopausal Women. AB - Roux-en-Y gastric bypass (RYGB) surgery is a highly effective treatment for obesity but negatively affects the skeleton. Studies of skeletal effects have generally examined areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), but DXA may be inaccurate in the setting of marked weight loss. Further, as a result of modestly sized samples of mostly premenopausal women and very few men, effects of RYGB by sex and menopausal status are unknown. We prospectively studied the effects of RYGB on skeletal health, including axial and appendicular volumetric BMD and appendicular bone microarchitecture and estimated strength. Obese adults (N = 48; 27 premenopausal and 11 postmenopausal women, 10 men) with mean +/- SD body mass index (BMI) 44 +/- 7 kg/m2 were assessed before and 6 and 12 months after RYGB. Participants underwent spine and hip DXA, spine QCT, radius and tibia HR-pQCT, and laboratory evaluation. Mean 12 month weight loss was 37 kg (30% of preoperative weight). Overall median 12-month increase in serum collagen type I C-telopeptide (CTx) was 278% (p < 0.0001), with greater increases in postmenopausal than premenopausal women (p = 0.049). Femoral neck BMD by DXA decreased by mean 5.0% and 8.0% over 6 and 12 months (p < 0.0001). Spinal BMD by QCT decreased by mean 6.6% and 8.1% (p < 0.0001); declines were larger among postmenopausal than premenopausal women (11.6% versus 6.0% at 12 months, p = 0.02). Radial and tibial BMD and estimated strength by HR-pQCT declined. At the tibia, detrimental changes in trabecular microarchitecture were apparent at 6 and 12 months. Cortical porosity increased at the radius and tibia, with more dramatic 12-month increases among postmenopausal than premenopausal women or men at the tibia (51.4% versus 18.3% versus 3.0%, p < 0.01 between groups). In conclusion, detrimental effects of RYGB on axial and appendicular bone mass and microarchitecture are detectable as early as 6 months postoperatively. Postmenopausal women are at highest risk for skeletal consequences and may warrant targeted screening or interventions. (c) 2017 American Society for Bone and Mineral Research. PMID- 29281129 TI - Electronic messaging and communication with living kidney donors. AB - New regulations require living kidney donor (LKD) follow-up for 2 years, but donor retention remains poor. Electronic communication (eg, text messaging and e mail) might improve donor retention. To explore the possible impact of electronic communication, we recruited LKDs to participate in an exploratory study of communication via telephone, e-mail, or text messaging postdonation; communication through this study was purely optional and did not replace standard follow-up. Of 69 LKDs recruited, 3% requested telephone call, 52% e-mail, and 45% text messaging. Telephone response rate was 0%; these LKDs were subsequently excluded from analysis. Overall response rates with e-mail or text messaging at 1 week, 1 month, 6 months, 1 year, and 2 years were 94%, 87%, 81%, 72%, and 72%. Lower response rates were seen in African Americans, even after adjusting for age, sex, and contact method (incidence rate ratio (IRR) nonresponse 2.07 5.8116.36 , P = .001). Text messaging had higher response rates than e-mail (IRR nonresponse 0.11 0.280.71 , P = .007). Rates of nonresponse were similar by sex (IRR 0.68, P = .4) and age (IRR 1.00, P > .9). In summary, LKDs strongly preferred electronic messaging over telephone and were highly responsive 2 years postdonation, even in this nonrequired, nonincentivized exploratory research study. These electronic communication tools can be automated and may improve regulatory compliance and postdonation care. PMID- 29281130 TI - Effect of Study Design on Sample Size in Studies Intended to Evaluate Bioequivalence of Inhaled Short-Acting beta-Agonist Formulations. AB - Pharmacodynamic studies that use methacholine challenge to assess bioequivalence of generic and innovator albuterol formulations are generally designed per published Food and Drug Administration guidance, with 3 reference doses and 1 test dose (3-by-1 design). These studies are challenging and expensive to conduct, typically requiring large sample sizes. We proposed 14 modified study designs as alternatives to the Food and Drug Administration-recommended 3-by-1 design, hypothesizing that adding reference and/or test doses would reduce sample size and cost. We used Monte Carlo simulation to estimate sample size. Simulation inputs were selected based on published studies and our own experience with this type of trial. We also estimated effects of these modified study designs on study cost. Most of these altered designs reduced sample size and cost relative to the 3-by-1 design, some decreasing cost by more than 40%. The most effective single study dose to add was 180 MUg of test formulation, which resulted in an estimated 30% relative cost reduction. Adding a single test dose of 90 MUg was less effective, producing only a 13% cost reduction. Adding a lone reference dose of either 180, 270, or 360 MUg yielded little benefit (less than 10% cost reduction), whereas adding 720 MUg resulted in a 19% cost reduction. Of the 14 study design modifications we evaluated, the most effective was addition of both a 90-MUg test dose and a 720-MUg reference dose (42% cost reduction). Combining a 180-MUg test dose and a 720-MUg reference dose produced an estimated 36% cost reduction. PMID- 29281131 TI - Can overcompensation increase crop production? AB - The two most pressing challenges to agriculture worldwide are feeding a rapidly growing human population and developing more sustainable agricultural practices that do not threaten human and ecosystem health. We address these challenges through research in plant-herbivore interactions, specifically overcompensatory responses in potato to herbivore damage. While herbivory is usually detrimental to most crops, some potato cultivars can overcompensate and increase crop productivity up to two-fold in response to herbivore damage. However, biotic and abiotic factors are known to influence compensatory responses. Here we tested if compensatory plant responses to herbivory increase productivity of potatoes under field conditions along gradients of altitude and landscape simplification in 15 different farms. Our results suggest that compensatory plant responses could double the mean productivity of a potato farm in relation to the productivity of undamaged plants. The compensatory response is best predicted by pest pressure on a farm with potato plants having the maximum productivity when 10% of the tubers are damaged and decreasing in productivity as pest pressure increases. To a lesser extent an interaction between altitude and landscape simplification did affect the compensatory response, suggesting that abiotic factors play an important role in compensation. Our results suggest that overcompensation-based management practices could be used to maximize yields on working potato farms. Further research is required to determine action thresholds (i.e. the damage levels at which pest control needs to be enacted to maximize yields and minimize insecticide use) to develop more sustainable ways of increasing yields in the future. PMID- 29281132 TI - Monoclonal gammopathies: Electronic subspecialty consultation. AB - IMPORTANCE: Electronic consultation (e-consult) is an important component of care for patients in the Veterans Health Administration who require subspecialty consultation but not urgent face-to-face evaluation. Monoclonal gammopathy of undetermined significance (MGUS) is a common reason for e-consult. While often benign, MGUS requires careful evaluation and persistent surveillance over time. OBJECTIVE: To identify areas to improve MGUS care delivery by e-consult. METHODS: We performed a retrospective review of our e-consult database and identified a cohort of 152 MGUS patients triaged for e-consult over a 5-year period (2010 2014). RESULTS: The median time to completion of an e-consult was 2 days. Ninety six percent of MGUS e-consults had a hemoglobin >10 g/dL, and 90% had a creatinine <2 mg/dL. While the majority of e-consults were low risk, paraprotein surveillance varied over time and tracked with consult utilization. With a median follow-up of 44 months, there were 6 documented progression events, representing a mean rate of progression of 1% per year. CONCLUSIONS: E-consult is a helpful mechanism for the evaluation of MGUS, reducing the need for outpatient appointments. However, timely risk stratification and persistent surveillance over time are critical for e-consult to work well. PMID- 29281133 TI - The impact of strength level on adaptations to combined weightlifting, plyometric, and ballistic training. AB - The purpose of this investigation was to determine whether the magnitude of adaptation to integrated ballistic training is influenced by initial strength level. Such information is needed to inform resistance training guidelines for both higher- and lower-level athlete populations. To this end, two groups of distinctly different strength levels (stronger: one-repetition-maximum (1RM) squat = 2.01 +/- 0.15 kg.BM-1 ; weaker: 1.20 +/- 0.20 kg.BM-1 ) completed 10 weeks of resistance training incorporating weightlifting derivatives, plyometric actions, and ballistic exercises. Testing occurred at pre-, mid-, and post training. Measures included variables derived from the incremental-load jump squat and the 1RM squat, alongside muscle activity (electromyography), and jump mechanics (force-time comparisons throughout the entire movement). The primary outcome variable was peak velocity derived from the unloaded jump squat. It was revealed that the stronger group displayed a greater (P = .05) change in peak velocity at mid-test (baseline: 2.65 +/- 0.10 m/s, mid-test: 2.80 +/- 0.17 m/s) but not post-test (2.85 +/- 0.18 m/s) when compared to the weaker participants (baseline 2.43 +/- 0.09, mid-test. 2.47 +/- 0.11, post-test: 2.61 +/- 0.10 m/s). Different changes occurred between groups in the force-velocity relationship (P = .001-.04) and jump mechanics (P <= .05), while only the stronger group displayed increases in muscle activation (P = .05). In conclusion, the magnitude of improvement in peak velocity was significantly influenced by pre-existing strength level in the early stage of training. Changes in the mechanisms underpinning performance were less distinct. PMID- 29281134 TI - Resilient patriarchy: public authority and women's (in)security in Karamoja, Uganda. AB - This paper draws on fieldwork conducted in 2011 and 2016 to explore the differing experiences of Karamojong women following the Government of Uganda's most recent disarmament programme. Besides being deprived of their guns, Karamojong communities have lost most of the cattle on which their livelihoods and way of life were centred. The study assesses whether or not women's experience of patriarchy has changed in these new circumstances, and, if so, how this impacts on their security and control of resources, or the absence of them. It maps, using information primarily supplied by women, public authorities from below, and evaluates if and how they respond to women's protection and survival needs, as well as if current development/humanitarian interventions are of sustainable benefit to Karamojong women. The paper concludes that apparent shifts in gender relations are probably superficial, contingent on continuing food aid, and that economic development and positive social change for women remain elusive. PMID- 29281135 TI - Gender, sexuality, and violence in humanitarian crises. AB - Gender, sexuality, and violence have attracted significant attention in the sphere of humanitarianism in recent years. While this shift builds on the earlier 'Gender and Development' approach and the 'Women, Peace, and Security Agenda', analytical depth is lacking in practice. Notably, 'gender' often means a singular concern for women, neglecting questions of agency and the dynamic and changing realities of gendered power relations. This introductory paper examines why this neglect occurs and proposes a more relational approach to gender. It explores how the contributions to this special issue of Disasters revisit classic gender issues pertaining to violence, livelihoods, and institutions in different settings of humanitarian emergencies, while expanding one's vision beyond them. It draws from the seven papers a number of lessons for humanitarianism, concerning the entangled nature of gender relations, the risks of the unintended effects of gender programming, and the importance of paying sustained attention to how gender relations unfold in a time of crisis. PMID- 29281136 TI - 'I followed the flood': a gender analysis of the moral and financial economies of forced migration. AB - What would a gender analysis of refugee crises reveal if one expanded the focus beyond female refugees, and acts of physical violence? This paper draws on qualitative research conducted in Denmark, Greece, Jordan, and Turkey in July and August 2016 to spotlight the gendered kinship, hierarchies, networks, and transactions that affect refugees. The coping strategies of groups often overlooked in the gender conversation are examined throughout this study, including those of male refugees and those making crossings outside of the context of a family unit. The analysis is theoretically situated at the intersection of critical humanitarianism and the politics of vulnerability, and rooted in debates about the feminisation of refugees and corresponding protection agendas. A key contribution of this work is the ethnographic tracing of how refugees embody these politics along their journeys. In closing, the paper sketches out some implications of the findings for humanitarian practice and identifies avenues for further research. PMID- 29281137 TI - Gender and enterprise in fragile refugee settings: female empowerment amidst male emasculation-a challenge to local integration? AB - This paper examines gender and enterprise in fragile refugee settings. Building on previous research in Afghanistan, it analyses refugee women's evolving economic lives and enterprise initiatives and related social dynamics in refugee communities. Case studies look specifically at two Islamic refugee contexts: Nairobi, Kenya (Somali refugees), and Irbid and Zarqa, Jordan (Syrian refugees). The discussion spotlights the precarious nature of refugee women's new practices and work norms under forced and strained circumstances, without a process of negotiation with male family members. In the case of longer-term refugees (Somalis), it describes new collective agency among refugee women, boosting support for new practices. The paper reflects on emerging gender roles and relations in such hostile conditions, particularly as men remain excluded and struggle for their own identity and authority. In addition, it draws attention to the gap relating to refugee men and policymaking, and highlights ways to address better their needs for refugee resilience, inclusion, and local integration. PMID- 29281138 TI - Women survivors and their children born of wartime sexual violence in northern Uganda. AB - Girls and women who bear children owing to wartime sexual violence committed by armed actors face challenges in gaining acceptance on return to their families and societies. This study analyses the lives of women survivors and their children born of wartime sexual violence in Uganda. It draws on a population based survey of 1,844 households in the Acholi and Lango sub-regions of northern Uganda, as well as on in-depth qualitative interviews conducted in 2014 and 2015 with 67 purposefully selected women survivors of wartime sexual violence. The study finds that: stigma is linked to broader gender discriminatory sociocultural norms and practices and changes under different circumstances; women's economic agency is essential to reducing stigma; households with members who suffered war related sexual violence experienced significantly higher rates of violence post conflict than did other households; and the passage of time is less of a determining factor in their acceptance and reintegration than previously thought. PMID- 29281139 TI - Beyond the hype? The response to sexual violence in the Democratic Republic of the Congo in 2011 and 2014. AB - The Democratic Republic of the Congo (DRC) has witnessed a high prevalence of sexual violence since the wars of the mid-1990s. The huge response to it commenced around the turn of the century, but turned to 'hype' towards 2010. The paper defines 'hypes' as phenomena characterised by a media frenzy, eagerness by non-governmental organisations, and pragmatic local responses. Interviews and analyses conducted in 2011 revealed misuse of services and misrepresentation at different levels. The paper goes on to review medical and legal assistance and to provide evidence of incremental improvements in the response since 2012. It has become better coordinated, with more engagement by the DRC government, more community-oriented, and has incorporated a broader notion of gender-based violence. Nonetheless, concern remains about its impact and its continued dependence on international resources. There is apprehension too about social reactions to the problems of corruption and impunity, seemingly adding to the confusion surrounding gender relations in the country. PMID- 29281140 TI - Policing men: militarised masculinity, youth livelihoods, and security in conflict-affected northern Uganda. AB - Relations between militaries and masculinities-and hegemonic masculinity and the state-are well-established in the literature on gender and development. However, there is less research on how militarised masculinities relate to state governance strategies. This paper, based on qualitative research conducted in northern Uganda between 2014 and 2017, offers a gender analysis of youths participating in informal security arrangements. Civilian male youths accept poorly paid or unpaid work in the informal security sector in the hope of gaining access to livelihoods that will enable them to fulfil masculine ideal-types. However, this arrangement denies them the resources necessary to achieve the ideal-type of civilian masculinity, as well as the state's military masculinity, which produces young men as subjects of the ruling regime. To reconfigure this relationship between civilian and militarised masculinities, one should understand informal security organisations in the context of alternative livelihood arrangements and take a long-term approach to the demilitarisation of the Ugandan state. PMID- 29281141 TI - 'That thing of human rights': discourse, emergency assistance, and sexual violence in South Sudan's current civil war. AB - One of the most widely covered aspects of the current conflict in South Sudan has been the use sexual violence by rival factions of the Sudan People's Liberation Movement/Army (SPLM/A) and other armed groups. While this has had the positive effect of ensuring that sexual violence is an integral component of intervention strategies in the country, it has also had a number of unintended consequences. This paper demonstrates how the narrow focus on sexual violence as a 'weapon of war', and the broader emergency lens through which the plight of civilians, especially women, has been viewed, are overly simplistic, often neglecting the root causes of such violence. More specifically, it highlights how dominant discourses on sexual violence in South Sudan's conflict have disregarded the historically violent civil-military relations that have typified the SPLM/A's leadership, and the structural violence connected with the local political economy of bride wealth and the associated commodification of feminine identities and bodies. PMID- 29281142 TI - Mullerian tract anomalies and urinary tract infections. PMID- 29281143 TI - The soluble guanylate cyclase stimulator IW-1973 prevents inflammation and fibrosis in experimental non-alcoholic steatohepatitis. AB - BACKGROUND AND PURPOSE: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation and fibrosis. Soluble guanylate cyclase (sGC) stimulation reduces inflammation and fibrosis in experimental models of lung, kidney and heart disease. Here, we tested whether sGC stimulation is also effective in experimental NASH. EXPERIMENTAL APPROACH: NASH was induced in mice by feeding a choline-deficient, l-amino acid-defined, high-fat diet. These mice received either placebo or the sGC stimulator IW-1973 at two different doses (1 and 3 mg.kg-1 .day-1 ) for 9 weeks. IW-1973 was also tested in high-fat diet (HFD) induced obese mice. Steatosis, inflammation and fibrosis were assessed by Oil Red O, haematoxylin-eosin, Masson's trichrome, Sirius Red, F4/80 and alpha-smooth muscle actin staining. mRNA expression was assessed by quantitative PCR. Levels of IW-1973, cytokines and cGMP were determined by LC-MS/MS, Luminex and enzyme immunoassay respectively. KEY RESULTS: Mice with NASH showed reduced cGMP levels and sGC expression, increased steatosis, inflammation, fibrosis, TNF-alpha and MCP-1 levels and up-regulated collagen types I alpha1 and alpha2, MMP2, TGF-beta1 and tissue metallopeptidase inhibitor 1 expression. IW-1973 restored hepatic cGMP levels and sGC expression resulting in a dose-dependent reduction of hepatic inflammation and fibrosis. IW-1973 levels were ~40-fold higher in liver tissue than in plasma. IW-1973 also reduced hepatic steatosis and adipocyte hypertrophy secondary to enhanced autophagy in HFD-induced obese mice. CONCLUSIONS AND IMPLICATIONS: Our data indicate that sGC stimulation prevents hepatic steatosis, inflammation and fibrosis in experimental NASH. These findings warrant further evaluation of IW-1973 in the clinical setting. PMID- 29281145 TI - The prevalence and severity of health problems in youth elite sports: A 6-month prospective cohort study of 320 athletes. AB - Little is known regarding the overall health of youth elite athletes. Our aim was to describe the prevalence and severity of health problems in a cohort of youth elite athletes representing a variety of endurance, team, and technical sports. Elite sport athletes (N = 260, 16.2 years) from different Sport Academy High Schools in Norway, and a group of their teammates (N = 60, 16.4 years) attending regular high schools, were included in the study. The Oslo Sports Trauma Research Centre (OSTRC) questionnaire on health problems was used to self-report injuries and illnesses for 26 weeks. At any given time, an average of 43% [95% CI: 37% 49%] of the elite sport athletes had some form of health problem and 25% [20% 31%] had substantial health problems. The prevalence of health problems was similar between the elite team sport athletes and their teammates, except for substantial injuries (22% [16%-30%] vs 10% [5%-20%]). Endurance sport athletes reported more illnesses (23% [15%-35%]) than technical and team sport athletes (10% [5%-20%] and 8% [4%-14%]). In contrast, technical and team sport athletes reported more injuries (36% [95% CI: 25-48] and 37% [95% CI 29-45]) compared to endurance sport athletes (15% [8%-25%]). The total impact of health problems was roughly split in thirds between overuse injuries (37%), acute injuries (34%), and illnesses (30%). This is the first prospective study to present self-reported injury and illness data in a large heterogeneous group of youth elite athletes, documenting a substantial impact of both injuries and illnesses on the health of this population. PMID- 29281144 TI - Size, growth, and density data for shallow-water sea urchins from Mexico to the Aleutian Islands, Alaska, 1956-2016. AB - Size, growth, and density have been studied for North American Pacific coast sea urchins Strongylocentrotus purpuratus, S. droebachiensis, S. polyacanthus, Mesocentrotus (Strongylocentrotus) franciscanus, Lytechinus pictus, Centrostephanus coronatus, and Arbacia stellata by various workers at diverse sites and for varying lengths of time from 1956 to present. Numerous peer reviewed publications have used some of these data but some data have appeared only in graduate theses or the gray literature. There also are data that have never appeared outside original data sheets. Motivation for studies has included fisheries management and environmental monitoring of sewer and power plant outfalls as well as changes associated with disease epidemics. Studies also have focused on kelp restoration, community effects of sea otters, basic sea urchin biology, and monitoring. The data sets presented here are a historical record of size, density, and growth for a common group of marine invertebrates in intertidal and nearshore environments that can be used to test hypotheses concerning future changes associated with fisheries practices, shifts of predator distributions, climate and ecosystem changes, and ocean acidification along the Pacific Coast of North America and islands of the north Pacific. No copyright restrictions apply. Please credit this paper when using the data. PMID- 29281146 TI - Comparison of the inflammatory and stress response between sprint interval swimming and running. AB - The aim of the study was to compare myocellular damage, metabolic stress, and inflammatory responses as well as circulating sodium (Na+ ) and potassium (K+ ) between a single sprint swimming and running training. Eighteen subjects regularly involved in swimming and running training for at least 2 years were recruited. The subjects performed 8 * 30 seconds "all out" exercise on different days either by running or by swimming in a random order. Blood was collected before each training session, after the cessation of exercise (post) and after 2 hours of rest (2 hours). We then analyzed tumor necrosis factor alpha (TNF alpha), interleukin 10 (IL-10), interleukin 6 (IL-6), cortisol, creatine kinase MB isoform (CK-MB), lactate dehydrogenase (LDH), K+ , and Na+ . Neither TNF-alpha nor IL-10 differed between swimming and running. Most of the subjects showed a non-statistically significant increase of LDH and CK-MB after swimming. On the other hand, IL-6 (P < .05) and cortisol (P < .05) were significantly lower after 2 hours of swimming than after running. In addition, post-exercise K+ was significantly lower (P < .001) for swimming than for running. Our results provide evidence of similar inflammatory responses between exercise modes but lower metabolic stress in response to swimming than in response to running. PMID- 29281147 TI - Homogenizing an urban habitat mosaic: arthropod diversity declines in New York City parks after Super Storm Sandy. AB - The frequency and intensity of hurricanes are increasing globally, and anthropogenic modifications in cities have created systems that may be particularly vulnerable to their negative effects. Organisms living in cities are exposed to variable levels of chronic environmental stress. However, whether chronic stress ameliorates or exacerbates the negative effects of hurricanes remains an open question. Here, we consider two hypotheses about the simultaneous consequences of acute disturbances from hurricanes and chronic stress from urbanization for the structure of urban arthropod communities. The tipping point hypothesis posits that organisms living in high stress habitats are less resilient than those in low stress habitats because they are living near the limits of their environmental tolerances; while the disturbance tolerance hypothesis posits that high stress habitats host organisms pre-adapted for coping with disturbance, making them more resilient to the effects of storms. We used a before-after-control-impact design in the street medians and city parks of Manhattan (New York City, New York, USA) to compare arthropod communities before and after Super Storm Sandy in sites that were flooded and unflooded during the storm. Our evidence supported the disturbance tolerance hypothesis. Significant compositional differences between street medians and city parks before the storm disappeared after the storm; similarly, unflooded city parks had significantly different arthropod composition while flooded sites were indistinguishable. These differences were driven by reduced occurrences and abundances of arthropods in city parks. Finally, those arthropod groups that were most tolerant to urban stress were also the most tolerant to flooding. Our results suggest that the species that survive in high stress environments are likely to be the ones that thrive in response to acute disturbance. As storms become increasingly common and extreme, this juxtaposition in responses to storm-associated disturbance may lead to diversity loss in cities, potentially leading entire urban landscapes to mirror the reduced diversity of street medians. PMID- 29281148 TI - Room-Temperature Phosphorescence in Pure Organic Materials: Halogen Bonding Switching Effects. AB - Organic room-temperature phosphorescence (ORTP), when combined with external stimuli-responsive capability, is very attractive for sensors and bio-imaging devices, but remains challenging. Herein, by doping two beta-iminoenamine-BF2 derivatives (S-2CN and S-2I) into a 4-iodoaniline (I-Ph-NH2 ) crystalline matrix, the formation of S-2CN???I-Ph-NH2 and S-2I???I-Ph-NH2 halogen bonds leads to bright-red RTP emissions from these two host-guest doped crystals (hgDCs) with quantum efficiencies up to 13.43 % and 15.96 %, respectively. Upon treatment with HCl, the competition of I-Ph-NH2 ?HCl formation against S-2I???I-Ph-NH2 halogen bonding switches off the red RTP from S-2I/I-Ph-NH2 hgDCs, whereas the stable halogen-bonded S-2CN???I-Ph-NH2 ensures red RTP from S-2CN/I-Ph-NH2 hgDCs remains unchanged. A security protection luminescence pattern by using these different HCl-responsive RTP behaviors was designed. PMID- 29281149 TI - Giant Glycosidase Inhibitors: First- and Second-Generation Fullerodendrimers with a Dense Iminosugar Shell. AB - The multivalent effect in glycosidase inhibition is a new topic in glycoscience that has emerged a few years ago, with the discovery of neoglycoclusters displaying strong binding enhancements over the corresponding monovalent inhibitor. Iminosugar-fullerene conjugates with high valencies have been prepared from iminosugar-terminated dendrons and a clickable fullerene hexa-adduct scaffold. The simultaneous grafting of twelve dendrons allows for a very fast dendritic growth thus limiting the number of synthetic steps required to prepare compounds with a high number of peripheral units. The grafting of first- and second-generation dendrons provided fullerodendrimers surrounded by 36 and 108 peripheral iminosugars, respectively. Inhibition studies have been carried out with a panel of glycosidases. In the particular case of Jack bean alpha mannosidase, the 108-valent nanoconstruct displays inhibition in the nanomolar range and an additional binding enhancement of one order of magnitude when compared to the 36-valent analogues. PMID- 29281150 TI - To distinguish flexible and rigid lumbar curve from MRI texture analysis in adolescent idiopathic scoliosis: A feasibility study. AB - BACKGROUND: Imaging in side bending, supine, traction, fulcrum, and push prone are examples of methods used to evaluate the curve reduction of scoliotic spine. However, being able to determine spine curve flexibility from MRI would eliminate the need of additional X-ray radiation related to radiograph acquisition in side bending. PURPOSE/HYPOTHESIS: To find specific texture features of lumbar postural muscles on MRI that can distinguish flexible from rigid lumbar scoliotic curves. We hypothesized that the changes occurring in postural muscles with scoliosis can be seen with MRI. STUDY TYPE: Retrospective study case control. POPULATION: With Institutional Review Board approval and informed consent, 15 adolescents with idiopathic scoliosis and scheduled for surgery were involved. FIELD STRENGTH/SEQUENCE: T1 -weighted MR images were performed on a 1.5T system using a spin echo sequence in the axial direction. ASSESSMENT: The spinal erector, quadratus lumborum and psoas major muscles were analyzed using textural features. STATISTICAL TESTS: Principal component analysis (PCA) and agglomerative hierarchical clustering (AHC) were used to classify the lumbar postural muscles and calculate performance metrics. The lumbar flexibility index, measured from suspension tests, was used as ground truth measurement. RESULTS: The five discriminant features (out of 34 tested features) obtained from PCA were able to keep over 90% of the variability of the dataset. The right and left spinal erector and the left psoas major had the highest performance metrics to classify the spinal curve flexibility, with an accuracy over 0.80, a sensitivity over 0.82, a specificity over 0.68, and a Matthews correlation coefficient over 0.57. DATA CONCLUSION: This study analyzed MRI using texture information of muscle to distinguish flexible from rigid scoliotic curves. Some postural muscle such as the spinal erector and the psoas major are more likely to reflect the curve flexibility of a scoliotic participant. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017. PMID- 29281151 TI - Quantitative intravoxel incoherent motion parameters derived from whole-tumor volume for assessing pathological complete response to neoadjuvant chemotherapy in locally advanced rectal cancer. AB - BACKGROUND: Many locally advanced rectal cancer (LARC) patients can benefit from neoadjuvant chemotherapy (NACT), with some achieving a pathological complete response (pCR). However, there is limited research reporting on the value of intravoxel incoherent motion (IVIM) in monitoring pCR in patients with LARC. PURPOSE: To identify whether IVIM parameters derived from whole-tumor volume (WTV) before and after NACT could accurately assess pCR in patients with LARC. STUDY TYPE: Prospective patient control study. POPULATION: Fifty-one patients with LARC before and after NACT, prior to surgery. FIELD STRENGTH/SEQUENCE: IVIM diffusion imaging at 3T. ASSESSMENT: Apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), and perfusion-related diffusion fraction (f) values were obtained on diffusion-weighted magnetic resonance images (DW-MRI) using WTV methods and calculated using a biexponential model before and after NACT. STATISTICAL TESTS: DWI-derived ADC and IVIM-derived parameters and their percentage changes (DeltaADC%, DeltaD%, DeltaD*%, and Deltaf%) were compared using independent-samples t-test and Mann-Whitney U-test between the pCR and non-pCR groups. The diagnostic performance of IVIM parameters and their percentage changes were evaluated using receiver operating characteristic curves. RESULTS: Compared with the non-pCR group, the pCR group exhibited significantly lower pre-ADCmean (P = 0.003) and pre-D values (P = 0.024), and significantly higher post-f (P = 0.002), DeltaADCmean % (P = 0.002), DeltaD% (P = 0.001), and Deltaf% values (P = 0.017). Receiver operating characteristic curves showed that the pre-D value had the best specificity (95.12%) and accuracy (86.27%) in predicting the pCR status, and DeltaD% had the highest area under the curve (0.832) in assessing the pCR response to NACT. DATA CONCLUSIONS: The IVIM-derived D value is a promising tool in predicting the pCR status before therapy. The percentage changes in D values after therapy may help assess the pCR status prior to surgery. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017. PMID- 29281152 TI - Selfish X chromosomes and speciation. AB - In two papers published at about the same time almost thirty years ago, Frank (Evolution, 45, 1991a, 262) and Hurst and Pomiankowski (Genetics, 128, 1991, 841) independently suggested that divergence of meiotic drive systems-comprising genes that cheat meiosis and genes that suppress this cheating-might provide a general explanation for Haldane's rule and the large X-effect in interspecific hybrids. Although at the time, the idea was met with skepticism and a conspicuous absence of empirical support, the tide has since turned. Some of the clearest mechanistic explanations we have for hybrid male sterility involve meiotic drive systems, and several other cases of hybrid sterility are suggestive of a role for meiotic drive. In this article, I review these ideas and their descendants and catalog the current evidence for the meiotic drive model of speciation. In addition, I suggest that meiotic drive is not the only intragenomic conflict to involve the X chromosome and contribute to hybrid incompatibility. Sexually and parentally antagonistic selection pressures can also pit the X chromosome and autosomes against each other. The resulting intragenomic conflicts should lead to co evolution within populations and divergence between them, thus increasing the likelihood of incompatibilities in hybrids. I provide a sketch of these ideas and interpret some empirical patterns in the light of these additional X-autosome conflicts. PMID- 29281153 TI - Microvascular perfusion of the placenta, developing fetal liver, and lungs assessed with intravoxel incoherent motion imaging. AB - BACKGROUND: In utero intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) provides a novel method for examining microvascular perfusion fraction and diffusion in the developing human fetus. PURPOSE: To characterize gestational changes in the microvascular perfusion fraction of the placenta, fetal liver, and lungs using IVIM-MRI. STUDY TYPE: Retrospective, cross-sectional study. SUBJECTS: Fifty-five datasets from 33 singleton pregnancies were acquired (17-36 gestational weeks). FIELD STRENGTH/SEQUENCE: In utero diffusion-weighted echo planar imaging at 1.5T and 3.0T with b-factors ranging from 0 to 900 s/mm2 in 16 steps. ASSESSMENT: Using the IVIM principle, microvascular perfusion fraction (f), pseudodiffusion (D*), and diffusion coefficients (d) were estimated for the placenta, liver, and lungs with a biexponential model. A free-form nonlinear deformation algorithm was used to correct for the frame-by-frame motion of the fetal organs and the placenta. The IVIM parameters were then compared to a Doppler ultrasound-based assessment of the umbilical artery resistance index. STATISTICAL TESTS: Pearson product-moment correlation coefficient (PMCC) to reveal outlier corrected correlations between Doppler and IVIM parameters. Gestational age-related changes were assessed using linear regression analysis (LR). RESULTS: Placental f (0.29 +/- 0.08) indicates high blood volume in the microvascular compartment, moderately increased during gestation (LR, R = 0.338), and correlated negatively with the umbilical artery resistance index (PMCC, R = 0.457). The f of the liver decreased sharply during gestation (LR, R = -0.436). Lung maturation was characterized by increasing perfusion fraction (LR, R = 0.547), and we found no gestational changes in d and D* values (LR, R = -0.013 and R = 0.051, respectively). The Doppler measurements of the umbilical artery and middle cerebral artery did not correlate with the IVIM parameters of the lungs and liver. DATA CONCLUSION: Gestational age-associated changes of the placental, liver, and lung IVIM parameters likely reflect changes in placental and fetal circulation, and characterize the trajectory of microstructural and functional maturation of the fetal vasculature. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017. PMID- 29281154 TI - The Chemist and the Architect. AB - To imagine a structure and then express it in material form is one of the most satisfying of human activities. It is pervasive throughout the arts and crafts and it is one of the defining features of architecture. It is also at the heart of synthetic chemistry. PMID- 29281155 TI - Keeping Health Care Affordable: One Way OHCA Does it. PMID- 29281156 TI - The idiopathic normal-pressure hydrocephalus Radscale: a radiological scale for structured evaluation. AB - BACKGROUND AND PURPOSE: Despite the important role of imaging in diagnosing idiopathic normal-pressure hydrocephalus (iNPH), a structured overall assessment of radiological signs is still lacking. The purpose of this study was to construct a radiological scale, composed of morphological signs of iNPH, and compare it with clinical symptoms. METHODS: In this prospective, population-based study of iNPH, 168 individuals (93 females) [mean age 75 (range 66-92) years] underwent computed tomography of the brain and a neurological examination with assessment of clinical symptoms according to Hellstrom's iNPH scale. Two radiologists, blinded to clinical data, independently evaluated and measured eight radiological parameters, i.e. Evans' index, callosal angle, size of temporal horns, narrow high-convexity sulci, dilated Sylvian fissures, focally dilated sulci, peri-ventricular hypodensities and bulging of the lateral ventricular roof. RESULTS: In a linear regression model, all parameters except ventricular roof bulging were significantly associated with clinical iNPH symptoms. The seven remaining parameters were summarized into a total iNPH Radscale score ranging from 0 to 12. There was a significant correlation (r = 0.55, P < 0.001) between the total iNPH Radscale score and clinical symptoms. The inter-rater agreement for the included radiological parameters was high (intraclass correlation, 0.74-0.97). CONCLUSION: The iNPH Radscale may become a valuable diagnostic screening tool, allowing a structured radiological assessment. A high iNPH Radscale score together with clinical symptoms should raise suspicion of iNPH, motivating further evaluation for shunt surgery. PMID- 29281157 TI - Serum neurofilament light chain in patients with acute cerebrovascular events. AB - BACKGROUND AND PURPOSE: Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months. RESULTS: We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score < 7, 13.1 pg/mL [interquartile range (IQR), 5.3-27.8]; NIHSS score 7-15, 16.7 pg/mL (IQR, 7.4-34.9); and NIHSS score > 15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P < 0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors. CONCLUSIONS: In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months. PMID- 29281158 TI - Pediatric renovascular hypertension: Treatment outcome according to underlying disease. AB - BACKGROUND: Renovascular hypertension (RVH) accounts for 5-10% of pediatric hypertension, and can be associated with underlying disease involving other organs. The purpose of this study was to evaluate the clinical characteristics and assess the treatment outcomes of Korean pediatric patients with RVH. METHODS: The medical records of 25 Korean pediatric patients with RVH were retrospectively reviewed. RESULTS: Twenty-four patients had underlying disease, and the most common cause was moyamoya disease (MMD; n = 10; 40%). Of 10 patients with MMD, seven had RVH prior to MMD. All patients required antihypertensive medication as the initial treatment and 22 patients subsequently underwent percutaneous transluminal angioplasty (PTA). The majority of patients with MMD had ostial lesions on angiography. Eight patients had favorable outcomes after the first PTA. One patient received nephrectomy, and two patients received bypass surgery because of restenosis after PTA and technical failure of PTA, respectively. During follow up, blood pressure was well-controlled in nine patients, but only four patients were able to discontinue medication. Eight patients had target organ damage of the brain, heart, and retina at the time of initial diagnosis, and five patients developed chronic kidney disease during follow up. CONCLUSION: The most common cause of RVH in Korean children is MMD, and RVH caused by MMD with an ostial lesion is associated with poor PTA outcomes. Angioplasty alone does not appear to control blood pressure effectively in MMD patients, and combined treatment is necessary to prevent target organ damage. PMID- 29281160 TI - Declining trends in adult physical activity in Australia? An alternative view. PMID- 29281159 TI - Non-alcoholic fatty liver disease is associated with stroke severity and progression of brainstem infarctions. AB - BACKGROUND AND PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is closely correlated to visceral obesity, dyslipidaemia, insulin resistance and type 2 diabetes mellitus. We sought to assess the association between a specific stroke subgroup, brainstem infarctions (BSIs) and NAFLD. Furthermore, we evaluated whether NAFLD is an independent risk factor in patients with BSIs. METHODS: Non alcoholic fatty liver disease was assessed in 306 patients with radiologically confirmed BSIs via liver ultrasound. Differences between patients with and without NAFLD were compared. Data associated with stroke severity and progression after admission were collected. RESULTS: Non-alcoholic fatty liver disease was found in 130 (42.5%) patients with acute BSIs; 58 (19.0%) had National Institutes of Health Stroke Scale scores >7 and 57 (18.6%) had progression after admission. Initial National Institutes of Health Stroke Scale scores, incidence of progression and stroke severity, and modified Rankin Scale scores at discharge were significantly higher in patients with NAFLD than in those without NAFLD. NAFLD was associated with stroke severity [Cox regression: hazard ratio (HR), 2.243; 95% confidence interval (CI), 1.254-4.013, P < 0.01]. This risk remained statistically significant after controlling for age, gender, diabetes mellitus and C-reactive protein (HR, 2.327; 95% CI, 1.252-4.324, P < 0.01). In addition, NAFLD was associated with progression (HR, 2.155; 95% CI, 1.201-3.865, P < 0.05) and remained significant after controlling for age, gender, diabetes mellitus, fibrinogen and C-reactive protein (HR, 2.378; 95% CI, 1.260-4.486, P < 0.01). CONCLUSIONS: These results suggest that NAFLD is a potential risk factor when evaluating the severity and progression of acute BSIs. This relationship is independent of classic risk factors and metabolic syndrome features. PMID- 29281161 TI - A patient decision aid for risk-reducing surgery in premenopausal BRCA1/2 mutation carriers: Development process and pilot testing. AB - BACKGROUND: BRCA1/2 mutation carriers' choice between risk-reducing salpingo oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making. DESIGN: Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process. SETTING AND PARTICIPANTS: Pre-menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands. MAIN OUTCOME MEASURES: IPDAS quality criteria, relevance, usability, clarity. RESULTS: The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step-by-step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process. DISCUSSION AND CONCLUSIONS: Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk-reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making. PMID- 29281162 TI - The Australian NHMRC guidelines for alcohol consumption and their portrayal in the print media: a content analysis of Australian newspapers. AB - OBJECTIVE: To measure and characterise unpaid coverage in the Australian print media of the 2001, 2007 and 2009 National Health and Medical Research Council (NHMRC) Australian Guidelines to Reduce Health Risks from Drinking Alcohol. METHODS: A total of 172 articles published in Australian newspapers between 1999 and 2014 were content analysed using a coding framework aimed to define the article descriptors, article prominence, content, slant and guidelines. RESULTS: The majority (62.2%) of articles were published between 2007 and 2009, the predominant topic being 'the National Health and Medical Research Council guidelines" with less than two-thirds (59.2%) of the articles mentioning the specific guidelines for reducing alcohol-related harm. CONCLUSIONS: There was low unpaid print newspaper coverage of the guidelines, which may contribute to low community knowledge of the guidelines. Implications for public health: This study provides a foundation for developing further studies and highlights the need to improve awareness of the guidelines. PMID- 29281163 TI - Potassium Amide-Catalyzed Benzylic C-H Bond Addition of Alkylpyridines to Styrenes. AB - The benzylic functionalization of alkylpyridines is an important pathway for pyridine derivatives synthesis. The reaction partners, however, were mostly limited to highly reactive polar electrophiles. Herein, we report a potassium amide-catalyzed selective benzylic C-H bond addition of alkylpyridines to styrenes. Potassium bis(trimethylsilyl)amide (KHMDS), a readily available Bronsted base, showed excellent catalytic activity and chemoselectivity. A series of alkylpyridine derivatives, including benzylic quaternary carbon substituted pyridines, were obtained in good to high yield. Preliminary mechanistic studies revealed that the deprotonation equilibrium is probably responsible for the excellent selectivity. PMID- 29281164 TI - Drawing conclusions from within-group comparisons and selected subsets of data leads to unsubstantiated conclusions: Letter regarding Malakellis et al. PMID- 29281165 TI - An intercept study to measure the extent to which New Zealand university students pre-game. AB - OBJECTIVE: We aimed to quantify the degree to which students pre-gamed in New Zealand, using self-report and breathalysers. METHODS: A total of 569 New Zealand undergraduate students were interviewed (men = 45.2%; first year = 81.4%) entering three university-run concerts. We asked participants to report how many drinks they had consumed, their self-reported intoxication and the duration of their pre-gaming session. We then recorded participants' Breath Alcohol Concentration (BrAC; ug/L) and the time they arrived at the event. RESULTS: The number of participants who reported consuming alcohol before the event was 504 (88.6%) and the number of standard drinks consumed was high (M=6.9; median=6.0). A total of 237 (41.7%) participants could not have their BrAC recorded due to having consumed alcohol <=10 minutes before the interview. The remaining 332 participants (57.3%) recorded a mean BrAC of 288.8ug/L (median=280.0 ug/L). Gender, off-campus accommodation, length of pre-gaming drinking session, and time of arrival at the event were all associated with increased pre-gaming. Conclusion and implications for public health: Pre-gaming was the norm for students. Universities must take pre-gaming into account; policy implications include earlier start times of events and limiting students' access to alcohol prior to events. PMID- 29281166 TI - A potential Human Rights Act in Queensland and inclusion of the right to health. AB - OBJECTIVE: To identify the level of public support for a Human Rights Act for Queensland (HRAQ) and for inclusion of the right to health by participants in a public inquiry process. METHODS: We reviewed the 492 written submissions to the Legal Affairs and Community Safety Committee's Inquiry into a potential HRAQ and the transcripts documenting the public hearings held by the Committee in 2016. RESULTS: A total of 465 written submissions were analysed; 419 (90%) were for a HRAQ. More than 80% of the 'for' submissions advocated the right to health's inclusion. At the seven public hearings, 72 persons made verbal submissions and most supported a HRAQ. Five major themes were identified in our synthesis of the public hearing transcripts. Three related specifically to health and human rights: 1) the need to consider the holistic health and human rights of Indigenous Queenslanders and Indigenous Queensland communities; 2) instilling a human rights culture in Queensland; and 3) access to health care and the underlying determinants of health. The other two themes related to the conduct of the Inquiry: 4) the importance of community participation in developing a HRAQ; and 5) concerns about the public consultation processes. CONCLUSION: This study found strong support in the majority of submissions for the Queensland Parliament to draft and enact a HRAQ, and for the inclusion of the right to health in such legislation. Implications for public health: The Queensland Parliament's enactment of a HRAQ that expressly included the right to health would increase the accountability and transparency of government health (and related) decision making and resource allocation, and would better identify and address health inequities across the state. This Act is imperative for improving the health and wellbeing of all Queenslanders, particularly rural and remote and Aboriginal and Torres Strait Islander Queenslanders. PMID- 29281167 TI - Authors' response to Letter to the Editor: ANZJPH-2017-220. PMID- 29281168 TI - Authors' response to Letter to the Editor: ANZJPH-2017-248. PMID- 29281170 TI - In Situ Optical Imaging of the Growth of Conjugated Polymer Aggregates. AB - Understanding the mechanisms that contribute to conjugated polymer aggregate formation and growth may yield enhanced control of aggregate morphology and functional properties on the mesoscopic scale. In situ optical imaging of the growth of MEH-PPV aggregates in real time in controlled swollen films shows that growth occurs through multiple mechanisms and is more complex than previously described. Direct evidence is provided for both Ostwald ripening and aggregate coalescence as operative modes of aggregate growth in solvent swollen films. These growth mechanisms have a distinct and strong impact on the evolution of morphological order of growing aggregates: while Ostwald ripening allows preservation of highly ordered morphology, aggregate coalescence occurs with no preferential orientation, leading to attenuation in degree of ordering. PMID- 29281169 TI - Epidemic forecasts as a tool for public health: interpretation and (re)calibration. AB - OBJECTIVE: Recent studies have used Bayesian methods to predict timing of influenza epidemics many weeks in advance, but there is no documented evaluation of how such forecasts might support the day-to-day operations of public health staff. METHODS: During the 2015 influenza season in Melbourne, Australia, weekly forecasts were presented at Health Department surveillance unit meetings, where they were evaluated and updated in light of expert opinion to improve their accuracy and usefulness. RESULTS: Predictive capacity of the model was substantially limited by delays in reporting and processing arising from an unprecedented number of notifications, disproportionate to seasonal intensity. Adjustment of the predictive algorithm to account for these delays and increased reporting propensity improved both current situational awareness and forecasting accuracy. CONCLUSIONS: Collaborative engagement with public health practitioners in model development improved understanding of the context and limitations of emerging surveillance data. Incorporation of these insights in a quantitative model resulted in more robust estimates of disease activity for public health use. Implications for public health: In addition to predicting future disease trends, forecasting methods can quantify the impact of delays in data availability and variable reporting practice on the accuracy of current epidemic assessment. Such evidence supports investment in systems capacity. PMID- 29281172 TI - Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal-Bisphosphonate Coordination Chemistry for Wound Healing. AB - Biomaterial-based regenerative approaches would allow for cost-effective off-the shelf solution for the treatment of wounds. Hyaluronan (HA)-based hydrogel is one attractive biomaterial candidate because it is involved in natural healing processes, including inflammation, granulation, and reepithelialization. Herein, dynamic metal-ligand coordination bonds are used to fabricate moldable supramolecular HA hydrogels with self-healing properties. To achieve reversible crosslinking of HA chains, the biopolymer is modified with pendant bisphosphonate (BP) ligands using carbodiimide coupling and chemoselective "click" reactions. Hydrogel is formed immediately after simple addition of silver (Ag+ ) ions to the solution of HA containing BP groups (HA-BP). Compared with previous HA-based wound healing hydrogels, the HA-BP.Ag+ hydrogel is highly suitable for clinical use as it can fill irregularly shaped wound defects without the need for premolding. The HA-BP.Ag+ hydrogel shows antimicrobial properties to both Gram positive and Gram-negative bacterial strains, enabling prevention of infections in wound care. In vivo evaluation using a rat full-thickness skin wound model shows significantly lower wound remaining rate and a thicker layer of regenerated epidermis as compared with the group left without treatment. The presented moldable and self-healing supramolecular HA hydrogel with "ready-to-use" properties possesses a great potential for regenerative wound treatment. PMID- 29281171 TI - Use of a functional mobility measure to predict discharge destinations for patients admitted to an older adult rehabilitation ward: A feasibility study. AB - OBJECTIVE: To investigate whether the discharge destination for older adults can be predicted using functional mobility as measured by the Modified Elderly Mobility Scale (MEMS), associated with demographic and primary reason for admission variables. METHODS: A retrospective cohort population audit of 257 patients admitted and discharged from four tertiary older adult rehabilitation wards in a three-month period. A number of predictor variables were considered alongside the discharge destination. RESULTS: Multinomial statistical modelling established that MEMS prior to (P < 0.001), MEMS on completion (P = 0.009) of rehabilitation physiotherapy and primary reason for admission (P = 0.002) were significant variables to predict discharge destination. The model correctly predicted 71% of observed patient discharge destinations. CONCLUSION: The MEMS in conjunction with primary reason for admission was able to predict discharge destination with 71% accuracy in a heterogeneous population of older adults following rehabilitation. PMID- 29281173 TI - High Crystalline Prussian White Nanocubes as a Promising Cathode for Sodium-ion Batteries. AB - Prussian blue and its analogues (PBAs) have been recognized as one of the most promising cathode materials for room-temperature sodium-ion batteries (SIBs). Herein, we report high crystalline and Na-rich Prussian white Na2 CoFe(CN)6 nanocubes synthesized by an optimized and facile co-precipitation method. The influence of crystallinity and sodium content on the electrochemical properties was systematically investigated. The optimized Na2 CoFe(CN)6 nanocubes exhibited an initial capacity of 151 mA h g-1 , which is close to its theoretical capacity (170 mA h g-1 ). Meanwhile, the Na2 CoFe(CN)6 cathode demonstrated an outstanding long-term cycle performance, retaining 78 % of its initial capacity after 500 cycles. Furthermore, the Na2 CoFe(CN)6 Prussian white nanocubes also achieved a superior rate capability (115 mA h g-1 at 400 mA g-1 , 92 mA h g-1 at 800 mA g-1 ). The enhanced performances could be attributed to the robust crystal structure and rapid transport of Na ions through large channels in the open-framework. Most noteworthy, the as-prepared Na2 CoFe(CN)6 nanocubes are not only low-cost in raw materials but also contain a rich sodium content (1.87 Na ions per lattice unit cell), which will be favorable for full cell fabrication and large-scale electric storage applications. PMID- 29281174 TI - Meta-STEPP with random effects. AB - We recently developed a method called Meta-STEPP based on the fixed-effects meta analytic approach to explore treatment effect heterogeneity across a continuous covariate for individual time-to-event data arising from multiple clinical trials. Meta-STEPP forms overlapping subpopulation windows (meta-windows) along a continuous covariate of interest, estimates the overall treatment effect in each meta-window using standard fixed-effects method, plots them against the continuous covariate, and tests for treatment-effect heterogeneity across the range of covariate values. Here, we extend this method using random-effects methods and find it to be more conservative than the fixed-effects method. Both the random- and fixed-effects Meta-STEPP are implemented in R. PMID- 29281175 TI - Starbon/High-Amylose Corn Starch-Supported N-Heterocyclic Carbene-Iron(III) Catalyst for Conversion of Fructose into 5-Hydroxymethylfurfural. AB - Iron-N-heterocyclic carbene complexes (Fe-NHCs) have come to prominence because of their applicability in diverse catalytic reactions, ranging from C-C cross coupling and C-X bond formation to substitution, reduction, polymerization, and dehydration reactions. The detailed synthesis, characterization, and application of novel heterogeneous Fe-NHC catalysts immobilized on mesoporous expanded high amylose corn starch (HACS) and Starbon 350 (S350) for facile fructose conversion into 5-hydroxymethylfurfural (HMF) is reported. Both catalyst types showed good performance for the dehydration of fructose to HMF when the reaction was tested at 100 degrees C with varying time (10 min, 20 min, 0.5 h, 1 h, 3 h and 6 h). For Fe-NHC/S350, the highest HMF yield was 81.7 % (t=0.5 h), with a TOF of 169 h 1 , fructose conversion of 95 %, and HMF selectivity of 85.7 %, whereas for Fe NHC/expanded HACS, the highest yield was 86 % (t=0.5 h), with a TOF of 206 h-1 , fructose conversion of 87 %, and HMF selectivity of 99 %. Iron loadings of 0.26 and 0.30 mmol g-1 were achieved for Fe-NHC/expanded starch and Fe-NHC/S350, respectively. PMID- 29281176 TI - The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome. AB - PURPOSE: The application of proteomics in chronic kidney disease (CKD) can potentially uncover biomarkers and pathways that are predictive of disease. EXPERIMENTAL DESIGN: Within this context, this study examines the relationship between the human plasma proteome and glomerular filtration rate (GFR) as measured by iohexol clearance in a cohort from Sweden (n = 389; GFR range: 8-100 mL min-1 /1.73 m2 ). A total of 2893 proteins are quantified using a modified aptamer assay. RESULTS: A large proportion of the proteome is associated with GFR, reinforcing the concept that CKD affects multiple physiological systems (individual protein-GFR correlations listed here). Of these, cystatin C shows the most significant correlation with GFR (rho = -0.85, p = 1.2 * 10-97 ), establishing strong validation for the use of this biomarker in CKD diagnostics. Among the other highly significant protein markers are insulin-like growth factor binding protein 6, neuroblastoma suppressor of tumorigenicity 1, follistatin related protein 3, trefoil factor 3, and beta-2 microglobulin. These proteins may indicate an imbalance in homeostasis across a variety of cellular processes, which may be underlying renal dysfunction. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, this study represents the most extensive characterization of the plasma proteome and its relation to GFR to date, and suggests the diagnostic and prognostic value of proteomics for CKD across all stages. PMID- 29281177 TI - Understanding TGEV-ETEC Coinfection through the Lens of Proteomics: A Tale of Porcine Diarrhea. AB - Porcine diarrhea and gastroenteritis are major causes of piglet mortality that result in devastating economic losses to the industry. A plethora of pathogens can cause these diseases, with the transmissible gastroenteritis virus (TGEV) and enterotoxigenic Escherichia coli K88 (ETEC) being two of the most salient. In the December 2017 issue of Proteomics Clinical Aplications, Xia and colleagues used comparative proteomics to shed light on how these microbes interact to cause severe disease . The authors discovered that TGEV induces an epithelial mesenchymal transition-like phenotype that augments cell adhesion proteins mediating the attachment of ETEC to intestinal epithelial cells. Moreover, coinfection was found to modulate several host proteins that could bolster pathogen persistence. Importantly, the authors observed that ETEC suppresses the production of inflammatory cytokines induced by TGEV, which may in turn promote the long-term survival of both microbes. PMID- 29281178 TI - A Novel Antihypertensive Peptide Identified in Thermolysin-Digested Rice Bran. AB - SCOPE: Hypertension is a risk factor for arteriosclerosis. In this study, we investigate the antihypertensive effect of protease-digested rice bran in a spontaneously hypertension rat (SHR) model. We also purify a novel antihypertensive peptide from the digest. METHODS AND RESULTS: Thermolysin digested rice bran (TRB) is administered to SHRs for 4 weeks, and systolic blood pressure (SBP) was measured weekly using the tail-cuff method. TRB shows an antihypertensive effect in a dose-dependent manner. TRB also reduces angiotensin I-converting enzyme (ACE) activity in lung tissue and serum troponin I levels. TRB is fractionated by HPLC and ACE-inhibitory activity in the HPLC fractions is measured. Peptides LRA and YY are identified from the two fractions with the strongest ACE-inhibitory activity. Amino acid sequence of these peptides are found in a vicilin-like seed storage protein, and identified in rice bran protein using the peptide mass fingerprint method. We confirm that LRA and YY are cleaved by thermolysin digestion of a model synthetic peptide. Orally administered LRA (0.25 mg kg-1 ) or YY (0.5 mg kg-1 ) lowers the SBP of SHRs at 4 h after administration. CONCLUSION: We identify a novel, orally active antihypertensive peptide, LRA from the digest of rice bran protein. PMID- 29281179 TI - A high parasite density environment induces transcriptional changes and cell death in Plasmodium falciparum blood stages. AB - : Transient regulation of Plasmodium numbers below the density that induces fever has been observed in chronic malaria infections in humans. This species transcending control cannot be explained by immunity alone. Using an in vitro system we have observed density dependent regulation of malaria population size as a mechanism to possibly explain these in vivo observations. Specifically, Plasmodium falciparum blood stages from a high but not low-density environment exhibited unique phenotypic changes during the late trophozoite (LT) and schizont stages of the intraerythrocytic cycle. These included in order of appearance: failure of schizonts to mature and merozoites to replicate, apoptotic-like morphological changes including shrinking, loss of mitochondrial membrane potential, and blebbing with eventual release of aberrant parasites from infected erythrocytes. This unique death phenotype was triggered in a stage-specific manner by sensing of a high-density culture environment. Conditions of glucose starvation, nutrient depletion, and high lactate could not induce the phenotype. A high-density culture environment induced rapid global changes in the parasite transcriptome including differential expression of genes involved in cell remodeling, clonal antigenic variation, metabolism, and cell death pathways including an apoptosis-associated metacaspase gene. This transcriptional profile was also characterized by concomitant expression of asexual and sexual stage specific genes. The data show strong evidence to support our hypothesis that density sensing exists in P. falciparum. They indicate that an apoptotic-like mechanism may play a role in P. falciparum density regulation, which, as in yeast, has features quite distinguishable from mammalian apoptosis. DATABASE: Gene expression data are available in the GEO databases under the accession number GSE91188. PMID- 29281180 TI - Obstetric fistula: a paradigm shift is needed in research and prevention. PMID- 29281181 TI - The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants. AB - Polymedicated neonates and young infants may be at risk of harmful cumulative exposure to toxic excipients like ethanol, propylene glycol and benzyl alcohol during routine clinical care. The aim of this study was to calculate the cumulative daily alcohol exposure (mg/kg/day) in polymedicated neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA). As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received >=2 medicinal products/day and infants >=3 medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA. Altogether, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products. In total, 45% (n = 288) of patients were exposed to an alcohol of interest; 2% (n = 14) were exposed to benzyl alcohol (BA), 38% (n = 237) to ethanol and 23% (n = 146) to propylene glycol (PG). Of the total number of prescriptions involving ethanol-containing medicinal products (n = 334), 51% would alone exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n = 174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563 mg/kg/day) or PG (954 mg/kg/day) exceeded the tolerance limits recommended by EMA 260.5 and 19.1 times, respectively. Tolerance limits for ethanol and PG as proposed by the EMA are frequently exceeded in polymedicated neonates and infants due to the cumulative effect of these alcohols. Alternative formulations may minimize excipient exposure. PMID- 29281182 TI - High dietary intake of branched-chain amino acids is associated with an increased risk of insulin resistance in adults. AB - BACKGROUND: The aim of this study was to investigate the association between branched-chain amino acid (BCAA) intake and markers of insulin metabolism in adults. METHODS: This cohort study was conducted within the framework of the Tehran Lipid and Glucose Study on 1205 subjects, aged >=20 years, who were followed-up for a mean of 2.3 years. Dietary intake of BCAAs, including valine, leucine, and isoleucine, was determined using a valid and reliable food frequency questionnaire. Hyperinsulinemia, beta-cell dysfunction, insulin resistance (IR), and insulin insensitivity were determined according to optimal cut-off values. Logistic regression was to estimate the occurrence of IR across tertiles of BCAA intake. RESULTS: The mean (+/- SD) age and BCAA intake of participants (43% male) at baseline were 42.7 +/- 13.1 years and 13.8 +/- 5.1 g/day, respectively. The incidence of hyperinsulinemia, beta-cell dysfunction, insulin insensitivity, and IR was 19.5%, 24.0%, 28.0%, and 12.5%, respectively. After adjustment for confounding variables, subjects in the highest tertile for total BCAAs (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.03-2.71), leucine (OR 1.75; 95% CI 1.09-2.82), and valine (OR 1.61; 95% CI 1.01-2.60) intake had a greater risk of incident IR than subjects in the lowest tertile. A higher intake of isoleucine was not associated with risk of incident IR. There was no association of total BCAAs, leucine, isoleucine, and valine intake with the risk of hyperinsulinemia, insulin insensitivity, or beta-cell dysfunction. CONCLUSION: The findings of this study support the hypothesis that higher intakes of BCAAs may have adverse effects on the development of IR. PMID- 29281184 TI - Gestational age and stillbirths: questions left unanswered. PMID- 29281183 TI - Development of an attract-and-kill co-formulation containing Saccharomyces cerevisiae and neem extract attractive towards wireworms. AB - BACKGROUND: Wireworms (Coleoptera: Elateridae) are major insect pests of worldwide relevance. Owing to the progressive phasing-out of chemical insecticides, there is great demand for innovative control options. This study reports on the development of an attract-and-kill co-formulation based on Ca alginate beads, which release CO2 and contain neem extract as a bioinsecticidal compound. The objectives of this study were to discover: (1) whether neem extract can be immobilized efficiently, (2) whether CO2 -releasing Saccharomyces cerevisiae and neem extract are suitable for co-encapsulation, and (3) whether co encapsulated neem extract affects the attractiveness of CO2 -releasing beads towards wireworms. RESULTS: Neem extract was co-encapsulated together with S. cerevisiae, starch and amyloglucosidase with a high encapsulation efficiency of 98.6% (based on measurement of azadirachtin A as the main active ingredient). Even at enhanced concentrations, neem extract allowed growth of S. cerevisiae, and beads containing neem extract exhibited CO2 -emission comparable with beads without neem extract. When applied to the soil, the beads established a CO2 gradient of >15 cm. The co-formulation containing neem extract showed no repellent effects and was attractive for wireworms within the first 24 h after exposure. CONCLUSION: Co-encapsulation of S. cerevisiae and neem extract is a promising approach for the development of attract-and-kill formulations for the control of wireworms. This study offers new options for the application of neem extracts in soil. (c) 2017 Society of Chemical Industry. PMID- 29281185 TI - Hepatitis C virus: Enslavement of host factors. AB - Hepatitis C virus (HCV) has infected over 170 million people world-wide. This infection causes severe liver damage that can progress to hepatocellular carcinoma leading to death of the infected patients. Development of a cell culture model system for the study of HCV infection in the recent past has helped the researchers world-wide to understand the biology of this virus. Studies over the past decade have revealed the tricks played by the virus to sustain itself, for as long as 40 years, in the host setup without being eliminated by the immune system. Today we understand that the host organelles and different cellular proteins are affected during HCV infection. This cytoplasmic virus has all the cellular organelles at its disposal to successfully replicate, from ribosomes and intracellular membranous structures to the nucleus. It modulates these organelles at both the structural and the functional levels. The vast knowledge about the viral genome and viral proteins has also helped in the development of drugs against the virus. Despite the achieved success rate to cure the infected patients, we struggle to eliminate the cases of recurrence and the non responders. Such cases might emerge owing to the property of the viral genome to accumulate mutations during its succeeding replication cycles which favours its survival. The current situation calls an urgent need for alternate therapeutic strategies to counter this major problem of human health. (c) 2017 IUBMB Life, 70(1):41-49, 2018. PMID- 29281186 TI - MicroRNA-204 deregulation in lung adenocarcinoma controls the biological behaviors of endothelial cells potentially by modulating Janus kinase 2-signal transducer and activator of transcription 3 pathway. AB - MicroRNAs (miRNAs) have been implicated in a wide range of biological processes including angiogenesis. MiR-204 was identified as a tumor suppressor in multiple cancer types, including lung adenocarcinoma. However, the function of miR-204 in lung tumor angiogenesis remains unknown. In this study, we found that the miR-204 expression was decreased in lung adenocarcinoma based on the cancer genome atlas (TCGA) analysis and gain-of-function experiment showed that miR-204 promoted cancer cell apoptosis and suppressed cell proliferation, migration in vitro and tumor growth in vivo. Functionally, both the tube formation and migration abilities of human umbilical vein endothelial cells (HUVECs) were suppressed by conditioned media from lung cancer A549 cells with miR-204 overexpression. Meanwhile, these conditioned media inhibited proliferation and promoted apoptosis in HUVECs. The key angiogenesis inducer hypoxia inducible factor-1alpha (HIF1alpha) and the pro-angiogenic mediators vascular endothelial growth factor and platelet-derived growth factor were decreased in A549 cells transfected with miR-204 mimics. Mechanistically, miR-204 could target Janus kinase 2 (JAK2) and further impaired signal transducer and activator of transcription 3 both in vitro and in vivo. Inhibition of JAK2 or signal transducer and activator of transcription 3 (STAT3) activity with small chemical inhibitors in A549 cells impaired lung adenocarcinoma angiogenesis in vitro. Meanwhile, conditional media from interleukin 6-treated lung normal epithelial cells significantly promoted tube formation of HUVEC, which was disturbed by miR-204 overexpression. Taken together, our findings demonstrate that miR-204 attenuates angiogenesis in lung adenocarcinoma potentially via JAK2-STAT3 pathway. Clinically, the miR 204/JAK2/STAT3 signaling pathway is a putative therapeutic target in lung adenocarcinoma. (c) 2017 IUBMB Life, 70(1):81-91, 2018. PMID- 29281187 TI - Review on hyperbaric oxygen treatment in femoral head necrosis. AB - BACKGROUND: Femoral head necrosis (FHN) is a common invalidating disease with an unclear etiology and pathophysiology that affects middle-aged people. FHN may lead to joint collapse and require invasive treatments. Because of its clinical and socioeconomic significance, an early diagnosis, staging and appropriate treatment are required. Unfortunately, to date a unique algorithm for the treatment of FHN has not been defined. OBJECTIVE: In this report we summarize the Tenth European Consensus Conference on hyperbaric medicine (April 2016, France), during which experts from Europe revised the list of accepted indications for hyperbaric oxygen (HBO2) treatment, including FHN. METHODS: In this report all aspects of osteonecrosis discussed during the meeting have been considered: pathophysiology,clinical presentation, standard management, HBO2 therapy and evidence-based review of its efficacy. All observations are based on a thorough review of the best available research and evidence-based medicine. CONCLUSIONS: The Consensus Conference in Lille established FHN as an indication for HBO2 therapy and suggested a protocols guideline to adopt for this pathology. PMID- 29281188 TI - Health care worker decompression sickness: incidence, risk and mitigation. AB - Inadvertent exposure to radiation, chemical agents and biological factors are well recognized hazards associated with the health care delivery system. Less well appreciated yet no less harmful is risk of decompression sickness in those who accompany patients as inside attendants (IAs) during provision of hyperbaric oxygen therapy. Unlike the above hazards where avoidance is practiced, IA exposure to decompression sickness risk is unavoidable. While overall incidence is low, when calculated as number of cases over number of exposures or potential for a case during any given exposure, employee cumulative risk, defined here as number of cases over number of IAs, or risk that an IA may suffer a case, is not. Commonly, this unique occupational environmental injury responds favorably to therapeutic recompression and a period of recuperation. There are, however, permanent and career-ending consequences, and at least two nurses have succumbed to their decompression insults. The intent of this paper is to heighten awareness of hyperbaric attendant decompression sickness. It will serve as a review of reported cases and reconcile incidence against largely ignored individual worker risk. Mitigation strategies are summarized and an approach to more precisely identify risk factors that might prompt development of consensus screening standards is proposed. PMID- 29281190 TI - Hyperbaric oxygen therapy as an adjuvant to source control in necrotizing soft tissue infections. AB - INTRODUCTION: Necrotizing soft tissue infections (NSTI) are rare but potentially lethal disorders, and adequate management is time- and resource-demanding. This study aims to assess whether variations in the treatment modalities - surgery, hyperbaric oxygen (HBO2) therapy and negative pressure wound therapy - had an impact on the length to definitive source control in NSTI patients who underwent HBO2. METHODS: This is a retrospective study of all NSTI patients treated with hyperbaric oxygen therapy between March 2007 and May 2015 at Unidade Local de Saude de Matosinhos (ULSM) Hyperbaric Unit. A multiple linear regression model was used to assess the impact of different treatment modalities in the posdiagnosis time until source control. RESULTS: 58 patients were included; overall mortality was 13.8%. Mean time until source control was 10.4 days (+/ 5.4). All patients were under empiric and broad-spectrum antibiotics on the day of diagnosis. Patients underwent an average of 0.62 (+/-0.29) surgical interventions and 1.06 (+/-0.52) HBO2 sessions per day. The regression model (R2=0.86) showed that after adjusting for other covariates, doubling the number of HBO2 sessions per day shortened source control by five days (? beta = -5.25; 95% CI -6.49 to 4.01), and for each day that HBO2 was delayed, source control was achieved one day later (beta = 1.03; 95% CI 0.82 to 1.24). CONCLUSIONS: More intensive HBO2 protocols with earlier and more frequent sessions shorten the time until definitive source control in necrotizing soft tissue infections, potentially lowering the impact of systemic effects of infection and complications associated with organ dysfunction. PMID- 29281189 TI - Influence of hyperoxia on diastolic myocardial and arterial endothelial function. AB - OBJECTIVE: Hyperoxia is known to influence cardiovascular and endothelial function, but it is unknown if there are differences between younger and older persons. The aim of this study was to monitor changes in myocardial diastolic function and flow-mediated dilatation (FMD) in younger and elderly volunteers, before and after exposure to relevant hyperbaric hyperoxia. METHODS: 51 male patients were separated into two groups for this study. Volunteers in Group 1 (n=28, mean age 26 +/-6, "juniors") and Group 2 (n=23, mean age 53 +/-9, "seniors") received standard HBO2 protocol (240kPa oxygen). Directly before and after hyperoxic exposure in a hyperbaric chamber we took blood samples (BNP, hs troponin-t), assessed the FMD and echocardiographic parameters with focus on diastolic function. RESULTS: After hyperoxia we observed a high significant decrease in heart rate and systolic/diastolic FMD. Diastolic function varied in both groups: E/A ratio showed a statistically significant increase in Group 1 and remained unchanged in Group 2. E/e' ratio showed a slight but significant increase in Group 1, whereas e'/a' ratio increased in both groups. Deceleration time increased significantly in all volunteers. Isovolumetric relaxation time remained unchanged and ejection fraction showed a decrease only in Group 2. There were no changes in levels of BNP and hs-troponin-t in either group. CONCLUSION: Hyperoxia seems to influence endothelial function differently in juniors and seniors: FMD decreases more in seniors, possibly attributable to pre-existing reduced vascular compliance. Hyperoxia-induced bradycardia induced a more pronounced improvement in diastolic function in juniors. The ability of Group 1 to cope with hyperoxia-induced effects did not work in the same manner as with Group 2. PMID- 29281191 TI - Hyperbaric oxygen suppresses growth of Klebsiella pneumoniae and enhances effect of tigecycline in vitro. AB - OBJECTIVES: (1) To examine whether hyperbaric oxygen (HBO2) will inhibit growth of multidrug-resistant Klebsiella pneumoniae (MDR-K. pneumoniae) and extensively drug-resistant Klebsiella pneumoniae (XDR-K. pneumoniae); (2) To determine whether the effect of tigecycline on XDR-K. pneumoniae will be enhanced by HBO2. METHODS: The effects of 1.5 hours of treatment with normoxia (21% O2, 1 atmosphere absolute/ATA) or HBO2 (100% O2, 2 ATA) on bacterial counts of eight isolates of MDR-K. pneumoniae and eight isolates of XDR-K. pneumoniae were studied. The effects of five hours of treatment with normoxia (21% O2, 1 ATA), tigecycline (21% O2, 1 ATA), HBO2 (100% O2, 3 ATA) or HBO2 + tigecycline (100% O2, 3 ATA) on proliferation of 10 isolates of XDR-K. pneumoniae were investigated. RESULTS: HBO2 at 100% O2, 2 ATA, 1.5 hours suppressed growth of MDR K. pneumoniae but had no effect on XDR-K. pneumoniae. HBO2 at 100% O2, 3 ATA, five hours enhanced the effects of tigecycline on XDR-K. pneumoniae. CONCLUSIONS: HBO2 in combination with or without tigecycline can be used to eliminate K. pneumoniae in vitro, and such treatment may be beneficial for patients with infections caused by K. pneumoniae. PMID- 29281192 TI - Dried salted plum consumption ameliorates hyperbaric oxygen therapy-induced otalgia severity at the first chamber session: a prospective randomized controlled study. AB - PURPOSE: One of the most common complications of hyperbaric oxygen (HBO2) therapy is middle ear barotrauma (MEB), occasionally causing otalgia. The objective of this study was to evaluate the effect of dried salted plum consumption on MEB and otalgia associated with HBO2 therapy. MATERIALS AND METHODS: Patients undergoing the first chamber session of HBO2 therapy were included in the present prospective randomized controlled trial. The Valsalva maneuver was administered to all patients before HBO2. The patients were randomly divided into two groups: one that ate a dried salted plum during HBO2 treatment and the other that did not. An otoscopic examination was performed after HBO2 therapy. The MEB was graded according to Teed scores. The degree of otalgia was recorded using the Visual Analog Scale (VAS). RESULTS: Ninety patients were enrolled. The overall incidence of MEB (Teed score grade 1~4) was 39.6% (21 of 53) for patients administered a dried salted plum versus 37.8% (14 of 37) for the control group (P=1.000). The incidence of mild MEB (Teed score grade 1~2) and severe MEB (Teed score Grade 3~4) between the two groups was not significantly different. Otalgia was present in 5.7% (3 of 53) of patients administered a dried salted plum versus 18.9% (7 of 37) for the control group (P=.085). No patients administered a dried salted plum had a VAS score >=4 for otalgia versus 10.8% (4 of 37) for the control group (P=.026). CONCLUSIONS: Dried salted plum consumption does not decrease the incidence of MEB, but may ameliorate the severity of first chamber session HBO2-induced otalgia. PMID- 29281193 TI - Quantitative Romberg's test in acute carbon monoxide poisoning treated by hyperbaric oxygen. AB - OBJECTIVE: The aim of this study was to evaluate whether monitoring of acute carbon monoxide-poisoned (COP) patients by means of quantitative Romberg's test (QR-test) during a hyperbaric oxygen (HBO2) therapy regimen could be a useful supplement in the evaluation of neurological status. METHODS: We conducted a retrospective study (2000-2014) in which we evaluated data containing quantitative sway measurements of acute COP patients (n = 58) treated in an HBO2 regimen. Each patient was tested using QR-test before and after each HBO2 treatment. Data were analyzed using linear mixed models (LMM). In each LMM, sway prior to HBO2 therapy was set as the fixed effect and change in sway after HBO2 therapy was set as the response variable. Patient, treatment number, weight and age were set as random effects for all LMMs. RESULTS: From the LMMs we found that larger values of sway prior to HBO2 produced a negative change in sway. We found no correlation between CO level and sway (P=0.1028; P=0.8764; P=0.4749; P=0.5883). Results showed that loss of visual input caused a significant increase in mean sway (P=0.028) and sway velocity (P?0.0001). CONCLUSIONS: The Quantitative Romberg's test is a fast, useful supplement to neurological evaluation and a potential valuable tool for monitoring postural stability during the course of treatment in acute COP patients. PMID- 29281194 TI - The Dewey monitor: Pulse oximetry can independently detect hypoxia in a rebreather diver. AB - Rebreather diving has one of the highest fatality rates per man hour of any diving activity in the world. The leading cause of death is hypoxia, typically from equipment or procedural failures. Hypoxia causes very few symptoms prior to causing loss of consciousness. Additionally, since the electronics responsible for controlling oxygen levels in rebreathers often control their alarm systems, frequently divers do not receive any external warnings. This study investigated the use of a forehead pulse oximeter as an independent warning device in the event of rebreather failure. Ten test subjects (seven male, three female, median age 29, range 26-35) exercised at a targeted rate of 2 L/minute oxygen consumption while on a non-functional rebreather breathing loop (mean consumption achieved 2.09 +/- 0.36 L/minute). Each subject was tested both at the surface and at pressurized depth of 77 fsw (starting pO2=0.7 atm). The data show that a pulse oximeter could be used to provide an Mk 16 rebreather diver with a minimum mean of 49 seconds (+/- 17 seconds SD) of warning time after a noticeable change in blood oxygen saturation (SpO2 <= 95%) but before any risk of loss of consciousness (calculated SpO2 <= 80%), so that the diver may take mitigating actions. No statistical difference in warning time was found between the tests at surface and at 77 fsw (P=0.46). PMID- 29281195 TI - Physiological responses to prolonged saturation diving: a field-based pilot study. AB - This study aimed to assess the effect of extreme environmental exposure during an operational saturation dive on airway inflammation (exhaled nitric oxide (FeNo)), components of fitness (flexibility and aerobic capacity) and blood hematological variables. Six saturation divers, who undertook a 26+/-0.5 day operational saturation dive were recruited to take part in this study. Participants completed a field-based repeated measure test battery on three occasions (pre-dive, post dive and 24 hours after saturation dive). Hemoglobin concentration was significantly (P?0.001) reduced from pre- (15.3+/-0.8 g/dL) to post-saturation (14.25+/-1.2 g/dL) dive but recovered toward baseline values within 24 hours (15.13+/-1.03 g/dL; P=0.04). Similarly, a reduction in plasma volume was observed in all participants from pre- to post-saturation dive trials. Airway inflammation response was non-significant, although a large inter-individual response was evident. Hip flexion, assessed by the sit and reach test did not change following the saturation dive. Data on aerobic capacity was collected in one participant only, due to practical difficulties in participant access. In summary, this is the first investigation to conduct a multiple-component field-based study on operational saturation divers. The findings for this exploratory study present interesting groundings for further investigation. PMID- 29281196 TI - Effects of prolonged and repeated immersions on heart rate variability and complexity in military divers. AB - BACKGROUND: The influence of prolonged and repeated water immersions on heart rate variability (HRV) and complexity was examined in 10 U.S. Navy divers who completed six-hour resting dives on five consecutive days. Pre-dive and during dive measures were recorded daily. METHODS: Dependent variables of interest were average heart rate (HR), time-domain measures of HRV [root mean square of successive differences of the normal RR (NN) interval (RMSSD), standard deviation of the NN interval (SDNN)], frequency-domain measures of HRV [low-frequency power spectral density (psd) (LFpsd), low-frequency normalized (LFnu), high-frequency psd (HFpsd), high-frequency normalized (HFnu), low-frequency/ high-frequency ratio (LF/HF)], and non-linear dynamics of HRV [approximate entropy (ApEn)]. A repeated-measures ANOVA was performed to examine pre-dive measure differences among baseline measures. Hierarchical linear modeling (HLM) was performed to test the effects of prolonged and repeated water immersion on the dependent variables. RESULTS: Pre-dive HR (P=0.005) and RMSSD (P?0.001) varied significantly with dive day while changes in SDNN approached significance (P=0.055). HLM indicated that HR decreased during daily dives (P=0.001), but increased across dive days (P=0.011); RMSSD increased during daily dives (P=0.018) but decreased across dive days (P?0.001); SDNN increased during daily dives (P?0.001); LF measures increased across dive days (LFpsd P?0.001; LFnu P?0.001), while HF measures decreased across dive days (HFpsd P?0.001; HFnu P?0.001); LF/HF increased across dive days (P?0.001); ApEn decreased during daily dives (P?0.02) and across dive days (P?0.001). CONCLUSIONS: These data suggest that the cumulative effect of repeated dives across five days results in decreased vagal tone and a less responsive cardiovascular system. PMID- 29281197 TI - Smoking cessation program among naval diver trainees in the Republic of Singapore Navy. AB - BACKGROUND: Since 2016, the Naval Diving Unit (NDU) of the Republic of Singapore Navy (RSN) has instituted a smoking cessation trial program for their trainees, instituting a blanket ban on smoking during training hours in order to promote smoking cessation and create a smoke-free culture among its servicemen. For the rest of RSN personnel, they would attend a more costly, established Health Promotion Board (HPB) smoking cessation program, which employs social support strategies, while they undergo basic training in the Navy Military Experts Institute (NMI). METHODOLOGY: We examined the outcomes and direct costs of the NDU smoking cessation trial program, compared with the HPB smoking cessation program in NMI. The primary outcome was self-reported smoking cessation at the end of six months. PRINCIPAL FINDINGS: The NDU smoking cessation program led to 50% reduction among smokers with no additional direct costs. It is comparable to a 59% reduction of smokers among trainees in the established HPB program, which costs US$1,955 per course in 2017. The results of both programs are not significantly different (chi2 = 0.34, P-value = 0.56). Neither program?s participants raised any nicotine withdrawal issues throughout. CONCLUSION: The results of the NDU smoking cessation program suggests that it is not inferior to the established HPB smoking cessation program. More studies should be done to identify factors leading to smoking cessation success among Naval Diver trainees compared to the established program, particularly since the NDU program was less costly and had no engagement with trained counselors. PMID- 29281198 TI - Alternobaric vertigo and facial baroparesis caused by scuba diving and relieved by chewing pineapple: a case report. AB - Equalization of middle ear pressure is an important consideration for scuba divers. When middle ear pressure is asymmetric, a diver may experience alternobaric vertigo. Moreover, individuals with an underlying temporal bone dehiscence are predisposed to facial baroparesis. An understanding on behalf of fellow divers and emergency responders to recognize and differentiate facial baroparesis from decompression illness is critical. Misdiagnosis may lead to inappropriate treatment or unwarranted stoppage of diving. There have been a few dozen reported cases of facial baroparesis in the literature, but few have included firsthand accounts. This report describes an incidence of unilateral facial baroparesis preceded by alternobaric vertigo, with commentary from divers who witnessed the individual experiencing the facial paresis. The facial weakness in this case resolved within 15 minutes after the diver chewed on fresh pineapple. This report suggests that alternobaric vertigo may be a harbinger of facial baroparesis. Upon resurfacing divers should consider prophylactic measures that help to dilate the Eustachian tube such as chewing, yawning and swallowing in order to minimize the risk of middle ear pressure-induced vertigo or facial paresis. PMID- 29281200 TI - UHMS announces position statement on low-pressure, soft-sided hyperbaric chambers. PMID- 29281199 TI - UHMS HBO2 committee chair questions FDA on incorrect info. PMID- 29281201 TI - [Changed percentage of myeloid-derived suppressor cells in the peripheral blood of prostate cancer patients and its clinical implication]. AB - Objective: To investigate the changes in the percentage of myeloid-derived suppressor cells (MDSCs) in the peripheral blood of prostate cancer (PCa) patients and explore the correlation of MDSCs and their subsets with the prognosis of PCa. METHODS: Using flow cytometry, we determined the percentage of MDSCs and the levels of Arg-1, iNOS and PD-L1 in the peripheral blood of 32 PCa patients and 25 healthy controls, detected the distribution of CD14+ Mo-MDSC and CD15+ PMN-MDSC subsets, and analyzed the correlation between the obtained parameters and the prognosis of PCa. RESULTS: Compared with the healthy controls, the PCa patients showed significant increases in the percentage of MDSCs (P<0.01) and levels of Arg-1, iNOS and PD-L1 in the peripheral blood. Statistically significant differences were observed in the distribution of the CD14+ Mo-MDSC and CD15+ PMN-MDSC subsets between the two groups(60.4% vs 72.2%, 29.5% vs 18.8%) (P<0.05). The percentages of MDSCs and Mo-MDSCs were remarkably correlated with the total survival rate of the PCa patients (P=0.025 and 0.017). CONCLUSIONS: The percentages of MDSCs and CD14+ Mo-MDSCs in the peripheral blood were correlated with the prognosis of PCa, which may provide a target or some evidence for the clinical treatment of PCa. PMID- 29281202 TI - [Anxiety and its inducing factors in men undergoing in vitro fertilization and embryo transfer]. AB - Objective: To explore the prevalence of anxiety and its inducing factors in men undergoing in vitro fertilization and embryo transfer (IVF-ET). METHODS: We randomly selected 202 men undergoing IVF-ET in the Infertility and Reproduction Center of the Second Xiangya Hospital of Central South University. On the first day of the IVF-ET cycle, we completed an investigation among the men using a self designed questionnaire, Self-Rating Anxiety Scale (SAS), Social Support Rating Scale (SSRS), and 3 subscales (marital satisfaction, husband-wife communication, and sexual relationship) of Olson Marital Inventory. RESULTS: Mild anxiety was found in 55 (27.2%) of the included men while the other 147 (72.8%) were non anxiety males. Compared with the non-anxiety group, the anxiety group showed significant decreases in the total SSRS score (38.65+/-4.87 vs 36.44+/-4.21), objective support score (9.22+/-1.82 vs 8.36+/-1.18), and utility degree of social support score (6.89+/-1.50 vs 6.24+/-1.61) on the first day of the treatment cycle (P<0.01) as well as in the total scores of marital satisfaction (103.04+/-9.97 vs 96.89+/-9.90), husband-wife communication (32.29+/-4.24 vs 30.56+/-5.43), and sexual relationship (38.03+/-5.27 vs 34.20+/-4.41) (P<0.05). There were statistically significant differences in the incidence rate of anxiety in the men with different housing conditions, monthly incomes, treatment costs, attitudes towards IVF-ET, pressure from social opinion, status of parenthood (P<0.01). Multivariate logistic regression analysis indicated that the major factors associated with anxiety included the attitude towards IVF-ET, pressure from social opinion, and sexual relationship in the men undergoing IVF-ET (P<0.05). CONCLUSIONS: The incidence rate of anxiety is high in males undergoing IVF-ET and it is associated with various factors. Psychological aid is needed to these male patients from the staff of the reproduction center. PMID- 29281203 TI - [Analysis of serum reproductive hormone levels in men with hyperlipemia in the urban area of Shijiazhuang]. AB - Objective: To investigate the aging-related changes of reproductive hormones in hyperlipemia men in the urban area of Shijiazhuang and the relationship between the levels of reproductive hormones and that of blood lipid. METHODS: We enrolled 297 males aged 25-65 years in this study, determined the levels of serum total testosterone (TT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), triglyeride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C) and fasting blood glucose (FBG), and compared the parameters among different age groups. RESULTS: The level of serum TT was decreased while that of FSH increased significantly in the 36-45 years group and that of LH elevated only in the 56-65 years old hyperlipemia males(P<0.05). No statistically significant changes were observed in PRL and E2 among different age groups. Spearman correlation analysis manifested that age was correlated negatively with TT, FSH, and LH (r=-0.266, 0.514, and 0.350, P<0.05), TT weakly negatively with TC and TG (r=-0.215 and -0.286, P<0.05) but weakly positively with HDL-C (r=0.281, P<0.01), and FSH and LH weakly positively with TG (r=0.282 and 0.343, P<0.05). Regression analysis showed age to be an independent influencing factor of TT, FSH and LH, while HDL-C to be that of TT. CONCLUSIONS: The levels of serum TT and FSH gradually change with aging and low TT and high FSH and LH are closely related to hyperlipemia in adult men. PMID- 29281204 TI - [Diagnostic criteria for late-onset hypogonadism: A preliminary study]. AB - Objective: To determine the stability of androgen indexes by analyzing the relationship of androgen indexes with the results of late-onset hypogonadism (LOH) questionnaire investigations, and offer some reference for the application of the diagnostic criteria for LOH released by The Chinese Society of Andrology in 2009. METHODS: This study included 1 003 males aged 40 years or older who had accomplished the questionnaires of Androgen Deficiency in Aging Males (ADAM), Aging Males' Symptoms Scale (AMS), and International Index of Erectile Function-5 (IIEF-5). We evaluated the correlation of androgen indexes with the results of the questionnaire investigation, repeated the examination of androgen indexes for the subjects with total testosterone (TT) <=11.5 nmol/L after an average of 1.5 years, and analyzed the factors inducing changes of androgen indexes. RESULTS: Free testosterone index (FTI) <= 0.42 (OR, 1.369) and calculated free testosterone (cFT) <= 0.3 nmol/L (OR, 1.302) were considered as the risk factors of LOH in AMS, and so were testosterone secretion index (TSI) <= 2.8 nmol/IU (OR, 1.679) and cFT <= 0.3 nmol/L (OR, 1.371) in IIEF-5. Paired t-test on the results of the examination performed twice showed significant differences in the levels of TT, TSI, cFT, and FT (P<0.05). CONCLUSIONS: Decreased testosterone may cause the diversity of LOH symptoms and hence the fluctuation of androgens. Therefore, the diagnosis of LOH depends on androgen indexes, varied symptoms in the questionnaires, and relief of the symptoms after testosterone therapy. PMID- 29281205 TI - [Ladder step strategy for surgical repair of congenital concealed penis in children]. AB - Objective: To assess the feasibility of the ladder step strategy in surgical repair of congenital concealed penis in children. METHODS: This study included 52 children with congenital concealed penis treated in the past two years by surgical repair using the ladder step strategy, which consists of five main steps: cutting the narrow ring of the foreskin, degloving the penile skin, fixing the penile skin at the base, covering the penile shaft, and reshaping the prepuce. The perioperative data of the patients were prospectively collected and statistically described. RESULTS: Of the 52 patients, 20 needed remodeling of the frenulum and 27 received longitudinal incision in the penoscrotal junction to expose and deglove the penile shaft. The advanced scrotal flap technique was applied in 8 children to cover the penile shaft without tension, the pedicled foreskin flap technique employed in 11 to repair the penile skin defect, and excision of the webbed skin of the ventral penis performed in another 44 to remodel the penoscrotal angle. The operation time, blood loss, and postoperative hospital stay were 40-100 minutes, 5-30 ml, and 3-6 days, respectively. Wound bleeding and infection occurred in 1 and 5 cases, respectively. Follow-up examinations at 3 and 6 months after surgery showed that all the children had a satisfactory penile appearance except for some minor complications (2 cases of penile retraction, 2 cases of redundant ventral skin, and 1 case of iatrogenic penile curvature). CONCLUSIONS: The ladder step strategy for surgical repair of congenital concealed penis in children is a simple procedure with minor injury and satisfactory appearance of the penis. PMID- 29281206 TI - [Modified morcellation procedure in holmium laser enucleation of the prostate]. AB - Objective: To evaluate the efficiency and safety of the modified versus conventional morcellation procedure in holmium laser enucleation of the prostate (HoLEP). METHODS: We treated 195 patients with benign prostatic hyperplasia (BPH) by HoLEP, using conventional morcellation for 100 cases and modified morcellation for the other 95. We recorded the morcellation time, the total volume of resected tissue, the rate of morcellation, and associated complications, and compared the data obtained between the two groups. RESULTS: The volumes of resected tissue were similar between the conventional and modified morcellation groups ([72.3+/ 19.8] vs [71.1+/-17.7] g, P>0.05). The morcellation time was significantly longer in the conventional than in the modified morcellation group ([12.8+/-2.8] vs [8.5+/-2.0] min, P<0.01), and the morcellation rate was remarkably lower in the former than in the latter ([4.9+/-1.4] vs [7.1+/-0.9] g/min, P<0.01). No statistically significant differences were observed in the incidence of complications, bladder injury for instance, between the two groups of patients. CONCLUSIONS: The modified morcellation procedure can be used for mocellation of various types of tissue, with a higher efficiency than the conventional technique, and therefore deserves wide clinical application. PMID- 29281207 TI - [High-frequency ultrasonography for diagnosis and differential diagnosis of acute scrotum in children]. AB - Objective: To analyze the high-frequency ultrasound image features of acute scrotum in children and explore the value of high-frequency ultrasonography in the diagnosis and differential diagnosis of the disease. METHODS: This retrospective study included 256 children aged 2 days to 14 years undergoing color Doppler ultrasonography at 2 hours to 3 days after onset of acute scrotum. We analyzed the morphology, internal echo and blood supply of the testis in comparison with the clinical and pathological results. RESULTS: Among the 256 cases, acute testicular torsion was found in 23, of which 16 were treated by complete resection the necrotic testis and the other 7 by surgical reduction of testicular torsion. Ultrasonographically, the involved testes presented different degrees of increase or decrease in volume, with uneven internal echoes, irregular hypoechoic flakes, and testicular hydrocele. Color Doppler flow imaging (CDFI) showed significant blood flow signals around the diseased testes but none within them. Acute testicular appendix torsion was found in 116 cases, in which ultrasonography manifested nodules with round or oval abnormal echoes between the upper pole of the testis and caput epididymidis, first hypoechoic and then gradually increased, heterogeneous internally. CDFI revealed enlarged epididymides and enriched testicular blood flow but no blood flow signals in the nodules. The 103 cases of acute epididymitis were ultrasonographically characterized by varied degrees of swelling of the involved epididymis with uneven internal echoes and rich blood flow signals on CDFI. Six of the cases were diagnosed as acute orchitis, with the ultrasonographic features of testicular swelling and low but uniform internal echoes, with rich blood flow signals on CDFI. Incarcerated inguinal hernia was confirmed in 15 cases, in which ultrasonography revealed intrusion of the hernia into the obviously enlarged scrotal sac with the mesentery and intestine in it, and blood flow visible on CDFI. Acute scrotal wall hematoma and edema was found in 8 cases, with the ultrasonographic characteristics of scrotal wall thickening, with visible blood flow signals on CDFI. CONCLUSIONS: High-frequency ultrasonography has a high sensitivity and specificity for acute scrotum in children, which can be applied as the first-choice clinical imaging modality and provide reliable evidence for the diagnosis and differential diagnosis of the disease. PMID- 29281208 TI - [Application of fast-track surgery concept in the perioperative nursing care of andrological patients: A randomized controlled study]. AB - Objective: To evaluate the application of the fast-track surgery (FTS) concept in the nursing care of andrological patients during the perioperative period. METHODS: A total of 200 males to be treated by andrological surgery were included in a control group and another 200 in an observation group, the former received conventional perioperative nursing care, while the latter underwent an FTS nursing care procedure including a variety of proven effective methods to reduce surgical stress and achieve a quick recovery during the perioperative period. Comparisons were made between the two groups of patients in the postoperative enterokinesia time, anal exhaust time, eating time, off-bed time, defecating time, bowel preparation complications, and degree of comfort and satisfaction. RESULTS: Compared with the controls, the patients in the observation group showed significantly earlier postoperative enterokinesia time ([5.8+/-0.9] vs [4.4+/ 1.4] h, P<0.01), anal exhaust time ([10.8+/-1.8] vs [7.7+/-2.0] h, P<0.01), eating time ([12.9+/-0.7] vs [6.3+/-0.7] h, P<0.01), off-bed time [14.3+/-2.7] vs [8.2+/-1.4] h, P<0.01), and defecating time ([49.2+/-2.6] vs [39.6+/-2.5] h, P<0.01), a lower incidence of bowel preparation complications (P<0.01), and a higher degree of comfort (P<0.01) and satisfaction ([97.5+/-0.7]% vs [99.4+/ +0.3] %, P<0.01). CONCLUSIONS: The FTS concept can be safely and effectively applied to the perioperative nursing care of andrological patients to achieve a faster recovery and higher degree of comfort and satisfaction postoperatively. PMID- 29281209 TI - [Zhibai Dihuang Decoction improves the activity of sperm mitochondrial respiratory chain complex in rats with Ureaplasma urealyticum infection]. AB - Objective: To investigate the effect of Zhibai Dihuang Decoction (ZDD) on the sperm mitochondrial respiratory chain complex (MRCC) in rats with Ureaplasma urealyticum (UU) infection. METHODS: Ninety male SD rats were randomly divided into five groups, sham operation, UU infection model control, ZDD (crude drug at 8.56 g per kg of the body weight per day), doxycycline (DC, at 20 mg per kg of the body weight per day), and ZDD+DC. The model of UU infection was established by injecting UU into the bladder of all the rats except those of the sham operation group. After modeling, the rats were treated intragastrically with respective drugs for 21 days and then executed and their epididymides harvested for examination of sperm quality and determination of the activities of sperm MRCCs I, II, III and IV by spectrophotometry. RESULTS: At 10 days after modeling, the UU-positive rates in the model control, sham operation, ZDD, DC and ZDD+DC groups were 92.9%, 0%, 33.3%, 26.7% and 20.0%, respectively, significantly higher in the model control than in the other groups (P<0.05). The epididymal sperm concentrations in the five groups were (0.97+/-0.23), (3.02+/-0.52), (1.21+/ 0.35), (1.02+/-0.31) and (1.52+/-0.28) *106 ml, the sperm motilities were (58.62+/-15.36), (80.45+/-7.21), (75.52+/-8.78), (68.43+/-10.25) and (78.25+/ 7.67)%, and rates of grade a+b sperm were (6.15+/-1.02), (10.32+/-1.14), (10.12+/ 1.08), (9.01+1.27) and (10.74+/-1.03)%, respectively, all remarkably lower in the model control than in the sham operation group (P<0.01), but markedly higher in the ZDD and ZDD+DC groups than in the model controls (P<0.05). The activities of MRCC I in the model control, sham operation, ZDD, DC and ZDD+DC groups were (31.54+/-16.25), (136.86+/-6.34), (100.68+/-14.41), (81.68+/-6.78) and (124.06+/ 5.54) MUmol/(min.mg), those of MRCC II were (9.50+/-3.86), (20.34+/-0.37), (10.88+/-1.04), (12.93+/-1.07) and (16.23+/-0.60) MUmol/(min.mg), those of MRCC III were (5.58+/-1.79), (19.60+/-0.61), (11.34+/-1.35), (13.87+/-1.23) and (15.96+/-0.69) MUmol/(min.mg), and those of MRCC IV were (9.54+/-1.34), (28.98+/ 3.33), (17.02+/-2.04), (18.41+/-2.67) and (21.66+/-2.93) MUmol/(min.mg), respectively, all significantly lower in the model control than in the sham operation group (P<0.01), with the activities of MRCCs I, III and IV remarkably higher in the ZDD, DC and ZDD+DC groups (P<0.01) and that of MRCC II higher in the DC and ZDD+DC groups than in the model control (P<0.05). CONCLUSIONS: ZDD can improve the epididymal sperm quality and the activity of the sperm MRCC in UU infected rats, which may be one of the mechanisms of ZDD acting on male infertility caused by UU infection. PMID- 29281210 TI - [Effects of Yishen Tonglong Capsules on sex hormone levels in mice with benign prostatic hyperplasia]. AB - Objective: To study the effect of Yishen Tonglong Capsules (YTC) on the sex hormone levels in the mouse model of benign prostatic hyperplasia (BPH). METHODS: The BPH model was made in male mice by subcutaneous injection of testosterone propionate at 5 mg per kg of the body weight per day for 3 weeks. Then the model animals were divided into five groups of 10 in each: model control, Longbishu Capsules (LBS), and high-, medium- and low-dose YTC. Another 10 mice were included as normal controls. The mice in the LBS group were treated intragastrically with LBS at 0.45 g per kg of the body weight, those in the high , medium- and low-dose YTC groups with YTC at 1.2, 0.6 and 0.3 g per kg of the body weight, and those in the model and normal control groups given the same volume of distilled water. After 8 weeks of treatment, the mice were sacrificed and their prostates taken for measurement of their wet weight, calculation of the prostatic index (PI), determination of the levels of serum testosterone (T), estradiol (E2) and E2/T ratio, and observation of the morphological changes of the prostate tissue under the light microscope. RESULTS: The wet weight of the prostate and PI were significantly decreased in the LBS and medium- and high-dose YTC groups as compared with the model control group (P<0.01). The serum T and E2 levels and E2/T ratio were (1.73+/-0.02) ng/ml, (73.08+/-1.03) pg/ml and 42.30+/ 0.53 in the normal control, (3.86+/-0.02) ng/ml, (145.79+/-0.88) pg/ml and 37.76+/-0.25 in the model control, (2.47+/-0.02) ng/ml, (95.87+/-0.47) pg/ml and 38.80+/-0.13 in the LBS, (2.91+/-0.03) ng/ml, (112.68+/-0.77) pg/ml and 38.80+/ 0.42 in the low-dose YTC, (2.77+/-0.02) ng/ml, (112.16+/-0.82) pg/ml and 40.56+/ 0.29 in the medium-dose YTC, and (2.75+/-0.03) ng/ml, (107.11+/-0.61) pg/ml and 38.92+/-0.36 in the high-dose YTC group, all with statistically significant differences between the model control and the other groups (P<0.05 or P<0.01). CONCLUSIONS: Yishen Tonglong Capsules significantly reduced the levels of serum T and E2 and elevated the E2/T ratio in the mouse model of BPH, which manifested the action mechanism of Yishen Tonglong Capsules in the treatment of BPH. PMID- 29281211 TI - [PI3K-Akt/LKB1-AMPK-mTOR-p70S6K/4EBP1 signaling pathways participate in the regulation of testis development and spermatogenesis: An update]. AB - Male infertility is closely associated with spermatogenesis disorders triggered by aberrant gene expression or abnormal signaling pathways in the testis. The mammalian target of rapamycin (mTOR) is a central regulator of cell metabolism, playing an important role in regulating cell proliferation, differentiation, translation, actin polymerization, cycle progression, energy metabolism, autophagy, and other cellular activities. PI3K-Akt and LKB1-AMPK, the two well defined classic signal transduction pathways, regulate the expressions of mTOR and its downstream p70S6K/4EBP1 through different molecular pathways. Recent studies show that mTOR-p70S6K/4EBP1 signaling participates in the regulation of the proliferation and differentiation of testicular cells and spermatogenesis. This review focuses on the role of PI3K-Akt/LKB1- AMPK-mTOR signaling cascades in testis development and spermatogenesis, providing some new perspectives for the studies of the molecular mechanism underlying male sterility. PMID- 29281213 TI - [Autophagy and phenotypic modulation of corpus cavernosum smooth muscle cells in hypoxia-induced erectile dysfunction]. AB - The correlation between hypoxia and erectile dysfunction (ED) has been universally acknowledged for decades in the academic world. The phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) is regarded as one of the factors of hypoxia-induced ED, but the underlying mechanisms remain unclear. Recent researches show some correlation between autophagy and phenotypic modulation of CCSMCs, which may be associated with the overexpressions of PDGF, TGF-beta, and vasoactive factors in the organism following hypoxia. PMID- 29281212 TI - [Transgenerational transmission mediated by small non-coding RNA in sperm]. AB - The presence of RNA has been confirmed in mature human sperm and plays an important role in altering the early events of embryos. Increasing evidence indicates that the expression of small non-coding RNAs can be changed by environmental exposures such as the structure of paternal diet and the status of stress. As the carriers of paternal information and epigenetic markers, small non coding RNAs can alter the development of early embryos and offspring and mediate transgenerational transmission, which offers a new target for the studies of the epigenetics of sperm. Sperm piRNA, microRNA and tRNA, which are widely present in male germ cells, can mediate transgenerational transmission via related regulation mechanisms. This review introduces some new findings about the transgenerational epigenetics concerning the three small non-coding RNAs in sperm and offers a novel insight into male reproduction. PMID- 29281214 TI - [New progress in precision diagnosis of prostate cancer]. AB - The morbidity of prostate cancer presents an obvious ascending tendency. Early diagnosis plays a crucial role in the diagnosis and treatment of prostate cancer. However, the methods widely used for its diagnosis mostly lack high specificity and sensitivity. This review introduces four methods for the detection of prostate cancer, which are PCA3 and TMPRSS2:ERG, the Kallikrein panel, MRGB, and the STHLM3 model, all based on molecular biology and superior to the traditional methods in both specificity and sensitivity. These methods are expected to contribute to the realization of precision diagnosis of prostate cancer. PMID- 29281216 TI - CMS to End ICD-10 Grace Period on October 1. PMID- 29281215 TI - [Impact of zearalenone on male fertility: An update]. AB - Zearalenone (ZEA) is a nonsteroidal estrogen-like mycotoxin widely distributed in maize, wheat, rice and other cereals with its derivants. It also presents in meat or dairy products or even in the aquatic ecosystem via rain, and thus can affect human health. ZEA affects the body function in various ways. On the one hand, it can disturb the synthesis of estrogen and its combination with the receptor, influence the reproductive ability via the estrogen signaling pathway, and cause the dysfunction of the reproductive systems. On the other hand, it can disturb the synthesis of DNA and proteins and result in lipid peroxidation and cytotoxicity by inducing the apoptosis of germ cells. It is known that exposure to different doses of ZEA can affect the female reproductive system by increasing the apoptosis of germ cells and inducing germ cell prematurity, sexual precocity, endocrine disorder, reproductive cycle disorder, and so on. But studies of its influence on the male reproductive system are relatively rare, especially about its unique male-related action mechanisms. This review presents an overview of the studies on the mechanisms of ZEA affecting male fertility and the phenotype changes in the male reproductive system after exposure to ZEA, hoping to provide some new ideas for the protection of human fertility. PMID- 29281240 TI - Correction. PMID- 29281241 TI - Correction. PMID- 29281242 TI - Effects of Imide-Orthoborate Dual-Salt Mixtures in Organic Carbonate Electrolytes on the Stability of Lithium Metal Batteries. AB - The effects of lithium imide and lithium orthoborate dual-salt electrolytes of different salt chemistries in carbonate solvents on the cycling stability of lithium (Li) metal batteries are systematically and comparatively investigated. Two imide salts (LiTFSI and LiFSI) and two orthoborate salts (LiBOB and LiDFOB) are chosen for this study and compared with the conventional LiPF6 salt. Density functional theory calculations indicate that the chemical and electrochemical stabilities rank in the following order: LiTFSI-LiBOB > LiTFSI-LiDFOB > LiFSI LiDFOB > LiFSI-LiBOB. The experimental cycling stability of the Li metal batteries with the electrolytes ranks in the following order: LiTFSI-LiBOB > LiTFSI-LiDFOB > LiFSI-LiDFOB > LiPF6 > LiFSI-LiBOB, which is in well accordance with the calculation results. The LiTFSI-LiBOB can effectively protect the Al substrate and form a more robust surface film on Li metal anode, while the LiFSI LiBOB results in serious corrosion to the stainless steel cell case and a thicker and looser surface film on Li anode. The key findings of this work emphasize that the salt chemistry is critically important for enhancing the interfacial stability of Li metal anode and should be carefully manipulated in the development of high-performance Li metal batteries. PMID- 29281243 TI - Modulating the Electrochemical Performances of Layered Cathode Materials for Sodium Ion Batteries through Tuning Coulombic Repulsion between Negatively Charged TMO2 Slabs. AB - Exploiting advanced layered transition metal oxide cathode materials is of great importance to rechargeable sodium batteries. Layered oxides are composed of negatively charged TMO2 slabs (TM = transition metal) separated by Na+ diffusion layers. Herein, we propose a novel insight, for the first time, to control the electrochemical properties by tuning Coulombic repulsion between negatively charged TMO2 slabs. Coulombic repulsion can finely tailor the d-spacing of Na ion layers and material structural stability, which can be achieved by employing Na+ cations to serve as effective shielding layers between TMO2 layers. A series of O3-type NaxMn1/3Fe1/3Cu1/6Mg1/6O2 (x = 1.0, 0.9, 0.8, and 0.7) have been prepared, and Na0.7Mn1/3Fe1/3Cu1/6Mg1/6O2 shows the largest Coulombic repulsion between TMO2 layers, the largest space for Na ion diffusion, the best structural stability, and also the longest Na-O chemical bond with weaker Coulombic attraction, thus leading to the best electrochemical performance. Meanwhile, the thermal stability depends on the Na concentration in pristine materials. Ex situ X-ray absorption (XAS) analysis indicates that Mn, Fe, and Cu ions are all electrochemically active components during insertion and extraction of sodium ion. This study enables some new insights to promote the development of advanced layered NaxTMO2 materials for rechargeable sodium batteries in the future. PMID- 29281244 TI - High-Density Lipoprotein Nanobiologics for Precision Medicine. AB - Nature is an inspirational source for biomedical engineering developments. Particularly, numerous nanotechnological approaches have been derived from biological concepts. For example, among many different biological nanosized materials, viruses have been extensively studied and utilized, while exosome research has gained much traction in the 21st century. In our body, fat is transported by lipoproteins, intriguing supramolecular nanostructures that have important roles in cell function, lipid metabolism, and disease. Lipoproteins' main constituents are phospholipids and apolipoproteins, forming a corona that encloses a hydrophobic core of triglycerides and cholesterol esters. Within the lipoprotein family, high-density lipoprotein (HDL), primarily composed of apolipoprotein A1 (apoA-I) and phospholipids, measuring a mere 10 nm, is the smallest and densest particle. Its endogenous character makes HDL particularly suitable as a nanocarrier platform to target a range of inflammatory diseases. For a decade and a half, our laboratories have focused on HDL's exploitation, repurposing, and reengineering for diagnostic and therapeutic applications, generating versatile hybrid nanomaterials, referred to as nanobiologics, that are inherently biocompatible and biodegradable, efficiently cross different biological barriers, and intrinsically interact with immune cells. The latter is facilitated by HDL's intrinsic ability to interact with the ATP-binding cassette receptor A1 (ABCA1) and ABCG1, as well as scavenger receptor type B1 (SR-BI). In this Account, we will provide an up-to-date overview on the available methods for extraction, isolation, and purification of apoA-I from native HDL, as well as its recombinant production. ApoA-I's subsequent use for the reconstitution of HDL (rHDL) and other HDL-derived nanobiologics, including innovative microfluidic based production methods, and their characterization will be discussed. The integration of different hydrophobic and amphiphilic imaging labels, including chelated radioisotopes and paramagnetic or fluorescent lipids, renders HDL nanobiologics suitable for diagnostic purposes. Nanoengineering also allows HDL reconstitution with core payloads, such as diagnostically active nanocrystals, as well as hydrophobic drugs or controlled release polymers for therapeutic purposes. The platform technology's specificity for inflammatory myeloid cells and methods to modulate specificity will be highlighted. This Account will build toward examples of in vivo studies in cardiovascular disease and cancer models, including diagnostic studies by magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). A translational success story about the escalation of zirconium-89 radiolabeled HDL (89Zr-HDL) PET imaging from atherosclerotic mice to rabbits and pigs and all the way to cardiovascular disease patients is highlighted. Finally, recent advances in nanobiologic-facilitated immunotherapy of inflammation are spotlighted. Lessons, success stories, and perspectives on the use of these nature-inspired HDL mimetics are an integral part of this Account. PMID- 29281245 TI - Photovoltaic Performance of Vapor-Assisted Solution-Processed Layer Polymorph of Cs3Sb2I9. AB - The presence of toxic lead (Pb) remains a major obstruction to the commercial application of perovskite solar cells. Although antimony (Sb)-based perovskite like structures A3M2X9 can display potentially useful photovoltaic behavior, solution-processed Sb-based perovskite-like structures usually favor the dimer phase, which has poor photovoltaic properties. In this study, we prepared a layered polymorph of Cs3Sb2I9 through solution-processing and studied its photovoltaic properties. The exciton binding energy and exciton lifetime of the layer-form Cs3Sb2I9 were approximately 100 meV and 6 ns, respectively. The photovoltaic properties of the layered polymorph were superior to those of the dimer polymorph. A solar cell incorporating the layer-form Cs3Sb2I9 exhibited an open-circuit voltage of 0.72 V and a power conversion efficiency of 1.5%-the highest reported for an all-inorganic Sb-based perovskite. PMID- 29281246 TI - Simultaneously Detecting Subtle and Intensive Human Motions Based on a Silver Nanoparticles Bridged Graphene Strain Sensor. AB - There is a growing demand for flexible electronic devices. In particular, strain sensors with high performance have attracted more and more attention, because they can be attached on clothing or human skin for applications in the real-time monitoring of human activities. However, monitoring human-body motions that include both subtle and intensive motions, and many strain sensors cannot meet the diverse demands simultaneously. In this work, a silver nanoparticles (Ag NPs) bridged graphene strain sensor is developed for simultaneously detecting subtle and intensive human motions. Ag NPs serve as many bridges to connect the self overlapping graphene sheets, which endows the strain sensor with many excellent performances. Because of the high sensitivity, with a large gauge factor (GF) of 475 and a strain range of >14.5%, high durability of the sensor has been achieved. Besides, the excellent consistency and repeatability of the fabrication process is verified. Furthermore, the model for explaining the working mechanism of the strain sensor is proposed. Most importantly, the designed wearable strain sensor can be applied in human motion detection, including large-scale motions and small-scale motions. PMID- 29281247 TI - Promising Dual-Doped Graphene Aerogel/SnS2 Nanocrystal Building High Performance Sodium Ion Batteries. AB - We report the effort in designing layered SnS2 nanocrystals decorated on nitrogen and sulfur dual-doped graphene aerogels (SnS2@N,S-GA) as anode material of SIBs. The optimized mass loading of SnS2 along with the addition of nitrogen and sulfur on the surface of GAs results in enhanced electrochemical performance of SnS2@N,S GA composite. In particular, the introduction of nitrogen and sulfur heteroatoms could provide more active sites and good accessibility for Na ions. Moreover, the incorporation of the stable SnS2 crystal structure within the anode results in the superior discharge capacity of 527 mAh g-1 under a current density of 20 mA g 1 upon 50 cycles. It maintains 340 mAh g-1 even the current density is increased to 800 mA g-1. Aiming to further systematically study mechanism of composite with improved SIB performance, we construct the corresponding models based on experimental data and conduct first-principles calculations. The calculated results indicate the sulfur atoms doped in GAs show a strong bridging effect with the SnS2 nanocrystals, contributing to build robust architecture for electrode. Simultaneously, heteroatom dual doping of GAs shows the imperative function for improved electrical conductivity. Herein, first-principles calculations present a theoretical explanation for outstanding cycling properties of SnS2@N,S-GA composite. PMID- 29281248 TI - Biosynthetic Mechanism of Luminescent ZnO Nanocrystals in the Mammalian Blood Circulation and Their Functionalization for Tumor Therapy. AB - The biosynthesis of nanoparticles in bioreactors using microbial, plant, or animal cells is at the forefront of nanotechnology. We demonstrated for the first time that luminescent, water-soluble ZnO nanocrystals (bio-ZnO NCs) can be spontaneously biosynthesized in the mammalian blood circulation, not in cells, when animals were fed with Zn(CH3COO)2 aqueous solution. Serum albumin, rather than metallothioneins or glutathione, proved to play the pivotal role in biosynthesis. The bio-ZnO NCs were gradually taken up in the liver and degraded and excreted in the urine. Thus, we propose that in mammals such as rodents, bovinae, and humans, excess metal ions absorbed into the cardiovascular system via the intestine can be transformed into nanoparticles by binding to serum albumin, forming a "provisional metal-pool", to reduce the toxicity of free metal ions at high concentration and regulate metal homeostasis in the body. Furthermore, the bio-ZnO NCs, which showed favorable biocompatibility, were functionalized with the anticancer drug daunorubicin and effectively achieved controlled drug release mediated by intracellular glutathione in tumor xenograft mice. PMID- 29281249 TI - Cosensitization of Structurally Simple Porphyrin and Anthracene-Based Dye for Dye Sensitized Solar Cells. AB - Since their introduction, dye-sensitized solar cells (DSCs) have achieved huge success at a laboratory level. Recently, research is concentrated to visualize large DSC modules at the commercial platform. In that aspect, we have tested structurally simple porphyrin-based dye SK6 and anthracene-based dye CW10 for DSCs application under simulated 1 sun (AM 1.5G) and indoor light sources. These two dyes can be easily synthesized and yet are efficient with cell performances of ca. 5.42% and ca. 5.75% (without coadsorbent/additive) for SK6 and CW10, respectively, under AM 1.5G illumination. The power conversion efficiency (PCE) of SK6 reported in this work is the highest ever reported; this is achieved by optimizing the adsorption of SK6 on TiO2 photoanode using the most suitable solvent and immersion period. Cosensitization of SK6 with CW10 on TiO2 surface has boosted cell performance further and achieved PCE of ca. 6.31% under AM 1.5G illumination. Charge-transfer properties of individual and cosensitized devices at TiO2/dye/electrolyte interface were examined via electrochemical impedance spectroscopy. To understand the cell performances under ambient light conditions, we soaked individual and cosensitized devices under T5 and light-emitting diode light sources in the range of 300-6000 lx. The PCE of ca. 22.91% under T5 light (6000 lx) with JSC = 0.883 mA cm-2, VOC = 0.646 V, and FF = 0.749 was noted for the cosensitized device, which equals a power output of 426 MUW cm-2. These results reveal that DSCs made of structurally simple dyes performed efficiently under both 1 sun (AM 1.5G) and indoor light conditions, which is undoubtedly a significant achievement when it comes to a choice of commercial application. PMID- 29281250 TI - Discovering the Genome-Wide Activity of CRISPR-Cas Nucleases. AB - Originally discovered as part of an adaptive bacterial defense system against the invasion of foreign phages, programmable CRISPR-Cas nucleases have emerged as remarkable enzymes with transformative potential for both biological research and clinical application. CRISPR-Cas nucleases likely evolved in their natural context to tolerate imperfect specificity in order to recognize mutant bacteriophages. However, in the context of biological research and clinical applications, high specificity is generally preferred. For therapeutic applications in particular, it is important to carefully and empirically define the genome-wide activity of engineered nucleases, as hundreds of millions to billions of cells may be modified in a single therapeutic dose. Over the past several years, a number of both cell-based and in vitro sensitive and unbiased genome-scale methods to define CRISPR-Cas nuclease specificity have been developed. These methods will play important complementary roles in better understanding their global specificity profiles and identifying optimal nucleases for applications that demand high precision editing. Improving the sensitivity of mutation detection by next-generation sequencing, developing assays to define the functional consequences of unintended off-target activity nuclease activity, and understanding the consequences of individual human genetic variation on gene editing activity will be important areas for future research and development. PMID- 29281251 TI - Quantification of Nucleic Acid Concentration in the Nanoparticle or Polymer Conjugates Using Circular Dichroism Spectroscopy. AB - The interface of nucleic acids and nanomaterials is among the most promising fields in recent years. Considerable efforts have been devoted to the development of novel systems based on the two components for various promising applications such as sensing, bioimaging, drug delivery, and theranostics. However, the determination of nucleic acid concentration in these systems remains as a challenge due to the interference of nanoparticles. To this end, we developed a simple, yet reliable, method to quantify the nucleic acid concentration in their nanoparticle or polymer conjugates based on circular dichroism (CD) spectroscopy. In this paper, three nucleic acids, namely, DNA sodium salt from calf thymus (NaDNA), DNA from herring sperm (hsDNA), and ribonucleic acid from torula yeast (tyRNA), were noncovalently conjugated to three nanoparticles. The concentrations of the three nucleic acids in their nanoparticle conjugates were successfully determined on the basis of CD spectra calibration curves. PMID- 29281252 TI - Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons. AB - Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers. PMID- 29281253 TI - Imidazolium Iodide-Doped PEDOT Nanofibers as Conductive Catalysts for Highly Efficient Solid-State Dye-Sensitized Solar Cells Employing Polymer Electrolyte. AB - The electrical conductivity and catalytic activity of nanofibrous poly(3,4 ethylenedioxythiophene)s (PEDOT NFs) was improved by redoping with dimethyl imidazolium iodide (DMII) as a charge transfer facilitator. Addition of the new DMII dopant into the PEDOT NFs reduced the concentration of dodecyl sulfate anions (DS-) predoped during the polymerization process and concomitantly enhanced the doping concentration of I- by ion exchange. Redoping with DMII increased the mobility of the PEDOT NFs by up to 18-fold and improved the conductivity due to the enhanced linearization, suppressed aggregation, and improved crystallinity of the PEDOT chains. The catalytic activity was also improved, primarily due to the increase in the compatibility and the effective surface area upon replacement of sticky DS- with the more basic and smaller I- of DMII on the surface of the PEDOT NFs. The charge-transfer resistance across the interface between the poly(ethylene oxide)-based solid polymer electrolyte and PEDOT NF counter electrode (CE) was thus reduced to a large extent, giving an energy conversion efficiency (ECE) of 8.52% for solid-state dye-sensitized solar cells (DSCs), which is even better than that achieved with Pt CE (8.25%). This is the highest ECE reported for solid-state DSCs with conductive polymer CEs under 1 sun conditions. PMID- 29281254 TI - Structural and Dynamical Characterization of DNA and RNA Quadruplexes Obtained from the GGGGCC and GGGCCT Hexanucleotide Repeats Associated with C9FTD/ALS and SCA36 Diseases. AB - A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene has been considered the major cause behind both frontotemporal dementia and amyotrophic lateral sclerosis, while a (GGGCCT) is associated with spinocerebellar ataxia 36. Recent experiments involving NMR, CD, optical melting and 1D 1H NMR spectroscopy, suggest that the r(GGGGCC) HR can adopt a hairpin structure with G-G mismatches in equilibrium with a G-quadruplex structure. G-Quadruplexes have also been identified for d(GGGGCC). As these experiments lack molecular resolution, we have used molecular dynamics microsecond simulations to obtain a structural characterization of the G-quadruplexes associated with both HRs. All DNA G quadruplexes, parallel or antiparallel, with or without loops are stable, while only parallel and one antiparallel (stabilized by diagonal loops) RNA G quadruplexes are stable. It is known that antiparallel G-quadruplexes require alternating guanines to be in a syn conformation that is hindered by the C3'-endo pucker preferred by RNA. Initial RNA antiparallel quadruplexes built with C2' endo sugars evolve such that the transition (C2'-endo)-to-(C3'-endo) triggers unwinding and buckling of the flat G-tetrads, resulting in the unfolding of the RNA antiparallel quadruplex. Finally, a parallel G-quadruplex stabilizes an adjacent C-tetrad in both DNA and RNA (thus effectively becoming a mixed quadruplex of 5 layers). The C-tetrad is stabilized by the stacking interactions with the preceding G-tetrad, by cyclical hydrogen bonds C(N4)-(O2), and by an ion between the G-tetrad and the C-tetrad. In addition, antiparallel DNA G quadruplexes also stabilize flat C-layers at the ends of the quadruplexes. PMID- 29281255 TI - Infrared Spectroscopic Imaging Advances as an Analytical Technology for Biomedical Sciences. PMID- 29281256 TI - Online 2D-LC-MS/MS Platform for Analysis of Glycated Proteome. AB - Glycated proteins are emerging as good indicators for diabetes and age related diseases. However, the platform for analysis of glycated proteome has been relatively less well established. We here introduce an online 2D-LC-HCD-MS/MS platform for comprehensive glycated peptide quantification. This platform includes a boronate affinity column in the first dimension for enrichment, reversed phase nanoLC column in the second dimension for separation, a benchtop Orbitrap mass spectrometer with HCD-MS/MS for peptide sequencing, and MaxQuant bioinformatics tool for identification and quantification of glycated peptides. This online 2D-LC-HCD-MS/MS platform has high enrichment efficiency with 85% of identified peptides in the enriched fraction as glycated, high sensitivity for detection of glycated peptides with LOD and LOQ at 1.2 and 2.4 pg, respectively, and high reproducibility with interday CVs < 20% for 80% of the glycated peptides. The number of glycated peptides quantified in in vitro glycated human plasma increased more than 3-fold using this platform in comparison to that obtained using 1D-LC-HCD-MS/MS platform without boronate affinity enrichment. Application of this online platform to human plasma identified 376 glycated peptides from 10 MUg of protein digests. This highly sensitive and reproducible online 2D platform is promising for glycated protein analysis of complex clinical samples. PMID- 29281257 TI - Nanoscale Correlated Disorder in Out-of-Equilibrium Myelin Ultrastructure. AB - Ultrastructural fluctuations at nanoscale are fundamental to assess properties and functionalities of advanced out-of-equilibrium materials. We have taken myelin as a model of supramolecular assembly in out-of-equilibrium living matter. Myelin sheath is a simple stable multilamellar structure of high relevance and impact in biomedicine. Although it is known that myelin has a quasi-crystalline ultrastructure, there is no information on its fluctuations at nanoscale in different states due to limitations of the available standard techniques. To overcome these limitations, we have used scanning micro X-ray diffraction, which is a unique non-invasive probe of both reciprocal and real space to visualize statistical fluctuations of myelin order of the sciatic nerve of Xenopus laevis. The results show that the ultrastructure period of the myelin is stabilized by large anticorrelated fluctuations at nanoscale, between hydrophobic and hydrophilic layers. The ratio between the total thickness of hydrophilic and hydrophobic layers defines the conformational parameter, which describes the different states of myelin. Our key result is that myelin in its out-of equilibrium functional state fluctuates point-to-point between different conformations showing a correlated disorder described by a Levy distribution. As the system approaches the thermodynamic equilibrium in an aged state, the disorder loses its correlation degree and the structural fluctuation distribution changes to Gaussian. In a denatured state at low pH, it changes to a completely disordered stage. Our results aim to clarify the degradation mechanism in biological systems by associating these states with ultrastructural dynamic fluctuations at nanoscale. PMID- 29281258 TI - Toward Practical, Subwavelength, Visible-Light Photolithography with Hyperlens. AB - The future success of semiconductor technology relies on the continuing reduction of the feature size, allowing more components per chip and higher speed. Optical metamaterial-based hyperlens exhibit the ability for spatial pattern compression from the micro- to nanoscale, potentially addressing the ever-increasing demand of photolithograpy for inexpensive, all-optical nanoscale pattern recoding. Here, we demonstrate a photolithography system enabling a feature size of 80 nm using a 405 nm laser source. To realize such a system, we developed a fabrication method to obtain very thick hyperbolic metamaterial enabling a hyperlens with a very large demagnification rate of 3.75. Finally, we discuss several steps necessary to transform the proposed technique into a practical solution for the visible light-based nanolithography. These include flattening of the inner surface of the hyperlens to increase the working area and integrating the proposed device into a conventional stepper system. PMID- 29281260 TI - Resonant Raman and Exciton Coupling in High-Quality Single Crystals of Atomically Thin Molybdenum Diselenide Grown by Vapor-Phase Chalcogenization. AB - We report a detailed investigation on Raman spectroscopy in vapor-phase chalcogenization grown, high-quality single-crystal atomically thin molybdenum diselenide samples. Measurements were performed in samples with four different incident laser excitation energies ranging from 1.95 eV ? Eex ? 2.71 eV, revealing rich spectral information in samples ranging from N = 1-4 layers and a thick, bulk sample. In addition to previously observed (and identified) peaks, we specifically investigate the origin of a peak near omega ~ 250 cm-1. Our density functional theory and Bethe-Salpeter calculations suggest that this peak arises from a double-resonant Raman process involving the ZA acoustic phonon perpendicular to the layer. This mode appears prominently in freshly prepared samples and disappears in aged samples, thereby offering a method for ascertaining the high optoelectronic quality of freshly prepared 2D-MoSe2 crystals. We further present an in-depth investigation of the energy-dependent variation of the position of this and other peaks and provide evidence of C exciton-phonon coupling in monolayer MoSe2. Finally, we show how the signature peak positions and intensities vary as a function of layer thickness in these samples. PMID- 29281259 TI - Development of Arrayed Colonic Organoids for Screening of Secretagogues Associated with Enterotoxins. AB - Enterotoxins increase intestinal fluid secretion through modulation of ion channels as well as activation of the enteric nervous and immune systems. Colonic organoids, also known as colonoids, are functionally and phenotypically similar to in vivo colonic epithelium and have been used to study intestinal ion transport and subsequent water flux in physiology and disease models. In conventional cultures, organoids exist as spheroids embedded within a hydrogel patty of extracellular matrix, and they form at multiple depths, impairing efficient imaging necessary to capture data from statistically relevant sample sizes. To overcome these limitations, an analytical platform with colonic organoids localized to the planar surface of a hydrogel layer was developed. The arrays of densely packed colonoids (140 MUm average diameter, 4 colonoids/mm2) were generated in a 96-well plate, enabling assay of the response of hundreds of organoids so that organoid subpopulations with distinct behaviors were identifiable. Organoid cell types, monolayer polarity, and growth were similar to those embedded in hydrogel. An automated imaging and analysis platform efficiently tracked over time swelling due to forskolin and fluid movement across the cell monolayer stimulated by cholera toxin. The platform was used to screen compounds associated with the enteric nervous and immune systems for their effect on fluid movement across epithelial cells. Prostaglandin E2 promoted increased water flux in a subset of organoids that resulted in organoid swelling, confirming a role for this inflammatory mediator in diarrheal conditions but also illustrating organoid differences in response to an identical stimulus. By allowing sampling of a large number of organoids, the arrayed organoid platform permits identification of organoid subpopulations intermixed within a larger group of nonresponding organoids. This technique will enable automated, large scale screening of the impact of drugs, toxins, and other compounds on colonic physiology. PMID- 29281261 TI - In Silico Study of Recognition between Abeta40 and Abeta40 Fibril Surfaces: An N Terminal Helical Recognition Motif and Its Implications for Inhibitor Design. AB - The recent finding that the surface of amyloid-beta (Abeta) fibril can recruit Abeta peptides and convert them into toxic oligomers has rendered fibril surfaces attractive as inhibition targets. Through extensive simulations with hybrid resolution and all-atom models, we have investigated how Abeta1-40 recognizes its own fibril surfaces. These calculations give a ~2.6-5.6 MUM half-saturation concentration of Abeta on the surface (cf. experimental value ~6 MUM). Abeta was found to preferentially bind to region 16-24 of Abeta40 fibrils through both electrostatic and van der Waals forces. Both terminal regions of Abeta contribute significantly to binding energetics. A helical binding pose of the N-terminal region of Abeta (Abeta3-14) not seen before is highly preferred on the fibril surface. Abeta3-14 in a helical form can arrange side chains with similar properties on the same sides of the helix and maximize complementary interactions with side chain arrays characteristic of amyloid fibrils. Helix formation on a fibril surface implies a helix-mediated mechanism for Abeta oligomerization catalyzed by fibrils. We propose an Abeta3-14 analogue that can exhibit enhanced helical character and interactions with Abeta fibrils and may thus be used as a template with which to pursue potent inhibitors of Abeta-fibril interactions. PMID- 29281262 TI - Binding of Zn(II) to Tropomyosin Receptor Kinase A in Complex with Its Cognate Nerve Growth Factor: Insights from Molecular Simulation and in Vitro Essays. AB - The binding of the human nerve growth factor (NGF) protein to tropomyosin receptor kinase A (TrkA) is associated with Alzhemeir's development. Owing to the large presence of zinc(II) ions in the synaptic compartments, the zinc ions might be bound to the complex in vivo. Here, we have identified a putative zinc binding site using a combination of computations and experiments. First, we have predicted structural features of the NGF/TrkA complex in an aqueous solution by molecular simulation. Metadynamics free energy calculations suggest that these are very similar to those in the X-ray structure. Here, the "crab" structure of the NGF shape binds tightly to two TrkA "pincers". Transient conformations of the complex include both more extended and more closed conformations. Interestingly, the latter features facial histidines (His60 and His61) among the N-terminal D1 D3 domains, each of which is a potential binding region for biometals. This suggests the presence of a four-His Zn binding site connecting the two chains. To address this issue, we investigated the binding of a D1-D3 domains' peptide mimic by stability constant and nuclear magnetic resonance measurements, complemented by density functional theory-based calculations. Taken together, these establish unambiguously a four-His coordination of the metal ion in the model systems, supporting the presence of our postulated binding site in the NGF/TrkA complex. PMID- 29281263 TI - Correction for the Hematocrit Bias in Dried Blood Spot Analysis Using a Nondestructive, Single-Wavelength Reflectance-Based Hematocrit Prediction Method. AB - The hematocrit (Hct) effect is one of the most important hurdles currently preventing more widespread implementation of quantitative dried blood spot (DBS) analysis in a routine context. Indeed, the Hct may affect both the accuracy of DBS methods as well as the interpretation of DBS-based results. We previously developed a method to determine the Hct of a DBS based on its hemoglobin content using noncontact diffuse reflectance spectroscopy. Despite the ease with which the analysis can be performed (i.e., mere scanning of the DBS) and the good results that were obtained, the method did require a complicated algorithm to derive the total hemoglobin content from the DBS's reflectance spectrum. As the total hemoglobin was calculated as the sum of oxyhemoglobin, methemoglobin, and hemichrome, the three main hemoglobin derivatives formed in DBS upon aging, the reflectance spectrum needed to be unmixed to determine the quantity of each of these derivatives. We now simplified the method by only using the reflectance at a single wavelength, located at a quasi-isosbestic point in the reflectance curve. At this wavelength, assuming 1-to-1 stoichiometry of the aging reaction, the reflectance is insensitive to the hemoglobin degradation and only scales with the total amount of hemoglobin and, hence, the Hct. This simplified method was successfully validated. At each quality control level as well as at the limits of quantitation (i.e., 0.20 and 0.67) bias, intra- and interday imprecision were within 10%. Method reproducibility was excellent based on incurred sample reanalysis and surpassed the reproducibility of the original method. Furthermore, the influence of the volume spotted, the measurement location within the spot, as well as storage time and temperature were evaluated, showing no relevant impact of these parameters. Application to 233 patient samples revealed a good correlation between the Hct determined on whole blood and the predicted Hct determined on venous DBS. The bias obtained with Bland and Altman analysis was 0.015 and the limits of agreement were -0.061 and 0.031, indicating that the simplified, noncontact Hct prediction method even outperforms the original method. In addition, using caffeine as a model compound, it was demonstrated that this simplified Hct prediction method can effectively be used to implement a Hct dependent correction factor to DBS-based results to alleviate the Hct bias. PMID- 29281264 TI - PIWI-Interacting RNA in Drosophila: Biogenesis, Transposon Regulation, and Beyond. AB - PIWI-interacting RNAs (piRNAs) are germline-enriched small RNAs that control transposons to maintain genome integrity. To achieve this, upon being processed from piRNA precursors, most of which are transcripts of intergenic piRNA clusters, piRNAs bind PIWI proteins, germline-specific Argonaute proteins, to form effector complexes. The mechanism of this piRNA-mediated transposon silencing pathway is fundamentally similar to that of siRNA/miRNA-dependent gene silencing in that a small RNA guides its partner Argonaute protein to target gene transcripts for repression via RNA-RNA base pairing. However, the uniqueness of this piRNA pathway has emerged through intensive genetic, biochemical, bioinformatic, and structural investigations. Here, we review the studies that elucidated the piRNA pathway, mainly in Drosophila, by describing both historical and recent progress. Studies in other species that have made important contributions to the field are also described. PMID- 29281265 TI - Responsive Nanomicellar Theranostic Cages for Metastatic Breast Cancer. AB - Precluding the progression of metastasis with early diagnosis of triple-negative breast cancer remains challenging due to lack of targeting specificity with poor diagnostic potential. Herein, an amphipathic chitosan-based targeted nanomicellar theranostics (30-45 nm) comprising doxorubicin-superparamagnetic iron oxide nanoparticles complexes (89.23%) with lower critical micelle concentration (0.1 MUg/mL) were developed. Micelles exhibit concentration-based contrast enhancement in MRI (r2 6.27 mM-1 s-1) and hyperthermia rather than thermal-ablation. This theranostics delivers doxorubicin under alternating magnetic field (480 kHz) and at endosomal pH (pH 5.2) while showing stability at pH 7.4. Anti-alphavbeta3 integrin antibody conjugation onto PEGylated micelles (62.3%) enhances micellar internalization into drug-resistant MDA-MB-231 after 1 h and magnetizes the cells after 6 h over that with nonconjugated micelles. Immigration of MDA-MB-231 and 4T1 cells retards after 24 h, while significant reduction of mitochondrial membrane potential is observed under hyperthermia. Intratumoral administration of nanomicelles in 4T1 orthotopic spontaneous metastasis model demonstrated antitumor and fibrosis mediated caging effect with simultaneous enhancement of MRI-T2 contrast. PMID- 29281267 TI - Capture and Reductive Transformation of Halogenated Pesticides by an Activated Carbon-Based Electrolysis System for Treatment of Runoff. AB - This study evaluates an electrochemical system to treat the halogenated pesticides, fipronil, permethrin, and bifenthrin, in urban runoff. Compared to the poor sorption capacity of metal-based electrodes, granular activated carbon (GAC)-based electrodes could sorb halogenated pesticides, permitting electrochemical degradation to occur over longer timescales than reactor hydraulic residence times. In a dual-cell configuration, a cathode constructed of loose GAC containing sorbed pesticides was separated from the anode by an ion exchange membrane to prevent chloride transport and oxidation to chlorine at the anode. When -1 V was applied to the cathode, fipronil concentrations declined by 92% over 15 h, releasing molar equivalents of chloride (2) and fluoride (6), suggesting complete dehalogenation of fipronil. An electrode constructed of crushed GAC particles attached to a carbon cloth current distributor achieved >90% degradation of fipronil, permethrin, and bifenthrin within 2 h under the same conditions. To evaluate a simpler single-cell configuration suitable for scale-up, two of the carbon cloth-based electrodes were placed in parallel without an ion-exchange membrane. For -1 V applied to the cathode, fipronil degradation was >95% over 2 h, and energy consumption declined with closer electrode spacing. However, chloride oxidation at the anode produced chlorine, and the anode degraded. Application of an alternating potential (-1 to +1 V at 0.0125 Hz) to the parallel-plate electrodes achieved >90% degradation of fipronil, bifenthrin, and permethrin over 4 h, releasing chloride at 50-70% of that expected for complete dechlorination. No loss of performance or formation of chlorine or halogenated byproducts was observed over 5 cycles of treating fipronil-spiked surface water. PMID- 29281266 TI - Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity. AB - MTH1 hydrolyzes oxidized nucleoside triphosphates, thereby sanitizing the nucleotide pool from oxidative damage. This prevents incorporation of damaged nucleotides into DNA, which otherwise would lead to mutations and cell death. The high level of reactive oxygen species in cancer cells leads to a higher level of oxidized nucleotides in cancer cells compared to that in nonmalignant cells, making cancer cells more dependent on MTH1 for survival. The possibility of specifically targeting cancer cells by inhibiting MTH1 has highlighted MTH1 as a promising cancer target. The progression of MTH1 inhibitors into the clinic requires animal studies, and knowledge of species differences in the potency of inhibitors is vitally important. We here show that the human MTH1 inhibitor TH588 is approximately 20-fold less potent with respect to inhibition of mouse MTH1 than the human, rat, pig, and dog MTH1 proteins are. We present the crystal structures of mouse MTH1 in complex with TH588 and dog MTH1 and elucidate the structural and sequence basis for the observed difference in affinity for TH588. We identify amino acid residue 116 in MTH1 as an important determinant of TH588 affinity. Furthermore, we present the structure of mouse MTH1 in complex with the substrate 8-oxo-dGTP. The crystal structures provide insight into the high degree of structural conservation between MTH1 proteins from different organisms and provide a detailed view of interactions between MTH1 and the inhibitor, revealing that minute structural differences can have a large impact on affinity and specificity. PMID- 29281268 TI - Hydrogen-Bonding Effects in Five-Coordinate High-Spin Imidazole-Ligated Iron(II) Porphyrinates. AB - The influence of hydrogen binding to the N-H group of coordinated imidazole in high-spin iron(II) porphyrinates has been studied. The preparation and characterization of new complexes based on [Fe(TPP)(2-MeHIm)] (TPP is the dianion of tetraphenylporphyrin) are reported. The hydrogen bond acceptors are ethanol, tetramethylene sulfoxide, and 2-methylimidazole. The last acceptor, 2-MeHIm, was found in a crystalline complex with two [Fe(TPP)(2-MeHIm)] sites, only one of which has the 2-methylimidazole hydrogen bond acceptor. This latter complex has been studied by temperature-dependent Mossbauer spectroscopy. All new complexes have also been characterized by X-ray structure determinations. The Fe-NP and Fe NIm bond lengths, and displacement of the Fe atom out of the porphyrin plane are similar to, but marginally different than, those in imidazole-ligated species with no hydrogen bond. All the structural and Mossbauer properties suggest that these new hydrogen-bonded species have the same electronic configuration as imidazole-ligated species with no hydrogen bond. These new studies continue to show that the effects of hydrogen bonding in five-coordinate high-spin iron(II) systems are subtle and challenging to understand. PMID- 29281269 TI - Total Synthesis of Aryl C-Glycoside Natural Products: Strategies and Tactics. AB - The aryl C-glycoside structure is, among the plenty of biologically active natural products, one of the distinct motifs embedded. Because of the potential bioactivity as well as the synthetic challenges, these structures have attracted considerable interest, and extensive research toward the total synthesis has been performed. This Review focuses on the synthetic strategies and tactics employed in the total synthesis of this class of natural products. The Introduction describes the historical background, structural features, and synthetic problems associated with aryl C-glycoside natural products. Next the Review summarizes the methods for constructing the aryl C-glycoside bonds. Completed total syntheses and, in some cases, selected examples of incomplete syntheses-of natural aryl C glycosides are also summarized. Finally described are the strategies for constructing polycyclic structures, which were utilized in the total syntheses. PMID- 29281270 TI - Upconversion Luminescence-Activated DNA Nanodevice for ATP Sensing in Living Cells. AB - Designer DNA nanodevices have attracted extensive interest for detection of specific targets in living cells. However, it still remains a great challenge to construct DNA sensing devices that can be activated at desired time with a remotely applied stimulus. Here we report a rationally designed, synthetic DNA nanodevice that can detect ATP in living cells in an upconversion luminescence activatable manner. The nanodevice consists of a UV light-activatable aptamer probe and lanthanide-doped upconversion nanoparticles which acts as the nanotransducers to operate the device in response to NIR light. We demonstrate that the nanodevice not only enables efficient cellular delivery of the aptamer probe into live cells, but also allows the temporal control over its fluorescent sensing activity for ATP by NIR light irradiation in vitro and in vivo. Ultimately, with the availability of diverse aptamers selected in vitro, the DNA nanodevice platform will allow NIR-triggered sensing of various targets as well as modulation of biological functions in living systems. PMID- 29281271 TI - Comment on Microbial Transglutaminase Used in Bread Preparation at Standard Bakery Concentrations Does Not Increase Immunodetectable Amounts of Deamidated Gliadin. PMID- 29281272 TI - Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules for Significantly Improved Cellular Uptake. AB - Mesoporous solids have been widely used in various biomedical areas such as drug delivery and tumor therapy. Although deformability has been recognized as a prime important characteristic influencing cellular uptake, the synthesis of deformable mesoporous solids is still a great challenge. Herein, deformable thioether-, benzene-, and ethane-bridged hollow periodic mesoporous organosilica (HPMO) nanocapsules have successfully been synthesized for the first time by a preferential etching approach. The prepared HPMO nanocapsules possess uniform diameters (240-310 nm), high surface areas (up to 878 m2.g-1), well-defined mesopores (2.6-3.2 nm), and large pore volumes (0.33-0.75 m3.g-1). Most importantly, the HPMO nanocapsules simultaneously have large hollow cavities (164 270 nm), thin shell thicknesses (20-38 nm), and abundant organic moiety in the shells, which endow a lower Young's modulus (EY) of 3.95 MPa than that of solid PMO nanoparticles (251 MPa). The HPMOs with low EY are intrinsically flexible and deformable in the solution, which has been well-characterized by liquid cell electron microscopy. More interestingly, it is found that the deformable HPMOs can easily enter into human breast cancer MCF-7 cells via a spherical-to-oval morphology change, resulting in a 26-fold enhancement in cellular uptake (43.1% cells internalized with nanocapsules versus 1.65% cells with solid counterparts). The deformable HPMO nanocapsules were further loaded with anticancer drug doxorubicin (DOX), which shows high killing effects for MCF-7 cells, demonstrating the promise for biomedical applications. PMID- 29281274 TI - Balancing the Hydrogen Evolution Reaction, Surface Energetics, and Stability of Metallic MoS2 Nanosheets via Covalent Functionalization. AB - We modify the fundamental electronic properties of metallic (1T phase) nanosheets of molybdenum disulfide (MoS2) through covalent chemical functionalization, and thereby directly influence the kinetics of the hydrogen evolution reaction (HER), surface energetics, and stability. Chemically exfoliated, metallic MoS2 nanosheets are functionalized with organic phenyl rings containing electron donating or withdrawing groups. We find that MoS2 functionalized with the most electron donating functional group (p-(CH3CH2)2NPh-MoS2) is the most efficient catalyst for HER in this series, with initial activity that is slightly worse compared to the pristine metallic phase of MoS2. The p-(CH3CH2)2NPh-MoS2 is more stable than unfunctionalized metallic MoS2 and outperforms unfunctionalized metallic MoS2 for continuous H2 evolution within 10 min under the same conditions. With regards to the entire studied series, the overpotential and Tafel slope for catalytic HER are both directly correlated with the electron donating strength of the functional group. The results are consistent with a mechanism involving ground-state electron donation or withdrawal to/from the MoS2 nanosheets, which modifies the electron transfer kinetics and catalytic activity of the MoS2 nanosheet. The functional groups preserve the metallic nature of the MoS2 nanosheets, inhibiting conversion to the thermodynamically stable semiconducting state (2H) when mildly annealed in a nitrogen atmosphere. We propose that the electron density and, therefore, reactivity of the MoS2 nanosheets are controlled by the attached functional groups. Functionalizing nanosheets of MoS2 and other transition metal dichalcogenides provides a synthetic chemical route for controlling the electronic properties and stability within the traditionally thermally unstable metallic state. PMID- 29281273 TI - Time-Gated Luminescence Detection of Enzymatically Produced Hydrogen Sulfide: Design, Synthesis, and Application of a Lanthanide-Based Probe. AB - Hydrogen sulfide (H2S) is now recognized as an important gaseous transmitter that is involved in a variety of biological processes. Here, we report the design and synthesis of a luminescent lanthanide biosensor for H2S, LP2-Cu(II)-Ln(III), a heterobinuclear metal complex that uses Cu(II) decomplexation to control millisecond-scale-lifetime-Tb(III)- or Eu(III)-emission intensity. LP2-Cu(II) Ln(III) responded rapidly, selectively, and with high sensitivity to aqueous H2S. The probe's potential for biological applications was verified by measuring the H2S generated by the slow-releasing chemical-sulfide-donor GYY4147, by cystathionine gamma-lyase (CSE), and by Na2S-stimulated HeLa cells. PMID- 29281275 TI - Atom-Precise Modification of Silver(I) Thiolate Cluster by Shell Ligand Substitution: A New Approach to Generation of Cluster Functionality and Chirality. AB - To realize the molecular design of new functional silver(I) clusters, a new synthetic approach has been proposed, by which the weakly coordinating ligands NO3- in a Ag20 thiolate cluster precursor can be substituted by carboxylic ligands while keeping its inner core intact. By rational design, novel atom precise carboxylic or amino acid protected 20-core Ag(I)-thiolate clusters have been demonstrated for the first time. The fluorescence and electrochemical activity of the postmodified Ag20 clusters can be modulated by alrestatin or ferrocenecarboxylic acid substitution. More strikingly, when chiral amino acids were used as postmodified ligands, CD-activity was observed for the Ag20 clusters, unveiling an efficient way to obtain atom-precise chiral silver(I) clusters. PMID- 29281276 TI - Screening Supramolecular Interactions between Carbon Nanodots and Porphyrins. AB - We present an in-depth investigation regarding the electron-accepting nature of pressure-synthesized carbon nanodots (pCNDs) in combination with porphyrins as excited-state electron donors. To this end, electrostatic attractions involving negative charges, which are present on the pCND surface, are essential to govern the hybrid assembly, on one hand, and charge separation, on the other hand. PMID- 29281278 TI - toxFlow: A Web-Based Application for Read-Across Toxicity Prediction Using Omics and Physicochemical Data. AB - We present toxFlow, a web application developed for enrichment analysis of omics data coupled with read-across toxicity prediction. A sequential analysis workflow is suggested where users can filter omics data using enrichment scores and incorporate their findings into a correlation-based read-across technique for predicting the toxicity of a substance based on its analogs. Either embedded or in-house gene signature libraries can be used for enrichment analysis. The suggested approach can be used for toxicity prediction of diverse chemical entities; however, this article focuses on the multiperspective characterization of nanoparticles and selects their neighbors based on both physicochemical and biological similarity criteria. In addition, visualization options are offered to interactively explore correlation patterns in the data, whereas results can be exported for further analysis. toxFlow is accessible at http://147.102.86.129:3838/toxflow . PMID- 29281277 TI - General and Facile Coating of Single Cells via Mild Reduction. AB - Cell surface modification has been extensively studied to enhance the efficacy of cell therapy. Still, general accessibility and versatility are remaining challenges to meet the increasing demand for cell-based therapy. Herein, we present a facile and universal cell surface modification method that involves mild reduction of disulfide bonds in cell membrane protein to thiol groups. The reduced cells are successfully coated with biomolecules, polymers, and nanoparticles for an assortment of applications, including rapid cell assembly, in vivo cell monitoring, and localized cell-based drug delivery. No adverse effect on cellular morphology, viability, proliferation, and metabolism is observed. Furthermore, simultaneous coating with polyethylene glycol and dexamethasone-loaded nanoparticles facilitates enhanced cellular activities in mice, overcoming immune rejection. PMID- 29281279 TI - Response to Comment by Calderon de la Barca and Sigala-Robles on Microbial Transglutaminase Used in Bread Preparation at Standard Bakery Concentrations Does Not Increase Immunodetectable Amounts of Deamidated Gliadin. PMID- 29281280 TI - Extraction of Gd3+ and UO22+ Ions Using Polystyrene Grafted Dibenzo Crown Ether (DB18C6) with Octanol and Nitrobenzene: A Molecular Dynamics Study. AB - Atomistic molecular dynamics (MD) simulations are performed in order to derive thermodynamic properties important to understand the extraction of gadolinium (Gd3+) and uranium dioxide (UO2) with dibenzo crown ether (DBCE) in nitrobenzene (NB) and octanol (OCT) solvents. The effect of polystyrene graft length, on DBCE, on the binding behavior of Gd3+ and UO22+ is investigated for the first time. Our simulation results demonstrate that the binding of Gd3+ and UO22+ onto the oxygens of crown ethers is favorable for polystyrene grafted crown ether in the organic solvents OCT and NB. The metal ion binding free energy (DeltaGBinding) in different solvent environments is calculated using the thermodynamic integration (TI) method. DeltaGBinding becomes more favorable in both solvents, NB and OCT, with an increase in the polystyrene monomer length. The metal ion transferability from an aqueous phase to an organic phase is estimated by calculating transfer free-energy calculations (DeltaGTransfer). DeltaGTransfer is significantly favorable for both Gd3+ and UO22+ for the transfer from the aqueous phase to the organic phase (i.e., NB and OCT) via ion-complexation to DBCE with an increase in polystyrene length. The partition coefficient (log P) values for Gd3+ and UO22+ show a 5-fold increase in separation capacity with polystyrene grafted DBCE. We corroborate the observed behavior by further analyzing the structural and dynamical properties of the ions in different phases. PMID- 29281281 TI - Corannulene-Based Coordination Cage with Helical Bias. AB - We report here the first corannulene-based molecular cage, constructed via metal induced self-assembly of corannulene-based ligands. In sharp contrast to those assembled via the planar pi-conjugated analogues of corannulene, at ambient and elevated temperatures, the molecular cage exists as an ensemble of four stereoisomers (two pairs of enantiomers), all of which possess a D5-symmetric (regardless of the counteranions) and inherently helical structure. Decreasing the temperature shifts the equilibrium between different pairs of enantiomers. At low temperature, only one pair of enantiomers is present. Helical bias for the cage could be efficiently achieved by inducing asymmetry with enantiopure anions. When nonenantiopure anions are used, the asymmetry induction abides by the "majority rule", i.e., the major enantiomer of the chiral anions controls the bias of helical sense of the cages. PMID- 29281282 TI - Concise Synthesis of Natural Phenylphenalenone Phytoalexins and a Regioisomer. AB - Concise total syntheses of the natural phytoalexins 2-hydroxy-8-(4 hydroxyphenyl)phenalen-1-one (1), 2-hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2), and hydroxyanigorufone (4), together with regioisomer 3 are accomplished in 11 or 12 steps. The synthetic strategy features a Friedel-Crafts acylation to construct the 1H-phenalen-1-one tricyclic core followed by a Suzuki cross coupling to obtain the target compounds. PMID- 29281283 TI - Understanding and Measurement for the Binding Energy of Hydrogen bonds of Biomass Derived Hydroxyl Compounds. AB - Experimental measurement for the binding energy of hydrogen-bonds (HBs) has long been an attractive and challenging topic in chemistry and biochemistry. In the present study, the binding energy of OH...O HBs can be determined by 1H NMR technique using a set of model biomass-derived hydroxyl compounds, including furfuryl alcohol, isosorbide, tetrahydrofurfuryl alcohol, and (S)-3 hydroxytetrahydrofuran. By performing concentration- and temperature-variation experiments, we put forward a modified Arrhenius-type equation, in which the compensated natural logarithm of the chemical shift (ln delta + Deltadelta) is linearly correlated with 1/T. HBs energies can be directly determined by the slope of the plot, and are substantiated by density functional theory (DFT) theoretical calculations. This study provides a reliable method to measure the binding energy of OH...O HBs in hydroxyl-containing biomass-derived feedstocks. PMID- 29281284 TI - Hydrophilic Solvation Dominates the Terahertz Fingerprint of Amino Acids in Water. AB - Spectroscopy in the terahertz frequency regime is a sensitive tool to probe solvation-induced effects in aqueous solutions. Yet, a systematic understanding of spectral lineshapes as a result of distinct solvation contributions remains terra incognita. We demonstrate that modularization of amino acids in terms of functional groups allows us to compute their distinct contributions to the total terahertz response. Introducing the molecular cross-correlation analysis method provides unique access to these site-specific contributions. Equivalent groups in different amino acids lead to look-alike spectral contributions, whereas side chains cause characteristic but additive complexities. Specifically, hydrophilic solvation of the zwitterionic groups in valine and glycine leads to similar terahertz responses which are fully decoupled from the side chain. The terahertz response due to H-bonding within the large hydrophobic solvation shell of valine turns out to be nearly indistinguishable from that in bulk water in direct comparison to the changes imposed by the charged functional groups that form strong H-bonds with their hydration shells. Thus, the hydrophilic groups and their solvation shells dominate the terahertz absorption difference, while on the same intensity scale, the influence of hydrophobic water can be neglected. PMID- 29281285 TI - Generation of Diversity Sets with High sp3 Fraction Using the Photoredox Coupling of Organotrifluoroborates and Organosilicates with Heteroaryl/Aryl Bromides in Continuous Flow. AB - The photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3-Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluoroborates. We have developed a generally useful, continuous flow Csp3-Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborates and silicate reagents. This universal protocol provides diversity sets from both primary and secondary coupling partners. This easily scalable procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high sp3 fraction. PMID- 29281286 TI - Shape and Core-Excited Resonances in Thiophene. AB - We present a comprehensive study of resonance formation in electron collisions with thiophene. Detailed calculations have been performed using the ab initio R matrix method. Absolute differential cross sections for electron impact excitation up to 18 eV and for two scattering angles, 90 and 135 degrees , have been measured. Agreement between the calculated and measured experimental cross sections is very good. Three shape resonances previously described, two of pi* character and one sigma*, as well as a number of resonances of core-excited or mixed character are identified and characterized in the calculations. The measured cross sections provide experimental confirmation for a number of the core-excited resonances. The link between these resonances and prior DEA experiments is discussed. PMID- 29281287 TI - Gas Phase Synthesis of Protonated Glycine by Chemical Dynamics Simulations. AB - In the present work, we investigated the reaction dynamics that will possibly lead to the formation of protonated glycine by an ion-molecule collision. In particular, two analogous reactions were studied: NH3OH+ + CH3COOH and NH2OH2+ + CH3COOH that were suggested by previous experiments to be able to form protonated glycine loosing a neutral water molecule. Chemical dynamics simulations show that both reactants can form a molecule with the mass of the protonated glycine but with different structures, if some translational energy is given to the system. The reaction mechanisms for the most relevant product isomers are discussed as well as the role of collision energy in determining reaction products. Finally, in comparing collision dynamics at room and at very low initial internal temperature of the reactants, the same behavior was obtained for forming the protonated glycine isomers products. This supports the use of standard gas phase ion-chemistry setups to study collision-induced reactivity as a model for astrophysical cold conditions, when some relative translation energy is given to the system. PMID- 29281288 TI - Reverse and Random Decoy Methods for False Discovery Rate Estimation in High Mass Accuracy Peptide Spectral Library Searches. AB - Spectral library searching (SLS) is an attractive alternative to sequence database searching (SDS) for peptide identification due to its speed, sensitivity, and ability to include any selected mass spectra. While decoy methods for SLS have been developed for low mass accuracy peptide spectral libraries, it is not clear that they are optimal or directly applicable to high mass accuracy spectra. Therefore, we report the development and validation of methods for high mass accuracy decoy libraries. Two types of decoy libraries were found to be suitable for this purpose. The first, referred to as Reverse, constructs spectra by reversing a library's peptide sequences except for the C terminal residue. The second, termed Random, randomly replaces all non-C-terminal residues and either retains the original C-terminal residue or replaces it based on the amino-acid frequency of the library's C-terminus. In both cases the m/z values of fragment ions are shifted accordingly. Determination of FDR is performed in a manner equivalent to SDS, concatenating a library with its decoy prior to a search. The utility of Reverse and Random libraries for target-decoy SLS in estimating false-positives and FDRs was demonstrated using spectra derived from a recently published synthetic human proteome project (Zolg, D. P.; et al. Nat. Methods 2017, 14, 259-262). For data sets from two large-scale label-free and iTRAQ experiments, these decoy building methods yielded highly similar score thresholds and spectral identifications at 1% FDR. The results were also found to be equivalent to those of using the decoy-free PeptideProphet algorithm. Using these new methods for FDR estimation, MSPepSearch, which is freely available search software, led to 18% more identifications at 1% FDR and 23% more at 0.1% FDR when compared with other widely used SDS engines coupled to postprocessing approaches such as Percolator. An application of these methods for FDR estimation for the recently reported "hybrid" library search (Burke, M. C.; et al. J. Proteome Res. 2017, 16, 1924-1935) method is also made. The application of decoy methods for high mass accuracy SLS permits the merging of these results with those of SDS, thereby increasing the assignment of more peptides, leading to deeper proteome coverage. PMID- 29281289 TI - Unraveling the Critical Role Played by Ado762'OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase. AB - Archaeal threonyl-tRNA synthetase (ThrRS) possesses an editing active site wherein tRNAThr that has been misaminoacylated with serine (i.e., Ser-tRNAThr) is hydrolytically cleaved to serine and tRNAThr. It has been suggested that the free ribose sugar hydroxyl of Ado76 of the tRNAThr (Ado762'OH) is the mechanistic base, promoting hydrolysis by orienting a nucleophilic water near the scissile Ser-tRNAThr ester bond. We have performed a computational study, involving molecular dynamics (MD) and hybrid ONIOM quantum mechanics/molecular mechanics (QM/MM) methods, considering all possible editing mechanisms to gain an understanding of the role played by Ado762'OH group. More specifically, a range of concerted or stepwise mechanisms involving four-, six-, or eight-membered transition structures (total of seven mechanisms) were considered. In addition, these seven mechanisms were fully optimized using three different DFT functionals, namely, B3LYP, M06-2X, and M06-HF. The M06-HF functional gave the most feasible energy barriers followed by the M06-2X functional. The most favorable mechanism proceeds stepwise through two six-membered ring transition states in which the Ado762'OH group participates, overall, as a shuttle for the proton transfer from the nucleophilic H2O to the bridging oxygen (Ado763'O) of the substrate. More specifically, in the first step, which has a barrier of 25.9 kcal/mol, the Ado762'-OH group accepts a proton from the attacking nucleophilic water while concomitantly transferring its proton onto the substrates C-Ocarb center. Then, in the second step, which also proceeds with a barrier of 25.9 kcal/mol, the Ado762'-OH group transfers its proton on the adjacent Ado763' oxygen, cleaving the scissile Ccarb-O3'Ado76 bond, while concomitantly accepting a proton from the previously formed C-OcarbH group. PMID- 29281290 TI - Understanding the Nature of Amino Acid Interactions with Pd(111) or Pd-Au Bimetallic Catalysts in the Aqueous Phase. AB - The interaction of methionine (Met) with different bimetallic-segregated surfaces comprising a uniform distribution of strips and islands of Au on the Pd(111) surface was examined using molecular dynamics (MD) simulations. Out of all the segregated and uniformly doped surfaces studied, the design of Pd-Au islands showed some reduction in the interaction energy (Eint = -43.7 kJ/mol) as compared to that of the pure Pd(111) surface (Eint = -50 kJ/mol) for a single Met molecule. However, at a higher coverage of 9 Met molecules/simulation cell, none of the Pd-Au alloy surfaces showed any improvement as compared to the Pd(111) surface. In order to develop a comprehensive understanding of the nature of the nonbonded interaction of aqueous biogenic impurities with the Pd catalyst surface, the MD study was extended to include a variety of aliphatic, S containing, aromatic, and polar amino acids. The potential of mean force (PMF) profiles were observed to be distinct for each class of amino acids with substantial differences among amino acids with acidic and basic side chains. The side chains of all the polar and aromatic amino acids showed direct contact with the surface while aliphatic amino acids had their hydrophobic side chain aligned away from the surface. Interestingly, lysine (Lys) and tyrosine (Tyr) were the only two amino acids which interacted preferentially via the distant backbone nitrogen and backbone oxygen, respectively, despite their side chains being in direct contact with the metal surface. The strength of interaction was correlated with the size of the amino acid; the interaction energies were observed to be the maximum for large molecules such as arginine (Arg, Eint = -87.7 kJ/mol) and tryptophan (Trp, Eint = -73.4 kJ/mol), while it was a minimum for aliphatic amino acids such as alanine (Ala, Eint = -10.9 kJ/mol). The study is focused on examining the sensitivity of the choice of the preferential interaction site, conformational preferences, and interaction energies to the side-chain specificity. PMID- 29281291 TI - Curvature-Mediated Assembly of Janus Nanoparticles on Membrane Vesicles. AB - Besides direct particle-particle interactions, nanoparticles adsorbed to biomembranes experience indirect interactions that are mediated by the membrane curvature arising from particle adsorption. In this Letter, we show that the curvature-mediated interactions of adsorbed Janus particles depend on the initial curvature of the membrane prior to adsorption, that is, on whether the membrane initially bulges toward or away from the particles in our simulations. The curvature-mediated interaction can be strongly attractive for Janus particles adsorbed to the outside of a membrane vesicle, which initially bulges away from the particles. For Janus particles adsorbed to the vesicle inside, in contrast, the curvature-mediated interactions are repulsive. We find that the area fraction of the adhesive Janus particle surface is an important control parameter for the curvature-mediated interaction and assembly of the particles, besides the initial membrane curvature. PMID- 29281293 TI - A Robust One-Step Approach to Ynamides. AB - A robust one-step synthetic strategy for ynamide with cheap and easily available stock chemicals vinyl dichlorides and electron deficient amides as the starting material is described. In the absence of transition-metal catalyst, the reaction proceeds under mild reaction conditions in open air and thus rendering a convenient operation. This strategy is not only suitable for both terminal and internal ynamide synthesis but also amenable for large-scale preparation. Broad substrate scopes with respect to vinyl dichloride as well as electron-deficient amide were observed. PMID- 29281292 TI - l-Cysteine-Conjugated Ruthenium Hydrous Oxide Nanomaterials with Anticancer Active Application. AB - Bioactive nanomaterials, namely: ruthenium hydrous oxide (or ruthenium oxy hydroxide), RuOx(OH)y and also a surface-conjugated novel material of the same within the template of an amino acid molecule, l-cysteine, have been studied. These compounds have been prepared through a simple wet chemical route, under physiological conditions, such that they could be suitably used in anticancer applications. Several physical methods were used for the nanomaterial characterization, e.g.: thermal analysis of the as prepared ruthenium hydrous oxide by differential scanning calorimetry (DSC) followed by thermal gravimetric analysis (TGA). This confirms that the material is a precursor for anhydrous nanocrystalline ruthenium oxide (RuO2), as is affirmed by powder X-ray diffraction pattern. Also, optical spectroscopic absorption (UV-vis and FT-IR) study of these nanoparticles (NPs) to ascertain their surface conjugation with l cysteine have been performed. Besides these, surface morphology of the NPs were studied by field emission scanning electron microscopy (FE-SEM) along with their elemental purity check through energy dispersive X-ray analysis (EDX). Their surface chemical microenvironments were examined by X-ray photo electron spectroscopy (XPS). The hydrodynamic size of the prepared NPs were measured through dynamic light scattering (DLS) studies. Further, biological consequences of these NPs on cancerous HeLa cells and their cytotoxicity effects have been reported with MTT assay, such an application has not been reported so far. PMID- 29281294 TI - Synthesis and Photodynamics of Tetragermatetrathia[8]circulene. AB - Tetragermatetrathia[8]circulene has successfully been synthesized from tetraiodotetrathienylene through palladium-catalyzed germylation and rhodium catalyzed intramolecular dehydrogenative cyclization. A single-crystal X-ray diffraction analysis elucidated that tetragermatetrathia[8]circulene has a highly symmetric, planar, and rigid structure. DFT calculations suggested that LUMO of tetragermatetrathia[8]circulene is stabilized due to sigma*-pi* interactions between sigma* orbitals of the Ge-C bonds and pi* orbitals of the thiophene rings. The excited dynamics of tetragermatetrathia[8]circulene have also been found to be significantly affected by the heavy-atom effect of the germanium atom. PMID- 29281296 TI - The Influence of Opponent-Related and Outcome-Related Memory on Repeated Aggressive Encounters in the Paradise Fish (Macropodus opercularis). AB - The aggressive behavior of male paradise fish (Macropodus opercularis) was studied. Fish were subjected to three aggressive encounters on consecutive days. If submissive males encountered the same opponent three times, the last aggressive encounter was very different than the first one. When the animals faced a new opponent each day, the changes were much less pronounced. We conclude that (1) fish are able to recognize their opponents at least one day after the encounter ("social recognition"), and (2) social recognition modifies the effect of prior defeat ("status-related memory") in subsequent encounters. PMID- 29281295 TI - Near-Field Plasmonic Probe with Super Resolution and High Throughput and Signal to-Noise Ratio. AB - Near-field scanning optical microscopy (NSOM) enables observation of light-matter interaction with a spatial resolution far below the diffraction limit without the need for a vacuum environment. However, modern NSOM techniques remain subject to a few fundamental restrictions. For example, concerning the aperture tip (a-tip), the throughput is extremely low, and the lateral resolution is poor; both are limited by the aperture size. Meanwhile, with regard to the scattering tip (s tip), the signal-to-noise ratio (SNR) appears to be almost zero; consequently, one cannot directly use the measured data. In this work, we present a plasmonic tip (p-tip) developed by tailoring subwavelength annuli so as to couple internal radial illumination to surface plasmon polaritons (SPPs), resulting in an ultrastrong, superfocused spot. Our p-tip supports both a radial symmetric SPP excitation and a Fabry-Perot resonance, and experimental results indicate an optical resolution of 10 nm, a topographic resolution of 10 nm, a throughput of 3.28%, and an outstanding SNR of up to 18.2 (nearly free of background). The demonstrated p-tip outperforms state-of-the-art NSOM tips and can be readily employed in near-field optics, nanolithography, tip-enhanced Raman spectroscopy, and other applications. PMID- 29281297 TI - Life History Patterns of Discorsopagurus schmitti, a Hermit Crab Inhabiting Polychaete Tubes. AB - Discorsopagurus schmitti is a hermit crab that inhabits empty polychaete tubes in the North Pacific. Here we describe some aspects of its life history (relative growth, population structure, reproductive biology, and incidence of parasitism) and discuss the relationships among them. Unlike most hermits, the two sexes of this species have similar size distributions. In both sexes, larger body size is accompanied by a higher reproductive output (larger clutch size in females and more intrasex competitive potential in males). The energy the females expend in egg production might be equaled in this species by the energy the males expend in supporting parasites. In fact, the extent of infestation by two rhizocephalans [Peltogaster boschmae and Thilacoplethus (=Thompsonia) reinhardi] is more pronounced in males, especially those in the larger size classes. However, rhizocephalans have little effect on their hosts; growth and secondary sexual characters are not influenced. The only morphological modification is the more frequent loss of the second pleopod. Infected hermits also showed a mock parental behavior, fanning the externae with the pleopods as ovigerous females fan their eggs. Larvae are released in sequential bursts, and hatching occurs exclusively at night, possibly to minimize predation by diurnal fishes. Hatching is also synchronized with neap tides, which might keep the larvae from being flushed out into open waters. In a species whose habitat (sabellarian bioherms) is rare and quite unpredictable, it is beneficial to retain larvae near the parental population. PMID- 29281298 TI - Taurine-like Immunoreactivity in the Motor Nerve Net of the Jellyfish Cyanea capillata. AB - Two antisera against the sulfonated amino acid taurine were applied to subumbrella tissue of the jellyfish Cyanea capillata. Taurine-immunoreactive nerve nets were found in both the ectoderm and endoderm. The ectoderm had two morphologically and immunocytochemically distinct populations of neurons, the motor nerve net (MNN), which was immunoreactive to the taurine-like molecule, and the diffuse nerve net (DNN), which was immunoreactive to the neuropeptide Phe-Met Arg-Phe-NH2 (FMRFamide). In the endoderm, immunoreactivity was found in the endodermal DNN. This localization was confirmed by double-labeling experiments, which also revealed that the endodermal DNN neurons may contain both taurine and FMRFamide-related peptide. The presence of a taurine immunoreactivity in the MNN supports the hypothesis that taurine or some chemically related compound is the neurotransmitter at synapses within the MNN of Cyanea. PMID- 29281299 TI - Responses of the Medaka Fish Egg (Oryzias latipes) to the Photolysis of Microinjected Nitrophenyl-EGTA, a Photolabile Calcium Chelator. AB - Photolabile calcium chelators (calcium cages) can be used to elevate cytosolic [Ca2+] at specific sites and times (1, 2, 3). They have been especially valuable in flash photolysis studies of muscle contraction (2) and secretion (4, 5). In the present report, I describe several responses of medaka eggs to thephotolysis of microinjected nitrophenyl-EGTA (NP-EGTA),a new calcium cage (6). When unfertilized eggs injected with NP-EGTA were irradiated with ultraviolet irradiation in a small region of the egg, the eggs were activated and ooplasm within the irradiated region contracted and accumulated there. Eggs into which NP EGTA was injected could also be fertilized. Subsequent irradiation of such eggs, in addition to causing the contraction and accumulation of ooplasm, also caused a global contraction of dividing blastomeres and the contraction and blebbing of embryonic cells for up to 4 days after fertilization. Injection of NP-EGTA had no apparent effect on the maturation offertilized eggs, which developed normally and hatched. PMID- 29281300 TI - Rapid Arm Movements in Stalked Crinoids. AB - Stalked crinoids in the family Isocrinidae have been observed to wave individual arms actively. Using video cameras mounted on a manned submersible, we studied these movements and investigated the factors that elicit them. Crinoids wave their arms in response to sand or detritus dropped on their crowns, to entanglement in tentacles of adjacent sea anemones, and to contact by small crustaceans that might steal from the food grooves. There was no evidence that arm waving functions in food collection. In most cases, the movements could be attributed directly to mechanical stimulation by some natural stimulus. The rapid effective stroke of an arm flexure is caused by contraction of dorsal longitudinal arm muscles. The slower return stroke results from the elastic recoil of large ligaments near the aboral sides of the arms. PMID- 29281301 TI - The Structure and Mode of Function of the Water Vascular System of a Brittlestar, Ophioderma appressum. AB - Unlike the asteroids, which have large madreporite structures, the ophiuroid Ophioderma appressum possesses only two small hidden madreporite pores. Experiments with labeled amino acids, fluorescent microbeads, and surgical obstruction show that small amounts of seawater do routinely enter these pores and become distributed throughout the water vascular system; but this uptake does not seem essential. The flagellated stone canal draws its fluid from the axial sinus, to which the pores connect through a tortuous ampulla. Thus, the stone canal mainly recirculates fluid from hyponeural (perihemal) passages. That perihemal fluid is augmented by seawater from the pores. As perihemal fluid moves towards the stone canal, it passes by or through the axial organ, where nutritive materials may be removed and passed into the hemal channels. Pressure generated by the stone canal forces flow out to the oral tube feet, polian vesicles, and, through valves, eventually to the arm tube feet. Inflation of the tube feet also might occur through osmotic mechanisms, but their activity was not impeded by raising the external osmotic level with dextran. Observations indicate that negative coelomic pressures must be generated during respiratory movements, and these could lead to sufficient body fluid production (by filtration) that the need for substantive madreporitic inflows would be alleviated. PMID- 29281302 TI - Inorganic Overgrowth of Aragonite on Molluscan Nacre Examined by Atomic Force Microscopy. AB - The nacre (mother-of-pearl) that forms the irridescent inner layers of mollusc shells is a highly ordered microlaminate composite of aragonite crystals and biopolymers with a strength and fracture resistance that far exceed those of the mineral crystals themselves. The processes governing the biofabrication of this material by the secretory cells of the mantle are complex and only partially understood. We have used the atomic force microscope (AFM) to investigate the aqueous solution conditions under which mineral growth can occur on the nacreous layer of the shell of the bivalve mollusc Atrina sp. In situ imaging of the mature nacre surface exposed to a pH-controlled environment of natural seawater with added carbonate ions reveals that inorganic overgrowth of aragonite can occur within the ranges of pH and inorganic ion concentrations found in the molluscan extrapallial fluid from which the mineral is produced during biological shell growth. Thus, we posit that once nucleation has occurred, nacreous tablets could grow inorganically in the extrapallial space; the role of proteins and other macromolecules may be limited to initiating growth or controlling morphology through selective adsorption and spatial constraint on the growing crystal. PMID- 29281303 TI - Direct Development in the Ascidian Molgula retortiformis (Verrill, 1871). AB - The cellular features of the ascidian Molgula retortiformis (Verrill, 1871), a direct developing species, were investigated with the aid of transmission electron microscopy, histochemistry, and immunocytochemistry. Developmental comparisons between direct and indirect developing ascidians will further our understanding of how developmental processes evolve. M. retortiformis eggs are surrounded by a follicular envelope comprising a layer of outer follicle cells attached to an acellular chorion. The cytoplasm of M. retortiformis eggs contains large quantities of yolk and glycogen. Immediately after hatching, at day 2.5 of development, the cells constituting a juvenile exhibited similar ultrastructural features, except that the larger, deeper cells contained more yolk and glycogen than the epidermal cells. Differentiated muscle cells were absent in newly hatched M. retortiformis juveniles, and acetylcholinesterase (AChE) activity was not detected. Immunocytochemistry experiments using a vertebrate intermediate filament antibody (NN18) support the idea that the failure of newly hatched M. retortiformis juveniles to develop muscle cells may be due to the absence of a factor localized in the egg myoplasm. This paper concludes with a discussion of the "substrate hypothesis" and the evolution of ascidian direct development. PMID- 29281304 TI - Prespawning Behavior, Spawning, and Development of the Brooding Starfish Leptasterias polaris. AB - Our study focused on the precise reproductive behavior of the starfish Leptasterias polaris (Muller and Troschel) before and during spawning--a subject of much speculation and evident ecological importance. Between the third week of December 1992 and mid-January 1993, we observed spawning in the laboratory that roughly corresponded to field observations in the Lower St. Lawrence Estuary. In experimental tanks provided with natural environmental conditions, the spawning was preceded by 7 to 8 weeks of complex aggregative interactions among the starfish. The individuals, which usually avoid each other, began to make discreet arm contact, which intensified with time and eventually led to the superposition of two or more starfish, independently of sex. The interactions seem to be associated with decreasing temperature, because aggregative and spawning behaviors were not observed under stable temperature conditions. Male spawning is first initiated when the temperature falls to about 2{deg}C during minimum daylength (<9 h.d-1). In seawater, the spermatozoa are negatively buoyant and tend to deposit as a sticky film on the substrate, where they enter a state of low activity. Stimulated by male spawning, females spawn on the layer of sperm, which is reactivated by contact with the oocytes, ensuring fertilization. In the laboratory, the fertilized eggs undergo first cleavage in 45 h, become brachiolaria in 40 days, and form fully developed young starfish within 5.5 to 6 months, synchronously with populations in the field. The embryos develop at the same rate even when not brooded, suggesting that the brooding behavior in L. polaris serves mainly to keep the eggs clean, healthy, and protected against predation. PMID- 29281305 TI - Elemental Distributions in Marine Bivalve Shells as Measured by Synchrotron X-Ray Fluorescence. AB - The concentrations of elements from Mn to Pb in the shells of Mercenaria mercenaria, Mya arenaria, and Argopecten irradians were measured using synchrotron x-ray fluorescence. This technique provides sensitivity as low as 1 ppm and resolution of 8 {mu}m. Elements were heterogeneously distributed, both on a large scale (several millimeters) and on a small scale (tens of micrometers). Large-scale variations were observed in the compositions of shell layers and in seasonal variations in strontium concentration. Small-scale changes in composition included elevated iron levels at the boundary between the prismatic and inner homogeneous shell of the hard clam, Mercenaria mercenaria. Variations in strontium concentrations were seen over time spans of several months, suggesting that this technique can be used to determine historical water temperatures. Elemental maps with a resolution of less than 10 {mu}m were produced. PMID- 29281306 TI - Osmoregulation in Dreissena polymorpha: the Importance of Na, Cl, K, and Particularly Mg. AB - Zebra mussels (Dreissena polymorpha) are unusual in that they cannot survive in Mg-deficient water. Analysis of blood samples from mussels obtained in the field indicated a Mg concentration of 1.5-2.0 mM immediately after animal collection. However, Mg concentration in the blood decreased rapidly when the mussels were transferred to Mg-free artificial pondwater (PW); the t1/2 was 24 h. Blood Mg decreased to the limits of detection within 2 weeks, and the time to 50% mortality was about 17 days in Mg-free PW. When Mg-depleted specimens of D. polymorpha were returned to PW containing Mg, the net flux was 3 MUmol Mg (g dry tissue.h)-1, and blood Mg concentration was restored within a day to 0.4-0.6 mM. Mussels depleted of Mg did not survive beyond 51 days. When mussels were acclimated to K-free pondwater (containing Mg), their osmoregulatory ability was impaired, and the total solute of the blood dropped from 30-36 to 21-24 mosm, with blood Na and Cl concentrations declining 30-50%. This ion-depleted condition was reversed within 45 h upon return of K to the pondwater bathing medium. D. polymorpha individuals were unable to survive beyond 5 days in deionized water and required minimal concentrations of Na, Cl, K, and Mg for prolonged storage (>51 days) under laboratory conditions. Mussels survived Ca-deficient solutions for more than 51 days, presumably because they were able to mobilize Ca from internal stores (shell) to maintain blood calcium at 1 mM. PMID- 29281307 TI - Oxygen Consumption Rates and Metabolic Enzyme Activities of Oceanic California Medusae in Relation to Body Size and Habitat Depth. AB - Oxygen consumption rates were measured in 14 species of hydromedusae and 5 species of bathypelagic coronate scyphomedusae. Analysis of all individuals of all species of medusae showed the familiar pattern of decreasing specific oxygen consumption rate with increasing wet weight of animals. Citrate synthase (CS), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), and pyruvate kinase (PK) activities were measured in more than 30 species of medusae. Octopine dehydrogenase, strombine dehydrogenase, and alanopine dehydrogenase were not detected in either hydromedusae or scyphomedusae. The allometric scaling phenomenon of decreasing activity in larger individuals was observed in Krebs cycle enzyme activities. LDH activities, on the other hand, increased with increasing wet weight. Most medusae were aerobically poised, with higher CS activities than LDH activities. However, several meso- and bathypelagic medusae, including the coronate scyphozoans Periphylla periphylla and Nausitho{e2dot} rubra, were anaerobically poised, possibly as a mechanism to assist in vertical migrations at low oxygen concentrations in the oxygen minimum layer. There is poor correlation between CS activities and oxygen consumption rates in these medusae when compared to previously investigated animals. To account for this poor correlation, we propose the hypothesis that medusan CS at the periphery of the maximum diffusion distance may be oxygen-limited and does not function at the normal in vivo rate. For pelagic medusae, there is no apparent decline in metabolic rate and metabolic potential, as determined by enzymatic activity, with increasing depth of occurrence, beyond the declines caused by the decrease in temperature with depth. These patterns are in contrast to the rapid declines in metabolic rates and metabolic potentials with depth that have been observed for pelagic fishes and crustaceans. Deep-living medusae have metabolic rates of a magnitude similar to those of bathypelagic fishes and crustaceans. PMID- 29281308 TI - Protogynous Sex Change in the Intertidal Isopod Gnorimosphaeroma oregonense (Crustacea: Isopoda). AB - In Crustacea, the dominant pattern of sequential hermaphroditism is protandry (sex change from male to female). Here we provide the first evidence from external morphology and population structure that Gnorimosphaeroma oregonense, an abundant, sexually dimorphic intertidal isopod, undergoes protogynous (female to male) sex change. In the field, 31% of females had rudimentary penes, suggesting sex change and laboratory growth experiments confirmed that females produced one brood of juveniles, then passed through a variable number of molts as immature males before becoming sexually mature males. Contrary to reports for other protogynous Crustacea, this study suggests that in G. oregonense sex change is not socially mediated, although it may be facultative, because a large percentage of laboratory-reared juvenile isopods developed directly into males. Potential adaptive explanations for protogyny are discussed in relation to protandry--the more common strategy in Crustacea. PMID- 29281309 TI - Small Size, Brooding, and Protandry in the Apodid Sea Cucumber Leptosynapta clarki. AB - The apodid sea cucumber Leptosynapta clarki exhibits the three commonly associated traits of small adult size (max. length 113 mm), brooding (intraovarian = viviparity), and hermaphroditism (protandric). Juvenile L. clarki are released from the ovary at a length of 1-2 mm in the early spring (April-May) and are reproductively active as males in the reproductive season (November) following their birth. In their second year, some individuals continue to reproduce as males, but others undergo protandric sex change to reproduce as females. Analysis of the relationship between size and sex revealed a "critical" size for sex change at a weight of 200-400 mg with a 1:1 sex ratio above 500 mg total weight. Transitional gonads with previtellogenic oocytes and mature spermatozoa were observed, suggesting that sex change is initiated prior to reproducing in the current reproductive season. A test of the allometric hypothesis on the association between small size and brooding found no evidence for scaling constraints on brood size in L. clarki. These allometric constraints may be avoided because of potentially low fertilization success and brooding within a distensible structure. The sequential hermaphroditism in L. clarki may additionally be a method to reduce inbreeding in a species with limited dispersal. PMID- 29281310 TI - Muscle and Nerve Terminal Fine Structure of a Primitive Crustacean, the Cephalocarid Hutchinsoniella macracantha. AB - Abdominal muscles of the cephalocarid Hutchinsoniella macracantha resemble the striated muscle fibers of other crustaceans, having regularly aligned sarcomeres that average 5 MUm in length; thick, wavy Z-lines; and orbits of eight thin filaments surrounding a thick filament. However, unlike most crustacean muscle fibers, the cephalocarid muscle fibers are not subdivided into myofibrils by elaboration of the longitudinally oriented sarcoplasmic reticulum. Consequently, elements of the transverse tubule and sarcoplasmic reticulum in the form of triads occur scattered over the entire fiber. Motor innervation is by means of scattered nerve terminals, populated with round synaptic vesicles, indicative of excitatory axons. By lacking myofibrils, the cephalocarid and ostracod muscle represents a much simpler condition than the myofibril-rich muscles of the other crustacean classes and signifies a primitive condition in its resemblance to the onycophoran muscle. PMID- 29281311 TI - Fertilization Between Closely Related Sea Urchins Is Blocked by Incompatibilities During Sperm-Egg Attachment and Early Stages of Fusion. AB - Closely related sea urchin species in the genus Echinometra from Hawaii and Guam have strong species-specificity of fertilization. Crosses between the two species found in Hawaii, E. mathaei and E. oblonga, were compared in order to determine which steps of gamete interaction are responsible for fertilization barriers. The acrosome reaction, attachment of sperm to eggs, and fusion of sperm and egg membranes were measured in crosses between species and compared to within-species controls. In all crosses, eggs induced the acrosome reaction in 50-100% of sperm within 20 s. However, eggs bound about 3-5 times fewer heterospecific than conspecific sperm. In addition, electrical continuity between heterospecific gametes was achieved rarely under conditions that allowed conspecific gametes to achieve it readily. Only two sperm-egg fusion events were recorded in more than 80 min of heterospecific sperm interaction on 22 eggs. Accordingly, species specific fertilization in these urchins results firstly from reduced attachment of the heterospecific sperm acrosomal process to the egg vitelline layer, and secondly from inability of attached heterospecific sperm to develop continuity with the egg plasma membrane. At both of these steps, incompatibilities are reciprocal. Thus a barrier to gene flow is mediated by molecular interactions during a specific part of the fertilization process, as the sperm acrosomal surface and the egg vitelline layer contact each other. Recognition molecules mediating these steps of fertilization may be capable of relatively rapid change, leading to species-specificity of fertilization. PMID- 29281312 TI - The Role of Podial Secretions in Adhesion in Two Species of Sea Stars (Echinodermata). AB - Individuals of Asterias rubens and Marthasterias glacialis use their podia in locomotion, anchorage, and feeding. Each podium consists of a stem with a disk at its tip. The stem allows the podium to lengthen, flex, and retract, and the disk allows the podium to adhere to the substratum. Adhesion of sea star podia seems to rely on the epidermal secretions of the disk and not on a mechanical sucker like operation. The disk epidermis is made up of five cell types: nonciliated secretory cells (NCS cells) of two different types (NCS1 and NCS2), both containing granules that are at least partly mucopolysaccharidic in composition; ciliated secretory cells (CS cells) containing small granules of unknown content; nonsecretory ciliated cells (NCS cells); and support cells. The epidermal cells of the podial disk are presumably functioning as a duogland adhesive system that is involved in an adhesive/deadhesive process. The following model is presented. Adhesive secretions are produced by NCS1 and NCS2 cells (both of them have extruded some of their secretory granules in attached podia). These secretions constitute a layer of adhesive material between the podium and the substratum, this layer being the footprint left by the podium after it has become detached from the substratum. Deadhesion, on the other hand, would be due to CS cell secretions. All these secretions would be controlled by stimuli perceived by the two types of ciliated cells (receptor cells), which presumably interact with the secretory cells via the nerve plexus. PMID- 29281313 TI - Glutamate Immunoreactivity in Non-neuronal Cells of the Sea Anemone Metridium senile. AB - The distribution of glutamate in the tentacles and oral disk of the sea anemone Metridium senile was investigated by wholemount immunohistochemistry with the use of a monoclonal antibody raised against the derivatization product {gamma}-L glutamyl-L-glutamic acid. Immunoreactivity was localized in one class of tentacle nematocysts and on their associated threads. These nematocysts were concentrated at the distal end of tentacles, none being found at the base of tentacles or in the oral disk. Muscle end-feet of epitheliomuscular cells also stained in the longitudinal muscle of tentacle ectoderm. In contrast, immunostaining in the oral disk was confined to ectodermal granule-containing cells overlying the radial muscle. These results support a role for glutamate as an osmolyte precursor in nematocysts but provide little clue as to the functional significance of this amino acid in muscle and gland cells. PMID- 29281314 TI - Quantification of L-Dopa and Dopamine in Squid Ink: Implications for Chemoreception. AB - Squid ink is an alarm substance that both confuses predators and alerts conspecifics to the presence of danger. Although the ejection of ink is a powerful visual stimulus, studies also indicate a chemical component to the signal. Squid ink is composed mainly of melanin pigments, but the nonpigmented portion of the ink contains the enzymes and precursors of melanin synthesis. Our previous behavioral studies showed that squid olfactory organs detect L-dopa, a key chemical in melanogenesis. Squid olfactory neurons also respond to dopamine, a biogenic amine not previously described in squid ink. We performed HPLC on ink taken from the ink sacs of adult Loligo opalescens. The ink was conjugated with orthophthaldialdehyde (OPA) and injected into the HPLC, and amine-containing compounds were detected fluorometrically. Standard curves constructed for L-dopa and dopamine allowed quantitation from individual ink sacs. We found that L-dopa was present in undiluted ink at a mean concentration of 1.15 mM and was significantly greater than the mean dopamine concentration of 0.19 mM. These values are greater than those at which both compounds are effective in behavioral and electrophysiological experiments. In addition we found that an unidentified antioxidant in the ink may prevent rapid oxidation of L-dopa and dopamine following dilution in seawater. PMID- 29281315 TI - Determining the relationship between body mass index, healthy lifestyle behaviors and social appearance anxiety. AB - The aim of this study was to describe the relationship between nutritional status, healthy lifestyle behaviors and social appearance anxiety of individuals aged 20-65 (n = 500). A significant, positive relationship was seen between body mass index and nutrition, and negative relationship between body mass index and spiritual development, interpersonal relations, stress management. There was a negative relationship between the ORTO-15 score and health responsibility, physical activity, nutrition, spiritual development, interpersonal relationships, stress management. There was also a negative relationship between the Social Appearance Anxiety Scale and spiritual development, interpersonal relationships. PMID- 29281316 TI - Retinal microvascular signs and incidence of abdominal aortic aneurysm: The Atherosclerosis Risk in Communities Study. AB - PURPOSE: To test the hypothesis that retinal microvascular abnormalities known to predict other cardiovascular diseases are associated prospectively with risk of abdominal aortic aneurysm. The rationale is that aortic aneurysm involves small vessel pathology that parallels, to some degree, retinal vasculopathy. METHODS: In 1993-1995, the Atherosclerosis Risk in Communities (ARIC) Study, a prospective population-based cohort, took retinal photographs of a randomly selected eye of 10,911 ARIC participants (initial mean age 60 years). Staff centrally graded the photographs using central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) indices. We followed participants for incidence of abdominal aortic aneurysm (n = 378 events), measured via medical record linkage from 1993-1995 through 2011. RESULTS: Wider venular diameters were associated with increased incidence of abdominal aortic aneurysm, with the hazard ratio (95% CI) being 1.61 (1.20, 2.16) for the highest versus lowest quartile of CRVE. However, adjustment for other abdominal aortic aneurysm risk factors, particularly smoking, eliminated the association of CRVE with abdominal aortic aneurysm. CRAE and frank retinopathy showed no association with abdominal aortic aneurysm incidence. CONCLUSION: This prospective study found that retinal vascular diameters and retinopathy are not associated with incidence of abdominal aortic aneurysm. PMID- 29281317 TI - Changes in movement transitions across a practice period in childhood apraxia of speech. AB - This study examined changes in speech motor control across a movement transition between sounds within a motor learning task in children with apraxia of speech (CAS) and typical development (TD). It was investigated whether oral articulator movement was refined with practice and whether practice gains generalized to words not included in the practice session. A total of 16 children (ages 5-6) with CAS (n = 8) and TD (n = 8) participated in this study. Novel and real word tokens were produced at three time points. Kinematic data was collected using facial motion tracking at each time point. Children completed a practice session following baseline data collection session that integrated motor learning principles. Three tokens were included in the practice session and the remaining stimuli assessed carryover of practice gains. Kinematic data was then collected immediately following practice and 3 days later. Kinematic analyses were conducted on the movement gesture for the first syllable of each word. Narrow transcription analyses examined speech production accuracy. Children in the CAS group displayed increased consonant and vowel accuracy only for the practised tokens. Adjustments to spatial control and movement variability were observed in the CAS group, though only for practised words. Children in the TD group altered spatial and temporal domains of movement and variability across both practised and non-practised tokens. Interestingly, the CAS group displayed a pattern of increased displacement along with decreased variability, which was not observed in the TD group. The degree to which these findings reflect facilitative or maladaptive changes are discussed. Results are also interpreted in relation to vowel properties, novel/real word status and variable practice of novel and real words. PMID- 29281318 TI - Job Satisfaction of People With Intellectual Disability: Associations With Job Characteristics and Personality. AB - To obtain an understanding of factors associated with job satisfaction of people with intellectual disability (ID), this study investigates the associations of job satisfaction with job characteristics (i.e., job demands, job resources) and personality, using the job demands-resources model. Data were gathered from 117 people and their employment support workers, using structured questionnaires adapted from well-established instruments. Job resources and age were positively associated with job satisfaction. Job demands and personality showed no significant direct associations with job satisfaction. Moderation analyses showed that for people with ID with high conscientiousness, enhanced job demands were associated with reduced job satisfaction, which was not the case for those with low conscientiousness. This study emphasizes the importance of job design. PMID- 29281319 TI - Autonomy Support, Need Satisfaction, and Motivation for Support Among Adults With Intellectual Disability: Testing a Self-Determination Theory Model. AB - The tenets of self-determination theory as applied to support were tested with structural equation modelling for 186 people with ID with a mild to borderline level of functioning. The results showed that (a) perceived autonomy support was positively associated with autonomous motivation and with satisfaction of need for autonomy, relatedness, and competence; (b) autonomous motivation and need satisfaction were associated with higher psychological well-being; (c) autonomous motivation and need satisfaction statistically mediated the association between autonomy support and well-being; and (d) satisfaction of need for autonomy and relatedness was negatively associated with controlled motivation, whereas satisfaction of need for relatedness was positively associated with autonomous motivation. The self-determination theory provides insights relevant for improving support for people with intellectual disability. PMID- 29281321 TI - Resumes en Francais. PMID- 29281320 TI - Sensory Behaviors in Minimally Verbal Children With Autism Spectrum Disorder: How and When Do Caregivers Respond? AB - Sensory behaviors are widely reported in autism spectrum disorder (ASD). However, the impact of these behaviors on families remains largely unknown. This study explored how caregivers of minimally verbal children with ASD responded to their child's sensory behaviors. Using a mixed-methods approach, we examined two variables for each endorsed child behavior: (1) Did the caregiver respond/try to change the behavior? and (2) What response did they employ? Caregivers did not differ in the frequency of responses to hypo- or hyper-responsive behaviors but employed different responses. Caregivers responded to more social sensory behaviors and predominately changed their own behavior in response to their child's. Our findings demonstrate how extensively caregivers adapt to their child's behaviors and vary their response dependent on behavior exhibited. PMID- 29281322 TI - Causes of Mortality in Older People With Intellectual Disability: Results From the HA-ID Study. AB - We aim to provide insight into the cause-specific mortality of older adults with intellectual disability (ID), with and without Down syndrome (DS), and compare this to the general population. Immediate and primary cause of death were collected through medical files of 1,050 older adults with ID, 5 years after the start of the Healthy Ageing and Intellectual Disabilities (HA-ID) study. During the follow-up period, 207 (19.7%) participants died, of whom 54 (26.1%) had DS. Respiratory failure was the most common immediate cause of death (43.4%), followed by dehydration/malnutrition (20.8%), and cardiovascular diseases (9.4%). In adults with DS, the most common cause was respiratory disease (73.3%), infectious and bacterial diseases (4.4%), and diseases of the digestive system (4.4%). Diseases of the respiratory system also formed the largest group of primary causes of death (32.1%; 80.4% was due to pneumonia), followed by neoplasms (17.6%), and diseases of the circulatory system (8.2%). In adults with DS, the main primary cause was also respiratory diseases (51.1%), followed by dementia (22.2%). PMID- 29281323 TI - Later Life Impacts of Social Participation on Parents of Adult Offspring With and Without Intellectual and Developmental Disabilities. AB - Social participation is an important resource for parents in old age, and may be particularly important for parents living with adult offspring with intellectual and developmental disabilities. To evaluate whether socializing with friends and family and participating in social organizations protects against depression in old age, this study examined parents of adult offspring with disabilities ( n = 164) and without disabilities ( n = 820). As expected, more socializing with friends and more participating in organizations were associated with fewer depressive symptoms for all parents. However, socializing with family members predicted fewer depressive symptoms only for parents co-residing with their adult offspring with disabilities, suggesting that socializing with family is particularly important for parents providing direct care to adults with disabilities. PMID- 29281325 TI - Resumenes al Espanol. PMID- 29281324 TI - Multimorbidity and Polypharmacy Are Independently Associated With Mortality in Older People With Intellectual Disabilities: A 5-Year Follow-Up From the HA-ID Study. AB - We studied the association between multimorbidity, polypharmacy, and mortality in 1,050 older adults (50+) with intellectual disability (ID). Multimorbidity (presence of >= 4 chronic health conditions) and polypharmacy (presence >= 5 chronic medication prescriptions) were collected at baseline. Multimorbidity included a wide range of disorders, including hearing impairment, thyroid dysfunction, autism, and cancer. Mortality data were collected during a 5-year follow-up period. Cox proportional hazards models were used to determine the independent association between multimorbidity and polypharmacy with survival. Models were adjusted for age, sex, level of ID, and the presence of Down syndrome. We observed that people classified as having multimorbidity or polypharmacy at baseline were 2.60 (95% CI = 1.86-3.66) and 2.32 (95% CI = 1.70 3.16) times more likely to decease during the follow-up period, respectively, independent of age, sex, level of ID, and the presence of Down syndrome. Although slightly attenuated, we found similar hazard ratios if the model for multimorbidity was adjusted for polypharmacy and vice versa. We showed for the first time that multimorbidity and polypharmacy are strong predictors for mortality in people with ID. Awareness and screening of these conditions is important to start existing treatments as soon as possible. Future research is required to develop interventions for older people with ID, aiming to reduce the incidence of polypharmacy and multimorbidity. PMID- 29281326 TI - Sixminute Stepper Test to Set Pulmonary Rehabilitation Intensity in Patients with COPD-A Retrospective Study - Letter to the Editor. PMID- 29281327 TI - Long-Term Nutritional Outcome and Health Related Quality of Life of Patients Following Esophageal Cancer Surgery: A Meta-Analysis. AB - Long term health related quality of life (HRQL) and nutritional outcome of patients following esophagectomy for cancer has become increasingly significant as the 5-year survival rate in this patient group is increasing. This meta analysis aims to investigate the HRQOL, nutritional impact symptoms and nutritional outcomes of patients following an esophagectomy at greater than 12 months after surgery. In studies reporting on HRQL as an outcome, global QOL score at 6-month compare to greater than 12-month showed no statistically significant difference (65.92 vs. 75.78, p = 0.07). Forty-one percent of patients reported a greater than 10% weight loss at six-month follow-up (95% CI: 20-65%; I2 = 94.27, p < 0.001), and at the greater than 12-month follow-up, 33% of patients had the greater than 10% weight loss (95% CI: 15-57%; I2 = 96.18, p < 0.001). At the 12-month or longer post esophagectomy, just over half the patients reported dysphagia (51%, 95% CI: 25-76%; I2 = 95.70, p < 0.001), nausea was reported by 11% (95% CI: 7-19%; I2 = 59.31, p = 0.09), dumping syndrome reported by 60% (95% CI: 43-76%; I2 = 96.92, p < 0.001). Symptoms such as dysphagia, diarrhea, reflux, dumping syndrome, and nausea were found to persist following esophagectomy. There were insufficient robust research investigating how these symptoms impact on the adequacy of dietary intake and micronutrient status. PMID- 29281329 TI - Ciliary Hovering in Larval Lancelets (=Amphioxus). AB - Larvae of lancelets (=amphioxus) are of special interest because they figure prominently in debates about vertebrate origins (1), can sometimes grow into a giant "amphioxides" form (2, 3), have a puzzling right-left asymmetry (4), and constitute a major zooplankton resource in parts of the Atlantic (5). By using improved methods (6, 7) to culture and observe healthy pre-metamorphic larvae in relatively deep containers, we demonstrated a prominent hovering behavior. The larvae spend most of their time suspended in midwater by metachronal beating of epidermal cilia. The body is usually tilted at an angle such that the anterior end and ventral side are oriented towards the water surface. This posture is maintained in the dark and in the light, although there is directional photosensitivity. Hovering may help account for the giant "amphioxides" and may be related to the curious asymmetry of the larval body. PMID- 29281328 TI - Altered Potassium Ion Channel Function as a Possible Mechanism of Increased Blood Pressure in Rats Fed Thermally Oxidized Palm Oil Diets. AB - Intake of thermally oxidized palm oil leads to cytotoxicity and alteration of the potassium ion channel function. This study investigated the effects of fresh and thermally oxidized palm oil diets on blood pressure and potassium ion channel function in blood pressure regulation. Male Wistar rats were randomly divided into three groups of eight rats. Control group received normal feed; fresh palm oil (FPO) and thermally oxidized palm oil (TPO) groups were fed a diet mixed with 15% (weight/weight) fresh palm oil and five times heated palm oil, respectively, for 16 weeks. Blood pressure was measured; blood samples, hearts, and aortas were collected for biochemical and histological analyses. Thermally oxidized palm oil significantly elevated basal mean arterial pressure (MAP). Glibenclamide (10-5 mmol/L) and tetraethylammonium (TEA; 10-3 mmol/L) significantly raised blood pressure in TPO compared with FPO and control groups. Levcromakalim (10-6 mmol/L) significantly (p < .01) reduced MAP by 32.0% in FPO and by 5.4% in TPO. NS1619 (10 mmol/L) significantly (p < .01) decreased MAP by 19.5% in FPO and by 8% in TPO. The TPO significantly (p < 0.01) increased the tissue levels of peroxide, total cholesterol, triglyceride, and low-density lipoprotein cholesterol while catalase and superoxide dismutase activities were significantly (p < .01) decreased compared with control and FPO groups. Histological alterations were prominent in aortas and hearts of rats in the TPO group. These results suggest that prolonged consumption of repeatedly heated palm oil increases MAP probably due to the attenuation of adenosine triphosphate-sensitive potassium (KATP) and large-conductance calcium-dependent potassium (BKCa) channels, tissue peroxidation, and altered histological structures of the heart and blood vessels. PMID- 29281330 TI - Heat Shock Protein Induction in Montastraea faveolata and Aiptasia pallida Exposed to Elevated Temperatures. AB - Frequent widespread episodes of coral bleaching have made researchers aware of the sensitivity of reef corals to moderately elevated temperatures and led us to investigate mechanisms of temperature stress tolerance in this group. One such mechanism may be the induced synthesis of heat shock proteins (hsps), which have been shown to play a role in thermotolerance in other organisms. However, induced synthesis of hsps in scleractinian corals was not reported until recently. Experiments were conducted in which Montastraea faveolata was exposed to high temperatures (up to 35{deg}C) for short periods (2 h). Under the conditions tested, the corals produced seven different hsps with approximate molecular weights of 95, 90, 78, 74, 33, 28, and 27 kDa. Another zooxanthellate species, the sea anemone Aiptasia pallida, also synthesized hsps during temperature stress, but fewer and with different molecular weights (82, 72, 68, and 48 kDa) than those produced by Montastraea. It now remains to be determined whether hsps are involved in differences in thermotolerance and susceptibility to bleaching within and between the various species of Montastraea, and between species of reef cnidarians. PMID- 29281331 TI - Cytoskeletal Architecture and Organelle Transport in Giant Syncytia Formed by Fusion of Hexactinellid Sponge Tissues. AB - Dissociated tissue from the hexactinellid sponge Rhabdocalyptus dawsoni adheres to coated substrates and aggregates by the fusion of tissue pieces to form a giant syncytium. Video microscopy shows that the pieces contact each other by way of lamellipodia or filopodia. Fusion, corroborated by evidence of dye spread, occurs about 1 hour after plating and is characterized by two-way transport of individual organelles, including nuclei, at an average rate of 2.15 {mu}m.s-1, and bulk streaming of cytoplasm at an average velocity of 1.72 {mu}m . s-1. In the cellular sponge Haliclona, by contrast, dye does not spread through aggregates and no streaming can be seen. That transport in Rhabdocalyptus is microtubule-based is indicated by the reversible inhibition of streaming caused by colcemid and nocodazole. Immunofluorescence and electron microscopy reveal an extensive network of microtubule bundles within the aggregates. The cytoskeleton also includes microfilament bundles that traverse aggregates and run around the periphery and giant, actindense rods that extend from the edges. Cytochalasin B reversibly disrupts the microfilamentous framework without blocking streaming. In contrast to demosponges where the cytoskeleton is organized on the basis of individual cells, in hexactinellids it provides a supporting framework and transport pathways within vast, multinucleate tissue masses. If we take this preparation as a model for tissue organization in the intact sponge, these findings support the view that hexactinellids are syncytial organisms, probably the largest in the animal kingdom, and suggest that food products may be distributed through the sponge intracellularly rather than by wandering amoebocytes. The findings strengthen the case for establishing the Hexactinellida as a subphylum within the Porifera. PMID- 29281332 TI - Bivalve Mollusc Hemocyte Behaviors: Characterization of Hemocyte Aggregation and Adhesion and Their Inhibition in the California Mussel (Mytilus californianus). AB - Within minutes of removal from the California mussel, Mytilus californianus hemocytes become sticky for one another and for foreign surfaces. We sought to understand the cell surface changes responsible for this altered state. Hemocyte aggregation and adhesion assays were used in experiments in which a variety of reagents potentially capable of interfering with aggregation were screened. Caffeine, nor-ethylmaleimide, cytochalasin B, and EDTA were completely or partially inhibitory towards aggregation and adhesion. However, RGD-containing peptides, glycosaminoglycans, protease inhibitors, heparin, or poly-L-lysine were without effect. Low temperature (4 degrees C) slowed hemocyte adhesion and hemocyte cohesion. Based on the findings, it appears that (1) Mytilus hemocyte aggregation, in vitro, is a two-step process that requires metabolic energy and divalent cations (calcium and magnesium), and is temperature-sensitive; and (2) Mytilus hemocyte adhesion and hemocyte aggregation are two associated but different cell behaviors. PMID- 29281333 TI - Calcitic Nacreous Ultrastructures in Bryozoans: Implications for Comparative Biomineralization of Lophophorates and Molluscs. AB - The occurrence of nacreous-type fabrics in bryozoans has broad implications for our understanding of similarities between lophophorate and molluscan biomineralization. Calcitic semi-nacreous ultrastructures in the skeletons of several species of cyclostome bryozoans belonging to the suborders Tubuliporina and Articulata are described. In these taxa semi-nacre is the dominant ultrastructure of the walls, and often succeeds a precursory fabric of tiny wedge shaped crystallites. The semi-nacre comprises laminar sheets of irregularly stacked, typically six-sided tablets with frequent screw dislocations. Tablets usually have inclined edges and an upper surface with a central depression. The surfaces of etched six-sided tablets have six subtriangular sectors: three soluble sectors alternating with three less-soluble sectors. The less-soluble sectors have outward-sloping edges and sometimes have slightly longer sides than the more soluble sectors, which have inward-sloping edges. Newly seeded crystallites comprise only the three less-soluble sectors separated by a 'trilete' suture. They are not nucleated on a particular sector type. Similar fabrics have previously been recorded in the cyclostome suborder Cancellata. The substructure of the calcitic semi-nacreous tablets of cyclostomes resembles molluscan aragonitic nacre, particularly that of bivalves, but differs in the precise arrangement of the sectors. Morphologically, the bryozoan semi-nacre is at least as similar to bivalve nacre as bivalve nacre is to gastropod and cephalopod nacre. The existence of a distinct substructure in the component tablets of molluscan nacre has been used as evidence that a greater evolutionary potential characterizes molluscan rather than lophophorate (bryozoans and brachiopods) biomineralization. This claim is contradicted by the recognition of substructured semi-nacre in cyclostome bryozoans. PMID- 29281334 TI - Changes in Larval Morphology in the Evolution of Benthic Development by Patiriella exigua (Asteroidea: Asterinidae), a Comparison with the Larvae of Patiriella Species with Planktonic Development. AB - Patiriella exigua (Lamarck) is a small asterinid sea star that deposits large eggs onto the substratum. Development is lecithotrophic and entirely benthic, proceeding without parental care. The embryos develop to the brachiolaria stage before hatching and there is no trace of a bipinnaria larva. In its early stage the larva of P. exigua resembles a planktonic brachiolaria in having one long central brachium and two short lateral brachia. By hatching, the brachia are equal in length, giving the larva a tripod-like appearance. Comparison of the larva of P. exigua with the brachiolaria of Patiriella species with planktonic development supports the hypothesis that the tripod larval form results from differential growth of the lateral brachia. At hatching, the P. exigua larva has a well-developed attachment complex composed of a large adhesive disk and three muscular brachia; the latter bear a striking resemblance to adult tube feet. This hypertrophic elaboration of the brachiolar complex is an adaptation for permanent benthic attachment. Internally, one large enterocoel forms at the anterior end of the archenteron. The archenteron then closes to form the rudiment for the adult gut. Metamorphosis involves gradual resorption of the brachiolar complex concomitant with formation of the first tube feet. The adhesive disk plays a major role in attachment during late metamorphosis but is gradually reduced to a plug of tissue as the tube feet become functional. Juvenile P. exigua are negatively geotactic and float on the water surface, behavior that may act as a mechanism for dispersal. The similarity of the early larva of P. exigua to planktonic brachiolariae suggests that the evolution of benthic lecithotrophy by this species involved modification of a planktonic larval form. These modifications include elimination and reduction of larval feeding structures, formation of one rather than three enterocoels, and hypertrophy of the brachiolar complex to form a tripod larva. Heterochronies in the ontogeny of P. exigua include the delay in hatching to the brachiolaria stage and the accelerated development of the juvenile form and adult skeleton. PMID- 29281335 TI - Reproductive Biology, Taxonomy, and Aspects of Chemical Ecology of Latrunculiidae (Porifera). AB - Sexual reproduction has been observed for the first time within the widely distributed sponge family, the Latrunculiidae. Latrunculia magnifica Keller 1889 was studied mainly in the northern Red Sea in the Gulf of Eilat and the Gulf of Suez. The sponge is hermaphroditic and viviparous. The embryo develops to a large (mean 868 +/- 144 {mu}m, max. 1200 {mu}m) parenchymella larva. The period of reproduction lasts for several months, ceasing only during the winter. Like oocytes, sperm appear to develop from archeocytes, which is uncommon among sponges. The presence of brooded larvae in L. magnifica supports the position of Latrunculiidae within the order Poecilosclerida, subclass Ceractinomorpha, rather than within the Tetractinomorpha. The absence of a periflagellar sleeve from around the base of the choanocyte's flagellum lends further support to this idea. Nuclear magnetic resonance (NMR) analysis of secondary metabolites within the sponge and its nudibranch predator (Chromodoris quadricolor) confirms that both species contain the same latrunculin homologue (either A or B). The latter finding indicates the presence of a compound derived from the diet (i.e., sponge) within the nudibranch. PMID- 29281336 TI - Experimental and Histological Studies of Four Life-History Stages of the Eastern Oyster, Crassostrea virginica, Exposed to a Cultured Strain of the Dinoflagellate Prorocentrum minimum. AB - Effects of the dinoflagellate Prorocentrum minimum (strain EXUV) upon four life history stages of the eastern oyster--embryos, feeding larvae, newly set spat, and juveniles--were investigated in laboratory exposure studies. Embryonic development was not affected significantly by living, heat-killed, or sonicated cells, or by growth-medium extracts from P. minimum cultures. Feeding larvae, however, showed poor growth and poor development of the digestive system when fed P. minimum, as compared with larvae fed Isochrysis sp. (strain T-ISO). Growth of larvae fed mixed P. minimum + Isochrysis diets was intermediate. Larvae and newly set spat that had been fed a diet of 1/3 P. minimum + 2/3 Isochrysis exhibited distinctive changes in digestive-system anatomy. Spat showed an abnormal accumulation of lipid in the stomach epithelium. Absorptive cells in the digestive glands of both larvae and spat contained accumulation bodies, often with a laminated, fibrous appearance in preparations for transmission electron microscopy. These accumulation bodies were PAS (periodic acid-Schiff) positive and may correspond to autolysosomal bodies within P. minimum cells. Juvenile oysters developed the ability to digest P. minimum, but only after a refractory period of about 2 weeks, during which most P. minimum was filtered but rejected as pseudofeces. The linking of accumulation bodies within absorptive cells of oyster digestive diverticula with dinoflagellate autolysosomal bodies suggests a mechanism by which some dinoflagellates interfere with feeding in phytoplankton grazers. PMID- 29281337 TI - Life-History Variation Among Three Temperate Hermit Crabs: The Importance of Size in Reproductive Strategies. AB - The supply and quality of empty gastropod shells may play important roles in the ecology and evolution of hermit crabs. We compare the life histories of three subtidal hermit crabs in Nantucket Harbor, Massachusetts: Pagurus annulipes, P. longicarpus, and P. pollicaris. Specifically, we examine seasonal patterns of reproduction in females, male and female size structure, reproductive effort, and temporal patterns of larval abundance. We also compare shell size among the three species. Life-history features vary with size among the three species. The smallest species (P. annulipes) reproduce soon after metamorphosis and have a high reproductive effort. The two larger species (P. longicarpus and P. pollicaris) delayed reproduction to an intermediate size, and have lower reproductive efforts than P. annulipes. There is no effect of body size on reproduction in P. annulipes, but there is a strong positive effect in P. longicarpus and P. pollicaris. Seasonal patterns of early stage larvae correlated with seasonal patterns of ovigery in all three species, with highest larval densities sampled in P. annulipes and P. longicarpus. Size differences among species were related to patterns of shell usage. Male and female P. annulipes were always found in large shells relative to body size. In comparison, male and female P. longicarpus and P. pollicaris were found in small shells compared to body size. We suggest that early maturity and high reproductive effort have evolved in response to a high risk of mortality associated with small shells. Delayed maturity and low reproductive effort are favored in species that reach a size refuge from shell-crushing predators. Effects of shell limitation are more likely to be common in large species and may also be an important selective in shaping hermit crab life histories. PMID- 29281339 TI - Food, eating behavior, and self-efficacy. PMID- 29281340 TI - Profiling the Use of Dietary Supplements by Brazilian Physical Education Professionals. AB - A survey was designed to examine the use of dietary supplements by Brazilian physical education professionals. The study included 131 Brazilian physical education professionals (83 men and 48 women). A descriptive statistical analysis was performed (mean, standard deviation, and absolute and relative frequencies). A chi-square test was applied to evaluate differences in use of dietary supplements according to particular variables of interest (p < .05). Forty-nine percent of respondents used dietary supplements. Approximately 59% of dietary supplement users took two or more kinds of supplements. Among users of supplements, men professionals (73%) consumed more dietary supplements than women (27%). The most-consumed dietary supplement was whey protein (80%). The results showed a higher use of dietary supplements by men. The most-consumed supplements were rich in protein. The consumption of dietary supplements by almost half of the participants in this study suggests that participants did not consider their dietary needs to be met by normal diet alone. PMID- 29281341 TI - Functional Foods and Nutraceuticals as Dietary Intervention in Chronic Diseases; Novel Perspectives for Health Promotion and Disease Prevention. AB - Functional foods describe the importance of foods in promoting health and preventing diseases aside their primary role of providing the body with the required amount of essential nutrients such as proteins, carbohydrates, vitamins, fats, and oils needed for its healthy survival. This review explains the interaction of functional food bioactive compounds including polyphenols (phenolic acids [hydroxybenzoic acids and hydroxycinnamic acids], flavonoids [flavonols, flavones, flavanols, flavanones, isoflavones, proanthocyanidins], stilbenes, and lignans), terpenoids, carotenoids, alkaloids, omega-3 and polyunsaturated fatty acids, among others with critical enzymes (alpha- amylase, alpha- glucosidase, angiotensin-I converting enzyme [ACE], acetylcholinesterase [AChE], and arginase) linked to some degenerative diseases (type-2 diabetes, cardiovascular diseases [hypertension], neurodegenerative diseases [Alzheimer's disease] and erectile dysfunction). Different functional food bioactive compounds may synergistically/additively confer an overwhelming protection against these degenerative diseases by modulating/altering the activities of these critical enzymes of physiological importance. PMID- 29281342 TI - A population-based survey of visual impairment and its correlates in Mahabubnagar district, Telangana State, India. AB - PURPOSE: To estimate the prevalence and correlates of visual impairment in Mahabubnagar district, Telangana, India. METHODS: Fifty-one clusters of 80 people (all ages) were sampled with probability proportionate to size. Households within clusters were selected through the compact segment sampling. Visual acuity (VA) was measured with a tumbling "E" chart. An Ophthalmic Assistant or Vision Technician examined people with VA<6/12 in either eye. Other impairments (hearing, physical) were clinically assessed and self-reported functional difficulties measured using the Washington Group Extended Set. People with visual impairment and age-sex matched controls with normal vision were interviewed about poverty, employment and education. RESULTS: 4,125 people were enumerated and 3,574 screened (86.6%). The prevalence of visual impairment (VA<6/12) was 8.0% (95% CI = 6.9-9.4%) and blindness was 0.4% (0.2-0.9%), and both increased rapidly with age. Uncorrected refractive error was the leading cause of visual impairment, and cataract the leading cause of blindness. Cataract surgical coverage (proportion of all cataracts that had received surgery) was relatively low (41% of people at VA<6/60), while the post-surgery outcomes were good (81% of operated eyes had presenting VA>=6/18). Among the 287 people with visual impairment, 15% had a moderate/severe physical impairment or epilepsy and 25% had a moderate/severe hearing impairment. Self-reported difficulties in vision were relatively closely related to visual acuity. People with visual impairment were more likely to be in the poorest quartile (OR = 1.9, 95% CI = 1.0-3.4) or unemployed (5.0, 2.2-10.0), compared to controls. CONCLUSIONS: Visual impairment was common in Mahabubnagar district, was mostly avoidable, and was correlated with poverty markers. PMID- 29281343 TI - Cooling-Induced Activation of the Pericardial Organs of the Spiny Lobster, Panulirus japonicus. AB - Ligamental nerves, extensions of the pericardial neurohemal organ of the spiny lobster, produce compound action potentials during cooling of the body, and become silent with warming. Heart-activators released from the pericardial organs into perfusate were collected from the antennule and leg stumps. The perfusate samples were bioassayed using the isolated heart and cardioarterial valves. The extent of heart activation was greatest in samples obtained during the first phase of cooling and was lowest during the initial phase of rewarming. The levels of cardioexcitor substances were clearly related to the firing behavior of the ligamental nerves. Moreover, one of the active factors produced responses identical to octopamine, a known pericardial organ amine. It is proposed that octopamine is released from the ligamental nerve terminals into the blood during cooling of the body. PMID- 29281344 TI - High Ammonia and Low pH in the Urine of the Ghost Crab, Ocypode quadrata. AB - Nitrogen excreted into the urine (<1 mM) has generally been considered a negligible component of total nitrogen output of crustaceans. But concentrations of ammonia >100 mM were found in the urine of laboratory-held Ocypode quadrata, suggesting that this notion might not be applicable to all crustaceans. To address this issue, hemolymph and urine were removed from freshly captured O. quadrata and analyzed for nitrogenous catabolites and major ions. Hemolymph composition was similar to that of other crustaceans, but the urine was acidic ({Xbar} pH = 5.50) and contained ammonia, often at >100 mM. Other nitrogenous catabolites in the urine (urea, amino acids, and uric acid) were much less concentrated: totaling <12 mM on average. The ionic composition of the urine was similar to that of other crustaceans, with the exception that Na was much less concentrated than Cl-. Total osmolality of hemolymph and urine was similar. The Na+/K+ ATPase activity was greater in the antennal glands than in the posterior gills of O. quadrata, suggesting that this enzyme is important for ammonia concentration and Na resorption. This pattern of enzyme activity was not present in two terrestrial brachyurans whose urine contains little ammonia. The evolutionary significance of high ammonia concentrations in the urine of ghost crabs is unclear. PMID- 29281345 TI - Calcium Buffer Injections Inhibit Ooplasmic Segregation in Medaka Eggs. AB - Injection of the weak (KD = 1.5 {mu}M) calcium buffer 5,5'-dibromo-BAPTA into fertilized medaka eggs inhibited the formation of the blastodisc at the animal pole, the movement of oil droplets toward the vegetal pole, and cytokinesis. These inhibitory actions were dependent upon the concentration of the buffer but were independent of free [Ca2+] in the injectate. Because this buffer has previously been shown to substantially suppress zones of elevated calcium at the animal and vegetal poles of the medaka egg, the results of the present study suggest that these zones are necessary for normal segregation of the ooplasm and its inclusions in the medaka egg. PMID- 29281346 TI - The Endocrine Pathway Responsible for Oocyte Maturation in the Inarticulate Brachiopod Glottidia. AB - An aqueous extract of lophophore from Glottidia pyramidata induces oocyte maturation and follicle cell retraction in pieces of ovary and spawning in intact animals. The extract does not act directly on large oocytes but indirectly, through some other cell type in the ovary. The activity of the extract is insensitive to boiling or protease treatment and passes through a filter with a molecular weight cutoff of 2000. Bromoadenosine 3'5' cyclic monophosphate and dibutyryl 3'5' cyclic monophosphate have the same oocyte-maturing and spawning inducing properties as lophophore extract. The active component in lophophore extract presumably affects somatic cells in the ovary, stimulating a rise in cyclic monophosphate levels in these cells, which then secrete a factor that causes oocyte maturation. PMID- 29281347 TI - Reproductive Cycling in Female Fundulus heteroclitus. AB - The ovaries of female Fundulus heteroclitus living in the northeastern Florida saltmarsh recrudesce in January and the fish initially spawn heavily during the subsequent full moons (a lunar pattern); they later spawn with less intensity during both the new and full moons (a semilunar pattern), and then regress in late September. In the laboratory, fish spawning against a vertical screen showed only semilunar periodicities, as observed for seven spawning groups under constant conditions (temperature 26 +/- 1 degrees C; photoperiod 14 h light to 10 h dark; excess food). Regardless of collection times (January, April, August, or September), these seven groups exhibited similar patterns of semilunar spawning for five to eight consecutive cycles whose periods (14.4 to 16.0 days) and phases (-1.7 to +8.4 days) were variable compared with concurrent full/new moon and spring tide cycles. These semilunar cycles, which occurred over the entire year in the laboratory, were thus free-running without entrainment and represent endogenous circasemilunar rhythms. In addition to annual and lunar/semilunar cycles, a tidal spawning cycle was also observed in the habitat. Fish apparently select the higher of the two semidiurnal tides for spawning, regardless of the daily light-dark cycle. This tidal cycle has not yet been tested in the laboratory. PMID- 29281348 TI - Endogenous Substrates for Energy Metabolism in Spermatozoa of the Sea Urchins Arbacia lixula and Paracentrotus lividus. AB - Energy metabolism was examined in the spermatozoa of the sea urchins Arbacia lixula and Paracentrotus lividus, which belong to the orders Arbacioida and Echinoida respectively. P. lividus spermatozoa contained various phospholipids and cholesterol, and their endogenous triglyceride (TG) content was quite low. After dilution of dry sperm in artificial seawater, the level of phosphatidylcholine (PC) decreased rapidly, but other phospholipids remained at constant levels. In contrast to those of P. lividus, the spermatozoa of A. lixula contained TG as well as phospholipids and cholesterol. Following incubation of A. lixula spermatozoa in artificial seawater, TG decreased, but there were no concomitant changes in the levels of phospholipids. Trace amounts of glycogen were present in both species. High lipase activity was demonstrated in A. lixula spermatozoa, but in P. lividus spermatozoa lipase activity was low and phospholipase A2 activity was high. It is thus concluded that A. lixula spermatozoa obtain energy for swimming through oxidation of endogenous TG, whereas P. lividus spermatozoa use PC as a substrate for energy metabolism. This suggests that the system of energy metabolism in spermatozoa is different in the orders Arbacioida and Echinoida. PMID- 29281349 TI - Functional Consequences of Phenotypic Plasticity in Echinoid Larvae. AB - Phenotypic plasticity in feeding structures has been described for several larvae of marine invertebrates, including four species of echinoids. In these echinoids, larvae grown with scarce food grow a longer ciliated band than larvae grown with abundant food. Such phenotypic plasticity may be functionally significant if longer ciliated bands permit higher feeding rates when food is scarce. We replicate an earlier result showing that larvae of a sand dollar, Dendraster excentricus, grow longer ciliated bands in culture with scarce food. We show that these larvae can capture suspended food particles at the tips of longer arms, and that longer ciliated bands result in higher maximum clearance rates. The maximum clearance rate is enhanced by this phenotypic plasticity both early and late in larval life. However, longer ciliated bands did not completely compensate for reduced food supply: larvae grown with scarce food needed more time to complete larval development and metamorphosed into smaller juvenile sand dollars relative to larvae grown with abundant food. PMID- 29281350 TI - Laboratory Studies on Molting and Growth of the Shore Crab, Hemigrapsus sanguineus de Haan, Parasitized by a Rhizocephalan Barnacle. AB - Molting of shore crabs (Hemigrapsus sanguineus) parasitized by rhizocephalans (Sacculina senta) was observed in the laboratory, and the growth of the molted crabs was compared with that of unparasitized animals. Molting of the host was obstructed by the infestation, but was still possible. After the release of several broods of larvae, the externa (the external reproductive system of the parasite) detached from the host. Subsequent molting occurred within 40 days in about 80% of the animals, but in the remainder, it was delayed for at most 4 months. Soon after molting, a new externa protruded from the abdomen of every crab. Thus, the life-span of the externa and the molting of the host would seem to be closely connected. In the female, the molt frequency was reduced, but the molt increment of the parasitized crabs was not different from that in the unparasitized ones. In the male, however, both the molt frequency and the molt increment were reduced. Thus, the annual growth of parasitized males and females was about half that of unparasitized crabs. PMID- 29281351 TI - Microtubule-Based Movements During Ooplasmic Segregation in the Medaka Fish Egg (Oryzias latipes). AB - We used time-lapse video microscopy to monitor the effects of cytochalasin D (CCD) and demecolcine on cytoplasmic streaming toward the animal pole of the medaka egg, the formation of the blastodisc at the animal pole, the movement of oil droplets in the cytoplasm toward the vegetal pole, and the saltatory movement of small cytoplasmic parcels toward the animal pole and vegetal pole. Cytochalasin D inhibited both cytoplasmic streaming toward the animal pole and the formation of the blastodisc, suggesting a role for microfilaments in these processes. However, CCD had no apparent effect on saltatory movement or on the movement of oil droplets toward the vegetal pole. Thus, the segregation of oil droplets toward the vegetal pole is not the result of the bulk movement of ooplasm toward the animal pole. In eggs treated with demecolcine, oil droplets did not move toward the vegetal pole but instead floated to the uppermost portion of the egg, and saltatory movement was absent, suggesting that microtubules are required for these movements. The effects of demecolcine on oil droplet movement and saltatory movement could be reversed by irradiating the eggs with UV light (360 nm). Using indirect immunofluorescence, we showed that irradiation of demecolcine-treated eggs with UV light regenerated microtubules within the irradiated region. The specificity of the mechanism responsible for the vegetal poleward movement of oil droplets was assessed by microinjecting droplets of five other fluids--mineral oil, silicone oil, vegetable oil, and two fluorinated aliphatic compounds--into the ooplasm. None of these fluids segregated with the endogenous oil droplets. These results suggest that a specific mechanism, probably involving microtubules, is responsible for the segregation of oil droplets to the vegetal pole. PMID- 29281352 TI - Expression of the Engrailed Gene Reveals Nine Putative Segment-Anlagen in the Embryonic Pleon of the Freshwater Crayfish Cherax destructor (Crustacea, Malacostraca, Decapoda). AB - Segment formation in the embryonic pleon of the freshwater crayfish Cherax destructor was analyzed by using the monoclonal antibody mAb 4D9 against the product of the segment-polarity gene engrailed. As in other body regions, engrailed is expressed in transverse stripes in the posterior portion of segments in the pleon. Nine engrailed stripes are formed in the pleon. The anterior six stripes correspond to the six pleon segments of adult eumalacostracan crustaceans. The uropods are clearly the appendages of the sixth pleon segment. The seventh engrailed stripe marks the anlage of a seventh ganglion. Stripes eight and nine are transient and disappear before morphogenesis begins. The engrailed stripes seven to nine are interpreted as vestiges of ancestral segments. The seventh segment anlage is thus a recapitulation of the seventh pleonic segment, which is retained in recent adult leptostracans and is considered to be part of the malacostracan ground plan. The stripes eight and nine might point still further back into the phylogeny of crustaceans or even mandibulates. The use of rhodamine-labeled phalloidin reveals that the terminal ganglion of adult crayfish is the fusion product of the anlagen of the sixth and seventh pleonic ganglia and an eighth hemiganglion that is devoid of engrailed expression. PMID- 29281353 TI - Microtubule Arrays During Ooplasmic Segregation in the Medaka Fish Egg (Oryzias latipes). AB - We used indirect immunofluorescence to study microtubule arrays in the medaka egg between fertilization (normalized time, Tn, - 0) and the first cleavage (Tn = 1.0). Eggs were fixed at various times after fertilization and examined with conventional fluorescence microscopy, laser scanning confocal microscopy, and three-dimensional fluorescence microscopy. Soon after the eggs were fertilized (Tn = 0.02), we saw microtubules oriented perpendicular to the plane of the plasma membrane but none parallel to the plasma membrane. Later (Tn = 0.08), we saw an array of microtubules oriented more or less parallel to the plasma membrane but having no apparent preferred orientation with respect to the animal vegetal axis of the egg. In the interpolar regions of the egg, this network increased in density by Tn = 0.24 and remained a constant feature of the ooplasm until the first cleavage. From Tn = 0.30 to 0.76 the polar regions of the egg contained dense arrays of organized microtubules. At the animal pole, microtubules radiated from a site near the pronuclei; while at the vegetal pole, an array of parallel microtubules was present. Injection of the weak (KD = 1.5 {mu}M) calcium buffer 5,5'-dibromo-BAPTA disrupted the radial pattern of microtubules near the animal pole but had no apparent effect on the parallel array of microtubules near the vegetal pole. Because this buffer has previously been shown to suppress a zone of elevated cytosolic calcium at the animal pole and to disrupt ooplasmic segregation in this egg, the results of the present study (1) are consistent with a model in which microtubules are required for ooplasmic segregation in the medaka egg, and (2) suggest that the normal function of a microtubule-organizing center at the animal pole of the egg requires a zone of elevated calcium. PMID- 29281354 TI - The Tidal Rhythm of Emergence, and the Seasonal Variation of This Synchrony, in an Intertidal Midge. AB - The emergence of an intertial midge was investigated at a site on the coast of the Inland Sea of Japan. The population emerging at this site was drawn from a single species of the genus Clunio, probably C. tsushimensis. Emergence was not synchronized with the day-night cycle, but with the tidal cycle. Moreover, the pattern of synchrony changed with season. A bimodal phase appeared in midwinter; but the pattern of synchrony shifted gradually, during January and February, from morning low tides to afternoon low tides, and a unimodal phase appeared in March. This pattern--i.e., synchrony with afternoon low tides--lasted until early October. In mid-October, the synchrony shifted to the morning low tides. Only a brief bimodal phase appeared in autumn. The phase modality was clearly correlated with the height of tides; i.e., when the low waters in a day were very different in height, emergence was synchronized only with the lower one (April to December). During January and February, the higher low tide, as well as the lower low tide, recedes considerably. The exposure of the larval habitat at the higher low tide may stimulate emergence, resulting in bimodal phases in midwinter. But the unimodal pattern in March cannot be accounted for by a simple synchrony with lower low tide, or with exposure of the larval habitat to the air; the day-night cycle not only would be one of the zeitgebers of the tidal rhythm in every season, but also must participate in the expression of the unimodal phase in spring. Furthermore, the number of midges that emerged each day fluctuated with a semilunar cycle with the season. The phase of this rhythm would be shifted by water temperature. PMID- 29281355 TI - The Role of the Cardioregulatory Nerves in Mediating Heart Rate Responses to Locomotion, Reduced Stroke Volume, and Neurohormones in Homarus americanus. AB - Control of decapod crustacean heart activity is believed to be dependent on the regulation of the cardiac ganglion by external input from the central nervous system as well as by circulating neurohormones. This study investigated the roles of these inputs on the heart rates of lobsters exercising on a treadmill. Heart rate increased rapidly at the onset of walking in control animals. This rapid phase was lost after the regulatory nerves were cut, but small increases still occurred. When stroke volume was reduced by cutting alary ligaments, the animals compensated by increasing heart rate; this compensation was lost when the regulatory nerves were cut. In resting animals, injection of serotonin, octopamine, and dopamine induced increases in heart rate. After the regulatory nerves were cut, only dopamine and serotonin injections caused increases in heart rate, suggesting that these amines act on the cardiac ganglion as independent effectors. PMID- 29281356 TI - The Functional Morphology of Starfish Tube Feet: The Role of a Crossed-Fiber Helical Array in Movement. AB - The morphology and mechanics of the tube feet, ampullae, and lateral and radial canals of the water vascular systems of Luidia clathrata and Astropecten articulatus (Echinodermata, Asteroidea) were analyzed. Histological methods, based on embedding in both paraffin and glycol methacrylate, were used to document the arrangement of muscle and connective tissue. The tube foot wall includes longitudinal muscles and connective tissue fibers, the latter arranged in a crossed-fiber helical array, with a fiber angle of about 67{deg} in elongated tube feet. No evidence was found for the circular rings of connective tissue reported in earlier studies; the appearance of rings is probably an artifact of folding. The ampullae are bilobed and include circumferentially arranged muscle fibers and connective tissue fibers aligned 90{deg} to the muscle. The lateral canals are short and equipped with oneway flap valves similar to those described for other echinoderms. The radial canal is thin-walled, nonmuscular, and enclosed in the connective tissue and ossicles of the ambulacrum. Frame-by-frame video analysis of both intact animals and animals with "windows" cut in the arm wall was used to document the movements of the tube feet and ampullae. No evidence was found for the previously suggested role of the radial canal in protracting the tube feet. The ampullae protract the tube feet and antagonize the tube foot musculature. The fiber angle of the connective tissue allows protraction and prevents dilation of the tube feet, and limits elongation of the ampullae. PMID- 29281357 TI - Ammonium Metabolism in the Green Hydra Symbiosis. AB - Inhibitors of enzymes of ammonium assimilation were used to test if assimilation of ammonium in the green hydra-Chlorella symbiosis was due to host or symbionts. Both methionine sulphoximine (MSX, an inhibitor of glutamine synthetase, found in both host and symbionts) and azaserine (AZS, an inhibitor of 2-oxoglutarate amido transferase, not found in the host) inhibited ammonium uptake by the intact symbiosis. MSX was taken up and caused predictable changes in pools of glutamate and glutamine in both freshly isolated symbionts and cultured ex-symbiotic Chlorella. However, after treatment of the intact symbiosis with MSX, no MSX was found in the symbiotic Chlorella, and glutamine and glutamate pools of both host and symbionts were unaffected. Although both MSX and AZS inhibited ammonium uptake by Chlorella, MSX caused seven times as much ammonium release from the intact symbiosis as did AZS. AZS treatment of the intact symbiosis caused an increase in glutamine pools in both host and symbionts, and AZS also competitively inhibited glutamine uptake by Chlorella. Further, ammonium treatment of intact hydra did not affect the nitrogen status of the algal symbionts, although it did cause a small increase in the number of algae in each digestive cell of the host. It is suggested that primary ammonium assimilation in the green hydra symbiosis occurs by means of animal glutamine synthetase, and that the resulting glutamine may be taken up and further processed by the symbiotic algae. Freshly isolated symbionts were able to process glutamine into glutamate even when incubated at low pH, which causes them to release a substantial proportion of fixed carbon as maltose. PMID- 29281358 TI - Odor Plumes and Animal Navigation in Turbulent Water Flow: A Field Study. AB - Turbulence causes chemical stimuli to be highly variable in time and space; hence the study of animal orientation in odor plumes presents a formidable challenge. Through combined chemical and physical measurements, we characterized the transport of attractant released by clam prey in a turbulent aquatic environment. Concurrently, we quantified the locomotory responses of predatory crabs successfully searching for sources of clam attractant. Our results demonstrate that both rheotaxis and chemotaxis are necessary for successful orientation. Perception of chemical cues causes crabs to move in the upstream direction, but feedback from attractant distributions directly regulates movement across-stream in the plume. Orientation mechanisms used by crabs difler from those employed by flying insects, the only other system in which navigation relative to odor plumes has been coupled with fluid dynamics. Insects respond to odors by moving upstream, but they do not use chemical distributions to determine across-stream direction, whereas crabs do. Turbulent eddy diffusivities in crab habitats are 100 to 1000 times lower than those of terrestrial grasslands and forests occupied by insects. Insects must respond to plumes consisting of highly dispersed, tiny filaments or parcels of odor. Crabs rely more heavily on spatial aspects of chemical stimulus distributions because their fluid dynamic environment creates a more stable plume structure, thus permitting chemotaxis. PMID- 29281359 TI - On the Giant Octopus (Octopus giganteus) and the Bermuda Blob: Homage to A. E. Verrill. AB - We have obtained samples of two large carcasses. One washed up on a beach in St. Augustine, Florida, in 1896 and has been occasionally attributed to a species of gigantic octopus (Octopus giganteus). The other carcass washed up on Bermuda in 1988 and has remained unidentified, although its gross morphology, except for a much smaller total mass, was remarkably similar to the Florida carcass. We have subjected both samples to electron microscopic and biochemical analyses. Our results show that both carcasses are masses of virtually pure collagen. Furthermore, neither sample has the biochemical characteristics of invertebrate collagen, nor the collagen fiber arrangement of octopus mantle. Instead, they are large pieces of vertebrate skin, the Bermuda sample from a poikilotherm and the Florida sample from a huge homiotherm. We conclude that there is no evidence to support the existence of Octopus giganteus. PMID- 29281360 TI - Evidence for Selection Against Heterozygotes: Post-Settlement Excess of Allozyme Homozygosity in a Cohort of the Chilean Oyster, Ostrea chilensis Philippi, 1845. AB - Reports of heterozygote deficiencies in electrophoretic surveys carried out in marine bivalves abound in the literature (1-6) but the mechanism or mechanisms producing this phenomenon have not been well defined. We report that, in the Chilean oyster (Ostrea chilensis), heterozygote deficiencies in a cohort obtained by mass spawning in the laboratory are not randomly distributed in time among genotypes. The eggs of the Chilean oyster are internally fertilized, and the larvae, which are brooded within the mantle cavity, have limited dispersal capabilities because of their extremely short pelagic stage (7). These features could allow mechanisms such as inbreeding or Wahlund effect to produce heterozygote deficiencies. However, we observed no significant heterozygote deficiencies in juveniles at 6 months of age; instead allozyme heterozygosity decreased over time. Inbreeding, Wahlund effect, aneuploidy, and null alleles are unlikely to be main causes of the heterozygosity deficiency in this cohort; if they were, the deficiency should be evident from the juvenile stage and would not necessarily increase over time (2, 5, 8, 9, 10). We suggest that selection against heterozygotes is the most probable cause of the increasing degree of heterozygote deficiency with age in this cohort of O. chilensis, a proposition that accords with data for other marine bivalve species (2, 4, 11). PMID- 29281361 TI - Protein-Membrane Interaction Is Essential to Normal Assembly of the Microsporidian Spore Invasion Tube. AB - Changes in the protein-membrane interaction during assembly of the microsporidian spore invasion tubes were followed by electron microscopy, by video imaging with differential interference contrast (DIC), and by the fluorescent probes 4',6 diamidino-2-phenylindole (DAPI) and 9-diethylamino-5H-benzo{alpha}phenoxazine-5 one (Nile red). Microsporidian spore invasion tubes form by the eversion of polar filament protein (PFP) and presumptive extrusion apparatus (EAP) membrane. Both of these components are essential for formation of the invasion tube. The results indicate that the behavior of the EAP membrane is greatly affected by the position and chemical state of the PFP at the eversion area that constitutes the advancing tube terminal assembly site (TAS). Visual evidence indicates that the EAP membrane is the vehicle for PFP and that this membrane also provides the envelope that surrounds the sporoplasm after its passage through the invasion tube. PMID- 29281362 TI - Types of Lamp for Homework and Myopia among Chinese School-Aged Children. AB - PURPOSE: We aim to determine the association of the types of lamp for homework including incandescent lamp, fluorescent lamp, and light-emitting diode (LED) lamp with the prevalence of myopia in Chinese children. METHODS: 2346 grade 7 students from ten middle schools (93.5% response rate) aged 13 to 14 years in Mojiang, a small county located in Southwestern China, participated in the study. Refractive error was measured with cycloplegia using an autorefractor by optometrists or trained technicians. An IOL Master was used to measure ocular biometric parameters including axial length (AL). Information regarding the types of lamp for homework af''ter schools was collected by questionnaires. RESULTS: Of all the study participants, 693 (29.5%) were affected by myopia, with the prevalence estimates being higher in girls (36.8%; 95% confidence interval [CI]: 34.0, 39.6) than in boys (22.8%; 95% CI: 20.4, 25.1) (P < 0.001). After adjusting for potential confounders such as gender, height, parental history of myopia, time on computer use, time on watching TV, time outdoors, and time on reading and writing, participants using LED lamps for homework had a more myopic refractive error and a longer AL compared with those using incandescent or fluorescent lamps. There were no significant differences in myopia prevalence between children using incandescent and fluorescent lamps for homework. The population attributable risk percentage for myopia associated with using LED lamps for homework after schools was 11.2%. CONCLUSIONS: Using LED lamps for homework after schools might contribute to the development of myopia among school-aged children. PMID- 29281363 TI - Regenerate Limb Bud Sufficient for Claw Reversal in Adult Snapping Shrimps. AB - The paired, bilaterally asymmetric snapper and pincer claws in the adult snapping shrimp Alpheus heterochelis were simultaneously autotomized at the beginning of an intermolt, and the resulting growth of the limb buds was characterized into several stages. At the next molt the limb buds emerged as newly regenerated claws of the same morphotype as their predecessors. Next, the paired claws were autotomized sequentially, with the second autotomy timed to different stages of limb bud growth at the first autotomy site. When the snapper is autotomized and a limb bud varying from stages 1 to 5 is allowed to develop at this site before the pincer is removed, the paired claws regenerate in their previous configuration. Similarly, claw asymmetry is retained when the pincer claw is removed first and an early limb bud (stage 1-2) is allowed to form at this site before the snapper is autotomized. However, claw asymmetry is reversed if an advanced limb bud (stage 3-5) is allowed to form at the pincer site before the snapper claw is removed. Under these conditions a snapper regenerates at the pincer site and a pincer at the snapper site. Because the limb bud at this pincer site regenerates as a snapper rather than a pincer, claw transformation has occurred, with the stage 3-5 limb bud substituting for an intact pincer. Therefore, the minimal requirement for pincer-to-snapper transformation is a stage 3-5 limb bud. We postulate that the newly transforming snapper claw restricts regeneration at the contralateral old snapper site to a pincer, thereby ensuring that claw bilateral asymmetry is present, albeit reversed. PMID- 29281364 TI - The Effects of Sperm Concentration, Sperm:Egg Ratio, and Gamete Age on Fertilization Success in Crown-of-Thorns Starfish (Acanthaster planci) in the Laboratory. AB - Laboratory experiments varying gamete concentrations and gamete age demonstrated significant reductions in fertilization success of the starfish Acanthaster planci (L.) with decreasing sperm concentration and increasing age of both eggs and sperm. The effect of aging in sperm was faster than that of eggs, and the speed of sperm aging increased with increasing dilution of sperm. Fertilization success was high over a wide range of sperm: egg ratios but declined rapidly at ratios less than 50, particularly at low sperm concentrations. A. planci gametes aged more slowly, and the loss of fertilizing capacity of sperm with dilution (the respiratory dilution effect) was far less, than in sea urchins. These characteristics provide a mechanism for enhanced fertilization success at given sperm concentrations and at greater distances and times from the point of gamete release, and may explain the higher fertilization rates achieved over longer distances in the wild by A. planci relative to sea urchins. Gametes would remain competent for longer periods at more dilute concentrations and so better achieve long-distance fertilization. Gametes obtained at the end of the breeding season were qualitatively different from those obtained early in the breeding season and showed reduced fertilization success for a given combination of variables, and different fertilization dynamics. PMID- 29281365 TI - Small-Scale Dispersion of Eggs and Sperm of the Crown-of-Thorns Starfish (Acanthaster planci) in a Shallow Coral Reef Habitat. AB - The dispersal of eggs and sperm of crown-of-thorns starfish, Acanthaster planci (L.), was measured in the field using an array of collectors up to 10 m downstream of a spawning starfish. Hydrodynamic measurements, gamete dispersal numerical models, and the gamete cloud dispersal measurements for the first time quantified the relationship between hydrodynamic conditions and the dispersion of eggs and sperm in the field. In general, gamete concentrations fell rapidly and logarithmically with distance from the spawning starfish; egg concentrations at 3 m were 1% of those near the starfish. Simplified dispersal models showed a good correspondence with these field data, and confirmed the observation that eggs rose higher in the water column and spread more laterally at low current speeds over the short spatial scales being considered. Fertilization rates, predicted from laboratory measurements of fertilization success and the gamete concentrations measured in the field, were estimated to be 90-100% within 1 m and 70-100% at 10 m. These results are explained by high success rates of fertilization (fertilizing capacity) at the measured dilutions, and were similar to fertilization rates previously measured by others for crown-of-thorns starfish in the field. Although the eggs were observed to spread upwards into the water column due to turbulence, laboratory measurements of sinking rates showed eggs to be very slightly negatively buoyant (median fall velocity of 0.072 mm.s-1), whereas sperm were neutrally buoyant. A significant fraction of eggs also entered the seabed near the starfish; the proportion decreased with increasing current strength. This process may provide a mechanism for enhanced fertilization of these gametes and/or a mechanism for self-recruitment to a given reef population. PMID- 29281366 TI - A Portable, Discrete-Sampling Submersible Plankton Pump and Its Use in Sampling Starfish Eggs. AB - The apparatus was designed to enable divers to obtain discrete replicate samples from known volumes of water. Relatively large volumes of water can be filtered without the need to maintain contact with or return to the surface. These attributes confer a high degree of flexibility in subsurface sampling situations. Although we used the equipment to sample the eggs of invertebrates, it could equally easily be used to sample other small, patchily distributed plankton. PMID- 29281367 TI - Morphogen-Based Chemical Flypaper for Agaricia humilis Coral Larvae. AB - Larvae of the scleractinian coral Agaricia humilis settle and metamorphose in response to chemosensory recognition of a morphogen on the surfaces of Hydrolithon boergesenii and certain other crustose coralline red algae. The requirement of the larva for this inducer apparently helps to determine the spatial pattern of recruitment in the natural environment. Previous research showed that the inducer is associated with the insoluble cell wall fraction of the recruiting algae or their microbial epibionts, and that a soluble but unstable fragment of the inducing molecule can be liberated by limited hydrolysis, either with alkali or with enzymes specific for cell wall polysaccharides. We now show that the parent morphogen can be solubilized by gentle decalcification of the algal cell walls with the chelators EGTA or EDTA, suggesting that the morphogen may be a component of the calcified recruiting alga itself, rather than a product of any noncalcified microbial epibionts. The solubilized inducer is subsequently purified by hydrophobic-interaction and DEAE chromatography. The purified, amphipathic morphogen retains activity when tightly bound to beads of a hydrophobic-interaction chromatography resin, and this activity (tested with laboratory-reared larvae) is identical in the ocean and the laboratory. We have attached the purified, resin-bound inducer to surfaces coated with a silicone adhesive and thus produced a potent artificial recruiting substratum--i.e., a morphogen-based chemical "flypaper" for A. humilis larvae. This material should prove useful in resolving the role of chemosensory recognition of morphogens in the control of substratum-specific settlement, metamorphosis, and recruitment and in the maintenance of species isolation mechanisms in the natural environment. PMID- 29281368 TI - Algal Symbiosis in Bunodeopsis: Sea Anemones with "Auxiliary" Structures. AB - This study describes the photobiology of two tropical species of the symbiotic sea anemone genus Bunodeopsis from Discovery Bay, Jamaica, B. antilliensis was found in shallow water (0.3m) and experienced higher irradiance levels than B. globulifera from deeper water (3 m). Both species contained symbiotic dinoflagellates of the genus Symbiodinium within the endodermal cells. The external morphology and expansion-contraction behavior of the two anemone species were closely linked to symbiont distribution. B. antilliensis had large vesicles (2.6 mm3), with 88.5% of the symbiont population in the lower column and basal disk and 11.5% in the tentacles and upper column, and was contracted under normal daylight illumination. In contrast, B. globulifera had small vesicles (0.2 mm3), with 55.5% of the symbionts in the lower column and basal disk and 44.5% in the tentacles and upper column, and was expanded under illumination. The photosynthetic physiology of the symbionts indicated that those from B. globulifera were adapted to lower host habitat irradiances than were those from B. antilliensis. The symbionts from B. globulifera had a significantly higher chlorophyll a content (7.34 +/- 0.77 pg.cell-1) and photosynthetic efficiency (0.24 MUgO2.106 cells.h-1/MUmol photons.m-2.s-1) and lower saturation irradiance (277 +/- 18 MUmol photons.m-2.s-1) than those from B. antilliensis, 4.51 +/- 0.29 pg.cell-1, 0.17 MUgO2.106 cells. h-1/MUmol photons.m-2.s-1 and 436 +/- 78 MUmol photons.m-2.s-1, respectively. The calculated rate of carbon translocation in both species of Bunodeopsis (97%) was high and reflected the low algal protein biomass ratios (2%) and population growth rates (<0.1.day-1). The CZAR values in B. antilliensis (109%) and B. globulifera (92%) suggest that both species are potentially autotrophic with respect to carbon available for animal respiration. PMID- 29281369 TI - Neurophysiological Correlates of the Behavioral Response to Light in the Sea Anemone Anthopleura elegantissima. AB - Neurophysiological responses to light in Anthopleura elegantissima do not involve the ectodermal slow system 1 (SS1). Activities in both the endodermal slow system 2 (SS2) and the through conducting nerve net (TCNN) change when the lighting changes, but the response is not consistent. Thus, photoreception in A. elegantissima probably occurs in the endoderm because SS2 and the TCNN are involved and SS1 is not. We hypothesize either that the photoreception occurs in sensory cells in a local nerve net, with the information then being transmitted to the muscles, or that the muscles themselves are light sensitive. In either case, the TCNN and SS2 become involved after the transduction, and as a consequence--rather than the cause--of muscular activation. The conducting systems of zooxanthellate specimens have a higher frequency of activity than those of apozooxanthellate individuals. PMID- 29281370 TI - Changes Occur in the Central Nervous System of the Nudibranch Berghia verrucicornis (Mollusca, Opisthobranchia) During Metamorphosis. AB - The structure of the larval and juvenile central nervous system (CNS) in Berghia verrucicornis, an aeolid nudibranch, was examined using 1-{mu}m serial sections. The CNS consists of paired optic, cerebral, pleural (also known as sub- and supra intestinal ganglia), pedal, and buccal ganglia, and a single visceral ganglion. A pleurovisceral loop is present. The organization of the CNS changes as the nudibranch undergoes metamorphosis. In general, there is a condensation of the CNS. The cerebral and pleural ganglia fuse to form the prominent cerebropleural ganglia. The single visceral ganglion fuses with the pleural portion of the left cerebropleural ganglion. The buccal ganglia enlarge and fully organize into a cortex of nerve cell bodies and medulla of nerve fibers. Rhinophoral ganglia develop anterior to each cerebropleural ganglion and a pair of nervous processes extend from each: one to the developing rhinophore and the other anteroventral toward the mouth and associated structures. These metamorphic changes are similar to those seen in other commonly studied opisthobranch species, suggesting that Berghia verrucicornis is an appropriate model for the developmental examination of structure and function in molluscan nervous systems. PMID- 29281371 TI - Energetics of the Ventilatory Piston Pump of the Lugworm, a Deposit-feeding Polychaete Living in a Burrow. AB - The aim of this study was to tentatively estimate the energy cost of breathing in the lugworm, Arenicola marina (L.), a gallery-dwelling, piston-pump breather that moves water in a tail-to-head direction. Each tested lugworm was placed in a horizontal glass tube. The caudal end of the tube was connected to a well-aerated seawater reservoir at 20{deg}C, and the cephalic end attached to a drop meter through a tube resistance. At the exit of the cephalic chamber the O2 tension was recorded via an in situ O2 electrode, and the hydrostatic pressure of the exhaled water was also recorded. Water flow rate, total O2 uptake rate {Mdot}TOTO2, O2 extraction coefficient, and the mechanical power necessary to pump water through the resistive anterior exit of the apparatus ({Wdot}MEC), were computed. The basal metabolic rate of each animal ({Mdot}CONFO2) was separately estimated by the confinement method. {Mdot}CONFO2 subtracted from {Mdot}TOTO2 approximates {Mdot}CBO2, the O2 uptake rate necessary to activate the piston-pump breathing mechanism and to ensure the corresponding mechanical work rate, {Wdot}MEC. The results show that the energy cost of breathing, {Mdot}CBO2, of the piston-pump breathing Arenicola is very high, with mean values approximating 47% of the {Mdot}TOTO2 value; that the mechanical power we measured, {Wdot}MEC, is very low; and that the mechanical-to-metabolic efficiency, the ratio {Wdot}MEC/{Mdot}CBO2, does not exceed 1%. These observations are compared to those obtained in other piston-pump breathers, such as Chaetopterus variopedatus and Urechis caupo, and in ciliary filter feeders including polychaetes, bivalves, and ascidians. PMID- 29281372 TI - In Vivo Studies of Suspension-Feeding Processes in the Eastern Oyster, Crassostrea virginica (Gmelin). AB - Suspension-feeding processes in the eastern oyster Crassostrea virginica (Gmelin, 1791) were examined, in vivo, with an endoscope linked to a video image-analysis system. We found that many of the previously published concepts of particle transport and processing in this species, obtained using surgically altered specimens or isolated organs, are incomplete or inaccurate. In particular, our observations demonstrate that (1) captured particles are transported along the gills by both mucociliary (marginal grooves) and hydrodynamic (basal tracts) processes; (2) the labial palps accept material from the gills both in mucus bound particle strings (transported in marginal grooves), and suspended in particle slurries (transported in basal tracts); (3) the labial palps reduce the cohesive integrity of the mucous strings and disperse and sort the entrapped particles; (4) particles are ingested in the form of a slurry; and (5) ciliary activity on the labial palps is independent of that on the lips, allowing the oyster to filter particles from suspension and produce pseudofeces without ingesting any particulate matter. Because many ostreids have the same plicate gill structure, we believe that our conclusions are applicable to other oyster species. In addition, the present observations are consistent with other endoscopic examinations recently made on bivalves in different families. We conclude that accepted theories of particle handling in suspension-feeding bivalve mollusks must be modified to accommodate observations made with the endoscope. PMID- 29281374 TI - Analysis of Acid Volatile Sulfide and Metals to Predict the Toxicity of Boston Harbor Sediments. PMID- 29281373 TI - Localization of the Chloroperoxidase of the Capitellid Polychaete Notomastus lobatus. AB - Antisera against the two constituent proteins of the chloroperoxidase enzyme of the capitellid polychaete Notomastus lobatus were used to identify and localize these polypeptides by immunoblotting and indirect immunofluorescence. Immunofluorescence staining showed the enzyme to be localized primarily in tissues of the tail region of the worm. Some reactivity was also observed in the epidermis of the mid-body, but none was seen in the head region. These immunofluorescence results were supported by immunoblotting experiments, which also showed that chloroperoxidase holoenzyme is localized in the tail. Immunological results were substantiated by the distribution of enzyme activity and the in vivo products of the chloroperoxidase, 4-bromophenol, 2,4 dibromophenol, and 2,4,6-tribromophenol. Chloroperoxidase is the principal enzyme involved in the production of bromoaromatics in N. lobatus. Localization of most of this enzyme in the tail region explains the detection of high levels of bromophenols in the tail, the most exposed portion of this head-down, deposit feeding worm. This pattern of bromoaromatic distribution is consistent with the hypothesis that the worms produce these compounds as defensive chemicals against epifaunal predators. PMID- 29281375 TI - Transmitter-Specific Subsets of Sensory Elements in the Prosobranch Osphradium. AB - The osphradium is a putative chemosensory organ of aquatic molluscs. Previously, we identified two distinct types of primary sensory neurons in the osphradial ganglion of freshwater pulmonates, one immunoreactive to leucine-enkephalin (LEnk ir) and another to FMRFamide (FMRFa-ir). In addition, NADPH diaphorase (NADPHd) positive elements apparently producing nitric oxide (NO) were demonstrated in the organ. In the present study, prosobranch molluscs, which have retained the osphradial sensory neurons within the epithelium, were studied. Both types of peptidergic neurons, as well as NADPHd-positive cells, were found within the epithelium or in a basiepithelial position in the relatively simple osphradium of the mesogastropod Littorina littorea and in the complex, bipectinate osphradium of the neogastropod Buccinum undatum. Similar evidence was also obtained for another mesogastropod, Ampullarius sp. Transmitter-specific sensory cell types like those discovered in the osphradium are also present as single neuroepithelial cells in other organs of the mantle complex in prosobranchs and in the pelecypod Anodonta cygnea. We suggest that evolutionarily conservative, transmitter-specific types of epithelial and neuroepithelial sensory cells predated the osphradium, which developed as the site of their concentration, while retaining characteristic subsets of sensory neurons. PMID- 29281376 TI - Homeoviscous Properties Implicated by the Interactive Effects of Pressure and Temperature on the Hydrothermal Vent Crab Bythograea thermydron. AB - Specimens of the hydrothermal vent crab Bythograea thermydron, collected from 13 degrees N on the East Pacific Rise, were exposed to pressures greater than those in their natural habitat over a range of temperatures to assess how increased hydrostatic pressure affects a species that requires high pressure to survive. We measured heart beat frequency and contraction waveform at pressures ranging from 28 MPa (normal environmental pressure for this species) to 62 MPa at 5 degrees , 10 degrees , and 20 degrees C. At 5 degrees C, increased hydrostatic pressure induced bradycardia or acardia in conjunction with marked disruption of the ventricular contraction waveform. The animals did not survive following decompression. The effects of increased pressure were less pronounced at 10 degrees C and almost negligible at 20 degrees C. Our results support previous findings at subambient pressures which suggest that the lipid bilayers of cell and organelle membranes are the primary sites affected by short-term pressure variation in deep-sea organisms. We also found evidence of an adaptive mechanism of pressure temperature interaction in these animals from the eurythermic habitat of the hydrothermal vents. PMID- 29281377 TI - Rate of Denitrification in Submerged Salt Marsh Sediments. PMID- 29281378 TI - Comparison of Phytoplankton and Ecosystem Gross Production in the Quashnet River, an Estuary of Waquoit Bay, Massachusetts. PMID- 29281379 TI - A Metamorphic Inducer in the Opisthobranch Haminaea callidegenita: Partial Purification and Biological Activity. AB - Larvae of Haminaea callidegenita (Mollusca: Cephalaspidea) were induced to metamorphose by a compound found in the gelatinous matrix composing most of the egg mass. A functionally similar compound isolated from adult tissue also induced metamorphosis in H. callidegenita larvae. Opisthobranchs are frequently induced to metamorphose by a specific prey item or a substrate characteristic of the adult habitat, but this is the first known instance of metamorphosis occurring in response to a compound produced by adult conspecifics. The inducer was purified from egg mass jelly (EMJ) by high pressure liquid chromatography (HPLC) and was found to be smaller than 1000 Da, polar, non-proteinaceous, and very stable. We isolated a compound of identical activity from egg masses produced by four other opisthobranch species, suggesting that the same or chemically similar compounds are intrinsic to opisthobranch egg masses. However, only H. callidegenita larvae metamorphosed in response to EMJ. Competent larvae of five other mollusc species did not respond to the partially purified EMJ inducer but did respond to a specific substrate associated with each species. The presence of the inducer within the egg mass causes an unusual developmental pattern in H. callidegenita, a poecilogonous species that produces both swimming veliger and crawling juvenile offspring. PMID- 29281380 TI - The Effects of Coupling Between the Oxic and Anoxic Layers of Sediment on Nutrient Release to Overlying Water. PMID- 29281381 TI - Locomotion in Developing Artemia Larvae: Mechanical Analysis of Antennal Propulsors Based on Large-Scale Physical Models. AB - A physical model of the swimming appendage (second antenna) of a larval Artemia was oscillated and translated through a tank of glycerine to determine how such a shape may be used to generate thrust at the intermediate Reynolds numbers at which it operates. Force on the model was measured by strain gauges and used to calculate coefficients of drag at a series of speeds and frequencies that represented flow regimes of different larval stages. Measured coefficients of drag (Cd) over this Reynolds number range ({approx}1-10) suggest that an expression for a cylinder perpendicular to flow at intermediate Reynolds number (Cd = 1 + 10 Re-2/3) best represents the changes in drag coefficients for this geometry. Unsteady forces were found to be a negligible portion of the force on the model in spite of a high ratio of frequency of oscillation to forward translational velocity (i.e., Strouhal number). Comparison of the thrust generated by the model with its fan of setae rigidly fixed versus passively flexing suggests that passive extension of setae can be influenced by relative limb and body speed. PMID- 29281383 TI - The Effect of Nutrient Loading on the Growth Rate of Two Species of Bivalves, Mercenaria mercenaria and Mya arenaria, in Estuaries of Waquoit Bay, Massachusetts. PMID- 29281382 TI - A Model of Rowing Propulsion and the Ontogeny of Locomotion in Artemia Larvae. AB - Newly hatched Artemia larvae use one pair of limbs to locomote. During development they gradually add additional limbs along the elongating trunk. As larvae grow, body length increases from about 0.4 mm to 4 mm, mean swimming speed increases from 1.8 mm s-1 to 9.9 mm s-1, and frequency of antennal beat decreases from 9.5 to 6.7 Hz. As new limbs are added, they become active in the metachronal rhythm of pre-existing limbs. The body velocity oscillates as early larvae swim; later larvae swim without a cyclic acceleration and deceleration of the body. The change in the pattern of swimming is correlated with the addition of propulsors and a transition in the relative importance of viscous and inertial effects that determine the propulsion in subsequent stages. Reynolds number (based on body length) increases from 2 to 37. A theoretical analysis of rowing propulsion at these intermediate Reynolds numbers shows that initial development of new limbs in Artemia larvae is unimportant for propulsion. Rowing propulsion at the low Reynolds numbers is drag-based; as Reynolds number increases, inertial effects become more important, and unsteady forces on the body become significant in the balance between limb and body. A glide of the body develops at the end of the powerstroke, and relative limb velocity changes. PMID- 29281384 TI - Long-Term Changes of Macroinfaunal Assemblages in Experimentally Enriched Salt Marsh Tidal Creeks. PMID- 29281385 TI - The Effects of Wind Speed and Direction on Stratification and Phytoplankton Production in an Estuary of Waquoit Bay, Massachusetts. PMID- 29281386 TI - Effects of Algal Biomass on Benthic Nitrogen Flux in Nutrient-Loaded Estuaries of Waquoit Bay, Massachusetts. PMID- 29281388 TI - Dissolved Organic Nitrogen in Groundwater Bordering Estuaries of Waquoit Bay, Massachusetts: Relations with Watershed Landscape Mosaics. PMID- 29281387 TI - Daily Variation in Phytoplankton Production in Two Subestuaries of Waquoit Bay, Massachusetts. PMID- 29281389 TI - The Growth and Consumption of Macroalgae in Estuaries: The Role of Invertebrate Grazers Along a Nutrient Gradient in Waquoit Bay, Massachusetts. PMID- 29281390 TI - The Effect of Coastal Land Use on Inorganic Nutrient Concentrations in Groundwater Entering Estuaries of Waquoit Bay, Massachusetts. PMID- 29281391 TI - From Watershed to Estuary: Assessment of Nutrient Loading, Retention, and Export from the Ipswich River Basin. PMID- 29281392 TI - Reproductive Potential and Genetics of Triploid Pacific Oysters, Crassostrea gigas (Thunberg). AB - The reproductive potential and genetics of triploidy were studied in the Pacific oyster. DNA content in sperm from triploids showed a single peak at 1.5c as determined by flow cytometry. In eggs from triploids, trivalents were the dominant form of synapsed chromosomes, although the degree of synapsis varied considerably within and among females. Some eggs went through complete synapsis and formed 10 trivalents, chromosomes; most had a mixture of 11-13 trivalents, bivalents, and univalents. Factorial matings were produced from diploid (D) and triploid (T) parent oysters, creating four crosses: DD, DT, TD, and TT (female first). Gametes from triploids were fully capable of fertilization. After fertilization, eggs from triploids went through two meioses and released two polar bodies as diploid eggs did. Karyological analyses showed that average ploidy of the resultant embryos was 2.0 n for DD, 2.46 n for DT, 2.52 n for TD, and 2.88 n for TT. Survival of fertilized eggs to metamorphosis and settlement was about 21% for DD, but considerably lower on other crosses: 0.0007% for DT, 0.0463% for TD, and 0.0085% for TT. Nine months after matings, all survivors from DT crosses were diploid. Survivors from TD crosses consisted of 33% diploids, 57% triploids, and 10% tetraploids. Survivors from the TT crosses consisted of 90% triploids, 4% diploids, and 6% mosaics. We hypothesize that differences in ploidy composition between DT and TD embryos and survivors were caused by pro-egg segregations that favor the retention, rather than loss, of extra chromosomes in the egg. The reproductive potential of triploids and evolutionary implications are discussed. PMID- 29281393 TI - Effects of Flow and Seston Availability on Scope for Growth of Benthic Suspension Feeding Invertebrates from the Gulf of Maine. AB - Metridium senile, the frilled sea anemone, and Modiolus modiolus, the northern horse mussel, are important members of benthic suspension-feeding assemblages at several rocky hard-bottom subtidal (30-35 m) sites in the Gulf of Maine. Measurements of food availability, rates of food capture, absorption efficiencies, and standard metabolic costs show that inshore populations of Metridium senile have a significantly lower scope for growth than offshore populations, despite higher mean concentrations of particulate organic matter inshore. Similar measurements and calculations for Modiolus modiolus reveal the opposite pattern. These differences persisted at both of these sites during two summers, 1989 and 1990, when differences in mean temperature were not physiologically significant. Thus temperature is precluded as the primary effect on metabolism and growth. We suggest that these physiological differences reflect a response to flow regime and food availability that appears to be manifested differently for Metridium senile and for Modiolus modiolus, a passive and an active suspension feeder, respectively. Results from a reciprocal transplant experiment, to measure growth rates, carried out over a one-year period support the calculated scope for growth during the season when maximum growth rates would be expected. The flux of seston appears to be an important factor affecting the organismal performance of the passive suspension feeder (M. senile), whereas the concentration of seston is more important for the active suspension feeder (M. modiolus). PMID- 29281394 TI - Dispersal Strategies of the Biota on an Oceanic Seamount: Implications for Ecology and Biogeography. AB - Cobb Seamount lies at 46{deg} 46'N, 130{deg} 48'W in the northeast Pacific 510 km due west of the Oregon coast. The isolated seamount rises 3000 m in a current field flowing from west to east. The seamount supports dense populations of fish and benthos. Collections and submersible observations of the benthic community produced a list of 117 species representing 13 phyla. The organisms present can nearly all be found on the North American Pacific coast, but the diversity is low. This paper presents an analysis of the larval dispersal modes of the benthos at Cobb Seamount. This remote seamount is dominated by species with either a short-lived or no planktonic larval phase. The preponderance of such larval strategies and the observation of abundant drifting kelp near the seamount suggest that rafting of adults may be an effective dispersal mode. The presence of a recirculating flow in the form of a modified Taylor cap appears important for trapping short-lived larvae on the seamount. However, because the water mass is replaced about every 17 days, medium and long-lived larvae would not be retained. The interplay between local currents, available dispersal vectors, and life-history strategies cannot be overlooked in the interpretation of marine biogeographic patterns. PMID- 29281395 TI - Patterns of Distribution of Two Barnacle Species on the Mangrove Crab, Scylla serrata. AB - Two lepadomorph barnacle species, Octolasmis angulata and O. cor, were commonly found living together in the branchial chambers of the mangrove crab, Scylla serrata. Patterns of distribution are a reflection of cyprid choice at crab ecdysis. Among the 6648 barnacles observed, there were roughly twice as many O. cor as O. angulata (3670 to 1758). The remaining barnacles were indistinguishable as to species and included 1014 immatures, 168 cyprids, and 38 peduncles. The spatial distributions of both O. angulata and O. cor on the gills of Scylla serrata are nonrandom, uneven, and do not reflect available surface area. Both species are distributed differently on the hypobranchial (inside) and epibranchial (outside) surfaces of the gills. Both species are distributed differently on the gills of immature (<70 mm carapace width) and mature (>70 mm) crabs. Our data also show that the distribution patterns vary with different densities. Support is presented for the hypothesis that current flow through the gill chamber may be an important factor influencing site selection by cyprids. PMID- 29281396 TI - An Ethogram of Body Patterning Behavior in the Squid Loligo vulgaris reynaudii on Spawning Grounds in South Africa. AB - Squids are capable of a high degree of visual signaling, most of which is expressed through the neurally controlled chromatophore organs in the skin. An accurate catalog (or ethogram) of these signals is an essential prerequisite to quantified behavioral analyses and experimentation. Body patterns such as those described here may also be useful for distinguishing between morphologically identical species or subspecies of commercial importance. The natural behavior of Loligo vulgaris reynaudii on spawning grounds was filmed by divers, and the body patterning repertoire was described in detail; 23 chromatic components, 4 postural components, and 9 locomotor components of body patterning were observed and correlated with different types of behaviors. Most of the chromatic components were expressed during intraspecific behaviors (e.g., agonistic behavior among males, courtship, mating) and, to a lesser extent, during interspecific interactions with fishes. Several of the most basic types of body patterns are described, the most distinctive of which are Lateral Display and White Flashing used between males in agonistic contests. This species is comparable to other Loligo spp. in its complexity of body patterning behavior. PMID- 29281397 TI - Nest-Site Selection in the Horseshoe Crab, Limulus polyphemus. AB - Like a number of other species, horseshoe crabs lay their eggs on beaches in the intertidal zone. The elevation of the beach on which they nest differs among populations. We examined two factors that potentially affect egg survival at different beach elevations: erosion and rate of development. We found no evidence that eggs buried at different elevations incur different risks of erosion by wave action. However, the optimal beach elevation for egg development differed between our two study sites, Florida and Delaware, and the difference was related to beach morphology. Rate of development increased with oxygen concentration, redox potential, and temperature, and all three of these factors changed with elevation. The nests in the lower beach failed to develop, especially in Florida, where the beach was fine-grained and poorly drained. The nests in the upper beach were prone to dessication, especially in Delaware, where the beach was course grained and well-drained. This means that differencces between sites in the optimal location for egg development coincided with horseshoe crab preferences in nestsite selection. We suggest that horseshoe crabs synchronize their nesting with the tides that reach the aerobic sediments on the beach, resulting in nesting patterns that differ with differences in tidal regimes and beach morphology. PMID- 29281398 TI - Subunit Composition and O2 Binding of the Crustacean Hemocyanins: Interspecific Relationships. AB - The monomeric subunit composition and oxygen binding properties of hemocyanins were examined in 9 taxonomic groups of 43 crustacean species and 1 hybrid. In native polyacrylamide electrophoresis the banding pattern was highly species specific, even in closely related congeners. In less closely related taxa, there was little apparent relationship between phylogenetic affinity and banding pattern. Within a taxonomic group, pH dependence was the most highly conserved and O2 affinity was the most diverse of the O2 binding properties investigated. In congeneric but not sibling species, O2 affinity was more highly correlated with an environmental variable such as temperature than with phylogenetic affinity. Only in very closely related groups found in similar environments were different O2 binding properties correlated with differences in particular electrophoretic bands. PMID- 29281399 TI - Energy Metabolism and Amino Acid Transport During Early Development of Antarctic and Temperate Echinoderms. AB - The rates of oxygen consumption by embryos of antarctic echinoderms (Acodontaster hodgsoni, Odontaster validus, Psilaster charcoti, and Sterechinus neumayeri) were compared to the biomas (ash-free dry organic weight) of the egg of each species. These species could survive for months to years (range: 10 months to 5 years) by relying solely on the reserves present in the egg. However, certain species did not use any of the egg's reserves during early development. Embryonic stages of O. validus (a species with planktotrophic larvae) did not decrease in lipid, protein, or total biomass during the first 35 days of development. During the first 42 days of development, embryos of A. hodgsoni (a species with lecithotrophic development) used protein as an energy source. For both species lipid composed 40 to 50% of egg biomass, but was not used as an energy reserve. Larvae of O. validus have a high-affinity transport system for amino acids dissolved in seawater (K1 = 1.3 {mu}M for alanine). The rate of alanine transport from a low concentration (50 nM) could supply 32% of the larva's metabolic needs. This is a 10-fold higher input to metabolism than was determined (3% at 50 nM) for larvae of a temperate asteroid, Asterina miniata. Larvae of antarctic echinoderms live in an environment where the food supply is low for most of the year. Relative to their metabolic rates, antarctic larvae have larger energy stores and planktotrophic larvae have higher nutrient transport capacities when compared to larvae from temperate regions. These physiological differences allow antarctic larvae to survive for long periods without particulate food. PMID- 29281400 TI - Temperature and the Larval Ecology of the Crown-of-Thorns Starfish, Acanthaster planci. AB - The recently reported dramatic population increases (outbreaks) of the coral eating crown-of-thorns starfish, Acanthaster planci, which have damaged many reefs in the Indo-Pacific, are ending (1), but questions remain about the factors that affect Acanthaster distribution and densities. For example, the narrow temperature tolerance (26 degrees or 27 degrees to 30 degrees or 31 degrees C) reported for Acanthaster's larval development (2) is problematic because Acanthaster occurs where temperatures do not rise into this range (3, 4). We have further examined some temperature relationships in Acanthaster's early development. Cleavage proceeded normally over a range of about 10 degrees C but specific limiting temperatures depended upon the geographic source of the parents or their recent history of temperature exposure. Hatched, swimming gastrulae continued normal development to bipinnaria throughout a temperature range of 13 degrees C. These results indicate that the narrow developmental temperature tolerances reported earlier for Acanthaster do not apply to all early developmental stages, and they add to the list of larval adaptations that can facilitate dispersal of Acanthaster larvae and propagation of outbreaks. PMID- 29281401 TI - Tailoring the Preparticipation Exam to Female Athletes. AB - In brief Although most of the preparticipation examination is similar for male and female patients, physicians can focus certain aspects of the exam to address female athletes' specific concerns. Menstrual dysfunction and disordered eating are two major potential problems, but other disorders, such as patellofemoral pain, are also more common in women and girls than in men and boys. PMID- 29281402 TI - pearls. PMID- 29281404 TI - Gentle Steps Toward Healthy Feet. PMID- 29281403 TI - forum. PMID- 29281405 TI - Casting Off Seasickness. PMID- 29281406 TI - Getting Patients to Protect Their Eyes During Sports. AB - Statistics and especially photographs can prove to patients that serious eye injuries can occur during a leisurely game of racquetball and even tennis. But getting players to actually wear certified polycarbonate eye guards can be challenging. Here are a few strategies to show patients that eye protection is essential to the game. PMID- 29281407 TI - scanning sports. PMID- 29281408 TI - Physical Therapy in Health Clubs. AB - As more and more health clubs establish physical therapy centers, many physicians may wonder whether the service does more than just expand club membership: Can patients get quality care in such trendy settings? By knowing the pros and cons of these centers, physicians can help patients get the most for their rehab dollar. PMID- 29281409 TI - nutrition and fitnessBreakfast Is for Champions. PMID- 29281410 TI - Can Older Be Better? AB - The Olympians in their 30s and even their 40s who are competing in Barcelona this month challenge conventional wisdom about the effects of aging on athletic performance. With recreational as well as elite athletes, aging itself may not be the main obstacle to long-term performance. Scheduling sufficient training time becomes increasingly difficult, as does recovering from injuries. PMID- 29281411 TI - Quadriceps Contusions. AB - In brief Quadriceps contusions can frustrate athletes, because the time away from athletic activity is variable and unpredictable. The determining factor in returning the patient to play safely is whether the patient has regained 120 degrees or more of knee flexion. Immobilization for the first 24 hours in 120 degrees of knee flexion- which preserves the needed flexion and minimizes intramuscular bleeding and spasms- accomplishes this goal quickly. Muscle stimulation and stretching also help the athlete recover quickly. PMID- 29281414 TI - QuikQuiz. PMID- 29281413 TI - Does Your Wolff-Parkinson-White Patient Need to Slow Down? AB - In brief Two healthy young athletes, a 22-year-old college football player and a 31-year-old elite runner, were evaluated for paroxysmal tachycardia. The football player's resting ECG showed the short PR interval and delta wave characteristic of Wolff-Parkinson-White syndrome. Electrophysiologic studies were required to diagnose accessory-pathway conduction in the runner. The high incidence of tachyarrhythmias seen among people who have this preexcitation syndrome makes detection essential. When such arrhythmias cannot be controlled with drug therapy, catheter ablation helps. PMID- 29281415 TI - Managing Toenail Trauma. AB - In brief Acute subungual hematoma or seroma of an active patient's toenail results from direct trauma or repetitive shear force to the nail apparatus. Though painful, the condition is usually benign. Accurate diagnosis of underlying nail bed injury or distal phalanx abnormality is needed for appropriate treatment and to prevent nail plate deformity. Evacuating the fluid quickly alleviates pain, allowing athletes to resume their activities. PMID- 29281416 TI - Women in Sports. PMID- 29281417 TI - Perfecting a Playing Cast for Hand and Wrist Injuries. AB - In brief In 21 years of treating patients who had hand and wrist injuries by using silicone rubber playing casts, clinicians have found that these casts effectively protect athletes during competition. The authors describe a straightforward method of fabricating a silicone rubber cast that allows athletes to return to play quickly. In a survey of 148 high school football players, athletes reported that the cast was safe and functional. PMID- 29281418 TI - Immediate Care of Facial Trauma. AB - In brief Most sports-related injuries to brief the face are minor, including simple lacerations, contusions, and lost teeth. Some maxillofacial injuries, however- such as facial fractures- can be severe and complicated, requiring quick action. Early diagnosis and treatment of soft tissue and bony injuries expedite healing and minimize scarring and disfigurement. Immediate injury management usually consists of such emergency steps as controlling the bleeding. PMID- 29281419 TI - Electro-spun Membranes as Scaffolds for Human Corneal Endothelial Cells. AB - BACKGROUND: Corneal endothelial dysfunction remains the most frequent indication for corneal transplantation, limited by donor material shortage, poor long-term graft survival, or allogeneic graft rejection. Therefore, tissue-engineered endothelial grafts (TEEG) represent a promising alternative to human donor tissue. In this study, we generated electro-spun scaffolds and tested these for their suitability for human corneal endothelial cell (hCEC) cultivation. METHODS: The polymers poly(methyl-methacrylate) (PMMA), poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL) were spun with equal parameters. HCEC-12 was cultured on the scaffolds for 3 to 7 days. Scaffolds were evaluated by light microscopy, porometry, light transmission, scanning electron microscopy (SEM), live/dead staining and cell viability assay. RESULTS: Electro-spun fibers from PMMA (2.99 +/- 0.24 um) showed significantly higher diameters than PCL (2.29 +/- 0.11 um; p = 0.003) and PLGA (1.84 +/- 0.21 um; p < 0.001), while fibers from PCL also showed larger diameters than those from PLGA (p = 0.002). PMMA scaffolds (26.77 +/- 17.48 um) had significantly larger interstitial spaces than those from PCL (13.30 +/- 5.47 um; p = 0.04) and PLGA (10.42 +/- 6.15 um; p = 0.002), while PCL and PLGA did not differ significantly (p = 0.26). SEM analysis revealed that only PLGA fibers preserved a normal HCEC-12 morphology. PLGA and PCL did not differ in cell number, death, or viability after 7 days of HCEC-12 cultivation. PMMA showed significantly higher cytotoxicity (p < 0.001; PLGA: 1626.2 +/- 183.8 RLU; PMMA: 841.9 +/- 92.7 RLU; PCL: 1580.2 +/- 171.02 RLU). CONCLUSIONS: The biodegradable PLGA and PCL electro-spun scaffolds resulted in equal biocompatibility, while PMMA showed cytotoxicity. Only PLGA preserved hCEC morphology and consequently seems to be a promising candidate for TEEG construction. PMID- 29281421 TI - The Interaction of Photoperiod and Temperature in Diapause Timing: A Copepod Example. AB - In many organisms, photoperiod and temperature are thought to be the most significant token cues for seasonally timed life history events, including diapause in arthropods. A common pattern in many species of terrestrial insects and several copepod species is the existence of a critical daylength on one side of which the animals do not enter diapause and on the other side of which they do. Temperature plays a secondary role as modifier of the critical daylength. In some species, however, including the freshwater copepod Diaptomus sanguineus, the fraction of females making subitaneous eggs (eggs that hatch immediately) undergoes a very gradual transition as daylength changes over the natural range of photoperiods experienced in nature. Here we show that temperature is as important as photoperiod in cuing diapause timing in a population of D. sanguineus living in Bullhead Pond, Rhode Island. When ecologically relevant photoperiod and temperature cues are provided in the laboratory, the copepods rapidly switch from producing subitaneous eggs to producing diapausing eggs in a way that is typical of the seasonal switch seen in the pond. We provide a graphical model that illustrates how copepod sensitivities to photoperiod and temperature interact to produce an abrupt transition, and we discuss how natural selection should act on D. sanguineus diapause response to produce the variation in diapause timing seen within and between natural populations. PMID- 29281420 TI - Procedural discourse performance in adults with severe traumatic brain injury at 3 and 6 months post injury. AB - BACKGROUND: There is limited research on communicative recovery during the early stages after a severe traumatic brain injury (TBI) in adults. METHODS AND PROCEDURES: In the current study 43 people with severe TBI described a simple procedure at 3 and 6 months post injury and this was compared to the description provided by 37 healthy speakers. Linguistic productivity and the presence of macrostructural discourse elements were analysed. MAIN OUTCOMES AND RESULTS: No change occurred in productivity in the TBI group between the two time points. There was increased use of relevant information (macrostructure) over time for the TBI group, reflecting improvement. People with TBI differed from controls in speech rate and in two out of three macrostructural categories at both time points, indicating difficulties even after 12 weeks of recovery. CONCLUSIONS: Overall, the quality, rather than the quantity of discourse was disordered for participants with TBI. Findings indicate that procedural discourse is sensitive to discourse deficits of people with TBI and can be used to map recovery during the sub-acute phase. PMID- 29281422 TI - Process-Specific Recruitment Cues in Marine Sedimentary Systems. AB - In marine sediments, many of the processes associated with high post-settlement mortality of infauna have similar effects on the sediment surface. In most cases the original sediment surface is either removed, buried, or mixed with subsurface sediment. The experiments reported here tested the ability of new juvenile infauna to discriminate between undisturbed and recently disturbed sediment surfaces (i.e., subsurface sediment exposed). Recently settled juveniles of two polychaete species (Nereis vexillosa and Arenicola cristata) and one bivalve species (Mercenaria mercenaria) were exposed to simulated erosional and mixing events as well as to fresh feces, burrow tailings, and feeding tracks. Where the disturbance buried or removed several millimeters of the sediment surface, the time to initiate burrowing or the percentage of individuals failing to burrow increased significantly over times and percentages for juveniles on undisturbed surfaces. In all cases the results were consistent with the hypothesis that new juveniles reject (or are significantly slower to burrow into) disturbed sediment surfaces, if the disturbance is less than several hours old. For example, 51% of nereid juveniles did not burrow when placed on subsurface sediments, whereas 100% burrowed into surface sediments; their average burrowing time on surface sediments was 29.3 s compared with 109.7 s on fecal mounds of arenicolid polychaetes or 106.1 s on burrow tailings of thalassinid crustaceans. Individuals that did not indicate acceptance of a sediment surface by burrowing were all rapidly eroded from the surface in the presence of flow. Erosion of nonburrowing individuals occurred within 90 s of initiation of flow. Burrowing individuals were not eroded. The decision as to the acceptability of a sediment was made within 30 s. These data imply that the new juveniles are utilizing cues associated with a process, the disturbance of surface sediments, in addition to the species-specific cues described elsewhere. PMID- 29281423 TI - Functional Significance of Varices in the Muricid Gastropod Ceratostoma foliatum. AB - Functional significance of varices in the muricid gastropod Ceratostoma foliatum was investigated from the standpoints of (1) frequency of landing in the two upside-down orientations after short vertical falls of less than five body lengths through seawater and energy costs of righting from these upside-down positions, and (2) scaling relationships of varix areas with other body dimensions. Field manipulations showed that C. foliatum occupied habitats that mostly permit short falls of less than five body lengths upon dislodgment, as might occur during predation by fish. After short vertical falls in the laboratory, animals landed 48% of the time on their aperture sides (upright), 15% on their right sides (on right and middle varices), and 37% on their left sides (on left and middle varices). These frequencies differed significantly from the expected frequencies calculated on the basis of the percentage circumference delineated by each varix pair (50%, 31%, and 19%, respectively). Righting from the right-side orientation was slower and four times more energetically costly than from the left-side orientation, underscoring the advantage conferred by animals, if not landing in the upright position after short falls, preferentially landing on their left sides. Removal of individual varices showed that the large, right varix is most influential in producing this "destabilization." Landings are biased to the side from which rightings are easiest due to a combination of the location of center of mass within the left side of the main body whorl and the broad right varix possibly acting as an upward-trailing vane. Morphometric relationships of shell length, live weight, varix areas, aperture dimensions, and labial spine (tooth) length were investigated over a wide range of body sizes in an attempt to infer varix function. Aperture area scaled allometrically with length. Right-, middle-, and left-varix areas also grew relatively larger as the animals increased in length. In contrast, combined varix areas around the aperture increased in direct proportion with aperture area, forming a broad shelf surrounding the aperture. We infer from this that, in addition to their effects on landing orientation from both long and short vertical falls, the varices of C. foliatum may function to protect the aperture, and thus protect the soft body parts that protrude from it during feeding and locomotion. PMID- 29281424 TI - Fine Structure of Spermatozoa of the Hagfish Eptatretus burgeri (Agnatha)1. AB - Live motile spermatozoa of the hagfish Eptatretus burgeri were obtained for the first time, and their fine structure was examined. The spermatozoon is characterized by an extremely long midpiece. Two of the four midpiece mitochondria are extensively elongated and extend through almost the entire length of the tail. The acrosome contains electron-dense and less dense materials in two different compartments. Amorphous subacrosomal material lies between the acrosome and the nucleus. No distinct perforatorium rod or filamentous structure was observed within the subacrosomal material. Two centrioles lie almost end to end in the nuclear fossa near the posterior end of the nucleus. The structure of the acrosomal complex in the hagfish, which is quite different from that in the lamprey, was compared to that of other chordates with respect to its function in sperm-egg interaction and phylogeny. PMID- 29281425 TI - Oxidase Activity Associated with the Elevation of the Penaeoid Shrimp Hatching Envelope. AB - When penaeoid shrimp spawn into seawater, the ova elevate a hatching envelope (HE) within 30-50 min. By 60 min after spawning, the bilayered HE is completely formed. In other animal systems, peroxidatic enzymes are responsible for the hardening of the extra-embryonic coat. In this study, observations are made consistent with the involvement of an oxidase in the assembly of the shrimp HE. As observed by electron microscopy, eggs of Sicyonia ingentis and Trachypenaeus similis spawned in seawaters containing peroxidase inhibitors had abnormally assembled HEs compared to control eggs in seawater. Dihydrotetramethylrosamine, an oxidase-sensitive fluorescent dye, supravitally stained the cortex of S. ingentis eggs at the time of initial HE formation. The HE fluoresced from elevation (40-50 min postspawn in S. ingentis) until 60-70 min postspawn. By first cleavage (90-120 min postspawn), HE staining was no longer visible, although staining persisted in the egg cortex. In eggs treated with the peroxidase inhibitors 3-amino-1,2,4-triazole or sodium sulfite, the egg cortex fluoresced, but no fluorescence appeared in the HE before, during, or after its elevation. PMID- 29281426 TI - Sensitivity of Metabolic Rate, Growth, and Fecundity of Tadpole Shrimp Triops longicaudatus to Environmental Variation. AB - The influence of fluctuations of ambient oxygen tensions and temperature on the rate of oxygen consumption (VO2) was determined for the tadpole shrimp, Triops longicaudatus. VO2 was oxygen dependent up to 185 torr PO2, and Q10 for oxygen consumption between 20 degrees and 30 degrees C was 1.9. From these results it was estimated that oxygen consumption increases more than 1100 MUl . g-1 . h-1 in T. longicaudatus for typical diurnal changes in temperature and oxygen in desert ephemeral pools. Elevated VO2 may be coupled with increased growth rate and fecundity, because these characteristics were highly sensitive to changes in ambient temperature and oxygen tension. Depressing mean daily temperatures by 2.3 degrees C significantly decreased body mass, whereas hyperoxia (200 torr) significantly increased growth compared to that of animals raised under hypoxic conditions (70 torr). Fecundity was dependent on animal mass and ambient oxygen tension. Thus, for a 22-day season, one T. longicaudatus female could produce 30 more eggs per 10 torr increase in oxygen tension and 43 more eggs per 1 degrees C change in mean daily temperature. These results indicate that there are selective pressures for metabolic sensitivity to the high temperature-high oxygen conditions of the ephemeral environments inhabited by T. longicaudatus. PMID- 29281427 TI - Microfilament Contraction Promotes Rounding of Tunic Slices: An Integumentary Defense System in the Colonial Ascidian Aplidium yamazii. AB - In Aplidium yamazii, when a slice of a live colony (approximately 0.5 mm thick) was incubated in seawater for 12 h, the slice became a round tunic fragment. This tunic rounding was inhibited by freezing of the slices, incubation with Ca2+-Mg2+ -free seawater, or addition of cytochalasin B. Staining of microfilaments in the slices with phalloidin-FITC showed the existence of a cellular network in the tunic. Contraction of this cellular network probably promotes rounding of the tunic slice. In electron microscopic observations, a new tunic cuticle regenerated at the surface of the round tunic fragments; the tunic cuticle did not regenerate in newly sliced specimens nor in specimens in which rounding was experimentally inhibited. Based on these results, an integumentary defense system is proposed in this species as follows. (1) When the colony is wounded externally, contraction of the cellular network promotes tunic contraction around the wound. (2) The wound is almost closed by tunic contraction. (3) Tunic contraction increases the density of the filamentous components of the tunic at the wound, and it may accelerate the regeneration of tunic cuticle there. PMID- 29281428 TI - QuikQuiz. PMID- 29281430 TI - Eating Right With Type II Diabetes. PMID- 29281429 TI - Diagnosing Shoulder Pain. AB - In brief When examining an athlete who has acute or chronic shoulder pain, the initial diagnostic imaging method should be plain film radiography. This technique identifies most fractures, dislocations, calcific deposits, and degenerative processes. Other common shoulder disorders may be more readily diagnosed with different techniques, including bone scan, arthrogram, MRI, computed arthrotomogram, or CT. PMID- 29281431 TI - Feet Under Force. AB - In brief Foot sprains and strains are as varied as the sports that produce them, and these injuries affect athletes at all competitive levels- even the weekend warrior. An understanding of how the foot's structures respond to trauma and of how to best elicit information through the physical exam can help a physician pinpoint the injury And determining injury severity can help focus the level of treatment needed for a sure-footed return to activity. PMID- 29281432 TI - Better Screening Without Higher Costs. PMID- 29281434 TI - Scanning sports. PMID- 29281433 TI - Treating Athletes Who Have Posttraumatic Headaches. AB - In brief Many sports injuries involve head trauma and subsequent posttraumatic headache. Three types of posttraumatic headache occur: migraine, cluster, and tension-type. Each type may be acute or chronic. Diagnosis requires ruling out organic causes and neurologic abnormalities. Treatment includes abortive and prophylactic therapies. PMID- 29281435 TI - Ruling Out Danger. AB - In brief Thoracic pain can stem from a variety of causes, some serious, some less so. In active patients, the source is usually musculoskeletal, originating from the spine, ribs, sternum, or anterior shoulder, but cardiac and other visceral pathology must be ruled out. A systematic approach to obtaining a detailed description of the patient's pain and making an exact anatomic diagnosis can help the clinician institute the most effective treatment. PMID- 29281436 TI - Severe Sports-Related Spleen Injury. AB - In brief Most minor spleen injuries can be managed conservatively, but severe splenic ruptures often require operative treatment. In this case report, however, a young football player who severely injured his spleen was able to recover nonoperatively because he was hemodynamically stable. His case highlights issues of diagnosis, injury classification, and treatment options, as well as when to return an athlete to play. PMID- 29281437 TI - When Wrestlers Slim to Win. AB - In brief High school wrestlers often select a weight class below their normal weight without considering how much weight they can safely lose. Body composition assessments provide objective estimates of minimum weight for competition. However, even if athletes follow medically accepted guidelines for minimum weight, losing weight may still affect their health and performance. Using a variety of techniques, primary care physicians can determine and interpret minimum weight estimates for young wrestlers and offer advice on safe weight loss. PMID- 29281438 TI - Preventing Sudden Death. AB - In brief Identifying all athletes at risk for exercise-related sudden death is difficult because reliable screening is expensive. And even if a perfect screening method existed, a very large number of athletes would need to be tested to find one at risk. Unfortunately, a standard history and physical exam do not readily identify the forms of congenital heart disease that can lead to exercise related sudden death. However, a history designed to identify symptomatic athletes and those with a family history of congenital heart disease may be the most practical screening method. PMID- 29281440 TI - Tips for Better Breathing. PMID- 29281441 TI - Forum. PMID- 29281439 TI - Emergencies in sports. PMID- 29281442 TI - Achilles Tendon Ruptures. AB - Despite the well-publicized injuries of US Olympics sprinter Mark Witherspoon and Atlanta Hawks star Dominique Wilkins, an Achilles tendon rupture is rare. But when it does occur-usually among middle-aged recreational athletes-the injury is sometimes misdiagnosed. A thorough history and physical exam will point physicians to the right diagnosis. PMID- 29281444 TI - Reducing Dislocations on the Field. AB - When an athlete dislocates a joint on the field, the team physician must decide whether to reduce the dislocation immediately or after x-rays. Several factors, including the physician's level of experience, point physicians to the appropriate choice. PMID- 29281447 TI - Scanning Sports. PMID- 29281445 TI - Pearls. PMID- 29281448 TI - Burning Calories-Naturally. PMID- 29281449 TI - QuikQuiz. PMID- 29281450 TI - Patellofemoral Pain. AB - In brief Prevalent but difficult to pin down, patellofemoral syndrome has long been a source of fascination and puzzlement. Approaching patellofemoral syndrome as merely a descriptive term encompassing a differential diagnosis allows for less empiric therapy. A thorough examination involving a history, physical, and judicious use of diagnostic imaging will elucidate most causes. Conservative treatment involving rest, stretching, strengthening, and pain relief will benefit most patients. PMID- 29281451 TI - Athletes With Disabilities. AB - In brief For the most part, active people who are disabled require medical care for typical sports-related cuts, sprains, and strains. However, disability related conditions such as bladder problems or pressure sores require specialized management to make activity safe. PMID- 29281452 TI - Relieving the Pain of Shin Splints. PMID- 29281453 TI - Are You Spoiling the Picnic? PMID- 29281454 TI - Penetrating Trauma. AB - In brief Three case studies describe potentially life-threatening injuries associated with javelin throwing. Although overuse, biomechanical, or stress related musculoskeletal disorders are more typical of javelin-related injuries, serious penetrating wounds do occur. Observing safety precautions can help prevent javelin impalement; careful on-field management can help contain those injuries that do occur. PMID- 29281455 TI - Have You Seen It All? PMID- 29281456 TI - Snuffing Out Smokeless Tobacco Use. AB - Major League Baseball's ban on players and staff using any type of tobacco during minor league games may provide physicians with a timely excuse to discuss smokeless tobacco with young patients. Chewing and dipping remain a significant health problem, especially among young men. Some athletes even associate smokeless tobacco with winning- a misconception that physicians can help eliminate. PMID- 29281457 TI - Pearls. PMID- 29281458 TI - Relieving Shoulder Pain Without Surgery. AB - In brief Active patients of all ages often experience shoulder pain, and a physical exam and radiographs may help detect an injury or a degenerative cause. Though the problems vary, a trial of nonsurgical management is generally the first line of treatment, which can include nonsteroidal anti-inflammatory drugs, corticosteriod injections, physical therapy, and rest. PMID- 29281459 TI - Palpitations With Exercise. PMID- 29281460 TI - Forum. PMID- 29281461 TI - Reliability of postural measures in elite badminton players using Posture Pro 8. AB - The Posture Pro software is used for photogrammetry assessment of posture and has been commercially available for several years. Along with symmetry-related measures, a Posture Number(r) is calculated to reflect the sum of postural deviations. Our aim was to investigate the intra- and inter-rater reliability of measures extracted using the Posture Pro 8 software without using reference markers on subjects. Four raters assessed the standing posture of 40 badminton players (20 males, 20 females) from anterior, lateral, and posterior photographs. Thirty-three postural measures were extracted using visual landmarks as guide. Reliability was quantified using intra-class correlation coefficient (ICC) and typical error of measurement (TEM). Overall, the intra-rater reliability was considered good to excellent for nearly all measures. However, only two measures had excellent inter-rater reliability, with 13 and 18 measures exhibiting good and fair inter-rater reliability, respectively. Posture Pro specific measures (n = 9) exhibited good-to-excellent intra-rater and fair-to-excellent inter-rater reliability, with small-to-moderate and small-to-large TEM, respectively. Overall, the Posture Pro 8 software can be considered a reliable tool for assessing a range of posture-relevant measures from photographs, particularly when performed by the same examiner. The Posture Number(r) demonstrated generally acceptable intra- and inter-rater reliability. Nonetheless, investigations on the validity, sensitivity, and interpretation of this measure are essential to confirm its clinical relevance. PMID- 29281462 TI - letters. PMID- 29281463 TI - scanning sports. PMID- 29281464 TI - sportspages. PMID- 29281465 TI - Riding the Wind in a Silent Sport. PMID- 29281466 TI - Temple Clinic: Good Care for All Athletes. PMID- 29281467 TI - Tony C. Comes Back on a Swing and a Prayer. PMID- 29281468 TI - Are High School Athletes Getting Good Health Care? PMID- 29281469 TI - Expand Your Mind, Shrink Your Waistline. PMID- 29281470 TI - Does Biking Cause Impotence? PMID- 29281471 TI - The Hazards of Exercising at Altitude. PMID- 29281472 TI - On the Sidelines. PMID- 29281473 TI - Keep Fit, Stretch the Rules. PMID- 29281474 TI - Minimizing the Hazards of Heat. PMID- 29281475 TI - Round Table: Balancing Heat Stress, Fluids, and Electrolytes. PMID- 29281476 TI - What Exercise to Prescribe for the Post-MI Patient. PMID- 29281477 TI - Psychiatrists Diagnosing the President - Moral Imperative or Ethical Violation? PMID- 29281478 TI - Assessment of Treatment Patterns for Metastatic Renal Cell Carcinoma in Brazil. AB - BACKGROUND: Although multiple therapies have emerged for the treatment of metastatic renal cell carcinoma (mRCC), it is unclear whether application of these agents is consistent in developed and developing countries. We sought to determine patterns of care for mRCC in Brazil as a representative developing country. MATERIAL AND METHODS: A commercial database was used to acquire information pertaining to patients with mRCC receiving treatment at private or public hospitals in Brazil between March 2013 and October 2016. Basic clinical and demographic criteria were available, as well as information to ascertain the International Metastatic Renal Cell Carcinoma Database Consortium risk. Treatment related data across multiple lines of therapy were collected. RESULTS: Of 4,379 patients assessed, 3,990 (91%) had metastatic disease, and 26%, 48%, and 26% of patients had good, intermediate, and poor International Metastatic Renal Cell Carcinoma Database Consortium risk disease, respectively. Although 3,149 patients (79%) received first-line therapy, only 641 (20%) and 152 (5%) received second- and third-line therapy, respectively. In the first-line setting, vascular endothelial growth factor-directed agents represented the most commonly used therapy, whereas in the second-line setting, vascular endothelial growth factor- and mammalian target of rapamycin-directed agents were used with similar frequency. Marked differences were seen in receipt of systemic therapy on the basis of treatment in private or public hospitals. CONCLUSION: Relative to developed countries, marked attrition is noted between each subsequent line of therapy in Brazil. Patterns of care also vary greatly in private and public settings, pointing to financial constraints as a potential cause for discordances in treatment. PMID- 29281481 TI - The True Nature of Herbs. PMID- 29281479 TI - Abscopal effect of radiation on bone metastases of breast cancer: A case report. AB - The abscopal effect is defined as the clearance of distant tumors after applying localized irradiation to a particular tumor site. It has been proposed that a mechanism for the abscopal effect might be the activation of the immune system, which leads to immunogenic tumor cell death. Here, we describe a woman with advanced breast cancer that received modified ablative radiation therapy that targeted her primary breast tumor. She experienced an apparent regression of metastatic mass in the thoracic spine. This case supported the hypothesis that the abscopal effect might be attributable to an activation of the systemic immune response. PMID- 29281482 TI - Managing Spondylolysis. AB - In brief Though spondylolysis is a possibility When a patient presents with acute low-back pain, the condition may not be apparent despite careful physical exam and radiographic studies. In this case of a competitive 13-year-old female athlete who had recurring lumbosacral pain, symptoms did not resolve with a trial of activity restriction and flexion exercises. After radiographs and a technetium bone scan detected subtle stress fractures, better results were obtained by immobilizing the region with an orthosis. For patients whose symptoms don't resolve with immobilization, surgery may be needed. PMID- 29281480 TI - Improved salt removal and power generation in a cascade of two hydraulically connected up-flow microbial desalination cells. AB - A novel two chamber up-flow microbial desalination cell (UMDC) was designed for evaluating desalination of real seawater with simultaneous wastewater treatment and energy generation. Two UMDCs were hydraulically connected in continuous flow mode (cascade mode) and operated at ten different hydraulic retention times (HRTs) [120 h to 12 h] and salt retention times (SRTs) [40 h to 4 h] for improved performance of chemical oxygen demand (COD) and salt removal. These UMDCs were operated at different combinations of high power (higher external resistance) and high current (low external resistance) mode to find the most suitable conditions for obtaining higher COD removal, salt removal, power production and current generation. The optimum HRT and SRT were 60 h and 40 h, respectively. The highest salt removal achieved was 72% at SRT of 40, while the highest COD removal was 83% at a HRT of 60 h. A maximum current density of 2.375 A/m2 was obtained, while the maximum power density was 5.879 W/m2. The obtained results give an overlook for the scale up of UMDCs in the future. In the entire system, membrane fouling is still a major problem. As the operation time increases, this resulted in low power generation and low salt removal efficiency. The UMDCs can function as sustainable and alternative solution for real wastewater treatment and seawater desalination with resource recovery and power production. PMID- 29281483 TI - The Telltale Heart. PMID- 29281484 TI - Chest Pain and Arrhythmia With Exercise. PMID- 29281485 TI - Anterior Shoulder Dislocations. AB - In brief The clinical diagnosis of anterior shoulder dislocations can be made by evaluating the mechanism of injury and noting limited arm adduction and shoulder rotation. In addition, the shoulder loses its normal rounded contour, and the acromion is unusually prominent. Prereduction x-rays are not always necessary but will confirm the clinical diagnosis. Reduction of the dislocation should be performed as quickly, gently, and safely as possible. Linear force via a self reduction technique or a simple, passive traction technique will lead to a successful reduction in the vast majority of patients. PMID- 29281489 TI - CME Self Test. PMID- 29281486 TI - Patella Dislocation. AB - In brief Whenever a patient has a patella dislocation, osteochondral fractures should be considered. A case study involving a 17-year-old swimmer whose knee was injured playing baseball details a patella dislocation that was accompanied by a defect of the medial patellar facet and a lateral impaction lesion of the lateral femoral gutter-both producing loose bodies. Careful physical examination and a radiographic series that includes anteroposterior, lateral, notch, and sunrise patella views assist in making an accurate diagnosis and guide the clinician to the appropriate treatment. Treatment involves a knee stabilizer followed by aggressive quadriceps strengthening. Loose bodies require arthroscopic surgery. PMID- 29281490 TI - Forum. PMID- 29281491 TI - Weighted Workouts. PMID- 29281492 TI - 'Flesh-Eating Bacteria'? PMID- 29281493 TI - Pneumothorax. AB - In brief A pneumothorax can accompany high-energy trauma, penetrating injury, or nonpenetrating impact, and spontaneous pneumothorax is common. No matter what the cause of the pneumothorax, however, rapid diagnosis is of utmost importance because this injury is a true on-field medical emergency. The key to expedient diagnosis is proper recognition of chest pain, dyspnea, and other telltale signs and symptoms. Auscultation and x-rays are usually required for a definitive diagnosis. Prompt treatment can help save the patient's life and includes maintaining the airway and monitoring vital signs. Often, tube thoracostomy is required to completely resolve the injury. PMID- 29281494 TI - Asymptomatic Aortic Insufficiency in a Runner. AB - In brief The case of an asymptomatic 21-year-old male college sprinter demonstrates that aortic insufficiency may go undiagnosed despite severe underlying cardiac pathology: A murmur detected during the preparticipation exam was the first sign. Activity modification was an important initial intervention. Echocardiography documented severe aortic regurgitation. An exercise multiple gated acquisition (MUGA) scan identified abnormal ejection fractions. After valve replacement, the patient's return to competition was guided by echocardiography, exercise testing, and input of the medical team and family. PMID- 29281495 TI - Pearls. PMID- 29281496 TI - Study of the occurrence and ecosystem danger of selected endocrine disruptors in the urban water cycle of the city of Bogota, Colombia. AB - Endocrine disruptors have been studied for their high occurrence in different environments including aquatic; however, in the context of developing countries, their occurrence, magnitude and potential threat have little information. This study involved the analysis of various components of the urban water cycle in the city of Bogota, Colombia. As a result, it was found that the compounds with the highest occurrence are plasticizers such as phthalates and bisphenol A, whereas among the drugs, carbamazepine presented the highest concentrations (0.68-31.45 ug L-1); the analysis of the threat coefficient (HQ) showed the importance of bis(2-ethylhexyl) phthalate (BEHP) and estrone (E1) that can reach surface waters from domestic and industrial discharges. PMID- 29281497 TI - Poly-Drug Use of Prescription Medicine among People with Opioid Use Disorder in China: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Opioid use disorder (OUD) causes substantial public health and social problems worldwide. Poly-drug use is common in people with OUD and increases morbidity and mortality. Investigation of the patterns and characteristics of poly-drug use of prescription medicine among opioid users is needed to develop appropriate prevention and intervention strategies. OBJECTIVES: To estimate the prevalence of poly-drug use of prescription medicine among people with OUD in China using meta-analysis. METHODS: We searched relevant epidemiological studies published before February 2017 in English and Chinese databases. The quality of included studies was assessed using the Agency for Healthcare Research and Quality scale. The pooled prevalences of prescription medicine use among people with OUD were estimated. RESULTS: We included 80 eligible studies in the meta analysis. The main prescription medicines were benzodiazepines (BZDs) and prescription opioid analgesics. The pooled prevalence of unclassified BZDs and prescription opioids was 40.6% and 23.2%, respectively. Diazepam was the most frequently co-used BZD (32.6%), followed by triazolam (32.1%), and estazolam (9.2%). Tramadol was the most commonly used prescription opioid (27.3%), followed by methadone (16.8%), buprenorphine (12.6%), pethidine (8.9%), morphine (6.5%), dihydroetorphine (3.9%), and codeine-containing cough syrup (3.7%). BZDs were mainly used for self-medication (56.1%), whereas prescription opioids were primarily coused for nonmedical purposes (69.4%). CONCLUSIONS: The results demonstrate that prescription medicine use is widespread among opioid users in China. There needs to be more consideration of poly-drug use, and early interventions and management strategies are needed to prevent poly-drug use among opioid users in China. PMID- 29281498 TI - Continuous and Quantitative Purification of T-Cell Subsets for Cell Therapy Manufacturing Using Magnetic Ratcheting Cytometry. AB - T-cell-based immunotherapies represent a growing medical paradigm that has the potential to revolutionize contemporary cancer treatments. However, manufacturing bottlenecks related to the enrichment of therapeutically optimal T-cell subpopulations from leukopak samples impede scale-up and scale-out efforts. This is mainly attributed to the challenges that current cell purification platforms face in balancing the quantitative sorting capacity needed to isolate specific T cell subsets with the scalability to meet manufacturing throughputs. In this work, we report a continuous-flow, quantitative cell enrichment platform based on a technique known as ratcheting cytometry that can perform complex, multicomponent purification targeting various subpopulations of magnetically labeled T cells directly from apheresis or peripheral blood mononuclear cell (PBMC) samples. The integrated ratcheting cytometry instrument and cartridge demonstrated enrichment of T cells directly from concentrated apheresis samples with a 97% purity and an 85% recovery of magnetically tagged cells. Magnetic sorting of different T-cell subpopulations was also accomplished on chip by multiplexing cell surface targets onto particles with differing magnetic strengths. We believe that ratcheting cytometry's quantitative capacity and throughput scalability represents an excellent technology candidate to alleviate cell therapy manufacturing bottlenecks. PMID- 29281499 TI - Associations between the combined physical activity environment, socioeconomic status, and obesity: a cross-sectional study. AB - AIMS: This study investigates associations between the combined physical activity environment and obesity and explores any sub-group effects by individual-level socioeconomic status. METHODS: In a large cross-sectional cohort ( n = 22,889) from the Yorkshire Health Study, body mass index was calculated using self reported height and weight and obesity was defined as a body mass index >= 30. The physical activity environment was split into 'unfavourable physical activity', 'moderately favourable physical activity' and 'favourable physical activity' environments. This was based on the count of parks and physical activity facilities within a 2 km radial buffer centred on home addresses. A favourable physical activity environment was defined as having >=1 physical activity facility and >=1 park, unfavourable as having no physical activity facility and park and any other combinations defined as moderately favourable. Logistic regression (odds ratios) identified associations with obesity. RESULTS: Relative to 'unfavourable physical activity environments', individuals within favourable physical activity environments were less likely to be obese (odds ratio = 0.90; 95% confidence interval = 0.82-0.97), and there was no effect for moderately favourable environment. Furthermore, once stratified by education level, this relationship was only present for those of higher education. CONCLUSION: Our findings provide novel UK evidence and is one of the first papers internationally that highlights the importance of considering the interplay of individual-level socioeconomic factors when investigating associations between the physical activity environment and obesity. PMID- 29281500 TI - Oxidation of azo and anthraquinonic dyes by peroxymonosulphate activated by UV light. AB - The photochemical degradation of two azo and two anthraquinonic dyes was performed using potassium peroxymonosulphate (Oxone(r)) activated by UV radiation. The fast decolourization of all dyes was observed within 6 min of UV irradiation, with corresponding dye decays higher than 80%. The kinetic rate constants of the dyes' decay were determined, along with the energetic efficiency of the photochemical treatment, taking into account the influence of a few anions commonly present in real wastewaters (i.e., chloride, nitrate, carbonate/bicarbonate and phosphate ions). Chloride and carbonate/bicarbonate ions enhanced dye degradation, whereas phosphate ions exerted an inhibitory effect, and nitrates did not have a predictable influence. The dye decolourization was not associated with efficient mineralization, as suggested by the lack of a significant total organic carbon (TOC) decrease, as well as by the low concentrations of a few detected low molecular weight by-products, including nitrate ions, formaldehyde and organic acids. High molecular weight by-products were also detected by mass spectrometry analysis. The investigated process may be proposed as a convenient pre-treatment to help dye degradation in wastewater during combined treatment methods. PMID- 29281502 TI - Corrigendum. PMID- 29281501 TI - Estimation of Cadmium uptake by tobacco plants from laboratory leaching tests. AB - The objective of the present study was to determine the impact of cadmium (Cd) concentration in the soil on its uptake by tobacco plants, and to compare the ability of diverse extraction procedures for determining Cd bioavailability and predicting soil-to-plant transfer and Cd plant concentrations. The pseudo-total digestion procedure, modified Tessier sequential extraction and six standard single-extraction tests for estimation of metal mobility and bioavailability were used for the leaching of Cd from a native soil, as well as samples artificially contaminated over a wide range of Cd concentrations. The results of various leaching tests were compared between each other, as well as with the amounts of Cd taken up by tobacco plants in pot experiments. In the native soil sample, most of the Cd was found in fractions not readily available under natural conditions, but with increasing pollution level, Cd amounts in readily available forms increased. With increasing concentrations of Cd in the soil, the quantity of pollutant taken up in tobacco also increased, while the transfer factor (TF) decreased. Linear and non-linear empirical models were developed for predicting the uptake of Cd by tobacco plants based on the results of selected leaching tests. The non-linear equations for ISO 14870 (diethylenetriaminepentaacetic acid extraction - DTPA), ISO/TS 21268-2 (CaCl2 leaching procedure), US EPA 1311 (toxicity characteristic leaching procedure - TCLP) single step extractions, and the sum of the first two fractions of the sequential extraction, exhibited the best correlation with the experimentally determined concentrations of Cd in plants over the entire range of pollutant concentrations. This approach can improve and facilitate the assessment of human exposure to Cd by tobacco smoking, but may also have wider applicability in predicting soil-to-plant transfer. PMID- 29281503 TI - Impact of metal ionic characteristics on adsorption potential of Ficus carica leaves using QSPR modeling. AB - The present study describes Quantitative Structure Property Relationship (QSPR) modeling to relate metal ions characteristics with adsorption potential of Ficus carica leaves for 13 selected metal ions (Ca+2, Cr+3, Co+2, Cu+2, Cd+2, K+1, Mg+2, Mn+2, Na+1, Ni+2, Pb+2, Zn+2, and Fe+2) to generate QSPR model. A set of 21 characteristic descriptors were selected and relationship of these metal characteristics with adsorptive behavior of metal ions was investigated. Stepwise Multiple Linear Regression (SMLR) analysis and Artificial Neural Network (ANN) were applied for descriptors selection and model generation. Langmuir and Freundlich isotherms were also applied on adsorption data to generate proper correlation for experimental findings. Model generated indicated covalent index as the most significant descriptor, which is responsible for more than 90% predictive adsorption (alpha = 0.05). Internal validation of model was performed by measuring [Formula: see text] (0.98). The results indicate that present model is a useful tool for prediction of adsorptive behavior of different metal ions based on their ionic characteristics. PMID- 29281504 TI - Swallowing a Spy - The Potential Uses of Digital Adherence Monitoring. PMID- 29281506 TI - Catching Casualties at the Foot of the Hill. PMID- 29281505 TI - 'If a Leg Hurts, Check for Very Close Veins'. PMID- 29281507 TI - editor's notes. PMID- 29281508 TI - sportspages. PMID- 29281509 TI - time out. PMID- 29281511 TI - For 'Ideal Football Weight' Assess Fat, Not Poundage. PMID- 29281510 TI - Spotting Success Traits in Olympic Contenders. PMID- 29281512 TI - Athletes: New Saints With Old Ideas. PMID- 29281513 TI - Faulty Bindings Increase Risk to Beginning Skiers. PMID- 29281514 TI - The Best Years of Their Lives. PMID- 29281515 TI - action arena. PMID- 29281516 TI - letters. PMID- 29281517 TI - Round Table: The Unstable Knee. PMID- 29281518 TI - When Doctors Test Themselves, the Prescription Is Exercise. PMID- 29281519 TI - Doctor and Broadcaster Team Up for Rose Bowl. PMID- 29281521 TI - Finding a Source of Low-Back Pain. PMID- 29281520 TI - Oral Trauma. AB - In brief Sports participation can result in three types of dental trauma: fracture, displacement, and avulsion. On-field physical exam and classification of dentoalveolar injury can expedite referral for definitive treatment. Emergency measures to control bleeding and store avulsed teeth can help preserve dental integrity. Physicians can help prevent dental trauma by promoting mouth guard use. PMID- 29281522 TI - Dyspnea, Light-Headedness, and Palpitations in a Young Weight Lifter. PMID- 29281523 TI - 1995 Annual Meeting of the American College of Sports Medicine. PMID- 29281524 TI - Relieving Anterior Knee Pain. PMID- 29281527 TI - Getting Hooked... to the Internet. PMID- 29281526 TI - CME Self Test. PMID- 29281528 TI - Chronic Pain After Ankle Sprain. AB - In brief Chronic pain following an ankle sprain is disabling for the active patient and a diagnostic challenge for the physician. With a differential diagnosis in mind and the relative benefits of imaging procedures in hand, the primary care physician can expediently come to a definitive diagnosis in most instances. Incomplete rehabilitation is most often the cause of chronic pain following an ankle sprain. The differential diagnosis also includes lateral ankle instability, previously undetected trauma, impingement disorder, congenital abnormality, and tumor. PMID- 29281529 TI - Helping Active Women Avoid Anemia. AB - In brief Many active women, especially those in sports that place a premium on a lean physique, don't consume enough iron, which puts them at risk for anemia. When evaluating an active woman's iron status, it's important to determine her hemoglobin baseline and identify various sources of iron loss from the medical history. Hemoglobin, hematocrit, and serum ferritin levels are most often the only laboratory values needed for evaluation. Treatment of anemia and iron deficiency focuses on improving iron intake through food and supplements and monitoring the patient's progress. Prevention tactics include diet counseling for those with known risk factors for anemia. PMID- 29281530 TI - Anterior Cruciate Ligament Avulsion in Active Adults. AB - In brief Anterior cruciate ligament (ACL) avulsion at the intercondylar eminence, though well recognized in the pediatric population, is uncommon in skeletally mature people. Unlike in children, this injury in adults is often associated with soft-tissue trauma such as tears of the meniscus and of other ligaments. X-rays are often diagnostic for avulsion, but MRI is often required to identify concomitant injuries. In adults, surgical repair restores normal ACL function. PMID- 29281531 TI - Water. PMID- 29281532 TI - Pearls. PMID- 29281533 TI - Results of Two Years of Exercise Training in Middle-Aged Men. PMID- 29281535 TI - Taking Winter in Stride Requires Proper Attire. PMID- 29281534 TI - So You've Been Asked to Be the Team Physician. PMID- 29281536 TI - a need to know. PMID- 29281537 TI - Where to Put the Blame for Muscle Pulls. PMID- 29281538 TI - Honing up the Homebody. PMID- 29281539 TI - Exercise and Hypertension. PMID- 29281540 TI - Business Invests in Employee Fitness. AB - In 1894, John H. Patterson of the National Cash Register Company in Dayton, Ohio, introduced morning and afternoon exercise breaks for his employees. Ten years later he installed a gym on the fourth floor, and in 1911, he opened a 325-acre park for his employees. Every fall Americans watch the results of another company fitness program: the Green Bay Packers, originally an employee team sponsored by the Indian Packing Company in Green Bay, Wisconsin. But it wasn't until about ten years ago that industry fitness programs really began to grow - in number and variety. They range from sessions led by interested employees to carefully controlled projects under full-time fitness directors. The facilities might be a local park or an elaborately equipped company gym. But reporters for The Physician and Sportsmedicine found that the programs had one theory in common: Increased fitness means increased production. PMID- 29281541 TI - Cowboys Court Injury in 'Battle of Survival'. PMID- 29281542 TI - letters. PMID- 29281544 TI - Facing the Mask Question. PMID- 29281543 TI - sportspages. PMID- 29281545 TI - A Time for Running. PMID- 29281547 TI - Nutrition and Athletics. PMID- 29281546 TI - Basic, Balanced Diet Meets Requirements of Athletes. PMID- 29281548 TI - lockerroom. PMID- 29281550 TI - 'Human Torpedo' MD Chooses Slower Pace. PMID- 29281549 TI - letters. PMID- 29281551 TI - Alcohol and Drugs in Sports. PMID- 29281552 TI - sportspages. PMID- 29281553 TI - Effects of Intraoral Mouth Guards on Ventilation. PMID- 29281554 TI - Hockey Masks Go On, Face Injuries Go Down. PMID- 29281555 TI - 'Too Great' a Risk Spurred Hockey Mask Development. PMID- 29281556 TI - Role of multiple substrates (spent mushroom compost, ochre, steel slag, and limestone) in passive remediation of metal-containing acid mine drainage. AB - The potential of selected materials in treating metal-rich acid mine drainage (AMD) has been investigated in a series of batch experiment. The efficiencies of both single and mixed substrates under two conditions i.e. low- and high concentration solutions containing heavy metals were evaluated. Synthetic metal containing AMD was used in the experiments treated using spent mushroom compost (SMC), ochre, steel slag (SS), and limestone. Different ratios of treatment materials were incorporated in the substrate mix and were tested in an anoxic condition. In the batch test, physicochemical parameters (pH, redox potential, total dissolved solids, conductivity, and Ca concentration) and heavy metals (Fe, Mn, Pb, Zn, and Al) were analysed. The mixed substrates have shown satisfactory performance in increasing pH with increasing Ca concentration and removing metals. It has been found that SS and ochre played an important role in the treatment of AMD. The results showed that the mixed substrates SM1 (i.e. 10% SMC mixed with 20% ochre, 30% steel slag, and 40% limestone) and SM2 (i.e. 20% SMC mixed with 30% ochre, 40% steel slag, and 10% limestone) were effective in increasing the pH from as low as 3.5-8.09, and removing heavy metals with more than 90% removal efficiencies. PMID- 29281557 TI - Gender Differences in the Relationships among Young Adults' Religiosity, Risk Perception, and Marijuana Use: A Moderated Mediation Model. AB - BACKGROUND: Studies show that religiosity is a protective factor against marijuana use. Given many religions' teachings to promote risk perception of substance use, risk perception possibly mediates the relationship between religiosity and marijuana use. Moreover, since males and females differ in religiosity, risk perception, and marijuana use, gender may moderate religiosity's indirect effect on marijuana use through risk perception and religiosity's direct effect on marijuana use. Despite substantial research on religiosity and adolescent marijuana use, little research has targeted the young adult population. OBJECTIVES: This study is the first to investigate the conditional nature of religiosity's influence on marijuana use through risk perception among young adults in the U.S. METHODS: Using a nationally representative sample from the 2014 National Survey on Drug Use and Health (N = 12,646), conditional process analysis was examined through significant test of the index of moderated mediation. Additionally, mediation analysis was conducted in male (n = 6042) and female (n = 6604) groups separately to further characterize the nature of the relationships. RESULTS: Religiosity's indirect effect on marijuana use through risk perception was found to be significantly different between males and females, while there were no gender differences in religiosity's direct effect on marijuana use. The indirect effect of religiosity on marijuana use via risk perception was significant among both males and females and was larger for females than males. CONCLUSION: Prevention interventions for young adults' marijuana use that incorporate religiosity should emphasize factors related to risk perception and have a gender informed perspective. Direction for future research is provided. PMID- 29281558 TI - Long non-coding RNA CEBPA-AS1 correlates with poor prognosis and promotes tumorigenesis via CEBPA/Bcl2 in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is one of the most aggressive and lethal malignancies affecting the head and neck region with a general 5-year survival rate about 50%. Long non-coding RNAs (lncRNAs) are believed to participate in diverse biological processes and are emerging as convenient and minimally invasive diagnostic/prognostic/therapeutic markers. The aim of this study was to explore CEBPA-AS1 role and mechanism in OSCC tumorigenesis. In this study, CEBPA AS1 localized in the cytoplasm and the peri-nuclear cellular compartment functioning as a potential oncogene up-regulated in OSCC was correlated with poor differentiation, lymph node metastasis and high clinical stage, which made it considered to be a prognostic biomarker. Silence of CEBPA-AS1 inhibited OSCC cells proliferation and induced cells apoptosis, migration and invasion by targeting CEBPA and via a novel pathway CEBPA/Bcl2. Our findings provided the first evidence for the lncRNA CEBPA-AS1 regulatory network in OSCC tumorigenesis, which might be helpful to improve the effects of clinical treatment in OSCC. PMID- 29281559 TI - Left atrial abnormality (LAA) as a predictor of ibrutinib-associated atrial fibrillation in patients with chronic lymphocytic leukemia. AB - Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for >= 2.5 mm wide >= 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion >= 40 msec in duration or terminal portion >= 1 mm deep or (3) PR interval >= 200 msec (intra atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2 37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity. PMID- 29281560 TI - High Rate of Return to Cycling After Hip Arthroscopy for Femoroacetabular Impingement Syndrome. AB - BACKGROUND: Femoroacetabular impingement syndrome (FAIS) is most commonly diagnosed in athletes who sustain repetitive flexion and rotational loading to their hip. The purpose of this study was to evaluate a patient's ability to return to cycling after hip arthroscopy for FAIS. HYPOTHESIS: There is a high rate of return to cycling after hip arthroscopy. STUDY DESIGN: Retrospective analysis. LEVEL OF EVIDENCE: Level 4. METHODS: Consecutive patients who had identified themselves as cyclists and had undergone hip arthroscopy for the treatment of FAIS were reviewed. Pre- and postoperative physical examinations, imaging, and patient-reported outcomes (PROs) scores, including the modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADL) and Sports-Specific (HOS-SS) subscales, and visual analog scale for pain, as well as a cycling-specific questionnaire, were assessed for all patients. RESULTS: A total of 58 patients (62% female; mean age, 30.0 +/- 7.1 years; mean body mass index, 23.2 +/- 2.7 kg/m2) were included. Prior to surgery, patients averaged 30 +/- 42 miles per week (range, 2-300 miles). Fifty-five patients (95%) were forced to discontinue cycling at an average of 7.5 +/- 6.2 months prior to surgery due to hip pain. Fifty-six patients (97%) returned to cycling at an average of 4.5 +/ 2.5 months after surgery, with 33 (59%) returning to a better level of cycling and 23 (41%) to the same cycling level. Postoperatively, there was no difference in the average number of miles patients completed per week compared with preoperative values ( P = 0.08). At a mean follow-up of 31.14 +/- 0.71 months (range, 24-48 months), all patients experienced significant improvements in mHHS, HOS-ADL, and HOS-SS PROs (all P < 0.0001), with an overall satisfaction rate of 91% +/- 13%. CONCLUSION: Recreational and competitive cyclists return to cycling 97% of the time after hip arthroscopy for FAIS, with most of these patients returning at an average of 4.5 months after surgery. This information is helpful in counseling patients on their expectations with regard to returning to cycling after hip arthroscopy for FAIS. CLINICAL RELEVANCE: Cyclists return to sport 97% of the time at an average of 4.5 months after hip arthroscopy for FAIS. PMID- 29281562 TI - Moral frames for lives worth living: Managing the end of life with dementia. AB - Narratives that frame the end of life with dementia as undignified reveal moral claims on which lives are considered worth living. These claims are deeply rooted in the medicalization of death and its appeal to dignity. Drawing from ethnographic fieldwork in nursing homes for people with dementia in The Netherlands, I demonstrate how the end of life with dementia is managed through such moral frames. Specifically, I elaborate on the production of lives (not) worth living and explore how family members welcomed the death of a loved one with dementia. I argue that the welcoming of death is not an act of indifference but can be seen as a form of care. PMID- 29281563 TI - A Shortened Screener Version of the Cultural Assessment of Risk for Suicide. AB - The current study aimed to establish a shortened version of the Cultural Assessment of Risk for Suicide (CARS) measure that can be more widely utilized under time constraints in clinical and applied settings. Based on a sample of 485 adults, confirmatory factor analysis, bivariate correlations, and Receiver Operating Characteristic analyses were employed to determine the most psychometrically valid shortened version. The 14-item, 8-factor CARS screener (CARS-S) evidenced high reliability, high correlation with the original full version of the CARS questionnaire, and high convergent validity with measures of other suicide-related constructs of depression, hopelessness, suicidal ideation, and lifetime suicide attempts. The suggested clinical cut-off is 38.5. The shortened CARS-S offers a time-efficient assessment of cultural suicide risk factors. PMID- 29281564 TI - Anxiety, Dispositional Mindfulness, and Sexual Desire in Men Consulting in Clinical Sexology: A Mediational Model. AB - This study aimed to examine dispositional mindfulness as a mediator of the relationship between anxiety and sexual desire in men consulting in clinical sexology. A sample of 105 adult men seeking sex therapy completed measures of dispositional mindfulness, anxiety, and sexual desire. Close to a third (28.7%) of participants reported lack or absence of sexual desire as their main reason to consult in sex therapy. Path analysis confirmed a mediation model and revealed that the association between anxiety and lower sexual desire was fully mediated by dispositional mindfulness. These findings suggest that mindfulness-based interventions may be a relevant component to integrate in the treatment of men who present anxiety symptoms and low sexual desire. PMID- 29281565 TI - Treatment of Amblyopia: Part 1. PMID- 29281567 TI - Editorial: translation of the 1955 monograph by Alfred Bangerter on the treatment of amblyopia. PMID- 29281568 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29281569 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29281570 TI - A Trial of Antibiotics for Smaller Skin Abscesses. PMID- 29281571 TI - A Trial of Antibiotics for Smaller Skin Abscesses. PMID- 29281572 TI - Obinutuzumab Treatment of Follicular Lymphoma. PMID- 29281573 TI - Obinutuzumab Treatment of Follicular Lymphoma. PMID- 29281574 TI - Ventriculoperitoneal-Shunt Placement for Normal-Pressure Hydrocephalus. PMID- 29281575 TI - Case 40-2017. A 32-Year-Old Woman with Headache, Abdominal Pain, Anemia, and Thrombocytopenia. PMID- 29281576 TI - Prices of Generic Drugs Associated with Numbers of Manufacturers. PMID- 29281577 TI - Toward Better-Quality Compounded Drugs - An Update from the FDA. PMID- 29281578 TI - Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets. PMID- 29281580 TI - Trials of Patent Foramen Ovale Closure. PMID- 29281579 TI - Safety of Magnetic Resonance Imaging in Patients with Cardiac Devices. AB - BACKGROUND: Patients who have pacemakers or defibrillators are often denied the opportunity to undergo magnetic resonance imaging (MRI) because of safety concerns, unless the devices meet certain criteria specified by the Food and Drug Administration (termed "MRI-conditional" devices). METHODS: We performed a prospective, nonrandomized study to assess the safety of MRI at a magnetic field strength of 1.5 Tesla in 1509 patients who had a pacemaker (58%) or an implantable cardioverter-defibrillator (42%) that was not considered to be MRI conditional (termed a "legacy" device). Overall, the patients underwent 2103 thoracic and nonthoracic MRI examinations that were deemed to be clinically necessary. The pacing mode was changed to asynchronous mode for pacing-dependent patients and to demand mode for other patients. Tachyarrhythmia functions were disabled. Outcome assessments included adverse events and changes in the variables that indicate lead and generator function and interaction with surrounding tissue (device parameters). RESULTS: No long-term clinically significant adverse events were reported. In nine MRI examinations (0.4%; 95% confidence interval, 0.2 to 0.7), the patient's device reset to a backup mode. The reset was transient in eight of the nine examinations. In one case, a pacemaker with less than 1 month left of battery life reset to ventricular inhibited pacing and could not be reprogrammed; the device was subsequently replaced. The most common notable change in device parameters (>50% change from baseline) immediately after MRI was a decrease in P-wave amplitude, which occurred in 1% of the patients. At long-term follow-up (results of which were available for 63% of the patients), the most common notable changes from baseline were decreases in P-wave amplitude (in 4% of the patients), increases in atrial capture threshold (4%), increases in right ventricular capture threshold (4%), and increases in left ventricular capture threshold (3%). The observed changes in lead parameters were not clinically significant and did not require device revision or reprogramming. CONCLUSIONS: We evaluated the safety of MRI, performed with the use of a prespecified safety protocol, in 1509 patients who had a legacy pacemaker or a legacy implantable cardioverter-defibrillator system. No long-term clinically significant adverse events were reported. (Funded by Johns Hopkins University and the National Institutes of Health; ClinicalTrials.gov number, NCT01130896 .). PMID- 29281581 TI - Trials of Patent Foramen Ovale Closure. PMID- 29281582 TI - Talaromyces marneffei Infection. PMID- 29281583 TI - Published intimate partner violence studies often differ from their trial registration records. AB - INTRODUCTION: Registering study protocols in a trial registry is important for methodologic transparency and reducing selective reporting bias. The objective of this investigation was to determine whether published studies of intimate partner violence (IPV) that had been registered matched the registration record on key study design elements. METHODS: We systematically searched three trial registries to identify registered IPV studies and the published literature for the associated publication. Two authors independently determined for each study whether key study elements in the registry matched those in the published paper. RESULTS: We included 66 studies published between 2006 and 2017. Nearly half (29/66, 44%) were registered after study completion. Many (26/66, 39%) had discrepancies regarding the primary outcome, and nearly two-thirds (42/66, 64%) had discrepancies in secondary outcomes. Discrepancies in study design were less frequent (13/66, 20%). However, large changes in sample size (26/66, 39%) and discrepancies in funding source (28/66, 42%) were frequently observed. CONCLUSIONS: Trial registries are important tools for research transparency and identifying and preventing outcome switching and selective outcome reporting bias. Published IPV studies often differ from their records in trial registries. Researchers should pay close attention to the accuracy of trial registry records. PMID- 29281584 TI - Parental Mediation in the Digital Era: Increasing Children's Critical Thinking May Help Decrease Positive Attitudes toward Alcohol. AB - We demonstrate in our research that discussion-based parental mediation may successfully decrease the negative effects that youth's engagement with alcohol brands on social media may have on attitudes toward alcohol through its effects on critical thinking. A clear pattern was found with positive mediation leading to unhealthy outcomes and negative mediation predicting healthier behaviors. Youth whose parents critiqued media messages reported more critical thinking skills, which predicted less interaction with alcohol brands on social media and fewer expectancies toward alcohol. On the other hand, youth whose parents endorsed media portrayals of drinking reported fewer critical thinking skills and were thus more likely to interact with alcohol brands on social media. Including a media literacy component in alcohol education that target parental strategies and that are conducive to discussion may lead to beneficial health outcomes in the digital era. PMID- 29281585 TI - Factors Associated with Exclusive Breastfeeding Practice among Nursing Mothers in rural areas of Enugu State and its Implications for Social Work Practice in Nigeria. AB - This study investigates factors that influence exclusive breastfeeding practice. Focus group discussions involving 60 nursing mothers from selected rural areas of Enugu State, Nigeria, was adopted. Thematic analysis was adopted in analyzing data collected. Findings show that nursing mothers in the study area are yet to fully accept the 6 months' practice of exclusive breastfeeding. Issues relating to culture, economic hardship, and support networks were revealed to exercise gross influence on practice of exclusive breastfeeding. The study concluded that professional support from social workers is very vital to achieving conformity to the practice. This can be done through awareness creation that would accommodate support networks, while adopting exclusive breastfeeding campaign models that have proven successful in other African nations. PMID- 29281586 TI - Honor-Related Suicide in the United States: A Study of National Violent Death Reporting System Data. AB - Personal honor is associated with culturally defined honor-norms and its loss may predicate suicide. This exploratory study aimed to identify honor-related suicides within a public health dataset and to compare them to other suicides. Honor-related suicides (n = 163) were identified from case narratives within the National Violent Death Reporting System dataset. The distribution of factors associated with honor-related suicide were compared with all other suicides (n = 54,333). Honor-related suicides were more likely associated with leaving a suicide note; discussing suicidal intent; criminal-legal, job and relationship problems; and suffering depression while being less likely to seek help for distress. They were not associated with gender or suicide method. Honor suicides were identified and appear to be most associated with public challenges to personal reputation. Implications for suicide prevention are discussed. PMID- 29281587 TI - The Effect of Auditory Cueing on the Spatial and Temporal Gait Coordination in Healthy Adults. AB - Walk ratio, defined as step length divided by cadence, indicates the coordination of gait. During free walking, deviation from the preferential walk ratio may reveal abnormalities of walking patterns. The purpose of this study was to examine the impact of rhythmic auditory cueing (metronome) on the neuromotor control of gait at different walking speeds. Forty adults (mean age 26.6 +/- 6.0 years) participated in the study. Gait characteristics were collected using a computerized walkway. In the preferred walking speed, there was no significant difference in walk ratio between uncued (walk ratio = .0064 +/- .0007 m/steps/min) and metronome-cued walking (walk ratio = .0064 +/- .0007 m/steps/min; p = .791). A higher value of walk ratio at the slower speed was observed with metronome-cued (walk ratio = .0071 +/- .0008 m/steps/min) compared to uncued walking (walk ratio = .0068 +/- .0007 m/steps/min; p < .001). The walk ratio was less at faster speed with metronome-cued (walk ratio = .0060 +/- .0009 m/steps/min) compared to uncued walking (walk ratio = .0062 +/- .0009 m/steps/min; p = .005). In healthy adults, the metronome cues may become an attentional demanding task, and thereby disrupt the spatial and temporal integration of gait at nonpreferred speeds. PMID- 29281588 TI - When Pornography Use Feels Out of Control: The Moderation Effect of Relationship and Sexual Satisfaction. AB - There is an understudied, meaningful distinction between high frequency of pornography use and the subjective feeling that this behavior is out of control. We examined whether the quality of a couple's relationship and sex life can strengthen or weaken the association between frequency of Internet pornography use and perceived lack of control over this behavior. In a sample of 1,036 participants, results showed that frequency of pornography use was more strongly associated with feeling out of control when relationship and sexual satisfaction were lower. Findings suggest that couple dissatisfaction puts the individual at risk of reporting out-of-control pornography use. PMID- 29281589 TI - Factors associated with attitudes toward seeking mental health treatment postpartum. AB - Attitudes toward seeking mental health treatment are a major predictor of seeking such treatment. Rates of seeking mental health treatment for postpartum depression are low despite contacts with health-care providers and available treatment. This study examined factors associated with four dimensions of attitude toward seeking mental health treatment among Israeli women in the postpartum period. Women (N = 1,059) were recruited (June 2008-February 2009) from a medical center's maternity department within the first two days following delivery and completed a sociodemographic survey and the Attitudes Toward Seeking Professional Psychological Help Scale. Low recognition of need for mental health treatment was associated with having a below average income and no personal and family depression history; low stigma tolerance was associated with being younger, having more children, and defining oneself as ultra-orthodox; low interpersonal openness was associated with having a below average income. Moreover, low confidence in mental health practitioners was associated with being younger and non-ultra-orthodox. Understanding which women are likely to score low on various dimensions of attitude can help target interventions for improving these factors, reducing barriers to receiving mental health treatment among specific groups of women. Research should continue to explore specific attitude dimensions among various populations. PMID- 29281590 TI - Quantification of 5-HT1A and 5-HT2A receptor Binding in Depressed Suicide Attempters and Non-Attempters. AB - OBJECTIVE: To determine serotonin system abnormalities related to major depression or previous suicidal behavior. METHODS: [11C]WAY100635, [18F]altanserin and positron emission tomography were used to compare 5-HT1A and 5-HT2A binding in MDD patients divided into eight past suicide attempters (>4yrs prior to scanning) and eight lifetime non-attempters, and both groups were compared to eight healthy volunteers. RESULTS: The two receptor types differed in binding pattern across brain regions from each other, but there were no differences in binding between healthy volunteers and the two depressed groups or between depressed suicide attempters and non-attempters. No effects of depression severity or lifetime aggression were observed for either receptor. CONCLUSION: Limitations of this study include small sample size and absence of high lethality suicide attempts in the depressed attempter group. No trait-like binding correlations with past suicide attempt or current depression were observed. Given the heterogeneity of nonfatal suicidal behavior, a larger sample study emphasizing higher lethality suicide attempts may find the serotonin biological phenotype seen in suicide decedents. PMID- 29281591 TI - Leisure-time physical inactivity and psychological distress in female-dominated occupations in Lithuania. AB - Poor mental health, manifesting as psychological distress, has become a leading problem recently; therefore, determining associated factors is important, especially in female-dominated occupations, as women are more prone to psychological distress than men, in part due to demands of both professional and domestic tasks. The objective of the present study was to investigate associations between leisure-time physical inactivity and psychological distress, accounting for the possible relation of psychosocial factors at work (job demands, job control, social support at work, workplace bullying) and life events in representative samples of family physicians, internal medicine department nurses and secondary-school teachers in Lithuania. In total, 323 family physicians, 748 internal medicine department nurses and 517 secondary-school teachers were interviewed during 2012-2014 in Lithuania. Godin leisure-time exercise, Goldberg General Health, Job content, and Negative acts questionnaires were administered. Logistic regression was used. A high proportion of family physicians, nurses and teachers were physically inactive during leisure. Leisure time physical inactivity was strongly associated with psychological distress, adjusting for age, workplace bullying, job demands, job control, social support at work and traumatic life events in all three female-dominated occupations. Efforts to increase leisure-time physical activity level in medical occupations could be beneficial. PMID- 29281592 TI - Individual-Based Compulsive Sexual Behavior Scale: Its Development and Importance in Examining Compulsive Sexual Behavior. AB - Compulsive sexual behavior comprises individual-based (e.g., sexual fantasies, compulsive sexual thoughts, masturbation) and partnered (e.g., interpersonal sexual conquests, repeated infidelity) facets. Most instruments for assessing compulsive sexual behavior, however, focus less on the individual-based facet and specifically on fantasies and compulsive thoughts. In the current research, we developed and validated an individual-based compulsive sexual behavior scale (I CSB). In Study 1 (N = 492), the factorial structure of the I-CSB was examined. In Study 2 (N = 406), we assessed I-CSB's convergent validity. In Study 3 (N = 112), we examined whether the I-CSB differentiates between individuals who suffer from compulsive sexual behavior and those who do not. Results revealed a four-factor structure for individual-based compulsive sexual behavior that is associated with an intense inner conflict regarding sexuality (high arousal contrasting with high sexual anxiety), and that accounts for approximately 75% of the differences between people with compulsive sexual behavior and controls. Results are discussed in light of the need for a broader understanding of compulsive sexual behavior. PMID- 29281593 TI - The Role of Patient-Provider Communication in Engagement and Re-engagement in HIV Treatment in Bamako, Mali: A Qualitative Study. AB - Mounting evidence in sub-Saharan Africa suggests poor patient-provider communication (PPC) negatively impacts patient engagement (retention in care and adherence to medication) in antiretroviral therapy (ART) programs. In Bamako, Mali, where 36% of ART patients are lost to follow-up within 12 months of initiating treatment, we aimed to define features of positive PPC according to patient values and explore the mechanisms by which these features may sustain engagement and re-engagement according to patient and provider experiences. We conducted 33 in-depth interviews and 7 focus groups with 69 patients and 17 providers in five ART clinics. Regarding sustaining engagement, participants highlighted "establishing rapport" as a foundational feature of effective PPC, but also described how "responding to emotional needs", "eliciting patient conflicts and perspective" and "partnering to mitigate conflicts" functioned to address barriers to engagement and increase connectedness to care. Patients who had disengaged felt that "communicating reacceptance" may have prompted them re engage sooner and that tailored "partnering to mitigate conflicts" would be more effective in sustaining re-engagement than the standard adherence education providers typically offer. Optimizing provider skills related to these key PPC features may help maximize ART patient engagement, ultimately improving health outcomes and decreasing HIV transmission in sub-Saharan Africa. PMID- 29281594 TI - Suicide Risk Assessment and Management in the Psychiatry Emergency Service: Psychiatric Provider Experience and Perceptions. AB - The objective of this study was to explore suicide risk identification and flow of patients with differing suicide risk through the Psychiatric Emergency Service (PES) to their clinical dispositions. 3 focus groups (N = 15 psychiatric providers working in the PES of a large urban teaching hospital) discussing suicide risk assessment in the PES were conducted, followed by thematic analysis. A total of 7 themes were identified in 624 coded passages. In focus groups conducted to explore suicide risk assessment, discussions shifted to broader matters, e.g., frustrations with the system in which the providers worked. 4 main messages emerged: screening tools cannot replace clinical judgment; the existing electronic health record is not efficient and sufficiently informative; competing demands challenge PES psychiatrists; and post-discharge patient outcome data are needed. These concerns suggest directions for improving patient care. PMID- 29281595 TI - Correlates of Suicidal Ideation and Self-harm in Early Childhood in a Cohort at Risk for Child Abuse and Neglect. AB - OBJECTIVES: This study provides prevalence and persistence rates of suicidal ideation and self-harm, and examines how child maltreatment types, mental health symptoms, and age 4 suicidal ideation and self-harm are associated with each suicidal outcome among 6-year-old children. METHODS: Participants were 1,090 caregivers assessed when their children were 4 and 6 years old from the Longitudinal Studies of Child Abuse and Neglect. Data were collected from the Child Behavior Checklist, Parent-Child Conflict Tactics Scales, and Child Protective Services. RESULTS: Persistence rates within each suicidal outcome were high. Failure to provide -a physical neglect subtype- was the only maltreatment type that independently predicted self-harm. Depressive/anxious symptoms and age 4 suicidal ideation were independently associated with age 6 suicidal ideation, whereas attention problems and age 4 self-harm predicted age 6 self-harm. CONCLUSION: Our findings align with the consensus emerging from adolescent studies that risk factors associate differentially with suicidal ideation and self-harm. PMID- 29281596 TI - Youth empowerment implementation project evaluation results: A program designed to improve the health and well-being of low-income African-American adolescents. AB - Adolescent obesity is a major health issue facing today's youth. This may be the first generation to have a lower life expectancy than their parents. The Youth Empowerment Implementation Project's (YEIP) goal was to increase fruit and vegetable intake, lower junk food consumption, and increase physical activity among low-income African-American youth living in the Midwest. Thirty middle school aged youth participated in an evidenced-based program (i.e., Botvin's Life Skills Training) and were engaged in health education and physical activities. The results from baseline to follow-up demonstrated a reduction in junk food intake for participants and an increase in fruit and vegetable intake but not for physical activity. The health behaviors of participants improved for three out of four indicators following the intervention. Limitations, future research, and implications for future programs are also discussed. PMID- 29281597 TI - Examining the contributions of a community coalition in addressing urban health determinants. AB - Community coalitions facilitate changes in community outcomes and conditions by addressing issues and determinants of health and well-being. The purpose of the present study was to examine the process of a community coalition, the Ivanhoe Neighborhood Council (INC), in addressing community-prioritized urban health determinants aimed at improving living conditions in a neighborhood in Kansas City, Missouri. Using an empirical case study design, the implementation of the community change framework supported through the Kauffman Neighborhood Initiative is examined. The results suggest that the INC was effective in implementing 117 community changes, and these changes were associated with modest improvements in targeted outcomes related to housing and crime. A 10 year follow-up probe indicates that the majority of recurring community changes were sustained. The results indicate that the comprehensive community initiative was important in facilitating community change that may have contributed to improvements in addressing urban health determinants. PMID- 29281598 TI - Community public health practicum in the Amazon region of Peru: Student experiences. AB - This article presents the experience of a community public health practicum in the Amazon region of Peru. The intervention model is based on the social determinants of health within a participatory approach illustrating the impact of the practicum on the students and on the families and communities. This experience can be instructive for developing countries that do not have an established infrastructure to ensure healthcare within their communities; in these countries, students can help to improve health by empowering families and communities. This paper describes the experience of two students who participated in the community practicum providing healthcare to families and communities. PMID- 29281599 TI - Unpacking barriers to healthy lifestyles from the perspective of youth with disabilities and their parents. AB - Adolescents and young adults with disabilities experience several health inequalities and challenges in maintaining healthy lifestyles. As a group, individuals with disabilities experience higher rates of obesity compared to youth without disabilities. This study was designed to examine the types of challenges experienced by youth with disabilities and parents of youth with disabilities in maintaining a healthy lifestyle. Strong evidence indicates that having a healthy lifestyle and preventing obesity are not only the result of an individual's behavior related to physical activity and consumption of healthy products but also several complex factors in the person's environment. This study was designed to understand the perceptions of youth with disabilities and their parents about the challenges they experience in engaging in physical activity and consuming healthy products, and ideas and strategies for promoting healthy lifestyles. Overall, youth with disabilities lack access to opportunities for engaging in physical activity as well as access to affordable foods. Implications for systems and policy changes are discussed. PMID- 29281600 TI - Community perspectives on substance use among Bhutanese and Iraqi refugees resettled in the United States. AB - Premigration trauma and postmigration stressors put refugees at high risk for mental health concerns, including substance use. However, there is limited systematic research on substance use in refugee communities exists. We conducted exploratory qualitative research to examine Bhutanese and Iraqi refugee perspectives related to the use of recreational substances after resettlement in the United States. Data were collected through separate focus groups with 28 Bhutanese and 22 Iraqi adult men. Focus groups were facilitated by an experienced clinician with an in-person interpreter, audiorecorded, and transcribed. Transcripts were checked for accurate translation and then analyzed using a conventional content analysis approach. Findings revealed similarities and differences between the two refugee groups with regard to recognizing excessive use, triggers for use, and preferred modes of outreach and intervention. Findings also revealed postmigration changes in substance use behaviors stemming from issues related to access, cost, and perceived legal ramifications. PMID- 29281601 TI - Health disparities: Understanding and promoting healthy communities. AB - This themed issue focuses on understanding and addressing several public health issues affecting communities today nationally and internationally. Health disparities, and global health in general, cover a large breadth of health concerns impossible to address in one issue. Here we provide a scope of some health disparities while focusing on health promotion and well-being of diverse populations, specifically within urban undeserved populations, rural communities in Peru, Roma minorities in Spain, and refugee communities. We focus on understanding contextual issue that affect health disparities as well as on examining the effectiveness of community-based interventions and community coalitions designed to address disparities. PMID- 29281602 TI - Improving community mental health services for people affected by political violence in Ayacucho, Peru. AB - This study describes a model to intervene in communities affected by the political violence impacting the Ayacucho region of Peru since 1980s. Many community members still experience psychosocial consequences to this day due primarily to grief. Thirty-eight professionals from different sectors in the area received specialized training and implemented five community projects that were accompanied and monitored in the field by a team of community psychologists. This article is grounded on the principles of participation, building community capacity, and community strengthening. We present the analysis of five community action plans implemented over a period of 14 months. The results show a process of internal strengthening of community services and the identification of new social and community resources among the people involved in the action plans. The implications of capacity building for improving community mental health are discussed. PMID- 29281603 TI - Shedding light on governance for Roma health inequities. AB - The health inequities suffered by the Roma population in Europe represent an alarming and unacceptable source of injustice. As the main ethnic minority in Europe, the gap between the health conditions of the Roma and the rest of the population poses a challenge to human rights and public health. Many political efforts have been deployed in Europe to tackle these inequities. However, they have fallen short, even causing paradoxical consequences. In this paper, we argue that previous political efforts have failed because they were developed from a neoliberal perspective, which perceives Roma health inequities as isolated ethnic problems for which there is no political accountability. Hence, there is a need for transformative political change that results in the protection of rights and self-governance to address health inequities experienced by Roma people. We propose a framework of health governance guided by the following principles: (a) effective involvement of multiple stakeholders by building collaborative capacity; (b) infusion of health perspectives in all policies and multisectoral actions; PMID- 29281604 TI - Results of the GLAGOV trial. AB - Statins therapy reduces atheroma in proportion to the reduction of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin--kexin type 9 (PCSK9) inhibitors are a new class of injectable human monoclonal antibodies shown to lower LDL-C when added to statin therapy. In a randomized, double-blind, placebo-controlled study, 968 patients with symptomatic coronary artery disease were treated with statins alone or combined with the PCSK9 inhibitor, evolocumab, and assessed for change in percent, total volume, and regression of coronary atheroma. Treatment with statins plus evolocumab achieved mean LDL-C levels of 36.6 mg/dL, produced atheroma regression with a mean change in percent of atheroma volume of about 1% (P < .001), and induced regression in a greater percentage of patients. The clinical benefits of LDL-C as low as 20 mg/dL shown in this trial warrant further investigation. PMID- 29281605 TI - Trends in cardiovascular risk profiles. AB - Outcomes for patients with coronary artery disease (CAD) have improved in the past 20 years likely due to advances in clinical care such as angiotensin converting enzyme inhibitors, antiplatelet agents, and reduced time to cardiac cauterization procedures. But how have the risk factors for CAD changed in the past 2 decades? Analysis of nearly 4,000 patients with ST-elevation myocardial infarction (STEMI) at a tertiary care center found that patients presenting with acute STEMI are younger and more obese than in the past. The prevalence of smoking, hypertension, and diabetes mellitus is also increasing. Primary and secondary prevention and aggressive efforts to modify risk factors for CAD is essential for further improvement in cardiovascular outcomes. PMID- 29281606 TI - Expanding indications for TAVR: The preferred procedure in intermediate-risk patients? AB - Transcatheter aortic valve replacement (TAVR) has steadily replaced surgical aortic valve replacement (SAVR) in symptomatic patients with severe aortic stenosis, primarily those at high risk for surgical complications. As TAVR use increases, spurred by technological advances in valve design and patient preferences for the less-invasive procedure, studies have provided data supporting the efficacy and safety of TAVR. Recently, TAVR has expanded to intermediate-risk patients, increasing the potential patient population. Although emerging evidence supports its use in lower-risk patients, some adverse events may limit its adoption in a wider patient population. These include stroke, paravalvular leak, valve durability, valve thrombosis, and need for pacemaker replacement. Ongoing clinical trials are expected to provide answers. PMID- 29281607 TI - CABG: A continuing evolution. AB - Use of coronary artery bypass grafting (CABG) has had a resurgence, as clinical trial data emerged showing that it remains the standard of care for patients with complex lesions. Debate exists regarding various factors, including endoscopic vs open vein-graft harvesting, single vs bilateral mammary artery grafts, radial artery vs saphenous vein grafts, right internal mammary artery vs radial artery grafts, and on-pump vs off-pump surgery. More recent developments include minimally invasive approaches, robotics, and hybrid revascularization, which are changing the risk-benefit ratio for this patient population. PMID- 29281608 TI - A new generation of drug-eluting stents: Indications and outcomes of bioresorbable vascular scaffolds. AB - Drug-eluting stents (DES) are increasingly being used as a less invasive alternative to coronary artery bypass grafting. Early generation DES had durable polymers that provided acceptable efficacy outcomes but had high rates of stent thrombosis leading to myocardial infarction and death. Second-generation DES have improved outcomes by reducing stent thrombosis and recurrent stenosis. Newer DES with biodegradable polymers have similar efficacy as second-generation DES, but have higher rates of stent thrombosis. This review compares outcomes of bioresorbable scaffolds and looks at stent technology developments that may improve outcomes. PMID- 29281609 TI - Improving the safety and efficacy of robotically assisted mitral valve surgery. AB - To improve outcomes with robotically assisted mitral valve surgery, Cleveland Clinic conducted a study evaluating outcomes in 1,000 consecutive cases. Primary areas of interest were to determine whether increased surgical experience with robotic techniques improved outcomes and to identify opportunities that could improve procedural processes. Results showed that these surgeries were effective and safe in terms of improvements in procedure time, transfusion rates, stroke risk, number of mitral valve replacements, and number of conversions to sternotomy. The development and implementation of a patient-selection algorithm halfway through the study further improved outcomes by refining patient eligibility criteria. This study showed that use of a focused preoperative assessment with an algorithm-driven patient selection process combined with increased technical expertise can enhance outcomes with robotic mitral valve surgery. PMID- 29281610 TI - Aortic replacement in cardiac surgery. AB - The number of aorta procedures performed annually in the United States has grown substantially during the past decade. Cleveland Clinic is a leader in research on the risk of aortic dissection in patients with a bicuspid or tricuspid aortic valve and associated aneurysm, which has led to changes in the recommendations of when to operate. Safety and efficacy data support more proactive treatment for most patients with thoracic aortic aneurysm and/or dissection with a growing emphasis on the need to provide life-long care to patients with aortic conditions. PMID- 29281611 TI - Association of of IL-1 receptor antagonist (IL-1RN) and interleukin-1beta genes (IL-1beta) polymorphisms with recurrent pregnancy loss in Iranian Azeri women. AB - Objective One of the most important problems in human reproduction is recurrent pregnancy loss (RPL). RPL is defined as three or more consecutive abortions in the first trimester of pregnancy. The association between the polymorphisms in the immunological factors and RPL was investigated. The aim of our study was to determine the association of interleukin receptor antagonist (IL-IRN) and interleukin-1beta (IL-1beta) polymorphisms with RPL in Iranian Azeri women. Materials and methods The study participants consisted of 100 women with RPL of Iranian Azeri origin. The control group comprised 100 age- and ethnically-matched healthy women of the same reproductive age. Genomic DNA was extracted from the whole blood and genotype determinations were performed using polymerase chain reaction (PCR) amplification followed by restriction fragment length polymorphism (RFLP) analysis. Results Our results showed no significant relationship between IL-1RN polymorphism and RPL. The homozygous state in -857 C/T variant was seen to be higher in RPL patients than in control subjects. Also frequency of wild type genotype was lower in RPL patients than in controls. However, this associations was not significant. Conclusion This study suggested that -511 C/T (rs16944) and 31 C/T (rs1143627) polymorphisms in IL-1beta gene may not be involved in RPL in Iranian Azeri women. Also the promoter polymorphism of the IL-1RN gene may not play a role in the susceptibility to RPL. PMID- 29281612 TI - Pressure-induced structural change in liquid GeI4. AB - The similarity in the shape of the melting curve of GeI4 to that of SnI4 suggests that a liquid-liquid transition as observed in liquid SnI4 is also expected to occur in liquid GeI4. Because the slope of the melting curve of GeI4 abruptly changes at around 3 GPa, in situ synchrotron diffraction measurements were conducted to examine closely the structural changes upon compression at around 3 GPa. The reduced radial distribution functions of the high- and low-pressure liquid states of GeI4 share the same feature inherent in the high-pressure (high density) and low-pressure (low-density) radial distribution functions of liquid SnI4. This feature allows us to introduce local order parameters that we may use to observe the transition. Unlike the transition in liquid SnI4, the transition from the low-pressure to the high-pressure structure seems sluggish. We speculate that the liquid-liquid critical point of GeI4 is no longer a thermodynamically stable state and is slightly located below the melting curve. As a result, the structural change is said to be a crossover rather than a transition. The behavior of the local-order parameters implies a metastable extension of the liquid-liquid phase boundary with a negative slope. PMID- 29281613 TI - Clinical Evaluation of Complications in Implant-Supported Dentures: A 4-Year Retrospective Study. AB - BACKGROUND Implants that can be used in the prosthetic rehabilitation of full and partial edentulous patients are now frequently used due to advances in dentistry. Despite advanced methods of applications, failures and complications can still be seen. The aim of our study was to evaluate clinical prosthetic values and complications that occurred during 4-year follow-up in implant-supported restorations. MATERIAL AND METHODS This retrospective study included 40 patients who received oral rehabilitation with an implant-supported prosthesis. A total of 162 implants were placed: 99 in the maxilla and 63 in the mandible. The prosthetic and surgical data were recorded. Data including prosthetic complications and implant loss were recorded and statistically analyzed using Cox proportional hazard regression analysis. RESULTS In total, 159 implants (98.14%) survived, 3 implants (1.86%) failed, and 100% of the protheses were successful. There were 62 dental implants used as abutments for removable dentures and 97 for fixed dentures. The most frequent prosthetic complications after placement of an implant-supported prosthesis were loss of retention, mucositis, abutment screw loosening, and fracture. Patient satisfaction after prosthesis use was also evaluated, showing that satisfaction was systematically increased. CONCLUSIONS To minimize the frequency of complications, protocols must be established from diagnosis to the completion of treatment and follow-up of implant-supported prostheses, especially in terms of adequate technical steps and careful radiographic evaluation of the components. PMID- 29281614 TI - Potential contribution of erythrocyte microRNA to secondary erythrocytosis and thrombocytopenia in congenital heart disease. AB - BackgroundChildren with cyanotic heart disease develop secondary erythrocytosis and thrombocytopenia via unknown mechanisms. Mature erythrocyte microRNAs may reflect clinical pathologies and cell differentiation processes pre-enucleation. This study evaluated erythrocyte microRNAs in children with cyanotic heart disease.MethodsErythrocyte microRNAs from children with cyanotic and acyanotic heart disease and without cardiac disease were quantified with Ion PGM System (n=10 per group). Differential expression was confirmed by quantitative PCR (qPCR; n=20 per group).ResultsMir-486-3p, mir-486-5p, and mir-155-5p increased in patients with cyanotic heart disease compared with those without heart disease: fold differences (95% confidence interval): mir-486-3p: 1.92 (1.14-3.23), P=0.011; mir-486-5p: 2.27 (1.41-3.65), P<0.001; and mir-155-5p: 1.44 (1.03-2.03), P=0.028. Mir-486-5p was increased, and let-7e-5p and mir-1260a were decreased in patients with acyanotic heart disease compared with those without heart disease: mir-486-5p: 1.66 (1.03-2.66), P=0.035; let-7e-5p: 0.66 (0.44-0.99), P=0.049; and mir-1260a: 0.53 (0.29-0.99), P=0.045.ConclusionSeveral microRNA levels changed in children with cyanotic and acyanotic heart disease. Mir-486-3p and -5p are associated with hematopoietic differentiation. Mir-486-3p regulates the erythroid vs. megakaryocyte lineage fate decision. Mir-155 is a hypoxia-inducible microRNA, whose overexpression inhibits megakaryocyte differentiation. Erythrocyte microRNA expression changes may contribute to erythrocytosis and thrombocytopenia in children with cyanotic heart disease. PMID- 29281615 TI - Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing TLR4 in a murine model. AB - BackgroundThe toll-like receptor 4 (TLR4) has been reported to play an important role in necrotizing enterocolitis (NEC). As an established regulator of TLR4, vitamin D has been demonstrated to be intestinal-protective. This study aims at finding out whether the vitamin D/vitamin D receptor (VDR) pathway ameliorates NEC by regulating TLR4.MethodsSerum 25-hydrovitamin D (25(OH)D) was tested and compared in 15 preterm infants with NEC, 12 preterm infants without known complications and 20 healthy term infants. Neonatal Wistar rats were grouped and NEC was induced through formula feeding and cold/asphyxia stress. Vitamin D and the vehicle were administered to compare the microscopic structure, apoptotic protein expression, intestinal barrier function, inflammatory response, and TLR4 expression.ResultsPreterm infants with NEC had significantly lower 25(OH)D levels than those without NEC and healthy subjects. VDR expression was suppressed, whereas TLR4 expression was elevated in the NEC intestine. Vitamin D may increase the survival rate, alleviate structure damage, and preserve intestinal barrier function. These were achieved partly through restoration of VDR and suppression of TLR4.ConclusionNEC infants have lower levels of vitamin D. The vitamin D/VDR pathway protects against intestinal injury of NEC partly through suppressing the expression of TLR4. PMID- 29281616 TI - Influence of the type of congenital heart defects on epithelial lining fluid composition in infants undergoing cardiac surgery with cardiopulmonary bypass. AB - BackgroundIn children with congenital heart disease (CHD), altered pulmonary circulation compromises gas exchange. Moreover, pulmonary dysfunction is a complication of cardiac surgery with cardiopulmonary bypass (CPB). No data are available on the effect of different CHDs on lung injury. The aim of this study was to analyze epithelial lining fluid (ELF) surfactant composition in children with CHD.MethodsTracheal aspirates (TAs) from 72 CHD children (age 2.9 (0.4-5.7) months) were obtained before and after CPB. We measured ELF phospholipids, surfactant proteins A and B (SP-A, SP-B), albumin, and myeloperoxidase activity. TAs from 12 infants (age 1.0 (0.9-2.9) months) with normal heart/lung served as controls.ResultsHeart defects were transposition of great arteries (19), tetralogy of Fallot (TOF, 20), atrial/ventricular septal defect (ASD/VSD, 22), and hypoplastic left heart syndrome (11). Increased levels of ELF SP-B were found in all defects, increased myeloperoxidase activity in all except the TOF, and increased levels of ELF albumin and SP-A only in ASD/VSD patients. Postoperatively, ELF findings remained unchanged except for a further increase in myeloperoxidase activity.ConclusionELF composition has distinctive patterns in different CHD. We speculate that a better knowledge of the ELF biochemical changes may help to prevent respiratory complications. PMID- 29281617 TI - Reference values for a fetal movement acceleration measurement recorder to count fetal movements. AB - BackgroundA newly developed fetal movement acceleration measurement recorder has made it possible to count gross movements for hours. The purpose of this study was to determine the normal reference values for such movements.MethodsOne hundred and six pregnant women recorded fetal movements by themselves when they slept at home weekly from 28 weeks to term. The normal reference values were determined based on the data that could be recorded for more than 4 h per night.ResultsA total of 2,458 h of data from 385 recordings from 64 women was available. The median ratio of 10-s periods in which fetal movements occurred to the total time interval was 17% at 28 gestational weeks, decreasing to ~6% at term. The number of fetal movements was 74 times/h, decreasing to 29 times at term. The number, the mean, and the longest durations of periods with no fetal movement, meaning no fetal movements were found for more than 5 min, were 1.56 times/h, 7.95 and 14.25 min, respectively, at 28 weeks, and increasing to 2.54 times, and 9.63 and 19.67 min, respectively, at term.ConclusionsThis study provides normal reference values for gross fetal movement count using the fetal movement acceleration measurement recorder. PMID- 29281619 TI - Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews. AB - BACKGROUND: Benzathine penicillin G (BPG) is the only recommended treatment to prevent mother-to-child transmission of syphilis. Due to recent reports of country-level shortages of BPG, an evaluation was undertaken to quantify countries that have experienced shortages in the past 2 years and to describe factors contributing to these shortages. METHODS AND FINDINGS: Country-level data about BPG shortages were collected using 3 survey approaches. First, a survey designed by the WHO Department of Reproductive Health and Research was distributed to 41 countries and territories in the Americas and 41 more in Africa. Second, WHO conducted an email survey of 28 US Centers for Disease Control and Prevention country directors. An additional 13 countries were in contact with WHO for related congenital syphilis prevention activities and also reported on BPG shortages. Third, the Clinton Health Access Initiative (CHAI) collected data from 14 countries (where it has active operations) to understand the extent of stock-outs, in-country purchasing, usage behavior, and breadth of available purchasing options to identify stock-outs worldwide. CHAI also conducted in-person interviews in the same 14 countries to understand the extent of stock-outs, in-country purchasing and usage behavior, and available purchasing options. CHAI also completed a desk review of 10 additional high-income countries, which were also included. BPG shortages were attributable to shortfalls in supply, demand, and procurement in the countries assessed. This assessment should not be considered globally representative as countries not surveyed may also have experienced BPG shortages. Country contacts may not have been aware of BPG shortages when surveyed or may have underreported medication substitutions due to desirability bias. Funding for the purchase of BPG by countries was not evaluated. In all, 114 countries and territories were approached to provide information on BPG shortages occurring during 2014-2016. Of unique countries and territories, 95 (83%) responded or had information evaluable from public records. Of these 95 countries and territories, 39 (41%) reported a BPG shortage, and 56 (59%) reported no BPG shortage; 10 (12%) countries with and without BPG shortages reported use of antibiotic alternatives to BPG for treatment of maternal syphilis. Market exits, inflexible production cycles, and minimum order quantities affect BPG supply. On the demand side, inaccurate forecasts and sole sourcing lead to under-procurement. Clinicians may also incorrectly prescribe BPG substitutes due to misperceptions of quality or of the likelihood of adverse outcomes. CONCLUSIONS: Targets for improvement include drug forecasting and procurement, and addressing provider reluctance to use BPG. Opportunities to improve global supply, demand, and use of BPG should be prioritized alongside congenital syphilis elimination efforts. PMID- 29281618 TI - Physiological models of the lateral superior olive. AB - In computational biology, modeling is a fundamental tool for formulating, analyzing and predicting complex phenomena. Most neuron models, however, are designed to reproduce certain small sets of empirical data. Hence their outcome is usually not compatible or comparable with other models or datasets, making it unclear how widely applicable such models are. In this study, we investigate these aspects of modeling, namely credibility and generalizability, with a specific focus on auditory neurons involved in the localization of sound sources. The primary cues for binaural sound localization are comprised of interaural time and level differences (ITD/ILD), which are the timing and intensity differences of the sound waves arriving at the two ears. The lateral superior olive (LSO) in the auditory brainstem is one of the locations where such acoustic information is first computed. An LSO neuron receives temporally structured excitatory and inhibitory synaptic inputs that are driven by ipsi- and contralateral sound stimuli, respectively, and changes its spike rate according to binaural acoustic differences. Here we examine seven contemporary models of LSO neurons with different levels of biophysical complexity, from predominantly functional ones ('shot-noise' models) to those with more detailed physiological components (variations of integrate-and-fire and Hodgkin-Huxley-type). These models, calibrated to reproduce known monaural and binaural characteristics of LSO, generate largely similar results to each other in simulating ITD and ILD coding. Our comparisons of physiological detail, computational efficiency, predictive performances, and further expandability of the models demonstrate (1) that the simplistic, functional LSO models are suitable for applications where low computational costs and mathematical transparency are needed, (2) that more complex models with detailed membrane potential dynamics are necessary for simulation studies where sub-neuronal nonlinear processes play important roles, and (3) that, for general purposes, intermediate models might be a reasonable compromise between simplicity and biological plausibility. PMID- 29281620 TI - Dual-strain genital herpes simplex virus type 2 (HSV-2) infection in the US, Peru, and 8 countries in sub-Saharan Africa: A nested cross-sectional viral genotyping study. AB - BACKGROUND: Quantitative estimation of the extent to which the immune system's protective effect against one herpes simplex virus type 2 (HSV-2) infection protects against infection with additional HSV-2 strains is important for understanding the potential for HSV-2 vaccine development. Using viral genotyping, we estimated the prevalence of HSV-2 dual-strain infection and identified risk factors. METHODS AND FINDINGS: People with and without HIV infection participating in HSV-2 natural history studies (University of Washington Virology Research Clinic) and HIV prevention trials (HIV Prevention Trials Network 039 and Partners in Prevention HSV/HIV Transmission Study) in the US, Africa, and Peru with 2 genital specimens each containing >=105 copies herpes simplex virus DNA/ml collected a median of 5 months apart (IQR: 2-11 months) were included. It is unlikely that 2 strains would be detected in the same sample simultaneously; therefore, 2 samples were required to detect dual-strain infection. We identified 85 HSV-2 SNPs that, in aggregate, could determine whether paired HSV-2 strains were the same or different with >90% probability. These SNPs were then used to create a customized high-throughput array-based genotyping assay. Participants were considered to be infected with more than 1 strain of HSV-2 if their samples differed by >=5 SNPs between the paired samples, and dual-strain infection was confirmed using high-throughput sequencing (HTS). We genotyped pairs of genital specimens from 459 people; 213 (46%) were men, the median age was 34 years (IQR: 27-44), and 130 (28%) were HIV seropositive. Overall, 272 (59%) people were from the US, 59 (13%) were from Peru, and 128 (28%) were from 8 countries in Africa. Of the 459 people, 18 (3.9%) met the criteria for dual-strain infection. HTS and phylogenetic analysis of paired specimens confirmed shedding of 2 distinct HSV-2 strains collected at different times in 17 pairs, giving an estimated dual-strain infection prevalence of 3.7% (95% CI = 2.0%-5.4%). Paired samples with dual-strain infection differed by a median of 274 SNPs in the UL_US region (range 129-413). Matching our observed dual-strain infection frequency to simulated data of varying prevalences and allowing only 2 samples per person, we inferred the true prevalence of dual strain infection to be 7%. In multivariable analysis, controlling for HIV status and continent of origin, people from Africa had a higher risk for dual-strain infection (risk ratio [RR] = 9.20, 95% CI = 2.05-41.32), as did people who were HIV seropositive (RR = 4.06, 95% CI = 1.42-11.56). CONCLUSIONS: HSV-2 dual-strain infection was detected in 3.7% of paired samples from individual participants, and was more frequent among people with HIV infection. Simulations suggest that the true prevalence of dual-strain infection is 7%. Our data indicate that naturally occurring immunity to HSV-2 may be protective against infection with a second strain. This study is limited by the inability to determine the timing of acquisition of the second strain. PMID- 29281621 TI - The translesion DNA polymerases Pol zeta and Rev1 are activated independently of PCNA ubiquitination upon UV radiation in mutants of DNA polymerase delta. AB - Replicative DNA polymerases cannot insert efficiently nucleotides at sites of base lesions. This function is taken over by specialized translesion DNA synthesis (TLS) polymerases to allow DNA replication completion in the presence of DNA damage. In eukaryotes, Rad6- and Rad18-mediated PCNA ubiquitination at lysine 164 promotes recruitment of TLS polymerases, allowing cells to efficiently cope with DNA damage. However, several studies showed that TLS polymerases can be recruited also in the absence of PCNA ubiquitination. We hypothesized that the stability of the interactions between DNA polymerase delta (Pol delta) subunits and/or between Pol delta and PCNA at the primer/template junction is a crucial factor to determine the requirement of PCNA ubiquitination. To test this hypothesis, we used a structural mutant of Pol delta in which the interaction between Pol3 and Pol31 is inhibited. We found that in yeast, rad18Delta associated UV hypersensitivity is suppressed by pol3-ct, a mutant allele of the POL3 gene that encodes the catalytic subunit of replicative Pol delta. pol3-ct suppressor effect was specifically dependent on the Rev1 and Pol zeta TLS polymerases. This result strongly suggests that TLS polymerases could rely much less on PCNA ubiquitination when Pol delta interaction with PCNA is partially compromised by mutations. In agreement with this model, we found that the pol3-FI allele suppressed rad18Delta-associated UV sensitivity as observed for pol3-ct. This POL3 allele carries mutations within a putative PCNA Interacting Peptide (PIP) motif. We then provided molecular and genetic evidence that this motif could contribute to Pol delta-PCNA interaction indirectly, although it is not a bona fide PIP. Overall, our results suggest that the primary role of PCNA ubiquitination is to allow TLS polymerases to outcompete Pol delta for PCNA access upon DNA damage. PMID- 29281622 TI - High-resolution global peptide-protein docking using fragments-based PIPER FlexPepDock. AB - Peptide-protein interactions contribute a significant fraction of the protein protein interactome. Accurate modeling of these interactions is challenging due to the vast conformational space associated with interactions of highly flexible peptides with large receptor surfaces. To address this challenge we developed a fragment based high-resolution peptide-protein docking protocol. By streamlining the Rosetta fragment picker for accurate peptide fragment ensemble generation, the PIPER docking algorithm for exhaustive fragment-receptor rigid-body docking and Rosetta FlexPepDock for flexible full-atom refinement of PIPER docked models, we successfully addressed the challenge of accurate and efficient global peptide protein docking at high-resolution with remarkable accuracy, as validated on a small but representative set of peptide-protein complex structures well resolved by X-ray crystallography. Our approach opens up the way to high-resolution modeling of many more peptide-protein interactions and to the detailed study of peptide-protein association in general. PIPER-FlexPepDock is freely available to the academic community as a server at http://piperfpd.furmanlab.cs.huji.ac.il. PMID- 29281623 TI - Full mutational mapping of titratable residues helps to identify proton-sensors involved in the control of channel gating in the Gloeobacter violaceus pentameric ligand-gated ion channel. AB - The Gloeobacter violaceus ligand-gated ion channel (GLIC) has been extensively studied by X-ray crystallography and other biophysical techniques. This provided key insights into the general gating mechanism of pentameric ligand-gated ion channel (pLGIC) signal transduction. However, the GLIC is activated by lowering the pH and the location of its putative proton activation site(s) still remain(s) unknown. To this end, every Asp, Glu, and His residue was mutated individually or in combination and investigated by electrophysiology. In addition to the mutational analysis, key mutations were structurally resolved to address whether particular residues contribute to proton sensing, or alternatively to GLIC gating, independently of the side chain protonation. The data show that multiple residues located below the orthosteric site, notably E26, D32, E35, and D122 in the lower part of the extracellular domain (ECD), along with E222, H235, E243, and H277 in the transmembrane domain (TMD), alter GLIC activation. D122 and H235 were found to also alter GLIC expression. E35 is identified as a key proton sensing residue, whereby neutralization of its side chain carboxylate stabilizes the active state. Thus, proton activation occurs allosterically to the orthosteric site, at the level of multiple loci with a key contribution of the coupling interface between the ECD and TMD. PMID- 29281625 TI - System identification of signaling dependent gene expression with different time scale data. AB - Cells decode information of signaling activation at a scale of tens of minutes by downstream gene expression with a scale of hours to days, leading to cell fate decisions such as cell differentiation. However, no system identification method with such different time scales exists. Here we used compressed sensing technology and developed a system identification method using data of different time scales by recovering signals of missing time points. We measured phosphorylation of ERK and CREB, immediate early gene expression products, and mRNAs of decoder genes for neurite elongation in PC12 cell differentiation and performed system identification, revealing the input-output relationships between signaling and gene expression with sensitivity such as graded or switch-like response and with time delay and gain, representing signal transfer efficiency. We predicted and validated the identified system using pharmacological perturbation. Thus, we provide a versatile method for system identification using data with different time scales. PMID- 29281624 TI - The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage. AB - RNA-DNA hybrids are naturally occurring obstacles that must be overcome by the DNA replication machinery. In the absence of RNase H enzymes, RNA-DNA hybrids accumulate, resulting in replication stress, DNA damage and compromised genomic integrity. We demonstrate that Mph1, the yeast homolog of Fanconi anemia protein M (FANCM), is required for cell viability in the absence of RNase H enzymes. The integrity of the Mph1 helicase domain is crucial to prevent the accumulation of RNA-DNA hybrids and RNA-DNA hybrid-dependent DNA damage, as determined by Rad52 foci. Mph1 forms foci when RNA-DNA hybrids accumulate, e.g. in RNase H or THO complex mutants and at short telomeres. Mph1, however is a double-edged sword, whose action at hybrids must be regulated by the Smc5/6 complex. This is underlined by the observation that simultaneous inactivation of RNase H2 and Smc5/6 results in Mph1-dependent synthetic lethality, which is likely due to an accumulation of toxic recombination intermediates. The data presented here support a model, where Mph1's helicase activity plays a crucial role in responding to persistent RNA-DNA hybrids. PMID- 29281626 TI - Integrated rare variant-based risk gene prioritization in disease case-control sequencing studies. AB - Rare variants of major effect play an important role in human complex diseases and can be discovered by sequencing-based genome-wide association studies. Here, we introduce an integrated approach that combines the rare variant association test with gene network and phenotype information to identify risk genes implicated by rare variants for human complex diseases. Our data integration method follows a 'discovery-driven' strategy without relying on prior knowledge about the disease and thus maintains the unbiased character of genome-wide association studies. Simulations reveal that our method can outperform a widely used rare variant association test method by 2 to 3 times. In a case study of a small disease cohort, we uncovered putative risk genes and the corresponding rare variants that may act as genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome patients. These variants were missed by a conventional approach that relied on the rare variant association test alone. PMID- 29281627 TI - An essential regulatory function of the DnaK chaperone dictates the decision between proliferation and maintenance in Caulobacter crescentus. AB - Hsp70 chaperones are well known for their important functions in maintaining protein homeostasis during thermal stress conditions. In many bacteria the Hsp70 homolog DnaK is also required for growth in the absence of stress. The molecular reasons underlying Hsp70 essentiality remain in most cases unclear. Here, we demonstrate that DnaK is essential in the alpha-proteobacterium Caulobacter crescentus due to its regulatory function in gene expression. Using a suppressor screen we identified mutations that allow growth in the absence of DnaK. All mutations reduced the activity of the heat shock sigma factor sigma32, demonstrating that the DnaK-dependent inactivation of sigma32 is a growth requirement. While most mutations occurred in the rpoH gene encoding sigma32, we also identified mutations affecting sigma32 activity or stability in trans, providing important new insight into the regulatory mechanisms controlling sigma32 activity. Most notably, we describe a mutation in the ATP dependent protease HslUV that induces rapid degradation of sigma32, and a mutation leading to increased levels of the house keeping sigma70 that outcompete sigma32 for binding to the RNA polymerase. We demonstrate that sigma32 inhibits growth and that its unrestrained activity leads to an extensive reprogramming of global gene expression, resulting in upregulation of repair and maintenance functions and downregulation of the growth-promoting functions of protein translation, DNA replication and certain metabolic processes. While this re-allocation from proliferative to maintenance functions could provide an advantage during heat stress, it leads to growth defects under favorable conditions. We conclude that Caulobacter has co-opted the DnaK chaperone system as an essential regulator of gene expression under conditions when its folding activity is dispensable. PMID- 29281628 TI - Internet-accessed sexually transmitted infection (e-STI) testing and results service: A randomised, single-blind, controlled trial. AB - BACKGROUND: Internet-accessed sexually transmitted infection testing (e-STI testing) is increasingly available as an alternative to testing in clinics. Typically this testing modality enables users to order a test kit from a virtual service (via a website or app), collect their own samples, return test samples to a laboratory, and be notified of their results by short message service (SMS) or telephone. e-STI testing is assumed to increase access to testing in comparison with face-to-face services, but the evidence is unclear. We conducted a randomised controlled trial to assess the effectiveness of an e-STI testing and results service (chlamydia, gonorrhoea, HIV, and syphilis) on STI testing uptake and STI cases diagnosed. METHODS AND FINDINGS: The study took place in the London boroughs of Lambeth and Southwark. Between 24 November 2014 and 31 August 2015, we recruited 2,072 participants, aged 16-30 years, who were resident in these boroughs, had at least 1 sexual partner in the last 12 months, stated willingness to take an STI test, and had access to the internet. Those unable to provide consent and unable to read English were excluded. Participants were randomly allocated to receive 1 text message with the web link of an e-STI testing and results service (intervention group) or to receive 1 text message with the web link of a bespoke website listing the locations, contact details, and websites of 7 local sexual health clinics (control group). Participants were free to use any other services or interventions during the study period. The primary outcomes were self-reported STI testing at 6 weeks, verified by patient record checks, and self-reported STI diagnosis at 6 weeks, verified by patient record checks. Secondary outcomes were the proportion of participants prescribed treatment for an STI, time from randomisation to completion of an STI test, and time from randomisation to treatment of an STI. Participants were sent a L10 cash incentive on submission of self-reported data. We completed all follow-up, including patient record checks, by 17 June 2016. Uptake of STI testing was increased in the intervention group at 6 weeks (50.0% versus 26.6%, relative risk [RR] 1.87, 95% CI 1.63 to 2.15, P < 0.001). The proportion of participants diagnosed was 2.8% in the intervention group versus 1.4% in the control group (RR 2.10, 95% CI 0.94 to 4.70, P = 0.079). No evidence of heterogeneity was observed for any of the pre-specified subgroup analyses. The proportion of participants treated was 1.1% in the intervention group versus 0.7% in the control group (RR 1.72, 95% CI 0.71 to 4.16, P = 0.231). Time to test, was shorter in the intervention group compared to the control group (28.8 days versus 36.5 days, P < 0.001, test for difference in restricted mean survival time [RMST]), but no differences were observed for time to treatment (83.2 days versus 83.5 days, P = 0.51, test for difference in RMST). We were unable to recruit the planned 3,000 participants and therefore lacked power for the analyses of STI diagnoses and STI cases treated. CONCLUSIONS: The e-STI testing service increased uptake of STI testing for all groups including high-risk groups. The intervention required people to attend clinic for treatment and did not reduce time to treatment. Service innovations to improve treatment rates for those diagnosed online are required and could include e-treatment and postal treatment services. e-STI testing services require long term monitoring and evaluation. TRIAL REGISTRATION: ISRCTN Registry ISRCTN13354298. PMID- 29281630 TI - Re-emerging and newly recognized sexually transmitted infections: Can prior experiences shed light on future identification and control? AB - How do we spot the next sexually transmitted infection? Kyle Bernstein and colleagues look for lessons from past discovery. PMID- 29281629 TI - Loss-of-function of the ciliopathy protein Cc2d2a disorganizes the vesicle fusion machinery at the periciliary membrane and indirectly affects Rab8-trafficking in zebrafish photoreceptors. AB - Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous organelles involved in transduction of environmental signals such as light sensation in photoreceptors. Concentration of signal detection proteins such as opsins in the ciliary membrane is achieved by RabGTPase-regulated polarized vesicle trafficking and by a selective barrier at the ciliary base, the transition zone (TZ). Dysfunction of the TZ protein CC2D2A causes Joubert/Meckel syndromes in humans and loss of ciliary protein localization in animal models, including opsins in retinal photoreceptors. The link between the TZ and upstream vesicle trafficking has been little explored to date. Moreover, the role of the small GTPase Rab8 in opsin-carrier vesicle (OCV) trafficking has been recently questioned in a mouse model. Using correlative light and electron microscopy and live imaging in zebrafish photoreceptors, we provide the first live characterization of Rab8-mediated trafficking in photoreceptors in vivo. Our results support a possibly redundant role for both Rab8a/b paralogs in OCV trafficking, based on co-localization of Rab8 and opsins in vesicular structures, and joint movement of Rab8-tagged particles with opsin. We further investigate the role of the TZ protein Cc2d2a in Rab8-mediated trafficking using cc2d2a zebrafish mutants and identify a requirement for Cc2d2a in the latest step of OCV trafficking, namely vesicle fusion. Progressive accumulation of opsin-containing vesicles in the apical portion of photoreceptors lacking Cc2d2a is caused by disorganization of the vesicle fusion machinery at the periciliary membrane with mislocalization and loss of the t-SNAREs SNAP25 and Syntaxin3 and of the exocyst component Exoc4. We further observe secondary defects on upstream Rab8 trafficking with cytoplasmic accumulation of Rab8. Taken together, our results support participation of Rab8 in OCV trafficking and identify a novel role for the TZ protein Cc2d2a in fusion of incoming ciliary-directed vesicles, through organization of the vesicle fusion machinery at the periciliary membrane. PMID- 29281632 TI - The vaginal microbiome and sexually transmitted infections are interlinked: Consequences for treatment and prevention. AB - In a Perspective for our Collection on STI research, Janneke van de Wijgert discusses the latest on how the vaginal microbiota predisposes women to acquisition of STIs and discusses future potential for clinical intervention. PMID- 29281631 TI - Local motion adaptation enhances the representation of spatial structure at EMD arrays. AB - Neuronal representation and extraction of spatial information are essential for behavioral control. For flying insects, a plausible way to gain spatial information is to exploit distance-dependent optic flow that is generated during translational self-motion. Optic flow is computed by arrays of local motion detectors retinotopically arranged in the second neuropile layer of the insect visual system. These motion detectors have adaptive response characteristics, i.e. their responses to motion with a constant or only slowly changing velocity decrease, while their sensitivity to rapid velocity changes is maintained or even increases. We analyzed by a modeling approach how motion adaptation affects signal representation at the output of arrays of motion detectors during simulated flight in artificial and natural 3D environments. We focused on translational flight, because spatial information is only contained in the optic flow induced by translational locomotion. Indeed, flies, bees and other insects segregate their flight into relatively long intersaccadic translational flight sections interspersed with brief and rapid saccadic turns, presumably to maximize periods of translation (80% of the flight). With a novel adaptive model of the insect visual motion pathway we could show that the motion detector responses to background structures of cluttered environments are largely attenuated as a consequence of motion adaptation, while responses to foreground objects stay constant or even increase. This conclusion even holds under the dynamic flight conditions of insects. PMID- 29281633 TI - Scalable multi-sample single-cell data analysis by Partition-Assisted Clustering and Multiple Alignments of Networks. AB - Mass cytometry (CyTOF) has greatly expanded the capability of cytometry. It is now easy to generate multiple CyTOF samples in a single study, with each sample containing single-cell measurement on 50 markers for more than hundreds of thousands of cells. Current methods do not adequately address the issues concerning combining multiple samples for subpopulation discovery, and these issues can be quickly and dramatically amplified with increasing number of samples. To overcome this limitation, we developed Partition-Assisted Clustering and Multiple Alignments of Networks (PAC-MAN) for the fast automatic identification of cell populations in CyTOF data closely matching that of expert manual-discovery, and for alignments between subpopulations across samples to define dataset-level cellular states. PAC-MAN is computationally efficient, allowing the management of very large CyTOF datasets, which are increasingly common in clinical studies and cancer studies that monitor various tissue samples for each subject. PMID- 29281634 TI - Competitiveness and survival of two strains of Glossina palpalis gambiensis in an urban area of Senegal. AB - BACKGROUND: In the Niayes area, located in the west of Senegal, only one tsetse species, Glossina palpalis gambiensis Vanderplank (Diptera: Glossinidae) was present. The Government of Senegal initiated and implemented an elimination programme in this area that included a sterile insect technique (SIT) component. The G. p. gambiensis strain (BKF) mass-reared at the Centre International de Recherche-Developpement sur l'Elevage en zone Subhumide (CIRDES) in Burkina Faso was used for the SIT component. METHODOLOGY/PRINCIPAL FINDINGS: Studies conducted in 2011 in four localities in the Niayes area (Pout, Sebikotane, Diacksao Peul and the Parc de Hann) showed that the BKF strain demonstrated inferior survival in the ecosystem of the Parc de Hann, a forested area in the city centre of the capital Dakar. Therefore, G. p. gambiensis flies from the Niayes area (SEN strain) were colonized. Here we compared the competitiveness and survival of the two strains (BKF and SEN) in the Parc de Hann. Released sterile males of the SEN colony showed a daily mortality rate of 0.08 (SD 0.08) as compared with 0.14 (SD 0.08) for the BKF flies but the difference was not significant (p-value = 0.14). However, the competitiveness of the SEN males was lower (0.14 (SD 0.10)) as compared with that of the BKF males (0.76 (SD 0.11)) (p-value < 10-3). CONCLUSIONS/SIGNIFICANCE: Based on the results of this study, it can be concluded that the BKF strain will remain the main strain to be used in the elimination programme. Despite the slightly longer survival of the SEN males in the Parc de Hann, the superior competitiveness of the BKF males is deemed more important for the SIT component, as their shorter survival rates can be easily compensated for by more frequent fly releases. PMID- 29281635 TI - Optical silencing of body wall muscles induces pumping inhibition in Caenorhabditis elegans. AB - Feeding, a vital behavior in animals, is modulated depending on internal and external factors. In the nematode Caenorhabditis elegans, the feeding organ called the pharynx ingests food by pumping driven by the pharyngeal muscles. Here we report that optical silencing of the body wall muscles, which drive the locomotory movement of worms, affects pumping. In worms expressing the Arch proton pump or the ACR2 anion channel in the body wall muscle cells, the pumping rate decreases after activation of Arch or ACR2 with light illumination, and recovers gradually after terminating illumination. Pumping was similarly inhibited by illumination in locomotion-defective mutants carrying Arch, suggesting that perturbation of locomotory movement is not critical for pumping inhibition. Analysis of mutants and cell ablation experiments showed that the signals mediating the pumping inhibition response triggered by activation of Arch with weak light are transferred mainly through two pathways: one involving gap junction-dependent mechanisms through pharyngeal I1 neurons, which mediate fast signals, and the other involving dense-core vesicle-dependent mechanisms, which mediate slow signals. Activation of Arch with strong light inhibited pumping strongly in a manner that does not rely on either gap junction-dependent or dense core vesicle-dependent mechanisms. Our study revealed a new aspect of the neural and neuroendocrine controls of pumping initiated from the body wall muscles. PMID- 29281636 TI - Healthcare provider perspectives on managing sexually transmitted infections in HIV care settings in Kenya: A qualitative thematic analysis. AB - BACKGROUND: The burden of sexually transmitted infections (STIs) has been increasing in Kenya, as is the case elsewhere in sub-Saharan Africa, while measures for control and prevention are weak. The objectives of this study were to (1) describe healthcare provider (HCP) knowledge and practices, (2) explore HCP attitudes and beliefs, (3) identify structural and environmental factors affecting STI management, and (4) seek recommendations to improve the STI program in Kenya. METHODS AND FINDINGS: Using individual in-depth interviews (IDIs), data were obtained from 87 HCPs working in 21 high-volume comprehensive HIV care centers (CCCs) in 7 of Kenya's 8 regions. Transcript coding was performed through an inductive and iterative process, and the data were analyzed using NVivo 10.0. Overall, HCPs were knowledgeable about STIs, saw STIs as a priority, reported high STI co-infection amongst people living with HIV (PLHIV), and believed STIs in PLHIV facilitate HIV transmission. Most used the syndromic approach for STI management. Condoms and counseling were available in most of the clinics. HCPs believed that having an STI increased stigma in the community, that there was STI antimicrobial drug resistance, and that STIs were not prioritized by the authorities. HCPs had positive attitudes toward managing STIs, but were uncomfortable discussing sexual issues with patients in general, and profoundly for anal sex. The main barriers to the management of STIs reported were low commitment by higher levels of management, few recent STI-focused trainings, high stigma and low community participation, and STI drug stock-outs. Solutions recommended by HCPs included formulation of new STI policies that would increase access, availability, and quality of STI services; integrated STI/HIV management; improved STI training; increased supervision; standardized reporting; and community involvement in STI prevention. The key limitations of our study were that (1) participant experience and how much of their workload was devoted to managing STIs was not considered, (2) some responses may have been subject to recall and social desirability bias, and (3) patients or clients of STI services were not interviewed, and therefore their inputs were not obtained. While considering these limitations, the number and variety of facilities sampled, the mix of staff cadres interviewed, the use of a standardized instrument, and the consistency of responses add strength to our findings. CONCLUSIONS: This study showed that HCPs understood the challenges of, and solutions for, improving the management of STIs in Kenya. Commitment by higher management, training in the management of STIs, measures for reducing stigma, and introducing new policies of STI management should be considered by health authorities in Kenya. PMID- 29281637 TI - Cell envelope stress in mycobacteria is regulated by the novel signal transduction ATPase IniR in response to trehalose. AB - The cell envelope of mycobacteria is a highly unique and complex structure that is functionally equivalent to that of Gram-negative bacteria to protect the bacterial cell. Defects in the integrity or assembly of this cell envelope must be sensed to allow the induction of stress response systems. The promoter that is specifically and most strongly induced upon exposure to ethambutol and isoniazid, first line drugs that affect cell envelope biogenesis, is the iniBAC promoter. In this study, we set out to identify the regulator of the iniBAC operon in Mycobacterium marinum using an unbiased transposon mutagenesis screen in a constitutively iniBAC-expressing mutant background. We obtained multiple mutants in the mce1 locus as well as mutants in an uncharacterized putative transcriptional regulator (MMAR_0612). This latter gene was shown to function as the iniBAC regulator, as overexpression resulted in constitutive iniBAC induction, whereas a knockout mutant was unable to respond to the presence of ethambutol and isoniazid. Experiments with the M. tuberculosis homologue (Rv0339c) showed identical results. RNAseq experiments showed that this regulatory gene was exclusively involved in the regulation of the iniBAC operon. We therefore propose to name this dedicated regulator iniBAC Regulator (IniR). IniR belongs to the family of signal transduction ATPases with numerous domains, including a putative sugar-binding domain. Upon testing different sugars, we identified trehalose as an activator and metabolic cue for iniBAC activation, which could also explain the effect of the mce1 mutations. In conclusion, cell envelope stress in mycobacteria is regulated by IniR in a cascade that includes trehalose. PMID- 29281638 TI - MPLasso: Inferring microbial association networks using prior microbial knowledge. AB - Due to the recent advances in high-throughput sequencing technologies, it becomes possible to directly analyze microbial communities in human body and environment. To understand how microbial communities adapt, develop, and interact with the human body and the surrounding environment, one of the fundamental challenges is to infer the interactions among different microbes. However, due to the compositional and high-dimensional nature of microbial data, statistical inference cannot offer reliable results. Consequently, new approaches that can accurately and robustly estimate the associations (putative interactions) among microbes are needed to analyze such compositional and high-dimensional data. We propose a novel framework called Microbial Prior Lasso (MPLasso) which integrates graph learning algorithm with microbial co-occurrences and associations obtained from scientific literature by using automated text mining. We show that MPLasso outperforms existing models in terms of accuracy, microbial network recovery rate, and reproducibility. Furthermore, the association networks we obtain from the Human Microbiome Project datasets show credible results when compared against laboratory data. PMID- 29281640 TI - Sexually transmitted infections-Research priorities for new challenges. AB - In an Editorial, Guest Editors Nicola Low and Nathalie Broutet discuss the Collection on sexually transmitted infections in the context of research priorities in the field. PMID- 29281639 TI - Isolation and sequencing of Dashli virus, a novel Sicilian-like virus in sandflies from Iran; genetic and phylogenetic evidence for the creation of one novel species within the Phlebovirus genus in the Phenuiviridae family. AB - Phlebotomine sandflies are vectors of phleboviruses that cause sandfly fever or meningitis with significant implications for public health. Although several strains of these viruses had been isolated in Iran in the late 1970's, there was no recent data about the present situation at the outset of this study. Entomological investigations performed in 2009 and 2011 in Iran collected 4,770 sandflies from 10 different regions. Based on morphological identification, they were sorted into 315 pools according to species, sex, trapping station and date of capture. A phlebovirus, provisionally named Dashli virus (DASHV), was isolated from one pool of Sergentomyia spp, and subsequently DASHV RNA was detected in a second pool of Phlebotomus papatasi. Genetic and phylogenetic analyses based on complete coding genomic sequences indicated that (i) DASHV is most closely related to the Iranian isolates of Sandfly fever Sicilian virus [SFSV], (ii) there is a common ancestor to DASHV, Sandfly fever Sicilian- (SFS) and SFS-like viruses isolated in Italy, India, Turkey, and Cyprus (lineage I), (iii) DASHV is more distantly related with Corfou and Toros viruses (lineage II) although common ancestry is supported with 100% bootstrap, (iii) lineage I can be subdivided into sublineage Ia including all SFSV, SFCV and SFTV except those isolated in Iran which forms sublineage Ib (DASHV). Accordingly, we suggest to approve Sandfly fever Sicilian virus species consisting of the all aforementioned viruses. Owing that most of these viruses have been identified in human patients with febrile illness, DASHV should be considered as a potential human pathogen in Iran. PMID- 29281642 TI - Transmission of Rift Valley fever virus from European-breed lambs to Culex pipiens mosquitoes. AB - BACKGROUND: Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus of the genus Phlebovirus that is highly pathogenic to ruminants and humans. The disease is currently confined to Africa and the Arabian Peninsula, but globalization and climate change may facilitate introductions of the virus into currently unaffected areas via infected animals or mosquitoes. The consequences of such an introduction will depend on environmental factors, the availability of susceptible ruminants and the capacity of local mosquitoes to transmit the virus. We have previously demonstrated that lambs native to the Netherlands are highly susceptible to RVFV and we here report the vector competence of Culex (Cx.) pipiens, the most abundant and widespread mosquito species in the country. Vector competence was first determined after artificial blood feeding of laboratory reared mosquitoes using the attenuated Clone 13 strain. Subsequently, experiments with wild-type RVFV and mosquitoes hatched from field-collected eggs were performed. Finally, the transmission of RVFV from viremic lambs to mosquitoes was studied. PRINCIPAL FINDINGS: Artificial feeding experiments using Clone 13 demonstrated that indigenous, laboratory-reared Cx. pipiens mosquitoes are susceptible to RVFV and that the virus can be transmitted via their saliva. Experiments with wild-type RVFV and mosquitoes hatched from field-collected eggs confirmed the vector competence of Cx. pipiens mosquitoes from the Netherlands. To subsequently investigate transmission of the virus under more natural conditions, mosquitoes were allowed to feed on RVFV-infected lambs during the viremic period. We found that RVFV is efficiently transmitted from lambs to mosquitoes, although transmission was restricted to peak viremia. Interestingly, in the mosquito-exposed skin samples, replication of RVFV was detected in previously unrecognized target cells. SIGNIFICANCE: We here report the vector competence of Cx. pipiens mosquitoes from the Netherlands for RVFV. Both laboratory-reared mosquitoes and well as those hatched from field-collected eggs were found to be competent vectors. Moreover, RVFV was transmitted efficiently from indigenous lambs to mosquitoes, although the duration of host infectivity was found to be shorter than previously assumed. Interestingly, analysis of mosquito-exposed skin samples revealed previously unidentified target cells of the virus. Our findings underscore the value of including natural target species in vector competence experiments. PMID- 29281641 TI - Development of a Multilocus Sequence Typing (MLST) scheme for Treponema pallidum subsp. pertenue: Application to yaws in Lihir Island, Papua New Guinea. AB - BACKGROUND: Yaws is a neglected tropical disease, caused by Treponema pallidum subsp. pertenue. The disease causes chronic lesions, primarily in young children living in remote villages in tropical climates. As part of a global yaws eradication campaign initiated by the World Health Organization, we sought to develop and evaluate a molecular typing method to distinguish different strains of T. pallidum subsp. pertenue for disease control and epidemiological purposes. METHODS AND PRINCIPAL FINDINGS: Published genome sequences of strains of T. pallidum subsp. pertenue and pallidum were compared to identify polymorphic genetic loci among the strains. DNA from a number of existing historical Treponema isolates, as well as a subset of samples from yaws patients collected in Lihir Island, Papua New Guinea, were analyzed using these targets. From these data, three genes (tp0548, tp0136 and tp0326) were ultimately selected to give a high discriminating capability among the T. pallidum subsp. pertenue samples tested. Intragenic regions of these three target genes were then selected to enhance the discriminating capability of the typing scheme using short readily amplifiable loci. This 3-gene multilocus sequence typing (MLST) method was applied to existing historical human yaws strains, the Fribourg-Blanc simian isolate, and DNA from 194 lesion swabs from yaws patients on Lihir Island, Papua New Guinea. Among all samples tested, fourteen molecular types were identified, seven of which were found in patient samples and seven among historical isolates or DNA. Three types (JG8, TD6, and SE7) were predominant on Lihir Island. CONCLUSIONS: This MLST approach allows molecular typing and differentiation of yaws strains. This method could be a useful tool to complement epidemiological studies in regions where T. pallidum subsp. pertenue is prevalent with the overall goals of improving our understanding of yaws transmission dynamics and helping the yaws eradication campaign to succeed. PMID- 29281644 TI - Seroprevalence of antibodies against chikungunya virus in Singapore resident adult population. AB - OBJECTIVES: We determined the seroprevalence of chikungunya virus (CHIKV) infection in the adult resident population in Singapore following local outbreaks of chikungunya fever (CHIKF) in 2008-2009. METHODS: Our cross-sectional study involved residual sera from 3,293 adults aged 18-79 years who had participated in the National Health Survey in 2010. Sera were tested for IgG antibodies against CHIKV and dengue virus (DENV) and neutralizing antibodies against CHIKV. RESULTS: The prevalence of CHIKV-neutralizing antibodies among Singapore residents aged 18 79 years was 1.9% (95% confidence interval: 1.4%- 2.3%). The CHIKV seroprevalence was highest in the elderly aged 70-79 years at 11.5%, followed by those aged 30 39 years at 3.1%. Men had significantly higher CHIKV seroprevalence than women (2.5% versus 1.3%, p = 0.01). Among the three main ethnic groups, Indians had the highest seroprevalence (3.5%) compared to Chinese (1.6%) and Malays (0.7%) (p = 0.02 and p = 0.01, respectively). Multivariable logistic regression identified adults aged 30-39 years and 70-79 years, men, those of Indian ethnicity and ethnic minority groups, and residence on ground floor of public and private housing apartments as factors that were significantly associated with a higher likelihood of exposure to CHIKV. The overall prevalence of anti-DENV IgG antibodies was 56.8% (95% CI: 55.1%- 58.5%), while 1.5% (95% CI: 1.1%- 2.0%) of adults possessed both neutralizing antibodies against CHIKV and IgG antibodies against DENV. CONCLUSIONS: Singapore remains highly susceptible to CHIKV infection. There is a need to maintain a high degree of vigilance through disease surveillance and vector control. Findings from such serological study, when conducted on a regular periodic basis, could supplement surveillance to provide insights on CHIKV circulation in at-risk population. PMID- 29281643 TI - 4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection. AB - BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice. METHODOLOGY/PRINCIPAL FINDINGS: Both acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart. CONCLUSIONS/SIGNIFICANCE: The positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life. PMID- 29281646 TI - Energy-saving method for technogenic waste processing. AB - Dumps of a mining-metallurgical complex of post-Soviet Republics have accumulated a huge amount of technogenic waste products. Out of them, Kazakhstan alone has preserved about 20 billion tons. In the field of technogenic waste treatment, there is still no technical solution that leads it to be a profitable process. Recent global trends prompted scientists to focus on developing energy-saving and a highly efficient melting unit that can significantly reduce specific fuel consumption. This paper reports, the development of a new technological method smelt layer of inversion phase. The introducing method is characterized by a combination of ideal stirring and ideal displacement regimes. Using the method of affine modelling, recalculation of pilot plant's test results on industrial sample has been obtained. Experiments show that in comparison with bubbling and boiling layers of smelt, the degree of zinc recovery increases in the layer of inversion phase. That indicates the reduction of the possibility of new formation of zinc silicates and ferrites from recombined molecules of ZnO, SiO2, and Fe2O3. Calculations show that in industrial samples of the pilot plant, the consumption of natural gas has reduced approximately by two times in comparison with fuming furnace. The specific fuel consumption has reduced by approximately four times in comparison with Waelz-kiln. PMID- 29281645 TI - Rates, indications, and outcomes of caesarean section deliveries: A comparison of tribal and non-tribal women in Gujarat, India. AB - BACKGROUND: Even though the caesarean section is an essential component of comprehensive obstetric and newborn care for reducing maternal and neonatal mortality, there is a lack of data regarding caesarean section rates, its determinants and health outcomes among tribal communities in India. OBJECTIVE: The aim of this study is to estimate and compare rates, determinants, indications and outcomes of caesarean section. The article provides an assessment on how the inequitable utilization can be addressed in a community-based hospital in tribal areas of Gujarat, India. METHOD: Prospectively collected data of deliveries (N = 19923) from April 2010 to March 2016 in Kasturba Maternity Hospital was used. The odds ratio of caesarean section was estimated for tribal and non-tribal women. Decomposition analysis was done to decompose the differences in the caesarean section rates between tribal and non-tribal women. RESULTS: The caesarean section rate was significantly lower among tribal compared to the non-tribal women (9.4% vs 15.6%, p-value < 0.01) respectively. The 60% of the differences in the rates of caesarean section between tribal and non-tribal women were unexplained. Within the explained variation, the previous caesarean accounted for 96% (p-value < 0.01) of the variation. Age of the mother, parity, previous caesarean and distance from the hospital were some of the important determinants of caesarean section rates. The most common indications of caesarean section were foetal distress (31.2%), previous caesarean section (23.9%), breech (16%) and prolonged labour (11.2%). There was no difference in case fatality rate (1.3% vs 1.4%, p value = 0.90) and incidence of birth asphyxia (0.3% vs 0.6%, p-value = 0.26) comparing the tribal and non-tribal women. CONCLUSION: Similar to the prior evidences, we found higher caesarean rates among non-tribal compare to tribal women. However, the adverse outcomes were similar between tribal and non-tribal women for caesarean section deliveries. PMID- 29281647 TI - Repeat multiparametric MRI in prostate cancer patients on active surveillance. AB - INTRODUCTION: This study was conducted to describe the changes in repeat multiparametric MRI (mpMRI) occurring in prostate cancer (PCa) patients during active surveillance (AS), and to study possible associations between mpMRI related parameters in predicting prostate biopsy (Bx) Gleason score (GS) upgrading >3+3 and protocol-based treatment change (TC). MATERIALS AND METHODS: The study cohort consisted of 76 AS patients with GS 3+3 PCa and at least two consecutive mpMRIs of the prostate performed between 2006-2015. Patients were followed according to the Prostate Cancer Research International Active Surveillance (PRIAS) protocol and an additional mpMRI. The primary end points were GS upgrading (GU) (>3+3) in protocol-based Bxs and protocol-based TC. RESULTS: Out of 76 patients, 53 (69%) had progression (PIRADS upgrade, size increase or new lesion[s]), while 18 (24%) had radiologically stable disease, and 5 (7%) had regression (PIRADS or size decrease, disappearance of lesion[s]) in repeat mpMRIs during AS. PIRADS scores of 4-5 in the initial mpMRI were associated with GU (p = 0.008) and protocol-based TC (p = 0.009). Tumour progression on repeat mpMRIs was associated with TC (p = 0.045) but not with GU (p = 1.00). PIRADS scores of 4-5 predict GU (sensitivity 0.80 [95% confidence interval (CI); 0.51-0.95, specificity 0.62 [95% CI; 0.52-0.77]) with PPV and NPV values of 0.34 (95% CI; 0.21-0.55) and 0.93 (95% CI; 0.80-0.98), respectively. CONCLUSION: mpMRI is a useful tool not only to select but also to monitor PCa patients on AS. PMID- 29281648 TI - Yew (Taxus) intoxication in free-ranging cervids. AB - Wild ruminants, including deer species (cervids) have incorrectly been regarded as refractory to yew (Taxus) intoxication. This assumption has been based upon anecdotal observations of individual deer browsing on yew over time without apparent adverse effect. A single case of yew intoxication was reported in a free ranging Norwegian moose (Alces alces) in 2008. The current report describes five additional cases of yew toxicosis in moose, seven in roe deer (Capreolus capreolus) and two in reindeer (Rangifer tarandus tarandus), all in Norway. The animals were found dead during the winter, close to or within gardens containing yew plants showing signs of browsing. Gross findings included lung congestion and edema, thoracic and pericardial effusion, bilateral heart dilatation, epi- and endocardial hemorrhage, and enlarged (congested) spleen. Yew plant remnants were detected in the rumen of all animals with the exception of a single moose. Histology revealed multifocal acute myocardial degeneration and necrosis with hemorrhage in roe deer, but not in the two other species. A qualitative high performance liquid chromatography-ion trap mass spectrometry analysis was used to tentatively identify five major Taxus alkaloids (taxines) in crude yew extracts and in heart and liver samples from the moose cases. All five major taxines were detected with good signal/noise ratio in tissue samples from the four moose with visible ruminal yew content, whereas lower levels of taxines were detected in the moose without visible ruminal yew content. Possible differences in interspecies tolerance to taxines and role of individual protective adaptation are discussed. PMID- 29281649 TI - Human adipose derived stem cells regress fibrosis in a chronic renal fibrotic model induced by adenine. AB - BACKGROUND AND AIMS: ADSCs transplantation had been shown in some experimental models of kidney damage that it improves kidney function and reduces fibrosis. In this study we evaluated the effect of human adipose tissue-derived stem cell (hADSC) therapy in a chronic kidney damage experimental model. METHODS: A chronic kidney injury was induced by daily orogastric administration of adenine (100mg/kg) to male Wistar rats for 28 days. hADSCs were isolated, expanded and characterized before transplantation. hADSC administration was performed in a tail vein at a dose of 2 x106 cells/animal. Animals were sacrificed at 7 days post-treatment. The percentage of fibrotic tissue, serum and urine levels of urea, creatinine, total protein and renal mRNA of COL1A1, TGFB1, CTGF, ACTA2, IL6, IL10, TNF were analyzed. RESULTS: hADSCs treatment significantly reduces kidney fibrosis, improves urea and creatinine serum and urine levels, and diminishes COL1A1, TGFB1, CTGF, ACTA2 mRNA kidney levels. CONCLUSIONS: These results showed that cell therapy using hADSCs improves renal function and reduces fibrosis. PMID- 29281650 TI - Explosive detonation causes an increase in soil porosity leading to increased TNT transformation. AB - Explosives are a common soil contaminant at a range of sites, including explosives manufacturing plants and areas associated with landmine detonations. As many explosives are toxic and may cause adverse environmental effects, a large body of research has targeted the remediation of explosives residues in soil. Studies in this area have largely involved spiking 'pristine' soils using explosives solutions. Here we investigate the fate of explosives present in soils following an actual detonation process and compare this to the fate of explosives spiked into 'pristine' undetonated soils. We also assess the effects of the detonations on the physical properties of the soils. Our scanning electron microscopy analyses reveal that detonations result in newly-fractured planes within the soil aggregates, and novel micro Computed Tomography analyses of the soils reveal, for the first time, the effect of the detonations on the internal architecture of the soils. We demonstrate that detonations cause an increase in soil porosity, and this correlates to an increased rate of TNT transformation and loss within the detonated soils, compared to spiked pristine soils. We propose that this increased TNT transformation is due to an increased bioavailability of the TNT within the now more porous post-detonation soils, making the TNT more easily accessible by soil-borne bacteria for potential biodegradation. This new discovery potentially exposes novel remediation methods for explosive contaminated soils where actual detonation of the soil significantly promotes subsequent TNT degradation. This work also suggests previously unexplored ramifications associated with high energy soil disruption. PMID- 29281651 TI - Life course epidemiology: Modeling educational attainment with administrative data. AB - BACKGROUND: Understanding the processes across childhood and adolescence that affect later life inequalities depends on many variables for a large number of individuals measured over substantial time periods. Linkable administrative data were used to generate birth cohorts and to study pathways of inequity in childhood and early adolescence leading to differences in educational attainment. Advantages and disadvantages of using large administrative data bases for such research were highlighted. METHODS: Children born in Manitoba, Canada between 1982 and 1995 were followed until age 19 (N = 89,763), with many time-invariant measures serving as controls. Five time-varying predictors of high school graduation-three social and two health-were modelled using logistic regression and a framework for examining predictors across the life course. For each time varying predictor, six temporal patterns were tested: full, accumulation of risk, sensitive period, and three critical period models. RESULTS: Predictors measured in early adolescence generated the highest odds ratios, suggesting the importance of adolescence. Full models provided the best fit for the three time-varying social measures. Residence in a low-income neighborhood was a particularly influential predictor of not graduating from high school. The transmission of risk across developmental periods was also highlighted; exposure in one period had significant implications for subsequent life stages. CONCLUSION: This study advances life course epidemiology, using administrative data to clarify the relationships among several measures of social behavior, cognitive development, and health. Analyses of temporal patterns can be useful in studying such other outcomes as educational achievement, teen pregnancy, and workforce participation. PMID- 29281652 TI - Basalt geochemistry reveals high frequency of prehistoric tool exchange in low hierarchy Marquesas Islands (Polynesia). AB - Exchange activities, formal or otherwise, serve a variety of purposes and were prominent in many Pacific Island societies, both during island settlement and in late prehistory. Recent Polynesian studies highlight the role of exchange in the region's most hierarchical polities where it contributed to wealth economies, emergent leadership, and status rivalry in late prehistory. Building on this research, we hypothesized that exchange in low hierarchy chiefdoms (kin-based polities where there are distinctions between commoners and elites but ranking within the latter is lacking, weak, or ephemeral) would differ in frequency and function from that associated with strongly hierarchical polities. We address this hypothesis through geochemical, morphological, and distributional analyses of stone tools on Nuku Hiva, Marquesas Islands. Non-destructive Energy-Dispersive X-ray Fluorescence (EDXRF) and destructive Wavelength-Dispersive X-ray Fluorescence (WDXRF) analyses of 278 complete and broken tools (adzes, chisels, preforms) from four valleys identify use of stone from at least seven sources on three islands: five on Nuku Hiva and one each on Eiao and Ua Pou. A functional analysis demonstrates that no tool form is limited to a particular source, while inter-valley distributions reveal that the proportions of non-local or extra valley tools (43 to 94%, mean = 77%) approximate or exceed results from other archipelagoes, including those from elite and ritual sites of Polynesian archaic states. Intra-valley patterns also are unexpected, with non-local stone tools being recovered from both elite and commoner residential areas in near-equal proportions. Our findings unambiguously demonstrate the importance of exchange in late prehistoric Marquesan society, at varied social and geographic scales. We propose the observed patterns are the result of elites using non-local tools as political currency, aimed at reinforcing status, cementing client-patron relations, and building extra-valley alliances, consistent with prestige societies elsewhere and early historic accounts from the Marquesan Islands. PMID- 29281653 TI - Genetic diversity and differentiation among insular honey bee populations in the southwest Indian Ocean likely reflect old geographical isolation and modern introductions. AB - With globalization the Western honey bee has become a nearly cosmopolitan species, but it was originally restricted to the Old World. This renowned model of biodiversity has diverged into five evolutionary lineages and several geographic "subspecies." If Apis mellifera unicolor is indubitably an African subspecies endemic to Madagascar, its relationship with honey bees from three archipelagos in the southwest Indian Ocean (SWIO) hotspot of biodiversity is misunderstood. We compared recent mtDNA diversity data to an original characterization of the nuclear diversity from honey bees in the Mascarenes and Comoros archipelagos, using 14 microsatellites, but also additional mtDNA tRNALeu cox2 analysis. Our sampling offers the most comprehensive dataset for the SWIO populations with a total of 3,270 colonies from 10 islands compared with 855 samples from Madagascar, 113 from Africa, and 138 from Europe. Comprehensive mitochondrial screening confirmed that honey bees from La Reunion, Mauritius, and Comoros archipelagos are mainly of African origin (88.1% out of 2,746 colonies) and that coexistence with European lineages occurs only in the Mascarenes. PCA, Bayesian, and genetic differentiation analysis showed that African colonies are not significantly distinct on each island, but have diversified among islands and archipelagos. FST levels progressively decreased in significance from European and African continental populations, to SWIO insular and continental populations, and finally among islands from the same archipelago. Among African populations, Madagascar shared a nuclear background with and was most closely related to SWIO island populations (except Rodrigues). Only Mauritius Island presented clear cytoplasmic disequilibrium and genetic structure characteristic of an admixed population undergoing hybridization, in this case, between A. m. unicolor and A. m. ligustica, A. m. carnica and A. m. mellifera-like individuals. Finally, global genetic clustering analysis helped to better depict the colonization and introduction pattern of honey bee populations in these archipelagos. PMID- 29281654 TI - Longitudinal effects of bilingualism on dual-tasking. AB - An ongoing debate surrounds whether bilinguals outperform monolinguals in tests of executive processing. The aim of this study was to investigate if there are long-term (10 year) bilingual advantages in executive processing, as indexed by dual-task performance, in a sample that were 40-65 years at baseline. The bilingual (n = 24) and monolingual (n = 24) participants were matched on age, sex, education, fluid intelligence, and study sample. Participants performed free recall for a 12-item list in three dual-task settings wherein they sorted cards either during encoding, retrieval, or during both encoding and retrieval of the word-list. Free recall without card sorting was used as a reference to compute dual-task costs. The results showed that bilinguals significantly outperformed monolinguals when they performed card-sorting during both encoding and retrieval of the word-list, the condition that presumably placed the highest demands on executive functioning. However, dual-task costs increased over time for bilinguals relative to monolinguals, a finding that is possibly influenced by retirement age and limited use of second language in the bilingual group. PMID- 29281655 TI - Evidence supporting oral sensitivity to complex carbohydrates independent of sweet taste sensitivity in humans. AB - Compared to simple sugars, complex carbohydrates have been assumed invisible to taste. However, two recent studies proposed that there may be a perceivable taste quality elicited by complex carbohydrates independent of sweet taste. There is precedent with behavioural studies demonstrating that rats are very attracted to complex carbohydrates, and that complex carbohydrates are preferred to simple sugars at low concentrations. This suggests that rats may have independent taste sensors for simple sugars and complex carbohydrates. The aim of this paper is to investigate oral sensitivities of two different classes of complex carbohydrates (a soluble digestible and a soluble non-digestible complex carbohydrate), and to compare these to other caloric and non-nutritive sweeteners in addition to the prototypical tastes using two commonly used psychophysical measures. There were strong correlations between the detection thresholds and mean intensity ratings for complex carbohydrates (maltodextrin, oligofructose) (r = 0.94, P < 0.001). There were no significant correlations between the detection thresholds of the complex carbohydrates (maltodextrin, oligofructose) and the sweeteners (glucose, fructose, sucralose, Rebaudioside A, erythritol) (all P > 0.05). However, moderate correlations were observed between perceived intensities of complex carbohydrates and sweeteners (r = 0.48-0.61, P < 0.05). These data provide evidence that complex carbohydrates can be sensed in the oral cavity over a range of concentrations independent of sweet taste sensitivity at low concentrations, but with partial overlap with sweet taste intensity at higher concentrations. PMID- 29281656 TI - Bark anatomy, chemical composition and ethanol-water extract composition of Anadenanthera peregrina and Anadenanthera colubrina. AB - The bark of Anadenanthera peregrina (L.) Speg and Anadenanthera colubrina (Vell.) Brenan were characterized in relation to anatomical and chemical features. The barks were similar and included a thin conducting phloem, a largely dilated and sclerified non-conducting phloem, and a rhyridome with periderms with thin phellem interspersed by cortical tissues. Only small differences between species were observed that cannot be used alone for taxonomic purposes. The summative chemical composition of A. peregrina and A. colubrina was respectively: 8.2% and 7.7% ash; 28.8% and 29.3% extractives; 2.4% and 2.6% suberin; and 18.9% lignin. The monosaccharide composition showed the predominance of glucose (on average 82% of total neutral sugars) and of xylose (9%). The ethanol-water extracts of A. peregrina and A. colubrina barks included a high content of phenolics, respectively: total phenolics 583 and 682 mg GAE/g extract; 148 and 445 mg CE/g extract; tannins 587 and 98 mg CE/g extract. The antioxidant activity was 238 and 269 mg Trolox/g extract. The barks of the Anadenanthera species are a potential source of polar extractives that will represent an important valorization and therefore contribute to improve the overall economic potential and sustainability of A. peregrina and A. colubrina. PMID- 29281657 TI - Indoles induce metamorphosis in a broad diversity of jellyfish, but not in a crown jelly (Coronatae). AB - Many animals go through one or more metamorphoses during their lives, however, the molecular underpinnings of metamorphosis across diverse species are not well understood. Medusozoa (Cnidaria) is a clade of animals with complex life cycles, these life cycles can include a polyp stage that metamorphoses into a medusa (jellyfish). Medusae are produced through a variety of different developmental mechanisms-in some species polyps bud medusae (Hydrozoa), in others medusae are formed through polyp fission (Scyphozoa), while in others medusae are formed through direct transformation of the polyp (Cubozoa). To better understand the molecular mechanisms that may coordinate these different forms of metamorphosis, we tested two compounds first identified to induce metamorphosis in the moon jellyfish Aurelia aurita (indomethacin and 5-methoxy-2-methylindole) on a broad diversity of medusozoan polyps. We discovered that indole-containing compounds trigger metamorphosis across a broad diversity of species. All tested discomedusan polyps metamorphosed in the presence of both compounds, including species representatives of several major lineages within the clade (Pelagiidae, Cyaneidae, both clades of Rhizostomeae). In a cubozoan, low levels of 5-methoxy-2 methylindole reliably induced complete and healthy metamorphosis. In contrast, neither compound induced medusa metamorphosis in a coronate scyphozoan, or medusa production in either hydrozoan tested. Our results support the hypothesis that metamorphosis is mediated by a conserved induction pathway within discomedusan scyphozoans, and possibly cubozoans. However, failure of these compounds to induce metamorphosis in a coronate suggests this induction mechanism may have been lost in this clade, or is convergent between Scyphozoa and Cubozoa. PMID- 29281658 TI - Attitudes and norms affecting scientists' data reuse. AB - The value of sharing scientific research data is widely appreciated, but factors that hinder or prompt the reuse of data remain poorly understood. Using the Theory of Reasoned Action, we test the relationship between the beliefs and attitudes of scientists towards data reuse, and their self-reported data reuse behaviour. To do so, we used existing responses to selected questions from a worldwide survey of scientists developed and administered by the DataONE Usability and Assessment Working Group (thus practicing data reuse ourselves). Results show that the perceived efficacy and efficiency of data reuse are strong predictors of reuse behaviour, and that the perceived importance of data reuse corresponds to greater reuse. Expressed lack of trust in existing data and perceived norms against data reuse were not found to be major impediments for reuse contrary to our expectations. We found that reported use of models and remotely-sensed data was associated with greater reuse. The results suggest that data reuse would be encouraged and normalized by demonstration of its value. We offer some theoretical and practical suggestions that could help to legitimize investment and policies in favor of data sharing. PMID- 29281659 TI - Immunogenicity of rotavirus vaccine (RotarixTM) in infants with environmental enteric dysfunction. AB - INTRODUCTION: Deployment of rotavirus vaccines has contributed to significant declines in diarrheal morbidity and mortality globally. Unfortunately, vaccine performance in low-middle income countries (LMICs) is generally lower than in developed countries. The cause for this has been associated with several host and maternal factors including poor water sanitation and hygiene (WASH) status, which are predominant in LMICs. More recently, environmental enteric dysfunction (EED) has specifically been hypothesized to contribute to poor vaccine uptake and response. The aim of this study was to examine the association between serological biomarkers of EED and seroconversion to rotavirus vaccine in Zambian infants. METHODS: This was a retrospective cohort study of 142 infants who had been fully immunized with RotarixTM, and had known seroconversion status. Seroconversion was defined as 4-fold or more increase in rotavirus-specific IgA titres between pre-vaccination and one month post-dose two vaccination. We performed ELISA assays to assess soluble CD14 (sCD14), Endotoxin Core IgG Antibodies (EndoCAb), intestinal fatty acid binding protein (i-FABP) and Zonulin according to the manufacturers protocols. Generalised linear model with family poisson, link-log and robust standard error was used to estimate the independent effects of biomarkers on seroconversion adjusting for important cofounders. RESULTS: The median concentration of Zonulin, Soluble CD14, EndoCaB, and IFABP were 209.3 (IQR = 39.7, 395.1), 21.5 (IQR = 21.5, 21.5), 0.3 (IQR = 0.3, 0.3), and 107.7 (IQR = 6.4, 1141.4) respectively. In multivariable analyses adjusting for the independent effect of other biomarkers and confounders (i.e. age of child at vaccination, breast-milk anti-rotavirus IgA, infant serum anti-rotavirus IgG, and IgA seropositivity at baseline), there was strong evidence of about 24% increase in seroconversion due to doubling Zonulin concentration (Adjusted risk ratio (aRR) = 1.24; 95% CI = 1.12 to1.37; p<0.0001). Similarly, we found about 7% increase in seroconversion due to doubling IFABP concentration (aRR = 1.07; 95% CI = 1.02 to 1.13; p = 0.006). CONCLUSION: We found that high levels of zonulin and IFABP played a role in seroconversion. It is plausible that increased gut permeability in EED allows greater uptake of the live virus within the vaccine, but later consequences result in deleterious local structural distortions and malabsorption syndromes. PMID- 29281660 TI - Technological variability in the Late Palaeolithic lithic industries of the Egyptian Nile Valley: The case of the Silsilian and Afian industries. AB - During the Nubia Salvage Campaign and the subsequent expeditions from the 1960's to the 1980's, numerous sites attributed to the Late Palaeolithic (~25-15 ka) were found in the Nile Valley, particularly in Nubia and Upper Egypt. This region is one of the few to have allowed human occupations during the dry Marine Isotope Stage 2 and is therefore key to understanding how human populations adapted to environmental changes at this time. This paper focuses on two sites located in Upper Egypt, excavated by the Combined Prehistoric Expedition: E71K18, attributed to the Afian industry and E71K20, attributed to the Silsilian industry. It aims to review the geomorphological and chronological evidence of the sites, present a technological analysis of the lithic assemblages in order to provide data that can be used in detailed comparative studies, which will allow discussion of technological variability in the Late Palaeolithic of the Nile Valley and its place within the regional context. The lithic analysis relies on the chaine operatoire concept combined with an attribute analysis to allow quantification. This study (1) casts doubts on the chronology of E71K18 and related Afian industry, which could be older or younger than previously suggested, highlights (2) distinct technological characteristics for the Afian and the Silsilian, as well as (3) similar technological characteristics which allow to group them under a same broad techno-cultural complex, distinct from those north or south of the area. PMID- 29281662 TI - A rich diversity of opercle bone shape among teleost fishes. AB - The opercle is a prominent craniofacial bone supporting the gill cover in all bony fish and has been the subject of morphological, developmental, and genetic investigation. We surveyed the shapes of this bone among 110 families spanning the teleost tree and examined its pattern of occupancy in a principal component based morphospace. Contrasting with expectations from the literature that suggest the local morphospace would be only sparsely occupied, we find primarily dense, broad filling of the morphological landscape, indicating rich diversity. Phylomorphospace plots suggest that dynamic evolution underlies the observed spatial patterning. Evolutionary transits through the morphospaces are sometimes long, and occur in a variety of directions. The trajectories seem to represent both evolutionary divergences and convergences, the latter supported by convevol analysis. We suggest that that this pattern of occupancy reflects the various adaptations of different groups of fishes, seemingly paralleling their diverse marine and freshwater ecologies and life histories. Opercle shape evolution within the acanthomorphs, spiny ray-finned fishes, appears to have been especially dynamic. PMID- 29281661 TI - The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat. AB - Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat's cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR 21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent. PMID- 29281663 TI - Circulating and broncho-alveolar interleukin-6 in relation to body temperature in an experimental model of bovine Chlamydia psittaci infection. AB - In rodent models of experimentally induced fever, the important role of interleukin-6 (IL-6) as a circulating endogenous pyrogen is well established. Studies employing larger animal species and real infections are scarce. Therefore, we assessed bioactive IL-6 in peripheral blood and in broncho-alveolar lavage fluid (BALF) of calves after intra-bronchial inoculation with vital Chlamydia psittaci (Cp), with inactivated Cp, or with BGM cells. Only calves inoculated with vital Cp developed fever (peak at 2-3 days after challenge) and significantly increased IL-6 activity. Controls inoculated with either inactivated Cp or BGM cells also expressed increased bioactive IL-6, but no fever developed. Activity of IL-6 in BALF was significantly higher compared to blood serum. This experimental model of Cp infection revealed no apparent relation between IL-6 in blood and body temperature, but did reveal a relation between IL 6 and other markers of inflammation in BALF. We conclude that a local inflammatory response in the lungs of infected calves caused fever, which developed by mechanisms including other mediators besides IL-6. PMID- 29281665 TI - Designing a more efficient, effective and safe Medical Emergency Team (MET) service using data analysis. AB - INTRODUCTION: Hospitals have seen a rise in Medical Emergency Team (MET) reviews. We hypothesised that the commonest MET calls result in similar treatments. Our aim was to design a pre-emptive management algorithm that allowed direct institution of treatment to patients without having to wait for attendance of the MET team and to model its potential impact on MET call incidence and patient outcomes. METHODS: Data was extracted for all MET calls from the hospital database. Association rule data mining techniques were used to identify the most common combinations of MET call causes, outcomes and therapies. RESULTS: There were 13,656 MET calls during the 34-month study period in 7936 patients. The most common MET call was for hypotension [31%, (2459/7936)]. These MET calls were strongly associated with the immediate administration of intra-venous fluid (70% [1714/2459] v 13% [739/5477] p<0.001), unless the patient was located on a respiratory ward (adjusted OR 0.41 [95%CI 0.25-0.67] p<0.001), had a cardiac cause for admission (adjusted OR 0.61 [95%CI 0.50-0.75] p<0.001) or was under the care of the heart failure team (adjusted OR 0.29 [95%CI 0.19-0.42] p<0.001). Modelling the effect of a pre-emptive management algorithm for immediate fluid administration without MET activation on data from a test period of 24 months following the study period, suggested it would lead to a 68.7% (2541/3697) reduction in MET calls for hypotension and a 19.6% (2541/12938) reduction in total METs without adverse effects on patients. CONCLUSION: Routinely collected data and analytic techniques can be used to develop a pre-emptive management algorithm to administer intravenous fluid therapy to a specific group of hypotensive patients without the need to initiate a MET call. This could both lead to earlier treatment for the patient and less total MET calls. PMID- 29281664 TI - Diversification rates, host plant shifts and an updated molecular phylogeny of Andean Eois moths (Lepidoptera: Geometridae). AB - Eois is one of the best-investigated genera of tropical moths. Its close association with Piper plants has inspired numerous studies on life histories, phylogeny and evolutionary biology. This study provides an updated view on phylogeny, host plant use and temporal patterns of speciation in Eois. Using sequence data (2776 bp) from one mitochondrial (COI) and one nuclear gene (Ef1 alpha) for 221 Eois species, we confirm and reinforce previous findings regarding temporal patterns of diversification. Deep diversification within Andean Eois took place in the Miocene followed by a sustained high rate of diversification until the Pleistocene when a pronounced slowdown of speciation is evident. In South America, Eois diversification is very likely to be primarily driven by the Andean uplift which occurred concurrently with the entire evolutionary history of Eois. A massively expanded dataset enabled an in-depth look into the phylogenetic signal contained in host plant usage. This revealed several independent shifts from Piper to other host plant genera and families. Seven shifts to Peperomia, the sister genus of Piper were detected, indicating that the shift to Peperomia was an easy one compared to the singular shifts to the Chloranthaceae, Siparunaceae and the Piperacean genus Manekia. The potential for close co evolution of Eois with Piper host plants is therefore bound to be limited to smaller subsets within Neotropical Eois instead of a frequently proposed genus wide co-evolutionary scenario. In regards to Eois systematics we confirm the monophyly of Neotropical Eois in relation to their Old World counterparts. A tentative biogeographical hypothesis is presented suggesting that Eois originated in tropical Asia and subsequently colonized the Neotropics and Africa. Within Neotropical Eois we were able to identify the existence of six clades not recognized in previous studies and confirm and reinforce the monophyly of all 9 previously delimited infrageneric clades. PMID- 29281667 TI - Urothelial MaxiK-activity regulates mucosal and detrusor metabolism. AB - There is increasing evidence for a role of MaxiK potassium channel-activity in regulating the metabolism and intracellular signaling of non-contractile bladder mucosal tissues. At present however no studies have determined the impact of urothelial MaxiK-activity on overall bladder metabolism. To address this we have investigated the effect of bladder lumen instillation of the MaxiK inhibitor, iberiotoxin (IBTX), on mucosal and detrusor metabolism using metabolomics. Since IBTX does not cross plasma membranes, when instilled into the bladder lumen it would only effect urothelially expressed MaxiK-activity. Surprisingly IBTX treatment caused more effect on the metabolome of the detrusor than mucosa (the levels of 17% of detected detrusor metabolites were changed in comparison to 6% of metabolites in mucosal tissue following IBTX treatment). In mucosal tissues, the major effects can be linked to mitochondrial-associated metabolism whereas in detrusor there were additional changes in energy generating pathways (such as glycolysis and the TCA cycle). In the detrusor, changes in metabolism are potentially a result of IBTX effecting MaxiK-linked signaling pathways between the mucosa and detrusor, secondary to changes in physiological activity or a combination of both. Overall we demonstrate that urothelial MaxiK-activity plays a significant role in determining mitochondrially-associated metabolism in mucosal tissues, which effects the metabolism of detrusor tissue. Our work adds further evidence that the urothelium plays a major role in determining overall bladder physiology. Since decreased MaxiK-activity is associated with several bladder pathophysiology's, the changes in mucosal metabolism reported here may represent novel downstream targets for therapeutic interventions. PMID- 29281668 TI - Plant invasion: Another threat to the Sao Paulo Marsh Antwren (Formicivora paludicola), a species on the verge of extinction. AB - During the past 100 years in densely populated south-eastern Brazil, wetlands have been severely transformed due to urbanization, agriculture and mining. The recently discovered Sao Paulo Marsh Antwren (Formicivora paludicola) is endemic to these wetlands, and is listed as "Critically Endangered" by the IUCN. The species is only found in an area of 1.42 km2, it has a sparse and fragmented distribution, low dispersal capacity, and has probably lost around 300 km2 of habitat in the past 100 years. Furthermore, very little is known about F. paludicola natural history, and so it is difficult to construct a robust conservation plan. Using Kernel home range estimations and the Adjusted-SD/Torus Shift test (a novel tool for animal-habitat association studies), we showed that the species avoids patches of the alien invasive ginger lily (Hedychium coronarium). Given the high density of their population (3.6 mature individuals/ha), F. paludicola could thrive in relatively small areas of suitable wetlands protected from human occupation and water contamination, however special attention should be paid to biological invasions, which may represent a serious threat to the remaining populations. Protecting a few small wetlands used by F. paludicola would be an important step towards general conservation and restoration of Atlantic Forest wetlands and its endemic endangered species. PMID- 29281666 TI - Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men. AB - INTRODUCTION: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin. METHODS: Statistical analyses of individual participant data from 12,330 male controls aged 25-85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates. RESULTS: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones. CONCLUSION: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption. PMID- 29281669 TI - Late Bronze Age climate change and the destruction of the Mycenaean Palace of Nestor at Pylos. AB - This paper offers new high-resolution oxygen and carbon isotope data from Stalagmite S1 from Mavri Trypa Cave, SW Peloponnese. Our data provide the climate background to the destruction of the nearby Mycenaean Palace of Nestor at Pylos at the transition from Late Helladic (LH) IIIB to LH IIIC, ~3150-3130 years before present (before AD 1950, hereafter yrs BP) and the subsequent period. S1 is dated by 24 U-Th dates with an averaged precision of +/-26 yrs (2sigma), providing one of the most robust paleoclimate records from the eastern Mediterranean for the end of the Late Bronze Age (LBA). The delta18O record shows generally wetter conditions at the time when the Palace of Nestor at Pylos was destroyed, but a brief period of drier conditions around 3200 yrs BP may have disrupted the Mycenaean agricultural system that at the time was likely operating close to its limit. Gradually developing aridity after 3150 yrs BP, i.e. subsequent to the destruction, probably reduced crop yields and helped to erode the basis for the reinstitution of a central authority and the Palace itself. PMID- 29281670 TI - Submovement control processes in discrete aiming as a function of space-time constraints. AB - There is preliminary evidence that there are several types of submovements in movement aiming that reflect different processes of control and can result from particular task constraints. The purpose of the study was to investigate the effect of movement space and time task criteria on the prevalence of different submovement control characteristics in discrete aiming. Twelve participants completed 3 distance x 5 time conditions each with 100 trials in a target-aiming movement task. The kinematic structure of the trajectory determined the prevalence of 5 submovement types (none; pre-peak, post-peak movement velocity; undershoot, overshoot). The findings showed that the overall number of submovements increased in the slower space-time conditions and was predominantly characterized by post-peak trajectory submovements rather than discrete overshoot submovements. Overshoot submovements were more frequent in the high average movement velocity and short time duration conditions. We concluded that there are qualitatively different distributional patterns of submovement types in discrete aiming tasks that are organized by the quantitative scaling of the average movement velocity arising from multiple control processes to meet the specific space-time task constraints. PMID- 29281671 TI - Short telomere length in IPF lung associates with fibrotic lesions and predicts survival. AB - Telomere maintenance dysfunction has been implicated in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). However, the mechanism of how telomere length is related to fibrosis in the lungs is unknown. Surgical lung biopsies of IPF patients typically show a heterogeneous pattern of non-fibrotic and fibrotic areas. Therefore, telomere length (TL) in both lung areas of patients with IPF and familial interstitial pneumonia was compared, specifically in alveolar type 2 (AT2) cells. Fluorescent in situ hybridization was used to determine TL in non fibrotic and fibrotic areas of 35 subjects. Monochrome multiplex quantitative polymerase chain reaction (MMqPCR) was used for 51 whole lung biopsies and blood TL measurements. For sporadic IPF subjects, AT2 cell TL in non-fibrotic areas was 56% longer than in fibrotic areas. No such difference was observed in the surrounding lung cells. In subjects carrying a telomerase reverse transcriptase (TERT) mutation, AT2 cell TL was significantly shorter than in sporadic subjects. However, no difference in surrounding cell TL was observed between these subject groups. Finally, using biopsy MMqPCR TL measurements, it was determined that IPF subjects with shortest lung TL had a significantly worse survival than patients with long TL. This study shows that shortening of telomeres critically affects AT2 cells in fibrotic areas, implying TL as a cause of fibrogenesis. Furthermore, short lung telomere length is associated with decreased survival. PMID- 29281672 TI - Effects of urbanization on host-pathogen interactions, using Yersinia in house sparrows as a model. AB - Urbanization strongly affects biodiversity, altering natural communities and often leading to a reduced species richness. Yet, despite its increasingly recognized importance, how urbanization impacts on the health of individual animals, wildlife populations and on disease ecology remains poorly understood. To test whether, and how, urbanization-driven ecosystem alterations influence pathogen dynamics and avian health, we use house sparrows (Passer domesticus) and Yersinia spp. (pathogenic for passerines) as a case study. Sparrows are granivorous urban exploiters, whose western European populations have declined over the past decades, especially in highly urbanized areas. We sampled 329 house sparrows originating from 36 populations along an urbanization gradient across Flanders (Belgium), and used isolation combined with 'matrix-assisted laser desorption ionization- time of flight mass spectrometry' (MALDI-TOF MS) and PCR methods for detecting the presence of different Yersinia species. Yersinia spp. were recovered from 57.43% of the sampled house sparrows, of which 4.06%, 53.30% and 69.54% were identified as Y. pseudotuberculosis, Y. enterocolitica and other Yersinia species, respectively. Presence of Yersinia was related to the degree of urbanization, average daily temperatures and the community of granivorous birds present at sparrow capture locations. Body condition of suburban house sparrows was found to be higher compared to urban and rural house sparrows, but no relationships between sparrows' body condition and presence of Yersinia spp. were found. We conclude that two determinants of pathogen infection dynamics, body condition and pathogen occurrence, vary along an urbanization gradient, potentially mediating the impact of urbanization on avian health. PMID- 29281673 TI - Taxonomic differences of gut microbiomes drive cellulolytic enzymatic potential within hind-gut fermenting mammals. AB - Host diet influences the diversity and metabolic activities of the gut microbiome. Previous studies have shown that the gut microbiome provides a wide array of enzymes that enable processing of diverse dietary components. Because the primary diet of the porcupine, Erethizon dorsatum, is lignified plant material, we reasoned that the porcupine microbiome would be replete with enzymes required to degrade lignocellulose. Here, we report on the bacterial composition in the porcupine microbiome using 16S rRNA sequencing and bioinformatics analysis. We extended this analysis to the microbiomes of 20 additional mammals located in Shubenacadie Wildlife Park (Nova Scotia, Canada), enabling the comparison of bacterial diversity amongst three mammalian taxonomic orders (Rodentia, Carnivora, and Artiodactyla). 16S rRNA sequencing was validated using metagenomic shotgun sequencing on selected herbivores (porcupine, beaver) and carnivores (coyote, Arctic wolf). In the microbiome, functionality is more conserved than bacterial composition, thus we mined microbiome data sets to identify conserved microbial functions across species in each order. We measured the relative gene abundances for cellobiose phosphorylase, endoglucanase, and beta-glucosidase to evaluate the cellulose-degrading potential of select mammals. The porcupine and beaver had higher proportions of genes encoding cellulose degrading enzymes than the Artic wolf and coyote. These findings provide further evidence that gut microbiome diversity and metabolic capacity are influenced by host diet. PMID- 29281675 TI - Northward range expansion of Ixodes scapularis evident over a short timescale in Ontario, Canada. AB - The invasion of the blacklegged tick, Ixodes scapularis into Ontario, Canada poses a significant risk to public health because it is a vector for numerous pathogens, including Borrelia burgdorferi sensu stricto, the causative agent of Lyme disease. Baseline field sampling in 2014 and 2015 detected I. scapularis and B. burgdorferi at sites across southern, eastern and central Ontario, including a hot spot in eastern Ontario. A "speed of spread" model for I. scapularis developed by Leighton and colleagues (2012) estimated that the tick's range was expanding northward at 46 km/year. In 2016, we revisited a subset of sites sampled in 2014 and 2015 to understand the changing nature of risk, and assess whether the rate of tick invasion is consistent with the speed of spread estimate. Ticks were collected via tick dragging at 17 out of 36 sites, 5 of which were new sites for I. scapularis. Samples were positive for B. burgdorferi at 8 sites. No other I. scapularis-borne pathogens were detected. Centrographic statistics revealed an increase in the dispersion of I. scapularis positive sites in eastern Ontario. Field data for each site were then compared to the model's predicted year of establishment for each census subdivision. Our findings illustrate that the range expansion of I. scapularis and the emergence of B. burgdorferi is ongoing, and provide short timescale evidence of the processes associated with I. scapularis spread. The range front appears to be moving at a rate of ~46 km/year, with colonization of the tick behind this range front occurring at a slower and heterogeneous rate. Assessment of site-level ecological factors did not provide any insight into the underlying processes that may be influencing the colonization of I. scapularis in specific areas. Ongoing field sampling is needed to monitor this dynamic process. This study highlights the current geographic risk associated with Lyme disease, which can be used to target public health interventions to the areas of greatest risk. PMID- 29281674 TI - Convergent evolution and topologically disruptive polymorphisms among multidrug resistant tuberculosis in Peru. AB - BACKGROUND: Multidrug-resistant tuberculosis poses a major threat to the success of tuberculosis control programs worldwide. Understanding how drug-resistant tuberculosis evolves can inform the development of new therapeutic and preventive strategies. METHODS: Here, we use novel genome-wide analysis techniques to identify polymorphisms that are associated with drug resistance, adaptive evolution and the structure of the phylogenetic tree. A total of 471 samples from different patients collected between 2009 and 2013 in the Lima suburbs of Callao and Lima South were sequenced on the Illumina MiSeq platform with 150bp paired end reads. After alignment to the reference H37Rv genome, variants were called using standardized methodology. Genome-wide analysis was undertaken using custom written scripts implemented in R software. RESULTS: High quality homoplastic single nucleotide polymorphisms were observed in genes known to confer drug resistance as well as genes in the Mycobacterium tuberculosis ESX secreted protein pathway, pks12, and close to toxin/anti-toxin pairs. Correlation of homoplastic variant sites identified that many were significantly correlated, suggestive of epistasis. Variation in genes coding for ESX secreted proteins also significantly disrupted phylogenetic structure. Mutations in ESX genes in key antigenic epitope positions were also found to disrupt tree topology. CONCLUSION: Variation in these genes have a biologically plausible effect on immunogenicity and virulence. This makes functional characterization warranted to determine the effects of these polymorphisms on bacterial fitness and transmission. PMID- 29281676 TI - Can mixed assessment methods make biology classes more equitable? AB - Many factors have been proposed to explain the attrition of women in science, technology, engineering and math fields, among them the lower performance of women in introductory courses resulting from deficits in incoming preparation. We focus on the impact of mixed methods of assessment, which minimizes the impact of high-stakes exams and rewards other methods of assessment such as group participation, low-stakes quizzes and assignments, and in-class activities. We hypothesized that these mixed methods would benefit individuals who otherwise underperform on high-stakes tests. Here, we analyze gender-based performance trends in nine large (N > 1000 students) introductory biology courses in fall 2016. Females underperformed on exams compared to their male counterparts, a difference that does not exist with other methods of assessment that compose course grade. Further, we analyzed three case studies of courses that transitioned their grading schemes to either de-emphasize or emphasize exams as a proportion of total course grade. We demonstrate that the shift away from an exam emphasis consequently benefits female students, thereby closing gaps in overall performance. Further, the exam performance gap itself is reduced when the exams contribute less to overall course grade. We discuss testable predictions that follow from our hypothesis, and advocate for the use of mixed methods of assessments (possibly as part of an overall shift to active learning techniques). We conclude by challenging the student deficit model, and suggest a course deficit model as explanatory of these performance gaps, whereby the microclimate of the classroom can either raise or lower barriers to success for underrepresented groups in STEM. PMID- 29281677 TI - Sunflower oil supplementation affects the expression of miR-20a-5p and miR-142-5p in the lactating bovine mammary gland. AB - Oil supplementation in dairy cattle diets is used to modulate milk fat composition, as well as the expression of mammary lipogenic genes, whose regulation remains unclear. MiRNAs are small non-coding RNA considered as crucial regulators of gene expression, offering clues to explain the mechanism underlying gene nutriregulation. The present study was designed to identify miRNAs whose expression in the cow mammary gland is modulated by sunflower oil supplementation. MiRNomes were obtained using RNAseq technology from the mammary gland of lactating cows receiving a low forage diet, supplemented or not with 4% sunflower oil. Among the 272 miRNAs characterized, eight were selected for RT qPCR validations, showing the significant down-regulation of miR-142-5p and miR 20a-5p by sunflower supplementation. These two miRNAs are predicted to target genes whose expression was reported as differentially expressed by sunflower supplementation. Among their putative targets, ELOVL6 gene involved in lipid metabolism has been studied. However, a first analysis did not show its significant down-regulation, in response to the over-expression of miR-142-5p, of miR-20a-5p, or both, in a bovine mammary epithelial cell line. However, a clearer understanding of the miRNA expression by lipid supplementation would help to decipher the regulation of lactating cow mammary gland in response to nutrition. PMID- 29281678 TI - The natural compound Jatrophone interferes with Wnt/beta-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer. AB - Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/beta-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/beta-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and beta-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) beta-catenin protein levels, but not total beta-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/beta-catenin signaling pathway. PMID- 29281679 TI - The photosynthetic bacteria Rhodobacter capsulatus and Synechocystis sp. PCC 6803 as new hosts for cyclic plant triterpene biosynthesis. AB - Cyclic triterpenes constitute one of the most diverse groups of plant natural products. Besides the intriguing biochemistry of their biosynthetic pathways, plant triterpenes exhibit versatile bioactivities, including antimicrobial effects against plant and human pathogens. While prokaryotes have been extensively used for the heterologous production of other classes of terpenes, the synthesis of cyclic triterpenes, which inherently includes the two-step catalytic formation of the universal linear precursor 2,3-oxidosqualene, is still a major challenge. We thus explored the suitability of the metabolically versatile photosynthetic alpha-proteobacterium Rhodobacter capsulatus SB1003 and cyanobacterium Synechocystis sp. PCC 6803 as alternative hosts for biosynthesis of cyclic plant triterpenes. Therefore, 2,3-oxidosqualene production was implemented and subsequently combined with different cyclization reactions catalyzed by the representative oxidosqualene cyclases CAS1 (cycloartenol synthase), LUP1 (lupeol synthase), THAS1 (thalianol synthase) and MRN1 (marneral synthase) derived from model plant Arabidopsis thaliana. While successful accumulation of 2,3-oxidosqualene could be detected by LC-MS analysis in both hosts, cyclase expression resulted in differential production profiles. CAS1 catalyzed conversion to only cycloartenol, but expression of LUP1 yielded lupeol and a triterpenoid matching an oxidation product of lupeol, in both hosts. In contrast, THAS1 expression did not lead to cyclic product formation in either host, whereas MRN1-dependent production of marnerol and hydroxymarnerol was observed in Synechocystis but not in R. capsulatus. Our findings thus indicate that 2,3-oxidosqualene cyclization in heterologous phototrophic bacteria is basically feasible but efficient conversion depends on both the respective cyclase enzyme and individual host properties. Therefore, photosynthetic alpha proteo- and cyanobacteria are promising alternative candidates for providing new bacterial access to the broad class of triterpenes for biotechnological applications. PMID- 29281680 TI - Characteristics of percutaneous core biopsies adequate for next generation genomic sequencing. AB - PURPOSE: Determine the characteristics of percutaneous core biopsies that are adequate for a next generation sequencing (NGS) genomic panel. MATERIALS AND METHODS: All patients undergoing percutaneous core biopsies in interventional radiology (IR) with samples evaluated for a 46-gene NGS panel during 1-year were included in this retrospective study. Patient and procedure variables were collected. An imaging-based likelihood of adequacy score incorporating targeting and sampling factors was assigned to each biopsied lesion. Univariate and multivariate logistic regression was performed. RESULTS: 153 patients were included (58.2% female, average age 59.5 years). The most common malignancy was lung cancer (40.5%), most common biopsied site was lung (36%), and average size of biopsied lesions was 3.8 cm (+/- 2.7). Adequacy for NGS was 69.9%. Univariate analysis showed higher likelihood of adequacy score (p = 0.004), primary malignancy type (p = 0.03), and absence of prior systemic therapy (p = 0.018) were associated with adequacy for NGS. Multivariate analysis showed higher adequacy for lesions with likelihood of adequacy scored 3 (high) versus lesions scored 1 (low) (OR, 7.82; p = 0.002). Melanoma lesions had higher adequacy for NGS versus breast cancer lesions (OR 9.5; p = 0.01). Absence of prior systemic therapy (OR, 6.1; p = 0.02) and systemic therapy 3 months before biopsy yielded greater adequacy for NGS. Lesions <3 cm had greater adequacy for NGS than larger lesions (OR 2.72, p = 0.02). CONCLUSION: As targeted therapy becomes standard for more cancers, percutaneous biopsy specimens adequate for NGS genomic testing will be needed. An imaging-based likelihood of adequacy score assigned by IR physicians and other pre-procedure variables can help predict the likelihood of biopsy adequacy for NGS. PMID- 29281681 TI - Depression and alcohol use disorder at antiretroviral therapy initiation led to disengagement from care in South Africa. AB - We sought to assess mental health at the time of antiretroviral therapy (ART) initiation and subsequent retention in care over a six-month follow-up period. A total of 136 people living with HIV in South Africa were administered surveys measuring demographic information and mental health indicators at the time of ART initiation. Follow-up was completed via chart abstraction to assess for six-month outcomes of retention in care and viral suppression. At enrollment, 45/136 (33%), 67/136 (49%), and 45/136 (33%) participants screened positive for depression, anxiety, and alcohol use disorder, respectively. After six months of follow-up, 96/136 (71%) participants remained in care; 35/87 (40.2%) participants who remained in care had a level <50 copies/mL. Those with depression (49% vs. 77% retained; p < 0.01) and those with alcohol use disorder (52% vs. 76% retained; p < 0.01) were less likely to be retained in care. In multivariable logistic regression, depression OR 3.46 (95% CI: 1.33, 7.97; p < 0.01) and alcohol abuse OR 3.89 (95% CI: 1.70, 8.97; p < 0.01) were independently associated with loss from care. These results emphasize the importance of mental health on early ART outcomes and the HIV care continuum. PMID- 29281682 TI - Overexpression of Map3k7 activates sinoatrial node-like differentiation in mouse ES-derived cardiomyocytes. AB - In vivo, cardiomyocytes comprise a heterogeneous population of contractile cells defined by unique electrophysiologies, molecular markers and morphologies. The mechanisms directing myocardial cells to specific sub-lineages remain poorly understood. Here we report that overexpression of TGFbeta-Activated Kinase (TAK1/Map3k7) in mouse embryonic stem (ES) cells faithfully directs myocardial differentiation of embryoid body (EB)-derived cardiac cells toward the sinoatrial node (SAN) lineage. Most cardiac cells in Map3k7-overexpressing EBs adopt markers, cellular morphologies, and electrophysiological behaviors characteristic of the SAN. These data, in addition to the fact that Map3k7 is upregulated in the sinus venous-the source of cells for the SAN-suggest that Map3k7 may be an endogenous regulator of the SAN fate. PMID- 29281683 TI - Patterns of objectively assessed physical activity and sedentary time: Are Nigerian health professional students complying with public health guidelines? AB - BACKGROUND: Understanding patterns of physical activity and sedentary time is important to effective population-wide primary prevention and control of non communicable diseases. This study examined the patterns of objectively assessed physical activity and sedentary time, and the prevalence of compliance with physical activity guidelines according to different public health recommendations in a sub-population of health professional students in Nigeria. METHODS: A cross sectional study was conducted among 102 health professional students (age = 19-34 years old, 43.1% women) of the University of Maiduguri, Nigeria. Participants wore Actigraph accelerometers on their waist for minimum of 5 days/week to objectively measure intensity and duration of physical activity and sedentary time. Prevalence and demographic patterns of physical activity and sedentary time were examined using descriptive and inferential statistics. RESULTS: The students spent most time in sedentary activity (458.6 +/- minutes/day, about 61% of daily time) and the least in vigorous-intensity activity (2.1 +/- 4.4 minutes/day, about 0.3% of daily time). Sedentary time was higher among older than younger students (P<0.038) and among medical laboratory science students than physiotherapy and nursing students (P = 0.046). Total physical activity was higher among nursing and medical students than medical laboratory science students (P = 0.041). Although, 85.3% of the students engaged in 150 minutes/week of moderate-to-vigorous physical activity, only 2.9% met the guideline of 75 minutes/week of vigorous intensity activity. CONCLUSIONS: Prevalence of sedentary time was high while that of vigorous-intensity activity was very low among health professional students in Nigeria. Compliance with physical activity guidelines was mainly through accumulation of moderate intensity activity. The results suggest that age and academic programme may influence physical activity level and sedentary behaviour of health professional students in Nigeria. These findings provide preliminary evidence that could be used to inform the needs to develop interventions to improve and support active lifestyle behaviour among students in Nigerian universities. PMID- 29281684 TI - Candida albicans-derived mannoproteins activate NF-kappaB in reporter cells expressing TLR4, MD2 and CD14. AB - The ability of soluble C. albicans 20A (serotype A) mannoprotein (CMP) to serve as a ligand for toll-like receptor 4 (TLR4) and its co-receptors was examined using commercially available and stably-transfected HEK293 cells that express human TLR4, MD2 and CD14, but not MR. These TLR4 reporter cells also express an NF-kappaB-dependent, secreted embryonic alkaline phosphatase (SEAP) reporter gene. TLR4-reporter cells exhibited a dose-dependent SEAP response to both LPS and CMP, wherein peak activation was achieved after stimulation with 40-50 MUg/mL of CMP. Incubation on polymyxin B resin had no effect on CMP's ligand activity, but neutralized LPS-spiked controls. HEK293 Null cells lacking TLR4 and possessing the same SEAP reporter failed to respond to LPS or CMP, but produced SEAP when activated with TNFalpha. Reporter cell NF-kappaB responses were accompanied by transcription of IL-8, TNFalpha, and COX-2 genes. Celecoxib inhibited LPS-, CMP-, and TNFalpha-dependent NF-kappaB responses; whereas, indomethacin had limited effect on LPS and CMP responses. SEAP production in response to C. albicans A9 mnn4Delta mutant CMP, lacking phosphomannosylations on N-linked glycans, was significantly greater (p <= 0.005) than SEAP responses to CMP derived from parental A9 (both serotype B). These data confirm that engineered human cells expressing TLR4, MD2 and CD14 can respond to CMP with NF kappaB activation and the response can be influenced by variations in CMP mannosylation. Future characterizations of CMPs from other sources and their application in this model may provide further insight into variations observed with TLR4 dependent innate immune responses targeting different C. albicans strains. PMID- 29281685 TI - Nanoparticle size and production efficiency are affected by the presence of fatty acids during albumin nanoparticle fabrication. AB - We have previously identified extensive glycation, bound fatty acids and increased quantities of protein aggregates in commercially available recombinant HSA (rHSA) expressed in Oryza sativa (Asian rice) (OsrHSA) when compared to rHSA from other expression systems. We propose these differences may alter some attributes of nanoparticles fabricated with OsrHSA, as studies have associated greater quantities of aggregates with increased nanoparticle diameters. To determine if this is the case, nanoparticles were fabricated with OsrHSA from various suppliers using ethanol desolvation and subsequent glutaraldehyde cross linking. All nanoparticles fabricated with OsrHSA showed larger diameters of approximately 20 to 90nm than particles fabricated with either defatted bovine serum albumin (DF-BSA) (100.9 +/- 2.8nm) or human plasma albumin (pHSA) (112.0 +/ 4.0nm). It was hypothesized that the larger nanoparticle diameters were due to the presence of bound fatty acids and this was confirmed through defatting OsrHSA prior to particle fabrication which yielded particles with diameters similar to those fabricated with pHSA. For additional conformation, DF-BSA was incubated with dodecanoic acid prior to desolvation yielding particles with significantly larger diameters. Further studies showed the increased nanoparticle diameters were due to the bound fatty acids modulating electrostatic interactions between albumin nanoparticles during the desolvation and not changes in protein structure, stability or generation of additional albumin oligomers. Finally the presence of dodecanoic acid was shown to improve doxorubicin loading efficiency onto preformed albumin nanoparticles. PMID- 29281686 TI - Personal relative deprivation associated with functional disorders via stress: An examination of fibromyalgia and gastrointestinal symptoms. AB - BACKGROUND: Personal relative deprivation is a negative social comparison process typified by self-comparison, negative appraisal, and resultant negative emotionality. Personal relative deprivation has been associated with poorer physical and mental health in several domains. It has been hypothesized that the deprivation-health link operates through a stress pathway. Stress has been specifically implicated in the onset and maintenance of functional disorders, including fibromyalgia and functional gastrointestinal disorders. Despite the theoretical links between personal deprivation, stress, and functional disorders, researchers have not assessed relationships between these variables. METHODS: We recruited community participants (n = 517; 54.9% female) to examine whether personal relative deprivation can account for variance in fibromyalgia and functional gastrointestinal symptoms beyond known demographic correlates of physical health. We also examined whether the relationships between personal relative deprivation and functional disorder symptoms are mediated by stress. RESULTS: Consistent with our hypotheses, personal relative deprivation accounted for symptom variance in fibromyalgia and functional gastrointestinal disorders beyond that accounted for by demographic variables alone. Further, self-reported stress was found to mediate relationships between personal relative deprivation and fibromyalgia and gastrointestinal symptoms. CONCLUSIONS: The current results support biopsychosocial models of physical health and suggest that, for patients presenting with functional disorders symptoms, a combination of biological and psychosocial interventions may be warranted. PMID- 29281687 TI - Vascularization and odontode structure of a dorsal ridge spine of Romundina stellina Orvig 1975. AB - There are two types of dermal skeletons in jawed vertebrates: placoderms and osteichthyans carry large bony plates (macromery), whereas chondrichthyans and acanthodians are covered by small scales (micromery). Fin spines are one of the last large dermal structures found on micromeric taxa and offer a potential source of histology and morphology that can be compared to those found on macromeric groups. Dermal fin spines offer a variety of morphology but aspects of their growth modes and homology are unclear. Here, we provide detailed descriptions of the microstructure and growth of a dorsal ridge spine from the acanthothoracid placoderm, Romundina stellina, using virtual three-dimensional paleohistological datasets. From these data we identify several layers of dentine ornamentation covering the lateral surfaces of the spine and reconstructed their growth pattern. We show that this spine likely grew posteriorly and proximally from a narrow portion of bone located along the leading edge of the spine. The spine is similarly constructed to the scales with a few exceptions, including the absence of polarized fibers distributed throughout the bone and the presence of a thin layer of perichondral bone. The composition of the spine (semidentine odontodes, dermal bone, perichondral bone) is identical to that of the Romundina dermal plates. These results illustrate the similarities and differences between the dermal tissues in Romundina and indicate that the spine grew differently from the dentinous fin spines from extant and fossil chondrichthyans. The morphology and histology of Romundina is most similar to the fin spine of the probable stem osteichthyan Lophosteus, with a well-developed inner cellular bony base and star shaped odontodes on the surface. Results from these studies will undoubtedly have impact on our understanding of fossil fin spine histology and evolution, contributing to the on-going revision of early gnathostome phylogeny. PMID- 29281688 TI - Home-based pre-exposure prophylaxis (PrEP) services for gay and bisexual men: An opportunity to address barriers to PrEP uptake and persistence. AB - Gay, bisexual, and other men who have sex with men (GBM) are disproportionately affected by the HIV epidemic. Despite the promise of pre-exposure prophylaxis (PrEP) in reducing HIV transmission risk, barriers for uptake and persistence exist. We sought to identify whether GBM in a nationwide cohort who have not yet initiated PrEP (n = 906) would prefer to get PrEP-related care from a primary care provider (PCP) compared to a specialist clinic or provider. We then sought to identify their level of interest and factors associated with preference for using home-based PrEP services (i.e., HB-PrEP), defined to participants as conducting HIV/STI self-testing from home with PrEP prescription mailing after an initial in-person clinic visit. We examined the associations of demographics, sexual HIV transmission risk, concern about frequent medical checkups associated with PrEP, health care access, and PrEP intentions with preferences for healthcare provider type and HB-PrEP. Concern about frequent medical checkups were associated with preferring a PCP for PrEP-related care, but men who perceived a barrier to bringing up the topic of PrEP with a doctor preferred a specialist clinic or provider more than a PCP. HB-PrEP was more appealing for younger men and those engaged in sexual HIV transmission risk, suggesting HB-PrEP could help reach GBM most vulnerable to HIV and in need of PrEP. HB-PrEP expansion has potential to increase PrEP uptake and persistence among GBM, particularly for men with barriers to clinic-based care and higher intentions to initiate PrEP. Clinical guidelines regarding HB-PrEP are needed to expand its use. PMID- 29281689 TI - Cut from the same cloth: The convergent evolution of dwarf morphotypes of the Carex flava group (Cyperaceae) in Circum-Mediterranean mountains. AB - Plants growing in high-mountain environments may share common morphological features through convergent evolution resulting from an adaptative response to similar ecological conditions. The Carex flava species complex (sect. Ceratocystis, Cyperaceae) includes four dwarf morphotypes from Circum Mediterranean mountains whose taxonomic status has remained obscure due to their apparent morphological resemblance. In this study we investigate whether these dwarf mountain morphotypes result from convergent evolution or common ancestry, and whether there are ecological differences promoting differentiation between the dwarf morphotypes and their taxonomically related large, well-developed counterparts. We used phylogenetic analyses of nrDNA (ITS) and ptDNA (rps16 and 5'trnK) sequences, ancestral state reconstruction, multivariate analyses of macro and micromorphological data, and species distribution modeling. Dwarf morphotype populations were found to belong to three different genetic lineages, and several morphotype shifts from well-developed to dwarf were suggested by ancestral state reconstructions. Distribution modeling supported differences in climatic niche at regional scale between the large forms, mainly from lowland, and the dwarf mountain morphotypes. Our results suggest that dwarf mountain morphotypes within this sedge group are small forms of different lineages that have recurrently adapted to mountain habitats through convergent evolution. PMID- 29281690 TI - Sensitivity and specificity of automated analysis of single-field non-mydriatic fundus photographs by Bosch DR Algorithm-Comparison with mydriatic fundus photography (ETDRS) for screening in undiagnosed diabetic retinopathy. AB - Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Early diagnosis through effective screening programs is likely to improve vision outcomes. The ETDRS seven-standard-field 35-mm stereoscopic color retinal imaging (ETDRS) of the dilated eye is elaborate and requires mydriasis, and is unsuitable for screening. We evaluated an image analysis application for the automated diagnosis of DR from non-mydriatic single-field images. Patients suffering from diabetes for at least 5 years were included if they were 18 years or older. Patients already diagnosed with DR were excluded. Physiologic mydriasis was achieved by placing the subjects in a dark room. Images were captured using a Bosch Mobile Eye Care fundus camera. The images were analyzed by the Retinal Imaging Bosch DR Algorithm for the diagnosis of DR. All subjects also subsequently underwent pharmacological mydriasis and ETDRS imaging. Non-mydriatic and mydriatic images were read by ophthalmologists. The ETDRS readings were used as the gold standard for calculating the sensitivity and specificity for the software. 564 consecutive subjects (1128 eyes) were recruited from six centers in India. Each subject was evaluated at a single outpatient visit. Forty-four of 1128 images (3.9%) could not be read by the algorithm, and were categorized as inconclusive. In four subjects, neither eye provided an acceptable image: these four subjects were excluded from the analysis. This left 560 subjects for analysis (1084 eyes). The algorithm correctly diagnosed 531 of 560 cases. The sensitivity, specificity, and positive and negative predictive values were 91%, 97%, 94%, and 95% respectively. The Bosch DR Algorithm shows favorable sensitivity and specificity in diagnosing DR from non-mydriatic images, and can greatly simplify screening for DR. This also has major implications for telemedicine in the use of screening for retinopathy in patients with diabetes mellitus. PMID- 29281691 TI - Impaired PGE2-stimulated Cl- and HCO3- secretion contributes to cystic fibrosis airway disease. AB - BACKGROUND: Airway mucociliary clearance (MCC) is an important defense mechanism against pulmonary infections and is compromised in cystic fibrosis (CF). Cl- and HCO3- epithelial transport are integral to MCC. During pulmonary infections prostaglandin E2 (PGE2) production is abundant. AIM: To determine the effect of PGE2 on airway Cl- and HCO3- secretion and MCC in normal and CF airways. METHODS: We examined PGE2 stimulated MCC, Cl- and HCO3- secretion using ferret trachea, human bronchial epithelial cell cultures (CFBE41o- with wildtype CFTR (CFBE41 WT) or homozygous F508del CFTR (CFBE41 CF) and human normal bronchial submucosal gland cell line (Calu-3) in Ussing chambers with or without pH-stat. RESULTS: PGE2 stimulated MCC in a dose-dependent manner and was partially impaired by CFTRinh-172. PGE2-stimulated Cl- current in ferret trachea was partially inhibited by CFTRinh-172, with niflumic acid eliminating the residual current. CFBE41 WT cell monolayers produced a robust Cl- and HCO3- secretory response to PGE2, both of which were completely inhibited by CFTRinh-172. CFBE41 CF cells exhibited no response to PGE2. In Calu-3 cells, PGE2 stimulated Cl- and HCO3- secretion. Cl- secretion was partially inhibited by CFTRinh-172, with additional inhibition by niflumic acid. HCO3- secretion was completely inhibited by CFTRinh 172. CONCLUSIONS: PGE2 stimulates bronchotracheal MCC and this response is decreased in CF. In CF airway, PGE2-stimulated Cl- and HCO3- conductance is impaired and may contribute to decreased MCC. There remains a CFTR-independent Cl current in submucosal glands, which if exploited, could represent a means of improving airway Cl- secretion and MCC in CF. PMID- 29281692 TI - Substance P signalling in primary motor cortex facilitates motor learning in rats. AB - Among the genes that are up-regulated in response to a reaching training in rats, Tachykinin 1 (Tac1)-a gene that encodes the neuropeptide Substance P (Sub P) shows an especially strong expression. Using Real-Time RT-PCR, a detailed time course of Tac1 expression could be defined: a significant peak occurs 7 hours after training ended at the first and second training session, whereas no up regulation could be detected at a later time-point (sixth training session). To assess the physiological role of Sub P during movement acquisition, microinjections into the primary motor cortex (M1) contralateral to the trained paw were performed. When Sub P was injected before the first three sessions of a reaching training, effectiveness of motor learning became significantly increased. Injections at a time-point when rats already knew the task (i.e. training session ten and eleven) had no effect on reaching performance. Sub P injections did not influence the improvement of performance within a single training session, but retention of performance between sessions became strengthened at a very early stage (i.e. between baseline-training and first training session). Thus, Sub P facilitates motor learning in the very early phase of skill acquisition by supporting memory consolidation. In line with these findings, learning related expression of the precursor Tac1 occurs at early but not at later time-points during reaching training. PMID- 29281693 TI - Expression of naturally ionic liquid-tolerant thermophilic cellulases in Aspergillus niger. AB - Efficient deconstruction of plant biomass is a major barrier to the development of viable lignocellulosic biofuels. Pretreatment with ionic liquids reduces lignocellulose recalcitrance to enzymatic hydrolysis, increasing yields of sugars for conversion into biofuels. However, commercial cellulases are not compatible with many ionic liquids, necessitating extensive water washing of pretreated biomass prior to hydrolysis. To circumvent this issue, previous research has demonstrated that several thermophilic bacterial cellulases can efficiently deconstruct lignocellulose in the presence of the ionic liquid, 1-ethyl-3 methylimadizolium acetate. As promising as these enzymes are, they would need to be produced at high titer in an industrial enzyme production host before they could be considered a viable alternative to current commercial cellulases. Aspergillus niger has been used to produce high titers of secreted enzymes in industry and therefore, we assessed the potential of this organism to be used as an expression host for these ionic liquid-tolerant cellulases. We demonstrated that 29 of these cellulases were expressed at detectable levels in a wild-type strain of A. niger, indicating a basic level of compatibility and potential to be produced at high levels in a host engineered to produce high titers of enzymes. We then profiled one of these enzymes in detail, the beta-glucosidase A5IL97, and compared versions expressed in both A. niger and Escherichia coli. This comparison revealed the enzymatic activity of A5IL97 purified from E. coli and A. niger is equivalent, suggesting that A. niger could be an excellent enzyme production host for enzymes originally characterized in E. coli, facilitating the transition from the laboratory to industry. PMID- 29281694 TI - Empirical analysis of pig welfare levels and their impact on pig breeding efficiency-Based on 773 pig farmers' survey data. AB - Few studies of the pig production efficiency are from the perspective of animal welfare. Therefore, this study conducted a comprehensive evaluation of pig welfare levels based on survey data from 773 pig farmers from 23 counties in the Chinese provinces of Hunan, Zhejiang, Guangdong, Guizhou, and Shanxi. This study used the Delphi method, Analytic Hierarchy Process (AHP), and Data Envelopment Analysis (DEA)-Tobit regression model to analyze farmers' pig production efficiency and its influencing factors. This paper found that most farmers' pig production efficiency is low, and the DEA is invalid. Only 2.9% of pig farmers' who breed pigs are at the optimal level in terms of welfare, and their production efficiency is relatively high. In contrast, 49.34% of the farmers are at the medium welfare level, and compared with the farmers at the optimal welfare level, these farmers' pig production efficiency is low. Additionally, the farmers' age, gender, and number of years of experience with pig breeding have a significant effect. Furthermore, the scale of pig breeding and feeding type, the agriculture facilities for the central treatment of waste in local areas, and the availability of local agricultural science and technology personnel have a considerable influence on pig production efficiency. PMID- 29281696 TI - The Great American Recession and forgone healthcare: Do widened disparities between African-Americans and Whites remain? AB - OBJECTIVE: During the Great Recession in America, African-Americans opted to forgo healthcare more than other racial/ethnic groups. It is not understood whether disparities in forgone care returned to pre-recession levels. Understanding healthcare utilization patterns is important for informing subsequent efforts to decrease healthcare disparities. Therefore, we examined changes in racial disparities in forgone care before, during, and after the Great Recession. DESIGN: Data were pooled from the 2006-2013 National Health Interview Survey. Forgone medical, mental, and prescription care due to affordability were assessed among African-Americans and Whites. Time periods were classified as: pre recession (May 2006-November 2007), early recession (December 2007-November 2008), late recession (December 2008-May 2010) and post-recession (June 2010 December 2013). Multivariable logistic regressions of race, interacted with time periods, were used to identify disparities in forgone care controlling for other demographics, health insurance coverage, and having a usual place for medical care across time periods. Adjusted Wald tests were performed to identify significant changes in disparities across time periods. RESULTS: The sample consisted of 110,746 adults. African-Americans were more likely to forgo medical care during the post- recession compared to Whites (OR = 1.16, CI = 1.06, 1.26); changes in foregone medical care disparities were significant in that they increased in the post-recession period compared to the pre-recession (OR = 1.17, CI = 1.08, 1.28 and OR = 0.89, CI = 0.77, 1.04, respectively, adjusted Wald Test p-value < 0.01). No changes in disparities were seen in prescription and mental forgone care. CONCLUSION: A persistent increase in forgone medical care disparities existed among African-Americans compared to Whites post-Great Recession and may be a result of outstanding issues related to healthcare access, cost, and quality. While health insurance is an important component of access to care, it alone should not be expected to remove these disparities due to other financial constraints. Additional strategies are necessary to close remaining gaps in care widened by the Great Recession. PMID- 29281697 TI - Extracting coherent tree-ring climatic signals across spatial scales from extensive forest inventory data. AB - Increasing access to extensively replicated and broadly distributed tree-ring collections has led to a greater use of these large data sets to investigate climate forcing on tree growth. However, the number of chronologies added to large accessible databases is declining and few are updated, while chronologies are often sparsely distributed and are more representative of marginal growing environments. On the other hand, National Forest Inventories (NFI), although poorly replicated at the plot level as compared to classic dendrochronological sampling, contain a large amount of tree-ring data with high spatial density designed to be spatially representative of the forest cover. We propose an a posteriori approach to validating tree-ring measurements and dating, selecting individual tree-ring width time series, and building average chronologies at various spatial scales based on an extensive collection of ring width measurements of nearly 94,000 black spruce trees distributed over a wide area and collected as part of the NFI in the province of Quebec, Canada. Our results show that reliable signals may be derived at various spatial scales (from 37 to 583,000 km2) from NFI increment core samples. Signals from independently built chronologies are spatially coherent with each other and well-correlated with independent reference chronologies built at the stand level. We thus conclude that tree-ring data from NFIs provide an extraordinary opportunity to strengthen the spatial and temporal coverage of tree-ring data and to improve coordination with other contemporary measurements of forest growth to provide a better understanding of tree growth-climate relationships over broad spatial scales. PMID- 29281695 TI - Maternal metabolism affects endometrial expression of oxidative stress and FOXL2 genes in cattle. AB - Intensive selection for milk production has led to reduced reproductive efficiency in high-producing dairy cattle. The impact of intensive milk production on oocyte quality as well as early embryo development has been established but few analyses have addressed this question at the initiation of implantation, a critical milestone ensuring a successful pregnancy and normal post-natal development. Our study aimed to determine if contrasted maternal metabolism affects the previously described sensory properties of the endometrium to the conceptus in cattle. Following embryo transfer at Day 7 post-oestrus, endometrial caruncular (CAR) and intercaruncular (ICAR) areas were collected at Day 19 from primiparous postpartum Holstein-Friesian cows that were dried-off immediately after parturition (i.e., never milked; DRY) or milked twice daily (LACT). Gene quantification indicated no significant impact of lactation on endometrial expression of transcripts previously reported as conceptus-regulated (PLET1, PTGS2, SOCS6) and interferon-tau stimulated (RSAD2, SOCS1, SOCS3, STAT1) factors or known as female hormone-regulated genes (FOXL2, SCARA5, PTGS2). Compared with LACT cows, DRY cows exhibited mRNA levels with increased expression for FOXL2 transcription factor and decreased expression for oxidative stress related genes (CAT, SOD1, SOD2). In vivo and in vitro experiments highlighted that neither interferon-tau nor FOXL2 were involved in transcriptional regulation of CAT, SOD1 and SOD2. In addition, our data showed that variations in maternal metabolism had a higher impact on gene expression in ICAR areas. Collectively, our findings prompt the need to fully understand the extent to which modifications in endometrial physiology drive the trajectory of conceptus development from implantation onwards when maternal metabolism is altered. PMID- 29281698 TI - The impact of persistent bacterial bronchitis on the pulmonary microbiome of children. AB - INTRODUCTION: Persistent bacterial bronchitis (PBB) is a leading cause of chronic wet cough in young children. This study aimed to characterise the respiratory bacterial microbiota of healthy children and to assess the impact of the changes associated with the development of PBB. Blind, protected brushings were obtained from 20 healthy controls and 24 children with PBB, with an additional directed sample obtained from PBB patients. DNA was extracted, quantified using a 16S rRNA gene quantitative PCR assay prior to microbial community analysis by 16S rRNA gene sequencing. RESULTS: No significant difference in bacterial diversity or community composition (R2 = 0.01, P = 0.36) was observed between paired blind and non-blind brushes, showing that blind brushings are a valid means of accessing the airway microbiota. This has important implications for collecting lower respiratory samples from healthy children. A significant decrease in bacterial diversity (P < 0.001) and change in community composition (R2 = 0.08, P = 0.004) was observed among controls, in comparison with patients. Bacterial communities within patients with PBB were dominated by Proteobacteria, and indicator species analysis showed that Haemophilus and Neisseria were significantly associated with the patient group. In 15 (52.9%) cases the dominant organism by sequencing was not identified by standard routine clinical culture. CONCLUSION: The bacteria present in the lungs of patients with PBB were less diverse in terms of richness and evenness. The results validate the clinical diagnosis, and suggest that more attention to bacterial communities in children with chronic cough may lead to more rapid recognition of this condition with earlier treatment and reduction in disease burden. PMID- 29281700 TI - Sparse Bayesian classification and feature selection for biological expression data with high correlations. AB - Classification models built on biological expression data are increasingly used to predict distinct disease subtypes. Selected features that separate sample groups can be the candidates of biomarkers, helping us to discover biological functions/pathways. However, three challenges are associated with building a robust classification and feature selection model: 1) the number of significant biomarkers is much smaller than that of measured features for which the search will be exhaustive; 2) current biological expression data are big in both sample size and feature size which will worsen the scalability of any search algorithms; and 3) expression profiles of certain features are typically highly correlated which may prevent to distinguish the predominant features. Unfortunately, most of the existing algorithms are partially addressing part of these challenges but not as a whole. In this paper, we propose a unified framework to address the above challenges. The classification and feature selection problem is first formulated as a nonconvex optimisation problem. Then the problem is relaxed and solved iteratively by a sequence of convex optimisation procedures which can be distributed computed and therefore allows the efficient implementation on advanced infrastructures. To illustrate the competence of our method over others, we first analyse a randomly generated simulation dataset under various conditions. We then analyse a real gene expression dataset on embryonal tumour. Further downstream analysis, such as functional annotation and pathway analysis, are performed on the selected features which elucidate several biological findings. PMID- 29281699 TI - Association of FLG single nucleotide variations with clinical phenotypes of atopic dermatitis. AB - BACKGROUND: FLG encodes a large protein called profilaggrin, which plays a key role in maintaining an effective skin barrier against the environment. In this study, we identified FLG single nucleotide variations (FLG-SNVs) and evaluated the association of FLG-SNVs with clinical phenotypes including atopic dermatitis (AD)-associated minor clinical features, presence of specific allergic sensitization, and serum parameters. METHODS: Eighty-one Korean patients with AD were enrolled. AD-associated minor clinical features as well as allergic rhinitis and asthma were diagnosed by specialists. FLG-SNVs were identified by Sanger sequencing of entire exons through long-range PCR. Allergic sensitization to a specific allergen was evaluated by multiple allergen simultaneous test. Serologic parameters such as serum eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) were measured. RESULTS: A total of seventy-three SNVs and 4 LOF mutations were successfully genotyped. rs71626704 and rs76413899 were significantly associated with a history of asthma and cheilitis (P = 0.002 and P = 0.033, respectively), however, the associations were not found statistically significant after adjustment by multiple comparisons. In addition, we detected haplotype blocks which were correlated with non-specific hand or foot dermatitis and scalp scale. We identified FLG-SNVs which were associated with sensitization to environmental allergens; rs62623409 and rs71625199 (P = 0.038 and P = 0.008, respectively). Patients with FLG P478S TT and history of allergic rhinitis showed a higher EDN level, and among those patients, the ones with asthma showed a higher ECP level. CONCLUSION: This study revealed the association of FLG-SNVs with AD-associated minor clinical features. We firstly identified rs71625199 which was associated with higher environmental allergic sensitization. We also suggest that FLG P478S is a kind of disease modifier which affects serologic parameters such as EDN and ECP. PMID- 29281701 TI - Deep vector-based convolutional neural network approach for automatic recognition of colonies of induced pluripotent stem cells. AB - Pluripotent stem cells can potentially be used in clinical applications as a model for studying disease progress. This tracking of disease-causing events in cells requires constant assessment of the quality of stem cells. Existing approaches are inadequate for robust and automated differentiation of stem cell colonies. In this study, we developed a new model of vector-based convolutional neural network (V-CNN) with respect to extracted features of the induced pluripotent stem cell (iPSC) colony for distinguishing colony characteristics. A transfer function from the feature vectors to the virtual image was generated at the front of the CNN in order for classification of feature vectors of healthy and unhealthy colonies. The robustness of the proposed V-CNN model in distinguishing colonies was compared with that of the competitive support vector machine (SVM) classifier based on morphological, textural, and combined features. Additionally, five-fold cross-validation was used to investigate the performance of the V-CNN model. The precision, recall, and F-measure values of the V-CNN model were comparatively higher than those of the SVM classifier, with a range of 87-93%, indicating fewer false positives and false negative rates. Furthermore, for determining the quality of colonies, the V-CNN model showed higher accuracy values based on morphological (95.5%), textural (91.0%), and combined (93.2%) features than those estimated with the SVM classifier (86.7, 83.3, and 83.4%, respectively). Similarly, the accuracy of the feature sets using five-fold cross validation was above 90% for the V-CNN model, whereas that yielded by the SVM model was in the range of 75-77%. We thus concluded that the proposed V-CNN model outperforms the conventional SVM classifier, which strongly suggests that it as a reliable framework for robust colony classification of iPSCs. It can also serve as a cost-effective quality recognition tool during culture and other experimental procedures. PMID- 29281702 TI - The Drosophila CLAMP protein associates with diverse proteins on chromatin. AB - Gaining new insights into gene regulation involves an in-depth understanding of protein-protein interactions on chromatin. A powerful model for studying mechanisms of gene regulation is dosage compensation, a process that targets the X-chromosome to equalize gene expression between XY males and XX females. We previously identified a zinc finger protein in Drosophila melanogaster that plays a sex-specific role in targeting the Male-specific lethal (MSL) dosage compensation complex to the male X-chromosome, called the Chromatin-Linked Adapter for MSL Proteins (CLAMP). More recently, we established that CLAMP has non-sex-specific roles as an essential protein that regulates chromatin accessibility at promoters genome-wide. To identify associations between CLAMP and other factors in both male and female cells, we used two complementary mass spectrometry approaches. We demonstrate that CLAMP associates with the transcriptional regulator complex Negative Elongation Factor (NELF) in both sexes and determine that CLAMP reduces NELF recruitment to several target genes. In sum, we have identified many new CLAMP-associated factors and provide a resource for further study of this little understood essential protein. PMID- 29281703 TI - The maternal environment interacts with genetic variation in regulating seed dormancy in Swedish Arabidopsis thaliana. AB - Seed dormancy is a complex adaptive trait that controls the timing of seed germination, one of the major fitness components in many plant species. Despite being highly heritable, seed dormancy is extremely plastic and influenced by a wide range of environmental cues. Here, using a set of 92 Arabidopsis thaliana lines from Sweden, we investigate the effect of seed maturation temperature on dormancy variation at the population level. The response to temperature differs dramatically between lines, demonstrating that genotype and the maternal environment interact in controlling the trait. By performing a genome-wide association study (GWAS), we identified several candidate genes that could presumably account for this plasticity, two of which are involved in the photoinduction of germination. Altogether, our results provide insight into both the molecular mechanisms and the evolution of dormancy plasticity, and can serve to improve our understanding of environmentally dependent life-history transitions. PMID- 29281704 TI - Phylogeography and population diversity of Simulium hirtipupa Lutz (Diptera: Simuliidae) based on mitochondrial COI sequences. AB - High morphological homogeneity and cryptic speciation may cause the diversity within Simuliidae to be underestimated. Recent molecular studies on population genetics and phylogeography have contributed to reveal which factors influenced the diversity within this group. This study aimed at examining the genetic diversity of Simulium hirtipupa Lutz, 1910 in populations from the biomes Caatinga, Cerrado, and Atlantic Forest. In this study, we carried out phylogeographic and population genetic analyses using a fragment of the mitochondrial gene COI. The 19 populations studied were clustered into seven groups, most of which are associated with geography indicating certain genetic structure. The northern region of the state of Minas Gerais is most likely the center of origin of this species. The average intergroup genetic distance was 3.7%, indicating the presence of cryptic species. The species tree as well as the haplotype network recovered all groups forming two major groups: the first comprises groups Gr-Bahia (in which the Sao Francisco river has not acted as geographical barrier), Gr-Pernambuco, and Gr-Mato Grosso do Sul. The second included groups comprising populations of the states of Goias, Tocantins, Minas Gerais, Bahia, Sao Paulo, and Espirito Santo. The mismatch distribution for groups was consistent with the model of demographic expansion, except for the Gr Central-East_1 group. The diversification in this group occurred about 1.19 Mya during the Pleistocene, influenced by paleoclimatic oscillations during the Quaternary glacial cycles. PMID- 29281705 TI - Anti-inflammatory effect of Allium hookeri on carrageenan-induced air pouch mouse model. AB - Inflammation is a commonly observed immune reaction, and rheumatoid arthritis is a particularly severe inflammatory disease. In this study, we used an air pouch mouse model to evaluate the anti-inflammatory potential of Allium hookeri, which has both been used as a culinary material and a traditional medicine in south eastern Asia for many years. Allium hookeri suppressed typical symptoms of inflammation, such as condensation of the air pouch membrane, and inhibited the expression of several inducible proinflammatory cytokines such as IL-1beta, IL-6, IL-13, and TNF-alpha. In order to determine the molecules modulating the inflammatory effect of carrageenan treatment, the components in Allium hookeri were analyzed by GC-MS, and linoleic acid, which have anti-inflammatory effect, was detected. From the results, we concluded that the anti-inflammatory effect of Allium hookeri might be attributed to linoleic acid, which could be promising candidates for anti-inflammatory drugs that have no adverse effects. PMID- 29281706 TI - A genome-wide study to identify genes responsible for oviduct development in chickens. AB - Molecular genetic tools provide a method for improving the breeding selection of chickens (Gallus gallus). Although some studies have identified genes affecting egg quality, little is known about the genes responsible for oviduct development. To address this issue, here we used a genome-wide association (GWA) study to detect genes or genomic regions that are related to oviduct development in a chicken F2 resource population by employing high-density 600 K single-nucleotide polymorphism (SNP) arrays. For oviduct length and weight, which exhibited moderate heritability estimates of 0.35 and 0.39, respectively, chromosome 1 (GGA1) explained 9.45% of the genetic variance, while GGA4 to GGA8 and GGA11 explained over 1% of the variance. Independent univariate genome-wide screens for oviduct length and weight detected 69 significant SNPs on GGA1 and 49 suggestive SNPs on GGA1, GGA4, and GGA8. One hundred and fourteen suggestive SNPs were associated with oviduct length, while 73 SNPs were associated with oviduct weight. The significant genomic regions affecting oviduct weight ranged from 167.79-174.29 Mb on GGA1, 73.16-75.70 Mb on GGA4, and 4.88-4.92 Mb on GGA8. The genes CKAP2, CCKAR, NCAPG, IGFBP3, and GORAB were shown to have potential roles in oviduct development. These genes are involved in cell survival, appetite, and growth control. Our results represent the first GWA analysis of genes controlling oviduct weight and length. The identification of genomic loci and potential candidate genes affecting oviduct development greatly increase our understanding of the genetic basis underlying oviduct development, which could have an impact on the selection of egg quality. PMID- 29281707 TI - Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis. AB - M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M. tuberculosis, a key component in the FASII system. Here, we aimed to evaluate the inhibitory activity of IQG-607 against promastigote and amastigote forms of Leishmania (Viannia) braziliensis isolated from patients with different clinical forms of L. braziliensis infection, including cutaneous, mucosal and disseminated leishmaniasis. Importantly, IQG-607 inhibited the proliferation of three different isolates of L. braziliensis promastigotes associated with cutaneous, mucosal and disseminated leishmaniasis. The IC50 values for IQG-607 ranged from 32 to 75 MUM, for these forms. Additionally, IQG-607 treatment decreased the proliferation of intracellular amastigotes in infected macrophages, after an analysis of the percentage of infected cells and the number of intracellular parasites/100 cells. IQG-607 reduced from 58% to 98% the proliferation of L. braziliensis from cutaneous, mucosal and disseminated strains. Moreover, IQG-607 was also evaluated regarding its potential toxic profile, by using different cell lines. Cell viability of the lineages Vero, HaCat and HepG2 was significantly reduced after incubation with concentrations of IQG-607 higher than 2 mM. Importantly, IQG-607, in a concentration of 1 mM, did not induce DNA damage in HepG2 cells, when compared to the untreated control group. Future studies will confirm the mechanism of action of IQG-607 against L. braziliensis. PMID- 29281708 TI - Protein-protein conjugate nanoparticles for malaria antigen delivery and enhanced immunogenicity. AB - Chemical conjugation of polysaccharide to carrier proteins has been a successful strategy to generate potent vaccines against bacterial pathogens. We developed a similar approach for poorly immunogenic malaria protein antigens. Our lead candidates in clinical trials are the malaria transmission blocking vaccine antigens, Pfs25 and Pfs230D1, individually conjugated to the carrier protein Exoprotein A (EPA) through thioether chemistry. These conjugates form nanoparticles that show enhanced immunogenicity compared to unconjugated antigens. In this study, we examined the broad applicability of this technology as a vaccine development platform, by comparing the immunogenicity of conjugates prepared by four different chemistries using different malaria antigens (PfCSP, Pfs25 and Pfs230D1), and carriers such as EPA, TT and CRM197. Several conjugates were synthesized using thioether, amide, ADH and glutaraldehyde chemistries, characterized for average molecular weight and molecular weight distribution, and evaluated in mice for humoral immunogenicity. Conjugates made with the different chemistries, or with different carriers, showed no significant difference in immunogenicity towards the conjugated antigens. Since particle size can influence immunogenicity, we tested conjugates with different average size in the range of 16-73 nm diameter, and observed greater immunogenicity of smaller particles, with significant differences between 16 and 73 nm particles. These results demonstrate the multiple options with respect to carriers and chemistries that are available for protein-protein conjugate vaccine development. PMID- 29281709 TI - Beyond greenness: Detecting temporal changes in photosynthetic capacity with hyperspectral reflectance data. AB - Earth's future carbon balance and regional carbon exchange dynamics are inextricably linked to plant photosynthesis. Spectral vegetation indices are widely used as proxies for vegetation greenness and to estimate state variables such as vegetation cover and leaf area index. However, the capacity of green leaves to take up carbon can change throughout the season. We quantify photosynthetic capacity as the maximum rate of RuBP carboxylation (Vcmax) and regeneration (Jmax). Vcmax and Jmax vary within-season due to interactions between ontogenetic processes and meteorological variables. Remote sensing-based estimation of Vcmax and Jmax using leaf reflectance spectra is promising, but temporal variation in relationships between these key determinants of photosynthetic capacity, leaf reflectance spectra, and the models that link these variables has not been evaluated. To address this issue, we studied hybrid poplar (Populus spp.) during a 7-week mid-summer period to quantify seasonally-dynamic relationships between Vcmax, Jmax, and leaf spectra. We compared in situ estimates of Vcmax and Jmax from gas exchange measurements to estimates of Vcmax and Jmax derived from partial least squares regression (PLSR) and fresh-leaf reflectance spectroscopy. PLSR models were robust despite dynamic temporal variation in Vcmax and Jmax throughout the study period. Within-population variation in plant stress modestly reduced PLSR model predictive capacity. Hyperspectral vegetation indices were well-correlated to Vcmax and Jmax, including the widely-used Normalized Difference Vegetation Index. Our results show that hyperspectral estimation of plant physiological traits using PLSR may be robust to temporal variation. Additionally, hyperspectral vegetation indices may be sufficient to detect temporal changes in photosynthetic capacity in contexts similar to those studied here. Overall, our results highlight the potential for hyperspectral remote sensing to estimate determinants of photosynthetic capacity during periods with dynamic temporal variations related to seasonality and plant stress, thereby improving estimates of plant productivity and characterization of the associated carbon budget. PMID- 29281710 TI - Maternal influenza immunization in Malawi: Piloting a maternal influenza immunization program costing tool by examining a prospective program. AB - BACKGROUND: This costing study in Malawi is a first evaluation of a Maternal Influenza Immunization Program Costing Tool (Costing Tool) for maternal immunization. The tool was designed to help low- and middle-income countries plan for maternal influenza immunization programs that differ from infant vaccination programs because of differences in the target population and potential differences in delivery strategy or venue. METHODS: This analysis examines the incremental costs of a prospective seasonal maternal influenza immunization program that is added to a successful routine childhood immunization and antenatal care program. The Costing Tool estimates financial and economic costs for different vaccine delivery scenarios for each of the major components of the expanded immunization program. RESULTS: In our base scenario, which specifies a donated single dose pre-filled vaccine formulation, the total financial cost of a program that would reach 2.3 million women is approximately $1.2 million over five years. The economic cost of the program, including the donated vaccine, is $10.4 million over the same period. The financial and economic costs per immunized pregnancy are $0.52 and $4.58, respectively. Other scenarios examine lower vaccine uptake, reaching 1.2 million women, and a vaccine purchased at $2.80 per dose with an alternative presentation. CONCLUSION: This study estimates the financial and economic costs associated with a prospective maternal influenza immunization program in a low-income country. In some scenarios, the incremental delivery cost of a maternal influenza immunization program may be as low as some estimates of childhood vaccination programs, assuming the routine childhood immunization and antenatal care systems are capable of serving as the platform for an additional vaccination program. However, purchasing influenza vaccines at the prices assumed in this analysis, instead of having them donated, is likely to be challenging for lower-income countries. This result should be considered as a starting point to understanding the costs of maternal immunization programs in low- and middle-income countries. PMID- 29281711 TI - Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. AB - Experimentally derived apparent permeabilities, Papp, through cell monolayers such as Caco-2 and MDCK are considered to be an in-vitro gold standard for assessing the uptake efficiency of drugs. Here, we present a mechanistic model that describes 'passive' Papp values (i.e., neglecting active transport) by accounting for the different resistances solutes encounter when permeating a cell monolayer. We described three parallel permeation pathways, namely a cytosolic-, paracellular-, and lateral route, each of which consists of a number of serial resistances. These resistances were accounted for via a mechanistic depiction of the underlying processes that are largely based on literature work. For the present Papp dataset, about as much chemicals are dominated by the cytosolic route as were dominated by the paracellular route, while the lateral route was negligible. For the cytosolic route by far the most chemicals found their main resistance in the various water layers and not in the membrane. Although correlations within the subclasses of chemicals dominated by a specific permeation route were rather poor, we could overall satisfyingly predict Papp for 151 chemicals at a pH of 7.4 (R2 = 0.77, RMSE = 0.48). For a specific evaluation of the intrinsic membrane permeability, Pm, a second experimental dataset based on experiments with black lipid membranes, BLM, was evaluated. Pm could be predicted for 37 chemicals with R2 = 0.91 and RMSE = 0.64 log units. PMID- 29281712 TI - Posture alteration as a measure to accommodate uneven ground in able-bodied gait. AB - Though the effects of imposed trunk posture on human walking have been studied, less is known about such locomotion while accommodating changes in ground level. For twelve able participants, we analyzed kinematic parameters mainly at touchdown and toe-off in walking across a 10-cm visible drop in ground level (level step, pre-perturbation step, step-down, step-up) with three postures (regular erect, ~30 degrees and ~50 degrees of trunk flexion from the vertical). Two-way repeated measures ANOVAs revealed step-specific effects of posture on the kinematic behavior of gait mostly at toe-off of the pre perturbation step and the step-down as well as at touchdown of the step-up. In preparation to step-down, with increasing trunk flexion the discrepancy in hip center of pressure distance, i.e. effective leg length, (shorter at toe-off versus touchdown), compared with level steps increased largely due to a greater knee flexion at toe-off. Participants rotated their trunk backwards during step down (2- to 3-fold backwards rotation compared with level steps regardless of trunk posture) likely to control the angular momentum of their whole body. The more pronounced trunk backwards rotation in trunk-flexed walking contributed to the observed elevated center of mass (CoM) trajectories during the step-down which may have facilitated drop negotiation. Able-bodied individuals were found to recover almost all assessed kinematic parameters comprising the vertical position of the CoM, effective leg length and angle as well as hip, knee and ankle joint angles at the end of the step-up, suggesting an adaptive capacity and hence a robustness of human walking with respect to imposed trunk orientations. Our findings may provide clinicians with insight into a kinematic interaction between posture and locomotion in uneven ground. Moreover, a backward rotation of the trunk for negotiating step-down may be incorporated into exercise-based interventions to enhance gait stability in individuals who exhibit trunk-flexed postures during walking. PMID- 29281713 TI - Correlations between specific patterns of spontaneous activity and stimulation efficiency in degenerated retina. AB - Retinal prostheses that are currently used to restore vision in patients suffering from retinal degeneration are not adjusted to the changes occurring during the remodeling process of the retina. Recent studies revealed abnormal rhythmic activity in the retina of genetic mouse models of retinitis pigmentosa. Here we describe this abnormal activity also in a pharmacologically-induced (MNU) mouse model of retinal degeneration. To investigate how this abnormal activity affects the excitability of retinal ganglion cells, we recorded the electrical activity from whole mounted retinas of rd10 mice and MNU-treated mice using a microelectrode array system and applied biphasic current pulses of different amplitude and duration to stimulate ganglion cells electrically. We show that the electrical stimulation efficiency is strongly reduced in degenerated retinas, in particular when abnormal activity such as oscillations and rhythmic firing of bursts of action potentials can be observed. Using a prestimulus pulse sequence, we could abolish rhythmic retinal activity. Under these conditions, the stimulation efficiency was enhanced in a few cases but not in the majority of tested cells. Nevertheless, this approach supports the idea that modified stimulation protocols could help to improve the efficiency of retinal prostheses in the future. PMID- 29281714 TI - Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF 2 in cancer cells. AB - Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2alpha (HIF-2alpha) subunit by the acetyltransferase/coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2alpha complex formation. In addition to promoting de novo transcription, Cbp and HIF-2alpha act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis. PMID- 29281715 TI - Correlation between the thickness of the crestal and buccolingual cortical bone at varying depths and implant stability quotients. AB - BACKGROUND/PURPOSE: Resonance frequency analysis (RFA) is clinically used in dentistry to access the stiffness of dental implants in surrounding bone. However, the clear advantages and disadvantages of this method are still inconclusive. The aim of this study was to investigate and compare implant stability quotient (ISQ) values obtained from RFA with parameters obtained from a cone beam computed tomography (CBCT) scan of the same region. MATERIALS AND METHODS: Nineteen implants (Conelog) were inserted in the posterior maxillary and mandibular partially edentulous regions of 16 patients. At the time of implant placement, the ISQ values were obtained using RFA (Osstell). CBCT was used to measure the thickness of the crestal, cortical, buccolingual cortical, and cancellous bone at 3, 6, and 9 mm below the crestal bone level, as indicated by radiographic markers. The ratio of the thickness of the cortical to cancellous bone at varying depths was also calculated and classified into 4 groups (Group 1 4). RESULTS: There was a strong correlation between the crestal cortical bone thickness and ISQ values (P<0.001). The thickness of the buccolingual cortical bone and ratio of the cortical to cancellous bone thickness at 3 mm were significantly related to the ISQ (P = 0.018 and P = 0.034, respectively). Furthermore, the ISQs in Group 1 were the highest compared with those in Group 2 and Group 3, whereas the CBCT parameters at 6 and 9 mm did not have any specific correlation with the ISQ values. CONCLUSION: This study showed that the ISQ values obtained from RFA highly correlated with the quantity and quality of bone 3 mm below the crestal bone level. The correlation between the ISQ and bone surrounding the implant site was dependent on the depth of measurement. Therefore, RFA can help to predict the marginal bone level, as confirmed in this study. PMID- 29281716 TI - Trends and patterns of antibiotic consumption in China's tertiary hospitals: Based on a 5 year surveillance with sales records, 2011-2015. AB - The consumption of antibiotics is a major driver in the development of antimicrobial resistance. This study aims to identify the trends and patterns of the total antibiotic consumption in China's tertiary hospitals from 2011 to 2015 by retrospectively analyzing aggregated monthly surveillance data on antibiotic sales made to 468 hospitals from 28 provinces. Antibiotic consumption was expressed in DDD per 1,000 inhabitants per day (DID). We compared population weighted antibiotic consumption patterns in China with European countries using indicators from the European Surveillance of Antimicrobial Consumption (ESAC). Total antibiotic consumption, including all the specific antibiotic class except for aminoglycoside antibacterials, were significantly increased during the study period from an average of 7.97 DID in 2011 to 10.08 DID in 2015. In 2015, the eastern regions of China consumed the most antibiotics using population denominator while the western regions consumed the most using inpatient denominator. Cephalosporins accounted for 28.6% of total DID, followed by beta lactam-beta-lactamase inhibitor combinations (20.0%), macrolides (17.4%), and fluoroquinolones (10.5%). Antibiotic in parenteral form accounted for nearly half of all antibiotics. Although over the past few years major efforts had been made to reduce the risks of excessive antibiotic use through antibiotic stewardship, total antibiotic consumption showed a significant upward trend during the study period. A consistent preference for cephalosporins, macrolides, beta-lactam-beta lactamase inhibitor combinations, as well as parenteral preparations was observed. PMID- 29281717 TI - Genetic origin of goat populations in Oman revealed by mitochondrial DNA analysis. AB - The Sultanate of Oman has a complex mosaic of livestock species and production systems, but the genetic diversity, demographic history or origins of these Omani animals has not been expensively studied. Goats might constitute one of the most abundant and important domestic livestock species since the Neolithic transition. Here, we examined the genetic diversity, origin, population structure and demographic history of Omani goats. Specifically, we analyzed a 525-bp fragment of the first hypervariable region of the mitochondrial DNA (mtDNA) control region from 69 Omani individuals and compared this fragment with 17 mtDNA sequences from Somalia and Yemen as well as 18 wild goat species and 1,198 previously published goat sequences from neighboring countries. The studied goat breeds show substantial diversity. The haplotype and nucleotide diversities of Omani goats were found equal to 0.983 +/- 0.006 and 0.0284 +/- 0.014, respectively. The phylogenetic analyses allowed us to classify Omani goats into three mtDNA haplogroups (A, B and G): haplogroup A was found to be predominant and widely distributed and accounted for 80% of all samples, and haplogroups B and G exhibited low frequencies. Phylogenetic comparisons with wild goats revealed that five of the native Omani goat populations originate from Capra aegagrus. Furthermore, most comparisons of pairwise population FST values within and between these five Omani goat breeds as well as between Omani goats and nine populations from nearby countries were not significant. These results suggest strong gene flow among goat populations caused by the extensive transport of goats and the frequent movements of human populations in ancient Arabia. The findings improve our understanding of the migration routes of modern goats from their region of domestication into southeastern Arabia and thereby shed light on human migratory and commercial networks during historical times. PMID- 29281718 TI - The burden of hepatitis B virus (HBV) infection, genotypes and drug resistance mutations in human immunodeficiency virus-positive patients in Northwest Ethiopia. AB - BACKGROUND: In sub-Saharan Africa, the hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections are endemic. Although there has been great progress in HIV care, universal HBV vaccination and care is lacking. In this study, we aimed to determine the prevalence of HBV, HBV genotypes, and drug resistance mutations in dual infected cases in a cohort of HIV patients in Northwest Ethiopia. METHODS: A total of 308 HIV-1 positive patients were enrolled into the study and tested for HBsAg in plasma. In HBsAg positive samples, HBV DNA was analyzed for HBV genotype using in-house nested PCR with HBV-specific pre core / core or surface primers, and for HBV drug resistance mutations (DRMs) in polymerase region. Odds ratio at 95% confidence interval was calculated. RESULTS: Of the 308 HIV-positive subjects, 62.7% were female, median age 38 years (range 18-68, IQR: 27-49), and the median CD4 count 405 cells/MUl (IQR: 75-734). Overall, 94.2% were on antiretroviral therapy (ART) frequently with combinations of Zidovudine (AZT)- Lamivudine (3TC)-Nevirapine (NVP). HBsAg was detected in 5.5% (95%CI 2.95-8.08%) of the study participants, of which the majority were infected with HBV genotype A (7A, 2E, 2D, 1C, 1 G). All HIV/HBV positive cases were on ART with anti-HBV activity (i.e., 3TC) and 3TC associated HBV DRMs (i.e., rtV173L, rtL180M, and rtM204V) were detected in 7/13 (53.8%) subjects. CONCLUSION: In this cross-sectional study of HIV-infected individuals, we found 5.5% HBV/HIV co-infected cases. Most were receiving the first generation anti-HBV therapy with a low genetic barrier to resistance, and several carried mutations associated with anti-HBV (3TC) drug resistance. These data underscore the importance of integrating HBV screening to the HIV treatment guidelines for better management and prevention of HBV-related liver disease. PMID- 29281721 TI - Physiological and biochemical responses involved in water deficit tolerance of nitrogen-fixing Vicia faba. AB - Climate change is increasingly impacting the water deficit over the world. Because of drought and the high pressure of the rising human population, water is becoming a scarce and expensive commodity, especially in developing countries. The identification of crops presenting a higher acclimation to drought stress is thus an important objective in agriculture. The present investigation aimed to assess the adaptation of three Vicia faba genotypes, Aguadulce (AD), Luz d'Otonio (LO) and Reina Mora (RM) to water deficit. Multiple physiological and biochemical parameters were used to analyse the response of the three genotypes to two soil water contents (80% and 40% of field capacity). A significant lower decrease in shoot, root and nodule dry weight was observed for AD compared to LO and RM. The better growth performance of AD was correlated to higher carbon and nitrogen content than in LO and RM under water deficit. Leaf parameters such as relative water content, mass area, efficiency of photosystem II and chlorophyll and carotenoid content were significantly less affected in AD than in LO and RM. Significantly higher accumulation of proline was correlated to the higher performance of AD compared to LO and RM. Additionally, the better growth of AD genotype was related to an important mobilisation of antioxidant enzyme activities such as ascorbate peroxidase and catalase. Taken together, these results allow us to suggest that AD is a water deficit tolerant genotype compared to LO and RM. Our multiple physiological and biochemical analyses show that nitrogen content, leaf proline accumulation, reduced leaf hydrogen peroxide accumulation and leaf antioxidant enzymatic activities (ascorbate peroxidase, guaiacol peroxidase, catalase and polyphenol oxidase) are potential biological markers useful to screen for water deficit resistant Vicia faba genotypes. PMID- 29281720 TI - Reversible dual inhibitor against G9a and DNMT1 improves human iPSC derivation enhancing MET and facilitating transcription factor engagement to the genome. AB - The combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of iPSCs and could be used for disease modelling, high throughput screenings and/or regenerative medicine applications. In this study, we showed that a new first-in class reversible dual G9a/DNMT1 inhibitor compound (CM272) improves the efficiency of human cell reprogramming and iPSC generation from primary cells of healthy donors and patient samples, using both integrative and non-integrative methods. Moreover, CM272 facilitates the generation of human iPSC with only two factors allowing the removal of the most potent oncogenic factor cMYC. Furthermore, we demonstrated that mechanistically, treatment with CM272 induces heterochromatin relaxation, facilitates the engagement of OCT4 and SOX2 transcription factors to OSKM refractory binding regions that are required for iPSC establishment, and enhances mesenchymal to epithelial transition during the early phase of cell reprogramming. Thus, the use of this new G9a/DNMT reversible dual inhibitor compound may represent an interesting alternative for improving cell reprogramming and human iPSC derivation for many different applications while providing interesting insights into reprogramming mechanisms. PMID- 29281719 TI - CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin. AB - The skin tuberculin test (TST), an example of a delayed-type hypersensitivity (DTH) reaction, is based on measuring the extent of skin induration to mycobacterial tuberculin (PPD). Little is known about the genetic basis of TST reactivity, widely used for diagnosing TB infection. The study investigated the relationship of the single base change polymorphic variants in CD14 gene (CD14( 159C/T)) with the development of DTH to PPD in BCG-vaccinated Polish Caucasian individuals. We found persistent lack of TST reactivity in about 40% of healthy subjects despite receiving more than one dose of BCG. The TST size was negatively correlated with the number of BCG inoculations. The distribution of C/T genotype was significantly more frequent among TST-negative compared with TST-positive individuals. The concentration of serum sCD14 was positively associated with mCD14 expression, but not with the TST status or CD14(-159C/T) polymorphism. A significant increase in mCD14 expression and serum sCD14 levels was found in TB group. We hypothesize that CD14(-159C/T) polymorphic variants might be one of genetic components in the response to attenuated M. bovis BCG bacilli. PMID- 29281722 TI - Cortical representation of different taste modalities on the gustatory cortex: A pilot study. AB - BACKGROUND: Right insular cortex is involved in taste discrimination, but its functional organization is still poorly known. In general, sensory cortices represent the spatial prevalence of relevant features for each sensory modality (visual, auditory, somatosensory) in an ordered way across the cortical space. Following this analogy, we hypothesized that primary taste cortex is organized in similar ordered way in response to six tastes with known receptorial mechanisms (sweet, bitter, sour, salt, umami, CO2). DESIGN: Ten normal subjects were enrolled in a pilot study. We used functional magnetic resonance imaging (fMRI), a high resolution cortical registration method, and specialized procedures of feature prevalence localization, to map fMRI responses within the right insular cortex, to water solutions of quinine hydrochloride (bitter), Acesulfamate K (sweet), sodium chloride (salt), mono potassium glutamate + inosine 5' mono phosphate (Umami), citric acid (sour) and carbonated water (CO2). During an fMRI scan delivery of the solutions was applied in pseudo-random order interleaved with cleaning water. RESULTS: Two subjects were discarded due to excessive head movements. In the remaining subjects, statistically significant activations were detected in the fMRI responses to all tastes in the right insular cortex (p<0.05, family-wise corrected for multiple comparisons). Cortical representation of taste prevalence highlighted two spatially segregated clusters, processing two and three tastes coupled together (sweet-bitter and salt-umami-sour), with CO2 in between. CONCLUSIONS: Cortical representation of taste prevalence within the right primary taste cortex appears to follow the ecological purpose of enhancing the discrimination between safe nutrients and harmful substances. PMID- 29281723 TI - Human immunodeficiency virus type-1 (HIV-1) evades antibody-dependent phagocytosis. AB - Fc gamma receptor (FcyR)-mediated antibody functions play a crucial role in preventing HIV infection. One such function, antibody-dependent phagocytosis (ADP), is thought to be involved in controlling other viral infections, but its role in HIV infection is unknown. We measured the ability of HIV-specific polyclonal and monoclonal antibodies (mAbs) to mediate the internalization of HIV 1 virions and HIV-1-decorated cells by phagocytes. To measure ADP of virions, we primarily used a green-fluorescent protein-expressing molecular clone of HIV 1JRFL, an R5, clinical isolate, in combination with polyclonal HIVIG or mAbs known to capture and/or neutralize HIV-1. THP-1 and U937 cells, as well as freshly isolated primary monocytes from healthy individuals, were used as phagocytic effector cells, and uptake of virions was measured by cytometry. We surprisingly found minimal or no ADP of virions with any of the antibodies. However, after coating virions with gp41 or with gp41-derived peptides, gp41- (but not gp120-) specific mAbs efficiently mediated phagocytosis. We estimated that a minimum of a few hundred gp41 molecules were needed for successful phagocytosis, which is similar to the number of envelope spikes on viruses that are readily phagocytosed (e.g. influenza virus). Furthermore, by employing fluorescence correlation spectroscopy, a well-established technique to measure particle sizes and aggregation phenomena, we found a clear association between virus aggregation and ADP. In contrast to virions themselves, virion-decorated cells were targets for ADP or trogocytosis in the presence of HIV-specific antibodies. Our findings indicate that ADP of virions may not play a role in preventing HIV infection, likely due to the paucity of trimers and the consequent inability of virion-bound antibody to cross-link FcyRs on phagocytes. However, ADP or trogocytosis could play a role in clearing HIV-infected cells and cells on the verge of infection. PMID- 29281725 TI - Intragenic recombination between two non-functional semi-dwarf 1 alleles produced a functional SD1 allele in a tall recombinant inbred line in rice. AB - Intragenic recombination is one of the most important sources of genetic variability. In our previous study, RI92 a tall line (160 cm of plant height) was observed in the cross progeny between two semi-dwarf indica cultivars Zhenshan 97 and Minghui 63. Genome-wide genotyping and sequencing indicated that the genome constitution of RI92 was completely from both parents. Bulk segregant analysis in a BC3F2 population revealed that "green revolution gene" semi-dwarf 1 (sd1) was most likely the gene controlling the tall plant height in RI92. Sequencing analysis of SD1 revealed that an intragenic recombination occurred between two parental non-functional sd1 alleles and generated a functional SD1 in RI92. Four fold high recombination rate in SD1 located bins to the genome-wide average was observed in two RIL populations, indicating recombination hotspot in the SD1 region. Intragenic recombination creates new alleles in the progeny distinct from parental alleles and diversifies natural variation. PMID- 29281724 TI - HSP90C interacts with PsbO1 and facilitates its thylakoid distribution from chloroplast stroma in Arabidopsis. AB - Arabidopsis plastidic HSP90C is an HSP90 family molecular chaperone that is required for chloroplast development and function. To understand the mechanism of action of HSP90C within the chloroplast, we conducted a yeast two-hybrid screening and revealed it interacts directly with the photosystem II extrinsic protein PsbO1, which performs a canonical function in the thylakoid lumen. To understand the biological significance of HSP90C-PsbO1 interaction, we investigated the role of HSP90C in modulating the stromal and thylakoid distribution of PsbO1GFP fusion protein. Fusion to GFP significantly delays the PsbO1 thylakoid transport and induces a variegation phenotype. Overexpression of HSP90C promotes the thylakoid distribution of PsbO1GFP and alleviates the leaf variegation. By tracking the chloroplast maturation during photomorphogenesis, we observed PsbO1GFP tends to form distinct fluorescent clusters within the stroma with delayed thylakoid membrane biogenesis, while HSP90C overexpression corrects these adverse effects. We also demonstrated that active HSP90C function is specifically required for stable accumulation of mature PsbO1GFP in thylakoid by using specific inhibitor geldanamycin. This study therefore not only identified novel HSP90C interactors, but also reports for the first time that PsbO1 enroute from the cytoplasm to thylakoid lumen is tightly regulated by the HSP90C chaperone complex in plastid stroma; whereas the proper HSP90C homeostasis is also critical for chloroplast maturation and function. PMID- 29281726 TI - Criteria for the prioritization of public health interventions for climate sensitive vector-borne diseases in Quebec. AB - Prioritizing resources for optimal responses to an ever growing list of existing and emerging infectious diseases represents an important challenge to public health. In the context of climate change, there is increasing anticipated variability in the occurrence of infectious diseases, notably climate-sensitive vector-borne diseases. An essential step in prioritizing efforts is to identify what considerations and concerns to take into account to guide decisions and thus set disease priorities. This study was designed to perform a comprehensive review of criteria for vector-borne disease prioritization, assess their applicability in a context of climate change with a diverse cross-section of stakeholders in order to produce a baseline list of considerations to use in this decision-making context. Differences in stakeholder choices were examined with regards to prioritization of these criteria for research, surveillance and disease prevention and control objectives. A preliminary list of criteria was identified following a review of the literature. Discussions with stakeholders were held to consolidate and validate this list of criteria and examine their effects on disease prioritization. After this validation phase, a total of 21 criteria were retained. A pilot vector-borne disease prioritization exercise was conducted using PROMETHEE to examine the effects of the retained criteria on prioritization in different intervention domains. Overall, concerns expressed by stakeholders for prioritization were well aligned with categories of criteria identified in previous prioritization studies. Weighting by category was consistent between stakeholders overall, though some significant differences were found between public health and non-public health stakeholders. From this exercise, a general model for climate-sensitive vector-borne disease prioritization has been developed that can be used as a starting point for further public health prioritization exercises relating to research, surveillance, and prevention and control interventions in a context of climate change. Multi-stakeholder engagement in prioritization can help broaden the range of criteria taken into account, offer opportunities for early identification of potential challenges and may facilitate acceptability of any resulting decisions. PMID- 29281728 TI - Vertebral cross-sectional growth: A predictor of vertebral wedging in the immature skeleton. AB - The degree of vertebral wedging, a key structural characteristic of spinal curvatures, has recently been found to be negatively related to vertebral cross sectional area (CSA). The purpose of this longitudinal study was to examine the relation between vertebral cross-sectional growth and vertebral wedging progression within the immature lumbar spine. Using magnetic resonance imaging (MRI), we analyzed the potential association between increases in lumbar vertebral CSA and changes in L5 vertebral wedging in 27 healthy adolescent girls (ages 9-13 years) twice within a two-year period. Vertebral CSA growth was negatively associated with changes in posteroanterior vertebral wedging (r = 0.61; p = 0.001). Multiple regression analysis showed that this relation was independent of gains in age, height, and weight. When compared to the 14 girls whose vertebral wedging progressed, the 13 subjects whose vertebral wedging decreased had significantly greater vertebral cross-sectional growth (0.39 +/- 0.25 vs. 0.75 +/- 0.23 cm2; p = 0.001); in contrast, there were no significant differences in increases in age, height, or weight between the two groups. Changes in posteroanterior vertebral wedging and the degree of lumbar lordosis (LL) positively correlated (r = 0.56, p = 0.002)-an association that persisted even after adjusting for gains in age, height, and weight. We concluded that in the immature skeleton, vertebral cross-sectional growth is an important determinant of the plasticity of the vertebral body; regression of L5 vertebral wedging is associated with greater lumbar vertebral cross-sectional growth, while progression is the consequence of lesser cross-sectional growth. PMID- 29281727 TI - Transcriptome dynamic of Arabidopsis roots infected with Phytophthora parasitica identifies VQ29, a gene induced during the penetration and involved in the restriction of infection. AB - Little is known about the responses of plant roots to filamentous pathogens, particularly to oomycetes. To assess the molecular dialog established between the host and the pathogen during early stages of infection, we investigated the overall changes in gene expression in A. thaliana roots challenged with P. parasitica. We analyzed various infection stages, from penetration and establishment of the interaction to the switch from biotrophy to necrotrophy. We identified 3390 genes for which expression was modulated during the infection. The A. thaliana transcriptome displays a dynamic response to P. parasitica infection, from penetration onwards. Some genes were specifically coregulated during penetration and biotrophic growth of the pathogen. Many of these genes have functions relating to primary metabolism, plant growth, and defense responses. In addition, many genes encoding VQ motif-containing proteins were found to be upregulated in plant roots, early in infection. Inactivation of VQ29 gene significantly increased susceptibility to P. parasitica during the late stages of infection. This finding suggests that the gene contributes to restricting oomycete development within plant tissues. Furthermore, the vq29 mutant phenotype was not associated with an impairment of plant defenses involving SA-, JA-, and ET-dependent signaling pathways, camalexin biosynthesis, or PTI signaling. Collectively, the data presented here thus show that infection triggers a specific genetic program in roots, beginning as soon as the pathogen penetrates the first cells. PMID- 29281730 TI - Correction: Systematic Review and Meta-Analysis of Detecting Galactomannan in Bronchoalveolar Lavage Fluid for Diagnosing Invasive Aspergillosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0043347.]. PMID- 29281731 TI - Epidemiology of chlamydial infection and disease in a free-ranging koala (Phascolarctos cinereus) population. AB - Chlamydial disease continues to be one of the main factors threatening the long term survival of the koala (Phascolarctos cinereus). Despite this, large epidemiological studies of chlamydial infection and disease in wild koala populations are lacking. A better understanding of the prevalence, transmission and pathogenesis is needed to improve control measures, such as the development of vaccines. We investigated the prevalence of Chlamydia pecorum infection and disease in 160 koalas in a peri-urban wild population in Queensland, Australia and found that 31% of koalas were Chlamydia PCR positive and 28% had clinically detectable chlamydial disease. Most infections were at the urogenital site (27%; both males and females) with only 14% at the ocular site. Interestingly, we found that 27% (4/15) of koalas considered to be sexually immature (9-13 months) were already infected with C. pecorum, suggesting that a significant percentage of animals are infected directly from their mother. Ocular infection levels were less prevalent with increasing age (8% in koalas older than 4 years), whereas the prevalence of urogenital tract infections remained high into older age (26% in koalas older than 4 years), suggesting that, after mother-to-young transmission, C. pecorum is predominantly a sexually transmitted infection. While 28% of koalas in this population had clinically detectable chlamydial disease (primarily urogenital tract disease), many PCR positive koalas had no detectable disease and importantly, not all diseased animals were PCR positive. We also observed higher chlamydial loads in koalas who were C. pecorum infected without clinical disease than in koalas who were C. pecorum infected with clinical disease. These results shed light on the potential mechanisms of transmission of C. pecorum in koalas and also guide future control measures, such as vaccination. PMID- 29281729 TI - Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3 K88 monomethylation. AB - The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated. Here, we identify that, contrary to its role in enhancing DNA virus replication, LSD1 limits RNA virus replication by demethylating and activating IFITM3 which is a host restriction factor for many RNA viruses. We have found that LSD1 is recruited to demethylate IFITM3 at position K88 under IFNalpha treatment. However, infection by either Vesicular Stomatitis Virus (VSV) or Influenza A Virus (IAV) triggers methylation of IFITM3 by promoting its disassociation from LSD1. Accordingly, inhibition of the enzymatic activity of LSD1 by Trans-2 phenylcyclopropylamine hydrochloride (TCP) increases IFITM3 monomethylation which leads to more severe disease outcomes in IAV-infected mice. In summary, our findings highlight the opposite role of LSD1 in fighting RNA viruses comparing to DNA viruses infection. Our data suggest that the demethylation of IFITM3 by LSD1 is beneficial for the host to fight against RNA virus infection. PMID- 29281734 TI - Safety of bridging antiplatelet therapy with the gpIIb-IIIa inhibitor tirofiban after emergency stenting in stroke. AB - BACKGROUND: In a proportion of stroke patients with acute large vessel occlusion permanent stent implantation is mandatory to achieve successful recanalization. The optimum platelet inhibition strategy after such emergency stenting is unknown. We therefore analyzed the outcome of early glycoprotein (gp) IIb/IIIa inhibitor treatment after emergency stenting in acute stroke. METHODS: Sixty patients with emergency stenting were identified in our stroke unit registry from 12/2010-06/2014 and analyzed retrospectively. All patients were bridged intravenously with the gpIIb/IIIa antagonist tirofiban immediately after the acute procedure until switching to oral aspirin and clopidogrel was performed. For comparison we studied 135 patients with M1 occlusion undergoing thrombectomy without stent implantation or tirofiban treatment in a propensity score-adjusted analysis. RESULTS: In the acute stenting group receiving tirofiban complications with 6 deaths during the hospital stay (10%), 2 reinfarctions (3%), 12 intracerebral hemorrhages (ICH; 20%) and 5 symptomatic ICH (8%) occurred. Thirty seven patients (62%) reached a moderate outcome of mRS 0-3 after 90 days. In the thrombectomy group without tirofiban administration the rate of deaths within hospital stay, the rate of ICH and outcome at day 90 were not different. CONCLUSION: In our retrospective study acute stenting with subsequent gpIIb/IIIa inhibition was not associated with an increased risk of ICH or in-hospital death. PMID- 29281733 TI - Adenoviral vaccine induction of CD8+ T cell memory inflation: Impact of co infection and infection order. AB - The efficacies of many new T cell vaccines rely on generating large populations of long-lived pathogen-specific effector memory CD8 T cells. However, it is now increasingly recognized that prior infection history impacts on the host immune response. Additionally, the order in which these infections are acquired could have a major effect. Exploiting the ability to generate large sustained effector memory (i.e. inflationary) T cell populations from murine cytomegalovirus (MCMV) and human Adenovirus-subtype (AdHu5) 5-beta-galactosidase (Ad-lacZ) vector, the impact of new infections on pre-existing memory and the capacity of the host's memory compartment to accommodate multiple inflationary populations from unrelated pathogens was investigated in a murine model. Simultaneous and sequential infections, first with MCMV followed by Ad-lacZ, generated inflationary populations towards both viruses with similar kinetics and magnitude to mono-infected groups. However, in Ad-lacZ immune mice, subsequent acute MCMV infection led to a rapid decline of the pre-existing Ad-LacZ-specific inflating population, associated with bystander activation of Fas-dependent apoptotic pathways. However, responses were maintained long-term and boosting with Ad-lacZ led to rapid re-expansion of the inflating population. These data indicate firstly that multiple specificities of inflating memory cells can be acquired at different times and stably co-exist. Some acute infections may also deplete pre existing memory populations, thus revealing the importance of the order of infection acquisition. Importantly, immunization with an AdHu5 vector did not alter the size of the pre-existing memory. These phenomena are relevant to the development of adenoviral vectors as novel vaccination strategies for diverse infections and cancers. (241 words). PMID- 29281735 TI - Correction: CT Chest and pulmonary functional changes in patients with HTLV associated myelopathy in the Eastern Brazilian Amazon. AB - [This corrects the article DOI: 10.1371/journal.pone.0186055.]. PMID- 29281732 TI - Association of papillomavirus E6 proteins with either MAML1 or E6AP clusters E6 proteins by structure, function, and evolutionary relatedness. AB - Papillomavirus E6 proteins bind to LXXLL peptide motifs displayed on targeted cellular proteins. Alpha genus HPV E6 proteins associate with the cellular ubiquitin ligase E6AP (UBE3A), by binding to an LXXLL peptide (ELTLQELLGEE) displayed by E6AP, thereby stimulating E6AP ubiquitin ligase activity. Beta, Gamma, and Delta genera E6 proteins bind a similar LXXLL peptide (WMSDLDDLLGS) on the cellular transcriptional co-activator MAML1 and thereby repress Notch signaling. We expressed 45 different animal and human E6 proteins from diverse papillomavirus genera to ascertain the overall preference of E6 proteins for E6AP or MAML1. E6 proteins from all HPV genera except Alpha preferentially interacted with MAML1 over E6AP. Among animal papillomaviruses, E6 proteins from certain ungulate (SsPV1 from pigs) and cetacean (porpoises and dolphins) hosts functionally resembled Alpha genus HPV by binding and targeting the degradation of E6AP. Beta genus HPV E6 proteins functionally clustered with Delta, Pi, Tau, Gamma, Chi, Mu, Lambda, Iota, Dyokappa, Rho, and Dyolambda E6 proteins to bind and repress MAML1. None of the tested E6 proteins physically and functionally interacted with both MAML1 and E6AP, indicating an evolutionary split. Further, interaction of an E6 protein was insufficient to activate degradation of E6AP, indicating that E6 proteins that target E6AP co-evolved to separately acquire both binding and triggering of ubiquitin ligase activation. E6 proteins with similar biological function clustered together in phylogenetic trees and shared structural features. This suggests that the divergence of E6 proteins from either MAML1 or E6AP binding preference is a major event in papillomavirus evolution. PMID- 29281736 TI - Characterizing first and third person viewpoints and their alternation for embodied interaction in virtual reality. AB - Empirical research on the bodily self has shown that the body representation is malleable, and prone to manipulation when conflicting sensory stimuli are presented. Using Virtual Reality (VR) we assessed the effects of manipulating multisensory feedback (full body control and visuo-tactile congruence) and visual perspective (first and third person perspective) on the sense of embodying a virtual body that was exposed to a virtual threat. We also investigated how subjects behave when the possibility of alternating between first and third person perspective at will was presented. Our results support that illusory ownership of a virtual body can be achieved in both first and third person perspectives under congruent visuo-motor-tactile condition. However, subjective body ownership and reaction to threat were generally stronger for first person perspective and alternating condition than for third person perspective. This suggests that the possibility of alternating perspective is compatible with a strong sense of embodiment, which is meaningful for the design of new embodied VR experiences. PMID- 29281737 TI - Correction: A study of the structural properties of sites modified by the O linked 6-N-acetylglucosamine transferase. AB - [This corrects the article DOI: 10.1371/journal.pone.0184405.]. PMID- 29281738 TI - Correction: Correlation of serum cartilage oligometric matrix protein (COMP) and interleukin-16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population. AB - [This corrects the article DOI: 10.1371/journal.pone.0184802.]. PMID- 29281740 TI - Correction: Trabecular bone in the calcaneus of runners. AB - [This corrects the article DOI: 10.1371/journal.pone.0188200.]. PMID- 29281739 TI - Lower temperatures reduce type I interferon activity and promote alphaviral arthritis. AB - Chikungunya virus (CHIKV) belongs to a group of mosquito-borne alphaviruses associated with acute and chronic arthropathy, with peripheral and limb joints most commonly affected. Using a mouse model of CHIKV infection and arthritic disease, we show that CHIKV replication and the ensuing foot arthropathy were dramatically reduced when mice were housed at 30 degrees C, rather than the conventional 22 degrees C. The effect was not associated with a detectable fever, but was dependent on type I interferon responses. Bioinformatics analyses of RNA Seq data after injection of poly(I:C)/jetPEI suggested the unfolded protein response and certain type I interferon responses are promoted when feet are slightly warmer. The ambient temperature thus appears able profoundly to effect anti-viral activity in the periphery, with clear consequences for alphaviral replication and the ensuing arthropathy. These observations may provide an explanation for why alphaviral arthropathies are largely restricted to joints of the limbs and the extremities. PMID- 29281742 TI - RNA elongation by respiratory syncytial virus polymerase is calibrated by conserved region V. AB - The large polymerase subunit (L) of non-segmented negative strand RNA viruses transcribes viral mRNAs and replicates the viral genome. Studies with VSV have shown that conserved region V (CRV) of the L protein is part of the capping domain. However, CRV folds over and protrudes into the polymerization domain, suggesting that it might also have a role in RNA synthesis. In this study, the role of respiratory syncytial virus (RSV) CRV was evaluated using single amino acid substitutions and a small molecule inhibitor called BI-D. Effects were analyzed using cell-based minigenome and in vitro biochemical assays. Several amino acid substitutions inhibited production of capped, full-length mRNA and instead resulted in accumulation of short transcripts of approximately 40 nucleotides in length, confirming that RSV CRV has a role in capping. In addition, all six variants tested were either partially or completely defective in RNA replication. This was due to an inability of the polymerase to efficiently elongate the RNA within the promoter region. BI-D also inhibited transcription and replication. In this case, polymerase elongation activity within the promoter region was enhanced, such that the small RNA transcribed from the promoter was not released and instead was elongated past the first gene start signal. This was accompanied by a decrease in mRNA initiation at the first gene start signal and accumulation of aberrant RNAs of varying length. Thus, in addition to its function in mRNA capping, conserved region V modulates the elongation properties of the polymerase to enable productive transcription and replication to occur. PMID- 29281741 TI - Host triacylglycerols shape the lipidome of intracellular trypanosomes and modulate their growth. AB - Intracellular infection and multi-organ colonization by the protozoan parasite, Trypanosoma cruzi, underlie the complex etiology of human Chagas disease. While T. cruzi can establish cytosolic residence in a broad range of mammalian cell types, the molecular mechanisms governing this process remain poorly understood. Despite the anticipated capacity for fatty acid synthesis in this parasite, recent observations suggest that intracellular T. cruzi amastigotes may rely on host fatty acid metabolism to support infection. To investigate this prediction, it was necessary to establish baseline lipidome information for the mammalian infective stages of T. cruzi and their mammalian host cells. An unbiased, quantitative mass spectrometric analysis of lipid fractions was performed with the identification of 1079 lipids within 30 classes. From these profiles we deduced that T. cruzi amastigotes maintain an overall lipid identity that is distinguishable from mammalian host cells. A deeper analysis of the fatty acid moiety distributions within each lipid subclass facilitated the high confidence assignment of host- and parasite-like lipid signatures. This analysis unexpectedly revealed a strong host lipid signature in the parasite lipidome, most notably within its glycerolipid fraction. The near complete overlap of fatty acid moiety distributions observed for host and parasite triacylglycerols suggested that T. cruzi amastigotes acquired a significant portion of their lipidome from host triacylglycerol pools. Metabolic tracer studies confirmed long chain fatty acid scavenging by intracellular T. cruzi amastigotes, a capacity that was significantly diminished in host cells deficient for de novo triacylglycerol synthesis via the diacylglycerol acyltransferases (DGAT1/2). Reduced T. cruzi amastigote proliferation in DGAT1/2-deficient fibroblasts further underscored the importance of parasite coupling to host triacylglycerol pools during the intracellular infection cycle. Thus, our comprehensive lipidomic dataset provides a substantially enhanced view of T. cruzi infection biology highlighting the interplay between host and parasite lipid metabolism with potential bearing on future therapeutic intervention strategies. PMID- 29281745 TI - Detecting Potential Underreporting of Suicide Ideation Among U.S. Military Personnel. AB - Using a military sample comprised largely of National Guard personnel, zero inflation negative binomial regression was applied to estimate the effects of indirect, nonface valid indicators of suicide ideation [Thwarted Belongingness (TB), Perceived Burdensomeness (PB), and Hopelessness], in predicting suicide ideation. Data from a sample of 497 military personnel (82.1% male; mage = 27.24; range = 18-59) were analyzed. TB and the interaction of TB with Hopelessness were significant predictors in the logistic regression, and in the negative binomial regression, the main effects of TB and hopelessness, and the interactions of TB with hopelessness and PB with hopelessness were significant. The findings further indicated that approximately 10% of those not reporting ideation would be predicted to be ideators. Clinically, these results indicate that, in samples reluctant to report ideation, the assessment of suicide risk may improve through the use of relevant measures that do not explicitly reference suicide thoughts. PMID- 29281744 TI - Antidiabetic cataract effects of GbE, rutin and quercetin are mediated by the inhibition of oxidative stress and polyol pathway. AB - One of the earliest critical secondary complications of diabetes is the opacification of the eye lens - a condition strictly associated with diabetic cataract. The study presented here was designed to investigate the effect of Ginkgo biloba extract (GbE), rutin and quercetin on streptozotocin (STZ) induced diabetic cataract (DC) rats. Ten weeks after administration of GbE, rutin and quercetin, the opacity of diabetic rats' lenses was graded under a slit lamp. Then, the levels of malondialdehyde (MDA), reduced glutathione (GSH), advanced glycosylation end products (AGEs), and the activities of aldose reductase (AR) were estimated. The DC-induced rats produced less GSH, higher levels of MDA and AGEs as well as elevated AR activity when compared to the normal group. Administration of GbE, rutin and quercetin remarkably inhibited the AR activity, stimulated the production of glutathione, and decreased the levels of MDA and AGEs in the lenses of DC-induced rats, which eventually delayed the progression of lens opacification in diabetic rats to various degrees. Our results revealed that quercetin had the highest significant (P<0.05) potential to delay the progression of STZ-induced diabetic cataract when compared with rutin and GbE. The mechanism dictating this interesting prowess of quercetin might be attributed to its AR inhibitory strength, anti-lipid peroxidation potential and anti-AGEs activity. PMID- 29281746 TI - Stored root carbohydrates can maintain root respiration for extended periods. AB - Tight coupling between below-ground autotrophic respiration and the availability of recently assimilated carbon (C) has become a paradigm in the ecophysiological literature. Here, we show that stored carbohydrates can decouple respiration from assimilation for prolonged periods by mobilizing reserves from transport roots to absorptive roots. We permanently disrupted the below-ground transfer of recently assimilated C using stem girdling and root trenching and measured soil CO2 efflux for over 1 yr in longleaf pine (Pinus palustris), a species that has large reserves of stored carbohydrates in roots. Soil CO2 efflux was not influenced by girdling or trenching through the 14-month observation period. Stored carbohydrate concentrations in absorptive roots were not affected by the disrupted supply of current photosynthate for over 1 yr; however, carbohydrate concentrations in transport roots decreased. Our results indicate that root respiration can be decoupled from recent canopy assimilation and that stored carbohydrates can be mobilized from transport roots to absorptive roots to maintain respiration for over 1 yr. This refines the current paradigm that canopy assimilation and below-ground respiration are tightly coupled and provides evidence of the mechanism and dynamics responsible for decoupling the above- and below-ground processes. PMID- 29281743 TI - HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes. AB - Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6 /- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro inflammatory cytokines and nitrite production after bacterial infection. Hdac6-/- BMDCs have a weakened phosphorylation of MAPK signalling in response to Lm infection, suggesting altered Toll-like receptor signalling (TLR). Compared with Hdac6+/+ counterparts, Hdac6-/- GM-CSF-derived and FLT3L-derived dendritic cells show weaker pro-inflammatory cytokine secretion in response to various TLR agonists. Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-kappaB induction after TLR stimuli. Hdac6-/- mice display low serum levels of inflammatory cytokine IL-6 and correspondingly an increased survival to a systemic infection with Lm. The impaired bacterial clearance in the absence of HDAC6 appears to be caused by a defect in autophagy. Hence, Hdac6-/- BMDCs accumulate higher levels of the autophagy marker p62 and show defective phagosome-lysosome fusion. These data underline the important function of HDAC6 in dendritic cells not only in bacterial autophagy, but also in the proper activation of TLR signalling. These results thus demonstrate an important regulatory role for HDAC6 in the innate immune response to intracellular bacterial infection. PMID- 29281747 TI - UNDERSTANDING THE CONNECTION BETWEEN ATTACHMENT TRAUMA AND MATERNAL SELF-EFFICACY IN DEPRESSED MOTHERS. AB - Maternal self-efficacy predicts sensitive and responsive caregiving. Low maternal self-efficacy is associated with a higher incidence of postpartum depression. Maternal self-efficacy and postpartum depression can both be buffered by social support. Maternal self-efficacy and postpartum depression have both been linked independently, albeit in separate studies, to the experience of violent trauma, childhood maltreatment, and spousal abuse. This study proposed a model in which postpartum depression mediates the relation between attachment trauma and maternal self-efficacy, with emotional support as a moderator. Participants were 278 first-time mothers of infants under 14 months. Cross-sectional data were collected online. Mothers completed questionnaires on attachment trauma, maternal self-efficacy, postpartum depression, and emotional support. A moderated mediation model was tested in a structural equation modeling framework using Mplus' estimate of indirect effects. Postpartum depression fully mediated the relation between trauma and maternal self-efficacy. Emotional support moderated only the pathway between postpartum depression and maternal self-efficacy. Attachment trauma's implications for maternal self-efficacy should be understood in the context of overall mental health. Mothers at the greatest risk for low maternal self-efficacy related to attachment trauma also are those suffering from postpartum depression. Emotional support buffered mothers from postpartum depression, though, which has implications for intervention and future research. PMID- 29281748 TI - Extreme prematurity, treated retinopathy, bronchopulmonary dysplasia and cerebral palsy are significant risk factors for ophthalmological abnormalities at 6.5 years of age. AB - AIM: This study evaluated the contributions of various prenatal and postnatal predictive factors to a documented high prevalence of ophthalmological abnormalities in children aged 6.5 years who were born extremely preterm. METHODS: We carried out a prospective population-based study of all children born in Sweden at a gestational age of 22 + 0 to 26 + 6 weeks based on the Extremely Preterm Infants in Sweden Study. The main outcome measures were a combined score of visual impairment, refractive errors and strabismus at 6.5 years of age. Models of univariate and multivariable regression were used to analyse potential prenatal and postnatal predictive factors at different clinically relevant time points from one minute after birth to 30 months. RESULTS: We focused on 399 known extremely preterm survivors and compared them to 300 full-term controls. Significant antecedents for ophthalmological abnormalities included prematurity per se, retinopathy of prematurity that required treatment, severe bronchopulmonary dysplasia and cerebral palsy. Severe intraventricular haemorrhage was no longer a significant risk factor when we adjusted it for the 30-month cognitive and neuromotor development outcomes. CONCLUSION: This time course risk analysis model showed a changing panorama of significant risk factors for ophthalmological abnormalities in children aged 6.5 years who were born extremely preterm. PMID- 29281749 TI - THERAPISTS' EXPERIENCES OF MOTHER-INFANT PSYCHOANALYTIC TREATMENT: A QUALITATIVE STUDY. AB - As part of a larger research project in Sweden, a qualitative study investigated psychotherapists' experiences of mother-infant psychoanalysis (MIP). A randomized controlled trial compared two groups of mother-infant dyads with psychological problems. One had received Child Health Center care, and the other received MIP. Previous articles on long-term effects have found that mothers who had received MIP were less depressed throughout a posttreatment period of 31/2 years, and their children showed better global functioning and psychological well-being. The present study's objectives were to describe the therapist's experiences of MIP and deepen the understanding of the MIP process. Six months after treatment began, all therapists were interviewed. Transcribed interviews with therapists from 10 (of 33 total) MIP treatments were randomly selected and analyzed in detail by thematic analysis. Therapists worked successfully with mother and infant together and found different ways of cooperation during MIP sessions. Therapists reported overall positive experiences; however, in cases where mothers needed more personal attention, it would be important to adapt the method to them. PMID- 29281750 TI - Urine dipstick tests can aid decision-making when treating infants with unexplained fever, but more research is needed. PMID- 29281751 TI - The NB-LRR gene Pm60 confers powdery mildew resistance in wheat. AB - Powdery mildew is one of the most devastating diseases of wheat. To date, few powdery mildew resistance genes have been cloned from wheat due to the size and complexity of the wheat genome. Triticum urartu is the progenitor of the A genome of wheat and is an important source for powdery mildew resistance genes. Using molecular markers designed from scaffolds of the sequenced T. urartu accession and standard map-based cloning, a powdery mildew resistance locus was mapped to a 356-kb region, which contains two nucleotide-binding and leucine-rich repeat domain (NB-LRR) protein-encoding genes. Virus-induced gene silencing, single-cell transient expression, and stable transformation assays demonstrated that one of these two genes, designated Pm60, confers resistance to powdery mildew. Overexpression of full-length Pm60 and two allelic variants in Nicotiana benthamiana leaves induced hypersensitive cell death response, but expression of the coiled-coil domain alone was insufficient to induce hypersensitive response. Yeast two-hybrid, bimolecular fluorescence complementation and luciferase complementation imaging assays showed that Pm60 protein interacts with its neighboring NB-containing protein, suggesting that they might be functionally related. The identification and cloning of this novel wheat powdery mildew resistance gene will facilitate breeding for disease resistance in wheat. PMID- 29281752 TI - Associations among arbuscular mycorrhizal fungi and seedlings are predicted to change with tree successional status. AB - Arbuscular mycorrhizal (AM) fungi in the soil may influence tropical tree dynamics and forest succession. The mechanisms are poorly understood, because the functional characteristics and abundances of tree species and AM fungi are likely to be codependent. We used generalized joint attribute modeling to evaluate if AM fungi are associated with three forest community metrics for a sub-tropical montane forest in Puerto Rico. The metrics chosen to reflect changes during forest succession are the abundance of seedlings of different successional status, the amount of foliar damage on seedlings of different successional status, and community-weighted mean functional trait values (adult specific leaf area [SLA], adult wood density, and seed mass). We used high-throughput DNA sequencing to identify fungal operational taxonomic units (OTUs) in the soil. Model predictions showed that seedlings of mid- and late-successional species had less leaf damage when the 12 most common AM fungi were abundant compared to when these fungi were absent. We also found that seedlings of mid-successional species were predicted to be more abundant when the 12 most common AM fungi were abundant compared to when these fungi were absent. In contrast, early-successional tree seedlings were predicted to be less abundant when the 12 most common AM fungi were abundant compared to when these fungi were absent. Finally, we showed that, among the 12 most common AM fungi, different AM fungi were correlated with functional trait characteristics of early- or late-successional species. Together, these results suggest that early-successional species might not rely as much as mid- and late-successional species on AM fungi, and AM fungi might accelerate forest succession. PMID- 29281753 TI - The interaction of drought and habitat explain space-time patterns of establishment in saguaro (Carnegiea gigantea). AB - The long-lived columnar saguaro cactus (Carnegiea gigantea) is among the most studied plants in the world. Long-term studies have shown saguaro establishment to be generally episodic and strongly influenced by precipitation and temperature. Water limitation through lower-than-average seasonal rainfall and elevated temperatures increasing evaporative loss can reduce survivorship of recent germinates. Thus, multi-year, extended drought could cause populations to decline as older saguaros die without replacement. Previous studies have related establishment to temporal variation in rainfall, but most studies have been on non-randomized plots in ideal habitat and thus might not have captured the full variability within the local area. We studied how saguaro establishment varied in space and which habitat features may buffer responses to drought on 36 4-ha plots located randomly across an elevation gradient, including substantial replication in landscape position (bajada, foothills, and slopes) in the two disjunct districts of Saguaro National Park in southern Arizona, USA. Recent, severe drought coincided with drastic declines in saguaro establishment across this ~25,000-ha area. Establishment patterns derived from the park-wide data set was strongly correlated with drought, but the Park's two districts and diversity of plots demonstrated substantially different population outcomes. Saguaro establishment was best explained by the interaction of drought and habitat type; establishment in bajada and foothill plots dropped to near-zero under the most severe periods of water limitation but remained higher in slope plots during the same time span. Combined with saguaro density estimates, these data suggest that the most suitable habitat type for saguaro establishment shifted to higher elevations during the time span of the recent drought. These results place into context the extent to which historical patterns of demography provide insight into future population dynamics in a changing climate and reveal the importance of understanding dynamics across the distribution of possible local habitat types with response to variation in weather. PMID- 29281754 TI - Peri-implant squamous cell carcinoma. AB - Peri-implant squamous cell carcinoma is an uncommon pathological manifestation, whereas peri-implantitis is commonly found in association with dental implants. Both present similarly with loss of supporting soft and hard tissue around dental implants; therefore, a careful differential diagnosis is required. The present case concerns a 62-year-old Japanese man who had a dental implant which had been in the left maxillary incisor region for 4 years who apparently developed peri implantitis. This did not respond to localized therapy and antibiotics so was referred for specialist surgical management. A biopsy confirmed it to be a squamous cell carcinoma rather than an inflammatory lesion. A literature review shows that this is an unusual presentation without a previous history of malignancy, mucosal disease or risk factors for cancers. Although rare, the possibility of peri-implant squamous cell carcinoma should be borne in mind by all practitioners who monitor implant patients. PMID- 29281755 TI - Predator-prey interactions cause apparent competition between marine zooplankton groups. AB - Predator-mediated apparent competition is an indirect negative interaction between two prey species mediated by a shared predator. Quantifying such indirect ecosystem effects is methodologically challenging but important for understanding ecosystem functioning. Still, there are few examples of apparent competition from pelagic marine environments. Using state-space statistical modeling, we here provide evidence for apparent competition between two dominant zooplankton groups in a large marine ecosystem, i.e., krill and copepods in the Barents Sea. This effect is mediated by a positive association between krill biomass and survival of the main planktivorous fish in the Barents Sea, capelin Mallotus villosus, and a negative association between capelin and copepod biomasses. The biomass of Atlantic krill species is expected to increase in the Barents Sea due to ongoing climate change, thereby potentially negatively affecting copepods through apparent competition. By demonstrating and quantifying apparent competition in a large marine ecosystem, our study paves the way for more realistic projections of indirect ecosystem effects of climate change and harvesting. PMID- 29281756 TI - The pulmonary vein meets the left atrium: The where and why of pulmonary vein isolation. PMID- 29281757 TI - Short-term outcomes and risk factors for pancreatic fistula after pancreatic enucleation: A single-center experience of 142 patients. AB - BACKGROUND: Enucleation is increasingly used for benign or low-grade pancreatic neoplasms. Enucleation preserves the pancreatic parenchyma as well as decreases the risk of long-term endocrine and exocrine dysfunction, but may be associated with a higher rate of postoperative pancreatic fistula (POPF). The aim of this study was to assess short-term outcomes, in particular, POPF. METHODS: Data were collected retrospectively from all 142 patients who underwent pancreatic enucleation between 2009 and 2014 in our institution were analyzed. RESULTS: Lesions were most frequently located in the head and uncinate process of the pancreas (60.6%), and the most common types were neuroendocrine neoplasms (52.1%). Overall morbidity was 66%, mainly due to POPF (53.5%), and severe morbidity was only 8.4%, including one death (0.7%). Clinical POPF (Grade B or C) occurred in 22 patients (15.5%). Independent risk factors for clinical POPF were age >=60 years, an episode of acute pancreatitis, and cystic morphology. Tumor size, coverage, histological differentiation, and prolonged operative time were not associated with the risk of POPF. CONCLUSIONS: Enucleation is a safe and feasible procedure for benign or low-grade pancreatic neoplasms. The rate of clinical POPF is acceptable, and clinical POPF occurs more frequently in elderly patients (>=60 years of age), patients with cystic neoplasms, or patients with an episode of acute pancreatitis. PMID- 29281758 TI - Impacts of domestication on the arbuscular mycorrhizal symbiosis of 27 crop species. AB - The arbuscular mycorrhizal (AM) symbiosis is key to plant nutrition, and hence is potentially key in sustainable agriculture. Fertilization and other agricultural practices reduce soil AM fungi and root colonization. Such conditions might promote the evolution of low mycorrhizal responsive crops. Therefore, we ask if and how evolution under domestication has altered AM symbioses of crops. We measured the effect of domestication on mycorrhizal responsiveness across 27 crop species and their wild progenitors. Additionally, in a subset of 14 crops, we tested if domestication effects differed under contrasting phosphorus (P) availabilities. The response of AM symbiosis to domestication varied with P availability. On average, wild progenitors benefited from the AM symbiosis irrespective of P availability, while domesticated crops only profited under P limited conditions. Magnitudes and directions of response were diverse among the 27 crops, and were unrelated to phylogenetic affinities or to the coordinated evolution with fine root traits. Our results indicate disruptions in the efficiency of the AM symbiosis linked to domestication. Under high fertilization, domestication could have altered the regulation of resource trafficking between AM fungi and associated plant hosts. Provided that crops are commonly raised under high fertilization, this result has important implications for sustainable agriculture. PMID- 29281759 TI - Assessment of Fracture Risk: Population Association Versus Individual Prediction. PMID- 29281760 TI - Long-Term Complications in Patients With Hypoparathyroidism Evaluated by Biochemical Findings: A Case-Control Study. AB - Hypoparathyroidism (HypoPT) is associated with an increased risk of various complications, but only few data are available on risk factors. Using a case control design, we assessed associations between biochemical findings and risk of different complications within a subpopulation of our previously identified Danish patients. We retrieved all biochemical data available on 431 (81% women) patients from the Central Region of Denmark, covering approximately 20% of the Danish population. Average age of patients was 41 years at time of diagnosis. Most patients (88%) had HypoPT due to surgery, mainly due to atoxic goiter and more than 95% were on treatment with calcium supplements and activated vitamin D. On average, time-weighted (tw) plasma levels of ionized calcium (Ca2+tw ) was 1.17 mmol/L (interquartile range [IQR], 1.14 to 1.21 mmol/L) and the calcium phosphate (CaxPtw ) product was 2.80 mmol2 /L2 (IQR, 2.51 to 3.03 mmol2 /L2 ). High phosphatetw levels were associated with increased mortality and risk of any infections, including infections in the upper airways. A high CaxPtw product was associated with an increased mortality and risk of renal disease. Compared to levels around the lower part of the reference interval, lower Ca2+tw levels were associated with an increased risk of cardiovascular diseases. Mortality and risk of infections, cardiovascular diseases, and renal diseases increased with number of episodes of hypercalcemia and with increased disease duration. Treatment with a relatively high dose of active vitamin D was associated with a decreased mortality and risk of renal diseases and infections. In conclusion, risk of complications in HypoPT is closely associated with disturbances in calcium phosphate homeostasis. (c) 2018 American Society for Bone and Mineral Research. PMID- 29281761 TI - Outcomes of kidney transplantations in children weighing 15 kilograms or less: a retrospective cohort study. AB - Kidney transplantation (KT) is often delayed in small children because of fear of postoperative complications. We report early- and long-term outcomes in children transplanted at <=15 kg in the two largest Belgian pediatric transplant centers. Outcomes before (period 1) and since the introduction of basiliximab and mycophenolate-mofetil in 2000 (period 2) were compared. Seventy-two KTs were realized between 1978 and 2016: 38 in period 1 and 34 in period 2. Organs came from deceased donors in 48 (67%) cases. Surgical complications occurred in 25 KTs (35%) with no significant difference between the two periods. At least one acute rejection (AR) occurred in 24 (33%) KTs with significantly less patients experiencing AR during period 2: 53% and 12% in period 1 and, period 2 respectively (P < 0.001). Graft survival free of AR improved significantly in period 2 compared with period 1: 97% vs. 50% at 1 year; 87% vs. 50% at 10 years post-KT (P = 0.003). Graft survival tended to increase over time (period 1: 74% and 63% at 1 and 5 years; period 2: 94% and 86% at 1 and 5 years; P = 0.07), as well as patient survival. Kidney transplantation in children <=15 kg remains a challenging procedure with 35% of surgical complications. However, outcomes improved and are nowadays excellent in terms of prevention of AR, patient and graft survival. PMID- 29281762 TI - Body mass index and mortality in patients with and without diabetes mellitus. AB - OBJECTIVE: Investigate the association between body mass index (BMI), length of stay (LOS), and mortality in hospitalized patients with and without diabetes mellitus (DM). METHODS: Historical prospectively collected data of adult patients hospitalized between 2011 and 2013. Body mass index was calculated according to measurement or self-report on admission and classified as follows: underweight (<18.5), normal weight (18.5-24.9), overweight (25-29.9), obese (30-34.9), and severely obese (>=35). The main outcomes were LOS, in-hospital, and end-of-follow up mortality. RESULTS: Cohort included 24 233 patients (53% male; mean age +/- SD, 65 +/- 18), including 7397 patients with DM (31%). Among patients with normal BMI, LOS was shorter compared with underweight patients, but it was longer compared with overweight and obese patients. Following multivariate adjustment, this difference remained significant only for patients with DM. There was a significant interaction between DM status and BMI group, in the models for in hospital and end-of-follow-up mortality. Compared with normal BMI, in-hospital mortality risk was increased by 80% and 100% for the underweight with and without DM, respectively. For patients with and without DM, in-hospital mortality risk was 30% to 40% lower among overweight and obese patients, and there was no difference between severely obese and normal weight patients. At the end-of follow-up, mortality risk was 1.6-fold and 1.7-fold higher among underweight patients with and without DM, respectively. For overweight, obese, and severely obese patients, mortality risk was decreased by 30% to 40% in those with DM and by 20% to 30% in those without DM. CONCLUSIONS: In hospitalized patients with and without DM, there was an inverse association between BMI and mortality. PMID- 29281763 TI - Addition of H2 Across a Cobalt-Phosphorus Bond. AB - Addition of H2 across the cobalt-phosphorus bond of (PPP)CoPMe3 (3) is demonstrated, where PPP is a monoanionic diphosphine pincer ligand with a central N-heterocyclic phosphido (NHP- ) donor. The chlorophosphine CoII complex (PPCl P)CoCl2 (2) can be generated through coordination of the chlorophosphine ligand (PPCl P, 1) to CoCl2 . Subsequent reduction of 2 with KC8 in the presence of PMe3 generates (PPP)CoPMe3 (3), in which both the phosphorus and cobalt centers have been reduced. The addition of 1 atm of H2 to complex 3 cleanly affords (PPH P)Co(H)PMe3 (4), in which H2 has ultimately been added across the metal phosphorus bond. Complex 4 was characterized spectroscopically and using computational methods to predict its geometry. PMID- 29281764 TI - Interferon regulatory factor 1 is essential for pathogenic CD8+ T cell migration and retention in the brain during experimental cerebral malaria. AB - Host immune response has a key role in controlling the progression of malaria infection. In the well-established murine model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA infection, proinflammatory Th1 and CD8+ T cell response are essential for disease development. Interferon regulatory factor 1 (IRF1) is a transcription factor that promotes Th1 responses, and its absence was previously shown to protect from ECM death. Yet the exact mechanism of protection remains unknown. Here we demonstrated that IRF1-deficient mice (IRF1 knockout) were protected from ECM death despite displaying early neurological signs. Resistance to ECM death was a result of reduced parasite sequestration and pathogenic CD8+ T cells in the brain. Further analysis revealed that IRF1 deficiency suppress interferon-gamma production and delayed CD8+ T cell proliferation. CXCR3 expression was found to be decreased in pathogenic CD8+ T cells, which limited their migration to the brain. In addition, reduced expression of adhesion molecules by brain endothelial cells hampered leucocyte retention in the brain. Taken together, these factors limited sequestration of pathogenic CD8+ T cells and consequently its ability to induce extensive damage to the blood-brain barrier. PMID- 29281765 TI - Psychosocial health of cochlear implant users compared to that of adults with and without hearing aids: Results of a nationwide cohort study. AB - OBJECTIVES: This study aimed to examine the psychosocial health status of adult cochlear implant (CI) users, compared to that of hearing aid (HA) users, hearing impaired adults without hearing aids and normally hearing adults. DESIGN: Cross sectional observational study, using both self-reported survey data and a speech in-noise test. SETTING: Data as collected within the Netherlands Longitudinal Study on Hearing (NL-SH) between September 2011 and June 2016 were used. PARTICIPANTS: Data from 1254 Dutch adults (aged 23-74), selected in a convenience sample design, were included for analyses. MEAN OUTCOME MEASURES: Psychosocial health measures included emotional and social loneliness, anxiety, depression, distress and somatisation. Psychosocial health, hearing status, use of hearing technology and covariates were measured by self-report; hearing ability was assessed through an online digit triplet speech-in-noise test. RESULTS: After adjusting for the degree of hearing impairment, HA users (N = 418) and hearing impaired adults (N = 247) had significantly worse scores on emotional loneliness than CI users (N = 37). HA users had significantly higher anxiety scores than CI users in some analyses. Non-significant differences were found between normally hearing (N = 552) and CI users for all psychosocial outcomes. CONCLUSIONS: Psychosocial health of CI users is not worse than that of hearing-impaired adults with or without hearing aids. CI users' level of emotional loneliness is even lower than that of their hearing-impaired peers using hearing aids. A possible explanation is that CI patients receive more professional and family support, and guidance along their patient journey than adults who are fitted with hearing aids. PMID- 29281766 TI - Temperature-driven selection on metabolic traits increases the strength of an algal-grazer interaction in naturally warmed streams. AB - Trophic interactions are important determinants of the structure and functioning of ecosystems. Because the metabolism and consumption rates of ectotherms increase sharply with temperature, there are major concerns that global warming will increase the strength of trophic interactions, destabilizing food webs, and altering ecosystem structure and function. We used geothermally warmed streams that span an 11 degrees C temperature gradient to investigate the interplay between temperature-driven selection on traits related to metabolism and resource acquisition, and the interaction strength between the keystone gastropod grazer, Radix balthica, and a common algal resource. Populations from a warm stream (~28 degrees C) had higher maximal metabolic rates and optimal temperatures than their counterparts from a cold stream (~17 degrees C). We found that metabolic rates of the population originating from the warmer stream were higher across all measurement temperatures. A reciprocal transplant experiment demonstrated that the interaction strengths between the grazer and its algal resource were highest for both populations when transplanted into the warm stream. In line with the thermal dependence of respiration, interaction strengths involving grazers from the warm stream were always higher than those with grazers from the cold stream. These results imply that increases in metabolism and resource consumption mediated by the direct, thermodynamic effects of higher temperatures on physiological rates are not mitigated by metabolic compensation in the long term, and suggest that warming could increase the strength of algal-grazer interactions with likely knock-on effects for the biodiversity and productivity of aquatic ecosystems. PMID- 29281767 TI - One-Step Synthesis of Nb2 O5 /C/Nb2 C (MXene) Composites and Their Use as Photocatalysts for Hydrogen Evolution. AB - Hydrogen production through facile photocatalytic water splitting is regarded as a promising strategy to solve global energy problems. Transition-metal carbides (MXenes) have recently drawn attention as potential co-catalyst candidates for photocatalysts. Here, we report niobium pentoxide/carbon/niobium carbide (MXene) hybrid materials (Nb2 O5 /C/Nb2 C) as photocatalysts for hydrogen evolution from water splitting. The Nb2 O5 /C/Nb2 C composites were synthesized by one-step CO2 oxidation of Nb2 CTx . Nb2 O5 grew homogeneously on Nb2 C after mild oxidation, during which some amorphous carbon was also formed. With an optimized oxidation time of 1.0 h, Nb2 O5 /C/Nb2 C showed the highest hydrogen generation rate (7.81 MUmol h-1 gcat-1 ), a value that was four times higher than that of pure Nb2 O5 . The enhanced performance of Nb2 O5 /C/Nb2 C was attributed to intimate contact between Nb2 O5 and conductive Nb2 C and the separation of photogenerated charge carriers at the Nb2 O5 /Nb2 C interface; the results presented herein show that transition-metal carbide are promising co-catalysts for photocatalytic hydrogen production. PMID- 29281768 TI - Genome characterization of piscine 'Scale drop and Muscle Necrosis syndrome' associated strain of Vibrio harveyi focusing on bacterial virulence determinants. AB - AIMS: Genomic characterization of Harveyi clade vibrio strain Y6 causing 'Scale drop and Muscle Necrosis syndrome' (SDMN) isolated from barramundi (Lates calcarifer) in Vietnam. METHODS AND RESULTS: A bacterial genome was sequenced using Illumina MiSeq platform. Multilocus sequence analysis confirmed that the bacterium belongs to Vibrio harveyi species. Further phylogenetic analysis inferred from core genome SNPs revealed a close relationship between our bacterium and the V. harveyi isolated from groupers in Taiwan and China. blastp results indicated that V. harveyi piscine strains carried numerous adhesin, secretion system, siderophore and toxin-related genes. Genome comparison between Y6 and 32 strains of V. harveyi from different origins showed that at least 17 potential virulence genes were present exclusively in the strain Y6. Many of these (six of 17 genes) were homologous to pyoverdine siderophore, a secreted high-affinity iron chelator, clusters originally found in Pseudomonas aeruginosa. Genome of V. harveyi Y6 was incorporated by a bacteriophage VHY6phi and replication protein of the phage was most similar to CTXphi described previously in Vibrio cholerae and Vibrio fischeri. However, the cholera toxin-encoding genes, namely ctxA and ctxB, were absent from VHY6phi, while the CTXphi enterotoxin gene (zonula occludens toxin; zot) remained intact. CONCLUSIONS: Several putative virulence genes and a phage carrying toxin gene were identified in the genomes of SDMN-associated V. harveyi Y6. SIGNIFICANCE AND IMPACT OF THE STUDY: This study confers genomic information of the piscine pathogenic V. harveyi which recently caused widespread mortality. Such information is of importance to gain insight into bacterial molecular pathogenesis. PMID- 29281770 TI - Here We Go Again - AMA Seeks to Restrict Nursing Practice. PMID- 29281771 TI - Detecting and Managing Our Stress. PMID- 29281772 TI - A Peer-to-Peer Mentoring Program for In-Center Hemodialysis: A Patient-Centered Quality Improvement Program. AB - A patient-centered quality improvement program implemented in one Virginia hemodialysis facility sought to determine if peer-to-peer (P2P) programs can assist patients on in-center hemodialysis with self-management and improve outcomes. Using a single-arm, repeatedmeasurement, quasi-experimental design, 46 patients participated in a four-month P2P intervention. Outcomes include knowledge, self-management behaviors, and psychosocial health indicators: self efficacy, perceived social support, hemodialysis social support, and healthrelated quality of life (HRQoL). Physiological health indicators included missed and shortened treatments, arteriovenous fistula placement, interdialytic weight gain, serum phosphorus, and hospitalizations. Mentees demonstrated increased knowledge, self-efficacy, perceived social support, hemodialysis social support, and HRQoL. Missed treatments decreased. Mentors experienced increases in knowledge, self-management, and social support. A P2P mentoring program for in center hemodialysis can benefit both mentees and mentors. PMID- 29281773 TI - Fluid and Electrolyte Management Across the Age Continuum. AB - Optional function of body systems depends upon fluid and electrolyte balance; however, across the lifespan, disorders of fluid and electrolytes offset this, and the causative factors are varied. Nurses play a major role in the management of fluid and electrolyte balance. This article focuses on the role total body water content, plasma proteins, kidney function, and drug metabolism have on the age-related physiology impacting fluid and electrolyte balance, and on nursing implications. PMID- 29281774 TI - Concept Clarification: Uncertainty in Individuals with Chronic Kidney Disease. AB - Uncertainty is often presented in the literature as a barrier to chronic kidney disease (CKD) management and end stage renal disease (ESRD) planning by individuals, but the definition of uncertainty has not been clarified for individuals with CKD. After reviewing the literature, a conceptual definition for uncertainty in individuals with CKD was developed. To further clarify this concept, exemplars of individuals with CKD who do and do not exhibit uncertainty are offered. This concept clarification may offer nephrology nurses additional insight into assessing and caring for individuals with CKD. PMID- 29281775 TI - Experiences of Patients with Chronic Kidney Disease and Their Family Members in an Advanced Practice Nurse-Led Counseling Service. AB - Chronic kidney disease (CKD) is a major health problem worldwide, but not enough is known about effective self-management interventions. In this qualitative study, we explore how outpatients with CKD Stages 1-5 (without renal replacement therapy) and their family members experienced an individually tailored CKD counseling service led by an advanced practice nurse (APN). Using thematic analysis, 10 pair interviews (N = 20) were conducted and analyzed stepwise. Findings revealed iterative processes along the course of the disease. Participants struggled with an incomprehensible diagnosis. An APN assisted them in their efforts to master CKD. The APN offered information, insights, and understanding. This support helped the families achieve a new outlook and filled some gaps in CKD care. Future development of the service should focus on slowing down CKD progression more effectively. Healthcare providers are encouraged to acknowledge the importance of ongoing guidance and the continuity of care in treating patients with CKD. PMID- 29281776 TI - Predictors of Fatigue among Female Patients on Hemodialysis. AB - The purposes of this study were to identify the level of fatigue and to examine the predictors of fatigue in female patients on hemodialysis. The subjects for this study were 130 female patients at one hemodialysis unit in northern Taiwan. On univariate analyses, patients with higher levels of fatigue were more likely to be older, and have less education, lower serum albumin levels, sleep disturbances, and perceived higher level of hemodialysis stressors. The findings of this study can help nephrology nurses recognize fatigue as an important nursing issue for female patients on hemodialysis. It is necessary to provide support, information, and alternative solutions for improving their fatigue. PMID- 29281777 TI - Focusing on the Fundamentals: Comparing and Contrasting Nursing Research and Quality Improvement. PMID- 29281778 TI - Telehealth for Home Dialysis Therapies. PMID- 29281779 TI - Inhibition of Autolysis by Lipase LipA in Streptococcus pneumoniae Sepsis. AB - More than 50% of sepsis cases are associated with pneumonia. Sepsis is caused by infiltration of bacteria into the blood via inflammation, which is triggered by the release of cell wall components following lysis. However, the regulatory mechanism of lysis during infection is not well defined. Mice were infected with Streptococcus pneumoniae D39 wild-type (WT) and lipase mutant (DeltalipA) intranasally (pneumonia model) or intraperitoneally (sepsis model), and survival rate and pneumococcal colonization were determined. LipA and autolysin (LytA) levels were determined by qPCR and western blotting. S. pneumoniae Spd_1447 in the D39 (type 2) strain was identified as a lipase (LipA). In the sepsis model, but not in the pneumonia model, mice infected with the DeltalipA displayed higher mortality rates than did the D39 WT-infected mice. Treatment of pneumococci with serum induced LipA expression at both the mRNA and protein levels. In the presence of serum, the DeltalipA displayed faster lysis rates and higher LytA expression than the WT, both in vitro and in vivo. These results indicate that a pneumococcal lipase (LipA) represses autolysis via inhibition of LytA in a sepsis model. PMID- 29281780 TI - Hepatocellular Carcinoma Arising in a Huge Hepatocellular Adenoma with Bone Marrow Metaplasia. AB - Hepatocellular adenoma (HCA) is the most common type of benign liver tumor, and its major complication is malignant transformation to hepatocellular carcinoma (HCC). Here, we report a case of HCC arising in HCA with bone marrow metaplasia in a 24-year-old Korean woman who presented with abdominal discomfort. A huge liver mass was found on abdominal ultrasonography. She underwent surgical hepatic resection, and the resected specimen was entirely involved by a 20-cm-sized tumor. Histological review revealed a well differentiated HCC arising from inflammatory HCA with beta-catenin nuclear positivity and bone marrow metaplasia that contained hematopoietic cells. This case was unique because malignant transformation, inflammatory type HCA, beta-catenin nuclear staining, and bone marrow metaplasia were simultaneously observed. Additionally, it should be noted that a large HCA with beta-catenin activation can undergo malignant transformation and should be surgically resected in a timely manner. PMID- 29281781 TI - Erdheim-Chester Disease Involving Lymph Nodes and Liver Clinically Mimicking Lymphoma: A Case Report. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis and multisystem disease. First described in 1930, there are no more than 750 cases reported. The etiology remains unknown, but a majority of cases of ECD and Langerhans cell histiocytosis were found to have clonal mutations involving genes of the mitogen-activated protein kinase pathway. We recently encountered a 53 year-old male patient with extensive ECD involving the systemic lymph nodes, pleura, liver, and long bones clinically mimicking malignant lymphoma. Biopsies were performed at multiple sites, including a pleural mass, an external iliac lymph node, bone marrow, and the liver. Based on histopathological and immunohistochemical findings of positivity for CD68 and negativity for CD1a and S 100, the patient was diagnosed with ECD. Interferon-alpha was administered as the first-line treatment, but the patient rapidly progressed to hepatic failure after 2 months of treatment. We report this rare case of ECD clinically mimicking malignant lymphoma and diagnosed by careful pathological review. PMID- 29281782 TI - Duodenal Adenocarcinoma of Brunner Gland Origin: A Case Report. AB - We report a case of adenocarcinoma originating from the duodenal Brunner glands in a 47-year-old female patient. The lesion was 0.8 cm in extent and located at the posterior wall of the first part of the duodenum. Histologically, the tumor showed transition from non-neoplastic Brunner glands through dysplastic epithelium into adenocarcinoma. The carcinoma cells were strongly positive for MUC6 protein, which is an epithelial marker for the Brunner glands. Tumor protein p53 was overexpressed in the carcinoma cells, but not in the non-neoplastic or dysplastic epithelium. Dystrophic calcification was predominant. This is the first case report of duodenal adenocarcinoma of Brunner gland origin in Korea. PMID- 29281783 TI - Long-Term Climatic and Anthropogenic Impacts on Streamwater Salinity in New York State: INCA Simulations Offer Cautious Optimism. AB - The long-term application of road salts has led to a rise in surface water chloride (Cl-) concentrations. While models have been used to assess the potential future impacts of continued deicing practices, prior approaches have not incorporated changes in climate that are projected to impact hydrogeology in the 21st century. We use an INtegrated CAtchment (INCA) model to simulate Cl- concentrations in the Tioughnioga River watershed. The model was run over a baseline period (1961-1990) and climate simulations from a range of GCMs run over three 30-year intervals (2010-2039; 2040-2069; 2070-2099). Model projections suggest that Cl- concentrations in the two river branches will continue to rise for several decades, before beginning to decline around 2040-2069, with all GCM scenarios indicating reductions in snowfall and associated salt applications over the 21st century. The delay in stream response is most likely attributed to climate change and continued contribution of Cl- from aquifers. By 2100, surface water Cl- concentrations will decrease to below 1960s values. Catchments dominated by urban lands will experience a decrease in average surface water Cl-, although moderate compared to more rural catchments. PMID- 29281784 TI - Determining Linear Free Energy Relationships in Peptide Fragmentation Using Derivatization and Targeted Mass Spectrometry. AB - The sequence complexity of a proteome is utilized with rational chemical derivatization to establish the linear free energy relationship (LFER) in order to investigate the collision-induced dissociation (CID) of peptides. The derivatization produces groups of peptides that have varying designer residues of aliphatic amino acids at the N-terminus but stay invariable for the rest of sequences, which are naturally occurring and uncontrolled. Collisional fragmentation of the derivatized peptides is advantageously monitored by liquid chromatography multiple-reaction-monitoring mass spectrometry. Systematically tuning the gas-phase basicity of the N-termini of peptides establishes LFERs that report the structural similarities and differences in CID of all the backbone amides of doubly protonated tryptic peptides. For the cleavage of an internal or C-terminal amide, the peptide N-terminus mainly affects the mobility of the N terminal proton instead of directly participating in the amide cleavage. In contrast, the terminal residue plays more pronounced roles in the cleavage of the first and second amide bonds. LFERs for the competition between the symmetric and asymmetric cleavage of the second amide bond support the protonated oxazolone structure for N-terminal fragments. This competition is affected locally by the chemistry of the first three residues and remotely by charge repulsion between the two protonation sites. PMID- 29281785 TI - Characterization of the Spectral Accuracy of an Orbitrap Mass Analyzer Using Isotope Ratio Mass Spectrometry. AB - Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) source coupled to the Q Exactive Plus has been extensively used in untargeted mass spectrometry imaging (MSI) analyses of biological tissue sections. Although the Orbitrap is a high-resolution and accurate-mass (HRAM) mass analyzer, these attributes alone cannot be used for the reliable identification of unknown analytes observed in complex biological matrices. Spectral accuracy (SA) is the ability of the mass spectrometer to accurately measure the isotopic distributions which, when used with high mass measurement accuracy (MMA), can facilitate the elucidation of a single elemental composition. To investigate the effects of different ion populations on an Orbitrap's SA and MMA, a solution of caffeine, the tetrapeptide MRFA, and ultramark was analyzed using a Q Exactive Plus across eight distinct automatic gain control (AGC) targets. The same compounds from the same lot numbers were also individually analyzed using isotope ratio mass spectrometry (IRMS) to accurately determine the isotopic abundance of 13C, 15N, and 34S. We demonstrated that at optimum absolute ion abundances the Orbitrap can be used to accurately count carbons, nitrogens, and sulfurs in samples with varying masses. Additionally, absolute monoisotopic ion abundances required for high SA were empirically determined by using the expected (IRMS) and experimental (Orbitrap) isotopic distributions to calculate the Pearson chi-square test. These thresholds for absolute ion abundances can be used in untargeted MSI studies to shorten an identification list by rapidly screening for isotopic distributions whose absolute ion abundances are high enough to accurately estimate the number of atoms. PMID- 29281786 TI - Detection of Volatile Organic Compounds in a Drop of Urine by Ultrasonic Nebulization Extraction Proton Transfer Reaction Mass Spectrometry. AB - Detection of volatile organic compounds (VOCs) in human urine has potential application value in screening for disease and toxin exposure. However, the current technologies are too slow to detect the concentration of VOCs in fresh urine. In this study, we developed a novel ultrasonic nebulization extraction proton transfer reaction mass spectrometry (UNE-PTR-MS) technology. The urinary VOCs can be rapidly extracted to gaseous VOCs using the UNE system and then delivered using a carrier gas to the PTR-MS instrument for rapid detection. The carrier gas flow and sample size were optimized to 100 mL/min and 100 MUL, respectively. The limits of detection (LODs) and response time of the UNE-PTR-MS were evaluated by detecting three VOCs that are common in human urine: methanol, acetaldehyde, and acetone. The LODs determined for methanol (4.47 MUg/L), acetaldehyde (1.98 MUg/L), and acetone (3.47 MUg/L) are 2-3 orders of magnitude lower than the mean concentrations of that in healthy human urine. The response time of the UNE-PTR-MS is 34 s and only 0.66 mL of urine is required for a full scan. The repeatability of this UNE-PTR-MS was evaluated, and the relative standard deviations of 5 independent determinations were between 4.62% and 5.21%. Lastly, the UNE-PTR-MS was applied for detection of methanol, acetaldehyde, and acetone in real human urine to test matrix effects, yielding relative recoveries of between 88.39% and 94.54%. These results indicate the UNE-PTR-MS can be used for the rapid detection of VOCs in a drop of urine and has practical potential for diagnosing disease or toxin exposure. PMID- 29281787 TI - Promoting Multivalent Antibody-Antigen Interactions by Tethering Antibody Molecules on a PEGylated Dendrimer-Supported Lipid Bilayer. AB - To efficiently isolate maximal quantity of circulating tumor cells (CTCs) and circulating tumor cell microembolis (CTMs) from patient blood by antibody coated microfluidics, a multifunctional, pegylated polyamidoamine-dendrimers conjugated supported lipid bilayer surface construct was proposed to enhance accessibility of antibody molecules to the antigen molecules on target CTCs. The combination of a hydrated, stretchable dendrimer and a laterally mobile supported lipid bilayer (SLB) provide attached antibody molecules with 2.5-dimensional chain movement, achieving multivalency between the surface antibody and cell antigen molecules. An over 170% enhancement is distinctive for Panc-1 cells that expresses low antigen level. Of seven pancreatic ductal adenocarcinoma patients, an average 440 single CTCs and 90 CTMs were collected in 2 mL of peripheral blood, which were 1.6 times and 2.3 times more, than those captured by the SLB-only microfluidics. In summary, we have demonstrated a material design to enhance multivalent antibody-antigen interaction, which is useful for rare cell enrichment and cancer detection. PMID- 29281788 TI - Synthesis and Characterization of Nitric Oxide-Releasing Platinum(IV) Prodrug and Polymeric Micelle Triggered by Light. AB - Herein, we report the proof of concept of photoresponsive chemotherapeutics comprising nitric oxide-releasing platinum prodrugs and polymeric micelles. Photoactivatable nitric oxide-releasing donors were integrated into the axial positions of a platinum(IV) prodrug, and the photolabile hydrophobic groups were grafted in the block copolymers. The hydrophobic interaction between nitric oxide donors and the photolabile groups allowed for the loading of platinum drugs and nitric oxide-releasing donors in the photolabile polymeric micelles. After cellular uptake of micelles, light irradiation induced the release of nitric oxide, which sensitized the cancer cells. Simultaneously, photolabile hydrophobic groups were cleaved from micelles, and the nitric oxide-releasing donor was altered to be more hydrophilic, resulting in the rapid release of platinum(IV) prodrugs. The strategy of using platinum(IV) prodrugs and nitric oxide led to enhanced anticancer effects. PMID- 29281789 TI - Designing Laplace Pressure Pattern for Microdroplet Manipulation. AB - Manipulation of arrayed tiny droplets is important in liquid dispersion, liquid transportation, bioassays, nucleation, integrated electronics, and various lab experiments that require delivering precise and minute volumes of droplets. Liquid dispensed from a small orifice or split from surface patterns are typical methods, but the acquired droplet diameters are similar to that of the nozzle and pattern. Here we demonstrate that tiny droplets with dimensions much smaller than the pattern can be arrayed advantageously through designing a Laplace pressure pattern based on conical morphology and wetting heterogeneity. The pattern could selectively resist liquid's motion and drive the capillary bridge breaking of macrodrop into arrayed tiny droplets at wettability boundaries. Arrayed picoliter droplets can be acquired on a submillimeter-scaled pattern with a feature size of several hundred micrometers. Through regulating the conical morphologies and the wetting heterogeneity, the volume and number of tiny droplets can be accurately controlled. As a paradigm, adopting droplets of nanoparticle dispersion, various arrayed functional assemblies can be fabricated. This integration of conical morphology and wetting heterogeneity offers a powerful kit for patterned microdroplets quantitative and locational manipulation and opens a new avenue to achieve functional units in a facile and high-throughput way. PMID- 29281790 TI - Disintegrable NIR Light Triggered Gold Nanorods Supported Liposomal Nanohybrids for Cancer Theranostics. AB - In this work, facile synthesis and application of targeted, dual therapeutic gold nanorods-liposome (GNR-Lipos) nanohybrid for imaging guided photothermal therapy and chemotherapy is investigated. The dual therapeutic GNR-Lipos nanohybrid consists of GNR supported, and doxorubicin (DOX) loaded liposome. GNRs not only serve as a photothermal agent and increase the drug release in intracellular environment of cancer cells, but also provide mechanical strength to liposomes by being decorated both inside and outside of bilayer surfaces. The designed nanohybrid shows a remarkable response for synergistic chemophotothermal therapy compared to only chemotherapy or photothermal therapy. The NIR response, efficient uptake by the cells, disintegration of GNR-Lipos nanohybrid, and synergistic therapeutic effect of photothermal and chemotherapy over breast cancer cells MDA-MB-231 are studied for the better development of a biocompatible nanomaterial based multifunctional cancer theranostic agent. PMID- 29281791 TI - Interfacial Forces Dictate the Pathway of Phospholipid Vesicle Adsorption onto Silicon Dioxide Surfaces. AB - The pathway of vesicle adsorption onto a solid support depends on the material composition of the underlying support, and there is significant interest in developing material-independent strategies to modulate the spectrum of vesicle substrate interactions on a particular surface. Herein, using the quartz crystal microbalance-dissipation (QCM-D) technique, we systematically investigated how solution pH and membrane surface charge affect vesicle adsorption onto a silicon dioxide surface. While vesicle adsorption and spontaneous rupture to form complete supported lipid bilayer (SLBs) occurred in acidic conditions, it was discovered that a wide range of adsorption pathways occurred in alkaline conditions, including (i) vesicle adsorption and spontaneous rupture to form complete SLBs, (ii) vesicle adsorption and spontaneous rupture to form incomplete SLBs, (iii) irreversible adsorption of intact vesicles, (iv) reversible adsorption of intact vesicles, and (v) negligible adsorption. In general, SLB formation became more favorable with increasingly positive membrane surface charge although there were certain conditions at which attractive electrostatic forces were insufficient to promote vesicle rupture. To rationalize these findings, we discuss how solution pH and membrane surface charge affect interfacial forces involved in vesicle-substrate interactions. Taken together, our findings present a comprehensive picture of how interfacial forces dictate the pathway of phospholipid vesicle adsorption onto silicon dioxide surfaces and offer a broadly applicable framework to characterize the interactions between phospholipid vesicles and inorganic material surfaces. PMID- 29281792 TI - Structural Identification and Kinetic Analysis of the in Vitro Products Formed by Reaction of Bisphenol A-3,4-quinone with N-Acetylcysteine and Glutathione. AB - Bisphenol A (BPA) has received considerable attention as an endocrine disrupting chemical and a possible substrate for genotoxic metabolites. BPA metabolism leads to formation of electrophilic o-quinones cable of binding to DNA and other endogenous nucleophiles. We have structurally identified the products resulting from the reaction of bisphenol A-3,4-quinone (BPAQ) with N-acetylcysteine (NAC) and glutathione (GSH). The major and minor isomers are both the result of 1,6 conjugate addition and are produced almost instantly in high yield. Reactions using 1.3 equiv of GSH showed the presence of a bis-glutathionyl adduct which was not observed using higher GSH concentration relative to BPAQ. NAC reactions with BPAQ showed no bis-N-acetylcysteinyl adducts. Stopped-flow kinetic analysis reveals the 1,6-conjugate additions to be reversible with a forward free energy of activation of 9.2 and 7.8 kcal/mol for the NAC and GSH reactions, respectively. The bimolecular forward rate constant at 19.4 degrees C was approximately three time faster for GSH compared to NAC, 1547 vs 496 M-1 s-1. The free energy of activation for the reverse reactions were similar, 11.7 and 11.2 kcal/mol for NAC and GSH, respectively. We plan to use this model system to further explore the mechanism of adduct formation between sulfur nucleophiles and o-quinones and the resulting chemical properties of both NAC and GSH adducts. PMID- 29281793 TI - Aspects of the Belousov-Zhabotinsky Reaction inside a Self-Oscillating Polymer Brush. AB - We have developed a novel polymer brush surface exhibiting autonomous swelling deswelling changes driven by the Belousov-Zhabotinsky (BZ) reaction, that is, the self-oscillating polymer brush. In this system, the ruthenium tris(2,2' bipyridine) [Ru(bpy)3] catalyst-conjugated polymer chains are densely packed on the solid substrate. It is expected that the BZ reaction in the polymer brush would be influenced by the immobilization effect of the catalyst. To clarify the effect of the immobilization of the catalyst on the self-oscillating polymer brush, the self-oscillating behavior of the polymer brush was investigated by comparing it with that of other self-oscillating polymer materials, the free polymer, and the gel particle under various initial substrate concentrations. The initial substrate dependency of the oscillating period for the polymer brush was found to be different from those for the free polymer and the gel particle. Furthermore, the oscillatory waveform was analyzed on the basis of the Field Koros-Noyes model. These investigations revealed that the dense immobilization of the self-oscillating polymer on the surface restricted accessibility for the Ru(bpy)3 moiety. These findings would be helpful in understanding the reaction diffusion mechanism in the polymer brush, which is a novel reaction medium for the BZ reaction. PMID- 29281794 TI - Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations. AB - Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM. Using recombinant NQO1, we showed that low nM concentrations of NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine quinone like metabolites in vitro. Hepatic NQO2 concentrations ranged from 2 to 31 MUM. NQO2 catalyzed the reduction of quinone-like metabolites derived from acetaminophen, clozapine, 4'-hydroxydiclofenac, mefenamic acid, amodiaquine, and carbamazepine. The reduction of the clozapine nitrenium ion supports association studies showing that NQO2 is a genetic risk factor for clozapine-induced agranulocytosis. The 5-hydroxydiclofenac quinone imine, which was previously shown to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified as a potent NQO2 inhibitor and was applied to further confirm the catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites remains to be established by identification of the physiologically relevant co-substrates, our results suggest an additional protective role of the NQO2 protein by non-enzymatic scavenging of quinone-like metabolites. Hepatic NQO1 activity in detoxication of quinone-like metabolites becomes especially important when other detoxication pathways are exhausted and NQO1 levels are induced. PMID- 29281795 TI - Viscocapillary Response of Gas Bubbles Probed by Thermal Noise Atomic Force Measurement. AB - We present thermal noise measurements of a vibrating sphere close to microsized air bubbles in water with an atomic force microscope. The sphere was glued at the end of a cantilever with a resonance frequency of few kHz. The subangstrom thermal motion of the microsphere reveals an elastohydrodynamic coupling between the sphere and the air bubble. The results are in perfect agreement with a model incorporating macroscopic capillarity and fluid flow on the bubble surface with full slip boundary conditions. PMID- 29281796 TI - Morphologic Properties of Cartilage Lesions in the Knee Arthroscopically Prepared by the Standard Curette Technique Are Inferior to Lesions Prepared by Specialized Chondrectomy Instruments. AB - BACKGROUND: Cartilage lesion preparation is an important component to cartilage repair procedures, given the effect of prepared lesion morphology on the formation of durable and well-integrated repair tissue. PURPOSE: To compare the quality of arthroscopic cartilage lesion debridement performed by (1) the standard curette (SC) technique and (2) specialized chondrectomy (CM) instruments, to provide technical guidance for optimization of cartilage lesion preparation in the setting of arthroscopic cartilage repair. STUDY DESIGN: Controlled laboratory study. METHODS: Articular cartilage lesions of standardized size (8 * 15 mm) were demarcated within the trochlea and femoral condyles of 20 human cadaver knee specimens. Orthopaedic surgeons performed arthroscopic lesion preparation using 2 techniques that consisted of SC preparation and preparation by CM instruments. A histologic comparative analysis was performed within each treatment group and between treatment groups to evaluate the morphology of prepared cartilage defects. RESULTS: The mean angle deviation from perpendicular of the cartilage wall at the front of the prepared cartilage lesions was significantly greater in the SC group versus the CM group (29.8 degrees +/- 21.4 degrees vs 7.7 degrees +/- 7.6 degrees , P < .001). In lesions prepared via the SC technique, the cartilage walls at the front of the prepared lesions were significantly less perpendicular than the cartilage walls at the rear of the lesions (29.8 degrees +/- 21.4 degrees vs 11.0 degrees +/- 10.3 degrees , P < .001), whereas lesions prepared by the CM technique demonstrated comparable verticality of surrounding cartilage walls at the front and rear aspects of the lesions (7.7 degrees +/- 7.6 degrees vs 9.4 degrees +/- 12.3 degrees , P = .827). Depth of lesion debridement was accomplished to the target level by the CM technique in 86% of prepared lesions, compared with 34% of lesions in the SC group. The prepared cartilage wall profile was characterized as the most ideal morphology in 55% of prepared lesions in the CM group, as opposed to 10% in the SC group. CONCLUSION: Arthroscopic cartilage lesion preparation with SC instruments results in superior perpendicularity of surrounding cartilage walls to subchondral bone and greater consistency of debrided lesion depth, as compared with the standard debridement technique with curettes. CLINICAL RELEVANCE: Arthroscopic preparation using standard curette technique leads to suboptimal morphologic characteristics of prepared lesions that likely affect the quality of repair tissue, compared to preparation using specialized chondrectomy instruments. PMID- 29281797 TI - Biomechanical Comparison of 3 Glenoid-Side Fixation Techniques for Superior Capsular Reconstruction. AB - BACKGROUND: Superior capsular reconstruction (SCR) was recently introduced as a treatment for irreparable superior rotator cuff tears in younger patients. Purpose/Hypothesis: The purpose was to assess the biomechanical strength of 3 methods for fixation of the graft to the glenoid for SCR. It was hypothesized that a 4-anchor technique would provide greater load to failure than 3-anchor techniques. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-six cadaveric specimens were randomized into 3 groups of previously established glenoid-side graft fixation techniques: (1) three 3.5-mm knotless screw-in anchors, (2) three 3.0-mm knotless push-in anchors, and (3) a 4-anchor hybrid construct with two 3.0-mm knotted push-in anchors and two 2.9-mm knotless push-in anchors. The repairs were cyclically loaded at 0.5 Hz from 10 to 200 N, then pulled to failure. Elongation, stiffness, maximum load at failure, and mode of failure were recorded and calculated. RESULTS: There were no significant differences in graft elongation or stiffness among the 3 techniques ( P > .37 and P > .26, respectively). Maximum load to failure was significantly greater in technique 1 (mean +/- SD, 427.85 +/- 119.70 N) than technique 3 (319.5 +/- 57.60 N) ( P = 0.024). There were no significant differences in load to failure between techniques 1 and 2 or between techniques 2 and 3. CONCLUSION: Glenoid-side graft fixation with 3 threaded 3.5-mm suture anchors showed a significant superior pull out strength when compared with a 4-anchor hybrid technique and thus might be recommended in SCR for patients with irreparable superior rotator cuff tears to achieve maximum stability. CLINICAL RELEVANCE: SCR presents a novel alternative for treatment of irreparable superior rotator cuff tears in younger patients. Glenoid fixation is essential to provide adequate fixation of the graft to prevent the humeral head from rising and to restore normal biomechanics. PMID- 29281798 TI - How Does the Presence of Unstable Chondral Lesions Affect Patient Outcomes After Partial Meniscectomy? The ChAMP Randomized Controlled Trial. AB - BACKGROUND: Chondral lesions are commonly encountered during arthroscopic partial meniscectomy (APM); however, it is unknown how these lesions affect postoperative outcomes. PURPOSE: The authors compared postoperative outcomes among patients with and without unstable chondral lesions 1 year after APM. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The authors conducted a secondary analysis of data from the ChAMP (Chondral Lesions and Meniscus Procedures) randomized controlled trial. They compared the following outcomes for patients with unstable chondral lesions that were left in situ and observed (CL-noDeb) versus patients without unstable chondral lesions (NoCL) at 1 year after APM: Western Ontario and McMaster Universities Osteoarthritis Index, Knee injury and Osteoarthritis Outcome Score, visual analog scale for pain, the Short Form Health Survey, range of motion, quadriceps circumference, and effusion. Multivariate linear regression was used to obtain mean differences (MDs) with corresponding 95% CIs adjusted for age, body mass index, and preoperative score (for postoperative scores). RESULTS: Compared with the CL-noDeb group, the NoCL group had greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index for pain (MD, 7.9, 95% CI: 2.7-13.1), stiffness (MD, 9.1, 95% CI: 1.9-16.3), and physical function (MD, 4.6, 95% CI: 0.1-9.0) and Knee injury and Osteoarthritis Outcome Score for pain (MD, 8.4, 95% CI: 2.7-14.0), function in sport and recreation (MD, 11, 95% CI: 3.0-19.1), and quality of life (MD, 10.4, 95% CI: 2.3-18.5). The NoCL group was less likely than the CL-noDeb group to have an effusion ( P = .02) 1 year after surgery. CONCLUSION: Patients undergoing APM without unstable chondral lesions had better outcomes than patients with unstable chondral lesions. PMID- 29281799 TI - Age Influences Biomechanical Changes After Participation in an Anterior Cruciate Ligament Injury Prevention Program. AB - BACKGROUND: The prevalence of anterior cruciate ligament (ACL) injuries increases during maturation and peaks during late adolescence. Previous studies suggested an age-related association between participation in injury prevention programs and reduction of ACL injury. However, few studies have investigated differences in biomechanical changes after injury prevention programs between preadolescent and adolescent athletes. Purpose/Hypothesis: The purpose was to investigate the influence of age on the effects of the FIFA Medical and Research Centre (F-MARC) 11+ injury prevention warm-up program on differences in biomechanical risk factors for ACL injury between preadolescent and adolescent female soccer players. It was hypothesized that the ACL injury risk factors of knee valgus angle and moment would be greater at baseline but would improve more after training for preadolescent athletes than adolescent athletes. It was further hypothesized that flexor-extensor muscle co-contraction would increase after training for both preadolescent and adolescent athletes. STUDY DESIGN: Controlled laboratory study. METHODS: Institutional Review Board-approved written consent was obtained for 51 preadolescent female athletes aged 10 to 12 years (intervention: n = 28, 11.8 +/- 0.8 years; control: n = 23, 11.2 +/- 0.6 years) and 43 adolescent female athletes aged 14 to 18 years (intervention: n = 22, 15.9 +/- 0.9 years; control: n = 21, 15.7 +/- 1.1 years). The intervention groups participated in 15 in-season sessions of the F-MARC 11+ program 2 times per week. Pre- and postseason motion capture data were collected during 4 tasks: preplanned cutting, unanticipated cutting, double-legged jump, and single-legged jump. Lower extremity joint angles and moments were estimated through biomechanical modeling. Knee flexor-extensor muscle co-contraction was estimated from surface electromyography. RESULTS: At baseline, preadolescent athletes displayed greater initial contact and peak knee valgus angles during all activities when compared with the adolescent athletes, but knee valgus moment was not significantly different between age groups. After intervention training, preadolescent athletes improved and decreased their initial contact knee valgus angle (-1.24 degrees +/ 0.36 degrees ; P = .036) as well as their peak knee valgus moment (-0.57 +/- 0.27 percentage body weight * height; P = .033) during the double-legged jump task, as compared with adolescent athletes in the intervention. Compared with adolescent athletes, preadolescent athletes displayed higher weight acceptance flexor-extensor muscle co-contraction at baseline during all activities ( P < .05). After intervention training, preadolescent athletes displayed an increase in precontact flexor-extensor muscle co-contraction during preplanned cutting as compared with adolescent intervention athletes (0.07 +/- 0.02 vs -0.30 +/- 0.27, respectively; P = .002). CONCLUSION: The F-MARC 11+ program may be more effective at improving some risk factors for ACL injury among preadolescent female athletes than adolescent athletes, notably by reducing knee valgus angle and moment during a double-legged jump landing. CLINICAL RELEVANCE: ACL prevention programs may be more effective if administered early in an athlete's career, as younger athletes may be more likely to adapt new biomechanical movement patterns. PMID- 29281800 TI - (Where) Is Functional Decline Isolating? Disordered Environments and the Onset of Disability. AB - The onset of disability is believed to undermine social connectedness and raise the risk of social isolation, yet spatial environments are seldom considered in this process. This study examines whether unruly home and neighborhood conditions intensify the association between disability onset and several dimensions of social connectedness. I incorporate longitudinal data from the National Social Life, Health, and Aging Project, which contains environmental evaluations conducted by trained observers ( N = 1,558). Results from Poisson, ordinal logistic, and linear regression models reveal heterogeneous consequences of disablement: disability onset was associated with reduced core network size, fewer friends, lower likelihood of social interaction, and less overall social connectedness-though mainly when accompanied by higher levels of household disorder. There was limited evidence that neighborhood disorder moderated consequences of disability. Findings point to the importance of the home as an environmental resource and underscore important contextual contingencies in the isolating consequences of disability. PMID- 29281801 TI - President Trump's Mental Health - Is It Morally Permissible for Psychiatrists to Comment? PMID- 29281802 TI - Errata. PMID- 29281803 TI - Errata. PMID- 29281805 TI - Errata. PMID- 29281804 TI - Errata. PMID- 29281806 TI - Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue. AB - : The objective of this study was to develop an injectable and biocompatible hydrogel that can deliver a cocktail of therapeutic biomolecules (secretome) secreted by human adipose-derived stem cells (hASCs) to the peri-infarct myocardium. Gelatin and Laponite(r) were combined to formulate a shear-thinning, nanocomposite hydrogel (nSi Gel) as an injectable carrier of secretome (nSi Gel+). The growth factor composition and the pro-angiogenic activity of the secretome were tested in vitro by evaluating the proliferation, migration and tube formation of human umbilical endothelial cells. The therapeutic efficacy of the nSi Gel + system was then investigated in vivo in rats by intramyocardial injection into the peri-infarct region. Subsequently, the inflammatory response, angiogenesis, scar formation, and heart function were assessed. Biocompatibility of the developed nSi Gel was confirmed by quantitative PCR and immunohistochemical tests which showed no significant differences in the level of inflammatory genes, microRNAs, and cell marker expression compared to the untreated control group. In addition, the only group that showed a significant increase in capillary density, reduction in scar area and improved cardiac function was treated with the nSi Gel+. Our in vitro and in vivo findings demonstrate the potential of this new secretome-loaded hydrogel as an alternative strategy to treat myocardial infarction. STATEMENT OF SIGNIFICANCE: Stem cell based-therapies represent a possible solution to repair damaged myocardial tissue by promoting cardioprotection, angiogenesis, and reduced fibrosis. However, recent evidence indicates that most of the positive outcomes are likely due to the release of paracrine factors (cytokines, growth factors, and exosomes) from the cells and not because of the local engraftment of stem cells. This cocktail of essential growth factors and paracrine signals is known as secretome can be isolated in vitro, and the biomolecule composition can be controlled by varying stem-cell culture conditions. Here, we propose a straightforward strategy to deliver secretome produced from hASCs by using a nanocomposite injectable hydrogel made of gelatin and Laponite(r). The designed secretome-loaded hydrogel represents a promising alternative to traditional stem cell therapy for the treatment of acute myocardial infarction. PMID- 29281807 TI - Spore forming bacteria infections and people who inject drugs: Implications for harm reduction. AB - BACKGROUND: There is no research on public health interventions that alert people who inject drugs (PWID) to clusters/outbreaks of severe bacterial infections. In Scotland, during the botulism cluster/outbreak of Dec 2014-July 2015 harm reduction (HR) messages detailed on a postcard (Botulism Postcard) were distributed to PWID between Feb-April 2015. We examined the impact of the Botulism Postcard on cluster/outbreak awareness, healthcare seeking and HR behaviours among PWID; and their views on such clusters/outbreaks. METHODS: The Botulism Postcard questionnaire survey was undertaken with 288 PWID recruited in Greater Glasgow and Clyde between May-August 2015. Multivariate logistic regression was undertaken. Between Oct 2015-January 2016 22 in-depth interviews were conducted with PWID in Glasgow and Edinburgh, these underwent thematic analysis. RESULTS: 38% (108/284) had never seen the postcard, 14% (40/284) had only seen it, 34% (98/284) read but not discussed it and 13% (38/284) had discussed it with service staff. Cluster/outbreak awareness was higher among those who had read (adjusted odds ratio (aOR) = 5.374, CI 2.394-11.349, p < 0.001) or discussed the postcard (aOR = 25.114, CI 3.188-190.550, p < 0.001); and symptom awareness was higher among those who had read (aOR = 2.664, CI 1.322 4.890, p < 0.001) or discussed the postcard (aOR = 6.707, CI 2.744 16.252, p < 0.001) than among those who had never seen it. The odds of introducing HR was higher among those who had discussed the postcard (AOR = 3.304 CI 1.425 7.660, p < 0.01) than those who had only read it. PWID learnt about clusters/outbreaks from several sources and despite concerns they continued to inject during such events. CONCLUSION: More widespread exposure to the Botulism Postcard during the outbreak/cluster was needed. The Botulism Postcard distributed to PWID may raise awareness of such events, the symptoms, and may encourage HR particularly when used as a tool by frontline staff to initiate discussion. Acknowledging that people continue to inject during clusters/outbreaks of such infections necessitates a pragmatic HR approach. PMID- 29281809 TI - Wastewater characterisation by combining size fractionation, chemical composition and biodegradability. AB - The potential for resource recovery from wastewater can be evaluated based on a detailed characterisation of wastewater. In this paper, results from fractionation and characterisation of two distinct wastewaters are reported. Using tangential flow filtration, the wastewater was fractionated into 10 size fractions ranging from 1 kDa to 1 mm, wherein the chemical composition and biodegradability were determined. Carbohydrates were dominant in particulate size fractions larger than 100 MUm, indicating a potential of cellulose recovery from these fractions. While the particulate size fractions between 0.65 and 100 MUm show a potential as a source for biofuel production due to an abundance of saturated C16 and C18 lipids. Both wastewaters were dominated by particulate (>0.65 MUm), and oligo- and monomeric (<1 kDa) COD. Polymeric (1-1000 kDa) and colloidal (1000 kDa-0.65 MUm) fractions had a low COD content, expected due to degradation in the sewer system upstream of the wastewater treatment plant. Biodegradation rates of particulate fractions increase with decreasing size. However, this was not seen in polymeric fractions where degradation rate was governed by chemical composition. Analytical validation of molecular weight and particle size distribution showed below filter cut-off retention of particles and polymers close to nominal cut-off, shifting the actual size distribution. PMID- 29281808 TI - Evaluation of the novel crAssphage marker for sewage pollution tracking in storm drain outfalls in Tampa, Florida. AB - CrAssphage are recently-discovered DNA bacteriophages that are prevalent and abundant in human feces and sewage. We assessed the performance characteristics of a crAssphage quantitative PCR (qPCR) assay for quantifying sewage impacts in stormwater and surface water in subtropical Tampa, Florida. The mean concentrations of crAssphage in untreated sewage ranged from 9.08 to 9.98 log10 gene copies/L. Specificity was 0.927 against 83 non-human fecal reference samples and the sensitivity was 1.0. Cross-reactivity was observed in DNA extracted from soiled poultry litter but the concentrations were substantially lower than untreated sewage. The presence of the crAssphage marker was monitored in water samples from storm drain outfalls during dry and wet weather conditions in Tampa, Florida. In dry weather conditions, 41.6% of storm drain outfalls samples were positive for the crAssphage marker and the concentrations ranged from 3.60 to 4.65 log10 gene copies/L of water. After a significant rain event, 66.6% of stormwater outlet samples were positive for the crAssphage marker and the concentration ranged from 3.62 to 4.91 log10 gene copies/L of water. The presence of the most commonly used Bacteroides HF183 marker in storm drain outfalls was also tested along with the crAssphage. Thirteen samples (55%) were either positive (i.e., both markers were present) or negative (i.e., both markers were absent) for both the markers. Due to the observed cross-reactivity of this marker with DNA extracted from poultry litter samples, it is recommended that this marker should be used in conjunction with additional markers such as HF183. Our data indicate that the crAssphage marker is highly sensitive to sewage, is adequately specific, and will be a valuable addition to the MST toolbox. PMID- 29281810 TI - Insights into Feast-Famine polyhydroxyalkanoate (PHA)-producer selection: Microbial community succession, relationships with system function and underlying driving forces. AB - The Feast-Famine (FF) process has been frequently used to select polyhydroxyalkanoate (PHA)-accumulating mixed cultures (MCs), but there has been little insight into the ecophysiology of the microbial community during the selection process. In three FF systems with well-defined conditions, synchronized variations in higher-order properties of MCs and complicate microbial community succession mainly including enrichment and elimination of non-top competitors and unexpected turnover of top competitors, were observed. Quantification of PHA accumulating function genes (phaC) revealed that the top competitors maintained the PHA synthesis by playing consecutive roles when the highly dynamic turnover occurred. Due to its specific physiological characteristics during the PHA accumulating process, Thauera strain OTU 7 was found to be responsible for the fluctuating SVI, which threatened the robustness of the FF system. This trait was also responsible for its later competitive exclusion by the other PHA-producer, Paracoccus strain OTU 1. Deterministic processes dominated the entire FF system, resulting in the inevitable microbial community succession in the acclimation phase and maintenance of the stable PHA-accumulating function in the maturation phase. However, neutral processes, likely caused by predation from bacterial phages, also occurred, which led to the unpredictable temporal dynamics of the top competitors. PMID- 29281811 TI - Enhanced dewaterability of sludge during anaerobic digestion with thermal hydrolysis pretreatment: New insights through structure evolution. AB - Comprehensive insights into the sludge digestate dewaterability were gained through porous network structure of sludge. We measured the evolution of digestate dewaterability, represented by the solid content of centrifugally dewatered cake, in high-solids sequencing batch digesters with and without thermal hydrolysis pretreatment (THP). The results show that the dewaterability of the sludge after digestion was improved by 3.5% (+/-0.5%) for unpretreated sludge and 5.1% (+/-0.4%) for thermally hydrolyzed sludge. Compared to the unpretreated sludge digestate, thermal hydrolysis pretreatment eventually resulted in an improvement of dewaterability by 4.6% (+/-0.5%). Smaller particle size and larger surface area of sludge were induced by thermal hydrolysis and anaerobic digestion treatments. The structure strength and compactness of sludge, represented by elastic modulus and fractal dimension respectively, decreased with increase of digestion time. The porous network structure was broken up by thermal hydrolysis pretreatment and was further weakened during anaerobic digestion, which correspondingly improved the dewaterability of digestates. The logarithm of elastic modulus increased linearly with fractal dimension regardless of the pretreatment. Both fractal dimension and elastic modulus showed linear relationship with dewaterability. The rheological characterization combined with the analysis of fractal dimension of sewage sludge porous network structure was found applicable in quantitative evaluation of sludge dewaterability, which depended positively on both thermal hydrolysis and anaerobic digestion. PMID- 29281812 TI - Dynamic joint stiffness of the ankle in healthy and rheumatoid arthritis post menopausal women. AB - The purpose of this study was to compare rheumatoid arthritis post-menopausal women (RAPW) with pathological involvement of the lower limb joints and age matched healthy post-menopausal women (AHPW) in regard to the dynamic joint stiffness of the ankle (DJSankle) during the stance phase of gait. Data were collected from 18 RAPW and 18 AHPW. Gait was assessed by a three-dimensional motion analysis system synchronised with a force plate. Subjects walked barefoot at natural and self-selected speed, performing 14 valid trials (comprising 7 left and 7 right foot-steps on a force plate). The stance phase was split into three sub-phases that corresponded to the three angular displacements of the ankle that occurred during this phase, namely, controlled plantar flexion (CPF), controlled dorsiflexion (CDF), and powered plantar flexion (PPF). A linear model represented each sub-phase and computed DJSankle. Model fitting was assessed by the coefficient of determination (R2). The coefficient of variation (CV) was used to assess intra-individual variability. In all sub-phases, R2 values for both groups were higher than 0.85. There were no differences in the R2 values among groups. RAPW showed a higher DJSankle during the CPF (p < 0.05). CDF and PPF yielded no differences among groups. During CPF, RAPW yielded a higher CV for DJSankle (p < 0.01). RAPW also yielded lower ankle angular displacements during CPF and PPF (p < 0.05). Findings suggested that the stance phase of RAPW and AHPW can be studied by a linear ankle 'moment of force -- angle' relationship. During CPF, RAPW exhibited excessive ankle stiffness and presented a higher intra-individual DJSankle variability. PMID- 29281813 TI - Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function. AB - Synaptopathies contributing to neurodevelopmental disorders are linked to mutations in synaptic organizing molecules, including postsynaptic neuroligins, presynaptic neurexins, and MDGAs, which regulate their interaction. The role of MDGA1 in suppressing inhibitory versus excitatory synapses is controversial based on in vitro studies. We show that genetic deletion of MDGA1 in vivo elevates hippocampal CA1 inhibitory, but not excitatory, synapse density and transmission. Furthermore, MDGA1 is selectively expressed by pyramidal neurons and regulates perisomatic, but not distal dendritic, inhibitory synapses. Mdga1-/- hippocampal networks demonstrate muted responses to neural excitation, and Mdga1-/- mice are resistant to induced seizures. Mdga1-/- mice further demonstrate compromised hippocampal long-term potentiation, consistent with observed deficits in spatial and context-dependent learning and memory. These results suggest that mutations in MDGA1 may contribute to cognitive deficits through altered synaptic transmission and plasticity by loss of suppression of inhibitory synapse development in a subcellular domain- and cell-type-selective manner. PMID- 29281814 TI - The Sexual Dimorphism of Dietary Restriction Responsiveness in Caenorhabditis elegans. AB - Organismal lifespan is highly plastic in response to environmental cues, and dietary restriction (DR) is the most robust way to extend lifespan in various species. Recent studies have shown that sex also is an important factor for lifespan regulation; however, it remains largely unclear how these two factors, food and sex, interact in lifespan regulation. The nematode Caenorhabditis elegans has two sexes, hermaphrodite and male, and only the hermaphrodites are essential for the short-term succession of the species. Here, we report an extreme sexual dimorphism in the responsiveness to DR in C. elegans; the essential hermaphrodites show marked longevity responses to various forms of DR, but the males show few longevity responses and sustain reproductive ability. Our analysis reveals that the sex determination pathway and the steroid hormone receptor DAF-12 regulate the sex-specific DR responsiveness, integrating sex and environmental cues to determine organismal lifespan. PMID- 29281815 TI - The NLR Protein NLRP6 Does Not Impact Gut Microbiota Composition. AB - NLRP6 is a Nod-like receptor expressed in the intestinal epithelium. Previous studies reported a protective role for NLRP6 against intestinal injury and colitis-associated carcinogenesis via the regulation and establishment of a healthy microbiota. However, these results were not obtained using littermate animals, leaving the possibility that the pro-colitogenic microbiota phenotype associated with knockout (KO) mice was stochastically acquired and genotype independent. Here, we analyzed the microbiota at three intestinal locations from Nlrp6-/- and wild-type (WT) littermates, either co-caged or individually caged after weaning. Our results demonstrate that NLRP6 does not significantly influence the intestinal microbiota at homeostasis, and they support a previously reported sex-biased microbial community structure. Moreover, WT and Nlrp6-/- littermate mice displayed comparable sensitivity to dextran sulfate sodium (DSS) induced colitis, although increased sensitivity was noted in KO females. Our results clarify the role of NLRP6 in microbiota and colitis control, and they highlight the importance of analyzing littermate animals in such studies. PMID- 29281816 TI - Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake. AB - Physiologic turnover of interstitial collagen is mediated by a sequential pathway in which collagen is fragmented by pericellular collagenases, endocytosed by collagen receptors, and routed to lysosomes for degradation by cathepsins. Here, we use intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all display vigorous endocytic collagen degradation. The cells engaged in this process are identified as tumor-associated macrophage (TAM)-like cells that degrade collagen in a mannose receptor-dependent manner. Accordingly, mannose receptor-deficient mice display increased intratumoral collagen. Whole transcriptome profiling uncovers a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies reveal that collagen-degrading TAMs originate from circulating CCR2+ monocytes. This study identifies a function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation. PMID- 29281817 TI - Targeted Elimination of Immunodominant B Cells Drives the Germinal Center Reaction toward Subdominant Epitopes. AB - Rapidly evolving pathogens such as HIV or influenza can quickly mutate their antigenic profiles, reducing the efficacy of conventional vaccines. Despite this challenge, functionally required epitopes are highly conserved among heterologous viral strains and represent a key vulnerability that could be targeted during vaccine development. As the antigenicity of these conserved epitopes is frequently subdominant, there is a critical need for innovative vaccination strategies designed to target these neutralizing epitopes. Here, we immunized mice with antigens containing discrete immunodominant and subdominant moieties and show that treatment with soluble heterologous antigen bearing only the immunodominant epitope selectively suppresses these germinal center (GC) B cells. By exploiting this intrinsic tolerance mechanism, we promote the expansion of subdominant B cells in the GC and the subsequent long-lived components of the humoral response. We propose that this strategy may be applied to elicit preferential expansion of subdominant B cells that recognize weakly immunogenic epitopes on microbial pathogens. PMID- 29281818 TI - Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models. AB - The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine rich HCDR3s. Our results show that Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate that V1V2-glycan bnAbs are more readily induced than CD4bs bnAbs, and define VH replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies. PMID- 29281819 TI - Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs. AB - During female mouse embryogenesis, two forms of X chromosome inactivation (XCI) ensure dosage compensation from sex chromosomes. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp), and this pattern is maintained in extraembryonic cell types. Epiblast cells, which give rise to the embryo proper, reactivate the Xp (XCR) and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI depend on the long non-coding RNA Xist. The ubiquitin ligase RLIM is required for iXCI in vivo and occupies a central role in current models of rXCI. Here, we demonstrate the existence of Rlim-dependent and Rlim-independent pathways for rXCI in differentiating female ESCs. Upon uncoupling these pathways, we find more efficient Rlim-independent XCI in ESCs cultured under physiological oxygen conditions. Our results revise current models of rXCI and suggest that caution must be taken when comparing XCI studies in ESCs and mice. PMID- 29281820 TI - Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes. AB - A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here, we find that DNA methylation of the TERT CpG island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter mutant cancers. Finally, in several cancers, DNA methylation levels at the TERT CGI correlate with altered patient survival. PMID- 29281821 TI - Identification of Oxa1 Homologs Operating in the Eukaryotic Endoplasmic Reticulum. AB - Members of the evolutionarily conserved Oxa1/Alb3/YidC family mediate membrane protein biogenesis at the mitochondrial inner membrane, chloroplast thylakoid membrane, and bacterial plasma membrane, respectively. Despite their broad phylogenetic distribution, no Oxa1/Alb3/YidC homologs are known to operate in eukaryotic cells outside the endosymbiotic organelles. Here, we present bioinformatic evidence that the tail-anchored protein insertion factor WRB/Get1, the "endoplasmic reticulum (ER) membrane complex" subunit EMC3, and TMCO1 are ER resident homologs of the Oxa1/Alb3/YidC family. Topology mapping and co-evolution based modeling demonstrate that Get1, EMC3, and TMCO1 share a conserved Oxa1-like architecture. Biochemical analysis of human TMCO1, the only homolog not previously linked to membrane protein biogenesis, shows that it associates with the Sec translocon and ribosomes. These findings suggest a specific biochemical function for TMCO1 and define a superfamily of proteins-the "Oxa1 superfamily" whose shared function is to facilitate membrane protein biogenesis. PMID- 29281822 TI - Real-Time Observation of Target Search by the CRISPR Surveillance Complex Cascade. AB - CRISPR-Cas systems defend bacteria and archaea against infection by bacteriophage and other threats. The central component of these systems are surveillance complexes that use guide RNAs to bind specific regions of foreign nucleic acids, marking them for destruction. Surveillance complexes must locate targets rapidly to ensure timely immune response, but the mechanism of this search process remains unclear. Here, we used single-molecule FRET to visualize how the type I-E surveillance complex Cascade searches DNA in real time. Cascade rapidly and randomly samples DNA through nonspecific electrostatic contacts, pausing at short PAM recognition sites that may be adjacent to the target. We identify Cascade motifs that are essential for either nonspecific sampling or positioning and readout of the PAM. Our findings provide a comprehensive structural and kinetic model for the Cascade target-search mechanism, revealing how CRISPR surveillance complexes can rapidly search large amounts of genetic material en route to target recognition. PMID- 29281823 TI - RNA-Independent DNA Cleavage Activities of Cas9 and Cas12a. AB - CRISPR-Cas systems provide bacteria and archaea with sequence-specific protection against invading mobile genetic elements. In the presence of divalent metal ions, Cas9 and Cas12a (formerly Cpf1) proteins target and cleave DNA that is complementary to a cognate guide RNA. The recognition of a protospacer adjacent motif (PAM) sequence in the target DNA by Cas9 and Cas12a is essential for cleavage. This RNA-guided DNA targeting is widely used for gene-editing methods. Here, we show that Francisella tularensis novicida (Fno) Cas12a, FnoCas9, and Streptococcus pyogenes Cas9 (SpyCas9) cleave DNA without a guide RNA in the presence of Mn2+ ions. Substrate requirements for the RNA-independent activity vary. FnoCas9 preferentially nicks double-stranded plasmid, SpyCas9 degrades single-stranded plasmid, and FnoCas12a cleaves both substrates. These observations suggest that the identities and levels of intracellular metals, along with the Cas9/Cas12a ortholog employed, could have significant impacts in genome editing applications. PMID- 29281824 TI - Single-Molecule Quantification of Translation-Dependent Association of mRNAs with the Endoplasmic Reticulum. AB - It is well established that mRNAs encoding secretory or membrane-bound proteins are translated on the surface of the endoplasmic reticulum (ER). The extent to which mRNAs that encode cytosolic proteins associate with the ER, however, remains controversial. To address this question, we quantified the number of cytosolic protein-encoding mRNAs that co-localize with the ER using single molecule RNA imaging in fixed and living cells. We found that a small but significant number of mRNAs that encode cytosolic proteins associate with the ER and show that this interaction is translation dependent. Furthermore, we demonstrate that cytosolic protein-encoding transcripts can remain on the ER with dwell times consistent with multiple rounds of translation and have higher ribosome occupancies than transcripts translated in the cytosol. These results advance our understanding of the diversity and dynamics of localized translation on the ER. PMID- 29281827 TI - Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs. AB - The PSD-95/SAPAP/Shank complex functions as the major scaffold in orchestrating the formation and plasticity of the post-synaptic densities (PSDs). We previously demonstrated that the exquisitely specific SAPAP/Shank interaction is critical for Shank synaptic targeting and Shank-mediated synaptogenesis. Here, we show that the PSD-95/SAPAP interaction, SAPAP synaptic targeting, and SAPAP-mediated synaptogenesis require phosphorylation of the N-terminal repeat sequences of SAPAPs. The atomic structure of the PSD-95 guanylate kinase (GK) in complex with a phosphor-SAPAP repeat peptide, together with biochemical studies, reveals the molecular mechanism underlying the phosphorylation-dependent PSD-95/SAPAP interaction, and it also provides an explanation of a PSD-95 mutation found in patients with intellectual disabilities. Guided by the structural data, we developed potent non-phosphorylated GK inhibitory peptides capable of blocking the PSD-95/SAPAP interaction and interfering with PSD-95/SAPAP-mediated synaptic maturation and strength. These peptides are genetically encodable for investigating the functions of the PSD-95/SAPAP interaction in vivo. PMID- 29281825 TI - Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias. AB - Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia. PMID- 29281826 TI - Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy. AB - The hallmark of spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons. PMID- 29281830 TI - Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis. AB - Most tumor cells exhibit obligatory demands for essential amino acids (EAAs), but the regulatory mechanisms whereby tumor cells take up EAAs and EAAs promote malignant transformation remain to be determined. Here, we show that oncogenic MYC, solute carrier family (SLC) 7 member 5 (SLC7A5), and SLC43A1 constitute a feedforward activation loop to promote EAA transport and tumorigenesis. MYC selectively activates Slc7a5 and Slc43a1 transcription through direct binding to specific E box elements within both genes, enabling effective EAA import. Elevated EAAs, in turn, stimulate Myc mRNA translation, in part through attenuation of the GCN2-eIF2alpha-ATF4 amino acid stress response pathway, leading to MYC-dependent transcriptional amplification. SLC7A5/SLC43A1 depletion inhibits MYC expression, metabolic reprogramming, and tumor cell growth in vitro and in vivo. These findings thus reveal a MYC-SLC7A5/SLC43A1 signaling circuit that underlies EAA metabolism, MYC deregulation, and tumorigenesis. PMID- 29281828 TI - The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission. AB - Neurotransmission is a tightly regulated Ca2+-dependent process. Upon Ca2+ influx, Synaptotagmin1 (Syt1) promotes fusion of synaptic vesicles (SVs) with the plasma membrane. This requires regulation at multiple levels, but the role of metabolites in SV release is unclear. Here, we uncover a role for isocitrate dehydrogenase 3a (idh3a), a Krebs cycle enzyme, in neurotransmission. Loss of idh3a leads to a reduction of the metabolite, alpha-ketoglutarate (alphaKG), causing defects in synaptic transmission similar to the loss of syt1. Supplementing idh3a flies with alphaKG suppresses these defects through an ATP or neurotransmitter-independent mechanism. Indeed, alphaKG, but not glutamate, enhances Syt1-dependent fusion in a reconstitution assay. alphaKG promotes interaction between the C2-domains of Syt1 and phospholipids. The data reveal conserved metabolic regulation of synaptic transmission via alphaKG. Our studies provide a synaptic role for alphaKG, a metabolite that has been proposed as a treatment for aging and neurodegenerative disorders. PMID- 29281829 TI - Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells. AB - Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells. Remarkably, the fitness of aneuploid cells improves or deteriorates upon genetically decreasing or increasing ceramides, respectively. Combined targeting of serine and sphingolipid synthesis could be exploited to specifically target cancer cells, the vast majority of which are aneuploid. PMID- 29281831 TI - Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer. AB - Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of BRAFV600E is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status. PMID- 29281833 TI - NLRP3 Controls the Development of Gastrointestinal CD11b+ Dendritic Cells in the Steady State and during Chronic Bacterial Infection. AB - The gastric lamina propria is largely uncharted immunological territory. Here we describe the evolution and composition of the gastric, small intestinal, and colonic lamina propria mononuclear phagocyte system during the steady state and infection with the gastric pathogen Helicobacter pylori. We show that monocytes, CX3CR1hi macrophages, and CD11b+ dendritic cells are recruited to the infected stomach in a CCR2-dependent manner. All three populations, but not BATF3 dependent CD103+ DCs, sample red fluorescent protein (RFP)+Helicobacter pylori (H. pylori). Mice reconstituted with human hematopoietic stem cells recapitulate several features of the myeloid cell-H. pylori interaction. The differentiation in and/or recruitment to gastrointestinal, lung, and lymphoid tissues of CD11b+ DCs requires NLRP3, but not apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC) or caspase-1, during steady-state and chronic infection. NLRP3-/- mice fail to generate Treg responses to H. pylori and control the infection more effectively than wild-type mice. The results demonstrate a non canonical inflammasome-independent function of NLRP3 in DC development and immune regulation. PMID- 29281832 TI - The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity. AB - Inflammasomes activate the protease caspase-1, which cleaves interleukin-1beta and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis. PMID- 29281834 TI - STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis. AB - Intestinal immune homeostasis is preserved by commensal bacteria interacting with the host to generate a balanced array of cytokines that are essential for wound repair and for combatting infection. Inflammatory bowel disease (IBD), which can lead to colitis-associated cancer (CAC), is thought to involve chronic microbial irritation following a breach of the mucosal intestinal epithelium. However, the innate immune pathways responsible for regulating these inflammatory processes remain to be fully clarified. Here, we show that commensal bacteria influence STING signaling predominantly in mononuclear phagocytes to produce both pro inflammatory cytokines as well as anti-inflammatory IL-10. Enterocolitis, manifested through loss of IL-10, was completely abrogated in the absence of STING. Intestinal inflammation was less severe in the absence of cGAS, possibly suggesting a role for cyclic dinucleotides (CDNs) indirectly regulating STING signaling. Our data shed insight into the causes of inflammation and provide a potential therapeutic target for prevention of IBD. PMID- 29281836 TI - A Global Interactome Map of the Dengue Virus NS1 Identifies Virus Restriction and Dependency Host Factors. AB - Dengue virus (DENV) infections cause the most prevalent mosquito-borne viral disease worldwide, for which no therapies are available. DENV encodes seven non structural (NS) proteins that co-assemble and recruit poorly characterized host factors to form the DENV replication complex essential for viral infection. Here, we provide a global proteomic analysis of the human host factors that interact with the DENV NS1 protein. Combined with a functional RNAi screen, this study reveals a comprehensive network of host cellular processes involved in DENV infection and identifies DENV host restriction and dependency factors. We highlight an important role of RACK1 and the chaperonin TRiC (CCT) and oligosaccharyltransferase (OST) complexes during DENV replication. We further show that the OST complex mediates NS1 and NS4B glycosylation, and pharmacological inhibition of its N-glycosylation function strongly impairs DENV infection. In conclusion, our study provides a global interactome of the DENV NS1 and identifies host factors targetable for antiviral therapies. PMID- 29281835 TI - Effector and Regulatory T Cells Roll at High Shear Stress by Inducible Tether and Sling Formation. AB - The adaptive immune response involves T cell differentiation and migration to sites of inflammation. T cell trafficking is initiated by rolling on inflamed endothelium. Tethers and slings, discovered in neutrophils, facilitate cell rolling at high shear stress. Here, we demonstrate that the ability to form tethers and slings during rolling is highly inducible in T helper 1 (Th1), Th17, and regulatory T (Treg) cells but less in Th2 cells. In vivo, endogenous Treg cells rolled stably in cremaster venules at physiological shear stress. Quantitative dynamic footprinting nanoscopy of Th1, Th17, and Treg cells uncovered the formation of multiple tethers per cell. Human Th1 cells also showed tethers and slings. RNA sequencing (RNA-seq) revealed the induction of cell migration and cytoskeletal genes in sling-forming cells. We conclude that differentiated CD4 T cells stabilize rolling by inducible tether and sling formation. These phenotypic changes approximate the adhesion phenotype of neutrophils and support CD4 T cell access to sites of inflammation. PMID- 29281837 TI - Shaping of Intestinal Microbiota in Nlrp6- and Rag2-Deficient Mice Depends on Community Structure. AB - Contradicting observations have been made regarding the relative contributions of immune sensors to shaping the microbiome, yet the reasons for these discrepancies are not fully understood. Here, we investigated the contribution of environmental factors in shaping the microbiome in mice deficient in adaptive immunity (Rag2-/ ) and Nlrp6, an immune sensor proposed to be involved in regulation of microbiota composition. In conventionally housed Nlrp6-/- mice, familial transmission has a significant effect on microbiota composition, complicating the analysis of genotype-dependent effects. Notably, after rederivation into standardized specific pathogen-free (SPF) conditions devoid of pathobionts, microbiota composition was indistinguishable between WT, Rag2-/-, and Nlrp6-/- mice. However, upon reintroduction of a pathobiont-containing community host, genotype dependent differences reappear, specifically affecting the relative abundance of pathobionts such as Helicobacter spp. Our results show that the impact of Nlrp6 and also of adaptive immunity on microbiota composition depends on community structure and primarily influences pathobionts but not commensals. PMID- 29281838 TI - The Role of Type VI Secretion System Effectors in Target Cell Lysis and Subsequent Horizontal Gene Transfer. AB - Bacteria use type VI secretion systems (T6SSs) to manipulate host cells during pathogenesis or to kill competing bacteria, which, in some cases, increases horizontal gene transfer. These functions largely depend on T6SS regulation, dynamics, and the set of effectors that the system delivers into the target cells. Here, we show that Acinetobacter baylyi ADP1 assembles a highly dynamic T6SS capable of killing and lysing bacterial cells. T6SS function depends on conserved T6SS components as well as Acinetobacter-specific genes of unknown function. Five different effectors, encoded next to VgrG or PAAR proteins and their cognate immunity proteins, cause distinct changes in the prey cells, resulting in various degrees of their lysis. Prey lysis correlates with the rate of DNA transfer from prey to predator, suggesting that lytic effectors are required for efficient T6SS-dependent horizontal gene transfer in naturally competent bacteria. PMID- 29281839 TI - Leading role of TBP in the Establishment of Complexity in Eukaryotic Transcription Initiation Systems. AB - While both archaeal and eukaryotic transcription initiation systems utilize TBP (TATA box-binding protein) and TFIIB (transcription factor IIB), eukaryotic systems include larger numbers of initiation factors. It remains uncertain how eukaryotic transcription initiation systems have evolved. Here, we investigate the evolutionary development of TBP and TFIIB, each of which has an intramolecular direct repeat, using two evolutionary indicators. Inter-repeat sequence dissimilarity (dDR, distance between direct repeats) indicates that the asymmetry of two repeats in TBP and TFIIB has gradually increased during evolution. Interspecies sequence diversity (PD, phylogenetic diversity) indicates that the resultant asymmetric structure, which is related to the ability to interact with multiple factors, diverged in archaeal TBP and archaeal/eukaryotic TFIIB during evolution. Our findings suggest that eukaryotic TBP initially acquired multiple Eukarya-specific interactors through asymmetric evolution of the two repeats. After the asymmetric TBP generated the complexity of the eukaryotic transcription initiation systems, its diversification halted and its asymmetric structure spread throughout eukaryotic species. PMID- 29281840 TI - Protein Expression Landscape of Mouse Embryos during Pre-implantation Development. AB - Pre-implantation embryo development is an intricate and precisely regulated process orchestrated by maternally inherited proteins and newly synthesized proteins following zygotic genome activation. Although genomic and transcriptomic studies have enriched our understanding of the genetic programs underlying this process, the protein expression landscape remains unexplored. Using quantitative mass spectrometry, we identified nearly 5,000 proteins from 8,000 mouse embryos of each stage (zygote, 2-cell, 4-cell, 8-cell, morula, and blastocyst). We found that protein expression in zygotes, morulas, and blastocysts is distinct from 2- to 8-cell embryos. Analysis of protein phosphorylation identified critical kinases and signal transduction pathways. We highlight key factors and their important roles in embryo development. Combined analysis of transcriptomic and proteomic data reveals coordinated control of RNA degradation, transcription, and translation and identifies previously undefined exon-junction-derived peptides. Our study provides an invaluable resource for further mechanistic studies and suggests core factors regulating pre-implantation embryo development. PMID- 29281841 TI - Developmental Emergence of Adult Neural Stem Cells as Revealed by Single-Cell Transcriptional Profiling. AB - Adult neural stem cells (NSCs) derive from embryonic precursors, but little is known about how or when this occurs. We have addressed this issue using single cell RNA sequencing at multiple developmental time points to analyze the embryonic murine cortex, one source of adult forebrain NSCs. We computationally identify all major cortical cell types, including the embryonic radial precursors (RPs) that generate adult NSCs. We define the initial emergence of RPs from neuroepithelial stem cells at E11.5. We show that, by E13.5, RPs express a transcriptional identity that is maintained and reinforced throughout their transition to a non-proliferative state between E15.5 and E17.5. These slowly proliferating late embryonic RPs share a core transcriptional phenotype with quiescent adult forebrain NSCs. Together, these findings support a model wherein cortical RPs maintain a core transcriptional identity from embryogenesis through to adulthood and wherein the transition to a quiescent adult NSC occurs during late neurogenesis. PMID- 29281843 TI - Liver Injury in Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome Measured by Diffusion-Weighted Magnetic Resonance Imaging. AB - OBJECTIVE: The objective of this study was to evaluate acute liver injury (ALI) detected by diffusion-weighted magnetic resonance imaging (MRI) and the associated laboratory findings in women with hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome. STUDY DESIGN: This was a retrospective, observational study of women with HELLP syndrome defined by serum aspartate aminotransferase (AST) levels >=100 U/L and thrombocytopenia with platelets <=100,000/uL. All women underwent MRI postpartum including diffusion-weighted imaging to estimate the volume of ALI with reconstructed apparent diffusion coefficient (ADC) maps. The ADC map and the volume of ALI were compared with laboratory abnormalities by Spearman's correlation analysis. RESULTS: From March 2013 through August 2015, 16 women with HELLP syndrome underwent MRI, and of these, 14 (88%) women had areas of increased signal intensity suggestive of ALI. Their median (range) maximum AST level was 262 (140-1,958) IU/L, and at the time of MRI, AST was 103 (36-1,426) IU/L. Both of these AST levels significantly correlated with ADC map as well as the volume of ALI (both p-values <0.001). CONCLUSION: Women with HELLP syndrome frequently exhibited areas of abnormal diffusion in the liver on diffusion-weighted MRI, suggestive of ALI. The extent of liver injury was significantly correlated with serum AST. PMID- 29281842 TI - Estimated Placental Volume and Gestational Age. AB - OBJECTIVE: The objective of this study was to validate estimated placental volume (EPV) across a range of gestational ages (GAs). STUDY DESIGN: Three hundred sixty-six patients from 2009 to 2011 received ultrasound scans between 11 + 0 and 38 + 6 weeks GA to assess EPV. An EPV versus GA best fit curve was generated and compared with published normative curves of EPV versus GA in a different population. A subanalysis was performed to explore the relationship between EPV and birth weight (BW). RESULTS: Analysis of EPV versus GA revealed a parabolic curve with the following best fit equation: EPV = (0.372 GA - 0.00364 GA2)3. EPV was weakly correlated with BW, and patients with an EPV in the bottom 50th percentile had 2.42 times the odds of having a newborn with a BW in the bottom 50th percentile (95% confidence interval: 1.27-4.68). Microscopic evaluation of two placentas corresponding to the smallest EPV outliers revealed significant placental pathology. CONCLUSION: Placental volume increases throughout gestation and follows a predictable parabolic curve, in agreement with the existing literature. Further validation is required, but EPV may have the potential for clinical utility as a screening tool in a variety of settings. PMID- 29281844 TI - [Decolonization of Health Care Workers In a Neonatal Intensive Care Unit Carrying a Methicillin-Susceptible Staphylococcus aureus Isolate]. AB - BACKGROUND: In 2016, an increased rate of methicillin-susceptible Staphylococcus aureus colonization was detected on a neonatal intensive care unit at the Leipzig University Hospital. Typing results showed a predominant spa-type t091. Considering nosocomial clustering, several infection prevention measures (e. g. intensified standard precautions, single-occupancy room, cohorted patients, continuing education of staff) were introduced, including staff screening followed by decolonization of colonized health care workers. METHODS: Staff members showing positive on screening carried out a 5-day decolonization program at home. Decolonization products containing octenidine as active ingredient were used first. At the earliest, 48 h after completing the procedure, the success of the intervention was tested (3 buccal and nasal swabs were taken on consecutive days). If 2 attempts at decolonization were not successful, staff members were provided with a mupirocin-containing nasal ointment instead of octenidine. RESULTS: Of 128 employees examined, 43 (33.6%) were identified as carriers of S. aureus. In 9 cases (20.9%; 9/43) the S. aureus matched with type t091. 2 carriers (4.7%; 2/43) of MRSA were detected as well. The first decolonization attempt against t091 and MRSA failed altogether. After a second decolonization, 3 cases became negative. Finally, 8 remaining staff members were decolonized successfully with mupirocin containing nasal ointment. CONCLUSIONS: Various reasons might explain the difficulties of decolonization such as the challenge of managing decolonization at home, inhibitory factors as well as inconsistent performance of decolonization measures. Additionally, differences between the preparations for the nasal decontamination may be considered. PMID- 29281845 TI - [ICF and the Term "Substantial Disability" in the German Bundesteilhabegesetz (BTHG)]. AB - The new law, called "Bundesteilhabegesetz" was rapidly approved by the German legislative institutions in December 2016. It was supposed to be a milestone demonstrating the change from paternalistic care to the right of autonomous participation in all parts of social life. This new law sought to offer new ways, but actually there remains a big space for interpretations in the implementation. The law proposal wanted to claim 5 from the nine areas of life from the ICF. That was not accepted. Until December 2019 there must be found a definition of "substantial disability". It must be clear, that this is no mathematical aspect. Each medical officer/doctor gives his expert decision to his best knowledge and belief. No other instrument would really respect the human dignity and could better guarantee justified social personal support. It must closely be observed until the year 2023 what will be realized in the implementation of this law. Each wrong headed development, which possibly prioritize financial aspects, should be acutely opposed. In this part all medical directors/doctors are required not only in the social medical but in the social political discussion, too. PMID- 29281846 TI - Men don't talk about their health, but will they CHAT? The potential of online holistic needs assessment in prostate cancer. PMID- 29281847 TI - Geographic variation in cone volatiles and pollinators in the thermogenic African cycad Encephalartos ghellinckii Lem. AB - Heat and odour production can have profound effects on pollination in cycads. It is therefore expected that these traits would co-vary geographically with pollinator assemblages. Such intraspecific variation, may lead to the evolution of pollination ecotypes, which can be an early stage of pollinator-mediated speciation. We measured cone temperatures using miniature temperature data loggers and examined the composition of cone volatile odours using headspace sampling and analysis with gas chromatography-mass spectrometry in four populations spanning the range of the African cycad Encephalartos ghellinckii. Pollinator assemblages were also investigated in three populations. Male and female cones were thermogenic at pollen shed and receptive stages, respectively, but patterns of thermogenesis did not vary among populations. Scent emissions from cones in populations in the Drakensberg Mountains were characterised by cis beta-ocimene, beta-myrcene and (3E)-1,3-octadiene, while camphene and alpha pinene were characteristic of scent emissions from cones in populations closer to the coast. These differences in volatile blends corresponded with differences in insect assemblages. These results confirm intraspecific variation in volatile emissions of E. ghellinckii and support the predictions that intraspecific variation in volatile emissions will be associated with shifts in pollinator assemblages. While further work needs to be done to test for local adaptation in this system, this preliminary evidence is consistent with the formation of pollination ecotypes in the E. ghellinckii species complex. PMID- 29281848 TI - Propensity matched comparative analysis of survival following chemoradiation or radical cystectomy for muscle-invasive bladder cancer. AB - OBJECTIVE: To compare survival outcome between chemoradiation therapy (CRT) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: We conducted a retrospective analysis of patients with MIBC (>=cT2, N0, M0) in the National Cancer Database (2004-2013). CRT was defined as a radiation dose of >=40 Gy and chemotherapy within 90 days of radiation. Descriptive statistics were used to compare groups. RC and CRT patients were propensity matched. Kaplan-Meier analysis was used to compare overall survival (OS). Multivariable Cox regression was used to determine predictors of survival. RESULTS: In all, 8 379 (6 606 RC and 1 773 CRT) patients met the inclusion criteria and 1 683 patients in each group were propensity matched. On multivariable extended Cox analysis, significant predictors of decreased OS were age, Charlson-Deyo Comorbidity score of 1, Charlson-Deyo Comorbidity score of 2, stage cT3-4, and urothelial histology. CRT was associated with decreased mortality at year 1 (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74 0.96; P = 0.01), but at 2 years (HR 1.4, 95% CI 1.2-1.6; P < 0.001) and 3 years onward (HR 1.5, 95% CI 1.2-1.8; P < 0.001) CRT was associated with increased mortality. The 5-year OS was greater for RC than for CRT (38% vs 30%, P = 0.004). CONCLUSIONS: Initially after treatment for MIBC the risk of mortality is lower with CRT compared to RC. However, at >=2 years after treatment the mortality risk favours RC. Patients who are suitable surgical candidates, with a low risk of morbidity, may be better served by RC. PMID- 29281849 TI - Of mice, rats, and men: Small animal model of hepatitis C virus infection. PMID- 29281851 TI - Commentary to "Patients not patents: drug research and development as a public enterprise". PMID- 29281852 TI - Evolution of cystectomy care over an 11-year period in a high-volume tertiary referral centre. AB - OBJECTIVES: To describe the evolution in radical cystectomy (RC) care over 11 years at a referral centre. PATIENTS AND METHODS: The clinical data of patients undergoing either open RC (ORC) or robot-assisted RC (RARC) for cT1-4aN0M0 bladder cancer (BCa) at our centre between January 2006 and December 2016 were retrospectively evaluated. Crude and propensity score-weighted log-binomial regression analyses were conducted to assess the association between pre- and peri-operative variables and the risk of reoperation, intensive care unit (ICU) admission and death <90 days after RC. RESULTS: A total of 814 patients were considered. The percentage of RARCs performed increased (from 10% to 100%) between 2006 and 2013. Overall, 29% of the patients received neoadjuvant chemotherapy (12-37% from 2006 to 2016). Despite no differences in terms of operating time, pelvic lymph node dissection (PLND) was more commonly attempted during RARC and extended PLND was more frequently performed in the RARC group (72% vs 19%; P < 0.001). Ileal conduit was the preferred urinary diversion in both groups, and more patients in the RARC group underwent neobladder construction (34% vs 14%; P < 0.001). The overall rates of re-intervention, ICU admission and death within 90 days of RC were 8.9%, 5.4% and 2.9%, respectively. On crude analysis, RARC was associated with a reduced risk of ICU admission (relative risk [RR] 0.42, 95% confidence interval [CI] 0.23-0.77; P = 0.005), reintervention (RR 0.58, 95% CI 0.37-0.90; P = 0.015) and death (RR 0.37, 95% CI 0.16-0.85; P = 0.020); however, these risk reductions were not statistically significant on weighted analyses. CONCLUSIONS: The introduction of RARC has coincided with a reduction in the rate of ICU admission, reoperation and death within 90 days of surgery, without compromising operating time, PLND extent or neobladder utilization. PMID- 29281850 TI - CD70 encoded by modified vaccinia virus Ankara enhances CD8 T-cell-dependent protective immunity in MHC class II-deficient mice. AB - The immunological outcome of infections and vaccinations is largely determined during the initial first days in which antigen-presenting cells instruct T cells to expand and differentiate into effector and memory cells. Besides the essential stimulation of the T-cell receptor complex a plethora of co-stimulatory signals not only ensures a proper T-cell activation but also instils phenotypic and functional characteristics in the T cells appropriate to fight off the invading pathogen. The tumour necrosis factor receptor/ligand pair CD27/CD70 gained a lot of attention because of its key role in regulating T-cell activation, survival, differentiation and maintenance, especially in the course of viral infections and cancer. We sought to investigate the role of CD70 co-stimulation for immune responses induced by the vaccine vector modified vaccinia virus Ankara-Bavarian Nordic(r) (MVA-BN(r) ). Short-term blockade of CD70 diminished systemic CD8 T cell effector and memory responses in mice. The dependence on CD70 became even more apparent in the lungs of MHC class II-deficient mice. Importantly, genetically encoded CD70 in MVA-BN(r) not only increased CD8 T-cell responses in wild-type mice but also substituted for CD4 T-cell help. MHC class II-deficient mice that were immunized with recombinant MVA-CD70 were fully protected against a lethal virus infection, whereas MVA-BN(r) -immunized mice failed to control the virus. These data are in line with CD70 playing an important role for vaccine induced CD8 T-cell responses and prove the potency of integrating co-stimulatory molecules into the MVA-BN(r) backbone. PMID- 29281853 TI - Racial disparity and survival outcomes between African-American and Caucasian American men with penile cancer. AB - OBJECTIVE: To determine whether there is a survival difference for African American men (AAM) versus Caucasian American men (CM) with penile squamous cell carcinoma (pSCC), particularly in locally advanced and metastatic cases where disease mortality is highest. PATIENTS AND METHODS: Using the Florida Cancer Data System, we identified men with pSCC from 2005 to 2013. We compared age, follow up, stage, race, and treatment type between AAM and CM. We performed Kaplan-Meier analysis for overall survival (OS) between AAM and CM for all stages, and for those with locally advanced and metastatic disease. A multivariable model was developed to determine significant predictors of OS. RESULTS: In all, 653 men (94 AAM and 559 CM) had pSCC and 198 (30%) had locally advanced and/or metastatic disease. A higher proportion of AAM had locally advanced and/or metastatic disease compared to CM (38 [40%] vs 160 [29%], P = 0.03). The median (interquartile range) follow-up for the entire cohort was 12.6 (5.4-32.0) months. For all stages, AAM had a significantly lower median OS compared to CM (26 vs 36 months, P = 0.03). For locally advanced and metastatic disease, there was a consistent trend toward disparity in median OS between AAM and CM (17 vs 22 months, P = 0.06). After adjusting for age, stage, grade, and treatment type, AAM with pSCC had a greater likelihood of death compared to CM (hazard ratio 1.64, P = 0.014). CONCLUSIONS: AAM have worse OS compared to CM with pSCC and this may partly be due to advanced stage at presentation. Treatment disparity may also contribute to lessened survival in AAM, but we were unable to demonstrate a significant difference in treatment utilisation between the groups. PMID- 29281855 TI - A totally new system is needed for drug research and development. PMID- 29281854 TI - Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance. AB - : We recently identified a histological subtype of hepatocellular carcinoma (HCC), designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this variant, we investigated its prognostic value in two large series of patients with HCC treated by either surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than six cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, alpha-fetoprotein level, satellite nodules, and vascular invasion). Multivariate analysis showed that MTM HCC subtype was an independent predictor of early and overall recurrence (surgical series: hazard ratio, 3.03; 95% confidence interval, 1.38-6.65; P = 0.006; and 2.76; 1.63-4.67; P < 0.001; RFA series: 2.37; 1.36-4.13; P = 0.002; and 2.19; 1.35-3.54; P = 0.001, respectively). Its prognostic value was retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness. No other baseline parameter was independently associated with recurrence in the RFA series. CONCLUSION: The MTM HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. (Hepatology 2018;68:103-112). PMID- 29281856 TI - Solar irradiance limits the long-term survival of Listeria monocytogenes in seawater. AB - : Seafood has often been implicated in outbreaks of food-borne illness caused by Listeria monocytogenes but the source of contamination is usually not known. In this study we investigated the possibility that this pathogen could survive in seawater for an extended time period. Freshly collected seawater samples were inoculated with 1 * 108 CFU per ml of L. monocytogenes EGD-e and survival was monitored by plate counting for up to 25 days. When incubated in the dark, either at ambient temperatures (4-14 degrees C) or at 16 degrees C, >104 CFU per ml survivors were present after 25 days. However, when the seawater cell suspensions were exposed to ambient light (solar irradiation) and temperatures, L. monocytogenes lost viability rapidly and no survivors could be detected after the 80 h time point. Both UV-A and visible light in the blue region of the spectrum (470 nm) were found to contribute to this effect. The stress inducible sigma factor sigmaB was found to play a role in survival of L. monocytogenes in seawater. Together these data demonstrate that solar irradiation is a critical determinant of L. monocytogenes survival in marine environments. The data further suggest the possibility of controlling this food-borne pathogen in food processing environments using visible light. SIGNIFICANCE AND IMPACT OF THE STUDY: Listeria monocytogenes is a food-borne bacterial pathogen capable of causing the life-threatening infection, listeriosis. In seafood the route of contamination from the environment is often not well understood as this pathogen is not generally thought to survive well in seawater. Here we provide evidence that L. monocytogenes is capable of surviving for long periods of time in seawater when light is excluded. Sunlight is demonstrated to have a significant effect on the survival of this pathogen in seawater, and both visible (470 nm) and UV-A light are shown to contribute to this effect. PMID- 29281857 TI - Outcomes of subsequent non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guerin after radical nephroureterectomy for upper urinary tract urothelial carcinoma. AB - OBJECTIVES: To describe the clinicopathological characteristics and prognosis of subsequent non-muscle-invasive bladder cancer (NMIBC) after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC), and particularly its response to intravesical Bacillus Calmette-Guerin (BCG). PATIENTS AND METHODS: An observational study was conducted in 1463 patients with UTUC who had undergone RNU and in 1555 patients with primary NMIBC. Of the 1463 patients with UTUC, 256 (17%) subsequently developed NMIBC (UTUC-NMIBC group) and were available for the analysis. The clinicopathological background and outcomes, including intravesical recurrence-free survival and bladder progression-free survival, were compared between the patients with UTUC-NMIBC and the patients with primary NMIBC treated with intravesical BCG. Propensity score matching was performed to adjust for the potential differences in the backgrounds of the two groups. To validate the utility of the CUETO scoring model in the UTUC-NMIBC group, risk scores were calculated and compared with the published probabilities for recurrence and progression. RESULTS: Compared with the unadjusted primary NMIBC group (n = 352), the UTUC-NMIBC group (n = 75) were found to have a worse prognosis for intravesical recurrence and progression, before propensity score matching. After propensity score matching for potential confounding factors, however, a worse prognosis was observed only for intravesical recurrence. The validation test of the CUETO scoring model for the UTUC-NMIBC group showed a significant difference in the rate of intravesical recurrence and progression for the 0-4 and 5-6 score groups between the UTUC-NMIBC group and the CUETO risk table reference data. CONCLUSION: Compared with the primary NMIBC group, the UTUC NMIBC group had a worse prognosis after intravesical BCG, especially with regard to intravesical recurrence. This suggests that patients with UTUC-NMIBC are inherently poor responders to BCG exposure. An optimal treatment strategy and risk scoring model to select patients for adjuvant intravesical BCG, chemotherapy or immediate radical cystectomy should be established. PMID- 29281859 TI - Another Case of Pacinian Corpuscle in a Lymph Node. PMID- 29281858 TI - Phosphatidylethanol Levels Among Incarcerated Women: The Influence of Pre incarceration Alcohol Consumption and Length of Abstinence. AB - BACKGROUND: Phosphatidylethanol (PEth) is a direct biomarker for alcohol that is formed shortly after alcohol use and may remain detectable in blood for weeks after alcohol consumption. There is little research on alcohol use factors that influence PEth elimination, especially among women. METHODS: Data were collected from 116 alcohol use-disordered women who were recently incarcerated. We used a 2 part model with logistic and linear components to examine whether alcohol consumption in the 2 weeks prior to incarceration and days since last alcoholic drink (operationalized as abstinence days prior to incarceration + days incarcerated) were associated with PEth detectability (>8 ng/ml) and level (ng/ml) in blood. RESULTS: Participants reported drinking an average of 10 drinks per day in the 2 weeks prior to incarceration. Days since last drink was negatively associated with PEth level (odds ratio [OR] = 0.97, 95% confidence interval [CI] = 0.93; 0.99) and being PEth detectable (OR = 0.96, 95% CI = 0.91; 0.99). Quantity of alcohol consumed prior to jail admission was associated with PEth detection (OR = 1.08; 95% CI = 1.03; 1.16), but not PEth level. CONCLUSIONS: Days since last alcoholic drink and drinks per day both influenced PEth detectability, but only days since last drink predicted PEth level among a large sample of women with alcohol use disorder in the criminal justice system. PMID- 29281860 TI - Subchondral Bone Radiodensity Patterns in the Glenoid Fossa of Ape and Human Scapulae. AB - Regions of denser subchondral bone deep to a joint's articular surface indicate locations where the joint experiences relatively higher or more frequent compressive trans-articular forces than less dense regions. Human clinically focused studies have hypothesized that regional variation of acquired with computed tomography osteoabsorptiomety (CT-OAM), in the scapular glenoid fossa (GF) is specifically related to forces arising from everyday rotator cuff muscle function. We test this hypothesis by investigating the relationship between rotator cuff function and GF HiRD subchondral bone patterns in a broader comparative context. CT-OAM was used on scapulae of chimpanzees, gibbons and humans to visualize HiRD subchondral bone patterns and assess regional (anterior posterior; superior-inferior) differences in HiRD concentrations within each group. Like patterns observed in humans, ape GFs show HiRD concentrations in anterior, posterior and superior regions. Gibbons exhibit significantly larger concentrations anteriorly, probably serving as a skeletal correlate of increased subscapularis activity during humeral internal rotation during arm-swinging locomotion. Chimpanzees exhibit relatively larger areas posteriorly (though not statistically significant), conceivably serving as a correlate of increased infraspinatus activity during humeral external rotation and retraction during knuckle-walking. All groups show relatively larger HiRD areas superiorly, likely correlating with forceful humeral abduction (rather than adduction) during routine upper limb use across behaviors. Subchondral bone HiRD patterns in the GF appear to correspond with normal and unbalanced rotator cuff activity and force production not only in humans, but also in other primates, thereby corroborating their value in human clinical studies and functional morphology research. Anat Rec, 301:776-785, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29281861 TI - Encountering the aftermath of medical error. PMID- 29281863 TI - Impact of abdominal shape on living liver donor outcomes in mini-incision right hepatic lobectomy: Comparison among 3 techniques. AB - Although minimally invasive techniques for living donor hepatectomy have been developed, the surgical feasibility and limitations remain to be elucidated. The risks and outcomes involved need to be better understood prior to their widespread application. The aim of this study was to assess feasibility of minimally invasive donor hepatectomy by reviewing our experience. A total of 99 living donor liver transplantations performed between 2000 and 2016 were retrospectively reviewed. All 99 living liver donors underwent right hepatectomy. The breakdown of the techniques is as follows: the standard technique in 33 patients; the laparoscopic-assisted minilaparotomy technique (hybrid technique group) in 19 patients; and the upper midline incision technique without laparoscopic assistance (minilaparotomy group) in 47 patients. An association between donor operative outcomes and body habitus, such as body mass index (BMI), abdominal truncal depth (approximated by celiac axis [CA] depth ratio), and umbilical circumference (UC) were assessed. Perioperative factors were compared between the standard technique and the minimally invasive technique. The minilaparotomy group had significantly shorter operative time (P = 0.046) and hospital stay (P = 0.005) than the standard technique group. Postoperative complication rates were similar between the 3 groups (P = 0.16). In the minilaparotomy group, greater BMI (P = 0.02), CA depth ratio (P = 0.04), and UC (P = 0.004) were found to be risk factors for postoperative complications. In the minilaparotomy group, CA depth ratio > 0.41, UC > 90 cm, and BMI > 30 kg/m2 were significantly associated with longer operative time and hospital stay. In the standard technique group, none of the body size factors were associated with postoperative outcomes. In conclusion, the minilaparotomy technique is safe and feasible, though technical difficulties may be encountered when performed on donors with larger body habitus. Ongoing efforts are required to ensure living donor safety. Liver Transplantation 24 516-527 2018 AASLD. PMID- 29281862 TI - Normothermic machine perfusion of donor livers without the need for human blood products. AB - Normothermic machine perfusion (NMP) enables viability assessment of donor livers prior to transplantation. NMP is frequently performed by using human blood products including red blood cells (RBCs) and fresh frozen plasma (FFP). Our aim was to examine the efficacy of a novel machine perfusion solution based on polymerized bovine hemoglobin-based oxygen carrier (HBOC)-201. Twenty-four livers declined for transplantation were transported by using static cold storage. Upon arrival, livers underwent NMP for 6 hours using pressure-controlled portal and arterial perfusion. A total of 12 livers were perfused using a solution based on RBCs and FFPs (historical cohort), 6 livers with HBOC-201 and FFPs, and another 6 livers with HBOC-201 and gelofusine, a gelatin-based colloid solution. Compared with RBC + FFP perfused livers, livers perfused with HBOC-201 had significantly higher hepatic adenosine triphosphate content, cumulative bile production, and portal and arterial flows. Biliary secretion of bicarbonate, bilirubin, bile salts, and phospholipids was similar in all 3 groups. The alanine aminotransferase concentration in perfusate was lower in the HBOC-201-perfused groups. In conclusion, NMP of human donor livers can be performed effectively using HBOC-201 and gelofusine, eliminating the need for human blood products. Perfusing livers with HBOC-201 is at least similar to perfusion with RBCs and FFP. Some of the biomarkers of liver function and injury even suggest a possible superiority of an HBOC-201-based perfusion solution and opens a perspective for further optimization of machine perfusion techniques. Liver Transplantation 24 528-538 2018 AASLD. PMID- 29281864 TI - Long-Term Effects of Neonatal Hyperoxia in Adult Mice. AB - The outcomes of premature infants have improved greatly; however, the health risks in adulthood are still relatively unclear. Bronchopulmonary dysplasia (BPD) in premature infants is a major risk factor for alteration in lung function and predisposition to respiratory morbidity, and is associated with hyperoxia. The study explores the effect of neonatal hyperoxia on organ systems in adult mice. Newborn mouse litters were randomized to 85%O2 or room air (RA) on P3 for 12 days; mice were sacrificed at P3, P7, P15, 3 months and 9 months. Lungs were assessed by histopathology, radial alveolar count, mean linear intercept, and alpha-Smooth muscle actin immunohistochemistry. Aortic assessment included histology, wall thickness, elastin, and collagen content. Glomerular histology and nephron number were assessed in the kidneys. Hyperoxia-exposed mice had progressive alveolar simplification and poor weight gain over time. Greater thickness of pulmonary arterioles by 3 months and a higher Fulton index by 9 months suggest worsening pulmonary hypertension. Aortic wall thickness to lumen ratio was greater with a lower aortic elastin-to-collagen ratio suggesting long term effects of neonatal hyperoxia. Hyperoxia-exposed mice at 9 months had smaller glomeruli as indicated by glomerular diameter and volume. Prolonged neonatal hyperoxia during the critical period of development induces irreversible lung damage, pulmonary hypertension and structural changes in the kidneys and aorta in adult mice. This could have implications for chronic adult diseases following exposure to high levels of oxygen in the newborn period. Anat Rec, 301:717-726, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29281865 TI - Cancer Screening Awareness and Practice in a Middle Income Country; A Systematic Review from Iran AB - Objective: Ageing population and noticeable changes in lifestyle in developing countries like Iran caused anincrease in cancer incidence. This requires organized cancer prevention and screening programs in population level,but most importantly community should be aware of these programs and willing to use them. This study exploredexisting evidence on public awareness and practice, as well as, adherence to cancer screening in Iranian population.Methods: Major English databases including Web of Science, PubMed, Scopus, and domestic Persian databases i.e.,SID, Magiran, and Barakat search engines were searched. All publications with focus on Iranian public awarenessabout cancer prevention, screening, and early detection programs which were published until August 2015, wereexplored in this systematic review. For this purpose, we used sensitive Persian phrases/key terms and English keywordswhich were extracted from medical subject headings (MeSH). Taking PRISMA guidelines into considerations eligibledocuments, were evaluated and abstracted by two separate reviewers. Results: We found 72 articles relevant to thistopic. Screening tests were known to, or being utilized by only a limited number of Iranians. Most Iranian women reliedon physical examination particularly self-examination, instead of taking mammogram, as the most standard test to findbreast tumors. Less than half of the average-risk adult populations were familiar with colorectal cancer risk factors andits screening tests, and only very limited number of studies reported taking at least one time colonoscopy or FOBT,at most 5.0% and 15.0%, respectively. Around half of women were familiar with cervical cancer and Pap-smear testwith less than 45% having completed at least one lifetime test. The lack of health insurance coverage was a barrier toparticipate in screening tests. Furthermore some people would not select to be screened only because they do not knowhow or where they can receive these services. Conclusion: Low awareness and suboptimal use of screening tests inIran calls for effective programs to enhance intention and compliance to screening, improving the patient-physiciancommunication, identifying barriers for screening and providing tailored public awareness and screening programs. PMID- 29281866 TI - Comparative Diagnostic Performance of Ultrasonography and 99mTc-Sestamibi Scintigraphy for Parathyroid Adenoma in Primary Hyperparathyroidism; Systematic Review and Meta- Analysis AB - Objective: Ultrasonography (US) and parathyroid scintigraphy (PS) with 99mTc-MIBI are common methods forpreoperative localization of parathyroid adenomas but there discrepancies exist with regard to diagnostic accuracy.The aim of the study was to compare PS and US for localization of parathyroid adenoma with a systematic reviewand meta-analysis of the literature. Methods: Pub Med, Scopus (EMbase), Web of Science and the reference lists ofall included studies were searched up to 1st January 2016. The search strategy was according PICO characteristics.Heterogeneity between the studies was accounted by P < 0.1. Point estimates were pooled estimate of sensitivity,specificity and positive predictive value of SPECT and ultrasonography with 99% confidence intervals (CIs) by poolingavailable data. Data analysis was performed using Meta-DiSc software (version 1.4). Results: Among 188 studies andafter deletion of duplicated studies (75), a total of 113 titles and abstracts were studied. From these, 12 studies wereselected. The meta-analysis determined a pooled sensitivity for scintigraphy of 83% [99% confidence interval (CI)96.358 -97.412] and for ultra-sonography of 80% [99% confidence interval (CI) 76-83]. Similar results for specificitywere also obtained for both approache. Conclusion: According this meta- analysis, there were no significant differencesbetween the two methods in terms of sensitivity and specificity. There were overlaps in 99% confidence intervals. Alsofeatures of the two methods are similar. PMID- 29281867 TI - Breast Cancer Risk From Modifiable and Non-Modifiable Risk Factors among Women in Southeast Asia: A Meta-Analysis AB - Objective: The aim of this study was to determine breast cancer risk from modifiable and non-modifiable factorsamong women in Southeast Asia. Methods: This meta-analysis was performed on research articles on breast cancer riskfactors in PubMed, ProQuest and EBSCO databases published between 1997 and October 2017. Pooled odds ratios (OR)are calculated using fixed and random-effect models. Data were processed using Review Manager 5.3 (RevMan 5.3).Results: From a total of 1,211 articles, 15 studies (1 cohort and 14 case control studies) met the criteria for systematicreview. Meta-analysis results showed that of the known modifiable risk factors for breast cancer, parity (nulipara) hadthe highest odd ratio (OR = 1.85 [95% CI 1.47-2.32]) followed by body mass index (overweight) (OR = 1.61 [95%CI 1.43-1.80]) and use of oral contraceptives (OR = 1.27 [95% CI 1.07 1.51]). Of non-modifiable risk factors, familyhistory of breast cancer had the highest odd ratio (OR = 2.53 [95% CI 1.25-5.09]), followed by age (>= 40 years)(OR = 1.53 [95% CI 1.34-1.76]) and menopausal status (OR = 1.44 [95% CI 1.26-1.65]). Conclusion: This analysisconfirmed associations between both modifiable risk factors (parity, body mass index and use of oral contraceptives)and non-modifiable risk factors (family history of breast cancer, age and menopausal status) with breast cancer. PMID- 29281868 TI - Positive Effects of Cognitive Behavioral Therapy on Depression, Anxiety and Stress of Family Caregivers of Patients with Prostate Cancer: A Randomized Clinical Trial AB - Background: The family caregivers of patients with cancer mightexperience various physical, mental, andspiritual difficulties, the neglect of which can causeseriousproblems for theentirefamily. If caregivers are left withoutappropriate treatment and intervention, their level of physical and mental health will substantially decrease-they will,in other words, become"hidden patients." Materials and Methods: The current study is a clinical trial of 80 familycaregivers of patients with prostate cancer, who were allocated to control and experimental groups. The experimentalgroup received 10 sessions of group cognitive behavioral therapy. The 21-item Depression Anxiety Stress Scales werecompleted before the intervention as well4 and 8 weeks after. Data were analyzed using descriptive statistics (meansand standard deviations) andvariousstatistical tests. Results: The results showed thatthecognitivebehavioral interventionreduceddepression, anxiety, and stress among familycaregivers. Conclusion: Because of the positive impact of thisintervention, its implementation in clinical care by nurses is recommended. PMID- 29281869 TI - Pattern of Pediatric Oncology Cases in the Western Region of Nepal AB - Childhood cancers form a rare and heterogeneous group which fortunately have a higher cure rate than adultcancers. A few non-profit organizations in Nepal have extended support to help patients suffering from cancer, buttheir main focus has been on adults. The objective of this study was to establish the pattern of childhood cancers in theWestern region of Nepal. We reviewed cases receiving external radiotherapy with both palliative and curative intentbetween 28th September 2010 and 30th September 2015 at the Department of Radiotherapy and Oncology, ManipalTeaching Hospital affiliated with Manipal College of Medical Sciences, Pokhara, Nepal. Of the total of 1217 cases,2.71% involved children. The gender distribution showed a male preponderance (M:F= 1.35:1). The patients' meanage was 11.4 years (range 2 - 14 years). Considering the caste, Brahmins and Gurungs constituted 33.0% and 21.2%,respectively, of children with cancer. PMID- 29281871 TI - Fine-Needle Aspiration Cytology of Carcinosarcoma in the Salivary Gland: An Extremely Rare Case Report. AB - Carcinosarcoma of the salivary gland is an extremely rare tumor that is composed of both malignant epithelial and mesenchymal components. Diagnosing carcinosarcoma with fine-needle aspiration cytology is challenging because of its overlapping cytomorphologic characteristics with other high-grade malignant salivary gland tumors. Among the many features, including pleomorphic oncocytoid epithelial components, necrotic background, and mitoses, recognizing the singly scattered atypical spindle cells is most essential in carcinosarcoma. We present a case of a 66-year-old male patient with characteristic features of carcinosarcoma, who was successfully treated by wide local excision and subsequent radiation therapy. PMID- 29281870 TI - Histopathological evaluation of liver fibrosis and cirrhosis regression. AB - The hepatic repair complex in the setting of cirrhosis has received increasing attention, as it implies the regression of cirrhosis, which was traditionally taken to be an irreversible state. In this brief review, the patterns of fibrosis, the existing staging systems for chronic liver disease and the histopathological features of cirrhosis regression are discussed. PMID- 29281872 TI - Prognoses and Clinical Outcomes of Primary and Recurrent Uveal Melanoma. AB - PURPOSE: Uveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood ofrecurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters. Materials and Methods: Prognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy. RESULTS: Forty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)-negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter >= 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival. CONCLUSION: Risk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes. PMID- 29281873 TI - Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer. AB - PURPOSE: Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored. Materials and Methods: Safety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectiveswere exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered. RESULTS: Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade >= 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastrointestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002). CONCLUSION: This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors. PMID- 29281874 TI - Survival and Functional Outcome after Treatment for Primary Base of Tongue Cancer: A Comparison of Definitive Chemoradiotherapy versus Surgery Followed by Adjuvant Radiotherapy. AB - PURPOSE: The purpose of this study was to compare the clinical and functional outcomes in patients with primary base of tongue (BOT) cancer who received definitive radiotherapy (RT) or surgery followed by radiotherapy (SRT). Materials and Methods: Between January 2002 andDecember 2016, 102 patientswith stage I-IVB primary BOT cancer underwent either definitive RT (n=46) or SRT (n=56), and treatment outcomeswere compared between two groups. The expression of p16 was also analyzed. RESULTS: The RT group had more patients with advanced T stage (T3 4) disease (58.7% vs. 35.7%, p=0.021) and who received chemotherapy (91.3% vs. 37.5%, p < 0.001) than the SRT group. At a median followup of 36.9 months (range, 3.3 to 181.5 months), the 5-year overall survival (OS) and disease-free survival (DFS) were 75.5% and 68.7%, respectively. With respect to treatment group, the 5 year OS and DFS in the RT and SRT groups did not differ significantly (OS, 68.7% vs. 80.5%, p=0.601; DFS, 63.1% vs. 73.1%, p=0.653). In multivariate analysis, OS differed significantly according to p16 expression (p16-negative vs. p16- positive; hazard ratio [HR], 0.145; 95% confidence interval [CI], 0.025 to 0.853; p=0.033). Regarding DFS, p16 expression (p16-negative vs. p16-positive; HR, 0.164; 95% CI, 0.045 to 0.598; p=0.006) showed a significant effect in multivariate analysis. Functional defects (late grade >= 3 dysphagia or voice alteration) were more frequently reported in the SRT than in the RT group (16.1% vs. 2.2%, p=0.021). CONCLUSION: Despite advanced disease, patients in the RT group showed comparable survival outcomes and better functional preservation than those in the SRT group. PMID- 29281875 TI - Knowledge, Attitudes, Preventive Practices and Screening Intention about Colorectal Cancer and the Related Factors among Residents in Guangzhou, China AB - Background: In Guangzhou, China, colorectal cancer (CRC) is the second most commonly diagnosed cancer.The government initiated a CRC screening program in 2015, and investigating the knowledge, attitudes, and practicestoward CRC would help facilitate the participation of the program. Methods: A cross-sectional survey was conductedfrom October 2014 to September 2015. Questionnaires were passed out with a cluster sample in 15 randomly selectedprimary schools of Guangzhou China, and one of each student's family members aged between 20 to 65 years oldwere included. Results: A total of 6839 questionnaires were obtained and the successful response rate was 78.5%.The majority (88.3%) of them were under 46 years old and female subjects accounted for 65.8%. Over 80% of therespondents knew that CRC was able to be cured by early diagnosis and treatment and that tobacco use, alcohol abuse,and dietary without enough fruits or vegetables may increase the risk of CRC, although a few knowledge scores wererelatively low, such as physical exercise as a protective factor and bowel habits change as a symptom suggestive ofCRC. In contrast, only 52.2% of the subjects were sure to participate in a future CRC screening provided by localgovernment. We further found that the higher level of knowledge about CRC risk and positive cancer preventive attitudeand practice were associated with higher education level, female gender, and positive family history. Conclusion: Theseresults suggested that the priority may be laid on improving the conversion from knowledge to practice to implementscreening program in Guangzhou, while efforts should also be made to improve public awareness about CRC. PMID- 29281876 TI - Concentration- Dependent Effects of Curcumin on 5-Fluorouracil Efficacy in Bladder Cancer Cells AB - Purpose: Curcumin (Cur), a herbal ingredient with anticancer properties, has been shown to inhibit growth ofmalignant cells in vivo and in vitro. However, studies on combination therapy of Cur with chemotherapeutic drugshave been limited. Here, effects of Cur on the cytotoxicity of 5-Fluorouracil (FU) were investigated with epithelialbladder cancer cells (EJ138) in vitro. Methods: EJ138 cells were treated with 5 and 15 MUM of Cur and/ or 100 MUMof FU. Cell viability was measured by sulforhodamine B colorimetric assay. The glucose concentration as an indexof cell metabolism was evaluated by an enzymatic method. Total oxidant and antioxidant capacities were estimatedby the ferrous oxidation-xylenol (FOX1) method and ferric reducing antioxidant power assay (FRAP), respectively.Results: Combination of 5 MUM Cur with FU significantly reduced its cytotoxicity in EJ138 cells, while 15 MUM Curcaused an opposite increase. Significant increase in glucose concentration at 24 h and decrease in the FRAP value at 48h incubation was observed in cells treated with FU in combination with Cur. There were no significant changes in totaloxidant capacity with the combination therapy. Conclusion: Our findings suggest a crucial role of Cur concentrationin regulating chemotherapeutic agent-induced cytotoxicity. Further investigations are needed to understand the precisemechanisms of action of Cur and determine appropriate doses with combination therapy for clinical application againsthuman cancers. PMID- 29281877 TI - Cellular and Molecular Changes in MNU-Induced Breast Tumours Injected with PF4 or bFGF AB - Background: Angiogenic activity has been considered to reflect important molecular events during breast tumourdevelopment. The present study concerned cellular and molecular changes of MNU-induced breast tumours subjectedto promotion and suppression of angiogenesis. Methods: Female Sprague Dawley rats at the age of 21 days receivedMNU at the dose 70 mg/kg of body weight by intraperitoneal injection. Three months post-carcinogen initiation,mammary tumours were palpated and their growth was monitored. When the tumour diameter reached 1.0 +/- 0.05 cm,rats were given bFGF or PF4 intratumourally at a dose of 10 MUg/tumour. Entire palpable tumour were subsequentlyexcised and subjected to histology examination, IHC staining, and RT-PCR. Results: No critical morphological changeswere observed between pro-angiogenic factor, bFGF, and control groups. However, increase of tumour size with morenecrotic and diffuse areas was notable in tumours after anti-angiogenic PF4 intervention. ER and PR mRNA expressionwas significantly up- and down-regulated in bFGF and PF4 groups, respectively. The trends were significantly associatedwith peri- and intratumoural MVD counts. However, irrespective of whether we promoted or inhibited angiogenesis,the expression of EGFR and ERBB2 continued to be significantly increased but this was not significantly associatedwith the MVD score. No significant differences in E-cadherin and LR gene expression were noted between interventionand control groups. Conclusion: ER and PR receptor expression shows consistent responses when tumour angiogenesisis manipulated either positively or negatively. Our study adds to current understanding that not only do we need totarget hormonal receptors, as presently practiced, but we also need to target endothelial receptors to successfully treatbreast cancer. PMID- 29281878 TI - Synthesis of (Hexaconazole-Zinc/Aluminum-Layered Double Hydroxide Nanocomposite) Fungicide Nanodelivery System for Controlling Ganoderma Disease in Oil Palm. AB - A fungicide, hexaconazole was successfully intercalated into the intergalleries of zinc/aluminum-layered double hydroxide (ZALDH) using the ion-exchange method. Due to the intercalation of hexaconazole, the basal spacing of the ZALDH was increased from 8.7 A in ZALDH to 29.4 A in hexaconazole-intercalated ZALDH (HZALDH). The intercalation of hexaconazole into the interlayer of the nanocomposite was confirmed using the Fourier-transform infrared (FTIR) study. This supramolecular chemistry intercalation process enhanced the thermal stability of the hexaconazole moiety. The fungicide loading was estimated to be 51.8%. The nanodelivery system also shows better inhibition toward the Ganoderma boninense growth than the counterpart, free hexaconazole. The results from this work have a great potential to be further explored for combating basal stem rot (BSR) disease in oil palm plantation. PMID- 29281879 TI - Synthesis of Polysubstituted 3-Aminothiophenes from Thioamides and Allenes via Tandem Thio-Michael Addition/Oxidative Annulation and 1,2-Sulfur Migration. AB - A facile synthetic method for the construction of 3-aminothiophenes from readily available thioamides and alllenes in the presence of a TBAI/TBHP catalyst system was developed. This protocol represents an efficient and straightforward way to access highly functionalized thiophenes in moderate to excellent yields under mild conditions, via a tandem thio-Michael addition, oxidative annulation, and 1,2-sulfur migration pathway. PMID- 29281880 TI - Flow-Cell-Induced Dispersion in Flow-through Absorbance Detection Systems: True Column Effluent Peak Variance. AB - Following a brief overview of the emergence of absorbance detection in liquid chromatography, we focus on the dispersion caused by the absorbance measurement cell and its inlet. A simple experiment is proposed wherein chromatographic flow and conditions are held constant but a variable portion of the column effluent is directed into the detector. The temporal peak variance (sigmat,obs2), which increases as the flow rate (F) through the detector decreases, is found to be well-described as a quadratic function of 1/F. This allows the extrapolation of the results to zero residence time in the detector and thence the determination of the true variance of the peak prior to the detector (this includes contribution of all preceding components). This general approach should be equally applicable to detection systems other than absorbance. We also experiment where the inlet/outlet system remains the same but the path length is varied. This allows one to assess the individual contributions of the cell itself and the inlet/outlet system.to the total observed peak. The dispersion in the cell itself has often been modeled as a flow-independent parameter, dependent only on the cell volume. Except for very long path/large volume cells, this paradigm is simply incorrect. PMID- 29281881 TI - Antibacterial [2-(Methacryloyloxy) ethyl] Trimethylammonium Chloride Functionalized Reduced Graphene Oxide/Poly(ethylene-co-vinyl alcohol) Multilayer Barrier Film for Food Packaging. AB - The objective of present work was to construct antibacterial [2-(methacryloyloxy) ethyl] trimethylammonium chloride functionalized reduced graphene oxide/poly(ethylene-co-vinyl alcohol) (MTAC-rGO/EVOH) multilayer barrier films by using layer-by-layer assembly under a parallel electric field. Besides barrier and mechanical properties, the antibacterial activities of the film and cytotoxicity of MTAC-rGO nanosheets were extensively investigated. The functionalization of rGO was achieved by grafting MTAC onto a graphene framework through C (sp3)-C bonds. The assembly of MTAC-rGO on the EVOH matrix not only significantly improved film mechanical strength, but also endowed the targeting film with outstanding moisture barrier even under a relative humidity of 99% (e.g., 0.019 g m-2 s-1 atm-1 for (MTAC-rGO/EVOH)20) besides good oxygen barrier (e.g., 0.07 cm3 m-2 d-1 atm-1 for (MTAC-rGO/EVOH)20). Among the testing films, MTAC-rGO/EVOH film had the best antibacterial activity, and the activity against S. aureus was better than E. coli. Meanwhile, the cytotoxicity of MTAC-rGO nanosheets was very low. Results suggest that MTAC-rGO/EVOH film may have great potential in food active packaging. PMID- 29281882 TI - Bioaccumulation of CeO2 Nanoparticles by Earthworms in Biochar-Amended Soil: A Synchrotron Microspectroscopy Study. AB - The interactions of nanoparticles (NPs) with biochar and soil components may substantially influence NP availability and toxicity to biota. In the present study, earthworms ( Eisenia fetida) were exposed for 28 days to a residential or agricultural soil amended with 0-2000 mg of CeO2 NP/kg and with biochar (produced by the pyrolysis of pecan shells at 350 and 600 degrees C) at various application rates [0-5% (w/w)]. After 28 days, earthworms were depurated and analyzed for Ce content, moisture content, and lipid peroxidation. The results showed minimal toxicity to the worms; however, biochar (350 or 600 degrees C) was the dominant factor, accounting for 94 and 84% of the variance for the moisture content and lipid peroxidation, respectively, in the exposed earthworms. For both soils with 1000 mg of CeO2/kg at 600 degrees C, biochar significantly decreased the accumulation of Ce in the worm tissues. Amendment with 350 degrees C biochar had mixed responses on Ce uptake. Analysis by micro X-ray fluorescence (MU-XRF) and micro X-ray absorption near edge structure (MU-XANES) was used to evaluate Ce localization, speciation, and persistence in CeO2- and biochar exposed earthworms after depuration for 12, 48, and 72 h. Earthworms from the 500 mg of CeO2/kg and 0% biochar treatments eliminated most Ce after a 48 h depuration period. However, in the same treatment and with 5% BC-600 (biochar pyrolysis temperature of 600 degrees C), ingested biochar fragments (~50 MUm) with Ce adsorbed to the surfaces were retained in the gut after 72 h. Additionally, Ce remained in earthworms from the 2000 mg of CeO2/kg and 5% biochar treatments after depuration for 48 h. Analysis by MU-XANES showed that, within the earthworm tissues, Ce remained predominantly as Ce4+O2, with only few regions (2-3 MUm2) where it was found in the reduced form (Ce3+). The present findings highlight that soil and biochar properties have a significant influence in the internalization of CeO2 NPs in earthworms; such interactions need to be considered when estimating NP fate and effects in the environment. PMID- 29281883 TI - Establishing an Artificial Pathway for Efficient Biosynthesis of Hydroxytyrosol. AB - Hydroxytyrosol (HT) is a valuable natural phenolic compound with strong antioxidant activity and various physiological and pharmaceutical functions. In this study, we established an artificial pathway for HT biosynthesis. First, efficient enzymes were selected to construct a tyrosol biosynthetic pathway. Aro10 from Saccharomyces cerevisiae was shown to be a better ketoacid decarboxylase than Kivd from Lactococcus lactis for tyrosol production. While knockout of feaB significantly decreased accumulation of the byproduct 4 hydroxyphenylacetic acid, overexpression of alcohol dehydrogenase ADH6 further improved tyrosol production. The titers of tyrosol reached 1469 +/- 56 mg/L from tyrosine and 620 +/- 23 mg/L from simple carbon sources, respectively. The pathway was further extended for HT production by overexpressing Escherichia coli native hydroxylase HpaBC. To enhance transamination of tyrosine to 4 hydroxyphenylpyruvate, NH4Cl was removed from the culture media. To decrease oxidation of HT, ascorbic acid was added to the cell culture. To reduce the toxicity of HT, 1-dodecanol was selected as the extractant for in situ removal of HT. These efforts led to an additive increase in HT titer to 1243 +/- 165 mg/L in the feeding experiment. Assembly of the full pathway resulted in 647 +/- 35 mg/L of HT from simple carbon sources. This work provides a promising alternative for sustainable production of HT, which shows scale-up potential. PMID- 29281884 TI - Binary Colloidal Crystal Layers as Platforms for Surface Patterning of Puroindoline-Based Antimicrobial Peptides. AB - The ability of bacteria to form biofilms and the emergence of antibiotic resistant strains have prompted the need to develop the next generation of antibacterial coatings. Antimicrobial peptides (AMPs) are showing promise as molecules that can address these issues, especially if used when immobilized as a surface coating. We present a method that explores how surface patterns together with the selective immobilization of an AMP called PuroA (FPVTWRWWKWWKG-NH2) can be used to both kill bacteria and also as a tool to study bacterial attachment mechanisms. Surface patterning is achieved using stabilized self-assembled binary colloidal crystal (BCC) layers, allowing selective PuroA immobilization to carboxylated particles using N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) hydrochloride/N-hydroxysuccinimide (NHS) coupling chemistry. Covalent immobilization of PuroA was compared with physical adsorption (i.e., without the addition of EDC/NHS). The AMP-functionalized colloids and BCC layers were characterized by X-ray photoelectron spectroscopy, zeta potentials, and matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Surface antimicrobial activity was assessed by viability assays using Escherichia coli. MALDI-TOF MS analysis revealed that although not all of PuroA was successfully covalently immobilized, a relatively low density of PuroA (1.93 * 1013 molecules/cm2 and 7.14 * 1012 molecules/cm2 for covalent and physical immobilization, respectively) was found to be sufficient at significantly decreasing the viability of E. coli by 70% when compared to that of control samples. The findings provide a proof of concept that BCC layers are a suitable platform for the patterned immobilization of AMPs and the importance of ascertaining the success of small-molecule grafting reactions using surface MALDI, something that is often assumed to be successful in the field. PMID- 29281885 TI - Nickel-Catalyzed Reductive Etherification of Aldehydes at Room Temperature: C-O vs C-C Bond Formation. AB - The reaction of secondary and tertiary benzyl alcohols activated by 2,4,6 trichloro-1,3,5-triazine (TCT) with aldehydes in the presence of NiCl2.dmg as a precatalyst in ethylene glycol afforded ethers at room temperature. A selective C O vs C-C bond formation was observed for the secondary and tertiary benzyl alcohols in comparison with primary ones. PMID- 29281886 TI - Is the Supporting Information the Venue for Reproducibility and Transparency? PMID- 29281887 TI - What is "New Physical Insight" in Surface Photocatalytic Water Splitting? PMID- 29281888 TI - Is the Supporting Information the Venue for Reproducibility and Transparency? PMID- 29281889 TI - Discovery of a semi-synthesized cyclolignan as a potent HIV-1 non-nucleoside reverse transcriptase inhibitor. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S) 3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 MUmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs. PMID- 29281890 TI - Analysis of "Dose Accuracy, Injection Force, and Usability Assessment of a New Half-Unit, Prefilled Insulin Pen". AB - Half-unit insulin pens (HUPs) offer finer gradation of insulin dosing than their integer-unit counterparts, tackling the inaccuracies of dose rounding that make it difficult for insulin-sensitive populations to achieve tight glycemic control. This article analyzes the first prefilled HUP, the Humalog Junior KwikPen, in the context of other, similar devices and the developing landscape of smart insulin pens. The Junior KwikPen's suitability for pediatric patients is assessed in reference to a recent study surveying its accuracy and usability under varying conditions intended to simulate real-world use. PMID- 29281891 TI - The Current Intermittent-Scanning CGM Device Situation in Japan: Only Adjunctive Use to SMBG Is Approved and the Latest Health Insurance Coverage Details. PMID- 29281892 TI - May the Z-Tracking Technique to Minimize or Avoid the Pain of Insulin Injection Be an Alternative to the 10-Second Waiting Technique? PMID- 29281893 TI - Adherence Over Time: The Course of Adherence to Customized Diabetic Insoles as Objectively Assessed by a Temperature Sensor. AB - BACKGROUND: Temperature sensors are an objective way to assess adherence to diabetic footwear. Good adherence is essential for the prevention of diabetic foot problems. Little is known about the long-term course of adherence in patients at risk for diabetic foot problems. METHOD: A temperature sensor was incorporated into the specialized footwear of patients with type 2 diabetes after their first plantar ulceration. Kaplan-Meier curve was used to analyze when patients started to become nonadherent (not wearing the footwear for two straight weeks). Gender effects on adherence were also analyzed. RESULTS: 26 patients with a mean observation time of 133.5 days could be analyzed. Mean wearing time of diabetic footwear was 4.2 +/- 3.6 h/day (Mdn = 3.4 h/day; interquartile range = 0.5-7.0 h/day) and on 51% of the days patients did not wear their footwear at all. Kaplan-Meier curve revealed that the mean time of adherence was 27.5 weeks. Men achieved a mean time of adherence of 30.5 weeks, while women only achieved 14 weeks. However, due to the small sample size, this difference was not statistically significant. CONCLUSIONS: Temperature sensors revealed a low long term adherence to diabetic footwear. Women seemed to be at a higher risk for earlier nonadherent behavior. Adherence to diabetic footwear should be closely monitored and tailored intervention strategies should be developed. PMID- 29281894 TI - Adeno-Associated Virus Serotype 2 Vector-Mediated Reintroduction of microRNA-19b Attenuates Hepatic Fibrosis. AB - Fibrotic liver injury is a significant healthcare burden in the United States. It represents a major cause of morbidity and mortality for which there are no effective Food and Drug Administration-approved treatment strategies. Fibrosis is considered a disruption of the normal wound healing responses mediated by fibroblastic cells, which are triggered and sustained by pro-fibrotic cytokines such as transforming growth factor beta 1 (TGF-beta1). TGF-beta1-mediated trans differentiation of hepatic stellate cells (HSCs) from quiescent to activated myofibroblasts is a pivotal event in the development of fibrosis. Activation is accompanied by global changes in microRNA (miR) expression. It has been previously reported that miR19b is decreased in activated HSCs and contributes to increased expression of TGF-beta receptor II and connective tissue growth factor, both confirmed targets of miR19b. An adeno-associated virus serotype 2 vector (AAV2) with a miR19b transgene downstream of enhanced green fluorescent protein under the murine collage alpha 1(I) promoter was developed specifically to target HSCs. Male Sprague Dawley rats (250 g) underwent sham or bile-duct ligation (BDL) surgery. Directly after BDL, rats received AAV2-miR19b, AAV2-control, or vehicle normal saline (NS) by portal-vein injection. After 2 weeks, the animals were euthanized, and blood was collected for alanine and aspartate aminotransferase, total and direct bilirubin, and alkaline phosphatase. Tissue was collected for RNA and protein extraction and histology. Fibrosis and measures of hepatic injury were significantly reduced in AAV2-miR19b-treated rats in combination with significant improvements in total and direct bilirubin. Histological analysis of collagen by PicroSirius Red staining revealed a ~50% reduction compared to AAV2 control or NS-injected animals. Pro-fibrotic markers, smooth-muscle alpha-actin, TGF-beta receptor II, and collagen alpha 2(I) mRNA and protein were significantly decreased compared to AAV2-control and NS groups. AAV2-mediated reintroduction of miR-19b, specifically expressed in HSCs, improved liver function, inhibited fibrosis, and improved measures of hepatic injury in a BDL model. PMID- 29281895 TI - Underreporting of Gender and Race/Ethnicity Differences in NIH-Funded Dementia Caregiver Support Interventions. AB - Women and racial/ethnic minority dementia caregivers have unique caregiving experiences and support needs. To ensure the identification of potentially important differences in outcomes within these groups, the amended National Institutes of Health (NIH) Policy on Inclusion of Women and Minorities mandates reporting by gender and race/ethnicity. The objective of this study was to determine the inclusion and reporting rates among NIH-funded dementia caregiver support interventions. A focused systematic literature review of studies published from 1994 to 2015 located 48 articles meeting inclusion criteria. The majority of studies included women and racial/ethnic minorities; however, 67% did not report results by gender or racial/ethnic group. Acknowledgment of underreporting was more common for race/ethnicity than gender. Our findings suggest limited NIH guideline compliance that may reflect a lack of awareness regarding potential gender disparities in caregiving roles. Ensuring NIH guideline compliance necessitates shared investments from researchers, editors, and reviewers to ensure group differences are systematically identified and reported. PMID- 29281896 TI - The Norwegian Computerized Adaptive Test of Personality Disorder-Static Form (CAT PD-SF): Reliability, Factor Structure, and Relationships With Personality Functioning. AB - The Computerized Adaptive Test of Personality Disorder-Static Form (CAT-PD-SF) is a self-report inventory developed to assess pathological personality traits. The current study explored the reliability and higher order factor structure of the Norwegian version of the CAT-PD-SF and the relationships between the CAT-PD traits and domains of personality functioning in an undergraduate student sample ( N = 375). In addition to the CAT-PD-SF, the short form of the Severity Indices of Personality Problems and the Brief Symptom Inventory were administered. The results showed that the Norwegian CAT-PD-SF has good score reliability. Factor analysis of the CAT-PD-SF scales indicated five superordinate factors that correspond to the trait domains of the alternative DSM-5 model for personality disorders. The CAT-PD traits were highly predictive of impaired personality functioning after controlling for psychological distress. It is concluded that the CAT-PD-SF is a promising tool for the assessment of personality disorder traits. PMID- 29281897 TI - The General Factor of Well-Being: Multinational Evidence Using Bifactor ESEM on the Mental Health Continuum-Short Form. AB - The Mental Health Continuum-Short Form (MHC-SF) is a widely used scale aimed at assessing three components of well-being: emotional, social, and psychological. The factor structure of the MHC-SF has been under debate over the past 10 years. The main goal of the present study was to examine the dimensionality of the MHC SF. Confirmatory factor analyses (CFA), bifactor CFA, exploratory structural equation modeling (ESEM), and bifactor ESEM were used to evaluate competing models of the MHC-SF structure. The total sample consisted of 7,521 participants from four countries: The Netherlands, Poland, Portugal, and Serbia. The results indicated that the three CFA factors were very highly related, and that a bifactor ESEM model provided the best fit to the data in all samples. Our findings provided support for the bifactor structure of well-being with a strong general factor explaining most of the variance in the items. PMID- 29281898 TI - alpha-glucosidase inhibitors isolated from Mimosa pudica L. AB - The aim of the study was to isolate digestive enzymes inhibitors from Mimosa pudica through a bioassay-guided fractionation approach. Repeated silica gel and sephadex LH 20 column chromatographies of bioactive fractions afforded stigmasterol, quercetin and avicularin as digestive enzymes inhibitors whose IC50 values as compared to acarbose (351.02 +/- 1.46 MUg mL-1) were found to be as 91.08 +/- 1.54, 75.16 +/- 0.92 and 481.7 +/- 0.703 MUg mL-1, respectively. In conclusion, M. pudica could be a good and safe source of digestive enzymes inhibitors for the management of diabetes in future. PMID- 29281899 TI - Forsskamide, a new ceramide from aerial parts of Forsskaolea tenacissima Linn. AB - Although the various folk medicine uses and the biological activity of Forsskaolea tenacissima L., few chemical constituents of this plant have been reported, this provoked us to make our study. Forsskamide, a new ceramide was isolated from aerial parts of F. tenacissima L. (Urticaceae). The chemical structure was established by different spectroscopic methods (1H, 13C-NMR, HMBC, HSQC, ROESY, FAB-MS and HR-FAB-MS). Forsskamide showed a moderate cytotoxic activity by (MTT) method against human colorectal carcinoma cell line (HCT-116) with IC50 33.25 MUM in comparison with 5-fluorouracil IC50 26.42 MUM. While, it did not show any activity against human hepatocarcinaoma cell line (HepG-2). PMID- 29281900 TI - Nangallenes A and B, halogenated nonterpenoid C15-acetogenins from the Bornean red alga Laurencia nangii. AB - Two new halogenated nonterpenoids C15-acetogenins, nangallenes A-B (1-2), together with two known halogenated compounds itomanallene A (3) and 2,10-dibromo 3-chloro-alpha-chamigrene (4), were isolated and identified from the organic extract of the marine red alga Laurencia nangii Masuda collected from the coastal waters in Semporna, Borneo. Their structures were established by means of spectroscopic analysis including IR, high-resolution electrospray ionization mass spectrometry (HRESI-MS), and 1D and 2D NMR techniques. All these metabolites were submitted for the antifungal assay against four species of selected marine fungi. Compounds 1-4 showed potent activity against Haliphthoros sabahensis and Lagenidium thermophilum. PMID- 29281901 TI - New 2-arylbenzofurans from the root bark of Artocarpus gomezianus and their alpha glucosidase inhibitory activity. AB - Two new 2-arylbenzofurans, namely 13-O-methyllakoochin B (1) and artogomezianin (2), were isolated from the root bark of Artocarpus gomezianus, along with six known compounds (3-8). The structures of new compounds were determined by spectroscopic and chemical methods. All of the isolates were evaluated for their alpha-glucosidase inhibitory activity. Artogomezianin (2) and lakoochin A (3) exhibited strong alpha-glucosidase inhibitory activity with IC50 values of 18.25 and 26.19 uM, respectively, as compared with the positive control acarbose. PMID- 29281902 TI - Treatment of Uterine Sarcoma with rAd-p53 (Gendicine) Followed by Chemotherapy: Clinical Study of TP53 Gene Therapy. AB - This study evaluated the efficacy of rAd-p53 (Gendicine(r)) followed by chemotherapy for the treatment of uterine sarcoma. Twelve cases of uterine sarcoma treated at Shengjing Hospital were retrospectively analyzed. Among the 12 patients, one had primary cancer, and 11 had recurrent cancer. For the recurrent cases, the interval between the first operation and diagnosis of recurrence, or progression-free survival time 1 (PFS1), was 1-18 months (median 3 months). All patients were treated with local application of rAd-p53 followed by chemotherapy (local injection of bleomycin and i.v. infusion of cisplatin, epirubicin, and isocyclophosphamide). Efficacy was evaluated, and the rates of complete remission (CR) and partial remission (PR) were calculated. During follow-up, PFS time 2 (PFS2) after the baseline period and overall survival (OS) time after the baseline period of rAd-p53 treatment data were obtained. The treatment resulted in one CR, seven PR, three with stable disease (SD), and one with progressive disease (PD). The remission rate (CR + PR) was 66.7%, and the responsive (CR + PR + SD) rate was 91.7%. PFS2 ranged from 2 to 62 months, with a median of 13 months, which is 10 months longer than that of PFS1; this difference was statistically significant (p = 0.0038). The OS time ranged from 6 to 62 months, with a median of 24 months. Following the combined treatment, four of the patients underwent a second debulking surgery. Of the two patients with liver metastases, one had CR of liver foci, and one had PR. Up to the follow-up date of the two patients who survived, one was tumor-free for 60 months. The PFS2 for the other patient was 39 months. This patient survived with tumor for 53 months with slow disease progression. The remaining 10 patients died. Local application of rAd-p53 combined with local injection of bleomycin and intravenous infusion of cisplatin, epirubicin and isocyclophosphamide was effective for treatment of uterine sarcoma, especially for patients with liver metastases. For patients with uterine sarcoma who do not have the opportunity for surgery, this regimen can be used as a new adjuvant therapy to obtain a surgical opportunity that allows further debulking of the tumor mass. PMID- 29281903 TI - Assessment of FGFR1 Over-Expression and Over-Activity in Lung Cancer Cells: A Toolkit for Anti-FGFR1 Drug Screening. AB - Lung cancer, caused mainly by smoking, is one of the most prevalent diseases in China, resulting in high mortality rates. The increasing incidence of chronic disease due to lung cancer places a huge burden on the welfare and cost to the Chinese society. Amplification of the fibroblast growth factor receptor 1 (FGFR1) is associated with high incidence and mortality in lung cancer patients. FGFR1 signaling is implicated in oncogenic traits such as proliferation, cell survival, angiogenesis, and migration. Targeting FGFR1 and its ligand basic FGF (bFGF) is a key step forward in developing new therapies for this crippling disease. Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer. In this study, A549, a lung adenocarcinoma cell line widely used in vitro as a model for drug metabolism and as a transfection host, was used to study FGFR1. A stable lentiviral FGFR1 over-expression system in lung cancer cells is described for the study of anti-lung cancer drug candidates targeting FGFR1. Ligand binding to FGFR1 activates the PI3K/Akt/mTOR signaling pathway and increases adhesion, invasion, and migration in this model. Using a unique FGF monoclonal antibody developed in the laboratory, the overactive PI3K pathway was effectively blocked, abrogating the negative metastatic signaling pathways in lung cancer cells. Importantly, this model provides an effective and simple screening kit for anti FGF1 drug compounds for lung cancer treatment and a tool for understanding the molecular mechanisms of the FGFR1 signaling pathway in lung cancer. Furthermore, this toolkit based on a FGFR1 lentiviral construct model is transferrable to study FGFR1 signaling in any type of cancer cell. PMID- 29281904 TI - Laccase grafted membranes for advanced water filtration systems: a green approach to water purification technology. AB - PURPOSE: Conventional wastewater treatment technologies are not good enough to completely remove all endocrine disrupting compounds (EDCs) from the water. Membrane separation systems have emerged as an attractive alternative to conventional clarification processes for waste and drinking water. Coupling of a membrane separation process with an enzymatic reaction has opened up new avenues to further enhance the quality of water. This review article deliberates the feasibility of implementing enzymatic membrane reactors has been deliberated. MATERIALS AND METHODS: A comprehensive study of conventional water treatment technologies was carried out and their shortcomings were pointed out. Research findings from the leading groups working on enzyme grafted membrane based water purification were summarized. This review also comprehends the patent documents pertinent to the technology of enzyme grafted membranes for water purification. RESULTS: Immobilization of an enzyme on a membrane improves the performance of membrane filtration, and processes for the treatment of polluted water. Research has started exploring the potential for laccase enzymes because it can catalyze the oxidation of a wide range of substrates, structurally comparable to EDCs, by a radical-catalyzed reaction mechanism, with corresponding reduction of oxygen to water in an electron transfer process. Further, in the presence of certain mediators, the substrate range of laccases can be further enhanced to non aromatic substrates. CONCLUSIONS: Removal of EDCs by laccase cross-linked enzyme aggregates in fixed-bed reactors or fluidized-bed reactors and laccase immobilized ultrafiltration (LIUF) membranes are proving their worth in water purification technology. The major operational issues with the use of LIUF membranes are enzyme instability in real wastewater and membrane fouling. In view of the above-stated characteristics, laccases are considered as the most promising enzyme for a greener and less expensive water purification technology. PMID- 29281906 TI - CMS Data: One Road to Quality Data Analytics. PMID- 29281907 TI - A new outlook for the British Journal of Community Nursing. PMID- 29281905 TI - Identifying Factors Associated With Mobility Decline Among Hospitalized Older Adults. AB - Hospitalization can negatively affect mobility among older adults. Early detection of older patients most at risk for mobility decline can lead to early intervention and prevention of mobility loss. This study's purpose was to identify factors from the International Classification of Functioning, Disability, and Health associated with mobility decline among hospitalized elders. We conducted a secondary analysis of data from 959 hospitalized adults age 65 and older. We estimated the effects of health conditions and environmental and personal factors on mobility decline using logistic regression. Almost half of the sample declined in mobility function during hospitalization. Younger age, longer length of hospital stay, having a hearing impairment, and non-emergency admit type were associated with mobility decline, after adjusting for covariates. Findings may be used to develop an evidence-based, risk-determination tool for hospitalized elders. Future research should focus on individual, environmental, and policy-based interventions promoting physical activity in the hospital. PMID- 29281908 TI - Examining the context of community nursing in Ireland and the impact of missed care. AB - As populations rise and many global health policies point towards community care, it is important that health care delivery meets demand. In Ireland, a study was undertaken on the level and context of missed care in community nursing. The study used a survey to identify the quantity of, and reasons for, missed care; a reference group to develop possible health economic implications for missed care, and a small sample of semi-structured interviews to consider the macro environment within which missed care occurred. This paper presents the findings of the health economics and qualitative data, and the study's implications for community nursing. PMID- 29281910 TI - Managing urinary incontinence in patients living with dementia. PMID- 29281909 TI - Changing roles in community health care: Delegation of insulin injections to health care support workers. AB - Diabetes is a common long-term condition affecting many people many of whom require support with their insulin injections at home. These injections are often carried out by community nurses if individuals are unable to self-manage their condition. This paper describes a pilot project where health care support workers were trained to administer insulin at home for suitable patients. Four patients took part in the pilot study and two support workers were trained to give the insulin injections. The project was evaluated well by all those who took part. It freed up 80 hours of nursing time while also providing the support workers with an extended scope of practice and associated increased in job satisfaction. No untoward medication errors were reported as a result of this initiative. This project will now be rolled out to the wider nursing teams with a staggered approach to the delivery of the training to ensure there is not a detrimental effect on patient care. PMID- 29281911 TI - Personal beliefs, culture and religion in community nursing care. PMID- 29281912 TI - Managing chronic obstructive pulmonary disease in the community setting. AB - Chronic obstructive pulmonary disease (COPD) is an umbrella term used to describe respiratory diseases characterised by airway obstruction. COPD is now an established and significant chronic disease, killing over 30 000 people in the UK every year. According to the World Health Organization, COPD will become the third biggest killer in the world by 2020. The financial and human cost of the disease is huge. To appreciate the pathophysiology of obstructive pulmonary diseases, it is first necessary to understand a number of important lung concepts. This article discusses the pathophysiology of COPD, highlighting the main mechanisms involved, provides an outline of the associated signs, symptoms and treatment of COPD and explore how health care professionals in the community/residential care settings can help manage and improve the quality of life for patients with COPD. PMID- 29281913 TI - Beginning with the end: The experience of dying in 2018. PMID- 29281914 TI - Are there enough district nurses? PMID- 29281915 TI - Maintaining peristomal skin integrity. PMID- 29281916 TI - Writing for publication: Sharing your clinical knowledge and skills. AB - Clinical nurses are ideally placed to write for publication in addition to those who work in academia who have this as an accepted part of their role. Nurses generate new evidence from their work in practice by carrying out research and audits and being involved in practice development projects, for example. This resource of knowledge needs to be shared with others, ideally in an international arena so that nurses can learn from each other. Nursing in the United Kingdom is now an all graduate profession and many nurses go on to study at both Masters and PhD level, providing writing from all levels of academic study that can be adapted for publication. It seems wrong to undertake a study and obtain findings and then choose not share this widely. Both a lack of confidence and time are cited as reasons why nurses do not write; however, to share knowledge with others is a duty as part of any nursing role for the improvement of staff working practices and patient care. All nurses need knowledge that is practical, experiential, and scientific; clinical nurses who write for publication can provide this. PMID- 29281917 TI - Recording advance decisions to refuse treatment. AB - An NHS trust recently agreed a L45 000 settlement with the family of a woman who was given treatment contrary to her advance decision for some 2 years before she died. In this article, Richard Griffith discusses the requirements for a valid applicable advance decision to refuse treatment and a district nurse's duty to record and give effect to the wishes expressed within it. PMID- 29281918 TI - How Could Agronomic Biofortification of Rice Be an Alternative Strategy with Higher Cost-Effectiveness for Human Iron and Zinc Deficiency in China? AB - BACKGROUND: Iron and zinc deficiencies affect human health globally, especially in developing countries. Agronomic biofortification, as a strategy for alleviating these issues, has been focused on small-scale field studies, and not widely applied while lacking of cost-effectiveness analysis (CEA). OBJECTIVE: We conducted the CEA of agronomic biofortification, expressed as USD per disability adjusted life years (DALYs) saved, to recommend a cost-effectiveness strategy that can be widely applied. METHODS: The DALYs were applied to quantify the health burden due to Fe and/or Zn deficiency and health cost of agronomic biofortification via a single, dual, or triple foliar spray of Fe, Zn, and/or pesticide in 4 (northeast, central China, southeast, and southwest) major Chinese rice-based regions. RESULTS: The current health burden by Fe or Zn malnutrition was 0.45 to 1.45 or 0.14 to 0.84 million DALYs for these 4 regions. Compared to traditional rice diets, the daily Fe and/or Zn intake from Fe and/or Zn biofortified rice increased, and the health burden of Fe and/or Zn deficiency decreased by 28% and 48%, respectively. The cost of saving 1 DALYs ranged from US$376 to US$4989, US$194 to US$2730, and US$37.6 to US$530.1 for the single, dual, and triple foliar Fe, Zn, and/or pesticide application, respectively, due to a substantial decrease in labor costs by the latter 2 applications. CONCLUSIONS: Agronomic biofortification of rice with the triple foliar spray of Fe, Zn, and pesticide is a rapidly effective and cost-effectiveness pathway to alleviate Fe and Zn deficiency for rice-based dietary populations. PMID- 29281919 TI - Terretonin M: A new meroterpenoid from the thermophilic Aspergillus terreus TM8 and revision of the absolute configuration of penisimplicins. AB - Terretonin M (1), a new highly oxygenated tetracyclic meroterpenoid, was isolated from the thermophilic fungus Aspergillus terreus TM8 together with 10 known metabolites: terrelumamide A, asterrelenin, 7-prenyl-indolyl-3-carbaldehyde, (3beta,5alpha,6beta)-3,5,6-trihydroxy-ergosta-7,22-diene, sitostenone, linoleic acid, ergosterol, uracil, p-hydroxy-benzoic acid, and indole-3-carboxylic acid. The chemical structure of the new compound was elucidated by extensive 1D, 2D NMR, and ESI HR mass measurements, and by comparison with literature data. The absolute configuration of 1 was resolved by analysis of its NOESY spectrum and comparison of its experimental ECD spectrum with DFT calculations. In parallel to this work, revision of the absolute configuration of penisimplicins 3a and 3b is proposed on the basis of their ECD and ORD data. The isolation and taxonomic characterisation of A. terreus TM8 is reported, and the antimicrobial activity of the crude extract and the isolated compounds was studied as well. PMID- 29281920 TI - Two new eremophilenolides from the roots of Ligulariopsis shichuana and their anti-phytopathogenic fungal and antifeedant activities. AB - Two new eremophilenolides, ligushicins A (1) and B (2), and two known compounds including beta-sitosterol and ursolic acid were isolated from Ligulariopsis shichuana. The structures of new compounds were established on the basis of 1D and 2D NMR data and HRESIMS data interpretation. The absolute configuration of new compounds was assigned by ECD spectroscopy, and that of ligushicins A (1) was confirmed by X-ray diffraction analysis. The antifungal and antifeedant activities of new compounds were evaluated against four plant pathogenic fungi and third-instar larvae of Plutella xylostella, respectively. Ligushicins A (1) and B (2) exhibited potent antifungal activity against Botrytis cinerea and Fusarium oxysporum with minimum inhibitory concentration (MIC) values ranging from 50 to 100 mg/L, while they also exhibited weak antifeedant activities. PMID- 29281921 TI - Circadian Clearance of a Fungal Pathogen from the Lung Is Not Based on Cell intrinsic Macrophage Rhythms. AB - Circadian rhythms govern immune cell function, giving rise to time-of-day variation in the recognition and clearance of bacterial or viral pathogens; to date, however, no such regulation of the host-fungal interaction has been described. In this report, we use murine models to explore circadian control of either fungal-macrophage interactions in vitro or pathogen clearance from the lung in vivo. First, we show that expression of the important fungal pattern recognition receptor Dectin-1 ( clec7a), from either bone marrow-derived or peritoneum-derived macrophages, is not under circadian regulation at either the level of transcript or cell surface protein expression. Consistent with this finding, the phagocytic activity of macrophages in culture against spores of the pathogen Aspergillus fumigatus also did not vary over time. To account for the multiple cell types and processes that may be coordinated in a circadian fashion in vivo, we examined the clearance of A. fumigatus from the lungs of immunocompetent mice. Interestingly, animals inoculated at night demonstrated a 2 fold enhancement in clearance compared with animals inoculated in the morning. Taken together, our data suggest that while molecular recognition of fungi by immune cells may not be circadian, other processes in vivo may still allow for time-of-day differences in fungal clearance from the lung. PMID- 29281922 TI - Development of a Ternary Near-Infrared Spectroscopy Brain-Computer Interface: Online Classification of Verbal Fluency Task, Stroop Task and Rest. AB - The majority of proposed NIRS-BCIs has considered binary classification. Studies considering high-order classification problems have yielded average accuracies that are less than favorable for practical communication. Consequently, there is a paucity of evidence supporting online classification of more than two mental states using NIRS. We developed an online ternary NIRS-BCI that supports the verbal fluency task (VFT), Stroop task and rest. The system utilized two sessions dedicated solely to classifier training. Additionally, samples were collected prior to each period of online classification to update the classifier. Using a continuous-wave spectrometer, measurements were collected from the prefrontal and parietal cortices while 11 able-bodied adult participants were cued to perform one of the two cognitive tasks or rests. Each task was used to indicate the desire to select a particular letter on a scanning interface, while rest avoided selection. Classification was performed using 25 iteration of bagging with a linear discriminant base classifier. Classifiers were trained on 10-dimensional feature sets. The BCI's classification decision was provided as feedback. An average online classification accuracy of [Formula: see text]% was achieved, representing an ITR of [Formula: see text] bits/min. The results demonstrate that online communication can be achieved with a ternary NIRS-BCI that supports VFT, Stroop task and rest. Our findings encourage continued efforts to enhance the ITR of NIRS-BCIs. PMID- 29281923 TI - Conflicts and con-fusions confounding compassion in acute care: Creating dialogical moral space. AB - BACKGROUND: Compassion, understood as empathy for another who is experiencing physical, mental, emotional and/or spiritual suffering, is an essential element of our shared understandings of nursing and the constitution of the professional nurse. Theoretical foundation: Charles Taylor account of ethics which concerns 'what or who is it good to be' rather than the predominant analytical moral philosophy approach which concentrates on 'what ought one to do' is the core concern of this discussion. An ontological appreciation of our shared human condition is the premise upon which the discussion is based. DISCUSSION: This article proposes that concept by opening a dialogical space, nurses can engage in reflection and sense making wherein they explore individually and collectively the conflicts and confusions encountered in their day-to-day work. Through their dialogues, nurses - individually and collectively - orient and reorient themselves and each other towards what they see as meaningful and purposeful in their lives and in doing so they are well positioned to reaffirm their commitment to compassion as a value which both anchors and orients their day-to-day work. IMPLICATIONS: The provision of opportunities in the workplace, in the form of dialogue, to articulate often unspoken assumptions and frameworks in which nursing work is carried out can not only initiate the building of pathways of support but also assist nurses reaffirm their compassion - arguably the essence of their nursing practice. PMID- 29281924 TI - One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells. AB - Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 uM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase 3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents. PMID- 29281926 TI - Investigation of genotoxic effects of paraben in cultured human lymphocytes. AB - Paraben is a phenolic derivative of benzoic acid extensively used as preservatives in food, pharmaceutical, and cosmetic industries due to its antimicrobial characteristics. The objective of this study was to evaluate the in vitro genotoxic effects of paraben in human lymphocyte cultures. Cells were analyzed by cytokinesis-block micronucleus (CBMN), chromosome aberration (CA), sister chromatid exchange (SCE), and comet tests. For CBMN, CA, and SCE assays, the human lymphocytes were isolated from healthy donors and incubated with 500, 250, 100, and 50 ug/mL of paraben for 24 and 48 h, and for comet assay, cells were exposed to 1000, 750, 500, and 250 ug/mL of paraben for an hour. Results showed that numbers of MN and SCEs were not significant in the cells exposed to paraben when compared to the solvent control. However, 500 and 250 ug/mL of paraben induced the CA after 24 h. Also, we observed a significant decrease in the cytokinesis-block proliferation index in cells exposed 250-500 ug/mL paraben for 24 h, and 100, 250, and 500 ug/mL for 48 h. The mitotic index was also decreased at all concentrations and periods. However, the proliferation index was statistically decreased at all concentrations after 48 h treatments. Only the highest concentration of paraben caused DNA migration (mean tail length) in human lymphocytes analyzed by Comet assay. Taken together, results indicated that paraben had cytotoxic effects and caused genotoxicity by affecting directly chromosomes and DNA in human lymphocyte cells in vitro, and may have genotoxic potential for human. PMID- 29281925 TI - Gastric-Type Endometrial Adenocarcinoma: Report of Two Cases in Patients From the United States. AB - Gastric-type adenocarcinomas of the uterine cervix have been described within the literature in detail; however, the description of gastric-type endometrial adenocarcinomas is a recent development, with only two cases originating from Japan in the world literature to date. According to these prior reports, the recognition of this pattern of differentiation is critical, as it is often associated with deep myoinvasion, positive regional lymph nodes, and poor outcome despite appropriate adjuvant treatment. We present two cases of endometrial adenocarcinoma with gastric-type differentiation in patients from the United States with superficial myoinvasion and positive patient outcomes. Gastric-type differentiation in endometrial adenocarcinomas is rare and likely underrecognized. Continued reporting of these cases is necessary to further understand the natural history and clinical implications of this entity. PMID- 29281927 TI - Neonatal screening for congenital CMV infection stresses the importance of maternal nonprimary infection even in an area where prenatal serology testing is common. AB - AIM AND METHODS: Dried blood spots from 2149 newborns were examined to diagnose congenital cytomegalovirus (cCMV). RESULTS: Prenatal CMV-IgG antibodies had been measured during prenatal care in 1287 (60.3%) of mothers and 980 (76.1%) of them were found seropositive. cCMV incidence was 0.47%. All newborns were asymptomatic; 9/10 were born post nonprimary maternal infection; two developed sensorineural hearing loss. CONCLUSIONS: In a country where prenatal CMV testing is common and therefore a false sense of control might prevail, nonprimary maternal infection should not be overlooked. Indeed, women of childbearing age should be educated on CMV prevention measures irrespectively to their serostatus. PMID- 29281928 TI - The silent world of young next of kin in mental healthcare. AB - BACKGROUND: Young next of kin to patients with mental health problems are faced with many challenges. It is important to focus on the special needs of children and adolescents as next of kin to ensure their welfare and prevent harm. RESEARCH QUESTIONS: We aimed to investigate young next of kin's need for information and involvement, to examine the ways they cope with situations involving coercion related to the treatment of their relative, and to identify ethical challenges. RESEARCH DESIGN: We conducted a qualitative study based on semi-structured, individual interviews. Participants and research context: Seven young next of kin aged 14-22 years participated in the study. The informants were recruited from a regional hospital trust in Norway. Ethical considerations: The study was approved by the National Data Protection Official for Research and based upon informed consent and confidentiality. FINDINGS: The adolescents wanted more information and described a need for increased interaction with their sick relative at the hospital. They struggled to keep their relationship with their relative intact, and they described communication problems in the family. Coercive treatment was perceived in a negative way. DISCUSSION: The study finds that there are ethical challenges at stake for young next of kin and their families other than those that are often emphasized by traditional healthcare, which often focuses on the individual patient's rights. These challenges are related to the young next of kin's needs for interconnectedness and for the preservation of relationships as well as challenges related to family communication and the need for information. CONCLUSION: The study finds a need for more family-oriented perspectives in both mental healthcare practices and healthcare ethics. PMID- 29281929 TI - Protective effect of aspirin against mitomycin C-induced carcinogenicity, assessed by the test for detection of epithelial tumor clones (warts) in Drosophila melanogaster. AB - The present study assessed the protective effect of aspirin against carcinogenicity induced by mitomycin C (MMC) by the test for detection of warts/epithelial tumor clones in Drosophila melanogaster. Larvae were treated with different concentrations of aspirin alone (10, 20 or 40 mg/mL) or aspirin in association with MMC. MMC and ultrapure water were employed as the positive and negative control, respectively. Antioxidant activity was determined using the DPPH method. For performing cytotoxicity assay on HeLa cells, the aspirin concentrations used ranged from 200 mmol/L to 3,125 mmol/L. For assessment of apoptosis and necrosis, cells were incubated for 24 h with complete medium in the absence (control group) or presence of aspirin (12.5 mmol/L and 25 mmol/L). The results obtained in the assessment of the possible carcinogenic effects of aspirin at the three concentrations tested indicate no statistically significant increase in tumor frequency compared to the negative control. The anticarcinogenic activity assessment, where the larvae of D. melanogaster were previously induced to tumor formation by MMC and later treated with aspirin, showed a statistically significant reduction in the number of tumors compared to the positive control. Antioxidant activity across the three aspirin concentrations (10, 20 or 40 mg/mL) ranged from 20.81% to 26.5%. It was observed that aspirin reduced growth viability of HeLa cells in a concentration-dependent manner in comparison with the control. These results indicate that aspirin did not induce tumors in Drosophila and reduced MMC-induced carcinogenicity. The antioxidant activity and apoptosis induction appear to be the main mechanisms involved in reducing the frequency of tumors. PMID- 29281930 TI - The Effect of Sensory Integration Therapy on Occupational Performance in Children With Autism. AB - Sensory processing problems and related dysfunctions are among the most common conditions in children with autism spectrum disorder (ASD). This study examined the effect of sensory integration therapy (SIT) on different aspects of occupational performance in children with ASD. The study was conducted on an intervention group ( n = 16) receiving SIT and a control group ( n = 15) with 3- to 8-year-old children with ASD. The Short Child Occupational Profile (SCOPE) was used to compare the two groups in terms of the changes in their occupational performance and the Sensory Profile (SP) was used to assess sensory problems. The intervention group showed significantly greater improvement in all the SCOPE domains, as well as in all the SP domains, except for the "emotional reactions" and "emotional/social responses" domains, ( p < .05). The effectiveness of SIT in improving occupational performance in children with ASD as a health-related factor is supported by our findings. PMID- 29281931 TI - Mutagenicity, anticancer activity and blood brain barrier: similarity and dissimilarity of molecular alerts. AB - The aim of the present work is an attempt to define computable measure of similarity between different endpoints. The similarity of structural alerts of different biochemical endpoints can be used to solve tasks of medicinal chemistry. Optimal descriptors are a tool to build up models for different endpoints. The optimal descriptor is calculated with simplified molecular input line entry system (SMILES). A group of elements (single symbol or pair of symbols) can represent any SMILES. Each element of SMILES can be represented by so-called correlation weight i.e. coefficient that should be used to calculate descriptor. Numerical data on the correlation weights are calculated by the Monte Carlo method, i.e. by optimization procedure, which gives maximal correlation coefficient between the optimal descriptor and endpoint for the training set. Statistically stable correlation weights observed in several runs of the optimization can be examined as structural alerts, which are promoters of the increase or the decrease of a biochemical activity of a substance. Having data on several runs of the optimization correlation weights, one can extract list of promoters of increase and list of promoters of decrease for an endpoint. The study of similarity and dissimilarity of the above lists has been carried out for the following pairs of endpoints: (i) mutagenicity and anticancer activity; (ii) mutagenicity and blood brain barrier; and (iii) blood brain barrier and anticancer activity. The computational experiment confirms that similarity and dissimilarity for pairs of endpoints can be measured. PMID- 29281932 TI - Ethically providing Routine HIV testing services to bereaved populations. AB - BACKGROUND: The delivery of public health policies may be in conflict with individualism. OBJECTIVES: To propose measures to ethically provide routine HIV testing services to persons visiting a funeral home. RESEARCH DESIGN: A document analysis of study documents and presentations made to an institutional review board. Participants and research context: Institutional review board members (both lay and professionals) and Study investigators attending an 'open session' where study investigators were invited to elaborate on some study procedures. Ethical considerations: Identities of all parties were anonymized. FINDINGS: Opt out approaches to HIV testing, grief counseling, relational ethics, and a modular consenting process were proposed to safeguard clients' autonomy. The golden-rule approach and protective empowering were suggested to protect clientele beneficence. DISCUSSION AND CONCLUSION: It is possible to ethically provide universal HIV testing and counseling services among grieving populations in this setting; elsewhere, this should be contextualized. PMID- 29281933 TI - Toxicity evaluation of magnetic iron oxide nanoparticles reveals neuronal loss in chicken embryo. AB - Magnetic iron oxide nanoparticles (IONs) display the ability to cross blood - brain barrier and are envisioned as diagnostic and therapeutic applications, but there are few studies on their potential embryonic toxicity in higher vertebrates. This study investigates interaction of IONs with egg albumen and its subsequent toxicity on chicken embryo. Physicochemical interactions of IONs with egg albumen revealed alterations in friccohesity and secondary structural changes due to weak Vander Waals forces. Toxicity assessment of IONs (10, 25, 50, 100, and 200 ug/ml doses) on chicken embryo accounted for 100% mortality at 200 ug/ml dose due to Fe2+ ions overload. However, lower doses (50 and 100 ug/ml) recorded decrement in whole weights and crown-rump lengths of chicken embryo possibly due to ION-albumen interactions. Histology of brain tissue revealed degeneration of neurons (50-60%) at 10-100 ug/ml dose range of IONs. Toxicity studies of IONs with diverse animal models are needed to set a toxicity benchmark for preventing embryonic toxicity prior to its use in biomedical applications. This is the first study on toxicity assessment of IONs in chicken embryo. PMID- 29281934 TI - Ethical challenges experienced by clinical research nurses:: A qualitative study. AB - BACKGROUND: Clinical investigation is a growing field employing increasing numbers of nurses. This has created a new specialty practice defined by aspects unique to nursing in a clinical research context: the objectives (to implement research protocols and advance science), setting (research facilities), and nature of the nurse-participant relationship. The clinical research nurse role may give rise to feelings of ethical conflict between aspects of protocol implementation and the duty of patient advocacy, a primary nursing responsibility. Little is known about whether research nurses experience unique ethical challenges distinct from those experienced by nurses in traditional patient-care settings. RESEARCH OBJECTIVES: The purpose of the study was to describe the nature of ethical challenges experienced by clinical research nurses within the context of their practice. RESEARCH DESIGN: The study utilized a qualitative descriptive design with individual interviews. Participants and research context: Participating nurses (N = 12) self-identified as having experienced ethical challenges during screening. The majority were Caucasian (90%), female (83%), and worked in outpatient settings (67%). Approximately 50% had > 10 years of research experience. Ethical considerations: The human subjects review board approved the study. Written informed consent was obtained. FINDINGS: Predominant themes were revealed: (1) the inability to provide a probable good, or/do no harm, and (2) dual obligations (identity as a nurse vs a research nurse). The following patterns and subthemes emerged: conflicted allegiances between protocol implementation, needs of the participant, desire to advance science, and tension between the nurse-patient therapeutic relationship versus the research relationship. DISCUSSION: Participants described ethical challenges specific to the research role. The issues are central to the nurse-participant relationship, patient advocacy, the nurse's role in implementing protocols, and/or advancing science. CONCLUSION: Ethical challenges related to the specialized role of clinical research nurses were identified. More research is warranted to fully understand their nature and frequency and to identify support systems for resolution. PMID- 29281935 TI - Bulge oligonucleotide as an inhibitory agent of bacterial topoisomerase I. AB - Bacterial topoisomerase I (Btopo I) was defined as potential target for discovery of new antibacterial compounds. Various oligonucleotides containing bulge structure were designed and synthesised as inhibitors to Btopo I in this investigation. The results of this study demonstrated that the designed oligonucleotides display high inhibitory efficiency on the activity of Btopo I and the inhibitory effect could be modulated by the amount of bulge DNA bases. The most efficient one among them showed an IC50 value of 63.1 nM in its inhibition on the activity of Btopo I. In addition, our studies confirmed that the designed oligonucleotide would induce irreversible damages to Btopo I and without any effects occur to eukaryotic topoisomerase I. It is our hope that the results provided in these studies could provide a novel way to inhibit Btopo I. PMID- 29281936 TI - A comparative study of HHHFNC and NCPAP in preventing reintubation in extreme preterm infants born at less than 30-week gestation. AB - INTRODUCTION: Despite recent advances in respiratory support, the wide use of antenatal steroids and surfactant-replacement therapy, respiratory problems continue to represent the leading cause of mortality in premature infants during the neonatal period. In the last few years, HHHFNC has been widely adopted as a mode of noninvasive respiratory support for infants with respiratory difficulties. However, data of the safety and efficacy of HHHFNC use in extremely premature infants are scarce. This study will aid in bridging the knowledge gap and sheds light on the efficacy and, more importantly, the safety of HHHFNC as noninvasive respiratory support for extremely premature infants. METHODS: This is a retrospective comparative study conducted at neonatal intensive care unit (NICU), Norfolk and Norwich University Hospital between 1 October 2010 and 31 December 2014. Data were collected from the medical notes and electronic records of the eligible patients. Participants' total number was 26, 9 patients in nCPAP group while HHHFNC group consisted of 17 patients. The participants' gestational age was ranging between 24 to 29 + 9 weeks who were supported by either nCPAP or HHHFNC after first extubation. Primary outcome was defined as the need for reintubation within 72-hour immediately postextubation, i.e. failure of noninvasive respiratory support. RESULTS: Study showed no statistically significant differences in either primary (nCPAP (9/2 [22%]), HHHFNC (17/2 [12%]; p = .59)) or secondary outcomes (Constant need for O2 in the first 4 weeks of life (p = .62), pneumothorax (p = 1.0), nasal injury (p = .35)). p Value for spontaneous bowel perforation was not computed, as there were no affected patients. CONCLUSIONS: The study demonstrates that HHHFNC is similarly safe and efficacious in comparison to nCPAP as noninvasive respiratory support for extremely premature infants' postextubation. PMID- 29281937 TI - Contrast-induced acute kidney injury: beware of the risk after coronary angiography. PMID- 29281938 TI - Pharmacophore-based virtual screening of catechol-o-methyltransferase (COMT) inhibitors to combat Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most significant neurodegenerative disorders and its symptoms mostly appear in aged people. Catechol-o methyltransferase (COMT) is one of the known target enzymes responsible for AD. With the use of 23 known inhibitors of COMT, a query has been generated and validated by screening against the database of 1500 decoys to obtain the GH score and enrichment value. The crucial features of the known inhibitors were evaluated by the online ZINC Pharmer to identify new leads from a ZINC database. Five hundred hits were retrieved from ZINC Pharmer and by ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering by using FAF-Drug-3 and 36 molecules were considered for molecular docking. From the COMT inhibitors, opicapone, fenoldopam, and quercetin were selected, while ZINC63625100_413 ZINC39411941_412, ZINC63234426_254, ZINC63637968_451, and ZINC64019452_303 were chosen for the molecular dynamics simulation analysis having high binding affinity and structural recognition. This study identified the potential COMT inhibitors through pharmacophore-based inhibitor screening leading to a more complete understanding of molecular-level interactions. PMID- 29281939 TI - Bone-specific alkaline phosphatase - a potential biomarker for skeletal growth assessment. AB - OBJECTIVE: The present study was aimed to assess levels of serum Bone-specific alkaline phosphatase (BALP) and serum Insulin-like growth factor-1 (IGF-1) and comparing with cervical vertebral maturation index (CVMI) stages. DESIGN: Cross sectional study. SETTING: Maulana Azad Institute of Dental Sciences, New Delhi, India. PARTICIPANTS: 150 subjects (75 males and 75 females) in the age group of 8 20 years. METHODS: Subjects were divided into six CVMI stages. Enzyme-linked immunosorbant assay was performed for the estimation of serum BALP and serum IGF 1 levels. Mann-Whitney U test was performed to compare mean ranks of serum BALP and serum IGF-1 with different CVMI stages. Spearman correlation between serum BALP and serum IGF-1 was done across 6 CVMI stages. RESULTS: Peak serum IGF-1 levels were found at CVMI stages 4 and 3 for males and females respectively. Peak levels for serum BALP were found at stage 3 for both genders with significant differences from other stages. A statistically significant correlation was seen between serum IGF-1 and serum BALP from CVMI stages 1 to 3 and 4 to 6 (p < .01). CONCLUSIONS: BALP showed promising results and can be employed as a potential biomarker for the estimation of growth status. PMID- 29281940 TI - The cognitive tools that support mentally constructing event and scene representations. AB - Constructing mental representations is critical for many cognitive tasks, yet it is unclear if forming different representations relies on distinct cognitive processes. We tested how episodic memory contributes to constructing scene and event-based mental scenarios as well as the effects of two types of imagery ability (object and spatial imagery) on this contribution. Forty participants were given a series of scenario cues that were classified as scenes (e.g., a beach) or events (e.g., a family meal) by independent raters. To these cues, the participants described the details of the associated mental representation. They also rated the representation for vividness, sense of presence, and if forming the representation stimulated the retrieval of an autobiographical memory. The resulting descriptions were then scored for number of contained episodic and non episodic details. We found participants generated more details - particularly episodic - for event than scene representations. Interestingly, episodic detail generation was predicted by subjective ratings for the scene and not event representations. Other rating differences were that scenes were experienced with a greater sense of presence and events were more likely to trigger autobiographical memory retrieval. Finally, we found dissociation in how object and spatial imagery ability related to event representations. For these representations, generating episodic and non-episodic details related to object and spatial imagery, respectively. These findings indicate how the nature of a representation directs contributions from episodic memory and are affected by imagery ability. PMID- 29281941 TI - A randomized controlled trial on the effect of behavioral strategies for adherence to oral antidiabetic drugs: study protocol. AB - BACKGROUND: Non-adherence to oral antidiabetics drugs (OADs) has been a common problem and may contribute to poor glycemic control. AIM: To describe an experimental study protocol that aims at implementing and evaluating the effect of the "action planning and coping planning" interventions on medication adherence to OADs in patients with type 2 diabetes mellitus (T2DM) in follow-up at primary care services. DESIGN: A randomized controlled trial. METHODS: Two groups (intervention and control) will be followed over a period of 105 days. The intervention group will receive a combination of the "action planning" and "coping planning" intervention strategies. There will be in-person meetings and phone calls to reinforce the intervention. The control group will receive the usual care from the health unit. CONCLUSIONS: It is hoped that this study will help health professionals to improve their approach with patients who have T2DM in relation to medication adherence. PMID- 29281942 TI - Two-stage pretreatment of excess sludge for electricity generation in microbial fuel cell. AB - Thermophiles hydrolysis and acidogens fermentation were sequentially adopted to pretreat excess sludge for microbial fuel cell (MFC) electricity production. The results indicated that MFC fed with the thermophiles-acidogens pretreated sludge (MFC AB), reached a higher removal of ammonia nitrogen than the MFC fed with the heating hydrolysis and acidogens fermentation pretreated sludge (MFC NB). However, compared with the MFC AB, MFC NB presented a better performance for removal of soluble chemical oxygen demand (SCOD) (90.08%) and protein (82.42%). As for the electricity production, MFC NB obtained higher voltage of 0.632 V and maximum power density with 1.05 W/m3 while MFC AB reached maximum voltage of 0.373 V and maximum power density of 0.58 W/m3. Bacterial 16S rRNA-based molecular microbial techniques showed that microbial communities on both MFC anode biofilms was diverse and different. The cooperation of fermentation bacteria and electricigen Shewanella baltica in the MFC NB may have contributed towards the improvement of electricity generation. PMID- 29281943 TI - Biological and Mechanical Factors Promote the Osteogenesis of Rabbit Artificial Vertebral Laminae: A Comparison Study. AB - Reconstruction of vertebral laminae without epidural scar formation has been challenging. The success of bone formation depends on the biological and mechanical conditions of the surrounding tissues. In this study, we aimed to investigate the roles of biological and mechanical factors in the osteogenesis of artificial laminae. Mesenchymal stem cells derived from rabbit umbilical cord Wharton's jelly were induced for osteogenic differentiation for 3 weeks before seeding on the hydroxyapatite-collagen I scaffolds to construct the tissue engineered laminae (TEL). TEL were then implanted into the fifth rabbit lumbar vertebrae in both orthotopic lamina (n = 30) and ectopic lamina (n = 30) groups. De novo laminae were examined through histological and radiographic analysis in the 2nd, 4th, 8th, 12th, and 16th weeks postimplantation. Our results showed that de novo laminae formed effectively in both groups, and the osteogenic gene expression levels and cancellous microstructure parameters of de novo laminae in the orthotopic lamina group were significantly higher than those in the ectopic lamina group. In conclusion, the biological stimulation of bone defect initiated the early onset osteogenesis, and the mechanical stimulation of cerebrospinal fluid pulsation stress promoted the osteogenesis of de novo laminae. PMID- 29281944 TI - Unveiling the Maelstrom of the Early Breast Cancer Trajectory. AB - Length and complexity of illness and treatment in early breast cancer mean that the acute phase may extend over months. Employing concepts of "trajectory" and "work" from chronic illness, we explored the temporality of the illness experience for women as it unfolded from diagnosis through acute treatment. We performed multiple, qualitative interviews with 14 women at critical points in their first year postdiagnosis. We differentiated between subphases of the acute breast cancer trajectory: becoming a person with breast cancer: a turning point; first steps in treatment: struggling to protect self-concept; being and feeling ill: "cure" as suffering; and conditional "recovering": an uncertain future. Each subphase represented the distinctive context in which illness management took place with consequences for the work women and those close to them engaged in, to manage the practical, emotional, relational, and existential demands of an illness that intruded every aspect of their lives. PMID- 29281945 TI - Maternal Knowing and Social Networks: Understanding First-Time Mothers' Search for Information and Support Through Online and Offline Social Networks. AB - The postpartum period is an exciting yet stressful time for first-time mothers, and although the experience may vary, all mothers need support during this crucial period. In Canada, there has been a shift for universal postpartum services to be offered predominantly online. However, due to a paucity of literature, it is difficult to determine the degree to which mothers' needs are being effectively addressed. The aim of this study was to examine and understand how first-time mothers accessed support and information (online and offline) during the first 6 months of their postpartum period. Using feminist poststructuralism methodology, data were collected from focus groups and e interviews, and analyzed using discourse analysis. Findings indicate that peer support is greatly valued, and mothers often use social media to make in-person social connections. Findings highlight how accessing support and information is socially and institutionally constructed and provide direction for health professionals to provide accessible postpartum care. PMID- 29281946 TI - Mothers' Experiences of Supporting Adolescent Children Through Long-Term Treatment for Substance Use Disorder. AB - Substance use disorder is a complex phenomenon that affects people in many different contexts. Adolescent substance abuse within families is a particular problem that merits ongoing study. In particular, the experiences of mothers in this context are not fully explored. In this narrative inquiry study, we explored the experiences of four mothers parenting children through long-term substance abuse treatment. Participants were recruited from a family-orientated long-term adolescent treatment center in Alberta, Canada. The mothers' experiences were explored within a three-dimensional narrative inquiry space of temporal, social, and situated experience. Four narrative accounts were co-composed, revealing personal, familial, social, and substance abuse-related complexities in mothers' experiences. Four narrative threads were also theorized: navigating complexities; loud silences; places, spaces, and the in-between; and living within one another's stories. These narrative threads are discussed in relation to health and social care practices. Recommendations for practice and research are made. PMID- 29281947 TI - An Exploration of Palliative Care Needs of People With End-Stage Renal Disease on Dialysis: Family Caregiver's Perspectives. AB - Patients with end-stage renal disease supported on dialysis experience high morbidity and mortality. Little is known about family caregiver experiences during the disease. Qualitative research methods were used to explore the experiences of family caregivers caring for patients receiving dialysis. In depth, semi-structured, in-person interviews were completed with 18 family caregivers in rural and urban settings. Interviews were audiotaped, transcribed verbatim, and analyzed using thematic and descriptive analysis. Major themes identified included challenges navigating the health system, caregiver burden, perceptions of palliative care, symptom management, and decision-making. Caregiver burdens are significant including physical, emotional, social, and economic dimensions. There is a need to recognize and improve support for family caregivers and increase collaboration with nephrology and palliative care services from commencement of dialysis until death and into bereavement. PMID- 29281948 TI - A patient with oxaliplatin immune-induced syndrome (OIIS) who also developed leucovorin and palonosetron-associated thrombocytopenia. AB - OBJECTIVES: We report a case of an 83 year old man who developed oxaliplatin immune-induced syndrome (OIIS) after his 19th cycle of FOLFOX (5FU, leucovorin, oxaliplatin). When oxaliplatin was omitted from his next cycle of chemotherapy he continues to show signs of drug-induced immune thrombocytopenia (DITP) and was found to have drug-dependent, platelet-reactive antibodies (DDPA) to leucovorin and palonosetron as well as oxaliplatin. METHODS: The patient was admitted for monitoring but required no transfusions and thrombocytopenia resolved without treatment during his first admission. Drug-dependent antibody testing was performed on his blood by the Blood Center of Wisconsin (Diagnostic Laboratories; Milwaukee, WI). RESULTS: No RBC or platelet IgG or IgM antibodies were detected in the absence of any drugs, but upon addition of palonosetron, leucovorin, or oxaliplatin, the tests became strongly positive for anti-RBC IgG and anti platelet IgG antibodies. DISCUSSION: Repeated administration of oxaliplatin can result in drug-induced immune thrombocytopenia (DITP) or autoimmune hemolytic anemia (AIHA). This phenomenon has recently been termed OIIS and may additionally include Evan's syndrome or thrombotic microangiopathy (TMA). Here we describe a patient who developed OIIS with drug-dependent, platelet-reactive antibodies (DDPA) to leucovorin and palonosetron. To our knowledge, these two drugs have never been described in the literature as a cause of DDPA. We suggest that OIIS in addition to oxaliplatin-induced thrombocytopenia may be associated with the development of DDPAs to other drugs causing clinically significant thrombocytopenia which is important to recognize and manage with discontinuation of provoking agents. PMID- 29281949 TI - A Brief History of Pediatric Exercise Physiology. PMID- 29281950 TI - Kartogenin Enhanced Chondrogenesis in Cocultures of Chondrocytes and Bone Mesenchymal Stem Cells. AB - Articular cartilage has poor capability of regeneration due to the avascular surrounding and low metabolic activity. Kartogenin (KGN), an emerging nonprotein heterocyclic compound, was screened to stimulate chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Coculturing BMSCs and chondrocytes was reported to overcome the shortcomings of forming fibroblastic and hypertrophic cartilages. In this study, KGN was incorporated into the Col-Tgel hydrogel to form a Gel/Cell/KGN complex, which fabricated an appropriate microenvironment for effective cartilage regeneration of BMSCs and/or chondrocytes. The complexes that incorporated KGN, BMSCs, and chondrocytes achieved higher lubricin expression and extracellular matrix production, such as characteristic glycosaminoglycans (GAGs) and collagen type II (COL II), compared to the monocultures of BMSCs or chondrocytes in vitro. The complexes compounding KGN, BMSCs, and chondrocytes (at an optimal ratio in the in vitro experiment) were transplanted into rat models to evaluate the repair effects. Our results suggested that the interaction between BMSCs and chondrocytes can substitute the use of growth factors to some degree and indicated the role of KGN in chondrogenesis induction. Besides, it is the first time (to our knowledge) that the expression of lubricin was found to be delayed in the coculture of mixed cells comparing with GAGs and COL II, which could be significant in cartilage tissue engineering. PMID- 29281951 TI - Gene Fusions in Thyroid Cancer. AB - BACKGROUND: Gene fusions are known in many cancers as driver or passenger mutations. They play an important role in both the etiology and pathogenesis of cancer and are considered as potential diagnostic and prognostic markers and possible therapeutic targets. The spectrum and prevalence of gene fusions in thyroid cancer ranges from single cases up to 80%, depending on the specific type of cancer. During last three years, massive parallel sequencing technologies have revealed new fusions and allowed detailed characteristics of fusions in different types of thyroid cancer. SUMMARY: This article reviews all known fusions and their prevalence in papillary, poorly differentiated and anaplastic, follicular, and medullary carcinomas. The mechanisms of fusion formation are described. In addition, the mechanisms of oncogenic transformation, such as altered gene expression, forced oligomerization, and subcellular localization, are given. CONCLUSION: The prognostic value and perspectives of the utilization of gene fusions as therapeutic targets are discussed. PMID- 29281952 TI - Kernel differential subgraph reveals dynamic changes in biomolecular networks. AB - Many major diseases, including various types of cancer, are increasingly threatening human health. However, the mechanisms of the dynamic processes underlying these diseases remain ambiguous. From the holistic perspective of systems science, complex biological networks can reveal biological phenomena. Changes among networks in different states influence the direction of living organisms. The identification of the kernel differential subgraph (KDS) that leads to drastic changes is critical. The existing studies contribute to the identification of a KDS in networks with the same nodes; however, networks in different states involve the disappearance of some nodes or the appearance of some new nodes. In this paper, we propose a new topology-based KDS (TKDS) method to explore the core module from gene regulatory networks with different nodes in this process. For the common nodes, the TKDS method considers the differential value (D-value) of the topological change. For the different nodes, TKDS identifies the most similar gene pairs and computes the D-value. Hence, TKDS discovers the essential KDS, which considers the relationships between the same nodes as well as different nodes. After applying this method to non-small cell lung cancer (NSCLC), we identified 30 genes that are most likely related to NSCLC and extracted the KDSs in both the cancer and normal states. Two significance functional modules were revealed, and gene ontology (GO) analyses and literature mining indicated that the KDSs are essential to the processes in NSCLC. In addition, compared with existing methods, TKDS provides a unique perspective in identifying particular genes and KDSs related to NSCLC. Moreover, TKDS has the potential to predict other critical disease-related genes and modules. PMID- 29281953 TI - Argo_CUDA: Exhaustive GPU based approach for motif discovery in large DNA datasets. AB - The development of chromatin immunoprecipitation sequencing (ChIP-seq) technology has revolutionized the genetic analysis of the basic mechanisms underlying transcription regulation and led to accumulation of information about a huge amount of DNA sequences. There are a lot of web services which are currently available for de novo motif discovery in datasets containing information about DNA/protein binding. An enormous motif diversity makes their finding challenging. In order to avoid the difficulties, researchers use different stochastic approaches. Unfortunately, the efficiency of the motif discovery programs dramatically declines with the query set size increase. This leads to the fact that only a fraction of top "peak" ChIP-Seq segments can be analyzed or the area of analysis should be narrowed. Thus, the motif discovery in massive datasets remains a challenging issue. Argo_Compute Unified Device Architecture (CUDA) web service is designed to process the massive DNA data. It is a program for the detection of degenerate oligonucleotide motifs of fixed length written in 15 letter IUPAC code. Argo_CUDA is a full-exhaustive approach based on the high performance GPU technologies. Compared with the existing motif discovery web services, Argo_CUDA shows good prediction quality on simulated sets. The analysis of ChIP-Seq sequences revealed the motifs which correspond to known transcription factor binding sites. PMID- 29281954 TI - MIMPFC: Identifying miRNA-mRNA regulatory modules by combining phase-only correlation and improved rough-fuzzy clustering. AB - MicroRNAs (miRNAs) play a key role in gene expression and regulation in various organisms. They control a wide range of biological processes and are involved in several types of cancers by causing mRNA degradation or translational inhibition. However, the functions of most miRNAs and their precise regulatory mechanisms remain elusive. With the accumulation of the expression data of miRNAs and mRNAs, many computational methods have been proposed to predict miRNA-mRNA regulatory relationship. However, most existing methods require the number of modules predefined that may be difficult to determine beforehand. Here, we propose a novel computational method to discover miRNA-mRNA regulatory modules by combining Phase-only correlation and improved rough-Fuzzy Clustering (MIMPFC). The proposed method is evaluated on three heterogeneous datasets, and the obtained results are further validated through relevant literatures, biological significance and functional enrichment analysis. The analysis results show that the identified modules are highly correlated with the biological conditions. A large part of the regulatory relationships found by MIMPFC has been confirmed in the experimentally verified databases. It demonstrates that the modules found by MIMPFC are biologically significant. PMID- 29281955 TI - Drug coated ballons for femoro-popliteal interventions. PMID- 29281956 TI - Do we have to change therapeutic considerations in peripheral arterial disease? PMID- 29281957 TI - When honesty and cheating pay off: the evolution of honest and dishonest equilibria in a conventional signalling game. AB - BACKGROUND: The reliability of signals is a key issue in the study of animal communication. Both empirical work and theoretical models show that communication need not be entirely honest, and thus signals can be deceitful. Aggressive communication appears to be a prime candidate for such deceitful communication, because bluffing has been described in several species. Bluffing in these situations are supposed to be maintained by frequency dependent selection where the fitness of a given type depends on the frequencies of the other types in the population. Previous efforts to model such a scenario through individual based simulations have yielded conflicting results. Studies have either found a rich set of polymorphic strategies including the traditional cheating scenario or found none. Thus, the modelling assumptions responsible for these diverging conclusions remain unclear. RESULTS: In this study, I investigate the effects of four modelling assumptions: the role of an extended strategy set, the initial population composition (seeding), the differences in pay-offs and finally different parameter spaces. I investigate the effects of these factors on the evolvability of both honest and mixed cheating strategies. I show that both honest and cheating equilibria readily evolve and that the investigated parameter range and the seeding of the starting populations have the greatest influence on the outcome. CONCLUSIONS: Both honest signalling and polymorphic cheating equilibria are more likely to evolve from a narrow strategy set than from a random mixture of strategies. A large potential strategy set is not a setback for the evolution of communication -honest or cheating- as long as the initial population is seeded with only a few strategies. In addition, different sections of the parameter space show consistently different behaviour. Thus, frequency dependent selection has the potential to explain various empirical observations that show consistent differences in aggressive behaviour. PMID- 29281958 TI - Novel methods for genotype imputation to whole-genome sequence and a simple linear model to predict imputation accuracy. AB - BACKGROUND: Accurate imputation plays a major role in genomic studies of livestock industries, where the number of genotyped or sequenced animals is limited by costs. This study explored methods to create an ideal reference population for imputation to Next Generation Sequencing data in cattle. METHODS: Methods for clustering of animals for imputation were explored, using 1000 Bull Genomes Project sequence data on 1146 animals from a variety of beef and dairy breeds. Imputation from 50 K to 777 K was first carried out to choose an ideal clustering method, using ADMIXTURE or PLINK clustering algorithms with either genotypes or reconstructed haplotypes. RESULTS: Due to efficiency, accuracy and ease of use, clustering with PLINK using haplotypes as quasi-genotypes was chosen as the most advantageous grouping method. It was found that using a clustered population slightly decreased computing time, while maintaining accuracy across the population. Although overall accuracy remained the same, a slight increase in accuracy was observed for groups of animals in some breeds (primarily purebred beef cattle from breeds with fewer sequenced animals) and for other groups, primarily crossbreed animals, a slight decrease in accuracy was observed. However, it was noted that some animals in each breed were poorly imputed across all methods. When imputed sequences were included in the reference population to aid imputation of poorly imputed animals, a small increase in overall accuracy was observed for nearly every individual in the population. Two models were created to predict imputation accuracy, a complete model using all information available including Euclidean distances from genotypes and haplotypes, pedigree information, and clustering groups and a simple model using only breed and an Euclidean distance matrix as predictors. Both models were successful in predicting imputation accuracy, with correlations between predicted and true imputation accuracy as measured by concordance rate of 0.87 and 0.83, respectively. CONCLUSIONS: A clustering methodology can be very useful to subgroup cattle for efficient genotype imputation. In addition, accuracy of genotype imputation from medium to high-density Single Nucleotide Polymorphisms (SNP) chip panels to whole-genome sequence can be predicted well using a simple linear model defined in this study. PMID- 29281960 TI - An analytical framework to derive the expected precision of genomic selection. AB - BACKGROUND: Formulae to predict the precision or accuracy of genomic estimated breeding values (GEBV) are important when modelling selection schemes. Simple versions of such formulae have been proposed in the past, based on a number of simplifying hypotheses, including absence of linkage disequilibrium and linkage between loci, a population made up of unrelated individuals, and that all genetic variability of the trait is explained by the genotyped loci. These formulae were based on approximations that were not always clear. The objective of this paper is to offer a unique framework to derive equations that predict the precision of GEBV from the size of the reference population and the heritability of and number of QTL controlling the quantitative trait. RESULTS: The exact formulation of the precision of GEBV involves the expectation of the inverse of a linear function of the genomic matrix, which cannot be calculated from simple algebra but can be approximated using a Taylor polynomial expansion. First order approximations performed better than the initial prediction equations published in the literature. Second order approximations produced almost perfect estimates of precision when compared to results obtained when simulating situations that agreed with the assumptions that were required to derive the precision equations. Using this proposed framework, we present several generalizations, including multi-trait genomic evaluation. CONCLUSIONS: Although further improvements are needed to account for the complexity of practical situations, the equations proposed here can be used to derive the precision of GEBV when comparing breeding schemes a priori. PMID- 29281959 TI - A comparison of genotyping-by-sequencing analysis methods on low-coverage crop datasets shows advantages of a new workflow, GB-eaSy. AB - BACKGROUND: Genotyping-by-sequencing (GBS), a method to identify genetic variants and quickly genotype samples, reduces genome complexity by using restriction enzymes to divide the genome into fragments whose ends are sequenced on short read sequencing platforms. While cost-effective, this method produces extensive missing data and requires complex bioinformatics analysis. GBS is most commonly used on crop plant genomes, and because crop plants have highly variable ploidy and repeat content, the performance of GBS analysis software can vary by target organism. Here we focus our analysis on soybean, a polyploid crop with a highly duplicated genome, relatively little public GBS data and few dedicated tools. RESULTS: We compared the performance of five GBS pipelines using low-coverage Illumina sequence data from three soybean populations. To address issues identified with existing methods, we developed GB-eaSy, a GBS bioinformatics workflow that incorporates widely used genomics tools, parallelization and automation to increase the accuracy and accessibility of GBS data analysis. Compared to other GBS pipelines, GB-eaSy rapidly and accurately identified the greatest number of SNPs, with SNP calls closely concordant with whole-genome sequencing of selected lines. Across all five GBS analysis platforms, SNP calls showed unexpectedly low convergence but generally high accuracy, indicating that the workflows arrived at largely complementary sets of valid SNP calls on the low coverage data analyzed. CONCLUSIONS: We show that GB-eaSy is approximately as good as, or better than, other leading software solutions in the accuracy, yield and missing data fraction of variant calling, as tested on low-coverage genomic data from soybean. It also performs well relative to other solutions in terms of the run time and disk space required. In addition, GB-eaSy is built from existing open-source, modular software packages that are regularly updated and commonly used, making it straightforward to install and maintain. While GB-eaSy outperformed other individual methods on the datasets analyzed, our findings suggest that a comprehensive approach integrating the results from multiple GBS bioinformatics pipelines may be the optimal strategy to obtain the largest, most highly accurate SNP yield possible from low-coverage polyploid sequence data. PMID- 29281961 TI - Correction to: Genomic evaluation for a three-way crossbreeding system considering breed-of-origin of alleles. AB - After publication of our article [1], we found a typo in the formula to build the genomic relationship matrix using allele frequencies across all genotyped pigs (matrix) and the genomic relationship matrix using breed-specific allele frequencies (matrix), and we noted that the description to this formula is not very clear. PMID- 29281962 TI - Variable selection models for genomic selection using whole-genome sequence data and singular value decomposition. AB - BACKGROUND: Non-linear Bayesian genomic prediction models such as BayesA/B/C/R involve iteration and mostly Markov chain Monte Carlo (MCMC) algorithms, which are computationally expensive, especially when whole-genome sequence (WGS) data are analyzed. Singular value decomposition (SVD) of the genotype matrix can facilitate genomic prediction in large datasets, and can be used to estimate marker effects and their prediction error variances (PEV) in a computationally efficient manner. Here, we developed, implemented, and evaluated a direct, non iterative method for the estimation of marker effects for the BayesC genomic prediction model. METHODS: The BayesC model assumes a priori that markers have normally distributed effects with probability [Formula: see text] and no effect with probability (1 - [Formula: see text]). Marker effects and their PEV are estimated by using SVD and the posterior probability of the marker having a non zero effect is calculated. These posterior probabilities are used to obtain marker-specific effect variances, which are subsequently used to approximate BayesC estimates of marker effects in a linear model. A computer simulation study was conducted to compare alternative genomic prediction methods, where a single reference generation was used to estimate marker effects, which were subsequently used for 10 generations of forward prediction, for which accuracies were evaluated. RESULTS: SVD-based posterior probabilities of markers having non-zero effects were generally lower than MCMC-based posterior probabilities, but for some regions the opposite occurred, resulting in clear signals for QTL-rich regions. The accuracies of breeding values estimated using SVD- and MCMC-based BayesC analyses were similar across the 10 generations of forward prediction. For an intermediate number of generations (2 to 5) of forward prediction, accuracies obtained with the BayesC model tended to be slightly higher than accuracies obtained using the best linear unbiased prediction of SNP effects (SNP-BLUP model). When reducing marker density from WGS data to 30 K, SNP-BLUP tended to yield the highest accuracies, at least in the short term. CONCLUSIONS: Based on SVD of the genotype matrix, we developed a direct method for the calculation of BayesC estimates of marker effects. Although SVD- and MCMC-based marker effects differed slightly, their prediction accuracies were similar. Assuming that the SVD of the marker genotype matrix is already performed for other reasons (e.g. for SNP-BLUP), computation times for the BayesC predictions were comparable to those of SNP-BLUP. PMID- 29281963 TI - Improved high-dimensional prediction with Random Forests by the use of co-data. AB - BACKGROUND: Prediction in high dimensional settings is difficult due to the large number of variables relative to the sample size. We demonstrate how auxiliary 'co data' can be used to improve the performance of a Random Forest in such a setting. RESULTS: Co-data are incorporated in the Random Forest by replacing the uniform sampling probabilities that are used to draw candidate variables by co data moderated sampling probabilities. Co-data here are defined as any type information that is available on the variables of the primary data, but does not use its response labels. These moderated sampling probabilities are, inspired by empirical Bayes, learned from the data at hand. We demonstrate the co-data moderated Random Forest (CoRF) with two examples. In the first example we aim to predict the presence of a lymph node metastasis with gene expression data. We demonstrate how a set of external p-values, a gene signature, and the correlation between gene expression and DNA copy number can improve the predictive performance. In the second example we demonstrate how the prediction of cervical (pre-)cancer with methylation data can be improved by including the location of the probe relative to the known CpG islands, the number of CpG sites targeted by a probe, and a set of p-values from a related study. CONCLUSION: The proposed method is able to utilize auxiliary co-data to improve the performance of a Random Forest. PMID- 29281964 TI - The molecular evolutionary dynamics of oxidative phosphorylation (OXPHOS) genes in Hymenoptera. AB - BACKGROUND: The primary energy-producing pathway in eukaryotic cells, the oxidative phosphorylation (OXPHOS) system, comprises proteins encoded by both mitochondrial and nuclear genes. To maintain the function of the OXPHOS system, the pattern of substitutions in mitochondrial and nuclear genes may not be completely independent. It has been suggested that slightly deleterious substitutions in mitochondrial genes are compensated by substitutions in the interacting nuclear genes due to positive selection. Among the four largest insect orders, Coleoptera (beetles), Hymenoptera (sawflies, wasps, ants, and bees), Diptera (midges, mosquitoes, and flies) and Lepidoptera (moths and butterflies), the mitochondrial genes of Hymenoptera exhibit an exceptionally high amino acid substitution rate while the evolution of nuclear OXPHOS genes is largely unknown. Therefore, Hymenoptera is an excellent model group for testing the hypothesis of positive selection driving the substitution rate of nuclear OXPHOS genes. In this study, we report the evolutionary rate of OXPHOS genes in Hymenoptera and test for evidence of positive selection in nuclear OXPHOS genes of Hymenoptera. RESULTS: Our analyses revealed that the amino acid substitution rate of mitochondrial and nuclear OXPHOS genes in Hymenoptera is higher than that in other studied insect orders. In contrast, the amino acid substitution rate of non-OXPHOS genes in Hymenoptera is lower than the rate in other insect orders. Overall, we found the dN/dS ratio of the nuclear OXPHOS genes to be higher in Hymenoptera than in other insect orders. However, nuclear OXPHOS genes with high dN/dS ratio did not always exhibit a high amino acid substitution rate. Using branch-site and site model tests, we identified various codon sites that evolved under positive selection in nuclear OXPHOS genes. CONCLUSIONS: Our results showed that nuclear OXPHOS genes in Hymenoptera are evolving faster than the genes in other three insect orders. The branch test suggested that while some nuclear OXPHOS genes in Hymenoptera show a signature of positive selection, the pattern is not consistent across all nuclear OXPHOS genes. As only few codon sites were under positive selection, we suggested that positive selection might not be the only factor contributing to the rapid evolution of nuclear OXPHOS genes in Hymenoptera. PMID- 29281965 TI - Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model. AB - BACKGROUND: Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed. METHODS: Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice. RESULTS: Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates. CONCLUSIONS: These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling. PMID- 29281966 TI - Global transcriptional landscape and promoter mapping of the gut commensal Bifidobacterium breve UCC2003. AB - BACKGROUND: Bifidobacterium breve represents a common member of the infant gut microbiota and its presence in the gut has been associated with host well being. For this reason it is relevant to investigate and understand the molecular mechanisms underlying the establishment, persistence and activities of this gut commensal in the host environment. RESULTS: The assessment of vegetative promoters in the bifidobacterial prototype Bifidobacterium breve UCC2003 was performed employing a combination of RNA tiling array analysis and cDNA sequencing. Canonical -10 (TATAAT) and -35 (TTGACA) sequences were identified upstream of transcribed genes or operons, where deviations from this consensus correspond to transcription level variations. A Random Forest analysis assigned the -10 region of B. breve promoters as the element most impacting on the level of transcription, followed by the spacer length and the 5'-UTR length of transcripts. Furthermore, our transcriptome study also identified rho-independent termination as the most common and effective termination signal of highly and moderately transcribed operons in B. breve. CONCLUSION: The present study allowed us to identify genes and operons that are actively transcribed in this organism during logarithmic growth, and link promoter elements with levels of transcription of essential genes in this organism. As homologs of many of our identified genes are present across the whole genus Bifidobacterium, our dataset constitutes a transcriptomic reference to be used for future investigations of gene expression in members of this genus. PMID- 29281967 TI - The effects of vitamin D administration on brain inflammatory markers in high fat diet induced obese rats. AB - BACKGROUND: Obesity induced brain inflammation is associated with cognitive disorders. We aimed to investigate the influence of vitamin D on hypothalamus and hippocampus inflammatory response in high-fat diet induced obese rats. METHODS: In the beginning of the study, 40 rats were divided into two groups: control diet and high fat diet (HFD) for 16 weeks; then each group subdivided into two groups including: N, ND + vitamin D, HFD and HFD + vitamin D. Vitamin D supplementation was done for 5 weeks at 500 IU/kg dosage. IL-6, IL-1beta, NF-Kbeta and acetylcholine (ACH) and brain derived neurotropic factor (BDNF) concentrations in hippocampus and hypothalamus homogenate samples were measured by commercial ELISA kits. RESULTS: Vitamin D administration, reduced food intake and weight gain in studied groups (P < 0.001). Vitamin D reduced hippocampus acetylcholine concentrations in ND + vitamin D group (P < 0.001). High fat diet increased hippocampus IL-6 concentrations significantly (P < 0.05) compared with normal diet receiving groups. Vitamin D could not have significant effects on IL-6 concentrations. Vitamin D administrations reduced IL-1beta, NF-Kbeta and acetylcholine concentration and BDNF concentrations in ND + vitamin D compared with ND group. These reductions were not significant in HFD + vitamin D versus HFD group. CONCLUSION: According to our results, vitamin D reduced food intake and weight gain and modulated the HFD induced inflammatory response in hippocampus and hypothalamus of high fat diet induced obesity. Therefore, this neurosteroid, can be suggested as a supplemental therapeutic tool in prevention of obesity related cognitive and neurodegenerative problems. PMID- 29281968 TI - Transcriptome analyses of immune tissues from three Japanese frogs (genus Rana ) reveals their utility in characterizing major histocompatibility complex class II. AB - BACKGROUND: In Japan and East Asia, endemic frogs appear to be tolerant or not susceptible to chytridiomycosis, a deadly amphibian disease caused by the chytrid fungus Batrachochytridium dendrobatidis (Bd). Japanese frogs may have evolved mechanisms of immune resistance to pathogens such as Bd. This study characterizes immune genes expressed in various tissues of healthy Japanese Rana frogs. RESULTS: We generated transcriptome data sets of skin, spleen and blood from three adult Japanese Ranidae frogs (Japanese brown frog Rana japonica, the montane brown frog Rana ornativentris, and Tago's brown frog Rana tagoi tagoi) as well as whole body of R. japonica and R. ornativentris tadpoles. From this, we identified tissue- and stage-specific differentially expressed genes; in particular, the spleen was most enriched for immune-related genes. A specific immune gene, major histocompatibility complex class IIB (MHC-IIB), was further characterized due to its role in pathogen recognition. We identified a total of 33 MHC-IIB variants from the three focal species (n = 7 individuals each), which displayed evolutionary signatures related to increased MHC variation, including balancing selection. Our supertyping analyses of MHC-IIB variants from Japanese frogs and previously studied frog species identified potential physiochemical properties of MHC-II that may be important for recognizing and binding chytrid related antigens. CONCLUSIONS: This is one of the first studies to generate transcriptomic resources for Japanese frogs, and contributes to further understanding the immunogenetic factors associated with resistance to infectious diseases in amphibians such as chytridiomycosis. Notably, MHC-IIB supertyping analyses identified unique functional properties of specific MHC-IIB alleles that may partially contribute to Bd resistance, and such properties provide a springboard for future experimental validation. PMID- 29281969 TI - Functional expression of CCL8 and its interaction with chemokine receptor CCR3. AB - BACKGROUND: Chemokines and their cognate receptors play important role in the control of leukocyte chemotaxis, HIV entry and other inflammatory diseases. Developing an effcient method to investigate the functional expression of chemokines and its interactions with specific receptors will be helpful to asses the structural and functional characteristics as well as the design of new approach to therapeutic intervention. RESULTS: By making systematic optimization study of expression conditions, soluble and functional production of chemokine C C motif ligand 8 (CCL8) in Escherichia coli (E. coli) has been achieved with approx. 1.5 mg protein/l culture. Quartz crystal microbalance (QCM) analysis exhibited that the purified CCL8 could bind with C-C chemokine receptor type 3 (CCR3) with dissociation equilibrium constant (K D) as 1.2 * 10-7 M in vitro. Obvious internalization of CCR3 in vivo could be detected in 1 h when exposed to 100 nM of CCL8. Compared with chemokine C-C motif ligand 11 (CCL11) and chemokine C-C motif ligand 24 (CCL24), a weaker chemotactic effect of CCR3 expressing cells was observed when induced by CCL8 with same concentration. CONCLUSION: This study delivers a simple and applicable way to produce functional chemokines in E. coli. The results clearly confirms that CCL8 can interact with chemokine receptor CCR3, therefore, it is promising area to develop drugs for the treatment of related diseases. PMID- 29281970 TI - Transcriptional effects of a positive feedback circuit in Drosophila melanogaster. AB - BACKGROUND: Synthetic systems that use positive feedback have been developed to control human disease vectors and crop pests. The tTAV system, which has been deployed in several insect species, relies on a positive feedback circuit that can be inhibited via dietary tetracycline. Although insects carrying tTAV fail to survive until adulthood in the absence of tetracycline, the exact reason for its lethality, as well as the transcriptomic effects of an active positive feedback circuit, remain unknown. RESULTS: We engineered the tTAV system in Drosophila melanogaster and investigated the effects of tTAV genome integration locus on the whole fly transcriptome during larval and adult life stages in four transgenic fly strains using gene expression microarrays. We found that while there were widespread effects on the transcriptome, the gene expression differences after removal of tetracycline were not consistent between integration sites. No specific region of the genome was affected, no common set of genes or pathways, nor did the integration site affect the transcripts in cis. CONCLUSION: Although the positive feedback tTAV system is effective at killing insect larvae regardless of where it is inserted in the genome, it does not exhibit a specific, consistent transcriptional signature. Instead, each insertion site is associated with broad, but different, transcriptional effects. Our results suggest that lethality may not be caused by a direct effect on transcription of a set of key genes or pathways. Instead, we propose that rather than a specific action of a tTAV protein, it is the stochastic transcriptional effects specific to each insertion site that contribute to the tTAV-induced mortality. PMID- 29281971 TI - Small RNA profiling for identification of miRNAs involved in regulation of saponins biosynthesis in Chlorophytum borivilianum. AB - BACKGROUND: MicroRNAs act as molecular regulator of cell signaling, plant growth and development, and regulate various primary and secondary plant metabolic processes. In the present study, deep sequencing of small RNAs was carried out to identify known and novel miRNAs from pharmaceutically important plant, Chlorophytum borivilianum. RESULTS: Total 442 known miRNAs and 5 novel miRNAs were identified from young leaf small RNA library. Experimental validation with stem loop RT-PCR confirmed the in silico identification. Based on transcriptome data of root and leaf of C. borivilianum, Oryza sativa, and Arabidopsis thaliana target gene prediction was done using psRNAtarget and mirRanda. BLAST2GO helped in localization of predicted targets and KEGG (Kyoto Encyclopedia for Genes and Genomes) pathway analysis concluded that miR9662, miR894, miR172, and miR166 might be involved in regulating saponin biosynthetic pathway. The correlation between miRNA and its target gene was further validated by RT-qPCR analysis. CONCLUSION: This study provides first elaborated glimpse of miRNA pool of C. borivilianum, which can help to understand the miRNA dependent regulation of saponin biosynthesis and to design further metabolic engineering experiment to enhance their contents in the plant. PMID- 29281972 TI - Mycoplasma genitalium: whole genome sequence analysis, recombination and population structure. AB - BACKGROUND: Although Mycoplasma genitalium is a common sexually transmitted pathogen causing clinically distinct diseases both in male and females, few genomes have been sequenced up to now, due mainly to its fastidious nature and slow growth. Hence, we lack a robust phylogenetic framework to provide insights into the population structure of the species. Currently our understanding of the nature and diversity of M. genitalium relies on molecular tests targeting specific genes or regions of the genome and knowledge is limited by a general under-testing internationally. This is set against a background of drug resistance whereby M. genitalium has developed resistance to mainly all therapeutic antimicrobials. RESULTS: We sequenced 28 genomes of Mycoplasma genitalium from temporally (1980-2010) and geographically (Europe, Japan, Australia) diverse sources. All the strain showed essentially the same genomic content without any accessory regions found. However, we identified extensive recombination across their genomes with a total of 25 regions showing heightened levels of SNP density. These regions include the MgPar loci, associated with host interactions, as well as other genes that could also be involved in this role. Using these data, we generated a robust phylogeny which shows that there are two main clades with differing degrees of genomic variability. SNPs found in region V of 23S rRNA and parC were consistent with azithromycin/erythromycin and fluoroquinolone resistances, respectively, and with their phenotypic MIC data. CONCLUSIONS: The sequence data here generated is essential for designing rational approaches to type and track Mycoplasma genitalium as antibiotic resistance increases. It represents a first approach to its population genetics to better appreciate the role of this organism as a sexually transmitted pathogen. PMID- 29281973 TI - Polymorphic duplicate genes and persistent non-coding sequences reveal heterogeneous patterns of mitochondrial DNA loss in salamanders. AB - BACKGROUND: Mitochondria are the site of the citric acid cycle and oxidative phosphorylation (OXPHOS). In metazoans, the mitochondrial genome is a small, circular molecule averaging 16.5 kb in length. Despite evolutionarily conserved gene content, metazoan mitochondrial genomes show a diversity of gene orders most commonly explained by the duplication-random loss (DRL) model. In the DRL model, (1) a sequence of genes is duplicated in tandem, (2) one paralog sustains a loss of-function mutation, resulting in selection to retain the other copy, and (3) the non-functional paralog is eventually deleted from the genome. Despite its apparent role in generating mitochondrial gene order diversity, little is known about the tempo and mode of random gene loss after duplication events. Here, we determine mitochondrial gene order across the salamander genus Aneides, which was previously shown to include at least two DRL-mediated rearrangement events. We then analyze these gene orders in a phylogenetic context to reveal patterns of DNA loss after mitochondrial gene duplication. RESULTS: We identified two separate duplication events that resulted in mitochondrial gene rearrangements in Aneides; one occurred at the base of the clade tens of millions of years ago, while the other occurred much more recently (i.e. within a single species), resulting in gene order polymorphism and paralogs that are readily identifiable. We demonstrate that near-complete removal of duplicate rRNA genes has occurred since the recent duplication event, whereas duplicate protein-coding genes persist as pseudogenes and duplicate tRNAs persist as functionally intact paralogs. In addition, we show that non-coding DNA duplicated at the base of the clade has persisted across species for tens of millions of years. CONCLUSIONS: The evolutionary history of the mitochondrial genome, from its inception as a bacterial endosymbiont, includes massive genomic reduction. Consistent with this overall trend, selection for efficiency of mitochondrial replication and transcription has been hypothesized to favor elimination of extra sequence. Our results, however, suggest that there may be no strong disadvantage to extraneous sequences in salamander mitochondrial genomes, although duplicate rRNA genes may be deleterious. PMID- 29281975 TI - A survey of prevalence of narrative and systematic reviews in five major medical journals. AB - BACKGROUND: Systematic reviews may provide less biased evidence than narrative reviews because they observe a strict methodology, similarly to primary studies. Hence, for clinical research questions, systematic reviews should be the study design of choice. It would be important to evaluate the prevalence and characteristics of narrative and systematic reviews published in prominent medical journals. Researchers and clinicians give great value to articles published in such scientific journals. This study sought to evaluate the prevalence and characteristics of narrative and systematic reviews in the five highest-ranked general medical journals and investigate the associations among type of review, number of citations, and impact factor (IF). METHODS: We surveyed the five highest-ranked medical journals (The New England Journal of Medicine, The Lancet, The Journal of the American Medical Association, The BMJ, and Annals of Internal Medicine) for narrative and systematic reviews published between June 2015 and June 2016. We independently selected and extracted the data from the reviews by strictly following the pre-determined eligibility criteria (Systematic and narrative reviews that focused on the management of diseases). We conducted regression analyses to investigate the associations among review type, number of citations, and IF. We also descriptively reported narrative reviews containing some methodology that might be reproducible. RESULTS: Two hundred seventy-five reviews were included: 75 (27%) systematic; 126 (46%) narrative with some methodology reported, and 74 (27%) narrative reviews. In comparison to systematic reviews, narrative reviews were more frequently published in journals with higher IF (risk ratio [RR] = 1.114 (95% CI 1.080 to 1.149). Systematic reviews received more citations than narrative reviews (group formed by narrative and narrative with some methodology reported (RR = 0.985 95% CI 0.978 to 0.991). CONCLUSIONS: Non-systematic evidence is the most prevalent type of evidence in reviews published in the five highest-ranked general medical journals. Narrative reviews were more frequently published in journals with higher IF. We recommend that journals limit their space for narrative information, and to address clinical research questions, these journals consider publishing systematic evidence exclusively. PMID- 29281974 TI - Development of an intervention to reduce antibiotic use for childhood coughs in UK primary care using critical synthesis of multi-method research. AB - BACKGROUND: Overuse of antibiotics contributes to the global threat of antimicrobial resistance. Antibiotic stewardship interventions address this threat by reducing the use of antibiotics in occasions or doses unlikely to be effective. We aimed to develop an evidence-based, theory-informed, intervention to reduce antibiotic prescriptions in primary care for childhood respiratory tract infections (RTI). This paper describes our methods for doing so. METHODS: Green and Krueter's Precede/Proceed logic model was used as a framework to integrate findings from a programme of research including 5 systematic reviews, 3 qualitative studies, and 1 cohort study. The model was populated using a strength of evidence approach, and developed with input from stakeholders including clinicians and parents. RESULTS: The synthesis produced a series of evidence based statements summarizing the quantitative and qualitative evidence for intervention elements most likely to result in changes in clinician behaviour. Current evidence suggests that interventions which reduce clinical uncertainty, reduce clinician/parent miscommunication, elicit parent concerns, make clear delayed or no-antibiotic recommendations, and provide clinicians with alternate treatment actions have the best chance of success. We designed a web-based within consultation intervention to reduce clinician uncertainty and pressure to prescribe, designed to be used when children with RTI present to a prescribing clinician in primary care. CONCLUSIONS: We provide a worked example of methods for the development of future complex interventions in primary care, where multiple factors act on multiple actors within a complex system. Our synthesis provided intervention guidance, recommendations for practice, and highlighted evidence gaps, but questions remain about how best to implement these recommendations. The funding structure which enabled a single team of researchers to work on a multi-method programme of related studies (NIHR Programme Grant scheme) was key in our success. TRIAL REGISTRATION: The feasibility study accompanying this intervention was prospectively registered with the ISRCTN registry ( ISRCTN23547970 ), on 27 June 2014. PMID- 29281976 TI - Serum total cholesterol and risk of cardiovascular and non-cardiovascular mortality in old age: a population-based study. AB - BACKGROUND: Whether the suggested inverse association between total cholesterol and mortality in old age varies according to cause of death and use of cholesterol medications remains to be elucidated. The aim of this study was to assess the associations of total cholesterol with cardiovascular and non cardiovascular mortality in old age, and to explore whether their associations vary by use of cholesterol-lowering medications. METHODS: The study participants included 3090 older adults (age >= 60 years, 63.7% women) from a population-based cohort study, i.e., the Swedish National study on Aging and Care in Kungsholmen, Stockholm. At baseline (2001-2004), data on demographic factors, lifestyles, cardiovascular risk factors, use of medications, global cognitive function, mobility limitation, and apolipoprotein E genotype were collected through interviews, clinical examinations, laboratory tests as well as from the Swedish national patient register. Vital statistics data (e.g., date and causes of death) till December 31, 2011 for all participants were derived from Swedish cause of death register. Data were analyzed using Cox proportional hazards model for all cause mortality and Fine-Gray competing risks regression model for cause-specific mortality controlling for multiple potential confounders. RESULTS: During 23,196 person-years of follow-up (median per person, 7.5 years), 1059 (34.3%) participants died. Compared to normal total cholesterol (<5.18 mmol/l), borderline-high (5.18-6.21 mmol/l) and high (>=6.22 mmol/l) total cholesterol were associated with a decreased risk of all-cause mortality, with the multiple adjusted hazard ratio (95% confidence interval, CI) of 0.71 (0.61-0.83) and 0.68 (0.57-0.80), respectively (P for trend <0.001). The competing risk regression models revealed that the reduced all-cause mortality associated with high total cholesterol (>=6.22 mmol/l)) was mainly due to the reduced risk of non cardiovascular mortality (hazard ratio = 0.67, 95% CI = 0.51-0.88). These associations were statistically evident only among individuals without use of cholesterol-lowering medications. CONCLUSIONS: The inverse association between high total cholesterol and reduced all-cause mortality in older adults is primarily due to non-cardiovascular mortality, especially among those who are not treated with cholesterol-lowering medications. PMID- 29281977 TI - N,N-disubstituted azines attenuate LPS-mediated neuroinflammation in microglia and neuronal apoptosis via inhibiting MAPK signaling pathways. AB - BACKGROUND: Activated microglia interact with astrocytes and neuronal cells to induce neuroinflammation, which can contribute to the pathogenesis and progression of Alzheimer's and Parkinson's disease. To identify the most effective anti-neuroinflammatory agent, we designed and synthesized a family of 13 new azine derivatives and investigated their anti-neuroinflammatory activities in LPS-activated BV-2 microglial cells. RESULTS: Out of 13 derivatives, compound 3 [4,4'-(1E,1'E,3E,3'E)-3,3'-(hydrazine-1,2-diylidene) bis-(prop-1-ene-1-yl-3 ylidene) bis-(2-methoxyphenol)] exhibited excellent anti-neuroinflammatory activities (IC50 = 12.47 uM), which protected neurons from microglia-mediated neurotoxicity. Specifically, the anti-neuroinflammatory effects of compound 3 inhibited MAPK signaling pathways through the inhibition of p38 and JNK mediated signaling and the production of pro-inflammatory cytokines, and inflammatory mediators. Additionally, compound 3 strongly exhibited neuroprotective effect by inhibiting LPS-mediated necrosis and apoptosis. Preliminary SAR analysis suggests that the presence of methoxyphenol and the substitution pattern within hydrazine may influence the anti-neuroinflammatory activity. FACS analysis also strongly supports the neuroprotective effect of compound 3. CONCLUSIONS: Based on our results, the compound 3 exhibited excellent anti-neuroinflammatory activity against LPS-activated microglia, which resulted in the inhibition of neuronal apoptosis and neuronal degeneration. PMID- 29281978 TI - Prevalence and control of hypertension among a Community of Elderly Population in Changning District of shanghai: a cross-sectional study. AB - BACKGROUND: Hypertension is considered a major public health challenge. It is the most important risk factor for cardiovascular disease and is a prominent risk for China's elderly population. However, few studies have addressed the effect of blood pressure control on elderly hypertension patients in China. In response, this study aimed to investigate the prevalence and control of hypertension in the elderly population in Shanghai's communities. METHODS: A secondary data analysis based on a government-financed health check-up program for an elderly population aged 65 and older from 2012 to 2014 was conducted in a central district of Shanghai. RESULTS: Of the 44,978 study participants, 20,305 (45.1%) were males and 24,673 (54.9%) were females. The participants' median age was 72. Half of the participants were overweight or obese (BMI >= 24.0 kg/m2). The prevalence of hypertension was 59.9%. In the 18,032 participants without prior diagnosis of hypertension, 5530 (30.7%) had increased blood pressure. Among the 26,946 confirmed hypertension patients, the proportions of treatment and blood pressure control were 32.8% and 43.4% respectively. Multivariate analysis showed that the uncontrolled hypertension was significantly associated with older age, being overweight or obese, a lower level of education, an unbalanced dietary pattern, regular drinking and non-comorbidities. CONCLUSIONS: The prevalence of hypertension was high in China's elderly population. The proportion of individuals who received treatment remained low, and blood pressure control was poor among hypertension patients. These results indicate that improvement of the ability to manage and control hypertension among urban elderly residents is urgently needed. PMID- 29281979 TI - Resistant and susceptible chicken lines show distinctive responses to Newcastle disease virus infection in the lung transcriptome. AB - BACKGROUND: Newcastle disease virus (NDV) is a threat to poultry production worldwide. A better understanding of mechanisms of resistance and susceptibility to this virus will improve measures for NDV prevention and control. Males and females from resistant Fayoumi and susceptible Leghorn lines were either challenged with a lentogenic strain of the virus or given a mock infection at 3 weeks of age. The lung transcriptomes generated by RNA-seq were studied using contrasts across the challenged and nonchallenged birds, the two lines, and three time points post-infection, and by using Weighted Gene Co-expression Network Analysis (WGNCA). RESULTS: Genetic line and sex had a large impact on the lung transcriptome. When contrasting the challenged and nonchallenged birds, few differentially expressed genes (DEG) were identified within each line at 2, 6, and 10 days post infection (dpi), except for the more resistant Fayoumi line at 10 dpi, for which several pathways were activated and inhibited at this time. The interaction of challenge and line at 10 dpi significantly impacted 131 genes (False Discovery Rate (FDR) <0.05), one of which was PPIB. Many DEG were identified between the Fayoumi and Leghorns. The number of DEG between the two lines in the challenged birds decreased over time, but increased over time in the nonchallenged birds. The nonchallenged Fayoumis at 10 dpi showed enrichment of immune type cells when compared to 2 dpi, suggesting important immune related development at this age. These changes between 10 and 2 dpi were not identified in the challenged Fayoumis. The energy allocated to host defense may have interrupted normal lung development. WGCNA identified important modules and driver genes within those modules that were associated with traits of interest, several of which had no known associated function. CONCLUSIONS: The lines' unique response to NDV offers insights into the potential means of their resistance and susceptibility. The lung transcriptome shows a unique response to lentogenic NDV compared to a previous study on the trachea of the same birds. It is important to analyze multiple tissues in order to best understand the chicken's overall response to NDV challenge and improve strategies to combat this devastating disease. PMID- 29281980 TI - Who is on the primary care team? Professionals' perceptions of the conceptualization of teams and the underlying factors: a mixed-methods study. AB - BACKGROUND: Due to the growing prevalence of elderly patients with multi morbidity living at home, there is an increasing need for primary care professionals from different disciplinary backgrounds to collaborate as primary care teams. However, it is unclear how primary care professionals conceptualize teams and what underlying factors influence their perception of being part of a team. Our research question is: What are primary care professionals' perceptions of teams and team membership among primary care disciplines and what factors influence their perceptions? METHODS: We conducted a mixed-methods study in the Dutch primary care setting. First, a survey study of 152 professionals representing 12 primary care disciplines was conducted, focusing on their perceptions of which disciplines are part of the team and the degree of relational coordination between professionals from different disciplinary backgrounds. Subsequently, we conducted semi-structured interviews with 32 professionals representing 5 primary care disciplines to gain a deeper understanding of the underlying factors influencing their perceptions and the (mis)alignment between these perceptions. RESULTS: Misalignments were found between perceptions regarding which disciplines are members of the team and the relational coordination between disciplines. For example, general practitioners were viewed as part of the team by helping assistants, (district) nurses, occupational therapists and geriatric specialized practice nurses, whereas the general practitioners themselves only considered geriatric specialized practice nurses to be part of their team. Professionals perceive multidisciplinary primary care teams as having multiple inner and outer layers. Three factors influence their perception of being part of a team and acting accordingly: a) knowing the people you work with, b) the necessity for knowledge exchange and c) sharing a holistic view of caregiving. CONCLUSION: Research and practice should take into account the misalignment between primary care professionals' perceptions of primary care teams, as our study notes variations in the conceptualization of primary care teams. To enhance teamwork between professionals from different disciplinary backgrounds, professionals acknowledge the importance of three underlying conditions: team familiarity, regular and structured knowledge exchange between all professionals involved in the care process and realizing and believing in the added value for patients of working as a team. PMID- 29281981 TI - Compliance of systematic reviews in ophthalmology with the PRISMA statement. AB - BACKGROUND: Systematic reviews and meta-analyses are becoming increasingly important methods to summarize published research. Studies of ophthalmology may present additional challenges because of their potentially complex study designs. The aim of this study was to evaluate the reporting quality of systematic reviews and meta-analyses on topics in ophthalmology to determine compliance with the PRISMA guidelines. We assessed articles published between 2010 and 2015 in the five major relevant journals with the highest impact factors. METHODS: The MEDLINE and EMBASE databases were searched to identify systematic reviews published between January 2010 and December 2015 in the following 5 major ophthalmology journals: Progress in Retinal and Eye Research, Ophthalmology, Archives of Ophthalmology, American Journal of Ophthalmology, and Survey of Ophthalmology. The screening, identification, and scoring of articles were independently performed by two teams, and the results were submitted to statistical analysis to determine medians, ranges, and 95% CIs. RESULTS: A total of 115 articles were included. The median compliance was 15 out of 27 items (56%), the range was 5-26 (26-96%), and the inter-quartile range was 10 (37%). Compliance was highest in items related to the 'description of rationale' (item 3, 100%) and sequentially lower in 'the general interpretation of results' (item 26, 96%) and 'the inclusion of a structured summary in the abstract' (item 2, 90%). Compliance was poorest in the items 'indication of review protocol and registration' (item 5, 9%), 'specification of risk of biases that may affect the cumulative evidence' (item 15, 24%), and 'description of clear objectives in the introduction' (item 4, 26%). CONCLUSION: The reporting quality of systematic reviews and meta-analyses in ophthalmology should be significantly improved. While we recommend the use of the PRISMA criteria as a guideline before journal submission, additional research aimed at identifying potential barriers to compliance may be required to improve compliance with PRISMA guidelines. PMID- 29281982 TI - Polyamines in the life of Arabidopsis: profiling the expression of S adenosylmethionine decarboxylase (SAMDC) gene family during its life cycle. AB - BACKGROUND: Arabidopsis has 5 paralogs of the S-adenosylmethionine decarboxylase (SAMDC) gene. Neither their specific role in development nor the role of positive/purifying selection in genetic divergence of this gene family is known. While some data are available on organ-specific expression of AtSAMDC1, AtSAMDC2, AtSAMDC3 and AtSAMDC4, not much is known about their promoters including AtSAMDC5, which is believed to be non-functional. RESULTS: (1) Phylogenetic analysis of the five AtSAMDC genes shows similar divergence pattern for promoters and coding sequences (CDSs), whereas, genetic divergence of 5'UTRs and 3'UTRs was independent of the promoters and CDSs; (2) while AtSAMDC1 and AtSAMDC4 promoters exhibit high activity (constitutive in the former), promoter activities of AtSAMDC2, AtSAMDC3 and AtSAMDC5 are moderate to low in seedlings (depending upon translational or transcriptional fusions), and are localized mainly in the vascular tissues and reproductive organs in mature plants; (3) based on promoter activity, it appears that AtSAMDC5 is both transcriptionally and translationally active, but based on it's coding sequence it seems to produce a non-functional protein; (4) though 5'-UTR based regulation of AtSAMDC expression through upstream open reading frames (uORFs) in the 5'UTR is well known, no such uORFs are present in AtSAMDC4 and AtSAMDC5; (5) the promoter regions of all five AtSAMDC genes contain common stress-responsive elements and hormone-responsive elements; (6) at the organ level, the activity of AtSAMDC enzyme does not correlate with the expression of specific AtSAMDC genes or with the contents of spermidine and spermine. CONCLUSIONS: Differential roles of positive/purifying selection were observed in genetic divergence of the AtSAMDC gene family. All tissues express one or more AtSAMDC gene with significant redundancy, and concurrently, there is cell/tissue-specificity of gene expression, particularly in mature organs. This study provides valuable information about AtSAMDC promoters, which could be useful in future manipulation of crop plants for nutritive purposes, stress tolerance or bioenergy needs. The AtSAMDC1 core promoter might serve the need of a strong constitutive promoter, and its high expression in the gametophytic cells could be exploited, where strong male/female gametophyte-specific expression is desired; e.g. in transgenic modification of crop varieties. PMID- 29281983 TI - Resource competition promotes tumour expansion in experimentally evolved cancer. AB - BACKGROUND: Tumour progression involves a series of phenotypic changes to cancer cells, each of which presents therapeutic targets. Here, using techniques adapted from microbial experimental evolution, we investigate the evolution of tumour spreading - a precursor for metastasis and tissue invasion - in environments with varied resource supply. Evolutionary theory predicts that competition for resources within a population will select for individuals to move away from a natal site (i.e. disperse), facilitating the colonisation of unexploited resources and decreasing competition between kin. RESULTS: After approximately 100 generations in environments with low resource supply, we find that MCF7 breast cancer spheroids (small in vitro tumours) show increased spreading. Conversely, spreading slows compared to the ancestor where resource supply is high. Common garden experiments confirm that the evolutionary responses differ between selection lines; with lines evolved under low resource supply showing phenotypic plasticity in spheroid spreading rate. These differences in spreading behaviour between selection lines are heritable (stable across multiple generations), and show that the divergently evolved lines differ in their response to resource supply. CONCLUSIONS: We observe dispersal-like behaviour and an increased sensitivity to resource availability in our selection lines, which may be a response to selection, or alternatively may be due to epigenetic changes, provoked by prolonged resource limitation, that have persisted across many cell generations. Different clinical strategies may be needed depending on whether or not tumour progression is due to natural selection. This study highlights the effectiveness of experimental evolution approaches in cancer cell populations and demonstrates how simple model systems might enable us to observe and measure key selective drivers of clinically important traits. PMID- 29281984 TI - The alarming problems of confounding equivalence using logistic regression models in the perspective of causal diagrams. AB - BACKGROUND: Confounders can produce spurious associations between exposure and outcome in observational studies. For majority of epidemiologists, adjusting for confounders using logistic regression model is their habitual method, though it has some problems in accuracy and precision. It is, therefore, important to highlight the problems of logistic regression and search the alternative method. METHODS: Four causal diagram models were defined to summarize confounding equivalence. Both theoretical proofs and simulation studies were performed to verify whether conditioning on different confounding equivalence sets had the same bias-reducing potential and then to select the optimum adjusting strategy, in which logistic regression model and inverse probability weighting based marginal structural model (IPW-based-MSM) were compared. The "do-calculus" was used to calculate the true causal effect of exposure on outcome, then the bias and standard error were used to evaluate the performances of different strategies. RESULTS: Adjusting for different sets of confounding equivalence, as judged by identical Markov boundaries, produced different bias-reducing potential in the logistic regression model. For the sets satisfied G-admissibility, adjusting for the set including all the confounders reduced the equivalent bias to the one containing the parent nodes of the outcome, while the bias after adjusting for the parent nodes of exposure was not equivalent to them. In addition, all causal effect estimations through logistic regression were biased, although the estimation after adjusting for the parent nodes of exposure was nearest to the true causal effect. However, conditioning on different confounding equivalence sets had the same bias-reducing potential under IPW-based-MSM. Compared with logistic regression, the IPW-based-MSM could obtain unbiased causal effect estimation when the adjusted confounders satisfied G-admissibility and the optimal strategy was to adjust for the parent nodes of outcome, which obtained the highest precision. CONCLUSIONS: All adjustment strategies through logistic regression were biased for causal effect estimation, while IPW-based-MSM could always obtain unbiased estimation when the adjusted set satisfied G admissibility. Thus, IPW-based-MSM was recommended to adjust for confounders set. PMID- 29281985 TI - Deep convolutional neural networks for pan-specific peptide-MHC class I binding prediction. AB - BACKGROUND: Computational scanning of peptide candidates that bind to a specific major histocompatibility complex (MHC) can speed up the peptide-based vaccine development process and therefore various methods are being actively developed. Recently, machine-learning-based methods have generated successful results by training large amounts of experimental data. However, many machine learning-based methods are generally less sensitive in recognizing locally-clustered interactions, which can synergistically stabilize peptide binding. Deep convolutional neural network (DCNN) is a deep learning method inspired by visual recognition process of animal brain and it is known to be able to capture meaningful local patterns from 2D images. Once the peptide-MHC interactions can be encoded into image-like array(ILA) data, DCNN can be employed to build a predictive model for peptide-MHC binding prediction. In this study, we demonstrated that DCNN is able to not only reliably predict peptide-MHC binding, but also sensitively detect locally-clustered interactions. RESULTS: Nonapeptide HLA-A and -B binding data were encoded into ILA data. A DCNN, as a pan-specific prediction model, was trained on the ILA data. The DCNN showed higher performance than other prediction tools for the latest benchmark datasets, which consist of 43 datasets for 15 HLA-A alleles and 25 datasets for 10 HLA-B alleles. In particular, the DCNN outperformed other tools for alleles belonging to the HLA-A3 supertype. The F1 scores of the DCNN were 0.86, 0.94, and 0.67 for HLA-A*31:01, HLA-A*03:01, and HLA-A*68:01 alleles, respectively, which were significantly higher than those of other tools. We found that the DCNN was able to recognize locally-clustered interactions that could synergistically stabilize peptide binding. We developed ConvMHC, a web server to provide user-friendly web interfaces for peptide-MHC class I binding predictions using the DCNN. ConvMHC web server can be accessible via http://jumong.kaist.ac.kr:8080/convmhc . CONCLUSIONS: We developed a novel method for peptide-HLA-I binding predictions using DCNN trained on ILA data that encode peptide binding data and demonstrated the reliable performance of the DCNN in nonapeptide binding predictions through the independent evaluation on the latest IEDB benchmark datasets. Our approaches can be applied to characterize locally-clustered patterns in molecular interactions, such as protein/DNA, protein/RNA, and drug/protein interactions. PMID- 29281986 TI - Preschool children in out-of-hours primary care - a questionnaire-based cross sectional study of factors related to the medical relevance of health problems. AB - BACKGROUND: Out-of-hours primary care (OOH-PC) is intended to provide medical care services for health problems that cannot wait until normal office hours. Children under five years of age represent about 19% of all OOH-PC contacts in Denmark, and the frequency of calls assessed as severe by health professionals is markedly lower for children than for other age groups. Several studies have questioned the appropriateness of the parents' use of OOH-PC. We aimed to identify factors associated with calls from parents of pre-school children concerning perceived non-severe health problems that were ranked by the triaging GPs as more appropriate for GP office hours (defined as 'medically irrelevant'). METHODS: We used data from a cross-sectional study performed in the Central Denmark Region for a 1-year period during 2010-2011. GPs in the OOH-PC assessed random contacts, and a questionnaire was subsequently sent to registered patients. Associations between different factors and the medical irrelevance of contacts were estimated with a generalised linear model to calculate the prevalence ratio (PR). RESULTS: Among all included 522 telephone consultations and 1226 face-to-face consultations, we identified 71 (13.6%) telephone consultations and 95 (7.8%) face-to-face consultations that were both assessed as non-severe by the parents and more appropriate for GP office hours by the GPs. For telephone consultations, contacts at other times than 4-8 pm on weekdays were statistically significantly associated with medical irrelevance. Additionally, symptoms of longer duration than 24 h were statistically significantly associated medical irrelevance. CONCLUSIONS: A large part of the calls to the Danish OOH-PC concern children. The results indicate that some of these calls are made for other than strictly medical reasons. To achieve more effective use of available resources, it might seem relevant to aim at directing more contacts directly to daytime care. However, future studies to enhance our knowledge on parents' motivation and behaviour would be recommendable. PMID- 29281987 TI - ORFeome-based identification of biomarkers for serodiagnosis of Mycobacterium tuberculosis latent infection. AB - BACKGROUND: The challenges posed by Mycobacterium tuberculosis infection require the gradual removal of the pool of latent tuberculosis infection (LTBI). The current cell-immune-based diagnostic tests used to identify LTBI individuals have several irreversible drawbacks. In the present study, we attempted to identify novel diagnostic antigens for LTBI. METHODS: A high-throughput glutathione S transferase (GST)-fusion technology was used to express over 409 TB proteins and sera from LTBI and healthy individuals was used to interrogate these GST-TB fusion proteins. RESULTS: Of 409 TB proteins, sixty-three reacted seropositive and defined the immuno-ORFeome of latent M. tuberculosis. Within the immuno ORFeome, the rare targets were predominantly latency-associated proteins and secreted proteins, while the preferentially recognized antigens tended to be transmembrane proteins. Six of novel highly-reactive antigens had the potential to distinguish LTBI from active TB and healthy individuals. A multiple-antigen combination set was selected through analysis of various combinations. A panel of 94 archived serum samples was used to validate the diagnostic performance of the multiple-antigen combination set, which had sensitivity of 66.1% (95% CI 52.9, 77.4) and specificity of 87.5% (95% CI 70.1, 95.1). CONCLUSION: These results provide experimental evidence of the immunogenicity of novel TB proteins that are suitable for the development of serodiagnostic tools for LTBI. PMID- 29281988 TI - Intravenous artesunate plus Artemisnin based Combination Therapy (ACT) or intravenous quinine plus ACT for treatment of severe malaria in Ugandan children: a randomized controlled clinical trial. AB - BACKGROUND: Severe malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence. METHODS: In a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda. RESULTS: We enrolled 300 participants and all were included in the intention to treat analysis. Baseline characteristics were similar across treatment arms. The median and interquartile range for number of days from baseline to parasite clearance was significantly lower among participants who received intravenous AS (2 (1-2) vs 3 (2-3), P < 0.001). Overall, 63.3% (178/281) of the participants had unadjusted parasitological treatment failure over the 42-day follow-up period. Molecular genotyping to distinguish re-infection from recrudescence was performed in a sample of 127 of the 178 participants, of whom majority 93 (73.2%) had re-infection and 34 (26.8%) had recrudescence. The 42 day risk of recrudescence did not differ with ACT administered. Adverse events were of mild to moderate severity and consistent with malaria symptoms. CONCLUSION: In this high transmission setting, we observed adequate initial treatment outcomes followed by very high rates of malaria re infection post severe malaria treatment. The impact of recurrent antimalarial treatment on the long term efficacy of antimalarial regimens needs to be investigated and surveillance mechanisms for resistance markers established since recurrent malaria infections are likely to be exposed to sub-therapeutic drug concentrations. More strategies for prevention of recurrent malaria infections in the most at risk populations are needed. TRIAL REGISTRATION: The study was registered with the Pan African Clinical Trial Registry ( PACTR201110000321348 ). PMID- 29281989 TI - Necrotizing soft tissue infection: clinical characteristics and outcomes at a reconstructive center in Jilin Province. AB - BACKGROUND: To investigate the clinical characteristics and treatment outcomes in necrotizing fasciitis (NF) patients in a reconstructive unit in northeastern China. METHODS: Medical records of patients diagnosed with and treated for NF in the extremities from November 2013 to December 2016 were retrospectively reviewed. Demographic data, clinical presentation, duration of signs and symptoms, location of infection, predisposing factors, causative microbiological organisms, laboratory risk indicator for necrotizing fasciitis (LRINEC) score, number of surgical debridements, length of hospital stay, treatments, and outcomes were recorded. RESULTS: A total of 39 consecutive patients were treated for severe NF (32 male and 7 female). Diabetes mellitus and blunt trauma were the most common risk factors (13 and 9 cases, respectively). The positive predictive value of the LRINEC score in NF diagnosis was 46.2%. Mean duration of signs and symptoms was 4.6 days. Staphylococcus aureus was the most commonly isolated bacteria (20 cases). All patients underwent their first debridement within 12 h of presentation (mean, 4.6 h). Mean number of surgical treatments was 2.8 (range, 2-5) per patient, including debridements. All patients survived, and mean length of hospital stay was 30.81 (range, 21-43) days. Three patients underwent limb amputation. CONCLUSIONS: In our clinical experience, early detection and aggressive debridement are the cornerstones of NF treatment. Antibiotic therapy and intensive care support is essential in severe cases of NF. Anaerobic tissue culture and frozen section biopsy could be adopted as routine tests for diagnosis and decision-making in NF. These findings should inform clinical decisions about the treatment of individual patients with NF. PMID- 29281990 TI - The global effect of maternal education on complete childhood vaccination: a systematic review and meta-analysis. AB - BACKGROUND: There is an established correlation between maternal education and reduction in childhood mortality. One proposed link is that an increase in maternal education will lead to an increase in health care access and vaccine uptake. Vaccinations are a central preventative child health tool, therefore demonstrating the importance of understanding factors that can improve coverage. This review aims to establish if there is a correlation between increasing maternal education and vaccine uptake and if this varies between continents, setting and time. METHODS: An electronic database search was conducted using Medline Ovid, Embase and The Cochrane Library using a combination of keywords and appropriate MeSH terms for maternal education and child vaccination. Bibliographies were also hand searched. Data was extracted and entered onto a Microsoft Excel spreadsheet and analysed using STATA 13.0 software. The primary outcome of effect size of maternal education on completion of childhood vaccinations was analysed at different levels. Secondary outcomes were explored using subgroup analyses of differences between continents, rural or urban settings, and dates. RESULTS: The online search yielded 3430 papers, 37 were included in this study. The analysis showed increasing child vaccination uptake with increasing maternal education. Overall, analysis showed that the odds of full childhood vaccination were 2.3 times greater in children whose mother received secondary or higher education when compared to children whose mother had no education. There was large variability in the effect size between the studies included. CONCLUSIONS: Improving maternal education is important for increasing childhood vaccination uptake and coverage. Further research is needed in higher income countries. TRIAL REGISTRATION: PROSPERO Registration No: CRD42016042409 . PMID- 29281991 TI - Superb microvascular imaging (SMI) compared with conventional ultrasound for evaluating thyroid nodules. AB - BACKGROUND: Superb microvascular imaging (SMI) for depiction of microvascular flow in thyroid nodules was compared with color/power Doppler imaging (CDI/PDI) and contrast-enhanced ultrasonography (CEUS). In addition, the diagnostic performance of conventional ultrasound combined with SMI for differentiating benign and malignant thyroid nodules was evaluated. METHODS: Preoperative conventional ultrasound consisting of gray-scale ultrasonography and CDI/PDI, followed by SMI and CEUS, was used to record 52 thyroid nodules. Two radiologists analyzed the gray-scale ultrasound signs and nodules' microvascular flow patterns to differentiate between benign (n = 13) and malignant nodules (n = 39). RESULTS: SMI was significantly more effective in the detection of microvascular flow signals than CDI/PDI. In malignant nodules, SMI depicted the presence of incomplete surrounding periphery microvasculature and of disordered heterogeneous internal microvasculature. Benign nodules showed complete surrounding periphery microvasculature (ring sign) and homogeneity internal branching. The accuracies of conventional ultrasound combined with CDI/ PDI, SMI, or CEUS for predicting malignancy were 67.31, 86.54, and 92.31%, respectively. The accuracy of SMI differed significantly from CDI/PDI (P = 0.012), but not from CEUS (P = 0.339). CONCLUSIONS: Microvascular flow and vessel branching in the peripheral and internal microvasculature of thyroid nodules is depicted with greater detail and clarity with SMI compared with conventional ultrasound. SMI offers a safe and low cost alternative to CEUS for differentiating between benign and malignant thyroid nodules. PMID- 29281992 TI - Rapidly-growing mycobacterial infection: a recognized cause of early-onset prosthetic joint infection. AB - BACKGROUND: Prosthetic joint infection (PJI) is a major complication of total hip and total knee arthroplasty (THA, TKA). Although mycobacteria are rarely the causative pathogens, it is important to recognize and treat them differently from non-mycobacterial infections. This study aimed to compare the clinical characteristics, associated factors and long-term outcomes of mycobacterial and non-mycobacterial PJI. METHODS: We conducted a retrospective case-control study of patients aged >=18 years who were diagnosed with PJI of the hip or knee at Siriraj Hospital from January 2000 to December 2012. Patient characteristics, clinical data, treatments and outcomes were evaluated. RESULTS: A total of 178 patients were included, among whom 162 had non-mycobacterial PJI and 16 had mycobacterial PJI. Rapidly growing mycobacteria (RGM) (11) and M. tuberculosis (MTB) (5) were the causative pathogens of mycobacterial PJI. PJI duration and time until onset were significantly different between mycobacterial and non mycobacterial PJI. Infection within 90 days of arthroplasty was significantly associated with RGM infection (OR 21.86; 95% CI 4.25-112.30; p < .001). Implant removal was associated with improved favorable outcomes at 6 months (OR 5.96; 95% CI 1.88-18.88; p < .01) and 12 months (OR 3.96; 95% CI 1.15-13.71; p = .03) after the infection. CONCLUSIONS: RGM were the major pathogens of early onset PJI after THA and TKA. Both a high clinical index of suspicion and mycobacterial cultures are recommended when medically managing PJI with negative cultures or non response to antibiotics. Removal of infected implants was associated with favorable outcomes. PMID- 29281993 TI - Vitamin E protects against extraskeletal calcification in uremic rats fed high fat diets. AB - BACKGROUND: High fat diets are implicated in the pathogenesis of metabolic syndrome, obesity and renal disease. Previous studies have revealed that high fat diets promote vascular calcification in uremic rats. Moreover, vitamin E has been shown to prevent uremic calcifications in genetically obese Zucker rats fed standard diet. The objective of this study was to investigate the influence of vitamin E supplementation on the development of extraskeletal calcifications in non-obese (wild type) uremic rats fed high fat diets. METHODS: Wistar rats (n = 32) were preconditioned by feeding either a normal (NF) or high fat (HF) diet for 45 days and subsequently were subjected to 5/6 nephrectomy (Nx). Just before performing the first Nx step, a blood sample (Pre-Nx) was obtained. After Nx rats were switched to a diet with 0.9% phosphorus and supplemented with calcitriol. Also, after Nx, half of the rats from each group (NF and HF) were treated with vitamin E (VitE) in the diet (30,000 mg/kg) and the other half were maintained on basic VitE requirements (27 mg/kg). Thus, rats were allotted to four experimental groups: Nx-NF (n = 8), Nx-NF-VitE (n = 8), Nx-HF (n = 8) and Nx-HF-VitE (n = 8). At the time of sacrifice (day 66), blood and tissue samples were obtained. RESULTS: Feeding a HF diet for 45 days did not increase body weight but elicited hyperglycemia, hypertriglyceridemia, an increase in plasma fibroblast growth factor 23 and a reduction in plasma calcitriol concentrations. After Nx, rats fed HF diet showed substantial extraskeletal calcification with aortic calcium content that was higher than in rats fed NF diet. Supplementation with VitE significantly (p < 0.05) reduced aortic (from 38.4 +/- 8.8 to 16.5 +/- 1.4 mg/g), gastric (from 5.6 +/- 2.7 to 1.2 +/- 0.4 mg/g) and pulmonary (from 1.8 +/- 0.3 to 0.3 +/- 0.2 mg/g) calcium content in rats on HF diets. CONCLUSIONS: Uremic rats fed HF diets developed more severe extraosseous calcifications than their normocaloric-fed counterparts and dietary VitE supplementation protected against uremic calcifications in rats fed HF diets. Thus, eating energy-rich foods should be discouraged in patients with renal disease and their deleterious effect may be ameliorated with adequate antioxidant supply. PMID- 29281994 TI - Successful treatment of cerebral aspergillosis: case report of a patient with T cell large granular lymphocytic leukemia (T-LGL). AB - BACKGROUND: Invasive aspergillosis involving patients with neutropenia or severe immunosuppression, such as patients with hematologic malignancies is associated with high mortality. Patients with T-cell large granular lymphocytic leukemia (T LGL) on the other hand are considered to be less vulnerable for severe opportunistic fungal infection as their course of disease is chronic and marked by less violent cytopenia then in e.g. Aplastic Anemia. Only neutropenia is regarded as independent risk factor for severe opportunistic infection in T-LGL patients. CASE PRESENTATION: We report a case of a 53 year old patient with T LGL, Immune-Thrombocytopenia (ITP) and combined antibody deficiency, who presented with fever and reduced general condition. The patient revealed a complicated infection involving the lungs and later the brain, with the presentation of vomiting and seizures. Broad microbiological testing of blood-, lung- and cerebrospinal fluid samples was inconclusive. In the absence of mycological proof, Aspergillus infection was confirmed by pathological examination of a brain specimen and finally successfully treated with liposomal amphotericin B and voriconazole, adopting a long-term treatment scheme. CONCLUSIONS: Beyond typical problems in the clinical practice involving fungal infections and hematologic malignancies, this case of invasive aspergillosis in a patient with T-LGL illustrates caveats in diagnosis, therapy and follow-up. Our data support careful ambulatory monitoring for patients with T-LGL, even in the absence of neutropenia. Especially those patients with combined hematologic malignancies and immune defects are at risk. Long-term treatment adhesion for 12 months with sufficient drug levels was necessary for sustained clearance from infection. PMID- 29281995 TI - Prevalence and correlates of frailty in an older rural African population: findings from the HAALSI cohort study. AB - BACKGROUND: Frailty is a key predictor of death and dependency, yet little is known about frailty in sub-Saharan Africa despite rapid population ageing. We describe the prevalence and correlates of phenotypic frailty using data from the Health and Aging in Africa: Longitudinal Studies of an INDEPTH Community cohort. METHODS: We analysed data from rural South Africans aged 40 and over. We used low grip strength, slow gait speed, low body mass index, and combinations of self reported exhaustion, decline in health, low physical activity and high self reported sedentariness to derive nine variants of a phenotypic frailty score. Each frailty category was compared with self-reported health, subjective wellbeing, impairment in activities of daily living and the presence of multimorbidity. Cox regression analyses were used to compare subsequent all-cause mortality for non-frail (score 0), pre-frail (score 1-2) and frail participants (score 3+). RESULTS: Five thousand fifty nine individuals (mean age 61.7 years, 2714 female) were included in the analyses. The nine frailty score variants yielded a range of frailty prevalences (5.4% to 13.2%). For all variants, rates were higher in women than in men, and rose steeply with age. Frailty was associated with worse subjective wellbeing, and worse self-reported health. Both prefrailty and frailty were associated with a higher risk of death during a mean 17 month follow up for all score variants (hazard ratios 1.29 to 2.41 for pre frail vs non-frail; hazard ratios 2.65 to 8.91 for frail vs non-frail). CONCLUSIONS: Phenotypic frailty could be measured in this older South African population, and was associated with worse health, wellbeing and earlier death. PMID- 29281996 TI - The diagnostic performance of 18F-FAMT PET and 18F-FDG PET for malignancy detection: a meta-analysis. PMID- 29281997 TI - Meta-analysis of the safety of voriconazole in definitive, empirical, and prophylactic therapies for invasive fungal infections. AB - BACKGROUND: Voriconazole has been used in the treatment and prophylaxis of invasive fungal infections (IFIs) while its wide use was limited by some frequent adverse events, especially neurotoxicity, hepatotoxicity and even renal disruption. The aim of this study was to comprehensively compare voriconazole induced toxicity, including tolerability, neurotoxicity, visual toxicity, hepatotoxicity and nephrotoxicity with the composite of other antifungals commonly used in clinic. METHODS: Bibliography databases were searched to select randomized controlled trials providing information about the incidence of toxicity referred above. A total of 4122 patients from 16 studies were included in the meta-analysis. RESULTS: Analysis of individual types of toxicity showed that there was a significant difference between voriconazole and the composite of other antifungal agents. The primary outcome, the tolerability of voriconazole was slightly inferior (OR = 1.71, 95% CI = 1.21-2.40, P = 0.002) and it is noteworthy that the probabilities of neurotoxicity and visual toxicity were around twice higher and six-fold for voriconazole compared with the counterpart (OR = 1.99, 95% CI = 1.05-3.75, P = 0.03 and OR = 6.50, 95% CI = 2.93-14.41, P < 0.00001, respectively). Hepatotoxicity was more common in voriconazole group (OR = 1.60, 95% CI = 1.17-2.19, P = 0.003) whereas its pooled risk of nephrotoxicity was about half of the composite of other five antifungal agents (OR = 0.46, 95% CI = 0.26-0.84, P = 0.01). CONCLUSION: Our analysis has revealed differences in multiple types of toxicity induced by VRC versus other antifungals and quantified the corresponding pooled risks, which could provide an alternative for patients with a certain antifungal intolerance and help the clinician to select the optimal intervention. PMID- 29281998 TI - Interaction of healthcare worker hands and portable medical equipment: a sequence analysis to show potential transmission opportunities. AB - BACKGROUND: While research has demonstrated the importance of a clean health care environment, there is a lack of research on the role portable medical equipment (PME) play in the transmission cycle of healthcare-acquired infections (HAIs). This study investigated the patterns and sequence of contact events among health care workers, patients, surfaces, and medical equipment in a hospital environment. METHODS: Research staff observed patient care events over six different 24 h periods on six different hospital units. Each encounter was recorded as a sequence of events and analyzed using sequence analysis and visually represented by network plots. In addition, a point prevalence microbial sample was taken from the computer on wheels (COW). RESULTS: The most touched items during patient care was the individual patient (850), bedrail (375), bed surface (302), and bed side Table (223). Three of the top ten most common subsequences included touching PME and the patient: computer on wheels ? patient (62 of 274 total sequences, 22.6%, contained this sequence), patient ? COW (20.4%), and patient ? IV pump (16.1%). The network plots revealed large interconnectedness among objects in the room, the patient, PME, and the healthcare worker. CONCLUSIONS: Our results demonstrated that PME such as COW and IV pump were two of the most highly-touched items during patient care. Even with proper hand sanitization and personal protective equipment, this sequence analysis reveals the potential for contamination from the patient and environment, to a vector such as portable medical equipment, and ultimately to another patient in the hospital. PMID- 29281999 TI - Invasive micropapillary carcinoma of the breast overexpresses MUC4 and is associated with poor outcome to adjuvant trastuzumab in HER2-positive breast cancer. AB - BACKGROUND: Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. METHODS: We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry. RESULTS: IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma. CONCLUSION: In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently monitored and/or receive additional therapies. PMID- 29282000 TI - The association between anemia and falls in community-living women and men aged 65 years and older from the fifth Tromso Study 2001-02: a replication study. AB - BACKGROUND: Falls are common among elderly people, and the risk increase with age. Falls are associated with both health and social consequences for the patient, and major societal costs. Identification of risk factors should be investigated to prevent falls. Previous studies have shown anemia to be associated with increased risk of falling, but the results are inconsistent. The aim of this study was to investigate the association between anemia and self reported falls among community-living elderly people. The study is a replication of the study by Thaler-Kall and colleagues from 2014, who studied the association between anemia and self-reported falls among 967 women and men 65 years and older in the KORA-Age study from 2009. METHODS: We included 2441 participants (54% women) 65 years and older from the population-based Tromso 5 Study 2001-2002. Logistic regression models were used to investigate the association between anemia (hemoglobin <12 g/dL in women and <13 g/dL in men) or hemoglobin level and self-reported falls last year, adjusted for sex, age, medication use and disability. Further, associations between combinations of anemia and frailty or disability, and falls, were investigated. RESULTS: No statistical significant associations were found between anemia and falls (OR 95% CI: 0.83, 0.50-1.37) or hemoglobin level and falls (OR, 95% CI: 0.94, 0.81-1.09), or with combinations of anemia and frailty or disability, and falls (OR, 95%: CI: 0.94, 0.40-2.22 and 0.78, 0.34-1.81, respectively). CONCLUSIONS: In this replication analysis, in accordance with the results from the original study, no statistically significant association between anemia or hemoglobin and falls was found among community living women and men aged 65 years or older. PMID- 29282001 TI - Nitrous oxide induced subacute combined degeneration with longitudinally extensive myelopathy with inverted V-sign on spinal MRI: a case report and literature review. AB - BACKGROUND: Nitrous oxide (N2O), a long-standing anesthetic, is also neurotoxic by interfering with the bioavailability of vitamin B12 if abused. A few case studies have reported the neurological and psychiatric complications of N2O. CASE PRESENTATION: Here, we reported a patient of N2O induced subacute combined degeneration (SCD) with longitudinally extensive myelopathy with inverted V-sign exhibiting progressive limb paresthesia and unsteady gait. CONCLUSIONS: This case raises the awareness of an important mechanism of neural toxicity of N2O, and clinical physicians should be well recognized this in the field of substance related disorders. PMID- 29282002 TI - Dietary supplement use among cancer survivors and the general population: a nation-wide cross-sectional study. AB - BACKGROUND: Use of dietary supplements among cancer survivors is common and controversial, but information on the amount of nutrients from supplements among cancer survivors is limited. We examined the amount of nutrients and their contribution to total nutrient intake from supplements and compared these data between cancer survivors and cancer-free individuals. We also identified factors associated with supplement use among cancer survivors. METHODS: We identified 400 cancer survivors and 10,387 cancer-free individuals, aged >= 19 years, from the fifth Korea National Health and Nutrition Examination Survey (KNHANES) V-1, 2 (2010, 2011). We calculated the amount of nutrients consumed from foods and supplements, the percent contributions of supplement nutrients to total nutrient intakes and cancer survivors' nutrient intakes relative to the Estimated Average Requirements (EARs) and the Tolerable Upper Intake Levels (ULs). We examined factors associated with supplement use among cancer survivors. RESULTS: We found that 33.3% of cancer survivors and 22.1% of cancer-free individuals reported the use of dietary supplements. Compared to cancer-free individuals, cancer survivors had higher intakes of riboflavin, folate, and iron from foods (p < 0.05 for each), and higher intakes of calcium (p = 0.05) and vitamin C (p = 0.01) from foods and supplements. The similar pattern was observed for the percent contributions to total nutrient intake. Cancer survivors had higher proportion of participants below EARs than cancer-free individuals for thiamin and niacin (p < 0.05 for each). The proportions of cancer survivors below the EARs were 61.2% for calcium, 49.1% for riboflavin, and 43.5% for folate and the proportions of cancer survivors above the ULs were 3.3% for iron, and 2.3% for vitamin A. For female cancer survivors, education above an elementary school level, moderate physical activity, low vegetable intake, and high circulating vitamin D levels were associated with supplement use. For male cancer survivors, living in an urban area, no consumption of alcohol, and lower energy intake, were associated with supplement use. CONCLUSIONS: Korean cancer survivors have higher rate of dietary supplement use and higher contribution from supplements to total nutrient intake than cancer-free individuals. Demographic and lifestyle factors were associated with supplement use among cancer survivors. PMID- 29282003 TI - Fluid status evaluation by inferior vena cava diameter and bioimpedance spectroscopy in pediatric chronic hemodialysis. AB - BACKGROUND: Evaluation of patient's dry weight remains challenging in chronic hemodialysis (HD) especially in children. Inferior Vena Cava (IVC) measurement was reported useful to assess fluid overload both in adults and children. METHODS: We performed a monocentric prospective study to evaluate the relation between predialytic IVC diameter measurements and hydration status evaluated by physicians and bioimpedance spectroscopy (BIS) and between IVC measurements and persistent hypertension. RESULTS: Forty-eight HD sessions in 16 patients were analyzed. According to physicians, patients were overhydrated in 84.5% of dialysis sessions, 20.8% according to BIS, and 0%, 4.1% and 20.8% according to IVC inspiratory, expiratory and collapsibility index reference curves respectively. There was no correlation between relative overhydration evaluated by BIS and IVC measurements z-scores (p = 0.20). Patients whose blood pressure normalized after HD had a more dilated maximal IVC diameter before dialysis session than patients with persistent hypertension (median - 0.07SD [-0.8; 0.88] versus -1.61SD [-2.18; -0.74] (p = 0.03)) with an optimal cut-off of -0.5 SD. CONCLUSIONS: In our study, IVC measurement is not reliable to assess fluid overload in children on HD and was not correlated with extracellular fluid volume assessed by BIS measurements. However, IVC measurements might be of interest in differentiating volume-dependant hypertension from volume-independant hypertension. PMID- 29282004 TI - Pathologic analysis of non-neoplastic parenchyma in renal cell carcinoma: a comprehensive observation in radical nephrectomy specimens. AB - BACKGROUND: This study provides a comprehensive examination of the histological features of non-neoplastic parenchyma in renal cell carcinoma (RCC). We prospectively collected radical nephrectomy (RN) specimens, to analyze the histological changes within peritumoral and distant parenchyma. METHODS: Data of patients who underwent RN and had no known history of diabetes, hypertension, hyperlipidemia, or chronic kidney disease etc., were prospectively collected. Tumor pseudo-capsule (PC), and parenchyma within 2 cm from tumor margin, were pathologically assessed. The parenchyma beyond PC or tumor margin was divided into 20 subsections of 1 mm in width. Histological changes, including chronic inflammation, glomerulosclerosis, arteriosclerosis and nephrosclerosis, were given scores of 0, 1, 2 or 3 for each subsection of each specimen, according to their severity. The 20 subsections of each specimen were further divided into four groups according to the distance from the tumor edge (group 1: 0-2 mm; group 2: 2-5 mm; group 3: 5-10 mm; group 4: 10-20 mm), to better compare the peritumoral parenchyma with the distant parenchyma. RESULTS: In total, 53 patients were involved in this study. All tumors were confirmed RCCs (clear cell vs. papillary vs. chromophobe were 83% vs. 5.7% vs. 11.3%, respectively), with a mean size of 5.6 cm. Histological changes were more severe in peritumoral parenchyma close to PC or tumor edge (0-5 mm), and less common within parenchyma more distant from the tumor (5-20 mm) (p < 0.001). chronic inflammation and nephrosclerosis were the most common changes especially in peritumoral parenchyma (0-2 mm). PC was present in 49 tumors (92.5%), and PC invasion occurred in 5 cases (10.2%). Mean PC thickness was 0.7 mm. PCs were more likely to be present in clear cell RCC or papillary RCC than in chromophobe RCC (100% vs. 100% vs. 33.3%, respectively; p < 0.001). CONCLUSIONS: Most RCCs have a well-developed PC, especially clear cell RCC. Histological changes mainly occur in peritumoral parenchyma, being rather uncommon in distant parenchyma. A compression band filled with severe histological changes was typically observed in renal parenchyma close to the tumor. Its preservation while performing an enucleation margin may not be entirely necessary. PMID- 29282005 TI - Diagnosing tuberculosis in hospitalized HIV-infected individuals who cannot produce sputum: is urine lipoarabinomannan testing the answer? AB - BACKGROUND: Up to one third of HIV-infected individuals with suspected TB are sputum-scarce. The Alere DetermineTM TB LAM Ag lateral flow strip test can be used to diagnose TB in HIV-infected patients with advanced immunosuppression. However, how urine LAM testing should be incorporated into testing algorithms and in the context of specific patient sub-groups remains unclear. METHODS: This study represents a post hoc sub-group analysis of data from a randomized multi center parent study. The study population consisted of hospitalized HIV-infected patients with suspected TB who were unable to produce sputum and who underwent urine LAM testing. The diagnostic utility of urine LAM for TB in this group was compared to the performance of urine LAM in patients who did produce a sputum sample in the parent study. RESULTS: There were a total of 187 and 2341 patients in the sputum-scarce and sputum-producing cohorts, respectively. 80 of the sputum scarce patients underwent testing with urine LAM. In comparison to those who did produce sputum, sputum-scarce patients had a younger age, a lower Karnofsky performance score, and a lower weight and BMI at admission. A greater proportion of sputum-scarce patients were urine LAM positive, compared to those who were able to produce sputum (31% vs. 21%, p = 0.04). A higher proportion of sputum scarce patients died within 8 weeks of admission (32% vs. 24%, p = 0.013). We inferred that 19% of HIV-infected sputum-scarce patients suspected of TB were diagnosed with tuberculosis by urine LAM testing, with an estimated positive predictive value of 63% (95% CI 43-82%). CONCLUSIONS: Urine LAM testing can effectively identify tuberculosis in HIV-infected patients who are at a higher risk of mortality yet are unable to generate a sputum sample for diagnostic testing. Our findings support the use of urine LAM testing in sputum-scarce hospitalized HIV-infected patients, and its incorporation into diagnostic algorithms for this patient population. PMID- 29282006 TI - Health care costs associated with hospital acquired complications in patients with chronic kidney disease. AB - BACKGROUND: Patients with CKD are at increased risk of potentially preventable hospital acquired complications (HACs). Understanding the economic consequences of preventable HACs, may define the scope and investment of initiatives aimed at prevention. METHODS: Adult patients hospitalized from April, 2003 to March, 2008 in Alberta, Canada comprised the study cohort. Healthcare costs were determined and categorized into 'index hospitalization' including hospital cost and in hospital physician claims, and 'post discharge' including ambulatory care cost, physician claims, and readmission costs from discharge to 90 days. Multivariable regression was used to estimate the incremental healthcare costs associated with potentially preventable HACs. RESULTS: In fully adjusted models, the median incremental index hospitalization cost was CAN-$6169 (95% CI; 6003-6336) in CKD patients with >=1 potentially preventable HACs, compared with those without. Post discharge incremental costs were 1471(95% CI; 844-2099) in those patients with CKD who developed potentially preventable HACs within 90 days after discharge compared with patients without potentially preventable HACs. Additionally, the incremental costs associated with >=1 potentially preventable HACs within 90 days from admission in patients with CKD were $7522 (95% CI; 7219-7824). A graded relation of the incremental costs was noted with the increasing number of complications. In patients without CKD but with >=1 preventable HACs incremental costs within 90 days from hospital admission was $6688 (95% CI: 6612-6723). CONCLUSIONS: Potentially preventable HACs are associated with substantial increases in healthcare costs in people with CKD. Investment in implementing targeted strategies to reduce HACs may have a significant benefit for patient and health system outcomes. PMID- 29282007 TI - The risk of nontuberculous mycobacterial infection in patients with Sjogren's syndrome: a nationwide, population-based cohort study. AB - BACKGROUND: Nontuberculous mycobacterial (NTM) infection in immunocompromized patients is currently a growing health concern, and we aimed to examine the relative risk of NTM infection in patients with Sjogren's syndrome (SS) compared with that in non-SS individuals. METHODS: We used the 2003-2012 Taiwanese National Health Insurance Research Database to identify 6554 incident SS cases during 2007-2012 and selected 98,310 non-SS controls matched (1:15) for age, gender, and the year of first SS diagnosis date after excluding those who had rheumatoid arthritis or systemic lupus erythematosus. RESULTS: We identified four NTM-infected patients in the SS group (three in the first year) and nine in the non-SS group (three in the first year). SS patients had a higher incidence rate of NTM infection than that in non-SS individuals (IRR, 7.56; 95% CI, 2.33-24.55), especially during the first year (IRR, 16.05; 95% CI, 3.24-79.51). After adjusting for potential confounders, the risk of NTM infection was not increased in SS patients during the entire follow-up period or during the first year, but the risk increased in SS patients treated with immunosuppressants during the entire follow-up period (HR, 17.77; 95% CI, 4.53-69.61), especially during the first year (HR, 33.33; 95% CI, 4.37-254.23). CONCLUSION: An increased risk of NTM infection was found in SS patients treated with immunosuppressants during the first year after SS diagnosis. PMID- 29282008 TI - Pricing appraisal of anti-cancer drugs in the South East Asian, Western Pacific and East Mediterranean Region. AB - BACKGROUND: Globally, cancer is one of the leading causes of mortality. High treatment cost, partly owing to higher prices of anti-cancer drugs, presents a significant burden on patients and healthcare systems. The aim of the present study was to survey and compare retail prices of anti-cancer drugs between high, middle and low income countries in the South-East Asia, Western Pacific and Eastern Mediterranean regions. METHODS: Cross-sectional survey design was used for the present study. Pricing data from ten counties including one from South East Asia, two from Western Pacific and seven from Eastern Mediterranean regions were used in this study. Purchasing power parity (PPP)-adjusted mean unit prices for 26 anti-cancer drug presentations (similar pharmaceutical form, strength, and pack size) were used to compare prices of anti-cancer drugs across three regions. A structured form was used to extract relevant data. Data were entered and analysed using Microsoft Excel(r). RESULTS: Overall, Taiwan had the lowest mean unit prices while Oman had the highest prices. Six (23.1%) and nine (34.6%) drug presentations had a mean unit price below US$100 and between US$100 and US$500 respectively. Eight drug presentations (30.7%) had a mean unit price of more than US$1000 including cabazitaxel with a mean unit price of $17,304.9/vial. There was a direct relationship between income category of the countries and their mean unit price; low-income countries had lower mean unit prices. The average PPP adjusted unit prices for countries based on their income level were as follows: low middle-income countries (LMICs): US$814.07; high middle income countries (HMICs): US$1150.63; and high income countries (HICs): US$1148.19. CONCLUSIONS: There is a great variation in pricing of anticancer drugs in selected countires and within their respective regions. These findings will allow policy makers to compare prices of anti-cancer agents with neighbouring countries and develop policies to ensure accessibility and affordability of anti-cancer drugs. PMID- 29282009 TI - STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials. AB - BACKGROUND: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis. METHODS: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation. DISCUSSION: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis. TRIAL REGISTRATIONS: New Zealand and Australia: ACTRN12612000584831 . Registered 30/05/2012. Canada: NCT02442492 . Registered 05/05/2015. Ireland: CT 900/572/1 . Registered 15/07/2015. The Netherlands: NCT02277132 . Registered 29/09/2014. United Kingdom: ISRCTN39133303 . Registered 31/07/2014. PMID- 29282010 TI - Survival benefit of hepatic resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis. AB - BACKGROUND: No consensus treatment has been reached for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Hepatic resection (HR) and transarterial chemoembolization (TACE) have been recommended as effective options, but which is better remains unclear. This meta-analysis is to compare the effectiveness of HR and TACE for HCC with PVTT patients. METHODS: The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched for comparing HR and TACE treating PVTT. RESULTS: Twelve retrospective studies with 3129 patients were included. A meta-analysis of 11 studies suggested that the 1-, 2-, 3-, and 5-year overall survival (OS) rates (OR = 0.48, 95% CI = 0.41-0.57, I2 = 37%, P < 0.00001; OR = 0.21, 95% CI = 0.12-0.38, I2 = 43%, P < 0.00001; OR = 0.35, 95% CI = 0.28-0.44, I2 = 53%, P < 0.00001; OR = 0.28, 95% CI = 0.14-0.54, I2 = 72%, P = 0.0001, respectively) favored HR over TACE. In a subgroup analysis, HR had better 1-, 2-,3, 5-year OS for type I PVTT (OR = 0.33, 95% CI = 0.17-0.64, I2 = 20%, P = 0.001; OR = 0.32, 95% CI = 0.16 0.63, I2 = 0%, P = 0.001; OR = 0.18, 95% CI = 0.09-0.36, I2 = 0%, P < 0.00001; OR = 0.07, 95% CI = 0.01-0.32, I2 = 0%, P = 0.0006, respectively) and better 1-, 3-, and 5-year OS for type II PVTT (OR = 0.37, 95% CI = 0.20-0.70, I2 = 59%, P = 0.002; OR = 0.22, 95% CI = 0.13-0.39, I2 = 0%, P < 0.00001; OR = 0.16; 95% CI = 0.03-0.91; I2 = 51%, P = 0.04, respectively). There was no difference in 1-, 3-, or 5-year OS between HR and TACE for type III PVTT (OR = 0.86, 95% CI = 0.61 1.21, I2 = 0%, P = 0.39; OR = 0.83, 95% CI = 0.42-1.64, I2 = 0%, P = 0.59; OR = 0.59, 95% CI = 0.06--6.04, I2 = 65%, P = 0.66, respectively). CONCLUSIONS: HR may lead to longer OS for some selected HCC patients with PVTT than TACE, especially for type I or II PVTT, with less difference being observed for type III or IV PVTT. PMID- 29282011 TI - Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study. AB - BACKGROUND: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC. METHODS: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman(r) PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors. RESULTS: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010). CONCLUSIONS: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup. TRIAL REGISTRATION: Registered in Direction Generale de la Sante the 1st July 2008 under the number DGS2008-0144. PMID- 29282012 TI - Comparison of line probe assay to BACTEC MGIT 960 system for susceptibility testing of first and second-line anti-tuberculosis drugs in a referral laboratory in South Africa. AB - BACKGROUND: The incidence of multidrug-resistant tuberculosis (MDR-TB) is increasing and the emergence of extensively drug-resistant tuberculosis (XDR-TB) is a major challenge. Controlling resistance, reducing transmission and improving treatment outcomes in MDR/XDR-TB patients is reliant on susceptibility testing. Susceptibility testing using phenotypic methods is labour intensive and time consuming. Alternative methods, such as molecular assays are easier to perform and have a rapid turn-around time. The World Health Organization (WHO) has endorsed the use of line probe assays (LPAs) for first and second line diagnostic screening of MDR/XDR-TB. METHODS: We compared the performance of LPAs to BACTEC MGIT 960 system for susceptibility testing of bacterial resistance to first-line drugs: rifampicin (RIF), isoniazid (INH), ethambutol (EMB), and second-line drugs ofloxacin (OFL) and kanamycin (KAN). One hundred (100) consecutive non-repeat Mycobacterium tuberculosis cultures, resistant to either INH or RIF or both, as identified by BACTEC MGIT 960 were tested. All isoniazid resistant cultures (n = 97) and RIF resistant cultures (n = 90) were processed with Genotype(r)MTBDRplus and Genotype(r)MTBDRsl line probe assays (LPAs). The agar proportion method was employed to further analyze discordant LPAs and the MGIT 960 isolates. RESULTS: The Genotype (r)MTBDRplus (version 2) sensitivity, specificity, PPV and NPV from culture isolates were as follows: RIF, 100%, 87.9, 58.3% and 100%; INH, 100%, 94.4%, 93.5% and 100%. The sensitivity, specificity PPV and NPV for Genotype (r) MTBDRsl (version 1 and 2) from culture isolates were as follows: EMB, 60.0%, 89.2%, 68.2% and 85.3%; OFL, 100%, 91.4%, 56.2% and 100%; KAN, 100%, 97.7%, 60.0% and 100%. Line probe assay showed an excellent agreement (k = 0.93) for INH susceptibility testing when compared to MGIT 960 system while there was good agreement (k = 0.6-0.7) between both methods for RIF, OFL, KAN testing and moderate agreement for EMB (k = 0.5). A high RIF mono-resistance (MGIT 960 33/97 and LPA 43/97) was observed. CONCLUSION: LPAs are an efficient and reliable rapid molecular DST assay for rapid susceptibility screening of MDR and XDR-TB. Using LPAs in high MDR/XDR burden countries allows for appropriate and timely treatment, which will reduce transmission rates, morbidity and improve treatment outcomes in patients. PMID- 29282014 TI - Spectrum (characteristics) of patients with chronic kidney disease (CKD) with increasing age in a major metropolitan renal service. AB - BACKGROUND: Aim of our study is to describe, in people with CKD, the demographic and clinical characteristics and outcomes with increasing age. The prevalence of CKD in Western populations, where longevity is the norm, is about 10-15%, but how age influence different characteristics of patients with CKD is largely not known. METHODS: One thousand two hundred sixty-five patients enrolled in the CKD.QLD registry at the Royal Brisbane and Women's Hospital were grouped according to age at consent i.e. <35, 35-44, 45-54, 55-64, 65-74, 75-84, 85+ years age groups, and were followed till start of renal replacement therapy (RRT), death, discharge or the censor date of September 2015. RESULTS: Age ranged from 17.6 to 98.5 years with medians of 70.1 and 69.9 years for males and females respectively: 7% were <35 years of age, with the majority (63%) >65 years old. The leading renal diagnoses changed from genetic real disease (GRD) and glomerulonephritis (GN) in the younger patients to renovascular disease (RVD) and hypertension (HTN) in older patients. With increasing age, there were often multiple renal disease diagnoses, more advanced stages of CKD, greater number of comorbidities, more frequent and more costly hospitalizations, and higher death rates. The rates of initiation of renal replacement therapy (RRT) rose from 4.5 per 100 person years in those age < 35 years to a maximum of 5.5 per 100 person years in 45-54 years age group and were lowest, at 0.5 per 100 person years in those >85 years. Mortality rates increased by age group from 1.3 to 17.0 per 100 person years in 35-44 year and 85+ year age groups respectively. Rates of hospitalization, length of stay and cost progressively increased from the youngest to eldest groups. Patients with diabetic nephropathy had highest incidence rate of RRT and death. The proportion of patients who lost more than 5mls/min/1.73m2 of eGFR during at least 12 months follow up increased from 13.3% in the youngest age group to 29.2% in the eldest. CONCLUSION: This is the first comprehensive view, with no exclusions, of CKD patients seen in a public renal specialty referral practice, in Australia. The age distribution of patients encompasses the whole of adult life, with a broader range and higher median value than patients receiving RRT. Health status ranged from a single system (renal) disease in young adults through, with advancing age, renal impairment as a component of, or accompanying multisystem diseases, to demands and complexities of support of frail or elderly people approaching end of life. This great spectrum demands a broad understanding and capacity of renal health care providers, and dictates a need for a wider scope of health services provision incorporating multiple models of care. PMID- 29282013 TI - An investigation of factors predicting the type of bladder antimuscarinics initiated in Medicare nursing homes residents. AB - BACKGROUND: To examine factors predicting type of bladder antimuscarinics (BAM) initiated in nursing home (NH) residents. METHODS: Incident BAM initiators following NH admission were identified by constructing a retrospective cohort from Medicare files and Minimum Data Set (MDS). Participants included all residents 65 years and older admitted in Medicare-certified NH between January 1, 2007 and December 31, 2008 who were prescribed BAM and had continuous Medicare (Part A, B, and D) enrollment. Patient characteristics, medications, and comorbidities were derived from Medicare enrollment and claims. NH characteristics and health status were derived from MDS assessments. The outcome was defined as type of BAM initiated after admission (selective, non-selective extended release, non-selective immediate release). Multinomial logistic regression using generalized estimating equation methodology determined which factors predicted the type of BAM initiated. RESULTS: Twelve thousand eight hundred ninety-nine NH residents initiating BAM therapy were identified; 13.38% of new users were prescribed selective BAM, 45.56% non-selective extended release, and 41.07% non-selective immediate release medications. In both sexes, significant predictors of BAM included region of nursing home, body mass index, cognitive performance score, frailty measures, activities of daily living, and measures of bladder continence. In women, history of fracture and fall-related injuries were significant predictors of type of BAM use, while race and indicators of balance were significant predictors of type of BAM use in men. Non pharmacological continence management strategies were not predictive of type of BAM initiation. CONCLUSIONS: Several factors are important in predicting type of BAM initiation in both women and men, but other factors are sex-specific. Some observed factors predicting the type of BAM initiated, such as other medications use, body mass index, or provider-related factors are potentially modifiable and could be used in targeted interventions to help optimize BAM use in this population. TRIAL REGISTRATION: Not applicable. PMID- 29282015 TI - Does azithromycin given to women in labour decrease ocular bacterial infection in neonates? A double-blind, randomized trial. AB - BACKGROUND: Vertical transmission can result in neonatal infection and disease. Reducing the transmission of bacterial pathogens from mother to infant may be an effective means of preventing neonatal infection, including bacterial conjunctivitis. METHODS: In a double-blind, randomized trial, we assessed the effect of administering a single dose of oral azithromycin to women in labour on bacterial colonization of the neonate. A reduction in purulent neonatal conjunctivitis was a secondary objective of the trial. Ocular samples were collected from the lower fornix of infants presenting with clinical signs of purulent conjunctivitis during the first eight weeks of life. Incidence of purulent conjunctivitis was compared between trial arms. Bacterial infection was assessed using PCR and incidence of purulent conjunctivitis due to bacteria was also compared between arms. RESULTS: Forty of 843 infants (4.7%) presented clinical signs of purulent conjunctivitis. No significant difference in incidence of purulent conjunctivitis was seen between azithromycin and placebo arms [4.3% (18/419) versus 5.2% (22/424), OR = 0.82, 95% CI (0.44,1.54), p = 0.628]. S. aureus was the most commonly identified pathogen, detected in 38% of cases. Incidence of purulent-conjunctivitis due to bacterial infection was lower in the azithromycin arm [1.2% (5/419) versus 3.8% (16/424), OR = 0.31, 95% CI (0.12 0.82), p = 0.025)]. The incidence of gram-positive bacteria was also lower in the azithromycin arm [1.0% (4/419) versus 3.3% (14/424), OR = 0.28, 95%CI (0.10 0.82), p = 0.029]. CONCLUSIONS: Oral azithromycin given to women during labour may have the potential to reduce the incidence of bacterial neonatal conjunctivitis. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01800942 , registration date 26 Feb 2013. PMID- 29282016 TI - Influence of corneal power on intraocular lens power of the second eye in the SRK/T formula in bilateral cataract surgery. AB - BACKGROUND: To evaluate the effect of different adjustments of the refractive outcome of the first eye according to corneal power (K) in order to improve the intraocular lens (IOL) power calculation of the second eye in the SRK/T formula. METHODS: One hundred thirty-four patients who underwent uncomplicated bilateral, sequential phacoemulsification with AcrySof IQ implantation were enrolled. The optimal partial adjustment of the refractive outcome of the first eye according to K was retrospectively analyzed using a regression formula. RESULTS: In all patients, the optimal partial adjustment of the refractive outcome of the first eye was calculated as 56%. For K values between 42.8 D and 44.6 D, the optimal partial adjustment was calculated as 30%; however, this adjustment of the first eye did not significantly improve the refractive outcome in the second eye of the subgroup with K values between 42.8 D and 44.6 D. For K values greater than 44.6 D or less than 42.8 D, the optimal partial adjustments were calculated as 69% and 81%, respectively. According to these results, the adjustment of the first eye significantly improved the refractive outcome in the second eye from 0.36 to 0.26 D (P < 0.001) in the entire data set. This result was significantly lower than that using a single partial adjustment (56%) (0.28 D; P = 0.027). CONCLUSIONS: For K values greater than 44.6 D or less than 42.8 D, an approximately 70-80% adjustment of the first eye error should be considered. In contrast, for K values between 42.8 D and 44.6 D, a 30% or less adjustment should be considered in the SRK/T formula. PMID- 29282017 TI - Assessment of visual morbidity amongst diabetic retinopathy at tertiary eye care center, Nepal: a cross-sectional descriptive study. AB - BACKGROUND: Diabetic retinopathy (DR) is one of the leading causes of preventable blindness in low and middle income countries. In Nepal, there are less studies regarding DR and they too are limited around Kathmandu valley. This study was done to assess visual morbidity in patients with DR at a peripheral tertiary eye care center of Nepal. METHODS: This was a prospective, hospital based, cross sectional study in which all consecutive cases of DR were evaluated. DR was classified according to Early Treatment Diabetic Retinopathy Study Research Group - report no. 10 Table A5-1 (Modified Airlie House Classification). Data entry and analysis was done in an SPSS unit version 20. Wherever applicable, variables were set as 100 eyes. RESULTS: Total number of patients included in this study was 50. Commonest age group was 50-69 yrs. (43/77 yrs.; min/max) comprising 80% of the total population (n = 50) and the predominant population was male (76%). Non proliferative diabetic retinopathy (NPDR) was found in 69%, proliferative diabetic retinopathy (PDR) in 31% and advanced diabetic eye disease (ADED) in 3% (n = 100). CONCLUSIONS: All the stages of DR were present at significant proportions in this study, noteworthy was the percentage of PDR. This study shows an urgency to gather a national data on DR, raise awareness among diabetics and train effective man power at a local level to diagnose DR at an early stage. PMID- 29282018 TI - Why gone too soon? Examining social determinants of neonatal deaths in northwest Ethiopia using the three delay model approach. AB - BACKGROUND: Without improving the survival of newborns, meaningful reduction in under-five mortality is difficult. Most neonatal deaths are preventable when appropriate and timely care is sought. In Ethiopia, there is lack of evidence on the type and contribution of delays in treatment seeking to neonatal deaths. METHODS: A community based social autopsy (SA) of 39 neonatal deaths was conducted from March 16 to 24, 2016 in Dabat Health and Demographic Surveillance System (HDSS) in northwest Ethiopia. The result was linked with verbal autopsy (VA) information completed for each of the deaths as part of the ongoing HDSS. The SA tool was adapted from INDEPTH Network. Three delay model approach was used to classify the delay types that contributed for the deaths investigated. Descriptive statistics was used to analyze the data. RESULTS: SA was completed for 37 (94.9%) of the 39 neonatal deaths. Of all the deaths, 51.3% (19/37) of them occurred within the first 24 h, 75.6% (28/37) within the first 6 days and the remaining in 7-28 days. Birth asphyxia was the leading cause of death (34%) followed by bacterial sepsis (31%) and prematurity (16%). The median time from recognition of illness to initiation of modern treatment was 1 day (IQR 1-2.5 days). Delay in treatment seeking outside home (delay one) was associated with 81% of the deaths. Delay in receiving care at a health facility (delay three) and delay in transport (delay two) were associated with 16 and 3% of the deaths, respectively. The major contributors of death for delay one were bacterial sepsis (33.3%), birth asphyxia (30%), unspecified illness (20%) and acute lower respiratory tract illnesses (6.7%). For delay three, the major causes of death included birth asphyxia (50%), prematurity (33.3%) and bacterial sepsis (16.7%). CONCLUSIONS: Delays created at home and at health facility were the major delays contributing to the death of newborns. More focus has to be given in improving delays at home and at health facility. PMID- 29282019 TI - Validation of the Farsi version of the revised Adolescent Sleep Hygiene Scale (ASHSr): a cross-sectional study. AB - BACKGROUND: Restoring sleep is associated with a broad variety of favorable cognitive, emotional, social and behavioral benefits during the day. This holds particularly true for adolescents, as maturational, social, cognitive, emotional and behavioral changes might unfavorably impact on adolescents' sleep. Among adolescents, poor sleep hygiene practices are a potentially modifiable risk factor that can be addressed via appropriate interventions. Accordingly, having reliable and valid self-report measures to assess sleep hygiene practices is essential to gauge individual responses to behavioral interventions and evaluate sleep hygiene recommendations. The aim of the present study therefore was to translate and to test the psychometric properties (internal consistency, test retest reliability, factorial and concurrent validity) of the Farsi/Persian version of the revised version of the Adolescent Sleep Hygiene Scale (ASHSr). METHOD: A total of 1013 adolescents (mean age: M = 15.4 years; SD = 1.2; range: 12-19 years; 42.9% females) completed the ASHSr and the Pittsburgh Sleep Quality Index (PSQI) in their classroom during an official school lesson. Further, 20% completed the ASHSr 6 weeks later to evaluate the test-retest reliability. Cronbach's alpha coefficients were calculated to examine internal consistency, confirmatory factor analysis (CFA) was used to test factorial validity, whereas concurrent validity and test-retest reliability were examined via correlation analyses. RESULTS: A first-order confirmatory factor analysis (CFA) corroborated the six-factor structure of the ASHSr, including a physiological, behavioral arousal, cognitive/emotional, daytime sleep, sleep environment, and sleep stability factor. A second-order CFA showed that a higher-order sleep hygiene construct explained sufficient variance in each factor. Cronbach's alpha values ranged between .71 and .75, correlations for test-retest reliability between .82 and .87. Significant correlations were found between most ASHSr scales and the PSQI indices. However, the magnitude of these correlations was weak. CONCLUSIONS: The Farsi/Persian version of the Adolescent Sleep Hygiene Scale can be used as a reliable and valid tool for evaluation of sleep hygiene practices among Farsi/Persian-speaking adolescents. PMID- 29282020 TI - Efficacy and safety of transepithelial corneal collagen crosslinking surgery versus standard corneal collagen crosslinking surgery for keratoconus: a meta analysis of randomized controlled trials. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of transepithelial corneal collagen crosslinking (transepithelial CXL) versus standard corneal collagen crosslinking (epithelium-off CXL) on keratoconus. METHODS: Eligible studies were identified by systematically searching PubMed, the Cochrane Library and Embase. Topographic parameters, corrected distant visual acuity (CDVA), uncorrected distant visual acuity (UDVA), and corneal thickness (CT) were assessed by the pooled weighted mean differences (WMDs) of the change from baseline to the end of follow up. Quality was assessed according to Cochrane handbook. And we used Review Manager to analysis the included trials. RESULTS: Three trials involving 244 eyes were evaluated, with 111 eyes in the standard CXL group and 133 eyes in the transepithelial CXL group. The pooled results showed that there were significant differences between the two groups in maximum keratometry (mean difference = 1.05D, 95% CI 0.19 to 1.92, P = 0.02)),and the standard CXL is more effective in decreasing the maximum keratometry at least 12 months after operation; the transepithelial CXL group gained more improvement in CDVA (mean difference = -0.07, 95% CI -0.12 to -0.02, P = 0.007);there were no significant differences in uncorrected distant visual acuity (UDVA) between the two groups (mean difference = -0.03, 95% CI -0.20 to 0.15, P = 0.75). A similar change was found in corneal thickness (mean difference = 4.35, 95% CI -0.43 to 9.13, P = 0.07)). CONCLUSIONS: The standard CXL is more effective in decreasing the maximum keratometry than the transepithelial CXL; the transepithelial CXL provided favorable visual outcomes; they both exhibit similar safety. PMID- 29282021 TI - Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden. AB - BACKGROUND: The tumor immune environment not only modulates the effects of immunotherapy, but also the effects of other anticancer drugs and treatment outcomes. These immune responses can be evaluated with tumor-infiltrating lymphocytes (TILs), which has frequently been verified clinically. On the other hand, residual cancer burden (RCB) evaluation has been shown to be a useful predictor of survival after neoadjuvant chemotherapy (NAC). In this study, RCB and TILs evaluations were combined to produce an indicator that we have termed "RCB-TILs", and its clinical application to NAC for breast cancer was verified by subtype-stratified analysis. METHODS: A total of 177 patients with breast cancer were treated with NAC. The correlation between RCB and TILs evaluated according to the standard method, and prognosis, including the efficacy of NAC, was investigated retrospectively. The RCB and TILs evaluations were combined to create the "RCB-TILs". Patients who were RCB-positive and had high TILs were considered RCB-TILs-positive, and all other combinations were RCB-TILs-negative. RESULTS: On multivariable analysis, being RCB-TILs-positive was an independent factor for recurrence after NAC in all patients (p < 0.001, hazard ratio = 0.048), triple-negative breast cancer (TNBC) patients (p = 0.018, hazard ratio = 0.041), HER2-positive breast cancer (HER2BC) patients (p = 0.036, hazard ratio = 0.134), and hormone receptor-positive breast cancer (HRBC) patients (p = 0.002, hazard ratio = 0.081). CONCLUSIONS: The results of the present study suggest that RCB-TILs is a significant predictor for breast cancer recurrence after NAC and may be a more sensitive indicator than TILs alone. PMID- 29282022 TI - Chromosomal instability induced by increased BIRC5/Survivin levels affects tumorigenicity of glioma cells. AB - BACKGROUND: Survivin, belonging to the inhibitor of apoptosis (IAP) gene family, is abundantly expressed in tumors. It has been hypothesized that Survivin facilitates carcinogenesis by inhibition of apoptosis resulting in improved survival of tumorigenic progeny. Additionally, Survivin plays an essential role during mitosis. Together with its molecular partners Aurora B, Borealin and inner centromere protein it secures bipolar chromosome segregation. However, whether increased Survivin levels contribute to progression of tumors by inducing chromosomal instability remains unclear. METHODS: We overexpressed Survivin in U251-MG, SVGp12, U87-MG, HCT116 and p53-deficient U87-MGshp53 and HCT116p53-/- cells. The resulting phenotype was investigated by FACS-assisted cell cycle analysis, Western Blot analysis, confocal laser scan microscopy, proliferation assays, spectral karyotyping and in a U251-MG xenograft model using immune deficient mice. RESULTS: Overexpression of Survivin affected cells with knockdown of p53, cells harboring mutant p53 and SV40 large T antigen, respectively, resulting in the increase of cell fractions harboring 4n and >4n DNA contents. Increased gammaH2AX levels, indicative of DNA damage were monitored in all Survivin-transduced cell lines, but only in p53 wild type cells this was accompanied by an attenuated S-phase entry and activation of p21waf/cip. Overexpression of Survivin caused a DNA damage response characterized by increased appearance pDNA-PKcs foci in cell nuclei and elevated levels of pATM S1981 and pCHK2 T68. Additionally, evolving structural chromosomal aberrations in U251-MG cells transduced with Survivin indicated a DNA-repair by non-homologous end joining recombination. Subcutaneous transplantation of U251-MG cells overexpressing Survivin and mycN instead of mycN oncogene alone generated tumors with shortened latency and decreased apoptosis. Subsequent SKY-analysis of Survivin/mycN-tumors revealed an increase in structural chromosomal aberrations in cells when compared to mycN-tumors. CONCLUSIONS: Our data suggest that increased Survivin levels promote adaptive evolution of tumors through combining induction of genetic heterogeneity with inhibition of apoptosis. PMID- 29282023 TI - Is meat consumption associated with depression? A meta-analysis of observational studies. AB - BACKGROUND: A number of epidemiological studies have examined the effect of meat consumption on depression. However, no conclusion has been reached. The aim of this study was to examine the relationship between meat consumption and depression. METHODS: The electronic databases of PUBMED and EMBASE were searched up to March 2017, for observational studies that examined the relationship between meat consumption and depression. The pooled odds ratio (OR) for the prevalence of depression and the relative risk (RR) for the incidence of depression, as well as their corresponding 95% confidence interval (CI), were calculated respectively (the highest versus the lowest category of meat consumption). RESULTS: A total of eight observational studies (three cross sectional, three cohort and two case-control studies) were included in this meta analysis. Specifically, six studies were related to the prevalence of depression, and the overall multi-variable adjusted OR suggested no significant association between meat consumption and the prevalence of depression (OR = 0.89, 95% CI: 0.65 to 1.22; P = 0.469). In contrast, for the three studies related to the incidence of depression, the overall multi-variable adjusted RR evidenced an association between meat consumption and a moderately higher incidence of depression (RR = 1.13, 95% CI: 1.03 to 1.24; P = 0.013). CONCLUSIONS: Meat consumption may be associated with a moderately higher risk of depression. However, it still warrants further studies to confirm such findings due to the limited number of prospective studies. PMID- 29282024 TI - Emotion regulation individual therapy for adolescents with nonsuicidal self injury disorder: a feasibility study. AB - BACKGROUND: Nonsuicidal self-injury (NSSI) is a serious health risk behavior that forms the basis of a tentative diagnosis in DSM-5, NSSI Disorder (NSSID). To date, established treatments specific to NSSI or NSSID are scarce. As a first step in evaluating the feasibility, acceptability, and utility of a novel treatment for adolescents with NSSID, we conducted an open trial of emotion regulation individual therapy for adolescents (ERITA): a 12-week, behavioral treatment aimed at directly targeting both NSSI and its proposed underlying mechanism of emotion regulation difficulties. METHODS: Seventeen girls (aged 13 17; mean = 15.31) with NSSID were enrolled in a study adopting an uncontrolled open trial design with self-report and clinician-rated assessments of NSSI and other self-destructive behaviors, emotion regulation difficulties, borderline personality features, and global functioning administered at pre-treatment, post treatment, and 6-month follow-up. Measures of NSSI and emotion regulation difficulties were also administered weekly during treatment. RESULTS: Ratings of treatment credibility and expectancy and the treatment completion rate (88%) were satisfactory, and both therapeutic alliance and treatment attendance were strong. Intent-to-treat analyses revealed significant improvements associated with large effect sizes in past-month NSSI frequency, emotion regulation difficulties, self destructive behaviors, and global functioning, as well as a medium effect size in past-month NSSI versatility, from pre- to post-treatment. Further, all of these improvements were either maintained or further improved upon at 6-month follow up. Finally, change in emotion regulation difficulties mediated improvements in NSSI over the course of treatment. CONCLUSIONS: Results suggest the acceptability, feasibility, and utility of this treatment for adolescents with NSSID. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02326012, December 22, 2014, retrospectively registered). PMID- 29282025 TI - Validating the psychiatric nurses methods of coping questionnaire: Arabic version. AB - BACKGROUND: The aim of the study was to undertake a psychometric analysis of the Psychiatric Nurses Methods of Coping Questionnaire (PNMCQ) - Arabic version when used to measure coping skills in psychiatric nurses in Jordan. METHOD: A descriptive, cross-sectional design was adopted in this study. A demographic questionnaire and the 35-item PNMCQ -Arabic were the measures used to collect data. RESULT: The PNMCQ demonstrated valid and reliable values when administered to psychiatric nurses in Jordan after it had been submitted to factor analysis. CONCLUSION: The development of PNMCQ: Arabic Version adequately measures coping skills in psychiatric nurses from a culturally appropriate context. Use of the tool can determine coping skills in psychiatric nurses with the view to positive staff development. Strategies identified based on results of the PNMCQ could ultimately result in better nurse retention and patient outcomes. PMID- 29282027 TI - Polyaxial locking plates in treating distal humeral fractures: a comparative randomized trial for clinical outcome. AB - BACKGROUND: Management of distal humeral fractures remains to be one of the most challenging aspects in trauma surgery. Low profile plating systems with variable angle screw fixation represent a crucial advancement to the established angular stable locking plates with considerable attention in current research. The aim of the prospective randomized trial was to review the preliminary results and patients' outcome following treatment with these newly developed implants and to rule out potential differences in fracture treatment of two different plating systems. METHODS: Twenty patients with distal humeral fractures (AO 13-A1 - AO 13 C3) were included in the current study since 2014. After completing the randomization plan, patients were distributed into two groups for different variable angle locking plates (DePuy Synthes(r) VA-LCP vs. Medartis(r) Aptus Elbow). Functional elbow scoring (ROM, MEPS, QuickDASH) served as primary outcome parameter, while radiological fracture consolidation served as secondary outcome parameter. Follow-ups were conducted 6 weeks, 12 weeks, 6 months and 12 months after the operation. RESULTS: Seventeen of 20 patients (85%) concluded all follow up examinations. Postoperative elbow extension deficiencies showed significant differences between the two groups in all follow-up examinations with a mean of O 18 +/- 7.4 degrees in the DePuy Synthes(r) VA-LCP group compared to a mean of O 6.5 +/- 7.5 degrees in the Medartis(r) Aptus Elbow group (p = 0.002) 12 months postoperatively. Functional scoring showed a disparate pattern. The Medartis(r) Aptus Elbow group achieved significantly better MEP scores during follow-up. However, the analysis of the QuickDash revealed better results of the DePuy Synthes(r) VA-LCP group in the first half and better results of the Medartis(r) Aptus Elbow group in the second half of the follow-up examination instead. CONCLUSIONS: Considering the complexity of distal humeral fractures, the usage of anatomically preshaped low profile variable angle locking plates for operative treatment leads to good clinical results. Even though there might be some advances of the Medartis(r) Aptus Elbow plating system concerning postoperative ROM and elbow function, a consistent difference in the overall clinical outcome between the two plating systems could not be detected. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03272490 Retrospectively Registered 1. September 2017. PMID- 29282026 TI - Recombinant human endostatin combined with radiotherapy inhibits colorectal cancer growth. AB - BACKGROUND: To examine the effects of recombinant human endostatin combined with radiotherapy on colorectal cancer HCT-116 cell xenografts in nude mice. METHODS: Forty male BALB/c nude mice were injected with human colorectal cancer HCT-116 cells to form xenografts and then randomized into the following 4 groups (each group comprised ten mice): a control group, an endostatin group (20 mg/kg endostatin once a day for 10 days), a radiotherapy group (a 6-Gy dose was administered via a 6-MV X-ray on day 5 post-inoculation), and a combination therapy group (radiotherapy with endostatin treatment). The tumor growth inhibition rate were detected. CD31, vascular endothelial growth factor (VEGF), and hypoxia inducible factor-1alpha (HIF-1alpha) expression and microvascular density (MVD) were evaluated by immunohistochemistry. The expression of VEGF protein was also detected by western blotting. RESULTS: The tumor growth inhibition rate in the radiotherapy with endostatin treatment group was significantly higher than those in endostatin group or radiotherapy group (77.67% vs 12.31% and 38.59%; n = 8 per group, P < 0.05). The results of immunohistochemistry showed that treatment with radiotherapy induced significant increases in CD31, VEGF, and HIF-1alpha expression and MVD compared with treatment with saline, while treatment with endostatin or radiotherapy with endostatin induced reductions in CD31, VEGF, and HIF-1alpha expression and MVD compared with treatment with saline (n = 8 per group, P < 0.05). The results of western blotting showed that VEGF protein expression in radiotherapy group was significantly increased compared with that in the control group. However, VEGF protein expression in the endostatin or radiotherapy with endostatin groups was significantly decreased compared with that in the control group (n = 8 per group, P < 0.05). CONCLUSIONS: Endostatin combined with radiotherapy can significantly inhibit HCT-116 cell xenograft growth, possibly by inhibiting angiogenesis and attenuating tumor cell hypoxia. PMID- 29282028 TI - A pilot study of the individual placement and support model for patients with chronic pain. AB - BACKGROUND: Individual Placement and Support (IPS) is an evidence-based work rehabilitation model with well-documented effects for people with mental illness. The model has, however, never been tested out for people with chronic pain. This pilot study aimed to investigate chronic pain patients' experiences with the IPS job support model. METHODS: We recruited eight consecutive patients referred for various chronic pain conditions at a hospital outpatient pain clinic. They were offered IPS job support as an integrated part of their interdisciplinary pain rehabilitation. The patients' experiences were investigated through semi structured interviews 3 months after inclusion in the study. RESULTS: The participants reported mostly positive experiences with IPS. One participant dropped out of the study after deterioration of symptoms, while the remaining participants were satisfied with the intervention. Particular helpful aspects of the IPS intervention were the follow-up from the employment specialist, focus on competitive employment, focus on work despite pain complaints, reframing work into something positive, administrative support, and practice in writing applications. No participants reported adverse experiences from the IPS intervention. Within a 12-months time frame, 3 of the 8 participants gained competitive employment. CONCLUSIONS: This is the first report of the IPS model of supported employment applied in an outpatient setting for chronic pain patients. The results suggest that IPS can be successfully integrated with interdisciplinary pain rehabilitation, and warrants large-scale testing in a randomized controlled trial. PMID- 29282029 TI - Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line. AB - BACKGROUND: Fatty acid synthase (FASN), the major enzyme in de novo fatty acid synthesis, is highly expressed in breast cancer and its expression is reduced by polyunsaturated fatty acids (PUFAs) in liver. We previously found a positive association between rat mammary tumor levels of the n-6 PUFA arachidonic acid (AA) and tumor weight. We examined the roles of the major n-3 PUFA, docosahexaenoic acid (DHA, 22:6n-3), and the major n-6 PUFA, AA, in FASN expression in, and proliferation of, human breast cancer MCF-7 cells. METHODS: The cells were treated for 48 h with BSA or 60 MUM BSA-bound DHA, AA, or oleic acid (OA, 18:1n-9), then were incubated with or without estradiol or insulin. Western blot and 3H-thymidine incorporation assay were used to determine the role of DHA on FASN regulation and MCF-7 cell proliferation. RESULTS: DHA, but neither AA nor OA, inhibits estradiol-induced and insulin-induced expression of the precursor of sterol regulatory element binding protein-1 (p-SREBP-1), its mature form (m-SREBP-1), and FASN. Estradiol or insulin stimulation increased the pAkt/Akt and pS6/S6 ratios, expression of p-SREBP-1, m-SREBP-1, and FASN, and cell proliferation, and these effects were decreased by DHA. The DHA-induced decrease in FASN expression resulted from reduced pAkt/Akt signaling and not pERK1/2/ERK1/2 signaling. In addition, DHA enhanced the inhibitory effect of LY294002 on pAkt signaling and expression of p-SREBP-1, m-SREBP-1, and FASN. However, addition of rapamycin, an inhibitor of the mTOR signaling pathways, 1 h before addition of estradiol or insulin increased the pAkt/Akt ratio and FASN expression, and this effect was inhibited by addition of DHA 48 h before rapamycin. CONCLUSION: We conclude that, in MCF-7 cells, DHA inhibits pAKT signaling and thus expression of p-SREBP-1, m-SREBP-1, and FASN and cell proliferation. PMID- 29282030 TI - Ratios for double silicone oil Endotamponade - in vitro observations may assist with ratio selection. AB - BACKGROUND: Silicone oil tamponade is more frequently reserved for cases of complex retinal detachment. We describe the effects of different variations in oil ratios with the relatively unknown technique of double oil tamponade. METHODS: Retrospective case note review of nine patients with complex rhegmatogenous retinal detachment (RD). All cases had both superior and inferior breaks, mostly with associated proliferative vitreoretinopathy (PVR). All cases were treated with pars plana vitrectomy (PPV) and a double silicone oil endotamponade (DSOE) of both heavy silicone oil and conventional 'light' silicone oil. Ratios were varied to suit different RD configurations. In vitro observations were studied to help direct these decisions. RESULTS: Anatomical success was achieved in all cases. Common complications were the same as those seen in single oil tamponade (elevated intraocular pressure, cystoid macular oedema (CMO), cataract and posterior capsule opacification. No single case of recurrent RD was seen whilst mixed oil remained in situ. CONCLUSIONS: Double silicone oil endotamponade is a safe and effective treatment for complex retinal detachments with superior and inferior breaks. Differences in oil ratios can be tailored to best fit the distribution of retinal pathology. In vitro observations may help to inform these choices. PMID- 29282031 TI - Competing with big business: a randomised experiment testing the effects of messages to promote alcohol and sugary drink control policy. AB - BACKGROUND: Evidence-based policies encouraging healthy behaviours are often strongly opposed by well-funded industry groups. As public support is crucial for policy change, public health advocates need to be equipped with strategies to offset the impact of anti-policy messages. In this study, we aimed to investigate the effectiveness of theory-based public health advocacy messages in generating public support for sugary drink/alcohol policies (increased taxes; sport sponsorship bans) and improving resistance to subsequent anti-policy messages typical of the sugary drink/alcohol industry. METHODS: We conducted a two-wave randomised online experiment assigning Australian adults to one of four health policies (sugary drink tax; sugary drink industry sports sponsorship ban; alcohol tax; alcohol industry sports sponsorship ban). Within each health policy, we randomised participants to one of five message conditions: (i) non-advocacy based message about the size and seriousness of the relevant health issue (control); (ii) standard pro-policy arguments alone; (iii) standard pro-policy arguments combined with an inoculation message (forewarning and directly refuting anti policy arguments from the opposition); (iv) standard pro-policy arguments combined with a narrative message (a short, personal story about an individual's experience of the health issue); or (v) standard pro-policy arguments combined with a composite inoculation and narrative message. At time 1, we exposed participants (n = 6000) to their randomly assigned message. Around two weeks later, we re-contacted participants (n = 3285) and exposed them to an anti-policy message described as being from a representative of the sugary drink/alcohol industry. Generalised linear models tested for differences between conditions in policy support and anti-industry beliefs at both time points. RESULTS: Only the standard argument plus narrative message increased policy support relative to control at time 1. The standard argument plus narrative and standard argument plus inoculation messages were effective at increasing resistance to the persuasive impact of anti-policy messages relative to control at time 2. CONCLUSIONS: Dissemination of advocacy messages using inoculation or narrative components can help strengthen public resistance to subsequent anti-policy messages from industry groups. PMID- 29282032 TI - Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study. AB - BACKGROUND: Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH. METHODS: We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints. RESULTS: In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naive. In patients with data available, mean +/- standard deviation 6MWD had increased by 33 +/- 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naive subgroups. CONCLUSIONS: Riociguat was well tolerated in patients with CTEPH who were treatment naive, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed. TRIAL REGISTRATION: ClinicalTrials.org NCT01784562 . Registered February 4, 2013. PMID- 29282033 TI - Adolescent reserve capacity, socioeconomic status and school achievement as predictors of mortality in Finland - a longitudinal study. AB - BACKGROUND: Despite robust evidence on the inverse relationship between socioeconomic status (SES) and mortality, deviations from expected results have been observed likely due to school achievement and psychosocial resources, termed as "reserve capacity." Since adolescence is a critical period in developing sound psychological and behavioural patterns and adolescent markers of SES were seldom used, we determine if family SES in adolescence predicts later mortality. We also study how reserve capacity (perceived health, health-promoting behaviour and social support) and school achievement modify this relationship and reduce the negative effects of low SES. METHODS: A longitudinal study was designed by linking baseline data on 12 to 18 year-old Finns in 1985-95 (N = 41,833) from the Adolescent Health and Lifestyle Surveys with register data on mortality and SES from Statistics Finland. Average follow-up time was 18.4 years with a total of 770,161 person-years. Cox regression models, stratified by sex, were fitted to determine the effects of variables measured during adolescence: family SES, reserve capacity and school achievement on mortality risk. RESULTS: All reserve capacity dimensions significantly predicted mortality in boys. Perceived health and social support predicted that in girls. Adolescents with the lowest school achievement were more than twice at risk of dying compared to those with better school performance. Low SES increased the risk of death in boys (Hazard ratios: 1.6, 95% CI 1.1-2.4) but not in girls. Reserve capacity and school achievement weakened the effects of low SES on boys' risk of death. CONCLUSIONS: High reserve capacity and good school achievement in adolescence significantly reduce the risk of mortality. In boys, these also mitigate the negative effect of low SES on mortality. These findings underscore the roles of reserve capacity and school achievement during adolescence as likely causal or modifying factors in SES health inequalities. PMID- 29282034 TI - Outcome of breast cancer screening in Denmark. AB - BACKGROUND: In Denmark, national roll-out of a population-based, screening mammography program took place in 2007-2010. We report on outcome of the first four biennial invitation rounds. METHODS: Data on screening outcome were retrieved from the 2015 and 2016 national screening quality reports. We calculated coverage by examination; participation after invitation; detection-, interval cancer- and false-positive rates; cancer characteristics; sensitivity and specificity, for Denmark and for the five regions. RESULTS: At the national level coverage by examination remained at 75-77%; lower in the Capital Region than in the rest of Denmrk. Detection rate was slightly below 1% at first screen, 0.6% at subsequent screens, and one region had some fluctuation over time. Ductal carcinoma in situ (DCIS) constituted 13-14% of screen-detected cancers. In subsequent rounds, 80% of screen-detected invasive cancers were node negative and 40% <=10 mm. False-positive rate was around 2%; higher for North Denmark Region than for the rest of Denmark. Three out of 10 breast cancers in screened women were diagnosed as interval cancers. CONCLUSIONS: High coverage by examination and low interval cancer rate are required for screening to decrease breast cancer mortality. Two pioneer local screening programs starting in the 1990s were followed by a decrease in breast cancer mortality of 22-25%. Coverage by examination and interval cancer rate of the national program were on the favorable side of values from the pioneer programs. It appears that the implementation of a national screening program in Denmark has been successful, though regional variations need further evaluation to assure optimization of the program. PMID- 29282036 TI - Circulating microRNA's as a diagnostic tool for hepatocellular carcinoma in a hyper endemic HIV setting, KwaZulu-Natal, South Africa: a case control study protocol focusing on viral etiology. AB - BACKGROUND: A wide range of studies has investigated the diagnostic proficiency of extracellular microRNAs (miRNAs) in hepatocellular cancer (HCC). HCC is expected to increase in Sub-Saharan Africa (SSA), due to endemic levels of viral infection (HBV/HIV), ageing and changing lifestyles. This unique aetiological background provides an opportunity for investigating potentially novel circulating miRNAs as biomarkers for HCC in a prospective study in South Africa. METHODS: This study will recruit HCC patients from two South African cancer hospitals, situated in Durban and Pietermaritzburg in the province of KwaZulu Natal. These cases will include both HBV mono-infected and HBV/HIV co-infected HCC cases. The control group will consist of two (2) age and sex-matched healthy population controls per HCC case randomly selected from a Durban based laboratory. The controls will exclude patients if they have any evidence of chronic liver disease. A standardised reporting approach will be adopted to detect, quantify and normalize the level of circulating miRNAs in the blood sera of HCC cases and their controls. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) will be employed to quantity extracellular miRNAs. Differences in concentration of relevant miRNA by case/control status will be assessed using the Wilcoxon rank-sum (Mann-Whitney U) test. Adjustment for multiple testing (Bonferroni correction), receiver operating curves (ROC) and optimal breakpoint analyses will be employed to identify potential thresholds for the differentiation of miRNA levels of HCC cases and their controls. DISCUSSION: Although there is a growing base of literature regarding the role of circulating miRNAs as biomarkers, this promising field remains a 'work in progress'. The aetiology of HBV infection in HCC is well understood, as well as it's role in miRNA deregulation, however, the mediating role of HIV infection is unknown. HCC incidence in SSA, including South Africa, is expected to increase significantly in the next decade. A combination of factors, therefore, offers a unique opportunity to identify candidate circulating miRNAs as potential biomarkers for HBV/HIV infected HCC. PMID- 29282035 TI - Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets. AB - BACKGROUND: Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. METHODS: Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. RESULTS: In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. CONCLUSIONS: CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4 positive tumor capillaries may represent a promising additional therapeutic strategy. PMID- 29282037 TI - A novel integrative procedure for identifying and integrating three-dimensions of objectively measured free-living sedentary behaviour. AB - BACKGROUND: The widely accepted definition of sedentary behaviour [SB] refers to any waking behaviour characterized by an energy expenditure <=1.5 metabolic equivalents [METs] while in a sitting or reclining posture. At present, there is no single field-based device which objectively measures sleep, posture and activity intensity simultaneously. The aim of this study was to develop a novel integrative procedure [INT] to combine information from two validated activity monitors on sleep, activity intensity and posture, the three key dimensions of SB. METHODS: Participants in this analysis were initially recruited from a series of three studies conducted between December 2014 and June 2016 at the University of Leeds. Sixty-three female participants aged 37.1 (13.6) years with a body mass index of 29.6 (4.7) kg/m2 were continuously monitored for 5-7 days with the SenseWear Armband [SWA] (sleep and activity intensity) and the activPAL [AP] (posture). Data from both activity monitors were analysed separately and integrated resulting in three measures of sedentary time. Differences in Sedentary time between the three measurement methods were assessed as well as how well the three measures correlated. RESULTS: The three measures of sedentary time were positively correlated, with the weakest relationship between SEDSWA (awake and <1.5 METs) and SEDAP (awake and sitting/lying posture) [r(61) = .37,p = .003], followed by SEDSWA and SEDINT (awake, <1.5 METs and sitting/lying posture) [r(61) = .58,p < .001], and the strongest relationship was between SEDAP and SEDINT [r(61) = .91,p < .001]. There was a significant difference between the three measures of sedentary time [F(1.18,73.15) = 104.70,p < .001]. Post-hoc tests revealed all three methods differed significantly from each other [p < .001]. SEDSWA resulted in the most sedentary time 11.74 (1.60) hours/day, followed by SEDAP 10.16 (1.75) hours/day, and SEDINT 9.10 (1.67) hours/day. Weekday and weekend day sedentary time did not differ for any of the measurement methods [p = .04-.25]. CONCLUSION: Information from two validated activity monitors was combined to obtain an objective measure of free-living SB based on posture and activity intensity during waking hours. The amount of sedentary time accumulated varied according to the definition of SB and its measurement. The novel data integration and processing procedures presented in this paper represents an opportunity to investigate whether different components of SB are differentially related to health end points. PMID- 29282038 TI - The prognostic value of TP53 mutations in hypopharyngeal squamous cell carcinoma. AB - BACKGROUND: TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC. METHODS: We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014. TP53 mutation status was determined by Sanger sequencing, and patients were classified into wild-type, missense mutation, and truncating mutation groups. Additionally, p53 expression was determined using immunohistochemistry in surgical specimens. RESULTS: TP53 mutations were identified in 39 (68%) patients. The 3-year disease-specific survival (DSS) rate of wild-type, missense mutation, and truncating mutation group were 94%, 61%, and 43%, respectively. The TP53 mutation group displayed significantly worse DSS and overall survival rates than the wild-type group (P = 0.01 and P = 0.007, respectively). Multivariate analyses revealed that the presence of TP53 mutations and >=4 metastatic lymph nodes were independent adverse prognostic factors for HPSCC. p53 immunopositivity was detected in 22 patients, including 5 (28%) and 17 (71%) patients in the wild-type and missense mutation groups, whereas none of the patients with truncating mutation exhibited p53 immunopositivity (P = 0.0001). CONCLUSION: The TP53 mutation status correlated with poor prognosis in surgically treated HPSCC patients. Specifically, truncating mutations which were not detected by p53 immunohistochemistry were predictive of worst survival. PMID- 29282040 TI - Case report: atypical presentation of vancomycin induced DRESS syndrome: a case report and review of the literature. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe hypersensitivity drug reaction involving the skin and multiple internal organ systems. The symptoms typically present with fever and skin rash, and rapidly progress to multiple organ failures. Vancomycin is a rare drug to cause DRESS syndrome with 23 cases reported to date. CASE PRESENTATION: We described a case of a 39 year-old man who was treated with vancomycin for osteomyelitis of the foot. The patient subsequently developed acute respiratory distress syndrome (ARDS) followed by rash and acute interstitial nephritis. These symptoms were improved by withdrawal of vancomycin and a pulsed corticosteroid regimen. According to the European Registry of Severe Cutaneous Adverse Reaction Criteria (RegiSCAR) (Kardaun et al, British Journal of Dermatology, 169:1071-1080, 2013), the probability of vancomycin induced DRESS syndrome was scored as "Definite". A literature search of vancomycin induced DRESS syndrome was also performed and the overall pulmonary involvement was estimated as 5%. To our knowledge, this was the first case reported with pulmonary involvement as the initial symptom. CONCLUSION: This is the first case to report pulmonary manifestation as the initial symptom in vancomycin induced DRESS syndrome. Prompt recognition of this entity can expedite proper treatment and hasten recovery. PMID- 29282039 TI - Plasma levels of alarmin HNPs 1-3 associate with lung dysfunction after cardiac surgery in children. AB - BACKGROUND: Early onset of lung injury is considerable common after cardiac surgery and is associated with increasing in morbidity and mortality, but current clinical predictors for the occurrence of this complication always have limited positive warning value. This study aimed to evaluate whether elevated plasma levels of human neutrophil peptides (HNPs) 1-3 herald impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB). METHODS: Consecutive children younger than 3 years old who underwent cardiac surgery were prospectively enrolled. Plasma concentrations of HNPs 1-3 and inflammatory cytokines were measured before, and immediately after CPB, as well as at 1 h, 12 h, and 24 h after CPB. RESULTS: Thirty patients were enrolled, 18 (60%) of whom were infants. Plasma levels of HNPs 1-3 and the pro inflammatory cytokine interleukin-6 (IL-6) significantly increased immediately after CPB (P < 0.001), while IL-8 increased 1 h after the CPB operation (P = 0.002). The anti-inflammatory cytokine IL-10 levels were also significantly elevated immediately after CPB compared with the baseline (P < 0.001). The stepwise multiple linear regression analysis showed that the plasma HNPs 1-3 levels immediately after CPB was independent correlated with the declined lung function, as reflected by the PaO2/FiO2 ratio on the first 2 days after operation (for the first day: OR, -1.067, 95% CI, -0.548 to -1.574; P < 0.001; for the second day: OR, -0.667, 95% CI, -0.183 to -1.148; P = 0.009) and prolonged mechanical ventilation time (OR, 0.039, 95% CI, 0.005 to 0.056; P = 0.011). Plasma levels of HNPs 1-3 and IL-10 returned to the baseline values, while IL-6 and IL-8 levels remained significantly higher than baseline 24 h after CPB (P <= 0.01). CONCLUSIONS: Elevated HNPs 1-3 levels immediately after CPB correlate with impaired lung function, and HNPs 1-3 could serve as a quantifiable early alarmin biomarker for onset of lung injury in infants and young children undergoing cardiac surgery with CPB. PMID- 29282041 TI - A novel compound heterozygous mutation of the SMARCAL1 gene leading to mild Schimke immune-osseous dysplasia: a case report. AB - BACKGROUND: Schimke immune-osseous dysplasia (SIOD, OMIM 242900) is characterized by spondyloepiphyseal dysplasia, T-cell deficiency, renal dysfunction and special facial features. SMARCAL1 gene mutations are determined in approximately 50% of patients diagnosed with SIOD. CASE PRESENTATION: The case presented here is that of a 6-year-old boy who was born at 33 weeks to healthy, non-consanguineous Chinese parents. He presented with short stature (95 cm; <3rd percentile) and proteinuria. Initially suspected of having IgM nephropathy, the patient was finally diagnosed with mild Schimke immune-osseous dysplasia. One novel mutation (p.R817H) and one well-known mutation (p.R645C) was identified in the SMARCAL1 gene. CONCLUSION: This report describes a clinical and genetic diagnostic model of mild SIOD. It also highlights the importance of molecular testing or clinical diagnosis and the guidance it provides in disease prognosis. PMID- 29282042 TI - Overexpression of EMMPRIN is associated with lymph node metastasis and advanced stage of non-small cell lung cancer: a retrospective study. AB - BACKGROUND: Previous studies show that overexpression of EMMPRIN involved in the malignant biological behavior of tumors. This investigation was to disclose the expression status of EMMPRIN in non-small cell lung cancer (NSCLC) and its clinical value for the diagnosis of NSCLC. METHODS: The expression of EMMPRIN was examined using immunohistochemistry and enzyme-linked immunosorbent assay. The clinical value of EMMPRIN was evaluated by drawing a receiver operating characteristic (ROC) curve. RESULTS: NSCLC tissues and serum exhibited higher expression levels of EMMPRIN than the normal control (p < 0.05), and the expression of the EMMPRIN was significantly associated with lymphatic invasion and advanced stage of NSCLC (p < 0.05). ROC curve suggested that the threshold level of serum EMMPRIN for distinguishing NSCLC from control group was 80.3 pg/mL, and displayed a sensitivity of 97.22% and a specificity of 95%. And higher EMMPRIN expression in serum and tissues appeared to be risk factors for NSCLC development (risk ratio =1.56 and 1.1). CONCLUSION: Overexpression of EMMPRIN was associated with lymphatic metastasis and advanced stage of NSCLC and test of serum EMMPRIN contributes to the NSCLC diagnosis. PMID- 29282043 TI - A one-day surgical-skill training course for medical students' improved surgical skills and increased interest in surgery as a career. AB - BACKGROUND: Despite many high-quality programs in basic surgical-skill education, the surgical skill of junior doctors varies widely. This, together with the waning interest in surgery as a career among medical students, is a serious issue confronted by hospitals and healthcare systems worldwide. We, therefore, developed and implemented an intensive one-day surgical-skill training course for two purposes; it would improve surgical skills and increase interest in surgery among medical students. METHODS: The surgical-skill training program is named Surgical Skill Weekend (SSW) and it includes hands-on training sessions for surgical-suturing techniques and advanced surgical procedures (i.e. laparoscopic and robot-assisted surgery), hybrid simulation sessions, and an operating-room session where aforementioned sessions are all put together. By the end of the program, students' improvements in surgical-suturing skills were assessed by experts in a form of checklist, and changes in the interest in a surgical career, if there were any, were answered by the students who participated in the program. RESULTS: A total of ninety-one (91) medical students participated in the 2015 and 2016 SSW courses. Their overall satisfaction level with the course was very high (Very satisfied: 78%, Quite satisfied: 22%). All of the participant's surgical suturing skills significantly improved (median score range: 14-20, P < 0.05) and their interest in a surgical career increased significantly (from 56% to 81%, P < 0.05) by completing the program. CONCLUSIONS: An intensive and comprehensive surgical-skill training program for medical students can not only improve surgical-suturing skills but also increase interest in surgery as a career. PMID- 29282044 TI - Ethanolic extract of Streblus asper leaves protects against glutamate-induced toxicity in HT22 hippocampal neuronal cells and extends lifespan of Caenorhabditis elegans. AB - BACKGROUND: Although such local herb as Streblus asper (family Moraceae) has long been recognized for traditional folk medicines and important ingredient of traditional longevity formula, its anti-neurodegeneration or anti-aging activity is little known. This study aimed to investigate the neuroprotective effect of S. asper leaf extracts (SA-EE) against toxicity of glutamate-mediated oxidative stress, a crucial factor contributing to the neuronal loss in age-associated neurodegenerative diseases and the underlying mechanism as well as to evaluate its longevity effect. METHODS: Using mouse hippocampal HT22 as a model for glutamate oxidative toxicity, we carried out MTT and LDH assays including Annexin V-FITC/propidium iodide staining to determine the SA-EE effect against glutamate induced cell death. Antioxidant activities of SA-EE were evaluated using the radical scavenging and DCFH-DA assays. To elucidate the underlying mechanisms, SA EE treated cells were analyzed for the expressions of mRNA and proteins interested by immunofluorescent staining, western blot analysis and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) techniques. The longevity effect of SA-EE was examined on C. elegans by lifespan assay. RESULTS: We demonstrate that a concentration-dependent reduction of glutamate induced cytotoxicity was significant after SA-EE treatment as measured by MTT and LDH assays. Annexin V-FITC/propidium iodide and immunofluorescent staining showed that co-treatment of glutamate with SA-EE significantly reduced apoptotic inducing factor (AIF)-dependent apoptotic cell death. DCFH-DA assay revealed that this extract was capable of dose dependently attenuating the ROS caused by glutamate. Western blot analysis and qRT-PCR showed that nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels in the nucleus, as well as mRNA levels of antioxidant-related genes under Nrf2 regulation were significantly increased by SA-EE. Furthermore, this extract was capable of extending the lifespan of C. elegans. CONCLUSIONS: SA-EE possesses both longevity effects and neuroprotective activity against glutamate-induced cell death, supporting its therapeutic potential for the treatment of age-associated neurodegenerative diseases. PMID- 29282045 TI - Balancing the local and the universal in maintaining ethical access to a genomics biobank. AB - BACKGROUND: Issues of balancing data accessibility with ethical considerations and governance of a genomics research biobank, Generation Scotland, are explored within the evolving policy landscape of the past ten years. During this time data sharing and open data access have become increasingly important topics in biomedical research. Decisions around data access are influenced by local arrangements for governance and practices such as linkage to health records, and the global through policies for biobanking and the sharing of data with large scale biomedical research data resources and consortia. METHODS: We use a literature review of policy relevant documents which apply to the conduct of biobanks in two areas: support for open access and the protection of data subjects and researchers managing a bioresource. We present examples of decision making within a biobank based upon observations of the Generation Scotland Access Committee. We reflect upon how the drive towards open access raises ethical dilemmas for established biorepositories containing data and samples from human subjects. RESULTS: Despite much discussion in science policy literature about standardisation, the contextual aspects of biobanking are often overlooked. Using our engagement with GS we demonstrate the importance of local arrangements in the creation of a responsive ethical approach to biorepository governance. We argue that governance decisions regarding access to the biobank are intertwined with considerations about maintenance and viability at the local level. We show that in addition to the focus upon ever more universal and standardised practices, the local expertise gained in the management of such repositories must be supported. CONCLUSIONS: A commitment to open access in genomics research has found almost universal backing in science and health policy circles, but repositories of data and samples from human subjects may have to operate under managed access, to protect privacy, align with participant consent and ensure that the resource can be managed in a sustainable way. Data access committees need to be reflexive and flexible, to cope with changing technology and opportunities and threats from the wider data sharing environment. To understand these interactions also involves nurturing what is particular about the biobank in its local context. PMID- 29282046 TI - Evaluation of pharmacodynamic properties and safety of Cinnamomum zeylanicum (Ceylon cinnamon) in healthy adults: a phase I clinical trial. AB - BACKGROUND: Cinnamon is considered as a treatment for many ailments in native medicine. Evidence suggests that Cinnamomum zeylanicum (CZ) has anti-microbial, anti-parasitic, anti-oxidant, blood glucose lowering properties and beneficial cardiovascular effects. The present study aims to evaluate Pharmacodynamic properties and safety of CZ in healthy adults using a Phase I Clinical Trial. METHODS: This phase I clinical trial was conducted at the Department of Pharmacology, Faculty of Medicine, University of Colombo, Sri Lanka. Thirty healthy adults were recruited for the study, conducted for a period of 3 months, with the dose of CZ (water extract) increased at monthly intervals (85 mg, 250 mg and 500 mg). Data collection was carried out at baseline and during each monthly follow up visit. Anthropometric, clinical and biochemical assessments were done at baseline and during follow up. Adverse effects and drug compliance was also evaluated. RESULTS: Twenty eight subjects completed the three months follow up. Mean age was 38.8 +/- 10.4 years and 50% were males. There were no significant changes in the anthropometric parameters during the three months follow up. Both systolic and diastolic blood pressure reduced significant during the 1st month and this reduction was sustained throughout follow up. Full blood count, renal function tests, liver function tests, fasting blood glucose, HDL-c, VLDL-d and triglycerides remained within the normal range without any significant alteration during the 3 months. A significant reduction in the TC (p < 0.05) and LDL-c (p < 0.001) was noted at the end of the 3 months follow up period. There were no serious adverse effects (including hypersensitivity) noted. In two participants dyspepsia necessitated the discontinuation of study participation. Drug compliance was between 85 and 95% during the study period. CONCLUSIONS: This is the first phase I clinical trial in health adults evaluating efficacy and safety of CZ. Our results demonstrate no significant side effects and toxicity of CZ, including hepatotoxicity and anti-coagulation properties. CZ demonstrated beneficial anti-hyperlipidaemic and blood pressure lowering effects among healthy adults. Further studies with larger samples and longer durations may be able to elucidate other side effects and better describe the pharmacodynamic properties. TRIAL REGISTRATION: SLCTR/2013/001 (Sri Lanka Clinical Trials Registry: http://www.slctr.lk/trials/106 ) (Date of Registration: 01/01/2013). PMID- 29282047 TI - The effects of patients initiated aggression on Chinese medical students' career planning. AB - BACKGROUND: Patient initiated aggression is common among Chinese health-care workers, reaching over 10,000 incidents annually (Jinyang web. http://6d.dxy.cn/article/55497 . 2013), and the tense doctor-patient relationship generates stress among medical students. Because of the paucity of data (few surveys pay attention to the effects of violence perpetrated by patients on medical students), this study aimed to characterize patient initiated aggression against medical students. METHODS: In this cross-sectional survey conducted at a medical school in West China in 2015, 157 medical students completed a self administered questionnaire and the Short Form-36, which assesses quality of life. The associations between patient initiated aggression exposure and medical students' career planning or quality of life were assessed using a chi-square test. RESULTS: Of the 157 medical students, 48 (30.6%) reported having suffered patient initiated aggression at least once during the previous year in the form of mental abuse (20.4%), offensive threat (14.6%), physical violence (8.3%), sexual harassment (verbal: 8.3% or physical: 1.6%), and extreme violence (physical violence leading to surgical treatment or hospitalization) (0.6%). Insufficient communication was the primary reason cited (27.2%). Emotional attack (mental abuse and offensive threat) occurrence differed among age groups (chi2 = 9.786, P = 0.020) and was ubiquitous among those aged >30 years old. Women were more likely than men to suffer physical violence (chi2 = 6.796, P = 0.009). Patient initiated aggression was not significantly associated with medical students' career planning or quality of life. CONCLUSIONS: In this study, patient initiated aggression, albeit common, as in the rest of China, did not appear to be associated with medical students' career planning or quality of life. However, the characteristics described can inform policymaking and the design of programs to minimize patient initiated aggression occurrence. PMID- 29282048 TI - Exploring factors associated with the uneven utilization of telemedicine in Norway: a mixed methods study. AB - BACKGROUND: Norway has a long history of using telemedicine, especially for geographical reasons. Despite the availability of promising telemedicine applications and the implementation of national initiatives and policies, the sustainability and scaling-up of telemedicine in the health system is still far from accomplished. The main objective of this study was to explore and identify the multi-level (micro, meso and macro) factors affecting telemedicine utilization in Norway. METHODS: We used a mixed methods approach. Data from a national registry were collected to analyze the use of outpatient visits and telemedicine contacts in Norway from 2009 to 2015. Interviews with key stakeholders at national, regional and local level helped complete and contextualize the data analysis and explore the main issues affecting the use of telemedicine by health authorities and hospitals. Relevant national documents were also used to support, contradict, contextualize or clarify information and data. RESULTS: Telemedicine use in Norway from 2009 to 2015 remained very low, not exceeding 0.5% of total outpatient activity at regional level and 0.1% at national level. All four regions used telemedicine. Of the 29 hospitals, 24 used it at least once over the 7-year period. Telemedicine was not used regularly everywhere, with some hospitals using it sporadically. Telemedicine was mostly used in selected specialties, including rehabilitation, neurosurgery, skin and venereal diseases. Three major themes affecting implementation and utilization of telemedicine in Norway emerged: (i) governance and strategy; (ii) organizational and professional dimensions; (iii) economic and financial dimensions. For each theme, a number of factors and challenges faced at different health care levels were identified. CONCLUSIONS: This study allowed shedding light on multi-level and interdependent factors affecting utilization of telemedicine in Norway. The identification of the main implementation and utilization challenges might support decision makers and practitioners in the successful scaling-up of telemedicine. This work provides a knowledge base useful to other countries which intend to implement telemedicine or other digital health services into their healthcare systems. PMID- 29282049 TI - Gender differences in job quality and job satisfaction among doctors in rural western China. AB - BACKGROUND: Few studies about gender differences in job quality and job satisfaction among medical professionals have been carried out in China. So the objectives of this study were to examine whether and to what extent gender differences existed in job quality and job satisfaction of doctors in rural western China. METHODS: From 2009 to 2011, a total of 1472 doctors from 103 selected county-level health care facilities in rural western China were recruited into the study. Information about the doctors' demographic characteristics, job quality, and job satisfaction was collected through a designed questionnaire. Besides examining gender differences in single dimensions of job quality and job satisfaction, principal component analysis was used to construct a composite job quality index to measure the differences in the comprehensive job quality, and exploratory factor analysis was applied to evaluate the differences in the overall job satisfaction. Chi-square test was used to calculate differences between proportions, and t-test was used to compare differences between means. RESULTS: Among the doctors, there were 705 males and 767 females (ratio 1:1.09). Male doctors had significantly higher monthly salaries, longer working hours, more times of night shifts per month, longer continuous working hours, and longer years of service at current facilities, and marginally significantly higher hourly wage and longer years of service in current professions. However, female doctors showed greater overall job qualities. Significant and marginally significant gender differences were only found in satisfaction with remuneration compared to workload, the chance of promotion and working environment. But female showed greater satisfaction in the overall job satisfaction and the factor including sub-aspects of working environment, remuneration compared to workload, the chance of promotion, utilization of subjective initiative, and sense of achievement. CONCLUSIONS: Gender differences in job quality and job satisfaction did exist among doctors in rural western China. The participating female doctors were shown to have better job quality and greater job satisfaction. PMID- 29282050 TI - Changes in professionals' beliefs following a palliative care implementation programme at a surgical department: a qualitative evaluation. AB - BACKGROUND: One ambition regarding palliative care is that it should be more accessible to patients and families regardless of care setting. Previous studies show many difficulties and shortcomings in the care of patients with palliative care needs in acute care facilities, but also challenges regarding efforts to implement palliative care. The aim of this study is to evaluate how the implementation of palliative care, using a combination of integration and consultation strategies, can change beliefs regarding palliative care among professionals in a surgical department. METHOD: In order to explore professionals' experiential outcome of an educational implementation strategy, a before-after qualitative design was used. The study was based on three focus group discussions. Two discussions were conducted before introducing the implementation strategy and one was conducted after. The participants consisted of five nurses and two specialist surgeons from a surgical department in Sweden. The focus group discussions revealed a variety of different attitudes and beliefs, which were analysed using qualitative systematic text condensation. RESULTS: Beliefs regarding palliative care were identified in seven areas; the importance of palliative care, working methods in palliative care, team collaboration in palliative care, collegial support, discussions about diagnosis, symptoms at the end of life, and families of patients in palliative care. Changes in beliefs were seen in all areas except one: team collaboration in palliative care. CONCLUSION: It is possible to change the beliefs of health care professionals in a surgical department regarding palliative care through the implementation of palliative knowledge. Beliefs were changed from an individual to a collective development where the group initiated a shared palliative working method. The changes observed were palliative care being described as more complex and participants differentiating between surgical care and palliative care. PMID- 29282051 TI - Microbiota dysbiosis in inflammatory bowel diseases: in silico investigation of the oxygen hypothesis. AB - BACKGROUND: Inflammatory bowel diseases (IBD), which include ulcerative colitis and Crohn's disease, cause chronic inflammation of the digestive tract in approximately 1.6 million Americans. A signature of IBD is dysbiosis of the gut microbiota marked by a significant reduction of obligate anaerobes and a sharp increase in facultative anaerobes. Numerous experimental studies have shown that IBD is strongly correlated with a decrease of Faecalibacterium prausnitzii and an increase of Escherichia coli. One hypothesis is that chronic inflammation induces increased oxygen levels in the gut, which in turn causes an imbalance between obligate and facultative anaerobes. RESULTS: To computationally investigate the oxygen hypothesis, we developed a multispecies biofilm model based on genome scale metabolic reconstructions of F. prausnitzii, E. coli and the common gut anaerobe Bacteroides thetaiotaomicron. Application of low bulk oxygen concentrations at the biofilm boundary reproduced experimentally observed behavior characterized by a sharp decrease of F. prausnitzii and a large increase of E. coli, demonstrating that dysbiosis consistent with IBD disease progression could be qualitatively predicted solely based on metabolic differences between the species. A diet with balanced carbohydrate and protein content was predicted to represent a metabolic "sweet spot" that increased the oxygen range over which F. prausnitzii could remain competitive and IBD could be sublimated. Host microbiota feedback incorporated via a simple linear feedback between the average F. prausnitzii concentration and the bulk oxygen concentration did not substantially change the range of oxygen concentrations where dysbiosis was predicted, but the transition from normal species abundances to severe dysbiosis was much more dramatic and occurred over a much longer timescale. Similar predictions were obtained with sustained antibiotic treatment replacing a sustained oxygen perturbation, demonstrating how IBD might progress over several years with few noticeable effects and then suddenly produce severe disease symptoms. CONCLUSIONS: The multispecies biofilm metabolic model predicted that oxygen concentrations of ~1 micromolar within the gut could cause microbiota dysbiosis consistent with those observed experimentally for inflammatory bowel diseases. Our model predictions could be tested directly through the development of an appropriate in vitro system of the three species community and testing of microbiota-host interactions in gnotobiotic mice. PMID- 29282052 TI - Identifying gaps in the continuum of care for hypertension and diabetes in two Indian communities. AB - BACKGROUND: Non-communicable diseases (NCDs) represent the largest, and fastest growing, burden of disease in India. This study aimed to quantify levels of diagnosis, treatment, and control among hypertensive and diabetic patients, and to describe demand- and supply-side barriers to hypertension and diabetes diagnosis and care in two Indian districts, Shimla and Udaipur. METHODS: We conducted household and health facility surveys, as well as qualitative focus group discussions and interviews. The household survey randomly sampled individuals aged 15 and above in rural and urban areas in both districts. The survey included questions on NCD knowledge, history, and risk factors. Blood pressure, weight, height, and blood glucose measurements were obtained. The health facility survey was administered in 48 health care facilities, focusing on NCD diagnosis and treatment capacity, including staffing, equipment, and pharmaceuticals. Qualitative data was collected through semi-structured key informant interviews with health professionals and public health officials, as well as focus groups with patients and community members. RESULTS: Among 7181 individuals, 32% either reported a history of hypertension or were found to have a systolic blood pressure >= 140 mmHg and/or diastolic >=90 mmHg. Only 26% of those found to have elevated blood pressure reported a prior diagnosis, and just 42% of individuals with a prior diagnosis of hypertension were found to be normotensive. A history of diabetes or an elevated blood sugar (Random blood glucose (RBG) >=200 mg/dl or fasting blood glucose (FBG) >=126 mg/dl) was noted in 7% of the population. Among those with an elevated RBG/FBG, 59% had previously received a diagnosis of diabetes. Only 60% of diabetics on treatment were measured with a RBG <200 mg/dl. Lower-level health facilities were noted to have limited capacity to measure blood glucose as well as significant gaps in the availability of first-line pharmaceuticals for both hypertension and diabetes. CONCLUSIONS: We found high rates of uncontrolled diabetes and undiagnosed and uncontrolled hypertension. Lower level health facilities were constrained by capacity to test, monitor and treat diabetes and hypertension. Interventions aimed at improving patient outcomes will need to focus on the expanding access to quality care in order to accommodate the growing demand for NCD services. PMID- 29282053 TI - Characterization of pediatric cystic fibrosis airway epithelial cell cultures at the air-liquid interface obtained by non-invasive nasal cytology brush sampling. AB - BACKGROUND: In vitro systems of primary cystic fibrosis (CF) airway epithelial cells are an important tool to study molecular and functional features of the native respiratory epithelium. However, undifferentiated CF airway cell cultures grown under submerged conditions do not appropriately represent the physiological situation. A more advanced CF cell culture system based on airway epithelial cells grown at the air-liquid interface (ALI) recapitulates most of the in vivo like properties but requires the use of invasive sampling methods. In this study, we describe a detailed characterization of fully differentiated primary CF airway epithelial cells obtained by non-invasive nasal brushing of pediatric patients. METHODS: Differentiated cell cultures were evaluated with immunolabelling of markers for ciliated, mucus-secreting and basal cells, and tight junction and CFTR proteins. Epithelial morphology and ultrastructure was examined by histology and transmission electron microscopy. Ciliary beat frequency was investigated by a video-microscopy approach and trans-epithelial electrical resistance was assessed with an epithelial Volt-Ohm meter system. Finally, epithelial permeability was analysed by using a cell layer integrity test and baseline cytokine levels where measured by an enzyme-linked immunosorbent assay. RESULTS: Pediatric CF nasal cultures grown at the ALI showed a differentiation into a pseudostratified epithelium with a mucociliary phenotype. Also, immunofluorescence analysis revealed the presence of ciliated, mucus-secreting and basal cells and tight junctions. CFTR protein expression was observed in CF (F508del/F508del) and healthy cultures and baseline interleukin (IL)-8 and IL-6 release were similar in control and CF ALI cultures. The ciliary beat frequency was 9.67 Hz and the differentiated pediatric CF epithelium was found to be functionally tight. CONCLUSION: In summary, primary pediatric CF nasal epithelial cell cultures grown at the ALI showed full differentiation into ciliated, mucus producing and basal cells, which adequately reflect the in vivo properties of the human respiratory epithelium. PMID- 29282054 TI - Educational program promoting regular physical exercise improves functional capacity and daily living physical activity in subjects with knee osteoarthritis. AB - BACKGROUND: Physical exercise and educational programs promote several benefits for patients with knee osteoarthritis (OA). However, little is known about the effects of educational programs promoting the regular practice of physical exercise. The purpose of the present study was to assess the effect of an interdisciplinary educational program, emphasizing the recommendation for regular practice of physical exercise, on functional capacity and daily living physical activity in individuals with knee OA. METHODS: Two hundred and thirty-nine individuals (50 men) with an established diagnosis of knee OA (degree I to IV in the Kelgreen and Lawrence scale) were randomly allocated into a multidisciplinary educational program (EDU; n = 112) or control group (CON; n = 127). Functional capacity (sit and reach, 6-min walking test (6MWT), timed up and down stairs test, timed up and go test (TUGT), and five times sit-to-stand test (FTSST)) and daily living physical activity (IPAQ, short version) were measured before, during (6 months) and after 12 months of follow-up. RESULTS: Body mass index reduced significantly (P < 0.05) after 6 months, and remained reduced after 12-month of follow-up in EDU, but not in CON. EDU group improved (P < 0.05) timed up and down stairs (19%), TUGT (32.5%) and FTSST (30%) performance after 6 months of follow up, which remained improved after 12 months of follow-up. Functional capacity did not change in CON, excepted for the timed up and down stairs performance that increased after 6 months (12%, P < 0.05), but returned to levels similar to baseline after 12 months of follow-up. There was also an increase (P < 0.05) in the prevalence of active and very active individuals, as well as a reduction (P < 0.05) in the prevalence of sedentary individuals in EDU group during follow-up. There were no significant changes on sit and reach and 6MWT performance during follow-up in both groups. CONCLUSIONS: The results suggest that an educational program emphasizing the recommendation for regular practice of physical exercise may be an effective tool for improving functional capacity and daily physical activity in individuals with knee OA. TRIAL REGISTRATION: NCT 02335034 , December 22, 2014. PMID- 29282055 TI - Knowledge, attitudes and practices of community pharmacists on generic medicines in Palestine: a cross-sectional study. AB - BACKGROUND: Generic substitution in several countries has become a common practice. Besides, it is considered as a major cost minimizing strategy meant to contain pharmaceutical expenditure without compromising healthcare quality. However, the safety and quality issues of generic products are of top concerns of general practitioners and health work professionals. This study aimed to investigate community pharmacist's knowledge, attitudes and practices toward generic medicines in Palestine. METHODS: This study was a cross-sectional observational study employing a self-administered questionnaire. The questionnaire was of four main sections: demographic and practice details of the participants, knowledge, attitudes and the influencing factors related to selection and dispensing of generic medicines. A convenience sampling technique was implemented in this study in which the data collection form was distributed in West Bank- Palestine among a set of practicing pharmacists. Mann-Whitney-U or Kruskal-Wallis tests were used to comparison of different issues as appropriate. P-values of <0.05 were considered significant. RESULTS: A total of 302 community pharmacists were interviewed, slightly more than half were males (52.3%). The mean knowledge score of participants regarding generic medicines was (5.91 +/- 1.27) where the highest score was 8 of 10. Knowledge score was not significantly influenced by any of the socio-demographic characteristics. Our data showed that most of included pharmacists in the study (95.4%) agreed that health authorities should implement bioequivalence policies prior to marketing approval of generics, while 87.4% of participants agreed that they should be given the right to substitute generics and the majority (62.3%) support generic substitution for brand name drugs in all cases when a generic is available The main two factors affect pharmacists' selection and dispensing of generic medicines are personal faith in the product (86.1%) and cost effectiveness of generic medicines (84.1%). CONCLUSIONS: Generic medicines substitution among pharmacists is widespread and prevalent. Our data found that participant pharmacists in Palestine had basic knowledge with regards to generic medicine. However, their knowledge score pertaining the technical and regulatory aspects of bioequivalence and pharmacokinetic parameters in particular was insufficient. PMID- 29282056 TI - Validation of the German revised version of the program in palliative care education and practice questionnaire (PCEP-GR). AB - BACKGROUND: The evaluation of the effectiveness of undergraduate palliative care education (UPCE) programs is an essential foundation to providing high-quality UPCE programs. Therefore, the implementation of valid evaluation tools is indispensable. Until today, there has been no general consensus regarding concrete outcome parameters and their accurate measurement. The Program in Palliative Care Education and Practice Questionnaire (German Revised Version; PCEP-GR) is a promising assessment tool for UPCE. The aim of the current study was to evaluate the psychometric properties of PCEP-GR and to demonstrate its feasibility for the evaluation of UPCE programs. METHODS: The practical feasibility of the PCEP-GR and its acceptance in medical students were investigated in a pilot study with 24 undergraduate medical students at Heinrich Heine University Dusseldorf, Germany. Subsequently, the PCEP-GR was surveyed in a representative sample (N = 680) of medical students in order to investigate its psychometric properties. Factorial validity was investigated by means of principal component analysis (PCA). Reliability was examined by means of split half-reliability analysis and analysis of internal consistency. After taking into consideration the PCA and distribution analysis results, an evaluation instruction for the PCEP-GR was developed. RESULTS: The PCEP-GR proved to be feasible and well-accepted in medical students. PCA revealed a four-factorial solution indicating four PCEP-GR subscales: preparation to provide palliative care, attitudes towards palliative care, self-estimation of competence in communication with dying patients and their relatives and self-estimation of knowledge and skills in palliative care. The PCEP-GR showed good split-half reliability and acceptable to good internal consistency of subscales. Attitudes towards palliative care slightly missed the criterion of acceptable internal consistency. The evaluation instruction suggests a global PCEP-GR index and four subscales. CONCLUSIONS: The PCEP-GR has proven to be a feasible, economic, valid and reliable tool for the assessment of UPCE that comprises self-efficacy expectation and relevant attitudes towards palliative care. PMID- 29282057 TI - In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine. AB - BACKGROUND: Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates the anti-malarial interaction of cryptolepine with standard anti malarials, as the search for new anti-malarial combinations continues. METHODS: The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. RESULTS: Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean SigmaFIC50s of 1.017 +/- 0.06 and 1.465 +/- 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean SigmaFIC50 = 0.287 +/- 0.10) whereas an antagonistic activity (mean SigmaFIC50 = 4.182 +/- 0.99) was seen with mefloquine. CONCLUSIONS: The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose combinations. PMID- 29282059 TI - Enhanced recovery after surgery program in Gynaecologic Oncological surgery in a minimally invasive techniques expert center. AB - BACKGROUND: Enhanced Recovery After Surgery Programs (ERP) includes multimodal approaches of perioperative patient's clinical pathways designed to achieve early recovery after surgery and a decreased length of hospital stay (LOS). METHODS: This observational study evaluated the implementation of ERP in gynaecologic oncological surgery in a minimally invasive techniques (MIT) expert center with more than 85% of procedures done with MIT. We compared a prospective cohort of 100 patients involved in ERP between December 2015 and June 2016 to a 100 patients control group, without ERP, previously managed in the same center between April 2015 and November 2015. All the included patients were referred for hysterectomy and/or pelvic or para-aortic lymphadenectomy for gynaecological cancer. The primary objective was to achieve a significant decrease of median LOS in the ERP group. Secondary objectives were decreases in proportion of patients achieving target LOS (2 days), morbidity and readmissions. RESULTS: Except a disparity in oncological indications with a higher proportion of endometrial cancer in the group with ERP vs. the group without ERP (42% vs. 22%; p = 0.003), there were no differences in patient's characteristics and surgical procedures. ERP were associated with decreases of median LOS (2.5 [0 to 11] days vs. 3 [1 to 14] days; p = 0.002) and proportion of discharged patient at target LOS (45% vs. 24%; p = 0.002). Morbidities occurred in 25% and 26% in the groups with and without ERP and readmission rates were respectively of 6% and 8%, without any significant difference. CONCLUSION: ERP in gynaecologic oncological surgery is associated with a decrease of LOS without increases of morbidity or readmission rates, even in a center with a high proportion of MIT. Although it is already widely accepted that MIT improves early recovery, our study shows that the addition of ERP's clinical pathways improve surgical outcomes and patient care management. PMID- 29282058 TI - Risk factors associated with academic difficulty in an Australian regionally located medical school. AB - BACKGROUND: Despite the highly selective admission processes utilised by medical schools, a significant cohort of medical students still face academic difficulties and are at a higher risk of delayed graduation or outright dismissal. METHODS: This study used survival analysis to identify the non academic and academic risk factors (and their relative risks) associated with academic difficulty at a regionally located medical school. Retrospective non academic and academic entry data for all medical students who were enrolled at the time of the study (2009-2014) were collated and analysed. Non-academic variables included age at commencement of studies, gender, Indigenous status, origin, first in family to go to University (FIF), non-English speaking background (NESB), socio-economic status (SES) and rurality expressed as Australian Standard Geographical Classification-Remoteness Area (ASGC-RA). Academic variables included tertiary entrance exam score expressed as overall position (OP) and interview score. In addition, post-entry mid- and end-of-year summative assessment data in the first and second years of study were collated. RESULTS: The results of the survival analysis indicated that FIF, Indigenous and very remote backgrounds, as well as low post-entry Year 1 (final) and Year 2 (mid year and final) examination scores were strong risk factors associated with academic difficulty. A high proportion of the FIF students who experienced academic difficulty eventually failed and exited the medical program. Further exploratory research will be required to identify the specific needs of this group of students in order to develop appropriate and targeted academic support programs for them. CONCLUSIONS: This study has highlighted the need for medical schools to be proactive in establishing support interventions/strategies earlier rather than later, for students experiencing academic difficulty because, the earlier such students can be flagged, the more likely they are able to obtain positive academic outcomes. PMID- 29282060 TI - Effects of gestational age and the mode of surgical abortion on postabortion hemorrhage and fever: evidence from population-based reproductive health survey in Georgia. AB - BACKGROUND: Every year around 50 million unintended pregnancies worldwide are terminated by induced abortion. Even in countries, where it is legalized and performed in a safe environment, abortion carries some risk of complications for women. Findings of researchers on the factors that influence the sequelae of abortion are controversial and inconsistent. This study evaluates the effects of gestational age and the method of surgical abortion (i.e., dilatation and curettage and vacuum aspiration) on the most common abortion complications: postabortion hemorrhage and fever. METHODS: We performed a secondary analysis of the data from the population-based Georgian Reproductive Health Survey 2010. Information on 1974 surgical abortions performed >30 days prior to the survey interview were analyzed during the study. Logistic regression statistical analysis was applied to compare the abortion sequelae that followed vacuum aspiration and dilatation and curettage at different gestational ages (<10 weeks and >=10 weeks). We examined two major early abortion-related complications: postabortion hemorrhage and febrile morbidity (fever >=38 degrees C). RESULTS: Postabortion hemorrhage was reported in 43 cases (1.9%), and febrile morbidity occurred in 44 cases (2%) among all of the surgical abortions. The abortions performed by dilatation and curettage were associated with an estimated fourfold increased risk of developing hemorrhage (OR 4.4, 95% CI 2.2-8.6) and a twofold increased risk of developing fever (OR 2.37, 95% CI 1.17-4.79) compared with the abortions that were performed via vacuum aspiration. The risk of postabortion hemorrhage (OR 1.9, 95% CI 0.8-4.4) or fever (OR 0.9, 95% CI 0.4-2.1) did not significantly differ at gestational age < 10 weeks and >=10 weeks. CONCLUSION: Vacuum aspiration was associated with reduced risks of postabortion hemorrhage and fever compared to dilatation and curettage. Gestational age >= 10 weeks was not found to be a predictive factor of immediate postabortion complications: hemorrhage and fever. PMID- 29282062 TI - Supraspinatus muscle elasticity measured with real time shear wave ultrasound elastography correlates with MRI spectroscopic measured amount of fatty degeneration. AB - BACKGROUND: Fatty Degeneration (FD) of the rotator cuff muscles influences functional and anatomical outcome after rotator cuff repair. The MRI based estimation of fatty degeneration is the gold standard. There is some evidence that Ultrasound elastography (EUS) can detect local differences of tissue stiffness in muscles and tendons. Shear-wave elastography (SWE) was evaluated to determine the extent to which shear wave velocity was associated with measures of fatty degeneration. MRI-spectroscopic fat measurement was used as a reference to quantify the amount of fat in the muscle belly. METHODS: Forty-two patients underwent SWE of the supraspinatus muscles at its thickest diameter. After ultrasound evaluation an MRI-spectroscopic fat measurement of the supraspinatus muscle was performed using the SPLASH-technique. A gel filled capsule was used to locate the measured area in the MRI. The values of shear wave velocity (SWV) measured with SWE and spectroscopic fat measurement were correlated statistically using Pearson's correlation test. RESULTS: Correlation of the fat amount measured with MRI-spectroscopy and the SWV measured with SWE was rho =0.82. Spectroscopic measured fat ratio of the supraspinatus muscle ranged from 0% to 77.41% and SWV from 1.59 m/s to 5.32 m/s. In 4 patients no sufficient SWE could be performed, these individuals showed a larger diameter of the overlying soft tissue. SWV measured with SWE showed a good correlation with MRI spectroscopic fat amount of the supraspinatus muscle. CONCLUSION: These preliminary data suggest that SWE may be a sufficient tool in detecting and estimating the amount of fatty degeneration in the supraspinatus muscle in real time. Large overlying soft tissue may be a limitation in performing sufficient EUS. Ethical Committee Approval: Nr: 156/14 Date 12th August 2014. LEVEL OF EVIDENCE: III. PMID- 29282061 TI - The human microbiome in evolution. AB - The trillions of microbes living in the gut-the gut microbiota-play an important role in human biology and disease. While much has been done to explore its diversity, a full understanding of our microbiomes demands an evolutionary perspective. In this review, we compare microbiomes from human populations, placing them in the context of microbes from humanity's near and distant animal relatives. We discuss potential mechanisms to generate host-specific microbiome configurations and the consequences of disrupting those configurations. Finally, we propose that this broader phylogenetic perspective is useful for understanding the mechanisms underlying human-microbiome interactions. PMID- 29282063 TI - Effect of ATP and Bax on the apoptosis of Eimeria tenella host cells. AB - BACKGROUND: Eimeria tenella (E. tenella) is a species of Eimeria that causes haemorrhagic caecal coccidiosis, resulting in major economic losses in the global poultry industry. After E. tenella infection, the amount of ATP and Bax in host cells showed highly significant changes. Therefore, it is necessary to investigate the effects of ATP and Bax on the apoptosis of E. tenella host cells. RESULTS: The ATP-treated group and the V5-treated group had higher E. tenella infection rates than the untreated group at 24, 48, 72, 96, and 120 h after infection with E. tenella. The results of flow cytometry showed that compared with the control group, the mitochondrial permeability transition pore (MPTP) opening in the untreated group was highly significantly increased (P < 0.01) at 4, 24, 48, 72, 96, and 120 h. Moreover, results from Hoechst-Annexin V-PI staining and flow cytometry showed that the rates of early apoptosis, late apoptosis, and necrosis in the untreated group were significantly lower (P < 0.05) or highly significantly lower (P < 0.01) than those of the control group at 4 h, while the rates of early apoptosis, late apoptosis, and necrosis in the untreated group were higher at varying degrees than those in the control group at 24-120 h (P < 0.05 or P < 0.01). After treatment with ATP and Bax inhibitors, the rates of early apoptosis, late apoptosis, and necrosis, in addition to the MPTP opening in both the ATP-treated and V5-treated groups, were significantly lower (P < 0.05) or highly significantly lower (P < 0.01) than those in the untreated group. CONCLUSIONS: ATP and Bax play important roles in regulating the apoptosis of E. tenella host cells. PMID- 29282064 TI - Q&A: Friends (but sometimes foes) within: the complex evolutionary ecology of symbioses between host and microbes. AB - Over the past decade, there has been a pronounced shift in the study of host microbe associations, with recognition that many of these associations are beneficial, and often critical, for a diverse array of hosts. There may also be pronounced benefits for the microbes, though this is less well empirically understood. Significant progress has been made in understanding how ecology and evolution shape simple associations between hosts and one or a few microbial species, and this work can serve as a foundation to study the ecology and evolution of host associations with their often complex microbial communities (microbiomes). PMID- 29282065 TI - Pulmonary edema following central nervous system lesions induced by a non- mouse adapted EV71 strain in neonatal BALB/c mice. AB - BACKGROUND: Enterovirus (EV) infection has been a serious health issue in Asia Pacific region. It has been indicated that the occurrence of fatal hand foot and mouth disease (HFMD) cases following EV71 infection is mainly attributed to pulmonary edema. However, the development of pulmonary disorders after EV71 infection remains largely unknown. To establish an EV71-infected animal model and further explore the underlying association of central nervous system (CNS) invasion with pulmonary edema, we isolated a clinical source EV71 strain (ZZ1350) from a severe case in Henan Province. METHODS: We evaluated the cytotoxicity of ZZ1350 strain and the susceptibility in 3-day-old BALB/c mice with intraperitoneal, intracerebral and intramuscular inoculation. Various histopathological and immunohistochemical techniques were applied to determine the target organs or tissue damage after infection. Correlation analysis was used to identify the relationship between CNS injury and pulmonary disorders. RESULTS: Our experimental results suggested that ZZ1350 (C4 subtype) had high cytotoxicity against African green monkey kidney (Vero) cells and human rhabdomyosarcoma (RD) cells and neonatal BALB/c mice were highly susceptible to the infection with ZZ1350 through three different inoculation routes (2 * 106 pfu/mouse) exhibiting severe neurological and respiratory symptoms that were similar to clinical observation. Viral replication was found in brain, spinal cord, skeletal muscle, lung, spleen, liver, heart of infected mice and these sections also showed histopathological changes. We found that brain histology score was positive correlated with lung histology score in total experimental mice and mice under the three inoculation routes (P < 0.05). At the same time, there were positive correlations between spinal cord score and lung score in total experimental mice and mice with intracerebral inoculation (P < 0.05). CONCLUSIONS: ZZ1350 strain is effective to establish animal model of EV71 infection with severe neurological and respiratory symptoms. The development of pulmonary disorders after EV71 infection is associated with severity of CNS damage. PMID- 29282066 TI - Resilient coping in the general population: standardization of the brief resilient coping scale (BRCS). AB - BACKGROUND: There has been a marked tendency for researchers, clinicians, and policy makers to shift their focus from risk to resilience. This should be assessed by comparing the outcome to a context specific reference group. The objectives of the study were to generate normative data for the BRCS for different age groups for men and women and to further investigate the construct validity and factor structure in a general population. METHODS: Nationally representative face-to face household surveys were conducted in Germany in 2013 (n = 2508). RESULTS: Normative data for the BRCS were generated for men and women (53.2% female) and different age levels (mean age (SD) of 49.7 (18.0) years). Men had significantly higher mean scores compared with women (14.9 [SD = 3.2] vs. 14.6 [SD = 3.1]). The results of the EFA and CFA clearly indicate a unidimensional solution with one factor. Furthermore, the invariance of the one factor model was tested for the whole sample across gender and six age groups. CONCLUSIONS: The normative data provide a framework for the interpretation and comparisons of resilience with other populations. PMID- 29282067 TI - The current situation of human resources for health in the province of Cabinda in Angola: is it a limitation to provide universal access to healthcare? AB - BACKGROUND: Angola is among sub-Saharan African countries dealing with a crisis of Human Resources for Health (HRH). The province of Cabinda, besides the efforts, still suffers from both HRH shortage and a badly distributed health workforce. In Cabinda, one can find urban concentration and rural shortages of healthcare professionals, many rural areas' healthcare facilities often secured only by basic or medium level HRH; and difficulties in developing HRH retention strategies in rural areas where most services are covered by foreign HRH. This study aims at analysing the situation of HRH in the province of Cabinda. It considers organizational issues, policies and practices resulting from the HRH strategy followed in the recent years, moreover the creation of a medical school. The context that affects the distribution of the health workforce is analysed to contribute to the development of evidence-based policies that promote a better HRH allocation in the poorest and distant villages in the province. METHODS: A mixed-methods study was developed, combining a quantitative and qualitative approach to analyse HRH situation in the province of Cabinda. Data was collected from key informants, selected by intentional sampling from public and private health organizations, to respond to a questionnaire and a semi-structured interview. Quantitative and qualitative data was analysed with descriptive and inferential statistics and content analysis respectively. The study was complemented by a comprehensive desk review. RESULTS: Results show a clear change in HRH data from 2011 to 2015 with significant fluctuations due to variations in retirement, migration and lack of regular public HRH recruitment tenders. HRH density is apparently better in rural when compared with urban areas. However, one should bear in mind that often HRH allocated to rural areas do not stay there, which leads to real geographical imbalances. Factors like lack of proper incentives for HRH retention and social support goes against significant HRH management efforts contributing to this result. Whereas HRH are financed by the State General Budget, the majority of health facilities are still dependent on the Provincial Health Secretariat budget. CONCLUSION: The study provides a broader view of the current HRH situation in Cabinda Province. Geographical imbalances and other issues with impact in delivering universal access to healthcare are highlighted. PMID- 29282069 TI - Health system's response for physician workforce shortages and the upcoming crisis in Ethiopia: a grounded theory research. AB - BACKGROUND: A rapid transition from severe physician workforce shortage to massive production to ensure the physician workforce demand puts the Ethiopian health care system in a variety of challenges. Therefore, this study discovered how the health system response for physician workforce shortage using the so called flooding strategy was viewed by different stakeholders. METHODS: The study adopted the grounded theory research approach to explore the causes, contexts, and consequences (at the present, in the short and long term) of massive medical student admission to the medical schools on patient care, medical education workforce, and medical students. Forty-three purposively selected individuals were involved in a semi-structured interview from different settings: academics, government health care system, and non-governmental organizations (NGOs). Data coding, classification, and categorization were assisted using ATLAs.ti qualitative data analysis scientific software. RESULTS: In relation to the health system response, eight main categories were emerged: (1) reasons for rapid medical education expansion; (2) preparation for medical education expansion; (3) the consequences of rapid medical education expansion; (4) massive production/flooding as human resources for health (HRH) development strategy; (5) cooperation on HRH development; (6) HRH strategies and planning; (7) capacity of system for HRH development; and (8) institutional continuity for HRH development. The demand for physician workforce and gaining political acceptance were cited as main reasons which motivated the government to scale up the medical education rapidly. However, the rapid expansion was beyond the capacity of medical schools' human resources, patient flow, and size of teaching hospitals. As a result, there were potential adverse consequences in clinical service delivery, and teaching learning process at the present: "the number should consider the available resources such as number of classrooms, patient flows, medical teachers, library...". In the future, it was anticipated to end in surplus in physician workforce, unemployment, inefficiency, and pressure on the system: "...flooding may seem a good strategy superficially but it is a dangerous strategy. It may put the country into crisis, even if good physicians are being produced; they may not get a place where to go...". CONCLUSION: Massive physician workforce production which is not closely aligned with the training capacity of the medical schools and the absorption of graduates in to the health system will end up in unanticipated adverse consequences. PMID- 29282068 TI - Advancing beyond the system: telemedicine nurses' clinical reasoning using a computerised decision support system for patients with COPD - an ethnographic study. AB - BACKGROUND: Telemedicine is changing traditional nursing care, and entails nurses performing advanced and complex care within a new clinical environment, and monitoring patients at a distance. Telemedicine practice requires complex disease management, advocating that the nurses' reasoning and decision-making processes are supported. Computerised decision support systems are being used increasingly to assist reasoning and decision-making in different situations. However, little research has focused on the clinical reasoning of nurses using a computerised decision support system in a telemedicine setting. Therefore, the objective of the study is to explore the process of telemedicine nurses' clinical reasoning when using a computerised decision support system for the management of patients with chronic obstructive pulmonary disease. The factors influencing the reasoning and decision-making processes were investigated. METHODS: In this ethnographic study, a combination of data collection methods, including participatory observations, the think-aloud technique, and a focus group interview was employed. Collected data were analysed using qualitative content analysis. RESULTS: When telemedicine nurses used a computerised decision support system for the management of patients with complex, unstable chronic obstructive pulmonary disease, two categories emerged: "the process of telemedicine nurses' reasoning to assess health change" and "the influence of the telemedicine setting on nurses' reasoning and decision-making processes". An overall theme, termed "advancing beyond the system", represented the connection between the reasoning processes and the telemedicine work and setting, where being familiar with the patient functioned as a foundation for the nurses' clinical reasoning process. CONCLUSION: In the telemedicine setting, when supported by a computerised decision support system, nurses' reasoning was enabled by the continuous flow of digital clinical data, regular video-mediated contact and shared decision-making with the patient. These factors fostered an in-depth knowledge of the patients and acted as a foundation for the nurses' reasoning process. Nurses' reasoning frequently advanced beyond the computerised decision support system recommendations. Future studies are warranted to develop more accurate algorithms, increase system maturity, and improve the integration of the digital clinical information with clinical experiences, to support telemedicine nurses' reasoning process. PMID- 29282070 TI - 9.4 T small animal MRI using clinical components for direct translational studies. AB - BACKGROUND: Magnetic resonance is a major preclinical and clinical imaging modality ideally suited for longitudinal studies, e.g. in pharmacological developments. The lack of a proven platform that maintains an identical imaging protocol between preclinical and clinical platforms is solved with the construction of an animal scanner based on clinical hard- and software. METHODS: A small animal magnet and gradient system were connected to a clinical MR system. Several hardware components were either modified or built in-house to achieve compatibility. The clinical software was modified to account for the different field-of-view of a preclinical MR system. The established scanner was evaluated using clinical QA protocols, and platform compatibility for translational research was verified against clinical scanners of different field strength. RESULTS: The constructed animal scanner operates with the majority of clinical imaging sequences. Translational research is greatly facilitated as protocols can be shared between preclinical and clinical platforms. Hence, when maintaining sequences parameters, maximum similarity between pulses played out on a human or an animal system is maintained. CONCLUSION: Coupling of a small animal magnet with a clinical MR system is a flexible, easy to use way to establish and advance translational imaging capability. It provides cost and labor efficient translational capability as no tedious sequence reprogramming between moieties is required and cross-platform compatibility of sequences facilitates multi-center studies. PMID- 29282071 TI - Analysis of the main active ingredients and bioactivities of essential oil from Osmanthus fragrans Var. thunbergii using a complex network approach. AB - BACKGROUND: Osmanthus fragrans has been used as folk medicine for thousands of years. The extracts of Osmanthus fragrans flowers were reported to have various bioactivities including free radical scavenging, anti-inflammation, neuroprotection and antitumor effects. However, there is still lack of knowledge about its essential oil. METHODS: In this work, we analyzed the chemical composition of the essential oil from Osmanthus fragrans var. thunbergii by GC MS. A complex network approach was applied to investigate the interrelationships between the ingredients, target proteins, and related pathways for the essential oil. Statistical characteristics of the networks were further studied to explore the main active ingredients and potential bioactivities of O. fragrans var. thunbergii essential oil. RESULTS: A total of 44 ingredients were selected from the chemical composition of O. fragrans var. thunbergii essential oil, and that 191 potential target proteins together with 70 pathways were collected for these compounds. An ingredient-target-pathway network was constructed based on these data and showed scale-free property as well as power-law degree distribution. Eugenol and geraniol were screened as main active ingredients with much higher degree values. Potential neuroprotective and anti-tumor effect of the essential oil were also found. A core subnetwork was extracted from the ingredient-target pathway network, and indicated that eugenol and geraniol contributed most to the neuroprotection of this essential oil. Furthermore, a pathway-based protein association network was built and exhibited small-world property. MAPK1 and MAPK3 were considered as key proteins with highest scores of centrality indices, which might play an important role in the anti-tumor effect of the essential oil. CONCLUSIONS: This work predicted the main active ingredients and bioactivities of O. fragrans var. thunbergii essential oil, which would benefit the development and utilization of Osmanthus fragrans flowers. The application of complex network theory was proved to be effective in bioactivities studies of essential oil. Moreover, it provides a novel strategy for exploring the molecular mechanisms of traditional medicines. PMID- 29282072 TI - A pilot study to understand feasibility and acceptability of stool and cord blood sample collection for a large-scale longitudinal birth cohort. AB - BACKGROUND: Few data are available to guide biological sample collection around the time of birth for large-scale birth cohorts. We are designing a large UK birth cohort to investigate the role of infection and the developing immune system in determining future health and disease. We undertook a pilot to develop methodology for the main study, gain practical experience of collecting samples, and understand the acceptability of sample collection to women in late pregnancy. METHODS: Between February-July 2014, we piloted the feasibility and acceptability of collecting maternal stool, baby stool and cord blood samples from participants recruited at prolonged pregnancy and planned pre-labour caesarean section clinics at University College London Hospital. Participating women were asked to complete acceptability questionnaires. RESULTS: Overall, 265 women were approached and 171 (65%) participated, with >=1 sample collected from 113 women or their baby (66%). Women had a mean age of 34 years, were primarily of white ethnicity (130/166, 78%), and half were nulliparous (86/169, 51%). Women undergoing planned pre labour caesarean section were more likely than those who delivered vaginally to provide >=1 sample (98% vs 54%), but less likely to provide maternal stool (10% vs 43%). Pre-sample questionnaires were completed by 110/171 women (64%). Most women reported feeling comfortable with samples being collected from their baby (<10% uncomfortable), but were less comfortable about their own stool (19% uncomfortable) or a vaginal swab (24% uncomfortable). CONCLUSIONS: It is possible to collect a range of biological samples from women around the time of delivery, and this was acceptable for most women. These data inform study design and protocol development for large-scale birth cohorts. PMID- 29282073 TI - Responsiveness of clinical tests for people with neck pain. AB - BACKGROUND: Responsiveness of a clinical test is highly relevant in order to evaluate the effect of a given intervention. However, the responsiveness of clinical tests for people with neck pain has not been adequately evaluated. The objective of the present study was to examine the responsiveness of four clinical tests which are low cost and easy to perform in a clinical setting, including the craniocervical flexion test, cervical active range of movement, test for the cervical extensors and pressure pain threshold testing. METHODS: This study is a secondary analysis of data collected in a previously published randomised controlled trial. Participants were randomized to either physical training, exercises and pain education combined or pain education only. Participants were tested on the clinical tests at baseline and at 4-month follow-up. An anchor based approach using Receiver Operator Characteristics (ROC) curves was used to evaluate responsiveness of the clinical tests. The Neck Disability Index was used to discriminate between those who had improved and those who were unchanged at the 4-month follow-up. Minimum Clinically Important Difference (MCID), together with sensitivity, specificity, positive and negative predictive values, in addition to positive and negative likelihood ratios were calculated. RESULTS: In total, 164 participants completed the 4 month follow up. One-hundred forty four participants were classified as unchanged whereas 20 patients were considered to be improved. Twenty-six participants didn't complete all of the clinical tests, leaving a total of 138 to be included for analyses. Area Under Curve (AUC) ranged from 0.50-0.62 for the clinical tests, and were all below an acceptable level. MCID was generally large, and the corresponding sensitivity and specificity was low with sensitivity ranging from 20 to 60%, and specificity from 54 to 86%. LR+ (0.8-2.07) and LR- (0.7-1.1) showed low diagnostic value for all variables, with PPV ranging from 12.1 to 26.1 and NPV ranging from 84.7 to 89.2. CONCLUSION: Responsiveness of the included clinical tests was generally low when using change in NDI score as the anchor from baseline to the 4-month follow up. Further investigations of responsiveness are warranted, possibly using other anchors, which to a higher degree resemble similar dimensions as the clinical tests. PMID- 29282074 TI - The Rap activator Gef26 regulates synaptic growth and neuronal survival via inhibition of BMP signaling. AB - In Drosophila, precise regulation of BMP signaling is essential for normal synaptic growth at the larval neuromuscular junction (NMJ) and neuronal survival in the adult brain. However, the molecular mechanisms underlying fine-tuning of BMP signaling in neurons remain poorly understood. We show that loss of the Drosophila PDZ guanine nucleotide exchange factor Gef26 significantly increases synaptic growth at the NMJ and enhances BMP signaling in motor neurons. We further show that Gef26 functions upstream of Rap1 in motor neurons to restrain synaptic growth. Synaptic overgrowth in gef26 or rap1 mutants requires BMP signaling, indicating that Gef26 and Rap1 regulate synaptic growth via inhibition of BMP signaling. We also show that Gef26 is involved in the endocytic downregulation of surface expression of the BMP receptors thickveins (Tkv) and wishful thinking (Wit). Finally, we demonstrate that loss of Gef26 also induces progressive brain neurodegeneration through Rap1- and BMP signaling-dependent mechanisms. Taken together, these results suggest that the Gef26-Rap1 signaling pathway regulates both synaptic growth and neuronal survival by controlling BMP signaling. PMID- 29282076 TI - The consequences of Ireland's culture of medical migration. AB - BACKGROUND: In recent years, Ireland has experienced a large-scale, outward migration of doctors. This presents a challenge for national policy makers and workforce planners seeking to build a self-sufficient medical workforce that trains and retains enough doctors to meet demand. Although, traditionally, medical migration has been considered beneficial to the Irish health system, austerity has brought a greater level of uncertainty to the health system and, with it, a need to reappraise the professional culture of migration and its impact on the Irish health system. METHODS: This paper illustrates how a culture of migration informs career and migration plans. It draws on quantitative data registration and migration data from source and destination countries-and qualitative data-in-depth interviews with 50 doctors who had undertaken postgraduate medical training in Ireland. RESULTS: Of 50 respondents, 42 highlighted the importance of migration. The culture of medical migration rests on two assumptions-that international training/experience is beneficial to all doctors and that those who emigrate will return to Ireland with additional skills and experience. This assumption of return is challenged by a new generation of doctors whose professional lives have been shaped by globalisation and by austerity. Global comparisons reveal the comparatively poor working conditions, training and career opportunities in Ireland and the relative attractiveness of a permanent career abroad. CONCLUSION: In light of these changes, there is a need to critically appraise the culture of medical migration to determine if and in what circumstances migration is appropriate to the needs of the Irish health system. The paper considers the need to reappraise the culture of medical migration and the widespread emigration that it promotes. PMID- 29282075 TI - Psychometric validation of a multi-dimensional capability instrument for outcome measurement in mental health research (OxCAP-MH). AB - BACKGROUND: Patient reported outcome measures (PROMs) are widely used in mental healthcare research for quality of life assessment but most fail to capture the breadth of health and non-health domains that can be impacted. We report the psychometric validation of a novel, multi-dimensional instrument based on Amartya Sen's capability approach intended for use as an outcome measure in mental health research. METHODS: The Oxford Capabilities Questionnaire for Mental Health (OxCAP MH) is a 16-item self-complete capability measure that covers multiple domains of functioning and welfare. Data for validation of the instrument were collected through a national randomised controlled trial of community treatment orders for patients with psychosis. Complete OxCAP-MH data were available for 172 participants. Internal consistency was established with Cronbach's alpha; an interclass correlation coefficient was used to assess test-retest reliability in a sub-sample (N = 50) tested one week apart. Construct validity was established by comparing OxCAP-MH total scores with established instruments of illness severity and functioning: EuroQol (EQ-5D), Brief Psychiatric Rating Scale (BPRS), Global Assessment of Functioning (GAF) and Objective Social Outcomes Index (SIX). Sensitivity was established by calculating standard error of measurement using distributional methods. RESULTS: The OxCAP-MH showed good internal consistency (Cronbach's alpha 0.79) and test-retest reliability (ICC = 0.86). Convergent validity was evidenced by strong correlations with the EQ-5D (VAS 0.52, p < .001) (Utility 0.45, p < .001), and divergent validity through more modest associations with the BPRS (-0.41, p < .001), GAF (0.24, p < .001) and SIX (0.12, p = ns). A change of 9.2 points on a 0-100 scale was found to be meaningful on statistical grounds. CONCLUSIONS: The OxCAP-MH has demonstrable reliability and construct validity and represents a promising multi-dimensional alternative to existing patient-reported outcome measures for quality of life used in mental health research. PMID- 29282077 TI - PDGFA/PDGFRalpha-regulated GOLM1 promotes human glioma progression through activation of AKT. AB - BACKGROUND: Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Here, we examined the role of GOLM1 in the development of human glioma. METHODS: qRT-PCR, immunohistochemistry, and western blot analysis were performed to evaluate GOLM1 levels in cell lines and a cohort of primary human glioma and non-neoplastic brain tissue samples. Glioma cell lines were modified with lentiviral constructs expressing short hairpin RNAs targeting GOLM1 or overexpressing the protein to assess function in proliferation, viability, and migration and invasion in vitro using EdU, CCK8, clone-forming, Transwell assays, 3D tumor spheroid invasion assay and in vivo in orthotopic implantations. Protein lysates were used to screen a membrane-based antibody array to identify kinases mediated by GOLM1. Specific inhibitors of PDGFRalpha (AG1296) and AKT (MK-2206) were used to examine the regulation of PDGFA/PDGFRalpha on GOLM1 and the underlying pathway respectively. RESULTS: qRT PCR, immunohistochemistry and western blot analysis revealed GOLM1 expression to be elevated in glioma tissues and cell lines. Silencing of GOLM1 attenuated proliferation, migration, and invasion of U251, A172 and P3#GBM (primary glioma) cells, while overexpression of GOLM1 enhanced malignant behavior of U87MG cells. We further demonstrated that activation of AKT is the driving force of GOLM1 promoted glioma progression. The last finding of this research belongs to the regulation of PDGFA/PDGFRalpha on GOLM1, while GOLM1 was also a key element of PDGFA/PDGFRalpha-mediated activation of AKT, as well as the progression of glioma cells. CONCLUSIONS: PDGFA/PDGFRalpha-regulated GOLM1 promotes glioma progression possibly through activation of a key signaling kinase, AKT. GOLM1 interference may therefore provide a novel therapeutic target and improve the efficacy of glioma treatment, particularly in the case of the proneural molecular subtype of human glioma. PMID- 29282078 TI - Short course hypofractionated whole breast irradiation after conservative surgery: a single institution phase II study. AB - BACKGROUND: To assess the oncologic outcomes of hypofractionated whole breast irradiation (Hypo-WBI). METHODS: Eligible patients had undergone breast conservative surgery for early breast cancer (pTis-2) and none/limited nodal involvement. Hypo-WBI consisted of 34 Gy in 10 daily fractions over 2 weeks to the whole breast three-dimensional conformal radiotherapy (3DCRT), followed by a single fraction of 8 Gy to the tumor bed after 1 week (electrons). Primary endpoint is freedom from ipsilateral breast tumor recurrence (IBTR). Minimum follow up for living & event-free patients is 3 yrs.; median follow up time of the whole analyzed patient population is 5.4 yrs. (range: 1.8-11.4 yrs). RESULTS: Two hundred fifty-one patients were accrued from 2004 to 2013. All patients underwent local excision of the primary tumor to negative margins. Four patients failed in the ipsilateral breast after a median time of 3.2 years (range: 1.7-5.7 yrs) for a 5-year IBTR-free survival of 98.7% (95%CI: 97.3%-100%). IBTR-free survival was significantly higher for patients with invasive cancer than for patients with intraductal carcinoma (p = 0.036). Within patients with invasive tumors, no clear trends or associations were detected between IBTR and age, grading, molecular subtype, pT or pN stage. At 5 years, the actuarial rates of GR2 fibrosis and GR2+ teleangectasia are 2.4% (95%CI: 0-6.5%) and 7.1% (95%CI: 0.4-13.7%), respectively. Cosmesis was scored as excellent/good by ~95% of patients and ~60% of clinicians. CONCLUSIONS: Hypo-WBI in 3 weeks allows excellent oncologic outcomes for invasive breast cancer after conservative surgery. Patients with intraductal carcinoma should be treated with Hypo-WBI only within a controlled study. TRIAL REGISTRATION: IRE-IFO Ethical and Scientific Committee (cod. RS61/04). PMID- 29282079 TI - Expitope 2.0: a tool to assess immunotherapeutic antigens for their potential cross-reactivity against naturally expressed proteins in human tissues. AB - BACKGROUND: Adoptive immunotherapy offers great potential for treating many types of cancer but its clinical application is hampered by cross-reactive T cell responses in healthy human tissues, representing serious safety risks for patients. We previously developed a computational tool called Expitope for assessing cross-reactivity (CR) of antigens based on tissue-specific gene expression. However, transcript abundance only indirectly indicates protein expression. The recent availability of proteome-wide human protein abundance information now facilitates a more direct approach for CR prediction. Here we present a new version 2.0 of Expitope, which computes all naturally possible epitopes of a peptide sequence and the corresponding CR indices using both protein and transcript abundance levels weighted by a proposed hierarchy of importance of various human tissues. RESULTS: We tested the tool in two case studies: The first study quantitatively assessed the potential CR of the epitopes used for cancer immunotherapy. The second study evaluated HLA-A*02:01-restricted epitopes obtained from the Immune Epitope Database for different disease groups and demonstrated for the first time that there is a high variation in the background CR depending on the disease state of the host: compared to a healthy individual the CR index is on average two-fold higher for the autoimmune state, and five-fold higher for the cancer state. CONCLUSIONS: The ability to predict potential side effects in normal tissues helps in the development and selection of safer antigens, enabling more successful immunotherapy of cancer and other diseases. PMID- 29282081 TI - Women's social networks and use of facility delivery services for uncomplicated births in North West Ethiopia: a community-based case-control study. AB - BACKGROUND: High maternal mortality has remained an unmet public health challenge in the developing world. Maternal mortality in Ethiopia is among the highest in the world. Since most maternal deaths occur during labor, delivery, and the immediate postpartum period, facility delivery with skilled birth attendants is recommended to reduce maternal mortality. Nonetheless, the majority of women in Ethiopia give birth at home. Individual attributes and availability and accessibility of services deter service utilization. The role of social networks that may facilitate or constrain service use is not well studied. METHODS: Community-based case-control study was conducted between February and March 2014 in Jabi Tehinan District, North West Ethiopia. Retrospective data were collected from 134 women who had uncomplicated births at health facilities and 140 women who had uncomplicated births at home within a year preceding the survey. Interviews were held with eight women who had uncomplicated births at health facilities and 11 who had uncomplicated births at home. The quantitative data were entered and analyzed using SPSS for Windows versions 16.0 and hierarchical logistic regression model was used for analysis. The qualitative data were transcribed verbatim and data were used to substantiate the quantitative data. RESULTS: The results indicated that social network variables were significantly associated with the use of health facilities for delivery. Taking social networks into account improved the explanation of facility use for delivery services over women's individual attributes. Women embedded within homogeneous network members (Adjusted OR 2.53; 95% CI: 1.26-5.06) and embedded within high SBA endorsement networks (Adjusted OR 7.97; 95% CI: 4.07-12.16) were more likely to deliver at health facilities than their counterparts. Women living in urban areas (Adjusted OR 3.32; 95% CI: 1.37-8.05) and had better knowledge of obstetric complications (Adjusted OR 3.01; 95% CI: 1.46-6.18) were more likely to deliver at health facilities. CONCLUSION: Social networks facilitate SBA utilization by serving as a reference for the behavior to deliver at health facilities. These findings inform health professionals and other stakeholders regarding the importance of considering women's social networks in designing intervention to increase the proportion of women who deliver at health facilities. PMID- 29282080 TI - Safety analysis over time: seven major changes to adverse event investigation. AB - BACKGROUND: Every safety-critical industry devotes considerable time and resource to investigating and analysing accidents, incidents and near misses. The systematic analysis of incidents has greatly expanded our understanding of both the causes and prevention of harm. These methods have been widely employed in healthcare over the last 20 years but are now subject to critique and reassessment. In this paper, we reconsider the purpose and value of incident analysis and methods appropriate to the healthcare of today. MAIN TEXT: The primary need for a revised vision of incident analysis is that healthcare itself is changing dramatically. People are living longer, often with multiple co morbidities which are managed over very long timescales. Our vision of safety analysis needs to expand concomitantly to embrace much longer timescales. Rather than think only in terms of the prevention of specific incidents, we need to consider the balance of benefit, harm and risks over long time periods encompassing the social and psychological impact of healthcare as well as physical effects. We argued for major changes in our approach to the analysis of safety events: assume that patients and families will be partners in investigation and where possible engage them fully from the beginning, examine much longer time periods and assess contributory factors at different time points in the patient journey, be more proportionate and strategic in analysing safety issues, seek to understand success and recovery as well as failure, consider the workability of clinical processes as well as deviations from them and develop a much more structured and wide-ranging approach to recommendations. CONCLUSIONS: Previous methods of incident analysis were simply adopted and disseminated with little research into the concepts, methods, reliability and outcomes of such analyses. There is a need for significant research and investment in the development of new methods. These changes are profound and will require major adjustments in both practical and cultural terms and research to explore and evaluate the most effective approaches. PMID- 29282082 TI - Associations between dietary factors and obesity-related biomarkers in healthy children and adolescents - a systematic review. AB - BACKGROUND: The obesity prevalence in children and adolescents has increased worldwide during the past 30 years. Although diet has been identified as one risk factor for developing obesity in this age group, the role of specific dietary factors is still unclear. One way to gain insight into the role of these factors might be to detect biomarkers that reflect metabolic health and to identify the associations between dietary factors and these biomarkers. This would enable nutrition-related metabolic changes to be detected early in life, which might be a promising strategy to prevent childhood obesity. However, existing literature offers only inconclusive evidence for diet and some of these obesity-related biomarkers (e.g., blood lipids). We thus conducted a systematic literature review to further examine eligible studies that investigate associations between dietary factors and 12 obesity-related biomarkers in healthy children and adolescents aged 3-18 years. METHODS: We searched the scientific databases PubMed/Medline and Web of Science Core Collection for potentially eligible articles. Our final literature search resulted in 2727 hits. After the selection process, we included 81 articles that reported on 1111 single observations on dietary factors and any of the obesity-related biomarkers. RESULTS: Around 81% of the total observations showed nonsignificant results. For many biomarkers we did not find enough observations to draw clear conclusions on possible associations between a dietary factor and the respective biomarker. In cases where we identified enough observations, the results were contradictory. Since these nonsignificant and inconclusive findings may impede the development of effective strategies against childhood obesity, this article takes a closer look at possible reasons for such findings. In addition, it provides action points for future research efforts. CONCLUSIONS: In conclusion, current evidence on associations between dietary factors and obesity-related biomarkers is inconclusive. We thus provided an overview on which specific limitations may impede current research. Such knowledge is necessary to enable future research efforts to better elucidate the role of diet in the early stages of obesity development. PMID- 29282083 TI - Tissue transglutaminase in astrocytes is enhanced by inflammatory mediators and is involved in the formation of fibronectin fibril-like structures. AB - BACKGROUND: During multiple sclerosis (MS) lesion formation, inflammatory mediators are produced by microglial cells and invading leukocytes. Subsequently, hypertrophic astrocytes fill the lesion and produce extracellular matrix (ECM) proteins that together form the astroglial scar. This is beneficial because it seals off the site of central nervous system (CNS) damage. However, astroglial scarring also forms an obstacle that inhibits remyelination of brain lesions. This is possibly an important cause for incomplete remyelination of the CNS in early stage MS patients and for failure of remyelination when the disease progresses. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme that can cross link proteins, appears in astrocytes in inflammatory MS lesions and may contribute to the rearrangement of ECM protein deposition and aggregation. METHODS: The effect of different inflammatory mediators on TG2 and fibronectin, an ECM protein, protein levels was examined in primary rat microglia and astrocytes by western blotting. Also, TG2 activity was analyzed in primary rat astrocytes by a TG activity assay. To determine the role of TG2 in the deposition and cross-linking of fibronectin, a TG2 inhibitor and TG2 knockdown astrocytes were used. RESULTS: Our data show that under inflammatory conditions in vitro, TG2 production is enhanced in astrocytes and microglia. We observed that in particular, astrocytes produce fibronectin that can be cross-linked and aggregated by exogenous TG2. Moreover, inflammatory stimulus-induced endogenously produced TG2 is involved in the appearance of morphological fibril-like fibronectin deposits but does not lead to cross-linked fibronectin aggregates. CONCLUSIONS: Our in vitro observations suggest that during MS lesion formation, when inflammatory mediators are produced, astrocyte-derived TG2 may contribute to ECM rearrangement, and subsequent astroglial scarring. PMID- 29282084 TI - R-100 improves pulmonary function and systemic fluid balance in sheep with combined smoke-inhalation injury and Pseudomonas aeruginosa sepsis. AB - BACKGROUND: Septic shock is a major cause of death in intensive care units around the world . The aim of the study was to investigate whether the novel drug R-100 (a superoxide degradation catalyst and nitric oxide donor) improves pulmonary function in a sheep model of septic shock caused by Pseudomonas aeruginosa and smoke inhalation. METHODS: Eleven female sheep were prepared surgically and randomly assigned to a treatment group (n = 5) or a control group (n = 6) after inhalation of cooled cotton smoke and airway instillation of live P. aeruginosa (2.5 * 1011 CFU) by bronchoscope under deep anesthesia and analgesia. The treatment group received an intravenous infusion of a total of 80 mg/kg of R-100 diluted in 500 mL of 5% dextrose. The control group was given 500 mL of 5% dextrose. All animals received intravenous lactated Ringer's solution to maintain a hematocrit level at baseline +/- 3%. Blood gas and hemodynamics were measured at baseline and then analyzed every 3 h during the 24-h study period. Results are expressed as mean +/- SEM. RESULTS: The treated animals showed significant improvement in their pulmonary gas exchange (PaO2/FiO2 ratio at 24 h: 246 +/- 29 vs. 90 +/- 40 mmHg control, P < 0.05). Pulmonary arterial pressures were reduced in the treated group (24 h: 26 +/- 1 vs. 30 +/- 2 cm mmHg control, P < 0.05). The treated animals also had an improved total fluid balance after 24 h (190 +/- 45/24 h mL vs. 595 +/- 234/24 h mL control, P < 0.05). CONCLUSIONS: Treatment with R-100 improves pulmonary gas exchange and blood oxygenation, and prevents a fluid imbalance in sheep subjected to smoke inhalation and P. aeruginosa. PMID- 29282085 TI - Effects of 12-week supplementation of marine Omega-3 PUFA-based formulation Omega3Q10 in older adults with prehypertension and/or elevated blood cholesterol. AB - BACKGROUNDS: To study the effects of supplementation of a marine omega-3 poly unsaturated fatty acids (n3-PUFA) formulation (Omega3Q10) in older adults with hypertension and/or hypercholesterolemia. METHODS: A total of 97 people were enrolled to receive 12-week supplementation of either Omega3Q10 (n = 48) or soybean oil (n = 49). Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and hypertension-related symptoms were determined before and after the supplementation. RESULTS: There were no baseline differences between the two groups. Omega3Q10 supplementation significantly reduced diastolic blood pressure (DBP) (from 81.6 +/- 5.3 mmHg to 79.3 +/- 5.2 mmHg, P < 0.05). Blood concentrations of TC and LDL-C decreased significantly and blood HDL-C level increased significantly after 12 weeks of Omega3Q10 (5.5 +/- 0.7 vs. 5.3 +/- 0.5, P < 0.05; 3.7 +/- 0.8 vs. 3.3 +/- 0.6, P < 0.05; 1.2 +/- 0.6 vs. 1.3 +/- 0.5, P < 0.05, respectively) and soybean oil supplementation (5.7 +/- 0.8 vs. 5.6 +/- 0.7, P < 0.05; 3.6 +/- 0.7 vs. 3.4 +/- 0.8, P < 0.05; 1.0 +/- 0.8 vs. 1.2 +/- 0.7, P < 0.05, respectively) but no group differences were found. A significantly greater proportion of the people in the Omega3Q10 group became free from headache and palpitations & chest tightness symptoms after the 12-week supplementation compared to that of the soybean oil group (95.5% vs. 71.4%, P < 0.01; 95.8 vs. 75.5%, P < 0.01, respectively). CONCLUSION: 12-week supplementation of Fish oil-based PUFA appear to be more effective in improving DBP and hypertension-related symptoms than soybean oil in old adults with hypertension and hypercholesterolemia although both supplementation improved TC, LDL-C and HDL-C concentrations. PMID- 29282087 TI - Do beneficiaries' views matter in healthcare purchasing decisions? Experiences from the Nigerian tax-funded health system and the formal sector social health insurance program of the National Health Insurance Scheme. AB - BACKGROUND: Purchasing is a health financing function that involves the transfer of pooled resources to providers on behalf of a covered population. Little attention has been paid to the extent to which the views of that population are reflected in purchasing decisions. This article explores how purchasers in two financing mechanisms: the Formal Sector Social Health Insurance Programme (FSSHIP) operating under the Nigerian National Health Insurance Scheme (NHIS), and the tax-funded health system perform their roles in light of their responsibilities to the populations. METHODS: A case study approach was adopted in which each financing mechanism is a case. Sixteen (16) in-depth interviews with purchasers and eight (8) focus group discussions with beneficiaries were held. Agency and organizational behavioural theories were used to characterise the purchaser-citizen relationships. A deductive framework approach was used to assess whether actions identified in a model of 'ideal' strategic purchasing actions were undertaken in each case. RESULTS: For both cases, mechanisms exist to reflect people's health needs in purchasing decisions, including quantitative and qualitative needs assessment, mechanisms to raise awareness of benefit entitlements and allow choice. However, purchasers do not use the mechanisms to effectively engage with and hold themselves accountable to the people. In the tax funded system, weak information systems and unclear communication channels between the purchaser and citizens constrain assessment of needs; while timeliness of health information and poor engagement practices of Health Maintenance Organisations (HMOs) are the main constraints in FSSHIP. Inadequate information sharing in both mechanisms limits beneficiaries' awareness of entitlements. Although beneficiaries of FSSHIP can choose providers, lack of information on the quality of services offered by providers constrains rational decision-making and the inability to change HMOs reduces HMO responsiveness to beneficiary needs. CONCLUSIONS: Responsiveness and accountability to beneficiaries are undervalued by purchasers in both financing mechanisms. In the tax-funded system, civil society organisations can facilitate engagement and accountability of purchasers and the people. In FSSHIP, NHIS needs to provide stronger stewardship of HMOs to promote effective engagement with members. Furthermore, the NHIS should introduce mechanisms that allow FSSHIP members to choose their own HMO, which could encourage HMOs to be more responsive to members. PMID- 29282086 TI - Mental health care for youth with rheumatologic diseases - bridging the gap. AB - Youth with rheumatologic diseases have a high prevalence of comorbid mental health disorders. Individuals with comorbid mental health disorders are at increased risk for adverse outcomes related to mental health as well as their underlying rheumatologic disease. Early identification and treatment of mental health disorders has been shown to improve outcomes, but current systems of care fall short in providing adequate mental health services to those in need. Pediatric rheumatologists are uniquely positioned to provide mental health screening and intervention for youth with rheumatologic diseases due to the frequency of patient encounters and ongoing therapeutic relationship with patients and families. However, additional training is likely required for pediatric rheumatologists to provide effective mental health care, and focusing efforts on providing trainees with mental health education is key to building competency. Potential opportunities for improved mental health education include development of clinical guidelines regarding mental health screening and management within pediatric rheumatology settings and incorporation of mental health didactics, workshops, and interdisciplinary clinic experiences into pediatric rheumatology fellowship curricula. Additional steps include mental health education for patients and families and focus on system change, targeting integration of medical and mental health care. Research is needed to better define the scope of the problem, determine effective strategies for equipping pediatric rheumatologists with skills in mental health intervention, and develop and implement sustainable systems for delivery of optimal mental health care to youth with rheumatologic diseases. PMID- 29282089 TI - Evaluation of a software module for adaptive treatment planning and re irradiation. AB - BACKGROUND: The aim of this work is to validate the Dynamic Planning Module in terms of usability and acceptance in the treatment planning workflow. METHODS: The Dynamic Planning Module was used for decision making whether a plan adaptation was necessary within one course of radiation therapy. The Module was also used for patients scheduled for re-irradiation to estimate the dose in the pretreated region and calculate the accumulated dose to critical organs at risk. During one year, 370 patients were scheduled for plan adaptation or re irradiation. All patient cases were classified according to their treated body region. For a sub-group of 20 patients treated with RT for lung cancer, the dosimetric effect of plan adaptation during the main treatment course was evaluated in detail. Changes in tumor volume, frequency of re-planning and the time interval between treatment start and plan adaptation were assessed. RESULTS: The Dynamic Planning Tool was used in 20% of treated patients per year for both approaches nearly equally (42% plan adaptation and 58% re-irradiation). Most cases were assessed for the thoracic body region (51%) followed by pelvis (21%) and head and neck cases (10%). The sub-group evaluation showed that unintended plan adaptation was performed in 38% of the scheduled cases. A median time span between first day of treatment and necessity of adaptation of 17 days (range 4-35 days) was observed. PTV changed by 12 +/- 12% on average (maximum change 42%). PTV decreased in 18 of 20 cases due to tumor shrinkage and increased in 2 of 20 cases. Re-planning resulted in a reduction of the mean lung dose of the ipsilateral side in 15 of 20 cases. CONCLUSION: The experience of one year showed high acceptance of the Dynamic Planning Module in our department for both physicians and medical physicists. The re-planning can potentially reduce the accumulated dose to the organs at risk and ensure a better target volume coverage. In the re-irradiation situation, the Dynamic Planning Tool was used to consider the pretreatment dose, to adapt the actual treatment schema more specifically and to review the accumulated dose. PMID- 29282088 TI - The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI. AB - BACKGROUND: Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. METHODS: This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. DISCUSSION: If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. TRIAL REGISTRATION: The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014-002665-30. PMID- 29282090 TI - Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA. METHODS: This Phase 1, open-label, multiple dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (>= 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated. RESULTS: Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUCtau) was 156.6 ng*h/mL in Cohort 1, 118.8 ng*h/mL in Cohort 2, and 142.5 ng*h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively. Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to Cmax (Tmax) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed. CONCLUSIONS: PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01513902 . PMID- 29282091 TI - Gender differences in patterns of drug use and sexual risky behaviour among crack cocaine users in Central Brazil. AB - BACKGROUND: The aim of this study was to compare sociodemographic characteristics, patterns of drug use, and risky sexual behaviour among female and male users of crack cocaine. METHODS: Between 2012 and 2013, we conducted a cross-sectional study of 919 crack cocaine users (783 men and 136 women) in Central Brazil using face-to-face interviews. Blood samples were collected to test for syphilis. The Chi-Square Automatic Interaction Detector (CHAID) was used to explore the differences between genders. We implemented two models: the first model included previous incarceration and variables related to patterns of drug use, and the second model included variables related to sexual risky behaviours and syphilis exposure. RESULTS: Women consumed more crack cocaine than men on a regular basis; however, poly-drug use was more common among men. More women than men reported exchanging sex for money and/or drugs and inconsistent condom use during sexual intercourse; women also reported more sexual partners. In addition, the frequency of sexual violence was higher for women than men. A higher proportion of women than men were positive for syphilis (27.2% vs. 9.2%; p < 0.001). The CHAID decision tree analysis identified seven variables that differentiated the genders: previous incarceration, marijuana use, daily crack cocaine consumption, age at first illicit drug use, sexual violence, exchange of sex for money and/or drugs, and syphilis exposure. CONCLUSION: Our findings demonstrate a difference in patterns of crack cocaine consumption and sexual risky behaviours between genders, thus indicating a need for gender-specific interventions in this population. PMID- 29282092 TI - Reporting quality of randomized controlled trials in patients with HIV on antiretroviral therapy: a systematic review. AB - BACKGROUND: To allow for correct evaluation of clinical trial results, readers require comprehensive, clear, and highly transparent information on the methodology used and the results obtained. This study aimed to evaluate the quality of reporting in articles on randomized controlled trials (RCTs) of antiretroviral therapy (ART) in the field of HIV/AIDS. METHODS: We searched for original articles on RCTs of ART developed in the field of HIV/AIDS in PubMed database by 5 April 2016. Searched articles were divided into three groups based on the revision year in which the Consolidated Standards of Reporting Trials (CONSORT) guidelines were published: Period 1 (1996-2001); Period 2 (2002-2010); and Period 3 (2011-2016). We evaluated the articles using the reporting rates of the 37 items in the CONSORT 2010 checklist, five items in the protocol deviation, and the three items in the ethics. RESULTS: Fifty-two articles were extracted and included in this study. Many of the reporting rates calculated using the CONSORT 2010 checklist showed a significantly increasing trend over the successive periods (65% in Period 1, 67% in Period 2, 79% in Period 3; p < 0.0001). The items with reporting rates < 50% were "the presence or absence of a protocol change and the reason for such a change," "randomization and blinding," and "where the full trial protocol can be accessed." Reporting rates of deviations were as low as < 30%, while the reporting rates for patient compliance were the highest (>80% in Period 3) among the five items. The reporting rates for obtaining informed consent and approval by the ethics committee or institutional review board were high (>88%), regardless of the time period assessed. CONCLUSION: In terms of representative RCT articles in the field of HIV/AIDS, the reporting rate of the items defined by CONSORT was approximately 70%, improving over the successive CONSORT statement revision periods. PMID- 29282093 TI - Timing of renal replacement therapy and long-term risk of chronic kidney disease and death in intensive care patients with acute kidney injury. AB - BACKGROUND: The optimal time to initiate renal replacement therapy (RRT) in intensive care unit (ICU) patients with acute kidney injury (AKI) is unclear. We examined the impact of early RRT on long-term mortality, risk of chronic kidney disease (CKD), and end-stage renal disease (ESRD). METHODS: This cohort study included all adult patients treated with continuous RRT in the ICU at Aarhus University Hospital, Skejby, Denmark (2005-2015). Data were obtained from a clinical information system and population-based registries. Early treatment was defined as RRT initiation at AKI stage 2 or below, and late treatment was defined as RRT initiation at AKI stage 3. Inverse probability of treatment (IPT) weights were computed from propensity scores. The IPT-weighted cumulative risk of CKD (estimated glomerular filtration rate < 60 ml/minute/1.73 m2), ESRD, and mortality was estimated and compared using IPT-weighted Cox regression. RESULTS: The mortality, CKD, and ESRD analyses included 1213, 303, and 617 patients, respectively. The 90-day mortality in the early RRT group was 53.6% compared with 46.0% in the late RRT group (HR 1.24, 95% CI 1.03-1.48). The 90-day to 5-year mortality was 37.7% and 41.5% in the early and late RRT groups, respectively (HR 0.95, 95% CI 0.70-1.29). The 5-year risk of CKD was 35.9% in the early RRT group and 44.9% in the late RRT group (HR 0.74, 95% CI 0.46-1.18). The 5-year risk of ESRD was 13.3% in the early RRT group and 16.7% in the late RRT group (HR 0.79, 95% CI 0.47-1.32). CONCLUSIONS: Early initiation was associated with increased 90 day mortality. In patients surviving to day 90, early initiation was not associated with a major impact on long-term mortality or risk of CKD and ESRD. Despite potential residual confounding due to the observational design, our findings do not support that early RRT initiation is superior to late initiation. PMID- 29282094 TI - Nasal high flow therapy in very low birth weight infants with mild respiratory distress syndrome: a single center experience. AB - BACKGROUND: Pulmonary disorders and respiratory failure represent one of the most common morbidities of preterm newborns admitted to neonatal intensive care units (NICUs). The use of nasal high-flow therapy (nHFT) has been more recently introduced into the NICUs as a non-invasive respiratory (NIV) support. METHODS: We performed a retrospective study to evaluate safety and effectiveness of nHFT as primary support for infants born < 29 weeks of gestation and/or VLBW presenting with mild Respiratory Distress Syndrome (RDS). The main outcome was the percentage of patients that did not need mechanical ventilation. Secondary outcomes were rate of bronchopulmonary dysplasia (BDP), air leaks, nasal injury, late onset sepsis (LOS), intraventricular hemorrhage (IVH), retinopathy (ROP), necrotizing enterocolitis (NEC), hemodynamically-significant patent ductus arteriosus (PDA) and death. RESULTS: Sixty-four preterm newborns were enrolled. Overall, 93% of enrolled patients did not need mechanical ventilation. In a subgroup analysis, 88.5% of infants < 29 weeks and 86.7% of infants ELBW (< 1000 g BW) did not need mechanical ventilation. BPD was diagnosed in 26.6% of preterms enrolled (Mild 20%, Moderate 4.5%, Severe 1.5%). In subgroup analysis, BPD was diagnosed in 53.9% of newborns with GA < 29 weeks, in 53.3% of ELBW newborns and in 11.1% of small for gestational age (SGA) newborns. Neither air leaks nor nasal injury were recorded as well as no exitus occurred. LOS, IVH, ROP, NEC and PDA occurred respectively in 16.1%, 0%, 7.8%, and 1.6% of newborns. CONCLUSIONS: According to our results, n-HFT seems to be effective as first respiratory support in preterm newborns with mild RDS. Further studies in a larger number of preterm newborns are required to confirm nHFT effectiveness in the acute phase of RDS. PMID- 29282095 TI - Impact of FHIT loss on the translation of cancer-associated mRNAs. AB - BACKGROUND: FHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5',5' triphosphates, including the m7GpppN 'caps' that are generated when mRNAs undergo 3'-5' decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules. RESULTS: Ribosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5'-UTR ribosome occupancy and this analysis also identified ribosome binding to 5'-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5'-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy. CONCLUSIONS: In summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit's genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy. PMID- 29282097 TI - The correlation between the coaptation height of mitral valve and mitral regurgitation after mitral valve repair. AB - BACKGROUND: To investigate the association between the coaptation height of mitral valve and mitral regurgitation after mitral valve repair. METHODS: From Sep 2014 to Jun 2015, 20 patients underwent mitral valve valvuloplasty for mitral regurgitation were included. Ring annuloplasty was performed in all cases. Mitral valve short-axis dimension (MVd), coaptation height (CH), Left ventricular ejection fraction (LVEF) were measured by the transesophageal echocardiography before the operation in operation room and 3 months and 12 months after the operation by the transthoracic echocardiography. A degree from 0 to 4 was used to measure the degree of mitral regurgitation. RESULTS: There were 14 patients with 0, 3 patients with 1, 3 patients with 2 of mitral regurgitation 12 months after the operation. CH (3.53 +/- 1.91 mm) increased significantly at 3 months (5.05 +/ 1.09 mm) and 12 months after operation (5.22 +/- 1.15 mm) (p < 0.05). MVd and LVEF were not significantly changed after mitral valve repair. Furthermore, CH after resuscitation have a statistically significant negative correlation with the degree of mitral regurgitation 12 months after operation. CONCLUSION: The mitral valve repair with mitral valve ring induce the morphologic change of the mitral valve structure. The increase of CH after mitral valve repair may be one of the main factors in regulation of mitral regurgitation. PMID- 29282096 TI - Exosomal proteins as potential markers of tumor diagnosis. AB - Liquid biopsy especially that of exosomes carries tumor-specific molecules and provides useful information during tumor development and progression in "real time." Exosomes are membrane-encapsulated vesicles, constantly released by multiple cells, including cancer cells, in large quantities, and are widely present in body fluids. Tumor exosomes can remodel a tumor-supportive microenvironment via cross-talk with target cells. Recent research has mainly focused on exosomal miRNAs and to a small degree on proteins. However, detecting the genome output (active proteins such as phosphoproteins) can provide more direct information about disease progression, such as in the early discovery and monitoring of cancers. This review highlights the unique features of exosomal proteins over traditional serological markers and summarizes their recent use in cancer diagnosis and prognosis. Furthermore, we describe the general protocols of research on exosome proteomics with an emphasis on their clinical use. PMID- 29282098 TI - The impact of maintaining serum potassium >=3.6 mEq/L vs >=4.5 mEq/L on the incidence of new-onset atrial fibrillation in the first 120 hours after isolated elective coronary artery bypass grafting - study protocol for a randomised feasibility trial for the proposed Tight K randomized non-inferiority trial. AB - BACKGROUND: Atrial fibrillation (AF) occurs in approximately one in three patients after cardiac surgery, and is associated with increased short-term and long-term mortality, intensive care unit (ICU) and hospital stay, and increased cost of care. In an attempt to reduce AF incidence in these patients, serum potassium (K+) levels are commonly maintained at the high end of normal (4.5-5.5 mEq/L). However, such potassium supplementation is without proven benefit, and is not without negative consequences. It carries clinical risk, negatively impacts patient experience and is both time-consuming and costly. This protocol describes a randomised controlled pilot trial to assess the feasibility of a proposed randomised non-inferiority trial to investigate the impact of maintaining serum potassium >= 3.6 mEq/L vs >= 4.5 mEq/L on the incidence of new-onset atrial fibrillation in the first 120 hours after isolated elective coronary artery bypass grafting. METHODS: Design: this is a randomized feasibility trial as a pilot for a randomized non-inferiority trial. PARTICIPANTS: are 160 patients undergoing isolated coronary artery bypass grafting at two centres. Allocation: patients will be randomized (1:1) to protocols aiming to maintain serum potassium at either >= 3.6 mEq/L ("relaxed control") or >= 4.5 mEq/L ("tight control"). Primary analytic aim: was to assess the feasibility and acceptability of planning and delivering the intervention and trial methods to inform a full-scale non inferiority trial. OUTCOME: the primary indicative efficacy outcome measures being field-tested are feasibility of participant recruitment and randomization, maintaining a protocol violation rate < 10%, and retaining 90% patient follow up 28 days after surgery. The primary clinical outcome measure of the future full "Tight K Study" will be incidence of AF after cardiac surgery. DISCUSSION: The Tight K Pilot will assess the feasibility of conducting the full trial, which is intended to confirm or refute the efficacy of current potassium management in preventing AF after cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03195647 . Registered on 23 May 2017. Last updated 19June 2017. PMID- 29282099 TI - The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis. AB - BACKGROUND: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome. METHODS/DESIGN: The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. DISCUSSION: Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. TRIAL REGISTRATION: FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011. EFFECTS: ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011 006130-16 . Registered on 8 August 2014. PMID- 29282100 TI - Subclavian oblique-axis catheterization technique. PMID- 29282101 TI - Association of physical activity with lung function in lung-healthy German adults: results from the KORA FF4 study. AB - BACKGROUND: In lung disease, physical activity (PA) yields beneficial health effects, but its association with the function of healthy lungs has rarely been studied. We investigated the association of accelerometer-based PA with spirometric indices, maximal inspiratory mouth pressure (PImax) and lung diffusion capacity in lung-healthy adults. METHODS: In total, 341 apparently lung healthy participants from the population-based KORA (Cooperative Health Research in the Region of Augsburg) FF4 cohort study (45% male, aged 48-68 years, 47% never smokers) completed lung function testing and wore ActiGraph accelerometers over a one week period at the hip. In adjusted regression analyses, moderate to vigorous PA (MVPA) was characterized as: sex-specific activity quartiles, achieving >= 10 consecutive minutes (yes vs. no), and meeting the WHO PA recommendations (yes vs. no). RESULTS: Positive associations of MVPA-quartiles with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and corresponding Global Lung Function Initiative z-scores were found. Subjects in the most active quartile (> 47 or > 50 min/day for females and males, respectively) had 142 ml [95% CI: 23, 260] higher FEV1 and 155 ml [95% CI: 10, 301] higher FVC than those in the least active quartile (< 17 or < 21 min/day for females and males, respectively); however these associations were stronger among ex-/current smokers. Achieving at least once 10 consecutive minutes of MVPA was only associated with higher PImax [beta-estimate: 0.57 kPa; 95% CI: 0.04, 1.10], remaining significant among never smokers. No associations were found with diffusion capacity or for reaching the WHO-recommended 150 min of MVPA/week in 10 min bouts. CONCLUSIONS: Although the effects were small, active subjects showed higher spirometric results. The observed associations were more pronounced among ever smokers suggesting a higher benefit of PA for subjects being at a higher risk for chronic lung diseases. PMID- 29282102 TI - LncRNA AK023391 promotes tumorigenesis and invasion of gastric cancer through activation of the PI3K/Akt signaling pathway. AB - BACKGROUND: Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer. METHODS: A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway. RESULTS: Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-kappaB, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer. CONCLUSIONS: The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer. PMID- 29282103 TI - Within-host evolution of Enterococcus faecium during longitudinal carriage and transition to bloodstream infection in immunocompromised patients. AB - BACKGROUND: Enterococcus faecium is a leading cause of hospital-acquired infection, particularly in the immunocompromised. Here, we use whole genome sequencing of E. faecium to study within-host evolution and the transition from gut carriage to invasive disease. METHODS: We isolated and sequenced 180 E. faecium from four immunocompromised patients who developed bloodstream infection during longitudinal surveillance of E. faecium in stool and their immediate environment. RESULTS: A phylogenetic tree based on single nucleotide polymorphisms (SNPs) in the core genome of the 180 isolates demonstrated several distinct clones. This was highly concordant with the population structure inferred by Bayesian methods, which contained four main BAPS (Bayesian Analysis of Population Structure) groups. The majority of isolates from each patient resided in a single group, but all four patients also carried minority populations in stool from multiple phylogenetic groups. Bloodstream isolates from each case belonged to a single BAPS group, which differed in all four patients. Analysis of 87 isolates (56 from blood) belonging to a single BAPS group that were cultured from the same patient over 54 days identified 30 SNPs in the core genome (nine intergenic, 13 non-synonymous, eight synonymous), and 250 accessory genes that were variably present. Comparison of these genetic variants in blood isolates versus those from stool or environment did not identify any variants associated with bloodstream infection. The substitution rate for these isolates was estimated to be 128 (95% confidence interval 79.82 181.77) mutations per genome per year, more than ten times higher than previous estimates for E. faecium. Within-patient variation in vancomycin resistance associated with vanA was common and could be explained by plasmid loss, or less often by transposon loss. CONCLUSIONS: These findings demonstrate the diversity of E. faecium carriage by individual patients and significant within-host diversity of E. faecium, but do not provide evidence for adaptive genetic variation associated with invasion. PMID- 29282104 TI - Association between continuous hyperosmolar therapy and survival in patients with traumatic brain injury - a multicentre prospective cohort study and systematic review. AB - BACKGROUND: Intracranial hypertension (ICH) is a major cause of death after traumatic brain injury (TBI). Continuous hyperosmolar therapy (CHT) has been proposed for the treatment of ICH, but its effectiveness is controversial. We compared the mortality and outcomes in patients with TBI with ICH treated or not with CHT. METHODS: We included patients with TBI (Glasgow Coma Scale <= 12 and trauma-associated lesion on brain computed tomography (CT) scan) from the databases of the prospective multicentre trials Corti-TC, BI-VILI and ATLANREA. CHT consisted of an intravenous infusion of NaCl 20% for 24 hours or more. The primary outcome was the risk of survival at day 90, adjusted for predefined covariates and baseline differences, allowing us to reduce the bias resulting from confounding factors in observational studies. A systematic review was conducted including studies published from 1966 to December 2016. RESULTS: Among the 1086 included patients, 545 (51.7%) developed ICH (143 treated and 402 not treated with CHT). In patients with ICH, the relative risk of survival at day 90 with CHT was 1.43 (95% CI, 0.99-2.06, p = 0.05). The adjusted hazard ratio for survival was 1.74 (95% CI, 1.36-2.23, p < 0.001) in propensity-score-adjusted analysis. At day 90, favourable outcomes (Glasgow Outcome Scale 4-5) occurred in 45.2% of treated patients with ICH and in 35.8% of patients with ICH not treated with CHT (p = 0.06). A review of the literature including 1304 patients from eight studies suggests that CHT is associated with a reduction of in-ICU mortality (intervention, 112/474 deaths (23.6%) vs. control, 244/781 deaths (31.2%); OR 1.42 (95% CI, 1.04-1.95), p = 0.03, I 2 = 15%). CONCLUSIONS: CHT for the treatment of posttraumatic ICH was associated with improved adjusted 90-day survival. This result was strengthened by a review of the literature. PMID- 29282105 TI - Risk factors for predicting increased surgical drain output in patients after anterior cervical corpectomy and fusion. AB - BACKGROUND: Although measures to reduce and treat the postoperative surgical drain output are discussed, along with the increased interest in causative factors related to the prevention and treatment reported by many studies, these are still controversial. METHODS: A retrospective study was conducted on a consecutive series of 217 patients who had underwent ACCF between January 2016 and March 2017. Patients were categorized based on normal or increased total drain output. These two groups were compared for demographic distribution and clinical data to investigate the predictive factors of increased drain output by multivariate analysis. RESULTS: The overall incidence rate of increased drain output after ACCF was 16.6%. There are no significant differences in sex, BMI, history of taking aspirin, and ASA classification between the two groups (P > 0.05). Of the patients with increased drain output, a significantly higher proportion of patients have OPLL in the surgical level, 18 (50.0%) versus 33 (18.2%) (P = 0.000). The mean age was 60.67 +/- 8.18 years versus 54.41 +/- 10.05 years (P = 0.001). Number of discs involved was 2.42 +/- 0.50 versus 2.02 +/- 0.65 (P = 0.001). Operation time was 112.22 +/- 16.49 min versus 105.21 +/- 17.89 min (P = 0.031). Intraoperative blood loss was 109.86 +/- 62.02 mL versus 87.83 +/- 56.40 mL (P = 0.036). Logistic regression analysis showed that age (OR, 1.075; p = 0.003), history of smoking (OR, 2.792; p = 0.021), OPLL in surgical level (OR, 2.107; p = 0.001), and number of discs involved (OR, 2.764; p = 0.003) maintained its significance in predicting likelihood of increased surgical drain output. CONCLUSIONS: The occurrence of increased drain output after ACCF is most likely multifactorial and is related to age, history of smoking, OPLL in surgical level, and number of discs involved. PMID- 29282106 TI - Ankle ligament reconstruction after wide resection of the osteosarcoma of the distal fibula: a case report. AB - BACKGROUND: Restoration of the lateral ankle after distal fibulectomy is a difficult reconstructive procedure. Many surgical techniques have been proposed. This report shows another fibular reconstructive option with promising outcome. CASE PRESENTATION: We report the case of a 30-year-old woman who presented with a solitary mass located in the lateral aspect of the ankle. The mass had grown rapidly for 2 months and caused increasing pain. Physical examination showed a 3.0 cm diameter tender, nonmobile hard mass in the lateral malleolus. Radiographs showed an osteolytic lesion involving the lateral cortex at the distal fibula. After incisional biopsy, pathologic examination found a well-differentiated intramedullary osteosarcoma. Neoadjuvant chemotherapy with doxorubicin was provided for 3 months prior to definitive surgical treatment. Magnetic resonance imaging showed persistent tumor in the biopsy site. After distal fibulectomy and wide resection, split tibialis posterior tendon transfer to the remaining peroneus brevis restored the stability of the ankle. The pain resolved within 3 months. The ankle was stable and no recurrence of the cancer was found at a 7 year follow-up. CONCLUSION: Reconstruction following distal fibulectomy and surrounding soft tissue resection responds favorably to split tibialis posterior transfer to the remaining peroneus brevis suggesting that this technique can provide a good and functional outcome. PMID- 29282107 TI - Thoracic ultrasound for pleural effusion in the intensive care unit: a narrative review from diagnosis to treatment. AB - Pleural effusion (PLEFF), mostly caused by volume overload, congestive heart failure, and pleuropulmonary infection, is a common condition in critical care patients. Thoracic ultrasound (TUS) helps clinicians not only to visualize pleural effusion, but also to distinguish between the different types. Furthermore, TUS is essential during thoracentesis and chest tube drainage as it increases safety and decreases life-threatening complications. It is crucial not only during needle or tube drainage insertion, but also to monitor the volume of the drained PLEFF. Moreover, TUS can help diagnose co-existing lung diseases, often with a higher specificity and sensitivity than chest radiography and without the need for X-ray exposure. We review data regarding the diagnosis and management of pleural effusion, paying particular attention to the impact of ultrasound. Technical data concerning thoracentesis and chest tube drainage are also provided. PMID- 29282108 TI - From cars to bikes - the feasibility and effect of using e-bikes, longtail bikes and traditional bikes for transportation among parents of children attending kindergarten: design of a randomized cross-over trial. AB - BACKGROUND: The present study aims to increase bicycling and level of physical activity (PA), and thereby promote health in parents of toddlers, by giving access to different bicycle types. There is a need for greater understanding of e bikes and their role in the transportation network, and further effects on PA levels and health. Moreover, longtail bikes could meet certain practical needs not fulfilled by e-bikes or traditional bikes, hence increased knowledge regarding their feasibility should be obtained. No previous studies have investigated whether providing an e-bike or a longtail bike over an extended period in a sample of parents of toddlers influence objectively assessed amount of bicycling and total PA level, transportation habits, cardiorespiratory fitness, body composition and blood pressure. METHODS: A randomized cross-over trial will be performed, entailing that participants in the intervention group (n = 18) complete the following intervention arms in random order: (i) three months access to an e-bicycle with trailer for child transportation (n = 6), (ii) three months access to a longtail bicycle (n = 6), and (iii) three months access to a regular bicycle with trailer (n = 6), in total nine months. Also, a control group (n = 18) maintaining usual transportation and PA habits will be included. A convenience sample consisting of 36 parents of toddlers residing in Kristiansand municipality, Southern Norway, will be recruited. Total amount of bicycling (distance and time), total level of PA, and transportation habits will be measured at baseline and in connection to each intervention arm. Cardiorespiratory fitness, body composition and blood pressure will be measured at baseline and post-intervention. Main outcome will be bicycling distance and time spent cycling. DISCUSSION: New knowledge relevant for the timely issues of public health and environmental sustainability will be provided among parents of toddlers, representing a target group of greatest importance. There is a call for research on the influence of e-bikes and longtail bikes on travel behavior and PA levels, and whether voluntary cycling could improve health. If the present study reveals promising results, it should be replicated in larger and more representative samples. Eventually, inclusion in national public health policies should be considered. TRIAL REGISTRATION: ID NCT03131518 , made public 26.04.2017. PMID- 29282109 TI - Simulated patient encounters to improve adolescent retention in HIV care in Kenya: study protocol of a stepped-wedge randomized controlled trial. AB - BACKGROUND: Adolescent-friendly policies aim to tailor HIV services for adolescents and young adults aged 10-24 years (AYA) to promote health outcomes and improve retention in HIV care and treatment. However, few interventions focus on improving healthcare worker (HCW) competencies and skills for provision of high-quality adolescent care. Standardized patients (SPs) are trained actors who work with HCWs in mock clinical encounters to improve clinical assessment, communication, and empathy skills. This stepped-wedge randomized controlled trial will evaluate a clinical training intervention utilizing SPs to improve HCW skills in caring for HIV-positive AYA, resulting in increased retention in care. METHODS/DESIGN: The trial will utilize a stepped-wedge design to evaluate a training intervention using SPs to train HCWs in assessment, communication, and empathy skills for AYA HIV care. We will recruit 24 clinics in Kenya with an active electronic medical record (EMR) system and at least 40 adolescents enrolled in HIV care per site. Stratified randomization by county will be used to assign clinics to one of four waves - time periods when they receive the intervention - with each wave including six clinics. From each clinic, up to 10 HCWs will participate in the training intervention. SP training includes didactic sessions in adolescent health, current guidelines, communication skills, and motivational interviewing techniques. HCW participants will rotate through seven standardized SP scenarios, followed by SP feedback, group debriefing, and remote expert evaluation. AYA outcomes will be assessed using routine clinic data. The primary outcome is AYA retention in HIV care, defined as returning for first follow-up visit within 6 months of presenting to care, or returning for a first follow-up visit after re-engagement in care in AYA with a previous history of being lost to follow-up. Secondary outcomes include HCW competency scores, AYA satisfaction with care, and AYA clinical outcomes including CD4 and viral load. Additional analyses will determine cost-effectiveness of the intervention. DISCUSSION: This trial will contribute valuable information to HIV programs in Kenya and other low-resource settings, providing a potentially scalable strategy to improve quality of care and retention in critical HIV services in this population. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02928900. Registered 26 August 2016. PMID- 29282110 TI - The joint associations of smoking and obesity with subsequent short and long sickness absence: a five year follow-up study with register-linkage. AB - BACKGROUND: Both smoking and obesity are separately associated with sickness absence. Unhealthy lifestyle habits and health conditions may occur concurrently yet studies focusing on their joint association are few. This study examined the joint associations of smoking and obesity with sickness absence (SA). METHODS: A mail survey among employees of the City of Helsinki, Finland, during 2000-2002 included data on obesity, smoking and covariates (N = 8960, response rate 67%, 80% women). These data were prospectively linked with register data on self- (1-3 days) and medically certified (4 days or longer) SA among those consenting to the linkage (n = 6986). Pregnant, underweight and those with missing data on key variables were excluded (n = 138). The total number of participants included in the analyses was 6847. The follow-up time was 5 years. Poisson regression was used to calculate rate ratios (RR). RESULTS: Among women and men smoking and obesity were associated with self-certified SA. Among women there was a joint association with self-certified SA (obese smokers RR 1.81, 95% CI 1.59-2.07). Among women and men smoking and obesity were jointly associated with medically certified SA (for obese smoking women RR 2.23, 95% CI 1.93-2.57, for obese smoking men RR 2.69, 95% CI 2.03-3.55). Associations remained after adjustments for socioeconomic position, working conditions, health behaviours and self-rated health. CONCLUSION: Both smoking and obesity are jointly associated with all lengths of sickness absence. Support measures for smoking cessation and prevention of obesity could likely to reduce SA. PMID- 29282111 TI - Challenges in implementing model-based phase I designs in a grant-funded clinical trials unit. AB - BACKGROUND: For a clinical trials unit to run its first model-based, phase I trial, the statistician, chief investigator, and trial manager must all acquire a new set of skills. These trials also require a different approach to funding and data collection. CHALLENGES AND DISCUSSION: From the statisticians' viewpoint, we highlight what is needed to move from running rule-based, early-phase trials to running a model-based phase I study as we experienced it in our trials unit located in the United Kingdom. Our example is CHARIOT, a dose-finding trial using the time-to-event continual reassessment method. It consists of three stages and aims to discover the maximum tolerated dose of the combination of radiotherapy, chemotherapy, and the ataxia telangiectasia mutated Rad3-related inhibitor M6620 (previously known as VX-970) in patients with oesophageal cancer. We present the challenges we faced in designing this trial and how we overcame them as a way of demystifying the conduct of a model-based trial in a grant-funded clinical trials unit. CONCLUSIONS: Although we appreciate that undertaking model-based trials requires additional time and effort, they are feasible to implement and, once suitable tools such as guiding publications and document templates become available, the design and set-up process will be easier and more efficient. PMID- 29282112 TI - Religious leaders' perceptions of advance care planning: a secondary analysis of interviews with Buddhist, Christian, Hindu, Islamic, Jewish, Sikh and Baha'i leaders. AB - BACKGROUND: International guidance for advance care planning (ACP) supports the integration of spiritual and religious aspects of care within the planning process. Religious leaders' perspectives could improve how ACP programs respect patients' faith backgrounds. This study aimed to examine: (i) how religious leaders understand and consider ACP and its implications, including (ii) how religion affects followers' approaches to end-of-life care and ACP, and (iii) their implications for healthcare. METHODS: Interview transcripts from a primary qualitative study conducted with religious leaders to inform an ACP website, ACPTalk, were used as data in this study. ACPTalk aims to assist health professionals conduct sensitive conversations with people from different religious backgrounds. A qualitative secondary analysis conducted on the interview transcripts focussed on religious leaders' statements related to this study's aims. Interview transcripts were thematically analysed using an inductive, comparative, and cyclical procedure informed by grounded theory. RESULTS: Thirty-five religious leaders (26 male; mean 58.6-years-old), from eight Christian and six non-Christian (Jewish, Buddhist, Islamic, Hindu, Sikh, Baha'i) backgrounds were included. Three themes emerged which focussed on: religious leaders' ACP understanding and experiences; explanations for religious followers' approaches towards end-of-life care; and health professionals' need to enquire about how religion matters. Most leaders had some understanding of ACP and, once fully comprehended, most held ACP in positive regard. Religious followers' preferences for end-of-life care reflected family and geographical origins, cultural traditions, personal attitudes, and religiosity and faith interpretations. Implications for healthcare included the importance of avoiding generalisations and openness to individualised and/ or standardised religious expressions of one's religion. CONCLUSIONS: Knowledge of religious beliefs and values around death and dying could be useful in preparing health professionals for ACP with patients from different religions but equally important is avoidance of assumptions. Community-based initiatives, programs and faith settings are an avenue that could be used to increase awareness of ACP among religious followers' communities. PMID- 29282113 TI - Lack of CT scanner in a rural emergency department increases inter-facility transfers: a pilot study. AB - OBJECTIVE: Rural emergency departments (EDs) are an important gateway to care for the 20% of Canadians who reside in rural areas. Less than 15% of Canadian rural EDs have access to a computed tomography (CT) scanner. We hypothesized that a significant proportion of inter-facility transfers from rural hospitals without CT scanners are for CT imaging. Our objective was to assess inter-facility transfers for CT imaging in a rural ED without a CT scanner. RESULTS: We selected a rural ED that offers 24/7 medical care with admission beds but no CT scanner. Descriptive statistics were collected from 2010 to 2015 on total ED visits and inter-facility transfers. Data was accessible through hospital and government databases. Between 2010 and 2014, there were respectively 13,531, 13,524, 13,827, 12,883, and 12,942 ED visits, with an average of 444 inter-facility transfers. An average of 33% (148/444) of inter-facility transfers were to a rural referral centre with a CT scan, with 84% being for CT scan. Inter-facility transfers incur costs and potential delays in patient diagnosis and management, yet current databases could not capture transfer times. Acquiring a CT scan may represent a reasonable opportunity for the selected rural hospital considering the number of required transfers. PMID- 29282114 TI - Risk factors for addiction among patients receiving prescribed opioids: a systematic review protocol. AB - BACKGROUND: Opioid addiction prevention has become an urgent public health priority, with several countries declaring a state of emergency due to rising death tolls from opioid abuse. Reducing the risk of developing addiction among opioid-naive patients exposed to prescribed opioids during the process of medical care may be an important primary prevention strategy. Our objective is to synthesize the available evidence about factors associated with the development of addiction among patients first exposed to prescribed opioids, with a focus on opioid-naive patients. METHODS: We will perform a systematic search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other databases in collaboration with a health information specialist using a comprehensive search strategy. We will also supplement our search with a scan of the grey literature to identify relevant ongoing and unpublished studies. We will include studies reporting on risk factors for opioid addiction in patients prescribed opioid analgesic therapy through a prescription from a licensed medical professional, with a focus on opioid-naive patients. We will exclude studies focusing on patients who are first exposed to illicit opioids, those who use prescription opioids for cancer pain, and/or who are palliative. Two reviewers will independently review titles, abstracts, and full texts for inclusion and exclusion criteria. They will then extract data from included full texts using standardized piloted data extraction forms and assess study quality through risk of bias assessment. We will synthesize the effect sizes of risk factors derived from clinically homogenous studies with similar designs and the remaining ones qualitatively. DISCUSSION: Understanding risk factors for opioid addiction among patients who require analgesia has the potential to inform clinical care and opioid prescribing guidelines aiming to reduce opioid addiction. We will also use this information as a starting point for developing interventions for primary prevention. PMID- 29282115 TI - Efficacy of anchoring the four-arm transvaginal mesh to the mid-urethra vs original surgery as a surgical correction for stress urine incontinence in coexisting anterior vaginal prolapse grades II and III: study protocol for a randomized controlled trial. AB - BACKGROUND: The prevalence of obesity with aging is escalating alarmingly; and pelvic organ prolapse (POP) and stress urinary incontinence (SUI) are now becoming a growing epidemic among the elderly. Synthetic transvaginal mesh has been employed with increasing popularity in the treatment of POP and is usually highly effective in controlling the principal symptoms of prolapse. However, studies have reported that mesh operations provide fairly unfavorable SUI cure rates. Therefore, additional anti-incontinence surgical strategies are increasingly being scrutinized to achieve better postoperative continence without any significant side-effects for patients with both POP and SUI. We hypothesize that the modification with the fixing of the mesh to the mid-urethra is superior to the original transvaginal mesh operation (TVM) with regard to anti incontinence. METHODS: One hundred and thirty patients diagnosed with POP-Q II III and concomitant SUI requiring surgical treatment will be included in this prospective, randomized, double-blind, controlled clinical trial. Patients will be randomly allocated to receive either original TVM (TVM group, n = 65) or modified TVM surgery (mTVM group, n = 65). As the primary outcome parameter, we will evaluate the objective SUI and POP cure rates. Secondary endpoints include postoperative morbidity as assessed with the International Urogynaecological Association classification and subjective prolapse and incontinence cure rates reported by questionnaires. DISCUSSION: Recognizing the importance of an additional surgical procedure for anti-incontinence management, we aim to investigate whether a stabilizing suturing of the mesh to the mid-urethra delivers superior SUI correction compared to the original prosthesis surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02935803. Registered on 20 May 2016. PMID- 29282116 TI - Sickness absence among municipal workers in a Brazilian municipality: a secondary data analysis. AB - BACKGROUND: Sickness absence, work disability associated with illness or injury, is a major public health problem worldwide. Some studies have investigated determinants of sickness absence among workers with shorter job tenure, but have only focused on certain diagnostic groups. Although it is well established that job tenure has an inverse relationship with work injury rate, less is known about its association with sickness absence for other disorders. Therefore, this study aimed to investigate the risk factors for incidence and duration of sickness absence according to diagnosis over a 7-year period. A dynamic cohort consisting of all permanent civil servants hired from 2005 to 2011 by the Goiania municipality-Brazil. Data of certified sickness absences longer than 3 days were analyzed. The incidence density was calculated per 1000 person-years in each ICD 10 category. The association between sickness absence and socio-demographic and occupational characteristics was examined using negative binomial regression models. RESULTS: 18,450 workers, mean age of 32 years, accumulated 14,909 episodes of sickness absence. Overall, the incidence density was 234.6 episodes per 1000 person years. Diagnostic groups with the highest incidence density of sickness absences were injuries (49.1), musculoskeletal disorders (31.3) and mental disorders (29.2). Factors predicting any sickness absence were female gender, older age, low education, being a health professional, multiple jobs and full-time employment. Mental health disorders were more common among education professionals, musculoskeletal disorders among blue collar workers and injuries among inspection workers. Prolonged time on sick leave was associated with male gender, older age groups, low education and income, blue-collar workers, more than one job contract and full time employment. CONCLUSIONS: These findings demonstrate a substantial sickness absentee burden and they provide relevant information for targeting prevention and health promotion policies to the most vulnerable occupational groups. PMID- 29282117 TI - A systematic review of adherence in Indigenous Australians: an opportunity to improve chronic condition management. AB - BACKGROUND: Indigenous Australians experience high rates of chronic conditions. It is often asserted Indigenous Australians have low adherence to medication; however there has not been a comprehensive examination of the evidence. This systematic literature review presents data from studies of Indigenous Australians on adherence rates and identifies supporting factors and impediments from the perspective of health professionals and patients. METHODS: Search strategies were used to identify literature in electronic databases and websites. The following databases were searched: Scopus, Medline, CINAHL Plus, PsycINFO, Academic Search Premier, Cochrane Library, Trove, Indigenous Health infonet and Grey Lit.org . Articles in English, reporting original data on adherence to long-term, self administered medicines in Australia's Indigenous populations were included. Data were extracted into a standard template and a quality assessment was undertaken. RESULTS: Forty-seven articles met inclusion criteria. Varied study methodologies prevented the use of meta-analysis. KEY FINDINGS: health professionals believe adherence is a significant problem for Indigenous Australians; however, adherence rates are rarely measured. Health professionals and patients often reported the same barriers and facilitators, providing a framework for improvement. CONCLUSIONS: There is no evidence that medication adherence amongst Indigenous Australians is lower than for the general population. Nevertheless, the heavy burden of morbidity and mortality faced by Indigenous Australians with chronic conditions could be alleviated by enhancing medication adherence. Some evidence supports strategies to improve adherence, including the use of dose administration aids. This evidence should be used by clinicians when prescribing, and to implement and evaluate programs using standard measures to quantify adherence, to drive improvement in health outcomes. PMID- 29282118 TI - Biofilm production and other virulence factors in Streptococcus spp. isolated from clinical cases of bovine mastitis in Poland. AB - BACKGROUND: Mastitis is a common disease in dairy cattle throughout the world and causes considerable economic losses each year. An important aetiological agent of this disease is bacteria of the genus Streptococcus; hence, exploring the mechanisms of virulence in these bacteria is an extremely important step for the development of effective prevention programmes. The purpose of our study was to determine the ability to produce biofilm and the occurrence of selected invasiveness factors among bacteria of the genus Streptococcus isolated from cattle with the clinical form of mastitis in northeastern Poland. RESULTS: Most of the isolates analysed demonstrated an ability to produce biofilm (over 70%). Virulence genes were searched for in the three most common streptococci in our experiment: S. agalactiae, S. uberis and S. dysgalactiae. For S. agalactiae, only four genes were confirmed: rib (33%), cylE (78%), bca (37%), and cfb (100%). The genes pavA, scpB, bac and lmb were not present in any of the tested strains. The dominant serotypes of the species were Ia (n = 8) and II (n = 8), in addition to some strains that were not classified in any of the groups (n = 6). Out of the eight selected genes for S. uberis (sua, pauA/skc, gapC, cfu, lbp, hasA, hasB, hasC), only one was not found (lbp). Finally, two genes were chosen for S. dysgalactiae (eno and napr), and their presence was confirmed in 76% and 86% of the strains, respectively. CONCLUSIONS: The experiment showed that strains of Streptococcus spp. isolated from dairy cattle with clinical cases of mastitis in the northeastern part of Poland possess several invasiveness factors that can substantially affect the course of the disease, and this should be considered when developing targeted prevention programmes. PMID- 29282119 TI - Improving prevention, monitoring and management of diabetes among ethnic minorities: contextualizing the six G's approach. AB - OBJECTIVE: People from Black, Asian and Minority Ethnic (BAME) groups are known to have an increased risk of developing diabetes and face greater barriers to accessing healthcare resources compared to their 'white British' counterparts. The extent of these barriers varies by demographics and different socioeconomic circumstances that people find themselves in. The purpose of this paper is to present and discuss a new framework to understand, disentangle and tackle these barriers so that improvements in the effectiveness of diabetes interventions for BAME communities can be achieved. RESULTS: The main mediators of lifestyle behavioural change are gender, generation, geography, genes, God/religion, and gaps in knowledge and economic resources. Dietary and cultural practices of these individuals significantly vary according to gender, generation, geographical origin and religion. Recognition of these factors is essential in increasing knowledge of healthy eating, engagement in physical activity and utilisation of healthcare services. Use of the six G's framework alongside a community centred approach is crucial in developing and implementing culturally sensitive interventions for diabetes prevention and management in BAME communities. This could improve their health outcomes and overall wellbeing. PMID- 29282120 TI - Can testing clinical significance reduce false positive rates in randomized controlled trials? A snap review. AB - OBJECTIVE: The use of minimum clinically important difference in the hypothesis formulation for superiority trials is similar in principle to the concept of non inferiority or equivalence trial. However, most clinical trials are analysed testing zero clinical difference. Since the minimum clinically important difference is pre-defined for power calculation, it is important to incorporate it in both the hypothesis testing and the interpretation of findings from clinical trials. RESULTS: We reviewed a set of 50 publications (25 with binary outcome, and 25 with survival time outcome). 20% of the 50 published trials that were statistically significant, were also clinically significant based on the minimum clinically important risk differences (or hazard ratio) used for their power calculations. This snap review seems to suggest that most published trials with statistically significant results were less likely to be clinically significant, which may partly explain the high false positive findings associated with findings from superiority trials. Furthermore, none of the reviewed publications explicitly used minimum clinically important difference in the interpretation of their findings. However, a systematic review is needed to critically appraise the impact of the current practice on false positive rate in published trials with significant findings. PMID- 29282121 TI - Advances in the genome-wide association study of chronic hepatitis B susceptibility in Asian population. AB - Chronic hepatitis B (CHB) is the most common chronic liver disease resulting from viral infection and has become a serious threat to human health. Each year, about 1.2 million people in the world die from diseases caused by chronic infection of hepatitis B virus. The genetic polymorphism is significantly associated with the susceptibility to chronic hepatitis B. Genome-wide association study was recently developed and has become an important tool to detect susceptibility genes of CHB. To date, a number of CHB-associated susceptibility loci and regions have been identified by scientists over the world. To clearly understand the role of susceptibility loci in the occurrence of CHB is important for the early diagnosis and prevention of CHB. PMID- 29282122 TI - Advice and care for patients who die by voluntarily stopping eating and drinking is not assisted suicide. AB - BACKGROUND: A competent patient has the right to refuse foods and fluids even if the patient will die. The exercise of this right, known as voluntarily stopping eating and drinking (VSED), is sometimes proposed as an alternative to physician assisted suicide. However, there is ethical and legal uncertainty about physician involvement in VSED. Are physicians advising of this option, or making patients comfortable while they undertake VSED, assisting suicide? This paper attempts to resolve this ethical and legal uncertainty. DISCUSSION: The standard approach to resolving this conundrum has been to determine whether VSED itself is suicide. Those who claim that VSED is suicide invariably claim that physician involvement in VSED amounts to assisting suicide. Those who claim that VSED is not suicide claim that physician involvement in VSED does not amount to assisting suicide. We reject this standard approach. CONCLUSION: We instead argue that, even if VSED is classified as a kind of suicide, physician involvement in VSED is not a form of assisted suicide. Physician involvement in VSED does not therefore fall within legal provisions that prohibit VSED. PMID- 29282123 TI - Impact of risk factors on functional status in maintenance hemodialysis patients. AB - OBJECTIVES: To survey by measuring patient's functional status which is crucial when end-stage renal disease patients begin a dialysis program. The influence of the disease on patients can be examined by the measurement of Karnofsky Performance Status (KPS) scores, together with a quality of life survey, and clinical variables. METHODS: The details for the dataset in the study were collected from patients receiving regular hemodialysis (HD) in one hospital, which were available retrospectively for 1166 patients during the 5-year study period. KPS scores were applied for quantifying functional status. To identify risk factors for functional status, clinical factors including demographics, laboratory data, and HD vintage were selected. This study applied a classification and regression tree approach (CART) and logistic regression to determine risk factors on functional impairment among HD patients. RESULTS: Ten risk factors were identified by CART and regression model (age, primary kidney disease subclass, treatment years, hemoglobin, albumin, creatinine, phosphorus, intact parathyroid hormone, ferritin, and cardiothoracic ratio). The results of logistic regression with selected interaction models showed older age or higher hematocrit, blood urea nitrogen, and glucose levels could significantly increase the log-odds of obtaining low KPS scores at in-person visits. CONCLUSIONS: In interaction results, the combination of older age with higher albumin level and higher creatinine level with longer HD treatment years could significantly decrease the log-odds of a low KPS score assessment during in-person visits. Age, hemoglobin, albumin, urea, creatinine levels, primary kidney disease subclass, and HD duration are the major determinants for functional status in HD patients. PMID- 29282124 TI - Memory retrieval in addiction: a role for miR-105-mediated regulation of D1 receptors in mPFC neurons projecting to the basolateral amygdala. AB - BACKGROUND: Drug addiction is a chronic brain disorder characterized by the compulsive use of drugs. The study of chronic morphine-induced adaptation in the brain and its functional significance is of importance to understand the mechanism of morphine addiction. Previous studies have found a number of chronic morphine-induced adaptive changes at molecular levels in the brain. A study from our lab showed that chronic morphine-induced increases in the expression of D1 receptors at presynaptic terminals coming from other structures to the basolateral amygdala (BLA) played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the neurocircuitry where the increased D1 receptors are located and how chronic morphine increases D1 receptor expression in specific neurocircuits remain to be elucidated. RESULTS: Our results show that chronic morphine induces a persistent increase in D1 receptor expression in glutamatergic terminals of projection neurons from the medial prefrontal cortex (mPFC) to the BLA, but has no influence on D1 receptor expression in projection neurons from the hippocampus or the thalamus to the BLA. This adaptation to chronic morphine is mediated by reduced expression of miR-105 in the mPFC, which results in enhanced D1 receptor expression in glutamatergic terminals of projection neurons from the mPFC to the BLA. Ex vivo optogenetic experiments show that a chronic morphine-induced increase in D1 receptor expression in glutamatergic terminals of projection neurons from the mPFC to the BLA results in sensitization of the effect of D1 receptor agonist on presynaptic glutamate release. mPFC to BLA projection neurons are activated by withdrawal associated environmental cues in morphine-withdrawal rats, and overexpression of miR-105 in the mPFC leads to reduced D1 receptor induction in response to chronic morphine in glutamatergic terminals of the projection neurons from the mPFC to the BLA, and a reduction in place aversion conditioned by morphine withdrawal. CONCLUSIONS: These results suggest that chronic morphine use induces a persistent increase in D1 receptors in glutamatergic terminals of projection neurons from the mPFC to the BLA via downregulation of miR-105 in the mPFC, and that these adaptive changes contribute to environmental cue-induced retrieval of morphine withdrawal memory. PMID- 29282125 TI - Food restriction during pregnancy and female offspring fertility: adverse effects of reprogrammed reproductive lifespan. AB - BACKGROUND: Food restriction during pregnancy can influence the health of the offspring during the adulthood. The aim of the present study was to examine the effect of maternal food restriction (MFR) on the reproductive performance in female rat offspring from the first (FR1) and second (FR2) generations. METHODS: Adult virgin Wistar female rats were given free access to tap water and were fed ad libitum on standard rodent chow, were mated with virgin adult males, and then were randomly divided into two groups: controls (that was fed ad libitum ) and food-restricted group (FR, that was given only 50% of ad libitum food throughout gestation). Their first (FR1) and the second (FR2) generation of offspring were fed ad libitum and sacrificed before puberty and at adulthood. Their ovaries were removed and their histology evaluated by estimating the number of follicles (total and at various stages of folliculogenesis), and the presence of multi nuclei oocytes and multi-oocyte follicles. RESULTS: Total number of ovarian follicles was lower in FR1 females at week 4 in comparison with controls, while it was not different in FR2 females vs. CONTROLS: The number of the primordial follicle was lower in FR1 and FR2 females vs. controls at both week 4 and at week 8. When compared to the controls, the follicles containing multi-nuclei oocytes were more frequent in ovaries from FR1 and FR2 females at week 4, and higher and lower respectively in ovaries form FR1 and FR2 females at week 8. CONCLUSION: MFR affects ovarian histology by inducing the development of abnormal follicles in the ovaries in first and second generation offspring. This finding could influence the ovarian function resulting in an early pubertal onset and an early decline in reproductive lifespan. PMID- 29282126 TI - The impact of a single round of community mass treatment with azithromycin on disease severity and ocular Chlamydia trachomatis load in treatment-naive trachoma-endemic island communities in West Africa. AB - BACKGROUND: Trachoma, a neglected tropical disease, is caused by ocular infection with Chlamydia trachomatis (Ct). The World Health Organization (WHO) recommends three annual rounds of community mass drug treatment with azithromycin (MDA) if the prevalence of follicular trachoma in 1-9 year olds (TF1-9) exceeds 10% at district level to achieve an elimination target of district-level TF1-9 below 5% after. To evaluate this strategy in treatment-naive trachoma-endemic island communities in Guinea Bissau, we conducted a cross-sectional population-based trachoma survey on four islands. The upper tarsal conjunctivae of each participant were clinically assessed for trachoma and conjunctival swabs were obtained (n = 1507). We used a droplet digital PCR assay to detect Ct infection and estimate bacterial load. We visited the same households during a second cross sectional survey and repeated the ocular examination and obtained conjunctival swabs from these households one year after MDA (n = 1029). RESULTS: Pre-MDA TF1-9 was 22.0% (136/618). Overall Ct infection prevalence (CtI) was 18.6% (25.4% in 1 9 year olds). Post-MDA (estimated coverage 70%), TF1-9 and CtI were significantly reduced (7.4% (29/394, P < 0.001) and 3.3% (34/1029, P < 0.001) (6.6% in 1-9 year olds, P < 0.001), respectively. Median ocular Ct load was reduced from 2038 to 384 copies/swab (P < 0.001). Following MDA cases of Ct infection were highly clustered (Moran's I 0.27, P < 0.001), with fewer clusters of Ct infection overall, fewer clusters of cases with high load infections and less severe disease. CONCLUSIONS: Despite a significant reduction in the number of clusters of Ct infection, mean Ct load, disease severity and presence of clusters of cases of high load Ct infection suggesting the beginning of trachoma control in isolated island communities, following a single round of MDA we demonstrate that transmission is still ongoing. These detailed data are useful in understanding the epidemiology of ocular Ct infection in the context of MDA and the tools employed may have utility in determining trachoma elimination and surveillance activities in similar settings. PMID- 29282128 TI - Improving learning and confidence through small group, structured otoscopy teaching: a prospective interventional study. AB - BACKGROUND: Otologic diseases are common and associated with significant health care costs. While accurate diagnosis relies on physical exam, existing studies have highlighted a lack of comfort among trainees with regards to otoscopy. As such, dedicated otoscopy teaching time was incorporated into the undergraduate medical curriculum in the form of a small group teaching session. In this study, we aimed to examine the effect of a small-group, structured teaching session on medical students' confidence with and learning of otoscopic examination. METHODS: Using a prospective study design, an otolaryngologist delivered an one-hour, small group workshop to medical learners. The workshop included introduction and demonstration of otoscopy and pneumatic otoscopy followed by practice with peer feedback. A survey exploring students' confidence with otoscopy and recall of anatomical landmarks was distributed before(T1), immediately after(T2), and 1 month following the session(T3). RESULTS: One hundred and twenty five learners participated from February 2016 to February 2017. Forty nine participants with complete data over T1-T3 demonstrated significant improvement over time in confidence (Wilk's lambda = .09, F(2,48) = 253.31 p < .001, eta 2 = .91) and learning (Wilk's lambda = 0.34, F(2,47) = 24.87 p < .001, eta 2 = .66). CONCLUSIONS: A small-group, structured teaching session had positive effects on students' confidence with otoscopy and identification of otologic landmarks. Dedicated otoscopy teaching sessions may be a beneficial addition to the undergraduate medical curriculum. PMID- 29282127 TI - Cross-cultural survey development: The Colon Cancer Screening Behaviors Survey for South Asian populations. AB - OBJECTIVE: The objective of this work was to develop a survey that considered cultural relevance and diversity of South Asian populations, with the aim of describing or predicting factors that influence colorectal cancer screening intention and adherence. The scientifically rigorous approach for survey development informed the final phase of an exploratory mixed method study. This initial survey was later cross-culturally translated and adapted into the Urdu language, and thereafter, items were cognitively tested for conceptual relevance among South Asian immigrants. RESULTS: The initial development of the Colon Cancer Screening Behaviours Survey for South Asian populations was completed using a number of steps. Development involved: the identification of key concepts and conceptual model; literature search for candidate measures and critical appraisal; and, expert consultation to select relevant measures. Five published surveys included measures that covered concepts relevant to South Asians and colorectal cancer screening behaviours. However, measures from these surveys missed content that emerged through parallel field work with South Asians, and additions were required along with item modifications. In the final stage, cross cultural translation and adaptation into Urdu, and cognitive testing were completed. Future research will require an examination of proposed relationships, and psychometric testing of measures in the survey. PMID- 29282129 TI - Dietary patterns, plasma vitamins and Trans fatty acids are associated with peripheral artery disease. AB - BACKGROUND: To investigate the association between dietary patterns (DP), plasma vitamins and trans fatty acids (TFAs) with the likelihood of peripheral artery disease (PAD). METHODS: National Health and Nutrition Examination Survey (NHANES) data for the years 1999-2002 were used. PAD was diagnosed by ankle brachial index assessment. Plasma concentrations of vitamins were measured using high performance liquid chromatography. Vitamin D levels were measured by radioimmunoassay. Analysis of covariance, principal components analysis (PCA) and adjusted logistic regression were applied, accounting for the survey design and sample weights. RESULTS: Of the 4864 eligible participants, 2482 (51.0%) were men and 269 (5.5%) had prevalent PAD. PCA uncovered three DPs which accounted for 56.8% of the variance in dietary nutrients consumption including DP1 (fatty acids and cholesterol), DP2 (minerals, vitamins and fiber), and DP3 (polyunsaturated fatty acids [PUFA]). PAD patients had a significantly higher serum concentrations of trans 9-octadecenoic acid and trans 9, trans 12-octadienoic acid as well as lower plasma levels of vitamin D, retinol, retinyl stearate and retinyl palmitate (p < 0.001 for all comparisons). In models adjusted for age, race, diabetes, cholesterol, hypertension, smoking and energy intake, individuals in the highest quartile of the DP1 had higher odds for PAD compared with those in the lowest quartile [(odds ratio (OR): 6.43, 95% confidence interval (CI): 2.00-20.63 p < 0.001], while those in the highest quartile of DP2 and DP3 had lower odds of PAD relative to those in the lowest quartile (OR:0.28, OR:0.44, respectively; p < 0.001 for both comparisons). CONCLUSION: We found that quality of diet, plasma vitamins and TFAs are associated with the likelihood of PAD. If confirmed in prospective studies, the possibility that dietary factors, plasma vitamins and TFAs might be valuable for preventing or delaying the clinical progression of PAD, should be investigated in intervention trials. PMID- 29282130 TI - What does not kill it makes it weaker: effects of sub-lethal concentrations of ivermectin on the locomotor activity of Anopheles aquasalis. AB - BACKGROUND: Malaria remains a major public health concern. Vector control measures based solely on insecticide treated nets (ITNs) and indoor residual spraying (IRS) have demonstrated not to be feasible for malaria elimination. It has been shown that ivermectin affects several aspects of Anopheles species biology. Along the Latin American seacoast, Anopheles aquasalis Curry plays an important role in malaria transmission. The observation of mosquitoes locomotor activity under laboratory conditions can reveal details of their daily activity rhythms, which is controlled by an endogenous circadian clock that seems to be influenced by external signals, such as light and temperature. In this study, we assessed basal locomotor activity and the effects of ivermectin on locomotor activity of the American malaria vector, An. aquasalis. METHODS: Adult females of Anopheles aquasalis used in experiments were three to five days post-emergence. Blood from one single subject was used to provide mosquito meals by membrane feeding assays. Powdered ivermectin compound was used to achieve different concentrations of drug as previously described. Fully engorged mosquitoes were individually placed into glass tubes and provided with 10% sucrose. Each tube was placed into a Locomotor Activity Monitor (LAM). The LAMs were kept inside an incubator under a constant temperature and a 12:12 h light:dark cycle. The average locomotor activity was calculated as the mean number of movements performed per mosquito in the period considered. Intervals of time assessed were adapted from a previous study. One-way ANOVA tests were performed in order to compare means between groups. Additionally, Dunnett's method was used for post hoc pairwise means comparisons between each group and control. Stata software version 13 was used for the analysis. RESULTS: Anopheles aquasalis showed a nocturnal and bimodal pattern for mosquitoes fed both control blood meals and sub lethal concentrations of ivermectin. In this species, activity peaks occurred at the beginning of the photophase and scotophase in the control group. The nocturnal activity is evident and higher just after the evening peak and maintains basal levels of locomotion throughout the scotophase. In the entire group analysis, locomotor activity means of experimental sets were significantly lower than control for each period of time evaluated. In the survival group, the locomotor activity means of all treatment sets were lower than control mosquitoes for all intervals of time when both the whole period and scotophase were assessed. When the middle of scotophase was evaluated, means were significantly lower for LC15 and LC25, but not LC5. For the beginning of photophase period, significant differences were detected only between control and LC5. When both the photophase and scotophase were assessed alone, no significant differences were found. Mean locomotor activity was significantly lower for dead group when compared to survival group for all experimental sets when whole period, photophase, and scotophase were assessed. CONCLUSIONS: Ivermectin seems to decrease locomotor activity of An. aquasalis at sub-lethal concentrations. The effects on locomotor activity increase according at higher ivermectin concentrations and are most evident during the whole scotophase as well as in the beginning and in the end of this phase, and sub-lethal effects may still be observed in the photophase. Findings presented in this study demonstrate that sub lethal ivermectin effects reduce mosquito locomotor activity, which could diminish vectorial capacity and therefore the malaria transmission. PMID- 29282131 TI - Cybathlon experiences of the Graz BCI racing team Mirage91 in the brain-computer interface discipline. AB - BACKGROUND: In this work, we share our experiences made at the world-wide first CYBATHLON, an event organized by the Eidgenossische Technische Hochschule Zurich (ETH Zurich), which took place in Zurich in October 2016. It is a championship for severely motor impaired people using assistive prototype devices to compete against each other. Our team, the Graz BCI Racing Team MIRAGE91 from Graz University of Technology, participated in the discipline "Brain-Computer Interface Race". A brain-computer interface (BCI) is a device facilitating control of applications via the user's thoughts. Prominent applications include assistive technology such as wheelchairs, neuroprostheses or communication devices. In the CYBATHLON BCI Race, pilots compete in a BCI-controlled computer game. METHODS: We report on setting up our team, the BCI customization to our pilot including long term training and the final BCI system. Furthermore, we describe CYBATHLON participation and analyze our CYBATHLON result. RESULTS: We found that our pilot was compliant over the whole time and that we could significantly reduce the average runtime between start and finish from initially 178 s to 143 s. After the release of the final championship specifications with shorter track length, the average runtime converged to 120 s. We successfully participated in the qualification race at CYBATHLON 2016, but performed notably worse than during training, with a runtime of 196 s. DISCUSSION: We speculate that shifts in the features, due to the nonstationarities in the electroencephalogram (EEG), but also arousal are possible reasons for the unexpected result. Potential counteracting measures are discussed. CONCLUSIONS: The CYBATHLON 2016 was a great opportunity for our student team. We consolidated our theoretical knowledge and turned it into practice, allowing our pilot to play a computer game. However, further research is required to make BCI technology invariant to non-task related changes of the EEG. PMID- 29282132 TI - Design and validation of a disease network of inflammatory processes in the NSG UC mouse model. AB - BACKGROUND: Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC patients: 'acute' and 'remodeling' and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rgammanull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. METHODS: Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. RESULTS: Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNgamma and TGFbeta1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNgamma, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFalpha and IFNgamma mRNA levels. CONCLUSIONS: The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in efficacy and potential mechanistic side effects. PMID- 29282134 TI - Small field dosimetry for the small animal radiotherapy research platform (SARRP). AB - BACKGROUND: Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on board CBCT image guidance. METHODS: In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture. RESULTS: Good agreement (between 1.7 3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time. CONCLUSIONS: FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility. PMID- 29282133 TI - Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease? AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that share genetic risk factors and pathological hallmarks. Intriguingly, these shared factors result in a high rate of comorbidity of these diseases in patients. Intracellular protein aggregates are a common pathological hallmark of both diseases. Emerging evidence suggests that impaired RNA processing and disrupted protein homeostasis are two major pathogenic pathways for these diseases. Indeed, recent evidence from genetic and cellular studies of the etiology and pathogenesis of ALS-FTD has suggested that defects in autophagy may underlie various aspects of these diseases. In this review, we discuss the link between genetic mutations, autophagy dysfunction, and the pathogenesis of ALS-FTD. Although dysfunction in a variety of cellular pathways can lead to these diseases, we provide evidence that ALS-FTD is, in many cases, an autophagy disease. PMID- 29282135 TI - IMPlementation of A Relatives' Toolkit (IMPART study): an iterative case study to identify key factors impacting on the implementation of a web-based supported self-management intervention for relatives of people with psychosis or bipolar experiences in a National Health Service: a study protocol. AB - BACKGROUND: Web-based interventions to support people to manage long-term health conditions are available and effective but rarely used in clinical services. The aim of this study is to identify critical factors impacting on the implementation of an online supported self-management intervention for relatives of people with recent onset psychosis or bipolar disorder into routine clinical care and to use this information to inform an implementation plan to facilitate widespread use and inform wider implementation of digital health interventions. METHODS: A multiple case study design within six early intervention in psychosis (EIP) services in England, will be used to test and refine theory-driven hypotheses about factors impacting on implementation of the Relatives' Education And Coping Toolkit (REACT). Qualitative data including behavioural observation, document analysis, and in-depth interviews collected in the first two EIP services (wave 1) and analysed using framework analysis, combined with quantitative data describing levels of use by staff and relatives and impact on relatives' distress and wellbeing, will be used to identify factors impacting on implementation. Consultation via stakeholder workshops with staff and relatives and co facilitated by relatives in the research team will inform development of an implementation plan to address these factors, which will be evaluated and refined in the four subsequent EIP services in waves 2 and 3. Transferability of the implementation plan to non-participating services will be explored. DISCUSSION: Observation of implementation in a real world clinical setting, across carefully sampled services, in real time provides a unique opportunity to understand factors impacting on implementation likely to be generalizable to other web-based interventions, as well as informing further development of implementation theories. However, there are inherent challenges in investigating implementation without influencing the process under observation. We outline our strategies to ensure our design is transparent, flexible, and responsive to the timescales and activities happening within each service whilst also meeting the aims of the project. TRIAL REGISTRATION: ISCTRN 16267685 (09/03/2016). PMID- 29282136 TI - In vitro biomechanical testing of the 3.5 mm LCP in torsion: a comparison of unicortical locking to bicortical nonlocking screws placed nearest the fracture gap. AB - OBJECTIVE: This biomechanical study compared the torsional strength and stiffness of a locking compression plate with all locking versus nonlocking screws and examined the effect of placing a locking unicortical or nonlocking bicortical screw nearest the fracture gap in a synthetic bone model. RESULTS: Synthetic bone models simulating a diaphyseal fracture without anatomic reduction were tested using four screw configurations: all bicortical locking (ABL), all bicortical nonlocking (ABN), a hybrid construct with a bicortical nonlocking screw nearest the fracture gap (BN), and a unicortical locking screw placed nearest the fracture gap (UL). Torsional stiffness, rotation and torque at failure were compared via ANOVA and post hoc pairwise comparisons (p < 0.05). ABN and BN had the highest stiffness (p < 0.01) with ABL greater than UL (p < 0.01). Rotation at failure was greatest for ABL (p < 0.01) with UL greater than ABN (p < 0.05). Unicortical locking screws nearest the fracture gap decreased stiffness, without significantly affecting torque or rotation at failure. Construct stiffness was found to exist in a very narrow range of 0.9-1.2 N m/deg with standard deviations of 0.1 N m/deg in all cases. The results of this study support the use of nonlocking screws in a hybrid construct to increase torsional stiffness. PMID- 29282137 TI - Central obesity and normal-weight central obesity among adults attending healthcare facilities in Buffalo City Metropolitan Municipality, South Africa: a cross-sectional study. AB - BACKGROUND: Central obesity (CO) confers a significant threat on the cardio metabolic health of individuals, independently of overall obesity. Disparities in the measures of fat distribution lead to misclassification of individuals who are at risk of cardio-metabolic diseases. This study sought to determine the prevalence and correlates of central obesity and normal-weight central obesity among adults attending selected healthcare facilities in Buffalo City Metropolitan Municipality (BCMM), South Africa, assess their health risk and examine the association between central obesity and cardio-metabolic diseases among adults with normal weight, measured by body mass index (BMI). METHODS: A cross-sectional survey of 998 adults was carried out at the three largest outpatient clinics in BCMM. Overall and central obesity were assessed using BMI, waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHTR). The WHO STEPwise questionnaire was used for data collection. Blood pressure and blood glucose were measured. Normal-weight central obesity was defined as CO among individuals with normal weight, as assessed by BMI. Health risk levels were assessed using the National Institute for Health and Clinical Excellence (NICE) BMI-WC composite index. Bivariate and multivariate analyses were used to determine the prevalence of CO, normal-weight central obesity and the predictors of CO. RESULTS: The mean age of participants was 42.6 (+/- 16.5) years. The prevalence of CO was 67.0, 58.0 and 71.0% by WC, WHR and WHTR, respectively. The prevalence of normal-weight central obesity was 26.9, 36.9 and 29.5% by WC, WHR and WHTR, respectively. About 41% of the participants had a very high health risk, 13% had increased risk or high risk and 33% had no health risk. Central obesity was significantly associated with hypertension but not associated with diabetes among those with normal weight (by BMI). Female sex, age over 30 years, marriage, secondary or tertiary level of education, non-smoking status, diabetes and hypertension significantly predicted central obesity among the study participants. CONCLUSION: The prevalence of central obesity among the study participants is high, irrespective of the defining criteria. One in three adults of normal weight had central obesity. Body mass index should therefore not be used alone for clinical assessment by healthcare workers in the study setting. PMID- 29282138 TI - The medial femoral wall can play a more important role in unstable intertrochanteric fractures compared with lateral femoral wall: a biomechanical study. AB - BACKGROUND: The major objective of the present study is to investigate the differences in the load and strain changes in the intertrochanteric region of human cadaveric femora between the loss of medial or lateral wall and after treatment with proximal femoral nail antirotation (PFNA). METHODS: After measuring the geometry of the proximal femur region and modeling the medial or lateral wall defect femoral models, six pairs of freshly frozen human femora were randomly assigned in the medial or lateral wall group. According to a single-leg stance model, an axial loading was applied, and the strain distribution was measured before and after PFNA implantation. The strains of each specimen were recorded at load levels of 350, 700, and 1800 N and the failure load. Paired t test was performed to assess the differences between two groups. RESULTS: The failure mode of almost all defect model femora was consistent with that of the simulated type of intertrochanteric fractures. After the PFNA implantation, the failure mode of almost all stabilized femora was caused by new lateral wall fractures. The failure load of the lateral wall group for defect model femora was significantly higher than that of the medial wall group (p < 0.001). However, the difference disappeared after the PFNA was implanted (p = 0.990). The axial stiffness in all defect model femora showed the same results (p < 0.001). After the PFNA implantation, the axial stiffness of the lateral wall group remained higher than that of the medial wall group (p = 0.001). However, the axial stiffness of the lateral wall group showed that the femora removed from the lateral wall were higher than the PFNA-stabilized femora (p = 0.020). For the axial strain in the anterior wall after the PFNA implantation, the strain of the lateral wall group was significantly lower than that of the medial group (p = 0.003). Nevertheless, for the axial strain of the posterior wall after the PFNA implantation, the strain of the medial wall group was significantly lower than that of the lateral group (p < 0.001). CONCLUSIONS: In summary, this study demonstrated that PFNA is an effective intramedullary fixation system for treating unstable intertrochanteric fractures. Compared with the lateral wall, the medial femoral wall is a more important part in the intertrochanteric region. We suggest that in treating intertrochanteric femoral fractures with medial wall fractures, the medial wall fragment should be reset and fixed as much as possible. PMID- 29282140 TI - Correction to: Neuropsychological and internalizing problems in acute central nervous system infections: a 1 year follow-up. AB - CORRECTION: The original article [1] contained an error mistakenly carried forward by the Production department handling this article whereby all authors' names were incorrectly inverted. The original article has now been corrected to reflect the correct names of all authors. PMID- 29282139 TI - Effective radiotherapeutic treatment intensification in patients with pancreatic cancer: higher doses alone, higher RBE or both? AB - Pancreatic cancer, especially in case of locally advanced stage has a poor prognosis. Radiotherapy in general can lead to tumor volume reduction, but further improvements, such as ion beam therapy have to be promoted in order to enable dose escalation, which in turn results in better local control rates and downsizing of the tumor itself. Ion beam therapy with its highly promising physical properties is also accompanied by distinct inter- and intrafractional challenges in case of robustness. First clinical results are promising, but further research in motion mitigation and biological treatment planning is necessary, in order to determine the best clinical rationales and conditions of ion beam therapy of pancreatic cancer. This review summarizes the current knowledge and studies on ion beam therapy of pancreatic cancer. PMID- 29282141 TI - Laparoscopic intersphincteric resection versus an open approach for low rectal cancer: a meta-analysis. AB - AIM: The aim of this study was to compare the short-term and mid-term effects of laparoscopic intersphincteric resection with the conventional open approach for patients with low rectal cancer through a meta-analysis. METHODS: The PubMed, EMBASE, Cochrane, and Ovid databases were searched for eligible studies until March 2017. Operation time, blood loss, circumferential resection margin-positive rate, distal margin length, number of resected lymph nodes, diverting stoma rate, postoperative overall morbidity, anastomotic leakage, and hospital stay were the main short-term effect endpoints. We also examined disease-free survival, overall survival, local recurrence, and post-operational anal function as secondary outcomes to evaluate the mid-term effects of laparoscopic surgery. RESULTS: Five studies involving 620 patients were included in the analyses. Compared with the open approach, the laparoscopic ISR had less blood loss (weighted mean difference [WMD] = - 214.65 ml, 95% CI [- 370.44, - 196.13], p < 0.01), less postoperative overall morbidity (OR = 0.58, 95% CI [0.40, 0.86], p < 0.01), and shorter duration of hospital stay (WMD = - 5.87 days, 95% CI [- 11.35, - 0.40], p < 0.05); however, the operation time was significantly longer in the laparoscopic group (WMD = 47.34 min, 95% CI [4.10, 90.58], p < 0.05). No other significant differences were observed. CONCLUSION: Laparoscopic ISR for low rectal cancer offers fewer complications and faster recovery, with similar operation quality and mid-term oncological results than the conventional approach. Although this technique is comparatively more complex than the conventional approach and requires practice, laparoscopic ISR shows great potential as a surgical option and deserves further clinical study. PMID- 29282142 TI - Promoting Recruitment using Information Management Efficiently (PRIME): a stepped wedge, cluster randomised trial of a complex recruitment intervention embedded within the REstart or Stop Antithrombotics Randomised Trial. AB - BACKGROUND: Few interventions are proven to increase recruitment in clinical trials. Recruitment to RESTART, a randomised controlled trial of secondary prevention after stroke due to intracerebral haemorrhage, has been slower than expected. Therefore, we sought to investigate an intervention to boost recruitment to RESTART. METHODS/DESIGN: We conducted a stepped-wedge, cluster randomised trial of a complex intervention to increase recruitment, embedded within the RESTART trial. The primary objective was to investigate if the PRIME complex intervention (a recruitment co-ordinator who conducts a recruitment review, provides access to bespoke stroke audit data exports, and conducts a follow-up review after 6 months) increases the recruitment rate to RESTART. We included 72 hospital sites located in England, Wales, or Scotland that were active in RESTART in June 2015. All sites began in the control state and were allocated using block randomisation stratified by hospital location (Scotland versus England/Wales) to start the complex intervention in one of 12 different months. The primary outcome was the number of patients randomised into RESTART per month per site. We quantified the effect of the complex intervention on the primary outcome using a negative binomial, mixed model adjusting for site, December/January months, site location, and background time trends in recruitment rate. RESULTS: We recruited and randomised 72 sites and recorded their monthly recruitment to RESTART over 24 months (March 2015 to February 2017 inclusive), providing 1728 site-months of observations for the primary analysis. The adjusted rate ratio for the number of patients randomised per month after allocation to the PRIME complex intervention versus control time before allocation to the PRIME complex intervention was 1.06 (95% confidence interval 0.55 to 2.03, p = 0.87). Although two thirds of respondents to the 6-month follow-up questionnaire agreed that the audit reports were useful, only six patients were reported to have been randomised using the audit reports. Respondents frequently reported resource and time pressures as being key barriers to running the audit reports. CONCLUSION: The PRIME complex intervention did not significantly improve the recruitment rate to RESTART. Further research is needed to establish if PRIME might be beneficial at an earlier stage in a prevention trial or for prevention dilemmas that arise more often in clinical practice. PMID- 29282143 TI - Azithromycin versus placebo for the treatment of HIV-associated chronic lung disease in children and adolescents (BREATHE trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Human immunodeficiency virus (HIV)-related chronic lung disease (CLD) among children is associated with substantial morbidity, despite antiretroviral therapy. This may be a consequence of repeated respiratory tract infections and/or dysregulated immune activation that accompanies HIV infection. Macrolides have anti-inflammatory and antimicrobial properties, and we hypothesised that azithromycin would reduce decline in lung function and morbidity through preventing respiratory tract infections and controlling systemic inflammation. METHODS/DESIGN: We are conducting a multicentre (Malawi and Zimbabwe), double blind, randomised controlled trial of a 12-month course of weekly azithromycin versus placebo. The primary outcome is the mean change in forced expiratory volume in 1 second (FEV1) z-score at 12 months. Participants are followed up to 18 months to explore the durability of effect. Secondary outcomes are FEV1 z score at 18 months, time to death, time to first acute respiratory exacerbation, number of exacerbations, number of hospitalisations, weight for age z-score at 12 and 18 months, number of adverse events, number of malaria episodes, number of bloodstream Salmonella typhi infections and number of gastroenteritis episodes. Participants will be followed up 3-monthly, and lung function will be assessed every 6 months. Laboratory substudies will be done to investigate the impact of azithromycin on systemic inflammation and on development of antimicrobial resistance as well as impact on the nasopharyngeal, lung and gut microbiome. DISCUSSION: The results of this trial will be of clinical relevance because there are no established guidelines on the treatment and management of HIV-associated CLD in children in sub-Saharan Africa, where 80% of the world's HIV-infected children live and where HIV-associated CLD is highly prevalent. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02426112 . Registered on 21 April 2015. PMID- 29282144 TI - Family level variation in Wolbachia-mediated dengue virus blocking in Aedes aegypti. AB - BACKGROUND: The mosquito vector Aedes aegypti is responsible for transmitting a range of arboviruses including dengue (DENV) and Zika (ZIKV). The global reach of these viruses is increasing due to an expansion of the mosquito's geographic range and increasing urbanization and human travel. Vector control remains the primary means for limiting these diseases. Wolbachia pipientis is an endosymbiotic bacterium of insects that has the ability to block the replication of pathogens, including flaviviruses such as DENV or ZIKV, inside the body of the vector. A strain of Wolbachia called wMel is currently being released into wild mosquito populations to test its potential to limit virus transmission to humans. The mechanism that underpins the virus blocking effect, however, remains elusive. METHODS: We used a modified full-sib breeding design in conjunction with vector competence assays in wildtype and wMel-infected Aedes aegypti collected from the field. All individuals were injected with DENV-2 intrathoracically at 5-6 days of age. Tissues were dissected 7 days post-infection to allow quantification of DENV and Wolbachia loads. RESULTS: We show the first evidence of family level variation in Wolbachia-mediated blocking in mosquitoes. This variation may stem from either genetic contributions from the mosquito and Wolbachia genomes or environmental influences on Wolbachia. In these families, we also tested for correlations between strength of blocking and expression level for several insect immunity genes with possible roles in blocking, identifying two genes of interest (AGO2 and SCP-2). CONCLUSIONS: In this study we show variation in Wolbachia mediated DENV blocking in Aedes aegypti that may arise from genetic contributions and environmental influences on the mosquito-Wolbachia association. This suggests that Wolbachia-mediated blocking may have the ability to evolve through time or be expressed differentially across environments. The long-term efficacy of Wolbachia in the field will be dependent on the stability of blocking. Understanding the mechanism of blocking will be necessary for successful development of strategies that counter the emergence of evolved resistance or variation in its expression under diverse field conditions. PMID- 29282145 TI - Parenteral nutrition during neoadjuvant chemotherapy for patients with non metastatic gastric or esophago-gastric cancer to reduce postoperative morbidity (PERCOG): study protocol for a randomized controlled trial. AB - BACKGROUND: The majority of patients with gastric or esophago-gastric cancer are at risk for malnutrition. Preoperative malnutrition was shown to increase the incidence of postoperative complications following abdominal surgery. However, it remains unclear if preoperative parenteral nutritional support during neoadjuvant chemotherapy (NACT) may be effective to reduce the rate of postoperative complications in these patients. METHODS/DESIGN: The PERCOG trial is a randomized controlled multicenter observer-blinded trial, investigating if the improvement of the general condition of patients with non-metastasized gastric cancer or cancer of the esophago-gastric junction during NACT by supplemental parenteral nutrition can decrease the postoperative Comprehensive Complication Index (CCI). Statistical analysis of the primary endpoint measure (CCI on postoperative day 30) will be based on the intention-to-treat population. The global level of significance is set at 5% and the sample size (n = 150) is determined to assure a power of 80%. DISCUSSION: The results of the PERCOG trial will provide high-level evidence for clinical recommendations regarding the administration of preoperative supportive parenteral nutrition and provide all participating patients the opportunity of an improved treatment. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00009451 . Registered on 3 July 2017. PMID- 29282146 TI - Do we know enough to recommend corticosteroids in acute respiratory distress syndrome? PMID- 29282147 TI - Spina bifida cystica and severe congenital bilateral talipes equinovarus in one twin of a monoamniotic pair: a case report. AB - BACKGROUND: Spina bifida and congenital talipes equinovarus (CTEV) are common congenital malformations which may occur together and increase morbidity. Monozygous twins are particularly at risk of these malformations and discordance in one type of malformation is typical. The occurrence of both spina bifida and CTEV in one twin of a monozygotic pair is rare. CASE PRESENTATION: A 22 year-old Cameroonian primigravida at 36 weeks of a twin gestation was received in our district hospital at the expulsive phase of labour on a background of sub-optimal antenatal care. A caesarean section indicated for cephalo-pelvic disproportion was performed and life monoamniotic male twins were extracted. The first twin was normal. The second twin had spina bifida cystica and severe bilateral CTEV. Routine postnatal care was ensured and at day 2 of life, the affected twin was evacuated to a tertiary hospital for proper management. He was later on reported dead from complications of hydrocephalus. CONCLUSIONS: Spina bifida cystica with severe bilateral CTEV in one twin of a monoamniotic pair illustrates the complexity in the interplay of causal factors of these malformations even among monozygotic twins who are assumed to share similar genetic and environmental features. The occurrence and poor outcome of the malformations was probably potentiated by poor antenatal care. With postnatal diagnoses, a better outcome was difficult to secure even with prompt referral. Early prenatal diagnoses and appropriate counseling of parents are cardinal. PMID- 29282148 TI - Acanthamoeba-mediated cytopathic effect correlates with MBP and AhLBP mRNA expression. AB - BACKGROUND: In recent years, the concern of Acanthamoeba keratitis has increased since the infection is often associated with contact lens use. Partial 18S rRNA genotypic identification of Acanthamoeba isolates is important to correlate with pathophysiological properties in order to evaluate the degree of virulence. This is the first report of genotypic identification for clinical isolates of Acanthamoeba from corneal scrapings of keratitis in Malaysia. This study is also the first to correlate the mRNA expression of MBP and AhLBP as virulent markers for axenic strains of Acanthamoeba. RESULTS: In this study, ten clinical isolates were obtained from corneal scrapings. Rns genotype and intra-genotypic variation at the DF3 region of the isolates were identified. Results revealed that all clinical isolates belonged to the T4 genotype, with T4/6 (4 isolates), T4/2 (3 isolates), T4/16 (2 isolates) and one new genotype T4 sequence (T4/36), being determined. The axenic clinical isolates were cytopathogenic to rabbit corneal fibroblasts. MBP and AhLBP mRNA expression are directly correlated to Acanthamoeba cytopathic effect. CONCLUSIONS: All ten Malaysian clinical isolates were identified as genotype T4 which is predominantly associated with AK. Measuring the mRNA expression of Acanthamoeba virulent markers could be useful in the understanding of the pathogenesis of Acanthamoeba keratitis. PMID- 29282149 TI - The effect of angiotensin II on blood pressure in patients with circulatory shock: a structured review of the literature. AB - BACKGROUND: Circulatory shock is a common syndrome with a high mortality and limited therapeutic options. Despite its discovery and use in clinical and experimental settings more than a half-century ago, angiotensin II (Ang II) has only been recently evaluated as a vasopressor in distributive shock. We examined existing literature for associations between Ang II and the resolution of circulatory shock. METHODS: We searched PubMed, MEDLINE, Ovid, and Embase to identify all English literature accounts of intravenous Ang II in humans for the treatment of shock (systolic blood pressure [SBP] <= 90 mmHg or a mean arterial pressure [MAP] <= 65 mmHg), and hand-searched the references of extracted papers for further studies meeting inclusion criteria. Of 3743 articles identified, 24 studies including 353 patients met inclusion criteria. Complete data existed for 276 patients. Extracted data included study type, publication year, demographics, type of shock, dosing of Ang II or other vasoactive medications, and changes in BP, lactate, and urine output. BP effects were grouped according to type of shock, with additional analyses completed for patients with absent blood pressure. Shock was distributive (n = 225), cardiogenic (n = 38), or from other causes (n = 90). Blood pressure as absent in 18 patients. RESULTS: For the 276 patients with complete data, MAP rose by 23.4% from 63.3 mmHg to 78.1 mmHg in response to Ang II (dose range: 15 ng/kg/min to 60 mcg/min). SBP rose by 125.2% from 56.9 mmHg to 128.2 mmHg (dose range: 0.2 mcg/min to a 1500 mcg bolus). A total of 271 patients with complete data were determined to exhibit a BP effect which was directly associated with Ang II. Subgroups (patients with cardiogenic, septic, and other types of shock) exhibited similar increases in BP. In patients with absent BP, deemed to be cardiac arrest, return of spontaneous circulation (ROSC) was achieved, and BP increased by an average of 107.3 mmHg in 11 of 18 patients. The remaining seven patients with cardiac arrest did not respond. CONCLUSIONS: Intravenous Ang II is associated with increased BP in patients with cardiogenic, distributive, and unclassified shock. A role may exist for Ang II in restoring circulation in cardiac arrest. PMID- 29282150 TI - Photoperiodic responses of Sahelian malaria mosquitoes Anopheles coluzzii and An. arabiensis. AB - BACKGROUND: Throughout large parts of sub-Saharan Africa, seasonal malaria transmission follows mosquito density, approaching zero during the dry season and peaking during the wet season. The mechanisms by which malaria mosquitoes survive the long dry season, when no larval sites are available remain largely unknown, despite being long recognized as a critical target for vector control. Previous work in the West African Sahel has led to the hypothesis that Anopheles coluzzii (formerly M-form Anopheles gambiae) undergoes aestivation (dry-season diapause), while Anopheles gambiae (s.s.) (formerly S-form An. gambiae) and Anopheles arabiensis repopulate each wet season via long-distance migration. The environmental cues used by these species to signal the oncoming dry season have not been determined; however, studies, mostly addressing mosquitoes from temperate zones, have highlighted photoperiod and temperature as the most common token stimuli for diapause initiation. We subjected newly established colonies of An. coluzzii and An. arabiensis from the Sahel to changes in photoperiod to assess and compare their responses in terms of longevity and other relevant phenotypes. RESULTS: Our results showed that short photoperiod alone and to a lesser extent, lower nightly temperature (representing the early dry season), significantly increased longevity of An. coluzzii (by ~30%, P < 0.001) but not of An. arabiensis. Further, dry season conditions increased body size but not relative lipid content of An. coluzzii, whereas body size of An. arabiensis decreased under these conditions. CONCLUSIONS: These species-specific responses underscore the capacity of tropical anophelines to detect mild changes (~1 h) in photoperiod and thus support the role of photoperiod as a token stimulus for An. coluzzii in induction of aestivation, although, these responses fall short of a complete recapitulation of aestivation under laboratory conditions. PMID- 29282151 TI - The changing face of clinical trials in the personalized medicine and immuno oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017). AB - In the past decade, the oncology community has witnessed major advances in the understanding of cancer biology and major breakthroughs in several different therapeutic areas, from solid tumors to hematological malignancies; moreover, the advent of effective immunotherapy approaches, such as immune-checkpoint blockade, is revolutionizing treatment algorithms in almost all oncology disease areas. As knowledge evolves and new weapons emerge in the "war against cancer", clinical and translational research need to adapt to a rapidly changing environment to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients.With this in mind, translational cancer researchers, oncology professionals, treatment experts, CRO and industry leaders, as well as patient representatives gathered in London, 16-17 March 2017, for The International Congress on Clinical Trials in Oncology and Hemato-Oncology (ICTO2017), to discuss the changing face of oncology clinical trials in the new era of personalized medicine and immuno-oncology. A wide range of topics, including clinical trial design in immuno-oncology, biomarker-oriented drug development paths, statistical design and endpoint selection, challenges in the design and conduct of personalized medicine clinical trials, risk-based monitoring, financing and reimbursement, as well as best operational practices, were discussed in an open, highly interactive format, favoring networking among all relevant stakeholders. The most relevant data, approaches and issues emerged and discussed during the conference are summarized in this report. PMID- 29282152 TI - Safety and efficacy of inspiratory muscle training for preventing adverse outcomes in patients at risk of prolonged hospitalisation. AB - BACKGROUND: The early institution of inspiratory muscle training on hospitalised patients with no established respiratory deficits could prevent in-hospital adverse outcomes that are directly or indirectly associated to the loss of respiratory muscle mass inherent to a prolonged hospital stay. The objective of the clinical trial is to assess the impact of inspiratory muscle training on hospital inpatient complications. METHODS: This is a double-blind randomised controlled trial. Subjects in the intervention group underwent an inspiratory muscle training loaded with 50% maximum inspiratory pressure twice daily for 4 weeks from study enrolment. Patients were randomly assigned to an inspiratory muscle training group or a sham inspiratory muscle training group. All patients received conventional physiotherapy interventions. Baseline and post-intervention respiratory and peripheral muscle strength, functionality (performance of activities of daily living), length of hospital stay, and death were evaluated. Clinical outcomes were assessed until hospital discharge. This study was approved by the Institutional Hospital Ethics Committee (03/2014). RESULTS: Thirty-one patients assigned to the inspiratory muscle training group and 34 to the sham inspiratory muscle training group were analysed. Patients in the inspiratory muscle training group had a shorter mean length of hospital stay (35.3 +/- 2.7 vs. 41.8 +/- 3.5 days, p < 0.01) and a lower risk of endotracheal intubation (relative risk (RR) = 0.36; 95% confidence interval (CI) 0.27-0.97; p = 0.03) as well as muscle weakness (RR = 0.36; 95% CI 0.19-0.98; p = 0.02) and mortality (RR = 0.23; 95% CI 0.2-0.94; p = 0.04). The risk of adverse events did not differ significantly between groups. CONCLUSION: Inspiratory muscle training was a protective factor against endotracheal intubation, muscle weakness, and mortality. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02459444 . Registered on 19 May 2015. PMID- 29282153 TI - Under control: how a dietary additive can restore the gut microbiome and proteomic profile, and improve disease resilience in a marine teleostean fish fed vegetable diets. AB - BACKGROUND: The constant increase of aquaculture production and wealthy seafood consumption has forced the industry to explore alternative and more sustainable raw aquafeed materials, and plant ingredients have been used to replace marine feedstuffs in many farmed fish. The objective of the present study was to assess whether plant-based diets can induce changes in the intestinal mucus proteome, gut autochthonous microbiota and disease susceptibility of fish, and whether these changes could be reversed by the addition of sodium butyrate to the diets. Three different trials were performed using the teleostean gilthead sea bream (Sparus aurata) as model. In a first preliminary short-term trial, fish were fed with the additive (0.8%) supplementing a basal diet with low vegetable inclusion (D1) and then challenged with a bacteria to detect possible effects on survival. In a second trial, fish were fed with diets with greater vegetable inclusion levels (D2, D3) and the long-term effect of sodium butyrate at a lower dose (0.4%) added to D3 (D4 diet) was tested on the intestinal proteome and microbiome. In a third trial, the long-term effectiveness of sodium butyrate (D4) to prevent disease outcome after an intestinal parasite (Enteromyxum leei) challenge was tested. RESULTS: The results showed that opposed forces were driven by dietary plant ingredients and sodium butyrate supplementation in fish diet. On the one hand, vegetable diets induced high parasite infection levels that provoked drops in growth performance, decreased intestinal microbiota diversity, induced the dominance of the Photobacterium genus, as well as altered the gut mucosal proteome suggesting detrimental effects on intestinal function. On the other hand, butyrate addition slightly decreased cumulative mortality after bacterial challenge, avoided growth retardation in parasitized fish, increased intestinal microbiota diversity with a higher representation of butyrate producing bacteria and reversed most vegetable diet-induced changes in the gut proteome. CONCLUSIONS: This integrative work gives insights on the pleiotropic effects of a dietary additive on the restoration of intestinal homeostasis and disease resilience, using a multifaceted approach. PMID- 29282154 TI - Using incentives to recruit physicians into behavioral trials: lessons learned from four studies. AB - OBJECTIVE: To describe lessons learned from the use of different strategies for recruiting physicians responsible for trauma triage, we summarize recruitment data from four behavioral trials run in the United States between 2010 and 2016. RESULTS: We ran a series of behavioral trials with the primary objective of understanding the influence of heuristics on physician decision making in trauma triage. Three studies were observational; one tested an intervention. The trials used different methods of recruitment (in-person vs. email), timing of the honorarium (pre-paid vs. conditional on completion), type of honorarium [a $100 gift card (monetary reward) vs. an iPad mini 2 (material incentive)], and study tasks (a vignette-based questionnaire, virtual simulation, and intervention plus virtual simulation). We recruited 989 physicians, asking each to complete a questionnaire or virtual simulation online. Recruitment and response rates were 80% in the study where we approached physicians in person, used a pre-paid material incentive, and required that they complete both an intervention plus a virtual simulation. They were 56% when we recruited physicians via email, used a monetary incentive conditional on completion of the task, and required that they complete a vignette-based questionnaire. Trial registration clinicaltrials.gov; NCT02857348. PMID- 29282155 TI - Choreoathetosis - an unusual adverse effect of dihydroartemisinin-piperaquine: a case report. AB - BACKGROUND: Dihydroartemisinin-piperaquine is a combination of dihydroartemisinin and piperaquine which is highly effective in the treatment of uncomplicated falciparum malaria. Its adverse effects are generally tolerable and temporary. Choreoathetosis, an involuntary movement disorder characterized by continuous irregular twisting of the body, is not a documented adverse effect of this medication. CASE PRESENTATION: A 41-year-old Cameroonian man of black African ethnicity was brought to our primary care hospital because over the previous 6 hours he had been experiencing involuntary twisting movements of his body and he no longer had control of his limbs. Earlier that day, he had been prescribed an appropriate dose of dihydroartemisinin-piperaquine in our hospital. The abnormal movements started approximately 3 hours after ingesting the first dose of the drug. The review of systems and his past history were unremarkable. On clinical examination, he was conscious and oriented but was unsteady and displayed continuous generalized irregular twisting movements combined with abrupt low amplitude flinging of his limbs. Dihydroartemisinin-piperaquine-induced generalized choreoathetosis was diagnosed. He was sedated with diazepam and dihydroartemisinin-piperaquine was discontinued. The antimalarial drug was substituted with artemether-lumefantrine combination. The clinical progress was good and he was discharged home after 72 hours. No further abnormalities were noted during 7 months of follow-up. CONCLUSION: Although dihydroartemisinin piperaquine is increasingly popular as a well-tolerated/efficacious antimalarial drug, clinicians must note the rare possibility of choreoathetosis as an adverse effect of this medication and educate patients accordingly. PMID- 29282157 TI - Impact of black soldier fly larvae meal on the chemical and nutritional characteristics of rainbow trout fillets. AB - The present research studied the effect of a dietary inclusion with Hermetia illucens larvae meal (Hi) on rainbow trout's fillets chemical composition. The effect of Hi inclusion in diets on rainbow trout chemical characteristics was evaluated. Trout were fed three different diets: control (C, no Hi inclusion), 25% and 50% of substitution of fish meal with Hi (Hi25 and Hi50, respectively). Fillets were analysed to quantify proximate composition, carbohydrates percentage, colour parameters, nucleotides concentration, fatty acids profile, volatile organic compounds (VOCs) and myofibrillar and sarcoplasmic concentrations. Diets did not affect proximate composition. Contrariwise, Hi50 diet decreased fillet yellowness and both substitution percentages affected negatively adenosine monophosphate concentration. Saturated fatty acids, mostly C12 : 0, increased their contents in relation with Hi inclusion at the expense of monounsaturated and polyunsaturated (both n-3 and n-6) fatty acids. Less modifications were reported in VOCs as only heptanal and octanal concentrations were affected, no new compounds appeared in relation with Hi inclusion. No modifications in proteins patterns were shown even if myofibrillar content decreased in trout fed Hi50. The results highlighted that chemical modifications occurred in fillets were related to the chemical composition of the H. illucens meal and to the percentage of inclusion in the diet. Substitution of fish meal with a precisely percentage of H. illucens meal could be a potential future solution in order to decrease the quantity of fish meal used in aquafeeds. PMID- 29282156 TI - Examining cancer survivorship trajectories: Exploring the intersection between qualitative illness narratives and quantitative screening instruments. AB - OBJECTIVE: This article examines the associations of quantitatively refined trajectories of adjustment to cancer survivorship determined by previously published qualitative narrative analysis. METHOD: Patients completed measures of cancer-related worry (Cancer Related Worries Scale), depression (Patient Health Questionnaire-9), posttraumatic growth (Benefit Finding Scale), and open-ended survey questions 6, 12, and 18 months postdiagnosis of head and neck, esophageal, gastric, or colorectal cancer. Previously published narrative analysis revealed five distinct survivorship "paths," which were combined into four paths in the present article: Moving On, Seeing the World Differently, Taking One Day at a Time, and Never the Same. To determine the association of qualitatively determined paths with quantitatively assessed adjustment (i.e., Cancer Related Worries Scale, Patient Health Questionnaire-9, Benefit Finding Scale), we used linear multilevel modeling to regress the adjustment variables on time, path, the time-by-path interaction, and relevant covariates (age, stage, cancer site, ethnicity, and Deyo score). RESULTS: There was a significant main effect of path on cancer worry, depression, and posttraumatic growth (p < 0.02 for all). Patients in the Moving On group reported consistently low worry, depression, and growth compared to the other groups. Patients in the Seeing the World Differently and Taking One Day at a Time paths both reported moderate worry and depression; but those in the Seeing the World Differently path reported the highest posttraumatic growth, whereas patients in the Taking One Day at a Time path reported little growth. Finally, patients in the Never the Same path reported the highest worry and depression but lowest posttraumatic growth. Significance of results This longitudinal study reinforces the notion that cancer survivorship is not a one-size-fits-all experience nor a dichotomized experience of "distress" or "no distress." Additionally, this hypothesis-generating study suggests future directions for potential self-report measures to help clinicians identify cancer survivors' trajectory to develop a more patient-centered survivorship care plan. PMID- 29282158 TI - A Randomized Trial to Determine Whether Wearing Short-Sleeved White Coats Reduces the Risk for Pathogen Transmission. PMID- 29282159 TI - Twins as Participants in Randomized Controlled Trials: A Review of Published Literature. AB - Monozygotic (MZ) and dizygotic (DZ) twins participate in research that partitions variance in health, disease, and behavior into genetic and environmental components. However, there are other innovative roles for twins in medical research. One such way is involving MZ and/or DZ twins in co-twin control designed randomized controlled trials (RCTs). To our knowledge, no reviews have been conducted that summarizes the involvement of twins in RCTs. Therefore, we conducted a systematic literature search using the U.S. Clinical Trials Database, NHS electronic databases, MEDLINE, EMBASE, and PsychINFO for RCTs on publications involving MZ and/or DZ twins as RCT participants. Out of the 186,027 clinical trials registered in the U.S. clinical trial register ClinicaTrails.gov, only six RCTs used twins as participants. From 1,598 articles identified in our search, 50 peer-reviewed English language publications met our pre-defined inclusion criteria. Sample sizes for RCTs have ranged from a total number of participants from 2 to 1,162; however, 32 (64%) studies had a sample size of 100 or less, and of those, 12 (24%) had fewer than 10. Both MZ and DZ twins have been recruited to the RCTs. In most instances (33/50) each twin from a pair were assigned to different study arms. Most of those studies included MZ twins only. Despite the methodological advantages, the use of MZ and DZ twins as participants in interventional RCTs appeared limited. The continuous development of innovative twin designs, especially RCTs, indicates that twin research can extend beyond the more widely recognized heritability estimates. PMID- 29282160 TI - Emotion Recognition Correlates With Social-Neuropsychiatric Dysfunction in Huntington's Disease. AB - OBJECTIVES: People with Huntington's disease (HD) experience poor social quality of life, relationship breakdown, and social withdrawal, which are mediated to some extent by socially debilitating neuropsychiatric symptoms, such as apathy and disinhibition. Social cognitive symptoms, such as impaired emotion recognition, also occur in HD, however, the extent of their association with these socially debilitating neuropsychiatric symptoms is unknown. Our study examined the relationship between emotion recognition and symptom ratings of apathy and disinhibition in HD. METHODS: Thirty-two people with premanifest or symptomatic-HD completed Part 1 of The Awareness of Social Inference Test (TASIT), which is a facial emotion recognition task. In addition, we obtained severity ratings for apathy and disinhibition on the Frontal Systems Behavior Scale (FrSBe) from a close family member. Our analyses used motor symptom severity as a proxy for disease progression. RESULTS: Emotion recognition performance was significantly associated with family-ratings of apathy, above and beyond their shared association with disease severity. We found a similar pattern for disinhibition ratings, which fell short of statistical significance. As expected, worse emotion recognition performance was correlated with higher severity in FrSBe symptom ratings. CONCLUSIONS: Our findings suggest that emotion recognition abilities relate to key socially debilitating neuropsychiatric symptoms in HD. Our results help to understand the functional significance of emotion recognition impairments in HD, and may have implications for the development of remediation programs aimed at improving patients' social quality of life. (JINS, 2018, 24, 417-423). PMID- 29282161 TI - Generalisation of fear in PTSD related to prolonged childhood maltreatment: an experimental study. AB - BACKGROUND: Fear responses are particularly intense and persistent in post traumatic stress disorder (PTSD), and can be evoked by unspecific cues that resemble the original traumatic event. Overgeneralisation of fear might be one of the underlying mechanisms. We investigated the generalisation and discrimination of fear in individuals with and without PTSD related to prolonged childhood maltreatment. METHODS: Sixty trauma-exposed women with (N = 30) and without (N = 30) PTSD and 30 healthy control participants (HC) underwent a fear conditioning and generalisation paradigm. In a contingency learning procedure, one of two circles of different sizes was associated with an electrical shock (danger cue), while the other circle represented a safety cue. During generalisation testing, online risk ratings, reaction times and fear-potentiated startle were measured in response to safety and danger cues as well as to eight generalisation stimuli, i.e. circles of parametrically varying size creating a continuum of similarity between the danger and safety cue. RESULTS: The increase in reaction times from the safety cue across the different generalisation classes to the danger cue was less pronounced in PTSD compared with HC. Moreover, PTSD participants expected higher risk of an aversive event independent of stimulus types and task. CONCLUSIONS: Alterations in generalisation constitute one part of fear memory alterations in PTSD. Neither the accuracy of a risk judgement nor the strength of the induced fear was affected. Instead, processing times as an index of uncertainty during risk judgements suggested a reduced differentiation between safety and threat in PTSD. PMID- 29282162 TI - Integrated regulatory network reveals novel candidate regulators in the development of negative energy balance in cattle. AB - Negative energy balance (NEB) is an altered metabolic state in modern high yielding dairy cows. This metabolic state occurs in the early postpartum period when energy demands for milk production and maintenance exceed that of energy intake. Negative energy balance or poor adaptation to this metabolic state has important effects on the liver and can lead to metabolic disorders and reduced fertility. The roles of regulatory factors, including transcription factors (TFs) and micro RNAs (miRNAs) have often been separately studied for evaluating of NEB. However, adaptive response to NEB is controlled by complex gene networks and still not fully understood. In this study, we aimed to discover the integrated gene regulatory networks involved in NEB development in liver tissue. We downloaded data sets including mRNA and miRNA expression profiles related to three and four cows with severe and moderate NEB, respectively. Our method integrated two independent types of information: module inference network by TFs, miRNAs and mRNA expression profiles (RNA-seq data) and computational target predictions. In total, 176 modules were predicted by using gene expression data and 64 miRNAs and 63 TFs were assigned to these modules. By using our integrated computational approach, we identified 13 TF-module and 19 miRNA-module interactions. Most of these modules were associated with liver metabolic processes as well as immune and stress responses, which might play crucial roles in NEB development. Literature survey results also showed that several regulators and gene targets have already been characterized as important factors in liver metabolic processes. These results provided novel insights into regulatory mechanisms at the TF and miRNA levels during NEB. In addition, the method described in this study seems to be applicable to construct integrated regulatory networks for different diseases or disorders. PMID- 29282163 TI - Development and evaluation of a six-day training program in supportive oncology research. AB - OBJECTIVE: Early career investigators have few opportunities for targeted training in supportive oncology research. To address this need, we developed, implemented, and evaluated an intensive, six-day workshop on methods in supportive oncology research for trainees and junior faculty across multiple disciplines. METHOD: A multidisciplinary team of supportive oncology researchers developed a workshop patterned after the clinical trials workshop offered jointly by the American Society of Clinical Oncology and American Association of Cancer Research. The curriculum included lectures and a mentored experience of writing a research protocol. Each year since 2015, the workshop has accepted and trained 36 early career investigators. Over the course of the workshop, participants present sections of their research protocols daily in small groups led by senior researchers, and have dedicated time to write and revise these sections. Primary outcomes for the workshop included the frequency of completed protocols by the end of the workshop, a pre- and posttest assessing participant knowledge, and follow-up surveys of the participants and their primary mentors. Result Over three years, the workshop received 195 applications; 109 early career researchers were competitively selected to participate. All participants (109/109, 100%) completed writing a protocol by the end of their workshop. Participants and their primary mentors reported significant improvements in their research knowledge and skills. Each year, participants rated the workshop highly in terms of satisfaction, value, and likelihood of recommending it to a colleague. One year after the first workshop, most respondents (29/30, 96.7%) had either submitted their protocol or written at least one other protocol. Significance of results We developed a workshop on research methods in supportive oncology. More early career investigators applied for the workshop than capacity, and the workshop was fully attended each year. Both the workshop participants and their primary mentors reported improvement in research skills and knowledge. PMID- 29282164 TI - Depth Resolution Dependence on Sample Thickness and Incident Energy in On-Axis Transmission Kikuchi Diffraction in Scanning Electron Microscope (SEM). AB - Transmission Kikuchi diffraction is an emerging technique aimed at producing orientation maps of the structure of materials with a nanometric lateral resolution. This study investigates experimentally the depth resolution of the on axis configuration, via a twinned silicon bi-crystal sample specifically designed and fabricated. The measured depth resolution varies from 30 to 65 nm in the range 10-30 keV, with a close to linear dependence with incident energy and no dependence with the total sample thickness. The depth resolution is explained in terms of two mechanisms acting concomitantly: generation of Kikuchi diffraction all along the thickness of the sample, associated with continuous absorption on the way out. A model based on the electron mean free path is used to account for the dependence with incident energy of the depth resolution. In addition, based on the results in silicon, the use of the mean absorption coefficient is proposed to predict the depth resolution for any atomic number and incident energy. PMID- 29282165 TI - In Vitro Effects of Sports and Energy Drinks on Streptococcus mutans Biofilm Formation and Metabolic Activity. AB - PURPOSE: Sports and energy drinks are being increasingly consumed and contain large amounts of sugars, which are known to increase Streptococcus mutans biofilm formation and metabolic activity. The purpose of this in vitro study was to investigate the effects of sports and energy drinks on S. mutans biofilm formation and metabolic activity. METHODS: S. mutans UA159 was cultured with and without a dilution (1:3 ratio) of a variety of sports and energy drinks in bacterial media for 24 hours. The biofilm was washed, fixed, and stained. Biofilm growth was evaluated by reading absorbance of the crystal violet. Biofilm metabolic activity was measured by the biofilm-reducing XTT to a water-soluble orange compound. RESULTS: Gatorade Protein Recovery Shake and Starbucks Doubleshot Espresso Energy were found to significantly increase biofilm (30-fold and 22-fold, respectively) and metabolic activity (2-fold and 3-fold, respectively). However, most of the remaining drinks significantly inhibited biofilm growth and metabolic activity. CONCLUSIONS: Several sports and energy drinks, with sugars or sugar substitutes as their main ingredients inhibited S. mutans biofilm formation. Among the drinks evaluated, Gatorade Protein Recovery Chocolate Shake and Starbucks Doubleshot Energy appear to have cariogenic potential since they increased the biofilm formation and metabolic activity of S. mutans. PMID- 29282166 TI - Gloss and Surface Roughness of Anterior Pediatric Zirconia Crowns. AB - PURPOSE: The purpose of this study was to determine gloss and surface roughness (Ra) of pediatric anterior zirconia crowns. METHODS: Gloss of labial and lingual surfaces of pediatric anterior zirconia crowns from three manufacturers was measured on 20 specimens using a small area gloss meter on each. Ra (MUm) was measured using a contact-type surface profilometer. Data were evaluated by analysis of variance and pair-wise comparison at the 0.05 level of significance. RESULTS: There were statistically significant interactions between surface location and crown type for both gloss and Ra scores. NuSmile had higher mean gloss scores and lower mean Ra scores than both Kinder Krowns and EZCrowns. Kinder Krowns showed lower mean gloss scores and higher Ra scores than other crown groups. CONCLUSION: Among all crowns, there was a trend of higher mean gloss paired with lower mean surface roughness, and lower mean gloss paired with higher mean Ra. Hand smoothed followed by mechanically polished zirconia crowns (NuSmile) displayed the highest mean gloss and lowest mean Ra compared to hybrid polishedglazed zirconia crowns (Kinder Krowns, EZCrowns). Of the hybrid polished glazed zirconia crowns, Kinder Krowns displayed the lowest mean gloss and highest mean Ra. PMID- 29282167 TI - Pediatric Dental Resident's Education on Children with Special Health Care Needs in the United States. AB - PURPOSE: To describe pediatric dental residents education as it pertains to children with special healthcare needs (CSHCN). METHODS: A web-based survey was administered to 80 program directors of pediatric dental residencies recognized by the American Academy of Pediatric Dentistry (AAPD). The survey identified demographic data and education and training methods pertaining to CSHCN. RESULTS: Forty surveys (50 percent) were received from programs in all six AAPD regions. Programs that treated 4,500 patients or less/year were statistically less likely to require a specific assessment and were less likely to use written tests to assess competency treating CSHCN. A specific special needs didactic course (88 percent) and journal articles (85 percent) were the most common didactic training methods. The majority of the programs (69 percent) offered more than 20 hours of didactic education. On average 36.3 percent of the patients treated in residencies reported to be CSHCN and each resident clinically treated and average of 13 CSHCN/week. One-third of the respondents planned to increase CSHCN education in the next three years. Almost 70 percent of respondents supported the standardization of a national curriculum regarding CSHCN. CONCLUSIONS: A wide disparity exists among residencies regarding education related to CSHCN. Most pediatric dental residency directors support the national standardization of CSHCN education. PMID- 29282168 TI - Oral Health Literacy as a Predictor of Dental Anxiety in Parents of Children Undergoing Dental Treatment. AB - PURPOSE: The purpose of this cross-sectional study was to evaluate the association between parents' dental anxiety (DA) and independent variables. METHODS: One hundred sixty-eight dyads of parents and six- to 12-year-old children who were undergoing treatment at a university pediatric dentistry clinic were recruited. Two examiners evaluated parents' DA and oral health literacy (OHL) using the Brazilian version of Corah's dental anxiety scale and the Brazilian Rapid Estimate of Adult Literacy in Dentistry (BREALD-30), respectively. Children's DA was reported by parents through the dental anxiety question (DAQ). Demographic data was also collected. A single examiner used the decayed, missing, and filled permanent teeth and primary teeth (DMFT/dmft) indices to assess the children's oral health status. The data analysis involved univariate and multivariate Poisson regression. RESULTS: In the multivariate regression, higher levels of parents' DA were associated with a household income equal to or less than the Brazilian monthly minimum wage (prevalence ratio [PR]=4.9; 95 percent confidence interval [CI]=2.1 to 11.7) and a lower degree of OHL (PR=1.68; 95 percent CI=1.01 to 2.8). Associations between parents' DA and children's DA and DMFT/dmft index were not found. CONCLUSION: Parents' dental anxiety was related to a low household income and low oral health literacy. PMID- 29282169 TI - Maternal Stress and Behavioral and Clinical Factors Associated with Dental Trauma in Schoolchildren. AB - PURPOSE: The purpose of this study was to evaluate associations between traumatic dental injury (TDI) and maternal stress and demographic, behavioral, and clinical characteristics of schoolchildren. METHODS: A cross-sectional investigation was conducted involving 396 eight- to 11- year-old schoolchildren in the city of Diamantina, Minas Gerais, Brazil. Maternal stress and demographic and behavioral (breastfeeding and non-nutritive sucking habits) factors were evaluated using a questionnaire. Overjet and TDI were recorded by a dentist who underwent training and a calibration exercise. Hierarchically-adjusted Poisson regression models were employed to determine factors associated with TDI. RESULTS: In the final regression model, the prevalence of TDI was 75 percent higher among schoolchildren who were breastfed for less than six months (prevalence ratio [PR]=1.75; 95% confidence interval [CI]=1.16 to 2.66), 72 percent higher among those who engaged in finger-/thumb-sucking after three years of age (PR=1.72; 95% CI=1.16 to 2.56) and 91 percent among those with overjet greater than three mm (PR=1.91; 95% CI=1.29 to 2.84). CONCLUSIONS: Breastfeeding duration, finger /thumb-sucking and increased overjet were associated with TDI. These factors were aggravated by maternal stress, but it lost its significance in the multivariate analysis. PMID- 29282170 TI - Provider Appearance: A Survey of Guardian and Patient Preference. AB - PURPOSE: The purposes of this study were to: (1) assess children's preferences for their pediatric dentist's attire; (2) assess guardians' preferences for their child's pediatric dentist's attire; and (3) determine which attributes are associated with different types of attire. This was a cross-sectional descriptive study using survey methodology with patients and parents who attended the pediatric dental clinic at Virginia Commonwealth University, Richmond, Va., USA. METHODS: A total sample of 100 guardians and 97 pediatric patients completed the computer-based questionnaire. Four subjects posed for photographs wearing various combinations of attire (professional, casual, white coat, scrubs). RESULTS: Among guardians, 56 percent reported preferring a provider in scrubs, with white coat the second most preferred attire (39 percent) for their children. For pediatric patients, scrubs were still most often selected, but at a lower rate (43 percent), and the white coat remained the second most preferred (37 percent). CONCLUSIONS: Children and parents have strong perceptions and preferences regarding their dentists' attire. PMID- 29282171 TI - Recurrent Gingival Squamous Papilloma: A Rare Finding in a Child. AB - Gingival squamous papilloma (SP) is a mucocutanous, benign proliferation rarely seen in the pediatric population. The majority of publications of affected younger patients have been confined to datasets from clinicopathologic investigations. A limited number of case reports in this age group have appeared in the literature, usually featuring primary gingival lesions. Recognition of recurrent gingival SPs in pediatric patients has been underappreciated. The purpose of this report is to present the case of a four-year-old boy with a gingival SP that recurred twice within 18 months and to increase awareness of this entity in children. PMID- 29282174 TI - SKINmed Partners with Dermatology Insights and Inquiries: Perfect Together. PMID- 29282172 TI - Management of a Permanent Maxillary Lateral Incisor with Vital Pulp and Necrotic Dens Invaginatus Type III. AB - This is a case report on the management of a vital lateral incisor with a radiolucent cervical area associated with the presence of necrotic pulp due to a dens invaginatus (DI) type III. A nine-year-old boy presented to a university pediatric dental clinic with dental trauma. The examination showed poor oral hygiene, an uncomplicated fracture in the permanent maxillary left central incisor, and a fistula near the permanent maxillary right lateral incisor. A radiograph showed that the right lateral incisor had incomplete root development and a type III DI. Although sensitive to thermal pulp testing, tracing of the fistula indicated that the radiolucent area was associated with the DI, extending laterally to the periodontal ligament. Endodontic treatment was performed only in the invagination, keeping the root canal of the lateral incisor vital. After two years of follow-up, complete root formation and injury repair associated with invagination were observed. PMID- 29282175 TI - Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation-Part II: Proactive Approach. PMID- 29282176 TI - Needlephilia versus Needlephobia. PMID- 29282177 TI - Vitamin D Deficiency and Atopic Dermatitis: Consider Disease, Race, and Body Mass. AB - Vitamin D deficiency causes rickets, but has been associated with various diseases, including atopic dermatitis (AD). This study analyzes serum vitamin D in pediatric medical center patients with AD and potential confounding factors. At Cardinal Glennon Children's Hospital, charts of 665 children with serum 25 hydroxyvitamin D levels taken between 2009 and 2013 were retrospectively reviewed. Defining vitamin D deficiency as <20 ng/mL, neither average 25 hydroxyvitamin D nor deficiency prevalence varied among disease groups, except for cystic fibrosis (CF), which demonstrated significantly higher average vitamin D and lower deficiency prevalence. Children with AD had the lowest prevalence of vitamin D sufficiency, without significant association with disease severity. No seasonal variation was detected. Strong correlations were observed between 25 hydroxyvitamin D levels, body mass index (BMI), and race. Our data showed no strong association between vitamin D levels and AD or AD severity. A strong association was noted between skin type and BMI. The lower prevalence of vitamin D deficiency among children with CF may be explained by lighter skin and lower BMI. A high prevalence of vitamin D insufficiency and deficiency as currently defined among children with dark skin and high BMI suggests a need to reevaluate normal vitamin D levels in these populations. PMID- 29282178 TI - Oral Mucosal Lesions in a Cross-Sectional Study of 200 Dermatologic Outpatients. AB - Oral mucosal lesions (OMLs) present with a variety of manifestations, emanating largely from tobacco chewing, smoking, and consumption of alcohol. Evolution of the lesions may be facilitated by poor oral hygiene and restorative dental materials, as well as by trauma, infections, and immune-mediated diseases. Two hundred consecutive patients seen at a pre-eminent dermatologic clinic formed the study group. They were interviewed about clinical manifestations, duration of the lesion, patient's age and sex, and incriminating factors. After informed consent had been gained, a thorough clinical examination was performed to define the precise morphology, site, and distribution of lesions. Confirmation of the clinical diagnosis by histopathology and other relevant techniques was confirmed. PMID- 29282179 TI - Characterization of Patients' Quality of Life and Experience in the Course of Acne Treatment. AB - Few studies provide qualitative data on the acne treatment experience. This study describes patients' personal experiences of acne treatment. Video interviews were made of 27 teenagers and young adults with acne treated for 12 weeks with adapalene/benzoyl peroxide gel. Transcripts were then coded and qualitatively analyzed. Four thematic domains affecting quality of life and experience were identified: clinical manifestations, self-perception, social placement, and perception of control. Successful treatment increased self-esteem and performance at work and school. Successful acne treatment improves patients' quality of life by improving appearance and self-perception, satisfaction with social placement, and perception of control. PMID- 29282180 TI - Safety and Antipruritic Efficacy of a Menthol-Containing Moisturizing Cream. AB - Itch is frequently associated with dermatoses characterized by a defective skin barrier. We formulated an itch-relieving moisturizing cream containing 3% menthol and ceramides. Our aim was to evaluate the safety and antipruritic efficacy of application of this cream in volunteers with and without skin diseases. Volunteers were asked to apply the cream for 1 month on a minimum body surface area of 6%. Safety was assessed by the absence of contact dermatitis or other side effects, using a self-administered questionnaire completed at 5 minutes, 1 week, and 1 month after application. To determine efficacy, volunteers with pruritic dermatoses were asked to grade their average itch intensity at baseline, 1 week, and 1 month after application. Sixty volunteers were recruited, of whom 41 had no skin disease; no adverse events were reported in the latter. Of the 19 volunteers with dermatoses, 18 reportedly had atopic dermatitis. One of the 60 volunteers stopped application due to stinging sensations induced by menthol. Itch scores of volunteers with dermatitis improved from baseline at 1 week (P=.01) and 1 month (P<.01) after application. Application of a 3% menthol containing moisturizing cream was safe in healthy individuals and participants with dermatitis. In the latter, itch scores were significantly reduced during follow-up. PMID- 29282181 TI - Hyaluronic Acid in Dermatology. AB - Hyaluronic acid (HA) is a major component of the extracellular matrix of the skin and plays an important role in the metabolism of the dermis. It has a key position in wound healing and tissue repair processes owing to its ability to maintain a humid environment favorable to healing and the stimulation of growth factors, cellular constituents, and the migration of various cells essential for healing. This review aims to describe briefly the physical, chemical, and biologic properties of HA, together with some details of the dermatologic indications of this unique molecule. PMID- 29282183 TI - Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids. AB - Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three part review. Part 2 focuses on scar revision for hypertrophic and keloids scars. Scar revision options for hypertrophic and keloid scars include corticosteroids, bleomycin, fluorouracil, verapamil, avotermin, hydrogel scaffold, nonablative fractional lasers, ablative and fractional ablative lasers, pulsed dye laser (PDL), flurandrenolide tape, imiquimod, onion extract, silicone, and scar massage. PMID- 29282184 TI - Compromising Patient Care: Gross Payment Disparities in Dermatopathology-Part II. PMID- 29282185 TI - Melanoma in Situ: The Power of One (Centimeter)? PMID- 29282186 TI - Blaschkoid (Linear and/or Bandlike) Psoriasis. PMID- 29282187 TI - Cellular Blue Nevus: An Unusual Localization. PMID- 29282188 TI - Vicente Pardo-Castello, MD (1892-1967). PMID- 29282189 TI - Cutaneous Mucormycosis: A Fatal Complication of Immunosuppressant Therapy for Pemphigus Vulgaris. AB - A 62-year-old man with no comorbidities presented to the outpatient department of our Institute with a history of extensive vesiculobullous and erosive skin lesions and oral erosions for 2 months and fever for 1 week. A diagnosis of pemphigus vulgaris was made based on histopathology and direct immunofluorescence of a skin biopsy specimen, and the patient was started on oral prednisolone 40 mg per day along with intravenous antibiotics (amoxicillin-clavulanic acid, gentamicin, and metronidazole) empirically, pending blood and skin swab culture and sensitivity reports. His biochemical and hematologic investigations revealed no abnormalities (hemoglobin 12.4 g/dl, leukocyte count 6500/mm3, platelet count 250,000/mm3), and blood and skin cultures were sterile. When the fever had subsided and while he was receiving antibiotics, he was administered intravenous dexamethasone-cyclophosphamide pulse therapy over 3 days. After this, he was discharged on oral amoxicllin/clavulinc acid 625 mg tid, prednisolone 40 mg daily, and cyclophosphamide 50 mg daily. At the time of discharge, the erosions on the anterior region of the chest were reepithelializing without any evidence of eschar. PMID- 29282190 TI - Immunologic Studies of Progesterone-Induced Neutrophilic Urticaria. AB - A 33-year-old woman presented with recurring pruritic, erythematous papules around the mouth and on the hands, of 1.5 years' duration. These flares typically began several days before her menstrual cycle and persisted for approximately 1 week. Physical examination revealed urticarial plaques on the neck. Due to the nature of the eruption, which corresponded with her menstrual cycle, a diagnosis of autoimmune progesterone urticaria was considered and workup pursued. PMID- 29282191 TI - Persisting Ulcerating Lesions After Cyclosporine Therapy for Erosions Found in Flexural Sites. AB - In February 2012, a patient with a 15-year history of painful, pruritic eruptions presented with a severe exacerbation that had lasted for the previous week. The patient also reported severe headaches, a fever of 38.9 degrees C (102.1 degrees F), a cough, and diarrhea, which had now resolved. Physical examination showed erythematous macerated patches with erosions in the left submammary region, bilateral axillae, and vaginal area (Figure 1), and greasy scale covering the scalp. Despite lessening of the lesions in the submammary region and abdomen with the administration of minocycline 100 mg twice per day and cyclosporine 100 mg three times per day, the patient continued to complain of persistent painful ulcerations in the labia majora and perianal area (Figure 2). The patient was started on acyclovir 400 mg three times per day for 10 days for positive herpes simplex viral culture and ampicillin for Proteus infection of the area. PMID- 29282192 TI - Mast Cell Activation Syndrome. AB - A 51-year-old woman with a history of asthma and Hashimoto's thyroiditis presented to the dermatology service with a chief complaint of "itchy bumpy rashes" that persisted beyond 24 hours. She noted that, 3 days prior to the onset of urticaria, a pyrroloquinoline quinone supplement had been started. The urticaria was accompanied by variable episodes of transient facial swelling and difficulty breathing. The patient noted that exposure to fish, nuts, and nonsteroidal anti-inflammatory drugs triggered facial swelling. Other reported findings included a 5-year history of diarrhea, sense of memory deterioration, concentration difficulties, and clinical manifestations of anomic aphasia. Although her allergy testing was "negative," she had been given the diagnoses of lactose intolerance and gastroesophageal reflux disease. Laboratory studies on initial presentation were significant for a positive history of antithyroperoxidase antibodies and elevated total complement activity. Medications included budesonide/formoterol, fluticasone/salmeterol, levothyroxine, albuterol, and fexofenadine 180 mg twice daily. Although her "rash" had initially responded to fexofenadine, it soon became refractory to treatment. Her family history was significant only for thyroid disease. PMID- 29282193 TI - Plantar Fibromatosis in a Mentally Challenged Man Treated with Intralesional Corticosteroids. AB - A 21-year-old mentally challenged man presented with a fixed plaque lesion on the right foot, which had been present for 10 years. Dermatologic examination revealed an erythematous, painful, firm, fixed plaque-nodular lesion on the plantar aspect of the right foot (Figure 1A). Nothing of distinction was noted from his family history or his laboratory tests. An incisional biopsy revealed parallel, regular bundles composed of uniform, plump spindle cells. Thin collagen fibers were seen in contact with and located between the spindle cells. This mass was separated from the surrounding soft tissue by an irregular, unclear border (Figure 2A). Immunohistochemically, the spindle cells showed diffuse, strong reactivity to vimentin (Figure 2B) and smooth muscle actin. PMID- 29282194 TI - Role of Immune Status in Chemotherapy-Induced Transient Acantholytic Dermatosis. AB - A 79-year-old man with a recent diagnosis of acute myeloblastic leukemia received induction chemotherapy with daunorubicin and cytarabine, plus moxifloxacin and fluconazole prophylaxis. Approximately 2 weeks later, an asymptomatic eruption appeared on his trunk. He then developed a neutropenic fever and was started on aztreonam, vancomycin, voriconazole, and amikacin and was transferred to our facility from an outside hospital. Micafungin was subsequently added, and the patient defervesced within a few days. PMID- 29282195 TI - Chloracne in a Farming Family. AB - An 11-year-old boy presented with a 1-year history of multiple comedonal lesions distributed over his body. The lesions (Figure 1) were densely distributed throughout his body. Ophthalmologic examination revealed hyperpigmented conjunctival mucosae and enlarged meibomian glands (Figure 2). His nails were also hyperpigmented. In addition, he had been coughing and had a fever, each present for a month. Significant laboratory studies included mild anemia (hemoglobin 11.6 gm%) and leukocytosis of 20,800. A chest x-ray was suggestive of interstitial lung disease. Similar lesions were present on his two siblings and parents. Additionally, his father had developed multiple, acne-like lesions, large abscesses, palmar and plantar peeling, and severe jaundice with hepatic failure. He had a history of frequent exposure to a pesticide mixed with a herbicide, as a result of leakage from a spray container. The patient was diagnosed with chloracne, based on the history, clinical features, and histologic examination. PMID- 29282196 TI - Multiple Treatment-Resistant Actinic Keratoses Secondary to Hydroxycarbamide. PMID- 29282197 TI - Sweet Syndrome Associated with Bilateral Nodular Scleritis. PMID- 29282198 TI - Advanced Therapy Treatment for Psoriasis: A Single-Site Retrospective Study of Prescribing Outcomes. PMID- 29282199 TI - Comparison of Glycated Hemoglobin Results Based on At-Home and In-Lab Dried Blood Spot Sampling to Routine Venous Blood Sampling In-Lab in Adult Patients With Type 1 or Type 2 Diabetes. AB - OBJECTIVES: Regular measurement of glycated hemoglobin (A1C) is logistically demanding. Home blotter-paper collection offers an alternative. This study tested the viability of at-home blotter-paper A1C measurement. METHODS: Objective: compare accuracy of A1C levels collected on blotter paper at home (home-blotter) and blotter-paper collection in laboratory (lab-blotter) with venous A1C (routine measurement). Agreement was assessed by Pearson correlation, Lin concordance correlation coefficient (CCC), positive and negative predictive values (PPVs, NPVs) and Bland-Altman plots and associated statistics. RESULTS: Home-blotter, lab-blotter and venous A1C correlated strongly (0.93, 0.93). Home- and lab blotter results were upwardly biased (0.387%, 0.1%). Bias increased with time. Bias correction provided agreement for both blotters (CCC >0.9); blotters correctly identifying levels above 7% (53 mmol/mol) were 100% for corrected home blotters and 87% (95% confidence interval) for corrected lab-blotters. NPVs (% blotters correctly identifying levels of 7% or lower [53 mmol/mol]) were 100% for corrected home-blotters and 83% for corrected lab-blotters. After correction, >92% of corrected blotters had errors of 8% or less. Of our subjects, 88.5% found home sampling preferable to routine laboratory sampling. CONCLUSIONS: Home blotter collection is an alternative to routine collection. PMID- 29282200 TI - Is YouTube Useful as a Source of Health Information for Adults With Type 2 Diabetes? A South Asian Perspective. AB - OBJECTIVES: To investigate the content, quality and popularity of information about type 2 diabetes available on YouTube. METHODS: We searched YouTube with the terms Diabetes, Diabetes type 2, Diabetes South Asians, Diabetes Punjabi and Diabetes Hindi to identify videos concerning type 2 diabetes. A team of health care providers independently classified the first 20 videos from each search as useful, misleading, or personal experience, rated them on a 5-point global quality scale (GQS) and categorized their content on a 26-point scale in duplicate. Useful videos were rated for reliability by using a 5-point modified DISCERN scale. Higher scores represent better quality, reliability and comprehensiveness. RESULTS: Of 100 videos, 71 met the inclusion criteria; 45 (63.4%) were rated as useful (median GQS, 3; interquartile range [IQR], 2 to 4); and 23 (32.4%) were deemed misleading (median GQS, 1; IQR, 1 to 2). Median reliability and content scores for useful videos were 3 (IQR, 2 to 3) and 5 (IQR, 3 to 10), respectively, and 6 videos met >= 4 of 5 reliability criteria. Overall, misleading videos were more popular than useful videos (median, 233 views/day; IQR, 26 to 523; vs. 8.3 views/day; IQR, 0.4 to 134.6; p<0.01). Culturally tailored videos were just as likely to be misleading and had similar GQS scores in comparison to nonculturally tailored videos (32.1% vs. 32.6% and 3 vs. 3, respectively). CONCLUSIONS: The quality of identified videos concerning type 2 diabetes was variable, and misleading videos were popular. Further creation and curation of high-quality video resources is required. PMID- 29282201 TI - MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic beta-Cells. AB - Although the mechanisms by which glucose regulates insulin secretion from pancreatic beta-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic beta EndoC-betaH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to beta cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human beta-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-betaH1 cells. These results highlight MondoA as a novel target in beta-cells that coordinates transcriptional response to elevated glucose levels. PMID- 29282202 TI - Immunoadsorption Followed by Rituximab as a Definitive Treatment for Insulin Autoimmune Syndrome (Hirata Syndrome): A Case Report. PMID- 29282204 TI - Surgical removal of a giant iris stromal cyst: an intraoperative optical coherence tomography-guided approach. AB - An 11-year-old girl was brought with the chief complaint of progressive diminution of vision in her right eye for the past 3 months. There was no history of ocular trauma or any ocular surgery. Systemic and family history was insignificant. Visual acuity was 20/20 in her left eye and counting finger close to face with projection of rays being accurate in her right eye. Slit lamp examination of her right eye showed large cystic lesion filling almost entire anterior chamber. With the help of various imaging modalities like anterior segment optical coherence tomography (OCT) and ultrasound biomicroscopy diagnosis of iris stromal cyst was confirmed. Right eye surgical removal of the iris stromal cyst was done under real-time imaging of intraoperative OCT (iOCT). Best corrected visual acuity at 6 months follow-up was 20/20 without any recurrence. iOCT-guided approach for complete removal of the iris cyst seems more promising. PMID- 29282203 TI - A Low-Fat Dietary Pattern and Diabetes: A Secondary Analysis From the Women's Health Initiative Dietary Modification Trial. AB - OBJECTIVE: We performed a secondary analysis to evaluate the effect of the Women's Health Initiative dietary intervention on incident diabetes and diabetes treatment in postmenopausal women. RESEARCH DESIGN AND METHODS: A total of 48,835 women were randomized to a comparison group or an intervention group that underwent a behavioral/nutritional modification program to decrease fat and increase vegetable, fruit, and grain intake for an average of 8.1 years. Ninety three percent of participants completed the intervention, and 71% participated in active follow-up through 30 September 2015 (median 17.3 years). We measured time to development of treated diabetes and progression from oral antihyperglycemic agents to insulin. Serum glucose and insulin were measured in a subsample of women (N = 2,324) at baseline and years 1, 3, and 6. RESULTS: During the trial, intervention group women had lower rates of initiation of insulin therapy (hazard ratio [HR] 0.74 [95% CI 0.59, 0.94]; P = 0.01). Moreover, women with baseline waist circumference >=88 cm (P interaction = 0.01) and worse metabolic syndrome scores (P interaction = 0.02) had the greatest reduction in risk of initiating insulin therapy. The decreased risk from the intervention was present during the cumulative follow-up (HR 0.88 [95% CI 0.78, 0.99]; P = 0.04). In participants with measured biomarkers (5.8% subsample) who had baseline glucose <100 mg/dL, the intervention reduced the risk of developing glucose >=100 mg/dL by 25% (odds ratio 0.75 [95% CI 0.61, 0.93]; P = 0.008). Adjustment for weight change did not alter the results. CONCLUSIONS: In this secondary analysis, a dietary intervention in postmenopausal women aimed at reducing fat and increasing intake of vegetables, fruits, and grains did not increase risk of diabetes and may have slowed progression. PMID- 29282206 TI - Colonic epithelium rejuvenation through YAP/TAZ. PMID- 29282207 TI - Risk Factors for the Development of Bladder and Bowel Dysfunction. AB - BACKGROUND: Patients with vesicoureteral reflux and concomitant bladder and bowel dysfunction (BBD) are at high risk for febrile urinary tract infections. Risk factors for BBD have been identified in retrospective studies without validated measures. METHODS: We conducted a secondary analysis of the Randomized Intervention for Children with Vesicoureteral Reflux and Careful Urinary Tract Infection Evaluation trials. The outcome of interest in the analysis of these children was the development of BBD, defined by using the dysfunctional voiding questionnaire, during any time point in the studies. We used multivariable logistic regression to determine the independent effects of sex, baseline percentile BMI, cohort status (Randomized Intervention for Children with Vesicoureteral Reflux versus Careful Urinary Tract Infection Evaluation), continuous antibiotic prophylaxis (yes or no), and reflux status (dilating versus nondilating) on the development of BBD. RESULTS: Three hundred and eighteen patients met inclusion criteria. The majority of patients (244 patients, 77%) were not toilet trained at baseline visit. The median baseline age (interquartile range) was 21 months (11-35 months), and 299 (94%) patients were girls. During the study period, 111 (35%) developed BBD. Baseline BMI percentile was not associated with BBD development (adjusted odds ratio [aOR] = 1.0; 95% confidence interval [CI]: 0.9-1.1), whereas female sex was highly associated with BBD development (aOR = 12.7; 95% CI: 1.6-98). Patients with dilating reflux at baseline were 2.1 times more likely to develop BBD (95% CI: 1.2-3.7). Antibiotic prophylaxis was not associated with BBD development (aOR = 0.8; 95% CI: 0.4-1.4). CONCLUSIONS: Dilating reflux and female sex were identified as risk factors for development of BBD, but neither BMI nor prophylactic antibiotics was associated with the development of BBD. PMID- 29282205 TI - Glycosphingolipid metabolic reprogramming drives neural differentiation. AB - Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo- to ganglio-series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self-contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate-limiting ganglioside-producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology. PMID- 29282208 TI - What's the Punchline?: Promoting Child and Teacher Resilience Through Pediatrician-Teacher Partnerships. PMID- 29282209 TI - The Burning Ring of Fire. PMID- 29282210 TI - ATP is stored in lamellar bodies to activate vesicular P2X4 in an autocrine fashion upon exocytosis. AB - Vesicular P2X4 receptors are known to facilitate secretion and activation of pulmonary surfactant in the alveoli of the lungs. P2X4 receptors are expressed in the membrane of lamellar bodies (LBs), large secretory lysosomes that store lung surfactant in alveolar type II epithelial cells, and become inserted into the plasma membrane after exocytosis. Subsequent activation of P2X4 receptors by adenosine triphosphate (ATP) results in local fusion-activated cation entry (FACE), facilitating fusion pore dilation, surfactant secretion, and surfactant activation. Despite the importance of ATP in the alveoli, and hence lung function, the origin of ATP in the alveoli is still elusive. In this study, we demonstrate that ATP is stored within LBs themselves at a concentration of ~1.9 mM. ATP is loaded into LBs by the vesicular nucleotide transporter but does not activate P2X4 receptors because of the low intraluminal pH (5.5). However, the rise in intravesicular pH after opening of the exocytic fusion pore results in immediate activation of vesicular P2X4 by vesicular ATP. Our data suggest a new model in which agonist (ATP) and receptor (P2X4) are located in the same intracellular compartment (LB), protected from premature degradation (ATP) and activation (P2X4), and ideally placed to ensure coordinated and timely receptor activation as soon as fusion occurs to facilitate surfactant secretion. PMID- 29282211 TI - Late Ca2+ Sparks and Ripples During the Systolic Ca2+ Transient in Heart Muscle Cells. AB - RATIONALE: The development of a refractory period for Ca2+ spark initiation after Ca2+ release in cardiac myocytes should inhibit further Ca2+ release during the action potential plateau. However, Ca2+ release sites that did not initially activate or which have prematurely recovered from refractoriness might release Ca2+ later during the action potential and alter the cell-wide Ca2+ transient. OBJECTIVE: To investigate the possibility of late Ca2+ spark (LCS) activity in intact isolated cardiac myocytes using fast confocal line scanning with improved confocality and signal to noise. METHODS AND RESULTS: We recorded Ca2+ transients from cardiac ventricular myocytes isolated from rabbit hearts. Action potentials were produced by electric stimulation, and rapid solution changes were used to modify the L-type Ca2+ current. After the upstroke of the Ca2+ transient, LCSs were detected which had increased amplitude compared with diastolic Ca2+ sparks. LCS are triggered by both L-type Ca2+ channel activity during the action potential plateau, as well as by the increase of cytosolic Ca2+ associated with the Ca2+ transient itself. Importantly, a mismatch between sarcoplasmic reticulum load and L-type Ca2+ trigger can increase the number of LCS. The likelihood of triggering an LCS also depends on recovery from refractoriness that appears after prior activation. Consequences of LCS include a reduced rate of decline of the Ca2+ transient and, if frequent, formation of microscopic propagating Ca2+ release events (Ca2+ ripples). Ca2+ ripples resemble Ca2+ waves in terms of local propagation velocity but spread for only a short distance because of limited regeneration. CONCLUSIONS: These new types of Ca2+ signaling behavior extend our understanding of Ca2+-mediated signaling. LCS may provide an arrhythmogenic substrate by slowing the Ca2+ transient decline, as well as by amplifying maintained Ca2+ current effects on intracellular Ca2+ and consequently Na+/Ca2+ exchange current. PMID- 29282212 TI - MUSCLEMOTION: A Versatile Open Software Tool to Quantify Cardiomyocyte and Cardiac Muscle Contraction In Vitro and In Vivo. AB - RATIONALE: There are several methods to measure cardiomyocyte and muscle contraction, but these require customized hardware, expensive apparatus, and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming, and only specialist researchers can quantify data. OBJECTIVE: Here, we describe and validate an automated, open source software tool (MUSCLEMOTION) adaptable for use with standard laboratory and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes, and pharmacological responses. METHODS AND RESULTS: MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in (1) 1-dimensional in vitro models, such as isolated adult and human pluripotent stem cell-derived cardiomyocytes; (2) 2-dimensional in vitro models, such as beating cardiomyocyte monolayers or small clusters of human pluripotent stem cell-derived cardiomyocytes; (3) 3-dimensional multicellular in vitro or in vivo contractile tissues, such as cardiac "organoids," engineered heart tissues, and zebrafish and human hearts. MUSCLEMOTION was effective under different recording conditions (bright-field microscopy with simultaneous patch clamp recording, phase contrast microscopy, and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement, such as optical flow, post deflection, edge-detection systems, or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. CONCLUSIONS: Using a single open-source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell, animal, and human models. PMID- 29282213 TI - Guidance for sports injury surveillance: the 20-year influence of the Australian Sports Injury Data Dictionary. AB - BACKGROUND: Injury prevention requires information about how, why, where and when injuries occur. The Australian Sports Injury Data Dictionary (ASIDD) was developed to guide sports injury data collection and reporting. Sports Medicine Australia (SMA) disseminated associated data collection forms and an online tool to practitioners and the sports community. This paper assesses the long-term value, usefulness and relevance of the ASIDD and SMA tools. METHODS: A systematic search strategy identified both peer-reviewed and grey literature that used the ASIDD and/or the SMA tools, during 1997-2016. A text-based search was conducted within 10 electronic databases, as well as a Google Image search for the SMA tools. Documents were categorised according to ASIDD use as: (1) collected injury data; (2) informed data coding; (3) developed an injury data collection tool and/or (4) reference only. RESULTS: Of the 36 peer-reviewed articles, 83% directly referred to ASIDD and 17% mentioned SMA tools. ASIDD was mainly used for data coding (42%), reference (36%), data collection (17%) or resource development (14%). In contrast, 86% of 66 grey literature sources referenced, used or modified the SMA data collection forms. CONCLUSIONS: The ASIDD boasts a long history of use and relevance. Its ongoing use by practitioners has been facilitated by the ready availability of specific data collection forms by SMA for them to apply to directly their settings. Injury prevention practitioners can be strongly engaged in injury surveillance activities when formal guidance is supported by user-friendly tools directly relevant to their settings and practice. PMID- 29282214 TI - Revising existing instruments for measuring bystander intervention opportunity and frequency of prosocial response for the prevention of sexual violence. AB - Institutions of higher education increasingly offer training programmes to engage students' as pro-social bystanders who can intervene in situations related to sexual violence. The purpose of this study was to assess the usage of a bystander behaviour measurement tool that captures both students' intervention opportunities and frequency of prosocial response. University undergraduate students in the Northwestern USA (n=474) completed online surveys in the Fall of 2016. Results show that students have opportunities to intervene in a variety of situations at the three levels of prevention for campus sexual violence and they do not always intervene. The frequency of students' prosocial bystander response ranged, for those with the opportunity, from 'never' to 'always'; students reported varying degrees of intervention frequency depending on the situation. A bystander intervention behaviour instrument measuring opportunity and frequency of response can be a valuable tool for assessing the effectiveness of bystander training programmes. PMID- 29282216 TI - Mind the gaps! Towards an ethical framework for genome editing. PMID- 29282217 TI - A unified reviewing format for grant applications and evaluations. PMID- 29282218 TI - A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance. AB - Previous studies have shown that loss of terminal sialic acid causes enhanced von Willebrand factor (VWF) clearance through the Ashwell-Morrell receptor (AMR). In this study, we investigated (1) the specific importance of N- vs O-linked sialic acid in protecting against VWF clearance and (2) whether additional receptors contribute to the reduced half-life of hyposialylated VWF. alpha2-3-linked sialic acid accounts for <20% of total sialic acid and is predominantly expressed on VWF O-glycans. Nevertheless, specific digestion with alpha2-3 neuraminidase (alpha2 3Neu-VWF) was sufficient to cause markedly enhanced VWF clearance. Interestingly, in vivo clearance experiments in dual VWF-/-/Asgr1-/- mice demonstrated enhanced clearance of alpha2-3Neu-VWF even in the absence of the AMR. The macrophage galactose-type lectin (MGL) is a C-type lectin that binds to glycoproteins expressing terminal N-acetylgalactosamine or galactose residues. Importantly, the markedly enhanced clearance of hyposialylated VWF in VWF-/-/Asgr1-/- mice was significantly attenuated in the presence of an anti-MGL inhibitory antibody. Furthermore, dose-dependent binding of human VWF to purified recombinant human MGL was confirmed using surface plasmon resonance. Additionally, plasma VWF:Ag levels were significantly elevated in MGL1-/- mice compared with controls. Collectively, these findings identify MGL as a novel macrophage receptor for VWF that significantly contributes to the clearance of both wild-type and hyposialylated VWF. PMID- 29282215 TI - The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design. AB - Zika and dengue viruses belong to the Flavivirus genus, a close group of antigenically related viruses that cause significant arthropod-transmitted diseases throughout the globe. Although infection by a given flavivirus is thought to confer lifelong protection, some of the patient's antibodies cross react with other flaviviruses without cross-neutralizing. The original antigenic sin phenomenon may amplify such antibodies upon subsequent heterologous flavivirus infection, potentially aggravating disease by antibody-dependent enhancement (ADE). The most striking example is provided by the four different dengue viruses, where infection by one serotype appears to predispose to more severe disease upon infection by a second one. A similar effect was postulated for sequential infections with Zika and dengue viruses. In this review, we analyze the molecular determinants of the dual antibody response to flavivirus infection or vaccination in humans. We highlight the role of conserved partially cryptic epitopes giving rise to cross-reacting and poorly neutralizing, ADE-prone antibodies. We end by proposing a strategy for developing an epitope-focused vaccine approach to avoid eliciting undesirable antibodies while focusing the immune system on producing protective antibodies only. PMID- 29282219 TI - Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. AB - Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALRdel/+ mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALRdel/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALRdel/+ HSCs were more proliferative in vitro, but neither CALRdel/+ nor CALRdel/del displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF. PMID- 29282220 TI - Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18 Mediated Inflammation-Independent Mechanism. AB - Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-kappaB activation and reduced expression of mature IL18, but not IL1beta, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1beta and IL1alpha activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1beta, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res; 78(5); 1293-307. (c)2017 AACR. PMID- 29282222 TI - A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2'-Deoxycytidine. AB - The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA-demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing H3K4me3 peaks. Furthermore, cells treated with the drug combination exhibited increased promoter and gene body H3K4me3 occupancy at DAC-responsive genes compared with DAC alone. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. KDM5i synergized with DAC to reduce the viability of luminal breast cancer cells in in vitro assays. Our study provides the first look into the molecular effects of a novel KDM5i compound and suggests that combinatorial inhibition along with DAC represents a new area to explore in translational epigenetics.Significance: This study offers a first look into the molecular effects of a novel KDM5 inhibitory compound, suggesting how its use in combination with DNA methylation inhibitors presents new opportunities to explore in translational cancer epigenetics. Cancer Res; 78(5); 1127-39. (c)2017 AACR. PMID- 29282221 TI - Brain-Mimetic 3D Culture Platforms Allow Investigation of Cooperative Effects of Extracellular Matrix Features on Therapeutic Resistance in Glioblastoma. AB - Glioblastoma (GBM) tumors exhibit potentially actionable genetic alterations against which targeted therapies have been effective in treatment of other cancers. However, these therapies have largely failed in GBM patients. A notable example is kinase inhibitors of EGFR, which display poor clinical efficacy despite overexpression and/or mutation of EGFR in >50% of GBM. In addressing this issue, preclinical models may be limited by the inability to accurately replicate pathophysiologic interactions of GBM cells with unique aspects of the brain extracellular matrix (ECM), which is relatively enriched in hyaluronic acid (HA) and flexible. In this study, we present a brain-mimetic biomaterial ECM platform for 3D culturing of patient-derived GBM cells, with improved pathophysiologic properties as an experimental model. Compared with orthotopic xenograft assays, the novel biomaterial cultures we developed better preserved the physiology and kinetics of acquired resistance to the EGFR inhibition than gliomasphere cultures. Orthogonal modulation of both HA content and mechanical properties of biomaterial scaffolds was required to achieve this result. Overall, our findings show how specific interactions between GBM cell receptors and scaffold components contribute significantly to resistance to the cytotoxic effects of EGFR inhibition.Significance: Three-dimensional culture scaffolds of glioblastoma provide a better physiological representation over current methods of patient derived cell culture and xenograft models. Cancer Res; 78(5); 1358-70. (c)2017 AACR. PMID- 29282223 TI - Combined Mutation of Apc, Kras, and Tgfbr2 Effectively Drives Metastasis of Intestinal Cancer. AB - Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. ApcDelta716 mutation caused intestinal adenomas and combination with Trp53R270H mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of ApcDelta716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either ApcDelta716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a ApcDelta716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upregulated genes in ApcDelta716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFbeta signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.Significance: These findings illuminate how key driver mutations in colon cancer cooperate to drive the development of metastatic disease, with potential implications for the development of suitable prevention strategies. Cancer Res; 78(5); 1334-46. (c)2017 AACR. PMID- 29282224 TI - Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility. AB - Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27-dependent proliferation toward CD70-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes. PMID- 29282225 TI - Risk of Invasive Pneumococcal Disease in Children with Sickle Cell Disease in England: A National Observational Cohort Study, 2010-2015. AB - OBJECTIVE: To describe the clinical presentation, risk factors, serotype distribution and outcomes of invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in the UK. DESIGN: Prospective national newborn screening for SCD and enhanced national IPD surveillance. PARTICIPANTS: Children with SCD born in England between 1 September 2010 and 31 August 2014 who developed laboratory-confirmed IPD by 31 December 2015. MAIN OUTCOMES AND MEASURES: Risk of IPD in children with SCD compared with children without SCD during the surveillance period. RESULTS: Eleven children homozygote for haemoglobin S (HbSS) and one double heterozygote for haemoglobin S and C (HbSC) developed IPD. Septicaemia (n=7) and lower respiratory tract infection (n=4) were the main clinical presentations, and serogroup 15 (not present in PCV13) was responsible for 73% (8/11) of cases. Three children with HbSS (27%) died compared with <5% nationally. Children with HbSS had a 49-fold (95% CI 27 to 89, P<0.001) higher risk of IPD compared with their peers without SCD. CONCLUSIONS: Children with SCD remain at increased risk of IPD despite national newborn screening, early penicillin prophylaxis and high pneumococcal vaccine uptake. They are also more likely to die of their infection compared with their peers without SCD. Most IPD cases are now due to serotypes not covered by PCV13. Healthcare professionals need to work more closely with families with SCD and local communities to emphasise the importance of penicillin prophylaxis, explore barriers, allay misguided beliefs and facilitate rapid access to healthcare. PMID- 29282227 TI - Identifying and Mitigating Risk of Violence in the Scientific Workplace. PMID- 29282226 TI - Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome. AB - Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1-4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear. PMID- 29282228 TI - On Publishing the Unpublishable. PMID- 29282229 TI - Current Risk Management Practices in Psychotherapy Supervision. AB - Psychotherapy competence is a core skill for psychiatry residents, and psychotherapy supervision is a time-honored approach to teaching this skill. To explore the current supervision practices of psychiatry training programs, a 24 item questionnaire was sent to all program directors of Accreditation Council for Graduate Medical Education (ACGME)-approved adult psychiatry programs. The questionnaire included items regarding adherence to recently proposed therapy supervision practices aimed at reducing potential liability risk. The results suggested that current therapy supervision practices do not include sufficient management of the potential liability involved in therapy supervision. Better protections for patients, residents, supervisors and the institutions would be possible with improved credentialing practices and better documentation of informed consent and supervision policies and procedures. PMID- 29282230 TI - Deconstructing Risk Management in Psychotherapy Supervision. AB - In the ongoing controversy over how much regulation and standardization to impose on clinical practice and research, it is not surprising that the activity of psychotherapy supervision should be swept up in the drive for uniformity. The managers amongst us want to regulate and institutionalize all aspects of practice. In opposition, many clinicians resist the relentless march toward the safety of uniformity travel alongside managerial imposition of regulations. Psychotherapy supervision's method of a close apprenticeship relationship between supervisor and trainee and its focus on the process and ethics of professional interaction stand at the humanistic core of what is otherwise becoming an increasingly mechanistic model of providing care to persons with mental illness. Our commentary picks up on these themes as it reviews the work by Mehrtens et al about strengthening awareness of liability in psychiatry residency training programs. We argue that the practice of psychiatry is overburdened by documentation requirements. In imposing further record-keeping on psychotherapy supervision, we lose much more than we gain. We recommend that the supervisory process focus on the characterological virtues essential to functioning as an ethical therapist. We also argue that self-protective rules place restraints on possibilities for imaginative insights and innovations in psychotherapy. PMID- 29282232 TI - The Competency Paradox in Somatic Disease. AB - Westmoreland et al. have reviewed factors associated with provider reluctance to initiate and judicial reluctance to authorize civil commitment and involuntary treatment for persons with severe anorexia nervosa. Their analysis of the legal, medical, and psychiatric elements that affect treatment outcomes contributes to professional understanding of a complex topic. Although their proposal to create guidelines for involuntary treatment for persons with eating disorders may be of clinical utility, guidelines should not be promulgated for the purposes of reaching judicial findings of law. PMID- 29282231 TI - Involuntary Treatment of Patients With Life-Threatening Anorexia Nervosa. AB - Anorexia nervosa has the highest mortality rate of any psychiatric illness. Predictors of mortality include chronicity of the illness, critically low body weight, and binging and purging behavior. Delusional beliefs body image, coupled with impaired judgment and cognition caused by starvation, often result in these patients adamantly resisting efforts to treat them. Guardianship, although useful in assisting with medical treatment decisions for patients with anorexia nervosa who are critically medically ill, is usually an inadequate intervention with respect to psychiatric treatment for these patients. Despite the severity and risk of the illness, there is often reluctance among providers to initiate involuntary treatment for patients with anorexia nervosa. Recent legal cases involving patients with anorexia nervosa have addressed the role of the committing court in authorizing treatment decisions and, in one case, opining that a patient was best served by receiving treatment in another state. Other related concerns addressed by the courts include ensuring that appropriate criteria are used for hospital admission, clarifying that the definition of grave disability as it pertains to anorexia does not require that the patient be close to death and that medications are often warranted in treating patients with the disease. PMID- 29282233 TI - Ethanol Forensic Toxicology. AB - Ethanol abuse can lead to negative consequences that oftentimes result in criminal charges and civil lawsuits. When an individual is suspected of driving under the influence, law enforcement agents can determine the extent of intoxication by measuring the blood alcohol concentration (BAC) and performing a standardized field sobriety test. The BAC is dependent on rates of absorption, distribution, and elimination, which are influenced mostly by the dose of ethanol ingested and rate of consumption. Other factors contributing to BAC are gender, body mass and composition, food effects, type of alcohol, and chronic alcohol exposure. Because of individual variability in ethanol pharmacology and toxicology, careful extrapolation and interpretation of the BAC is needed, to justify an arrest and assignment of criminal liability. This review provides a summary of the pharmacokinetic properties of ethanol and the clinical effects of acute intoxication as they relate to common forensic questions. Concerns regarding the extrapolation of BAC and the implications of impaired memory caused by alcohol-induced blackouts are discussed. PMID- 29282234 TI - Validation of CRAFFT for Use in Youth Correctional Institutions in Lagos, Nigeria. AB - Substance-related disorders (SRD) are common psychiatric morbidities among adolescents within youth correctional systems. Identification and treatment of SRDs is critical for successful reformation and reintegration. Lack of simple, structured, valid, brief screening instruments that can be easily administered and scored by lay workers militates against screening for SRDs. We present the results of the reliability and concurrent validity of the CRAFFT (acronym for Car, Relax, Alone, Forget, Friends, and Trouble) substance abuse screening instrument among residents of youth correctional facilities in Lagos, Nigeria. Adolescents who screened positive on CRAFFT were further assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) to determine whether they met diagnostic criteria for SRDs. The mean CRAFFT scores for all the adolescents (n = 178) was 0.66 (SD +/- 1.45). A total of 23 (12.9%) had CRAFFT scores of >1.00. The CRAFFT instrument has good internal consistency (Cronbach's alpha = 0.85) and 2-week test reliability (Spearman correlation = 0.979; p < .001). At a cutoff point of >1.00, CRAFFT had the best sensitivity and specificity (area under the curve = 0.889; 95% confidence interval 0.765-1.000) among the participants. As validated, the CRAFFT is a reliable instrument for screening for SRDs in incarcerated youth. PMID- 29282235 TI - The Forensic Mental Health Services Census of Forensic Populations in State Facilities. AB - This article focuses on the development of a Forensic Mental Health Services Census (FMHSC), proposed to differentiate between five different patient populations institutionalized in state facilities. The FMHSC would comprise patients who are civilly committed for mental illness or sexual dangerousness, those found incompetent to stand trial, those committed after a verdict of not guilty by reason of insanity, and those voluntarily committed. The census would be performed by state mental health authorities for each of these populations within the particular jurisdiction and then would be reported to a national coordinating organization. These data are important because of the large number of persons involved and the significant resources devoted to the management and treatment of each involuntary group. The census is necessary for clinical, research, and policy purposes, to provide more rational management of these populations, both within and across jurisdictions. PMID- 29282236 TI - Probable Standards of Care for Suicide Risk Assessment. AB - The legal standard of care for assessing and responding to suicide risk has historically been ambiguous, creating inconsistency in the testimony of forensic experts and uncertainty about clinical responsibilities among practitioners. In this article, I rigorously apply the legal concept of reasonable care to identify clinical activities that courts could collectively consider as evidence of reasonably careful suicide risk assessments. I derived six clinical activities, which I refer to as probable standards, from a review of legal scholarship in tort law, court cases involving suicidal behavior, and forensic papers on suicide risk assessment. I discuss the basis for each probable standard and offer commentary to aid in their interpretation. My intention is not to define the legal standard of care for suicide risk assessments (only courts can do so) or to create a clinical practice guideline, but to establish legally informed reference points to assist forensic experts in providing objective, consistent, and compelling testimony. PMID- 29282237 TI - Temptations for The Expert Witness. PMID- 29282238 TI - Behavioral Addictions and Criminal Responsibility. AB - Certain behavioral addictions pose difficult and unresolved problems for the criminal justice system. These disorders are characterized by strong desire states and may be associated with illegal behaviors that are committed to support the addiction. In this article, we begin with a general account of criminal responsibility and provide the legally relevant phenomenology and cognitive features of behavioral addictions. We then discuss how the legal system has approached two behavioral addictions, gambling disorder and kleptomania, during criminal trials and at sentencing. The conclusion summarizes an approach to the adjudication of behavioral addiction-related criminal behavior. PMID- 29282239 TI - Prescribing Opioid Replacement Therapy in U.S. Correctional Settings. AB - Opioid addiction is a chronic, relapsing disorder associated with criminality, unemployment, infectious diseases, and legal problems. Such addictions are typically over-represented in correctional populations. Inmates with untreated opioid addiction often relapse shortly after release into the community, thereby increasing the risk of overdose, serious illnesses (HIV, hepatitis C) and psychosocial problems (e.g., crimes, recidivism, and reincarceration). There are three U.S. Food and Drug Administration-approved medications for the treatment of opioid use disorder: methadone, buprenorphine, and naltrexone. Opioid replacement therapies (ORTs) are associated with significant benefits, including reducing the incidences of HIV, criminality, and opioid-related mortality. However, most opioid-dependent Americans who are incarcerated are forced to discontinue ORT upon prison entry. This article offers a rationale for providing ORT to addicted prisoners while incarcerated and providing appointments with outpatient providers for continued treatment. PMID- 29282240 TI - Prohibition of Persons With Mental Illness From Gun Ownership Under Tyler. AB - The U.S. Supreme Court's Heller and McDonald decisions are the most important legal affirmations of the right of U.S. citizens to possess and bear firearms under the Second Amendment. Heller and McDonald are also significant in citing persons with mental illness as an exceptional group, whose right may be restricted by the U.S. Government. From 1968 onward, federal and state governments have enacted legislation prohibiting gun ownership by persons with mental illness who have been involuntarily committed to an institution or deemed by a legal authority to be dangerous or mentally incompetent. The U.S. Sixth Circuit Court of Appeals in its first Tyler decision (Tyler I) placed limitations on legislation that restricts persons with mental illness from owning firearms. In its second decision (Tyler II), the appellate court reversed and remanded the case to the district court with instruction to apply "intermediate scrutiny" to determine whether this statute was constitutionally applied to appellant Charles Tyler, whose right to possess firearms was restricted in 1985 after a singular involuntary commitment during a transitory mental health crisis. Although it applies only to the Sixth Circuit, Tyler could have precedential influence on gun restrictions for persons with mental illness in other jurisdictions. PMID- 29282241 TI - Balancing Sexual Expression and Risk of Harm in Elderly Persons with Dementia. AB - Assessing decision-making capacity in older individuals with dementia, now known as major neurocognitive disorder (MND), is a complex and challenging endeavor. There is a dearth of literature that touches on the sensitive and controversial topic of sexuality in institutionalized settings, despite the rapid increase in the global population of older individuals. In this article, we assert that evaluations of sexual expression in institutionalized older individuals with MND is essential, as there are concerns specific to risks and benefits of sexual expression in elderly persons with MND that should be considered. Jurisdictions differ in the interpretation of capacity to consent to sexual activity, and there are also discrepancies in policies regarding assessment of sexual activity in residents in long-term care facilities. In addition, there is controversy within the literature regarding how to assess capacity to consent to sexual activity in elderly persons with MND. We discuss some of the proposed methods and consider ways that the evaluee's life narrative can help explore the various prongs of capacity. PMID- 29282242 TI - Arteriosclerosis, Thrombosis, and Vascular Biology. PMID- 29282243 TI - Extracellular Vesicles Act as Messengers of Macrophages Sensing Atherogenic Stimuli. PMID- 29282244 TI - Oxidized Lipid Uptake by Scavenger Receptor CD36 (Cluster of Differentiation 36) Modulates Endothelial Surface Properties and May Contribute to Atherogenesis. PMID- 29282245 TI - Knockdown of Delta-5 Fatty Acid Desaturase Is More Than Just a Fad. PMID- 29282246 TI - X Marks the Spot: The Profound Impact of Sex on Aortic Disease. PMID- 29282248 TI - Correction to: Lymphangiogenesis Facilitates Initial Lymph Formation and Enhances the Dendritic Cell Mobilizing Chemokine CCL21 Without Affecting Migration. PMID- 29282247 TI - Highlighting Diabetes Mellitus: The Epidemic Continues. PMID- 29282249 TI - Phosphate-dependent luminal ATP metabolism regulates transcellular calcium transport in intestinal epithelial cells. AB - Extracellular low phosphate strongly enhances intestinal calcium absorption independently of active vitamin D [1,25(OH)2D3] signaling, but the underlying mechanisms remain poorly characterized. To elucidate the phosphate-dependent regulation of calcium transport, we investigated part of the enteral environment that is involved in 1,25(OH)2D3-independent calcium absorption, which responds to dietary phosphate levels in mice that lack intestinal vitamin D receptor ( Vdr) activity. Impaired calcium absorption in intestinal Vdr-null mice was improved by dietary phosphate restriction. Accordingly, calcium transport in cultured intestinal epithelial cells was increased when the apical side was exposed to low phosphate levels (0.5 mM) compared with normal or high phosphate levels (1.0 or 5.0 mM, respectively). Mechanistically, low phosphate increased ATP in the apical side medium and allowed calcium entry into epithelial cells via the P2X7 purinoreceptor, which results in increased calcium transport. We found that luminal ATP was regulated by the release and degradation of ATP at the epithelium, and phosphate restriction increased ATP release from epithelial cells via connexin-43 hemichannels. Furthermore, ATP degradation by ectonucleotide pyrophosphatase-1 was reduced, which was caused by the reduction of the MAPK cascade. These findings indicate that luminal ATP metabolism regulates transcellular calcium transport in the intestine by an 1,25(OH)2D3-independent mechanism in response to dietary phosphate levels.-Uekawa, A., Yamanaka, H., Lieben, L., Kimira, Y., Uehara, M., Yamamoto, Y., Kato, S., Ito, K., Carmeliet, G., Masuyama, R. Phosphate-dependent luminal ATP metabolism regulates transcellular calcium transport in intestinal epithelial cells. PMID- 29282250 TI - Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. AB - Obesity is a chronic organismal stress that disrupts multiple systemic and tissue specific functions. In this study, we describe the impact of obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity alters the composition of the HSC compartment and its activity in response to hematopoietic stress. The impact of obesity on HSC function is progressively acquired but persists after weight loss or transplantation into a normal environment. Mechanistically, we establish that the oxidative stress induced by obesity dysregulates the expression of the transcription factor Gfi1 and that increased Gfi1 expression is required for the abnormal HSC function induced by obesity. These results demonstrate that obesity produces durable changes in HSC function and phenotype and that elevation of Gfi1 expression in response to the oxidative environment is a key driver of the altered HSC properties observed in obesity. Altogether, these data provide phenotypic and mechanistic insight into durable hematopoietic dysregulations resulting from obesity. PMID- 29282251 TI - gammadelta T cells provide the early source of IFN-gamma to aggravate lesions in spinal cord injury. AB - Immune responses and neuroinflammation are critically involved in spinal cord injury (SCI). gammadelta T cells, a small subset of T cells, regulate the inflammation process in many diseases, yet their function in SCI is still poorly understood. In this paper, we demonstrate that mice deficient in gammadelta T cells (TCRdelta-/- ) showed improved functional recovery after SCI. gammadelta T cells are detected at the lesion sites within 24 hours after injury and are predominantly of the Vgamma4 subtype and express the inflammatory cytokine IFN gamma. Inactivating IFN-gamma signaling in macrophages results in a significantly reduced production of proinflammatory cytokines in the cerebrospinal fluid (CSF) of mice with SCIs and improves functional recovery. Furthermore, treatment of SCI with anti-Vgamma4 antibodies has a beneficial effect, similar to that obtained with anti-TNF-alpha. In SCI patients, gammadelta T cells are detected in the CSF, and most of them are IFN-gamma positive. In conclusion, manipulation of gammadelta T cell functions may be a potential approach for future SCI treatment. PMID- 29282252 TI - Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor. AB - Iron-restricted human anemias are associated with the acquisition of marrow resistance to the hematopoietic cytokine erythropoietin (Epo). Regulation of Epo responsiveness by iron availability serves as the basis for intravenous iron therapy in anemias of chronic disease. Epo engagement of its receptor normally promotes survival, proliferation, and differentiation of erythroid progenitors. However, Epo resistance caused by iron restriction selectively impairs proliferation and differentiation while preserving viability. Our results reveal that iron restriction limits surface display of Epo receptor in primary progenitors and that mice with enforced surface retention of the receptor fail to develop anemia with iron deprivation. A mechanistic pathway is identified in which erythroid iron restriction down-regulates a receptor control element, Scribble, through the mediation of the iron-sensing transferrin receptor 2. Scribble deficiency reduces surface expression of Epo receptor but selectively retains survival signaling via Akt. This mechanism integrates nutrient sensing with receptor function to permit modulation of progenitor expansion without compromising survival. PMID- 29282253 TI - Maturation of hematopoietic stem cells from prehematopoietic stem cells is accompanied by up-regulation of PD-L1. AB - Hematopoietic stem cells (HSCs) mature from pre-HSCs that originate in the major arteries of the embryo. To identify HSCs from in vitro sources, it will be necessary to refine markers of HSCs matured ex vivo. We purified and compared the transcriptomes of pre-HSCs, HSCs matured ex vivo, and fetal liver HSCs. We found that HSC maturation in vivo or ex vivo is accompanied by the down-regulation of genes involved in embryonic development and vasculogenesis, and up-regulation of genes involved in hematopoietic organ development, lymphoid development, and immune responses. Ex vivo matured HSCs more closely resemble fetal liver HSCs than pre-HSCs, but are not their molecular equivalents. We show that ex vivo matured and fetal liver HSCs express programmed death ligand 1 (PD-L1). PD-L1 does not mark all pre-HSCs, but cell surface PD-L1 was present on HSCs matured ex vivo. PD-L1 signaling is not required for engraftment of embryonic HSCs. Hence, up-regulation of PD-L1 is a correlate of, but not a requirement for, HSC maturation. PMID- 29282254 TI - Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells. AB - Upon infection with an intracellular pathogen, cytotoxic CD8+ T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained. To study the spectrum of T cell differentiation, we have analyzed an infection with mouse cytomegalovirus, a persistent-latent virus that elicits different cytotoxic T cell responses characterized as acute resolving or inflationary. Our results show that FOXO1 is continuously required for all the phenotypic characteristics of memory-effector T cells such that with acute inactivation of the gene encoding FOXO1, T cells revert to a short-lived effector phenotype, exhibit reduced viability, and manifest characteristics of anergy. PMID- 29282255 TI - Pregnancy exposure to air pollution and early childhood respiratory health in the Norwegian Mother and Child Cohort Study (MoBa). AB - OBJECTIVES: It is unclear whether maternal air pollution exposure during pregnancy induces changes in the developing respiratory system of a child and whether it has consequences for respiratory health in early childhood. We investigated associations between exposure to moderate levels of air pollution during pregnancy and early childhood lower respiratory tract infections (LRTI) and wheezing. METHODS: This study used a subgroup of 17 533 participants in the Norwegian Mother and Child Cohort Study. Air pollution levels at residential addresses were estimated using land use regression models, and back-extrapolated to the period of each pregnancy. Information on LRTI and wheezing and lifestyle factors was collected from questionnaires completed by mothers during pregnancy and when the child was 6 and 18 months of age. RESULTS: Moderate mean levels of NO2 (13.6 ug/m3, range 0.01-60.4) exposure at residential address during pregnancy were not statistically associated with LRTI and wheezing. No association was found per 10 ug/m3 change in NO2 exposure and LRTI before the age of 6 months (adjusted risk ratio (RR) 0.99; 95% CI 0.84 to 1.17), or between 6 and 18 months of age (adjusted RR 1.05; 95% CI 0.94 to 1.16). Similarly, we found no association per 10 ug/m3 change in NO2 exposure and wheezing between 6 and 18 months of age (adjusted RR 1.02; 95% CI 0.97 to 1.07). CONCLUSIONS: There were no statistically significant associations for moderate levels of pregnancy NO2 exposure and respiratory health outcomes during early childhood in overall analyses. PMID- 29282256 TI - Comprehensive assessment of health education and health promotion in five non communicable disease demonstration districts in China: a cross-sectional study. AB - OBJECTIVES: This study aims to develop assessment indicators of health education and promotion for non-communicable disease (NCD) demonstration districts in China and to identify significant factors associated with NCD health education and promotion work. METHODS: Three complementary techniques were used to conduct this study in Hunan Province, China, between late 2013 and 2015. The Delphi technique was used to develop weighted assessment indicators, followed by the rank sum ratio (RSR) to normalise the weights through rank conversion. Lastly, the technique for order of preference by similarity to ideal solution was conducted to assess five randomly selected NCD demonstration districts representing five different orientations in the province. RESULTS: A total of 24 assessment indicators were constructed covering the following sections: organisational management, fund support, personnel supplies, health education and promotion, people's awareness of NCDs, management and control of patients with NCD, satisfaction with health education and promotion and health literacy of residents. Five districts were selected as samples for evaluation (Furong District, Ziyang District, Shaodong County, Shuangfeng County and Luxi County). Performance varied among the sites, with Furong District greatly surpassing the other sites, especially in fund support, media promotion, technical support for publicity materials, community promotion and supportive environment supplies. The latter four factors were also much greater in the second-ranked Luxi County site than those in the other sites (except Furong District). CONCLUSIONS: There were gaps in health education and promotion work in NCD demonstration districts in Hunan Province. The districts that performed better had obvious advantages in fund support, media promotion, technical support, community promotion and supportive environment supplies. Our study provided both a methodological reference and an assessment indicator framework for similar future studies. PMID- 29282257 TI - Barriers and facilitators of physical activity in knee and hip osteoarthritis: a systematic review of qualitative evidence. AB - : Physical activity (PA), including engagement in structured exercise, has a key role in the management of hip and knee osteoarthritis (OA). However, maintaining a physically active lifestyle is a challenge for people with OA. PA determinants in this population need to be understood better so that they can be optimised by public health or healthcare interventions and social policy changes. OBJECTIVES: The primary aim of this study is to conduct a systematic review of the existing qualitative evidence on barriers and facilitators of PA for patients with hip or knee OA. Secondary objective is to explore differences in barriers and facilitators between (1) lifestyle PA and exercise and (2) PA uptake and maintenance. METHODS: Medline, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, SPORTDiscus, Scopus, Grey literature and qualitative journals were searched. Critical Appraisal Skills Programme Qualitative checklist and Lincoln and Guba's criteria were used for quality appraisal. Thematic synthesis was applied. FINDINGS: Ten studies were included, seven focusing on exercise regimes, three on overall PA. The findings showed a good fit with the biopsychosocial model of health. Aiming at symptom relief and mobility, positive exercise experiences and beliefs, knowledge, a 'keep going' attitude, adjusting and prioritising PA, having healthcare professionals' and social support emerged as PA facilitators. Pain and physical limitations; non positive PA experiences, beliefs and information; OA-related distress; a resigned attitude; lack of motivation, behavioural regulation, professional support and negative social comparison with coexercisers were PA barriers. All themes were supported by high and medium quality studies. Paucity of data did not allow for the secondary objectives to be explored. CONCLUSION: Our findings reveal a complex interplay among physical, personal including psychological and social environmental factors corresponding to the facilitation and hindrance of PA, particularly exercise, engagement. Further research on the efficacy of individualised patient education, psychological interventions or social policy change to promote exercise engagement and lifestyle PA in individuals with lower limb OA is required. TRIAL REGISTRATION NUMBER: CRD42016030024. PMID- 29282258 TI - Is sexual minority status associated with poor sleep quality among adolescents? Analysis of a national cross-sectional survey in Chinese adolescents. AB - OBJECTIVES: Recent studies have suggested that sexual minorities are more likely to have poor sleep quality. This study aims to explore sleep quality among sexual minority adolescents and examines the association between sexual minority status and sleep quality. DESIGN: Cross-sectional survey. SETTING: A total of 506 high schools in seven Chinese provinces. PARTICIPANTS: A total of 150 822 students in grades 7-12 completed the questionnaires, and 123 459 students who reported being aware of their sexual orientation were included in analyses. MAIN OUTCOME MEASURES: The Pittsburgh Sleep Quality Index, sexual attraction and school bullying victimisation. RESULTS: Of the 123 459 students who were analysed, 5.00% self-reported as sexual minorities. Only 26.67% of sexual minority students slept 8 or more hours/day, which is less than their heterosexual peers (35.70%; chi2=130.04, P<0.001). Of the total sample, 22.41% of the students reported poor sleep quality, and this prevalence was significantly higher in sexual minority students than in heterosexual students (32.56% vs 21.87%; chi2=281.70, P<0.001). After controlling for social demographics, lifestyle and depressive symptoms, sexual minority students had higher odds of poor sleep quality (adjusted OR=1.41, 95% CI 1.31 to 1.51) than their heterosexual peers. The indirect effect of school bullying victimisation (standardised beta estimate=0.007, 95% CI 0.006 to 0.009) was significant, indicating that school bullying victimisation partially mediated the association between sexual minority status and sleep quality. CONCLUSIONS: Our study suggested that poor sleep quality was common in sexual minority adolescents, and more attention should be paid to sleep problems in this population. Conducting interventions to reduce school bullying behaviours is an important step to improving sleep quality in sexual minority adolescents. Further, studies are warranted that focus on the risk factors and mechanisms of and interventions for sleep problems in sexual minority adolescents. PMID- 29282259 TI - Exercise response in Parkinson's disease: insights from a cross-sectional comparison with sedentary controls and a per-protocol analysis of a randomised controlled trial. AB - OBJECTIVES: To investigate the acute and adaptation cardiovascular and metabolic training responses in people with Parkinson's disease (pwP). DESIGN: (1) A cross sectional study of exercise response of pwP compared with sedentary controls and (2) an interventional study of exercise training in pwP. SETTING: Community leisure facilities. PARTICIPANTS: pwP (n=83) and sedentary controls (n=55). INTERVENTIONS: Study 1 included participants from a two-arm-parallel single-blind phase II randomised controlled trial (RCT), that undertook a baseline maximal incremental exercise test and study 2 included those randomised to the exercise group in the RCT, who completed a 6-month weekly exercise programme (n=37). The intervention study 2 was a prescribed exercise program consisting of sessions lasting 60 min, two times a week over a 6-month period. The control group followed the same protocol which derived the same cardiorespiratory parameters, except that they were instructed to aim for a cadence of ~60 revolutions per minute and the unloaded phase lasted 3 min with an initial step of 25 W. PRIMARY AND SECONDARY OUTCOME MEASURES: Stepwise incremental exercise test to volitional exhaustion was the primary outcome measure. RESULTS: Study 1 showed higher maximum values for heart rate (HR), VO2 L/min, VCO2 L/min and ventilation L/min for the control group; respiratory exchange ratio (RER), perceived exertion and O2 pulse (VO2 L/min/HR) did not differ between groups. In study 2, for pwP who adhered to training (n=37), RER increased significantly and although there was no significant change in aerobic capacity or HR response, reduced blood pressure was found. CONCLUSIONS: An abnormal cardiovascular response to exercise was observed in pwP compared to controls. After the exercise programme, metabolic deficiencies remained for pwP. These observations add to the pathogenic understanding of PD, acknowledge an underling metabolic contribution and support that certain cardiovascular symptoms may improve as a result of this type of exercise. PMID- 29282260 TI - Chronic non-bacterial osteitis from the patient perspective: a health services research through data collected from patient conferences. AB - OBJECTIVE: Although chronic non-bacterial osteitis (CNO) is an ever-increasingly recognised illness in the paediatric community and the adult healthcare community, a study to assess diagnosing, treatment and the psychosocial aspect of CNO from a large population pool was not available. We aimed to investigate CNO from the patient perspective. DESIGN: Health services research, patient survey. SETTING: Ludwig-Maximilians-University (LMU) Pediatric Rheumatology Department CNO Conferences held in June 2013 and June 2015. PARTICIPANTS: Using a patient survey developed by the LMU Pediatric Rheumatology Department, 105 patients from ages 5 to 63 years were assessed regarding CNO to include epidemiological data, medical history and treatment, initial symptoms, diagnostic procedures, current symptoms, associated diseases, current treating physicians, absences in school and work due to illness and the impact of illness on patient, family and friends. RESULTS: Active CNO was reported in 90% of patients present, with 73% being women and 27% being men. An overwhelming majority (70%) reported being diagnosed within 18 months of onset of symptoms; however, the initial diagnoses were wide-ranged to include malignancies in 36% to bacterial osteomyelitis in 30%, where the majority were treated with an antibiotic and/or were biopsied. When asked about the psychosocial aspect of this illness, 83% reported that non-bacterial osteitis (NBO) negatively impacted the family, 79% reported that NBO has negatively affected either school or work and 56% reported a negative impact on friendships. CONCLUSION: Delay of diagnosis, living with differential diagnoses like malignancies and finding specialists for medical care are a few examples of what leads patients into searching for more information. The negative impact on daily life including family relationships, friendships and work/school highlights a need for better psychosocial support such as guidance counselling or psychological support due to three-quarters of patients receiving no such said support. PMID- 29282261 TI - ABC Index: quantifying experienced burden of COPD in a discrete choice experiment and predicting costs. AB - OBJECTIVE: The Assessment of Burden of COPD (ABC) tool supports shared decision making between patient and caregiver. It includes a coloured balloon diagram to visualise patients' scores on burden indicators. We aim to determine the importance of each indicator from a patient perspective, in order to calculate a weighted index score and investigate whether that score is predictive of costs. DESIGN: Discrete choice experiment. SETTING AND PARTICIPANTS: Primary care and secondary care in the Netherlands. 282 patients with chronic obstructive pulmonary disease (COPD) and 252 members of the general public participated. METHODS: Respondents received 14 choice questions and indicated which of two health states was more severe. Health states were described in terms of specific symptoms, limitations in physical, daily and social activities, mental problems, fatigue and exacerbations, most of which had three levels of severity. Weights for each item-level combination were derived from a Bayesian mixed logit model. Weights were rescaled to construct an index score from 0 (best) to 100 (worst). Regression models were used to find a classification of this index score in mild, moderate and severe that was discriminative in terms of healthcare costs. RESULTS: Fatigue, limitations in moderate physical activities, number of exacerbations, dyspnoea at rest and fear of breathing getting worse contributed most to the burden of disease. Patients assigned less weight to dyspnoea during exercise, listlessness and limitations with regard to strenuous activities. Respondents from the general public mostly agreed. Mild, moderate and severe burden of disease were defined as scores <20, 20-39 and >=40. This categorisation was most predictive of healthcare utilisation and annual costs: ?1368, ?2510 and ?9885, respectively. CONCLUSIONS: The ABC Index is a new index score for the burden of COPD, which is based on patients' preferences. The classification of the index score into mild, moderate and severe is predictive of future healthcare costs. TRIAL REGISTRATION NUMBER: NTR3788; Post-results. PMID- 29282263 TI - Feasibility of 2-D ultrasound shear wave elastography of fetal lungs in case of threatened preterm labour: a study protocol. AB - INTRODUCTION: 2-D ultrasound shear wave elastography (SWE) could be considered as a new noninvasive tool for monitoring fetal lung development based on evaluation of mechanical properties during pregnancy. Interesting results are available concerning the use of SWE on developing organs, especially on premature infants and animal models. The main objective in this study is to evaluate the feasibility of 2-D SWE in human fetal lungs between 24 and 34 weeks of gestation (WG). The secondary objective is to modellise fetal lung-to-liver elastography ratio (LLE ratio) and to assess variations between normal lung and lung surfactant-enriched after a corticosteroids course indicated for a threatened preterm labour (TPL). METHODS/DESIGN: A prospective case-control study will be performed between 24 and 34 WG. Fetal lungs and liver will be explored by SWE into two groups: fetuses of women with an uncomplicated pregnancy (control group) and fetuses of women with a TPL requiring administration of corticosteroids (cases group). LLE ratio will be defined as the value of the lung elasticity divided by the value of the liver elasticity.Primary judgement criterion is the value of elasticity modulus expressed in kilopascal. Lungs and liver will be explored through three measurements to define the most reproducible regions with the lowest intra- and inter-observer variability. Feasibility will be evaluated by assessing the number of examinations performed and the number of examinations with interpretable results. Intra- and inter-observer reproducibility will be evaluated by means of the intra-class correlation coefficient. ETHICS AND DISSEMINATION: Approval of the study protocol was obtained from the human ethical research committee (Comite de Protection des Personnes EST II, process number 15/494) and the French National Agency for Medicines and Health Products Safety (process number 2015-A01575-44). All participants will sign a statement of informed consent. TRIAL REGISTRATION NUMBER: NCT02870608; Recruiting. PMID- 29282262 TI - BRain health and healthy AgeINg in retired rugby union players, the BRAIN Study: study protocol for an observational study in the UK. AB - INTRODUCTION: Relatively little is known about the long-term health of former elite rugby players, or former sportspeople more generally. As well as the potential benefits of being former elite sportspersons, there may be potential health risks from exposures occurring during an individual's playing career, as well as following retirement. Each contact sport has vastly different playing dynamics, therefore exposing its players to different types of potential traumas. Current evidence suggests that these are not necessarily comparable in terms of pathophysiology, and their potential long-term adverse effects might also differ. There is currently limited but increasing evidence that poorer age-related and neurological health exists among former professional sportsmen exposed to repetitive concussions; however the evidence is limited on rugby union players, specifically. METHODS AND ANALYSIS: We present the protocol for a cross-sectional study to assess the association between self-reported history of concussion during a playing career, and subsequent measures of healthy ageing and neurological and cognitive impairment. We are recruiting a sample of approximately 200 retired rugby players (former Oxford and Cambridge University rugby players and members of the England Rugby International Club) aged 50 years or more, and collecting a number of general and neurological health-related outcome measures though validated assessments. Biomarkers of neurodegeneration (neurofilaments and tau) will be also be measured. Although the study is focusing on rugby union players specifically, the general study design and the methods for assessing neurological health are likely to be relevant to other studies of former elite sportspersons. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of London School of Hygiene and Tropical Medicine (reference: 11634-2). It is intended that results of this study will be published in peer-reviewed medical journals, communicated to participants, the general public and all relevant stakeholders. PMID- 29282264 TI - Comparing the diagnostic accuracy of five common tumour biomarkers and CA19-9 for pancreatic cancer: a protocol for a network meta-analysis of diagnostic test accuracy. AB - INTRODUCTION: Surgical resection is the only curative treatment for patients with resectable pancreatic cancer. Unfortunately, 80%-85% of patients present with locally advanced or metastatic unresectable pancreatic cancer at the time of diagnosis. Detection of pancreatic cancer at early stages remains a great challenge due to lack of accurate detection tests. Recommendations in existing clinical practice guidelines on early diagnosis of pancreatic cancer are inconsistent and based on limited evidence. Most of them endorse measuring serum CA19-9 as a complementary test, but also state that it is not recommended for diagnosing early pancreatic cancer. There are currently no other tumour-specific markers recommended for diagnosing early pancreatic cancer. This study aims to evaluate and compare the accuracy of five common tumour biomarkers (CA242,carcino embryonic antigen (CEA)), CA125, microRNAs and K-ras gene mutation) and CA19-9 and their combinations for diagnosing pancreatic cancer using network meta analysis method, and to rank these tests using a superiority index. METHODS AND ANALYSIS: PubMed, EMBASE and the Cochrane Central Register of Controlled Trials will be searched from inception to April 2017. The search will include the above mentioned tumour biomarkers for diagnosing pancreatic cancer, including CA19-9. The risk of bias for each study will be independently assessed as low, moderate or high using criteria adapted from the Quality Assessment of Diagnostic Accuracy Studies 2. Network meta-analysis will be performed using STATA V.12.0 and R software V.3.4.1. The competing diagnostic tests will be ranked by a superiority index. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required since this study is a network meta-analysis based on published studies. The results of this network meta-analysis will be submitted to a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42017064627. PMID- 29282265 TI - Does the implementation of a novel intensive care discharge risk score and nurse led inpatient review tool improve outcome? A prospective cohort study in two intensive care units in the UK. AB - OBJECTIVE: To develop a clinical prediction model for poor outcome after intensive care unit (ICU) discharge in a large observational data set and couple this to an acute post-ICU ward-based review tool (PIRT) to identify high-risk patients at the time of ICU discharge and improve their acute ward-based review and outcome. DESIGN: Retrospective patient cohort of index ICU admissions between June 2006 and October 2011 receiving routine inpatient review. Prospective cohort between March 2012 and March 2013 underwent risk scoring (PIRT) which subsequently guided inpatient ward-based review. SETTING: Two UK adult ICUs. PARTICIPANTS: 4212 eligible discharges from ICU in the retrospective development cohort and 1028 patients included in the prospective intervention cohort. INTERVENTIONS: Multivariate analysis was performed to determine factors associated with poor outcome in the retrospective cohort and used to generate a discharge risk score. A discharge and daily ward-based review tool incorporating an adjusted risk score was introduced. The prospective cohort underwent risk scoring at ICU discharge and inpatient review using the PIRT. OUTCOMES: The primary outcome was the composite of death or readmission to ICU within 14 days of ICU discharge following the index ICU admission. RESULTS: PIRT review was achieved for 67.3% of all eligible discharges and improved the targeting of acute post-ICU review to high-risk patients. The presence of ward-based PIRT review in the prospective cohort did not correlate with a reduction in poor outcome overall (P=0.876) or overall readmission but did reduce early readmission (within the first 48 hours) from 4.5% to 3.6% (P=0.039), while increasing the rate of late readmission (48 hours to 14 days) from 2.7% to 5.8% (P=0.046). CONCLUSION: PIRT facilitates the appropriate targeting of nurse-led inpatient review acutely after ICU discharge but does not reduce hospital mortality or overall readmission rates to ICU. PMID- 29282266 TI - Senior high-cost healthcare users' resource utilization and outcomes: a protocol of a retrospective matched cohort study in Canada. AB - INTRODUCTION: Senior high-cost users (HCUs) are estimated to represent 60% of all HCUs in Ontario, Canada's most populous province. To improve our understanding of individual and health system characteristics related to senior HCUs, we will examine incident senior HCUs to determine their incremental healthcare utilisation and costs, characteristics of index hospitalisation episodes, mortality and their regional variation across Ontario. METHODS AND ANALYSIS: A retrospective, population-based cohort study using administrative healthcare records will be used. Incident senior HCUs will be defined as Ontarians aged >=66 years who were in the top 5% of healthcare cost users during fiscal year 2013 but not during fiscal year 2012. Each HCU will be matched to three non-HCUs by age, sex and health planning region. Incremental healthcare use and costs will be determined using the method of recycled predictions. We will apply multivariable logistic regression to determine patient and health service factors associated with index hospitalisation and inhospital mortality during the incident year. The most common causes of admission will be identified and contrasted with the most expensive hospitalised conditions. We will also calculate the ratio of inpatient costs incurred through admissions of ambulatory care sensitive conditions to the total inpatient expenditures. The magnitude of variation in costs and health service utilisation will be established by calculating the extremal quotient, the coefficient of variation and the Gini mean difference for estimates obtained through multilevel regression analyses. ETHICS AND DISSEMINATION: This study has been approved by Hamilton Integrated Research Ethics Board (ID#1715-C). The results of the study will be distributed through peer-reviewed journals. They also will be disseminated at research events in academic settings, national and international conferences as well as with presentations to provincial health authorities. PMID- 29282267 TI - Stepped care approach for medial tibiofemoral osteoarthritis (STrEAMline): protocol for a randomised controlled trial. AB - INTRODUCTION: Current guidelines recommend tailored interventions to optimise knee osteoarthritis (OA) management. However, models of care still have a 'one size fits all' approach, which is suboptimal as it ignores patient heterogeneity. This study aims to compare a stepped care strategy with standard care for overweight and obese persons with medial tibiofemoral OA. METHODS AND ANALYSIS: Participants will be randomised into two groups (85 each). The intervention will receive a diet and exercise programme for 18 weeks in the first step of the study. Disease remission will then be assessed using the Patient Acceptable Symptom State (PASS). PASS is defined as the highest level of symptom beyond which patients consider themselves well and takes into account pain intensity, patient's global assessment of disease activity and degree of functional impairment. In the second step, participants in remission will continue with diet and exercise. If remission is not achieved, participants will be assigned in a hierarchical order to cognitive behavioural therapy, knee brace or muscle strengthening for 12 weeks. The intervention will be decided based on their clinical presentation for symptoms of depression and varus malalignment. Participants without depression or varus malalignment will undertake a muscle strengthening programme. The control group will receive educational material related to OA management. Main inclusion criteria are age >=50 years, radiographic medial tibiofemoral OA, body mass index (BMI) >=28 kg/m2, knee pain >=40 (Visual Analogue Scale, 0-100), PASS (0-100) >32 for pain and global assessment, and 31 for functional impairment. Outcomes will be measured at 20 week and 32-week visits. The primary outcome is disease remission at 32 weeks. Other outcomes include functional mobility; patient-reported outcomes; BMI; waist hip ratio; quadriceps strength; symptoms of depression, anxiety and stress; and knee range of motion. The analysis will be performed according to the intention to-treat principle. ETHICS AND DISSEMINATION: The local ethics committee approved this protocol (HREC/14/HAWKE/381). Dissemination will occur through presentations at international conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12615000227594. PMID- 29282269 TI - Effect of second child intent on delivery mode after Chinese two child policy implementation: a cross sectional and prospective observational study of nulliparous women in Chongqing. AB - OBJECTIVES: To assess the influence of second child intent on the delivery preferences and final delivery modes of nulliparous women, particularly caesarean delivery on maternal request (CDMR), after implementation of China's two child policy. DESIGN: Cross sectional and prospective observational study. SETTING: A tertiary teaching hospital in Chongqing, China. PARTICIPANTS: 1000 low risk nulliparous women were initially involved, and were divided into two groups based on their intent on having a second child. 814 women who completed all interviews were analysed. MAIN OUTCOME MEASURES: Preferred mode of delivery in second trimester and at admission; final delivery mode, CDMR. RESULTS: 814 women who completed all interviews were analysed, in whom 51.2% intended to have a second child. The preference for caesarean delivery (CD) at the second trimester between the intent and no intent group was 6.2% versus 17.9% (adjusted RR 0.35, 95% CI 0.20 to 0.63) and increased to 24.2% versus 37.3% (adjusted RR 0.65, 95% CI 0.45 to 0.94) at admission, respectively. The overall CD rates between the two groups were 41.0% versus 50.4% (adjusted RR 0.84, 95% CI 0.60 to 1.18), and the CDMR rates were 16.7% versus 29.0% (adjusted RR 0.56, 95% CI 0.37 to 0.86), respectively. CONCLUSIONS: Women who intend to have a second child are less likely to request a CD, and high rates of CD and CDMR in nulliparous women may have decreased after implementation of China's two child policy. PMID- 29282268 TI - Is computer-assisted instruction more effective than other educational methods in achieving ECG competence among medical students and residents? Protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Although ECG interpretation is an essential skill in clinical medicine, medical students and residents often lack ECG competence. Novel teaching methods are increasingly being implemented and investigated to improve ECG training. Computer-assisted instruction is one such method under investigation; however, its efficacy in achieving better ECG competence among medical students and residents remains uncertain. METHODS AND ANALYSIS: This article describes the protocol for a systematic review and meta-analysis that will compare the effectiveness of computer-assisted instruction with other teaching methods used for the ECG training of medical students and residents. Only studies with a comparative research design will be considered. Articles will be searched for in electronic databases (PubMed, Scopus, Web of Science, Academic Search Premier, CINAHL, PsycINFO, Education Resources Information Center, Africa Wide Information and Teacher Reference Center). In addition, we will review citation indexes and conduct a grey literature search. Data extraction will be done on articles that met the predefined eligibility criteria. A descriptive analysis of the different teaching modalities will be provided and their educational impact will be assessed in terms of effect size and the modified version of Kirkpatrick framework for the evaluation of educational interventions. This systematic review aims to provide evidence as to whether computer-assisted instruction is an effective teaching modality for ECG training. It is hoped that the information garnered from this systematic review will assist in future curricular development and improve ECG training. ETHICS AND DISSEMINATION: As this research is a systematic review of published literature, ethical approval is not required. The results will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement and will be submitted to a peer-reviewed journal. The protocol and systematic review will be included in a PhD dissertation. PROSPERO REGISTRATION NUMBER: CRD42017067054; Pre-results. PMID- 29282270 TI - Frailty measurement and outcomes in interventional studies: protocol for a systematic review of randomised control trials. AB - INTRODUCTION: Frailty is associated with reduced functional capacity, decreased resistance to stressors and is predictive of a range of adverse health outcomes, including dependency, hospitalisation and mortality. Early identification of frailty may prevent, reduce and postpone adverse health outcomes. However, there is a need for additional evidence to guide decision-making for the care of frail patients since frail persons are frequently excluded from studies, the differential impact of frailty is often not examined in clinical trials and few large-scale clinical trials examining frail cohorts have been conducted. Randomised control trials (RCTs) published to date have used a diverse range of definitions of frailty, as well as a variety of outcome measures. The objective of this systematic review is to comprehensively characterise the frail populations enrolled and the end points reported in frailty RCTs. METHODS AND ANALYSIS: We will identify all RCTs reporting on the outcome of interventions in adult (age >=18 years) frail populations as defined by authors, in all settings of care. Databases will include MEDLINE, CINAHL, EMBASE, PsycInfo, Global Health, the Joanna Briggs database and Cochrane Library. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction, inter-rater reliability, risk of bias assessment and evaluation of the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. ETHICS AND DISSEMINATION: This systematic review will comprehensively identify RCTs including frail patients to identify how frailty is measured and which outcomes are reported. The results of this systematic review may inform clinicians caring for persons with frailty, facilitate conduct of future RCTs and inform future efforts to develop common data elements and core outcomes for frailty studies. Our findings will be disseminated through conference presentation and publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42017065233. PMID- 29282272 TI - Our Health Counts Toronto: using respondent-driven sampling to unmask census undercounts of an urban indigenous population in Toronto, Canada. AB - OBJECTIVES: To provide evidence of the magnitude of census undercounts of 'hard to-reach' subpopulations and to improve estimation of the size of the urban indigenous population in Toronto, Canada, using respondent-driven sampling (RDS). DESIGN: Respondent-driven sampling. SETTING: The study took place in the urban indigenous community in Toronto, Canada. Three locations within the city were used to recruit study participants. PARTICIPANTS: 908 adult participants (15+) who self-identified as indigenous (First Nation, Inuit or Metis) and lived in the city of Toronto. Study participants were generally young with over 60% of indigenous adults under the age of 45 years. Household income was low with approximately two-thirds of the sample living in households which earned less than $C20 000 last year. PRIMARY AND SECONDARY OUTCOME MEASURES: We collected baseline data on demographic characteristics, including indigenous identity, age, gender, income, household type and household size. Our primary outcome asked: 'Did you complete the 2011 Census Canada questionnaire?' RESULTS: Using RDS and our large-scale survey of the urban indigenous population in Toronto, Canada, we have shown that the most recent Canadian census underestimated the size of the indigenous population in Toronto by a factor of 2 to 4. Specifically, under conservative assumptions, there are approximately 55 000 (95% CI 45 000 to 73 000) indigenous people living in Toronto, at least double the current estimate of 19 270. CONCLUSIONS: Our indigenous enumeration methods, including RDS and census completion information will have broad impacts across governmental and health policy, potentially improving healthcare access for this community. These novel applications of RDS may be relevant for the enumeration of other 'hard-to-reach' populations, such as illegal immigrants or homeless individuals in Canada and beyond. PMID- 29282271 TI - Circulating tumour cells as a potential screening tool for lung cancer (the AIR study): protocol of a prospective multicentre cohort study in France. AB - INTRODUCTION: Lung cancer (LC) is the leading cause of death from cancer. Early diagnosis of LC is of paramount importance in terms of prognosis. The health authorities of most countries do not accept screening programmes based on low dose chest CT (LDCT), especially in Europe, because they are flawed by a high rate of false-positive results, leading to a large number of invasive diagnostic procedures. These authorities advocated further research, including companion biological tests that could enhance the effectiveness of LC screening. The present project aims to validate early diagnosis of LC by detection and characterisation of circulating tumour cells (CTCs) in a peripheral blood sample taken from a prospective cohort of persons at high-risk of LC. METHODS AND ANALYSIS: The AIR Project is a prospective, multicentre, double-blinded, cohort study conducted by a consortium of 21 French university centres. The primary objective is to determine the operational values of CTCs for the early detection of LC in a cohort of asymptomatic participants at high risk for LC, that is, smokers and ex-smokers (>=30 pack-years, quitted <=15 years), aged >=55 years, with chronic obstructive pulmonary disease (COPD). The study participants will undergo yearly screening rounds for 3 years plus a 1-year follow-up. Each round will include LDCT plus peripheral blood sampling for CTC detection. Assuming 5% prevalence of LC in the studied population and a 10% dropout rate, a total of at least 600 volunteers will be enrolled. ETHICS AND DISSEMINATION: The study sponsor is the University Hospital of Nice. The study was approved for France by the ethical committee CPP Sud-Mediterranee V and the ANSM (Ministry of Health) in July 2015. The findings of the trial will be disseminated through peer-reviewed journals and national and international conference presentations. TRIAL REGISTRATION NUMBER: NCT02500693. PMID- 29282273 TI - Association of socioeconomic status with outcomes in older adult community dwelling patients after visiting the emergency department: a retrospective cohort study. AB - OBJECTIVES: Older adults frequently visit the emergency department (ED). Socioeconomic status (SES) has an important impact on health and ED utilisation; however, the association between SES and ED utilisation in elderly remains unclear. The aim of this study was to investigate the association between SES in older adult patients visiting the ED on outcomes. DESIGN: A retrospective study. PARTICIPANTS: Older adults (>=65 years) visiting the ED, in the Netherlands. SES was stratified into tertiles based on average household income at zip code level: low (?2300/month). PRIMARY OUTCOMES: Hospitalisation, inhospital mortality and 30-day ED return visits. Effect of SES on outcomes for all groups were assessed by logistic regression and adjusted for confounders. RESULTS: In total, 4828 older adults visited the ED during the study period. Low SES was associated with a higher risk of hospitalisation among community-dwelling patients compared with high SES (adjusted OR 1.3, 95% CI 1.1 to 1.7). This association was not present for intermediate SES (adjusted OR 1.1, 95% CI 0.95 to 1.4). Inhospital mortality was comparable between the low and high SES group, even after adjustment for age, comorbidity and triage level (low OR 1.4, 95% CI 0.8 to 2.6, intermediate OR 1.3, 95% CI 0.8 to 2.2). Thirty-day ED revisits among community-dwelling patients were also equal between the SES groups (low: adjusted OR 1.0, 95% CI 0.7 to 1.4, and intermediate: adjusted OR 0.8, 95% CI 0.6 to 1.1). CONCLUSION: In older adult ED patients, low SES was associated with a higher risk of hospitalisation than high SES. However, SES had no impact on inhospital mortality and 30-day ED revisits after adjustment for confounders. PMID- 29282274 TI - Developing and validating a novel multisource comorbidity score from administrative data: a large population-based cohort study from Italy. AB - OBJECTIVE: To develop and validate a novel comorbidity score (multisource comorbidity score (MCS)) predictive of mortality, hospital admissions and healthcare costs using multiple source information from the administrative Italian National Health System (NHS) databases. METHODS: An index of 34 variables (measured from inpatient diagnoses and outpatient drug prescriptions within 2 years before baseline) independently predicting 1-year mortality in a sample of 500 000 individuals aged 50 years or older randomly selected from the NHS beneficiaries of the Italian region of Lombardy (training set) was developed. The corresponding weights were assigned from the regression coefficients of a Weibull survival model. MCS performance was evaluated by using an internal (ie, another sample of 500 000 NHS beneficiaries from Lombardy) and three external (each consisting of 500 000 NHS beneficiaries from Emilia-Romagna, Lazio and Sicily) validation sets. Discriminant power and net reclassification improvement were used to compare MCS performance with that of other comorbidity scores. MCS ability to predict secondary health outcomes (ie, hospital admissions and costs) was also investigated. RESULTS: Primary and secondary outcomes progressively increased with increasing MCS value. MCS improved the net 1-year mortality reclassification from 27% (with respect to the Chronic Disease Score) to 69% (with respect to the Elixhauser Index). MCS discrimination performance was similar in the four regions of Italy we tested, the area under the receiver operating characteristic curves (95% CI) being 0.78 (0.77 to 0.79) in Lombardy, 0.78 (0.77 to 0.79) in Emilia-Romagna, 0.77 (0.76 to 0.78) in Lazio and 0.78 (0.77 to 0.79) in Sicily. CONCLUSION: MCS seems better than conventional scores for predicting health outcomes, at least in the general population from Italy. This may offer an improved tool for risk adjustment, policy planning and identifying patients in need of a focused treatment approach in the everyday medical practice. PMID- 29282275 TI - S100A4 regulates macrophage invasion by distinct myosin-dependent and myosin independent mechanisms. AB - S100A4, a member of the S100 family of Ca2+-binding proteins, is a key regulator of cell migration and invasion. Our previous studies showed that bone marrow derived macrophages from S100A4-/- mice exhibit defects in directional motility and chemotaxis in vitro and reduced recruitment to sites of inflammation in vivo. We now show that the loss of S100A4 produces two mechanistically distinct phenotypes with regard to macrophage invasion: a defect in matrix degradation, due to a disruption of podosome rosettes caused by myosin-IIA overassembly, and a myosin-independent increase in microtubule acetylation, which increases podosome rosette stability and is sufficient to inhibit macrophage invasion. Our studies point to S100A4 as a critical regulator of matrix degradation, whose actions converge on the dynamics and degradative functions of podosome rosettes. PMID- 29282276 TI - The neuron-specific formin Delphilin nucleates nonmuscle actin but does not enhance elongation. AB - The formin Delphilin binds the glutamate receptor, GluRdelta2, in dendritic spines of Purkinje cells. Both proteins play a role in learning. To understand how Delphilin functions in neurons, we studied the actin assembly properties of this formin. Formins have a conserved formin homology 2 domain, which nucleates and associates with the fast-growing end of actin filaments, influencing filament growth together with the formin homology 1 (FH1) domain. The strength of nucleation and elongation varies widely across formins. Additionally, most formins have conserved domains that regulate actin assembly through an intramolecular interaction. Delphilin is distinct from other formins in several ways: its expression is limited to Purkinje cells, it lacks classical autoinhibitory domains, and its FH1 domain has minimal proline-rich sequence. We found that Delphilin is an actin nucleator that does not accelerate elongation, although it binds to the barbed end of filaments. In addition, Delphilin exhibits a preference for actin isoforms, nucleating nonmuscle actin but not muscle actin, which has not been described or systematically studied in other formins. Finally, Delphilin is the first formin studied that is not regulated by intramolecular interactions. We speculate how the activity we observe is consistent with its localization in the small dendritic spines. PMID- 29282277 TI - Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations. AB - Mutant Tau (MAPT) can lead to frontotemporal lobar degeneration (FTLD). Previous studies associated MAPT mutations and altered function with aneuploidy and chromosome instability in human lymphocytes and in Drosophila development. Here we examine whether FTLD-causing mutations in human MAPT induce aneuploidy and apoptosis in the mammalian brain. First, aneuploidy was found in brain cells from MAPT mutant transgenic mice expressing FTLD mutant human MAPT. Then brain neurons from mice homozygous or heterozygous for the Tau (Mapt) null allele were found to exhibit increasing levels of aneuploidy with decreasing Tau gene dosage. To determine whether aneuploidy leads to neurodegeneration in FTLD, we measured aneuploidy and apoptosis in brain cells from patients with MAPT mutations and identified both increased aneuploidy and apoptosis in the same brain neurons and glia. To determine whether there is a direct relationship between MAPT-induced aneuploidy and apoptosis, we expressed FTLD-causing mutant forms of MAPT in karyotypically normal human cells and found that they cause aneuploidy and mitotic spindle defects that then result in apoptosis. Collectively, our findings reveal a neurodegenerative pathway in FTLD-MAPT in which neurons and glia exhibit mitotic spindle abnormalities, chromosome mis-segregation, and aneuploidy, which then lead to apoptosis. PMID- 29282278 TI - Gravin regulates centrosome function through PLK1. AB - We propose to understand how the mitotic kinase PLK1 drives chromosome segregation errors, with a specific focus on Gravin, a PLK1 scaffold. In both three-dimensional primary prostate cancer cell cultures that are prone to Gravin depletion and Gravin short hairpin RNA (shRNA)-treated cells, an increase in cells containing micronuclei was noted in comparison with controls. To examine whether the loss of Gravin affected PLK1 distribution and activity, we utilized photokinetics and a PLK1 activity biosensor. Gravin depletion resulted in an increased PLK1 mobile fraction, causing the redistribution of active PLK1, which leads to increased defocusing and phosphorylation of the mitotic centrosome protein CEP215 at serine-613. Gravin depletion further led to defects in microtubule renucleation from mitotic centrosomes, decreased kinetochore-fiber integrity, increased incidence of chromosome misalignment, and subsequent formation of micronuclei following mitosis completion. Murine Gravin rescued chromosome misalignment and micronuclei formation, but a mutant Gravin that cannot bind PLK1 did not. These findings suggest that disruption of a Gravin-PLK1 interface leads to inappropriate PLK1 activity contributing to chromosome segregation errors, formation of micronuclei, and subsequent DNA damage. PMID- 29282279 TI - Renitence vacuoles facilitate protection against phagolysosomal damage in activated macrophages. AB - As professional phagocytes, macrophages are susceptible to endolysosomal membrane damage inflicted by the pathogens and noxious particles they ingest. Whether macrophages have mechanisms for limiting such damage is not well understood. Previously, we reported a phenomenon, termed "inducible renitence," in which lipopolysaccharide (LPS) activation of macrophages protected their endolysosomes against damage initiated by the phagocytosis of silica beads. To gain mechanistic insight into the process, we analyzed the kinetics of renitence and morphological features of LPS-activated versus resting macrophages following silica bead mediated injury. We discovered novel vacuolar structures that form in LPS activated but not resting macrophages following silica bead phagocytosis. Because of their correlation with renitence and damage-resistant nature, we termed these structures "renitence vacuoles" (RVs). RVs formed coincident with silica bead uptake in a process associated with membrane ruffling and macropinocytosis. However, unlike normal macropinosomes (MPs), which shrink within 20 min of formation, RVs persisted around bead-containing phagosomes. RVs fused with lysosomes, whereas associated phagosomes typically did not. These findings are consistent with a model in which RVs, as persistent MPs, prevent fusion between damaged phagosomes and intact lysosomes and thereby preserve endolysosomal integrity. PMID- 29282280 TI - Ligand-specific binding forces of LFA-1 and Mac-1 in neutrophil adhesion and crawling. AB - Lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) and their counterreceptors such as intercellular cell adhesion molecules (ICAM-1 and ICAM-2), junctional adhesion molecules (JAM-A, JAM-C), and receptors for advanced glycation end products (RAGE) are crucial for promoting polymorphonuclear leukocyte (neutrophil, PMN) recruitment. The underlying mechanisms of ligand-specific bindings in this cascade remain incompletely known. We compared the dynamic force spectra for various LFA-1/Mac-1-ligand bonds using single-molecule atomic force microscopy (AFM) and tested their functions in mediating PMN recruitment under in vitro shear flow. Distinct features of bond rupture forces and lifetimes were uncovered for these ligands, implying their diverse roles in regulating PMN adhesion on endothelium. LFA-1 dominates PMN adhesion on ICAM-1 and ICAM-2, while Mac-1 mediates PMN adhesion on RAGE, JAM-A, and JAM-C, which is consistent with their bond strength. All ligands can trigger PMN spreading and polarization, in which Mac-1 seems to induce outside-in signaling more effectively. LFA-1-ICAM-1 and LFA-1/Mac-1-JAM-C bonds can accelerate PMN crawling under high shear stress, presumably due to their high mechanical strength. This work provides new insight into basic molecular mechanisms of physiological ligands of beta2 integrins in PMN recruitment. PMID- 29282281 TI - Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants. AB - Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality. Owing to the many metabolic functions fulfilled by peroxisomes, PBD pathology is complex and incompletely understood. Besides accumulation of peroxisomal educts (like very-long-chain fatty acids [VLCFAs] or branched-chain fatty acids) and lack of products (like bile acids or plasmalogens), many peroxisomal defects lead to detrimental mitochondrial abnormalities for unknown reasons. We generated Pex19 Drosophila mutants, which recapitulate the hallmarks of PBDs, like absence of peroxisomes, reduced viability, neurodegeneration, mitochondrial abnormalities, and accumulation of VLCFAs. We present a model of hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of free fatty acids as the cause for mitochondrial damage in consequence of peroxisome loss in Pex19 mutants. Hyperactive Hnf4 signaling leads to up-regulation of lipase 3 and enzymes for mitochondrial beta-oxidation. This results in enhanced lipolysis, elevated concentrations of free fatty acids, maximal beta-oxidation, and mitochondrial abnormalities. Increased acid lipase expression and accumulation of free fatty acids are also present in a Pex19-deficient patient skin fibroblast line, suggesting the conservation of key aspects of our findings. PMID- 29282282 TI - Force-dependent binding of vinculin to alpha-catenin regulates cell-cell contact stability and collective cell behavior. AB - The shaping of a multicellular body and repair of adult tissues require fine- tuning of cell adhesion, cell mechanics, and intercellular transmission of mechanical load. Adherens junctions (AJs) are the major intercellular junctions by which cells sense and exert mechanical force on each other. However, how AJs adapt to mechanical stress and how this adaptation contributes to cell-cell cohesion and eventually to tissue-scale dynamics and mechanics remains largely unknown. Here, by analyzing the tension-dependent recruitment of vinculin, alpha catenin, and F-actin as a function of stiffness, as well as the dynamics of GFP tagged wild-type and mutated alpha-catenins, altered for their binding capability to vinculin, we demonstrate that the force-dependent binding of vinculin stabilizes alpha-catenin and is responsible for AJ adaptation to force. Challenging cadherin complexes mechanical coupling with magnetic tweezers, and cell-cell cohesion during collective cell movements, further highlight that tension-dependent adaptation of AJs regulates cell-cell contact dynamics and coordinated collective cell migration. Altogether, these data demonstrate that the force-dependent alpha-catenin/vinculin interaction, manipulated here by mutagenesis and mechanical control, is a core regulator of AJ mechanics and long range cell-cell interactions. PMID- 29282283 TI - Relief from nitrogen starvation triggers transient destabilization of glycolytic mRNAs in Saccharomyces cerevisiae cells. AB - Nitrogen replenishment of nitrogen-starved yeast cells resulted in substantial transcriptome changes. There was an unexplained rapid, transient down-regulation of glycolytic genes. This unexpected result prompted us to search for the factors controlling these changes, among which is the possible involvement of different nutrient-sensing pathways such as the TORC1 and cAMP/PKA pathways. To that end, the effects of various gene deletions or chemical blocking agents were tested by investigating the expression of PGK1, one of the glycolytic genes most affected after nitrogen replenishment. We report here that several factors affected glycolytic mRNA stability, among which were glucose sensing, protein elongation, nitrogen metabolism, and TOR signaling. Ammonium sensing was not involved in the response, but ammonium metabolism was required. Thus, our results suggest that, in the presence of glucose, carbon/nitrogen cross-talk is likely involved in the response to nitrogen upshift. Our data suggest that posttranscriptional control of glycolytic gene expression may be an important response to nitrogen replenishment. PMID- 29282284 TI - Moesin is involved in polarity maintenance and cortical remodeling during asymmetric cell division. AB - An intact actomyosin network is essential for anchoring polarity proteins to the cell cortex and maintaining cell size asymmetry during asymmetric cell division of Drosophila neuroblasts (NBs). However, the mechanisms that control changes in actomyosin dynamics during asymmetric cell division remain unclear. We find that the actin-binding protein, Moesin, is essential for NB proliferation and mitotic progression in the developing brain. During metaphase, phosphorylated Moesin (p Moesin) is enriched at the apical cortex, and loss of Moesin leads to defects in apical polarity maintenance and cortical stability. This asymmetric distribution of p-Moesin is determined by components of the apical polarity complex and Slik kinase. During later stages of mitosis, p-Moesin localization shifts more basally, contributing to asymmetric cortical extension and myosin basal furrow positioning. Our findings reveal Moesin as a novel apical polarity protein that drives cortical remodeling of dividing NBs, which is essential for polarity maintenance and initial establishment of cell size asymmetry. PMID- 29282285 TI - Cross-linkers both drive and brake cytoskeletal remodeling and furrowing in cytokinesis. AB - Cell shape changes such as cytokinesis are driven by the actomyosin contractile cytoskeleton. The molecular rearrangements that bring about contractility in nonmuscle cells are currently debated. Specifically, both filament sliding by myosin motors, as well as cytoskeletal cross-linking by myosins and nonmotor cross-linkers, are thought to promote contractility. Here we examined how the abundance of motor and nonmotor cross-linkers affects the speed of cytokinetic furrowing. We built a minimal model to simulate contractile dynamics in the Caenorhabditis elegans zygote cytokinetic ring. This model predicted that intermediate levels of nonmotor cross-linkers are ideal for contractility; in vivo, intermediate levels of the scaffold protein anillin allowed maximal contraction speed. Our model also demonstrated a nonlinear relationship between the abundance of motor ensembles and contraction speed. In vivo, thorough depletion of nonmuscle myosin II delayed furrow initiation, slowed F-actin alignment, and reduced maximum contraction speed, but partial depletion allowed faster-than-expected kinetics. Thus, cytokinetic ring closure is promoted by moderate levels of both motor and nonmotor cross-linkers but attenuated by an over-abundance of motor and nonmotor cross-linkers. Together, our findings extend the growing appreciation for the roles of cross-linkers in cytokinesis and reveal that they not only drive but also brake cytoskeletal remodeling. PMID- 29282286 TI - Arabidopsis thaliana rapid alkalinization factor 1-mediated root growth inhibition is dependent on calmodulin-like protein 38. AB - Arabidopsis thaliana rapid alkalinization factor 1 (AtRALF1) is a small secreted peptide hormone that inhibits root growth by repressing cell expansion. Although it is known that AtRALF1 binds the plasma membrane receptor FERONIA and conveys its signals via phosphorylation, the AtRALF1 signaling pathway is largely unknown. Here, using a yeast two-hybrid system to search for AtRALF1-interacting proteins in Arabidopsis, we identified calmodulin-like protein 38 (CML38) as an AtRALF1-interacting partner. We also found that CML38 and AtRALF1 are both secreted proteins that physically interact in a Ca2+- and pH-dependent manner. CML38-knockout mutants generated via T-DNA insertion were insensitive to AtRALF1, and simultaneous treatment with both AtRALF1 and CML38 proteins restored sensitivity in these mutants. Hybrid plants lacking CML38 and having high accumulation of the AtRALF1 peptide did not exhibit the characteristic short-root phenotype caused by AtRALF1 overexpression. Although CML38 was essential for AtRALF1-mediated root inhibition, it appeared not to have an effect on the AtRALF1-induced alkalinization response. Moreover, acridinium-labeling of AtRALF1 indicated that the binding of AtRALF1 to intact roots is CML38-dependent. In summary, we describe a new component of the AtRALF1 response pathway. The new component is a calmodulin-like protein that binds AtRALF1, is essential for root growth inhibition, and has no role in AtRALF1 alkalinization. PMID- 29282287 TI - The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms. AB - Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: 1) unseeded in solution; 2) seeded in solution; and 3) membrane mediated. In solution, aggregation proceeded in a highly stepwise manner, in which the individual domains (N terminus containing 17 amino acids (N17), polyQ, and proline-rich domain (PRD)) become ordered at very different rates. The aggregation was initiated by an early oligomer requiring a pathogenic, expanded Gln length and N17 alpha-helix formation. In the second phase, beta-sheet forms in the polyQ. The slowest step is the final structural maturation of the PRD. This stepwise mechanism could be bypassed by seeding, which potently accelerated aggregation and was a prerequisite for prion-like spreading in vivo Remarkably, membranes could catalyze aggregation even more potently than seeds, in a process that caused significant membrane damage. The N17 governed membrane-mediated aggregation by anchoring Httex1 to the membrane, enhancing local concentration and promoting collision via two-dimensional diffusion. Considering its central roles in solution and in membrane-mediated aggregation, the N17 represents an attractive target for inhibiting multiple pathways. Our approach should help evaluate such inhibitors and identify diagnostic markers for the misfolded forms identified here. PMID- 29282288 TI - Structure-based virtual screening identifies a small-molecule inhibitor of the profilin 1-actin interaction. AB - Profilin 1 (Pfn1) is an important regulator of the actin cytoskeleton and plays a vital role in many actin-based cellular processes. Therefore, identification of a small-molecule intervention strategy targeted against the Pfn1-actin interaction could have broad utility in cytoskeletal research and further our understanding of the role of Pfn1 in actin-mediated biological processes. Based on an already resolved Pfn1-actin complex crystal structure, we performed structure-based virtual screening of small-molecule libraries to seek inhibitors of the Pfn1 actin interaction. We identified compounds that match the pharmacophore of the key actin residues of Pfn1-actin interaction and therefore have the potential to act as competitive inhibitors of this interaction. Subsequent biochemical assays identified two candidate compounds with nearly identical structures that can mitigate the effect of Pfn1 on actin polymerization in vitro As a further proof of-concept test for cellular effects of these compounds, we performed proximity ligation assays in endothelial cells (ECs) to demonstrate compound-induced inhibition of Pfn1-actin interaction. Consistent with the important role of Pfn1 in regulating actin polymerization and various fundamental actin-based cellular activities (migration and proliferation), treatment of these compounds reduced the overall level of cellular filamentous (F) actin, slowed EC migration and proliferation, and inhibited the angiogenic ability of ECs both in vitro and ex vivo In summary, this study provides the first proof of principle of small molecule-mediated interference with the Pfn1-actin interaction. Our findings may have potential general utility for perturbing actin-mediated cellular activities and biological processes. PMID- 29282289 TI - Efficient farnesylation of an extended C-terminal C(x)3X sequence motif expands the scope of the prenylated proteome. AB - Protein prenylation is a post-translational modification that has been most commonly associated with enabling protein trafficking to and interaction with cellular membranes. In this process, an isoprenoid group is attached to a cysteine near the C terminus of a substrate protein by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I or II (GGTase-I and GGTase-II). FTase and GGTase-I have long been proposed to specifically recognize a four-amino acid CAAX C-terminal sequence within their substrates. Surprisingly, genetic screening reveals that yeast FTase can modify sequences longer than the canonical CAAX sequence, specifically C(x)3X sequences with four amino acids downstream of the cysteine. Biochemical and cell-based studies using both peptide and protein substrates reveal that mammalian FTase orthologs can also prenylate C(x)3X sequences. As the search to identify physiologically relevant C(x)3X proteins begins, this new prenylation motif nearly doubles the number of proteins within the yeast and human proteomes that can be explored as potential FTase substrates. This work expands our understanding of prenylation's impact within the proteome, establishes the biologically relevant reactivity possible with this new motif, and opens new frontiers in determining the impact of non-canonically prenylated proteins on cell function. PMID- 29282290 TI - Phosphoinositide conversion in endocytosis and the endolysosomal system. AB - Phosphoinositides (PIs) are phospholipids that perform crucial cell functions, ranging from cell migration and signaling to membrane trafficking, by serving as signposts of compartmental membrane identity. Although phosphatidylinositol 4,5 bisphosphate, 3-phosphate, and 3,5-bisphosphate are commonly considered as hallmarks of the plasma membrane, endosomes, and lysosomes, these compartments contain other functionally important PIs. Here, we review the roles of PIs in different compartments of the endolysosomal system in mammalian cells and discuss the mechanisms that spatiotemporally control PI conversion in endocytosis and endolysosomal membrane dynamics during endosome maturation and sorting. As defective PI conversion underlies human genetic diseases, including inherited myopathies, neurological disorders, and cancer, PI-converting enzymes represent potential targets for drug-based therapies. PMID- 29282291 TI - Regulation of redox balance in cancer and T cells. AB - Reactive oxygen species (ROS) mediate redox signaling necessary for numerous cellular functions. Yet, high levels of ROS in cells and tissues can cause damage and cell death. Therefore, regulation of redox homeostasis is essential for ROS dependent signaling that does not incur cellular damage. Cells achieve this optimal balance by coordinating ROS production and elimination. In this Minireview, we discuss the mechanisms by which proliferating cancer and T cells maintain a carefully controlled redox balance. Greater insight into such redox biology may enable precisely targeted manipulation of ROS for effective medical therapies against cancer or immunological disorders. PMID- 29282292 TI - The radical SAM protein HemW is a heme chaperone. AB - Radical S-adenosylmethionine (SAM) enzymes exist in organisms from all kingdoms of life, and all of these proteins generate an adenosyl radical via the homolytic cleavage of the S-C(5') bond of SAM. Of particular interest are radical SAM enzymes, such as heme chaperones, that insert heme into respiratory enzymes. For example, heme chaperones insert heme into target proteins but have been studied only for the formation of cytochrome c-type hemoproteins. Here, we report that a radical SAM protein, the heme chaperone HemW from bacteria, is required for the insertion of heme b into respiratory chain enzymes. As other radical SAM proteins, HemW contains three cysteines and one SAM coordinating an [4Fe-4S] cluster, and we observed one heme per subunit of HemW. We found that an intact iron-sulfur cluster was required for HemW dimerization and HemW-catalyzed heme transfer but not for stable heme binding. A bacterial two-hybrid system screen identified bacterioferritins and the heme-containing subunit NarI of the respiratory nitrate reductase NarGHI as proteins that interact with HemW. We also noted that the bacterioferritins potentially serve as heme donors for HemW. Of note, heme that was covalently bound to HemW was actively transferred to a heme depleted, catalytically inactive nitrate reductase, restoring its nitrate reducing enzyme activity. Finally, the human HemW orthologue radical SAM domain containing 1 (RSAD1) stably bound heme. In conclusion, our findings indicate that the radical SAM protein family HemW/RSAD1 is a heme chaperone catalyzing the insertion of heme into hemoproteins. PMID- 29282293 TI - RNA polymerase II is released from the DNA template during transcription-coupled repair in mammalian cells. AB - In mammalian cells, bulky DNA adducts located in the template but not the coding strand of genes block elongation by RNA polymerase II (RNAPII). The blocked RNAPII targets these transcription-blocking adducts to undergo more rapid excision repair than adducts located elsewhere in the genome. In excision repair, coupled incisions are made in the damaged DNA strand on both sides of the adduct. The fate of RNAPII in the course of this transcription-coupled repair (TCR) pathway is unclear. To address the fate of RNAPII, we used methods that control transcription to initiate a discrete "wave" of elongation complexes. Analyzing genome-wide transcription and repair by next-generation sequencing, we identified locations of elongation complexes and transcription-repair coupling events in genes throughout the genome. Using UV-exposed human skin fibroblasts, we found that, at the dose used, a single wave of elongation complexes was blocked within the first 25 kb of genes. TCR occurred where the elongation complexes were blocked, and repair was associated with the dissociation of these complexes. These results indicate that individual elongation complexes do not engage in multiple rounds of TCR with successive lesions. Our results are consistent with a model in which RNAPII is dissociated after the dual incision of the transcription blocking lesion, perhaps by Cockayne syndrome group B translocase, or during the synthesis of a repair patch. PMID- 29282294 TI - Exceptionally high-affinity Ras binders that remodel its effector domain. AB - The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule-binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naive library and their evolution to afford versions with midpicomolar affinity to Ras. A series of biochemical experiments indicated that these miniproteins bind to the Ras effector domain as dimers, and high-resolution crystal structures revealed that these miniprotein dimers bind Ras in an unprecedented mode in which the Ras effector domain is remodeled to expose an extended pocket that connects two isolated pockets previously found to engage small-molecule ligands. We also report a Ras point mutant that stabilizes the protein in the open conformation trapped by these miniproteins. These findings provide new tools for studying Ras structure and function and present opportunities for the development of both miniprotein and small-molecule inhibitors that directly target the Ras proteins. PMID- 29282295 TI - Common fibrillar spines of amyloid-beta and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors. AB - Amyloid-beta (Abeta) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues and are associated with Alzheimer's disease (AD) and type II diabetes (T2D), respectively. Individuals with T2D have an increased risk of developing AD, and conversely, AD patients have an increased risk of developing T2D. Evidence suggests that this link between AD and T2D might originate from a structural similarity between aggregates of Abeta and hIAPP. Using the cryoEM method microelectron diffraction, we determined the atomic structures of 11-residue segments from both Abeta and hIAPP, termed Abeta(24-34) WT and hIAPP(19-29) S20G, with 64% sequence similarity. We observed a high degree of structural similarity between their backbone atoms (0.96-A root mean square deviation). Moreover, fibrils of these segments induced amyloid formation through self- and cross-seeding. Furthermore, inhibitors designed for one segment showed cross-efficacy for full-length Abeta and hIAPP and reduced cytotoxicity of both proteins, although by apparently blocking different cytotoxic mechanisms. The similarity of the atomic structures of Abeta(24-34) WT and hIAPP(19-29) S20G offers a molecular model for cross-seeding between Abeta and hIAPP. PMID- 29282296 TI - Galectin-8-mediated selective autophagy protects against seeded tau aggregation. AB - Assembled tau can transfer between cells and seed the aggregation of soluble tau. This process is thought to underlie the amplification and propagation of tau inclusions throughout the brain in neurodegenerative diseases, including Alzheimer's disease. An understanding of the mechanisms involved may provide strategies for limiting assembled tau propagation. Here, we sought to determine how assembled tau seeds gain access to the cytosol and whether this access triggers cellular defenses. We show that tau assemblies enter cells through clathrin-independent endocytosis and escape from damaged endomembranes into the cytosol, where they seed the aggregation of soluble tau. We also found that the danger receptor galectin-8 detects damaged endomembranes and activates autophagy through recruitment of the cargo receptor nuclear dot protein 52 (NDP52). Inhibition of galectin-8- and NDP52-dependent autophagy increased seeded tau aggregation, indicating that autophagy triggered by damaged endomembranes during the entry of assembled tau seeds protects against tau aggregation, in a manner similar to cellular defenses against cytosol-dwelling microorganisms. A second autophagy cargo receptor, p62, then targeted seeded tau aggregates. Our results reveal that by monitoring endomembrane integrity, cells reduce entry of tau seeds into the cytosol and thereby prevent seeded aggregation. The mechanisms described here may help inform the development of therapies aimed at inhibiting the propagation of protein assemblies in neurodegenerative diseases. PMID- 29282297 TI - Development of Multimarker Diagnostic Models from Metabolomics Analysis for Gestational Diabetes Mellitus (GDM). AB - Although metabolomics are desirable to understand the pathophysiology of gestational diabetes mellitus (GDM), comprehensive metabolomic studies of GDM are rare. We aimed to offer a holistic view of metabolites alteration in GDM patients and investigate the possible multimarker models for GDM diagnosis. Biochemical parameters and perinatal data of 131 GDM cases and 138 controls were collected. Fasting serum samples at 75 g oral glucose tolerance test were used for metabolites by ultra performance liquid chromatography-quadrupole-time of flight mass spectrometry, ultra performance liquid chromatography-triple triple quadrupole-mass spectrometry and gas chromatography- time-of- flight mass spectrometry platforms. Significant changes were observed in free fatty acids, bile acids, branched chain amino acids, organic acids, lipids and organooxygen compounds between two groups. In receiver operating characteristic (ROC) analysis, different combinations of candidate biomarkers and metabolites in multimarker models achieved satisfactory discriminative abilities for GDM, with the values of area under the curve (AUC) ranging from 0.721 to 0.751. Model consisting of body mass index (BMI), retinol binding protein 4 (RBP4), n acetylaspartic acid and C16:1 (cis-7) manifested the best discrimination [AUC 0.751 (95% CI: 0.693-0.809), p < 0.001], followed by model consisting of BMI, Cystatin C, acetylaspartic acid and 6,7-diketoLCA [AUC 0.749 (95% CI: 0.691 0.808), p < 0.001]. Metabolites alteration reflected disorders of glucose metabolism, lipid metabolism, amino acid metabolism, bile acid metabolism as well as intestinal flora metabolism in GDM state. Multivariate models combining clinical markers and metabolites have the potential to differentiate GDM subjects from healthy controls. PMID- 29282299 TI - An Anti-GDNF Family Receptor Alpha 1 (GFRA1) Antibody-Drug Conjugate for the Treatment of Hormone Receptor-Positive Breast Cancer. AB - Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line-derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638-49. (c)2017 AACR. PMID- 29282298 TI - beta-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models. AB - Colorectal carcinomas harbor well-defined genetic abnormalities, including aberrant activation of Wnt/beta-catenin and MAPK pathways, often simultaneously. Although the MAPK pathway can be targeted using potent small-molecule drugs, including BRAF and MEK inhibitors, beta-catenin inhibition has been historically challenging. RNAi approaches have advanced to the stage of clinical viability and are especially well suited for transcriptional modulators, such as beta-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacologic agents. Using a recently described tumor-selective nanoparticle containing a beta-catenin-targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of colorectal cancer, melanoma, and hepatocellular carcinoma. At dose levels that were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing colorectal cancer liver metastases. In addition, pharmacologic silencing of beta-catenin mRNA was effective against tumors that are inherently resistant or that acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/beta-catenin and MAPK pathway mutations. Mol Cancer Ther; 17(2); 544-53. (c)2017 AACR. PMID- 29282300 TI - Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid-Derived Suppressor Cells. AB - Myeloid-derived suppressor cells (MDSC) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T-cell-mediated antitumor immunity, but mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B 1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduce MDSC activity. Using in vitro T-cell proliferation assays, data show that HDL NPs specifically bind SCARB1 to inhibit MDSC activity. In murine cancer models, HDL NP treatment significantly reduces tumor growth, metastatic tumor burden, and increases survival due to enhanced adaptive immunity. Flow cytometry and IHC demonstrate that HDL NP-mediated suppression of MDSCs increased CD8+ T cells and reduced Treg cells in the metastatic tumor microenvironment. Using transgenic mice lacking SCARB1, in vivo data clearly show that the HDL NPs specifically target this receptor for suppressing MDSCs. Ultimately, our data provide a new mechanism and targeted therapy, HDL NPs, to modulate a critical innate immune cell checkpoint to enhance the immune response to cancer. Mol Cancer Ther; 17(3); 686-97. (c)2017 AACR. PMID- 29282301 TI - Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice. AB - A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101-induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild type p53 phenotype and MDM2 expression in vitro and in vivo When given for a period of 2 weeks (20 mg/kg/day, 3*/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2. Mol Cancer Ther; 17(2); 497-507. (c)2017 AACR. PMID- 29282302 TI - Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis. AB - Inhibiting the glutamate/cystine antiporter system xc-, a key antioxidant defense machinery in the CNS, could trigger a novel form of regulated necrotic cell death, ferroptosis. The underlying mechanisms of system xc--dependent cell demise were elucidated using primary oligodendrocytes (OLs) treated with glutamate to block system xc- function. Pharmacological analysis revealed ferroptosis as a major contributing factor to glutamate-initiated OL death. A sphingolipid profile showed elevations of ceramide species and sphingosine that were preventable by inhibiting of an acid sphingomyelinase (ASM) activity. OL survival was enhanced by both downregulating ASM expression and blocking ASM activity. Glutamate induced ASM activation seems to involve posttranscriptional mechanisms and was associated with a decreased GSH level. Further investigation of the mechanisms of OL response to glutamate revealed enhanced reactive oxygen species production, augmented lipid peroxidation, and opening of the mitochondrial permeability transition pore that were attenuated by hindering ASM. Of note, knocking down sirtuin 3, a deacetylase governing the mitochondrial antioxidant system, reduced OL survival. The data highlight the importance of the mitochondrial compartment in regulated necrotic cell death and accentuate the novel role of ASM in disturbing mitochondrial functions during OL response to glutamate toxicity, which is essential for pathobiology in stroke and traumatic brain injury. PMID- 29282303 TI - Inhibition of the Deubiquitinase Usp14 Diminishes Direct MHC Class I Antigen Presentation. AB - Infected or transformed cells must present peptides derived from endogenous proteins on MHC class I molecules to be recognized and targeted for elimination by Ag-specific cytotoxic T cells. In the first step of peptide generation, proteins are degraded by the proteasome. In this study, we investigated the role of the ubiquitin-specific protease 14 (Usp14), a proteasome-associated deubiquitinase, in direct Ag presentation using a ligand-stabilized model protein expressed as a self-antigen. Chemical inhibition of Usp14 diminished direct presentation of the model antigenic peptide, and the effect was especially pronounced when presentation was restricted to the defective ribosomal product (DRiP) form of the protein. Additionally, presentation specifically from DRiP Ags was diminished by expression of a catalytically inactive form of Usp14. Usp14 inhibition did not appreciably alter protein synthesis and only partially delayed protein degradation as measured by a slight increase in the half-life of the model protein when its degradation was induced. Taken together, these data indicate that functional Usp14 enhances direct Ag presentation, preferentially of DRiP-derived peptides, suggesting that the processing of DRiPs is in some ways different from other forms of Ag. PMID- 29282305 TI - Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models. AB - Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-alpha by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases. PMID- 29282304 TI - Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. AB - Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT2R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease like Ptges-/- mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C4 synthase (Ltc4s). Administrations of either LTC4 (the parent cysLT) or the selective CysLT2R agonist N-methyl LTC4 to allergen sensitized wild type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT2R dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT2R dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC4-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT2R prior to inhalation challenge of Ptges-/- mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT2R signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT2R-targeted drugs may interrupt these processes. PMID- 29282306 TI - Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF beta and Engagement of CD85j. AB - NK cells play important roles during immunosurveillance against tumors and viruses as they trigger cytotoxicity against susceptible cells and secrete proinflammatory cytokines such as IFN-gamma. In addition, upon activation, macrophages can become proinflammatory (M1) or anti-inflammatory (M2) cells. Although the consequences of the cross-talk between M1 and NK cells are known, the outcome of the cross-talk between M2 and NK cells remains ill-defined. Therefore, in the current work, we investigated the outcome and the underlying mechanisms of the interaction between resting or stimulated human NK cells with M1 or M2. We observed a lower percentage of activated NK cells that produced less IFN-gamma upon coculture with M2. Also, CD56dim NK cells cocultured with M2 displayed lower degranulation and cytotoxic activity than NK cells cocultured with M1. Soluble TGF-beta and M2-driven upregulation of CD85j (ILT-2) on NK cells accounted for the diminished IFN-gamma production by CD56bright NK cells, whereas M2-driven upregulation of CD85j on NK cells accounted for the generation of hyporesponsive CD56dim NK cells with limited degranulation and cytotoxic capacity. Accordingly, M2 expressed higher amounts of HLA-G, the main ligand for CD85j, than M1. Hyporesponsiveness to degranulation in NK cells was not restored at least for several hours upon removal of M2. Therefore, alternatively activated macrophages restrain NK cell activation and effector functions through different mechanisms, leading to NK cells that display diminished IFN-gamma production and at least a transiently impaired degranulation ability. These results unravel an inhibitory circuit of possible relevance in pathological situations. PMID- 29282307 TI - Cutting Edge: Low-Affinity TCRs Support Regulatory T Cell Function in Autoimmunity. AB - Regulatory T cells (Tregs) use a distinct TCR repertoire and are more self reactive compared with conventional T cells. However, the extent to which TCR affinity regulates the function of self-reactive Tregs is largely unknown. In this study, we used a two-TCR model to assess the role of TCR affinity in Treg function during autoimmunity. We observed that high- and low-affinity Tregs were recruited to the pancreas and contributed to protection from autoimmune diabetes. Interestingly, high-affinity cells preferentially upregulated the TCR-dependent Treg functional mediators IL-10, TIGIT, GITR, and CTLA4, whereas low-affinity cells displayed increased transcripts for Areg and Ebi3, suggesting distinct functional profiles. The results of this study suggest mechanistically distinct and potentially nonredundant roles for high- and low-affinity Tregs in controlling autoimmunity. PMID- 29282308 TI - B Cell-Intrinsic MyD88 Signaling Promotes Initial Cell Proliferation and Differentiation To Enhance the Germinal Center Response to a Virus-like Particle. AB - Although TLR signaling in B cells has been implicated in the germinal center (GC) responses during viral infections and autoimmune diseases, the underlying mechanism is unclear. Bacterial phage Qbeta-derived virus-like particle (Qbeta VLP) contains TLR ligands, which can enhance Qbeta-VLP-induced Ab response, including GC response, through TLR/MyD88 signaling in B cells. In this study, by examining Ag-specific B cell response to Qbeta-VLP, we found that lack of B cell MyD88 from the beginning of the immune response led to a more severe defect in the GC scale than abolishing MyD88 at later time points of the immune response. Consistently, B cell-intrinsic MyD88 signaling significantly enhanced the initial proliferation of Ag-specific B cells, which was accompanied with a dramatic increase of plasma cell generation and induction of Bcl-6+ GC B cell precursors. In addition, B cell-intrinsic MyD88 signaling promoted strong T-bet expression independent of IFN-gamma and led to the preferential isotype switching to IgG2a/c. Thus, by promoting the initial Ag-specific B cell proliferation and differentiation, B cell-intrinsic MyD88 signaling enhanced both T-independent and T-dependent Ab responses elicited by Qbeta-VLP. This finding will provide additional insight into the role of TLR signaling in antiviral immunity, autoimmune diseases, and vaccine design. PMID- 29282310 TI - Correction: The Adaptor 3BP2 Is Required for KIT Receptor Expression and Human Mast Cell Survival. PMID- 29282309 TI - Identification of a Multipotent Progenitor Population in the Spleen That Is Regulated by NR4A1. AB - The developmental fate of hematopoietic stem and progenitor cells is influenced by their physiological context. Although most hematopoietic stem and progenitor cells are found in the bone marrow of the adult, some are found in other tissues, including the spleen. The extent to which the fate of stem cells is determined by the tissue in which they reside is not clear. In this study, we identify a new progenitor population, which is enriched in the mouse spleen, defined by cKit+CD71lowCD24high expression. This previously uncharacterized population generates exclusively myeloid lineage cells, including erythrocytes, platelets, monocytes, and neutrophils. These multipotent progenitors of the spleen (MPPS) develop from MPP2, a myeloid-biased subset of hematopoietic progenitors. We find that NR4A1, a transcription factor expressed by myeloid-biased long term hematopoietic stem cells, guides the lineage specification of MPPS. In vitro, NR4A1 expression regulates the potential of MPPS to differentiate into erythroid cells. MPPS that express NR4A1 differentiate into a variety of myeloid lineages, whereas those that do not express NR4A1 primarily develop into erythroid cells. Similarly, in vivo, after adoptive transfer, Nr4a1-deficient MPPS contribute more to erythrocyte and platelet populations than do wild-type MPPS. Finally, unmanipulated Nr4a1-/- mice harbor significantly higher numbers of erythroid progenitors in the spleen compared with wild-type mice. Together, our data show that NR4A1 expression by MPPS limits erythropoiesis and megakaryopoeisis, permitting development to other myeloid lineages. This effect is specific to the spleen, revealing a unique molecular pathway that regulates myeloid bias in an extramedullary niche. PMID- 29282311 TI - A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif. AB - The CD4+CD25+FOXP3+ regulatory T cells (Tregs) mediate immunological self tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-beta, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene. We found that miR-4281, an miRNA specifically expressed in hominids, can potently and specifically upregulate FOXP3 expression by directly interacting with the TATA box motif in the human FOXP3 promoter. Consequently, miR-4281 significantly accelerated the differentiation of human naive cells to induced Tregs (iTregs) that possess immune suppressor functions and weaken the development of graft versus-host disease in a humanized mouse model. Interestingly, iTregs induced by the combination of TGF-beta, IL-2, and chemically synthesized miR-4281 were more stable and functional than those induced by TGF-beta and IL-2 alone. Moreover, we found that the IL-2/STAT5 signal transduction upregulates FOXP3 expression not only through the classical pathway, but also by enhancing the expression of the miR-4281 precursor gene (SNCB) and, correspondingly, miR-4281. This study reveals a novel mechanism regulating FOXP3 expression and human iTreg development and, therefore, offers a new therapeutic target to manipulate immunosuppressive system. PMID- 29282312 TI - Nlrp12 Mediates Adverse Neutrophil Recruitment during Influenza Virus Infection. AB - Exaggerated inflammatory responses during influenza A virus (IAV) infection are typically associated with severe disease. Neutrophils are among the immune cells that can drive this excessive and detrimental inflammation. In moderation, however, neutrophils are necessary for optimal viral control. In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat containing receptor family member Nlrp12 in modulating neutrophilic responses during lethal IAV infection. Nlrp12-/- mice are protected from lethality during IAV infection and show decreased vascular permeability, fewer pulmonary neutrophils, and a reduction in levels of neutrophil chemoattractant CXCL1 in their lungs compared with wild-type mice. Nlrp12-/- neutrophils and dendritic cells within the IAV infected lungs produce less CXCL1 than their wild-type counterparts. Decreased CXCL1 production by Nlrp12-/- dendritic cells was not due to a difference in CXCL1 protein stability, but instead to a decrease in Cxcl1 mRNA stability. Together, these data demonstrate a previously unappreciated role for Nlrp12 in exacerbating the pathogenesis of IAV infection through the regulation of CXCL1 mediated neutrophilic responses. PMID- 29282313 TI - Exploring the RNA landscape of endothelial exosomes. AB - Exosomes are small extracellular vesicles of around 100 nm of diameter produced by most cell types. These vesicles carry nucleic acids, proteins, lipids, and other biomolecules and function as carriers of biological information in processes of extracellular communication. The content of exosomes is regulated by the external and internal microenvironment of the parent cell, but the intrinsic mechanisms of loading of molecules into exosomes are still not completely elucidated. In this study, by the use of next-generation sequencing we have characterized in depth the RNA composition of healthy endothelial cells and exosomes and provided an accurate profile of the different coding and noncoding RNA species found per compartment. We have also discovered a set of unique genes preferentially included (or excluded) into vesicles. Moreover, after studying the enrichment of RNA motifs in the genes unequally distributed between cells and exosomes, we have detected a set of enriched sequences for several classes of RNA. In conclusion, our results provide the basis for studying the involvement of RNA-binding proteins capable of recognizing RNA sequences and their role in the export of RNAs into exosomes. PMID- 29282314 TI - Productivity, biodiversity, and pathogens influence the global hunter-gatherer population density. AB - The environmental drivers of species distributions and abundances are at the core of ecological research. However, the effects of these drivers on human abundance are not well-known. Here, we report how net primary productivity, biodiversity, and pathogen stress affect human population density using global ethnographic hunter-gatherer data. Our results show that productivity has significant effects on population density globally. The most important direct drivers, however, depend on environmental conditions: biodiversity influences population density exclusively in low-productivity regions, whereas pathogen stress does so in high productivity regions. Our results also indicate that subtropical and temperate forest biomes provide the highest carrying capacity for hunter-gatherer populations. These findings document that environmental factors play a key role in shaping global population density patterns of preagricultural humans. PMID- 29282315 TI - Dynamics and mechanisms of intracellular calcium waves elicited by tandem bubble induced jetting flow. AB - One of the earliest events in cellular mechanotransduction is often an increase in intracellular calcium concentration associated with intracellular calcium waves (ICWs) in various physiologic or pathophysiologic processes. Although cavitation-induced calcium responses are believed to be important for modulating downstream bioeffects such as cell injury and mechanotransduction in ultrasound therapy, the fundamental mechanisms of these responses have not been elucidated. In this study, we investigated mechanistically the ICWs elicited in single HeLa cells by the tandem bubble-induced jetting flow in a microfluidic system. We identified two distinct (fast and slow) types of ICWs at varying degrees of flow shear stress-induced membrane deformation, as determined by different bubble standoff distances. We showed that ICWs were initiated by an extracellular calcium influx across the cell membrane nearest to the jetting flow, either primarily through poration sites for fast ICWs or opening of mechanosensitive ion channels for slow ICWs, which then propagated in the cytosol via a reaction diffusion process from the endoplasmic reticulum. The speed of ICW (CICW ) was found to correlate strongly with the severity of cell injury, with CICW in the range of 33 MUm/s to 93 MUm/s for fast ICWs and 1.4 MUm/s to 12 MUm/s for slow ICWs. Finally, we demonstrated that micrometer-sized beads attached to the cell membrane integrin could trigger ICWs under mild cavitation conditions without collateral injury. The relation between the characteristics of ICW and cell injury, and potential strategies to mitigate cavitation-induced injury while evoking an intracellular calcium response, may be particularly useful for exploiting ultrasound-stimulated mechanotransduction applications in the future. PMID- 29282316 TI - Silk-based multilayered angle-ply annulus fibrosus construct to recapitulate form and function of the intervertebral disc. AB - Recapitulation of the form and function of complex tissue organization using appropriate biomaterials impacts success in tissue engineering endeavors. The annulus fibrosus (AF) represents a complex, multilamellar, hierarchical structure consisting of collagen, proteoglycans, and elastic fibers. To mimic the intricacy of AF anatomy, a silk protein-based multilayered, disc-like angle-ply construct was fabricated, consisting of concentric layers of lamellar sheets. Scanning electron microscopy and fluorescence image analysis revealed cross-aligned and lamellar characteristics of the construct, mimicking the native hierarchical architecture of the AF. Induction of secondary structure in the silk constructs was confirmed by infrared spectroscopy and X-ray diffraction. The constructs showed a compressive modulus of 499.18 +/- 86.45 kPa. Constructs seeded with porcine AF cells and human mesenchymal stem cells (hMSCs) showed ~2.2-fold and ~1.7-fold increases in proliferation on day 14, respectively, compared with initial seeding. Biochemical analysis, histology, and immunohistochemistry results showed the deposition of AF-specific extracellular matrix (sulfated glycosaminoglycan and collagen type I), indicating a favorable environment for both cell types, which was further validated by the expression of AF tissue specific genes. The constructs seeded with porcine AF cells showed ~11-, ~5.1-, and ~6.7-fold increases in col Ialpha 1, sox 9, and aggrecan genes, respectively. The differentiation of hMSCs to AF-like tissue was evident from the enhanced expression of the AF-specific genes. Overall, the constructs supported cell proliferation, differentiation, and ECM deposition resulting in AF-like tissue features based on ECM deposition and morphology, indicating potential for future studies related to intervertebral disc replacement therapy. PMID- 29282318 TI - SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate RORgammat activity in a PKC-theta-dependent manner. AB - Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORgammat) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORgammat in vivo to promote the functional dominance of RORgammat over Foxp3 and thus establishing an unopposed Th17 differentiation program. In the absence of SRC1, T cell polarization resulted in decreased IL-17+ and increased Foxp3+ cells during both in vitro differentiation and in vivo development of experimental autoimmune encephalomyelitis. Mechanistically, T cell receptor (TCR) signaling molecule protein kinase C theta (PKC-theta)-mediated phosphorylation of SRC1 is important for inducing enhanced RORgammat-SRC1 interaction, stable DNA binding, and resultant IL-17A transcription. Furthermore, phospho-SRC1-mediated recruitment of CARM1 induced prominent asymmetric dimethylation of H3R17 while preventing repressive H3K9 trimethylation and hence further modifying the IL-17 locus for optimal transcription. Moreover, binding of phospho-SRC1 to RORgammat displaced bound Foxp3, leading to prompt degradation of the dissociated Foxp3 via a ubiquitin-proteosomal pathway and hence reversing the inhibitory action of Foxp3 on RORgammat activity. Thus, SRC1 acts as a crucial molecular mediator to integrate positive PKC-theta-dependent TCR signals to induce peak RORgammat activity and establish phenotypic dominance of Th17 over the iTreg pathway. PMID- 29282317 TI - Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. AB - The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes. PMID- 29282319 TI - Expression of an active Galphas mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance. AB - Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the alpha-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD. Here, we have developed a conditional tetracycline (Tet)-inducible animal model expressing the GalphasR201C in the skeletal stem cell (SSC) lineage (Tet-GalphasR201C/Prrx1 Cre/LSL-rtTA-IRES-GFP mice), which develops typical FD bone lesions in both embryos and adult mice in less than 2 weeks following doxycycline (Dox) administration. Conditional GalphasR201C expression promoted PKA activation and proliferation of SSCs along the osteogenic lineage but halted their differentiation to mature osteoblasts. Rather, as is seen clinically, areas of woven bone admixed with fibrous tissue were formed. GalphasR201C caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. GalphasR201C expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for Galphas-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant Galphas expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options. PMID- 29282320 TI - Detection of synchronous brain activity in white matter tracts at rest and under functional loading. AB - Functional MRI based on blood oxygenation level-dependent (BOLD) contrast is well established as a neuroimaging technique for detecting neural activity in the cortex of the human brain. While detection and characterization of BOLD signals, as well as their electrophysiological and hemodynamic/metabolic origins, have been extensively studied in gray matter (GM), the detection and interpretation of BOLD signals in white matter (WM) remain controversial. We have previously observed that BOLD signals in a resting state reveal structure-specific anisotropic temporal correlations in WM and that external stimuli alter these correlations and permit visualization of task-specific fiber pathways, suggesting variations in WM BOLD signals are related to neural activity. In this study, we provide further strong evidence that BOLD signals in WM reflect neural activities both in a resting state and under functional loading. We demonstrate that BOLD signal waveforms in stimulus-relevant WM pathways are synchronous with the applied stimuli but with various degrees of time delay and that signals in WM pathways exhibit clear task specificity. Furthermore, resting-state signal fluctuations in WM tracts show significant correlations with specific parcellated GM volumes. These observations support the notion that neural activities are encoded in WM circuits similarly to cortical responses. PMID- 29282322 TI - Antagonistic regulation of trafficking to Caenorhabditis elegans sensory cilia by a Retinal Degeneration 3 homolog and retromer. AB - Sensory neurons often possess cilia with elaborate membrane structures that are adapted to the sensory modality of the host cell. Mechanisms that target sensory transduction proteins to these specialized membrane domains remain poorly understood. Here, we show that a homolog of the human retinal dystrophy gene Retinal Degeneration 3 (RD3) is a Golgi-associated protein required for efficient trafficking of a sensory receptor, the receptor-type guanylate cyclase GCY-9, to cilia in chemosensory neurons of the nematode Caenorhabditis elegans The trafficking defect caused by mutation of the nematode RD3 homolog is suppressed in vivo by mutation of key components of the retromer complex, which mediates recycling of cargo from endosomes to the Golgi. Our data show that there exists a critical balance in sensory neurons between the rates of anterograde and retrograde trafficking of cargo destined for the sensory cilium and this balance requires molecular specialization at an early stage of the secretory pathway. PMID- 29282321 TI - A mixed modality approach towards Xi reactivation for Rett syndrome and other X linked disorders. AB - The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset, including neurodevelopmental disorders, Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome, also affects females. These disorders lack disease-specific treatment. Because female cells carry two X chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here, we focus on methyl-CpG binding protein 2 (MECP2) restoration for RTT and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X inactivation. We identify a mixed modality approach combining an Xist antisense oligonucleotide and a small-molecule inhibitor of DNA methylation, which, together, achieve 30,000-fold MECP2 up-regulation from the Xi in cultured cells. Combining a brain specific genetic Xist ablation with short-term 5-aza-2'-deoxycytidine (Aza) treatment models the synergy in vivo without evident toxicity. The Xi is selectively reactivated. These experiments provide proof of concept for a mixed modality approach for treating X-linked disorders in females. PMID- 29282323 TI - Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor. AB - Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti-PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1. Among these proteins, signaling lymphocytic activation molecule associated protein (SAP) was functionally and mechanistically analyzed for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and overexpression blocked PD-1 function. T cells from patients with X-linked lymphoproliferative disease (XLP), who lack functional SAP, were hyperresponsive to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly, signaling downstream of PD-1 in purified T cell subsets did not correlate with PD 1 surface expression but was inversely correlated with intracellular SAP levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular shield of key tyrosine residues that are targets for the tyrosine phosphatase SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients with XLP. PMID- 29282324 TI - Biphasic functions for the GDNF-Ret signaling pathway in chemosensory neuron development and diversification. AB - The development of the taste system relies on the coordinated regulation of cues that direct the simultaneous development of both peripheral taste organs and innervating sensory ganglia, but the underlying mechanisms remain poorly understood. In this study, we describe a novel, biphasic function for glial cell line-derived neurotrophic factor (GDNF) in the development and subsequent diversification of chemosensory neurons within the geniculate ganglion (GG). GDNF, acting through the receptor tyrosine kinase Ret, regulates the expression of the chemosensory fate determinant Phox2b early in GG development. Ret-/- mice, but not Retfx/fx ; Phox2b-Cre mice, display a profound loss of Phox2b expression with subsequent chemosensory innervation deficits, indicating that Ret is required for the initial amplification of Phox2b expression but not its maintenance. Ret expression is extinguished perinatally but reemerges postnatally in a subpopulation of large-diameter GG neurons expressing the mechanoreceptor marker NF200 and the GDNF coreceptor GFRalpha1. Intriguingly, we observed that ablation of these neurons in adult Ret-Cre/ERT2; Rosa26LSL-DTA mice caused a specific loss of tactile, but not chemical or thermal, electrophysiological responses. Overall, the GDNF-Ret pathway exerts two critical and distinct functions in the peripheral taste system: embryonic chemosensory cell fate determination and the specification of lingual mechanoreceptors. PMID- 29282326 TI - Neurocognitive functioning and cerebrovascular reactivity after carotid endarterectomy. AB - OBJECTIVE: To evaluate in patients with TIA and ipsilateral high-grade internal carotid artery (ICA) stenosis whether changes in cognitive performance and cerebral hemodynamics occurred after carotid endarterectomy (CEA) and to explore their relationship. METHODS: Participants were patients who underwent CEA, had TIA within the last 6 months, and had an ipsilateral severe ICA stenosis. Coloured Progressive Matrices (CPM) plus Complex Figure Copy Test (CFCT) and phonemic (ph) plus categorical (ca) Verbal Fluency (VF) tests were performed to assess right and left hemisphere cognitive functions, respectively. Hemodynamics was assessed with transcranial Doppler ultrasonography by means of the cerebral vasomotor reactivity (CVR) to hypercapnia. RESULTS: A total of 137 patients were included. Before CEA, patients with right ICA obtained lower scores on the CPM and CFCT; patients with left ICA stenosis performed worse on the phonemic and categorical VF tests. The CVR was decreased on the side of the stenosis. At 6 months from CEA, CVR and cognitive performance were significantly improved. The performance change in cognitive tests exploring the revascularized hemisphere was positively associated with the ipsilateral CVR variation (CPM: R2 for linear regression = 0.759, adjR2 = 0.737; CFCT: R2 = 0.734, adjR2 = 0.710; (ph)VF: R2 = 0.774, adjR2 = 0.749; (ca)VF: R2 = 0.732, adjR2 = 0.703). CONCLUSION: Cognitive performance was enhanced at 6 months since CEA, and the improvement was related to the CVR increase. Cerebral hemodynamics may be an independent and potentially reversible determinant of cognitive dysfunction in severe carotid artery disease. PMID- 29282325 TI - Creation of disease-inspired biomaterial environments to mimic pathological events in early calcific aortic valve disease. AB - An insufficient understanding of calcific aortic valve disease (CAVD) pathogenesis remains a major obstacle in developing treatment strategies for this disease. The aim of the present study was to create engineered environments that mimic the earliest known features of CAVD and apply this in vitro platform to decipher relationships relevant to early valve lesion pathobiology. Glycosaminoglycan (GAG) enrichment is a dominant hallmark of early CAVD, but culture of valvular interstitial cells (VICs) in biomaterial environments containing pathological amounts of hyaluronic acid (HA) or chondroitin sulfate (CS) did not directly increase indicators of disease progression such as VIC activation or inflammatory cytokine production. However, HA-enriched matrices increased production of vascular endothelial growth factor (VEGF), while matrices displaying pathological levels of CS were effective at retaining lipoproteins, whose deposition is also found in early CAVD. Retained oxidized low-density lipoprotein (oxLDL), in turn, stimulated myofibroblastic VIC differentiation and secretion of numerous inflammatory cytokines. OxLDL also increased VIC deposition of GAGs, thereby creating a positive feedback loop to further enrich GAG content and promote disease progression. Using this disease-inspired in vitro platform, we were able to model a complex, multistep pathological sequence, with our findings suggesting distinct roles for individual GAGs in outcomes related to valve lesion progression, as well as key differences in cell-lipoprotein interactions compared with atherosclerosis. We propose a pathogenesis cascade that may be relevant to understanding early CAVD and envision the extension of such models to investigate other tissue pathologies or test pharmacological treatments. PMID- 29282327 TI - Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI). METHODS: The guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus. RESULTS: MCI prevalence was 6.7% for ages 60-64, 8.4% for 65-69, 10.1% for 70-74, 14.8% for 75-79, and 25.2% for 80-84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures. MAJOR RECOMMENDATIONS: Clinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C). PMID- 29282328 TI - Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study. AB - OBJECTIVE: To examine whether genetically predicted variation in circulating insulin-like growth factor 1 (IGF1) or its binding protein, IGFBP3, are associated with risk of Alzheimer disease (AD), using a mendelian randomization study design. METHODS: We first examined disease risk by genotypes of 9 insulin like growth factor (IGF)-related single nucleotide polymorphisms (SNPs) using published summary genome-wide association statistics from the International Genomics of Alzheimer's Project (IGAP; n = 17,008 cases; 37,154 controls). We then assessed whether any SNP-disease results replicated in an independent sample derived from the Swedish Twin Registry (n = 984 cases; 10,304 controls). RESULTS: Meta-analyses of SNP-AD results did not suggest that variation in IGF1, IGFBP3, or the molar ratio of these affect AD risk. Only one SNP appeared to affect AD risk in IGAP data. This variant is located in the gene FOXO3, implicated in human longevity. In a meta-analysis of both IGAP and secondary data, the odds ratio of AD per FOXO3 risk allele was 1.04 (95% confidence interval 1.01-1.08; p = 0.008). CONCLUSIONS: These findings suggest that circulating IGF1 and IGFBP3 are not important determinants of AD risk. FOXO3 function may influence AD development via pathways that are independent of IGF signaling (i.e., pleiotropic actions). PMID- 29282329 TI - MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study. AB - OBJECTIVE: To investigate the feasibility of microRNA (miRNA) levels in CSF as biomarkers for prodromal Huntington disease (HD). METHODS: miRNA levels were measured in CSF from 60 PREDICT-HD study participants using the HTG protocol. Using a CAG-Age Product score, 30 prodromal HD participants were selected based on estimated probability of imminent clinical diagnosis of HD (i.e., low, medium, high; n = 10/group). For comparison, participants already diagnosed (n = 15) and healthy controls (n = 15) were also selected. RESULTS: A total of 2,081 miRNAs were detected and 6 were significantly increased in the prodromal HD gene expansion carriers vs controls at false discovery rate q < 0.05 (miR-520f-3p, miR 135b-3p, miR-4317, miR-3928-5p, miR-8082, miR-140-5p). Evaluating the miRNA levels in each of the HD risk categories, all 6 revealed a pattern of increasing abundance from control to low risk, and from low risk to medium risk, which then leveled off from the medium to high risk and HD diagnosed groups. CONCLUSIONS: This study reports miRNAs as CSF biomarkers of prodromal and diagnosed HD. Importantly, miRNAs were detected in the prodromal HD groups furthest from diagnosis where treatments are likely to be most consequential and meaningful. The identification of potential biomarkers in the disease prodrome may prove useful in evaluating treatments that may postpone disease onset. CLINICALTRIALSGOV IDENTIFIER: NCT00051324. PMID- 29282331 TI - In large vessel occlusive stroke, time is brain... but collaterals are time. PMID- 29282332 TI - Collateral response modulates the time-penumbra relationship in proximal arterial occlusions. AB - OBJECTIVE: While clinical benefit from thrombolysis decreases with increase in time from stroke onset, the relationship of acute physiologic tissue compartments and collateral response to stroke onset time remains unclear. METHODS: We studied consecutive patients with proximal arterial occlusions (n = 355) with whole-brain perfusion CT with CT angiography within 6 hours of stroke onset. Penumbra and core were defined using voxel-based thresholds. Tissue mismatch was defined as the ratio of penumbra to core. Collateral scores were assessed using a previously validated visual score. RESULTS: Mean (SD) age was 72.1 (12.4) years, median (interquartile range) NIH Stroke Scale score 16 (4), mean (SD) time to imaging 152.5 (69.7) minutes. Penumbra volume (Spearman rho = 0.119, p = 0.026) and mismatch increased (Spearman rho = 0.115, p = 0.030) with time from onset. Core volume decreased (Spearman rho = -0.112, p = 0.035) while collateral scores increased with time (Spearman rho = 0.117, p = 0.028). On multivariable regression, good collateral scores predicted longer time since onset (beta = 0.101, p = 0.039) while mismatch was not a predictor (beta = 0.001, p = 0.351). Good collateral score was the strongest independent predictor of final infarct volume and improvement in clinical deficit. CONCLUSIONS: In our large patient cohort study of proximal arterial occlusions, we found an incremental collateral response and preserved penumbral volume with time. Thus, tissue viability can be maintained in this time window (0-6 hours) after stroke if leptomeningeal collaterals are able to sustain the penumbra. Our findings suggest that a longer therapeutic window may exist for intra-arterial intervention and that multimodal imaging may have a role in strokes of unknown onset time. PMID- 29282333 TI - Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study. AB - OBJECTIVE: To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications. METHODS: This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted. RESULTS: The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses <=100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group. CONCLUSION: The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses. PMID- 29282334 TI - Comment: Unraveling DNA sequence to identify cerebral indicators of dementia risk. PMID- 29282335 TI - CSF microRNA in patients with Huntington disease. PMID- 29282336 TI - CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP. AB - OBJECTIVE: To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). METHODS: We compared the ability of baseline CSF beta-amyloid1-42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. RESULTS: Higher CSF NfL concentration predicted more rapid decline (biomarker * time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate-corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p <= 0.029 and 0.008, respectively). CONCLUSIONS: Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease. PMID- 29282330 TI - Whole genome sequence analyses of brain imaging measures in the Framingham Study. AB - OBJECTIVE: We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. METHODS: We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants. RESULTS: We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 * 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 * 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 * 10-3) were confirmed. Gene-based tests detected associations (p <= 2.3 * 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways. CONCLUSIONS: Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings. PMID- 29282338 TI - Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression. AB - OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ~1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues. PMID- 29282339 TI - COL4A1 and fetal vascular origins of schizencephaly. PMID- 29282337 TI - Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. AB - OBJECTIVE: To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample. METHODS: Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent beta-amyloid (Abeta) and tau ([18F]AV1451) PET and lumbar puncture. CSF biomarkers (Abeta42, total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Abeta-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations. RESULTS: [18F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Abeta-positive AD and non-AD conditions (area under the curve 0.92-0.94; <=0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [18F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau (r = 0.75 vs 0.57 for t-tau and -0.49 for Abeta42). When restricted to Abeta-positive patients with AD, [18F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Abeta42 (r = 0.02). On voxelwise analysis, [18F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [18F]AV1451-PET, but not CSF biomarkers. CONCLUSION: [18F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [18F]AV1451 distinguish AD from non-AD conditions. PMID- 29282340 TI - [From 'Involuntary Movements' to 'Movement Disorders']. AB - Apart from the term 'involuntary movements', the term 'movement disorders' encompasses not only classical hyperkinesias but also hypokinesias including catalepsy or apraxia. It enables us to understand abnormal movements by their phenomena instead of by their localization. To advance the grasping of movement disorders, we discuss the clinical and pathophysiological features of abnormal movements in catatonia/catalepsy, anti-NMDAR encephalitis, paroxysmal dyskinesias, stiff person/leg syndrome, corticobasal degeneration/syndrome, and hysteria. Particular emphasis is placed on the roles of consciousness/unconsciousness, voluntariness/involuntariness, paroxysmal/sustained aspects, and cortical/subcortical networks. PMID- 29282342 TI - [Motor Symptoms of Autoimmune Encephalopathies]. AB - Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. At least 20 types of autoimmune encephalopathies have been discovered, with the most common type being Hashimoto encephalopathy. In clinical situations, we often observe that patients with autoimmune encephalopathy are misdiagnosed because they exhibit signs similar to those observed in functional psychogenic movement, conversion, or somatoform disorders. We clinically examined over 100 patients with autoimmune encephalopathy. These patients primarily demonstrated motor disturbances, mostly with give-way weakness, sensory abnormalities, and involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. In addition, we observed memory loss, psychogenic non-epileptic seizures, epilepsy, and autonomic symptoms in our patients. To diagnose autoimmune encephalopathies, we propose that a combination of neurological symptoms indicating "diffuse brain damage" be used. "Diffuse brain damage" is a proof of several symptoms, such as give-way weakness; motor symptoms such as paralysis, smoothness disorder of exercise, involuntary movements, and difficulty to sustain; abnormal sensations such as pain, abnormal perception of various parts, and impaired vibration sensation; deterioration of higher order functions such as memory and learning ability; and impairment of the visual processing system and various visual abnormalities. As patients with autoimmune encephalitis exhibit diffuse involvement, the presence of these symptoms was entirely understandable. Over three such abnormal findings could indicate diffuse brain damage. Owing to the regular understanding in neurology, most patients tend to be diagnosed with somatoform disorders. Thus, physicians should not diagnose somatoform disorders without first excluding autoimmune encephalopathy. PMID- 29282341 TI - [Tourette Syndrome: Clinical Features and Pathophysiology]. AB - Tourette syndrome (TS) is a neuropsychiatric disorder with the onset in childhood. TS is a form of tic disorders, and characterized by the motor and vocal tics, and comorbidities such as attention deficit hyperkinetic and obsessive compulsive disorders. These symptoms appear age dependently, showing a wax and wane course, and subside or abolish by the late teens. Pathophysiology of TS involves the dysfunction of both motor and non-motor basal ganglia-thalamo cortical circuitries. The nigrostriatal dopamine (DA) system takes the exponential decrement at the striatum. In TS, this decrement is accelerated in association with DA-D2 receptor super-sensitivity, which disinhibits the descending and ascending output pathways of the basal ganglia. Disinhibited motor basal ganglia-thalamo-cortical circuitries develop the specific tics according to the target sites. Hypofunction of the 5-hydroxytriptophan (5-HT) neurons of the brainstem innervate the striatum involved in non-motor basal ganglia-thalamo cortical circuitries and cause the obsessive compalsive disorder and other behavioral disorders. The associated DA-D2 receptor supersensitivity is assumed to be a consequence of the developmental abnormalities and not due to denervation supersensitivity. The treatments of TS aim to correct the 5-HT hypofunction by improving the environmental factors and super-sensitized DA receptors medically by a small dose of levodopa and/or aripiprazole. PMID- 29282343 TI - [Diagnosis of Psychogenic Non-Epileptic Seizure: How Can We Detect It Prior to Video-Electroencephalography Monitoring]. AB - It is highly recommended not to base the diagnosis of psychogenic non-epileptic seizures (PNES) on one single sign. Yet, the combination of several symptoms may be highly indicative of PNES. The aim of this paper is to demonstrate that some combinations of symptoms are more easily recorded and that some are more indicative of PNES. We review and analize various symptom combinations including convulsions, falling, and impaired consciousness. Further, we examine and discuss all individual symptoms that are known to be associated with PNES. PMID- 29282344 TI - [Symptoms and Pathophysiology of Dyskinesias]. AB - Symptomatic characteristics and recent advances in understanding the pathophysiology of tardive dyskinesias and levodopa-induced dyskinesias were reviewed. After the advent of atypical antipsychotics, tardive dyskinesias became less frequent, at least as observed during a short-term follow up. The dopamine supersensitivity hypothesis stating that blockade of dopamine D2 receptors by antipsychotics makes D2 receptors more sensitive to dopamine, has long been proposed. However, the true mechanisms remain to be determined. Three types of levodopa-induced dyskinesias-peak-dose dyskinesia, off-period dystonia and diphasic dyskinesia-were described. The pathomechanisms of peak-dose dyskinesia have been demonstrated in recent years. The priming process involved in peak-dose dyskinesia is as follows: (1) marked fluctuation of dopamine concentration occurs in the synaptic clefts of striatal neurons after each levodopa dose, (2) cortico striatal synapses of the striatal spiny neurons of the direct pathway become supersensitive, (3) there is increased production of GABA in the spiny neurons and excessive storage of GABA in their axon terminals, (4) following this, each dose of levodopa causes excessive release of GABA into the output nuclei of the basal ganglia, resulting in abnormal firing of the neurons in these nuclei. Thus, peak-dose dyskinesia occurs after levodopa dose. PMID- 29282345 TI - [Drug-Induced Akathisia]. AB - Akathisia consists of subjective inner restlessness, such as awareness of the inability to remain seated, restless legs, fidgetiness, and the desire to move constantly, and of objective increased motor phenomena, such as body rocking, shifting from foot to foot, stamping in place, crossing and uncrossing legs, pacing around. Although the broad definition of akathisia includes the inner and motor restlessness observed in patients with idiopathic Parkinson's disease, post encephalitic parkinsonism, and restless legs syndrome, here we exclusively focus on the narrow definition of antipsychotic-induced akathisia. The most reliable treatment for acute akathisia is the reduction or the withdrawal of antipsychotic medication. However, this is often not possible because it may worsen the patients' mental condition. Various pharmacological agents have been used for the treatment of this condition. These include anticholinergic agents (e.g., biperiden and trihexyphenidyl), benzodiazepines, beta-adrenoceptor blockers (e.g., propranolol), and serotonin 2A receptor antagonists (e.g., mianserin, cyproheptadine, and mirtazapine). PMID- 29282346 TI - [Modulation of Metacognition with Decoded Neurofeedback]. AB - Humans often assess their confidence in their own perception, e.g., feeling "confident" or "certain" of having seen a friend, or feeling "uncertain" about whether the phone rang. The neural mechanism underlying the metacognitive function that reflects subjective perception still remains under debate. We have previously used decoded neurofeedback (DecNef) to demonstrate that manipulating the multivoxel activation patterns in the frontoparietal network modulates perceptual confidence without affecting perceptual performance. The results provided clear evidence for a dissociation between perceptual confidence and performance and suggested a distinct role of the frontoparietal network in metacognition. PMID- 29282347 TI - [A Case of Kanji Agraphia Resulting from Intracerebral Hemorrhage on the Left Temporal Lobe Associated with Multiple Dural Arteriovenous Fistulas]. AB - A 60-year-old, right-handed man suffered from mild word finding difficulties and kanji agraphia. Brain computed tomography revealed left temporal lobe hemorrhage, and cerebral angiogram revealed multiple dural arteriovenous fistulas (d-AVFs) in the left anterior cranial fossa and middle cranial fossa. Surgical shunt ablation was performed, and the lesions were obliterated completely. Analysis of the kanji agraphia during neuropsychological rehabilitation showed similar symptoms to those of the left posterior inferior temporal lobe lesion. Re-evaluation of magnetic resonance imaging showed multiple microbleeds on the left inferior temporal lobe, which could be responsible for the kanji agraphia. In this case, analysis of clinical symptoms with careful neuropsychological examination was important for understanding these pathologies. (Received March 21, 2017; Accepted June 21, 2017; Published December 1, 2017). PMID- 29282348 TI - [A Case of Cowden Syndrome Associated with Lhermitte-Duclos Disease]. AB - A 24-year-old woman slowly developed mild unsteadiness of gait. Neurological examination revealed mild dysmetria of the left upper and lower limbs. Standing and gait were unsteady, and tandem gait was impossible. Cranial magnetic resonance imaging (MRI) showed an enlarged left cerebellar hemisphere with striated lines, a characteristic finding of Lhermitte-Duclos disease. She also had papules on the forehead, goiter, lactating adenoma, glycogenic acanthosis in the esophagus, cafe-au-lait spot, and hemangioma and keratosis on the dorsum of foot. The diagnosis of Cowden syndrome was established by finding the mutation in the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene. Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas in a variety of tissues. Recognition of Lhermitte-Duclos disease as a neurological condition of Cowden syndrome is important, and once the diagnosis of Lhermitte-Duclos disease is made, a close physical investigation is necessary because the hamartomas tend to develop malignancies. (Received March 15, 2017; Accepted July 24, 2017; Published December 1, 2017). PMID- 29282349 TI - Norovirus-like VP1 particles exhibit isolate dependent stability profiles. AB - Noroviruses are the main cause of viral gastroenteritis with new variants emerging frequently. There are three norovirus genogroups infecting humans. These genogroups are divided based on the sequence of their major capsid protein, which is able to form virus-like particles (VLPs) when expressed recombinantly. VLPs of the prototypical GI.1 Norwalk virus are known to disassemble into specific capsid protein oligomers upon alkaline treatment. Here, native mass spectrometry and electron microscopy on variants of GI.1 and of GII.17 were performed, revealing differences in terms of stability between these groups. Beyond that, these experiments indicate differences even between variants within a genotype. The capsid stability was monitored in different ammonium acetate solutions varying both in ionic strength and pH. The investigated GI.1 West Chester isolate showed comparable disassembly profiles to the previously studied GI.1 Norwalk virus isolate. However, differences were observed with the West Chester being more sensitive to alkaline pH. In stark contrast to that, capsids of the variant belonging to the currently prevalent genogroup GII were stable in all tested conditions. Both variants formed smaller capsid particles already at neutral pH. Certain amino acid substitutions in the S domain of West Chester relative to the Norwalk virus potentially result in the formation of these T = 1 capsids. PMID- 29282350 TI - Assessment Tools for Use in Patients with Meniere Disease: An Update. AB - A number of electrophysiological tests have been proposed for the initial diagnostic assessment or for the follow-up phase of patients affected by Meniere disease. The most common are: (i) vestibular evoked myogenic potentials (VEMPs); (ii) electrocochleography (ECochG); and (iii) otoacoustic emissions (OAEs). This paper presents the latest clinical developments with these 3 testing modalities. The PubMed, Embase, and Cinahl databases were searched from 2006 to December 2016. Full-text articles were obtained in cases where the title, abstract, or key words suggested that the study may be eligible for this review. The medical subject heading (MeSH) terms included the following: Meniere, hearing threshold, vestibule, otoacoustic emissions, inner ear, ECochG, VEMPs. There were 368 identified papers, out of which 87 were eligible for inclusion. Overall the data in the literature are still limited and the recommended procedures have not reached an international consensus. From the available data, one can conclude that none of the electrophysiological tests could be considered as pathognomonic, for the diagnosis of Meniere disease: presently, the tests could be mostly used in a supportive role to the clinical diagnosis. Hopefully, in the future, improved technology in electrophysiological testing could contribute to the development of better strategies for the diagnosis of Meniere disease. PMID- 29282351 TI - Marked 18-Fuorine-Fluorodeoxyglucose (FDG) Avidity of an Intrapulmonary Typical Carcinoid Tumor Manifesting as a Bronchocele in an Asymptomatic Middle-Aged Woman. AB - BACKGROUND Intrapulmonary carcinoid tumors (ICTs) are malignant, slow-growing tumors classified as either: i) typical, less aggressive, well-differentiated tumors or ii) atypical, more aggressive, poorly-differentiated tumors. Most typical carcinoid tumors originate in the central airway and present with symptoms related to bronchial obstruction. In contrast, atypical carcinoids tend to occur more peripherally and are generally detected incidentally as a solitary pulmonary nodule (SPN). Typical carcinoid tumors usually do not exhibit increased metabolic activity on positron emission tomography with 18-fuorine fluorodeoxyglucose (FDG PET) as would be expected for malignant tumors. In this case report, we present an unusual case of a typical, well-differentiated, peripheral carcinoid tumor showing marked FDG avidity manifesting as a bronchocele. We discuss the differential diagnoses and describe the diagnostic approach undertaken in this exemplary case of a common clinical problem. CASE REPORT A left upper-lobe, peripheral, 2-cm pulmonary nodule was incidentally identified on chest radiography of an asymptomatic 67-year-old female patient. Chest CT scan with intravenous (IV) contrast showed a noncalcified nodule with a branching pattern. Further evaluation with FDG PET/CT scan demonstrated marked FDG avidity. Post-surgical biopsy revealed a typical, well-differentiated, intrapulmonary carcinoid tumor. CONCLUSIONS Carcinoid tumors of the lung remain a diagnostic challenge for primary care physicians and radiologists due to their diverse clinical and radiological presentations. Peripheral carcinoid tumors usually present as an asymptomatic peripheral, solitary, pulmonary nodule, but isolated peripheral bronchocele has been described, as in our case. In addition, caution must be taken when utilizing FDG PET/CT scan for the evaluation of a possible lung carcinoid tumor, as an accurate value range of FDG uptake for diagnosis of these tumors has not been defined. PMID- 29282352 TI - Sooner or later: does early human milk fortification improve outcomes? PMID- 29282353 TI - Noninvasive ventilation strategies: which to choose? PMID- 29282354 TI - Using polyethylene plastic bag to prevent moderate hypothermia during transport in very low birth weight infants: a randomized trial. AB - OBJECTIVE: Hypothermia remains a significant problem among very low birth weight (VLBW) infants. The use of occlusive polyethylene plastic bags immediately after birth has been proven to be effective for preterm infants to reduce hypothermia. This study aims to determine whether placing VLBW infants in plastic bags during transport reduces hypothermia. STUDY DESIGN: Study infants were randomly assigned to a standard thermoregulation protocol or to a standard thermoregulation protocol with placement of the torso and lower extremities inside a polyethylene plastic bag during transport. The primary outcome measures were axillary temperature before and after transport and the occurrence of moderate hypothermia upon neonatal intensive care unit admission. RESULT: The 108 VLBW infants recruited into the study were randomized to the plastic bag (n = 54) group or to standard group (n = 54) and had similar baseline characteristics. VLBW infants in the plastic bag group had a lower rate of moderate hypothermia (3.7 vs 27.8%; risk ratio 0.10; confidence interval 0.02-0.46; P < 0.001) and higher axillary temperatures (36.4 +/- 0.4 degrees C vs 35.9 +/- 0.9 degrees C; P = 0.001) upon NICU admission compared to infants receiving standard care. CONCLUSION: Placing VLBW infants in polyethylene plastic bags during transport reduces the occurrence of hypothermia, especially moderate hypothermia. PMID- 29282355 TI - Low expression of a Ddm7/Ldm7-hybrid mutant (D/Ldm7) in the novel haplotype H-2nc identified in atopic dermatitis model NC/Nga mice. AB - Environmental factors and the major histocompatibility complex (MHC) are involved in the pathogenesis of atopic dermatitis (AD). However, MHC type (H2 haplotype) of AD model mice NC/Nga is poorly understood. Alloreactive CD8+ or CD4+ T cells in NC/Nga strongly responded to each antigen-presenting cells (A/J: H-2a, C57BL/6: H-2b, BALB/c: H-2d, or C3H/HeJ: H-2k), suggesting that NC/Nga has other H2 haplotype. Polymorphic microsatellite (CA)n repeats in TNF-alpha gene differ based on the H2 haplotype at present. NC/Nga's (CA)n repeats (n = 19) were different from other examined strains, A/J (n = 14), BALB/c (n = 14), C3H/HeJ (n = 16), and C57BL/6 (n = 20). Using flow cytometry and genotyping, we demonstrated the NC/Nga H2 haplotype had a unique phenotype (Kd, I-Ak, and I-Ek) in which Dd and Ld lacked as protein despite sensitive mRNA detection. The loss of Dd and Ld was caused by forming a unique Ddm7/Ldm7-hybrid mutant (D/Ldm7). We propose to call this novel H2 haplotype the "H-2nc," and provide the important information regarding the AD research using NC/Nga mice. PMID- 29282356 TI - Long non-coding RNA DLEU1 predicts poor prognosis of gastric cancer and contributes to cell proliferation by epigenetically suppressing KLF2. AB - Currently, accumulating documents have paid great attention to the critical role of long non-coding RNAs. The long non-coding RNAs DLEU1 has been demonstrated to be dysregulated in many solid tumors and hematological malignancies. However, the detailed descriptions about its potential roles and molecular mechanism in gastric cancer (GC) are still blurry. As for our research, it was found out that DLEU1 was observably intensified in GC tissues and cell lines. And highly expressed DLEU1 was relevant to tumor size, advanced stage of pathology and lymph node metastasis in GC patients. Silenced DLEU1 obviously suppressed proliferation via leading to the cell cycle arrest and inducing cell apoptosis of GC. Furthermore, mechanistic experiments uncovered that DLEU1 could recruit LSD1 (lysine specific demethylase 1) to the promoter regions of KLF2 and then suppressed its transcription. In addition, rescue assays revealed that the oncogenic function mediated by DLEU1 in GC was partly by regulating KLF2. Collectively, our findings manifested that DLEU1 might serve as an oncogene in GC. PMID- 29282357 TI - Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. AB - In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age >=65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events. On multivariate analysis, prior arterial events (<0.0001), hyperlipidemia (p = 0.03), and hypertension (p = 0.02) predicted subsequent arterial events. In comparison, prior venous events (p = 0.05), leukocytosis >=11 * 109/L (p = 0.002), and major hemorrhage (p = 0.02) were predictors of subsequent venous events. Salient associations with arterial thrombosis included age >= 60 years, hypertension, diabetes, hyperlipidemia and normal karyotype whereas age <= 60 years, females, palpable splenomegaly and history of major hemorrhage were associated with venous thrombosis. TET2 or ASXL1 mutations did not impact arterial nor venous thrombosis. In conclusion, we identify distinct associations for arterial versus venous thrombosis in PV and confirm that a prior arterial or venous thrombotic event is the most reliable predictor of subsequent events. PMID- 29282358 TI - Convective radiofrequency water vapor thermal therapy for benign prostatic hyperplasia: a single office experience. AB - BACKGROUND: Convective radiofrequency water vapor thermal therapy with the Rezum system is a relatively new treatment for benign prostatic hyperplasia (BPH). We present results from a single surgeon in an office setting. METHODS: A retrospective review of 129 patients from a single surgeon who underwent the Rezum procedure was performed. All patients were at least 4 months out from treatment. International prostate symptom scores (IPSS), maximum flow rates (Qmax), residual urine volumes, medication usage, and adverse events were monitored. Data were analyzed at baseline, 15-45 days, 46-90 days, and 91-180 days after treatment. A scripted patient questionnaire was attempted over the phone to all patients. It was administered by a resident and medical student who do not work in the provider's office. RESULTS: Maximal effects were noted at the 91-180 day interval. IPSS improved from a baseline of 18.3 to 6.9 and Qmax from 10.5 to 16.8 mL/s. Improvements were independent of starting symptom score, median lobe treatment, and prostate size. There was a 17% prostate volume reduction based on TRUS and 14% based on PSA. The most common adverse events were urinary tract infections (17%) and transient urinary retention (14%). In total 90% of patients were able to come off their BPH medications and 86% of patients would recommend the procedure to a friend. CONCLUSIONS: Rezum radiofrequency water vapor thermal therapy offers a minimally invasive option for BPH management with moderate improvement in symptoms and flow rate. The results appear to be independent of prostate size or presence of a median lobe, and have now been replicated in a single office setting. PMID- 29282359 TI - The molecular biology of prostate cancer: current understanding and clinical implications. AB - BACKGROUND: With continuous progress over the past few decades in understanding diagnosis, treatment, and genetics, much has been learned about the prostate cancer-diagnosed genome. METHODS: A comprehensive MEDLINE(r) and Google scholar literature search was conducted using keyword variations relating to the genetics of prostate cancer such as chromosomal alterations, androgen receptor, castration resistant, inheritance, polymorphisms, oncogenes, metastasis, biomarkers, and immunotherapy. RESULTS: Traditionally, androgen receptors (AR) have been the focus of research. Recently, identification of recurrent chromosomal alterations that lead to either multiplication of regions (gain-of-function) or deletion of regions (loss-of-function) has opened the door to greater genetic accessibility. These chromosomal aberrations lead to variation in copy number and gene expression. Some of these chromosomal alterations are inherited, while others undergo somatic mutations during disease progression. Inherited gene mutations that make one susceptible to prostate cancer have been identified with familial linked studies. Somatic genes that progress tumorigenesis have also been identified. Research on the molecular biology of prostate cancer has characterized these genes into tumor suppressor genes or oncogenes. Additionally, genome-wide assay studies have identified many high-risk single-nucleotide polymorphisms recurrent throughout the prostate cancer-diagnosed genome. Castration-resistant prostate cancer is the most aggressive form of prostate cancer, and its research has elucidated many types of mutations associated with AR itself, including enhanced expression and amplification, point mutations, and alternative splicing. Understanding the molecular biology of prostate cancer has permitted more accurate identification using advanced biomarkers and therapy for aggressive forms using immunotherapy. CONCLUSIONS: An age-related disease, prostate cancer commands profound attention. With increasing life expectancy and the continuous pursuit of it, prostate cancer is a powerful obstacle best defeated using targeted therapies specifically designed for the unique molecular profile of the malignancy. PMID- 29282360 TI - Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study. AB - BACKGROUND: Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA independent, study-mandated prostate biopsies. METHODS: We conducted a post hoc analysis of data from 4974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. >=7), were examined using multivariable logistic regression. RESULTS: High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (OR per 10 mg/dL 1.05; 95% CI 1.00-1.09; p = 0.048), but cholesterol was unrelated to either overall or low grade prostate cancer risk (p-values >0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values >0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (OR per 10 mg/dL 1.08; 95% CI 1.01-1.16; p = 0.033) and high-grade prostate cancer (OR per 10 mg/dL 1.14; 95% CI 1.01-1.28; p = 0.034). CONCLUSIONS: In REDUCE, where all men received PSA independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link. PMID- 29282361 TI - Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia. AB - Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols. Two-year cumulative incidence of symptomatic ON was 10.6%. Two BCL2L11 polymorphisms, the 891T>G (rs2241843) in all QcALL patients and 29201C>T (rs724710) in high-risk group were significantly associated with ON, P = 0.009 and P = 0.003, respectively. The association remained significant in multivariate model (HR891TT = 2.4, 95% CI 1.2-4.8, P = 0.01 and HR29201CC = 5.7, 95% CI 1.6-20.9, P = 0.008). Both polymorphisms influenced viability of dexamethasone treated lymphoblastoid cell lines (P <= 0.03). The 891T>G influenced Bim gamma isoform levels (0.03) and its association with ON was also confirmed in replication DFCI cohort (N = 168, P = 0.03). QcALL children had a high incidence of ON during therapy, which was highly associated with BCL2L11 polymorphisms. PMID- 29282362 TI - Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer. AB - The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II-III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters. PMID- 29282363 TI - The impact of genetic polymorphisms on CYP1A2 activity in humans: a systematic review and meta-analysis. AB - A large interindividual variation in the activity of cytochrome P450 1A2 (CYP1A2) raises concern about therapeutic failure or toxicity when medical professionals prescribe drugs extensively metabolized by CYP1A2. To date, a number of studies have assessed the association between genetic polymorphisms and CYP1A2 activity; however, there are controversies as to the functional importance of CYP1A2 polymorphisms on the metabolism of CYP1A2 substrates. This systematic review and meta-analysis assessed the effects of genetic polymorphisms on CYP1A2 activity, as measured by caffeine metabolism, in a total of 3570 individual subjects. Higher enzyme activity was observed among those who were homozygous or heterozygous for the -163C>A polymorphism (rs762551), when compared to the wild type individuals (SMD = 0.40, 95%CI = 0.12-0.68, p = 0.005; SMD = 0.32, 95%CI = 0.11-0.54, p = 0.003, respectively) and this was more pronounced among smokers (SMD = 0.92, 95%CI = 0.27-1.57, p = 0.005; SMD = 0.56, 95%CI = 0.22-0.90, p = 0.001, respectively). For other CYP1A2 polymorphisms, altered caffeine metabolic ratios were not seen. Our results indicate the functional importance of -163C>A polymorphism on CYP1A2 inducibility in humans. PMID- 29282364 TI - Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B cell acute lymphoblastic leukemia. AB - Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) >= 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR 3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity. PMID- 29282365 TI - Genetic and clinic predictors of new onset diabetes mellitus after transplantation. AB - New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36 1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development. PMID- 29282367 TI - Sean Harper. PMID- 29282368 TI - Sage gets an antidepressant lift. PMID- 29282369 TI - First in vivo gene-editing drugs enter the clinic. PMID- 29282370 TI - Immunotherapy: Vaccine patch to treat melanoma. PMID- 29282366 TI - JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. AB - This corrects the article DOI: 10.1038/nrd.2017.201. PMID- 29282372 TI - Market watch: Upcoming market catalysts in Q1 2018. PMID- 29282373 TI - Cancer: Inhibiting DNA damage signalling. PMID- 29282371 TI - Cancer immunotherapy: Microbes matter. PMID- 29282374 TI - Boehringer Ingelheim experiments with open-access chemical probes. PMID- 29282375 TI - Can innate immune system targets turn up the heat on 'cold' tumours? PMID- 29282376 TI - Technology: New method for endogenous protein degradation. PMID- 29282377 TI - Cancer: Targeting telomeres. PMID- 29282378 TI - Revealing the glass transition in shape memory polymers using Brillouin spectroscopy. AB - Emerging medical devices which employ shape memory polymers (SMPs) require precise measurements of the glass transition temperature (Tg) to ensure highly controlled shape recovery kinetics. Conventional techniques like differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) have limitations that prevent utilization for certain devices, including limited accuracy and the need for sacrificial samples. In this report, we employ an approach based on Brillouin spectroscopy to probe the glass transition of SMPs rapidly, remotely, and nondestructively. Further, we compare the Tg obtained from Brillouin scattering with DMA- and DSC-measured Tg to demonstrate the accuracy of Brillouin scattering for this application. We conclude that Brillouin spectroscopy is an accurate technique for obtaining the glass transition temperature of SMPs, aligning closely with the most common laboratory standards while providing a rapid, remote, and nondestructive method for the analysis of unique polymeric medical devices. PMID- 29282379 TI - TOWARDS A MULTI-SCALE AGENT-BASED PROGRAMMING LANGUAGE METHODOLOGY. AB - Living tissues are dynamic, heterogeneous compositions of objects, including molecules, cells and extra-cellular materials, which interact via chemical, mechanical and electrical process and reorganize via transformation, birth, death and migration processes. Current programming language have difficulty describing the dynamics of tissues because: 1: Dynamic sets of objects participate simultaneously in multiple processes, 2: Processes may be either continuous or discrete, and their activity may be conditional, 3: Objects and processes form complex, heterogeneous relationships and structures, 4: Objects and processes may be hierarchically composed, 5: Processes may create, destroy and transform objects and processes. Some modeling languages support these concepts, but most cannot translate models into executable simulations. We present a new hybrid executable modeling language paradigm, the Continuous Concurrent Object Process Methodology (CCOPM) which naturally expresses tissue models, enabling users to visually create agent-based models of tissues, and also allows computer simulation of these models. PMID- 29282380 TI - Biofuels, Bioenergy and the Bioeconomy in North and South. PMID- 29282381 TI - A Silent Asymptomatic Solid Pancreas Tumor in a Nonsmoking Athletic Female: Pancreatic Ductal Adenocarcinoma. AB - A silent solid endocrine tumor of pancreas, intraductal adenocarcinoma of pancreas, is the fourth leading cancer-related death in the US. However, it is expected to become the third leading cause by 2030 owing to delayed diagnosis and slow progress in management. Chronic pancreatitis is at risk for pancreatic ductal adenocarcinoma (PDAC). PDAC is diagnostic with transabdominal sonogram, blood test such as carbohydrate antigen 19-9 (CA 19-9), and imaging. PDAC has a dismal prognosis. The survival rate in 5 years is barely 6%, while late detection rate is 80-85% with unresectable stage upon diagnosis. Here, we present a 51-year old asymptomatic female with intermittent constipation and abdominal pain for 1 month with obstructive jaundice with PDAC with liver metastasis. PMID- 29282382 TI - Massive Upper and Lower GI Bleed from Simultaneous Primary (AL) Amyloidosis of the Stomach and Transverse Colon in a Patient with Multiple Myeloma. AB - Symptomatic primary (amyloid light-chain or AL) amyloidosis of the gastrointestinal (GI) tract is very rare. Most of the patients with symptomatic involvement of the GI tract present with altered motility, malabsorption, or bleeding. We report a case of gastric and colonic amyloidosis on anticoagulation presenting with massive upper and lower GI bleeding. A 67-year-old lady known to have multiple myeloma and AL amyloidosis on rivaroxaban presented with massive upper GI bleeding. Esophagogastroduodenoscopy showed a mass lesion (3 * 7 cm) located along the greater curvature in the body/antrum with active bleeding. Mucosal biopsies revealed amyloid deposition. She underwent partial gastrectomy and recovered well after surgery, and was discharged home on rivaroxaban. The patient presented again 4 weeks after discharge with bleeding per rectum, and a colonoscopy revealed a large mass in the proximal transverse colon with active bleeding. Biopsy of the mass showed amyloid deposition. At this point, the patient declined any further intervention. Rivaroxaban was discontinued, the rectal bleeding stopped, and she was discharged home with no further episodes of GI bleed. Amyloidosis of the GI tract presenting with massive GI bleed is extremely rare and is thought to be related to small-vessel fragility due to amyloid infiltration and impaired hemostasis caused by factor X deficiency. Even though GI bleeding with amyloidosis is spontaneous, use of anticoagulation could activate such episodes in these patients. Caution should be exercised with the use of anticoagulation in patients with amyloidosis involving the GI tract, and colonoscopy should be considered in patients with gastric amyloidosis. PMID- 29282383 TI - Intussusception due to an Inverted Meckel's Diverticulum Diagnosed by Double Balloon Enteroscopy. AB - An 18-year-old man presented after undergoing multiple investigations for abdominal pain. Retrograde double-balloon enteroscopy showed a protruding red lesion in the ileum with small ulcers, approximately 75 cm proximal to the ileocecal valve, resulting in an intussusception. An inverted Meckel's diverticulum was strongly suspected. Pressure was applied to the protruding lesion using contrast medium injection after wedging the lumen with a balloon. The intussusception partially reduced, avoiding the need for emergent surgery. Endoscopic tattooing was performed to mark the lesion for subsequent resection. Elective laparoscopy-assisted surgery with minimum laparotomy revealed an inverted Meckel's diverticulum, which was resected. PMID- 29282385 TI - Internal Hernia into the Treitz Fossa after Pancreaticoduodenectomy. AB - The development of an internal hernia into the Treitz fossa after pancreaticoduodenectomy has not been previously reported. We herein present such a case with a brief review of the literature. A 43-year-old man who had undergone pancreaticoduodenectomy with reconstruction of the digestive tract by the Child method at our hospital 7 months previously presented with abdominal pain. Computed tomography showed intestinal ileus with formation of a small intestinal loop that was suspected to be an internal hernia. Intraoperatively, we found that the dilated small intestine had entered the upper side of the abdomen from the ligament of Treitz. We detached the intestine from the hernia and placed it in its normal position. The ligament of Treitz at the hernia orifice was closed with sutures. The patient remained in good health and was discharged from the hospital 18 days after the second operation. Suturing of the Treitz fossa at the time of pancreaticoduodenectomy may be important to prevent the formation of an internal hernia. PMID- 29282384 TI - Hepatocyte Nuclear Factor 1alpha-Mutated Hepatocellular Adenomas: An Atypical Presentation. AB - Hepatocellular adenomas (HCAs) are rare benign monoclonal hepatic tumors that commonly occur in females (3-4 per 100,000 women) due to the use of oral contraceptives, its primary risk factor. Recently, HCAs have been classified into 4 distinct subtypes according to genotypic and phenotypic characteristics and clinical features: inflammatory HCA (40-50%), which are hypervascular with marked peliosis and a tendency to bleed; hepatocyte nuclear factor 1alpha (HNF1A) mutated HCA (H-HCA, 30-40%) that are diffusely steatotic and rarely undergo malignant transformation; beta-catenin activated HCA (10-15%), which frequently undergo malignant transformation and may seem hepatocellular carcinoma on imaging; and unclassified HCA (10-25%). In this study, we report the case of a 23 year-old female oral contraceptive user with H-HCA. Usually, H-HCA is considered to be nonsevere in most cases and often requires outpatient follow-up. However, in this case, the injury had substantially increased in volume and evolved with a major bleeding frame, which was an unusual finding for this subtype of adenoma. The therapeutic used for this patient was a laparoscopic left hepatic segmentectomy. Thus, the choice of treatment to be performed in a patient with H HCA can depend on the tumor size (>5 cm), the outcome of previous bleeding, and the risk of bleeding recurrence. PMID- 29282387 TI - Gastric Adenocarcinoma with Dual Differentiation toward Neuroendocrine and alpha Fetoprotein-Producing Features: Report of 2 Cases. AB - Some gastric carcinomas show composite features of neuroendocrine carcinoma (NEC) and alpha-fetoprotein (AFP)-producing carcinoma, which are very rare; only a few cases have been reported to date. We reviewed an additional 2 such cases of gastric carcinoma, which were both advanced aggressive tumors showing regional lymph node metastasis and distant metastasis. Both cases were accompanied by ordinary adenocarcinoma forms, implying that they had preceded the NEC and AFP producing carcinoma components. A distinctive feature was the finding suggestive of dual differentiation of tumor cells to neuroendocrine and AFP-producing phenotypes, which was identified even in the metastatic tumor in the regional lymph node. Because both tumors predominantly showed poorly differentiated forms, the final pathologic diagnosis must rely on the immunohistochemistry. Pathologists should always keep in mind the existence of such tumors for the correct diagnosis of some gastric carcinomas with specific phenotypes, especially in pathologic diagnosis on biopsy. PMID- 29282386 TI - Microvillus Inclusion Disease Variant in an Infant with Intractable Diarrhea. AB - Microvillus inclusion disease (MVID) is a rare autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea. We report a case of MVID variant with a homozygous gene mutation in syntaxin 3 (STX3). The patient is a male Saudi infant who presented shortly after birth with severe vomiting, metabolic acidosis, and mild diarrhea. Electron microscopy study for small intestinal biopsy was consistent with MVID. MYO5B gene mutation was excluded; subsequently, whole exome sequencing (WES) was performed, which revealed homozygous gene mutation in STX3. Using WES in clinical environment can be a useful tool for diagnosing difficult and rare inherited congenital enteropathies. PMID- 29282388 TI - A Rare Case of Intraductal Tubulopapillary Neoplasm of the Pancreas Rupturing and Causing Acute Peritonitis. AB - An intraductal tubulopapillary neoplasm (ITPN) is a very rare pancreatic tumor. Here we report an extremely rare case of an ITPN rupturing and causing acute peritonitis. A 50-year-old woman presented with left flank pain and vomiting. A computed tomography (CT) scan revealed gigantic multilocular cysts in the pancreatic tail and massive fluid collection in the abdominal cavity. The serum, urine, and abdominal fluid amylase levels were highly elevated, so she was conservatively treated with intraperitoneal drainage and antibiotics for a diagnosis of ruptured pancreatic cysts. After this patient recovered, a CT scan revealed a 2-cm low-density mass located in the body of the pancreas. This was diagnosed as a pancreatic ductal adenocarcinoma of the pancreatic body with an intraductal papillary mucinous neoplasm, and a distal pancreatectomy was performed. The tumor was composed of cuboidal high-grade dysplastic cells proliferating in a tubulopapillary growth pattern without mucin production. An immunohistochemical examination revealed that the tumor cells were positive for MUC1 and CK7, but negative for MUC5AC. These features led to the final diagnosis of ITPN. In this case, the solid ITPN growth obstructed the lumen of the main pancreatic duct, and the intraductal pressure of the distal side rose gradually. Then, pancreatic cysts formed and burst into the abdominal cavity when the intraductal pressure was at its maximum. However, an ITPN consists of high-grade atypical cells derived from the pancreatic ductal epithelium in principle, so the rupture may be an independent risk factor for peritonitis carcinomatosa in the future. PMID- 29282389 TI - Listeria Monocytogenes Brain Abscess in Crohn's Disease Treated with Adalimumab. AB - Listeria monocytogenes is a gram-positive bacterium that causes listeriosis. Brain abscess is a very uncommon manifestation of listeriosis and has not been reported to be associated with adalimumab (humira), one of the approved medications for treating Crohn's disease. A 45-year-old female with Crohn's disease presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She was on prednisone and 6-mercaptopurine. She had started taking adalimumab 17 days prior to admission. She had signs of toxicity, confusion, and nuchal rigidity, but showed neither central nervous system deficits nor focal deficits. The laboratory results revealed Gram-positive coccobacillus, positive blood and cerebrospinal fluid culture for Listeria monocytogenes, and a 5 * 5 mm ring-enhancing lesion of brain abscess on MRI. After holding off 6-mercaptopurine and adalimumab, her mental status improved on the next day. Finally, she was discharged on day 7 of hospitalization with ampicillin 2 g intravenously every 4 h for a total of 2 weeks. Two weeks later, the follow-up MRI showed a 2-mm area of residual enhancement in the left temporal lobe at the site of the previous brain abscess. Adalimumab, as a tumor necrosis factor (TNF)-alpha inhibitor, carries a risk of triggering opportunistic infection, such as listeriosis. With an altered mental status or neurological signs in patients receiving TNF-alpha antagonizing agent, physicians should suspect bacterial infection in the central nervous system and promptly initiate treatment for brain abscess if needed. PMID- 29282390 TI - Autoimmune Hepatitis: A Risk Factor for Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a very aggressive and lethal tumor, which arises from the epithelial cells of bile ducts. CCA comprises about 3% of all gastrointestinal malignancies and its incidence is on the rise in the recent years. Anatomically, it is classified into intrahepatic, perihilar, or extrahepatic (distal) CCA. There are a number of risk factors associated with CCA including primary sclerosing cholangitis, fibropolycystic liver disease, parasitic infection, viral hepatitis, chronic liver disease, and genetic disorders like Lynch syndrome. Autoimmune hepatitis is also recently reported to have an association with development of CCA. We report an interesting case of perihilar CCA in the setting of autoimmune hepatitis along with a literature review. This case highlights the importance of early treatment and close clinical follow-up of patients with autoimmune hepatitis for development of CCA. PMID- 29282391 TI - Multifocal Mass Lesions in Autoimmune Pancreatitis. AB - A 59-year-old male patient with jaundice was referred to our hospital because of mass lesions in the pancreatic head and tail. An immunological examination revealed an elevated serum IgG4 level. Computed tomography showed two clear boundary mass lesions in the pancreatic head and tail. Magnetic resonance imaging showed that the mass lesions exhibited low intensity on T1-weighted images and iso-intensity on T2-weighted images. Magnetic resonance cholangiopancreatography showed an obstruction of the main pancreatic duct in the pancreatic head and tail. The possibility of malignant tumors could not be ruled out; therefore, we performed total pancreatectomy. A histopathological examination of the nodular lesions revealed severe lymphoplasmacytic infiltration and inflammatory change around the pancreatic ducts. Immunohistochemistry revealed diffuse infiltration of IgG4-positive plasma cells in the nodules. According to these pathological findings, we diagnosed the patient with IgG4-related multifocal mass lesions of autoimmune pancreatitis (AIP). It is difficult to distinguish between focal type AIP and pancreatic cancer. We herein report a rare case of multifocal mass lesions in AIP and include bibliographical comments. PMID- 29282392 TI - Diffuse Dermal Angiomatosis of the Breast: A Distinct Entity in the Spectrum of Cutaneous Reactive Angiomatoses - Clinicopathologic Study of Two Cases and Comprehensive Review of the Literature. AB - Diffuse dermal angiomatosis (DDA) is a rare reactive angioproliferation in the skin and considered to be a subtype in the group of cutaneous reactive angiomatoses. DDA is clinically characterized by livedoid patches and plaques with tender ulceration. Its histologic features are a reactive diffuse proliferation of bland endothelial cells and pericytes within the dermis, forming small capillary vessels. Previously described cases of DDA most commonly involved the limbs and were associated with a wide spectrum of predisposing comorbidities, especially advanced atherosclerotic vascular disease and arteriovenous fistula. However, several cases of DDA of the breast (DDAB) have been reported in recent years. In this study we present 2 additional patients with DDAB and review all 36 cases of DDAB published in the literature. We describe the clinical and histopathologic characteristics, hypothesized pathogenetic mechanisms, and predisposing conditions of this rare skin disorder and discuss treatment options. The breast is a more commonly involved site of DDA than previously believed. DDAB typically occurs in middle-aged women and is associated with macromastia, overweight or obesity, and probably smoking. Predisposing comorbid conditions differ from those of DDA involving other parts of the body, making DDAB a unique clinicopathologic entity in the spectrum of cutaneous reactive angiomatoses. Currently there is no consensus on the best therapeutic approach. Isotretinoin and other medical therapies have been used with limited success. Breast reduction surgery appears to be a viable treatment option for DDAB in women with macromastia and might provide definitive healing. PMID- 29282393 TI - CD30+ Cutaneous Anaplastic Large-Cell Lymphoma of the Upper Eyelid: A Case Report. AB - CD30+ cutaneous anaplastic large-cell lymphoma is part of the CD30+ T-cell lymphoproliferative disorders. This type of lymphoma is in most cases indolent, with a high survival rate. We report the case of a 59-year-old patient with a 1 month lasting crusty lesion of the upper eyelid. Eyelid involvement is very uncommon, as the most frequent locations are the trunk and the limbs. PMID- 29282394 TI - Treatment of Multiple Actinic Keratosis and Field of Cancerization with Topical Piroxicam 0.8% and Sunscreen 50+ in Organ Transplant Recipients: A Series of 10 Cases. AB - Organ transplant recipient (OTR) subjects are at high risk of skin cancer such as squamous cell carcinoma and basal cell carcinoma. Actinic keratosis (AK) is considered the precursor of these non-melanoma skin cancers. Sun protection is mandatory in subjects with AK and this preventive strategy is very important in OTR. Treatment of the field of cancerization is also crucial to reduce the risk of recurrence of skin lesions in AK and non-melanoma skin cancer patients. Activation of cyclooxygenase 1 and 2 enzymes plays an important role in the pathogenesis of skin cancers. Topical application of cyclooxygenase inhibitors such as diclofenac and, more recently, piroxicam has shown to reduce AK lesions in immunocompetent subjects. A medical device containing piroxicam and SPF 50+ sunscreen filters (P+SS) has been demonstrated to be effective in reducing AK lesions and improving the field of cancerization. We report the effect of P+SS, applied for 16 weeks, in a case series of 10 OTR subjects with multiple AK lesions. P+SS treatment was associated with a relevant AK lesion reduction (>75%) in 7 patients (with a complete clearance in 3 subjects) with an improvement in the field of cancerization. This medical device could be considered a promising long-term curative and preventive treatment in OTR patients at high risk of non melanoma skin cancers. PMID- 29282395 TI - Lichen Planus Pemphigoides Induced by Enalapril: A Case Report and a Review of Literature. AB - Lichen planus pemphigoides (LPP) is a rare autoimmune bullous dermatosis. The clinical presentation of LPP may mimic bullous pemphigoid making the diagnosis difficult. A thorough clinical, histopathological, and immunological evaluation is essential for the diagnosis of LPP. The etiology is largely idiopathic; however, there are several case reports of drug-induced LPP. We report an 81-year old Thai woman with underlying hypertension and type 2 diabetes mellitus who presented with a 4-week history of multiple tense bullae initially on the hands and feet that subsequently expanded to the trunk and face. Enalapril was commenced to control hypertension. The histopathology and direct immunofluorescence were compatible with LPP. Circulating anti-basement antibodies BP180 was also positive. The patient was treated with topical corticosteroid with a modest effect. Enalapril was discontinued and complete resolution of LPP occurred within 12 weeks. There was no recurrence after a 1-year follow-up period. To the best of our knowledge, we present the first case of enalapril induced LPP. Early recognition and prompt discontinuation of the culprit drug allow resolution of the disease. Medication given for LPP alone, without cessation of the offending drug, may not change the course of this condition. PMID- 29282396 TI - Carcinoma Cuniculatum of the Right Thenar Region with Bone Involvement and Lymph Node Metastases. AB - Squamous cell carcinoma (SCC) is the second most common type of skin cancer after basal cell carcinoma (BCC). The overall prevalence of BCC is 3 times higher than that of SCC, but this can vary when looking at specific locations such as the hand, where SCC is much more common than BCC. Carcinoma (or epithelioma) cuniculatum is a rare variant of SCC. It was originally described as a verrucous carcinoma of the soles. Exceptionally, it can arise in other parts of the skin. We report a rare case of carcinoma cuniculatum of the right thenar region with bone and lymph node involvement. PMID- 29282397 TI - Swan Neck Deformity Mimicking Claw Hand Caused by Arthritis in Leprosy. AB - Swan neck deformity is a hyperextension of the proximal interphalangeal (PIP) joints and flexion of the distal interphalangeal (DIP) joints. Claw hand is a hyperextension of the metacarpal joints and flexion of the PIP joints, accompanied by reduced motor strength. A 23-year-old female, who was released from leprosy treatment, presented with a bend of the second to fifth fingers of both hands. There was hyperextension of the PIP joints and flexion of the DIP joints from the second to fifth fingers of both hands, thickening of the ulnar nerves, and hypoesthesia without motor impairment of the fourth and fifth fingers of both hands. Radiograph examination revealed cupping of the base of the proximal phalangeal joints of the second, third, and fifth fingers of the left hand and of the second and fifth fingers of the right hand. Additionally, narrowing of the metacarpophalangeal joints of the second, third, and fifth fingers of the right hand and sclerosis of the second and fifth fingers of the right hand were also observed. Claw hand is frequently reported in leprosy, while swan neck deformity is frequently reported in rheumatoid arthritis. To our knowledge, this is the first reported case with swan neck deformity caused by arthritis in leprosy. PMID- 29282398 TI - Fenofibrate-Induced Lichenoid Drug Eruption: A Rare Culprit. AB - A lichenoid drug eruption is a rare side effect which can occur following the administration of several different medications. Here we describe a unique case of fenofibrate as the causative agent of a lichenoid drug eruption. This case highlights a rare and clinically significant dermatologic side effect of fenofibrate. In addition, we report a potential familial association which underscores the potential for underlying genetic mechanisms to be contributory to lichenoid drug eruptions. A reminder of the physical characteristics of lichen planus, knowledge of the temporal relation between administration of medications and a lichenoid drug eruption, recognition of the effect of UV exposure on lichenoid drug eruptions, and realization for the potential of symptoms to persist despite discontinuation of an offending agent can aid practitioners in promptly diagnosing lichenoid drug eruptions and initiating appropriate therapy. PMID- 29282399 TI - Chronic Retinal Necrosis Severely Complicated by Neovascular Glaucoma: A Case Report. AB - Background: Chronic retinal necrosis (CRN) is a rare chronic granular necrotizing retinitis that was first described in 2013. CRN is characterized by intraocular inflammation accompanied by occlusive vasculitis, granular retinitis, and slowly progressing necrosis around the retina in a host with partial immune dysfunction. Cytomegalovirus (CMV) is reported to be a causative agent. There are several ocular complications such as retinal detachment and neovascular glaucoma; however, there has been no description of a clinical manifestation of neovascular glaucoma in CRN. We herein present a case of severe neovascular glaucoma in association with CRN. Case Presentation: An 80-year-old man was referred to our hospital with poor control of inflammation and intraocular pressure (IOP). The IOP in his left eye was 29 mm Hg. Anterior chamber cells (2+) and keratic precipitates were observed. In the peripheral retina, vitreous opacities and granular necrotizing retinitis were noticed. Fluorescein angiography revealed extensive retinal nonperfusion area from the macula lesion to the periphery. PCR analysis of aqueous humor showed the presence of CMV. A diagnosis of CRN was made soon afterwards. Antiviral drug and systemic corticosteroid were administered. The treatment temporally resolved the symptom; however, panretinal photocoagulation and intravitreal injection of bevacizumab were performed to treat iris neovascularization. During the follow-up, trabeculectomy was performed because of poor IOP control. At the final visit, severe uncontrolled neovascular glaucoma caused hyphema, and his left eye lost light perception. Conclusion: The prognosis of CRN is poor because of severe neovascular glaucoma and careful observation and active treatments are necessary. PMID- 29282400 TI - Diagnostic and Therapeutic Approach in a Case of Severe Post-Traumatic Hyphema with Subtotal Iridodialysis. AB - Purpose: To report our diagnostic ultrasound-based approach and surgical strategy in a case of severe blunt trauma with complete hyphema, 270 degrees iris disinsertion, and traumatic subluxated cataract. Case Report: A 70-year-old male was referred to our hospital for a blunt trauma in his right eye. A complete examination revealed visual acuity consisting in light perception, a complete hyphema, and an intraocular pressure of 45 mm Hg with moderate pain. Our diagnostic approached was ultrasound based with B-scan examination showing some vitreous hemorrhage and ultrasound biomicroscopy showing a large iris disinsertion of 270 degrees with the iris entirely dislocated in the inferior sector of the anterior chamber. The patient was hospitalized and a systemic and topical treatment was started to lower intraocular pressure. Our surgery consisted in a single-step approach with removal of traumatic cataract with scleral fixation of an intraocular lens and iridoplasty. Conclusion: In our patient, the single-step surgery, supported by anterior and posterior ultrasound imaging, achieved a satisfactory anatomical and functional outcome. PMID- 29282401 TI - Recurrent Vitreous Hemorrhage from an Optic Nerve Retinal Arterial Macroaneurysm. AB - Objective: To report a case of recurrent vitreous hemorrhage from an optic nerve retinal arterial macroaneurysm (ONRAM) successfully treated with intraoperative endolaser. Patient and Methods: A 92-year-old woman on oral aspirin and warfarin anticoagulation for atrial fibrillation developed three episodes of dense vitreous hemorrhage from an ONRAM. Due to failure of the vitreous hemorrhage to clear spontaneously, a total of three pars plana vitrectomy (PPV) procedures were performed along with a 1.25-mg intravitreal bevacizumab injection after the third episode of hemorrhage. During the third PPV procedure, a 25-gauge 532-nm green diode laser endoprobe was used to deliver low-power (100 mW) and long-duration (500 ms) laser spots directly on the ONRAM to induce intraoperative shrinkage of the ONRAM. Results: After the endolaser treatment, the macroaneurysm showed involution due to fibrosis without any adverse effects on retinal circulation or visual field defect. No recurrence of vitreous hemorrhage was noted after 2 years of follow-up. Conclusion: Oral anticoagulant use may have been responsible for the atypical clinical course in our patient. Laser photocoagulation, including intraoperative endolaser photocoagulation, may be considered in selected cases of symptomatic ONRAMs. PMID- 29282402 TI - Acute Endophthalmitis Caused by Leuconostoc spp. following Intravitreal Bevacizumab Injection. AB - We present a case of acute endophthalmitis caused by Leuconostoc spp. following intravitreal bevacizumab injection. An 86-year-old immunocompetent female developed acute endophthalmitis after intravitreal injection of bevacizumab for neovascular age-related macular degeneration. The patient presented with pain, visual acuity of hand motions, hypopyon, and dense vitritis 96 h after treatment. She was treated with vitreous and anterior chamber tap followed by intravitreal injections of 1 mg vancomycin, 2.25 mg ceftazidime, and 400 MUg dexamethasone. Cultures revealed growth of Leuconostoc spp., a genus of gram-positive bacteria that is inherently resistant to vancomycin. Due to persistent inflammation, pars plana vitrectomy (PPV) with intravitreal injection of 0.4 mg amikacin was performed 16 days later, followed by resolution of endophthalmitis and return of vision to 20/40. In conclusion, the management of acute endophthalmitis caused by Leuconostoc spp., a gram-positive coccobacillus, can be particularly challenging due to its inherent resistance to vancomycin. PPV with intravitreal amikacin led to resolution of endophthalmitis. Our case expands the number of cases of endophthalmitis caused by Leuconostoc spp. and highlights the possibility of Leuconostoc-related endophthalmitis in an outpatient setting in an immunocompetent host. PMID- 29282403 TI - Epiretinal Membrane in Dome-Shaped Macula Complicated with Serous Retinal Detachment: Transient Efficacy of Surgery. AB - Dome-shaped macula (DSM) is an entity recently described as a convex anterior protrusion of the macular area within a posterior myopic staphyloma. Specific complications were associated with DSM, like serous retinal detachment (SRD). We describe a woman presenting with a decreased vision at 20/50. SD-OCT scans were performed, showing a macular bulge. SRD was present and an epiretinal membrane could also be observed. Fluorescein angiography and indocyanin green angiography did not show any leakage nor choroidal neovascularization. Epiretinal membrane peeling was performed, and 3 months after surgery, SRD completely disappeared. However, SRD reappeared 1 year after surgery and enlarged within 2 years following surgery. In conclusion, two mechanisms could be considered for physiopathology of SRD: first, the epiretinal membrane may have exerted traction on the macular retina, second, vitreous body might constitute a tank for cytokines and/or other factors, triggering subretinal fluid accumulation, leading to SRD. PMID- 29282404 TI - Baerveldt Scleral Patch Graft Abscess Secondary to Coagulase-Negative Staphylococcus. AB - We report the case of a 69-year-old female who underwent a Baerveldt implant placement for severe-stage primary open-angle glaucoma and developed a bacterial infection of the conjunctiva and abscess of the scleral patch graft with subsequent tube exposure. The infection was identified 3 weeks postoperatively and a topical antibiotic was immediately initiated. A concurrent systemic staphylococcal infection was discovered by an outside physician and oral cephalexin was initiated. Despite antibiotic treatment, the conjunctival erosion progressed, and tube revision was required. Culture of the abscess revealed coagulase-negative Staphylococcus. As alluded to above, the patient also had multiple abscesses on the skin that cultured positive for Staphylococcus aureus. To our knowledge, this is the first case in the literature of coagulase-negative Staphylococcus causing an early postoperative abscess of the scleral patch graft following glaucoma drainage device placement. PMID- 29282405 TI - Erratum: Veronica officinalis Product Authentication Using DNA Metabarcoding and HPLC-MS Reveals Widespread Adulteration with Veronica chamaedrys. AB - [This corrects the article on p. 378 in vol. 8, PMID: 28674497.]. PMID- 29282406 TI - Corrigendum: Pectins, Endopolygalacturonases, and Bioenergy. AB - [This corrects the article on p. 1401 in vol. 7, PMID: 27703463.]. PMID- 29282408 TI - Behavioural and Psychological Symptoms of Dementia: Correlates and Impact on Caregiver Distress. AB - Aims: To evaluate the behavioural and psychological symptoms of dementia (BPSD), to determine their correlation with types and stages of dementia and patient demographics, and to assess the impact on caregiver distress. Methods: This cross sectional study recruited consecutive dementia patients and caregivers who attended our cognitive clinic. Standard criteria were used to classify types of dementia. BPSD were assessed with the Neuropsychiatric Inventory, and its distress scale was used for caregiver distress. Results: Of a total 107 patients, nearly all (99.1%) had at least one BPSD; 71% had >=4 symptoms. Most frequent were apathy and agitation, followed by irritability, sleep and appetite disorders, and mood disorders; disinhibition and euphoria were least frequent. BPSD were less prominent with increasing age; males showed more agitation. Apathy and eating disorders were more prevalent in the rural community. BPSD were highest in frontotemporal dementia (FTD), followed by dementia with Lewy bodies (DLB), and least in vascular dementia. Hallucinations were more common in DLB, aberrant motor behaviour in FTD. All domains of BPSD, except for anxiety and euphoria, were more prominent with increasing severity of dementia. Increasing BPSD (except for euphoria) caused higher caregiver distress. Conclusion: BPSD are universally present, bear correlates with dementia type and severity, and cause significant caregiver distress. PMID- 29282407 TI - Dementia and Hospital Readmission Rates: A Systematic Review. AB - Background: Although community-dwelling persons with dementia have an increased risk of hospital readmission, no systematic review has examined the contribution of dementia to readmissions. Summary: We examined articles in English, with no restrictions on publication dates, from Medline, PubMed, PsycINFO, CINAHL, and EMBASE. Keywords used were dementia, Alzheimer disease, frontotemporal lobar degeneration, elderly, frontotemporal dementia, executive function, brain atrophy, frontal lobe atrophy, cognitive impairment, readmission, readmit, rehospitalization, patient discharge, and return visit. Of 404 abstracts identified, 77 articles were retrieved; 12 were included. Four of 5 cohort studies showed significantly increased readmission rates in patients with dementia. On average the absolute increase above the comparison groups was from 3 to 13%. Dementia was not associated with readmission in 7 included case-control studies. Key Message: Findings suggest a small increased risk of hospital readmission in individuals with dementia. More study is needed. PMID- 29282409 TI - Longitudinal Changes in Performance on Cognitive Screening Tests in Patients with Mild Cognitive Impairment and Alzheimer Disease. AB - Background: Neuropsychological tests that can track changes in cognitive functions after diagnosis of Alzheimer disease (AD) and mild cognitive impairment (MCI), including episodic memory, should be further developed. Methods: The participants of our study consisted of 22 mild AD patients and 11 MCI patients. They were followed up for 2 years. Brief cognitive screening tests were administered to the participants. Longitudinal changes in test performance were evaluated and analyzed. Results: In this longitudinal study, the Scenery Picture Memory Test (SPMT) showed significant changes over 2 years in both MCI and AD participants. The Mini-Mental State Examination (MMSE) and Word Fluency Test vegetable showed significant changes only in AD participants. Other tests all showed little or no decline in results. Conclusions: The SPMT can be a useful tool for effectively observing changes during follow-up of MCI and AD patients. PMID- 29282410 TI - Cerebrospinal Fluid S100B and Alzheimer's Disease Biomarkers in Hip Fracture Patients with Delirium. AB - Objectives: This study aimed to investigate the relationship between cerebrospinal fluid (CSF) S100B astrocyte-derived protein and delirium and to perform stratified analyses according to clinical and CSF markers of dementia. Methods: We performed a prospective cohort study in a university hospital setting. The participants were patients admitted for hip fracture (n = 98) or for elective surgery (n = 50). Delirium was assessed daily perioperatively in hip fracture patients using the Confusion Assessment Method. A consensus-based diagnosis of prefracture dementia was made using all available information. CSF was drawn at the onset of spinal anesthesia. S100B and phosphorylated tau (P-tau) concentrations were measured using electrochemiluminescence immunoassay and enzyme-linked immunosorbent assays, respectively. Results: In the hip fracture population (n = 98) there was no significant difference in CSF S100B concentrations between patients with ongoing preoperative (i.e., prevalent) delirium (n = 36, median [interquartile range] 1.11 MUg/L [0.91-1.29]) and patients who never developed delirium (n = 46, 1.08 MUg/L [0.92-1.28], p = 0.92). In patients without preoperative delirium, those who developed delirium postoperatively (i.e., incident delirium) (n = 16, 1.38 MUg/L [1.08-1.62]) had higher concentrations of S100B than the 46 who never did (p = 0.013). This difference was confined to patients with pathological concentrations of P-tau (>=60 ng/L, n = 38). We also found that P-tau and S100B were correlated in CSF in the elective surgery patients. Conclusions: CSF S100B was elevated in patients with incident delirium who also had pathological levels of the Alzheimer disease biomarker P-tau, suggesting vulnerability caused by a preexisting process of astrocytic activation and tau pathology. PMID- 29282411 TI - Fear of Falling and Cognitive Impairments in Elderly People with Hip Fractures. AB - Background/Aim: The purpose of this study was to investigate the estimated prevalence of dementia and the relationship between cognitive impairment and fear of falling in patients with hip fractures. Methods: Analysis 1 included 100 patients with hip fractures. Analysis 2 included a subgroup of subjects with >=75 years of functional independence: 46 patients with hip fractures and 46 control subjects without hip fractures, and presence or absence of dementia. We used an informant-rated questionnaire including the AD8 for screening for dementia, the Barthel Index for assessing activities of daily living, and the Short Falls Efficacy Scale-International (FES-I) for assessing fear of falling. Results: The estimated prevalence of dementia was 66% in patients with hip fractures. There were significant fracture and dementia effects, with significant covariate effects of age and gender on the Short FES-I scores. Conclusion: Our results suggested that more than two-thirds of patients with hip fractures had dementia. Fear of falling may reflect not only physical functions but also cognitive impairments. PMID- 29282412 TI - A Review on the Assessment of the Efficacy of Common Treatments in Polycystic Ovarian Syndrome on Prevention of Diabetes Mellitus. AB - Objective: Polycystic ovarian syndrome (PCOS) is a common condition amongst women of reproductive age that can result in increased mortality and morbidity in women due to increased risk of diabetes mellitus and cardiovascular diseases. The aim of this systematic review was to assess the effectiveness of common treatments of PCOS on the predictors of diabetes in non-diabetic PCOS women. Materials and methods: An extensive search was performed on the publications in three medical databases including pubmed, scopus and google scholar from 1995 till 2017. The articles were screened based on their quality and included in this systematic review. A total of 25 articles including cohort, randomised controlled trial, review and meta-analysis were included in the review. Results: This systematic review revealed that the effect of lifestyle modification might be low in PCOS subjects due to high drop-out rate while the benefits of this intervention including weight and fat reduction may not be achieved by medical interventions. Metformin treatment may result in improvements in insulin sensitivity while its weight reduction effect is still not documented in PCOS subjects. Thiazolidendiones might be tolerated by the PCOS subjects and may result in similar effects as metformin but this effect should be documented by further studies. Conclusion: Combination of lifestyle modification with metformin or thiazolidinedions might improve the outcome of the prevention strategies. On the other hand this study revealed a different response to treatments in non-obese compared with obese PCOS subjects. PMID- 29282413 TI - Effects of Social Support and Self-Efficacy on Maternal Prenatal Cares Among the First-Time Pregnant Women, Iranshahr, Iran. AB - Objective: Social support and perceived self-efficacy affect health-related behaviors and play an important role on mothers' adaptability with pregnancy. This paper aims to study the impact of educational interventions based on social support and perceived self-efficacy on maternal prenatal care. Materials and methods: The present study is a before after experimental study in which 90 first time pregnant women were randomly selected and divided into two 45- participants experimental and control groups. Data were collected from 21 January to 20 May 2016. Determining the validity and reliability of the questionnaire, we used the panel of experts and Cronbach's alpha. The data collected from the two groups were compared before and 3 months after intervention and were analyzed by SPSS 18. Results: Unlike the control subjects, there was a significant difference in maternal prenatal cares before and after an educational intervention between the scores of social support and perceived self-efficacy in the experimental group (p < 0.05). Before intervention, the average score of the experimental group was 12.62 +/- 2.63 that rose to 17.71 +/- 1.56, three months after the educational intervention, which is statistically significant (p < 0.05). There was a direct and positive relation between self-efficacy and maternal prenatal cares (p = 0.000, r = 0.538). Social support and self-efficacy predicted the variance of maternal cares by 69.2%. Conclusion: Developing an educational program based on social support and perceived self-efficacy on maternal prenatal cares is helpful and efficient. The health system, family and society are in charge of making facilities and opportunities to improve social support and perceived self efficacy in pregnant women, resulting in improved maternal prenatal cares. PMID- 29282414 TI - Level of Vitamin E in Follicular Fluid and Serum and Oocyte Morphology and Embryo Quality in Patients Undergoing IVF Treatment. AB - Objective: This study aimed to determine the relationship between vitamin E in the follicular fluid (FF) and serum with oocyte morphology and embryo quality. Materials and methods: A cross-sectional study was conducted on serum samples, FF samples, oocytes, and embryos collected from 50 women undergoing in vitro fertilization in the Alzahra Hospital, Rasht, Iran from March to August 2014. Vitamin E level was measured using HPLC. Oocyte morphology and embryo quality were evaluated during inverted optical microscopy. Results: Totally 434 oocytes and 199 embryos were examined. Most frequently the metaphase II (MII) oocytes were observed at the 0.35-1 mg/dl level of vitamin E in FF (89.2%) and the 1-5 mg/dl level of vitamin E in serum (86.1%). The odds of having MII oocytes at the level of 0.35-1 mg/dl (OR = 2.48, 95% CI = 1.24-4.94) and 1.5-2 mg/dl (OR = 2.51, 95% CI = 1.02-6.19) of vitamin E in FF was significantly higher compared to level of 2-7.4 mg/dl. The effect of vitamin E serum level on oocyte maturation was not significant. The odds of having embryo with Z1 or Z2 quality, at the 10-15 mg/dl level of vitamin E in serum (OR = 6.45, 95% CI = 1.18-35.22), compared to the 15 20 mg/dl level, was significantly higher. The effect of vitamin E levels in FF on the embryo quality was not significant. Conclusion: At certain levels of vitamin E in the FF, oocytes with higher maturation and at certain levels of vitamin E in serum, embryo with higher quality can be achieved. PMID- 29282415 TI - Comparison of the Effects of Dry Cupping and Acupressure at Acupuncture Point (BL23) on the Women with Postpartum Low Back Pain (PLBP) Based on Short Form McGill Pain Questionnaires in Iran: A Randomized Controlled Trial. AB - Objective: To evaluate the effects of acupuncture branches on postpartum low back pain severity among the primiparous subjects visiting the selected educational centers affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. Materials and methods: This clinical trial was conducted on 150 (each group of 50 people) cases in 2012. Cupping therapy was done every other day in four 15-20 minute sessions a week. Besides, acupressure was applied according to the circular model for 20 minutes. The patients filled out the short form McGill Pain Questionnaires. Then, the data were analyzed using the SPSS statistical software (v. 16) and repeated measurements and Chi-square tests. Results: In the cupping group, the mean difference of postpartum Low Back Pain intensity reached from 31.8 +/- 10.8 before the intervention to 9.0 +/- 6.7, 7.5 +/- 6.6, and 4.1 +/- 3.6 immediately, 24 hours, and 2 weeks after the intervention, respectively and the results of repeated measures ANOVA showed a significant difference between the three follow-up periods (p < 0.05). On the other hand, this measure reached from 31.1 +/- 11.0 before the intervention to 22.1 +/- 7.3, 16.2+/-6.0, and 11.7 +/- 5.3 immediately, 24 hours, and 2 weeks after the intervention, respectively in the acupressure group. Conclusion: The study results showed that these modalities could sedate the pain. Therefore, they can be applied as efficient treatments for reducing the low back pain. PMID- 29282416 TI - Effect of Exposure to Air Pollution on Placental Weight in Isfahan-Iran. AB - Objective: To determine the effect of Air Quality Index (AQI) in the first trimester of pregnancy on birth weight, placental weight, and the ratio of placental weight to the birth weight (pw-bw) in Isfahan. Materials and methods: This cross-sectional study was done on 312 consecutive pregnant women in Beheshti Hospital in Isfahan city in 2013. Information on air pollution was received from the Environmental department of Isfahan. Average exposure to air pollution in the first trimester of pregnancy was calculated for eachpregnant woman. In order to compare quantitative and qualitative variables, analysis of variance (ANOVA), and chi-square were applied. After that, the multiple linear regression analysis was used to assess the association the Air Quality Index (AQI) on birth weight, placental weight and the ratio of pw-bw. Potential confounders including age, baby gender, smoking of husband, maternal BMI, maternal occupation, and education and mother's residential area were considered. A statistical significant association were considered for P-value less than 0.05. Results: The findings showed that there is inverse relationship between exposure to air pollution and placental weight in the first trimester of pregnancy after controlling potential confounders (beta = -2.57, p-value = 0.008). The inverse relationship between air pollution and the ratio of pw-bw was found. (beta = -0.001, p-value = 0.002). Conclusion: The results of this study suggest that air pollution is associated with newborns' health which in turn is a warning alarm for considering some actions in both sides of reducing the air pollution and teaching the pregnant women about the adverse effects of air pollution on the pregnancy outcomes. PMID- 29282417 TI - Association of Blood and Seminal Plasma Cadmium and Lead Levels With Semen Quality in Non-Occupationally Exposed Infertile Men in Abakaliki, South East Nigeria. AB - Objective: To evaluate association of blood and seminal plasma lead and cadmium with sperm quality of non-occupationally exposed male partners of couples with infertility. Materials and methods: A cross-sectional study was conducted on 75 men aged 20-45 years (mean = 37.1 +/- 7.0 yrs.) with infertility recruited from the Fertility Clinic of a hospital in Abakaliki. Sperm count done in accordance with the WHO guidelines was used to classify the participants as normospamia, oligospermia and azospermia. Atomic absorption spectrophotometer was used to determine lead and cadmium levels in plasma from blood and semen. Results: There were 15 azospermics, 22 oligospermics and 36 normospermics. Seminal and blood plasma cadmium as well as blood plasma lead were significantly (p < 0.01) higher in azospermic and oligospermic men compared to normospermic men. However, while seminal plasma lead was significantly (p < 0.05) higher in oligospermic and normospernic men than in azospermic men, the seminal plasma lead was comparable between oligospermic and normospermic men. Significant inverse associations (p < 0.01) were found between blood and seminal cadmium levels and sperm count, motility and morphology; blood lead was inversely correlated with sperm count only. Conclusion: The study suggests that environmental exposure to cadmium and lead may contribute to development of poor sperm quality and infertility in men of reproductive age in Nigeria. PMID- 29282418 TI - Effect of Vaginal Hygiene Module to Attitudes and Behavior of Pathological Vaginal Discharge Prevention Among Female Adolescents in Slemanregency, Yogyakarta, Indonesia. AB - Objective: To determine the effect of vaginal hygiene module to attitudes and behavior of pathological vaginal discharge prevention in adolescent girls in Sleman Regency, Yogyakarta, Indonesia. Materials and methods: This present study is a quasi experiment with pretest and post-test control group design. A total of 80 female students was selected randomly from two secondary schools at the study site and then distributed equally to control and experimental group. Only participants in the experimental group were given self-learning vaginal hygiene module to maintain vaginal cleanliness. A questionnaire was used as an instrument to measure the attitudes and behavior of vaginal discharge prevention. Paired and independent sample t-tests with significance level (p value) at 0.05 and Confidence Interval (CI) of 95%were employed to compare the mean difference. Results: There is a significant difference in the students' attitude and practice of pathological vaginal discharge prevention between intervention and control group. The students who have been exposed to vaginal hygiene module for six months showed better attitudes and practice in pathological vaginal discharge prevention compared to their counterpart in control group who do not receive any module. Conclusion: The present study implied that vaginal hygiene module can be provided widely for female adolescents at their early puberty. District health officers may work closely with schools' health promoter to reach the students and create a supportive environment for reproductive health discussion and forum in order to achieve better adolescents' reproductive health status. PMID- 29282419 TI - Reproductive Health Services Utilization and Associated Factors Among Adolescents in Anchar District, East Ethiopia. AB - Objective: To assess reproductive health service utilization and associated factors among adolescents in Anchar District, West Hararghe Zone, Oromia Region, East Ethiopia. Materials and methods: A community based cross-sectional study using quantitative and qualitative method of data collection was applied from March 1to 30, 2013. Simple random sampling method was used for quantitative and Purposive sampling technique used for qualitative method. Four hundred two adolescents were interviewed for quantitative study. Four focus groups and ten in depth interviews were conducted for qualitative study. Binary and Multiple logistic regressions were used for association at p < 0.05 using SPSS Version 16.0 software. Qualitative data was transcribed, and result was presented by narration. Results: Forty two (39.3%) female adolescents have ever used family planning. One hundred eight four (45.8%) adolescents have ever used VCT services. Males were 5.25 times more likely to use VCT than females (AOR = 5.25,C.I = 1.07, 25.87) and those perceived themselves as high risk for HIV were 8.22 times more likely to use VCT than their counterparts (AOR = 8.22, C.I = 1.065, 35.49). Lack of adolescent reproductive health services, Harmful Traditional Practices, lack of privacy and inconvenient service hour were reasons for not utilizing the service. Conclusion: More than half of adolescents were not utilizing family planning, and VCT services. Therefore, intensified effort is needed to increase utilization of these services for adolescents. PMID- 29282420 TI - Rapid identification of pathogens responsible for necrotizing fasciitis on an integrated microfluidic system. AB - Necrotic fasciitis (NF) is a particularly aggressive and serious infection of the fascia that can penetrate into the musculature and internal organs, resulting in death if not treated promptly. In this work, an integrated microfluidic system composed of micropumps, microvalves, and micromixers was used to automate the detection of pathogens associated with NF. The entire molecular diagnostic process, including bacteria isolation, lysis, nucleic acid amplification and optical detection steps, was enacted on this developed system. Mannose binding lectin coated magnetic beads were first used as probes to isolate all bacteria in a sample. In this work, polymerase chain reaction assays featuring primers specific to genes from each of four NF-causing bacteria (Vibrio vulnificus, Aeromonas hydrophila, and methicillin-sensitive and resistant Staphylococcus aureus) were used to rapidly and exclusively verify the presence of the respective bacterial strains, and the limits of detection were experimentally found to be 11, 1960, 14, and 11 400 colony forming units/reaction, respectively; all values reflect improvement over ones reported in literature. This integrated microfluidic chip may then be valuable in expediting diagnosis and optimizing treatment options for those with NF; such diagnostic improvements could ideally diminish the need for amputation and even reduce the morality rate associated with this life-threatening illness. PMID- 29282421 TI - A new look at bubbles during biofilm inoculation reveals pronounced effects on growth and patterning. AB - Specially designed microfluidic bioflow cells were used to temporarily trap microbubbles during different inoculation stages of Pseudomonas sp. biofilms. Despite being eliminated many hours before biofilm appearance, templated growth could occur at former bubble positions. Bubble-templated growth was either continuous or in ring patterns, depending on the stage of inoculation when the bubbles were introduced. Templated biofilms were strongly enhanced in terms of their growth kinetics and structural homogeneity. High resolution confocal imaging showed two separate bubble-induced bacterial trapping modes, which were responsible for the altered biofilm development. It is concluded that static bubbles can be exploited for fundamental improvements to bioreactor performance, as well as open new avenues to study isolated bacteria and small colonies. PMID- 29282422 TI - High-throughput separation of cells by dielectrophoresis enhanced with 3D gradient AC electric field. AB - We propose a novel, high-performance dielectrophoretic (DEP) cell-separation flow chamber with a parallel-plate channel geometry. The flow chamber, consisting of a planar electrode on the top and an interdigitated-pair electrode array at the bottom, was developed to facilitate the separation of cells by creating a nonuniform AC electric field throughout the volume of the flow chamber. The operation and performance of the device were evaluated using live and dead human epithermal breast (MCF10A) cells. The separation dynamics of the cell suspension in the flow chamber was also investigated by numerically simulating the trajectories of individual cells. A theoretical model to describe the dynamic cell behavior under the action of DEP, including dipole-dipole interparticle, viscous, and gravitational forces, was developed. The results demonstrated that the live cells traveling through the flow chamber congregated into sites where the electric field gradient was minimal, in the middle of the flow stream slightly above the centerlines of the grounded electrodes at the bottom. Meanwhile, the dead cells were trapped on the edges of the high-voltage electrodes at the bottom. Cells were thus successfully separated with a remarkably high separation ratio (~98%) at the appropriately tuned field frequency and applied voltage. The numerically predicted behavior and spatial distribution of the cells during separation also showed good agreement with those observed experimentally. PMID- 29282424 TI - Cancer Care in 2016: The ASCO State of Cancer Care Report and the Role of Advanced Practitioners. PMID- 29282423 TI - Establishment of medical education upon internalization of virtue ethics: bridging the gap between theory and practice. AB - During medical training, students obtain enough skills and knowledge. However, medical ethics accomplishes its goals when, together with training medical courses, it guides students behavior towards morality so that ethics-oriented medical practice is internalized. Medical ethics is a branch of applied ethics which tries to introduce ethics into physicians' practice and ethical decisions; thus, it necessitates the behavior to be ethical. Therefore, when students are being trained, they need to be supplied with those guidelines which turn ethical instructions into practice to the extent possible. The current text discusses the narrowing of the gap between ethical theory and practice, especially in the field of medical education. The current study was composed using analytical review procedures. Thus, classical ethics philosophy, psychology books, and related articles were used to select the relevant pieces of information about internalizing behavior and medical education. The aim of the present study was to propose a theory by analyzing the related articles and books. The attempt to fill the gap between medical theory and practice using external factors such as law has been faced with a great deal of limitations. Accordingly, the present article tries to investigate how and why medical training must take internalizing ethical instructions into consideration, and indicate the importance of influential internal factors. Virtue-centered education, education of moral emotions, changing and strengthening of attitudes through education, and the wise use of administrative regulations can be an effective way of teaching ethical practice in medicine. PMID- 29282425 TI - Experiences of Nurse Practitioners in Communicating Bad News to Cancer Patients. PMID- 29282426 TI - How Checkpoint Inhibitors Are Changing the Treatment Paradigm in Solid Tumors: What Advanced Practitioners in Oncology Need to Know. AB - The immune system plays an active role in controlling and eradicating cancer. T cells, an essential component of the adaptive immune system, have a number of surface receptors (called "checkpoints") that can help either to sustain activation or suppress T-cell function. Many malignancies have developed ways to exploit these receptors to suppress T-cell function, enabling them to continue to grow. Anticancer immunotherapy in general, and checkpoint inhibitor therapy specifically, is a unique approach to cancer treatment that strives to harness the body's own immune system to generate an adequate response against cancer cells. Several checkpoint inhibitors are approved for the treatment of metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma. These and other agents in this class are being investigated for their safety and efficacy in a variety of solid and hematologic malignancies. Advanced practitioners (APs) play a critical role in caring for patients treated with checkpoint inhibitors. It is essential for APs to be aware of the mechanism of action of these agents, patterns of response seen with this type of therapy, and presentation of immune related adverse events related to these agents to ensure timely and successful treatment. Rapid evaluation/diagnostics and treatment are essential for optimal management and prevention of end-organ disease, and treatment of immune-related adverse effects requires a multidisciplinary approach. PMID- 29282428 TI - A Missed Opportunity: Understanding the Value of Documenting Occupational Exposure to Carcinogens in Adults With Acute Leukemia. PMID- 29282427 TI - Biomarkers/Molecular Targets, Immunotherapy, and Treatments for Non-Small Cell Lung Cancer. AB - For decades, the prognosis for patients with advanced-stage non-small cell lung cancer (NSCLC) was bleak, with chemotherapy offering limited benefit and much toxicity. Now, with mutational testing, new generations of targeted therapies, and emerging immunotherapies, the treatment horizon for these patients has greatly expanded. In this article, the authors review molecular targets, biomarkers, as well as immune checkpoint inhibitors, which are having a major impact on the management of this patient population. PMID- 29282429 TI - Elotuzumab: The First Monoclonal Antibody for the Treatment of Multiple Myeloma. PMID- 29282430 TI - Palbociclib Plus Letrozole for the Treatment of Metastatic Breast Cancer: An Illustrative Case Scenario. AB - CASE STUDY Betty, a 66-year-old white female, was diagnosed with stage IIB, T2N1M0, estrogen receptor/progesterone receptor-positive, HER2-negative breast cancer in 2007. It was detected on screening mammography when she was age 59, and she was confirmed to be postmenopausal at the time. She has no family history of breast cancer. Betty has never smoked but enjoys drinking alcohol, normally with dinner and typically limited to 1 drink of hard liquor per day. Her medical history includes type 2 diabetes mellitus and hypertension, which are adequately controlled with metformin and lisinopril. Betty is married and a retired teacher. She has four healthy adult children and five grandchildren. She noted that although she was always thin as a child, she was never able to lose the weight she gained during her pregnancies. Currently, her body mass index (BMI) is around 29 kg/m2. She enjoys ballroom dancing with her husband, gardening, and walking her dog and she is an active member at her church. Betty and her family were shocked to hear about her diagnosis. After a discussion with her oncologist, a treatment plan was devised. Her Eastern Cooperative Oncology Group performance status at diagnosis was 0. Initial treatment consisted of neoadjuvant chemotherapy with dose-dense doxorubicin/cyclophosphamide (AC) * 4 cycles followed by weekly paclitaxel * 12 cycles. Betty tolerated treatment relatively well. However, she was hospitalized once after cycle 3 of AC for neutropenic fever. Her subsequent cycle was followed with pegfilgrastim. Repeat imaging after AC treatment revealed a good overall response. Other adverse effects from treatment included fatigue and nausea for a few days after each cycle. Residual grade 1 neuropathy secondary to her treatment with paclitaxel, with a potential contribution from her history of diabetes, was a long-term complication. Following completion of her neoadjuvant therapy, she had a lumpectomy and then radiation therapy. Adjuvant endocrine therapy with the aromatase inhibitor (AI) anastrozole was given for 5 years, which she completed in late 2012. Bone health was monitored with dual-energy x-ray absorptiometry screening. Mild osteopenia was noted during AI therapy, and she was given twice-daily calcium plus vitamin D supplementation. Annual surveillance diagnostic breast mammography along with biannual history and physical examinations showed no signs of disease recurrence. PMID- 29282431 TI - Review of the New American Cancer Society Guidelines for Breast Cancer Screening for Women at Average Risk. PMID- 29282432 TI - When Should I Have a Mammogram? Recent Changes in ACS Mammography Guidelines: Implications for Practice. PMID- 29282433 TI - Understanding Breast Cancer Knowledge and Barriers to Treatment Adherence: A Qualitative Study Among Breast Cancer Survivors. AB - Disparities in breast cancer treatment receipt are common and multifactorial. Data are limited on how knowledge about one's breast cancer and understanding treatment rationales may impact treatment completion. In this qualitative analysis, we explored barriers to care with a focus on knowledge. We conducted 18 in-depth interviews with women from diverse socioeconomic backgrounds who were treated at Dana-Farber Cancer Institute (n = 12; Boston, MA) and Columbia University Medical Center (n = 6; New York, NY) and had undergone neo/adjuvant breast cancer treatment within the prior 3 years. Interviews focused on treatments received, adherence, barriers experienced, and questions related to breast cancer knowledge and treatment rationales. We analyzed transcribed interview recordings in N'Vivo using a two-stage coding process that allowed for both preconfigured and emergent themes. Answers for breast cancer knowledge were confirmed using medical records. In our analysis, over one-third of women reported incomplete therapy, including never initiating treatment, stopping treatment prematurely, or missing/delaying treatments due to logistical reasons (childcare, transportation) or patient preferences. Others reported treatment modifications because of provider recommendations. Nearly all women were able to accurately describe the rationale for recommended treatments. Among 17 women for whom medical records were available, women correctly reported 18-71% of their tumor characteristics; incorrect reporting was not consistently associated with treatment incompletion. In conclusion, logistical issues and patient preferences were the main reasons for incomplete therapy in our study. Understanding of treatment rationale was high, but breast cancer knowledge was variable. Further assessment of how knowledge may impact cancer care is warranted. PMID- 29282435 TI - Efficient Cancer Detection Using Multiple Neural Networks. AB - The inspection of live excised tissue specimens to ascertain malignancy is a challenging task in dermatopathology and generally in histopathology. We introduce a portable desktop prototype device that provides highly accurate neural network classification of malignant and benign tissue. The handheld device collects 47 impedance data samples from 1 Hz to 32 MHz via tetrapolar blackened platinum electrodes. The data analysis was implemented with six different backpropagation neural networks (BNN). A data set consisting of 180 malignant and 180 benign breast tissue data files in an approved IRB study at the Aurora Medical Center, Milwaukee, WI, USA, were utilized as a neural network input. The BNN structure consisted of a multi-tiered consensus approach autonomously selecting four of six neural networks to determine a malignant or benign classification. The BNN analysis was then compared with the histology results with consistent sensitivity of 100% and a specificity of 100%. This implementation successfully relied solely on statistical variation between the benign and malignant impedance data and intricate neural network configuration. This device and BNN implementation provides a novel approach that could be a valuable tool to augment current medical practice assessment of the health of breast, squamous, and basal cell carcinoma and other excised tissue without requisite tissue specimen expertise. It has the potential to provide clinical management personnel with a fast non-invasive accurate assessment of biopsied or sectioned excised tissue in various clinical settings. PMID- 29282434 TI - The Inspired Sinewave Technique: A Comparison Study With Body Plethysmography in Healthy Volunteers. AB - The inspired sinewave technique is a noninvasive method to measure airway dead space, functional residual capacity, pulmonary blood flow, and lung inhomogeneity simultaneously. The purpose of this paper was to assess the repeatability and accuracy of the current device prototype in measuring functional residual capacity, and also participant comfort when using such a device. To assess within session repeatability, six sinewave measurements were taken over two-hour period in 17 healthy volunteers. To assess day-to-day repeatability, measurements were taken over 16 days in 3 volunteers. To assess accuracy, sinewave measurements were compared to body plethysmography in 44 healthy volunteers. Finally, 18 volunteers who experienced the inspired sinewave device, body plethysmography and spirometry were asked to rate the comfort of each technique on a scale of 1-10. The repeatability coefficients for dead space, functional residual capacity, and blood flow were 48.7 ml, 0.48L, and 2.4L/min respectively. Bland-Altman analyses showed a mean BIAS(SD) of -0.68(0.42)L for functional residual capacity when compared with body plethysmography. 14 out of 18 volunteers rated the inspired sinewave device as their preferred technique. The repeatability and accuracy of functional residual capacity measurements were found to be as good as other techniques in the literature. The high level of comfort and the non-requirement of patient effort meant that, if further refined, the inspired sinewave technique could be an attractive solution for difficult patient groups such as very young children, elderly, and ventilated patients. PMID- 29282436 TI - U-47700: An Emerging Threat. AB - Illicit opioid use continues to be an ever-growing problem in the United States. The rise of synthetic opioids is an emerging threat that is beginning to draw attention over the past few years. Herein, we present an overview of the rise of a synthetic opioid known as U-47700. We describe U-47700's history, legal status, ease of obtainment, consequences of its use, and a proposal to increase the awareness of this synthetic opioid. PMID- 29282438 TI - Management of Unruptured Traumatic Middle Meningeal Artery Pseudoaneurysms through Onyx Embolization. AB - Traumatic pseudoaneurysms of the middle meningeal artery (MMA) represent less than 1% of all intracranial aneurysms, and occur mostly in association with temporal bone fractures following head trauma. Given the unknown natural history, it is unclear whether they should be treated. We present two cases of MMA pseudoaneurysms discovered during trauma workups. The first patient is a 44-year old male with severe traumatic brain injury (TBI) following a motor vehicle accident. The patient was found to have two right-sided middle meningeal artery pseudoaneurysms that were treated successfully with Onyx(r) (Medtronic, Minneapolis, MN) embolization. The second patient is a 56-year-old male that sustained a severe TBI and skull fracture following a motorcycle collision. Angiography demonstrated an unruptured right MMA aneurysm, which was also treated successfully with Onyx embolization. MMA pseudoaneurysms occur rarely in the setting of severe traumatic injuries. In select patients, treatment by an experienced neuro-interventionalist can prevent highly morbid future intracranial hemorrhages with minimal risk of complications. PMID- 29282437 TI - The Utility of Social Media in Providing Information on Zika Virus. AB - Introduction In 2015, there was an outbreak of Zika virus in Brazil that spread throughout the Americas. The association of Zika virus with birth defects in infants born to infected pregnant women created concern for women of childbearing age. Social media is an important platform for health promotion, communication, and education on preventative methods during Zika virus outbreaks. Methods We evaluated the utility of social media on providing information regarding Zika virus. Facebook, Instagram, Twitter, and YouTube were utilized for our study. A search of the term "#Zikavirus" on Twitter and Instagram, and "Zika virus" on Facebook and YouTube was performed. The first 50 search results were analyzed from each source. Only English, Spanish, or Portuguese results were included. Results were categorized into three groups: "Useful", "Not Useful", or "Misleading". Results Search was conducted on December 17th, 2016, with 185 results. Forty (21.6%) were from Facebook, 50 (27%) from Twitter, 48 (25.9%) from YouTube, and 47 (25.4%) from Instagram. A total of 104 (56.22%) results were "Useful", 67 (36.2%) "Not Useful", and 14 (7.5%) were "Misleading". There were significantly more "Useful" results compared to "Not Useful" and "Misleading" results (Fisher's exact: p < 0.0001). Conclusion Social media is a useful resource for providing relevant information on Zika virus. Young women can utilize social media for Zika virus information. The role of social media in public health should be further investigated and established. Patient education interventions should focus on social media impact on behavior modification and education of public to recognize useful information. PMID- 29282440 TI - Transient Smartphone Blindness: Precaution Needed. AB - The transient smartphone blindness (TSB) is a relatively new phenomenon that affects vision. However, it warrants immediate attention by the physicians and the smartphone users, lest it leads to long-term consequences such as blindness. PMID- 29282439 TI - Diffuse Nocardial Spinal Subdural Empyema: Diagnostic Dilemma and Treatment Options. AB - Nocardiosis of the central nervous system and spine, in particular, is a rare infection with significant morbidity and mortality. Treatment is usually with antibiotics and surgical drainage or biopsy. The authors report a case of a 49 year-old man who presented with chronic lower back pain and paraplegia. He was found to have spinal subdural empyema caused by Nocardia farcinica. Laminectomy and sampling of the subdural collection were performed, and the patient was treated with triple intravenous antibiotics (linezolid, amikacin and ciprofloxacin). There was no neurological recovery at follow-up. Spinal nocardiosis should be considered in the differential diagnosis of immunocompromised patients who present with diffuse spinal epidural/subdural or spinal cord abscesses, appropriately unresponsive to antibiotics. Our case provides an insight into the management challenges of this rare disease. PMID- 29282441 TI - Platelet Transfusion Thresholds Among Children Admitted to a Pediatric Intensive Care Unit. AB - Objective To evaluate the threshold for platelet transfusion in children admitted to a pediatric intensive care unit (PICU). This is a retrospective chart review study, conducted at our tertiary level PICU and is related to critically ill pediatric patients who required platelet transfusion. Methods We retrieved the target patient population data from our blood bank database. The patients were subdivided into four subgroups: hematologic (hematologic malignancies, bone marrow suppression, hemolytic anemia, and sickle cell disease), surgical (post surgical, trauma and acute bleeding), the unstable fraction of inspired oxygen (FiO2 > 0.6 and/or inotropic support), and the stable patients. Critically ill children between one month and 21 years of age were enrolled. We excluded patients who underwent extracorporeal membrane oxygenation (ECMO). Results A total of 197 transfusion episodes in 64 patients were analyzed. The distribution of transfusions episodes included hematologic 82% (n=161), surgical 7% (n=13), unstable 8% (n=16), stable 3% (n=7). The mean standard deviation (SD) of pre transfusion platelet count (x1000) in all the patients and children in hematologic, surgical, unstable and stable groups were 29 (22), 29 (19), 47 (46), 28 (19), and 24 (14), respectively. The platelet count threshold for transfusion among the surgical group was higher compared to hematologic and unstable groups (p <0.001; analysis of variance (ANOVA) with multiple comparison tests). The mean platelet count during all episodes increased from 29 (22) to 71 (57) (p <0.05; paired t-test). The post-transfusion increase in platelet count was significantly higher among surgical and unstable patients compared to hematologic patients (p <0.001; ANOVA with multiple comparison tests). Conclusion The most common indication for platelet transfusion in the pediatric intensive care unit (PICU) is the underlying hematologic condition. The platelet count threshold for transfusion varied with the clinical condition and is higher among the surgical patients. The rise of platelet count after transfusion was higher among the surgical and unstable patients. PMID- 29282442 TI - Impact of CyberKnife Radiosurgery on Overall Survival and Various Parameters of Patients with 1-3 versus >= 4 Brain Metastases. AB - Introduction This study's objective is to compare the overall survivals (OSs) and various parameters of patients with 1-3 versus >= 4 brain metastases post CyberKnife radiosurgery (CKRS) (Accuray, Sunnyvale, California) alone. Methods Charts of 150 patients, from 2009-2014, treated with only CKRS for brain metastases were reviewed retrospectively for overall survival (OS) and patient, tumor, and imaging characteristics. Parameters included demographics, Eastern Cooperative Oncology Group (ECOG) performance scores, number and control of extracranial disease (ECD) sites, cause of death (COD), histology, tumor volume (TV), and post-CKRS whole brain radiotherapy (WBRT). The imaging characteristics assessed were time of complete response (CR), partial response (PR), stable imaging or local failure (LF), and distal brain failure (DBF). Patients and their data were divided into those with 1-3 (group 1) versus >= 4 brain metastases (group 2). For each CR and LF patient, absolute neutrophil count (ANC), absolute lymphocyte count (ALC)), and ANC/ALC ratio (NLR) were obtained, when available, at the time of CKRS. Results Both group 1 and group 2 had a median OS of 13 months. The patient median age for the 115 group 1 patients versus the 35 group 2 patients was 62 versus 56 years. Group 1 had slightly more males and group 2, females. The predominant ECOG score for each group was 1 and the number of ECD sites was one and two, respectively. Uncontrolled ECD occurred in the majority of both group 1 and group 2 patients. The main COD was ECD in both groups. The prevalent tumor histology for groups 1 and 2 was non-small cell lung carcinoma. Median TVs were 1.08 cc versus 1.42 cc for groups 1 and 2, respectively. The majority of patients in both groups did not undergo post-CKRS WBRT. Imaging outcomes were LC (CR, PR, or stable imaging) in 93 (80.9%) and 26 (74.3%) group 1 and 2 patients, of whom 32 (27.8%) and six (17.1%) had CR; 38 (33.0%) and 18 (51.4%), PR and 23 (20.0%) and two (5.7%), stable imaging; LF was the outcome in 22 (19.1%) and nine (25.7%) patients, and DBF occurred in 62 (53.9%) and 21 (60.0%), respectively. Uni- and multivariable analyses showed the independent parameters of a lower ECOG score, a greater number of ECD sites and uncontrolled ECD were significantly associated with greater mortality risk with and without accounting for other covariates. At CKRS, 19 group 1 and 2 CR patients had a mean ANC of 5.88 K/uL and a mean ALC of 1.31 K/uL and 13 (68%) of 19 had NLRs <= five, while 11 with LFs had a mean ANC of 5.22 K/uL and a mean ALC of 0.93 K/uL and seven (64%) had NLRs > five. An NLR <= five and high ALC was associated with a CR and an NLR > five and a low ALC with an LF. Conclusions Median OS post-CKRS was 13 months for both patients with 1-3 brain metastases and with >= 4. This is the only study in the literature to evaluate OS in patients with 1-3 and >= 4 brain metastases who were treated with CKRS alone. For groups 1 and 2 patients combined, 119 (79.3%) had LC and 38 (25.3%) had CR. The ANC, ALC, and NLR values are likely predictive of CR and LF outcomes. PMID- 29282443 TI - First Ever Use of Proton Stereotactic Body Radiation Therapy Delivered with Curative Intent to Bilateral Synchronous Primary Renal Cell Carcinomas. AB - Limited therapeutic options exist for inoperable bilateral kidney tumors. We report the first ever use of proton therapy to treat primary renal cell carcinoma (RCC) and the first report of proton stereotactic body radiation therapy (SBRT) for RCC in an inoperable patient with synchronous RCCs treated with proton SBRT. The patient is a 47-year-old 450-pound female with multiple medical comorbidities, including Stage 3 chronic kidney disease (CKD), who was found to have bilateral renal masses during work-up for cellulitis and sepsis. Following resolution of her sepsis, subsequent cross-sectional imaging demonstrated interval growth of the left renal mass to 4.4 x 4.8 cm and the right renal mass to 2.0 x 2.6 cm. Bilateral biopsies were performed, with pathology revealing Furhman Grade 1-2 clear cell RCC on both sides. A customized SBRT plan delivered a total dose of 3,000 cGy in five fractions to the bilateral kidneys every other day using proton beam therapy. The patient experienced no grade > 1 acute adverse toxicities from proton therapy, and now at one year after treatment, she has had no clinical symptoms of late radiation-induced toxicities. Although a marginal decline in post-treatment glomerular filtration rate (GFR) was observed (baseline 34 mL/min/1.73m2, one-year post-SBRT 29 mL/min/1.73m2), the patient remains asymptomatic and without a requirement for intervention. In presenting a case in which proton SBRT was performed safely and effectively for a medically complex patient with inoperable synchronous bilateral RCC, we suggest that proton therapy is a promising therapeutic approach for even unilateral primary RCC where preservation of renal function is of importance and should be considered for medically inoperable patients. Further experience is needed to determine the optimal dose and fractionation regimen for renal SBRT with proton therapy. PMID- 29282444 TI - Obstructive Sleep Apnea Presenting as Non-epileptic Spells: A Unique Combination. AB - Obstructive sleep apnea (OSA), an increasingly prevalent sleep disorder, has been extensively studied in both clinical and scientific settings. In most cases, the diagnosis of sleep apnea is straightforward with patients having symptoms of snoring, choking or gasping for air while asleep and witnessed apneas. However, sleep apnea is known to present in some unusual ways. We present a case of a 61 year-old male, with recently diagnosed obstructive sleep apnea (currently not on continuous positive airway pressure (CPAP)) and a history of seizure-like events since the age of 18 years, who came to the epilepsy monitoring unit (EMU) for spell characterization of his frequent seizure-like episodes. A continuous video electroencephalogram (vEEG) performed in order to determine the semiology of these spells showed that all the spells were triggered by an arousal from sleep with an associated apneic event. He was started on positive airway pressure (PAP) therapy, which resulted in the gradual decline in the number as well as the severity of his seizure-like spells. Based on the observations from vEEG monitoring and the patient's response, we concluded these seizure-like events as non-epileptic spells, triggered by apnea-related arousals in the context of OSA. PMID- 29282445 TI - Curated Collection for Educators: Five Key Papers about the Flipped Classroom Methodology. AB - The flipped classroom (FC) pedagogy is becoming increasingly popular in medical education due to its appeal to the millennial learner and potential benefits in knowledge acquisition. Despite its popularity and effectiveness, the FC educational method is not without challenges. In this article, we identify and summarize several key papers relevant to medical educators interested in exploring the FC teaching methodology. The authors identified an extensive list of papers relevant to FC pedagogy via online discussions within the Academic Life in Emergency Medicine (ALiEM) Faculty Incubator. This list was augmented by an open call on Twitter (utilizing the #meded, #FOAMed, and #flippedclassroom hashtags) yielding a list of 33 papers. We then conducted a three-round modified Delphi process within the authorship group, which included both junior and senior clinician educators, to identify the most impactful papers for educators interested in FC pedagogy. The three-round modified Delphi process ranked all of the selected papers and selected the five most highly-rated papers for inclusion. The authorship group reviewed and summarized these papers with specific consideration given to their value to junior faculty educators and faculty developers interested in the flipped classroom approach. The list of papers featured in this article serves as a key reading list for junior clinician educators and faculty developers interested in the flipped classroom technique. The associated commentaries contextualize the importance of these papers for medical educators aiming to optimize their understanding and implementation of the flipped classroom methodology in their teaching and through faculty development. PMID- 29282446 TI - Refractory Adult Onset Still's Disease. AB - It is often a challenge and a dilemma for clinicians encountering patients with pyrexia of unknown origin. Numerous tests performed to determine the underlying cause often give inconclusive results. We present a 52-year-old man with undulating fever for more than 10 months with persistent hyperferritinaemia, and negative immunological and serological markers. Despite corticosteroids, disease modifying anti-rheumatic agents and immune-modulator therapy, he succumbed to the illness. A diagnosis of refractory Adult onset Still's disease complicated by haemophagocytic lymphohistiocytosis was made. PMID- 29282448 TI - Origin of the blueshift of water molecules at interfaces of hydrophilic cyclic compounds. AB - Water molecules at interfaces of materials exhibit enigmatic properties. A variety of spectroscopic studies have observed a high-frequency motion in these water molecules, represented by a blueshift, at both hydrophobic and hydrophilic interfaces. However, the molecular mechanism behind this blueshift has remained unclear. Using Raman spectroscopy and ab initio molecular dynamics simulations, we reveal the molecular mechanism of the blueshift of water molecules around six monosaccharide isomers. In the first hydration shell, we found weak hydrogen bonded water molecules that cannot have a stable tetrahedral water network. In the water molecules, the vibrational state of the OH bond oriented toward the bulk solvent strongly contributes to the observed blueshift. Our work suggests that the blueshift in various solutions originates from the vibrational motions of these observed water molecules. PMID- 29282447 TI - Kinetic isotope effects and how to describe them. AB - We review several methods for computing kinetic isotope effects in chemical reactions including semiclassical and quantum instanton theory. These methods describe both the quantization of vibrational modes as well as tunneling and are applied to the ?H + H2 and ?H + CH4 reactions. The absolute rate constants computed with the semiclassical instanton method both using on-the-fly electronic structure calculations and fitted potential-energy surfaces are also compared directly with exact quantum dynamics results. The error inherent in the instanton approximation is found to be relatively small and similar in magnitude to that introduced by using fitted surfaces. The kinetic isotope effect computed by the quantum instanton is even more accurate, and although it is computationally more expensive, the efficiency can be improved by path-integral acceleration techniques. We also test a simple approach for designing potential-energy surfaces for the example of proton transfer in malonaldehyde. The tunneling splittings are computed, and although they are found to deviate from experimental results, the ratio of the splitting to that of an isotopically substituted form is in much better agreement. We discuss the strengths and limitations of the potential-energy surface and based on our findings suggest ways in which it can be improved. PMID- 29282449 TI - Quantum criticality in the spin-1/2 Heisenberg chain system copper pyrazine dinitrate. AB - Low-dimensional quantum magnets promote strong correlations between magnetic moments that lead to fascinating quantum phenomena. A particularly interesting system is the antiferromagnetic spin-1/2 Heisenberg chain because it is exactly solvable by the Bethe-Ansatz method. It is approximately realized in the magnetic insulator copper pyrazine dinitrate, providing a unique opportunity for a quantitative comparison between theory and experiment. We investigate its thermodynamic properties with a particular focus on the field-induced quantum phase transition. Thermal expansion, magnetostriction, specific heat, magnetization, and magnetocaloric measurements are found to be in excellent agreement with exact Bethe-Ansatz predictions. Close to the critical field, thermodynamics obeys the expected quantum critical scaling behavior, and in particular, the magnetocaloric effect and the Gruneisen parameters diverge in a characteristic manner. Beyond its importance for quantum magnetism, our study establishes a paradigm of a quantum phase transition, which illustrates fundamental principles of quantum critical thermodynamics. PMID- 29282450 TI - Impact of complex topology of porous media on phase separation of binary mixtures. AB - Porous materials, which are characterized by the large surface area and percolated nature crucial for transport, play an important role in many technological applications including battery, ion exchange, catalysis, microelectronics, medical diagnosis, and oil recovery. Phase separation of a mixture in such a porous structure should be strongly influenced by both surface wetting and strong geometrical confinement effects. Despite its fundamental and technological importance, however, this problem has remained elusive for a long time because of the difficulty associated with the complex geometry of pore structures. We overcome this by developing a novel phase-field model of two coupled order parameters, the composition field of a binary mixture and the density field of a porous structure. We find that demixing behavior in complex pore structures is severely affected by the topological characteristics of porous materials, contrary to the conventional belief that it can be inferred from the behavior in a simple cylindrical pore. Our finding not only reveals the physical mechanism of demixing in random porous structures but also has an impact on technological applications. PMID- 29282452 TI - The Promise of Intranasal Esketamine as a Novel and Effective Antidepressant. PMID- 29282453 TI - The PHQ-2 in Dermatology-Standardized Screening for Depression and Suicidal Ideation. PMID- 29282451 TI - Aggregation-induced emission in lamellar solids of colloidal perovskite quantum wells. AB - The outstanding excitonic properties, including photoluminescence quantum yield (etaPL), of individual, quantum-confined semiconductor nanoparticles are often significantly quenched upon aggregation, representing the main obstacle toward scalable photonic devices. We report aggregation-induced emission phenomena in lamellar solids containing layer-controlled colloidal quantum wells (QWs) of hybrid organic-inorganic lead bromide perovskites, resulting in anomalously high solid-state etaPL of up to 94%. Upon forming the QW solids, we observe an inverse correlation between exciton lifetime and etaPL, distinct from that in typical quantum dot solid systems. Our multiscale theoretical analysis reveals that, in a lamellar solid, the collective motion of the surface organic cations is more restricted to orient along the [100] direction, thereby inducing a more direct bandgap that facilitates radiative recombination. Using the QW solids, we demonstrate ultrapure green emission by completely downconverting a blue gallium nitride light-emitting diode at room temperature, with a luminous efficacy higher than 90 lumen W-1 at 5000 cd m-2, which has never been reached in any nanomaterial assemblies by far. PMID- 29282454 TI - Interventions for Nongenital Molluscum Contagiosum in Persons Without Immune Deficiency. AB - Clinical Question: How effective and safe are treatments for nongenital molluscum contagiosum in persons without immune deficiency? Bottom Line: Compared with placebo, imiquimod, 5%, cream was not more effective in clearing molluscum contagiosum and caused more local adverse effects, including application site reactions, in children aged 2 to 12 years; because high-quality evidence for other interventions is lacking, allowing for natural resolution of the infection remains a reasonable approach. PMID- 29282455 TI - The Value of Established Relationships Between Primary Care Clinicians and Specialists. PMID- 29282456 TI - Assessment of the Diameter of Pigmented Skin Lesions With and Without a Ruler. PMID- 29282457 TI - Outcomes After Adjustable Gastric Banding. PMID- 29282458 TI - Association of Uterine Leiomyomas With Central Centrifugal Cicatricial Alopecia. PMID- 29282459 TI - Outcomes After Adjustable Gastric Banding-Reply. PMID- 29282460 TI - Cutaneous Diphtheria Mimicking Pyoderma Gangrenosum. PMID- 29282461 TI - Choosing Successful Residents. PMID- 29282462 TI - Evaluation of Validity Evidence for Personality, Emotional Intelligence, and Situational Judgment Tests to Identify Successful Residents. AB - Importance: The ability to identify candidates who will thrive and successfully complete their residency is especially critical for general surgery programs. Objective: To assess the extent to which 3 screening tools used extensively in industrial selection settings-emotional intelligence (EQ), personality profiles, and situational judgment tests (SJTs)-could identify successful surgery residents. Design, Setting, and Participants: In this analysis, personality profiles, EQ assessments, and SJTs were administered from July through August 2015 to 51 postgraduate year 1 through 5 general surgery residents in a large general surgery residency program. Associations between these variables and residency performance were investigated through correlation and hierarchical regression analyses. Interventions: Completion of EQ, personality profiles, and SJT assessments. Main Outcomes and Measures: Performance in residency as measured by a comprehensive performance metric. A score of zero represented a resident whose performance was consistent with that of their respective cohort's performance; below zero, worse performance; and greater than zero, better performance. Results: Of the 61 eligible residents, 51 (84%) chose to participate and 22 (43%) were women. US Medical Licensing Examination Step 1 (USMLE1), but not USMLE2, emerged as a significant factor (t2,49 = 1.98; beta = 0.30; P = .03) associated with overall performance. Neither EQ facets nor overall EQ offered significant incremental validity over USMLE1 scores. Inclusion of the personality factors did not significantly alter the test statistic and did not explain any additional portion of the variance. By contrast, inclusion of SJT scores accounted for 15% more of the variance than USMLE1 scores alone, resulting in a total of 25% of the variance explained by both USMLE1 and SJT scores (F2,57 = 7.47; P = .002). Both USMLE1 (t = 2.21; P = .03) and SJT scores (t = 2.97; P = .005) were significantly associated with overall resident performance. Conclusions and Relevance: This study found little support for the use of EQ assessment and only weak support for some distinct personality factors (ie, agreeableness, extraversion, and independence) in surgery resident selection. Performance on the SJT was associated with overall resident performance more than traditional cognitive measures (ie, USMLE scores). These data support further exploration of these 2 screening assessments on a larger scale across specialties and institutions. PMID- 29282465 TI - Outcomes After Adjustable Gastric Banding. PMID- 29282464 TI - Association of Informal Clinical Integration of Physicians With Cardiac Surgery Payments. AB - Importance: To reduce inefficiency and waste associated with care fragmentation, many current programs target greater clinical integration among physicians. However, these programs have led to only modest Medicare spending reductions. Most programs focus on formal integration, which often bears little resemblance to actual physician interaction patterns. Objectives: To examine how physician interaction patterns vary between health systems and to assess whether variation in informal integration is associated with care delivery payments. Design, Setting, and Participants: National Medicare data from January 1, 2008, through December 31, 2011, identified 253 545 Medicare beneficiaries (aged >=66 years) from 1186 health systems where Medicare beneficiaries underwent coronary artery bypass grafting (CABG) procedures. Interactions were mapped between all physicians who treated these patients-including primary care physicians and surgical and medical specialists-within a health system during their surgical episode. The level of informal integration was measured in these networks of interacting physicians. Multivariate regression models were fitted to evaluate associations between payments for each surgical episode made on a beneficiary's behalf and the level of informal integration in the health system where the patient was treated. Exposures: The informal integration level of a health system. Main Outcomes and Measures: Price-standardized total surgical episode and component payments. Results: The total 253 545 study participants included 175 520 men (69.2%; mean [SD] age, 74.51 [5.75] years) and 78 024 women (34.3%; 75.67 [5.91] years). One beneficiary of the 253 545 participants did not have sex information. The low level of informal clinical integration included 84 598 patients (33.4%; mean [SD] age, 75.00 [5.93] years); medium level, 84 442 (33.30%; 74.94 [5.87] years); and high level, 84 505 (33.34%; 74.66 [5.72] years) (P < .001). Informal integration levels varied across health systems. After adjusting for patient, health-system, and community factors, higher levels of informal integration were associated with significantly lower total episode and component payments (beta coefficients for informal integration were -365.87 [95% CI, -451.08 to -280.67] for total episode payments, -182.63 [-239.80 to -125.46] for index hospitalization, -43.13 [-55.53 to -30.72] for physician services, 74.48 [-103.45 to -45.51] for hospital readmissions, and -62.04 [-88.00 to 36.07] for postacute care; P < .001 for each association). When beneficiaries were treated in health systems with higher informal integration, the greatest savings of lower estimated payments were from hospital readmissions (13.0%) and postacute care services (5.8%). Conclusions and Relevance: Informal integration is associated with lower spending. Although most programs that seek to promote clinical integration are focused on health systems' formal structures, policy makers may also want to address informal integration. PMID- 29282463 TI - Prevalence of Work-Related Musculoskeletal Disorders Among Surgeons and Interventionalists: A Systematic Review and Meta-analysis. AB - Importance: Physicians in procedural specialties are at high risk for work related musculoskeletal disorders (MSDs). This has been called "an impending epidemic" in the context of the looming workforce shortage; however, prevalence estimates vary by study. Objectives: To estimate the prevalence of work-related MSDs among at-risk physicians and to evaluate the scope of preventive efforts. Data Sources and Study Selection: Systematic search in MEDLINE (Ovid), Embase (Elsevier), Web of Science, PubMed (National Center for Biotechnology Information), and 2 clinical trial registries, without language restriction, for studies reporting on the prevalence and prevention of work-related MSDs among at risk physicians published until December 2016. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analyses and systematic reviews of observational studies were used. At-risk physicians were defined as surgeons and medical interventionalists. Studies reporting on specific disorders or pain assessed with validated instruments were included. Data Extraction and Synthesis: Study characteristics; disease prevalence for the neck, shoulder, back, and upper extremity; and measures of resulting disability were recorded. Study estimates were pooled using random-effects meta-analytic models. Main Outcomes and Measures: Career prevalence of injuries and 12-month prevalence of pain. Results: Among 21 articles (5828 physicians [mean age, 46.0 years; 78.5% male; 12.8 years in practice; 14.4 hours performing procedures per week]) included in this systematic review and meta-analysis, pooled crude prevalence estimates of the most common work-related MSDs were degenerative cervical spine disease in 17% (457 of 2406 physicians) (95% CI, 12%-25%), rotator cuff pathology in 18% (300 of 1513 physicians) (95% CI, 13%-25%), degenerative lumbar spine disease in 19% (544 of 2449 physicians) (95% CI, 5%-16%), and carpal tunnel syndrome in 9% (256 of 2449 physicians) (95% CI, 5%-16%). From 1997 to 2015, the prevalence of degenerative cervical spine disease and degenerative lumbar spine disease increased by 18.3% and 27%, respectively. Pooled prevalence estimates for pain ranged from 35% to 60% and differed by assessment instrument. Of those with a work-related MSD, 12% (277 of 2319 physicians) (95% CI, 7%-18%) required a leave of absence, practice restriction or modification, or early retirement. Heterogeneity was considerable for all crude analyses (mean I2 = 93.5%) but was lower for sensitivity analyses (mean I2 = 72.3%). Interventions focused on products and behaviors. Twelve at-risk specialties described a gross lack of awareness and an unmet need for ergonomics education. Conclusions and Relevance: Prevalence estimates of work-related MSDs among at-risk physicians appear to be high. Further research is needed to develop and validate an evidence-based applied ergonomics program aimed at preventing these disorders in this population. PMID- 29282466 TI - Trends in Country-Specific Surgical Randomized Clinical Trial Publications. PMID- 29282467 TI - Complete Revascularization for Percutaneous Coronary Intervention: The Devil Is in the Details. PMID- 29282468 TI - Tramadol Extended Release and Opioid Withdrawal Management-Legal Implications. PMID- 29282469 TI - Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. AB - Importance: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective: To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Results: Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration: clinicaltrials.gov identifier: NCT01998958. PMID- 29282471 TI - Association of Coronary Vessel Characteristics With Outcome in Patients With Percutaneous Coronary Interventions With Incomplete Revascularization. AB - Importance: Many studies have compared outcomes for incomplete revascularization (IR) among patients undergoing percutaneous coronary interventions (PCI), but little is known about whether outcomes are related to the nature of the IR. Objective: To determine whether some coronary vessel characteristics are associated with worse outcomes in patients with PCI with IR. Design, Setting, and Participants: New York's PCI registry was used to examine mortality (median follow-up, 3.4 years) as a function of the number of vessels that were incompletely revascularized, the stenosis in those vessels, and whether the proximal left anterior descending artery was incompletely revascularized after controlling for other factors associated with mortality for patients with and without ST-elevation myocardial infarction (STEMI). This was a multicenter study (all nonfederal PCI hospitals in New York State) that included 41 639 New York residents with multivessel coronary artery disease undergoing PCI in New York State between January 1, 2010, and December 31, 2012. Exposures: Percutaneous coronary interventions, with complete and incomplete revascularization. Main Outcomes and Measures: Medium-term mortality. Results: For patients with STEMI, the mean age was 62.8 years; 26.2% were women, 11.9% were Hispanic, and 81.5% were white. For other patients, the mean age was 66.6 years, 29.1% were women, 11.3% were Hispanic, and 79.1% were white. Incomplete revascularization was very common (78% among patients with STEMI and 71% among other patients). Patients with IR in a vessel with at least 90% stenosis were at higher risk than other patients with IR. This was not significant among patients with STEMI (17.18% vs 12.86%; adjusted hazard ratio [AHR], 1.16; 95% CI, 0.99-1.37) and significant among patients without STEMI (17.71% vs 12.96%; AHR, 1.15; 95% CI, 1.07-1.24). Similarly, patients with IR in 2 or more vessels had higher mortality than patients with completely revascularization and higher mortality than other patients with IR among patients with STEMI (20.37% vs 14.39%; AHR, 1.35; 95% CI, 1.15-1.59) and among patients without STEMI (20.10% vs 12.86%; AHR, 1.17; 95% CI, 1.09-1.59). Patients with proximal left anterior descending artery vessel IR had higher mortality than other patients with IR (20.09% vs 14.67%; AHR, 1.31; 95% CI, 1.04-1.64 for patients with STEMI and 20.78% vs 15.62%; AHR, 1.11; 95% CI, 1.01-1.23 for patients without STEMI). More than 20% of all PCI patients had IR of 2 or more vessels and more than 30% had IR with more than 90% stenosis. Conclusions and Relevance: Patients with IR are at higher risk of mortality if they have IR with at least 90% stenosis, IR in 2 or more vessels, or proximal left anterior descending IR. PMID- 29282470 TI - Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression: A Randomized Clinical Trial. AB - Importance: More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression. Objective: To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression. Design, Setting, and Participants: A randomized, sham-controlled, double-blind trial (the Bipolar Depression Electrical Treatment Trial [BETTER]) was conducted from July 1, 2014, to March 30, 2016, at an outpatient, single-center academic setting. Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale (HDRS-17) scores higher than 17. Data were analyzed in the intention-to treat sample. Interventions: Ten daily 30-minute, 2-mA, anodal-left and cathodal right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6. Main Outcomes and Measures: Change in HDRS-17 scores at week 6. Results: Fifty-nine patients (40 [68%] women), with a mean (SD) age of 45.9 (12) years participated; 36 (61%) with bipolar I and 23 (39%) with bipolar II disorder were randomized and 52 finished the trial. In the intention to-treat analysis, patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham (betaint = -1.68; number needed to treat, 5.8; 95% CI, 3.3-25.8; P = .01). Cumulative response rates were higher in the active vs sham groups (67.6% vs 30.4%; number needed to treat, 2.69; 95% CI, 1.84-4.99; P = .01), but not remission rates (37.4% vs 19.1%; number needed to treat, 5.46; 95% CI, 3.38-14.2; P = .18). Adverse events, including treatment-emergent affective switches, were similar between groups, except for localized skin redness that was higher in the active group (54% vs 19%; P = .01). Conclusions and Relevance: In this trial, tDCS was an effective, safe, and tolerable add-on intervention for this small bipolar depression sample. Further trials should examine tDCS efficacy in a larger sample. Trial Registration: clinicaltrials.gov Identifier: NCT02152878. PMID- 29282473 TI - Tramadol Extended-Release and Opioid Withdrawal Management-Legal Implications Reply. PMID- 29282472 TI - Assessing Changes in Alcohol Use and Alcohol Use Disorder Prevalence in the United States: Evidence From National Surveys From 2002 Through 2014. PMID- 29282474 TI - Tutorial: Assessment and Analysis of Polysyllables in Young Children. AB - Purpose: Polysyllables, words of 3 or more syllables, represent almost 30% of words used in American English. The purpose of this tutorial is to support speech language pathologists' (SLPs') assessment and analysis of polysyllables, extending the focus of published assessment tools that focus on sampling and analyzing children's segmental accuracy and/or the presence of phonological error patterns. Method: This tutorial will guide SLPs through a review of 53 research papers that have explored the use of polysyllables in assessment, including the sampling and analysis procedures used in different research studies. The tutorial will also introduce two new tools to analyze and interpret polysyllable speech samples: the Word-Level Analysis of Polysyllables (WAP; Masso, 2016b) and the Framework of Polysyllable Maturity (Framework; Masso, 2016a). Results: Connected speech and single-word sampling tasks were used across the 53 studies to elicit polysyllables, and a number of analysis methods were reported, including measures of segmental accuracy and measures of structural and suprasegmental accuracy. The WAP and the Framework extend SLPs' depth of analysis of polysyllables. Conclusion: SLPs need a range of clinical tools to support the assessment and analysis of polysyllables. A case study comparing different speech analysis methods demonstrates the clinical value in utilizing the WAP and the Framework to interpret children's polysyllable productions in addition to traditional methods of speech sampling and analysis. PMID- 29282475 TI - Reframing the Value Proposition of Coronary Artery Bypass Graft Bundles. PMID- 29282476 TI - Effects of Environmental Contamination and Acute Toxicity of N-Nitrate on Early Life Stages of Endemic Arboreal Frog, Polypedates cruciger (Blyth, 1852). AB - This study investigated the potential toxic effects of environmentally relevant nitrate concentrations on development, growth, and mortality of early life stages of common hour-glass tree frog, Polypedates cruciger. Tadpoles from hatchlings through pre-adult were exposed to environmentally relevant nitrate concentrations detected in Mirissa, Sri Lanka. Newly hatched, external gill stage, and internal gill stage tadpoles were exposed to potassium nitrate for bioassay tests. No behavioral changes or abnormalities were observed in control and nitrate-induced group. However, detected environmental nitrate concentration significantly increased (p < 0.05) the growth of the tadpoles up to 25 days old. Results revealed that newly hatched and external gill stage was more susceptible to the nitrate pollution than internal gill stage. The results suggest that environmentally relevant nitrate can cause mortality on the amphibian population in ecosystems associated with agro-pastoral activities through altering the growth and direct toxicological effects on the survivorship. PMID- 29282477 TI - 2018: Celebrating Volume 100. PMID- 29282478 TI - Tumor necrosis factor-alpha stimulates human amelotin gene transcription in gingival epithelial cells. AB - OBJECTIVE: Amelotin (AMTN) is an enamel protein that is localized in the basal lamina of ameloblasts in their maturation stage and the internal basal lamina of junctional epithelium (JE) and it is suggested that AMTN could be involved in the dentogingival attachment. To elucidate the transcriptional regulation of human AMTN gene in inflamed gingiva, we have analyzed the effect of tumor necrosis factor-alpha (TNF-alpha) on the expression of AMTN gene in Ca9-22 and Sa3 human gingival epithelial cells. MATERIALS AND METHODS: Total RNAs were extracted from Ca9-22 and Sa3 cells after stimulation by TNF-alpha (10 ng/ml). AMTN mRNA and protein levels were measured by real-time PCR and Western blotting. Transient transfection analyses were completed using the various lengths of human AMTN gene promoter constructs with or without TNF-alpha. Gel mobility shift and chromatin immunoprecipitation assays were performed to investigate the transcription factors bindings to the human AMTN gene promoter by TNF-alpha. RESULTS: TNF-alpha (10 ng/ml) increased AMTN mRNA and protein levels after 12 h. TNF-alpha induced luciferase activities of human AMTN gene promoter constructs (- 211AMTN, - 353AMTN, and - 501AMTN). TNF-alpha-induced luciferase activities were partially inhibited in the mutation - 353AMTN constructs that included 3-bp mutations in CCAAT enhancer-binding protein 1 (C/EBP1), C/EBP2 and Ying Yang 1 (YY1) elements. Transcriptional activities induced by TNF-alpha were inhibited by protein kinase A, Src-tyrosine kinase, MEK1/2, p38 kinase, NF-kappaB, and PI3-kinase inhibitors. Gel shift assays showed that TNF-alpha increased nuclear proteins binding to two types of C/EBP elements (C/EBP1 and C/EBP2) and YY1 element. The results of the chromatin immunoprecipitation assays showed that C/EBPbeta binding to C/EBP1 and C/EBP2, and YY1 binding to YY1 were increased by TNF-alpha. CONCLUSIONS: These findings demonstrated that TNF-alpha stimulates AMTN gene transcription in human gingival epithelial cells via C/EBP1, C/EBP2, and YY1 elements in the human AMTN gene promoter. PMID- 29282479 TI - What drives the relationship between combat and alcohol problems in soldiers? The roles of perception and marriage. AB - BACKGROUND: While the relationship between combat exposure and alcohol problems is well-established, the role of perceptions of trauma is less understood. The goal of this study was to explore associations between National Guard (NG) and reserve soldiers' perceptions of combat experiences as traumatic and alcohol problems, and to examine marital satisfaction as a possible protective factor. METHODS: The Operation: SAFETY study recruited US Army Reserve and NG soldiers and their partners to complete a questionnaire covering many physical and mental health, military service, and substance use topics. Negative binomial regression models examined the impact of perceived trauma of combat experiences on alcohol problems (N = 198). The potential role of marital satisfaction as a resiliency factor was also examined. RESULTS: The perception of combat experiences as traumatic was associated with increased risk of alcohol problems (risk ratio [RR] = 1.06, 95% confidence interval [CI] 1.01, 1.12; p = 0.024). Combat exposure itself showed no relationship. Marital satisfaction had a significant interaction with perceived combat trauma on alcohol problems (RR = 0.90, 95% CI 0.81, 0.99, p = 0.046), such that soldiers who perceived combat exposure as moderately-highly traumatic were less likely to have alcohol problems when they rated their marital satisfaction highly. CONCLUSIONS: Our results demonstrate that the perception of combat experiences as traumatic may be a greater contributor to adverse outcomes, such as alcohol problems, than mere combat exposure. They also demonstrate the importance of marital satisfaction as a resiliency factor, particularly at the highest levels of trauma. PMID- 29282481 TI - Trials on ischemic stroke treatment: mission accomplished? PMID- 29282482 TI - Hip fracture trends in the United States, 2002 to 2015. AB - : An analysis of United States (US) Medicare claims data from 2002 to 2015 for women aged >= 65 years found that age-adjusted hip fracture rates for 2013, 2014, and 2015 were higher than projected, resulting in an estimated increase of more than 11,000 hip fractures. INTRODUCTION: Hip fractures are a major public health concern due to high morbidity, mortality, and healthcare expenses. Previous studies have reported a decrease in the annual incidence of hip fractures in the US beginning in 1995, coincident with the introduction of modern diagnostic tools and therapeutic agents for osteoporosis. In recent years, there has been less bone density testing and fewer prescriptions for osteoporosis treatments. The large osteoporosis treatment gap raises concern of possible adverse effects on hip fracture rates. METHODS: We assessed hip fracture incidence in the US to determine if the previous decline in hip fracture incidence continued. Using 2002 to 2015 Medicare Part A and Part B claims for women >= 65 years old, we calculated age-adjusted hip fracture rates, weighting to the 2014 population. RESULTS: We found that hip fracture rates declined each year from 2002 to 2012 and then plateaued at levels higher than projected for years 2013, 2014, and 2015. CONCLUSIONS: The plateau in age-adjusted hip fracture incidence rate resulted in more than 11,000 additional estimated hip fractures over the time periods 2013, 2014, and 2015. We recommend further study to assess all factors contributing to this remarkable change in hip fracture rate and to develop strategies to reduce the osteoporosis treatment gap. PMID- 29282484 TI - Improvement of outcomes in patients with pelvic fractures and hemodynamic instability after the establishment of a Korean regional trauma center. AB - PURPOSE: Despite using a multidisciplinary treatment approach, the mortality rate of patients with hemodynamic instability from severe pelvic fractures is still 40 60%. We evaluated the improvement of outcomes in this patient population after the establishment of a regional trauma center in Korea. METHODS: We retrospectively reviewed the medical charts of 50 patients with hemodynamic instability due to pelvic fractures between March 2011 and November 2016. Patients were divided into two groups: the pre-trauma center (PTC) group (n = 23) and trauma center (TC) group (n = 27). RESULTS: Sixteen (32.0%) patients died of exsanguination. Patients in the TC group had shorter trauma resuscitation room stay (101 vs 273 min, p < 0.001) and underwent preperitoneal pelvic packing (PPP) more frequently (88.9 vs 8.7%, p < 0.001) than those in the PTC group. During the TC period, emergent procedures such as PPP and pelvic angiography were performed more frequently (92.6 vs 39.1%, p < 0.001). Although there was no statistical difference in the overall mortality rate between groups, patients in the TC group had less mortality due to hemorrhage (18.5 vs 47.8%, p = 0.027). Logistic regression analysis demonstrated that initial systolic blood pressure and establishment of trauma center were independent protective factors of mortality from hemorrhage [odds ratio (OR) 0.957, 95% confidence interval (CI) 0.926-0.988, p = 0.007; OR 0.134, 95% CI 0.028-0.633, p = 0.011]. CONCLUSIONS: Since the regional trauma center was established, emergent procedures such as pelvic angiography and PPP were performed more frequently, and mortality due to exsanguination was significantly decreased. PMID- 29282483 TI - Soluble TREM-1 Serum Level can Early Predict Mortality of Patients with Sepsis, Severe Sepsis and Septic Shock. AB - Early prognostic prediction of sepsis is essential in adjusting therapeutic protocols to prevent deterioration and reduce mortality. We compared the predictive value of the serum concentration of the soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) for 28-day mortality and for the development of severe sepsis or septic shock on the third day with the levels of interleukin (IL)-6, C-reactive protein (CRP) and procalcitonin (PCT). The study was conducted on 85 patients with sepsis. sTREM-1, CRP, PCT and IL-6 concentrations were measured upon study inclusion (day 0) and on days 1, 2, 3 and 5. APACHE II, SAPS II and SOFA scores were analyzed. The sTREM-1 levels (pg/ml) were higher in non-survivors than in survivors at admission (773 vs. 391, p < 0.001) and on days 1, 2, 3 and 5. In predicting the development of severe sepsis, the highest AUCs were found for PCT (0.744, 95% CI 0.638-0.85) and sTREM-1 (0.664, 95% CI 0.55-0.778); and in septic shock prediction, for PCT (0.766, 95% CI 0.665-0.867) and IL-6 (0.707, 95% CI 0.595-0.819). sTREM-1 positively correlated with APACHE II, SAPS II and SOFA scores. At inclusion, significant AUC for predicting 28-day mortality was 0.772 for the sTREM-1 (95% CI 0.672-0.871), 0.858 for APACHE II (95% CI 0.768-0.948), 0.847 for SAPS II (95% CI 0.733-0.96), 0.806 for SOFA score (95% CI 0.698-0.915). sTREM-1 can early predict the 28-day sepsis mortality, although its effectiveness is lower in comparison with clinical severity scores. PMID- 29282485 TI - Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue. AB - Long non-coding RNAs represent a fraction of the transcriptome that is being increasingly recognized. For most of them no function has been allocated so far. Here, we describe the nature and function of a novel non-protein-coding transcript, named WISP1-AS1, discovered in human renal proximal tubule cells exposed to the carcinogenic nephrotoxin ochratoxin A. WISP1-AS1 overlaps parts of the fourth intron and fifth exon of the Wnt1-inducible signaling pathway protein 1 (WISP1) gene. The transcript is 2922 nucleotides long, transcribed in antisense direction and predominantly localized in the nucleus. WISP1-AS1 is expressed in all 20 samples of a human tissue RNA panel with the highest expression levels detected in uterus, kidney and adrenal gland. Its expression was confirmed in primary tissues of human kidneys. In addition, WISP1-AS1 is expressed at higher levels in renal cell carcinoma (RCC) cell lines compared to primary proximal tubule cells as well as in RCC lesions than in the adjacent healthy control tissue from the same patient. Using specific gapmer antisense oligonucleotides to prevent its upregulation, we show that WISP1-AS1 (1) does not influence the mRNA expression of WISP1, (2) affects transcriptional regulation by Egr-1 and E2F as revealed by RNA-sequencing, enrichment analysis and reporter assays, and (3) modulates the apoptosis-necrosis balance. In summary, WISP1-AS1 is a novel lncRNA with modulatory transcriptional function and the potential to alter the cellular phenotype in situations of stress or oncogenic transformation. However, its precise mode of action and impact on cellular functions require further investigations. PMID- 29282486 TI - Patient-specific instrumentation in Oxford unicompartmental knee arthroplasty is reliable and accurate except for the tibial rotation. AB - PURPOSE: Patient-specific instrumentation (PSI) is a technique to plan and position the prosthesis components in unicompartmental knee arthroplasty (UKA) surgery. This study assesses whether the definitive component position in the frontal, sagittal and axial plane is according to the preoperative plan, based on the hypothesis that PSI is accurate. METHODS: Twenty-six patients who had PSI Oxford UKA surgery were included prospectively. The component position in vivo was determined with a postoperative CT-scan and compared with the planned component position using MRI-based digital 3D imaging. Adjustments to the preoperative plan and implanted component sizes during surgery were recorded. RESULTS: Intraoperatively, no femoral adjustments were performed; 12 tibial re resections were necessary. The median absolute deviation from the plan in degrees (range) in the frontal, sagittal and axial plane was 1.8 degrees (- 1.5 degrees 6.5 degrees ), 2.0 degrees (- 6.5 degrees -8.0 degrees ) and 1.0 degrees (- 1.5 degrees -5.0 degrees ) for the femoral component, and 2.5 degrees (- 1.0 degrees -6.0 degrees ), 3.0 degrees (- 1.0 degrees -5.0 degrees ) and 5.0 degrees (- 6.5 degrees -12.5 degrees ) for the tibial component. The femoral component is positioned 0.5 (- 1 degrees -2.5 degrees ) mm more lateral and 0.8 (- 1.0 degrees -2.5 degrees ) mm more anterior. The tibial component is positioned 2.0 (- 5.0 0.0) mm more lateral and 1.3 (- 3.0-6.0) mm more distal. The femoral and tibial default plans were changed four times (15.4%) and nine times (34.6%), respectively, before approval by the surgeon. CONCLUSION: PSI in Oxford UKA surgery is reliable and accurately translates the preoperative plan into the in vivo situation, except for the tibial rotational position. The preoperative planning is a crucial step in avoiding re-resections that can cause angular deviations in prosthesis position, especially in tibial component rotational position. It is advised to avoid re-resections and to consider this while planning the PSI procedure. LEVEL OF EVIDENCE: Prospective comparative study Level II. PMID- 29282487 TI - Temporal ventriloquism along the path of apparent motion: speed perception under different spatial grouping principles. AB - The coordination of intramodal perceptual grouping and crossmodal interactions plays a critical role in constructing coherent multisensory percepts. However, the basic principles underlying such coordinating mechanisms still remain unclear. By taking advantage of an illusion called temporal ventriloquism and its influences on perceived speed, we investigated how audiovisual interactions in time are modulated by the spatial grouping principles of vision. In our experiments, we manipulated the spatial grouping principles of proximity, uniform connectedness, and similarity/common fate in apparent motion displays. Observers compared the speed of apparent motions across different sound timing conditions. Our results revealed that the effects of sound timing (i.e., temporal ventriloquism effects) on perceived speed also existed in visual displays containing more than one object and were modulated by different spatial grouping principles. In particular, uniform connectedness was found to modulate these audiovisual interactions in time. The effect of sound timing on perceived speed was smaller when horizontal connecting bars were introduced along the path of apparent motion. When the objects in each apparent motion frame were not connected or connected with vertical bars, the sound timing was more influential compared to the horizontal bar conditions. Overall, our findings here suggest that the effects of sound timing on perceived speed exist in different spatial configurations and can be modulated by certain intramodal spatial grouping principles such as uniform connectedness. PMID- 29282489 TI - The LI-RADS adventure-a personal statement. PMID- 29282488 TI - Outcome of surgery for nerve injury following total hip arthroplasty. AB - PURPOSE: During hip replacement, nerves in the operative field can be injured accidently. Additional surgical procedures can help restore function and reduce pain if there has been no recovery. METHODS: One-hundred sixty-two patients presented with nerve injuries, and 113 were candidates for surgical treatment. The author performed 91 procedures on the injured limb (80 patients; 11 had 2 procedures) consisting of shortening, sympathectomy, tendon transfer, neurolysis or nerve repair/graft and 30 spinal and three fibular-neck decompressions. A meaningful recovery was defined as an increase of >1 level in strength or a reduction of >2 points on the visual analogue (VAS) pain scale. RESULTS: Of 21 shortening procedures, 15 improved; of 12 nerve repair/grafting procedures, four improved. No patient >55 years of age made a meaningful recovery from a nerve repair/graft. One obturator nerve was resected and did not improve, and two were buried in muscle and had less pain. Of seven sympathectomies, six had less dysesthetic pain. Of 28 nerves treated with neurolysis, 24 made a meaningful recovery, with 13 making a near complete recovery. Of three fibular decompressions, two recovered completely. Of 20 tendon transfers, 18 made a meaningful recovery. Of 30 spinal decompressions, 25 made a meaningful recovery. There were six (5.3%) surgical complications (2 worsening pain, 2 infections, 2 deformities from tendon transfer). CONCLUSIONS: If a sciatic, femoral or obturator nerve injury due to hip replacement does not recover spontaneously, additional surgical procedures can be of benefit. PMID- 29282490 TI - Stenotic Breast Malformation and Its Reconstructive Surgical Correction: A New Concept from Minor Deformity to Tuberous Breast. PMID- 29282491 TI - Opinions on the Treatment Strategy After Breast Augmentation by Polyacrylamide Hydrogel Injection. PMID- 29282493 TI - Plastic and Non-plastic Debris Ingestion in Three Gull Species Feeding in an Urban Landfill Environment. AB - Plastic debris is recognized as a widespread, common and problematic environmental pollutant. An important consequence of this pollution is the ingestion of plastic debris by wildlife. Assessing the degree to which different species ingest plastics, and the potential effects of these plastics on their health are important research needs for understanding the impacts of plastic pollution. We examined debris (plastic and other types) ingestion in three sympatric overwintering gull species (Herring gulls Larus smithsonianus, Great Black-backed Gulls Larus marinus, and Iceland Gulls Larus glaucoides) to understand how debris ingestion differs among species, age classes and sexes in gulls. We also assessed how plastic burdens were associated with body condition to investigate how gulls may be affected by debris ingestion. There were no differences among the species, age classes or sexes in the incidence of debris ingestion (plastic or otherwise), the mass or number of debris pieces ingested. We found no correlation between ingested plastics burdens and individual condition. Gulls ingested plastic debris, but also showed high levels of other debris types as well, including metal, glass and building materials, including a metal piece of debris found within an abscess in the stomach. Thus, when the health effects of debris ingestion on gulls, and other species that ingest debris, is of interest, either from a physical or chemical perspective, it may be necessary to consider all debris types and not just plastic burdens as is often currently done for seabirds. PMID- 29282492 TI - The Use of Fecal Calprotectin Levels in the Fontan population. AB - The Fontan procedure was first performed in the seventies as a palliation for patients with single ventricle physiology. A feared complication after a Fontan procedure is the development of protein losing enteropathy (PLE). Systemic inflammation has a negative effect on the intestinal barrier integrity, which has supported the use of steroids in this setting. To the best of our knowledge there are no studies linking intestinal inflammation in patients with PLE after Fontan. The objective of this study was to identify the presence of intestinal inflammation measured by FC in patients with PLE after a Fontan procedure. A cross-sectional analysis was performed examining 23 stool samples from 23 Fontan patients for both Fecal alpha-1-antitrypsin (FA1AT) and FC with and without PLE. The median FC was 21 mcg/gm of stool (IQR: 15.7-241 mcg/gm of stool), and the median FA1AT was 40 mg/dL (IQR: 30-220 mg/dL). The median FC and FA1AT were significantly higher in the PLE group than in the Non-PLE group (p = 0.002 and p < 0.0001, respectively). Significantly elevated levels of FC were demonstrated in Fontan patients with PLE, which correlated with the elevated levels of FA1AT. Inversely, levels of FC in Fontan patients without suspected PLE were within the normal range. To our knowledge, this is the first study to demonstrate intestinal inflammation using FC in the setting of PLE within this cohort, and may prove to be useful as a diagnostic tool in its treatment. PMID- 29282494 TI - Incidence of neutropenia and use of granulocyte colony-stimulating factors in multiple myeloma: is current clinical practice adequate? AB - Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia. PMID- 29282495 TI - Detection rate and proximal shift tendency of adenomas and serrated polyps: a retrospective study of 62,560 colonoscopies. AB - PURPOSE: The purpose of this study is to estimate the detection rates of adenomas and serrated polyps and to identify proximalization and associate risk factors in patients from Southern China. METHODS: Consecutive patients undergoing colonoscopy from 2004 to 2013 in Guangzhou were included. The proportions of proximal adenomas to advanced adenomas and serrated polyps were compared and potential predictors were evaluated. RESULTS: Colonoscopies (n = 62,560) were performed, and 11,427 patients were diagnosed with polyps. Detection rates for adenomas, hyperplastic polyps, and serrated adenomas were 12.0, 2.5, and 0.2 patients per 100 colonoscopies. When comparing the 1st (2004-2008) to the 2nd period (2009-2013), adenoma and serrated polyp detection in proximal and distal colon both increased significantly (proximal colon [adenoma 3.9 vs. 6.1 patients/100 colonoscopies, P < 0.001; serrated polyp 0.4 vs. 1.1 patients/100 colonoscopies, P < 0.001]; distal colon [adenoma 6.6 vs. 7.2 patients/100 colonoscopies, P = 0.003; serrated polyp 1.2 vs. 2.4 patients/100 colonoscopies, P < 0.001]). Advanced adenoma detection increased over these two periods only in proximal colon (1st vs. 2nd period: 1.5 vs. 2.4 patients/100 colonoscopies, P < 0.001), not the distal colon (P = 0.114). Multivariate analyses showed that diagnostic period was an independent predictor for adenoma proximalization (OR = 1.36, 95% CI 1.25-1.48, P < 0.001), but not for advanced adenomas (P = 0.117) or serrated polyps (P = 0.928). CONCLUSIONS: Adenomas and serrated polyps were increasingly detected throughout the colon, whereas advanced adenomas were only in proximal colon. A proximal shift tendency detected by colonoscopy was observed for adenomas, but not advanced adenomas or serrated polyps, in Southern China. The screening for proximal polyps should be emphasized and colonoscopy might be a preferred initial screening tool. PMID- 29282497 TI - Internal Fusion: exact correlation of transrectal ultrasound images of the prostate by detailed landmarks over time for targeted biopsies or follow-up. AB - PURPOSE: Innovative imaging modalities are applied for diagnosing and follow-up of prostate cancer (PCa). To perform authentic targeted biopsies and evaluate prostate changes, it is essential to reliably identify and hit targets in their true anatomical location over time. A newly described image correlation method (Internal Fusion) allows precise correlation of serial transrectal ultrasound (TRUS) images in vitro and vivo. Identifiable morphologic structures such as prostatic calcifications define internal anchor points (Internal Landmarks) to facilitate exact correlation. METHODS: After verification of Internal Fusion in vitro, 83 patients were included from January to August 2017 with at least one prior series of 5-mm spaced TRUS images stored as computed tomographic (US-CT) online data set. Two experienced operators collected new images in correlation with each cross-section of the previous examinations based on Internal Landmarks. RESULTS: Of the 83 patients, fifty (60%) had prior negative biopsies. Fourteen (17%) wished US-CT targeted biopsies and PCa were detected in 7/14 patients (50%). Overall, accurate imaging correlations were attained in 369/397 slices (93%). In initial and repeat biopsy, 31/31 and 35/35 images could be correlated detecting PCa in 5/8 (63%) and 2/6 patients (33%). The longest observation of prostate changes over time (Trend Monitoring) with accurate image correlation was 8 years and 6 months. CONCLUSIONS: Internal Fusion by Internal Landmarks ensures exact correlation in long-term follow-up. It is possible to precisely monitor trends in prostate tissue changes. In case of PCa suspicion, biopsies could be targeted with high accuracy by Internal Fusion, even over time. PMID- 29282496 TI - Management of complex polyps of the colon and rectum. AB - PUPRPOSE: Benign polyps that are technically challenging and unsafe to remove via polypectomy are known as complex polyps. Concerns regarding safety and completeness of resection dictate they undergo advanced endoscopic techniques, such as endoscopic mucosal resection or surgery. We provide a comprehensive overview of complex polyps and current treatment options. METHODS: A review of the English literature was conducted to identifyarticles describing the management of complex polyps of the colon and rectum. RESULTS: Endoscopic mucosal resection is the standard of care for the majority of complex polyps. Only polyps that fail endoscopic mucosal resection or are highly suspicious of invasive cancer but which cannot be removed endoscopically warrant surgery. CONCLUSION: Several factors influence the treatment of a complex polyp; therefore, there cannot be a "one-size-fitsall" approach. Treatment should be tailored to the lesion's characteristics, the risk of adverse events, and the resources available to the treating physician. PMID- 29282498 TI - Boronate affinity solid-phase extraction of cis-diol compounds by a one-step electrochemically synthesized selective polymer sorbent. AB - A rational-designed conductive sorbent, poly(thiophene-3-boronic acid) electrochemically deposited on a carbon fiber bundle, was applied for boronate affinity extraction. The coated carbon fiber bundle packed into a poly(ether ether ketone) tube was then successfully used for online solid-phase microextraction-high-performance liquid chromatography analysis of cis-diol compounds. Three kinds of catecholamines (namely, adrenaline, noradrenaline, and dopamine) were used as the test analytes. Good extraction efficiency (more than 600-fold), low limits of detection (0.2 ng.mL-1 for adrenaline, 0.1 ng.mL-1 for noradrenaline and dopamine), and wide linear ranges were obtained. The method was demonstrated to be efficient for analysis of catecholamines in spiked plasma samples, with good recoveries in the range of 92.5-95.71%. This work exhibited several significant advantages, including ease of use, high specificity, and high extraction efficiency. It has been demonstrated that such an electrochemically synthesized sorbent has great potential for research involving cis-diol compounds. Graphical abstract Electrochemical modification, packing of fiber bundles, and extraction mechanism. PEEK poly(ether ether ketone). PMID- 29282499 TI - Quantitative proteomic analysis of murine white adipose tissue for peritoneal cancer metastasis. AB - Cancer metastasis risk increases in older individuals, but the mechanisms for this risk increase are unclear. Many peritoneal cancers, including ovarian cancer, preferentially metastasize to peritoneal fat depots. However, there is a dearth of studies exploring aged peritoneal adipose tissue in the context of cancer. Because adipose tissue produces signals which influence several diseases including cancer, proteomics of adipose tissue in aged and young mice may provide insight into metastatic mechanisms. We analyzed mesenteric, omental, and uterine adipose tissue groups from the peritoneal cavities of young and aged C57BL/6J mouse cohorts with a low-fraction SDS-PAGE gelLC-MS/MS method. We identified 2308 protein groups and quantified 2167 groups, among which several protein groups showed twofold or greater abundance differences between the aged and young cohorts. Cancer-related gene products previously identified as significant in another age-related study were found altered in this study. Several gene products known to suppress proliferation and cellular invasion were found downregulated in the aged cohort, including R-Ras, Arid1a, and heat shock protein beta1. In addition, multiple protein groups were identified within single cohorts, including the proteins Cd11a, Stat3, and Ptk2b. These data suggest that adipose tissue is a strong candidate for analysis to identify possible contributors to cancer metastasis in older subjects. The results of this study, the first of its kind using uterine adipose tissue, contribute to the understanding of the role of adipose tissue in age-related alteration of oncogenic pathways, which may help elucidate the mechanisms of increased metastatic tumor burden in the aged. Graphical abstract We analyzed mesenteric, omental, and uterine adipose tissue groups from the peritoneal cavities of young and aged C57BL/6J mouse cohorts with a low-fraction SDS-PAGE gelLC-MS/MS method. These fat depots are preferential sites for many peritoneal cancers. The results of this study, the first of its kind using uterine adipose tissue, contribute to the understanding of the role of adipose tissue in age-related alteration of oncogenic pathways, which may help elucidate the mechanisms of increased metastatic tumor burden in the aged. PMID- 29282500 TI - Metabolism of a sea lamprey pesticide by fish liver enzymes part A: identification and synthesis of TFM metabolites. AB - The sea lamprey (Petromyzon marinus) is a destructive invasive species in the Great Lakes that contributed to the collapse of native fish populations in the mid-1900s. 3-Trifluoromethyl-4-nitrophenol (TFM) is a selective pesticide that has been applied to sea lamprey infested tributaries of the Great Lakes to kill larvae since the 1960s and has reduced the populations by as much as 90%. However, the metabolism of TFM by sea lamprey and non-target species is not fully illuminated. Elucidation of TFM metabolism is critical for understanding its mode of action and possible environmental impact. Here, we describe the screening, identification, synthesis and structural characterization of TFM metabolites in livers from sea lamprey and three non-target species that differ in their ability to survive TFM exposure. We identified glucuronidation, sulfation, N-acetylation, glutathione conjugation, and aromatic nitro group reduction as potential detoxification mechanisms. Seven metabolites were synthesized for use as markers of TFM metabolism in fish. Quantitative 1H NMR was used to assay synthesized metabolite stock solutions that were then used as standard material to develop a quantitative LC-MS/MS method for TFM metabolites. PMID- 29282501 TI - Confirmatory surface analysis of equivocal documents with pigment-based gel inks via laser desorption laser postionization mass spectrometry imaging. AB - Laser desorption laser postionization time-of-flight mass spectrometry (L2MS) was applied for unambiguous discrimination of pigment-based inks in blue, black, and red gel pens and molecular imaging of equivocal documents in a quasi-non destructive way. In comparison to laser desorption mass spectrometry (LD-MS), additional discriminatory information on ink components is acquired uniquely, facilitating the distinct differentiation of various pigmented gel inks. More importantly, diversified images of additional characteristic ions achieved using L2MS offer reliable support to discriminate forged documents and decipher important hidden contents. Apart from minimized matrix effect and maximized ionization yield, direct and confirmatory identification of forged documents is achieved successfully without solvent or matrix involved, not only eliminating unwanted damage and contamination to the samples but significantly shortening the overall analysis time. In addition, L2MS is a minimally destructive approach with tiny analyte consumption. With these appealing qualities, L2MS imaging is poised to be a powerful tool for confirmatory surface analysis of complex pigment-based samples. Graphical Abstract Weight and see: Highly distinct and comprehensive images of counterfeit documents with blue-pigmented gel inks are achieved successfully, due to the high sensitivity and increased ion yield of laser desorption laser postionization time-of-flight mass spectrometry. The hidden important contents of the obliterated documents are visually deciphered with the help of the additional chemical information. PMID- 29282502 TI - Autoinflammation in rheumatic and musculoskeletal disorders. PMID- 29282503 TI - A morphological comparison of the extraforaminal ligament between the cervical and thoracic regions. AB - PURPOSE: The current study was conducted to clarify the morphology of the extraforaminal ligament (EFL) at the cervicothoracic junction and to compare the attachment of the EFL and the positional relation between the EFL and the spinal nerves, additionally to clarify the details within the connecting bundles at the cervicothoracic junction. MATERIALS AND METHODS: The EFLs from the 4th cervical to the 4th thoracic vertebrae were dissected in 56 sides of 28 Japanese cadavers (11 males, 17 females). The range of age was 62.0-99.0 years. In addition, connecting bundles were analyzed by histological examination. RESULTS: Ventral to the spinal nerve, the capsulotransverse ligament (CTL), transforaminal ligament (TFL) and the ligament between the 7th cervical vertebra and the 1st rib were attached to the transverse process and rib. The EFL ventral to the 1st thoracic nerve was not observed in all sides. Dorsal to the spinal nerve, the anterior part of the superior costotransverse ligament (ASCL) and the ligament homologous to the ASCL were attached to the transverse process and rib. The superior radiating ligament (SRL) and the ligament homologous to the SRL were identified. The connecting bundles identified between the 7th cervical and the 1st thoracic nerve were histologically confirmed to consist of nerves and vessels. CONCLUSIONS: The EFLs at the cervicothoracic junction were found to be homologous. The connecting bundles were observed between the 7th cervical and the 1st thoracic nerve. Interestingly, the 1st thoracic level alone might be a unique level at the cervicothoracic junction. PMID- 29282504 TI - Bacteriophages as Biological Control Agents of Enteric Bacteria Contaminating Edible Oysters. AB - Bacterial contamination on seafood resulting from unhygienic food-handling practices causes foodborne diseases and significant revenue losses. Moreover, control measures are complicated by a high prevalence of antibiotic-resistant bacteria. Alternative measures such as the phage therapy, therefore, is considered as an environmental and consumer-friendly biological control strategy for controlling such bacterial contamination. In this study, we determined the effectiveness of a bacteriophage cocktail in controlling E. coli strains [JM 109, ATCC 13706 and the, extended spectrum beta-lactamase resistant strain (ATCC BAA 196)] and S. enterica subsp. enterica (ATCC 13311) as single and combined contaminants of the edible oysters. Five different E. coli-specific phages (belonging to the Siphoviridae family) and a Salmonella phage (belonging to the Tectiviridae family) were successfully isolated from sewage water samples taken from a local sewage treatment plan in the Sunshine Coast region of Australia. Phage treatments applied to the pathogens when they were presented on the oysters as either single or combined hosts, resulted in significant decrease of the number of these bacteria on edible oysters. Results obtained indicated that bacteriophages could have beneficial applications in oyster-processing plants in controlling pathogenic bacterial infestations. This study thus contributes towards ongoing international efforts into the effective use of bacteriophages for biological control purposes. PMID- 29282506 TI - The Use of a Pre-operative Carbohydrate Drink in Patients with Diabetes Mellitus: A Prospective, Non-inferiority, Cohort Study. AB - BACKGROUND: Pre-operative fasting leads to insulin resistance and increased metabolic stress in non-diabetic patients. Consumption of a carbohydrate drink may alleviate these deleterious effects. Patients with diabetes mellitus represent over 15% of the surgical population, yet concerns over hyperglycemia and aspiration have excluded patients with diabetes mellitus from studies assessing the utility of pre-operative carbohydrate drinks. OBJECTIVE: To assess for a clinically significant increase in pre-operative blood glucose concentration (defined as >2 mmol/L) in patients with diabetes consuming a pre operative carbohydrate drink. METHODS: A prospective observational non inferiority cohort study of 106 subjects with diabetes mellitus was undertaken to assess the effect of consuming a pre-operative carbohydrate drink in surgical patients. All patients with diabetes mellitus undergoing surgery (including but not limited to cardiac, neurologic, urologic, and general surgical procedures) were enrolled. Subjects were instructed to consume two carbohydrate-rich drinks, one before sleeping the evening prior to surgery and another on the day of surgery. RESULTS: In total, 43% of subjects were fully compliant with the pre operative carbohydrate drink regimen. There were no significant differences between the fully compliant and non-compliant subjects with respect to baseline characteristics. Consumption of a pre-operative carbohydrate drink was determined to be non-inferior to fasting in terms of pre-operative blood glucose concentration (absolute difference 0.23 mmol/L, 95% CI: -1.00 to 1.45 mmol/L, p non-inferiority < 0.01). Neither group was found to be superior in terms of pre operative blood glucose concentration, hyperglycemia, or length of stay. CONCLUSIONS: These findings function as a step toward ensuring pre-operative carbohydrate drinks are safe in patients with diabetes undergoing surgery. PMID- 29282505 TI - Impact of a Multidisciplinary Team Approach for Managing Advanced and Recurrent Colorectal Cancer. AB - BACKGROUND: The wide variety of treatment strategies makes clinical decision making difficult in advanced and recurrent colorectal cancer cases. Many hospitals have started multidisciplinary team (MDT) meetings comprising a team of dedicated specialists for discussing cases. MDTs for selected cases that are difficult to diagnose and treat are alternatives to regular MDTs. This study's aim was to determine the impact of a MDT for colorectal cancer on clinical decision-making. METHODS: Cases were discussed when clinical specialists had difficulty making decisions alone. All processes done by the MDT were then recorded in prospectively designed medical case forms. RESULTS: From Jan 2011 to Dec 2014, 1383 cases were discussed. A total of 549 (39.8%) case forms were completed for patients with newly diagnosed colorectal cancer, whereas 833 (60.2%) were completed for those with recurrent diseases. The MDT altered the proposed treatment of the referring physician in 179 (13%) cases. In 85 of the 179 (47.5%) altered cases, the radiologist's review of clinical information affected the diagnosis and decision. Furthermore, 152 of the 1383 MDT decisions were not implemented. Treatment intent, therapeutic plan, and alteration of decision were important reasons for not following the MDT's recommendation. CONCLUSION: Case discussions in MDT meetings resulted in altered clinical decisions in >10% cases. Implementation rates after MDT discussions might be affected by the treatment decision-making process. Imperfect decisions made by individual physicians can be decreased by the multidisciplinary decision-making process. PMID- 29282507 TI - Recovery of Voice After Reconstruction of the Recurrent Laryngeal Nerve and Adjuvant Nimodipine. AB - BACKGROUND: Transection injury to the recurrent laryngeal nerve (RLN) has been associated with permanent vocal fold palsy, and treatment has been limited to voice therapy or local treatment of vocal folds. Microsurgical repair has been reported to induce a better function. The calcium channel antagonist nimodipine improves functional recovery after experimental nerve injury and also after cranial nerve injury in patients. This study aims to present voice outcome in patients who underwent repair of the RLN and received nimodipine during regeneration. METHODS: From 2002-2016, 19 patients were admitted to our center with complete unilateral injury to the RLN and underwent microsurgical repair of the RLN. After nerve repair, patients received nimodipine for 2-3 months. Laryngoscopy was performed repeatedly up to 14 months postoperatively. The Voice Handicap Index (VHI) was administered, and patients' maximum phonation time (MPT) was recorded during the follow-up. RESULTS: All patients recovered well after surgery, and nimodipine was well tolerated with no dropouts. None of the patients suffered from atrophy of the vocal fold, and some patients even showed a small ab/adduction of the vocal fold on the repaired side with laryngoscopy. During long-term follow-up (>3 years), VHI and MPT normalized, indicating a nearly complete recovery from unilateral RLN injury. CONCLUSIONS: In this cohort study, we report the results of the first 19 consecutive cases at our center subjected to reconstruction of the RLN and adjuvant nimodipine treatment. The outcome of the current strategy is encouraging and should be considered after iatrogenic RLN transection injuries. PMID- 29282508 TI - A Nomogram to Predict Prognosis in Malignant Pleural Mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare malignancy with heterogeneous outcomes. This study was aimed to develop a nomogram to precisely and visually predict survival of MPM patients. METHODS: Data from Surveillance, Epidemiology, and End Results database (1973-2014) on MPM were screened and retrieved. The prognostic effects of variables, including age, sex, race, year of diagnosis, laterality, histology, tumor stage, surgery, chemotherapy, and radiotherapy were analyzed using Kaplan-Meier method and Cox proportional hazard model. A nomogram was formulated to predict overall survival of MPM patients. RESULTS: A total of 1092 cases who met inclusion criteria were included in this study. The overall 1-, 2-, and 3-year survival rate in the entire cohort was 45.1, 23.0, and 12.1%, with median survival of 11 months. Cox regression analysis showed that age (P < 0.001), race (P = 0.003), histology type (P < 0.001), T stage (P < 0.001), M stage (P < 0.001), TNM stage (P < 0.001), cancer-directed surgery (P < 0.001), and chemotherapy (P < 0.001) were all independent prognostic factors of MPM patients. A nomogram was established based on the results of multivariate analysis. The internal bootstrap resampling approach suggested the nomogram had sufficient discriminatory power with the C-index of 0.705 (95% CI 0.681-0.729). The calibration plots also demonstrated good consistence between the prediction and the observation. CONCLUSIONS: We developed a nomogram to accurately predict clinical outcomes of MPM patients based on individual characteristics. Risk stratification by the survival nomogram could optimize individual therapies and follow-up. PMID- 29282509 TI - Predicted Coronary Heart Disease Risk Decreases in Obese Patients After Laparoscopic Sleeve Gastrectomy. AB - PURPOSE: To assess the reduction of 6 and 12 months postoperatively of Framingham risk score in morbidly obese patients with laparoscopic sleeve gastrectomy (LSG). MATERIAL AND METHODS: In total, 870 morbid obesity patients received LSG in Taipei Medical University Hospital from June 2007 to June 2014 were retrospectively studied preoperatively, 6 and 12 months after surgery. The coronary heart disease risk was calculated using Framingham risk score. RESULTS: The body mass index in men and women decreased from 43.3 +/- 6.9, 39.2 +/- 6.0 kg/m2 preoperatively to 32.9 +/- 6.7, 31.0 +/- 5.2 kg/m2 and to 30.4 +/- 5.6 , 28.2 +/- 4.7 kg/m2, respectively, at 6 and 12 months after surgery (P < 0.0001). At 6 and 12 months after LSG, there was a marked improvement on lipid profile as well as a significant decline in the prevalence of diabetes mellitus, systemic hypertension, and smoking. The Framingham risk score in men and women reduced from 3.2 +/- 5.7, 6.1 +/- 5.7 preoperatively to 1.4 +/- 5.9, 3.3 +/- 5.9 and 0.1 +/- 6.2, 2.8 +/- 6.1, respectively, at 6 and 12 months after surgery (P < 0.0001). CONCLUSIONS: Laparoscopic sleeve gastrectomy is efficient not only in the reduction of obesity and its related comorbidities but also in decreasing the long-term coronary event risk. Early intervention for the high-risk group is strongly recommended. PMID- 29282510 TI - Changes in Clinical Practice Reduce the Rate of Anastomotic Leakage After Colorectal Resections. AB - BACKGROUND: Anastomotic leakage is a serious clinical problem after colorectal resections and is associated with a significantly increased length of stay, morbidity and mortality. The aim of the present study was to evaluate the effect of changes in clinical practice on anastomotic leakage rate after colorectal resections. METHODS: Retrospective cohort study based on prospectively collected data. All 894 patients with primary anastomosis after colorectal resection at a tertiary referral center between 2006 and 2013 were analyzed. Changes in clinical practice aiming at reducing the rate of anastomotic leakages were introduced in January 2010 and were characterized by exclusion of perioperative nonsteroidal anti-inflammatory drugs, introduction of intra-operative goal-directed fluid therapy and avoidance of primary anastomoses in emergency resections. The study population was divided into two groups, one treated before and one after the introduction of changes in clinical practice. Groups were compared regarding patient characteristics and incidence of anastomotic leakage. RESULTS: The cumulative incidence of anastomotic leakage after colorectal resections decreased from 10.0% (41 of 409) to 4.5% (22 of 485) after changing clinical practice, relative risk 0.45 (95% CI 0.27-0.75, p = 0.002). The adjusted odds ratio was 0.45 (0.26-0.78, p = 0.004). A separate analysis showed a decrease after colon resections from 9.1% (23 of 252) to 4.5% (14 of 310), relative risk 0.49 (0.26 0.94, p = 0.039), and from 11.5% (18 of 157) to 4.6% (8 of 175) after rectal resections, relative risk 0.40 (0.18-0.89, p = 0.024). CONCLUSION: Implementing a structured change of clinical practice can significantly reduce the anastomotic leakage rate after colorectal resections. TRIAL REGISTRATION: Clinical trial registration number: ACTRN12617001497392. PMID- 29282511 TI - Locoregional Tumor Extension and Preoperative Smoking are Significant Risk Factors for Early Recurrence After Esophagectomy for Cancer. AB - BACKGROUND: Tumor recurrence during the first year after oncological esophagectomy has been reported in up to 17-66% of patients. However, little is known as to the risk factors potentially associated with this adverse outcome. The aim of this retrospective observational study was to identify clinically relevant parameters associated with early recurrence. METHODS: All patients with squamous cell cancer or adenocarcinoma of the esophagus or gastroesophageal junction, operated with curative intent in our center from 2000 to 2014, were screened for this study. Univariate analysis was conducted to identify variables potentially associated with early recurrence, and clinically relevant parameters with P < 0.1 were included in multiple logistic regression. Survival analyses were conducted with the Kaplan-Meier method. Significance threshold was set at P < 0.05. RESULTS: Among the 164 included patients, 46 (28%) presented early recurrence. Eight patients (17.4%) had locoregional and 38 patients (82.6%) metastatic recurrence. Advanced T and N stages, lymph node capsular effraction, a high positive-to-resected lymph node ratio, positive resection margins, poor response to neoadjuvant treatment, preoperative active smoking, malnutrition and dysphagia were associated with early recurrence on a univariate level. In multivariable analysis, preoperative smoking (OR 2.76, 95% CI 1.28-6.17), pT stage (OR 1.72, 95% CI 1.18-2.58) and an increased positive-to-resected lymph node ratio (OR 6.72, 95% CI 1.08-48.51) remained independently associated with ER. CONCLUSION: Our study identified both patient- and tumor-related parameters as risk factors for early recurrence after oncological esophagectomy. Of particular interest, active smoking was significantly associated with this adverse outcome, highlighting the importance of preoperative smoking cessation. PMID- 29282512 TI - 14-French Pigtail Catheters for Traumatic Hemothorax/Hemopneumothorax: Size Does Not Matter. PMID- 29282514 TI - Measuring Outcomes of Clinical Care: Victorian Emergency Laparotomy Audit Using Quality Investigator. AB - BACKGROUND: The Australian and New Zealand Audit of Surgical Mortality (ANZASM) National Report 2015 found that within the cohort of audited deaths, 85% were emergencies with acute life-threatening conditions, and by far, the most common procedures were laparotomy and colorectal procedures. Emergency laparotomy outcomes have shown improvement through audit and reporting in the UK. The purpose of this study was to determine the outcome of emergency laparotomy in the state of Victoria, Australia. METHOD: The Dr Foster Quality Investigator (DFQI) database was interrogated for a set of Australian Classification of Health Intervention (ACHI) codes defined by the authors as representing an emergency laparotomy. The dataset included patients who underwent emergency laparotomy from July 2007 to July 2016 in all Victorian hospitals. RESULTS: There were 23,115 emergency laparotomies conducted over 9 years in 66 hospitals. Inpatient mortality was 2036/23,115 (8.8%). Mortality in the adult population increased with age and reached 18.1% in those patients that were 80 years or older. 51.3% were females, and there was no significant difference in survival between genders. Patients with no recorded comorbidities had a mortality of 4.3%, whereas those with > 5 comorbidities had 19.3% mortality. CONCLUSION: Administrative data accessed via a tool such as DFQI can provide useful population data to guide further evidence-based improvement strategies. The mortality for emergency laparotomy within Victorian hospitals is comparable, if not better than that seen in overseas studies. There is a need to continue routine audit of mortality rates and implement systems improvement where necessary. PMID- 29282513 TI - International Study of the Epidemiology of Paediatric Trauma: PAPSA Research Study. AB - OBJECTIVES: Trauma is a significant cause of morbidity and mortality worldwide. The literature on paediatric trauma epidemiology in low- and middle-income countries (LMICs) is limited. This study aims to gather epidemiological data on paediatric trauma. METHODS: This is a multicentre prospective cohort study of paediatric trauma admissions, over 1 month, from 15 paediatric surgery centres in 11 countries. Epidemiology, mechanism of injury, injuries sustained, management, morbidity and mortality data were recorded. Statistical analysis compared LMICs and high-income countries (HICs). RESULTS: There were 1377 paediatric trauma admissions over 31 days; 1295 admissions across ten LMIC centres and 84 admissions across five HIC centres. Median number of admissions per centre was 15 in HICs and 43 in LMICs. Mean age was 7 years, and 62% were boys. Common mechanisms included road traffic accidents (41%), falls (41%) and interpersonal violence (11%). Frequent injuries were lacerations, fractures, head injuries and burns. Intra-abdominal and intra-thoracic injuries accounted for 3 and 2% of injuries. The mechanisms and injuries sustained differed significantly between HICs and LMICs. Median length of stay was 1 day and 19% required an operative intervention; this did not differ significantly between HICs and LMICs. No mortality and morbidity was reported from HICs. In LMICs, in-hospital morbidity was 4.0% and mortality was 0.8%. CONCLUSION: The spectrum of paediatric trauma varies significantly, with different injury mechanisms and patterns in LMICs. Healthcare structure, access to paediatric surgery and trauma prevention strategies may account for these differences. Trauma registries are needed in LMICs for future research and to inform local policy. PMID- 29282515 TI - Impact of the Weekday of Surgery on Outcome in Gastric Cancer Patients who Underwent D2-Gastrectomy. AB - BACKGROUND: The impact of the weekday of surgery in major elective cases of the upper-GI has been discussed controversially. The objective of this study was to assess whether weekday of surgery influences outcome in patients undergoing D2 gastrectomy. MATERIALS AND METHODS: Patients who underwent D2-gastrectomy for gastric adenocarcinoma between 1996 and 2016 were included. Weekday of surgery was recognized, and subgroups were analyzed regarding clinical and histopathological differences. Survival analysis was performed based on weekday of surgery, and early weekdays (Monday-Tuesday) were compared with late weekdays (Wednesday-Friday). RESULTS: In total, 460 patients, 71% male and 29% female, were included into analysis. The median age was 65 years. Distribution to each weekday was equal and ranged from 86 cases (Wednesday) to 96 cases (Tuesday). The pT, pN and M category and the rate of patients who underwent neoadjuvant treatment did not show significant differences (p = 0.641; p = 0.337; p = 0.752; p = 0.342, respectively). The subgroups did not differ regarding the number of dissected lymph nodes and rate of R-1/2 resections (p = 0.590; p = 0.241, respectively). Survival analysis showed a median survival of 43 months (95% CI 31 55 months), and there was no single weekday or a combination of weekdays (Mon/Tue vs Wed/Thu/Fri) with a significant favorable or worse outcome (p = 0.863; p = 0.30, respectively). The outcome did not differ regarding mortality within the first 90 days after surgery (p = 0.948). CONCLUSIONS: The present study does not show any evidence for a significant impact of weekday of surgery on short- and long-term outcome of patients undergoing gastrectomy for gastric adenocarcinoma. PMID- 29282516 TI - The morbidity of sexual dysfunction of 125 Chinese women following different types of radical hysterectomy for gynaecological malignancies. AB - PURPOSE: Due to early detection and effective treatment, quality of sexual life of patients with gynaecological malignancies has become an important issue. However, the morbidity of sexual dysfunction and the proportion of different kinds of sexual dysfunction after radical hysterectomy are unclear. The aim of the current study was to assess the morbidity of sexual dysfunction and to conduct multivariate logistic regression analysis of patients' sexual dysfunction. METHODS: Between July 2007 and December 2012, 125 women underwent radical hysterectomy, modified radical hysterectomy, and nerve-sparing radical hysterectomy were administered a self-reported sexual function questionnaire. RESULTS: The preoperative, and 1- and 2-year postoperative sexual dysfunction rates were 50.5% (50/99), 86.9% (93/107), and 92.3% (72/78), respectively. The incidence rates of sexual desire disorders before operation, at postoperative year 1, and at postoperative year 2 were 14.7% (14/95), 42.1% (45/107), and 51.9% (40/77), respectively. The preoperative incidence rates of sexual arousal disorders, orgasmic disorders, and sexual pain disorders were 18.4% (18/98), 51.1% (48/94), and 10.9% (11/101), respectively. At postoperative years 1 and 2, these were 38.8% (31/80), 81.0% (64/79), and 24.4% (20/82), and 49.1% (26/53), 84.6% (44/52), and 30.2% (16/53), respectively. Multivariable regression analysis revealed that age, preserved ovary, preserved posterior vaginal wall length, preoperative stage, radiotherapy, and education background were risk factors associated with sexual dysfunction. CONCLUSION: The patients following radical hysterectomy had a high incidence of sexual dysfunction, which plateaued in postoperative years 1 and 2. PMID- 29282517 TI - 11C-MET PET/MRI for detection of recurrent glioma. AB - INTRODUCTION: Radiological assessment of brain tumors is widely based on the Radiology Assessment of Neuro-Oncology (RANO) criteria that consider non-specific T1 and T2 weighted images. Limitation of the RANO criteria is that they do not include metabolic imaging techniques that have been reported to be helpful to differentiate treatment related changes from true tumor progression. In the current study, we assessed if the combined use of MRI and PET with hybrid 11C-MET PET/MRI can improve diagnostic accuracy and diagnostic confidence of the readers to differentiate treatment related changes from true progression in recurrent glioma. METHODS: Fifty consecutive patients with histopathologically proven glioma were prospectively enrolled for a hybrid 11C-MET PET/MRI to differentiate recurrent glioma from treatment induced changes. Sole MRI data were analyzed based on RANO. Sole PET data and in a third evaluation hybrid 11C-MET-PET/MRI data were assessed for metabolic respectively metabolic and morphologic glioma recurrence. Diagnostic performance and diagnostic confidence of the reader were calculated for the different modalities, and the McNemar test and Mann-Whitney U Test were applied for statistical analysis. RESULTS: Hybrid 11C-MET PET/MRI was successfully performed in all 50 patients. Glioma recurrence was diagnosed in 35 of the 50 patients (70%). Sensitivity and specificity were calculated for MRI (86.11% and 71.43%), for 11C-MET PET (96.77% and 73.68%), and for hybrid 11C-MET PET/MRI (97.14% and 93.33%). For diagnostic accuracy hybrid 11C-MET-PET/MRI (96%) showed significantly higher values than MRI alone (82%), whereas no significant difference was found for 11C-MET PET (88%). Furthermore, by rating on a five point Likert scale significantly higher scores were found for diagnostic confidence when comparing 11C-MET PET/MRI (4.26 +/- 0,777) to either PET alone (3.44 +/- 0.705) or MRI alone (3.56 +/- 0.733). CONCLUSION: This feasibility study showed that hybrid PET/MRI might strengthen RANO classification by adding metabolic information to conventional MRI information. Future studies should evaluate the clinical utility of the combined use of 11C-MET PET/MRI in larger patient cohorts. PMID- 29282519 TI - Individual- and Species-Specific Skin Microbiomes in Three Different Estrildid Finch Species Revealed by 16S Amplicon Sequencing. AB - An animals' body is densely populated with bacteria. Although a large number of investigations on physiological microbial colonisation have emerged in recent years, our understanding of the composition, ecology and function of the microbiota remains incomplete. Here, we investigated whether songbirds have an individual-specific skin microbiome that is similar across different body regions. We collected skin microbe samples from three different bird species (Taeniopygia gutatta, Lonchura striata domestica and Stagonopleura gutatta) at two body locations (neck region, preen gland area). To characterise the skin microbes and compare the bacterial composition, we used high-throughput 16S rRNA amplicon sequencing. This method proved suitable for identifying the skin microbiome of birds, even though the bacterial load on the skin appeared to be relatively low. We found that across all species, the two evaluated skin areas of each individual harboured very similar microbial communities, indicative of an individual-specific skin microbiome. Despite experiencing the same environmental conditions and consuming the same diet, significant differences in the skin microbe composition were identified among the three species. The bird species differed both quantitatively and qualitatively regarding the observed bacterial taxa. Although each species harboured its own unique set of skin microbes, we identified a core skin microbiome among the studied species. As microbes are known to influence the host's body odour, our findings of an individual-specific skin microbiome might suggest that the skin microbiome in birds is involved in the odour production and could encode information on the host's genotype. PMID- 29282518 TI - Current status of theranostics in prostate cancer. AB - The aim of this review is to report on the current status of prostate-specific membrane antigen (PSMA)-directed theranostics in prostate cancer (PC) patients. The value of 68Ga-PSMA-directed PET imaging as a diagnostic procedure for primary and recurrent PC as well as the role of evolving PSMA radioligand therapy (PRLT) in castration-resistant (CR)PC is assessed. The most eminent data from mostly retrospective studies currently available on theranostics of prostate cancer are discussed. The current knowledge on 68Ga-PSMA PET/CT implicates that primary staging with PET/CT is meaningful in patients with high-risk PC and that the combination with pelvic multi parametric (mp)MR (or PET/mpMR) reaches the highest impact on patient management. There may be a place for 68Ga-PSMA PET/CT in intermediate-risk PC patients as well, however, only a few data are available at the moment. In secondary staging for local recurrence, 68Ga-PSMA PET/mpMR is superior to PET/CT, whereas for distant recurrence, PET/CT has equivalent results and is faster and cheaper compared to PET/mpMR. 68Ga-PSMA PET/CT is superior to 18F / 11Choline PET/CT in primary staging as well as in secondary staging. In patients with biochemical relapse, PET/CT positivity is directly associated with prostate-specific antigen (PSA) increase and amounts to roughly 50% when PSA is raised to <=0.5 ng/ml and to >=90% above 1 ng/ml. Significant clinical results have so far been achieved with the subsequent use of radiolabeled PSMA ligands in the treatment of CRPC. Accumulated activities of 30 to 50 GBq of 177Lu-PSMA ligands seem to be clinically safe with biochemical response and PERCIST/RECIST response in around 75% of patients along with xerostomia in 5-10% of patients as the only notable side effect. On the basis of the current literature, we conclude that PSMA-directed theranostics do have a major clinical impact in diagnosis and therapy of PC patients. We recommend that 68Ga-PSMA PET/CT should be performed in primary staging together with pelvic mpMR in high-risk patients and in all patients for secondary staging, and that PSMA-directed therapy is a potent strategy in CRPC patients when other treatment options have failed. The combination of PSMA-directed therapy with existing therapy modalities (such as 223Ra-chloride or androgen deprivation therapy) has to be explored, and prospective clinical multicenter trials with theranostics are warranted. PMID- 29282520 TI - TGFbeta counteracts LYVE-1-mediated induction of lymphangiogenesis by small hyaluronan oligosaccharides. AB - During tissue injury, inflammation, and tumor growth, enhanced production and degradation of the extracellular matrix glycosaminoglycan hyaluronan (HA) can lead to the accumulation of small HA (sHA) oligosaccharides. We have previously reported that accumulation of sHA in colorectal tumors correlates with lymphatic invasion and lymph node metastasis, and therefore, investigated here are the effects of sHA on the lymphatic endothelium. Using cultured primary lymphatic endothelial cells (LECs) and ex vivo and in vivo lymphangiogenesis assays, we found that in contrast to high-molecular-weight HA (HMW-HA), sHA of 4-25 disaccharides in length can promote the proliferation of LECs and lymphangiogenesis in a manner that is dependent on their size and concentration. At pathophysiologically relevant concentrations found in tumor interstitial fluid, sHA is pro-proliferative, acts synergistically with VEGF-C and FGF-2, and stimulates the outgrowth of lymphatic capillaries in ex vivo lymphangiogenesis assays. In vivo, intradermally injected sHA acts together with VEGF-C to increase lymphatic vessel density. Higher concentrations of sHA were found to induce expression of the anti-lymphangiogenic cytokine TGFbeta in LECs, which serves to counter-regulate sHA-induced LEC proliferation and lymphangiogenesis. Using appropriate knockout mice and blocking antibodies, we found that the effects of sHA are mediated by the sialylated form of the lymphatic HA receptor LYVE-1, but not by CD44 or TLR-4. These data are consistent with the notion that accumulation of sHA in tumors may contribute to tumor-induced lymphangiogenesis, leading to increased dissemination to regional lymph nodes. KEY MESSAGES : sHA promotes lymphangiogenesis primarily through increased LEC proliferation sHA induces proliferation in a narrow concentration window due to upregulated TGFbeta Smaller HA oligosaccharides more potently induce proliferation than larger ones VEGF-C and FGF-2-induced LEC proliferation and lymphangiogenesis is augmented by sHA Sialylated LYVE-1, but not CD44 or TLR-4, mediate the effects of sHA on LEC. PMID- 29282521 TI - Engineered exosomes emerging from muscle cells break immune tolerance to HER2 in transgenic mice and induce antigen-specific CTLs upon challenge by human dendritic cells. AB - : We recently described a novel biotechnological platform for the production of unrestricted cytotoxic T lymphocyte (CTL) vaccines. It relies on in vivo engineering of exosomes, i.e., nanovesicles constitutively released by all cells, with full-length antigens of choice upon fusion with an exosome-anchoring protein referred to as Nefmut. They are produced upon intramuscular injection of a DNA vector and, when uploaded with a viral tumor antigen, were found to elicit an immune response inhibiting the tumor growth in a model of transplantable tumors. However, for a possible application in cancer immunotherapy, a number of key issues remained unmet. Among these, we investigated: (i) whether the immunogenic stimulus induced by the engineered exosomes can break immune tolerance, and (ii) their effectiveness when applied in human system. As a model of immune tolerance, we considered mice transgenic for the expression of activated rat HER2/neu which spontaneously develop adenocarcinomas in all mammary glands. When these mice were injected with a DNA vector expressing the product of fusion between Nefmut and the extracellular domain of HER2/neu, antigen-specific CD8+ T lymphocytes became readily detectable. This immune response associated with a HER2-directed CTL activity and a significant delay in tumor development. On the other hand, through cross-priming experiments, we demonstrated the effectiveness of the engineered exosomes emerging from transfected human primary muscle cells in inducing antigen specific CTLs. We propose our CTL vaccine platform as part of new immunotherapy strategies against tumors expressing self-antigens, i.e., products highly expressed in oncologic lesions but tolerated by the immune system. KEY MESSAGES: We established a novel, exosome-based method to produce unrestricted CTL vaccines. This strategy is effective in breaking the tolerance towards tumor self antigens. Our method is also useful to elicit antigen-specific CTL immunity in humans. These findings open the way towards the use of this antitumor strategy in clinic. PMID- 29282522 TI - The incidence of malignancy in clinically benign cystic lesions of the lateral neck: our experience and proposed diagnostic algorithm. AB - AIM: Solitary cystic masses of the lateral neck in an adult patient can pose a diagnostic dilemma. Malignancy must be ruled out since metastases arising from H&N cancers may mimic the presentation of benign cystic masses. Only a small number of studies have investigated the diagnostic management and malignancy rate of clinically benign solitary cervical cystic lesions. There are no established guidelines for the diagnostic evaluation. METHODS: Retrospective review of the clinical, cytological, radiological, and pathological records of all adult patients (> 18 years) operated on for second branchial cleft cysts (BrCC) between 1/2008-2010/2016. Patients with apparent primary H&N malignancy, history of H&N cancer or irradiation, preoperative fine needle aspiration (FNA) of highly suggestive or confirmed malignancy, missing pertinent data, or age less than 18 years were excluded from analysis. RESULTS: 28 patients were diagnosed as having BrCC. The diagnosis was based on clinical findings, FNA cytology, and typical sonographic features. The histologic analysis determined an overall rate of malignancy of 10.7% (3/28): two patients had metastatic papillary thyroid carcinoma, and one patient had metastatic tonsillar squamous cell carcinoma. Purely cystic features on pre-operative ultrasound was the only significant predictor for true BrCC on final histology (p = .02). CONCLUSIONS: Occult malignancy is not rare among adult patients presenting with a solitary cystic mass of the lateral neck. A diagnostic algorithm is proposed. Further studies are needed to establish the appropriate workup and management of an adult patient presenting with a solitary cystic mass of the lateral neck. PMID- 29282523 TI - Amiodarone-associated bilateral vestibulopathy. AB - BACKGROUND: Bilateral vestibulopathy (BVP) is a debilitating disorder characterized by the hypofunction of both vestibular end organs or nerves. The most frequent identifiable causes of BVP are ototoxic drug effects, infectious and autoimmune disorders. The majority of cases, however, remain idiopathic. METHODS: Medical records of patients diagnosed with idiopathic BVP were examined in five dizziness clinics. RESULTS: We identified 126 patients with "idiopathic" BVP. Out of these, 15 patients had a history of Amiodarone treatment before the diagnosis of BVP, resulting in a 12% prevalence. CONCLUSION: The present report supports the hypothesis that Amiodarone can cause BVP. Vestibular examination in patients taking Amiodarone and suffering from balance-related symptoms are recommended, to recognize this adverse effect as early as possible and allow for an informed judgement on a potential dose reduction or withdrawal for recovery of the vestibular function. PMID- 29282524 TI - Perilunate fracture-dislocations: clinical and radiological results of 21 cases. AB - BACKGROUND: Perilunate dislocations and fracture-dislocations are a subcategory of the carpal instability complex. Herein, we report our university hospital experience with this complex injury. The goal of our study was to find predictive factors and quantify the development of arthritis and lunate necrosis. We tried to measure the impact of arthritis on hand function. METHODS: Between January 2000 and December 2014, 21 patients underwent surgery for perilunate dislocations and perilunate fracture-dislocations of the wrist in our tertiary university center. Mean patient age was 29.3 +/- 10.0 years (range 18-49 years). All displacements were posterior. They were reviewed both clinically and radiologically. RESULTS: Complications included misdiagnosed Essex-Lopresti-like lesion in one case, insufficient reposition of the carpus in two cases (LT in one case, SL in one case), and iatrogenic injury to the radial artery immediately sutured in one case. All 3 cases underwent a second procedure with satisfactory outcome. After a mean follow-up of 112 +/- 60 months (range 12-210 months), the average Cooney score was 80 +/- 19 (range 50-125). The mean PRWE score was 10 +/- 8 (range 0-25). The mean DASH score was 40 +/- 13 (range 30-75 months). Mean pain on load, measured with VAS was 1.1 +/- 1.6; Clinical examination assessed a mean wrist extension/flexion of 42.4 degrees +/- 17.2 degrees /48.4 degrees +/- 15.2 degrees . Mean wrist ulnar/radial deviation was, respectively, 22.9 degrees +/- 11.3 degrees /15.3 degrees +/- 7.0 degrees . Mean pro/supination was, respectively, 75.2 degrees +/- 11.5 degrees /76.3 degrees +/- 8.1 degrees . Mean pinch strength was 9.4 +/- 2.2 kg (87.4 +/- 17.7% of the contralateral side). Mean power strength was 41.9 +/- 9.9 kg (76.2 +/- 19.2% of the contralateral side). Two patients had a scaphoid non-union identified on their most recent imaging. The mean carpal height ratio was 0.53 +/- 0.05 (range 0.44 0.65). All except one patient developed arthritis: Grade 1 in 11 patients, Grade 2 in 3 patients, and Grade 3 in the remaining 6 patients. Age, length of follow up, and loss of reduction were significantly associated with wrist arthritis (p < 0.001). Lunate avascular necrosis assessed by magnetic resonance imaging was present in 6 patients: Stage 2 in 4 patients, Stage 3a in 1 patient, and Stage 3b in the remaining patient. All these patients' intraoperative findings showed lesion of the cartilage of the radial side of the lunate. However, the small number of patients who developed lunate necrosis did not allow satisfactory statistical analysis. CONCLUSIONS: This retrospective study demonstrates good functional results despite the high rate of radiological wrist arthritis. Age, length of follow-up, and loss of reduction were significantly associated with wrist arthritis in our series. PMID- 29282525 TI - Long-term outcome of pigmented villonodular synovitis of the hip after joint preserving therapy. AB - INTRODUCTION: Pigmented villonodular synovitis (PVNS) is a rare, destructive synovial disease that affects the hip joint the second most common after the knee. However, in contrast, joint preserving surgery in the hip joint is considered to be significantly more difficult or even impossible due to earlier occurrence of osteochondral dissemination and surgical difficulties. Today, earlier diagnosis due to the generous use of MRI and modern surgical strategies raise hope for improved outcomes. METHODS: Since 2005, six patients with PVNS of the hip and a minimal follow-up of 2 years underwent joint preserving surgery in our institution (mean age 20.5 years, range 14-27). After PVNS was suspected in the MRI and confirmed by arthroscopic biopsy (four diffuse, two focal forms), synovectomy was carried out in 5 patients via surgical hip dislocation and in one focal case via arthroscopy. In diffuse forms, adjuvant radiosynoviorthesis (RSO) was conducted 6-8 week postoperatively. MRI and clinical examinations were performed during follow-up. RESULTS: After a mean follow-up of 8 years (range 35 141 months), five of six patients did not show recurrence or secondary osteoarthritis. Clinical outcome evaluation resulted in a mean modified Harris Hip Score of 91 points (range 67-100 points). A 21-year-old patient with a diffuse form and advanced osteochondral involvement at the time of diagnosis was eventually treated by total hip arthroplasty. CONCLUSION: In cases without osteochondral involvement, recurrence-free long-term results without progression of joint degeneration can be achieved by joint preserving therapy. PMID- 29282526 TI - Triplex real-time PCR for detection of Crithidia mellificae and Lotmaria passim in honey bees. AB - Currently, light microscopic examination of cell morphology cannot discriminate Crithidia mellificae and Lotmaria passim with 100% certainty. Here, a minor groove-binding (MGB) probe-based multiplex real-time PCR assay was developed for the simultaneous and quantitative detection of C. mellificae and L. passim in honey bees. A conserved Hymenoptera 18S rRNA gene was built in as an internal control that allows accurate detection of PCR inhibition and failure of DNA extraction. The newly developed assay was also applied to field samples. Of 21 honey bee colonies (446 bees) sampled from six counties in both central and eastern Massachusetts, 3 colonies (14.29%) and 8 bees (1.79%) were infected with L. passim, and 1 colony (4.76%) and 1 bee (0.22%) with C. mellificae. Our data showed a low rate of trypanosomatid infection, and L. passim was more prevalent than C. mellificae in honey bee samples in Massachusetts. PMID- 29282527 TI - Prevalence and diversity of avian Haemosporida infecting songbirds in southwest Michigan. AB - Avian blood parasites from the genera Plasmodium, Haemoproteus, and Leucocytozoon (Haemosporida) affect hosts in numerous ways. They influence species interactions, host behavior, reproductive success, and cause pathology and mortality in birds. The Great Lakes region of North America has extensive aquatic and wetland habitat and supports a diverse vector community. Here we describe the community of bird-infecting Haemosporida in southwest Michigan and their host associations by measuring parasite prevalence, diversity, and host breadth across a diverse community of avian hosts. Over 700 songbirds of 55 species were screened for Haemosporida infection across southwest Michigan, including 11 species that were targeted for larger sample sizes. In total, 71 parasite lineages infected over 40% of birds. Of these, 42 were novel, yet richness estimates suggest that approximately half of the actual parasite diversity in the host community was observed despite intensive sampling of multiple host species. Parasite prevalence varied among parasite genera (7-24%) and target host species (0-85%), and parasite diversity was consistently high across most target species. Host breadth varied widely across the most prevalent parasite lineages, and we detected around 60% of host species richness for these parasite lineages. We report many new lineages and novel host-parasite associations, but substantial parasite diversity remains undiscovered in the Midwest. PMID- 29282528 TI - Surgical treatment of a gauzoma with associated obliterative arteriopathy and review of the literature. AB - We report a case of a 50-year-old woman whose 0.5 mm middle cerebral artery (MCA) aneurysm was treated with gauze wrapping at an outside facility. She returned 9 months later with seizures and an inflammatory process in the region of the prior aneurysm. Surgical re-exploration at that time was aborted. Two years later, she presented with a gauzoma associated with local inflammatory response and severe narrowing of the MCA. A common carotid artery to MCA bypass was performed, followed by surgical removal of the gauze and inflammatory material. Over a 3 month period, she recovered with significant improvement in her preoperative neurological deficits. PMID- 29282531 TI - Kir2.1 channels set two levels of resting membrane potential with inward rectification. AB - Strong inward rectifier K+ channels (Kir2.1) mediate background K+ currents primarily responsible for maintenance of resting membrane potential. Multiple types of cells exhibit two levels of resting membrane potential. Kir2.1 and K2P1 currents counterbalance, partially accounting for the phenomenon of human cardiomyocytes in subphysiological extracellular K+ concentrations or pathological hypokalemic conditions. The mechanism of how Kir2.1 channels contribute to the two levels of resting membrane potential in different types of cells is not well understood. Here we test the hypothesis that Kir2.1 channels set two levels of resting membrane potential with inward rectification. Under hypokalemic conditions, Kir2.1 currents counterbalance HCN2 or HCN4 cation currents in CHO cells that heterologously express both channels, generating N shaped current-voltage relationships that cross the voltage axis three times and reconstituting two levels of resting membrane potential. Blockade of HCN channels eliminated the phenomenon in K2P1-deficient Kir2.1-expressing human cardiomyocytes derived from induced pluripotent stem cells or CHO cells expressing both Kir2.1 and HCN2 channels. Weakly inward rectifier Kir4.1 or inward rectification-deficient Kir2.1*E224G mutant channels do not set such two levels of resting membrane potential when co-expressed with HCN2 channels in CHO cells or when overexpressed in human cardiomyocytes derived from induced pluripotent stem cells. These findings demonstrate a common mechanism that Kir2.1 channels set two levels of resting membrane potential with inward rectification by balancing inward currents through different cation channels such as hyperpolarization-activated HCN channels or hypokalemia-induced K2P1 leak channels. PMID- 29282532 TI - Remediating Contaminant Plumes in Groundwater with Shallow Excavations Containing Coarse Reactive Media. AB - A groundwater flow and mass transport model tested the capability of shallow excavations filled with coarse, reactive media to remediate a hypothetical unconfined aquifer with a maximum saturated thickness of 5 m. Modeled as contaminant sinks, the rectangular excavations were 10 m downgradient of an initial contaminant plume originating from a source at the top of the aquifer. The initial plume was approximately 259 m long, 23 m wide, and 5 m thick, with a downgradient tip located approximately 100 m upgradient of the site boundary. The smallest trench capable of preventing offsite migration was 11 m long (measured perpendicular to groundwater flow), 4 m wide (measured parallel to groundwater flow), and 3 m deep. Results of this study suggest that shallow trenches filled with coarse filter media that partially penetrate unconfined aquifers may be a viable alternative for remediating contaminated groundwater at some sites. PMID- 29282529 TI - The development of skeletal muscle hypertrophy through resistance training: the role of muscle damage and muscle protein synthesis. AB - Resistance training (RT)-induced skeletal muscle hypertrophy is a highly intricate process. Despite substantial advances, we are far from understanding exactly how muscle hypertrophy develops during RT. The aim of the present review is to discuss new insights related to the role of skeletal muscle damage and muscle protein synthesis (MPS) in mediating RT-induced hypertrophy. Specifically, the thesis that in the early phase of RT (<= 4 previous RT sessions) increases in muscle cross-sectional area are mostly attributable to muscle damage-induced muscle swelling; then (after ~ 10 sessions), a modest magnitude of muscle hypertrophy ensues; but only during a latter phase of RT (after ~ 18 sessions) is true muscle hypertrophy observed. We argue that the initial increases in MPS post RT are likely directed to muscle repair and remodelling due to damage, and do not correlate with eventual muscle hypertrophy induced by several RT weeks. Increases in MPS post-RT session only contribute to muscle hypertrophy after a progressive attenuation of muscle damage, and even more significantly when damage is minimal. Furthermore, RT protocols that do not promote significant muscle damage still induce similar muscle hypertrophy and strength gains compared to conditions that do promote initial muscle damage. Thus, we conclude that muscle damage is not the process that mediates or potentiates RT-induced muscle hypertrophy. PMID- 29282530 TI - Determinants, analysis and interpretation of the muscle compound action potential (M wave) in humans: implications for the study of muscle fatigue. AB - The compound muscle action potential (M wave) has been commonly used to assess the peripheral properties of the neuromuscular system. More specifically, changes in the M-wave features are used to examine alterations in neuromuscular propagation that can occur during fatiguing contractions. The utility of the M wave is based on the assumption that impaired neuromuscular propagation results in a decrease in M-wave size. However, there remains controversy on whether the size of the M wave is increased or decreased during and/or after high-intensity exercise. The controversy partly arises from the fact that previous authors have considered the M wave as a whole, i.e., without analyzing separately its first and second phases. However, in a series of studies we have demonstrated that the first and second phases of the M wave behave in a different manner during and after fatiguing contractions. The present review is aimed at five main objectives: (1) to describe the mechanistic factors that determine the M-wave shape; (2) to analyze the various factors influencing M-wave properties; (3) to emphasize the need to analyze separately the first and second M-wave phases to adequately identify and interpret changes in muscle fiber membrane properties; (4) to advance the hypothesis that it is an increase (and not a decrease) of the M-wave first phase which reflects impaired sarcolemmal membrane excitability; and (5) to revisit the involvement of impaired sarcolemmal membrane excitability in the reduction of the force generating capacity. PMID- 29282533 TI - Modeling of Electric Demand for Sustainable Energy and Management in India Using Spatio-Temporal DMSP-OLS Night-Time Data. AB - Changes in the pattern of electric power consumption in India have influenced energy utilization processes and socio-economic development to greater extent during the last few decades. Assessment of spatial distribution of electricity consumption is, thus, essential for projecting availability of energy resource and planning its infrastructure. This paper makes an attempt to model the future electricity demand for sustainable energy and its management in India. The nighttime light database provides a good approximation of availability of energy. We utilized defense meteorological satellite program-operational line-scan system (DMSP-OLS) nighttime satellite data, electricity consumption (1993-2013), gross domestic product (GDP) and population growth to construct the model. We also attempted to examine the sensitiveness of electricity consumption to GDP and population growth. The results revealed that the calibrated DMSP and model has provided realistic information on the electric demand with respect to GDP and population, with a better accuracy of r 2 = 0.91. The electric demand was found to be more sensitive to GDP (r = 0.96) than population growth (r = 0.76) as envisaged through correlation analysis. Hence, the model proved to be useful tool in predicting electric demand for its sustainable use and management. PMID- 29282534 TI - Computerized cognitive training in prostate cancer patients on androgen deprivation therapy: a pilot study. AB - PURPOSE: Prostate cancer patients who have undergone androgen deprivation therapy (ADT) may experience cognitive impairment, yet there is an unmet need for nonpharmacological interventions to address cognitive impairment in this population. This study examines the feasibility, acceptability, and preliminary efficacy of a home-based computerized cognitive training (CCT) program to treat cancer-related cognitive impairment. METHODS: Sixty men who had received >= 3 months of ADT were screened for at least mild cognitive or neurobehavioral impairment and randomized to 8 weeks of CCT or usual care. Follow-up assessments occurred immediately post-intervention or equivalent (T2) and 8 weeks later (T3). The acceptability of CCT was also assessed. RESULTS: Feasibility:A priori feasibility thresholds were partially met (i.e., randomization rate > 50%, retention rate > 70% excluding CCT drop-outs, but < 70% for intent-to-treat). Acceptability: Participants were mostly satisfied with CCT and found it somewhat enjoyable, though barriers to uptake existed. Preliminary efficacy: Linear mixed models indicated significant time by group effects favorable to CCT in reaction time (p = .01), but unfavorable to CCT in verbal and visual memory (ps < .05). Memory was temporarily suppressed in the CCT group at T2, but normalized by T3. There was no effect of CCT on self-reported cognitive functioning, neurobehavioral functioning, nor quality of life. CONCLUSIONS: This study provides tentative support for the feasibility and acceptability of CCT to treat mild cognitive impairment in ADT patients. CCT had a beneficial effect on reaction time, but temporarily suppressed memory. CCT's benefits may be limited to a narrow area of functioning. Larger-scale studies are needed. PMID- 29282536 TI - Inflammatory and infectious pathology of the gastrointestinal tract: an introduction. PMID- 29282535 TI - Percutaneous versus surgical strategy for tracheostomy: a systematic review and meta-analysis of perioperative and postoperative complications. AB - PURPOSE: Tracheostomy is one of the most frequently performed procedures in intensive care medicine. The two main approaches are open surgical tracheostomy (ST) and percutaneous dilatational tracheostomy (PDT). This systematic review summarizes and analyzes the existing evidence regarding perioperative and postoperative parameters of safety. METHODS: A systematic literature search was conducted in the Cochrane Library, EMBASE, LILACS, and MEDLINE to identify all randomized controlled trials (RCTs) comparing complications of ST and PDT and to define the strategy with the lower risk of potentially life-threatening events. Risk of bias was assessed using the criteria outlined in the Cochrane Handbook. RESULTS: Twenty-four citations comprising 1795 procedures (PDT: n = 926; ST: n = 869) were found suitable for systematic review. No significant difference in the risk of a potentially life-threatening event (risk difference (RD) 0.01, 95% CI - 0.03 to 0.05, P = 0.62, I 2 = 47%) was found between PDT and ST. There was no difference in mortality (RD - 0.00, 95% CI - 0.01 to 0.01, P = 0.88, I 2 = 0%). An increased rate of technical difficulties was shown for PDT (RD 0.04, 95% CI 0.01, 0.08, P = 0.01, I 2 = 60%). Stomal infection occurred more often with ST (RD - 0.05, 95% CI - 0.08 to - 0.02, P = 0.003, I 2 = 60%). Both techniques can be safely performed on the ICU. Meta-analysis of the duration of procedure was not possible owing to high heterogeneity (I 2 = 99%). CONCLUSION: ST and PDT are safe techniques with low incidence of complications. Both techniques can be performed successfully in an ICU setting. ST can be performed on every patient whereas PDT is restricted by several contraindications like abnormal anatomy, previous surgery, coagulopathies, or difficult airway of the patient. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015021967. PMID- 29282537 TI - Subfossil markers of climate change during the Roman Warm Period of the late Holocene. AB - Abundant bog oak trunks occur in alluvial deposits of the Raba River in the village of Targowisko (southern Poland). Several of them contain galleries of the great capricorn beetle (Cerambyx cerdo L.). A well-preserved subfossil larva and pupa, as well as adults of this species, are concealed in some of the galleries. These galleries co-occur with boring galleries of other insects such as ship timber beetles (Lymexylidae) and metallic wood borers (Buprestidae). A dry larva of a stag beetle (Lucanidae) and a mite (Acari) have been found in the C. cerdo galleries. Selected samples of the trunks and a sample of the C. cerdo larva were dated, using radiocarbon and dendrochronological methods, to the period from 45 BC to AD 554; one sample was dated to the period from 799 to 700 BC. Accumulation of the channel alluvia containing the bog oak trunks is synchronous with the Roman Warm Period (late antiquity/Early Mediaeval times). The most recent part of this period correlates with massive accumulations of fallen oak trunks noted from various river valleys in the Carpathian region and dated to AD 450-570. The results indicate that C. cerdo was more abundant within the study area during the Roman Warm Period than it is today. PMID- 29282538 TI - Barometric pressure change and heart rate response during sleeping at ~ 3000 m altitude. AB - We investigated effects of change in barometric pressure (P B) with climate change on heart rate (HR) during sleep at 3000 m altitude. Nineteen healthy adults (15 males and four females; mean age 32 years) participated in this study. We measured P B (barometry) and HR (electrocardiography) every minute during their overnight stay in a mountain lodge at ~ 3000 m. We also measured resting arterial oxygen saturation (SpO2) and evaluated symptoms of acute mountain sickness (AMS) by using the Lake Louise Questionnaire at 2305 and 3000 m, respectively. P B gradually decreased during the night at the speed of approximately - 0.5 hPa/h. We found that HR during sleep decreased linearly as P B decreased in all subjects, with significance (r = 0.492-0.893; all, P < 0.001). Moreover, cross correlation analysis revealed that HR started to decrease after ~ 15 min following the decrease in P B, on average. SpO2 was 93.8 +/- 1.7% at 2305 m before climbing, then decreased significantly to 90.2 +/- 2.2% at the lodge before going to bed, and further decreased to 87.5 +/- 2.7% after waking (all, P < 0.05). Four of the 19 subjects showed a symptom of AMS after waking (21%). Further, the decrease in HR in response to a given decrease in P B (DeltaHR/DeltaPB) was negatively related with a decrease in SpO2 from before going to bed to after waking at 3000 m (r = - 0.579, P = 0.009) and with total AMS scores after waking (r = 0.489, P = 0.033). PMID- 29282539 TI - The Global Spine Care Initiative: a systematic review of individual and community based burden of spinal disorders in rural populations in low- and middle-income communities. AB - PURPOSE: The purpose of this review was to synthesize literature on the burden of spinal disorders in rural communities to inform the Global Spine Care Initiative care pathway and model of care for their application in medically underserved areas and low- and middle-income countries. METHODS: A systematic review was conducted. Inclusion criteria included all age groups with nonspecific low back pain, neck pain, and associated disorders, nonspecific thoracic spinal pain, musculoskeletal chest pain, radiculopathy, or spinal stenosis. Study designs included observational study design (case-control, cross-sectional, cohort, ecologic, qualitative) or review or meta-analysis. After study selection, studies with low or moderate risk of bias were qualitatively synthesized. RESULTS: Of 1150 potentially relevant articles, 43 were eligible and included in the review. All 10 low and 18 moderate risk of bias studies were cross-sectional, 14 of which included rural residents only. All studies included estimates of low back pain prevalence, one included neck pain and one reported estimates for spinal disorders other than back or neck pain. The prevalence of low back pain appears greater among females and in those with less education, psychological factors (stress, anxiety, depression), and alcohol consumers. The literature is inconsistent as to whether back pain is more common in rural or urban areas. High risk of bias in many studies, lack of data on disability and other burden measures and few studies on conditions other than back and neck pain preclude a more comprehensive assessment of the individual and community-based burden of spinal disorders in less-developed communities. CONCLUSION: We identified few high-quality studies that may inform patients, providers, policymakers, and other stakeholders about spinal disorders and their burden on individuals and communities in most rural places of the developing world. These findings should be a call to action to devote resources for high-quality research to fill these knowledge gaps in medically underserved areas and low and middle-income countries. These slides can be retrieved under Electronic Supplementary Material. PMID- 29282540 TI - Expression analyses of Dusp22 (Dual-specificity phosphatase 22) in mouse tissues. AB - Dusp22 (dual-specificity phosphatase 22) is considered to regulate various cellular processes through the regulation of protein dephosphorylation. In this study, we prepared a specific antibody against Dusp22, anti-Dusp22, and carried out expression analyses with mouse tissues and cultured cell lines. Western blotting analyses demonstrated a tissue-dependent expression profile of Dusp22 in the adult mouse, and strongly suggested the presence of isoforms with larger molecular masses. In fibroblast NIH3T3 cells, while both endogenous and Myc tagged Dusp22 was diffusely distributed in the cytoplasm, Myc-Dusp22 was partially colocalized with actin cytoskeleton. From the obtained results, anti Dusp22 was found to be a useful tool for biochemical and cell biological analyses of Dusp22. PMID- 29282542 TI - Using Hidden Markov Models to characterise intermittent social behaviour in fish shoals. AB - The movement of animals in groups is widespread in nature. Understanding this phenomenon presents an important problem in ecology with many applications that range from conservation to robotics. Underlying all group movements are interactions between individual animals and it is therefore crucial to understand the mechanisms of this social behaviour. To date, despite promising methodological developments, there are few applications to data of practical statistical techniques that inferentially investigate the extent and nature of social interactions in group movement. We address this gap by demonstrating the usefulness of a Hidden Markov Model approach to characterise individual-level social movement in published trajectory data on three-spined stickleback shoals (Gasterosteus aculeatus) and novel data on guppy shoals (Poecilia reticulata). With these models, we formally test for speed-mediated social interactions and verify that they are present. We further characterise this inferred social behaviour and find that despite the substantial shoal-level differences in movement dynamics between species, it is qualitatively similar in guppies and sticklebacks. It is intermittent, occurring in varying numbers of individuals at different time points. The speeds of interacting fish follow a bimodal distribution, indicating that they are either stationary or move at a preferred mean speed, and social fish with more social neighbours move at higher speeds, on average. Our findings and methodology present steps towards characterising social behaviour in animal groups. PMID- 29282541 TI - Creatine phosphate disodium salt protects against Dox-induced cardiotoxicity by increasing calumenin. AB - Inhibiting endoplasmic reticulum stress (ERS)-induced apoptosis may be a new therapeutic target in cardiovascular diseases. Creatine phosphate disodium salt (CP) has been reported to have cardiovascular protective effect, but its effects on ERS are unknown. The aim of this study was to identify the mechanism by which CP exerts its cardioprotection in doxorubicin (Dox)-induced cardiomyocytes injury. In our study, neonatal rats cardiomyocytes (NRC) was randomly divided into control group, model group, and treatment group. The cell viability and apoptosis were detected. grp78, grp94, and calumenin of the each group were monitored. To investigate the role of calumenin, Dox-induced ERS was compared in control and down-regulated calumenin cardiomyocytes. Our results showed that CP decreased Dox-induced apoptosis and relieved ERS. We found calumenin increased in Dox-induced apoptosis with CP. ERS effector C/EBP homologous protein was down regulated by CP and it was influenced by calumenin. CP could protect NRC by inhibiting ERS, this mechanisms may be associated with its increasing of calumenin. PMID- 29282543 TI - Characterization of bactericidal efficiency, cell selectivity, and mechanism of short interspecific hybrid peptides. AB - Facing rising global antibiotics resistance, physical membrane-damaging antimicrobial peptides (AMPs) represent promising antimicrobial agents. Various strategies to design effective hybrid peptides offer many advantages in overcoming the adverse effects of natural AMPs. In this study, hybrid peptides from different species were investigated, and three hybrid antimicrobial peptides, LI, LN, and LC, were designed by combining the typical fragment of human cathelicidin-derived LL37 with either indolicidin, pig nematode cecropin P1 (CP-1) or rat neutrophil peptide-1 (NP-1). In an aqueous solution, all hybrid peptides had an unordered conformation. In simulated membrane conditions, the hybrid peptide LI displayed more beta-turn and beta-hairpin structures, whereas LN and LC folded into alpha-helix structures. The three interspecific hybrid peptides LI, LN, and LC exhibited different levels of antimicrobial activity against Gram-positive and Gram-negative bacteria. LI demonstrated the highest antimicrobial activity and cell selectivity. The results of the swimming motility indicated that LI repressed bacterial motility in a concentration-dependent method. Endotoxin binding assay demonstrated that hybrid peptide LI conserved the binding ability to LPS (polyanionic lipopolysaccharides) of its parental peptides. Fluorescence assays, flow cytometry, and SEM further revealed that hybrid peptide LI acted through different bacteriostatic mechanisms than LL37 and indolicidin and that LI killed bacterial cells via membrane damage. In summary, this study demonstrated that hybrid peptide LI produced by interspecific hybrid synthesis possessed strong cell selectivity and is a promising therapeutic candidate for drug-resistant bacteria infection. PMID- 29282544 TI - Diet-induced glucose homeostasis dysregulation is enhanced by taurine supplementation in ovariectomized mice. AB - Low levels of estrogens are associated with obesity-related comorbidities. Mice with lower levels of estrogens are thereby more sensitive to the effects of a high-fat-diet (HFD) for the development of glucose intolerance and insulin resistance. Studies in vivo have demonstrated that taurine (TAU) supplementation prevents glucose and insulin resistance. Thus, we aimed to investigate the potential beneficial effects of TAU supplementation on glucose homeostasis of mice with low levels of estrogens fed with a HFD. 3-month-old female C57BL/6J mice underwent bilateral ovariectomy (OVX). After 1 week of recovery, mice were divided into 4 groups and either received: a standard chow diet (OVXC), chow diet plus drinking water enriched with 3% of TAU (OVXCT), HFD (OVXH), and HFD plus supplementation of TAU (OVXHT) for 14 weeks. Exposure to the HFD increased adiposity and plasma levels of glucose and insulin. Contrary to our prediction, the addition of TAU enhanced the deleterious effects of the HFD. Glucose and insulin tolerance tests (ipGTT and ipITT) indicated that mice maintained on the HFD + TAU had worse glucose intolerance and insulin resistance that was linked to lower insulin signaling in skeletal muscle and liver. Insulin secretion of isolated pancreatic islets of OVXH mice was higher than OVXC, and the addition of TAU associated with a HFD did not modulate insulin secretion, suggesting a failure of pancreatic beta cells of OVXHT mice. These results suggest that despite the beneficial reports of TAU, it should be used cautiously in situations where the levels of estrogens are low. PMID- 29282546 TI - Complete genome sequence and phylogenetic analysis of megalocytivirus RSIV-Ku: A natural recombination infectious spleen and kidney necrosis virus. AB - Megalocytiviruses are classified into three genotypes, infectious spleen and kidney necrosis virus (ISKNV), red seabream virus (RSIV), and turbo reddish body iridovirus (TRBIV), based on the major capsid protein and ATPase genes. However, only a few complete genome sequences have been obtained. This paper reports the complete genome sequence and phylogenetic analysis of an RSIV-Ku strain megalocytivirus. The genome sequence comprises 111,154 bp, has 132 putative open reading frames, and is homologous mostly to ISKNV, except for the sequence in the region 58981-66830, which is more closely related to that of the RSIV genotype. The results imply that RSIV-Ku is actually a natural recombinant virus. PMID- 29282545 TI - Relationship between Pb and Cd accumulations in house crow, their habitat, and food content from Klang area, Peninsular Malaysia. AB - Heavy metal pollution has become a global concern due to accumulation in tissue and transferable effects to humans via the food chain. This study focused on monitoring the accumulation of cadmium (Cd) and lead (Pb) in surface soil and body content: bone, heart, brain, liver, lung, muscle, kidney, feathers, feces, and gizzard contents of house crow Corvus splendens in the Klang region, Malaysia. The results revealed the occurrence of Pb and Cd in all biological samples from house crows, food contents, and surface soil samples. Heart and kidney accrued high amounts of Cd, while high amounts of Pb were found to accumulate in bones and feathers. Major discrepancies were also discovered in the concentrations of metals between juvenile and adults, as well as female and male bird samples. Concentrations of Pb and Cd in house crow internal tissues correlated significantly with that of bird feathers, but none could be established with that of surface soil. In addition, a significant correlation was observed between Pb concentration in the internal tissues to that of the feces, but the same was not the case when compared with the surface soil concentration. Metal accrual in the house crows feathers and feces may be through a long-term transmission via the food chain, which are eliminated from feathers via molting. This may suggest the utility of molted breast feathers of house crow in the bio monitoring of Cd and Pb contamination, whereas feces of house crow appear only to be suitable for the bio-monitoring of Pb contamination. PMID- 29282547 TI - Complete genome sequence and analysis of ictalurid herpesvirus 2. AB - Ictalurid herpesvirus 2 (IcHV-2) has been causing substantial losses in the black bullhead aquaculture industry since the 1990s. Using next-generation sequencing, the genome of IcHV-2 was completely sequenced and analysed in this study. The complete genome was found to be 142,925 bp in size, containing 77 predicted protein-coding regions, including 12 ORFs that appear to have a homologue in every alloherpesvirus genome sequenced to date. The genome organization of the IcHV-2 shows high similarity to that of IcHV-1, the founding member of the genus Ictalurivirus within the family Alloherpesviridae. A unique sequence region of 101 kbp is flanked by terminal direct repeats of 20 kbp. Thirteen of the 77 putative genes do not show homology to any known genes with sequences in public databases; six of them are found in the repeat regions. Analysis of the whole genome confirms the previously established taxonomic position of IcHV-2. PMID- 29282548 TI - The QUALYOR (QUalite Osseuse LYon Orleans) study: a new cohort for non invasive evaluation of bone quality in postmenopausal osteoporosis. Rationale and study design. AB - : The diagnostic performance of densitometry is inadequate. New techniques of non invasive evaluation of bone quality may improve fracture risk prediction. Testing the value of these techniques is the goal of the QUALYOR cohort. INTRODUCTION: The bone mineral density (BMD) of postmenopausal women who sustain osteoporotic fracture is generally above the World Health Organization definition for osteoporosis. Therefore, new approaches to improve the detection of women at high risk for fracture are warranted. METHODS: We have designed and recruited a new cohort to assess the predictive value of several techniques to assess bone quality, including high-resolution peripheral quantitative computerized tomography (HRpQCT), hip QCT, calcaneus texture analysis, and biochemical markers. We have enrolled 1575 postmenopausal women, aged at least 50, with an areal BMD femoral neck or lumbar spine T-score between - 1.0 and - 3.0. Clinical risk factors for fracture have been collected along with serum and blood samples. RESULTS: We describe the design of the QUALYOR study. Among these 1575 women, 80% were aged at least 60. The mean femoral neck T-score was - 1.6 and the mean lumbar spine T-score was -1.2. This cohort is currently being followed up. CONCLUSIONS: QUALYOR will provide important information on the relationship between bone quality variables and fracture risk in women with moderately decreased BMD. PMID- 29282549 TI - Heavy metal concentrations in roadside soil and street dust from Petra region, Jordan. AB - Concentrations of Cd, Cu, Fe, Pb, and Zn were measured in the samples of street dust and surface roadside soil before Jordan switched to unleaded fuel usage. The samples were collected from Petra, the most tourist-attractive site in Jordan. The samples were analyzed for heavy metals by atomic absorption spectrophotometry. Our results show that the distribution of metals in the soil samples is affected by wind direction in the investigated area. The highest level of metals was found in the eastern parts of the roads due to the westerly dominant wind in the studied area. The contamination levels of metals decrease as the distance from the edge of the road increases. In the roadside soil samples, the means for the concentrations of the metals at 1 m from the east side of the main road are 1.0, 19.1, 3791.4, 177.0, and 129.0 mg kg-1 for Cd, Cu, Fe, Pb, and Zn, respectively. In the samples of street dust, the means of the concentrations of the metals in the investigated area are 9.7, 11.8, 4694.4, 31.6, and 24.8 mg kg-1 for Cd, Cu, Fe, Pb, and Zn, respectively. In conclusion, the lithogenic origins (traffic emissions) are responsible for the diffusion of these metals in the studied region. PMID- 29282550 TI - Bioactive calcium silicate/poly-epsilon-caprolactone composite scaffolds 3D printed under mild conditions for bone tissue engineering. AB - The present study provides a solvent-free processing method for establishing the ideal porous 3-dimension (3D) scaffold filled with different ratios of calcium silicate-based (CS) powder and polycaprolactone (PCL) for 3D bone substitute application. Characterization of hybrid scaffolds developed underwent assessments for physicochemical properties and biodegradation. Adhesion and growth of human Wharton's Jelly mesenchymal stem cells (WJMSCs) on the CS/PCL blended scaffold were investigated in vitro. Cell attachment and morphology were examined by scanning electron microscope (SEM) and confocal microscope observations. Colorimetric assay was tested for assessing cell metabolic activity. In addition, RT-qPCR was also performed for the osteogenic-related and angiogenesis-related gene expression. As a result, the hydrophilicity of the scaffolds was further significantly improved after we additive CS into PCL, as well as the compressive strength up to 5.8 MPa. SEM showed that a great amount of precipitated bone-like apatite formed on the scaffold surface after immersed in the simulated body fluid. The 3D-printed scaffolds were found to enhance cell adhesion, proliferation and differentiation. Additionally, results of osteogenesis and angiogenesis proteins were expressed obviously greater in the response of WJMSCs. These results indicate the CS/PCL composite exhibited a favorable bioactivity and osteoconductive properties that could be served as a promising biomaterial for bone tissue engineering scaffolds. PMID- 29282551 TI - A 3D visualization of the substituent effect : A brief analysis of two components of the operational formula of dual descriptor for open-shell systems. AB - Six organometallic compounds coming from a basic Mo-based complex were analyzed from the perspective of the dual descriptor in order to detect subtle influences that a substituent group could exert on the reactive core at a long range. Since the aforementioned complexes are open-shell systems, the used operational formula for the dual descriptor is that one defined for those aforementioned systems, which was then compared with spin density. In addition, dual descriptor was decomposed into two terms, each of which was also applied on every molecular system. The obtained results indicated that components of dual descriptor could become more useful than the operational formula of dual descriptor because differences exerted by the substituents at the para position were better detected by components of dual descriptor rather than the dual descriptor by itself. PMID- 29282552 TI - Combined QM/MM and Monte Carlo study for redox leveling in Mn and Fe superoxide dismutase. AB - Superoxide dismutases (SOD) are vital enzymes for disproportionation of superoxide molecules in mammals. Despite the high similarity between the Mn-SOD and Fe-SOD, they are inactive if the metals in the active sites are exchanged. Here, we use DFT, QM/MM and Monte Carlo sampling to optimize the crystal structure and to calculate the mid-point potential for the native and substituted Mn/Fe-SOD. The optimized DFT and QM/MM structures of the Mn-SOD show a major conformational change for the conserved TYR34 compared to the X-ray structure. These changes reduce the distance between TYR34 and Mn ion to 2.59 A, which yields a lower reduction potential for the Mn. On contrary, there is no significant difference between optimized and crystal structures in the Fe-SOD. The calculated E m values starting from the DFT structures of the active sites show similar pattern, in good agreement with those observed experimentally. However, the calculated E m values starting with the QM/MM structures that include the whole protein are significantly higher due to the desolvation penalty. In addition, the pK a values for the water ligand in the reduced state Mn(II) and Fe(II) were calculated. The water pK a in Mn-SOD is higher than that in Fe-SOD by 3.5 pH units, which is similar to the shift measured experimentally. Finally, we investigated the role of HIS30 and the effect of its protonation state on the E m values. PMID- 29282553 TI - Muscle strength is associated with bone health independently of muscle mass in postmenopausal women: the Japanese population-based osteoporosis study. AB - There are conflicting reports on whether muscle strength is associated with bone mineral density (BMD) independently of muscle mass. Here, we examined the association between muscle strength and BMD in a representative population of Japanese women. Cross-sectional data from 680 postmenopausal women, who were participants in the 15th-year follow-up survey of the Japanese Population-based Osteoporosis cohort study, were analyzed. Areal BMD (aBMD) at the femoral neck and lumbar spine, whole-body bone mineral density, and appendicular skeletal muscle mass (ASM, kg) were measured by dual-energy X-ray absorptiometry. The ASM index (ASMI, kg/m2) was calculated as ASM divided by height squared (m2). Grip strength (kg) was measured as an indicator of muscle strength. Grip strength showed significantly (P < 0.05) positive relationships with aBMDs at several skeletal sites after adjusting for ASMI and age (standardized partial regression coefficient (beta) = 0.102 at femoral neck, beta = 0.126 at lumbar spine). Adjusted means of aBMD at the femoral neck and lumbar spine showed significant increasing trends from the lowest to highest tertile of grip strength. Our findings indicate that muscle strength is associated with aBMD at several sites independently of muscle mass in Japanese postmenopausal women. Thus, postmenopausal women with strong muscle strength tend to have a healthy bone status regardless of muscle size. PMID- 29282554 TI - Soccer helps build strong bones during growth: a systematic review and meta analysis. AB - : The aim of this study was to analyze the effects of soccer practice on bone in male and female children and adolescents. MEDLINE, PubMed, SPORTDiscus and Web of Science databases were searched for scientific articles published up to and including October 2016. Twenty-seven studies were included in this systematic review (13 in the meta-analysis). The meta-analysis was performed by using OpenMeta[Analyst] software. It is well documented that soccer practice during childhood provides positive effects on bone mineral content (BMC) and density (BMD) compared to sedentary behaviors and other sports, such as tennis, weightlifting, or swimming. Furthermore, soccer players present higher BMC and BMD in most weight-bearing sites such as the whole body, lumbar spine, hip, and legs. Moreover, bone differences were minimized between groups during prepuberty. Therefore, the maturity status should be considered when evaluating bone. According to meta-analysis results, soccer practice was positively associated with whole-body BMD either in males (mean difference 0.061; 95%CI, 0.042-0.079) or in females (mean difference 0.063; 95%CI, 0.026-0.099). CONCLUSION: Soccer may be considered a sport that positively affects bone mass during growth. Pubertal soccer players presented increased bone mass compared to controls or other athletes; however, these bone differences are minimized during the prepubertal stage. What is known: * It has been described that childhood and adolescence are important periods for bone mass and structure. * Previous studies have demonstrated that soccer participation improves bone mass in male and female children and adolescents. What is new: * The differences between soccer players and controls are more marked during puberty than prepuberty. * Weight-bearing sites such as lumbar spine, hip, femoral neck, trochanter, intertrochanteric region and both legs are particularly sensitive to soccer actions. PMID- 29282556 TI - Identification and expression of a unique neonatal variant of the GABAA receptor alpha3 subunit. AB - The GABAA receptor provides the majority of inhibitory neurotransmission in the adult central nervous system but in immature brain is responsible for much of the excitatory drive, a requirement for normal brain development. It is well established that GABAA receptor subunit expression changes across the course of brain development. In the present study, we have identified a splice variant of the GABAA receptor alpha3 subunit which appears unique to the developing brain, referred to here as the GABAA receptor alpha3 subunit neonatal variant (GABAA receptor alpha3N). RT-PCR and sequence analysis revealed splicing of exon 8 of the alpha3 subunit. Western blot analysis showed expression of GABAA receptor alpha3N in the cortex of several neonatal species and significantly reduced expression of this splice variant in the corresponding adult brains. Expression was evident in multiple brain regions and decreased across development in the pig. Fractionation revealed differential cellular localisation in the parietal cortex, hippocampus and thalamus of the full-length GABAA receptor alpha3 and GABAA receptor alpha3N. Immunoprecipitation showed direct interaction with the GABAA receptor subunits alpha1 and gamma2 but not with gephyrin. PMID- 29282555 TI - Green Adeptness in the Synthesis and Stabilization of Copper Nanoparticles: Catalytic, Antibacterial, Cytotoxicity, and Antioxidant Activities. AB - Copper nanoparticles (CuNPs) are of great interest due to their extraordinary properties such as high surface-to-volume ratio, high yield strength, ductility, hardness, flexibility, and rigidity. CuNPs show catalytic, antibacterial, antioxidant, and antifungal activities along with cytotoxicity and anticancer properties in many different applications. Many physical and chemical methods have been used to synthesize nanoparticles including laser ablation, microwave assisted process, sol-gel, co-precipitation, pulsed wire discharge, vacuum vapor deposition, high-energy irradiation, lithography, mechanical milling, photochemical reduction, electrochemistry, electrospray synthesis, hydrothermal reaction, microemulsion, and chemical reduction. Phytosynthesis of nanoparticles has been suggested as a valuable alternative to physical and chemical methods due to low cytotoxicity, economic prospects, environment-friendly, enhanced biocompatibility, and high antioxidant and antimicrobial activities. The review explains characterization techniques, their main role, limitations, and sensitivity used in the preparation of CuNPs. An overview of techniques used in the synthesis of CuNPs, synthesis procedure, reaction parameters which affect the properties of synthesized CuNPs, and a screening analysis which is used to identify phytochemicals in different plants is presented from the recent published literature which has been reviewed and summarized. Hypothetical mechanisms of reduction of the copper ion by quercetin, stabilization of copper nanoparticles by santin, antimicrobial activity, and reduction of 4-nitrophenol with diagrammatic illustrations are given. The main purpose of this review was to summarize the data of plants used for the synthesis of CuNPs and open a new pathway for researchers to investigate those plants which have not been used in the past. Graphical abstract Proposed Mechanism for Antibacterial activity of copper nanoparticles. PMID- 29282557 TI - Regioselective alkali metal reduction of dibenzocyclooctadiene lignan derivatives, demethoxylation followed by dehalogenation. AB - The regioselective demethoxylation and dehalogenation of dihalogenated dibenzocyclooctadiene lignans derivatives were realized in a one-step reaction with excellent yields in the sodium and t-butanol reaction system. PMID- 29282558 TI - Synchronous bilateral pheochromocytomas and paraganglioma with novel germline mutation in MAX: a case report. AB - BACKGROUND: Recent advance of genetic testing has contributed to the diagnosis of hereditary pheochromocytoma and paraganglioma (PPGL). The clinical characteristics of hereditary PPGL are varying among the types of mutational genes. It is still difficult to specify the pathognomonic symptoms in the case of rare genetic mutations. Here, we report the case of synchronous bilateral pheochromocytomas and paraganglioma with novel MYC associated factor X (MAX) gene mutation. CASE PRESENTATION: A 24-year-old female had hyperhidrosis and hypertension. Her urine test showed high normetanephrine and vanillylmandelic acid. Enhanced computed tomography revealed three enhanced masses in right adrenal gland, left adrenal gland, and left renal hilus. She was diagnosed with PPGL. Because 123I-metaiodobenzylguanidine scintigraphy indicated the accumulations in the left adrenal gland mass and the left renal hilus mass and not in the right adrenal gland mass, we performed laparoscopic left adrenalectomy and extirpation of the left renal hilus mass to preserve the right adrenocortical function. However, her symptoms recurred shortly after the operation presumably due to unveiling of the activity of the right pheochromocytoma. Following right adrenalectomy as the second operation, the catecholamine levels declined to normal range. Her genetic testing indicated the novel germline mutation in MAX gene (c.70_73 del AAAC/p.Lys24fs*40). CONCLUSIONS: MAX germline mutation is recently identified as a rare cause of hereditary PPGL. The deletion mutation in MAX gene in this patient has never reported before. In the case of bilateral pheochromocytomas, the surgical indication should be decided considering each patient's genetic background. Due to the possibility for other types of malignant tumors, close follow-up is essential for MAX mutation carriers. PMID- 29282559 TI - Characterization of the rice NLA family reveals a key role for OsNLA1 in phosphate homeostasis. AB - BACKGROUND: Phosphate (Pi), an essential mineral nutrient for plant development and reproduction, is one of the main components of fertilizers in modern agriculture. Previous research demonstrated that AtNLA1 mediates ubiquitination of Pi transporters in the plasma membrane and triggers their endocytosis and degradation in Arabidopsis. In this study, we researched the function of NLA homologous proteins in Pi homeostasis in rice. FINDINGS: Two OsNLA homologs from rice (Oryza sativa L.) were identified by bioinformatics and phylogenetic analysis and designated OsNLA1 and OsNLA2. The OsNLA1 clustered with Arabidopsis AtNLA1, was expressed higher than OsNLA2 and was transcriptionally repressed under Pi-deficient condition. Loss-of-function of OsNLA1 caused P overaccumulation and growth inhibitions in both root and shoot under Pi sufficient condition. Furthermore, mutation of OsNLA1 affected expression of Pi tranporters and root hair development under Pi-sufficient and/or Pi-deficient conditions. CONCLUSIONS: OsNLA1 plays a key role in maintaining phosphate homeostasis in rice. PMID- 29282560 TI - Effects of corticopuncture (CP) and low-level laser therapy (LLLT) on the rate of tooth movement and root resorption in rats using micro-CT evaluation. AB - The aim of this study was to compare the rate of tooth displacement, quantity of root resorption, and alveolar bone changes in five groups: corticopuncture (CP), low-level laser therapy (LLLT), CP combined with LLLT (CP + LLLT), control (C), and negative control (NC). A total of 60 half-maxilla from 30 male Wistar rats (10 weeks old) were divided randomly into five groups: three (CP, LLLT, and CP + LLLT) test groups with different stimulation for accelerated-tooth-movement (ATM), one control (C) group, and one negative control (NC) group with no tooth movement. Nickel-titanium coil springs with 50 g of force were tied from the upper left and right first molars to micro-implants placed behind the maxillary incisors. For the CP and CP + LLLT groups, two perforations in the palate and one mesially to the molars were performed. For the LLLT and CP + LLLT groups, GaAlAs diode laser was applied every other day for 14 days (810 nm, 100 mW, 15 s). The tooth displacements were measured directly from the rat's mouth and indirectly from microcomputer (micro-CT) tomographic images. Bone responses at the tension and compression sites and root resorption were analyzed from micro-CT images. The resulting alveolar bone responses were evaluated by measuring bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular thickness (TbTh). Root resorption crater volumes were measured on both compression and tension sides of mesial and distal buccal roots. The tooth displacement in the CP + LLLT group was the greatest when measured clinically, followed by the CP, LLLT, and control groups (C and NC), respectively (p <0.05). The tooth movements measured from micro-CT images showed statistically higher displacement in the CP and CP + LLLT groups compared to the LLLT and control groups. The BMD, BV/TV, and TbTh values were lower at the compression side and higher at the tension side for all three test groups compared to the control group. The root resorption crater volume of the distal buccal root was higher in the control group, followed by CP, LLLT, and CP + LLLT, mostly at the compression site. Combining corticopuncture and low-level laser therapy (CP + LLLT) produced more tooth displacement and less root resorption at the compression side. The combined technique also promoted higher alveolar bone formation at the tension side. PMID- 29282561 TI - Optical properties of P3HT and N2200 polymers: a performance study of an optimally tuned DFT functional. AB - The optical properties of systems composed of the polymers PolyeraActivInkTM N2200 and P3HT are experimentally and theoretically investigated using UV-Vis spectroscopy and time-dependent density functional theory calculations, respectively. From a theoretical point of view, we carried out an analysis considering several functionals and model oligomers of different sizes to mimic the polymers. As our studies were performed with and without solvents, a first important result regards the fact that, by considering solvent effects, a better agreement between theoretical and experimental results could be achieved. Our findings also show that an optimally tuned functional is better suited to describe the experimental absorption profile than a hybrid one for the flexible polymer (P3HT). For the almost rigid polymer considered here (N2200), on the other hand, hybrid functionals may perform better than tuned functionals. PMID- 29282562 TI - ILM peeling in rhegmatogenous retinal detachment; does it improve the outcome? PMID- 29282563 TI - Development of a test grid using Eye Movement Perimetry for screening glaucomatous visual field defects. AB - BACKGROUND: Eye Movement Perimetry (EMP) uses Saccadic Eye Movement (SEM) responses for visual field evaluation. Previous studies have demonstrated significant delay in initiation of SEMs among glaucoma patients in comparison with healthy subjects. The aim of the current study was to develop an EMP-based screening grid to identify glaucomatous visual field defects. METHODS: An interactive test consisting of 36 locations and two stimulus contrasts (162 cd/m2 and 190 cd/m2 on a background of 140 cd/m2) was evaluated in 54 healthy subjects and 50 primary glaucoma patients. Each subject was presented a central fixation target combined with the random projection of Goldmann size III peripheral targets. Instructions were given to look at each peripheral target on detection and then re-fixate at the central fixation target while the saccades were assessed using an eye tracker. From each seen peripheral target, the Saccadic Reaction Time (SRT) was calculated for contrast level 162 cd/ m2. These values were used to plot Receiver Operating Characteristic (ROC) curves for each test locations and the Area Under the Curve (AUC) values were used to identify the locations with highest susceptibility to glaucomatous damage. Each stimulus location with an AUC less than 0.75 along with its mirrored test location around the horizontal axis were eliminated from the grid. RESULTS: The mean age was 48.1 +/- 16.6 years and 50.0 +/- 14.5 years for healthy subjects and glaucoma patients respectively. A significant increase of SRT values by 76.5% (p < 0.001) was found in glaucoma patients in comparison with the healthy subjects. From the ROC analysis, ten out of 36 locations meeting the cut-off criteria of AUC were eliminated resulting in a new grid containing 26 test locations. SRT values were significantly different (p < 0.05) between the healthy subjects and glaucoma irrespective of the grids used. CONCLUSIONS: The present study resulted in a screening grid consisting of 26 locations predominantly testing nasal, superior and inferior areas of the visual field. An internal validation of the modified grid showed 90.4% of screening accuracy which makes it a potential approach for population based glaucoma screening. PMID- 29282564 TI - Primary rhegmatogenous retinal detachment: risk factors for macular involvement. AB - PURPOSE: Rhegmatogenous retinal detachment (RD) has diagnostically been divided into macula-OFF or macula-ON. The aim of this study was to describe the demographics and primary outcome of patients with RD following surgery with respect to the macular status, and to determine risk factors for macular involvement. METHODS: This prospective, observational, mono-centric cohort study was conducted at the Jules-Gonin Eye Hospital, from February 2015 until March 2017. The study included 194 eligible patients with primary RD. All patients underwent surgical treatment after baseline clinical examination. The dataset was analyzed using descriptive and analytic statistics. RESULTS: A total of 52.6% (102/194) of patients presented with macula-OFF RD. Mean age was 63.9 +/- 12.0 vs. 59.7 +/- 11.2 years in the OFF and ON group, respectively. There were 129 men (66.5%) and 65 (33.5%) women, and there were significantly more right eyes affected [right vs. left eyes 123 (63.4%) vs. 71 (36.6%), p = 0.000]. Significantly more myopes (<-3D) presented with a macula-ON RD (p = 0.04). There were more phakic patients in the cohort (55.7%), and phakic eyes were more likely to present with macula-ON RD (p = 0.01). Multivariate modeling showed that pseudophakic lens status and eyes with axial length less than 25 mm (p = 0.06) are independent predictive factors for macula-OFF RD (p = 0.02), whereas sex and laterality were not risk factors for macular involvement. CONCLUSION: Pseudophakic lens status and axial length < 25 mm are independent predictive factors for macula-OFF RD. While pseudophakic lens status is a recognized risk factor for RD, shorter axial length has not been previously identified as a risk factor for the macula-OFF RD. PMID- 29282565 TI - HawkRank: a new scoring function for protein-protein docking based on weighted energy terms. AB - Deciphering the structural determinants of protein-protein interactions (PPIs) is essential to gain a deep understanding of many important biological functions in the living cells. Computational approaches for the structural modeling of PPIs, such as protein-protein docking, are quite needed to complement existing experimental techniques. The reliability of a protein-protein docking method is dependent on the ability of the scoring function to accurately distinguish the near-native binding structures from a huge number of decoys. In this study, we developed HawkRank, a novel scoring function designed for the sampling stage of protein-protein docking by summing the contributions from several energy terms, including van der Waals potentials, electrostatic potentials and desolvation potentials. First, based on the solvation free energies predicted by the Generalized Born model for ~ 800 proteins, a SASA (solvent accessible surface area)-based solvation model was developed, which can give the aqueous solvation free energies for proteins by summing the contributions of 21 atom types. Then, the van der Waals potentials and electrostatic potentials based on the Amber ff14SB force field were computed. Finally, the HawkRank scoring function was derived by determining the most optimal weights for five energy terms based on the training set. Here, MSR (modified success rate), a novel protein-protein scoring quality index, was used to assess the performance of HawkRank and three other popular protein-protein scoring functions, including ZRANK, FireDock and dDFIRE. The results show that HawkRank outperformed the other three scoring functions according to the total number of hits and MSR. HawkRank is available at http://cadd.zju.edu.cn/programs/hawkrank . PMID- 29282566 TI - Marker assisted pyramiding of Bph6 and Bph9 into elite restorer line 93-11 and development of functional marker for Bph9. AB - BACKGROUND: The brown planthopper (BPH) has become the most destructive and a serious threat to the rice production in Asia. Breeding the resistant varieties with improved host resistance is the most effective and ecosystem-friendly strategy of BPH biological management. As host resistance was always broken down by the presence of the upgrading BPH biotype, the more resistant varieties with novel resistance genes or pyramiding known identified BPH resistance genes would be needed urgently for higher resistant level and more durability of resistance. RESULTS: Here, we developed near isogenic lines of Bph9 (NIL-Bph9) by backcrossing elite cultivar 93-11 with Pokkali (harboring Bph9) using marker assisted selection (MAS). Subsequently, we pyramided Bph6 and Bph9 in 93-11 genetic background through MAS. The resulting Bph6 and Bph9 pyramided line LuoYang69 had stronger antixenotic and antibiosis effects on BPH and exhibited significantly enhanced resistance to BPH than near isogenic lines NIL-Bph6 and NIL-Bph9. LuoYang69 derived hybrids, harboring heterozygous Bph6 and Bph9 genes, also conferred high level of resistance to BPH. Furthermore, LuoYang69 did not affect the elite agronomic traits and rice grain quality of 93-11. The current study also developed functional markers for Bph9. Using functional dominant marker, we screened and evaluated worldwide accessions of rice germplasm. Of the 673 varieties tested, 8 cultivars were identified to harbor functional Bph9 gene. CONCLUSION: The development of Bph6 and Bph9 pyramided line LuoYang69 provides valuable resource to develop hybrid rice with highly and durable BPH resistance. The development of functional markers will promote MAS of Bph9. The identified Bph9 containing cultivars can be used as new sources for BPH resistance breeding programs. PMID- 29282567 TI - Demonstration of Direct Nose-to-Brain Transport of Unbound HIV-1 Replication Inhibitor DB213 Via Intranasal Administration by Pharmacokinetic Modeling. AB - Intranasal administration could be an attractive alternative route of administration for the delivery of drugs to the central nervous system (CNS). However, there are always doubts about the direct transport of therapeutics from nasal cavity to the CNS since there are only limited studies on the understanding of direct nose-to-brain transport. Therefore, this study aimed to (1) investigate the existence of nose-to-brain transport of intranasally administered HIV-1 replication inhibitor DB213 and (2) assess the direct nose-to-brain transport of unbound HIV-1 replication inhibitor DB213 quantitatively by a pharmacokinetic approach. Plasma samples were collected up to 6 h post-dosing after administration via intranasal or intravenous route at three bolus doses. In the brain-uptake study, the plasma, whole brain, and cerebrospinal fluid (CSF) were sampled between 15 min and 8 h post-dosing. All samples were analyzed with LC/MS/MS. Plasma, CSF, and brain concentration versus time profiles were analyzed with nonlinear mixed-effect modeling. Structural model building was performed by NONMEM (version VII, level 2.0). Intranasal administration showed better potential to deliver HIV-1 replication inhibitor DB213 to the brain with 290-fold higher brain to plasma ratio compared with intravenous administration. Based on that, a model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) was developed and demonstrated 72.4% of total absorbed unbound HIV 1 replication inhibitor DB213 after intranasal administration was transported directly into the brain through nose-to-brain pathway. PMID- 29282569 TI - Emergence and establishment of KPC-2-producing ST11 Klebsiella pneumoniae in a general hospital in Shanghai, China. AB - The aim of this study was to investigate the characteristics of carbapenem resistant Klebsiella pneumoniae (CRKP) collected during an outbreak in a Chinese teaching hospital and to provide insights into the prevention and control of nosocomial infection. We collected unique CRKP clinical isolates from 2009 to 2013. Antibiotic-resistant genes were identified by polymerase chain reaction (PCR) and sequencing. The isolates were typed using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Plasmids were classified using a PCR-based incompatibility/replicon typing method and a replicon sequence typing method. Conjugation experiments were performed to evaluate the transferability of carbapenem-resistant genes. Whole genome sequencing (WGS) was conducted to further investigate the genetic background of the isolates. Infection control practices were reviewed throughout the study period. Klebsiella pneumoniae sequence type (ST) 11 emerged in 2010 and acquired the bla KPC-2 gene by 2011. From 2011 to 2013, ST11 KPC-2-producing CRKP (G type) prevailed as the most common CRKP in our hospital, causing a prolonged outbreak. The majority of these CRKP strains possess an IncFII plasmid, with Tn1721-bla KPC 2-DeltaTn3-IS26 bearing the genetic structure for bla KPC-2. Infection prevention control measures available at the time contained the initial outbreak, but had no effect on the spread of CRKP later. This study demonstrated the seriousness concerning the spread of KPC-2-producing ST11 CRKP in a Chinese hospital, indicating that current prevention and control strategies for carbapenem resistant Enterobacteriaceae (CRE) nosocomial infection need to be investigated and adjusted. PMID- 29282570 TI - Ralph Josiah Patrick Wedgwood (1924-2017). PMID- 29282568 TI - Development of a sensitive PCR-dot blot assay to supplement serological tests for diagnosing Lyme disease. AB - Laboratory diagnosis of Lyme disease is difficult and presently dependent on detecting Borrelia burgdorferi-specific antibodies in patient serum with the disadvantage that the immune response to B. burgdorferi can be weak or variable, or alternatively, the slow and inefficient culture confirmation of B. burgdorferi. PCR tests have previously shown poor sensitivity and are not routinely used for diagnosis. We developed a sensitive and specific Lyme Multiplex PCR-dot blot assay (LM-PCR assay) applicable to blood and urine samples to supplement western blot (WB) serological tests for detecting B. burgdorferi infection. The LM-PCR assay utilizes specific DNA hybridization to purify B. burgdorferi DNA followed by PCR amplification of p66 [corrected] and OspA gene fragments and their detection by southern dot blots. Results of the assay on 107 and 402 clinical samples from patients with suspected Lyme disease from Houston, Texas or received at the IGeneX laboratory in Palo Alto, California, respectively, were analyzed together with WB findings. The LM-PCR assay was highly specific for B. burgdorferi. In the Texas samples, 23 (21.5%) patients antibody-negative in WB assays by current US Centers for Disease Control (CDC) recommended criteria were positive by LM-PCR performed on urine, serum or whole blood samples. With IGeneX samples, of the 402 LM-PCR positive blood samples, only 70 met the CDC criteria for positive WBs, while 236 met IGeneX criteria for positive WB. Use of the LM-PCR assay and optimization of current CDC serological criteria can improve the diagnosis of Lyme disease. PMID- 29282571 TI - Controversies of the classification of TMA and the terminology of aHUS. PMID- 29282572 TI - Arterioportal shunting, splanchnic capillary perfusion, and the effects of colloids during capnoperitoneum in neonatal and adolescent pigs. AB - BACKGROUND: Clinical and experimental data indicate that neonates are sensitive to the CO2 pneumoperitoneum. An impaired splanchnic perfusion during laparoscopy in adults has been reported. We recently confirmed that intravenous colloids improve macrocirculatory function in neonates. We aimed to determine the impact of CO2 pneumoperitoneum on the perfusion of splanchnic organs in the young including effects of colloid application. METHODS: Male piglets (n = 25) were divided into four groups: (1) neonatal controls, (2) neonates with crystalloid restitution, (3) neonates with colloidal restitution, and (4) adolescents with crystalloid restitution. Animals were ventilated and subjected to a 3-h, 10 mmHg CO2 pneumoperitoneum followed by 2 h resuscitation. Hepatic, splanchnic, and arteriovenous shunt perfusion was assessed via central and portal venous catheters. Capillary organ flow was detected by fluorescent microspheres. The rate of bile flow was measured. RESULTS: The neonatal crystalloid group showed a significant decrease in the intestinal capillary perfusion at the end of the recovery period. This was not detectable in the adolescent and colloid group. There was a significant increase in microcirculatory arterioportal shunt flow during the CO2 pneumoperitoneum in both neonatal groups but not in the sham and adolescent groups (p < 0.05). Hepatic arterial perfusion increased after insufflation in all groups and dropped during capnoperitoneum to levels of about 70% baseline. There was no significant impairment of splanchnic perfusion or bile flow as a result of the pneumoperitoneum in all groups. CONCLUSIONS: Capillary perfusion of the abdominal organs was stable during capnoperitoneum and recovery in adolescents and neonates with colloid restitution, but not with crystalloid restitution. Significant arterioportal shunting during capnoperitoneum could affect hepatic microcirculation in neonates. Our data confirm that moderate pressure capnoperitoneum has no major effect on the perfusion of abdominal organs in neonates with adequate substitution. PMID- 29282573 TI - Endoscopic full-thickness resection of gastric and duodenal subepithelial lesions using a new, flat-based over-the-scope clip. AB - BACKGROUND: Surgical resection of upper gastrointestinal (GI) subepithelial tumors (SETs) is associated with significant morbidity and mortality. A new over the-scope (OTS) clip can be used for endoscopic full-thickness resection (eFTR). We aimed to prospectively evaluate feasibility and safety of upper GI eFTR with a new, flat-based OTS clip. METHODS: Consecutive patients with a gastric or duodenal SET < 20 mm were prospectively included. After identification of the lesion, the clip was placed and lesions were resected. Patients were followed for 1 month to assess severe adverse events (SAEs); 3-6 months after eFTR, endoscopy was performed. RESULTS: eFTR was performed on 13 lesions in 12 patients: 7 gastric and 6 duodenal SETs. Technical success was achieved in 11 cases (85%). In all 11 cases, R0-resection was achieved. In all 6 duodenal cases and in one gastric case, FTR was achieved (64%). One SAE (pain) was observed after eFTR of a gastric SET. After eFTR of duodenal SETs, several SAEs were observed: perforation (n = 1), microperforation (n = 3), and hemorrhage (n = 1). During follow-up endoscopy, the clip was no longer in situ in most patients (7 of 10; 70%). CONCLUSIONS: eFTR with this new flat-based OTS clip is feasible and effective. Although gastric eFTR was safe, eFTR in the duodenum was complicated by (micro)perforation in several patients. Therefore, the design of the clip or the technique of resection needs further refinement to improve safety of resection of SET in thin-walled areas such as the duodenum before being applied in clinical practice. Dutch trial register: NTR5023. PMID- 29282574 TI - C-reactive protein in predicting major postoperative complications are there differences in open and minimally invasive colorectal surgery? Substudy from a randomized clinical trial. AB - BACKGROUND: In search of improvement of patient assessment in the postoperative phase, C-reactive protein (CRP) is increasingly being studied as an early marker for postoperative complications following major abdominal surgery. Several studies reported an attenuated immune response in minimally invasive surgery, which might affect interpretation of postoperative CRP levels. The aim of the present study was to compare the value of CRP as a predictor for major postoperative complications in patients undergoing open versus laparoscopic colorectal surgery. METHODS: A subgroup analysis from a randomized clinical trial (LAFA-trial) was performed, including all patients with non-metastasized colorectal cancer. In the LAFA trial, patients were randomized to open or laparoscopic segmental colectomy. In a subgroup of 79 patients of the LAFA trial, postoperative assessment of CRP levels was conducted routinely preoperatively and 1, 2, 24 and 72 h after surgery. RESULTS: Thirty-seven patients were randomized to the open group and 42 patients to the laparoscopic group. Major complications occurred in 19% of laparoscopic procedures and 13.5% of open procedures (p = 0.776). CRP levels rise following surgical procedures. In uncomplicated cases, the rise in CRP levels was significantly lower at 24 and 72 h following laparoscopic resection in comparison to open resection. No differences in CRP levels were observed when comparing open and laparoscopic resection in patients with major complications. CONCLUSION: In patients with an uncomplicated postoperative course, CRP levels were lower following minimally invasive resection, possibly due to decreased operative trauma. No differences in CRP were observed stratified for surgical technique in patients with major complications. These results suggest that CRP may be applied as a marker for major postoperative complications in both open and minimally invasive colorectal surgery. Future research should aim to assess the role of standardized postoperative CRP measurements. PMID- 29282575 TI - Factors influencing discharge disposition after colectomy. AB - BACKGROUND: Factors associated with discharge destination after colectomy despite accounting for surgical morbidity have not previously been well characterized. This study aims to evaluate perioperative predictors for extended care after complicated and uncomplicated colectomy. METHODS: Patients admitted from home for elective colectomy were identified from the American College of Surgeons, National Surgical Quality Improvement Program, 2012-2013 general and colectomy targeted datasets. Patients who were discharged home (DH) were compared to those discharged to facility (DF) for patient, disease, treatment, and pre-discharge postoperative adverse events. Patients without any 30-day postoperative complication were similarly compared. RESULTS: Of 19,527 patients undergoing elective colectomy, 18,128 (92.8%) were discharged home and 1399 (7.2%) patients to other facilities. When there was no postoperative complication, these rates were 96.3 and 3.7%, respectively. On multivariable analysis, factors associated with DF included female gender, functional dependence, weight loss, ASA class >= 3, open and stoma surgery, and development of postoperative complications. For patients without postoperative complications, increasing age, functional dependence, and ASA score >= 3 were associated with DF. Preoperative bowel preparation, albumin, a minimally invasive surgical approach, and length of stay < 5 days were significantly associated with reduced DF. CONCLUSION: The majority of perioperative factors associated with extended care after colectomy are patient driven. The adoption of oral antibiotics as bowel preparation, minimally invasive surgery, and accelerated recovery protocols may reduce post-acute care placement after elective colectomy. PMID- 29282576 TI - Application of a simple, affordable quality metric tool to colorectal, upper gastrointestinal, hernia, and hepatobiliary surgery patients: the HARM score. AB - BACKGROUND: Quality is the major driver for both clinical and financial assessment. There remains a need for simple, affordable, quality metric tools to evaluate patient outcomes, which led us to develop the HospitAl length of stay, Readmission and Mortality (HARM) score. We hypothesized that the HARM score would be a reliable tool to assess patient outcomes across various surgical specialties. METHODS: From 2011 to 2015, we identified colorectal, hepatobiliary, upper gastrointestinal, and hernia surgery admissions using the Vizient Clinical Database. Individual and hospital HARM scores were calculated from length of stay, 30-day readmission, and mortality rates. We evaluated the correlation of HARM scores with complication rates using the Clavien-Dindo classification. RESULTS: We identified 525,083 surgical patients: 206,981 colorectal, 164,691 hepatobiliary, 97,157 hernia, and 56,254 upper gastrointestinal. Overall, 53.8% of patients were admitted electively with a mean HARM score of 2.24; 46.2% were admitted emergently with a mean HARM score of 1.45 (p < 0.0001). All HARM components correlated with patient complications on logistic regression (p < 0.0001). The mean length of stay increased from 3.2 +/- 1.8 days for a HARM score < 2 to 15.1 +/- 12.2 days for a HARM score > 4 (p < 0.001). In elective admissions, for HARM categories of < 2, 2-< 3, 3-4, and > 4, complication rates were 9.3, 23.2, 38.8, and 71.6%, respectively. There was a similar trend for increasing HARM score in emergent admissions as well. For all surgical procedure categories, increasing HARM score, with and without risk adjustment, correlated with increasing severity of complications by Clavien-Dindo classification. CONCLUSIONS: The HARM score is an easy-to-use quality metric that correlates with increasing complication rates and complication severity across multiple surgical disciplines when evaluated on a large administrative database. This inexpensive tool could be adopted across multiple institutions to compare the quality of surgical care. PMID- 29282577 TI - Wound protectors in reducing surgical site infections in lower gastrointestinal surgery: an updated meta-analysis. AB - BACKGROUND: Surgical site infection (SSI) is a common complication in gastrointestinal surgery. Wound protection devices are being increasingly used in the attempt to reduce infection rates. We performed a meta-analysis to determine if wound protectors reduce the incidence of SSIs in lower gastrointestinal surgery. METHODS: MEDLINE and EMBASE databases were searched between 1946 and 2016. Randomized controlled trials comparing wound protector versus no wound protector in lower gastrointestinal surgery were included. Our primary outcome was surgical site infection. Subgroup analysis was conducted comparing single ring versus dual-ring wound protectors. RESULTS: Twelve RCTs with 3029 participants were included. There was a significant decrease in the odds of developing SSI in the wound protector group (OR 0.64, 95% CI 0.45-0.90, P < 0.01, I 2 = 55%). There was evidence of a subgroup effect (P = 0.01) with dual-ring wound protectors associated with significantly lower incidence of SSIs (OR 0.31, 95% CI 0.18-0.52, P < 0.0001, I 2 = 12%), which was not appreciated in the single ring group (OR 0.84, 95% CI 0.67-1.04, P = 0.11, I 2 = 0%). CONCLUSIONS: Wound protector use is associated with decreased odds of developing SSI in patients undergoing lower gastrointestinal surgery. There was a subgroup effect when comparing dual-ring to single-ring devices. PMID- 29282578 TI - MicroRNA-21-Mediated Inhibition of Mast Cell Degranulation Involved in the Protective Effect of Berberine on 2,4-Dinitrofluorobenzene-Induced Allergic Contact Dermatitis in Rats via p38 Pathway. AB - The study aimed to investigate the effect of berberine on allergic contact dermatitis (ACD) in rats and explore its underlying mechanisms. Firstly, ACD model was established by sensitizing and challenging with 2,4 dinitrofluorobenzene (DNFB) topically, and the rats were treated with berberine. Ear swelling was assessed, and cytokine, IgE, and histamine productions were measured. The ear biopsies were obtained for histology analysis. Additionally, rat peritoneal mast cells (RPMCs) were isolated for detection of microRNA-21 (miR 21) expression, mitogen-activated protein kinase (MAPK) signaling, and MC degranulation. Lastly, RPMCs were transfected with miR-21 mimic or miR-21 inhibitor to investigate the relationship between miR-21 and p38 pathway in MC. Our results showed that berberine significantly attenuated ear swelling in DNFB induced ACD (ACD vs high dose of berberine 0.48 +/- 0.03 vs. 0.33 +/- 0.03 mm, P < 0.01), inhibited inflammatory cell infiltration (86 +/- 5.16 vs. 58 +/- 4.32 cells/mm2, P < 0.01), reduced MC recruitment (61 +/- 4.07 vs. 39 +/- 3.42 mast cells/mm2, P < 0.01), as well as decreased inflammatory cytokine, IgE, and histamine productions (all P < 0.05). Berberine treatment inhibited miR-21 expression, suppressed beta-hexosaminidase and histamine release, and prevented p38 phosphorylation (all P < 0.05), which was abrogated by pretreatment with miR 21 overexpression. These findings indicate that miR-21-mediated inhibition of MC degranulation is involved in the anti-ACD effect of berberine via inhibiting p38 pathway, which provide a new insight into the immunopharmacological role of berberine and suggest its potential application for the treatment of allergic inflammation, such as ACD. PMID- 29282579 TI - Accuracy of outside radiologists' reports of computed tomography exams of emergently transferred patients. AB - PURPOSE: Growing numbers of patient with advanced imaging being transferred to trauma centers has resulted in increased numbers of outside CT scans received at trauma centers. This study examines the degree of agreement between community radiologists' interpretations of the CT scans of transferred patients and trauma center radiologists' reinterpretation. METHODS: All CT scans of emergency transfer patients received over a 1 month period were reviewed by an emergency radiologist. Patients were classified as trauma or non-trauma and exams as neuro or non-neuro. Interpretive discrepancies between the emergency radiologist and community radiologist were classified as minor, moderate, or major. Major discrepancies were confirmed by review of a second emergency radiologist. Discrepancy rates were calculated on a per-patient and per exam basis. RESULTS: Six hundred twenty-seven CT scans of 326 patients were reviewed. Major discrepancies were encountered in 52 (16.0%, 95% CI 12.2-20.5) patients and 53 exams (8.5%, 95% CI 6.5-10.5). These were discovered in 46 trauma patients (21.6%, 95% CI 16.4-27.9) compared to six non-trauma patients (5.3%, 95% CI 2.2 11.7) (P < 0.001). A significant difference in the major discrepancy rate was also found between non-neuro and neuro exams (12.4 vs 3.3%, respectively, P < 0.001), primarily due to discrepancies in trauma patients, rather than non-trauma patients. CONCLUSIONS: Potentially management-changing interpretive changes affected 16% of transferred patients and 8.5% of CT exams over a 1 month period. Trauma center reinterpretations of community hospital CT scans of transferred patients provide valuable additional information to the clinical services caring for critically ill patients. PMID- 29282580 TI - Savanna chimpanzee (Pan troglodytes verus) nesting ecology at Bagnomba (Kedougou, Senegal). AB - We studied the nesting behavior of the critically endangered West African chimpanzee (Pan troglodytes verus). We assumed that the nesting data stemmed from a single, unhabituated community at the Bagnomba hill site in the savanna woodlands of southeastern Senegal. The aim of this study was to examine chimpanzees' nesting habits in terms of the tree species utilized and sleeping nest heights. We recorded a total of 550 chimpanzee nests at Bagnomba between January 2015 and December 2015. The chimpanzees here made nests in particular tree species more often than others. The majority of nests (63%) were in two tree species: Diospyros mespiliformis and Pterocarpus erinaceus. The average height of nesting trees was 10.54 m (SD 3.91, range, 0.0-29.0 m) and average nest height was 7.90 m (SD 3.62, range, 0.0-25.0 m). The result of a linear regression analysis (r = 0.7874; n = 550; p < 0.05) is consistent with a preference for nesting at a particular height. Bagnomba chimpanzees rarely made ground nests (0.36% of nests), but the presence of any ground nesting was unexpected, given that at least one leopard (Panthera pardus) also occupied the hill. This knowledge will enable stakeholders involved in the protection of chimpanzees specifically and of biodiversity in general to better understand chimpanzee ecology and inform a conservation action plan in Senegal where the survival of this species is threatened. PMID- 29282582 TI - Rural-urban differences in surgical treatment, regional lymph node examination, and survival in endometrial cancer patients. AB - PURPOSE: Endometrial cancer (EC) is the most common gynecological malignancy and one of few cancers with an increasing US mortality rate. Rural patients may have less access to specialty care affecting their receipt of surgery and adequate lymphadenectomy (AL). We sought to assess rural-urban differences in EC surgery, lymphadenectomy, and survival. METHODS: We analyzed data from the Surveillance Epidemiology and End Results database on EC patients (2004-2013). We performed univariate analyses to compare rural and urban patients on demographic and clinical characteristics and receipt of nodal examination and AL. We assessed rural-urban differences in trends of receipt of AL, performed logistic regression to evaluate differences in receipt of surgery, nodal examination, and AL, and performed survival analysis. RESULTS: Rural patients were less likely to have any lymph nodes removed, had a smaller median number removed, and a smaller proportion had AL. Even after controlling for established risk factors, rural patients had lower odds of lymph node examination and adequate AL than urban patients and also had poorer survival. CONCLUSIONS: Future research should continue to assess the association between access to care and disparities in surgical care and the effect of these disparities on survival. PMID- 29282581 TI - Cumulative culture in nonhumans: overlooked findings from Japanese monkeys? AB - Cumulative culture, generally known as the increasing complexity or efficiency of cultural behaviors additively transmitted over successive generations, has been emphasized as a hallmark of human evolution. Recently, reviews of candidates for cumulative culture in nonhuman species have claimed that only humans have cumulative culture. Here, we aim to scrutinize this claim, using current criteria for cumulative culture to re-evaluate overlooked qualitative but longitudinal data from a nonhuman primate, the Japanese monkey (Macaca fuscata). We review over 60 years of Japanese ethnography of Koshima monkeys, which indicate that food-washing behaviors (e.g., of sweet potato tubers and wheat grains) seem to have increased in complexity and efficiency over time. Our reassessment of the Koshima ethnography is preliminary and nonquantitative, but it raises the possibility that cumulative culture, at least in a simple form, occurs spontaneously and adaptively in other primates and nonhumans in nature. PMID- 29282583 TI - High-quality human preimplantation embryos actively influence endometrial stromal cell migration. AB - PURPOSE: The purpose of this paper is to study whether human preimplantation embryos regulate endometrial stromal cell (hESC) migration. METHODS: Primary hESCs were isolated from fertile patients undergoing hysterectomy for benign conditions (uterine scar niche n = 3, dysmenorrhea n = 2; no hormonal treatment). Migration and proliferation assays were performed by culturing decidualized or non-decidualized hESCs in the presence of embryo conditioned medium (ECM) from high-quality embryos (fragmentation <= 20%) or from low-quality embryos (fragmentation > 20%) or in non-conditioned medium from the same dishes (control). ECM samples from 425 individually cultured human embryos were used in this study. RESULTS: ECM from high-quality embryos, i.e., with a low percentage of fragmentation, actively stimulated decidualized hESC migration (p < 0.001). This effect was consistent throughout embryonic development from cleavage stage embryos with 2-7 cells (high quality vs. control; p = 0.036), 8-18 cells (high quality vs. control; p < 0.001) to morulae (high quality vs. control; p = 0.003). Additionally, linear regression analysis showed that hESC migration was influenced by embryo quality (fragmentation, beta - 0.299; p = 0.025) and not developmental stage (cell number, beta 0.177; p = 0.176) or maternal age (beta - 0.036; p = 0.78). Opposite to decidualized hESCs, the migration response of non decidualized hESCs was inhibited by ECM from high-quality embryos (p = 0.019). ECM from low-quality embryos, i.e., with a high percentage of fragmentation, did not cause an altered migration response in decidualized hESCs (p = 0.860) or non decidualized hESCs (p = 0.986). Furthermore, ECM of both high- and low-quality human embryos did not influence the number of proliferating cells (p = 0.375) and the cell cycle time (p = 0.297) of non-decidualized or decidualized hESCs. CONCLUSION: This study reveals a mechanism by which high-quality human preimplantation embryos actively interact with the endometrium to increase their chances of successful implantation. PMID- 29282584 TI - Psychometric Properties of the Spanish Version of the Broad Autism Phenotype Questionnaire: Strengths, Weaknesses, and Future Improvements. AB - The Broad autism phenotype (BAP) refers to a set of subclinical behavioural characteristics qualitatively similar to those presented in Autism spectrum disorders (ASDs). The BAP questionnaire (BAPQ) has been widely used to assess the BAP both in relatives of ASD people and within the general population. The current study presents the first Spanish version of the BAPQ (BAPQ-SP) and analyses its psychometric properties, including validity evidences based on the BAPQ scores relationship with other variables. Our results only support the use of the Aloof and Rigid sub-scales to assess this phenotype, whereas Pragmatic Language sub-scale seems to be the main source of misfit. This research represents a first step in the study of the BAP features in the Spanish population. PMID- 29282586 TI - Genetic Counsellors and Private Practice: Professional Turbulence and Common Values. AB - Genetic counsellors face tensions between past and future identities: between established values and goals, and a broadening scope of settings and activities. This study examines the advent of genetic counsellors in private practice in Australia and New Zealand from the perspectives of the small numbers working in this sector and those who have only worked in public practice. Semi-structured interviews were conducted with 16 genetic counsellors who had experience in private practice, and 14 genetic counsellors without private sector experience. Results demonstrated that circumstantial and personal factors can mitigate the challenges experienced and the amount of support desired by those who had established a private practice, and those who were employed by private companies. Notably, most participants with private sector experience perceived themselves to be viewed negatively by other genetic counsellors. Most participants without private sector experience expressed concern that the challenges they believed genetic counsellors face in private practice may impact service quality, but wished to address such concerns by providing appropriate support. Together, our results reinforce that participants in private and public sectors are strong advocates for peer support, multidisciplinary team work, and professional development. These core values, and seeking understanding of different circumstances and support needs, will enable genetic counsellors in different sectors to move forward together. Our results suggest supports that may be acted upon by members of the profession, professional groups, and training programs, in Australia, New Zealand, and overseas. PMID- 29282587 TI - Rethinking the autonomic nervous system: genetics and cell fate. PMID- 29282585 TI - As a painkiller: a review of pre- and postnatal non-steroidal anti-inflammatory drug exposure effects on the nervous systems. AB - Diclofenac sodium (DS) is commonly used for the treatment of acute and chronic pain, even for extended periods of time. Over the years, DS has been associated with toxicity in nervous tissue, in addition to its anti-inflammatory properties. Basic neurobiological research has enhanced our understanding of the biological and pathological outcomes of toxicity. Several studies have suggested DS-induced cytotoxicity in the nervous system. Prenatal toxicities of DS are thought to be capable of leading to postnatal defects. This review describes the morphoquantitative, histological and pathological effects of DS on the central and peripheral nervous systems. Knowledge of these effects may assist with the development of a suitable therapeutic approach. In addition, understanding the mechanism of DS-dependent neuronal impairments may contribute to selection of appropriate antioxidant therapy. PMID- 29282588 TI - Impact of specialist rehabilitation services on hospital length of stay and associated costs. AB - BACKGROUND: Provision of specialist rehabilitation services in North Yorkshire and Humberside may be suboptimal. Local commissioning bodies need to prioritise investments in health care, but previous studies provide limited evidence to inform the decision to expand existing services on the basis of cost effectiveness. We examine the impact of specialist rehabilitation services in the subregion on hospital length of stay (LoS) and associated costs compared to routine care. METHODS: Comparison of hospital LoS and associated costs in centres with greater access (Hull) and limited access (i.e. routine care, York and Northern Lincolnshire), to specialist rehabilitation services for patients with complex disabilities following illness or injury, using Hospital Episodes Statistics data. RESULTS: Average LoS and duration costs by Healthcare Resource Group (HRG) were lower for the majority of patients with greater access to specialist rehabilitation compared to routine care. Difference in LoS between groups widened with level of complexity within each HRG. For the more frequent HRG codes, the LoS difference was as high as 34 days longer for York compared to Hull and L7900 more costly. CONCLUSION: Rehabilitation patients within York and Northern Lincolnshire areas appear to have longer LoS and higher associated costs compared to those admitted to the Hull Trust. This analysis suggests that specialist rehabilitation may be cost saving compared to routine care and supports the case for expansion of the existing services to improve coverage in the area. PMID- 29282589 TI - Perineal skin recurrence on the site of Lone Star Retractor: case report. AB - BACKGROUND: Local recurrence of colorectal cancer is a major cause of morbidity and mortality that usually implies a worse prognosis. Its etiopathogenesis is still a subject of debate. Recurrence on the perineal wound caused by anal retractor device is rarely reported. CASE PRESENTATION: We present the case of a 75-year-old woman with perineal skin recurrence on the site of Lone Star RetractorTM from rectal adenocarcinoma. The patient underwent a curative proctectomy followed by a hand-sewn coloanal anastomosis using Lone Star RetractorTM 2 years ago for a tumor of the lower rectum. The recurrence was most likely caused by the seeding of exfoliated tumor cells into the perianal skin which was abraded by the retractor. CONCLUSION: This case is the fourth case reported in the literature and highlights the importance of the use of less traumatic endoanal retractors to prevent such perianal recurrence. Recurrence on the perineal wound caused by anal retractor device is rare but possible. Further studies are needed to define preventive measures able to reduce cutaneous implants. PMID- 29282590 TI - Culture and Context in Mental Health Diagnosing: Scrutinizing the DSM-5 Revision. AB - This article examines the revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and its claim of incorporating a "greater cultural sensitivity." The analysis reveals that the manual conveys mixed messages as it explicitly addresses the critique of being ethnocentric and having a static notion of culture yet continues in a similar fashion when culture is applied in diagnostic criteria. The analysis also relates to current trends in psychiatric nosology that emphasize neurobiology and decontextualize distress and points to how the DSM-5 risks serving as an ethnic dividing line in psychiatry by making sociocultural context relevant only for some patients. PMID- 29282591 TI - Performance of regional oxygen saturation monitoring by near-infrared spectroscopy (NIRS) in pediatric inter-hospital transports with special reference to air ambulance transports: a methodological study. AB - The aim of the present study was to evaluate the performance of regional oxygen saturation (rSO2) monitoring with near infrared spectroscopy (NIRS) during pediatric inter-hospital transports and to optimize processing of the electronically stored data. Cerebral (rSO2-C) and abdominal (rSO2-A) NIRS sensors were used during transport in air ambulance and connecting ground ambulance. Data were electronically stored by the monitor during transport, extracted and analyzed off-line after the transport. After removal of all zero and floor effect values, the Savitzky-Golay algorithm of data smoothing was applied on the NIRS signal. The second order of smoothing polynomial was used and the optimal number of neighboring points for the smoothing procedure was evaluated. NIRS-data from 38 pediatric patients was examined. Reliability, defined as measurements without values of 0 or 15%, was acceptable during transport (> 90% of all measurements). There were, however, individual patients with < 90% reliable measurements during transport, while no patient was found to have < 90% reliable measurements in hospital. Satisfactory noise reduction of the signal, without distortion of the underlying information, was achieved when 20-50 neighbors ("window-size") were used. The use of NIRS for measuring rSO2 in clinical studies during pediatric transport in ground and air-ambulance is feasible but hampered by unreliable values and signal interference. By applying the Savitzky-Golay algorithm, the signal-to-noise ratio was improved and enabled better post-hoc signal evaluation. PMID- 29282592 TI - Systematic exploration of multiple drug binding sites. AB - BACKGROUND: Targets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms. RESULTS: To overcome such limitations, the present study introduces Wrap 'n' Shake (WnS), an atomic resolution method that systematically "wraps" the entire target into a monolayer of ligand molecules. Functional binding sites are extracted by a rapid molecular dynamics shaker. WnS is tested on biologically important systems such as mitogen activated protein, tyrosine-protein kinases, key players of cellular signaling, and farnesyl pyrophosphate synthase, a target of antitumor agents. PMID- 29282593 TI - Reasoning Abilities and Potential Correlates Among Jordanian School Children. AB - Objectives To investigate factors related to reasoning skills in 434 school children aged 5-9 years. Methods The Leiter International Performance Scale Revised was used to assess reasoning skills. Demographic, work and family income data, information on child's daily behavior and school academic achievement were provided by the participating children's parents. Results Reasoning scores increased by 4.56 points with increasing subject's age, 1.71 points with increasing level of father's occupation, 1.86 points with each increase in the subject's GPA, 1.13 points with consumption of breakfast at home and 1.81 points when child slept more hours. Having a father who smoked and living in a rural area decreased scores in reasoning. Conclusions for Practice Screening of reasoning and associated factors is essential for a comprehensive and accurate understanding of the child's abilities and limitations. Understanding the child's reasoning abilities is critical for establishing intervention goals and planning therapeutic activities. PMID- 29282594 TI - Risk factors for failed urethrocutaneous fistula repair after transverse preputial island flap urethroplasty in pediatric hypospadias. AB - OBJECTIVES: We review our experience in urethrocutaneous fistula (UCF) repair after transverse preputial island flap urethroplasty (Duckett) in pediatric hypospadias to investigate the risk factors for unsuccessful outcome. METHODS: Two hundred and nineteen UCFs repairs conducted in our center from January 2015 to December 2016 after Duckett technique were retrospectively reviewed and 182 had a follow-up for more than 6 months. The age of patients, size, localization and numbers of UCFs, interval time of two operations, length of neourethra, times of UCFs repairs, complications other than UCFs, hospital of primary surgery and postoperative infection were analyzed as potential risk factors. Stratified analysis and assessment of additive interaction were performed to have a better understanding of the relation between the risk factors. Logistic regression analysis was used for multivariate analysis. RESULTS: UCF repairs were succeeded in 121 (66.5%) and failed in 61 (33.5%) at first operation. In the univariate analysis, size and numbers of UCFs (P = 0.01 and P = 0.035, respectively), interval time of two operations (P = 0.042) and hospital of primary surgery (P = 0.02) were statistically related with the outcome. In the multivariate analysis, UCF >= 2 (OR 2.71, 95%, CI 1.095-6.692, P = 0.031), size >= 2 mm (OR 2.45, 95% CI 1.267-4.757, P = 0.08) and primary surgery not at our hospital (OR 2.21, 95% CI 1.094-4.126, P = 0.026) were identified as independent risk factors for unsuccessful outcome. In the stratified analysis, multiplicative interaction between the 3 risk factors was not found. CONCLUSIONS: Our study suggested that UCF repairs after transverse preputial island flap urethroplasty were easier to fail if the UCF was >= 2 mm, the numbers of UCFs was >= 2, or the surgeon had less experience. The age of patients, site of UCFs, interval time of two operations, length of neourethra, times of UCFs repairs, complications other than UCF and postoperative infection were not significantly related to the success rate of UCF repair. PMID- 29282596 TI - A Poroelasticity Theory Approach to Study the Mechanisms Leading to Elevated Interstitial Fluid Pressure in Solid Tumours. AB - Although the mechanisms responsible for elevated interstitial fluid pressure (IFP) in tumours remain obscure, it seems clear that high IFP represents a barrier to drug delivery (since the resulting adverse pressure gradient implies a reduction in the driving force for transvascular exchange of both fluid and macromolecules). R. Jain and co-workers studied this problem, and although the conclusions drawn from their idealized mathematical models offered useful insights into the causes of elevated IFP, they by no means gave a definitive explanation for this phenomenon. In this paper, we use poroelasticity theory to also develop a macroscopic mathematical model to describe the time evolution of a solid tumour, but focus our attention on the mechanisms responsible for the rise of the IFP, from that for a healthy interstitium to that measured in malignant tumours. In particular, we discuss a number of possible time scales suggested by our mathematical model and propose a tumour-dependent time scale that leads to results in agreement with experimental observations. We apply our mathematical model to simulate the effect of "vascular normalization" (as proposed by Jain in Nat Med 7:987-989, 2001) on the IFP profile and discuss and contrast our conclusions with those of previous work in the literature. PMID- 29282595 TI - Perceptual Experience Norms for 506 Russian Nouns: Modality Rating, Spatial Localization, Manipulability, Imageability and Other Variables. AB - A number of new psycholinguistic variables has been proposed during the last years within embodied cognition framework: modality experience rating (i.e., relationship between words and images of a particular perceptive modality-visual, auditory, haptic etc.), manipulability (the necessity for an object to interact with human hands in order to perform its function), vertical spatial localization. However, it is not clear how these new variables are related to each other and to such traditional variables as imageability, AoA and word frequency. In this article, normative data on the modality (visual, auditory, haptic, olfactory, and gustatory) ratings, vertical spatial localization of the object, manipulability, imageability, age of acquisition, and subjective frequency for 506 Russian nouns are presented. Strongest correlations were observed between olfactory and gustatory modalities (.81), visual modality and imageability (.78), haptic modality and manipulability (.7). Other modalities also significantly correlate with imageability: olfactory (.35), gustatory (.24), and haptic (.67). Factor analysis divided variables into four groups where visual and haptic modality ratings were combined with imageability, manipulability and AoA (the first factor); word length, frequency and AoA formed the second factor; olfactory modality was united with gustatory (the third factor); spatial localization only is included in the fourth factor. Present norms of imageability and AoA are consistent with previous as correlation analysis has revealed. The complete database can be downloaded from supplementary material. PMID- 29282597 TI - Mathematical Analysis of the Transmission Dynamics of HIV Syphilis Co-infection in the Presence of Treatment for Syphilis. AB - The re-emergence of syphilis has become a global public health issue, and more persons are getting infected, especially in developing countries. This has also led to an increase in the incidence of human immunodeficiency virus (HIV) infections as some studies have shown in the recent decade. This paper investigates the synergistic interaction between HIV and syphilis using a mathematical model that assesses the impact of syphilis treatment on the dynamics of syphilis and HIV co-infection in a human population where HIV treatment is not readily available or accessible to HIV-infected individuals. In the absence of HIV, the syphilis-only model undergoes the phenomenon of backward bifurcation when the associated reproduction number ([Formula: see text]) is less than unity, due to susceptibility to syphilis reinfection after recovery from a previous infection. The complete syphilis-HIV co-infection model also undergoes the phenomenon of backward bifurcation when the associated effective reproduction number ([Formula: see text]) is less than unity for the same reason as the syphilis-only model. When susceptibility to syphilis reinfection after treatment is insignificant, the disease-free equilibrium of the syphilis-only model is shown to be globally asymptotically stable whenever the associated reproduction number ([Formula: see text]) is less than unity. Sensitivity and uncertainty analysis show that the top three parameters that drive the syphilis infection (with respect to the associated response function, [Formula: see text]) are the contact rate ([Formula: see text]), modification parameter that accounts for the increased infectiousness of syphilis-infected individuals in the secondary stage of the infection ([Formula: see text]) and treatment rate for syphilis-only infected individuals in the primary stage of the infection ([Formula: see text]). The co-infection model was numerically simulated to investigate the impact of various treatment strategies for primary and secondary syphilis, in both singly and dually infected individuals, on the dynamics of the co-infection of syphilis and HIV. It is observed that if concerted effort is exerted in the treatment of primary and secondary syphilis (in both singly and dually infected individuals), especially with high treatment rates for primary syphilis, this will result in a reduction in the incidence of HIV (and its co-infection with syphilis) in the population. PMID- 29282599 TI - Histologic Predictors of Recurrence in Mucinous Appendiceal Tumors with Peritoneal Dissemination after HIPEC. AB - BACKGROUND: Mucinous appendiceal tumors (MAT) are rare neoplasms that can metastasize to the peritoneum and often are treated with cytoreductive surgery (CRS) and HIPEC. Pathologic classification and outcomes vary, but standardized histologic definitions are emerging. We sought to evaluate outcomes in this disease after CRS/HIPEC using standardized pathologic criteria. METHOD: Outcomes of MAT with peritoneal metastases (PM) after CRS/HIPEC from 2007 to 2015 were reviewed at our institution. Standardized histologic categories per WHO and consensus definitions were used: low-grade appendiceal mucinous neoplasm (LAMN), low-grade adenocarcinoma (LGAC), or high-grade adenocarcinoma (HGAC) primary tumors; and acellular mucin (AM), low-grade mucinous carcinoma peritonei (LGMCP), or high-grade mucinous carcinoma peritonei (HGMCP) peritoneal metastases. Cox proportional hazards model was used identify predictors of progression-free survival (PFS) by univariate and multivariate analyses. RESULTS: A total of 183 patients undergoing 197 CRS/HIPECs were included. Among 75 patients with primary histology review, there were 33 (44.0%) LAMNs, 28 (37.3%) LGACs, and 14 (18.7%) HGACs. Peritoneal histology was benign in 6 (3.0%), AM in 33 (16.8%), LGMCP in 114 (57.9%), and HGMCP in 44 (22.3%). PFS was not reached for AM, 34.3 months for LGMCP, and 16.8 months for HGMCP (p < 0.001). Peritoneal histology predicted PFS on multivariate analysis (hazard ratio 9.82 and 24.60 for LGMCP and HGMCP, respectively, vs. AM, p < 0.001). Among the LGMCP group, CEA and completeness of cytoreduction (CC score) predicted PFS on multivariate analysis. CONCLUSIONS: Standardized peritoneal histology in patients with PM from MAT predicts PFS and patients with low-grade histology can be further discriminated by CEA and CC score. PMID- 29282598 TI - Upf proteins: highly conserved factors involved in nonsense mRNA mediated decay. AB - Over 10% of genetic diseases are caused by mutations that introduce a premature termination codon in protein-coding mRNA. Nonsense-mediated mRNA decay (NMD) is an essential cellular pathway that degrades these mRNAs to prevent the accumulation of harmful partial protein products. NMD machinery is also increasingly appreciated to play a role in other essential cellular functions, including telomere homeostasis and the regulation of normal mRNA turnover, and is misregulated in numerous cancers. Hence, understanding and designing therapeutics targeting NMD is an important goal in biomedical science. The central regulator of NMD, the Upf1 protein, interacts with translation termination factors and contextual factors to initiate NMD specifically on mRNAs containing PTCs. The molecular details of how these contextual factors affect Upf1 function remain poorly understood. Here, we review plausible models for the NMD pathway and the evidence for the variety of roles NMD machinery may play in different cellular processes. PMID- 29282600 TI - Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Metastases from Endometrial Cancer. AB - BACKGROUND: More information is needed for selection of patients with peritoneal metastases from endometrial cancer (EC) to undergo cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This study analyzed clinical, pathologic, and treatment data for patients with peritoneal metastases from EC who underwent CRS plus HIPEC at two tertiary centers. The outcome measures were morbidity, overall survival (OS), and progression-free survival (PFS) during a median 5 year follow-up period. Uni- and multivariate analyses were performed to identify significant factors related to outcome. RESULTS: A total of 33 patients met the inclusion criteria and completed the follow-up period. At laparotomy, the median peritoneal cancer index (PCI) was 15 (range 3-35). The CRS procedure required a mean 8.3 surgical procedures per patient, and for 22 patients (66.6%), a complete cytoreduction was achieved. The mean hospital stay was 18 days, and major morbidity developed in 21% of the patients. The operative mortality was 3%. When surgery ended, HIPEC was administered with cisplatin 75 mg/m2 for 60 min at 43 degrees C. During a median follow-up period of 73 months, Kaplan-Meier analysis indicated a 5 year OS of 30% (median 33.1 months) and a PFS of 15.5% (median 18 months). Multivariate analysis identified the completeness of cytoreduction (CC) score as the only significant factor independently influencing OS. Logistic regression for the clinicopathologic variables associated with complete cytoreduction (CC0) for patients with metachronous peritoneal spread from EC who underwent secondary CRS plus HIPEC identified the PCI as the only outcome predictor. CONCLUSIONS: For selected patients with peritoneal metastases from EC, when CRS leaves no residual disease, CRS plus HIPEC achieves outcomes approaching those for other indications such as colon and ovarian carcinoma. PMID- 29282601 TI - Decreased Use of Sphincter-Preserving Procedures Among African Americans with Rectal Cancer. AB - BACKGROUND: Improved multimodality rectal cancer treatment has increased the use of sphincter-preserving surgery. This study sought to determine whether African American (AA) patients with rectal cancer receive sphincter-preserving surgery at the same rate as non-AA patients. METHODS: The study used the Nationwide Inpatient Sample for years 1998-2012 to compare AA and non-AA patients with rectal cancer undergoing low anterior resection or abdominoperineal resection. The logistic regression model was used to adjust for age, gender, admission type, Elixhauser comorbidity index, and hospital factors such as size, location (urban vs.rural), teaching status, and procedure volume. RESULTS: The search identified 22,697 patients, 1600 of whom were identified as AA. After adjustment for age and gender, the analysis showed that AA patients were less likely to undergo sphincter-preserving surgery than non-AA patients [odds ratio (OR) 0.70; 95% confidence interval (CI) 0.63-0.78; p < 0.0001). After further adjustment for the Elixhauser comorbidity index, admission type, hospital-specific factors, and insurance status, the analysis showed that AA patients still were less likely to undergo sphincter-preserving surgery (OR 0.78; 95% CI 0.70-0.87; p < 0.0001). Although the proportion of non-AA patients undergoing sphincter-preserving surgery increased during the study period (p = 0.0003), this trend was not significant for the AA patients (p = 0.13). CONCLUSION: In this data analysis, the AA patients with rectal cancer had lower rates of sphincter-preserving surgery than the non-AA patients, even after adjustment for patient- and hospital specific factors. Further work is required to elucidate why. Eliminating racial disparities in rectal cancer treatment should continue to be a priority for the surgical community. PMID- 29282602 TI - Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Elderly: Is It Reasonable? A Meta-Analysis. AB - BACKGROUND: Whether cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is safe and worthwhile for elderly patients remains unclear. This meta-analysis of outcomes after CRS plus HIPEC for the elderly aimed to generate a higher level of evidence and precise indications for these patients. METHODS: A systematic literature search for studies reporting postoperative outcomes after CRS plus HIPEC for elderly patients was performed in the MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Knowledge Conference Proceedings Citation Index-Science, and Google Scholar databases. The included studies evaluated the overall 30-day postoperative morbidity, 90-day postoperative mortality, grade 3 or higher postoperative morbidity, rates of anastomotic leaks, reoperation and readmission, and length of hospital stay. RESULTS: The inclusion criteria were met by 13 retrospective studies involving 2544 patients. Considering only comparative studies, the 90-day postoperative mortality was significantly increased for elderly patients [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.88; I 2 = 79%]. The 30-day grade 3 or higher postoperative morbidity was increased in the patients 70 years of age or older (14.5%; 95% CI 8.1-24.4 vs. 32.3%; 95% CI 22.4-44.0%; p = 0.004; I 2 = 85%). The overall 30-day postoperative morbidity, rates of anastomotic leaks, reoperation and readmission, and length of hospital stay were not affected by age. CONCLUSIONS: Treatment of the elderly with CRS plus HIPEC was associated with increased severe postoperative morbidity and mortality. However, these conclusions should be weighted given the existence of major biases in the included studies. Age alone probably would not be a formal contraindication, but frailty should be taken into account. Further prospective studies are needed. PMID- 29282603 TI - Perioperative Risk Calculator Predicts Long-Term Oncologic Outcome for Patients with Esophageal Carcinoma. AB - BACKGROUND: Few risk models have been provided to predict long-term prognosis after esophagectomy. This study investigated the reliability of a risk calculator as well as classification and regression trees analysis for predicting long-term prognosis after esophagectomy for esophageal cancer. METHODS: The study enrolled 438 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between July 2000 and June 2016. Patients who underwent R0 or R1 resection or esophagectomy with combined resection of other organs were included. The authors investigated the usefulness of a risk model for 30-day mortality and operative mortality described in their previous report for predicting long-term prognosis after esophagectomy. RESULTS: The 438 patients (377 men and 61 women) in this study had a 5-year overall survival (OS) rate of 62.8% and a disease-free survival rate of 54.3%. The OS was higher for the patients with 30-day mortality risk model values lower than 0.675% than for those with values higher than 0.675% (p < 0.001). The cutoff values for prediction were shown to be significant risk factors in the multivariate analysis. The risk calculator was validated by comparing the cutoff values with Harrell's C-index values of clinical stage. For overall risk, the C-index of operative mortality was 0.697, and the C-index of cStage was 0.671. CONCLUSIONS: The risk calculator was useful for predicting recurrence and death after esophagectomy. Furthermore, because the C-index of the risk model for operative mortality was higher than for clinical tumor-node metastasis stage, this risk-scoring system may be more useful clinically. PMID- 29282605 TI - miR-155 in cancer drug resistance and as target for miRNA-based therapeutics. AB - Small non-coding microRNAs (miRNAs) are instrumental in physiological processes, such as proliferation, cell cycle, apoptosis, and differentiation, processes which are often disrupted in diseases like cancer. miR-155 is one of the best conserved and multifunctional miRNAs, which is mainly characterized by overexpression in multiple diseases including malignant tumors. Altered expression of miR-155 is found to be associated with various physiological and pathological processes, including hematopoietic lineage differentiation, immune response, inflammation, and tumorigenesis. Furthermore, miR-155 drives therapy resistance mechanisms in various tumor types. Therefore, miR-155-mediated signaling pathways became a potential target for the molecular treatment of cancer. In this review, we summarize the current findings of miR-155 in hematopoietic lineage differentiation, the immune response, inflammation, and cancer therapy resistance. Furthermore, we discuss the potential of miR-155-based therapeutic approaches for the treatment of cancer. PMID- 29282604 TI - OsLAP6/OsPKS1, an orthologue of Arabidopsis PKSA/LAP6, is critical for proper pollen exine formation. AB - BACKGROUND: Male fertility is crucial for rice yield, and the improvement of rice yield requires hybrid production that depends on male sterile lines. Although recent studies have revealed several important genes in male reproductive development, our understanding of the mechanisms of rice pollen development remains unclear. RESULTS: We identified a rice mutant oslap6 with complete male sterile phenotype caused by defects in pollen exine formation. By using the MutMap method, we found that a single nucleotide polymorphism (SNP) variation located in the second exon of OsLAP6/OsPKS1 was responsible for the mutant phenotype. OsLAP6/OsPKS1 is an orthologous gene of Arabidopsis PKSA/LAP6, which functions in sporopollenin metabolism. Several other loss-of-function mutants of OsLAP6/OsPKS1 generated by the CRISPR/Cas9 genomic editing tool also exhibited the same phenotype of male sterility. Our cellular analysis suggested that OsLAP6/OsPKS1 might regulate pollen exine formation by affecting bacula elongation. Expression examination indicated that OsLAP6/OsPKS1 is specifically expressed in tapetum, and its product is localized to the endoplasmic reticulum (ER). Protein sequence analysis indicated that OsLAP6/OsPKS1 is conserved in land plants. CONCLUSIONS: OsLAP6/OsPKS1 is a critical molecular switch for rice male fertility by participating in a conserved sporopollenin precursor biosynthetic pathway in land plants. Manipulation of OsLAP6/OsPKS1 has potential for application in hybrid rice breeding. PMID- 29282606 TI - Appraisal Support from Natural Mentors, Self-worth, and Psychological Distress: Examining the Experiences of Underrepresented Students Transitioning Through College. AB - The current study explored whether cumulative appraisal support from as many as five natural mentors (i.e., nonparental adults from youth's pre-existing social networks who serve a mentoring role in youth's lives) led to reduced symptoms of depression and anxiety via improved global self-worth among underrepresented college students. Participants in the current study included 340 college students (69% female) attending a 4-year, predominantly White institution of higher education. Participants were first-generation college students, students from economically disadvantaged backgrounds, and/or students from underrepresented racial/ethnic minority groups. Participants completed surveys during the Fall and Spring of their first year of college and in the Spring of their second and third years of college. Results of the structural equation model (including gender, race/ethnicity, and extraversion as covariates) indicated that greater total appraisal support from natural mentoring relationships predicted decreases in students' psychological distress via increases in self-worth (indirect effects assessed via boot-strapped confidence intervals; 95% CI). The strength of association between appraisal support and self-worth was not moderated by the proportion of academic natural mentors. Findings from the current study extend previous research by measuring multiple natural mentoring relationships and pinpointing supportive exchanges that may be of particular consequence for the promotion of healthy youth development. Institutional efforts to reinforce pre existing natural mentoring relationships and encourage the onset of new natural mentoring relationships may serve to bolster the well-being and success of underrepresented students attending predominantly White universities. PMID- 29282607 TI - Mechanism of the reconstruction of aqueous outflow drainage. AB - Glaucoma is the leading cause of irreversible blindness worldwide. The reconstruction of aqueous outflow drainage (RAOD) has recently been proposed to aid in restoring aqueous outflow drainage in primary open-angle glaucoma. However, the mechanism of RAOD remains to be fully understood. Based on literature review and research studies, the potential mechanisms of RAOD are the following: (i) Circumferential dilation of the Schlemm's canal (SC) and surrounding collector channels. (ii) Instant formation of microcracks through RAOD procedures. (iii) Formation of more pores, and local detachment between the SC endothelium (SCE) and basement membrane. (iv) Activation of stem cells by constant mechanical stress caused by the tensional suture placed at the anterior part of the SC. (v) Reversal of trabecular meshwork (TM) herniation. (vi) Mobilization of the reserve of the aqueous drainage. (vii) Change of SCE phenotype. (viii) Mechanosensing and mechanotransducing of TM. PMID- 29282608 TI - Dietary Application of the Probiotic Lactobacillus plantarum 426951 Enhances Immune Status and Growth of Rainbow Trout (Oncorhynchus mykiss) Vaccinated Against Yersinia ruckeri. AB - This study was aimed to assess the effect of oral application of Lactobacillus plantarum (2 * 107 CFU g-1 feed) as a probiotic on growth performance and immune status of vaccinated rainbow trout (29.5 +/- 2 g) to yersiniosis at 16 +/- 2 degrees C for 72 days. Fish were randomly allocated into 12 fiber glass tanks (4100 L) at a density of 80 fish per tank (240 fish per treatment). The results revealed that the activity of lysozyme and alkaline phosphatase was significantly higher in immunized fish fed with diet supplemented with probiotic (vaccine +probiotic) than that in the immunized group fed with basal diet (vaccine group) while no significant differences in levels of hematological parameters, complements, total IgM, proteins, and the intestine lactic acid bacteria (LAB) were detected. Also, significantly a better growth performance in terms of feed conversion ratio, weight gain, and thermal growth coefficient was seen in the vaccine + probiotic group than that in the vaccine group. These results indicate that feeding probiotic after vaccination can enhance the efficacy of immersion vaccination to Yersinia ruckeri. PMID- 29282609 TI - Changes in Immunity, Expression of some Immune-Related Genes of Shabot Fish, Tor grypus, Following Experimental Infection with Aeromonas hydrophila: Effects of Autochthonous Probiotics. AB - In this study, the effects of orally administrated two native probiotics (Lactobacillus plantarum and Lactobacillus delbrueckii ssp. bulguricus), isolated from the intestine of Shabot fish, Tor grypus, on some immune response parameters and immune-related genes expression against Aeromonas hydrophila in T. grypus were evaluated. Four hundred and eighty juveniles weighing 45 +/- 10 g were randomly divided into four groups (with three replications) and fed with the experimental diet containing 5 * 107 cfu g-1 of L. plantarum (G1), Lactobacillus bulgaricus (G2), Lactobacillus casei (G3), and a control diet (without probiotics) for 60 continuous days. At the end of the dietary treatments, fish were challenged with a lethal concentration of A. hydrophila (5 * 108 CFU ml-1) via intra peritoneal (i.p) injection. Blood and head kidney samples were taken from six fish in each treatment before challenging and 6, 12, 24, and 48 h and also 7 days after injection. The results showed that lysozyme, complement, bactericidal, and NBT activity of probiotic-treated groups were significantly elevated (P < 0.05). The IL-8, IL-1beta, and TNF-alpha gene expressions were significantly higher in all probiotic-treated groups (P < 0.05). Meanwhile, a high direct correlation was observed between serum immune parameters and expression of immune-related genes (P < 0.0001); furthermore, the highest correlation (R 2 = 0.634, P < 0.0001) was recorded between IL-1beta expression and NBT activity. It can be concluded that not only two native probiotics strains stimulate serum immune responses parameters and immune-related gene expression in T. grypus, but also a high correlation was seen among these indices. The study suggests that gastrointestinal colonization is preferred for host specificity as the strain previously derived from shabot fish displayed better colonization than the non-indigenous bacteria strain such as L. casei. Therefore, these native probiotics bacteria can be accounted as suitable candidates to immune stimulation in fish. PMID- 29282610 TI - Trends of foodborne diseases in China: lessons from laboratory-based surveillance since 2011. AB - Foodborne disease is one of the most important public health issues worldwide. China faces various and unprecedented challenges in all aspects of the food chain. Data from laboratory-based foodborne disease surveillance systems from 2013 to 2016, as well as different regions and ages, can be found along with differences in the patterns of pathogens detected with diverse characteristics. Vibrio parahaemolyticus has been the leading cause of infectious diarrhea in China, especially among adults in coastal regions. Salmonella has been a serious and widely distributed pathogen responsible for substantial socioeconomic burden. Shigella was mostly identified in Northwest China and the inland province (Henan) with less-developed regions among children under 5 years. Data from foodborne disease outbreak reporting system from 2011 to 2016 showed that poisonous animals and plant factors responsible for most deaths were poisonous mushrooms (54.7%) in remote districts in southwest regions. The biological hazard that caused most cases reported (42.3%) was attributed to V. parahaemolyticus, the leading cause of foodborne outbreaks. In this review, we summarize the recent monitoring approach to foodborne diseases in China and compare the results with those in developed countries. PMID- 29282611 TI - Calibration Curves in Quantitative Ligand Binding Assays: Recommendations and Best Practices for Preparation, Design, and Editing of Calibration Curves. AB - The accuracy of reported sample results is contingent upon the quality of the assay calibration curve, and as such, calibration curves are critical components of ligand binding and other quantitative methods. Regulatory guidance and lead publications have defined many of the requirements for calibration curves which encompass design, acceptance criteria, and selection of a regression model. However, other important aspects such as preparation and editing guidelines have not been addressed by health authorities. The goal of this publication is to answer many of the commonly asked questions and to present a consensus and the shared views of members of the ligand binding assay (LBA) community on topics related to calibration curves with focus on providing recommendations for the preparation and editing of calibration curves. PMID- 29282612 TI - The Role of Synapsins in Neurological Disorders. AB - Synapsins serve as flagships among the presynaptic proteins due to their abundance on synaptic vesicles and contribution to synaptic communication. Several studies have emphasized the importance of this multi-gene family of neuron-specific phosphoproteins in maintaining brain physiology. In the recent times, increasing evidence has established the relevance of alterations in synapsins as a major determinant in many neurological disorders. Here, we give a comprehensive description of the diverse roles of the synapsin family and the underlying molecular mechanisms that contribute to several neurological disorders. These physiologically important roles of synapsins associated with neurological disorders are just beginning to be understood. A detailed understanding of the diversified expression of synapsins may serve to strategize novel therapeutic approaches for these debilitating neurological disorders. PMID- 29282615 TI - Predictors of active arterial hemorrhage on angiography in pelvic fracture patients. AB - PURPOSE: To determine predictors of active angiographic hemorrhage in pelvic fracture patients. MATERIALS AND METHODS: This retrospective study included 66 trauma patients who had major hemorrhages due to pelvic fractures, and who underwent pelvic angiography between January 2012 and December 2014. The study population comprised 31 males and 35 females (mean age 44.2 +/- 20.7 years). The main outcome was active hemorrhage on pelvic angiography. Clinical and imaging variables including demographics, hemodynamic parameters, injury severity, types of pelvic fracture, laboratory data, blood transfusions and CT findings were analyzed. Multivariate logistic regression was used to identify predictors of active angiographic hemorrhage. RESULTS: Of the 66 study patients included, 41 patients had active angiographic hemorrhage. These patients had more blood transfusions, higher activated partial thromboplastin times and higher rates of contrast extravasation on CT (p < 0.05). Three independent predictors of active angiographic hemorrhage were identified, including contrast extravasation on CT (OR: 74.6, p < 0.001), more than 8 units of RBC transfusions (OR: 12.5, p = 0.018) and ISS >= 16 (OR: 11.1, p = 0.029). CONCLUSION: Contrast extravasation on CT, high volume RBC transfusions and ISS >= 16 can help us to select pelvic fracture patients for angiography more precisely. PMID- 29282616 TI - Non-invasive Cerebellar Stimulation: Moving Towards Clinical Applications for Cerebellar and Extra-Cerebellar Disorders. AB - The field of non-invasive stimulation of the cerebellum is quickly expanding. The anatomical structure of the cerebellum with a high density of neurons in the superficial layer, its electrical properties, and its participation in numerous closed-loop circuits involved in motor, cognitive, and affective operations both in children and in adults make of the cerebellum a target with very high potential for neuromodulation of both cerebellar and extra-cerebellar disorders, in neurology, psychiatry, and neurosurgery. A common research effort is required to extract the optimal parameters of stimulation and to identify how non-invasive stimulation of the cerebellum modifies cerebellar plasticity and functional connectivity in remote cortical and subcortical areas. A patient stratification should be considered. PMID- 29282617 TI - Crus I in the Rodent Cerebellum: Its Homology to Crus I and II in the Primate Cerebellum and Its Anatomical Uniqueness Among Neighboring Lobules. AB - In the human cerebellum, the crus I and crus II lobules (or the ansiform lobule), which are implicated in cognitive and visuomotor functions, are significantly expanded compared to other anterior and posterior lobules, which are involved mainly in somatosensorimotor function. In applying rodent models, it is essential to identify the lobules that are homologous to human crus I and crus II. Observation of the lobular structure in human, macaque, marmoset, rat, and mouse has indicated that human crus I and II are homologous to crus I in rodents (referred to as "ansiform area, AA"). This new lobular definition is supported by lobule-based mapping of the olivocerebellar climbing fiber and Purkinje cell (PC) projection patterns in rodents; crus II and simple lobules are innervated by the mediocaudal part of each inferior olive subnucleus and project to the dorsal part of the cerebellar nuclei, while crus I (or the AA) is innervated by the rostrolateral part of each inferior olive subnucleus and projects to the ventral part of the cerebellar nuclei. Concerning zebrin stripes, the central lobules (lobules VI-VII and AA or crus I in rodents) show a laterally expanded arrangement solely of positive stripes. Our recent analysis has shown that this arrangement of zebrin-positive stripes in the AA originates from their developmental process. Between E14.5 and E17.5, lateral protrusion and shift has been observed in the domains of protocadherin 10-positive PC subsets (which would become zebrin-positive later) in the central area of the immature cerebellum that eventually becomes lobules VI-VII and AA or crus I. These data suggest that the AA (or crus I in rodents) is a unique lobule in the mammalian cerebellum which is characterized by distinct connectivity from neighboring lobules, a massive expansion in skillful primates, and the formation of longitudinal stripes different from that in neighboring anterior and posterior lobules. PMID- 29282614 TI - Update on Molecular Imaging in Parkinson's Disease. AB - Advances in radionuclide tracers have allowed for more accurate imaging that reflects the actions of numerous neurotransmitters, energy metabolism utilization, inflammation, and pathological protein accumulation. All of these achievements in molecular brain imaging have broadened our understanding of brain function in Parkinson's disease (PD). The implementation of molecular imaging has supported more accurate PD diagnosis as well as assessment of therapeutic outcome and disease progression. Moreover, molecular imaging is well suited for the detection of preclinical or prodromal PD cases. Despite these advances, future frontiers of research in this area will focus on using multi-modalities combining positron emission tomography and magnetic resonance imaging along with causal modeling with complex algorithms. PMID- 29282618 TI - Hair Mineral and Trace Element Contents as Reliable Markers of Nutritional Status Compared to Serum Levels of These Elements in Children Newly Diagnosed with Inflammatory Bowel Disease. AB - Patients with inflammatory bowel disease (IBD) are at high risk for nutritional deficiencies because of long-term inflammation in the gut mucosa and decreased oral intake. Because inflammation responses affect serum micronutrient concentrations, serum levels are limited in reflecting body nutrient status in acute and chronic illness. We investigated the usefulness of measuring trace elements in hair as reliable markers of nutritional status compared to serum levels in children with IBD. We retrospectively analyzed pediatric patients newly diagnosed with Crohn's disease (n = 49) and ulcerative colitis (n = 16) and controls (n = 29) from 2012 to 2016. Serum micronutrient levels, inflammatory markers, and hair trace element content were evaluated and compared at the time of diagnosis and before initiating treatment. Serum calcium (p < 0.001), iron (p < 0.001), zinc (p = 0.013), selenium (p = 0.008), albumin (p < 0.001), prealbumin (p < 0.001), hemoglobin and hematocrit (p < 0.001), and WBC (p = 0.001) and lymphocytes (p < 0.001) differed significantly between the groups. After adjustment for the erythrocyte sedimentation rate, serum zinc and selenium levels were no longer significantly different between the groups (p < 0.062 and p < 0.057, respectively). Following hair analysis for mineral and trace elements, iron (p = 0.033), selenium (p = 0.017), and manganese (p = 0.009) differed significantly between the groups. Serum micronutrient levels need cautious interpretation in conjunction with inflammatory markers. Hair mineral and trace element measurement may support understanding micronutrient status in children with IBD. PMID- 29282613 TI - Regulation of Pain and Itch by TRP Channels. AB - Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level. PMID- 29282619 TI - Dickkopf 1 protein circulating levels as a possible biomarker of functional disability and chronic damage in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an inflammatory disease characterized by joint destruction, deformity, lower functionality, and decrease in life expectancy. Wingless signaling pathway (Wnt) has been recently involved in bone homeostasis. Studies suggest that overexpression of the pathway inhibitors, like the Dickkopf 1 protein (DKK1), has been implicated in bone destruction. The objective of this study is to compare circulating levels of DKK1 in different groups of patients with disease activity (remission, low, moderate, high activity,) and functionality status. Three hundred seventy-nine patients with RA were evaluated between March 2015 and November 2016. Disease activity was evaluated by disease activity score 28 with C-reactive protein (DAS28CPR), simplified and clinical disease activity scores (SDAI, CDAI), routine assessment of patient index data 3 (RAPID3), functional status using Multidimensional Health Assessment Questionnaire (MD-HAQ), and the Steinbrocker functional classification. DKK1 levels were measured by ELISA. The mean age was 60.7 +/- 13.9 years. Disease duration was 13.2 +/- 10.9 years. Higher levels of DKK1 were not associated with disease activity by CDAI (p = 0.70), SDAI (p = 0.84), DAS28CRP (p = 0.80), or RAPID3 (p = 0.70). Interestingly higher levels of DKK1 were significantly associated to lower functional status evaluating by the Steinbrocker classification (p = 0,013), severe disability by MD-HAQ (p = 0,004), and variables associated with joint destruction like osteoporosis, higher titles of rheumatoid factor, smoking, and increased hospital admissions related to RA. Higher levels of DKK1 were found in patients with lower functional status. This association was not found in patients with greater disease activity by CDAI, SDAI, DAS28, and RAPID3. This could be explained by more structural damage; DKK1 could be used as a biomarker of joint destruction in RA. PMID- 29282620 TI - Correction to: Date palm waste biochars alter a soil respiration, microbial biomass carbon, and heavy metal mobility in contaminated mined soil. AB - Unfortunately, in the original publication of the article, Prof. Yang Sik Ok's affiliation was incorrectly published. The author's affiliation is as follows. PMID- 29282621 TI - Correction to: Date palm waste-derived biochar composites with silica and zeolite: synthesis, characterization and implication for carbon stability and recalcitrant potential. AB - Unfortunately, in the original publication of the article, Prof. Yong Sik Ok's affiliation was incorrectly published. PMID- 29282622 TI - Correction to: Potential toxicity of trace elements and nanomaterials to Chinese cabbage in arsenic- and lead-contaminated soil amended with biochars. AB - Unfortunately, in the original publication of the article, Prof. Yong Sik Ok's affiliation was incorrectly published. The author's affiliation is as follows. PMID- 29282623 TI - Correction to: Adsorption antagonism and synergy of arsenate(V) and cadmium(II) onto Fe-modified rice straw biochars. AB - Unfortunately, in the original publication of the article, Prof. Yong Sik Ok's affiliation was incorrectly published. The author's affiliation is as follows. PMID- 29282624 TI - Correction to: Heavy metal-induced oxidative stress on seed germination and seedling development: a critical review. AB - Unfortunately, in the original publication of the article, Prof. Yong Sik Ok's affiliation was incorrectly published. The author's affiliation is as follows. PMID- 29282625 TI - Desmoplastic Small Round Cell Tumor: A Rare Case of Extraluminal Bowel Obstruction and Review of the Literature. PMID- 29282626 TI - Detoxification of aflatoxins on prospective approach: effect on structural, mechanical, and optical properties under pressures. AB - Aflatoxins are sequential of derivatives of coumarin and dihydrofuran with similar chemical structures and well-known carcinogenic agent. Many studies performed to detoxify aflatoxins, but the result is not ideal. Therefore, we studied structural, infrared spectrum, mechanical, and optical properties of these compounds in the aim of perspective physics. Mulliken charge distributions and infrared spectral analysis performed to understand the structural difference between the basic types of aflatoxins. In addition, the effect of pressure, different polarized, and incident directions on their structural changes was determined. It is found that AFB1 is most stable structure among four basic types aflatoxins (AFB1, AFB2, AFG1, and AFG2), and IR spectra are analyzed to exhibit the difference on structures of them. The mechanical properties of AFB1 indicate that the structure of this toxin can be easily changed by pressure. The real [Formula: see text] and imaginary [Formula: see text] parts of the dielectric function, and the absorption coefficient [Formula: see text] and energy loss spectrum [Formula: see text] were also obtained under different polarized and incident directions. Furthermore, biological experiments needed to support the toxic level of AFB1 using optical technologies. PMID- 29282627 TI - Association Between Splenic Contraction and the Systemic Inflammatory Response After Acute Ischemic Stroke Varies with Age and Race. AB - Animal models have demonstrated the deleterious contribution of splenic immunocytes on secondary brain injury after stroke. While previous work has demonstrated splenic contraction (SC) in patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH), no clinical studies have examined the relationship between the systemic inflammatory response syndrome (SIRS) with SC in stroke patients. This is a retrospective analysis of a previous prospective observational study where daily spleen sizes were evaluated in 178 acute stroke patients. Spleen contraction was based on previously established normograms of healthy volunteers from the same study. SC from the first 24 h of stroke onset was evaluated against criteria for SIRS for the first 5 days of admission after AIS. Ninety-one patients had verified AIS without concurrent infection at admission. SIRS was not associated with SC at admission. African-American patients with early SIRS had higher odds of having SC. Older patients with persistent SIRS at 72 h had lower odds of SC. At 48 h, there was significantly higher lymphocytosis and lower neutrophils present in patients with SC. Patients with SIRS at 72 h were more likely to have worse discharge mRS. This study provides evidence for an association among SC and SIRS in African-American patients suggesting that spleen changes could be a biomarker for detecting SIRS in this population. Our data also indicate a counter association between SC and a lack of SIRS in patients older than 75. Further studies are needed to ascertain how age affects this association. PMID- 29282629 TI - Inflammatory Bowel Disease Is Not a Contraindication for Bariatric Surgery. AB - BACKGROUND: Inflammatory bowel diseases (IBD) are listed as a contraindication for bariatric surgery in various guidelines due to a theoretical higher complication risk. Therefore, little is known about safety and efficacy of bariatric surgery in IBD patients. AIM: We assessed the safety and efficacy of bariatric surgery and postoperative quality of life (QoL) in IBD patients. SETTING: The study was conducted in a large peripheral hospital in the Netherlands. METHODS: All IBD patients who underwent bariatric surgery in our facility were included. Complications, mortality, reoperations, and micronutrient deficiencies were analyzed. Weight loss was assessed 6, 12, and 24 months after surgery. Postoperative QoL was assessed using a disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Forty-five patients were included in this study, all diagnosed with IBD (16 ulcerative colitis (UC) and 29 Crohn's disease (CD)) prior to bariatric surgery. Bariatric procedures included Roux-en-Y gastric bypass, sleeve gastrectomy, gastric banding, and revisional surgery. There was no mortality in the entire follow-up period and there were no major perioperative complications. Two major complications in two CD patients occurred during follow-up, gastro-enterostomy bleeding and pyelonephritis with secondary pancreatitis. Mean percentage (+/- SD) of overall excess weight loss (%EWL) and total body weight loss (%TBWL), 12 months after surgery, were 62.9 +/- 27.1 and 26.2 +/- 10.6%, respectively. Twenty-four months postoperatively, mean overall %EWL and %TBWL were similar for both UC and CD patients and were 62.9 +/- 31.0 and 26.6 +/- 12.2, respectively. Mean Bariatric Analysis and Reporting Outcome System (BAROS) score was 3.34 +/- 2.42. Median total IBDQ score was 170.8 (min. 77; max. 218). Both scores did not differ significantly between UC and CD patients. CONCLUSION: As bariatric procedures appear safe and effective in this CU and CD population, one could question why bariatric surgery is contraindicated in the patients. Nevertheless, close lifelong monitoring to assure safety and a favorable outcome remains essential. PMID- 29282628 TI - Patient-Specific Modeling of Stented Coronary Arteries Reconstructed from Optical Coherence Tomography: Towards a Widespread Clinical Use of Fluid Dynamics Analyses. AB - The recent widespread application of optical coherence tomography (OCT) in interventional cardiology has improved patient-specific modeling of stented coronary arteries for the investigation of local hemodynamics. In this review, the workflow for the creation of fluid dynamics models of stented coronary arteries from OCT images is presented. The algorithms for lumen contours and stent strut detection from OCT as well as the reconstruction methods of stented geometries are discussed. Furthermore, the state of the art of studies that investigate the hemodynamics of OCT-based stented coronary artery geometries is reported. Although those studies analyzed few patient-specific cases, the application of the current reconstruction methods of stented geometries to large populations is possible. However, the improvement of these methods and the reduction of the time needed for the entire modeling process are crucial for a widespread clinical use of the OCT-based models and future in silico clinical trials. PMID- 29282630 TI - Response to the Comment on: Effects of Laparoscopic Roux-en-Y Gastric Bypass for Type 2 Diabetes Mellitus: Comparison of BMI > 30 and < 30 kg/m2. PMID- 29282631 TI - Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c Src Protein with UM-164. AB - UM-164, a potent Src/p38 inhibitor, is a promising lead compound for developing the first targeted therapeutic strategy against triple-negative breast cancer (TNBC). However, lack of understanding of conformational features of UM-164 in complex with Src serves a challenge in the rational design of novel Src dual inhibitors. Herein, we provide an in-depth insight into conformational features of Src-UM-164 using different computational approaches. This involved molecular dynamics (MD) simulation, principal component analysis (PCA), thermodynamics calculations, dynamic cross-correlation (DCCM) analysis, and hydrogen bond formation. Findings from this study revealed that (1) the binding of UM-164 to Src induces a more stable and compact conformation; (2) the binding of UM-164 results in increased correlation among the active site residue; (3) the presence of multiple phenyl rings and fluorinated phenyl group in UM-164 contributes to the steric effect; (4) a relatively high-binding free energy estimated for the Src-UM-164 system is affirmative of its experimental potency; (5) hydrophobic packing contributes significantly to the drug binding in Src-UM-164; and (6) observed increase in H-bond distance of interacting residue atoms and Dasatinib compared to UM-164. Findings from this study can serve as a baseline in the design of novel Src inhibitors with dual inhibitory properties. PMID- 29282632 TI - Effects of cilostazol and renin-angiotensin system (RAS) blockers on the renal disease progression of Korean patients: a retrospective cohort study. AB - Background Decline in estimated glomerular filtration rate (eGFR) is an important surrogate marker for the assessment of renal function. Addition of a second agent to angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) treatment may improve current therapeutic strategies aimed at suppressing renal disease progression. Objective To determine the effect of cilostazol in combination with ACEI or ARB treatment on the decline in eGFR. Setting A tertiary hospital in Korea. Method In an observational cohort study, we analyzed 5505 patients who were prescribed ACEI or ARB and cilostazol or other antiplatelet agents. Main outcome measure The primary outcome assessed was worsening of renal function defined as a 30% decline in eGFR per year. The secondary outcomes included commencement of dialysis, renal transplantation, death, myocardial infarction, and ischemic stroke. Results Following propensity score matching, eGFR decreased over time in the majority of patients, but the decline was less in patients in the cilostazol treated (CT) group of stage 1-2 category compared to the cilostazol untreated (CU) group (OR 0.80; 95% CI 0.66 0.98). In the subgroup analysis, the strongest effect in slowing eGFR decline was observed in CT patients at a high risk of diabetes (OR 0.782; 95% CI 0.615-0.993) and the elderly (OR 0.693; 95% CI 0.504-0.953) in the stage 1-2 category. No significant increase in cardiovascular risk was observed between the CT and CU groups. Conclusion Treatment with cilostazol plus ACEI or ARB was observed to prevent worsening of renal progression in patients in the stages 1-2. PMID- 29282633 TI - Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. AB - INTRODUCTION: This study assessed the safety and efficacy of ertugliflozin (an oral sodium-glucose cotransporter 2 inhibitor) vs. glimepiride in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. METHODS: This phase III, double-blind, non-inferiority study (NCT01999218) randomized patients with HbA1c >= 7.0% and <= 9.0% on stable metformin >= 1500 mg/day 1:1:1 to ertugliflozin 15 or 5 mg once-daily (QD), or glimepiride (titrated from 1 mg QD). The primary hypothesis was that ertugliflozin 15 mg was non-inferior to glimepiride on HbA1c (non-inferiority criterion: upper bound of the 95% confidence interval [CI] about the treatment difference < 0.3%). RESULTS: Mean baseline HbA1c of randomized patients (N = 1326) was 7.8%. Mean and median doses of glimepiride were 3.0 mg/day throughout the study. At week 52, the least squares mean change (95% CI) from baseline in HbA1c was - 0.6% (- 0.7, - 0.5), - 0.6% (- 0.6, - 0.5), and - 0.7% (- 0.8, - 0.7) in the ertugliflozin 15 mg, ertugliflozin 5 mg, and glimepiride groups, respectively. The between-group difference for ertugliflozin 15 mg and glimepiride of 0.1% (- 0.0, 0.2) met the pre-specified non-inferiority criterion. Relative to glimepiride, greater body weight and systolic blood pressure (SBP) reductions were observed with ertugliflozin. The overall incidence of adverse events (AEs) was similar across groups. The incidence of symptomatic hypoglycemia and genital mycotic infection (GMI) were, respectively, lower and higher with ertugliflozin relative to glimepiride. The incidences of urinary tract infection and hypovolemia AEs were not meaningfully different among the groups. CONCLUSIONS: Ertugliflozin 15 mg was non-inferior to glimepiride in reducing HbA1c when added to metformin in patients with T2DM. Ertugliflozin had an acceptable safety profile and resulted in less hypoglycemia and more GMIs than glimepiride. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01999218. PMID- 29282634 TI - Concise Commentary: Breathing New Life into Antisecretory Medications. PMID- 29282635 TI - Endoscopic Submucosal Dissection of Early Gastric Cancer in Patients with Liver Cirrhosis. AB - BACKGROUND AND OBJECTIVES: Endoscopic submucosal dissection (ESD) has become widely accepted method for treating early gastric cancer (EGC), but little is known about its role in patients with liver cirrhosis (LC). The aims of this study were to evaluate the outcomes of ESD in treating EGC in patients with LC. METHODS: The multicenter retrospective study identified 43 patients with chronic hepatitis B (CHB)-related cirrhosis undergoing ESD for treating EGC. The patients (LC group) were subdivided into two groups based on their Child-Pugh classification (CP-class): 32 with CP-class A (LC-A) and 11 with CP-class B (LC B). The patients were compared to 47 non-cirrhotic CHB patients who underwent ESD (CHB group). Eight patients had a past history of hepatocellular carcinoma (HCC) prior to ESD, but no patients had viable HCC when ESD was performed. RESULTS: Procedural outcomes (en bloc, lateral/basal margins resection) and post procedural complications (bleeding or perforation) did not differ significantly between the LC and CHB groups or between the LC-A and LC-B groups. No patients experienced worsening of the Child-Pugh score 1 month after ESD compared with the baseline score. During a median observation period of 66 months, the recurrence rates of gastric cancers were similar between the LC and CHB groups (5-year recurrence rates: 2.4 vs. 2.3%, p = 0.925), and all recurrent gastric cancers were completely resected by additional ESD. The overall mortality rate was increased in the LC group (5-year mortality rates: 17.9 vs. 5.7%, p = 0.034), and 8 of 10 deaths were attributed to liver-related diseases (such as HCC, complications of portal hypertension, hepatic failure). CONCLUSIONS: ESD is feasible in patients with EGC and comorbid LC, even those with CP-class B cirrhosis. Their prognosis depends on LC-related diseases and not recurrent EGC. PMID- 29282636 TI - Vonoprazan: A Novel and Potent Alternative in the Treatment of Acid-Related Diseases. AB - Although proton pump inhibitors (PPIs) have been used widely, acid-related diseases are still associated with a huge burden on the health care system. Recently, the efficacy and safety of a new acid suppressant named vonoprazan in the treatment of acid-related diseases have been evaluated by a series of studies. As a novel potassium-competitive acid blocker, vonoprazan may provide reversible acid suppression by preventing K+ from binding to gastric H+/K+ ATPase. It has been clinically used for the short-term treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Helicobacter pylori (H. pylori) infection in Japan. The healing rate of GERD and gastric ulcers by vonoprazan is more than 95 and 90%, respectively; also, it is effective in curing PPI-resistant GERD. It increases H. pylori eradication rate to more than 88% as part of both first-line and second-line therapy. It is also effective in the eradication of clarithromycin-resistant H. pylori strains. All of these short-term studies show vonoprazan is safe and well-tolerated. As a safe and effective acid inhibitor, vonoprazan might be a novel alternative in the treatment of acid-related diseases. PMID- 29282637 TI - Changing Epidemiology of Upper Gastrointestinal Hemorrhage in the Last Decade: A Nationwide Analysis. AB - BACKGROUND: Upper gastrointestinal hemorrhage (UGIH) is common and carries substantial mortality requiring frequent hospitalizations. AIM: To investigate trends in etiology and outcome of UGIH in hospitalized patients in the USA. METHODS: Retrospective, observational cohort study of the Nationwide Inpatient Sample from 2002 to 2012 was carried out. UGIH was identified in hospitalizations with a principle ICD-9-CM diagnosis of UGIH or secondary diagnosis of UGIH with a principal diagnosis of hematemesis, blood in stool, or gastrointestinal bleeding. Age 18 years or older was required for inclusion, and elective admissions and transferred patients were excluded. RESULTS: The hospitalization rate of UGIH in the USA decreased by 21% from 2002 to 2012, from 81 to 67 cases per 100,000 population (p < 0.01). The greatest declines occurred for gastritis and PUD, which decreased by 55 and 30%, respectively (p < 0.01). There were increases in neoplasm, Dieulafoy lesions, angiodysplasia, and esophagitis, which increased by 50, 33, 32 and 20%, respectively (p < 0.01). The all-cause inpatient mortality rate of UGIH decreased 28% from 2.6 per 100 cases in 2002 to 1.9 in 2012 (p < 0.01). The greatest decline occurred for esophagitis, Mallory-Weiss tear, and neoplasm, which decreased by 39% (p < 0.01), 36% (p = 0.02), and 36% (p < 0.01), respectively. The rate of hospitalization for bleeding caused by esophageal varices remained constant and low (approximately 2%) throughout the study period; the mortality for esophageal varices also remained constant at 6-7%. CONCLUSIONS: The epidemiology of UGIH hemorrhage appears to be shifting, with a decline in PUD and gastritis; an increase in hospitalization rate for neoplasm, Dieulafoy lesions, angiodysplasia, and esophagitis; and a reduction in overall mortality. The decreasing hospitalization rate and mortality rate of UGIH suggest population trends in use of treatments for PUD, improved hemostatic techniques, and overall care. PMID- 29282638 TI - Efficacy and Safety of Lumen-Apposing Metal Stents in Management of Pancreatic Fluid Collections: Are They Better Than Plastic Stents? A Systematic Review and Meta-Analysis. AB - BACKGROUND AND AIMS: Endoscopic ultrasound (EUS)-guided transmural drainage has been increasingly utilized as a first-line therapeutic modality for drainage of pancreatic fluid collections (PFC). Recently, lumen-apposing metal stents (LAMS) have been utilized for management of PFCs. We conducted a systematic review and meta-analysis to evaluate the cumulative efficacy and safety of LAMS in the management of PFC (primary outcome). We also compared the efficacy and safety of LAMS with multiple plastic stents (MPS) in the management of PFC (secondary outcome). METHODS: We searched Medline, Embase and Cochrane databases from inception to November 5, 2016, to identify studies (with >= 10 patients) reporting technical success, clinical success, and adverse events (AE) of EUS guided transmural drainage of PFC using LAMS. Weighted pooled rates (WPR) were calculated for technical success, clinical success and AE. Risk ratios (RR) were calculated and pooled to compare LAMS with MPS in terms of technical success, clinical success, and AE. Pooled mean difference (MD) was calculated to compare the number of endoscopic sessions required by each type of stent to achieve clinical success. All analyses were done using random effects model. RESULTS: Eleven studies with 688 patients were included in this meta-analysis. WPR for technical success of LAMS in PFC management was 98% (96, 99%), (I 2 = 15%). WPR for clinical success was 93% (89, 96%) with moderate heterogeneity (I 2 = 50%). There was no difference in clinical success for pseudocysts (PP) versus walled off pancreatic necrosis (WON) (P = 0.51). WPR for AE was 13% (9, 20%), (I 2 = 64%). AE were 10% more in WON as compared to PP (P = 0.009). Most common AE requiring intervention was stent migration (4.2%), followed by infection (3.8%), bleeding (2.4%), and stent occlusion (1.9%). Six studies with 504 patients compared the performance of LAMS with MPS. Pooled RR for technical success was 1.71 (0.38, 7.37). Pooled RR for clinical success was 0.37 (0.20, 0.67) in favor of LAMS. Pooled RR for AE was 0.39 (0.18, 0.84), (I 2 = 50%). Pooled MD for number of endoscopic sessions was - 0.84 (- 1.69, 0.01). CONCLUSIONS: LAMS seem to have excellent efficacy and safety in the management of PFCs. They may be preferred over plastic stents as they are associated with better clinical success and lesser adverse events. PMID- 29282639 TI - Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis. AB - BACKGROUND: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. AIMS: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. METHODS: Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17beta-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17beta-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array. RESULTS: In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17beta-estradiol than in male rats. 17beta-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage. CONCLUSIONS: Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females. PMID- 29282640 TI - High Incidence of Recurrent Crohn's Disease Following Colectomy for Ulcerative Colitis Revealed with Long Follow-Up. AB - BACKGROUND AND AIMS: Ulcerative colitis (UC) patients with progression of their disease despite optimized medical therapy may warrant "curative" proctocolectomy with end ileostomy or ileo-anal pouch (IPAA) anastomosis. The aim of our study was to assess the incidence of later recurrent ileitis that lead to altering the initial diagnosis to Crohn's disease (CD). METHODS: A retrospective analysis was conducted on the inflammatory bowel disease database at Lenox Hill Hospital. The database consisted of patients that were diagnosed with UC or CD based on clinical assessment, endoscopic appearance, gross and histological examination, and imaging between 1960 and 2015. The post-colectomy follow-up period was at least 10 years. Recurrent disease was classified by evidence of transmural inflammation in the distal ileum, fistulizing disease, or stricturing disease. RESULTS: From our IBD database, we identified 128 patients who underwent elective or urgent colectomy with the preoperative diagnosis of UC. Thirty-two (25%) had either an IPAA or end ileostomy with documented recurrence of inflammation in the small bowel mucosa consistent with CD. There was no significant difference between the type of surgical approach and the chance of recurrent disease (p = .20). The average time to clinically significant recurrence was 5 years. CONCLUSION: The incidence of recurrent CD following colectomy for ulcerative colitis, when followed postoperatively for an average of 20 years, was 25%, considerably more than previously reported. Patients who come to colectomy for ulcerative colitis and are followed for at least 10 years show a high incidence of recurrent Crohn's disease in the ileostomy or ileo-anal pouch. Extended follow up should be included in patients coming to colectomy for ulcerative colitis before they should be considered cured of their disease. PMID- 29282643 TI - Venous circulation and the invisible hand. PMID- 29282642 TI - Sex differences and the effect of instruction on reorientation abilities by humans. AB - This study examined whether differences in the amount of information provided to men and women, in the form of verbal instruction, influenced their encoding during a reorientation task. When a navigator needs to orient, featural (e.g., colour or texture) and geometry (e.g., metric information) are used to determine which direction to begin traveling. The current study used a spatial reorientation task to examine how men and women use featural and geometric cues and whether the content of the task's instructions influenced how these cues were used. Participants were trained to find a target location in a rectangular room with distinctive objects situated at each corner. Once the participants were accurately locating the target, various tests manipulating the spatial information were conducted. We found both men and women encoded the featural cues, and even though the features provided reliable information, participants generally showed an encoding of geometry. However, when participants were not provided with any information about the spatial aspects of the task in the instructions, they failed to encode geometry. We also found that women used distant featural cues as landmarks when the featural cue closest to the target was removed, whereas men did not. Yet, when the two types of cues were placed in conflict, both sexes weighed featural cues more heavily than geometric cues. The content of the task instructions also influenced how cues were relied upon in this conflict situation. Our results have important implications for our understanding of how spatial cues are used for reorientation. PMID- 29282644 TI - A case of nephrogenic syndrome of inappropriate antidiuresis caused by carbamazepine. AB - We report a case of nephrogenic syndrome of inappropriate antidiuresis caused by carbamazepine (CBZ). CBZ, an antiepileptic drug, is known to cause hyponatremia. The mechanism is generally considered to be inappropriate secretion of antidiuretic hormone, whereas an experimental study suggests a direct effect of CBZ on the kidney by stimulating vasopressin receptor. An 18-year-old male with atypical autism and epilepsy has been treated with CBZ and clobazam since age 9 and 10 years, respectively. At age 11, he was found to have asymptomatic hyponatremia. He had the habit of drinking tea approximately 3 L/day. The low plasma osmolality and high urine osmolality and sodium concentration in the presence of normal thyroid and adrenal function were compatible with syndrome of inappropriate excretion of antidiuretic hormone. His plasma vasopressin level, however, was undetectable. Urine cyclic AMP level was higher than expected from urine osmolality despite the suppressed plasma arginine vasopressin. With fluid restriction, hyponatremia improved. CBZ tapering begun later in the course maintained normal serum sodium concentrations with less strict water intake. This case demonstrates the direct effect of CBZ stimulating vasopressin receptor in the kidney leading to nephrogenic syndrome of inappropriate diuresis. PMID- 29282641 TI - The Efficacy of Cognitive Intervention in Mild Cognitive Impairment (MCI): a Meta Analysis of Outcomes on Neuropsychological Measures. AB - Cognitive training in MCI may stimulate pre-existing neural reserves or recruit neural circuitry as "compensatory scaffolding" prompting neuroplastic reorganization to meet task demands (Reuter-Lorenz & Park, 2014). However, existing systematic reviews and meta-analytic studies exploring the benefits of cognitive interventions in MCI have been mixed. An updated examination regarding the efficacy of cognitive intervention in MCI is needed given improvements in adherence to MCI diagnostic criteria in subject selection, better defined interventions and strategies applied, increased use of neuropsychological measures pre- and post-intervention, as well as identification of moderator variables which may influence treatment. As such, this meta-analytic review was conducted to examine the efficacy of cognitive intervention in individuals diagnosed with mild cognitive impairment (MCI) versus MCI controls based on performance of neuropsychological outcome measures in randomized controlled trials (RCT). RCT studies published from January 1995 to June 2017 were obtained through source databases of MEDLINE-R, PubMed, Healthstar, Global Health, PSYCH INFO, and Health and Psychological Instruments using search parameters for MCI diagnostic category (mild cognitive impairment, MCI, pre-Alzheimer's disease, early cognitive decline, early onset Alzheimer's disease, and preclinical Alzheimer's disease) and the intervention or training conducted (intervention, training, stimulation, rehabilitation, or treatment). Other inclusion and exclusion criteria included subject selection based on established MCI criteria, RCT design in an outpatient setting, MCI controls (active or passive), and outcomes based on objective neuropsychological measures. From the 1199 abstracts identified, 26 articles met inclusion criteria for the meta-analyses completed across eleven (11) countries; 92.31% of which have been published within the past 7 years. A series of meta-analyses were performed to examine the effects of cognitive intervention by cognitive domain, type of training, and intervention content (cognitive domain targeted). We found significant, moderate effects for multicomponent training (Hedges' g observed = 0.398; CI [0.164, 0.631]; Z = 3.337; p = 0.001; Q = 55.511; df = 15; p = 0.000; I 2 = 72.978%; tau 2 = 0.146) as well as multidomain-focused strategies (Hedges' g = 0.230; 95% CI [0.108, 0.352]; Z = 3.692; p < 0.001; Q = 12.713; df = 12; p = 0.390; I 2 = 5.612; tau 2 = 0.003). The effects for other interventions explored by cognitive domain, training type, or intervention content were indeterminate due to concerns for heterogeneity, bias, and small cell sizes. In addition, subgroup and meta regression analyses were conducted with the moderators of MCI category, mode of intervention, training type, intervention content, program duration (total hours), type of control group (active or passive), post-intervention follow-up assessment period, and control for repeat administration. We found significant overall effects for intervention content with memory focused interventions appearing to be more effective than multidomain approaches. There was no evidence of an influence on outcomes for the other covariates examined. Overall, these findings suggest individuals with MCI who received multicomponent training or interventions targeting multiple domains (including lifestyle changes) were apt to display an improvement on outcome measures of cognition post-intervention. As such, multicomponent and multidomain forms of intervention may prompt recruitment of alternate neural processes as well as support primary networks to meet task demands simultaneously. In addition, interventions with memory and multidomain forms of content appear to be particularly helpful, with memory-based approaches possibly being more effective than multidomain methods. Other factors, such as program duration, appear to have less of an influence on intervention outcomes. Given this, although the creation of new primary network paths appears strained in MCI, interventions with memory-based or multidomain forms of content may facilitate partial activation of compensatory scaffolding and neuroplastic reorganization. The positive benefit of memory-based strategies may also reflect transfer effects indicative of compensatory network activation and the multiple pathways involved in memory processes. Limitations of this review are similar to other meta-analysis in MCI, including a modest number studies, small sample sizes, multiple forms of interventions and types of training applied (some overlapping), and, while greatly improved in our view, a large diversity of instruments used to measure outcome. This is apt to have contributed to the presence of heterogeneity and publication bias precluding a more definitive determination of the outcomes observed. PMID- 29282645 TI - Can Increased Educational Attainment Among Lower-Educated Mothers Reduce Inequalities in Children's Skill Development? AB - A rich tradition of stratification research has established a robust link between mothers' education and the skills in children that forecast children's own mobility. Yet, this research has failed to consider that many U.S. women are now completing their education after having children. Such a trend raises questions about whether increases in mothers' educational attainment can improve their children's skill development and whether these gains are enough to reduce inequalities in skills compared with children whose mothers completed the same degree before they were born. To answer these questions, we draw on a nationally representative sample of mothers and children participating in the National Longitudinal Surveys (NLSY79 and CNLY), random- and fixed-effects techniques, and repeated measures of children's cognitive and noncognitive skills. Contrary to existing research and theory, our results reveal that educational attainment obtained after children's births is not associated with an improvement in children's skills. Such findings offer substantial refinement to a long-standing model of intergenerational mobility by suggesting that the intergenerational returns to mother's education are weaker when education is acquired after children are born. Results also highlight the limits of two-generation policy approaches to reducing inequality in future generations. PMID- 29282647 TI - Pericytes: The Role of Multipotent Stem Cells in Vascular Maintenance and Regenerative Medicine. AB - Blood vessels consist of an inner endothelial cell layer lining the vessel wall and perivascular pericytes, also known as mural cells, which envelop the vascular tube surface. Pericytes have recently been recognized for their central role in blood vessel formation. Pericytes are multipotent cells that are heterogeneous in their origin, function, morphology and surface markers. Similar to other types of stem cells, pericytes act as a repair system in response to injury by maintaining the structural integrity of blood vessels. Several studies have shown that blood vessels lacking pericytes become hyperdilated and haemorrhagic, leading to vascular complications ranging from diabetic retinopathy to embryonic death. The role of pericytes is not restricted to the formation and development of the vasculature: they have been shown to possess stem cell-like characteristics and may differentiate into cell types from different lineages. Recent discoveries regarding the contribution of pericytes to tumour metastasis and the maintenance of tumour vascular supply and angiogenesis have led researchers to propose targeting pericytes with anti-angiogenic therapies. In this review, we will examine the different physiological roles of pericytes, their differentiation potential, and how they interact with surrounding cells to ensure the integrity of blood vessel formation and maintenance. PMID- 29282648 TI - A scintigraphic demonstration of a solitary orbital Paget's disease. PMID- 29282649 TI - Correction to: Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review. AB - In the original publication, the given and family name of the author Mohammad Hassan Murad was incorrect. This has been corrected with this erratum. PMID- 29282646 TI - Targeting therapeutics to endothelium: are we there yet? AB - Vascular endothelial cells represent an important therapeutic target in many pathologies, including inflammation, oxidative stress, and thrombosis; however, delivery of drugs to this site is often limited by the lack of specific affinity of therapeutics for these cells. Selective delivery of both small molecule drugs and therapeutic proteins to the endothelium has been achieved through the use of targeting ligands, such as monoclonal antibodies, directed against endothelial cell surface markers, particularly cell adhesion molecules (CAMs). Careful selection of target molecules and targeting agents allows for precise delivery to sites of inflammation, thereby maximizing therapeutic drug concentrations at the site of injury. A good understanding of the physiological and pathological determinants of drug and drug carrier pharmacokinetics and biodistribution may allow for a priori identification of optimal properties of drug carrier and targeting agent. Targeted delivery of therapeutics such as antioxidants and antithrombotic agents to the injured endothelium has shown efficacy in preclinical models, suggesting the potential for translation into clinical practice. As with all therapeutics, demonstration of both efficacy and safety are required for successful clinical implementation, which must be considered not only for the individual components (drug, targeting agent, etc.) but also for the sum of the parts (e.g., the drug delivery system), as unexpected toxicities may arise with complex delivery systems. While the use of endothelial targeting has not been translated into the clinic to date, the preclinical results summarized here suggest that there is hope for successful implementation of these agents in the years to come. PMID- 29282650 TI - Trajectories of Return to Work Among People on Sick Leave with Mood or Anxiety Disorders: Secondary Analysis from a Randomized Controlled Trial. AB - Purpose The return to work (RTW) of people with mood and anxiety disorders is a heterogeneous process. We aimed to identify prototypical trajectories of RTW over a two-year period in people on sick leave with mood and anxiety disorders, and investigate if socio-demographic or clinical factors predicted trajectory membership. Methods We used data from the randomized IPS-MA trial (n = 283), evaluating a supported employment intervention for participants with recently diagnosed mood or anxiety disorders. Information on "weeks in employment in the past 6 months" was measured after 1/2, 1, 1 1/2 and 2 years, using data from a nationwide Danish register (DREAM). Latent growth mixture modelling analysis was carried out to identify trajectories of RTW and logistic regression analyses were used to estimate predictors for trajectory membership. Results Four trajectory classes of RTW were identified; non-RTW [70% (196/283)] (practically no return to work); delayed-RTW [19% (56/283)] (6 months delay before full RTW); rapid unstable-RTW [7% (19/283)] (members rapidly returned to work, but only worked half the time); and the smallest class, rapid-RTW [4% (12/283)] (members rapidly reached full employment, but later experienced a decrease in weeks of employment). Self-reported disability score according to the SDS, not living with a partner, and readiness to change on the CQ scale were found to be significantly associated with RTW. Conclusion The trajectories identified support that many do not benefit from vocational rehabilitation, or experience difficulties sustaining employment; enhanced support of this patient group is still warranted.Trial registration: http://www.clinicaltrials.gov (Identifier: NCT01721824). PMID- 29282652 TI - Task-irrelevant sounds influence both temporal order and apparent-motion judgments about tactile stimuli applied to crossed and uncrossed hands. AB - It has been suggested that judgments about the temporal-spatial order of successive tactile stimuli depend on the perceived direction of apparent motion between them. Here we manipulated tactile apparent-motion percepts by presenting a brief, task-irrelevant auditory stimulus temporally in-between pairs of tactile stimuli. The tactile stimuli were applied one to each hand, with varying stimulus onset asynchronies (SOAs). Participants reported the location of the first stimulus (temporal order judgments: TOJs) while adopting both crossed and uncrossed hand postures, so we could scrutinize skin-based, anatomical, and external reference frames. With crossed hands, the sound improved TOJ performance at short (<=300 ms) and at long (>300 ms) SOAs. When the hands were uncrossed, the sound induced a decrease in TOJ performance, but only at short SOAs. A second experiment confirmed that the auditory stimulus indeed modulated tactile apparent motion perception under these conditions. Perceived apparent motion directions were more ambiguous with crossed than with uncrossed hands, probably indicating competing spatial codes in the crossed posture. However, irrespective of posture, the additional sound tended to impair potentially anatomically coded motion direction discrimination at a short SOA of 80 ms, but it significantly enhanced externally coded apparent motion perception at a long SOA of 500 ms. Anatomically coded motion signals imply incorrect TOJ responses with crossed hands, but correct responses when the hands are uncrossed; externally coded motion signals always point toward the correct TOJ response. Thus, taken together, these results suggest that apparent-motion signals are likely taken into account when tactile temporal-spatial information is reconstructed. PMID- 29282651 TI - Introgression, Generational Expression and Salinity Tolerance Conferred by the Pea DNA Helicase 45 Transgene into Two Commercial Rice Genotypes, BR28 and BR47. AB - DNA helicase (PDH45) from the pea plant (Pisum sativum) is a member of the DEAD box protein family and plays a vital regulatory role in saline stress tolerance in plants. We previously reported that over-expression of PDH45 gene confers both seedling and reproductive stage salinity tolerance to a Bangladeshi rice landrace, Binnatoa (BA). In this study, transgenic BA-containing PDH45 (?) was crossed with two different farmer-popular BRRI rice varieties (?), BR28 and BR47, in a contained net house. F1 plants positive for the transgene and having recipient phenotype were advanced from F1 to F5. Expression of the PDH45 gene was detected in all generations. The expression level of PDH45 was 200-fold higher in the donor compared to the two recipient genotypes but without any effect on their salt stress tolerance ability in various assays. Under 120 mM NaCl stress at seedling stage, all rice genotypes showed vigorous growth, higher chlorophyll content, lower electrolyte leakage and lower LDS (Leaf Damage Score) compared to their corresponding wild types. At the reproductive stage under continuous salinity stress at 80 mM NaCl, the cross-bred lines BR28 and BR47 showed significantly better spikelet fertility and yield per plant, which were two- and 2.5-folds, respectively, than their corresponding wild types. The PDH45 transgene was observed to increase the expression of 6 salt stress-related downstream genes at 150 mM NaCl stress to similar differential degrees in the donor and recipient genotypes. However, the expression of OsLEA was significantly higher in transgenic BR28 compared to transgenic BR47, where the latter shows comparatively higher salt tolerance. The study shows stability of transgene expression across generations. It also demonstrates that there may be an effect of background genotype on transgene expression. Moreover, some downstream effects of the transgene may also be genotype-specific. PMID- 29282654 TI - Associations of self-esteem with body mass index and body image among Saudi college-age females. AB - PURPOSE: To examine the association of self-esteem with the body mass index (BMI), perceived body image (BI), and desired BI of college-age Saudi females. METHODS: A cross-sectional study was conducted with 907 randomly selected females using a multistage stratified cluster sampling technique. Self-esteem and BI were assessed using the Rosenberg Self-Esteem Scale and Stunkard Figure Rating Scale, respectively. RESULTS: The prevalence of low self-esteem was only 6.1% among college females; however, this percentage was higher (9.8%) among overweight or obese participants. The total self-esteem scores showed significant negative correlations with actual BMI and perceived BI, but not with desired BI. Meanwhile, multivariate analyses revealed significant differences in total self esteem scores according to obesity/overweight status and perceived BI group, but not desired BI group. CONCLUSION: Despite the high prevalence of overweight and obesity in Saudi Arabia, few Saudi college females have low self-esteem. In addition, body weight, BMI, perceived BI, and the BMI corresponding to the perceived BI all significantly differed between females with low self-esteem and those with normal self-esteem. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 29282653 TI - Oral health in geroscience: animal models and the aging oral cavity. AB - Age is the single greatest risk factor for many diseases, including oral diseases. Despite this, a majority of preclinical oral health research has not adequately considered the importance of aging in research aimed at the mechanistic understanding of oral disease. Here, we have attempted to provide insights from animal studies in the geroscience field and apply them in the context of oral health research. In particular, we discuss the relationship between the biology of aging and mechanisms of oral disease. We also present a framework for defining and utilizing age-appropriate rodents and present experimental design considerations, such as the number of age-points used and the importance of genetic background. While focused primarily on rodent models, alternative animal models that may be particularly useful for studies of oral health during aging, such as companion dogs and marmoset monkeys, are also discussed. We hope that such information will aid in the design of future preclinical studies of geriatric dental health, thus allowing more reliability for translation of such studies to age-associated oral disease in people. PMID- 29282655 TI - A novel and highly efficient AAV6 mutant. AB - Adeno-associated virus has been gaining prominence in its use as a highly secure virus gene vector with low immunogenicity in the field of human gene therapy. However, wild-type adeno-associated virus sometimes has low transduction efficiency for certain tissues or cells both in vivo and in vitro. Thus, achieving the desired level of expression often requires a large dose. Large doses of viral injection in clinical applications will not only trigger the body's immune response but will come at a high production cost. To improve the transduction efficiency of adeno-associated virus 6 (AAV6), we herein used fusion PCR to mutate a specific amino acid of the VP2 region of the wild-type AAV6 (AAV6 WT) and obtained AAV6-S663L, AAV6Y705 + 731F + T492A, AAV6Y705 + 731F + T492 V + S663 V and so on. We concluded that AAV6-S663L was the most efficient AAV6 mutant. When HEK293 cells were infected in vitro with a virus at a multiplicity of infection value of 1000, the transduction rate of AAV6-WT was only 43.8%, while that of AAV6-S663L was 83.9%. This highly efficient AAV6 mutant is highly significant for the future use of AAV6 in gene therapy. PMID- 29282657 TI - Giant panda protection should not stay in paper. PMID- 29282658 TI - Community structure of grassland ground-dwelling arthropods along increasing soil salinities. AB - Ground-dwelling arthropod communities are influenced by numerous biotic and abiotic factors. Little is known, however, about the relative importance of vegetation structure and abiotic environmental factors on the patterns of ground dwelling arthropod community across a wide range of soil salinities. Here, a field survey was conducted to assess the driving forces controlling ground dwelling arthropod community in the salinized grasslands in the Hexi Corridor, Gansu Province, China. The data were analyzed by variance partitioning with canonical correspondence analysis (CCA). We found that vegetation structure and edaphic factors were at least of similar importance to the pattern of the whole ground-dwelling arthropod community. However, when all collected ground-dwelling arthropods were categorized into three trophic guilds (predators, herbivores, and decomposers), as these groups use different food sources, their populations were controlled by different driving forces. Predators and decomposers were mainly determined by biotic factors such as vegetation cover and aboveground plant biomass and herbivores by plant density and vegetation cover. Abiotic factors were also major determinants for the variation occurring in these guilds, with predators strongly affected by soil electrical conductivity (EC) and the content of fine particles (silt + clay, CS), herbivores by soil N:P, EC, and CS, and decomposers by soil EC and organic matter content (SOM). Since plant cover, density, and aboveground biomass can indicate resource availability, which are mainly constrained by soil N:P, EC, CS, and SOM, we consider that the ground dwelling arthropod community in the salinized grasslands was mainly influenced by resource availability. PMID- 29282656 TI - Utility of high-throughput DNA sequencing in the study of the human papillomaviruses. AB - The Papillomaviridae family is probably the most diverse group of viruses that affect vertebrates. The study of the relationship between infection by certain types of human papillomavirus (HPV) and the development of neoplastic epithelial lesions is of particular interest because of the high prevalence of HPV-related carcinomas in populations of developing countries. To understand the mechanisms of infection and their association with different clinical manifestations, molecular tools play an important role in the description of new types of HPV, the characterization of effector properties of the viral factors, the specific diagnosis and monitoring of HPV types, and the alteration patterns at genetic level in the host. Technological advances in the field of DNA sequencing have led to the development of different next-generation sequencing systems, allowing obtaining a large amount of data and broadening the applications to study viral diseases. In this review, we summarize the main approaches and their perspectives where the use of massively parallel sequencing has been proved as a useful tool in the research of the HPV infection. PMID- 29282660 TI - Upscaling the pollutant emission from mixed recycled aggregates under compaction for civil applications. AB - In general terms, plant managers of sites producing construction wastes assess materials according to concise, legally recommended leaching tests that do not consider the compaction stage of the materials when they are applied on-site. Thus, the tests do not account for the real on-site physical conditions of the recycled aggregates used in civil works (e.g., roads or embankments). This leads to errors in estimating the pollutant potential of these materials. For that reason, in the present research, an experimental procedure is designed as a leaching test for construction materials under compaction. The aim of this laboratory test (designed specifically for the granular materials used in civil engineering infrastructures) is to evaluate the release of pollutant elements when the recycled aggregate is tested at its commercial grain-size distribution and when the material is compacted under on-site conditions. Two recycled aggregates with different gypsum contents (0.95 and 2.57%) were used in this study. In addition to the designed leaching laboratory test, the conventional compliance leaching test and the Dutch percolation test were performed. The results of the new leaching method were compared with the conventional leaching test results. After analysis, the chromium and sulphate levels obtained from the newly designed test were lower than those obtained from the conventional leaching test, and these were considered more seriously pollutant elements. This result confirms that when the leaching behaviour is evaluated for construction aggregates without density alteration, crushing the aggregate and using only the finest fraction, as is done in the conventional test (which is an unrealistic situation for aggregates that are applied under on-site conditions), the leaching behaviour is not accurately assessed. PMID- 29282659 TI - An ecological risk investigation of marine sediment from the northern Mediterranean coasts (Aegean Sea) using multiple methods of pollution determination. AB - The aim of this study is an assessment of metal pollution levels in Aegean Sea sediment. Sediment samples collected from 7 different locations (Yenikoy, Edremit, Ayvalik, Dikili, Aliaga, Hekimadasi, and Ildir) along the northern Mediterranean region of Turkey were investigated for 11 elements (Cu, Fe, Zn, V, Cd, Ni, As, Pb, Mn, Co, and Cr). Graphite furnace atomic absorption spectrophotometry (GFAAS) and flame atomic absorption spectrophotometry (FAAS) were used for elemental analysis. The findings were evaluated with sediment assessment methods by taking two different values as a reference and then investigating the adverse biological effects of elemental profiles on living organisms. Pb, Mn, As, Cd, and Cr concentrations were within a moderate to significant range in terms of contamination factor [Formula: see text]), albeit varying according to reference and location. The most problematic region and elements regarding the enrichment factor (EF) was Ayvalik and As, Ni, Cu, Pb, Co, and Cd. However, according to the EF, the anthropogenic effect was not at an alarming level. This was further supported by the results of the geoaccumulation index (Igeo). The findings of the modified degree of contamination (mC d ) and the pollution load index (PLI) suggested that the accumulation was greatest in Ayvalik, and the least in Hekimadasi and Ildir. The location with the highest elemental total toxic unit (SigmaTU) was Edremit. The effect of the existing element profile on organisms was 21% in this location when the mean effect range median quotient (m-ERM-q) was considered. As and Ni concentrations in all stations were found to be higher than threshold effect level (TEL) and Effect Range Low (ERL). Ni levels in Edremit exceeded the probable effect level (PEL) and Effect Range Median (ERM). Toxic unit (TU) values of these two elements in all stations ranged from 59.30 to 80.43%. PMID- 29282661 TI - Factors that affect the willingness of residents to pay for solid waste management in Hong Kong. AB - In Hong Kong, problems involving solid waste management have become an urgent matter in recent years. To solve these problems, the Hong Kong government proposed three policies, namely, waste charging, landfill extension, and development of new incinerators. In this study, a large sample questionnaire survey was conducted to examine the knowledge and attitude of residents on the three policies, the amount of their daily waste disposal, and their willingness to pay (WTP). Results reveal that only 22.7% of respondents are aware of the earliest time that one of the landfills will be sated, and more than half of respondents support the three policies. However, more than one third of residents (36.1%) are unwilling to pay the minimum waste charge amount of HK$30 estimated by the Council for Sustainable Development in Hong Kong. Logit model results indicate that five key factors affect WTP, namely, knowledge of residents on the timing of landfill fullness, degree of support in waste charge policy, amount of daily waste disposal, age, and income. These results suggest that strong and rigorous promotional and educational programs are needed to improve the knowledge and positive attitude of residents towards recycling methods and the three policies. However, subsidy should be provided to low-income groups who cannot afford to pay the waste charge. PMID- 29282662 TI - Production of an environmentally friendly fuel with the aid of ultrasonic waves from a new plant source, and the investigation of its effect on pollutants reduction in a CI engine. AB - In this study, methyl ester of Sisymbrium plant seed oil with the chemical formula of C18H34O2 is produced for the first time, with the aid of ultrasonic waves and in the presence of a nanocatalyst. After measuring its characteristics and comparing with ASTM standard, it is tested and evaluated with different ratios of diesel fuel in a single-cylinder diesel engine. The reactions are accomplished in a flask by an ultrasonic processor unit and in the presence of CaO-MgO nanocatalyst. The engine tests were conducted based on the engine short time experiment. The results showed that with the increment of biodiesel ratio in the fuel blend, pollutants level of CO, HC, and smoke opacity are decreased comparing diesel fuel due to the improvement of the combustion process, and the amount of NOx emission is increased owing to high pressure and temperature of the combustion chamber. Also, produced biodiesel fuel causes an increment in the fuel consumption and exhaust gasses temperature. Overall, with regard to its effects on the engine and also being a native and easy cultivation plant, it can be resulted that Sisymbrium oil biodiesel and its blends with diesel fuel can be applied as an alternative fuel. PMID- 29282663 TI - Adsorptive removal capacity of gravel for metal cations in the absence/presence of competitive adsorption. AB - Locally available and low cost granular gravel as an adsorbent material was employed to determine its capacity to remove metal cations Cu(II), Fe(II), Ni(II), and Zn(II) from single metal solution and landfill leachate samples. Adsorption kinetics and mechanism under different parameters including dosage, time, and pH were studied. It was found that the experimental results fitted to the Freundlich model suggesting an adsorption process on a multilayer heterogeneous surface for both single metal solution and landfill leachate samples. The adsorption of metal cations followed second-order kinetics occurring in a single step on the surface of gravel. The order of removal efficiency of metals was found to be Cu(II)(98%) > Fe(II)(87.5%) > Zn(II)(76.05%) > Ni(II)(36.38%) in single metal solution and Cu(II)(98.3%) > Fe(II)(83%) > Zn(II)(48%) > Ni(II)(27.32%) in landfill leachate sample at pH 7. The regeneration efficiency of the metals adsorbed on the gravel resulted in the order of Fe(II)(99.54%) > Cu(II)(99%) > Ni(II)(49.46%) > Zn (II)(2.25%). PMID- 29282664 TI - Dynamic linkages between road transport energy consumption, economic growth, and environmental quality: evidence from Pakistan. AB - The focus of the present research work is to investigate the dynamic relationship between economic growth, road transport energy consumption, and environmental quality. To this end, we rely on time series data for the period 1971 to 2014 in the context of Pakistan. To use sulfur dioxide (SO2) emission from transport sector as a new proxy for measuring environmental quality, the present work employs time series technique ARDL which allows energy consumption from the transport sector, urbanization, and road infrastructure to be knotted by symmetric relationships with SO2 emissions and economic growth. From the statistical results, we confirm that road infrastructure boosts economic growth. Simultaneously, road infrastructure and urbanization hampers environmental quality and causes to accelerate emission of SO2 in the atmosphere. Furthermore, economic growth has a diminishing negative impact on total SO2 emission. Moreover, we did not find any proof of the expected role of transport energy consumption in SO2 emission. The acquired results directed that care should be taken in the expansion of road infrastructure and green city policies and planning are required in the country. PMID- 29282665 TI - Antifouling booster biocide extraction from marine sediments: a fast and simple method based on vortex-assisted matrix solid-phase extraction. AB - This paper reports the development of an analytical method employing vortex assisted matrix solid-phase dispersion (MSPD) for the extraction of diuron, Irgarol 1051, TCMTB (2-thiocyanomethylthiobenzothiazole), DCOIT (4,5-dichloro-2-n octyl-3-(2H)-isothiazolin-3-one), and dichlofluanid from sediment samples. Separation and determination were performed by liquid chromatography tandem-mass spectrometry. Important MSPD parameters, such as sample mass, mass of C18, and type and volume of extraction solvent, were investigated by response surface methodology. Quantitative recoveries were obtained with 2.0 g of sediment sample, 0.25 g of C18 as the solid support, and 10 mL of methanol as the extraction solvent. The MSPD method was suitable for the extraction and determination of antifouling biocides in sediment samples, with recoveries between 61 and 103% and a relative standard deviation lower than 19%. Limits of quantification between 0.5 and 5 ng g-1 were obtained. Vortex-assisted MPSD was shown to be fast and easy to use, with the advantages of low cost and reduced solvent consumption compared to the commonly employed techniques for the extraction of booster biocides from sediment samples. Finally, the developed method was applied to real samples. Results revealed that the developed extraction method is effective and simple, thus allowing the determination of biocides in sediment samples. PMID- 29282666 TI - Influence of multiwall carbon nanotubes on the toxicity of 17beta-estradiol in the early life stages of zebrafish. AB - Due to increasing use and release, both multiwall carbon nanotubes (MWCNTs) and 17beta-estradiol (E2) may co-exist and interact with each other in aquatic environments. However, little is known about their combined effects on non-target organisms, especially in the presence of other environmental factors. In this study, the interplay between MWCNTs and E2 in the early life stages of zebrafish was investigated, focusing on the alterations in estrogenic responses with and without other environmental factors. There were no significant differences in the hatchability, mortality, or physical development of zebrafish in any treatments. Compared with E2 exposure, the E2-induced estrogenic responses (vtg1, vtg3, and esr1 genes) in zebrafish were markedly reduced to baseline by the presence of MWCNTs in most cases, indicating a strong protective effect. Furthermore, this inhibitive effect was not significantly changed by the preloading of natural organic matter (NOM) on MWCNTs. Nevertheless, the addition of ammonia nitrogen in the mixtures of MWCNTs and E2 alleviated the protective effect of MWCNTs, resuscitating the E2-induced estrogenic responses in zebrafish. These findings highlight the influence of carbon nanomaterials on the bioavailability of co contaminants in organisms. The widespread environmental factors in natural environments should also be taken into consideration when the combined toxicity of nanomaterials and contaminants is discussed. PMID- 29282668 TI - Biochar-enhanced composts reduce the potential leaching of nutrients and heavy metals and suppress plant-parasitic nematodes in excessively fertilized cucumber soils. AB - Excessive fertilization is a common agricultural practice that has largely reduced soil nutrient retention capacity and led to nutrient leaching in China. To reduce nutrient leaching, in this study, we evaluated the application of biochar, compost, and biochar-compost on soil properties, leaching water quality, and cucumber plant growth in soils with different nutrient levels. In general, the concentrations of nutrients and heavy metals in leaching water were higher under high-nutrient conditions than under low-nutrient conditions. Both biochar and compost efficiently enhanced soil cation exchange capacity (CEC), water holding capacity (WHC), and microbial biomass carbon (MBC), nitrogen (MBN), and phosphorus (MBP), reduced the potential leaching of nutrients and heavy metals, and improved plant growth. The efficiency of biochar and compost in soil CEC, WHC, MBC, MBN, and MBP and plant growth was enhanced when applied jointly. In addition, biochar and biochar-enhanced compost efficiently suppressed plant parasitic nematode infestation in a soil with high levels of both N and P. Our results suggest that biochar-enhanced compost can reduce the potential environmental risks in excessively fertilized vegetable soils. PMID- 29282667 TI - Changes in primary and secondary metabolites of Mentha aquatica L. exposed to different concentrations of manganese. AB - This experiment was conducted in order to determine the effects of different concentrations of manganese (Mn) on the levels and correlations of multiple primary and secondary metabolites in Mentha aquatica. With this aim, four levels of Mn concentrations were used as follows: basic Hoagland's solution (control), 40, 80, and 160 MUM of Mn supplied as MnSO4.H2O. The results indicated that the biomass and the contents of photosynthetic pigments and soluble carbohydrates were higher in the plants that were treated with the moderate concentrations of Mn (40 and 80 MUM) than the control and 160 MUM-treated plants. On the other hand, the contents of flavonoids, anthocyanins, malonaldehyde (MDA), hydrogen peroxide (H2O2), and the activities of antioxidant enzymes (total superoxide dismutase (SOD), catalase (CAT), and peroxidase (POX)) were progressively increased with the enhancement of Mn concentration in the nutrient solution. In addition, there were clear differences in the content and chemical composition of essential oils among the control and treatment groups. In this study, 1,8 cineole, menthofuran, and beta-caryophyllene were the most abundant constituents of essential oils in both the control and Mn-treated plants. The correlation analysis between pairs of the primary and secondary metabolites showed that there were positive and negative correlations among the variables when the Mn concentration was increased in the nutrient solution. These findings clearly display a positive effect of Mn up to 80 MUM in the nutrient solution on the growth of M. aquatica. PMID- 29282669 TI - Co-treatment of flotation waste, neutralization sludge, and arsenic-containing gypsum sludge from copper smelting: solidification/stabilization of arsenic and heavy metals with minimal cement clinker. AB - Flotation waste of copper slag (FWCS), neutralization sludge (NS), and arsenic containing gypsum sludge (GS), both of which are difficult to dispose of, are major solid wastes produced by the copper smelting. This study focused on the co treatment of FWCS, NS, and GS for solidification/stabilization of arsenic and heavy metals with minimal cement clinker. Firstly, the preparation parameters of binder composed of FWCS, NS, and cement clinker were optimized to be FWCS dosage of 40%, NS dosage of 10%, cement clinker dosage of 50%, mill time of 1.5 h, and water-to-binder ratio of 0.25. On these conditions, the unconfined compressive strength (UCS) of the binder reached 43.24 MPa after hydration of 28 days. Then, the binder was used to solidify/stabilize the As-containing GS. When the mass ratio of binder-to-GS was 5:5, the UCS of matrix can reach 11.06 MPa after hydration of 28 days, meeting the required UCS level of MU10 brick in China. Moreover, arsenic and other heavy metals in FWCS, NS, and GS were effectively solidified or stabilized. The heavy metal concentrations in leachate were much lower than those in the limits of China standard leaching test (CSLT). Therefore, the matrices were potential to be used as bricks in some constructions. XRD analysis shows that the main hydration products of the matrix were portlandite and calcium silicate hydrate. These hydration products may play a significant role in the stabilization/solidification of arsenic and heavy metals. PMID- 29282670 TI - Localized Nasopharyngeal Amyloidosis: A Clinicopathologic Series of 7 Cases with a Literature Review. AB - Localized nasopharyngeal amyloidosis is an extremely rare entity with only 25 cases described in the English and German literature. We present a case series of seven patients with localized nasopharyngeal amyloidosis and combine the findings with a thorough review the literature. PMID- 29282671 TI - Sinonasal Tract Solitary Fibrous Tumor: A Clinicopathologic Study of Six Cases with a Comprehensive Review of the Literature. AB - Solitary fibrous tumors (SFTs) are well recognized in the head and neck region, but rarely arise in the sinonasal tract (SNT). Six primary SNT SFTs were identified in the files of Southern California Permanente Medical Group between 2006 and 2017. The patients included five males and one female ranging in age from 33 to 72 years (mean 52 years), most of whom presented clinically with nasal obstruction. Three tumors involved the nasal cavity alone, one involved the paranasal sinuses, and two involved both the nasal cavity and paranasal sinuses. Histologically, the tumors were characterized by a variably cellular proliferation of cytologically bland spindle cells within a collagenous stroma with prominent interspersed branching vessels. Mitotic activity was low (range 0 2 per 10 high power fields) and there was no evidence of pleomorphism or tumor necrosis. Surface ulceration was noted. By immunohistochemistry, the lesional cells were positive for CD34, STAT6 and bcl-2. Clinical follow up information was available for all patients (range 32-102 months; mean 72 months). There were no recurrences or metastases and all were alive with no evidence of disease at last follow-up. SFTs rarely affect the SNT, but should be considered in the differential diagnosis of SNT mesenchymal lesions. Immunohistochemical expression of STAT6 can aid in diagnosis and separation of SFT from other spindle cell lesions occurring at this anatomic site. In combination with cases reported in the literature, primary SNT SFT behave in an indolent manner with conservative treatment. PMID- 29282672 TI - Successful Treatment of Refractory Vitiligo with a Combination of Khellin and 308 nm Excimer Lamp: An Open-Label, 1-Year Prospective Study. AB - INTRODUCTION: Phototherapy is the cornerstone of treatment of vitiligo. The 308 nm excimer lamp (EL) induces T cell apoptosis and the stimulation of melanocyte proliferation. Khellin is a furanochromone with a chemical structure close to psoralens. The objective of the study was to evaluate the safety and efficacy of 1-year treatment of recalcitrant vitiligo with a combination of 308-nm EL and khellin. METHODS: Twenty patients with resistant vitiligo were included. Khellin was applied 45 min before irradiation with EL, twice a week, at a dose of 250 mJ/cm2. The repigmentation was assessed in four categories: excellent repigmentation (ER) (> 75% repigmentation), good repigmentation (GR) (50-75% repigmentation), moderate repigmentation (MR) (25-50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation). RESULTS: An ER was observed in 45% of patients (9/20), 5/20 (25%) achieved a GR, 3/20 (15%) an MR, and 3/20 (15%) a PR. Better response was observed on the face, neck, upper limb, hands, and abdomen. The mean number of procedures was 54.1 and the mean cumulative dose was 2967.5 mJ/cm2. Six months after the last session no recurrences were observed. CONCLUSION: The combination of 308-nm EL and khellin is a safe and effective treatment and represents a new alternative therapy for vitiligo. Further comparative controlled randomized investigations are needed to confirm these promising results with the appropriate therapeutic protocols. PMID- 29282673 TI - The Microbiome-Gut-Behavior Axis: Crosstalk Between the Gut Microbiome and Oligodendrocytes Modulates Behavioral Responses. AB - Environmental and dietary stimuli have always been implicated in brain development and behavioral responses. The gut, being the major portal of communication with the external environment, has recently been brought to the forefront of this interaction with the establishment of a gut-brain axis in health and disease. Moreover, recent breakthroughs in germ-free and antibiotic treated mice have demonstrated the significant impact of the microbiome in modulating behavioral responses in mice and have established a more specific microbiome-gut-behavior axis. One of the mechanisms by which this axis affects social behavior is by regulating myelination at the prefrontal cortex, an important site for complex cognitive behavior planning and decision-making. The prefrontal cortex exhibits late myelination of its axonal projections that could extend into the third decade of life in humans, which make it susceptible to external influences, such as microbial metabolites. Changes in the gut microbiome were shown to alter the composition of the microbial metabolome affecting highly permeable bioactive compounds, such as p-cresol, which could impair oligodendrocyte differentiation. Dysregulated myelination in the prefrontal cortex is then able to affect behavioral responses in mice, shifting them towards social isolation. The reduced social interactions could then limit microbial exchange, which could otherwise pose a threat to the survival of the existing microbial community in the host and, thus, provide an evolutionary advantage to the specific microbial community. In this review, we will analyze the microbiome gut-behavior axis, describe the interactions between the gut microbiome and oligodendrocytes and highlight their role in the modulation of social behavior. PMID- 29282674 TI - Correction to: Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers. AB - The article "Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a PhysiologicallyBased Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers", written by Aiqun Li, Karen Yeo, Devin Welty, Haojing Rong, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 02nd November, 2017 without open access. PMID- 29282675 TI - Electropenetrography (EPG): a Breakthrough Tool Unveiling Stink Bug (Pentatomidae) Feeding on Plants. AB - In this article, we review and discuss the potential use of EPG (electropenetrography) as a powerful tool to unveil the feeding process of phytophagous stink bugs (pentatomids). These bugs are relatively big and vigorous, which presents a problem during wiring (i.e., attachment of the gold wire on the bug's pronotum) for use in EPG. Once this challenge was overcome, using the sand paper-and-wire technique, several species have been studied using EPG, yielding waveforms that, coupled with histological studies, revealed the ingestion sites on different host plants. These sites include vascular tissues (xylem and phloem), parenchyma tissue, and seed endosperm. Stink bugs usually feed by secreting a gelling saliva to create a salivary sheath that surrounds the stylets and anchors/supports/lubricates them. However, using the cell rupture feeding strategy and the tactic of combined laceration (mechanical movements of the stylets) and maceration (action of chemical enzymes) breaks the plant cells enabling ingestion. The number of ingestion events and their duration is variable according to the feeding site. Waveforms generated have typical patterns according to the feeding site. Recent studies with several species of stink bugs have started to demonstrate the potential of EPG as a tool to unveil their feeding behavior. This may also be useful in the applied field of stink bug management, such as the development and screening of resistant genotypes and the action of chemical insecticides affecting their feeding and survivorship. PMID- 29282677 TI - The Dawning of Translational Breast Cancer: From Bench to Bedside. AB - Breast cancer is one of the world's leading causes of death in women. Although tumor initiation and progression are predominantly driven by somatic or acquired (epi) genetic alterations that govern signaling abnormalities, growing evidence suggests that the inflammatory microenvironments of cancer also play a role. Molecular characterization of breast cancer biology is essential for high efficient management of this disease in clinical practice. Translating basic research into clinically valuable biomarkers for diagnosis, prognosis, and prediction of response to treatment and into precisely targeted therapies is crucial for the development of precision medicine in breast cancer. Such a process is known as "from bench to bedside." In this chapter, we will present an overview of breast cancer pathogenesis and selected translational advances in multistage clinical settings and aim to illustrate the dawning of precision medicine implementation in managing human breast malignancies. PMID- 29282676 TI - Surveillance on The Safety and Efficacy of Ambrisentan (Volibris Tablet 2.5 mg) in Patients with Pulmonary Arterial Hypertension in Real Clinical Practice: Post marketing Surveillance (Interim Analysis Report). AB - BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH. METHODS: PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated. RESULTS: Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (>= 2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment. CONCLUSION: The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with previous clinical trials in Japan and the rest of the world. Thus, these results provided another corroboration of the tolerability of ambrisentan and we continue to monitor proper use information via the post-marketing surveillance to ensure any new safety signals are identified in a timely manner (ClinTrial.gov: NCT01406327). PMID- 29282678 TI - Biomarker Studies in Early Detection and Prognosis of Breast Cancer. AB - Breast cancer is characterized with enormous heterogeneity, which represents the major hurdle for accurate diagnosis and curative therapy. It is generally believed that genome unstability and molecular evolvability underlie the robustness of cancer cells in hostile microenvironment and their resilience to therapeutic intervention. Conventional histopathological classification of breast cancer falls short of providing sufficient prognostic and predictive power, and thus biomarkers indicative of tumor intrinsic features at molecular levels have been actively pursued in biomedical researches. Currently, a number of molecular biomarkers are being used in standard clinical practice, including the hormone receptors for breast cancer subtyping and several genes involved in genome maintenance for prediction of breast cancer susceptibility. In addition, a number of biomarkers of single genes or multigene signatures have been approved for clinical use for breast cancer prognosis. A growing body of molecular biomarkers are being studied and tested to facilitate disease diagnosis and management, especially for breast cancer early detection, accurate prediction of metastatic behaviors, and selection of therapy. However, most of them are still at the preclinical stages. Finally, biomarkers of noninvasive protocols, such as serological molecules, have advantages in detection convenience over other biomarker types and therefore are of particular interest in translational and clinical development to improve diagnosis, prognosis, and treatment. PMID- 29282679 TI - The Preventive Intervention of Hereditary Breast Cancer. AB - Approximately 5-10% of breast cancer is considered to be hereditary. Familial breast cancers exhibit a dominant hereditary pattern, which typically have an early age of onset and are accompanied by symptoms of ovarian cancer, bilateral breast cancer, or male breast cancer. BRCA gene mutation carriers should be regarded as high-risk groups for breast cancer, which necessitates early examination of breast cancer. Studies have built up kinds of predictive models and recommended that female BRCA mutation carriers should receive breast self test training and take monthly breast self-examination. Familial or hereditary breast cancer family members are high-risk groups, and their risks of breast cancer can be reduced by chemoprevention, including dietary composition adjustment and application of endocrine drugs. In recent years, large-scale clinical trials have shown the important role of chemoprevention in reducing the occurrence of hereditary breast cancer. Prophylactic mastectomy is also suitable for healthy women with high breast cancer risk factors. It can reduce the incidence rate of breast cancer in high-risk women by 90% and decrease the breast cancer mortality rate in medium-risk and high-risk women by 100% and 81%, respectively. PMID- 29282680 TI - Predicting and Overcoming Chemotherapeutic Resistance in Breast Cancer. AB - Our understanding of breast cancer and its therapeutic approach has improved greatly due to the advancement of molecular biology in recent years. Clinically, breast cancers are characterized into three basic types based on their immunohistochemical properties. They are triple-negative breast cancer, estrogen receptor (ER) and progesterone receptor (PR)-positive-HR positive breast cancer, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Even though these subtypes have been characterized, assessment of a breast cancer's receptor status is still widely used to determine whether or not a targeted therapy could be applied. Moreover, drug resistance is common in all breast cancer types despite the different treatment modalities applied. The development of resistance to different therapeutics is not mutually exclusive. It seems that tumor could be resistant to multiple treatment strategies, such as being both chemoresistant and monoclonal antibody resistant. However, the underlying mechanisms are complicated and need further investigation. In this chapter, we aim to provide a brief review of the different types of breast cancer and their respective treatment strategies. We also review the possible mechanisms of potential drug resistance associated with each treatment type. We believe that a better understanding of the drug resistance mechanisms can lead to a more effective and efficient therapeutic success. PMID- 29282681 TI - Studies on DNA Damage Repair and Precision Radiotherapy for Breast Cancer. AB - Radiotherapy acts as an important component of breast cancer management, which significantly decreases local recurrence in patients treated with conservative surgery or with radical mastectomy. On the foundation of technological innovation of radiotherapy setting, precision radiotherapy of cancer has been widely applied in recent years. DNA damage and its repair mechanism are the vital factors which lead to the formation of tumor. Moreover, the status of DNA damage repair in cancer cells has been shown to influence patient response to the therapy, including radiotherapy. Some genes can affect the radiosensitivity of tumor cell by regulating the DNA damage repair pathway. This chapter will describe the potential application of DNA damage repair in precision radiotherapy of breast cancer. PMID- 29282682 TI - Targeted Therapies Against Growth Factor Signaling in Breast Cancer. AB - Breast cancer is the most prevalent female malignancy throughout the world. Conventional treatment strategies for breast cancer consist of chemotherapy, radiation, surgery, chemoradiation, hormone therapy, and targeted therapies. Among them, targeted therapies show advantages to reduce cost and toxicity for being possible for individualized treatments based on the intrinsic subtypes of breast cancer. With deeper understanding of key signaling pathways concerning tumor growth and survival, growth factor-controlled signaling pathways are frequently dysregulated in the development and progression of breast cancer. Thus, targeted therapies against growth factor-mediated signaling pathways have been shown to have promising efficacy in both preclinical animal models and human clinical trials. In this chapter, we will briefly introduce inhibitors and monoclonal antibodies that target the main growth factor-modulated scenarios including epidermal growth factor receptor (EGFR), transforming growth factor beta (TGF-beta), insulin-like growth factor 1 receptor (IGF1R), and fibroblast growth factor receptor (FGFR) signaling pathways in breast cancer therapy. PMID- 29282683 TI - Targeting Stemness: Implications for Precision Medicine in Breast Cancer. AB - The genomic landscape of breast cancer has been delineated in recent years. Advances in molecular characterization and targeting strategies are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual patient in the era of precision medicine. Cancer stem cells (CSCs) are a subpopulation in the tumor which have the capability of self-renewal and differentiation. Breast CSCs have important clinical implications as they account for tumor initiation, maintenance, metastasis, therapy resistance, and relapse. In this chapter, we will introduce approaches used to characterize breast CSCs, crucial pathways involved in regulating cancer stemness, and implications of breast CSCs in the precision diagnosis and treatment of breast cancer. We will also discuss novel compounds and therapeutic strategies that selectively target breast CSCs. Integration of breast CSC-related molecular diagnosis and targeted therapy into the clinical workflow of precision medicine has the potential to deliver more effective treatment to breast cancer patients. PMID- 29282684 TI - Disrupting Tumor Angiogenesis and "the Hunger Games" for Breast Cancer. AB - Angiogenesis, one of the hallmarks of cancers, has become an attractive target for cancer therapy since decades ago. It is broadly thought that upregulation of angiogenesis is involved in tumor progression and metastasis. Though tumor vessels are tortuous, disorganized, and leaky, they deliver oxygen and nutrients for tumor development. Based on this knowledge, many kinds of drugs targeting angiogenesis pathways have been developed, such as bevacizumab. However, the clinical outcomes of anti-angiogenesis therapies are moderate in metastatic breast cancer as well as in metastatic colorectal cancer and non-small cell lung cancer, even combined with traditional chemotherapy. In this chapter, the morphologic angiogenesis patterns and the key molecular pathways regulating angiogenesis are elaborated. The FDA-approved anti-angiogenesis drugs and current challenges of anti-angiogenesis therapy are described. The strategies to overcome the barriers will also be elucidated. PMID- 29282686 TI - Perspectives of Reprogramming Breast Cancer Metabolism. AB - Reprogramming of cellular metabolism is one of the hallmarks of breast cancer. Breast cancer cells remodel metabolic network to maintain their transformed state and survive in a harsh tumor microenvironment. Dysregulated metabolism further interacts with cellular signaling and epigenetics to promote breast cancer development. Meanwhile, breast cancer stem cells exhibit unique metabolic features, which are critical for therapeutic resistance and tumor recurrence. Besides, aberrant metabolism of breast cancer cells reshapes tumor microenvironment, such as promoting cancer vascularization and sabotaging tumor immunity, to accelerate tumor progression. These special metabolic traits not only open vulnerabilities of breast cancer by targeting essential metabolic pathways but also provide promising diagnostic and prognostic biomarkers to facilitate clinical investigations. Studies in the last few decades have significantly advanced our understanding of mechanisms underlying the reprogramming of breast cancer metabolism and metabolic regulation of breast cancer biology. Targeting tumor metabolism serves as a potentially effective therapeutic approach to suppress breast cancer. PMID- 29282685 TI - Key Factors in Breast Cancer Dissemination and Establishment at the Bone: Past, Present and Future Perspectives. AB - Bone metastases associated with breast cancer remain a clinical challenge due to their associated morbidity, limited therapeutic intervention and lack of prognostic markers. With a continually evolving understanding of bone biology and its dynamic microenvironment, many potential new targets have been proposed. In this chapter, we discuss the roles of well-established bone markers and how their targeting, in addition to tumour-targeted therapies, might help in the prevention and treatment of bone metastases. There are a vast number of bone markers, of which one of the best-known families is the bone morphogenetic proteins (BMPs). This chapter focuses on their role in breast cancer-associated bone metastases, associated signalling pathways and the possibilities for potential therapeutic intervention. In addition, this chapter provides an update on the role receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) play on breast cancer development and their subsequent influence during the homing and establishment of breast cancer-associated bone metastases. Beyond the well-established bone molecules, this chapter also explores the role of other potential factors such as activated leukocyte cell adhesion molecule (ALCAM) and its potential impact on breast cancer cells' affinity for the bone environment, which implies that ALCAM could be a promising therapeutic target. PMID- 29282687 TI - Metabolic Changes During Cancer Cachexia Pathogenesis. AB - Wasting of adipose tissue and skeletal muscle is a hallmark of metastatic cancer and a major cause of death. Like patients with cachexia caused by other chronic infections or inflammatory diseases, the cancer subject manifests both malnutrition and metabolic stress. Both carbohydrate utilization and amino acid incorporation are decreased in the muscles of cancer cachexia patients. Cancer cells affect host metabolism in two ways: (a) their own metabolism of nutrients into other metabolites and (b) circulating factors they secrete or induce the host to secrete. Accelerated glycolysis and lactate production, i.e., the Warburg effect and the resultant increase in Cori cycle activity, are the most widely discussed metabolic effects. Meanwhile, although a large number of pro-cachexia circulating factors have been found, such as TNFa, IL-6, myostatin, and PTHrp, none have been shown to be a dominant factor that can be targeted singly to treat cancer cachexia in humans. It is possible that given the complex multifactorial nature of the cachexia secretome, and the personalized differences between cancer patients, targeting any single circulating factor would always be insufficient to treat cachexia for all patients. Here we review the metabolic changes that occur in response to tumor growth and tumor-secreted factors during cachexia. PMID- 29282688 TI - Cell Cycle Regulation in Treatment of Breast Cancer. AB - Cell cycle progression and cell proliferation are under precise and orchestrated control in normal cells. However, uncontrolled cell proliferation caused by aberrant cell cycle progression is a crucial characteristic of cancer. Understanding cell cycle progression and its regulation sheds light on cancer treatment. Agents targeting cell cycle regulators (such as CDKs) have been considered as promising candidates in cancer treatment. Although the first generation pan-CDK inhibitors failed in clinical trials because of their adverse events and low efficacy, new selective CDK 4/6 inhibitors showed potent efficacy with tolerable safety in preclinical and clinical studies. Here we will review the mechanisms of cell cycle regulation and targeting key cell cycle regulators (such as CDKs) in breast cancer treatment. Particularly, we will discuss the mechanism of CDK inhibitors in disrupting cell cycle progression, the use of selective CDK4/6 inhibitors in treatment of advanced, hormone receptor (HR) positive postmenopausal breast cancer patients, and other clinical trials that aim to extend the utilization of these agents. PMID- 29282689 TI - BRCA Gene Mutations and Poly(ADP-Ribose) Polymerase Inhibitors in Triple-Negative Breast Cancer. AB - Breast cancer is the most common cancer in women worldwide. Treatment is chosen according to its hormone receptor status and human epidermal growth factor receptor 2 (HER2) status. Among the four main clinically set subtypes, hormone receptor-negative/HER2-negative subtype, also called triple-negative subtype (TNBC), is the most aggressive type with limited choices of therapy. However, recent research has provided important new insights into effective treatments for this subtype. One molecular target that has gained attention is the BRCA gene. BRCA proteins are involved in the maintenance of genomic integrity, therefore playing an important role as a "caretaker" DNA repair protein. Approximately 5% of all breast cancer patients are BRCA mutation carriers, and among the patients with BRCA mutations, 57.1% have the clinical TNBC subtype, showing a high association between BRCA mutations and TNBCs. When cells lack either BRCA1 or BRCA2, all types of homology-directed repairs are compromised, and poly(ADP ribose) (PAR) polymerase (PARP) acts as a backup system to maintain the genome, consequently making the cells highly sensitive to PARP1 inhibitors. PARP inhibitors have shown promising activity in preclinical and early clinical trials, and today, phase III trials are ongoing. In this chapter, we discuss the mechanism and the role of PARP inhibitors in BRCA-mutated breast cancers and further elaborate the clinical potential of PARP inhibitors as well as their barriers. PMID- 29282690 TI - Targeting the Epigenome as a Novel Therapeutic Approach for Breast Cancer. AB - Breast cancer is one of complex diseases that are influenced by environment. Various genetic and epigenetic alterations are provoking causes of breast carcinogenesis. Dynamic epigenetic regulation including DNA methylation and histone modification induces dysregulation of genes related to proliferation, apoptosis, and metastasis in breast cancer. DNA methylation is strongly associated with the repression of transcription through adding to the methyl group by DNA methyltransferases (DNMTs), and tumor suppressor genes such as CCND2 and RUNX3 have been investigated to undergo hypermethylation at promoter region in breast cancer. In addition, histone deacetylases (HDACs) contribute to transcriptional repression by removing acetyl group at lysine residues leading to tumorigenesis. Since epigenetic changes are reversible, therapeutic approaches have been applied with epigenetic modification drugs such as DNMT inhibitors and HDAC inhibitors. In this chapter, we will summarize the feature of epigenetic markers in breast cancer cells and the effect of single or combination of epigenetic reagents for breast cancer therapy. PMID- 29282691 TI - Progress in Vaccine Therapies for Breast Cancer. AB - Therapeutic cancer vaccines aim to treat pre-existing cancer by boosting the patient's own immune system, which is an attractive strategy for cancer treatment. The cancer vaccines have mainly been designed to elicit antitumor T cell immune responses that recognize and eradicate cancer. The advantages of cancer immunotherapy with cancer vaccines include a) high specificity of tumor antigen, b) minimal vaccine-related adverse events, and c) long-lasting immunity boosted by cancer vaccine which is important to control tumor relapse. In this chapter, we discuss identification of tumor antigens in breast cancer (e.g., cancer-testis antigens, neoantigens, HER2/neu, MUC1), the vaccine delivery systems utilized in breast cancer treatment (e.g., peptide vaccines, dendritic cell-based vaccines, and whole tumor cell-based vaccines), as well as clinical trials with therapeutic breast cancer vaccines. Moreover, new-generation clinical trials of breast cancer vaccines will aim at employing personalized vaccines designed to harness robust immune response to a custom-made neoantigen in the patient with breast cancer. Combination of vaccination and other forms of cancer therapy such as chemotherapy, radiotherapy, targeted therapy with monoclonal antibody, or immune checkpoint blockade will be required to achieve potent and durable antitumor clinical benefits. PMID- 29282692 TI - Tumor Associated Macrophages as Therapeutic Targets for Breast Cancer. AB - Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor stroma. TAMs promote tumor growth by suppressing immunocompetent cells, including neovascularization and supporting cancer stem cells. In the chapter, we discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and developing potential strategies to increase the efficacy of breast cancer treatment. PMID- 29282693 TI - New Approaches in CAR-T Cell Immunotherapy for Breast Cancer. AB - Despite significant advances in surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of death from malignant tumors among women. Immunotherapy has recently become a critical component of breast cancer treatment with encouraging activity and mild safety profiles. CAR-T therapy using genetically modifying T cells with chimeric antigen receptors (CAR) is the most commonly used approach to generate tumor specific T cells. It has shown good curative effect for a variety of malignant diseases, especially for hematological malignancies. In this review, we briefly introduce the history and the present state of CAR research. Then we discuss the barriers of solid tumors for CARs application and possible strategies to improve therapeutic response with a focus on breast cancer. At last, we outlook the future directions of CAR-T therapy including managing toxicities and developing universal CAR-T cells. PMID- 29282694 TI - Immune Checkpoint Blockade in Breast Cancer Therapy. AB - Cancer immunotherapy is emerging as the most promising novel strategy for cancer treatment. Cancer immunotherapy is broadly categorized into three forms: immune checkpoint modulation, adoptive cell transfer, and cancer vaccine. Immune checkpoint blockade is demonstrated as the most clinically effective treatment with low immune-related adverse events (irAE). Blockade of PD-1/PD-L1 and CTLA-4 has achieved remarkable success in treating various types of tumors, which sparks great interests in this therapeutic strategy and expands the role of immune checkpoint blockade in treating tumors including breast cancer. Based on the notable results obtained from clinical trials, the United States' Food and Drug Administration (FDA) has approved multiple CTLA-4 monoclonal antibodies as well as the PD-1/PD-L1 monoclonal antibodies for treatment of different types of tumors. The theories of immunoediting, T-cell exhaustions, and co-stimulatory/co inhibitory pathways are immunological foundations for immune checkpoint blockade therapy. Breast cancers such as triple negative breast cancer and HER-2 negative breast cancer respond to immune checkpoint blockade therapy due to their high immunogenicity. PD-1/PD-L1 blockade has just received FDA approval as a standard cancer therapy for solid tumors such as breast cancer. Development of immune checkpoint blockade focuses on two directions: one is to identify proper biomarkers of immune checkpoint blockade in breast cancer, and the other is to combine therapies with PD-1/PD-L1 blockade antibodies to achieve optimal clinical outcomes. PMID- 29282695 TI - Strategies and Progress of Endocrine Therapy for Patients with Metastatic Breast Cancer. AB - Breast cancer is one of the most prevalent cancers and the leading causes of cancer mortality in women worldwide and in China. For hormone receptor-positive (HR+) breast cancer, accounting for approximately 60-80% of breast cancer, endocrine therapy (ET) is the primary treatment strategy. For patients with HR+ metastatic breast cancer (MBC), there are many endocrine-based treatment options that can improve long-term outcomes and optimize quality of life. With the emergence and availability of new and effective agents, the options for ET have expanded in the last two decades. Although hormone therapy has been a standard of care for many decades, treatment must be individualized based on tumor biology and extent of disease. For example, the patients with impending organ failure may be treated with induction chemotherapy to improve organ function, followed by ET. For the patients who develop metastatic disease while on adjuvant ET, particularly when associated with organ failure, or for those with low expression of hormone receptors or expression of HER2, chemotherapy again may be a preferred initial treatment. ET blocks estrogen-driven tumor growth through different mechanisms; however, HR+ MBC can be intrinsically resistant or may acquire resistance to the treatment. Several targeted agents have been approved to use in combination with ET to improve response and delay development of resistance. PMID- 29282696 TI - Cardiac Biomarkers Release in Preadolescent Athletes After an High Intensity Exercise. AB - INTRODUCTION: An elevation of cardiac troponins has been described in healthy athletes after endurance exercises. The clinical significance of this increase is unclear and the lack of awareness of this phenomenon may lead to inappropriate management of these subjects. AIM: We sought to determine wether an intensive cycling training could determine a biomarkers elevation. METHODS: We evaluated serum high sensitivity cardiac troponin T, NH(2)-terminal pro-brain natriuretic peptide, CK-MB and CK in 21 healthy male preadolescent athletes (age 9.2 +/- 1.7 years) after an intensive cycling training prolonged until muscular exhaustion (mean duration 16'41"). During exercise heart rhythm and rate were monitored with Holter. RESULTS: 62% of the group had an elevation of cardiac biomarkers: specifically, 6 children had an increase in troponin levels; 3 of them had an elevation of pro-brain natriuretic peptides as well. Pro-brain natriuretic peptides resulted increased in 9 subjects. There was no relation between troponin elevation and heart rate, age or exercise duration; subjects with increased pro brain natriuretic peptides had mean and maximal heart rates lower than children with normal natriuretic peptides levels. Other sports were performed in 50% of subjects with normal troponins and only in 17% of those with increased values. CONCLUSIONS: A short, high-intensity exercise caused an elevation of cardiac biomarkers in 62% of our subjects. The grade of training may influence the release of troponin and this increase is probably related to a temporary discrepancy between O2 delivery and consumption. Increases in natriuretic peptides levels are possibly expression of different adaptations to exercise. PMID- 29282697 TI - Regulation of SAP102 Synaptic Targeting by Phosphorylation. AB - Synapse-associated protein 102 (SAP102) is a scaffolding protein highly expressed early in development and plays a critical role in mediating glutamate receptor trafficking during synaptogenesis. Mutations in human SAP102 have been reported to cause intellectual disability, which is thought to be due to mislocalization of the mutant protein. However, little is known about the regulation of SAP102 synaptic targeting. Here, we investigate the role of phosphorylation of SAP102 in regulating its synaptic targeting. Previous studies have shown that synaptic targeting of SAP102 is regulated by C-terminal splicing. We now identify a phosphorylation site, serine 632, within the C-terminal alternatively spliced region, which is phosphorylated by casein kinase II (CK2). We show that Ser632 on SAP102 is phosphorylated in vitro, in heterologous cells, and in neurons. Moreover, we demonstrate that synaptic enrichment of SAP102 is increased by Ser632 phosphorylation. Consistently, elevation of synaptic activity that suppresses Ser632 phosphorylation reduces synaptic enrichment of SAP102. Furthermore, the mobility of SAP102 is decreased by Ser632 phosphorylation. Therefore, not only SAP102 synaptic targeting but also its mobility is regulated by Ser632 phosphorylation. These data provide evidence for a novel mechanism in regulating SAP102 function and glutamate receptor trafficking. PMID- 29282698 TI - Elevated Surfactant Protein Levels and Increased Flow of Cerebrospinal Fluid in Cranial Magnetic Resonance Imaging. AB - Surfactant proteins (SPs) are a multifunctional group of proteins, responsible for the regulation of rheological properties of body fluids, host defense, and cellular waste clearance. Their concentrations are changed in cerebrospinal fluid (CSF) of patients suffering from communicating hydrocephalus. Hydrocephalic conditions are accompanied by altered CSF flow dynamics; however, the association of CSF-SP concentrations and CSF flow has not yet been investigated. Hence, the aim of this study was to evaluate the association between SP concentrations in the CSF and marked CSF flow phenomena at different anatomical landmarks of CSF spaces. Sixty-one individuals (15 healthy subjects and 46 hydrocephalus patients) were included in this study. CSF specimens were analyzed for SP-A, SP-B, SP-C, and SP-D concentrations by the use of enzyme-linked immunosorbent assays (ELISA). CSF flow was evaluated in axial T2_turbo inversion recovery magnitude (TIRM) weighted and sagittal T2-weighted magnetic resonance imaging sections using a 4 grade scale (1-no flow, 2-subtle flow, 3-moderate flow, and 4-strong flow). CSF SP concentrations (mean +/- standard deviation) of the overall collective were as follows: SP-A = 0.73 +/- 0.58 ng/ml, SP-B = 0.17 +/- 0.93 ng/ml, SP-C = 0.95 +/- 0.75 ng/ml, and SP-D = 7.43 +/- 5.17 ng/ml. The difference between healthy controls and hydrocephalic patients regarding CSF concentrations of SP-A (0.34 +/ 0.22 vs. 0.81 +/- 0.59 ng/ml) and SP-C (0.48 +/- 0.29 vs. 1.10 +/- 0.79 ng/ml) revealed to be statistically significant as calculated by means of ANOVA (p values of 0.022 and 0.007, respectively). CSF flow voids were detectable at all investigated landmarks of the CSF spaces (foramina of Monro, third ventricle, mesencephalic aqueduct, prepontine cistern, fourth ventricle, cisterna magna, and craniocervical junction). CSF flow voids, reported as mean +/- standard deviation, revealed to be significantly increased in hydrocephalic patients compared to controls as calculated by means of ANOVA (respective p values are given in brackets following values of descriptive statistics) at the following sites: foramina of Monro (1.60 +/- 0.91 vs. 2.37 +/- 0.99, p = 0.01), fourth ventricle (1.67 +/- 0.98 vs. 2.52 +/- 1.05, p = 0.007), and the cisterna magna (1.93 +/- 1.10 vs. 2.72 +/- 1.13, p = 0.022). Spearman's rank order calculation identified significant correlations for CSF flow voids at the foramina of Monro and the third ventricle with SP-A (r = 0.429, p = 0.001 and r = 0.464, p < 0.001) and CSF flow void at the mesencephalic duct with SP-D (r = - 0.371, p = 0.039). Furthermore, SP-C showed a moderate inverse correlation with age (r = - 0.302, p = 0.022). The present study confirmed statistically significant differences in SP CSF concentrations between healthy controls and hydrocephalic patients. Additionally, significant correlations between SP concentrations in CSF with increased CSF flow were identified. These findings underline the role of SPs as regulators of CSF rheology. PMID- 29282699 TI - Dizziness in the emergency department: an update on diagnosis. AB - This review aims to assist emergency physicians in finding the underlying aetiology when a patient presents with dizziness to the emergency department. After reading this review, the emergency physician will be able to consider the most relevant differential diagnoses and have an idea about dangerous aetiologies that require immediate action. The emergency physician will also know what diagnostic steps need to be taken at what time, such as the three-component HINTS Test (Head Impulse, Nystagmus, and Test-of-Skew), which helps with distinguishing central from peripheral causes of the acute vestibular syndrome. Furthermore, episodic vestibular syndromes and chronic vestibular syndromes are discussed in detail. The five most frequent categories of dizziness are vasovagal syncope / orthostatic hypotension (22.3%), vestibular causes (19.9%), fluid and electrolyte disorders (17.5%), circulatory/pulmonary causes (14.8%) and central vascular causes (6.4%). Given that it would neither be economical nor practical to send all patients to specialists from the start, we present general guidelines for the diagnostic workup of patients presenting with dizziness to the emergency department. This review will focus on epidemiology, aetiologies, differential diagnoses and diagnostics. Treatment is described in a separate article. PMID- 29282700 TI - Time trends of positivity rates from foodborne pathogen testing in Switzerland, 2003 to 2012. AB - BACKGROUND: Campylobacteriosis and salmonellosis are important foodborne diseases in Europe, including in Switzerland. In 2014, notification rates for Switzerland were 92.9 per 100 000 population for campylobacteriosis and 15.2 per 100 000 population for salmonellosis. These notification rates originate from laboratory based surveillance whereby positive test results are reported to the National Notification System for Infectious Diseases. Consequently, notification rates do not directly correspond to the disease burden among the population as the number of positive tests depends on patients' healthcare-seeking behaviour, stool sampling rates and other factors. METHODS: We assessed laboratory positivity rates (proportion of positive tests among all tests performed) of diagnostic tests for Campylobacter and Salmonella from five private laboratories in Switzerland between 2003 and 2012. We analysed demographic characteristics, temporal and spatial distribution of test numbers and positivity rates. Predictors for a positive test and disease seasonality were assessed with logistic regression analyses. RESULTS: A total of 135 122 (13 095 positive) Campylobacter tests and 136 997 (2832 positive) Salmonella tests were obtained with positive tests corresponding to 20.4% and 17.2% of notified campylobacteriosis and salmonellosis cases, respectively. The number of tests conducted annually increased for both pathogens by 51% from 2003 to 2012. Annual positivity rates of Campylobacter increased from 7.6 to 11.1% and rates of Salmonella decreased from 2.7 to 1.5%. The largest increases in annual Campylobacter positivity rates were observed for patients older than 85 years (+193.7%), followed by children aged 5-9 years (+131.9%). Positivity rates and test numbers for both diseases by month or calendar week showed a distinct seasonality, with peak rates for Salmonella occurring in autumn and for Campylobacter in summer and at the turn of the year. These findings were independent of patients' age and sex. CONCLUSIONS: Both positivity rates and notification rates showed increasing trends for Campylobacter and decreasing trends for Salmonella, suggesting that these trends reflect changes in disease epidemiology at population level. The continuous assessment of positivity rates remains important to appropriately interpret changes observed in the notification system especially considering the increasing use of multiplex polymerase chain reaction test panels where multiple pathogens are tested simultaneously. PMID- 29282701 TI - Towards ICF implementation in menopause healthcare: a systematic review of ICF application in Switzerland. AB - AIMS OF THE STUDY: To present a systematic literature review on the application and degree of implementation of the International Classification of Functioning, Disability and Health (ICF) across different health conditions and regions in Switzerland in order to develop an ICF classification of the climacteric syndrome in the medium term. METHODS: A systematic literature search was conducted through Embase and Medline covering the period between 2011 and August 2016. Inclusion criteria were the term ICF in title or abstract and Switzerland as the workplace of the first author. Identified publications were analysed as descriptive statistics. RESULTS: A total of 83 articles were included in the analysis. Forty seven different first authors from 24 different institutions were identified. The majority of publications were from Swiss Paraplegic Research (68.7%) and focused on neurology (31.3%). Forty-six cohort studies were identified. In most of them, the ICF was used to set up a general language for comparing patients' information (82.9%). Only one paper from the medical specialty gynaecology was identified; this was on breast cancer. No paper on the menopause was found. CONCLUSION: In Switzerland, the ICF is actively used in various areas of healthcare, especially in the field of neurology and rehabilitation. There is a need for ICF core sets in other medical fields, such as menopause healthcare, in order to accomplish the goal of the European Menopause and Andropause Society, which is a healthcare model for healthy menopause and aging. PMID- 29282702 TI - Treatment of dizziness: an interdisciplinary update. AB - This review provides an update on interdisciplinary treatment for dizziness. Dizziness can have various causes and the treatment offered should depend on the cause. After reading this article, the clinician will have an overview of current treatment recommendations. Recommendations are made for the most prevalent causes of dizziness including acute and chronic vestibular syndromes, vestibular neuritis, benign paroxysmal positional vertigo, endolymphatic hydrops and Meniere's disease, vestibular paroxysmia and vestibular migraine, cardiac causes, transient ischaemic attacks and strokes, episodic ataxia type 2, persistent postural-perceptual dizziness, bilateral vestibulopathy, degenerative, autoimmune and neoplastic diseases, upbeat- and downbeat nystagmus. Recommendations include clinical approaches (repositioning manoeuvres), medication (adding, removing or changing current medication depending on aetiology), vestibular physiotherapy, ergotherapy and rehabilitation, treatment of chest pain or stroke units and surgical interventions. If symptoms are acute and severe, medication with antivertigo agents is recommended as a first step, for a maximum period of 3 days. Following initial symptom control, treatment is tailored depending on aetiology. To assist the clinician in obtaining a useful overview, the level of evidence and number needed to treat are reported whenever possible based on study characteristics. In addition, warnings about possible arrhythmias due to medication are issued, and precautions to enable these to be avoided are discussed. PMID- 29282703 TI - Serum 25-hydroxyvitamin D levels and intramuscular vitamin D3 supplementation among Eritrean migrants recently arrived in Switzerland. AB - In a cross-sectional screening programme, we assessed serum vitamin D levels in adult Eritrean refugees recently arrived in Switzerland. Median vitamin D level among 107 participants (95 males and 12 females) was 27 nmol/l (interquartile range 23-42 nmol/l), 86% had insufficient vitamin D levels (<=50 nmol/l) and 36% severe deficiency (<25 nmol/l). In 29 participants who received single-dose intramuscular vitamin D substitution (300 000 IU), median vitamin D levels increased from 25 to 35 nmol/l after 3 months (p = 0.005); only 11 (38%) reached sufficient vitamin D levels. Eritrean migrants should be routinely screened for vitamin D deficiency. Single-dose intramuscular supplementation appeared to be insufficient to achieve optimal levels in the majority of participants. PMID- 29282704 TI - Diet, medication use and drug intake during pregnancy: data from the consecutive Swiss Health Surveys of 2007 and 2012. AB - OBJECTIVE: The aim of this work was to gain knowledge on the health status of pregnant women in Switzerland, especially their attitude to and decisions about diet, use of medication and consumption of drugs, including alcohol and tobacco. METHODS: Data collected by the consecutive Swiss Health Surveys of 2007 and 2012 on sociodemographic and lifestyle characteristics (including nutrition), type and intake of medication, use of alcohol, tobacco and illicit drugs of the female population were analysed. To compare pregnant with non-pregnant women, a group of 10 times as many non-pregnant women (reference group, n = 3090) was matched with all the participating women who said they were pregnant at the time of the survey (pregnant group, n = 309). The two groups were then compared. RESULTS: The pregnant and non-pregnant participant groups were comparable with respect to most sociodemographic characteristics and both showed a high awareness of health related issues. Significantly more pregnant than non-pregnant women revealed a high nutritional awareness, claiming to pay attention to what they ate (78.3 vs 73.0%). Frequent consumption of milk products and fish, and moderate consumption of meat were found more often in the pregnant group. Use of medication was comparable between the two groups, except that pregnant women took pain killers less frequently than did non-pregnant women (30.0 vs 61.5%) and relied more often on prescribed medication. Pregnant women were more restrictive in their alcohol consumption than non-pregnant women. Nevertheless, 10.0 and 1.9% of the pregnant women declared consumption of wine and beer, respectively, in the previous 7 days. Regular smoking was less frequent in the pregnant group than in the reference group (11.7 vs 30.3%) and less intensive (pregnant smokers smoked 3.6 cigarettes fewer per day). A few pregnant women (1.9%) said they consumed marijuana; no other illicit drugs were mentioned. CONCLUSIONS: In Switzerland, women of child-bearing age revealed high general health-awareness. During pregnancy, a considerable proportion of the women adapted their diet and seemed to refrain from using pain killers and from consuming alcohol, tobacco and illicit drugs. However, since a fairly large minority of the pregnant women mentioned drinking alcohol and/or smoking tobacco, further preventive work is needed. PMID- 29282705 TI - Changing Healthcare Service Delivery to Improve Health Outcomes For Older Adults: Opportunities Not to Be Missed. PMID- 29282706 TI - The association of RAR-related orphan receptor A (RORA) gene polymorphisms with the risk of asthma. AB - Asthma is a common, heterogeneous chronic respiratory disease characterized by chronic inflammation of the airway, airway hyperreactivity, and airway remodeling. The RAR-related orphan receptor A (RORA) gene has been identified for the pathogenesis of asthma. The purpose of this research was to investigate the relationship between RORA gene polymorphisms and asthma susceptibility in the Chinese Zhuang population. This was a case-control study including 231 children with asthma and 343 healthy controls. The RORA gene polymorphisms were measured by the polymerase chain reaction-ligase detection reaction genotyping assays and confirmed by sequencing. The distribution of the genotype frequencies of the RORA rs11071559 C>T was significantly different in the group of cases and the healthy children (P < 0.05). By haplotype analyses, the haplotype TT (rs7164773/rs11071559) was statistically significant between asthmatics and nonasthmatics, but the association was not significant after correction for multiple comparisons. Our results provided evidence that the RORA rs11071559C>T polymorphism was associated with an elevated susceptibility to pediatric asthma in the Chinese Zhuang population. PMID- 29282707 TI - A novel mutation in the HPGD gene causing primary hypertrophic osteoarthropathy with digital clubbing in a Pakistani family. AB - Primary hypertrophic osteoarthropathy (PHO) is a congenital multisystemic entity characterized by three major clinical symptoms: pachydermia, periostosis, and digital clubbing. Recently it has been reported that pathogenic mutations in two genes are known to be associated with PHO: HPGD and SLCO2A1. In the present study, a five-generation consanguineous Pakistani family harboring primary hypertrophic osteoarthropathy in autosomal-recessive pattern was ascertained. Whole genome single nucleotide polymorphisms (SNPs) genotyping and sequence analysis revealed a novel homozygous missense mutation (c.577T?C) of the human HPGD gene in all affected members of the family. The study presented here demonstrate the first case of primary hypertrophic osteoarthropathy reported in Pashtun population. PMID- 29282708 TI - p.X654R IDUA variant among Thai individuals with intermediate mucopolysaccharidosis type I and its residual activity as demonstrated in COS-7 cells. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a rare autosomal-recessive disorder caused by defects in alpha-L-iduronidase (IDUA), a lysosomal enzyme encoded by the IDUA gene. Herein, we characterized IDUA mutations underlying mucopolysaccharidosis type I intermediate form (Hurler-Scheie syndrome) and its molecular pathogenic mechanisms. METHODS: Clinical data, activity of the IDUA enzyme in leukocytes, and a mutation of the IDUA gene were analyzed. Pathogenesis associated with an IDUA mutation was further investigated by evaluating the mutant cDNA sequence, protein expression and activity in COS-7 cells. RESULTS: Five unrelated patients were identified to have clinical diagnosis of intermediate form of MPS I (Hurler-Scheie) and exhibited low-to-absent levels of leukocyte IDUA activity. Genetic analysis revealed homozygous c.*1T>C (p.X654R) mutation in two patients and compound heterozygosity between the c.*1T>C and another allele including c.265G>A (p.R89Q), c.935G>A (p.W312X), or c.1138 C>T (p.Q380X), each in a single patient. Sequencing the 3'RACE product of the c.*1T>C (p.X654R) allele indicated a 38-amino acids elongation of the mutant protein. COS 7 cells expressing IDUA with the mutations exhibited extremely low levels or complete absence of enzyme activity compared to wild-type IDUA. Western blot analysis detected no protein in p.W312X and p.Q380X samples, while an elevated molecular mass and a different pattern of protein bands were found in p.X654R specimen compared with the wild type IDUA. CONCLUSIONS: Mutational spectrum underlying intermediate MPS I is expanded. Our data suggest that the p.X654R is an intermediate IDUA mutant allele with residual enzyme activity. It can lead to intermediate or milder form of MPS I depending on another associated allele. PMID- 29282709 TI - Neurodevelopmental origins of abnormal cortical morphology in dissociative identity disorder. AB - OBJECTIVE: To examine the two constitutes of cortical volume (CV), that is, cortical thickness (CT) and surface area (SA), in individuals with dissociative identity disorder (DID) with the view of gaining important novel insights into the underlying neurobiological mechanisms mediating DID. METHODS: This study included 32 female patients with DID and 43 matched healthy controls. Between group differences in CV, thickness, and SA, the degree of spatial overlap between differences in CT and SA, and their relative contribution to differences in regional CV were assessed using a novel spatially unbiased vertex-wise approach. Whole-brain correlation analyses were performed between measures of cortical anatomy and dissociative symptoms and traumatization. RESULTS: Individuals with DID differed from controls in CV, CT, and SA, with significantly decreased CT in the insula, anterior cingulate, and parietal regions and reduced cortical SA in temporal and orbitofrontal cortices. Abnormalities in CT and SA shared only about 3% of all significantly different cerebral surface locations and involved distinct contributions to the abnormality of CV in DID. Significant negative associations between abnormal brain morphology (SA and CV) and dissociative symptoms and early childhood traumatization (0 and 3 years of age) were found. CONCLUSIONS: In DID, neuroanatomical areas with decreased CT and SA are in different locations in the brain. As CT and SA have distinct genetic and developmental origins, our findings may indicate that different neurobiological mechanisms and environmental factors impact on cortical morphology in DID, such as early childhood traumatization. PMID- 29282710 TI - The dimensionality of individual niche variation. AB - The inherently multidimensional nature of the niche has not yet been integrated into the investigation of individual niche specialization within populations. We propose a framework for modeling the between- and within-individual components of the population niche as a set of variance-covariance matrices, which can be visualized with ellipses or ellipsoids. These niche components can be inferred using multiple response mixed models, and can incorporate diverse types of data, including diet composition, stable isotopes, spatial location, and other continuous measures of niche dimensions. We outline how considering both individual and population niches in multiple dimensions may enhance our understanding of key concepts in ecology and evolution. Considering multiple dimensions as well as the within-individual component of variation can lead to more meaningful measures of niche overlap between species. The impact of a population on its food web or ecosystem can depend on the degree of individual variation (via Jensen's inequality), and we suggest how the dimensionality of individual specialization could amplify this effect. Finally, we draw from concepts in quantitative genetics and the study of animal personalities to propose new hypotheses about the ecological and evolutionary basis of niche shifts in multiple dimensions. We illustrate key ideas using empirical data from sea otters, wetland frogs, and threespine stickleback, and discuss outstanding questions about the consequences of multidimensional niche variation. Setting variation among individuals in an explicitly multivariate framework has the potential to transform our understanding of a range of ecological and evolutionary processes. PMID- 29282711 TI - More invaders do not result in heavier impacts: The effects of non-native bullfrogs on native anurans are mitigated by high densities of non-native crayfish. AB - With accelerating species introductions in an era of globalization, co-occurring alien species have become increasingly common. Understanding the combined ecological impacts of multiple invaders is not only crucial for wildlife managers attempting to ameliorate biodiversity loss, but also provides key insights into invasion success and species coexistence mechanisms in natural ecosystems. Compared with much attentions given to single-invader impacts, little is known about the impacts of multiple co-occurring invaders. The American bullfrog (Lithobates catesbeianus = Rana catesbeiana) and the red swamp crayfish (Procambarus clarkii) are two aquatic invasive species in many different areas of the globe. They coexist with native anurans in a variety of permanent lentic waters, which provide an ideal model system to explore the combined effects of multiple invaders from different trophic levels on native species. Based on a global diet analysis covering 34 native and invasive bullfrog populations, and data from 10-year field surveys across 157 water bodies in the Zhoushan Archipelago, China, we observed a reduced impact of bullfrogs on native anurans at high crayfish densities when the two invaders co-occurred. The global diet analysis showed that crayfish occurrence reduced the number of native anuran prey consumed by bullfrogs in both native and invasive populations. After accounting for pseudoreplication of different observations among water bodies, islands, and survey time, model averaging analyses based on GLMMs showed a negative relationship between bullfrog density and native anuran densities for field observations of invasive bullfrogs alone and co-invaded observations with low crayfish density. However, this negative relationship disappeared when the two invaders co-occurred with high crayfish density. Structural equation modelling (SEM) analyses further validated that the impacts of bullfrogs on native frogs were mitigated by the negative interactions between crayfish and bullfrogs. Our results provide novel evidence of a density-dependent antagonistic effect of two sympatric invaders from different trophic levels on native species. This study highlights the importance of considering complex interactions among co-invaders and native species when prioritizing conservation and management actions and will facilitate the development of a more precise framework to predict invasion impacts. PMID- 29282712 TI - Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas. AB - Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information. PMID- 29282713 TI - Factors associated with non-response at health-related quality of life follow-up in a septic shock trial. AB - BACKGROUND: Follow-up of intensive care unit (ICU) patients often includes health related quality of life (HRQoL) surveying, but non-responders hamper the interpretation. Our aim was to assess factors for non-response to HRQoL survey in ICU patients with septic shock at follow-up in a clinical trial. METHODS: In a post hoc follow-up registry study, we assessed all the Danish survivors in the Transfusion-Requirements in Septic Shock trial patients, who were mailed the Short Form 36-item Survey (SF-36) 1-year after randomization. We used covariates from the trial database merged with covariates from nation-wide registries using the unique national identification number to explore possible factors for not responding. Five covariates were pre-specified to be included in the primary multivariate analysis: age, number of days in hospital from randomization to follow-up, level of education, cohabitation and employment status at follow-up. We compared the mortality from 1-year survival (2012-2014) till end of final follow-up (January 2016) between non-responders and responders. RESULTS: We assessed 308 survivors of whom 108 (35%) were non-responders. In the primary analysis lower age (odds ratio 1.03, 95% CI [1.01-1.05]), more admission days in hospital (1.006 [1.001-1.011]) and living alone (4.33 [2.46-7.63]) were associated with non-responding, whereas the level of education and employment status were not. Non-responders had a hazard ratio of 1.63 [0.97-2.72] for mortality from 1-year follow-up to final follow-up as compared to the responders. CONCLUSION: Being younger, spending more days in hospital and living alone were all associated with non-response at 1-year HRQoL follow-up among ICU patients with septic shock. PMID- 29282714 TI - Bottom-up processes mediated by social systems drive demographic traits of coral reef fishes. AB - Ectotherms exhibit considerable plasticity in their life-history traits. This plasticity can reflect variability in environmental and social factors, but the causes of observed patterns are often obscured with increasing spatial scales. We surveyed dichromatic parrotfishes across the northern Great Barrier Reef to examine variation in body size distributions and concomitant size at sex change (L?50 ) against hypotheses of directional influence from biotic and abiotic factors known to affect demography. By integrating top-down, horizontal, and bottom-up processes, we demonstrate a strong association between exposure regimes (which are known to influence nutritional ecology and mating systems) and both body size distribution and L?50 (median length at female-to-male sex change), with an accompanying lack of strong empirical support for other biotic drivers previously hypothesized to affect body size distributions. Across sites, body size was predictably linked to variation in temperature and productivity, but the strongest predictor was whether subpopulations occurred at sheltered mid and inner shelf reefs or at wave-exposed outer shelf reef systems. Upon accounting for the underlying influence of body size distribution, this habitat-exposure gradient was highly associated with further L?50 variation across species, demonstrating that differences in mating systems across exposure gradients affect the timing of sex change beyond variation concomitant with differing overall body sizes. We posit that exposure-driven differences in habitat disturbance regimes have marked effects on the nutritional ecology of parrotfishes, leading to size related variation in mating systems, which underpin the observed patterns. Our results call for better integration of life-history, social factors, and ecosystem processes to foster an improved understanding of complex ecosystems such as coral reefs. PMID- 29282715 TI - Dynamic occupancy modelling reveals a hierarchy of competition among fishers, grey foxes and ringtails. AB - Determining how species coexist is critical for understanding functional diversity, niche partitioning and interspecific interactions. Identifying the direct and indirect interactions among sympatric carnivores that enable their coexistence is particularly important to elucidate because they are integral for maintaining ecosystem function. We studied the effects of removing nine fishers (Pekania pennanti) on their population dynamics and used this perturbation to elucidate the interspecific interactions among fishers, grey foxes (Urocyon cinereoargenteus) and ringtails (Bassariscus astutus). Grey foxes (family: Canidae) are likely to compete with fishers due to their similar body sizes and dietary overlap, and ringtails (family: Procyonidae), like fishers, are semi arboreal species of conservation concern. We used spatial capture-recapture to investigate fisher population numbers and dynamic occupancy models that incorporated interspecific interactions to investigate the effects members of these species had on the colonization and persistence of each other's site occupancy. The fisher population showed no change in density for up to 3 years following the removals of fishers for translocations. In contrast, fisher site occupancy decreased in the years immediately following the translocations. During this same time period, site occupancy by grey foxes increased and remained elevated through the end of the study. We found a complicated hierarchy among fishers, foxes and ringtails. Fishers affected grey fox site persistence negatively but had a positive effect on their colonization. Foxes had a positive effect on ringtail site colonization. Thus, fishers were the dominant small carnivore where present and negatively affected foxes directly and ringtails indirectly. Coexistence among the small carnivores we studied appears to reflect dynamic spatial partitioning. Conservation and management efforts should investigate how intraguild interactions may influence the recolonization of carnivores to previously occupied landscapes. PMID- 29282716 TI - Targeting DNA repair: the genome as a potential biomarker. AB - Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next-generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high-grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29282717 TI - Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1 linked amyotrophic lateral sclerosis mice. AB - Cystatin C (CysC) is a major protein component of Bunina bodies, which are a pathological hallmark observed in the remaining motor neurons of patients with amyotrophic lateral sclerosis (ALS). Dominant mutations in the SOD1 gene, encoding Cu/Zn superoxide dismutase (SOD1), are causative for a subset of inherited ALS cases. Our previous study showed that CysC exerts a neuroprotective effect against mutant SOD1-mediated toxicity in vitro; however, in vivo evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC in vivo using a mouse model of ALS in which the ALS-linked mutated SOD1 gene is expressed (SOD1G93A mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1G93A mice extended their survival times. Administered CysC was predominantly distributed in ventral horn neurons including motor neurons, and induced autophagy through AMP-activated kinase activation to reduce the amount of insoluble mutant SOD1 species. Moreover, PGC-1alpha, a disease modifier of ALS, was restored by CysC through AMP-activated kinase activation. Finally, the administration of CysC also promoted aggregation of CysC in motor neurons, which is similar to Bunina bodies. Taken together, our findings suggest that CysC represents a promising therapeutic candidate for ALS. PMID- 29282718 TI - Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients. AB - Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38 0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8+ T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29282719 TI - IL-12/IL-18-preactivated donor NK cells enhance GVL effects and mitigate GvHD after allogeneic hematopoietic stem cell transplantation. AB - Adoptive transfer of donor NK cells has the potential of mediating graft-versus leukemia (GVL) effect while suppressing acute graft-versus-host-disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these beneficial effects are limited by the transient function of adoptively transferred NK cells. Previous studies demonstrate that cytokine-induced memory like NK cells that are preactivated by IL-12, IL-15, and IL-18 have enhanced effector functions and long life span in vivo. Here, we investigated the effects of IL-12/18-preactivated and IL-12/15/18-preactivated donor NK cells on GVL and aGVHD in a murine model of allo-HSCT. We found that both IL-12/18- and IL 12/15/18-preactivated NK cells mediated stronger GVL effect than control NK cells mainly due to their elevated activation/cytotoxicity and sustained proliferative potential. Interestingly, we observed that although both IL-12/18- and IL 12/15/18-preactivated NK cells significantly inhibited severe aGVHD, only the IL 12/18-preactivated NK cells maintained the beneficial effect of donor NK cells on mild aGVHD. The IL-12/15/18-preactivated NK cell infusion accelerated aGVHD in the fully-mismatched mild aGVHD model. Our results demonstrated that IL-12/18 preactivated NK cells displayed sustained and enhanced GVL functions, and could mitigate aGVHD despite the severity of the disease. IL-12/18-preactivated donor NK cell infusion may be an effective and safe adoptive therapy after allo-HSCT. PMID- 29282720 TI - Revealing the glioma cancer stem cell interactome, one niche at a time. AB - Glioblastoma (GBM) cancer stem cells (CSCs) are insidious. They extensively infiltrate brain tissue, resist radiotherapy and chemotherapy, and are thought to represent the ultimate drivers of disease progression. New research has identified CD109, a GPI-anchored protein, on a population of perivascular CSCs. Investigation of primary human tumour tissue suggests a role for CD109-expressing CSCs in the progression from low-grade to high-grade glioma, and animal modelling reveals a critical role for CD109 in the maintenance of the GBM CSC phenotype. Furthermore, CD109-expressing CSCs appear to drive the proliferation of adjacent non-stem tumour cells (NSTCs) in a rare example of CSC-NSTC cooperative interaction. With this Commentary, we highlight the newly revealed biology of CD109, and offer a synthesis of the published information on glioma CSCs in a variety of anatomical growth zones. We also discuss the landscape of interacting cells within GBM tumours, emphasizing the few reported examples of pro tumourigenic, interactive tumour cell partnerships, as well as a variety of tumour cell-non-transformed neural cell interactions. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29282721 TI - State Medicaid Expansions for Parents Led to Increased Coverage and Prenatal Care Utilization among Pregnant Mothers. AB - OBJECTIVE: To evaluate impacts of state Medicaid expansions for low-income parents on the health insurance coverage, pregnancy intention, and use of prenatal care among mothers who became pregnant. DATA SOURCES/STUDY SETTING: Person-level data for women with a live birth from the 1997-2012 Pregnancy Risk Assessment Monitoring System. DATA COLLECTION/EXTRACTION METHODS: The sample was restricted to women who were already parents using information on previous live births and combined with information on state Medicaid policies for low-income parents. STUDY DESIGN: I used a measure of expanded generosity of state Medicaid eligibility for low-income parents to estimate changes in health insurance, pregnancy intention, and prenatal care for pregnant mothers associated with Medicaid expansion. PRINCIPAL FINDINGS: I found an increase in prepregnancy health insurance coverage and coverage during pregnancy among pregnant mothers, as well as earlier initiation of prenatal care, associated with the expansions. Among pregnant mothers with less education, I found an increase in the adequacy of prenatal care utilization. CONCLUSIONS: Expanded Medicaid coverage for low income adults has the potential to increase a woman's health insurance coverage prior to pregnancy, as well as her insurance coverage and medical care receipt during pregnancy. PMID- 29282722 TI - Estimating the Cost of Providing Foundational Public Health Services. AB - OBJECTIVE: To estimate the cost of resources required to implement a set of Foundational Public Health Services (FPHS) as recommended by the Institute of Medicine. STUDY DESIGN: A stochastic simulation model was used to generate probability distributions of input and output costs across 11 FPHS domains. We used an implementation attainment scale to estimate costs of fully implementing FPHS. DATA COLLECTION/EXTRACTION METHODS: We use data collected from a diverse cohort of 19 public health agencies located in three states that implemented the FPHS cost estimation methodology in their agencies during 2014-2015. PRINCIPAL FINDINGS: The average agency incurred costs of $48 per capita implementing FPHS at their current attainment levels with a coefficient of variation (CV) of 16 percent. Achieving full FPHS implementation would require $82 per capita (CV=19 percent), indicating an estimated resource gap of $34 per capita. CONCLUSIONS: Substantial variation in costs exists across communities in resources currently devoted to implementing FPHS, with even larger variation in resources needed for full attainment. Reducing geographic inequities in FPHS may require novel financing mechanisms and delivery models that allow health agencies to have robust roles within the health system and realize a minimum package of public health services for the nation. PMID- 29282723 TI - Comparison of Electronic Health Record-Based and Claims-Based Diabetes Care Quality Measures: Causes of Discrepancies. AB - OBJECTIVE: To investigate magnitude and sources of discrepancy in quality metrics using claims versus electronic health record (EHR) data. STUDY DESIGN: Assessment of proportions of HbA1c and LDL testing for people ascertained as diabetic from the respective sources. Qualitative interviews and review of EHRs of discrepant cases. DATA COLLECTION/EXTRACTION: Claims submitted to Rhode Island Medicaid by three practice sites in 2013; program-coded EHR extraction; manual review of selected EHRs. PRINCIPAL FINDINGS: Of 21,030 adult Medicaid beneficiaries attributed to a primary care patient at a site by claims or EHR data, concordance on assignment ranged from 0.30 to 0.41. Of patients with concordant assignment, the ratio of patients ascertained as diabetic by EHR versus claims ranged from 1.06 to 1.14. For patients with concordant assignment and diagnosis, the ratio based on EHR versus claims ranged from 1.08 to 18.34 for HbA1c testing, and from 1.29 to 14.18 for lipid testing. Manual record review of 264 patients discrepant on diagnosis or testing identified problems such as misuse of ICD-9 codes, failure to submit claims, and others. CONCLUSIONS: Claims data underestimate performance on these metrics compared to EHR documentation, by varying amounts. Use of claims data for these metrics is problematic. PMID- 29282726 TI - Issue Information - Info for Authors. PMID- 29282724 TI - The Impact of Enhanced Critical Care Training and 24/7 (Tele-ICU) Support on Medicare Spending and Postdischarge Utilization Patterns. AB - OBJECTIVE: To estimate the effect of implementing a tele-ICU and a critical care residency training program for advanced practice providers on service utilization and total Medicare episode spending. DATA SOURCES/STUDY SETTINGS: Medicare claims data for fee-for-service beneficiaries at 12 large, inpatient hospitals in the Atlanta Hospital Referral Region. STUDY DESIGN: Difference-in-differences design where changes in spending and utilization for Medicare beneficiaries eligible for treatment in participating ICUs was compared to changes in a comparison group of clinically similar beneficiaries treated at similar hospitals' ICUs in the same hospital referral region. EXTRACTION METHODS: Using Medicare claims data from January 2010 through June 2015, we defined measures of Medicare episode spending during the ICU stay and subsequent 60 days after discharge, and utilization measures within 30 and 60 days after discharge. PRINCIPAL FINDINGS: Implementation of the advanced practice provider residency program and tele-ICU was associated with a significant reduction in average Medicare spending per episode, primarily driven by reduced readmissions within 60 days and substitution of home health care for institutional postacute care. CONCLUSIONS: Innovations in workforce training and technology specific to the ICU may be useful in addressing the shortage of intensivist physicians, yielding benefits to patients and payers. PMID- 29282731 TI - Cognitive-behavioural therapy for adult attention-deficit hyperactivity disorder: a proof of concept randomised controlled trial. AB - OBJECTIVE: To investigate efficacy, patient acceptability and feasibility of formulation-based cognitive-behavioural therapy (CBT) for adults with attention deficit hyperactivity disorder (ADHD). NICE guidelines for adult ADHD recommend further research into psychological treatments. METHOD: Sixty participants with adult ADHD were randomly allocated to treatment as usual (TAU) vs. TAU plus up to 16 sessions of individual formulation-based CBT for ADHD. RESULTS: Adding formulation-based CBT to TAU for ADHD significantly improved ADHD symptoms on the Barkley Current Symptoms Scale and scores on the Work and Social Adjustment Scale. Adjusted effect sizes (ES) were 1.31 and 0.82 respectively. There were also significant improvements on secondary outcomes including independently evaluated clinical global improvement, self-rated anxiety, depression, global distress and patient satisfaction (adjusted effect sizes 0.52-1.01). CONCLUSIONS: This is the first randomised controlled trial to provide preliminary evidence of efficacy and acceptability of individual formulation-based CBT for ADHD when added to TAU over TAU alone. This approach now needs to be tested in a larger multicentred randomised controlled trial. PMID- 29282732 TI - Restoration of cellulase activity in the inactive cellulosomal protein Cel9V from Ruminiclostridium cellulolyticum. AB - Ruminiclostridium cellulolyticum produces extracellular cellulosomes which contain interalia numerous family-9 glycoside hydrolases, including the inactive Cel9V. The latter shares the same organization and 79% sequence identity with the active cellulase Cel9E. Nevertheless, two aromatic residues and a four-residue stretch putatively critical for the activity are missing in Cel9V. Introduction of one Trytophan and the four-residue stretch restored some weak activity in Cel9V, whereas the replacement of its catalytic domain by that of Cel9E generated a fully active cellulase. Altogether our data indicate that a series of mutations in the catalytic domain of Cel9V lead to an essentially inactive cellulase. PMID- 29282733 TI - Nickel and cobalt release from earrings and piercing jewellery - analytical results of a German survey in 2014. AB - BACKGROUND: Nickel and cobalt are important metal allergens, and more knowledge on the levels of exposure to these from everyday contacts is needed. OBJECTIVES: To report the results of a repeat routine surveillance scheme in the Federal Republic of Germany on the release of nickel and cobalt. METHODS: Fifteen laboratories assessed earrings and piercing jewellery items from 12 of the states in 2014, complying with EN 1811:2011 + AC:2012 and using atomic absorption spectrometry, inductively coupled plasma mass spectrometry and inductively coupled plasma optical emission spectrometry for quantification. Kaplan-Meier analysis for left-censored data was employed to account for measurements below the limit of quantification. RESULTS: Nickel release exceeded 0.35 ug/cm2 per week in 26 of 160 piercing posts (16.2%), and 0.88 ug/cm2 per week in 2.0-5.9% of other parts, that is, the current respective 'pass' thresholds, with no change from the previous 2008 survey. The level of cobalt release was lower than that of nickel release, and also significantly lower than in the previous survey. CONCLUSIONS: The finding of the highest level of nickel release from piercing posts, with their deliberately lower threshold of acceptability, is worrying, as is the largely unchanged overall level of nickel release. A regulation on cobalt release is currently lacking; risk assessment and management based on dose elicitation data are needed. PMID- 29282734 TI - Arborescent lycophyte growth in the late Carboniferous coal swamps. PMID- 29282735 TI - A tough life in utero doesn't necessarily make for a stiff future: sex matters for aortic passive mechanics. PMID- 29282736 TI - Clinical pitfalls in misoprostol-based medical management of first-trimester induced and presumed spontaneous abortion. AB - When administered inappropriately, first-trimester misoprostol management of induced or spontaneous abortion can result in loss or damage of a continuing pregnancy. Despite these serious consequences, such misoprostol exposures continue to occur. Unfortunately, contributing factors and preventive measures receive little attention. We describe the cases of 4 women in whom misoprostol was inappropriately administered during management of induced and presumed spontaneous abortion. In each case, careful adherence to published clinical guidance could have avoided the exposures. PMID- 29282737 TI - From bad to worse: when lung cancer complicates idiopathic pulmonary fibrosis. AB - Patients with idiopathic pulmonary fibrosis have a significantly increased risk for the development of lung cancer. The morbidity and mortality of this disease combination are substantial, and, unfortunately, there are currently few data to help guide clinicians in its diagnosis and treatment. In a recent issue of this journal, Hwang et al presented one of the first studies to evaluate lung cancer in patients with idiopathic pulmonary fibrosis at the molecular level. They demonstrate variants in regulators of the cell cycle, which are known to be important in malignant transformation and may also be important in the pathogenesis of idiopathic pulmonary fibrosis. Further understanding of the pathogenic overlap between lung cancer and idiopathic pulmonary fibrosis could help point the direction to specific diagnostic modalities and targeted treatment of both conditions in the future. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29282738 TI - Signalling of vasodilatation across an exercise transient. PMID- 29282739 TI - Clinical acceptability of the sense_assess(c) kids: Children and youth perspectives. AB - BACKGROUND: The sense_assess(c) kids is a standardised, norm-referenced assessment designed to measure the functional somatosensation capacity of the upper limb of children with cerebral palsy. The objective of the current study was to determine if the sense_assess(c) kids was clinically acceptable to children and youth. METHODS: A questionnaire was completed by participants following administration of the sense_assess(c) kids by a trained occupational therapist. Twenty-six children with spastic hemiplegic cerebral palsy (aged 6-15 years six months; mean 10 years eight months; 16 boys) were recruited. Participants responded to questions regarding the administration and level of difficulty of the sense_assess(c) kids using a Q-Sort of 'like' and 'dislike', Likert scales and short answers. Content analysis was applied. RESULTS: Twenty one of twenty-six children, indicated that they were 'very happy' or 'happy' with the administration process of the sense_assess(c) kids. Most participants indicated that they liked the sensation they felt in the hand when tested. CONCLUSION: This study has demonstrated the acceptability of sense_assess(c) kids for the population for whom it is intended. PMID- 29282740 TI - Use of Tunisian flavored olive oil as anisakicidal agent in industrial anchovy marinating process. AB - BACKGROUND: Natural compounds are more frequently used against Anisakis, responsible for the important fish-borne disease anisakidosis. The aim of the study was to evaluate the effectiveness of enriched Tunisian olive oil with different spices (cumin, turmeric, clove, thyme, and lemon) against Anisakis larvae type 1. RESULTS: In vitro experiment: larvae were submerged separately in the aforementioned oils and then examined to check viability. For each oil, LT50 and LT100 were calculated. Turmeric and cumin oils are the most effective against the parasites; followed by lemon, thyme and clove oils. For the in vivo experiment, turmeric and cumin oils were tested in anchovy fillets previously artificially parasitized with L3 larvae. Cumin was the most effective against parasites (dead after 5 days) compared with turmeric (8 days). For the two oils, the resulting odor was pleasant, as was the taste, while changes in color were much more evident in turmeric fillets. CONCLUSION: All the flavored oils demonstrated a good nematodical action against Anisakis. Cumin oil was the most effective against encysted larvae. Turmeric oil showed the best activity in the in vitro experiment. The use of flavored oils in the marinating process could represent an efficient strategy to devitalize Anisakis. (c) 2017 Society of Chemical Industry. PMID- 29282741 TI - Vox Sanguinis International Forum on application of fetal blood grouping. PMID- 29282742 TI - Evaluation of the impact of a personalized postdonation short messaging service on the retention of whole blood donors. AB - BACKGROUND: Short messaging service (SMS) is routinely used by blood collection agencies to remind donors about appointments but has been applied less frequently in interventions to increase return behavior. This study aimed to investigate whether receipt of a personalized postdonation SMS promoted donor retention. STUDY DESIGN AND METHODS: A postdonation SMS was sent to 2605 whole blood donors who had donated at one of six donor centers in Australia from April to July 2015 and left without making a forward appointment. Once their donation was dispatched to a hospital or facility an SMS was sent informing the donor of the hospital or town to which their blood was dispatched. Donor's return behavior over 12 months was examined, comparing with a control group of donors who donated at the same donor centers but did not receive an SMS. RESULTS: Donors who received the SMS had increased odds of returning to donate within 12 months, with 70.3% of these donors returning (adjusted odds ratio, 1.49; 95% confidence interval, 1.30-1.71), compared with 62.6% of donors who did not receive the SMS. The SMS was effective in retaining first-time, novice, and established donors at 12 months, but had no effect on experienced donors. The timing of the receipt of the SMS postdonation had no impact on donor retention. CONCLUSION: This study highlights the potential of utilizing a postdonation SMS that informs donors where their blood has been dispatched as a cost-effective tool to increase retention, particularly among new donors, who are traditionally more difficult to retain. PMID- 29282743 TI - Mitochondrial DNA multiplex real-time polymerase chain reaction inhibition assay for quality control of pathogen inactivation by ultraviolet C light in platelet concentrates. AB - BACKGROUND: Several ultraviolet (UV) light-based pathogen inactivation (PI) technologies for platelet (PLT) products have been developed or are under development. Upon implementation of PI technologies, quality control measures are required to ensure consistent efficiency of the treatment process. Previous reports showed that amotosalen/UVA and riboflavin/UV-based PI technologies induce modifications of the PLT-derived mitochondrial DNA (mtDNA) that can be detected by polymerase chain reaction (PCR) inhibition assays. In this study, we sought to establish a PCR inhibition assay to document the impact of ultraviolet C (UVC) treatment with the THERAFLEX UV-Platelets system on the mitochondrial genome in PLT concentrates (PCs). STUDY DESIGN AND METHODS: A multiplex real-time PCR inhibition assay with simultaneous short-amplicon (143 bp) and long-amplicon (794 bp) amplification was developed to detect mtDNA modifications in PLTs after UVC treatment. Assay performance was tested in UVC-treated and untreated, plasma reduced pooled PCs, and apheresis PCs and challenged using PCs manufactured for a clinical trial under routine-like conditions. RESULTS: UVC illumination of PLTs resulted in dose-dependent inhibition of mtDNA amplification for the larger amplicon. Amplification of the shorter amplicon was not affected by UVC treatment. Evaluation of 283 blinded apheresis and pooled PLT samples from routine-like PC production resulted in prediction of UVC treatment status with 100% accuracy. CONCLUSION: The proposed dual-amplicon size real-time mtDNA PCR assay effectively detects nucleic acid damage induced by UVC illumination of PLTs and could be useful as an informative indicator of PI quality of the THERAFLEX UV Platelets system. PMID- 29282745 TI - Vox Sanguinis International Forum on application of fetal blood grouping: summary. PMID- 29282744 TI - Effect of extrusion temperature and screw speed on properties of oat and rice flour extrudates. AB - BACKGROUND: Whole oat and rice flours were mixed to develop instant flours by a high pressure and low mechanical shear extrusion process. The screw profile was designed aiming to obtain an infant food with gelatinized starch and high hydration ability. Response surface methodology was selected to study the impact of operating parameters such as temperature and screw speed (73-186 degrees C; 109-391 rpm) on physicochemical and pasting properties of the final extruded product. The main challenge of this study was to process high oats content, since they are characterized by high lipid and fiber content, which impact on material processing. RESULTS: The optimal response was achieved at 170 degrees C and 350 rpm. The optimal expansion ratio, bulk density, water absorption index, and water solubility index were 2.24, 289.65 kg m-3 , 6.42 g g-1 , and 4.75 g g-1 respectively. Overall, both temperature and screw speed affected the responses studied, except for water absorption index (only screw speed affected this response). Although lipids from oats reduce the expansion ratio of extrudates compared with samples containing higher starch proportions, their lipids protect the starch granules from mechanical degradation when higher screw speed values are used. As a result, both ungelatinized and gelatinized starches may be found in extrudates, which was confirmed by pasting property analyses. CONCLUSION: High oat content may be efficiently processed by optimizing the extruder conditions (temperature, screw speed, and profile), improving the nutritional properties of the final product. (c) 2017 Society of Chemical Industry. PMID- 29282746 TI - Valve morphogenesis in Diploneis smithii (Bacillariophyta). AB - Diploneis species have perhaps the most complex valve structure among pennate diatoms. The development of this structure was studied in Diploneis smithii and begins with the formation of a primary band, which then develops secondary arms at both poles and the center, as in the classic Chiappino-Volcani model of raphid diatom ontogeny. Spine-like projections grow out from the primary band and secondary arms to establish the transapical ribs (virgae) of the mature valve and themselves develop spines, which are spaced first oppositely and then alternately and fuse with each other to delimit the stria pores. Subsequently, new pattern and structures develop both externally (formation of bifurcating projections that fuse to delimit the outer, sieve-like layer of the valve) and internally (growth and fusion of flanges from the first-formed ribs to create the longitudinal canals and deposition of a hymenate strip over the internal face of each stria). Comparisons are made with morphogenesis in other diatoms. Diploneis smithii ontogeny suggests how very slight developmental changes might have created the very variable external morphology of Diploneis species. It also indicates that the longitudinal canals of Diploneis and Fallacia have different origins, since the porous external wall is not formed as a unilaterally attached flap in Diploneis and the canal is internal to the first-formed rib-stria system in Diploneis, but external to it in Fallacia. PMID- 29282747 TI - Effect of harvest time on the levels of phytochemicals, free radical-scavenging activity, alpha-amylase inhibition and bile acid-binding capacity of spinach (Spinacia oleracea). AB - BACKGROUND: Spinach is a green leafy vegetable that is rich in health-promoting compounds. The present study analyzed the levels of phytochemicals and health promoting properties of spinach harvested at 20, 30, 40, 50 and 60 days after planting. RESULTS: The time of harvest had a significant effect on nitrate levels, which increased from 1909 +/- 70.6 ug g-1 (20 days) to 3668 +/- 101.3 ug g-1 (40 days) and then decreased to 974 +/- 164 ug g-1 (60 days). Lutein and chlorophylls a and b were found to be maximum at 60 days, whereas beta-carotene was higher at 50 days. Liquid chromatography/high-resolution quadrupole time-of flight tandem mass spectrometry (LC/HR-QTOF-MS) was used to identify 12 flavonoids, and their tentative fragmentation pathways have been proposed. Spinach harvested at 30 and 60 days exhibited significantly higher 2,2-diphenyl-1 picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical-scavenging activities and inhibition of amylase. The levels of total phenolics ranged from 885 +/- 35.1 to 1162 +/- 112.4 ug g-1 in the samples. In vitro bile acid-binding capacity showed that glycochenodeoxycholate and glycodeoxycholate were bound to maximum levels in all spinach samples. CONCLUSION: The harvest time has a major effect on the levels of phytochemicals and health-beneficial properties, which indicates that consumption of both baby and mature spinach will provide maximum health benefits. (c) 2017 Society of Chemical Industry. PMID- 29282748 TI - Exploring the relevance of thiophene rings as bridge unit in acceptor-bridge donor dyes on self-aggregation and performance in DSSCs. AB - The possibility of dye charge recombination in DSSCs remains a challenge for the field. This consists of: (a) back-transfer from the TiO2 to the oxidized dye and (b) intermolecular electron transfer between dyes. The latter is attributed to dye aggregation due to dimeric conformations. This leads to poor electron injection which decreases the photocurrent conversion efficiency. Most organic sensitizers are characterized by an Acceptor-Bridge-Donor (A-Bridge-D) arrangement that is commonly employed to provide charge separation and, therefore, lowering the unwanted back-transfer. Here, we address the intermolecular electron transfer by studying the dimerization and photovoltaic performance of a group of A-Bridge-D structured dyes. Specifically, eight famous sulfur containing pi-bridges were analyzed (A and D remained fixed). Through quantum mechanical and molecular dynamics approaches, it was found that the formation of weakly stabilized dimers is allowed. The dyes with covalently bonded and fused thiophene rings as Bridges, 6d and 7d as well as 8d with a fluorene, would present high aggregation and, therefore, high probability of recombination processes. Conversely, using TiO2 cluster and surface models, delineated the shortest bridges to improve the adsorption energy and the stability of the system. Finally, the elongation of the bridge up to 2 and 3 units and their photovoltaic parameters were studied. These results showed that all the sensitizers are able to provide similar photocurrent outcomes, regardless of whether the bridge is elongated. (c) 2017 Wiley Periodicals, Inc. PMID- 29282749 TI - Compared proteomic analysis of 8- and 32-week-old postnatal porcine ovaries. AB - : Pigs share many anatomical and physiological features with humans, offering a unique and viable model for biomedical research. Tandem mass tag method followed by mass spectrometry analysis was utilized to identify peptides (47,405), proteins (14,701), and protein groups (7634) in ovaries of 8- and 32-week-old postnatal Banna miniature pigs. After annotation and analysis by Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology, the proteins were identified as being involved in hormone metabolic pathways and maintenance, proliferation, and regulation of stem cells. In addition, we found 638 differentially expressed proteins between ovaries of 8- and 32-week-old postnatal Banna miniature pigs. We used Interactive Pathway Explorer to produce an overview of pig ovarian proteomics. Compared with those of the 8-week-old group, the proteins enriched in metabolism of steroid hormones, metabolism of lipids, and energy metabolism pathway were upregulated in the 32-week-old group, indicating physiological characteristics of sexual maturity. These findings have implications in applications of biomedicine. SIGNIFICANCE OF THE STUDY: Pigs share many anatomical and physiological features with humans, offering a unique and viable model for biomedical research. In this study, we used tandem mass tag quantitative proteomics to describe, for the first time, protein expression patterns of postnatal pig ovaries. Proteins involved in hormone metabolic pathways and maintenance, proliferation, and regulation of stem cells were identified. With further analysis by Interactive Pathway Explorer, proteins enriched in metabolism of steroid hormones, metabolism of lipids, and energy metabolism pathway were upregulated in the 32-week-old group, indicating physiological characteristics of sexual maturity. These findings have implications in applications of biomedicine. PMID- 29282750 TI - An erythematous raised dermatofibroma-like nodule. PMID- 29282751 TI - Ring a ring o'roses, a patient with Kaposi's? Pazopanib, pazopanib, it might go away. Mediterranean (classic) Kaposi sarcoma responds to the tyrosine kinase inhibitor pazopanib after multiple lines of standard therapy. PMID- 29282753 TI - Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T-type Ca2+ channel in mouse sensory neurons. AB - T-type Ca2+ channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T-type Ca2+ channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca2+ concentration ([Ca2+ ]i ), which were suppressed by selective T-type Ca2+ channel blockers. RT-PCR showed that mouse sensory neurons expressed all subtypes of T type Ca2+ channel. The magnitude of 15K-induced [Ca2+ ]i increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1-/- mouse sensory neurons. TRPA1 blockers diminished the [Ca2+ ]i responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl-induced [Ca2+ ]i increases even in AITC sensitive neurons. TRPV1 blockers did not inhibit the 15K-induced [Ca2+ ]i increase regardless of the sensitivity to capsaicin. [Ca2+ ]i responses to TRPA1 agonist were enhanced by co-application with 15K. These pharmacological data suggest the possibility of functional interaction between T-type Ca2+ channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca2+ , we hypothesize that Ca2+ entered via T-type Ca2+ channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T-type Ca2+ channel may be a potential target for TRPA1-related pain. PMID- 29282752 TI - Self-gated golden angle spiral cine MRI for coronary endothelial function assessment. AB - PURPOSE: Depressed coronary endothelial function (CEF) is a marker for atherosclerotic disease, an independent predictor of cardiovascular events, and can be quantified non-invasively with ECG-triggered spiral cine MRI combined with isometric handgrip exercise (IHE). However, MRI-CEF measures can be hindered by faulty ECG-triggering, leading to prolonged breath-holds and degraded image quality. Here, a self-gated golden angle spiral method (SG-GA) is proposed to eliminate the need for ECG during cine MRI. METHODS: SG-GA was tested against retrospectively ECG-gated golden angle spiral MRI (ECG-GA) and gold-standard ECG triggered spiral cine MRI (ECG-STD) in 10 healthy volunteers. CEF data were obtained from cross-sectional images of the proximal right and left coronary arteries in a 3T scanner. Self-gating heart rates were compared to those from simultaneous ECG-gating. Coronary vessel sharpness and cross-sectional area (CSA) change with IHE were compared among the 3 methods. RESULTS: Self-gating precision, accuracy, and correlation-coefficient were 7.7 +/- 0.5 ms, 9.1 +/- 0.7 ms, and 0.93 +/- 0.01, respectively (mean +/- standard error). Vessel sharpness by SG-GA was equal or higher than ECG-STD (rest: 63.0 +/- 1.7% vs. 61.3 +/- 1.3%; exercise: 62.6 +/- 1.3% vs. 56.7 +/- 1.6%, P < 0.05). CSA changes were in agreement among the 3 methods (ECG-STD = 8.7 +/- 4.0%, ECG-GA = 9.6 +/- 3.1%, SG GA = 9.1 +/- 3.5%, P = not significant). CONCLUSION: CEF measures can be obtained with the proposed self-gated high-quality cine MRI method even when ECG is faulty or not available. Magn Reson Med 80:560-570, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29282754 TI - Explained variation in shared frailty models. PMID- 29282755 TI - Fatal Cache Valley virus meningoencephalitis associated with rituximab maintenance therapy. PMID- 29282756 TI - Influenza B virus infection and Stevens-Johnson syndrome. AB - A 2-year-old boy with influenza B infection and rapidly worsening targetoid skin lesions with mucosal involvement was diagnosed with Stevens-Johnson syndrome (SJS) and treated with oseltamivir and intravenous immunoglobulin, with resolution of illness. Subsequent quadrivalent inactivated influenza vaccine was well tolerated. This case highlights the rarity of SJS in the setting of influenza B infection and addresses the safety of administering subsequent influenza vaccines to such individuals. PMID- 29282757 TI - Level of neutral alpha-1,4-glucosidase in seminal plasma of Chinese men. AB - Neutral alpha-1,4-glucosidase (NAG) is a crucial biomarker for the function of epididymis and is reported to be associated with semen quality. However, the correlation between NAG and Chinese semen quality has never been reported. This study aimed to investigate the level of NAG in the seminal plasma of Chinese men. A total of 394 cases of seminal plasma samples from normal, subfertile and infertile men were enrolled in this study. Male subfertility was caused by teratozoospermia, asthenospermia, severe oligozoospermia, asthenoteratozoospermia, oligoasthenospermia and oligoasthenoteratozoospermia. Male infertility was resulted from azoospermatism. The level of NAG was detected by spectrophotometry. Results showed that the level of NAG in normal men was significantly higher than that in subfertile and infertile men (p = .000). Meanwhile, the level of NAG in subfertile men was significantly greater than that in infertile men (p = .000). In addition, a significant difference was observed in normozoospermia, teratozoospermia, asthenospermia, severe oligozoospermia, asthenoteratozoospermia, oligoasthenospermia, oligoasthenoteratozoospermia and azoospermatism (p < .05). In conclusion, these data indicate that NAG is a crucial marker for assessing seminal plasma quality in Chinese men, which might be helpful for the assistant diagnosis of male infertility. PMID- 29282759 TI - Effect of l-arginine addition on long-term storability of ram semen. AB - This study was conducted to investigate the effect of l-arginine addition on long term storability of ram semen. Six Akkaraman rams were used as material. Semen samples were collected. Pooled samples were diluted and were divided into six equal aliquots. While aliquot 1 was kept as control, the stock solutions including 0.1, 0.5, 1, 5 and 10 mm l-arginine were added to other aliquots. All aliquots were routinely frozen in 0.25-ml straws at -130 degrees C liquid nitrogen vapour and stored in liquid nitrogen -196 degrees C until being analysed. The equilibrated and thawed sperm motility, membrane integrity and arginase activity were evaluated. While the 10 mm l-arginine supplementation significantly (p < .001) decreased equilibrated sperm motility, the 5 mm significantly (p < .05) increased the membrane integrity and arginase activity in comparison with the control group. The motility (p < .001) and membrane integrity (p < .01) were determined to be highest in 0.5 mm group, while significant reductions were observed in motility (p < .001) of 10 mm group and arginase activity (p < .05) of 1, 10 mm groups as compared to the control group. It was concluded that in vitro addition of 0.5 mm l-arginine to ram semen may be useful, but 10 mm may be harmful to spermatozoa quality during long-term storage. PMID- 29282758 TI - Noise in the Machine: Alternative Pathway Sampling is the Rule During DNA Replication. AB - The astonishing efficiency and accuracy of DNA replication has long suggested that refined rules enforce a single highly reproducible sequence of molecular events during the process. This view was solidified by early demonstrations that DNA unwinding and synthesis are coupled within a stable molecular factory, known as the replisome, which consists of conserved components that each play unique and complementary roles. However, recent single-molecule observations of replisome dynamics have begun to challenge this view, revealing that replication may not be defined by a uniform sequence of events. Instead, multiple exchange pathways, pauses, and DNA loop types appear to dominate replisome function. These observations suggest we must rethink our fundamental assumptions and acknowledge that each replication cycle may involve sampling of alternative, sometimes parallel, pathways. Here, we review our current mechanistic understanding of DNA replication while highlighting findings that exemplify multi-pathway aspects of replisome function and considering the broader implications. PMID- 29282760 TI - Development and implementation of a novel panel consisting 20 markers for the detection of genetic causes of male infertility. AB - Azoospermia factor (AZF) genes are involved in spermatogenesis. Deletions in the region of these genes have been recognised as a major genetic cause of infertility due to defects in spermatogenesis. Klinefelter syndrome (KS) is the other main cause of male infertility. This study was performed to establish a novel method for the detection of genetic causes of infertility in males and also to investigate the prevalence, extent and position of Y chromosome microdeletions in Iranian infertile men. We developed a newly designed panel of fluorescent multiplex-PCR method to amplify 20 markers (15 sequence-tagged sites (STSs) markers which are placed in the Y chromosome AZF region, 2 short tandem repeats (STRs) and 3 segmental duplications (SDs)). This multifunctional method is for the simultaneous detection of Y chromosome microdeletions and KS. Among 149 studied infertile men, one was detected to suffer from KS and seven (4.7%) were detected with the presence of one or more deleted STS loci. The main cause of infertility for the remaining patients would be nongenetic factors. This strategy is represented as a fast and accurate method to determine the frequencies of different AZF microdeletions which are suitable for use in clinical purposes. PMID- 29282761 TI - Heparin-induced haemorrhagic bullous dermatosis. AB - BACKGROUND: Heparin-induced haemorrhagic bullous dermatosis (HBD) is a rare but probably underdiagnosed reaction to heparin, with 26 cases reported in the English literature. Currently, there is no consensus regarding the treatment. AIM: To assess our new cases of HBD and review the previously reported cases, in order to draw conclusions about this adverse skin reaction to heparin. METHODS: A PubMed search was performed for articles containing the terms '(heparin-induced AND (blister OR bulla OR bullae)) OR (hemorrhagic bullous dermatosis AND heparin) OR heparin bullous dermatosis'. Descriptive statistical data analysis was performed using Microsoft Excel. RESULTS: We assessed five new cases of HBD. In addition, our literature search revealed 26 previously reported patients. Combining these, we found that the mean +/- SD age of patients with HBD was 71.4 +/- 14 years. HBD affects men more commonly than women (men 22/31; P = 0.02). Patients develop tense bullae most frequently on the extremities, approximately 8 days (mean +/- SD 7.5 +/- 6.4 days) after starting treatment with a heparin product, usually enoxaparin. CONCLUSIONS: The typical clinical course is spontaneous resolution within days to weeks irrespective of continuation of heparin therapy. Because of its self-limiting nature, interruption of heparin therapy may not be required. PMID- 29282763 TI - Predicting stability limits for pure and doped dicationic noble gas clusters undergoing coulomb explosion: A parallel tempering based study. AB - We have used a replica exchange Monte-Carlo procedure, popularly known as Parallel Tempering, to study the problem of Coulomb explosion in homogeneous Ar and Xe dicationic clusters as well as mixed Ar-Xe dicationic clusters of varying sizes with different degrees of relative composition. All the clusters studied have two units of positive charges. The simulations reveal that in all the cases there is a cutoff size below which the clusters fragment. It is seen that for the case of pure Ar, the value is around 95 while that for Xe it is 55. For the mixed clusters with increasing Xe content, the cutoff limit for suppression of Coulomb explosion gradually decreases from 95 for a pure Ar to 55 for a pure Xe cluster. The hallmark of this study is this smooth progression. All the clusters are simulated using the reliable potential energy surface developed by Gay and Berne (Gay and Berne, Phys. Rev. Lett. 1982, 49, 194). For the hetero clusters, we have also discussed two different ways of charge distribution, that is one in which both positive charges are on two Xe atoms and the other where the two charges are at a Xe atom and at an Ar atom. The fragmentation patterns observed by us are such that single ionic ejections are the favored dissociating pattern. (c) 2017 Wiley Periodicals, Inc. PMID- 29282765 TI - Relationships between total testicular volume, reproductive parameters and surrogate measures of adiposity in men presenting for couple's infertility. AB - The objective of this study was to investigate the relationships between total testicular volume (TTV), reproductive parameters and adiposity measures: body mass index, waist circumference and waist-to-height ratio. Semen analysis was performed, and reproductive hormone levels were measured in 2,672 male patients (mean age 32.6) due to couple's infertility. Significant, positive correlations between semen parameters and the TTV were found. Gonadotrophins were negatively related to the TTV, and testosterone was not related to the TTV. Three anthropometric parameters were negatively correlated to the total sperm count, and sperm concentration seen in men with a TTV of <=46 ml. In the case of a TTV >46 ml, only the semen volume was inversely correlated with WC and WHtR. These changes occurred from a WHtR >=0.56, WC >=102 cm and BMI >=29 and were more pronounced between WHtR and the TTV. Adiposity was associated with a significant testosterone level decline but did not have a major impact on the gonadotrophin levels. This study shows the divergent results in sperm parameters in different TTV groups in the presence of central adiposity. PMID- 29282764 TI - Sample size determination for jointly testing a cause-specific hazard and the all cause hazard in the presence of competing risks. AB - This article considers sample size determination for jointly testing a cause specific hazard and the all-cause hazard for competing risks data. The cause specific hazard and the all-cause hazard jointly characterize important study end points such as the disease-specific survival and overall survival, which are commonly used as coprimary end points in clinical trials. Specifically, we derive sample size calculation methods for 2-group comparisons based on an asymptotic chi-square joint test and a maximum joint test of the aforementioned quantities, taking into account censoring due to lost to follow-up as well as staggered entry and administrative censoring. We illustrate the application of the proposed methods using the Die Deutsche Diabetes Dialyse Studies clinical trial. An R package "powerCompRisk" has been developed and made available at the CRAN R library. PMID- 29282766 TI - Erythroferrone and iron status parameters levels in pediatric patients with iron deficiency anemia. AB - OBJECTIVES: To investigate the link between serum erythroferrone (ERFE) levels and iron status parameters in pediatric patients with iron deficiency anemia. METHODS: The study consisted of 66 children (36 with iron deficiency anemia and 30 healthy age- and gender-matched controls) who were investigated for serum levels of iron, total iron-binding capacity (TIBC) using automated chemistry analyzer, serum ferritin using electrochemiluminescence immunoassay and ERFE by specific enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Serum erythroferrone levels in iron deficiency anemia patients (191.55 +/- 83.74 pg/mL) were significantly higher than those in control group (42.22 +/- 16.55 pg/mL) (P < .001). In iron deficiency anemia patients, serum erythroferrone concentrations correlated negatively with hemoglobin concentration (r = -.39; P = .01), serum iron (r = -.63; P < .001), transferrin saturation (r = -.66; P < .001), and serum ferritin (r = -.46; P = .004) while positive correlation was observed between serum erythroferrone concentrations and TIBC (r = .62; P < .001) CONCLUSION: The newly identified erythroferrone hormone may act as physiological hepcidin suppressor in cases with iron deficiency anemia, and so it may serve as a specific promising target of therapy in such cases. PMID- 29282767 TI - Pain assessment practices in Swedish and Norwegian neonatal care units. AB - BACKGROUND: The use of measurement scales to assess pain in neonates is considered a prerequisite for effective management of pain, but these scales are still underutilised in clinical practice. AIM: The aim of this study was to describe and compare pain assessment practices including the use of pain measurement scales in Norwegian and Swedish neonatal care units. METHODS: A unit survey investigating practices regarding pain assessment and the use of pain measurement scales was sent to all neonatal units in Sweden and Norway (n = 55). All Norwegian and 92% of Swedish units responded. RESULTS: A majority of the participating units (86.5%) assessed pain. Swedish units assessed and documented pain and used pain measurement scales more frequently than Norwegian units. The most frequently used scales were different versions of Astrid Lindgren's Pain Scale (ALPS) in Sweden and Echelle Douleur Inconfort Noveau-Ne (EDIN), ALPS and Premature Infant Pain Profile (PIPP) in Norway. Norwegian head nurses had more confidence in their pain assessment method and found the use of pain measurement scales more important than their Swedish colleagues. CONCLUSION: The persisting difference between Swedish and Norwegian units in pain assessment and the use of pain measurement scales are not easily explained. However, the reported increased availability and reported use of pain measurement scales in neonatal care units in both countries may be seen as a contribution towards better awareness and recognition of pain, better pain management and potentially less suffering for vulnerable neonates. PMID- 29282768 TI - Effects of pain treatment on sleep in nursing home patients with dementia and depression: A multicenter placebo-controlled randomized clinical trial. AB - OBJECTIVE: To investigate the effects of pain treatment on sleep in nursing home (NH) patients with dementia and depression. METHODS: A multicenter, 2-armed, double-blinded, placebo-controlled, randomized clinical trial conducted between August 2014 and September 2016. One hundred six long-term patients from 47 NHs in Norway with dementia and depression according to the Mini-Mental State Examination and the Cornell Scale for Depression in Dementia were included. Patients received stepwise pain treatment in which those who did not use analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets; those who already used pain treatment were allocated to buprenorphine transdermal system (max. 10 MUg/h/7 days) or placebo transdermal patches. Sleep was assessed continuously for 14 days by actigraphy, 1 week of baseline measurement, and 1 week of ongoing treatment. The following sleep parameters were evaluated: total sleep time, sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset, early morning awakening (EMA), and number of wake bouts. RESULTS: In the intervention group (paracetamol/buprenorphine), SE (70%-72%), SOL (32-24 min), and EMA (50-40 min) improved compared with the control group (SE, 70%-67%; SOL, 47-60 min; EMA, 31-35 min). Treatment effects were significant (P < .01, P < .05, and P < .05, respectively). CONCLUSION: Compared with placebo, pain treatment improved sleep as measured with actigraphy. This implies that sleep, pain, and depression in NH patients should be critically evaluated and that pain treatment should be considered to be a potentially beneficial treatment. PMID- 29282769 TI - Glial M6B stabilizes the axonal membrane at peripheral nodes of Ranvier. AB - Glycoprotein M6B and the closely related proteolipid protein regulate oligodendrocyte myelination in the central nervous system, but their role in the peripheral nervous system is less clear. Here we report that M6B is located at nodes of Ranvier in peripheral nerves where it stabilizes the nodal axolemma. We show that M6B is co-localized and associates with gliomedin at Schwann cell microvilli that are attached to the nodes. Developmental analysis of sciatic nerves, as well as of myelinating Schwann cells/dorsal root ganglion neurons cultures, revealed that M6B is already present at heminodes, which are considered the precursors of mature nodes of Ranvier. However, in contrast to gliomedin, which accumulates at heminodes with or prior to Na+ channels, we often detected Na+ channel clusters at heminodes without any associated M6B, indicating that it is not required for initial channel clustering. Consistently, nodal cell adhesion molecules (NF186, NrCAM), ion channels (Nav1.2 and Kv7.2), cytoskeletal proteins (AnkG and betaIV spectrin), and microvilli components (pERM, syndecan3, gliomedin), are all present at both heminodes and mature nodes of Ranvier in Gpm6b null mice. Using transmission electron microscopy, we show that the absence of M6B results in progressive appearance of nodal protrusions of the nodal axolemma, that are often accompanied by the presence of enlarged mitochondria. Our results reveal that M6B is a Schwann cell microvilli component that preserves the structural integrity of peripheral nodes of Ranvier. PMID- 29282771 TI - Consistency of the Moreau CLL score. AB - BACKGROUND: The Moreau score is essential for the diagnosis of B-cell lymphoproliferative disorders (B-LPD). METHODS: We assessed the consistency of the Moreau score in a series of 138 patients with at least two samples involved by a B-LPD (316 samples) other than germinal center-derived malignancies, hairy cell leukemia, and mantle cell lymphomas. Patients with evidence of two distinct B-LPDs were also excluded. RESULTS: We found 53 inconsistencies in 44 of 138 (32%) patients. FMC7 was the most inconsistent (18 cases) and CD5 the least (5 cases). CD200 was inconsistent in 6 of 67 (9%) cases. The most important predictive factor for the finding of antigenic inconsistencies was sampling of a different anatomic site. Other factors, including number of samples, time between samples, or cytogenetic group, were not predictive. For the most part, these inconsistencies did not appear to be clinically relevant. CONCLUSION: Inconsistencies in the Moreau score are common, supporting the importance of integrated laboratory diagnosis. However, the practical implications of these antigenic inconsistencies are probably limited. PMID- 29282770 TI - Effect of Continuous Digital Hypothermia on Lamellar Inflammatory Signaling When Applied at a Clinically-Relevant Timepoint in the Oligofructose Laminitis Model. AB - BACKGROUND: Although continuous digital hypothermia (CDH) protects lamellae from injury in the oligofructose (OF) model of sepsis-related laminitis (SRL), conflicting results exist from these studies regarding effects of CDH on lamellar inflammatory events. HYPOTHESIS/OBJECTIVES: To determine the effect of CDH on lamellar inflammatory events in normal and OF-treated horses when instituted at a clinically relevant time point (onset of clinical signs of sepsis in this model). ANIMALS: Standardbred geldings (n = 15) aged 3-11 years were used. METHODS: In a randomized, controlled discovery study, animals were administered either OF (OF group, n = 8) or water (CON group, n = 8) by nasogastric tube and CDH was initiated in one forelimb (ICE) 12 hours later. Lamellar tissue samples were collected 24 hours after initiation of CDH (ICE and ambient [AMB] forelimbs). Lamellar mRNA concentrations of inflammatory mediators and lamellar leukocyte numbers were assessed using qPCR and immunohistochemistry, respectively; values from four sample groups (CON AMB, OF AMB, CON ICE, and OF ICE) were analyzed using mixed model linear regression. RESULTS: Although lamellar mRNA concentrations of multiple inflammatory mediators (IL-1beta, IL-6, CXCL1, MCP2, COX-2) were increased after OF administration (OF AMB group versus CON AMB; P < 0.05), only 2 inflammatory mediators (IL-6 and COX-2) and lamellar leukocyte numbers were decreased with CDH (OF ICE versus OF AMB; P < 0.05). CONCLUSIONS AND CLINICAL IMPORTANCE: Continuous digital hypothermia initiated at a time point similar to that commonly used clinically (clinical onset of sepsis) resulted in a more focused inhibition of inflammatory signaling. PMID- 29282772 TI - Planning without action and action without planning? Examining a regional health system's efforts to improve patient flow, 1998-2013. AB - Most health care organizations engage in formal and informal planning, yet their improvement initiatives may remain disjointed and reactive. Research on organizational decision-making has found that the "discovery" approach (seek and assess multiple options before selecting one) outperforms "idea imposition" (identify 1 option, then gather information to [dis]confirm it), yet is observed relatively infrequently. Might this imply that discovery frequently collapses before fruition? This qualitative study sought to better understand the planning action disjunction, as observed in 1 organization, by comparing its planning processes against the discovery approach. It focused on a Canadian regional health system's recurrent, unsuccessful attempts to improve patient flow. Through extensive document review supplemented by interviews with 62 managers, it identified all relevant regional plans/reports produced during a 15-year period and followed each recommendation forward in time to discover its fate. Each report presented a lengthy, unprioritized list of disparate recommendations, few of which progressed to full implementation. It appeared that decision-makers repeatedly embarked on a discovery approach, but rapidly allowed it to splinter into multiple idea-imposition approaches; numerous options were generated, but never evaluated against each other. Thus, the product of each planning process was not a coherent strategy but a list of disconnected actions. PMID- 29282773 TI - Selective Base-free Transfer Hydrogenation of alpha,beta-Unsaturated Carbonyl Compounds using iPrOH or EtOH as Hydrogen Source. AB - Commercially available Ru-MACHOTM -BH is an active catalyst for the hydrogenation of several functional groups and for the dehydrogenation of alcohols. Herein, we report on the new application of this catalyst to the base-free transfer hydrogenation of carbonyl compounds. Ru-MACHOTM -BH proved to be highly active and selective in this transformation, even with alpha,beta-unsaturated carbonyl compounds as substrates. The corresponding aliphatic, aromatic and allylic alcohols were obtained in excellent yields with catalyst loadings as low as 0.1 0.5 mol % at mild temperatures after very short reaction times. This protocol tolerates iPrOH and EtOH as hydrogen sources. Additionally, scale up to multi gram amounts was performed without any loss of activity or selectivity. An outer sphere mechanism has been proposed and the computed kinetics and thermodynamics of crotonaldehyde and 1-phenyl-but-2-en-one are in perfect agreement with the experiment. PMID- 29282774 TI - Adult moyamoya disease associated with abundant phosphorylated tau accumulation in the brainstem: Report of a case with autopsy findings. AB - We report the case of a 72-year-old Japanese woman with moyamoya disease (MMD). She experienced her first intracerebral hemorrhage (ICH) at the age of 32 years, and had nine ICHs and/or intraventricular hemorrhages during the following 40 years. Cerebral angiograms and vascular pathologies at autopsy confirmed that the patient suffered from MMD. Macroscopically, there were brown-colored changes in the subarachnoid space, mainly at the base of the brain and around the cerebellar hemispheres. Microscopically, hemosiderin deposits were observed mainly in the old hemorrhagic lesions and on the surface of the brainstem and cerebellum. Many AT8-immunoreactive neurons and neurites were observed in the pons and midbrain, mainly in the locus ceruleus and reticular formation in the midbrain. Several AT8 immunoreactive neurons and neurites were positive for Gallyas silver staining. A few tiny and short AT8-immunoreactive processes were observed in the molecular, Purkinje cell and granular layers of the cerebellum. There were a few phosphorylated tau accumulations in the cerebrum without senile plaques. Lewy pathologies and transactive response DNA-binding protein 43 kDa proteinopathy were not detected. We suspect that oxidative stress after repeated bleedings with long-term courses in the ventricles and subarachnoid space may accelerate phosphorylated tau accumulation in the brainstem. To our knowledge, this is the first report of MMD with tauopathy in the brainstem. PMID- 29282775 TI - Ti-Catalyzed Hydroamination for the Synthesis of Amine-Containing pi-Conjugated Materials. AB - A series of conjugated enamines were prepared by Ti catalyzed anti-Markovnikov hydroamination. The synthetic route is efficient with yields of up to 94 % and the 100 % atom efficiency of the reaction means that these products are easily isolated and purified. Due to the extended conjugated system, the enamine tautomers were observed exclusively in both solid and solution phases, as determined by X-ray crystallography and NMR spectroscopy. These new conjugated molecules, with N incorporated into the backbone, show interesting photophysical properties including photo-luminescent quantum yields of up to 0.26. Notably, through the incorporation of B to give a donor-acceptor pi-conjugated system, a redshift of approximately 100 nm is observed for the emission maximum along with the anticipated solvatochromic shifts. PMID- 29282776 TI - Synthetic Glycans and Glycomimetics: A Promising Alternative to Natural Polysaccharides. AB - A large quantity of polysaccharide-derived conjugate vaccines have been developed to combat various pathogenic infections. Another prominent polysaccharide, heparin, is listed as an essential drug by the World Health Organization (WHO) to treat thrombus. One of their common problems is that they all derive from natural polysaccharides. Specifically, capsular polysaccharides are mainly obtained from bacterial fermentation and unfractionated heparin is extracted from animal tissues such as porcine mucosa. The quality of natural polysaccharides is inconsistent and traces of contamination would cause a disaster. By contrast, the use of chemical or chemoenzymatic methods could provide structurally homogeneous and quality-controlled glycans. To date, large numbers of polysaccharide fragments and their analogues have been synthesized and evaluated. Some of them even showed comparable activities to their corresponding natural polysaccharides. Here, the latest advances in these synthetic glycan analogues ranging from carbohydrate-based vaccines, heparin-related therapeutics and glycomimetics of polysaccharides are summarized. PMID- 29282777 TI - Silver@Nitrogen-Doped Carbon Nanorods as a Highly Efficient Electrocatalyst for the Oxygen Reduction Reaction in Alkaline Media. AB - In recent years, various platinum-free catalysts for the oxygen reduction reaction (ORR) have attracted great attention due to the limited natural abundance and high cost of platinum. Herein, Ag@N-C (N-C: nitrogen-doped carbon) nanorods for the ORR were synthesized through chemical polymerization and pyrolysis methods by using pyrrole and silver nitrate as raw materials. Pyrolysis could significantly increase the specific surface area of as-synthesized catalysts and convert pyrrolic-N into graphitic-N and pyridinic-N. The results of electrochemical tests show that the Ag@N-C-900 catalyst (pyrolyzed at 900 degrees C) exhibits highly efficient ORR catalytic activity, improved stability, and better methanol resistance in comparison to that of Pt/C catalyst in alkaline media. PMID- 29282778 TI - Global Structural Flexibility of Metalloproteins Regulates Reactivity of Transition Metal Ion in the Protein Core: An Experimental Study Using Thiol subtilisin as a Model Protein. AB - The functions of metal-containing proteins (metalloproteins) are determined by the reactivities of transition metal ions at their active sites. Because protein macromolecular structures have several molecular degrees of freedom, global structural flexibility may also regulate the properties of metalloproteins. However, the influence of this factor has not been fully delineated in mechanistic studies of metalloproteins. Accordingly, we have investigated the relationship between global protein flexibility and the characteristics of a transition metal ion in the protein core using thiol-subtilisin (tSTL) with a Cys coordinated Cu2+ ion as a model system. Although tSTL has two Ca2+ -binding sites, the Ca2+ -binding status hardly affects its secondary structure. Nevertheless, guanidinium-induced denaturation and amide H/D exchange indicated the increase in the structural flexibility of tSTL by the removal of bound Ca2+ ions. Electron paramagnetic resonance and absorption spectral changes have revealed that the protein flexibility determines the characteristics of a Cu2+ ion in tSTL. Therefore, global protein flexibility should be recognized as an important factor that regulates the properties of metalloproteins. PMID- 29282779 TI - Dynamics underlying interictal to ictal transition in temporal lobe epilepsy: insights from a neural mass model. AB - We propose an approach that combines a neural mass model and clinical intracranial electroencephalographic (iEEG) recordings to explore the potential pathophysiological mechanisms (at the neuronal population level) of ictogenesis. Thirty iEEG recordings from 10 temporal lobe epilepsy (TLE) patients around seizure onset were investigated. Physiologically meaningful parameters [average excitatory (Ae ), slow (B), and fast (G) inhibitory synaptic gain] were identified during interictal to ictal transition. Four ratios (Ae /G, Ae /B, Ae /(B + G), and B/G) were derived from these parameters, and their evolution over time was analyzed. The excitation/inhibition ratio increased around seizure onset and decreased before seizure offset, indicating the impairment and re-emergence of excitation/inhibition balance around seizure onset and before seizure offset, respectively. Moreover, the slow inhibition may have an earlier effect on excitation/inhibition imbalance. We confirm the decrease in excitation/inhibition ratio upon seizure termination in human temporal lobe epilepsy, as revealed by optogenetic approaches both in vivo in animal models and in vitro. The increase in excitation/inhibition ratio around seizure occurrence could be an indicator to detect seizures. PMID- 29282780 TI - Synergistic Chemical Synthesis and Self-Assembly Lead to Three-Dimensional b Oriented MFI Superstructures with Selective Adsorption and Luminescence Properties. AB - Higher-order organization of inorganic nanoparticles with hierarchical architectures and tailored functionality is crucial in the nanofabrication of advanced materials. Here we demonstrate that three-dimensional b-oriented MFI superstructures can be organized by synergistic chemical synthesis and self assembly. The organization is accomplished by vapor treatment of tetrapropylammonium hydroxide (TPAOH)-coated inorganic/bacterial cellulose scaffolds. TPA+ acts to direct nucleation and to mediate crystal morphology leading to oriented assembly of MFI crystals along crystallographic b-axis, whereas bacterial cellulose holds the oriented assembly together forming three dimensional superstructures with macroporosity. Self-supporting monoliths of the macroporous MFI show outstanding selective adsorption for para-xylene and high adsorption capacity for volatile organic compounds. Incorporating luminescent molecules imparts the macroporous monoliths the new property of adsorption tunable luminescence that may act as an optical sensor indicating the level of adsorption. The current work opens a novel space for rational organization of hierarchical materials with tailored architectures and multifunctionality. PMID- 29282781 TI - Consideration of use opportunities, novel products, and user modes in cannabis monitoring, research, and policy: a response to the commentary. PMID- 29282782 TI - [Ca2+ ]i modulation of cAMP-stimulated ciliary beat frequency via PDE1 in airway ciliary cells of mice. AB - NEW FINDINGS: What is the central question of this study? The ciliary beat frequency (CBF) of the airway is controlled by [Ca2+ ]i . However, the effects of a reduction in [Ca2+ ]i on CBF are still controversial (an increase, a decrease or no change). What is the main finding and its importance? This study demonstrated that [Ca2+ ]i directly regulates CBF (direct action) and also indirectly regulates CBF via cAMP accumulation controlled by Ca2+ -dependent PDE1 activity (indirect action). The final CBF is determined by the balance of direct and indirect actions. PDE1 plays crucial roles in the regulation of airway CBF. ABSTRACT: [Ca2+ ]i plays crucial roles in the regulation of ciliary beat frequency (CBF) and ciliary bend angle (CBA) of airway cilia. Moreover, Ca2+ dependent PDE1A existing in the CBF-regulating metabolon of cilia modifies the CBF by regulating the cAMP accumulation. This study demonstrated that the CBF is regulated by a direct and an indirect action of [Ca2+ ]i ; the direct action changes CBF mediated via [Ca2+ ]i , and the indirect action changes CBF mediated via cAMP, the accumulation of which is controlled by PDE1 activity. Upon reducing [Ca2+ ]i to various levels, the direct action decreases CBF and the indirect action increases CBF. The final CBF is determined by the extent of cAMP accumulation, which is determined by the amount of inhibition of PDE1 activity, dependent on a reduction in [Ca2+ ]i ; a slight decrease induced by a nominally Ca2+ -free solution (no cAMP accumulation via PDE1) decreases CBF, and an extreme decrease induced by 50 MUm BAPTA-AM increases CBF via cAMP accumulation by inhibiting PDE1 in a similar manner to a PDE1 inhibitor (8MmIBMX). The increase in CBA in response to a reduction in [Ca2+ ]i is smaller than the increase in CBF, because no PDE1A exists in the CBA-regulating metabolon. On the contrary, an increase in [Ca2+ ]i induced by ionomycin, which decreases cAMP accumulation by PDE1A activation, caused a slower procaterol-stimulated increase in CBF than that decreased by a Ca2+ -free solution. A decrease in [Ca2+ ]i stimulates cAMP accumulation, whereas an increase in [Ca2+ ]i inhibits cAMP accumulation in airway ciliary cells. Thus, changes in [Ca2+ ]i modulate CBF and CBA via cAMP accumulation by controlling the activity of PDE1. PMID- 29282783 TI - The Spanish version of the Self-Determination Inventory Student Report: application of item response theory to self-determination measurement. AB - BACKGROUND: A new measure of self-determination, the Self-Determination Inventory: Student Report (Spanish version), has recently been adapted and empirically validated in Spanish language. As it is the first instrument intended to measure self-determination in youth with and without disabilities, there is a need to further explore and strengthen its psychometric analysis based on item response patterns. METHOD: Through item response theory approach, this study examined item observed distributions across the essential characteristics of self determination. RESULTS: The results demonstrated satisfactory to excellent item functioning patterns across characteristics, particularly within agentic action domains. Increased variability across items was also found within action-control beliefs dimensions, specifically within the self-realisation subdomain. CONCLUSIONS: These findings further support the instrument's psychometric properties and outline future research directions. PMID- 29282784 TI - Temperature fluctuations during development reduce male fitness and may limit adaptive potential in tropical rainforest Drosophila. AB - Understanding the potential for organisms to tolerate thermal stress through physiological or evolutionary responses is crucial given rapid climate change. Although climate models predict increases in both temperature mean and variance, such tolerances are typically assessed under constant conditions. We tested the effects of temperature variability during development on male fitness in the rainforest fly Drosophila birchii, by simulating thermal variation typical of the warm and cool margins of its elevational distribution, and estimated heritabilities and genetic correlations of fitness traits. Reproductive success was reduced for males reared in warm (mean 24 degrees C) fluctuating (+/-3 degrees C) vs. constant conditions but not in cool fluctuating conditions (mean 17 degrees C), although fluctuations reduced body size at both temperatures. Male reproductive success under warm fluctuating conditions was similar to that at constant 27 degrees C, indicating that briefly exceeding critical thermal limits has similar fitness costs to continuously stressful conditions. There was substantial heritable variation in all traits. However, reproductive success traits showed no genetic correlation between treatments reflecting temperature variation at elevational extremes, which may constrain evolutionary responses at these ecological margins. Our data suggest that even small increases in temperature variability will threaten tropical ectotherms living close to their upper thermal limits, both through direct effects on fitness and by limiting their adaptive potential. PMID- 29282785 TI - Cognitive factors and post-partum depression: What is the influence of general personality traits, rumination, maternal self-esteem, and alexithymia? AB - OBJECTIVES: The objective was to assess the impact of cognitive factors on post partum depression (PPD) symptoms. Because most of the literature data concern the immediate post-partum period or the first year post-partum, we notably sought to assess the longer term impact of cognitive factors on the symptoms of PPD. METHODS: Two studies were performed. In a pilot study, 1-month post-partum, 63 women filled out a sociodemographic information sheet and completed the abbreviated, revised Eysenck Personality Questionnaire, the Ruminative Responses Scale, the Maternal Self-Report Inventory, and the Edinburgh Post-Natal Depression Scale. In the main study, 124 women additionally completed the Toronto Alexithymia Scale. The main study population was divided into 2 subgroups: women in the first year post-partum (n = 74) and those in the second year post-partum (n = 50). RESULTS: In the pilot study performed 1-month post-partum, brooding rumination and low self-esteem were significant predictors of the PPD symptom intensity. Neuroticism, brooding rumination, and low maternal self-esteem were also significant predictors of the PPD symptoms reported in the first year post partum. Lastly, ruminative thoughts and alexithymia were significant predictors of the PPD symptoms reported in the second year post-partum. CONCLUSIONS: Our results suggest that alexithymia may be an important predictor of the incidence of this condition. The observation of differences in the PPD models as a function of the post-partum period may open up opportunities for developing novel PPD prevention/treatment programs. PMID- 29282786 TI - Methods and tools for assessing the impact of genetic variations: The 2017 Annual Scientific Meeting of the Human Genome Variation Society. PMID- 29282787 TI - Development and evaluation of the Expressions of Moral Injury Scale-Military Version. AB - There is consensus that military personnel can encounter a far more diverse set of challenges than researchers and clinicians have historically appreciated. Moral injury (MI) represents an emerging construct to capture behavioural, social, and spiritual suffering that may transcend and overlap with mental health diagnoses (e.g., post-traumatic stress disorder and major depressive disorder). The Expressions of Moral Injury Scale-Military Version (EMIS-M) was developed to provide a reliable and valid means for assessing the warning signs of a MI in military populations. Drawing on independent samples of veterans who had served in a war-zone environment, factor analytic results revealed 2 distinct factors related to MI expressions directed at both self (9 items) and others (8 items). These subscales generated excellent internal consistency and temporal stability over a 6-month period. When compared to measures of post-traumatic stress disorder, major depressive disorder, and other theoretically relevant constructs (e.g., forgiveness, social support, moral emotions, and combat exposure), EMIS-M scores demonstrated strong convergent, divergent, and incremental validity. In addition, although structural equation modelling findings supported a possible general MI factor in Study 2, the patterns of associations for self- and other directed expressions yielded evidence for differential validity with varying forms of forgiveness and combat exposure. As such, the EMIS-M provides a face valid, psychometrically validated tool for assessing expressions of apparent MI subtypes in research and clinical settings. Looking ahead, the EMIS-M will hopefully advance the scientific understanding of MI while supporting innovation for clinicians to tailor evidence-based treatments and/or develop novel approaches for addressing MI in their work. PMID- 29282789 TI - Two different strategies of host manipulation allow parasites to persist in intermediate-definitive host systems. AB - Trophically transmitted parasites start their development in an intermediate host, before they finish the development in their definitive host when the definitive host preys on the intermediate host. In intermediate-definitive host systems, two strategies of host manipulation have been evolved: increasing the rate of transmission to the definitive host by increasing the chance that the definitive host will prey on the intermediate host, or increasing the lifespan of the parasite in the intermediate host by decreasing the predation chance when the intermediate host is not yet infectious. As the second strategy is less well studied than the first, it is unknown under what conditions each of these strategies is prevailed and evolved. We analysed the effect of both strategies on the presence of parasites in intermediate-definitive host systems with a structured population model. We show that the parasite can increase the parameter space where it can persist in the intermediate-definitive host system using one of these two strategies of host manipulation. We found that when the intermediate host or the definitive host has life-history traits that allow the definitive host to reach large population densities, that is high reproduction rate of the intermediate host or high conversion efficiency of the definitive host (efficiency at which the uninfected definitive host converts caught intermediate hosts into offspring), respectively, evolving manipulation to decrease the predation chance of the intermediate host will be more beneficial than manipulation to increase the predation chance to enhance transmission. Furthermore, manipulation to decrease the predation chance of the intermediate host results in higher population densities of infected intermediate hosts than manipulation that increases the predation chance to enhance transmission. Our study shows that host manipulation in early stages of the parasite development to decrease predation might be a more frequently evolved way of host manipulation than is currently assumed. PMID- 29282788 TI - MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects. AB - Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis. PMID- 29282790 TI - An evaluation of a specialist firesetting treatment programme for male and female mentally disordered offenders (the FIP-MO). AB - Individuals who set deliberate fires are frequently encountered by clinicians working in forensic mental health services. However, little attention has been paid to developing standardised treatment for this behaviour, and few evaluations of treatment have been conducted in forensic mental health services. This study evaluates a new standardised group cognitive behavioural treatment programme for individuals residing in forensic psychiatric hospitals who have engaged in deliberate firesetting (The Firesetting Intervention Programme for Mentally Disordered Offenders; FIP-MO). Sixty-three male and female patients with a history of deliberate firesetting commenced FIP-MO treatment. Patients who met the referral criteria for treatment but who resided at hospitals where FIP-MO treatment was not available were recruited as a treatment as usual comparison group. The treatment group completed a battery of psychometric assessments pre- and post-treatment, with the comparison group completing these at similar time points. Results showed that patients who completed the FIP-MO made significant improvements post-treatment, relative to the comparison group on fire-related measures (e.g., problematic interest and associations with fire) and anger expression. Further, effect size calculations showed that the treatment group made larger pre-post treatment shifts on the majority of outcome measures compared to the comparison group. These findings suggest that FIP-MO treatment is effective for reducing some of the key factors associated with deliberate firesetting. PMID- 29282792 TI - The effect of working in an infection isolation room on hospital nurses' job satisfaction. AB - AIMS: To examine how the nature of working in a carbapenemase-producing Klebsiella pneumoniae infection isolation room affects nurses' job performance and job satisfaction. BACKGROUND: Job satisfaction is under intensive research as a factor in the retention of nursing staff. METHODS: In a cross-sectional design study, a convenience sample of 87 registered nurses who had worked in carbapenemase-producing Klebsiella pneumoniae isolation rooms in a tertiary medical centre in Israel answered a self-administered questionnaire. Data were analysed by descriptive statistics, Pearson correlation coefficients, t tests, one-way ANOVA and multiple regression analysis. RESULTS: Job satisfaction was significantly correlated with perceived knowledge of carbapenemase-producing Klebsiella pneumoniae, with personal experience of working in an isolation room and the perceived level of professional functioning. Multiple regression analysis found that the quality of the nurses' personal experience of isolation room work and their perceived level of professional functioning there explained 33% of the variance in job satisfaction. CONCLUSIONS AND IMPLICATIONS FOR NURSING MANAGEMENT: Managers need to take into account that prolonged work in isolation can negatively impinge upon both performance and job satisfaction. Managers can consider refraining from lengthy nurse assignment to the isolation room. This would also apply to other areas of nursing practice where work is performed in isolation. PMID- 29282793 TI - Centralisation of acute stroke services in London: Impact evaluation using two treatment groups. AB - The bundling of clinical expertise in centralised treatment centres is considered an effective intervention to improve quality and efficiency of acute stroke care. In 2010, 8 London Trusts were converted into Hyper Acute Stroke Units. The intention was to discontinue acute stroke services in 22 London hospitals. However, in reality, provision of services declined only gradually, and 2 years later, 15% of all patients were still treated in Trusts without a Hyper Acute Stroke Unit. This study evaluates the impact of centralising London's stroke care on 7 process and outcome indicators using a difference-in-difference analysis with two treatment groups, Hyper Acute and discontinued London Trusts, and data on all stroke patients recorded in the hospital episode statistics database from April 2006 to April 2014. The policy resulted in improved thrombolysis treatment and lower rates of pneumonia in acute units. However, 6 indicators worsened in the Trusts that were meant to discontinue services, including deaths within 7 and 30 days, readmissions, brain scan rates, and thrombolysis treatment. The reasons for these results are difficult to uncover and could be related to differences in patient complexity, data recording, or quality of care. The findings highlight that actual implementation of centralisation policies needs careful monitoring and evaluation. PMID- 29282794 TI - Developmental Change in Sibling Support and School Commitment Across Adolescence. AB - School commitment typically declines across adolescence, but the family-level factors that explain this decline have not been fully characterized. This study investigated sibling support as a family resource in predicting school commitment across 7th-10th grade using a sample of 444 adolescents (Mages = 12.61, 13.59, 14.59, 15.58 years). Results showed that sibling support linearly increased and school commitment decreased and stabilized, independently, over time. Sibling support positively predicted school commitment in seventh grade and across time, suggesting that having supportive siblings may help to offset adolescents' declines in school commitment. Furthermore, having a brother enhanced this association versus having a sister. These findings provide insight into ways to help youth maintain school commitment across the middle- to high school transition. PMID- 29282795 TI - Interplay of foot and mouth disease virus with cell-mediated and humoral immunity of host. AB - Foot and mouth disease virus (FMDV) causes a communicable disease of cloven hoofed animals, resulting in major economic losses during disease outbreaks. Like other members of the Picornaviridae FMDV has a relatively short infectious cycle; initiation of infection and dissemination, with production of infectious virions occurs in less than a week. The components of innate immunity as well as cell mediated and humoral immunity play a crucial role in control of FMDV. However, it has been shown in vitro using a mouse model that FMDV has evolved certain mechanisms to counteract host immune responses ensuring its survival and spread. The viral leader proteinase, L pro, deters interferon beta (IFN-beta) mRNA synthesis, thus, inhibiting host cell translation. Another viral proteinase, 3C pro, disrupts host cell transcription by cleaving histone H3. A transient lymphopenia in swine as a consequence of FMDV infection has also been observed, but the mechanism involved and viral protein(s) associated with this process are not clearly understood. In this review, we have covered the interaction of FMDV with different immune cells including lymphocytes and antigen presenting cells and their consequences. PMID- 29282796 TI - Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene. AB - The ornithine transcarbamylase (OTC) gene is on the X chromosome and its product catalyzes the formation of citrulline from ornithine and carbamylphosphate in the urea cycle. About 10%-15% of patients, clinically diagnosed with OTC deficiency (OTCD), lack identifiable mutations in the coding region or splice junctions of the OTC gene on routine molecular testing. We collected DNA from such patients via retrospective review and by prospective enrollment. In nine of 38 subjects (24%), we identified a sequence variant in the OTC regulatory regions. Eight subjects had unique sequence variants in the OTC promoter and one subject had a novel sequence variant in the OTC enhancer. All sequence variants affect positions that are highly conserved in mammalian OTC genes. Functional studies revealed reduced reporter gene expression with all sequence variants. Two sequence variants caused decreased binding of the HNF4 transcription factor to its mutated binding site. Bioinformatic analyses combined with functional assays can be used to identify and authenticate pathogenic sequence variants in regulatory regions of the OTC gene, in other urea cycle disorders or other inborn errors of metabolism. PMID- 29282797 TI - Decision curve analysis as a framework to estimate the potential value of screening or other decision-making aids. AB - OBJECTIVES: There is an increasing debate about the impact of mental health screening. We illustrate the use of a decision making framework that can be applied when there is no sufficient data to support a traditional cost-benefit analysis. METHODS: We conducted secondary analyses of data from 459 male prisoners who were screened upon intake. We compared the potential benefit of different approaches (screening, history taking, and universal interventions) to allocating treatment resources using decision curve analysis. RESULTS: Screening prisoners for distress at typical levels of sensitivity (75%) and specificity (71%) were estimated to provide the greatest net benefit if between 2 and 5 false positives per detected illness are tolerable. History taking and self-harm screening provide the largest net benefit when only 1 or 2 false positives per detected illness would be tolerable. The benefits of screening were less among those without a recent psychiatric history, ethnic minorities, and those with fewer psychosocial needs. CONCLUSIONS: Although screening has potential to increase detection of treatment, important subgroup differences exist. Greater consideration of responses to positive screens or alternatives to screening are needed to maximize the impact of efforts to improve detection and treatment of mental illness. PMID- 29282798 TI - Estimating a cost-effectiveness threshold for the Spanish NHS. AB - The cost of generating a quality-adjusted life year (QALY) within a National Health Service provides an approximation of the average opportunity cost of funding decisions. This information can be used to inform a cost-effectiveness threshold. The aim of this paper is to estimate the cost per QALY at the Spanish National Health Service. We exploit variation across 17 regional health services and the exogenous changes in expenditure that took place as a consequence of the economic crisis over 5 years of data. We conduct fixed effect models and use an instrumental variable approach to test for potential remaining endogeneity. Our results show that health expenditure has a positive and significant effect on population health, with an average spending elasticity of 0.07. This translates into a cost per QALY of between 22,000? and 25,000?. These values are below the cost-effectiveness threshold figure of 30,000? commonly cited in Spain. PMID- 29282799 TI - A beginner's guide to gene editing. AB - NEW FINDINGS: What is the topic of this review? This review summarizes the development of gene editing from early proof-of-concept studies in the 1980s to contemporary programmable and RNA-guided nucleases, which enable rapid and precise alteration of DNA sequences of almost any living cell. What advances does it highlight? With an average of one clustered regularly interspaced short palindromic repeat (CRISPR) Cas9 paper published every 4 h in 2017, this review cannot highlight all new developments, but a number of key improvements, including increases in efficiency, a range of new options to reduce off-target effects and plans for CRISPR to enter clinical trials in 2018, are discussed. ABSTRACT: Genome editing enables precise changes to be made in the genome of living cells. The technique was originally developed in the 1980s but largely limited to use in mice. The discovery that a targeted double-stranded break at a unique site in the genome, close to the site to be changed, could substantially increase the efficiency of editing raised the possibility of using the technique in a broader range of animal models and, potentially, human cells. But the challenge was to identify reagents that could create targeted breaks at a unique genomic location with minimal off-target effects. In 2005, the demonstration that programmable zinc finger nucleases (ZFNs) could perform this task led to a number of proof-of-concept studies, but a limitation was the ease with which effective ZFNs could be produced. In 2009, the development of TAL effector nucleases (TALENs) increased the specificity of gene editing and the ease of design and production. However, it was not until 2013 and the development of the clustered regularly interspaced short palindromic repeat (CRISPR) Cas9/guide RNA that gene editing became a research tool that any laboratory could use. PMID- 29282800 TI - Height-income association in developing countries: Evidence from 14 countries. AB - OBJECTIVES: The purpose of this study was to assess whether the height-income association is positive in developing countries, and whether income differences between shorter and taller individuals in developing countries are explained by differences in endowment (ie, taller individuals have a higher income than shorter individuals because of characteristics such as better social skills) or due to discrimination (ie, shorter individuals have a lower income despite having comparable characteristics). METHODS: Instrumental variable regression, Oaxaca Blinder decomposition, quantile regression, and quantile decomposition analyses were applied to a sample of 45 108 respondents from 14 developing countries represented in the Research on Early Life and Aging Trends and Effects (RELATE) study. RESULTS: For a one-centimeter increase in country- and sex-adjusted median height, real income adjusted for purchasing power parity increased by 1.37%. The income differential between shorter and taller individuals was explained by discrimination and not by differences in endowments; however, the effect of discrimination decreased at higher values of country- and sex-adjusted height. CONCLUSIONS: Taller individuals in developing countries may realize higher income despite having characteristics similar to those of shorter individuals. PMID- 29282801 TI - Augmentative Approaches in Family-Based Treatment for Adolescents with Restrictive Eating Disorders: A Systematic Review. AB - OBJECTIVE: To systematically review the literature reporting outcomes of augmentative family-based treatment (FBT) interventions for adolescents with restrictive eating disorders (EDs). METHOD: Articles were identified through a systematic search of five electronic databases (PsycINFO, MEDLINE, EMBASE, CINAHL, Cochrane Database). RESULTS: Thirty articles were included, reporting on FBT augmentations featuring adjunctive treatment components, modified treatment structure and/or content with adherence to FBT principles, and adaptations allowing FBT delivery in different settings. All reported significant improvements in weight and/or ED symptoms at end-of-treatment, although few compared augmentative and standard FBT interventions and good quality follow-up data was generally lacking. CONCLUSIONS: There is early evidence for the effectiveness of augmentative FBT-based approaches in facilitating weight and/or ED symptom improvements for adolescents with restrictive EDs. There remains a lack of robust evidence demonstrating superior effects of such approaches over standard FBT, and further controlled studies are required to expand on the current evidence. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 29282802 TI - Impact of cellular restriction gene (TRIM5alpha, BST-2) polymorphisms on the acquisition of HIV-1 and disease progression. AB - BACKGROUND: TRIM5alpha and BST-2 are cellular restriction factors affecting the HIV-1 infection and its progression. Genetic variability in these genes alters the expression pattern. Hence, we aimed to examine the impact of the TRIM5alpha (rs10838525, rs7127617 and rs904375) and BST2 (rs3217318 and rs71694748) polymorphisms on the acquisition of HIV-1 and its progression. METHODS: Genotyping of TRIM5alpha and BST-2 polymorphisms was performed in a total of 153 HIV-infected patients and 158 unrelated healthy individuals using a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant differences were found in the genotype frequencies of TRIM5alpha polymorphisms between HIV patients and healthy controls. BST-2 Delta19/i19 and i19/i19+ Delta19/i19 genotypes appeared more frequently in HIV patients compared to healthy controls (10.4% versus 7.0%, p = 0.20; 11.10% versus 7.6%, p = 0.16). The BST-2 i19 allele was associated with the acquisition of HIV-1 [odds ratio (OR) = 2.76, p = 0.030)]. TRIM5alpha haplotypes ATG and ACA elevated the risk, whereas haplotype ATA reduced the risk for the acquisition of HIV-1 (OR = 1.92, p = 0.026; OR = 4.88, p = 0.016; OR = 0.31, p = 0.014). BST-2 Delta19/i19 and i19/i19+ Delta19/i19 genotypes were more prevalent in patients with early HIV disease stage compared to healthy controls (15.9% versus 7.0%, p = 0.096; 15.9% versus 7.6%, p = 0.12). The prevalence of TRIM5alpha rs7127617 CC and BST-2 Delta19/i19 genotypes was observed to be higher in alcohol-using HIV patients compared to non-users (27.8% versus 20.0%, p = 0.35, 22.2% versus 10.0%, p = 0.24). CONCLUSIONS: TRIM5alpha haplotypes and the BST-2 i19 allele may significantly affect the modulation of HIV-1 acquisition and its progression. TRIM5alpha rs7127617 CC and BST-2 Delta19/i19 genotypes in alcohol-using HIV patients elevated the risk of HIV disease progression. PMID- 29282803 TI - Hair Follicle Stem Cell Faith Is Dependent on Chromatin Remodeling Capacity Following Low-Dose Radiation. AB - The main function of the skin, to protect against the environment, is supported by the activity of different stem cell populations. The main focus of this study was elucidating the coping mechanisms of stem cells against the stimulation of constant exposure to genotoxic stresses, both endogenous and exogenous, to ensure long-term function. Investigation of various mouse strains, differing in their DNA repair capacity, enables us to clarify fractionated low-dose irradiation (LDR)-induced consequences for different stem cell populations of the murine hair follicle (HF) in their physiological stem cell niche. Using microscopic techniques combined with flow cytometry, we could show that LDR induces accumulation of persisting; pKu70-independent 53BP1-foci ("chromatin alterations") in heterochromatic regions of the HF stem cells (HFSCs). These remaining chromatin-alterations result in varying stem cell consequences. CD34 positive HFSCs react by ataxia telangiectasia mutated-dependent, premature senescence, which correlates with global chromatin compaction, whereby apoptosis is prevented by the activity of DNA-dependent protein kinase catalytic subunit. However, distinctively highly damaged HFSCs seem to be sorted out of the niche by differentiation, transferring their chromatin-alterations to more proliferative G protein-coupled receptor 5-positive stem cells. Consequentially, the loss of basal HFSCs is compensated by increased proliferation within the stem cell pool. Despite the initial success of these mechanisms in stem cell population maintenance, the combined effect of the chromatin-alterations and the modification in stem cell pool composition may lead to downstream long-term functional loss of tissue or organs. Stem Cells 2018;36:574-588. PMID- 29282804 TI - In Vitro Modeling of Congenital Heart Defects Associated with an NKX2-5 Mutation Revealed a Dysregulation in BMP/Notch-Mediated Signaling. AB - The Nkx2-5 gene codes for a transcription factor that plays a critical role in heart development. Heterozygous mutations in NKX2-5 in both human and mice result in congenital heart defects (CHDs). However, the molecular mechanisms by which these mutations cause the disease are still unknown. Recently, we have generated the heterozygous mouse model of the human CHDs associated mutation NKX2-5 R142C (Nkx2-5R141C/+ mouse ortholog of human NKX2-5 R142C variant) that developed septal and conduction defects. This study generated a heterozygous Nkx2-5 R141C mouse embryonic stem cell line (Nkx2-5R141C/+ mESCs) to model CHDs in vitro. We observed that Nkx2-5R141C/+ mESCs display an alteration in the expression of genes that are essential for normal heart development. Furthermore, the reduced cardiomyogenesis is paralleled by a reduction in nuclear import of Nkx2-5 protein. Examination of the Nkx2-5R141C/+ embryos at E8.5 revealed a transient loss of cardiomyogenesis, which is consistent with the phenotype observed in vitro. Moreover, gene expression profiling of Nkx2-5R141C/+ cells at an early stage of cardiac differentiation revealed pronounced deregulation of several cardiac differentiation and function genes. Collectively, our data showed that heterozygosity for the R141C mutation results in disruption of the cellular distribution of Nkx2-5 protein, a transient reduction in cardiomyogenesis that may disrupt the early patterning of the heart, and this, in turn, affects the intricate orchestration of signaling pathways leading to downregulation of Bone morphogenetic protein (BMP) and Notch signaling. Therefore, we have developed mESCs model of a human CHD, providing an in vitro system to examine early stages of heart development, which are otherwise difficult to study in vivo. Stem Cells 2018;36:514-526. PMID- 29282805 TI - When structure leads to sex: Untangling signals in population genetic data sets. AB - A robust signal of population structure often provides the first glimpse into the evolutionary history of a species and its populations. In this issue of Molecular Ecology, new work from Louis Bernatchez's group (Benestan et al., ) starts with an investigation of apparent structure in two marine species and concludes with an identification of sex-linked genes, and in the process provides a model for robust analysis. Structure is the genetic signal left by natural selection as well as by neutral processes like migration and gene flow. Neutral areas of the genome can reveal the geographical relationships and related gene flow between populations over time and space, while selection can resist the natural genomic turnover created by recombination and generate adaptive structure between populations that can be detected. However, artefacts in a data set can easily hide the true signal of structure; mutation, whether it is a true appearance of a recent, minor allele, or more commonly, an error in SNP calling or molecular library construction, can easily conceal patterns of population structure (e.g., geographical structure in mackerel, Rodriguez-Ezpeleta et al. ()). A demographic structure that results from the most "forceful" evolutionary processes can overwhelm another signal generated by other, unrelated phenotypes. For example, the structure among diverged freshwater and marine threespine stickleback populations results from such strong selection and linkage disequilibrium across the genome that it impairs the ability to disentangle the genetic basis of particular evolved morphological traits (e.g., opercle development, Alligood ()). Finally, there might be conflicting inferences for what underlies structure patterns. Structure may be created by differential patterns of meiotic recombination, and genetic maps are a reliable means for identifying genomic regions that resist recombination. But, without additional information (Anderson et al., ), it can be difficult to distinguish the recombination-suppressing effect of a segregating genomic inversion (Small et al., ) from that of sex linked selection. PMID- 29282806 TI - Gene expression profiling in embryonic chicken ovary during asymmetric development. AB - The reproductive system in female birds arises as bilateral asymmetrical anlagen, excluding the birds of prey. Earlier, histological and messenger RNA (mRNA) expression profile studies of several genes related to gonadal sex differentiation in chicken embryos tried to elucidate the query of this asymmetry in a scattered manner. To understand the matter precisely, we have focused on mRNA expression of a cohort of genes (FSHR, CYP19A1, caspase 3, caspase 8) in second half of the embryonic days (E10-E18). The established role of leptin in development of the embryo and its expression in the embryonic ovary also drove us to check leptin receptor (LEPR) expression in the ovary. Increased expression of FSHR and CYP19A1 in the left ovary compared with that in the right ovary was identified (P < 0.05), promoting preferential left ovarian development and functionality. Significant high expression (P < 0.05) of the apoptotic genes in the right ovary were also involved here. Leptin probably has no direct influence on ovarian asymmetry as no significant variation in gonadal mRNA expression of LEPR was observed within the same experimental days. We propose that asymmetric expression of this cohort of genes (FSHR, CYP19A1, caspase 3, caspase 8) leads to the development of dimorphic gonads during embryogenesis. PMID- 29282807 TI - Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy-induced neuropathy. AB - BACKGROUND: Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a serious dose-limiting neurotoxic effect of cancer drug treatment. The underlying mechanism(s) of this debilitating condition, which lacks effective drug treatment, is incompletely understood. However, neural-immune interactions, involving increased expression and release of cytokines, are believed to be involved. Here, we examined, in the paclitaxel rat model of CIPNP, whether plasma levels of 24 cytokines/chemokines change after paclitaxel treatment, and whether blocking of signalling of some of those cytokines would reverse/attenuate behavioural signs of CIPNP. METHODS: To achieve these objectives luminex, pharmacological and behavioural experiments were performed on male Wistar rats (250-300 g) 31 days after the last injection of paclitaxel (1 mg/kg, i.p. on four alternate days) as well as on control (vehicle-treated) rats. RESULTS: Compared with control rats, plasma levels of IL-1alpha, IL-1beta, IL-6, TNF-alpha, INF gamma and MCP-1 were significantly upregulated in paclitaxel-treated rats. Blocking of TNF-alpha signalling with etanercept (2 mg/kg, i.p.) or IL-1beta with IL-1 receptor antagonist (IL-1ra; 3 mg/kg, i.p.), significantly attenuated established mechanical and cold hypersensitivity as well as spontaneous pain behaviour (spontaneous foot lifting) 24 and 48 h postdrug treatment. Pharmacological blockade of MCP-1/CCL2 signalling with a highly selective CCR2 receptor antagonist (S504393, 5 mg/kg, i.p.) also significantly reduced evoked, but not spontaneous, pain behaviours of CIPNP in paclitaxel-treated rats at the same time points. CONCLUSIONS: The findings support the notion that cytokines/chemokines, particularly TNF-alpha, IL-1 and MCP-1, are involved in the pathophysiology of CIPNP and suggest that strategies that target their inhibition may be effective in treating CIPNP. SIGNIFICANCE: This study demonstrates that paclitaxel-treated rats exhibit, in addition to indices of mechanical and cold hypersensitivity, a behavioural sign of spontaneous pain, the principal compliant of patients with neuropathic pain. This was accompanied by upregulation in plasma levels of key cytokines/chemokines (IL-1alpha, IL-1beta, IL-6, TNF-alpha, INF gamma and MCP-1) 31 days post-treatment. However, it is noteworthy that cytokine release, rather than nerve injury per se, may be causative of NP in this model of CIPNP. Nevertheless, our findings that pharmacological blockade of TNF-alpha, IL 1beta and MCP-1 attenuated both evoked and spontaneous pain suggest that strategies that target inhibition of these cytokines may be effective in treating CIPNP. PMID- 29282808 TI - Donor base management: painting Gabriel's horn - Comment on Beckman et al., 2016. PMID- 29282809 TI - Serious hazards of transfusion - conference report: celebration of 20 years of UK haemovigilance. AB - The Annual SHOT Report for incidents in 2016 was published on July 12 and celebrated of 20 years of UK haemovigilance. Components are very safe, related in part to risk-reduction measures triggered by SHOT reporting. Transfusion-related acute lung injury is now very rare (all plasma components are provided from male donors), and infection transmission is also uncommon - a single transmission of hepatitis E in 2016 and no bacterial transmissions. Human factors (errors) account for 87% of all reports. Deaths and major morbidity most often result from transfusion-associated circulatory overload. Wrong transfusions and deaths from ABO-incompatible transfusion can be reduced by correct bedside checks. It is notable that information technology systems may not be safe. Standardisation is required for flags and alerts. SHOT key recommendations include: assess patients for transfusion-associated circulatory overload prior to transfusion. Be like a pilot - use a bedside checklist when setting up the transfusion. PMID- 29282811 TI - Advances in transfusion medicine RCPath, November 2016. PMID- 29282812 TI - Frequency and circumstances of falls for people with Charcot-Marie-Tooth disease: A cross sectional survey. AB - OBJECTIVE: People with Charcot-Marie-Tooth (CMT) disease may be at risk of falls due to distal muscle weakness and sensory impairment. We aimed to understand the frequency of falls in a cohort, where they occurred, injury and to what people attributed the possible cause. DESIGN: A cross-sectional survey design was used. It was sent by post to ascertain the frequency of falls and near falls, plus the circumstances of the last three falls events they could recall. SETTING: The survey was administered to 252 people with CMT who were patients at a specialist neuromuscular centre. PARTICIPANTS: People were approached who had a clinical diagnosis by a neuromuscular specialist neurologist. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Falls Event Questionnaire. RESULTS: Responses were received from 107 people with CMT. Falls and near falls were reported by 86% of survey respondents. The majority of falls occurred at home, and muscular weakness appeared to be blamed the most, with participants describing tripping due to foot drop or joints giving way. A similar pattern was observed for near falls, but they tended to be more frequent. Moderate and major injuries were relatively rare, with the majority of falls resulting in scrapes and bruises or the faller feeling shaken by the experience. DISCUSSION: The impact of falls is far reaching, in terms of injury risk and the consequences of the fear of falling. Interventions to improve balance and reduce falls are an important rehabilitation focus for people with CMT. PMID- 29282814 TI - Assessment of job satisfaction in people with intellectual disabilities: Towards best-practice recommendations. AB - BACKGROUND: The current body of research on job satisfaction of people with intellectual disability is based on highly diverse measures, originating both from the general population and people with intellectual disability. This heterogeneity represents a possible confounder. Best-practice approaches for the assessment of job satisfaction are hence needed. METHOD: Using systematic literature review, job satisfaction measures were identified and analyzed with regard to their applicability for people with intellectual disability. Identified best-practice measures (JDI/JIGS as well as RSM-WS) were subsequently applied in the course of a pilot study with 129 employees of sheltered workshops. Comprehension, reliability and validity were assessed. RESULTS: The three identified instruments exhibit high reliability and validity. Comprehension was sufficient for JDI and JIGS but better for RSM-WS. CONCLUSIONS: The JDI/JIGS represent a feasible measures of job satisfaction allowing for comparisons with the general population. In samples with more severe intellectual disabilities, the RSM-WS is preferable. PMID- 29282813 TI - Extinction and reinstatement of an operant responding maintained by food in different models of obesity. AB - A major problem in treating obesity is the high rate of relapse to abnormal food taking habits after maintaining an energy balanced diet. Alterations of eating behavior such as compulsive-like behavior and lack of self-control over food intake play a critical role in relapse. In this study, we used an operant paradigm of food-seeking behavior on two different diet-induced obesity models, a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity or for unhealthy food regularly consumed in our societies. A reduced operant performance and motivation for the hedonic value of palatable chocolate pellets was revealed in both obesity mouse models. However, only mice exposed to high-fat diet showed an increased compulsive-like behavior in the absence of the reinforcer further characterized by impaired operant learning, enhanced impulsivity and intensified inflexibility. We used principal component analysis to globally identify the specific behaviors responsible for the differences among diet groups. Learning impairment and inflexible behaviors contributed to a first principal component, explaining the largest proportion of the variance in the high-fat diet mice phenotype. Reinforcement, impulsion and compulsion were the main contributors to the second principal component explaining the differences in the chocolate-mixture mice behavioral phenotype. These behaviors were not exclusive of chocolate group because some high-fat individuals showed similar values on this component. These data indicate that extended access to hypercaloric diets differentially modifies operant behavior learning, behavioral flexibility, impulsive-like and compulsive-like behavior, and these effects were dependent on the exposure to each specific diet. PMID- 29282815 TI - Prevalence of and risk factors for cerebral microbleeds among adult patients with haemophilia A or B. AB - INTRODUCTION: Cerebral microbleeds (CMBs) represent clinically silent haemorrhagic events. Cerebral microbleeds (CMBs) portend negative neurovascular and cognitive outcomes in the general population and are associated with cognitive impairment in persons with haemophilia (PWH). Prevalence, patterns, and risk factors for CMBs in PWH have not been directly compared to persons without coagulopathy. AIM: To examine prevalence, patterns, and risk factors for CMBs in PWH vs normal controls. METHODS: Adults with haemophilia A or B and haemostatically normal controls were recruited. Subjects were excluded if taking an antithrombotic agent other than low-dose aspirin (<100 mg). All subjects underwent T2*MRI of the brain; scans were reviewed independently by two neuroradiologists blinded to subject group to determine the presence of CMBs. RESULTS: We recruited 31 PWH and 32 controls. Human immunodeficiency virus (HIV) and history of hepatitis C virus (HCV) infection were more prevalent in PWH; smoking was more common among controls. Cardiovascular (CV) risk factors were similar between groups. Prevalence of CMBs was 35% in PWH and 25% in controls (P = .42). Among PWH, advanced age, history of HCV infection, and CV risk factors were associated with CMBs. Multiple and large (>5 mm) CMBs were seen only in PWH. CONCLUSIONS: Cerebral microbleeds (CMBs) are common in adults with haemophilia, but not clearly more prevalent than in haemostatically normal controls. In PWH, older age, HCV infection, CV risk factors, and the presence of an inhibitor were associated with CMBs. Large CMBs and multiple CMBs may be more prevalent in PWH than in the general population. The clinical impact of CMBs in PWH requires further study. PMID- 29282816 TI - Methamphetamine binge administration dose-dependently enhanced negative affect and voluntary drug consumption in rats following prolonged withdrawal: role of hippocampal FADD. AB - While prior studies have established various interacting mechanisms and neural consequences (i.e. monoaminergic nerve terminal damage) that might contribute to the adverse effects caused by methamphetamine administration, the precise mechanisms that mediate relapse during withdrawal remain unknown. This study evaluated the long-term consequences of binge methamphetamine administration (three pulses/day, every 3 hours, 4 days, i.p.; dose-response: 2.5, 5 and 7.5 mg/kg) in adult Sprague-Dawley rats at two behavioral levels following 25 days of withdrawal: (1) negative affect (behavioral despair-forced-swim test, and anhedonia-1% sucrose consumption, two-bottle choice test) and (2) voluntary methamphetamine consumption (20 mg/l, two-bottle choice test). Striatal and hippocampal brain samples were dissected to quantify monoamines content by high performance liquid chromatography and to evaluate neurotoxicity (dopaminergic and serotonergic markers) and neuroplasticity markers [i.e. cell fate regulator (Fas associated protein with death domain) FADD] by Western blot. The results showed that methamphetamine administration induced dose-dependent negative effects during prolonged withdrawal in adult rats. In particular, rats treated repeatedly with methamphetamine (7.5 mg/kg) showed (1) enhanced negative affect-increased anhedonia associated with behavioral despair, (2) increased voluntary methamphetamine consumption, (3) enhanced neurotoxicity-decreased dopamine and metabolites in striatum and decreased serotonin in hippocampus, (4) altered neuroplasticity markers-decreased FADD protein and increased p-FADD/FADD balance selectively in hippocampus and (5) higher consumption rates of methamphetamine that were associated with lower FADD content in hippocampus. These results confirm that methamphetamine withdrawal dose-dependently induced negative affect and decreased monoamines content, while also increased voluntary methamphetamine consumption and suggested a role for hippocampal FADD neuroplasticity in these drug-withdrawal adaptations. PMID- 29282817 TI - Effects of different gestation housing types on reproductive performance of sows. AB - This study evaluated the effects of different gestation housing types on reproductive performance of sows. A total of 60 sows (218 +/- 24 kg body weight) with mixed parity were used. During gestation, 28 sows were housed in groups with electronic sow feeders (space allowance = 1.26 m2 /sow) and 32 sows were housed in individual stalls (space allowance = 1.20 m2 /sow). Sows from both housing types were moved to farrowing crates on day 109 of gestation and stayed until weaning (18 days post-farrowing). Typical corn-soybean meal diets were provided to sows during gestation and lactation. Measurements were reproductive performance of sows at farrowing as well as performance of sows and their litter during lactation. Similar total numbers of piglets born at farrowing were observed for sows gestated in both housing types. However, group-housed gestation sows had more mummies (0.321 vs. 0.064; P < 0.05) and stillbirths (0.893 vs. 0.469; P = 0.073) at farrowing than individual-housed gestation sows. Consequently, individual-housing type had higher percentage of piglets born alive (95.5 vs. 90.4%; P < 0.05) than the group-housing type. Therefore, improved reproductive performance of sows from individual gestating housing was confirmed in this study. PMID- 29282818 TI - Effect of severe obesity in childhood and adolescence on risk of type 2 diabetes in youth and early adulthood in an American Indian population. AB - OBJECTIVES: The risk of early-onset type 2 diabetes associated with the severity of obesity in youth is not well understood. This study aims to determine metabolic alterations and type 2 diabetes risk among American Indian children who are obese or severely obese. METHODS: Incidence rates of diabetes before 20 years (youth-onset) and 45 years were computed in 2728 children who were from 5 to <10 years and 4317 adolescents who were from 10 to <18 years without diabetes examined between 1965 and 2007. Obesity was defined as age-sex-adjusted body mass index (BMI) >=95th percentile, and its severity was quantified as the percentage of the 95th percentile (%BMIp95 ). RESULTS: In the younger cohort, 0.9% of those non-obese and 2.9% of those with 100% to <120%BMIp95 had impaired glucose tolerance (IGT) compared to 8.6% of those with >=140%BMIp95 . In the older cohort, 2.9% of those non-obese and 9.8% of those with 100% to <120%BMIp95 had IGT compared to 13.3% of those with >=160%BMIp95 . The incidence of youth-onset diabetes was 3.8 and 4.9/1000 person-years in the child and adolescent cohorts, respectively, and before the age of 45 was 12.3 and 16.8/1000 person-years, respectively. Incidence rates of youth-onset diabetes in those with the most severe obesity (>=140%BMIp95 ) were 2.3 to 5.1 times as high as in those with the least severe obesity (100 to <120%BMIp95 ), and for onset of diabetes before the age of 45 were 1.6 to 2.2 times as high. CONCLUSIONS: Severe obesity in an American Indian population is a major driver of type 2 diabetes developing in adolescents and young adults. PMID- 29282819 TI - Platelet activation is a preoperative risk factor for the development of thromboembolic complications in patients with continuous-flow left ventricular assist device. AB - AIMS: To correlate the dynamics of platelet activation with the development of thromboembolic events in patients with continuous-flow left ventricular assist device (cf-LVAD). METHODS AND RESULTS: The platelet activity state (PAS) assay was utilized to evaluate platelet activation in 68 cf-LVAD patients implanted with the HeartMate II (n = 15, 22%), HeartMate 3 (n = 15, 22%), or HeartWare HVAD (n = 38, 56%). PAS was measured preoperatively, early post-implant, and at long term follow-up (1, 3, 6, 12, 18, and 24 months post-implant). PAS was also measured at the occurrence of adverse events in patients who developed thrombotic complications. Data on patient demographics, medical history, antithrombotic therapy, and coagulation parameters were also analysed. Over a median follow-up of 602 (234-942) days, PAS values did not increase over time in the overall population (P = 0.15). However, PAS measured at event was 15-fold higher in the six patients (9%) who suffered pump thrombosis (n = 2) or ischaemic stroke (n = 4) vs. the rest of the population [6.67% (5.59%-11.98%) vs. 0.45% (0.33%-0.75%); P = 0.012], despite comparable coagulation profile. Pre-implant PAS values were 4.5-fold higher in these patients [1.90% (1.24%-3.17%) vs. 0.42% (0.32%-0.72%); P = 0.006]. Neither preoperative variables nor the type of the pump or the antiplatelet strategy were associated with a higher risk of complications. CONCLUSIONS: Thrombotic events are associated with altered PAS values. Moreover, baseline elevated PAS values in patients who developed thrombotic events suggest patient-specific tendency to post-implant thromboembolic complications. Prospectively, systematic monitoring of PAS might guide the development of refined patient-tailored antithrombotic strategies and the technological improvement of LVAD design. PMID- 29282820 TI - Ergosterol is mainly located in the cytoplasmic leaflet of the yeast plasma membrane. AB - Transbilayer lipid asymmetry is a fundamental characteristic of the eukaryotic cell plasma membrane (PM). While PM phospholipid asymmetry is well documented, the transbilayer distribution of PM sterols such as mammalian cholesterol and yeast ergosterol is not reliably known. We now report that sterols are asymmetrically distributed across the yeast PM, with the majority (~80%) located in the cytoplasmic leaflet. By exploiting the sterol-auxotrophic hem1Delta yeast strain we obtained cells in which endogenous ergosterol was quantitatively replaced with dehydroergosterol (DHE), a closely related fluorescent sterol that functionally and accurately substitutes for ergosterol in vivo. Using fluorescence spectrophotometry and microscopy we found that <20% of DHE fluorescence was quenched when the DHE-containing cells were exposed to membrane impermeant collisional quenchers (spin-labeled phosphatidylcholine and trinitrobenzene sulfonic acid). Efficient quenching was seen only after the cells were disrupted by glass-bead lysis or repeated freeze-thaw to allow quenchers access to the cell interior. The extent of quenching was unaffected by treatments that deplete cellular ATP levels, collapse the PM electrochemical gradient or affect the actin cytoskeleton. However, alterations in PM phospholipid asymmetry in cells lacking phospholipid flippases resulted in a more symmetric transbilayer distribution of sterol. Similarly, an increase in the quenchable pool of DHE was observed when PM sphingolipid levels were reduced by treating cells with myriocin. We deduce that sterols comprise up to ~45% of all inner leaflet lipids in the PM, a result that necessitates revision of current models of the architecture of the PM lipid bilayer. PMID- 29282821 TI - Experimental evolution of infectious behaviour in a facultative ectoparasite. AB - Parasitic lifestyles have evolved many times in animals, but how such life history strategies evolved from free-living ancestors remains a great puzzle. Transitional symbiotic strategies, such as facultative parasitism, are hypothesized evolutionary stepping stones towards obligate parasitism. However, to consider this hypothesis, heritable genetic variation in infectious behaviour of transitional symbiotic strategies must exist. In this study, we experimentally evolved infectivity and estimated the additive genetic variation in a facultative parasite. We performed artificial selection experiments in which we selected for either increased or decreased propensity to infect in a facultatively parasitic mite (Macrocheles muscaedomesticae). Here, infectiousness was expressed in terms of mite attachment to a host (Drosophila hydei) and modelled as a threshold trait. Mites responded positively to selection for increased infectivity; realized heritability of infectious behaviour was significantly different from zero and estimated to be 16.6% (+/-4.4% SE). Further, infection prevalence was monitored for 20 generations post-selection. Selected lines continued to display relatively high levels of infection, demonstrating a degree of genetic stability in infectiousness. Our study is the first to provide an estimate of heritability and additive genetic variation for infectious behaviour in a facultative parasite, which suggests natural selection can act upon facultative strategies with important implications for the evolution of parasitism. PMID- 29282822 TI - Climate warming and land-use changes drive broad-scale floristic changes in Southern Sweden. AB - Land-use changes, pollution and climate warming during the 20th century have caused changes in biodiversity across the world. However, in many cases, the environmental drivers are poorly understood. To identify and rank the drivers currently causing broad-scale floristic changes in N Europe, we analysed data from two vascular plant surveys of 200 randomly selected 2.5 * 2.5 km grid squares in Scania, southernmost Sweden, conducted 1989-2006 and 2008-2015, respectively, and related the change in frequency (performance) of the species to a wide range of species-specific plant traits. We chose traits representing all plausible drivers of recent floristic changes: climatic change (northern distribution limit, flowering time), land-use change (light requirement, response to grazing/mowing, response to soil disturbance), drainage (water requirement), acidification (pH optimum), nitrogen deposition and eutrophication (N requirement, N fixation ability, carnivory, parasitism, mycorrhizal associations), pollinator decline (mode of reproduction) and changes in CO2 levels (photosynthetic pathway). Our results suggest that climate warming and changes in land-use were the main drivers of changes in the flora during the last decades. Climate warming appeared as the most influential driver, with northern distribution limit explaining 30%-60% of the variance in the GLMM models. However, the relative importance of the drivers differed among habitat types, with grassland species being affected the most by cessation of grazing/mowing and species of ruderal habitats by on-going concentration of both agriculture and human population to the most productive soils. For wetland species, only pH optimum was significantly related to species performance, possibly an effect of the increasing humification of acidic water bodies. An observed relative decline of mycorrhizal species may possibly be explained by decreasing nitrogen deposition resulting in less competition for phosphorus. We found no effect of shortage or decline of pollinating lepidopterans and bees. PMID- 29282823 TI - Evaluation of aggression in Australian after-hours doctor home-visit services. AB - RATIONALE, AIMS, AND OBJECTIVES: Minimizing the risks and distress arising from aggression in after-hours house call (AHHC) services will help improve service quality in the industry. Unfortunately, no national study has ever evaluated this in Australian AHHCs. Apart from reducing this gap, findings from this work will have global relevance given the rising popularity of the AHHC industry worldwide. METHODS: A survey of all 300 doctors employed by the National Home Doctor Service, Australia's largest AHHC service provider. A validated electronic questionnaire was used to examine the doctors' experiences over a 12-month period. RESULTS: There were 168 valid responses (56% response rate). Aggression prevalence was 47.1%, and just over half (51.8%) of the cases came from the patients. "Verbal aggression" was the commonest (48.3%). Others are "threats" (26.6%), "vexatious complaints" (13.3%), "property damage" (4.2%), "physical violence" (4.2%), "sexual harassment" (2.8%), and "stalking" (0.7%). Majority of the respondents were concerned (90.2%) and apprehensive (75.2%) regarding the risks. Doctors who have experienced aggression were more likely to express apprehension (OR = 3.99; CI = 1.54-10.31; P = 0.004), while those that have attained Postgraduate Fellowships (Vocationally Registered) were less likely to report experiences of aggression (OR = 0.28; CI = 0.09-0.84; P = 0.02). Even though a higher proportion of females were concerned (92.3% vs 89.6%) and apprehensive (82.1% vs 73.6%) compared with males, these differences were not statistically significant (Fisher's Exact Tests: P = 1.000 and 0.469, respectively). CONCLUSION: Aggression in Australian AHHC affects nearly 1-in-2 practitioners, with high levels of concern and apprehension being expressed. Concerned companies should do more to ensure that their doctors attain PG fellowships, as this is linked to lower reports of aggression. Where possible, family and friends need to be involved in patient care, as nearly half of the reported aggressions come from them. PMID- 29282824 TI - Flowering in grassland predicted by CO2 and resource effects on species aboveground biomass. AB - Continuing enrichment of atmospheric CO2 may change plant community composition, in part by altering the availability of other limiting resources including soil water, nutrients, or light. The combined effects of CO2 enrichment and altered resource availability on species flowering remain poorly understood. We quantified flowering culm and ramet production and biomass allocation to flowering culms/ramets for 10 years in C4 -dominated grassland communities on contrasting soils along a CO2 concentration gradient spanning pre-industrial to expected mid-21st century levels (250-500 MUl/L). CO2 enrichment explained up to 77% of the variation in flowering culm count across soils for three of the five species, and was correlated with flowering culm count on at least one soil for four of five species. In contrast, allocation to flowering culms was only weakly correlated with CO2 enrichment for two species. Flowering culm counts were strongly correlated with species aboveground biomass (AGB; R2 = .34-.74), a measure of species abundance. CO2 enrichment also increased soil moisture and decreased light levels within the canopy but did not affect soil inorganic nitrogen availability. Structural equation models fit across the soils suggested species-specific controls on flowering in two general forms: (1) CO2 effects on flowering culm count mediated by canopy light level and relative species AGB (species AGB/total AGB) or by soil moisture effects on flowering culm count; (2) effects of canopy light level or soil inorganic nitrogen on flowering and/or relative species AGB, but with no significant CO2 effect. Understanding the heterogeneity in species responses to CO2 enrichment in plant communities across soils in edaphically variable landscapes is critical to predict CO2 effects on flowering and other plant fitness components, and species potential to adapt to future environmental changes. PMID- 29282825 TI - Inclusion of Bacillus amyloliquefaciens strain TOA5001 in the diet of broilers suppresses the symptoms of coccidiosis by modulating intestinal microbiota. AB - Coccidiosis is an intestinal parasitic infection and one of the most prevalent and economically damaging diseases of chickens. Furthermore, coccidia-induced mucogenesis promotes secondary colonization by Clostridium perfringens, a major pathogen of chickens that causes necrotic enteritis. Our previous work found that supernatant of a culture of Bacillus amyloliquefaciens strain TOA5001 (BA) inhibited the growth of C. perfringens on Gifu anaerobic broth medium. Accordingly, we evaluated the effectiveness of dietary BA administration in inhibiting C. perfringens colonization of the intestine in broilers that were experimentally infected with coccidia. Ten healthy broilers from a BA supplemented (2 * 105 colony-forming units/g of feed) broiler group and 10 from a non-treated group were challenged with Eimeria tenella and E. maxima (5000 oocysts of each species/chick) at 28 days old. At 36 days old, five chicks from each group were slaughtered, whereas the remaining five in each group were killed at 49 days old. Dietary BA administration into Eimeria-challenged birds reduced coccidial symptoms such as intestinal lesions. It also modified the cecal microbiota through suppressing C. perfringens and E. coli colonization, and inducing domination of Faecalibacterium prausnitzii, the Lactobacillus group and unknown Lachnospiraceae genera by bacterial DNA-based metagenome analyses. B. amyloliquefaciens TOA5001 supplementation suppressed the symptoms of coccidiosis by modulating cecal microbiota in Eimeria-challenged broilers. PMID- 29282826 TI - Rational Design, Binding Studies, and Crystal-Structure Evaluation of the First Ligand Targeting the Dimerization Interface of the 14-3-3zeta Adapter Protein. AB - 14-3-3 Proteins play a central role in signalling pathways in cells: they interact as gatekeeper proteins with a huge number of binding partners. Their function as hub for intracellular communication can explain why these adapter proteins are associated with a wide range of diseases. How they control the various cellular mechanisms is still unclear, but it is assumed that the dimeric nature of the 14-3-3 proteins plays a key role in their activity. Here, we present, to the best of our knowledge, the first example of a small molecule binding to the 14-3-3zeta dimerisation interface. This compound was designed by rational in silico optimisation of a peptidic ligand identified from biochemical screening of a peptidic library, and the binding was characterised by UV/Vis spectroscopy, microscale thermophoresis, multiscale simulations, and X-ray crystallography. PMID- 29282828 TI - Carbon Monoxide Oxidation by Polyoxometalate-Supported Gold Nanoparticulate Catalysts: Activity, Stability, and Temperature- Dependent Activation Properties. AB - Nanoparticulate gold supported on a Keggin-type polyoxometalate (POM), Cs4 [alpha SiW12 O40 ]?n H2 O, was prepared by the sol immobilization method. The size of the gold nanoparticles (NPs) was approximately 2 nm, which was almost the same as the size of the gold colloid precursor. Deposition of gold NPs smaller than 2 nm onto POM (Au/POM) was essential for a high catalytic activity for CO oxidation. The temperature for 50 % CO conversion was -67 degrees C. The catalyst showed extremely high stability for at least one month at 0 degrees C with full conversion. The catalytic activity and the reaction mechanism drastically changed at temperatures higher than 40 degrees C, showing a unique behavior called a U shaped curve. It was revealed by IR measurement that Audelta+ was a CO adsorption site and that adsorbed water promoted CO oxidation for the Au/POM catalyst. This is the first report on CO oxidation utilizing Au/POMs catalysts, and there is a potential for expansion to various gas-phase reactions. PMID- 29282827 TI - Links between sleep and daytime behaviour problems in children with Down syndrome. AB - BACKGROUND: In the general population, sleep problems have an impact on daytime performance. Despite sleep problems being common among children with Down syndrome, the impact of sleep problems on daytime behaviours in school-age children with Down syndrome is an understudied topic. Our study examined the relationship between parent-reported and actigraphy-measured sleep duration and sleep quality with parent and teacher reports of daytime behaviour problems among school-age children with Down syndrome. METHOD: Thirty school-age children with Down syndrome wore an actigraph watch for a week at home at night. Their parent completed ratings of the child's sleep during that same week. Their parent and teacher completed a battery of measures to assess daytime behaviour. RESULTS: Parent reports of restless sleep behaviours on the Children's Sleep Habits Questionnaire, but not actigraph-measured sleep efficiency, was predictive of parent and teacher behavioural concerns on the Nisonger Child Behaviour Rating Form and the Vanderbilt ADHD Rating Scales. Actigraph-measured sleep period and parent-reported sleep duration on the Children's Sleep Habits Questionnaire was predictive of daytime parent-reported inattention. Actigraph-measured sleep period was predictive of parent-reported hyperactivity/impulsivity. CONCLUSION: The study findings suggest that sleep problems have complex relationships to both parent-reported and teacher-reported daytime behaviour concerns in children with Down syndrome. These findings have implications for understanding the factors impacting behavioural concerns and their treatment in school-age children with Down syndrome. PMID- 29282829 TI - Electrochemical oxidation of phosphatidylethanolamines studied by mass spectrometry. PMID- 29282830 TI - Redesigning the patient classification system in China: A pilot study. AB - The current prototype patient classification system in China has not been updated for over six decades. In the present study, we adopted a hybrid patient classification method using both disease severity and activities of daily living scores to classify patients. The time motion approach was used to measure the direct nursing time of 551 general acute care patients. We found that patients in old Categories according to ability of self-care and disease severity 1-4 received approximately 7.1, 4.6, 3.4, and 4.5 h of direct nursing care, and the number of hours was not significantly different between Categories 2, 3, and 4. In contrast, patients in new Categories 1-4 received approximately 10.1, 6.9, 4.4, and 2.4 h of direct nursing care in 24 h. The nursing hours were significantly different between all pairings of the new categories. The new classification system can be used to make nursing care assignments and adjust staffing. PMID- 29282832 TI - HIV prevalence among first-presentation psychotic patients. AB - OBJECTIVES: First-episode psychosis is a frequent emergency department (ED) presentation that may potentially be secondary to an underlying life-threatening HIV-related condition. The aim of this study was to determine the prevalence of HIV infection in patients presenting with a first episode of psychosis. METHODS: Medical records of 159 consecutive African, Asian, White and mixed ethnicity patients presenting to a tertiary academic hospital ED with a first episode of psychotic features were prospectively reviewed. RESULTS: Of the 159 subjects, 63 (39.6%) were HIV positive. An underlying medical condition was the most common aetiology of psychosis in both HIV-positive (84.2%) and HIV-negative (35.4%) subjects, but was significantly more common in HIV-positive individuals (P < 0.001). Substance-induced psychotic disorders and other primary psychiatric disorders were significantly more common in subjects without HIV infection (P < 0.001 and P < 0.001, respectively). While there were more men in the HIV-negative group (66.7%), gender distribution was almost equal in the HIV-infected group (49.2% male). Overall, as well as in both groups, most subjects were of African race, were unemployed and had not completed high school. CONCLUSIONS: Co occurrence of HIV infection was a frequent finding in first-episode psychotic individuals residing in a high-prevalence HIV setting. These individuals are more likely to have an underlying medical condition precipitating the onset of psychosis, not to have been initiated on antiretroviral therapy and to present with a low CD4 cell count and high HIV viral load. PMID- 29282831 TI - Bmi1+ Progenitor Cell Dynamics in Murine Cornea During Homeostasis and Wound Healing. AB - The outermost layer of the eye, the cornea, is renewed continuously throughout life. Stem cells of the corneal epithelium reside in the limbus at the corneal periphery and ensure homeostasis of the central epithelium. However, in young mice, homeostasis relies on cells located in the basal layer of the central corneal epithelium. Here, we first studied corneal growth during the transition from newborn to adult and assessed Keratin 19 (Krt19) expression as a hallmark of corneal maturation. Next, we set out to identify a novel marker of murine corneal epithelial progenitor cells before, during and after maturation, and we found that Bmi1 is expressed in the basal epithelium of the central cornea and limbus. Furthermore, we demonstrated that Bmi1+ cells participated in tissue replenishment in the central cornea. These Bmi1+ cells did not maintain homeostasis of the cornea for more than 3 months, reflecting their status as progenitor rather than stem cells. Finally, after injury, Bmi1+ cells fueled homeostatic maintenance, whereas wound closure occurred via epithelial reorganization. Stem Cells 2018;36:562-573. PMID- 29282833 TI - Primary cutaneous pleomorphic rhabdomyosarcoma in the periocular region. PMID- 29282835 TI - Registered Reports: introducing a new article format in Developmental Science. PMID- 29282834 TI - Mother still knows best: Maternal influence uniquely modulates adolescent reward sensitivity during risk taking. AB - Adolescent decision-making is highly sensitive to input from the social environment. In particular, adult and maternal presence influence adolescents to make safer decisions when encountered with risky scenarios. However, it is currently unknown whether maternal presence confers a greater advantage than mere adult presence in buffering adolescent risk taking. In the current study, 23 adolescents completed a risk-taking task during an fMRI scan in the presence of their mother and an unknown adult. Results reveal that maternal presence elicits greater activation in reward-related neural circuits when making safe decisions but decreased activation following risky choices. Moreover, adolescents evidenced a more immature neural phenotype when making risky choices in the presence of an adult compared to mother, as evidenced by positive functional coupling between the ventral striatum and medial prefrontal cortex. Our results underscore the importance of maternal stimuli in bolstering adolescent decision-making in risky scenarios. PMID- 29282836 TI - Geometric patterns of time-delay plots from different cardiac rhythms and arrhythmias using short-term EKG signals. AB - OBJECTIVE: To date, no systematic work has been intended to describe spatio temporal patterns of cardiac rhythms using only short series of RR intervals, to facilitate visual or computerized-aided identification of EKG motifs for use in clinical practice. The aim of this study was to detect and classify eye-catching geometric patterns of Poincare time-delay plots from different types of cardiac rhythms and arrhythmias using short-term EKG signals. METHODS: Approximately 150 300 representative, consecutive beats were retrieved from 24-h Holter registers of 100 patients with different heart rhythms. Two-dimensional Poincare charts were created, and the resulting geometric patterns were transformed into representative familiar eye-catching drawings to interpret different arrhythmias. RESULTS: Poincare plot representation of RR interval data revealed a wide variety of visual patterns: (i) comet-shaped for sinus rhythm; (ii) torpedo-shaped for sinus bradycardia; (iii) cigarette-shaped for sinus tachycardia; (iv) butterfly shaped for sinus tachycardia and isolated atrial premature complexes; (v) arrow shaped for isolated premature complexes and inappropriate sinus tachycardia; (vi) inverted fan-shaped for sinus rhythm with frequent atrial premature complexes; (vii) tornado-shaped for atrial flutter and atrial tachycardia; and (viii) fan shaped for atrial fibrillation. CONCLUSIONS: Modified Poincare plots with smoothed lines connecting successive points could accurately classify different types of arrhythmias based on short RR interval sequence variability. Characteristic emergent patterns can be visually identified and eventually could be distinguished by an automatic classification system able to discern between arrhythmias. This work provides an alternative method to interpret time-delay plots obtained from short-term EKG signal recordings. PMID- 29282837 TI - Do reef corals age? AB - Hydra is emerging as a model organism for studies of ageing in early metazoan animals, but reef corals offer an equally ancient evolutionary perspective as well as several advantages, not least being the hard exoskeleton which provides a rich fossil record as well as a record of growth and means of ageing of individual coral polyps. Reef corals are also widely regarded as potentially immortal at the level of the asexual lineage and are assumed not to undergo an intrinsic ageing process. However, putative molecular indicators of ageing have recently been detected in reef corals. While many of the large massive coral species attain considerable ages (>600 years) there are other much shorter-lived species where older members of some populations show catastrophic mortality, compared to juveniles, under environmental stress. Other studies suggestive of ageing include those demonstrating decreased reproduction, increased susceptibility to oxidative stress and disease, reduced regeneration potential and declining growth rate in mature colonies. This review aims to promote interest and research in reef coral ageing, both as a useful model for the early evolution of ageing and as a factor in studies of ecological impacts on reef systems in light of the enhanced effects of environmental stress on ageing in other organisms. PMID- 29282838 TI - The inositol pyrophosphate pathway in health and diseases. AB - Inositol pyrophosphates (IPPs) are present in organisms ranging from plants, slime moulds and fungi to mammals. Distinct classes of kinases generate different forms of energetic diphosphate-containing IPPs from inositol phosphates (IPs). Conversely, polyphosphate phosphohydrolase enzymes dephosphorylate IPPs to regenerate the respective IPs. IPPs and/or their metabolizing enzymes regulate various cell biological processes by modulating many proteins via diverse mechanisms. In the last decade, extensive research has been conducted in mammalian systems, particularly in knockout mouse models of relevant enzymes. Results obtained from these studies suggest impacts of the IPP pathway on organ development, especially of brain and testis. Conversely, deletion of specific enzymes in the pathway protects mice from various diseases such as diet-induced obesity (DIO), type-2 diabetes (T2D), fatty liver, bacterial infection, thromboembolism, cancer metastasis and aging. Furthermore, pharmacological inhibition of the same class of enzymes in mice validates the therapeutic importance of this pathway in cardio-metabolic diseases. This review critically analyses these findings and summarizes the significance of the IPP pathway in mammalian health and diseases. It also evaluates benefits and risks of targeting this pathway in disease therapies. Finally, future directions of mammalian IPP research are discussed. PMID- 29282840 TI - Erratum. PMID- 29282841 TI - Differences in food and nutrient intakes between Australian- and Asian-born women living in Australia: Results from the Australian Longitudinal Study on Women's Health. AB - AIM: To determine differences in food and nutrient intakes between Australian- and Asian-born women living in Australia. METHODS: Data were obtained from the Australian Longitudinal Study on Women's Health, including 6461 women born in Australia or Asia who completed food frequency questionnaires in 2001 and 2013. Diet was assessed using the Dietary Questionnaire for Epidemiological Studies version 2. Longitudinal generalised estimating-equation modelling was performed to determine the effect of country of birth and survey year on fruit and vegetable intake. RESULTS: Asian-born women ate more cereals, soybeans and fish but less vegetables, legumes, dairy, meat and meat products than Australian-born women both in 2001 and in 2013. Asian-born women ate less cereals, rice and noodles, meat and its products (P < 0.05) in 2013 than in 2001. The earlier people came to Australia, the less their rice and noodle intake per day. However, the reverse was demonstrated regarding vegetable intake. Asian-born women had a lower daily intake of fat, calcium, zinc, thiamin, riboflavin, folate and retinol compared with those born in Australia. CONCLUSIONS: Asian-born women living in Australia show different food and nutrient intakes from Australian-born women, although their diets tend to deviate from typical Asian characteristics and approach a Western diet. PMID- 29282839 TI - Effect of chopping time and heating on 1 H nuclear magnetic resonance and rheological behavior of meat batter matrix. AB - The effect of chopping time and heating on physicochemical properties of meat batters was investigated by low-field nuclear magnetic resonance and rheology technology. Cooking loss and L* increased while texture profile analysis index decreased between chopping 5 and 6 min. The relaxation time T21 (bound water) and its peak area ratio decreased, while the ratio of T22 peak area (immobilized water) in raw meat batters gradually increased with the extension of chopping time. However, T22 was opposite after being heated and a new component T23 (free water) appeared (T2i is the spin - spin relaxation time for the ith component.). The initial damping factor (Tan delta) gradually decreased and there were significant difference between 4 and 5 min of chopping time. There were significantly positive correlations between the ratio of peak area of T22 and chopping time, the storage modulus (G'), cooking loss, and L*, respectively. Continued chopping time could improve the peak area proportion of T22 in raw meat batters. Further, the higher the peak area proportion of T22 in raw meat batters, the cooking loss of heated meat gel was higher. Also, the stronger the mobility of immobilized water in meat batter, the higher the L* of the fresh meat batters. Thus, it is revealed that the physicochemical properties of meat batter are significantly influenced by chopping time which further affects the water holding capacity and the texture of emulsification gel. PMID- 29282842 TI - Evolution within the fungal genus Verticillium is characterized by chromosomal rearrangement and gene loss. AB - The fungal genus Verticillium contains ten species, some of which are notorious plant pathogens causing vascular wilt diseases in host plants, while others are known as saprophytes and opportunistic plant pathogens. Whereas the genome of V. dahliae, the most notorious plant pathogen of the genus, has been well characterized, evolution and speciation of other members of the genus received little attention thus far. Here, we sequenced the genomes of the nine haploid Verticillium spp. to study evolutionary trajectories of their divergence from a last common ancestor. Frequent occurrence of chromosomal rearrangement and gene family loss was identified. In addition to ~11 000 genes that are shared at least between two species, only 200-600 species-specific genes occur. Intriguingly, these species-specific genes show different features than the shared genes. PMID- 29282843 TI - The meaning of suicidal behaviour from the perspective of senior nursing undergraduate students. AB - The meaning ascribed to suicidal behaviours may influence the quality of the care provided to people at risk of suicide. Such a phenomenon has yet to be properly investigated amongst nursing undergraduate students, the aim of this study being to gain an understanding of the meanings of suicidal behaviour for a particular group of nurses. The study, which utilized grounded theory, was conducted in Brazil in 2016-2017 with 30 undergraduate students. The findings indicated that suicidal behaviour, classified according to the individual beliefs and judgements of the participants, presented a significant barrier to the delivery of care and was complex and multifaceted care phenomenon. Participants were often reluctant to discuss the topic, seemingly wanting to distance themselves from the care of persons exhibiting suicidal behaviour, and to avoid professional engagements relating to suicide prevention. Significant work is required in raising both an awareness and knowledge of suicidal behaviour befitting the promotion of tolerance, emotional competency, resilience, and empathy amongst nursing students. PMID- 29282844 TI - Randomized controlled trial evaluating a novel community eye care programme for elderly individuals with visual impairment. AB - IMPORTANCE: The novel intervention was effective at improving compliance to appropriate tertiary eye care after community eye screening. BACKGROUND: Elderly individuals from low socio-economic background with visual impairment (VI) often do not attend tertiary care, even if significant eye diseases are detected while in the community. We evaluate a novel incentive care scheme (ICS) to improve compliance to appropriate follow-up after community eye screening. DESIGN: Randomized controlled trial in a population-based setting was conducted. PARTICIPANTS: A total of 140 elderly individuals with VI (visual acuity <6/12, mean age +/- SD = 66.6 +/- 8.9 years, 46.4% female) were included. METHODS: Participants were randomized to either ICS (N = 72) or usual care (UC; N = 68). ICS incorporated patient education, social support and financial assistance to assist individuals in attending tertiary eye care. UC comprised of a standard referral letter and advice. MAIN OUTCOME MEASURE: Primary outcome included compliance to eye care referral. Secondary outcomes included best-corrected visual acuity and vision-related quality of life assessed at baseline and 3 months. RESULTS: Participants receiving the ICS intervention had higher rates of compliance to tertiary eye care attendance compared to UC (31.9% vs. 16.2%, respectively, P = 0.027). While we observed an overall significant improvement in best-corrected visual acuity at 3 months in both groups (P < 0.05), we found no significant differences in Rasch-transformed vision-related quality of life scores between groups (all P > 0.05). Identified barriers for tertiary healthcare access included patient attitudes and financial- and health-related barriers. CONCLUSION AND RELEVANCE: Our pilot RCT found that ICS improved adherence to appropriate tertiary eye care referrals after community eye screening in elderly people with VI. PMID- 29282845 TI - Clusters of functional domains to identify older persons at risk of disability. AB - AIM: To date, there is no consensus on which set of variables should be used to identify older persons at risk of disability in activities of daily living. The present study aimed to: (i) evaluate how different deficits cluster in a population of community-dwelling older persons; and (ii) investigate whether the discriminative capacity of physical performance measures towards the development of disability might be improved by adding psychological, social and environmental indicators. METHODS: Data are from 709 non-disabled older persons participating in the "Invecchiare in Chianti" study. We carried out a cluster analysis of 12 deficits in multiple functional domains, selected from the available frailty assessment instruments. Then, participants were assigned to a group, based on the obtained clusters of variables. For each group, we measured the prognostic capacity and the predictive ability for 6-year disability. RESULTS: The analysis showed a "physical" cluster (including weight loss, reduced grip strength/gait speed/physical activity, impaired balance, environmental barriers) and a "psychosocial" cluster (e.g. living alone, depression, low income). Thus, participants were classified into four groups according to the presence of a physical and/or psychosocial cluster. Compared with the "fit" group, the relative risks of becoming disabled in the "physical," "psychosocial" and "mixed" deficit groups were 2.23 (95% CI 0.71-7.00), 1.52 (95% CI 0.62-3.75) and 6.37 (95% CI 2.83-14.33), respectively. The positive and negative predictive values for the "physical," "psychosocial" and "mixed" deficit groups were, respectively, 9% and 87%, 6% and 83%, and 27% and 94%. CONCLUSIONS: As expected, physical and psychosocial deficits cluster predominantly into different groups. Even when both are considered simultaneously, the ability to predict incident disability is still insufficient. Geriatr Gerontol Int 2018; 18: 685-691. PMID- 29282846 TI - Meta-analysis of transcutaneous electrical nerve stimulation for relief of spinal pain. AB - : We conducted a systematic review and meta-analysis analysing the existing data on transcutaneous electrical nerve stimulation (TENS) or interferential current (IFC) for chronic low back pain (CLBP) and/or neck pain (CNP) taking into account intensity and timing of stimulation, examining pain, function and disability. Seven electronic databases were searched for TENS or IFC treatment in non specific CLBP or CNP. Four reviewers independently selected randomized controlled trials (RCTs) of TENS or IFC intervention in adult individuals with non-specific CLBP or CNP. Primary outcomes were for self-reported pain intensity and back specific disability. Two reviewers performed quality assessment, and two reviewers extracted data using a standardized form. Nine RCTs were selected (eight CLBP; one CNP), and seven studies with complete data sets were included for meta-analysis (655 participants). For CLBP, meta-analysis shows TENS/IFC intervention, independent of time of assessment, was significantly different from placebo/control (p < 0.02). TENS/IFC intervention was better than placebo/control, during therapy (p = 0.02), but not immediately after therapy (p = 0.08), or 1-3 months after therapy (p = 0.99). Analysis for adequate stimulation parameters was not significantly different, and there was no effect on disability. This systematic review provides inconclusive evidence of TENS benefits in low back pain patients because the quality of the studies was low, and adequate parameters and timing of assessment were not uniformly used or reported. Without additional high-quality clinical trials using sufficient sample sizes and adequate parameters and outcome assessments, the outcomes of this review are likely to remain unchanged. SIGNIFICANCE: These data highlight the need for additional high-quality RCTs to examine the effects of TENS in CLBP. Trials should consider intensity of stimulation, timing of outcome assessment and assessment of pain, disability and function. PMID- 29282847 TI - Genotoxicity, biochemical, and biodistribution studies of magnesium oxide nano and microparticles in albino wistar rats after 28-day repeated oral exposure. AB - Increased utilization and exposure levels of Magnesium oxide (MgO) nanoparticles (NPs) to humans and environment may raise unexpected consequences. The goal of this study was to evaluate the toxicological implications of MgO NPs and MPs after 28 day repeated oral administration in Wistar rats with three different doses (250, 500, and 1000 mg/kg). The MgO particles were characterised systematically in order to get more insights of the toxicological behaviour. MgO NPs induced significant DNA damage and aberrations in chromosomes. Moreover, hepatic enzymes released into the systemic circulation caused significant elevated levels of physiological enzymes in blood. NPs could interfere with proteins and enzymes and alter the redox balance in cell environment. Significant accumulation of Mg in all tissues and clearance via urine and faeces was noted in size dependent kinetics. Oral administration of MgO NPs altered the biochemical and genotoxic parameters in dose dependent and gender independent manner. PMID- 29282848 TI - Radiation Dose Exposure for Lumbar Transforaminal Epidural Steroid Injections and Facet Joint Blocks Under CT vs. Fluoroscopic Guidance. AB - BACKGROUND: Transforaminal epidural steroid injections (TFESIs) and facet joint blocks can be performed under fluoroscopy or computed tomography (CT) guidance. The purpose of this retrospective cohort study was to compare patient radiation dose for lumbar TFESIs and facet joint blocks under CT guidance vs. fluoroscopic guidance. METHODS: The primary outcome of this retrospective cohort study was the difference between the estimated effective dose (ED) of CT guidance and fluoroscopic guidance for TFESIs and facet joint blocks. Patients who had undergone these procedures with both CT and fluoroscopic guidance were eligible for this study. Dose-length product for CT-guided procedures and dose-area product for fluoroscopic-guided procedures were retrospectively collected and converted to ED. Within- or between-group comparisons were performed with appropriate nonparametric tests, using a P value of < 0.05 to indicate statistical significance. RESULTS: The 42 patients included in this study underwent a total of 100 procedures. The median estimated ED differed significantly between CT-guided injections and fluoroscopic-guided injections (1.59 mSv (interquartile range [IQR] 0.78 to 3.09) vs. 0.19 mSv (IQR 0.11 to 0.30) (Wilcoxon signed rank test, P < 0.001). CONCLUSIONS: The study results suggest that TFESIs and facet joint blocks performed with CT guidance are associated with more than 8 times higher patient radiation dose exposure compared to fluoroscopic guidance. There needs to be more vigilance with regards to CT guidance in interventional pain procedures. PMID- 29282849 TI - Laser-assisted removal of all ceramic fixed dental prostheses: A comprehensive review. AB - OBJECTIVE: The aim of this comprehensive review was to assess the effectiveness of erbium lasers in the removal of all ceramic fixed dental prostheses (FDPs). OVERVIEW: Indexed databases were searched without language or time restriction up to and including December 2017 using different combinations of the following keywords: "lasers"; "phototherapy"; "crowns"; "prostheses and implants"; "inlays"; "ceramics"; "dental porcelain"; "zirconium"; "removal"; "debonding"; "fixed dental prostheses"; "veneers"; "laminates"; and "fixed bridge." All levels of available evidence including experimental studies, case reports and case series were included. Six clinical studies reporting a total of 13 cases and 6 experimental studies were included. Results from all studies showed that erbium lasers are effective reducing the shear bond strengths of all ceramic FDPs, in terms of easy removal of the restorations with none or minimal damage to teeth or ceramic surfaces. CONCLUSION: Laser-assisted removal of all ceramic FDPs is a promising treatment protocol. Further well-designed controlled clinical trials and longitudinal prospective studies are needed to determine the precise laser parameters and duration of irradiation that could be used for removal of ceramic restorations with varying thicknesses. CLINICAL SIGNIFICANCE: Benefits of lasers over mechanical instrumentation for crown removal encompass efficient restoration retrievability without restoration or teeth surfaces damages; and relatively easier and time effective procedure with no prerequisite for anesthetic agents. It is however imperative for clinicians to be well-trained and exhibit adequate knowledge regarding recommended power settings and laser-safety parameters with reference to interactions between light and different tissues and ceramics. PMID- 29282850 TI - Endoscopic navigation system with extended field of view using augmented reality technology. AB - BACKGROUND: While endoscopic skull base surgery (ESBS) has emerged as an alternative surgical option, the limited field of view of the endoscope may lead to the surgeon's fatigue and discomfort. METHODS: The developed navigation system includes extended augmented reality (AR), which can provide an extended viewport to a conventional endoscopic view by overlaying 3D anatomical models generated from preoperative medical images onto endoscope images. To enhance the accuracy of the developed system, we adopted state-of-the-art endoscopic calibration and tracking techniques based on an optical tracking system. RESULTS: The mean spatial errors of AR was ~1 mm, which falls in the acceptable range of accuracy for ESBS. For the simulated surgical tasks with the developed system, the number and duration of error events were decreased. CONCLUSIONS: The results show that the human subject can perform the task more precisely and safely with the developed AR-based navigation system than with the conventional endoscopic system. PMID- 29282852 TI - Tooth injuries: Knowledge of parents of public school students from the city of Alfenas, Minas Gerais, Brazil. AB - BACKGROUND/AIMS: The prognosis of traumatized teeth can be optimized if appropriate procedures are following at the time of the accident. The aim of this study was to evaluate the level of knowledge of students' parents from a group of Brazilian schools regarding fracture and tooth avulsion in permanent teeth. METHODS: Parents of 802 students were interviewed using a pre-tested questionnaire designed to explore how they would manage their child's dental avulsion or fracture. RESULTS: Among the parents, 8.6% reported their child had already suffered tooth injuries. Concerning dental fracture, 49.5% considered the possibility of bonding the tooth fragment and, for dental avulsion, 65.5% considered tooth replantation. Approximately 33.5% of parents would take the child to the dental office in case of fracture or dental avulsion, and of those, 66.2% would do so immediately. Further, 69.5% (for fracture) and 70.4% (for avulsion) would do so regardless of symptoms; only 24.2% and 21.3%, respectively, would seek care only if there was pain. In case of avulsion, 22.3% of those interviewed would store the tooth in liquid, such as saline solution (17.8%), water (16.4%) and fresh milk (12.2%). CONCLUSION: Parents had partial and insufficient knowledge as to the proper approach to be adopted in cases of fracture and dental avulsion. Previous experience of dental trauma was not related to more appropriate behavior regarding these injuries. PMID- 29282851 TI - Generation and characterization of mice with mesenchyme-specific deletion of the entire ESET histone methyltransferase protein. AB - ESET protein (also known as SETDB1) catalyzes methylation of histone H3 at lysine 9 (H3-K9). In addition to the full-length transcript, mouse ESET gene also gives rise to alternative spicing variants encoding truncated proteins capable of retaining interaction with other epigenetic enzymes. To completely eliminate full length ESET and its splicing variants, we have generated a conditional ESET allele with exon 4 flanked by two loxP sites for Cre-mediated DNA deletion and downstream frame-shift mutation of the entire coding region. Mating with Prx1-Cre mice and analysis of the resultant embryos revealed that mesenchyme-specific knockout of exon 4 completely eliminates full-length ESET and its truncated protein products, leading to profound defects in both the flat bones and long bones, ectopic hypertrophy of growth plate chondrocytes and downregulation of Indian hedgehog protein. In addition, exon 4 deletion results in reduced thickness of articular cartilage in E17.5 embryos, whereas deletion of exons 15 16 fails to do so. These findings offer us a useful tool to further study epigenetic regulation in a truly ESET-null background, and demonstrate that ESET plays a critical role in the control of chondrocyte hypertrophy and skeletal development. PMID- 29282853 TI - Contrast-enhanced ultrasound using bolus injections of contrast agent for assessment of postprandial microvascular blood volume in human skeletal muscle. AB - Methods capable of measuring blood flow in a tissue-specific manner are needed. The purpose of this study was to investigate whether contrast-enhanced ultrasound (CEUS) using bolus injections of SonoVue(r) is an useful method for assessing postprandial changes in microvascular perfusion in the vastus lateralis muscle. Ten healthy, young subjects were recruited for this study. Six subjects participated in washout and reproducibility protocols to assess washout time of SonoVue(r) and the reproducibility of the method when measuring microvascular blood volume (MBV). Six subjects (two of which also participated in the washout and reproducibility protocols) participated in exercise and nutrition protocols, to assess the ability of the method to detect changes in MBV in response to these interventions. Intraday variation (coefficients of variation) for MBV indices, as assessed by peak signal intensity (PI) or mean plateau signal intensity (mPI), was high (PI: 19 +/- 4.2%; mPI: 23 +/- 3.3%). The exercise protocol induced significant increases in MBV indices (PI:+113%, P?0.0001; mPI:+218%, P?0.0001) acutely after exercise cessation. There were no changes in MBV indices in response to feeding during the nutrition protocol (PI: P = 0.51; mPI: P = 0.51). We conclude that CEUS using bolus injections of SonoVue(r) is not capable of detecting changes in MBV of vastus lateralis in response to feeding. This is probably due to the low reproducibility of the method. However, the method is capable of measuring changes in MBV in response to exercise. This method could therefore be used when investigating exercise-induced changes in microvascular perfusion. PMID- 29282854 TI - Thermo-triggered Release of CRISPR-Cas9 System by Lipid-Encapsulated Gold Nanoparticles for Tumor Therapy. AB - CRISPR/Cas9 system is a powerful toolbox for gene editing. However, the low delivery efficiency is still a big hurdle impeding its applications. Herein, we report a strategy to deliver Cas9-sgPlk-1 plasmids (CP) by a multifunctional vehicle for tumor therapy. We condensed CPs on TAT peptide-modified Au nanoparticles (AuNPs/CP, ACP) via electrostatic interactions, and coated lipids (DOTAP, DOPE, cholesterol, PEG2000-DSPE) on the ACP to form lipid-encapsulated, AuNPs-condensed CP (LACP). LACP can enter tumor cells and release CP into the cytosol by laser-triggered thermo-effects of the AuNPs; the CP can enter nuclei by TAT guidance, enabling effective knock-outs of target gene (Plk-1) of tumor (melanoma) and inhibition of the tumor both in vitro and in vivo. This AuNPs condensed, lipid-encapsulated, and laser-controlled delivery system provides a versatile method for high efficiency CRISPR/Cas9 delivery and targeted gene editing for treatment of a wide spectrum of diseases. PMID- 29282855 TI - Junction-Free Electrospun Ag Fiber Electrodes for Flexible Organic Light-Emitting Diodes. AB - Fabrication of junction-free Ag fiber electrodes for flexible organic light emitting diodes (OLEDs) is demonstrated. The junction-free Ag fiber electrodes are fabricated by electrospun polymer fibers used as an etch mask and wet etching of Ag thin film. This process facilitates surface roughness control, which is important in transparent electrodes based on metal wires to prevent electrical instability of the OLEDs. The transmittance and resistance of Ag fiber electrodes can be independently adjusted by controlling spinning time and Ag deposition thickness. The Ag fiber electrode shows a transmittance of 91.8% (at 550 nm) at a sheet resistance of 22.3 Omega ?-1 , leading to the highest OLED efficiency. In addition, Ag fiber electrodes exhibit excellent mechanical durability, as shown by measuring the change in resistance under repeatable mechanical bending and various bending radii. The OLEDs with Ag fiber electrodes on a flexible substrate are successfully fabricated, and the OLEDs show an enhancement of EQE (~19%) compared to commercial indium tin oxide electrodes. PMID- 29282856 TI - Chemical Composition of Essential Oils from Thymus vulgaris, Cymbopogon citratus, and Rosmarinus officinalis, and Their Effects on the HIV-1 Tat Protein Function. AB - New drugs would be beneficial to fight resistant HIV strains, in particular those capable of interfering with essential viral functions other than those targeted by highly active antiretroviral therapy drugs. Despite the central role played by Tat protein in HIV transcription, a search for vegetable extracts able to hamper this important viral function was never carried out. In this work, we evaluated the chemical composition and possible interference of essential oil from Thymus vulgaris, Cananga odorata, Cymbopogon citratus, and Rosmarinus officinalis with the Tat/TAR-RNA interaction and with Tat-induced HIV-1 LTR transcription. GC/MS Analysis demonstrated the biodiversity of herbal species translated into essential oils composed of different blends of terpenes. In all of them, 4 - 6 constituents represent from 81.63% to 95.19% of the total terpenes. Essential oils of Thymus vulgaris, Cymbopogon citratus, and Rosmarinus officinalis were active in interfering with Tat functions, encouraging further studies to identify single terpenes responsible for the antiviral activity. In view of the quite different composition of these essential oils, we concluded that their interference on Tat function depends on specific terpene or a characteristic blend. PMID- 29282857 TI - An Electrosynthesized 3D Porous Molybdenum Sulfide/Graphene Film with Enhanced Electrochemical Performance for Lithium Storage. AB - Molybdenum sulfide/graphene composites are promising anode materials for lithium ion batteries (LIBs). In this work, MoSx /graphene composite film with an ideal 3D porous structure is developed via a facile and straightforward electrochemical route. The MoSx nanoparticles are uniformly anchored on the graphene nanosheets that are randomly arranged, resulting in MoSx /graphene composites with well developed porous structure. Benefiting from such structure and the synergistic effect from two components, this material shows a high specific capacity over 1200 mA h g-1 , an excellent rate performance, and superior cycling stability. The dominating pseudocapacitive behavior in Li storage contributes to the outstanding rate capacity. Importantly, this kind of novel material can be easily produced as 3D microelectrodes for microscaled LIBs that are highly demanded for autonomous microelectronic systems. PMID- 29282858 TI - Release of vancomycin and tobramycin from polymethylmethacrylate cements impregnated with calcium polyphosphate hydrogel. AB - The influence of calcium polyphosphate (CPP) gel incorporation on the release of vancomycin and tobramycin from polymethyl methacrylate (PMMA) cement (Simplex P, SP) has been studied. Adding 10% CPP gel to SP led to a much lower burst release of vancomycin and considerably extended release of both vancomycin and tobramycin up to 24 weeks. Antibiotics released from this new material retain their bactericidal activity for up to 15 weeks. The improvement in the antibiotic release is mainly due to the molecular interactions of antibiotics with embedded CPP polyphosphate chains as confirmed by Raman spectroscopy analysis. The inclusion of CPP hydrogel also increased the SP surface roughness and pore sizes, leading to a higher release rate of antibiotics. The new material is biocompatible and has similar handling properties and mechanical strength as compared to SP cements. We believe that incorporating CPP gel provides a better and usable drug carrier for PMMA cement. (c) 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2827-2840, 2018. PMID- 29282859 TI - Structural and Electronic Descriptors of Catalytic Activity of Graphene-Based Materials: First-Principles Theoretical Analysis. AB - Characteristic features of the d-band in electronic structure of transition metals are quite effective as descriptors of their catalytic activity toward oxygen reduction reaction (ORR). With the promise of graphene-based materials to replace precious metal catalysts, descriptors of their chemical activity are much needed. Here, a site-specific electronic descriptor is proposed based on the pz (pi) orbital occupancy and its contribution to electronic states at the Fermi level. Simple structural descriptors are identified, and a linear predictive model is developed to precisely estimate adsorption free energies of OH (DeltaGOH ) at various sites of doped graphene, and it is demonstrated through prediction of the most optimal site for catalysis of ORR. These structural descriptors, essentially the number of ortho, meta, and para sites of N/B-doped graphene sheet, can be extended to other doped sp2 hybridized systems, and greatly reduce the computational effort in estimating DeltaGOH and site-specific catalytic activity. PMID- 29282860 TI - Unexpected spatial stability of water chemistry in headwater stream networks. AB - Understanding how water and solutes enter and propagate through freshwater landscapes in the Anthropocene is critical to protecting and restoring aquatic ecosystems and ensuring human water security. However, high hydrochemical variability in headwater streams, where most carbon and nutrients enter river networks, has hindered effective modelling and management. We developed an analytical framework informed by landscape ecology and catchment hydrology to quantify spatiotemporal variability across scales, which we tested in 56 headwater catchments, sampled periodically over 12 years in western France. Unexpectedly, temporal variability in dissolved carbon, nutrients and major ions was preserved moving downstream and spatial patterns of water chemistry were stable on annual to decadal timescales, partly because of synchronous variation in solute concentrations. These findings suggest that while concentration and flux cannot be extrapolated among subcatchments, periodic sampling of headwaters provides valuable information about solute sources and subcatchment resilience to disturbance. PMID- 29282861 TI - Biological Functions and Current Advances in Isolation and Detection Strategies for Exosome Nanovesicles. AB - Exosomes are nanoscale (~30-150 nm) extracellular vesicles of endocytic origin that are shed by most types of cells and circulate in bodily fluids. Exosomes carry a specific composition of proteins, lipids, RNA, and DNA and can work as cargo to transfer this information to recipient cells. Recent studies on exosomes have shown that they play an important role in various biological processes, such as intercellular signaling, coagulation, inflammation, and cellular homeostasis. These functional roles are attributed to their ability to transfer RNA, proteins, enzymes, and lipids, thereby affecting the physiological and pathological conditions in various diseases, including cancer and neurodegenerative, infectious, and autoimmune diseases (e.g., cancer initiation, progression, and metastasis). Due to these unique characteristics, exosomes are considered promising biomarkers for the diagnosis and prognosis of various diseases via noninvasive or minimally invasive procedures. Over the last decade, a plethora of methodologies have been developed for analyzing disease-specific exosomes using optical and nonoptical tools. Here, the major biological functions, significance, and potential role of exosomes as biomarkers and therapeutics are discussed. Furthermore, an overview of the most commonly used techniques for exosome analysis, highlighting the major technical challenges and limitations of existing techniques, is presented. PMID- 29282862 TI - Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects. AB - When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation. PMID- 29282863 TI - A foretold hepatitis A outbreak in France. PMID- 29282864 TI - Sun protective behaviors at an outdoor entertainment event in Australia. AB - An observational study was conducted to examine the use of sun protective hats, clothing, and sunglasses of people attending an outdoor entertainment event in an area of high-to-extreme ultraviolet radiation in New South Wales, Australia. Armidale is unique, as it is a highly-elevated area, almost 1000 m above sea level, and temperatures are often mild with very high-to-extreme levels of ultraviolet radiation. Four trained data collectors observed attendees as they entered the event, and recorded their use of sun protective hats, clothing, and sunglasses. While more than half of the attendees wore sun protective hats, only 14% wore sun protective clothing. Broad-brimmed hats were considered sun protective, while sun protective clothing was defined by shirts with at least three-quarter-length sleeves. Females were more likely to wear both a sun protective hat and clothing than males, and children were less protected than adults. Legislative changes are required to ensure that organizers of outdoor events have a legal responsibility to provide a safe environment for attendees, including strategies to help reduce ultraviolet radiation exposure. PMID- 29282866 TI - Body clocks: Time for the Nobel Prize. PMID- 29282865 TI - Membrane localization of a Myb3 transcription factor regulated by a TvCyP1 cyclophilin in the parasitic protozoan Trichomonas vaginalis. AB - In Trichomonas vaginalis, a TvCyP1 cyclophilin was previously demonstrated to regulate the nuclear translocation of Myb1 and Myb3, which respectively repress and activate transcription of an adhesion protein ap65-1 gene. In the present study, TvCyP1 was found to bind to Myb3 at sites spanning 54 Gly-Pro55 and 72 Gly Pro73 with differential affinities. When Gly54 and Gly72 in Myb3 were both mutated, the mutant protein was restrained on outer membranes of hydrogenosomes and some cytoplasmic vesicles. In the purified Myb3 protein complex, a high molecular weight Myb3-interacting protein (Myb3IPhmw ) and a 72-kDa heat shock protein (TvHSP72) were identified and characterized, with direct binding of Myb3 to Myb3IPhmw and TvHSP72 confirmed in vitro. When cell lysates were fractionated by the differential and gradient centrifugations, TvCyP1 and Myb3 were always associated with membrane fractions enriched with Myb3IPhmw and Myb1, as well as hydrogenosomes and VMyb organelle fractions. Mutations of Gly54 and/or Gly72 resulted in membrane redistribution of Myb3 and the aberrant assembly of the Myb3 protein complex. Consistent with these findings, the involvement of TvCyP1 in membrane distribution of Myb3, and dissociation of Myb3 from TvCyP1 protein complex were demonstrated, with direct interactions between TvCyP1 and Myb3IPhmw and that between TvCyP1 and TvHSP72, confirmed in vitro. These observations suggest that TvCyP1 directly binds to Myb3 and some of its interacting proteins to mediate serial conformational switches of Myb3 for its transition from the membrane compartments toward the nucleus. PMID- 29282868 TI - Epigenetic changes mediating transition to chronic kidney disease: Hypoxic memory. PMID- 29282867 TI - Dispersion-assisted quick and simultaneous extraction of 30 pesticides from alcoholic and non-alcoholic drinks with the aid of experimental design. AB - The presence of pesticides in food items and beverages is a big threat to humankind, and their quantitative estimation with high precision and accuracy is always a challenge for analytical chemists. Hence, a simple and rapid method is proposed for the simultaneous determination of 30 pesticides in beverages (alcoholic and non-alcoholic drinks). The proposed method hyphenated with triple quadrupole liquid chromatography mass spectrometry has only 2 min chromatographic runtime for the analysis of all the pesticides. All the factors affecting the extraction yield have been optimized using an experimental design; and under optimized conditions, the developed method has been validated. The detection limits for all the pesticides were in the range of 0.001-0.348 MUg/L with good linearity in the concentration range of 0.01-80.0 MUg/L. The coefficient of determination was in the range of (R2 ) >= 0.977 to 0.999 for all the pesticides. The method was also checked for the precision of the relative standard deviation, which was below 4.75 (intra-day) and 8.96% (inter-day). The recovery of the method was 92-138%. PMID- 29282869 TI - Emission analysis of Tb3+ -and Sm3+ -ion-doped (Li2 O/Na2 O/K2 O) and (Li2 O + Na2 O/Li2 O + K2 O/K2 O + Na2 O)-modified borosilicate glasses. AB - Four series of borosilicate glasses modified by alkali oxides and doped with Tb3+ and Sm3+ ions were prepared using the conventional melt quenching technique, with the chemical composition 74.5B2 O3 + 10SiO2 + 5MgO + R + 0.5(Tb2 O3 /Sm2 O3 ) [where R = 10(Li2 O /Na2 O/K2 O) for series A and C, and R = 5(Li2 O + Na2 O/Li2 O + K2 O/K2 O + Na2 O) for series B and D]. The X-ray diffraction (XRD) patterns of all the prepared glasses indicate their amorphous nature. The spectroscopic properties of the prepared glasses were studied by optical absorption analysis, photoluminescence excitation (PLE) and photoluminescence (PL) analysis. A green emission corresponding to the 5 D4 -> 7 F5 (543 nm) transition of the Tb3+ ions was registered under excitation at 379 nm for series A and B glasses. The emission spectra of the Sm3+ ions with the series C and D glasses showed strong reddish-orange emission at 600 nm (4 G5/2 ->6 H7/2 ) with an excitation wavelength lambdaexci = 404 nm (6 H5/2 ->4 F7/2 ). Furthermore, the change in the luminescence intensity with the addition of an alkali oxide and combinations of these alkali oxides to borosilicate glasses doped with Tb3+ and Sm3+ ions was studied to optimize the potential alkali-oxide-modified borosilicate glass. PMID- 29282870 TI - Chemical profiling of bioactive constituents in hop cones and pellets extracts by online comprehensive two-dimensional liquid chromatography with tandem mass spectrometry and direct infusion Fourier transform ion cyclotron resonance mass spectrometry. AB - Humulus lupulus L. (hop) is highly interesting from a nutraceutical perspective. The hop phytocomplex contains a wide range of bioactive metabolites, and its characterization is challenging. To tackle such a task, for the first time we applied and compared a combined approach consisting of online comprehensive two dimensional liquid chromatography with tandem mass spectrometry and direct infusion Fourier transform ion cyclotron mass spectrometry. A reversed phase * reversed phase approach with a shifted gradient in the second dimension ensured selectivity and two-dimensional space coverage. Hyphenation with an ion trap time of-flight analyzer led to the identification of 83 compounds in 70 min, comprising a novel quercetin derivative and six unknown bitter acids. On the other hand, the direct infusion method was able to identify 40 analytes (except isomers) with high mass accuracy (<= 0.1 ppm) in less than 1 min analysis time. The developed approach can be used in a complementary way, combining the separation capability and high informative spectra of two-dimensional liquid chromatography tandem mass spectrometry with the ultra-high mass accuracy of direct infusion, for potential compound discovery or the accurate profiling of bioactive compounds in different hop cultivars as well as for monitoring processing and storage of hop-based products. PMID- 29282871 TI - Minimally invasive esthetic ridge preservation with growth-factor enhanced bone matrix. AB - OBJECTIVES: Extraction socket preservation procedures are critical to successful esthetic implant therapy. Conventional surgical approaches are technique sensitive and often result in alteration of the soft tissue architecture, which then requires additional corrective surgical procedures. This case series report presents the ability of flapless surgical techniques combined with a growth factor-enhanced bone matrix to provide esthetic ridge preservation at the time of extraction for compromised sockets. CLINICAL CONSIDERATIONS: When considering esthetic dental implant therapy, preservation, or further enhancement of the available tissue support at the time of tooth extraction may provide an improved esthetic outcome with reduced postoperative sequelae and decreased treatment duration. Advances in minimally invasive surgical techniques combined with recombinant growth factor technology offer an alternative for bone reconstruction while maintaining the gingival architecture for enhanced esthetic outcome. The combination of freeze-dried bone allograft (FDBA) and rhPDGF-BB (platelet-derived growth factor-BB) provides a growth-factor enhanced matrix to induce bone and soft tissue healing. CONCLUSIONS: The use of a growth-factor enhanced matrix is an option for minimally invasive ridge preservation procedures for sites with advanced bone loss. Further studies including randomized clinical trials are needed to better understand the extent and limits of these procedures. CLINICAL SIGNIFICANCE: The use of minimally invasive techniques with growth factors for esthetic ridge preservation reduces patient morbidity associated with more invasive approaches and increases the predictability for enhanced patient outcomes. By reducing the need for autogenous bone grafts the use of this technology is favorable for patient acceptance and ease of treatment process for esthetic dental implant therapy. PMID- 29282873 TI - Reconsidering the Psychosocial-Behavioral Evaluation Required Prior to Bariatric Surgery. PMID- 29282874 TI - Connection between Lithium Coordination and Lithium Diffusion in [Pyr12O1 ][FTFSI] Ionic Liquid Electrolytes. AB - The use of highly concentrated ionic liquid-based electrolytes results in improved rate capability and capacity retention at 20 degrees C compared to Li+ dilute systems in Li-metal and Li-ion cells. This work explores the connection between the bulk electrolyte properties and the molecular organization to provide insight into the concentration dependence of the Li+ transport mechanisms. Below 30 mol %, the Li+ -containing species are primarily smaller complexes (one Li+ cation) and the Li+ ion transport is mostly derived from the vehicular transport. Above 30 mol %, where the viscosity is substantially higher and the conductivity lower, the Li+ -containing species are a mix of small and large complexes (one and more than one Li+ cation, respectively). The overall conduction mechanism likely changes to favor structural diffusion through the exchange of anions in the first Li+ solvation shell. The good rate performance is likely directly influenced by the presence of larger Li+ complexes, which promote Li+ -ion transport (as opposed to Li+ -complex transport) and increase the Li+ availability at the electrode. PMID- 29282875 TI - Evaluating methods to visualize patterns of genetic differentiation on a landscape. AB - With advances in sequencing technology, research in the field of landscape genetics can now be conducted at unprecedented spatial and genomic scales. This has been especially evident when using sequence data to visualize patterns of genetic differentiation across a landscape due to demographic history, including changes in migration. Two recent model-based visualization methods that can highlight unusual patterns of genetic differentiation across a landscape, SpaceMix and EEMS, are increasingly used. While SpaceMix's model can infer long distance migration, EEMS' model is more sensitive to short-distance changes in genetic differentiation, and it is unclear how these differences may affect their results in various situations. Here, we compare SpaceMix and EEMS side by side using landscape genetics simulations representing different migration scenarios. While both methods excel when patterns of simulated migration closely match their underlying models, they can produce either un-intuitive or misleading results when the simulated migration patterns match their models less well, and this may be difficult to assess in empirical data sets. We also introduce unbundled principal components (un-PC), a fast, model-free method to visualize patterns of genetic differentiation by combining principal components analysis (PCA), which is already used in many landscape genetics studies, with the locations of sampled individuals. Un-PC has characteristics of both SpaceMix and EEMS and works well with simulated and empirical data. Finally, we introduce msLandscape, a collection of tools that streamline the creation of customizable landscape-scale simulations using the popular coalescent simulator ms and conversion of the simulated data for use with un-PC, SpaceMix and EEMS. PMID- 29282872 TI - Psychotic-spectrum symptoms, cumulative adversity exposure and substance use among high-risk girls. AB - AIM: Psychotic-spectrum symptoms are linked to trauma, substance/alcohol use (SAU), criminality/violence and poor functional outcomes, supporting the need for early detection in vulnerable populations. To better understand high-risk girls' mental health, we assessed: (1) psychotic-spectrum symptoms; (2) cumulative trauma, adversity and loss exposures (C-TALE) and adversity-indicators (symptoms, maladaptive coping, stressor-reactivity); and SAU risk-factors; and (3) relationships among psychotic-spectrum symptoms, adversity-indicators and SAU risk-factors. METHODS: We administered the Structured Clinical Interviews for Psychotic Spectrum, and Trauma and Loss Spectrum to 158 adolescent delinquent girls. RESULTS: Girls' psychotic-spectrum profiles were similar to previously reported adult psychotic patients and characterized by typical symptoms (hallucinations/delusions, reported largely SAU-independent), interpersonal sensitivity, schizoid traits and paranoia (over-interpretation, anger over reactivity, hypervigilance). Auditory/visual hallucinations (55.7%), delusions (92.4%), ideas of reference (96.8%) and adversity (90.0% >=10/24 C-TALE-types) were common. Mean loss (4) and trauma (8) onset-age occurred before SAU-onset (12). Significant positive correlations were found among psychotic-spectrum symptoms, stressor-reactivity, C-TALE, adversity-indicators; and number of SAU types; and a negative correlation occurred between psychotic-spectrum symptoms and earlier alcohol use onset. After controlling for number of SAU-types, stressor-reactivity and adversity-related numbing individually had the largest associations with total psychotic-spectrum symptoms (b = 2.6-4.3). Girls averaged more than 4 maladaptive coping strategies (e.g., 24.8% attempted suicide) in response to adversity, amplifying potential health-disparities. No racial/ethnic differences emerged on psychotic-spectrum symptoms. CONCLUSIONS: This symptom constellation during adolescence likely interferes with social and academic functioning. Whether representing a prodromal phase, trauma-response or cross diagnostic psychopathology, accurate early detection and appropriate treatment of psychotic-spectrum symptoms are warranted to improve functional outcomes in vulnerable populations. PMID- 29282876 TI - 2-(N-Methylbenzyl)pyridine: A Potential Liquid Organic Hydrogen Carrier with Fast H2 Release and Stable Activity in Consecutive Cycles. AB - The liquid organic hydrogen carrier (LOHC) 2-(N-methylbenzyl)pyridine (MBP) shows good potential for H2 storage based on reversible hydrogenation and dehydrogenation, with an H2 storage density of 6.15 wt %. This material and the corresponding perhydro product (H12 -MBP) are liquids at room temperature. Remarkably, H2 release is much faster from H12 -MBP over Pd/C than from the benchmark perhydro benzyltoluene over Pt/C at lower temperatures than 270 degrees C, owing to the addition of N atom into the benzene ring. Since this positive effect is unfavorable to the hydrogenation reaction, more Ru/Al2 O3 catalyst or prolonged reaction time must be applied for complete H2 storage. Experiments with repeated hydrogenation-dehydrogenation cycles reveal that reversible H2 storage and release are possible without degradation of the MBP/H12 -MBP pair. The prepared MBP satisfies the requirements for chemical stability, handling properties, and cytotoxicity testing. PMID- 29282877 TI - Multifunctional Shape-Memory Polymer Foams with Bio-inspired Antimicrobials. AB - Despite a number of clinically available hemostats, uncontrolled bleeding is the primary cause of trauma-related death. Shape-memory polymer (SMP) foams have a number of desirable properties for use as hemostats, including shape recovery to enable delivery into bleed sites, biocompatibility, and rapid blood clotting. To expand upon this material system, the current work aims to incorporate phenolic acids, which are honey-based antimicrobial agents, into SMP foams. We showed that cinnamic acid (CA) can be utilized as a monomer in SMP synthesis to provide foams with comparable pore structure and retained cytocompatibility. The addition of CA enabled tuning of thermal and shape-memory properties within clinically relevant ranges. Furthermore, the modified foams demonstrated initial and sustained antimicrobial effects against gram-positive and gram-negative bacteria. These multifunctional scaffolds demonstrate potential for use as hemostats to improve upon current hemorrhage treatments and provide a new tool in tuning the biological and material properties of SMP foams. PMID- 29282878 TI - Is food refusal in autistic children related to TAS2R38 genotype? AB - : Several studies suggest that atypical eating behaviors, in particular food selectivity, are more frequent in children with autism spectrum disorder (ASD). A link between bitter taste perception, namely PROP/PTC sensitivity and food preferences is known in healthy children. The aim of this study is to investigate whether genetic variants of the TAS2R38 taste receptor responsible for different bitter sensitivity could affect foods preferences and consequently food refusal in ASD children. We recruited 43 children with ASD and 41 with normotypic development (TD) with or without food selectivity, aged between 2 and 11 years. Children were characterized for bitter sensitivity by means of PROP strips and FACS analysis and genotyped for TAS2R38 polymorphisms. Food selectivity was assessed by a validated food preference questionnaire filled by parents. A statistically significant correlation between PROP sensitivity and food refusal was observed. Furthermore, a prevalence of the PAV-sensitive haplotype compared to the AVI-insensitive one was seen in ASD children with food selectivity. In agreement with the initial hypothesis the results show that food refusal in ASD children is mediated by bitter taste sensitivity thus suggesting that the bitter sensitivity test may be used as a device to orientate tailored food proposals for the practical management of food selectivity in ASD. Autism Res 2018, 11: 531 538. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A variation of the gene TAS2R38, associated with bitter taste sensitivity, can cause a different perception of some foods. In particular, some children are hypersensitive to bitterness and show a more restricted repertoire of accepted foods. We evaluate bitter sensitivity in ASD children with or without food selectivity, through a simple bitter taste test with edible strips. The results show that food refusal in ASD children can be mediated by bitter taste sensitivity thus suggesting that the bitter sensitivity test may be used as a device to orientate tailored food proposals for the practical management of food selectivity in ASD. PMID- 29282879 TI - A Modularly Designable Vesicle for Sequentially Multiple Loading. AB - The vesicle is one of the most intriguing platforms for drug delivery, which is believed to improve drug efficacy. In the past few decades, a great deal of materials have been explored to make vesicles, including lipids, block copolymers, dendrons, erythrocyte membranes, and even DNA. Other than shape and size control, most efforts are focused on achieving certain functions, for example, an abundance of stimuli-responsive features are introduced to vesicles, which can be applied to controllable release, such as pH, redox, light, radiation, enzyme etc. Besides, crosslinking or pegylation is used to increase vesicles' stability and elongate circulation time. By incorporating affinity ligands, vesicles can further accumulate to diseased cells or tissues to achieve targeting properties. Recently, multidrug delivery is believed to show a synergy effect in cancer therapy and has become a new direction in this field. However, coloading hydrophilic-hydrophobic small molecules, oligonucleotides, and peptides in the same size- and shape-controlled vesicle through a stepwise manner with high efficiency is still challenging. Herein, a modularly designable vesicle is reported for sequential multiple loading based on frame-guided assembly, which is believed to be an outstanding platform for drug delivery in the future. PMID- 29282880 TI - Comparison of the restricted mean survival time with the hazard ratio in superiority trials with a time-to-event end point. AB - With the emergence of novel therapies exhibiting distinct mechanisms of action compared to traditional treatments, departure from the proportional hazard (PH) assumption in clinical trials with a time-to-event end point is increasingly common. In these situations, the hazard ratio may not be a valid statistical measurement of treatment effect, and the log-rank test may no longer be the most powerful statistical test. The restricted mean survival time (RMST) is an alternative robust and clinically interpretable summary measure that does not rely on the PH assumption. We conduct extensive simulations to evaluate the performance and operating characteristics of the RMST-based inference and against the hazard ratio-based inference, under various scenarios and design parameter setups. The log-rank test is generally a powerful test when there is evident separation favoring 1 treatment arm at most of the time points across the Kaplan Meier survival curves, but the performance of the RMST test is similar. Under non PH scenarios where late separation of survival curves is observed, the RMST-based test has better performance than the log-rank test when the truncation time is reasonably close to the tail of the observed curves. Furthermore, when flat survival tail (or low event rate) in the experimental arm is expected, selecting the minimum of the maximum observed event time as the truncation timepoint for the RMST is not recommended. In addition, we recommend the inclusion of analysis based on the RMST curve over the truncation time in clinical settings where there is suspicion of substantial departure from the PH assumption. PMID- 29282881 TI - The Negative Influence of Adiposity Extends to Intraindividual Variability in Cognitive Control Among Preadolescent Children. AB - OBJECTIVE: The objective of this study was to investigate the relationship between adiposity and cognition by using mean accuracy, mean reaction time, and intraindividual variability (IIV) among preadolescents. METHODS: Children 7 to 9 years old (N = 233, 133 females) underwent dual-energy x-ray absorptiometry and a maximal oxygen consumption test to assess whole-body adiposity and aerobic fitness relative to fat-free mass (VO2 FF), respectively. Attentional inhibition was assessed by using a modified flanker task. IIV was assessed as standard deviation of reaction time and as a coefficient of variation of reaction time (CVRT). Hierarchical linear regression analyses were performed to examine the relationships between adiposity and cognitive measures following the adjustment of significant demographic factors, intelligence quotient, and VO2 FF. RESULTS: Whole-body adiposity was negatively related to congruent trial mean accuracy and reaction time and to CVRT in both the congruent and incongruent trials. Differences in cognitive function across weight status were selectively evident for measures of IIV, such that children with overweight/obesity (>= 85th BMI-for age percentile) exhibited higher CVRT for both the congruent and incongruent trials. CONCLUSIONS: This work provides additional evidence linking childhood obesity to poorer cognitive function and includes novel data extending the negative influence of adiposity to measures of intraindividual response variability in cognitive control, even after accounting for intellectual abilities, aerobic fitness, and demographic factors. PMID- 29282882 TI - Recent progress in immune-based interventions to prevent HIV-1 transmission to children. AB - Globally, 150,000 new paediatric human immunodeficiency virus type 1 (HIV-1) infections occurred in 2015. There remain complex challenges to the global elimination of paediatric HIV-1 infection. Thus, for the global community to achieve elimination of new paediatric HIV-1 infections, innovative approaches need to be explored. Immune-based approaches to prevention of mother-to-child transmission (MTCT) may help fill some of the remaining gaps and provide new opportunities to achieve an AIDS-free generation. Immune-based interventions to prevent MTCT of HIV-1 may include paediatric HIV vaccines and passive immunization approaches. Recent discoveries providing evidence of robust immune responses to HIV in infants open new and exciting prospects for paediatric HIV vaccines. Moreover, successful vaccination of infants has a different set of requirements than vaccination of adults and may be easier to achieve. Proof-of concept has been established over the last two decades that passively administered HIV-1 Env-specific monoclonal antibody (mAbs) can prevent chimeric simian human immunodeficiency virus (SHIV) transmission to newborn nonhuman primates. There has been tremendous progress in isolating and characterizing broadly neutralizing antibodies to HIV, and clinical testing of these antibodies for treatment and prevention in both infants and adults is a major effort in the field. Immune-based interventions need to be actively explored as they can provide critically important tools to address persistent challenges in MTCT prevention. It is a pivotal time for the field with active discussions on the best strategy to further reduce HIV infection of infants and accomplish the World Health Organization Fast-Track 2030 goals to eliminate new paediatric HIV infections. PMID- 29282883 TI - Measuring polarization changes in the human outer retina with polarization sensitive optical coherence tomography. AB - Morphological changes in the outer retina such as drusen are established biomarkers to diagnose age-related macular degeneration. However, earlier diagnosis might be possible by taking advantage of more subtle changes that accompany tissues that bear polarization-altering properties. To test this hypothesis, we developed a method based on polarization-sensitive optical coherence tomography with which volumetric data sets of the macula were obtained from 10 young (<25 years) and 10 older (>54 years) subjects. All young subjects and 5 of the older subjects had retardance values induced by the retinal pigment epithelium and Bruch's membrane (RPE-BM) complex that were just above the noise floor measurement (5 degrees -13 degrees at 840 nm). In contrast, elevated retardance, up to 180 degrees , was observed in the other 5 older subjects. Analysis of the degree of polarization uniformity (DOPU) demonstrates that reduced DOPU (<0.4) in the RPE is associated with elevated double pass phase retardation (DPPR) below the RPE-BM complex, suggesting that the observed elevated DPPR in older subjects is the result of increased scattering or polarization scrambling. Collectively, our measurements show that the outer retina can undergo dramatic change in its polarization properties with age, and in some cases still retain its clinically normal appearance. PMID- 29282884 TI - A sticky wicket: Overexpression of integrin alpha 11 is sufficient for cardiac fibrosis. PMID- 29282885 TI - Effects of varying degrees of partial bladder outlet obstruction on urinary bladder function of rats: A novel link to inflammation, oxidative stress and hypoxia. AB - OBJECTIVES: The aim of the present study was to investigate the effects of different degrees of obstruction, and the roles of inflammation, oxidative stress, and hypoxia parameters on bladder function. METHODS: Thirty male Sprague Dawley rats were divided into 3 groups (n = 10 in each group): (i) sham-operated control; (ii) severe partial bladder outlet obstruction (PBOO); and (iii) moderate PBOO. Severe and moderate PBOO were induced by urethral ligation using 3 Fr and 4-Fr catheters, respectively, for 6 weeks. After 6 weeks, the in vitro contractile responses to carbachol, electrical field stimulation, ATP and KCl were measured in bladder strips. In addition, mRNA and protein expression of nuclear factor kappa B (NF-kappaB) hypoxia-inducible factor (HIF) and nuclear factor, erythroid 2-like 2 (Nrf2) in bladder were determined by real-time polymerase chain reaction and western blotting. Malondialdehyde (MDA) levels in bladder tissues were also determined. RESULTS: Rats in the severe PBOO group had the highest bladder weight. Detrusor strips from rats in the severe PBOO group exhibited 61%-82% smaller contractile responses to all four stimuli than those from the sham-operated group. Activity of NF-kappaB as an inflammatory marker was increased in the severe PBOO group, whereas HIF-1alpha and HIF-2beta protein levels were increased significantly in the moderate PBOO group. A master regulator of oxidative stress, Nrf2 expression was increased in all obstructed rats. MDA levels were higher in the severe PBOO group than in sham-operated group. CONCLUSION: The results of the present study reveal the importance of oxidative stress-induced NF-kappaB signaling in bladder dysfunction with severe obstruction. Altered HIF signaling may contribute to the functional impairment after PBOO. Novel and evolving therapies targeting oxidative and/or inflammatory pathways may be a reasonable strategy for the management of lower urinary tract symptoms or benign prostatic hyperplasia. PMID- 29282886 TI - Biorefining of platinum group metals from model waste solutions into catalytically active bimetallic nanoparticles. AB - Bacteria can fabricate platinum group metal (PGM) catalysts cheaply, a key consideration of industrial processes and waste decontaminations. Biorecovery of PGMs from wastes is promising but PGM leachates made from metallic scraps are acidic. A two-step biosynthesis 'pre-seeds' metallic deposits onto bacterial cells benignly; chemical reduction of subsequent metal from acidic solution via the seeds makes bioscaffolded nanoparticles (NPs). Cells of Escherichia coli were seeded using Pd(II) or Pt(IV) and exposed to a mixed Pd(II)/Pt(IV) model solution under H2 to make bimetallic catalyst. Its catalytic activity was assessed in the reduction of Cr(VI), with 2 wt% or 5 wt% preloading of Pd giving the best catalytic activity, while 1 wt% seeds gave a poorer catalyst. Use of Pt seeds gave less effective catalyst in the final bimetallic catalyst, attributed to fewer and larger initial seeds as shown by electron microscopy, which also showed a different pattern of Pd and Pt deposition. Bimetallic catalyst (using cells preloaded with 2 wt% Pd) was used in the hydrogenation of soybean oil which was enhanced by ~fourfold using the bimetallic catalyst made from a model waste solution as compared to 2 wt% Pd preloaded cells alone, with a similar selectivity to cis C18:1 product as found using a Pd-Al2 O3 commercial catalyst. PMID- 29282887 TI - Air-assisted dispersive liquid-liquid microextraction based on a new hydrophobic deep eutectic solvent for the preconcentration of benzophenone-type UV filters from aqueous samples. AB - Deep eutectic solvents are considered as new and green solvents that can be widely used in analytical chemistry such as microextraction. In the present work, a new dl-menthol-based hydrophobic deep eutectic solvent was synthesized and used as extraction solvents in an air-assisted dispersive liquid-liquid microextraction method for preconcentration and extraction of benzophenone-type UV filters from aqueous samples followed by high-performance liquid chromatography with diode array detection. In an experiment, the deep eutectic solvent formed by dl-menthol and decanoic acid was added to an aqueous solution containing the UV filters, and then the mixture was sucked up and injected five times by using a glass syringe, and a cloudy state was achieved. After extraction, the solution was centrifuged and the upper phase was subjected to high-performance liquid chromatography for analysis. Various parameters such as the type and volume of the deep eutectic solvent, number of pulling, and pushing cycles, solution pH and salt concentration were investigated and optimized. Under the optimum conditions, the developed method exhibited low limits of detection and limits of quantitation, good linearity, and precision. Finally, the proposed method was successfully applied to determine the benzophenone-type filters in environmental water samples with relative recoveries of 88.8-105.9%. PMID- 29282888 TI - Comprehensive study of interaction between biocompatible PEG-InP/ZnS QDs and bovine serum albumin. AB - Polyethylene glycol (PEG) surface modified biocompatible InP/ZnS quantum dots (QDs) act as a potential alternative for conventional carcinogenic cadmium-based quantum dots for in vivo and in vitro studies. Comprehensively, we studied the interaction between a model protein bovine serum albumin (BSA) and PEGylated toxic free InP/ZnS QDs using various spectroscopic tools such as absorption, fluorescence quenching, time resolved and synchronous fluorescence spectroscopic measurements. These studies principally show that tryptophan (Trp) residues of BSA have preferable binding affinity towards PEG-InP/ZnS QDs surface and a blue shift in Trp fluorescence emission is a signature of conformational changes in its hydrophobic microenvironment. Photoluminescence (PL) intensity of Trp is quenched by ground state complex formation (static quenching) at room temperature. However, InP/ZnS@BSA conjugates become unstable with increasing temperature and PL intensity of Trp is quenched via dynamic quenching by PEG InP/ZnS QDs. Experimentally determined thermodynamic parameters for these conjugates have shown spontaneity, entropy driven and exothermic nature of bio conjugation. The calculated binding affinity (n ? 1, Hill coefficient) suggest that the affinity of InP/ZnS QDs for a BSA protein is not dependent on whether or not other BSA proteins are already bound to the QD surface. Energy transfer efficiency (E), Trp residue to InP/ZnS QDs distances and energy transfer rate (kT ) were all obtained from FOrster resonance energy. PMID- 29282889 TI - Comparison of reverse hybridization and ompA sequencing methods applied on Chlamydia trachomatis strains from Tunisia. AB - Two techniques based on ompA amplification of Chlamydia trachomatis were compared, being reverse hybridization (RHM) and ompA sequencing (OSA), to investigate the concordance between them and to study the epidemiological relevance of each method. In addition, phylogenetic analysis was performed on the ompA sequences. One hundred and seven C. trachomatis positive samples from Tunisian patients and female sex workers were analyzed using both the RHM and ompA sequencing. The overall genovar distribution obtained with both techniques was very similar. The RHM identified nine genovars, being B, D, E, F, G, H, I, J and K, where B, I, J, and K were only found in mixed infections versus 7 types for the OSA being D, E, F, G, H, I, and K. The agreement between both typing techniques was 87.8%. Both methods showed that genovar E was the most predominant type. In 24.3% of the analyzed samples, mixed infections were detected. In 96.1% of these, the genovar identified by OSA was also detected using the RHM. OmpA sequencing allowed determination of six genovar types that could not be typed using RHM. The analyses of ompA nucleotide variation in the 107 clinical specimens detected ompA genovar variants with distinct ompA mutational patterns for types D2, G1, G2, and H1. In conclusion, RHM and OSA showed a high agreement in C. trachomatis genotyping results with each having their specific benefits. PMID- 29282891 TI - Identification of a novel gene pairs signature in the prognosis of gastric cancer. AB - Current prognostic signatures need to be improved in identifying high-risk patients of gastric cancer (GC). Thus, we aimed to develop a reliable prognostic signature that could assess the prognosis risk in GC patients. Two microarray datasets of GSE662254 (n = 300, training set) and GSE15459 (n = 192, test set) were included into analysis. Prognostic genes were screened to construct prognosis-related gene pairs (PRGPs). Then, a penalized Cox proportional hazards regression model identified seven PRGPs, which constructed a prognostic signature and divided patients into high- and low-risk groups according to the signature score. High-risk patients showed a poorer prognosis than low-risk patients in both the training set (hazard ratios [HR]: 6.086, 95% confidence interval [CI]: 4.341-8.533) and test set (1.773 [1.107-2.840]). The PRGPs signature also achieved a higher predictive accuracy (concordance index [C-index]: 0.872, 95% CI: 0.846-0.897) than two existing molecular signatures (0.706 [0.667-0.744] for a 11-gene signature and 0.684 [0.642-0.726] for a 24-lncRNA signature) and TNM stage (0.764 [0.715-0.814]). In conclusion, our study identified a novel gene pairs signature in the prognosis of GC. PMID- 29282890 TI - Efficacy, safety and pharmacokinetics of subcutaneous azacitidine in Chinese patients with higher risk myelodysplastic syndromes: Results from a multicenter, single-arm, open-label phase 2 study. AB - BACKGROUND: Azacitidine safety and efficacy were established in studies of mainly Caucasian patients. Differences in drug metabolism enzymes between Caucasian and East Asian populations prevent extrapolation of drug effects between these groups. This phase 2 study evaluated azacitidine safety, efficacy and pharmacokinetics in patients with higher-risk myelodysplastic syndromes (HR-MDS) in mainland China. METHODS: Patients aged >=18 years with HR-MDS were to receive subcutaneous azacitidine 75 mg/m2 /day for 7 days per 28-day cycle, for >=6 cycles. Pharmacokinetic blood samples were collected in cycle 1 predose on days 5 7, and postdose on day 7. Pharmacokinetic outcomes are descriptively compared with those of a historical North American cohort. RESULTS: Of 72 participants, 46 (64%) completed >=6 cycles. Response rate was 96%, driven primarily by stable disease (94%); one patient achieved complete remission. Hematologic improvement was attained by 53% of patients. Azacitidine mean plasma concentration versus time profiles were similar in shape for Chinese (n = 12) and North American (n = 45) patients. Maximum plasma concentration (Cmax ) was higher in Chinese patients; however, mean azacitidine exposure (1190 ng.h/mL) was similar to the North American cohort (1021 ng.h/mL). Most common grade 3-4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (69%) and neutropenia (67%). CONCLUSIONS: Azacitidine was safe and effective in Chinese patients with HR-MDS. Clinical outcomes were comparable to those for primarily Caucasian patients in the phase 3 AZA-001 study. Cmax differences between Chinese and North American patients were not associated with differences in TEAE frequency or severity. No initial azacitidine dose adjustment is required for Chinese patients with HR-MDS. PMID- 29282892 TI - Determination of major aromatic constituents in vanilla using an on-line supercritical fluid extraction coupled with supercritical fluid chromatography. AB - An on-line supercritical fluid extraction coupled with supercritical fluid chromatography method was developed for the determination of four major aromatic constituents in vanilla. The parameters of supercritical fluid extraction were systematically investigated using single factor optimization experiments and response surface methodology by a Box-Behnken design. The modifier ratio, split ratio, and the extraction temperature and pressure were the major parameters which have significant effects on the extraction. While the static extraction time, dynamic extraction time, and recycle time had little influence on the compounds with low polarity. Under the optimized conditions, the relative extraction efficiencies of all the constituents reached 89.0-95.1%. The limits of quantification were in the range of 1.123-4.747 MUg. The limits of detection were in the range of 0.3368-1.424 MUg. The recoveries of the four analytes were in the range of 76.1-88.9%. The relative standard deviations of intra- and interday precision ranged from 4.2 to 7.6%. Compared with other off-line methods, the present method obtained higher extraction yields for all four aromatic constituents. Finally, this method has been applied to the analysis of vanilla from different sources. On the basis of the results, the on-line supercritical fluid extraction-supercritical fluid chromatography method shows great promise in the analysis of aromatic constituents in natural products. PMID- 29282894 TI - Second primary acute lymphoblastic leukemia in adults: a SEER analysis of incidence and outcomes. AB - We conducted a surveillance epidemiology and end results (SEER)-based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (>=18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5-year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de-novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age >=65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5-year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10-1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58 1.95, P < 0.001). Hematological-1M sites had significantly higher SIRs (hematological-SIR 7.35; solid-SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5-year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer. PMID- 29282895 TI - Utility of an abbreviated version of the stanford-binet intelligence scales (5th ed.) in estimating 'full scale' IQ for young children with autism spectrum disorder. AB - : The fifth edition of the Stanford-Binet Intelligence scales allows 'full scale' IQ (FSIQ) to be estimated using an abridged version of the test-the abbreviated battery IQ (ABIQ). Set within a public early intervention team service, the current cross-sectional study investigated the utility of the ABIQ in estimating FSIQ for 40 children with autism spectrum disorder (ASD) aged 3-5 years. A strong ABIQ-FSIQ association was yielded (r = 0.89; r2 = 0.808) and the ABIQ did not over-estimate mean FSIQ above a clinically-relevant threshold; however, clinically significant over-estimation occurred in 17.5% of individual cases. While the findings provide support for the utility of the ABIQ in estimating FSIQ for young children with ASD, caution relating to the over-estimation of FSIQ is warranted. Careful clinical judgment-ideally based on examination of previous cognitive assessment results (if available), thorough interactional observations, and close multi-disciplinary consultation-is necessary to determine the applicability of the ABIQ to individual cases. Autism Res 2018, 11: 503-508. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We investigated the utility of a shortened version of the Stanford-Binet Intelligence Scales in estimating IQ for 40 young children with autism spectrum disorder (ASD). The findings provide qualified support for the instrument: acceptably accurate IQ estimation was achieved for most cases; but not so for a sizeable minority (17.5%). Careful clinical judgment is necessary to determine the applicability of the ABIQ to individual cases. PMID- 29282893 TI - Autophagy: novel applications of nonsteroidal anti-inflammatory drugs for primary cancer. AB - In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy. PMID- 29282896 TI - Rapid, controllable, one-pot and room-temperature aqueous synthesis of ZnO:Cu nanoparticles by pulsed UV laser and its application for photocatalytic degradation of methyl orange. AB - Zinc oxide (ZnO) and ZnO:Cu nanoparticles (NPs) were synthesized using a rapid, controllable, one-pot and room-temperature pulsed UV-laser assisted method. UV laser irradiation was used as an effective energy source in order to gain better control over the NPs size and morphology in aqueous media. Parameters effective in laser assisted synthesis of NPs such as irradiation time and laser shot repetition rate were optimized. Photoluminescence (PL) spectra of ZnO NPs showed a broad emission with two trap state peaks located at 442 and 485 nm related to electronic transition from zinc interstitial level (IZn ) to zinc vacancy level (VZn ) and electronic transition from conduction band to the oxygen vacancy level (VO ), respectively. For ZnO:Cu NPs, trap state emissions disappeared completely and a copper (Cu)-related emission appeared. PL intensity of Cu-related emission increased with the increase in concentration of Cu2+ , so that for molar ratio of Cu:Zn 2%, optimal value of PL intensity was obtained. The photocatalytic activity of Cu-doped ZnO revealed 50 and 100% increasement than that of undoped NPs under UV and visible irradiation, respectively. The enhanced photocatalytic activity could be attributed to smaller crystal size, as well as creation of impurity acceptor levels (T2 ) inside the ZnO energy band gap. PMID- 29282897 TI - Uniaxial strain of cultured mouse and rat cardiomyocyte strands slows conduction more when its axis is parallel to impulse propagation than when it is perpendicular. AB - AIM: Cardiac tissue deformation can modify tissue resistance, membrane capacitance and ion currents and hence cause arrhythmogenic slow conduction. Our aim was to investigate whether uniaxial strain causes different changes in conduction velocity (theta) when the principal strain axis is parallel vs perpendicular to impulse propagation. METHODS: Cardiomyocyte strands were cultured on stretchable custom microelectrode arrays, and theta was determined during steady-state pacing. Uniaxial strain (5%) with principal axis parallel (orthodromic) or perpendicular (paradromic) to propagation was applied for 1 minute and controlled by imaging a grid of markers. The results were analysed in terms of cable theory. RESULTS: Both types of strain induced immediate changes of theta upon application and release. In material coordinates, orthodromic strain decreased theta significantly more (P < .001) than paradromic strain (2.2 +/- 0.5% vs 1.0 +/- 0.2% in n = 8 mouse cardiomyocyte cultures, 2.3 +/- 0.4% vs 0.9 +/- 0.5% in n = 4 rat cardiomyocyte cultures, respectively). The larger effect of orthodromic strain can be explained by the increase in axial myoplasmic resistance, which is not altered by paradromic strain. Thus, changes in tissue resistance substantially contributed to the changes of theta during strain, in addition to other influences (eg stretch-activated channels). Besides these immediate effects, the application of strain also consistently initiated a slow progressive decrease in theta and a slow recovery of theta upon release. CONCLUSION: Changes in cardiac conduction velocity caused by acute stretch do not only depend on the magnitude of strain but also on its orientation relative to impulse propagation. This dependence is due to different effects on tissue resistance. PMID- 29282898 TI - A Perspective on Proteomics of Infectious Diseases. AB - Pneumonia, HIV/AIDS, tuberculosis, malaria and several other diseases caused by pathogens largely contribute to the enormous burden of infectious diseases. Over the last few decades, the impact of infectious diseases on a population has been drastic and remains a major health concern even today. Despite advances in science and technology in this era of health and development, there is a substantial knowledge gap in our understanding of the molecular basis of these infectious diseases. The availability of valuable genomic information for a number of pathogens and their hosts has improved our understanding of disease pathogenesis but has not always been useful in addressing important biological questions. The primary reason lies in the fact that genes do not best reflect the status of a cell. Proteins represent the functional molecules of a cell and are ultimately responsible for controlling most aspects of cellular function. Their existence as different isoforms owing to posttranslational modifications suggests that many proteins can be produced by the same gene. Furthermore, not all mRNAs are translated at all times justifying the need to develop additional tools to study proteins as separate molecular entities. Their presence or absence under disease conditions, varying levels, different forms, and functions need to be carefully studied to understand molecular alterations in response to a disease. Here, we describe the applications of proteomics-based approaches to study infectious diseases with a note on the objectives of the Human Proteome Project (HPP)-Human Infectious Diseases (HID) project under the HUPO's flagship program. PMID- 29282899 TI - Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: impact of clinical risk factors and sustained response. AB - The widespread use of high-dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long-term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first-line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long-term survivors. Achievement of complete response (CR) post-ASCT was associated with prolonged progression-free survival (PFS) in the whole cohort and with significantly superior overall survival (OS) in the subgroup of patients receiving novel agent based induction therapy. Landmark analyses performed at 1, 3, and 5 years post ASCT revealed that sustainment of any response had a highly significant influence on survival with no significant differences between sustained CR and sustained inferior responses. Furthermore, outcome was independently improved by administration of maintenance therapy. A subset of patients did experience long term survival >15 years. However, conditional survival demonstrated a persistent risk of myeloma-associated death and cumulative relative survival curves did not show development of a clear plateau, even in prognostically advantageous groups. In conclusion, in this large retrospective study, sustained response after first line ASCT was found to be a major prognostic factor for OS independent of depth of sustained response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions to prolong responses achieved post-ASCT may be essential to reach long-term survival, especially in the setting of persisting residual disease. PMID- 29282900 TI - Barriers to Effective Case Management for Disabled Patients on Hemodialysis. AB - The present study examined the performance level and its related factors on the process of case management for disabled patients on hemodialysis. Case management performance was evaluated at three stages: patient assessment, making a care plan, and monitoring/evaluation. Candidates for targeting the factors relating to performance included four dimensions: nursing care level, physical malfunction, cognitive malfunction, and barriers to service were used as patient factors; the period of case management for the patient and the knowledge of dialysis emerged as case manager factors; work load was included as an organizational factor; and community resources for these services and communication with surrounding persons were included as system factors. Self-administrated questionnaires were collected from 391 case managers of patients with hemodialysis certified long-term insurance. These were introduced by the dialysis facilities that a member of the Japanese Association of Dialysis Physicians belonged to. Case managers were asked questions about their management of each individual case. The results indicate, for example, that poor knowledge of dialysis is significantly related to poor patient assessment, inadequate development of a care plan, and lower levels of monitoring/evaluation. In addition, work overload and diabetic nephropathy as the primary kidney disease were also found to be significantly related to poor patient assessment. Increasing the opportunity for case managers to learn about dialysis may be needed for better case management performance in respect of the hemodialysis of disabled patients. PMID- 29282901 TI - AKT3 drives adenoid cystic carcinoma development in salivary glands. AB - Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K-AKT-mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients. PMID- 29282902 TI - Construction of green fluorescence protein mutant to monitor STT3B-dependent N glycosylation. AB - Oligosaccharyltransferases (OSTs) mediate the en bloc transfer of N-glycan intermediates onto the asparagine residue in glycosylation sequons (N-X-S/T, X?P). These enzymes are typically heteromeric complexes composed of several membrane-associated subunits, in which STT3 is highly conserved as a catalytic core. Metazoan organisms encode two STT3 genes (STT3A and STT3B) in their genome, resulting in the formation of at least two distinct OST isoforms consisting of shared subunits and complex specific subunits. The STT3A isoform of OST primarily glycosylates substrate polypeptides cotranslationally, whereas the STT3B isoform is involved in cotranslational and post-translocational glycosylation of sequons that are skipped by the STT3A isoform. Here, we describe mutant constructs of monomeric enhanced green fluorescent protein (mEGFP), which are susceptible to STT3B-dependent N-glycosylation. The endoplasmic reticulum-localized mEGFP (ER mEGFP) mutants contained an N-glycosylation sequon at their C-terminus and exhibited increased fluorescence in response to N-glycosylation. Isoform-specific glycosylation of the constructs was confirmed by using STT3A- or STT3B-knockout cell lines. Among the mutant constructs that we tested, the ER-mEGFP mutant containing the N185 -C186 -T187 sequon was the best substrate for the STT3B isoform in terms of glycosylation efficiency and fluorescence change. Our results suggest that the mutant ER-mEGFP is useful for monitoring STT3B-dependent post translocational N-glycosylation in cells of interest, such as those from putative patients with a congenital disorder of glycosylation. PMID- 29282903 TI - Nanocarrier-Mediated Photochemotherapy and Photoradiotherapy. AB - Photothermal therapy (PTT) and photodynamic therapy (PDT) both utilize light to induce a therapeutic effect. These therapies are rapidly gaining importance due to the noninvasiveness of light and the limited adverse effect associated with these treatments. However, most preclinical studies show that complete elimination of tumors is rarely observed. Combining PDT and PTT with chemotherapy or radiotherapy can improve the therapeutic outcome and simultaneously decrease side effects of these conventional treatments. Nanocarriers can help to facilitate such a combined treatment. Here, the most recent advancements in the field of photochemotherapy and photoradiotherapy, in which nanocarriers are employed, are reviewed. PMID- 29282905 TI - The World Journal of Men's Health Has Been Accepted for Coverage in Science Citation Index (SCI) Expanded. PMID- 29282904 TI - Human T cell responses to Dengue and Zika virus infection compared to Dengue/Zika coinfection. AB - INTRODUCTION: Zika virus (ZIKV) and dengue virus (DENV) co-circulated during latest outbreaks in Brazil, hence, it is important to evaluate the host cross reactive immune responses to these viruses. So far, little is known about human T cell responses to ZIKV and no reports detail adaptive immune responses during DENV/ZIKV coinfection. METHODS: Here, we studied T cells responses in well characterized groups of DENV, ZIKV, or DENV/ZIKV infected patients and DENV exposed healthy donors. We evaluated chemokine receptors expression and single/multifunctional frequencies of IFNgamma, TNF, and IL2-producing T cells during these infections. Even without antigenic stimulation, it was possible to detect chemokine receptors and IFNgamma, TNF, and IL2-producing T cells from all individuals by flow cytometry. Additionally, PBMCs' IFNgamma response to DENV NS1 protein and to polyclonal stimuli was evaluated by ELISPOT. RESULTS: DENV and ZIKV infections and DENV/ZIKV coinfections similarly induced expression of CCR5, CX3CR1, and CXCR3 on CD4 and CD8 T cells. DENV/ZIKV coinfection decreased the ability of CD4+ T cells to produce IFNgamma+ , TNF+ , TNF + IFNgamma+ , and TNF + IL2+ , compared to DENV and ZIKV infections. A higher magnitude of IFNgamma response to DENV NS1 was found in donors with a history of dengue infection, however, a hyporesponsiveness was found in acute DENV, ZIKV, or DENV/ZIKV infected patients, even previously infected with DENV. CONCLUSION: Therefore, we emphasize the potential impact of coinfection on the immune response from human hosts, mainly in areas where DENV and ZIKV cocirculate. PMID- 29282906 TI - What Can We Do for Chronic Scrotal Content Pain? AB - Chronic scrotal content pain remains one of the more challenging urological problems to manage. This is a frustrating disorder to diagnose and effectively treat for both the patient and clinician, as no universally accepted treatment guidelines exist. Many patients with this condition end up seeing physicians across many disciplines, further frustrating them. The pathogenesis is not clearly understood, and the treatment ultimately depends on the etiology of the problem. This article reviews the current understanding of chronic scrotal content pain, focusing on the diagnostic work-up and treatment options. PMID- 29282907 TI - Special Section Guest Editorial: Translational Biophotonics. AB - This guest editorial introduces the Special Section on Translational Biophotonics. PMID- 29282908 TI - [Interaction between SPAG6 and TAC1 proteins]. AB - Objective: To construct eukaryotic expression plasmids of the Tac1 gene and explore the interaction between TAC1 and sperm-associated antigen 6 (SPAG6). METHODS: RNA was extracted from the heart, liver, spleen, lung, kidney, brain, muscle, and testis of 10 Kunming male mice and, after reverse transcription into cDNA, the expression of Tac1 in the above tissues was observed by RT-PCR. Tac1/pEGFP-N2 and Tac1/pGADT7 recombinant plasmids were constructed and Tac1/pEGFP-N2 was transfected into CHO and COS-1 cells, followed by localization and detection of the protein expression of TAC1 by immunofluorescence staining and Western blot. The interaction between TAC1 and SPAG6 was determined by yeast two-hybrid experiment and Western blot. RESULTS: Tac1 was expressed mainly in the testis, brain and heart. The results of restriction enzyme digestion and sequencing indicated successful construction of the recombinant plasmids, with the restriction fragment length of 390 bp. TAC1 was localized in the whole body of the CHO cells when transfected alone, but expressed in the microtubule of the cells when cotransfected with SPAG6, with the molecular weight of 40 000. Yeast two-hybrid experiment showed the colonies of TAC1 and SPAG6 on the culture plate without Leu, Trp and His, both contained in the yeast fusion protein. CONCLUSIONS: The Tac1 recombinant plasmid was constructed successfully and the interaction between TAC1 and SPAG6 was confirmed with the plasmid. PMID- 29282909 TI - [Geinsten inhibits the proliferation of VCaP castration-resistant prostate cancer cells]. AB - Objective: To explore the inhibitory effect of genistein (GEN) on the proliferation of VCaP castration-resistant prostate cancer (CRPC) cells. METHODS: VCaP CRPC cells were treated with GEN at the concentrations of 0, 12.5, 25, 50, 100, and 200 MUmol/L for 24, 48, and 72 hours followed by determination of their proliferation by CCK-8 assay and their cycle by flow cytometry. The expression of Ki-67 in the cells was detected by immunocytochemistry and the levels of PSA, Cyclin D1, PCNA, and P53 determined by Western blot. RESULTS: After 72 hours of treatment with GEN at 12.5, 25, 50, 100, and 200 MUmol/L, the inhibition rates of the VCaP cells were (25.38+/-0.02)%, (31.14+/-0.29)%, (45.27+/-0.03)%, (52.19+/ 0.05)%, and (68.21+/-0.19)%, respectively, all significantly higher than in the 0 MUmol/L group ([10.08+/-0.02]%)(P<0.05). GEN caused the arrest of the VCaP cells in the G2/M phase (P<0.05) and inhibited the expression of Ki-67. The expressions of PSA, Cyclin D1, and PCNA were gradually down-regulated while that of P53 up regulated with the increased concentration of GEN (P<0.05). CONCLUSIONS: GEN inhibits the proliferation of VCaP CRPC cells by arresting the cell cycle with related protein expression changes. PMID- 29282910 TI - [Hypoxia promotes the growth and invasiveness of prostate cancer cells by down regulating miR-132 in vitro]. AB - Objective: To explore the expression of miR-132 in prostate cancer and its effects on the growth and invasiveness of prostate cancer cells and the influence of hypoxia on the level of miR-132 and biological behavior of prostate cancer cells. METHODS: Real time PCR was used to measure the expression level of miR-132 in the prostate cancer tissue, analyze its relationship with the clinical stage and Gleason score of prostate cancer, and determine the influence of hypoxia on the miR-132 level in the human prostate cancer PC3 cell line in vitro. Sulfor hodamine B chromatometry and Matrigel invasion assay were employed to detect the effects of hypoxia and miR-132 mimic plasmid transfection on the viability and invasiveness of PC3 cells in vitro. RESULTS: The miR-132 level in the prostate cancer was significantly declined to 52.38% (in T1-T2 stages) and 21.59% (in T3 T4 stages) of that in the cancer-adjacent tissue (both P<0.01). In hypoxia, the expression of miR-132 was significantly decreased in the PC3 cells (P<0.01). After 48 and 72 hours of transfection with miR-132 mimic plasmid, the viability of the PC3 cells was markedly reduced (P<0.05 or P<0.01), and their invasiveness decreased by 57.5% after 48 hours (P<0.01). However, there was no significant difference in the viability or invasiveness of the PC3 cells transfected with miR 132 mimic plasmid between normoxia and hypoxia. CONCLUSIONS: The reduced expression of miR-132 is closely related to the clinical stage and Gleason score of prostate cancer. Hypoxia increases the viability and invasiveness of prostate cancer cells in vitro by down-regulating the expression of miR-132 and consequently may promote the growth and metastasis of prostate cancer. PMID- 29282911 TI - [Aging-related change of erectile function and the expression of SIRT1]. AB - Objective: To explore aging-related changes in erectile function and the expressions of SIRT1 and other relevant factors in rats. METHODS: We divided 40 male SD rats into four age groups of equal number: 2-month-old (2 mo), 8-month old (8 mo), 14-month-old (14 mo), and 20-month-old (20 mo), measured the intracavernous pressure (ICP), mean arterial pressure (MAP), and ICP/MAP ratio by electrostimulation of the cavernous nerve, evaluated fibrosis in the corpus cavernosum by Masson's trichrome staining, detected the expressions of SIRT1, P53, and FOXO3a by Western blot, and determined the levels of NO and cGMP using the NO/cGMP kit. RESULTS: Both the ICP/MAP ratio and the cGMP level were elevated with aging, reaching the peak at 8 months and then gradually decreased. Masson staining showed an aging-related increase of collagen fibers in the corpus cavernosum.The expression of SIRT1 was reduced while those of P53 and FOXO3a increased with aging. CONCLUSIONS: Aging-related erectile dysfunction may be attributed to the reduced activity of the NO/cGMP pathway, apoptosis and oxidative stress, and SIRT1 may play a role in aging-related erectile dysfunction. PMID- 29282912 TI - [Expression of long noncoding RNA LINC01358 in prostate cancer and its effect on the proliferation and migration of prostate cancer cells]. AB - Objective: To explore the expression of long noncoding RNA (lncRNA) LINC01358 in prostate cancer (PCa) and its effect on the proliferation and migration of PCa cells. METHODS: The lncRNA array was used to screen differentially expressed lncRNAs in PCa and the corresponding carcinoma-adjacent normal tissues from 3 patients. The expressions of LINC01358 in the primary PCa, metastatic PCa, and carcinoma-adjacent tissues were compared using the PCa dataset of the Memorial Sloan Kettering Cancer Center (MSKCC). The data obtained were validated by determining the expression of LINC01358 in the PCa and carcinoma-adjacent tissues of another 10 patients by quantitative real time PCR (qRT-PCR). The effects of lncRNA LINC01358 on the proliferation of DU145 cells and migration of PCa cells were detected by MTT and Transwell assay, respectively. RESULTS: Totally, 79 differentially expressed lncRNAs in the lncRNA array, 36 highly and the other 43 lowly expressed in the PCa tissue. LINC01358 was up-regulated in the cancerous tissue. According to the MSKCC data, the LINC01358 expression was markedly higher in metastatic PCa (5.81+/-0.19, n = 19) and primary PCa (5.47+/-0.04, n = 131) than in the PCa-adjacent tissue (5.15+/-0.07, n = 29) and significantly correlated with postoperative biochemical relapse of the malignancy (P<0.05). qRT PCR indicated a remarkably higher expression of LINC01358 in the PCa than in the carcinoma-adjacent tissue (6.02+/-1.12 vs 3.21+/-0.21, P<0.05). Transfection of the DU145 cells with siRNA significantly decreased the level of LINC01358 and inhibited the proliferation and migration of the PCa cells. CONCLUSIONS: LINC01358 is highly expressed in the PCa tissue and knockdown of LINC01358 may inhibit the proliferation and migration of PCa cells. LncRNA LINC01358 may be involved in the development and progression of PCa and become an index for the early diagnosis as well as a new target for the gene therapy of the malignancy. PMID- 29282913 TI - [Hypogonadism and the quality of life in male patients with type-2 diabetes mellitus]. AB - Objective: To compare the level of testosterone between type-2 diabetes mellitus (T2DM) patients and healthy controls and to investigate the status of hypogonadism and the influence of hypopgonadism on the quality of life. METHODS: We collected serum total testosterone (TT), free testosterone (FT), sex hormone binding globulin (SHBG), and other clinical data from 166 T2DM patients aged over 30 years and 186 age-matched healthy controls. We investigated the quality of life (QoL) of the two groups of subjects using the questionnaires of Androgen Deficiency in Aging Males (ADAM), Aging Male Symptoms (AMS), 36-Item Short-Form Health Survey (SF-36), and Special Quality of Life for Diabetes Mellitus (DSQL). RESULTS: The level of calculated FT (cFT) was remarkably lower in the T2DM patients than in the healthy controls (P<0.05), but no statistically significant differences were observed between the two groups in the levels of TT, bio available testosterone (Bio-T), and SHBG. The T2DM males with hypogonadism showed significant differences from those without in age, height, systolic blood pressure, and creatinine (P<0.05). Based on the criteria of cFT <0.3 nmol/L and AMS score >=27, the incidence rate of hypogonadism was 51.81% in the T2DM patients, 31.58% in the 30-39 yr group, 32.50% in the 40-49 yr group, 50% in the 50-59 yr group, 69.23% in the 60-69 yr group, and 77.27% in the >=70 yr group, elevated by 77.4% with the increase of 10 years of age (OR = 1.774, P<0.001). The AMS score was significantly correlated with the scores of DSQL (r = 0.557, P<0.001) and SF-36 (r = -0.739, P<0.001) in the T2DM patients. CONCLUSIONS: T2DM patients have lower levels of cFT than healthy men, accompanied with a higher incidence of hypogonadism. Age is a main risk factor of hypogonadism. Severer testosterone deficiency symptoms are associated with lower scores of QoL in T2DM males. PMID- 29282914 TI - [Level of serum inhibin B for predicting the results of testicular sperm extraction in azoospermia patients]. AB - Objective: To investigate the value of serum inhibin B (InhB) in predicting the results of testicular sperm extraction (TESE) in patients with azoospermia. METHODS: This study included 191 cases of obstructive azoospermia (OA), 360 cases of nonobstructive azoospermia (NOA), and 100 male controls with normal semen parameters. According to whether sperm was found in TESE, the NOA patients were divided into a sperm-absence group (TESE-, n=127) and a sperm-presence group (TESE+, n=233). Blood samples were collected from the subjects between 8:00 and 10:00 am for measurement of the levels of serum InhB. The specificity and sensitivity of serum InhB predicting TESE outcome were analyzed with receiver operating characteristics curve (ROC). RESULTS: The serum InhB level was significantly lower in the TESE- group ([19.7+/-34.8] pg/ml) than in the OA ([106.8+/-66.2] pg/ml), TESE+ ([98.2+/-62.4] pg/ml) and normal control group ([108.3+/-65.0] pg/ml) (P<0.01), but there were no statistically significant differences among the latter three groups (P>0.05). Analysis of ROC showed that the best cut-off value of serum InhB was 19.1 pg/ml. Under the cut-off value, AUCROC was 0.88, specificity 84.2%, sensitivity 90.1%, and accuracy 88.1%. CONCLUSIONS: The serum InhB level is a good and non-invasively obtained index of spermatogenesis and should be measured for predicting the results of TESE. PMID- 29282915 TI - [Pathologic features of the epididymis in patients with epididymal obstructive azoospermia: Observation of 11 cases]. AB - Objective: To search for potential therapeutic targets for epididymal obstructive azoospermia (EOA) secondary to epididymal infection by observing the pathologic features and analyzing the possible pathophysiologic mechanisms of the disease. METHODS: Eleven 28-53 years old infertile men with the history of epididymal infection were enrolled in this study, all diagnosed with azoospermia by routine semen examination and centrifugation. EOA was confirmed by further examinations of reproductive hormones and seminal plasma biochemical markers and scrotal ultrasonography, followed by surgical exploration and observation of the pathological characteristics of the epididymis. RESULTS: The gross epididymal specimen showed fluid accumulation in the epididymal tube to be the main pathologic feature. Under the microscope, the epididymal duct lumen was structurally intact but distended and with no sperm. Most of the cases revealed no inflammatory cell invasion in the wall of the duct. A small number of the patients with a longer course of disease exhibited cell infiltration in the lumen, hyperblastosis and glassy degeneration of the interstitial fibers, and scattered infiltration of lymphocytes and acidocytes in addition to expansion of the epididymal duct. CONCLUSIONS: EOA secondary to epididymal infection is pathologically characterized mainly by fluid accumulation in the epididymal duct, and its pathogenesis remains to be further studied. PMID- 29282916 TI - [Gene expression profiling of peripheral blood mononuclear cells in patients with secondary syphilis]. AB - Objective: To analyze the gene expression profiling characteristics of peripheral blood mononuclear cells (PBMCs) from patients with secondary syphilis, and gain an insight into the host molecular immune mechanisms involved in Treponema pallidum infection. METHODS: Using genome-based high-throughput Illumina sequencing technology, we comprehensively determined the transcriptional difference in PBMCs from 4 secondary syphilis patients and 4 healthy controls, followed by real time PCR to validate the results of Illumina sequencing. RESULTS: Totally, 78 differentially expressed genes were found in the PBMCs of the secondary syphilis patients, among which 16 were associated with the immune system. Significant upregulation was observed in the expressions of pro inflammatory cytokines and related receptors, such as TNF receptor super-family member 17 (TNFRSF17), IL-17C, IL-21, IL-31 receptor A (IL-31RA), chemokine C-X-C motif ligand 10 (CXCL10), and chemokine (C-C motif) ligand 1 (CCL1), as well as the transcripts for the CD4+ T lymphocytes activation markers CD38, Fc-mediated phagocytosis receptors (FcgammaR1A, FcgammaR3B), and complement (C2, SERPING1). CONCLUSIONS: Systemic innate and adaptive immune effecter molecules are involved in the host clearance mechanism of secondary syphilis. PMID- 29282917 TI - [Effects of Yishen Shengjing Capsules on semen quality and gonadal hormone levels in rats with dibutyl phthalate-induced reproductive function injury]. AB - Objective: To study the possible pathogenesis of infertility caused by dibutyl phthalate (DBP) and investigate the effects of Yishen Shengjing Capsules (YSC, kidney-tonifying and essence-producing capsules) on DBP-induced reproductive function injury and its possible action mechanisms in male Wistar rats. METHODS: Models of DBP-induced reproductive function injury were made in 80 male Wistar rats and another 20 were used as blank controls. After modeling, the model rats were randomly divided into a model control, a high-dose YSC, a medium-dose YSC, and a low-dose YSC group. Four weeks after intervention, all the animals were sacrified for observation of the histomorphologic changes in the testis under the light microscope, measurement of sperm concentration, motility and abnormality, and determination of the levels of serum testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by radioimmunoassay. RESULTS: Compared with the blank controls, the model rats showed obvious pathological changes in testicular histomorphology, significantly decreased sperm concentration and motility, increased sperm abnormality, reduced contents of serum T and LH, and elevated the level of serum FSH (P<0.01). After 4 weeks of medication, the animals of the high-, medium-, and low-dose YSC groups, in comparison with the model controls, exhibited different degrees of recovery from testicular histomorphological damage, remarkably increased sperm concentration and motility, decreased sperm abnormality, elevated levels of serum T and LH, and reduced content of serum FSH (P<0.01). There were statistically significant differences in all the parameters above between the high-dose YSC and medium- and low-dose YSC groups (P<0.01). CONCLUSIONS: DBP reduces sperm motility and concentration, increases sperm abnormality, causes damage to the morphological structure of the rat testis, decreases the contents of serum T and LH, and elevates the level of the serum FSH. Yishen Shengjing Capsules can improve DBP induced productive function injury, increase sperm motility and concentration, decrease sperm abnormality, elevate the level of serum T and LH, reduce the content of serum FSH, improve the morphological structure of the testis, and thus promote the reproductive function of the male rat. PMID- 29282918 TI - [Cynomorium songaricum improves sperm count and motility and serum testosterone level and promotes proliferation of undifferentiated spermatogonia in oligoasthenospermia rats]. AB - Objective: To investigate the effects of cynomorium songaricum (CS) decoction on the testis weight, serum testosterone level, and sperm parameters of rats with oligoasthenospermia (OAS), explore its action mechanism of improving the proliferation of undifferentiated spermatogonial cells, and provide some experimental and theoretical evidence for the development of new Chinese drugs for OAS. METHODS: Thirty 8-week-old male SD rats were randomly divided into five groups of equal number: blank control, model control, high-dose CS, medium-dose CS, and low-dose CS. OAS models were established by intraperitoneal injection of cyclophosphamide and, a month later, treated intragastrically with normal saline or CS at 2, 1, and 0.5 g per kg of the body weight per day, all for 4 weeks. Then, the testes of the animals were harvested to obtain the testicular weight, sperm concentration and motility, and the level of serum testosterone (T), detect the expressions of the transcription factor 1 (Oct4), Thy-1 cell surface antigen (Thy1), promyelocytic leukemia zinc finger (PLZF), KIT proto-oncogene receptor tyrosine kinase (C-kit) and glial cell-derived neurotrophic factor (GDNF) in the testis tissue of the rats in the low-dose CS group by real-time PCR. RESULTS: The testis weights in the blank control, model control, high-dose CS, medium-dose CS, and low-dose CS groups were (1.52+/-0.06), (1.55+/-0.06), (1.43+/-0.30), (1.35+/ 0.40) and (1.34+/-0.04) g, respectively, not significantly different in the blank and model controls from those in the CS groups (P>0.05). The visual field sperm count per 10 HP was significantly increased in the high-, medium-, and low-dose CS groups (202+/-20, 196+/-5 and 216+/-25) as compared with the blank and model controls (200+/-15 and 134+/-30) (P<0.05). The mRNA expressions of the Oct4, Thy1, PLZF and GDNF genes were remarkably higher in the low-dose CS group than in the controls (P<0.05), but that of the C-kit gene showed no significant difference from the latter (P>0.05). The visual field sperm motility per 10 HP was markedly increased in the blank control ([52.1+/-5.5]%), model control ([38.1+/-2.5]%), high-dose CS ([59.1+/-9.5]%), medium-dose CS ([58.7+/-9.5]%), and low-dose CS ([49.6+/-1.0]%) groups, and so was the level of serum testosterone ([190+/-87.5], [82.5+/-25.8], [229+/-75.6], [331+/-86.7] and [185+/ 82.4] mmol/L), both remarkably higher in the CS groups than in the model controls (P<0.05) but with no statistically significant difference between the CS groups and the blank controls (P>0.05). CONCLUSIONS: CS can significantly improve sperm concentration, sperm motility and serum T level in OAS rats, probably by inducing the expression of GDNF in the rat Sertoli cells, promoting the proliferation of undifferentiated spermatogonial cells, and enhancing spermatogenesis. PMID- 29282920 TI - [Influence of holmium laser and thulium laser enucleation of the prostate on erectile function]. AB - In recent years, holmium laser enucleation of the prostate (HoLEP) and thulium laser enucleation of the prostate (ThuLEP) have been widely used in the treatment of benign prostatic hyperplasia (BPH) because of their significant clinical effects, high safety, and low incidence of complications. With the improvement of living standards, BPH patients care about not only the improvement of lower urinary-tract symptoms (LUTS) secondary to BPH but also that of sexual function, especially erectile function, after treatment. However, there are comparatively few studies about the effects of HoLEP and ThuLEP on erectile function and relevant opinions are quite controversial. Most studies reported that HoLEP and ThuLEP did not impair erectile function, but some showed that a few patients experienced a decrease of erectile function after operation. Before surgery, urologists should explain clearly to the patients the potential impact on sexual function, as mental factors may also induce erectile dysfunction. This study presents an overview of recent studies about the infuence of HoLEP and ThuLEP on erectile function. PMID- 29282919 TI - [ICSI with testicular or epididymal sperm for patients with obstructive azoospermia: A systematic review]. AB - Objective: To assess the effects of testicular sperm and epididymal sperm on the outcomes of ICSI for patients with obstructive azoospermia. METHODS: We searched PubMed, MEDLINE, EMBASE, Cochrane, CNKI, VIP, CBM, and Wanfang Database up to December 2015 for published literature relevant to ICSI with testicular or epididymal sperm for obstructive azoospermia patients. According to the inclusion and exclusion criteria, two reviewers independently conducted literature screening, data extraction and quality assessment of the included trials, followed by meta-analysis with the RevMan 5.3 software. RESULTS: A total of 14 studies were identified, involving 1 278 patients and 1 553 ICSI cycles. ICSI with epididymal sperm exhibited a significantly higher fertilization rate than that with testicular sperm (RR = 1.08, 95% CI 1.05-1.11, P<0.01). No statistically significant differences were observed between the epididymal and testicular sperm groups in the rates of cleavage (RR = 1.04, 95% CI 0.99-1.10, P = 0.13), good-quality embryo (RR = 1.01, 95% CI 0.93-1.09,P = 0.85), implantation (RR = 1.14, 95% CI 0.75-1.73, P = 0.55), clinical pregnancy (RR = 1.14, 95% CI 0.98-1.31, P = 0.08), and miscarriage (RR = 0.86, 95% CI 0.53-1.39,P = 0.54). CONCLUSIONS: ICSI with epididymal sperm yields a markedly higher fertilization rate than that with testicular sperm, but has no statistically significant differences from the latter in the rates of cleavage, good-quality embryo, implantation, clinical pregnancy, and miscarriage in the treatment of obstructive azoospermia. PMID- 29282921 TI - [Urethroplasty for male urethral stricture: Application and outcomes]. AB - Urethroplasty is now the optimal option for the treatment of male urethral stricture. The rapid development of tissue substitution techniques over the past decades provides a great possibility of achieving good long-term outcomes of urethroplasty. Necessary techniques required for urethroplasty, such as those to present the position, length and severity of the stricture and precisely evaluate the quality of the transplanted tissue, are critical for the success of surgery. This review focuses on the application and outcomes of adoptable uretheroplasty for male urethral strictures in different anatomical positions. PMID- 29282922 TI - [Surgical treatment of femoral intertrochanteric fractures]. PMID- 29282923 TI - [Comparison of clinical effect betweem reconstructing femoral calcar and proximal femoral antirotation nail for the treatment of unstable femoral intertrochanteric fracture in elderly patients]. AB - OBJECTIVE: To compare the clinical effects of two methods of internal fixation in treating unstable femoral intertrochanteric fractures in elderly patients. METHODS: From August 2009 to August 2014, 68 elderly patients with unstable femoral intertrochanteric fracture treated with locking proximal femur plate and auxiliary short reconstructed plate (reconstructing calcar group) and proximal femoral nail antirotation (PFNA group) with clinical course from 1 to 3 days were retrospectively analyzed. In reconstructing calcar group, there were 30 patients including 8 males and 22 females, aged from 63 to 85 years old with an average of (73.41+/-5.12) years old, the fractures were classified to type AO 31-A2.2 in 12 cases, A2.3 in 11 cases, A3.3 in 7 cases according to AO/ASIF classification. In PFNA group, there were 38 patients including 10 males and 28 females, aged from 65 to 90 years old with an average of (74.26+/-4.53) years old, the fractures were classified to type AO 31-A2.2 in 15 cases, A2.3 in 13 cases, A3.3 in 10 cases. All fracture were caused by injury, leading pain and swelling. Femoral intertrochanteric fracture was confirmed by X ray films. The data of each group were collected for statistical analysis on the following aspects: the incision length, operation time, blood loss volume, postoperative partial weight bearing standing time, clinical healing time of fracture, postoperative complications, and hip functional score of Harris. RESULTS: All incisions were healed at stage I. In the aspect of postoperative complications, there were 1 case of screw blade cutting and 1 case of deep venous thrombosis in PFNA group; there was 1 case of deep venous thrombosis in the reconstructing calcar group (chi2=0.000, P=1.000). Patients were followed up from 20 to 24 months with an average of 22.5 months. There were no significant in postoperative partial weight bearing standing time, postoperative complications, hip functional score of Harris between two group. There were significant in the incision length, operation time, blood loss volume, clinical healing time of fracture. In the incision length, operation time, blood loss volume, clinical healing time of fracture, the PFNA group was significantly differently less than that of the reconstructing calcar group (P<0.001). In the clinical healing time of fracture, the PFNA group was significantly differently less than that of the reconstructing calcar group (P<0.05). CONCLUSIONS: For the treatment of unstable femoral intertrochanteric fractures in elderly patients, reconstructing calcar and PFNA are both effective, and proximal femoral intramedullary nails may be the best choice, which can be simpler operation, smaller incision and less healing time. PMID- 29282924 TI - [Clinical observation of improved proximal femoral locking plate in treating osteoporotic intertrochanteric fractures]. AB - OBJECTIVE: To investigate the effects of proximal femoral locking plate (PFP) in treating osteoporotic intertrochanteric fractures and to analyze the failure cases. METHODS: Totally 32 patients with osteoporotic intertrochanteric fractures of Evans I and II were treated with improved locking PFP, including 17 males and 15 females with an average age of 77.3 years old ranging from 70 to 86 years old. After operation, according to Harris hip scores, the hip function and therapeutic effects were evaluated. RESULTS: The observed 32 patients' operative time was (60.5+/-15.7) min, intraoperative blood loss was (128.8+/-73.6) ml;perioperative blood transfusion was (224.0+/-72.7) ml. Hospitalization time was from 14 to 20 d with an average of 17.2 d. All patients were followed up from 6 to 18 months with an average of 14.1 months. The fracture healing time was from 3 to 6 months with an average of 3.1 months. One patient occurred internal fixation loosening and screw backward, 4 cases occurred urinary tract infection, 1 patient died of cardiovascular disease for 6 months postoperative, 2 patients died of a stroke for 1 year postoperative. No incision deep infection, peri internal fixation fractures, lower extremity deep venous thrombosis, internal fixation breakage, nonunion, severe coax vara and coax valgus occurred. The final Harris score was 89.74+/-6.84, the result was excellent in 10 cases, good in 16 cases, fair in 4 cases, and poor in 2 cases. CONCLUSIONS: Locking PFP can provide relative stable fixation to proximal end of osteoporotic femoral fractures, which is a good choice for the treatment of intertrochanteric fractures. It could provide stableness of fractures and bone union, even avoid screws loose or slide out. PMID- 29282925 TI - [Imaging characteristics and the operative effect of the irreducible femoral intertrochanteric fractures]. AB - OBJECTIVE: To analyse the imaging characteristics of the irreducible femoral intertrochanteric fracture and evaluate the operative effect of closed poking reduction and intramedullary nail fixation. METHODS: From December 2011 to October 2015, 28 patients with irreducible femoral intertrochanteric fracture were treated by closed poking reduction and intramedullary nail fixation including 12 males and 16 females with an average age of 72 years old ranging from 58 to 89 years old. According to AO classification: 5 cases were type A2.1, 10 cases were type A2.2, 13 cases were type A3.3. The postoperative complications were observed, and the postoperative X ray were used to evaluate the fracture healing, and the Harris score was used to evaluate the hip joint function. RESULTS: Preoperative X rays for determine irreducible femoral intertrochanteric fracture was difficult, but dimensional CT had characteristic performance: the fracture near the end displaced forward rotation. Operation time was 45 to 100 minutes with an average of 65 minutes. Intraoperative bleeding was 80 to 300 ml with an average of 160 ml. Two cases died within 3 months after operation, 26 patients were followed up for 6 to 12 months with an average of 8.4 months. Fracture healing time was 12 to 16 weeks with an average of 13.6 weeks. Two cases occurred inversion deformity.There were no wound infection, nonunion and fracture fixation failure. Hip Harris score was 86.7+/-5.3 at the last follow up, the result was excellent in 14 cases, good in 12 cases. CONCLUSIONS: Dimensional CT can be very good to predict the fracture of the irreducible femoral intertrochanteric fracture. Closed poking reduction and intramedullary nail fixation for the treatment of the irreducible femoral intertrochanteric fracture has satisfactory clinical result. PMID- 29282926 TI - [Clinical characteristics and treatment of AO/OTA A2.3 intertrochanteric fractures with posterior coronal plane fractures]. AB - OBJECTIVE: To explore the characteristics, the operative techniques and effect of AO/OTA A2.3 intertrochanteric fractures with posterior coronal fractures. METHODS: From January 2011 to January 2014, 33 patients suffered from AO/OTA A2.3 intertrochanteric fractures with posterior coronal fractures were treated with proximal femoral anti rotation nail, included 15 males and 18 females, with an average age of (73.1+/-8.2) years old ranged from 61 to 92 years old. According to AO/OTA classification, all cases were type A2.3 fracture. All cases were closed fractures and treated with limited open reduction and internal fixation. The postoperative hip function was evaluated by Harris score. RESULTS: One case was died at 19 days after operation, 32 cases were followed up from 9 to 24 months with an average of (16.3+/-5.1) months. Bone union time was from 6 to 9 months with an average of (7.2+/-1.5) months according to X rays. At the final followed up, Harris scores were 76 to 95 points with an average of (85.3+/-5.6) points;13 cases were classified as excellent, 16 as good, and 3 as fair. CONCLUSIONS: AO/OTA A2.3 intertrochanteric fracture with posterior coronal fractures is a special type and unstable, it's difficult to reset. It needs to be fixed with proximal femoral anti rotation nail by limited open reduction. It is necessary that postoperative rehabilitation should be chosen individually. PMID- 29282927 TI - [Comparison of the effect of total hip arthroplasty through mini invasive direct anterior approach during learning curve period and posterolateral approach for the treatment of femoral head necrosis]. AB - OBJECTIVE: To compare clinical results of treating femoral head necrosis staged Ficat III or IV with total hip arthroplasty (THA) between mini invasive direct anterior approach (DAA) and posterolateral approach. METHODS: From January 2008 to December 2009, 48 patients with femoral head necrosis staged Ficat III or IV treated with THA were compared and analyzed. There were 21 patients in mini invasive direct anterior approach group including 11 males and 10 females with an average age of (65.2+/-4.3) years old;while there were 27 patients in posterolateral approach group including 16 males and 11 females with an average age of (63.6+/-4.0) years old. Operative time, blood loss during operation, bed rest time and complications of two groups were observed and compared. Acetabular abduction and stem shaft angle were measured 1 month after operation and compared between two groups. Postoperative Harris Hip scoring and VAS scoring were applied for evaluating hip function and pain at 1, 6 months and 5 years after operation respectively. RESULTS: All patients were followed up for 48 to 73 months with an average of 60.4 months. Operative time, blood loss in DAA group was (78.30+/ 5.08) min, (351.30+/-21.46) ml, respectively, in posterolateral approach group was (75.61+/-10.60) min, (362.20+/-26.15) ml, and no significant differences between two groups. Bed rest time in DAA group was (2.05+/-1.10) days, better than that of in posterolateral approach which was (3.30+/-1.35) days. No significant differences were found between two groups in acetabular abduction and stem shaft angle at 1 month after operation. There was no significant differences between two groups in HHS and VAS score at 1, 6 months and 5 years after operation. There was 1 case with injury of ascending branch of the lateral circumflex femoral artery, 1 case with great trochanter fracture and 1 case with superficial infection in DAA group, 1 case with dislocation in posterolateral group. No prosthesis loosening occurred in two groups. CONCLUSIONS: Both DAA and posterolateral approach are effective in treating femoral head necrosis staged Ficat III or IV, and could obtain excellent outcomes. However, DAA seemed to has disadvantage in learing curve compared posteriolateral approach in complex cases. PMID- 29282928 TI - [Incidence and anatomic distribution of venous thromboembolism following primary total hip and knee arthroplasty: a prospective observational study]. AB - OBJECTIVE: To analyze the incidence and anatomic distribution of venous thrombosis after total hip and knee arthroplasty by using the data of the patients with primary total hip and knee replacement. METHODS: From December 2013 to December 2014, total hip and knee arthroplasty were performed in 1 686 patients, of which 928 were THA and 758 were TKA. Before and after discharge, all patients were routinely performed double lower limb vein color Doppler ultrasound, the conventional use of anti fibrinolytic drugs, postoperative anticoagulation for 14 d. The types and distribution of thrombosis after operation were statistical analysis. RESULTS: Among 928 cases of primary total hip arthroplasty, there were 30 cases of thrombosis, 27 cases of isolated muscle vein thrombosis, followed by the involvement of the anterior or posterior tibial vein thrombosis, no central thrombosis. Among 758 cases of primary total knee arthroplasty, there were 87 cases of thrombosis, 81 cases peripheral thrombosis, 4 cases of thrombus of center type, the remaining 2 cases for mixed thrombus;74 patients with thrombosis involving a single vein, 65 cases involved muscle vein, 4 cases of femoral vein, 3 cases of posterior tibial vein, 2 cases of superficial vein; 13 cases of thrombosis involving multiple veins, involving muscle vein, posterior tibial veins, the peroneal veins and popliteal vein in 2 or 3 branches. The comparison results showed that the incidence of thrombosis after total knee arthroplasty was higher, the difference was statistically significant (P<0.001), and more prone to central thrombosis and multiple venous involvement. CONCLUSIONS: The incidence of thrombosis in patients with primary hip and knee replacement is low, and the incidence and anatomic distribution of the patients with primary hip and knee replacement are different. PMID- 29282929 TI - [Comparison of different modes of using tranexamic acid administration on reducing hidden blood loss in total hip arthroplasty]. AB - OBJECTIVE: To compare the clinical efficacy of using tranexamic acid in different ways to reduce the hidden blood loss in patients who receiving total hip arthroplasty (THA). METHODS: Totally 68 patients with osteonecrosis of the femeral head treated by total hip arthroplasty in our hospital from February 2010 to July 2015 were randomly divided into the intravenous drip group (group A) and the topical application group (group B). In group A, there were 19 males and 15 females, with an average age of (62.0+/-6.4) years old, preoperative average hemoglobin was (121.30+/-8.15) g/L, average Hematocrit was (0.470+/-0.039) L/L. In group B, there were 18 males and 16 females, with an average age of (64.0+/ 7.5) years old, preoperative average hemoglobin was (125.28+/-9.37) g/L, average Hematocrit was (0.490+/-0.041) L/L. The operation incision were performed through the posterolateral approach and the normal operation mode, biological prosthesis was selected. Through different ways the tranexamic acid was used to control of intraoperative and postoperative bleeding. Tranexamic acid was intra articular injection as a dose of 10 mg/kg 10 min to patient before anesthesia in intravenous drip group. In topic group, 3 g of tranexamic acid was dissolved in 120 ml saline and divided into three equal parts, then two pieces of gauze were immersed in 40 ml tranexamic acid solution. One gauze with 40 ml tranexamic acid was used to soak the acetabulum for 5 minutes after the acetabular preparation, another gauze was inserted in the femoral canal for 5 minutes after femoral canal broach preparation. The remaining 40 ml tranexamic acid fluid was injected into the hip joint after fascia closure. Place the drainage tube and clip it for 3 hours. Hemoglobin (Hb) and Hematocrit (Hct) were recorded at 72 hours after operation. The total blood loss, dominant blood loss, and hidden blood loss were calculated. RESULTS: In group A, postoperative hemoglobin difference before and after operation was (32.34+/-7.42) g/L, total blood loss was (833.6+/-81.4) ml, the hidden blood loss was (276.3+/-57.9) ml, red blood cell volume was (10.1+/ 1.4) L/L;In group B, hemoglobin difference before and after operation was (28.2+/ 6.1) g/L, total blood loss was (792.5+/-61.8) ml, the hidden blood loss was (297.5+/-50.3) ml, red blood cell volume was (9.2+/-1.2) L/L. There was no statistical significance about those aspect (P>0.05). Compared of blood coagulation function between two groups, in group A: PT (12.78+/-2.03) s, APTT (34.27+/-3.91) s, INR (32.34+/-7.42); and in group B: PT (13.17+/-2.19) s, APTT (32.36+/-3.18) s, INR (28.24+/-6.14). There was no significant differences also (P>0.05). CONCLUSIONS: Compared with intravenous application, topical application of tranexamic acid could also effectively reduce total blood loss and hidden blood loss, postoperative blood transfusion rate in primary total hip arthroplasty, while does not increase the risk of DVT. PMID- 29282930 TI - [Short term clinical outcome of total hip arthroplasty for the treatment of Crowe IV congenital dysplasia of the hip in adults]. AB - OBJECTIVE: To evaluate the short term clinical effects and surgery methods of the total hip arthroplasty (THA)for the treatment of Crowe type IV congenital dysplasia of hip (CDH) in adults. METHODS: From March 2013 to March 2015, 20 patients (20 hips) with Crowe type IV CDH in adults were underwent THA, including 4 males and 16 females, with an average age of 52 years old ranged from 32 to 68 years old. All the cementless acetabular cups were placed at the original anatomic location. S-ROM prosthesis was adopted together with subtrochanteric transverse osteotomy in femoral side. All the patients were evaluated by using the Modified Harris Hip Score. Radiographic evaluations were made preoperatively and during follow up. RESULTS: The incisions were healed by first intention. There was no hip dislocation events and venous thrombosis occurred. All patients were followed up for 8 to 60 months with an average of 38.1 months. Postoperative X ray films showed all acetabular prosthesis were in true acetabulum. No nonunion and loosening were found in all patients. Harris score at final follow up improved from preoperative 50.90+/-9.35 to postoperative 90.25+/-3.16. The difference was statistically significant (P<0.05). There were 1 patient with femoral split fracture, 1 patient with nerve injury, 1 patient with heterotopic ossification of Brooker I. The hip function of all patients was good, the pain was disappeared. CONCLUSIONS: THA with S-ROM prosthesis and subtrochanteric osteotomy is an effective method for the treatment of Crowe type IV CDH in adults. The recent clinical curative effect is satisfied. PMID- 29282931 TI - [Treatment of distal femur nonunion with bone defect by less invasive stabilization system and fibular strut graft]. AB - OBJECTIVE: To evaluate the therapeutic effects of less invasive stabilization system distal femur (LISS-DF) combined with fibular struts graft for distal femur nonunions and bone defects. METHODS: A total of 12 patients with distal femur nonunion and bone defect were underwent revision operation with locked plating, plus a nonvascularized autologous fibular strut bone graft from June 2007 to September 2014, including 10 males and 2 females with an average age of (56.2+/ 14.1) years old ranging from 30 to 77 years old. The mean time from the initial trauma to the last revision operation was (16.4+/-5.5) months (ranged from 9 to 26 months). All cases were atrophic nonunions according to Weber-Cech classification and type B1 (bone loss) according to Paley classification. All patients were followed up and evaluated with clinical and imaging results. The KSS (American Knee Society Score) scores including knee clinical score and knee functional score were compared before and after the treatment. RESULTS: All patients were followed up from 12 to 17 months with an average of (13.7+/-1.9) months. All nonunions healed with an average time of (6.2+/-1.3) months (ranged from 4 to 8 months). The average range of movement (ROM) of the knee was improved from (67.1+/-29.6) degrees preoperatively to (102.5+/-13.6) degrees at the last follow up. KSS scores including knee pain, range of motion, clinical and functional score were significantly different before and after operation. No such complications as infection, hardware loosening or breakage occurred postoperatively. CONCLUSIONS: LIFF-DF fixation and autologous fibular strut bone graft facilitated the successful treatment of distal femur nonunions with bone defects. PMID- 29282932 TI - [Endobutton and cortical screw fixation for the treatment of distal tibiofibular syndesmosis separated]. AB - OBJECTIVE: To analyze the treatment effect of Endobutton plate cable system for the treatment of the distal tibiofibular syndesmosis injury. METHODS: Total 38 patients with tibiofibular syndesmosis separation treated by surgical operation from October 2011 to October 2013 were analyzed retrospectively. According to internal fixation, 38 cases were divided into two groups involving group A (cortical screw fixation) and group B (Endobutton plate cable system fixation). In group A, there were 26 patients including 16 males and 10 females with an average age of (37.90+/-4.67) years old ranging from 19 to 63 years old; 14 cases were on the left and 12 on the right;involving 8 cases of Weber-Denis type B, 18 cases of Weber-Denis type C; according to Lauge-Hanson typing, 9 cases of supination external rotation (SER), 10 cases of pronation abduction (PAB), 7 cases of pronation external rotation (PER). In group B, there were 12 cases including 7 males and 5 females, with an average age of (38.70+/-6.03) years old ranging from 20 to 55 years old;6 cases were on the left and 6 cases on the right;involving 4 cases of Weber-Denis type B and 8 cases of Weber-Denis; involving 7 cases of PER, 3 cases of SER, 2 cases of PAB. The operative time, intraoperative blood loss, surgery cost, hospital stay time, the wound healing, pain score at 1 month after operation, and the load time were recorded and evaluated. According to reviewing of X rays regulary, the healing of fracture were assessed, the function outcomes of ankle was evaluated according to the Ankle Hind Foot Scale of American Orthopaedic Foot and Ankle Society. RESULTS: All patients were followed up for 8 to 18 months with an average of 13.5 months. There were no statistical significance in intraoperative blood loss, hospital stay time, average load time and postoperative pain score at 1 month after operation between two groups (P>0.05). Duration of operation, the operative time were significantly shorter in cortical screw group;however, the average cost of hospitalization was significantly higher in Endobutton group. No significant differences were found between two groups in outcome of radiographic measurement. The X rays of 36 patients showed well healing of fracture, normal mortise and no distal tibiofibular syndesmosis separation. AOFAS score at the final follow up in group A was (87.50+/-8.67) scores, 18 cases got excellent result, 4 cases were good, and 4 cases were fair. AOFAS score at the final follow up in group B was (86.23+/-7.42) scores, 7 cases obtained excellent result, 4 cases were good and 1 case was fair; AOFAS score between two groups were no significant difference (P>0.05). CONCLUSIONS: Endobutton plate cable system is a dynamic capital equipment in treating the tibiofibular syndesmosis separation, it has a similar outcome compared with the screw, but without screw fractured and do not regular remove after operation. The patients could take the functional exercises earlier. PMID- 29282933 TI - [Treatment of Vancouver type B1 periprosthetic femoral fracture with locked plate and xenogenic bony plate]. AB - OBJECTIVE: To analyze the therapeutic effect of plate cable system and cortical strut bone graft in the prosthesis revision of the total hip arthroplasty for the treatment of Vancouver type B1 periprosthetic femoral fracture. METHODS: A total of 8 patients were selected from January 2006 to January 2013, including 6 males and 2 females, aged from 56 to 74 years old (62.52 years old on average). All the cases were treated by the long plate cable system and appropriate cortical strut bone graft. Harris score was used to evaluate the hip functions before and after the operation. Prosthesis stability and the bony union were assessed by the digital radiography. RESULTS: All the patients were followed up for 45 months on average ranging from 24 to 60 months after operation. All the fractures reached union, and there was no infection, stem loosening, nonunion and malunion. The Harris score was 28.45+/-5.78 before operation, which was improved to 83.46+/ 10.21 after operation. X ray showed that the prosthesis was stable, and the host bone and bone graft achieved bony union in 7 patients;and the other 1 patient need further operation of revision around the loose stem. CONCLUSIONS: The prosthesis revision of the total hip arthroplasty with the locking plate and cortical strut bone graft used for the Vancouver type B1 periprosthetic proximal femur fractures has the advantages of simple manipulation, less complications, good recovery of the hip function and can improve bone quality to provide favorable conditions for operation of revision. PMID- 29282935 TI - [Therapeutic effect and safety of microendoscopic discectomy versus conventional open discectomy for the treatment of lumbar disc herniation: a Meta analysis]. AB - OBJECTIVE: To conduct a meta analysis of studies comparing theapeutic effect and safety of microendoscopic discectomy to conventional open discectomy in the treatment of lumbar disc herniation in China. METHODS: A systematic literature retrieval was conducted in the Chinese Bio medicine Database, CNKI database, Chongqin VIP database and Wangfang database. The statistical analysis was performed using a RevMan 4.2 software. The comparison included excellent rate, operation times, blood loss, periods of bed rest and resuming daily activities, hospital stay or hospital stay after surgery, and complications of microendoscopic discectomy versus conventional open discectomy. RESULTS: The search yielded 20 reports, which included 2 957 cases treated by microendoscopic discectomy and 2 130 cases treated by conventional open discectomy. There were 12, 11, 7, 5, 4 and 4 reports which had comparison of operation times, blood loss, period of bed rest, periods of resuming daily activities, hospital stay and hospital stay after surgery respectively. Complications were mentioned in 10 reports. Compared to patients treated by open discectomy, patients treated by microendoscopic discectomy had a higher excellent rates [OR=1.29, 95%CI (1.03, 1.62)], less blood loss[OR=-63.67, 95%CI (-86.78, -40.55)], less period of bed rest[OR=-15.33, 95%CI (-17.76, -12.90)], less period of resumption of daily activities [OR=-24.41, 95%CI (-36.86, -11.96)], less hospital stay [OR=-5.00, 95%CI (-6.94, -3.06)] or hospital stay after surgery [OR=-7.47, 95%CI (-9.17, 5.77) respectively. However, incidence of complications and operation times were proved no significant different between microendoscopic discectomy and open discectomy. CONCLUSIONS: Microendoscopic discectomy and conventional open discectomy in treatment of lumbar disc herniation are both safe, effective; incidence of complications are nearly. Patients with lumbar disc herniation treated by microendoscopic discectomy have fewer blood loss, shorter periods of bed rest and hospital stay, and resume daily activities faster. Techniques are selected according to indications, microendoscopic discectomy should be carried out when conjunct indications occur. PMID- 29282934 TI - [Effect of lipid accumulation after spinal cord injury in autofluorescence intensity of injury site]. AB - OBJECTIVE: To investigate the relationship between lipid accumulation and autofluorescence intensity of injury site after spinal cord injury (SCI), and explore whether CuSO4 can eliminate autofluorescence in the injury site after SCI. METHODS: Thirty six Wild Type mice at age of 8 to 12 weeks (weight 18 to 24 g) were randomly divided into normal control group (n=4) and SCI group (n=32). Respectively, 8 mice of SCI group were sacrificed randomly at 1 week, 2 weeks, 4 weeks and 8 weeks after injury. Frozen sections of spinal cord tissue with injury site at the center were made to observe autofluorescence under green channel of fluorescence microscope (Specimens of normal control group were taken from the same segment of the spinal cord, and fixed with 4% paraformaldehyde solution). Oil Red O staining was applied to visualize the lipid accumulation in the injury site, and correlation between lipid accumulation and autofluorescence intensity was analyzed. Furthermore, sections were incubated with CuSO4 buffer to eliminate autofluorescence, and CuSO4 concentration and incubation time was optimized. RESULTS: No obvious autofluorescence or lipid staining was found in normal spinal cord tissue sections. By contrast, autofluorescence appeared in the injury site of spinal cord sections, and the intensity increased with passing time after injury. Oil Red O staining showed that lipid accumulated in the injury site with passing time after injury as well, and the correlation between lipid accumulation and autofluorescence intensity was positive. After incubation with CuSO4 buffer, the autofluorescence in the injury site was significantly reduced, especially after optimizing CuSO4 concentration and incubation time. CONCLUSIONS: Lipid accumulation may play an important role to determine the autofluorescence intensity of injury site after SCI, and the autofluorescence intensity can be used as a simple index for evaluating lipid peroxidation damage. Optimized method of using CuSO4 can significantly reduce the autofluorescence in the injury site after SCI, which will be beneficial to the application of immunofluorescence staining technique in the study of SCI. PMID- 29282936 TI - [Treatment of posterolateral tibial plateau fractures through an extended anterolateral approach]. AB - OBJECTIVE: To study the methods and therapeutic effects of posterolateral tibial plateau fractures with an extended anterolateral approach. METHODS: From January 2011 to December 2013, 15 patients with posterolateral tibial plateau fractures were treated by extended anterolateral approach, including 9 males and 6 females, with an average age of (38.4+/-7.7) years old ranging from 23 to 70 years old. Seven patients were on the left knees and 8 patients were on the right knees. The injury causes included traffic accidents in 6 cases, falling from height in 7 cases, and falling down when walking in 2 cases. The time from injury to operation was 2 to 14 days (means 5.6 days). RESULTS: All patients were followed up with an average of 19.7 months ranging from 12 to 30 months. All patients were followed with anteroposterior and lateral X ray and CT films, which showed anatomic reduction or near anatomic reduction. The follow up CT scan showed an anatomic reduction in 14 patients and step and gap measurement of 3 mm in 1 case. The average radiographic bony union time was 9.6 weeks (ranged from 8 to 14 weeks). There were no wound complications, nonunion, plate loosening or breakage, valgus knee deformity, or fracture redisplacement. No patients sustained neural or vascular injuries, with knee extension of (2.1+/-2.1) degrees and knee flexion of (120.6+/-18.9) degrees at the final follow up. The total Rasmussen score averaged (25.0+/-2.8) points, the result was excellent in 10 cases, good in 4 cases, fair in 1 case. CONCLUSIONS: The extended anterolateral approach has the advantage of allowing visualization of the posterolateral tibial plateau fragments, therefore facilitating its reduction. The approach also ensures safe and adequate posterior placement of a lateral buttress plate because the plate can be placed more posteriorly than can occur through an anterolateral approach. PMID- 29282937 TI - [Prevention and treatment of the related complications of tibial fractures bone defect by bone transport]. AB - OBJECTIVE: To explore the therapeutic methods for the prevention and treatment of tibial bone defect and bone transport related complications. METHODS: From January 2012 to June 2015, 38 cases of bone defect of tibia were treated by bone transport technique treatment, including 26 males and 12 females, with an average age of 49.0 years old ranging from 36 to 66 years old. All patients were open fractures. The length of bone defect of 38 patients was 4 to 9.6 cm with an average of 5.2 cm. The force line and bone carrying rate were adjusted in time after operation. Patients insisted on loading. RESULTS: All patients were followed up for 17 to 36 months with an average of 24 months. Among them, 19 patients got natural healing in involution end;the other 18 cases respectively got healing after accordion technology in 10 cases, auxiliary internal fixation of bone graft after corresponding processing in 8 cases, 1 patient for dottiness, pneumonia, the knee joint dislocation, diabetes, cerebral palsy sequela was difficult to care, patients' families urged amputation surgery, so the amputation processing. The time of moving the bone transport was 4 to 10 months with an average of 7.1 months. Move length was 5 to 11.6 cm with an average of 8.0 cm. According to tibial stem diagnostic criteria of Johner-Wruhs score, 11 cases were excellent, 18 cases were good, 6 cases were moderate and 3 cases were poor. In addition to 1 case of amputation, the remaining cases were cured, no infection recurrence, re fracture and so on. CONCLUSIONS: Bone transport method is an effective method for the treatment of bone defect of tibia, but the existence of many complications is to limit the clinical application of the main factors, including shifting when the distance is too long the long reprojected line offset (bone exposure), nail tract infection, pin loosening, subsidence of soft tissue, loss of function of knee and ankle joint, pull a callus is not long, the contact ends were nonunion. PMID- 29282938 TI - [Clinical research of vacuum sealing drainage combined with artificial dermis for the treatment of ankle and foot soft tissue defects]. AB - OBJECTIVE: To investigate the effect of vacuum sealing drainage (VSD) combined with artificial dermis for treatment of the ankle and foot soft tissue defects. METHODS: A total of 15 patients with skin and soft tissue defect of ankle and foot were treated from January 2011 to December 2013, including 10 males and 5 females, with an average age of 32.5 years old ranging from 3 to 55 years old, involving 8 cases by traffic accident, 2 cases by machine accident, 5 cases by crush injury;8 cases with soft tissue exposure, 2 cases with tendor exposure, 5 cases with bone exposure. VSD was used to cover the wounds and continuous negative pressure drainage after debridement, the wounds covered with artificial dermis after the second granulation tissue grew well, again VSD was used to cover the wounds and negative pressure suction was applied, after 7 to 14 days negative pressure closed drainage was removed, free skin graft was transplanted above the artificial dermis, sterile gauze was used to compression bandage. RESULTS: All cases were followed up for 3 to 14 months with an average of 6.5 months. Skin graft of 15 of patients survived after transplantation, artificial dermis graft interval was 7 to 14 days with an average of 9.5 days. There was no obvious scar hyperplasia and contracture, no obvious pigmentation, appearance and functional recovery. CONCLUSIONS: After the implantation of artificial dermis and traditional skin graft method need for 2 to 3 weeks, vacuum sealing drainage technique combined with artificial dermis in treatment of soft tissue defect of foot and ankle skin has advantages of simple operation, significantly shorten the time of the second phase of the skin, without flap to repair, little injury to donor skin area, wound healing quality high, clinical effect of satisfaction. PMID- 29282939 TI - [Treatment of the mid and distal segment humeral fractures through modified posterior approach]. AB - OBJECTIVE: To summarize clinical result of the modified posterior approach for the treatment of the mid and distal segment humeral fractures. METHODS: Between January 2006 and December 2010, 26 patients with the mid and distal segment humeral fractures were treated with the open reduction and plate fixation by the modified posterior approach including 17 males and 9 females with an average of (37.1+/-1.5) years old ranging from 24 to 50 years old. The time from humeral fractures to operation were from 8 hours to 6 days with an average of (3.3+/-0.6) d. The elbow function were assessed by Morrey-Bryan. RESULTS: There was no procedure related complications occurred. No neurologic injury and wound infection after operation occurred. All patients were followed up from 22 to 48 months with an average of (30.1+/-1.6) months. The humeral fractures were confirmed healing. The clinical results of Morrey and Bryan were excellent in 19 cases (94.6+/-1.8), good in 7 cases (86.5+/-1.2). CONCLUSIONS: The modified posterior approach avoided injury of triceps muscle and improved postoperative triceps function. The technique may be particularly useful in the treatment of the mid and distal segment humeral fractures. PMID- 29282940 TI - [Metastatic clear cell carcinoma of the patella: a case report]. PMID- 29282941 TI - [Research progress on positioning accuracy of acetabulum prosthesis]. AB - In order to prevent the dislocation of total hip arthroplasty (THA) and reduce the wear rate, the position of the acetabular component in THA is very important. However, due to the influence of many potential factors, the accurate implantation of the acetabular component in the operation is still a challenge. Lewinnek safety zone positioning the cup anteversion angle (15+/-10) degrees , abduction (40+/-10) degrees , has been regarded as acetabular prosthesis installation standards, in an attempt to reduce the risk of instability, but there are still reported a dislocation. Based on the Lewinnek safety zone, Ha proposed the use of acetabular anatomical landmarks. According to patient specific shape positioning the position of the acetabular component methods are used to determine the specificity of the target area, thereby reducing the impact of hip replacement, and to maintain a lower liner wear rate. Image navigation system can improve the positioning of acetabular cup, but it is affected by many factors, such as high cost, difficult operation and so on. PMID- 29282942 TI - [Research progress on total ankle replacement]. AB - Total ankle replacement (TAR) is considered as a treatment option for end stage ankle arthritis. This treatment was abandoned due to the early failure prosthesis in the past. However, with recently advancements in ankle prosthesis design and improved surgical techniques, TAR has made great progress and the indications are expanding. Many studies have shown acceptable mid term and long term results of TAR, and it is worth looking forward to the prospect. Advantages of TAR over arthrodesis include improvement in joint range of motion, better gait activity, and decreased incidence of adjacent joint arthritis. With the further development, TAR will be considered as gold standard for the treatment of end stage ankle arthritis instead of the ankle arthrodesis. However, there are still many problems of TAR need to be solved in this present stage of development, including higher economic costs, lower survival rate, and higher revision rate. Patients and surgeons should have confidence in TAR, also need to choose this treatment with careful consideration. PMID- 29282943 TI - [A new understanding of the diagnosis and treatment of knee osteoarthritis]. PMID- 29282944 TI - [Clinical observation of effectiveness in the treatment of senile knee osteoarthritis with the inactivation of myofascial trigger points---108 cases reports]. AB - OBJECTIVE: To study clinical treatment effects of inactivating myofascial trigger points with needling and muscle stretching for the treatment of knee osteoarthritis(OA). METHODS: Retrospective analyses were made to investigate the clinical data of pain clinic outpatient in our hospital from 2010 to 2014, and 108 patients with knee OA, including 35 males and 73 females, were treated with acupuncturing of myofascial trigger points and stretching of muscles and structure around knee. The puncturing of trigger points, and the back and forth movement of needle were required to elicit local twitch response of muscle. After acupuncture treatment, muscle stretch around the knee joint was performed by a therapist. All patients must do homework of self stretching exercise. The extent of stretching should be to gradually increased under a tolerable pain. The ROM and walking pain VAS scores were measured before and after whole therapy and were statistically analyzed during 1 year of follow up. RESULTS: All the patients were followed up, and 95 patients had no pain after 1 year. The VAS scores were improved from preoperative severe 7.6+/-0.5, moderate 4.9+/-0.7, to mild 1.9+/ 0.6 and painless 0.3+/-0.2. CONCLUSIONS: The walking pain of knee OA might be alleviated by the acupuncture and stretch to inactivate the myofascial trigger point. PMID- 29282945 TI - [A short term clinical study of fibular osteotomy for knee osteoarthritis]. AB - OBJECTIVE: To study clinical effects of fibular osteotomy for the treatment of knee osteoarthritis. METHODS: From January 2015, 12 patients (15 knees) with knee osteoarthritis were treated with fibular osteotomy. The main symptom was interval inside pain. All the patients were female with an average age of 61.3 years old. Early postoperative ambulation of joints was carried out after surgery, and the corresponding radiographic assessment before and after operations were performed with record. Finally, the following indicators were analyzed:VAS, KSS, HSS, respectively before, 2 days and 2 months after the operation. RESULTS: The average hospitalization time was (6.0+/-2.4) days, and the time of unilateral operation was (33.3+/-8.4) minutes without significant bleeding. There were no obvious complications such as wound infection, delayed healing and nerve damage. All the patients could walk around 1 day after operations with a chief complaint of the obvious reduction or disappear of the interval medial knee pain. The VAS score, HSS score and KSS clinical score were significantly improved 2 days after surgery compared to the scores before operation. These above scores and functional score were significantly improved 2 months after operation compared to the scores before operation. X ray films of the weight bearing knees were taken 2 days after surgery, showing increased height of medial joint space to some extent compared to that before operation. CONCLUSIONS: A fibular osteotomy has been proved to significantly reduce the postoperative pain and facilitate the good recovery of joint function with the advantages of simple surgical procedures and slighttrauma. Therefore, it is an effective method for the treatment of knee osteoarthritis with varus deformity. PMID- 29282946 TI - [Measurements and analyses of full length weight bearing X ray radiographs of bilateral lower extremities in patients with knee osteoarthritis]. AB - OBJECTIVE: To reveal the characteristics of anatomical and mechanical axes in lower extremities by analyzing full length weight bearing X ray radiographsin patients with knee osteoarthritis(OA). METHODS: From June 2015 to May 2016, the lower extremity CTA was performed for 20 patients with vascular diseases, and these patients without OA were assigned to the normal group. There were 7 males and 13 females, ranging in age from 24 to 72 years old with an average age of 63.2 years old. The weight bearing full length X ray radiographs of the lower extremities were taken for 53 patients with knee OA, and these patients were assigned to the OA group. There were 10 males and 43 females, ranging in age from 52 to 80 years old with an average age of 64.7 years old. The osteoarthritis group were divided into two groups:varus knee group and valgus knee group. The femoral shaft double condyle angle(F), tibial shaft plateau angle(T), joint gap angle(JS), femoral tibial angle(FT), hip knee ankle angle(HKA), knee physiological valgus angle(KPV), and femoral offset were measured. The SPSS 21.0 was used to analyze the statistical data. RESULTS: The mean F were (79.9+/-2.3) degrees and (81.4+/-3.5) degrees , T were (93.8+/-3.7) degrees and (94.6+/-2.7) degrees , JS were (1.7+/-1.0) degrees and (2.1+/-2.5) degrees , FT were (175.4+/ 4.0) degrees and (178.1+/-6.3) degrees , HKA were (181.4+/-4.1) degrees and (184.3+/-6.9) degrees , KPV were (6.0+/-1.0) degrees and (6.2+/-1.5) degrees , offset were (38.5+/-6.5) mm and (38.1+/-9.2) mm in the normal and OA group respectively. There was a significant difference in the KPV between varus knee and valgus knee groups(t=2.956, P=0.005), and the greater mean KPV was found in varus knee. Positive correlations were found between KPV and age(r=0.241, P=0.016), as well as between KPV and offset (r=0.946, P=0.000). CONCLUSIONS: The average KPV in patients with knee OA was 6.2 degrees in the present study, and the KPVs were also positively correlated with the patients' ages and the femoral offsets. The average KPV in the varus knee was greater than that of the valgus knee, and the difference was about 1 degrees . The changes of mechanical parameters of lower limb may be one of the risks for developing knee OA. Analyzing the full length weight bearing X ray radiographs of the lower extremities preoperatively will be helpful to determine a individualized osteotomy method for patients. PMID- 29282947 TI - [Medium and long term results of high tibial osteotomy for the treatment of knee joint osteoarthritis]. AB - OBJECTIVE: To analyze the medium and long term results of high tibial osteotomy(HTO) for the treatment of knee joint osteoarthritis(OA). METHODS: From January 2001 to December 2005, 45 patients(63 knees)with medial compartment OA were treated with HTO, including 10 males (15 knees) and 35 females (48 knees), ranging in age from 45 to 64 years old with an average of (55.76+/-5.54) years old. Preoperative normal anteroposterior and lateral X ray films of weight bearing knee were conducted, with an accurate measurement of the femoral tibial angle(FTA), and the mass of lateral tibial osteotomy was determined according to the preoperative FTA. Routine HTO was performed after epidural anesthesia. Most patients were treated with middle part fibulae osteotomy, and some patients were treated with the release of proximal tibiofibular joints. The functional exercise no weight bearing ambulation and weight bearing exercise began on the second day after operation 2 weeks after operation and 8 to 10 weeks after operation respectively. All the cases should be examined with X ray postoperatively on the second day, 8 to 10 weeks, 6 months, 1 year after operation and once a year. The VAS, HSS and KSS were used to evaluate knee pain, deformity, function, and range of motion preoperatively, 3 to 5 years postoperatively, 10 to 14 years postoperatively in all the patients. RESULTS: Forty three patients (61 knees) were followed up for more than 10 years. All the incisions were healed at the first stage. The bone healing was achieved 8 to 10 weeks after operation. The knee joint was evaluated according to the HSS standard 10 to 14 years after operation, and the average score was 76.24+/-5.27. Twenty seven patients got an excellent result, 25 good, 7 fair and 2 poor. The VAS, HSS and KSS scores of postoperative 3 to 5 years and 10 to 14 years were better than those of before operation. There were no obvious differences of scores between postoperative 3 to 5 years and postoperative 10 to 14 years. CONCLUSIONS: The long term curative effect of high tibial osteotomy in the treatment of knee OA(medial compartment arthritis) is satisfied, if the indications for surgical treatment are appropriate, and postoperative active exercises are performed. PMID- 29282948 TI - [Case control study on ultrasound guided microtraumatic treatment of acute subacromial bursitis]. AB - OBJECTIVE: To evaluate the efficacy of ultrasound guided microtraumatic treatment of acute subacromial bursitis. METHODS: The patients with shoulder pain from June 2012 to March 2014 were treated with musculoskeletal bone ultrasound examination. A total of 120 patients were diagnosed with acute subacromial bursitis, who were randomized divided into two groups:US guided injection group(ultrasound group) and palpation guided injection group(closed group). The patients in each group were injected with a mixture of 3.5 ml Betamethasone compound lidocaine mixture and 2.5 ml Sodium hyaluronate into the subacromial bursa. The outcome measures were the visual analog scale(VAS) for analyzing pain degree, the night rest pain and Constant-Murley score for detecting shoulder function, rate of secondary injection, and comprehensive effect. The VAS, the night rest pain and CMS were evaluated before, 1 day, 1 week, and 1 month after the injection. RESULTS: After treatment, the shoulder pain and function were improved. One day and 1 week after the injection, the VAS between the two groups were compared. The pain improvement in ultrasonic group was better than in the traditional group, and the difference was statistically significant(P<0.05). In the two groups, the night rest pain was relieved after treatment, and 1 day after the injection, the night rest pain in the ultrasonic group was significantly lower than that in the traditional group(P<0.05). One day, 1 week and 1 mouth after the injection, the CMS between the two groups were compared, and the improvement of CMS in the ultrasonic group was significantly better than that in the traditional group(P<0.05). The patient number with secondary injection in the ultrasonic group was 13 cases, which was significantly less than that in the closed group 45 cases(P<0.05). The recovery number of ultrasonic group was significantly better than that of the traditional group(P<0.05). CONCLUSIONS: The ultrasound guided microtraumatic treatment of acute subacromial bursitis worked faster than traditional closed therapy. The short term curative effect and the comprehensive curative effect is better than the traditional closed treatment. The US guided subacromial injection technique is effective in guiding the needle into the subacromial bursa in patients with acute subacromial bursitis. PMID- 29282949 TI - [Arthroscopic reduction and utilization of Suture Bridge tech reconstructing footprint area structure for the treatment of anterior cruciate ligament avulsion fracture]. AB - OBJECTIVE: To evaluate the preliminary curative effect of arthroscopic reduction and utilization of Suture Bridge tech reconstructing footprint area structure for anterior cruciate ligament avulsion fracture. METHODS: From March 2010 to September 2012, 6 patients suffered anterior cruciate ligament avulsion fracture were treated with arthroscopic Suture bridge fixation for anterior cruciate ligament tibial side footprint reconstruction. There were 2 males and 4 females, ranging in age from 14 to 52 years old. There were 2 cases of type III and 4 cases of type IV displaced fractures classified by Meyers-McKeever-Zaricznyj. Preoperative ADT and Lachman tests were positive. RESULTS: All the patients was follow up more than 2 years. Postoperative ADT and Lachman tests were negative without limitation of knee extension. Postoperative X ray and MRI showed that displaced fracture with a good reduction and union, recovered normal shapeness of ACL. The postoperative Lysholm and IKDC scores at different time points(3 months, 1 year, 2 years after operation) improved significantly comparing with preoperative, and the differences were statistically significant (P<0.01). CONCLUSIONS: Suture Bridge tech reconstructing footprint area structure for ACL avulsion fracture is an effective and safe method, especially for adolescent patients with unclosed epiphysis and comminuted avulsion fracture. PMID- 29282950 TI - [Case control study on the biodegradable barbed sutures in total knee arthroplasty]. AB - OBJECTIVE: To compare with the clinical outcomes of barbed sutures and routine sutures in total knee arthroplasty. METHODS: From September 2013 to June 2014, total 116 patients with knee osteoarthritis (OA) who underwent primary unilateral total knee arthroplasty (TKA) were enrolled in the series. There were 68 patients in the test group (T), including 58 females and 10 males, with an average age of (65.26+/-8.50) years old. There were 48 patients in the control group (C), including 41 females and 7 males, with an average age of (64.43+/-10.08) years old. Absorbable barbed sutures were selected in test group for capsule continuous closure, while coated absorbable VICRYL Plus Sutures were used in control group for continuous hemstick closure. Coated VICRYL Plus Sutures and skin stapler were selected for subcutaneous and skin closures respectively in both groups. Closure time, wound associated complications and postoperative hospital stay as well as special events were recorded, compared and analyzed. RESULTS: The mean closure time in test group was shorter, which were(21.65+/-4.11) minutes (ranged, 15 to 32 minutes), comparing with (31.83+/-4.55) minutes in control group (ranged, 22 to 45 minutes), with a significant difference(P=0.000). No significant differences were found in wound associated complications (chi2=1.451, P=0.161) or mean postoperative hospital stay (T:5.68+/-1.36, C:5.46+/-1.29, P=0.407). However, ratio of complications was higher in test group (21/68 versus 10/48), and the most commom complication was continuous effusion. CONCLUSIONS: Barbed suture can significantly shorten the closure time, but leads to a higher incidence of wound complications, therefore the method requires more professional technique and more cautious postoperative observation. PMID- 29282951 TI - [MRI diagnosis of osteochondral lesions in the talus and the dynamic follow up analysis after osteochondral transplantation]. AB - OBJECTIVE: To investigate MRI findings of osteochondral lesions in the talus;to evaluate the value of MRI in diagnosing and determining the stage of osteochondral lesions;to analyze the follow up clinical value of MRI in osteochondral transplantation of autologous bone. METHODS: A total of 79 patients from February 2013 to March 2015 had been retrospectively analyzed. All the patients were treated in our hospital. The ankle arthroscopy results were used as the reference standard, and the accuracy of MRI in diagnosis and Hepple staging had been investigated. Fifteen patients with cartilage transplantation of autologous bone were followed up with MRI examination and evaluation of cartilage repair score(MOCART) after one year. The values of MRI in the postoperative follow up were analyzed. RESULTS: Hepple staging of 79 patients was shown as follows:7 cases of stage I, 12 cases of stage II, 24 cases of stage III, 16 cases of stage IV, and 20 cases of stage V. Ankle arthroscopy grading of 59 patients in this group(in addition of 20 cases of stage V):2 cases of grade A, 2 cases of grade B, 4 cases of grade C, 14 cases of grade D, 22 cases of grade E, and 15 cases of grade F. The accuracy rate of MRI in determining Hepple V was set at 100%, and Hepple stage I corresponds to the arthroscopic A, B, C stage, stage II corresponds to D stage, stage III corresponds to E stage, stage IV corresponds to F stage. The accuracy rate of MRI in determining Hepple stage I to IV was 87.5%, 85.7%, 95.4% and 93.3% respectively. After cartilage transplantation of autologous bone, MRI of 15 patients showed cartilage surface in transplanted area was smooth, bone healed well, and the surrounding edema disappeared. The MOCART was 30 to 80 scores with an average score 59.0+/-15.6;9 cases of these 15 patients were(9/15, 60%) higher than 60 score. CONCLUSIONS: MRI plays a significant role in clinical diagnosis and staging of the talus osteochondral injury. As a method of long term follow up after cartilage transplantation, MRI can well evaluate the rapair of the postoperative osteochondral injury. PMID- 29282952 TI - [Randomized controlled trials of needle knife therapy combined with rotation traction manipulation for the treatment of cervical spondylotic radiculopathy]. AB - OBJECTIVE: To compare the therapeutic effects between needle knife therapy combined with rotation traction manipulation and rotation traction manipulation for the treatment of cervical spondylotic radiculopathy. METHODS: From November 2013 to June 2015, 80 patients with cervical spondylotic radiculopathy meeting the inclusion criteria were divided into two groups randomly:the control group in which 39 patients were treated with rotation traction manipulation, and the treatment group in which 41 patients were treated with needle knife combined with rotation traction manipulation. The patients in the control group were treated once dayly for 2 weeks, which was 1 course. The patients in the treatment group were treated with needle knife firstly once a week for 2 weeks, which was 1 course;then were treated with the same methods as the patients in the control group. The symptoms, signs score and the therapeutic effects of the two groups before and after treatment were observed. RESULTS: After treatment, symptoms and signs scores declined in both groups(P<0.05). The results of the treatment group were better than effects in the control group(P<0.05). In the treatment group, 19 patients got an excellent result, 16 good, 5 fair and 1 bad;while in the control group, 10 patients got an excellent result, 10 good, 16 fair and 3 bad;the results of the treatment group were better than the results of the control group(P<0.01). CONCLUSIONS: Needle knife combined with rotation traction manipulation is an effective method for the treatment of cervical spondylotic radiculopathy, which is better than using manipulation method simply. Needle knife therapy has follow advantages:improving local blood circulation, reducing local content of pain substance, increasing production of substances resisting pain, opening channels and collaterals, and make body reaching new static and dynamic balance on the new foundation. PMID- 29282953 TI - [Case control study on clinical effects of arthroscopic treatment for stenosing tenosynovitis of radial styloid process]. AB - OBJECTIVE: To investigate the clinical effect of arthroscopic treatment for stenosing tenosynovitis of radial styloid process. METHODS: Ninety nine patients diagnosed as stenosing tenosynovitis of radial styloid process from August, 2009 to July, 2013 were divided into three groups, including arthroscopic treatment group(32 cases), traditional operation group (34 cases) and local blocking therapy group(33 cases). Ache, tenderness, swollen situations and movement degrees of wrist joints and thumbs were observed before treatment and one week and one month after treatment. Total effective rates were calculated. RESULTS: Pain score of the wrist and thumb in activity state was lower in arthroscopic treatment group and traditional operation group than that in local blocking therapy group one week and one month after treatment(P=0.044, 0.039). Local pain score was lower in arthroscopic treatment group and traditional operation group than that in local blocking therapy group one month after treatment(P=0.017). The total symptom score was lower in arthroscopic treatment group and traditional operation group than that in local blocking therapy group one week and one month after treatment(P=0.007, 0.015). The effective rates one week after treatment in arthroscopic treatment group, traditional operation group and local blocking therapy group were respectively 96.9%, 94.1% and 84.8%, without significant differences(P=0.213). The effective rates one month after treatment in these three groups were respectively 93.8%, 97.1% and 72.7%, with significant differences(P=0.006). CONCLUSIONS: Compared with traditional operation and local blocking therapy, arthroscopic treatment has certain effects for the treatment of stenosing tenosynovitis of radial styloid process, with less operation trauma and complications, and it is worthy of clinical promotion. PMID- 29282954 TI - [Case control study on clinical effects of sacrococcygeal manipulation in the treatment of coccyx pain]. AB - OBJECTIVE: To study the clinical efficacy of sacral manual therapy in the treatment of coccygodynia. METHODS: From November 2013 to July 2015, 184 patients with sacrococcygeal pain were divided into treatment group and control group. There were 26 males and 65 females in the treatment group, with an average age of (39.63+/-11.62) years old. In the control group, there were 31 males and 62 females, with an average age of (41.47+/-11.56) years old. The patients in the treatment group were treated with sacrococcygeal massage therapy, 3 times a week for 2 weeks. The patients in the control group were treated with Diclofenac Diethylamine Emulgel, 2 times a day for 2 weeks. The VAS pain score, score in rating scale of sacrococcygeal pain and degree of tenderness were obtained on the first day of treatment, 2, 7, 14 days and 3 months after treatment to evaluate clinical results. RESULTS: When comparing the VAS pain score of sacrococcygeal pain within the two groups, the differences began to reach statistical significance on the second day(P<0.001). The chagne of VAS pain scores, the change of scores in rating scale of sacrococcygeal pain and the degree of tenderness in the treatment group were all significontly larger that those in the contral group from the second day. CONCLUSIONS: The curative effect of sacral manipulation group is better than that of Diclofenac Diethylamine Emulgel group in the treatment of sacrococcygeal pain. PMID- 29282955 TI - [Risk factors for multiple level osteoporosis vertebral compression fractures]. AB - OBJECTIVE: To identify risk factors associated with patients suffered multiple level osteoporosis vertebral compression fractures(OVCFs). METHODS: From March 2011 to March 2015, 199 patients suffered osteoporotic were classified into multiple level OVCFs group and single level OVCF group. Multivariate logistic regression analysis were performed to identify risks factors associated with multiple level OVCFs. RESULTS: All the patients underwent OVCF, including 71 multiple level OVCFs and 128 single level OVCF. There were no differences in the age, gender, BMI, hypertension and diabetes between two groups. While multiple level OVCFs were associated with spinal deformity index SDI[(2<=SDI<4, OR=2.587, 95% CI(1.148, 5.828);SDI>=-4, OR=7.775, 95% CI(3.272, 18.478)], BMD[(T<-4.5SD, OR=2.608, 95% CI(1.038, 6.551)]. CONCLUSIONS: SDI and BMD might be the risk factors for multiple level OVCFs. PMID- 29282956 TI - [Case control study on the treatment of acromioclavicular dislocation with Endobutton plates combined with an anchor]. AB - OBJECTIVE: To compare the clinical effect of Endobutton plates combined with an anchor and clavicle hook plate in the treatment of acromioclavicular dislocation. METHODS: From January 2012 to August 2014, 83 patients with Rockwood type III acromioclavicular dislocation underwent surgical treatments. Among them, 34 patients were treated with Endobutton plate and anchor repair(Endobutton group), including 23 males and 11 females, and the mean age was(39.0+/-6.3) years old (26 to 51 years old); the average time from injury to operation was(4.1+/-1.3) days(3 to 7 days);the injured side:14 left, 20 right; the dislocation in 28 patients dues to fall, 6 patients dues traffic accident. There were 49 patients treated with clavicular hook plate(hook plate group), including 33 males and 16 females;the mean age was(37.9+/-6.3) years old (27 to 53 years old); the average time from injury to operation was(4.1+/-1.1) days (2 to 7 days);the injured side: 18 left, 31 right;the dislication in 36 patients dues to fall, 13 patients dues traffic accidents. The indexes such as intraoperative bleeding volume, operation time, incision size, postoperative complication and postoperative coracoclavicular space, shoulder joint function, and life quality were compared between two groups. RESULTS: In the hook plate group with 49 patients, the plates in 43 patients were removed at the secondary operation, and 32 patients had shoulder pain or limited active range. Thirty four patients in the Endobutton group had no pain symptoms and limited active range. All the patients did not suffer acromioclavicular dislocation again. There was no significant difference between the two groups in operation time, and intraoperative bleeding volume(P>0.05). The incision length in the hook plate group was longer than that in Endobutton group(P<0.05). The coracoclavicular space of the uninjured and injured side in two groups respectively had no significant differences, and the coracoclavicular space in the injured side between two group had no significant difference(P>0.05). There were no significant differences of Constant score and SF-36 between two groups 2 months after operation(P>0.05). Sixteen months after operation, the Constant score in the injured side of both groups was higher than that in 2 months postoperative. But the Constant score in the injured side of hook plate group was higher than that in Endobutton group(P<0.05). The Constant score in the uninjured side had no significant differences between two group(P>0.05). In hook plate group, the Constant score in the uninjured side was higher than that in the injured side. In Endobutton group, there were no significant differences of Constant score between two sides. The 16 month postoperative SF-36 in the injured side of both groups was higher than the 2 month postoperative one, but 16 month postoperative SF-36 in hook plate group was lower than that in Endobutton group (P<0.05). CONCLUSIONS: Endobutton plate combined with an anchor can effectively fix Rockwood type III or more acute acromioclavicular dislocation. The method has less complications, avoiding secondary removal of internal fixation. PMID- 29282957 TI - [Comparative study on curative effects of different methods for the treatment of the "floating shoulder injuries"]. AB - OBJECTIVE: To investigate the clinical curative effects of different methods for the treatment of "floating shoulder injuries". METHODS: A total of 56 patients with "floating shoulder injuries" from February 2006 to August 2014 were enrolled in the study, including 12 patients[7 males and 5 females with an average age of(45.08+/-13.47)years old]treated by non operation (group A), 29 patients[18 males and 11 females with an average age of(37.28+/-10.43) years old]treated by internal plate fixation of the fracture of the clavicle(group B), 15 patients(11 males, 4 females; average age of 36.20+/-9.50 years) treated by internal plate fixation of the fracture of the clavicle and the scapular(group C). Functional outcomes of injured shoulder joints were assessed using Herscovici and Constant Murley Shoulder Outcome score. RESULTS: There was a significant difference on operative time and intra operative blood loss between group B and group C(P=0.000). There were significant differences of functional outcomes among three groups(P=0.000). The shoulder joint function of group A and group B, group A and group C were significantly different(P=0.000), while there was no significant difference between Group B and Group C. CONCLUSIONS: Operation treatment for "floating shoulder injuries" has obvious advantages for the functional recovery of shoulder joint, and the risk for the single fixation treatment of clavicle is lower. PMID- 29282958 TI - [Study on optimization of a fewest layer measuring method of osteonecrotic area in femoral head]. AB - OBJECTIVE: To optimize a measuring method of osteonecrotic area by analyzing the average osteonecrotic areas and osteonecritic volume using multi layer MR images. METHODS: The MRI images of 87 cases (120 hips) of ONFH(ARCO II) were collected retrospectively from January 2011 to January 2012 in Wangjing Hospital of China Academy of Chinese Medicine Science. PHILIPS Achieval 1.5T MR was used to obtain coronal TSE T1 weighted (T1W) images. The scanning parameters were shown as follows:slice thickness, 3.5 mm; gap, 0.3 mm; images repetition time(TR), 500 ms;echo time(TE), 20 ms;field of view (FOV), 374 mm;total 12 layers. According to the distribution rule of osteonecrotic lesion, the layer of coronal T1-weighted imaging showing most of femoral neck was marked as layer 0(L0). The layers before L0 were marked in sequence L1, L2, L3, L4... , and the layers after L0 were marked in sequence L-1, L-2, L-3, L-4... . Auto CAD 2007 was used to measure the percentage of osteonecrotic area and calcu late the average data, and then decreased the layer from low to high layer successively based on frequency of osteonecrotic occurrences. First, the layer with lowest frequency of osteonecrotic occurrenoses L3 was removed, then calculated the average osteonecrotic area of the ramaining 8 layers. L5, L4, L-2, L-1, L3 layers were gradually removed, resulting in the calculation of avereage osteonecrotic areas in 7, 6, 5, 4, 3 layers. These areas were compared to the osteonecrotic volume in MR imagings, leading to the optimization of the fewest layer measuring method of osteonecrotic area using a statistical analysis. RESULTS: The percentage of osteonecrotic volume in 120 hips was 0.333+/-0.151. The average osteonecrotic areas of 9 to 3 layers were 0.321+/-0.117, 0.317+/-0.136, 0.312+/-0.147, 0.333+/ 0.153, 0.348+/-0.172, 0.365+/-0.174, 0.377+/-0.202 respectively. There were no statistical differences of the average osteonecrotic areas and osteonecrotic volume in 9 to 3 layers(P>0.05), but when the osteonecrotic layers were reduced to 3, there were statistical differences(P<0.05). Total 120 hips were grouped according to osteonecrotic volume based on ARCO staging criteria, among them, 12 hips were grade A, 43 were B, 65 were C. According to average osteonecrotic areas of 4 layers, 10 hips were A grade, 32 were B, 78 were C. There were no statistical differences between two methods(P>0.05). There was a high degree of concordance among two methods. CONCLUSIONS: The results of 4(L0, L1, L2, L3) layers measuring method and osteonecrotic volume measuring method are similar. The 4 layers measuring method is an accurate, convenient, valuable method measuring the esteonecrotic area with the fewest layers, which is worth to be popularized in clinical application. PMID- 29282959 TI - [Wrist arthroscopy assisted reduction and Herbert screw fixation for the treatment of type B distal radius fractures]. AB - OBJECTIVE: To explore the clinical efficacy of internal fixation with arthroscope assistance in type B fractures of distal radius. METHODS: From June 2013 to July 2015, 28 cases of type B distal radius fracture patients were enrolled into the study, including 15 males and 13 females with an average age of 45.3 years old ranging from 17 to 69 years old. These patients were treated with manipulative and poking reduction wrist arthroscopy, internal fixation with Herbert screws and repair of articular soft tissue, and the course of disease was 4 to 7 days after injury. Injured patients had the typical signs of distal radius fracture with confirming of X ray and CT imaging. Finally, no other fractures, no neurovascular injury, no other severe diseases and no surgical cortraindications were identified. According to the classification of AO/OTA, there were 8 cases of type B1, 7 cases of type B2, 13 cases of type B3. Patients were followed up for fracture healing, wrist joint function recovery, and curative effect. RESULTS: The 28 cases of type B distal radius fractures were followed up with an average of(12.1+/-1.4) months, all fractures were healed, palmer tilt angle was(15.2+/ 3.4) degrees , ulnar drift angles was(20.4+/-6.4) degrees . Wrist functions were evaluated according to Cooney system and rated as excellent in 21 cases, good in 5 cases and fair in 2 cases. Intraoperative arthroscopy showed the tear of scapholunate ligaments in 3 cases, tear of in lunotriguetal ligaments in 1 case, and TFCC tear in 16 cases. CONCLUSIONS: Wrist arthroscopy assisted treatment of distal radius fracture type B can make the recovery of joint surface roughness to a great extent. The application of Herbert screw brings in the small trauma, and the postoperative recovery time is short, reducing the incidence of traumatic arthritis and preventing the chronic pain or inastbility of the wrist in the future. PMID- 29282961 TI - [Mechanisms involved in the effect of aerobic exercise on knee osteoarthritis]. AB - With the aging of the population, the incidence of knee osteoarthritis (KOA) is increasing year by year. Exercise is one of the none medicine therapies in KOA rehabilitation. When making proper KOA exercise prescription, it's necessary to consider about the mechanisms involved in the interaction between exercise and articular cartilage, and obey the principle of choosing right programs, moderate frequency and intensity avoiding the injury of articular cartilage. The standard of KOA sport prescription is still controversial, so the mechanisms involved in the effect of aerobic exercise on protecting and damaging the articular cartilage need further research. PMID- 29282960 TI - [Chondroid lipoma:a case report]. PMID- 29282962 TI - [Research and progress on diagnosis and treatment of intervertebral space infection]. AB - As the disc surgery were extensively developed, the incidence of intervertebral space infection was significantly increased. Due to a lack of specificity, early diagnosis is difficult and it is prone to misdiagnose. Intervertebral disc puncture sampling microorganism culture is a gold standard of antibiotic selection, but the positive detection rate needs to be improved. At present, different medical institutions have different opinious in epidemiology, treatment experiences, the choice of antibiotic treatment, the course of treatment and the way of operation. In recent years, magnetic resonance imaging, fluorine deoxidization glucose positron emission computed tomography scanning, the imaging application mediated percutaneous intervertebral disc, spinal puncture percutaneous endoscopic debridement and lavage drainage and percutaneous internal fixation combined with anterior posterior incision provide more choices for early diagnosis and treatment. Intervertebral infection should attract more attention to the prevention, early diagnosis, early specific pathogens. Doctors' experience and patients' actual situation should be considered when choosing a appropriate treatment. During the treatment, we should be closely monitored laboratory indexes and timely adjust plan of the treatment, and shorten the treatment time and prevent other complications through the auxiliary treatment. PMID- 29282963 TI - Trials of Patent Foramen Ovale Closure. PMID- 29282964 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29282965 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29282966 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29282967 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29282968 TI - Angiotensin II for the Treatment of Vasodilatory Shock. PMID- 29282969 TI - A Trial of Antibiotics for Smaller Skin Abscesses. PMID- 29282970 TI - A Trial of Antibiotics for Smaller Skin Abscesses. PMID- 29282971 TI - Biocatalytic Self-Assembly on Magnetic Nanoparticles. AB - Combining (bio)catalysis and molecular self-assembly provides an effective approach for the production and processing of self-assembled materials by exploiting catalysis to direct the assembly kinetics and hence controlling the formation of ordered nanostructures. Applications of (bio)catalytic self-assembly in biologically interfacing systems and in nanofabrication have recently been reported. Inspired by self-assembly in biological cells, efforts to confine catalysts on flat or patterned surfaces to exert spatial control over molecular gelator generation and nanostructure self-assembly have also emerged. Building on our previous work in the area, we demonstrate in this report the use of enzymes immobilized onto magnetic nanoparticles (NPs) to spatially localize the initiation of peptide self-assembly into nanofibers around NPs. The concept is generalized for both an equilibrium biocatalytic system that forms stable hydrogels and a nonequilibrium system that normally has a preset lifetime. Characterization of the hydrogels shows that self-assembly occurs at the site of enzyme immobilization on the NPs to give rise to gels with a "hub-and-spoke" morphology, where the nanofibers are linked through the enzyme-NP conjugates. This NP-controlled arrangement of self-assembled nanofibers enables both remarkable enhancements in the shear strength of hydrogel systems and a dramatic extension of the hydrogel stability in the nonequilibrium system. We are also able to show that the use of magnetic NPs enables the external control of both the formation of the hydrogel and its overall structure by application of an external magnetic field. We anticipate that the enhanced properties and stimuli responsiveness of our NP-enzyme system will have applications ranging from nanomaterial fabrication to biomaterials and biosensing. PMID- 29282972 TI - Threshold Switching Induced by Controllable Fragmentation in Silver Nanowire Networks. AB - Silver nanowire (Ag NW) networks have been widely studied because of a great potential in various electronic devices. However, nanowires usually undergo a fragmentation process at elevated temperatures due to the Rayleigh instability that is a result of reduction of surface/interface energy. In this case, the nanowires become completely insulating due to the formation of randomly distributed Ag particles with a large distance and further applications are hindered. Herein, we demonstrate a novel concept based on the combination of ultraviolet/ozone irradiation and a low-temperature annealing process to effectively utilize and control the fragmentation behavior to realize the resistive switching performances. In contrast to the conventional fragmentation, the designed Ag/AgOx interface facilitates a unique morphology of short nanorod like segments or chains of tiny Ag nanoparticles with a very small spacing distance, providing conduction paths for achieving the tunneling process between the isolated fragments under the electric field. On the basis of this specific morphology, the Ag NW network has a tunable resistance and shows volatile threshold switching characteristics with a high selectivity, which is the ON/OFF current ratio in selector devices. Our concept exploits a new function of Ag NW network, i.e., resistive switching, which can be developed by designing a controllable fragmentation. PMID- 29282973 TI - Amine-Modulated/Engineered Interfaces of NiMo Electrocatalysts for Improved Hydrogen Evolution Reaction in Alkaline Solutions. AB - The interface between electrolytes and electrocatalysts would largely determine their corresponding activity and stability. Herein, modulating the surface characteristics of NiMo nanoparticles by various adsorbed amines gives the tunability on their interfacial properties and subsequently improves their catalytic performance for hydrogen evolution reaction (HER) in alkaline solutions. Diamines can significantly improve their HER activity by decreasing the charge-transfer resistance and modulating the electronic structures of interfacial active sites. Importantly, among various amines, ethylenediamine facilitates the HER activity of NiMo with a remarkable decrease of 268 mV in the overpotential to reach 10 mA cm-2 as compared with that of the unmodified NiMo in 1.0 M KOH. This method provides a novel strategy of regulating the interfacial properties to strengthen the catalytic performance of electrocatalysts. PMID- 29282974 TI - New, Efficient, and Reliable Air Electrode Material for Proton-Conducting Reversible Solid Oxide Cells. AB - Driven by the demand to minimize fluctuation in common renewable energies, reversible solid oxide cells (RSOCs) have drawn increasing attention for they can operate either as fuel cells to produce electricity or as electrolysis cells to store electricity. Unfortunately, development of proton-conducting RSOCs (P RSOCs) faces a major challenge of poor reliability because of the high content of steam involved in air electrode reactions, which could seriously decay the lifetime of air electrode materials. In this work, a very stable and efficient air electrode, SrEu2Fe1.8Co0.2O7-delta (SEFC) with layer structure, is designed and deployed in P-RSOCs. X-ray diffraction analysis and High-angle annular dark filed scanning transmission electron microscopy images of SEFC reveal that Sr atoms occupy the center of perovskite slabs, whereas Eu atoms arrange orderly in the rock-salt layer. Such a special structure of SEFC largely depresses its Lewis basicity and therefore its reactivity with steam. Applying the SEFC air electrode, our button switches smoothly between both fuel cell and electrolysis cell (EC) modes with no obvious degradation over a 135 h long-term test under wet H2 (~3% H2O) and 10% H2O-air atmospheres. A record of over 230 h is achieved in the long-term stability test in the EC mode, doubling the longest test that had been previously reported. Besides good stability, SEFC demonstrates great catalytic activity toward air electrode reactions when compared with traditional La0.6Sr0.4Co0.2Fe0.8O3-delta air electrodes. This research highlights the potential of stable and efficient P-RSOCs as an important part in a sustainable new energy power system. PMID- 29282975 TI - Correction to Bexarotene Does Not Clear Amyloid Beta Plaques but Delays Fibril Growth: Molecular Mechanisms. PMID- 29282976 TI - Improved Ferroelectric Switching Endurance of La-Doped Hf0.5Zr0.5O2 Thin Films. AB - Hf0.5Zr0.5O2 thin films are one of the most appealing HfO2-based ferroelectric thin films, which have been researched extensively for their applications in ferroelectric memory devices. In this work, a 1 mol % La-doped Hf0.5Zr0.5O2 thin film was grown by plasma-assisted atomic layer deposition and annealed at temperatures of 450 and 500 degrees C to crystallize the film into the desired orthorhombic phase. Despite the use of a lower temperature than that used in previous reports, the film showed highly promising ferroelectric properties-a remnant polarization of ~30 MUC/cm2 and switching cycle endurance up to 4 * 1010. The performance was much better than that of undoped Hf0.5Zr0.5O2 thin films, demonstrating the positive influence of La doping. Such improvements were mainly attributed to the decreased coercive field (by ~30% compared to the undoped film), which allowed for the use of a lower applied field to drive the cycling tests while maintaining a high polarization value. La doping also decreased the leakage current by ~3 orders of magnitude compared to the undoped film, which also contributed to the strongly improved endurance. Nonetheless, the La-doped film required a larger number of wake-up cycles (~106 cycles) to reach a saturated remnant polarization value. This behavior might be explained by the increased generation of oxygen vacancies and slower migration of these vacancies from the interface to the bulk region. However, the maximum number of wake-up cycles was less than 0.01% of the total possible cycles, and therefore, initializing the film to the maximum performance state would not be a serious burden. PMID- 29282977 TI - Comparison of Different Strategies for the Development of Highly Sensitive Electrochemical Nucleic Acid Biosensors Using Neither Nanomaterials nor Nucleic Acid Amplification. AB - Currently, electrochemical nucleic acid-based biosensing methodologies involving hybridization assays, specific recognition of RNA/DNA and RNA/RNA duplexes, and amplification systems provide an attractive alternative to conventional quantification strategies for the routine determination of relevant nucleic acids at different settings. A particularly relevant objective in the development of such nucleic acid biosensors is the design of as many as possible affordable, quick, and simple methods while keeping the required sensitivity. With this aim in mind, this work reports, for the first time, a thorough comparison between 11 methodologies that involve different assay formats and labeling strategies for targeting the same DNA. The assayed approaches use conventional sandwich and competitive hybridization assays, direct hybridization coupled to bioreceptors with affinity for RNA/DNA duplexes, multienzyme labeling bioreagents, and DNA concatamers. All of them have been implemented on the surface of magnetic beads (MBs) and involve amperometric transduction at screen-printed carbon electrodes (SPCEs). The influence of the formed duplex length and of the labeling strategy have also been evaluated. Results demonstrate that these strategies can provide very sensitive methods without the need for using nanomaterials or polymerase chain reaction (PCR). In addition, the sensitivity can be tailored within several orders of magnitude simply by varying the bioassay format, hybrid length or labeling strategy. This comparative study allowed us to conclude that the use of strategies involving longer hybrids, the use of antibodies with specificity for RNA/DNA heteroduplexes and labeling with bacterial antibody binding proteins conjugated with multiple enzyme molecules, provides the best sensitivity. PMID- 29282978 TI - Inhibition of P-Glycoprotein Mediated Efflux in Caco-2 Cells by Phytic Acid. AB - Phytic acid (IP6) is a natural phosphorylated inositol, which is abundantly present in most cereal grains and seeds. This study investigated the effects of IP6 regulation on P-glycoprotein (P-gp) and its potential mechanisms using in situ and in vitro models. The effective permeability of the typical P-gp substrate rhodamine 123 (R123) in colon was significantly increased from (1.69 +/ 0.22) * 10-5 cm/s in the control group to (3.39 +/- 0.417) * 10-5 cm/s (p < 0.01) in the 3.5 mM IP6 group. Additionally, IP6 can concentration-dependently decrease the R123 efflux ratio in both Caco-2 and MDCK II-MDR1 cell monolayers and increase intracellular R123 accumulation in Caco-2 cells. Furthermore, IP6 noncompetitively inhibited P-gp by impacting R123 efflux kinetics. The noncompetitive inhibition of P-gp by IP6 was likely due to decreases in P-gp ATPase activity and P-gp molecular conformational changes induced by IP6. In summary, IP6 is a promising P-gp inhibitor candidate. PMID- 29282979 TI - Signal Amplified Gold Nanoparticles for Cancer Diagnosis on Paper-Based Analytical Devices. AB - In this work, we report a highly sensitive colorimetric sensing strategy for cancer biomarker diagnosis using gold nanoparticles (AuNPs) labeled with biotinylated poly(adenine) ssDNA sequences and streptavidin-horseradish peroxidase for enzymatic signal enhancement. By adopting this DNA-AuNP nanoconjugate sensing strategy, we were able to eliminate the complicated and costly thiol-binding process typically used to modify AuNP surfaces with ssDNA. In addition, different antibodies can be introduced to the AuNP surfaced via electrostatic interactions to provide highly specific recognition sites for biomolecular sensing. Moreover, multiple, simultaneous tests can be rapidly performed with low sample consumption by incorporating these surface-modified AuNPs into a paper-based analytical device that can be read using just a smartphone. As a result of these innovations, we were able to achieve a detection limit of 10 pg/mL for a prostate specific antigen in a test that could be completed in as little as 15 min. These results suggest that the proposed paper platform possesses the capability for sensitive, high-throughput, and on-site prognosis in resource-limited settings. PMID- 29282980 TI - 135-Day Interventions of Yam Dioscorin and the Dipeptide Asn-Trp (NW) To Reduce Weight Gains and Improve Impaired Glucose Tolerances in High-Fat Diet-Induced C57BL/6 Mice. AB - The C57BL/6J mice were fed a 135-day normal diet or a high-fat diet (HFD) without, or concurrent with, a single yam dioscorin (80 mg/kg) or dipeptide NW (40 mg/kg) intervention every day. The final body weights (g) of mice were 26.1 +/- 1.4, 34.97 +/- 2.1, 31.75 +/- 2.6, and 31.66 +/- 3.1, respectively, for normal diet-fed, HFD-fed, dioscorin-intervened, and NW-intervened group. The mice in both intervened groups showed similar less weight gains and had significant differences (P < 0.05) compared to those in the HFD group under the same cumulative HFD intakes. The blood biochemical index of mice with dioscorin interventions showed significantly lower contents in total cholesterol and low density lipoprotein, and NW interventions showed significantly lower total triglyceride contents compared to those of the HFD group (P < 0.05). Both intervened mice exhibited similar reductions in total visceral lipid contents and have significant differences compared to those of the HFD group (P < 0.05). The dioscorin intervention was better than NW interventions in lowering blood glucose levels by oral glucose tolerance tests and both showed significant differences (P < 0.05) compared to those in the HFD group. Yam dioscorin or dipeptide NW will potentially be used for preventive functional foods of less body weight gains and impaired glucose tolerance controls, which require further clinical trial investigations. PMID- 29282981 TI - Bronsted-Acid-Catalyzed Asymmetric Three-Component Reaction of Amines, Aldehydes, and Pyruvate Derivatives. Enantioselective Synthesis of Highly Functionalized gamma-Lactam Derivatives. AB - Chiral phosphoric acids are efficient organocatalysts for the asymmetric three component reaction of amines, aldehydes, and pyruvate derivatives. Simultaneous condensation of amines with both carbonylic compounds followed by a hydrogen bonding activated nucleophilic addition of enamines to imines affords densely functionalized enantioenriched 1,5-dihydro-2H-pyrrol-2-ones. These substrates can be used in subsequent diastereoselective transformations to afford enantiopure gamma-lactam derivatives. PMID- 29282982 TI - Beyond Simple Cartoons: Challenges in Characterizing Electrochemical Biosensor Interfaces. AB - Design and development of surface-based biosensors is challenging given the multidisciplinary nature of this enterprise, which is certainly the case for electrochemical biosensors. Self-assembly approaches are used to modify the surface with capture probes along with electrochemical methods for detection. Complex surface structures are created to improve the probe-target interaction. These multicomponent surface structures are usually idealized in schematic representations. Many rely on the analytical performance of the sensor surface as an indication of the quality of the surface modification strategy. While directly linked to the eventual device, arguments for pursuing a more extensive characterization of the molecular environments at the surface are presented as a path to understanding how to make electrochemical sensors that are more robust, reliable with improved sensitivity. This is a complex task that is most often accomplished using methods that only report the average characteristics of the surface. Less often applied are methods that are sensitive to the probe (or adsorbate) present in nonideal configurations (e.g., aggregates, clusters, nonspecifically adsorbed). Though these structures may compose a small fraction of the overall modified surface, they have an uncertain impact on sensor performance and reliability. Addressing this issue requires application of imaging methods over a variety of length scales (e.g., optical microscopy and/or scanning probe microscopy) that provide valuable insight into the diversity of surface structures and molecular environments present at the sensing interface. Furthermore, using in situ analytical methods, while complex, can be more relevant to the sensing environment. Reliable measurements of the nature and extent of these features are required to assess the impact of these nonideal configurations on the sensing process. The development and use of methods that can characterize complex surface based biosensors is arguably required, highlighting the need for a multidisciplinary approach toward the preparation and analysis of the biosensor surface. In many ways, representing the surface without reliance on overly simplified cartoons will highlight these important considerations for improving sensor characteristics. PMID- 29282983 TI - Subnanomolar Sensitivity of Filter Paper-Based SERS Sensor for Pesticide Detection by Hydrophobicity Change of Paper Surface. AB - As a cost-effective approach for detecting trace amounts of pesticides, filter paper-based SERS sensors have been the subject of intensive research. One of the hurdles to overcome is the difficulty of retaining nanoparticles on the surface of the paper because of the hydrophilic nature of the cellulose fibers in paper. This reduces the sensitivity and reproducibility of paper-based SERS sensors due to the low density of nanoparticles and short retention time of analytes on the paper surface. In this study, filter paper was treated with alkyl ketene dimer (AKD) to modify its property from hydrophilic to hydrophobic. AKD treatment increased the contact angle of the aqueous silver nanoparticle (AgNP) dispersion, which consequently increased the density of AgNPs. The retention time of the analyte was also increased by preventing its rapid absorption into the filter paper. The SERS signal was strongly enhanced by the increased number of SERS hot spots owing to the increased density of AgNPs on a small contact area of the filter surface. The reproducibility and sensitivity of the SERS signal were optimized by controlling the distribution of AgNPs on the surface of the filter paper by adjusting the concentration of the AgNP solution. Using this SERS sensor with a hydrophobicity-modified filter paper, the spot-to-spot variation of the SERS intensity of 25 spots of 4-aminothiophenol was 6.19%, and the limits of detection of thiram and ferbam as test pesticides were measured to be 0.46 nM and 0.49 nM, respectively. These proof-of-concept results indicate that this paper based SERS sensor can serve for highly sensitive pesticide detection with low cost and easy fabrication. PMID- 29282984 TI - Cholesterol Oxidase/Triton X-100 Parked Microelectrodes for the Detection of Cholesterol in Plasma Membrane at Single Cells. AB - The classic electrochemical analysis of plasma membrane cholesterol at single cells utilizes a cholesterol oxidase modified microelectrode that oxidizes local cholesterol efflux from the plasma membrane to generate hydrogen peroxide for the electrochemical quantification. In this letter, a mixture of cholesterol oxidase and Triton X-100 was filled in the microcapillary that could park at the Pt layer coated tip due to slow hydrodynamic flow. During the contact of the tip with the cellular membrane, Triton X-100 at the tip permeabilized the contacted membrane to release cholesterol for the reaction with cholesterol oxidase. As compared with the linkage of cholesterol oxidase at the electrode surface, the oxidase parked in aqueous solution at the tip had a higher turnover rate resulting in larger electrochemical signal for single cell analysis. More charge collected at acyl-coA:cholesterol acyltransferase (ACAT) inhibited cells supported that this novel detection strategy could monitor the flunctation of membrane cholesterol at single cells. The successful detection of plasma membrane cholesterol at single cells using the oxidase parked microelectrode will provide a special strategy for the fabrication of biosensor that permits the integration of more molecules without functional groups at the electrode to measure active and inactive molecules in the plasma membrane. Moreover, the larger electrochemical signals collected could further increase the spatial resolution for single cell electrochemical analysis. PMID- 29282985 TI - Chemical Structure, Ensemble and Single-Particle Spectroscopy of Thick-Shell InP ZnSe Quantum Dots. AB - Thick-shell (>5 nm) InP-ZnSe colloidal quantum dots (QDs) grown by a continuous injection shell growth process are reported. The growth of a thick crystalline shell is attributed to the high temperature of the growth process and the relatively low lattice mismatch between the InP core and ZnSe shell. In addition to a narrow ensemble photoluminescence (PL) line-width (~40 nm), ensemble and single-particle emission dynamics measurements indicate that blinking and Auger recombination are reduced in these heterostructures. More specifically, high single-dot ON-times (>95%) were obtained for the core-shell QDs, and measured ensemble biexciton lifetimes, tau2x ~ 540 ps, represent a 7-fold increase compared to InP-ZnS QDs. Further, high-resolution energy dispersive X-ray (EDX) chemical maps directly show for the first time significant incorporation of indium into the shell of the InP-ZnSe QDs. Examination of the atomic structure of the thick-shell QDs by high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) reveals structural defects in subpopulations of particles that may mitigate PL efficiencies (~40% in ensemble), providing insight toward further synthetic refinement. These InP-ZnSe heterostructures represent progress toward fully cadmium-free QDs with superior photophysical properties important in biological labeling and other emission-based technologies. PMID- 29282986 TI - Synthesis of Double-Modified Xyloside Analogues for Probing the beta4GalT7 Active Site. AB - Monosubstituted naphthoxylosides have been shown to function as substrates for, and inhibitors of, the enzyme beta4GalT7, a key enzyme in the biosynthetic pathway leading to glycosaminoglycans and proteoglycans. In this article, we explore the synthesis of 16 xyloside analogues, modified at two different positions, as well as their function as inhibitors of and/or substrates for the enzyme. Seemingly simple compounds turned out to require complex synthetic pathways. A meta-analysis of the synthetic work shows that, regardless of the abundance of methods available for carbohydrate synthesis, even simple modifications can turn out to be problematic, and double modifications present additional challenges due to conformational, steric, and stereoelectronic effects. PMID- 29282987 TI - Total Synthesis of Highly Oxygenated Bisabolane Sesquiterpene Isolated from Ligularia lankongensis: Relative and Absolute Configurations of the Natural Product. AB - The relative and absolute configurations of an oxygenated bisabolane natural product, isolated from Ligularia lankongensis, were determined by synthesis. All four possible stereoisomers and their tiglate analogues were synthesized from R-( )-carvone, and their 1H and 13C NMR spectra were compared to establish the 6R,8S,10S configuration. The stereoselective synthesis of the natural product was also achieved, featuring Brown allylation, vanadium-catalyzed epoxidation, and the Mitsunobu reaction. PMID- 29282988 TI - Enhancement of Laser-Induced Breakdown Spectroscopic Signals in a Liquid Jet with Glow Discharge. AB - In this work, emission signals of laser-induced breakdown (LIBS) plasma of a flowing liquid jet in the absence and presence of an air-supported glow discharge have been investigated. In combination with a needle-to-needle glow discharge, a Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (1064 nm, 5 ns) with power density ~1010 W/cm2 was used to generate a plasma from a liquid jet. Emission lines of Mg, Ca, Al, Li, Na, and K all showed significant enhancements in the presence of the glow discharge. Lower continuum background was also observed. Mechanisms of the line emission enhancement and continuum radiation reduction were discussed. PMID- 29282989 TI - Using a therapeutic companion robot for dementia symptoms in long-term care: reflections from a cluster-RCT. AB - OBJECTIVES: We undertook a cluster-randomised controlled trial exploring the effect of a therapeutic companion robot (PARO) compared to a look-alike plush toy and usual care on dementia symptoms of long-term care residents. Complementing the reported quantitative outcomes , this paper provides critical reflection and commentary on individual participant responses to PARO, observed through video recordings , with a view to informing clinical practice and research. METHOD: A descriptive, qualitative design with five participants selected from the PARO intervention arm of the trial. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000508673). RESULTS: The five participants and their responses to PARO are presented in terms of three issues: i.) Different pre-intervention clinical presentations and different responses; ii.) Same individual, different response - the need for continual assessment and review; and iii.) The ethics of giving and retrieving PARO. Implications for clinical practice and future research are discussed in relation to each issue. CONCLUSION: The findings suggest that one approach does not fit all, and that there is considerable variation in responses to PARO. A number of recommendations are discussed to aid the delivery of psychosocial interventions with PARO in practice, as well as to guide future research. PMID- 29282990 TI - Amazing Athletes With Ordinary Habits: Why Is Changing Behavior So Difficult? PMID- 29282991 TI - Identification of Uranium Minerals in Natural U-Bearing Rocks Using Infrared Reflectance Spectroscopy. AB - The identification of minerals, including uranium-bearing species, is often a labor-intensive process using X-ray diffraction (XRD), fluorescence, or other solid-phase or wet chemical techniques. While handheld XRD and fluorescence instruments can aid in field applications, handheld infrared (IR) reflectance spectrometers can now also be used in industrial or field environments, with rapid, nondestructive identification possible via analysis of the solid's reflectance spectrum providing information not found in other techniques. In this paper, we report the use of laboratory methods that measure the IR hemispherical reflectance of solids using an integrating sphere and have applied it to the identification of mineral mixtures (i.e., rocks), with widely varying percentages of uranium mineral content. We then apply classical least squares (CLS) and multivariate curve resolution (MCR) methods to better discriminate the minerals (along with two pure uranium chemicals U3O8 and UO2) against many common natural and anthropogenic background materials (e.g., silica sand, asphalt, calcite, K feldspar) with good success. Ground truth as to mineral content was attained primarily by XRD. Identification is facile and specific, both for samples that are pure or are partially composed of uranium (e.g., boltwoodite, tyuyamunite, etc.) or non-uranium minerals. The characteristic IR bands generate unique (or class-specific) bands, typically arising from similar chemical moieties or functional groups in the minerals: uranyls, phosphates, silicates, etc. In some cases, the chemical groups that provide spectral discrimination in the longwave IR reflectance by generating upward-going (reststrahlen) bands can provide discrimination in the midwave and shortwave IR via downward-going absorption features, i.e., weaker overtone or combination bands arising from the same chemical moieties. PMID- 29282994 TI - Hierarchical clustering analysis framework of mutually exclusive crash causation parameters for regional road safety strategies. AB - Hierarchical clustering analysis framework is developed to identify benchmark and critical regions for effective road safety strategies. The regions are grouped based on agglomeration coefficient of mutually exclusive crash causation parameters. Subsequently, regions from groups with lower than a threshold index value are selected as benchmark for the poorly performing critical counterparts. Euclidean distance-based Ward's, median and centroid clustering techniques are explored through a case study of Indian states and Union Territories. As per data between 2006 and 2015, fatal crash percentages of driving under influence of drug and alcohol, excessive speeding, vehicle malfunction and road conditions related crash causation parameters, severity index and its growth rate are assessed based on respective threshold values of 6.35%, 43.28%, 2.42%, 1.79%, 26.7 and 3.1%. These are the national average of respective indices. It demonstrated the unique application of hierarchical clustering analysis in benchmark and critical region identification. PMID- 29282992 TI - Enhanced anti-hepatocarcinoma efficacy by GLUT1 targeting and cellular microenvironment-responsive PAMAM-camptothecin conjugate. AB - The efficient targeting of drugs to tumor cell and subsequent rapid drug release remain primary challenges in the development of nanomedicines for cancer therapy. Here, we constructed a glucose transporter 1 (GLUT1)-targeting and tumor cell microenvironment-sensitive drug release Glucose-PEG-PAMAM-s-s-Camptothecin-Cy7 (GPCC) conjugate to tackle the dilemma. The conjugate was characterized by a small particle size, spherical shape, and glutathione (GSH)-sensitive drug release. In vitro tumor targeting was explored in monolayer (2D) and multilayer tumor spheroid (3D) HepG2 cancer cell models (GLUT1+). The cellular uptake of GPCC was higher than that in the control groups and that in normal L02 cells (GLUT1-), likely due to the conjugated glucose moiety. Moreover, the GPCC conjugate exhibited stronger cytotoxicity, higher S arrest and enhanced apoptosis and necrosis rate in HepG2 cells than control groups but not L02 cells. However, the cytotoxicity of GPCC was lower than that of free CPT, which could be explained by the slower release of CPT from the GPCC compared with free CPT. Additional in vivo tumor targeting experiments demonstrated the superior tumor targeting ability of the GPCC conjugate, which significantly accumulated in tumor meanwhile minimize in normal tissues compared with control groups. The GPCC conjugate showed better pharmacokinetic properties, enabling a prolonged circulation time and increased camptothecin area under the curve (AUC). These features contributed to better therapeutic efficacy and lower toxicity in H22 hepatocarcinoma tumor-bearing mice. The GLUT1-targeting, GSH-sensitive GPCC conjugate provides an efficient, safe and economic approach for tumor cell targeted drug delivery. PMID- 29282995 TI - Nose to brain transport pathways an overview: potential of nanostructured lipid carriers in nose to brain targeting. AB - Many of the therapeutics used for the treatment of brain disorders are not effective and not delivered to the brain due to the complex structure and its barriers. In recent years, many advanced approaches have emerged for the brain drug delivery. Intranasal drug delivery is one of non-invasive approach has gained interest because of direct transport of drugs circumventing the brain barriers through olfactory and trigeminal nerve pathways. Eventhough through these pathways the therapeutics have direct access to the brain, the main limitations of this approach are only limited drug absorption, and nasal permeability. To overcome the issues related to the brain targeting via nasal drug delivery encourage the development of novel drug delivery by combining with nanotechnology. This article will discuss pathways of drug transport form nose to brain, toxicity of nanoparticles role and need of nanostructured lipid carriers (NLCs) and recent advance in combination of NLCs with intranasal drug delivery for targeting the brain. PMID- 29282997 TI - Development and psychometric properties of the Healthy Aging Activity Engagement Scale (HAAE). AB - OBJECTIVES: Accumulating research indicates that engaging in healthy lifestyle behaviors (e.g. exercise, cognitive and social engagement, stress reduction) can prevent illness and disability as people age and improve mental health. The Healthy Aging Activity Engagement (HAAE) scale was developed to holistically assess an individual's level of engagement in healthy aging behaviors across multiple health domains. METHODS: Participants were 275 healthy younger, midlife and older adults. Participants rated engagement in 38 healthy aging lifestyle behaviors over the past 7 days on a scale from 1 (strongly disagree) to 5 (strongly agree). RESULTS: Traditional measurement analysis and Rasch modelling techniques resulted in a 32-item scale with three subscales representing biologic health, social and cognitive strategies, and health safeguard behaviors. With the exception of the health safeguard subscale, the HAAE total score and subscales demonstrated good internal consistency, test-retest reliability, convergent and discriminant validity, and responsiveness to a program designed to promote engagement in healthy brain aging behaviors. DISCUSSION: With further validation, the HAAE may be useful for holistic clinical assessment of behaviors that promote healthy aging, support brain and mental health, and for treatment planning. Furthermore, the HAAE can be used to measure the outcome of multi-domain lifestyle interventions. PMID- 29282998 TI - Clinical significance of neuregulin 4 (NRG4) in gestational diabetes mellitus. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is defined as glucose intolerance detected during pregnancy. GDM is increasing worldwide and is associated with adverse maternal and fetal outcomes. Neuregulin 4 (NGR4) is epidermal growth factor like signaling molecule. It plays an important role in cell to cell communication furthermore recent studies indicate that NRG4 may work as a novel adipokine with a possible role in maintaining energy and metabolic homeostasis. The aim of the present study was to assess serum NRG4 levels along with several metabolic parameters in patients diagnosed with gestational diabetic mellitus. MATERIALS AND METHODS: In this prospective cross-sectional study, the study group was composed of 63 women with GDM and 64 healthy pregnant women matched for age, body mass index (BMI) and gestational age. Blood samples were collected at the 24 28th gestational weeks. Serum NRG4, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, glucose levels during 75-gr OGTT, fasting insulin, glycosylated hemoglobin A1c (HbA1c), alanine aminotransferase (ALT) and creatinine levels were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) values were calculated. RESULTS: Serum NRG4 values were significantly elevated in the GDM group compared to the control group (p < .001). Multivariate linear regression analyzes revealed that BMI (beta = 0.910, p < .001), glucose 2-h OGTT (beta = 0.866, p < .001) and HOMA-IR (beta = 0.222, p < .001) independently and positively predicted NRG4 levels. CONCLUSIONS: Serum NRG4 levels were associated with metabolic parameters of GDM. The present study can be considered to be a guide for future studies to clarify the pathophysiology of NGR4 in GDM patients. PMID- 29282999 TI - The concept of chronotypes and its clinical importance for depressive disorders. AB - Chronobiology and chronobiological research deal with time-dependent physiological processes and behavioral correlates as well as their adaptation to environmental conditions. Chronobiological research is presently focused on the impact of circadian rhythms on human behavior. In the last three decades, chronobiology has established itself as an independent area of research evolving to an important field of clinical psychology and psychiatry. In this overview, the results of studies on the clinical importance of chronotypes are summarized. The main focus is on the role of chronotype in depressive disorders. PMID- 29283000 TI - Topographic cues guide the attachment of diatom cells and algal zoospores. AB - Surface topography plays a key role in the colonization of substrata by the colonizing stages of marine fouling organisms. For the innovation of marine antifouling coatings, it is essential to understand how topographic cues affect the settlement of these organisms. In this study, tapered, spiked microstructures and discrete honeycombs of varying feature dimensions were designed and fabricated in order to examine the influence of topography on the attachment of zoospores of the green macroalga Ulva linza and cells of the diatom (microalga) Navicula incerta. Contrasting results were obtained with these two species of algae. Indeed, the preferred location of cells of N. incerta was dominated by attachment point theory, which suggested a positive correlation between the density of cells adhering and the amount of available attachment points, while the settlement of spores of U. linza was mainly regulated by both Wenzel roughness and local binding geometry. PMID- 29283001 TI - Decision-making competence in younger and older adults: which cognitive abilities contribute to the application of decision rules? AB - Older adults perform worse than younger adults when applying decision rules to choose between options that vary along multiple attributes. Although previous studies have shown that general fluid cognitive abilities contribute to the accurate application of decision rules, relatively little is known about which specific cognitive abilities play the most important role. We examined the independent roles of working memory, verbal fluency, semantic knowledge, and components of executive functioning. We found that age-related decline in applying decision rules was statistically mediated by age-related decline in working memory and verbal fluency. Our results have implications for theories of aging and decision-making. PMID- 29283002 TI - Twenty-three years (1993-2015) of homicide trends in the Transkei region of South Africa. AB - Background Transkei is regarded as a rural part of South Africa. It was one of the black homelands where rigorous apartheid was practised. The incidence of firearm-related deaths used to be very high, but after the implementation of the Firearm Control Act in 2002, the trend changed. However, the murder rate is still a major public-health problem in this region of South Africa. Objective The aim of this study was to investigate 23 years (1993-2015) of homicide trends in the Transkei region of South Africa. Method A review of records of medico-legal autopsies performed at Mthatha Forensic Pathology Laboratory from 1993 to 2015 was undertaken. Results Between 1993 and 2015, the number of autopsies performed on people who had died unnatural deaths was 24,693. The records of 12,618 (51%) autopsies on victims of homicide between 1993 and 2015 were available for study. The average rate of murder was 85/100,000 of the population in this region. Of these deaths, on average 34/100,000 were caused by sharp-edged instruments, 30/100,000 by gunshot wounds and 21/100,000 by blunt trauma. The rate of murder of males was significantly higher than that of females, with a ratio of 5.7:1, and over the period of 23 years covered by this study, the incidence was highest (30.5/100,000) in the young age group between 21 and 30 years. Conclusion The rate of homicide is very high in the Transkei region of South Africa. It needs urgent intervention to curb unnecessary deaths. PMID- 29283003 TI - A particular case of accidental asphyxiation. AB - The case reported involved a 60-year-old man with psychiatric illness who was found dead at his home. He was almost naked and showed signs of death by violent asphyxiation, which led to the suspicion of homicide. Autopsy findings showed foreign material in the trachea and larynx. However, the partially digested content in his stomach, the study of the gastric content and the microscopic analysis of the airways made it possible to define this as accidental death due to inhalation of material from a diaper. Toxicological analysis detected the presence of phenytoin, valproic acid, and phenobarbital in his blood, with values within the therapeutic ranges. This is certainly a peculiar case, as particularly evident after careful review of the literature on deaths by asphyxiation in psychiatric patients. Furthermore, this study highlights the importance of a full autopsy and microscopic evaluation of any foreign bodies. PMID- 29283004 TI - Elimination of contaminating amplified short tandem repeat products by autoclaving and ultraviolet irradiation. AB - DNA contamination can result in false interpretation of short tandem repeat (STR) DNA typing. Proper decontamination is particularly required in forensic DNA laboratories where probative value of the evidence may be affected. The aim of this study was to establish an effective DNA decontamination procedure for amplified STR products focusing on laboratory-related contamination. We verified the effectiveness of thermally and temporally extended autoclaving and ultraviolet irradiation for the elimination of contaminating amplified STR products. STR amplification products were prepared using a control genomic DNA template and generated using the AmpFlSTR(r) Identifiler(r) Plus and Yfiler(r) polymerase chain reaction amplification kits. In this study, the contaminants were dried before decontamination treatment, which resembles actual contamination situations. One microlitre of amplified STR products was eliminated by a combination of autoclaving (128 degrees C, 420 min) and UV irradiation (60 J/cm2). Our results reveal that the combination treatment represents an effective DNA decontamination procedure and a practicable method in standard level laboratories. Finally, we propose a comprehensive approach for forensic DNA laboratories to implement to minimise contamination issues and guarantee provision of authentic results. PMID- 29283005 TI - Use of Promogran to treat venous leg ulcers. AB - Based on the outcome of a series of symposia, this series aims to answer the question, 'what is compromised wound healing and how do we increase our understanding of chronic wounds?' Ultimately, we hope to explore the feasibility of developing a chronicity predictor. Many venous leg ulcers fail to heal when treated with compression and dressings that simply create a moist wound environment. Promogran is designed not only to produce a moist wound environment but also to inhibit protease activity, counteract a pro-oxidant environment, protect growth factors and modulate fibroblast activity. In two case reports concerning hard-to-heal venous leg ulcers, use of Promogran resulted in reduced exudation and stimulation of healing. Clinical observations found with these ulcers were consistent with Promogran's proposed mode of action. PMID- 29283006 TI - Regional arterial stiffness in central and peripheral arteries is differentially related to endothelial dysfunction assessed by brachial flow-mediated dilation in metabolic syndrome. AB - The interrelationship between endothelial function and arterial stiffness may be different for central and peripheral arteries due to their structural and functional differences. The study aims to assess the interrelationship between central and peripheral vascular function and haemodynamics in metabolic syndrome. Thirty-seven patients [63.0 (57.5-66.0) years, 68.4% males] of metabolic syndrome (National Cholesterol Education Program - Adult Treatment Panel-III criteria) were studied. Carotid-femoral, carotid-radial pulse wave velocity and augmentation index (AIx@75) were assessed using applanation tonometry. Endothelial function was evaluated by brachial flow-mediated dilation using B mode ultrasonography. Central and peripheral pressures were measured by radial tonometry and sphygmomanometer, respectively. Carotid-radial pulse wave velocity correlated significantly with peripheral diastolic blood pressure ( r = 0.33, p = 0.04) and inversely with flow-mediated dilation ( r = -0.61, p = 0.0001). AIx@75 correlated significantly with carotid-femoral pulse wave velocity ( r = 0.35, p = 0.03) and with aortic pulse pressure ( r = 0.43, p = 0.01). In principal component analysis, an inverse relationship was observed between flow-mediated dilation and carotid-radial pulse wave velocity but not with carotid-femoral pulse wave velocity. Regional arterial stiffness assessed by pulse wave velocity in central-elastic and peripheral-muscular arteries differentially relates to endothelial dysfunction. The central arteries might be predominantly influenced by endothelial dysfunction-induced structural changes, while the peripheral arteries are majorly affected by functional alterations. PMID- 29283007 TI - How to Write a Systematic Review of the Literature. AB - This article provides a step-by-step approach to conducting and reporting systematic literature reviews (SLRs) in the domain of healthcare design and discusses some of the key quality issues associated with SLRs. SLR, as the name implies, is a systematic way of collecting, critically evaluating, integrating, and presenting findings from across multiple research studies on a research question or topic of interest. SLR provides a way to assess the quality level and magnitude of existing evidence on a question or topic of interest. It offers a broader and more accurate level of understanding than a traditional literature review. A systematic review adheres to standardized methodologies/guidelines in systematic searching, filtering, reviewing, critiquing, interpreting, synthesizing, and reporting of findings from multiple publications on a topic/domain of interest. The Cochrane Collaboration is the most well-known and widely respected global organization producing SLRs within the healthcare field and a standard to follow for any researcher seeking to write a transparent and methodologically sound SLR. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), like the Cochrane Collaboration, was created by an international network of health-based collaborators and provides the framework for SLR to ensure methodological rigor and quality. The PRISMA statement is an evidence-based guide consisting of a checklist and flowchart intended to be used as tools for authors seeking to write SLR and meta-analyses. PMID- 29283008 TI - Journal Editors: Are We Friend of Foe? PMID- 29283012 TI - PATEO syndrome: periarticular thenar erythema with onycholysis. PMID- 29283013 TI - Interneuron Cooperativity in Cortical Circuits. AB - Neocortical neurons tend to be coactive in groups called ensembles. However, sometimes, individual neurons also spike alone, independent of the ensemble. What processes regulate the transition between individual and cooperative action? Inspired by classical work in biochemistry, we apply the concept of neuronal cooperativity to explore this question. With a focus on neocortical inhibitory interneurons, we offer a working definition of neuronal cooperativity, review its recorded incidences and proposed mechanisms, and describe experimental approaches that will demonstrate and further describe this action. We suggest that cooperativity of "neuron teams" is manifested in vivo through their coactivity, as well as via the action of individual "soloist neurons" in the low end of the sigmoidal cooperativity curve. Finally, we explore the evidence for and implications of individual and team action of neurons. PMID- 29283014 TI - Versatility and Flexibility of Cortical Circuits. AB - Cortical circuits are known to be plastic and adaptable, as shown by an impressive body of evidence demonstrating the ability of cortical circuits to adapt to changes in environmental stimuli, development, learning, and insults. In this review, we will discuss some of the features of cortical circuits that are thought to facilitate cortical circuit versatility and flexibility. Throughout life, cortical circuits can be extensively shaped and refined by experience while preserving their overall organization, suggesting that mechanisms are in place to favor change but also to stabilize some aspects of the circuit. First, we will describe the basic organization and some of the common features of cortical circuits. We will then discuss how this underlying cortical structure provides a substrate for the experience- and learning-dependent processes that contribute to cortical flexibility. PMID- 29283015 TI - Negative pressure ventilation enhances acinar perfusion in isolated rat lungs. AB - We compared acinar perfusion in isolated rat lungs ventilated using positive or negative pressures. The lungs were ventilated with air at transpulmomary pressures of 15/5 cm H2O, at 25 breaths/min, and perfused with a hetastarch solution at Ppulm art/PLA pressures of 10/0 cm H2O. We evaluated overall perfusability from perfusate flows, and from the venous concentrations of 4-um diameter fluorescent latex particles infused into the pulmonary circulation during perfusion. We measured perfusion distribution from the trapping patterns of those particles within the lung. We infused approximately 9 million red fluorescent particles into each lung, followed 20 min later by an infusion of an equal number of green particles. In positive pressure lungs, 94.7 +/- 2.4% of the infused particles remained trapped within the lungs, compared to 86.8 +/- 5.6% in negative pressure lungs ( P <= 0.05). Perfusate flows averaged 2.5 +/- 0.1 mL/min in lungs ventilated with positive pressures, compared to 5.6 +/- 01 mL/min in lungs ventilated with negative pressures ( P <= 0.05). Particle infusions had little effect on perfusate flows. In confocal images of dried sections of each lung, red and green particles were co-localized in clusters in positive pressure lungs, suggesting that acinar vessels that lacked particles were collapsed by these pressures thereby preventing perfusion through them. Particles were more broadly and uniformly distributed in negative pressure lungs, suggesting that perfusion in these lungs was also more uniformly distributed. Our results suggest that the acinar circulation is organized as a web, and further suggest that portions of this web are collapsed by positive pressure ventilation. PMID- 29283017 TI - Tinnitus: Prospects for Pharmacological Interventions With a Seesaw Model. AB - Chronic tinnitus, the perception of lifelong constant ringing in ear, is one capital cause of disability in modern society. It is often present with various comorbid factors that severely affect quality of life, including insomnia, deficits in attention, anxiety, and depression. Currently, there are limited therapeutic treatments for alleviation of tinnitus. Tinnitus can involve a shift in neuronal excitation/inhibition (E/I) balance, which is largely modulated by ion channels and receptors. Thus, ongoing research is geared toward pharmaceutical approaches that modulate the function of ion channels and receptors. Here, we propose a seesaw model that delineates how tinnitus-related ion channels and receptors are involved in homeostatic E/I balance of neurons. This review provides a thorough account of our current mechanistic understanding of tinnitus and insight into future direction of drug development. PMID- 29283016 TI - Pericytes Make Spinal Cord Breathless after Injury. AB - Traumatic spinal cord injury is a devastating condition that leads to significant neurological deficits and reduced quality of life. Therapeutic interventions after spinal cord lesions are designed to address multiple aspects of the secondary damage. However, the lack of detailed knowledge about the cellular and molecular changes that occur after spinal cord injury restricts the design of effective treatments. Li and colleagues using a rat model of spinal cord injury and in vivo microscopy reveal that pericytes play a key role in the regulation of capillary tone and blood flow in the spinal cord below the site of the lesion. Strikingly, inhibition of specific proteins expressed by pericytes after spinal cord injury diminished hypoxia and improved motor function and locomotion of the injured rats. This work highlights a novel central cellular population that might be pharmacologically targeted in patients with spinal cord trauma. The emerging knowledge from this research may provide new approaches for the treatment of spinal cord injury. PMID- 29283018 TI - A practical clinical kinematic model for the upper limbs. AB - A novel clinically practical upper limb model is introduced that has been developed through clinical use in children and adults with neurological conditions to guide surgery to the elbow and wrist. This model has a minimal marker set, minimal virtual markers, and no functional joint centres to minimise the demands on the patient and duration of data collection. The model calculates forearm supination independently from the humerus segment, eliminating any errors introduced by poor modelling of the shoulder joint centre. Supination is calculated by defining the forearm segment twice, from the distal and proximal ends: first, using the ulna and radial wrist markers as a segment defining line and second using the medial and lateral elbow markers as a segment defining line. This is comparable to the clinical measurement of supination utilising a goniometer and enables a reduced marker set, with only the elbow, wrist, and hand markers to be applied when only the wrist and forearm angles are of interest. A sensitivity analysis of the calculated elbow flexion-extension angles to the position of the glenohumeral joint centre is performed on one healthy female subject, aged 20 years, during elbow flexion and a forward reaching task. A comparison of the supination angles calculated utilising the novel technique compared to the rotation between the humeral and forearm segments is also given. All angles are compared to a published kinematic model that follows the recommendations of the International Society of Biomechanics. PMID- 29283019 TI - Effects of different foot progression angles and platform settings on postural stability and fall risk in healthy and medial knee osteoarthritic adults. AB - This study aims to investigate the effects of varying toe angles at different platform settings on Overall Stability Index of postural stability and fall risk using Biodex Balance System in healthy participants and medial knee osteoarthritis patients. Biodex Balance System was employed to measure postural stability and fall risk at different foot progression angles (ranging from -20 degrees to 40 degrees , with 10 degrees increments) on 20 healthy (control group) and 20 knee osteoarthritis patients (osteoarthritis group) randomly (age: 59.50 +/- 7.33 years and 61.50 +/- 8.63 years; body mass: 69.95 +/- 9.86 kg and 70.45 +/- 8.80 kg). Platform settings used were (1) static, (2) postural stability dynamic level 8 (PS8), (3) fall risk levels 12 to 8 (FR12) and (4) fall risk levels 8 to 2 (FR8). Data from the tests were analysed using three-way mixed repeated measures analysis of variance. The participant group, platform settings and toe angles all had a significant main effect on balance ( p <= 0.02). Platform settings had a significant interaction effect with participant group F(3, 144) = 6.97, p < 0.01 and toe angles F(21, 798) = 2.83, p < 0.01. Non significant interactions were found for group * toe angles, F(7, 266) = 0.89, p = 0.50, and for group * toe angles * settings, F(21, 798) = 1.07, p = 0.36. The medial knee osteoarthritis group has a poorer postural stability and increased fall risk as compared to the healthy group. Changing platform settings has a more pronounced effect on balance in knee osteoarthritis group than in healthy participants. Changing toe angles produced similar effects in both the participant groups, with decreased stability and increased fall risk at extreme toe-in and toe-out angles. PMID- 29283020 TI - GABA-from Inhibition to Cognition: Emerging Concepts. AB - Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA. PMID- 29283021 TI - Structural plasticity and thermal stability of the histone-like protein from Spiroplasma melliferum are due to phenylalanine insertions into the conservative scaffold. AB - The histone-like (HU) protein is one of the major nucleoid-associated proteins of the bacterial nucleoid, which shares high sequence and structural similarity with IHF but differs from the latter in DNA-specificity. Here, we perform an analysis of structural-dynamic properties of HU protein from Spiroplasma melliferum and compare its behavior in solution to that of another mycoplasmal HU from Mycoplasma gallisepticum. The high-resolution heteronuclear NMR spectroscopy was coupled with molecular-dynamics study and comparative analysis of thermal denaturation of both mycoplasmal HU proteins. We suggest that stacking interactions in two aromatic clusters in the HUSpm dimeric interface determine not only high thermal stability of the protein, but also its structural plasticity experimentally observed as slow conformational exchange. One of these two centers of stacking interactions is highly conserved among the known HU and IHF proteins. Second aromatic core described recently in IHFs and IHF-like proteins is considered as a discriminating feature of IHFs. We performed an electromobility shift assay to confirm high affinities of HUSpm to both normal and distorted dsDNA, which are the characteristics of HU protein. MD simulations of HUSpm with alanine mutations of the residues forming the non-conserved aromatic cluster demonstrate its role in dimer stabilization, as both partial and complete distortion of the cluster enhances local flexibility of HUSpm. PMID- 29283022 TI - CNS Injury: Posttranslational Modification of the Tau Protein as a Biomarker. AB - The ideal biomarker for central nervous system (CNS) trauma in patients would be a molecular marker specific for injured nervous tissue that would provide a consistent and reliable assessment of the presence and severity of injury and the prognosis for recovery. One candidate biomarker is the protein tau, a microtubule associated protein abundant in the axonal compartment of CNS neurons. Following axonal injury, tau becomes modified primarily by hyperphosphorylation of its various amino acid residues and cleavage into smaller fragments. These posttrauma products can leak into the cerebrospinal fluid or bloodstream and become candidate biomarkers of CNS injury. This review examines the primary molecular changes that tau undergoes following traumatic brain injury and spinal cord injury, and reviews the current literature in traumatic CNS biomarker research with a focus on the potential for hyperphosphorylated and cleaved tau as sensitive biomarkers of injury. PMID- 29283023 TI - Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons. AB - The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions. PMID- 29283024 TI - Assessment of executive functions in children and adolescents with acquired brain injury (ABI) using a novel complex multi-tasking computerised task: The Jansari assessment of Executive Functions for Children (JEF-C(c)). AB - OBJECTIVES: The Jansari assessment of Executive Functions for Children (JEF-C(c)) is a new non-immersive computerised assessment of executive functions. The objectives of the study were to test the feasibility and validity of JEF-C(c) in children and adolescents with acquired brain injury (ABI). METHODS: Twenty-nine patients with ABI aged 10-18 years and 30 age-and gender-matched controls were tested. Participants performed JEF-C(c), Wechsler Abbreviated Scale of Intelligence (WASI) and the Behavioural Assessment of the Dysexecutive Syndrome for Children (BADS-C), while parents completed the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire. RESULTS: The JEF-C(c) task proved feasible in patients with ABI. The internal consistency was medium (Cronbach's alpha = 0.62 and significant intercorrelations between individual JEF-C(c) constructs). Patients performed significantly worse than controls on most of the JEF-C(c) subscales and total score, with 41.4% of participants with ABI classified as having severe executive dysfunction. No significant correlations were found between JEF-C(c) total score, the BRIEF indices, and the BADS-C. Significant correlations were found between JEF-C(c) and demographic characteristics of the sample and intellectual ability, but not with severity/medical variables. CONCLUSION: JEF-C(c) is a playful complex task that appears to be a sensitive and ecologically valid assessment tool, especially for relatively high-functioning individuals. PMID- 29283025 TI - Polycomb Repressive Complex 2: Emerging Roles in the Central Nervous System. AB - The polycomb repressive complex 2 (PRC2) is responsible for catalyzing both di- and trimethylation of histone H3 at lysine 27 (H3K27me2/3). The subunits of PRC2 are widely expressed in the central nervous system (CNS). PRC2 as well as H3K27me2/3, play distinct roles in neuronal identity, proliferation and differentiation of neural stem/progenitor cells, neuronal morphology, and gliogenesis. Mutations or dysregulations of PRC2 subunits often cause neurological diseases. Therefore, PRC2 might represent a common target of different pathological processes that drive neurodegenerative diseases. A better understanding of the intricate and complex regulatory networks mediated by PRC2 in CNS will help to develop new therapeutic approaches and to generate specific brain cell types for treating neurological diseases. PMID- 29283026 TI - Restoring Motor Functions After Stroke: Multiple Approaches and Opportunities. AB - More than 1.5 million people suffer a stroke in Europe per year and more than 70% of stroke survivors experience limited functional recovery of their upper limb, resulting in diminished quality of life. Therefore, interventions to address upper-limb impairment are a priority for stroke survivors and clinicians. While a significant body of evidence supports the use of conventional treatments, such as intensive motor training or constraint-induced movement therapy, the limited and heterogeneous improvements they allow are, for most patients, usually not sufficient to return to full autonomy. Various innovative neurorehabilitation strategies are emerging in order to enhance beneficial plasticity and improve motor recovery. Among them, robotic technologies, brain-computer interfaces, or noninvasive brain stimulation (NIBS) are showing encouraging results. These innovative interventions, such as NIBS, will only provide maximized effects, if the field moves away from the "one-fits all" approach toward a "patient-tailored" approach. After summarizing the most commonly used rehabilitation approaches, we will focus on NIBS and highlight the factors that limit its widespread use in clinical settings. Subsequently, we will propose potential biomarkers that might help to stratify stroke patients in order to identify the individualized optimal therapy. We will discuss future methodological developments, which could open new avenues for poststroke rehabilitation, toward more patient-tailored precision medicine approaches and pathophysiologically motivated strategies. PMID- 29283027 TI - Serine/threonine phosphatase 5 (PP5C/PPP5C) regulates the ISOC channel through a PP5C-FKBP51 axis. AB - Pulmonary endothelial cells express a store-operated calcium entry current ( Isoc), which contributes to inter-endothelial cell gap formation. Isoc is regulated by a heterocomplex of proteins that includes the immunophilin FKBP51. FKBP51 inhibits Isoc by mechanisms that are not fully understood. In pulmonary artery endothelial cells (PAECs) we have shown that FKBP51 increases microtubule polymerization, an event that is critical for Isoc inhibition by FKBP51. In neurons, FKBP51 promotes microtubule stability through facilitation of tau dephosphorylation. However, FKBP51 does not possess phosphatase activity. Protein phosphatase 5 (PP5C/PPP5C) can dephosphorylate tau, and similar to FKBP51, PP5C possesses tetratricopeptide repeats (TPR) that mediate interaction with heat shock protein-90 (HSP90) chaperone/scaffolding complexes. We therefore tested whether PP5C contributes to FKBP51-mediated inhibition of Isoc. Both siRNA mediated suppression of PP5C expression in PAECs and genetic disruption of PP5C in HEK293 cells attenuate FKBP51-mediated inhibition of Isoc. Reintroduction of catalytically competent, but not catalytically inactive PP5C, restored FKBP51 mediated inhibition of Isoc. PAEC cell fractionation studies identified both PP5C and the ISOC heterocomplex in the same membrane fractions. Further, PP5C co precipitates with TRPC4, an essential subunit of ISOC channel. Finally, to determine if PP5C is required for FKBP51-mediated inhibition of calcium entry induced inter-endothelial cell gap formation, we measured gap area by wide-field microscopy and performed biotin gap quantification assay and electric cell substrate impedance sensing (ECIS(r)). Collectively, the data presented indicate that suppression of PP5C expression negates the protective effect of FKBP51. These observations identify PP5C as a novel member of the ISOC heterocomplex that is required for FKBP51-mediated inhibition of Isoc. PMID- 29283028 TI - CXCL12/CXCR4/CXCR7 Chemokine Axis in the Central Nervous System: Therapeutic Targets for Remyelination in Demyelinating Diseases. AB - The chemokine CXCL12 plays a vital role in regulating the development of the central nervous system (CNS) by binding to its receptors CXCR4 and CXCR7. Recent studies reported that the CXCL12/CXCR4/CXCR7 axis regulates both embryonic and adult oligodendrocyte precursor cells (OPCs) in their proliferation, migration, and differentiation. The changes in the expression and distribution of CXCL12 and its receptors are tightly associated with the pathological process of demyelination in multiple sclerosis (MS), suggesting that modulating the CXCL12/CXCR4/CXCR7 axis may benefit myelin repair by enhancing OPC recruitment and differentiation. This review aims to integrate the current findings of the CXCL12/CXCR4/CXCR7 signaling pathway in the CNS and to highlight its role in oligodendrocyte development and demyelinating diseases. Furthermore, this review provides potential therapeutic strategies for myelin repair by analyzing the relevance between the pathological changes and the regulatory roles of CXCL12/CXCR4/CXCR7 during MS. PMID- 29283030 TI - Design and optimization of noscapine nanosuspensions and study of its cytotoxic effect. PMID- 29283029 TI - Hemodynamic profile of pulmonary hypertension (PH) in ARDS. AB - Acute respiratory distress syndrome (ARDS) is a diffuse lung injury that leads to a severe acute respiratory failure. Traditional diagnostic criteria for pulmonary hypertension (PH), in this situation, may be unreliable due to the effects of positive pressure ventilation and vasoactive agents. The aim of this study is to describe the hemodynamic characteristics of PH secondary to ARDS, in relation with respiratory parameters. We assessed the hemodynamic, respiratory function, and ventilator parameters in a cohort of 38 individuals with ARDS-associated PH defined by mean pulmonary arterial pressure (mPAP) >= 25 mmHg. Individual characteristics: PaO2/FiO2 = 110 +/- 60 mmHg, alveolar-arterial oxygen gradient (A-aO2) = 549 +/- 148.9 mmHg, positive end-expiratory pressure (PEEP) = 8.7 +/- 3.5 cmH2O, pulmonary static compliance (Cstat) = 30 +/- 12.1 L*cmH2O-1, mPAP = 35.4 +/-6.6 mmHg, pulmonary artery wedge pressure (PAWP) = 15.6 +/- 5.5 mmHg, cardiac index (CI) = 3.4 +/- 1.2 L/min/m2, pulmonary vascular resistance (PVR) = 3.3 +/- 1.6 Wood units (WU), right atrial pressure (RAP) = 13.4 +/- 5.4 mmHg, diastolic pulmonary gradient (DPG) = 12.6 +/- 6.5 mmHg, and trans-pulmonary gradient (TPG) = 19.7 +/- 7.7 mmHg. The composite marker-DPG >7 mmHg and PVR > 3 WU-is associated with lower CI ( P = 0.016), higher mPAP ( P = 0.003), and lower pulmonary static compliance ( P = 0.028). We confirmed a poor prognosis of ARDS associated with PH, with a 50% survival rate after 17 days. We observed that the survival rate at 28 days was better in the case of improvement in the PaO2/FiO2 ratio in the first 24 h (log rank P = 0.003). ARDS associated with PH is a severe condition with a very poor survival rate. The composite marker DPG > 7 mmHg and PVR > 3 WU seemed to better describe the hemodynamic and respiratory dysfunction. The improvement in PaO2/FiO2 ratio in the first 24 h defined a better survival in our cohort of patients. PMID- 29283031 TI - Epoprostenol discontinuation in patients with pulmonary arterial hypertension: a complex medical and social problem. PMID- 29283032 TI - Integrated bio-oxidation and adsorptive filtration reactor for removal of arsenic from wastewater. AB - Recently, removal of arsenic from different industrial effluent discharged using simple, efficient and low-cost technique has been widely considered. In this study, removal of arsenic (As) from real wastewater has been studied employing modified bio-oxidation followed by adsorptive filtration method in a novel continuous flow through the reactor. This method includes biological oxidation of ferrous to ferric ions by immobilized Acidothiobacillus ferrooxidans bacteria on granulated activated carbon (GAC) in fixed bed bio-column reactor with the adsorptive filtration unit. Removal efficiency was optimized regarding the initial flow rate of media and ferrous ions concentration. Synthetic wastewater sample having different heavy metal ions such as Arsenic (As), Cobalt (Co), Chromium (Cr), Copper (Cu), Iron (Fe), Lead (Pb) and Manganese (Mn) were also used in the study. The structural and surface changes occurring after the treatment process were scrutinized using FT-IR and Scanning Electron Microscopy (SEM) analysis. The finding showed that not only arsenic can be removed considerably in the bioreactor system, but also removing efficiency was much more (<90%) for other heavy metals in real wastewater sample. The results from TCPL test confirms that solid spent media was non-hazardous and can be safely disposed of. This study verified that combination of bio-oxidation with adsorptive filtration method improves the removal efficiency of arsenic and other heavy metal ions in wastewater sample. PMID- 29283033 TI - Hospitals as factories of medical garbage. AB - Over the course of the twentieth century, as hospitals cleaned up, they came to produce more and more rubbish. Beginning in the 1970s and gaining pace in the 1980s and 1990s, single-use plastic items (syringes, blood bags, tubing) saturated everyday medical practice across the globe. This essay brings the question of plastic to bear upon the longer history of twentieth century sanitary science. The widespread adoption of single-use disposable medical plastics consolidated a century's worth of changes in medical hygiene. As strange as it may seem today, the initial uptake of medical plastics was not driven primarily by concerns about hygiene. Plastic began as a mid-century technology of convenience and durability. It was not until the end of the twentieth century that it morphed into a powerful symbol and instrument of medical hygiene. Today, both patients and practitioners have embraced plastic as an indispensable technology of clean medicine. The procession of single-use medical plastics through everyday medicine now comprises a constant, if disposable, infrastructure of medical hygiene. This new processional infrastructure of disposable hygiene has produced another, albeit unintended, consequence. This new regime has exponentially increased hospitals' material outputs. In so doing, plastic has refigured the ecologies of everyday medicine. Plastic hygiene has rendered hospitals factories of medical garbage. PMID- 29283034 TI - 'The fragile medical: the slippery terrain between medicine, anthropology and societies'. PMID- 29283035 TI - Of sacraments, sacramentals and anthropology: is anthropological explanation sacramental? AB - This paper suggests that what is usually called a cultural misunderstanding of biomedical disease categories may be construed as a biomedical and anthropological misunderstanding of cultural categories. This is premised on the fact that anthropology often functions as an intimate double and handmaiden of biomedicine, in so far as it refuses to countenance the possibility of theurgic aetiologies in the realm of what is called 'mental illness'. Such a refusal displaces native explanations of divine or demonic agency to human agency. This is best elucidated by examining the unexamined religious beliefs of Anglo European anthropology, which appears to be the terra firma of its emic explanatory categories. The paper attempts to demonstrate this by proposing that while native explanations are akin to the sacraments, anthropological explanations are akin to sacramentals (holy water, the cross, the scapular, verbal blessings). While the sacraments, like divine agency, operate ex opere operato, the sacramentals are dependent on the disposition of the recipient and on the good offices of the church, as they operate ex opere operantis ecclesiae (from the work of the working church), as well as ex opere operantis (from the work of the working one). If the sacraments are efficacious as it is work done by Christ alone, and akin to work done by the possessing agent, sacramentals are efficacious as they are also dependent on human agency. In other words, anthropological explanations are, at best, 'sacramental' as they replace emic theurgic explanations by etic ones, where human agency in the form of the priest, the institution of the church, and the lay person who is the recipient of divine dispensation, also have a role to play; or, as is often the case, the only role to play. PMID- 29283036 TI - From distress to disease: a critique of the medicalisation of possession in DSM 5. AB - This paper critiques the category of possession-form dissociative identity disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) published in 2013 by the American Psychiatric Association (APA). The DSM as an index of psychiatry pathologises possession by categorising it as a form of dissociative identity disorder. Drawing upon ethnographic fieldwork, this paper argues that such a pathologisation medicalises possession, which is understood as a non-pathological condition in other contexts such as by those individuals who manifest possession at a temple in Kerala, South India. Through medicalising and further by creating distinctions between acceptable and pathological possession, the DSM converts a form of distress into a disease. This has both conceptual and pragmatic implications. The temple therefore becomes reduced to a culturally acceptable site for the manifestation of a mental illness in a form that is culturally available and possession is explained solely through a biomedical framework, denying alternative conceptualisations and theories which inform possession. By focussing on the DSM-5 classification of possession and the limitations of such a classification, this paper seeks to posit an alternative conceptualisation of possession by engaging with three primary areas which are significant in the DSM categorisation of possession: the DSM's conceptualisation of self in the singular, the distinction between pathological and non pathological forms of possession, and the limitations of the DSM's equation of the condition of possession with the manifestation of possession. Finally, the paper briefly highlights alternative conceptualisations of possession, which emerged from the perspective of those seeking to heal possession at the Chottanikkara temple. PMID- 29283037 TI - A critique of medicalisation: three instances. AB - By briefly exploring three different examples where the existence of mental illness and developmental delay has been presumed, this paper sheds light on the way what Foucault calls the emergence of a regime of truth, i.e. where something that does not exist is made to exist through the construction of a system of truth around it. The first example concerns the direct marketing of pharmaceutical products to consumers in the US, the second the use of psychology in semi-post-Cold War Korea, and the third the persisting authority of psychology in the treatment of the developmentally delayed. While these instances are not innately connected, looking at these as part of the process by which the authoritative knowledge is established will help us understand, albeit partially, the mechanism by which mental illness penetrates our lives as truth, and how this regime of truth is supported by the authority of psychology, psychiatry and psychoanalysis, what Foucault calls the 'psy-function,' reinforcing the medicalisation of our lives. PMID- 29283038 TI - Humanitarian quarantine in practice: medicine, religion and leprosy in New Caledonia. AB - Medicine and religion worked in close synchronisation during the leprosy outbreak of New Caledonia (1890-1950). Once isolation of leprosy-affected people became mandatory doctors and missionaries came together to promote a particular form of medical practice that tied charitable zeal with cutting-edge medical research, developing a sophisticated set of medical practices that catered for the soul as well as the body. Such practices went hand-in-hand with ideas developed by doctors in the earlier stages of the epidemic about the way in which the disease had entered the Kanak (local Melanesian) population. Doctors and missionaries admitted that immoral colonial channels had upset the delicate balance of local social and biological rhythms. Yet they also believed that the highly contagious nature of the outbreak was linked to the inferior state of Kanak. This paper aims to highlight the way in which the leprosaria system in New Caledonia represented a double-edged moral high-ground within the French medical colonial narrative. It tracks the complex way in which emotionally charged arguments about contagion, science and spirituality constructed an ideology of humanitarian quarantine which was used to justify a highly aggressive form of medical biocontrol. PMID- 29283039 TI - In vitro and in vivo delivery of atorvastatin: A comparative study of anti inflammatory activity of atorvastatin loaded copolymeric micelles. AB - Statins have been shown to exert 'pleiotropic effects' independent of their cholesterol lowering actions that include anti-inflammatory properties. In this study we synthesized mono methoxy poly (ethylene glycol)-poly (epsilon caprolactone) (mPEG-PCL) di block copolymers. The structure of the copolymers was characterized by H nuclear magnetic resonance, Fourier-transform infrared spectroscopy, differential scanning calorimetry and gel permeation chromatography techniques. In this method, atorvastatin was encapsulated within micelles through a single-step nano-precipitation method, leading to the formation of atorvastatin loaded mPEG-PCL (atorvastatin/mPEG-PCL) micelles. The resulting micelles were characterized further by various techniques such as dynamic light scattering and atomic force microscopy. In this study the anti-inflammatory activity of atorvastatin and atorvastatin/mPEG-PCL micelles on acute models of inflammation are analyzed, to compare the effect of indometacin in rats. Carrageenan induces rat paw edema; six animals of each group (10 groups) received indometacin, atorvastatin, and atorvastatin/mPEG-PCL micelles orally 1, 6, 12 and 24 h before carrageenan injection in paw. The paw edema thickness measured at 1, 2, 3 and 4 h after injection and percentage inhibition of edema in various groups were calculated. The results showed that the zeta potential of micelles was about 16.6 mV and the average size was 81.7 nm. Atorvastatin was encapsulated into mPEG PCL micelles with loading capacity of 14.60 +/- 0.96% and encapsulation efficiency of 62.50 +/- 0.84%. Atorvastatin and atorvastatin/mPEG-PCL micelles showed significant anti-inflammatory activity in the present study. The anti inflammatory activity of atorvastatin and atorvastatin/mPEG-PCL micelles was significant in comparison with indometacin. Atorvastatin/mPEG-PCL micelles showed more anti-inflammatory activity than atorvastatin. This study revealed the anti inflammatory activity of atorvastatin and atorvastatin/mPEG-PCL micelles and suggested the statins have a potential inflammatory activity along with its lipid lowering properties. Contrary to anti-inflammatory effects, the pro-inflammatory responses are independent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition and can be mediated directly by atorvastatin. PMID- 29283040 TI - "Just Say It Like It Is!" Use of a Community-Based Participatory Approach to Develop a Technology-Driven Food Literacy Program for Adolescents. AB - FuelUp&Go! is a technology-driven food literacy program consisting of six in person skill building sessions as well as fitness trackers, text messages, and a companion website. A community-based participatory research approach was used with adolescents who were recruited to participate in a Kid Council. Qualitative data were collected about the use of surveys, program activities, recipes, technology and text messages, and music and incentives. Changes suggested by Kid Councilmembers informed the design and development of a pilot program. Participants were recruited for the pilot program and completed pre- and postintervention surveys. The results indicated food-related knowledge remained low but increased from baseline to follow-up. Attitudes toward vegetables and physical activity increased slightly. Self-reported participation in physical activity and consumption of sugar-added beverages moved in positive directions. These findings suggest that community-based participatory research approach is an effective approach to engage adolescents in the development of a technology driven food literacy program. PMID- 29283041 TI - Interactive Malaria Education Intervention and Its Effect on Community Participant Knowledge: The Malaria Awareness Program in Vhembe District, Limpopo, South Africa. AB - Malaria is preventable and treatable, yet remains the most prevalent parasitic endemic disease in Africa. This article analyzes prospective observational data from the Malaria Awareness Program (MAP), an interactive malaria education initiative led by home-based care workers to improve participant knowledge of malaria as a precursor to increased uptake of malaria control interventions in the Vhembe District, Limpopo, South Africa. Between 2012 and 2016, 1,330 individuals participated in MAP. MAP's effectiveness was measured through pre- and post-participation surveys assessing knowledge in malaria transmission, symptoms, prevention, and treatment. The primary analysis assessed differences in knowledge between individuals who completed MAP ( n = 499) and individuals who did not complete MAP ( n = 399). The adjusted odds of correct malaria knowledge score versus partially correct or incorrect score among MAP completers was 3.3 and 2.8 times greater for transmission and prevention, respectively ( p values<.001). A subanalysis assessed knowledge improvement among participants who completed both pre- and post-MAP intervention surveys ( n = 266). There was a 21.4% and 10.5% increase in the proportion of participants who cited correct malaria transmission and prevention methods, respectively. Future research should assess behavioral changes toward malaria prevention and treatment as a result of an intervention and examine incidence changes in the region. PMID- 29283042 TI - Rethinking the Role of the Angular Gyrus in Remembering the Past and Imagining the Future: The Contextual Integration Model. AB - Despite consistent activation on tasks of episodic memory, the precise contribution of the left angular gyrus (AG) to mnemonic functions remains vigorously debated. Mounting evidence suggests that AG activity scales with subjective ratings of vividness and confidence in recollection, with further evidence pointing to its involvement during construction of detailed and coherent future simulations. Lesion studies, however, indicate that damage to the AG does not render patients amnesic on standard source and associative memory paradigms. To reconcile these findings, we present the Contextual Integration Model as a unifying framework that couches the mnemonic role of the AG in terms of multimodal integration and representation of contextual information across temporal contexts. Irrespective of whether one is remembering the past or constructing future or hypothetical scenarios, the Contextual Integration Model holds that the core elements of an event (i.e., the who, what, when, where) are bound within the medial temporal lobes while the multimodal details, which give rise to perceptually rich recollection, are integrated and represented in the AG. Building on previous work, the Contextual Integration Model therefore provides a comprehensive exposition of the mnemonic and constructive functions of the AG across temporal contexts, offering a novel test-bed for future work. PMID- 29283044 TI - Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic disease. AB - Symptomatic patients with residual pulmonary perfusion defects or vascular lesions but no pulmonary hypertension at rest are diagnosed with chronic thromboembolic disease (CTED). Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but data regarding the safety and efficacy of BPA in patients with CTED are lacking. We report a prospective series of ten consecutive patients with CTED who underwent 35 BPA interventions (median of four per patient) at two German institutions. All patients underwent a comprehensive diagnostic workup at baseline and 24 weeks after their last intervention. BPA was safe, with one pulmonary vascular injury and subsequent self-limiting pulmonary bleeding as the only complication (2.9% of the interventions, 10% of the patients). After the procedures, World Health Organization functional class, 6 min walking distance, pulmonary vascular resistance, and pulmonary arterial compliance improved, and NT-proBNP concentrations declined in 9/10 patients. BPA may be a new treatment option for carefully selected patients with CTED. A larger, prospective, international registry is required to confirm these results. PMID- 29283045 TI - Glucose-lowering Strategies in Diabetes: Pharmacological Development of New Antidiabetic Drugs. AB - BACKGROUND: Insulin increases glucose uptake in muscles and fat and inhibits hepatic glucose production, thus serving as the primary regulator of the blood glucose level. In type 2 diabetes, insufficient insulin release and suppressed insulin action [named insulin resistance] lead to increased glucose production in liver and decreased glucose uptake by muscles and fat tissues, resulting in elevated blood glucose concentration which is dangerous to human health. Therefore, the anti-diabetic therapies are aimed at inhibiting excess blood glucose. METHODS: A comparative analysis of two distinct glucose-lowering modes was used to develop a new feedback model for the purpose of identification of pharmacological targets in diabetes treatment. RESULTS: The current brief opinion proposes an original feedback control of glucose-lowering regulation and its models which allow comparing two distinct strategies of glucose level correction, i.e., one of them allows reducing the increased threshold of insulin resistance, whereas the other allows overcoming this threshold/barrier using exogenous insulin treatment. Also, this analytic research presents selected examples comparing the influence of the two analyzed strategies on the normalization of glucose metabolism, their therapeutic potential and side effects associated with additional weight gain. These models show the pathological mechanism by which exogenous insulin provokes formation of a "vicious cycle" by its side effects associated with additional weight gain. CONCLUSION: The presented model and findings can contribute to the development of new anti-diabetic targets and drugs with minimal side effects. PMID- 29283046 TI - Vitamin D Increases Abeta140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients. AB - BACKGROUND: Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of beta-amyloid (Abeta) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo. OBJECTIVE: To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Abeta1-40 plasma levels in MCI and very early AD (VEAD) patients. METHOD: Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D 11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Abeta1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months. RESULTS: Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Abeta1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation. CONCLUSION: Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process. PMID- 29283047 TI - Is it All Said for NSAIDs in Alzheimer's Disease? Role of Mitochondrial Calcium Uptake. AB - OBJECTIVES: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX dependent and independent mechanisms have been proposed, including gamma secretase that cleaves the amyloid precursor protein (APP) and yields amyloid beta peptide (Abeta). METHODS: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Abeta oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low uM range and prevent mitochondrial Ca2+ overload induced by Abeta oligomers and/or N-methyl-D aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (DeltaPsi) leading to cell death. RESULTS: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD. PMID- 29283043 TI - Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series). AB - Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development. PMID- 29283048 TI - Compensatory Shift of Subcallosal Area and Paraterminal Gyrus White Matter Parameters on DTI in Patients with Alzheimer Disease. AB - OBJECTIVE: Alzheimer disease is traditionally conceptualized as a disease of brain gray matter, however, studies with diffusion tensor imaging have demonstrated that Alzheimer disease also involves alterations in white matter integrity. We measured number of tracts, tracts length, tract volume, quantitative anisotropy and general fractional anisotropy of neuronal tracts in subcallosal area, paraterminal gyrus and fornix in patients with Alzheimer disease and healthy age-matched controls. Our hypothesis was that patients with Alzheimer disease should exhibit decrease in the integrity of these white matter structures that are crucial for semantic memory function. METHODS: For our study were selected 24 patients with confirmed Alzheimer disease diagnosis and 24 healthy controls (AD center, Department of Neurology, Charles University, Prague, Czech Republic). Statistically significant differences between the patients with Alzheimer disease and the control group were found both on the left and right fornices but only concerning the tract numbers and tract length. The subcallosal area and paraterminal gyrus showed statistically significant differences between the patients with Alzheimer disease and the control group, but only on the left side and only associated with the tract volume and quantitative anisotropy. CONCLUSION: Our explanation for these findings lies in the severe hippocampal atrophy (and subsequent loss of function) with compensatory hypertrophy of the subcallosal area and paraterminal gyrus neuronal fibers that occurs in Alzheimer's disease, as an adaptation to the loss of projection from the hippocampal formation via fornix. PMID- 29283049 TI - Editorial: Targeting of Cancer Cells and Tumor Microenvironment: Perspectives for Personalized Therapy. PMID- 29283050 TI - Antibiotics Associated Disorders and Post-biotics Induced Rescue in Gut Health. AB - The gut microbiota plays significant roles in the human body during all spheres' of life and influences innate immunity, promotes granulocyte signaling and provides resistance during pathogenic colonization of the gut; crucial for a healthy life. Antibiotics directly affect the gut microbiota that consequently alters the basic biological processes and imposes severe consequences in population falling under different age groups. In this article, we assessed the differences in microbial colonization and immune function of the intestinal tract in infants, adults, and the aged people and also examined the recent reports describing the impacts of antibiotics on infant microbiome assembly and functioning. The age old techniques have been compared to modern ones in relation to the functioning of the gut microbiome to draw inferences on significant impacts of various microbiota on human life starting from the womb, through infancy, adulthood and old age. It was observed that data is limited to different classes or origin of populace depicting variations in food habits and/or suffering from heavy metal associated diseases after continuous exposure to heavy metals/ metalloids/ biocides. Such extreme environmental factors significantly modulate the microbiota and assist in creating a 'co-resistant' gene pool that influences gut health. In the light of this finding, it is important to analyze the 'co-resistant' gene pool existing in gut-microbiome which supports to recoup and establish a healthy life. The hypothesis of 'postbiotics' is under process and their associations with antibiotic turn to be new-insight in antibiotic therapy. On one hand, postbiotics provide a great opportunity to understand the mechanism of action against pathobionts; on the other; they lead to postulation of newer pharmabiotic products and pharmacological strategies for better gut health. PMID- 29283051 TI - Antithrombotic Strategies in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention. AB - The optimal strategy of antithrombotic therapy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention remains to be a question to be answered. The major challenge in such population is the balance between the benefit of reduced stroke and coronary ischemic events, against the risk of increased bleeding complications. Thus, both thrombotic and bleeding risk assessments should be included into clinical decision-making process for such patients. Currently, there is limited evidence based on randomized trials with adequate power to show the superiority of any strategy in the beneficial profile of safety and efficacy, thus limited recommendations are provided by clinical guidelines. Given the recent advancement in this field, our review provided an overview of the available risk stratification schemes for stroke and bleeding risk for AF patients, discussed the multiple questions in the optimal regimens of oral antiplatelet and anticoagulation therapy, and summarized evidence and recommendations related to long-term antithrombotic therapy for AF patients receiving stent implications. PMID- 29283052 TI - Thrombolytic Therapy in the Current ERA: Myocardial Infarction and Beyond. AB - Thrombolytic therapy kick-started the era of modern cardiology but in the last few decades it has been largely supplanted by primary percutaneous coronary intervention (PCI) as the go-to treatment for acute myocardial infarction. However, these agents remain important for vast populations without access to primary PCI and acute ischemic stroke. More innovative uses have recently come up for the treatment of a variety of conditions. This article summarizes the history, evidence base and current use of thrombolytics in cardiovascular disease. PMID- 29283053 TI - Structural and Design Evolution of Bio-resorbable Scaffolds: The Journey so Far. AB - BACKGROUND: Coronary stenting has now become a gold standard to prevent or counteract narrowing and obstruction of coronary vessels due to disease or injury. While the use of stents has been successful in this situation, they are not without drawbacks and concerns. Restenosis and stent thrombosis after an interventional procedure are the dreaded side effects resulting from the body's natural response to a foreign object in the vasculature. New developments in drug eluting stents, such as biodegradable materials could mitigate some of the problems like stent thrombosis, at least late stent thrombosis. METHODS: The goal of this work is to identify how the structural and design components of bio resorbable scaffolds (BRS) evolved and get translated into clinical outcomes. All the BRS articles were identified by an internet based search and relevant articles were included in the review. RESULTS: The evolution of BRS from concept to current form is examined and the possible future course this field might turn discussed. CONCLUSION: The BRS field has evolved learning from DES terrain but this technology has its own advantages and limitations. Newer generation of bio resorbable scaffolds will be required to replace current generation of technologically advanced DES. PMID- 29283054 TI - Drug-Coated Balloons Applications in Interventional Cardiology. AB - BACKGROUNDS: Drug coated balloons (DCBs) are new on stented-based anti proliferative drug delivery systems, recently introduced in interventional cardiology. Their primary aim is to transfer an anti-proliferative drug to reduce the subsequent neo-intima hyperplasia and to maintain the normal vessel diameter and function. METHODS: A review of the most recent influential studies about DCBs in all the fields of interventional cardiology has been performed. RESULTS: As demonstrated by different studies, DCBs have different theoretical advantages over Drug Eluting Stents (DESs), especially for the treatment of some endovascular lesions, as In-Stent Restenosis (ISR), coronary bifurcations, small vessels disease and peripheral artery disease at femoropopliteal and below the knee sites. CONCLUSION: Despite the need of further studies are needed to elucidate the optimal use of DCBs their current use in interventional cardiology appears promising. PMID- 29283055 TI - The Role of Angiogenesis in Coronary Artery Disease: A Double-Edged Sword: Intraplaque Angiogenesis in Physiopathology and Therapeutic Angiogenesis for Treatment. AB - Angiogenesis is described as a sprouting and growth process of new blood vessels from pre-existing vasculature. The relationship between angiogenesis and coronary artery disease (CAD) is double-sided. On one hand, angiogenesis within plaques is responsible for facilitating the growth and vulnerability of plaques by causing intraplaque hemorrhage and inflammatory cell influx, and overabundance of erythrocytes and inflammatory cells within a plaque probably causes plaque rupture, further leading to acute coronary syndrome. Therefore, inhibiting intraplaque angiogenesis has been considered as a potential therapeutic target for CAD. On the other hand, aiming at improving reperfusion to the ischemic myocardium in patients with CAD, angiogenesis promoting has been utilized as a therapeutic approach to expand myocardial microvascular network. Current strategies include direct administration of angiogenic growth factors (protein therapy), promoting angiogenic genes expression in vivo (gene therapy), and delivering stem cells (cell therapy) or exosomes (cell free therapy). This article will start by clarifying the basic concept of angiogenesis, interpret the mechanism of excessive intraplaque angiogenesis in atherosclerosis, and discuss its role in the growth and vulnerability of plaques. Then we will focus on the four distinct strategies of therapeutic angiogenesis. Despite promising animal studies and smallscale clinical trials of therapeutic angiogenesis in patients with ischemic heart disease, investigations have far not shown definite evidence of clinical efficacy. Hence, while acknowledging future work that remains to be done to validate the clinical results, we reviewed the critical challenges in this arena and highlighted the exciting progress that has occurred recently. PMID- 29283056 TI - Drug-Coated Balloons: Technologies and Clinical Applications. AB - The progress and development of drug-coated balloons (DCBs) represents an emerging alternative treatment in peripheral and coronary artery diseases, particularly when a non-stent approach is necessary. Several studies and meta analyses have evaluated the clinical outcomes of DCBs in different lesions and this review aims to compile the progress and updated clinical data of DCB strategy in both peripheral artery diseases (PAD) and coronary artery diseases (CAD). The review highlights that clinical data has encouraged the use of DCB for applications in PAD and in the treatment of coronary in-stent restenosis (ISR). The employment of DCB in side branch treatment of bifurcation lesions has been reported to be feasible and safe, with good angiographic and clinical outcome. The use of DCB for arteriovenous fistula and grafts stenoses is a promising strategy, but more clinical data is required to draw reliable conclusions. The limitations and impact of the current generation of DCBs will be discussed and the clinical development of newer generation of the device is also covered in this review. PMID- 29283057 TI - Advanced Strategies in the Diagnosis and Treatment of Patients with Coronary Artery Disease and Heart Failure: When Heart Failure Causes Ischemia and Angiotensin Converting Enzyme Inhibitor and Betablockers Helps in Diuresis. AB - In the diagnosis and management of patients with Coronary Artery Disease (CAD) and chronic Left Ventricular (LV) dysfunction or Heart Failure (HF), there are many uncertainties because of the non-specificity of the symptoms and signs of HF. Usually, severe CAD causes LV dysfunction. However, not rarely, LV dysfunction is the cause or aggravation of ischemia to many subsets of patients with or without CAD. In this article, the care of patients with CAD with LV dysfunction, along with the challenges of diagnosing asymptomatic HF and the criteria for monitoring success are presented. Then the evidence of LV dysfunction triggering or aggravating ischemia is discussed. The newest methodology of assessing the venous blood volume which causes the main presentations of HF when its filling capacity is exceeded will also be presented in details. In summary, the effects of fluid mobilization by conventional medications for CAD (e.g Angiotensin Converting Enzyme Inhibitors (ACEI) or Beta blockers (BB) and their therapeutic mechanisms are discussed. The goal of this review is to present the cardiologist consultants strong scientific evidence of detrimental interaction between CAD and LV dysfunction and the therapeutic action of ACEI and BB in the mobilization of venous fluid. As a result, the management of patients with CAD and HF could be exercised on an advanced level of expertise. PMID- 29283059 TI - Viral Heart Disease and Acute Coronary Syndromes - Often or Rare Coexistence? AB - BACKGROUND: Clinical presentation of viral myocarditis can mimic acute coronary syndrome and making diagnosis of viral heart disease (VHD) may be challenging. The presence of coronary artery disease (CAD) does not always exclude VHD and these entities can coexist. However, the incidence of co-occurrence of CAD and VHD is not precisely known. Moreover, inflammatory process caused by viruses may result in atherosclerotic plaque destabilization. METHODS: The goal of this work is to summarize the current knowledge about co-occurrence of VHD and CAD. This article presents the importance of inflammatory process in both diseases and helps to understand pathophysiological mechanisms underlying their coexistence. It provides information about making differential diagnosis between these entities, including clinical presentation, noninvasive imaging features and findings in endomyocardial biopsy. Although currently there are no standard therapy strategies in coexistence of VHD and CAD, we present some remarkable aspects of treatment of patients, in whom VHD co-occurs with CAD. RESULTS: Viral heart disease may occur both in patients without and with atherosclerotic plaques in coronary arteries. Destabilization of atherosclerotic plaques in coronary arteries can be facilitated by inflammatory process. Increased inflammatory infiltrates in the coronary lesions of patients with VHD can lead to plaques' instability and consequently trigger acute coronary syndrome. CONCLUSION: In this article we attempted to present that co-occurrence of VHD and CAD may have therapeutic implications and as specific antiviral treatment is currently available, proper diagnosis and treatment can improve patient's condition and prognosis. PMID- 29283058 TI - Safety Strategies of Genetically Engineered T Cells in Cancer Immunotherapy. AB - T-cell therapy using genetically engineered T cells modified with either T cell receptor or chimeric antigen receptor holds great promise for cancer immunotherapy. The concerns about its toxicities still remain despite recent successes in clinical trials. Temporal and spatial control of the engineered therapeutic T cells may improve the safety profile of these treatment regimens. To achieve these goals, numerous approaches have been tested and utilized including the incorporation of a suicide gene, the switch-mediated activation, the combinatorial antigen recognition, etc. This review will summarize the toxicities caused by engineered T cells and novel strategies to overcome them. PMID- 29283060 TI - Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease. AB - BACKGROUND: Diabetic dyslipidemia has specifics that differ from dyslipidemia in patients without diabetes, which contributes to accelerated atherosclerosis equally as dysglycemia. The aim of this study was to deduce the interdependence of diabetic dyslipidemia and cardiovascular diseases (CVD), therapeutic strategies and the risk of diabetes development with statin therapy. METHOD: We conducted a literature review of English articles through PubMed, PubMed Central and Cochrane, on the role of diabetic dyslipidemia in atherosclerosis, the antilipemic treatment with statins, and the role of statin therapy in newly developed diabetes, by using key words: atherosclerosis, diabetes mellitus, diabetic dyslipidemia, CVD, statins, nicotinic acid, fibrates, PCSK9 inhibitors. RESULTS: hyperglycemia and dyslipidemia cannot be treated separately in patients with diabetes. It seems that dyslipidemia plays one of the key roles in the development of atherosclerosis. High levels of TG, decreased levels of HDL-C and increased levels of small dense LDL- C particles in the systemic circulation are the most specific attributes of diabetic dyslipidemia, all of which originate from an inflated flux of free fatty acids occurring due to the preceding resistance to insulin, and exacerbated by elevated levels of inflammatory adipokines. Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention. The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate - intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD. Statins alone are thought to possess a small, although of statistical significance, risk of incident diabetes, outweighed by their benefits. CONCLUSION: As important as hyperglycemia and glycoregulation are in CVD development in patients with diabetes, diabetic dyslipidemia plays an even more important role. Statins remain the cornerstone of antilipemic treatment in diabetic dyslipidemia, and their protective effects in CVD progression overcome the risk of statin- associated incident diabetes. PMID- 29283061 TI - Preface. PMID- 29283062 TI - Platelets Structure, Function and Modulator Capacity in Replacement Therapy. AB - INTRODUCTION: Patients with severe thrombocytopenia are presumed to be at increased risk for bleeding, and consequently it has been a standard practice for the past four decades to give allogeneic platelet transfusions to severely thrombocytopenic patients as supportive care. Platelet transfusions may be given either prophylactically to reduce the risk of bleeding, in the absence of clinical hemorrhage (prophylactic transfusions), or to control active bleeding when present (therapeutic transfusions). CONCLUSION: Here we review the structure and function of platelets and discuss the mechanisms of alloimmunization to platelet transfusion. PMID- 29283063 TI - Antiplatelet Potential of Plant-Derived Glycosides as Possible Lead Compounds. AB - BACKGROUND: Blood platelets are crucial for maintaining hemostasis and several events in the woundhealing. However, platelet up-regulation leads to the development and the complications of several cardiovascular diseases. For the effective management of these complications, several synthetic drugs are in clinical practice such as aspirin, warfarin and other drugs. since a long time. But some adverse reactions like aspirin resistance and bleed disorders cause patient incompliance and reduce their therapeutic potential. Thus, the search for potent and safer antiplatelet agents is of great interest. METHODS: Various search engines such as Google, GoogleScholar, PubMed and ScienceDirect were used for the search of antiplatelet glycosides. All peered review journals were considered in the review. RESULTS: Glycoside is a class of naturally-occurring organic compounds that are frequently found in the plant kingdom. Similarly, platelet aggregation beyond the purpose of hemostasis is the underlying cause of blood clottingrelated diseases. The results showed strong potential of plant derived glycosides in various preclinical studies. CONCLUSIONS: This review presents a thorough understanding of plant-derived glycosides as antiplatelet agents with a possible mechanism of action based on the existing literature. In addition, this review discusses the possibility of formulating antiplatelet medications from plant glycosides with strong safety profile. On the basis of strong finding, clinical studies are recommended to ascertain their therapeutic utility. PMID- 29283064 TI - Glycogen Synthase Kinase-3beta as a Putative Therapeutic Target for Bipolar Disorder. AB - BACKGROUND: Bipolar disorder (BD) is a debilitating mental ailment characterized by recurrent episodes of mania and depression. Primary mood-stabilizing drugs like lithium and valproate alleviate the hypomanic or mild to moderate manic episodes in patients with BD. One of the extensively studied underlying mechanisms for these pharmacological interventions is inhibition of intracellular signaling cascades associated with glycogen synthase kinase-3 beta (GSK-3beta), a multi-functional serine-threonine kinase. OBJECTIVE AND METHOD: To summarize the different mechanistic aspects associated with GSK-3beta signaling involved in the pathophysiology of BD and highlights drug discovery approaches pursued for the development of GSK-3beta inhibition with detailed strength, weakness, opportunity, and threat (SWOT) analysis. In this review, we endeavor to establish the correlation between neuronal GSK-3beta inhibition and anti-manic response of different therapeutics used for the treatment of patients with BD. RESULTS: The gene depletion or pharmacological inhibition of GSK-3beta reproduces some of the behavioral effects of lithium including reduction of depression- and manic-like behaviors in rodents, which attested the intracellular GSK- 3beta inhibition as one of the critical steps in mediating behavioral effect of mood-stabilizers. Furthermore, converging evidence supported the participation of GSK-3beta in the regulation of various neurobehavioral functions governed by neurotransmitters dopamine and serotonin. Apart from its crucial involvement in the mechanism of action of mood stabilizers, GSK-3beta signaling pathways have also received attention for their role in the effects of psychoactive therapies like antidepressants, antipsychotics, and neurotrophic factors. CONCLUSION: We anticipate that the GSK-3beta could be a druggable target for several incurable neuropsychiatric disorders including BD. PMID- 29283065 TI - We are not Alone in Our Body: Insights into the Involvement of Microbiota in the Etiopathogenesis and Pharmacology of Mental Illness. AB - BACKGROUND: The etiopathogenesis of psychiatric disorders is still not completely understood. Growing evidence supports the hypothesis that mental illness and related disturbances do not necessarily originate in the brain. Inflammation has been suggested to play a central role in psychiatric disorders and altered levels of peripheral cytokines have been reported in several studies. Recently, it has emerged that bacteria populating the human gut could modulate low-grade inflammation, as well as high-order brain functions, including mood and behavior. These bacteria constitute the microbiota, a large population comprising 40,000 bacterial species and 1,800 phila involved in key processes important to maintain body homeostasis. METHOD: In this review, we present and discuss studies exploring the role of dysbiosis and products of the gutmicrobiota in the pathogenesis of psychiatric disorders, as well as their potential involvement in mediating the effect of antidepressants, mood stabilizers, and antipsychotics. RESULTS: Although this field is still at its early stage of development, a growing number of studies suggest that an altered composition of the gut microbiota, together with translocation of bacterial products into the systemic circulation, might play a role in the pathogenesis of psychiatric disorders as well as in response to psychotropic medications. CONCLUSION: An altered composition and functioning of gut microbiota have been reported in psychiatric disorders, and recent findings suggest that gut bacteria could be involved in modulating the efficacy of psychotropic medications. PMID- 29283066 TI - Herbal Medicine as an Alternative Treatment in Autism Spectrum Disorder: A Systematic Review. AB - BACKGROUND: This review focuses on the efficacy and safety of herbal medicines in the management of autism spectrum disorder (ASD) in humans and animals. METHOD: PubMed, Scopus, Google Scholar, Web of Science, and Science Direct databases were searched up to October 30, 2016. The key terms used were "ASD", "Asperger", "autism", "healing plants", "herbal medicine", and "medicinal plants". In each database, the searches consisted of each of three key terms describing the disorder and subtypes plus each of the terms describing the therapy. All human and animal studies on the effects of herbs with the key outcome of change in autism symptoms were included. In vitro studies were excluded. RESULTS: From the publications perused in the initial database, 3157 results were identified, reviewed and a total of 23 studies were included. Preclinical studies using critically validated models were conducted, with some promising preliminary results. Data availability on controlled clinical studies is currently very limited. The use of different methodologies and the very small number of patients raise doubts about the effects of these preparations. CONCLUSION: Available data do not yet allow us to suggest the effectiveness of herbal medicines as an add-on in the treatment of ASD symptoms. PMID- 29283068 TI - Influence of genetic polymorphisms on mycophenolic acid pharmacokinetics and patient outcomes in renal transplantation. AB - Mycophenolic acid (MPA) is an immunosuppressive drug widely used in the treatment of organ transplantation and autoimmune diseases. Pharmacokinetics and pharmacodynamics of MPA varies between individuals, the potential reasons being the genetic polymorphisms in key enzymes, drug transporters and target proteins of MPA, involving uridine diphosphate glucuronosyltransferase enzymes, organic anion transport polypeptides, multidrug resistance-associated protein 2, inosine monophosphate dehydrogenase and others. These genetic polymorphisms are associated with the metabolism, efficacy and toxicity of MPA, thus resulting in different MPA exposure and patient outcomes. Genetic variations in immune response mediators are also responsible for renal transplant outcomes. In this review, we summarize MPA-related single nucleotide polymorphisms (SNPs) in the clinical randomized controlled trials and cohort studies of renal transplant patients in recent 15 years, and try to provide pharmacogenomics information for drug selection and dose adjustment, aiming to improve drug efficacy and reduce side effects in clinical application of MPA. PMID- 29283067 TI - Safety Limits of Antidepressant Use Plus Combinations: Focus on Cardiovascular Function. AB - BACKGROUND: Antidepressants have been widely prescribed for depression, anxiety, sleep disorders, and in the management of behavioural symptoms of adult-old patients. Although generally safe, newer generation antidepressants are not devoid of the risk of inducing clinically relevant adverse events. OBJECTIVES: To investigate the association between newer generation antidepressants and the occurrence of cardiovascular adverse events and electrocardiogram (ECG) abnormalities. METHOD: Studies were included in the review according to the following criteria: a) clinical trials (placebo-controlled or not) or case reports; b) short- or long-term interventions with antidepressants; c) prescription of newer generation antidepressants as first-line treatment; d) samples of adult or adult-old patients. From a total of 301 articles addressing the association between antidepressants and cardiovascular adverse events as primary or secondary outcomes, we selected 30 controlled clinical trials and 10 case reports. RESULTS: In most clinical studies, the effects of antidepressants on cardiac function are usually computed as secondary outcome variables, however with limited information. Conversely, case reports tend to present more comprehensive sets of clinical and laboratorial parameters, but the generalization of such data is limited by the small number of observations. The occurrence of QTc prolongation (with increased risk of torsade de pointes) has been reported. Aging, higher dosages of antidepressants, drug interaction, and pre-existing cardiovascular comorbidities were found as risk factors for the aforementioned cardiovascular and ECG abnormalities. CONCLUSION: Prescribing antidepressants requires caution given their potential impact on cardiac function, and the clinician should carefully monitor cardiovascular and ECG parameters particularly in cases with underlying heart disease. PMID- 29283069 TI - Structure Activity Relationship of Venom Toxins Targeting Potassium Channels. AB - BACKGROUND: Peptide toxins are naturally occurring rich sources of highly specific bioactive compounds from venomous animals acting on various types of ion channels. OBJECTIVE: This study mainly highlights targeting of one of the largest families of ion channels i.e. potassium channels via venom toxins. METHOD: Data for reported venom toxins from diverse species is gathered and analyzed at sequence and structural extent. RESULTS: The similarities and differences among toxins have been demonstrated along with structure activity relationship of potassium channels with these toxins. CONCLUSION: This review highlights the importance of functionally important residues and structural scaffolds of venoms interacting with potassium channels. PMID- 29283070 TI - Pharmacogenomics of methotrexate: Current status and future outlook. AB - BACKGROUND: Methotrexate (MTX) is a folate analogue with high therapeutic efficiency in the treatment of cancers and autoimmune diseases. The efficacy and toxicity of MTX may be altered by genetic polymorphisms in genes involved in MTX metabolic pathway. Personalized pharmacotherapy based on gene polymorphisms enables a more efficient, compatible and cost-effective treatment of patients. OBJECTIVE: Present article aims to review genetic polymorphisms associated with MTX pharmacokinetics, toxicity, and outcome, and try to point out future development directions of individualized MTX therapy. METHOD: Details regarding the pharmacogenetics and pharmacogenomics of MTX are obtained from PubMed literatures. CONCLUSION: The influences of single nucleotide polymorphisms (SNPs) in genes involved in MTX pathway are controversial. Many pharmacogenetic associations are disease specific and race specific. The present studies have almost limited to some certain ethnic groups and diseases. The data from these studies are not convincing enough to draw far-reaching conclusions about the applicability of MTX pharmacogenetics in clinical practice. Studies with large scale and multiple centers are needed in the future. MTX-PG inhibits folic metabolism through three mechanisms. TS, MTHFR and ATIC are the rate-limiting enzymes separately. The function of SNPs in these genes is often one-sided. Works focusing on the analysis of polymorphism in MTX transporters should be more efficient and meaningful. PMID- 29283071 TI - Silk Fibroin Based Drug Delivery Applications: Promises and Challenges. AB - BACKGROUND: Silk Fibroin (SF), a natural source material obtained from Bombyx mori, has been widely enlisted as biomaterial having outstanding mechanical properties. SF has been reported as one of the propitious bio-polymers for various drug delivery systems, as well as drug delivery vehicle. OBJECTIVE: This review is a summary of comprehensive applications of silk fibroin in various drug delivery systems, and also to present the current opportunities and requirements by furnishing a definitive assessment on silk fibroin as a polymer. RESULTS: SF has been reported as one of the propitious bio-polymers for various drug delivery systems, as well as drug delivery vehicle. SF is inestimable owing to its non toxic and non-antigenic character, except for the firmness formation whilst being stored at lower temperature. Unlike other polymeric biomaterials, SF is regenerated in aqueous systems in defined temperature, pressure and pH, which is one of its major advantages in formulation. SF nanoparticles are also used to deliver proteins and peptides. Recently, SF has been used to deliver anti-cancer agents like paclitaxel, doxorubicin, floxuridine, and methotrexate, and including the natural product curcumin, has shown to elicit significant biological activity when compared to their conventional form. Interestingly, SF has shown to be a promising biomaterial for implantables and injectable drug delivery applications. CONCLUSION: In the present review, we have summarized the physical and chemical properties, biocompatibility and non-immunogenic characters of SF and its applications in various drug delivery systems. PMID- 29283072 TI - Onset of Hypertension in Leflunamide Treated Low Socioeconomic Rheumatoid Arthritis Patients: An unseen iceberg. AB - OBJECTIVE: To determine the frequency of new-onset hypertension in patients with Rheumatoid arthritis taking leflunomide, in comparison with methotrexate in Asian setting. MATERIAL AND METHODS: Perspective case-control study was conducted in 2014 in a tertiary care hospital located in Karachi Pakistan. Adult patients having rheumatoid arthritis were randomly prescribed leflunomide or methotrexate. Patients having chronic hypertension, proteinuria and chronic kidney disease were excluded. Patients were monthly followed for blood pressure and heart rate measurements. Hypertension was defined using JNC 7 criteria. RESULTS: Out of 144 patients enrolled, 80 patients received Leflunomide while 64 were started on methotrexate. Mean systolic blood pressure in leflunomide group at the start and at the end of study was 108.5 and 135.4mmHg respectively, while in methotrexate group mean systolic BP was 109.8 and 110.5 mmhg respectively. After one year follow up 33 out of 80 (41%) patients receiving leflunomide had pre-hypertension or hypertension, while only 3 out of 64 patients (4.7%) receiving methotrexate had hypertension. CONCLUSION: Risk of developing hypertension in patient receiving Leflunomide is much higher in Asian population like Pakistan as compared to western population. PMID- 29283073 TI - Patients' illness perceptions of type 2 diabetes: A scoping review. AB - BACKGROUND: People's personal perceptions, or illness representations, of type 2 diabetes can act as barriers to successful self-management. INTRODUCTION: Understanding patients' subjective perceptions of type 2 diabetes can aid the design of evidence-based care and appropriate educational programmes. This scoping review provides a narrative account of previous knowledge of patients' illness representations of type 2 diabetes. METHOD: Quantitative and qualitative studies that explored patients' illness representations of type 2 diabetes, as defined by Leventhal's Common Sense Model, were included. RESULTS: Thirty four studies were identified for this review, but only 14 studies were carried out in a general population of people with diabetes. Illness representations varied across study populations. While it is clear that the perceptions of ethnic minorities and marginalised groups are embedded in their historical and cultural backgrounds, it is also important to understand the views of the wider population. CONCLUSION: The review highlights the need for self-management interventions to reflect the target population's representations of type 2 diabetes in order to inform interventions and clinical practice. PMID- 29283074 TI - Genetic susceptibility in family members of Egyptian hepatitis C virus infected patients: role of Interleukin-12 B gene polymorphism. AB - AIM: The research was conducted to study Interleukin (IL)-12B gene polymorphism in families of Hepatitis C virus (HCV) infected patients in Egypt. METHODS: Three hundreds HCV patients, 860 family members and 100 healthy subjects were studied. All family members were screened for HCV antibodies by enzyme-linked immunosorbent assay (ELISA). Positive cases were examined using Real-Time polymerase chain reaction (PCR) to confirm the presence of HCV ribonucleic acid (RNA) and detect the viral load. Molecular study of IL-12B gene was carried out on all patients, family members and controls using PCR and restriction enzyme analysis. RESULTS: HCV infection was confirmed in 10.6% of family members. The distribution of IL-12B gene polymorphism 1188 A/C in patients was 2.3%, 45.7% and 52% for C/C, A/C and A/A genotypes respectively, in infected family members was 3.3%, 41.7%, 55%, in non-infected family members was 4.5%, 43.5% and 52% for C/C, A/C and A/A genotypes respectively and in control was 5%, 36% and 59% for C/C, A/C and A/A genotypes respectively. The frequency of the C/C, A/C and A/A genotype was not significantly different between the studied groups. CONCLUSIONS: IL-12B gene polymorphism has no role in intrafamilial transmission of HCV. PMID- 29283075 TI - Evaluation of Farnesoid X Receptor Target Gene Induction in Human Hepatocytes: Amino Acid Conjugation. AB - BACKGROUND: The nuclear hormone receptor, Farnesoid X Receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition. OBJECTIVE: This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e., Bile Acid-CoA Synthetase (BACS) and bile acid-CoA: amino acid Nacetyltransferase (BAT). These genes have been shown to be inducible by FXR agonists in rat models, however, to date no studies have been conducted in a human hepatocyte model. RESULTS: In human hepatocytes, treatment with the FXR agonists GW4064 (1.0 uM) and WAY362450 (0.1 uM) did not significantly induce the mRNA expression of BACS and BAT genes. However, other target genes associated with FXR activation, such as Bile Salt Export Pump (BSEP), Short Heterodimer Partner (SHP), Multidrug Resistance associated Protein 2 (MRP2) and Multidrug Resistance Protein 3 (MDR3), were upregulated. Interestingly, a follow up study conducted in rat hepatocytes indicated that GW4064 induced the BACS gene while WAY362450 induced the BAT gene, confirming literature results that these genes can be induced in rat. CONCLUSION: In conclusion, there appears to be some species differences in the activation of FXR target genes. PMID- 29283076 TI - The Value of Electronically Extracted Data for Auditing Outpatient Antimicrobial Prescribing. AB - OBJECTIVE The optimal approach to auditing outpatient antimicrobial prescribing has not been established. We assessed how different types of electronic data including prescriptions, patient-visits, and International Classification of Disease, Tenth Revision (ICD-10) codes-could inform automated antimicrobial audits. DESIGN Outpatient visits during 2016 were retrospectively reviewed, including chart abstraction, if an antimicrobial was prescribed (cohort 1) or if the visit was associated with an infection-related ICD-10 code (cohort 2). Findings from cohorts 1 and 2 were compared. SETTING Primary care clinics and the emergency department (ED) at the Iowa City Veterans Affairs Medical Center. RESULTS In cohort 1, we reviewed 2,353 antimicrobial prescriptions across 52 providers. ICD-10 codes had limited sensitivity and positive predictive value (PPV) for validated cases of cystitis and pneumonia (sensitivity, 65.8%, 56.3%, respectively; PPV, 74.4%, 52.5%, respectively). The volume-adjusted antimicrobial prescribing rate was 13.6 per 100 ED visits and 7.5 per 100 primary care visits. In cohort 2, antimicrobials were not indicated in 474 of 851 visits (55.7%). The antimicrobial overtreatment rate was 48.8% for the ED and 59.7% for primary care. At the level of the individual prescriber, there was a positive correlation between a provider's volume-adjusted antimicrobial prescribing rate and the individualized rates of overtreatment in both the ED (r=0.72; P<.01) and the primary care setting (r=0.82; P=0.03). CONCLUSIONS In this single-center study, ICD-10 codes had limited sensitivity and PPV for 2 infections that typically require antimicrobials. Electronically extracted data on a provider's rate of volume-adjusted antimicrobial prescribing correlated with the frequency at which unnecessary antimicrobials were prescribed, but this may have been driven by outlier prescribers. Infect Control Hosp Epidemiol 2018;39:64-70. PMID- 29283077 TI - Species distribution, sequence types and antimicrobial resistance of Acinetobacter spp. from cystic fibrosis patients. AB - Acinetobacter spp. are important healthcare pathogens, being closely linked to antibiotic resistance and outbreaks worldwide. Although such species are rarely observed in patients with cystic fibrosis (CF), we describe the characteristics of 53 strains of Acinetobacter spp. isolated from the sputum of 39 Brazilian patients with CF. The species distribution was A. baumannii (n = 29), A. pittii (n = 13), A. nosocomialis (n = 8), A. seifertii (n = 1), A. soli (n = 1) and A. variabilis (n = 1) determined by partial rpoB gene sequencing. Sixteen strains (10 A. baumannii, 3 A. pittii and 3 A. nosocomialis) were multidrug-resistant (MDR) by disk diffusion test (30%) and eight MDR carbapenem-resistant A. baumannii strains harboured the bla OXA-23-like oxacillinase gene. Thirty-three sequence types (STs) were identified by multilocus sequence typing of which eight were novel (A. baumannii: 843, 844, 845, 847, 848; A. pitti: 643; A. nosocomialis: 862 and A. seifertii: 846); six STs (2 A. baumannii, 3 A. pittii and 1 A. nosocomialis) were found in more than one patient. Four strains of A. baumannii were assigned to two common clonal complexes (CCs), namely, CC1 (ST1, ST20 and ST160), and CC79 (ST79). This study underlines the extensive species diversity of Acinetobacter spp. strains in CF lung infections which may present difficulties for therapy due to significant antimicrobial resistance. PMID- 29283078 TI - Open the Border to U.S.-Trained Emergency Physicians. PMID- 29283079 TI - Differential Contributions of Selective Attention and Sensory Integration to Driving Performance in Healthy Aging and Alzheimer's Disease. AB - OBJECTIVES: Patients with Alzheimer's disease (AD) demonstrate deficits in cross cortical feature binding distinct from age-related changes in selective attention. This may have consequences for driving performance given its demands on multisensory integration. We examined the relationship of visuospatial search and binding to driving in patients with early AD and elderly controls (EC). METHODS: Participants (42 AD; 37 EC) completed search tasks requiring either luminance-motion (L-M) or color-motion (C-M) binding, analogs of within and across visual processing stream binding, respectively. Standardized road test (RIRT) and naturalistic driving data (CDAS) were collected alongside clinical screening measures. RESULTS: Patients performed worse than controls on most cognitive and driving indices. Visual search and clinical measures were differentially related to driving behavior across groups. L-M search and Trail Making Test (TMT-B) were associated with RIRT performance in controls, while C-M binding, TMT-B errors, and Clock Drawing correlated with CDAS performance in patients. After controlling for demographic and clinical predictors, L-M reaction time significantly predicted RIRT performance in controls. In patients, C-M binding made significant contributions to CDAS above and beyond demographic and clinical predictors. RIRT and C-M binding measures accounted for 51% of variance in CDAS performance in patients. CONCLUSIONS: Whereas selective attention is associated with driving behavior in EC, cross-cortical binding appears most sensitive to driving in AD. This latter relationship may emerge only in naturalistic settings, which better reflect patients' driving behavior. Visual integration may offer distinct insights into driving behavior, and thus has important implications for assessing driving competency in early AD. (JINS, 2018, 24, 486-497). PMID- 29283081 TI - Editorial. PMID- 29283082 TI - An appreciation of Professor John Lewis. PMID- 29283080 TI - Complementary and alternative medicine contacts by persons with mental disorders in 25 countries: results from the World Mental Health Surveys. AB - AIMS: A substantial proportion of persons with mental disorders seek treatment from complementary and alternative medicine (CAM) professionals. However, data on how CAM contacts vary across countries, mental disorders and their severity, and health care settings is largely lacking. The aim was therefore to investigate the prevalence of contacts with CAM providers in a large cross-national sample of persons with 12-month mental disorders. METHODS: In the World Mental Health Surveys, the Composite International Diagnostic Interview was administered to determine the presence of past 12 month mental disorders in 138 801 participants aged 18-100 derived from representative general population samples. Participants were recruited between 2001 and 2012. Rates of self-reported CAM contacts for each of the 28 surveys across 25 countries and 12 mental disorder groups were calculated for all persons with past 12-month mental disorders. Mental disorders were grouped into mood disorders, anxiety disorders or behavioural disorders, and further divided by severity levels. Satisfaction with conventional care was also compared with CAM contact satisfaction. RESULTS: An estimated 3.6% (standard error 0.2%) of persons with a past 12-month mental disorder reported a CAM contact, which was two times higher in high-income countries (4.6%; standard error 0.3%) than in low- and middle-income countries (2.3%; standard error 0.2%). CAM contacts were largely comparable for different disorder types, but particularly high in persons receiving conventional care (8.6-17.8%). CAM contacts increased with increasing mental disorder severity. Among persons receiving specialist mental health care, CAM contacts were reported by 14.0% for severe mood disorders, 16.2% for severe anxiety disorders and 22.5% for severe behavioural disorders. Satisfaction with care was comparable with respect to CAM contacts (78.3%) and conventional care (75.6%) in persons that received both. CONCLUSIONS: CAM contacts are common in persons with severe mental disorders, in high-income countries, and in persons receiving conventional care. Our findings support the notion of CAM as largely complementary but are in contrast to suggestions that this concerns person with only mild, transient complaints. There was no indication that persons were less satisfied by CAM visits than by receiving conventional care. We encourage health care professionals in conventional settings to openly discuss the care patients are receiving, whether conventional or not, and their reasons for doing so. PMID- 29283083 TI - The risk of urinary retention following robot-assisted radical prostatectomy and its impact on early continence outcomes. AB - INTRODUCTION: We aimed to evaluate the risk factors of acute urinary retention (AUR) following robot-assisted radical prostatectomy (RARP), as well as the relationship of AUR with early continence outcomes. METHODS: The records of 740 consecutive patients who underwent RARP by two experienced surgeons at our institution were retrospectively reviewed from a prospectively collected database. Multiple factors, including age, body mass index (BMI), international prostate symptom score (IPSS), prostate volume, presence of median lobe, nerve preservation status, anastomosis time, and catheter removal time (Day 4 vs. 7), were evaluated as risk factors for AUR using univariate and multivariate analysis. The relation between AUR and early return of continence (one and three months) post-RARP was also evaluated. RESULTS: The incidence of clinically significant vesico-urethral anastomotic (VUA) leak and AUR following catheter removal were 0.9% and 2.2% (17/740), respectively. In men who developed AUR, there was no significant relationship with regards to age, BMI, IPSS, prostatic volume, median lobe, nerve preservation, or anastomosis time; however, the incidence of AUR was significantly higher for men with catheter removal at Day 4 (4.5% [16/351]) vs. Day 7 (0.2% [1/389]) (p=0.004). Moreover, patients with early removal of the catheter (Day 4) who developed AUR had an earlier one-month return of 0-pad continence 87.5% (14/16) compared to patients without AUR 45.6% (153/335), with no significant difference at three months. CONCLUSIONS: While AUR is an uncommon complication of RARP, its incidence is much higher than VUA leakage. Further, it is often not well-discussed during patient counselling preoperatively. Moreover, earlier return of urinary continence was observed in patients experiencing AUR following RARP exclusively with catheter removal at Day 4. Future studies are warranted to validate the long-term impact of AUR on continence outcomes. PMID- 29283084 TI - Mirabegron as adjuvant treatment for patients with interstitial cystitis/bladder pain syndrome. AB - INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) patients represent a heterogeneous group with pain and urinary storage symptoms and varying responses to current treatment options. The novel beta-3 agonist, mirabegron, has been shown to improve storage symptoms of patients with bladder overactivity; however, its effect on symptoms in the IC/BPS population has yet to be studied. METHODS: Patients diagnosed at a single IC centre with IC/BPS undergoing standard therapy were treated with additional daily mirabegron 25 mg and seen in followup post-treatment. Patients completed the Interstitial Cystitis Symptom Index and Problem Index (ICSI/ICPI), and the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF) prior to and following mirabegron treatment. Global (NRS) and symptom-specific outcomes were assessed by comparing the pre- and post-treatment mean scores using tailed-t test (p<0.05 considered statistically significant). RESULTS: A total of 23 patients were available for review pre- and post-mirabegron treatment. There was no significant difference in ICSI (p=0.448), ICPI (p=0.352), or PUF (p=0.869) pre- and post-treatment. Analysis of symptom-specific outcomes show statistically significant improvements in urgency (p=0.048); however, no statistically significant improvements in frequency (p=0.951) or pain (p=0.952) were observed with mirabegron therapy. CONCLUSIONS: IC/BPS patients treated with mirabegron had improvement of urinary urgency, but no significant benefit in terms of pain or urinary frequency. This data suggests that mirabegron's role in the IC/BPS patient should be that of adjuvant treatment to ameliorate urgency. PMID- 29283085 TI - Outcomes of revision surgery for difficult to catheterize continent channels in a multi-institutional cohort of adults. AB - INTRODUCTION: The study aimed to describe the strategies of surgical revision for catheterizable channel obstruction and their outcomes, including restenosis and new channel incontinence. METHODS: We retrospectively queried the charts of adults who underwent catheterizable channel revision or replacement from 2000 2014 for stomal stenosis, channel obstruction, or difficulty with catheterization at the Universities of Minnesota, Michigan, and Utah. The primary endpoint was channel patency as measured by freedom from repeat surgical intervention. Secondary endpoints included post-revision incontinence and complication rates. Revision surgeries were classified by strategy into "above fascia," "below fascia," and "channel replacement" groupings. RESULTS: A total of 51 patients who underwent 68 repairs (age 18-82 years old; mean 45) were identified who met our inclusion criteria. Channel patency was achieved in 66% at a median 19 months post-revision for all repair types. There was no difference in patency by the type of channel being revised, but there was based on revision technique, with channel replacement and above the fascia repairs being more successful (p=0.046). Channel incontinence occurred in 40% and was moderate to severe in 12%. The type of channel being revised was strongly associated (p=0.003) with any postoperative channel incontinence. Surgical complications occurred in 29% of all revision procedures, although most were low-grade. CONCLUSIONS: Surgical revision of continent catheterizable channels for channel obstruction can be performed with acceptable rates of durable patency and incontinence; however, the surgeon needs to have experience in complex urinary diversion and familiarity with a variety of surgical revision strategies. PMID- 29283086 TI - Images: Port site recurrence on followup imaging after adrenalectomy for adrenocortical carcinoma - first indicator of carcinomatosis. PMID- 29283087 TI - Preoperative sarcopenia status is associated with lymphovascular invasion in upper tract urothelial carcinoma patients treated with radical nephroureterectomy. AB - INTRODUCTION: Sarcopenia is a novel concept representing skeletal muscle wasting and has been identified as a prognostic factor for several cancers. The aims of this study were to evaluate the prognostic significance of sarcopenia and the relationship between sarcopenia and poor pathological findings in upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). METHODS: We identified 123 UTUC patients who underwent RNU between 2003 and 2014. We assessed sarcopenia by measuring the area of skeletal muscle at the third lumber vertebra on preoperative computed tomography scans. Sarcopenia was classified based on a sex-specific consensus definition. We investigated whether sarcopenia predicts clinical outcomes, such as cancer death and poor pathological findings at RNU. RESULTS: A total of 50 (40.7%) patients had sarcopenia. In a multivariate Cox regression analysis, sarcopenia was not associated with cancer specific survival (CSS), and lymphovascular invasion (LVI) (hazard ratio 5.88; p=0.002) was the only independent risk factor for CSS. A multivariate logistic regression analysis showed that sarcopenia independently correlated with the LVI status (odds ratio 2.36; p=0.025). LVI was positive in 27 of 50 (54%) and 25 of 73 (34%) patients with and without sarcopenia, respectively (p=0.029). CONCLUSIONS: Preoperative sarcopenia predicted the LVI status, which was a strong prognostic factor for UTUC patients after RNU. PMID- 29283088 TI - Compliance of the recurrent renal stone former with current best practice guidelines. AB - INTRODUCTION: Patient compliance to best practice guidelines is a significant factor in preventing renal stone recurrence. While patient compliance has been historically poor, there remains a paucity of data in the renal stone setting. We evaluated compliance of the recurrent renal stone former with current Canadian Urological Association (CUA) best practice guidelines. METHODS: A prospective, cross-sectional study design was used to evaluate patient compliance. Recurrent renal stone former patients were consecutively recruited from McMaster's Institute of Urology and completed a one-time questionnaire developed in accordance with CUA best practice guidelines. Questionnaire sections included: 1) demographics; 2) interaction(s) and satisfaction with their healthcare provider; and 3) knowledge, attitudes, and compliance with best practices. RESULTS: A total of 300 patients were enrolled in the study; 55.3% were men, 69.5% had a history of stone surgery, while 23.7% had a positive family history. Participants perceived satisfactory education from their urologist and primary care physician 82.7% and 59.7% of the time, respectively (p<0.05). Nearly a quarter of patients (22.8%) perceived their stone disease to be severe and 67.1% of patients believed in the efficacy of preventative stone measures. Overall, 45.8% of patients were compliant with CUA best practice guidelines. The majority of patients (72.6%) complied with high fluid intake, the most critical stone preventative practice. CONCLUSIONS: Consistent with previous studies, compliance to dietary recommendations in this evaluation of recurrent stone formers was low. Study findings may be attributed to insufficient knowledge translation, lack of perceived disease severity, and/or patient uncertainty in the importance of preventative stone practices. PMID- 29283089 TI - Epidemiology of renal cancer in developing countries: Review of the literature. AB - INTRODUCTION: Renal cell carcinoma (RCC) is the ninth most common cancer in men, and the 14th most common cancer in women. It has been reported that the incidence of RCC is rising. These changes are more common in developed countries because of better screening programs and disease registry. The aim of this article is to review the epidemiology of RCC around the world. METHODS: A literature review of four databases was performed: PubMed, Embase, Lilacs, and Scielo. Studies of incidence, prevalence, mortality, and survival of RCC were taken from different countries. Studies included were published in the last 10 years. Two reviewers independently selected the studies. RESULTS: A total of 5275 references were reviewed by title and abstract. In the end, 42 references were selected for full text review. The global incidence and prevalence of cancer vary. The highest incidence was described in North America and Northern Europe. In Canada, by 2007 the incidence was 17.9/100 000 and 10.3/100 000 in males and females, respectively. Developing countries like Colombia have fewer incidence rates, with less information in poor-income areas. CONCLUSIONS: We have seen a rise in the incidence and mortality of RCC globally. There is an association between RCC and smoking, obesity, hypertension, and socioeconomic status. Seeing the epidemiological data from some regions in developing countries and the lack of specialists in those places, it can be deduced there is underreporting of the disease that reveals the need to improve both surveillance and disease registration programs, especially in these countries. PMID- 29283090 TI - Prenatally detected, unilateral, high-grade hydronephrosis: Can we predict the natural history? AB - INTRODUCTION: Fetal hydronephrosis (HN) occurs in approximately 5% of pregnancies and its prognosis depends mainly on the grade of the dilation. We attempted to determine the fate of isolated, unilateral, high-grade HN in children with antenatal diagnosis, emphasizing the risk factors for progression. METHODS: We retrospectively evaluated 424 children (690 kidney units) with antenatal HN in the period between 2010 and 2014. We included only those patients with isolated high-grade HN (Society for Fetal Urology [SFU] Grade 3 or 4). Patients with bilateral HN or unilateral HN associated with dilated ureter or reflux and patients with missed followup were excluded. The prognosis of HN (whether improved, stabilized, or progressed) and the need for surgical intervention in this subset of patients was evaluated. RESULTS: A total of 44 children (34 boys and 10 girls) were identified. Ultrasounds showed SFU Grade 3 HN in 24 (54%) and SFU Grade 4 HN in 20 (46%). After a mean followup of three years (range 1-5), 10 children (23%) needed surgical intervention; four Grade 3 HN (16%) and six Grade 4 HN (30%). The majority of children with differential renal function (DRF) >=40% (69.5%) were stable or improved. Five girls (50%) and five boys (17%) progressed and required surgical intervention. No patient with a renal pelvis anteroposterior diameter (APD) <1.5 cm needed surgical intervention. CONCLUSIONS: Infants with isolated, unilateral, high-grade HN might be managed conservatively. Male gender, DRF >=40%, SFU Grade 3 HN, and APD <1.5 cm were favourable prognostic factors. PMID- 29283091 TI - The management of rectal bleeding following transrectal prostate biopsy: A review of the current literature. AB - INTRODUCTION: Since the advent of prostate-specific antigen (PSA)-based testing, transrectal ultrasound (TRUS)-guided prostate biopsy has become a standard part of the diagnostic pathway for prostate cancer (PCa). Rectal bleeding is one of the common side effects of this transrectal route. While rectal bleeding is usually mild and self-limiting, it can be life-threatening. In this article, we examine rectal bleeding post-TRUS-guided prostate biopsy and explore the literature to evaluate techniques and strategies aimed at preventing and managing this common and important complication. METHODS: A PubMed literature search was carried out using the keywords "transrectal-prostate-biopsy-bleed." A search of the bibliography of reviewed studies was also conducted. Additionally, papers in non-PubMed-listed journals of which the authors were aware were appraised. RESULTS: Numerous modifiable risk factors for this bleeding complication exist, particularly anticoagulants/antiplatelets and the number of core biopsies taken. Successfully described corrective measures for such rectal bleeding include tamponade (digital/packs/catheter/tampon/condom), endoscopic sclerotherapy/banding/clipping, radiological embolization, and surgical intervention. CONCLUSIONS: We advocate early consultation with the colorectal/gastroenterology and interventional radiology services and a progressive, stepwise approach to the management of post-biopsy rectal bleeding, starting with resuscitation and conservative tamponade measures, moving to endoscopic hemostasis +/- radiological embolization +/- transanal surgical methods. Given the infrequent but serious nature of major rectal bleeding after TRUS biopsy, we recommend the establishment of centralized databases or registries forthwith to prospectively capture such data. To the best of our knowledge, this is the first comprehensive look specifically at the management of post-TRUS biopsy rectal bleeding. PMID- 29283092 TI - Trends in the training of female urology residents in Canada. AB - INTRODUCTION: There is limited research on why women do or do not choose a career in urology. Considering the increasing proportion of female medical students, we assessed for trends in female applicants to urology programs in Canada and their post-residency career choices. METHODS: Data from the Canadian Residency Matching Service (CaRMS) was used (1998-2015). Trends in the proportions of females applying and matching to surgical subspecialties, and applying and matching to urology were computed. Surveys were sent to urology program directors to assess female residents' chosen career paths over the last decade. RESULTS: A significant increasing trend in the proportion of females applying to urology as their first choice program was found (0.19 in 1998-99 to 0.27 in 2012-15; p=0.04). An increasing trend in the proportion of females successfully matching to urology was found, although it was not statistically significant (0.13 in 1998 99 to 0.24 in 2012-15; p=0.07). This was in keeping with the trends found for surgical programs overall. Female graduates choose a variety of career paths, with urogynecology being the most common fellowship (26%). CONCLUSIONS: The last two decades has seen an increase in the proportion of female students applying to urology in Canada. Female urology graduates pursue a variety of career paths. It remains imperative that both female and male medical students have early exposure and education about our subspecialty to ensure we continue to recruit the most talented candidates. PMID- 29283093 TI - Anterior Cervical Disc Fusion Does not Affect the Presence of Cervical Vestibular Evoked Myogenic Potential. AB - OBJECTIVE: Cervical spondylosis and cervical disk herniation are the most frequent forms of degenerative disease in the cervical spine. Surgical treatment mainly includes anterior cervical disk fusion. However, information concerning vestibular-evoked myogenic potential (VEMP) recording in patients undergoing cervical spine surgery is limited. The present prospective study aimed to investigate the effect of anterior disk fusion surgery on cervical VEMP (cVEMP) parameters. MATERIALS AND METHODS: Twenty-five patients were enrolled in this study, and 20 patients (10 men and 10 women) completed cVEMP testing. Patient ages ranged from 29 to 76 y (mean, 52 y). Patients with conductive hearing loss or vestibular dysfunction were excluded. The cVEMP test was recorded preoperatively and 1 and 4 months postoperatively. Air-conducted tone-bursts of 500 Hz were used. RESULTS: We found no statistically significant difference between the preoperative and postoperative cVEMP values. CONCLUSION: Cervical spine surgery (anterior cervical disk fusion) for treating cervical spondylosis does not appear to affect the presence of cVEMP or the parameters of cVEMP, when using air-conducted tone-bursts of 500 Hz. Moreover, cVEMP testing can be used in the postoperative phase for evaluating vertigo in patients who have undergone anterior cervical disk fusion. PMID- 29283094 TI - A Comparison of Cochlear Nerve Size in Normal-Hearing Adults Using Magnetic Resonance Imaging. AB - OBJECTIVE: Cochlear implantation is a clinical and cost-effective treatment for severe hearing loss. Cochlear nerve size assessment by magnetic resonance imaging (MRI) has been investigated for use as a prognostic indicator following cochlear implantation. This study aimed to further that research by assessing nerve size in normal-hearing adults for symmetry. MATERIALS AND METHODS: Patients with tinnitus presenting to our center retrospectively had their nerve size assessed by MRI. RESULTS: The study found no significant differences between right and left cochlear nerves in normal-hearing adults, supporting our hypothesis of symmetry in these individuals. This was a previously unproven and uninvestigated hypothesis. CONCLUSION: Nerve size assessment should remain an active area of research in otological disease. PMID- 29283095 TI - Evaluation of Cervical Vestibular Evoked Myogenic Potential in Subjects with Chronic Noise Exposure. AB - OBJECTIVE: Noise has been recognized as a major cause of cochlear damage resulting in both tinnitus and hearing loss. On the other hand, damage to the vestibular system, especially the saccule, can be considered as a potential problem. The cervical vestibular-evoked myogenic potentials (cVEMPs) have been established as a clinical test of measuring both sac-cular and inferior vestibular nerve function. Therefore, it is thought to be sensitive to the noise induced damage to the vestibular system. Accordingly, this study was designed to assess the vestibular system in subjects exposed to noise during work by using cVEMPs. MATERIALS AND METHODS: This study was performed in over 60 adult males who were divided into a study group (consisting of 40 adult males) with history of chronic occupational noise exposure and with variable degree of hearing levels and a control group consisting of 20 healthy adults with normal peripheral hearing, with no history of noise exposure and no vestibular complaints. cVEMP recordings were elicited using 95dB nHL click stimuli. RESULTS: There was statistically significant prolonged cVEMP latency of the P13 and N23 waves of the study versus the control groups. As regard to the sense of imbalance, there were significant prolonged cVEMPs latencies in present versus absent sense of imbalance. However, there were statistically insignificant reduced cVEMP amplitudes in present versus absent sense of imbalance. CONCLUSION: Chronic noise exposure damages the vestibular system especially the saccule in addition to cochlear damage. PMID- 29283096 TI - The Role of Topical Thymoquinone in the Treatment of Acute Otitis Externa; an Experimental Study in Rats. AB - OBJECTIVE: The aim of this experimental study was to compare the dose-related effect of topical thymoquinone (TQ) with other topical agents used in the management of acute otitis externa (AOE) in a rat model. MATERIALS AND METHODS: Forty-eight male Wistar albino rats were divided into six groups each with eight rats per group. Group I was the control group with no external otitis, whereas external otitis were created in the other five groups (study groups). Dexamethasone, 0.1% TQ, 0.4% TQ, ciprofloxacin, and 0.9% saline (NaCl) drops was applied once daily in Groups II-VI, respectively. The treatment was administered regularly for 10 days. Pathologic and microbiologic evaluation were performed. Pathologically, the thicknesses of the stroma and the epithelium in the external auditory canal (EAC) were measured using an occulometer. Edema in the stroma, density of inflammatory cells and blood vessels, presence of fibroblasts, and changes in collagen fibers in the EAC were evaluated in five different areas to obtain the area of highest concentration and classified into four grades (0=no change, 1=mild, 2=moderate, 3=severe). RESULTS: The higher concentration of TQ (0.4%) was more effective than dexamethasone and 0.1% TQ with respect to antibacterial and the anti-inflammatory properties. CONCLUSION: TQ, particularly at a concentration of 0.4%, may be considered for topical application alone in the treatment of AOE, without any requirement for a combined treatment. PMID- 29283097 TI - Efficacy of Platelet-Rich Plasma on Fat Grafts in the Repair of Tympanic Membrane Perforations: An Experimental Study. AB - OBJECTIVE: We investigated the use of autologous platelet-rich plasma (PRP) to improve the success rate of fat graft myringoplasty in perforated tympanic membranes of rats. MATERIALS AND METHODS: A total of 20 healthy Wistar albino female rats were divided into two groups. In Group 1, the left tympanic membranes were perforated and grafted with a fat graft that was harvested from the inguinal region. In Group 2, the left tympanic membranes were perforated, and a fat graft was also harvested from the inguinal region. Then, the fat was soaked in 0.5 mL PRP and grafted at the perforation. After the procedure, the rats were examined, and the graft situation was assessed at 3, 5, 7, 10, and 14 days. All of the rats were sacrificed 21 days after perforation, and a histopathological examination was made. RESULTS: We compared fat graft histopathological and otomicroscopic findings between the groups. While we did not observe graft rejections in Group 2, we saw 1 case of graft rejection in Group 1. In the histopathological examination, PRP prevents fat graft resorption by the terms of the adipocyte area, granulation tissue area, and vacuolization area. CONCLUSION: This study demonstrated the efficacy of fat grafts prepared with PRP on rat tympanic membranes. The fat graft with PRP did not statistically improve the success rate compared to the graft without PRP. Histopatologic findings of the study showed that PRP prevents fat graft resorption. Further studies are needed to further examine the advantages of the graft with PRP. PMID- 29283098 TI - Electrophysiological and Histopathological Evaluation of Effects of Sodium-2 Mercaptoethanesulfonate Used for Middle Ear Surgery on Facial Nerve Functions. AB - OBJECTIVE: Sodium-2-mercaptoethanesulfonate (MESNA) is widely used in medicine because of its antioxidant and mucolytic effects. In recent years, it has been used in otologic surgery. Because it cleaves disulfide bonds, it is used to easily dissect the epithelial matrix in cholesteatoma and atelectasis. In this study, we hypothesized that MESNA does not have any toxic effect on the facial nerve, and the effects of MESNA on the facial nerve were examined histologically and electrophysiologically. MATERIALS AND METHODS: Twenty Wistar albino rats were used. Groups A and B were designated as the control and sham groups, respectively. The animals in groups C and D were administered 20% and 50% of MESNA solution, respectively, after the facial nerve was exposed in the parotid region. Electromyography (EMG) measurements were performed preoperatively and postoperatively at 4 weeks. The animals were subsequently euthanized; facial nerve samples were taken for histopathological examination. RESULTS: When EMG parameters were compared within and between each group, preoperative and postoperative results were not statistically significantly different. Histopathological examination showed that MESNA did not cause any inflammation, granulation tissue, or foreign body reaction. CONCLUSION: To the best of our knowledge, the effects of MESNA on facial nerve functions have not been investigated. In this study, the effects of MESNA after direct application to the facial nerve were examined electrophysiologically and histologically, and it was determined that MESNA did not cause any toxic effects. It was concluded that MESNA can, therefore, be safely used during middle ear surgery. PMID- 29283099 TI - Radiological Evaluation of Inner Ear with Computed Tomography in Patients with Unilateral Non-Pulsatile Tinnitus. AB - OBJECTIVE: The objective of this research was to investigate the possible relationship between tinnitus and certain bony inner ear structures using computed tomography (CT). MATERIALS AND METHODS: This was a prospective, controlled, double-blind study. The subjects of the study were divided into the following three groups: group 1 (G1), patients with unilateral sensorineural hearing loss (SNHL) and unilateral non-pulsatile tinnitus in the same ear; group 2 (G2), patients with normal hearing and unilateral non-pulsatile tinnitus; and group 3 (G3), healthy volunteers with neither tinnitus nor hearing loss. The basal turn length, internal acoustic canal (IAC) width and length, bony cochlear nerve canal (BCNC) width, and IAC diameter at the porus acousticus internus (PAI) were measured. RESULTS: The mean BCNC width was significantly narrower in G1 and G2 than in the control group (G3) (p<0.001). For patients in G2, BCNC width was significantly narrower in ears with tinnitus (p<0.001) than in ears without tinnitus. The mean IAC diameter at PAI was also narrower in the G1 patients (p=0.007) compared with the other groups. CONCLUSION: The results of this study suggest that CT evaluation of the inner ear structures is important in patients with tinnitus. According to the results, a narrow BCNC may cause phantom sensations and be related to cochlear nerve dysfunction. Therefore, it is recommended that clinicians evaluate BCNC carefully while assessing such patients. PMID- 29283101 TI - The Reliability and Validity of "Dokuz Eylul University Meniere's Disease Disability Scale". AB - OBJECTIVE: Meniere's Disease (MD) is a chronic, non-life threatening inner ear disease, with attacks of disabling vertigo, progressive hearing loss, and tinnitus as the major symptoms. All three symptoms, separately or in combination, cause great distress and have a considerable impact on the quality of life of the patients. The aims of this study were to develop a disease-specific quality of life survey for patients with MD and to analyze the relationships between the audiovestibular findings and the survey. MATERIALS AND METHODS: Following Ear Nose-Throat examination and audiovestibular tests, the Dokuz Eylul University Meniere's Disease Disability Scale (DEU-MDDS) and Turkish version of the Dizziness Handicap Inventory (DHI-T) were administered to 93 patients with definite MD. Reliability and validity analyses of the scale were performed. RESULTS: There were 45 (48.4%) male and 48 (51.6%) female patients and the mean age was 48.9+/-12.1 years. Cronbach's alpha was 0.92 and intraclass correlation coefficients of the DEU-MMDS were significant (p<0.001). Results of the Goodness of Fit Statistics showed that the expression levels of the items were high and the correlation coefficients of each item with the scale were sufficient. There was a statistically significant correlation between DHI-T scores and MDDS. DEU MDDS was not related to the vestibular tests, age or gender (p>0.05). CONCLUSION: The MDDS is a valid and reliable scale as a disease-specific quality of life questionnaire for patients with MD. PMID- 29283100 TI - The Efficacy of Magnetic Resonance Imaging for the Diagnosis of Superior Semicircular Canal Dehiscence. AB - OBJECTIVE: This study aimed to evaluate the efficacy of magnetic resonance imaging (MRI) for diagnosing superior semicircular canal dehiscence (SSCD). MATERIALS AND METHODS: The radiological records of patients who were admitted to our clinic with complaints of otologic and neuro-otologic symptoms between October 2014 and December 2015 were retrospectively reviewed. Among these patients, those who underwent both computed tomography and MRI and were reported to have SSCD in the temporal bone on at least one side were included in the study group. MRI records of patients with a confirmed diagnosis were then assessed for the presence of SSCD. RESULTS: The left and right semicircular canals of 52 patients were evaluated in this study. The sensitivity and specificity of MRI in the diagnosis of SSCD was 89.06% and 90%, respectively. The positive and negative predictive values were 93.44% and 83.72%, respectively. CONCLUSION: The use of multiplanar reformats and angulation techniques during MRI assessment of patients with neuro-otologic symptoms can improve the diagnostic process for patients with SSCD. This may allow early diagnosis of the disease by using just one imaging method, which would also reduce the costs per patient during the diagnosis period. PMID- 29283102 TI - Use of Vasodilators In Idiopathic Sudden Sensorineural Hearing Loss: A Systematic Review. AB - To compare the effect of vasodilators with that of corticosteroids in patients with idiopathic sudden sensorineural hearing loss (ISSHL). A search in PubMed, Cochrane, and Embase was conducted. Two reviewers screened the data sources to identify articles that comply with predefined inclusion criteria. Studies that compared the therapeutic effect of vasodilators with prednisone or placebo in patients with ISSHL were identified. Five articles were selected, involving a total of 611 patients. The odds ratios for perceptive hearing levels (pure tone average) post treatment varied between 0.58 and 2.18. One study demonstrated a cumulative effect (optimal hearing recovery) when vasodilators and glucocorticoids were combined (odds ratio, 1.82). Vasodilators have no beneficial effect on the treatment of ISSHL. Some evidence suggests that a combination of vasodilators with steroid treatment results in better hearing outcome than the use of corticosteroids alone. PMID- 29283103 TI - A View of the Therapy for Bell's Palsy Based on Molecular Biological Analyses of Facial Muscles. AB - OBJECTIVE: Details regarding the molecular biological features of Bell's palsy have not been widely reported in textbooks. We genetically analyzed facial muscles and clarified these points. MATERIALS AND METHODS: We performed genetic analysis of facial muscle specimens from Japanese patients with severe (House Brackmann facial nerve grading system V) and moderate (House-Brackmann facial nerve grading system III) dysfunction due to Bell's palsy. Microarray analysis of gene expression was performed using specimens from the healthy and affected sides, and gene expression was compared. Changes in gene expression were defined as an affected side/healthy side ratio of >1.5 or <0.5. RESULTS: We observed that the gene expression in Bell's palsy changes with the degree of facial nerve palsy. Especially, muscle, neuron, and energy category genes tended to fluctuate with the degree of facial nerve palsy. CONCLUSION: It is expected that this study will aid in the development of new treatments and diagnostic/prognostic markers based on the severity of facial nerve palsy. PMID- 29283104 TI - Repair of Tegmen Tympani Defect Presenting with Spontaneous Cerebrospinal Fluid Otorrhea Using the Middle Cranial Fossa Approach. AB - Spontaneous cerebrospinal fluid (CSF) otorrhea frequently occurs without temporal bone trauma, fracture, surgery, or any identifiable causes. It is usually associated with tegmen tympani defects of the temporal bone in adults. The congenital origin theory and the arachnoid granulation theory have been accepted to explain the tegmen tympani defect. Magnetic resonance imaging (MRI) and computed tomography (CT) are used to show the defects, brain tissue, and the meninges. We recently encountered three cases of spontaneous CSF otorrhea with a defect on the tegmental plate of the temporal bone. High-resolution CT (HRCT) scan of the temporal bones showed the tegmen tympani defects. The defects were successfully repaired with temporal muscle fascia or fascia lata graft and fibrin glue using the middle cranial fossa approach via craniotomy. PMID- 29283105 TI - Hearing Loss in Takayasu's Arteritis: A Role for Hyperbaric Oxygen Therapy? PMID- 29283106 TI - Electronic Structure of Fe1.08Te bulk crystals and epitaxial FeTe thin films on Bi2Te3. AB - The electronic structure of thin films of FeTe grown on Bi$_2$Te$_3$ is investigated using angle-resolved photoemission spectroscopy, scanning tunneling microscopy and first principles calculations. As a comparison, data from cleaved bulk ?FeTe taken under the same experimental conditions is also presented. Due to the substrate and thin film symmetry, FeTe thin films grow on Bi$_2$Te$_3$ in three domains, rotated by 0$^{?circ}$, 120$^{?circ}$, and 240$^{?circ}$. This results in a superposition of photoemission intensity from the domains, complicating the analysis. However, by combining bulk and thin film data, it is possible to partly disentangle the contributions from three domains. We find a close similarity between thin film and bulk electronic structure and an overall good agreement with first principles calculations, assuming a p-doping shift of 65~meV for the bulk and a renormalization factor of around 2. By tracking the change of substrate electronic structure upon film growth, we find indications of an electron transfer from the FeTe film to the substrate. No significant change of the film's electronic structure or doping is observed when alkali atoms are dosed onto the surface. This is ascribed to the film's high density of states at the Fermi energy. This behavior is also supported by the ab-initio calculations. PMID- 29283107 TI - From amorphous to nanocrystalline: the effect of nanograins in an amorphous matrix on the thermal conductivity of hot-wire chemical-vapor deposited silicon films. AB - We have measured the thermal conductivity of amorphous and nanocrystalline silicon films with varying crystalline content from 85 K to room temperature. The films were prepared by the hot-wire chemical-vapor deposition, where the crystalline volume fraction is determined by the hydrogen (H2) dilution ratio to the processing silane gas (SiH4), R = H2/SiH4. We varied R from 1 to 10, where the films transform from amorphous for R < 3 to mostly nanocrystalline for larger R. Structural analyses show that the nanograins, averaging from 2 to 9 nm in sizes with increasing R, are dispersed in the amorphous matrix. The crystalline volume fraction increases from 0 to 65% as R increases from 1 to 10. The thermal conductivities of the two amorphous silicon films are similar and consistent with the most previous reports with thicknesses no larger than a few MUm deposited by a variety of techniques. The thermal conductivities of the three nanocrystalline silicon films are also similar, but are about 50-70% higher than those of their amorphous counterparts. The heat conduction in nanocrystalline silicon films can be understood as the combined contribution in both amorphous and nanocrystalline phases, where increased conduction through improved nanocrystalline percolation path outweighs increased interface scattering between silicon nanocrystals and the amorphous matrix. PMID- 29283108 TI - Electrochemical synthesis of self-organized TiO2 crystalline nanotubes without annealing. AB - This work demonstrates that upon anodic polarization in an aqueous fluoride containing electrolyte, TiO2 nanotube array films can be formed with a well defined crystalline phase, rather than an amorphous one. The crystalline phase was obtained avoiding any high temperature annealing. We studied the formation of nanotubes in an HF/H2O medium and the development of crystalline grains on the nanotube wall, and we found a facile way to achieve crystalline TiO2 nanotube arrays through a one-step anodization. The crystallinity of the film was influenced by the synthesis parameters, and the optimization of the electrolyte composition and anodization conditions (applied voltage and time) were carried out. For comparison purposes, crystalline anatase TiO2 nanotubes were also prepared by thermal treatment of amorphous nanotubes grown in an organic bath (ethylene glycol/NH4F/H2O). The morphology and the crystallinity of the nanotubes were studied by field emission gun-scanning electron microscopy (FEG-SEM) and Raman spectroscopy, whereas the electrochemical and semiconducting properties were analyzed by means of linear sweep voltammetry, impedance spectroscopy, and Mott-Schottky plots. X-ray photoelectron spectroscopy (XPS) and ultraviolet photoelectron spectroscopy (UPS) allowed us to determine the surface composition and the electronic structure of the samples and to correlate them with the electrochemical data. The optimal conditions to achieve a crystalline phase with high donor concentration are defined. PMID- 29283109 TI - An eigenvalue approach to quantum plasmonics based on a self-consistent hydrodynamics method. AB - Plasmonics has attracted much attention not only because it has useful properties such as strong field enhancement, but also because it reveals the quantum nature of matter. To handle quantum plasmonics effects, ab initio packages or empirical Feibelman d-parameters have been used to explore the quantum correction of plasmonic resonances. However, most of these methods are formulated within the quasi-static framework. The self-consistent hydrodynamics model offers a reliable approach to study quantum plasmonics because it can incorporate the quantum effect of the electron gas into classical electrodynamics in a consistent manner. Instead of the standard scattering method, we formulate the self-consistent hydrodynamics method as an eigenvalue problem to study quantum plasmonics with electrons and photons treated on the same footing. We find that the eigenvalue approach must involve a global operator, which originates from the energy functional of the electron gas. This manifests the intrinsic nonlocality of the response of quantum plasmonic resonances. Our model gives the analytical forms of quantum corrections to plasmonic modes, incorporating quantum electron spill-out effects and electrodynamical retardation. We apply our method to study the quantum surface plasmon polariton for a single flat interface. PMID- 29283110 TI - The plasma-induced formation of silver nanocrystals in aqueous solution and their catalytic activity for oxygen reduction. AB - Ag nanocrystals with different architectures are synthesized using a submerged plasma discharge without the involvement of any chemicals. The Ag architecture relies on the electron density in the plasma that could enable the Ag ions to be reduced instantaneously to generate a large number of small Ag nanoparticles. With a low electron density of 7.1 * 10-22 m-3, the Ag nanowires with a corrugated structure induced by twinning and stacking faults are formed along the entire longitudinal <111> direction. However, with a high electron density 13.7 * 10-22 m-3, the Ag nanodendrites are constructed with a defect-free structure. Due to the unique structure composed of twins and stacking faults, the Ag nanowires show a specific current density that is 2.7 times higher than the Ag nanodendrites towards the oxygen reduction reaction. This work not only suggests a synthetic route to the formation of nanowires with structural defects but also offers a rational design of electrocatalysts with enhanced catalytic activity. PMID- 29283111 TI - Enhanced hydrogen storage capacity of Ni/Sn-coated MWCNT nanocomposites. AB - The hydrogen storage capacity of Ni-Sn, Ni-Sn/multi-walled carbon nanotube (MWCNT) and Ni/Sn-coated MWCNT electrodes was investigated by using a chronopotentiometry method. The Sn layer was electrochemically deposited inside pores of nanoscale Ni foam. The MWCNTs were put on the Ni-Sn foam with nanoscale porosities using an electrophoretic deposition method and coated with Sn nanoparticles by an electroplating process. X-ray diffraction and energy dispersive spectroscopy results indicated that the Sn layer and MWCNTs are successfully deposited on the surface of Ni substrate. On the other hand, a field emission scanning electron microscopy technique revealed the morphology of resulting Ni foam, Ni-Sn and Ni-Sn/MWCNT electrodes. In order to measure the hydrogen adsorption performed in a three electrode cell, the Ni-Sn, Ni-Sn/MWCNT and Ni/Sn-coated MWCNT electrodes were used as working electrodes whereas Pt and Ag/AgCl electrodes were employed as counter and reference electrodes, respectively. Our results on the discharge capacity in different electrodes represent that the Ni/Sn-coated MWCNT has a maximum discharge capacity of ~30 000 mAh g-1 for 20 cycles compared to that of Ni-Sn/MWCNT electrodes for 15 cycles (~9500 mAh g-1). By increasing the number of cycles in a constant current, the corresponding capacity increases, thereby reaching a constant amount for 20 cycles. PMID- 29283112 TI - Bat-inspired integrally actuated membrane wings with leading-edge sensing. AB - This paper presents a numerical investigation on the closed-loop performance of a two-dimensional actuated membrane wing with fixed supports. The proposed concept mimics aerodynamic sensing and actuation mechanisms found in bat wings to achieve robust outdoor flight: firstly, variable membrane tension, which is obtained in bats through skeleton articulation, is introduced through a dielectric-elastomer construction; secondly, leading-edge airflow sensing is achieved with bioinspired hair-like sensors. Numerical results from a coupled aero-electromechanical model show that this configuration can allow for the tracking of prescribed lift coefficient signals in the presence of disturbances from atmospheric gusts. In particular, disturbance measurements through the hair sensor (a feedforward control strategy) are seen to provide substantial advantage with respect to a reactive (feedback) control strategy determining a reduction of the oscillations of the lift coefficient. PMID- 29283113 TI - Indian Journal of Ophthalmology: Right on track. PMID- 29283114 TI - Vascular lesions of the orbit: Conceptual approach and recent advances. PMID- 29283115 TI - One-minute ophthalmology: Spend just a minute to challenge your skills. PMID- 29283116 TI - Soft drusen or not? PMID- 29283117 TI - Refractive lenticule extraction small incision lenticule extraction: A new refractive surgery paradigm. AB - Small incision lenticule extraction (SMILE), a variant of refractive lenticule extraction technology is becoming increasingly popular, as a flapless and minimally invasive form of laser vision correction (LVC) for the treatment of myopia and myopic astigmatism. This review aims at summarizing the principles, surgical technique, and clinical outcomes in terms of visual and refractive results, safety, efficacy, postoperative dry eye, aberrations, and biomechanics of SMILE and its comparison with other conventional techniques of LVC, such as laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). Recent advancements in the laser frequency and energy delivery patterns, instrumentation, and surgical techniques have shown significant improvement in the visual recovery and outcomes after SMILE, compared to the initial results published by Sekundo and Shah et al. Most of the recently published literature on long-term outcomes of SMILE shows excellent stability of the procedure, especially for higher myopia. In terms of the postoperative dry eye, SMILE shows a clear advantage over LASIK as numerous studies have shown significant differences about the Schirmer's, Tear film break up time, corneal sensitivity, and corneal nerve regeneration to be better following SMILE compared to LASIK. There is some evidence that since the Bowman's membrane (BM) and the anterior lamellae remain intact after SMILE, this may be a potential advantage for corneal biomechanics over LASIK and PRK where the BM is either severed or ablated, respectively, however, the data on biomechanics are inconclusive at present. Overall, this procedure has proved to be promising, delivering equivalent, or better visual and refractive results to LASIK and providing clear advantage in terms of being a flapless, minimally invasive procedure with minimal pain and postoperative discomfort thus offering high patient satisfaction. PMID- 29283119 TI - Demodex and rosacea: Is there a relationship? AB - PURPOSE: The objective of the study is to compare the frequency of Demodex on the eyelash follicle of patients with rosacea and referents without rosacea or ophthalmological disorders. METHODS: This is a comparative, open, observational, and cross-sectional study that included 41 patients diagnosed with rosacea and 41 referents without rosacea diagnosis or ophthalmic alterations. The individuals underwent a slit-lamp examination in which two eyelashes per eyelid were removed with fine forceps. The presence of Demodex was sought by direct visualization under a light microscope. The results were expressed as "positive" when at least one mite on one lash was found and "negative" when no mite was identified. Chi square test was used to compare the presence of mites in both groups. RESULTS: Eighty-two study individuals (45 females and 37 males) were included, of which 41 patients were diagnosed with rosacea and 41 were without rosacea or ophthalmic alterations. The average mean age was 37 years with a minimum of 19 and a maximum of 87 years. Of the 41 patients with rosacea, 31 had erythematotelangiectatic rosacea and 10 had papulopustular rosacea. There were no patients with phymatous or ocular rosacea. The presence of Demodex was found in 32 patients: 24 patients with rosacea diagnosis (16 of the erythematotelangiectatic subtype and 8 of papulopustular subtype) and 8 patients without rosacea or ophthalmic alterations (P <= 0.001). CONCLUSION: Rosacea was found to be a statistically significant risk factor for Demodex infestation in eyelashes, irrespective of age and sex, with a higher prevalence in papulopustular variety. PMID- 29283118 TI - Optical coherence tomography: A guide to interpretation of common macular diseases. AB - Optical coherence tomography is a quick, non invasive and reproducible imaging tool for macular lesions and has become an essential part of retina practice. This review address the common protocols for imaging the macula, basics of image interpretation, features of common macular disorders with clues to differentiate mimickers and an introduction to choroidal imaging . It includes case examples and also a practical algorithm for interpretation. PMID- 29283121 TI - Ocular surface inflammation in dry eye disease: What we know and what we do not. PMID- 29283120 TI - Correlation of interleukin-33 with Th cytokines and clinical severity of dry eye disease. AB - PURPOSE: The purpose of this study is to determine the tear and serum protein levels of interleukin-33 (IL-33) and its correlation with Th cytokines and disease severity in dry eye (DE) syndrome. METHODS: Tear and serum samples were collected from 30 healthy volunteers, 30 DE patients with non-Sjogren's syndrome DE (NSSDE) and 30 DE patients with primary SSDE. The eight most frequent symptoms of DE were scored. All patients underwent corneal and conjunctival staining, tear film breakup time (TBUT), and Schirmer I test. The serum and tear levels of IL-33 were measured by enzyme-linked immunosorbent assay. The levels of IL-33 expression and its correlation with Th cytokines and disease severity were also analyzed. RESULTS: We found that symptom scores and corneal staining grade were significantly higher in SSDE group compared with NSSDE and control group, whereas the results of TBUT and Schirmer I test were significantly lower in SSDE group compared with NSSDE and control group. The tear levels of IL-33 were significantly increased in tears of SSDE patients compared with those of controls and NSSDE patients (P < 0.05). Moreover, the elevated tear levels of IL-33 were positively correlated with symptom scores but negatively correlated with tear film breakup time and Schirmer I test in both NSSDE and SSDE patients (P < 0.05). The tear levels of IL-33 of both NSSDE and SSDE patients were also positively correlated with tear levels of IL-4 and IL-5 (P < 0.05). Correlation between the serum levels of IL-33 with Th1/17/Treg cytokines was not found. CONCLUSION: Elevated tear levels of IL-33 were associated with the Th2 cytokines and disease severity of DE. Therefore, IL-33 may have important roles in the immunopathogenesis of the DE. PMID- 29283122 TI - Results of simple limbal epithelial transplantation in unilateral ocular surface burn. AB - PURPOSE: This study aimed to report the long-term outcomes of autologous Simple Limbal Epithelial Transplantation (SLET) performed for unilateral limbal stem cell deficiency (LSCD) following chemical burn at a tertiary eye center in North India. METHODS: This was a single-center prospective interventional case series of patients who developed unilateral LSCD after suffering from ocular surface burns and who underwent SLET between October 2012 and May 2016 with a follow-up period of at least 6 months. The primary outcome measure was restoration of a completely epithelized, stable, and avascular corneal surface. The secondary outcome measure was percentage of eyes, which reported visual gain. RESULTS: The study included 30 eyes of 30 patients, 18 adults and 12 children, at a median follow-up of 1.1 years (range: 6 months to 3.5 years), 21 of 30 eyes (70%; 95% confidence interval, 53.6%-86.2%) maintained successful outcome. Visual acuity gain was seen in 71.4% of successful cases. The clinical factors associated with failure were identified as acid injury, severe symblepharon at the time of presentation, and SLET combined with penetrating keratoplasty (PK). CONCLUSION: Autologous SLET is an effective limbal cell transplantation technique for the treatment of unilateral LSCD. It is especially beneficial for centers where cell cultivation laboratory is unavailable. Presence of severe symblepharon, which requires PK peroperatively , has poor outcome. PMID- 29283123 TI - Simple limbal epithelial transplantation: Impactful innovation. PMID- 29283124 TI - Topical chemotherapy for giant ocular surface squamous neoplasia of the conjunctiva and cornea: Is surgery necessary? AB - PURPOSE: The purpose of this study is to report on the efficacy and safety of topical chemotherapy alone for giant ocular surface squamous neoplasia (OSSN). METHODS: In this retrospective, interventional series, 10 eyes with giant OSSN underwent exfoliative biopsy to confirm the diagnosis followed by application of interferon alpha 2b (IFN alpha2b) and/or 5 fluorouracil, 1% (5FU). Reported outcome measures were tumor response, visual acuity, recurrence, systemic metastasis, and treatment complications. RESULTS: Ten patients (3 female, 7 male) had a mean age of 73 (median, 69; range 40-89) years. Mean tumor diameter was 13.1 (median, 12.3; range 8.2-19.4) mm. Five (50%) eyes were treated with IFN alpha2b alone; 1 (10%) with 5-FU alone and 4 (40%) required both IFN-alpha2b and 5-FU. The mean duration of treatment was 3, 0.5, and 6.4 months for IFN-alpha2b alone, 5-FU alone, and both IFN-alpha2b and 5-FU respectively. Complete tumor response was observed in all 10 cases at mean follow-up of 12.8 (median, 11.5; range, 3-25) months. Complications noted were transient irritation and burning (n = 4), dry eyes (n = 2), and transient flu-like symptoms (n = 2). There was no evidence of chemotherapy-related symblepharon, stem cell deficiency, scleral thinning, or corneal opacity. There were no tumor recurrences, and no patient required surgical excision or cryotherapy. CONCLUSION: Topical chemotherapy was a safe and effective treatment, inducing complete regression in all cases of giant OSSN in this series. There were no sight-limiting complications. PMID- 29283125 TI - Factors affecting the serological testing of cadaveric donor cornea. AB - PURPOSE: The purpose of this study was to evaluate the serological profile of the eye donors and to study the influence of various factors on serological test results. METHODS: A cross-sectional, observational study was conducted, and data of 509 donors were reviewed from the records of eye bank from December 2012 to June 2017. Various details of donors analyzed included the age, sex of the donor, cause of death, source of tissue, time since blood collection after death, macroscopic appearance of blood sample, and details of discarded tissues. Serological examination of blood was performed for human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus (HCV), venereal disease research laboratory (VDRL), and serology reports reactive or nonreactive were analyzed. RESULTS: Among the 509 donors, 295 (58%) were male, and 420 (82.50%) belonged to age group >=60 years. Most donors (354, 69.5%) died due to cardiac arrest. Macroscopically, sera were normal in the majority of 488 (95.9%) cases. Among 509 donors, 475 (93.3%) were nonreactive, 12 (2.4%) donors were found to be reactive to hepatitis B surface antigen (HBsAg), and 1 (0.2%) was reactive to HCV, but no donor serology was reactive to HIV or VDRL. Twenty-one (4.12%) donors' sera were not fit for serological testing. Among all donors, 475 (93.32%) donors were accepted and 34 (6.67%) were rejected or discarded on the basis of serological testing. Cause of death and macroscopic aspect of sera influenced the serological results in a highly significant manner (P = 0.00). Acceptance or rejection of the donor was significantly influenced by the serological results of the donor (P = 0.00). CONCLUSION: The seroprevalence among eye donor for HBsAg and HCV was 12 (2.4%) and 1 (0.2%), respectively. Factors such as cause of death and macroscopic aspect of sera influence the serological results. Time since blood collection or sampling will not show any impact on viral serological results if postmortem sampling will be done in < 10 hours(h) after death which can improve the safety and utility of the donor cornea. PMID- 29283126 TI - Comparison of surgical outcomes between canaloplasty and trabeculectomy with mitomycin C at 2-year follow-up: A longitudinal cohort study. AB - PURPOSE: To compare operative outcomes of patients after canaloplasty and trabeculectomy with mitomycin C (MMC) through 2-year follow-up. METHODS: We included 31 eyes of 31 patients with primary open-angle glaucoma (POAG) who underwent canaloplasty and 37 eyes of 37 patients with POAG who underwent trabeculectomy with MMC with 24 months of postoperative follow-up. All surgeries were performed by a single surgeon between January 2005 and May 2011. Failure was defined as intraocular pressure (IOP> 18 or <4 mmHg at 2 years), second operative procedure, or loss of light perception. Change in IOP, visual acuity (VA), glaucoma medications, and complication rates at 24 months were analyzed. RESULTS: Caucasians made up to half of the patients included in this study (58% vs. 43%) while the rest where either African Americans (32% vs. 43%) or Hispanic (10% vs. 14%) patients between the canaloplasty and trabeculectomy group. Both groups showed significant reduction in IOP from baseline at 24 months. Trabeculectomy patients had a greater mean reduction of IOP compared to canaloplasty patients (12.2 +/- 12 vs. 4.7 +/- 7.5, P = 0.003) and also achieved lower IOP at 24 months (12.2 +/- 4.1 vs. 14.9 +/- 6.0, P = 0.03). Postoperative glaucoma medication use was less in the trabeculectomy group (n = 0, interquartile range [IQR] 0-2) compared to those in whom canaloplasty was performed (n = 2, IQR 0-3, P = 0.02). VA showed no statistical change in either group over 2 years. Overall failure rates at 2 years were comparable between the two groups: 32% for trabeculectomy and 26% for canaloplasty (P = 0.6). Subgroup analysis revealed a lower failure rate in Caucasions (15%) when compared to Blacks (42%) and Hispanics/others (50%, P = 0.03). CONCLUSION: Canaloplasty and trabeculectomy both achieved significant reduction in IOP with comparable success rates. Trabeculectomy can achieve a greater reduction in IOP while requiring fewer medications however is associated with more intensive postoperative care and frequent interventions. Pigmented populations have worse outcomes compared to Caucasians. PMID- 29283127 TI - Rescue of failing or failed trabeculectomy blebs with slit-lamp needling and adjunctive mitomycin C in Indian eyes. AB - PURPOSE: The aim of this study is to investigate the efficacy and safety of needling-revision augmented with a high dose of mitomycin C (MMC) in failing or failed blebs after trabeculectomy in Indian eyes. METHODS: Prospective, noncomparative, interventional study. All patients (>18 years) who had raised intraocular pressure (IOP) following trabeculectomy (>6 weeks and <2 years), who had a flat bleb, bleb encapsulation, and/or required antiglaucoma medication (AGM) for IOP control were eligible for inclusion. MMC was injected subconjunctivally at least 1/2 hour before the needling procedure was carried out at the slit lamp in the outpatient's clinic. RESULTS: Thirty-nine eyes of 38 patients were included. The median follow-up was 20 months and time interval between trabeculectomy and needle revision was 113 days. Initially, in all cases, aqueous flow was re-established with a raised bleb; 7 eyes required repeat needling. IOP decreased from median 24 mmHg (Q1 21, Q3 27, interquartile range [IQR] 6, range 18-35) preneedling to median 14 mmHg (Q1 10, Q3 16, IQR 6, range 6 18) postneedling at last follow-up (P < 0.0001, 95% confidence interval [CI]: 8.2 13.0). The use of AGM reduced from median 1 (Q1 0, Q3 3, IQR 3, range 0-4) preneedling to median 0 postneedling (P < 0.0001, 95% CI: 1-2). Complete success was seen in 28 eyes (71.8%, 95% CI: 71.1%-96.4%); another 5 eyes (12.8%) were controlled with AGM (qualified success) with overall success of 84.6%. Most complications were transient in nature with resolution within 1 week. One patient developed hypotony, and another developed a late bleb leak. CONCLUSION: Needling revision augmented with high-dose MMC, at the slit lamp, effectively rescues failing or failed filtration, and appears to be safe. PMID- 29283128 TI - Age and myopia associated optical coherence tomography of retina and choroid in pediatric eyes. AB - PURPOSE: To evaluate the association between retinal and choroidal thickness and volume along with choroidal vessel volume in children using optical coherence tomography (OCT) images. METHODS: 113 normal eyes of children ranging from 5-17 years of age were imaged with a clinical OCT scanner (Optovue Inc., Fremont, USA). The retina, choroid and choroidal vessels were automatically segmented with algorithms. Parameters evaluated were thickness and volume. Location specific analyses of thickness were also performed at a distance of 2.5 mm from foveal center. Multivariate analyses of variance were used to analyze the effect of age and myopia. Manual segmentation of the fovea and subfoveal choroid thickness was also performed to compare with the algorithm segmentation. RESULTS: There was excellent agreement between manual and automatic segmentation (intra-class correlation of 0.95). Within the same eye, total retinal and choroid thickness of nasal and temporal location were significantly lower than the superior and inferior thickness (P < 0.0001). With age (P = 0.026) and myopia (P < 0.001), foveal thickness increased. Choroid volume, vessel volume and temporal choroid thickness increased with increasing myopia (P < 0.05). There was significant positive correlation between choroid volume and retinal volume (r = 0.62, P < 0.0001), choroid volume and vessel volume (r = 0.48, P < 0.0001), and with foveal thickness (r = 0.31, P = 0.009). Choroid vessel volume also showed significant positive correlations with the other metrics (P < 0.05). CONCLUSION: Retinal and choroidal structural features were quantified simultaneously from OCT images. Magnitude of myopia had a greater effect on retino-choroid features than age in children. PMID- 29283129 TI - Retinal pigment epithelium aperture: A late-onset complication in adult-onset foveomacular vitelliform dystrophy. AB - PURPOSE: The purpose of the study was to report aperture of retinal pigment epithelium (RPE) as a late complication and an unreported finding during the natural course of adult-onset foveomacular vitelliform dystrophy (AFVD). METHODS: Four diagnosed cases of AFVD followed for a period ranging from 4 to 8 years. All patients had documented records of clinical examination, fundus autofluorescence and fluorescein angiography, and spectral domain-optical coherence tomography at regular intervals. RESULTS: Besides the known stages in the natural course of AFVD, RPE aperture was noted as an additional finding during the vitelliruptive stage of the disease. The vitelliform material was noted beneath the disrupted RPE before disappearance. Accumulation of vitelliform material continued even after the vitelliruptive stage. CONCLUSION: RPE aperture may represent an ongoing process in the natural course of AFVD. PMID- 29283130 TI - Color Doppler imaging of the retrobulbar circulation and plasmatic biomarkers of vascular risk in age-related macular degeneration: A pilot study. AB - PURPOSE: To evaluate preliminarily and compare the level of plasmatic biomarkers of vascular risk in patients with and without exudative age-related macular degeneration (ARMD) and to relate it to vascular resistance alterations in the ophthalmic artery (OA), central retinal artery (CRA), posterior temporal ciliary artery (PTCA), and posterior nasal ciliary artery (PNCA). METHODS: Color Doppler imaging of the OA, CRA, PTCA, and PNCA was performed in 30 eyes of 30 cataract patients (control group) as well as in 30 eyes of 30 patients with naive exudative ARMD (study group), measuring the peak systolic velocity, end-diastolic velocity (EDV), and Pourcelot resistive index (RI). Likewise, in both groups, a blood test was performed to determine the plasmatic levels of homocysteine, C reactive protein (CRP), B12 vitamin, and folic acid. RESULTS: A positive and significant correlation was found between the level of CRP and RI of the OA in the ARMD group (r = 0.498, P = 0.005), with an increased RI in all arteries compared to controls, although differences only reached statistical significance for the PTCA (P = 0.035). Likewise, a significantly lower EDV for the CRA was found in ARMD eyes compared to controls (P = 0.041). In the study group, significantly higher plasmatic levels of homocysteine (P = 0.042) and CRP (P = 0.046) were found. In contrast, no significant differences were found between groups in the levels of folic acid (P = 0.265) and B12 vitamin (P = 0.520). CONCLUSION: The decrease of the choroidal perfusion related to hyperhomocysteinemia, and increase in the CRP plasmatic levels may play an etiological role on the exudative ARMD. This should be investigated in future studies with larger samples of patients. PMID- 29283131 TI - The diagnostic accuracy of single- and five-field fundus photography in diabetic retinopathy screening by primary care physicians. AB - PURPOSE: The aim is to evaluate the diagnostic accuracy of digital fundus photography in diabetic retinopathy (DR) screening at a single university hospital. METHODS: This was a cross-sectional hospital-based study. One hundred and ninety-eight diabetic patients were recruited for comprehensive eye examination by two ophthalmologists. Five-field fundus photographs were taken with a digital, nonmydriatic fundus camera, and trained primary care physicians then graded the severity of DR present by single-field 45 degrees and five-field fundus photography. Sensitivity and specificity of DR grading were reported using the findings from the ophthalmologists' examinations as a gold standard. RESULTS: When fundus photographs of the participants' 363 eyes were analyzed for the presence of DR, there was substantial agreement between the two primary care physicians, kappa = 0.6226 for single-field and 0.6939 for five-field photograph interpretation. The sensitivity and specificity of DR detection with single-field photographs were 70.7% (95% Confidence interval [CI]; 60.2%-79.7%) and 99.3% (95% CI; 97.4%-99.9%), respectively. Sensitivity and specificity for five-field photographs were 84.5% (95% CI; 75.8%-91.1%) and 98.6% (95% CI; 96.5%-99.6%), respectively. The receiver operating characteristic was 0.85 (0.80-0.90) for single-field photographs and 0.92 (0.88-0.95) for five-field photographs. CONCLUSION: The sensitivity and specificity of fundus photographs for DR detection by primary care physicians were acceptable. Single- and five-field digital fundus photography each represent a convenient screening tool with acceptable accuracy. PMID- 29283132 TI - Efficiency of fenofibrate in facilitating the reduction of central macular thickness in diabetic macular edema. AB - PURPOSE: The purpose of this study is to study the benefit of addition of oral fenofibrate to the current regimen of diabetic macular edema (DME) management and quantify its effect on macular thickness and visual function in DME. METHODS: Fifty-three eyes of 50 patients were randomized into treatment (Group A) (oral fenofibrate 160 mg/day) and control groups (Group B). Both groups underwent treatment of DME as per the standard treatment protocol of our hospital including intravitreal injections (anti-vascular endothelial growth factor/steroid) and grid laser. Patients were followed up every 2 months to note the visual acuity and central macular thickness (CMT) for 6 months. RESULTS: Our groups were matched with respect to age (P = 0.802), mean diabetic age (P = 0.878), serum HbA1C levels (P = 0.523), and serum triglyceride levels (P = 0.793). The mean reduction in CMT was 136 MU in Group A and 83 MU in Group B at the end of 6 months. This difference was statistically significant (P = 0.031). Visual acuity improvement was 0.15 in Group A and 0.11 in Group B at the end of 6 months (P = 0.186). On subgroup analysis in Group A, we found that there was no difference in reduction of CMT between hypertensives and normotensives (P = 0.916), in patients with normal triglyceride levels and increased triglyceride levels (P = 0.975). CONCLUSION: Addition of fenofibrate to the standard protocol of DME management seems to facilitate reduction of CMT and probably have an added benefit on the visual functions. PMID- 29283133 TI - Use and validation of mirrorless digital single light reflex camera for recording of vitreoretinal surgeries in high definition. AB - PURPOSE: The purpose of this study is to describe the use of commercial digital single light reflex (DSLR) for vitreoretinal surgery recording and compare it to standard 3-chip charged coupling device (CCD) camera. METHODS: Simultaneous recording was done using Sony A7s2 camera and Sony high-definition 3-chip camera attached to each side of the microscope. The videos recorded from both the camera systems were edited and sequences of similar time frames were selected. Three sequences that selected for evaluation were (a) anterior segment surgery, (b) surgery under direct viewing system, and (c) surgery under indirect wide-angle viewing system. The videos of each sequence were evaluated and rated on a scale of 0-10 for color, contrast, and overall quality Results: Most results were rated either 8/10 or 9/10 for both the cameras. A noninferiority analysis by comparing mean scores of DSLR camera versus CCD camera was performed and P values were obtained. The mean scores of the two cameras were comparable for each other on all parameters assessed in the different videos except of color and contrast in posterior pole view and color on wide-angle view, which were rated significantly higher (better) in DSLR camera. CONCLUSION: Commercial DSLRs are an affordable low-cost alternative for vitreoretinal surgery recording and may be used for documentation and teaching. PMID- 29283134 TI - WINROP algorithm for prediction of sight threatening retinopathy of prematurity: Initial experience in Indian preterm infants. AB - PURPOSE: To determine the efficacy of the online monitoring tool, WINROP (https://winrop.com/) in detecting sight-threatening type 1 retinopathy of prematurity (ROP) in Indian preterm infants. METHODS: Birth weight, gestational age, and weekly weight measurements of seventy preterm infants (<32 weeks gestation) born between June 2014 and August 2016 were entered into WINROP algorithm. Based on weekly weight gain, WINROP algorithm signaled an alarm to indicate that the infant is at risk for sight-threatening Type 1 ROP. ROP screening was done according to standard guidelines. The negative and positive predictive values were calculated using the sensitivity, specificity, and prevalence of ROP type 1 for the study group. 95% confidence interval (CI) was calculated. RESULTS: Of the seventy infants enrolled in the study, 31 (44.28%) developed Type 1 ROP. WINROP alarm was signaled in 74.28% (52/70) of all infants and 90.32% (28/31) of infants treated for Type 1 ROP. The specificity was 38.46% (15/39). The positive predictive value was 53.84% (95% CI: 39.59-67.53) and negative predictive value was 83.3% (95% CI: 57.73-95.59). CONCLUSION: This is the first study from India using a weight gain-based algorithm for prediction of ROP. Overall sensitivity of WINROP algorithm in detecting Type 1 ROP was 90.32%. The overall specificity was 38.46%. Population-specific tweaking of algorithm may improve the result and practical utility for ophthalmologists and neonatologists. PMID- 29283135 TI - Retinal nerve fiber layer and ganglion cell layer changes on optical coherence tomography in early multiple sclerosis and optic neuritis cases. AB - PURPOSE: To study the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) changes on optical coherence tomography in early multiple sclerosis (MS) patients. METHODS: A prospective cohort study was conducted at a tertiary care center. Patients of early MS (expanded disability status scale <3) with or without optic neuritis (ON) and idiopathic ON were included. Twenty age-matched individuals were taken as controls. Changes in RNFL and GCL thickness were evaluated along with the correlation with visual function parameters such as visual acuity, contrast sensitivity, and visual evoked response at first visit and again at six months. RESULTS: Forty-four patients of MS with or without ON (24 and 20 patients respectively), 29 patients with idiopathic ON, and 20 healthy controls constituted the cohorts. Mean LogMAR best-corrected visual acuity was found to be significantly reduced in all groups except fellow eyes (FE) of ON group. Mean values of average RNFL thickness and values in superior, temporal, and inferior quadrant were significantly reduced. Similarly, overall mean values of average GCL-inner plexiform layer (IPL) thickness and values in superior, superonasal, superotemporal, inferonasal, and inferotemporal quadrant were significantly reduced in all groups except FE of ON group (P < 0.05). All the visual parameters significantly correlated with GCL + IPL thickness. CONCLUSION: GCL + IPL thickness is a more sensitive clinical structural marker than RNFL in early MS with/without ON and ON patients and correlates with all the visual parameters better than RNFL thickness. PMID- 29283136 TI - Single-pass four-throw pupilloplasty for angle-closure glaucoma. AB - Angle-closure glaucoma is characterized by appositional or synechial closure of the anterior chamber angle with glaucomatous field defects that may or may not be associated with a pupillary block. Surgical pupilloplasty with single-pass four throw technique helps to alleviate the appositional closure along with the breakage of peripheral anterior synechia, thereby increasing the aqueous outflow and decreasing intraocular pressure. PMID- 29283137 TI - Optic nerve aplasia. PMID- 29283138 TI - Chronic papilledema in a child with classical tuberous sclerosis. PMID- 29283139 TI - Congenital retinal macrovessels. PMID- 29283140 TI - Aripiprazole-induced transient myopia: A rare entity. AB - Aripiprazole is a new drug for the treatment of adults with schizophrenia. Ocular side effects of aripiprazole are very rare. Review of literature revealed few cases of aripiprazole-induced myopia. We report a rare case of aripiprazole induced transient myopia. A 22-year-old female patient presented to the department of psychiatry with worsening of symptoms of schizophrenia and was started on aripiprazole. She presented with complaints of blurring of vision in both eyes for 1 week which started on the 3rd day following the use of aripiprazole. Anterior segment examination revealed a shallow anterior chamber and narrow angles. Intraocular pressure was normal. A diagnosis of aripiprazole induced acute myopia was made and the treating psychiatrist was advised to stop the medication. At 2-week follow-up, the unaided visual acuity improved to 20/20 in both the eyes. Ophthalmologists should be aware of the myopic shift that may occur as an ocular side effect with aripiprazole. PMID- 29283141 TI - Bilateral disciform keratitis of presumed adenoviral etiology. AB - Adenoviral conjunctivitis may lead to subepithelial corneal infiltrates as a late complication. Herein, we aim to present a 19-year-old healthy female, who developed bilateral disciform keratitis three weeks after suffering adenoviral conjunctivitis. She presented with widespread subepithelial corneal infiltrates in addition to central corneal edema with white distinct border resembling immune stromal ring, as well as Descemet's folds and keratic precipitates in the central area. Following topical corticosteroid and ganciclovir for 10 days, her condition improved. After 1 month, she had another episode. Short-term topical corticosteroids in addition to long-term topical cyclosporine and nonpreserved artificial tears were able to prevent further recurrences. PMID- 29283142 TI - Bilateral idiopathic spontaneous filtering bleb with ectopia lentis: A case report and review of literature. AB - A 26-year-old male presented with superior filtering bleb with scleral thinning, dislocated lens, and hypotony in both the eyes. His cornea was normal without any sign of ectasia, and there was no history of recurrent redness, trauma, or surgery in either eye. Anterior segment optical coherence tomography did not reveal communicating fistula between the anterior chamber and subconjunctival space. Physical examination and blood investigations did not reveal any systemic association. He was diagnosed to have spontaneous filtering bleb, which is a rare condition observed with ocular or systemic abnormalities. PMID- 29283143 TI - Ocular infections caused by Scedosporium apiospermum: A case series. AB - The aim of our retrospective study is to report a case series of ocular infections caused by a rare fungus, Scedosporium apiospermum, in a South Indian population. Thirteen cases of culture-positive S. apiospermum infections diagnosed between January 2011 and March 2016 were included in this study. The parameters evaluated were predisposing factors, treatment and final clinical outcome. The most common mode of presentation was keratitis (84.6%) followed by sclerokeratitis (15.3%). The predisposing factors involved were unspecified foreign body injury (30.7%), organic matter injury (15.3%), uncontrolled diabetes (7.6%), and recent manual small-incision cataract surgery (7.6%). Five cases (38.46%) had no predisposing factor. Of the 11 keratitis cases, nine (69.2%) responded well to combination medical therapy while one case (7.6%) required therapeutic keratoplasty. One case was lost to follow-up. Both cases which presented with sclerokeratitis showed no response to medico-surgical treatment progressing to panophthalmitis and evisceration. PMID- 29283144 TI - Swept-source optical coherence tomography of an optic disc melanocytoma: The importance of the hyperreflective foci. AB - Optic disc melanocytoma (ODM) has been considered as a benign tumor with few reports of malignant transformation. We present swept-source optical coherence tomography (SSOCT) imaging of a case of ODM. As attaining histopathology is impossible in most cases, we discuss the possibility of using SSOCT as a tool for ruling out choroidal invasion or juxtapapillary melanoma. PMID- 29283146 TI - Branch retinal artery occlusion post-penetrating globe injury with intraocular foreign body. AB - Intraocular foreign body (IOFB) in cases of penetrating eye injury accounts for an important indication of vitreoretinal intervention following ocular trauma. Vascular occlusion as a complication of IOFB is rare. Here we present a case of a 34-year-old male with post-traumatic cataract and an intraocular metallic foreign body (IOFB) lodged in the superficial layers of the retina inferotemporal to the disc, causing an inferotemporal branch retinal artery occlusion. The case was managed by lensectomy with pars plana vitrectomy and IOFB removal followed by a second procedure of secondary IOL implantation. Final best-corrected visual acuity improved to 6/24. This case highlights an unusual sequelae following penetrating ocular trauma. PMID- 29283145 TI - Optical coherence tomography angiography features of bilateral retinopathy associated with Chikungunya fever. AB - A 66-year-old male patient presented with decreased vision in both eyes following episode of Chikungunya fever. Examination revealed bilateral retinal lesions with stippled pigmentary changes at the level of the choriocapillaris, involving the macula in the left eye. The retinopathy consisted of outer retinal disruption and retinochoroidal flow abnormalities detected using with additional imaging, including spectral-domain optical coherence tomography (OCT), autofluorescence, and OCT angiography (OCTA). The index case report describes unique OCTA findings in both eyes of an elderly male secondary to Chikungunya fever. Using the technique of OCTA, insights into the mechanisms of visual damage in viral retinopathies such as Chikungunya fever can be understood. PMID- 29283147 TI - Bilateral proliferative retinopathy in B-cell acute lymphoblastic leukemia. AB - A 4-year-old child with B-cell acute lymphoblastic leukemia presented with vitreous hemorrhage due to proliferative retinopathy in both eyes. Pars plana vitrectomy was performed in both eyes to clear nonresolving vitreous hemorrhage after systemic stabilization. Visual recovery was limited by the disc drag in the right eye and subfoveal exudation in the left eye. Etiopathogenesis and management of proliferative retinopathy in acute leukemias are discussed. PMID- 29283148 TI - Combined approach to management of periocular arteriovenous malformation by interventional radiology and surgical excision. AB - Periorbital arteriovenous malformations (AVMs) are congenital lesions that may cause significant morbidity such as amblyopia, cosmetic disfigurement, or chronic pain. Due to the rarity of these lesions, they are frequently misdiagnosed and treated inappropriately. We managed a 6-year-old girl with preseptal AVM by endovascular embolization followed by complete surgical excision after 2 days. She was previously diagnosed as capillary hemangioma and was being treated with intralesional steroid injections and oral propranolol. Neuroimaging revealed an AVM fed by the branches of both external and internal carotid arteries and drained by the superior ophthalmic vein. Endovascular embolization with glue followed by complete surgical excision of the lesion was done. The resultant cosmetic and functional outcome was gratifying. Diagnosis and management of periorbital AVM remain a challenge requiring a multidisciplinary approach involving interventional radiologist and trained oculoplastic surgeons. Combined endovascular embolization followed by surgical excision proved safe and effective. PMID- 29283149 TI - Unilateral isolated superior ophthalmic vein thrombosis. AB - Superior ophthalmic vein (SOV) thrombosis is an uncommon orbital pathology that can present with sudden onset proptosis, conjunctival injection, and visual disturbance. SOV thrombosis is frequently secondary to a cavernous sinus pathology. A 32-year-old female with a known history of autoimmune hemolytic anemia presented with sudden painful proptosis left eye, and on imaging, she was found to have SOV thrombosis without cavernous sinus involvement. She was diagnosed with unilateral isolated SOV thrombosis and was managed conservatively. A careful history and clinical evaluation can help diagnose such rare disorders and initiate appropriate therapy. PMID- 29283150 TI - A multidisciplinary approach to sphenoid wing dysplasia presenting with pulsatile proptosis in neurofibromatosis Type 1: A rare case report. AB - Neurofibromatosis (NF) with sphenoid wing dysplasia is a rare clinical entity. Herewith, we present a case of NF with sphenoid wing dysplasia which presented with pulsatile progressive proptosis. Other ocular symptoms or visual disturbances were absent. Diagnosis of the condition was not easy and the management was a challenging task which needed multidisciplinary approach as there were ocular, neurological, orthopedic, and dermatological manifestations. With neurosurgical intervention, reconstruction of the sphenoid wing was possible. Proptosis was corrected without any disturbance of vision. PMID- 29283151 TI - Unusual intraconal localization of orbital giant cell angiofibroma. AB - Giant cell angiofibroma (GCA) is a recently reported rare soft-tissue tumor that can develop in various sites including orbit. Orbital GCAs were mainly located in the eyelid or extraconal regions such as lacrimal gland and conjunctiva. We report an atypical case of a GCA arising in the intraconal area of the orbit in a 65-year-old male patient. The tumor was excised in total by lateral orbitotomy. Histological and immunohistochemical features were consistent with the diagnosis of GCA. No recurrence was observed during the follow-up of over 2 years. GCA is a rare tumor that should be considered in the differential diagnosis of intraconal orbital tumors. Complete surgical removal is the current optimal treatment option. PMID- 29283152 TI - Intravascular Papillary Endothelial Hyperplasia as an unusual diagnosis for peri orbital tumour - A case report. AB - Intravascular papillary endothelial hyperplasia (IPEH) is a rare cause of orbital mass which can affect healthy individuals of any age/sex/race/region. It usually requires a histopathological examination, characterized by the appearance of papillary proliferation of vascular endothelial cells within the lumen of the blood vessel, for the final diagnosis. One should be aware that this is a highly vascular lesion which can cause excessive intraoperative bleeding and incomplete removal can lead to recurrences. IPEH of the orbit/eyelid has been reported in few parts of the world as isolated case reports but none from India so far. PMID- 29283153 TI - Bilateral medial rectus palsy due to midbrain infarction following concussion head injury. AB - Here, we report a rare case of bilateral medial rectus palsy following closed head injury. An adult male had an accidental fall which rendered him unconscious. This was followed by diplopia and restricted ocular motility. He received supportive medical therapy. He was examined for systemic medical and ophthalmic findings. Routine laboratory tests and imaging techniques were employed as per the symptoms. Diffusion-weighted imaging on magnetic resonance imaging proved it to be a rare presentation of small bilateral midbrain infarct. He recovered fully after 8 months. PMID- 29283154 TI - Idiopathic intracranial hypertension associated with anaemia, secondary to antiretroviral drug in a human immunodeficiency virus positive patient. AB - Papilledema in a patient with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome is an alarming finding. Any condition giving rise to raised intracranial tension (ICT) can cause papilledema, and in these patients, it could be secondary to opportunistic infections like meningitis to neoplasm. We report a case of a 28-year old female with HIV on antiretroviral therapy, who presented to us, with papilledema. Her fundus examination revealed superficial hemorrhages and Roth's spots along with papilledema. Patient was diagnosed with idiopathic intracranial hypertension (IIH), and all other possible systemic associations were ruled out. Her blood tests showed severe anemia. The papilledema and retinal changes resolved with treatment of anemia. This is a rare presentation of IIH in HIV positive patient due to anemia, secondary to zidovudine adverse effect. PMID- 29283155 TI - Transcanalicular laser-assisted dacryocystorhinostomy: First report from Oman. PMID- 29283156 TI - Training: The way we do it. PMID- 29283157 TI - Intravitreal bevacizumab. PMID- 29283158 TI - Comment on: "Case report of a secondary macular hole closure after intravitreal bevacizumab therapy in a patient with retinal pigment epithelial detachment". PMID- 29283159 TI - Response to comment on "Case report of a secondary macular hole closure after intravitreal bevacizumab therapy in a patient with retinal pigment epithelial detachment". PMID- 29283160 TI - Comment on: "Multimodal imaging in dominant cystoid macular dystrophy". PMID- 29283161 TI - Response to comment on "Multimodal imaging in dominant cystoid macular dystrophy". PMID- 29283162 TI - Comment on "Impact of expansion of telemedicine screening for retinopathy of prematurity in India". PMID- 29283163 TI - Response to comment on "Impact of expansion of telemedicine screening for retinopathy of prematurity in India". PMID- 29283164 TI - Comment on "Prevalence of ocular morbidity in school going children in West Uttar Pradesh". PMID- 29283165 TI - Response to comment on "Prevalence of ocular morbidity in school going children in West Uttar Pradesh". PMID- 29283166 TI - Erratum: Evaluating ocular blood flow. AB - [This corrects the article DOI: 10.4103/ijo.IJO_330_17.]. PMID- 29283167 TI - Erratum: Long-term results of trypan blue dye irrigation in the capsular bag to prevent posterior capsule opacification: A randomized trial. AB - [This corrects the article DOI: 10.4103/ijo.IJO_454_17.]. PMID- 29283168 TI - Corrigendum: Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study. AB - This corrects the article DOI: 10.1038/ajg.2017.494. PMID- 29283169 TI - Haematological cancer: Brentuximab effective in untreated Hodgkin lymphoma. PMID- 29283171 TI - DRAW: the value of anatomical drawing in the 21st century. PMID- 29283172 TI - Prostate cancer: A valuable tool for prediction of repeat biopsy pathology. PMID- 29283170 TI - Perioperative events influence cancer recurrence risk after surgery. AB - Surgery is a mainstay treatment for patients with solid tumours. However, despite surgical resection with a curative intent and numerous advances in the effectiveness of (neo)adjuvant therapies, metastatic disease remains common and carries a high risk of mortality. The biological perturbations that accompany the surgical stress response and the pharmacological effects of anaesthetic drugs, paradoxically, might also promote disease recurrence or the progression of metastatic disease. When cancer cells persist after surgery, either locally or at undiagnosed distant sites, neuroendocrine, immune, and metabolic pathways activated in response to surgery and/or anaesthesia might promote their survival and proliferation. A consequence of this effect is that minimal residual disease might then escape equilibrium and progress to metastatic disease. Herein, we discuss the most promising proposals for the refinement of perioperative care that might address these challenges. We outline the rationale and early evidence for the adaptation of anaesthetic techniques and the strategic use of anti adrenergic, anti-inflammatory, and/or antithrombotic therapies. Many of these strategies are currently under evaluation in large-cohort trials and hold promise as affordable, readily available interventions that will improve the postoperative recurrence-free survival of patients with cancer. PMID- 29283173 TI - CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats. AB - Triptolide is the most active ingredient of Tripterygium wilfordii Hook F, which is used to treat rheumatoid arthritis. (5R)-5-Hydroxytriptolide is a hydroxylation derivative of triptolide with a reduced toxicity. To investigate the metabolic enzymes of the two compounds and the drug-drug interactions with enzyme inducers or inhibitors, a series of in vitro and in vivo experiments were conducted. In vitro studies using recombinant human cytochrome P450 enzyme demonstrated that cytochrome P450 3A4 (CYP3A4) was predominant in the metabolism of triptolide and (5R)-5-hydroxytriptolide, accounting for 94.2% and 64.2% of the metabolism, respectively. Pharmacokinetics studies were conducted in male SD rats following administration of triptolide or (5R)-5-hydroxytriptolide (0.4 mg/kg, po). The plasma exposure to triptolide and (5R)-5-hydroxytriptolide in the rats was significantly increased when co-administered with the CYP3a inhibitor ritonavir (30 mg/kg, po) with the values of AUC0-infinity (area under the plasma concentration-time curve from time zero extrapolated to infinity) being increased by 6.84 and 1.83 times, respectively. When pretreated with the CYP3a inducer dexamethasone (50 mg.kg-1.d-1, for 3 d), the AUC0-infinity values of triptolide and (5R)-5-hydroxytriptolide were decreased by 85.4% and 91.4%, respectively. These results suggest that both triptolide and (5R)-5-hydroxytriptolide are sensitive substrates of CYP3a. Because of their narrow therapeutic windows, clinical drug-drug interaction studies should be carried out to ensure their clinical medication safety and efficacy. PMID- 29283174 TI - Nucleus Accumbens, a new sleep-regulating area through the integration of motivational stimuli. PMID- 29283175 TI - EBP50 suppresses the proliferation of MCF-7 human breast cancer cells via promoting Beclin-1/p62-mediated lysosomal degradation of c-Myc. AB - c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer. PMID- 29283176 TI - Correction to: Ind Biotechnol 2017;13(5):219-220, DOI: 10.1089/ind.2017.29098.vjs. AB - [This corrects the article on p. 219 in vol. 13, PMID: 29066941.]. PMID- 29283177 TI - Comparison of postoperative ultrasound criteria to predict unassisted use of arteriovenous fistulas for hemodialysis. AB - INTRODUCTION: Arteriovenous fistulas (AVF) frequently fail to mature. Postoperative ultrasounds provide objective measurements to predict unassisted AVF use for hemodialysis (unassisted use) and guide interventions to salvage nonmaturing AVFs. The optimal ultrasound criteria to assess AVF maturation are uncertain. We analyzed data from a multicenter, randomized, controlled, clinical trial to compare 2 published ultrasound maturation criteria used to predict unassisted AVF use for hemodialysis. METHODS: We retrospectively analyzed prospective data on 105 patients undergoing new AVF creation, who underwent standardized postoperative ultrasounds at 6 and 12 weeks to measure AVF diameter and blood flow. Unassisted AVF use was defined as successful cannulation for >=90 days without requiring prior surgical or percutaneous interventions. Two ultrasound criteria were assessed: (i) National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative criteria: AVF outflow vein lumen diameter >=6 mm and blood flow >=600 mL/min; and (ii) University of Alabama at Birmingham (UAB) criteria: AVF outflow vein lumen diameter >=4 mm and blood flow >=500 mL/min. Performance characteristics were calculated for both criteria. RESULTS: Compared to the NKF criteria, the UAB criteria had a higher sensitivity (89 vs.68%), but a lower specificity (42 vs. 70%) for unassisted AVF use. For radiocephalic AVFs, the UAB criteria had higher sensitivity (86 vs. 46%) and lower specificity (58 vs. 83%). For brachiocephalic AVFs, both UAB and NKF had high sensitivity (90 and 80%) but low specificity (21 and 53%), respectively. CONCLUSIONS: Using the UAB ultrasound criteria would minimize unnecessary early interventions in AVFs likely to mature without an intervention, but would delay interventions in AVFs that are unlikely to mature. The UAB criteria may be preferred in patients receiving a radiocephalic AVF. PMID- 29283178 TI - IMPLEMENTATION OF AN EVIDENCED-BASED PARENTING PROGRAM IN A COMMUNITY MENTAL HEALTH SETTING. AB - The process of mental health intervention implementation with vulnerable populations is not well-described in the literature. The authors worked as a community-partnered team to adapt and pilot an empirically supported intervention program for mothers of infants and toddlers in an outpatient mental health clinic that primarily serves a low-income community. We used qualitative ethnographic methods to document the adaption of an evidence-based intervention, Mothering from the Inside Out, and the pilot implementation in a community mental health clinic. Seventeen mothers and their identified 0- to 84-month-old children were enrolled in the study. Key lessons from this implementation include (a) the importance of formative work to build community relationships and effectively adapt the intervention to meet the needs of the therapists and their clients, (b) the importance of designing plans for training and reflective supervision that fit within the flow of the clinic and can tolerate disruptions, and (c) that use of an interdisciplinary approach is feasible with the development of a plan for communication and the support of a trained reflective clinical supervisor. These key lessons advance the scientific knowledge available to healthcare managers and researchers who are looking to adapt mental health clinical interventions previously tested in clinical trials to implementation in community settings. PMID- 29283179 TI - A comparison study between endoscope-assisted and the standard approach in the harvesting of the free rectus femoris muscle flap. AB - BACKGROUND: Endoscopic harvesting of muscle flaps is well described for gracilis, latissimus dorsi, gastrocnemius, and pectoralis major amongst others. So far there has been no description of endoscopic harvesting of the rectus femoris muscle as a free flap. The purpose of this study was to compare the perioperative outcomes of harvesting the free rectus femoris muscle flap endoscopically as compared to the standard approach. METHODS: Fifty patients with lower limb defects reconstructed with free rectus femoris muscle flap between January 2014 and December 2016 were included in this study. Their ages ranged from 37 years old to 92 years old. The flaps were harvested with both the standard and endoscopical method. Comparative data between the two methods collected included: age, gender, comorbid illnesses, flap size, defect size, reconstruction time, and flap survival rate RESULTS: Twenty patients underwent flap harvesting endoscopically and 30 were harvested with the standard technique. Their mean ages were 67 +/- 9.4 and 65 +/- 14 years old respectively (P = .47). The defect size was 96 +/- 60 cm2 versus 81 +/- 74 cm2 (P = .45). The flap size was 72 +/- 34 cm2 in the endoscopic group and 60 +/- 42 cm2 in the standard group (P = .52). The mean total reconstruction time in the endoscopic group was 228 +/- 48 minutes and 216 +/- 64 minutes in the standard group (P = .50). There was no significant difference between flap survival (P = N/A), complication rates (P = .33), and length of admission (P = .84) in the two groups. CONCLUSION: Endoscope-assisted harvesting of a free rectus femoris muscle flap is a feasible option and permits a small scar at the donor site. PMID- 29283180 TI - Effects of incorporating nonmodified sweet potato (Ipomoea batatas) flour on wheat pasta functional characteristics. AB - : The effects of substituting wheat flour using fractions of blanched or nonblanched sweet potato flour on produced pasta functional characteristics were investigated. The use of sweet potato flour to replace fractions of wheat flour, regardless of blanching treatment, resulted in significant (p < .05) increase in water holding capacity (WHC), cooked pasta water uptake and solid leaching out and freeze-thaw stability of produced pasta. For instance, treatment containing 40% of nonblanched sweet potato flour and held at 55C resulted in 27% point increase in WHC compared to the control. Sweet potato flour was also contributed to the decrease in treatments pasting viscosities and in cooked pasta hardness. Cooked pasta hardness was significantly (p < .05) decreased from 255.6 N to 187.5, and 152.6 N when using 15% blanched and 40% nonblanched sweet potato flour replacements, respectively. Flow behavior index of wheat flour treatments containing fractions of sweet potato flour were fitted in a shear thinning model. Quality indices of pasta made using fractions of sweet potato were equivalent to or sometimes superior to that of the control sample. Results indicated the possible enhancement of pasta nutritional quality including firmness, cooking loss, and water uptake without impairing consumer acceptability. PRACTICAL APPLICATIONS: The use of sweet potato flour in pasta would enhance the nutritional and physicochemical properties of developed pasta and pasta products. Furthermore, since sweet potato is not cultivated most of the year; sweet potato flour pasta would be better utilized in food processing and is expected to enhance sweet potato consumption year around. PMID- 29283182 TI - Continuous spike-wave during sleep: treating an epilepsy without seizures. PMID- 29283183 TI - Breast reconstruction in a patient with a ventriculoperitoneal shunt using a DIEP flap. PMID- 29283181 TI - Loss of constitutive functional gamma-aminobutyric acid type A-B receptor crosstalk in layer 5 pyramidal neurons of human epileptic temporal cortex. AB - OBJECTIVE: gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in adult central nervous system, and profound alterations of GABA receptor functions are linked to temporal lobe epilepsy (TLE). Here we describe the functional relationships between GABA receptors type B (GABAB R) and type A (GABAA R) in human temporal cortex and how TLE affects this aspect of GABAergic signaling. METHODS: Miniature inhibitory postsynaptic currents (mIPSCs) were recorded by patch-clamp techniques from human L5 pyramidal neurons in slices from temporal cortex tissue obtained from surgery. RESULTS: We describe a constitutive functional crosstalk between GABAB Rs and GABAA Rs in human temporal layer 5 pyramidal neurons, which is lost in epileptic tissues. The activation of GABAB Rs by baclofen, in addition to the expected reduction of mIPSC frequency, produced, in cortex of nonepileptic patients, the prolongation of mIPSC rise and decay times, thus increasing the inhibitory net charge associated with a single synaptic event. Block of K+ channels did not prevent the increase of decay time and charge. Protein kinase A (PKA) blocker KT5720 and pertussis toxin inhibited the action of baclofen, whereas 8Br-cAMP mimicked the GABAB R action. The same GABAB R-mediated modulation of GABAA Rs was observed in pyramidal neurons of rat temporal cortex, with both PKA and PKC involved in the process. In cortices from TLE patients and epileptic rats, baclofen lost its ability to modulate mIPSCs. SIGNIFICANCE: Our results highlight the association of TLE with functional changes of GABAergic signaling that may be related to seizure propagation, and suggest that the selective activation of a definite subset of nonpresynaptic GABAB Rs may be therapeutically useful in TLE. PMID- 29283184 TI - Basic understanding and therapeutic approaches to target toll-like receptors in cancerous microenvironment and metastasis. AB - Toll-like receptors (TLRs) are transmembrane components that sense danger signals, like damage- and pathogen-associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders. In pathological conditions, such as cancer, they can present both tumor and receptor-specific roles. Although the roles of individual TLRs in various cancers have been described, the effects of targeting TLRs to treat cancer and prevent metastasis are still controversial. A growing body of literature has suggested contribution of both activators and inhibitors of TLR signaling pathway for cancer treatment, dependent on several context-specific factors. In short, TLRs can play dual roles with contradictory outcomes in neoplastic conditions. This hampers the development of TLR-based therapeutic interventions. A better understanding of the interwoven TLR pathways in cancerous microenvironment is necessary to design TLR-based therapies. In this review, we consider the molecular mechanisms of TLRs signaling and their involvement in tumor progression. Therapeutic modalities targeting TLRs for cancer treatment are discussed as well. PMID- 29283185 TI - Genetic polymorphism and decreased expression of HLA class II DP genes are associated with HBV reactivation in patients treated with immunomodulatory agents. AB - Hepatitis B virus (HBV) reactivation can be triggered by immunosuppressive chemotherapy. HLA class II molecules may play a role in HBV reactivation. Genetic polymorphism and mRNA expression of HLA class II were examined in patients with latent HBV infection treated with immunosuppressive therapies. Subjects with resolved HBV infection who had undergone treatment with immunosuppressive chemotherapies were retrospectively enrolled (n = 42) and divided into reactivated (n = 9) and non-reactivated groups (n = 33). Patients were genotyped for 17 single nucleotide polymorphisms (SNPs) within HLA class II DPA1, and DPB1, and mRNA expression levels of HLA class II genes were assessed. The frequency of the AA genotype of rs872956, a SNP in HLA-DPB1, was significantly higher in the reactivated group than in the non-reactivated group (55.6% vs 12.1%, P < 0.05). The frequencies of the T allele and non-AA genotypes (AT/TT) of rs3116996 (located in DPB1) were significantly higher in the reactivated group (T allele frequency: 16.7% vs 0.0% [P < 0.01], non-AA genotype frequency: 22.2% vs 0.0% [P < 0.05]). Multivariate logistic regression identified the AA genotype of rs872956 as an independent protective factor against HBV reactivation (odds ratio [OR] = 18.1, 95% confidence interval [CI] = 2.6-126.7, P < 0.01). mRNA expression of HLA DPB1 was lower in the HBV reactivated group than in the non-reactivated group (median 276.1 +/- 165.6/beta-actin vs 371.4 +/- 407.5/beta-actin [P < 0.05]). These results suggest the involvement of HLA class II molecules in HBV reactivation after treatment with immunomodulatory agents. PMID- 29283186 TI - Reflectance confocal microscopy for the diagnosis of tinea nigra. PMID- 29283187 TI - Cell Size Control via an Unstable Accumulating Activator and the Phenomenon of Excess Mitotic Delay. AB - Unstable Accumulating Activator models for cellular size control propose an activator that accumulates in a size-dependent manner and triggers cell cycle progression once it has reached a certain threshold. Having a short half life makes such an activator responsive to changes in cell size and makes specific predictions for how cells respond to perturbation. In particular, it explains the curious phenomenon of excess mitotic delay. Excess mitotic delay, first observed in Tetrahymena in the '50s, is a phenomenon in which a pulse of protein synthesis inhibition causes a delay in mitotic entry that is longer than the pulse and that gets longer the later in the cell cycle the pulse is delivered. The interpretation of this phenomenon championed by Zeuthen and Mitchison in the '60s and '70s is that an unstable activator of mitosis is degraded during the pulse and has to be resynthesized to a threshold level to trigger mitosis; small cells have more time to resynthesize the activator before mitosis and so suffer less excess delay, whereas, large cells have less time thus suffer greater excess delay. Fifty years later, with our detailed understanding of cell cycle biochemistry, we can identify and test candidate Unstable Accumulating Activators. Here I review the field and further develop this concept. PMID- 29283188 TI - Analyzing Horizontal Transfer of Transposable Elements on a Large Scale: Challenges and Prospects. AB - Whoever compares the genomes of distantly related species might find aberrantly high sequence similarity at certain loci. Such anomaly can only be explained by genetic material being transferred through other means than reproduction, that is, a horizontal transfer (HT). Between multicellular organisms, the transferred material will likely turn out to be a transposable element (TE). Because TEs can move between loci and invade chromosomes by replicating themselves, HT of TEs (HTT) profoundly impacts genome evolution. Yet, very few studies have quantified HTT at large taxonomic scales. Indeed, this task currently faces difficulties that range from the variable quality of available genome sequences to limitations of analytical procedures, some of which have been overlooked. Here we review the many challenges that an extensive analysis of HTT must overcome, we expose biases and limits of current methods, suggest solutions or workarounds, and reflect upon approaches that could be developed to better quantify this phenomenon. PMID- 29283189 TI - Non-motor symptoms in childhood dystonia? New perspectives. PMID- 29283190 TI - Manipulation, salience, and nudges. AB - Cass Sunstein and Richard Thaler recommend helping people make better decisions by employing 'nudges', which they define as noncoercive methods of influencing choice for the better. Not surprisingly, healthcare practitioners and public policy professionals have become interested in whether nudges might be a promising method of improving health-related behaviors without resorting to heavy handed methods such as coercion, deception, or government regulation. Many nudges seem unobjectionable as they merely improve the quality and quantity available for the decision-maker. However, other nudges influence decision-making in ways that do not involve providing more and better information. Nudges of this sort raise concerns about manipulation. This paper will focus on noninformational nudges that operate by changing the salience of various options. It will survey two approaches to understanding manipulation, one which sees manipulation as a kind of pressure, and one that sees it as a kind of trickery. On the pressure view, salience nudges do not appear to be manipulative. However, on the trickery view (which the author favors), salience nudges will be manipulative if they increase the salience so that it is disproportionate to that fact's true relevance and importance for the decision at hand. By contrast, salience nudges will not be manipulative if they merely highlight some fact that is true and important for the decision at hand. The paper concludes by providing examples of both manipulative and nonmanipulative salience nudges. PMID- 29283191 TI - The clustering and morphology of chondrocytes in normal and mildly degenerate human femoral head cartilage studied by confocal laser scanning microscopy. AB - Chondrocytes are the major cell type present in hyaline cartilage and they play a crucial role in maintaining the mechanical resilience of the tissue through a balance of the synthesis and breakdown of extracellular matrix macromolecules. Histological assessment of cartilage suggests that articular chondrocytes in situ typically occur singly and demonstrate a rounded/elliptical morphology. However, there are suggestions that their grouping and fine shape is more complex and that these change with cartilage degeneration as occurs in osteoarthritis. In the present study we have used confocal laser scanning microscopy and fluorescently labelled in situ human chondrocytes and advanced imaging software to visualise chondrocyte clustering and detailed morphology within grade-0 (non-degenerate) and grade-1 (mildly degenerate) cartilage from human femoral heads. Graded human cartilage explants were incubated with 5-chloromethylfluorescein diacetate and propidium iodide to identify the morphology and viability, respectively, of in situ chondrocytes within superficial, mid- and deep zones. In grade-0 cartilage, the analysis of confocal microscope images showed that although the majority of chondrocytes were single and morphologically normal, clusters (i.e. three or more chondrocytes within the enclosed lacunar space) were occasionally observed in the superficial zone, and 15-25% of the cell population exhibited at least one cytoplasmic process of ~ 5 MUm in length. With degeneration, cluster number increased (~ 50%) but not significantly; however, the number of cells/cluster (P < 0.001) and the percentage of cells forming clusters increased (P = 0.0013). In the superficial zone but not the mid- or deep zones, the volume of clusters and average volume of chondrocytes in clusters increased (P < 0.001 and P < 0.05, respectively). The percentage of chondrocytes with processes, the number of processes/cell and the length of processes/cell increased in the superficial zone of grade-1 cartilage (P = 0.0098, P = 0.02 and P < 0.001, respectively). Processes were categorised based on length (L0 - no cytoplasmic processes; L1 < 5 MUm; 5 < L2 <= 10 MUm; 10 < L3 <= 15 MUm; L4 > 15 MUm). With cartilage degeneration, for chondrocytes in all zones, there was a significant decrease (P = 0.015) in the percentage of chondrocytes with 'normal' morphology (i.e. L0), with no change in the percentage of cells with L1 processes; however, there were significant increases in the other categories. In grade-0 cartilage, chondrocyte clustering and morphological abnormalities occurred and with degeneration these were exacerbated, particularly in the superficial zone. Chondrocyte clustering and abnormal morphology are associated with aberrant matrix metabolism, suggesting that these early changes to chondrocyte properties may be associated with cartilage degeneration. PMID- 29283192 TI - Functional and phenotypical analysis of IL-6-secreting CD4+ T cells in human adipose tissue. AB - Emerging evidence indicates that a dynamic interplay between the immune system and adipocytes contributes to the disturbed homeostasis in adipose tissue of obese subjects. Recently, we observed IL-6-secretion by CD4+ T cells from the stromal vascular fraction (SVF) of the infrapatellar fat pad (IFP) of knee osteoarthritis patients directly ex vivo. Here we show that human IL-6+ CD4+ T cells from SVF display a more activated phenotype than the IL-6- T cells, as evidenced by the expression of the activation marker CD69. Analysis of cytokines secretion, as well as expression of chemokine receptors and transcription factors associated with different Th subsets (Treg, Th1, Th2, Th17 and Tfh) revealed that IL-6-secreting CD4+ T cells cannot be assigned to a conventional Th subset. TCRbeta gene analysis revealed that IL-6+ and IL-6- CD4+ T cells appear clonally unrelated to each other, suggesting a different specificity of these cells. In line with these observations, adipocytes are capable of enhancing IL-6 production by CD4+ T cells. Thus, IL-6+ CD4+ T cells are TCRalphabeta T cells expressing an activated phenotype potentially resulting from an interplay with adipocytes that could be involved in the inflammatory processes in the OA joint. PMID- 29283193 TI - Synthesis of d-mannitol-based crown ethers and their application as catalyst in asymmetric phase transfer reactions. AB - A few new d-mannitol-based monoaza-15-crown-5 type chiral lariat ethers and 18 crown-6 type macrocycles were synthesized. These crown compounds were used as phase transfer catalysts in asymmetric Michael addititons and in a Darzens condensation under mild conditions to afford the corresponding products in a few cases in good to excellent enantioselectivities. In the Michael addition of diethyl acetoxymalonate to trans-chalcone, in the addition of diethyl acetamidomalonate to beta-nitrostyrene, in the reaction of diethyl bromomalonate with benzylidene malononitriles, in the cyclopropanation reaction of diethyl bromomalonate and 2-benzylidene-1,3-indandione, and in the Darzens condensation of alpha-chloroacetophenone with benzaldehyde, maximum enantioselectivities of 39%, 65%, 99%, 56%, and 62%, respectively, were obtained in the presence of the d mannitol-based macrocycles as the catalysts. PMID- 29283195 TI - Why Bond Critical Points Are Not "Bond" Critical Points. AB - Equating (3,-1) critical points (CPs), derived from the topological analysis of the electron densities, to chemical bonds has triggered a lot of confusion in recent years. Part of this confusion stems from calling these CPs "bond" CPs (BCPs). While the origin of this terminology is traceable to the late seventies and beginning of eighties, when it sounded reasonable, new computational studies conducted on molecular electron densities cast serious doubt on the supposed universal equivalence between the chemical bonds and (3,-1) CPs. Herein, recent computational studies are briefly reviewed to demonstrate why (3,-1) CPs are not indicators of chemical bonds. It is discussed why this confusing terminology needs to be changed and reemphasized that (3,-1) CPs should be called "line" critical points (LCPs). The proposed terminology detaches the topological properties of molecular electron densities from any a priori chemical interpretation. Such detachment, if adopted by other authors, will hopefully prevent further misinterpretation of the data emerging from the quantum theory of atoms in molecules (QTAIM). PMID- 29283194 TI - Photo-responsive Bioactive Surfaces Based on Cucurbit[8]uril-Mediated Host-Guest Interactions of Arylazopyrazoles. AB - A photoswitchable arylazopyrazole (AAP) derivative binds with cucurbit[8]uril (CB[8]) and methylviologen (MV2+ ) to form a 1:1:1 heteroternary host-guest complex with a binding constant of Ka =2*103 m-1 . The excellent photoswitching properties of AAP are preserved in the inclusion complex. Irradiation with light of a wavelength of 365 and 520 nm leads to quantitative E- to Z- isomerization and vice versa, respectively. Formation of the Z-isomer leads to dissociation of the complex as evidenced using 1 H NMR spectroscopy. AAP derivatives are then used to immobilize bioactive molecules and photorelease them on demand. When Arg Gly-Asp-AAP (AAP-RGD) peptides are attached to surface bound CB[8]/MV2+ complexes, cells adhere and can be released upon irradiation. The heteroternary host-guest system offers highly reversible binding properties due to efficient photoswitching and these properties are attractive for designing smart surfaces. PMID- 29283196 TI - Columnar Self-Assembly of Electron-Deficient Dendronized Bay-Annulated Perylene Bisimides. AB - Three new heteroatom bay-annulated perylene bisimides (PBIs) have been synthesized by microwave-assisted synthesis in excellent yield. N-annulated and S annulated perylene bisimides exhibited columnar hexagonal phase, whereas Se annulated perylene bisimide exhibited low temperature columnar oblique phase in addition to the high temperature columnar hexagonal phase. The cup shaped bay annulated PBIs pack into columns with enhanced intermolecular interactions. In comparison to PBI, these molecules exhibited lower melting and clearing temperature, with good solubility. A small red shift in the absorption was seen in the case of N-annulated PBI, whereas S- and Se-annulated PBIs exhibited blue shifted absorption spectra. Bay-annulation increased the HOMO and LUMO levels of the N-annulated perylene bisimide, whereas a slight increase in the LUMO level and a decrease in the HOMO levels were observed in the case of S- and Se annulated perylene bisimides, in comparison to the simple perylene bisimide. The band gaps of PBI and PBI-N were almost same, whereas an increase in the band gaps were observed in the case of S- and Se-annulated PBIs. The tendency to freeze in the ordered glassy columnar phase for PBI-N and PBI-S will help to overcome the charge traps due to crystallization, which are detrimental to one-dimensional charge carrier mobility. These solution processable electron deficient columnar semiconductors possessing good thermal stability may form an easily accessible promising class of n-type materials. PMID- 29283197 TI - Investigation on the interaction of catalase with sodium lauryl sulfonate and the underlying mechanisms. AB - As a classic type of anionic surfactants, sodium lauryl sulfonate (SLS) might change the structure and function of antioxidant enzyme catalase (CAT) through their direct interactions. However, the underlying molecular mechanism is still unknown. This study investigated the direct interaction of SLS with CAT molecule and the underlying mechanisms using multi-spectroscopic methods, isothermal titration calorimetry, and molecular docking studies. No obvious effects were observed on CAT structure and activity under low SLS concentration exposure. The particle size of CAT molecule decreased and CAT activity was slightly inhibited under high SLS concentration exposure. SLS prefers to bind to the interface of CAT mainly via van der Waals' forces and hydrogen bonds. Subsequently, SLS interacts with the amino acid residues around the heme groups of CAT via hydrophobic interactions and might inhibit CAT activity. PMID- 29283198 TI - A classical twin study of PTSD symptoms and resilience: Evidence for a single spectrum of vulnerability to traumatic stress. AB - BACKGROUND: To examine shared genetic and environmental risk factors across PTSD symptoms and resilience. METHODS: Classical twin study of 2010-2012 survey data conducted among 3,318 male twin pairs in the Vietnam Era Twin Registry. Analyses included: (a) estimates of genetic and environmental influences on PTSD symptom severity (as measured by the PTSD Checklist) and resilience (assessed with the Connor-Davidson Resilience Scale-10); (b) development of a latent model of traumatic stress, spanning both PTSD and resilience; and (c) estimates of genetic and environmental influences on this spectrum. RESULTS: The heritability of PTSD was 49% and of resilience was 25%. PTSD and resilience were correlated at r = .59, and 59% of this correlation was attributable to a single genetic factor, whereas the remainder was due to a single non-shared environment factor. Resilience was also influenced by common and unique environmental factors not shared with PTSD, but there was no genetic factor specific to resilience. Confirmatory factor analysis supported the Development of a revised phenotype reflecting the broader dimension of traumatic stress, with biometric models suggesting increased heritability (66%) of this spectrum compared to PTSD or resilience individually. CONCLUSIONS: Genetic factors contribute to a single spectrum of traumatic stress reflecting resilience at one end and high symptom severity at the other. This carries implications for phenotype refinement in the search for molecular genetic markers of trauma-related psychopathology. Rather than focusing only on genetic risk for PTSD, molecular genetics research may benefit from evaluation of the broader spectrum of traumatic stress. PMID- 29283200 TI - Forskolin ameliorates mancozeb-induced testicular and epididymal toxicity in Wistar rats by reducing oxidative toxicity and by stimulating steroidogenesis. AB - In the present study, we have tested the beneficial effects of forskolin in protecting the mancozeb-induced reproductive toxicity in rats. Adult male Wistar rats were exposed to either mancozeb (500 mg/kg body weight/day) or forskolin (5 mg/kg body weight/day) or both for 65 days and analyzed for spermatogenesis and steroidogenesis and testicular and epididymal oxidative toxicity. A significant decrease in daily sperm production, epididymal sperm count, motile, viable, and hypo-osmotic swelling-tail swelled sperm was observed in mancozeb-treated rats. The activity levels of testicular 3beta-hydroxysteroid dehydrogenase and 17beta hydroxysteroid dehydrogenase and circulatory testosterone levels were significantly decreased in mancozeb-treated rats. Exposure to mancozeb resulted in a significant decrease in glutathione levels and superoxide dismutase and catalase activity levels with an increase in lipid peroxidation levels in the testes and epididymis. Coadministration of forskolin mitigated the mancozeb induced oxidative toxicity and suppressed steroidogenesis and spermatogenesis. PMID- 29283199 TI - Synthesis and investigation of the conversion reactions of pyrimidine-thiones with nucleophilic reagent and evaluation of their acetylcholinesterase, carbonic anhydrase inhibition, and antioxidant activities. AB - The conversion reactions of pyrimidine-thiones with nucleophilic reagent were studied during this scientific research. For this purpose, new compounds were synthesized by the interaction between 1,2-epoxy propane, 1,2-epoxy butane, and 4 chlor-1-butanol and pyrimidine-thiones. These pyrimidine-thiones derivatives (A K) showed good inhibitory action against acetylcholinesterase (AChE), and human carbonic anhydrase (hCA) isoforms I and II. AChE inhibition was in the range of 93.1 +/- 33.7-467.5 +/- 126.9 nM. The hCA I and II were effectively inhibited by these compounds, with Ki values in the range of 4.3 +/- 1.1-9.1 +/- 2.7 nM for hCA I and 4.2 +/- 1.1-14.1 +/- 4.4 nM for hCA II. On the other hand, acetazolamide clinically used as CA inhibitor showed Ki value of 13.9 +/- 5.1 nM against hCA I and 18.1 +/- 8.5 nM against hCA II. The antioxidant activity of the pyrimidine-thiones derivatives (A-K) was investigated by using different in vitro antioxidant assays, including Cu2+ and Fe3+ reducing, 1,1-diphenyl-2 picrylhydrazyl (DPPH* ) radical scavenging, and Fe2+ chelating activities. PMID- 29283202 TI - Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders. AB - AIM: Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. METHODS: We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. RESULTS: Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine to-thymine transitions, half of which were in CpG dinucleotides. CONCLUSION: Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases. PMID- 29283201 TI - Evaluation of the interaction between proliferation, oxidant-antioxidant status, Wnt pathway, and apoptosis in zebrafish embryos exposed to silver nanoparticles used in textile industry. AB - Antimicrobial textile products are developing rapidly as an important part of functional textiles. Silver nanoparticles (AgNPs) are nanotechnology products with antimicrobial properties. However, exposure to nanoparticles in daily life is an important issue for public health, still being updated. Aim was to evaluate the effects of AgNPs on the development of zebrafish embryos focusing on Wnt pathway, proliferation, oxidant-antioxidant status, and apoptosis. The expressions of ccnd1 and gsk3beta were determined by RT-PCR, whereas beta-catenin and proliferative cell antigen (PCNA) expressions were determined immunohistochemically. Lipid peroxidation, superoxide dismutase, and glutathione S-transferase activities were determined spectrophotometrically. Apoptosis was determined using acridine orange staining. Oxidant status, apoptosis, immunohistochemical PCNA, and beta catenin staining increased, whereas ccnd1 and antioxidant enzyme activities decreased in AgNPs-exposed embryos in a dose dependent manner. Our results indicate the interaction of possible mechanisms that may be responsible for the toxic effects of AgNPs in zebrafish embryos. PMID- 29283204 TI - Binding language: structuring sentences through precisely timed oscillatory mechanisms. AB - Syntactic binding refers to combining words into larger structures. Using EEG, we investigated the neural processes involved in syntactic binding. Participants were auditorily presented two-word sentences (i.e. pronoun and pseudoverb such as 'I grush' and 'she grushes', for which syntactic binding can take place) and wordlists (i.e. two pseudoverbs such as 'pob grush' and 'pob grushes', for which no binding occurs). Comparing these two conditions, we targeted syntactic binding while minimising contributions of semantic binding and of other cognitive processes such as working memory. We found a converging pattern of results using two distinct analysis approaches: one approach using frequency bands as defined in previous literature, and one data-driven approach in which we looked at the entire range of frequencies between 3 and 30 Hz without the constraints of pre defined frequency bands. In the syntactic binding (relative to the wordlist) condition, a power increase was observed in the alpha and beta frequency range shortly preceding the presentation of the target word that requires binding, which was maximal over frontal-central electrodes. Our interpretation is that these signatures reflect that language comprehenders expect the need for binding to occur. Following the presentation of the target word in a syntactic binding context (relative to the wordlist condition), an increase in alpha power maximal over a left-lateralised cluster of frontal-temporal electrodes was observed. We suggest that this alpha increase relates to syntactic binding taking place. Taken together, our findings suggest that increases in alpha and beta power are reflections of distinct the neural processes underlying syntactic binding. PMID- 29283203 TI - Synthesis, Structure, and Cytotoxicity of a New Sulphanyl-Bridged Thiadiazolyl Saccharinate Conjugate: The Relevance of S???N Interaction. AB - Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl] 1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an S???N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5 methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents. PMID- 29283205 TI - Mapping international impact of Danish neuroscience from 2004 to 2015 using tailored scientometric methodology. PMID- 29283206 TI - Osseointegration and foreign body reaction: Titanium implants activate the immune system and suppress bone resorption during the first 4 weeks after implantation. AB - BACKGROUND: Osseointegration mechanisms are still not entirely understood. PURPOSE: The present pilot study aims at demonstrating the involvement of the immune system in the process of osseointegration around titanium implants, comparing bone healing in the presence and absence of a titanium implant. MATERIALS AND METHODS: Fifteen New Zealand White rabbits had one osteotomy performed at each of the distal femurs; on one side, no implant was placed (sham) and on the other side a titanium implant was introduced. Subjects were sacrificed at 10 and 28 days for gene expression analysis (three subjects each time point) and for decalcified qualitative histology (six subjects each time point). At 10 days, the three subjects for gene expression analysis were part of the six subjects for histology. RESULTS: Gene expression analysis: at 10 days, ARG1 was significantly up-regulated around titanium, indicating an activation of M2 macrophages. At 28 days CD11b, ARG1, NCF-1, and C5aR1 were significantly up regulated, indicating activation of the innate immune system, respectively M1 macrophages, M2-macrophages and group 2-innate lymphoid cells, neutrophils, and the complement system; on the other hand, the bone resorption markers RANKL, OPG, cathepsin K, and TRAP were significantly down-regulated around titanium. HISTOLOGY: at 10 days new bone formation is seen around both sham and titanium sites, separating bone marrow from the osteotomy/implant site; at 28 days no bone trabeculae is seen on the sham site, which is healing at the original cortical level, whereas around titanium implants, bone continues into organization of more mature cortical-like bone, forming a layer between the implant and the bone marrow. CONCLUSIONS: The presence of a titanium implant during bone healing activates the immune system and displays type 2 inflammation, which is likely to guide the host-biomaterial relationship. At the same time, bone resorption is suppressed around titanium sites compared to sham sites after 4 weeks of implantation, suggesting a shift to a more pronounced bone forming environment. This suggests two important steps in osseointegration: identification of the titanium foreign body by the immune system and the development of a bone forming environment, that at tissue level translates into bone build-up on the titanium surface and can be perceived as an attempt to isolate the foreign body from the bone marrow space. PMID- 29283207 TI - Hard tissue volume stability of guided bone regeneration during the healing stage in the anterior maxilla: A clinical and radiographic study. AB - BACKGROUND: Guided bone regeneration (GBR) is currently the most widely used technique to reconstruct localized peri-implant bone defects. OBJECTIVES: To evaluate hard tissue volume stability during the healing stage of GBR with particulate bone graft and resorbable collagen membrane. MATERIALS AND METHODS: Twenty-eight patients who were missing a single maxillary incisor and required implant placement combined with GBR were randomly assigned to 2 groups: submerged (n = 14) and transmucosal (n = 14) healing groups. Cone-beam computed tomography (CBCT) was performed before, immediately after and 6 months post-surgery. The 3 sets of CBCT data were three-dimensionally reconstructed and superimposed. Horizontal hard tissue alterations at different vertical levels were recorded. The relative position and distances from the boundary line of the bony defect envelope to the outlines of the augmented ridge were determined immediately post augmentation and 6 months after healing. RESULTS: Augmented ridge underwent horizontal volume reduction during the healing period. Vertical levels (P = .000) rather than healing strategies (submerged or transmucosal) (P = .182) had statistically significant impacts on the reduction width. The boundary line of the ridge defect envelope located within the bony profile immediately after surgery, but outside of the bony profile after 6 months. CONCLUSIONS: GBR with resorbable membrane and particulate bovine bone would undergo horizontal volume reduction during the healing stage. New bone formation at the coronal site may only be predictable within the bony envelope. PMID- 29283208 TI - Microphysiological Analysis Platform of Pancreatic Islet beta-Cell Spheroids. AB - The hallmarks of diabetics are insufficient secretion of insulin and dysregulation of glucagon. It is critical to understand release mechanisms of insulin, glucagon, and other hormones from the islets of Langerhans. In spite of remarkable advancements in diabetes research and practice, robust and reproducible models that can measure pancreatic beta-cell function are lacking. Here, a microphysiological analysis platform (MAP) that allows the uniform 3D spheroid formation of pancreatic beta-cell islets, large-scale morphological phenotyping, and gene expression mapping of chronic glycemia and lipidemia development is reported. The MAP enables the scaffold-free formation of densely packed beta-cell spheroids (i.e., multiple array of 110 bioreactors) surrounded with a perfusion flow network inspired by physiologically relevant microenvironment. The MAP permits dynamic perturbations on the beta-cell spheroids and the precise controls of glycemia and lipidemia, which allow us to confirm that cellular apoptosis in the beta-cell spheroid under hyperglycemia and hyperlipidemia is mostly dependent to a reactive oxygen species-induced caspase mediated pathway. The beta-cells' MAP might provide a potential new map in the pathophysiological mechanisms of beta cells. PMID- 29283209 TI - Encapsulated Optically Responsive Cell Systems: Toward Smart Implants in Biomedicine. AB - Managing increasingly prevalent chronic diseases will require close continuous monitoring of patients. Cell-based biosensors may be used for implantable diagnostic systems to monitor health status. Cells are indeed natural sensors in the body. Functional cellular systems can be maintained in the body for long-term implantation using cell encapsulation technology. By taking advantage of recent progress in miniaturized optoelectronic systems, the genetic engineering of optically responsive cells may be combined with cell encapsulation to generate smart implantable cell-based sensing systems. In biomedical research, cell-based biosensors may be used to study cell signaling, therapeutic effects, and dosing of bioactive molecules in preclinical models. Today, a wide variety of genetically encoded fluorescent sensors have been developed for real-time imaging of living cells. Here, recent developments in genetically encoded sensors, cell encapsulation, and ultrasmall optical systems are highlighted. The integration of these components in a new generation of biosensors is creating innovative smart in vivo cell-based systems, bringing novel perspectives for biomedical research and ultimately allowing unique health monitoring applications. PMID- 29283210 TI - UBE2A deficiency in two siblings: A novel splicing variant inherited from a maternal germline mosaicism. AB - UBE2A deficiency is a syndromic condition of X-linked intellectual disability (ID) characterized by typical dysmorphic features that include synophrys, prominent supraorbital ridges, almond-shaped, and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, micropenis, and onychodystrophy. To date, only seven familial UBE2A intragenic mutations and nine larger microdeletions encompassing UBE2A have been reported. Here, we describe two siblings with X-linked ID and typical clinical features of UBE2A deficiency caused by a novel hemizygous variant, identified by massively parallel sequencing of X-exome. The synonymous c.330G>A substitution in UBE2A modifies the last nucleotide of exon 5, causing the exon skipping and resulting in an out-of-frame transcript, likely encoding for a truncated form of the ubiquitin-conjugating enzyme E2 A. As confirmed by deep sequencing, the c.330G>A substitution in UBE2A was undetectable in genomic DNA from maternal blood cells, suggesting that the recurrent UBE2A deficiency observed in males of this family is caused by a maternal germline mosaicism. PMID- 29283211 TI - Differentiating Research, Quality Improvement, and Case Studies to Ethically Incorporate Pregnant Women. AB - Pregnant women have been called therapeutic orphans because data supporting common interventions, medications, health teaching, and models of care are meager. The generation of quality evidence benefits from proactive approaches that ensure ethical standards are met to protect participants. The purpose of this article is to differentiate among health care, quality improvement, and research and to discuss ethical involvement of women who are pregnant and potentially childbearing in these initiatives. Health care is provided to protect and improve individual health. Quality improvement aims to enhance delivery of care for all those receiving care in particular settings. Research, whether retrospective or prospective, is designed to contribute to generalizable knowledge. This review includes vignettes to distinguish between research, quality improvement, and case study dissemination and to highlight the value of publication of information with applicability beyond a single site. As a community, perinatal care providers will be able to contribute more evidence to guide care if they err on the side of seeking institutional review board approval for activities that examine the care and outcomes of pregnant women and the fetus. Traditional research activities, including clinical trials, remain crucial. However, to fill gaps in knowledge, we must expedite our ability to report informative cases, examine clinical data, share lessons learned during quality improvement campaigns, and publish and disseminate these findings. Accelerating improvements in care demands expansion of the evidence base. PMID- 29283212 TI - Low-Intensity Ultrasound Upregulates the Expression of Cyclin-D1 and Promotes Cellular Proliferation in Human Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (hMSCs) hold great potential for cellular based therapeutics and tissue engineering applications and their expansion is an interesting prospect due to their low availability from in vivo sources. Therefore, this study investigated the effect of continuous-wave low-intensity ultrasound (LIUS) at 5.0-MHz and 14.0-kPa (<20 mW cm-2 ) on the proliferative capacity, colony-formation efficiency, genetic stability, and differentiation potential of hMSCs. Additionally, potential signaling pathways involved in LIUS mediated proliferation of hMSCs are studied. Compared to non-stimulated controls, LIUS-treated hMSCs shows a 1.9-fold greater colony-forming efficiency and 2.5 fold higher rate of cell proliferation, respectively. Differential staining and qRT-PCR analysis for selective chondrogenic, osteogenic, and adipogenic markers further confirmed that the LIUS treatment did not impact the multipotency of hMSCs. LIUS-treated hMSCs expressed normal male karyotype. The synthesis of cyclin-D1, a master regulator of cellular proliferation, is upregulated under LIUS and its enhanced mRNA expression under LIUS is noted to be mediated by the activation of both MAPK/ERK and PI3K/AKT pathways. In conclusion, LIUS promotes proliferation and self-renewal capacity of hMSCs. PMID- 29283213 TI - Phenotypic heterogeneity of POMT2 gene variants. PMID- 29283214 TI - A Strategy to Boost H2 Generation Ability of Metal-Organic Frameworks: Inside Outside Decoration for the Separation of Electrons and Holes. AB - Inhibiting the recombination of electron and holes plays an essential role in photocatalytic process, particularly for metal-organic frameworks (MOFs), which had long been anticipated as high-efficient photocatalysts. Herein, we introduce a new strategy to make efficient separation of electrons and holes for the MOF based photocatalyst, UiO-66-NH2 . At first, encapsulation of Pt nanoparticles (NPs) into UiO-66-NH2 (Pt@U6N) to shorten the electrons transport distance inside of MOF crystals, then using graphene oxide to wrap the external surface of Pt@U6N to facilitate the electrons transfer on the surface. The designed structure was found to possess superior H2 -generation ability compared to only inside or outside decorated samples, highlighting that the enhanced property strongly correlates with the inhibited recombination of electrons and holes by the inside/outside modification strategy. These findings suggest a synergistic effect of Pt NPs and graphene oxide on UiO-66-NH2 and reveal a new modification strategy to enhance the catalytic activity of the photocatalysts. PMID- 29283215 TI - Sequential Multivariate Cell Culture Modeling at Multiple Scales Supports Systematic Shaping of a Monoclonal Antibody Toward a Quality Target. AB - The development of cell culture processes is highly complex and requires a large number of experiments on various scales to define the design space of the final process and fulfil the regulatory requirements. This work follows an almost complete process development cycle for a biosimilar monoclonal antibody, from high throughput screening and optimization to scale-up and process validation. The key goal of this analysis is to apply tailored multivariate tools to support decision-making at every stage of process development. A toolset mainly based on Principal Component Analysis, Decision Trees, and Partial Least Square Regression combined with a Genetic Algorithm is presented. It enables to visualize the sequential improvement of the high-dimensional quality profile towards the target, provides a solid basis for the selection of effective process variables and allows to dynamically predict the complete set of product quality attributes. Additionally, this work shows the deep level of process knowledge which can be deduced from small scale experiments through such multivariate tools. The presented methodologies are generally applicable across various processes and substantially reduce the complexity, experimental effort as well as the costs and time of process development. PMID- 29283216 TI - A Lipidomics Approach to Identifying Key Lipid Species Involved in VEGF-Inhibitor Mediated Attenuation of Bleomycin-Induced Pulmonary Fibrosis. AB - PURPOSE: Poor molecular characterization of idiopathic pulmonary fibrosis (IPF) has led to insufficient understanding of the pathogenesis of the disease, resulting in lack of effective therapies and poor prognosis. Particularly, the role of lipid imbalance due to impaired lipid metabolism in the pathogenesis of IPF has been poorly studied. EXPERIMENTAL DESIGN: The authors have used shotgun lipidomics in a bleomycin (BLM) mouse model of pulmonary fibrosis with vascular endothelial growth factor (VEGF)-inhibitor CBO-P11 as a therapeutic measure, to identify a comprehensive set of lipids that contribute to the pathogenesis of pulmonary fibrosis. RESULTS: The authors report that attenuation of BLM-induced fibrotic response with CBO-P11 cotreatment is accompanied by a decrease in total lipid content and specific downregulation of lipids, which are upregulated in response to BLM treatment. CONCLUSION AND CLINICAL RELEVANCE: Dysregulated lipids identified in this study hold the potential of being future biomarkers for IPF. PMID- 29283217 TI - Microbioreactor Systems for Accelerated Bioprocess Development. AB - In recent years, microbioreactor (MBR) systems have evolved towards versatile bioprocess engineering tools. They provide a unique solution to combine higher experimental throughput with extensive bioprocess monitoring and control, which is indispensable to develop economically and ecologically competitive bioproduction processes. MBR systems are based either on down-scaled stirred tank reactors or on advanced shaken microtiter plate cultivation devices. Importantly, MBR systems make use of optical measurements for non-invasive, online monitoring of important process variables like biomass concentration, dissolved oxygen, pH, and fluorescence. The application range of MBR systems can be further increased by integration into liquid handling robots, enabling automatization and, thus standardization, of various handling and operation procedures. Finally, the tight integration of quantitative strain phenotyping with bioprocess development under industrially relevant conditions greatly increases the probability of finding the right combination of producer strain and bioprocess control strategy. This review will discuss the current state of the art in the field of MBR systems and we can readily conclude that their importance for industrial biotechnology will further increase in the near future. PMID- 29283218 TI - Identifying the Genotypes of Hepatitis B Virus (HBV) with DNA Origami Label. AB - The hepatitis B virus (HBV) genotyping may profoundly affect the accurate diagnosis and antiviral treatment of viral hepatitis. Existing genotyping methods such as serological, immunological, or molecular testing are still suffered from substandard specificity and low sensitivity in laboratory or clinical application. In a previous study, a set of high-efficiency hybridizable DNA origami-based shape ID probes to target the templates through which genetic variation could be determined in an ultrahigh resolution of atomic force microscopy (AFM) nanomechanical imaging are established. Here, as a further confirmatory research to explore the sensitivity and applicability of this assay, differentially predesigned DNA origami shape ID probes are also developed for precisely HBV genotyping. Through the specific identification of visualized DNA origami nanostructure with clinical HBV DNA samples, the genetic variation information of genotypes can be directly identified under AFM. As a proof-of concept, five genotype B and six genotype C are detected in 11 HBV-infected patients' blood DNA samples of Han Chinese population in the single-blinded test. The AFM image-based DNA origami shape ID genotyping approach shows high specificity and sensitivity, which could be promising for virus infection diagnosis and precision medicine in the future. PMID- 29283219 TI - Role of the Nucleus as a Sensor of Cell Environment Topography. AB - The proper integration of biophysical cues from the cell vicinity is crucial for cells to maintain homeostasis, cooperate with other cells within the tissues, and properly fulfill their biological function. It is therefore crucial to fully understand how cells integrate these extracellular signals for tissue engineering and regenerative medicine. Topography has emerged as a prominent component of the cellular microenvironment that has pleiotropic effects on cell behavior. This progress report focuses on the recent advances in the understanding of the topography sensing mechanism with a special emphasis on the role of the nucleus. Here, recent techniques developed for monitoring the nuclear mechanics are reviewed and the impact of various topographies and their consequences on nuclear organization, gene regulation, and stem cell fate is summarized. The role of the cell nucleus as a sensor of cell-scale topography is further discussed. PMID- 29283221 TI - Tumor Microenvironment-Enabled Nanotherapy. AB - Cancer is now one of the world's leading threats to human health. With the development of oncology in both biology and biomedicine, it has been demonstrated that abnormal physiochemical conditions and dysregulated biosynthetic intermediates in tumor microenvironment (TME) play a pivotal role in enabling tumor cells to defend or evade the damage by traditional clinical tumor therapeutics including surgery, chemotherapy, radiotherapy, etc. The fast advances of TME-enabled theranostic nanomedicine have offered promising perspectives, strategies, and approaches for combating cancer based on the novel concept of TME-enabled nanotherapy. In this comprehensive review, the origins of TME (e.g., enhanced permeability and retention effect, overexpressed biosynthetic intermediates, mild acidic nature, redox potentials, hypoxia) are initially introduced and discussed, followed by detailed discussion and overview on the state-of-the-art progresses in TME-enabled antitumor nanotherapies (e.g., chemo/chemodynamic therapy, photodynamic therapy, radiotherapy). Finally, the obstacles and challenges of future development on TME-enabled nanotherapies for further clinical translation are outlooked. PMID- 29283222 TI - Welcome to 2018. PMID- 29283220 TI - Recent Advances in Extrusion-Based 3D Printing for Biomedical Applications. AB - Additive manufacturing, or 3D printing, has become significantly more commonplace in tissue engineering over the past decade, as a variety of new printing materials have been developed. In extrusion-based printing, materials are used for applications that range from cell free printing to cell-laden bioinks that mimic natural tissues. Beyond single tissue applications, multi-material extrusion based printing has recently been developed to manufacture scaffolds that mimic tissue interfaces. Despite these advances, some material limitations prevent wider adoption of the extrusion-based 3D printers currently available. This progress report provides an overview of this commonly used printing strategy, as well as insight into how this technique can be improved. As such, it is hoped that the prospective report guides the inclusion of more rigorous material characterization prior to printing, thereby facilitating cross-platform utilization and reproducibility. PMID- 29283225 TI - Label-Free Imaging of Nanoparticle Uptake Competition in Single Cells by Hyperspectral Stimulated Raman Scattering. AB - Imaging and quantification of nanoparticles in single cells in their most natural condition are expected to facilitate the biotechnological applications of nanoparticles and allow for better assessment of their biosafety risks. However, current imaging modalities either require tedious sample preparation or only apply to nanoparticles with specific physicochemical characteristics. Here, the emerging hyperspectral stimulated Raman scattering (SRS) microscopy, as a label free and nondestructive imaging method, is used for the first time to investigate the subcellular distribution of nanoparticles in the protozoan Tetrahymena thermophila. The two frequently studied nanoparticles, polyacrylate-coated alpha Fe2 O3 and TiO2 , are found to have different subcellular distribution pattern as a result of their dissimilar uptake routes. Significant uptake competition between these two types of nanoparticles is further discovered, which should be paid attention to in future bioapplications of nanoparticles. Overall, this study illustrates the great promise of hyperspectral SRS as an analytical imaging tool in nanobiotechnology and nanotoxicology. PMID- 29283224 TI - Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study. AB - BACKGROUND: Approximately half of the patients presenting with new-onset heart failure (HF) have HF with preserved left ventricular ejection fraction (HFpEF) and HF with mid-range left ventricular ejection fraction (HFmrEF). These patients have neurohormonal activation like that of HF with reduced ejection fraction; however, beta-blockers and angiotensin-converting enzyme inhibitors have not been shown to improve their outcomes, and current treatment for these patients is symptom based and empiric. Sympathoinhibition using parasympathetic stimulation has been shown to improve central and peripheral aspects of the cardiac nervous system, reflex control, induce myocyte cardioprotection, and can lead to regression of left ventricular hypertrophy. Beneficial effects of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) have also been observed in several animal models of HFpEF, suggesting a potential role for ART in patients with this disease. METHODS: The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Patients with Heart Failure and Preserved Ejection Fraction (ANTHEM-HFpEF) study is designed to evaluate the feasibility, tolerability, and safety of ART using right cervical VNS in patients with chronic, stable HFpEF and HFmrEF. Patients with symptomatic HF and HFpEF or HFmrEF fulfilling the enrolment criteria will receive chronic ART with a subcutaneous VNS system attached to the right cervical vagus nerve. Safety parameters will be continuously monitored, and cardiac function and HF symptoms will be assessed every 3 months during a post-titration follow-up period of at least 12 months. CONCLUSIONS: The ANTHEM-HFpEF study is likely to provide valuable information intended to expand our understanding of the potential role of ART in patients with chronic symptomatic HFpEF and HFmrEF. PMID- 29283226 TI - Synthetic Cells Synthesize Therapeutic Proteins inside Tumors. AB - Synthetic cells, artificial cell-like particles, capable of autonomously synthesizing RNA and proteins based on a DNA template, are emerging platforms for studying cellular functions and for revealing the origins-of-life. Here, it is shown for the first time that artificial lipid-based vesicles, containing the molecular machinery necessary for transcription and translation, can be used to synthesize anticancer proteins inside tumors. The synthetic cells are engineered as stand-alone systems, sourcing nutrients from their biological microenvironment to trigger protein synthesis. When pre-loaded with template DNA, amino acids and energy-supplying molecules, up to 2 * 107 copies of green fluorescent protein are synthesized in each synthetic cell. A variety of proteins, having molecular weights reaching 66 kDa and with diagnostic and therapeutic activities, are synthesized inside the particles. Incubating synthetic cells, encoded to secrete Pseudomonas exotoxin A (PE) with 4T1 breast cancer cells in culture, resulted in killing of most of the malignant cells. In mice bearing 4T1 tumors, histological evaluation of the tumor tissue after a local injection of PE-producing particles indicates robust apoptosis. Synthetic cells are new platforms for synthesizing therapeutic proteins on-demand in diseased tissues. PMID- 29283227 TI - Cyclic AMP: Second Messenger as the First Messenger. AB - Cell-to-cell communications and autocrine/paracrine regulations are mediated by an extracellular signaling network involving secretion of a variety of different factors, hormones, neurotransmitters, and other signaling molecules that are recognized in an extracellular medium by multiple molecular receptors operating in the plasma membrane of cells. Most of plasma membrane receptors belong to the superfamily of heptahelical receptors, many of which are coupled by G-proteins to adenylate cyclase responsible for cAMP production in the cell cytoplasm. The canonical role of cAMP in cell physiology is to serve as a second messenger and universal regulator of intracellular processes. Meanwhile, increasing body of evidence leaves little doubts that stimulated cells can release cAMP into intercellular space, where it may serve as signaling molecule in cell-to-cell communications and autocrine regulations. This review considers the basic concept on mechanisms of intracellular and extracellular signaling with cAMP as the second and first messenger. PMID- 29283228 TI - Integration the Highest Function of Brain as the Basis of Cognition. AB - Based on the process needs, motivations and emotions, are describing molecular, cellular and systemic mechanisms of goal-direction motivated behavior. Goal direction behavior is impossible without the orientation in space and forming a cognitive map. This process implements the hippocampus, via the neocortical connections. The hippocampus is linked to the amygdala, which is involved in the implementation of emotional behavior and organizing emotionally intense cognitive map or context of the environment. PMID- 29283229 TI - Gasotransmitters: Physiological Role and Involvement in the Pathogenesis of the Diseases. AB - In recent decades, it has been found the existence of a new class of biologically active substances - gaseous mediators (gasotransmitters), performing in the cells the signaling function and with high specificity involved in the intercellular and intracellular communication. This review characterizes the main gasotransmitters: nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide and polysulfides. Their physiological role and involvement in the pathogenesis of diseases is described. Basic information about main gasotransmitters is generalized in the original table. Nitrate-Nitrite background, which is a chemical background of the existence of modern man, affects the intra- and intercellular signaling system, alters the ultrastructure of neurons, neuron neuron and neuron-glia interaction, eliminates the effects of endogenous gasotransmitters and affects the average life expectancy. In accordance with the principle of cyclicity is proposed and substantiated the hypothesis of the existence of "hydrogen sulfide cycle", combining three sulfur-containing gasotransmitters. It is suggested that the cyclic organization of gasotransmitters in the cells and the whole body can be due to the existence of a global principle of cyclicity, which can spread its influence on almost all the structural and functional levels in the animate and inanimate nature. PMID- 29283230 TI - Canonical and Noncanonical Mechanisms of Glucocorticoid Stress Hormones Action. AB - Hormones of stress, glucocorticoids, regulate numerous physiological processes and functions. These hormonal effects involve diverse mechanisms of action. Glucocorticoid receptors (GRs) are transcription factors which regulate gene expression by canonical mechanism of the hormone action through interaction with specific nucleotide sequence (GRE) in the regulatory region of the gene. The effects of the canonical mechanism develop for several hours. Non-genomic rapid effects of the hormone emerged in seconds- minuets and supposed to be associated with yet not identified receptor in the plasma membrane. In addition to these slow and rapid hormonal actions, one more slow non-canonical mechanism of glucocorticoid action become increasingly evident. This mechanism is based on protein-protein interactions of GRs with other transcription factors. The main modern concepts of canonical, non-canonical and membrane mechanisms of hormone action are discussed in the review. PMID- 29283231 TI - The Role of Transposable Elements in Ontogenesis. AB - The article describes the role of transposable elements in the ontogenesis of eukaryotes. Adaptive and controlled transposition of mobile elements occurs at different stages of development of an organism, causing dramatic changes in the regulation of gene expression, representing a cascade of reactions inherited genome evolutionary fixed at the species level. At this cascade of reactions involved regulatory system of tissue-specific expression of proteins splice variants in connection with the role of adaptive genes mosaic structure to numerous transpositions and the interconnectedness of mechanisms their evolutionary stabilization. Important role in the transposition of mobile elements and their interaction with groups of genes play epigenetic mechanisms - DNA methylation, histone modification, the expression of non-coding RNA. The genome structures responsible for the epigenetic regulation can have a transposons origin. In contrast to the previously established hypotheses on transpositions of mobile elements in the ontogenesis as a chaotic process, causing the destabilization of genotype, with a modern viewpoint, this mechanism has a species-specific patterns, formed evolutionarily. Mechanisms of the evolutionary transformation of genomes by natural selection create a relatively stable complex regulatory epigenetic characteristics of transpositions in the process of individual development, acting among individuals of the same species. The stability of the complex genomic information regulation in ontogenesis provides a specific set of transposons. Changing this regulation set transposons can cause fatal for the development of events. Dysregulation of transposons, not involved in the developmental restructuring, can give the inheritance of these changes. The aging process is a consequence of the evolutionary relationship of species-specific features of the regulation of mobile elements in ontogenesis, aimed at continuity and continuous increase in living matter for maximum adaptability. In the overall scheme of ontogenetic development process can be described as a way to implement the established evolutionary genomic information in time by means of gradually stabilized complex interaction of regulators of transpositions of mobile elements of the genome with a differentiated pattern of gene expression and regulation of splicing variants of their products. These transpositions vary with each cell division, especially by implementing the expression of sets of genes, the products of which affect the nature of the further transposition and change of regulation in the subsequent stages of development of an organism. PMID- 29283232 TI - Current Theory on the Cerebral Mechanisms of Hypoxic PRE- and Postconditioning. AB - An exposure of the organism to several episodes of mild hypoxia results in the development of brain hypoxic/ischemic tolerance, as well as cross-tolerance to the stressful factors of psychoemotional nature. Such kind of preconditioning by mild hypoxia functions as "alarm signalization" by I.P. Pavlov, preparing the organism and, in particularly, brain to the forthcoming harmful event. Dose dependent action of hypoxia on the brain can be considered as one particular case of the general phenomenon termed hormesis, or neurohormesis. Endogenous defense processes launched by the hypoxic preconditioning and leading to the development of cerebral tolerance are associated with activation of intracellular signal cascades, transcriptional factors, regulatory proteins and expression of pro adaptive genes and their products in the susceptible brain regions. Important mechanism of systemic adaptation induced by hypoxic preconditioning includes modifications of pituitary-adrenal axis aimed at enhancement of its adaptive resources. All these components are involved in the neuroprotective processes in three sequential phases - initiation, induction, and expression. Important role belongs also to epigenetic mechanisms controlling the activity of pro-adaptive genes. In contrast to the preconditioning, hypoxic postconditioning is comparatively novel phenomenon and therefore its mechanisms are less studied. The involvement of hypoxia-inducible factor HIF-1, and non-specific protective processes as up-regulation of anti-apoptotic factors and neurotrophines. PMID- 29283233 TI - Endogenous Sensitizer of Beta-Adrenergic Receptors (ESBAR) as a Component of Humoral Links Element of Autonomic Nervous System and Its Analogs (Review). AB - Kirov State Medical Academy, Kirov The results of the 20-years studies of the presence in blood serum and other body fluids of endogenous modulators of adrenergic and M-cholinergic impact a A COMPONENT of humoral element of autonomic nervous system. The article is devoted to the endogenous sensitizer of beta adrenergic receptor (ESBAR) - water-soluble low molecular weight substances, analogues of which are histidine, tryptophan, tyrosine, mildronat and preduktal. It is shown, that separate dilutions of human serum and animal (as a source of ESBAR) and ESBAR - analogues ways to enhance the effectiveness of activation of beta-adrenoceptors (AR) of smooth muscle (uterus, coronary and renal arteries, trachea, stomach), myocardium and erythrocytes and platelets (respectively influenced of histidine and tryptophan). It is reported? that content of ESBAR in human serum (according to the titers of its dilution) depends on the sex and the presence of somatic diseases, and at women are also on the stage of reproduction and obstetric complications It is discussed hossible mechanisms of ESBAR action, its physiological role, including as a component of beta-adrenoreceptor myometrium inhibitory mechanism, as well as the prospect of the use of analogues ESBAR, including for the prevention of preterm labor, and for the treatment of bronchial asthma, coronary heart disease, hypertension and heart failure. PMID- 29283234 TI - Epigenetic Mechanisms of Long-Term Effects of Mother-Infant Relationship on Physiology and Behavior of the Offspring. AB - The quality of mother-infant relationship in the early postnatal period influences the neurophysiology and behavior of adult animals via epigenetic mechanisms. The most studied target of long-term effects of early life events on physiology and behavior is hypothalamic-pituitary-adrenal axis, in particular, epigenetic programming of glucocorticoid receptor gene expression. Inhibition of histone deacetylases is a tool for epigenetic modulation of nervous system plasticity. Using this approach, it was demonstrated that epigenetic mechanisms play an important role in physiological and behavioral modifications. It is also promising tool for reversing the negative effects of disturbances in the mother infant relationship early in life. To date, however, the use of histone deacetylase inhibitors is widespread in adult animals, while studies in the early postnatal period are still scarce despite their relevance. PMID- 29283235 TI - Possible Mechanisms of Influence of Various Concentrations of Acetylcholine on Hippocampal Functioning. AB - Analysis of features of influence of acetylcholine on the hippocampal functioning was performed basing on the modulation rules for the efficacy of excitatory and inhibitory synaptic transmission we earlier proposed, and also on the known data about location of pre- and postsynaptic muscarine and nicotinic receptors. According to these rules, activation of postsynaptic muscarine M1/M3 and nicotinic receptors should promote long-term potentiation of excitatory and depressions (LTD) of inhibitory input to a neuron, whereas action on M2/M4 receptors should promote LTD of excitatory input and a decrease in neuromodulator release. If inhibitory input is stronger than excitatory, LTP (LTD) of excitatory input to the interneuron should promote LTD (LTP) of excitatory input to a target cell. It follows from the proposed mechanism that a lowing concentration of acetylcholine in the hippocampus, a decrease in density of M1/ M3 and a4p2 receptors, and augmenting binding of M2 receptors must lead to a depression of responses of pyramidal neurons in SA3 and SA1 fields to signals from the entorhinal cortex. Thereof, interaction of the semantic information, stored in the cortex, with the information of an episode-, stored in the hippocampus must be hindered and this effect can underlie disturbances of recall of stored information at Alzheimer's disease. PMID- 29283236 TI - The JAM Family of Molecules and Their Role in the Regulation of Physiological and Pathological Processes. AB - The review covers the main functions of the family of adhesion molecules JAMs (Junctional adhesion molecules). This review provides information about the role of the molecules JAM-AH, JAM-BH and JAM-CF in the occurrence of pathological conditions, including diseases of the nervous and cardiovascular systems, atherosclerosis, thrombosis and malignant growth. A molecule JAM-C and JAM-C directly affect platelet's adhesion to endothelial and dendritic cells, neutrophils, and other types of leukocytes, which makes their involvement in the regulation of hemostasis, and migration processes. JAM-A has an effect on the inflammatory response, leading to impaired cognitive function in HIV infection. JAM-B is involved in suppression of tumor growth in patients with Down syndrome. It is described the role of molecule JAM-A and JAM-C in the pathogenesis of hypertension, hypertensive crisis, atherosclerosis, cardiac abnormalities in the syndrome of Jacobson. Molecules JAM-B and JAM-C reduce the growth and invasion of human gliomas, and JAM-A has static effect against breast cancer. JAM-A molecule, JAM-B and JAM-C are involved in the development of inflammatory reactions and pathological neoangiogenesis in the cornea. The molecule JAM-C is involved in differentiation and polarization photoreceptors of the retina. The review provides own data of the authors, suggests the presence of epigenetic mechanisms of regulation of expression of the family of molecules JAMs, carried out with the direct participation of peptide geroprotectors. PMID- 29283237 TI - Memory, Cognition and the Endogenous Evoked Potentials of the Brain: the Estimation of the Disturbance of Cognitive Functions and Capacity of Working Memory Without the Psychological Testing. AB - Cognition, cognitive and memory impairments is widely discussed in the literature, especially in the psycho physiological and the neurologic. In essence, this literature is dedicated to the psycho physiological tests, different scales. However, instrument neurophysiologic methods not so widely are used for these purposes. This review is dedicated to the instrument methods of neurophysiology, in particular to the endogenous evoked potentials method R 300 (by characteristic latency 300 ms), in the estimation of cognitive functions and memory, to their special features dependent on age and to special features to their changes with the pathology. Method cognitive EP - R 300 is the response of the brain, recorded under the conditions of the identification of the significant distinguishing stimulus, it facilitates the inspection of cognitive functions and memory in the healthy persons and patients with different manifestation of cognitive impairments. In the review it is shown on the basis of literature and our own data, that working (operative) memory and the capacity of the working memory it can be evaluated with the aid of the indices R 300 within the normal subject and with the pathology. Testing with the estimation of working memory according to latent period of the peak R 300 can be carried out and when conducting psychological testing is not possible for any reasons. Together with these cognitive EP are used for evidence pharmacotherapy of many neurotropic drugs. PMID- 29283238 TI - Molecular Mechanisms of Action of Gas Transmitters NO, CO and H2S in Smooth Muscle Cells and Effect of NO-generating Compounds (Nitrates and Nitrites) on Average Life Expectancy. AB - Gaseous signaling molecules (gas transmitters) take an especial position among the numerous signaling molecules involved in the regulation of both intracellular processes that occur in different types of cells and cell-cell interactions. At present time, gas transmitters include three molecules whose enzymatic systems of synthesis and degradation, physiological action and intracellular effectors, the change of which under the action of gas transmitters may result in physiological and/or pathophysiological effects are well- determined. These molecules include nitrogen oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S). They are involved in the regulation of functions of various organs and systems of the human body, including the circulatory system. Interaction of NO, CO and H2S with various enzymatic and structural components of endothelial and, especially, smooth muscle cells has a significant impact on vascular tone and blood pressure. Furthermore, the crossing of NO-, CO- and H2S-mediated signaling pathways at common effectors and interaction with each other can determine the end, resulting functional response of the cell. The knowledge of the molecular targets of gas transmitters' action, the structure of the binding centers for gas transmitters and their interaction with each other may be essential in the development of methods of regulation of these signaling systems by targeted, directed action. This review summarizes the molecular mechanisms of the NO, CO and H2S interaction with the main targets, which carry out their regulatory effect on vascular smooth muscle cells. Also we describe here different ways of cross-regulation of NO-, CO and H2S-dependent signaling pathways. We analyzed NO-synthase and nitrite reductase systems of nitric oxide cycle and discuss the nitrate-nitrite background of the existence of modern man, which can substantially modify the signaling system, the metabolism of virtually all cell ultrastructure of neurons, neuron-neuron and neuron-glial interactions and exerts its influence on socially significant diseases that can affect the quality and the average life expectancy. PMID- 29283239 TI - Diabetes, from the Origins of the Problem to the Nobel Prize. Bioethics. AB - Analysis of scientific works from the creation of an experimental model of diabetes before discovery insulin was done. Emphasized is the priority of the Russian pathologist L. W. Sobolew (1876-1919) in the discovery of the endocrine function of the pancreas in experimental animals - rabbits, dogs, cats. In 1923 Canadian scientists Banting and Macleod were awarded the Nobel prize for the discovery of insulin. However, the methods and the idea of Nobel laureates were the same that had been developed 20 years earlier by the Russian scientists. Currently, the incidence of diabetes and related pathologies of organs and systems are growing. The use of animals in experimental biology and medicine will continue for the foreseeable future. The benefits to science and medicine derived from the use of animals in research are undeniable, but this process inevitably increases the responsibility of researchers. It is required constant work on improvement of the experimental methods in order to minimize pain, stress, and the number of animals used in the experiment. PMID- 29283240 TI - Highly Efficient TADF Polymer Electroluminescence with Reduced Efficiency Roll off via Interfacial Exciplex Host Strategy. AB - Solution-processed organic light-emitting diodes (s-OLED) consisting of TAPC/TmPyPB interfacial exciplex host and polymer PAPTC TADF emitter are prepared, simultaneously displaying ultralow voltages (2.50/2.91/3.51/4.91 V at luminance of 1/100/1000/1000 cd m-2), high efficiencies (14.9%, 50.1 lm W-1), and extremely low roll-off rates (J50 of 63.16 mA cm-2, L50 of ca. 15000 cd m-2). Such performance is distinctly higher than that of pure-PAPTC s-OLED. Compared to pure-PAPTC, the advanced emissive layer structure of TAPC:PAPTC/TmPyPB is unique in much higher PL quantum yield (79.5 vs 36.3%) and nearly 4-fold enhancement in kRISC of the PAPTC emitter to 1.48 * 107 s-1. PMID- 29283241 TI - Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's Disease. AB - Multiple pathogenic factors [e.g., amyloid-beta (Abeta), metal ions, metal-bound Abeta (metal-Abeta), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chemical properties (e.g., oxidation potentials) of our molecules and their coverage of reactivities toward the pathological targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among our compounds (1 3), 1 with the lowest oxidation potential is able to noticeably modify the aggregation of both metal-free Abeta and metal-Abeta, as well as scavenge free radicals. Compound 2 with the moderate oxidation potential significantly alters the aggregation of Cu(II)-Abeta42. The hardly oxidizable compound, 3, relative to 1 and 2, indicates no noticeable interactions with all pathogenic factors, including metal-free Abeta, metal-Abeta, and free radicals. Overall, our studies demonstrate that the design of small molecules as chemical tools able to control distinct pathological components could be achieved via fine-tuning of structures and properties. PMID- 29283242 TI - Correction to Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis. PMID- 29283243 TI - Discovery of a 29-Amino-Acid Reactive Abiotic Peptide for Selective Cysteine Arylation. AB - The regio- and chemoselective modification of proteins or peptides with chemical reagents is often challenging. One approach to overcome this problem involves identifying abiotic polypeptide sequences that react with specific small molecules. Toward this goal, we profiled ~5 * 1013 randomized 30-mer peptides using mRNA display and high-throughput sequencing in search of polypeptides that can undergo cysteine arylation with a water-soluble perfluoroarene. Within this vast chemical space, we discovered a cysteine-containing sequence with a second order rate constant of 0.29 M-1 s-1 for arylation. An N- and C-terminal truncation reduced the reaction rate, as did the addition of denaturants. When the reactive peptide was covalently fused to the enzyme Sortase A, we observed regiospecific arylation at a single cysteine site, leaving the enzyme's active site cysteine unchanged. Taken together, these results demonstrate that long polypeptides of defined sequence, when matched with the appropriate reactive group, can be used for selective arylation of cysteine in water. PMID- 29283244 TI - Bacterial Adhesion Is Affected by the Thickness and Stiffness of Poly(ethylene glycol) Hydrogels. AB - Despite lacking visual, auditory, and olfactory perception, bacteria sense and attach to surfaces. Many factors, including the chemistry, topography, and mechanical properties of a surface, are known to alter bacterial attachment, and in this study, using a library of nine protein-resistant poly(ethylene glycol) (PEG) hydrogels immobilized on glass slides, we demonstrate that the thickness or amount of polymer concentration also matters. Hydrated atomic force microscopy and rheological measurements corroborated that thin (15 MUm), medium (40 MUm), and thick (150 MUm) PEG hydrogels possessed Young's moduli in three distinct regimes, soft (20 kPa), intermediate (300 kPa), and stiff (1000 kPa). The attachment of two diverse bacteria, flagellated Gram-negative Escherichia coli and nonmotile Gram-positive Staphylococcus aureus was assessed after a 24 h incubation on the nine PEG hydrogels. On the thickest PEG hydrogels (150 MUm), E. coli and S. aureus attachment increased with increasing hydrogel stiffness. However, when the hydrogel's thickness was reduced to 15 MUm, a substantially greater adhesion of E. coli and S. aureus was observed. Twelve times fewer S. aureus and eight times fewer E. coli adhered to thin-soft hydrogels than to thick soft hydrogels. Although a full mechanism to explain this behavior is beyond the scope of this article, we suggest that because the Young's moduli of thin-soft and thick-soft hydrogels were statistically equivalent, potentially, the very stiff underlying glass slide was causing the thin-soft hydrogels to feel stiffer to the bacteria. These findings suggest a key takeaway design rule; to optimize fouling-resistance, hydrogel coatings should be thick and soft. PMID- 29283245 TI - Genetically Targeted Ratiometric and Activated pH Indicator Complexes (TRApHIC) for Receptor Trafficking. AB - Fluorescent protein-based pH sensors are useful tools for measuring protein trafficking through pH changes associated with endo- and exocytosis. However, commonly used pH-sensing probes are ubiquitously expressed with their protein of interest throughout the cell, hindering our ability to focus on specific trafficking pools of proteins. We developed a family of excitation ratiometric, activatable pH responsive tandem dyes, consisting of a pH sensitive Cy3 donor linked to a fluorogenic malachite green acceptor. These cell-excluded dyes are targeted and activated upon binding to a genetically expressed fluorogen activating protein and are suitable for selective labeling of surface proteins for analysis of endocytosis and recycling in live cells using both confocal and superresolution microscopy. Quantitative profiling of the endocytosis and recycling of tagged beta2-adrenergic receptor (B2AR) at a single-vesicle level revealed differences among B2AR agonists, consistent with more detailed pharmacological profiling. PMID- 29283246 TI - Graphene Surface Acoustic Wave Sensor for Simultaneous Detection of Charge and Mass. AB - We have combined a graphene field-effect transistor (GFET) and a surface acoustic wave (SAW) sensor on a LiTaO3 substrate to create a graphene surface acoustic wave (GSAW) sensor. When a SAW propagates in graphene, an acoustoelectric current (IA) flows between two attached electrodes. This current has unique electrical characteristics, having both positive and negative peak values with respect to the electrolyte-gate voltage (VEg) in solution. We found that IA is controlled by VEg and the amplitude of the SAW. It was also confirmed that the GSAW sensor detects changes of electrical charge in solution like conventional GFET sensors. Furthermore, the detection of amino-group-modified microbeads was performed by employing a GSAW sensor in a phthalate buffer solution at pH 4.1. The hole current peak shifted to the lower left in the IA-VEg characteristics. The left shift was caused by charge detection by the GFET and can be explained by an increase of amino groups that have positive charges at pH 4.1. In contrast, the downward shift is thought to be due to a reduction in the amplitude of the propagating SAW because of an increase in the mass loading of microbeads. This mass loading was detected by the SAW sensor. Thus, we have demonstrated that the GSAW sensor is a transducer capable of the simultaneous detection of charge and mass, which indicates that it is an attractive platform for highly sensitive and multifunctional solution sensing. PMID- 29283247 TI - Artificial Molecular Machines in Nanotheranostics. AB - Due to their dynamic nature and excellent stimuli-responsiveness resulting from noncovalent driving forces, artificial molecular machines (AMMs) show great promise in cancer theranostics. In this Perspective, we introduce the potential applications of AMMs in controlled drug delivery, bioorthogonal catalysis, imaging, and cell membrane permeabilization, with the goal of enhancing cancer diagnosis and therapy. We expect this preliminary discussion will garner multidisciplinary interest from scientists to advance AMMs and to expand their future clinical applications. PMID- 29283248 TI - Photoluminescence of Gold Nanorods: Purcell Effect Enhanced Emission from Hot Carriers. AB - We demonstrate, experimentally and theoretically, that the photon emission from gold nanorods can be viewed as a Purcell effect enhanced radiative recombination of hot carriers. By correlating the single-particle photoluminescence spectra and quantum yields of gold nanorods measured for five different excitation wavelengths and varied excitation powers, we illustrate the effects of hot carrier distributions evolving through interband and intraband transitions and the photonic density of states on the nanorod photoluminescence. Our model, using only one fixed input parameter, describes quantitatively both emission from interband recombination and the main photoluminescence peak coinciding with the longitudinal surface plasmon resonance. PMID- 29283249 TI - Live Cell Visualization of Multiple Protein-Protein Interactions with BiFC Rainbow. AB - As one of the most powerful tools to visualize PPIs in living cells, bimolecular fluorescence complementation (BiFC) has gained great advancement during recent years, including deep tissue imaging with far-red or near-infrared fluorescent proteins or super-resolution imaging with photochromic fluorescent proteins. However, little progress has been made toward simultaneous detection and visualization of multiple PPIs in the same cell, mainly due to the spectral crosstalk. In this report, we developed novel BiFC assays based on large-Stokes shift fluorescent proteins (LSS-FPs) to detect and visualize multiple PPIs in living cells. With the large excitation/emission spectral separation, LSS-FPs can be imaged together with normal Stokes shift fluorescent proteins to realize multicolor BiFC imaging using a simple illumination scheme. We also further demonstrated BiFC rainbow combining newly developed BiFC assays with previously established mCerulean/mVenus-based BiFC assays to achieve detection and visualization of four PPI pairs in the same cell. Additionally, we prove that with the complete spectral separation of mT-Sapphire and CyOFP1, LSS-FP-based BiFC assays can be readily combined with intensity-based FRET measurement to detect ternary protein complex formation with minimal spectral crosstalk. Thus, our newly developed LSS-FP-based BiFC assays not only expand the fluorescent protein toolbox available for BiFC but also facilitate the detection and visualization of multiple protein complex interactions in living cells. PMID- 29283250 TI - Sensitive Western-Blot Analysis of Azide-Tagged Protein Post Translational Modifications Using Thermoresponsive Polymer Self-Assembly. AB - Western-blot (WB) is a powerful analytical technique for protein identification in complex biological samples and has been widely used in biological studies for decades. Detection specificity and sensitivity of WB largely relies on quality of the antibodies and performance of the conjugated HRP. However, the application of WB analysis for the detection of protein post-translational modifications (PTMs) is hampered by the low abundance of protein PTMs and by the limited availability of antibodies that specifically differentiate various kinds of PTMs from their protein substrates. Therefore, new recognition mechanisms and signal amplification strategies for WB analysis of protein PTMs is in high demand. In this work, we prepared a soluble polymer that detects various azide-tagged PTM proteins in WB analysis using triarylphosphine and HRP modified thermoresponsive polymer. Specific and efficient detection of azide-tagged PTM protein is achieved via the bioorthogonal reaction between azide and triarylphosphine. More importantly, the chemiluminiscent signal in the WB analysis is largely amplified by the temperature induced self-assembly of numerous thermoresponsive polymer chains carrying multiple HRPs. As a result, approximately 100 times more sensitive detection than commercial antibodies is achieved by this method using standard PTM proteins. Though, this new reagent does not directly detect native PTMs in cell, tissue or blood samples, it still has important application potential in protein PTM studies, considering the wide availability of azide tagging techniques to a variety of PTMs. PMID- 29283251 TI - Ferroelastic Phase Transition and Switchable Dielectric Constant in Heterometallic Niccolite Formate Frameworks. AB - Four heterometallic formate frameworks templated by various alkylamine cations with the general formula [cat][GaIIIMnII(HCOO)6] {cat is MA (CH3NH3+) for 1, DMA [(CH3)2NH2+] for 2, EtA (CH3CH2NH3+) for 3, and DEtA [(CH3CH2)2NH2+] for 4} have been prepared and characterized by X-ray diffraction, differential scanning calorimetry, and dielectric studies. All of the complexes have niccolite-like structures, which possess the same [GaMn(HCOO)6]- anionic framework with binodal (412.63)(49.66) topology; only the counterions in the cavity are different. Complex 4 undergoes a reversible ferroelastic phase transition around 220 K accompanied by a thermally switchable dielectric constant transition triggered by the freezing of the order-disorder DEtA cations. PMID- 29283252 TI - Negative Differential Conductance in Polyporphyrin Oligomers with Nonlinear Backbones. AB - We study negative differential conductance (NDC) effects in polyporphyrin oligomers with nonlinear backbones. Using a low-temperature scanning tunneling microscope, we selectively controlled the charge transport path in single oligomer wires. We observed robust NDC when charge passed through a T-shape junction, bistable NDC when charge passed through a 90 degrees kink and no NDC when charge passed through a 120 degrees kink. Aided by density functional theory with nonequilibrium Green's functions simulations, we attributed this backbone-dependent NDC to bias-modulated hybridization of the electrode states with the resonant transport molecular orbital. We argue this mechanism is generic in molecular systems, which opens a new route of designing molecular NDC devices. PMID- 29283253 TI - Drinking Water Disinfection Byproducts (DBPs) and Human Health Effects: Multidisciplinary Challenges and Opportunities. AB - While drinking water disinfection has effectively prevented waterborne diseases, an unintended consequence is the generation of disinfection byproducts (DBPs). Epidemiological studies have consistently observed an association between consumption of chlorinated drinking water with an increased risk of bladder cancer. Out of the >600 DBPs identified, regulations focus on a few classes, such as trihalomethanes (THMs), whose concentrations were hypothesized to correlate with the DBPs driving the toxicity of disinfected waters. However, the DBPs responsible for the bladder cancer association remain unclear. Utilities are switching away from a reliance on chlorination of pristine drinking water supplies to the application of new disinfectant combinations to waters impaired by wastewater effluents and algal blooms. In light of these changes in disinfection practice, this article discusses new approaches being taken by analytical chemists, engineers, toxicologists and epidemiologists to characterize the DBP classes driving disinfected water toxicity, and suggests that DBP exposure should be measured using other DBP classes in addition to THMs. PMID- 29283254 TI - Electronic and Steric Control of the Spin-Crossover Behavior in [(CpR)2Mn] Manganocenes. AB - A computational study of the spin-crossover behavior in the family [(CpR)2Mn] (R = Me, iPr, tBu) is presented. Using the OPBE functional, the different electronic and steric effects over the metal's ligand field are studied, and trends in the spin-crossover-temperature (T1/2) behavior are presented in terms of the cyclopentadienyl (Cp) ligand functionalization. Our calculations outlined a delicate balance between both electronic and steric effects. While an increase in the number of electron-donating groups increases the spin-crossover temperature (T1/2) to the point that the transition is suppressed and only the low-spin state is observed, steric effects play an opposite role, increasing the distance between the Cp rings, which in turns shifts T1/2 to lower values, eventually stabilizing the high-spin state. Both effects can be rationalized by exploring the electronic structure of such systems in terms of the relevant d-based molecular orbitals. PMID- 29283255 TI - Green Algae as Carriers Enhance the Bioavailability of 14C-Labeled Few-Layer Graphene to Freshwater Snails. AB - The waterborne exposure of graphene to ecological receptors has received much attention; however, little is known about the contribution of food to the bioaccumulation potential of graphene. We investigated the effect of algal food on the uptake and distribution of 14C-labeled few-layer graphene (FLG) in freshwater snails, a favorite food for Asian people. In a water-only system, FLG (~158 MUg/L) was ingested by and accumulated in the snails. Adding algae to the water significantly enhanced FLG accumulation in the snails, with a bioaccumulation factor of 2.7 (48 h exposure). Approximately 92.5% of the accumulated FLG was retained in the intestine; in particular, the accumulated FLG in the intestine was able to pass through the intestinal wall and enter the intestinal epithelial cells. Of them, 1.3% was subsequently transferred/internalized to the liver/hepatocytes, a process that was not observed in the absence of the algae. Characterizations data further suggested that both of the extra- and intracellular FLG in the algae (the algae-bound fraction was 30.2%) significantly contributed to the bioaccumulation. Our results provide the first evidence that algae as carriers enhanced FLG bioavailability to the snails, as well as the potential of FLG exposure to human beings through consuming the contaminated snails. PMID- 29283256 TI - Switchable Synthesis of 3-Substituted 1H-Indazoles and 3,3-Disubstituted 3H Indazole-3-phosphonates Tuned by Phosphoryl Groups. AB - 3-Alkyl/aryl-1H-indazoles and 3-alkyl/aryl-3H-indazole-3-phosphonates were synthesized efficiently through a 1,3-dipolar cycloaddition reaction between alpha-substituted alpha-diazomethylphosphonates and arynes under simple reaction conditions. The product distribution was controlled by the phosphoryl group, which acted both as a tuning group and a traceless group in the reaction. PMID- 29283257 TI - Alveolarides: Antifungal Peptides from Microascus alveolaris Active against Phytopathogenic Fungi. AB - Three novel cyclodepsipeptides, alveolarides A (1), B (2), and C (3), each possessing the rare 2,3-dihydroxy-4-methyltetradecanoic acid unit and a beta phenylalanine amino acid residue, along with the known peptide scopularide were isolated and identified from the culture broth of Microascus alveolaris strain PF1466. The pure compounds were evaluated for biological activity, and alveolaride A (1) provided strong in vitro activity against the plant pathogens Pyricularia oryzae, Zymoseptoria tritici, and Ustilago maydis. Moderate activity of alveolaride A was observed under in planta conditions against Z. tritici, Puccinia triticina, and Phakopsora pachyrhizi. Structures of 1, 2, and 3 were determined by detailed analysis of NMR (1D and 2D) and mass spectrometry data. The partial absolute configuration of alveolaride A (1) was established. PMID- 29283258 TI - Bluish-White Luminescence in Rare-Earth-Free Vanadate Garnet Phosphors: Structural Characterization of LiCa3MV3O12 (M = Zn and Mg). AB - Extensive attention has been focused toward studies on inexpensive and rare-earth free garnet-structure vanadate phosphors, which do not have a low optical absorption due to the luminescence color being easily controlled by its high composition flexibility. However, bluish emission phosphors with a high quantum efficiency have not been found until now. In this study, we successfully discovered bluish-white emitting, garnet structure-based LiCa3MV3O12 (M = Zn and Mg) phosphors with a high quantum efficiency, and the detailed crystal structure was refined by the Rietveld analysis technique. These phosphors exhibit a broad band emission spectra peak at 481 nm under near UV-light excitation at 341 nm, indicating no clear difference in the emission and excitation spectra. A very compact tetrahedral [VO4] unit is observed in the LiCa3MV3O12 (M = Zn and Mg) phosphors, which is not seen in other conventional garnet compounds, and generates a bluish-white emission. In addition, these phosphors exhibit high quantum efficiencies of 40.1% (M = Zn) and 44.0% (M = Mg), respectively. Therefore, these vanadate garnet phosphors can provide a new blue color source for LED devices. PMID- 29283259 TI - Formal Total Syntheses of (-)- and (+)-Actinophyllic Acid. AB - The formal total syntheses of (-)-actinophyllic acid and its enantiomer starting from the same chiral intermediate are reported. The synthesis features a photoredox organocatalytic asymmetric alkylation to generate the original C15 chirality, a photocatalytic C-H functionalization of 3-methylindole in flow for constructing the C16 all-carbon quaternary center, a regioselective 1,3-dipolar cycloaddition, and an intramolecular Henry reaction to assemble the pentacyclic core of the target molecule. PMID- 29283260 TI - Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma. AB - This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150* against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma. PMID- 29283261 TI - Engineering Biocompatible Hydrogels from Bicomponent Natural Nanofibers for Anticancer Drug Delivery. AB - Natural hydrogels have attracted extensive research interest and shown great potential for many biomedical applications. In this study, a series of biocompatible hydrogels was reported based on the self-assembly of positively charged partially deacetylated alpha-chitin nanofibers (alpha-DECHN) and negatively charged 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibers (TOCNF) for anticancer drug delivery. The formation mechanisms of the alpha-DECHN/TOCNF hydrogels with different mixing proportions were studied, and their morphological, mechanical, and swelling properties were comprehensively investigated. Additionally, the drug delivery performance of the hydrogels was compared via sustained release test of an anticancer drug (5 fluorouracil). The results showed that the hydrogel with higher physical cross linking degree exhibited a higher drug loading efficiency and drug release percentage. PMID- 29283262 TI - Production of Antifungal p-Aminobenzoic Acid in Lysobacter antibioticus OH13. AB - Among Lysobacter species, Lysobacter antibioticus has been demonstrated to be an interesting source of antimicrobial metabolites for the biocontrol of plant diseases. Although the antibacterial activity was attributed to N-oxide phenazines, the active compounds involved in the antifungal function remained unknown. In this work, an antifungal compound was isolated and identified as p aminobenzoic acid (pABA). Antifungal activity screening revealed that pABA shows activity against a number of plant pathogens. The genes involved in the synthetic route of this compound in OH13 were identified. Further, the production of pABA was optimized by modification of the carbon source using engineered L. antibioticus OH13 strains. PMID- 29283263 TI - Correction to Maximum Likelihood Calibration of the UNRES Force Field for Simulation of Protein Structure and Dynamics. PMID- 29283265 TI - Ruthenium(II)-Catalyzed Direct C-H Arylation of Indoles with Arylsilanes in Water. AB - The ruthenium(II)-catalyzed, heteroatom-directed C-H arylation of indoles with arylsilanes in water has been developed. The method represents the first example of a ruthenium(II)-catalyzed oxidative C-H arylation in water/aqueous media as a sustainable solvent for C-H functionalization. The reaction enables the synthesis of a wide range of indoles with exquisite selectivity for arylation at the C-2 position. Preliminary mechanistic studies indicate reversibility of the C-H ruthenation step under the developed reaction conditions. PMID- 29283264 TI - Redesigning the Coumarin Scaffold into Small Bright Fluorophores with Far-Red to Near-Infrared Emission and Large Stokes Shifts Useful for Cell Imaging. AB - Among the palette of previously described fluorescent organic molecules, coumarins are ideal candidates for developing cellular and molecular imaging tools due to their high cell permeability and minimal perturbation of living systems. However, blue-to-cyan fluorescence emission is usually difficult in in vivo applications due to the inherent toxicity and poor tissue penetration of short visible light wavelengths. Here, we introduce a new family of coumarin based fluorophores, nicknamed COUPY, with promising photophysical properties, including emission in the far-red/near-infrared (NIR) region, large Stokes shifts, high photostability, and excellent brightness. COUPY fluorophores were efficiently synthesized in only three linear synthetic steps from commercially available precursors, with the N-alkylation of a pyridine moiety being the key step at the end of the synthetic route, as it allows for the tuning of the photophysical properties of the resulting dye. Owing to their low molecular weights, COUPY dyes show excellent cell permeability and accumulate selectively in nucleoli and/or mitochondria of HeLa cells, as their far-red/NIR fluorescence emission is easily detected at a concentration as low as 0.5 MUM after an incubation of only 20 min. We anticipate that these coumarin scaffolds will open a way to the development of novel coumarin-based far-red to NIR emitting fluorophores with potential applications for organelle imaging and biomolecule labeling. PMID- 29283267 TI - Formation of [2]- and [3]Rotaxanes through Bridging under Kinetic and Thermodynamic Control. AB - An efficient synthesis of a doubly stranded [3]rotaxane has been developed through bridging of a pseudo[3]rotaxane featuring two axle components. Reversible azine formation was effective as the bridging reaction. Kinetic and thermodynamic conditions provided the [2]- and [3]rotaxanes, respectively. PMID- 29283266 TI - Colloidal-Quantum-Dot Ring Lasers with Active Color Control. AB - To improve the photophysical performance of colloidal quantum dots for laser applications, sophisticated core/shell geometries have been developed. Typically, a wider bandgap semiconductor is added as a shell to enhance the gain from the quantum-dot core. This shell is designed to electronically isolate the core, funnel excitons to it, and reduce nonradiative Auger recombination. However, the shell could also potentially provide a secondary source of gain, leading to further versatility in these materials. Here we develop high-quality quantum-dot ring lasers that not only exhibit lasing from both the core and the shell but also the ability to switch between them. We fabricate ring resonators (with quality factors up to ~2500) consisting only of CdSe/CdS/ZnS core/shell/shell quantum dots using a simple template-stripping process. We then examine lasing as a function of the optical excitation power and ring radius. In resonators with quality factors >1000, excitons in the CdSe cores lead to red lasing with thresholds at ~25 MUJ/cm2. With increasing power, green lasing from the CdS shell emerges (>100 MUJ/cm2) and then the red lasing begins to disappear (>250 MUJ/cm2). We present a rate-equation model that can explain this color switching as a competition between exciton localization into the core and stimulated emission from excitons in the shell. Moreover, by lowering the quality factor of the cavity we can engineer the device to exhibit only green lasing. The mechanism demonstrated here provides a potential route toward color-switchable quantum-dot lasers. PMID- 29283269 TI - Why Do I Have to Drive Now? Post Hoc Explanations of Takeover Requests. AB - OBJECTIVE: It was investigated whether providing an explanation for a takeover request in automated driving influences trust in automation and acceptance. BACKGROUND: Takeover requests will be recurring events in conditionally automated driving that could undermine trust as well as acceptance and, therefore, the successful introduction of automated vehicles. METHOD: Forty participants were equally assigned to either an experimental group provided with an explanation of the reason for a takeover request or a control group without explanations. In a simulator drive, both groups experienced three takeover scenarios that varied in the obviousness of their causation. Participants rated their acceptance before and after the drive and rated their trust before and after each takeover situation. RESULTS: All participants rated acceptance on the same high level before and after the drive, independent of the condition. The control group's trust ratings remained unchanged by takeover requests in all situations, but the experimental group showed decreased trust after experiencing a takeover caused by roadwork. Participants provided with explanation felt more strongly that they had understood the system and the reasons for the takeovers. CONCLUSION: A takeover request did not lower trust or acceptance. Providing an explanation for a takeover request had no impact on trust or acceptance but increased the perceived understanding of the system. APPLICATION: The results provide insights into users' perception of automated vehicles, takeover situations, and a fundament for future interface design for automated vehicles. PMID- 29283268 TI - Radial Growth of Self-Catalyzed GaAs Nanowires and the Evolution of the Liquid Ga Droplet Studied by Time-Resolved in Situ X-ray Diffraction. AB - We report on a growth study of self-catalyzed GaAs nanowires based on time resolved in situ X-ray structure characterization during molecular-beam-epitaxy in combination with ex situ scanning-electron-microscopy. We reveal the evolution of nanowire radius and polytypism and distinguish radial growth processes responsible for tapering and side-wall growth. We interpret our results using a model for diameter self-stabilization processes during growth of self-catalyzed GaAs nanowires including the shape of the liquid Ga-droplet and its evolution during growth. PMID- 29283270 TI - An East-West comparison of self-care barriers in heart failure. AB - BACKGROUND: Barriers in heart failure self-care contribute to heart failure hospitalizations, but geographic differences have not been well-studied. We aimed to compare self-care barriers in heart failure patients managed at tertiary centers in an Eastern (Singapore) versus a Western (USA) nation. METHODS: Acute heart failure patients were prospectively assessed with a standardized instrument comprising of 47 distinct self-care barriers. The multi-equation generalized structural equation model was used to evaluate for geographic differences in barriers experienced, and association of barriers with outcomes. RESULTS: Patient related factors accounted for six out of 10 most prevalent self-care barriers among the 90 patients, with a median number of 11 barriers reported per patient. The Western patients reported a higher level of barriers when compared with their Eastern counterparts (median (interquartile range) 15 (9-24) versus 9 (4-16), p=0.001), after adjusting for demographics and co-morbidities. Many of these differences could be explained by geographic differences between the countries. There was no significant difference identified in all-cause mortality (19.4% versus 10.2%) and heart failure re-hospitalization (41.9% versus 45.8%) at six months between the groups. CONCLUSIONS: Self-care barriers are highly prevalent among acute heart failure patients, and differ substantially between East and West, but were not associated with geographic differences in outcomes. PMID- 29283271 TI - Erratum. PMID- 29283272 TI - "Oh, I'm Not Alone": Experiences of HIV-Positive Men Who Have Sex With Men in a Health Navigation Program to Promote Timely Linkage to Care in Guatemala City. AB - Men who have sex with men (MSM) are disproportionately affected by HIV in Guatemala and may benefit from health navigation programs designed to support timely linkage to HIV care. We conducted qualitative in-depth interviews with MSM (n = 19) linked to care within days of their diagnosis with the support of a health navigator. We used narrative analysis and systematic coding to identify themes related to HIV diagnosis and experiences with navigators. Participants experienced strong feelings of fear upon receiving a positive HIV test result. This fear led to social isolation and limited reliance on family and friend networks for support. Health navigators developed strong relationships with participants by providing the emotional support they were lacking and supporting them to overcome their fear and other structural barriers to HIV care, including stigma. Findings support the important role of navigation for MSM in Guatemala and could be transferable to other settings in Latin America. PMID- 29283273 TI - HIV-Risk Behaviors of Men Who Perpetrate Intimate Partner Violence in Rakai, Uganda. AB - Little is known about men who perpetrate IPV in communities also at risk for HIV infection. Using data from the Rakai Community Cohort Study (RCCS), five survey rounds were used (n = 21,157, observation from n = 10,618 men) to examine HIV risk and prevention behaviors among men who reported acts of violence against their wife/primary partner in the past 12 months. Overall, 10.4% men reported perpetrating physical violence and 17.3% perpetrating verbal violence, 3.1% reported sexual violence, 3.1% used violence to have sex with their wife/partner, and 1.1% used verbal coercion. Factors associated with IPV were: age 20-24 years, lower socio-economic status, being married, no male circumcision, drinking alcohol before sex, no consistent condom use, multiple sex partners in the past 12 months, multiple partners ever, and working in a bar. Protective HIV behaviors predicted fewer reports of perpetration and HIV-risk behaviors predicted more reports of perpetrating IPV. PMID- 29283274 TI - Using an Innovative Telehealth Model to Support Community Providers Who Deliver Perinatal HIV Care. AB - Mountain West AETC (AIDS Education and Training Center) ECHO (Extension for Community Healthcare Outcomes), a longitudinal HIV telemen-toring program, connects community providers and a multidisciplinary specialist team at the University of Washington. The program employs focused lectures and real-time case discussions to educate and support providers in low-resource and rural settings. We assessed the impact of the program on management of perinatal HIV through surveying community providers who participate, and reviewing cases presented by providers for consultation. One hundred percent of providers who presented a perinatal HIV case for ECHO consultation reported that presentation "very much" impacted management of the case, and 93% of survey respondents reported that ECHO participation helped them stay up to date on national perinatal HIV guidelines. All 13 cases had the successful outcome of prevention of mother-to-child transmission of HIV. The ECHO model can effectively support and educate community providers who care for HIV-infected pregnant women. PMID- 29283275 TI - HIV Testing, Stigma, and Risk: A Comparison of Church Leaders and Their Congregants. AB - The involvement of African American churches in HIV testing and prevention is a viable community-based strategy in efforts to reduce rates of HIV among African Americans; however, church members' beliefs and attitudes are often barriers to successful implementation. This study aimed to compare church leaders and congregants regarding HIV testing behaviors, HIV-related stigma, HIV knowledge, and perceived risk. This comparative, cross-sectional study used self-reporting questionnaires across six churches in Baltimore, Maryland. Of the 173 participants (68 leaders, 105 congregants), leaders and congregants had equally high levels of HIV knowledge and equally low levels of HIV stigma, but leaders had higher homosexuality stigma than congregants t(169) = 1.773, p = .039. Congregants had higher perceived HIV risk t(170) = 3.814, p < .001, and were more likely to be tested annually for HIV than leaders, c2(1) = 8.940, p = .002. Given the higher rates of stigma, lower perceived risk and lower likelihood to be tested, interventions should focus on changing the beliefs and behaviors of church leadership to promote implementation of HIV efforts. PMID- 29283277 TI - Understanding HIV Transmission and Illness Stigma: A Relationship Revisited in Rural Rwanda. AB - Integrating an understanding of HIV transmission with structural-behavioral prevention approaches remains a priority in low prevalence rural regions in Africa. Many national indicators use categorical survey responses which do not capture the cultural nuances of HIV transmission knowledge that potentially reify stigmatizing treatment of persons living with HIV (PL-HIV). We examined the relationship between quantitative and qualitative measures of HIV knowledge and four forms of stigma (individual attitudes, felt normative, social distance, and stigma perceived by PLHIV) among 200 rural residents in Rwanda. Forty-two percent qualitatively reported concurrent accurate and partial knowledge of HIV transmission. Being more knowledgeable about HIV transmission was associated with less desire for social distancing from PLHIV. Our findings highlight the continued importance of reinforcing an accurate understanding of HIV transmission and correcting misinformation by drawing on quantitative and qualitative assessments of HIV knowledge as critical arms of HIV stigma reduction programs in low prevalence rural regions. PMID- 29283276 TI - Engaged for Change: A Community-Engaged Process for Developing Interventions to Reduce Health Disparities. AB - The science underlying the development of individual, community, system, and policy interventions designed to reduce health disparities has lagged behind other innovations. Few models, theoretical frameworks, or processes exist to guide intervention development. Our community-engaged research partnership has been developing, implementing, and evaluating efficacious interventions to reduce HIV disparities for over 15 years. Based on our intervention research experiences, we propose a novel 13-step process designed to demystify and guide intervention development. Our intervention development process includes steps such as establishing an intervention team to manage the details of intervention development; assessing community needs, priorities, and assets; generating intervention priorities; evaluating and incorporating theory; developing a conceptual or logic model; crafting activities; honing materials; administering a pilot, noting its process, and gathering feedback from all those involved; and editing the intervention based on what was learned. Here, we outline and describe each of these 13 steps. PMID- 29283279 TI - Virtual peer-delivered memory intervention: a single-case experimental design in an adolescent with chronic memory impairment. AB - BACKGROUND: Children and adolescents with chronic memory impairment may develop coping strategies that enable functioning, yet these often remain undetectable using traditional psychometric measures. Personalized intervention studies that promote the use of such strategies designed specifically for use by this young cohort are scarce. OBJECTIVE: To investigate the effect of a novel virtual reality peer-delivered memory intervention on the everyday functioning and well being of SE, a 17-year-old female with a history of chronic verbal memory issues, impaired autobiographical event recall and elevated mood symptoms. RESEARCH DESIGN: A single-case ABA experimental design study was used to assess change. METHODS: Following initial baseline assessment using objective neuropsychological and subjective functional questionnaires and intervention training, case SE used the intervention daily for 3 weeks before repeating key outcome measures. RESULTS: Using non-overlap of all pairs and qualitative feedback analysis, the results revealed a significant increase in event recall and self-reported positive changes to levels of everyday functioning. CONCLUSION: Supporting autobiographical event recall and prospective memory via a virtual peer-delivered intervention may lead to reduction in cognitive load, and benefit overall well being and everyday functioning. PMID- 29283282 TI - Full Disclosure. PMID- 29283283 TI - Epidemiology of objectively measured bedtime and chronotype in US adolescents and adults: NHANES 2003-2006. AB - BACKGROUND: We propose a method for estimating the timing of in-bed intervals using objective data in a large representative US sample, and quantify the association between these intervals and age, sex, and day of the week. METHODS: The study included 11,951 participants 6 years and older from the National Health and Nutrition Examination Survey (NHANES) 2003-2006, who wore accelerometers to measure physical activity for seven consecutive days. Participants were instructed to remove the device just before the nighttime sleep period and put it back on immediately after. This nighttime period of non-wear was defined in this paper as the objective bedtime (OBT), an objectively estimated record of the in bed interval. For each night of the week, we estimated two measures: the duration of the OBT (OBT-D) and, as a measure of the chronotype, the midpoint of the OBT (OBT-M). We estimated day-of-the-week-specific OBT-D and OBT-M using gender specific population percentile curves. Differences in OBT-M (chronotype) and OBT D (the amount of time spent in bed) by age and sex were estimated using regression models. RESULTS: The estimates of OBT-M and their differences among age groups were consistent with the estimates of chronotype obtained via self report in European populations. The average OBT-M varied significantly by age, while OBT-D was less variable with age. In the reference group (females, aged 17 22 years), the average OBT-M across 7 days was 4:19 AM (SD = 30 min) and the average OBT-D was 9 h 19 min (SD = 12 min). In the same age group the average OBT D was 18 minutes shorter for males than for females, while the average OBT-M was not significantly different between males and females. The most pronounced differences were observed between OBT-M of weekday and weekend nights. In the reference group, compared to the average OBT-M of 3:50 am on Monday through Thursday nights, there was a 57-minute delay in OBT-M on Friday nights (entering the weekend), a 69-minute delay on Saturday nights (staying in the weekend), and a 23-minute delay on Sunday night (leaving the weekend). For both OBT-M and OBT D, in most age groups and for most days of the week, there were no statistically significant differences between males and females, except for OBT-D on Wednesdays and Thursdays, with males having 31 (p-value < 0.05) and 45 (p-value < 0.05) minutes shorter OBT-D, respectively. CONCLUSIONS: The proposed measures, OBT-D and OBT-M, provide useful information of time in bed and chronotype in NHANES 2003-2006. They identify within-week patterns of bedtime and can be used to study associations between the bedtime and the large number of health outcomes collected in NHANES 2003-2006. PMID- 29283285 TI - The therapeutic value of cranioplasty in individuals with brain injury. AB - PRIMARY OBJECTIVE: To examine the effect of cranioplasty on recovery. RESEARCH DESIGN: Retrospective cohort study. METHOD AND PROCEDURES: Retrospective chart review conducted in 2011 and 2012 on adult inpatients with craniectomy who completed a continuous episode of inpatient rehabilitation before and after receiving their cranioplasty. Patients were matched 1:1 or age, gender, functional level at admission, injury severity and length of stay with inpatients who completed rehabilitation before cranioplasty. Main outcome measures include FIMTM (Functional Independence Measure) and FIMTM efficiency [(FIMTM discharge - FIMTMadmission)/number of days in rehabilitation]. To examine within and between group differences, analyses included paired and independent t-tests, Pearson correlations and chi-square analyses. RESULTS: Twenty-six individuals (13 from the cranioplasty group and 13 from the comparison group) were analysed. FIMTM efficiency increased following cranioplasty [0.29 to 0.61; t(12) = -2.77, p = 0.017]. The mean FIMTM efficiency for the cranioplasty group was below that of the comparison group prior to cranioplasty [0.28 +/- 0.37 and 0.39 +/- 0.32, p = .41], but increased following cranioplasty [0.61 +/- 0.71 and 0.39 +/- 0.32, p = .32]. An improvement in FIMTM efficiency following cranioplasty was more commonly seen among individuals with less severe brain injuries (75%, chi2 = 3.8, df = 1, p = 0.053). CONCLUSION: Rate of recovery increased following cranioplasty and exceeded that of the comparison group suggesting that cranioplasty may contribute to improvement. PMID- 29283284 TI - Endothelial dysfunction occurs independently of adipose tissue inflammation and insulin resistance in ovariectomized Yucatan miniature-swine. AB - In rodents, experimentally-induced ovarian hormone deficiency increases adiposity and adipose tissue (AT) inflammation, which is thought to contribute to insulin resistance and increased cardiovascular disease risk. However, whether this occurs in a translationally-relevant large animal model remains unknown. Herein, we tested the hypothesis that ovariectomy would promote visceral and perivascular AT (PVAT) inflammation, as well as subsequent insulin resistance and peripheral vascular dysfunction in female swine. At sexual maturity (7 months of age), female Yucatan mini-swine either remained intact (control, n = 9) or were ovariectomized (OVX, n = 7). All pigs were fed standard chow (15-20 g/kg), and were euthanized 6 months post-surgery. Uterine mass and plasma estradiol levels were decreased by ~10-fold and 2-fold, respectively, in OVX compared to control pigs. Body mass, glucose homeostasis, and markers of insulin resistance were not different between control and OVX pigs; however, OVX animals exhibited greater plasma triglycerides and triglyceride:HDL ratio. Ovariectomy enhanced visceral adipocyte expansion, although this was not accompanied by brachial artery PVAT adipocyte expansion, AT inflammation in either depot, or increased systemic inflammation assessed by plasma C-reactive protein concentrations. Despite the lack of AT inflammation and insulin resistance, OVX pigs exhibited depressed brachial artery endothelial-dependent vasorelaxation, which was rescued with blockade of endothelin receptor A. Together, these findings indicate that in female Yucatan mini-swine, increased AT inflammation and insulin resistance are not required for loss of ovarian hormones to induce endothelial dysfunction. PMID- 29283286 TI - Missed medical appointments during shifts to and from daylight saving time. AB - Transitions into and out of Daylight Saving Time (DST) can provide insights into how a minor change to a regular sleep-wake cycle can inadvertently affect health. We examined the relationship between DST and missed medical appointments. Using a large dataset, the proportion of missed appointments were examined prior and post spring and autumn clock changes. As predicted, the number of missed medical appointments significantly increased following the spring (forward) clock change and the week of the clock change. This trend was reversed following the transition out of DST. The implications of scheduling appointments around DST to increase attendance are discussed. PMID- 29283287 TI - Hypopituitarism 3 and 12 months after traumatic brain injury and subarachnoid haemorrhage. AB - OBJECTIVE: High prevalence of hypopituitarism (HP) has been reported after traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH). The aim of the study was to prospectively evaluate the prevalence and progression of HP in patients after TBI and SAH in Icelandic population. DESIGN: A 12 month prospective single-centre study. METHODS AND PROCEDURES: A total of 27 patients were included, 15 patients with TBI and 12 patients with SAH. Pituitary function was evaluated with baseline hormone measurements and diagnostic tests. An insulin tolerance test was used unless contraindicated, then the GHRH-arginine test and Synachten test were used. RESULTS: At three months, 16.7% (2/12) of the patients had HP after TBI and 33.3% (4/12) after SAH. At 12 months, 21.4% (3/14) of patients had HP after TBI and 9.1% (1/11) after SAH. Gonadotropin deficiency was the most common deficiency at 3 months and GH and gonadotropin deficiency at 12 months. CONCLUSIONS: There is a considerable risk of HP after TBI and reason to study pituitary function further in patients with SAH. We believe that neuroendocrine evaluation is important in these patients. Since recovery commonly occurs 12 months after the event, evaluation should be performed after that time if not clinically indicated earlier. PMID- 29283288 TI - A novel method for the rapid detection of post-translationally modified visinin like protein 1 in rat models of brain injury. AB - BACKGROUND: Although elevated serum levels of visinin-like protein 1 (VILIP-1), a neuron-specific calcium sensor protein, are associated with ischaemic stroke, only a single study has evaluated VILIP-1 as a biomarker of traumatic brain injury (TBI). The current proof-of-concept study was designed to determine whether serum VILIP-1 levels increase post-injury in a well-characterized rat unilateral cortical contusion model. METHODS: Lateral flow devices (LFDs) rapidly (< 20 min) detected trace serum levels (pg/mL) of VILIP-1 in a small input sample volume (10 uL). Temporal profiles of serum levels at baseline and post-injury were measured in male Sprague Dawley rats subjected to very mild-, mild unilateral-cortical contusion, or naive surgery and in male Sprague Dawley rats following a diffuse TBI or sham surgery. RESULTS: Mean serum levels were significantly elevated by 0.5 h post-injury and remained so throughout the temporal profile compared with baseline in very mild and mild unilateral contusions but not in naive surgeries. Serum levels were also elevated in a small cohort of animals subjected to a diffuse TBI injury. CONCLUSIONS: Overall, the current study demonstrates that the novel LFD is a reliable and rapid point-of care diagnostic for the detection and quantification of serum levels of UB-VILIP 1 in a clinically relevant time frame. PMID- 29283289 TI - Molecular characterization of perivascular drainage pathways in the murine brain. AB - Perivascular compartments surrounding central nervous system (CNS) vessels have been proposed to serve key roles in facilitating cerebrospinal fluid flow into the brain, CNS waste transfer, and immune cell trafficking. Traditionally, these compartments were identified by electron microscopy with limited molecular characterization. Using cellular markers and knowledge on cellular sources of basement membrane laminins, we here describe molecularly distinct compartments surrounding different vessel types and provide a comprehensive characterization of the arachnoid and pial compartments and their connection to CNS vessels and perivascular pathways. We show that differential expression of plectin, E cadherin and laminins alpha1, alpha2, and alpha5 distinguishes pial and arachnoid layers at the brain surface, while endothelial and smooth muscle laminins alpha4 and alpha5 and smooth muscle actin differentiate between arterioles and venules. Tracer studies reveal that interconnected perivascular compartments exist from arterioles through to veins, potentially providing a route for fluid flow as well as the transport of large and small molecules. PMID- 29283290 TI - Real-time quantitative monitoring of cerebral blood flow by laser speckle contrast imaging after cardiac arrest with targeted temperature management. AB - Brain injury is the main cause of mortality and morbidity after cardiac arrest (CA). Changes in cerebral blood flow (CBF) after reperfusion are associated with brain injury and recovery. To characterize the relative CBF (rCBF) after CA, 14 rats underwent 7 min asphyxia-CA and were randomly treated with 6 h post resuscitation normothermic (36.5-37.5C) or hypothermic- (32-34C) targeted temperature management (TTM) (N = 7). rCBF was monitored by a laser speckle contrast imaging (LSCI) technique. Brain recovery was evaluated by neurologic deficit score (NDS) and quantitative EEG - information quantity (qEEG-IQ). There were regional differences in rCBF among veins of distinct cerebral areas and heterogeneous responses among the three components of the vascular system. Hypothermia immediately following return of spontaneous circulation led to a longer hyperemia duration (19.7 +/- 1.8 vs. 12.7 +/- 0.8 min, p < 0.01), a lower rCBF (0.73 +/- 0.01 vs. 0.79 +/- 0.01; p < 0.001) at the hypoperfusion phase, a better NDS (median [25th-75th], 74 [61-77] vs. 49 [40-77], p < 0.01), and a higher qEEG-IQ (0.94 +/- 0.02 vs. 0.77 +/- 0.02, p < 0.001) compared with normothermic TTM. High resolution LSCI technique demonstrated hypothermic TTM extends hyperemia duration, delays onset of hypoperfusion phase and lowered rCBF, which is associated with early restoration of electrophysiological recovery and improved functional outcome after CA. PMID- 29283292 TI - Morphological, molecular and hormonal adaptations to early morning versus afternoon resistance training. AB - It has been clearly established that maximal force and power is lower in the morning compared to noon or afternoon hours. This morning neuromuscular deficit can be diminished by regularly training in the morning hours. However, there is limited and contradictory information upon hypertrophic adaptations to time-of day-specific resistance training. Moreover, no cellular or molecular mechanisms related to muscle hypertrophy adaptation have been studied with this respect. Therefore, the present study examined effects of the time-of-day-specific resistance training on muscle hypertrophy, phosphorylation of selected proteins, hormonal concentrations and neuromuscular performance. Twenty five previously untrained males were randomly divided into a morning group (n = 11, age 23 +/- 2 yrs), afternoon group (n = 7, 24 +/- 4 yrs) and control group (n = 7, 24 +/- 3 yrs). Both the morning and afternoon group underwent hypertrophy-type of resistance training with 22 training sessions over an 11-week period performed between 07:30-08:30 h and 16:00-17:00 h, respectively. Isometric MVC was tested before and immediately after an acute loading exclusively during their training times before and after the training period. Before acute loadings, resting blood samples were drawn and analysed for plasma testosterone and cortisol. At each testing occasion, muscle biopsies from m. vastus lateralis were obtained before and 60 min after the acute loading. Muscle specimens were analysed for muscle fibre cross-sectional areas (CSA) and for phosphorylated p70S6K, rpS6, p38MAPK, Erk1/2, and eEF2. In addition, the right quadriceps femoris was scanned with MRI before and after the training period. The control group underwent the same testing, except for MRI, between 11:00 h and 13:00 h but did not train. Voluntary muscle strength increased significantly in both the morning and afternoon training group by 16.9% and 15.2 %, respectively. Also muscle hypertrophy occurred by 8.8% and 11.9% (MRI, p < 0.001) and at muscle fibre CSA level by 21% and 18% (p < 0.01) in the morning and afternoon group, respectively. No significant changes were found in controls within these parameters. Both pre- and post-training acute loadings induced a significant (p < 0.001) reduction in muscle strength in all groups, not affected by time of day or training. The post loading phosphorylation of p70S6Thr421/Ser424 increased independent of the time of day in the pre-training condition, whereas it was significantly increased in the morning group only after the training period (p < 0.05). Phosphorylation of rpS6 and p38MAPK increased acutely both before and after training in a time-of day independent manner (p < 0.05 at all occasions). Phosphorylation of p70S6Thr389, eEF2 and Erk1/2 did not change at any time point. No statistically significant correlations were found between changes in muscle fibre CSA, MRI and cell signalling data. Resting testosterone was not statistically different among groups at any time point. Resting cortisol declined significantly from pre- to post-training in all three groups (p < 0.05). In conclusion, similar levels of muscle strength and hypertrophy could be achieved regardless of time of the day in previously untrained men. However, at the level of skeletal muscle signalling, the extent of adaptation in some parameters may be time of day dependent. PMID- 29283291 TI - Structural insights into humanization of anti-tissue factor antibody 10H10. AB - Murine antibody 10H10 raised against human tissue factor is unique in that it blocks the signaling pathway, and thus inhibits angiogenesis and tumor growth without interfering with coagulation. As a potential therapeutic, the antibody was humanized in a two-step procedure. Antigen-binding loops were grafted onto selected human frameworks and the resulting chimeric antibody was subjected to affinity maturation by using phage display libraries. The results of humanization were analyzed from the structural perspective through comparison of the structure of a humanized variant with the parental mouse antibody. This analysis revealed several hot spots in the framework region that appear to affect antigen binding, and therefore should be considered in human germline selection. In addition, some positions in the Vernier zone, e.g., residue 71 in the heavy chain, that are traditionally thought to be crucial appear to tolerate amino acid substitutions without any effect on binding. Several humanized variants were produced using both short and long forms of complementarity-determining region (CDR) H2 following the difference in the Kabat and Martin definitions. Comparison of such pairs indicated consistently higher thermostability of the variants with short CDR H2. Analysis of the binding data in relation to the structures singled out the ImMunoGeneTics information system(r) germline IGHV1-2*01 as dubious owing to two potentially destabilizing mutations as compared to the other alleles of the same germline and to other human germlines. PMID- 29283293 TI - Resource Planning in Glaucoma: A Tool to Evaluate Glaucoma Service Capacity. AB - BACKGROUND: The National Patient Safety Agency (2009) publication advising timely follow-up of patients with established glaucoma followed several reported instances of visual loss due to postponed appointments and patients lost to follow-up. The Royal College of Ophthalmologists Quality Standards Development Group stated that all hospital appointments should occur within 15% of the intended follow-up period. AIM: To determine whether: 1. Glaucoma follow-up appointments at a teaching hospital occur within the requested time 2. Appointments are requested at appropriate intervals based on the NICE Guidelines 3. The capacity of the glaucoma service is adequate Methods: A two-part audit was undertaken of 98 and 99 consecutive patients respectively attending specialist glaucoma clinics. In the first part, the reasons for delayed appointments were recorded. In the second part the requested follow-up was compared with NICE guidelines where applicable. Based on the findings, changes were implemented and a re-audit of 100 patients was carried out. RESULTS: The initial audit found that although clinical decisions regarding follow-up intervals were 100% compliant with NICE guidelines where applicable, 24% of appointments were delayed beyond 15% of the requested period, due to administrative errors and inadequate capacity, leading to significant clinical deterioration in two patients. Following the introduction of an electronic appointment tracker and increased clinical capacity created by extra clinics and clinicians, the re-audit found a marked decrease in the percentage of appointments being delayed (9%). CONCLUSIONS: This audit is a useful tool to evaluate glaucoma service provision, assist in resource planning for the service and bring about change in a non confrontational way. It can be widely applied and adapted for use in other medical specialities. PMID- 29283295 TI - Instantaneous Reproductive Effort in Female American Oysters, Crassostrea virginica, Measured by a New Immunoprecipitation Assay. AB - An immunoprecipitation assay was developed for measuring instantaneous reproductive effort in female American oysters, Crassostrea virginica. Oysters were injected with 14C-leucine and incubated in situ for 1 to 30 h periodically throughout the annual gametogenic cycle. Gonadal protein labeled with 14C-leucine was precipitated from an oyster homogenate with rabbit anti-oyster egg IgG as the primary antibody. Antibody-oyster egg protein complex was further purified by immunoadsorption with staphylococcal protein A cell suspension. The quantity of oyster eggs was determined by single-ring immunodiffusion. A mathematical model was developed to calculate the instantaneous reproductive rate of oysters and to estimate the number of days required from the initiation of gonadal development to spawning. The oyster population was lightly to moderately infected with a protozoan parasite, Perkinsus marinus. A negative correlation between the intensity of infection and the rate of gonadal production suggests that P. marinus retards the rate of gamete development. The seasonal cycle of gamete production determined by direct measurements of egg protein production was not equivalent to that determined by standard gonadal-somatic index (GSI), except at the most basic level. GSI was highest during the spring spawning peak, but the rate of gamete production was highest in the fall. Accordingly, the two measurements, rate versus standing crop (volume of gonad), reveal a substantially different picture about the details of the spawning season. Estimates of the time required to reach spawning condition ranged from several weeks to 1 or 2 months; these values agree with published estimates derived from less direct methods. Direct rate measurements thus seem to accurately reflect the true rate at which gametic tissue is produced in the field. A positive correlation between oyster size and the estimated days to spawn suggests that larger oysters require longer to prepare to spawn. Furthermore, the range in observed somatic and gametic growth emphasizes the conservatism of somatic growth and the volatility of gonadal growth that is borne out by the results of population dynamics models of oysters. PMID- 29283294 TI - Evaluating the role of clinical pharmacists in pre-procedural anticoagulation management. AB - OBJECTIVES: While physicians are typically responsible for managing perioperative warfarin, clinic pharmacists may improve pre-procedural decision-making. We assessed the impact of pharmacist-driven care for chronic warfarin-treated patients undergoing outpatient right heart catheterization (RHC). METHODS: 200 warfarin patients who underwent RHC between January 2012 and September 2015 were analyzed. Pharmacist-care (n = 79) was compared to the usual care model (n = 121). The primary outcome was a composite of (1) documentation of anticoagulation plan, (2) holding warfarin at least 5 days prior to procedure, (3) guideline congruent low molecular weight heparin (LMWH) bridging, and (4) correct LMWH dosing if bridging deemed necessary. Chi-squared test performed to assess the role of pharmacist. A multivariable logistic regression analysis was performed to the composite endpoint, adjusted for the month of procedure. RESULTS: Compared to the usual care model, pharmacist-driven care (OR 4.69, 95% CI 1.73-12.71, p = 0.002) and date of the procedure (OR 1.06/month, 95% CI 1.01-1.10, p = 0.011) were independently associated with the primary composite outcome. Of the individual outcome components, pharmacist-driven care was only associated with documentation (96.2% vs. 67.8%, OR 9.19, 95% CI 2.19-38.62, p = 0.002). Remaining components including hold warfarin for at least 5 days, appropriate bridging and correct LMWH dosing were not significantly associated with pharmacist-care. CONCLUSIONS: Pharmacist-care is associated with better guideline-based anticoagulation management, but this was primarily driven by improved documentation. The impact of pharmacist managed peri-procedural anticoagulation on clinical outcomes remains unknown. PMID- 29283296 TI - Multiple Modes of Asexual Reproduction by Tropical and Subtropical Sea Star Larvae: an Unusual Adaptation for Genet Dispersal and Survival. AB - Sea star larvae (Echinodermata: Asteroidea), collected from the subtropical Northwest Atlantic Ocean, exhibited three distinct modes of asexual reproduction. A number of different bipinnariae and brachiolariae reproduced by paratomous cloning of the posterolateral arms. This morphogenesis was identical to that of larvae assignable to the genus Luidia. A second mode of asexual reproduction involves the autotomization of an anterior portion of the preoral lobe. Primary larvae with preoral lobes of varying sizes and free-swimming preoral lobes of various stages of morphological development were simultaneously collected. The free-swimming preoral lobes developed complete digestive systems and ultimately assumed the form of typical bipinnaria larvae. Asexual reproduction by larvae may also take the form of budding. The released individual is either a blastula- or gastrulastage embryo. Subsequent development to a bipinnariastage secondary larva, with the possible exception of coelom formation, appears to occur through the events associated with normal larval development. These diverse methods of asexual propagation provide a common mechanism to increase the length of larval life and amplify the number of individuals. Thus asexual reproduction by larvae should increase the likelihood of genet representation in the next generation. PMID- 29283297 TI - A Substance Inducing the Loss of Premature Embryos From Ovigerous Crabs. AB - The embryos of an estuarine terrestrial crab (akate-gani; Sesarma haematocheir) are attached by a funiculus to ovigerous hairs on the maternal pleopods, and are ventilated by the female until hatching occurs. When females were kept in a small quantity of diluted seawater (about 10%), hatching and larval release occurred in all cases. In contrast, when the medium was hatch water (i.e., the filtered medium into which larvae had been released), most ovigerous females liberated their embryos prematurely, but hatching did not occur. The egg masses (cluster of embryos) carried by these females were not released as usual, but were gradually extruded from the brooding chamber, and within a few days all had dropped to the bottom of the beaker. No morphological changes were found on the outer egg membrane, the funiculus, or the coat investing the ovigerous hairs of females kept in hatch water. But the ovigerous hairs did slip easily out of the coat, and this caused the extrusion of the egg masses. The active factor--called incubation disrupting substance--was stable with freezing, but heat-labile. In normal females (i.e., those not treated with hatch water), broken egg cases and funiculi remain for a time after hatching with the coat on the ovigerous hairs, but they are gone by the morning after hatching. So the secretion of this incubation disrupting substance may participate in cleaning the ovigerous hairs of old investing coats and funiculi after larval release, thus preparing for the attachment of the next clutch of embryos. In addition, this substance may play a role in hatching. PMID- 29283298 TI - Ingestion of Ultraplankton by the Planktonic Larvae of the Crown-of-Thorns Starfish, Acanthaster planci. AB - There has been a debate over whether the growth and development of the larvae of the crown-of-thorns starfish Acanthaster planci are severely food-limited. This debate has raised a range of questions, including the one relating to the role of heterotrophic bacteria in the nutrition of larvae. In this study, the feeding rate of larvae on bacteria as well as on other ultraplankton (<5 {mu}m) was determined by counting the number of the fluorescence-labeled cells (FLC) in the gut after short incubation. Preliminary experiments showed no detrimental effect of the fluorescence dye (5-(4,6-dichlorotriazin-2-yl) aminofluorescein) on the development of larvae and demonstrated the usefulness of FLC in feeding experiments as food particles analogous to living cells of ultraplankton. There was no evidence that larvae ingested bacteria. Larvae did ingest two strains of photosynthetic cyanobacteria, which had equivalent spherical diameters (ESD) of 1 and 1.8 {mu}m, but these tiny cells were cleared more than 10 times slower than the larger algae Phaeodactylum tricornutum (4.7 {mu}m ESD) and Dunaliella tertiolecta (5.1 {mu}m ESD). Regardless of the size of FLC used, the clearance rate (volume of water cleared per animal per unit time) increased by 50-120%, as larvae developed from the late bipinnaria stage to the late brachiolaria stage. These results show that larvae may derive a sizable proportion of their nutrition from ultraplankton, but not from bacteria. PMID- 29283299 TI - Chromosomal Proteins of the Sperm of a Cephalochordate (Branchiostoma floridae) and an Agnathan (Petromyzon marinus): Compositional Variability of the Nuclear Sperm Proteins of Deuterostomes. AB - We have isolated and characterized for the first time the chromosomal proteins from the nucleus of the sperm of a lancelet (amphioxus) Branchiostoma floridae (Hubbs, 1922) (Phylum Chordata: Subphylum Cephalochordata) and of a lamprey Petromyzon marinus (Linnaeus, 1758) (Phylum Chordata: Subphylum Vertebrata: Class Agnatha). In the first case, the major protein component of the sperm-chromatin of a lancelet is a highly specialized protamine-like (PL) protein that has structural and compositional features similar to those of PL-III from bivalve mollusks. In contrast, the chromatin of the sperm of the lamprey has a structural arrangement and protein composition (histones) very similar to that found in the somatic cells of all eukaryotic organisms. Among the deuterostomes, chromosomal protein variability is considerably greater in representatives of the Phylum Chordata than in echinoderms. The possible evolutionary significance of these findings is discussed. PMID- 29283300 TI - Occurrence and Distribution of RFamide-Positive Neurons Within the Polyps of Coryne sp. (Hydrozoa, Corynidae). AB - The neuronal network of the hydrozoan polyp Coryne sp. contains RFamide-positive neurons. Within the body column, these neurons are centralized in a basal ring and a distal field of ganglionic cells surrounding the peristome. The capitate tentacles are traversed by thick RFamide-positive neurites. Their pericarya are centralized in the knobby heads of the tentacles, forming a brightly fluorescing plaque after immunolabeling with an antibody against the RFamide sequence. Numerous dendrite-like extensions project from these cells towards the cell bodies of the nematocytes. The possible role of these dendrites in communication between adjacent nematocytes is discussed. PMID- 29283301 TI - Quantitative Branching Geometry of the Vascular System of the Blue Crab, Callinectes sapidus (Arthropoda, Crustacea): A Test of Murray's Law in an Open Circulatory System. AB - Murray's law predicts that there will be a radius-cubed relationship between the parent and daughter vessels of a branching system of vessels that carry the flow of a fluid, a relationship that theoretically minimizes the costs of building, maintaining, and operating the system. The vascular system of the blue crab, Callinectes sapidus, was replicated by corrosion casting at physiological pressures; vessel diameters were measured off the casts and used to calculate a junction exponent for each branch point. This study is the first quantitative description of the vascular branching geometry in an open circulatory system. The mean value derived from the arctan-transformed junction exponent distribution, 3.020, was not significantly different from the value of 3 predicted by Murray's law. The phylogenetic distance of arthropods from the animals previously studied in this context, sponges and mammals, is evidence for three independent evolutions of this branching relationship in biological fluid transport systems. PMID- 29283302 TI - In Situ Spawning of Hydrothermal Vent Tubeworms (Riftia pachyptila). AB - Riftia pachyptila, the giant vestimentiferan tubeworm, dominates the biomass of many hydrothermal vent sites in the Gulf of California (Guaymas Basin) and on the East Pacific Rise and Galapagos Spreading Center (1). The worms typically occur in large clumps or thickets as mixed populations of males andfemales. On a dive series made by the submersible Alvin in the vicinity of 9{deg}50'N on the East Pacific Rise, I observed spawning tubeworms while I was sampling associated fauna. This note presents a brief account of the spawning activity. PMID- 29283303 TI - Regional Differences in Methyl Farnesoate Production by the Lobster Mandibular Organ. AB - Visual examination of the mandibular organ (MO) from the lobster, Homarus americanus, disclosed two distinct morphological regions: a fan-folded region along one edge of the gland, and a smooth, unfolded region comprising the rest of the gland. Because MOs produce methyl farnesoate (MF), the MF content of both regions was measured. In freshly dissected glands, more than 95% of the MF was found in the fan-folded region of the gland. In MO sections incubated with [3H methyl]methionine (a radiolabeled precursor of MF), more than 90% of MF synthesis was found in the fan-folded region. Eyestalk ablation, a procedure that increases MO activity, caused the MF content of MOs to increase more than 130-fold, but had little effect on the regional distribution of MF. Histological observations indicated that these two regions had different cellular compositions. The fan folded region contained two cell types (A and B). The A cells were mitotically active and appeared to be undifferentiated. The B cells contained a large number of small vacuoles. The unfolded region was largely composed of a third cell type (C). The C cells were large and morphologically complex, containing many mitochondria and large vacuolar-like structures. They contained relatively few small vacuoles. On the basis of appearance and location, B cells appear to be the likely site of MF synthesis. The physiological importance of C cells is unknown. PMID- 29283304 TI - Sperm Diffusion Models and In Situ Confirmation of Long-Distance Fertilization in the Free-Spawning Asteroid Acanthaster planci. AB - This study was undertaken to compare fertilization rates of the sea star Acanthaster planci that were predicted using sperm diffusion models with those that were determined under natural conditions in the field. During experimentally induced spawnings, measured fertilization rates for broadcast eggs were high. More than 70% of the eggs were fertilized at distances as great as 8 m downstream from a single spawning male starfish, and more than 20% were fertilized at separations of more than 60 m. Fertilization was still measurable, at 5.8%, 100 m downstream. Lateral diffusion of sperm away from the axis of flow produced fertilization rates of 13.8% at 8 m normal to the flow and 32 m downstream. The large volumes of sperm released by male A. planci are the primary cause of high rates of fertilization for eggs derived from widely spaced individuals. Models of sperm diffusion using high sperm release rates such as those found in this starfish accurately confirmed the fertilization rates measured in situ for two populations of A. planci with widely differing rates of sperm release. We observed some changes in starfish density and degree of aggregation in the study population for spawning periods during two spawning seasons, though these were not striking. High levels of aggregation may not be necessary for fertilization success in this starfish, due to the potential for long-distance fertilization and the probability that, for any spawning starfish, the total number of zygotes formed will be greater at some distance from the point of spawning. Although fertilization rates in areas distant from the sperm source were relatively low, the total area for potential gamete encounters is much greater and may make a large contribution to net fertilization. We predict that other behaviors, such as migration to shallow water, commonly associated with spawning in A. planci and other marine invertebrates will have measurable impacts on fertilization success. The potential for high levels of fertilization in A. planci was realized during natural spawnings. Fertilization rates as high as 99% were recorded when levels of spawning synchrony were high. PMID- 29283305 TI - Ontogeny of Osmoregulatory Structures in the Shrimp Penaeus japonicus (Crustacea, Decapoda). AB - The ontogeny of differentiated osmoregulatory epithelia in the branchial chamber (gills, branchiostegite, pleura, epipodite) was studied by transmission electron microscopy throughout the postembryonic development of Penaeus japonicus. These epithelia are characterized by typical cytological features, including apical microvilli and numerous basal infoldings associated with mitochondria. Differentiated osmoregulatory structures are not observed in the early larval stages: nauplii and zoea 1. In the next larval stages, zoeas and mysis, gills and epipodites are developed as buds only, but osmoregulatory epithelia are observed in the branchiostegites and pleurae. The differentiated structures of the branchiostegites and pleurae are still present in postlarvae but disappear in juveniles and adults. Gills and epipodites develop progressively in the postlarval stages, with early differentiation of osmoregulatory epithelia in the epipodites. In juveniles and adults, the gill epithelium is poorly differentiated; in contrast, abundant differentiated osmoregulatory structures are observed in the epipodites. Ontogenetical comparisons of these observations with previous studies in the same species reveal strong correlations between the development of osmoregulatory epithelia, the ability to osmoregulate, the activity of Na+-K+ ATPase, and salinity tolerance during the postembryonic development of Penaeus japonicus. PMID- 29283306 TI - Circadian PER2 protein oscillations do not persist in cycloheximide-treated mouse embryonic fibroblasts in culture. AB - It is not known whether the endogenous mammalian core clock proteins sustain measurable oscillations in cells in culture where de novo translation is pharmacologically inhibited. We studied here the mammalian core clock protein PER2, which undergoes robust circadian oscillations in both abundance and phosphorylation. With a newly developed antibody that enables tracing the endogenous PER2 protein oscillations over circadian cycles with cultured mouse embryonic fibroblast cells, we provide evidence that PER2 does not persist noticeable circadian rhythms when translation is inhibited. PMID- 29283307 TI - Using the California Verbal Learning Test, Second Edition as an embedded performance validity measure among individuals with TBI and individuals with psychiatric disorders. AB - OBJECTIVE: Among embedded performance validity tests (PVTs), little research addresses the use of Total Hits and Total False Positives from the California Verbal Learning Test, Second Edition (CVLT-II) in spite of low sensitivity, particularly in psychiatric samples. METHOD: This study examined the classification accuracy of these two measures in individuals with psychiatric disorders or mild traumatic brain injury (MTBI). These samples were separated into two groups using the criteria of passing all PVTs versus failing 2 or more PVTs. They were also compared to a criterion group of moderate to severe traumatic brain injury (M-STBI) patients who passed all PVTs. The sample included 176 individuals consecutively referred for neuropsychological testing (mean age = 46.31, SD = 15.30; mean education = 13.07, SD = 2.50, 52.3% males; 91.2% Caucasian) who met study criteria. RESULTS: For classification accuracy, Total Hits in the psychiatric group had excellent classification accuracy (Area Under the Curve [AUC] = .82; Sensitivity = .47; Specificity = .90), whereas Total False Positives (AUC = .49) demonstrated poor classification accuracy. The MTBI group had similar results, with Total Hits having excellent classification accuracy (AUC = .88; Sensitivity = .60; Specificity = .90), whereas Total False Positive (AUC = .62) did not. CONCLUSIONS: Results provide preliminary support for using Total Hits; however, Total False Positives were ineffective in identifying non credible patients with psychiatric disorders or MTBI. Total Hits also compared favorably to other embedded CVLT measures. PMID- 29283308 TI - Normal values for calprotectin in stool samples of infants from the population based longitudinal born into life study. AB - Faecal calprotectin is a protein used as a diagnostic marker for inflammatory bowel diseases. We determined upper limits for normal calprotectin values for neonatal, 6, 12 and 24 months old children using a turbidimetric immunoassay in a cohort of Swedish children. The advantage of the method is that opposite to previously used enzyme-linked immunosorbent assay (ELISA) method, it enables measuring single samples, and thus, shortens the analysis time significantly. There were 72 samples (41.7% female) collected neonatally, 63 samples (34.9% female) at 6 months, 60 samples (40.0% female) at 12 months and 51 samples (43.1% female) at 24 months. The upper limits for normal values were 233, 615, 136 and 57 ug mg-1 for infants aged 0, 6, 12 and 24 months, respectively. PMID- 29283309 TI - Circadian variations in the clinical presentation of headaches among migraineurs: A study using a smartphone headache diary. AB - : Migraines occur within certain time frames. Nevertheless, information regarding circadian variation in the clinical presentation of migraine is limited. We investigated circadian variations in the clinical presentation of migraine using a smartphone headache diary (SHD). We enrolled adult participants with the diagnosis of migraine according to the third beta edition of the International Classification of Headache Disorders. Participants were asked to log in to the SHD every day for 90 days to record the occurrence of headaches. We compared the occurrence and clinical presentation of headaches during four 6-hour quadrants per day (00:00-05:59, 06:00-11:59, 12:00-17:59, and 18:00-23:59). Migraine-type headache was defined as a headache attack that fulfilled all criteria of migraine, except for the criterion regarding typical headache duration. Eighty two participants kept a dairy for at least 50% of the study period and recorded 1491 headache attacks. Among the 1491 headache attacks, 474 (31.8%) were classified as migraine-type headaches and 1017 (68.2%) were classified as non migraine-type headaches. All headaches, migraine-type headaches and non-migraine type headaches occurred most frequently between 06:00 and 11:59, and least frequently between 18:00 and 23:59, and between 00:00 and 05:59. Migrainous headache characteristics, such as unilateral pain, pulsating quality, severe headache intensity, aggravation by movement, nausea, photophobia, and phonophobia presented most frequently between 06:00 and 11:59, and least frequently between 18:00 and 23:59, and 00:00 and 05:59 among 1491 all headache attacks. Headache clinical presentation as well as headache occurrence exhibited circadian periodicity among migraineurs. ABBREVIATIONS: SHD: smartphone headache diary; ICHD-3 beta: the third edition beta version of the International Classification of Headache Disorders. PMID- 29283310 TI - Mixture-based gatekeeping procedures in adaptive clinical trials. AB - Clinical trials with data-driven decision rules often pursue multiple clinical objectives such as the evaluation of several endpoints or several doses of an experimental treatment. These complex analysis strategies give rise to "multivariate" multiplicity problems with several components or sources of multiplicity. A general framework for defining gatekeeping procedures in clinical trials with adaptive multistage designs is proposed in this paper. The mixture method is applied to build a gatekeeping procedure at each stage and inferences at each decision point (interim or final analysis) are performed using the combination function approach. An advantage of utilizing the mixture method is that it enables powerful gatekeeping procedures applicable to a broad class of settings with complex logical relationships among the hypotheses of interest. Further, the combination function approach supports flexible data-driven decisions such as a decision to increase the sample size or remove a treatment arm. The paper concludes with a clinical trial example that illustrates the methodology by applying it to develop an adaptive two-stage design with a mixture based gatekeeping procedure. PMID- 29283311 TI - snoRNAs associate with mRNA 3' processing complex: New wine in old bottles. AB - 3' end processing is required for the maturation of all eukaryotic RNAs. Current model suggests that canonical mRNA 3' processing is carried out exclusively within a protein complex termed mRNA 3' processing complex. In a recent study, by using RNA-biotin based pull-down assay and high-throughput sequencing, we reported that a subset of small nucleolar RNAs (snoRNAs) were physically associated with this macromolecular machinery. Through detailed characterization of one of these snoRNAs, SNORD50A, we revealed that non-coding RNA, such as snoRNA, may play a regulatory role in mRNA 3' processing. Our results provided novel insight into both the regulatory mechanism of mRNA 3' processing and the non-canonical functions of snoRNAs. PMID- 29283312 TI - Humiliated fury is not universal: the co-occurrence of anger and shame in the United States and Japan. AB - : It has been widely believed that individuals transform high-intensity shame into anger because shame is unbearably painful. This phenomenon was first coined "humiliated fury," and it has since received empirical support. The current research tests the novel hypothesis that shame-related anger is not universal, yet hinges on the cultural meanings of anger and shame. Two studies compared the occurrence of shame-related anger in North American cultural contexts (where shame is devalued and anger is valued) to its occurrence in Japanese contexts (where shame is valued and anger is devalued). In a daily-diary study, participants rated anger and shame feelings during shame situations that occurred over one week. In a vignette study, participants rated anger and shame in response to standardised shame vignettes that were generated in previous research by either U.S. or Japanese respondents. Across the two studies, and in line with previous research on humiliated fury, shame predicted anger for U.S. PARTICIPANTS: Yet, neither in the daily diary study nor for the Japanese-origin vignettes, did we find shame-related anger in Japanese participants. Only when presented with U.S.-origin vignettes, did Japanese respondents in the vignette study report shame-related anger. The findings suggest that shame-related anger is a culture-specific phenomenon. PMID- 29283315 TI - Comparison of central hemodynamic parameters for young basketball athletes and control group. AB - BACKGROUND: Long-term exercise training may have negative effects on cardiovascular functions. Measurement and calculation of central hemodynamic parameters can comprehensively evaluate the cardiovascular functions. This study aims to compare the central hemodynamics between young basketball athletes and matched controls. METHODS: Total 19 young long-term trained male basketball athletes and 17 matched male recreationally active controls participated. The central hemodynamic parameters such as central blood pressure, pulse pressure, heart rate (HR), augmentation index normalised to 75 bpm (AIx@HR75), augmentation index (AIx), ejection duration (ED), sub-endocardial viability ratio (SEVR) were measured, and total peripheral resistance (TPR), stroke volume (SV) and cardiac output (CO) were calculated. Non-parameter tests and t-test were used to analyse the central hemodynamic parameters between athletes and controls. RESULTS: HR (56 +/- 5 bpm versus 79 +/- 9 bpm, p < .001), AIx@HR75 (-8 +/- 10% versus -1 +/- 10%, p < .05), ED (28 +/- 2% versus 36 +/- 3%, p < .001) and TPR (0.004 +/- 0.006 mmHg s/mL versus 0.012 +/- 0.006 mmHg s/mL, p < .001) were significantly lower in basketball athletes compared to the controls. SEVR (231 +/- 32% versus 159 +/- 21%, p < .001) and SV (154 +/- 50 mL versus 101 +/- 43 mL, p < .01) were significantly higher in basketball athletes than those in the controls. However, there were no significant differences in central blood pressure, pulse pressure, AIx and CO between them. CONCLUSIONS: There is no negative effect on central hemodynamics in young basketball athletes after long-term exercise training. The young basketball athletes have a higher myocardial perfusion, higher efficiency of blood supply, stronger vascular functions and better balance of myocardial oxygen of supply and demand than the controls in this central hemodynamic parameters analysis. PMID- 29283314 TI - Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke. AB - The current study focuses on the ability to improve cognitive function after stroke with interventions administered at delayed/chronic time points. In light of recent studies demonstrating delayed GABA antagonists improve motor function, we utilized electrophysiology, biochemistry and neurobehavioral methods to investigate the role of alpha5 GABAA receptors on hippocampal plasticity and functional recovery following ischemic stroke. Male C57Bl/6 mice were exposed to 45 min transient middle cerebral artery occlusion and analysis of synaptic and functional deficits performed 7 or 30 days after recovery. Our findings indicate that hippocampal long-term potentiation (LTP) is impaired 7 days after stroke and remain impaired for at least 30 days. We demonstrate that ex vivo administration of L655,708 reversed ischemia-induced plasticity deficits and importantly, in vivo administration at delayed time-points reversed stroke-induced memory deficits. Western blot analysis of hippocampal tissue reveals proteins responsible for GABA synthesis are upregulated (GAD65/67 and MAOB), increasing GABA in hippocampal interneurons 30 days after stroke. Thus, our data indicate that both synaptic plasticity and memory impairments observed after stroke are caused by excessive tonic GABA activity, making inhibition of specific GABA activity at delayed timepoints a potential therapeutic approach to improve functional recovery and reverse cognitive impairments after stroke. PMID- 29283313 TI - Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation. AB - The expression patterns of endogenous circular RNA (circRNA) molecules during epidermal stem cell (EpSC) differentiation have not previously been explored. Here, we show that circRNAs are abundantly expressed in EpSCs and that their expression change dramatically during differentiation in a coordinated manner. Overall, circRNAs are expressed at higher levels in the differentiated cells, and many upregulated circRNAs are derived from developmental genes, including four different circRNAs from DLG1. The observed changes in circRNA expression were largely independent of host gene expression, and circRNAs independently upregulated upon differentiation are more prone to AGO2 binding and have more predicted miRNA binding sites compared to stably expressed circRNAs. In particular, upregulated circRNAs from the HECTD1 and ZNF91 genes have exceptionally high numbers of AGO2 binding sites and predicted miRNA target sites, and circZNF91 contains 24 target sites for miR-23b-3p, which is known to play important roles in keratinocyte differentiation. We also observed that upregulated circRNAs are less likely to be flanked by homologues inverted Alu repeats compared to stably expressed circRNAs. This coincide with DHX9 being upregulated in the differentiated keratinocytes. Finally, none of the circRNAs upregulated upon differentiation were also upregulated upon DNMT3A or DNMT3B knockdown, making it unlikely that epigenetic mechanisms are governing the observed circRNA expression changes. Together, we provide a map of circRNA expression in EpSCs and their differentiated counterparts and shed light on potential function and regulation of differentially expressed circRNAs. PMID- 29283316 TI - Influence of facial hair length, coarseness, and areal density on seal leakage of a tight-fitting half-face respirator. AB - BACKGROUND: OSHA regulations state that an employer shall not permit tight fitting respirators to be worn by employees who have facial hair that comes between the skin and facepiece seal. Studies have shown that facial hair in the face seal zone can increase penetration and decrease the fit factor (FF), although the relationship between the amount and characteristics of facial hair and the increase in penetration is not well quantified. This article examines the influence of facial hair length, areal density, and coarseness on FF for one model of half-face elastomeric negative-pressure air purifying respirator. APPROACH: Quantitative fit tests (QNFT) were performed on 19 subjects with beards initially 0.500-in long and subsequently trimmed to 0.250, 0.125, and 0.063 in, then after a razor shave. Three fit tests were performed at each of the 5 lengths, for 285 total tests. The average diameter and areal density of cheek and chin hair were measured. Penetration was modeled as a function of hair length category, beard areal density, and hair coarseness. RESULTS: FF decreased with beard length, especially beyond 0.125 in. However, passing FF scores were achieved on all tests by all subjects at the smooth shave and 0.063 in conditions, and 98% of tests were passed at 0.125 in; seven subjects passed all tests at all conditions. Chin and cheek areal densities were significantly different and were only weakly correlated. Beard hair diameters were normally distributed across subjects (mean 76 um, standard deviation 7.4 um). Beard length and areal density, but not coarseness, were statistically significant predictors of fit using an arcsine transformed penetration model. FF decreased with increasing beard length, especially beyond 0.125 in, although FF with a "stubble" beard did not differ significantly from a smooth shave. FF also decreased with increasing areal beard hair density. CONCLUSION: Beard length and areal density negatively influence FF. However, tight-fitting half-face negative-pressure respirator fit tests can achieve adequate fit factor scores even with substantial facial hair in the face seal area. PMID- 29283317 TI - Quinoline's influence on nitrogen removal performance and microbial community composition of the anammox process. AB - This study aimed to evaluate the effects of quinoline on nitrogen removal performance and microbial community of an anaerobic biofilm reactor with anammox activity. Results showed that 20 mg L-1 quinoline addition leading the ammonia and nitrite removal efficiency of the ABR reduced from about 90% to 40%. Illumina MiSeq sequencing study indicated that microbial community structure and composition varied with the additive of quinoline. Planctomycetes and Bacteroidetes, decreased in abundance, suggested that quinoline adversely affects the anammox metabolism within the anammox reactor. The distribution of the anammox bacteria was affected by quinoline addition. Ca. Jettenia prevailed over the other two anammox bacteria (Brodica and Kuenenia) in the recovered phase. PMID- 29283318 TI - Surgical smoke control with local exhaust ventilation: Experimental study. AB - This experimental study aimed to evaluate airborne particulates and volatile organic compounds (VOCs) from surgical smoke when a local exhaust ventilation (LEV) system is in place. Surgical smoke was generated from human tissue in an unoccupied operating room using an electrocautery surgical device for 15 min with 3 different test settings: (1) without LEV control; (2) control with a wall irrigation suction unit with an in-line ultra-low penetration air filter; and (3) control with a smoke evacuation system. Flow rate of LEVs was approximately 35 L/min and suction was maintained within 5 cm of electrocautery interaction site. A total of 6 experiments were conducted. Particle number and mass concentrations were measured using direct reading instruments including a condensation particle counter (CPC), a light-scattering laser photometer (DustTrak DRX), a scanning mobility particle sizer (SMPS), an aerodynamic particle sizer (APS), and a viable particle counter. Selected VOCs were collected using evacuated canisters using grab, personal and area sampling techniques. The largest average particle and VOCs concentrations were found in the absence of LEV control followed by LEV controls. Average ratios of LEV controls to without LEV control ranged 0.24-0.33 (CPC), 0.28-0.39 (SMPS), 0.14-0.31 (DustTrak DRX), and 0.26-0.55 (APS). Ethanol and isopropyl alcohol were dominant in the canister samples. Acetaldehyde, acetone, acetonitrile, benzene, hexane, styrene, and toluene were detected but at lower concentrations (<500 MUg/m3) and concentrations of the VOCs were much less than the National Institute for Occupational Safety and Health recommended exposure limit values. Utilization of the LEVs for surgical smoke control can significantly reduce but not completely eliminate airborne particles and VOCs. PMID- 29283319 TI - Highly efficient removal of hazardous aromatic pollutants by micro-nano spherical carbons synthesized from different chemical activation methods: a comparison study. AB - Glucose-derived micro-nano spherical activated carbon (GAC) was synthesized through two-stage and three-stage chemical activation processes in different impregnation ratios (K2CO3: precursor). GAC was characterized by nitrogen adsorption/desorption isotherm, point of zero charge, scanning electron microscope, and Fourier transform infrared. The prepared spherical GAC and commercial non-spherical AC were applied to remove a cationic dye (methylene green 5; MG5), an anionic dye (acid red 1; AR1), and phenol. The batch adsorption experiments were conducted to analyse the effects of different operation conditions (i.e. solution pH, contact time, initial adsorbate concentration, temperature, and desorbing agent) on the adsorption process. The adsorption equilibrium was rapidly reached in kinetic experiments with a removal rate of 47 83% (within 1 min). The three-stage process-synthesized GAC exhibited the highest adsorption capacity, with the maximum adsorption capacity reaching at 1365 mg/g for MG5, 562 mg/g for AR1, and 322 mg/g for phenol adsorption. The process of MG5 and AR1 adsorption was endothermic (+DeltaH degrees ), while phenol adsorption was exothermic (-DeltaH degrees ). The primary adsorption mechanism was pore filling and pi-pi interactions. The pore of spherical GAC might be easily enlarged than that of non-spherical AC when the temperature of solution increased. Therefore, the spherical activated carbon can server as a green promising and renewable adsorbent for efficiently remove hazardous aromatic pollutants from aquatic environment. PMID- 29283320 TI - Firefighter attitudes, norms, beliefs, barriers, and behaviors toward post-fire decontamination processes in an era of increased cancer risk. AB - Firefighters are exposed to carcinogens such as volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) during fires and from their personal protective equipment (PPE). Recent research has shown that decontamination processes can reduce contamination on both gear and skin. While firefighter cultures that honor dirty gear are changing, little is known about current attitudes and behaviors toward decontamination in the fire service. Four hundred eighty-five firefighters from four departments completed surveys about their attitudes, beliefs, perceived norms, barriers, and behaviors toward post-fire decontamination processes. Overall, firefighters reported positive attitudes, beliefs, and perceived norms about decontamination, but showering after a fire was the only decontamination process that occurred regularly, with field decontamination, use of cleansing wipes, routine gear cleaning, and other behaviors all occurring less frequently. Firefighters reported time and concerns over wet gear as barriers to decontamination. PMID- 29283321 TI - Resuspension of house dust and allergens during walking and vacuum cleaning. AB - Conventional wisdom has been that hard, resilient surfaces resuspend fewer particles than carpeted surfaces, however, exceptions to this have been demonstrated and uncertainty remains about the factors that lead to this resuspension, notably, the effect of vacuum cleaning on either increasing or reducing resuspension from flooring. The purpose of this study was to determine how resuspension of house dust by aerodynamic size or particle type, including cat allergen and bacterial endotoxin, is affected by flooring, dust loading, embedding dust, and walking/cleaning activities. House dust was blown in and allowed to settle in a walk-in chamber after overnight deposition followed by walking or a vacuum cleaning procedure. Using an aerosol particle sizer and large volume air samplers at different heights in the chamber, concentrations of airborne particles, resuspension rates, and fractions were computed for four types of flooring conditions during six walking activities. Carpeting resulted in significantly more airborne cat allergen and airborne endotoxin than a laminate floor. Height does have an effect on measured allergen over carpet and this is apparent with concentrations at the infant and adult air samplers. Walking on laminate flooring resuspends less house dust than walking on an equally dusty carpeted floor, where dust is entirely on the surface of the carpet. However, vacuum cleaning a laminate floor resuspended more dust than vacuum cleaning carpets, at large particle sizes of 5 um and 10 um. Activities following a deep cleaning of hard resilient or a carpeted surface is likely to leave no differences in resuspended particles between them. PMID- 29283322 TI - Optimal river monitoring network using optimal partition analysis: a case study of Hun River, Northeast China. AB - River monitoring networks play an important role in water environmental management and assessment, and it is critical to develop an appropriate method to optimize the monitoring network. In this study, an effective method was proposed based on the attainment rate of National Grade III water quality, optimal partition analysis and Euclidean distance, and Hun River was taken as a method validation case. There were 7 sampling sites in the monitoring network of the Hun River, and 17 monitoring items were analyzed once a month during January 2009 to December 2010. The results showed that the main monitoring items in the surface water of Hun River were ammonia nitrogen (NH4+-N), chemical oxygen demand, and biochemical oxygen demand. After optimization, the required number of monitoring sites was reduced from seven to three, and 57% of the cost was saved. In addition, there were no significant differences between non-optimized and optimized monitoring networks, and the optimized monitoring networks could correctly represent the original monitoring network. The duplicate setting degree of monitoring sites decreased after optimization, and the rationality of the monitoring network was improved. Therefore, the optimal method was identified as feasible, efficient, and economic. PMID- 29283323 TI - Phage Therapy against Streptococcus pneumoniae: Modern Tool to Control Pneumonia. AB - Phage therapy is important for treatment of drug-resistant pathogens as compared to antibiotics in this modern era. Since 1966, bacteriophages have been used as antibacterial agents and played a very crucial role in the expansion of molecular biology. Bacteriophages have been used to treat infection in Western medicine along with antibiotics. Antibacterial agents against the antibiotic resistance strains have been discovered. The lytic bacteriophage used for treatment in conventional phage therapy have shown hopeful results in human clinical cases. In animal models and in vitro studies, phages are used as therapeutics. Bacterial pathogens decreased with use of dual therapy of antibiotics and phages. Variation in intracellular targets of the type II DNA topoisomerases acquired by recombination with the fluoroquinolones have shown resistance. This review summarizes the role of Streptococcus pneumoniae in phage therapy. The study condenses the biochemical and structural data described for Streptococcus. pneumoniae biofilms. PMID- 29283324 TI - Association between HIF1alpha 1772 C/T Polymorphism and Breast Cancer Susceptibility: A Systematic Review. AB - Studies have reached conflicting conclusions about the association of the 1772 C/T polymorphism in the hypoxia-inducible factor 1alpha (HIF1alpha) gene with breast cancer risk. To address this, we performed a meta-analysis of relevant studies in the included literature. Data were collected from the electronic databases PubMed and EMBase. The association was assessed by determination of the odds ratio (OR) and the corresponding 95% confidence interval (95% CI). A total of seven articles involving 2343 cases and 2246 controls were analyzed in our meta-analysis. Overall, we found no significant association between the HIF1alpha C1772T polymorphism and breast cancer (TT vs. CC: OR = 1.33, 95% CI = 0.49-3.63; CT vs. CC: OR = 1.07, 95% CI = 0.90-1.27; dominant model: OR = 1.10, 95% CI = 0.93-1.30; recessive model: OR = 1.32, 95% CI = 0.50-3.49). In stratified analysis by ethnic group, a statistically significant association was observed in Asians. Our findings demonstrated that the 1772 C/T polymorphism in the HIF1alpha gene might be a risk factor for the development of breast cancer in Asians. PMID- 29283325 TI - Emerging Trends in Non-Interferon-Based Genotype-Specific Antiviral Agents: Pharmaceutical Perspectives. AB - Hepatitis C virus (HCV) presents a serious global health threat. Initially, the health-care community mainly focused on interferon (IFN)-based therapeutic options to eradicate HCV, but with the passage of time, these applications became unsuitable due to some serious side effects related to the use of IFN. In recent years, research conducted on different phases of HCV's life cycle has opened a new gateway for the use of a direct-acting new generation of anti-HCV agents. Their safer and ultrarapid response has made possible the introduction of triple therapy and use of IFN-free therapeutic treatment strategies. However, the high cost of these successful therapies has raised serious concerns, particularly in low-income countries, and this has forced pharmaceutical scientists to explore more cost-effective IFN-free alternatives for the treatment of HCV. In this article, we have briefly summarized the latest data regarding the research and development of non-IFN-based antiviral agents. The studies mentioned in this article highlight the significance of non-IFN-based direct-acting antiviral (DAA) agents. Economical alternative anti-HCV agents are expected to become available in the near future for better and more cost-effective treatments of HCV. PMID- 29283326 TI - Sirtuins in Brain Aging and Neurological Disorders. AB - The many ways of aging have been and continue to be investigated. For this reason, over many years, several studies have resolved some of the genetic details underlying aging processes. It resulted in the identification of a yeast gene known as Sir2, which is a longevity modulator. Sir2 and SIRT1 are the mammalian homologs of yeast genes. Sirtuins (including SIRT1) play an important role in aging of the brain and the metabolic regulation pathway in mammals. Aging in the brain is caused by the loss of neurophysiologic functions due to neurodegeneration. The sirtuin family plays a central role in the beneficial effects of calorie restriction (CR). CR is linked with an increase in life span and decrease in the risk of diseases related to the brain. Sirtuins may be helpful for us in studying the process of aging and treatment of diseases related with aging. PMID- 29283327 TI - Genetically Modified Aedes aegypti to Control Dengue: A Review. AB - Dengue is an acute infectious disease of viral etiology characterized by lymphadenopathy, leucopenia, headache, biphasic fever, pain in various parts of the body, rashes, and extreme physical weakness. It is a vector-borne disease caused by a positive-stranded RNA virus of the family Flaviviridae, genus Flavivirus. Dengue inflicts a significant health, economic, and social burden on populations of endemic areas. Dengue virus is transmitted to humans by the mosquito vector Aedes aegypti. Vaccines against dengue viruses have been claimed to be developed, but as yet no effective treatment is available. Alternative therapeutic strategies to overcome this disease and its spread are direly needed. A traditional sterile insect technique (SIT) harms the health of male insects, leading to their reduced ability to compete for wild-type female insects for breeding. Oxitec (Abingdon, UK) has developed genetically modified (GM) strains of A. aegypti via the release of insects carrying a dominant lethal (RIDL) strategy. RIDL male mosquitoes offer a resolution to many of the limitations of traditional SIT, which has resulted in reduced application of SIT in mosquitoes. The technique using RIDL mosquitoes is considered to be ecologically friendly and specific. Homing endonuclease genes, also called selfish genes, can also be used in genetic modification methods in such a way that the vector population and its competency can be reduced. GM mosquitoes carrying a gene that transcribes RNA interference can also be crucial to control expression of RNA viruses. The RNA virus interference pathway is one of the most critical components of the innate immune system of insects that can frustrate a variety of RNA viruses such as Flaviviruses. Here, we summarize and focus on alternative techniques used to control dengue spread. PMID- 29283328 TI - N-myc Downstream-Regulated Gene 1 and Endometriosis: A Minireview. AB - NDRG1 (N-myc downstream-regulated gene 1) was previously considered to be a differentiation-related gene. However, many other functions of NDRG1 have since been identified, including proliferation, migration, invasion, and vascularization of tumor cells. Currently regarded as a tumor suppressor in most studies, NDRG1 is abundant in prostate, brain, kidney, placental, and intestinal tissues. It is expressed in normal endometrium, with higher expression occurring in the secretory phase. NDRG1 was first identified as an inhibitor of signaling pathways associated with the pathology of endometriosis. The NDRG1 protein regulation of endometriosis is assumed to be associated with several important pathways. This review summarizes the relationship between NDRG1 and endometriosis, focusing on the potential function of NDRG1 in endometriosis through signaling pathways and discusses the additional research that is required for future studies. PMID- 29283329 TI - Association between the Epithelial Cadherin - 160C/A Polymorphism and Colorectal Cancer Risk: Evidence from a Meta-Analysis. AB - The aim of the present study was to assess the association between the epithelial cadherin (CDH1) -160C/A polymorphism and colorectal cancer (CRC) using a meta analysis. A literature search of PubMed, Embase, and Web of Science databases was performed for relevant studies. Statistical analyses were carried out using Stata 12.0 to combine all of the relevant studies. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. Eight studies with 7231 cases and 7080 controls were included. The meta-analysis results showed that the CDH1 -160C/A polymorphism was significantly associated with CRC risk (AA vs. CC: OR = 0.98, 95% CI = 0.71-1.36; CA vs. CC: OR = 0.92, 95% CI = 0.86-0.99; dominant model: OR = 1.01, 95% CI = 0.81-1.26; recessive model: OR = 0.91, 95% CI = 0.81-1.02). In the subgroup analysis based on ethnicity, significant association was found between the CDH1 -160C > A polymorphism and CRC risk in Caucasians. In conclusion, the CDH1 -160C/A polymorphism may be a susceptible predictor for the risk of CRC in Caucasians. PMID- 29283330 TI - miRNA in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Approaches. AB - Hepatocellular carcinoma (HCC) is a worldwide disease. Because therapeutic measures are ineffective, HCC currently has a poor prognosis. The main causes of HCCs are alcoholism, hepatitis, and metabolic syndrome. Normally hygieinic studies revealed that there is lower survival rate of HCC. MicroRNAs (miRNAs) consist of short noncoding sequences of RNA (20 to 24 nucleotides), which posttranscriptionally regulate the expression of the protein coding genes. MicroRNAs have been proposed to be prospective therapeutic molecules and targets. For testing miRNA-based therapies, HCC is a remarkable model because it may be targeted by delivery of oligonucleotides. Current studies show a beginning for analyzing the therapeutic prospects of miRNAs or anti-miRNAs. Generally, antitumor activity of miRNAs has been observed. PMID- 29283331 TI - Mechanism of Hepatitis C Virus-Induced Diabetes Mellitus. AB - The hepatitis C virus (HCV), the most predominant cause of liver failure worldwide, is associated with the development of diabetes mellitus (DM) and insulin resistance (IR), both in vivo and in vitro. DM and IR aggravate the rate of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most studies have revealed that patients with HCV are at a greater risk of developing type 2 diabetes (T2D), compared with controls or patients with hepatitis B. In the same way, patients with T2D are highly prone to severe HCV clinical outcomes and increased progression to fibrosis and cirrhosis, ultimately leading to HCC. HCV interferes with the insulin-signaling pathway by modulating cellular gene expression such as up-regulation of inflammatory cytokine tumor necrosis factor alpha, hypophosphorylation of insulin receptor substrate-1 and -2, phosphorylation of protein kinase B (Akt), up-regulation of gluconeogenic genes, accumulation of lipids, and targeting of lipid storage organelles. Owing to the pathological association between HCV and DM, the possibility of HCV eradication, resulting in reduced morbidity and mortality rate due to T2D, cannot be ruled out. HCV diabetes-associated IR can be targeted for HCV therapy. However, few such studies have revealed that IR minimizes (interferes with) the response rate of interferon/ribavirin treatment. PMID- 29283332 TI - Diverse Signaling Pathways and Current Status of Molecular Targeted Treatments for Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of death associated with cancer. Various molecular mechanisms are involved in HCC development. Alterations in these molecular mechanisms include chromosomal instability, gene mutations, and variations in protein expressions. A number of cell signaling pathways that are associated with the occurrence of apoptosis, cell proliferation, and angiogenesis provide new prospects for the development of HCC treatments. Newly designed, potential therapeutic regimens target specific receptors, kinases, and vital proteins. Sorafenib is the only FDA-approved drug for HCC treatment, and it has been found that the complex genomic aberrations in HCC can be overcome using combination therapy. For example, therapeutic benefits have been gained using sorafenib with doxorubicin, oxaliplatin, cisplatin, and monoclonal antibodies. In addition, elumetinib, carbozantinib, and refametinib may be effective when used in combination with sorafenib. Drugs that target several signaling pathways have shown promising results in phase 3 clinical trials, and clinical studies using these drugs have changed the management strategy for HCC, particularly with the use of combination therapeutic regimens. Such research has improved the current standards of care and influenced clinical decision making. PMID- 29283333 TI - Neurosteroids and Ischemic Stroke: Progesterone a Promising Agent in Reducing the Brain Injury in Ischemic Stroke. AB - Progesterone (P4), a well-known neurosteroid, is produced by ovaries and placenta in females and by adrenal glands in both sexes. Progesterone is also synthesized by central nervous system (CNS) tissues to perform various vital neurological functions in the brain. Apart from performing crucial reproductive functions, it also plays a pivotal role in neurogenesis, regeneration, cognition, mood, inflammation, and myelination in the CNS. A substantial body of experimental evidence from animal models documents the neuroprotective role of P4 in various CNS injury models, including ischemic stroke. Extensive data have revealed that P4 elicits neuroprotection through multiple mechanisms and systems in an integrated manner to prevent neuronal and glial damage, thus reducing mortality and morbidity. Progesterone has been described as safe for use at the clinical level through different routes in several studies. Data regarding the neuroprotective role of P4 in ischemic stroke are of great interest due to their potential clinical implications. In this review, we succinctly discuss the biosynthesis of P4 and distribution of P4 receptors (PRs) in the brain. We summarize our work on the general mechanisms of P4 mediated via the modulation of different PR and neurotransmitters. Finally, we describe the neuroprotective mechanisms of P4 in ischemic stroke models and related clinical prospects. PMID- 29283334 TI - Relationship between Topoisomerase II Alpha Overexpression and Prognosis in Chinese Gastric Cancer Patients. AB - The aim of this study was to investigate topoisomerase II alpha (TOP2alpha) overexpression and its association with clinicopathological features and prognosis in gastric cancer (GC) patients. All selected GC patients at Affiliated Hospital of Qinghai University and Cancer Hospital, Chinese Academy of Medical Sciences, between December 2009 and December 2011, had formalin-fixed and paraffin-embedded tumor tissues. The patients received a telephone follow-up or in-/outpatient review, and their clinicopathological features and prognoses were analyzed. Also, the relationship between TOP2alpha expression and postoperative chemotherapy in GC patients was estimated. The results of the study showed that TOP2alpha overexpression correlated with location of tumor, depth of invasion, and pTNM stage. Moreover, it was associated with lower 5-year overall survival (OS) in noncardia GC patients younger than 60 years, with multivariate analysis demonstrating that it was an independent prognostic factor for these patients. Univariate analysis and multivariate analysis showed that TOP2alpha overexpression was associated with worse 5-year OS in noncardia GC patients <= 60 years receiving postoperative chemotherapy. TOP2alpha overexpression exhibited associations with location of tumor, depth of invasion, pTNM stage, and postoperative chemotherapy, making it a potential target for early diagnosis of GC patients. In addition, TOP2alpha overexpression was shown to be a predictor of 5-year OS in both noncardia GC patients <= 60 years and noncardia GC patients <= 60 years and receiving postoperative chemotherapy. PMID- 29283335 TI - Molecular Mechanisms of UVA-Induced Melanoma. AB - Cutaneous melanoma is a deadly skin cancer, resulting from malignant transformation of melanocytes. Long-wave ultraviolet radiation (315-400 nm) is able to damage DNA, cause mutations, and induce melanoma. However, the exact mechanisms of UVA-induced cutaneous melanoma remain a matter of debate. In this review, we give a brief characterization of the most important elements in the photobiology of UVA in melanomagenesis. PMID- 29283336 TI - Photothermal Therapy Employing Gold Nanoparticle- Loaded Macrophages as Delivery Vehicles: Comparing the Efficiency of Nanoshells Versus Nanorods. AB - Macrophages (Ma) loaded with gold based nanoparticles, which convert near infrared light to heat, have been studied as targeted transport vectors for photothermal therapy (PTT) of tumors. The purpose of the experiments reported here was to compare the efficacy of gold-silica nanoshells (AuNS) and gold nanorods (AuNR) in macrophage mediated PTT. PTT efficacy was evaluated in hybrid glioma spheroids consisting of human glioma cells and either AuNS or AuNR loaded Ma, designated MaNS and MaNR respectivly. Spheroids were irradiated for 10 min. with light from an 810 nm diode laser at irradiances ranging from 0 to 28 W/cm2. PTT efficacy was determined from spheroid growth over a 14-day period. The uptake by Ma of pegylated AuNR (3.9 +/- 0.9 %) was twice that of pegylated AuNS, (7.9 +/ 0.7 %). Hybrid spheroids consisting of a 5:1 ratio of glioma cells to loaded Ma exhibited significant growth inhibition with MaNS when subjected to irradiances of 7 W/cm2 or greater. In contrast, no significant growth inhibition was observed for the MaNR hybrid spheroids at this 5:1 ratio, even at the highest irradiance investigated (28 W/cm2). Although AuNR were taken up by Ma in larger numbers then AuNS, MaNS were shown to have greater PTT efficacy compared to MaNR for equivalent numbers of loaded Ma. PMID- 29283337 TI - Oncocytic Adreno Cortical Tumors: Pathological Features of 16 Cases and Review of the Literature. AB - Oncocytic neoplasms of the adrenal gland are extremely rare tumors. These tumors differ from their nononcocytic counterparts in some respects. The aim of this study was to review and discuss the clinical, histological, and immunohistochemical features of as well as the prognosis for these rare tumors. In total, 16 cases diagnosed as adrenocortical oncocytic neoplasms between January 2011 and December 2016 were included in the study. The demographic data, gross characteristics, histological data, and immunohistochemical data (Chromogranin-A, Synaptophysin, alpha-Inhibin, Melan-A, Ki67, PHH3) were reevaluated. The follow-up data for these patients were added in January 2017. Of the 16 cases, 12 were adrenocortical adenoma, 1 was borderline adrenocortical tumor, and 3 were adrenocortical carcinoma. The tumors equally affected both genders. The tumors were not generally large. Tumor cells had pleomorphic nuclei in ten cases, but it was more obvious in one case. The mitotic figure count was low in most tumors. Atypical mitosis and necrosis were observed in three and four tumors, respectively. None of cases included sinusoidal invasion, vascular invasion, or capsular invasion. We detected the expression of at least one specific marker (e.g., Melan-A, Inhibin-alpha) of the adrenal cortex in all tumors. None of the tumors were immunoreactive for Chromogranin-A. Ki-67 proliferation index was lower than 5% in all cases except three oncocytic carcinomas. In two cases, PHH3 positivity was not seen, while it was lower than 3 of 10 high-powered fields in ten cases and higher in 4 cases. All patients were alive and disease free except for two patients with adrenocortical carcinoma. In conclusion, determining the clinical, histological, and immunohistochemical characteristics of these extremely rare tumors can provide important information for early diagnosis, treatment, and follow-up of these cases. PMID- 29283338 TI - Aqueous Extract of Smokeless Tobacco (gutkha) Deregulates Tumor Suppressor and DNA Repair Response in a Murine Model of Smokeless Tobacco Use. AB - The effect of smokeless tobacco (gutkha) was investigated by treating male and female Swiss Albino mice with an aqueous extract of smokeless tobacco (AEST). AEST was administered at a dose of 25 mg kg-1 body weight per day for different time periods (6, 12, 16, and 24 weeks), and control animals were provided only drinking water without AEST for the same period. Control and AEST-treated mice were observed for different oxidative stress parameters, nitric oxide (NO) release, and myeloperoxidase (MPO) release, and they were evaluated for alterations in tumor suppressor and DNA repair responses in the liver and spleen. Both male and female mice treated with AEST showed significant increase in lipid peroxidation, protein carbonylation, and NO and MPO release in the liver and spleen compared to age- and gender-matched controls. The significant decline in tumor suppressor p53 protein levels, likely mediated by concomitantly upregulated levels of Mdm2, was observed. We also observed a significant decline in the levels of DNA repair proteins Brca2 and Ape-1 compared to the respective controls. Thus, AEST induces oxidative stress, inflammation, and significantly lowers tumor suppressor and DNA repair responses. These factors may work in conjunction to increase the risk for certain diseases, including cancer. PMID- 29283339 TI - KAI1/CD82, Metastasis Suppressor Gene as a Therapeutic Target for Non-Small-Cell Lung Carcinoma. AB - Lung cancer is the most frequent malignancy and the leading cause of cancer related death worldwide; it is the second most common cancer, comprising 1.69 million deaths worldwide per year. Among these, 85% of lung cancers are non-small cell lung carcinoma (NSCLC). Metastasis is common in NSCLC patients and are responsible for most deaths. Kang-Ai 1 (KAI1), a tumor metastasis suppressor gene also known as Cluster of Differentiation 82 (CD82), is a member of the membrane tetraspanin protein family, which are capable of inhibiting the metastatic process in NSCLC. KAI1/CD82 suppresses metastasis via multiple mechanisms regulating inhibition of cell motility, adhesion, fusion, and proliferation. KAI1 may attenuate signaling to shut down metastatic colonization through attenuation of epidermal growth factor receptor (EGFR) signaling and inhibition of the Wnt signaling pathways. In this review, we focus on the differential expression of KAI1/CD82, a tumor metastasis suppressor gene that can inhibit cancer invasion and cell metastasis during NSCLC. The differential expression of KAI1/CD82 could prove to be of novel therapeutic significance in treating malignant tumors and in reducing their metastatic potential. PMID- 29283340 TI - Heat stress promotes longevity in budding yeast by relaxing the confinement of age-promoting factors in the mother cell. AB - Although individuals of many species inexorably age, a number of observations established that the rate of aging is modulated in response to a variety of mild stresses. Here, we investigated how heat stress promotes longevity in yeast. We show that upon growth at higher temperature, yeast cells relax the retention of DNA circles, which act as aging factors in the mother cell. The enhanced frequency at which circles redistribute to daughter cells was not due to changes of anaphase duration or nuclear shape but solely to the downregulation of the diffusion barrier in the nuclear envelope. This effect depended on the PKA and Tor1 pathways, downstream of stress-response kinase Pkc1. Inhibition of these responses restored barrier function and circle retention and abrogated the effect of heat stress on longevity. Our data indicate that redistribution of aging factors from aged cells to their progeny can be a mechanism for modulating longevity. PMID- 29283341 TI - Regulation of posterior body and epidermal morphogenesis in zebrafish by localized Yap1 and Wwtr1. AB - The vertebrate embryo undergoes a series of dramatic morphological changes as the body extends to form the complete anterior-posterior axis during the somite forming stages. The molecular mechanisms regulating these complex processes are still largely unknown. We show that the Hippo pathway transcriptional coactivators Yap1 and Wwtr1 are specifically localized to the presumptive epidermis and notochord, and play a critical and unexpected role in posterior body extension by regulating Fibronectin assembly underneath the presumptive epidermis and surrounding the notochord. We further find that Yap1 and Wwtr1, also via Fibronectin, have an essential role in the epidermal morphogenesis necessary to form the initial dorsal and ventral fins, a process previously thought to involve bending of an epithelial sheet, but which we now show involves concerted active cell movement. Our results reveal how the Hippo pathway transcriptional program, localized to two specific tissues, acts to control essential morphological events in the vertebrate embryo. PMID- 29283342 TI - Acoustic Radiation Force-Induced Creep-Recovery (ARFICR): A Noninvasive Method to Characterize Tissue Viscoelasticity. AB - Ultrasound shear wave elastography is a promising noninvasive, low cost, and clinically viable tool for liver fibrosis staging. Current shear wave imaging technologies on clinical ultrasound scanners ignore shear wave dispersion and use a single group velocity measured over the shear wave bandwidth to estimate tissue elasticity. The center frequency and bandwidth of shear waves induced by acoustic radiation force depend on the ultrasound push beam (push duration, -number, etc.) and the viscoelasticity of the medium, and therefore are different across scanners from different vendors. As a result, scanners from different vendors may give different tissue elasticity measurements within the same patient. Various methods have been proposed to evaluate shear wave dispersion to better estimate tissue viscoelasticity. A rheological model such as the Kelvin-Voigt model is typically fitted to the shear wave dispersion to solve for the elasticity and viscosity of tissue. However, these rheological models impose strong assumptions about frequency dependence of elasticity and viscosity. Here, we propose a new method called Acoustic Radiation Force Induced Creep-Recovery (ARFICR) capable of quantifying rheological model-independent measurements of elasticity and viscosity for more robust tissue health assessment. In ARFICR, the creep-recovery time signal at the focus of the push beam is used to calculate the relative elasticity and viscosity (scaled by an unknown constant) over a wide frequency range. Shear waves generated during the ARFICR measurement are also detected and used to calculate the shear wave velocity at its center frequency, which is then used to calibrate the relative elasticity and viscosity to absolute elasticity and viscosity. In this paper, finite-element method simulations and experiments in tissue mimicking phantoms are used to validate and characterize the extent of viscoelastic quantification of ARFICR. The results suggest that ARFICR can measure tissue viscoelasticity reliably. Moreover, the results showed the strong frequency dependence of viscoelastic parameters in tissue mimicking phantoms and healthy liver. PMID- 29283344 TI - Supervised Classification of the Accuracy of the Time Delay Estimation in Ultrasound Elastography. AB - The accuracy of time-delay estimation (TDE) in ultrasound elastography is usually measured by calculating the value of normalized cross correlation (NCC) at the estimated displacement. NCC value, however, could be very high at a displacement estimate with large error, a well-known problem in TDE referred to as peak hopping. Furthermore, NCC value could suffer from jitter error, which is due to electric noise and signal decorrelation. Herein, we propose a novel method to assess the accuracy of TDE by investigating the NCC profile around the estimated time-delay. We extract several features from the NCC profile, and utilize support vector machine to classify peak-hopping and jitter error. The results on simulation, phantom, and in vivo data show the significant improvement of the proposed algorithm compared to the state of the art techniques. PMID- 29283343 TI - Cardiac Lesion Mapping In Vivo Using Intracardiac Myocardial Elastography. AB - Radio frequency (RF) ablation of the myocardium is used to treat various cardiac arrhythmias. The size, spacing, and transmurality of lesions have been shown to affect the success of the ablation procedure; however, there is currently no method to directly image the size and formation of ablation lesions in real time. Intracardiac myocardial elastography (ME) has been previously used to image the decrease in cardiac strain during systole in the ablated region as a result of the lesion formation. However, the feasibility of imaging multiple lesions and identifying the presence of gaps between lesions has not yet been investigated. In this paper, RF ablation lesions ( ) were generated in the left ventricular epicardium in three anesthetized canines. Two sets of two lesions each were created in close proximity to one another with small gaps (1.5 and 4 cm), while one set of two lesions was created directly next to each other with no gap. A clinical intracardiac echocardiography system was programmed to transmit a custom diverging beam sequence at 600 Hz and used to image the ablation site before and after the induction of ablation lesions. Cumulative strains were estimated over systole using a normalized cross-correlational displacement algorithm and a least squares strain kernel. Afterward, lesions were excised and subjected to tetrazolium chloride staining. Results indicate that intracardiac ME was capable of imaging the reduction in systolic strain associated with the formation of an ablation lesion. Furthermore, lesion sets containing gaps were able to be distinguished from lesion sets created with no gaps. These results indicate that the end-systolic strain measured using intracardiac ME may be used to image the formation of lesions induced during an RF ablation procedure, in order to provide critical assessment of lesion viability during the interventional procedure. PMID- 29283345 TI - Recovery of the Complete Data Set From Focused Transmit Beams. AB - The focused transmit beam is a standard tool for clinical ultrasound scanning, concentrating energy from a number of array elements toward an imaging target. However, above and below the transmit focus, much of the energy in the beam is spread in a broadened main lobe and long off-axis tails that are ignored by conventional beamforming methods. This paper proposes a method to decompose a set of focused transmit beams into their constituent components-diverging waves from individual array elements. The recovery of this complete data set enables synthetic transmit focusing at all points in the field of view without beam shape or focal depth artifacts commonly associated with virtual source synthetic aperture beamforming. An efficient frequency-domain linear decoding implementation is introduced. The principles of the method are demonstrated both in transmit field simulations and experimental imaging. At depth, up to a 9.6-dB improvement in electronic signal-to-noise ratio and 8.9-dB improvement in contrast were observed in comparison with conventional dynamic receive beamforming. The proposed method is broadly applicable to existing scan sequences and requires only channel data for processing. PMID- 29283346 TI - Phased Array Focusing for Acoustic Wireless Power Transfer. AB - Wireless power transfer (WPT) through acoustic waves can achieve higher efficiencies than inductive coupling when the distance is above several times the transducer size. This paper demonstrates the use of ultrasonic phased arrays to focus power to receivers at arbitrary locations to increase the power transfer efficiency. Using a phased array consisting of 37 elements at a distance nearly 5 times the receiver transducer diameter, a factor of 2.6 increase in efficiency was achieved when compared to a case equivalent to a single large transducer with the same peak efficiency distance. The array has a total diameter of 7 cm, and transmits through air at 40 kHz to a 1.1-cm diameter receiver, achieving a peak overall efficiency of 4% at a distance of 5 cm. By adjusting the focal distance, the efficiency can also be maintained relatively constant at distances up to 9 cm. Numerical models were developed and shown to closely match the experimental energy transfer behavior; modeling results indicate that the efficiency can be further doubled by increasing the number of elements. For comparison, an inductive WPT system was also built with the diameters of the transmitting and receiving coils equivalent to the dimensions of the transmitting ultrasonic phased array and receiver transducer, and the acoustic WPT system achieved higher efficiencies than the inductive WPT system when the transmit-to-receive distance is above 5 cm. In addition, beam angle steering was demonstrated by using a simplified seven-element 1-D array, achieving power transfer less dependent on receiver placement. PMID- 29283347 TI - A Hybrid Boundary Element Model for Simulation and Optimization of Large Piezoelectric Micromachined Ultrasonic Transducer Arrays. AB - A hybrid boundary element model is proposed for the simulation of large piezoelectric micromachined ultrasonic transducer (PMUT) arrays in immersion. Multiphysics finite element method (FEM) simulation of a single-membrane structure is used to determine stiffness and piezoelectrically induced actuation loading of the membranes. To simulate the arrays of membranes in immersion, a boundary element method is employed, wherein membrane structures are modeled by a surface mesh that is coupled mechanically by mass, stiffness, and damping matrices, and acoustically by a mutual impedance matrix. A multilevel fast multipole algorithm speeds up computation time and reduces memory usage, enabling the simulation of thousands of membranes in a reasonable time. The model is validated with FEM for a small 3 3 matrix array for both square and circular membrane geometries. Two practical optimization examples of large PMUT arrays are demonstrated: membrane spacing of a 7 7 matrix array with circular membranes, and material choice and top electrode coverage of a 32-element linear array with 640 circular membranes. In addition, a simple analytical approach to electrode optimization based on normal mode theory is verified. PMID- 29283348 TI - Unbiased Charged Circular CMUT Microphone: Lumped-Element Modeling and Performance. AB - An energy-consistent lumped-element equivalent circuit model for charged circular capacitive micromachined ultrasonic transducer (CMUT) cell is derived and presented. It is analytically shown and experimentally verified that a series dc voltage source at the electrical terminals is sufficient to model the charging in CMUT. A model-based method for determining this potential from impedance measurements at low bias voltages is presented. The model is validated experimentally using an airborne CMUT, which resonates at 103 kHz. Impedance measurements, reception measurements at resonance and off-resonance, and the transient response of the CMUT are compared with the model predictions. PMID- 29283349 TI - Calculation of Volumetric Sound Field of Pulsed Air-Coupled Ultrasound Transducers Based on Single-Plane Measurements. AB - Quantitative and reproducible air-coupled ultrasound (ACU) testing requires characterization of the volumetric pressure fields radiated by ACU probes. In this paper, a closed-form reradiation method combining the Rayleigh-Sommerfeld integral and time-reversal acoustics is proposed, which allows calculation of both near- field and far-field based on a single-plane measurement. The method was validated for both 3-D (circular, square) and 2-D (rectangular) planar transducers in the 50-230 kHz range. The pressure fields were scanned with a calibrated microphone. The measurement window was at least four times the size of the transducer area and the grid step size was one third of the wavelength. Best results were observed by acquiring the measurement plane at near-field distance. The method accurately reproduces pulsed ultrasound waveforms and pressure distributions (RMSE <2.5% in far field and <5.5% in near field), even at the transducer radiation surface. The effects of speed of sound drifts during the scan in the pressure were negligible (RMSE <0.3%). The reradiation method clearly outperforms conventional baffled piston models. Possible applications are transducer manufacture control (imperfections at radiation surface) and calibration (on-axis pressure, side lobes, and beamwidth) together with generation of accurate source functions for quantitative nondestructive evaluation inverse problems. PMID- 29283350 TI - Backward-Mode Photoacoustic Imaging Using Illumination Through a CMUT With Improved Transparency. AB - In this paper, we describe a capacitive micromachined ultrasonic transducer (CMUT) with improved transparency for photoacoustic imaging (PAI) with backside illumination. The CMUT was fabricated on a glass substrate with indium-tin oxide bottom electrodes. The plate was a 1.5- silicon layer formed over the glass cavities by anodic bonding, with a 1- silicon nitride passivation layer on top. The fabricated device shows approximately 30%-40% transmission in the wavelength range from 700 to 800 nm and approximately 40%-60% transmission in the wavelength range from 800 to 900 nm, which correspond to the wavelength range commonly used for in vivo PAI. The center frequency of the CMUT was 3.62 MHz in air and 1.4 MHz in immersion. Two preliminary PAI experiments were performed to demonstrate the imaging capability of the fabricated device. The first imaging target was a 0.7 mm diameter pencil lead in vegetable oil as a line target with a subwavelength cross section. A 2-mm-diameter single CMUT element with an optical fiber bundle attached to its backside was linearly scanned to reconstruct a 2-D cross sectional PA image of the pencil lead. We investigated the spurious signals caused by the light absorption in the 1.5- silicon plate. For pencil lead as a strong absorber and also a strong reflector, the received echo signal due to the acoustic excitation generated by the absorption in silicon is approximately 30 dB lower than the received PA signal generated by the absorption in pencil lead at the wavelength of 830 nm. The second imaging target was a "loop-shape" polyethylene tube filled with indocyanine green solution ( ) suspended using fishing lines in a tissue-mimicking material. We formed a 3-D volumetric image of the phantom by scanning the transducer in the - and -directions. The two experimental imaging results demonstrated that CMUTs with the proposed structure are promising for PAI with backside illumination. PMID- 29283351 TI - Plastic Strain Determination With Nonlinear Ultrasonic Waves Using In Situ Integrated Piezoelectric Ultrasonic Transducers. AB - The detection of plastic deformation of metallic alloy materials with second harmonic Rayleigh ultrasonic wave is first investigated using direct-write piezoelectric ultrasonic transducers, in which piezoelectric poly(vinylidenefluoride/ trifluoroethylene) [P(VDF/TrFE)] polymer coatings and electrodes are directly deposited, processed, and patterned on the alloy to be evaluated. Rayleigh ultrasonic signals, generated by the direct-write transducers on titanium alloy specimens, are characterized by a laser scanning vibrometer. The results show that acoustic nonlinearity increases with plastic strain, and an increase of ~40% in the acoustic nonlinearity corresponding to a plastic strain of 5.1%. The measurement data and technical features with the use of the direct write transducers are compared with the conventional discrete angle beam piezoelectric transducer. The results and analyses show that compared with the conventional discrete angle beam piezoelectric transducers, implementation of the direct-write piezoelectric transducers has significant technical advantages and is promising for applications in determining nonlinear ultrasonic waves and plastic strain of structural materials. PMID- 29283352 TI - Ultraino: An Open Phased-Array System for Narrowband Airborne Ultrasound Transmission. AB - Modern ultrasonic phased-array controllers are electronic systems capable of delaying the transmitted or received signals of multiple transducers. Configurable transmit-receive array systems, capable of electronic steering and shaping of the beam in near real-time, are available commercially, for example, for medical imaging. However, emerging applications, such as ultrasonic haptics, parametric audio, or ultrasonic levitation, require only a small subset of the capabilities provided by the existing controllers. To meet this need, we present Ultraino, a modular, inexpensive, and open platform that provides hardware, software, and example applications specifically aimed at controlling the transmission of narrowband airborne ultrasound. Our system is composed of software, driver boards, and arrays that enable users to quickly and efficiently perform research in various emerging applications. The software can be used to define array geometries, simulate the acoustic field in real time, and control the connected driver boards. The driver board design is based on an Arduino Mega and can control 64 channels with a square wave of up to 17 Vpp and /5 phase resolution. Multiple boards can be chained together to increase the number of channels. The 40-kHz arrays with flat and spherical geometries are demonstrated for parametric audio generation, acoustic levitation, and haptic feedback. PMID- 29283353 TI - Flow Field Imaging With Ultrasonic Guided Waves for Exploring Metallic Melts. AB - Ultrasonic guided waves enable flow measurements under harsh conditions, which are important, for instance, to monitor and optimize industrial solidification processes. The usage of single mode waveguides overcomes the problem of overheating the transducers, but requires a mechanical scanning for imaging. A multimode waveguide can carry the information of an image, but a scrambling of the signals occurs due to multiple reflections at the waveguide's boundaries. We propose a new approach to overcome the scrambling and enable flow imaging through a short waveguide: the time-reversal virtual array (TRVA) method. The time invariance of the wave equation in a linear medium allows the refocusing on a limited set of calibrated points, which form the virtual array. This virtual array can conceptually be treated as a phased array. In this paper, the TRVA has been characterized theoretically, numerically, and experimentally. For the first time, a planar velocity measurement of a rotating flow in liquid gallium-indium tin is demonstrated through a borosilicate waveguide at room temperature. A comparison with reference measurements showed good agreement. PMID- 29283354 TI - Ultrasound Detection Using Acoustic Apertures. AB - Ultrasound detection is commonly performed by piezoelectric transducers that are optimized for a specific application. Since the piezoelectric technology is not configurable, transducers designed for one application may not be compatible with other applications. In addition, some designs of ultrasound transducers may be difficult to implement owing to production constraints. In this paper, we propose a simple, low-cost method to reconfigure the geometry of ultrasound transducers. The technique is based on using apertures in thin sheets of acoustic blockers. We experimentally demonstrate this method for an ultrasound transducer with a central frequency of 1 MHz and show that it can emulate detectors of various sizes. An added advantage of this technique is its capability to achieve semi isotropic detection sensitivity due to diffraction when the aperture size is comparable to the acoustic wavelength even when the angular sensitivity of the transducer is inherently limited. PMID- 29283355 TI - Incorporating an Optical Clock Into a Time Scale. AB - This paper discusses the results of a simulation of a time scale based on continuously operating commercial hydrogen masers and an optical frequency standard that does not operate continuously as a clock. The simulation compares the performance of this time scale with one that is based on the same commercial devices but incorporates a continuously operating cesium fountain instead of the optical standard. The results are independent of the detailed characteristics of the optical frequency standard; the only requirement is that the optical device be much more stable than the masers in the ensemble. We discuss two methods for realizing the results of this simulation in an operational time scale. PMID- 29283356 TI - 4D non-local means post-filtering for cardiac gated SPECT. AB - Cardiac gated images often suffer from increased noise in single photon emission computed tomography (SPECT) due to reduced data counts compared to non-gated studies. We investigate a spatiotemporal post-processing approach based on a non local means (NLM) filter for suppressing the noise in gated SPECT images. In this filter, the output at a voxel location is computed from a weighted average of voxels in its four-dimensional (4D) neighborhood, wherein the filter coefficients are adjusted according to the similarity level in the local image pattern of individual voxels with respect to the output voxel. This adaptive property allows the filter to achieve noise reduction while avoiding excessive blur of the heart wall. In the experiments, we first evaluated the accuracy of the proposed NLM filtering approach using simulated SPECT imaging data. We then demonstrated the approach on eight sets of clinical acquisitions. In addition, we also explored the robustness of the NLM filter with imaging dose reduced by 50% in these clinical acquisitions. The quantitative results show that 4D NLM filtering could effectively reduce the noise level in gated images, leading to more accurate reconstruction of the myocardium. Compared to spatial filtering alone, using temporal filtering in NLM could reduce the mean-squared-error of the myocardium by 55.63% and improve the left ventricle resolution by 19.92%. It could also improve the visibility of perfusion defects in gated images. Similar results are also observed on the clinical acquisitions both at standard dose and at 50% reduced dose. The 4D NLM results are also found to be comparable to that of a motion-compensated 4D reconstruction approach which is computationally more demanding. PMID- 29283357 TI - First results of a highly granulated 3D CdTe detector module for PET. AB - We present the performance of a highly granulated 3D detector module for PET, consisting of a stack of pixelated CdTe detectors. Each detector module has 2 cm * 2 cm * 2 cm of CdTe material, subdivided into 4000 voxels, where each voxel has size 1 mm * 1 mm * 2 mm and is connected to its own read-out electronics via a BiSn solder ball. Each read-out channel consists of a preamp, a discriminator, a shaper, a peak-and-hold circuit and a 10 bits SAR ADC. The preamp has variable gain where at the maximum gain the ADC resolution is equivalent to 0.7 keV. Each ASIC chip reads 100 CdTe pixel channels and has one TDC to measure the time stamp of the triggered events, with a time resolution of less than 1 ns. With the bias voltage set at -250 V mm-1 and for 17838 working channels out of a total of 20 000, we have obtained an average energy resolution of 2.2% FWHM for 511 keV photons. For 511 keV photons that have undergone Compton scattering, we measured an energy resolution of 3.2% FWHM. A timing resolution for PET coincidence events of 60 ns FWHM was found. PMID- 29283359 TI - Validation of a Monte Carlo code system for grid evaluation with interference effect on Rayleigh scattering. AB - Anti-scatter grids are commonly used in x-ray imaging systems to reduce scatter radiation reaching the image receptor. Anti-scatter grid performance and validation can be simulated through use of Monte Carlo (MC) methods. Our recently reported work has modified existing MC codes resulting in improved performance when simulating x-ray imaging. The aim of this work is to validate the transmission of x-ray photons in grids from the recently reported new MC codes against experimental results and results previously reported in other literature. The results of this work show that the scatter-to-primary ratio (SPR), the transmissions of primary (T p), scatter (T s), and total (T t) radiation determined using this new MC code system have strong agreement with the experimental results and the results reported in the literature. T p, T s, T t, and SPR determined in this new MC simulation code system are valid. These results also show that the interference effect on Rayleigh scattering should not be neglected in both mammographic and general grids' evaluation. Our new MC simulation code system has been shown to be valid and can be used for analysing and evaluating the designs of grids. PMID- 29283360 TI - The influence of dilution on the offline measurement of exhaled nitric oxide. AB - OBJECTIVE: Measurement of fractional exhaled nitric oxide (FeNO) is used to determine the presence and severity of eosinophilic airway inflammation in asthma and other wheezing illnesses. The gold standard of online measurement during a single prolonged exhalation is not suitable for use in young children. The international guidelines for offline measurements recommend collection of exhaled gas in an appropriate reservoir for later analysis in young children. The apparatus required for gas collection, however, creates dead space within the system, which may result in sample dilution and hence inaccuracy. Our objective was to investigate the effect such dilution might have on the accuracy of offline FeNO by comparing the results to online results. APPROACH: Thirty-five adult subjects without respiratory disease underwent online measurement of FeNO and, thereafter, undertook offline FeNO measurements via exhalation into a collection reservoir using one, five or ten inhalation-exhalation cycles. Fifteen of the subjects also exhaled using the five-breath technique via apparatus with additional dead space. An equation incorporating dead space volume and the number of breaths was used to predict the degree of dilution; the predicted results were compared to the measured results. MAIN RESULTS: The median (IQR) FeNO from a one breath technique (22 (15-28) ppb was not significantly different to online values (19 (12-27) ppb, p = 1.00), but the results from the five-breath technique (11 (4-19) ppb, p < 0.0001), the ten-breath technique (6 (4-15) ppb, p < 0.0001) and the additional dead space experiment (6 (3-8) ppb, p = 0.0006) were significantly lower than online FeNO. Measured values were consistently significantly different to those predicted by the dilution equation, even when incorporating the exact exhaled volume of gas. SIGNIFICANCE: Offline FeNO results may be inaccurate when subjects are unable to fill the collection reservoir with a single exhalation, thus the technique may not be suitable for preschool children. PMID- 29283361 TI - A carbon CT system: how to obtain accurate stopping power ratio using a Bragg peak reduction technique. AB - In this study, we investigate the performance of the Gunma University Heavy Ion Medical Center's ion computed tomography (CT) system, which measures the residual range of a carbon-ion beam using a fluoroscopy screen, a charge-coupled-device camera, and a moving wedge absorber and collects CT reconstruction images from each projection angle. Each 2D image was obtained by changing the polymethyl methacrylate (PMMA) thickness, such that all images for one projection could be expressed as the depth distribution in PMMA. The residual range as a function of PMMA depth was related to the range in water through a calibration factor, which was determined by comparing the PMMA-equivalent thickness measured by the ion CT system to the water-equivalent thickness measured by a water column. Aluminium, graphite, PMMA, and five biological phantoms were placed in a sample holder, and the residual range for each was quantified simultaneously. A novel method of CT reconstruction to correct for the angular deflection of incident carbon ions in the heterogeneous region utilising the Bragg peak reduction (BPR) is also introduced in this paper, and its performance is compared with other methods present in the literature such as the decomposition and differential methods. Stopping power ratio values derived with the BPR method from carbon-ion CT images matched closely with the true water-equivalent length values obtained from the validation slab experiment. PMID- 29283362 TI - Improved field emission properties of a-Fe2O3 nanoflakes with current aging treatment and morphology optimization. AB - a-Fe2O3 nanomaterials were synthesized by thermal oxidation of pure iron foil, and the effects of current aging treatment and morphology on their field emission properties were systematically investigated. Current aging treatment was found to be an efficient method to improve the field emission properties of a-Fe2O3 nanoflakes. Emission current density was largely enhanced from 0.05 to 5.70 mA/cm2 under an applied electrical field of 7.8 MV/m, and their threshold field decreased from larger than 11.0 to 6.6 MV/m after current aging treatment. The mechanism of the improvement in field emission performance of a-Fe2O3 nanoflakes induced by current aging treatment is discussed. a-Fe2O3 nanostructures with various morphology were synthesized by adjusting growth temperatures between 300 450C to optimize its morphology. a-Fe2O3 nanoflakes synthesized under 350C were superior field emitters: low threshold of 5.1 MV/m, high current density of 63.4 mA/cm2 and stable emission, which demonstrated that a-Fe2O3 nanoflakes could be a promising material for application as field emitters. PMID- 29283363 TI - Dual functional NaYF4:Yb3+, Er3+@NaYF4:Yb3+, Nd3+ core-shell nanoparticles for cell temperature sensing and imaging. AB - Lanthanide-doped up-conversion nanoparticles (UCNPs) provide a remote temperature sensing approach to monitoring biological microenvironments. In this research, the UCNPs of NaYF4:Yb3+, Er3+@NaYF4:Yb3+, Nd3+ with hexagonal (beta)-phase were synthesized and applied in cell temperature sensing as well as imaging after surface modification with meso-2, 3-dimercaptosuccinic acid. In the core-shell UCNPs, Yb3+ ions were introduced as energy transfer media between sensitizers of Nd3+ and activators of Er3+ to improve Er3+emission and prevent their quenching behavior due to multiple energy levels of Nd3+. Under the excitations of 808 nm and 980 nm lasers, the NaYF4:Yb3+, Er3+@NaYF4:Yb3+, Nd3+ nanoparticles exhibited an efficient green band with two emission peaks at 525 nm and 545 nm, respectively, which originated from the transitions of 2H11/2 -> 4I15/2 and 4S3/2 -> 4I15/2 for Er3+ ions. We demonstrate that an occurrence of good logarithmic linearity exists between the intensity ratio of these two emission peaks and the reciprocal of the inside or outside temperature of NIH-3T3 cells. A better thermal stability is proved through temperature-dependent spectra with a heating cooling cycle. The obtained viability of NIH-3T3 cells is greater than 90% after incubations of about 12 and 24 (h), and they possess a lower cytotoxicity of UCNPs. This work provides a method for monitoring the cell temperature and its living state from multiple dimensions including temperature response, cell images and visual up-conversion fluorescent color. PMID- 29283364 TI - Antitumor and Immunoregulatory Activities of Seleno-beta-Lactoglobulin on S180 Tumor-Bearing Mice. AB - Degeneration of immune organs like thymus and spleen has been discovered in tumor bearing mice; which increases the difficulties on oncotherapy. More effective drugs which target the protection of immune organs are expected to be researched. In this study; we aim to analyze the antitumor and immunoregulatory activities of seleno-beta-lactoglobulin (Se-beta-lg) on S180 tumor-bearing mice. Results indicated that Se-beta-lg exhibited a remarkable inhibitory effect on S180 solid tumors with the inhibition rate of 48.38%; and protected the thymuses and spleens of S180-bearing mice. In addition, Se-beta-lg could also balance the proportions of CD4+ and CD8+ T cells in spleens; thymuses and peripheral bloods; and improve Levels of IL-2; IFN-gamma; TNF-alpha in mice serums. beta-lg showed weaker bioactivities while SeO2 showed stronger toxicity on mice. Therefore our results demonstrated that Se-beta-lg possessed stronger antitumor and immunoregulatory activities with lower side effects and had the potential to be a novel immunopotentiator and antitumor agent. PMID- 29283365 TI - Structure, Chemical Analysis, Biosynthesis, Metabolism, Molecular Engineering, and Biological Functions of Phytoalexins. AB - Plants in their natural environment are facing large numbers of pathogenic microorganisms, mainly fungi and bacteria.[...]. PMID- 29283366 TI - Molecularly Imprinted Microrods via Mesophase Polymerization. AB - The aim of the present research work was the synthesis of molecularly imprinted polymers (MIPs) with a rod-like geometry via "mesophase polymerization". The ternary lyotropic system consisting of sodium dodecyl sulfate (SDS), water, and decanol was chosen to prepare a hexagonal mesophase to direct the morphology of the synthesized imprinted polymers using theophylline, methacrylic acid, and ethylene glycol dimethacrylate as a drug model template, a functional monomer, and a crosslinker, respectively. The obtained molecularly imprinted microrods (MIMs) were assessed by performing binding experiments and in vitro release studies, and the obtained results highlighted good selective recognition abilities and sustained release properties. In conclusion, the adopted synthetic strategy involving a lyotropic mesophase system allows for the preparation of effective MIPs characterized by a rod-like morphology. PMID- 29283368 TI - Schottky Emission Distance and Barrier Height Properties of Bipolar Switching Gd:SiOx RRAM Devices under Different Oxygen Concentration Environments. AB - In this study, the hopping conduction distance and bipolar switching properties of the Gd:SiOx thin film by (radio frequency, rf) rf sputtering technology for applications in RRAM devices were calculated and investigated. To discuss and verify the electrical switching mechanism in various different constant compliance currents, the typical current versus applied voltage (I-V) characteristics of gadolinium oxide RRAM devices was transferred and fitted. Finally, the transmission electrons' switching behavior between the TiN bottom electrode and Pt top electrode in the initial metallic filament forming process of the gadolinium oxide thin film RRAM devices for low resistance state (LRS)/high resistance state (HRS) was described and explained in a simulated physical diagram model. PMID- 29283367 TI - Surveillance of Environmental and Procedural Measures of Infection Control in the Operating Theatre Setting. AB - The microbiological contamination of operating theatres and the lack of adherence to best practices by surgical staff represent some of the factors affecting Surgical Site Infections (SSIs). The aim of the present study was to assess the microbiological quality of operating settings and the staff compliance to the SSI evidence-based control measures. Ten operating rooms were examined for microbiological contamination of air and surfaces, after cleaning procedures, in "at rest" conditions. Furthermore, 10 surgical operations were monitored to assess staff compliance to the recommended practices. None of the air samples exceeded microbiological reference standards and only six of the 200 surface samples (3.0%) were slightly above recommended levels. Potentially pathogenic bacteria and moulds were never detected. Staff compliance to best practices varied depending on the type of behaviour investigated and the role of the operator. The major not compliant behaviours were: pre-operative skin antisepsis, crowding of the operating room and hand hygiene of the anaesthetist. The good environmental microbiological quality observed is indicative of the efficacy of the cleaning-sanitization procedures adopted. The major critical point was staff compliance to recommended practices. Awareness campaigns are therefore necessary, aimed at improving the organisation of work so as to facilitate compliance to operative protocols. PMID- 29283369 TI - Contamination of Tea and Tea Infusion with Polycyclic Aromatic Hydrocarbons. AB - The aim of this work was to validate the method of determination of polycyclic aromatic hydrocarbons (PAHs), i.e., benzo(a)pyrene and sum of benzo(a)pyrene, benz(a)anthracene, benzo(b)fluoranthene and chrysene in different types of tea, as well as to assess the transfer of these contaminants from tea to tea infusion. The research materials were popular types of black, green, red and white tea. Quantitative and qualitative determination of PAHs was performed by High Performance Liquid Chromatography with fluorimetric detection (HPLC-FLD). The samples were prepared by QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) technique followed by cleaning-up by dispersion solid-phase extraction (d SPE). Values of limit of detection and limit of quantification obtained in the validation of the method were lower than the respective maximum values given in Commission Regulation (EU) No. 836/2011. The level of contamination of popular teas commercially available on the Polish market with PAHs is similar to that of teas available in other countries, with a very large variation in the concentration of each of the compounds. The highest benzo(a)pyrene and Sigma4PAHs contents (209 +/- 42 MUg/kg and 756 +/- 151 MUg/kg, respectively) were found for black tea leaves. The transfer of Sigma4PAHs from black tea to tea infusions was 0.48%, while it was 1.55-1.72% for red, white and green teas. PMID- 29283370 TI - Trauma and Pain in Family-Orientated Societies. AB - People from family-oriented societies in particular, in addition to having a post traumatic stress disorder (PTSD) suffer from chronic pain and physical complaints. Such people have a different understanding of physical illness and pain and, compared to patients from western societies, have different ideas on healing, even when confronted with the therapist. Hitherto, these factors have not been sufficiently taken into account in modern, multi-module therapy approaches. Trauma can be perceived via pain and physical complaints, whereby the pain is not restricted to one part of the body but is seen as covering the body as a whole. Therefore, in the treatment and above all in the patient-therapist relationship, it is necessary to understand what importance is attached to the perceived pain in relation to the trauma. The afflicted body expresses the trauma in the shape of its further-reaching consequences such as the patient's social, collective, economic and cultural sensitivity. Therefore, for the effective treatment of trauma and chronic pain, it is necessary to use a multi-modal, interdisciplinary, and culture-sensitive approach when treating patients from traditional cultural backgrounds. PMID- 29283371 TI - A Distributed Wireless Camera System for the Management of Parking Spaces. AB - The importance of detection of parking space availability is still growing, particularly in major cities. This paper deals with the design of a distributed wireless camera system for the management of parking spaces, which can determine occupancy of the parking space based on the information from multiple cameras. The proposed system uses small camera modules based on Raspberry Pi Zero and computationally efficient algorithm for the occupancy detection based on the histogram of oriented gradients (HOG) feature descriptor and support vector machine (SVM) classifier. We have included information about the orientation of the vehicle as a supporting feature, which has enabled us to achieve better accuracy. The described solution can deliver occupancy information at the rate of 10 parking spaces per second with more than 90% accuracy in a wide range of conditions. Reliability of the implemented algorithm is evaluated with three different test sets which altogether contain over 700,000 samples of parking spaces. PMID- 29283372 TI - Neuroprotective Effects and Mechanisms of Curcumin-Cu(II) and -Zn(II) Complexes Systems and Their Pharmacological Implications. AB - Alzheimer's disease (AD) is the main form of dementia and has a steadily increasing prevalence. As both oxidative stress and metal homeostasis are involved in the pathogenesis of AD, it would be interesting to develop a dual function agent, targeting the two factors. Curcumin, a natural compound isolated from the rhizome of Curcuma longa, is an antioxidant and can also chelate metal ions. Whether the complexes of curcumin with metal ions possess neuroprotective effects has not been evaluated. Therefore, the present study was designed to investigate the protective effects of the complexes of curcumin with Cu(II) or Zn(II) on hydrogen peroxide (H2O2)-induced injury and the underlying molecular mechanisms. The use of rat pheochromocytoma (PC12) cells, a widely used neuronal cell model system, was adopted. It was revealed that curcumin-Cu(II) complexes systems possessed enhanced O2.--scavenging activities compared to unchelated curcumin. In comparison with unchelated curcumin, the protective effects of curcumin-Cu(II) complexes systems were stronger than curcumin-Zn(II) system. Curcumin-Cu(II) or -Zn(II) complexes systems significantly enhanced the superoxide dismutase, catalase, and glutathione peroxidase activities and attenuated the increase of malondialdehyde levels and caspase-3 and caspase-9 activities, in a dose-dependent manner. The curcumin-Cu(II) complex system with a 2:1 ratio exhibited the most significant effect. Further mechanistic study demonstrated that curcumin-Cu(II) or -Zn(II) complexes systems inhibited cell apoptosis via downregulating the nuclear factor kappaB (NF-kappaB) pathway and upregulating Bcl-2/Bax pathway. In summary, the present study found that curcumin Cu(II) or -Zn(II) complexes systems, especially the former, possess significant neuroprotective effects, which indicates the potential advantage of curcumin as a promising agent against AD and deserves further study. PMID- 29283373 TI - Stereoselective Synthesis, Synthetic and Pharmacological Application of Monoterpene-Based 1,2,4- and 1,3,4-Oxadiazoles. AB - Stereoselective synthesis of monoterpene-based 1,2,4- and 1,3,4-oxadiazole derivatives was accomplished starting from alpha,beta-unsaturated carboxylic acids, obtained by the oxidation of (-)-2-carene-3-aldehyde and commercially available (-)-myrtenal. 1,2,4-Oxadiazoles were prepared in two steps via the corresponding O-acylamidoxime intermediates, which then underwent cyclisation induced by tetrabutylammonium fluoride (TBAF) under mild reaction conditions. Stereoselective dihydroxylation in highly stereospecific reactions with the OsO4/NMO (N-methylmorpholine N-oxide) system produced alpha,beta-dihydroxy 1,2,4 oxadiazoles. Pinane-based 1,3,4-oxadiazoles were obtained similarly from acids by coupling with acyl hydrazines followed by POCl3-mediated dehydrative ring closure. In the case of the arane counterpart, the rearrangement of the constrained carane system occurred with the loss of chirality under the same conditions. Stereoselective dihydroxylation with OsO4/NMO produced alpha,beta dihydroxy 1,3,4-oxadiazoles. The prepared diols were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. All compounds were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines by means of the MTT assay with the O-acylated amidoxime intermediates exerting remarkable antiproliferative action. PMID- 29283374 TI - Tongue Abnormalities Are Associated to a Maternal Folic Acid Deficient Diet in Mice. AB - It is widely accepted that maternal folic acid (FA) deficiency during pregnancy is a risk factor for abnormal development. The tongue, with multiple genes working together in a coordinated cascade in time and place, has emerged as a target organ for testing the effect of FA during development. A FA-deficient (FAD) diet was administered to eight-week-old C57/BL/6J mouse females for 2-16 weeks. Pregnant dams were sacrificed at gestational day 17 (E17). The tongues and heads of 15 control and 210 experimental fetuses were studied. In the tongues, the maximum width, base width, height and area were compared with width, height and area of the head. All measurements decreased from 10% to 38% with increasing number of weeks on maternal FAD diet. Decreased head and tongue areas showed a harmonic reduction (Spearman nonparametric correlation, Rho = 0.802) with respect to weeks on a maternal FAD diet. Tongue congenital abnormalities showed a 10.9% prevalence, divided in aglossia (3.3%) and microglossia (7.6%), always accompanied by agnathia (5.6%) or micrognathia (5.2%). This is the first time that tongue alterations have been related experimentally to maternal FAD diet in mice. We propose that the tongue should be included in the list of FA-sensitive birth defect organs due to its relevance in several key food and nutrition processes. PMID- 29283376 TI - Differential Selective Pressures Experienced by the Aurora Kinase Gene Family. AB - Aurora kinases (AKs) are serine/threonine kinases that are essential for cell division. Humans have three AK genes: AKA, AKB, and AKC. AKA is required for centrosome assembly, centrosome separation, and bipolar spindle assembly, and its mutation leads to abnormal spindle morphology. AKB is required for the spindle checkpoint and proper cytokinesis, and mutations cause chromosome misalignment and cytokinesis failure. AKC is expressed in germ cells, and has a role in meiosis analogous to that of AKB in mitosis. Mutation of any of the three isoforms can lead to cancer. AK proteins possess divergent N- and C-termini and a conserved central catalytic domain. We examined the evolution of the AK gene family using an identity matrix and by building a phylogenetic tree. The data suggest that AKA is the vertebrate ancestral gene, and that AKB and AKC resulted from gene duplication in placental mammals. In a nonsynonymous/synonymous rate substitution analysis, we found that AKB experienced the strongest, and AKC the weakest, purifying selection. Both the N- and C-termini and regions within the kinase domain experienced differential selection among the AK isoforms. These differentially selected sequences may be important for species specificity and isoform specificity, and are therefore potential therapeutic targets. PMID- 29283375 TI - Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities? AB - Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-alpha, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures. PMID- 29283378 TI - A New Method for Sensing Soil Water Content in Green Roofs Using Plant Microbial Fuel Cells. AB - Green roofs have many benefits, but in countries with semiarid climates the amount of water needed for irrigation is a limiting factor for their maintenance. The use of drought-tolerant plants such as Sedum species, reduces the water requirements in the dry season, but, even so, in semiarid environments these can reach up to 60 L m-2 per day. Continuous substrate/soil water content monitoring would facilitate the efficient use of this critical resource. In this context, the use of plant microbial fuel cells (PMFCs) emerges as a suitable and more sustainable alternative for monitoring water content in green roofs in semiarid climates. In this study, bench and pilot-scale experiments using seven Sedum species showed a positive relationship between current generation and water content in the substrate. PMFC reactors with higher water content (around 27% vs. 17.5% v/v) showed larger power density (114.6 and 82.3 MUW m-2 vs. 32.5 MUW m-2). Moreover, a correlation coefficient of 0.95 (+/-0.01) between current density and water content was observed. The results of this research represent the first effort of using PMFCs as low-cost water content biosensors for green roofs. PMID- 29283377 TI - Gate Tunable Transport in Graphene/MoS2/(Cr/Au) Vertical Field-Effect Transistors. AB - Two-dimensional materials based vertical field-effect transistors have been widely studied due to their useful applications in industry. In the present study, we fabricate graphene/MoS2/(Cr/Au) vertical transistor based on the mechanical exfoliation and dry transfer method. Since the bottom electrode was made of monolayer graphene (Gr), the electrical transport in our Gr/MoS2/(Cr/Au) vertical transistors can be significantly modified by using back-gate voltage. Schottky barrier height at the interface between Gr and MoS2 can be modified by back-gate voltage and the current bias. Vertical resistance (Rvert) of a Gr/MoS2/(Cr/Au) transistor is compared with planar resistance (Rplanar) of a conventional lateral MoS2 field-effect transistor. We have also studied electrical properties for various thicknesses of MoS2 channels in both vertical and lateral transistors. As the thickness of MoS2 increases, Rvert increases, but Rplanar decreases. The increase of Rvert in the thicker MoS2 film is attributed to the interlayer resistance in the vertical direction. However, Rplanar shows a lower value for a thicker MoS2 film because of an excess of charge carriers available in upper layers connected directly to source/drain contacts that limits the conduction through layers closed to source/drain electrodes. Hence, interlayer resistance associated with these layers contributes to planer resistance in contrast to vertical devices in which all layers contribute interlayer resistance. PMID- 29283379 TI - A Metabolomic and Lipidomic Serum Signature from Nonhuman Primates Administered with a Promising Radiation Countermeasure, Gamma-Tocotrienol. AB - The development of radiation countermeasures for acute radiation syndrome (ARS) has been underway for the past six decades, leading to the identification of multiple classes of radiation countermeasures. However, to date, only two growth factors (Neupogen and Neulasta) have been approved by the United States Food and Drug Administration (US FDA) for the mitigation of hematopoietic acute radiation syndrome (H-ARS). No radioprotector for ARS has been approved by the FDA yet. Gamma-tocotrienol (GT3) has been demonstrated to have radioprotective efficacy in murine as well as nonhuman primate (NHP) models. Currently, GT3 is under advanced development as a radioprotector that can be administered prior to radiation exposure. We are studying this agent for its safety profile and efficacy using the NHP model. In this study, we analyzed global metabolomic and lipidomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of flight mass spectrometry (QTOF-MS) in serum samples of NHPs administered GT3. Our study, using 12 NHPs, demonstrates that alterations in metabolites manifest only 24 h after GT3 administration. Furthermore, metabolic changes are associated with transient increase in the bioavailability of antioxidants, including lactic acid and cholic acid and anti-inflammatory metabolites 3 deoxyvitamin D3, and docosahexaenoic acid. Taken together, our results show that the administration of GT3 to NHPs causes metabolic shifts that would provide an overall advantage to combat radiation injury. This initial assessment also highlights the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3. PMID- 29283380 TI - Dairy Products Intake and Endometrial Cancer Risk: A Meta-Analysis of Observational Studies. AB - Observational studies have suggested inconsistent findings on the relationship between dairy products intake and endometrial cancer risk. This study aimed to conduct a meta-analysis to evaluate this correlation; moreover, databases including PubMed, ISI Web of Science, and Embase were screened for relevant studies up to 26 February 2017. The inverse variance weighting method and random effects models were used to calculate the overall OR (odds ratio) values and 95% confidence interval (CI). A total of 2 cohort study and 16 case-control studies were included in the current analysis. No significant association was observed between endometrial cancer risk and the intake of total dairy products, milk, or cheese for the highest versus the lowest exposure category (total dairy products (14 studies): OR 1.04, 95% CI: 0.97-1.11, I2 = 73%, p = 0.000; milk (6 studies): 0.99, 95% CI: 0.89-1.10, I2 = 0.0%, p = 0.43; cheese (5 studies): 0.89, 95% CI: 0.76-1.05, I2 = 39%, p = 0.16). The only cohort study with a total of 456,513 participants reported a positive association of butter intake with endometrial cancer risk (OR = 1.14; 95% CI = 1.03-1.26, I2 = 2.6%, p = 0.31). There was a significant negative association of dairy products intake and endometrial cancer risk among women with a higher body mass index (BMI) (5 studies, OR 0.66, 95% CI = 0.46-0.96, I2 = 75.8%, p = 0.002). Stratifying the analyses by risk factors including BMI should be taken into account when exploring the association of dairy products intake with endometrial cancer risk. Further well-designed studies are needed. PMID- 29283382 TI - Thiopurine Drugs Repositioned as Tyrosinase Inhibitors. AB - Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 MUM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 MUM) was comparable to that of the well-known inhibitor kojic acid (13 MUM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 MUM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors. PMID- 29283381 TI - Therapeutic Applications of Targeted Alternative Splicing to Cancer Treatment. AB - A growing body of studies has documented the pathological influence of impaired alternative splicing (AS) events on numerous diseases, including cancer. In addition, the generation of alternatively spliced isoforms is frequently noted to result in drug resistance in many cancer therapies. To gain comprehensive insights into the impacts of AS events on cancer biology and therapeutic developments, this paper highlights recent findings regarding the therapeutic routes of targeting alternative-spliced isoforms and splicing regulators to treatment strategies for distinct cancers. PMID- 29283383 TI - Targeted alpha Therapies for the Treatment of Bone Metastases. AB - The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using alpha-emitting drugs known as targeted alpha therapies. The use of alpha radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that alpha-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted alpha therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice. PMID- 29283385 TI - Natural Rubber/Dendrimer Modified Montmorillonite Nanocomposites: Mechanical and Flame-Retardant Properties. AB - A series of flame-retardant nanocomposites were established based on compounding of natural rubber (NR) and dendrimer modified flame-retardant organic montmorillonite (FR-DOMt). The merits of these nanocomposites were focused on their better mechanical and flame-retardant properties. X-ray diffractometer (XRD) together with scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis revealed that exfoliation, intercalation, or aggregation status in the NRmatrix can be achieved by addition of different amounts of FR-DOMt. The sound effects of blend ratio of FR-DOMt on mechanical, thermal stability, and flame-retardant (FR) properties of NR were studied. The NR/FR-DOMt-20 composite possessed the highest tensile strength, and this resulted from complicated interactions between layered silicates and elastomers. In addition, with loading of 20 phr of FR-DOMt, the flammability parameters of NR, such as heat release rate (HRR), smoke evolution area (SEA), and carbon monoxide (CO) concentration, were obviously reduced from cone calorimeter analysis. PMID- 29283384 TI - High-Mobility Group Box 1 Mediates Fibroblast Activity via RAGE-MAPK and NF kappaB Signaling in Keloid Scar Formation. AB - Emerging studies have revealed the involvement of high-mobility group box 1 (HMGB1) in systemic fibrotic diseases, yet its role in the cutaneous scarring process has not yet been investigated. We hypothesized that HMGB1 may promote fibroblast activity to cause abnormal cutaneous scarring. In vitro wound healing assay with normal and keloid fibroblasts demonstrated that HMGB1 administration promoted the migration of both fibroblasts with increased speed and a greater traveling distance. Treatment of the HMGB1 inhibitor glycyrrhizic acid (GA) showed an opposing effect on both activities. To analyze the downstream mechanism, the protein levels of extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) were measured by western blot analysis. HMGB1 increased the expression levels of ERK1/2, AKT, and NF-kappaB compared to the control, which was suppressed by GA. HMGB1 promoted both normal and keloid fibroblasts migration to a degree equivalent to that achieved with TGF-beta. We concluded that HMGB1 activates fibroblasts via the receptor for advanced glycation end product (RAGE)-mitogen-activated protein kinases (MAPK) and NF kappaB interaction signaling pathways. Further knowledge of the relationship of HMGB1 with skin fibrosis may lead to a promising clinical approach to manage abnormal scarring. PMID- 29283386 TI - The Abrogation of Phosphorylation Plays a Relevant Role in the CCR5 Signalosome Formation with Natural Antibodies to CCR5. AB - The exposure to CCR5 (CC chemokine receptor 5) specific natural antibodies in vitro produces a Class B beta-arrestin2-dependent CCR5 retention with the aid of ERK1, due to the formation of a CCR5 signalosome, which remains stable for at least 48 h. Considering that beta-arrestins and MAPKs are receptive to environmental signals, their signal complexes could be one of the key junction for GPCRs internalization related signal transduction. Here, we demonstrate that, in T cells, the phosphorylation status of either CCR5 receptor or ERK1 protein is necessary to drive the internalized receptor into the early endosomes, forming the CCR5 signalosome. In particular, our data show that beta-arrestin2/ERK1 complex is a relevant transducer in the CCR5 signaling pathway. Understanding the mechanism of CCR5 regulation is essential for many inflammatory disorders, tumorigenesis and viral infection such as HIV. PMID- 29283388 TI - Evolutionary Dynamics of the W Chromosome in Caenophidian Snakes. AB - The caenophidian (assigned also as "advanced") snakes are traditionally viewed as a group of reptiles with a limited karyotypic variation and stable ZZ/ZW sex chromosomes. The W chromosomes of the caenophidian snakes are heterochromatic, and pioneering studies demonstrated that they are rich in repetitive elements. However, a comparative study of the evolutionary dynamics of the repetitive content of the W chromosome across the whole lineage is missing. Using molecular cytogenetic techniques, we explored the distribution of four repetitive motifs (microsatellites GATA, GACA, AG and telomeric-like sequences), which are frequently accumulated in differentiated sex chromosomes in vertebrates, in the genomes of 13 species of the caenophidian snakes covering a wide phylogenetic spectrum of the lineage. The results demonstrate a striking variability in the morphology and the repetitive content of the W chromosomes even between closely related species, which is in contrast to the homology and long-term stability of the gene content of the caenophidian Z chromosome. We uncovered that the tested microsatellite motifs are accumulated on the degenerated, heterochromatic W chromosomes in all tested species of the caenophidian snakes with the exception of the Javan file snake representing a basal clade. On the other hand, the presence of the accumulation of the telomeric-like sequences on the caenophidian W chromosome is evolutionary much less stable. Moreover, we demonstrated that large accumulations of telomeric-like motifs on the W chromosome contribute to sexual differences in the number of copies of the telomeric and telomeric-like repeats estimated by quantitative PCR, which might be confusing and incorrectly interpreted as sexual differences in telomere length. PMID- 29283387 TI - The Role of Chromosomal Instability in Cancer and Therapeutic Responses. AB - Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses. PMID- 29283389 TI - Identification of Host Defense-Related Proteins Using Label-Free Quantitative Proteomic Analysis of Milk Whey from Cows with Staphylococcus aureus Subclinical Mastitis. AB - Staphylococcus aureus is the most common contagious pathogen associated with bovine subclinical mastitis. Current diagnosis of S. aureus mastitis is based on bacteriological culture of milk samples and somatic cell counts, which lack either sensitivity or specificity. Identification of milk proteins that contribute to host defense and their variable responses to pathogenic stimuli would enable the characterization of putative biomarkers of subclinical mastitis. To accomplish this, milk whey samples from healthy and mastitic dairy cows were analyzed using a label-free quantitative proteomics approach. In total, 90 proteins were identified, of which 25 showed significant differential abundance between healthy and mastitic samples. In silico functional analyses indicated the involvement of the differentially abundant proteins in biological mechanisms and signaling pathways related to host defense including pathogen-recognition, direct antimicrobial function, and the acute-phase response. This proteomics and bioinformatics analysis not only facilitates the identification of putative biomarkers of S. aureus subclinical mastitis but also recapitulates previous findings demonstrating the abundance of host defense proteins in intramammary infection. All mass spectrometry data are available via ProteomeXchange with identifier PXD007516. PMID- 29283391 TI - Reconfigurable Coplanar Waveguide (CPW) and Half-Mode Substrate Integrated Waveguide (HMSIW) Band-Stop Filters Using a Varactor-Loaded Metamaterial-Inspired Open Resonator. AB - An open ring resonator (ORR) loaded with a varactor diode is designed and implemented in order to achieve high-performance tunable band-stop filters in planar technology with a compact size. This varactor-loaded ORR (VLORR) is versatile. It allows a shunt connection with different planar waveguide sections. In this paper, it has been connected to a coplanar waveguide (CPW) and a half mode substrate integrated waveguide (HMSIW). As a reverse bias voltage is applied to the VLORR, a continuous tuning over the resulting stop-band can be achieved. To illustrate the possibilities of the VLORR, three prototypes have been designed, fabricated, and characterized. The three prototypes show an outstanding performance, with a rejection level at the resonant frequency and a tuning range greater than 12 dB and 85%, respectively. This VLORR has high potential value in microwave communication systems to eliminate unwanted signals. PMID- 29283390 TI - Genotypic and Phylogenetic Insights on Prevention of the Spread of HIV-1 and Drug Resistance in "Real-World" Settings. AB - HIV continues to spread among vulnerable heterosexual (HET), Men-having-Sex with Men (MSM) and intravenous drug user (IDU) populations, influenced by a complex array of biological, behavioral and societal factors. Phylogenetics analyses of large sequence datasets from national drug resistance testing programs reveal the evolutionary interrelationships of viral strains implicated in the dynamic spread of HIV in different regional settings. Viral phylogenetics can be combined with demographic and behavioral information to gain insights on epidemiological processes shaping transmission networks at the population-level. Drug resistance testing programs also reveal emergent mutational pathways leading to resistance to the 23 antiretroviral drugs used in HIV-1 management in low-, middle- and high income settings. This article describes how genotypic and phylogenetic information from Quebec and elsewhere provide critical information on HIV transmission and resistance, Cumulative findings can be used to optimize public health strategies to tackle the challenges of HIV in "real-world" settings. PMID- 29283392 TI - New Method for Differentiation of Granuloviruses (Betabaculoviruses) Based on Multitemperature Single Stranded Conformational Polymorphism. AB - Baculoviruses have been used as biopesticides for decades. Recently, due to the excessive use of chemical pesticides there is a need for finding new agents that may be useful in biological protection. Sometimes few isolates or species are discovered in one host. In the past few years, many new baculovirus species have been isolated from environmental samples, thoroughly characterized and thanks to next generation sequencing methods their genomes are being deposited in the GenBank database. Next generation sequencing (NGS) methodology is the most certain way of detection, but it has many disadvantages. During our studies, we have developed a method based on Polymerase chain reaction (PCR) followed by Multitemperature Single Stranded Conformational Polymorphism (MSSCP) which allows for distinguishing new granulovirus isolates in only a few hours and at low-cost. On the basis of phylogenetic analysis of betabaculoviruses, representative species have been chosen. The alignment of highly conserved genes-granulin and late expression factor-9, was performed and the degenerate primers were designed to amplify the most variable, short DNA fragments flanked with the most conserved sequences. Afterwards, products of PCR reaction were analysed by MSSCP technique. In our opinion, the proposed method may be used for screening of new isolates derived from environmental samples. PMID- 29283393 TI - Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Biodistribution after Intravenous Dosing in Rats. AB - Relative biodistribution of FDA-approved innovator and generic sodium ferric gluconate (SFG) drug products was investigated to identify differences in tissue distribution of iron after intravenous dosing to rats. Three equal cohorts of 42 male Sprague-Dawley rats were created with each cohort receiving one of three treatments: (1) the innovator SFG product dosed intravenously at a concentration of 40 mg/kg; (2) the generic SFG product dosed intravenously at a concentration of 40 mg/kg; (3) saline dosed intravenously at equivalent volume to SFG products. Sampling time points were 15 min, 1 h, 8 h, 1 week, two weeks, four weeks, and six weeks post-treatment. Six rats from each group were sacrificed at each time point. Serum, femoral bone marrow, lungs, brain, heart, kidneys, liver, and spleen were harvested and evaluated for total iron concentration by ICP-MS. The ICP-MS analytical method was validated with linearity, range, accuracy, and precision. Results were determined for mean iron concentrations (ug/g) and mean total iron (whole tissue) content (ug/tissue) for each tissue of all groups at each time point. A percent of total distribution to each tissue was calculated for both products. At any given time point, the overall percent iron concentration distribution did not vary between the two SFG drugs by more than 7% in any tissue. Overall, this study demonstrated similar tissue biodistribution for the two SFG products in the examined tissues. PMID- 29283394 TI - Optically Tunable Magnetoresistance Effect: From Mechanism to Novel Device Application. AB - The magnetoresistance effect in sandwiched structure describes the appreciable magnetoresistance effect of a device with a stacking of two ferromagnetic layers separated by a non-magnetic layer (i.e., a sandwiched structure). The development of this effect has led to the revolution of memory applications during the past decades. In this review, we revisited the magnetoresistance effect and the interlayer exchange coupling (IEC) effect in magnetic sandwiched structures with a spacer layer of non-magnetic metal, semiconductor or organic thin film. We then discussed the optical modulation of this effect via different methods. Finally, we discuss various applications of these effects and present a perspective to realize ultralow-power, high-speed data writing and inter-chip connection based on this tunable magnetoresistance effect. PMID- 29283395 TI - Study on Zinc Oxide-Based Electrolytes in Low-Temperature Solid Oxide Fuel Cells. AB - Semiconducting-ionic conductors have been recently described as excellent electrolyte membranes for low-temperature operation solid oxide fuel cells (LT SOFCs). In the present work, two new functional materials based on zinc oxide (ZnO)-a legacy material in semiconductors but exceptionally novel to solid state ionics-are developed as membranes in SOFCs for the first time. The proposed ZnO and ZnO-LCP (La/Pr doped CeO2) electrolytes are respectively sandwiched between two Ni0.8Co0.15Al0.05Li-oxide (NCAL) electrodes to construct fuel cell devices. The assembled ZnO fuel cell demonstrates encouraging power outputs of 158-482 mW cm-2 and high open circuit voltages (OCVs) of 1-1.06 V at 450-550 degrees C, while the ZnO-LCP cell delivers significantly enhanced performance with maximum power density of 864 mW cm-2 and OCV of 1.07 V at 550 degrees C. The conductive properties of the materials are investigated. As a consequence, the ZnO electrolyte and ZnO-LCP composite exhibit extraordinary ionic conductivities of 0.09 and 0.156 S cm-1 at 550 degrees C, respectively, and the proton conductive behavior of ZnO is verified. Furthermore, performance enhancement of the ZnO-LCP cell is studied by electrochemical impedance spectroscopy (EIS), which is found to be as a result of the significantly reduced grain boundary and electrode polarization resistances. These findings indicate that ZnO is a highly promising alternative semiconducting-ionic membrane to replace the electrolyte materials for advanced LT-SOFCs, which in turn provides a new strategic pathway for the future development of electrolytes. PMID- 29283397 TI - Ultrasound Guidance for Botulinum Neurotoxin Chemodenervation Procedures. AB - Injections of botulinum neurotoxins (BoNTs) are prescribed by clinicians for a variety of disorders that cause over-activity of muscles; glands; pain and other structures. Accurately targeting the structure for injection is one of the principle goals when performing BoNTs procedures. Traditionally; injections have been guided by anatomic landmarks; palpation; range of motion; electromyography or electrical stimulation. Ultrasound (US) based imaging based guidance overcomes some of the limitations of traditional techniques. US and/or US combined with traditional guidance techniques is utilized and or recommended by many expert clinicians; authors and in practice guidelines by professional academies. This article reviews the advantages and disadvantages of available guidance techniques including US as well as technical aspects of US guidance and a focused literature review related to US guidance for chemodenervation procedures including BoNTs injection. PMID- 29283398 TI - Application of a Multimedia Service and Resource Management Architecture for Fault Diagnosis. AB - Nowadays, the complexity of global video products has substantially increased. They are composed of several associated services whose functionalities need to adapt across heterogeneous networks with different technologies and administrative domains. Each of these domains has different operational procedures; therefore, the comprehensive management of multi-domain services presents serious challenges. This paper discusses an approach to service management linking fault diagnosis system and Business Processes for Telefonica's global video service. The main contribution of this paper is the proposal of an extended service management architecture based on Multi Agent Systems able to integrate the fault diagnosis with other different service management functionalities. This architecture includes a distributed set of agents able to coordinate their actions under the umbrella of a Shared Knowledge Plane, inferring and sharing their knowledge with semantic techniques and three types of automatic reasoning: heterogeneous, ontology-based and Bayesian reasoning. This proposal has been deployed and validated in a real scenario in the video service offered by Telefonica Latam. PMID- 29283399 TI - Synthesis and Biological Evaluation of New Thiosemicarbazone Derivative Schiff Bases as Monoamine Oxidase Inhibitory Agents. AB - Twenty-six novel thiosemicarbazone derivative B1-B26 were synthesized via condensation reactions between the corresponding thiosemicarbazides and aldehydes. The chemical characterization of the compounds was carried out by infrared (IR), mass (MS), proton and carbon nuclear magnetic resonance (1H- and 13C-NMR) spectroscopic analyses. The compounds were investigated for their monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitory activity and most of them were more potent against MAO-A enzyme when compared with MAO-B enzyme. N-Cyclohexyl-2-[4-[(4-chlorophenyl)thio]benzylidene]hydrazine-1 carbothioamide (B24) was the most active compound against MAO-A. The enzyme kinetics study revealed that compound B24 has a reversible and competitive mode of binding. Interaction modes between compound B24 and MAO-A were clarified by docking studies. In addition, the favourable absorption, distribution, metabolism, and excretion (ADME) properties and non-toxic nature of compound B24 make this compound a promising MAO-A inhibitor. PMID- 29283396 TI - Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. AB - CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted. PMID- 29283400 TI - Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-2. AB - Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...]. PMID- 29283401 TI - Evaluation of Pictorial Dietary Assessment Tool for Hospitalized Patients with Diabetes: Cost, Accuracy, and User Satisfaction Analysis. AB - Although nutritional screening and dietary monitoring in clinical settings are important, studies on related user satisfaction and cost benefit are still lacking. This study aimed to: (1) elucidate the cost of implementing a newly developed dietary monitoring tool, the Pictorial Dietary Assessment Tool (PDAT); and (2) investigate the accuracy of estimation and satisfaction of healthcare staff after the use of the PDAT. A cross-over intervention study was conducted among 132 hospitalized patients with diabetes. Cost and time for the implementation of PDAT in comparison to modified Comstock was estimated using the activity-based costing approach. Accuracy was expressed as the percentages of energy and protein obtained by both methods, which were within 15% and 30%, respectively, of those obtained by the food weighing. Satisfaction of healthcare staff was measured using a standardized questionnaire. Time to complete the food intake recording of patients using PDAT (2.31 +/- 0.70 min) was shorter than when modified Comstock (3.53 +/- 1.27 min) was used (p < 0.001). Overall cost per patient was slightly higher for PDAT (United States Dollar 0.27 +/- 0.02) than for modified Comstock (USD 0.26 +/- 0.04 (p < 0.05)). The accuracy of energy intake estimated by modified Comstock was 10% lower than that of PDAT. There was poorer accuracy of protein intake estimated by modified Comstock (<40%) compared to that estimated by the PDAT (>71%) (p < 0.05). Mean user satisfaction of healthcare staff was significantly higher for PDAT than that for modified Comstock (p < 0.05). PDAT requires a shorter time to be completed and was rated better than modified Comstock. PMID- 29283402 TI - Real-Time Monitoring and Analysis of Zebrafish Electrocardiogram with Anomaly Detection. AB - Heart disease is the leading cause of mortality in the U.S. with approximately 610,000 people dying every year. Effective therapies for many cardiac diseases are lacking, largely due to an incomplete understanding of their genetic basis and underlying molecular mechanisms. Zebrafish (Danio rerio) are an excellent model system for studying heart disease as they enable a forward genetic approach to tackle this unmet medical need. In recent years, our team has been employing electrocardiogram (ECG) as an efficient tool to study the zebrafish heart along with conventional approaches, such as immunohistochemistry, DNA and protein analyses. We have overcome various challenges in the small size and aquatic environment of zebrafish in order to obtain ECG signals with favorable signal-to noise ratio (SNR), and high spatial and temporal resolution. In this paper, we highlight our recent efforts in zebrafish ECG acquisition with a cost-effective simplified microelectrode array (MEA) membrane providing multi-channel recording, a novel multi-chamber apparatus for simultaneous screening, and a LabVIEW program to facilitate recording and processing. We also demonstrate the use of machine learning-based programs to recognize specific ECG patterns, yielding promising results with our current limited amount of zebrafish data. Our solutions hold promise to carry out numerous studies of heart diseases, drug screening, stem cell-based therapy validation, and regenerative medicine. PMID- 29283403 TI - Preliminary Findings that a Targeted Intervention Leads to Altered Brain Function in Children with Fetal Alcohol Spectrum Disorder. AB - Children with fetal alcohol spectrum disorder (FASD) exhibit behavioral dysregulation, executive dysfunction, and atypical function in associated brain regions. Previous research shows early intervention mitigates these outcomes but corresponding brain changes were not studied. Given the Alert(r) Program for Self Regulation improves behavioral regulation and executive function in children with FASD, we asked if this therapy also improves their neural functioning in associated regions. Twenty-one children with FASD aged 8-12 years were randomized to the Alert(r)-treatment (TXT; n = 10) or waitlist-control (WL; n = 11) conditions. They were assessed with a Go-NoGo functional magnetic resonance imaging (fMRI) paradigm before and after training or the wait-out period. Groups initially performed equivalently and showed no fMRI differences. At post-test, TXT outperformed WL on NoGo trials while fMRI in uncorrected results with a small volume correction showed less activation in prefrontal, temporal, and cingulate regions. Groups also demonstrated different patterns of change over time reflecting reduced signal at post-test in selective prefrontal and parietal regions in TXT and increased in WL. In light of previous evidence indicating TXT at post-test perform similar to non-exposed children on the Go-NoGo fMRI paradigm, our findings suggest Alert(r) does improve functional integrity in the neural circuitry for behavioral regulation in children with FASD. PMID- 29283405 TI - The Impact of Bronchodilator Therapy on Systolic Heart Failure with Concomitant Mild to Moderate COPD. AB - In older adults, chronic obstructive pulmonary disease (COPD) is commonly associated with heart failure with reduced ejection fraction (HFrEF), and the high prevalence of this combination suggests that customized treatment is highly necessary in patients with COPD and HFrEF. To investigate whether the treatment of COPD with tiotropium, an anticholinergic bronchodilator, reduces the severity of heart failure in patients with HFrEF complicated by mild to moderate COPD, forty consecutive participants were randomly divided into two groups and enrolled in a crossover design study. Group A inhaled 18 MUg tiotropium daily for 28 days and underwent observation for another 28 days. Group B completed the 28-day observation period first and then received tiotropium inhalation therapy for 28 days. Pulmonary and cardiac functions were measured on days 1, 29, and 56. In both groups, 28 days of tiotropium inhalation therapy substantially improved the left ventricular ejection fraction (from 36.3 +/- 2.4% to 41.8 +/- 5.9%, p < 0.01, in group A; from 35.7 +/- 3.8% to 41.6 +/- 3.8%, p < 0.01, in group B) and plasma brain natriuretic peptide levels (from 374 +/- 94 to 263 +/- 92 pg/mL, p < 0.01, in group A; from 358 +/- 110 to 246 +/- 101 pg/mL, p < 0.01, in group B). Tiotropium inhalation therapy improves pulmonary function as well as cardiac function, and reduces the severity of heart failure in patients with compensated HFrEF with concomitant mild to moderate COPD. PMID- 29283404 TI - Key Clinical Factors Predicting Adipokine and Oxidative Stress Marker Concentrations among Normal, Overweight and Obese Pregnant Women Using Artificial Neural Networks. AB - Maternal obesity has been related to adverse neonatal outcomes and fetal programming. Oxidative stress and adipokines are potential biomarkers in such pregnancies; thus, the measurement of these molecules has been considered critical. Therefore, we developed artificial neural network (ANN) models based on maternal weight status and clinical data to predict reliable maternal blood concentrations of these biomarkers at the end of pregnancy. Adipokines (adiponectin, leptin, and resistin), and DNA, lipid and protein oxidative markers (8-oxo-2'-deoxyguanosine, malondialdehyde and carbonylated proteins, respectively) were assessed in blood of normal weight, overweight and obese women in the third trimester of pregnancy. A Back-propagation algorithm was used to train ANN models with four input variables (age, pre-gestational body mass index (p-BMI), weight status and gestational age). ANN models were able to accurately predict all biomarkers with regression coefficients greater than R2 = 0.945. P BMI was the most significant variable for estimating adiponectin and carbonylated proteins concentrations (37%), while gestational age was the most relevant variable to predict resistin and malondialdehyde (34%). Age, gestational age and p-BMI had the same significance for leptin values. Finally, for 8-oxo-2' deoxyguanosine prediction, the most significant variable was age (37%). These models become relevant to improve clinical and nutrition interventions in prenatal care. PMID- 29283406 TI - Disturbance-Estimated Adaptive Backstepping Sliding Mode Control of a Pneumatic Muscles-Driven Ankle Rehabilitation Robot. AB - A rehabilitation robot plays an important role in relieving the therapists' burden and helping patients with ankle injuries to perform more accurate and effective rehabilitation training. However, a majority of current ankle rehabilitation robots are rigid and have drawbacks in terms of complex structure, poor flexibility and lack of safety. Taking advantages of pneumatic muscles' good flexibility and light weight, we developed a novel two degrees of freedom (2-DOF) parallel compliant ankle rehabilitation robot actuated by pneumatic muscles (PMs). To solve the PM's nonlinear characteristics during operation and to tackle the human-robot uncertainties in rehabilitation, an adaptive backstepping sliding mode control (ABS-SMC) method is proposed in this paper. The human-robot external disturbance can be estimated by an observer, who is then used to adjust the robot output to accommodate external changes. The system stability is guaranteed by the Lyapunov stability theorem. Experimental results on the compliant ankle rehabilitation robot show that the proposed ABS-SMC is able to estimate the external disturbance online and adjust the control output in real time during operation, resulting in a higher trajectory tracking accuracy and better response performance especially in dynamic conditions. PMID- 29283407 TI - Extraction of a Novel Cold-Water-Soluble Polysaccharide from Astragalus membranaceus and Its Antitumor and Immunological Activities. AB - The polysaccharides of Astragalus membranaceus have received extensive study and attention, but there have been few reports on the extraction of these polysaccharides using cold water (4 degrees C). In this study, we fractionated a novel cold-water-soluble polysaccharide (cAMPs-1A) from Astragalus membranaceus with a 92.00% carbohydrate content using a DEAE-cellulose 52 anion exchange column and a Sephadex G-100 column. Our UV, Fourier-transform infrared spectroscopy (FTIR), high-performance gel permeation chromatography, and ion chromatography analysis results indicated the monosaccharide composition of cAMPs 1A with 1.23 * 104 Da molecular weight to be fucose, arabinose, galactose, glucose, and xylose, with molar ratios of 0.01:0.06:0.20:1.00:0.06, respectively. The UV spectroscopy detected no protein and nucleic acid in cAMPs-1A. We used FTIR analysis to characterize the alpha-d-pyranoid configuration in cAMPs-1A. In addition, we performed animal experiments in vivo to evaluate the antitumor and immunomodulatory effects of cAMPs-1A. The results suggested that cAMPs-1A oral administration could significantly inhibit tumor growth with the inhibitory rate of 20.53%, 36.50% and 44.49%, respectively, at the dosage of 75,150, and 300 mg/kg. Moreover, cAMPs-1A treatment could also effectively protect the immune organs, promote macrophage pinocytosis, and improve the percentages of lymphocyte subsets in the peripheral blood of tumor-bearing mice. These findings demonstrate that the polysaccharide cAMPs-1A has an underlying application as natural antitumor agents. PMID- 29283408 TI - Solution-Processed Gallium-Tin-Based Oxide Semiconductors for Thin-Film Transistors. AB - We investigated the effects of gallium (Ga) and tin (Sn) compositions on the structural and chemical properties of Ga-Sn-mixed (Ga:Sn) oxide films and the electrical properties of Ga:Sn oxide thin-film transistors (TFTs). The thermogravimetric analysis results indicate that solution-processed oxide films can be produced via thermal annealing at 500 degrees C. The oxygen deficiency ratio in the Ga:Sn oxide film increased from 0.18 (Ga oxide) and 0.30 (Sn oxide) to 0.36, while the X-ray diffraction peaks corresponding to Sn oxide significantly reduced. The Ga:Sn oxide film exhibited smaller grains compared to the nanocrystalline Sn oxide film, while the Ga oxide film exhibited an amorphous morphology. We found that the electrical properties of TFTs significantly improve by mixing Ga and Sn. Here, the optimum weight ratio of the constituents in the mixture of Ga and Sn precursor sols was determined to be 1.0:0.9 (Ga precursor sol:Sn precursor sol) for application in the solution-processed Ga:Sn oxide TFTs. In addition, when the Ga(1.0):Sn(0.9) oxide film was thermally annealed at 900 degrees C, the field-effect mobility of the TFT was notably enhanced from 0.02 to 1.03 cm2/Vs. Therefore, the mixing concentration ratio and annealing temperature are crucial for the chemical and morphological properties of solution-processed Ga:Sn oxide films and for the TFT performance. PMID- 29283409 TI - Omentin-A Novel Adipokine in Respiratory Diseases. AB - Adipokines, secreted by the adipose tissue, are extensively involved in the regulation and maintenance of various physiological and pathological processes, including insulin sensitivity, energy expenditure, glucose and lipid metabolism, inflammatory activity, neuroendocrine activity, immunity, cancer, homeostasis, angiogenesis, cardiovascular function, breeding and bone metabolism, and all functions of the endocrine-reproductive system axis. Omentin is a recently identified adipokine, which has become a research hotspot due to its pleiotropic effects on various diseases. However, the specific receptor for omentin has not been identified so far. In this study, we report that omentin levels fluctuate in various diseases. In addition, we have focused on the pleiotropic roles of omentin in pulmonary diseases, as it may act as a biomarker for malignant pleural mesothelioma (MPM) and is related to disease severity. Omentin may play significant roles in other pulmonary diseases, such as asthma, obstructive sleep apnea syndrome (OSAS), pulmonary arterial hypertension (PAH), acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD). This review summarizes the advances in current knowledge and future trends, which may provide a concise and general view on omentin and its effects on pulmonary biology. PMID- 29283411 TI - Reactive Fabrication and Effect of NbC on Microstructure and Tribological Properties of CrS Co-Based Self-Lubricating Coatings by Laser Cladding. AB - The CrS/NbC Co-based self-lubricating composite coatings were successfully fabricated on Cr12MoV steel surface by laser clad Stellite 6, WS2, and NbC mixed powders. The phase composition, microstructure, and tribological properties of the coatings ware investigated by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive spectrometer (EDS), as well as dry sliding wear testing. Based on the experimental results, it was found reactions between WS2 and Co-based alloy powder had occurred, which generated solid-lubricant phase CrS, and NbC play a key role in improving CrS nuclear and refining microstructure of Co-based composite coating during laser cladding processing. The coatings were mainly composed of gamma-Co, CrS, NbC, Cr23C6, and CoCx. Due to the distribution of the relatively hard phase of NbC and the solid lubricating phase CrS, the coatings had better wear resistance. Moreover, the suitable balance of CrS and NbC was favorable for further decreasing the friction and improving the stability of the contact surfaces between the WC ball and the coatings. The microhardness, friction coefficient, and wear rate of the coating 4 (Clad powders composed of 60 wt % Stellite 6, 30 wt % NbC and 10 wt % WS2) were 587.3 HV0.5, 0.426, and 5.61 * 10-5 mm3/N.m, respectively. PMID- 29283410 TI - Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature. AB - Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56 75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS like traits. PMID- 29283412 TI - Design and Implementation of a Coastal-Mounted Sensor for Oil Film Detection on Seawater. AB - The routine surveillance of oil spills in major ports is important. However, existing techniques and sensors are unable to trace oil and micron-thin oil films on the surface of seawater. Therefore, we designed and studied a coastal-mounted sensor, using ultraviolet-induced fluorescence and fluorescence-filter systems (FFSs), to monitor oil spills and overcome the disadvantages of traditional surveillance systems. Using seawater from the port of Lingshui (Yellow Sea, China) and six oil samples of different types, we found that diesel oil's relative fluorescence intensity (RFI) was significantly higher than those of heavy fuel and crude oils in the 180-300 nm range-in the 300-400 nm range, the RFI value of diesel is far lower. The heavy fuel and crude oils exhibited an opposite trend in their fluorescence spectra. A photomultiplier tube, employed as the fluorescence detection unit, efficiently monitored different oils on seawater in field experiments. On-site tests indicated that this sensor system could be used as a coastal-mounted early-warning detection system for oil spills. PMID- 29283414 TI - Optical Microfiber Technology for Current, Temperature, Acceleration, Acoustic, Humidity and Ultraviolet Light Sensing. AB - Optical microfibers possess excellent optical and mechanical properties that have been exploited for sensing. We highlight the authors' recent work in the areas of current, temperature, acceleration, acoustic, humidity and ultraviolet-light sensing based on this exquisite technology, and the advantages and challenges of using optical microfibers are discussed. PMID- 29283413 TI - Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS/MS and MS Imaging Techniques. AB - Elevated circulating uremic toxins are associated with a variety of symptoms and organ dysfunction observed in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are representative uremic toxins that exert various harmful effects. We recently showed that IS induces metabolic alteration in skeletal muscle and causes sarcopenia in mice. However, whether organ-specific accumulation of IS and PCS is associated with tissue dysfunction is still unclear. We investigated the accumulation of IS and PCS using liquid chromatography/tandem mass spectrometry in various tissues from mice with adenine induced CKD. IS and PCS accumulated in all 15 organs analyzed, including kidney, skeletal muscle, and brain. We also visualized the tissue accumulation of IS and PCS with immunohistochemistry and mass spectrometry imaging techniques. The oral adsorbent AST-120 prevented some tissue accumulation of IS and PCS. In skeletal muscle, reduced accumulation following AST-120 treatment resulted in the amelioration of renal failure-associated muscle atrophy. We conclude that uremic toxins can accumulate in various organs and that AST-120 may be useful in treating or preventing organ dysfunction in CKD, possibly by reducing tissue accumulation of uremic toxins. PMID- 29283415 TI - Applications, Surface Modification and Functionalization of Nickel Nanorods. AB - The growing number of nanoparticle applications in science and industry is leading to increasingly complex nanostructures that fulfill certain tasks in a specific environment. Nickel nanorods already possess promising properties due to their magnetic behavior and their elongated shape. The relevance of this kind of nanorod in a complex measurement setting can be further improved by suitable surface modification and functionalization procedures, so that customized nanostructures for a specific application become available. In this review, we focus on nickel nanorods that are synthesized by electrodeposition into porous templates, as this is the most common type of nickel nanorod fabrication method. Moreover, it is a facile synthesis approach that can be easily established in a laboratory environment. Firstly, we will discuss possible applications of nickel nanorods ranging from data storage to catalysis, biosensing and cancer treatment. Secondly, we will focus on nickel nanorod surface modification strategies, which represent a crucial step for the successful application of nanorods in all medical and biological settings. Here, the immobilization of antibodies or peptides onto the nanorod surface adds another functionality in order to yield highly promising nanostructures. PMID- 29283416 TI - In Vitro Selection of a Single-Stranded DNA Molecular Recognition Element against the Pesticide Fipronil and Sensitive Detection in River Water. AB - Fipronil is a commonly used insecticide that has been shown to have environmental and human health risks. The current standard methods of detection for fipronil and its metabolites, such as GC-MS, are time consuming and labor intensive. In this study, a variant of systematic evolution of ligands by exponential enrichment (SELEX), was utilized to identify the first single-stranded DNA (ssDNA) molecular recognition element (MRE) that binds to fipronil with high affinity (Kd = 48 +/- 8 nM). The selected MRE displayed low cross binding activity on various environmentally relevant, structurally unrelated herbicides and pesticides, in addition to broad-spectrum binding activity on major metabolites of fipronil and a structurally similar pesticide in prepared river samples. Additionally, a proof-of-principle fluorescent detection assay was developed by using the selected ssDNA MRE as a signal-reporting element, with a limit of detection of 105 nM in a prepared river water sample. PMID- 29283417 TI - Activation Profile Analysis of CruCA4, an alpha-Carbonic Anhydrase Involved in Skeleton Formation of the Mediterranean Red Coral, Corallium rubrum. AB - CruCA4, a coral alpha-carbonic anhydrase (CA, EC 4.2.1.1) involved in the biomineralization process of the Mediterranean red coral, Corallium rubrum, was investigated for its activation with a panel of amino acids and amines. Most compounds showed considerable activating properties, with a rather well defined structure-activity relationship. The most effective CruCA4 activators were d-His, 4-H2N-l-Phe, Histamine, Dopamine, Serotonin, 1-(2-Aminoethyl)-piperazine, and l Adrenaline, with activation constants in the range of 8-98 nM. Other amines and amino acids, such as d-DOPA, l-Tyr, 2-Pyridyl-methylamine, 2-(2-Aminoethyl) pyridine and 4-(2-Aminoethyl)-morpholine, were submicromolar CruCA4 activators, with KA ranging between 0.15 and 0.93 uM. Since it has been shown that CA activators may facilitate the initial phases of in-bone mineralization, our study may be relevant for finding modulators of enzyme activity, which can enhance the formation of the red coral skeleton. PMID- 29283418 TI - Chrysin Induces Antidiabetic, Antidyslipidemic and Anti-Inflammatory Effects in Athymic Nude Diabetic Mice. AB - Extensive knowledge of diabetes and its complications is helpful to find new drugs for proper treatment to stop degenerative changes derived from this disease. In this context, chrysin (5,7-dihydroxyflavone) is a natural product that occurs in a variety of flowers and fruits with anti-inflammatory and antidiabetic effects, among others. Thus, a diabetic model in athymic nude mice was developed and used to establish the ability of chrysin to decrease the secretion of pro-inflammatory cytokines. Also, it was determined the acute (50 mg/kg) and sub-acute (50 mg/kg/day/10 days) antidiabetic and antihyperlipidemic activities after the period of time treatment. Results indicate that chrysin has significant acute antihyperglycemic and antidiabetic effects in nude diabetic mice (p < 0.05). Moreover, triglyceride blood levels were reduced and IL-1beta and TNF-alpha were diminished after 10 days' treatment compared with control group (p < 0.05). In conclusion, it was found that chrysin could produce similar effects as metformin, a drug used for the treatment of diabetes, since both test samples decreased glucose and triglycerides levels, they impaired the generation of pro-inflammatory cytokines involved in the development of diabetes and its consequences, such as atherosclerosis and other cardiovascular diseases. PMID- 29283419 TI - Aluminum Matrix Composite (AlSi7Mg2Sr0.03/SiCp) Pistons Obtained by Mechanical Mixing Method. AB - Metal matrix composites are undoubtedly a group of advanced engineering materials. Compared to unreinforced matrix material, they are characterized by increased strength, greater stiffness, increased wear resistance, better mechanical properties and dimensional stability at elevated temperatures as well as lower density. Due to its very favorable tribological properties for many years research has been conducted on the application of MMC in friction node. The article presents important technological aspects related to the production and properties of composite pistons. Under industrial conditions, a composite suspension (AlSi7Mg2Sr0.03/SiCp 10 vol %) was prepared to allow casting of the semi-finished pistons series. Machining parameters of the working surfaces of the piston were selected on the basis of the turning test made on PCD, PCNM and uncoated carbide tools. The tribological properties of the composite pistons were determined on the basis of the pin-on-disc and the abrasion wear. The scuffing tests carried out under real operating conditions have confirmed the possibility of using composite pistons in air compressors. PMID- 29283420 TI - Genome Sequencing and Assembly by Long Reads in Plants. AB - Plant genomes generated by Sanger and Next Generation Sequencing (NGS) have provided insight into species diversity and evolution. However, Sanger sequencing is limited in its applications due to high cost, labor intensity, and low throughput, while NGS reads are too short to resolve abundant repeats and polyploidy, leading to incomplete or ambiguous assemblies. The advent and improvement of long-read sequencing by Third Generation Sequencing (TGS) methods such as PacBio and Nanopore have shown promise in producing high-quality assemblies for complex genomes. Here, we review the development of sequencing, introducing the application as well as considerations of experimental design in TGS of plant genomes. We also introduce recent revolutionary scaffolding technologies including BioNano, Hi-C, and 10* Genomics. We expect that the informative guidance for genome sequencing and assembly by long reads will benefit the initiation of scientists' projects. PMID- 29283421 TI - Automatic Classification of Sub-Techniques in Classical Cross-Country Skiing Using a Machine Learning Algorithm on Micro-Sensor Data. AB - The automatic classification of sub-techniques in classical cross-country skiing provides unique possibilities for analyzing the biomechanical aspects of outdoor skiing. This is currently possible due to the miniaturization and flexibility of wearable inertial measurement units (IMUs) that allow researchers to bring the laboratory to the field. In this study, we aimed to optimize the accuracy of the automatic classification of classical cross-country skiing sub-techniques by using two IMUs attached to the skier's arm and chest together with a machine learning algorithm. The novelty of our approach is the reliable detection of individual cycles using a gyroscope on the skier's arm, while a neural network machine learning algorithm robustly classifies each cycle to a sub-technique using sensor data from an accelerometer on the chest. In this study, 24 datasets from 10 different participants were separated into the categories training-, validation- and test-data. Overall, we achieved a classification accuracy of 93.9% on the test-data. Furthermore, we illustrate how an accurate classification of sub-techniques can be combined with data from standard sports equipment including position, altitude, speed and heart rate measuring systems. Combining this information has the potential to provide novel insight into physiological and biomechanical aspects valuable to coaches, athletes and researchers. PMID- 29283422 TI - Hyperglycemia Augments the Adipogenic Transdifferentiation Potential of Tenocytes and Is Alleviated by Cyclic Mechanical Stretch. AB - Diabetes mellitus is associated with damage to tendons, which may result from cellular dysfunction in response to a hyperglycemic environment. Tenocytes express diminished levels of tendon-associated genes under hyperglycemic conditions. In contrast, mechanical stretch enhances tenogenic differentiation. However, whether hyperglycemia increases the non-tenogenic differentiation potential of tenocytes and whether this can be mitigated by mechanical stretch remains elusive. We explored the in vitro effects of high glucose and mechanical stretch on rat primary tenocytes. Specifically, non-tenogenic gene expression, adipogenic potential, cell migration rate, filamentous actin expression, and the activation of signaling pathways were analyzed in tenocytes treated with high glucose, followed by the presence or absence of mechanical stretch. We analyzed tenocyte phenotype in vivo by immunohistochemistry using an STZ (streptozotocin) induced long-term diabetic mouse model. High glucose-treated tenocytes expressed higher levels of the adipogenic transcription factors PPARgamma and C/EBPs. PPARgamma was also highly expressed in diabetic tendons. In addition, increased adipogenic differentiation and decreased cell migration induced by high glucose implicated a fibroblast-to-adipocyte phenotypic change. By applying mechanical stretch to tenocytes in high-glucose conditions, adipogenic differentiation was repressed, while cell motility was enhanced, and fibroblastic morphology and gene expression profiles were strengthened. In part, these effects resulted from a stretch-induced activation of ERK (extracellular signal-regulated kinases) and a concomitant inactivation of Akt. Our results show that mechanical stretch alleviates the augmented adipogenic transdifferentiation potential of high glucose-treated tenocytes and helps maintain their fibroblastic characteristics. The alterations induced by high glucose highlight possible pathological mechanisms for diabetic tendinopathy. Furthermore, the beneficial effects of mechanical stretch on tenocytes suggest that an appropriate physical load possesses therapeutic potential for diabetic tendinopathy. PMID- 29283425 TI - Molecular Basis for Converting (2S)-Methylsuccinyl-CoA Dehydrogenase into an Oxidase. AB - Although flavoenzymes have been studied in detail, the molecular basis of their dioxygen reactivity is only partially understood. The members of the flavin adenosine dinucleotide (FAD)-dependent acyl-CoA dehydrogenase and acyl-CoA oxidase families catalyze similar reactions and share common structural features. However, both enzyme families feature opposing reaction specificities in respect to dioxygen. Dehydrogenases react with electron transfer flavoproteins as terminal electron acceptors and do not show a considerable reactivity with dioxygen, whereas dioxygen serves as a bona fide substrate for oxidases. We recently engineered (2S)-methylsuccinyl-CoA dehydrogenase towards oxidase activity by rational mutagenesis. Here we characterized the (2S)-methylsuccinyl CoA dehydrogenase wild-type, as well as the engineered (2S)-methylsuccinyl-CoA oxidase, in detail. Using stopped-flow UV-spectroscopy and liquid chromatography mass spectrometry (LC-MS) based assays, we explain the molecular base for dioxygen reactivity in the engineered oxidase and show that the increased oxidase function of the engineered enzyme comes at a decreased dehydrogenase activity. Our findings add to the common notion that an increased activity for a specific substrate is achieved at the expense of reaction promiscuity and provide guidelines for rational engineering efforts of acyl-CoA dehydrogenases and oxidases. PMID- 29283426 TI - A Compound Sensor for Simultaneous Measurement of Packing Density and Moisture Content of Silage. AB - Packing density and moisture content are important factors in investigating the ensiling quality. Low packing density is a major cause of loss of sugar content. The moisture content also plays a determinant role in biomass degradation. To comprehensively evaluate the ensiling quality, this study focused on developing a compound sensor. In it, moisture electrodes and strain gauges were embedded into an ASABE Standard small cone for the simultaneous measurements of the penetration resistance (PR) and moisture content (MC) of silage. In order to evaluate the performance of the designed sensor and the theoretical analysis being used, relevant calibration and validation tests were conducted. The determination coefficients are 0.996 and 0.992 for PR calibration and 0.934 for MC calibration. The validation indicated that this measurement technique could determine the packing density and moisture content of the silage simultaneously and eliminate the influence of the friction between the penetration shaft and silage. In this study, we not only design a compound sensor but also provide an alternative way to investigate the ensiling quality which would be useful for further silage research. PMID- 29283427 TI - Electrochemical Impedance Analysis of a PEDOT:PSS-Based Textile Energy Storage Device. AB - A textile-based energy storage device with electroactive PEDOT:PSS (poly(3,4 ethylenedioxythiophene)/poly(4-styrenesulfonate)) polymer functioning as a solid state polyelectrolyte has been developed. The device was fabricated on textile fabric with two plies of stainless-steel electroconductive yarn as the electrodes. In this study, cyclic voltammetry and electrochemical impedance analysis were used to investigate ionic and electronic activities in the bulk of PEDOT:PSS and at its interfaces with stainless steel yarn electrodes. The complex behavior of ionic and electronic origins was observed in the interfacial region between the conductive polymer and the electrodes. The migration and diffusion of the ions involved were confirmed by the presence of the Warburg element with a phase shift of 45 degrees (n = 0.5). Two different equivalent circuit models were found by simulating the model with the experimental results: (QR)(QR)(QR) for uncharged and (QR)(QR)(Q(RW)) for charged samples. The analyses also showed that the further the distance between electrodes, the lower the capacitance of the cell. The distribution of polymer on the cell surface also played important role to change the capacitance of the device. The results of this work may lead to a better understanding of the mechanism and how to improve the performance of the device. PMID- 29283424 TI - Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A. AB - Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21-23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA-mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that CKS1B, CXCL1, and GPRC5A are putative targets of miR-204 and elucidated that miR-204 acted as potential tumor suppressor and, therefore, are useful as a promising therapeutic target for gastric cancer. PMID- 29283428 TI - Structure Related Inhibition of Enzyme Systems in Cholinesterases and BACE1 In Vitro by Naturally Occurring Naphthopyrone and Its Glycosides Isolated from Cassia obtusifolia. AB - Cassia obtusifolia Linn. have been used to improve vision, inflammatory diseases, and as hepatoprotective agents and to promote urination from ancient times. In the present study, we investigated the influence of glycosylation of components of C. obtusifolia and structure-activity relationships (SARs) with respect to the inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which are related to Alzheimer's disease (AD). All six C. obtusifolia-derived compounds, rubrofusarin (1), rubrofusarin 6-O-beta-d-glucopyranoside (2), rubrofusarin 6-O beta-d-gentiobioside (3), nor-rubrofusarin 6-O-beta-d-glucoside (4), isorubrofusarin 10-O-beta-d-gentiobioside (5), and rubrofusarin 6-O-beta-d triglucoside (6) showed promising inhibitory activity against AChE/BACE1. Compounds 3 and 4 showed most significant inhibition against AChE and BACE1, respectively. The SARs results emphasized the importance of gentiobiosyl moiety in the rubrofusarin for AChE inhibition, whereas the presence of hydroxyl group at C-8 and the glucosyl moiety at the C-6 position in the nor-rubrofusarin appeared to largely determine BACE1 inhibition. Kinetics and docking studies showed the lowest binding energy and highest affinity for mixed-type inhibitors, 3 and 4. Hydrophobic bonds interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. These results suggest that C. obtusifolia and its constituents have therapeutic potential, and that the SARs of its active components are further explored with a view towards developing a treatment for AD. PMID- 29283423 TI - Covalent Organic Frameworks: From Materials Design to Biomedical Application. AB - Covalent organic frameworks (COFs) are newly emerged crystalline porous polymers with well-defined skeletons and nanopores mainly consisted of light-weight elements (H, B, C, N and O) linked by dynamic covalent bonds. Compared with conventional materials, COFs possess some unique and attractive features, such as large surface area, pre-designable pore geometry, excellent crystallinity, inherent adaptability and high flexibility in structural and functional design, thus exhibiting great potential for various applications. Especially, their large surface area and tunable porosity and pi conjugation with unique photoelectric properties will enable COFs to serve as a promising platform for drug delivery, bioimaging, biosensing and theranostic applications. In this review, we trace the evolution of COFs in terms of linkages and highlight the important issues on synthetic method, structural design, morphological control and functionalization. And then we summarize the recent advances of COFs in the biomedical and pharmaceutical sectors and conclude with a discussion of the challenges and opportunities of COFs for biomedical purposes. Although currently still at its infancy stage, COFs as an innovative source have paved a new way to meet future challenges in human healthcare and disease theranostic. PMID- 29283430 TI - A Concept of Thermographic Method for Non-Destructive Testing of Polymeric Composite Structures Using Self-Heating Effect. AB - Traditional techniques of active thermography require an external source of energy used for excitation, usually in the form of high power lamps or ultrasonic devices. In this paper, the author presents an alternative approach based on the self-heating effect observable in polymer-based structures during cyclic loading. The presented approach is based on, firstly, determination of bending resonance frequencies of a tested structure, and then, on excitation of a structure with a multi-harmonic signal constructed from the harmonics with frequencies of determined resonances. Following this, heating-up of a tested structure occurs in the location of stress concentration and mechanical energy dissipation due to the viscoelastic response of a structure. By applying multi-harmonic signal, one ensures coverage of the structure by such heated regions. The concept is verified experimentally on artificially damaged composite specimens. The results demonstrate the presented approach and indicate its potential, especially when traditional methods of excitation with an external structure for thermographic inspection cannot be applied. PMID- 29283429 TI - The Dark Side of IFN-gamma: Its Role in Promoting Cancer Immunoevasion. AB - Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-gamma, it has also been involved in promoting an outgrowth of tumor cells with immunoevasive phenotype suggesting an existence of a dark "tumor-promoting" side effect of IFN-gamma. In this review, we will summarize this multi-functional role of IFN-gamma in tumor context, how it promotes changes in tumor phenotype towards increased fitness for growth in immunocompetent host. Furthermore, we summarize how IFN-gamma is involved in homeostatic or cancer-triggered mechanisms to establish an immunosuppressive tumor microenvironment. PMID- 29283432 TI - How Magnetic Disturbance Influences the Attitude and Heading in Magnetic and Inertial Sensor-Based Orientation Estimation. AB - With the advancements in micro-electromechanical systems (MEMS) technologies, magnetic and inertial sensors are becoming more and more accurate, lightweight, smaller in size as well as low-cost, which in turn boosts their applications in human movement analysis. However, challenges still exist in the field of sensor orientation estimation, where magnetic disturbance represents one of the obstacles limiting their practical application. The objective of this paper is to systematically analyze exactly how magnetic disturbances affects the attitude and heading estimation for a magnetic and inertial sensor. First, we reviewed four major components dealing with magnetic disturbance, namely decoupling attitude estimation from magnetic reading, gyro bias estimation, adaptive strategies of compensating magnetic disturbance and sensor fusion algorithms. We review and analyze the features of existing methods of each component. Second, to understand each component in magnetic disturbance rejection, four representative sensor fusion methods were implemented, including gradient descent algorithms, improved explicit complementary filter, dual-linear Kalman filter and extended Kalman filter. Finally, a new standardized testing procedure has been developed to objectively assess the performance of each method against magnetic disturbance. Based upon the testing results, the strength and weakness of the existing sensor fusion methods were easily examined, and suggestions were presented for selecting a proper sensor fusion algorithm or developing new sensor fusion method. PMID- 29283431 TI - RAD4 and RAD23/HMR Contribute to Arabidopsis UV Tolerance. AB - In plants, exposure to solar ultraviolet (UV) light is unavoidable, resulting in DNA damage. Damaged DNA causes mutations, replication arrest, and cell death, thus efficient repair of the damaged DNA is essential. A light-independent DNA repair pathway called nucleotide excision repair (NER) is conserved throughout evolution. For example, the damaged DNA-binding protein Radiation sensitive 4 (Rad4) in Saccharomyces cerevisiae is homologous to the mammalian NER protein Xeroderma Pigmentosum complementation group C (XPC). In this study, we examined the role of the Arabidopsis thaliana Rad4/XPC homologue (AtRAD4) in plant UV tolerance by generating overexpression lines. AtRAD4 overexpression, both with and without an N-terminal yellow fluorescent protein (YFP) tag, resulted in increased UV tolerance. YFP-RAD4 localized to the nucleus, and UV treatment did not alter this localization. We also used yeast two-hybrid analysis to examine the interaction of AtRAD4 with Arabidopsis RAD23 and found that RAD4 interacted with RAD23B as well as with the structurally similar protein HEMERA (HMR). In addition, we found that hmr and rad23 mutants exhibited increased UV sensitivity. Thus, our analysis suggests a role for RAD4 and RAD23/HMR in plant UV tolerance. PMID- 29283433 TI - ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis. AB - For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting item sets through rule-based methodology. Thus, it has advantages to find causal effect relationships between the transcripts. In this work, we introduce two new rule-based similarity measures-weighted rank-based Jaccard and Cosine measures and then propose a novel computational framework to detect condensed gene co expression modules ( C o n G E M s) through the association rule-based learning system and the weighted similarity scores. In practice, the list of evolved condensed markers that consists of both singular and complex markers in nature depends on the corresponding condensed gene sets in either antecedent or consequent of the rules of the resultant modules. In our evaluation, these markers could be supported by literature evidence, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and Gene Ontology annotations. Specifically, we preliminarily identified differentially expressed genes using an empirical Bayes test. A recently developed algorithm-RANWAR-was then utilized to determine the association rules from these genes. Based on that, we computed the integrated similarity scores of these rule-based similarity measures between each rule-pair, and the resultant scores were used for clustering to identify the co-expressed rule-modules. We applied our method to a gene expression dataset for lung squamous cell carcinoma and a genome methylation dataset for uterine cervical carcinogenesis. Our proposed module discovery method produced better results than the traditional gene-module discovery measures. In summary, our proposed rule based method is useful for exploring biomarker modules from transcriptomic data. PMID- 29283434 TI - Elevation of the head during intensive care management in people with severe traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a major public health problem and a fundamental cause of morbidity and mortality worldwide. The burden of TBI disproportionately affects low- and middle-income countries. Intracranial hypertension is the most frequent cause of death and disability in brain-injured people. Special interventions in the intensive care unit are required to minimise factors contributing to secondary brain injury after trauma. Therapeutic positioning of the head (different degrees of head-of-bed elevation (HBE)) has been proposed as a low cost and simple way of preventing secondary brain injury in these people. The aim of this review is to evaluate the evidence related to the clinical effects of different backrest positions of the head on important clinical outcomes or, if unavailable, relevant surrogate outcomes. OBJECTIVES: To assess the clinical and physiological effects of HBE during intensive care management in people with severe TBI. SEARCH METHODS: We searched the following electronic databases from their inception up to March 2017: Cochrane Injuries' Specialised Register, CENTRAL, MEDLINE, Embase, three other databases and two clinical trials registers. The Cochrane Injuries' Information Specialist ran the searches. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) involving people with TBI who underwent different HBE or backrest positions. Studies may have had a parallel or cross-over design. We included adults and children over two years of age with severe TBI (Glasgow Coma Scale (GCS) less than 9). We excluded studies performed in children of less than two years of age because of their unfused skulls. We included any therapeutic HBE including supine (flat) or different degrees of head elevation with or without knee gatch or reverse Trendelenburg applied during the acute management of the TBI. DATA COLLECTION AND ANALYSIS: Two review authors independently checked all titles and abstracts, excluding references that clearly didn't meet all selection criteria, and extracted data from selected studies on to a data extraction form specifically designed for this review. There were no cases of multiple reporting. Each review author independently evaluated risk of bias through assessing sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. MAIN RESULTS: We included three small studies with a cross-over design, involving a total of 20 participants (11 adults and 9 children), in this review. Our primary outcome was mortality, and there was one death by the time of follow-up 28 days after hospital admission. The trials did not measure the clinical secondary outcomes of quality of life, GCS, and disability. The included studies provided information only for the secondary outcomes intracranial pressure (ICP), cerebral perfusion pressure (CPP), and adverse effects.We were unable to pool the results as the data were either presented in different formats or no numerical data were provided. We included narrative interpretations of the available data.The overall risk of bias of the studies was unclear due to poor reporting of the methods. There was marked inconsistency across studies for the outcome of ICP and small sample sizes or wide confidence intervals for all outcomes. We therefore rated the quality of the evidence as very low for all outcomes and have not included the results of individual studies here. We do not have enough evidence to draw conclusions about the effect of HBE during intensive care management of people with TBI. AUTHORS' CONCLUSIONS: The lack of consistency among studies, scarcity of data and the absence of evidence to show a correlation between physiological measurements such as ICP, CCP and clinical outcomes, mean that we are uncertain about the effects of HBE during intensive care management in people with severe TBI.Well-designed and larger trials that measure long-term clinical outcomes are needed to understand how and when different backrest positions can affect the management of severe TBI. PMID- 29283435 TI - Fitting motivational content and process: A systematic investigation of fit between value framing and self-regulation. AB - OBJECTIVE: Values are often phrased as ideals that people seek to approach, but they can also be conceptualized as counter-ideals that people seek to avoid. We aimed to test whether individuals endorse more strongly values that are framed in line with their predominant self-regulatory motivation, using individual difference scales in promotion/prevention (Higgins, 1997) and in behavioral approach/inhibition (Carver & White, 1994). To address this systematically, we developed approach- and avoidance-framed versions of the Portrait Value Questionnaire-RR (PVQ-RR; Schwartz et al., 2012). METHOD: Participants completed approach- and avoidance-framed PVQ-RR versions in two studies measuring regulatory focus or motivational orientation (together 414 U.S. adults, 48% female, ages 18-69) and one study manipulating motivational orientation (39 UK high school students, 79% female, ages 16-19). RESULTS: Value framing consistently interacted with both self-regulation variables. However, a fit between self-regulation and value framing resulted in greater value endorsement only for promotion-focused and approach-oriented (not prevention-focused and avoidance-oriented) participants. This may be because values are more naturally understood as ideal states that people seek to approach. CONCLUSIONS: Our findings provide first insights into the psychological process of person-value framing fit affecting value endorsement. We discuss implications for cross cultural value research and research on value-congruent behavior. PMID- 29283436 TI - Storage stability of egg sticks fortified with omega-3 fatty acids. AB - BACKGROUND: Egg sticks fortified with omega-3 polyunsaturated fatty acids (omega 3 PUFAs) were developed by replacing egg yolk with salmon, algae, and flax oils. Egg sticks were cooked before analysis. Quality indicators for storage stability under different packaging and temperature were determined throughout a 28-day storage. Egg sticks were vacuum and non-vacuum packed. Further, both packaging treatments were divided into two storage temperatures of 4 and 10 degrees C. Quality indicators were determined every 7 days, including pH, syneresis, texture, color, microbial growth, proximate composition, fatty acid profile, and lipid oxidation. RESULTS: Vacuum-packed egg sticks stored at 4 degrees C had slower degradation over time than all other treatments; however, they also had higher syneresis, harder texture, and higher anaerobic growth. Although vacuum packaging slowed lipid oxidation, it had limited effect on prevention of omega-3 PUFAs degradation; whereas refrigeration (4 degrees C) seemed to prevent degradation of omega-3 PUFAs better than it could slow lipid oxidation. CONCLUSION: Based on the results, it can be concluded that both vacuum packaging and refrigeration at 4 degrees C decrease degradation of egg sticks developed in the present study during storage. Under these conditions, egg sticks may maintain stability for at least 21 days of storage. (c) 2017 Society of Chemical Industry. PMID- 29283437 TI - Analytic survey of 57 cases of oral metastases. AB - BACKGROUND: Oral lesions have been reported among the first signs of an undiagnosed metastatic disease. Accurate diagnosis of an occult metastasis remains critical in determining the treatment course. Previous studies regarding oral metastatic tumors present varied data regarding the most frequent metastases to the oral cavity. These discrepancies echo the changes in incidence rates for certain malignancies over time and demonstrate the need for periodic updates in oral metastasis studies. METHODS: Using Text Information Extraction System, a de identified pathology database, we compiled 57 cases over a period of 19 years using key terms to search for oral metastases. RESULTS: For both males and females, the most common primary sites were lung (21.1%), liver (12.3%), breast (10.5%), kidney (10.5%), and colorectal (8.8%). We found an equal number of lung and breast metastases in females and metastases from the liver to be the most prevalent for males. In most of our cases (54.9%), the patient had no history of the primary malignancy and the oral lesion preceded awareness of the widespread cancer. CONCLUSIONS: As a departure from many previous case series, we found lung and breast metastases to be equally numerous in women and liver as the most common oral metastasis in men. Also, we identified a tendency for the patient to present with a previous history in certain malignancies, such as breast cancer, whereas in other malignancies, such as renal cell carcinoma, our data demonstrated a propensity to present in the oral cavity without history of a primary tumor. PMID- 29283438 TI - Spontaneous pulmonary adenosquamous carcinoma in a free-living black capuchin monkey (Sapajus nigritus). AB - Pulmonary neoplasia is rare among wild New World primates. We report the gross, microscopical, and immunohistochemical features of a primary multicentric pulmonary adenosquamous carcinoma in a free-living black capuchin monkey (Sapajus nigritus). Herein, the spectrum of pulmonary neoplasms in non-human primates is widened and briefly reviewed. PMID- 29283439 TI - Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy. AB - OBJECTIVE: Autosomal-recessive mutations in TBCK cause intellectual disability of variable severity. Although the physiological function of TBCK remains unclear, loss-of-function mutations are associated with inhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Given that mTORC1 signaling is known to regulate autophagy, we hypothesized that TBCK-encephalopathy patients with a neurodegenerative course have defects in autophagic-lysosomal dysfunction. METHODS: Children (n = 8) of Puerto Rican (Boricua) descent affected with homozygous TBCK p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK-/- patient-derived fibroblasts by immunostaining and assayed autophagic markers by western assay. Free sialylated oligosaccharide profiles were assayed in patient's urine and fibroblasts. RESULTS: The neurological phenotype of children with TBCK p.R126X mutations, which we call TBCK-encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, and epilepsy. Systemic features include coarse facies, dyslipidemia, and osteoporosis. TBCK-/- fibroblasts in vitro exhibit increased numbers of LC3+ autophagosomes and increased autophagic flux by immunoblots. Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine. INTERPRETATION: TBCKE is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently observed in patients with the p.R126X mutation. We provide evidence that inappropriate autophagy in the absence of cellular stressors may play a role in this disorder, and that mTORC1 activation may ameliorate the autophagic-lysosomal system dysfunction. Free oligosaccharide profiles could serve as a novel biomarker for this disorder as well as a tool to evaluate potential therapeutic interventions. Ann Neurol 2018;83:153-165. PMID- 29283440 TI - Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. AB - Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It was approved by the U.S. Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and it is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article. Common adverse events are reviewed, and management strategies for select adverse events are discussed. Implications for contemporary practitioners are also provided because use of this novel agent is likely to increase as more studies are completed. PMID- 29283441 TI - Pathological mechanisms underlying single large-scale mitochondrial DNA deletions. AB - OBJECTIVE: Single, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle. METHODS: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large-scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction. RESULTS: We have defined 3 "classes" of single, large-scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class. INTERPRETATION: Combining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex-specific protein-encoding genes. Furthermore, removal of mt-tRNA genes impacts specific complexes only at high deletion levels, when complex-specific protein-encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115-130. PMID- 29283443 TI - Letter on 'European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis'. PMID- 29283442 TI - Myeloid cell plasticity in the evolution of central nervous system autoimmunity. AB - OBJECTIVE: Myeloid cells, including macrophages and dendritic cells, are a prominent component of central nervous system (CNS) infiltrates during multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Although myeloid cells are generally thought to be proinflammatory, alternatively polarized subsets can serve noninflammatory and/or reparative functions. Here we investigate the heterogeneity and biological properties of myeloid cells during central nervous system autoimmunity. METHODS: Myeloid cell phenotypes in chronic active MS lesions were analyzed by immunohistochemistry. In addition, immune cells were isolated from the CNS during exacerbations and remissions of EAE and characterized by flow cytometric, genetic, and functional assays. RESULTS: Myeloid cells expressing inducible nitric oxide synthase (iNOS), indicative of a proinflammatory phenotype, were detected in the actively demyelinating rim of chronic active MS lesions, whereas macrophages expressing mannose receptor (CD206), a marker of alternatively polarized human myeloid cells, were enriched in the quiescent lesion core. During EAE, CNS-infiltrating myeloid cells, as well as microglia, shifted from expression of proinflammatory markers to expression of noninflammatory markers immediately prior to clinical remissions. Murine CNS myeloid cells expressing the alternative lineage marker arginase-1 (Arg1) were partially derived from iNOS+ precursors and were deficient in activating encephalitogenic T cells compared with their Arg1- counterparts. INTERPRETATION: These observations demonstrate the heterogeneity of CNS myeloid cells, their evolution during the course of autoimmune demyelinating disease, and their plasticity on the single cell level. Future therapeutic strategies for disease modification in individuals with MS may be focused on accelerating the transition of CNS myeloid cells from a proinflammatory to a noninflammatory phenotype. Ann Neurol 2018;83:131-141. PMID- 29283444 TI - Vasodilator dysfunction and oligodendrocyte dysmaturation in aging white matter. AB - OBJECTIVE: Microvascular brain injury (mVBI) is a common pathological correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter (WM) injury (WMI). VCID appears to arise from chronic recurrent white matter ischemia that triggers oxidative stress and an increase in total oligodendrocyte lineage cells. We hypothesized that mVBI involves vasodilator dysfunction of white matter penetrating arterioles and aberrant oligodendrocyte progenitor cell (OPC) responses to WMI. METHODS: We analyzed cases of mVBI with low Alzheimer's disease neuropathological change in prefrontal cortex WM from rapid autopsies in a population-based cohort where VCID frequently occurs. Arteriolar vasodilator function was quantified by videomicroscopy. OPC maturation was quantified using lineage specific markers. RESULTS: Acetylcholine-mediated arteriolar dilation in mVBI was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis-defined WMI was positively associated with increased OPCs and was negatively associated with decreased mature oligodendrocytes. INTERPRETATION: Selectively impaired vasodilator function of WM penetrating arterioles in mVBI occurs in association with aberrant differentiation of OPCs in WMI, which supports that myelination disturbances in VCID are related to disrupted maturation of myelinating oligodendrocytes. Ann Neurol 2018;83:142-152. PMID- 29283445 TI - Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry. AB - An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry has been developed and validated for simultaneous measurement of four tyrosine kinase inhibitors used for renal cell carcinoma and their metabolites in human plasma. Despite their similar structures, it is difficult to measure plasma levels of these compounds simultaneously using optimal MS parameters for each compound because a quantitative range exceeding 50,000-fold is required. To overcome this problem, we used a linear range shift technique using in-source collision-induced dissociation. Linearity ranges of sorafenib, sorafenib N-oxide, sunitinib, N desethyl sunitinib, axitinib and pazopanib were 100-10,000, 10-1,000, 1-100, 1 100, 1-100 and 500-50,000 ng/mL, respectively. The intra- and inter-day precision and accuracy were high, and coefficients of variation and relative error were <10.3% and within +/-11.8%, respectively. The matrix effects of all analytes ranged from 87.7 to 114.8%. Extraction recoveries and overall recoveries showed small extraction loss (<15.0%) for all analytes. Moreover, all cancer patient samples used in this study were successfully quantified and fell within the linear range of measurement. Therefore, this novel analytical system using in source collision-induced dissociation has sufficient performance to measure plasma concentrations of these four tyrosine kinase inhibitors and their metabolites for therapeutic drug monitoring. PMID- 29283446 TI - Potential cardiac risk of immune-checkpoint blockade as anticancer treatment: What we know, what we do not know, and what we can do to prevent adverse effects. AB - Cancer immunotherapy has become a well-established treatment option for some cancers after the development of a family of drugs targeting the so-called immune checkpoints, such as CTLA4 and PD-1 with PD-L1. These co-receptors/ligands inhibit the activation of T-cell, thus preventing an excessive inflammatory response. Tumors exploit these pathways to induce immune tolerance to themselves. Thus, the main effect of checkpoint-blocking drugs is to awake an immune response primarily directed against cancer cells. Nonetheless, as the immune response elicited by these drugs is not completely tumor-specific, their use may actually cause several adverse effects, including adverse cardiovascular effects. In this review, we will discuss the principles and potentiality of immunotherapy for cancer treatment, the experimental and clinical data on the role of CTLA4 and PD 1 with PD-L1 as immune-checkpoints in the cancer environment and in the cardiovascular system, and strategies aimed at preventing possible cardiovascular adverse effects of immune-checkpoint blockers. PMID- 29283447 TI - Hepatocellular carcinoma in a free-living marmoset (Callithrix sp.) with concomitant biliary trematodiasis. AB - Hepatocellular carcinoma (HCC) is rare in New World primates. We report the gross, microscopical, and immunocytochemical features of a spontaneous HCC in a free-living marmoset (Callithrix sp.). Hepatitis B and C virus and aflatoxin immunohistochemistry were negative; however, concomitant intra- and extrahepatic biliary trematodiasis could have played a role. PMID- 29283448 TI - Pharmacokinetics and Safety of Momelotinib in Subjects With Hepatic or Renal Impairment. AB - Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open-label, parallel-group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200-mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least-squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration-time curve from time 0 to infinity [AUCinfinity ] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUCinfinity was increased (GMR, 197%; 90%CI, 129%-301%), and M21 AUCinfinity was decreased (GMR, 52%; 90%CI, 34%-79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced. PMID- 29283449 TI - Oxaprozin prodrug as safer nonsteroidal anti-inflammatory drug: Synthesis and pharmacological evaluation. AB - Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In order to circumvent the GI complications, oxaprozin was amended as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. Dextran of average molecular weight (60,000-90,000 Da) was exploited as a carrier in the process of oxaprozin prodrug production by esterification. The structural profiles of the synthesized oxaprozin prodrug were characterized by FT IR and NMR spectroscopy. The oxaprozin prodrug possessed optimal molecular weight, lipophilicity, partition coefficient, protein binding, and degree of substitution of 52.4%. The release of oxaprozin upon hydrolysis of the prodrug in both simulated gastric fluid and simulated intestinal fluid followed first-order kinetics with 55.2 min of half-life. Varied ADME properties of the prodrug resulted upon Schrodinger's QikProp tool application. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a remarkable decrease in the ulcer index and being devoid of antigenicity in experimental animals. Thus, it is evident that oxaprozin prodrug is a safer oral NSAID without causing any ulcerations. PMID- 29283451 TI - Investigating the influence of intraindividual changes in perceived stress symptoms on injury risk in soccer. AB - Research has shown that high levels of stress and stress responsivity can increase the risk of injuries. However, most of the research that has supported this notion has focused on between-person relationships, ignoring the relationships at the within-person level. As a result, the objective of this study was to investigate if within-person changes in perceived stress symptoms over a 1-month time period could predict injury rates during the subsequent 3 months. A prospective design with two measurement points (Time 1-at the beginning of the season and Time 2-1 month into the season) was utilized. A total of 121 competitive soccer players (85 males and 36 females; Mage = 18.39, SD = 3.08) from Sweden and the United States completed the Kessler Psychological Distress Scale (KPDS) and a demographic sheet at Time 1. The KPDS was also completed at Time 2, and all acute injuries that occurred during the subsequent 3-month period were recorded. A Bayesian latent change scores model was used to determine whether within-person changes in stress symptoms could predict the risk of injury. Results revealed that there was a credible positive effect of changes in stress symptoms on injury rates, indicating that an increase in reported stress symptoms was related to an increased risk for injury. This finding highlights the importance of creating caring and supportive sporting environments and relationships and teaching stress management techniques, especially during the earlier portion of competitive seasons, to possibly reduce the occurrence of injuries. PMID- 29283450 TI - The effect of fasting status on lipids, lipoproteins, and inflammatory biomarkers assessed after hospitalization for an acute coronary syndrome: Insights from PROVE IT-TIMI 22. AB - BACKGROUND: For decades, fasting for 8 to 12 hours has been recommended for measurement of lipid profiles. The effect of fasting on low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) has been described in healthy cohorts and those with stable disease states. Recently, guidelines suggested that fasting may not be necessary due to its small effect on lipid measures. Little is known, however, regarding whether the impact of fasting is altered in the setting of an acute coronary syndrome (ACS). HYPOTHESIS: We hypothesized that the post-ACS period would minimally effect the impact of fasting status on lipid measurements. METHODS: We evaluated the association of fasting on lipid and other biomarkers at the randomization visit, which occurred at a median of 7 days after the onset of an ACS, as well as during follow-up, in a cohort of 4177 subjects from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. RESULTS: Fasting samples were independently associated with a higher LDL-C of 4.1 mg/dL and apolipoprotein-B 100 of 2.6 mg/dL as well as a lower TG of 21.0 mg/dL and high-sensitivity C reactive protein of 0.48 mg/dL. The relative difference was 3.8% for LDL-C and 11.3% for TG. Fasting did not change total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), or apolipoprotein C-III. CONCLUSIONS: Although fasting does impact lipid measurements, the effect on LDL-C is small (about 4 mg/dL), both early after ACS and during follow-up. These data provide support for recent guidelines that no longer advocate for fasting lipid samples, including in the setting of ACS. PMID- 29283452 TI - Comparative analysis of prodigiosin isolated from endophyte Serratia marcescens. AB - : Extraction of pigments from endophytes is an uphill task. Up till now, there are no efficient methods available to extract the maximum amount of prodigiosin from Serratia marcescens. This is one of the important endophytes of Beta vulgaris L. The present work was carried out for the comparative study of six different extraction methods such as homogenization, ultrasonication, freezing and thawing, heat treatment, organic solvents and inorganic acids to evaluate the efficiency of prodigiosin yield. Our results demonstrated that highest extraction was observed in ultrasonication (98.1 +/- 1.7%) while the lowest extraction by freezing and thawing (31.8 +/- 3.8%) methods. However, thin layer chromatography, high-performance liquid chromatography and Fourier transform infrared data suggest that bioactive pigment in the extract was prodigiosin. To the best of our knowledge, this is the first comprehensive study of extraction methods and identification and purification of prodigiosin from cell biomass of Ser. marcescens isolated from Beta vulgaris L. SIGNIFICANCE AND IMPACT OF THE STUDY: The prodigiosin family is a potent drug with anticancer, antimalarial, antibacterial, antifungal, antiproliferative and immunosuppressive activities. Moreover, it has immense potential in pharmaceutical, food and textile industries. For the industrial perspective, it is essential to achieve purified, high yield and cost-effective extraction of prodigiosin. To the best of our knowledge, this is the first comprehensive study on prodigiosin extraction and also the first report on endophyte Serratia marcescens isolated from Beta vulgaris L. The significance of our results is to extract high amount and good quality prodigiosin for commercial application. PMID- 29283453 TI - Hydration of copper(II) amino acids complexes. AB - Hydration of the copper(II) bis-complexes with glycine, serine, lysine, and aspartic acid was studied by DFT and MD simulation methods. The distances between copper(II) and water molecules in the 1st and 2nd coordination shells, the average number of water molecules and their mean residence times in the hydration shells were calculated. Good agreement was observed between the values obtained and those found by DFT and NMR relaxation methods. Influence of the functional groups of the ligands and the cis-trans isomerism of the complexes on the structural and dynamical parameters of the hydration shells was displayed and explained. Analysis of the MD trajectories reveals the competition for a copper(II) axial position between water molecules or water molecules and the functional chain groups of the ligands and confirms the suggestion on the pentacoordination of copper(II) in such complexes. MD simulations show that only one axial position of Cu(II) is basically occupied at each time step while in average the coordination number more than 5 is observed. (c) 2017 Wiley Periodicals, Inc. PMID- 29283454 TI - Design, development and optimization of a transungual duple nail lacquer for onychomycosis therapy. PMID- 29283457 TI - Corrigendum. PMID- 29283458 TI - Aluminum bioavailability and toxicity to aquatic organisms: Introduction to the special section. PMID- 29283459 TI - Characterization of the facial microbiome in twins discordant for rosacea. AB - Previously, we determined that genetic and environmental factors contributed equally towards rosacea in twins. To assess an environmental factor, we characterized the malar cheek bacterial microbiome from twins discordant for rosacea. We found no significant difference in facial microbiome alpha and beta diversity between related twins discordant for rosacea. However, the relative percentage abundance of Gordonia and Geobacillus, low-abundant genera, was positively and negatively associated with rosacea severity, respectively. Our data demonstrate a significant correlation between facial microbiome and severity of rosacea in genetically matched twins and importantly that overall microbiome composition is largely unchanged. PMID- 29283460 TI - A novel scale for measurement of acquired dermal macular hyperpigmentation severity. PMID- 29283461 TI - A pathway-based association analysis identified FMNL1-MAP3K14 as susceptibility genes for leprosy. AB - The nuclear transcription factor-kappaB (NF-kappaB) plays a pivotal role in controlling both innate and adaptive immunity and regulates the expressions of many immunological mediators. Abundant evidences have showed the importance of NF kappaB pathway in the host immune responses against Mycobacterium leprae in the development of leprosy. However, no particular association study between leprosy and NF-kappaB pathway-related gene polymorphisms was reported. Here, we performed a large-scale and two-stage candidate association study to investigate the association between 94 NF-kappaB pathway-related genes and leprosy. Our results showed that rs58744688 was significantly associated with leprosy (P = 7.57 * 10-7 , OR = 1.12) by combining the previous genomewide association data sets and four independent validation sample series, consisting of a total of 4631 leprosy cases and 6413 healthy controls. This founding implicated that MAP3K14 and FMNL1 were susceptibility genes for leprosy, which suggested the involvement of macrophage targeting and NF-kappaB pathway in the development of leprosy. PMID- 29283462 TI - Role of T helper 17 cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients. AB - BACKGROUND: Alopecia areata (AA) is an organ-specific autoimmune disease with T cell-mediated attack of hair follicle autoantigens. As T helper 17 (Th17) cells and T regulatory (Treg) cells are crucially involved in the pathogenesis, the role of Th17 and Treg cytokines has not been studied yet. OBJECTIVE: To determine whether AA is associated with alterations in lesional and serum Th17 and Treg cytokines and studied whether they were associated with clinical type. METHODS: Scalp skin samples from 45 patients and eight normal controls were obtained for PCR specific for IFN-gamma, TNF-alpha, TGF-beta, IL-1, IL-2, IL-4, IL-10, IL-12A, IL-13, IL-17, IL-22 and IL-23. Serum cytokines were measured from 55 patients and 15 normal controls using ELISA. RESULTS: Lesional IL-17 and IL-22 were significantly increased in patient group. Moreover, positive correlations were shown between lesional IL-17, IL-22 and disease severity. Serum IL-1, IL-17, TNF alpha and TGF-beta were significantly increased, and positive correlation was shown between serum IL-17 and disease severity. CONCLUSION: These results showed significantly high Th17 cytokines in both lesion and serum in AA patients, which may highlight a functional role of these cytokines in the pathogenesis of AA. PMID- 29283463 TI - Neck rejuvenation by direct anterior medial cervicoplasty: the modified zigzag plasty according to Tschopp. AB - BACKGROUND: Conventional cervicofacial rhytidectomy has become the standard treatment of skin excess of the ageing neck. However, some patients want to avoid an extensive surgical procedure, especially if the anterior neck is the predominant problem zone. OBJECTIVE: To report on the efficacy and safety of a zigzag-shaped skin excision combined with platysma plication. METHODS AND MATERIALS: We present a retrospective case review series of six female patients. Skin excess was marked preoperatively using the skin pinching technique, then transferred to a zigzag-shaped area and finally excised using the method according to Tschopp, which is described. Patients were followed up for at least 1 year. RESULTS: All patients (age: 55-82 years, median: 65 years) were very satisfied with the results. On an overall patient satisfaction scale of 1-10 (1 being the best), the scars were graded on average 1.85 (median: 2) 1 year after surgery. No scar hypertrophy, functional impairment, nerve damage or other serious complications were observed. CONCLUSION: In selected patients, the direct anterior zigzag-shaped excision poses an effective, safe and easy surgical option for both skin excess and fat excess and platysma banding. The technique is easily reproducible, with low morbidity and high patient satisfaction. PMID- 29283464 TI - TGF-beta2 and TGF-beta3 from cultured beta-amyloid-treated or 3xTg-AD-derived astrocytes may mediate astrocyte-neuron communication. AB - Astrocytes participate in the development and resolution of neuroinflammation in numerous ways, including the release of cytokines and growth factors. Among many, astrocytes release transforming growth factors beta (TGF-beta) TGF-beta1, TGF beta2 and TGF-beta3. TGF-beta1 is the most studied isoform, while production and release of TGF-beta2 and TGF-beta3 by astrocytes have been poorly characterized. Here, we report that purified cultures of hippocampal astrocytes produce mainly TGF-beta3 followed by TGF-beta2 and TGF-beta1. Furthermore, astrocytes release principally the active form of TGF-beta3 over the other two. Changes in release of TGF-beta were sensitive to the calcineurin (CaN) inhibitor FK506. Starvation had no effect on TGF-beta1 and TGF-beta3 while TGF-beta2 mRNA was significantly up-regulated in a CaN-dependent manner. We further investigated production and release of astroglial TGF-beta in Alzheimer's disease-related conditions. Oligomeric beta-amyloid (Abeta) down-regulated TGF-beta1, while up-regulating TGF beta2 and TGF-beta3, in a CaN-dependent manner. In cultured hippocampal astrocytes from 3xTg-AD mice, TGF-beta2 and TGF-beta3, but not TGF-beta1, were up regulated, and this was CaN-independent. In hippocampal tissues from symptomatic 3xTg-AD mice, TGF-beta2 was up-regulated with respect to control mice. Finally, treatment with recombinant TGF-betas showed that TGF-beta2 and TGF-beta3 significantly reduced PSD95 protein in cultured hippocampal neurons, and this effect was paralleled by conditioned media from Abeta-treated astrocytes or from astrocytes from 3xTg-AD mice. Taken together, our data suggest that TGF-beta2 and TGF-beta3 are produced by astrocytes in a CaN-dependent manner and should be investigated further in the context of astrocyte-mediated neurodegeneration. PMID- 29283465 TI - Delta(but not theta)-band cortical entrainment involves speech-specific processing. AB - Cortical oscillations phase-align to the quasi-rhythmic structure of the speech envelope. This speech-brain entrainment has been reported in two frequency bands, that is both in the theta band (4-8 Hz) and in the delta band (<4 Hz). However, it is not clear if these two phenomena reflect passive synchronization of the auditory cortex to the acoustics of the speech input, or if they reflect higher processes involved in actively parsing speech information. Here, we report two magnetoencephalography experiments in which we contrasted cortical entrainment to natural speech compared to qualitative different control conditions (Experiment 1: amplitude-modulated white-noise; Experiment 2: spectrally rotated speech). We computed the coherence between the oscillatory brain activity and the envelope of the auditory stimuli. At the sensor-level, we observed increased coherence for the delta and the theta band for all conditions in bilateral brain regions. However, only in the delta band (but not theta), speech entrainment was stronger than either of the control auditory inputs. Source reconstruction in the delta band showed that speech, compared to the control conditions, elicited larger coherence in the right superior temporal and left inferior frontal regions. In the theta band, no differential effects were observed for the speech compared to the control conditions. These results suggest that whereas theta entrainment mainly reflects perceptual processing of the auditory signal, delta entrainment involves additional higher-order computations in the service of language processing. PMID- 29283466 TI - Improved segmental myocardial strain reproducibility using deformable registration algorithms compared with feature tracking cardiac MRI and speckle tracking echocardiography. AB - BACKGROUND: Segmental myocardial strain using feature tracking (FT) cardiac MRI is not acceptable due to poor reproducibility. PURPOSE: To assess the reproducibility of left ventricle (LV) segmental myocardial strain measured by deformation registration algorithm (DRA). STUDY TYPE: Prospective clinical trial. SUBJECTS: Sixteen healthy volunteers and 28 hypertrophic cardiomyopathy (HCM) patients. FIELD STRENGTH/SEQUENCE: Retrospective ECG gating cardiac MRI imaging was performed at 3.0T with a steady-state free precession (SSFP) sequence. ASSESSMENT: LV global and segmental myocardial strains were analyzed by DRA, FT, and speckle tracking echocardiography (STE) by two experienced observers and the reproducibility of global and segmental strains were compared. STATISTICAL TESTS: Reproducibility was tested by coefficient of variation (COV) and intraclass correlation coefficient (ICC). Receiver operator curves as well as comparison of areas under the curve (AUC) were analyzed. RESULTS: DRA showed the best observer agreement on segmental strain evaluated by ICC, LS (longitudinal strain): intraobserver variability range (0.98,1.00), interobserver variability range (0.83,0.92), CS (circumferential strain): intraobserver variability range (0.90,0.99), interobserver variability range (0.80,0.97), RS (radial strain): intraobserver variability range (0.84,0.99), interobserver variability range (0.85,0.99). Segmental LS, CS, and RS agreements evaluated by COV for FT and STE were poor. LV global myocardial strain of HCM was significantly lower than controls for all applied techniques, but global CS by DRA had better accuracy compared to FT or STE for distinguishing HCM from healthy subjects: AUC 0.880 (DRA) vs. 0.577 (FT) or 0.736 (STE), P < 0.05. DATA CONCLUSIONS: DRA is a reliable and robust analysis tool for segmental myocardial strain. Global CS by DRA allows discrimination between HCM and normal controls with better accuracy compared with FT and STE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2018;48:404-414. PMID- 29283467 TI - Characterizing synchrony patterns across cognitive task stages of associative recognition memory. AB - Numerous studies seek to understand the role of oscillatory synchronization in cognition. This problem is particularly challenging in the context of complex cognitive behavior, which consists of a sequence of processing steps with uncertain duration. In this study, we analyzed oscillatory connectivity measures in time windows that previous computational models had associated with a specific sequence of processing steps in an associative memory recognition task (visual encoding, familiarity, memory retrieval, decision making, and motor response). The timing of these processing steps was estimated on a single-trial basis with a novel hidden semi-Markov model multivariate pattern analysis (HSMM-MVPA) method. We show that different processing stages are associated with specific patterns of oscillatory connectivity. Visual encoding is characterized by a dense network connecting frontal, posterior, and temporal areas as well as frontal and occipital phase locking in the 4-9 Hz theta band. Familiarity is associated with frontal phase locking in the 9-14 Hz alpha band. Decision making is associated with frontal and temporo-central interhemispheric connections in the alpha band. During decision making, a second network in the theta band that connects left temporal, central, and occipital areas bears similarity to the neural signature for preparing a motor response. A similar theta band network is also present during the motor response, with additionally alpha band connectivity between right-temporal and posterior areas. This demonstrates that the processing stages discovered with the HSMM-MVPA method are indeed linked to distinct synchronization patterns, leading to a closer understanding of the functional role of oscillations in cognition. PMID- 29283469 TI - Phase II trial of eribulin mesylate in recurrent or metastatic salivary gland malignancies. AB - BACKGROUND: This study examined the microtubule inhibitor eribulin in recurrent/metastatic salivary gland cancers (RMSGCs), a disease where no therapeutic standard exists. METHODS: This phase II clinical trial treated patients with progressive recurrent/metastatic salivary gland cancers with eribulin 1.4 mg/m2 i.v. on days 1 and 8 of a 21-day cycle until disease progression/unacceptable toxicities. The primary endpoint was the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 objective response rate. RESULTS: Between May 2012 and August 2015, 29 patients were enrolled in this study. The median age was 63 years (range 34-75 years) and 20 of the subjects were men (69%). The most common histologies were adenoid cystic carcinoma (ACC; n = 11) and adenocarcinoma (n = 4). Neutropenia was the most common toxicity (grade 3; n = 5; 17% and grade 4 n = 3; 10%). The objective responses were observed in 3 of 29 patients (10%), 20 of 29 patients (69%) demonstrated a decrement in tumor size, and disease control was observed in 26 of 29 patients (90%). CONCLUSION: Although the objective responses to eribulin were uncommon, disease control was observed in the majority of patients. PMID- 29283468 TI - Noninvasive Electrical Stimulation for the Treatment of Chronic Ocular Pain and Photophobia. AB - INTRODUCTION: "Dry eye" or "keratoconjunctivitis sicca" is a multifactorial disease estimated to have a worldwide prevalence of 5-33%. Conventional therapies targeting the ocular surface with artificial tears, anti-inflammatories, punctal closure, eyelid hygiene, and antibiotics do not provide relief in all patients, especially those with neuropathic-like ocular complaints (wind hyperalgesia and photophobia). We anticipated that ocular transcutaneous electrical nerve stimulation (TENS) would alleviate symptoms of ocular pain, photophobia, and dryness in these latter individuals. METHODS: All individuals who received electrical stimulation between May 10, 2016 and April 6, 2017 for the treatment of chronic ocular pain at the oculofacial pain clinic of the Miami Veterans Administration Hospital were included in this retrospective review. All patients had symptoms of dryness along with other neuropathic-like symptoms (e.g., photophobia) and minimal signs of tear dysfunction. Ocular pain intensity, symptoms of dryness, and light sensitivity were compared pre-treatment and five min post-treatment via a two-tailed paired Student's t-test. RESULTS: The use of TENS significantly reduced the mean pain intensity in both the right and left eyes five min after treatment compared to prior to treatment (p < 0.05, paired t test). The use of TENS significantly decreased light sensitivity in both eyes (p < 0.05). The findings for symptoms of dryness, however, were equivocal with a significant decrease in the left eye but not the right (p < 0.05, paired t-test). DISCUSSION: Our data indicate that TENS may similarly provide analgesia in patients with dry eye symptoms as it does for many other chronic pain conditions. Furthermore, the noted effect on symptoms of photophobia and dryness suggest that all may be linked by similar trigeminal-thalamic-cortical pathways. Prospective studies with electrical stimulation of dry eye are needed to further elucidate its benefit and mechanism of action. PMID- 29283471 TI - Cyclic Polymer Grafts That Lubricate and Protect Damaged Cartilage. AB - Tissue-reactive graft copolymers were designed to protect the cartilage against enzymatic degradation and restore its lubrication properties during the early stages of osteoarthritis (OA). The copolymers feature a poly(glutamic acid) (PGA) backbone bearing hydroxybenzaldehyde (HBA) functions and cyclic poly(2-methyl-2 oxazoline) (PMOXA) side chains. PGA-PMOXA-HBA species chemisorb on the degraded tissue via Schiff bases and expose the biopassive and lubricious PMOXA cyclic grafts at the interface. The smaller hydrodynamic radius by cyclic PMOXA side chains coupled to the intrinsic absence of chain ends generate denser and more lubricious films on cartilage when compared to those produced by copolymers bearing linear PMOXA. Topology effects demonstrate how the introduction of cyclic polymers within tissue-reactive copolymers substantially improve their tribological and biopassive properties, suggesting a plethora of possible applications for cyclic macromolecules in biomaterials formulations. PMID- 29283470 TI - Effect of a glucagon receptor antibody (REMD-477) in type 1 diabetes: A randomized controlled trial. AB - The aim of the current study (Clinical trial reg. no. NCT02715193, clinicaltrials.gov) was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycaemic control and insulin use were evaluated in outpatient and inpatient settings, before and after a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI, 47%, 4%) lower 1 day after dosing with REMD-477 than with placebo (P = .02). Continuous glucose monitoring during post-treatment days 6 to 12 showed that average daily glucose was 27 mg/dL lower (P < .001), percent time-in-target-range (70-180 mg/dL) was ~25% greater (~3.5 h/d) (P = .001), and percent time-in-hyperglycaemic-range (> 180 mg/dL) was ~40% lower (~4 h/d) (P = .001) in the REMD-477 group than in the placebo group, without a difference in percent time-in-hypoglycaemic-range (<70 mg/dL). No serious adverse events were reported. Glucagon receptor antagonism decreases insulin requirements and improves glycaemic control in patients with type 1 diabetes. PMID- 29283472 TI - Seed germination and seedling allogamy in Rosmarinus officinalis: the costs of inbreeding. AB - Self-pollination by geitonogamy is likely in self-compatible plants that simultaneously expose a large number of flowers to pollinators. However, progeny of these plants is often highly allogamous. Although mechanisms to increase cross pollination have been identified and studied, their relative importance has rarely been addressed simultaneously in plant populations. We used Rosmarinus officinalis to explore factors that influence the probability of self fertilisation due to geitonogamy or that purge its consequences, focusing on their effects on seed germination and allogamy rate. We experimentally tested the effect of geitonogamy on the proportion of filled seeds and how it influences germination rate. During two field seasons, we studied how life history and flowering traits of individuals influence seed germination and allogamy rates of their progeny in wild populations at the extremes of the altitudinal range. The traits considered were plant size, population density, duration of the flowering season, number of open flowers, flowering synchrony among individuals within populations and proportion of male-sterile flowers. We found that most seeds obtained experimentally from self-pollination were apparently healthy but empty, and that the proportion of filled seeds drove the differences in germination rate between self- and cross-pollination experiments. Plants from wild populations consistently had low germination rate and high rate of allogamy, as determined with microsatellites. Germination rate related positively to the length of the flowering season, flowering synchrony and the ratio of male-sterile flowers, whereas the rate of allogamous seedlings was positively related only to the ratio of male-sterile flowers. Rosemary plants purge most of the inbreeding caused by its pollination system by aborting the seeds. This study showed that the rates of seed germination and allogamy of the seedlings depend on a complex combination of factors that vary in space and time. Male sterility of flowers, length of the flowering season and flowering synchrony of individuals within populations all favour high rates of cross-pollination, therefore increasing germination and allogamy rates. Flowering traits appear to be highly plastic and respond to local and seasonal conditions. PMID- 29283473 TI - International statistical classification of diseases and related health problems coding underestimates the incidence and prevalence of acute kidney injury and chronic kidney disease in general medical patients. AB - BACKGROUND: The international classification of diseases (ICD) code is frequently used to identify renal impairment in epidemiological research. However, Australian studies examining accuracy of this administrative data in coding kidney injury are lacking. AIMS: To compare the ICD 10 coding with the kidney disease: improving global outcomes (KDIGO) criteria in diagnosing acute kidney injury (AKI) and/or chronic kidney disease (CKD). METHODS: A retrospective study of 325 patients admitted to general medicine during January 2012 was performed. Sensitivity and specificity of ICD 10 in identifying AKI and CKD were calculated using KDIGO as gold standard. RESULTS: The sensitivities of ICD 10 in identifying AKI and CKD were low for both (59.5% and 54.1%), but the specificities were high (86.2% and 90.2%). Using KDIGO criteria, we identified 72 AKI (22%), 56 CKD (17%), 64 AKI on CKD (19%) and 133 controls (40%). Compared to the control group, patients with AKI and AKI on CKD had longer length of stay (3.2 vs 4.9 days and 3.2 vs 4.8 days, P = 0.20). Renal impairment groups had increased in-hospital mortality rate (5% control, 6% AKI, 10% CKD, 9% AKI on CKD) and re-admission rate within 30 days (13% control, 20% AKI, 25% CKD, 26% AKI on CKD). After adjusting for age, gender and comorbidities, the difference in outcomes was not statistically significant. CONCLUSION: This study shows that ICD 10 fails to identify almost half of the patients with AKI (40.5%) and CKD (45.9%) in our cohort. A total of 60% had evidence of renal impairment as defined by KDIGO. PMID- 29283474 TI - The work and challenges of care managers in the implementation of collaborative care: A qualitative study. AB - : WHAT IS KNOWN ON THE SUBJECT?: In collaborative care models between psychiatry and general practice, mental health nurses are used as care managers who carry out the treatment of patients with anxiety or depression in general practice and establish a collaborating relationship with the general practitioner. Although the care manager is the key person in the collaborative care model, there is little knowledge about this role and the challenges involved in it. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Our study shows that before the CMs could start treating patients in a routine collaborative relationship with GPs, they needed to carry out an extensive amount of implementation work. This included solving practical problems of location and logistics, engaging GPs in the intervention, and tailoring collaboration to meet the GP's particular preferences. Implementing the role requires high commitment and an enterprising approach on the part of the care managers. The very experienced mental health nurses of this study had these skills. However, the same expertise cannot be presumed in a disseminated model. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: When introducing new collaborative care interventions, the care manager role should be well defined and be well prepared, especially as regards the arrival of the care manager in general practice, and supported during implementation by a coordinated leadership established in collaboration between hospital psychiatry and representatives from general practice. ABSTRACT: Introduction In collaborative care models for anxiety and depression, the care manager (CM), often a mental health nurse, has a key role. However, the work and challenges related to this role remain poorly investigated. Aim To explore CMs' experiences of their work and the challenges they face when implementing their role in a collaborative care intervention in the Capital Region of Denmark. Methods Interviews with eight CMs, a group interview with five CMs and a recording of one supervision session were analysed by thematic analysis. Results The CM carried out considerable implementation work. This included finding suitable locations; initiating and sustaining communication with the GPs and maintaining their engagement in the model; adapting to the patient population in general practice; dealing with personal security issues, and developing supportive peer relations and meaningful supervision. Discussion We compare our findings to previous studies of collaborative care and advanced nursing roles in general practice. The importance of organizational leadership to support the CM's bridge-building role is emphasized. Implications for practice The planners of new collaborative care interventions should not only focus on the CM's clinical tasks but also on ensuring the sufficient organizational conditions for carrying out the role. PMID- 29283476 TI - Marijuana and pregnancy. PMID- 29283477 TI - Opioid addiction and borderline personality disorder. PMID- 29283475 TI - The importance of integrated left atrial evaluation: From hypertension to heart failure with preserved ejection fraction. AB - AIM: Functional analysis and measurement of left atrium are an integral part of cardiac evaluation, and they represent a key element during non-invasive analysis of diastolic function in patients with hypertension (HT) and/or heart failure with preserved ejection fraction (HFpEF). However, diastolic dysfunction remains quite elusive regarding classification, and atrial size and function are two key factors for left ventricular (LV) filling evaluation. Chronic left atrial (LA) remodelling is the final step of chronic intra-cavitary pressure overload, and it accompanies increased neurohormonal, proarrhythmic and prothrombotic activities. In this systematic review, we aim to purpose a multi-modality approach for LA geometry and function analysis, which integrates diastolic flow with LA characteristics and remodelling through application of both traditional and new diagnostic tools. METHODS: The most important studies published in the literature on LA size, function and diastolic dysfunction in patients with HFpEF, HT and/or atrial fibrillation (AF) are considered and discussed. RESULTS: In HFpEF and HT, pulsed and tissue Doppler assessments are useful tools to estimate LV filling pressure, atrio-ventricular coupling and LV relaxation but they need to be enriched with LA evaluation in terms of morphology and function. An integrated evaluation should be also applied to patients with a high arrhythmic risk, in whom eccentric LA remodelling and higher LA stiffness are associated with a greater AF risk. CONCLUSION: Evaluation of LA size, volume, function and structure are mandatory in the management of patients with HT, HFpEF and AF. A multi-modality approach could provide additional information, identifying subjects with more severe LA remodelling. Left atrium assessment deserves an accurate study inside the cardiac imaging approach and optimised measurement with established cut-offs need to be better recognised through multicenter studies. PMID- 29283479 TI - What's next: Parity, the affordable care act and the American psychiatric association. PMID- 29283478 TI - Editorial. PMID- 29283480 TI - The need to incorporate smoking cessation into behavioral health treatment. PMID- 29283481 TI - Policy making in substance use treatment should be evidence-based. PMID- 29283482 TI - Implementation challenges of the final rule of Title 42 of the Code of Federal Regulations part 2: can privacy endure in an era of electronic health information exchange? PMID- 29283483 TI - Issue Information - Editorial Board. PMID- 29283484 TI - The opioid crisis is a wicked problem. PMID- 29283485 TI - THC potency needs to be tracked. PMID- 29283487 TI - Issue Information - ToC. PMID- 29283486 TI - Toward precision medicine in addiction treatment. PMID- 29283488 TI - Practice in the face of a lethal epidemic. PMID- 29283490 TI - Addiction and the law. PMID- 29283489 TI - Ketamine as a bridging agent in opioid maintenance therapy. PMID- 29283491 TI - Will removal of black box warning get psychiatrists to move on tobacco? PMID- 29283492 TI - Systematic review of studies of mental health nurses' experience of anger and of its relationships with their attitudes and practice. AB - : WHAT IS KNOWN ON THE SUBJECT?: It is generally felt that it is helpful for mental health nurses to control their emotions during their work. There are different approaches, but there is growing acceptance that different emotions may need different coping strategies. There is lots of evidence that nurses sometimes feel anger in a number of situations, but the research about anger in mental health nurses has never been examined as a whole. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: We have systematically identified all previous research where nurses completed measures that tried to measure their anger in certain situations, compared it to other people or investigated how it affected them or what its relationship was with their practice. Only a few studies have measured nurses' anger. However, it seems that while nurses are not generally angrier than any other group, they do often feel anger in relation to management of patient aggression and their job situation more generally. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Anger is the most commonly reported problematic emotion for mental health nurses. It may influence their practice and affect their well-being. This has implications for staff support and training. ABSTRACT: Introduction Emotional regulation is important in mental health nursing practice, but individual emotions may require different regulation strategies. There is ample evidence that nurses experience anger specifically during their work, for example when experiencing patient aggression. It is, therefore, important to consolidate what is known about how anger manifests in mental health nursing practice. AIM: We aimed to systematically identify, evaluate and synthesize results from studies about mental health nurses and anger, where anger was measured objectively. METHODS: Systematic literature review based on PRISMA guidelines. RESULTS: We identified 12 studies. A range of validated and nonvalidated instruments was used. Mental health nurses may have lower levels of anger than normative samples, but anger is commonly reported as an issue for them. Anger was studied in relation to its links with (1) clinical management of patients, notably violence containment; and (2) employment issues more generally, notably job motivation. Anger is related to nurses' attitudes about the acceptability of coercion, but there is no evidence that it results in more coercion. IMPLICATIONS FOR PRACTICE: Nurses should be aware of the potential influence of anger on their practice. Anger, specifically, should be considered when supporting mental health nurses, for example in clinical supervision. Emotional regulation training should target anger. PMID- 29283494 TI - Genetic association of complement component 2 variants with chronic hepatitis B in a Korean population. AB - BACKGROUND & AIMS: Numerous single nucleotide polymorphisms associated with an increased risk of liver diseases, chronic hepatitis B and chronic hepatitis B related hepatocellular carcinoma have been identified. In this study, we scrutinized the genetic effects of C2 variants, which were conflicting in previous results, on the risk of chronic hepatitis B in a Korean population. METHODS: We genotyped 22 common C2 genetic variants of 977 chronic hepatitis B cases including 302 chronic hepatitis B-related hepatocellular carcinoma cases and 785 population controls. Statistical analysis was performed to examine the effects of genotype on the risk of chronic hepatitis B and chronic hepatitis B related hepatocellular carcinoma. RESULTS: Logistic regression analyses showed that six C2 single nucleotide polymorphisms had significant associations with the risk of chronic hepatitis B and chronic hepatitis B-related hepatocellular carcinoma among the Korean subjects. Stepwise analysis revealed that causal markers (rs9267665 and rs10947223) were identified among the C2 variants (stepwise P = 3.32 * 10-9 and 2.04 * 10-5 respectively). In further conditional analysis with previous chronic hepatitis B-associated loci, these two single nucleotide polymorphisms were independently associated with the risk of chronic hepatitis B. In addition, we investigated the ability of genetic risk scores combining 12 multi-chronic hepatitis B loci to predict the risk of chronic hepatitis B. Individuals with higher genetic risk scores showed increased risk for chronic hepatitis B. CONCLUSIONS: Our results suggested that the C2 gene might be a susceptibility locus for chronic hepatitis B in Korean populations. The cumulative genetic effects may contribute to future etiological explanations for chronic hepatitis B. PMID- 29283493 TI - The Checklist of Unit Behaviours (CUB): Validation within a Canadian outpatient day hospital programme. AB - : WHAT IS KNOWN ON THE SUBJECT?: The psychometrics of the CUB measure have been tested within an inpatient psychiatric setting. Results show that the CUB has two factors that reflect patients' approach and avoidance of dimensions of the treatment milieu, and that an increase of approach and decrease of avoidance are correlated with discharge. No empirical research has examined the validity of the CUB in a day hospital programme. WHAT THIS ARTICLE ADDS TO EXISTING KNOWLEDGE?: This study was the first to address the validity of this questionnaire within a psychiatric day hospital setting. This now allows other mental health service providers to use this questionnaire following administration of patient engagement interventions (such as behavioural activation), which are routinely used within this type of a setting. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Our results can enable healthcare providers to employ an effective and psychometrically validated tool in a day hospital setting to measure treatment outcomes and provide reflections of patients' approach behaviours and avoidance behaviours. ABSTRACT: Introduction We evaluated the Checklist of Unit Behaviours (CUBs) questionnaire in a novel mental health setting: a day hospital within a large acute care general hospital. No empirical evidence exists, as of yet, to look at the validity of this measure in this type of a treatment setting. The CUB measures two factors, avoidance or approach, of the patients' engagement with the treatment milieu within the previous 24 hr. Aim A confirmatory factor analysis (CFA) was conducted to validate the CUB's original two factor structure in an outpatient day programme. Methods Psychiatric outpatients (n = 163) completed the CUB daily while participating in a day hospital programme in Toronto, Canada. Results A CFA was used to confirm the CUB factors but resulted in a poor fitting model for our sample, chi2 (103) = 278.59, p < .001, CFI = 0.80, RMSEA = 0.10, SRMR = 0.10. Questions 5, 8 and 10 had higher loadings on a third factor revealed through exploratory factor analysis. We believe this factor, "Group Engagement," reflects the construct of group-related issues. Discussion The CUB was a practical and useful tool in our psychiatric day hospital setting at a large acute care general hospital. Implications for practice Our analysis identified group engagement, a critical variable in day programmes, as patients have autonomy regarding staying or leaving the programme. PMID- 29283495 TI - Impact of sensor-controlled variable-rate fungicide application on yield, senescence and disease occurrence in winter wheat fields. AB - BACKGROUND: Field experiments examining target-oriented variable-rate fungicide spraying were performed in 2015 and 2016. The spray volume was adapted in real time to the local green coverage level of winter wheat (Triticum aestivum L.), which was detected using a camera sensor. RESULTS: Depending on the growth heterogeneity in the three strip trials in 2015, fungicide savings in the sensor sprayed strip compared with the adjacent uniformly sprayed strip were 44%, 45% and 1%. In the 2016 field trial, the saving was 12%. There was no greater level of senescence or disease occurrence, and no higher yield losses in the camera controlled variable-rate sprayed strips compared with the adjacent uniformly sprayed strips. CONCLUSIONS: From an ecological and economical point of view, sensor-controlled variable-rate spraying technology, which uses the level of green crop coverage as the plant parameter to adapt the spray volume locally, can be an alternative to the common practice of uniform spraying. (c) 2017 Society of Chemical Industry. PMID- 29283496 TI - Quantitative assessment of cancer cell morphology and motility using telecentric digital holographic microscopy and machine learning. AB - The noninvasive, fast acquisition of quantitative phase maps using digital holographic microscopy (DHM) allows tracking of rapid cellular motility on transparent substrates. On two-dimensional surfaces in vitro, MDA-MB-231 cancer cells assume several morphologies related to the mode of migration and substrate stiffness, relevant to mechanisms of cancer invasiveness in vivo. The quantitative phase information from DHM may accurately classify adhesive cancer cell subpopulations with clinical relevance. To test this, cells from the invasive breast cancer MDA-MB-231 cell line were cultured on glass, tissue culture treated polystyrene, and collagen hydrogels, and imaged with DHM followed by epifluorescence microscopy after staining F-actin and nuclei. Trends in cell phase parameters were tracked on the different substrates, during cell division, and during matrix adhesion, relating them to F-actin features. Support vector machine learning algorithms were trained and tested using parameters from holographic phase reconstructions and cell geometric features from conventional phase images, and used to distinguish between elongated and rounded cell morphologies. DHM was able to distinguish between elongated and rounded morphologies of MDA-MB-231 cells with 94% accuracy, compared to 83% accuracy using cell geometric features from conventional brightfield microscopy. This finding indicates the potential of DHM to detect and monitor cancer cell morphologies relevant to cell cycle phase status, substrate adhesion, and motility. (c) 2017 International Society for Advancement of Cytometry. PMID- 29283497 TI - Downregulation of STRAP promotes tumor growth and metastasis in hepatocellular carcinoma via reducing PTEN level. AB - The serine-threonine kinase receptor-associated protein (STRAP) has been implicated in multiple human cancers. However, its expression and function are currently unclear and controversial in different tissue types. In the present study, we report that aberrant downregulation of STRAP in hepatocellular carcinoma (HCC) facilitated tumor cell growth and metastasis in a phosphatase and tensin homologue (PTEN)-dependent manner. Immunohistochemical analysis and quantitative real-time polymerase chain reaction results indicated that STRAP was frequently downregulated in HCC samples. Functionally, knockdown of STRAP by RNA inference in HCC cells promoted proliferation and migration in vitro and tumorigenicity and lung metastasis in vivo. Through detecting the expression of some tumor-related genes using western blot analysis, we found the tumor suppressor PTEN was decreased upon STRAP silencing. Further analyses demonstrated that silenced STRAP led to PTEN protein degradation. Immunohistochemical analysis revealed that STRAP expression was closely associated with PTEN expression in 30 cases of HCC samples. These findings strongly suggest that STRAP plays an inhibitory role in HCC via regulating PTEN expression and could be a potential therapeutic target for this disease. (c) 2017 IUBMB Life, 70(2):120-128, 2018. PMID- 29283499 TI - Pharyngeal airway changes following maxillary expansion or protraction: A meta analysis. AB - The aim of this meta-analysis was to investigate the changes in airway dimensions after rapid maxillary expansion (RME) and facemask (FM) protraction. Using PubMed, Medline, ScienceDirect and Web of Science, only controlled clinical trials, published up to November 2016, with RME and/or FM as keywords that had >=6 months follow-up period were included in this meta-analysis. The changes in pharyngeal airway dimension in both two-dimensional and three-dimensional images were included in the analysis. Nine studies met the criteria. There are statically significant changes in upper airway and nasal passage airway in the intervention groups as compared to the control groups, assessed in two dimensional and three-dimensional images. However , in the lower airway and the airway below the palatal plane, no statistically significant changes are seen in 2D and 3D images. RME/FM treatments might increase the upper airway space in children and young adolescents. However, more RCTs and long-term cohort studies are needed to further clarify the effects on pharyngeal airway changes. PMID- 29283500 TI - Identification of a novel nucleophosmin-interaction motif in the tumor suppressor p14arf. AB - The tumor suppressor p14arf interacts, in response to oncogenic signals, with the p53 E3-ubiquitin ligase HDM2, thereby resulting in p53 stabilization and activation. In addition, it also exerts tumor-suppressive functions in p53 independent contexts. The activities of p14arf are regulated by the nucleolar chaperone nucleophosmin (NPM1), which controls its levels and cellular localization. In acute myeloid leukemia with mutations in the NPM1 gene, mutated NPM1 aberrantly translocates in the cytosol carrying with itself p14arf that is subsequently degraded, thus impairing the p14arf-HDM2-p53 axis. In this work we investigated the complex between these two proteins by means of NMR and other techniques. We identified a novel NPM1-interacting motif in the C-terminal region of p14arf, which corresponds to its predicted nucleolar localization signal. This motif recognizes a specific region of the NPM1 N-terminal domain and, upon binding, the two proteins form soluble high molecular weight complexes. By NMR, we identified critical residues on both proteins involved in the interaction. Collectively, our data provide a structural framework to rationalize the overall assembly of the p14arf-NPM1 supramolecular complexes. A number of p14arf cancer associated mutations cluster in this motif and their effect on the interaction with NPM1 was also analyzed. PMID- 29283498 TI - Neuronal RNA-binding protein HuD regulates addiction-related gene expression and behavior. AB - The neuronal RNA-binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuDOE ). When this set was further limited to genes in the knowledgebase of addiction-related genes database (KARG) that contains predicted HuD-binding sites in their 3' untranslated regions (3'UTRs), we found that HuD regulates networks that have been associated with addiction like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction-related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild-type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuDOE and wild-type mice in CPP and found that HuDOE mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIalpha and BDNF. These findings suggest HuD involvement in addiction-related behaviors such as cocaine conditioning and seeking, through increased plasticity-related gene expression. PMID- 29283501 TI - Nicorandil for the prevention of contrast-induced nephropathy: A meta-analysis of randomized controlled trials. AB - INTRODUCTION: Nicorandil has been suggested as a preventative strategy against the incidence of contrast-induced nephropathy (CIN). However, results of relevant randomized controlled trials (RCTs) were inconsistent. AIMS: We performed a meta analysis of RCTs to evaluate the preventive efficacy of periprocedural treatment of nicorandil against the incidence of CIN. METHODS: Relevant RCTs were identified via search of PubMed, Embase, and Cochrane's Library databases. Results were pooled using a random-effect model. Subgroup analyses were performed to evaluate the potential influence of administering routes on the efficacy of nicorandil against CIN incidence. RESULTS: Four RCTs with 709 patients were included. Treatment of nicorandil significantly reduced the incidence of CIN as compared with controls (risk ration [RR]: 0.38, 95% confidence interval [CI]: 0.19 ~ 0.74, P = .005) with moderate heterogeneity (I2 = 33%). Results of subsequent subgroup analysis showed that nicorandil significantly reduced the risk of CIN if orally administered (RR: 0.32, P < .001), but did not if intravenously administered (RR: 0.47, I2 = 68%). Moreover, treatment with nicorandil was associated with significantly less increment of SCr (weight mean difference [WMD]: -3.98%, P < .001) and a tendency of less increment of cystatin C (WMD: -3.86%, P = .08) after 48-hour contrast exposure as compared with controls. CONCLUSIONS: Periprocedural treatment with nicorandil may be preventative against the incidence of CIN in patients undergoing contrast exposure. The influence of periprocedural nicorandil on clinical outcome in these patients deserves further investigation. PMID- 29283502 TI - Estimation of jaw-opening forces in adults. AB - OBJECTIVES: To estimate maximum jaw-opening forces in healthy participants of diverse ancestry and to estimate whether opening forces are associated with sex, age and anthropometric parameters such as height, weight and BMI. SETTING AND SAMPLE POPULATION: One hundred and forty-nine participants aged 20-60 years with overall good oral and general health. Exclusion criteria included myofascial or neck pain, symptomatic temporomandibular joint disorders (TMD), current orthodontic treatment or the absence of a natural dentition. MATERIAL AND METHODS: Jaw-opening forces were measured with an adjustable rigid extra-oral device connected to a 1000 N load cell. Seven attempts were recorded, with 10 seconds interval. Median force values were obtained after discarding the first and last attempt. The height and weight of each participant were measured and recorded, alongside age, sex and ethnicity. RESULTS: Men had greater maximum opening force median values than women (P < .001). Median (IQR) values for women were 41.16 N (30.44) and 79.00 N for men (63.86). Jaw-opening force values were poorly associated with biological and anthropometric parameters. CONCLUSION: In this study, which included a large sample of participants of broad age range and from a demographically diverse background, jaw-opening force values were greater in males than in females; however, force values were poorly associated with biological and anthropometric parameters. Future studies should explore the potential of this method as a screening tool for TMJ disorders and other conditions. PMID- 29283503 TI - Introducing images in medicine and grand rounds. PMID- 29283504 TI - Association of postprandial and fasting plasma glucose with HbA1c across the spectrum of glycaemic impairment in type 2 diabetes. PMID- 29283505 TI - Application of flipped classroom pedagogy to the human gross anatomy laboratory: Student preferences and learning outcomes. AB - To improve student preparedness for anatomy laboratory dissection, the dental gross anatomy laboratory was transformed using flipped classroom pedagogy. Instead of spending class time explaining the procedures and anatomical structures for each laboratory, students were provided online materials to prepare for laboratory on their own. Eliminating in-class preparation provided the opportunity to end each period with integrative group activities that connected laboratory and lecture material and explored clinical correlations. Materials provided for prelaboratory preparation included: custom-made, three dimensional (3D) anatomy videos, abbreviated dissection instructions, key atlas figures, and dissection videos. Data from three years of the course (n = 241 students) allowed for analysis of students' preferences for these materials and detailed tracking of usage of 3D anatomy videos. Students reported spending an average of 27:22 (+/-17:56) minutes preparing for laboratory, similar to the 30 minutes previously allocated for in-class dissection preparation. The 3D anatomy videos and key atlas figures were rated the most helpful resources. Scores on laboratory examinations were compared for the three years before the curriculum change (2011-2013; n = 242) and three years after (2014-2016; n = 241). There was no change in average grades on the first and second laboratory examinations. However, on the final semi-cumulative laboratory examination, scores were significantly higher in the post-flip classes (P = 0.04). These results demonstrate an effective model for applying flipped classroom pedagogy to the gross anatomy laboratory and illustrate a meaningful role for 3D anatomy visualizations in a dissection-based course. Anat Sci Educ 11: 385-396. (c) 2017 American Association of Anatomists. PMID- 29283506 TI - Inductive reasoning 2.0. AB - Inductive reasoning entails using existing knowledge to make predictions about novel cases. The first part of this review summarizes key inductive phenomena and critically evaluates theories of induction. We highlight recent theoretical advances, with a special emphasis on the structured statistical approach, the importance of sampling assumptions in Bayesian models, and connectionist modeling. A number of new research directions in this field are identified including comparisons of inductive and deductive reasoning, the identification of common core processes in induction and memory tasks and induction involving category uncertainty. The implications of induction research for areas as diverse as complex decision-making and fear generalization are discussed. This article is categorized under: Psychology > Reasoning and Decision Making Psychology > Learning. PMID- 29283507 TI - Evaluation of Bioequivalence Between 0.5-mg Dutasteride Capsules Manufactured by GlaxoSmithKline and an Existing Formulation: A Randomized Study in Healthy Japanese Male Volunteers. PMID- 29283508 TI - The Lack of Nasolacrimal Ducts in Plethodontid Salamanders? AB - Nasolacrimal ducts are a terrestrial vertebrate adaptation and appear to have co evolved with orbital glands. Although plethodontid salamanders possess orbital glands, a recent study concluded that plethodontid salamanders lack nasolacrimal ducts. Functionally, the absence of nasolacrimal ducts closes the route for orbital gland secretion passage into the nasal and vomeronasal organ cavities. Orbital glands have been implicated in enhancement of vomeronasal function so loss could have important implications for communication. Multiple older studies depict or discuss nasolacrimal ducts in plethodontid salamanders. Interestingly, the only consensus between recent and older literature is that Desmognathus lacks nasolacrimal ducts. To determine if plethodontid salamanders truly lack nasolacrimal ducts, we sectioned plethodontid salamander heads for general histological examination of species from the majority of the plethodontid tribes. From our representative sample, we found only two species that completely lacked nasolacrimal ducts (Desmognathus fuscus and Eurycea tynerensis) and one species that possessed nasolacrimal ducts that ended blindly before reaching the nasal cavities (E. spelaea). Bayesian ancestral state reconstruction resulted in the presence of nasolacrimal ducts on the branch leading to Plethodontidae and both subfamilies within Plethodontidae, with two independent losses in Desmognathus and Eurycea. Anat Rec, 301:765-775, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29283509 TI - Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor alpha-mediated activation. AB - INTRODUCTION: Cardiovascular disease is the main cause of mortality and morbidity in the industrialized world. Incretin-mimetic compounds such as exenatide are currently used in the treatment of type 2 diabetes. AIMS: We investigated the effects of incretin drugs on apoptosis, adhesion molecule expression, and concentration of extracellular matrix (ECM) metalloproteinases under inflammatory conditions within the context of atherosclerotic plaque formation of both human coronary artery endothelial cells (hCAECs) and human aortic endothelial cells (hAoECs). TNF-alpha-stimulated hCAEC and hAoEC were treated with exenatide (1 and 10 nmol/L) and GLP-1 (10 and 100 nmol/L) then evaluated for caspase 3/7 activity and assayed for protein levels of adhesion molecules sICAM-1, sVCAM-1, and P selectin. Concentrations of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-9, and their inhibitors-tissue inhibitor of metalloproteinases (TIMPs), TIMP-1, TIMP 2 were also measured to evaluate the effects on extracellular matrix turnover within an inflammatory environment. Intracellular signaling pathways were evaluated via transfection of endothelial cells with a GFP vector under the NF kappaB promoter. RESULTS: Our experimental data suggest that GLP-1 receptor (GLP 1R) agonists downregulate activation of NF-kappaB and adhesion molecules ICAM and VCAM, but not P-selectin, in both endothelial cell lines. Exendin-4 and GLP-1 modulate the expression of MMPs and TIMPs, with statistically significant effects observed at high concentrations of both incretins. Expressive modulation may be mediated by NF-kappaB as observed by activation of the vector when stimulated under inflammatory conditions. CONCLUSION: These findings indicate that GLP-1 analogs have anti-inflammatory properties in endothelial cells that may play an important role in preventing atherosclerosis. PMID- 29283510 TI - Towards automated cancer screening: Label-free classification of fixed cell samples using wavelength modulated Raman spectroscopy. AB - The ability to provide quantitative, objective and automated pathological analysis would provide enormous benefits for national cancer screening programmes, in terms of both resource reduction and improved patient wellbeing. The move towards molecular pathology through spectroscopic methods shows great promise, but has been restricted by spectral quality, acquisition times and lack of direct clinical application. In this paper, we present the application of wavelength modulated Raman spectroscopy for the automated label- and fluorescence free classification of fixed squamous epithelial cells in suspension, such as those produced during a cervical smear test. Direct comparison with standard Raman spectroscopy shows marked improvement of sensitivity and specificity when considering both human papillomavirus (sensitivity +12.0%, specificity +5.3%) and transformation status (sensitivity +10.3%, specificity +11.1%). Studies on the impact of intracellular sampling location and storage effects suggest that wavelength modulated Raman spectroscopy is sufficiently robust to be used in fixed cell classification, but requires further investigations of potential sources of molecular variation in order to improve current clinical tools. PMID- 29283511 TI - Structural plasticity of mini-M conotoxins - expression of all mini-M subtypes by Conus regius. AB - : The mini-M conotoxins are peptidic scaffolds found in the venom of cones snails. These scaffolds are tightly folded structures held together by three disulfide bonds with a CC-C-C-CC arrangement (conotoxin framework III) and belong to the M Superfamily of conotoxins. Here, we describe mini-M conotoxins from the venom of Conus regius, a Western Atlantic worm-hunting cone snail species using transcriptomic and peptidomic analyses. These C. regius conotoxins belong to three different subtypes: M1, M2, and M3. The subtypes show little sequence homology, and their loop sizes (intercysteine amino acid chains) vary significantly. The mini-Ms isolated from dissected venom contains preferentially hydroxylated proline residues, thus augmenting the structural reach of this conotoxin class. Using 2D-NMR methods, we have determined the 3D structure of reg3b, an M2 subtype conotoxin, which shows a constrained multi-turn scaffold. The structural diversity found within mini-M conotoxin scaffolds of C. regius is indicative of structural hypervariability of the conotoxin M superfamily that is not seen in other superfamilies. These stable minimalistic scaffolds may be investigated for the development of engineered peptides for therapeutic applications. DATABASES: Sequences are available in GenBank under accession numbers MF588935-MF588952. Structural data are available in the RCSB protein database under the accession code 6BX9. PMID- 29283512 TI - Catalytic Water Oxidation by Iridium-Modified Carbonic Anhydrase. AB - Carbonic anhydrase (CA) is a ubiquitous metalloenzyme with a Zn cofactor coordinated to trigonal histidine imidazole moieties in a tetrahedral geometry. Removal of the Zn cofactor in CA and subsequent binding of Ir afforded CA[Ir]. Under mild and neutral conditions (30 degrees C, pH 7), CA[Ir] exhibited water oxidizing activity with a turnover frequency (TOF) of 39.8 min-1 , which is comparable to those of other Ir-based molecular catalysts. Coordination of Ir to the apoprotein of CA is thermodynamically preferred and is associated with an exothermic energy change (DeltaH) of -10.8 kcal mol-1 , which implies that the CA apoprotein is stabilized by Ir binding. The catalytic oxygen-evolving activity of CA[Ir] is displayed only if Ir is bound to CA, which functions as an effective biological scaffold that activates the Ir center for catalysis. The results of this study indicate that the histidine imidazoles at the CA active site could be exploited as beneficial biological ligands to provide unforeseen biochemical activity by coordination to a variety of transition-metal ions. PMID- 29283513 TI - Oblique scanning 2-photon light-sheet fluorescence microscopy for rapid volumetric imaging. AB - Light-sheet fluorescence microscopy (LSFM) is a powerful tool for biological studies because it allows for optical sectioning of dynamic samples with superior temporal resolution. However, LSFM using 2 orthogonally co-aligned objectives requires a special sample geometry, and volumetric imaging speed is limited due to physical sample translation. This paper describes an oblique scanning 2-photon LSFM (OS-2P-LSFM) that eliminates these limitations by using a single objective near the sample and a refractive scanning-descanning system. This system also provides improved light-sheet confinement against scattering by using a 2-photon Bessel beam. The OS-2P-LSFM hold promise for studying structural, functional and dynamic aspects of living tissues and organisms because it allows for high-speed, translation-free and scattering-robust 3D imaging of large biological specimens. PMID- 29283514 TI - An Animal Model of Local Breast Cancer Recurrence in the Setting of Autologous Fat Grafting for Breast Reconstruction. AB - Autologous fat grafting after breast cancer surgery is commonly performed, but concerns about oncologic risk remain. To model the interaction between fat grafting and breast cancer cells, two approaches were employed. In the first approach, graded numbers of viable MDA-MB-231 or BT-474 cells were admixed directly into human fat grafts and injected subcutaneously into immune-deficient mice to determine if the healing graft is a supportive environment for the tumor. In the second approach, graded doses of MDA-MB-231 cells were suspended in Matrigel and injected into the mammary fat pads of mice. Two weeks after the tumor cells engrafted, 100 MUL of human adipose tissue was grafted into the same site. Histologically, MDA-MB-231 cells seeded within fat grafts were observed and stained positive for human-specific pan-cytokeratin and Ki67. The BT-474 cells failed to survive when seeded within fat grafts at any dose. In the second approach, MDA-MB-231 cells had a strong trend toward lower Ki67 staining at all doses. Regression analysis on all groups with fat grafts and MDA-MB-231 revealed fat tissue was associated with lower cancer cell Ki67 staining. Healing fat grafts do not support the epithelial BT-474 cell growth, and support the mesenchymal MDA-MB-231 cell growth only at doses ten times greater than in Matrigel controls. Moreover, fat grafts in association with MDA-MB-231 cancer cells already present in the wound resulted in decreased tumor proliferation and increased fibrosis. These findings suggest that clinical fat grafting does not induce breast cancer cell growth, and may even have a suppressive effect. Stem Cells Translational Medicine 2018;7:125-134. PMID- 29283516 TI - Regenerative Medicine: Progressing Toward Cures. PMID- 29283515 TI - A Preview of Selected Articles. PMID- 29283517 TI - Silver-Catalyzed Efficient Synthesis of Oxindoles and Pyrroloindolines via alpha Aminoalkylation of N-Arylacrylamides with Amino Acid Derivatives. AB - alpha-Aminoalkylation of N-arylacrylamides with amino acid derivatives was achieved by silver-catalysis in moderate to high yields. The reaction provides an efficient strategy for the synthesis of functionalized oxindoles, and is suitable for a wide range of N-arylacrylamides and amino acids, both of which are inexpensive and readily available. The oxindoles obtained were readily transformed into densely functionalized pyrroloindolines by deprotection and cyclization in one pot. PMID- 29283518 TI - Digestive and Nondigestive Functions of Rodents' Salivary Glands. AB - Major salivary glands play a role not only in digestion, but also in regulation of other functions in rodents. In this review, we analyzed and summarized the data about the rodents' parotid, submandibular and sublingual salivary glands functions, which is not limited to the production of saliva and action of its hydrolytic enzymes on food in the oral cavity. In recent decades significantly expanded understanding of major salivary glands nondigestive functions. They are involved in excretion of metabolic products, maintaining fluid and electrolyte balance. Special attention has been paid to the characteristics of specific (parotin, sialorphin, etc.) and nonspecific (epidermal growth factor, nerve growth factor, kallikrein, etc.) active substances of the major salivary glands and their involvement in wound healing, mineral metabolism, regulation of hematopoiesis and immunity system. Summarized and analyzed major salivary glands endocrine function in the organs and systems. Available literature data suggest: the structure of the major salivary glands, as well as the synthesis and secretion of a number of biologically active substances are controlled by sex hormones. In turn, these biologically active factors of the salivary glands, as epidermal growth factor, and parotin, sialorphin, whose expression is regulated by androgens, have an impact on the morphological and functional state of the gonads. Thus, major salivary glands operate a wide range of functions and involved in the regulation of sexual behavior of reproductive function and maintaining homeostasis in the body. PMID- 29283520 TI - Sensitivity of T-Lymphocytes to Hormones of the Anterior Pituitary Gland. AB - The review provides information about the features of the sensitivity of thymocytes, lymphoid organs' cells and T-lymphocytes of peripheral blood to the hormones secreted by anterior pituitary gland's cells: growth hormone, thyrotropin, adrenocorticotropic hormone, prolactin and beta-endorphin. Some aspects of the T-lymphocytes's response to humoral signals from the hypophysis are shown in the article. Also the pituitary hormones' role in the regulation of proliferation, differentiation, and cytokine production of T-lymphocytes in normal and pathological conditions of the organism being discussed. PMID- 29283522 TI - President's Page: Alphabet soup.... PMID- 29283521 TI - Editorial: Giving Caesar what is Caesar's. PMID- 29283523 TI - Guest Editorial PMID- 29283524 TI - The Influence of Vesalius' Fabrica on Surgery in the 16th & 17th century. AB - The innovation in anatomy, brought about by Andreas Vesalius1, particularly by means of hisFabrica, has had an important influence on the practice of surgery2. Various surgeons of the16th and the 17th century have implemented different approaches in operative techniques,based on the anatomical knowledge drawn upon the Fabrica.Examples are given in this paper concerning Pierre Franco, Ambroise Pare, Giovanni Andreadella Croce, Girolamo Fabrici d'Acquapendente, Wilhelm Fabry von Hilden and Paul Barbette,who all, in one way or another, have proposed surgical techniques that required preciseanatomical understanding, which was provided by the new Vesalian anatomy of the humanbody.The concept, adopted by many medico-historical scholars, that the anatomy of Vesalius hadonly limited repercussions on Modern Surgery, therefore needs reconsideration. PMID- 29283525 TI - Copies of Vesalius' De Humani Corporis Fabrica in the USA. AB - The purpose of this study was to confirm the locations in the United States of America (USA)of the first (1543) and second edition (1555) of the De humani Corporis Fabrica authored byAndreas Vesalius.Contacts were made at institutions of higher learning, museums, libraries and an update oflocations of previous studies in 1943 and 1984. A total of 64 copies of the 1543 Fabrica and58 copies of the 1555 Fabrica were recorded in University and Institutional Libraries in theUSA. Twenty-Six (54%) out of 48 locations having both editions.The majority of locations recorded by Cushing in 1943 and subsequently by Horowitz andCollins in 1984 are still in their original collections. Location and dual ownership in privatecollections were more difficult to locate. PMID- 29283526 TI - Vesalius: His Presence in New Spain. AB - In this paper we present a review of Mexican medical literature in the 16th and 17th centuries,analyzing the presence of Vesalius anatomical contributions and the conservation of Galenteachings in the official circles. We start with the anecdotal identification of don Carlos, son ofPhilip II, with Gregorio Lopez, a hermit living in New Spain in the second half of the 16thcentury, as a legendary possibility of being a celebrated patient of Vesalius.After a short review of the birth and early diffusion of Vesalius anatomy in Spain, we analyzethe early anatomical and surgical books written and published in New Spain; those of AlonsoLopez de Hinojosos (1578, 1595), Agustin Farfan (1592), Juan de Barrios (1607), GeronimoBezerra and Diego Osorio y Peralta (1685), identifying their acceptance or negation of thevalidity of Vesalius' discoveries and the tensions existing between those two intellectualpositions. In the following pages we will present and discuss the nature, dimensions andimpact of Vesalius' Fabrica knowledge in the medical thought of Colonial Mexico. PMID- 29283528 TI - Vesalius, Rontgen and the origins of Modern Anatomy. AB - The discovery of X-rays in 1895 by Wilhelm Conrad Rontgen transformed our understandingof both the physical world and our understanding of ourselves. Traditional anatomy as shownby Andreas Vesalius was learnt from dissection of the supine deceased body. Radiologyshowed anatomy in the living in a manner previously not possible, and has transformed ouranatomical understanding, particularly of human growth and variation. PMID- 29283527 TI - Vesalius' legacy. The Tabulae pictae of Girolamo Fabrici d' Acquapendente. AB - Girolamo Fabrici d'Acquapendente (ca.1533-1619) left a rich collection of anatomicalpaintings in colours, which are today preserved in the Marciana Library in Venice.The third series, entitled De Anatomia Capitis Cerebri Nervorum, contains the only knownillustrations by Fabrici regarding neuroanatomy since, apart from them, he never published onthe nervous system.For this reason, a thorough study of these plates is pivotal to a better understanding of hiscontribution to the knowledge of the Nervous System.A recently found unpublished manuscript reporting on a lesson of Fabrici, given in theAnatomical Theather in Padua, constitutes to this day the only written description, howeverindirect, of this subject by him. PMID- 29283529 TI - Neuroimaging Five Hundred Years Later AB - The rapid technological progress of these last decades has brought refined instruments toneuroradiologists and consequently to anatomists, physiologists, neuroscientists. A shortoutline is given on recent advancements in the field. Looking at these wonderful images wemust not forget the works of our predecessors, to whom we owe an inextinguishablegratitude. PMID- 29283530 TI - Andreas Vesalius and his hoaxes, con variazioni. AB - Andreas Vesalius's popularity increases with every anniversary. The commemorations in2014/2015, the quincentenary of his birth, were no exception and may mark the turning pointin Vesalius research. Hoaxes surrounding the life and death of this famed anatomist, some ofwhich have survived despite strong counter evidence published some fifty, and even onehundred, years ago are finally dying out, while new myths are swiftly nipped in the budthanks to today's speed of publication and communication. PMID- 29283531 TI - Visualizing Vesalius. AB - The anatomist whose name became a trademark for all that is high standard in medicine wasmore engaging and nuanced than his portrait suggests.Padua was the epicenter of the Italian Renaissance in the XVI century, a place of unparalleledartistic and intellectual attainments where Vesalius started the revolutionary road towards thedevelopment of medical knowledge. PMID- 29283532 TI - The Art of Vesalius: The continuing influence of "De Humani Corporis Fabrica" on Art. AB - A search for the intimate relationship between art and science in the study of the human bodyinevitably leads to the beautiful pictures of Vesalius' Fabrica.Medical artists and scientific researchers alike discover the enhanced power of text andiconography in transmitting knowledge as well as beauty of expression.Pursuing this goal, a facial reconstruction was made of Vesalius' portrait in the Fabrica.Final proof of the correctness of this reconstruction will be given when Vesalius' s grave andremains may be found on the island of Zakynthos where Vesalius died and was buried.Meanwhile medical artists continue to give their vision on anatomy, the human body and itsintangible soul. PMID- 29283533 TI - Ethical Aspects of the Hippocratic Corpus text De arte. AB - The practice of medicine is a complex situation from an ethical point of view in the modern Western societies. But some very simple principles could help the immediate and effective response, at least to a percentage of the problems encountered. Such assistance can be derived from the writings of the Hippocratic Corpus, not only from the so-called ethical or theoretical texts. In this direction, the book titled De arte contains remarks about the right way of practicing medicine and the skills needed by the doctor. PMID- 29283534 TI - Clinical Question: In women who have undergone breast cancer surgery, including lymph node removal, do blood pressure measurements taken in the ipsilateral arm increase the risk of lymphedema? AB - Throughout the healthcare industry fears of taking blood pressure in arm of patients who have undergone breast cancer surgery have been propagated for decades and continue to be recommended by multiple medical societies and healthcare organizations. However, these precautions are not well based on evidence-based medicine and may have a more historical and traditional basis. The purpose of this study was to review current evidence-based research as well as current guidelines regarding ipsilateral arm blood pressure measurements in women who have undergone breast surgery for cancer including lymph node removal. PMID- 29283535 TI - Could we gain insights from the past? Considerations on the 2015 Noble Prize in Physiology or Medicine. AB - One of the winners of the 2015 Nobel Prize in Physiology or Medicine drew inspiration for her research from Traditional Chinese Medicine (TCM). Beginning with a brief history of such a research, some remarks are offered on the event. It is argued that two (however interacting) streams of TCM seem to coexist today in China: one that has embraced modernization and another one that has striven to preserve its distinctiveness with respect to entitled to contribute to medical pluralism. PMID- 29283536 TI - Did Jean Francois Barbe Anticipate Charles Darwin? AB - The publication of Charles Darwin's On the Origin of Species in 1859 is widely suppose to have initiated a revolution in science. In 1837, he broke with dogmatic fixism and argued that the adaptation of populations to their local environment was the cause of transmutation. Some contributors helped him start his reasoning: he indeed expressed his indebtedness to Samuel Rowley for having called his attention to Charles Wells' notions of natural selection. Darwin was certainly not the first to suggest the idea of evolution as an alternative to the creation of species by God. We report on a medical thesis published in 1837 being concluded by an unexpected and important statement related to the appearance of mammals on Earth. It remained unknown but it constitutes a link between the transformative thought of Lamarck and Geoffroy Saint Hilaire, and Darwin's work. PMID- 29283537 TI - Harry Goldblatt (1891-1977): Pathologist and Medical Researcher. AB - Harry Goldblatt (1891-1977) was an American pathologist whose research and experiments on renovascular hypertension were an important contribution to understanding and treating this disease. His life and his legacy are discussed in this paper. PMID- 29283538 TI - Patient perceptions of the care received from their anesthesiologist: a survey study. AB - CONTEXT: Observed disconnect between patient knowledge and choice of anesthesiologist. OBJECTIVES: Assess opportunities to improve perceptions about anesthesiology as a profession, and for patient education on the scope of anesthesia practice. DESIGN: Prospective Study. SETTING: Academic institution and tertiary care hospital in Oklahoma, USA. PARTICIPANTS: 238 patients with a scheduled procedure involving general anesthesia were approached and consented before surgery. Minors, in-patients, pregnant women, prisoners, and non-native English speakers were excluded. Post-procedure, 156 of the consented patients were administered a verbal, eight-question survey in the post-operative are of the hospital. The other 82 patients who had originally consented to the study were excluded for various reasons detailed in the case report. INTERVENTIONS: Study was conducted through surveys over a seven-week period on random patients who consented to answer the survey questions. Main outcome measures: Study confirmed the hypothesis, but also brought out secondary findings. RESULTS: Of the 156 patients surveyed, 19 (12%) knew their anesthesiologist's name, and only 15 (9.6%) said that they knew anything about the anesthesiologist's practice or qualifications. T-test analysis comparing satisfaction with the whole hospital environment to other satisfaction questions showed satisfaction with surgeon, nursing staff, and anesthesiologist were all significantly higher than satisfaction with whole hospital environment (p < 0.05). All T-tests performed were two-tailed tests. CONCLUSIONS: Study indicates that patients know little about their anesthesiologists, and are unlikely to select their own anesthesiologist. Improving patients' knowledge about the anesthesiologists' roles and competencies might be accomplished by providing a list of names and specific practice competencies, or by having an online site of practice information easily accessible. PMID- 29283539 TI - [In process] AB - Savoy, annexed by the French Revolution from 1792 to 1815, became again Sardinian within the kingdom of Piedmont-Sardinia until 1860, the year of annexation to France. These changes have not prevented many students from Savoy to come to France for their medical studies, mostly in Paris. While disorganized by the Revolution, medical training and education systems were put in order as of 1803. The Theses of 142 Savoy students (found largely thanks to foreign students in Paris file prepared by Pierre Moulinier) could be consulted in the archives of the Bibliotheque interuniversitaire de sante de Paris. Accordingly, were studied the geographical origin of candidates, thesis topics, age of the students, the philanthropic Savoisienne society of Paris, the Savoy students who exercised in Paris, the students who were former militaries and the doctors who had a local or national political mandate. A similar study at the Faculty of Turin would allow to better understand the migratory flows of these students. PMID- 29283541 TI - [In process] AB - At the end of the Middle Ages, in 1492, the Hotel-Dieu de Paris was still and establishment of charity intended to receive thepoor which came there to find a shelter and some food. Three centuries later, just before the French Revolution, it became an establishment of care mainly destined to receive the patients, to feed them, take care of them and if possible cure them. This medicalization of the Hotel-Dieu de Paris is related to the progressive emergence of the medical function, which resulted in the creation and the development of a doctor's and surgeon's profession, but also in the development of the apothecary and its drugs. In this context, the diet plays a central part, because it happens to supplies. It would not be until the eve of the French Revolution that it would be integrated in the doctor's prescription and became a dietetic item. PMID- 29283540 TI - In non-pregnant patients over the age of 18 with symptomatic bacterial vaginosis, does the addition of oral or vaginal probiotics compared to standard antibiotic use alone, decrease time to recurrence? PMID- 29283542 TI - [In process] AB - This passages of this discussion are related tot he VIIth book of the Metamorphoses. In the first extract Ovid illustrates the scientific method by which Medea rejuvenates Aeson, her father-in-law; in the second episode, Medea applies the same "treatment" to Baccus' nurturers, with a similar result. Then there's a famous hoax against Pelias: Medea, pretending to rejuvenate the old tyrant, kills him. The sham uses an accurate simulation of medicine's professional gestures and actions, that are similar to the ones of the previous episode to all the appearances: reflection and diagnosis, prognosis, patient;s anaesthesia, administration of the medications, surgery, etc. The restitution ad integrum belongs to the field of magic, but the described therapeutic procedure belongs to the medicine, and it adheres to the rules of the theory of the humors. The intentional reversal of the outcome in Pelias; mockery leads to an ethical issue about the mistrust against the doctors, a problem that was very rooted in Roman culture. PMID- 29283543 TI - Tropical Colonial Ports: Shifting concepts, 1500s-1800s AB - Based on a study of the history of exploration and settlement in North Australia in the 18th and 19th centuries, I became particularly interested in the concept of a 'good port' in the tropics and how in time this concept shifted. The threat of fevers played a significant part in these shifts. In this overview, I examine how similar shifts in the concept of a good port occurred in the maritime silk and spice routes of South and Shout East Asia. PMID- 29283544 TI - Editorial. PMID- 29283545 TI - Clinical Question: In post-partum first-time mothers, what interventions are successful for helping women sustain exclusive breast feeding for one month or more? PMID- 29283546 TI - Priapism: What cause: mental illness, psychotropic medications or poly-substance abuse? AB - We present a case of priapism in a homeless patient with a psychiatric history of major depression, PTSD, polysubstance abuse (alcohol and cocaine) and past psychotropic medication use who was admitted to a local hospital for suicidal ideation. Priapism is a serious urological and a medical emergency which has often been associated with psychotropic medications (including the antidepressant trazodone), use of marijuana and alcohol, and other factors. This clinical case highlights the additive risks of medications and comorbid conditions in contributing to onset of priapism, emphasizing the importance of any pre-existing medical illness, diagnoses, and comorbid mental illnesses. Moreover, clinicians should consider potential side effects of all medications used and their drug interactions as they manage patients who develop this condition. PMID- 29283547 TI - Clinical Inquiry-In women who have undergone breast cancer surgery, including lymph node removal, do blood pressure measurements taken in the ipsilateral arm increase the risk of lymphedema? AB - Throughout the healthcare industry fears of taking blood pressure in the arms of patients who have undergone breast cancer surgery have been propagated for decades and continue to be recommended by multiple medical societies and healthcare organizations. However, these precautions are not well based on evidence-based medicine and may have a more historical and traditional basis. The purpose of this study was to review current evidence-based research as well as current guidelines regarding ipsilateral blood pressure measurements in women who have undergone breast surgery for cancer including lymph node removal. PMID- 29283548 TI - Granulocyte Colony-Stimulating Factor Nanocarriers for Stimulation of the Immune System (Part I): Synthesis and Biodistribution Studies. AB - In the field of cancer immunotherapy, an original approach consists of using granulocyte colony-stimulating factor (G-CSF) to target and activate neutrophils, cells of the innate immune system. G-CSF is a leukocyte stimulating molecule which is commonly used in cancer patients to prevent or reduce neutropenia. We focused herein on developing a G-CSF nanocarrier which could increase the in vivo circulation time of this cytokine, keeping it active for targeting the spleen, an important reservoir of neutrophils. G-CSF-functionalized silica and gold nanoparticles were developed. Silica nanoparticles of 50 nm diameter were functionalized by a solid phase synthesis approach. The technology enabled us to incorporate multiple functionalities on the surface such as a PEG as hydrophilic polymer, DTPA as 111In chelating agent and G-CSF. The gold nanocarrier consisted of nanoparticles of 2-3 nm diameter elaborated with DTPA groups on the surface and functionalized with G-CSF. We studied the particle biodistribution in mice with special attention to organs involved in the immune system. The two nanocarriers with similar functionalization of surface showed different pathways in mice, probably due to their difference in size. Considering the biodistribution after G-CSF functionalization, we confirmed that the protein was capable of modifying the pharmacokinetics by increasing the nanocarrier concentration in the spleen, a reservoir of G-CSF receptor expressing cells. PMID- 29283549 TI - Detection of Impurities in Organic Crystals by High-Accuracy Terahertz Absorption Spectroscopy. AB - Quantitative detection of impurities in organic crystals was demonstrated by accurately measuring absorption frequencies using a continuous wave gallium phosphide terahertz spectrometer. THz spectra of l-asparagine monohydrate doped with l-aspartic acid at 0.05 to 12.5 wt % were obtained at 10 K. The three lowest frequency absorption peaks were baseline-resolved, allowing them to be examined independently. Using a least-squares curve fitting technique, impurities were detected at levels as low as 500 ppm. The sensitivity and detection limits of the technique depended strongly on the nature of both the host and the impurities. The projected limit of detection using the current system, given optimal materials, was estimated to be 51.7 ppm. In addition to quantitative assessments, impurities may also be identified by comparing frequency shifts of multiple absorptions. PMID- 29283550 TI - Spatiotemporal Characteristics of Intercellular Calcium Wave Communication in Micropatterned Assemblies of Single Cells. AB - Micropatterned substrates offer a unique possibility to define and control spatial organization of biological cells at the microscale, which greatly facilitates investigations of the cell-to-cell communication in vitro. Here, we developed a simple micropatterning strategy to resolve various spatiotemporal characteristics of intercellular calcium wave (ICW) communication among isolated BV-2 microglial cells. By using a single-ring assembly, we found that the direction of the initial transmitter secretion was strongly correlated with the site of the cell at which the mechanical stimulus triggering the ICWs was imposed. By using multiring assemblies, we observed that the response ratio of the same outmost cells 160 MUm away from the center increased from 0% in the single-ring assembly to 9.6% in the four-ring assembly. This revealed that cells located in the interring acted as regenerative amplifiers for the ICWs generated by the central cell. By using a special oval-type micropattern, we found that calcium mobilization in lamellipodia of a fusiform BV-2 microglia cell occurred 2.9 times faster than that in the middle part of the cell, demonstrating a higher region-specific sensitivity of lamellipodia to the transmitter. Taken together, our micropatterning strategy opened up new experimental prospects to study ICWs and revealed novel spatiotemporal characteristics of ICW communication including stimulation site-dependent secretion, regenerative propagation, and region specific cell sensitivity. PMID- 29283551 TI - Mechanism and Structure of gamma-Resorcylate Decarboxylase. AB - gamma-Resorcylate decarboxylase (gamma-RSD) has evolved to catalyze the reversible decarboxylation of 2,6-dihydroxybenzoate to resorcinol in a nonoxidative fashion. This enzyme is of significant interest because of its potential for the production of gamma-resorcylate and other benzoic acid derivatives under environmentally sustainable conditions. Kinetic constants for the decarboxylation of 2,6-dihydroxybenzoate catalyzed by gamma-RSD from Polaromonas sp. JS666 are reported, and the enzyme is shown to be active with 2,3 dihydroxybenzoate, 2,4,6-trihydroxybenzoate, and 2,6-dihydroxy-4-methylbenzoate. The three-dimensional structure of gamma-RSD with the inhibitor 2-nitroresorcinol (2-NR) bound in the active site is reported. 2-NR is directly ligated to a Mn2+ bound in the active site, and the nitro substituent of the inhibitor is tilted significantly from the plane of the phenyl ring. The inhibitor exhibits a binding mode different from that of the substrate bound in the previously determined structure of gamma-RSD from Rhizobium sp. MTP-10005. On the basis of the crystal structure of the enzyme from Polaromonas sp. JS666, complementary density functional calculations were performed to investigate the reaction mechanism. In the proposed reaction mechanism, gamma-RSD binds 2,6-dihydroxybenzoate by direct coordination of the active site manganese ion to the carboxylate anion of the substrate and one of the adjacent phenolic oxygens. The enzyme subsequently catalyzes the transfer of a proton to C1 of gamma-resorcylate prior to the actual decarboxylation step. The reaction mechanism proposed previously, based on the structure of gamma-RSD from Rhizobium sp. MTP-10005, is shown to be associated with high energies and thus less likely to be correct. PMID- 29283552 TI - Tellurophene-Based Random Copolymers for High Responsivity and Detectivity Photodetectors. AB - Organic photodetectors (OPDs) have attracted great attention because of their advantages including tunable response range, easy processability, and flexibility. Various conjugated polymers have been developed for high-performing OPDs. Herein, a series of tellurophene-based random copolymers containing two typical electron-withdrawing units naphthalene diimide (NDI) and perylene diimide (PDI) are designed and synthesized. Through varying the ratio of PDI/NDI moieties of the analogous polymers, the optophysical properties and film morphology, together with photodetector performances, are systematically tuned. It was demonstrated that the photodetectors based on the polymer with the molar ratio of PDI/NDI units of 70/30 possessed strong photoinduced absorption and favorable morphology via transient absorption spectra and atomic force microscopy studies. As a result, a high responsivity about 19.1 A/W at 600 nm and an excellent detectivity more than 1012 Jones ranging from 350 to 600 nm were successfully achieved, which are among the highest values for OPDs and comparable to inorganic counterparts. PMID- 29283554 TI - Nitrogen-Doped Carbon Nanodots-Ionogels: Preparation, Characterization, and Radical Scavenging Activity. AB - Hybrid diimidazolium-based ionogels were obtained by dispersing nitrogen-doped carbon nanodots (NCNDs) in ionic liquid (IL) solutions and by using dicationic organic salts as gelators. The properties of the NCND-ionogels were studied in terms of thermal stability, mechanical strength, morphology, rheological, and microscopic analyses. Insights into the formation of the hybrid soft material were attained from kinetics of sol-gel phase transition and from estimating the size of the aggregates, obtained from opacity and resonance light-scattering measurements. We demonstrate that, on one hand, NCNDs were able to favor the gel formation both in the presence of gelating and nongelating ILs. On the other hand, the gelatinous matrix retains and, in some cases, improves the properties of NCNDs. The NCND-ionogels showed the typical fluorescence emission of the carbon dots and a notable antiradical activity, with higher efficiency as compared to the single components. The presented hybrid materials hold great promise for topical applications in antioxidant fields. PMID- 29283553 TI - Mechanism of N2 Reduction Catalyzed by Fe-Nitrogenase Involves Reductive Elimination of H2. AB - Of the three forms of nitrogenase (Mo-nitrogenase, V-nitrogenase, and Fe nitrogenase), Fe-nitrogenase has the poorest ratio of N2 reduction relative to H2 evolution. Recent work on the Mo-nitrogenase has revealed that reductive elimination of two bridging Fe-H-Fe hydrides on the active site FeMo-cofactor to yield H2 is a key feature in the N2 reduction mechanism. The N2 reduction mechanism for the Fe-nitrogenase active site FeFe-cofactor was unknown. Here, we have purified both component proteins of the Fe-nitrogenase system, the electron delivery Fe protein (AnfH) plus the catalytic FeFe protein (AnfDGK), and established its mechanism of N2 reduction. Inductively coupled plasma optical emission spectroscopy and mass spectrometry show that the FeFe protein component does not contain significant amounts of Mo or V, thus ruling out a requirement of these metals for N2 reduction. The fully functioning Fe-nitrogenase system was found to have specific activities for N2 reduction (1 atm) of 181 +/- 5 nmol NH3 min-1 mg-1 FeFe protein, for proton reduction (in the absence of N2) of 1085 +/- 41 nmol H2 min-1 mg-1 FeFe protein, and for acetylene reduction (0.3 atm) of 306 +/- 3 nmol C2H4 min-1 mg-1 FeFe protein. Under turnover conditions, N2 reduction is inhibited by H2 and the enzyme catalyzes the formation of HD when presented with N2 and D2. These observations are explained by the accumulation of four reducing equivalents as two metal-bound hydrides and two protons at the FeFe cofactor, with activation for N2 reduction occurring by reductive elimination of H2. PMID- 29283556 TI - Nanochannels Photoelectrochemical Biosensor. AB - Nanochannels have brought new opportunities for biosensor development. Herein, we present the novel concept of a nanochannels photoelectrochemical (PEC) biosensor based on the integration of a unique CuxO-nanopyramid-islands (NPIs) photocathode, an anodic aluminum oxide (AAO) membrane, and alkaline phosphatase (ALP) catalytic chemistry. The CuxO-NPIs photocathode possesses good performance, and further assembly with AAO yields a designed architecture composed of vertically aligned, highly ordered nanoarrays on top of the CuxO-NPIs film. After biocatalytic precipitation (BCP) was stimulated within the channels, the biosensor was used for the successful detection of ALP activity. This study has not only provided a novel paradigm for an unconventional nanochannels PEC biosensor, which can be used for general bioanalytical purposes, but also indicated that the new concept of nanochannel-semiconductor heterostructures is a step toward innovative biomedical applications. PMID- 29283555 TI - Acid-Free Preparation of Cellulose Nanocrystals by TEMPO Oxidation and Subsequent Cavitation. AB - Softwood bleached kraft pulp (SBKP) and microcrystalline cellulose (MCC) were oxidized using a 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated system. The TEMPO-oxidized SBKP prepared with 10 mmol/g NaClO (SBKP-10) had a higher mass recovery ratio and higher carboxylate content than the other prepared celluloses including the TEMPO-oxidized MCCs. The SBKP-10 was then exposed to cavitation induced forces through sonication in water for 10-120 min to prepare aqueous dispersions of needle-like TEMPO-oxidized cellulose nanocrystals (TEMPO-CNCs) with homogeneous width of 3.5 to 3.6 nm and average lengths of ~200 nm. The average chain lengths of the cellulose molecules that make up the TEMPO-CNCs were less than half the average lengths of the TEMPO-CNCs. Compared with conventional CNCs prepared by acid hydrolysis, the TEMPO-CNCs prepared by the acid-free and dialysis-free process exhibited higher mass recovery ratios, significantly higher amounts of surface anionic groups, and smaller and more homogeneous widths. PMID- 29283557 TI - alpha,beta-Unsaturated Aldehyde-Induced Delays in Nucleotide Excision Repair and the Contribution of Reactive Oxygen Species. AB - Aldehydes are widespread environmental and industrial compounds to which humans are frequently exposed. Despite their significant health risk, the mechanisms underlying aldehyde toxicity are poorly understand. We recently demonstrated that cigarette sidestream smoke (CSS) inhibited nucleotide excision repair (NER), and this was attributed to aldehydes in CSS. In the present study, we examined the influence of saturated and unsaturated aldehydes on NER. The human keratinocyte cell line, HaCaT, was treated with aldehydes and then exposed to UVB. Saturated aldehydes did not show toxicity, whereas alpha,beta-unsaturated aldehydes caused cell death, which was markedly enhanced by UV exposure. The speed of NER was examined by the detection of pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) using ELISA and local UV irradiation assay. The repair of 6-4PPs was markedly reduced by alpha,beta-unsaturated aldehydes, but not by saturated aldehydes, and this was attributed to a delay in the recruitment of repair proteins (TFIIH and XPG) to DNA damage sites. Reactive oxygen species (ROS) were produced after a treatment with alpha,beta-unsaturated aldehydes, and hydrogen peroxide (H2O2) inhibited the repair of 6-4PPs, similar to alpha,beta-unsaturated aldehydes. H2O2 inhibited the accumulation of XPA and XPG at DNA damage sites, whereas TFIIH showed the same recruitment with or without H2O2. These results suggest that an exposure to alpha,beta-unsaturated aldehydes, not saturated aldehydes inhibits NER by delaying the recruitment of NER proteins to DNA damage sites, and alpha,beta-unsaturated aldehyde-induced ROS production may partially play a role in this process. PMID- 29283558 TI - A New Editorial Team for CRT. PMID- 29283559 TI - Granulocyte-Colony Stimulating Factor Nanocarriers for Stimulation of the Immune System (Part II): Dose-Dependent Biodistribution and In Vivo Antitumor Efficacy in Combination with Rituximab. AB - The purpose of immuno-modulation is to increase or restore the action of immunocompetent cells against tumors with or without the use of monoclonal antibodies. The innate immune system is a key player in various pathological situations, but cells of this system appear to be inhibited or insufficiently active in malignancy or severe infectious diseases. The present study was designed to investigate therapeutic value of nanoparticles (NPs) coupled with bioactive hematopoietic growth factors acting on the innate immune system. The use of nanoparticles (NPs) allowing multimodal detection and multifunctional grafting are currently of great interest for theranostic purposes. In the present work, we have evaluated the impact of the number of granulocyte-colony stimulating factor (G-CSF) grafted on the surface on the NPs on the biodistribution in mice thanks to indium 111 radiolabeling. Furthermore, we have investigated whether grafted G-CSF NPs could stimulate the immune innate system and enhance the therapeutic efficacy of the monoclonal antibody rituximab in mice bearing human lymphoma xenografts. Following intravenous (i.v.) administration of NP-DTPA and NP-DTPA/G-CSF-X high levels of radioactivity were observed in the liver. Furthermore, spleen uptake was correlated with the number of G-CSF molecules grafted on the surface of the NPs. Combining NP-DTPA/G-CSF-34 with rituximab strongly reduced RL tumor growth compared to rituximab alone or in combination with conventional G-CSF + rituximab. The use of highly loaded G-CSF NPs as immune adjuvants could enhance the antitumor activity of therapeutic monoclonal antibodies by amplifying tumor cell destruction by innate immune cells. PMID- 29283560 TI - Targeted Drug Delivery and Treatment of Endoparasites with Biocompatible Particles of pH-Responsive Structure. AB - Biomaterials conceived for vectorization of bioactives are currently considered for biomedical, biological, and environmental applications. We have produced a pH sensitive biomaterial composed of natural source alginate and chitosan polysaccharides for application as a drug delivery system via oral administration. The composite particle preparation was in situ monitored by means of isothermal titration calorimetry. The strong interaction established between the macromolecules during particle assembly led to 0.60 alginate/chitosan effective binding sites with an intense exothermic effect and negative enthalpy variation on the order of a thousand kcal/mol. In the presence of model drugs mebendazole and ivermectin, with relatively small and large structures, respectively, mebendazole reduced the amount of chitosan monomers available to interact with alginate by 27%, which was not observed for ivermectin. Nevertheless, a state of intense negative Gibbs energy and large entropic decrease was achieved, providing evidence that formation of particles is thermodynamically driven and favored. Small-angle X-ray scattering provided further evidence of similar surface aspects independent of the presence of drug. The physical responses of the particles to pH variation comprise partial hydration, swelling, and the predominance of positive surface charge in strong acid medium, whereas ionization followed by deprotonation leads to compaction and charge reversal rather than new swelling in mild and slightly acidic mediums, respectively. In vivo performance was evaluated in the treatment of endoparasites in Corydoras fish. Systematically with a daily base oral administration, particles significantly reduced the infections over 15 days of treatment. The experiments provide evidence that utilizing particles granted and boosted the action of the antiparasitic drugs, leading to substantial reduction or elimination of infection. Hence, the pH-responsive particles represent a biomaterial with prominent characteristics that is promising for the development of targeted oral drug delivery. PMID- 29283562 TI - Influence of Constraints within a Cyclic Polymer on Solution Properties. AB - Cyclic polymers with internal constraints provide new insight into polymer properties in solution and bulk and can serve as a model system to explain the stability and mobility of cyclic biomacromolecules. The model system used in this work consisted of cyclic polystyrene structures, all with a nearly identical molecular weight, designed with 0-3 constraints located at strategic sites within the cyclic polymer, with either 4 or 6 branch points. The total number of branch points (or arms) within the cyclic ranged from 0 to 18. Molecular dynamic (MD) simulations showed that as the number of arms increased within the cyclic structure, the radius of gyration and the hydrodynamic radius generally decreased, suggesting the greater number of constraints resulted in a more compact polymer chain. The simulations further showed that the excluded volume was much greater for the cyclics compared to a linear polymer at the same molecular weight. The spirocyclic, a structure consisting of three rings joined in series, showed significant excluded volume effects in agreement with experimental data; the reason for which is unclear at this stage. Interestingly, under a size exclusion chromatography flow, the radius of hydration for all the cyclic structures increased compared with the DLS data, and could be explained from the greater swelling of the rings perpendicular to the flow found from previous simulations on rings. This data suggests that the greater compactness, greater excluded volume and structural rearrangements under flow of constrained cyclic polymers could be used to provide a physical basis for understanding greater stability and activity of cyclic biological macromolecules. PMID- 29283563 TI - Spatial Position Regulates Power of Tryptophan: Discovery of a Major-Groove Specific Nuclear-Localizing, Cell-Penetrating Tetrapeptide. AB - Identification of key amino acids is required for development of efficient cell penetrating peptides (CPPs) and has tremendous implications in medicine. Extensive research work has enlightened us about the importance of two amino acids, arginine and tryptophan, in cell penetration. Here, we present a top-down approach to show how spatial positions of two tryptophans regulate the cellular entry and nuclear localization. This enables us to develop short, non-toxic tetrapeptides with excellent potential for cell penetration and nuclear localization. Among them, Glu-Thr-Trp-Trp (ETWW) emerges as the most promising. Results suggest that it enters into cancer cells following an endocytic pathway and binds at the major groove of nuclear DNA, where successive tryptophan plays major role. We subsequently show that it is not a P-glycoprotein substrate and is non-toxic to PC12-derived neurons, suggesting its excellent potential as a CPP. Furthermore, its potential as a CPP is validated in multi-cellular 3D cell culture (spheroid) and in in vivo mice model. This study provides major fundamental insights about the positional importance of tryptophan and opens new avenues toward the development of next-generation CPPs and major-groove-specific anticancer drugs. PMID- 29283564 TI - Kinetics of Decomposition of Thiocyanate in Natural Aquatic Systems. AB - Rates of thiocyanate degradation were measured in waters and sediments of marine and limnic systems under various redox conditions, oxic, anoxic (nonsulfidic, nonferruginous, nonmanganous), ferruginous, sulfidic, and manganous, for up to 200-day period at micromolar concentrations of thiocyanate. The decomposition rates in natural aquatic systems were found to be controlled by microbial processes under both oxic and anoxic conditions. The Michaelis-Menten model was applied for description of the decomposition kinetics. The decomposition rate in the sediments was found to be higher than in the water samples. Under oxic conditions, thiocyanate degradation was faster than under anaerobic conditions. In the presence of hydrogen sulfide, the decomposition rate increased compared to anoxic nonsulfidic conditions, whereas in the presence of iron(II) or manganese(II), the rate decreased. Depending on environmental conditions, half lives of thiocyanate in sediments and water columns were in the ranges of hours to few dozens of days, and from days to years, respectively. Application of kinetic parameters presented in this research allows estimation of rates of thiocyanate cycling and its concentrations in the Archean ocean. PMID- 29283561 TI - Human P450 CYP17A1: Control of Substrate Preference by Asparagine 202. AB - CYP17A1 is a key steroidogenic enzyme known to conduct several distinct chemical transformations on multiple substrates. In its hydroxylase activity, this enzyme adds a hydroxyl group at the 17alpha position of both pregnenolone and progesterone at approximately equal rates. However, the subsequent 17,20 carbon carbon scission reaction displays variable substrate specificity in the numerous CYP17A1 isozymes operating in vertebrates, manifesting as different Kd and kcat values when presented with 17alpha-hydroxypregnenlone (OHPREG) versus 17alpha hydroxyprogesterone (OHPROG). Here we show that the identity of the residue at position 202 in human CYP17A1, thought to form a hydrogen bond with the A-ring alcohol substituent on the pregnene- nucleus, is a key driver of this enzyme's native preference for OHPREG. Replacement of asparagine 202 with serine completely reverses the preference of CYP17A1, more than doubling the rate of turnover of the OHPROG to androstenedione reaction and substantially decreasing the rate of formation of dehydroepiandrosterone from OHPREG. In a series of resonance Raman experiments, it was observed that, in contrast with the case for the wild-type protein, in the mutant the 17alpha alcohol of OHPROG tends to form a H-bond with the proximal rather than terminal oxygen of the oxy-ferrous complex. When OHPREG was a substrate, the mutant enzyme was found to have a H bonding interaction with the proximal oxygen that is substantially weaker than that of the wild type. These results demonstrate that a single-point mutation in the active site pocket of CYP17A1, even when far from the heme, has profound effects on steroidogenic selectivity in androgen biosynthesis. PMID- 29283565 TI - Shape-Control of Pt-Ru Nanocrystals: Tuning Surface Structure for Enhanced Electrocatalytic Methanol Oxidation. AB - Despite the fact that both electrochemical experiments and density functional theory calculations have testified to the superior electrocatalytic activity and CO-poisoning tolerance of platinum-ruthenium (PtRu) alloy nanoparticles toward the methanol oxidation reaction (MOR), the facet-dependent electrocatalytic properties of PtRu nanoparticles are scarcely revealed because it is extremely difficult to synthesize well-defined facets-enclosed PtRu nanocrystals. Herein, we for the first time report a general synthesis of ultrathin PtRu nanocrystals with tunable morphologies (nanowires, nanorods, and nanocubes) through a one-step solvothermal approach and a systematic investigation of the structure-directing effects of different surfactants and the formation mechanism by control experiments and time-dependent studies. In addition, we utilize these {100} and {111} facets-enclosed PtRu nanocrystals as model catalysts to evaluate the electrocatalytic characteristics of the MOR on different facets. Remarkably, {111}-terminated PtRu nanowires exhibit much higher stability and electrocatalytic mass activity toward MOR, which are 2.28 and 4.32 times higher than those of {100}-terminated PtRu nanocubes and commercial Pt/C, respectively, indicating that PtRu {111} facets possess superior methanol oxidation activity and CO-poisoning resistance relative to {100} facets. Our present work provides a series of well-defined PtRu nanocrystals with tunable facets which would be ideal model electrocatalysts for fundamental research in fuel cell electrocatalysis. PMID- 29283566 TI - Interaction Mode and Regioselectivity in Vitamin B12-Dependent Dehalogenation of Aryl Halides by Dehalococcoides mccartyi Strain CBDB1. AB - The bacterium Dehalococcoides, strain CBDB1, transforms aromatic halides through reductive dehalogenation. So far, however, the structures of its vitamin B12 containing dehalogenases are unknown, hampering clarification of the catalytic mechanism and substrate specificity as basis for targeted remediation strategies. This study employs a quantum chemical donor-acceptor approach for the Co(I) substrate electron transfer. Computational characterization of the substrate electron affinity at carbon-halogen bonds enables discriminating aromatic halides ready for dehalogenation by strain CBDB1 (active substrates) from nondehalogenated (inactive) counterparts with 92% accuracy, covering 86 of 93 bromobenzenes, chlorobenzenes, chlorophenols, chloroanilines, polychlorinated biphenyls, and dibenzo-p-dioxins. Moreover, experimental regioselectivity is predicted with 78% accuracy by a site-specific parameter encoding the overlap potential between the Co(I) HOMO (highest occupied molecular orbital) and the lowest-energy unoccupied sigma-symmetry substrate MO (sigma*), and the observed dehalogenation pathways are rationalized with a success rate of 81%. Molecular orbital analysis reveals that the most reactive unoccupied sigma-symmetry orbital of carbon-attached halogen X (sigmaC-X*) mediates its reductive cleavage. The discussion includes predictions for untested substrates, thus providing opportunities for targeted experimental investigations. Overall, the presently introduced orbital interaction model supports the view that with bacterial strain CBDB1, an inner-sphere electron transfer from the supernucleophile B12 Co(I) to the halogen substituent of the aromatic halide is likely to represent the rate determining step of the reductive dehalogenation. PMID- 29283567 TI - Hidden Beneath the Surface: Origin of the Observed Enantioselective Adsorption on PdGa(111). AB - We unravel the origin of the recently observed striking enantioselectivity of the PdGa(111) surface with respect to the adsorption of a small organic molecule, 9 ethynylphenanthrene, using first-principles calculations. It turns out that the key ingredient to understand the experimental evidence is the appropriate description of van der Waals interactions beyond the widely employed atomic pairwise approximation. A recently developed van der Waals-inclusive density functional method, which encompasses dielectric screening effects, reveals the origin of the experimentally observed enantioselectivity and provides conclusive evidence of chiral recognition on a bimetallic surface driven by dispersion interactions. The incorporation of dielectric screening leads to a renormalization of the dispersion interaction range, allowing for the appropriate weighting of the molecule-substrate interactions at intermediate distances between 2.5 and 5 A. Our findings have implications for the structure and stability of complex organic/inorganic systems where dielectric screening effects are expected to be of general importance. PMID- 29283568 TI - Polymer Self-Assembly into Unique Fractal Nanostructures in Solution by a One Shot Synthetic Procedure. AB - A fractal nanostructure having a high surface area is potentially useful in sensors, catalysts, functional coatings, and biomedical and electronic applications. Preparation of fractal nanostructures on solid substrates has been reported using various inorganic or organic compounds. However, achieving such a process using polymers in solution has been extremely challenging. Here, we report a simple one-shot preparation of polymer fractal nanostructures in solution via an unprecedented assembly mechanism controlled by polymerization and self-assembly kinetics. This was possible only because one monomer was significantly more reactive than the other, thereby easily forming a diblock copolymer microstructure. Then, the second insoluble block containing poly(p phenylenevinylene) (PPV) without any side chains spontaneously underwent self assembly during polymerization by an in situ nanoparticlization of conjugated polymers (INCP) method. The formation of fractal structures in solution was confirmed by various imaging techniques such as atomic force microscopy, transmission electron microscopy (TEM), and cryogenic TEM. The diffusion-limited aggregation theory was adopted to explain the branching patterns of the fractal nanostructures according to the changes in polymerization conditions such as the monomer concentration and the presence of additives. Finally, after detailed kinetic analyses, we proposed a plausible mechanism for the formation of unique fractal nanostructures, where the gradual formation and continuous growth of micelles in a chain-growth-like manner were accounted for. PMID- 29283569 TI - Structure and Phase Transformation in the Giant Magnetostriction Laves-Phase SmFe2. AB - As one class of the most important intermetallic compounds, the binary Laves phase is well-known for its abundant magnetic properties. Samarium-iron alloy system SmFe2 is a prototypical Laves compound that shows strong negative magnetostriction but relatively weak magnetocrystalline anisotropy. SmFe2 has been identified as a cubic Fd3m structure at room temperature; however, the cubic symmetry, in principle, does not match the spontaneous magnetization along the [111]cubic direction. Here we studied the crystal structure of SmFe2 by high resolution synchrotron X-ray powder diffraction, X-ray total scattering, and selected-area electron diffraction methods. SmFe2 is found to adopt a centrosymmetric trigonal R3m structure at room temperature, which transforms to an orthorhombic Imma structure at 200 K. This transition is in agreement with the changes of easy magnetization direction from [111]cubic to [110]cubic direction and is further evidenced by the inflection of thermal expansion behavior, the sharp decline of the magnetic susceptibility in the field-cooling-zero field cooling curve, and the anomaly in the specific heat capacity measurement. The revised structure and phase transformation of SmFe2 could be useful to understand the magnetostriction and related physical properties of other RM2-type pseudocubic Laves-phase intermetallic compounds. PMID- 29283570 TI - Heterologous Biosynthesis of Nodulisporic Acid F. AB - Nodulisporic acids comprise a group of valuable indole diterpenes that exhibit potent insecticidal activities. We report the identification of a gene cluster in the genome of the filamentous fungus Hypoxylon pulicicidum (Nodulisporium sp.) that contains genes responsible for the biosynthesis of nodulisporic acids. Using Penicillium paxilli as a heterologous host, and through pathway reconstitution experiments, we identified the function of four genes involved in the biosynthesis of the nodulisporic acid core compound, nodulisporic acid F (NAF). Two of these genes (nodM and nodW) are especially significant as they encode enzymes with previously unreported functionality: nodM encodes a 3 geranylgeranylindole epoxidase capable of catalyzing only a single epoxidation step to prime formation of the distinctive ring structure of nodulisporic acids, and nodW encodes the first reported gene product capable of introducing a carboxylic acid moiety to an indole diterpene core structure that acts as a reactive handle for further modification. Here, we present the enzymatic basis for the biosynthetic branch point that gives rise to nodulisporic acids. PMID- 29283571 TI - Traceless Silylation of beta-C(sp3)-H Bonds of Alcohols via Perfluorinated Acetals. AB - We report the silylation of primary C-H bonds located beta to secondary and tertiary alcohols by exploiting perfluorinated esters as traceless directing groups. The conversion of a secondary or tertiary alcohol to a perfluoroalkyl ester and conversion of the ester to the corresponding silyl acetals by hydrosilylation allows for selective beta-C(sp3)-H silylation catalyzed by the combination of [Ir(cod)OMe]2 and Me4Phen (3,4,7,8-tetramethyl-1,10 phenanthroline) to form 6-membered dioxasilinane. Tamao-Fleming oxidation of these dioxasilinane leads to 1,2 diols. The developed sequence was applied to a series of natural products containing hydroxyl groups. PMID- 29283572 TI - Remote C-H Hydroxylation by an alpha-Ketoglutarate-Dependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs. AB - Selective C-H functionalization at distal positions remains a highly challenging problem in organic synthesis. Though Nature has evolved a myriad of enzymes capable of such feat, their synthetic utility has largely been overlooked. Here, we functionally characterize an alpha-ketoglutarate-dependent dioxygenase (Fe/alphaKG) that selectively hydroxylates the delta position of various aliphatic amino acids. Kinetic analysis and substrate profiling of the enzyme show superior catalytic efficiency and substrate promiscuity relative to other Fe/alphaKGs that catalyze similar reactions. We demonstrate the practical utility of this transformation in the concise syntheses of a rare alkaloid, manzacidin C, and densely substituted amino acid derivatives with remarkable step efficiency. This work provides a blueprint for future applications of Fe/alphaKG hydroxylation in complex molecule synthesis and the development of powerful synthetic paradigms centered on enzymatic C-H functionalization logic. PMID- 29283573 TI - Cosputtered Calcium Manganese Oxide Electrodes for Water Oxidation. AB - Calcium manganese oxide films were prepared by cosputter deposition from Mn and CaMnO3 targets and evaluated for their suitability as catalysts for the oxygen evolution reaction (OER). Scanning electron microscopy (SEM) revealed a compact morphology for the as-deposited films and the formation of nanorodlike features on the surfaces after annealing at 600 degrees C. X-ray-photoelectron spectroscopy analysis showed that the surface oxidation state is close to +III (as in Mn2O3) for the as-deposited films and increases slightly to a mixture of III and IV after annealing occurs in dry air at 400-600 degrees C. Glancing incidence X-ray diffraction (GIXRD) suggested that the CaMnxOy films are amorphous even when heated to 600 degrees C. However, transmission electron microscopy (TEM) showed that there is actually a polycrystalline component of the film, which best matches Mn3O4 (hausmannite with the average Mn oxidation state of ~+2.7) but may have a slightly expanded unit cell because of the incorporation of Ca. Electrochemical analyses revealed that the as-deposited CaMnxOy films were OER-inactive. In contrast, annealing at 400 or 600 degrees C resulted in an increase of ~15-fold in the current densities, which reached j ? 1.5 mA.cm-2 at OER overpotentials of eta ~ 550 mV in cyclic voltammetry (CV) sweeps. For the same eta, annealed CaMnxOy electrodes also showed good electrochemical stabilities during 2 h of electrolysis, as rather constant steady-state current densities of j ? 0.4-0.5 mA.cm-2 were observed. The thicknesses and surface morphologies of the CaMnxOy films did not change during the electrochemical measurements, indicating that corrosion was negligible. In comparison with a previous study in which Ca-free thin layers of MnOx were evaluated, the results demonstrate that Ca2+ incorporation can enhance the OER activity of MnOx electrocatalysts prepared by sputter deposition. This work provides guidance for designing new electrodes for water oxidation on the basis of the abundant and nontoxic elements manganese and calcium. PMID- 29283574 TI - X-ray Generated Recombination Exciplexes of Substituted Diphenylacetylenes with Tertiary Amines: A Versatile Experimental Vehicle for Targeted Creation of Deep Blue Electroluminescent Systems. AB - Customizable and technology-friendly functional materials are one of the mainstays of emerging organic electronics and optoelectronics. We show that recombination exciplexes of simple substituted diphenylacetylenes with tertiary amines can be a convenient source of tunable deep-blue emission with possible applications in organic electroluminescent systems. The optically inaccessible exciplexes were produced via recombination of radiation-generated radical ion pairs in alkane solution, which mimics charge transport and recombination in the active layer of practical organic light-emitting diodes in a simple solution based experiment. Despite varying and rather poor intrinsic emission properties, diphenylacetylene and its prototypical methoxy (donor) or trifluoromethyl (acceptor) monosubstituted derivatives readily form recombination exciplexes with N,N-dimethylaniline and other tertiary amines that produce emission with maxima ranging from 385 to 435 nm. The position of emission band maximum linearly correlates with readily calculated gas-phase electron affinity of the corresponding diphenylacetylene, which can be used for fast computational prescreening of the candidate molecules, and various substituted diphenylacetylenes can be synthesized via relatively simple and universal cross coupling reactions of Sonogashira and Castro. Together, the simple solution-based experiment, computationally cheap prescreening method, and universal synthetic strategy may open a very broad and chemically convenient class of compounds to obtain OLEDs and OLED-based multifunctional devices with tunable emission spectrum and high conversion efficiency that has yet not been seriously considered for these purposes. PMID- 29283575 TI - In Vitro and in Silico Competitive Binding of Brominated Polyphenyl Ether Contaminants with Human and Gull Thyroid Hormone Transport Proteins. AB - Tetradecabromo-1,4-diphenoxybenzene (TeDB-DiPhOBz) is a highly brominated additive flame retardant (FR). Debrominated photodegradates of TeDB-DiPhOBz are hydroxylated in vitro in liver microsomal assays based on herring gulls (Larus argentatus), including one metabolite identified as 4"-OH-2,2',2",4-tetrabromo DiPhOBz. Chemically related methoxylated tetra- to hexabromo-DiPhOBzs are known contaminants in herring gulls. Collectively, nothing is currently known about biological effects of these polybrominated (PB) DiPhOBz-based compounds. The present study investigated the potential thyroidogenicity of 2,2',2",4-tetrabromo (TB)-DiPhOBz along with its para-methoxy (MeO)- and hydroxy-(OH)-analogues, using an in vitro competitive protein binding assay with the human thyroid hormone (TH) transport proteins transthyretin (hTTR) and albumin (hALB). This model para-OH-TB DiPhOBz was found to be capable of competing with thyroxine (T4) for the binding site on hTTR and hALB. In silico analyses were also conducted using a 3D homology model for gull TTR, to predict whether these TB-DiPhOBz-based compounds may also act as ligands for an avian TH transport protein despite evolutionary differences with hTTR. This analysis found all three TB-DiPhOBz analogues to be potential ligands for gull TTR and have similar binding efficacies to THs. Results indicate structure-related differences in binding affinities of these ligands and suggest there is potential for these contaminants to interact with both mammalian and avian thyroid function. PMID- 29283576 TI - Accurate Quantitation and Analysis of Nitrofuran Metabolites, Chloramphenicol, and Florfenicol in Seafood by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry: Method Validation and Regulatory Samples. AB - We developed and validated a method for the extraction, identification, and quantitation of four nitrofuran metabolites, 3-amino-2-oxazolidinone (AOZ), 3 amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), semicarbazide (SC), and 1 aminohydantoin (AHD), as well as chloramphenicol and florfenicol in a variety of seafood commodities. Samples were extracted by liquid-liquid extraction techniques, analyzed by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and quantitated using commercially sourced, derivatized nitrofuran metabolites, with their isotopically labeled internal standards in-solvent. We obtained recoveries of 90-100% at various fortification levels. The limit of detection (LOD) was set at 0.25 ng/g for AMOZ and AOZ, 1 ng/g for AHD and SC, and 0.1 ng/g for the phenicols. Various extraction methods, standard stability, derivatization efficiency, and improvements to conventional quantitation techniques were also investigated. We successfully applied this method to the identification and quantitation of nitrofuran metabolites and phenicols in 102 imported seafood products. Our results revealed that four of the samples contained residues from banned veterinary drugs. PMID- 29283577 TI - Reduction Mechanisms of Cu2+-Doped Na2O-Al2O3-SiO2 Glasses during Heating in H2 Gas. AB - Controlling valence state of metal ions that are doped in materials has been widely applied for turning optical properties. Even though hydrogen has been proven effective to reduce metal ions because of its strong reducing capability, few comprehensive studies focus on practical applications because of the low diffusion rate of hydrogen in solids and the limited reaction near sample surfaces. Here, we investigated the reactions of hydrogen with Cu2+-doped Na2O Al2O3-SiO2 glass and found that a completely different reduction from results reported so far occurs, which is dominated by the Al/Na concentration ratio. For Al/Na < 1, Cu2+ ions were reduced via hydrogen to metallic Cu, distributing in glass body. For Al/Na > 1, on the other hand, the reduction of Cu2+ ions occurred simultaneously with the formation of OH bonds, whereas the reduced Cu metal moved outward and formed a metallic film on glass surface. The NMR and Fourier transform infrared results indicated that the Cu2+ ions were surrounded by Al3+ ions that formed AlO4, distorted AlO4, and AlO5 units. The diffused H2 gas reacted with the Al-O-...Cu+ units, forming Al-OH and metallic Cu, the latter of which moved freely toward glass surface and in return enhanced H2 diffusion. PMID- 29283579 TI - How Inert, Perturbing, or Interacting Are Cryogenic Matrices? A Combined Spectroscopic (Infrared, Electronic, and X-ray Absorption) and DFT Investigation of Matrix-Isolated Iron, Cobalt, Nickel, and Zinc Dibromides. AB - The interactions of FeBr2, CoBr2, NiBr2, and ZnBr2 with Ne, Ar, Kr, Xe, CH4, and N2 matrices have been investigated using IR, electronic absorption, and X-ray absorption spectroscopies as well as DFT calculations. ZnBr2 is linear in all of the matrices. NiBr2 is linear in all but N2 matrices, where it is severely bent. For FeBr2 and CoBr2 there is a more gradual change, with evidence of nonlinearity in Xe and CH4 matrices as well as N2. In the N2 matrices, the presence of nuNN modes blue-shifted from the "free" N2 values indicates the presence of physisorbed species, and the magnitude of the blue shift correlates with the shift in the nu3 mode of the metal dibromide. In the case of NiCl2 and NiBr2, chemisorbed species are formed after photolysis, but only if deposition takes place below 10 K. There was no evidence for chemisorbed species for NiF2 and FeBr2, and in the case of CoBr2 the evidence was not strong. PMID- 29283578 TI - CuH-Catalyzed Asymmetric Reduction of alpha,beta-Unsaturated Carboxylic Acids to beta-Chiral Aldehydes. AB - The copper hydride (CuH)-catalyzed enantioselective reduction of alpha,beta unsaturated carboxylic acids to saturated aldehydes is reported. This protocol provides a new method to access a variety of beta-chiral aldehydes in good yields, with high levels of enantioselectivity and broad functional group tolerance. A reaction pathway involving a ketene intermediate is proposed based on preliminary mechanistic studies and density functional theory calculations. PMID- 29283580 TI - Elevated Temperature Photophysical Properties and Morphological Stability of CdSe and CdSe/CdS Nanoplatelets. AB - Elevated temperature optoelectronic performance of semiconductor nanomaterials remains an important issue for applications. Here we examine 2D CdSe nanoplatelets (NPs) and CdS/CdSe/CdS shell/core/shell sandwich NPs at temperatures ranging from 300 to 700 K using static and transient spectroscopies as well as in situ transmission electron microscopy. NPs exhibit reversible changes in PL intensity, spectral position, and emission line width with temperature elevation up to ~500 K, losing a factor of ~8 to 10 in PL intensity at 400 K relative to ambient. Temperature elevation above ~500 K yields thickness dependent, irreversible degradation in optical properties. Electron microscopy relates stability of the core-only NP morphology up to 555 and 600 K for the four and five monolayer NPs, respectively, followed by sintering and evaporation at still higher temperatures. Reversible PL loss, based on differences in decay dynamics between time-resolved photoluminescence and transient absorption, results primarily from hole trapping in both NPs and sandwich NPs. PMID- 29283581 TI - Ratio-Dependent Synergism of a Doxorubicin and Olaparib Combination in 2D and Spheroid Models of Ovarian Cancer. AB - Ovarian cancer is the fourth leading cause of death in women in developed countries. Even though patients with the most lethal form of the disease (HGSOC; high grade serous ovarian cancer) respond well to initial treatment, they often relapse with progressively resistant disease. Inhibitors of the poly(ADP-ribose) polymerase (PARP) enzymes are a relatively new class of molecularly targeted small molecule drugs that show promise in overcoming resistance. The present study explores the combination of a DNA damaging agent, doxorubicin (DOX), with the PARP inhibitor, olaparib (OLP), in order to achieve optimal synergy of both drugs in serous ovarian cancer. This drug combination was evaluated and optimized in 2D monolayers and 3D multicellular tumor spheroids (MCTS) using a genetically and histologically characterized panel of nine OC cell lines with or without BRCA1 or BRCA2 mutations. Combination index (CI) values of DOX and OLP were determined using the Chou and Talalay method. The potency of this drug combination was found to rely heavily on the molar ratios at which the two drugs are combined. In general, MCTS growth inhibition was reflective of the patterns predicted by the CI values obtained in monolayers. Promising combination ratios identified in this study warrant further preclinical and clinical investigation. PMID- 29283582 TI - A d-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells. AB - The current prognosis of glioma patients remains poor after intensive multimodal treatments, which is partially due to the existence of the blood-brain tumor barrier (BBTB). In the present study, a novel "bifunctional ligand" (termed DVS) was developed by retro-inverso isomerization. DVS is a ligand of integrins highly expressed on glioma cells and tumor neovasculature. DVS exhibited exceptional stability in serum and demonstrated significantly higher targeting efficiency for glioma and HUVEC cells compared with the parent L-peptide. As a result, DVS modified micelles (DVS-MS) exhibited high encapsulation efficiency of doxorubicin, ideal size distribution, and sustained release behavior of the payload. In vivo studies showed that DVS-MS could target and efficiently deliver fluorescence to tumor cells and tumor vasculature not only in the mice bearing subcutaneous tumors but also in those bearing intracranial tumors. Moreover, doxorubicin loaded DVS modified micelles exerted potent tumor growth inhibitory activity against subcutaneous and intracranial human glioma in comparison to drug loaded plain micelles and LVS modified micelles. Therefore, DVS appears to be a suitable targeting ligand with potential applications for glioma targeted drug delivery. PMID- 29283583 TI - Dynamic Control of Nanocavities with Tunable Metal Oxides. AB - Fabry-Perot metal-insulator-metal (MIM) nanocavities are widely used in nanophotonic applications due to their extraordinary electromagnetic properties and deeply subwavelength dimensions. However, the spectral response of nanocavities is usually controlled by the spatial separation between the two reflecting mirrors and the spacer's refractive index. Here, we demonstrate static and dynamic control of Fabry-Perot nanocavities by inserting a plasmonic metasurface, as a passive element, and a gallium doped-zinc oxide (Ga:ZnO) layer as a dynamically tunable component within the nanocavities' spacer. Specifically, by changing the design of the silver (Ag) metasurface one can "statically" tailor the nanocavity response, tuning the resonance up to 200 nm. To achieve the dynamic tuning, we utilize the large nonlinear response of the Ga:ZnO layer near the epsilon near zero wavelength to enable effective subpicosecond (<400 fs) optical modulation (80%) at reasonably low pump fluence levels (9 mJ/cm2). We demonstrate a 15 nm red shift of a near-infrared Fabry-Perot resonance (lambda ? 1.16 MUm) by using a degenerate pump probe technique. We also study the carrier dynamics of Ga:ZnO under intraband photoexcitation via the electronic band structure calculated from first-principles density functional method. This work provides a versatile approach to design metal nanocavities by utilizing both the phase variation with plasmonic metasurfaces and the strong nonlinear response of metal oxides. Tailorable and dynamically controlled nanocavities could pave the way to the development of the next generation of ultrafast nanophotonic devices. PMID- 29283584 TI - Structured DNA Aptamer Interactions with Gold Nanoparticles. AB - DNA aptamers that bind biomolecular targets are of interest as the recognition element in colorimetric sensors based on gold nanoparticles (AuNP), where sensor functionality is related to changes in AuNP colloidal stability upon target binding. In order to understand the role of target binding on DNA-AuNP colloidal stability, we have used high-resolution NMR to characterize the interactions of the 36 nucleotide cocaine-binding aptamer (MN4) and related aptamers with AuNPs, cocaine, and cocaine metabolites. Changes in the aptamer imino proton NMR spectra with low (20 nM) concentrations of AuNP show that the aptamers undergo fast exchange adsorption on the nanoparticle surface. An analysis of the spectral changes and the comparison with modified MN4 aptamers shows that the AuNP binding domain is localized on stem two of the three-stemmed aptamer. The identification of an AuNP recognition domain allows for the incorporation of AuNP binding functionality into a wide variety of aptamers. AuNP-induced spectral changes are not observed for the aptamer-AuNP mixtures in the presence of cocaine, demonstrating that aptamer absorption on the AuNP surface is modulated by aptamer target interactions. The data also show that the DNA-AuNP interactions and sensor functionality are critically dependent on aptamer folding. PMID- 29283585 TI - Protected Chloroethyl and Chloropropyl Amines as Conformationally Unrestricted Annulating Reagents. AB - The purpose of this letter is to document the use of protected chloroethyl and chloropropyl amines as conformationally unrestricted ambiphilic reagents that undergo annulation reactions with Michael acceptors. This reaction is wide in scope and utilizes reagents that are commercially available, inexpensive, and stable. Furthermore, this reaction is easy to execute and proceeds rapidly. PMID- 29283586 TI - Palladium-Catalyzed, Norbornene-Mediated, ortho-Amination ipso-Amidation: Sequential C-N Bond Formation. AB - A palladium-catalyzed, norbornene-mediated ortho- and ipso-C-N bond-forming Catellani reaction is reported. This reaction proceeds through a sequential intermolecular amination followed by intramolecular cyclization of a tethered amide. The products, ortho-aminated dihydroquinolinones, were generated in moderate to good yields and are present in bioactive molecules. This work highlights the challenge of competing intra- vs intermolecular palladium catalyzed processes. PMID- 29283587 TI - Vocal conditioning in kea parrots (Nestor notabilis). AB - In laboratory studies of vocal behavior in animals, subjects are normally isolated in a sound-insulated chamber for recording, but such socially isolated conditions may reduce the chances that they will vocalize. Indeed, past studies using such methods have faced the challenge that subjects remained silent. Knowledge of conditions under which subjects are more likely to vocalize could thus improve experimental design. This study investigated (a) whether kea (Nestor notabilis) could be trained to increase vocal production using operant conditioning and (b) the conditions under which such training was feasible. We found that visual contact with other kea increased the chances that a subject would vocalize spontaneously, therefore making training through positive reinforcement possible. In the conditions where kea could only hear but not see the rest of the group, they were much less likely to vocalize. Subjects were quickly trained to increase vocal production while in visual contact with other kea, and the training remained effective even when visual access later was removed. The procedure described here could be used as a first step in future laboratory studies of vocal behavior, carried out before subjects are isolated, to overcome the challenge of inducing isolated subjects to vocalize. (PsycINFO Database Record PMID- 29283588 TI - Do capuchin monkeys (Sapajus apella) know the contents of memory traces?: A study of metamemory for compound stimuli. AB - Whereas evidence has accumulated that nonhuman animals have access to the strength of their memory trace, it is unclear whether such metamemory contains components, as proposed by Hampton (2005). We assessed whether capuchin monkeys could recognize details of memorized items using a delayed matching-to-sample task. We used compound stimuli separable into 2 dimensions, "what" and "where." Two monkeys were trained to memorize both "what" and "where" a sample was and answer both/either "what" and/or "where" the sample was depending on each task after a delay. In Experiment 1, the monkeys were tested on a modified delayed matching-to-sample task with selectable task option. In some trials, the monkeys could choose which task they wanted to do. In other trials, they were forced to choose a specific task because the other icon had no effect. Results showed that both monkeys selected the task at which they were better in forced trials, but accuracy in chosen trials was not significantly higher than that in forced trials. In Experiment 2, we inserted stimuli that could individually interfere with "what" or "where" after the sample and before the matching test to manipulate task difficulty, and tested whether monkeys would choose the easier task, that is, with the noninterfered-with dimension. However, task choice was unaffected by the interfering stimuli. These results did not support the hypothesis that capuchin monkeys metacognitively monitor detailed contents of their memory traces. We suggest that working memory load might have affected performance, and advocate further research to test this possibility with simpler tasks. (PsycINFO Database Record PMID- 29283589 TI - Experience with featural-cue reliability influences featural- and geometric-cue use by mice (Mus musculus). AB - Orienting is a critical skill for all mobile animals. Two commonly studied visual components used to guide orientation in an environment are geometric (e.g., distance or direction) and featural cues (e.g., color or texture). Previous research has shown that visual-cue use and cue weighing can depend on the navigator's previous experience, the nature and reliability of the cues, and genetic factors. Accordingly, the domestic mouse (Mus musculus) is a species of increasing interest because of its potential as a model for human neurological disorders with associated spatial disorientation, as is seen in Alzheimer's disease. In the present study, adult C57BL/6 mice were trained to search for a hidden food reward in one corner of a rectangular environment with featural information displayed continuously along the walls. After training, one group of mice was given a block of testing in which the featural information was removed, followed by a second block of testing in which the featural information was put in conflict with the learned configuration of featural and geometric cues. A second group of mice was given the same set of tests, but in the reverse order. Our results show that the mice incidentally encoded the geometry of the environment if they had experience with featural cues being unreliable prior to tests, during which featural cues were completely removed (unstable). Furthermore, we found when featural and geometric cues provide conflicting spatial information, this unreliability of featural cues over the course of the study may influence cue weighing. (PsycINFO Database Record PMID- 29283591 TI - Measuring physiological influence in dyads: A guide to designing, implementing, and analyzing dyadic physiological studies. AB - Scholars across domains in psychology, physiology, and neuroscience have long been interested in the study of shared physiological experiences between people. Recent technological and analytic advances allow researchers to examine new questions about how shared physiological experiences occur. Yet comprehensive guides that address the theoretical, methodological, and analytic components of studying these processes are lacking. The goal of this article is to provide such a guide. We begin by addressing basic theoretical issues in the study of shared physiological states by presenting five guiding theoretical principles for making psychological inferences from physiological influence-the extent to which one dyad member's physiology predicts the other dyad member's physiology at a future time point. Second, keeping theoretical and conceptual concerns at the forefront, we outline considerations and recommendations for designing, implementing, and analyzing dyadic psychophysiological studies. In so doing, we discuss the different types of physiological measures one could use to address different theoretical questions. Third, we provide three illustrative examples in which we estimate physiological influence, using the stability and influence model. We conclude by providing detail about power analyses for the model and by comparing the strengths and limitations of this model with preexisting models. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29283590 TI - Tutorial: The practical application of longitudinal structural equation mediation models in clinical trials. AB - The study of mediation of treatment effects, or how treatments work, is important to understanding and improving psychological and behavioral treatments, but applications often focus on mediators and outcomes measured at a single time point. Such cross-sectional analyses do not respect the implied temporal ordering that mediation suggests. Clinical trials of treatments often provide repeated measures of outcomes and, increasingly, of mediators as well. Repeated measurements allow the application of various types of longitudinal structural equation mediation models. These provide flexibility in modeling, including the ability to incorporate some types of measurement error and unmeasured confounding that can strengthen the robustness of findings. The usual approach is to identify the most theoretically plausible model and apply that model. In the absence of clear theory, we put forward the option of fitting a few theoretically plausible models, providing a type of sensitivity analysis for the mediation hypothesis. In this tutorial, we outline how to fit several longitudinal mediation models, including simplex, latent growth and latent change models. This will allow readers to learn about one type of model that is of interest, or about several alternative models, so that they can take this sensitivity approach. We use the Pacing, Graded Activity, and Cognitive Behavioral Therapy: A Randomized Evaluation (PACE) trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) as a motivating example and describe how to fit and interpret various longitudinal mediation models using simulated data similar to those in the PACE trial. The simulated data set and Mplus code and output are provided. (PsycINFO Database Record PMID- 29283592 TI - Development and validation of a measure of maladaptive social-evaluative beliefs characteristic of social anxiety disorder in youth: The Report of Youth Social Cognitions (RYSC). AB - Recent research has started to examine the applicability of influential adult models of the maintenance of social anxiety disorder (SAD) to youth. This research is limited by the lack of psychometrically validated measures of underlying constructs that are developmentally appropriate for youth. One key construct in adult models of SAD is maladaptive social-evaluative beliefs. The current study aimed to develop and validate a measure of these beliefs in youth, known as the Report of Youth Social Cognitions (RYSC). The RYSC was developed with a clinical sample of youth with anxiety disorders (N = 180) and cross validated in a community sample of youth (N = 305). In the clinical sample, the RYSC exhibited a 3-factor structure (negative evaluation, revealing self, and positive impression factors), good internal consistency, and construct validity. In the community sample, the 3-factor structure and the internal consistency of the RYSC were replicated, but the test of construct validity showed that the RYSC had similarly strong associations with social anxiety and depressed affect. The RYSC had good test-retest reliability overall, although the revealing self subscale showed lower temporal stability which improved when only older participants were considered (age >=9 years). The RYSC in general was also shown to discriminate between youth with and without SAD although the revealing self subscale again performed suboptimally but improved when only older participants were considered. These findings provide psychometric support for the RYSC and justifies its use with youth in research and clinical settings requiring the assessment of maladaptive social-evaluative beliefs. (PsycINFO Database Record PMID- 29283593 TI - Complementary exploratory and confirmatory factor analyses of the French WISC-V: Analyses based on the standardization sample. AB - Interpretation of the French Wechsler Intelligence Scale for Children-Fifth Edition (French WISC-V; Wechsler, 2016a) is based on a 5-factor model including Verbal Comprehension (VC), Visual Spatial (VS), Fluid Reasoning (FR), Working Memory (WM), and Processing Speed (PS). Evidence for the French WISC-V factorial structure was established exclusively through confirmatory factor analyses (CFAs). However, as recommended by Carroll (1995); Reise (2012), and Brown (2015), factorial structure should derive from both exploratory factor analysis (EFA) and CFA. The first goal of this study was to examine the factorial structure of the French WISC-V using EFA. The 15 French WISC-V primary and secondary subtest scaled scores intercorrelation matrix was used and factor extraction criteria suggested from 1 to 4 factors. To disentangle the contribution of first- and second-order factors, the Schmid and Leiman (1957) orthogonalization transformation (SLT) was applied. Overall, no EFA evidence for 5 factors was found. Results indicated that the g factor accounted for about 67% of the common variance and that the contributions of the first-order factors were weak (3.6 to 11.9%). CFA was used to test numerous alternative models. Results indicated that bifactor models produced better fit to these data than higher order models. Consistent with previous studies, findings suggested dominance of the general intelligence factor and that users should thus emphasize the Full Scale IQ (FSIQ) when interpreting the French WISC-V. (PsycINFO Database Record PMID- 29283594 TI - The choice is yours: Infants' expectations about an agent's future behavior based on taking and receiving actions. AB - Our social world is rich with information about other people's choices, which subsequently inform our inferences about their future behavior. For individuals socialized within the American cultural context, which places a high value on autonomy and independence, outcomes that are the result of an agent's own choices may hold more predictive value than similar outcomes that are the result of another person's choices. Across two experiments we test the ontogeny of this phenomenon; that is, whether infants are sensitive to the causal history associated with an agent's acquisition of an object. We demonstrate that on average, 12.5-month-old American infants view taking actions as a better indication of an agent's future behavior than are receiving actions. Furthermore, there were significant individual differences in the extent to which infants perceived object receipt to be indicative of future behavior. Specifically, the less autonomous infants were perceived to be (by their parents), socialized to be, and behaved, the more they viewed object receipt as indicative of future behavior. The results are discussed in terms of the role of individual and cultural experience in early understanding of intentional action. (PsycINFO Database Record PMID- 29283595 TI - Language specificity in the relation of maternal education to bilingual children's vocabulary growth. AB - The robust relation between maternal education and child language that is observed in monolingual populations has not been reliably replicated among bilingual children from immigrant families in the United States. We hypothesized that a variable that operates in immigrant populations-the language in which mothers achieved their highest level of education, is relevant to the benefits of maternal education to children's language growth. The participants were 92 U.S. born bilingually developing children (47 boys, 45 girls) with native Spanish speaking immigrant mothers. The mothers varied both in their level of education and in the language (English or Spanish) in which they had achieved their highest level of education. The children's expressive vocabulary in English and Spanish was assessed at 6-month intervals between 30 and 60 months. Four sets of multilevel models, which included estimates of children's relative amount of input in each language and mothers' age of arrival, found that maternal level of education in English was significantly related to children's English skill, but not their Spanish skill, and that maternal level of education in Spanish was related to children's Spanish skill, but not their English skill. These language specific relations between mothers' levels of education and their children's language development potentially explain previous findings in immigrant populations. These findings further argue that maternal education benefits children's language because education changes mothers' use of the language in which that education was achieved. There was no evidence of a language general benefit of education, as might arise from increased knowledge of child development. (PsycINFO Database Record PMID- 29283596 TI - Overt and covert attention in infants revealed using steady-state visually evoked potentials. AB - Although looking-time methods have long been used to measure infant attention and investigate aspects of cognitive development, steady-state visually evoked potential (SSVEP) measures may be more sensitive or practical in some contexts. Here, we demonstrate habituation of infants' SSVEP amplitudes to a flickering checkerboard stimulus, and recovery of attention upon presentation of a novel checkerboard stimulus. This modulation of SSVEP amplitude was more robust than the modulation of looking time. In addition, we provide evidence of enhanced SSVEPs in response to covertly attended checkerboards flickering in peripheral visual fields, even while infants are fixating a central stimulus. These experiments provide the first evidence of habituation and recovery of infant SSVEP amplitudes, as well as the first evidence of sustained infant covert attention using SSVEPs. SSVEPs may be a sensitive, efficient measure for use in studying early cognitive development, in particular infants' overt and covert attention. (PsycINFO Database Record PMID- 29283598 TI - A longitudinal growth mixture model of child disclosure to parents across adolescence. AB - The present study used a person-centered approach to examine heterogeneity in children's patterns of routine disclosure (i.e., sharing information regarding their whereabouts and activities to parents) across adolescence and explored predictors and outcomes of different trajectories. Participants included 500 adolescents (51% female, 67% White, 33% single-parent families) who completed questionnaires every year from age 12 to age 18. Growth mixture modeling suggested that the majority of adolescents (82%) experienced a gradual decrease in disclosure to parents across adolescence, while another group (13%) reported low and stable disclosure, and a third group (5%) a steep decrease and leveling out over time. Group membership varied as a function of predictors at age 12 (delinquency, prosocial behavior, maternal warmth) and of outcomes at age 18 (delinquency, substance use, depression, prosocial behavior). The discussion focuses on the implications of this person-centered approach for adolescent disclosure to parents across adolescence. (PsycINFO Database Record PMID- 29283597 TI - PTSD as a moderator of a parenting intervention for military families. AB - The stress of multiple deployments and exposure to combat places service members at risk for posttraumatic stress disorder (PTSD), which may detrimentally affect parenting. Evidence-based parenting programs have been successful in promoting adaptive parenting practices among families exposed to stress. However, the effects of preventive interventions on parenting may vary by military parent's PTSD. The current study includes families who participated in a randomized controlled trial of a parenting intervention for military families known as After Deployment, Adaptive Parenting Tools (ADAPT). Families were randomized to either a 14-week, group-based parenting program or a comparison group. Participants included families with 4- to 12-year-old children in which at least 1 parent deployed to Iraq or Afghanistan (N = 336; 945 individuals). Structural equation modeling was used to examine parent self-reported PTSD as a potential moderator of the relationship between intent-to-treat status and effective parenting practices 12 months postbaseline while accounting for baseline effective parenting, length and number of deployments, and family demographics. Father PTSD was a significant moderator, such that the intervention was less effective for fathers who met clinical levels of PTSD. No significant moderation effects were found among mothers. These findings may have important implications for the development of future evidence-based parenting programs. (PsycINFO Database Record PMID- 29283599 TI - Perfectionism Is Increasing Over Time: A Meta-Analysis of Birth Cohort Differences From 1989 to 2016. AB - From the 1980s onward, neoliberal governance in the United States, Canada, and the United Kingdom has emphasized competitive individualism and people have seemingly responded, in kind, by agitating to perfect themselves and their lifestyles. In this study, the authors examine whether cultural changes have coincided with an increase in multidimensional perfectionism in college students over the last 27 years. Their analyses are based on 164 samples and 41,641 American, Canadian, and British college students, who completed the Multidimensional Perfectionism Scale (Hewitt & Flett, 1991) between 1989 and 2016 (70.92% female, Mage = 20.66). Cross-temporal meta-analysis revealed that levels of self-oriented perfectionism, socially prescribed perfectionism, and other oriented perfectionism have linearly increased. These trends remained when controlling for gender and between-country differences in perfectionism scores. Overall, in order of magnitude of the observed increase, the findings indicate that recent generations of young people perceive that others are more demanding of them, are more demanding of others, and are more demanding of themselves. (PsycINFO Database Record PMID- 29283600 TI - Job design for mindful work: The boosting effect of psychosocial safety climate. AB - Despite a surge in workplace mindfulness research, virtually nothing is known about how organizations can cultivate everyday mindfulness at work. Using the extended job demands-resources model, we explored daily psychological demands and job control as potential antecedents of daily mindfulness, and the moderating effect of psychosocial safety climate (PSC, which relates to the value organizations place on psychological health at work). We also examined the relationship between mindfulness and learning to augment understanding of the benefits of everyday mindfulness at work. A sample of 57 employees, primarily working in education, health care, and finance, completed a diary for five days within a 2-week period, covering mindfulness, psychological demands, job control, and learning. PSC was measured in a baseline survey, with individual ratings combined with those of up to four colleagues to tap objective (shared) climate. Hierarchical linear modeling showed that daily psychological demands were negatively related to daily mindfulness, and daily job control was positively related to daily mindfulness especially as PSC increased. Additionally, daily mindfulness was positively associated with daily workplace learning. This study is one of the first to identify work-related antecedents to everyday mindfulness. The findings suggest that (a) to support everyday mindfulness at work, jobs must be designed with manageable demands and a variety of tasks that allow for creativity and skill discretion, and (b) the benefits of mindfulness interventions for employee psychological health and well-being may not be sustainable unless employees have influence over when and how they do their work, in the "right" climate. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29283601 TI - The more, the better? Curvilinear effects of job autonomy on well-being from vitamin model and PE-fit theory perspectives. AB - In organizational psychology research, autonomy is generally seen as a job resource with a monotone positive relationship with desired occupational outcomes such as well-being. However, both Warr's vitamin model and person-environment (PE) fit theory suggest that negative outcomes may result from excesses of some job resources, including autonomy. Thus, the current studies used survey methodology to explore cross-sectional relationships between environmental autonomy, person-environment autonomy (mis)fit, and well-being. We found that autonomy and autonomy (mis)fit explained between 6% and 22% of variance in well being, depending on type of autonomy (scheduling, method, or decision-making) and type of (mis)fit operationalization (atomistic operationalization through the separate assessment of actual and ideal autonomy levels vs. molecular operationalization through the direct assessment of perceived autonomy (mis)fit). Autonomy (mis)fit (PE-fit perspective) explained more unique variance in well being than environmental autonomy itself (vitamin model perspective). Detrimental effects of autonomy excess on well-being were most evident for method autonomy and least consistent for decision-making autonomy. We argue that too-much-of-a good-thing effects of job autonomy on well-being exist, but suggest that these may be dependent upon sample characteristics (range of autonomy levels), type of operationalization (molecular vs. atomistic fit), autonomy facet (method, scheduling, or decision-making), as well as individual and organizational moderators. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29283602 TI - Personal costs and benefits of employee intrapreneurship: Disentangling the employee intrapreneurship, well-being, and job performance relationship. AB - Ample studies have confirmed the benefits of intrapreneurship (i.e., employee behaviors that contribute to new venture creation and strategic renewal activities) for firm performance, but research on the personal costs and benefits of engaging in intrapreneurial activities for employees is lacking. Building on job demands-resources and reinforcement sensitivity theories, we examined how employees' reinforcement sensitivity qualified the relationship among their intrapreneurial behavior, subjective well-being, and other-rated job performance. Using a sample of 241 employee dyads, the results of moderated mediation analyses confirmed that employee intrapreneurship related positively to work engagement for employees high (vs. low) in sensitivity to rewards (behavioral approach system), which subsequently related positively to innovativeness and in-role performance and negatively to work avoidance. In contrast, employee intrapreneurship related positively to exhaustion for employees high (vs. low) in sensitivity to punishments (behavioral inhibition system), which subsequently related positively to work avoidance and negatively to in-role performance (but not to innovativeness). Theoretical and practical implications are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29283603 TI - Incivility and Employee Performance, Citizenship, and Counterproductive Behaviors: Implications of the Social Context. AB - Drawing from the transactional model of stress, we examined how the social context moderates employees' behavioral responses to workplace incivility. On the basis of data from 384 employees nested in 41 groups, we observed a 3-way, cross level interaction between individually experienced incivility, group incivility differentiation, and group silence predicting supervisor-rated employee performance, citizenship, and counterproductive behaviors. Specifically, employees' own incivility experiences predicted lower performance and citizenship behavior and higher counterproductive behavior in groups where members received highly different incivility treatment and kept silent. These findings indicate that contextual characteristics of one's workgroup have an impact on how employees appraise and respond to workplace incivility. (PsycINFO Database Record PMID- 29283604 TI - Orthographic effects in second-language spoken-word recognition. AB - Evidence from both alphabetic and nonalphabetic languages has suggested the role of orthography in the processing of spoken words in individuals' native language (L1). Less evidence has existed for such effects in nonnative (L2) spoken-word processing. Whereas in L1 orthographic representations are learned only after phonological representations have long been established, in L2 the sound and spelling of words are often learned in conjunction; this might predict stronger orthographic effects in L2 than in L1 spoken processing. On the other hand, lexical codes are typically less integrated and stable in L2 than in L1, which might entail less pronounced orthographic effects. To explore this issue, Tibetan Chinese bilinguals judged whether Chinese spoken words presented in pairs were related in meaning. Some of the unrelated word pairs were orthographically related, and critically, this orthographic overlap induced a significant increase in response latencies. Compared to previous results from L1 listeners with the identical procedure, the orthographic effect for L2 listeners was more pronounced. These findings indicate that orthographic information is involuntarily accessed in native and nonnative spoken-word recognition alike and that it may play a more important role in the latter compared to the former. (PsycINFO Database Record PMID- 29283605 TI - Cognates facilitate switches and then confusion: Contrasting effects of cascade versus feedback on language selection. AB - The current study investigated the hypothesis that cognates (i.e., translation equivalents that overlap in form, e.g., lemon is limon in Spanish) facilitate language switches. Spanish-English bilinguals were cued to switch languages while repeatedly naming pictures with cognate versus noncognate names in separate (Experiment 1) or mixed (Experiments 2 and 3) blocks. In all 3 experiments, on the first presentation of each picture, cognates elicited significantly smaller switch costs and were produced faster than noncognates only on switch trials. However, cognate switch-facilitation effects were eliminated (Experiment 2) or reversed (i.e., larger switch costs for cognates than noncognates, in Experiment 3) in mixed blocks with the repeated presentation of a stimulus, largely because of the increasingly slower responses for cognates on switch trials. Cognates may facilitate switches because of increased dual-language activation, which is inhibited on nonswitch trials. With repeated presentation of the same pictures, dual-language activation may feed backup to the lexical level, increasing competition for selection. In contrast, when naming pictures in a cognate block, bilinguals may avoid discrimination problems at the lexical level by adaptively focusing less on activation at the phonological level. Cross-language overlap in phonology appears to influence language selection at both the phonological and lexical levels, involving multiple cognitive mechanisms and reflecting both automatic processes and rapid adaptation to contextual variations in the extent of dual-language activation. (PsycINFO Database Record PMID- 29283606 TI - Lexical inhibition due to failed prediction: Behavioral evidence and ERP correlates. AB - During sentence processing, comprehenders form expectations regarding upcoming material, and may even predict a specific word. Previous event-related potential (ERP) studies have shown that disconfirmed predictions elicit a post-N400 positivity (PNP) with two distinct distributions. A frontal-PNP (f-PNP) is elicited when an unexpected but congruent word appears instead of a highly predictable word, whereas an anomalous word elicits a posterior-PNP. The current study tested the hypothesis that during the processing of a sentence, the predicted word is inhibited to enable the integration of unexpected but congruent material, and that this inhibitory process is reflected in the f-PNP component. In contrast, anomalous continuations, which are not compatible with the preceding context, do not induce inhibition. Experiment 1 used cross-modal lexical priming to test inhibition patterns of predicted words, demonstrating inhibition when integration of a congruent-unexpected word was needed, but not when an anomaly was encountered. Experiment 2 showed that the inhibition observed in Experiment 1 is specific to the predicted word and does not stem from competition between two congruent continuations. In Experiment 3 we recorded ERPs using the same materials, and found that the f-PNP component is elicited under the same conditions giving rise to behavioral inhibition, and that the two are correlated, thus providing preliminary support for the hypothesis that this component reflects an inhibitory process. (PsycINFO Database Record PMID- 29283607 TI - Retuning of lexical-semantic representations: Repetition and spacing effects in word-meaning priming. AB - Current models of word-meaning access typically assume that lexical-semantic representations of ambiguous words (e.g., 'bark of the dog/tree') reach a relatively stable state in adulthood, with only the relative frequencies of meanings and immediate sentence context determining meaning preference. However, recent experience also affects interpretation: recently encountered word-meanings become more readily available (Rodd et al., 2016, 2013). Here, 3 experiments investigated how multiple encounters with word-meanings influence the subsequent interpretation of these ambiguous words. Participants heard ambiguous words contextually-disambiguated towards a particular meaning and, after a 20- to 30 min delay, interpretations of the words were tested in isolation. We replicate the finding that 1 encounter with an ambiguous word biased the later interpretation of this word towards the primed meaning for both subordinate (Experiments 1, 2, 3) and dominant meanings (Experiment 1). In addition, for the first time, we show cumulative effects of multiple repetitions of both the same and different meanings. The effect of a single subordinate exposure persisted after a subsequent encounter with the dominant meaning, compared to a dominant exposure alone (Experiment 1). Furthermore, 3 subordinate word-meaning repetitions provided an additional boost to priming compared to 1, although only when their presentation was spaced (Experiments 2, 3); massed repetitions provided no such boost (Experiments 1, 3). These findings indicate that comprehension is guided by the collective effect of multiple recently activated meanings and that the spacing of these activations is key to producing lasting updates to the lexical-semantic network. (PsycINFO Database Record PMID- 29283608 TI - "Imagine a clinical world without family systems thinking." AB - Collaborative family health care acknowledges the importance of family and social context to yield a comprehensive understanding of health. In this editorial, we return to the concept of family systems thinking. (PsycINFO Database Record PMID- 29283610 TI - Adverse childhood experiences: Screening and health in children from birth to age 5. AB - INTRODUCTION: Adverse childhood experiences (ACEs) have lifetime consequences for health and development. This study examined whether there is evidence to support a screening approach that assesses children's current exposures to risks that act as proxies for ACEs, measured in a way that falls below a threshold of explicit abuse, neglect, or illegal behavior. METHOD: We used data collected during routine home visitations of at-risk children aged 0-5. Home visitors used the Family Map Inventories (FMI; Whiteside-Mansell et al., 2007) to screen ACEs and measure health outcomes, and the Ages and Stages Questionnaire (3rd ed.; ASQ-3; Squires, Twombly, Bricker, & Potter, 2009) to screen child development. Parents (N = 2,004) were 28 years of age on average and most were White (60%). Children were 32 months of age on average and equally divided on gender (51% male). RESULTS: Children were exposed at rates of 27%, 17%, 11%, and 11% to 1, 2, 3, and 4 or more FMI-ACEs, respectively. Logistic regressions revealed significant associations between FMI-ACE scores and health environments and outcomes for children, including health risks in the home (e.g., safety and secondhand smoke exposure), underuse of preventive health care, and overuse of emergency medical treatment. In terms of development, having four or more FMI-ACEs was associated with the child having a chronic health condition and screening at risk for delay in at least one area of development. DISCUSSION: Findings highlight the potential use of questionnaires and in-home observations to measure and intervene in potentially developing ACEs. Further, our screening was associated with children whose health was at risk very early in development. (PsycINFO Database Record PMID- 29283609 TI - "Miscarried helping" in adults with Type 2 diabetes: Helping for Health Inventory Couples. AB - OBJECTIVE: Family-partner support has been associated with better blood glucose control, self-care adherence, and quality of life in adult patients with Type 2 diabetes (T2D). "Miscarried helping" has described interactions between youth with chronic diseases and their family members, in which a family member is helpful, but efforts are perceived as negative by the patient. Miscarried helping has not, however, been measured in adults with diabetes, which was the purpose of our study. METHOD: Data from a randomized clinical trial (n = 268) were analyzed to establish the psychometric properties and correlates of an adaptation of a measure of miscarried helping developed in pediatric populations, for use with adults with T2D. RESULTS: The Helping for Health Inventory-Couples Version (HHI C) was found to have three underlying factors and demonstrated adequate internal consistency across time (alpha at baseline = .86, 4 months = .87, 8 months = .86, and 12 months = .83) and showed high test-retest reliability (p < .01) over a 12 month period. Convergent validity was partially supported, because baseline HHI-C was positively associated with maladaptive conflict resolution strategies (p = .03) and negatively associated with adaptive conflict resolution strategies (p = .04) and diabetes knowledge (p < .01). The HHI-C did not correlate with body mass index or hemoglobin A1c, a measure of glycemic control. The HHI-C was positively associated with diabetes distress (p < .01) and depressive symptoms (p = .01). DISCUSSION: This study is the 1st known reporting of the psychometric properties of a measure of miscarried helping for adults with T2D. This valid measure of miscarried helping could be useful in future studies evaluating novel, relationship-based approaches to assist adults with T2D in disease management. (PsycINFO Database Record PMID- 29283611 TI - Exploring attrition, fidelity, and effectiveness of wraparound services among low income youth of different racial backgrounds. AB - INTRODUCTION: Wraparound services (i.e., community-based collaborative care) for children with severe mental health needs have been reported as effective. Yet, no attention has been given to aggregating treatment results across racially and economically diverse groups of youth. While controlling for socioeconomic status (i.e., free/reduced lunch status) this study explored potential racial disparities in response to wraparound services. METHOD: Data from a diverse statewide sample (N = 1,006) of low-income youth (ages 6-18 years) identified as having a serious emotional disturbance were analyzed for differences in wraparound attrition, fidelity, and effectiveness. RESULTS: African American youth receiving free/reduced lunch failed to complete wraparound services at significantly higher rates when compared to Caucasian youth. For those who met treatment goals (i.e., completed services), mean intervention fidelity scores showed services to be implemented similarly across youth. Furthermore, wraparound services resulted in improvements in mental health functioning, though racial background and attrition status impacted exit scores. DISCUSSION: Collaborative community-based mental health services improve youth outcomes and physicians and school personnel should strive to be part of these teams. Further research is needed to more closely examine the challenges of helping youth to meet the goals associated with their wraparound services. Relatively higher service attrition rates in low-income African American youth warrants further investigation. (PsycINFO Database Record PMID- 29283612 TI - Moving effective treatment for posttraumatic stress disorder to primary care: A randomized controlled trial with active duty military. AB - INTRODUCTION: Many military service members with PTSD do not receive evidence based specialty behavioral health treatment because of perceived barriers and stigma. Behavioral health providers in primary care can deliver brief, effective treatments expanding access and reducing barriers and stigma. The purpose of this randomized clinical trial was to determine if a brief cognitive-behavior therapy delivered in primary care using the Primary Care Behavioral Health model would be effective at reducing PTSD and co-occurring symptoms. METHOD: A total of 67 service members (50 men, 17 women) were randomized to receive a brief, trauma focused intervention developed for the primary care setting called Prolonged Exposure for Primary Care (PE-PC) or a delayed treatment minimal contact control condition. Inclusion criteria were significant PTSD symptoms following military deployment, medication stability, and interest in receiving treatment for PTSD symptoms in primary care. Exclusion criteria were moderate or greater risk of suicide, severe brain injury, or alcohol/substance use at a level that required immediate treatment. Assessments were completed at baseline, posttreatment/postminimal contact control, and at 8-week and 6-month posttreatment follow-up points. Primary measures were the PTSD Symptom Scale Interview and the PTSD Checklist-Stressor-Specific. RESULTS: PE-PC resulted in larger reduction in PTSD severity and general distress than the minimal contact control. Delayed treatment evidenced medium to large effects comparable to the immediate intervention group. Treatment benefits persisted through the 6-month follow-up of the study. DISCUSSION: PE-PC delivered in integrated primary care is effective for the treatment of PTSD and co-occurring symptoms and may help reduce barriers and stigma found in specialty care settings. (PsycINFO Database Record PMID- 29283613 TI - Family members' experiences supporting adults with chronic illness: A national survey. AB - INTRODUCTION: Family and friends often help chronically ill adults manage their conditions. Information about specific ways supporters help with disease management, and their experiences with and concerns about helping are lacking. This study describes key roles and concerns of family members who support the health management of adults with chronic illness, and compares experiences of health supporters living in and outside of support recipients' homes. METHODS: Data were obtained from a national internet survey of 1,722 adults selected to represent the U.S. POPULATION: Detailed survey questions were completed by 703 respondents who reported providing regular disease-management help to at least one functionally-independent family member or friend with at least one of five chronic conditions (diabetes, heart failure, chronic lung disease, arthritis, depression). RESULTS: Current supporters assisted 834 chronically ill adults: 257 receiving in-home support and 577 receiving out-of-home support. Current supporters spent 2.1 hours/week on average helping their support recipient with health care, and 21.2% attended their recipient's health care appointments. Many recipients discussed crucial concerns about medication side effects (47.0%) and trouble paying for medications (32.0%) with supporters. However, 41.0% of supporters reported insufficient information about recipients' health conditions and regimen to be helpful. In-home supporters reported arguing more often with support recipients, but also received more information from recipients' health care providers than out-of-home supporters. DISCUSSION: Family and friends have significant potential to influence patients' chronic illness self-management. Programs to engage chronically ill patients' families to support self-management could provide information and skills targeting needs identified by supporters. (PsycINFO Database Record PMID- 29283614 TI - Significant others' weight-related comments and their associations with weight control behavior, muscle-enhancing behavior, and emotional well-being. AB - INTRODUCTION: This large mixed-method study examines the prevalence of reported positive and negative weight-related comments from significant others and ways in which they are associated with weight-control and muscle-enhancing behaviors and emotional well-being in young adults. METHOD: As part of Project EAT (Eating and Activity in Teens and Young Adults)-IV, survey data were provided by 1,436 young adult men and women with a significant other in 2015-2016 (mean age = 31.1 years; 58.6% women). Independent variables included the reported frequency of receiving positive or negative comments about body shape or size; written examples of positive comments were qualitatively coded for subtypes. Analysis of covariance, adjusting for body mass index, tested associations between comments and weight control behaviors, muscle-enhancing behaviors, and various measures of emotional well-being (i.e., body satisfaction, self-esteem, and depressive symptoms). RESULTS: About twice as many participants received positive comments from their significant others compared to negative comments (75% vs. 36%). Receiving positive and/or negative comments was related to body satisfaction, self-esteem, and depressive symptoms but was largely unrelated to weight-control and muscle enhancing behaviors. In almost all cases, receiving no comments was associated with significantly better well-being than was receiving only negative comments. There were few differences in weight-control or muscle-enhancing behaviors or emotional well-being across subtypes of positive comments. DISCUSSION: Reporting the receipt of negative comments from significant others was associated with poorer emotional well-being than was receiving positive comments or no weight related comments at all. Therapists and other health professionals working with couples should consider advising young adults on the apparent advantages of providing positive feedback regarding weight and shape or abstaining from commenting altogether. (PsycINFO Database Record PMID- 29283615 TI - "Take your time, then follow your heart:" Previvors' advice for communicating about family planning after testing positive for a BRCA genetic variant. AB - INTRODUCTION: The purpose of this study was to identify previvors' strategies for communicating about family planning after testing positive for a variant of the "breast cancer gene" (BRCA). METHOD: Semistructured interviews were conducted with 20 women currently in committed romantic relationships, but who had not yet completed family planning upon finding out about their BRCA mutation status. RESULTS: Data analysis produced three categories of participant advice given to newly diagnosed previvors. Participants advised the following: (a) the importance of engaging in two-way dialogue with their partners/spouses across the life span of the partnership, (b) seeking information on new technologies and information regarding family-planning and genetic-cancer-prevention decision-making, as well as recognizing where to go for different support needs, and (c) managing and acknowledging emotions surrounding their BRCA-related health decisions. DISCUSSION: Previvors who have already had family-planning and genetic-cancer risk conversations had important advice for newly diagnosed previvors. Practical advice for starting and managing conversations with partners/spouses, family members, and friends are discussed. (PsycINFO Database Record PMID- 29283616 TI - Attachment-informed mentorship. AB - Attachment theory has been widely integrated into how clinicians view personal development and enduring relationships. Through the burgeoning field of interpersonal neurobiology, this model has also been applied to adult professional, training, and family relationships. However, the medical and integrated care literature currently lacks attempts to apply attachment principles to the mentorship relationships that are created between trainees and the faculty of a training program. Through this conceptual article, the authors introduce the attachment-informed mentorship model to bridge this gap. It is based on seven guiding principles that we hope can assist mentors and mentees: (a) Mentorship is an enduring relationship focused on the professional and personal development of the mentee. (b) Lived experience leads to attachment styles. (c) The mentoring relationship evolves across training. (d) The mentor and training program provide a secure base for the mentee. (e) The mentor and program provide a safe haven for the mentee. (f) Both mentor and mentee should address ruptures in trust. (g) Other roles may conflict with the mentor role. (PsycINFO Database Record PMID- 29283617 TI - Treating PTSD in primary care: One small step is one giant leap. AB - Comments on an article by J. A. Cigrang et al. (see record 2017-56601-006). At first glance, the article by Cigrang et al. is another in a long line of randomized clinical trials of psychotherapy for a common condition. Under closer scrutiny, however, it is a groundbreaking study that challenges many commonly held beliefs about effective interventions for posttraumatic stress disorder (PTSD). Cigrang et al. have begun to change the status quo with this study within the DoD. The same protocol is now in the early stages of implementation as a pilot in the VA's Patient Aligned Care Team (VA equivalent of the Patient Centered Medical Home). In addition to treating PTSD, cognitive processing therapy (CPT) and prolonged exposure may provide relief for individuals suffering from symptoms significant enough to cause distress but not rising to the level of precision needed for a diagnosis of PTSD: the bread and butter of integrated primary care. Although a significant step forward, the study by Cigrant et al. is only a beginning. There is obviously a need for replication and possible enhancements of this exposure treatment. There are other condensed versions of CPT being developed and tested as well. Many questions remain. (PsycINFO Database Record PMID- 29283618 TI - Mentorship during transitions. AB - Mentorship has been repeatedly shown to be a necessary component of successful professional development. However, effective mentorship can be elusive to define insofar as "you know it when you have it," but it is hard to match the objective qualities of mentorship with the subjective experience of effective and helpful mentoring. This article explores the Collaborative Family Healthcare Association's mentorship program from the perspective of one mentor and two mentees over the course of a yearlong formal relationship. During the year, both mentees had to navigate significant transitions, including changing jobs and having a baby; these experiences are relevant for many new career professionals. (PsycINFO Database Record PMID- 29283619 TI - Five-year-old historian. AB - In this poem, the author describes a doctor talking with a five-year-old child who has been brought to the hospital after being in a car accident with his/her mother and brother. The child is not able to remember the mother's name, but the doctor continues to talk with the child. (PsycINFO Database Record PMID- 29283620 TI - Two minutes. AB - In this poem the author describes a nervous teenage girl who is in a doctor's office with her grandmother for a pregnancy test. The doctor tries to ease the tension. The teenager and grandmother are relieved when they are told the result of the test is negative. (PsycINFO Database Record PMID- 29283621 TI - "Joy" in practice requires workforce well-being. AB - In this column, the president of the Collaborative Family Healthcare Association notes that the national conversation about physician burnout has recently shifted to discussing the importance of finding joy in practice. However, she is concerned the current culture of medicine, hidden curricula in medical training, a draconian financial system, and an emotionally ill-prepared workforce may preclude sustained joy in practice. Formal curricula do not include resiliency skills, mindfulness, cognitive flexibility and reframing, conflict-resolution skills, emotional-regulation skills, or how to practice empathy and compassion without crumbling from vicarious trauma. With all the emphasis on technical proficiency, there has been insufficient emphasis on strategies for maintaining personal well-being. To the extent investment follows what we measure, the well being of the entire health care workforce is a worthwhile data point to chase. Collaborative Family Healthcare Association membership is infused with the knowledge and skills to design and promote health care teams and systems that can foster, measure, and sustain joy. (PsycINFO Database Record PMID- 29283623 TI - Award for Distinguished Scientific Contributions: Mahzarin R. Banaji. AB - The American Psychological Association Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. Mahzarin R. Banaji is a recipient of the 2017 award for her work in collaboration with Anthony G. Greenwald. Banaji is cited "for identifying how the ordinary cognitive processes can produce biases in evaluating ourselves and others." Banaji's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283624 TI - Award for Distinguished Scientific Contributions: Anthony G. Greenwald. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. Anthony G. Greenwald is a recipient of the 2017 award for his work in collaboration with Mahzarin R. Banaji. Greenwald "identified prejudice against the null hypothesis among researchers and unintended prejudices toward social groups among everyone." Greenwald's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283625 TI - The implicit revolution: Reconceiving the relation between conscious and unconscious. AB - In the 1970s, memory researchers converged on interesting phenomena observed in Korsakoff-syndrome amnesic patients. These patients' performances on difficult tasks were reliably improved by practice sessions from which they could recall nothing. Related findings of indirect memory effects in college students triggered wide attention to phenomena that, in 1985, were first identified as implicit memory. Within a decade, the indirect measurement methods of implicit memory research had spread to social psychologists' studies of attitudes and stereotypes. After another two decades, the methods and findings of this developing revolution have revised understanding of how past learning, operating in ways that bypass conscious awareness, nevertheless shapes conscious judgment and perception. This revolution in psychological thinking is on the cusp of reconceiving the relation between unconscious and conscious mental process. Further, it demands researchers' careful attention to justification for many self report measures that are now routinely treated as face-valid. (PsycINFO Database Record PMID- 29283626 TI - Award for Distinguished Scientific Contributions: Gordon D. Logan. AB - The American Psychological Association Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. Gordon D. Logan is a recipient of the 2017 award "for his contributions to the foundations of cognitive psychology as a field, the study of skill acquisition, automaticity, and cognitive control in particular," and insights into cognitive disturbances in clinical disorders. Logan's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283627 TI - Taking control of cognition: An instance perspective on acts of control. AB - Cognitive control is often viewed as an ability or as an interaction between higher and lower level systems. This article takes an instance perspective, articulating the view that cognitive control is accomplished by a multiplicity of specific acts of control tailored to accomplish specific adjustments to the cognitive system in specific circumstances. Acts of control take states of the cognitive system and states of the world as inputs, perform computations, and produce changes in the state of the cognitive system as output. Acts of control take measurable time. They are voluntary and specific, and they can be learned. The article addresses acts of control for inhibiting responses, shifting attention, and switching tasks, describing how to measure their durations and assess whether they are voluntary and specific. It concludes by reconciling ability, interactive systems, and instance perspectives and considering implications for research and practice. (PsycINFO Database Record PMID- 29283628 TI - Distinguished Scientific Contributions: Robert Plomin. AB - The American Psychological Association Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. Robert Plomin is a recipient of the 2017 award "for leading the transformation of behavioral genetics from an isolated and sometimes vilified scientific outpost to a fully integrated mainstay of scientific psychology." Plomin's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283630 TI - Award for Distinguished Scientific Applications of Psychology: Jacquelynne S. Eccles. AB - The American Psychological Association Award for Distinguished Scientific Applications of Psychology is presented to a person who, in the opinion of the Committee on Scientific Awards, has made distinguished theoretical or empirical advances leading to the understanding or amelioration of important practical problems. Jacquelynne S. Eccles is the recipient of the 2017 award, "for her seminal contributions to our understanding of how social contexts shape child and adolescent development." Eccles's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283632 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Sara N. Burke. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Sara N. Burke, for her groundbreaking work on the impact of age on the perirhinal cortex and associative memory and perception processes. Burke's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283633 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Kathryn Paige Harden. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Kathryn Paige Harden, for demonstrating "how to integrate genetic knowledge with the classical clinical and developmental insights into human behavior." Harden's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283634 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Mark J. Landau. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Mark J. Landau, for "his innovative contributions to understanding how existential concerns drive people toward particular conceptions of their world and how metaphors are used to imbue reality with meaning." Landau's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283635 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Adam M. Leventhal. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Adam M. Leventhal, for "exceptional contributions to our understanding of susceptibility to substance use disorders among vulnerable populations." Leventhal's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283636 TI - Award for Distinguished Scientific Early Career Contributions: Lara A. Ray. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Lara A. Ray, for "her substantive and innovative research on mechanisms that underlie alcohol and tobacco use disorders and for leveraging that knowledge to develop new, personalized treatment approaches for these disorders." Ray's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283637 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Nicole M. Stephens. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Nicole M. Stephens, for "groundbreaking research that leverages social psychological theories of culture and the self to understand fundamental psychological differences between working- and middle-class Americans." Stephens's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283638 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Jessica K. Witt. AB - The APA Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2017 award winners is Jessica K. Witt, for "outstanding contributions to our understanding of how action influences perception." Witt's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283640 TI - Award for Distinguished Senior Career Contributions to Psychology in the Public Interest: Gail S. Goodman. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2016 recipient of the Award for Distinguished Senior Career Contributions to Psychology in the Public Interest is Gail S. Goodman. She was selected for her innovative basic and applied research examining the relations between childhood trauma, attachment, memory and suggestibility, and child well-being, which helped shape evidence-based practices and policies. Goodman's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283641 TI - Psychological counseling and accuracy of memory for child sexual abuse. AB - Tens of thousands of child sexual abuse (CSA) cases are reported to authorities annually. Although some of the child victims obtain psychological counseling or therapy, controversy exists about the potential consequences for the accuracy of victims' memory of CSA, both in childhood and adulthood. Yet, delaying needed therapeutic intervention may have detrimental effects on the victims' well-being and recovery. To address this controversy, this study examined whether psychological counseling during a CSA prosecution predicts accuracy or inaccuracy of long-term memory for CSA. Participants (N = 71) were CSA victims who took part in a longitudinal study of memory and legal involvement. Data regarding participants' counseling attendance during the prosecution and details of their CSA cases were gathered throughout legal involvement and shortly thereafter (Time 1). Ten to 16 years later (Time 2), participants were questioned about a range of topics, including the alleged abuse. Time 1 counseling attendance significantly predicted more correct answers to abuse-related questions and (for corroborated cases) fewer overreporting responses at Time 2. Counseling was unrelated to underreporting responses. These results held even with other potential influences, such as abuse severity, victim-defendant relationship, posttraumatic stress disorder criteria met, testifying in the case, and delay, were statistically controlled. Although further research is needed, this study provides evidence that psychological counseling received by CSA victims during or shortly after prosecutions may improve later memory for abuse-related information. (PsycINFO Database Record PMID- 29283642 TI - Award for Distinguished Early Career Contributions to Psychology in the Public Interest: Kevin L. Nadal. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2017 recipient of the Award for Distinguished Early Career Contributions to Psychology in the Public Interest is Kevin L. Nadal, who has advanced "scholarship on stigma through his work on microaggressions related to sexual orientation, gender identity and expression, race/ethnicity, and religion." Nadal's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283643 TI - "Let's get in formation": On becoming a psychologist-activist in the 21st century. AB - Throughout the history of the United States, there have been many social movements that have resulted in an array of historic societal outcomes-ranging from the end of racial segregation to women's voting rights to the legalization of same-sex marriages. Despite the positive outcomes derived from political activism, many psychologists have struggled with how to advocate for social justice while maintaining their professional responsibilities and ethical boundaries. The current article reviews the historical ways that psychologists have participated in political movements-from the use of psychological research in landmark U.S. Supreme Court cases to psychologist-led pushes for policy changes in psychology, medicine, and other mental health related fields. Next, a critical review provides some of the major controversies or dilemmas regarding psychology, social justice, and political participation-including (a) ethical concerns and professional boundaries, (b) the utility of political neutrality in psychology, (c) psychologists' balance and self-care, (d) psychologists' lack of advocacy training, and (e) beliefs concerning the role of social justice advocacy in psychology. Finally, the article concludes with a discussion of the concept "psychologist-activist"-highlighting the many ways that psychologists across various subfields and institutions can combat oppression on individual, interpersonal, group, and institutional levels. (PsycINFO Database Record PMID- 29283645 TI - Award for Distinguished Contributions to Research in Public Policy: Saul M. Kassin. AB - APA's Award for Distinguished Contributions to Research in Public Policy is given to a psychologist who has made a distinguished empirical and/or theoretical contribution to research in public policy, either through a single extraordinary achievement or a lifetime of work. Saul M. Kassin is the 2017 recipient of this award for his extensive scholarship into understanding how and why suspects make false confessions, leading to greater understanding of the science of confessions and reforms to policy and practice. Kassin's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283646 TI - False confessions: How can psychology so basic be so counterintuitive? AB - Recent advances in DNA technology have shined a spotlight on thousands of innocent people wrongfully convicted for crimes they did not commit-many of whom had been induced to confess. The scientific study of false confessions, which helps to explain this phenomenon, has proved highly paradoxical. On the one hand, it is rooted in reliable core principles of psychology (e.g., research on reinforcement and decision-making, obedience to authority, and confirmation biases). On the other hand, false confessions are highly counterintuitive if not inconceivable to most people (e.g., as seen in actual trial outcomes as well as studies of jury decision making). This article describes both the psychology underlying false confessions and the psychology that predicts the counterintuitive nature of this same phenomenon. It then notes that precisely because they are so counterintuitive, false confessions are often "invisible," resulting in a form of inattentional blindness, and are slow to change in the face of contradiction, illustrating belief perseverance. This article concludes by suggesting ways in which psychologists can help to prevent future miscarriages of justice by advocating for reforms to policy and practice and helping to raise public awareness. (PsycINFO Database Record PMID- 29283648 TI - Award for Distinguished Career Contributions to Education and Training in Psychology: Nancy S. Elman. AB - The Award for Distinguished Career Contributions to Education and Training in Psychology is given in recognition of the efforts of psychologists who have made distinguished contributions to education and training, who have produced imaginative innovations, or who have been involved in the developmental phases of programs in education and training in psychology. The Career designation is added to the award at the discretion of the Education and Training Awards Committee to recognize continuous significant contributions made over a lifelong career in psychology. The 2017 recipient of this award is Nancy S. Elman, whose leadership roles have brought significant advancements for the education and training of psychologists. Her award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283650 TI - Award for Distinguished Contributions of Applications of Psychology to Education and Training: James Wilcox Lichtenberg. AB - The Award for Distinguished Contributions of Applications of Psychology to Education and Training acknowledges psychologists who contribute to new teaching methods or solutions to learning problems through research findings or evidence based practices. The 2017 recipient is James Wilcox Lichtenberg, whose scholarship has had "important impacts on the definition, training, and evaluation of professional practice." His award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283652 TI - APA/Psi Chi Edwin B. Newman Graduate Research Award: Samantha F. Anderson. AB - The Edwin B. Newman Graduate Research Award is given jointly by Psi Chi and the American Psychological Association. The award was established to recognize young researchers at the beginning of their professional lives and to commemorate both the 50th anniversary of Psi Chi and the 100th anniversary of psychology as a science (dating from the founding of Wundt's laboratory). The 2017 recipient is Samantha F. Anderson, who was chosen for "an exceptional research paper that responds to psychology's 'replication crisis' by outlining a broader view of success in replication." Her award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283654 TI - APA Award for Distinguished Professional Contributions to Applied Research: Cameron J. Camp. AB - The Award for Distinguished Professional Contributions to Applied Research is given to a psychologist whose research has led to important discoveries or developments in the field of applied psychology. The 2017 recipient is Cameron J. Camp, whose innovative programs have informed psychologists in working with dementia patients to improve their living skills and enhance their independence. Camp's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283656 TI - Award for Distinguished Professional Contributions to Independent Practice: Mary O'Leary Wiley. AB - The Award for Distinguished Professional Contributions to Independent Practice is intended to recognize outstanding independent practitioners in psychology. The award is given to a psychologist working in an area of clinical specialization, health services provision, or consulting, and services provided to any patient population or professional clientele in an independent setting. The 2017 recipient is Mary O'Leary Wiley, who has demonstrated exemplary service in the areas of child treatment and trauma as well as adoption, raising awareness of social contexts. She has also contributed significant leadership in areas of professional practice such as mentorship and ethics. Wiley's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283657 TI - Adoption research, practice, and societal trends: Ten years of progress. AB - Adoption involves the legal transfer of parental rights and responsibilities from a child's birth parents to adults who will raise the child (Reitz & Watson, 1992). Research related to adoption has expanded over the past 10 years and has incorporated more focus on implications for practice and public policy. This expansion has reflected increased awareness of the lived experience of adopted individuals, in addition to that of adoptive families and birth or first parents and families, collectively known as the adoption kinship network (Grotevant & McRoy, 1998). Trends discussed included research and social trends or movements (2007-2017) since the publication of the final article in a series of articles in the psychological literature related to adoption in The Counseling Psychologist (Baden & Wiley, 2007; Lee, 2003; O'Brien & Zamostny, 2003; Wiley & Baden, 2005; Zamostny, O'Brien, Baden, & Wiley, 2003; Zamostny, Wiley, O'Brien, Lee, & Baden, 2003). This article summarizes the social trends and research related to adoption over the last 10 years, including longitudinal and meta-analytic studies, increased research and conceptualization of ethnic and racial identity development, research on microaggressions, and research on diverse adoptive families, including those with gay and lesbian parents. Social trends included increased knowledge related to Internet accessibility, genetic information, continued focus on openness, and viewing adoption through a more critical lens. Implications are discussed for the development of programs that enhance competence of mental health professionals and adoption professionals in adoption competent practice. (PsycINFO Database Record PMID- 29283659 TI - Award for Distinguished Professional Contributions to Institutional Practice: Linda R. Mona. AB - The APA Awards for Distinguished Professional Contributions to Institutional Practice are intended to recognize outstanding practitioners in institutional settings in psychology. The 2017 award winner is Linda R. Mona, whose treatment of veterans with disabilities has advanced treatment with respect to sexual health. Her clinical work and advocacy for psychology practice have received national recognition. Mona's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283660 TI - Disability culturally competent sexual healthcare. AB - Though cultural competence and inclusion of diverse identities are increasingly emphasized in psychological training and practice, sexual health and well-being among people with disabilities (PWD) continue to be underrecognized areas in which disability cultural competence is needed. The experience of disability is best conceptualized as an interaction between physical, sensory, or cognitive differences and environmental and sociocultural contexts that facilitate or impede adaptive functioning; these complex interactions, coupled with an individual's age, gender, ethnicity, religious background, and sexual orientation, often inform one's sexual health and well-being. Disability can be thought of as a minority cultural status-a marginalized and stigmatized identity. Given the imperative that psychologists must be culturally competent and self aware, as well as the centrality of sexual health and well-being to quality of life including among PWD, assessment of sexuality as a facet of overall well being among individuals with physical disabilities should be part of routine clinical practice. A discussion of disability cultural competence is offered as a foundation to explore disability sexual health and wellness competence in clinical assessment. The disability and sexuality health care competency model is introduced to address the need for evidence-based sexual health and wellness assessment of PWD. Specific conceptual and behavioral sexuality and disability competencies that correspond to the provision and facilitation of these services are delineated. (PsycINFO Database Record PMID- 29283662 TI - APA/APAGS Award for Distinguished Graduate Student in Professional Psychology: Octavio Andres Santos. AB - The APA/APAGS Award for Distinguished Graduate Student in Professional Psychology is awarded annually by the APA Board of Professional Affairs (BPA) and the American Psychological Association of Graduate Students (APAGS) to a graduate student who has demonstrated outstanding practice and application of psychology. The 2017 award winner is Octavio Andres Santos, who has demonstrated through several initiatives "effective engagement with advocacy, professional organizations, and research in the area of health disparities and multicultural/multilingual assessment." Santos's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283664 TI - Award for Distinguished Contributions to the International Advancement of Psychology: Mary P. Koss. AB - The Award for Distinguished Contributions to the International Advancement of Psychology is given to individuals who have made sustained and enduring contributions to international cooperation and the advancement of knowledge in psychology. The 2017 award winner is Mary P. Koss, whose "stellar research, consultation, and advocacy on sexual violence against women and girls...has contributed to the integration of women's rights as an integral part of human rights." Her award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 29283665 TI - Victim voice in reenvisioning responses to sexual and physical violence nationally and internationally. AB - Internationally and in the United States many victims of sexual assault and domestic violence are unserved, underserved, or ill-served, especially those from the most vulnerable populations. Programs developed in the United States are routinely exported to developing countries but often without success. Notably, the failures seen internationally resemble those in the United States and are related to structural and attitudinal-cultural factors. Many victims do not disclose, and if they do seek services, they often report that available options mismatch their objectives, present accessibility challenges, disempower their pursuit of justice, and fail to augment needed resources. A deeper understanding of obstacles to effective service provision is needed if the United States is to continue to be an international partner in victim response and violence prevention. This article builds on what is known about service delivery challenges in U.S. programs to envision a path forward that concomitantly accommodates anticipation of shrinking resources, by (a) reviewing illustrative services and feedback from victims about utilizing them; (b) examining structural inequalities and the intersections of personal and contextual features that both increase vulnerability to victimization and decrease accessibility and acceptability of services; (c) advocating for reintroduction of direct victim voice into response planning to enhance reach and relevance; and (d) reorienting delivery systems, community partnerships, and Coordinated Community Response teams. The authors suggest as the way forward pairing direct victim voice with open-minded listening to expressed priorities, especially in vulnerable populations, and designing services accordingly. Through a process that prioritizes adaptation to diverse needs and cultures, U.S models can increase desirability, equity, and thrift at home as well as enhance international relevance. (PsycINFO Database Record PMID- 29283667 TI - International Humanitarian Award: Kathryn L. Norsworthy. AB - The International Humanitarian Award recognizes extraordinary humanitarian services and activism by psychologists, including professional and volunteer work conducted primarily in the field with underserved populations. The 2017 award winner is Kathryn L. Norsworthy, for work as an educator, activist, and scholar of international humanitarian work. Among her notable achievements, she has "helped to strengthen the identity of Nepali, Thai, and Burmese women, assisted them in preventing and confronting human rights abuses, and contributed to their mobilization as influential leaders." Her award citation, biography, and selected bibliography are presented here. (PsycINFO Database Record PMID- 29283668 TI - Mindful activism: Embracing the complexities of international border crossings. AB - I am one of many psychologists from the minority world, or Global North, who regularly travel to the Global South, or majority world, to engage in activist research and practice. Drawing on postcolonial and decolonial frameworks, this testimonio discusses tensions and complexities that arise in these transnational border crossings, particularly given the current internationalization movement in U.S. psychology. A testimonio is a first-person narrative of experiences with oppression, resilience, and empowerment, that can "re-script history . . . and re inscribe otherwise ignored stories" (Smith, 2010, p. 21). Following a description of a decolonizing praxis of mindful activism (Norsworthy & Khuankaew, 2006), I chronicle several examples of challenges my colleagues from Thailand and Burma and I have traversed in our efforts to employ a decolonial feminist liberation approach in our work in Southeast Asia. (PsycINFO Database Record PMID- 29283669 TI - Systems Thinking and Systems-Based Practice Across the Health Professions: An Inquiry Into Definitions, Teaching Practices, and Assessment. AB - : Phenomenon: Systems thinking is the cornerstone of systems-based practice (SBP) and a core competency in medicine and health sciences. Literature regarding how to teach or apply systems thinking in practice is limited. This study aimed to understand how educators in medicine, physical therapy, physician assistant, nursing, and speech-language pathology education programs teach and assess systems thinking and SBP. APPROACH: Twenty-six educators from seven different degree programs across the five professions were interviewed and program descriptions and relevant course syllabi were reviewed. Qualitative analysis was iterative and incorporated inductive and deductive methods as well as a constant comparison of units of data to identify patterns and themes. FINDINGS: Six themes were identified: 1) participants described systems thinking as ranging across four major levels of healthcare (i.e., patient, care team, organization, and external environment); 2) participants associated systems thinking with a wide range of activities across the curriculum including quality improvement, Inter professional education (IPE), error mitigation, and advocacy; 3) the need for healthcare professionals to understand systems thinking was primarily externally driven; 4) participants perceived that learning systems thinking occurred mainly informally and experientially rather than through formal didactic instruction; 5) participants characterized systems thinking content as interspersed across the curriculum and described a variety of strategies for teaching and assessing it; 6) participants indicated a structured framework and inter-professional approach may enhance teaching and assessment of systems thinking. Insights: Systems thinking means different things to different health professionals. Teaching and assessing systems thinking across the health professions will require further training and practice. Tools, techniques, taxonomies and expertise outside of healthcare may be used to enhance the teaching, assessment, and application of systems thinking and SBP to clinical practice; however, these would need to be adapted and refined for use in healthcare. PMID- 29283671 TI - Photobiological Effects at Earth's Surface Following a 50 pc Supernova. AB - We investigated the potential biological impacts at Earth's surface of stratospheric O3 depletion caused by nearby supernovae known to have occurred about 2.5 and 8 million years ago at about 50 pc distance. New and previously published atmospheric chemistry modeling results were combined with radiative transfer modeling to determine changes in surface-level solar irradiance and biological responses. We find that UVB irradiance is increased by a factor of 1.1 to 2.8, with large variation in latitude, and seasonally at high-latitude regions. Changes in UVA and PAR (visible light) are much smaller. DNA damage (in vitro) is increased by factors similar to UVB, while other biological impacts (erythema, skin cancer, cataracts, marine phytoplankton photosynthesis inhibition, and plant damage) are increased by smaller amounts. We conclude that biological impacts due to increased UV irradiance in this SN case are not mass extinction level but might be expected to contribute to changes in species abundances; this result fits well with species turnover observed around the Pliocene-Pleistocene boundary. Key Words: UV radiation-Supernovae-Ozone-Radiative transfer. Astrobiology 18, 481-490. PMID- 29283672 TI - Measurement of the Retention Time of Different Ophthalmic Formulations with Ultrahigh-Resolution Optical Coherence Tomography. AB - : Purpose/aim of the study: The purpose of this study was to measure the pre corneal retention time of two marketed formulations (eye drops and eye gel) of a steroid-antibiotic fixed combination (FC) containing 0.1% dexamethasone and 0.3% netilmicin. MATERIALS AND METHODS: Pre-corneal retention time was evaluated in 16 healthy subjects using an ultrahigh-resolution anterior segment spectral domain optical coherence tomography (OCT). All subjects randomly received both formulations of the FC (Netildex, SIFI, Italy). Central tear film thickness (CTFT) was measured before instillation (time 0) and then after 1, 10, 20, 30, 40 50, 60 and 120 min. The pre-corneal retention time was calculated by plotting CTFT as a function of time. Differences between time points and groups were analyzed by Student's t-test. RESULTS: CTFT increased significantly after the instillation of the eye gel formulation (p < 0.001). CTFT reached its maximum value 1 min after instillation and returned to baseline after 60 min. No effect on CTFT was observed after the instillation of eye drops. The difference between the two formulations was statistically significant at time 1 min (p < 0.0001), 10 min (p < 0.001) and 20 min (p < 0.01). CONCLUSIONS: The FC formulated as eye gel was retained on the ocular surface longer than the corresponding eye drop solution. Consequently, the use of the eye gel might extend the interval between instillations and decrease the frequency of administration. PMID- 29283670 TI - Home-based Physical Activity Coaching, Physical Activity, and Health Care Utilization in Chronic Obstructive Pulmonary Disease. Chronic Obstructive Pulmonary Disease Self-Management Activation Research Trial Secondary Outcomes. AB - RATIONALE: Physical inactivity among patients with chronic obstructive pulmonary disease is associated with exacerbations requiring high-cost health care utilization including urgent, emergent, and hospital care. OBJECTIVES: To examine the effectiveness of a behavioral lifestyle physical activity intervention combined with chronic obstructive pulmonary disease self-management education to prevent high-cost health care utilization. METHODS: This was an analysis of secondary outcomes of the Chronic Obstructive Pulmonary Disease Self-Management Activation Research Trial, a two-arm randomized trial of stable adult outpatients with chronic obstructive pulmonary disease recruited from primary care and pulmonary clinics. Following a 6-week self-management education run-in period, participants were randomized to usual care or to a telephone-delivered home-based health coaching intervention over 20 weeks. Secondary outcomes of physical activity and health care utilization were determined by self-report 6, 12, and 18 months after randomization. Associations between treatment allocation arm and these secondary outcomes were examined using log-binomial and Poisson regression models. RESULTS: A total of 325 outpatients with stable chronic obstructive pulmonary disease were enrolled in the trial. Their average age was 70.3 years (standard deviation, 9.5), and 50.5% were female; 156 were randomized to usual care and 149 to the intervention. A greater proportion of participants reported being persistently active over the 18-month follow-up period in the intervention group (73.6%) compared with the usual care group (57.8%) (mean difference, 15.8%; 95% confidence interval, 4.0-27.7%). This association varied by severity of forced expiratory volume in 1 second impairment (P for interaction = 0.09). Those in the intervention group with moderate impairment (forced expiratory volume in 1 second, 50-70% predicted), more frequently reported being persistently active compared with the usual care (86.0 vs. 65.1%; mean difference, 20.9%; 95% confidence interval, 5.7-36.1%). Patients with severe and very severe forced expiratory volume in 1 second impairment (forced expiratory volume in 1 second < 50% predicted) in the intervention group also reported being persistently active more frequently compared with usual care (63.3 vs. 50.8%; mean difference, 12.6%; 95% confidence interval, -4.7 to 29.8). The intervention was associated with a lower rate of lung-related utilization (adjusted rate ratio, 0.38; 95% confidence interval, 0.23-0.63) only among participants with severe spirometric impairment. CONCLUSIONS: Our results demonstrate that a feasible and generalizable home-based coaching intervention may decrease sedentary behavior and increase physical activity levels. In those with severe chronic obstructive pulmonary disease, this intervention may reduce lung disease-related health care utilization. Clinical trial registered with www.clinicaltrials.gov (NCT01108991). PMID- 29283673 TI - A mixed methods assessment of the barriers and readiness for meeting the SNAP depth of stock requirements in Baltimore's small food stores. AB - We sought to understand Baltimore corner store owners' awareness of and readiness for the then-approved Supplemental Nutrition Assistance Program depth of stock requirements and assess potential barriers and solutions. In-depth interviews and stocking observations were conducted in 17 corner stores in low-income food deserts of Baltimore City. Corner store owners conveyed little to no awareness of the pending depth of stock changes. Only two stores were currently ready for the requirements. Low customer demand, high amounts of potential spoilage, and unfair pricing at the wholesaler were identified by store owners as barriers to stocking required foods. PMID- 29283675 TI - Depth-Dependent Out-of-Plane Young's Modulus of the Human Cornea. AB - : Purpose/Aim: Despite their importance in accurate mechanical modeling of the cornea, the depth-dependent material properties of the cornea have only been partially elucidated. In this work, we characterized the depth-dependent out-of plane Young's modulus of the central and peripheral human cornea with high spatial resolution. MATERIALS AND METHODS: Central and peripheral corneal buttons from human donors were subjected to unconfined axial compression followed by stress relaxation for 30 min. Sequences of fluorescent micrographs of full thickness corneal buttons were acquired throughout the experiment to enable tracking of fluorescently labeled stromal keratocyte nuclei and measurements of depth-dependent infinitesimal strains. The nominal (gross) out-of-plane Young's modulus and drained Poisson's ratio for each whole specimen was computed from the equilibrium stress and overall tissue deformation. The depth-dependent (local) out-of-plane Young's modulus was computed from the equilibrium stress and local tissue strain based on an anisotropic model (transverse isotropy). RESULTS: The out-of-plane Young's modulus of the cornea exhibited a strong dependence on in plane location (peripheral versus central cornea), but not depth. The depth dependent out-of-plane Young's modulus of central and peripheral specimens ranged between 72.4-102.4 kPa and 38.3-58.9 kPa. The nominal out-of-plane Young's modulus was 87 +/- 41.51 kPa and 39.9 +/- 15.28 kPa in the central and peripheral cornea, while the drained Poisson's ratio was 0.05 +/- 0.02 and 0.07 +/- 0.04. CONCLUSIONS: The out-of-plane Young's modulus of the cornea is mostly independent of depth, but not in-plane location (i.e. central vs. peripheral). These results may help inform more accurate finite element computer models of the cornea. PMID- 29283674 TI - Patient Narratives as a Teaching Tool: A Pilot Study of First-Year Medical Students and Patient Educators Affected by Intellectual/Developmental Disabilities. AB - PROBLEM: People with intellectual and developmental disabilities (IDD) face complex biopsychosocial challenges and are medically underserved. This is in part due to insufficient resources and supports but can also be attributed to a lack of adequate physician training in addressing the unique needs of this population. INTERVENTION: This study aimed to introduce 1st-year medical students to the IDD population using a blended educational experience that included video narratives of and direct interactions with people affected by IDD. The goal of this intervention was to promote person-centered attitudes and communication among early medical trainees. CONTEXT: The study recruited 27 first-year medical students and randomly assigned each to 1 of 2 groups. The control group received an introductory video lecture about IDD healthcare, followed by a quiz. The narrative group received the same lecture, followed by reflective discussion of videos featuring people living with IDD sharing their perspectives and stories. All students then participated in 4 simulated clinical encounters with patient educators (PEs) who have lived experiences of IDD. Focus groups were conducted with students following the simulated encounters to explore their experiences and perceptions of this blended learning activity. Moreover, secondary quantitative data were collected to assess students' performance in the clinical encounters, along with self-reports of comfort, confidence, and competence of interacting with people with IDD (pre- and postparticipation). OUTCOME: All students thought that the blended educational experience was valuable and enjoyable, commenting on the importance of adaptable language and engagement of people with IDD, as well as the merits of reflecting on patient narratives. Students also discussed feelings of discomfort stemming from a lack of knowledge and previous exposure to IDD and how this discomfort might motivate them to learn more and develop their skills further. In addition, descriptive analyses revealed that students in the narrative group showed greater self-rated measures of comfort, confidence, and competence compared to control; they also had higher mean performance scores across all PE interview stations. LESSONS LEARNED: PEs add a powerful real-life dimension to communication skills teaching and have been shown to be a valuable educational modality. Moreover, exposure to and reflection on video-based patient narratives are useful ways of teaching medical students about patients' lived experiences and promoting person-centered communication, both within and beyond IDD. PMID- 29283676 TI - The Effect of Solithromycin, a Cationic Amphiphilic Drug, on the Proliferation and Differentiation of Human Meibomian Gland Epithelial Cells. AB - PURPOSE: We previously discovered that azithromycin (AZM) acts directly on immortalized human meibomian gland epithelial cells (IHMGECs) to stimulate their lipid and lysosome accumulation and overall differentiation. We hypothesize that this phospholipidosis-like effect is due to AZM's cationic amphiphilic drug (CAD) nature. If our hypothesis is correct, then other CADs (e.g., solithromycin [SOL]) should be able to duplicate AZM's action on IHMGECs. Our purpose was to test this hypothesis. MATERIALS AND METHODS: IHMGECs were cultured in the presence of vehicle or SOL (2, 10, or 20 ug/ml) for up to 7 days under proliferating or differentiating conditions. Positive (epidermal growth factor and bovine pituitary extract for proliferation; AZM for differentiation) and negative (vehicle) controls were included with the experiments. IHMGECs were evaluated for cell number, neutral lipid content, and lysosome accumulation. RESULTS: Our results demonstrate that SOL induces a rapid and dose-dependent increase in the accumulation of neutral lipids and lysosomes in HMGECs. The lysosomal effects were most prominent with the 10 and 20 ug/ml doses, and occurred earlier (i.e., 1 day) with SOL than with the AZM (10 ug/ml) control. The effects of SOL and AZM on IHMGEC differentiation were essentially the same after 3 days of culture. SOL did not influence the proliferation of HMGECs during a 7-day time period. CONCLUSIONS: Our results support our hypothesis that SOL, a CAD, is able to reproduce AZM's impact on lysosome and lipid accumulation, as well as the differentiation, of HMGECs. The effect of SOL on lysosome appearance was faster than that of AZM. PMID- 29283677 TI - On the Weak Mortality Returns of the Prison Boom: Comparing Infant Mortality and Homicide in the Incarceration Ledger. AB - The justifications for the dramatic expansion of the prison population in recent decades have focused on public safety. Prior research on the efficacy of incarceration offers support for such claims, suggesting that increased incarceration saves lives by reducing the prevalence of homicide. We challenge this view by arguing that the effects of mass incarceration include collateral infant mortality consequences that call into question the number of lives saved through increased imprisonment. Using an instrumental variable estimation on state-level data from 1978 to 2010, this article simultaneously considers the effects of imprisonment on homicide and infant mortality to examine two of the countervailing mortality consequences of mass incarceration. Results suggest that while incarceration saves lives by lowering homicide rates, these gains are largely offset by the increases in infant mortality. Adjusted figures that count the number of increased infant deaths attributable to incarceration suggest that the mortality benefits of imprisonment over the past three decades are 82% lower than previously thought. PMID- 29283678 TI - Pitch Volume and Glenohumeral and Hip Motion and Strength in Youth Baseball Pitchers. AB - CONTEXT: Increased pitch volume and altered glenohumeral (GH) and hip range of motion (ROM) and strength contribute to injury risk in baseball pitchers. Although these factors affect one another, whether they are related is unknown. OBJECTIVE: To examine relationships among cumulative and seasonal pitch volume, ROM, and strength of the GH and hip joints in youth baseball pitchers. DESIGN: Cross-sectional study. SETTING: Baseball practice facilities. PATIENTS OR OTHER PARTICIPANTS: A total of 28 healthy baseball pitchers (age = 13.9 +/- 2.9 years). MAIN OUTCOME MEASURE(S): A demographic and pitching questionnaire was used to quantify pitch volume. Glenohumeral internal-rotation (IR) and external rotation (ER) ROM and strength of the throwing arm; total arc of motion (IR + ER ROM); and bilateral hip IR, ER, and total arc of motion ROM and strength in IR, ER, and abduction were measured. A goniometer was used to assess ROM; a handheld dynamometer, to assess strength. Frequency analyses and bivariate correlations (age covariate) described data and identified relationships. RESULTS: Correlations between years of competitive play and increased strength in lead-leg hip IR ( r = 0.52, P = .02) and abduction ( r = 0.48, P = .04) and stance-leg hip IR ( r = 0.45, P = .05) were fair to good. The number of months played in the last year had a fair correlation with decreased GH IR strength ( r = -0.39, P = .04) and increased stance-leg hip IR strength ( r = 0.44, P = .05). Limited pitch time had a fair correlation with increased GH ER ROM ( r = 0.40, P = .04) and an excellent correlation with increased lead-leg hip IR ROM ( r = 0.79, P < .001). Increased innings pitched per game had a fair to good correlation with decreased GH IR strength ( r = -0.41, P = .04) and stance-leg hip ER ROM ( r = -0.53, P = .03). More pitches per game had a fair to good correlation with increased GH ER ROM ( r = 0.44, P = .05) and decreased stance-leg hip ER ROM ( r = -0.62, P = .008). CONCLUSIONS: The significant relationships identified in this study suggest the need to further examine youth and adolescent cumulative and seasonal pitch guidelines. PMID- 29283679 TI - Influence of Short-Term Orthokeratology to Corneal Tangent Modulus: A Randomized Study. AB - PURPOSE: Influence of orthokeratology on corneal biomechanics is equivocal using Ocular Response Analyzer, ORA. Implementing indentation method, corneal tangent modulus was measured and monitored in short-term orthokeratology. MATERIALS AND METHODS: Sixteen young subjects with refractive errors between -4D to -5D sphere and astigmatism within -1.50D were recruited. One randomly selected eye wore orthokeratology lens (treatment), and the fellow eye wore conventional rigid gas permeable lens (control). Lenses were worn for 30 and 60 minutes and one night separately with a week of washout period in between. The first two visits were randomly scheduled and before the overnight visit. Eyes were kept closed during all the lens wearing periods. Corneal radius, thickness, and biomechanics (using both ORA and an indentation device) were compared between eyes prior to each visit, and then before and after lens wear. Associations between baseline corneal biomechanics and central cornea from overnight visit were investigated. RESULTS: Corneal parameters were similar in each visit before lens wear. Significant corneal flattening was observed in treatment eyes, and flattening increased with wearing time. Control eyes showed no significant corneal curvature changes. Corneal resistance factor (CRF) reduced by 0.42mmHg (+/- 0.68mmHg) after 30 minutes of orthokeratology treatment. Corneal hysteresis (CH) reduced by 0.42mmHg (+/- 0.63mmHg) in control eyes from overnight wear. Both eyes showed stable tangent modulus, E, throughout the study. A lower CH (r = 0.51, p = 0.046) and a higher E (r = 0.53, p = 0.037) at baseline was significantly associated with greater corneal flattening along the flattest meridian in treatment eyes. CONCLUSIONS: Short-term orthokeratology had no significant effect on corneal tangent modulus. Changes in CH and CRF could be related to their intrinsic measurement variability. Corneal tangent modulus provided another measure of corneal biomechanics. Long-term study is required to investigate predictive role of corneal biomechanics in orthokeratology. PMID- 29283680 TI - Effects of Selective Serotonin Reuptake Inhibitors on Macular Ganglion Cell Complex Thickness and Peripapillary Retinal Nerve Fiber Layer Thickness. AB - PURPOSE: To evaluate macular ganglion cell complex (GCC) thickness and peripapillary retinal nerve fiber layer (RNFL) thickness in patients treated with SSRIs. METHODS: The present study included 62 eyes of 31 patients who were using SSRIs and 60 eyes of 30 healthy, age- and gender-matched control subjects. All patients underwent a full ophthalmological examination in which macular thickness, GCC thickness, and peripapillary RNFL thickness were measured using optical coherence tomography (OCT). The Mann-Whitney U test was used to compare the patients' group with the age- and gender-matched control group. Pearson correlation analyses were also performed to assess the relationships between macular thickness, GCC thickness, RNFL thickness, and the duration of SSRI usage. RESULTS: The mean duration of SSRI usage was 29.96 +/- 27.19 (range 6-120) months. The foveal thickness was 253.48 +/- 22.77um in the patients' group and 266.60 +/- 20.64 um in the control group; the difference between the groups was statistically significant. In addition, the perifoveal GCC thickness in the inferonasal and inferotemporal quadrant were significantly smaller thinner in the patient group (Mann-Whitney U test, p = 0.021and p = 0.013, respectively). CONCLUSIONS: Our results suggest a relation between SSRIs and decreased retinal GCC thickness and RNFL thickness. Future long-term prospective studies should elucidate the actual effect of SSRIs on GCC and RNFL thickness. PMID- 29283681 TI - Short-Term Air Pollution and Incident Pneumonia. A Case-Crossover Study. AB - RATIONALE: The relationship between air pollution and pneumonia is poorly understood. OBJECTIVES: To examine relationships between short-term air pollution exposure and number and severity of pneumonia cases along the Wasatch Front in Utah, a region with periodic high levels of outdoor air pollution. METHODS: We applied time-stratified case-crossover analyses with distributed lag to patients presenting to seven emergency departments with pneumonia over a 2-year period. We compared levels of particulate matter less than or equal to 2.5 MUm in aerodynamic diameter, nitrogen dioxide, and ozone at patient residences with emergency department cases, hospitalizations, objectively defined severe pneumonia, and mortality. We calculated direct cost impacts of particulate matter less than or equal to 2.5 MUm in aerodynamic diameter reduction. RESULTS: We evaluated 4,336 pneumonia cases in seven hospitals. Among adults aged 65 years and older, we found consistently positive associations between particulate matter less than or equal to 2.5 MUm in aerodynamic diameter within 6 days of presentation and instances of pneumonia (Lag Day 1 adjusted odds ratio, 1.35 per 10 MUg/m3 over 12 MUg/m3; 95% confidence interval, 1.16-1.57), severe pneumonia (Lag Day 1 adjusted odds ratio, 1.38; 95% confidence interval, 1.06-1.80), and inpatient mortality (Lag Day 5 adjusted odds ratio, 1.50; 95% confidence interval, 1.03-2.16). Smaller associations were found between nitrogen dioxide exposure and pneumonia occurrence, severity, and inpatient and 30-day mortality. Ozone exposure was modestly associated with increased instance and severity of pneumonia in younger adults. Particulate matter less than or equal to 2.5 MUm in aerodynamic diameter and nitrogen dioxide effects were greatest in colder months, and ozone effects were greatest in warmer months. Reduction of particulate matter less than or equal to 2.5 MUm in aerodynamic diameter levels to less than 12.0 mg/m3 could prevent 76-112 cases of pneumonia per year in these hospitals serving approximately half of the Wasatch Front's population, reducing direct medical facility costs by $807,000 annually. CONCLUSIONS: Among older adults, short-term ambient particulate matter less than or equal to 2.5 MUm in aerodynamic diameter exposure is associated with more emergency department visits and hospitalizations for pneumonia, severe pneumonia, increased mortality, and increased healthcare costs. Nitrogen dioxide and ozone modestly increase pneumonia risk and illness severity. PMID- 29283682 TI - Domiciliary High-Flow Nasal Cannula Oxygen Therapy for Patients with Stable Hypercapnic Chronic Obstructive Pulmonary Disease. A Multicenter Randomized Crossover Trial. AB - RATIONALE: A growing evidence base suggests a benefit of using high-flow nasal cannula oxygen therapy in the acute setting. However, the clinical benefit of domiciliary use of high-flow nasal cannula oxygen therapy in patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease remains unclear. OBJECTIVES: To evaluate the efficacy and safety of high flow nasal cannula oxygen therapy use in patients with stable chronic obstructive pulmonary disease. METHODS: We conducted a multicenter, randomized crossover trial comparing high-flow nasal cannula oxygen therapy plus long-term oxygen therapy with long-term oxygen therapy only in 32 adults with stable hypercapnic chronic obstructive pulmonary disease. Participants were randomized to receive either 6 weeks of high-flow nasal cannula oxygen therapy/long-term oxygen therapy using the myAIRVO 2 device followed by another 6 weeks of long-term oxygen therapy only or long-term oxygen therapy only followed by high-flow nasal cannula oxygen therapy/long-term oxygen therapy. The primary outcome was the change in quality of life as assessed by St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease. A linear mixed-effects model was used to account for treatment effect, time effect, allocation effect, and participant effect. RESULTS: Of 32 study participants, 29 completed the study. At the end of 12 weeks, high-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment improved the mean total St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease score compared with long-term oxygen therapy only (7.8 points; 95% confidence interval, 3.7 to 11.9; P < 0.01). Similarly, high flow nasal cannula oxygen therapy/long-term oxygen therapy treatment improved the arterial partial pressure of carbon dioxide (adjusted treatment effect, -4.1 mm Hg; 95% confidence interval, -6.5 to -1.7 mm Hg), pH (adjusted treatment effect, +0.02; 95% confidence interval, 0.01 to 0.02), and median nocturnal transcutaneous carbon dioxide pressure (adjusted treatment effect, -5.1 mm Hg; 95% confidence interval, -8.4 to -1.8 mm Hg). High-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment did not improve the arterial partial pressure of oxygen, dyspnea, spirometry, lung volume, 6-minute walk test, or physical activity. The most frequent high-flow nasal cannula oxygen therapy related adverse event encountered was nocturnal sweating (n = 6 [20.7%]). Four severe adverse events occurred (two in each group) and were deemed unrelated to the intervention. CONCLUSIONS: Six weeks of treatment with high-flow nasal cannula oxygen therapy improved health-related quality of life and reduced hypercapnia in patients with stable hypercapnic chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT02545855) and www.umin/ac.jp (UMIN000017639). PMID- 29283683 TI - Period Prevalence and Perceived Side Effects of Hormonal Contraceptive Use and the Menstrual Cycle in Elite Athletes. AB - PURPOSE: To identify the period prevalence of hormonal contraceptive (HC) use and characterize the perceived side effects associated with the menstrual cycle and HC use. METHODS: A total of 430 elite female athletes completed a questionnaire to assess the period prevalence of HC use, the reasons for initiation and discontinuation of HCs, and the side effects experienced by HC and non-HC users. Descriptive statistics, between-groups comparisons, and associations between categorical variables were calculated. RESULTS: Of athletes studied, 49.5% were currently using HCs and 69.8% had used HCs at some point. Combined oral contraceptives were most commonly used (68.1%), with 30.0% using progestin-only contraceptives (implant = 13.1%, injection = 3.7%, and intrauterine system = 2.8%). Perceived negative side effects were more common with progestin-only HC use (39.1%) compared with combined-HC use (17.8%; P = .001) and were most prevalent in implant users (53.6%; P = .004). HC users reported perceived positive side effects relating to their ability to predict and/or manipulate the timing, frequency, and amount of menstrual bleeding. Non-HC users had a menstrual cycle length of 29 (5) d and 77.4% reported negative side effects during their menstrual cycle, primarily during days 1-2 of menstruation (81.6%). CONCLUSIONS: Approximately half of elite athletes used HCs, and progestin-only contraceptive users reported greater incidences of negative side effects, especially with the implant. Because of the high interindividual variability in reported side effects, athletes and practitioners should maintain an open dialogue to pursue the best interests of the athlete. PMID- 29283684 TI - An overview of surgical treatment modalities and emerging transcatheter interventions in the management of tricuspid valve regurgitation. AB - INTRODUCTION: Tricuspid valve regurgitation (TR) is frequently encountered and is most often functional (FTR) in nature. Surgical tricuspid valve (TV) treatment is well established in specialized centers. While transcatheter therapy for other valve disease is well established, interventional treatment of TV disease is still in its early stages. With the increasing adoption of catheter-based treatments, there is a growing interest in and need for interventional treatments for TR. An extensive literature search was methodologically performed aiming for an integrative review paper. Areas covered: This review will discuss the current surgical treatment modalities and emerging transcatheter interventions in the management of TR. Furthermore, this review will describe the pathophysiology of functional tricuspid regurgitation (FTR), and the new 2017 ESC/EACTS guidelines for the management of TR. Finally, a five-year view into the future will be stated. Expert commentary: At their center, the authors have an aggressive approach for the treatment of FTR owing to its significant impact on perioperative as well as late postoperative morbidity and mortality. The authors perform TV ring annuloplasty when substantial annular dilation (>=45mm) is observed. In the future, percutaneous TV technologies might become an alternative option to treat TR patients with high surgical risk selectively. PMID- 29283687 TI - Recall erythema phenomenon following Er:YAG laser treatment: two case studies and literature review. AB - Recall erythema is a phenomenon occurring when an area of epidermis treated with laser is later exposed to a trigger, most often sunlight or hot water, causing erythema in the zone of laser treatment after post-treatment erythema has already resolved. Radiation recall dermatitis is a more specific subtype of recall erythema in which an area treated with radiation is subjected to another exposure causing erythema in the area of previous radiation. Cases of recall dermatitis after laser treatment are extremely rare and have only been reported with diode neodymium-doped yttrium aluminum garnet lasers. We report two cases of recall dermatitis following erbium-doped yttrium aluminum garnet resurfacing laser triggered by exposure to either hot water or direct sunlight, and in one case, radioablation of the thyroid gland. We will also provide a brief literature review of recall dermatitis in the setting of laser surgery. PMID- 29283688 TI - Efficacy of protein extracts from medium of Adipose-derived stem cells via microneedles on Asian skin. AB - OBJECTIVES: To explore efficacy of protein extracts from medium of Adipose derived stem cells (ADSCs) via microneedles on Asian skin in a double-blind, split-face, randomized, control study. METHODS: Thirty volunteers received the treatment, left-side and right-side of their face were randomly assigned to test side and control side. The protein extracts from medium of ADSCs were applied via microneedles into the test side and ultrapure water was applied into the control side. The only person who knew what was being used by each subject on each side of the face was the therapist. Clinical evaluation including instrument test and self-questionnaire was performed by independent observers before and after the treatment, which lasted for 3 months. RESULTS: All subjects completed the study. Compared to ultrapure water, the protein extracts from medium of ADSCs showed a statistically significant improvement for melanin index, skin brightness, gloss, skin roughness, elasticity, and wrinkles (p < 0.05). More than 70% of the participants described that all wrinkles, firmness, elasticity, hydration, whitening, and radiance were strongly improved in the test side. CONCLUSIONS: Protein extracts from medium of ADSCs presented anti-aging and whitening efficacy via microneedles on Asian skin without skin adverse side. PMID- 29283689 TI - Physiological and Physical Responses According to the Game Surface in a Soccer Simulation Protocol. AB - PURPOSE: Recent studies have shown that soccer players' responses are similar on natural grass (NG) and artificial turf (AT), but they did not control the mechanical properties of these surfaces. This work aimed to analyze the influence of the game surface on amateur soccer players' physical and physiological responses using a soccer simulation protocol. METHODS: A total of 16 amateur players performed 3 bouts of the soccer simulation protocol on AT, and, on another day, 3 bouts on NG. The mechanical properties of both surfaces were recorded. The order of surfaces was randomly established for each participant. Physiological responses of players were assessed before and after the 6-repeated sprints test existing at the midpoint of each bout. Fatigue (% best; % diff) and general variables (total time; best time, mean time; maximum speed) for both the repeated sprint test (RST) and the agility tests (nonlinear actions at maximum speed) incorporated into the soccer simulation protocol were also analyzed. RESULTS: The 2 surfaces displayed different mechanical properties. Physical responses were found similar for both surfaces (P > .05) before and after the RST. There were no surface differences in sprint times or fatigue variables for the RST (P > .05). The agility test was faster on AT than on NG in bout 1 (average speed [+1.17 km/h;P = .037]; agility test cut time [-0.31 s; P = .027] and best time [-0.52 s; P = .042]). CONCLUSIONS: The differences in the mechanical properties of the 2 surfaces are not sufficient to cause differences in the physiological and physical responses of soccer players, although they may affect turns and cuts. PMID- 29283690 TI - How Fast Is a Horizontal Squat Jump? AB - : Velocity strength training requires exercise modalities that allow athletes to reach very high movement velocity, which is limited during vertical movements involving body weight. PURPOSE: To quantify the mechanical outputs developed during horizontal squat jumps (HSJs), notably the movement velocity, in comparison with vertical squat jumps (SJs) with and without loads. METHODS: Thirteen healthy male athletes performed SJs without additional loads (SJ0) and with a load of ~60% of body mass (SJ60), and during HSJs performed lying on a roller device with (assisted HSJ [AHSJ]) and without (HSJ) rubber-band assistance. Instantaneous lower-limb extension velocity, force, and power output were measured and averaged over the push-off phase. RESULTS: The force was significantly higher during SJ60 than during SJ0, which was higher than during HSJ and AHSJ. Extension velocity was significantly different across all conditions, with 0.86 (0.07), 1.29 (0.10), 1.59 (0.19), and 1.83 (0.19) m.s-1 for SJ60, SJ0, HSJ, and AHSJ conditions, respectively. Differences in force and velocity values between SJ0 and the other conditions were large to extremely large. Differences were observed in power values only between SJ60 and SJ0, SJ60 and AHSJ, and SJ0 and HSJ. CONCLUSIONS: HSJ modalities allow athletes to reach very to extremely largely greater lower-limb extension velocities (HSJ +24.0% [16%], AHSJ +42.8% [17.4%]) compared to those achieved during SJ0. HSJ and AHSJ modalities are inexpensive and practical modalities to train limb-extension velocity capabilities, that is, the ability of the neuromuscular system to produce force at high contraction velocities. PMID- 29283692 TI - Intracyclic Variation of Force and Swimming Performance. AB - CONTEXT: In front-crawl swimming, the upper limbs perform alternating movements with the aim of achieving a continuous application of force in the water, leading to lower intracyclic velocity variation (dv). This parameter has been identified as a crucial criterion for swimmers' evaluation. PURPOSE: To examine the assessment of intracyclic force variation (dF) and to analyze its relationship with dv and swimming performance. METHODS: A total of 22 high-level male swimmers performed a maximal-effort 50-m front-crawl time trial and a 30-s maximal-effort fully tethered swimming test, which were randomly assigned. Instantaneous velocity was obtained by a speedometer and force by a strain-gauge system. RESULTS: Similarity was observed between the tests, with dF attaining much higher magnitudes than dv (P < .001; d = 8.89). There were no differences in stroke rate or in physiological responses between tethered and free swimming, with a high level of agreement for the stroke rate and blood lactate increase. Swimming velocity presented a strong negative linear relationship with dF (r = -.826, P < .001) and a moderate negative nonlinear relationship with dv (r = .734, P < .01). With the addition of the maximum impulse to dF, multiple-regression analysis explained 83% of the free-swimming performance. CONCLUSIONS: Assessing dF is a promising approach for evaluating a swimmer's performance. From the experiments, this new parameter showed that swimmers with higher dF also present higher dv, leading to a decrease in performance. PMID- 29283691 TI - Relationships Between the External and Internal Training Load in Professional Soccer: What Can We Learn From Machine Learning? AB - PURPOSE: Machine learning may contribute to understanding the relationship between the external load and internal load in professional soccer. Therefore, the relationship between external load indicators (ELIs) and the rating of perceived exertion (RPE) was examined using machine learning techniques on a group and individual level. METHODS: Training data were collected from 38 professional soccer players over 2 seasons. The external load was measured using global positioning system technology and accelerometry. The internal load was obtained using the RPE. Predictive models were constructed using 2 machine learning techniques, artificial neural networks and least absolute shrinkage and selection operator (LASSO) models, and 1 naive baseline method. The predictions were based on a large set of ELIs. Using each technique, 1 group model involving all players and 1 individual model for each player were constructed. These models' performance on predicting the reported RPE values for future training sessions was compared with the naive baseline's performance. RESULTS: Both the artificial neural network and LASSO models outperformed the baseline. In addition, the LASSO model made more accurate predictions for the RPE than did the artificial neural network model. Furthermore, decelerations were identified as important ELIs. Regardless of the applied machine learning technique, the group models resulted in equivalent or better predictions for the reported RPE values than the individual models. CONCLUSIONS: Machine learning techniques may have added value in predicting RPE for future sessions to optimize training design and evaluation. These techniques may also be used in conjunction with expert knowledge to select key ELIs for load monitoring. PMID- 29283693 TI - Anterograde Transport in Axons of the Retinal Ganglion Cells and its Relationship to the Intraocular Pressure during Aging in Mice with Hereditary Pigmentary Glaucoma. AB - PURPOSE: To establish a relationship between impairment of the anterograde axonal transport (AAT) in the axons of the retinal ganglion cells and the intraocular pressure (IOP) during aging in mice with hereditary glaucoma. METHODS: Quantitative in vivo approach based on manganese enhanced magnetic resonance imaging was developed in order to evaluate AAT in 3-, 6-, and 14-month old DBA/2J mice that develop age-dependent pigmentary glaucoma or age-matched C57Bl/6 mice that do not develop any retinal disease. Unilateral intravitreous administration of MnCl2 solution was followed 24 h later by MRI performed to obtain spin-lattice relaxation times (T1) for regions of interest encompassing the superior colliculi (SC) and the lateral geniculate nuclei (LGN). From the MRI scans, the estimates of Mn2+ concentrations in SC and LGN contralateral to the injection site, hence the efficiency of AAT in ON, were obtained. IOP and eye morphology was also monitored. RESULTS: In C57Bl/6 mice, AAT to SC was decreasing with age, 30% decrease was noted between 3 and 14 months. The decrease in axonal transport to LGN was less pronounced in this strain. In 3-month-old DBA/2J mice, axonal transport to SC was 30% lower than in 3-month-old C57Bl/6 mice but no significant decrease was noted in 6-month-old animals. However, a decrease of over 95% in axonal transport both to SC and LGN was noted in 14-month-old DBA/2J mice. DBA/2J mice exhibited a sharp increase in IOP at 6 months, which reversed at 14 months but displayed age-dependent elongation of the eyeball and deepening of the anterior chamber. CONCLUSION: Failure of AAT to SC of DBA/2J mice during development of pigmentary glaucoma does not follow closely changes in IOP and eye morphology. The relationship between IOP and AAT in optic nerve and tract is complex and may reflect preconditioning mechanism. PMID- 29283694 TI - In Vivo Study of the Long Term Structural Changes Induced by Macular Argon Laser. AB - PURPOSE: To assess the long-term structural changes induced by macular argon laser using en face optical coherence tomography (OCT). MATERIALS AND METHODS: We reviewed the charts and OCT pictures of patients who had undergone macular laser for diabetic macular edema at least four years ago. Clinical parameters were recorded for each eye, including laser settings. We obtained En face pictures, that were flattened at the RPE (retinal pigment epithelium) plane. We then measured the retinal surface covered by laser marks and the maximal diameter of the largest identified lesion at this plane. The most superficial level of neurosensory retinal damage as well as the total retinal thickness at this location were measured from the RPE. We also measured the distance between the RPE and the deeper plane at which laser marks were detected. RESULTS: 21 eyes of 16-patients were analyzed. The mean age (+/-SD) was 61.7 +/- 15.5 years. Patients had undergone macular laser 6.5 +/- 2.8 years prior to entering our study. In 16 eyes the most superficial laser marks were detected at the inner plexiform/inner nuclear layers. The level of neurosensory retinal damage was 159 +/- 48 microns over the RPE (62.6 +/- 18.3% of the retinal thickness). The deepest level at which laser marks were retrieved was 125 +/- 110 microns below the RPE. The growth of laser marks was correlated to time (Pearson's correlation coefficient = 0.23; p = 0.1). CONCLUSIONS: Argon laser marks gradually expand in the horizontal and vertical axes. The damage induced by argon laser in the neurosensory retina often reaches inner layers. PMID- 29283695 TI - Effect of the PreBind Engagement Process on Scrum Timing and Stability in the 2013-16 Six Nations. AB - This study examined whether changes in scrum engagement laws from the "crouch touch-set" in 2013 to the "PreBind" engagement from 2014 onward have led to changes in scrum characteristics, specifically timing, in international rugby union. Duration and outcomes were identified for all scrums occurring in the 2013 16 Six Nations (N = 60 games) using video analysis. Scrum duration increased after the introduction of the PreBind engagement from 59 s in 2013 to 69 s in 2016 (P = .024, effect size = 0.93). A significant increase in mean contact duration per scrum occurred when prebinding was adopted (P < .05), moving from 7.5 s under the crouch-touch-set process to 8.5, 10.0, and 10.8 s with PreBind in 2014, 2015, and 2016 (effect size = 0.71, 2.05, and 3.0, respectively). The number of scrum resets and collapsed scrums, along with early engagement and pulling down infringements, was lower under the PreBind process. Overall, the PreBind engagement resulted in longer scrums with significant increases observed in overall and contact durations, with improved stability-related characteristics. The longer contact time is a consequence of increased stability with a shift from high-energy impact to a sustained push phase with a lower force that is a benefit to player welfare. PMID- 29283698 TI - Transitions to Home Mechanical Ventilation: The Experiences of Canadian Ventilator-Assisted Adults and Their Family Caregivers. AB - RATIONALE: Several studies have explored the experience of ventilator-assisted individual (VAIs) living at home with family caregivers. However, few explore the experiences of these individuals as they transition from a hospital setting to living at home with a view to identifying modifiable processes that could optimize transition. OBJECTIVE: This descriptive, qualitative study sought to elucidate barriers to, and facilitators of, transition to home mechanical ventilation (HMV) from the perspective of Canadian VAIs and their family caregivers. METHODS: Participant recruitment occurred through hospital and community respiratory clinicians based in the four Canadian provinces of Alberta, British Columbia, Ontario, and Saskatchewan. Semi-structured telephone or face-to face interviews at home were undertaken with 33 individuals including 19 VAIs and 14 family caregivers between 3 to 24 months of transitioning to HMV. Interview data was analyzed using content analysis. RESULTS: Formal teaching of knowledge and skills relevant to HMV within the hospital setting prior to transition was perceived as having an immediate and enduring positive impact on transition. However, family-clinician conflict, information gaps, and persistent lack of trained personal support workers (PSWs) to provide care in the home contributed to maladjustment relating to transition. Participants strongly recommended improved transitional care in the form of respiratory health professional telephone support, home outreach, in addition to training of PSWs. CONCLUSION: Transition to HMV is a complex and demanding process. Extended HMV training and support may be helpful in mediating adjustment challenges thus reducing stress, caregiver burden and improving health related quality of life for VAIs and family caregivers. PMID- 29283696 TI - The Neuromuscular Determinants of Unilateral Jump Performance in Soccer Players Are Direction-Specific. AB - PURPOSE: To investigate differences in neuromuscular factors between elite and nonelite players and to establish which factors underpin direction-specific unilateral jump performance. METHODS: Elite (n = 23; age, 18.1 [1.0] y; body mass index, 23.1 [1.8] kg.m-2) and nonelite (n = 20; age, 22.3 [2.7] y; body mass index, 23.8 [1.8] kg.m-2) soccer players performed 3 unilateral countermovement jumps (CMJs) on a force platform in the vertical, horizontal-forward, and medial directions. Knee extension isometric maximum voluntary contraction torque was assessed using isokinetic dynamometry. Vastus lateralis fascicle length, angle of pennation, quadriceps femoris muscle volume (Mvol), and physiological cross sectional area (PCSA) were assessed using ultrasonography. Vastus lateralis activation was assessed using electromyography. RESULTS: Elite soccer players presented greater knee extensor isometric maximum voluntary contraction torque (365.7 [66.6] vs 320.1 [62.6] N.m; P = .045), Mvol (2853 [508] vs 2429 [232] cm3; P = .001), and PCSA (227 [42] vs 193 [25] cm2; P = .003) than nonelite. In both cohorts, unilateral vertical and unilateral medial CMJ performance correlated with Mvol and PCSA (r >= .310, P <= .043). In elite soccer players, unilateral vertical and unilateral medial CMJ performance correlated with upward phase vastus lateralis activation and angle of pennation (r >= .478, P <= .028). Unilateral horizontal-forward CMJ peak vertical power did not correlate with any measure of muscle size or activation but correlated inversely with angle of pennation (r = -.413, P = .037). CONCLUSIONS: While larger and stronger quadriceps differentiated elite from nonelite players, relationships between neuromuscular factors and unilateral jump performance were shown to be direction specific. These findings support a notion that improving direction-specific muscular power in soccer requires improving a distinct neuromuscular profile. PMID- 29283700 TI - Relapsing Polychondritis Is a Lung Disease: My Story. PMID- 29283699 TI - Physician-Level Variation in Outcomes of Mechanically Ventilated Patients. AB - RATIONALE: Physicians are increasingly being held accountable for patient outcomes, yet their specific contribution to the outcomes remains uncertain. OBJECTIVES: To determine variation in outcomes of mechanically ventilated patients among intensivists, as well as associations between intensivist experience and patient outcomes. METHODS: We performed a retrospective cohort study of mechanically ventilated Medicare fee-for-service patients in acute care hospitals in Pennsylvania using administrative, clinical, and physician data from Centers for Medicare and Medicaid Services and the American Medical Association from 2008 and 2009. We identified intensivists by training background, board certification, and claims for services provided to patients admitted to an intensive care unit. We assigned patients to intensivists for outcome attribution based on submitted claims for critical care and in-patient services. We estimated the physician-specific adjusted odds ratios (ORs) for 30-day mortality using a hierarchical model with a random effect for physician, adjusted for patient and hospital characteristics. We tested for independent association of physician experience with patient outcomes using mixed-effects regression for the primary outcome of 30-day mortality. We defined physician experience in two ways: years since training completion ("duration") and annual number of mechanically ventilated patients ("volume"). RESULTS: We assigned 345 physicians to 11,268 patients. The 30-day mortality was 43% and median hospital length of stay was 11 days (interquartile range = 6-18). The physician adjusted OR varied from 0.72 to 1.64 (median = 0.99; interquartile range = 0.92-1.09). A total of 48% of physicians was outliers, with an adjusted OR significantly different from 1. However, among intensivists, physician experience was not associated with 30-day mortality (duration OR = 1.00 per additional year; 95% confidence interval = 1.00 1.01; volume OR = 1.00 per additional patient; 95% confidence interval = 1.00 1.00). CONCLUSIONS: Intensivists independently contribute to outcomes of Medicare patients who undergo mechanical ventilation, as evidenced by the variation in risk-adjusted mortality across intensivists. However, physician experience does not underlie this relationship between intensivists, suggesting the need to identify modifiable physician factors to improve outcomes. PMID- 29283701 TI - An Investigation of Factors that Influence Hygiene Practices at a Small Day Care Center. AB - The aim of this study was to explore factors that influence hygiene practices at small day care centers. It examines the effect of food hygiene training on hygiene practices and investigates the correlations between the hygienic status of food handlers' hands and that of kitchen utensils. Furthermore, it determines the influences of demographic and facility-related factors on hygiene practices in small day care centers. A total of 56 food handlers at 49 day care centers in the Gyeongnam area of South Korea participated in hygiene training. The results of the study showed that after two training sessions, the ATP bioluminescence levels of knives ( P < 0.01), cutting boards ( P < 0.01), food handlers' hands ( P < 0.001), and UV disinfection cabinets ( P < 0.01) decreased. After training, the total scores on the inspection checklist were significantly improved ( P < 0.05). Strong associations between the microbial quality of hands and kitchen utensils were seen. Classification and regression tree analysis identified important factors that influence hygiene practices at small food service kitchens, such as status of registration with the government certification authority, length of food handlers' working experience and their age, and maximum number of people served. This study helps to broaden our knowledge of food hygiene issues in small day care centers. PMID- 29283702 TI - Survival of Salmonella and Escherichia coli in Two Different Soil Types at Various Moisture Levels and Temperatures. AB - With the increased consumption of fresh produce, a proportional increase in numbers of produce-related foodborne illness has been observed. An estimate of foodborne illness during 1998 to 2008 attributed ~46% of the incidences to produce. Any foodborne illness associated with produce can have devastating consequences to the industry. The most recent data from the Centers for Disease Control and Prevention implicate leafy vegetables, vine-stalk vegetables, root vegetables, and sprouts as the most common cause of produce-related foodborne outbreaks. Excess rainfall or flooding, mainly by altering levels of soil moisture and oxygen content, affects the microbial community in soil. The goal of this research was to determine the survivability of a three-serovar Escherichia coli and a five-serovar Salmonella enterica cocktail in microcosms prepared with Candler sand (CS) and Orangeburg sandy loam (OSL) soils. Microcosms were prepared with low, medium, and high volumetric water contents and were incubated at 20 and 30 degrees C. Serotyping was used to determine which E. coli or Salmonella serovar(s) from each cocktail persisted. Microcosm inoculation levels were ~7.0 log CFU/g. Sampling for CS and OSL microcosms incubated at 20 degrees C ended on day 364 and 357, respectively. The reduction of Salmonella and E. coli to below the limit of detection (extinction) in CS microcosms (incubated at 30 degrees C at all volumetric water content [VWC] levels) was reached on day 168 and 56, respectively. Extinction of Salmonella and E. coli in OSL microcosms (incubated at 30 degrees C at all VWCs) was reached on day 168 and 224, respectively. Of the Salmonella and E. coli serovars analyzed, Salmonella Javiana persisted the longest in both soil types, whereas E. coli O104:H4 and E. coli O145 persisted the longest in CS and OSL microcosms, respectively. Results from the current study suggest that soil type and temperature influenced pathogen persistence in CS and OSL soils more than moisture level and pathogen type. PMID- 29283703 TI - Growth of Yersinia pseudotuberculosis Strains at Different Temperatures, pH Values, and NaCl and Ethanol Concentrations. AB - Maximum growth temperature and growth limits in Luria-Bertani broth at different pH values and NaCl and ethanol concentrations were determined for 49 Yersinia pseudotuberculosis strains representing serotypes O:1, O:2, O:3, O:4, and O:5. In addition, the ability of the strains to grow at 0 degrees C and the growth parameters at 1 degrees C were determined. The maximum growth temperatures measured by Gradiplate temperature incubator varied between 42.2 and 43.7 degrees C. All strains were able to grow at 0 degrees C in Luria-Bertani broth within 17 days of incubation. At 1 degrees C, differences were observed among strains in the maximum growth rates and area under the curve values based on optical density data, which suggests that some Y. pseudotuberculosis strains adapt faster to colder conditions. The mean maximum growth rates and area under the curve values at 1 degrees C, as well as the mean maximum growth temperatures, were statistically significantly higher among serotype O:1 strains compared with O:3 strains and among biotype 1 compared with biotype 2 strains. All strains grew at pH 4.5, whereas none of the strains were able to grow at pH 4.2. The highest pH at which growth was observed varied between 9.0 and 9.3. For 14 strains the maximum NaCl concentration at which growth was observed was 4.8%, whereas 35 of the strains were able to grow at 5.0% NaCl. None of the strains showed growth at 5.2% NaCl. All strains were able to grow at 4.5% ethanol concentration (v/v), whereas 5.0% ethanol concentration was completely inhibitory to all strains. The observed limited physiological diversity among various Y. pseudotuberculosis strains may stem from the genetic homogeneity of the species. PMID- 29283706 TI - Athlete's Foot. PMID- 29283704 TI - Reliability, Validity, and Sensitivity of a Novel Smartphone-Based Eccentric Hamstring Strength Test in Professional Football Players. AB - PURPOSE: To evaluate the test-retest reliability, sensitivity, and concurrent validity of a smartphone-based method for assessing eccentric hamstring strength among male professional football players. METHODS: A total of 25 healthy male professional football players performed the Chinese University of Hong Kong (CUHK) Nordic break-point test, hamstring fatigue protocol, and isokinetic hamstring strength test. The CUHK Nordic break-point test is based on a Nordic hamstring exercise. The Nordic break-point angle was defined as the maximum point where the participant could no longer support the weight of his body against gravity. The criterion for the sensitivity test was the presprinting and postsprinting difference of the Nordic break-point angle with a hamstring fatigue protocol. The hamstring fatigue protocol consists of 12 repetitions of the 30-m sprint with 30-s recoveries between sprints. Hamstring peak torque of the isokinetic hamstring strength test was used as the criterion for validity. RESULTS: A high test-retest reliability (intraclass correlation coefficient = .94; 95% confidence interval, .82-.98) was found in the Nordic break-point angle measurements. The Nordic break-point angle significantly correlated with isokinetic hamstring peak torques at eccentric action of 30 degrees /s (r = .88, r2 = .77, P < .001). The minimal detectable difference was 8.03 degrees . The sensitivity of the measure was good enough that a significance difference (effect size = 0.70, P < .001) was found between presprinting and postsprinting values. CONCLUSION: The CUHK Nordic break-point test is a simple, portable, quick smartphone-based method to provide reliable and accurate eccentric hamstring strength measures among male professional football players. PMID- 29283705 TI - Asthmonia: A clinical definition of a commonly used colloquial term. AB - OBJECTIVE: To describe the clinical characteristics of pediatric asthmonia, a syndrome in which children have both an acute asthma exacerbation and a concomitant diagnosis of community acquired pneumonia. METHODS: A retrospective chart review was conducted on children admitted to Connecticut Children's Medical Center in the pediatric emergency department from January 1, 2012 to December 31, 2012. Children with asthma and pneumonia were identified using ICD-9 codes 493 (asthma) or 482 (pneumonia). In this study, we defined asthmonia, a third group, based on the following criteria: (1) history of asthma based on documentation in the past medical history section of the chart, (2) documented wheezing on presentation, (3) administration of bronchodilator(s), and (4) new focal infiltrate on chest radiograph during ED visit. The three nonoverlapping groups (asthma, pneumonia, and asthmonia) were described. RESULTS: Three hundred and sixty-eight children were identified for our study population. In the study population, 66.0% (N = 243) had asthma, 20.4% (N = 75) pneumonia, and 13.6% (N = 50) met our definition of asthmonia. We found that 84.0% (N = 42) of children who met asthmonia criteria in our study were treated with antibiotic therapies. Also, 28.0% (N = 14) of children who met asthmonia criteria had documented fever during admission or by parent report. CONCLUSIONS: This study defined clinical features of the coexistence of pneumonia in children with asthma. Overall, these children frequently presented with fever and were treated with antibiotics. More studies are needed to better elucidate this clinical entity and its ramifications. PMID- 29283707 TI - Scanning Sports. PMID- 29283708 TI - Pearls. PMID- 29283709 TI - Take the Sting Out of Stress. PMID- 29283710 TI - Managing Ear Trauma. AB - In brief Sports in which the ear may sustain blows or experience changes in ambient pressure can pose dangers to the ear. Possible injuries include "cauliflower ear"- classic to wrestlers- auricular lacerations, auricular avulsions, and barotrauma. Prompt treatment can preserve ear structure and function. Properly protecting the ear is the best defense against trauma. PMID- 29283711 TI - Stopping Skin Assailants: Fungi, Yeasts, and Viruses. AB - In brief Activity can cause or exacerbate certain skin conditions. Sweaty skin is a warm, moist environment for fungi and yeasts, and sports participation may transmit or worsen a viral condition such as herpes simplex. Specialized medication regimens and topical treatments can sometimes prevent a flare-up or minimize activity interruptions. PMID- 29283712 TI - QuikQuiz. PMID- 29283714 TI - Vague Upper-Extremity Symptoms? AB - In brief Thoracic outlet syndrome is a brief commonly missed cause of upper extremity pain and musculoskeletal symptoms. Understanding the anatomy of the cervicoaxillary canal and proximal limb, etiology of the syndrome, evaluation of clinical symptoms, and differential diagnosis of thoracic outlet pain can lead to proper rehabilitation of the disorder. PMID- 29283713 TI - Forum. PMID- 29283715 TI - Could You Cover the Olympics? PMID- 29283716 TI - Stress: How to Help Patients Cope. AB - Stress plays a significant role in more than half of the complaints that bring patients to a physician's office. Stress can overlap and interact with many physical illnesses, making both overdiagnosis and underdiagnosis dangers. A few well-targeted questions and an appropriate workup can often clarify whether stress is involved. And some simple interventions, such as prescribing exercise and offering patients the handout on page 71, will put most patients on the road to healthier coping. PMID- 29283718 TI - Hip and Pelvis Avulsion Fractures in Adolescents. AB - In brief Avulsion fractures at the seven Pelvis and hip apophyses may occur more often than reported. Because radiographs are often not obtained, these injuries may commonly be dismissed as sprains and strains. With rare exceptions, avulsion fractures can be treated conservatively- much, in fact, like a sprain or strain. However, because a 'fracture' is involved, an accurate diagnosis generally helps ensure compliance, avoiding the possibility of nonunion or malunion. PMID- 29283717 TI - Jumping on the 'Bran Wagon'. PMID- 29283719 TI - Instituting the Updated CPR Protocol. AB - In brief Because the team physician may be called on to provide basic life support for athletes or spectators, knowing the latest CPR protocol is essential in developing an emergency response plan and training personnel. Practice with removing protective equipment and performing cardiopulmonary resuscitation on a mannequin can be helpful. PMID- 29283722 TI - In the Middle of the Bell Curve. PMID- 29283723 TI - Practice Guidelines. PMID- 29283725 TI - What to Do When You're Eating for Two. PMID- 29283724 TI - Practice Guidelines Take Center Court. AB - In brief An unintended result of practice brief guidelines, meant to codify and streamline high-quality patient care, is their role in the courtroom: to attack or to defend the delivery of medical care to athletes. Researchers predict that patients' attorneys will make greater use of practice guidelines in malpractice claims. The best tactic sports medicine physicians can use to prevent claims is to become familiar with and adopt applicable practice guidelines. Also, physicians need to know when they're deviating from the guidelines and how to defend such decisions. PMID- 29283726 TI - CME Self Test. PMID- 29283728 TI - Pectoralis Major Rupture. AB - In brief Rupture of the pectoralis major brief muscle and tendon, which occurs most frequently among weight lifters but has been reported in many sports, can most often be diagnosed based on the history and physical exam. Surgical intervention for complete ruptures has a clear advantage over conservative therapy. Athletes of all levels can be expected to return to near preinjury levels of participation following surgery and a well-constructed, supervised rehabilitation program. This should involve immobilization followed by range- of motion exercises and strength training of gradually increasing resistance. PMID- 29283730 TI - Giving Injuries the Cold Treatment. PMID- 29283729 TI - Pearls. PMID- 29283731 TI - Sports Medicine Fellowships for Physicians. PMID- 29283732 TI - Seroprevalence and Manifestations of Ocular Toxoplasmosis in Patients with Schizophrenia. AB - PURPOSE: Recent studies have linked infectious agents such as Toxoplasma gondii to schizophrenia. We investigated the seroprevalence of T. gondii and conducted ophthalmologic examinations in schizophrenia patients and controls to identify lesions suggestive of ocular toxoplasmosis. METHODS: During 2015 and 2016, 34 schizophrenia patients and 85 healthy controls underwent ophthalmologic examination and anti-T. gondii IgG and IgM antibody measurements by chemiluminescence. RESULTS: Schizophrenia patients had a higher prevalence of anti-T. gondii IgG positivity than controls (91.18% [95% confidence interval (CI), 77.04%-96.95%] vs. 70.59% [95% CI, 60.18%-79.21%]; p = 0.017). Anti-T. gondii IgM antibodies (acute form) were not detected in any patient. One (3%) schizophrenic patient and two (2.4%) control patients presented fundoscopic scarring. CONCLUSION: The seropositivity rate was significantly higher among schizophrenia patients than among controls (p = 0.017). There was no association between the presence of fundoscopic scarring and schizophrenia (p = 1.000). PMID- 29283733 TI - The Quantification of Within-Week Session Intensity, Duration, and Intensity Distribution Across a Season in Australian Football Using the Session Rating of Perceived Exertion Method. AB - CONTEXT: Team-sport training requires the daily manipulation of intensity, duration, and frequency, with preseason training focusing on meeting the demands of in-season competition and training on maintaining fitness. PURPOSE: To provide information about daily training in Australian football (AF), this study aimed to quantify session intensity, duration, and intensity distribution across different stages of an entire season. METHODS: Intensity (session ratings of perceived exertion; CR-10 scale) and duration were collected from 45 professional male AF players for every training session and game. Each session's rating of perceived exertion was categorized into a corresponding intensity zone, low (<4.0 arbitrary units), moderate (>=4.0 and <7.0), and high (>=7.0), to categorize session intensity. Linear mixed models were constructed to estimate session duration, intensity, and distribution between the 3 preseason and 4 in-season periods. Effects were assessed using linear mixed models and magnitude-based inferences. RESULTS: The distribution of the mean session intensity across the season was 29% low intensity, 57% moderate intensity, and 14% high intensity. While 96% of games were high intensity, 44% and 49% of skills training sessions were low intensity and moderate intensity, respectively. Running had the highest proportion of high intensity training sessions (27%). Preseason displayed higher training-session intensity (effect size [ES] = 0.29-0.91) and duration (ES = 0.33-1.44), while in season game intensity (ES = 0.31-0.51) and duration (ES = 0.51-0.82) were higher. CONCLUSIONS: By using a cost-effective monitoring tool, this study provides information about the intensity, duration, and intensity distribution of all training types across different phases of a season, thus allowing a greater understanding of the training and competition demands of Australian footballers. PMID- 29283734 TI - Pearls. PMID- 29283735 TI - Musculoskeletal Medicine. PMID- 29283736 TI - Foot Odor. PMID- 29283737 TI - Contraindications to Athletic Participation. AB - In brief Sports activities promote health and fitness for most participants, but for some, activity can complicate an illness or even be fatal. This article, the first of a two- part series on contraindications to activity, examines the cardiac, respiratory, and central nervous system conditions that warrant activity disqualification and provides guidelines about when it's safe for patients to participate. PMID- 29283738 TI - Immediate Management of Epistaxis. AB - In brief Epistaxis typically originates from the nasal septum when the nasal mucosa overlying a dilated blood vessel is injured. Epistaxis may, however, signal an underlying condition such as a coagulation disorder, so the treating physician must be alert for signs of serious illness. Most nosebleeds stop spontaneously within 5 minutes with or without pressure to the forehead, nose, or upper lip. Some require anterior nasal packing. A few arise from posterior arteries and require anterior-posterior nasal packing and a referral. PMID- 29283742 TI - CME Self Test. PMID- 29283741 TI - Hamstring Strains. AB - In brief Strains to the hamstring muscle group are prevalent and, unfortunately, often recurrent, with prolonged rehabilitation and persistent disability. Most hamstring injuries are of a single muscle near the muscle-tendon junction. Rarely, the hamstring muscle group may avulse from the ischial tuberosity. The diagnosis can usually be made by history and physical exam, but MRI can be used to help pinpoint the extent and location of the injury. Initial treatment typically consists of rest, ice, compression, elevation, and pain relief. There is no consensus on optimal rehabilitation, but functional exercises with stretching and strengthening have been emphasized. PMID- 29283743 TI - Neuroretinitis Secondary to Bartonella Henselae in a Patient with Myelinated Retinal Nerve Fibers: Diagnostic Dilemmas and Treatment. AB - PURPOSE: To report an unusual case of Bartonella henselae neuroretinitis (BHNR) in a patient with myelinated retinal nerve fibers (MRNFs). METHODS: A 56-year-old male presented for a consultation, because of a decrease in visual acuity from his right eye. Onset was unclear and the patient was not sure if this was a new symptom. RESULTS: Fundoscopy revealed MRNF without any other clinical findings. After 2 weeks, the patient returned complaining of further visual acuity decrease. Fundoscopy disclosed macular star formation. The patient was treated with azithromycin. The visual acuity deteriorated to 20/400 and we added systemic corticosteroids with slight improvement of the visual fields but minimal visual gain to 20/160. Serology test results were positive for BH (IgG titers>1/256). CONCLUSIONS: Co-existence of BHNR and MRNF can create diagnostic dilemmas. The presence of myelinated nerve sheath in combination with the expected swelling in neuroretinitis may have caused an irreversible mechanical nerve damage. PMID- 29283744 TI - Core Temperature Responses to Cold-Water Immersion Recovery: A Pooled-Data Analysis. AB - PURPOSE: To examine the effect of postexercise cold-water immersion (CWI) protocols, compared with control (CON), on the magnitude and time course of core temperature (Tc) responses. METHODS: Pooled-data analyses were used to examine the Tc responses of 157 subjects from previous postexercise CWI trials in the authors' laboratories. CWI protocols varied with different combinations of temperature, duration, immersion depth, and mode (continuous vs intermittent). Tc was examined as a double difference (DeltaDeltaTc), calculated as the change in Tc in CWI condition minus the corresponding change in CON. The effect of CWI on DeltaDeltaTc was assessed using separate linear mixed models across 2 time components (component 1, immersion; component 2, postintervention). RESULTS: Intermittent CWI resulted in a mean decrease in DeltaDeltaTc that was 0.25 degrees C (0.10 degrees C) (estimate [SE]) greater than continuous CWI during the immersion component (P = .02). There was a significant effect of CWI temperature during the immersion component (P = .05), where reductions in water temperature of 1 degrees C resulted in decreases in DeltaDeltaTc of 0.03 degrees C (0.01 degrees C). Similarly, the effect of CWI duration was significant during the immersion component (P = .01), where every 1 min of immersion resulted in a decrease in DeltaDeltaTc of 0.02 degrees C (0.01 degrees C). The peak difference in Tc between the CWI and CON interventions during the postimmersion component occurred at 60 min postintervention. CONCLUSIONS: Variations in CWI mode, duration, and temperature may have a significant effect on the extent of change in Tc. Careful consideration should be given to determine the optimal amount of core cooling before deciding which combination of protocol factors to prescribe. PMID- 29283746 TI - "Shall We Dance?" Older Adults' Perspectives on the Feasibility of a Dance Intervention for Cognitive Function. AB - We explored perceptions of social dance as a possible intervention to improve cognitive function in older adults with subjective memory complaints. A total of 30 participants (19 females; mean age = 72.6 years; SD = 8.2) took part in the study. This included 21 participants who had self-reported subjective memory complaints and nine spouses who noticed spousal memory loss. Semistructured interviews were conducted, and a thematic analysis was used to analyze the data. Three main themes were constructed: (a) dance seen as a means of promoting social interaction; (b) chronic illness as a barrier and facilitator to participation; and (c) social dance representing nostalgic connections to the past. Overall, the participants were positive about the potential attractiveness of social dance to improve cognitive and social functioning and other aspects of health. In future research, it is important to examine the feasibility of a social dance intervention among older adults with subjective memory complaints. PMID- 29283745 TI - Polymerase Chain Reaction and Goldmann-Witmer Coefficient Testing in the Diagnosis of Infectious Uveitis in HIV-positive and HIV-negative Patients in South Africa. AB - PURPOSE: To use polymerase chain reaction (PCR) and Goldmann-Witmer coefficient (GWC) calculation to diagnose infectious uveitis. METHODS: Prospective cross sectional study. RESULTS: Twenty-seven of 106 patients had positive PCR and/or GWC results on aqueous humor (AH) sampling and 15 of 27 (55.6%) were HIV positive. Patients with non-anterior uveitis (NAU) were more likely to be HIV+ (p = 0.005). More than 1 possible pathogen was identified in 9 of 27 patients of whom 7 were HIV+. The final clinical diagnosis was discordant with AH findings in 9 of 27 cases. A positive EBV PCR result was associated with a discordant diagnosis (p = 0.001). All cases of herpetic anterior uveitis (42.9% HIV+) tested PCR-/GWC+ while all cases of herpetic NAU tested PCR+/GWC- (83.3% HIV+). All rubella virus cases were PCR+/GWC+. CONCLUSION: PCR is useful to diagnose herpetic NAU in HIV+ patients while GWC is useful to diagnose herpetic anterior uveitis. PMID- 29283747 TI - Dietary and Physical Activity Outcomes Determine Energy Balance in U.S. Adults Aged 50-74 Years. AB - This study identified which energy expenditure (EE) and dietary intake outcomes determine EE from doubly-labeled water (DLW) in U.S. older adults (n = 681; 45.9% male; mean age 63.2). A secondary data analysis using baseline data from The Interactive Diet and Activity Tracking in AARP (IDATA) study was conducted. Stepwise linear regressions identified predictor outcomes of EE from DLW within sexes. Outcomes included data from ActiGraph accelerometers, Community Healthy Activities Model Program for Seniors (CHAMPS) self-report activity questionnaire, Automated Self-Administered 24-hour dietary recall, Dietary History Questionnaire II (DHQ II), and resting EE. Energy expenditure by ActiGraph in males predicted EE from DLW (R2 = 0.33, p < .001). EE from ActiGraph and total dietary fiber from DHQ II predicted EE from DLW in females (R2 = 0.44, p < .001). The CHAMPS closely matched EE from DLW when considering resting EE. These findings can be used to assess energy balance in a non-invasive manner in older adults. PMID- 29283748 TI - Femoral Neck Stress in Older Adults During Stair Ascent and Descent. AB - A detailed understanding of the hip loading environment is needed to help prevent hip fractures, minimize hip pain, rehabilitate hip injuries, and design osteogenic exercises for the hip. The purpose of this study was to compare femoral neck stress during stair ascent and descent and to identify the contribution of muscles and reaction forces to the stress environment in mature adult subjects (n = 17; age: 50-65 y). Motion analysis and inverse dynamics were combined with musculoskeletal modeling and optimization, then used as input to an elliptical femoral neck cross-sectional model to estimate femoral neck stress. Peak stress values at the 2 peaks of the bimodal stress curves (stress vs time plot) were compared between stair ascent and descent. Stair ascent had greater compressive stress than descent during the first peak at the anterior (ascent: 18.0 [7.9] MPa, descent: -12.9 [5.4] MPa, P < .001) and posterior (ascent: -34.4 [10.9] MPa, descent: -27.8 [10.1] MPa, P < .001) aspects of the femoral neck cross section. Stair descent had greater tensile stress during both peaks at the superior aspect (ascent: 1.3 [7.0] MPa, descent: 24.8 [9.7] MPa, peak 1: P < .001; ascent: 15.7 [6.1] MPa, descent: 18.0 [8.4] MPa, peak 2: P = .03) and greater compressive stress during the second peak at the inferior aspect (ascent: -43.8 [9.7] MPa, descent: -51.1 [14.3] MPa, P = .004). Understanding this information can provide a more comprehensive view of bone loading at the femoral neck for older population. PMID- 29283749 TI - Reply to R. Obeid et al. PMID- 29283750 TI - Evidence for Implicit-But Not Unconscious-Processing of Object-Scene Relations. AB - Is consciousness necessary for integration? Findings of seemingly high-level object-scene integration in the absence of awareness have challenged major theories in the field and attracted considerable scientific interest. Lately, one of these findings has been questioned because of a failure to replicate, yet the other finding was still uncontested. Here, we show that this latter finding slowed-down performance on a visible target following a masked prime scene that includes an incongruent object-is also not reproducible. Using Bayesian statistics, we found evidence against unconscious integration of objects and scenes. Put differently, at the moment, there is no compelling evidence for object-scene congruency processing in the absence of awareness. Intriguingly, however, our results do suggest that consciously experienced yet briefly presented incongruent scenes take longer to process, even when subjects do not explicitly detect their incongruency. PMID- 29283751 TI - Good Choice, Bad Judgment: How Choice Under Uncertainty Generates Overoptimism. AB - We examine a fundamental feature of choice under uncertainty: Overestimating an alternative makes one more likely to choose it. If people are naive to this structural feature, then they will tend to have erroneously inflated expectations for the alternatives they choose. In contrast to theories of motivated reasoning, this theory suggests that individuals will overestimate chosen alternatives even before they make their choice. In four studies, we found that students and managers exhibited behavior consistent with naivete toward this relationship between estimation error and choice, leaving them overoptimistic about their chosen alternatives. This overoptimism from choosing positive error is exacerbated when the true values of the alternatives are close together, when there is more uncertainty about the values of alternatives, and when there are many alternatives to choose from. Our results illustrate how readily overoptimism emerges as a result of statistical naivete, even in the absence of a desire to justify one's decision after the choice. PMID- 29283752 TI - New Agent May Help in Soft Tissue Therapy. PMID- 29283754 TI - Round Table: Guidelines to Help You in Giving On-Field Care. PMID- 29283753 TI - Put Pressure on for Quicker Recovery. PMID- 29283755 TI - Tell Me, Doctor. PMID- 29283756 TI - Revisiting a Vanished Breed: Football's Doctor Coaches. PMID- 29283757 TI - Blistering the Track - and Drivers - in Stock Racing. PMID- 29283758 TI - winners and losers. PMID- 29283759 TI - If Sports Medicine Is Your Bag - Equip It Well. PMID- 29283760 TI - Stopping Spear Tackling-Will the Challenge Be Met? PMID- 29283762 TI - Is Spear Tackling 'Safe and Effective' - or 'Abusive and Illogical'? PMID- 29283761 TI - letters. PMID- 29283763 TI - gameplan. PMID- 29283764 TI - Taking a Whack at Table Tennis. PMID- 29283765 TI - Running: How Far, How Fast? PMID- 29283766 TI - You Think Hockey Is Rough? Take a Look at Box Lacrosse! PMID- 29283767 TI - scanning sports. PMID- 29283768 TI - Can We Stop Spearing? PMID- 29283769 TI - sportspages. PMID- 29283770 TI - Teaching a New 'Love' in Tennis. PMID- 29283771 TI - Adolescence Strikes Twice. PMID- 29283772 TI - Effects of Alcohol: Dehydration or Overhydration? PMID- 29283773 TI - scanning sports. PMID- 29283774 TI - brief reports. PMID- 29283775 TI - Tennis Is Its Own Fitness Program, Pro Says. PMID- 29283776 TI - letters. PMID- 29283778 TI - editor's notes. PMID- 29283779 TI - The Search for Strength. PMID- 29283780 TI - Is Sportsmedicine a Specialty? PMID- 29283781 TI - Advantages of a Simple Treadmill Exercise Program. AB - Every physician knows the frustration of trying to get patients into a running program for exercise; the treadmill can be an effective alternative program. PMID- 29283782 TI - Reducing Risks in Hockey: Analysis of Equipment and Injuries. AB - An understanding of the types of impacts and how they occur can lead to better equipment design and reduced risks in ice hockey. The author analyzes the data and offers specific suggestions for improved equipment. PMID- 29283783 TI - Medical Problems of a Professional Hockey Team: A Three-Season Experience. AB - Over a three-season period, a Southern Hockey League team sustained 233 injuries, ranging from spinal and skull fractures to lacerations and abrasions. The authors outline measures to help prevent these injuries. PMID- 29283785 TI - The Effects of Training on the Aging Process. PMID- 29283784 TI - Exercise for a Lifetime: An Educational Effort. AB - A new approach on learning to live healthy is being enthusiastically received in colleges-and offers lessons that family physicians can pass on to all their patients. PMID- 29283786 TI - Comparison of Efficacy and Safety of Loteprednol Etabonate 0.5% and Topical Dexamethasone 1% in Post-Vitrectomy Inflammation. AB - PURPOSE: To compare the efficacy and safety of postoperative topical loteprednol etabonate (LE) 0.5% with dexamethasone (DEX) 0.1% for the treatment of inflammation following pars plana vitrectomy (PPV). METHODS: A total of 150 eyes of 150 patients who underwent transconjunctival PPV for various diagnoses were included in this prospective, randomized study. The patients were assigned into two groups as Group LE (n = 75) and Group DEX (n = 75). Intraocular inflammation, intraocular pressure (IOP), and the intensity of postoperative pain were compared between the groups. RESULTS: The mean IOP was higher in the patients treated with DEX (p > 0.05). The need for anti-glaucoma medications was significantly lower in Group LE (5.3%) than in Group DEX (17.3%) (p = 0.020). Tyndall scores were less in Group DEX at postoperative Days 1 (p = 0.01) and 3 (p = 0.017). On Day 1, it was more likely for patients to have mild or moderate pain in Group LE (p < 0.001). On Day 3, the number of the patients with no pain was higher in Group DEX (p = 0.005). CONCLUSIONS: Although DEX is more effective in the early postoperative days, LE appears to be as effective in controlling inflammatory response following PPV in the long-term. Topical LE is associated with less increase in the IOP and a lower need for anti-glaucoma medications. PMID- 29283787 TI - In Response to Laovirojjanakul W, Acharya N and Gonzales JA's "Ultra-Widefield Fluorescein Angiography in Intermediate Uveitis". AB - We read with great interest the article by Laovirojjanakul et al. on ultra widefield fluorescein angiography in intermediate uveitis. We would like to share a similar case of chronic intermediate uveitis highlighting a fern-like pattern of diffuse vascular leakage on fluorescein angiography, with good visual acuity, absence of clinically active inflammation, and a similar fluorescein angiography picture over a follow-up of 4 years. PMID- 29283788 TI - Investigating the disease association of USH2A p.C759F variant by leveraging large retinitis pigmentosa cohort data. PMID- 29283789 TI - Corrigendum: Free Will and Punishment: A Mechanistic View of Human Nature Reduces Retribution. AB - Original article: Shariff, A. F., Greene, J. D., Karremans, J. C., Luguri, J. B., Clark, C. J., Schooler, J. W., . . . Vohs, K. D. (2014). Free will and punishment: A mechanistic view of human nature reduces retribution. Psychological Science, 25, 1563-1570. doi:10.1177/0956797614534693. PMID- 29283790 TI - Smoking, B Vitamins, and Lung Cancer: The Chicken or the Egg Causality Dilemma. PMID- 29283791 TI - Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. AB - Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for >= 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of >= 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation. PMID- 29283793 TI - Physical Activity Preferences Among Older Adults: A Systematic Review. AB - The objective of this study was to identify preferences for physical activity among adults aged 65 years and over. A systematic review was conducted. A search strategy without language and date restriction (up until March 31, 2017) was developed for PubMed, CINAHL, PsycINFO, ERIC, and SPORTDiscus. Study selection and data extraction were performed independently by two reviewers. A total of 21 independent primary studies were included in the systematic review. Irrespective of the methodologies used and samples, a majority of older adults prefer to walk and engage in physical activity continuously for about 30 min. These findings are mainly generalizable to White females from the United States. Two-thirds of the studies were at high risk of selection bias, which suggests additional caution when interpreting the review findings. Nonetheless, policymakers, community organizations, and healthcare providers should consider walkability in their efforts to promote physical activity in older adults. PMID- 29283792 TI - Weight Loss Strategies in Combat Sports and Concerning Habits in Mixed Martial Arts. AB - CONTEXT: Combat sports are typically divided into weight classes, and body-mass manipulation to reach a weight class is commonplace. Previous research suggests that weight loss practices in mixed martial arts (MMA) may be more extreme than in other combat sports. PURPOSE: To investigate the magnitude of weight loss and the prevalence of weight loss strategies in different combat sports. METHODS: Competitors (N = 637) from Brazilian jiu-jitsu, boxing, judo, MMA, Muay Thai/kickboxing, taekwondo, and wrestling completed an online questionnaire seeking information regarding their weight loss practices. RESULTS: Body-mass manipulation was commonly undertaken by all combat-sport athletes, with a particularly high incidence of gradual dieting, increased exercise, and fluid restriction. Skipping meals was higher in taekwondo and wrestling (84%) compared with the other combat sports (~58%), whereas training in heated rooms and forced oral fluid loss (spitting) was higher in wrestling (83% and 47%, respectively) compared with other combat sports (~45% and ~19%, respectively). MMA athletes reported the highest usage of sauna (76%) and water loading (67%) while also reporting the second-highest use of training in rubber/plastic suits (63%). CONCLUSIONS: Body-mass manipulation was present in all combat sports, with the prevalence and magnitude of acute weight loss greater in MMA. The incidence of and practices reported will help support staff be fully aware of the variety of methods these athletes and coaches may use to achieve weight loss. Additionally, the results could aid regulatory bodies in the further development of policies on weight cutting. PMID- 29283794 TI - Position Sense Dysfunction Affects Proximal and Distal Arm Joints in Children with Developmental Coordination Disorder. AB - It is unclear, whether proprioceptive dysfunction in developmental coordination disorder (DCD) is localized affecting only specific joints or whether it is generalized affecting proximal and distal joints. Thus, this study assessed position sense acuity at the elbow and wrist in twenty children with DCD (age: 9 11 yrs.) using a joint position matching paradigm. Position sense bias (systematic error) at either joint was not significantly higher in DCD children when compared to typically developing children (TD). However, DCD children exhibited significantly lower position sense precision (random error) than TD children at both elbow and wrist. That is, response reliability to proprioceptive stimuli is altered in DCD. Our findings are consistent with a view that proprioceptive dysfunction in DCD is generalized in nature. PMID- 29283797 TI - Measuring Sleep in Vulnerable Older Adults: A Comparison of Subjective and Objective Sleep Measures. AB - OBJECTIVES: This study compared subjective (questionnaire) and objective (actigraphy) sleep assessments, and examined agreement between these methods, in vulnerable older adults participating in a Veterans Administration Adult Day Health Care (ADHC) program. METHODS: 59 ADHC participants (95% male, mean age = 78 years) completed sleep questionnaires and 72 continuous hours of wrist actigraphy. Linear regression was used to examine agreement between methods and explore discrepancies in subjective/objective measures. RESULTS: Disturbed sleep was common, yet there was no agreement between subjective and objective sleep assessment methods. Compared with objective measures, one-half of participants reported worse sleep efficiency (SE) on questionnaires while one-quarter over estimated SE. Participants reporting worse pain had a greater discrepancy between subjective and objective SE. CONCLUSIONS: Vulnerable older adults demonstrated unique patterns of reporting sleep quality when comparing subjective and objective methods. Additional research is needed to better understand how vulnerable older adults evaluate sleep problems. CLINICAL IMPLICATIONS: Objective and subjective sleep measures may represent unique and equally important constructs in this population. Clinicians should consider utilizing both objective and subjective sleep measures to identify individuals who may benefit from behavioral sleep treatments, and future research is needed to develop and validate appropriate sleep assessments for vulnerable older adults. PMID- 29283799 TI - Personal Trainers: A Formula for Fitness? AB - While not yet exactly commonplace, personal trainers have graduated from muscle gyms to the mainstream, and physicians increasingly are recommending them to patients as part of an ongoing health program. But the trick is knowing how to find them and when to recommend them. PMID- 29283798 TI - "One Size Does Not Fit All:" A Proposed Ecological Model for Human Trafficking Intervention. AB - The problem of human trafficking continues to be one of the vilest human rights abuse and manifestation of social injustice around the world. A lot of antitrafficking efforts have been put in place. However, there is still a lot of emphasis on the criminal aspect of the problem. This has meant that human and practical aspects of the problem have not received sufficient attention, including assessing the problem, victims, and perpetrators in their environments. The ecological perspective helps practitioners, researchers, and policy makers to better understand the problem. This article uses the main concepts in this theory to frame the problem. Discussions are directed toward understanding the different aspects of the problem from an ecological perspective. PMID- 29283800 TI - scanning sports. PMID- 29283801 TI - Getting Into the Game. AB - Innovations in equipment and changes in social attitudes continue to tear down the barriers to sports participation, allowing people who have disabilities to take part in nearly every athletic activity. However, many patients still don't know about the array of opportunities, such as the Paralympics, which took place in September. Physicians are in a unique position to help them discover these sports events and fitness options. PMID- 29283804 TI - QuikQuiz. PMID- 29283803 TI - Sound Treatment Strategies for Active Hypertensives. AB - In brief Physicians must base their exercise recommendations for hypertensive patients on imprecise guidelines. Based on what the patient's hypertension workup reveals, physicians predict how the patient will likely respond to dynamic and static exercise. After the clinician rules out underlying disease and target organ damage, non-pharmacologic and, possibly, pharmacologic therapy may return the patient's blood pressure to normal levels. Cautious participation recommendations are based on the patient's response to treatment. PMID- 29283805 TI - Diagnosing Acute Thigh Compartment Syndrome. AB - In brief A sailboarder suffered an acute brief thigh compartment syndrome following a severe quadriceps contusion. Physical signs and interstitial pressure readings helped in making a prompt diagnosis of this uncommon injury, and the patient recovered fully after fasciotomy. PMID- 29283806 TI - Plantar Warts: Like Running on Rocks. PMID- 29283807 TI - When to Prescribe a Knee Brace. AB - In brief Knee bracing can affect an athbrief lete's performance or rehabilitation, and the decision to brace can have ethical and liability implications as well. When prescribing a brace, a clinician must take into account brace function, construction, and the type of support it can provide for the athlete's knee. Sports medicine professionals can ensure patient compliance by prescribing a comfortable, yet functional, brace and by letting them know what to realistically expect from wearing the device. PMID- 29283808 TI - Plantar Warts. AB - In brief Plantar warts can be difficult to brief treat. Many eventually resolve without treatment, but patients may want therapies that will quickly return them to pain-free activity. And though seemingly countless remedies have been concocted, no cure exists. Treatment options include chemical, immunologic, and surgical techniques. Physicians must take care to select therapy that does not cause discomfort, loss of function, or long-term problems. PMID- 29283809 TI - Subtalar Dislocations in Basketball Players. AB - In brief A US Marine sustained a medial subtalar dislocation while playing basketball in mid-cut tennis shoes. Though such dislocations generally involve high-impact mechanisms, this case supports previous indications of a sports related mechanism. Generally, conservative treatment involving closed reduction under general anesthesia is adequate, as it was with this patient. Some cases may require surgery. An MRI obtained 8 weeks postinjury revealed possible damage to the articular cartilage of the talus. Preventive strategies may include appropriate shoes, suspended wood floors, and conditioning. PMID- 29283811 TI - Fluid Facts. PMID- 29283810 TI - Burners. AB - In brief The authors surveyed 201 NCAA brief Division III football players about their experiences with transient brachial plexopathy. Of the 201 players, 65% had suffered this injury during their college careers, 52% during the 1991; football season and 57% recurrently. Of the injured players, 70% said they had had burners that they did not report to anyone. To reduce the incidence and frequency of this common, often unreported injury, the authors suggest physicians watch more closely for signs and symptoms on the field, ask patients about the injury during preparticipation exams, and prescribe conditioning exercises and equipment modifications. PMID- 29283812 TI - Breaking the Risk of Falls. AB - Falls are a major cause of injury, disability, dependence, and even death among elderly people. Various exercises and activities will improve musculoskeletal strength and thus reduce the risk of falling and the risk of injury when falls do occur. Proper shoes and a safe exercise environment will decrease patients' chances of falling while engaged in the very activity that is supposed to help them prevent falls. PMID- 29283813 TI - pearls. PMID- 29283814 TI - forum. PMID- 29283815 TI - When Workouts Are a Gas. PMID- 29283816 TI - Impact of Disease Disclosure on Stigma: An Experimental Investigation of College Students' Reactions to Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a serious chronic illness that affects 1 in 200 people in the United States with the majority of new cases of IBD diagnosed in young people under the age of 35. Despite the growing number of people who are diagnosed each year, the consequences of health-related stigma faced by young people grappling with the effects of IBD are understudied. This experimental investigation explored the existence of enacted stigma among college students, a population that faces many social and psychological challenges due to the added emotional stresses brought about by the transition from high school and adolescence to college and adulthood. Results indicate that enacted stigma among college students toward other students with IBD decreases when disclosure of the disease is present. Results also suggest that greater knowledge of the nature and symptoms of IBD positively correlates to decreased stigma. PMID- 29283817 TI - scanning sports. PMID- 29283819 TI - American Orthopedic Society for Sports Medicine. PMID- 29283818 TI - a need to know. PMID- 29283820 TI - Nutrition for an Active Life-Style. PMID- 29283821 TI - Stay at Home When You Travel. PMID- 29283822 TI - Opportunity and the Arthroscope. PMID- 29283823 TI - Correction and Prevention of Bicycle Saddle Problems. AB - In brief The bicycle is a commonly used exercise modality, and a number of injuries occur with its use. Among the problems associated with the saddle are rashes, boils, granulomas, urethritis, and ischemic neuropathy of the penis. Prevention of these maladies can be accomplished through proper hygiene, cycling clothing, bicycle size, and saddle position. PMID- 29283824 TI - Catastrophic Eye Injury in a Football Player. AB - In brief Although catastrophic eye injuries are rare in collegiate football, this varsity defensive tackle sustained a giant inferior retinal tear with a partially detached retina when another player's thumb went through his face mask. The retina was surgically repaired, and the player's vision in that eye is 20/20 with a contact lens. He continues to play football as an offensive tackle. PMID- 29283825 TI - Articular Fractures of the Dome of the Talus. AB - In brief Osteochondral fractures of the talar dome are often overlooked because the symptoms are similar to ankle sprains. The most common site of fracture is on either the superolateral or superomedial margin of the dome. Lateral lesions are caused by inversion and dorsiflexion of the ankle, while medial lesions result from inversion and plantar flexion. Careful inspection of x-ray films is the only way to diagnose an acute injury. Surgical treatment is usually required to avoid a long period of immobilization. PMID- 29283826 TI - In-Season Strength Training in Major League Baseball Players. AB - In brief Major League Baseball players were divided into control (n=6) and experimental groups (n=14) during the 1978 season. The experimental group participated in a strength training program in addition to game activities. The control group participated only in games and game-related activities. At the end of the season members of the experimental group were significantly stronger than members of the control group and had reduced absolute and relative body fat and increased lean body weight. They also had a higher degree of muscle symmetry between antagonistic muscle groups. Improvements in strength occurred without reducing range of motion or increasing muscle bulk. PMID- 29283827 TI - Low Back Pain in Young Athletes. AB - In brief Low back pain is one of the most common complaints of athletes, and the differential diagnosis is challenging because the cause can be biomechanical, neoplastic, infectious, developmental, or traumatic. The author reviews diagnostic steps from medical history and physical examination to the use of bone scans, myelography, and tomography. He also reviews injuries and diseases specific to the adolescent spine and urges physicians to use flexibility exercises to correct the athlete's problem while allowing sports participation to continue. Treatment goals should include pain relief and prevention of further lumbar segment injury. PMID- 29283828 TI - Concussion in Athletes. AB - In brief In mild concussion there is a transient disturbance of neurological function but no loss of consciousness. In the moderate form there is a loss of consciousness for less than five minutes, usually with some retrograde posttraumatic amnesia. The severe category covers loss of consciousness for longer than five minutes, wandering eye movements, and lack of purposeful responses. Loss of short-term memory and coordination are the two primary deficits that occur after concussion. An athlete who loses consciousness should not participate again that day; any athlete who remains unconscious for more than several minutes should be hospitalized. An athlete who has had more than one concussion in a season can return to play when he or she is free of neurological disturbance. PMID- 29283830 TI - Sports Medicine Clinics: Are Guidelines Necessary? AB - Sports medicine clinics have sprung up to meet the demands of recreational athletes. But there is no unified system of evaluating their services, staff, and facilities. PMID- 29283829 TI - Bicycle Interval Training for Cardiovascular Fitness. AB - In brief Bicycling can be a viable alternative to jogging for cardiovascular fitness. However, little research demonstrates the level of intensity and duration necessary to produce a cardiovascular training effect. This study gives the results of seven weeks of bicycle interval training on college women and men aged 20 to 24. There were four workouts per week of progressively increasing intensity and duration. The experimental group improved Vo2 max by almost 6 ml.kg 1. min-1. There were no injuries during the training period. PMID- 29283831 TI - Fatalities and Catastrophic Injuries in Football. AB - In brief Football fatality and catastrophic injury data for 1976 through 1981 are compared with earlier data. The purpose is to analyze the data in regard to rule and equipment changes that have taken place in football since 1976 and to demonstrate the reduction in fatalities and catastrophic injuries. Fatality data for 1981 show five high school and two college fatalities. In 1981 there were five permanent spinal cord injuries in high schools and one in college. PMID- 29283832 TI - Fitness Testing in Family Practice. AB - In brief Family physicians can and should help patients establish individualized wellness programs. The author explains a successful format used for five years by a private family physician practice in Kansas. The group stresses preventive medicine and prescribes regular aerobic exercise to encourage positive life-style changes in exercise, diet, and cigarette smoking. PMID- 29283833 TI - Learning to Sail With the Offshore Sailing School. AB - You can learn to sail (and build your vocabulary) at any of Offshore's five bases from New England to the British Virgin Islands. Off-duty sailors can snorkel, swim, golf, and play tennis. PMID- 29283834 TI - Arthroscopy-1982. AB - Arthroscopy is perhaps the most expensive diagnostic procedure in orthopedic surgery. The author points out areas in which he feels it is most useful and most often abused. PMID- 29283835 TI - Crowded Urban Pathways Create Perils for Exercisers. AB - The growing popularity of jogging, bicycling, and roller skating on exercise trails is forcing cities to control traffic flow. PMID- 29283836 TI - letters. PMID- 29283839 TI - names and faces. PMID- 29283838 TI - brief reports. PMID- 29283842 TI - Shinsplints Taping. PMID- 29283841 TI - Sports Medicine Conferences. PMID- 29283843 TI - Silica exposure in a mining exploration operation. AB - BACKGROUND: Though there is extensive research on occupational exposure in production mines, there is limited information on exposure during the exploration phase of mining. METHODS: Air samples were collected in a core processing facility in Northern Ontario, Canada. All samples were analyzed for respirable dust (NIOSH 0600) and respirable crystalline silica (NIOSH 7602). Mean exposure levels were estimated and differences in exposure between work areas were investigated. RESULTS: Sixteen personal and nine area air samples were collected. Respirable dust exposure ranged from < LOD to 2.24mg-m-3; respirable silica exposure ranged from < LOD to 0.055mg-m-3. Silica concentrations were higher among workers in the core cutting and core sorting (pulp and reject) areas, as compared to those in the core logging area. CONCLUSIONS: Workers employed in core processing facilities as part of mining exploration activities are exposed to respirable silica; exposure controls may be needed. PMID- 29283845 TI - The Relationship of Intraoral Protective Devices to Athletic Injuries and Athletic Performance. PMID- 29283844 TI - names and faces. PMID- 29283846 TI - A Better Way to Do Your Best. PMID- 29283847 TI - Richard H. Dominguez, MD: To Stretch or Not to Stretch? AB - Richard Dominguez may have achieved some recent notoriety for his stance on static stretching, but that is a small part of his overall involvement in sports medicine. PMID- 29283848 TI - The Status of Sports Dentistry. PMID- 29283849 TI - Preparticipation Exams: Just 'A Lick and A Promise'? AB - Most physicians view annual exams for high school athletes as a wasteful repetition of what can be a valuable screening effort. But high schools are clinging to the 'annual' as an injury liability crutch. PMID- 29283850 TI - brief reports. PMID- 29283851 TI - Diet and Exercise Programs for Coronary Heart Disease: Better Late Than Never. AB - It makes sense to reduce dietary fat and increase exercise, but scientists can't prove that it reverses atherosclerosis. PMID- 29283853 TI - scanning sports. PMID- 29283852 TI - Osteochondritis Dissecans as a Cause of Posterior Heel Pain. AB - In brief Osteochondritis dissecans of the calcaneus is a condition that results in a small fragment of bone and cartilage being deposited between the calcaneus and the Achilles tendon and causes pain on the posterior aspect of the calcaneus. This paper discusses how the condition can be differentiated from other causes of posterior heel pain so a proper treatment plan can be started. Two case histories of individuals with different levels of activity are presented to demonstrate this condition. PMID- 29283854 TI - Does Aerobic Dance Offer More Fun Than Fitness? AB - Aerobic dance is extremely popular, but many still question its intensity and its value as a modality for cardiovascular training. PMID- 29283855 TI - Mouth Protectors in Junior Football Players. AB - In brief This study tested Sta-Guard and Proform mouth protectors that were worn by 280 football players aged 9 to 12 years. Laboratory studies were also conducted to test tensile and tear strength, dynamic modulus and resilience, and hardness. The players received new mouth guards every two weeks for 12 weeks and reported any problems with gagging, taste, speech, feel, and durability. Ninety percent of the boys preferred the Sta-Guard mouth protector, stating that it was softer, more resilient, and more comfortable than the Proform mouth guard. PMID- 29283856 TI - Sports Medicine Directory 1982. PMID- 29283857 TI - Who Speaks for Sports Medicine? PMID- 29283858 TI - A Survey of 1981 College Lacrosse Injuries. AB - In brief The authors compiled data from 20 National Collegiate Athletic Association lacrosse teams to study the relationship between injuries, protective equipment, and game rules. Athletic trainers for each team kept track of Injuries as they occurred. The 586 players sustained 306 injuries for an injury rate of 52.2%. Half the injuries occurred in the lower extremities, which have no protective equipment. The trunk and arms received 39.8% of the injuries, and the head and face received 9.8%, even though the players are required to wear helmets and face masks. Fewer than 10% of the athletes wore mouth guards. The authors concluded that lacrosse equipment and rules need further study. PMID- 29283859 TI - letters. PMID- 29283860 TI - Exercise Programs for Children: A Way to Prevent Heart Disease? AB - In brief Physical activity patterns of 59 children were determined by recording heart rates before and during an exercise intervention program for coronary heart disease risk. Twenty-six children engaged in 25-minute aerobic activity sessions four days a week for eight months; the control group took regular physical education classes. Baseline data revealed that both groups had similar activity patterns, that the children seldom attained a heart rate greater than 160 beats min-1, and that the boys expended significantly more energy per day than the girls. The activity patterns of children in the experimental group improved significantly. PMID- 29283861 TI - a need to know. PMID- 29283862 TI - Menstrual Patterns in Female Runners. AB - In brief Approximately 350 female runners in the 1980 Boston Marathon and the Bonne Bell 10-km race answered a questionnaire about running and menstrual history. Most of the women (69.4%) continued to menstruate regularly, 19.3% menstruated at irregular or infrequent intervals, and 3.4% had not menstruated during the previous year. Although there was a statistically significant trend toward fewer menstrual periods in runners with low body weight and high training mileage, less than one fourth of the women had both low weight and high mileage. The authors suggest that physicians seek explanations besides running when evaluating female runners with menstrual irregularity. PMID- 29283863 TI - Secondary Risk Factors for Heart Disease. PMID- 29283864 TI - Sleep Disturbances in Athletes. AB - In brief Many athletes experience sleep disturbances at some time during their careers. Most often these disruptions are due to the stresses of competition or constant travel. This article discusses the protective nature of sleep and its two phases: rapid eye movement (REM) and non-REM. Since sleep loss affects both fine and gross motor activity, the author suggests practical strategies to help athletes get the sleep they need to train and compete and argues that drug therapy is not a solution. PMID- 29283866 TI - The Impact of Measuring Patient-Reported Outcome Measures on Quality of and Access to Palliative Care. AB - BACKGROUND: Measuring performance for palliative care is complex as care is delivered in many sites, over time and jointly to the patient and family. Measures of structural processes do not necessarily capture aspects that are important to patients and families nor reflect holistic multidisciplinary outcomes of care. This article focuses on the question as to whether measurement of patient-reported outcome measures improves the outcomes of quality and access to palliative care. OBJECTIVES: To review the international evidence that measurement of indicators of desired outcomes improves the quality of and access to palliative care, in order to apply them to the Canadian context. DESIGN: Rapid review. SETTING: Canadian context. FINDINGS: This review identified six systematic reviews and forty-seven studies that describe largely national efforts to arrive at a consensus as to what needs to be measured to assess quality of palliative care. Patient-reported outcome measures (PROMs) are becoming more prevalent, with emerging evidence to suggest that their measurement improves outcomes that are important to patients. Several Canadian initiatives are in place, including the Canadian Partnership Against Cancer's efforts, in conjunction with other partners, to develop common quality measures. Results from Australia's Palliative Care Outcomes Collaborative demonstrate that patient centered improvements in palliative care can be measured by using patient reported outcomes derived at the point of care and delivered nationally. CONCLUSIONS: Measurement of quality palliative and end-of-life care is very complex. It requires that both administrative data and PROMs be assessed to reflect outcomes that are important to patients and families. Australia's national initiative is a promising exemplar for continued work in this area. PMID- 29283867 TI - The Impact of Public Health Awareness Campaigns on the Awareness and Quality of Palliative Care. AB - OBJECTIVE: The right to health includes a right of access to good quality palliative care, but inequalities persist. Raising awareness is a key plank of the public health approach to palliative care, but involves consideration of subjects most of us prefer not to address. This review addresses the question: "do public health awareness campaigns effectively improve the awareness and quality of palliative care"? BACKGROUND: The evidence shows that public awareness campaigns can improve awareness of palliative care and probably improve quality of care, but there is a lack of evidence about the latter. METHODS: Rapid review and synthesis. RESULTS: A comprehensive public awareness campaign about palliative care (including advance care planning and end-of-life decision making) should be based on clear and shared terminology, use well piloted materials, and the full range of mass media to suit different ages, cultures, and religious/spiritual perspectives. Arts and humanities have a role to play in allowing individuals and communities to express experiences of illness, death, and grief and encourage conversation and thoughtful reflection. There is evidence about key factors for success: targeting, networking, and use of specific, measurable, achievable, realistic time-bound objectives; continuous evaluation; and complementarity to national and international policy. DISCUSSION: Campaigns should be located within the framework of public health promotion and the synergy between short national mass media campaigns and longer term local community action initiatives carefully considered. National and local projects to raise awareness should identify and address any barriers at the level of individuals, communities, and systems of care, for example, literacy skills and unequal access to resources. PMID- 29283868 TI - A Review of the Essential Components of Quality Palliative Care in the Home. AB - OBJECTIVE: The home is an important and often preferable setting of palliative care. While much research has demonstrated the benefits of specialized palliative homecare on patient and system outcomes, there has been little delineation of the underlying components of these efficacious programs. We synthesized the essential elements of palliative homecare from a combined review of successful programs, perspectives of patients and caregivers, and views of healthcare providers in palliative care. METHODS: Five unique palliative homecare studies were included in the rapid review and synthesis-(1) systematic review of the components of efficacious programs; (2) in-depth analysis of 11 effective community-based teams; (3) survey of bereaved caregivers; (4) survey of the general public; and (5) interviews of providers and administrators. A qualitative approach was used to identify transcending themes across the studies. RESULTS: Six essential elements of quality palliative homecare were common across the studies: (1) Integrated teamwork; (2) Management of pain and physical symptoms; (3) Holistic care; (4) Caring, compassionate, and skilled providers; (5) Timely and responsive care; and (6) Patient and family preparedness. CONCLUSIONS: Our metasynthesis of effective palliative homecare models, as well as, the values of those who use and provide these services, illuminates the underpinning elements of quality home based care for patients with a life-limiting illness. However, the application of these elements must be relevant to the local community context. To create impactful, sustainable homecare programs, it is critical to capitalize on existing processes, partnerships, and assets. PMID- 29283869 TI - Evaluating Public Engagement for a Consensus Development Conference. AB - BACKGROUND: Effectively engaging Canadians to help improve the quality and delivery of healthcare to dying Canadians is a priority for healthcare administrators and policy makers. This report shares our evaluation and learnings, applying a series of strategies to encourage policy formation. The Palliative Care Matters consensus development conference held in Ottawa on November 7-9, 2016 brought together members of the public, stakeholders, scientific experts, and a lay panel of interested Canadians to examine Canadian public opinions on palliative care and question experts on how palliative care could be enhanced. OBJECTIVE: This report shares our evaluation and learnings applying a series of strategies to encourage policy formation. METHODS: An evaluation was conducted to measure the short, intermediate, and identify long term outcomes of the conference. The overall performance of the conference for public engagement from November 2016 to mid June 2017 is shared. RESULTS AND CONCLUSION: The outcome of the conference was positive. It was attended and watched online by over 400 participants, received national print, radio and television coverage, and generated high exposure and engagement on social media. Survey results showed that the majority of steering committee, expert, and lay panel members felt a high level of engagement and agreed that the engagement process was successful. Evaluation will be conducted on an ongoing basis for at least another year. PMID- 29283870 TI - Resources for Educating, Training, and Mentoring Nurses and Unregulated Nursing Care Providers in Palliative Care: A Review and Expert Consultation. AB - BACKGROUND: Nurses and nursing care providers provide the most direct care to patients at end of life. Yet, evidence indicates that many feel ill-prepared for the complexity of palliative care. OBJECTIVE: To review the resources required to ensure adequate education, training, and mentorship for nurses and nursing care providers who care for Canadians experiencing life-limiting illness and their families. METHODS: This is a systematic search and narrative review in the Canadian context. RESULTS: Six previous reviews and 26 primary studies were identified. Studies focusing on regulated nurses indicated that even amid variability in content, delivery methods, and duration, palliative education improves nurses' knowledge, confidence, attitudes, and communication abilities, and decreases nurses' stress. Results from palliative education in undergraduate curriculum were less definitive. However, studies on palliative simulation in undergraduate education suggest that it improves knowledge and confidence. Studies focusing on educating nursing care providers, either alone or in collaboration with regulated nurses, indicated positive outcomes in knowledge, confidence, communication, identification of clients who are dying, abilities to interact with patients and families, and a better understanding of their own contributions to care. Curricular resources in Canada have been developed. However, there is no dedicated and funded capacity-building strategy. DISCUSSION: Resources exist to support palliative education for nurses and nursing care providers. Furthermore, the evidence suggests good outcomes from this education. However, there is no dedicated strategy for implementing those resources. Furthermore, there is little evidence of the critical role of knowledge translation in preparing nurses and nursing care providers for evidence-informed palliative practice. PMID- 29283871 TI - Resources for Educating, Training, and Mentoring All Physicians Providing Palliative Care. AB - This article presents a rapid review of the published literature and available resources for educating Canadian physicians to provide palliative and end-of-life care. Several key messages emerge from the review. First, there are many palliative care educational resources already available for Canadian physicians. Second, the many palliative care education resources are often not used in physician training. Third, we know that some palliative care educational interventions are inexpensive and scalable, while others are costly and time consuming; we know very little about which palliative care educational interventions impact physician behavior and patient care. Fourth, two palliative care competency areas in particular can be readily taught: symptom management and communication skill (e.g., breaking bad news and advance care planning). Fifth, palliative care educational interventions are undermined by the "hidden curriculum" in medical education; interventions must be accompanied by continuing education and faculty development to create lasting change in physician behavior. Sixth, undergraduate and postgraduate medical training is shifting from a time based training paradigm to competency-based training and evaluation. Seventh, virtually every physician in Canada should be able to provide basic palliative care; physicians in specialized areas of practice should receive palliative care education that is tailored to their area, rather than generic educational interventions. For each key message, one or more implications are provided, which can serve as recommendations for a framework to improve palliative care as a whole in Canada. PMID- 29283872 TI - Education, Training, and Mentorship of Caregivers of Canadians Experiencing a Life-Limiting Illness. AB - BACKGROUND: Research suggests that caregiver preparedness is essential to minimizing the negative impacts of caregiving. Not being prepared is associated with fear, anxiety, stress, and feelings of insufficiency/uncertainty specific to the caregiver role. OBJECTIVE: To determine what resources are required to ensure adequate education, training, and mentorship for caregivers of Canadians experiencing a life-limiting illness. DESIGN: Informed by the Ispos Reid survey, the methods for this article involved a rapid literature review that addressed caregiver experiences, needs and issues as they related to health, quality of life, and well-being. RESULTS: Given the burden of care, caregiver education, training, and mentorship are suggested to be best met through the palliative navigator model, wherein the patient-caregiver dyad is recognized as an integrated unit of care. CONCLUSIONS: The palliative navigator approach is a key role in the education, training, and mentorship of caregivers. PMID- 29283873 TI - Rapid Review and Synthesis of the Palliative Care Matters Scientific Evidence. AB - BACKGROUND: This article details the methods used for a rapid literature review. OBJECTIVE: The eight scientific articles contained in this Palliative Care Matters supplemental issue synthesize and interpret evidence from the rapid review process outlined in this study. METHODS: The methods of the rapid review were adopted from the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA-P) statement of PRISMA. RESULTS: The current article contains the literature search strategies for both gray and academic literature, resource eligibility criteria for inclusion and exclusion, and tables and figures to outline the literature search process, and delimit the number of resource items captured at each step in the process. PMID- 29283874 TI - A Call for Integrated and Coordinated Palliative Care. AB - Integrated palliative care is viewed as having the potential to improve service coordination, efficiency, and quality outcomes for patients and family carers. However, the majority of Canadians do not have access to regional, comprehensive, integrated palliative care. Work needs to be directed toward planning palliative care services that is integrated into the healthcare and social care system. To further this goal, it is important to have a conceptual understanding of the meaning of integrated care and its expression in organizational models for the provision of palliative care. PMID- 29283875 TI - Consensus Development Conference: Promoting Access to Quality Palliative Care in Canada. AB - OBJECTIVE: This article outlines the development and implementation of a consensus development conference (CDC). BACKGROUND: As a rapid method for data synthesis, a CDC affords a timely and methodic means of evaluating data to effect change in healthcare policy. METHODS: The CDC methodology was adopted for the Palliative Care Matters initiative due to its engagement with the public, scientific community, and palliative care stakeholders. RESULTS: It requires the involvement of seven key groups/roles to successfully effect change: a manager, steering committee, scientific expert panel, public lay panel, a lay-panel facilitator, a public audience, and the media for dissemination. DISCUSSION: This article also details the background information and guiding principles on which the Palliative Care Matters initiative was formed. A Canadian Reference Working Group was formed to develop the Palliative Care Matters guiding principles into six scientific questions. The scientific articles in this supplemental issue each present evidence and expert recommendations that speak to one of the Palliative Care Matters scientific questions. PMID- 29283877 TI - Canadians' Views on Palliative Care. AB - Palliative Care Matters is a national initiative designed to develop consensus on the steps that need to be taken now to ensure Canadians can access high-quality palliative care services as part of Canada's universal healthcare model. Covenant Health and the Canadian Partnership Against Cancer joined with leading national health organizations to lead this initiative, resulting in a Consensus Development Conference in November 2016. Six questions were identified by experts in the field to form the basis of the conference. The questions were first explored with Canadians through focus groups to assess views toward the topics. The qualitative research results were then used to develop an online survey conducted with 1540 Canadians to gauge views on palliative care. The survey results identified what essential elements should be included in a palliative care (and home care) program. Canadians express a desire for palliative healthcare providers to have "specialized certifications" and they have a moderate level of self-confidence in their own palliative caregiving knowledge and abilities. Awareness of palliative care is not widespread in Canada, but support for a modest educational public health campaign is prevalent. Canadians also strongly support national palliative care standards and integration into the Canada Health Act, but simultaneously express financial concerns regarding the associated costs required. The public opinion survey results were used as part of the deliberations at the Consensus Development Conference, culminating in a consensus statement being issued to inform potential policy options and implementation plans for palliative care in Canada. PMID- 29283876 TI - A National Palliative Care Strategy for Canada. AB - OBJECTIVE: To identify barrier to achieving universal access to high quality palliative care in Canada, review published national strategies and frameworks to promote palliative care, examine key aspects that have been linked to successful outcomes, and make recommendations for Canada. BACKGROUND: In 2014, the World Health Organization called on members to develop and implement policies to ensure palliative care is integrated into national health services. METHODS: Rapid review supplemented by the author's personal files, outreach to colleagues within the international palliative care community, review of European Association for Palliative Care publications, and a subsequent search of the table of contents of the major palliative care journals. RESULTS: Frameworks were found for 10 countries ranging from detailed and comprehensive multi-year strategies to more general approaches including laws guaranteeing access to palliative care services for "dying" patients or recommendations for the development of clinical infrastructure. Few formal evaluations were found minimal comparative data exist regarding the quality of care, access to palliative care services, timing of access in the disease trajectory, and patient and family satisfaction with care. Factors that appear to be associated with success include: 1) input and early involvement of senior policy makers; 2) comprehensive strategies that address major barriers to universal access and that involve the key constituents; 3) a focus on enhancing the evidence base and developing a national system of quality reporting; and 4) substantial and sustained government investment. DISCUSSION: Comprehensive national strategies appear to improve access to high quality palliative care for persons with serious illness and their families. Such strategies require sustained government funding and address barriers related to infrastructure, professional and public education, workforce shortages, and an inadequate evidence base. PMID- 29283879 TI - The Action Level. PMID- 29283878 TI - Occupational CNS aspergillosis in an immunocompetent individual a diagnostic challange. AB - INTRODUCTION: Immunocompetent individuals are rarely affected by Aspergillus species and its prime importance lies in immunocompromised patients where it can cause disease, ranging from primarily pulmonary infections to dissemination anywhere in the body. Invasive aspergillosis (IA) occurs in patients with risk factors including prolonged neutropenia, neutrophil dysfunction, patient on cytotoxic drugs, steroid therapy, hematological malignancy, AIDS or in patients with bone marrow transplantation. A recently documented risk factor for IA is the exposure to environmental aspergillus spores at construction sites which makes it an important public health issue. We report here a case of primary CNS aspergillosis in an immunocompetent person who was initially diagnosed as a case of meningioma, and had a history of working in an area with excessive ongoing construction. He had no other primary focus of infection anywhere in the body. He was timely diagnosed and broad spectrum antifungals were started immediately. MATERIAL AND METHODS: The brain biopsy and pus sampleas were subjected to direct microscopy using KOH mount and lactophenol cotton blue (LPCB) stain and culture on Sabourad's Dextrose Agar in Microbiology laboratory. Later patient was started on fluconazole and caspofungin. RESULTS: Thin, hyaline, septate hyphae on direct microscopy and growth of Aspergillus flavus on SDA culture were observed. The patient improved only with antifungals, without surgery. DISCUSSION: This case study highlights the importance of keeping the differential diagnosis of Aspergillus spp. in mind even in individuals with no immunodeficiency. The immunocompetent individuals have better prognosis and if timely diagnosed, can be treated even without surgery. The prevalence of aspergillus spores at construction and demolition sites makes it an important public health issue, hence precautions must be advocated at these sites. PMID- 29283880 TI - Obesity Prevention Interventions in US Public Schools: Are Schools Using Programs That Promote Weight Stigma? AB - INTRODUCTION: Despite substantial research on school-based obesity prevention programs, it is unclear how widely they are disseminated. It is also unknown whether schools use obesity programs that inadvertently promote weight stigma or disordered weight-control behaviors. METHODS: In spring 2016, we distributed an online survey about school wellness programming to a simple random sample of US public school administrators (N = 247 respondents; 10.3% response rate). We analyzed survey responses and conducted immersion/crystallization analysis of written open-ended responses. RESULTS: Slightly less than half (n = 117, 47.4%) of schools offered any obesity prevention program. Only 17 (6.9%) reported using a predeveloped program, and 7 (2.8%) reported using a program with evidence for effectiveness. Thirty-seven schools (15.0%) reported developing intervention programs that focused primarily on individual students' or staff members' weight rather than nutrition or physical activity; 28 schools (11.3% of overall) used staff weight-loss competitions. School administrators who reported implementing a program were more likely to describe having a program champion and adequate buy in from staff, families, and students. Lack of funding, training, and time were widely reported as barriers to implementation. Few administrators used educational (n = 12, 10.3%) or scientific (n = 6, 5.1%) literature for wellness program decision making. CONCLUSION: Evidence-based obesity prevention programs appear to be rarely implemented in US schools. Schools may be implementing programs lacking evidence and programs that may unintentionally exacerbate student weight stigma by focusing on student weight rather than healthy habits. Public health practitioners and researchers should focus on improving support for schools to implement evidence-based programs. PMID- 29283881 TI - Predictors of Severe Obesity in Low-Income, Predominantly Hispanic/Latino Children: The Texas Childhood Obesity Research Demonstration Study. AB - INTRODUCTION: The objective of this study was to identify predictors of severe obesity in a low-income, predominantly Hispanic/Latino sample of children in Texas. METHODS: This cross-sectional analysis examined baseline data on 517 children from the secondary prevention component of the Texas Childhood Obesity Research Demonstration (TX CORD) study; data were collected from September 2012 through February 2014. Self-administered surveys were used to collect data from parents of children who were aged 2 to 12 years, had a body mass index (BMI) in the 85th percentile or higher, and resided in Austin, Texas, or Houston, Texas. Multivariable logistic regression models adjusted for sociodemographic covariates were used to examine associations of children's early-life and maternal factors (large-for-gestational-age, exclusive breastfeeding for >=4 months, maternal severe obesity [BMI >=35.0 kg/m2]) and children's behavioral factors (fruit and vegetable consumption, physical activity, screen time) with severe obesity (BMI >=120% of 95th percentile), by age group (2-5 y, 6-8 y, and 9-12 y). RESULTS: Across all ages, 184 (35.6%) children had severe obesity. Among children aged 9 to 12 years, large-for-gestational-age at birth (odds ratio [OR] = 2.31; 95% confidence interval [CI], 1.13-4.73) was significantly associated with severe obesity. Maternal severe obesity was significantly associated with severe obesity among children aged 2 to 5 years (OR = 2.67; 95% CI, 1.10-6.47) and 9 to 12 years (OR = 4.12; 95% CI, 1.84-9.23). No significant association was observed between behavioral factors and severe obesity in any age group. CONCLUSION: In this low income, predominantly Hispanic/Latino sample of children, large-for-gestational age and maternal severe obesity were risk factors for severe obesity among children in certain age groups. Promoting healthy lifestyle practices during preconception and prenatal periods could be an important intervention strategy for addressing childhood obesity. PMID- 29283883 TI - Screening of the five different wild, traditional and industrial Saccharomyces cerevisiae strains to overproduce bioethanol in the batch submerged fermentation. PMID- 29283882 TI - Sildenafil, a phosphodiesterase-5 inhibitor, offers protection against carbon tetrachloride-induced hepatotoxicity in rat. AB - BACKGROUND: Elevation of phosphodiesterase-5 (PDE5) activity converts cyclic guanosine monophosphate (cGMP) to 5'-GMP, a mechanism that could be associated with drug-mediated hepatotoxicity. This study investigated whether selective inhibition of PDE5 by sildenafil could offer protection against hepatotoxicity induced by carbon tetrachloride (CCl4). METHODS: CCl4 (0.5 mL/kg) was administered intraperitoneally to induce hepatotoxicity. The control group received normal saline. Sildenafil (5 mg, 10 mg, and 20 mg/kg, p.o.) was administered to CCl4-treated rats. RESULTS: CCl4 significantly increased the serum levels of gamma glutamyl transferase (gamma-GT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and reduced total protein (TP) (p<0.05). Pretreatment with sildenafil moderately reduced ALP, AST, and ALT activities with modest increase in TP level. CCl4 induced changes in the antioxidant status of the liver were significantly improved by sildenafil, especially at the lowest dose of 5 mg/kg by elevating the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) and preventing lipid peroxidation (p<0.05). Sildenafil did not significantly alter the total cholesterol and triglyceride levels. However, high-density lipoprotein (HDL) level was significantly increased by sildenafil (p<0.05). CONCLUSIONS: The results from this study suggest that sildenafil, when used at low doses, may be a useful pharmacological protective agent against CCl4-induced hepatotoxicity. PMID- 29283884 TI - A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas. AB - High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas and the expression levels of 136 genes involved in DNA metabolism and G1/S phase transition. In 79 samples downloaded from The Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most significant association with shorter time to relapse and poorer survival of patients. A hierarchical clustering approach assembled most tumors with high levels of CDK6 mRNA into one group. These tumors tend to cumulate mutations activating the Wnt/beta-catenin pathway and show reduced MIR506 expression. Actually, the level of MIR506 RNA is inversely correlated with the levels of both CDK6 and CTNNB1 (encoding beta-catenin). Together these results indicate that high CDK6 expression is found in aggressive tumors with activated Wnt/beta-catenin pathway. Thus we tested the impact of Food and Drug Administration-approved CDK4 and CDK6 inhibitors, namely palbociclib and ribociclib, on SW-13 and NCI-H295R cells. While both drugs reduced viability and induced senescence in SW-13 cells, only palbociclib was effective on the retinoblastoma protein (pRB)-negative NCI-H295R cells, by inducing apoptosis. In NCI-H295R cells, palbociclib induced an increase of the active form of Glycogen Synthase Kinase 3beta (GSK3beta) responsible for the reduced amount of active beta-catenin, and altered the amount of AXIN2 mRNA. Taken together, these data underline the impact of CDK4 and CDK6 inhibitors in treating adrenocortical carcinomas. PMID- 29283885 TI - Transfer of autologous mitochondria from adipose tissue-derived stem cells rescues oocyte quality and infertility in aged mice. AB - Elder women suffer from low or loss of fertility because of decreasing oocyte quality as maternal aging. As energy resource, mitochondria play pivotal roles in oocyte development, determining oocyte quality. With advanced maternal age, increased dysfunctions emerge in oocyte mitochondria, which decrease oocyte quality and its developmental potential. Mitochondria supplement as a possible strategy for improving egg quality has been in debate due to ethnic problems. Heterogeneity is an intractable problem even transfer of germinal vesicle, spindle, pronuclei or polar body is employed. We proposed that the autologous adipose tissue-derived stem cell (ADSC) mitochondria could improve the fertility in aged mice. We found that autologous ADSC mitochondria could promote oocyte quality, embryo development and fertility in aged mice, which may provide a promising strategy for treatment of low fertility or infertility in elder women. PMID- 29283886 TI - Clock mediates liver senescence by controlling ER stress. AB - Accumulated evidence indicates that circadian genes regulate cell damage and senescence in most mammals. Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) regulate longevity in many organisms. However, the specific mechanisms of the relationship between the circadian clock and the two stress processes in organisms are poorly understood. Here, we show that Clock-mediated Pdia3 expression is required to sustain reactive oxidative reagents and ER stress. First, ER stress and ROS are strongly activated in the liver tissue of Clock?19 mutant mice, which exhibit a significant aging phenotype. Next, transcription of Pdia3 is mediated by the circadian gene Clock, but this process is affected by the Clock?19 mutant due to the low affinity of the E-box motif in the promoter. Finally, ablation of Pdia3 with siRNA causes ER stress with sustained phosphorylation of PERK and eIF1alpha, resulting in exaggerated up regulation of UPR target genes and increased apoptosis as well as ROS. Moreover, the combined effects result in an imbalance of cell homeostasis and ultimately lead to cell damage and senescence. Taken together, this study identified the circadian gene Clock as a regulator of ER stress and senescence, which will provide a reference for the clinical prevention of aging. PMID- 29283888 TI - VCP represses pathological cardiac hypertrophy. PMID- 29283889 TI - Two-dimensional CsPbBr3/PCBM heterojunctions for sensitive, fast and flexible photodetectors boosted by charge transfer. AB - Inorganic halide perovskites exhibited promising potentials for high-performance wide-band photodetectors (PDs) due to their high light absorption coefficients, long carrier diffusion length and wide light absorption ranges. Here, we report two-dimensional (2D) CsPbBr3/PCBM heterojunctions for sensitive, fast and flexible PDs, whose performances can be greatly boosted by the charge transfer through the energy-aligned interface. The 2D CsPbBr3 nanosheets with high crystallinity were fabricated via a simple solution-process at room temperature, and then assembled into flexible heterojunctions films with polymerphenyl-C61 butyric acid methyl ester (PCBM). Significantly, the efficient and fast charge transfer at the heterojunctions interface was evidenced by the obvious photoluminescence quenching and variation of recombination dynamics. Subsequently, such heterojunctions PD exhibited an enhanced responsivity of 10.85 A W-1 and an ultrahigh detectivity of 3.06 * 1013 Jones. In addition, the PD shows a broad linear dynamic range of 73 dB, a fast response speed with rise time of 44 MUs and decay time of 390 MUs, respectively. Moreover, the PD lying on polyethylene terephthalate substrates exhibited an outstanding mechanical flexibility and a robust electrical stability. These results could provide a new avenue for integration of 2D perovskites and organic functional materials and for high-performance flexible PDs. PMID- 29283890 TI - Environmental Health: Advancing Emancipatory Policies for the Common Good. AB - Human health is substantially impacted by the state of the environment, and environmental degradation has a disproportionate impact on persons with less immediate access to financial and social power. This article calls for upstream nursing action to address the natural environment in order to turn about health injustices and improve health for all. Such action would move nursing towards a greater actualization of the nursing environmental domain. The health impacts of climate change, air and water quality, and toxic chemical exposure are substantiated and specific policy leadership recommendations are proposed. Recommended actions include work to build environmental health literacy and empowerment, advocacy for regulatory protection and enforcement, and environmental engagement within health care systems. PMID- 29283887 TI - Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. AB - Colorectal cancer is a global disease with increasing incidence. Mortality is largely attributed to metastatic spread and therefore, a mechanistic dissection of the signals which influence tumor progression is needed. Cancer stroma plays a critical role in tumor proliferation, invasion and chemoresistance. Here, we sought to identify and characterize exosomal microRNAs as mediators of stromal tumor signaling. In vitro, we demonstrated that fibroblast exosomes are transferred to colorectal cancer cells, with a resultant increase in cellular microRNA levels, impacting proliferation and chemoresistance. To probe this further, exosomal microRNAs were profiled from paired patient-derived normal and cancer-associated fibroblasts, from an ongoing prospective biomarker study. An exosomal cancer-associated fibroblast signature consisting of microRNAs 329, 181a, 199b, 382, 215 and 21 was identified. Of these, miR-21 had highest abundance and was enriched in exosomes. Orthotopic xenografts established with miR-21-overexpressing fibroblasts and CRC cells led to increased liver metastases compared to those established with control fibroblasts. Our data provide a novel stromal exosome signature in colorectal cancer, which has potential for biomarker validation. Furthermore, we confirmed the importance of stromal miR-21 in colorectal cancer progression using an orthotopic model, and propose that exosomes are a vehicle for miR-21 transfer between stromal fibroblasts and cancer cells. PMID- 29283891 TI - Lee Geropalliative Caring Model: A Situation-Specific Theory for Older Adults. AB - This article describes the Lee Geropalliative Caring Model (GCM), a situation specific theory that guides geropalliative care, defined as the care of older adults in the last 2 years of life. Underpinned by the theory of human caring, the GCM offers a framework for achieving the person/family outcome of well-being by suggesting caring interventions within 4 priority domains: aligning care, keeping safe, comforting body/mind/spirit, and facilitating transitions to persons with late-stage illness, including frailty and dementia. The GCM can be used to inform practice, policy, education, and research. PMID- 29283892 TI - School Nurses' Awareness and Attitudes Toward Commercial Sexual Exploitation of Children. AB - Human trafficking is a global, multibillion-dollar industry. Most victims are female and more than half are children. At-risk youth continue to attend school with school nurses on the frontline of this health crisis. Using the Peace and Power Conceptual Model, a mixed-methods study was conducted to explore school nurses' awareness, attitudes, and role perceptions in the prevention of commercial sexual exploitation of children. Six peace-power versus power-over power themes and 4 subthemes were identified: "exposure/knowledge, "collaboration," "role boundaries," and "creating respite space." Policy efforts should focus on improving practice conditions for school nurses to support the prevention of commercial sexual exploitation of children. PMID- 29283893 TI - Out-of-system Care and Recording of Patient Characteristics Critical for Comparative Effectiveness Research. AB - BACKGROUND: It is unclear how out-of-system care or electronic health record (EHR) discontinuity (i.e., receiving care outside of an EHR system) may affect validity of comparative effectiveness research using these data. We aimed to compare the misclassification of key variables in patients with high versus low EHR continuity. METHODS: The study cohort comprised patients ages >=65 identified in electronic health records from two US provider networks linked with Medicare insurance claims data from 2007 to 2014. By comparing electronic health records and claims data, we quantified EHR continuity by the proportion of encounters captured by the EHRs (i.e., "capture proportion"). Within levels of EHR continuity, for 40 key variables, we quantified misclassification by mean standardized differences between coding based on EHRs alone versus linked claims and EHR data. RESULTS: Based on 183,739 patients, we found that mean capture proportion in a single electronic health record system was 16%-27% across two provider networks. Patients with highest level of EHR continuity (capture proportion >= 80%) had 11.4- to 17.4-fold less variable misclassification, when compared with those with lowest level of EHR continuity (capture proportion< 10%). Capturing at least 60% of the encounters in an EHR system was required to have reasonable variable classification (mean standardized difference <0.1). We found modest differences in comorbidity profiles between patients with high and low EHR continuity. CONCLUSIONS: EHR discontinuity may lead to substantial misclassification in key variables. Restricting comparative effectiveness research to patients with high EHR continuity may confer a favorable benefit (reducing information bias) to risk (losing generalizability) ratio. PMID- 29283894 TI - Incretin-based Drugs and the Incidence of Colorectal Cancer in Patients with Type 2 Diabetes. AB - BACKGROUND: Evidence on the safety of the incretin-based drugs (glucagon-like peptide-1 [GLP-1] analogues and dipeptidyl peptidase-4 [DPP-4] inhibitors) with respect to colorectal cancer is contradictory. The objective of this study was to determine whether use of incretin-based drugs is associated with risk of incident colorectal cancer in patients with type 2 diabetes. METHODS: Using data from the UK Clinical Practice Research Datalink, we identified a cohort of 112,040 patients newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2015. We modeled use of GLP-1 analogues and DPP-4 inhibitors as time varying variables and compared them with use of sulfonylureas. We lagged exposures by 1 year for latency and to reduce reverse causality and detection bias. We used time-dependent Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals of incident colorectal cancer associated with the use of GLP-1 analogues and DPP-4 inhibitors overall, by cumulative duration of use and by time since initiation. RESULTS: During 388,619 person years of follow-up, there were 733 incident colorectal cancer events (incidence rate: 1.9 per 1,000 person-years). Use of GLP-1 analogues was not associated with colorectal cancer incidence (hazard ratio: 1.0; 95% confidence interval = 0.7, 1.6), nor was use of DPP-4 inhibitors (hazard ratio: 1.2; 95% confidence interval = 1.0, 1.5). There was no evidence of a duration-response relation for either drug. CONCLUSIONS: The results of this large population-based study indicate that use of incretin-based drugs is not associated with colorectal cancer incidence among patients with type 2 diabetes. PMID- 29283895 TI - Critical Size Defects for Bone Regeneration Experiments in the Dog Mandible: A Systematic Review. AB - OBJECTIVES: To perform a systematic literature review of studies involving critical size defects (CSDs) in the dog mandible and calvarium to find out the common characteristics of CSDs. MATERIALS AND METHODS: Internet search of the literature was performed on June 2016 based on specific keywords. The search process included 5 databases. The Animal Research Reporting In Vivo Experiment (ARRIVE) guidelines was used to assess the quality of the included studies. RESULTS: Nine studies have met the inclusion criteria and subjected to quality evaluation. All the defects (N = 156) were located in the mandible. Only 2 articles showed randomized controlled studies, whereas the remaining 7 were nonrandomized controlled studies. The geometry of the defects was either rectangular, box, cylindrical (circular), arch, or saddle shaped. CONCLUSION: There is a lack of homogeneity in reporting data on CSDs in the dog mandible. Future animal studies should include a negative control group for an objective comparison and evaluation of any new biomedical materials. More awareness is needed for the Animal Research Reporting In Vivo Experiment (ARRIVE) guidelines to improve data reporting, which can facilitate comparison and reproducibility of future studies. PMID- 29283896 TI - Biological and Technical Complications of Splinted or Nonsplinted Dental Implants: A Decision Tree for Selection. AB - PURPOSE: To present an in-depth review on splinting versus nonsplinting the restorations of adjacent dental implants, in addition to discussing biological and technical complications associated with either choice; and to provide the clinician with a decision tree that serves in everyday judgments when it comes to addressing this issue. MATERIALS AND METHODS: A comprehensive literature review was performed for articles comparing success of splinted versus nonsplinted dental implants. RESULTS: There is no evidence to suggest that implementing either prosthetic design results in higher implant survival. Both designs tend to have their own set of complications, but there is compelling evidence to suggest that splinted restorations generally have less technical complications. CONCLUSION: Either splinting or nonsplinting are valid options for restoring adjacent implants, but each tend to face different biological and technical complications. Knowing which patients are more likely to face particular complications is strategic to provide patients with successful restorations. PMID- 29283897 TI - Influence of Trainee Experience on Choice of Orthopaedic Subspecialty Fellowship. AB - INTRODUCTION: Most orthopaedic surgery residents elect to pursue additional subspecialty training; however, factors influencing the choice of subspecialty and the ways that these factors change during training are not well understood. The aim of this investigation was to determine, on the basis of a trainee's postgraduate year (PGY), whether variability exists in factors valued when choosing a specific subspecialty. METHODS: We emailed an online survey (intended for distribution to current trainees) to a list of orthopaedic surgery residency program coordinators in the United States. The survey queried demographic information, PGY level, and the importance of 14 discrete factors in the selection of fellowship specialty according to a Likert scale rating from 1 to 4. RESULTS: There were 359 respondents representing an even distribution of PGY levels. Junior trainees assigned greater relative value to geographic location, on-call responsibilities, financial compensation, and the tradition of the residency program, whereas senior trainees assigned greater relative value to variety of cases and intellectual stimulation (all P < 0.05). DISCUSSION: The differences seen in factors valued based on trainee experience may highlight the relative importance of greater exposure to the breadth of orthopaedic surgical practice during training and increasing awareness of clinical competencies and responsibilities. CONCLUSIONS: When deciding on orthopaedic subspecialty choice, junior trainees value lifestyle factors relatively more than do senior trainees, whereas senior trainees value case variety and stimulation relatively more than junior trainees do. PMID- 29283898 TI - Compliance With the AAOS Guidelines for Treatment of Osteoarthritis of the Knee: A Survey of the American Association of Hip and Knee Surgeons. AB - INTRODUCTION: The American Academy of Orthopaedic Surgeons (AAOS) published a series of evidence-based guidelines for treatment of knee osteoarthritis (OA). We studied compliance with these guidelines among orthopaedic surgeons. METHODS: We sent a survey to members of the American Association of Hip and Knee Surgeons. It included five clinical vignettes based on the Kellgren-Lawrence radiographic system for classification of knee OA. Respondents selected treatment currently supported or not supported by the AAOS guidelines. RESULTS: Of 345 responses, the frequency of use of recommended interventions was 80%, 82%, 21%, 50%, and 98% for OA at stages 0 through 4, respectively. For stage 2 and stage 3 OA, intra articular hyaluronic acid was the most commonly selected intervention not recommended by the AAOS. DISCUSSION: Apparently, AAOS guidelines on the treatment of OA have not reached the orthopaedic community, resulting in lack of treatment consensus and continued use of modalities with no proven patient benefits. CONCLUSIONS: Management of moderate to severe knee OA does not align with AAOS guidelines. We encourage researchers to conduct clinical trials to identify the role of intra-articular corticosteroids in treating this condition. PMID- 29283899 TI - Effects of Mat Pilates on Physical Functional Performance of Older Adults: A Meta analysis of Randomized Controlled Trials. AB - OBJECTIVE: The present meta-analysis aimed to examine evidence from randomized controlled trials to determine the effects of mat Pilates on measures of physical functional performance in the older population. DESIGN: A search was conducted in the MEDLINE/PubMed, Scopus, Scielo, and PEDro databases between February and March 2017. Only randomized controlled trials that were written in English, included subjects aged 60 yrs who used mat Pilates exercises, included a comparison (control) group, and reported performance-based measures of physical function (balance, flexibility, muscle strength, and cardiorespiratory fitness) were included. The methodological quality of the studies was analyzed according to the PEDro scale and the best-evidence synthesis. The meta-analysis was conducted with the Review Manager 5.3 software. RESULTS: The search retrieved 518 articles, nine of which fulfilled the inclusion criteria. High methodological quality was found in five of these studies. Meta-analysis indicated a large effect of mat Pilates on dynamic balance (standardized mean difference = 1.10, 95% confidence interval = 0.29-1.90), muscle strength (standardized mean difference = 1.13, 95% confidence interval = 0.30-1.96), flexibility (standardized mean difference = 1.22, 95% confidence interval = 0.39-2.04), and cardiorespiratory fitness (standardized mean difference = 1.48, 95% confidence interval = 0.42-2.54) of elderly subjects. CONCLUSIONS: There is evidence that mat Pilates improves dynamic balance, lower limb strength, hip and lower back flexibility, and cardiovascular endurance in elderly individuals. Furthermore, high-quality studies are necessary to clarify the effects of mat Pilates on other physical functional measurements among older adults. PMID- 29283900 TI - Corneal Biomechanical Properties and Central Corneal Thickness in Pediatric Noninfectious Uveitis: A Controlled Study. AB - OBJECTIVE: To compare the corneal biomechanics, intraocular pressure (IOP), and central corneal thickness (CCT) of 37 patients with pediatric noninfectious uveitis with 36 healthy children. METHODS: Corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated and corneal-compensated IOP (IOPg and IOPcc, respectively), and CCT were measured. RESULTS: The mean CRF was significantly lower in the pediatric uveitic eyes than controls (9.7+/-1.9 vs. 10.8+/-1.5 mm Hg, P=0.009), whereas there was no significant difference for mean CH, IOPg, IOPcc, and CCT between the two groups (10.1+/-1.9 vs. 10.8+/-1.7, 12.9+/-3.3 vs. 13.9+/-3.1, 13.8+/-2.8 vs. 13.6+/-3.2 mm Hg, and 550.7+/-49.5 vs. 555.1+/-33.5 MUm, respectively, all P>0.05). The CCT values correlated with CH and CRF, with a Pearson correlation of 0.511 and 0.670 (P=0.013 and P<0.001, respectively), whereas disease duration did not correlate with any corneal biomechanics or CCT in pediatric uveitic eyes (all P>0.05). CONCLUSIONS: Pediatric noninfectious uveitic eyes have lower CRF than controls but the CH, IOPg, IOPcc, and CCT values are similar. PMID- 29283901 TI - Vertebroplasty and Kyphoplasty for Metastatic Spinal Lesions: A Systematic Review. AB - INTRODUCTION: The spine is the most common site of bone metastases. Vertebroplasty (VP) and kyphoplasty (KP) have been proposed as potential minimally invasive therapeutic options for metastatic spinal lesion (MSL) pain. However, the efficacy of VP and KP on MSL pain is currently unclear. OBJECTIVE: The aim of this study was to assess the effects of VP and KP compared with each other, usual care, or other treatments on pain, disability, and quality of life following MSL. METHODS: We included randomized controlled trials and prospective nonrandomized controlled clinical trials assessing VP or KP for the treatment of pain following MSL without cord compression. We searched MEDLINE, EMBASE, PubMed, and CENTRAL. RESULTS: The literature search revealed 387 citations. Of these, 9 trials met all eligibility criteria and were included in the qualitative analysis. In total, there were 622 patients enrolled in the trials and of them 432 were in the surgical treatment group (92 received KP, 97 received VP, 134 received VP and chemotherapy, 68 received VP and radiotherapy, and 41 received Kiva implant) and 190 were in the nonsurgical treatment group (83 received chemotherapy, 46 received radiotherapy, and 61 received other treatment). Using the grading of recommendations assessment, development and evaluation approach, pain (low-quality evidence) and functional scores (very low-quality evidence) improved more with VP plus chemotherapy than with chemotherapy alone (pain: mean difference, -3.01; 95% confidence interval, -3.21 to -2.80; functional score: mean difference, 15.46; 95% confidence interval, 13.58-17.34). KP seemed to lead to significantly greater improvement in pain, disability, and health-related quality of life (HRQoL) compared with nonsurgical management. VP plus Iodine-125 seemed to lead to significantly greater improvement in pain and disability in comparison with VP alone. VP plus radiochemotherapy resulted in better pain relief and HRQoL postoperatively in comparison with routine radiochemotherapy. There was low-quality evidence to prove that surgical treatment significantly decreases pain, and improves functional score and HRQoL following MSL in comparison with nonsurgical management. CONCLUSION: On the basis of the analysis of currently published trial data, it is unclear whether VP for MSL provides benefits over KP. LEVEL OF EVIDENCE: Level 2. PMID- 29283902 TI - Herpesviridae Infection: Prevention, Screening, and Management. AB - Bacterial, viral, and parasitic pathogens add significant morbidity and even mortality to pregnancy-with adverse effects extending to both the gravida and the newborn. Three herpesviruses deserve considerable attention given the effects of perinatal infection on obstetric outcomes, specifically maternal and neonatal morbidity. In the following review, we will provide a description of cytomegalovirus, herpes simplex virus, and varicella zoster virus. For each viral pathogen, we will describe the epidemiology, natural history, screening and diagnosis modalities, treatments, and implications for antepartum care. Furthermore, we will highlight future directions of work in reducing the morbidities associated with these viral pathogens. PMID- 29283903 TI - Patient-centered Contraceptive Counseling and Prescribing. AB - Learning how to best meet a patient's contraceptive needs improves her chances of using her birth control consistently and is crucial to providing patient-centered care. The best contraceptive method for an individual patient is the one that is safe and that she is most comfortable using. Women's health care providers must be equipped to talk to each patient about her needs and options. The shared decision-making model in contraceptive counseling allows the patient and provider to work together in order to meet a patient's needs while remaining medically safe. PMID- 29283904 TI - Role of Full-spectrum Endoscopy in Colorectal Cancer Screening: Randomized Trial. AB - GOALS: The aim of this study was to compare a new, full-spectrum endoscope (Fuse; EndoChoice, Alpharetta, GA) to standard forward-viewing colonoscopy in the detection of colorectal neoplasms. BACKGROUND: Colonoscopy, the gold standard for the detection of colorectal cancer, fails to detect 22% to 28% of polyps, increasing the risk of interval cancer. Endoscopic improvement of the adenoma detection rate decrease interval carcinomas. Full-spectrum endoscopy (FUSE) (330 degree field of view), in a tandem study, has been shown to reduce the adenoma miss rate. STUDY: Prospective, randomized study of 249 patients in patients referred from the colorectal screening program with a positive fecal occult blood test (FOBT). Patients were randomized to standard forward-viewing colonoscopy (170 degrees) or to full-spectrum colonoscopy with the Fuse system (330 degrees). Study variables were the adenoma detection rate, the polyp detection rate, the mean number of adenomas per procedure, the lesions detected according to the location, morphology and size, cecal intubation rate, total procedure time, insertion time to the cecum, therapeutic success, and adverse events. RESULTS: The Fuse system did not produce a significantly higher adenoma detection rate than standard forward-viewing colonoscopy (FUSE 73.1% vs. standard colonoscopy 68.1%; P=0.47) but did have a significantly longer insertion time (FUSE 6.2 min vs. standard colonoscopy 4.2 min; P< 0.001). Further analysis failed to reveal any significant difference in polyp/adenoma detection rates by lesion size or colonic section. CONCLUSIONS: FUSE did not detect significantly more colorectal neoplasia than forward viewing colonoscopy in a medium-risk CRC screening population with positive FOBT. PMID- 29283905 TI - Efficacy and Safety of Flexible Endoscopic Management of Zenker's Diverticulum. AB - Zenker's diverticulum (ZD), a pulsion diverticulum of hypopharynx is a rare but treatable cause of morbidity in geriatric population. Traditionally a surgical disease but due to its associated high morbidity, flexible endoscopy has become a lucrative option. We reviewed 997 patients from 23 original studies who underwent flexible endoscopic diverticulotomy (FED) of ZD. Composite technical and clinical success rate for the study cohort was 99.4% and 87.9%, respectively. Composite failure rate was 10.0% but close to half of them (45.3%) had success with repeat endoscopic intervention. Composite rate for symptom recurrence after long-term follow-up was 13.6% but more than half (61.8%) had success with repeat endoscopic intervention. Bleeding (6.6%) and perforation (5.3%) were 2 most common complications of FED. All bleeding events were successfully managed with observation or endoscopic therapy. Majority of perforation events (4.4%) were successfully managed with conservative care and only 0.9% required invasive management. No mortality was reported. Efficacy and safety of FED of ZD remained same irrespective of diverticulum size or prior surgical/endoscopic treatment. FED with diverticuloscope (FEDD) and FED with cap (FEDC) had comparable technical success rate (99.6% vs. 100.0%) but FEDD had higher clinical success rate compared with FEDC (86.8% vs. 75.4%). FEDD had twice the risk of symptom recurrence than FEDC (16.5% vs. 9.5%). FEDD had a comparable bleeding risk to FEDC (3.3% vs. 4.0%) but a much lower perforation rate (2.3% vs. 10.3%). Upper esophageal sphincterotomy and adequate length of septotomy are the cornerstones of FED. FED can be considered a safe and efficacious treatment modality for patients with ZD. PMID- 29283906 TI - New therapeutic strategies for high-risk acute myeloid leukemia. AB - PURPOSE OF REVIEW: Treatments for acute myeloid leukemia (AML) had remained essentially unchanged for several years; however, the advent of molecular testing has generated insight into the biology of this disease which is now being translated into clinical practice. New treatment strategies which improve drug delivery and exploit cellular targets are changing the landscape of how we treat this disease. RECENT FINDINGS: Induction therapy is in the process of changing for several patient populations. The introduction of CPX-351 offers a novel strategy for treating patients with therapy-related AML or AML with myelodysplasia-related changes; gemtuzumab ozogamicin may become incorporated into standard induction therapy, especially for patients with core-binding factor leukemias; and for older adults, combination therapy with venetoclax may offer a more efficacious strategy than the single-agent regimens previously used. Additionally, targeted therapies are now becoming available for patients with mutations in FMS-like tyrosine kinase 3 (FLT3) or isocitrate dehydrogenase 2 (IDH2), ushering in an era of personalized medicine in the treatment of AML. SUMMARY: The US Food and Drug Administration approval of several agents in 2017 will change the way AML treatment is approached and will offer both clinicians and patients a new armamentarium with which to treat this disease. PMID- 29283907 TI - When should patients receive consolidation chemotherapy before allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission? AB - PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for patients with acute myeloid leukemia. Despite the associated graft-versus-leukemia effect, leukemia relapse remains the most common cause of treatment failure after alloHCT. Here, we review the available data on whether there is an advantage in providing pretransplant consolidation chemotherapy prior to alloHCT. RECENT FINDINGS: Randomized controlled studies are lacking. Data derive largely from four large retrospective registry studies. These analyses are consistent in demonstrating the lack of any survival benefit for pretransplant consolidation chemotherapy once a patient achieves a complete remission and a donor is readily available. These results are valid across conditioning regimen intensities, donor sources, and doses of cytarabine administered during consolidation. SUMMARY: Available evidence suggests that patients with acute myeloid leukemia in first complete remission for whom a suitable donor is readily available should not be given pretransplant consolidation before proceeding to alloHCT, regardless of conditioning regimen intensity and that transplantation should be offered promptly at the time remission is achieved without undue delay. Nevertheless, patients for whom a suitable donor is not readily available after achieving first remission, should probably receive 'bridging' consolidation chemotherapy while waiting for a donor to be identified in an attempt to decrease the risk of early disease recurrence before transplantation. The role of minimal residual disease and genetic markers in directing consolidation choices are unclear to date. PMID- 29283908 TI - Have haploidentical transplants replaced umbilical cord transplants for acute leukemias? AB - PURPOSE OF REVIEW: Haploidentical stem cell transplantation (Haplo SCT) and umbilical cord blood stem cell transplantation (UCB SCT) have emerged over the past two to three decades as viable sources of alternative donor SCT when a human leukocyte antigen matched donor is not available. However, which of these two donor types is optimal for patients with leukemia in need of allografting is unknown. RECENT FINDINGS: For patients with acute leukemia, results of UCB SCT have been improved by the use of double umbilical cord units and emerging ex-vivo expansion technologies. However, the costs associated with procuring double cord units and high transplant-related mortality due to delayed immunological reconstitution and infections, particularly in adult patients, remain a problem. Recently, Haplo SCT has become an increasingly utilized alternative donor source. While improvements of ex-vivo T-cell depletion platforms continue, emergence of T cell-replete platforms, such as the use of post-transplantation cyclophosphamide (PTCy), is increasingly being utilized in treating acute leukemia patients. PTCy based Haplo SCT is gaining popularity among transplant clinicians due to its relatively easy learning curve, low cost, low incidence of graft-versus-host disease, and favorable survival in acute leukemia patients. SUMMARY: The clinical question of whether Haplo SCT should replace UCB SCT needs to be answered by ongoing randomized trials. However, the rapidly increasing adoption of Haplo SCT worldwide as the viable alternative for patients without a human leukocyte antigen-matched donor has seemingly addressed the question ahead of scientific judgment. PMID- 29283909 TI - An update on the pathogenesis of cholesterol gallstone disease. AB - PURPOSE OF REVIEW: Gallstone disease is a major epidemiologic and economic burden worldwide, and the most frequent form is cholesterol gallstone disease. RECENT FINDINGS: Major pathogenetic factors for cholesterol gallstones include a genetic background, hepatic hypersecretion of cholesterol, and supersaturated bile which give life to precipitating cholesterol crystals that accumulate and grow in a sluggish gallbladder. Additional factors include mucin and inflammatory changes in the gallbladder, slow intestinal motility, increased intestinal absorption of cholesterol, and altered gut microbiota. Mechanisms of disease are linked with insulin resistance, obesity, the metabolic syndrome, and type 2 diabetes. The role of nuclear receptors, signaling pathways, gut microbiota, and epigenome are being actively investigated. SUMMARY: Ongoing research on cholesterol gallstone disease is intensively investigating several pathogenic mechanisms, associated metabolic disorders, new therapeutic approaches, and novel strategies for primary prevention, including lifestyles. PMID- 29283910 TI - Involvement in Root Cause Analysis and Patient Safety Culture Among Hospital Care Providers. AB - BACKGROUND: The experience feedback committee (EFC) is a tool designed to involve medical teams in patient safety management, through root cause analysis within the team. OBJECTIVE: The aim of the study was to determine whether patient safety culture, as measured by the Hospital Survey on Patient Safety Culture (HSOPS), differed regarding care provider involvement in EFC activities. METHODS: Using the original data from a cross-sectional survey of 5064 employees at a single university hospital in France, we analyzed the differences in HSOPS dimension scores according involvement in EFC activities. RESULTS: Of 5064 eligible employees, 3888 (76.8%) participated in the study. Among the respondents, 440 (11.3%) participated in EFC activities. Experience feedback committee participants had a more developed patient safety culture, with 9 of the 12 HSOPS dimension scores significantly higher than EFC nonparticipants (overall effect size = 0.31, 95% confidence interval = 0.21 to 0.41, P < 0.001). A multivariate analysis of variance indicated that all 12 dimension scores, taken together, were significantly different between EFC participants and nonparticipants (P < 0.0001), independently of sex, hospital department, and healthcare profession category. The largest differences in scores related to the "feedback and communication about error," "organizational learning," and "Nonpunitive response to error" dimensions. The analysis of the subgroup of professionals who worked in a department with a productive EFC, defined as an EFC implementing at least five actions per year, showed a higher patient safety culture level for seven of the 12 HSOPS dimensions (overall effect size = 0.19, 95% confidence interval = 0.10 to 0.27, P < 0.001). DISCUSSION AND CONCLUSIONS: Participation in EFC activities was associated with higher patient safety culture scores. The findings suggest that root cause analysis in the team's routine may improve patient safety culture. PMID- 29283912 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY IN PURTSCHER RETINOPATHY. AB - PURPOSE: To describe paracentral acute middle maculopathy associated with Purtscher retinopathy, particularly in Purtscher flecken lesions as a retinal complication in a case secondary to fractures of long bones. METHODS: Case report. RESULTS: A 16-year-old boy with bilateral paracentral scotomata presented with bilateral paracentral acute middle maculopathy as part of Purtscher retinopathy in both eyes as consequence of tibia and fibula fractures. CONCLUSION: Paracentral acute middle maculopathy is one of the optical coherence tomography findings in Purtscher retinopathy. PMID- 29283911 TI - DYNAMIC RETINA VESSEL COLOR CHANGE DURING OCULAR COMPRESSION IN SEVERE LIPEMIA RETINALIS. AB - PURPOSE: The aim of this study was to describe dynamic color change in retinal vessels from white to coral pink due to externally applied ocular pressure in a 6 week-old infant with lipemia retinalis secondary to type 1b familial hyperlipoproteinemia. METHODS: Fundus images and fluorescein angiogram were taken with RetCam3 camera. Color photographs of pooled blood were taken during phlebotomy. RESULTS: Genetic analysis revealed a rare genetic mutation in the APOC2 gene, a lipoprotein lipase activator. Intraocular pressure applied to the globe induced a color change in the retinal arteries from white to coral pink. Disruption in laminar flow leading to this change is described. CONCLUSION: This is the first report to attribute the retinal vessel color change to disrupted laminar flow and the intermixing of larger erythrocytes and smaller chylomicrons in a patient with lipemia retinalis. In addition, this is a rare example of congenital hyperlipidemia in the offspring of nonconsanguineous parents. PMID- 29283913 TI - Vestibular Outcome After Cochlear Implantation Is Not Related to Surgical Technique: A Double Blinded, Randomized Clinical Trial of Round Window Approach Versus Cochleostomy. AB - OBJECTIVE: To establish whether the round window approach (RWA) leads to less vestibular dysfunction and dizziness than the standard cochleostomy approach (SCA) during cochlear implant (CI) surgery, as assessed using the video head impulse test (vHIT).Additionally, objective findings were compared with the subjective dizziness perceived by the patient. STUDY DESIGN: Double blinded, clinical randomized trial. SETTING: University Hospital. PATIENTS: Fifty-two ears from 46 patients were included. Inclusion criterion was a gain value more than 0.50. INTERVENTION: Patients were randomized to the RWA or the SCA. Evaluation with the vHIT was performed before surgery, 1 day after surgery, and 1 month after surgery. Subjective dizziness was measured using a visual analogue scale (VAS) and the dizziness handicap inventory (DHI). MAIN OUTCOME MEASURES: Gain values and the incidence of catch-up saccades. RESULTS: Three out of 23 patients in the SCA group experienced catch-up saccades compared with no patients in the RWA group, indicating the occurrence of objective vestibular dysfunction after CI surgery; the difference was not statistically significant. The VAS increased in both groups the day after surgery. The difference between the groups was not statistically significant. No statistically significant changes in the gain value or the DHI score could were observed between the two groups. CONCLUSION: No statistically significant difference between the cochleostomy approach and the round window approach using the vHIT and subjective dizziness perceived by the patient was found. PMID- 29283914 TI - Cochlear Implantation After Partial or Subtotal Cochleoectomy for Intracochlear Schwannoma Removal-A Technical Report. AB - OBJECTIVE: To describe the technique for surgical tumor removal, cochlear implant (CI) electrode placement and reconstruction of the surgical defect in patients with intracochlear schwannomas. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Ten patients (five men, five women, mean age 48 +/- 12 yr) with profound or severe to profound hearing loss due to intralabyrinthine schwannomas with intracochlear location. INTERVENTIONS: Surgical tumor removal through extended round window approach, partial or subtotal cochleoectomy with or without labyrinthectomy and reconstruction of the surgical defect with cartilage, perichondrium or temporal muscle fascia, and bone pate. Eight patients received a cochlear implant in the same procedure. MAIN OUTCOME MEASURES: Retrospective evaluation of clinical outcome including safety aspects (adverse events) and audiological performance at early follow up in cases of cochlear implantation. RESULTS: The tumor was successfully removed in all cases without macroscopic (operation microscope and endoscope) tumor remnants in the bony labyrinth apart from one case with initial transmodiolar growth. One patient needed revision surgery for labyrinthine fistula. At short-term follow up (3-month post-surgery), good hearing results with the cochlear implant were obtained in all but one patient with a word recognition score of 100% for numbers, and 64 +/- 14% for monosyllables (at 65 dB SPL in quiet). CONCLUSIONS: Surgical tumor removal and cochlear implantation is a promising treatment strategy in the management of intralabyrinthine schwannoma with intracochlear location, further extending the indication range for cochlear implantation. It is, however, of importance to observe the long-term outcome in these patients and to address challenges like follow up with magnetic resonance imaging. PMID- 29283915 TI - Diagnostic power and healthcare resource consumption of a dedicated workflow algorithm designed to manage thoracic impedance alerts in heart failure patients by remote monitoring. AB - PURPOSE: Modern cardiac implantable devices provide diagnostic information on several physiological variables which are associated with worsening heart failure, creating an opportunity for early intervention to prevent heart failure symptoms and hospitalizations. We evaluated diagnostic accuracy and workload of a remote monitoring (RM) workflow algorithm which leverages intrathoracic impedance and other device diagnostics. METHODS: In our RM workflow a team of expert nurses was responsible for continuity of care, direct relationship with patients and implementation of a specific protocol to evaluate RM alerts and to limit unnecessary resource consumption. Each patient was univocally assigned to a reference nurse. End points were diagnostic accuracy, healthcare utilization, defined as any hospital admission, and actionability of alerts, defined as medication change or other clinical action. RESULTS: One-hundred twenty-six consecutive patients with implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator were followed for a median time of 23 months. Out of 2176 remote transmissions, 893 (41%) in 111 patients (88.1%) showed clinically relevant events triggered by 574 alerts [2.2 (95% confidence interval = 2.0-2.4) per patient per year]. Among 309 alerts with intrathoracic impedance crossing, heart failure deterioration was confirmed in 116 (37.5%). Clinical actions followed 76/116 (65.5%) true heart failure alerts and 17/193 (8.8%) false-positive alerts (P < 0.001). In particular, drug therapy change followed 72/116 (62.1%) true heart failure alerts and 15/193 (7.8%) false positive alerts (P < 0.001). Healthcare utilization occurred in 65.5% true heart failure alerts and in 24.9% false-positive alerts (P < 0.001). CONCLUSION: A dedicated workflow algorithm results in more focused clinical surveillance leading to prompt detection and treatment of acute heart failure events without wasting healthcare resource. PMID- 29283917 TI - Anesthetic Management and Procedural Outcomes of Patients Undergoing Off-Pump Transapical Implantation of Artificial Chordae to Correct Mitral Regurgitation: Case Series of 76 Patients. AB - BACKGROUND: Transapical implantation of artificial chordae using the NeoChord system (NeoChord Inc, Minneapolis, MN) is an emerging beating-heart technique for correction of mitral regurgitation (MR) through a minimally invasive left minithoracotomy. The purpose of the study was to describe the anesthetic management and procedural success of patients undergoing this procedure. METHODS: All patients (n = 76) who underwent mitral valve repair with the NeoChord system in our institution from December 2011 to December 2016 were included in this observational prospective study. Balanced anesthesia with a combination of fentanyl, propofol, and sevoflurane was used in all patients. Each patient's core temperature was maintained at >36 degrees C whenever possible. Two- and 3 dimensional transesophageal echocardiography was used in all patients to navigate the device to the posterior mitral valve leaflet (68 of 76 patients), anterior mitral valve leaflet (3 of 76 patients), or both leaflets (5 of 76 patients). After effective leaflet capture, the artificial chordae were deployed. Position and function of the artificial chordae were assessed by evaluating the degree of MR when the neochordae were tensed. After surgery, all patients were transferred to the intensive care unit. RESULTS: The mean age of the patients was 60 +/- 13 years (range, 33-87 years), and the male/female ratio was 52/24. Most patients had severe MR (grade 4+ in 25 [33%] patients, grade 3+ in 51 [67%] patients). The average preoperative EuroSCORE II was 1.23% +/- 1.16% (range, 0.46%-4.23%). The median duration of the procedure was 120 minutes (interquartile range [IQR] 115 145 minutes). After the procedure, 42 (56%) patients had trivial MR, 27 (36%) had grade 1+ MR, 4 (5%) had grade 2+ MR, and 2 (3%) had >2+ MR. One patient underwent conversion to conventional mitral valve repair due to perforation of the posterior mitral valve leaflet. The whole procedure was well tolerated by the patients, with hemodynamics remaining stable in the majority of the cases. Only 20 (26%) patients needed low-dose inotropic support perioperatively. All patients had an uneventful postoperative course. The median time to extubation was 4 hours (IQR, 2.6-6), and the length of intensive care unit stay was 22 hours (IQR, 21 24). Five (6.6%) patients required allogeneic blood products. CONCLUSIONS: Anesthesia for transapical NeoChord implantation can be safely performed under beating-heart conditions, with low perioperative morbidity and rare blood transfusions. Transesophageal echocardiography is crucial for the guidance, safety, and effectiveness of the procedure. PMID- 29283916 TI - Heating and Cooling Rates With an Esophageal Heat Exchange System. AB - BACKGROUND: The Esophageal Cooling Device circulates warm or cool water through an esophageal heat exchanger, but warming and cooling efficacy in patients remains unknown. We therefore determined heat exchange rates during warming and cooling. METHODS: Nineteen patients completed the trial. All had general endotracheal anesthesia for nonthoracic surgery. Intraoperative heat transfer was measured during cooling (exchanger fluid at 7 degrees C) and warming (fluid at 42 degrees C). Each was evaluated for 30 minutes, with the initial condition determined randomly, starting at least 40 minutes after induction of anesthesia. Heat transfer rate was estimated from fluid flow through the esophageal heat exchanger and inflow and outflow temperatures. Core temperature was estimated from a zero-heat-flux thermometer positioned on the forehead. RESULTS: Mean heat transfer rate during warming was 18 (95% confidence interval, 16-20) W, which increased core temperature at a rate of 0.5 degrees C/h +/- 0.6 degrees C/h (mean +/- standard deviation). During cooling, mean heat transfer rate was -53 (-59 to 48) W, which decreased core temperature at a rate of 0.9 degrees C/h +/- 0.9 degrees C/h. CONCLUSIONS: Esophageal warming transferred 18 W which is considerably less than the 80 W reported with lower or upper body forced-air covers. However, esophageal warming can be used to supplement surface warming or provide warming in cases not amenable to surface warming. Esophageal cooling transferred more than twice as much heat as warming, consequent to the much larger difference between core and circulating fluid temperature with cooling (29 degrees C) than warming (6 degrees C). Esophageal cooling extracts less heat than endovascular catheters but can be used to supplement catheter-based cooling or possibly replace them in appropriate patients. PMID- 29283919 TI - Exploring Beyond the Duration of Analgesia: Can Adjuncts Improve More Meaningful Outcomes in Obstetric Patients? PMID- 29283918 TI - Clinical Utility of Intraoperative Motor-Evoked Potential Monitoring to Prevent Postoperative Spinal Cord Injury in Thoracic and Thoracoabdominal Aneurysm Repair: An Audit of the Japanese Association of Spinal Cord Protection in Aortic Surgery Database. AB - BACKGROUND: Spinal cord ischemic injury is the most devastating sequela of descending and thoracoabdominal aortic surgery. Motor-evoked potentials (MEPs) have been used to intraoperatively assess motor tract function, but it remains unclear whether MEP monitoring can decrease the incidence of postoperative motor deficits. Therefore, we reviewed multicenter medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open surgery and endovascular repair) to assess the association of MEP monitoring with postoperative motor deficits. METHODS: Patients included in the study underwent descending or thoracoabdominal aortic repair at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery between 2000 and 2013. Using multivariable mixed-effects logistic regression analysis, we investigated whether intraoperative MEP monitoring was associated with postoperative motor deficits at discharge after open and endovascular aortic repair. RESULTS: We reviewed data from 1214 patients (open surgery, 601 [49.5%]; endovascular repair, 613 [50.5%]). MEP monitoring was performed in 631 patients and not performed in the remaining 583 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. Multivariable logistic regression analysis revealed that postoperative motor deficits at discharge did not have a significant association with MEP monitoring (adjusted odds ratio [OR], 1.13; 95% confidence interval [CI], 0.69-1.88; P = .624), but with other factors: history of neural deficits (adjusted OR, 6.08; 95% CI, 3.10-11.91; P < .001), spinal drainage (adjusted OR, 2.14; 95% CI, 1.32-3.47; P = .002), and endovascular procedure (adjusted OR, 0.45; 95% CI, 0.27-0.76; P = .003). The sensitivity and specificity of MEP <25% of control value for motor deficits at discharge were 37.8% (95% CI, 26.5%-49.5%) and 95.5% (95% CI, 94.7%-96.4%), respectively. CONCLUSIONS: MEP monitoring was not significantly associated with motor deficits at discharge. PMID- 29283920 TI - Does Lactate Affect the Association of Early Hyperglycemia and Multiple Organ Failure in Severely Injured Blunt Trauma Patients? AB - BACKGROUND: Early hyperglycemia is associated with multiple organ failure (MOF) after traumatic injury; however, few studies have considered the contribution of depth of clinical shock. We hypothesize that when considered simultaneously, glucose and lactate are associated with MOF in severely injured blunt trauma patients. METHODS: We performed a retrospective investigation at a single tertiary care trauma center. Inclusion criteria were patient age >=18 years, injury severity score (ISS) >15, blunt mechanism of injury, and an intensive care unit length of stay >48 hours. Patients with a history of diabetes or who did not survive the initial 48 hours were excluded. Demographics, injury severity, and physiologic data were recorded. Blood glucose and lactate values were collected from admission through the initial 24 hours of hospitalization. Multiple metrics of glucose and lactate were calculated: the first glucose (Glucadm, mg/dL) and lactate (Lacadm, mmol/L) at hospital admission, the mean initial 24-hour glucose (Gluc24hMean, mg/dL) and lactate (Lac24hMean, mmol/L), and the time-weighted initial 24-hour glucose (Gluc24hTW) and lactate (Lac24hTW). These metrics were divided into quartiles. The primary outcome was MOF. Separate Cox proportional hazard models were generated to assess the association of each individual glucose and lactate metric on MOF, after controlling for ISS, admission shock index, and disposition to the operating room after hospital admission. We assessed the interaction between glucose and lactate metrics in the multivariable models. Results are reported as hazard ratios (HRs) for an increase in the quartile level of glucose and lactate measurements, with 95% confidence intervals (CIs). RESULTS: A total of 507 severely injured blunt trauma patients were evaluated. MOF occurred in 46 of 507 (9.1%) patients and was associated with a greater median ISS (33.5, interquartile range [IQR]: 22-41 vs 27, IQR: 21-34; P < .001) and a greater median admission shock index (0.82, IQR: 0.68-1.1 vs 0.73, IQR: 0.60-0.91; P = .02). Patients who were transferred to the operating room after the initial trauma resuscitation were also more likely to develop MOF (20 of 119, 14.4% vs 26 of 369, 7.1%; P = .01). Three separate Cox proportional regression models demonstrated the following HR for an increase in the individual glucose metric quartile and MOF, while controlling for confounding variables: Glucadm HR: 1.35, 95% CI, 1.02-1.80; Gluc24hMean HR: 1.63, 95% CI, 1.14-2.32; Gluc24hTW HR: 1.14, 95% CI, 0.86-1.50. Three separate Cox proportional hazards models also demonstrated the following HR for each individual lactate metric quartile while controlling for the same confounders, with MOF again representing the dependent variable: Lacadm HR: 1.94, 95% CI, 1.38-2.96; Lac24hMean HR: 1.68, 95% CI, 1.22 2.31; Lac24hTW HR: 1.49, 95% CI, 1.10-2.02. When metrics of both glucose and lactate were entered into the same model only lactate remained significantly associated with MOF: Lacadm HR: 1.86, 95% CI, 1.29-2.69, Lac24hMean HR: 1.54, 95% CI, 1.11-2.12, and Lac24hTW HR: 1.48, 95% CI, 1.08-2.01. There was no significant interaction between lactate and glucose variables in relation to the primary outcome. CONCLUSIONS: When glucose and lactate are considered simultaneously, only lactate remained significantly associated with MOF in severely injured blunt trauma patients. PMID- 29283921 TI - A Simulation Study to Evaluate Improvements in Anesthesia Work Environment Contamination After Implementation of an Infection Prevention Bundle. AB - BACKGROUND: Microbiological contamination of the anesthesia work environment (AWE) is a potential source of health care-associated infections. Medication syringes, stopcocks, and many other areas are routinely contaminated during anesthetic care, and adherence to hand hygiene recommendations is poor. Using a simulation model, we investigated whether AWE contamination could be reduced by implementing an intervention bundle focused on infection prevention. METHODS: Twenty-five anesthesia providers were enrolled in this nonrandomized simulation scenario crossover design study. Subjects were asked to complete 2 general anesthesia scenarios in a mock operating room: a baseline scenario and an intervention scenario in which the bundle was implemented. The bundle included: double gloving before intubation, confining all airway equipment to 1 area, and performing hand hygiene before touching the anesthesia cart. Before each scenario, a manikin's oropharynx and face were marked with ultraviolet fluorescent tracers. After each scenario, the AWE was inspected with a ultraviolet light source to detect contaminant, and all sites were photographed. A blinded observer scored the images for the presence or absence of tracer at 20 sites. Videos of the scenarios were analyzed for duration and number of hand hygiene and glove removal events. Data were analyzed using a mixed effects model. Subjects completed a survey about their experience and the value of the scenarios. RESULTS: The intervention was associated with a decreased subject contamination score of 4.0 (95% confidence interval, 2.2-5.6; P < .001), a 27% reduction in score between baseline and intervention scenarios. Some sites were universally contaminated despite the intervention (eg, laryngoscope handles). The intervention had a statistically significant impact on reducing contamination on medication syringes and the anesthesia cart. There was no significant difference in time needed to complete baseline and intervention scenarios. The majority of subjects felt that the simulations had significant value and would affect their future clinical behavior. CONCLUSIONS: Our results support the concept of an infection prevention bundle in reducing AWE contamination. Anesthesia providers deliver care in a unique environment in which "clean" and "contaminated" tasks are performed rapidly and often in parallel. Linking hand hygiene to specific high-impact tasks such as administering medications, designating areas for contaminated equipment, and double gloving before airway management are simple steps that can be implemented rapidly and are compatible with timely patient care. Our study has improved awareness of infection prevention issues in our department, and has highlighted simple and achievable actions that have the potential to reduce health care-associated infections. PMID- 29283922 TI - In Response. PMID- 29283924 TI - Comparison of Changes in Central Corneal Thickness During Corneal Collagen Cross Linking, Using Isotonic Riboflavin Solutions With and Without Dextran, in the Treatment of Progressive Keratoconus. AB - PURPOSE: To compare intraoperative changes in central corneal thickness (CCT) during corneal cross-linking, using 2 different isotonic riboflavin solutions either with dextran or with hydroxy propyl methylcellulose, in the treatment of progressive keratoconus. METHODS: In this retrospective study, we analyzed records of corneal thickness measurements, taken during various steps of cross linking. Cross-linking was performed using either isotonic riboflavin with dextran (group A) or isotonic riboflavin with hydroxy propyl methylcellulose (without dextran) (group B). CCT measurements were recorded before and after epithelial removal, after saturation with respective isotonic riboflavin solution, after use of hypotonic riboflavin in selected cases, and after ultraviolet A (UV-A) application. A mixed-way analysis of variance was conducted on CCT readings within each group and between both groups, and p < 0.05 was considered significant. RESULTS: In group A (100 cases), after saturation with isotonic riboflavin, CCT was decreased by a mean of 51.4 MUm (12.1%). In 64%, CCT was <400 MUm and additional hypotonic riboflavin was used. After UV-A irradiation, CCT was decreased by a mean of 46.7 MUm (11.4%). In group B (100 cases), after saturation with isotonic riboflavin, CCT was increased by a mean of 109.4 MUm (26.1%). After UV-A exposure, CCT was increased by a mean of 59.2 MUm (11.2%). There was a substantial main effect for time on CCT during corneal cross linking (CXL), p < 0.001, within both groups. The main effect comparing CCT readings between groups A and B was also significant, p < 0.001. CONCLUSIONS: During cross-linking, isotonic riboflavin with dextran causes a significant decrease in corneal thickness, whereas dextran-free isotonic riboflavin causes a significant increase in corneal thickness, thus facilitating the procedure. PMID- 29283925 TI - Reply. PMID- 29283926 TI - Interactions of Propofol With Human Voltage-gated Kv1.5 Channel Determined by Docking Simulation and Mutagenesis Analyses. AB - Propofol blocks the voltage-gated human Kv1.5 (hKv1.5) channel by preferentially affecting in its open state. A previous mutational study suggested that several amino acids within the pore region of the hKv1.5 channel are involved in mediating the blocking action of propofol. The present investigation was undertaken to elucidate the predicted binding modes of propofol within the pore cavity of the open-state hKv1.5 channel, using computational docking and mutagenesis approaches. The docking simulation using a homology model of the hKv1.5 channel, constructed based on the crystal structure of the Kv1.2 channel, predicted that propofol was positioned at the base of the pore cavity of hKv1.5 channel, adjacent to 4 amino acids Thr479, Thr480, Val505, and Ile508, and formed arene-H interactions with Val505. The patch-clamp experiments on wild-type and mutant hKv1.5 channels constructed by site-directed mutagenesis revealed that the blocking potency of propofol was significantly reduced in T480A, V505A, and I508A but not in T479A mutants compared with wild-type hKv1.5 channel. These computational docking and experimental mutational analyses suggest that propofol is positioned at the base of the pore cavity and forms functional contact with Thr480, Val505, and Ile508 to directly block the hKv1.5 channel. PMID- 29283927 TI - Are Informal Caregivers of Persons With Dementia Open to Extending Medical Aid in Dying to Incompetent Patients? Findings From a Survey Conducted in Quebec, Canada. AB - Euthanasia is a controversial and complex issue, especially when involving incompetent patients. On December 10, 2015, Quebec became the first Canadian province to give access to medical aid in dying (MAiD) (ie, euthanasia performed by a physician) to competent patients who satisfy strictly defined criteria. Less than 2 years later, Quebec is considering extending MAiD to incompetent patients who made an advance request. With the objective of contributing scientific data to current societal debates, we conducted a survey among 471 informal caregivers of persons with dementia, reached through Alzheimer Societies. We used a series of vignettes featuring a person with Alzheimer disease to investigate respondents' attitudes towards MAiD. The response rate was 69%. Two-thirds [68%; 95% confidence interval, 63%-73%] found it acceptable to extend MAiD to an incompetent patient at an advanced stage of Alzheimer disease who had made a written request while competent, and 91% (95% confidence interval, 87%-94%) found it acceptable at the terminal stage. Self-determination was the most widely endorsed argument in favor of access to MAiD for incompetent patients. Findings suggest strong support among informal caregivers for extending MAiD to incompetent patients, provided they are terminally-ill and had made a written request before losing capacity. PMID- 29283928 TI - Maximal Upper Body Strength and Oxygen Uptake are Associated with Performance in High-Level 200-M Sprint Kayakers. AB - Current training and monitoring methods in sprint kayaking are based on the premise that upper-body muscular strength and aerobic power are both important for performance, but limited evidence exists to support this premise in high level athletes. Relationships between measures of strength, maximal oxygen uptake (VO2max) and 200-m race times in kayakers competing at national-to-international levels were examined. Data collected from Australian Canoeing training camps and competitions for 7 elite, 7 national and 8 club level male sprint kayakers were analyzed for relationships between maximal isoinertial strength (3-RM bench press, bench row, chin-up and deadlift), VO2max on a kayak ergometer, and 200-m race time. Correlations between race time and bench press, bench row, chin-up, and VO2max were -0.80, -0.76, -0.73, -0.02 and 0.71, respectively (90% confidence limits ~+/-0.17). The multiple correlation coefficient for 200-m race time with bench press and VO2max was 0.84. Errors in prediction of 200-m race time in regression analyses were extremely large (~4%) in relation to the smallest important change of 0.3%. However, from the slopes of the regressions, the smallest important change could be achieved with a 1.4% (+/-0.5%) change in bench press strength and a 0.9% (+/-0.5%) change in VO2max. Substantial relationships were found between upper-body strength or aerobic power and 200-m performances. These measures may not accurately predict individual performance times, but would be practicable for talent identification purposes. Training aimed at improving upper-body strength or aerobic power in lowerperforming athletes could also enhance the performance in 200-m kayak sprints. PMID- 29283929 TI - The Effect of Three Different Maximal Concentric Velocity Squat Protocols on MAPK Phosphorylation and Endocrine Responses. AB - The purpose of this study was to determine the effect of three different back squat protocols on intra-cellular signaling, endocrine responses, and power fatigue. Nine recreationally trained males (X+/-SD; age: 21.4+/-0.6yrs; height: 177.8+/-5.1cm; weight: 78.7+/-9.7kg), completed three maximal concentric velocity squat protocols in a randomized order. Testing protocols consisted of 5 sets of 10 repetitions at 30% of 1RM; 5 sets of 5 repetitions at 70% of 1RM; and 5 sets of 3 repetitions at 90% of 1RM. Average system power for each set was obtained with a tethered external dynamometer. Pre- and post-exercise blood draws were analyzed for lactate, testosterone, hGH, and cortisol. Muscle biopsies assessed pre- and post-exercise extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 phosphorylation via western blotting. Cortisol, hGH, and lactate increased post exercise (p<0.05), but did not differ between protocols (p>0.05). Testosterone was unaltered (p>0.05). Average power was lower for the 90% protocol than for the 30% protocol across all sets (p<0.01). Average power was lower after the fourth and fifth set compared to the first and second set in the 90% protocol only (p<0.05). The ratio of phosphorylated-to-total ERK1/2 was higher post-exercise after 90% protocol only (p<0.05). The ratio of phosphorylated-to-total p38 was unaltered post-exercise (p>0.05). Resistance load appears to affect power fatigue across the five sets of resistance exercise. This study found modest changes in ERK1/2 and no changes in p38 phosphorylation following maximal concentric velocity squats. Exercise volume, modality, and training status of subjects may account for these findings. PMID- 29283930 TI - A comparison of the effects of endurance training on alternate days and on consecutive four days each week for eight weeks on the abundance of PGC-1alpha, CaMKII, NRF-1, mtTFA and COXIV proteins in rat skeletal muscle. AB - The aim of this study was to compare the effects of two training protocols, training on alternate days (A) or on consecutive four days followed by three days of rest in each week (C) for eight weeks, on selected proteins involved in the biogenesis and function of mitochondria in skeletal muscle. Eighty male SD rats were randomly allocated into 10 groups (n=8 each), including Pre and Post control groups, and A or C training groups with 8, 16, 24 and 32 training sessions, respectively. The vastus lateralis and soleus muscle samples were obtained 24 hours after the last training session, or at rest for the controls. The abundance of the proteins for PGC-1alpha, CaMKII, NRF-1, mtTFA and COXIV was analysed by Western blotting. Analysis of the results with two-way ANOVA showed no significant effect and interaction (training protocol by duration) in abundance of the proteins by the two protocols. However, fold changes normalized to control showed significant increases COXIV of the soleus muscle at most time points in both A and C training as indicated by Krumkal-Wallis H tests. There were significant correlations found between the abundance of the measured proteins of the vastus lateralis. The findings suggest that the two training protocols with the same intensity and total volume of work would not make a significant difference in respect of the changes in the targeted proteins. Alternative regulatory factors and the responses in different types of muscles to the training programs need to be examined in future research. PMID- 29283931 TI - Resistance Exercise Training Is More Effective than Interval Aerobic Training in Reducing Blood Pressure During Sleep in Hypertensive Elderly Patients. AB - Bertani, RF, Campos, GO, Perseguin, DM, Bonardi, JMT, Ferriolli, E, Moriguti, JC, and Lima, NKC. Resistance exercise training is more effective than interval aerobic training in reducing blood pressure during sleep in hypertensive elderly patients. J Strength Cond Res 32(7): 2085-2090, 2018-An appropriate fall in blood pressure (BP) during sleep is known to be related to a lower cardiovascular risk. The objective of this study was to compare the effect of different types of training on hypertensive elderly patients under treatment in terms of pressure variability assessed by the nocturnal decline in BP. Hypertensive elderly subjects under pharmacological treatment were randomly assigned to the following groups: 12 weeks of continuous aerobic training, interval aerobic training (IA), resistance training (R), or control (C). All subjects underwent ambulatory BP monitoring before and 24 hours after the last exercise session. The results were assessed using the mixed effects model. A greater nocturnal decline in diastolic BP compared with the wakefulness period was observed in R in comparison with C (11.0 +/- 4.1 vs. 6.0 +/- 5.7 mm Hg and p = 0.01) and with IA (11.0 +/- 4. vs. 6.5 +/- 5.1 mm Hg and p = 0.02). No fall in BP during a 24-hour period was observed in training groups compared with C, perhaps because the subjects were mostly nondippers, for whom the effect of training on BP is found to be lower. In conclusion, resistance training promoted a greater nocturnal fall in BP among hypertensive elderly subjects under treatment compared with IA subjects. PMID- 29283932 TI - Glomerular Filtration Rate is Unchanged By Ultramarathon. AB - THE MAIN PROBLEM: Acute kidney injury (AKI) is reported as a common complication of marathon and ultramarathon running. In previous studies AKI was diagnosed on the basis of the creatinine level in serum and estimated glomerular filtration rate (eGFR). In the present study we calculated eGFR and also measured creatinine clearance after every 25 km of a 100 km run. METHODS: 20 healthy, amateur runners (males, mean age 40.75 +/- 7.15 years, mean weight 76.87 +/- 8.39 kg) took part in a 100 km run on a track. Blood and urine were collected before the run, after every 25 km and 12 hours after the run. RESULTS: 17 runners completed the study. There was increase in creatinine, urea and uric acid observed after 100 km (p < 0.05). The mean increase in creatinine was 0.21 mg/dl (24.53%). 5 runners fulfilled the Acute Kidney Injury Network (AKIN) criteria of AKI. The eGFR according to the MDRD (modification of diet in renal disease), CKD-EPI (chronic kidney disease epidemiology collaboration) and Cockcroft-Gault formulas was significantly decreased after the run (p < 0.05). Otherwise, creatinine clearance calculated from creatinine level in both serum and urine remained stable. CONCLUSIONS: In contrast to the majority of previous studies, we did not observe any decrease in the kidney function during an ultramarathon. In this study the creatinine clearance, which is the best routine laboratory method to determine glomerular filtration rate was used. There is no evidence that long running is harmful for kidney. PMID- 29283933 TI - A Preventive Model for Muscle Injuries: A Novel Approach based on Learning Algorithms. AB - INTRODUCTION: The application of contemporary statistical approaches coming from Machine Learning and Data Mining environments to build more robust predictive models to identify athletes at high risk for injury might support injury prevention strategies of the future. PURPOSE: The purpose was to analyze and compare the behavior of numerous machine learning methods to select the best performing injury risk factor model to identify athlete at risk for lower extremity muscle injuries (MUSINJ). METHODS: A total of 132 male professional soccer and handball players underwent a preseason screening evaluation that included personal, psychological, and neuromuscular measures. Furthermore, injury surveillance was used to capture all the MUSINJ occurring in the 2013/2014 seasons. The predictive ability of several models built by applying a range of learning techniques were analyzed and compared. RESULTS: There were 32 MUSINJ over the follow-up period, 21 (65.6%) of which corresponded to the hamstrings, 3 to the quadriceps (9.3%), 4 to the adductors (12.5%), and 4 to the triceps surae (12.5%). A total of 13 injures occurred during training and 19 during competition. Three players were injured twice during the observation period so the first injury was used, leaving 29 MUSINJ that were used to develop the predictive models. The model generated by the SmooteBoost technique with a cost sensitive ADTree as the base classifier reported the best evaluation criteria (area under the receiver operating characteristic curve score, 0.747; true positive rate, 65.9%; true negative rate, 79.1) and hence was considered the best for predicting MUSINJ. CONCLUSIONS: The prediction model showed moderate accuracy for identifying professional soccer and handball players at risk for MUSINJ. Therefore, the model developed might help in the decision-making process for injury prevention. PMID- 29283934 TI - Raw and Count Data Comparability of Hip-Worn ActiGraph GT3X+ and Link Accelerometers. AB - : To enable inter- and intrastudy comparisons it is important to ascertain comparability among accelerometer models. PURPOSE: The purpose of this study was to compare raw and count data between hip-worn ActiGraph GT3X+ and GT9X Link accelerometers. METHODS: Adults (n = 26 (n = 15 women); age, 49.1 +/- 20.0 yr) wore GT3X+ and Link accelerometers over the right hip for an 80-min protocol involving 12-21 sedentary, household, and ambulatory/exercise activities lasting 2-15 min each. For each accelerometer, mean and variance of the raw (60 Hz) data for each axis and vector magnitude (VM) were extracted in 30-s epochs. A machine learning model (Montoye 2015) was used to predict energy expenditure in METs from the raw data. Raw data were also processed into activity counts in 30-s epochs for each axis and VM, with Freedson 1998 and 2011 count-based regression models used to predict METs. Time spent in sedentary, light, moderate, and vigorous intensities was derived from predicted METs from each model. Correlations were calculated to compare raw and count data between accelerometers, and percent agreement was used to compare epoch-by-epoch activity intensity. RESULTS: For raw data, correlations for mean acceleration were 0.96 +/- 0.05, 0.89 +/- 0.16, 0.71 +/- 0.33, and 0.80 +/- 0.28, and those for variance were 0.98 +/- 0.02, 0.98 +/- 0.03, 0.91 +/- 0.06, and 1.00 +/- 0.00 in the X, Y, and Z axes and VM, respectively. For count data, corresponding correlations were 1.00 +/- 0.01, 0.98 +/- 0.02, 0.96 +/- 0.04, and 1.00 +/- 0.00, respectively. Freedson 1998 and 2011 count-based models had significantly higher percent agreement for activity intensity (95.1% +/- 5.6% and 95.5% +/- 4.0%) compared with the Montoye 2015 raw data model (61.5% +/- 27.6%; P < 0.001). CONCLUSIONS: Count data were more highly comparable than raw data between accelerometers. Data filtering and/or more robust raw data models are needed to improve raw data comparability between ActiGraph GT3X+ and Link accelerometers. PMID- 29283935 TI - The Effects of Sex and Motoneuron Pool on Central Fatigue. AB - PURPOSE: It is uncertain if sex influences central fatigue because the reduction in voluntary activation (VA) has been reported as not different between the sexes for elbow flexors (EF) but greater in males compared with females for knee extensors. This disparity could result from the facilitatory and inhibitory effects of group III/IV muscle afferents on flexor versus extensor motoneurons, respectively. The purpose of this study was to examine central fatigue and motoneuron responsiveness of EF and elbow extensors (EE) in males and females. METHODS: Twenty-two participants (11 females) performed a 2-min isometric maximal voluntary contraction of EF and EE (on separate days) followed by 2 min of recovery. EMG potentials were recorded from biceps or triceps brachii in response to the stimulation of the brachial plexus (Mmax), corticospinal tract (cervicomedullary motor evoked potential [CMEP]), and motor cortex (motor evoked potential [MEP]). Superimposed and resting doublets (for determining VA) were evoked via muscle belly stimulation of biceps or triceps brachii. Only CMEP and superimposed doublets were recorded during fatigue. RESULTS: There was no effect of sex on CMEP area for either muscle group during fatigue or recovery. During the 2 min after EE fatigue, mean normalized CMEP and MEP area were ~85% and ~141% of control, indicating inhibition and facilitation of the motoneurons and motor cortex, respectively. VA during recovery was significantly reduced in males but not females for the EF, and unchanged in either sex for the EE. CONCLUSION: The findings do not support the concept that equivocal findings regarding sex differences in central fatigue are related to augmented effects of group III/IV afferent feedback in males compared with females. PMID- 29283936 TI - A Patient With Submerged Sinonasal Angiosarcoma After Resection of Underlying Organizing Hematoma. AB - A 30-year-old female patient with facial pain diagnosed as organizing hematoma of maxillary sinus by biopsy and imaging studies, and subsequently tumor was resected via an endoscope-assisted midfacial degloving approach. The tumor was histopathologically confirmed as organizing hematoma. In 3-week follow-up, asymptomatic emerging mass was observed at the same site, and needed a revision endoscopic resection. On pathologic examination, a low-grade angiosarcoma was identified, not organizing hematoma. After postoperative radiotherapy, she has been a status of no evidence of disease. This report emphasizes that complete and delicate resection of sinonasal tumor should be made to prevent recurrence and submerged malignant potential. PMID- 29283937 TI - Piezosurgery for Treatment of Large Recurrent Mandibular Osteoma. AB - BACKGROUND: Osteomas are infrequent benign bone tumors of uncertain etiology. They are usually situated at extremities and their occurrence in the jaws is relatively rare. There are 3 types of osteoma: central, peripheral, and extraskeletal. Preoperative presumptive diagnosis is performed by means of radiography using orthopantomographs, computerized tomographs, or cone beam scans. Treatment is surgical and consists of careful exeresis and curettage of the adjacent tissue. In recent years, piezoelectric surgery has been used to treat bone pathologies in the maxillofacial area, orthopedic surgery, and neurosurgery. When used for the exeresis of a bone lesion, the device minimizes risks and eliminates possible complications arising from affectation of the vascular and nerve structures close to the lesion. OBJECTIVE: This clinical report describes a peripheral mandibular osteoma situated in the left mandibular basilar which recurred 45 years after surgical treatment at another center. METHODS: For resection, the surgical approach followed the scar remaining from the earlier surgery and was performed using piezoelectric surgery. Surgery did not cause hemorrhagic complications, affect the sensitivity of the left labial menton, or cause paralysis of the lower lip. CONCLUSIONS: Based on the present patient, it may be concluded that mandibular osteoma treatment by means of piezoelectric surgery makes precise exeresis possible with less affectation of the important surrounding structures such as the inferior alveolar nerve and the marginal mandibular branch of the facial nerve. PMID- 29283938 TI - Immediate Hypoglossal-Facial Anastomosis in Patients With Facial Interruption. AB - Hypoglossal-facial anastomosis provides excellent motor supply to the mimetic muscles of the face when there is no chance of recovery of the damaged facial nerve. However, to achieve optimal results, the timing of facial nerve surgery based on electrophysiological testing and clinical evaluation requires close follow-up of the patient. Functional results after delayed surgery are not predictable and depend on the number of surviving fibers, type of injury, severity of damage, degree of infiltration of inflammatory cells, and local fibrosis. Facial hypertonia, synkinesis, and involuntary mass movement are the major problems of delayed reanimation of the facial nerve. Surgery in the vicinity of the facial nerve always aims to preserve neural integrity. However, immediate facial nerve grafting is sometimes required. We present our experience with 4 patients having normal facial function prior to surgery. The facial nerve was severed due to tumor infiltration and instantaneously reconstructed with the hypoglossal nerve. Two patients had House-Brackmann grade-II 10 days and 28 months after surgery, respectively, and another 2 patients had House-Brackmann grade-III facial paralysis 2 weeks and 6 months after surgery, respectively. PMID- 29283939 TI - Rabdomyosarcoma of the Mandible: An Uncommon Clinical Presentation. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Most patients present with a mass in the head and neck region, urogenital region, or with distal extremity involvement. The authors describe a challenging case of a 6-year-old male patient presenting with mandibular RMS. The clinical/radiographic/tomographic evaluations classified the tumor as an advanced stage (stage IV), with a mass of 6.0 cm involving the left side of the mandible and parotid region. The biopsy revealed round, spindled, and pleomorphic cells with hyperchromatic nuclei and rare larger rhabdomyoblasts with eosinophilic cytoplasm. The diagnosis was of embryonal RMS. The patient was referred for treatment with cycles of chemotherapy; however, pulmonary and bone marrow metastasis were identified. Radiotherapy and local surgery with microvascular reconstruction were performed later; however, the patient died after a few months. Early diagnosis is critical for a good prognosis and cure of patients with RMS. Correct diagnosis considering also the histological subtype is important for adequate treatment, which according to the literature is not uniform probably because of the rarity of this neoplasm. PMID- 29283940 TI - Evaluation of Intersegmental Displacement After Mandibular Setback Split Ramus Osteotomy Using Modified L-Shaped Monocortical Plate: Cone-Beam Computed Tomography Superimposition. AB - PURPOSE: The purpose of the current study is to compare intersegmental displacements after mandibular setback sagittal split ramus osteotomy (SSRO) using 4 types of osteosynthesis methods. PATIENTS AND METHODS: This is a retrospective study of 53 subjects who presented underwent bilateral setback SSRO at Pusan National University Hospital from January 2009 to December 2013. The subjects were divided into 4 groups according to the osteosynthesis method applied: group A-modified L-type monocortical plate; B-conventional miniplate; group C-bicortical screws; group D-metal and absorbable screws. To obtain the intersegmental displacement, the mean of the differences of the 3-dimensional from T0 (2 days after surgery) to T1 (6 months after surgery) was calculated for the right and left condylar heads (condylion, Cd) and the right and left coronoid processes (Cps) using 3-dimensional imaging software (Ondemand 3D; Cybermed Co, Seoul, Korea). RESULTS: For the condylion in the x, y, z coordinate system, in group A, there were significant differences in the y-axis for the right and left Cd; in group B, significant differences in the y-axis for the right Cd and in the y- and z-axes for the left Cd; in group C, no significant differences in the axis for the Cd; and in group D, there were significant differences in the y- and z axes for the right Cd and in the x- and y-axes for the left Cd. For the Cps, the results are not much different from the condylion movement in all group. CONCLUSION: In the current study, group C manifested the greatest displacement for the healing period. Group A did not show the significant difference to group B. In view of these results, modified L-shaped monocortical plate can be applied for osteosynthesis effectively. PMID- 29283941 TI - Tripaddled Anterolateral Thigh Flap for the Reconstruction of Extensively Full Thickness Cheek Defects by Stacking Two Skin Paddles as Kiss Pattern. AB - Extended anterolateral thigh (ALT) flap can provide a large amount of skin to reconstruct the extensively full-thickness defects of cheek. However when the width of 1 skin paddle exceeds 8 cm, it always results in that the donor site cannot be closed primarily and need to be covered by split-thickness skin grafting, which delivers lots of impacts on the functional and cosmetic outcome of the thigh. The aim of this study was to introduce the authors' modification of stacking 2 skin paddles of the tripaddled ALT flap to reconstruct the extensive full-thickness defects in the cheek after the radical ablasion of advanced buccal squamous cell carcinoma. Ten patients of advanced buccal squamous cell carcinoma between March 2014 and December 2016 were enrolled in the authors' hospital. All the patients were received the soft-tissue reconstructions for the extensively full-thickness cheek defects by using the tripaddled ALT chimeric flaps. Among 3 skin paddles, the distal paddle was used to reconstruct the inner mucosa defect, and the other 2 large skin paddles were stacked side by side for outer mega cheek defect. The mean area of the intraoral defect was 32.2 cm and the mean area of the extraoral defect was 106.34 cm. The mean width of the outer skin defect was 9.5 cm. All the flaps survived and all the donor sites were closed primarily. So, stacking 2 skin paddles of a tripaddled ALT flap as a kiss pattern is a novel modification on conventional flap design to provide customized coverage for extensive and full-thickness buccal defects while minimizing donor-site morbidity. PMID- 29283942 TI - Destructive Fibrosarcoma of the Maxillary Sinus. AB - Paranasal fibrosarcoma of nasal cavity and paranasal sinuses is a very rare malignant tumor. It is usually presented with nasal obstruction and epistaxis. In this clinical report, clinical symptoms, pathogenesis, and treatment principles of a paranasal fibrosarcoma originating from the right maxillary sinus and obstructing the right nasal passage are discussed.A 55-year-old male patient was admitted to the authors clinic with complaints of nasal obstruction and epistaxis lasting for 2 years. Anterior rhinoscopy revealed a mass lesion which obstructed the right nasal passage and caused frequent epistaxis. An opacity consistent with soft tissue lesion which was originated from the right maxillary sinus and filled the right nasal passage was observed in paranasal tomography. Magnetic resonance imaging revealed that the mass lesion was contrasted. Tumor was seen to erode orbital floor, and lateral and anterior walls of the maxillary sinus. Biopsy result was reported as papilloma. The patient was treated with Denker approach as anterior wall of the maxillary sinus was eroded by the tumor lesion and the mass lesion was excised. The patient received postoperative radiotherapy as pathological diagnosis was reported as paranasal fibrosarcoma. PMID- 29283944 TI - A Giant Osteoma of the Ethmoid Sinus. AB - Osteomas are slow-growing, benign bony tumors. Most are asymptomatic. Paranasal sinus osteoma in the pediatric population is rare; hence, there are few reports of symptomatic osteomas. The authors report the case of a giant ethmoid sinus osteoma in an 11-year-old girl who presented with diplopia and proptosis. Total excision and reconstruction of the medial orbital wall were performed via a coronal approach. The postoperative period was uneventful, the child's vision improved, and a good cosmetic result was obtained. PMID- 29283943 TI - Can Tumor Size Be a Predictive Factor of Olfactory Dysfunction After Endoscopic Endonasal Trans-Sphenoidal Approach? AB - BACKGROUND AND OBJECTIVE: The aim of this study is to investigate the relationships between tumor size, nasal symptoms including olfactory function, and posoperative atrophic mucosal changes after the endoscopic endonasal transsphenoidal approach (EETSA). METHODS: This was a retrospective review of the medical records of 112 patients who underwent the 2 nostrils/4 hands EETSA with bilateral modified nasoseptal rescue flaps between February 2009 and January 2016. Pre- and postoperative paranasal sinus computed tomography, nasal cavity endoscopic images, the Connecticut Chemosensory Clinical Research Center (CCCRC) test, Cross-Cultural Smell Identification Test (CCSIT), the Nasal Obstruction Symptoms Evaluation, and the Sino-Nasal Outcome Test-20 were conducted. Nasal mucosal changes as determined by endoscopy were divided into 4 groups: normal to normal, Group A; atrophy to atrophy, Group B; normal to atrophy, Group C; and atrophy to more atrophy, Group D. The Mimics program was used to calculate nasal cavity volume changes after surgery. RESULTS: There were significant differences between pre- and postoperative olfactory function as reflected by the CCCRC (P < 0.001) and CCSIT (P < 0.001) scores. There was also a correlation between tumor size and olfactory function scores such as the CCCRC (P = 0.012) or CCSIT (P = 0.015). Moreover, nasal mucosal atrophic changes were related to tumor size and olfactory function tests. CONCLUSION: The tumor size was related to olfactory function and atrophic mucosal changes. Therefore, patients with large tumors should be informed that, after the EETSA, their olfaction may be altered and that nasal symptoms related to mucosal atrophy could occur. PMID- 29283945 TI - Computer-Assisted Volumetric Analysis and Quantitatively Anophthalmic Orbit Reconstruction With Dorsalis Pedis Flap and Bone Graft. AB - Current approaches to orbit reconstruction are based on the assumption of facial symmetry and surgeons' experiences, and the reconstructed orbits are not precise. Through computer-assisted volumetric quantitative analysis, the volume of the bony orbit, and the volume of the soft tissues in both the anophthalmic orbit and the contralateral orbit are calculated in 39 anophthalmic patients. The rib graft is used for orbit reconstruction; the dosalis pedis flap and lipo-injection were used for soft tissue reconstruction and skin socket reconstruction. The size and the shape of the rib graft and soft tissues were designed according to the volumetric analysis. The size and the shape of the skin socket were designed according to measurement during surgery. Asymmetry eye sockets with adequate size were created in the 37 patients. Two patients presented with a poor asymmetry with the contralateral orbit, and got gradual extrusion of the eye prosthesis 4 months after operation, which was because of necrosis of the flaps. The flaps were remedied by frontal island flap and skin grafting. Further surgeries, such as lipoinjection, lid surgery, and canthoplasty, were applied to improve the surgical results. The eye prostheses fitted well in all of the reconstructed sockets using this technique. Our studies suggest that the computer-assisted volumetric analysis technique combined with quantitative bone graft and dorsalis pedis flap transfer, +/- lipoinjection proved to be an accurate method and a quality assurance for optimization of bony orbit, soft tissue and skin socket reconstruction, and promised a successful postoperative outcome for patients' functional and esthetic appearance. PMID- 29283946 TI - Rhinogenic Contact Point Headache: Surgical Treatment Versus Medical Treatment. AB - Rhinogenic contact point headache (RCPH) is a headache syndrome secondary to mucosal contact points in the sinonasal cavities, in the absence of inflammatory signs, hyperplastic mucosa, purulent discharge, sinonasal polyps, or masses. It may result from pressure on the nasal mucosa due to anatomic variations among which the septal deviation, septal spur, and concha bullosa, are the most commonly observed. In recent years, RCPH has remained a subject of controversy regarding both its pathogenesis and treatment. This study aimed to investigate the effect of surgical and medical treatment of pain relief in patients with RCPH, evaluating the intensity, duration, and frequency of headaches, and the impact of different treatments on quality of life. Ninety-four patients with headache, no symptoms or signs of acute and chronic sinonasal inflammation and who present with intranasal mucosal contact points positive to the lidocaine test were randomized into 2 equal groups and given medical or surgical treatment. The authors used visual analog scale, number of hours, and days with pain to characterize the headache and Migraine Disability Assessment score (MIDAS) to assess the migraine disability score before and 3 to 6 months after treatment. After treatment the severity, duration, and frequency of the headache decreased significantly (P < 0.001, P < 0.001, and P = 0.031, respectively) as well as the MIDAS in the surgical group compared with medical group. Our results suggest that surgical removal of mucosal contact points is more effective than local medical treatment improving the therapeutic outcomes in patients with contact point headache. PMID- 29283947 TI - A Study on Environmental Factors for Nonsyndromic Cleft Lip and/or Palate. AB - The aim of the study was to investigate the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCL/P) in Yantai District, China. A retrospective case-control study was carried out. A total of 236 NSCL/P children were selected from Department of Oral and Maxillofacial Surgery of Yantai Stomatological Hospital between September 2013 and December 2016 as cases; 209 controls were chosen from other diagnosis in the same department during the same period. The 2 groups matched age and sex. The parents of participants were inquired regarding the risk factors, and the answers were filled in a questionnaire by physicians. Chi-square and multivariate logistic regression analysis were used to analysis the data. There was significantly increased NSCL/P risk with high maternal age (P =0.002), family history (P = 0.001), abortion history (P = 0.033), poor parental education level (P = 0.008), maternal smoking (P = 0.044), maternal alcohol (P = 0.039), common cold or fever (P = 0.035), drug use (P = 0.006), and maternal stress (P = 0.049). Reduced NSCL/P risk was found with folic acid supplementation (P = 0.005), adequate maternal age (P = 0.002), and high parental education (P = 0.001). The proper amount of folic acid, the appropriate age of childbearing, and the high education were the protective factors of NSCL/P, whereas family history, abortion history, drug use during pregnancy, maternal tobacco and alcohol, and maternal stress were the risk factors for NSCL/P in Yantai District, China. PMID- 29283948 TI - Comments on "Outer Fascia of Orbicularis Oculi Muscle as an Anchoring Target Tissue in Double Eyelid Surgery". PMID- 29283949 TI - Changes in Corneal Curvature After Epiblepharon Surgery in Children. AB - PURPOSE: We aimed to determine the change in corneal topography for 2-different corneal zones and 4-quadrants after epiblepharon correction in children. METHODS: We retrospectively reviewed 39 patients (74 eyes) who underwent epiblepharon surgery. Keratometry measurements of corneal curvature were performed for 2 optical zones defined as circular areas with a radius of 3 and 5 mm from the corneal apex. Each optical zone was divided into quadrants (nasal, superior, temporal, and inferior). Keratometry readings for each quadrant of zone were compared between the preoperative and postoperative examinations (at 1, 3, and 6 months). The correlation between corneal astigmatism and curvature change was analyzed for each quadrant of the 3-mm optical zone. RESULTS: At 1 month postoperatively, the inferior and superior quadrants of the 3-mm optical zone became significantly flatter compared with the preoperative state, and this phenomenon became more pronounced at 3 months postoperatively (P < 0.05). However, no significant postoperative change in corneal curvature was noted for any quadrant of the 5-mm optical zone. There was a statistically significant correlation between the change in astigmatism and corneal curvature for the superior and inferior quadrants of the 3-mm optical zone (R = 0.394, P < 0.05; R = 0.460, P < 0.05; respectively). CONCLUSIONS: Astigmatism reduction was affected by corneal flatness in the inferior rather than the superior quadrant. Epiblepharon surgery results in reduction of corneal steepness at the vertical axis of the 3-mm optical zone, which correlates to astigmatism reduction. PMID- 29283950 TI - Evaluating Resident Perspectives on International Humanitarian Missions. AB - BACKGROUND: Opportunities for international missions are highly sought after by medical students, residents, and attending plastic surgeons. The educational benefits and ethical considerations of trainees participating in these ventures have been extensively debated. At the time of this writing, many surgical training programs lack the necessary infrastructure or funds to support missions of this sort. Despite the increasing interest, the perceived benefit of international work has not yet been well studied. The authors seek to evaluate residents' perspectives on the personal and educational benefits of international mission work. METHODS: A 24-item online questionnaire was designed to measure residents' perspectives on humanitarian missions. Residents' perceptions on how participation in these missions may have influenced their career path were also evaluated. This questionnaire was disseminated to the plastic surgery residents in Accreditation Council for Graduate Medical Education (ACGME) accredited programs in the United States during the 2015 to 2016 academic year. RESULTS: Of the 123 responses collected, 49 (40%) indicated that they had participated in international mission work prior to beginning residency, while 74 (60%) had not. Fifty-seven percent (n = 25) of those who had participated agreed that this experience impacted their choice to pursue plastic surgery as a specialty. Twenty nine (24%) participated in 1 or more missions during residency. The most common type of mission work focused on cleft lip/palate repairs (n = 24) followed by nonsurgical medical relief (n = 18) and general plastics/combined (n = 6). Most respondents reported trips lasting 6 to 8 days (n = 29, 48%), though several reported trips lasting 9 to 10 days (n = 6, 10%) and 11 days or more (n = 16, 27%). When asked about the volume of procedures performed, 32 (65%) reported participating in more than 15 procedures, with 15 (31%) residents reporting participation in 26 procedures or more. When asked to evaluate the educational benefits in light of the 6 core competencies from the ACGME, there was an overwhelmingly positive response. CONCLUSIONS: Residents perceive international mission experiences to be valuable for professional development as well as an effective tool for surgical education, particularly in the setting of competency based education goals and these ventures should be supported by training programs. An appropriately planned mission experience can impact the professional and educational development of the trainee. PMID- 29283951 TI - Knee Arthrodesis in a Patient with Charcot Neuroarthropathy Secondary to Familial Amyloid Polyneuropathy: A Case Report. AB - CASE: We report a rare case of severe Charcot neuroarthropathy of the knee secondary to familial amyloid polyneuropathy, which was treated surgically with a knee arthrodesis. This treatment allowed an early symptomatic and functional improvement and a short consolidation time without any major complications. CONCLUSION: Neuropathy is the earliest and most major burden in patients with familial amyloid polyneuropathy; it requires careful evaluation and adequate treatment aimed at preventing or slowing the progression of secondary damage, involving Charcot neuroarthropathy, that may occur. Surgical arthrodesis with antegrade intramedullary nailing may be appropriate in a patient with severe Charcot neuroarthropathy of the knee. PMID- 29283952 TI - Is there still a role for vancomycin in skin and soft-tissue infections? AB - PURPOSE OF REVIEW: Skin and soft-tissue infections (SSIs) are among the commonest infections encountered in clinical practice. Spread of methicillin-resistant Staphylococcus aureus SSIs continues to increase in both health care and community settings and presents a challenge for the best treatment choice. Vancomycin has been the mainstay of SSIs treatment, but recently its use has been questioned because of concerns about its efficacy, tolerability, and unfavorable pharmacokinetic/pharmacodynamic profile. The purpose of this review is to establish the current role for vancomycin in light of the literature published from January 2007 to September 2017 on comparison with both old and new alternatives. RECENT FINDINGS: Meta-analyses show better clinical and microbiological outcomes for drugs approved for the treatment of SSI, including those sustained by methicillin-resistant S. aureus, in the last 10 years than for vancomycin. The newer glycopeptides and linezolid decrease the total treatment costs compared with vancomycin, by reducing the length of stay or avoiding the hospitalization. SUMMARY: Vancomycin is noninferior in efficacy and safety to all comparator drugs, including the newest on the market. However, the SSI treatment evidence base presents several shortcomings limiting the clinical applicability of the results. High-level clinical trials should be performed to obtain results that can be generalized and applied effectively in clinical practice. PMID- 29283953 TI - Content, Accessibility, and Dissemination of Disaster Information via Social Media During the 2016 Louisiana Floods. AB - CONTEXT: Social media is becoming increasingly integrated into disaster response communication strategies of public health and emergency response agencies. OBJECTIVE: We sought to assess the content, accessibility, and dissemination of social media communications made by government agencies during a disaster response. DESIGN: A cross-sectional analysis of social media posts made by federal, state, and local government, public health and emergency management agencies before, during, and after the 2016 Louisiana floods was conducted to determine their content, accessibility, and dissemination by level of government and time relative to disaster onset. SETTING: Facebook and/or Twitter posts made by public agencies involved in the response to the 2016 Louisiana Flooding events (FEMA Disaster Declaration [DR-4277]) published between August 4 and September 16, 2016, publicly available online between February 21 and March 31, 2017, were included in the analysis. MAIN OUTCOME MEASURE: Content: The text of each post was assessed to determine whether it contained information on provision of situational awareness; addressing misconception, actionable requests; mental, behavioral, and emotional support; and/or recovery and rebuilding resources. Accessibility: A Flesh-Kincaid grade level of each post was calculated, and information on post language, originality, hyperlinks, visuals, videos, or hash tag was recorded. Dissemination: The average number of reacts/likes, shares/retweets, and comments per post was calculated. RESULTS: Most posts contained information related to situational awareness and recovery resources. There was an increase in messages during the first week of the disaster at all levels. Few posts were made in languages other than English. Compared with state and federal posts, local Facebook posts averaged fewer reacts, comments, and shares throughout the analysis period. CONCLUSIONS: Government agencies may maximize the use of social media platforms for disaster communications by establishing their social media network in advance of a disaster and by applying established guidelines on disaster social media use. PMID- 29283954 TI - The Local Health Department Mandate and Capacity for Community Engagement in Emergency Preparedness: A National View Over Time. AB - CONTEXT: Local health departments (LHDs) perform the highly valued, yet time- and staff-intensive work of community engagement in public health emergency preparedness (CE-PHEP) when the Great Recession has had lingering effects on their organizational capacity. OBJECTIVE: Track the extent to which LHDs still embrace collaborative, whole community approaches to PHEP in a historically low resource environment. DESIGN: National survey in 2015 of LHDs using a self administered online questionnaire regarding LHD practices and resources for CE PHEP first fielded in 2012 ("The Community Engagement for Public Health Emergency Preparedness Survey"). Differences in 2015 survey responses were reviewed, and comparisons made between 2012 and 2015 responses. SETTING: Randomized sample of 811 LHDs drawn from 2565 LHDs that were invited to participate in the 2010 National Profile of LHDs and participated in the 2012 CE-PHEP survey. Sample selection was stratified by geographic location and size of population served. PARTICIPANTS: Emergency preparedness coordinators reporting on the LHDs they serve. MAIN OUTCOME MEASURE: Community engagement in public health emergency preparedness intensity as measured by a scoring system that valued specific practices on the basis of the community capacity and public participation they represented. RESULTS: Survey response was 30%; 243 LHDs participated. The CE-PHEP activities and intensity scores remained unchanged from 2012 to 2015. Local health departments that reported having an explicit CE-PHEP policy and experienced CE-PHEP staff member--2 of the top 3 predictors of CE-PHEP intensity- have dropped between 2012 and 2015. The numbers of LHDs with a CE-PHEP budget, also an important predictor of intensity, have not increased in a statistically significant way during that same period. CONCLUSIONS: Local health departments appear to be in a CE-PHEP holding pattern, presumably pushed forward by the doctrinal focus on partner-centered preparedness but held back by capacity issues, in particular, limited staff and partner support. Local health departments operating in low-resource environments are encouraged to formalize their CE-PHEP policy to advance performance in this arena. PMID- 29283955 TI - Effects of Reaching National Goals on HIV Incidence, by Race and Ethnicity, in the United States. AB - CONTEXT: Human immunodeficiency virus (HIV) incidence and prevalence in the United States are characterized by significant disparities by race/ethnicity. National HIV care goals, such as boosting to 90% the proportion of persons whose HIV is diagnosed and increasing to 80% the proportion of persons living with diagnosed HIV who are virally suppressed, will likely reduce HIV incidence, but their effects on HIV-related disparities are uncertain. OBJECTIVE: We sought to understand by race/ethnicity how current HIV care varies, the level of effort required to achieve national HIV care goals, and the effects of reaching those goals on HIV incidence and disparities. DESIGN: Using a dynamic model of HIV transmission, we identified 2016 progress along the HIV care continuum among blacks, Hispanics, and whites/others compared with national 2020 goals. We examined disparities over time. SETTING: United States. PARTICIPANTS: Beginning in 2006, our dynamic compartmental model simulated the sexually active US population 13 to 64 years of age, which was stratified into 195 subpopulations by transmission group, sex, race/ethnicity, age, male circumcision status, and HIV risk level. MAIN OUTCOME MEASURE: We compared HIV cumulative incidence from 2016 to 2020 when goals were reached compared with base case assumptions about progression along the HIV care continuum. RESULTS: The 2016 proportion of persons with diagnosed HIV who were on treatment and virally suppressed was 50% among blacks, 56% among Hispanics, and 61% among whites/others, compared with a national goal of 80%. When diagnosis, linkage, and viral suppression goals were reached in 2020, cumulative HIV incidence fell by 32% (uncertainty range: 18% 37%) for blacks, 25% (22%-31%) for Hispanics, and 25% (21%-28%) for whites/others. Disparity measures changed little. CONCLUSIONS: Achieving national HIV care goals will require different levels of effort by race/ethnicity but likely will result in substantial declines in cumulative HIV incidence. HIV related disparities in incidence and prevalence may be difficult to resolve. PMID- 29283956 TI - Examining the Association Between Psychiatric Disorders and Cocaine Binges: Results From the COSMO Study. AB - OBJECTIVES: Although cocaine binges and mental health problems have both been identified as significant risk factors for different health hazards, little is known about the relationship between mental health and cocaine binging. Hence, the aim of this study is to examine the association between psychiatric disorders and cocaine binge. METHODS: Participants were part of a prospective cohort study of individuals who either smoke or inject cocaine. The dependent variable, namely a cocaine binge within the past month, was defined as the repetitive use of large quantities of cocaine until the individual was unable to access more of the drug or was physically unable to keep using. Psychiatric disorders were assessed using the Composite International Diagnostic Interview and the Diagnostic Interview Schedule questionnaires. Logistic regression models were performed to examine the association between cocaine binging and psychiatric disorders, adjusting for potential confounders. RESULTS: Of the 492 participants, 24.4% reported at least 1 cocaine binging episode during the prior month. Among the study population, 48.0% met the criteria for antisocial personality disorder (ASPD), 45.5% for anxiety disorders, and 28.2% for mood disorders. Participants with ASPD were more likely to binge (adjusted odds ratio 1.73, 95% confidence interval 1.10-2.73), whereas those with a mood disorder were not. The association between anxiety disorders and cocaine binging was significant only in univariate analyses. CONCLUSION: ASPD increased the odds of reporting cocaine binge in our study population. These results highlight the need for a better understanding of the specific dimensions of ASPD that contribute to the increased risk of unsafe drug use behaviors. PMID- 29283957 TI - Early Tracheostomy in Patients With Traumatic Cervical Spinal Cord Injury Appears Safe and May Improve Outcomes. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To characterize outcomes associated with tracheostomy timing following traumatic cervical spinal cord injury (CSCI). SUMMARY OF BACKGROUND DATA: The morbidity associated with cervical spine trauma is substantially increased in the setting of concomitant CSCI. Despite recent evidence, it remains uncertain if early tracheostomy following traumatic CSCI can improve outcomes. METHODS: From January 1, 2007 to December 31, 2015, retrospective chart review identified 70 patients who presented to a single Level 1 trauma center with traumatic CSCI and received tracheostomy for management of respiratory compromise. Patients were subdivided into two groups based on time from initial intubation to tracheostomy procedure: early (tracheostomy <=7 d from initial intubation) and late (>7 d from initial intubation). RESULTS: This series included 75.7% males and 24.3% females with mean age 50.5 years. A chest injury was present in 31.4% of patients. AIS A was the most common AIS score (41.4%), and 70.1% of patients had an injury level at C4 or above. Early tracheostomy was performed in 52.4% of patients. Factors most predictive of early tracheostomy were more severe AIS score (odds ratio [OR] = 1.72) and higher neurological level of injury (OR = 1.91) (P < 0.001, pseudo-R = 0.241). Controlling for AIS and neurological level of injury, early tracheostomy was associated with fewer ventilator days (23.9 vs. 36.9, P = 0.0268), fewer days to decannulation (53.0 vs. 74.3, P = 0.0075), and shorter intensive care unit (ICU) stays (20.7 vs. 26.0, P = 0.0217). Rates of pneumonia, surgical site infection, in-hospital mortality, 90-day mortality, and 90-day readmission rates were not different between groups. CONCLUSION: Tracheostomy within 7 days of intubation may improve respiratory outcomes in patients with traumatic CSCI, regardless of level or severity of injury, without increasing complication rates. LEVEL OF EVIDENCE: 4. PMID- 29283959 TI - Neuroplastic Surgery: The New Innovation in the Educational Process of Craniofacial Surgery. PMID- 29283958 TI - Risk of Pneumonia After Vertebral Compression Fracture in Women With Low Bone Density: A Population-Based Study. AB - STUDY DESIGN: Retrospective large population-based study. OBJECTIVE: The aim of this study is to elucidate the association between vertebral compression fractures (VCFs) and pneumonia. SUMMARY OF BACKGROUND DATA: VCF is known to be associated with impaired pulmonary function. However, the risk of developing pneumonia after new-onset VCF has not been evaluated. METHODS: The data source was the National Health Screening Program Cohort, a population-based sample cohort of national health screening enrolees. Elderly women with low bone density identified during the life transition period health check-up were target population. Patients with newly diagnosed isolated VCF after the health check-up except those with cervical VCF were included as exposure group. Matched individuals still free of any type of VCF from the same population were included as control group with case/control ratio 3:1. The time to first occurrence of pneumonia were analyzed with Cox-regression analysis. RESULTS: From the target population (N = 24,773), we matched 867 patients exposed to new-onset isolated VCFs with 2601 controls. In a multivariable Cox-regression analysis, isolated VCF was identified as an independent risk factor for development of a pneumonia (adjusted hazard ratio, 1.48; 95% confidence interval 1.14-1.91). Among the subtypes of VCF, thoracic/thoracolumbar VCF was independently associated with increased risk of pneumonia (adjusted hazard ratio, 2.13; 95% confidence interval 1.47-3.08). CONCLUSION: Isolated VCF, especially those involving thoracic region, was associated with increased risk of pneumonia. LEVEL OF EVIDENCE: 4. PMID- 29283960 TI - Trauma laparoscopy from 1925 to 2017: Publication history and study demographics of an evolving modality. PMID- 29283961 TI - Injuries associated with police use of force. AB - BACKGROUND: Use of force [UOF] by police can result in serious injuries and fatalities. The risk of significant injuries associated with different force modalities is poorly defined. We sought to determine the incidence of police UOF and compare the likelihood of significant injury with different force modalities. METHODS: A prospective multicenter observational study of all UOF incidents was conducted via mandatory UOF investigations at three mid-sized police agencies over a two year period. Expert physicians reviewed police and medical records to determine injury severity using a priori injury severity stratification criteria. RESULTS: There were 893 UOF incidents, representing a UOF rate of 0.086% of 1,041,737 calls for service (1 in 1167) and 0.78% of 114,064 criminal arrests(1 in 128). Suspects were primarily young (mean age, 31 years; range, 12-86 years) males (89%). The 1,399 force utilizations included unarmed physical force (n = 710, 51%), CEWs (504, 30%), chemical (88, 6.3%), canines (47, 3.4%), impact weapons (9, 0.6%), kinetic impact munitions (8, 0.6%), firearms (6, 0.4%), and other (27, 1.9%). Among 914 suspects, 898 (98%) sustained no or mild injury after police UOF. Significant (moderate or severe) injuries occurred in 16 (1.8%) subjects. Logistic regression analysis shows these are most associated with firearm and canine use. There was one fatality (0.1%) due to gunshots. No significant injuries occurred among 504 CEW uses (0%; 95% confidence interval, 0.0-0.9%). Of the 355 suspects transported to a medical facility, 78 (22%) were hospitalized. The majority of hospitalizations were unrelated to UOF (n = 59, 76%), whereas a minority (n = 19, 24%) were due to injuries related to police UOF. CONCLUSION: Police UOF is rare. When force is used officers most commonly rely on unarmed physical force and CEWs. Significant injuries are rare. Transport for medical evaluation is a poor surrogate for significant injury due to UOF. LEVEL OF EVIDENCE: Epidemiological, level II. PMID- 29283962 TI - Variability of child access prevention laws and pediatric firearm injuries. AB - BACKGROUND: State-level child access prevention (CAP) laws impose criminal liability on adults who negligently allow children access to firearms. The CAP laws can be further divided into strong CAP laws which impose criminal liability for negligently stored firearms and weak CAP laws that prohibit adults from intentionally, knowingly, and/or recklessly providing firearms to a minor. We hypothesized that strong CAP laws would be associated with a greater reduction in pediatric firearm injuries than weak CAP laws. METHODS: We constructed a cross sectional national study using the Healthcare Cost and Utilization Project-Kids Inpatient Database from 2006 and 2009 using weighted counts of firearm-related admissions among children younger than 18 years. Poisson regression was used to estimate the association of CAP laws with pediatric firearm injuries. RESULTS: After adjusting for race, sex, age, and socioeconomic income quartile, strong CAP laws were associated with a significant reduction in all (incidence rate ratio, 0.70; 95% confidence interval, 0.52-0.93), self-inflicted (incidence rate ratio, 0.46; 95% confidence interval, 0.26-0.79), and unintentional (incidence rate ratio, 0.56; 95% confidence interval, 0.43-0.74) pediatric firearm injuries. Weak CAP laws, which only impose liability for reckless endangerment, were associated with an increased risk of all pediatric firearm injuries. CONCLUSION: The association of CAP laws on hospitalizations for pediatric firearm injuries differed greatly depending on whether a state had adopted a strong CAP law or a weak CAP law. Implementation of strong CAP laws by each state, which require safe storage of firearms, has the potential to significantly reduce pediatric firearm injuries. LEVEL OF EVIDENCE: Prognostic and epidemiology study, level III. PMID- 29283963 TI - Clinical relevance of a p-value: Does TXA save lives after trauma or post-partum hemorrhage? PMID- 29283964 TI - The American Association for the Surgery of Trauma uniform grading of hemorrhagic emergency general surgery diseases. PMID- 29283965 TI - Raising the standards on whole blood. PMID- 29283966 TI - Undertriage in trauma: Does an organized trauma network capture the major trauma victim? A statewide analysis. AB - BACKGROUND: Proper triage of critically injured trauma patients to accredited trauma centers (TCs) is essential for survival and patient outcomes. We sought to determine the percentage of patients meeting trauma criteria who received care at non-TCs (NTCs) within the statewide trauma system that exists in the state of Pennsylvania. We hypothesized that a substantial proportion of the trauma population would be undertriaged to NTCs with undertriage rates (UTR) decreasing with increasing severity of injury. METHODS: All adult (age >=15) hospital admissions meeting trauma criteria (ICD-9, 800-959; Injury Severity Score [ISS], > 9 or > 15) from 2003 to 2015 were extracted from the Pennsylvania Health Care Cost Containment Council (PHC4) database, and compared with the corresponding trauma population within the Pennsylvania Trauma Systems Foundation (PTSF) registry. PHC4 contains all hospital admissions within PA while PTSF collects data on all trauma cases managed at designated TCs (Level I-IV). The percentage of patients meeting trauma criteria who are undertriaged to NTCs was determined and Network Analyst Location-Allocation function in ArcGIS Desktop was used to generate geospatial representations of undertriage based on ISSs throughout the state. RESULTS: For ISS > 9, 173,022 cases were identified from 2003 to 2015 in PTSF, while 255,263 cases meeting trauma criteria were found in the PHC4 database over the same timeframe suggesting UTR of 32.2%. For ISS > 15, UTR was determined to be 33.6%. Visual geospatial analysis suggests regions with limited access to TCs comprise the highest proportion of undertriaged trauma patients. CONCLUSION: Despite the existence of a statewide trauma framework for over 30 years, approximately, a third of severely injured trauma patients are managed at hospitals outside of the trauma system in PA. Intelligent trauma system design should include an objective process like geospatial mapping rather than the current system which is driven by competitive models of financial and health care system imperatives. LEVEL OF EVIDENCE: Epidemiological study, level III; Therapeutic, level IV. PMID- 29283967 TI - Pediatric appendicitis: Is referral to a regional pediatric center necessary? AB - BACKGROUND: Acute appendicitis is the most common emergent surgical procedure performed among children in the United States, with an incidence exceeding 80,000 cases per year. Appendectomies are often performed by both pediatric surgeons and adult general/trauma and acute care (TACS) surgeons. We hypothesized that children undergoing appendectomy for acute appendicitis have equivalent outcomes whether a pediatric surgeon or a TACS surgeon performs the operation. METHODS: A retrospective chart review was performed for patients 6 to 18 years of age, who underwent appendectomy at either a regional children's hospital (Children's Hospital of Colorado [CHCO], n = 241) or an urban safety-net hospital (n = 347) between July 2010 and June 2015. The population of patients operated on at the urban safety-net hospital was further subdivided into those operated on by pediatric surgeons (Denver Health Medical Center [DHMC] pediatric surgeons, n = 68) and those operated on by adult TACS surgeons (DHMC TACS, n = 279). Baseline characteristics and operative outcomes were compared between these patient populations utilizing one-way analysis of variance and chi test for independence. RESULTS: When comparing the CHCO and DHMC TACS groups, there were no differences in the proportion of patients with perforated appendicitis, operative time, rate of operative complications, rate of postoperative infectious complications, or rate of 30-day readmission. Length of stay was significantly shorter for the DHMC TACS group than that for the CHCO group. CONCLUSIONS: Our data demonstrate that among children older than 5 years undergoing appendectomy, length of stay, risk of infectious complications, and risk of readmission do not differ regardless of whether they are operated on by pediatric surgeons or adult TACS surgeons, suggesting resources currently consumed by transferring children to hospitals with access to pediatric surgeons could be allocated elsewhere. LEVEL OF EVIDENCE: Therapeutic/Care management, level III. PMID- 29283968 TI - Transfer and nontransfer patients in isolated low-grade blunt pediatric solid organ injury: Implications for regionalized trauma systems. AB - BACKGROUND: Regionalization of trauma care is a national priority and hospitalization for blunt abdominal trauma, which may include transfer, is common among children. The objective of this study was to determine whether there were differences in mortality, treatment, or length of stay between patients treated at or transferred to a higher level trauma center and those not transferred and admitted to a lower level trauma center. METHODS: Cohort from Washington state trauma registry from 2000 to 2014 of patients 16 years or younger with isolated Grade I-III spleen, liver, or kidney injury. RESULTS: Among 54,034 patients 16 years or younger, the trauma registry captured 1177 (2.2%) patients with isolated low grade solid organ injuries; 226 (19.2%) presented to a higher level trauma center, 600 (51.0%) presented to a lower level trauma center and stayed there for care, and 351 (29.8%) were transferred to a higher level trauma center. Forty (3.4%) patients underwent an abdominal operation. Among the 950 patients evaluated initially at a lower level trauma center, the risk of surgery did not differ significantly between those who were not transferred compared to those who were (relative risk, 2.19; 95% confidence interval, 0.80-6.01). The risk of total splenectomy was no different for patients who stayed at a lower level trauma center compared with those who were transferred to a higher level trauma center (RR, 0.84; 95% CI, 0.33-2.16). Nontransferred patients had a 0.63 (95% confidence interval, 0.45-0.88) times lower risk of staying in the hospital for an additional day compared with patients who were transferred to a higher level trauma center. One patient died. CONCLUSION: Few pediatric patients with isolated low grade blunt solid organ injury require intervention and thus may not need to be transferred; trauma systems should revise their transfer policies. Prevention of unnecessary transfers is an opportunity for cost savings in pediatric trauma. LEVEL OF EVIDENCE: Therapeutic/Care management, level III. PMID- 29283969 TI - Development of a trauma system and optimal placement of trauma centers using geospatial mapping. AB - BACKGROUND: The care of patients at individual trauma centers (TCs) has been carefully optimized, but not the placement of TCs within the trauma systems. We sought to objectively determine the optimal placement of trauma centers in Pennsylvania using geospatial mapping. METHODS: We used the Pennsylvania Trauma Systems Foundation (PTSF) and Pennsylvania Health Care Cost Containment Council (PHC4) registries for adult (age >=15) trauma between 2003 and 2015 (n = 377,540 and n = 255,263). TCs and zip codes outside of PA were included to account for edge effects with trauma cases aggregated to the Zip Code Tabulation Area centroid of residence. Model assumptions included no previous TCs (clean slate); travel time intervals of 45, 60, 90, and 120 minutes; TC capacity based on trauma cases per bed size; and candidate hospitals >=200 beds. We used Network Analyst Location-Allocation function in ArcGIS Desktop to generate models optimally placing 1 to 27 TCs (27 current PA TCs) and assessed model outcomes. RESULTS: At a travel time of 60 minutes and 27 sites, optimally placed models for PTSF and PHC4 covered 95.6% and 96.8% of trauma cases in comparison with the existing network reaching 92.3% or 90.6% of trauma cases based on PTSF or PHC4 inclusion. When controlled for existing coverage, the optimal numbers of TCs for PTSF and PHC4 were determined to be 22 and 16, respectively. CONCLUSIONS: The clean slate model clearly demonstrates that the optimal trauma system for the state of Pennsylvania differs significantly from the existing system. Geospatial mapping should be considered as a tool for informed decision-making when organizing a statewide trauma system. LEVEL OF EVIDENCE: Epidemiological study/Care management, level III. PMID- 29283970 TI - Prehospital spine immobilization/spinal motion restriction in penetrating trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma (EAST). AB - BACKGROUND: Spine immobilization in trauma has remained an integral part of most emergency medical services protocols despite a lack of evidence for efficacy and concern for associated complications, especially in penetrating trauma patients. We reviewed the published evidence on the topic of prehospital spine immobilization or spinal motion restriction in adult patients with penetrating trauma to structure a practice management guideline. METHODS: We conducted a Cochrane style systematic review and meta-analysis and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology to construct recommendations. Qualitative and quantitative analyses were used to evaluate the literature on the critical outcomes of mortality, neurologic deficit, and potentially reversible neurologic deficit. RESULTS: A total of 24 studies met inclusion criteria, with qualitative review conducted for all studies. We used five studies for the quantitative review (meta-analysis). No study showed benefit to spine immobilization with regard to mortality and neurologic injury, even for patients with direct neck injury. Increased mortality was associated with spine immobilization, with risk ratio [RR], 2.4 (confidence interval [CI], 1.07-5.41). The rate of neurologic injury or potentially reversible injury was very low, ranging from 0.002 to 0.076 and 0.00034 to 0.055, with no statistically significant difference for neurologic deficit or potentially reversible deficit, RR, 4.16 (CI, 0.56-30.89), and RR, 1.19 (CI, 0.83-1.70), although the point estimates favored no immobilization. CONCLUSION: Spine immobilization in penetrating trauma is associated with increased mortality and has not been shown to have a beneficial effect on mitigating neurologic deficits, even potentially reversible neurologic deficits. We recommend that spine immobilization not be used routinely for adult patients with penetrating trauma. LEVEL OF EVIDENCE: Systematic review with meta-analysis study, level III. PMID- 29283971 TI - A combat relevant model for the creation of acute lung injury in swine. PMID- 29283972 TI - Prognostic significance of day-by-day variability of home blood pressure on progression to macroalbuminuria in patients with diabetes. AB - OBJECTIVES: Previously, we have shown in cross-sectional analysis of patients with type 2 diabetes mellitus that the presence of diabetic nephropathy is associated with increased home blood pressure (HBP) variability. We now examine the prognostic significance of HBP variability in substantially the same cohort. METHODS: We performed a prospective cohort study of type 2 diabetes patients. We analyzed 714 patients. Major exclusion criteria are missing data of urinary albumin excretion and newly prescribed or stopped renin-angiotensin system inhibitors during 2-year follow-up. Patients were instructed to perform triplicate morning and evening HBP measurements for 14 consecutive days. We computed day-by-day HBP variability as within-patient standard deviation (SD) and coefficient of variation (CV) of measurements. RESULTS: During the follow-up period of 2 years, 23 patients progressed to macroalbuminuria. The changing risk of progression to macroalbuminuria with increasing day-by-day variability of morning SBP was better depicted using smoothing spline analyses. Patients with greater SD of morning SBP tended to significantly progress to macroalbuminuria [odds ratio: 5.24 (95% confidence interval: 2.10-13.03; P > 0.001)]. Patients with greater CV of morning SBP also tended to significantly progress to macroalbuminuria [odds ratio: 3.36 (95% confidence interval: 1.39-8.12; P = 0.007)]. CONCLUSION: Day-by-day variability of morning SBP was proven as an independent predictor for progression to macroalbuminuria in patients with type 2 diabetes. PMID- 29283973 TI - Tenascin-C promotes chronic pressure overload-induced cardiac dysfunction, hypertrophy and myocardial fibrosis. AB - AIMS: Left ventricular (LV) hypertrophy is characterized by cardiomyocyte hypertrophy and interstitial fibrosis ultimately leading to increased myocardial stiffness and reduced contractility. There is substantial evidence that the altered expression of matrix metalloproteinases (MMP) and Tenascin-C (TN-C) are associated with the progression of adverse LV remodeling. However, the role of TN C in the development of LV hypertrophy because of chronic pressure overload as well as the regulatory role of TN-C on MMPs remains unknown. METHODS AND RESULTS: In a knockout mouse model of TN-C, we investigated the effect of 10 weeks of pressure overload using transverse aortic constriction (TAC). Cardiac function was determined by magnetic resonance imaging. The expression of MMP-2 and MMP-9, CD147 as well as myocardial fibrosis were assessed by immunohistochemistry. The expression of TN-C was assessed by RT-qPCR and ELISA. TN-C knockout mice showed marked reduction in fibrosis (P < 0.001) and individual cardiomyocytes size (P < 0.01), in expression of MMP-2 (P < 0.05) and MMP-9 (P < 0.001) as well as preserved cardiac function (P < 0.01) in comparison with wild-type mice after 10 weeks of TAC. In addition, CD147 expression was markedly increased under pressure overload (P < 0.01), irrespectively of genotype. TN-C significantly increased the expression of the markers of hypertrophy such as ANP and BNP as well as MMP-2 in H9c2 cells (P < 0.05, respectively). CONCLUSION: Our results are pointed toward a novel signaling mechanism that contributes to LV remodeling via MMPs upregulation, cardiomyocyte hypertrophy as well as myocardial fibrosis by TN-C under chronic pressure overload. PMID- 29283974 TI - The role of distal tubule and collecting duct sodium reabsorption in sunitinib induced hypertension. AB - OBJECTIVE: Antiangiogenic receptor tyrosine kinase inhibitors (RTKI) induce arterial hypertension which may limit their use. Renal fractional sodium excretion (FENa) is reduced in early RTKI-induced hypertension, whereas fractional lithium excretion is unaltered. Therefore, we tested the hypothesis that activated distal tubule and collecting duct sodium reabsorption contributes to RTKI-induced hypertension. METHODS: Amiloride-sensitive and hydrochlorothiazide (HCTZ)-sensitive fractional sodium reabsorption (FRNa) and renal epithelial sodium channel (ENaC) as well as sodium chloride cotransporter (NCC) abundances were determined in sunitinib-treated and control rats. The antihypertensive effects of amiloride and HCTZ were investigated by radiotelemery. RESULTS: After 4 days of treatment, mean arterial pressure was 20 mmHg higher, FENa was lower (0.32 +/- 0.08% vs. 0.65 +/- 0.14%; P < 0.05), and renal medullary-ENaC protein abundance was higher in sunitinib-treated rats than in controls. Amiloride-sensitive FRNa was 2.37 +/- 0.52% in sunitinib-treated rats vs. 2.66 +/- 0.44% in controls (n.s.). HCTZ increased FENa by a similar magnitude without affecting amiloride-sensitive FRNa in both groups. After 14 days of treatment, renal medullary beta-ENaC protein abundance was higher in rats that received sunitinib than in controls, whereas alpha-ENaC, gamma-ENaC, and NCC abundances were similar in both groups. Amiloride and HCTZ reduced the sunitinib induced mean arterial pressure rise by 8 +/- 3 mmHg (P < 0.05) and 12 +/- 2 mmHg (P < 0.05), respectively, without additive effects when combined. CONCLUSION: ENaC-dependent and thiazide-sensitive sodium-retaining mechanisms are not overactive in sunitinib-induced hypertension but ENaC blockers and in particular thiazides may be suitable for its treatment. PMID- 29283975 TI - Sympathetic baroreceptor regulation during hypoxic hypotension in humans: new insights. AB - BACKGROUND: Baroreceptor activation by a continuous infusion of phenylephrine selectively abolishes the muscle sympathetic nerve activity (MSNA) response to hypoxia in humans. Baroreceptor deactivation enhances the MSNA rise during hypoxia in animals. Whether this is true in humans is unknown and was tested in the present study. METHODS: We assessed MSNA responses elicited by isocapnic hypoxia (10% O2 in N2) during baroreflex loading and unloading with phenylephrine and nitroprusside, respectively, in 19 healthy volunteers. The study was randomized and placebo-controlled. RESULTS: Phenylephrine and nitroprusside increased and decreased, respectively, blood pressure during normoxia and hypoxia, whereas the reverse occurred for heart rate and MSNA (all P < 0.001 vs. placebo). As compared with normoxia, cardiac barosensitivity decreased during the infusion of placebo and nitroprusside in the presence of hypoxia, as well as sympathetic barosensitivity during the infusion of nitroprusside (all P < 0.05). Three patients even disclosed a reduction in arterial pressure, which became apparent at the third minute of hypoxia and worsened steadily thereafter (SBP: 91 +/- 7 mmHg; DBP 47 +/- 9 mmHg), in spite of a gradual rise in heart rate of 20 +/ 4 bpm. Changes in baroreceptor loading conditions did not affect ventilation during normoxia and hypoxia. CONCLUSION: Cardiac and sympathetic baroreceptor sensitivity decrease during baroreceptor unloading in the presence of peripheral chemoreceptor activation. Normal humans have limited reflex capabilities to sustain simultaneous reductions in oxygen and pressure, and may experience hemodynamic instability episodes in such condition. PMID- 29283976 TI - Decreased Tidal Volume With Increased Height, but not Colloid Transfusion, is Associated With Worse Outcomes and Postoperative Pneumonia After Coil Embolization of Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study. AB - BACKGROUND: The tidal volume setting as well as colloid transfusion during the peri-operative period after intracranial aneurysm is controversial. A multicenter retrospective study was conducted to determine whether or not an increased tidal volume setting and colloid transfusion are associated with poor outcomes and postoperative pulmonary complications after intracranial aneurysm. METHOD: Data from endovascular coiling to treat intracranial aneurysms that took place between 30 March 2014 and 30 March 2016 were collected in a multicenter chart. The primary outcomes were better (defined as a Modified Rankin scores [MRS] <=2) and worse outcomes (MRS >=3). Secondary outcomes included pneumonia and non-pneumonia in patients with intracranial aneurysms. Univariate analysis, bivariate logistic regression, Spearman correlation, and a linear regression model were performed to account for the association between peri-operative risk factors and different outcomes. RESULTS: Bivariate logistic analysis showed that worse outcomes were correlated with height, Hunt and Hess scores (HHS), and Fisher grade (P < 0.05). There was no significant association between colloid transfusion and worse outcomes and postoperative pneumonia (P > 0.05). Postoperative pneumonia incidence was associated with increased height in a population with intracranial aneurysms (P < 0.05). The Spearman correlation and a linear regression model suggested that increased height was significantly correlated with lower tidal volume setting (per unit of body weight; P < 0.05). CONCLUSION: Decreased tidal volume with increased height, but not colloid transfusion, was independently associated with worse outcomes and postoperative pneumonia across a spectrum of risk profiles. These findings may help to improve practice decisions regarding tidal volume settings. PMID- 29283977 TI - Divergent Effects of Hypertonic Fluid Resuscitation on Renal Pathophysiological and Structural Parameters in Rat Model of Lower Body Ischemia/Reperfusion-Induced Sterile Inflammation. AB - The pathogenesis of acute kidney injury (AKI) is characterized by the deterioration of tissue perfusion and oxygenation and enhanced inflammation. The purpose of this study was to investigate whether or not the hemodynamic and inflammatory effects of hypertonic saline (HS) protect the kidney by promoting renal microcirculatory oxygenation and possible deleterious effects of HS due to its high sodium content on renal functional and structural injury following ischemia/reperfusion. Mechanically ventilated and anesthetized rats were randomly divided into four groups (n = 6 per group): a sham-operated control group; a group subjected to renal ischemia for 45 min by supra-aortic occlusion followed by 2 h of reperfusion (I/R); and I/R group treated with a continuous i.v. infusion (5 mL/kg/h) of either % 0.9 NaCl (IR+NS) or %10 NaCl (I/R+HS) after releasing the clamp. Systemic and renal hemodynamic, renal cortical (CMUPO2), and medullar microcirculatory pO2 (MMUPO2) are measured by the oxygen-dependent quenching of the phosphorescence lifetime technique. Renal functional, inflammatory, and tissues damage parameters were also assessed. HS, but not NS, treatment restored I/R-induced reduced mean arterial pressure, CMUPO2, renal oxygen deliver (DO2ren), and consumption (VO2ren). HS caused a decrease in tubular sodium reabsorption (TNa) that correlated with an elevation of fractional sodium excretion (EFNa) and urine output. HS had an anti-inflammatory effect by reducing the levels TNF-alpha, IL-6, and hyaluronic acid in the renal tissue samples as compared with the I/R and I/R+NS groups (P < 0.05). HS treatment was also associated with mild acidosis and an increased renal tubular damage. Despite HS resuscitation improving the systemic hemodynamics, microcirculatory oxygenation, and renal oxygen consumption as well as inflammation, it should be limited or strictly controlled for long-term use because of provoking widespread renal structural damage. PMID- 29283978 TI - Hibernation-Based Approaches in the Treatment of Hemorrhagic Shock. AB - Hemorrhagic shock is the leading cause of preventable death after trauma. Hibernation-based treatment approaches have been of increasing interest for various biomedical applications. Owing to apparent similarities in tissue perfusion and metabolic activity between severe blood loss and the hibernating state, hibernation-based approaches have also emerged for the treatment of hemorrhagic shock. Research has shown that hibernators are protected from shock induced injury and inflammation. Utilizing the adaptive mechanisms that prevent injury in these animals may help alleviate the detrimental effects of hemorrhagic shock in non-hibernating species. This review describes hibernation-based preclinical and clinical approaches for the treatment of severe blood loss. Treatments include the delta opioid receptor agonist D-Ala-Leu-enkephalin (DADLE), the gasotransmitter hydrogen sulfide, combinations of adenosine, lidocaine, and magnesium (ALM) or D-beta-hydroxybutyrate and melatonin (BHB/M), and therapeutic hypothermia. While we focus on hemorrhagic shock, many of the described treatments may be used in other situations of hypoxia or ischemia/reperfusion injury. PMID- 29283979 TI - Inhibition of RHO Kinase by Fasudil Attenuates Ischemic Lung Injury After Cardiac Arrest in Rats. AB - Lung injury is a common complication after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and Rho kinase (ROCK) may be involved in the process of this injury. In this study, we aimed to study the effects of ROCK inhibition by fasudil on lung injury induced by asphyxial CA and CPR in rats. A total of 130 rats were randomized into three groups: Sham, Control, and Fasudil intervention group. Animals in the Fasudil intervention group were intraperitoneally administered with 10 mg/kg of the drug, 1 h before inducing CA. Rats in the Control group received equivalent volume of saline and were subjected to the same experimental procedures with as the Fasudil group. Blood was collected and lungs were harvested at 3, 6, 12, 24, and 48 h after return of spontaneous circulation (ROSC) for blood gas and biochemical analysis. Fasudil significantly increased the partial pressure of oxygen and pH in arterial blood, as well as attenuated lung histological injury and lung edema after ROSC. Additionally, it significantly decreased lung inflammatory response (decreased levels of tumor necrosis factor-alpha and interleukin-6, and myeloperoxidase activity) and oxidative stress (decreased malonaldehyde level and increased superoxide dismutase activity) after ROSC. Using western blot analysis, we found that fasudil inhibited both isoforms ROCK1 and ROCK2, and intercellular adhesion molecule-1; nevertheless, it increased vascular endothelial cadherin protein expression after ROSC. Our study suggested that the Rho kinase signaling pathway is critical for CA-induced lung injury and fasudil has protective effects on lung injury after CA and CPR. PMID- 29283980 TI - 3D SURGICAL VIEWING SYSTEM IN OPHTHALMOLOGY: Perceptions of the Surgical Team. PMID- 29283981 TI - COLORADO AGE-RELATED MACULAR DEGENERATION REGISTRY: Design and Clinical Risk Factors of the Cohort. AB - PURPOSE: To study new and existing risk factors related to age-related macular degeneration (AMD) phenotypes in a Colorado cohort. METHODS: Age-related macular degeneration was categorized into early, intermediate, or advanced forms. Controls (n = 180) were patients with cataract and no AMD. Demographic and clinical data were gathered by patient interview and verified by chart review. Image data were reviewed by vitreoretinal specialists. Statistical analysis included univariable and multivariate logistic regression analysis (P < 0.05). RESULTS: Among the 456 patients with AMD, 157 (34.4%), 80 (17.6%), and 219 (48.0%) had the early/intermediate, geographic atrophy, and neovascular forms of the disease, respectively. Adjusted for age, African-American race was associated with a reduced risk of early/intermediate (adjusted odds ratio [AOR] = 0.08, confidence interval [CI] = 0.01-0.67) and neovascular AMD (AOR = 0.15, CI = 0.03 0.72). A family history of AMD was a risk factor for early/intermediate (AOR = 4.08, CI = 2.30-7.25), geographic atrophy (AOR = 8.62, CI = 3.77-19.7), and neovascular AMD (AOR = 3.76, CI = 2.16-6.56). A history of asthma was related to the early/intermediate form of AMD (AOR = 2.34, CI = 1.22-4.46). CONCLUSION: Studying AMD in specific populations may reveal novel risk factors such as our finding of a relationship between asthma history and AMD. PMID- 29283982 TI - Stigma of psychiatric diseases and psychiatry. AB - The aim of this review is evaluate stigma seen among people suffering from psychiatric disorders. We will show the negative effects of stigma on psychiatric services and evaluate the importance of continiuous anti-stigma programs. It is encouraging that new anit-stigma programmes are developed. The aim of this program is the restoration of dignity to patients and institutions. Media play an important role in shaping the view of an average person on psychiatric patients and most programms use media as a mediator to promote a positive attitude to psychiatric disorders. Apart from ignorance, fear and hostility they have to deal with self-stigma, as well. Through anti-stigma programs, psychoeducation of patients and families about the disorder and treatment options we can give them an acitve role in the treatment, restore dignity, self-confidence, quality of life and reintegrate them into the society. PMID- 29283983 TI - Psychiatry between Glorification and Stigmatization. AB - In psychiatry, stigma means negative marking of the person only because s(he) has a diagnosis of mental disease, and usually this refers to schizophrenia. Stigmatization is related to prejudice, i.e. negative attitudes that are deeply rooted on false beliefs that schizophrenia cannot be treated. In principle, stigma is caused by combination of ignorance and fear which represents the basis of the creation of entrenched myths and prejudice. From a historical point of view, schizophrenia as a disease remains for public, one of the medical areas that are related to fear, a sense of discomfort, prejudice and avoidance. A combination of difficult mental disease, discrimination and stigmatization can be devastating for mentally disabled patients. Throughout history, stigma played significant role in patient's emotional and social isolation from other people deepening their suffering. A common consequence of stigma is discrimination which represents violation of basic human rights. Mentally disabled patients are often unjustifiably seen as dangerous, incapable, irresponsible which causes their isolation, homelessness and economic collapse. Thereby, possibilities for normal life, work, treatment, rehabilitation and social integration are decreased. PMID- 29283984 TI - Stigmatization of Mentally Ill Patients through Media. AB - The stigmatization of mentally ill patients has negative labelling, marginalization and exclusion of people simply because they have a mental illness. Stigma has negative consequences for the individual and his family, as well as for psychiatry as a profession and the entire community. Stigma weakens the mentally ill, reinforcing a sense of alienation, which has negative consequences on the course of the illness. The media can inform the public about the treatment of mentally ill patients by conveying correct information, who can then act positively towards improving the quality of treatment. Stigma and self stigma create a feeling of low self-esteem and fear of rejection, due to which mentally ill people avoid the media and very rarely speak publicly about their illness. The realization of information rights is very delicate and it is reflected through two opposing but substantially equivalent human rights: 1. Right to information, 2. Right to privacy. Which of the two rights will get advantage depends on the circumstances of each case and journalism ethics. The relationship of psychiatry with the media and especially the media with psychiatry must be extremely correct and professional, based on facts, and not on the pursuit of media sensationalism. The media can significantly reduce the current level of stigmatization of the mentally ill by adequate and correct reports, and thereby facilitate their role in family and society. Lack of knowledge and understanding of mental illness contributes to stigmatization. Education of patients, their families and journalists is crucial if we want to better understand people with mental illness and reduce stigma. PMID- 29283985 TI - Antipsychiatry as the Stigma. AB - The authors presents their perspectives on the relationship between antipsychiatry and the stigma of mental illness. The present paper aims to provide a short review of the basic principles of the antipsychiatric movement, and to discuss the atitudes of its most important theorists. The authors searched recent literature, as well as drawing upon some of the basic antipsychiatric texts. Antipsychiatry dates from 18th century, and as an international movement it emerged during the 1960s as part of the historic tumult of the period rather than as a result of the evolution of scientific ideas. During that period psychiatrists began to see heredity as the cause of mental illness, became pessimistic about restoring patients to sanity, and adopted essentially a custodial approach to care that included use of physical restraints. Radical attitudes of antipsychiatry gave a significant incentive to review psychiatric theory and practice, especially with protecting the rights of mental patients and giving importance not only to somatic, but mental, social and spiritual sides of human existence. But, at the same time, they led to unwarranted attacks on psychiatry as a medical discipline, encouraged different views of its stigmatization and in a certain measure affected the weakening of social awareness about the importance of medical and institutional care for the mentally ill persons. After the 1970s, the antipsychiatry movement became increasingly less influential, due in particular to the rejection of its politicized and reductionistic understanding of psychiatry. PMID- 29283986 TI - Stigma and Suicide. AB - Suicide is one of the major mental health problems in the world. It is estimated that one million suicide are committed per year and that after every suicide six people from the surrounding suffer or develop major life changes. After suicide survivors are at higher risk of developing major psychological changes and suicidal ideations as well. They go through the complicated process of grief which is specifically characterized by the felling of guilt, shame, denial and anger. The griefing process, more often than in other causes of death, doesn't integrate but is complicated with prolonged grief. This represents a very favorable state for perceiving stigma. Stigma is most often defined as a mark of disgrace or infamy; a stain or reproach, as on one's reputation. In suicide we talk about public and self stigma. Both forms of stigma can separately cause social isolation, demoralization, the felling of hopelessness and other consequences that interfere with the previous functioning. Because of the high incidence of psychological changes after stigma it is crucial for the bereaved to have close mental health services. But stigma is a barrier to treatment seeking. After suicide most survivors fell stigmatized but it is not yet known which factors modify the perception of stigma. Other causes of death like natural death are less related to stigma. On the other side traumatic death like an accident or homicide seem to be related to perception of stigma in the same way survivors perceive after suicide. Suicide and stigma are related in a two way direction meaning that suicide can cause stigma but stigma can lead to suicidal thoughts as well. Even suicide attempters fell stigmatized by colleagues, medical staff and their closest surrounding. There is a need for interventions. The effect of broad anti-stigma campaigns and targeted programs still have to be examines. In clinical settings, interventions that reduce self stigma, stigma-stress and shame might successfully reduce suicidality. PMID- 29283987 TI - The Stigma of Mental Illness and Recovery. AB - Stigma and recovery "from" and "in" mental illness are associated in many various ways. While recovery gives opportunities, makes person stronger, gives purpose and meaning to their lives and leads to social inclusion, in the same time stigma reduces opportunities, reduces self-esteem and self-efficacy, reduces the belief in own abilities and contributes to social exclusion through discrimination. The recovery of a person with mental illness means to get and keep hope, to understand their own possibilities and impossibilities, active living, to be autonomous, to have a social identity and to give meaning and purpose of our own lives. The care system, recovery-oriented, provides help and support to people with mental disorders in his/her recovery, which contributes to reduction of self stigma, to the elimination of stigmatizing attitudes and beliefs in mental health services which consequently may have a positive reflection in reducing the stigma of mental illness in the community. It is important to look at the stigma and recovery from the perspective of individual experience of each person with a mental illness in the process of recovery. A support to the recovery concept and the development of a recovery-oriented system of care should be one of the key segments of any strategy to combat the stigma of mental illness. Also, the cultural and the social stigma aspects of stigma would be taken into account in the developing of the recovery concept and on the recovery-oriented care system. PMID- 29283988 TI - Stigma and Mental Disorders in Developmental Age. AB - Most mental disorders begin during developmental age. Different misinformation about mental illnesses cause anxiety, create stereotypes and promote stigma. Stigma has been identified as a likely key factor in mental health services access and utilization, particularly under-utilization of existing services especially in children with mental disorders. Stigma is a problem with which parents / carers face child emotional and behavioral problems when they seek professional help. Very often they avoid to seek professional help due to existing stigmatized attitudes leading to lack of treatment. Poor mental health is strongly related to other health and development concerns in young people, notably lower educational achievements, substance abuse and violence. The paper presents influence of mental disorders in developmentale age and consequence of mental stigma on psychosocial function on children and adolescent. PMID- 29283989 TI - Methods to Fight Mental Illness Stigma. AB - Mental illness stigma is still widely spread and present in all the cultures and nations. Even more, during the last half of century there hasn't been much change in the perception of mentally ill persons as "incurable and dangerous individuals incapable of living on their own". The significance of mental illness stigma is determined by the size of its negative effect on mentally ill individuals, their family members, and the psychiatric service as well as on the society as a whole. In order to reduce the negative effects of stigma on the life of mentally ill individuals as well as to provide equal lifestyle in the community, at the beginning of the 1990s the World Health Organization recommended a global and decisive fight against the mental health stigma and discrimination. Since then three effective methods proliferated in fighting the mental illness stigma. These methods consist of combining education, contact with stigmatized group representatives and protest. To achieve better efficiency of anti-stigma program, the fight should be led by citizens of all age groups, especially younger people, the media, health care providers involved in treating the patients, but also the patients themselves as well as their family members. PMID- 29283990 TI - The Effects of Berberine on Concanavalin A-Induced Autoimmune Hepatitis (AIH) in Mice and the Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase (AMPK) Pathway. AB - BACKGROUND Berberine, a herbal extract, has been reported to protect against inflammatory disorders. The adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway can be activated by berberine and inhibited by the synthetic, reversible AMP-competitive inhibitor, Compound C. The aim of this study was to investigate the effects of berberine on concanavalin A (Con A) induced autoimmune hepatitis (AIH) in mice via the AMPK pathway. MATERIAL AND METHODS BALB/c mice were treated with berberine, with or without Compound C, followed by treatment with Con A. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Liver tissue histology was performed to evaluate hepatic injury and AIH. Cytokine levels in serum and hepatic tissue were measured by enzyme-linked immunoassay (ELISA) and used quantitative polymerase chain reaction (qPCR). Levels of phosphorylated acetyl coenzyme-A carboxylase (ACC), representing AMPK activation, were detected by Western blotting. RESULTS Serum ALT and AST levels were significantly reduced by berberine (100 and 200 mg/kg/day) in mice with Con A-induced hepatitis. Berberine also reduced Con A-induced hepatocyte swelling, cell death, and infiltration of leukocytes. Serum levels of tumor necrosis factor (TNF)-alpha, interferon (IF) gamma, interleukin (IL)-2, and IL-1beta were reduced by berberine pre-treatment; levels of serum IL-10, an anti-inflammatory cytokine, was elevated. These protective effects of berberine on Con-A-induced AIH were reversed by treatment with Compound C. CONCLUSIONS In a murine model of Con A-induced AIH, berberine treatment reduced hepatic injury via activation of the AMPK pathway. Further studies are recommended to determine the potential therapeutic role for berberine in AIH. PMID- 29283991 TI - Arabidopsis choline transporter-like 1 (CTL1) regulates secretory trafficking of auxin transporters to control seedling growth. AB - Auxin controls a myriad of plant developmental processes and plant response to environmental conditions. Precise trafficking of auxin transporters is essential for auxin homeostasis in plants. Here, we report characterization of Arabidopsis CTL1, which controls seedling growth and apical hook development by regulating intracellular trafficking of PIN-type auxin transporters. The CTL1 gene encodes a choline transporter-like protein with an expression pattern highly correlated with auxin distribution and is enriched in shoot and root apical meristems, lateral root primordia, the vascular system, and the concave side of the apical hook. The choline transporter-like 1 (CTL1) protein is localized to the trans Golgi network (TGN), prevacuolar compartment (PVC), and plasma membrane (PM). Disruption of CTL1 gene expression alters the trafficking of 2 auxin efflux transporters-Arabidopsis PM-located auxin efflux transporter PIN-formed 1 (PIN1) and Arabidopsis PM-located auxin efflux transporter PIN-formed 3 (PIN3)-to the PM, thereby affecting auxin distribution and plant growth and development. We further found that phospholipids, sphingolipids, and other membrane lipids were significantly altered in the ctl1 mutant, linking CTL1 function to lipid homeostasis. We propose that CTL1 regulates protein sorting from the TGN to the PM through its function in lipid homeostasis. PMID- 29283992 TI - Common genes associated with antidepressant response in mouse and man identify key role of glucocorticoid receptor sensitivity. AB - Response to antidepressant treatment in major depressive disorder (MDD) cannot be predicted currently, leading to uncertainty in medication selection, increasing costs, and prolonged suffering for many patients. Despite tremendous efforts in identifying response-associated genes in large genome-wide association studies, the results have been fairly modest, underlining the need to establish conceptually novel strategies. For the identification of transcriptome signatures that can distinguish between treatment responders and nonresponders, we herein submit a novel animal experimental approach focusing on extreme phenotypes. We utilized the large variance in response to antidepressant treatment occurring in DBA/2J mice, enabling sample stratification into subpopulations of good and poor treatment responders to delineate response-associated signature transcript profiles in peripheral blood samples. As a proof of concept, we translated our murine data to the transcriptome data of a clinically relevant human cohort. A cluster of 259 differentially regulated genes was identified when peripheral transcriptome profiles of good and poor treatment responders were compared in the murine model. Differences in expression profiles from baseline to week 12 of the human orthologues selected on the basis of the murine transcript signature allowed prediction of response status with an accuracy of 76% in the patient population. Finally, we show that glucocorticoid receptor (GR)-regulated genes are significantly enriched in this cluster of antidepressant-response genes. Our findings point to the involvement of GR sensitivity as a potential key mechanism shaping response to antidepressant treatment and support the hypothesis that antidepressants could stimulate resilience-promoting molecular mechanisms. Our data highlight the suitability of an appropriate animal experimental approach for the discovery of treatment response-associated pathways across species. PMID- 29283993 TI - QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PMID- 29283994 TI - Timing of chronic hepatitis B diagnosis after migration and its determinants among Sub-Saharan African migrants living in France. AB - OBJECTIVE: In European countries, chronic hepatitis B (CHB) disproportionately affects migrants from medium- and high-endemic areas and is largely underdiagnosed. To inform policy and improve screening strategies, we measured the timing of CHB diagnosis after migration and its determinants among sub Saharan migrants living in the Paris metropolitan area (France). DESIGN: The PARCOURS study is a retrospective life-event history survey conducted in health care services in 2012-2013 among 779 migrants from sub-Saharan Africa who were receiving care for CHB. We investigated the timing of CHB diagnosis from the time of arrival in France using the Kaplan-Meier method and characteristics associated with CHB diagnosis since the time of arrival in France using discrete-time multivariate logistic regression models. RESULTS: The median CHB diagnosis occurred during the fourth year spent in France for men and during the second year spent in France for women. Among men, the probability of CHB diagnosis increased during years with (versus without) a temporary resident permit (aOR: 1.6, 95%CI: 1.1-2.2), a precarious accommodation (aOR: 1.7, 95%CI: 1.1-2.6), and hospitalization (aOR: 7.7, 95%CI: 3.4-15.1). Among women, CHB diagnosis was more likely to occur during years with unemployment (aOR: 1.9, 95%CI: 1.1-3.94), pregnancy (aOR: 6.6, 95%CI: 3.5-12.5) and hospitalization (aOR: 9.0, 95%CI: 2.95 32.3). For both sexes, the probability of CHB diagnosis was higher among those who migrated to France because they were threatened in their country. CONCLUSION: This study shows that social hardships (residential, economic, administrative) and contact with the health care system after arrival in France hasten access to a CHB diagnosis. PMID- 29283995 TI - Protection by extra virgin olive oil against oxidative stress in vitro and in vivo. Chemical and biological studies on the health benefits due to a major component of the Mediterranean diet. AB - We report the results of in vivo studies in Caenorhabditis elegans nematodes in which addition of extra virgin olive oil (EVOO) to their diet significantly increased their life span with respect to the control group. Furthermore, when nematodes were exposed to the pesticide paraquat, they started to die after two days, but after the addition of EVOO to their diet, both survival percentage and lifespans of paraquat-exposed nematodes increased. Since paraquat is associated with superoxide radical production, a test for scavenging this radical was performed using cyclovoltammetry and the EVOO efficiently scavenged the superoxide. Thus, a linear correlation (y = -0.0838x +19.73, regression factor = 0.99348) was observed for superoxide presence (y) in the voltaic cell as a function of aliquot (x) additions of EVOO, 10 MUL each. The originally generated supoeroxide was approximately halved after 10 aliquots (100 MUL total). The superoxide scavenging ability was analyzed, theoretically, using Density Functional Theory for tyrosol and hydroxytyrosol, two components of EVOO and was also confirmed experimentally for the galvinoxyl radical, using Electron Paramagnetic Resonance (EPR) spectroscopy. The galvinoxyl signal disappeared after adding 1 MUL of EVOO to the EPR cell in 10 minutes. In addition, EVOO significantly decreased the proliferation of human leukemic THP-1 cells, while it kept the proliferation at about normal levels in rat L6 myoblasts, a non-tumoral skeletal muscle cell line. The protection due to EVOO was also assessed in L6 cells and THP-1 exposed to the radical generator cumene hydroperoxide, in which cell viability was reduced. Also in this case the oxidative stress was ameliorated by EVOO, in line with results obtained with tetrazolium dye reduction assays, cell cycle analysis and reactive oxygen species measurements. We ascribe these beneficial effects to EVOO antioxidant properties and our results are in agreement with a clear health benefit of EVOO use in the Mediterranean diet. PMID- 29283996 TI - Genome-wide association study and genetic diversity analysis on nitrogen use efficiency in a Central European winter wheat (Triticum aestivum L.) collection. AB - To satisfy future demands, the increase of wheat (Triticum aestivum L.) yield is inevitable. Simultaneously, maintaining high crop productivity and efficient use of nutrients, especially nitrogen use efficiency (NUE), are essential for sustainable agriculture. NUE and its components are inherently complex and highly influenced by environmental factors, nitrogen management practices and genotypic variation. Therefore, a better understanding of their genetic basis and regulation is fundamental. To investigate NUE-related traits and their genetic and environmental regulation, field trials were evaluated in a Central European wheat collection of 93 cultivars at two nitrogen input levels across three seasons. This elite germplasm collection was genotyped on DArTseq(r) genotypic platform to identify loci affecting N-related complex agronomic traits. To conduct robust genome-wide association mapping, the genetic diversity, population structure and linkage disequilibrium were examined. Population structure was investigated by various methods and two subpopulations were identified. Their separation is based on the breeding history of the cultivars, while analysis of linkage disequilibrium suggested that selective pressures had acted on genomic regions bearing loci with remarkable agronomic importance. Besides NUE, genetic basis for variation in agronomic traits indirectly affecting NUE and its components, moreover genetic loci underlying response to nitrogen fertilisation were also determined. Altogether, 183 marker-trait associations (MTA) were identified spreading over almost the entire genome. We found that most of the MTAs were environmental-dependent. The present study identified several associated markers in those genomic regions where previous reports had found genes or quantitative trait loci influencing the same traits, while most of the MTAs revealed new genomic regions. Our data provides an overview of the allele composition of bread wheat varieties anchored to DArTseq(r) markers, which will facilitate the understanding of the genetic basis of NUE and agronomically important traits. PMID- 29283997 TI - Maternal influenza vaccine strategies in Kenya: Which approach would have the greatest impact on disease burden in pregnant women and young infants? AB - BACKGROUND: Recent influenza surveillance data from Africa suggest an important burden of influenza-associated morbidity and mortality. In tropical countries where influenza virus transmission may not be confined to a single season alternative strategies for vaccine distribution via antenatal care (ANC) or semiannual campaigns should be considered. METHODS: Using data on monthly influenza disease burden in women of child-bearing age and infants aged 0-5 months in Kenya from 2010-2014, we estimated the number of outcomes (illnesses, medical visits, hospitalizations, and deaths) that occurred and that may have been averted through influenza vaccination of pregnant women using: 1) a year round immunization strategy through ANC, 2) annual vaccination campaigns, and 3) semiannual vaccination campaigns. RESULTS: During 2010-2014, influenza resulted in an estimated 279,047 illnesses, 36,276 medical visits, 1612 hospitalizations and 243 deaths in pregnant women and 157,053 illnesses, 65,177 medical visits, 4197 hospitalizations, and 755 deaths in infants aged 0-5 months in Kenya. Depending on the mode of distribution and the vaccine coverage achieved, 12.8 31.4% of influenza-associated disease in pregnant women and 11.6-22.1% in infants aged 0-5 months might have been prevented through maternal influenza immunization. In this model, point estimates for influenza-associated disease averted through maternal vaccination delivered year-round in ANC or semiannually in campaigns were higher than vaccination delivered in a single annual campaign, but confidence intervals overlapped. CONCLUSIONS: Vaccinating pregnant women against influenza can reduce the burden of influenza-associated illness, hospitalization and death in both pregnant women and their young infants. Alternative immunization strategies may avert more influenza-associated disease in countries where influenza virus transmission occurs throughout the year. PMID- 29283998 TI - Method for enhancing single-trial P300 detection by introducing the complexity degree of image information in rapid serial visual presentation tasks. AB - The application of electroencephalogram (EEG) generated by human viewing images is a new thrust in image retrieval technology. A P300 component in the EEG is induced when the subjects see their point of interest in a target image under the rapid serial visual presentation (RSVP) experimental paradigm. We detected the single-trial P300 component to determine whether a subject was interested in an image. In practice, the latency and amplitude of the P300 component may vary in relation to different experimental parameters, such as target probability and stimulus semantics. Thus, we proposed a novel method, Target Recognition using Image Complexity Priori (TRICP) algorithm, in which the image information is introduced in the calculation of the interest score in the RSVP paradigm. The method combines information from the image and EEG to enhance the accuracy of single-trial P300 detection on the basis of traditional single-trial P300 detection algorithm. We defined an image complexity parameter based on the features of the different layers of a convolution neural network (CNN). We used the TRICP algorithm to compute for the complexity of an image to quantify the effect of different complexity images on the P300 components and training specialty classifier according to the image complexity. We compared TRICP with the HDCA algorithm. Results show that TRICP is significantly higher than the HDCA algorithm (Wilcoxon Sign Rank Test, p<0.05). Thus, the proposed method can be used in other and visual task-related single-trial event-related potential detection. PMID- 29283999 TI - Alternative therapeutics for self-limiting infections-An indirect approach to the antibiotic resistance challenge. AB - Alternative therapeutics for infectious diseases is a top priority, but what infections should be the primary targets? At present there is a focus on therapies for severe infections, for which effective treatment is most needed, but these infections are hard to manage, and progress has been limited. Here, we explore a different approach. Applying an evolutionary perspective to a review of antibiotic prescription studies, we identify infections that likely make a large contribution to resistance evolution across multiple taxa but are clinically mild and thus present easier targets for therapeutics development. Alternative therapeutics for these infections, we argue, would save lives indirectly by preserving the high efficacy of existing antibiotics for the patients who need them the most. PMID- 29284000 TI - Oestrogen receptor negative early operable primary breast cancer in older women Biological characteristics and long-term clinical outcome. AB - BACKGROUND: Older women are at the greatest risk of breast cancer development and a considerable number present with comorbidities. Although the majority of breast cancers in this age group express oestrogen receptor (ER), which makes endocrine therapy (primary or adjuvant) feasible, given the huge size of the elderly population, there remains a significant number of patients, in absolute term, whose tumours do not express ER and their management is challenging. METHODS: Of a consecutive series of 1,758 older (>=70 years) women with early operable primary breast cancer managed in a dedicated service from 1973-2010, 252(14.3%) had ER-negative (histochemical (H) score <=50) tumours. Their clinical outcome was retrospectively reviewed and tumour samples collected from diagnostic core biopsies were analysed for progesterone receptor (PgR), HER2 and Ki67 using immunohistochemistry. RESULTS: The commonest primary treatment was surgery (N = 194, 77%) followed by primary endocrine therapy (14.3%), primary radiotherapy (5.6%) and supportive treatment only (3.1%). Among the patients undergoing surgery, most of them had grade 3 (78.1%) and node-negative disease (62.2%). Some of them (21.1%) received postoperative radiotherapy. At a median follow-up of 37.5 months, 117 patients had died, out of which 48.6% were due to breast cancer. For those who underwent surgery, the regional and local recurrence rates were 2% and 1.1% per annum respectively. For those who received primary endocrine therapy, 38% progressed at 6 months, however all patients who had primary radiotherapy achieved clinical benefit at 6 months. Regardless of treatment given, the 5-year breast cancer specific and overall survival rates were 70% and 50% respectively. Biological analysis based on good quality needle core biopsy specimensfrom181 patients showed that 26.8% (N = 49), 16.9% (N = 31) and 70.7% (N = 70)expressed positivity for PgR, HER2 and Ki67 respectively. No correlation between these biomarkers and breast cancer specific survival was demonstrated. CONCLUSION: Oestrogen receptor negative early operable primary breast cancer in older women is associated with poor prognostic features in terms of biology and clinical outcome. Surgery appears to produce the best outcome as a primary treatment, however for those where neither surgery nor chemotherapy is appropriate, primary radiotherapy can be beneficial. PMID- 29284001 TI - DNase-capture reveals differential transcription factor binding modalities. AB - We describe DNase-capture, an assay that increases the analytical resolution of DNase-seq by focusing its sequencing phase on selected genomic regions. We introduce a new method to compensate for capture bias called BaseNormal that allows for accurate recovery of transcription factor protection profiles from DNase-capture data. We show that these normalized data allow for nuanced detection of transcription factor binding heterogeneity with as few as dozens of sites. PMID- 29284002 TI - A new vesicle trafficking regulator CTL1 plays a crucial role in ion homeostasis. AB - Ion homeostasis is essential for plant growth and environmental adaptation, and maintaining ion homeostasis requires the precise regulation of various ion transporters, as well as correct root patterning. However, the mechanisms underlying these processes remain largely elusive. Here, we reported that a choline transporter gene, CTL1, controls ionome homeostasis by regulating the secretory trafficking of proteins required for plasmodesmata (PD) development, as well as the transport of some ion transporters. Map-based cloning studies revealed that CTL1 mutations alter the ion profile of Arabidopsis thaliana. We found that the phenotypes associated with these mutations are caused by a combination of PD defects and ion transporter misregulation. We also established that CTL1 is involved in regulating vesicle trafficking and is thus required for the trafficking of proteins essential for ion transport and PD development. Characterizing choline transporter-like 1 (CTL1) as a new regulator of protein sorting may enable researchers to understand not only ion homeostasis in plants but also vesicle trafficking in general. PMID- 29284003 TI - Identifying cholera "hotspots" in Uganda: An analysis of cholera surveillance data from 2011 to 2016. AB - BACKGROUND: Despite advance in science and technology for prevention, detection and treatment of cholera, this infectious disease remains a major public health problem in many countries in sub-Saharan Africa, Uganda inclusive. The aim of this study was to identify cholera hotspots in Uganda to guide the development of a roadmap for prevention, control and elimination of cholera in the country. METHODOLOGY/PRINCIPLE FINDINGS: We obtained district level confirmed cholera outbreak data from 2011 to 2016 from the Ministry of Health, Uganda. Population and rainfall data were obtained from the Uganda Bureau of Statistics, and water, sanitation and hygiene data from the Ministry of Water and Environment. A spatial scan test was performed to identify the significantly high risk clusters. Cholera hotspots were defined as districts whose center fell within a significantly high risk cluster or where a significantly high risk cluster was completely superimposed onto a district. A zero-inflated negative binomial regression model was employed to identify the district level risk factors for cholera. In total 11,030 cases of cholera were reported during the 6-year period. 37(33%) of 112 districts reported cholera outbreaks in one of the six years, and 20 (18%) districts experienced cholera at least twice in those years. We identified 22 districts as high risk for cholera, of which 13 were near a border of Democratic Republic of Congo (DRC), while 9 districts were near a border of Kenya. The relative risk of having cholera inside the high-risk districts (hotspots) were 2 to 22 times higher than elsewhere in the country. In total, 7 million people were within cholera hotspots. The negative binomial component of the ZINB model shows people living near a lake or the Nile river were at increased risk for cholera (incidence rate ratio, IRR = 0.98, 95% CI: 0.97 to 0.99, p < .01); people living near the border of DRC/Kenya or higher incidence rate in the neighboring districts were increased risk for cholera in a district (IRR = 0.99, 95% CI: 0.98 to 1.00, p = .02 and IRR = 1.02, 95% CI: 1.01 to 1.03, p < .01, respectively). The zero inflated component of the ZINB model yielded shorter distance to Kenya or DRC border, higher incidence rate in the neighboring districts, and higher annual rainfall in the district were associated with the risk of having cholera in the district. CONCLUSIONS/SIGNIFICANCE: The study identified cholera hotspots during the period 2011-2016. The people located near the international borders, internationally shared lakes and river Nile were at higher risk for cholera outbreaks than elsewhere in the country. Targeting cholera interventions to these locations could prevent and ultimately eliminate cholera in Uganda. PMID- 29284004 TI - Outbreaks of acute gastroenteritis associated with a re-emerging GII.P16-GII.2 norovirus in the spring of 2017 in Jiangsu, China. AB - A total of 64 acute gastroenteritis outbreaks with 2,953 patients starting in December of 2016 and occurring mostly in the late spring of 2017 were reported in Jiangsu, China. A recombinant GII.P16-GII.2 norovirus variant was associated with 47 outbreaks (73.4%) for the gastroenteritis epidemic, predominantly occurring in February and March of 2017. Sequence analysis of the RNA-dependent RNA polymerase (RdRp) and capsid protein of the viral isolates from these outbreaks confirmed that this GII.P16-GII.2 strain was the GII.P16-GII.2 variant with the intergenotypic recombination, identified in Taiwan, Hong Kong, and other cities in China in 2016. This GII.P16-GII.2 recombinant variant appeared to a re emerging strain, firstly identified in 2011-2012 from Japan and USA but might be independently originated from other GII.P16-GII.2 variants for sporadic and outbreaks of gastroenteritis in Japan and China before 2016. Further identification of unique amino acid mutations in both VP1 and RdRp of NoV strain as shown in this report may provide insight in explaining its structural and antigenic changes, potentially critical for the variant recombinant to gain its predominance in causing regional and worldwide epidemics. PMID- 29284005 TI - Surveillance of strongyloidiasis in Spanish in-patients (1998-2014). AB - BACKGROUND: Strongyloides stercoralis is a parasite that causes strongyloidiasis, a neglected tropical disease. S. stercoralis is a soil-transmitted helminth that is widely distributed in tropical and subtropical regions of the world. Strongyloidiasis can occur without any symptoms or as a chronic infection characterized by mild, unspecific symptoms such as pruritus, abdominal pain or discomfort; respiratory impairment also may manifest as a potentially fatal hyperinfection or disseminated infection. Most studies on strongyloidiasis in Spain have been related to chronic forms in immigrants or travellers from endemic zones and have mainly analysed out-patient populations. Studies of the impact of strongyloidiasis cases admitted to hospitals in Spain are lacking. Therefore, the aim of this study was to analyse the impact of strongyloidiasis in hospital care in Spain. METHODOLOGY: We designed a retrospective descriptive study using the Minimum Basic Data Set (MBDS, CMBD in Spanish) for inpatients with ICD-9: 127.2 (strongyloidiasis) diagnoses admitted to hospitals in the Spanish National Health System between 1998 and 2014. PRINCIPAL FINDINGS: A total of 507 hospitalizations with diagnosis of strongyloidiasis were recorded, 324 cases (63.9%) were males. The mean (+/-SD) age was 42.1+/-20.1 years. The impact of strongyloidiasis on the total population of Spain was 0.06 cases per 105 person-years, and the infection burden increased progressively over time (from 0.01 cases per 105 person-years in 1999 to 0.10 cases per 105 person-years in 2014). 40 cases (7.9%) died. The total cost was approximately ?8,681,062.3, and the mean cost per patient was ?17,122.4+/-97,968.8. CONCLUSIONS: Our data suggest that strongyloidiasis is frequent in Spain and is increasing in incidence. Therefore, it would be desirable to improve the oversight and surveillance of this condition. Due to the fact that strongyloidiasis can be fatal, we believe that there is a need to establish risk categories for inclusion in national guidelines/protocols for screening individuals at risk of developing strongyloidiasis. PMID- 29284007 TI - Effects of low molecular sugars on the retrogradation of tapioca starch gels during storage. AB - The effects of low molecular sugars (sucrose, glucose and trehalose) on the retrogradation of tapioca starch (TS) gels stored at 4 degrees C for different periods were examined with different methods. Decrease in melting enthalpy (DeltaHmelt) were obtained through differential scanning calorimetry analysis. Analysis of decrease in crystallization rate constant (k) and increase in semi crystallization time (tau1/2) results obtained from retrogradation kinetics indicated that low molecular sugars could retard the retrogradation of TS gels and further revealed trehalose as the best inhibitor among the sugars used in this study. Fourier transform infrared (FTIR) analysis indicated that the intensity ratio of 1047 to 1022 cm-1 was increased with the addition of sugars in the order of trehalose > sucrose > glucose. Decrease in hardness parameters and increase in springiness parameters obtained from texture profile analysis (TPA) analysis also indicated that low molecular sugars could retard the retrogradation of TS gels. The results of FTIR and TPA showed a consistent sugar effect on starch retrogradation with those of DSC and retrogradation kinetics analysis. PMID- 29284006 TI - SM22alpha suppresses cytokine-induced inflammation and the transcription of NF kappaB inducing kinase (Nik) by modulating SRF transcriptional activity in vascular smooth muscle cells. AB - Vascular smooth muscle cell (VSMC) phenotypic modulation is characterized by the downregulation of SMC actin cytoskeleton proteins. Our published study shows that depletion of SM22alpha (aka SM22, Transgelin, an actin cytoskeleton binding protein) promotes inflammation in SMCs by activating NF-kappaB signal pathways both in cultured VSMCs and in response to vascular injury. The goal of this study is to investigate the underlying molecular mechanisms whereby SM22 suppresses NF kappaB signaling pathways under inflammatory condition. NF-kappaB inducing kinase (Nik, aka MAP3K14, activated by the LTbetaR) is a key upstream regulator of NF kappaB signal pathways. Here, we show that SM22 overexpression suppresses the expression of NIK and its downstream NF-kappaB canonical and noncanonical signal pathways in a VSMC line treated with a LTbetaR agonist. SM22 regulates NIK expression at both transcriptional and the proteasome-mediated post-translational levels in VSMCs depending on the culture condition. By qPCR, chromatin immunoprecipitation and luciferase assays, we found that Nik is a transcription target of serum response factor (SRF). Although SM22 is known to be expressed in the cytoplasm, we found that SM22 is also expressed in the nucleus where SM22 interacts with SRF to inhibit the transcription of Nik and prototypical SRF regulated genes including c-fos and Egr3. Moreover, carotid injury increases NIK expression in Sm22-/- mice, which is partially relieved by adenovirally transduced SM22. These findings reveal for the first time that SM22 is expressed in the nucleus in addition to the cytoplasm of VSMCs to regulate the transcription of Nik and its downstream proinflammatory NF-kB signal pathways as a modulator of SRF during vascular inflammation. PMID- 29284008 TI - Off-hours presentation is associated with short-term mortality but not with long term mortality in patients with ST-segment elevation myocardial infarction: A meta-analysis. AB - BACKGROUND: The association between off-hours presentation and mortality in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. We performed a meta-analysis to assess the impact of off-hours presentation on short- and long-term mortality among STEMI patients. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from their inception to 10 July 2016. Studies were eligible if they evaluated the relationship of off-hours (weekend and/or night) presentation with short- and/or long-term mortality. RESULTS: A total of 30 studies with 33 cohorts involving 192,658 STEMI patients were included. Off hours presentation was associated with short-term mortality (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12, P = 0.004) but not with long-term mortality (OR 1.00, 95% CI 0.94-1.07, P = 0.979). No significant heterogeneity was observed. The outcomes remained the same after sensitivity analyses and trim and fill analyses. Subgroup analyses showed that STEMI patients undergoing primary percutaneous coronary intervention do not have a higher risk of short term mortality (OR 1.061, 95% CI 0.993-1.151). In addition, higher mortality was observed only during hospitalization (OR 1.072, 95% CI 1.022-1.125), not at the 30-day, 1-year or long-term follow-ups. CONCLUSIONS: Off-hours presentation was associated with an increase in short-term mortality, but not long-term mortality, among STEMI patients. Clinical approaches to decrease short-term mortality regardless of the time of presentation should be evaluated in future studies. PMID- 29284009 TI - HIV-1 envelope sequence-based diversity measures for identifying recent infections. AB - Identifying recent HIV-1 infections is crucial for monitoring HIV-1 incidence and optimizing public health prevention efforts. To identify recent HIV-1 infections, we evaluated and compared the performance of 4 sequence-based diversity measures including percent diversity, percent complexity, Shannon entropy and number of haplotypes targeting 13 genetic segments within the env gene of HIV-1. A total of 597 diagnostic samples obtained in 2013 and 2015 from recently and chronically HIV-1 infected individuals were selected. From the selected samples, 249 (134 from recent versus 115 from chronic infections) env coding regions, including V1 C5 of gp120 and the gp41 ectodomain of HIV-1, were successfully amplified and sequenced by next generation sequencing (NGS) using the Illumina MiSeq platform. The ability of the four sequence-based diversity measures to correctly identify recent HIV infections was evaluated using the frequency distribution curves, median and interquartile range and area under the curve (AUC) of the receiver operating characteristic (ROC). Comparing the median and interquartile range and evaluating the frequency distribution curves associated with the 4 sequence-based diversity measures, we observed that the percent diversity, number of haplotypes and Shannon entropy demonstrated significant potential to discriminate recent from chronic infections (p<0.0001). Using the AUC of ROC analysis, only the Shannon entropy measure within three HIV-1 env segments could accurately identify recent infections at a satisfactory level. The env segments were gp120 C2_1 (AUC = 0.806), gp120 C2_3 (AUC = 0.805) and gp120 V3 (AUC = 0.812). Our results clearly indicate that the Shannon entropy measure represents a useful tool for predicting HIV-1 infection recency. PMID- 29284011 TI - Genetic variability of Taenia solium cysticerci recovered from experimentally infected pigs and from naturally infected pigs using microsatellite markers. AB - The adult Taenia solium, the pork tapeworm, usually lives as a single worm in the small intestine of humans, its only known definitive host. Mechanisms of genetic variation in T. solium are poorly understood. Using three microsatellite markers previously reported [1], this study explored the genetic variability of T. solium from cysts recovered from experimentally infected pigs. It then explored the genetic epidemiology and transmission in naturally infected pigs and adult tapeworms recovered from human carriers from an endemic rural community in Peru. In an initial study on experimental infection, two groups of three piglets were each infected with proglottids from one of two genetically different tapeworms for each of the microsatellites. After 7 weeks, pigs were slaughtered and necropsy performed. Thirty-six (92.3%) out of 39 cysts originated from one tapeworm, and 27 (100%) out of 27 cysts from the other had exactly the same genotype as the parental tapeworm. This suggests that the microsatellite markers may be a useful tool for studying the transmission of T. solium. In the second study, we analyzed the genetic variation of T. solium in cysts recovered from eight naturally infected pigs, and from adult tapeworms recovered from four human carriers; they showed genetic variability. Four pigs had cysts with only one genotype, and four pigs had cysts with two different genotypes, suggesting that multiple infections of genetically distinct parental tapeworms are possible. Six pigs harbored cysts with a genotype corresponding to one of the identified tapeworms from the human carriers. In the dendrogram, cysts appeared to cluster within the corresponding pigs as well as with the geographical origin, but this association was not statistically significant. We conclude that genotyping of microsatellite size polymorphisms is a potentially important tool to trace the spread of infection and pinpoint sources of infection as pigs spread cysts with a shared parental genotype. PMID- 29284010 TI - Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. AB - BACKGROUND: Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort. METHODS: Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate by investigator review per Response Evaluation Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016. RESULTS: Of 137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had PD L1-positive tumors, of which 23 were enrolled. Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment. Most patients (n = 15, 65%) experienced progressive disease. One partial response occurred in a patient (4%) with MSI-high CRC. CONCLUSION: Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population. (Clinicaltrials.gov registration: NCT02054806). PMID- 29284012 TI - Chikungunya virus emergence in the Lao PDR, 2012-2013. AB - In May 2012, the first authenticated cases of active chikungunya virus infection were detected in Champasak Province, Southern Laos. Analysis of series of human samples and mosquito specimens collected during the outbreak and over the year that followed the emergence enabled the drawing up of a map of the progression of CHIKV and the establishment of a full genetic characterization of the virus. PMID- 29284013 TI - Creating a stem cell niche in the inner ear using self-assembling peptide amphiphiles. AB - The use of human embryonic stem cells (hESCs) for regeneration of the spiral ganglion will require techniques for promoting otic neuronal progenitor (ONP) differentiation, anchoring of cells to anatomically appropriate and specific niches, and long-term cell survival after transplantation. In this study, we used self-assembling peptide amphiphile (PA) molecules that display an IKVAV epitope (IKVAV-PA) to create a niche for hESC-derived ONPs that supported neuronal differentiation and survival both in vitro and in vivo after transplantation into rodent inner ears. A feature of the IKVAV-PA gel is its ability to form organized nanofibers that promote directed neurite growth. Culture of hESC-derived ONPs in IKVAV-PA gels did not alter cell proliferation or viability. However, the presence of IKVAV-PA gels increased the number of cells expressing the neuronal marker beta-III tubulin and improved neurite extension. The self-assembly properties of the IKVAV-PA gel allowed it to be injected as a liquid into the inner ear to create a biophysical niche for transplanted cells after gelation in vivo. Injection of ONPs combined with IKVAV-PA into the modiolus of X-SCID rats increased survival and localization of the cells around the injection site compared to controls. Human cadaveric temporal bone studies demonstrated the technical feasibility of a transmastoid surgical approach for clinical intracochlear injection of the IKVAV-PA/ONP combination. Combining stem cell transplantation with injection of self-assembling PA gels to create a supportive niche may improve clinical approaches to spiral ganglion regeneration. PMID- 29284014 TI - Isolation and characterization of a N4-like lytic bacteriophage infecting Vibrio splendidus, a pathogen of fish and bivalves. AB - A novel virulent bacteriophage, vB_VspP_pVa5, infecting a strain of Vibrio splendidus was isolated from a sea-cage aquaculture farm in Greece, and characterized using microbiological methods and genomic analysis. Bacteriophage vB_VspP_pVa5 is a N4-like podovirus with an icosahedral head measuring 85 nm in length and a short non-contractile tail. The phage had a narrow host range infecting only the bacterial host, a latent period of 30 min and a burst size of 24 virions per infected bacterium. Its genome size was 78,145 bp and genomic analysis identified 107 densely-packed genes, 40 of which could be annotated. In addition to the very large virion encapsulated DNA-dependent RNA polymerase which is the signature of the N4-like genus, an interesting feature of the novel phage is the presence of a self-splicing group I intron in the thymidylate synthase gene. A tRNAStop interrupted by a ~2.5kb open reading frame-containing area was also identified. The absence of genes related to lysogeny along with the high efficacy observed during in vitro cell lysis trials, indicate that the vB_VspP_pVa5 is a potential candidate component in a bacteriophage cocktail suitable for the biological control of V. splendidus in aquaculture. PMID- 29284015 TI - Has information on suicide methods provided via the Internet negatively impacted suicide rates? AB - Suicide rates in Germany consistently decreased from 1991 to 2006, but this trend was reversed in 2007. Underlying this reversal were large increases in suicides due to gassing in females and in being overrun in males. During a similar time period (2005-2013), Asian and some Western countries have also observed abrupt increases in suicides due to certain gasses, and the availability of "how-to" information on the Internet about these painless methods of suicide is thought to play a role in their increased use. This study used data from the Federal Statistics Office of Germany to examine current trends in overall suicide mortality in Germany (2007-2015) as well by age, gender, and suicide methods. Also assessed was whether suicides via newly emergent methods are associated with the frequency of corresponding Internet searches using data from Google Trends. Joinpoint regression analyses indicated significant increases in the overall suicide rate (Average Annual Percentage Change (AAPC) = 2.37%) for females, but not males. The largest annual increases were observed in gassing self intoxication suicides (AAPC = 13.93%), the majority of which involved carbon monoxide. The increase in gassing suicides was larger in females (500%), compared to males (164%). The frequency of suicides by gassing was significantly associated with Internet searches for "carbon monoxide poisoning" for both male and female subgroups, independent of age group. This study provides the updated suicide surveillance data that are necessary for suicide prevention activities. Results are congruent with the recent abrupt rises in carbon monoxide suicides in other countries. PMID- 29284016 TI - Modeling cooperating micro-organisms in antibiotic environment. AB - Recent experiments with the bacteria Paenibacillus vortex reveal a remarkable strategy enabling it to cope with antibiotics by cooperating with a different bacterium-Escherichia coli. While P. vortex is a highly effective swarmer, it is sensitive to the antibiotic ampicillin. On the other hand, E. coli can degrade ampicillin but is non-motile when grown on high agar percentages. The two bacterial species form a shared colony in which E. coli is transported by P. vortex and E. coli detoxifies the ampicillin. The paper presents a simplified model, consisting of coupled reaction-diffusion equations, describing the development of ring patterns in the shared colony. Our results demonstrate some of the possible cooperative movement strategies bacteria utilize in order to survive harsh conditions. In addition, we explore the behavior of mixed colonies under new conditions such as antibiotic gradients, synchronization between colonies and possible dynamics of a 3-species system including P. vortex, E. coli and a carbon producing algae that provides nutrients under illuminated, nutrient poor conditions. The derived model was able to simulate an asymmetric relationship between two or three micro-organisms where cooperation is required for survival. Computationally, in order to avoid numerical artifacts due to symmetries within the discretizing grid, the model was solved using a second order Vectorizable Random Lattices method, which is developed as a finite volume scheme on a random grid. PMID- 29284017 TI - A low-cost solution for documenting distribution and abundance of endangered marine fauna and impacts from fisheries. AB - Fisheries bycatch is a widespread and serious issue that leads to declines of many important and threatened marine species. However, documenting the distribution, abundance, population trends and threats to sparse populations of marine species is often beyond the capacity of developing countries because such work is complex, time consuming and often extremely expensive. We have developed a flexible tool to document spatial distribution and population trends for dugongs and other marine species in the form of an interview questionnaire supported by a structured data upload sheet and a comprehensive project manual. Recognising the effort invested in getting interviewers to remote locations, the questionnaire is comprehensive, but low cost. The questionnaire has already been deployed in 18 countries across the Indo-Pacific region. Project teams spent an average of USD 5,000 per country and obtained large data sets on dugong distribution, trends, catch and bycatch, and threat overlaps. Findings indicated that >50% of respondents had never seen dugongs and that 20% had seen a single dugong in their lifetimes despite living and fishing in areas of known or suspected dugong habitat, suggesting that dugongs occurred in low numbers. Only 3% of respondents had seen mother and calf pairs, indicative of low reproductive output. Dugong hunting was still common in several countries. Gillnets and hook and line were the most common fishing gears, with the greatest mortality caused by gillnets. The questionnaire has also been used to study manatees in the Caribbean, coastal cetaceans along the eastern Gulf of Thailand and western Peninsular Malaysia, and river dolphins in Peru. This questionnaire is a powerful tool for studying distribution and relative abundance for marine species and fishery pressures, and determining potential conservation hotspot areas. We provide the questionnaire and supporting documents for open-access use by the scientific and conservation communities. PMID- 29284018 TI - Changes of microbial population and N-cycling function genes with depth in three Chinese paddy soils. AB - Microbial communities play critical roles in soil nitrogen (N) cycle; however, we have limited understanding of the distribution of N-cycling microbial groups in deeper soil horizons. In this study, we used quantitative PCR to characterize the changes of microbial populations (16S rRNA and 18S rRNA) and five key N-cycling gene abundances involved in N fixation (nifH), ammonia oxidation (amoA) by ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA), and nitrite reduction (nirS and nirK) along profiles (0-100 cm depth) of different paddy soils from three regions (Hailun, Changshu, Yingtan) across China from north to south. We found that most microbial and N-cycling functional genes significantly decreased with soil depth; however, AOA were enriched in deeper soil layers (20 40 cm). The abundances of microbial and N-cycling functional genes generally decreased by one to two orders of magnitude in the deeper horizons relative to topsoils. The AOA gene abundance was higher than that of AOB in the paddy soil profile, and the nirS and nirK abundances were dominant in topsoil and deeper soil, respectively. All N functional genes except AOA were more abundant in Changshu than Hailun and Yingtan. High abundances and low vertical changes of N cycling genes in Changshu suggest more dynamic N-transformations in this region. Correlation analysis showed that soil properties and climate parameters had a significant relationship with N-cycling gene abundances. Moreover, the abundance of different N-cycling genes was affected by different environmental parameters, which should be studied further to explore their roles in N cycling for sustainable agriculture and environmental management. PMID- 29284019 TI - Right-wing authoritarianism and stereotype-driven expectations interact in shaping intergroup trust in one-shot vs multiple-round social interactions. AB - Trust towards unrelated individuals is often conditioned by information about previous social interactions that can be derived from either personal or vicarious experience (e.g., reputation). Intergroup stereotypes can be operationalized as expectations about other groups' traits/attitudes/behaviors that heavily influence our behavioral predictions when interacting with them. In this study we investigated the role of perceived social dimensions of the Stereotype Content Model (SCM)-Warmth (W) and Competence (C)-in affecting trusting behavior towards different European national group members during the Trust Game. Given the well-known role of ideological attitudes in regulating stereotypes, we also measured individual differences in right-wing authoritarianism (RWA). In Experiment 1, we designed an online survey to study one-shot intergroup trust decisions by employing putative members of the European Union states which were also rated along SCM dimensions. We found that low-RWA participants' trusting behavior was driven by perceived warmth (i.e., the dimension signaling the benevolence of social intentions) when interacting with low-C groups. In Experiment 2, we investigated the dynamics of trust in a multiple-round version of the European Trust Game. We found that in low-RWA participants trusting behavior decreased over time when interacting with high-W groups (i.e., expected to reciprocate trust), but did not change when interacting with low-W groups (i.e., expected not to reciprocate trust). Moreover, we found that high-RWA participants' trusting behavior decreased when facing low-W groups but not high-W ones. This suggests that low-RWA individuals employ reputational priors but are also permeable to external evidence when learning about others' trustworthiness. In contrast, high-RWA individuals kept relying on stereotypes despite contextual information. These results confirm the pivotal role played by reputational priors triggered by perceived warmth in shaping social interactions. PMID- 29284020 TI - Health status by gender, hair color, and eye color: Red-haired women are the most divergent. AB - Red hair is associated in women with pain sensitivity. This medical condition, and perhaps others, seems facilitated by the combination of being red-haired and female. We tested this hypothesis by questioning a large sample of Czech and Slovak respondents about the natural redness and darkness of their hair, their natural eye color, their physical and mental health (24 categories), and other personal attributes (height, weight, number of children, lifelong number of sexual partners, frequency of smoking). Red-haired women did worse than other women in ten health categories and better in only three, being particularly prone to colorectal, cervical, uterine, and ovarian cancer. Red-haired men showed a balanced pattern, doing better than other men in three health categories and worse in three. Number of children was the only category where both male and female redheads did better than other respondents. We also confirmed earlier findings that red hair is naturally more frequent in women than in men. Of the 'new' hair and eye colors, red hair diverges the most from the ancestral state of black hair and brown eyes, being the most sexually dimorphic variant not only in population frequency but also in health status. This divergent health status may have one or more causes: direct effects of red hair pigments (pheomelanins) or their by-products; effects of other genes that show linkage with genes involved in pheomelanin production; excessive prenatal exposure to estrogen (which facilitates expression of red hair during fetal development and which, at high levels, may cause health problems later in life); evolutionary recentness of red hair and corresponding lack of time to correct negative side effects; or genetic incompatibilities associated with the allele Val92Met, which seems to be of Neanderthal origin and is one of the alleles that can cause red hair. PMID- 29284021 TI - Temporal trends in educational inequalities in non-communicable diseases in Korea, 2007-2015. AB - BACKGROUND: Socioeconomic inequalities in non-communicable diseases are known to exist; however there is a paucity of research describing the secular trends in these inequalities. To this end, the current study aims to explore the recent time trends in social patterning of selected non-communicable diseases among Korean adults between 2007 and 2015. METHODS: Using data from the Korea National Health and Nutrition Examination Survey (KNHANES), temporal trends in socioeconomic inequalities in diabetes, arthritis, asthma and depressive symptoms were assessed across three time points. Respondents were adults aged 20 years or over (N = 47,091, 20,180 men and 26,911 women). Socioeconomic circumstance was assessed based on highest level of educational attainment. We estimated prevalence ratios with 95% confidence intervals using Poisson regression with robust variance estimation (adjusted for age, smoking status, alcohol consumption, obesity, and physical activity) separately for men and women. The magnitude of the inequalities was computed using the relative index of inequality (RII). RESULTS: In men, diabetes was not associated with educational attainment, while there was evidence of a negative association in women across surveys. Similar inverse associations were found with arthritis and depressive symptoms, but these associations were less clear for asthma. RII showed a non-significant increasing trend in educational disparities in depressive symptoms. Meanwhile, relative inequalities in diabetes, arthritis and asthma have narrowed. These trends were, in general, more pronounced in women. CONCLUSIONS: The findings of this study indicate higher burden of selected NCDs among the lower educational groups, particularly among women. In addition, our results indicated some improvements in inequalities in diabetes, arthritis and asthma in recent years. These findings have important implications for understanding the causes of social patterning of NCDs and for the targeting of effective interventions. PMID- 29284022 TI - A transcriptomics approach uncovers novel roles for poly(ADP-ribosyl)ation in the basal defense response in Arabidopsis thaliana. AB - Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) or loss of Arabidopsis thaliana PARG1 (poly(ADP-ribose) glycohydrolase) disrupt a subset of plant defenses. In the present study we examined the impact of altered poly(ADP ribosyl)ation on early gene expression induced by the microbe-associate molecular patterns (MAMPs) flagellin (flg22) and EF-Tu (elf18). Stringent statistical analyses and filtering identified 178 genes having MAMP-induced mRNA abundance patterns that were altered by either PARP inhibitor 3-aminobenzamide (3AB) or PARG1 knockout. From the identified set of 178 genes, over fifty Arabidopsis T DNA insertion lines were chosen and screened for altered basal defense responses. Subtle alterations in callose deposition and/or seedling growth in response to those MAMPs were observed in knockouts of At3g55630 (FPGS3, a cytosolic folylpolyglutamate synthetase), At5g15660 (containing an F-box domain), At1g47370 (a TIR-X (Toll-Interleukin Receptor domain)), and At5g64060 (a predicted pectin methylesterase inhibitor). Over-represented GO terms for the gene expression study included "innate immune response" for elf18/parg1, highlighting a subset of elf18-activated defense-associated genes whose expression is altered in parg1 plants. The study also allowed a tightly controlled comparison of early mRNA abundance responses to flg22 and elf18 in wild-type Arabidopsis, which revealed many differences. The PARP inhibitor 3-methoxybenzamide (3MB) was also used in the gene expression profiling, but pleiotropic impacts of this inhibitor were observed. This transcriptomics study revealed targets for further dissection of MAMP-induced plant immune responses, impacts of PARP inhibitors, and the molecular mechanisms by which poly(ADP-ribosyl)ation regulates plant responses to MAMPs. PMID- 29284023 TI - Growth phenotype analysis of heme synthetic enzymes in a halophilic archaeon, Haloferax volcanii. AB - Halophilic euryarchaea lack many of the genes necessary for the protoporphyrin dependent heme biosynthesis pathway previously identified in animals and plants. Bioinformatic analysis suggested the presence of two heme biosynthetic processes, an Fe-coproporphyrinogen III (coproheme) decarboxylase (ChdC) pathway and an alternative heme biosynthesis (Ahb) pathway, in Haloferax volcanii. PitA is specific to the halophilic archaea and has a unique molecular structure in which the ChdC domain is joined to the antibiotics biosynthesis monooxygenase (ABM) like domain by a histidine-rich linker sequence. The pitA gene deletion variant of H. volcanii showed a phenotype with a significant reduction of aerobic growth. Addition of a protoheme complemented the phenotype, supporting the assumption that PitA participates in the aerobic heme biosynthesis. Deletion of the ahbD gene caused a significant reduction of only anaerobic growth by denitrification or dimethylsulfoxide (DMSO) respiration, and the growth was also complemented by addition of a protoheme. The experimental results suggest that the two heme biosynthesis pathways are utilized selectively under aerobic and anaerobic conditions in H. volcanii. The molecular structure and physiological function of PitA are also discussed on the basis of the limited proteolysis and sequence analysis. PMID- 29284024 TI - Diabetes-related changes in the protein composition and the biomechanical properties of human retinal vascular basement membranes. AB - Basement membranes (BMs) are specialized sheets of extracellular matrix that outline epithelial cell layers, muscle fibers, blood vessels, and peripheral nerves. A well-documented histological hallmark of progressing diabetes is a major increase in vascular BM thickness. In order to investigate whether this structural change is accompanied by a change in the protein composition, we compared the proteomes of retinal vascular BMs from diabetic and non-diabetic donors by using LC-MS/MS. Data analysis showed that seventeen extracellular matrix (ECM)-associated proteins were more abundant in diabetic than non-diabetic vascular BMs. Four ECM proteins were more abundant in non-diabetic than in diabetic BMs. Most of the over-expressed proteins implicate a complement-mediated chronic inflammatory process in the diabetic retinal vasculature. We also found an up-regulation of norrin, a protein that is known to promote vascular proliferation, possibly contributing to the vascular remodeling during diabetes. Many of the over-expressed proteins were localized to microvascular aneurisms. Further, the overall stoichiometry of proteins was changed, such that the relative abundance of collagens in BMs from diabetic patients was higher than normal. Biomechanical measurements of vascular BM flat mounts using AFM showed that their outer surface was softer than normal. PMID- 29284025 TI - Clinical management and risk reduction in women with low-grade squamous intraepithelial lesion cytology: A population-based cohort study. AB - We analyzed the management and risk of subsequent cervical intraepithelial neoplasm 3 (CIN3) and invasive cervical cancer in women with low-grade squamous intraepithelial lesion (LSIL) cytology. A total of 53,293 women with a new diagnosis of cytologic LSIL were identified in Taiwan's national cervical screening registration database. Based on the retrieved clinical management data, the incidence of subsequent CIN3+ lesions was determined, and the hazard ratios (HRs) were estimated using a Cox proportional hazards model. The average follow up was 5.02 years. A total of 988 women developed CIN3+ lesions during this period, with an overall incidence of 369.3 women per 100,000 person-years. Cryotherapy and conization/loop electrosurgical excision procedure (LEEP) decreased the subsequent risk of CIN3+ lesions in women younger than 50 years (HR 0.49, 95% confidence interval [CI] 0.37-0.64, p<0.0001 for cryotherapy; HR 0.39, 95% CI 0.27-0.55, p<0.0001 for LEEP). Cryotherapy and conization/LEEP were two significant protective factors for developing CIN3+ lesions, especially in women with biopsy-proven CIN1 (HR 0.55, 95% CI 0.37-0.82, p = 0.003 for cryotherapy; HR 0.43, 95% CI 0.24-0.77, p = 0.005 for LEEP). These results suggest that when women are first screened LSIL and lack prior abnormal cervical cytology, cryotherapy should be one of the treatment options. Younger women with a histological biopsy diagnosis of CIN1 were most likely to benefit from cryotherapy. PMID- 29284026 TI - A Monte Carlo simulation approach for estimating the health and economic impact of interventions provided at a student-run clinic. AB - BACKGROUND: Student Run Clinics (SRCs) are a common aspect of medical education, present at more than half of US medical schools, and noted for providing care to communities that might otherwise lack access, including the uninsured and underinsured. To date, few studies have rigorously quantified the health and economic benefits of SRCs, and the present study remedies that. METHODS AND FINDINGS: We used Monte Carlo simulations to estimate the health impact of common preventive health interventions applied to individuals in quality-adjusted life years (QALYs). We then used those measurements to estimate the health and economic impact of United Community Clinic (UCC), a student-run clinic in Philadelphia, PA. We found that with an annual operating budget of $50,000, UCC saves 6.5 QALYs, corresponding to over $850,000 saved. CONCLUSIONS: Using Monte Carlo simulation methods, the health and economic impact of SRCs can be reasonably estimated to demonstrate the utility of SRCs and justify their growing importance in the healthcare delivery landscape of the US. PMID- 29284027 TI - Effects of an intervention with teachers in the physical education context: A Self-Determination Theory approach. AB - Framed within Self-Determination Theory, the purpose of the present study was to test the effects of a training program with physical education (PE) teachers. Participants were 21 high school PE teachers (experimental group, n = 10; control group, n = 11), and their 836 students, aged 12 to 16 years. Teachers in the experimental group received a training program consisting of strategies to support autonomy, competence, and relatedness need satisfaction. A repeated measures ANCOVA was carried out for each dependent variable. After the intervention, students in the experimental group significantly increased their scores on autonomy support, relatedness support, autonomy satisfaction, autonomous motivation, controlled motivation, and intention to be physically active, as compared to the control group. These findings emphasize the utility of a training program with PE teachers to promote the students' psychological need satisfaction, and hence, self-determined motivation toward PE classes. PMID- 29284028 TI - A microfluidic thermometer: Precise temperature measurements in microliter- and nanoliter-scale volumes. AB - Measuring the temperature of a sample is a fundamental need in many biological and chemical processes. When the volume of the sample is on the microliter or nanoliter scale (e.g., cells, microorganisms, precious samples, or samples in microfluidic devices), accurate measurement of the sample temperature becomes challenging. In this work, we demonstrate a technique for accurately determining the temperature of microliter volumes using a simple 3D-printed microfluidic chip. We accomplish this by first filling "microfluidic thermometer" channels on the chip with substances with precisely known freezing/melting points. We then use a thermoelectric cooler to create a stable and linear temperature gradient along these channels within a measurement region on the chip. A custom software tool (available as online Supporting Information) is then used to find the locations of solid-liquid interfaces in the thermometer channels; these locations have known temperatures equal to the freezing/melting points of the substances in the channels. The software then uses the locations of these interfaces to calculate the temperature at any desired point within the measurement region. Using this approach, the temperature of any microliter-scale on-chip sample can be measured with an uncertainty of about a quarter of a degree Celsius. As a proof-of-concept, we use this technique to measure the unknown freezing point of a 50 microliter volume of solution and demonstrate its feasibility on a 400 nanoliter sample. Additionally, this technique can be used to measure the temperature of any on-chip sample, not just near-zero-Celsius freezing points. We demonstrate this by using an oil that solidifies near room temperature (coconut oil) in a microfluidic thermometer to measure on-chip temperatures well above zero Celsius. By providing a low-cost and simple way to accurately measure temperatures in small volumes, this technique should find applications in both research and educational laboratories. PMID- 29284030 TI - Reliability demonstration test for load-sharing systems with exponential and Weibull components. AB - Conducting a Reliability Demonstration Test (RDT) is a crucial step in production. Products are tested under certain schemes to demonstrate whether their reliability indices reach pre-specified thresholds. Test schemes for RDT have been studied in different situations, e.g., lifetime testing, degradation testing and accelerated testing. Systems designed with several structures are also investigated in many RDT plans. Despite the availability of a range of test plans for different systems, RDT planning for load-sharing systems hasn't yet received the attention it deserves. In this paper, we propose a demonstration method for two specific types of load-sharing systems with components subject to two distributions: exponential and Weibull. Based on the assumptions and interpretations made in several previous works on such load-sharing systems, we set the mean time to failure (MTTF) of the total system as the demonstration target. We represent the MTTF as a summation of mean time between successive component failures. Next, we introduce generalized test statistics for both the underlying distributions. Finally, RDT plans for the two types of systems are established on the basis of these test statistics. PMID- 29284031 TI - Perceptions of scientific research literature and strategies for reading papers depend on academic career stage. AB - Reading primary research literature is an essential skill for all scientists and students on science degree programmes, however little is known about how researchers at different career stages interact with and interpret scientific papers. To explore this, we conducted a survey of 260 undergraduate students and researchers in Biological Sciences at a research intensive UK university. Responses to Likert scale questions demonstrated increases in confidence and skill with reading the literature between individuals at each career stage, including between postdoctoral researchers and faculty academics. The survey indicated that individuals at different career stages valued different sections of scientific papers, and skill in reading the results section develops slowly over the course of an academic career. Inexperienced readers found the methods and results sections of research papers the most difficult to read, and undervalued the importance of the results section and critical interpretation of data. These data highlight a need for structured support with reading scientific literature at multiple career stages, and for senior academics to be aware that junior colleagues may prioritise their reading differently. We propose a model for the development of literature processing skills, and consider the need for training strategies to help inexperienced readers engage with primary literature, and therefore develop important skills that underpin scientific careers. We also encourage researchers to be mindful of language used when writing papers, and to be more inclusive of diverse audiences when disseminating their work. PMID- 29284029 TI - CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). AB - Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM. PMID- 29284032 TI - Prevalence of anemia and associated factors among school children in Gondar town public primary schools, northwest Ethiopia: A school-based cross-sectional study. AB - BACKGROUND: Anemia is a global public health problem affecting 305 million school children (SC) worldwide. It has deleterious effects in SC, including lower school achievement due to impaired cognitive development and physical growth, fatigue and poor attention span, and increased morbidity because of reduced resistance to infection. Hence, the aim of this study was to assess the prevalence and associated factors of anemia among SC attending public primary schools in Gondar town, northwest Ethiopia. METHODS: A school-based cross sectional study was conducted on a total of 523 SC aged from 6-14 years old. Multi-stage sampling followed by systematic random sampling techniques were employed to select study participants. Data on socio-demographic and socio-economic characteristics, and dietary status of children were collected using pre-tested structured questionnaire through face-to-face interview of children's caregivers. Anthropometric measurements were taken. Hemoglobin (Hb) concentration was determined by using HemoCue 301+analyser. Stool and blood samples were collected in the school premises, and examined for intestinal and hemoparasites, respectively. Data were entered into Epi Info version 3.5.3 and transferred to SPSS version 20 for analysis. Bivariate and multivariate binary logistic regression models were fitted to identify associated factors of anemia. P-value < 0.05 was considered as statistically significant. RESULT: Of the total SC participated in the study, 269 (51.4%) were males. The median (inter quartile range (IQR)) age was 12 (10-13) years, and 332 (63.5%) of them were in the age group 11-14 years. About 81 (15.5%; 95%CI: 12.4%, 18.7%) of them were anemic: 56 (69.1%) and 25 (38.9%) of them were mildly and moderately anemic, respectively. Low maternal education (AOR = 2.30; 95%CI: 1.11, 4.78), stunting (AOR = 2.22; 95%CI: 1.30, 3.80), severe food insecurity (AOR = 5.11; 95%CI: 1.53, 17.13), and soil-transmitted helminthic (STH) infection (AOR = 7.13; 95%CI: 3.16, 16.86) were found significantly associated with anemia. CONCLUSION: Anemia among SC was found to be a mild public health problem. It was strongly associated with low maternal education, food insecurity, stunting and intestinal helminthic infection. Focused policies and strategies towards the above factors should be designed to reduce anemia among SC. PMID- 29284033 TI - The moderating role of social support on depression and anxiety for gastric cancer patients and their family caregivers. AB - BACKGROUND: There is a consensus that cancer care should go beyond physical care as cancer patients and their family caregivers experience psychological burden, financial difficulty, as well as social relation issues. The current study aimed to investigate the moderating impact of social support on depression and anxiety of cancer patients and their family caregivers. METHODS: Gastric cancer patients and their family caregivers who visited a university medical center in Seoul were approached for participation in the study. Fifty-two pairs of adult patients and caregivers participated in the study. Along with demographic information and the physical condition of the patients, such as pre-operation cancer stage and the type of gastrectomy, social support, depression, and anxiety were measured for patients and caregivers, respectively. RESULTS: In the first round of analysis, patients' depression was associated with age, while patients' anxiety was related to income. On the other hand, caregivers' depression was not associated with patients' health and living arrangement. In the second round of analysis to examine the moderating effect of social support, patients' income and social support were related to depression and anxiety, but the interaction of income and social support was only observed for anxiety. For caregivers, no interaction effects were found. Social support decreased the negative effects of low income status on the patients. CONCLUSION: While the income of the families with cancer cannot be adjusted in the short-term, their experience of social support can be managed by a proper support system. Diverse implications in medical settings are discussed. PMID- 29284035 TI - Effects on schooling function in mackerel of sub-lethal capture related stressors: Crowding and hypoxia. AB - The selectivity of fishing gears with respect to fish species and size is important, both for fisheries management and fishing operations. Purse seining is an efficient, environmentally friendly fish capture methodology generally targeting single species aggregations, but once a fish school has been selected and surrounded by the seine, there is no selections for individual size, species or catch quantity. A common practice for evaluating the catch is to haul the seine to a point where physical samples or inspections of catch composition can be made. The release process is called slipping and may lead to mortality in the released fish. The objective of this study was to simulate a crowding situation and investigate how the behaviour was affected in response to increased fish density, decreased oxygen levels, or a combination of the two, and to see if there is a behavioural measure that can be used to set safe crowding limits. The experiment was conducted on Mackerel (Scomber scombrus) held in net pens. The volume of the net pen was reduced to increase fish density, and a tarpaulin bag was wrapped around the pen to reduce the oxygen levels. Oxygen, fish density and space occupancy was monitored during the experiment, and the behavioural reactions was assessed using an imaging sonar. The main result was that the schooling function, i.e. the response to a predator model, was significantly reduced during crowding but not in response to hypoxia. There were some indications of a slow recovery of the function post-treatment. We conclude that crowding causes behavioural responses that occur before densities that induce fish mortality. Consequently, there is a behavioural response that could be used as a proxy for setting safe crowding limits. PMID- 29284034 TI - Development of a novel Francisella tularensis Live Vaccine Strain expressing ovalbumin provides insight into antigen-specific CD8+ T cell responses. AB - Progress towards a safe and effective vaccine for the prevention of tularemia has been hindered by a lack of knowledge regarding the correlates of protective adaptive immunity and a lack of tools to generate this knowledge. CD8+ T cells are essential for protective immunity against virulent strains of Francisella tularensis, but to-date, it has not been possible to study these cells in an antigen-specific manner. Here, we report the development of a tool for expression of the model antigen ovalbumin (OVA) in F. tularensis, which allows for the study of CD8+ T cell responses to the bacterium. We demonstrate that in response to intranasal infection with the F. tularensis Live Vaccine Strain, adoptively transferred OVA-specific CD8+ T cells expand after the first week and produce IFN gamma but not IL-17. Effector and central memory subsets develop with disparate kinetics in the lungs, draining lymph node and spleen. Notably, OVA-specific cells are poorly retained in the lungs after clearance of infection. We also show that intranasal vaccination leads to more antigen-specific CD8+ T cells in the lung-draining lymph node compared to scarification vaccination, but that an intranasal booster overcomes this difference. Together, our data show that this novel tool can be used to study multiple aspects of the CD8+ T cell response to F. tularensis. Use of this tool will enhance our understanding of immunity to this deadly pathogen. PMID- 29284036 TI - Effect of innate antiviral glycoproteins in breast milk on seroconversion to rotavirus vaccine (Rotarix) in children in Lusaka, Zambia. AB - INTRODUCTION: Rotavirus vaccines have been introduced into national immunization programmes to mitigate morbidity and mortality associated rotavirus diarrhoea. Lower vaccine effectiveness has however been noted in low-middle income countries, but little is known about the role of maternal components found in breast milk. This study assessed the effect of lactoferrin, lactadherin, and tenascin-c on rotavirus vaccine seroconversion. METHODS: This was a retrospective cohort study of 128 infants who had been fully immunized with RotarixTM. Serum samples were collected from the infant at baseline and one month after second rotavirus vaccine dose. Breast milk samples were collected from mothers at baseline. Standard ELISA was used to determine titres of rotavirus-specific immunologlobulin G and A in breast milk and serum as well as concentrations of lactoferrin, lactadherin, and tenascin-c. Poisson regression model with robust standard error was used to estimate the effect of breast milk components on seroconversion. The components were modelled on log base 2 so that the effect would be interpreted as a doubling of the concentration. RESULTS: In a multivariable analysis adjusting for maternal age, maternal HIV status, seropositivity at baseline, sex, age of child at vaccination as well as breast milk IgA and IgG, we found evidence of independent effect of LA (Adjusted IRR = 0.95; 95% CI = 0.91-0.99; P = 0.019) on seroconversion while there was no evidence for TNC (Adjusted IRR = 1.00; 95% CI = 0.85-1.17; P = 0.967) and LF (Adjusted RR = 1.01; 95% CI = 0.96-1.05); P = 0.802). We explored the joint effects of the three components but we found no evidence (Adjusted RR = 0.95; 95% CI = 0.81; P = 0.535). CONCLUSION: High breast milk concentrations of lactadherin might play a role in infant's failure to seroconvert to rotavirus vaccines. Further research to understand this observed association is an important consideration. PMID- 29284037 TI - Novel avian paramyxovirus isolated from gulls in Caspian seashore in Kazakhstan. AB - Three isolates APMV/gull/Kazakhstan/5976/2014, APMV/gull/Kazakhstan/ 5977/2014 and APMV/gull/Kazakhstan/5979/2014, were obtained from independent samples during annual surveillance for avian influenza and paramyxoviruses in wild birds from the Caspian Sea coast in Western Kazakhstan, and were initially identified as putative paramyxoviruses on the basis of electron microscopy. Hemagglutination Inhibition Assays with antisera to nine known APMV serotypes (APMV1-9) indicated no relation to any of them. Next generation sequencing of whole genome sequences indicated the three isolates were genetically identical, and had a nucleotide structure typical for all APMVs, consisting of six genes 3'-NP-P-M-F-HN-L-5'. Phylogenetic analyses, and assessment of amino acid identities, suggested the most closely related lineages to be APMV-2, 8, 10 and 15, but the novel isolate had less than 64% identity to them and all other known avian paramyxoviruses. This value was above levels considered to generally define other APMV serotypes. Estimates of the evolutionary divergence of the nucleotide sequences of the genomes of APMVs have shown that novel Kazakhstan APMV strain was closest to APMV 2, APMV-8, APMV-10 and APMV-15, with calculated distance values of 2.057, 2.058, 2.026 and 2.286 respectively, which is above values considered to differentiate other serotypes (observed minimum was 1.108 between APMV-1 and recently isolated APMV/UPO216/Korea). Together, the data suggest that isolate APMV/gull/Kazakhstan/5976/2014 and other two should be considered as the first representative of a novel APMV-20 group, and is the first time that avian paramyxoviruses have been found infecting members of the gull family, extending the known taxonomic host range. PMID- 29284038 TI - Comparative analysis of the end-joining activity of several DNA ligases. AB - DNA ligases catalyze the repair of phosphate backbone breaks in DNA, acting with highest activity on breaks in one strand of duplex DNA. Some DNA ligases have also been observed to ligate two DNA fragments with short complementary overhangs or blunt-ended termini. In this study, several wild-type DNA ligases (phage T3, T4, and T7 DNA ligases, Paramecium bursaria chlorella virus 1 (PBCV1) DNA ligase, human DNA ligase 3, and Escherichia coli DNA ligase) were tested for their ability to ligate DNA fragments with several difficult to ligate end structures (blunt-ended termini, 3'- and 5'- single base overhangs, and 5'-two base overhangs). This analysis revealed that T4 DNA ligase, the most common enzyme utilized for in vitro ligation, had its greatest activity on blunt- and 2-base overhangs, and poorest on 5'-single base overhangs. Other ligases had different substrate specificity: T3 DNA ligase ligated only blunt ends well; PBCV1 DNA ligase joined 3'-single base overhangs and 2-base overhangs effectively with little blunt or 5'- single base overhang activity; and human ligase 3 had highest activity on blunt ends and 5'-single base overhangs. There is no correlation of activity among ligases on blunt DNA ends with their activity on single base overhangs. In addition, DNA binding domains (Sso7d, hLig3 zinc finger, and T4 DNA ligase N-terminal domain) were fused to PBCV1 DNA ligase to explore whether modified binding to DNA would lead to greater activity on these difficult to ligate substrates. These engineered ligases showed both an increased binding affinity for DNA and increased activity, but did not alter the relative substrate preferences of PBCV1 DNA ligase, indicating active site structure plays a role in determining substrate preference. PMID- 29284039 TI - From in vivo to in vitro: Major metabolic alterations take place in hepatocytes during and following isolation. AB - The liver plays a key role in maintaining physiological homeostasis and hepatocytes are largely responsible for this. The use of isolated primary hepatocytes has become an essential tool for the study of nutrient physiology, xenobiotic metabolism and several liver pathologies. Since hepatocytes are removed from their normal environment, the isolation procedure and in vitro culture of primary hepatocytes is partially known to induce undesired metabolic changes. We aimed to perform a thorough metabolic profiling of primary cells before, during and after isolation using state-of-the-art techniques. Extensive metabolite measurements using HPLC were performed in situ in the liver, during hepatocyte isolation using the two-step collagenase perfusion method and during in vitro cell culture for up to 48 hours. Assessment of mitochondrial respiratory capacity and ATP-linked respiration of isolated primary hepatocytes was performed using extracellular flux analysis. Primary hepatocytes displayed a drastic decrease in antioxidative-related metabolites (NADPH, NADP, GSH and GSSG) during the isolation procedure when compared to the in situ liver (P<0.001). Parallel assessment of citric acid cycle activity showed a significant decrease of up to 95% in Acetyl-CoA, Isocitrate/Citrate ratio, Succinate, Fumarate and Malate in comparison to the in situ liver (P<0.001). While the levels of several cellular energetic metabolites such as Adenosine, AMP, ADP and ATP were found to be progressively reduced during the isolation procedure and cell culture (P<0.001), higher ATP/ADP ratio and energy charge level were observed when primary cells were cultured in vitro compared to the in situ liver (P<0.05). In addition, a significant decrease in the respiratory capacity occurred after 24 hours in culture. Interestingly, this was not associated with a significant modification of ATP-linked respiration. In conclusion, major metabolic alterations occur immediately after hepatocytes are removed from the liver. These changes persist or increase during in vitro culture. These observations need to be taken into account when using primary hepatocytes for the study of metabolism or liver physiopathology. PMID- 29284040 TI - Correction: Introduced bullfrogs are associated with increased Batrachochytrium dendrobatidis prevalence and reduced occurrence of Korean treefrogs. AB - [This corrects the article DOI: 10.1371/journal.pone.0177860.]. PMID- 29284041 TI - Correction: Discerning morpho-anatomical, physiological and molecular multiformity in cultivated and wild genotypes of lentil with reconciliation to salinity stress. AB - [This corrects the article DOI: 10.1371/journal.pone.0177465.]. PMID- 29284042 TI - Genome-wide evolutionary dynamics of influenza B viruses on a global scale. AB - The global-scale epidemiology and genome-wide evolutionary dynamics of influenza B remain poorly understood compared with influenza A viruses. We compiled a spatio-temporally comprehensive dataset of influenza B viruses, comprising over 2,500 genomes sampled worldwide between 1987 and 2015, including 382 newly sequenced genomes that fill substantial gaps in previous molecular surveillance studies. Our contributed data increase the number of available influenza B virus genomes in Europe, Africa and Central Asia, improving the global context to study influenza B viruses. We reveal Yamagata-lineage diversity results from co circulation of two antigenically-distinct groups that also segregate genetically across the entire genome, without evidence of intra-lineage reassortment. In contrast, Victoria-lineage diversity stems from geographic segregation of different genetic clades, with variability in the degree of geographic spread among clades. Differences between the lineages are reflected in their antigenic dynamics, as Yamagata-lineage viruses show alternating dominance between antigenic groups, while Victoria-lineage viruses show antigenic drift of a single lineage. Structural mapping of amino acid substitutions on trunk branches of influenza B gene phylogenies further supports these antigenic differences and highlights two potential mechanisms of adaptation for polymerase activity. Our study provides new insights into the epidemiological and molecular processes shaping influenza B virus evolution globally. PMID- 29284043 TI - Complex patterns of concomitant medication use: A study among Norwegian women using paracetamol during pregnancy. AB - BACKGROUND: Studies on medication safety in pregnancy often rely on an oversimplification of medication use into exposed or non-exposed, without considering intensity and timing of use in pregnancy, or concomitant medication use. This study uses paracetamol in pregnancy as the motivating example to introduce a method of clustering medication exposures longitudinally throughout pregnancy. The aim of this study was to use hierarchical cluster analysis (HCA) to better identify clusters of medication exposure throughout pregnancy. METHODS: Data from the Norwegian Mother and Child Cohort Study was used to identify subclasses of women using paracetamol during pregnancy. HCA with customized distance measure was used to identify clusters of medication exposures in pregnancy among children at 18 months. RESULTS: The pregnancies in the study (N = 9 778) were grouped in 5 different clusters depending on their medication exposure profile throughout pregnancy. CONCLUSION: Using HCA, we identified and described profiles of women exposed to different medications in combination with paracetamol during pregnancy. Identifying these clusters allows researchers to define exposure in ways that better reflects real-world medication usage patterns. This method could be extended to other medications and used as pre analysis for identifying risks associated with different profiles of exposure. PMID- 29284045 TI - Polarization of concave domains by traveling wave pinning. AB - Pattern formation is one of the most fundamental yet puzzling phenomena in physics and biology. We propose that traveling front pinning into concave portions of the boundary of 3-dimensional domains can serve as a generic gradient maintaining mechanism. Such a mechanism of domain polarization arises even for scalar bistable reaction-diffusion equations, and, depending on geometry, a number of stationary fronts may be formed leading to complex spatial patterns. The main advantage of the pinning mechanism, with respect to the Turing bifurcation, is that it allows for maintaining gradients in the specific regions of the domain. By linking the instant domain shape with the spatial pattern, the mechanism can be responsible for cellular polarization and differentiation. PMID- 29284044 TI - Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. AB - Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model. PMID- 29284046 TI - IRSp53 accumulates at the postsynaptic density under excitatory conditions. AB - IRSp53 (BAIAP2) is an abundant protein at the postsynaptic density (PSD) that binds to major PSD scaffolds, PSD-95 and Shanks, as well as to F-actin. The distribution of IRSp53 at the PSD in cultured hippocampal neurons was examined under basal and excitatory conditions by immuno-electron microscopy. Under basal conditions, label for IRSp53 is concentrated at the PSD. Upon depolarization by application of a medium containing 90 mM K+, the intensity of IRSp53 label at the PSD increased by 36+/-7%. Application of NMDA (50 MUM) yielded 53+/-1% increase in the intensity of IRSp53 label at the PSD compared to controls treated with APV, an NMDA antagonist. The accumulation of IRSp53 label upon application of high K+ or NMDA was prominent at the deeper region of the PSD (the PSD pallium, lying 40-120 nm from the postsynaptic plasma membrane). IRSp53 molecules that accumulate at the distal region of the PSD pallium under excitatory conditions are too far from the plasma membrane to fulfill the generally recognized role of the protein as an effector of membrane-bound small GTPases. Instead, these IRSp53 molecules may have a structural role organizing the Shank scaffold and/or linking the PSD to the actin cytoskeleton. PMID- 29284047 TI - Self-reported prevalence of pests in Dutch households and the use of the health belief model to explore householders' intentions to engage in pest control. AB - Pests in the home are a health risk because they can be vectors for infectious disease, contribute to allergies and cause damage to buildings. The aims of this study were to record which categories of pests were reported in homes and to use a social cognition model, the health belief model, to investigate which psychological factors influence householders' intentions to control pests. An online questionnaire was completed by 413 respondents between 11 September and 31 November 2015. A large majority of respondents reported pests in or around their home within the previous year. The prevalences were: flying insects 98%, crawling insects 85%, rodents 62%, birds 58%, and moles 20%. Regression analysis for the health belief model revealed that perceiving greater benefits and fewer barriers to pest control and expecting severe consequences of zoonotic infections predicted higher intention to control pests. Intentions towards pest control were not influenced by perceiving oneself as susceptible to catching a disease from pests or health motivation (striving towards a healthy lifestyle). Intentions to engage in pest control were lower for households reporting bird prevalence. The findings suggest that interventions aimed at improving the effectiveness of domestic pest control should focus on increasing the benefits that individuals associate with effective pest control, lowering barriers, and on underlining the severity of the diseases that pests may carry. PMID- 29284048 TI - The mediating effect of body mass index on the relationship between smoking and hip or knee replacement due to primary osteoarthritis. A population-based cohort study (the HUNT Study). AB - To investigate the total effect of smoking on total hip or knee replacement (THR/TKR) due to primary osteoarthritis (OA) and to quantify the indirect effect of smoking through body mass index (BMI). Participants from the Nord-Trondelag Health Study (the HUNT Study) were linked to the Norwegian Arthroplasty Register to detect the first THR or TKR due to primary OA. A mediation analysis was used to decompose the total effect of smoking into a direct and indirect effect. BMI was considered a mediator in the analysis. All effects were estimated as hazard ratios (HRs) with 95% confidence intervals (CIs). The indirect effect of smoking mediated through BMI was expressed as a percentage (proportion*100). In total 55 188 participants were followed up during 17.2 years (median). We identified 1322 THRs and 754 TKRs. For men, the total effect of current vs. never smoking revealed a decreased risk of THR (HR 0.59, 95% CI 0.46-0.76) and TKR (HR 0.47, 95% CI 0.32-0.66). For women, current smoking increased the risk of THR (HR 1.34, 95% CI 1.11-1.60). For men, 6% and 7% of the risk reduction for THR and TKR, respectively, was mediated by BMI. We found a negative association between smoking and THR or TKR for men. On the contrary, smoking was associated with increased risk of THR for women. Most of the effect of smoking on joint replacement risk remained unexplained by BMI. PMID- 29284049 TI - Leishmania (Viannia) braziliensis infection in wild small mammals in ecotourism area of Brazil. AB - Leishmaniases are parasitic diseases transmitted to mammalian hosts by sand fly vectors (Diptera: Psychodidae). Despite the increasing occurrence of visceral and cutaneous leishmaniasis cases in urban centers, their transmission still occur primarily in wild environments and may be associated with professional activities and recreation, such as ecotourism. The Reserva Particular do Patrimonio Natural Santuario do Caraca (RPPNSC) is one of the largest ecotourism attractions in the State of Minas Gerais, Brazil, and comprises an area of environmental preservation with 11,233 hectares presenting a transitional vegetation between Cerrado and Atlantic Forest. The present study describes the abundance of small mammals in RPPNSC, the isolation and identification of Leishmania in five wild animals. Small mammals were bimonthly trapped along 6 trails within the RPPNSC with 10 Tomahawk traps each. Two trails were located in peridomiciliary areas near tourist lodging facilities, and four trails were located at sites visited by tourists in forest areas. The most prevalent species were Akodon cursor, Cerradomys subflavus and Oligoryzomys nigripes. Six isolates of Leishmania were obtained from these animals and identified as Leishmania braziliensis through HSP70-PCR RFLP method. Leishmania spp. DNA was detected by kDNA-PCR method and isolated by biphasic culture. Studies point to some of the captured species as potential wild reservoirs of Leishmania, suggesting they may be involved in the transmission cycle in these wild environments. PMID- 29284050 TI - The decreasing range between dry- and wet- season precipitation over land and its effect on vegetation primary productivity. AB - One consequence of climate change is the alteration of global water fluxes, both in amount and seasonality. As a result, the seasonal difference between dry- (p < 100 mm/month) and wet-season (p > 100 mm/month) precipitation (p) has increased over land during recent decades (1980-2005). However, our analysis expanding to a 60-year period (1950-2009) showed the opposite trend. This is, dry-season precipitation increased steadily, while wet-season precipitation remained constant, leading to reduced seasonality at a global scale. The decrease in seasonality was not due to a change in dry-season length, but in precipitation rate; thus, the dry season is on average becoming wetter without changes in length. Regionally, wet- and dry-season precipitations are of opposite sign, causing a decrease in the seasonal variation of the precipitation over 62% of the terrestrial ecosystems. Furthermore, we found a high correlation (r = 0.62) between the change in dry-season precipitation and the trend in modelled net primary productivity (NPP), which is explained based on different ecological mechanisms. This trend is not found with wet-season precipitation (r = 0.04), These results build on the argument that seasonal water availability has changed over the course of the last six decades and that the dry-season precipitation is a key driver of vegetation productivity at the global scale. PMID- 29284051 TI - Morphological and colour morph clines along an altitudinal gradient in the meadow grasshopper Pseudochorthippus parallelus. AB - Many animals show altitudinal clines in size, shape and body colour. Increases in body size and reduction in the length of body appendices in colder habitats are usually attributed to improved heat conservation at lower surface-to-volume ratios (known as Bergmann's and Allen's rule, respectively). However, the patterns are more variable and sometimes reversed in small ectotherms that are affected by shortened growing seasons. Altitude can also affect colouration. The thermal melanism hypothesis predicts darker colours under cooler conditions because of a thermoregulatory advantage. Darker colours may also be favoured at high altitudes for reasons of UV protection or habitat-dependent crypsis. We studied altitudinal variation in morphology and colour in the colour-polymorphic meadow grasshopper Pseudochorthippus parallelus based on 563 individuals from 17 populations sampled between 450 and 2,500 m asl. Pronotum length did not change with altitude, while postfemur length decreased significantly in both sexes. Tegmen (forewing) length decreased in males, but not in females. The results indicate that while body size, as best quantified by pronotum length, was remarkably constant, extended appendices were reduced at high altitudes. The pattern thus follows Allen's rule, but neither Bergmann's nor converse Bergmann's rule. These results indicate that inference of converse Bergmann's rule based on measurements from appendices should be treated with some caution. Colour morph ratios showed significant changes in both sexes from lowland populations dominated by green individuals to high-altitude populations dominated by brown ones. The increase of brown morphs was particularly steep between 1,500 and 2,000 m asl. The results suggest shared control of colour in males and females and local adaptation along the altitudinal gradient following the predictions of the thermal melanism hypothesis. Interestingly, both patterns, the reduction of body appendices and the higher frequency of brown individuals, may be explained by a need for efficient thermoregulation under high-altitude conditions. PMID- 29284052 TI - Is there a "weekend effect" in kidney transplantation? AB - The 'weekend effect' describes increased adverse outcomes after weekend hospitalization. We examined weekend-weekday differences in the outcome of 580 patients following renal transplantation (RTx, brain dead donors) between January 2007 and December 2014 at our center. 3-year patient and graft survival, incidence of delayed graft function (DGF), acute rejections and estimated glomerular filtration rate (eGFR, CKD-EPI) at 1 year as well as surgical complications were assessed. Of all 580 transplants, 416 (71.7%) were performed on weekdays (Monday-Friday) and 164 (28.3%) on weekends (Saturday-Sunday). 3-year patient and graft survival, frequencies of DGF, acute rejections and 1-year eGFR as well as length of hospital stay were similar between RTx patients transplanted on weekdays or weekends, respectively. However, a noticeable difference was detected with regard to surgical complications which were more frequent in RTx patients transplanted on weekends. All results remained consistent across all definitions of weekend status. Our results suggest that weekend transplant status does not affect functional short-term and long-term outcomes after RTx. The standardized protocols and operationalized processes applied in RTx might contribute to this finding and may provide a model for other medical procedures that are performed on weekends to improve efficiency and outcomes. The higher rate of surgical complications after weekend RTx needs further elaboration to fully assess the presence of a weekend effect in RTx. PMID- 29284053 TI - ESBL-producing Escherichia coli in Swedish gulls-A case of environmental pollution from humans? AB - ESBL-producing bacteria are present in wildlife and the environment might serve as a resistance reservoir. Wild gulls have been described as frequent carriers of ESBL-producing E. coli strains with genotypic characteristics similar to strains found in humans. Therefore, potential dissemination of antibiotic resistance genes and bacteria between the human population and wildlife need to be further investigated. Occurrence and characterization of ESBL-producing E. coli in Swedish wild gulls were assessed and compared to isolates from humans, livestock and surface water collected in the same country and similar time-period. Occurrence of ESBL-producing E. coli in Swedish gulls is about three times higher in gulls compared to Swedish community carriers (17% versus 5%) and the genetic characteristics of the ESBL-producing E. coli population in Swedish wild gulls and Swedish human are similar. ESBL-plasmids IncF- and IncI1-type carrying ESBL genes blaCTX-M-15 or blaCTX-M-14 were most common in isolates from both gulls and humans, but there was limited evidence of clonal transmission. Isolates from Swedish surface water harbored similar genetic characteristics, which highlights surface waters as potential dissemination routes between wildlife and the human population. Even in a low-prevalence country such as Sweden, the occurrence of ESBL producing E. coli in wild gulls and the human population appears to be connected and the occurrence of ESBL-producing E. coli in Swedish gulls is likely a case of environmental pollution. PMID- 29284054 TI - Risk and protective factors of health-related quality of life in children and adolescents: Results of the longitudinal BELLA study. AB - AIMS: Cross-sectional studies demonstrated associations of several sociodemographic and psychosocial factors with generic health-related quality of life (HRQoL) in children and adolescents. However, little is known about factors affecting the change in child and adolescent HRQoL over time. This study investigates potential psychosocial risk and protective factors of child and adolescent HRQoL based on longitudinal data of a German population-based study. METHODS: Data from the BELLA study gathered at three measurement points (baseline, 1-year and 2-year follow-ups) were investigated in n = 1,554 children and adolescents aged 11 to 17 years at baseline. Self-reported HRQoL was assessed by the KIDSCREEN-10 Index. We examined effects of sociodemographic factors, mental health problems, parental mental health problems, as well as potential personal, familial, and social protective factors on child and adolescent HRQoL at baseline as well as over time using longitudinal growth modeling. RESULTS: At baseline, girls reported lower HRQoL than boys, especially in older participants; low socioeconomic status and migration background were both associated with low HRQoL. Mental health problems as well as parental mental health problems were negatively, self-efficacy, family climate, and social support were positively associated with initial HRQoL. Longitudinal analyses revealed less increase of HRQoL in girls than boys, especially in younger participants. Changes in mental health problems were negatively, changes in self-efficacy and social support were positively associated with the change in HRQoL over time. No effects were found for changes in parental mental health problems or in family climate on changes in HRQoL. Moderating effects for self-efficacy, family climate or social support on the relationships between the investigated risk factors and HRQoL were not found. CONCLUSION: The risk factor mental health problems negatively and the resource factors self-efficacy and social support positively affect the development of HRQoL in young people, and should be considered in prevention programs. PMID- 29284056 TI - Durum wheat diversity for heat stress tolerance during inflorescence emergence is correlated to TdHSP101C expression in early developmental stages. AB - The predicted world population increase along with climate changes threatens sustainable agricultural supply in the coming decades. It is therefore vital to understand crops diversity associated to abiotic stress response. Heat stress is considered one of the major constrains on crops productivity thus it is essential to develop new approaches for a precocious and rigorous evaluation of varietal diversity regarding heat tolerance. Plant cell membrane thermostability (CMS) is a widely used method for wheat thermotolerance assessment although its limitations require complementary solutions. In this work we used CMS assay and explored TdHSP101C genes as an additional tool for durum wheat screening. Genomic and transcriptomic analyses of TdHSP101C genes were performed in varieties with contrasting CMS results and further correlated with heat stress tolerance during fertilization and seed development. Although the durum wheat varieties studied presented a very high homology on TdHSP101C genes (>99%) the transcriptomic assessment allowed the discrimination between varieties with good CMS results and its correlation with differential impacts of heat treatment during inflorescence emergence and seed development on grain yield. The evidences here reported indicate that TdHSP101C transcription levels induced by heat stress in fully expanded leaves may be a promising complementary screening tool to discriminate between durum wheat varieties identified as thermotolerant through CMS. PMID- 29284055 TI - Impact of numeracy on understanding of prostate cancer risk reduction in PSA screening. AB - Prostate-specific antigen (PSA) screening for prostate cancer in men of average risk remains controversial. Patients' ability to incorporate risk reduction data into their decision-making may depend on their numeracy. We assessed the impact of patients' numeracy on their understanding of the risk reduction benefits of PSA screening. Men attending a general internal medicine clinic were invited to complete a survey. Four versions of the survey each included a three-item numeracy test and PSA risk reduction data, framed one of four ways: absolute (ARR) versus relative risk reduction (RRR), with or without baseline risk (BR). Respondents were asked to adjust their perceived risk of prostate-cancer mortality using the data presented. Accuracy of risk reduction was evaluated relative to how risk data were framed. Among a total of 200 respondents, a majority incorrectly answered one or more of the numeracy items. Overall accuracy of risk adjustment was only 20%. Accuracy varied with data framing: when presented with RRR, respondents were 13% accurate without BR and 31% accurate with BR; when presented with ARR, they were 0% accurate without BR and 35% accurate with BR. Including BR data significantly improved accuracy for both RRR (P = 0.03) and ARR groups (P < 0.01). Accuracy was significantly related to numeracy; numeracy scores of 0, 1, 2, and 3 were associated with accuracy rates of six, five, nine, and 36 percent, respectively (P < 0.01). Overall, numeracy was significantly associated with the accuracy of interpreting quantitative benefits of PSA screening. Alternative methods of communicating risk may facilitate shared decision-making in the use of PSA screening for early detection of prostate cancer. PMID- 29284057 TI - Computational fluid dynamics (CFD) using porous media modeling predicts recurrence after coiling of cerebral aneurysms. AB - OBJECTIVE: This study aimed to predict recurrence after coil embolization of unruptured cerebral aneurysms with computational fluid dynamics (CFD) using porous media modeling (porous media CFD). METHOD: A total of 37 unruptured cerebral aneurysms treated with coiling were analyzed using follow-up angiograms, simulated CFD prior to coiling (control CFD), and porous media CFD. Coiled aneurysms were classified into stable or recurrence groups according to follow-up angiogram findings. Morphological parameters, coil packing density, and hemodynamic variables were evaluated for their correlations with aneurysmal recurrence. We also calculated residual flow volumes (RFVs), a novel hemodynamic parameter used to quantify the residual aneurysm volume after simulated coiling, which has a mean fluid domain > 1.0 cm/s. RESULT: Follow-up angiograms showed 24 aneurysms in the stable group and 13 in the recurrence group. Mann-Whitney U test demonstrated that maximum size, dome volume, neck width, neck area, and coil packing density were significantly different between the two groups (P < 0.05). Among the hemodynamic parameters, aneurysms in the recurrence group had significantly larger inflow and outflow areas in the control CFD and larger RFVs in the porous media CFD. Multivariate logistic regression analyses demonstrated that RFV was the only independently significant factor (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = 0.016). CONCLUSION: The study findings suggest that RFV collected under porous media modeling predicts the recurrence of coiled aneurysms. PMID- 29284058 TI - Metabolically healthy obese individuals present similar chronic inflammation level but less insulin-resistance than obese individuals with metabolic syndrome. AB - The Metabolic Syndrome (MetS) is a cluster of cardiometabolic risk factors, usually accompanied by the presence of insulin resistance (IR) and a systemic subclinical inflammation state. Metabolically healthy obese (MHO) individuals seem to be protected against cardiometabolic complications. The aim of this work was to characterize phenotypically the low-grade inflammation and the IR in MHO individuals in comparison to obese individuals with MetS and control non obese. We studied two different populations: 940 individuals from the general population of Buenos Aires and 518 individuals from the general population of Venado Tuerto; grouped in three groups: metabolically healthy non-obese individuals (MHNO), MHO and obese individuals with MetS (MSO). Inflammation was measured by the levels of hs-CRP (high-sensitivity C reactive protein), and we found that MHO presented an increase in inflammation when compared with MHNO (Buenos Aires: p<0.001; Venado Tuerto: p<0.001), but they did not differ from MSO. To evaluate IR we analyzed the HOMA (Homoeostatic Model Assessment) values, and we found differences between MHO and MSO (Buenos Aires: p<0.001; Venado Tuerto: p<0.001), but not between MHNO and MHO. In conclusion, MHO group would be defined as a subgroup of obese individuals with an intermediate phenotype between MHNO and MSO individuals considering HOMA, hs-CRP and central obesity. PMID- 29284059 TI - Spatiotemporal gait characteristics in patients with COPD during the Gait Real time Analysis Interactive Lab-based 6-minute walk test. AB - BACKGROUND AND AIM: Overground gait assessment is limited by the analysis of multiple strides or both spatiotemporal gait characteristics, while fixed speed treadmill walking restricts natural gait speed variations. The Gait Real-time Analysis Interactive Lab (GRAIL)-based 6-minute walk test (6MWT) enables 3D motion analysis and self-paced treadmill walking, and could provide insight in gait alterations in patients with chronic obstructive pulmonary disease (COPD). The aim of this study is to compare spatiotemporal gait characteristics between patients with COPD and healthy elderly during the GRAIL-based 6MWT. MATERIALS AND METHODS: Eighty COPD patients (60% male; 62+/-7 years; FEV1:56+/-19% predicted) and 38 healthy elderly (63% male; 62+/-6 years; FEV1:119+/-17% predicted) performed two GRAIL-based 6MWTs. Mean differences and coefficient of variation of spatiotemporal gait characteristics were calculated using the trial with the largest walk distance. Sub-analyses were conducted to account for walking speed differences between groups, and muscle strength and COPD severity within the patient group. RESULTS: COPD patients showed increased temporal gait characteristics, decreased stride and step lengths, and increased gait variability compared to healthy elderly (p<0.01). Stride length variability remained increased in COPD after correction for walking speed (MD:0.98%, CI:0.36 1.61, p = 0.003). Reduced quadriceps strength did not translate into altered gait characteristics, while COPD severity is associated with stride time (left MD: 0.02s, CI:-0.04-0.01, p = 0.003; right MD:-0.02s, CI:-0.04-0.01, p = 0.003). DISCUSSION: COPD patients performed the GRAIL-based 6MWT differently compared to healthy elderly. Further research should use other variability measures to investigate gait characteristics in COPD, to assess subtle alterations in gait and to enable development of rehabilitation strategies to improve gait, and possibly balance and fall risk in COPD. Other lower limb muscle groups should be considered when investigating gait alterations in COPD. CONCLUSION: COPD patients have different gait characteristics compared to healthy elderly. Independent of walking speed, COPD patients demonstrate increased stride length variability during the GRAIL-based 6MWT compared to healthy elderly. PMID- 29284060 TI - Sex differences shape the response to infectious diseases. PMID- 29284061 TI - Correction: Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles. AB - [This corrects the article DOI: 10.1371/journal.pone.0157852.]. PMID- 29284063 TI - Retraction: Berberine Improves Kidney Function in Diabetic Mice via AMPK Activation. PMID- 29284062 TI - Effects of cross-bridge compliance on the force-velocity relationship and muscle power output. AB - Muscles produce force and power by utilizing chemical energy through ATP hydrolysis. During concentric contractions (shortening), muscles generate less force compared to isometric contractions, but consume greater amounts of energy as shortening velocity increases. Conversely, more force is generated and less energy is consumed during eccentric muscle contractions (lengthening). This relationship between force, energy use, and the velocity of contraction has important implications for understanding muscle efficiency, but the molecular mechanisms underlying this behavior remain poorly understood. Here we used spatially-explicit, multi-filament models of Ca2+-regulated force production within a half-sarcomere to simulate how force production, energy utilization, and the number of bound cross-bridges are affected by dynamic changes in sarcomere length. These computational simulations show that cross-bridge binding increased during slow-velocity concentric and eccentric contractions, compared to isometric contractions. Over the full ranges of velocities that we simulated, cross-bridge cycling and energy utilization (i.e. ATPase rates) increased during shortening, and decreased during lengthening. These findings are consistent with the Fenn effect, but arise from a complicated relationship between velocity-dependent cross-bridge recruitment and cross-bridge cycling kinetics. We also investigated how force production, power output, and energy utilization varied with cross bridge and myofilament compliance, which is impossible to address under typical experimental conditions. These important simulations show that increasing cross bridge compliance resulted in greater cross-bridge binding and ATPase activity, but less force was generated per cross-bridge and throughout the sarcomere. These data indicate that the efficiency of force production decreases in a velocity dependent manner, and that this behavior is sensitive to cross-bridge compliance. In contrast, significant effects of myofilament compliance on force production were only observed during isometric contractions, suggesting that changes in myofilament compliance may not influence power output during non-isometric contractions as greatly as changes in cross-bridge compliance. These findings advance our understanding of how cross-bridge and myofilament properties underlie velocity-dependent changes in contractile efficiency during muscle movement. PMID- 29284064 TI - Policies for biosimilar uptake in Europe: An overview. AB - BACKGROUND: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. OBJECTIVES: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. METHODS: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. RESULTS: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. CONCLUSIONS: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market. PMID- 29284066 TI - Digital Stratigraphy: Contextual Analysis of File System Traces in Forensic Science. AB - This work introduces novel methods for conducting forensic analysis of file allocation traces, collectively called digital stratigraphy. These in-depth forensic analysis methods can provide insight into the origin, composition, distribution, and time frame of strata within storage media. Using case examples and empirical studies, this paper illuminates the successes, challenges, and limitations of digital stratigraphy. This study also shows how understanding file allocation methods can provide insight into concealment activities and how real world computer usage can complicate digital stratigraphy. Furthermore, this work explains how forensic analysts have misinterpreted traces of normal file system behavior as indications of concealment activities. This work raises awareness of the value of taking the overall context into account when analyzing file system traces. This work calls for further research in this area and for forensic tools to provide necessary information for such contextual analysis, such as highlighting mass deletion, mass copying, and potential backdating. PMID- 29284067 TI - Comparison of outcome and cost among open, laparoscopic, and robotic surgical treatments for rectal cancer: A propensity score matched analysis of nationwide inpatient sample data. AB - BACKGROUND: Population-based studies evaluating outcomes of different approaches for rectal cancer are scarce. METHODS: We conducted a retrospective cohort study using the Nationwide Inpatient Sample database between 2008 and 2012. We compared the outcomes and costs among rectal cancer patients undergoing robotic, laparoscopic, or open surgeries using propensity scores for adjusted and matched analysis. RESULTS: We identified 194 957 rectal cancer patients. Over the 5-year period, the annual admission number decreased by 13.9%, the in-hospital mortality rate decreased by 32.2%, while the total hospitalization cost increased by 13.6%. Compared with laparoscopic surgery, robotic surgery had significantly lower length of stay (LOS) (OR 0.69, 95%CI 0.57-0.84), comparable wound complications (OR 1.08, 95%CI 0.70-1.65) and higher cost (OR 1.42, 95%CI 1.13-1.79), while open surgery had significantly longer LOS (OR 1.38, 95%CI 1.19-1.59), more wound complications (OR 1.49, 95%CI 1.08-1.79), and comparable cost (OR 0.92, 95%CI 0.79-1.07). There were no difference in in-hospital mortality among three approaches. CONCLUSIONS: Laparoscopic surgery was associated with better outcomes than open surgery. Robotic surgery was associated with higher cost, but no advantage over laparoscopic surgery in terms of mortality and complications. Studies on cost-effectiveness of robotic surgery may be warranted. PMID- 29284068 TI - The role and outcomes of palliative surgery for retroperitoneal sarcoma. AB - Categories of noncurative surgery for retroperitoneal sarcoma include: i) grossly incomplete resection (R2) of primary or locally recurrent tumor; ii) resection in the setting of distant metastatic disease; and iii) true palliative-intent symptom-directed surgery. The value of R2 resection is debatable, since most series do not report initial operative intent. Debulking surgery provides symptom relief in the majority of patients, but relief is generally not durable. Quality of life is poorly studied. PMID- 29284065 TI - Inner tegument proteins of Herpes Simplex Virus are sufficient for intracellular capsid motility in neurons but not for axonal targeting. AB - Upon reactivation from latency and during lytic infections in neurons, alphaherpesviruses assemble cytosolic capsids, capsids associated with enveloping membranes, and transport vesicles harboring fully enveloped capsids. It is debated whether capsid envelopment of herpes simplex virus (HSV) is completed in the soma prior to axonal targeting or later, and whether the mechanisms are the same in neurons derived from embryos or from adult hosts. We used HSV mutants impaired in capsid envelopment to test whether the inner tegument proteins pUL36 or pUL37 necessary for microtubule-mediated capsid transport were sufficient for axonal capsid targeting in neurons derived from the dorsal root ganglia of adult mice. Such neurons were infected with HSV1-DeltaUL20 whose capsids recruited pUL36 and pUL37, with HSV1-DeltaUL37 whose capsids associate only with pUL36, or with HSV1-DeltaUL36 that assembles capsids lacking both proteins. While capsids of HSV1-DeltaUL20 were actively transported along microtubules in epithelial cells and in the somata of neurons, those of HSV1-DeltaUL36 and -DeltaUL37 could only diffuse in the cytoplasm. Employing a novel image analysis algorithm to quantify capsid targeting to axons, we show that only a few capsids of HSV1 DeltaUL20 entered axons, while vesicles transporting gD utilized axonal transport efficiently and independently of pUL36, pUL37, or pUL20. Our data indicate that capsid motility in the somata of neurons mediated by pUL36 and pUL37 does not suffice for targeting capsids to axons, and suggest that capsid envelopment needs to be completed in the soma prior to targeting of herpes simplex virus to the axons, and to spreading from neurons to neighboring cells. PMID- 29284070 TI - Evaluation of fluorescence-guided surgery agents in a murine model of soft tissue fibrosarcoma. AB - BACKGROUND AND OBJECTIVES: Soft tissue sarcomas (STS) are mesenchymal malignancies. Treatment mainstay is surgical resection with negative margins +/- adjuvant treatment. Fluorescence-guided surgical (FGS) resection can delineate intraoperative margins; FGS has improved oncologic outcomes in other malignancies. This novel strategy may minimize resection-associated morbidity while improving local tumor control. METHODS: We evaluate the tumor-targeting specificity and utility of fluorescence-imaging agents to provide disease specific contrast. Mice with HT1080 fibrosarcoma tumors received one of five probes: cetuximab-IRDye800CW (anti-EGFR), DC101-IRDye800CW (anti-VEGFR-2), IgG IRDye800CW, the cathepsin-activated probe Prosense750EX, or the small molecule probe IntegriSense750. Tumors were imaged daily using open- and closed-field fluorescence imaging systems. Tumor-to-background ratios (TBR) were evaluated. On peak TBR days, probe sensitivity was evaluated. Tumors were stained and imaged microscopically. RESULTS: At peak, closed-field imaging TBR of cetuximab IRDye800CW (16.8) was significantly greater (P < 0.0001) than Integrisense750 (7.0), Prosense750EX (5.8), and DC101-IRDye800CW (3.7). All agents successfully localized as little as 1.0 mg of tumor tissue in the post-resection bed; cetuximab-IRDye800CW generated the greatest contrast (2.5). Cetuximab-IRDye800CW revealed strong tumor affinity microscopically; tumor fluorescence intensity was significantly greater (P < 0.0004) than 0.2 mm away from tumor border. CONCLUSION: This study demonstrates cetuximab-IRDye800CW superiority. FGS has the potential to improve post-resection morbidity and mortality by improving disease detection. PMID- 29284069 TI - Laterally and Temporally Controlled Intracellular Staining by Light-Triggered Release of Encapsulated Fluorescent Markers. AB - Fluorescent molecular markers were encapsulated. The capsules were additionally modified with plasmonic nanoparticles. The encapsulated markers were endocytosed by cells. Upon light stimulation the plasmonic nanoparticles generated heat, which opened the encapsulation and transiently perforated the endosomal/lysosomal membrane surrounding the capsule, thus allowing for release of the marker into the cytosol. Fluorescence labeling of different intracellular compartments was demonstrated in this way. Most important, the cells do not need to be fixed and perforated, as the molecular markers are introduced into cells by endocytosis and subsequent light-induced release. Thus this technique allows for intracellular fluorescence labeling of living cells. PMID- 29284071 TI - Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction. AB - The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia. PMID- 29284074 TI - 2017 Annual Meeting of the American Society for Bone and Mineral Research, Colorado Convention Center, Denver, CO, USA - September 8-11, 2017. PMID- 29284073 TI - Testing the Use of Pigs as Human Proxies in Decomposition Studies. AB - Pigs are a common human analogue in taphonomic study, yet data comparing the trajectory of decomposition between the two groups are lacking. This study compared decomposition rate and gross tissue change in 17 pigs and 22 human remains placed in the Forensic Investigation Research Station in western Colorado between 2012 and 2015. Accumulated degree days (ADD) were used to assess the number of thermal units required to reach a given total body score (TBS) (1) which was used as the measure of decomposition. A comparison of slopes in linear mixed effects model indicated that decomposition rates significantly differed between human donors and pig remains chi2(1) = 5.662, p = 0.017. Neither the pig nor the human trajectory compared well to the TBS model. Thus, (i) pigs are not an adequate proxy for human decomposition studies, and (ii) in the semiarid environment of western Colorado, there is a need to develop a regional decomposition model. PMID- 29284072 TI - Adjuvant therapy is associated with improved survival after curative resection for hilar cholangiocarcinoma: A multi-institution analysis from the U.S. extrahepatic biliary malignancy consortium. AB - BACKGROUND: Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection. METHODS: We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis. RESULTS: A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded. CONCLUSIONS: AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease. PMID- 29284075 TI - Atraumatic restorative treatment versus conventional restorative treatment for managing dental caries. AB - BACKGROUND: Dental caries is a sugar-dependent disease that damages tooth structure and, due to loss of mineral components, may eventually lead to cavitation. Dental caries is the most prevalent disease worldwide and is considered the most important burden of oral health. Conventional treatment methods (drill and fill) involve the use of rotary burs under local anaesthesia. The need for an electricity supply, expensive handpieces and highly trained dental health personnel may limit access to dental treatment, especially in underdeveloped regions.To overcome the limitations of conventional restorative treatment, the Atraumatic Restorative Treatment (ART) was developed, mainly for treating caries in children living in under-served areas of the world where resources and facilities such as electricity and trained manpower are limited. ART is a minimally invasive approach which involves removal of decayed tissue using hand instruments alone, usually without use of anaesthesia and electrically driven equipment, and restoration of the dental cavity with an adhesive material (glass ionomer cement (GIC), composite resins, resin-modified glass-ionomer cement (RM-GICs) and compomers). OBJECTIVES: To assess the effects of Atraumatic Restorative Treatment (ART) compared with conventional treatment for managing dental caries lesions in the primary and permanent teeth of children and adults. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 22 February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 1), MEDLINE Ovid (1946 to 22 February 2017), Embase Ovid (1980 to 22 February 2017), LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 22 February 2017) and BBO BIREME Virtual Health Library (Bibliografia Brasileira de Odontologia; 1986 to 22 February 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least six months' follow-up that compared the effects of ART with a conventional restorative approach using the same or different restorative dental materials to treat caries lesions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data from included studies and assessed the risk of bias in those studies. We used standard methodological procedures expected by Cochrane to evaluate risk of bias and synthesise data. Where pooling was appropriate we conducted meta-analyses using the random-effects model. We assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: We included a total of 15 eligible studies randomising 3760 participants in this review. The age of participants across the studies ranged from 3 to 101 years, with a mean of 25.42 years. 48% of participants were male. All included studies were published between 2002 and 2016. Two of the 15 studies declared that the financial support was from companies that manufacture restorative material. Five studies were individually randomised parallel-group studies; six were cluster-randomised parallel-group studies; and four were randomised studies that used a split-mouth design. Eleven studies evaluated the effects of ART on primary teeth only, and four on permanent teeth. The follow-up period of the included studies ranged from 6 months to 36 months. We judged all studies to be at high risk of bias.For the main comparison of ART compared to conventional treatment using the same material: all but two studies used high viscosity glass ionomer (H-GIC) as the restorative material; one study used a composite material; and one study used resin-modified glass ionomer cement (RM GIC)).Compared to conventional treatment using H-GIC, ART may increase the risk of restoration failure in the primary dentition, over a follow-up period from 12 to 24 months (OR 1.60, 95% CI 1.13 to 2.27, five studies; 643 participants analysed; low-quality evidence). Our confidence in this effect estimate is limited due to serious concerns over risk of performance and attrition bias. For this comparison, ART may reduce pain during procedure compared with conventional treatment (MD -0.65, 95% CI -1.38 to 0.07; 40 participants analysed; low-quality evidence)Comparisons of ART to conventional treatment using composite or RM-GIC were downgraded to very low quality due to indirectness, imprecision and high risk of performance and attrition bias. Given the very low quality of the evidence from single studies, we are uncertain about the restoration failure of ART compared with conventional treatment using composite over a 24-month follow up period (OR 1.11, 95% CI 0.54 to 2.29; one study; 57 participants) and ART using RM-GIC in the permanent teeth of older adults with root caries lesions over a six-month follow-up period (OR 2.71, 95% CI 0.94 to 7.81; one study; 64 participants).No studies reported on adverse events or costs. AUTHORS' CONCLUSIONS: Low-quality evidence suggests that ART using H-GIC may have a higher risk of restoration failure than conventional treatment for caries lesions in primary teeth. The effects of ART using composite and RM-GIC are uncertain due to the very low quality of the evidence and we cannot rely on the findings. Most studies evaluated the effects of ART on the primary dentition.Well-designed RCTs are required that report on restoration failure at clinically meaningful time points, as well as participant-reported outcomes such as pain and discomfort. Due to the potential confounding effects from the use of different dental materials, a robust body of evidence on the effects of ART compared with conventional treatment using the same restoration material is necessary. We identified four ongoing trials that could provide further insights into this area. PMID- 29284077 TI - Hepatobiliary and Pancreatic: Hepatic nodules in a patient with familial adenomatous polyposis and colorectal adenocarcinoma. PMID- 29284076 TI - Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease. AB - BACKGROUND: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy. METHODS: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively. RESULTS: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9). CONCLUSIONS: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients. PMID- 29284078 TI - Hepatobiliary and Pancreatic: Pregnancy induced hepatic veno-occlusive disease requiring liver transplantation. PMID- 29284079 TI - Gastrointestinal: Next-generation DASE in extensive bile duct stone disease: Introducing "dilation-assisted cholangioscopic stone extraction" (DACSE). PMID- 29284080 TI - Inadequate storage of subcutaneous biological agents by patients with inflammatory bowel disease: Another factor driving loss of response? PMID- 29284081 TI - Multilamellar-to-Unilamellar Transition Induced by Diphenylalanine in Lipid Vesicles. AB - In the present work, we investigate the effect of two short phenylalanine-based peptides on lipid membranes. A simplified model membrane composed of lecithin vesicles was used to incorporate different amounts of the two amino acid sequences, the dimmer l,l-diphenylallanine (FF) and the trimmer cysteine diphenylallanine (CFF). Spectroscopic and scattering techniques were applied to probe in detail the structural behavior of lipid membranes in the presence of the peptides. The experimental results demonstrate that both peptides are located mainly at the interface of the membrane interacting with phosphate groups modifying membrane thickness and flexibility. The multilamellar structure of the vesicles is preserved with inclusion of small amounts of FF, accompanied by changes in membrane thickness and elasticity. Finally, a multi- to unilamellar transition is observed as a result of peptide self-association into a crystalline structure onto the membrane interface. PMID- 29284083 TI - Ecotoxicology Goes on a Chip: Embracing Miniaturized Bioanalysis in Aquatic Risk Assessment. AB - Biological and environmental sciences are, more than ever, becoming highly dependent on technological and multidisciplinary approaches that warrant advanced analytical capabilities. Microfluidic lab-on-a-chip technologies are perhaps one the most groundbreaking offshoots of bioengineering, enabling design of an entirely new generation of bioanalytical instrumentation. They represent a unique approach to combine microscale engineering and physics with specific biological questions, providing technological advances that allow for fundamentally new capabilities in the spatiotemporal analysis of molecules, cells, tissues, and even small metazoan organisms. While these miniaturized analytical technologies experience an explosive growth worldwide, with a substantial promise of a direct impact on biosciences, it seems that lab-on-a-chip systems have so far escaped the attention of aquatic ecotoxicologists. In this Critical Review, potential applications of the currently existing and emerging chip-based technologies for aquatic ecotoxicology and water quality monitoring are highlighted. We also offer suggestions on how aquatic ecotoxicology can benefit from adoption of microfluidic lab-on-a-chip devices for accelerated bioanalysis. PMID- 29284082 TI - Sporobeads: The Utilization of the Bacillus subtilis Endospore Crust as a Protein Display Platform. AB - Upon starvation, the soil bacterium Bacillus subtilis forms an intracellular, metabolically inactive endospore. Its core contains the DNA, encased by three protein layers protecting it against a multitude of environmental threats. The outermost layer, the crust, harbors great potential as a protein-displaying platform: a gene of interest can be translationally fused to a crust protein gene, resulting in endospores displaying the desired protein on their surface. To unlock this potential in a standardized fashion, we designed a suite of 12 vectors (Sporovectors), based on the BioBrick cloning standard. With these vectors, proteins can easily be fused N- or C-terminally to the six crust proteins CotV, CotW, CotX, CotY, CotZ, and CgeA under the control of the strongest crust gene promoter PcotYZ. All Sporovectors were evaluated with GFP and two different laccases. On the basis of our data, CotY and CotZ represent the best anchor proteins. But there are significant differences in activity and functional stability between the two tested laccases. Our vector suite is a powerful tool to generate and evaluate a vast variety of functionalized endospores. It allows quickly identifying the best anchor and fusion site for the protein of interest. Our findings demonstrate that the crust of B. subtilis endospores is an inexpensive and easy platform for displaying different proteins of interest. PMID- 29284084 TI - Editorial. PMID- 29284085 TI - Inhibition of beta-Amyloid Aggregation through a Designed beta-Hairpin Peptide. AB - Designing peptide-based drugs to target the beta-sheet-rich toxic intermediates during the aggregation of amyloid-beta 1-42 (Abeta1-42) has been a major challenge. In general, beta-sheet breaker peptides (BSBPs) are designed to complement the enthalpic interactions with the aggregating protein, and entropic effects are usually ignored. Here, we have developed a conformationally constrained cyclic BSBP by the use of an unnatural amino acid and a disulfide bond. We show that our peptide strongly inhibits the aggregation of Abeta1-42 in a concentration-dependent manner. It stabilizes the random coil conformation of Abeta1-42 monomers and inhibits the secondary structural transition to a beta sheet-rich conformation which allows Abeta1-42 to oligomerize in an ordered assembly during its aggregation. Our cyclic peptide also rescues the toxicity of soluble aggregates of Abeta1-42 toward neuronal cells. However, it significantly loses its potency in the conformationally relaxed acyclic form. It appears that limiting the loss of conformational entropy of the BSBP ligand can play a very important role in the attainment of conformations for precise and tight binding, making them a potent inhibitor for Abeta1-42 amyloidosis. PMID- 29284087 TI - Surpassing Single Line Width Active Tuning with Photochromic Molecules Coupled to Plasmonic Nanoantennas. AB - Active plasmonic nanostructures with tunable resonances promise to enable smart materials with multiple functionalities, on-chip spectral-based imaging and low power optoelectronic devices. A variety of tunable materials have been integrated with plasmonic structures, however, the tuning range in the visible regime has been limited to less than the line width of the resonance resulting in small on/off ratios. Here we demonstrate dynamic tuning of plasmon resonances up to 71 nm through multiple cycles by incorporating photochromic molecules into plasmonic nanopatch antennas. Exposure to ultraviolet (UV) light switches the molecules into a photoactive state enabling dynamic control with on/off ratios up to 9.2 dB and a tuning figure of merit up to 1.43, defined as the ratio between the spectral shift and the initial line width of the plasmonic resonance. Moreover, the physical mechanisms underlying the large spectral shifts are elucidated by studying over 40 individual nanoantennas with fundamental resonances from 550 to 720 nm revealing good agreement with finite-element simulations. PMID- 29284086 TI - Antimicrobial Peptide K0-W6-Hya1 Induces Stable Structurally Modified Lipid Domains in Anionic Membranes. AB - Considering the known different mode of action of antimicrobial peptides in zwitterionic and anionic cell membranes, the present work compares the action of the antimicrobial peptide K0-W6-Hya1 (KIFGAIWPLALGALKNLIK-NH2) with zwitterionic and negatively charged model membranes, namely, liposomes composed of phosphatidylcholine (PC) and phosphatidylglycerol (PG) membranes, and a mixture of the two. Differential scanning calorimetry (DSC), steady state fluorescence of the Trp residue, dynamic light scattering (DLS), and measurement of the leakage of an entrapped fluorescent dye (carboxyfluorescein, CF) were performed with large unilamellar vesicles (LUVs). All techniques evidenced the different action of the peptide in zwitterionic and anionic vesicles. Trp fluorescence spectroscopy shows that the differences are related not only to the partition of the cationic peptide in zwitterionic and anionic membranes, but also to the different penetration depth of the peptide into the lipid bilayers: Trp goes deeper into negatively charged membranes, both in the gel and fluid phases, than into zwitterionic ones. DSC shows that the peptide is strongly attached to anionic bilayers, giving rise to the coexistence of two different lipid regions, one depleted of peptide and another one peptide-disturbed, possibly a stable or transient polar pore, considering the leakage of CF. This contrasts with the homogeneous effect produced by the peptide in zwitterionic membranes, probably related to peptide-membrane diffusion. Moreover, in mixed bilayers (PC:PG), the peptide sequesters negatively charged lipids, creating peptide-rich anionic lipid regions, strongly disturbing the membrane. The distinct structural interaction displayed by the peptide in PC and PG membranes could be related to the different mechanisms of action of the peptide in anionic prokaryotic and zwitterionic eukaryotic cell membranes. PMID- 29284088 TI - Engineering 1-Alkene Biosynthesis and Secretion by Dynamic Regulation in Yeast. AB - Microbial production of fatty acid-derived hydrocarbons offers a great opportunity to sustainably supply biofuels and oleochemicals. One challenge is to achieve a high production rate. Besides, low efficiency in secretion will cause high separation costs, and it is therefore desirable to have product secretion. Here, we engineered the budding yeast Saccharomyces cerevisiae to produce and secrete 1-alkenes by manipulation of the fatty acid metabolism, enzyme selection, engineering the electron transfer system and expressing a transporter. Furthermore, we implemented a dynamic regulation strategy to control the expression of membrane enzyme and transporter, which improved 1-alkene production and cell growth by relieving the possible toxicity of overexpressed membrane proteins. With these efforts, the engineered yeast cell factory produced 35.3 mg/L 1-alkenes with more than 80% being secreted. This represents a 10-fold improvement compared with earlier reported hydrocarbon production by S. cerevisiae. PMID- 29284089 TI - Natural Silicon Isotopic Signatures Reveal the Sources of Airborne Fine Particulate Matter. AB - Airborne particulate pollution is a critical environmental problem affecting human health and sustainable development. Understanding of the sources of aerosol particles is of extreme importance for regional air pollution control. Here we show that natural Si isotopic signature can be used as a new tool to elucidate the sources of fine particulate matter (PM2.5). Through the analysis of Si isotopic composition (delta30Si) of PM2.5 and its primary sources collected in a typical pollution region - Beijing, we recognized the direct source tracing ability of Si isotopes for PM2.5. The different primary sources of PM2.5 had different Si isotopic signatures. The delta30Si value of PM2.5 ranged from 1.990/00 to -0.010/00 and showed a distinct seasonal trend (isotopically lighter in spring/winter and heavier in summer/autumn). The variations in delta30Si of PM2.5 revealed that Si-isotopically light sources were important sources for Beijing's severe haze pollution and that coal burning was a major cause for the aggregating haze weather in spring/winter in Beijing. We also analyzed several typical haze events by using Si isotopic signatures. As the first study on the natural Si isotopes in the atmospheric environment, this study may reveal an important tool to advance the particulate pollution research and control. PMID- 29284090 TI - Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity. AB - Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46 fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry. PMID- 29284091 TI - Free Energy Profile of NaCl in Water: First-Principles Molecular Dynamics with SCAN and omegaB97X-V Exchange-Correlation Functionals. AB - Properties of water and aqueous ionic solutions are of great scientific interest because they play a central role in the atmosphere, biological environments, and various industrial processes. Employing two advanced exchange-correlation (XC) approximations, omegaB97X-V and SCAN, in first-principles molecular dynamics simulations, we calculate the potential of mean force of NaCl in water as a function of the ion separation distance. Compared to the commonly used GGA-PBE functional, both of these XC functionals perform much better in simulating liquid water at room temperature for obtaining structural properties. The potential of mean force of NaCl in water exhibits two minima corresponding to two distinct types of ion pairing. omegaB97X-V predicts that the contact ion pair is energetically more stable than the solvent-separated ion pair. The SCAN functional, however, predicts the opposite stability order, similarly to other XC functionals such as PBE. This is notable especially since classical molecular dynamics simulations with widely used force-field models predict greater stability for the contact ion pair. We also discuss how the electronic structures of water molecules and ions depend on the XC approximations. omegaB97X-V and SCAN approximations noticeably improve the description of electron charge on Cl- ion in water while the charge on Na+ ion does not vary appreciably among the three XC functionals. PMID- 29284095 TI - Three-Year Effects of Deproteinization on the In Vitro Durability of Resin/Dentin Eroded Interfaces. AB - OBJECTIVE: To evaluate the effect of sodium hypochlorite on the immediate and three-year bonding properties of a resin-eroded dentin interface produced by one of two adhesive strategies. METHODS AND MATERIALS: Forty-eight molars were randomly assigned to six experimental groups, according to the combination of the adhesive strategy (etch-and-rinse and self-etch) and the dentin surface (control groups without erosion, eroded dentin surface [ED], and eroded dentin surface + NaOCl 5.2% [ED + NaOCl]). After completing restoration, specimens were stored in water (37 degrees C) for 24 hours and then sectioned into resin-dentin beams (0.8 mm2) to be tested under tension (0.5 mm/min) immediately thereafter or after three years of water storage. To assess nanoleakage (NL), specimens were immersed in silver nitrate solution and examined by scanning electron microscopy at both time points. The dentin-etching pattern was examined under a scanning electron microscope. Data were subjected to appropriate statistical analysis (alpha=0.05) Results: In both strategies, a more pronounced and significant reduction of the microtensile bond strength (MUTBS) values was observed for the ED groups ( p=0.0001) after three years. However, in the ED + NaOCl group, MUTBS values were maintained after three years of water storage. Furthermore, application of NaOCl to eroded dentin significantly reduced the immediate NL values and also preserved these values after three years of water storage for both adhesive strategies ( p>0.05). When considering the ED group, a superficial removal of the smear layer and enlarged lumen tubules in comparison to control were present. However, for ED + NaOCl, there was a total removal of the smear layer and significant numbers of collagen fibrils were exposed. CONCLUSION: The use of NaOCl may maintain the long term stability of a resin-eroded dentin interface formed by etch-and-rinse and self-etch adhesives. PMID- 29284092 TI - Aggregate Size Dependence of Amyloid Adsorption onto Charged Interfaces. AB - Amyloid aggregates are associated with a range of human neurodegenerative disorders, and it has been shown that neurotoxicity is dependent on aggregate size. Combining molecular simulation with analytical theory, a predictive model is proposed for the adsorption of amyloid aggregates onto oppositely charged surfaces, where the interaction is governed by an interplay between electrostatic attraction and entropic repulsion. Predictions are experimentally validated against quartz crystal microbalance-dissipation experiments of amyloid beta peptides and fragmented fibrils in the presence of a supported lipid bilayer. Assuming amyloids as rigid, elongated particles, we observe nonmonotonic trends for the extent of adsorption with respect to aggregate size and preferential adsorption of smaller aggregates over larger ones. Our findings describe a general phenomenon with implications for stiff polyions and rodlike particles that are electrostatically attracted to a surface. PMID- 29284096 TI - Real-time Light Transmittance Monitoring for Determining Polymerization Completeness of Conventional and Bulk Fill Dental Composites. AB - OBJECTIVES: To monitor the real-time changes in light transmittance during composite curing and to use transmittance data to determine the curing times required for a complete polymerization. METHODS: Three conventional and three bulk fill composites were cured with two light-emitting diode curing units at layer thicknesses of 2 mm and 4 mm. The real-time light transmittance data were collected by a UV-Vis spectrometer in the wavelength range of 350-550 nm, plotted against time (t) and fitted to an exponential function f(t), whose first derivative DeltaT(t) = df(t)/dt represented the rate of transmittance change. As the changing transmittance reflects structural changes that occur during polymerization, DeltaT(t) > 0 was considered to indicate an ongoing polymerization, whereas DeltaT(t) values approaching zero suggested a complete polymerization. This principle was used to determine times required for a complete polymerization (tcomplete) for each material/thickness/curing unit combination. RESULTS: Light transmittance was significantly influenced by the material type, sample thickness, and curing unit, amounting to 2.9%-27.0% for the bulk fill and 0.7%-16.7% for the conventional composites. The values of tcomplete amounted to 15.3-23.3 seconds for the bulk fill composites at 2 mm, 20.2-33.3 seconds for the conventional composites at 2 mm, 26.9-42.1 seconds for the bulk fill composites at 4 mm, and 40.1-59.8 seconds for the conventional composites at 4 mm. Additionally, an exponential relationship was discovered between the light transmittance and tcomplete. CONCLUSIONS: Some of the tcomplete values considerably exceeded the curing times recommended by the manufacturers. PMID- 29284097 TI - Effectiveness of LED/Laser Irradiation on In-Office Dental Bleaching after Three Years. AB - The present in vivo randomized, triple-blinded, and split-mouth clinical study evaluated the effectiveness of a hybrid light (HL) source on the color change, stability, and tooth sensitivity in patients submitted to different in-office bleaching techniques. Twenty volunteers were divided into two groups and four subgroups. A split-mouth design was conducted to compare two in-office bleaching techniques (with and without light activation): 35% Lase Peroxide Sensy (LPS) + HL: 35% hydrogen peroxide (HP) + HL; 35% LPS: 35% HP; 25% LPS + HL: 25% HP + HL; and 35% Whiteness HP (WHP): 35% HP. For the groups activated with HL, the HP was applied on the enamel surface three consecutive times using a 3 * 2-minute protocol (three HL activations for two minutes each, with a 30-second interval for a total of seven minutes and 30 seconds) for each gel application, totaling 22 minutes and 30 seconds. For the other groups, HP was applied 3 * 15 minutes, totaling 45 minutes. A spectrophotometer was used to measure the color change (DeltaE) before the treatment and 24 hours, one week, and one, 12, and 36 months after. A visual analog scale was used to evaluate the tooth sensitivity before the treatment, immediately following treatment, 24 hours, and one week after. Analysis of variance, Tukey's, Kruskall-Wallis, and Wilcoxon tests, all with alpha = 0.05 were performed. Statistical analysis did not reveal any significant differences (DeltaE) between the in-office bleaching techniques with or without HL in the periods evaluated; the activation with HL required 50% less time to achieve such results. The groups without HL presented statistical differences for DeltaE when comparing 24 hours with the other follow-up times (intergroup) and an increase in tooth sensitivity in the initial periods. All techniques and bleaching agents were effective on bleaching during a 36-month evaluation of color stability. The groups activated with HL presented lower sensitivity and required a lower activation time. PMID- 29284098 TI - India Meets the Challenge and Goes for Gold. AB - This Editorial was initially printed in the March 2017 issue of the Indian Journal of Dental Research. They have graciously allowed us to reprint it here. PMID- 29284099 TI - Replacement of a Missing Maxillary Central Incisor Using a Direct Fiber Reinforced Fixed Dental Prosthesis: A Case Report. AB - The use of the direct fiber-reinforced fixed dental prosthesis (FDP) restorative technique presented in this article will result in an ideal restoration considering both esthetics and function in a single appointment. Although indirect techniques are available and may be used, they are time-consuming, resulting in higher cost; therefore, a simplified approach combining a prebonded fiber-reinforced mesh with a sculptable micro-hybrid composite will deliver an acceptable esthetic result with proper function. PMID- 29284100 TI - Cuspal Deflection in Premolar Teeth Restored with Bulk-Fill Resin-Based Composite Materials. AB - The present study investigated the effect of three high-viscosity bulk-fill resin based composite materials on cuspal deflection in natural teeth. Thirty-two sound maxillary premolar teeth with large slot mesio-occlusal-distal cavities were distributed into four groups (n=8). Three groups were restored with bulk-fill resin composite materials (Tetric EvoCeram Bulk Fill, Ivoclar Vivadent, Schaan, Liechtenstein; x-tra fil, VOCO, Cuxhaven, Germany; and SonicFill, Kerr, Orange, CA, USA) in a single 4-mm increment. The conventional composite group, Filtek Z100 (3M ESPE, St Paul, MN, USA), was used to restore the cavities in 2-mm increments. Cusp deflection was recorded postirradiation using a Nikon measurescope UM-2 (Nikon, Tokyo, Japan) by measuring the changes in the bucco palatal widths of the teeth at five minutes, 24 hours, and 48 hours after completion of the restorations. Cuspal deflection was significantly higher in the conventional composite than in the Tetric EvoCeram Bulk Fill ( p=0.0031), x-tra fil ( p=0.0029), and SonicFill Bulk ( p=0.0002) groups. There were no significant differences in cuspal deflection among the three bulk-fill materials (all p<0.05). In conclusion, all the investigated bulk-fill resin composites exhibited cuspal deflection values that were smaller than those associated with a conventional incrementally placed resin composite. PMID- 29284101 TI - Effect of Finishing and Polishing on Roughness and Gloss of Lithium Disilicate and Lithium Silicate Zirconia Reinforced Glass Ceramic for CAD/CAM Systems. AB - OBJECTIVE: To assess the efficacy of dedicated finishing/polishing systems on roughness and gloss of VITA Suprinity and IPS e.max CAD. METHOD: A total of 24 blocks of Suprinity and 24 of e.max were cut into a wedge shape using an InLab MC XL milling unit. After crystallization, the 24 Suprinity wedges were divided into four subgroups: group A.1: Suprinity Polishing Set Clinical used for 30 seconds and group A.2: for 60 seconds; group A.3: VITA Akzent Plus Paste; and group A.4: spray. The 24 e.max wedges (group B) were divided into four subgroups according to the finishing procedure: group B.1: Optrafine Ceramic Polishing System for 30 seconds and group B.2: for 60 seconds; group B.3: IPS e.max CAD Crystall/Glaze paste; and group B.4: spray. After finishing/polishing, gloss was assessed with a glossmeter and roughness evaluated with a profilometer. Results were analyzed by applying a two-way analysis of variance for gloss and another for roughness (alpha=0.05). One specimen per each subgroup was observed with a scanning electron microscope. RESULTS: For roughness, materials and surface were significant factors ( p<0.001). Suprinity exhibited significantly lower roughness than e.max. Also the Material-Surface Treatment interaction was statistically significant ( p=0.026). For gloss, both material and surface treatment were significant factors ( p<0.001). VITA Suprinity showed significantly higher gloss than e.max. Also the Material-Surface Treatment interaction was statistically significant ( p<0.001). CONCLUSIONS: Manual finishing/polishing for 60 seconds and glazing paste are the most effective procedures in lowering the roughness of CAD/CAM silica-based glass ceramics. Manual finishing/polishing for 60 seconds allows milled silica-based glass ceramics to yield a higher gloss. VITA Suprinity displayed higher polishability than IPS e.max CAD. PMID- 29284102 TI - Does Finishing and Polishing of Restorative Materials Affect Bacterial Adhesion and Biofilm Formation? A Systematic Review. AB - Biofilm (bacterial plaque) accumulation on the surface of restorative materials favors the occurrence of secondary caries and periodontal inflammation. Surface characteristics of restorations can be modified by finishing and/or polishing procedures and may affect bacterial adhesion. The aim of this systematic review was to characterize how finishing and polishing methods affect the surface properties of different restorative materials with regard to bacterial adhesion and biofilm formation. Searches were carried out in MEDLINE-PubMed, EMBASE, Cochrane-CENTRAL, and LILACS databases. From 2882 potential articles found in the initial searches, only 18 met the eligible criteria and were included in this review (12 with in vitro design, four with in situ design, and two clinical trials). However, they presented high heterogeneity regarding materials considered and methodology for evaluating the desired outcome. Risk bias analysis showed that only two studies presented low risk (whereas 11 showed high and five showed medium risk). Thus, only descriptive analyses considering study design, materials, intervention (finishing/polishing), surface characteristics (roughness and surface free energy), and protocol for biofilm formation (bacterial adhesion) could be performed. Some conclusions could be drawn: the impact of roughness on bacterial adhesion seems to be related not to a roughness threshold (as previously believed) but rather to a range, the range of surface roughness among different polishing methods is wide and material dependent, finishing invariably creates a rougher surface and should always be followed by a polishing method, each dental material requires its own treatment modality to obtain and maintain as smooth a surface as possible, and in vitro designs do not seem to be powerful tools to draw relevant conclusions, so in vivo and in situ designs become strongly recommended. PMID- 29284103 TI - Faculty Posting. PMID- 29284104 TI - Online Only Articles. AB - On occasion we receive manuscripts that we would like to publish, but do not have the page room to include in the print journal. For the full article, please go to www.jopdentonline.org or enter the provided address into your address bar. PMID- 29284105 TI - A Novel Enamel and Dentin Etching Protocol Using alpha-hydroxy Glycolic Acid: Surface Property, Etching Pattern, and Bond Strength Studies. AB - OBJECTIVES: To determine the use of alpha-hydroxy glycolic acid (GA) as a surface pretreatment for dental restorative applications. The etching pattern of GA pretreatment of dental hard tissues was assessed by surface microhardness and scanning electron microscopy (SEM). The effectiveness of GA surface etching on the enamel and dentin resin bond strengths was assessed using two etchant application modes (rubbing and no rubbing) and three adhesive systems (Single Bond [SB], One Step Plus [OSP], and Scotchbond Universal [SBU]). METHODS: Knoop microhardness measurements were carried out on polished enamel and dentin surfaces before and after treatment with 35% GA, 35% phosphoric acid (PA), or distilled water (control group) for 30 seconds. The microtensile bond strength test was carried out on enamel and dentin. Ultrastructural analysis of the surface and interfacial interaction was qualitatively accomplished using SEM. RESULTS: Etching with either PA or GA significantly decreased the enamel microhardness, with GA being significantly less aggressive than PA ( p<0.001), while both acids showed similar decreases in dentin microhardness ( p=0.810). SEM revealed similar etching patterns of GA and PA, while apparently a thinner hybrid layer was observed for GA groups. In dentin, the bond strengths were statistically similar between PA and GA groups, regardless of the etchant application mode ( p>0.05). However, rubbing of GA enhanced the bond strength to enamel. PA and GA significantly increased the SBU bond strength to enamel when compared to SB and OSP ( p<0.05). CONCLUSIONS: GA effectively etched enamel and dentin surfaces, resulting in bond strength values similar to those associated with traditional PA. GA is a suitable enamel and dentin surface etchant for adhesive restorative procedures. PMID- 29284106 TI - Ultrathin Monolithic Zirconia Veneers: Reality or Future? Report of a Clinical Case and One-year Follow-up. AB - Yttria-stabilized polycrystalline zirconia ceramics have greatly advanced over the past few years. High-translucent zirconia is a newly introduced ceramic that affords high strength and esthetics and that has significantly increased the clinical indications of monolithic zirconia restorations. Thus, the purpose of this case report was to evaluate the performance of ultrathin monolithic zirconia veneers adhesively luted to enamel surfaces after minimally invasive preparations; in addition, we aimed at presenting a clinical protocol for zirconia surface treatment in order to promote bonding effectiveness to resin cement. This type of restoration presented very acceptable esthetic results and decreased the risk of fracturing the veneer during try-in and clinical use. The results were still satisfactory after one-year follow-up. However, randomized, prospective, controlled clinical trials are required to determine the long-term clinical durability of this treatment. PMID- 29284107 TI - Assessing the Appearance and Fluorescence of Resin-Infiltrated White Spot Lesions With Caries Detection Devices. AB - OBJECTIVE: This in vitro study examined the effectiveness of caries detector devices in assessing the ability of resin infiltration (RI) (Icon, DMG-Hamburg, Hamburg, Germany) to improve the optical properties of enamel white spot lesions (WSLs). METHODS AND MATERIALS: Ten caries-free third molars were used. Photographs, a subjective visual assessment of the photographs, fluorescent camera (FC) images using the Spectra (Air Techniques, Melville, NY, USA), and laser fluorescent (LF) readings using the DIAGNOdent (KaVo, Biberach, Germany) were obtained from each tooth's buccal surface. Specimens were coated with nail polish leaving a rectangular window on the buccal surface and placed in pH 4.5 lactic acid gel for two weeks to create a WSL. The WSLs were analyzed by the same methods. RI was applied to half of each WSL; final photographs were then taken, and caries detector assessments were conducted. FC images were converted to grayscale, and the fluorescent image's brightness intensity was measured using ImageJ. Data were analyzed with analysis of variance and Tukey-Kramer honestly significant difference test. Significance was set at alpha=0.05. RESULTS: Subjective assessment of the photographs showed that RI improved the appearance of the WSLs so that they resembled intact enamel. Mean FC-brightness intensities for intact, demineralized, and demineralized RI-treated areas were 159.6 +/- 9.2, 123.4 +/- 7.2, and 160.9 +/- 11.5, respectively. There were no significant differences in fluorescent intensity between the intact and RI areas ( p=0.58). The demineralized areas had significantly lower fluorescent intensity than both the RI-treated and intact areas ( p<0.001). LF values did not differ significantly between intact, demineralized, or RI-treated areas. CONCLUSIONS: This study demonstrates the ability of RI to restore artificial WSLs to the esthetics and fluorescence of intact enamel. The FC can be used to assess the optical properties of WSLs and the impact of RI on these properties. PMID- 29284109 TI - Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice. AB - Rapid eye movement sleep deprivation distorts the body's homeostasis and results in oxidative breakdown which may be responsible for a variety of neurological disorders. Some naturally occurring compounds of plant origin with antioxidant and neuroprotective properties are known to attenuate the detrimental effects of REM sleep deprivation. Morin hydrate, a flavonoid from Mulberry has demonstrated antioxidant and neuroprotective activities but its effect in sleep disturbed mice is unknown. The study was designed to explore the neuroprotective effect of Morin hydrate on 48 h. REM sleep deprivation-induced behavioural impairments and neuronal damage in mice. Mice were allotted into six treatment groups (n = 6): groups 1 and 2 received vehicle (10 ml/kg normal saline), groups 3-5 received Morin hydrate (5, 10, 20 mg/kg i.p) while group 6 received ginseng (25 mg/kg) which served as the reference drug. Treatment was performed daily for 5 days and animals were sleep-deprived on the last 48 h. Various behavioural tests (Elevated plus maze, Y-maze, locomotor activity) followed by oxidative parameters (malondialdehyde, nitric oxide, reduced glutathione) and histolopathological changes in the Cornu ammonis 1 (CA1) region of the hippocampus were assessed. Data were analysed using ANOVA at alpha0.05. Morin hydrate (5, 10, 20 mg/kg) significantly enhanced memory performance, improves anxiolytic-like behaviour, reverses hyperlocomotion, restored depleted reduced glutathione, attenuated raised malondialdehyde and nitric oxide levels as compared to control animals and protects against loss of hippocampal neurons. Results of this present study suggest that Morin hydrate possess neuroprotective effects against sleep deprivation-induced behavioural impairments, oxidative stress and neuronal damage. PMID- 29284108 TI - Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model - are we there yet? AB - A number of factors (biogenic amine deficiency, genetic, environmental, immunologic, endocrine factors and neurogenesis) have been identified as mechanisms which provide unitary explanations for the pathophysiology of depression. Rather than a unitary construct, the combination and linkage of these factors have been implicated in the pathogenesis of depression. That is, environmental stressors and heritable genetic factors acting through immunologic and endocrine responses initiate structural and functional changes in many brain regions, resulting in dysfunctional neurogenesis and neurotransmission which then manifest as a constellation of symptoms which present as depression. PMID- 29284111 TI - Digoxin Benefit Varies by Risk of Heart Failure Hospitalization: Applying the Tufts MC HF Risk Model. AB - BACKGROUND: Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization. METHODS AND RESULTS: We conducted a post hoc analysis of the Digitalis Investigator Group (DIG) studies, randomized controlled trials of digoxin vs placebo in participants with heart failure and left ventricular ejection fraction <=45% (main DIG study, n = 6800) or >45% (ancillary DIG study, n = 988). Using a previously derived multistate model to risk-stratify DIG study participants, we determined the differential treatment effect on hospitalization and mortality outcomes. There was a 13% absolute reduction in the risk of any heart failure hospitalizations (39% vs 52%; odds ratio 0.58; 95% confidence interval 0.47-0.71) in the digoxin vs placebo arms in the highest-risk quartile, compared with a 3% absolute risk reduction for any heart failure hospitalization (17% vs 20%; odds ratio 0.84; 95% confidence interval, 0.66-1.08) in the lowest risk quartile. There were 12 fewer total all-cause hospitalizations per 100 person-years in the highest-risk quartile compared with an increase of 8 hospitalizations per 100 person-years in the lowest-risk quartile. There was neutral effect of digoxin on mortality in all risk quartiles and no interaction between baseline risk and the effect of digoxin on mortality (P = .94). CONCLUSIONS: Participants in the DIG study at higher risk of hospitalization as identified by a multistate model were considerably more likely to benefit from digoxin therapy to reduce heart failure hospitalization. PMID- 29284110 TI - Efficacy of Lenvatinib, a multitargeted tyrosine kinase inhibitor, on laser induced CNV mouse model of neovascular AMD. AB - Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Although intravitreal injection of anti-VEGF antibodies and VEGF Trap have significant clinical benefits, the complications of intravitreal injection, drug resistance and patient compliance still need to be concerned. In this study, the effects of an orally administered multi-targeted tyrosine kinase inhibitor (Lenvatinib, E7080) were evaluated in vitro and in vivo on neovascular AMD mouse model. The results showed that E7080 effectively inhibited the proliferation, migration and tubule formation of human choroidal microvascular endothelial cells (HCMECs), and suppressed the angiogenesis of zebrafish subintestinal vessels without causing malformation. The anti-angiogenic effect of E7080 on the laser-induced choroidal neovascularization (CNV) mouse model by oral administration of 10 mg/kg/day was observed. The fluorescein angiography showed CNV leakage area in treatment group vs control group was 3.407 +/- 0.2939 vs 5.202 +/- 0.9001 (P = .0133) at day 7th post laser-induced CNV, 1.138 +/- 0.4334 vs 3.122 +/- 0.3466 (P = .0064) at day 14th, 1.401 +/- 0.6577 vs 2.781 +/- 0.9815 (P = .00262) at day 21th respectively. Moreover, pharmacokinetics analysis in rat retina showed that E7080 rapidly penetrated the blood-retina barrier to retina through oral administration. The T1/2 in retina was 3.81 +/- 0.77 h, the Tmax was 4.60 +/- 0.73 h, the AUC0-infinity was 110448.51 +/- 18532.51 h*ng/g after a single dose administration analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In conclusion, our study suggested that orally administered E7080 can be a novel therapeutic strategy for neovascular AMD. PMID- 29284112 TI - Wounds That Would Not Heal: Pyoderma Gangrenosum. PMID- 29284113 TI - Thoracoabdominal Aneurysm in a Professional Body Builder. PMID- 29284114 TI - A Depressing Diagnostic Error. PMID- 29284115 TI - Straight Talk About Chronic Lyme Disease. PMID- 29284116 TI - The potential therapeutic effects of ergothioneine in pre-eclampsia. AB - Ergothioneine (ERG), is a water-soluble amino acid that is derived entirely from dietary sources. It has received much attention as a therapeutic agent due to its anti-oxidant properties, and there are claims of preferential accumulation within high oxidative stress organs. Pre-eclampsia, a condition accompanied by increased oxidative stress, is one of the leading causes of maternal morbidity and mortality. Despite intense research efforts, its aetiologies remain somewhat unclear and there are still no effective treatment options. Clinical trials of the anti-oxidants vitamin C and vitamin E have proven largely ineffective with little improvement in clinical outcome or even a negative response. This could be explained in part by their inability to permeate the plasma and mitochondrial membranes and scavenge mitochondria-derived superoxide species, and for the former by the fact that it is actually a pro-oxidant in the presence of unliganded iron. ERG accumulates within tissues through the action of a specific organic cation transporter, SLC22A4 (previously referred to as OCTN1), which is possibly also expressed in mammalian mitochondria. Mitochondrial dysfunction has been implicated in a variety of vascular diseases including pre-eclampsia. This review discusses the use of ERG as a possibly mitochondrial-targeted anti oxidant, focusing on its physical properties, potential mechanisms of action, safety profile and administration in relation to pregnancies complicated by pre eclampsia. PMID- 29284117 TI - Knockdown of AMPKalpha decreases ATM expression and increases radiosensitivity under hypoxia and nutrient starvation in an SV40-transformed human fibroblast cell line, LM217. AB - BACKGROUND: Presence of unperfused regions containing cells under hypoxia and nutrient starvation contributes to radioresistance in solid human tumors. It is well known that hypoxia causes cellular radioresistance, but little is known about the effects of nutrient starvation on radiosensitivity. We have reported that nutrient starvation induced decrease of mTORC1 activity and decrease of radiosensitivity in an SV40-transformed human fibroblast cell line, LM217, and that nutrient starvation induced increase of mTORC1 activity and increase of radiosensitivity in human liver cancer cell lines, HepG2 and HuH6 (Murata et al., BBRC 2015). Knockdown of mTOR using small interfering RNA (siRNA) for mTOR suppressed radiosensitivity under nutrient starvation alone in HepG2 cells, which suggests that mTORC1 pathway regulates radiosensitivity under nutrient starvation alone. In the present study, effects of hypoxia and nutrient starvation on radiosensitivity were investigated using the same cell lines. METHODS: LM217 and HepG2 cells were used to examine the effects of hypoxia and nutrient starvation on cellular radiosensitivity, mTORC1 pathway including AMPK, ATM, and HIF-1alpha, which are known as regulators of mTORC1 activity, and glycogen storage, which is induced by HIF-1 and HIF-2 under hypoxia and promotes cell survival. RESULTS: Under hypoxia and nutrient starvation, AMPK activity and ATM expression were increased in LM217 cells and decreased in HepG2 cells compared with AMPK activity under nutrient starvation alone or ATM expression under hypoxia alone. Under hypoxia and nutrient starvation, radiosensitivity was decreased in LM217 cells and increased in HepG2 cells compared with radiosensitivity under hypoxia alone. Under hypoxia and nutrient starvation, knockdown of AMPK decreased ATM activity and increased radiation sensitivity in LM217 cells. In both cell lines, mTORC1 activity was decreased under hypoxia and nutrient starvation. Under hypoxia alone, knockdown of mTOR slightly increased ATM expression but did not affect radiosensitivity in LM217. Under hypoxia and nutrient starvation, HIF-1alpha expression was suppressed and glycogen storage was reduced. CONCLUSION: Our data suggest that AMPK regulates ATM expression and partially regulates radiosensitivity under hypoxia and nutrient starvation. The molecular mechanism underlying the induction of ATM expression by AMPK remains to be elucidated. PMID- 29284119 TI - A duetting perspective on avian song learning. AB - Avian song learning has a rich history of study and has become the preeminent system for understanding the ontogeny of vocal communication in animals. Song learning in birds has many parallels with human language learning, ranging from the neural mechanisms involved to the importance of social factors in shaping signal acquisition. While much has been learned about the process of song learning, virtually all of the research done to date has focused on temperate species, where often only one sex (the male) sings. Duetting species, in which both males and females learn to sing and learn to combine their songs into temporally coordinated joint displays, could provide many insights into the processes by which vocal learning takes place. Here we highlight three key features of song learning-neuroendocrine control mechanisms, timing and life history stages of song acquisition, and the role of social factors in song selection and use-that have been elucidated from species where only males sing, and compare these with duetting species. We summarize what is known about song learning in duetting species and then provide several suggestions for fruitful directions for future research. We suggest that focusing research efforts on duetting species could significantly advance our understanding of vocal learning in birds and further cement the importance of avian species as models for understanding human conversations and the processes of vocal learning more broadly. PMID- 29284118 TI - DANFIN functions as an inhibitor of transcription factor NF-kappaB and potentiates the antitumor effect of bortezomib in multiple myeloma. AB - Nuclear factor-kappaB (NF-kappaB) proteins are transcription factors that play key roles in regulating most immune responses and cell death. Constitutively active NF-kappaB has been shown to exhibit chemoresistance by inducing anti apoptosis in tumor cells. Multiple myeloma is known as a constitutive NF-kappaB activating disease, and the proteasome inhibitor bortezomib is used to treat multiple myeloma and mantle cell lymphoma. We demonstrate here that DANFIN (N,N' bis-(2,4-dimethyl-phenyl)-ethane-1,2-diamine) functions as an inhibitor of the p65 family proteins and induces chemosensitization to bortezomib in multiple myeloma. DANFIN was found to be an inhibitor of interactions between p65 and IkappaBalpha without the inhibition of the DNA binding activity of the p65 protein. In addition, DANFIN affected the IkappaBalpha binding region in Rel Homology Domain (RHD) and suppressed the nuclear translocalization of the p65 protein in cells. Furthermore, in multiple myeloma cells, DANFIN suppressed the expression level of NF-kappaB target genes and induced apoptosis. The combination therapy of DANFIN with bortezomib dramatically enhanced the apoptosis of multiple myeloma cells and indicated a remarkable anti-tumor effect in a multiple-myeloma xenograft mouse model. PMID- 29284120 TI - Colorimetric immunoassays for the screening and specificity evaluation of molecules disturbing VEGFs/VEGFRs interactions. AB - Angiogenesis and its involved proteins, particularly Vascular Endothelial Growth Factor family (VEGFs) and VEGF receptors (VEGFRs), have been considered as a target of therapeutic interest for numerous inflammatory and vascular diseases. Acting on this biological process through interaction with VEGFs or VEGFRs has received considerable attention. Indeed, VEGFs and VEGFRs are currently targeted by drugs such as monoclonal antibodies. The feasibility of a therapeutic strategy based on blocking the VEGF/VEGFR interaction by using ligands "other-than biologics" is also explored. To help to the discovery of new molecules, screening assays have been developed, particularly to evaluate the VEGFA/VEGFR1 interaction. Despite the therapeutic importance of VEGFB and PlGF (Placental Growth Factor), no assays have been developed to evaluate molecules against their interactions with VEGFR1. Here, we present new versatile colorimetric immunoassays to screen and evaluate the specific interaction of discovered molecules with different growth factors (VEGFA, VEGFB, PlGF) and receptors (VEGFR1, VEGFR2). These tests, based on competitive immunoassay format, will provide essential information on specificity and selectivity of molecules for their targets and will help to work on the pharmaco-modulation of molecules for targeting one specific interaction. PMID- 29284121 TI - Performance qualification for reproducible Surface Plasmon Resonance analysis. AB - Surface Plasmon Resonance Biosensors (SPR) are one of the most powerful tools to characterize protein binding, e.g. for drug discovery, like target identification, ligand fishing, assay development, lead selection and manufacturing quality control. However, there is increasing concern about its reproducibility in the light of the reproducibility crisis. Therefore an appropriate analytical instrument qualification (AIQ) is required for quality assurance of SPR instruments. AIQ is a prerequisite for analytical method validation and it is consisting of four parts, Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). PQ regularly executed is supposed to continuously control the performance of the instrument under actual running conditions. In this work a performance qualification method was developed for the SPR instrument Biacore X100. This method is suitable for the routinely control of the instrument performance for antibody-antigen binding measurements. Control charts were designed to get a clearly representable and easy implementable tool to check the critical parameters. These control charts and a straightforward protocol now allow the design and application of an individual performance qualification procedure that can be used in the laboratory routine. They serve as reference for individual standard operation procedures (SOPs). PMID- 29284122 TI - Application of elastin-based nanoparticles displaying antibody binding domains for a homogeneous immunoassay. AB - Nanoparticles are small size-controlled particles from 1 to 100 nm diameters and characterized by their structure, base material and functional units displayed on their surfaces. In this study, protein-based nanoparticles composed of a hydrophobic elastin-like peptide unit, a hydrophilic aspartic acid-rich peptide unit and displaying antibody binding domains on their surfaces, were designed and genetically synthesized. The constituent fusion proteins, termed ELP-D-C, were found to exist in monomeric form (ELP-D-C/monomer) at low temperature. Above the phase transition temperature, however, ELP-D-C was found to rapidly self-assemble to form spherical micelles (ELP-D-C/micelle) with a hydrophobic core and diameters of ~40 nm. Furthermore, ELP-D-C/micelle were shown to display antibody binding domains on their surfaces, which allowed for immobilization of antibodies and subsequent formation of large, visually detectable complexes in the presence of target molecule (antigen), whose sizes increased in proportion to the target molecule concentration. The observed target molecule concentration-dependent complex formation suggests that ELP-D-C/micelle may be useful as base particles in applications such as homogeneous turbidity immunoassays. PMID- 29284124 TI - Unhidden Figures. PMID- 29284123 TI - Conversion of Robot-assisted Partial Nephrectomy to Radical Nephrectomy: A Prospective Multi-institutional Study. AB - OBJECTIVE: To assess the incidence and factors affecting conversion from robot assisted partial nephrectomy (RAPN) to radical nephrectomy. METHODS: Between November 2014 and February 2017, 501 patients underwent attempted RAPN by 22 surgeons at 14 centers in 9 countries within the Vattikuti Collaborative Quality Initiative database. Patients were permanently logged for RAPN prior to surgery and were analyzed on an intention-to-treat basis. Multivariable logistic regression with backward stepwise selection of variables was done to assess the factors associated with conversion to radical nephrectomy. RESULTS: Overall conversion rate was 25 of 501 (5%). Patients converted to radical nephrectomy were older (median age [interquartile range] 66.0 [61.0-74.0] vs 59.0 [50.0 68.0], P = .012), had higher body mass index (BMI) (median 32.8 [24.9-40.9] vs 27.8 [24.6-31.5] kg/m2, P = .031), higher age-adjusted Charlson comorbidity score (median 6.0 [4.0-7.0] vs 4.0 [3.0-5.0], P <.001), higher American Society of Anesthesiologists score (score >=3; 13/25 (52.0%) vs 130/476 (27.3%), P = .021), Preoperative estimated glomerular filtration rate (P = .141), clinical tumor stage (P = .145), tumor location (P = .140), multifocality (P = .483), and RENAL (radius, exophytic/endophytic properties, nearness of tumor to the collecting system or sinus in millimeters, and anterior/posterior location relative to polar lines) nephrometry score (P = .125) were not significantly different between the groups. On multivariable analysis, independent predictors for conversion were BMI (odds ratio [95% confidence interval]; 1.070 [1.018-1.124]; P = .007) and Charlson score (odds ratio [95% confidence interval]; 1.459 [1.179-1.806]; P = .001). CONCLUSION: RAPN was associated with a low rate of conversion. Independent predictors of conversion were BMI and Charlson score. Tumor factors such as clinical stage, location, multifocality, or RENAL score were not associated with increased risk of conversion. PMID- 29284125 TI - Principles of Systems Biology, No. 24. AB - This month: compressed sensing (Cleary/Regev), metabolism (Rabinowitz, Gilmore, Chandrasekaran), microbiology (Coles, Cooper/Hasty), phosphosite stoichiometry by proteomics (Kirschner), interaction networks (Pappu, Tan, Babu/Emili), immunology (Luksza/Greenbaum), mechanosensitive transcription (Elosegui-Artola/Roca Cusachs). PMID- 29284126 TI - Metabolic Models of Protein Allocation Call for the Kinetome. AB - The flux of metabolites in the living cell depend on enzyme activities. Recently, many metabolic phenotypes have been explained by computer models that incorporate enzyme activity data. To move further, the scientific community needs to measure the kinetics of all enzymes in a systematic way. PMID- 29284127 TI - Decoding Signal Processing at the Single-Cell Level. AB - The feedforward circuitry regulating ERK-dependent early response genes acts as a signal integrator rather than a signal persistence detector. PMID- 29284128 TI - Understanding Disease Variants through the Lens of Protein Interactions. AB - High-density interaction mapping of mitochondrial proteins provides clues to molecular mechanisms implicated in the progression of neurological disorders. PMID- 29284129 TI - Tackling Antibiotic Resistance with Systems-Level Perspective. AB - Quantitative dissection of regulatory motifs could lead to new ways to fight antibiotic resistance. PMID- 29284130 TI - Guidelines for Developing Successful Short Advanced Courses in Systems Medicine and Systems Biology. PMID- 29284131 TI - Identification of Human Lineage-Specific Transcriptional Coregulators Enabled by a Glossary of Binding Modules and Tunable Genomic Backgrounds. PMID- 29284133 TI - Protective effects of thymol on LPS-induced acute lung injury in mice. AB - Thymol, a naturally occurring phenol isolated from thyme, has been known to exhibit anti-inflammatory and anti-oxidative effects. The aim of this study was to determine the effect of thymol on acute lung injury (ALI) within an lipopolysaccharide (LPS)-induced mouse model. ELISA and western blotting were performed to detect the pro-inflammatory cytokines and signaling pathways. The myeloperoxidase (MPO) activity and MDA content in lung tissues, lung wet/dry (W/D) ratio and histopathological examination were detected. The results showed that thymol inhibit LPS-induced TNF-alpha, IL-6 and IL-1beta production in BALF. Furthermore, thymol significantly reduced the MPO activity, MDA content, lung wet/dry weight ratio and histopathological changes induced by LPS. In addition, thymol inhibited LPS-induced NF-kappaB signaling pathway and up-regulated the expression of Nrf2 and HO-1. In conclusion, we found that thymol had anti inflammatory and anti-oxidative effects against LPS-induced ALI and the mechanism was through suppressed NF-kappaB signaling pathway and activating Nrf2 signaling pathway. PMID- 29284134 TI - Antigenic and pathogenicity activities of Ralstonia solanacearum race 3 biovar 2 molecularly identified and detected by indirect ELISA using polyclonal antibodies generated in rabbits. AB - Eight molecular-characterized isolates of Ralstonia solanacearum from potato belonging to race 3 biovar 2, their virulence were evaluated on potato cv. Lady Rosette, tomato cv. Strain B, eggplant cv. Balady and pepper cv. Balady and showed high virulence on potato and tomato, and lower virulence on eggplant and pepper. A laboratory study conducted to produce polyclonal antibodies against the potato brown rot bacterium; R. solanacearum cells were generated in female New Zealand white rabbits. A modification were made on the technique of indirect enzyme-linked immunosorbent assay (ELISA) to improve the sensitivity of detection, including antigenic and sensitivity to R. solanacearum race 3 biovar 2 isolates. Determination of the optimum period to collect the antiserum (including, polyclonal antibodies) showed that the best collection dates were at 14, 3 and 7 days, in that order. The efficiency of the antiserum was compared among 42 isolates that cause potato brown rot disease; our polyclonal antiserum (14 days) reacted positively with all tested isolates at a dilution of 1:6.4 * 103. Data indicated the different reactions of eight R. solanacearum isolates at various dilutions (1:1.6 * 103 to 1:5.12 * 106) at 14 days against polyclonal antiserumat a concentration of approximately 1 * 108 CFU/mL and we found the lowest detection level by the indirect ELISA technique was 106 CFU/mL. Finally we recommended the reasonable sensitivity results of the ELISA technique to detect the bacterial pathogen given than the cost of this technique if much lower than that of other expensive molecular techniques. PMID- 29284132 TI - Prevalence of human influenza virus in Iran: Evidence from a systematic review and meta-analysis. AB - This systematic review and meta-analysis was conducted to consolidate the information on the prevalence of the human influenza virus, including H1N1 and H3N2 as well as B-type influenza across Iran from 2000 to December 2016. The literature search was based on keywords including "influenza and Iran", "human influenza", "prevalence", "relative frequency", "incidence", and "drug" in MEDLINE (PubMed), Web of Science, Scopus, ScienceDirect, the Iranian Research Institute for Information Science and Technology (IranDoc), the Regional Information Centre for Science & Technology (RICeST), and the Scientific Information Database (SID). The literature search revealed 25 prevalence and seven drug resistance studies. In order to investigate the publication bias among studies, funnel plots and Egger's test were used. Additionally, the statistical tests of I2, Chi2, and Tau2 were computed, and the results were visualized with forest plots. A high level of I2 and Chi2 were obtained among studies, which are representative of the high variation and remarkable heterogeneity between studies. This may be because of various methodologies applied in the studies such as study design, age groups, and different populations. The prevalence of influenza H1N1, H3N2, and B in Iran have not yet been well evaluated. The heterogeneity among studies reveals that more attention should be paid to considering various factors, including gender, population size, and underlying conditions. PMID- 29284136 TI - Skin sensitisation quantitative risk assessment (QRA) based on aggregate dermal exposure to methylisothiazolinone in personal care and household cleaning products. AB - Contact allergy to preservatives is an important public health problem. Ideally, new substances should be evaluated for the risk on skin sensitisation before market entry, for example by using a quantitative risk assessment (QRA) as developed for fragrances. As a proof-of-concept, this QRA was applied to the preservative methylisothiazolinone (MI), a common cause of contact allergy. MI is used in different consumer products, including personal care products (PCPs) and household cleaning products (HCPs). Aggregate exposure to MI in PCPs and HCPs was therefore assessed with the Probabilistic Aggregated Consumer Exposure Model (PACEM). Two exposure scenarios were evaluated: scenario 1 calculated aggregate exposure on actual MI product concentrations before the restricted use in PCPs and scenario 2 calculated aggregate exposure using the restrictions for MI in PCPs. The QRA for MI showed that in scenarios 1 and 2, the proportion of the population at risk for skin sensitisation is 0.7% and 0.5%, respectively. The restricted use of MI in PCPs does not seem very effective in lowering the risk on skin sensitization. To conclude, it is important to consider aggregate exposure from the most important consumer products into consideration in the risk assessment. PMID- 29284137 TI - Grapefruit and its biomedical, antigenotoxic and chemopreventive properties. AB - Grapefruit (Citrus paradisi Mcfad) is a perenifolium tree 5-6 m high with a fruit of about 15 cm in diameter, protected by the peel we can find about 11-14 segments (carpels), each of which is surrounded by a membrane and each containing the juice sacs, as well as the seeds. The fruit is made up of numerous compounds, and is known to have nutritive value because of the presence of various vitamins and minerals, among other chemicals. The fruit is also used in the field of gastronomy. Information has been accumulated regarding the participation of the fruit structures in a variety of biomedical, antigenotoxic and chemopreventive effects, surely related with the presence of the numerous chemicals that have been determined to constitute the fruit. Such studies have been carried out in different in vitro and in vivo experimental models, and in a few human assays. The information published so far has shown interesting results, therefore, the aims of the present review are to initially examine the main characteristics of the fruit, followed by systematization of the acquired knowledge concerning the biomedical, antigenotoxic and chemopreventive effects produced by the three main structures of the fruit: peel, seed, and pulp. PMID- 29284135 TI - Are by-products from beeswax recycling process a new promising source of bioactive compounds with biomedical properties? AB - During the process of beeswax recycling, many industrial derivatives are obtained. These matrices may have an interesting healthy and commercial potential but to date they have not been properly studied. The aim of the present work was to evaluate the proximal and phytochemical composition, the antioxidant capacity and cytotoxic effects of two by-products from beeswax recycling process named MUD 1 and MUD 2 on liver hepatocellular carcinoma. Our results showed that MUD 1 presented the highest (P < .05) fiber, protein, carbohydrate, polyphenol and flavonoid concentration, as well as the highest (P < .05) total antioxidant capacity than the MUD 2 samples. MUD1 exerted also anticancer activity on HepG2 cells, by reducing cellular viability, increasing intracellular ROS levels and affecting mitochondrial functionality in a dose-dependent manner. We showed for the first time that by-products from beeswax recycling process can represent a rich source of phytochemicals with high total antioxidant capacity and anticancer activity; however, further researches are necessary to evaluate their potentiality for human health by in vivo studies. PMID- 29284138 TI - Psychiatry & the psychedelic drugs. Past, present & future. AB - The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called 'psychoneurotic' disorders sometimes benefited considerably from their tendency to 'loosen' otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub optimal, although a recent systematic review in unipolar mood disorder and a meta analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29284139 TI - Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway. AB - Sonic Hedgehog (Shh) signaling plays key regulatory roles in embryonic development and postnatal homeostasis and repair. Modulation of the Shh pathway is known to cause malformations and malignancies associated with dysregulated tissue growth. However, our understanding of the molecular mechanisms by which Shh regulates cellular proliferation is incomplete. Here, using mouse embryonic fibroblasts, we demonstrate that the Forkhead box gene Foxd1 is transcriptionally regulated by canonical Shh signaling and required for downstream proliferative activity. We show that Foxd1 deletion abrogates the proliferative response to SHH ligand while FOXD1 overexpression alone is sufficient to induce cellular proliferation. The proliferative response to both SHH ligand and FOXD1 overexpression was blocked by pharmacologic inhibition of cyclin-dependent kinase signaling. Time-course experiments revealed that Shh pathway activation of Foxd1 is followed by downregulation of Cdkn1c, which encodes a cyclin-dependent kinase inhibitor. Consistent with a direct transcriptional regulation mechanism, we found that FOXD1 reduces reporter activity of a Fox enhancer sequence in the second intron of Cdkn1c. Supporting the applicability of these findings to specific biological contexts, we show that Shh regulation of Foxd1 and Cdkn1c is recapitulated in cranial neural crest cells and provide evidence that this mechanism is operational during upper lip morphogenesis. These results reveal a novel Shh-Foxd1-Cdkn1c regulatory circuit that drives the mitogenic action of Shh signaling and may have broad implications in development and disease. PMID- 29284140 TI - Effective connectivity during working memory and resting states: A DCM study. AB - Although the relationship between resting-state functional connectivity and task related activity has been addressed, the relationship between task and resting state directed or effective connectivity - and its behavioral concomitants - remains elusive. We evaluated effective connectivity under an N-back working memory task in 24 participants using stochastic dynamic causal modelling (DCM) of 7 T fMRI data. We repeated the analysis using resting-state data, from the same subjects, to model connectivity among the same brain regions engaged by the N back task. This allowed us to: (i) examine the relationship between intrinsic (task-independent) effective connectivity during resting (Arest) and task states (Atask), (ii) cluster phenotypes of task-related changes in effective connectivity (Btask) across participants, (iii) identify edges (Btask) showing high inter-individual effective connectivity differences and (iv) associate reaction times with the similarity between Btask and Arest in these edges. We found a strong correlation between Arest and Atask over subjects but a marked difference between Btask and Arest. We further observed a strong clustering of individuals in terms of Btask, which was not apparent in Arest. The task-related effective connectivity Btask varied highly in the edges from the parietal to the frontal lobes across individuals, so the three groups were clustered mainly by the effective connectivity within these networks. The similarity between Btask and Arest at the edges from the parietal to the frontal lobes was positively correlated with 2-back reaction times. This result implies that a greater change in context-sensitive coupling - from resting-state connectivity - is associated with faster reaction times. In summary, task-dependent connectivity endows resting-state connectivity with a context sensitivity, which predicts the speed of information processing during the N-back task. PMID- 29284141 TI - Optimization of Haemophilus influenzae adhesin transmembrane domain expression in Escherichia coli. AB - To obtain a high yield of the transmembrane domain of Haemophilus influenzae adhesin (HiaTD) in Escherichia coli, we attempted to express the HiaTD with and without a signal sequence using a T7 expression system. The expression level of HiaTD after induction was followed by quantification of the purified HiaTD, flow cytometric analysis of the outer membrane integrated HiaTD, and immunoblotting assay of fractionated cell lysate. In the expression system with a signal sequence, although the amount of cell-surface-expressed HiaTD increased over time, the number of HiaTD-expressing cells decreased, probably because of plasmid instability. As a result, the amount of purified HiaTD reached a plateau at 2 h postinduction. Although expression without the signal sequence provides a large amount of proteins as inclusion bodies in some membrane proteins, HiaTD expressed without a signal sequence was not observed as inclusion bodies and seemed to be assembled into the outer membrane during or after cell lysis. PMID- 29284142 TI - The Uterus From Inside to Out, Top to Bottom. PMID- 29284143 TI - Long-Term Safety of Short-Term Administration of Filgrastim (rhG-CSF) and Leukophresis Procedure in Healthy Children: Application of Peripheral Blood Stem Cell Collection in Pediatric Donors. AB - Administration of filgrastim (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) (Neupogen) in healthy donors to mobilize hematopoietic stem cells (HSCs) is a widespread practice in adults. Application of peripheral blood stem cell (PBSC) collection in normal pediatric donors is scarce due to ethical issues. Hence, there are insufficient data on the long-term impact of PBSC procedure in healthy children. This retrospective study aimed to evaluate the early and late adverse effects of PBSC donation in pediatric donors. Bone marrow and PBSC procedures and known adverse events of each technique were completely explained to parents and when applicable to children and written informed consent was obtained. rhG-CSF was administered for 4 days. HSCs were collected on the fifth day through continuous-flow apheresis and donors were followed for 30 days. Manual chart review was performed to collect short-term complications. Donors' health status was assessed via a questionnaire. A total of 145 healthy pediatric donors with a median age of 10 years at the time of donation (2 to 15 years) were followed for a median of 4.8 years (range, 1.2 to 14.2 years). The most frequent symptoms of rhG-CSF administration were fatigue (5%) and headache (3%). Thirty five (24%) donors experienced hypocalcaemia during apheresis procedure that quickly responded to treatment. Two pregnancies occurred after rhG-CSF administration that resulted in normal births. We did not encounter any serious adverse events, including neoplastic disorders and death in this study. rhG-CSF and leukophresis procedure were well-tolerated in this study and all children completed the donation process without interruption or reduction of rhG-CSF dosage. Our results suggest that rhG-CSF is a safe drug in healthy children for the purpose of HSC mobilization. PMID- 29284144 TI - Trophic predator-prey relationships promote transport of microplastics compared with the single Hypoaspis aculeifer and Folsomia candida. AB - Although the roles of earthworms and soil collembolans in the transport of microplastics have been studied previously, the effects of the soil biota at different trophic levels and interspecific relationships remain poorly understood. Here, we examine three soil microarthropod species to explore their effects on the transport of microplastics. The selected Folsomia candida and Hypoaspis aculeifer are extensively used model organisms, and Damaeus exspinosus is a common and abundant indigenous species in China. A model food chain (prey collembolan and predator-mite) was structured to test the role of the predator prey relationship in the transport of microplastics. Commercial Polyvinyl chloride (PVC) particles (Diameter: 80-250 MUm) were selected as the test microplastics, because large amounts of PVC have persisted and accumulated in the environment. Synchronized soil microarthropods were held in plates for seven days to determine the movement of microplastics. The 5000 microplastic particles were carefully placed in the center of each plate prior to the introduction of the animals. Our results clearly show that all three microarthropod species moved and dispersed the microplastics in the plates. The 0.54%, 1.8% and 4.6% of the added microplastic particles were moved by collembolan, predatory mite and oribatid mite, respectively. Soil microarthropods (<0.2 cm) transported microplastic particles up to 9 cm. The avoidance behavior was observed in the collembolans in respect of the microplastics. The predatory -prey relationship did promote the transport of microplastics in the plates, increasing transport by 40% compared with the effects of adding single species (P < .05). Soil microarthropods commonly occur in surface soils (0-5 cm) and, due to their small body size, they can enter soil pores. Our results therefore suggest that the movement of microplastics by soil microarthropods may influence the exposure of other soil biota to microplastics and change the physical properties of soils. PMID- 29284145 TI - IFNb of black carp functions importantly in host innate immune response as an antiviral cytokine. AB - Type I interferons (IFN-Is) play an important role in the antiviral immune response in teleost fishes. In this study, one type I interferon (bcIFNb) from black carp (Mylopharyngodon piceus) has been cloned and characterized. The full length cDNA of bcIFNb gene consists of 806 nucleotides and the predicted bcIFNb protein contains 188 amino acids. Basing on the cysteine number and evolutionary position, bcIFNb was classified into group II type I IFN. q-PCR analysis demonstrated that bcIFNb mRNA level varied in vivo and ex vivo in response to different stimuli. bcIFNb was detected in both the whole cell lysate and the supernatant media of HEK293T cells or EPC cells transfected with bcIFNb through immunoblot assay. IFN stimulated genes (ISGs) were greatly upregulated when the host cells were treated with the bcIFNb-containing conditioned media. EPC cells showed greatly enhanced antiviral ability when the cells were transfected with bcIFNb or treated with the bcIFNb-containing conditioned media before GCRV or SVCV infection. Glycosidase digestion analysis determined that bcIFNb was modified with N-linked glycosylation, which occurred on the Asn (N) of 92 site of this cytokine. The un-glycosylated mutant bcIFNb-N92Q presented the similar antiviral ability as that of wild type bcIFNb, which demonstrated that N-linked glycosylation did not contribute directly to the antiviral property of this fish cytokine. PMID- 29284146 TI - Antioxidative and immunostimulatory effect of dietary cinnamon nanoparticles on the performance of Nile tilapia, Oreochromis niloticus (L.) and its susceptibility to hypoxia stress and Aeromonas hydrophila infection. AB - An experiment was conducted to evaluate the effect of dietary cinnamon nanoparticles (CNP) on the growth performance, antioxidant and digestive enzymes activities, and innate immunity of Nile tilapia, Oreochromis niloticus (L.). Fish (9.7 +/- 0.3 g) were fed on diets enriched with 0.0, 0.25, 0.5, 1.0, 3.0, 5.0, and 10.0 g CNP/kg diet for 8 weeks. After the feeding trial, fish were challenged against hypoxia stress or pathogenic bacteria (Aeromonas hydrophila) infection. Fish performance was significantly improved with increasing CNP levels over the control diet. Furthermore, only crude protein contents in whole-fish body were significantly higher in CNP-fed fish than those fed the control diet. Antioxidant stimulated activity was observed with dietary CNP where malondialdehyde (MDA) level and activities of superoxide dismutase (SOD) and catalase (CAT) increased significantly, whereas glutathione peroxidase (GPx) activity decreased significantly in CNP-fed fish. Likewise, CNP supplementation induced the secretion of protease, lipase, and amylase, which were maximized at 3.0-10.0 g CNP/kg diet. All innate immunity variables i.e. nitrous oxide (NO), nitro blue tetrazolium (NBT), and lysozyme activity were significantly higher in CNP-fed fish than the control one. No fish mortality was observed during hypoxia stress among all treatments, but CNP administration protected the fish against A. hydrophila infection. No mortality was observed in fish fed 3.0-10.0 g CNP/kg diet after bacterial challenge; meanwhile the mortality of fish fed the control diet was 66.7%. This study evoked that dietary CNP enhanced the performance, antioxidant and digestive enzymes activity, and innate immunity of Nile tilapia and its optimum level is 3.0 g CNP/kg diet. PMID- 29284147 TI - Effects of dietary supplementation of four strains of lactic acid bacteria on growth, immune-related response and genes expression of the juvenile sea cucumber Apostichopus japonicus Selenka. AB - A feeding experiment was conducted to evaluate the effects of four strains of lactic acid bacteria (LAB) [i.e. Lactobacillus plantarum LL11 (LP), Weissella confuse LS13 (WC), Lactococcus lactis LH8 (LL) and Enterococcus faecalis LC3 (ES)] isolated from marine fish on growth, immune response and expression levels of immune-related gens in body wall of juvenile sea cucumber Apostichopus japonicus. As a result, sea cucumber had better growth performance fed supplementation of LP and ES than the control group (P < .05). Survival rate in each LAB supplementation group was significantly higher than that in control group after Vibrio splendidus challenge (P < .05). In regards to the enzyme activities, LP supplementation significantly imporved the enzyme activities of alkaline phosphatase (AKP) (P < .05), acid phosphatase (ACP) and superoxide dismutase (SOD), ES supplementation significantly imporved AKP activity (P < .05), and WC supplementation significantly imporved ACP activity (P < .05). However, lysozyme (LSZ) activity was not significantly changed in the four LAB supplementation treatments (P > .05). For the gene expression levels, different expression patterns were observed among four groups, heat shock proteins (HSP60, HSP70 and HSP90) and caspase-2 showed dramatic up-regulation at 30 d while NF kappa-B transcription factor p65 was down-regulated at 15 d and up-regulated at 30 d, and nitric oxide synthase was down-regulated at both timepoints in almost all the four groups. In conclusion, the four LAB strains screened from marine fish supplemented in diets indicated positive effects on immune response for A. japonicus, especially, the L. plantarum LL11 and E. faecalis LC3 indicated better growth performance. PMID- 29284148 TI - iTRAQ-based comparative proteome analysis for molecular mechanism of defense against acute ammonia toxicity in Pacific White shrimp Litopenaeus vannamei. AB - In the practical farming of Litopenaeus vannamei, the intensive culture system and environmental pollution usually results in a high concentration of ammonia, which brings large detrimental effects to shrimp, such as increasing the susceptibility to pathogens and even causing high mortality. We have revealed that the survival time under acute ammonia stress varied substantially among different families and obtained ammonia-tolerant (LV_T) and ammonia-sensitive (LV_S) families. In order to understand the molecular mechanism of defense against ammonia toxicity in shrimp, we performed iTRAQ LC-MS/MS proteomic analysis between LV_T and LV_S groups of L. vannamei under acute ammonia stress to identify the key proteins and pathways that play an effective role for against ammonia toxicity. By comparative proteome analysis, 202 significantly differentially proteins (DEPs) were identified in LV_T compared to LV_S, and most of the DEPs (60%) were up-regulated. Excepting for the proteins without function reporting, the meaningful finding is that 77.8% of the DEPs have been reported mainly involving in immune defense and stress tolerant in crustacean species, such as hemocyanin, Rab7, Rab GTPase, Rac1, alpha 2 macroglobulin, Bip, peroxiredoxin, Cu/Zn SOD, glutathione peroxidase, thioredoxin, calreticulin, and Elongation Factor 1-alpha, etc. These DEPs might potentially play important role in against ammonia toxicity, and it also reflected a relation between ammonia tolerance and pathogen resistance. In addition, a total of 10 significantly changed KEGG pathways were detected, and the network diagram of these KEGG pathways showed that more critical nodes were up-regulated, which involved in protein synthesis and transport, and against stress stimuli. This study provided important information for understanding the molecular mechanism of defense against ammonia toxicity in shrimp at whole protein level. PMID- 29284149 TI - Percutaneous sacroiliac screw versus anterior plating for sacroiliac joint disruption: A retrospective cohort study. AB - BACKGROUND: Sacroiliac joint disruption (SJD) is a common cause of pelvic ring instability. Clinically, percutaneous unilateral S1 sacroiliac screw and anterior plating are always applied to manage SJD. The objective of this study is to elaborate their respective therapeutic traits. MATERIALS AND METHODS: Patients with SJD fixed with unilateral S1 sacroiliac screw or anterior plating from June 2011 to June 2015 were recruited into this study and were divided into two groups: group A (unilateral sacroiliac screw) and group B (anterior plating). Surgical time, blood loss, frequency of intraoperative fluoroscopy and complications were reviewed. Postoperative radiograph and CT were conducted to assess the reduction quality. Fracture healing was evaluated by radiograph performed at each follow-up. Majeed score was recorded at the final follow-up to assess the functional outcome. RESULTS: Thirty-eight patients were included in group A and thirty-two patients in group B in this study. There was no significant difference in the demographic data of the two groups. A significant difference existed in the results for average operation time (P = .022) and blood loss (P = .000) between group A and group B. The mean frequency of intraoperative fluoroscopy was 15.82 in group A and 3.94 in group B (P = .000). All the fractures healed in this study. The rates of satisfactory reduction quality and functional outcome showed no significant difference between the two groups (P > .05). The complication rate was 15.79% (6/38) in group A and 9.38% (3/32) in group B (P = .660). CONCLUSION: Compared with anterior plating, percutaneous unilateral S1 sacroiliac screw usage is less invasive; however, more intraoperative X-ray exposure and permanent neurologic damage may accompany this procedure. PMID- 29284150 TI - Men, main victims of hidradenitis suppurativa (A prospective cohort study). AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease presenting as painful subcutaneous nodules, characterized by multiple abscess, inter-networking sinus tracts. We present the option of surgical treatment involving wide surgical excision and methods of reconstruction as well as the rate of recurrence. METHOD: This study reviewed 44 sites in 21 patients with moderate to extensive HS treated surgically in our hospital from 2000 to 2016, with a follow up of at least 24 months. RESULTS: A total number of 44 operative procedures were performed during the study period with 13.6% (6 sites) involving axilla, 38.6% (17 sites) involving the gluteal area, 29.5% (13 sites) involving the perineal and perianal area and 11.4% (5 sites) involving the inguinal region, 4.5% (2 sites) involving the scrotal area, and 1.3% (one case) retrorectal abscess. CONCLUSION: Conservative treatment methods have little or no effects especially on gluteal, perineal/perianal and axillary hidradenitis suppurativa. The morbidity associated with the established disease is significant, and the only successful treatment is wide surgical excision. PMID- 29284152 TI - Catalpol ameliorates hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway. AB - Type 2 diabetes is characterized by insulin resistance in target tissues and hyperglycemia. Catalpol is a natural product isolated from the root of Rehmannia glutinosa, which has been reported to produce the effect of anti-diabetes in recent reports. The goal of the current study is to investigate the therapeutic effects of catalpol on hepatic insulin resistance in type 2 diabetes and elucidate the underlying cellular mechanisms. Type 2 diabetes in vivo was induced by combined high-fat diet (HFD) and streptozotocin (STZ) injection in C57BL/6J mice. Insulin resistance in vitro was induced by glucosamine administration in HepG2 cells. Catalpol exhibited the effects decreasing hepatic gluconeogenesis and increasing hepatic glycogen synthesis both in vivo and in vitro. Additionally, catalpol improved hepatic NADPH oxidase type 4 (NOX4)-mediated oxidative stress and activated hepatic AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro. The effects of catalpol on preventing gluconeogenesis and increasing glycogen synthesis in glucosamine-induced HepG2 cells were prevented by pretreatment with LY294002, the inhibitor of PI3K. Furthermore, the effect of catalpol on depriving glucosamine-induced insulin resistance was prevented by knockdown of NOX4 or AMPK with short interfering RNA (siRNA) in HepG2 cells. Moreover, the suppressive effect of catalpol on glucosamine-induced NOX4 over-expression was weakened by knockdown of AMPK with siRNA. Taken together, these findings suggested that catalpol ameliorated hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway. PMID- 29284151 TI - Laparoscopic vs open hepatectomy for hepatocellular carcinoma in patients with cirrhosis: A meta-analysis of the long-term survival outcomes. AB - BACKGROUND: In patients with hepatocellular carcinoma (HCC) and cirrhosis, laparoscopic hepatectomy (LH) confers short-term benefits over open hepatectomy (OH) but the long-term outcomes of this procedure are unclear. This systematic review aims to compare the long-term survival outcomes of LH and OH for patients with HCC and underlying cirrhosis. METHODS: EMBASE, MEDLINE and Scopus databases were searched from date of inception to 7th October 2016. Controlled clinical studies comparing LH to OH for HCC in cirrhotic patients, which reported long term overall and disease-free survival were included. The studies were evaluated using the MOOSE guidelines and Newcastle-Ottawa Scale. Data were extracted and analysed using a fixed-effects model. RESULTS: Five non-randomised, retrospective observational studies representing 888 patients were included. LH was associated with significantly lower tumour recurrence [OR: 0.65, 95% CI: 0.48, 0.89]. LH conferred greater overall survival at 1- [HR: 0.41, 95% CI: 0.25, 0.68], 3- [HR: 0.63, 95% CI: 0.46, 0.87] and 5-years [HR: 0.60, 95% CI: 0.45, 0.80]. With LH, there was higher disease-free survival at 1-year [HR: 0.71, 95% CI: 0.53, 0.96], but not at 3- [HR: 0.89, 95% CI: 0.70, 1.14]; and 5-years [HR: 0.85, 95% CI: 0.70, 1.04]. CONCLUSIONS: Laparoscopic surgery is associated with comparable postoperative and survival outcomes in patients with HCC and underlying cirrhosis. With careful selection of patients, this approach is safe, feasible and advantageous. PMID- 29284153 TI - Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers. AB - RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands differs from that of all other receptor protein-tyrosine kinases owing to the requirement for additional GDNF family receptor-alpha (GFRalpha) co-receptors (GFRalpha1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma. In contrast, RET fusion proteins have been reported in papillary thyroid and non-small cell lung adenocarcinomas. More than a dozen fusion partners of RET have been described in papillary thyroid carcinomas, most frequently CCDC6-RET and NCOA4-RET. RET-fusion proteins, commonly KIF5B-RET, have also been found in non-small cell lung cancer (NSCLC). Several drugs targeting RET have been approved by the FDA for the treatment of cancer: (i) cabozantinib and vandetanib for medullary thyroid carcinomas and (ii) lenvatinib and sorafenib for differentiated thyroid cancers. In addition, alectinib and sunitinib are approved for the treatment of other neoplasms. Each of these drugs is a multikinase inhibitor that has activity against RET. Previous X-ray studies indicated that vandetanib binds within the ATP-binding pocket and forms a hydrogen bond with A807 within the RET hinge and it makes hydrophobic contact with L881 of the catalytic spine which occurs in the floor of the adenine-binding pocket. Our molecular modeling studies indicate that the other antagonists bind in a similar fashion. All of these antagonists bind to the active conformation of RET and are therefore classified as type I inhibitors. The drugs also make variable contacts with other residues of the regulatory and catalytic spines. None of these drugs was designed to bind preferentially to RET and it is hypothesized that RET-specific antagonists might produce even better clinical outcomes. Currently the number of new cases of neoplasms bearing RET mutations or RET-fusion proteins is estimated to be about 10,000 per year in the United States. This is about the same as the incidence of chronic myelogenous leukemia for which imatinib and second and third generation BCR-Abl non-receptor protein-tyrosine kinase antagonists have proven clinically efficacious and which are commercially successful. These findings warrant the continued development of specific antagonists targeting RET-driven neoplasms. PMID- 29284154 TI - Risks of using the natural defence of commensal bacteria as antibiotics call for research and regulation. PMID- 29284155 TI - Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus beta-lactams. AB - Enterobacteriaceae bloodstream infections (EB-BSIs) are a common manifestation of Gram-negative sepsis and are initially managed with empirical intravenous antibiotics. Upon stabilisation and source control, patients are often transitioned to an oral agent. Fluoroquinolones (FQs) plays a prominent role in stepdown therapy for severe infections owing to favourable pharmacokinetic parameters; however, serious adverse events (AEs) have been documented with their use. A total of 224 adults with EB-BSI initiated on empirical intravenous antibiotics with stepdown to oral beta-lactam (BLM) (n = 84) or FQ (n = 140) were studied to compare clinical success and identify risk factors for treatment failure. Subgroups of early versus late oral stepdown and short versus extended duration of therapy (DOT) were assessed. Stepdown therapy with oral BLM was non inferior to oral FQ (86.9% vs. 87.1%; mean difference 0.2%, 97.5% CI -10.3 to 10.7). Microbiological success (94.0% vs. 97.9%; P > 0.05) and 30-day re admission (14.3% vs. 14.3%; P > 0.05) were similar. Patients were more likely to complete their BLM course without an AE compared with FQs (91.7% vs. 82.1%; P = 0.049). Clinical success was comparable between early and late stepdown (86.7% vs. 87.5%; P > 0.05) and short versus extended DOT (88.2% vs. 86.7%; P > 0.05). Negative predictors of clinical success identified by logistic regression were complicated diabetes (OR = 0.35, 95% CI 0.15-0.83) and urinary abnormality (OR = 0.39, 95% CI 0.16-0.94). These findings suggest that oral BLMs were non-inferior to FQs as stepdown therapy for EB-BSI, with less AEs. PMID- 29284156 TI - Vancomycin dosing in chronic high-flux haemodialysis: a systematic review. AB - The aim of this study was to systematically evaluate whether non-weight-based dosing (non-WBD) or weight-based dosing (WBD) of vancomycin leads to a higher proportion of patients achieving the pharmacokinetic/pharmacodynamic target. Studies from January 1985 to February 2017 were identified through Cochrane, MEDLINE and Embase databases. Those conducted in adults with end-stage renal disease receiving high-flux haemodialysis (HD) and intravenous vancomycin were included. The primary outcome was the proportion of patients with a pre-HD vancomycin concentration of 15-20 mg/L and/or an area under the concentration time curve/minimum inhibitory concentration (AUC/MIC) ratio >=400. Of the 3948 studies screened, 5 met the inclusion criteria. The proportion of patients with pre-HD concentrations between 15-20 mg/L were 35% (non-WBD) and 13% (WBD) post loading dose. During maintenance dosing, the proportion of patients with pre-HD concentrations between 15-20 mg/L were 37% (non-WBD) and 50-67% (WBD). The proportion of pre-HD concentrations <15 mg/L was greater in the non-WBD group post-loading dose but was similar between the non-WBD and WBD group during maintenance dosing. One study reported that all patients had an AUC/MIC >= 400 for micro-organisms with an MIC <= 1 mg/L for weight-based maintenance dosing. The limited data suggest that WBD may be preferential as there was a smaller proportion of pre-HD concentrations falling below 15 mg/L. However, larger well designed studies of higher quality are required to provide guidance for vancomycin dosing in the high-flux HD setting. Future research should focus on reporting AUC/MIC ratios and exploring clinical outcomes in this patient population. PMID- 29284157 TI - Characterization of the cervical bacterial community in dairy cows with metritis and during different physiological phases. AB - For the development of disease prevention and intervention strategies, a better understanding of the dynamics and interactions within cervical bacterial communities in both healthy cows and cows with metritis is required. Understanding the complexity and ecology of microorganisms in the vagina of dairy cows with metritis and during different physiological phases is critical for developing strategies to balance microorganism content. To gain deeper insight into fluctuations within the cervical microbiota, swab samples were collected from 40 Holstein dairy cows, and16S rDNA amplicon sequencing was used to analyze cervical bacterial diversity. Meanwhile, vaginal bacterial composition was analyzed during different physiological phases, including the formative (CF), gestational (CG), and postpartum (CP) stages, and in cows with metritis (CM). The results revealed a complex profile with extensive differences in the cervical bacterial composition. A total of 678,043clean 16S rDNA V4-V6 reads were gained, and 1877 Operational Taxonomic Units (OTUs) were observed after calculation. At both the phylum and genus levels, the top 10 bacteria by percentage were the same when comparing the CF, CG, and CP groups of cows, with some variation in abundance. At the phylum level, the cervical microbial community in the CF, CG, and CP groups included mainly Firmicutes, which accounted for 39.3%, 48.3%, and 49.6% of the total microbial composition of each group, respectively. However, the cervical bacterial community in the CM group consisted of mostly Bacteroidetes, which accounted for 72.6% of the total microbial composition. The second major bacterial community in the CF and CG groups of cows was Proteobacteria, which accounted for 28.3%and 30.1% of the total microbial compositions of these groups, respectively, while the second major bacterial community in the CP group was Bacteroidetes (23.5%). However, in the CM group, the second major bacterial community was Fusobacteria, which accounted for18.0% of the total microbial composition. At the genus level, the cervical bacterial community in the CM group of cows was dominated by Porphyromonas(44.4%) and Fusobacterium(12.1%), while Porphyromonas accounted for only 1.3%, 1.1%, and 1.4% of the total microbial compositions of the CF, CG, and CP groups, respectively. Likewise, Fusobacterium accounted for 2.3%, 0.7%, and 4.7% of the total microbial compositions of the CF, CG, and CP groups, respectively. The results demonstrate that cervical bacterial diversity decreases in cows with metritis and that the predominant bacterial genera are Porphyromonas and Fusobacterium. Cervical bacterial diversity was rich in all observed physiological phases, and the predominant bacterial phylum was Firmicutes. Pregnancy had little effect on the cervical bacterial community; however, there were increases in the abundances of pathogenic species in postpartum cows. Cervical bacterial diversity decreased in cows with metritis, however, due to the highly dynamic and complex course of metritis, the relationship between cervical bacterial diversity and metritis requires further investigation. PMID- 29284158 TI - Optimized polymer coating for magnesium alloy-based bioresorbable scaffolds for long-lasting drug release and corrosion resistance. AB - Magnesium (Mg) alloy-based bioresorbable scaffolds (BRSs) are attracting interest as next-generation stents. However, because medical Mg alloy materials degrade relatively quickly in physiological media, surface corrosion protection via biodegradable polymer coatings is important for clinical applications. Herein, the influence of biodegradable polymer coatings on the BRS corrosion was investigated. First, elution of the drug sirolimus (SRL) from various biodegradable polymers was estimated, including poly(d,l-lactic acid) (PDLLA), poly(d,l-lactic acid-co-epsilon-caprolactone) (PLCL) and poly(epsilon caprolactone) (PCL). Among these, the PDLLA polymer exhibited the slowest release and the best character as a drug reservoir because of its slow degradation rate and semi-glass state in a biological environment. However, the corrosion rate of the PDLLA-coated Mg alloy (AZ31)-based platform was as rapid as the non-coated platform, while critical defects, cracking and desorption were observed in the PDLLA layer. Coatings comprising PCL and PLCL exhibited a prolonged platform corrosion resistance compared with that of PDLLA. To combine the advantages of each polymer, therefore, a pre-coating of PCL or PLCL was applied to the interface between the platform and the external SRL-loaded PDLLA layer. This layering exhibited an enhanced platform corrosion resistance, and will be an important foundational procedure for the development of a coronary scaffold comprising magnesium alloys. PMID- 29284159 TI - Characteristics and clinical outcomes of living renal donors in Hong Kong. AB - INTRODUCTION: In Asia, few reports are available on the outcomes for living renal donors. We report the short- and long-term clinical outcomes of individuals following living donor nephrectomy in Hong Kong. METHODS: We retrospectively reviewed the characteristics and clinical outcomes of all living renal donors who underwent surgery from January 1990 to December 2015 at a teaching hospital in Hong Kong. Information was obtained from hospital records and territory-wide electronic patient records. RESULTS: During the study period, 83 individuals underwent donor nephrectomy. The mean (+/- standard deviation) follow-up time was 12.0 +/- 8.3 years, and the mean age at nephrectomy was 37.3 +/- 10.0 years. A total of 44 (53.0%), four (4.8%), and 35 (42.2%) donors underwent living donor nephrectomy via an open, hand-port assisted laparoscopic, and laparoscopic approach, respectively. The overall incidence of complications was 36.6%, with most being grade 1 or 2. There were three (9.4%) grade 3a complications; all were related to open donor nephrectomy. The mean glomerular filtration rate was 96.0 +/- 17.5 mL/min/1.73 m2 at baseline and significantly lower at 66.8 +/- 13.5 mL/min/1.73 m2 at first annual follow-up (P<0.01). The latest mean glomerular filtration rate was 75.6% +/- 15.1% of baseline. No donor died or developed renal failure. Of the donors, 14 (18.2%) developed hypertension, two (2.6%) had diabetes mellitus, and three (4.0%) had experienced proteinuria. CONCLUSION: The overall perioperative outcomes are good, with very few serious complications. The introduction of a laparoscopic approach has decreased perioperative blood loss and also shortened hospital stay. Long-term kidney function is satisfactory and no patients developed end-stage renal disease. The incidences of new-onset medical diseases and pregnancy-related complications were also low. PMID- 29284160 TI - Developmental biology, the stem cell of biological disciplines. AB - Developmental biology (including embryology) is proposed as "the stem cell of biological disciplines." Genetics, cell biology, oncology, immunology, evolutionary mechanisms, neurobiology, and systems biology each has its ancestry in developmental biology. Moreover, developmental biology continues to roll on, budding off more disciplines, while retaining its own identity. While its descendant disciplines differentiate into sciences with a restricted set of paradigms, examples, and techniques, developmental biology remains vigorous, pluripotent, and relatively undifferentiated. In many disciplines, especially in evolutionary biology and oncology, the developmental perspective is being reasserted as an important research program. PMID- 29284161 TI - Ultrasound-Guided Corticosteroid Injection in Patients with Carpal Tunnel Syndrome: Efficacy of Intra-Epineurial Injection. AB - PURPOSE: To identify the ultrasound (US) findings of intra-epineurial corticosteroid injection during US-guided hydrodissection in patients with carpal tunnel syndrome (CTS), and to determine their clinical relevance in relation to treatment outcomes. MATERIALS AND METHODS: We performed 101 US-guided hydrodissections and corticosteroid injections in 101 patients with CTS, and evaluated their pre- and post-injection US findings. We categorized these injections into two groups based on the occurrence of intra-epineurial injection. We also recorded clinical data including sex, age, side of injection, BMI, and the duration of pre-injection CTS-related discomfort. The outcomes were measured using the Likert satisfaction scale and Boston Carpal Tunnel Questionnaire (BCTQ) scores. The clinical data, cross-sectional area of the median nerve (CSA-MN) at the inlet of the carpal tunnel measured on US images, and the symptom relief for the patients receiving intra-epineurial and extra-epineurial injection were compared. RESULTS: The intra-epineurial injection rate was 38.6 % in the 101 US guided injections. The clinical data, pre-injection CSA-MN at the inlet of the carpal tunnel, and pre-injection BCTQ scores showed no significant intergroup differences (p > 0.05). The group with intra-epineurial injections had significantly decreased CSA-MN (difference in means, 2.5 mm2; p < 0.0001), greater patient satisfaction (p = 0.002), and lower BCTQ scores (p < 0.05) than the group with extra-epineurial injections. CONCLUSION: We characterized the US findings of intra-epineurial corticosteroid injection during US-guided hydrodissection. Intra-epineurial injection provided a more meaningfully reduction in edema of the MN, greater patient satisfaction, and greater symptom relief than extra-epineurial injection. PMID- 29284162 TI - Re: National Breast Reconstruction Utilization in the Setting of Postmastectomy Radiotherapy: Two-Stage Implant-Based Breast Reconstruction. PMID- 29284163 TI - Geometric Three-Dimensional End-to-Side Microvascular Anastomosis: A Simple and Reproducible Technique. AB - BACKGROUND: End-to-side (ETS) anastomoses are useful when preservation of distal vascularity is critical. The ideal ETS microanastomosis should maintain a wide aperture and have a smooth take-off point to minimize turbulence, vessel spasm, and thrombogenicity of the suture line. We have developed a unique, dependable, and reproducible geometric technique for ETS anastomoses, and analyze its efficacy in our series of patients. METHODS: The geometric ETS technique involves creating a three-dimensional (3D) diamond-shaped defect on the recipient vessel wall, followed by a slit incision of the donor vessel to create a "spatula" fitting this defect. This technique removes sutures from the point of most turbulent blood flow while holding the recipient vessel open with a patch vesselplasty effect. We perform a retrospective review of a single surgeon's experience using this technique. RESULTS: The geometric 3D ETS technique was used in 87 free flaps with a total of 102 ETS anastomoses in a wide range of cases including head and neck, trunk and genitourinary, and extremity reconstruction. Overall, free flap success rates were 98%. CONCLUSIONS: The geometric 3D ETS technique creates a wide anastomosis, minimizes turbulence inducing thrombogenicity, and mechanically holds the recipient vessel open. It is reliable and reproducible, and when performed properly has been shown to have high rates of success in a large group of free tissue transfer patients. PMID- 29284164 TI - Current Practices in the Management of Postoperative Arterial Vasospasm in Microsurgery. AB - BACKGROUND: Postoperative microvascular arterial vasospasm is a rare clinical entity. There are no published management algorithms and also the pathophysiology of this phenomenon has not been elucidated. METHODS: An email survey of American Society for Reconstructive Microsurgery (ASRM) and World Society for Reconstructive Microsurgery (WSRM) members regarding their experiences with postoperative arterial vasospasm was conducted, returning 116 responses. A comprehensive literature search was conducted regarding the current body of knowledge on this entity. RESULTS: Sixty-five percent of respondents encountered cases where postoperative arterial vasospasm was clearly the cause of flap ischemia. The majority (62%) of surgeons believed a damaged segment of the artery was responsible for the spasm, with technical issues cited as the most likely cause. Sixty-two percent and 50% of surgeons used segmental resection of the recipient and donor vessels, respectively.Rated for proclivity to vasospasm, superficial inferior epigastric artery (SIEA) was the flap, superior thyroid artery (STA) the recipient vessel, and the lower limb the anatomic region most frequently mentioned.Most widely used management strategies were: topical vasodilators (91%), adventitial stripping (82%), and dilation of recipient and donor vessels (76%). Over 50% of surgeons used some type of vessel resection technique. CONCLUSIONS: When flap ischemia is encountered without mechanical issues or thrombus, vasospasm can be the root cause. Certain vessels (SIEA, STA) and anatomic regions (lower limb) pose a higher risk for this phenomenon. When a vessel is affected, it is common practice to excise the questionable segment and use a graft as needed. Vessel resection as part of a multimodal approach can result in a reasonable salvage rate. PMID- 29284165 TI - Lactate Threshold as a Measure of Aerobic Metabolism in Resistance Exercise. AB - In resistance training, load intensity is usually calculated as the percentage of a maximum repetition (1RM) or maximum number of possible repetitions (% of 1RM). Some studies have proposed a lactate threshold (LT) intensity as an optimal approach for concurrent training of cardiorespiratory endurance and muscle strength, as well as an alternative in resistance training. The objective of the present study was to analyze the results obtained in research evaluating the use of LT in resistance training. A keyword and search tree strategy identified 14 relevant articles in the Dialnet, Elsevier, Medline, Pubmed, Scopus and Web of Science databases. Based on the studies analyzed, the conclusion was that the LT in resistance exercises can be determined either by mathematical methods or by visual inspection of graphical plots. Another possibility is to measure the intensity at which LT might coincide with the first ventilatory threshold (VT1). Since performing an exercise session at one's LT intensity has been shown to accelerate the cardiorespiratory response and induce neuromuscular fatigue, this intensity could be used to set the training load in a resistance training program. PMID- 29284166 TI - Functional Screening Tests: Interrelationships and Ability to Predict Vertical Jump Performance. AB - There are several methods used in sports science to identify asymmetries in athletes, given their purported relevance to injury prevention and performance optimization. We aimed to verify whether asymmetries provided by isokinetic assessments, jump tests, and tensiomyography (TMG) are associated with each other, and whether their respective functional indices are related to jumping ability. TMG parameters, unilateral and bilateral squat-jump (SJ) and countermovement-jump (CMJ) performances, and peak torque in knee-extension and flexion with angular velocities of 60o/s and 300o/s for twenty-four soccer players were retained for analyses. Asymmetry was detected by examining the percentage difference between dominant and non-dominant legs. The median-split technique was used to identify the best and worst performers in SJ and CMJ tests. Results revealed that the asymmetries detected in the three different methods were not interrelated. Curiously, better performances in SJ and CMJ tests were associated with higher asymmetry levels. Furthermore, only the knee-extension peak torque at both angular velocities was correlated moderately to largely (r=0.48-0.66) with jump performance. Despite their recognized ability to predict the risk of injury, the absence of interrelationships between TMG, isokinetic tests, and unilateral jumps precludes their single use as a unique functional screening diagnostic. Finally, and very importantly, lower-limb asymmetry is not necessarily related to impaired vertical jump performance in soccer players. PMID- 29284168 TI - Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder. AB - Neuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient. PMID- 29284167 TI - Regenerative Medicine/Cardiac Cell Therapy: Adult/Somatic Progenitor Cells. AB - Preclinical data suggested that somatic stem or progenitor cells derived induce and/or support endogenous repair mechanisms of the myocardium. Such cell populations were clearly shown to promote neovascularization in postischemic tissue, and some evidence also indicated transdifferentiation into cardiomyocytes. In the clinical setting, however, many attempts to regenerate damaged myocardium with a variety of autologous and allogeneic somatic progenitors have failed to generate the expected therapeutic efficacy. Currently, efforts are being made to select specific cellular subpopulations, modify somatic cells to augment their regenerative capacity, improve delivery methods, and develop markers selection of potentially responding patients. Cardiac surgical groups have pioneered and continue to advance the field of cellular therapies. While the initial excitement has subsided, the field has evolved into one of the pillars of surgical research and benefits from novel methods such as cellular reprogramming, genetic modification, and pluripotent stem cell technology. This review highlights developments and controversies in somatic cardiac cell therapy and provides a comprehensive overview of completed and ongoing clinical trials. PMID- 29284169 TI - Facing the Facts. PMID- 29284170 TI - [Radiological Diagnoses in the Context of Emigration: Infectious diseases]. PMID- 29284172 TI - ? PMID- 29284173 TI - Response to: Confidence in the ATTUNE Knee is Driven by Real-World Scientific Evidence: Response to Bonutti et al. Article. PMID- 29284171 TI - Post-TAVI Follow-Up with MDCT of the Valve Prosthesis: Technical Application, Regular Findings and Typical Local Post-Interventional Complications. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has evolved into an alternative procedure to surgical valve replacement for high-risk patients with aortic valve stenosis. Despite technical innovations, there is still a risk of complications during and after the intervention. After a TAVI procedure, ECG gated multidetector computed tomography (MDCT) plays an important role in the early diagnosis of local complications. In this article, we explain for the first time how the technical acquisition of MDCT in the region of the aortic root is performed as post-interventional control of the TAVI prosthesis. In the second part normal post-interventional findings of different prosthetic valves as well as classic and uncommon complications in the implant area will be illustrated in several case studies. METHODS: In this review the current literature from PubMed about ECG-gated MDCT after TAVI is summarized and structured. It is supplemented by several case studies from our institution. RESULTS AND CONCLUSION: Using retrospectively ECG-gated MDCT, an aortic valve prosthesis after TAVI can be visualized with high spatial resolution in several phases of the cardiac cycle. Images of the implanted aortic valve at all time points of the cardiac cycle enable a functional analysis of prosthetic leaflets similar to echocardiography. MDCT is superior to transthoracic echocardiography with respect to the direct detection of prosthetic leaflet thrombosis. The position of the device in relation to the coronary ostia and correct unfolding of the stent frame need to be evaluated. There are different types of stents carrying the valve leaflets with distinct ideal positions. Any stent should cover the left ventricular outflow tract (LVOT) along its whole circumference. Life-threatening complications in the implant area, such as annulus rupture, can be diagnosed reliably with CT. KEY POINTS: . ECG-gated multidetector CT (MDCT) after transcatheter aortic valve implantation (TAVI) can provide early detection of postinterventional complications of the prosthetic valve and the aortic root.. . MDCT is superior to echocardiography with respect to the direct detection of prosthetic leaflet thrombosis.. . MDCT can also reveal hypokinesia of the thrombotic valve leaflets.. . Correct position of the device und unfolding of the stent frame differ according to the type of prosthesis.. . The integrity of the native aortic root should be carefully assessed.. CITATION FORMAT: . Soschynski M, Capilli F, Ruile P et al. Post-TAVI Follow-Up with MDCT of the Valve Prosthesis: Technical Application, Regular Findings and Typical Local Post Interventional Complications. Fortschr Rontgenstr 2018; 190: 521 - 530. PMID- 29284174 TI - Bilayer Matrix Autologous Chondrocyte Implantation without Bone Graft for Knee Osteochondral Lesion Less than 8 mm Deep. AB - This article investigates the clinical and radiological results of bilayer matrix autologous chondrocyte implantation (MACI) membrane technique in the treatment of shallow osteochondral defects. An analysis was made of eight patients who were operated on using the bilayer MACI (Genzyme Biosurgery, Cambridge, MA) technique (mean age: 20.2 years, mean defect size: 3.8 cm2, mean defect depth: 6.2 +/- 0.9 mm, and mean follow-up time: 22.1 +/- 5.3 [14-26.1] months). According to the defect, the first membrane was secured to the base of the defect with the cells facing up, and the second membrane was implanted on top of the first membrane with the cells facing down using fibrin glue. Clinical assessment was performed with modified Cincinnati and Tegner Lysholm scores. Patients were evaluated using 3-Tesla magnetic resonance imaging (3T MRI) with a 15-channel transmit knee coil in the 6th, 12th, and 24th months postoperatively. Magnetic observation of cartilage repair tissue (MOCART) scoring was used to evaluate the cartilage tissue. The mean modified Cincinnati score was 36.4 (21-48) preoperatively and 84.2 (81-90) at 6 months postoperatively, 87.2 (82-92) at 12 months, and 89.6 (85 94) at 24 months (p < 0.05). The postoperative results were evaluated as excellent. The mean Tegner Lysholm score was 36.4 (21-48) preoperatively and 88.2 (84-92), 90.2 (84-95), and 90.4 (86-95) at 6, 12, and 24 months postoperatively (p < 0.05). According to the 3T MRI findings, the mean modified MOCART scores were 8 in the preimplantation period, 38 in the 6th postoperative month, 70 in the 12th postoperative month, and 79 in the 24th postoperative month (p < 0.05). The 2-year follow-up MRI showed good regeneration, healing, and integration developing in time in cartilage tissue. In the treatment of shallow osteochondral defects, the bilayer MACI technique can be an alternative to filling the defect with bone graft. PMID- 29284175 TI - Surgical Management of Simultaneous Anterior Cruciate Ligament and Patellar Tendon Ruptures: A Systematic Review. AB - This study performs a systematic review to determine (1) if a significant difference exists in return to preinjury activity level between one- and two stage treatment of combined anterior cruciate ligament (ACL) and patellar tendon (PT) tears; and (2) if a significant difference exists in the number of postoperative complications between the two differing surgical treatment approaches. A systematic review was performed using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered on PROSPERO. MEDLINE, Cochrane Central Register of Controlled Trials, SCOPUS, and Sport Discus were searched for English language level I-IV evidence studies on either one- (simultaneous) or two-stage (sequential) surgical treatment of simultaneously sustained ipsilateral ACL and PT tears. The approach to initial evaluation, diagnosis, treatment, and outcomes were qualitatively analyzed. Methodological quality assessment of all included studies was completed using the Methodological Index for Non-randomized Studies (MINORS). The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to assess quality of evidence and provide strength of recommendation. Statistical analyses were done using Fischer's exact test. Eleven articles (18 patients; 83% males; mean age, 31.1 +/- 10.1 years; mean follow-up, 2.2 +/- 1.7 years; and mean MINORS 7.8/16) were analyzed. Eight patients had a one-stage procedure (primary PT repair and ACL reconstruction), and 10 patients underwent a two-stage procedure (primary PT repair first followed by ACL reconstruction) with mean 28 +/- 45.7 weeks (5 weeks-3 years) between surgeries. The rate for return to preinjury activity level after surgery was not significantly different between one- (88%) and two-stage (100%) (p = 0.444). There was a significantly higher complication rate (p = 0.023) in the one-stage (stiffness, instability, and patella baja) versus two-stage surgery (no complications). There was no significant difference in return to preinjury activity level between one- and two stage PT repair and ACL reconstruction. However, the one-stage combined surgery had a significantly higher complication rate compared with two-stage surgery. The level of evidence is IV. PMID- 29284176 TI - Bone-Patellar Tendon-Bone Autograft versus Hamstring Tendon Autograft for Anatomical Anterior Cruciate Ligament Reconstruction with Three-Dimensional Validation of Femoral and Tibial Tunnel Positions. AB - The purpose of this retrospective study was to first compare the clinical outcome of anatomical double-bundle (DB) anterior cruciate ligament reconstruction (ACLR) with hamstring tendon (HT) autografts and anatomical rectangular tunnel ACLR with bone-patellar tendon-bone (BPTB) autografts. Secondly, we aimed to demonstrate the quantitative locations of the femoral and tibial tunnel apertures using postoperative three-dimensional computed tomography (3D CT). Twenty-five patients underwent anatomical rectangular tunnel ACLR using BPTB grafts (Group B) and 23 patients underwent anatomical DB ACLR using HT grafts (Group H). All patients underwent subjective postoperative evaluations using the Lysholm score and Knee Injury and Osteoarthritis Outcome Score. Patients also underwent objective evaluations by the International Knee Documentation Committee score, the Lachman test, the pivot-shift test, and range of motion. In addition, we quantitatively assessed anterior knee stability using a KneeLax3 arthrometer and thigh strength. All evaluations except for thigh strength were assessed for a minimum 2 years of follow-up period. Femoral and tibial tunnel aperture locations were quantitatively evaluated postoperatively using 3D CT images in all patients. BPTB grafts showed significantly better anterior knee stability than HT grafts (0.1 mm versus 1.1 mm, p = 0.01), although there were no significant differences in other objective and all subjective evaluations between the two graft types. Morphometric analysis of femoral and tibial tunnel locations revealed that the two procedures were based on the same anatomical concept. In conclusion, BPTB grafts showed significantly better anterior knee stability than HT grafts, although no significant differences in other objective evaluations and all subjective evaluations were detected between the two graft types in anatomical ACLR. Additional 3D CT data validated the anatomical concepts of these two procedures. PMID- 29284177 TI - Preclinical efficacy and immunogenicity assessment to show that a chimeric Plasmodium falciparum UB05-09 antigen could be a malaria vaccine candidate. AB - Although it is generally agreed that an effective vaccine would greatly accelerate the control of malaria, the lone registered malaria vaccine MosquirixTM has an efficacy of 30%-60% that wanes rapidly, indicating a need for improved second-generation malaria vaccines. Previous studies suggested that immune responses to a chimeric Plasmodium falciparum antigen UB05-09 are associated with immune protection against malaria. Herein, the preclinical efficacy and immunogenicity of UB05-09 are tested. Growth inhibition assay was employed to measure the effect of anti-UB05-09 antibodies on P. falciparum growth in vitro. BALB/c mice were immunized with UB05-09 and challenged with the lethal Plasmodium yoelii 17XL infection. ELISA was used to measure antigen-specific antibody production. ELISPOT assays were employed to measure interferon-gamma production ex vivo after stimulation with chimeric UB05-09 and its constituent antigens. Purified immunoglobulins raised in rabbits against UB05-09 significantly inhibited P. falciparum growth in vitro compared to that of its respective constituent antigens. A combination of antibodies to UB05-09 and the apical membrane antigen (AMA1) completely inhibited P. falciparum growth in culture. Immunization of BALB/c mice with recombinant UB05-09 blocked parasitaemia and protected them against lethal P. yoelii 17XL challenge infection. These data suggest that UB05-09 is a malaria vaccine candidate that could be developed further and used in conjunction with AMA1 to create a potent malaria vaccine. PMID- 29284178 TI - What is the current practice of therapists in the measurement of somatosensation in children with cerebral palsy and other neurological disorders? AB - BACKGROUND/AIM: Somatosensation is the ability to detect and recognise body sensations such as touch, vibration, pressure, pain, temperature and proprioception. Cerebral palsy is a neurological disorder that is often accompanied by impairments in somatosensation. Current somatosensory assessments have limited psychometrics established for use with these children. The aim of this study was to identify therapists' current practice and perspectives related to the assessment of somatosensation in children with neurological disorders. METHODS: A cross-sectional questionnaire was used to identify the somatosensory assessments currently used in clinical practice, time allocated to assessment, and therapists' satisfaction and confidence using the available assessments of somatosensation. The questionnaire was adapted from a previously utilised questionnaire that identified therapists' use of somatosensory assessments with adults post-stroke. RESULTS: A total of 135 therapists responded to the questionnaire. Seventy-nine (92%) occupational therapists and 44 (89.7%) physiotherapists indicated that they currently assessed or treated children with somatosensory deficits. Sixty-four (82.1%) occupational therapists and 38 (86.3%) physiotherapists regarded assessment of somatosensation in children with neurological disorders as important to very important. However, only seven (8.8%) occupational therapists and seven (15.9%) physiotherapists reported confidence in their ability to do so. The methods with which therapists detect and measure somatosensory impairment in children with neurological disorders are variable, with non-standardised and/or informal assessments most frequently used. CONCLUSION: Despite there being recommendations of best practice for the assessment of specific domains of somatosensation in children with cerebral palsy, current practice does not yet mirror these recommendations. Additionally, therapists have low satisfaction and confidence with what they are currently using, highlighting the need for a comprehensive and standardised assessment of somatosensation for use in children with neurological disorders. PMID- 29284179 TI - Differences in pain thresholds elicited by intraoral electrical stimuli between individuals with and without diabetes mellitus. AB - There is little evidence of sensation in individuals with diabetes mellitus (DM) in the dental research field. We investigated whether pain thresholds (PTs) differ between individuals with and without DM (non-DM; NDM). To this end, we assessed whether PTs obtained from the oral cavity, hands, and feet differed from each other and across groups, and whether PTs differed for the three current frequencies used for testing (2000 Hz, 250 Hz, and 5 Hz). Pain threshold measurements were obtained from the oral mucosa and the tips of the fingers and toes of 56 volunteers, including 21 individuals with DM (12 men and 9 women, average age: 72.1 +/- 4.7 years) and 35 NDM individuals (17 males and 18 females, average age: 51.2 +/- 23.9 years) using the Neurometer CPT/C(r) device to deliver electrical stimulation. A single operator obtained PT measurements from around the left greater palatine foramen and from the tip of the left first finger and of the left great toe. Individuals with DM had significantly lower PT values than those without DM. The PT values for the oral cavity, hands, and feet differed significantly from each other (foot > hand, foot > oral cavity, hand > oral cavity). Moreover, there was a significant difference in the PT values for 5 Hz and 2000 Hz, as well as for 250 Hz and 2000 Hz. This study concluded that PT values derived from DM participants are lower than those from NDM participants, although PT measurements varied across regions and with current frequency. PMID- 29284180 TI - Study of top ballet school students revealed large deficiencies in their body weight and body fat. AB - AIM: This study assessed the nutritional status and physical activity levels of 150 female students aged 10-18 from three top Polish ballet schools, where the most promising dancers go on to pursue professional ballet careers. METHODS: We analysed the girls' body composition, physical activity level (PAL) and PAL coefficient. The ballet students also completed a questionnaire. RESULTS: The results revealed large deficiencies in the body weight and body fat of the young ballerinas. The mean body mass index (BMI) for the group was 16.8 kg/m2 . Polish centile charts showed that 18% of the girls had BMIs below the norm and 54% had a lower than average body fat content, with a mean of 15.6%. The body fat content was lowest (13.8%) in the 13- to 15-year age group. On average, girls aged 10-12 had 15.7% body fat, while girls aged 16-18 had 18.4%. The mean values for the anthropometric measurements were higher in older girls. The majority (72%) of the respondents reported high physical activity levels, defined as more than 15 hours of exercise per week. CONCLUSION: Special attention should be paid to low BMIs and body fat in young ballet school dancers aged 10-15 years. PMID- 29284181 TI - Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study. AB - Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track(r) CMV, a novel IFN-gamma ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88-92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track(r) CMV is a highly sensitive IFN-gamma ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042). PMID- 29284183 TI - Predicting reactivity threshold in children with anaphylaxis to peanut. AB - BACKGROUND: Peanut allergy necessitates dietary restrictions, preferably individualized by determining reactivity threshold through an oral food challenge (OFC). However, risk of systemic reactions often precludes OFC in children with severe peanut allergy. OBJECTIVE: We aimed to determine whether clinical and/or immunological characteristics were associated with reactivity threshold in children with anaphylaxis to peanut and secondarily, to investigate whether these characteristics were associated with severity of the allergic reaction during OFC. METHODS: A double-blinded placebo-controlled food challenge (DBPCFC) with peanut was performed in 96 5- to 15-year-old children with a history of severe allergic reactions to peanut and/or sensitization to peanut (skin prick test [SPT] >=3 mm or specific immunoglobulin E [s-IgE] >=0.35 kUA/L). Investigations preceding the DBPCFC included a structured interview, SPT, lung function measurements, serological immunology assessment (IgE, IgG and IgG4 ), basophil activation test (BAT) and conjunctival allergen provocation test (CAPT). International standards were used to define anaphylaxis and grade the allergic reaction during OFC. RESULTS: During DBPCFC, all 96 children (median age 9.3, range 5.1-15.2) reacted with anaphylaxis (moderate objective symptoms from at least two organ systems). Basophil activation (CD63+ basophils >=15%), peanut SPT and the ratio of peanut s-IgE/total IgE were significantly associated with reactivity threshold and lowest observed adverse events level (LOAEL) (all P < .04). Basophil activation best predicted very low threshold level (<3 mg of peanut protein), with an optimal cut-off of 75.8% giving a 93.5% negative predictive value. None of the characteristics were significantly associated with the severity of allergic reaction. CONCLUSION AND CLINICAL RELEVANCE: In children with anaphylaxis to peanut, basophil activation, peanut SPT and the ratio of peanut s-IgE/total IgE were associated with reactivity threshold and LOAEL, but not with allergy reaction severity. PMID- 29284184 TI - Disparate patterns of thermal adaptation between life stages in temperate vs. tropical Drosophila melanogaster. AB - Many terrestrial ectothermic species exhibit limited variation in upper thermal tolerance across latitude. However, these trends may not signify limited adaptive capacity to increase thermal tolerance in the face of climate change. Instead, thermal tolerance may be similar among populations because behavioural thermoregulation by mobile organisms or life stages may buffer natural selection for thermal tolerance. We compared thermal tolerance of adults and embryos among natural populations of Drosophila melanogaster from a broad range of thermal habitats around the globe to assess natural variation of thermal tolerance in mobile vs. immobile life stages. We found no variation among populations in adult thermal tolerance, but embryonic thermal tolerance was higher in tropical strains than in temperate strains. We further report that embryos live closer to their upper thermal limits than adults - that is, thermal safety margins are smaller for embryos than adults. F1 hybrid embryos from crosses between temperate and tropical populations had thermal tolerance that matched that of tropical embryos, suggesting the dominance of heat-tolerant alleles. Together, our findings suggest that thermal selection has led to divergence in embryonic thermal tolerance but that selection for divergent thermal tolerance may be limited in adults. Further, our results suggest that thermal traits should be measured across life stages to better predict adaptive limits. PMID- 29284182 TI - Cryptococcosis and cryptococcal meningitis: New predictors and clinical outcomes at a United States academic medical centre. AB - As the diagnosis of cryptococcosis is challenging in low-prevalence settings, uncovering predictive factors can improve early diagnosis and timely treatment. The aim of the study was to relate clinical outcomes to predictive variables for the presence of cryptococcosis. A retrospective case-control study matched by collection date, age and gender at a 1:2 ratio (55 cases and 112 controls) was performed in case patients diagnosed with Cryptococcus infection at the University of Colorado Hospital between 2000 and 2017 (n = 167). A bivariate and a forward, stepwise multivariable logistic regression model were performed to identify predictors of cryptococcosis infection. In an adjusted multivariable model, cryptococcal infection was significantly associated with the presence of respiratory symptoms, hyponatremia, lung disease or corticosteroids. Additionally, cryptococcal meningitis was associated with headaches, corticosteroids or increased CSF protein. Conversely, a reduced risk of cryptococcosis was associated with hypertension or peripheral monocytosis. Cryptococcal meningitis leads to subsequent hearing impairment (16% vs 4% (control), P = .013), muscle weakness (40% vs 20%, P = .021), cognitive deficits (33% vs 6%, P = .0001) or any adverse outcome (84% vs 29%, P = .0001). We uncovered novel clinical predictors for the presence of cryptococcal infection or cryptococcal meningitis. This study in patients at a low-prevalence US medical centre underscores the importance of early diagnosis in this population. PMID- 29284186 TI - Repeatability of gait analysis measurements in Thoroughbreds in training. AB - BACKGROUND: With the view of implementing gait symmetry measurements in Thoroughbreds in training for early detection of injuries, repeatability of inertial measurement unit (IMU) gait parameters needs to be established. OBJECTIVES: To assess the variation of head and pelvis movement symmetry in Thoroughbreds in training. STUDY DESIGN: Repeated observations in horses in race training. METHODS: Daily and weekly repeat gait assessments were conducted in 14 Thoroughbreds equipped with IMUs on poll, sacrum and right (RTC) and left (LTC) tuber coxae. Gait was assessed in trot, in-hand, on a level concrete surface. Difference between vertical displacement minima and maxima and range of motion (ROM) were obtained. Ranges containing 50% (median), 75, 90 and 95% of absolute daily and weekly differences were calculated and intraclass correlation coefficients (ICC) calculated for daily and weekly repeats. RESULTS: Median absolute daily differences ranged from 4 to 7 mm and median weekly differences from 4 to 8 mm. 90% of daily differences were between 9 and 16 mm and 90% of weekly differences between 11 and 19 mm. ICC values were found on average across sensors and gait parameters as 0.73 (ranging from 0.40 to 0.92 across parameters) for daily repeats and as 0.65 (0.27 to 0.91) for weekly repeats. MAIN LIMITATIONS: Horses were of varying training and movement asymmetry levels, and no veterinary lameness examination was conducted. CONCLUSIONS: Daily and weekly repeat gait assessments in this group of Thoroughbreds in training show lower ICC values than previously reported from within-day repeats in horses during lameness examinations. We recommend conducting repeatability studies for specific groups of horses when planning long-term studies aiming at identifying horses at risk of injury. PMID- 29284187 TI - Sex-antagonistic genes, XY recombination and feminized Y chromosomes. AB - The canonical model of sex-chromosome evolution predicts that sex-antagonistic (SA) genes play an instrumental role in the arrest of XY recombination and ensuing Y chromosome degeneration. Although this model might account for the highly differentiated sex chromosomes of birds and mammals, it does not fit the situation of many lineages of fish, amphibians or nonavian reptiles, where sex chromosomes are maintained homomorphic through occasional XY recombination and/or high turnover rates. Such situations call for alternative explanatory frameworks. A crucial issue at stake is the effect of XY recombination on the dynamics of SA genes and deleterious mutations. Using individual-based simulations, we show that a complete arrest of XY recombination actually benefits females, not males. Male fitness is maximized at different XY recombination rates depending on SA selection, but never at zero XY recombination. This should consistently favour some level of XY recombination, which in turn generates a recombination load at sex-linked SA genes. Hill-Robertson interferences with deleterious mutations also impede the differentiation of sex-linked SA genes, to the point that males may actually fix feminized phenotypes when SA selection and XY recombination are low. We argue that sex chromosomes might not be a good localization for SA genes, and sex conflicts seem better solved through the differential expression of autosomal genes. PMID- 29284185 TI - Effect of FH535 on in vitro maturation of porcine oocytes by inhibiting WNT signaling pathway. AB - Wingless-int (WNT) signaling pathway is vital to modulate life processes, including cell fate determination, cell differentiation, cell proliferation, cell apoptosis and embryogenesis. To demonstrate the uncertain effect of the canonical WNT signaling pathway on oocyte maturation, immature porcine oocytes were collected and cultured in vitro with the WNT/beta-catenin inhibitor FH535. The concentrations of FH535 were selected as 0.00, 0.01, 0.10, 1.00 and 10.00 MUmol/L. The results showed that the optimum concentration of FH535 on oocyte maturation was 1.00 MUmol/L. In this concentration, the proportion of MII oocytes increased (P < 0.05). The rate of cleavage was the same with the control (P > 0.05), while the rate of blastocysts in the 1.00 MUmol/L FH535 treated group was higher than that of control (P < 0.01). Additionally, the average number of nuclei in blastocysts raised significantly (P < 0.05). The inhibition of WNT could regulate expression of maturation-related genes, including Cdc-2, Bmp-15, Gdf-9 and Mos. In the 1.00 MUmol/L FH535 treated group, the messenger RNA level of beta-catenin showed no significant change compared to the control (P > 0.05), but the protein abundance was decreased (P < 0.05). This study revealed that the inhibition of FH535 on the WNT signaling pathway could promote the maturation of porcine oocytes and altered gene expressions in vitro. PMID- 29284188 TI - Repeated doses of salbutamol and aeroallergen sensitisation both increased salbutamol-induced hypoxia in children and adolescents with acute asthma. AB - AIM: We aimed to identify the frequency, magnitude and risk factors of salbutamol induced hypoxia in children with acute asthma. METHODS: This study was conducted at Hacettepe University on children who presented to the paediatric allergy clinic or the paediatric emergency room with acute asthma between July 2014 and June 2015. Vital signs, pulse oximetry-defined oxygen saturation and modified pulmonary index scores were evaluated before and after the first, second and third doses of nebulised salbutamol and repeated one and 10 days later. RESULTS: We included 304 patients (65.7% male) from median age of 5.3 years (range 1-18 years). Salbutamol-induced hypoxia was detected in 14.7%, 3.9% and 1.3%, respectively, after the first, second and third doses of salbutamol. The risk factors for hypoxia were younger age and a higher modified pulmonary index score, but the risk factors for salbutamol-induced hypoxia were the number of salbutamol doses given in the last six hours and the presence of aeroallergen sensitisation. The maximum decrease in oxygen saturation after salbutamol was %5. CONCLUSION: Although bronchodilators are the first-line treatment for acute asthma, they caused modest hypoxaemia, especially at repeated doses and, or, in patients with aeroallergen sensitisation. PMID- 29284189 TI - Underestimation of N2 O emissions in a comparison of the DayCent, DNDC, and EPIC models. AB - Process-based models are increasingly used to study agroecosystem interactions and N2 O emissions from agricultural fields. The widespread use of these models to conduct research and inform policy benefits from periodic model comparisons that assess the state of agroecosystem modeling and indicate areas for model improvement. This work provides an evaluation of simulated N2 O flux from three process-based models: DayCent, DNDC, and EPIC. The models were calibrated and validated using data collected from two research sites over five years that represent cropping systems and nitrogen fertilizer management strategies common to dairy cropping systems. We also evaluated the use of a multi-model ensemble strategy, which inconsistently outperformed individual model estimations. Regression analysis indicated a cross-model bias to underestimate high magnitude daily and cumulative N2 O flux. Model estimations of observed soil temperature and water content did not sufficiently explain model underestimations, and we found significant variation in model estimates of heterotrophic respiration, denitrification, soil NH4+ , and soil NO3- , which may indicate that additional types of observed data are required to evaluate model performance and possible biases. Our results suggest a bias in the model estimation of N2 O flux from agroecosystems that limits the extension of models beyond calibration and as instruments of policy development. This highlights a growing need for the modeling and measurement communities to collaborate in the collection and analysis of the data necessary to improve models and coordinate future development. PMID- 29284190 TI - Vegetation cover in relation to socioeconomic factors in a tropical city assessed from sub-meter resolution imagery. AB - Fine-scale information about urban vegetation and social-ecological relationships is crucial to inform both urban planning and ecological research, and high spatial resolution imagery is a valuable tool for assessing urban areas. However, urban ecology and remote sensing have largely focused on cities in temperate zones. Our goal was to characterize urban vegetation cover with sub-meter (<1 m) resolution aerial imagery, and identify social-ecological relationships of urban vegetation patterns in a tropical city, the San Juan Metropolitan Area, Puerto Rico. Our specific objectives were to (1) map vegetation cover using sub-meter spatial resolution (0.3-m) imagery, (2) quantify the amount of residential and non-residential vegetation, and (3) investigate the relationship between patterns of urban vegetation vs. socioeconomic and environmental factors. We found that 61% of the San Juan Metropolitan Area was green and that our combination of high spatial resolution imagery and object-based classification was highly successful for extracting vegetation cover in a moist tropical city (97% accuracy). In addition, simple spatial pattern analysis allowed us to separate residential from non-residential vegetation with 76% accuracy, and patterns of residential and non residential vegetation varied greatly across the city. Both socioeconomic (e.g., population density, building age, detached homes) and environmental variables (e.g., topography) were important in explaining variations in vegetation cover in our spatial regression models. However, important socioeconomic drivers found in cities in temperate zones, such as income and home value, were not important in San Juan. Climatic and cultural differences between tropical and temperate cities may result in different social-ecological relationships. Our study provides novel information for local land use planners, highlights the value of high spatial resolution remote sensing data to advance ecological research and urban planning in tropical cities, and emphasizes the need for more studies in tropical cities. PMID- 29284191 TI - Chronosequence predictions are robust in a Neotropical secondary forest, but plots miss the mark. AB - Tropical secondary forests (TSF) are a global carbon sink of 1.6 Pg C/year. However, TSF carbon uptake is estimated using chronosequence studies that assume differently aged forests can be used to predict change in aboveground biomass density (AGBD) over time. We tested this assumption using two airborne lidar datasets separated by 11.5 years over a Neotropical landscape. Using data from 1998, we predicted canopy height and AGBD within 1.1 and 10.3% of observations in 2009, with higher accuracy for forest height than AGBD and for older TSFs in comparison to younger ones. This result indicates that the space-for-time assumption is robust at the landscape-scale. However, since lidar measurements of secondary tropical forest are rare, we used the 1998 lidar dataset to test how well plot-based studies quantify the mean TSF height and biomass in a landscape. We found that the sample area required to produce estimates of height or AGBD close to the landscape mean is larger than the typical area sampled in secondary forest chronosequence studies. For example, estimating AGBD within 10% of the landscape mean requires more than thirty 0.1 ha plots per age class, and more total area for larger plots. We conclude that under-sampling in ground-based studies may introduce error into estimations of the TSF carbon sink, and that this error can be reduced by more extensive use of lidar measurements. PMID- 29284192 TI - Clinical signs, imaging findings, and outcome in twelve cats with internal ophthalmoparesis/ophthalmoplegia. AB - OBJECTIVE: To retrospectively evaluate the clinical signs, imaging findings, and outcome of feline internal ophthalmoparesis/ophthalmoplegia. PROCEDURE: Medical records were reviewed from 2008 to 2015. Inclusion criteria included cats that presented with internal ophthalmoparesis/ophthalmoplegia, underwent diagnostic imaging, and had follow-up information available. RESULTS: Twelve cases of feline internal ophthalmoparesis/ophthalmoplegia were identified. Nine cats were unilaterally affected, and three cats were bilaterally affected. Affected cats had a median age of 10.54 years (range 5.75 to 13.17), and both sexes of varying breeds were affected (nine males; three females). Clinical signs including abnormal mental status (n = 9; 75%) and additional neurologic abnormalities (n = 10; 83%) were observed. Magnetic resonance imaging and/or computed tomography (MRI/CT) of the head were performed in ten cats, revealing a mass lesion in all cases with varying locations. Multicentric lymphoma was diagnosed in two cats via abdominal ultrasound and cytology. All twelve cats were euthanized due to deterioration of clinical signs and/or quality-of-life concerns. Median time from diagnosis to euthanasia was 3.5 days (range 0 to 80 days). CONCLUSIONS: Feline internal ophthalmoparesis/ophthalmoplegia rarely presents as the sole clinical sign in a referral hospital. Advanced imaging (MRI/CT) may be necessary to reach a definitive diagnosis in these cases. However, abdominal ultrasound would be advocated in cats with systemic clinical signs as a less expensive and less invasive diagnostic test to further investigate the possible etiology of internal ophthalmoparesis/ophthalmoplegia prior to advanced imaging. Feline cases with internal ophthalmoparesis/ophthalmoplegia associated with other intracranial signs and/or systemic clinical signs have a poor prognosis. PMID- 29284193 TI - Epidemiology of ocular disorders presumed to be inherited in three small Italian dog breeds in Italy. AB - OBJECTIVE: To describe the prevalence and the types of eye disorders that are known or presumed to be inherited (KP-HED) in three small Italian dog breeds. ANIMALS: Three small Italian dog breeds: Maltese, Bolognese, and Italian Greyhound. PROCEDURES: All dogs of the breeds selected for this prospective observational study that underwent a complete ophthalmic examination between 1994 and 2015 were included. General and proportional KP-HED prevalence with 95% confidence intervals were reported. RESULTS: Three hundred and six of 462 dogs were affected by at least one KP-HED (66.2%; 95% CI: 61.8%-70.4%). In the entire population, the five most common KP-HED were cataract (n = 122; rate on the total number of KP-HED: 31.4%), entropion (n = 56; 14.4%), keratoconjunctivitis sicca (n = 33; 8.5%), retinal dysplasia (n = 24; 6.2%), and persistent pupillary membrane (iris to iris) (n = 21; 5.4%). The most common KP-HED in each breed were cataracts in the Maltese (35.1%) and in the Bolognese (24.2%), and presentation of vitreous in the anterior chamber in the Italian Greyhound (46.7%). CONCLUSIONS: Clinicians should be aware of KP-HED that commonly affect three small Italian dog breeds. Breed standards should be reconsidered, and breeding programs should be directed at limiting such disorders. PMID- 29284194 TI - Chronic Calf Pain Caused by Fibroma-Induced Chronic Inflammation Around the Tibial and Peroneal Nerves that Was Misdiagnosed as Centralized Neuropathic Pain: A Case Report. AB - INTRODUCTION: The etiology of calf pain varies widely; therefore, it is difficult to diagnose and requires careful history taking and physical examination by primary care unit physicians. Because ultrasonography is easy to perform, cheap, and readily available to physicians during a routine consultation, it is the first choice of modality for the evaluation of calf pain. However, simple inflammation around the nerve should also be considered as a possible etiology. Here we describe a 35-year-old man with chronic pain in the right calf that was actually caused by fibroma-induced chronic inflammation around the tibial and peroneal nerves but misdiagnosed as centralized neuropathic pain. CASE REPORT: The patient presented with chronic pain and a tingling sensation in the right calf. He had a slowly growing tibial nerve neurilemmoma that was excised at 28 years of age; however, the pain and tingling sensation persisted. He visited several hospitals for 7 years and was misdiagnosed with peripheral nerve injury induced neuropathic pain. At 35 years of age, he visited our hospital for further evaluation. Ultrasonography revealed a mass in the popliteal region, which was excised and confirmed to be a fibroma via histopathological analysis. Severe inflammation was observed in the operative field. His symptoms finally ameliorated after this surgery. CONCLUSION: The findings from this case suggest that ultrasonography should be used as the primary modality for the evaluation of calf pain. Although the features of unresolved calf pain are similar to those of neuropathic pain, more curable etiologies should be considered. PMID- 29284195 TI - Extracellular matrix influence in Streptococcus mutans gene expression in a cariogenic biofilm. AB - Caries etiology is biofilm-diet-dependent. Biofilms are highly dynamic and structured microbial communities enmeshed in a three-dimensional extracellular matrix. The study evaluated the expression dynamics of Streptococcus mutans genes associated with exopolysaccharides (EPS) (gtfBCD, gbpB, dexA), lipoteichoic acids (LTA) (dltABCD, SMU_775c) and extracellular DNA (eDNA) (lytST, lrgAB, ccpA) during matrix development within a mixed-species biofilm of S. mutans, Actinomyces naeslundii and Streptococcus gordonii. Mixed-species biofilms using S. mutans strains UA159 or DeltagtfB formed on saliva-coated hydroxyapatite discs were submitted to a nutritional challenge (providing an abundance of sucrose and starch). Biofilms were removed at eight developmental stages for gene expression analysis by quantitative polymerase chain reaction. The pH of spent culture media remained acidic throughout the experimental periods, being lower after sucrose and starch exposure. All genes were expressed at all biofilm developmental phases. EPS- and LTA-associated genes had a similar expression profile for both biofilms, presenting lower levels of expression at 67, 91 and 115 hours and a peak of expression at 55 hours, but having distinct expression magnitudes, with lower values for DeltagtfB (eg, fold-difference of ~382 for gtfC and ~16 for dltB at 43 hours). The eDNA-associated genes presented different dynamics of expression between both strains. In UA159 biofilms lrgA and lrgB genes were highly expressed at 29 hours (which were ~13 and ~5.4 times vs DeltagtfB, respectively), whereas in DeltagtfB biofilms an inverse relationship between lytS and lrgA and lrgB expression was detected. Therefore, the deletion of gtfB influences dynamics and magnitude of expression of genes associated with matrix main components. PMID- 29284196 TI - Genome-wide survey and phylogenetic analysis of histone acetyltransferases and histone deacetylases of Plasmodium falciparum. AB - Malaria parasites can readily sense and adapt to environmental changes, thus making the control and eradication of this disease difficult. Molecular studies have unraveled a very tightly coordinated transcriptional machinery governed by complex regulatory mechanisms including chromatin modification and spatiotemporal compartmentalization. Histone modifying enzymes play key roles in the regulation of chromatin modification and gene expression, which are associated with cell cycle progression, antigenic variation and immune evasion. Here, we present a comprehensive review of the key regulators of the Plasmodium falciparum histone acetylome; histone acetyltransferases (HATs); and histone deacetylases (HDACs). We describe the genome-wide occurrence of HATs and HDACs in the P. falciparum genome and identify novel, as well as previously unclassified HATs. We re-confirm the presence of five known HDACs and identify, a novel putative HDAC. Interestingly, we identify several HATs and HDACs with unique and noncanonical domain combinations indicating their involvement in other associated functions. Moreover, the phylogenetic analyses of HATs and HDACs suggest that many of them are close to the prokaryotic systems and thus potential candidates for drug development. Our review deciphers the phylogeny of HATs and HDACs of the malaria parasite, investigates their role in drug-resistance generation, and highlights their potential as therapeutic targets. PMID- 29284198 TI - Signals from the south; humpback whales carry messages of Antarctic sea-ice ecosystem variability. AB - Southern hemisphere humpback whales (Megaptera novaeangliae) rely on summer prey abundance of Antarctic krill (Euphausia superba) to fuel one of the longest-known mammalian migrations on the planet. It is hypothesized that this species, already adapted to endure metabolic extremes, will be one of the first Antarctic consumers to show measurable physiological change in response to fluctuating prey availability in a changing climate; and as such, a powerful sentinel candidate for the Antarctic sea-ice ecosystem. Here, we targeted the sentinel parameters of humpback whale adiposity and diet, using novel, as well as established, chemical and biochemical markers, and assembled a time trend spanning 8 years. We show the synchronous, inter-annual oscillation of two measures of humpback whale adiposity with Southern Ocean environmental variables and climate indices. Furthermore, bulk stable isotope signatures provide clear indication of dietary compensation strategies, or a lower trophic level isotopic change, following years indicated as leaner years for the whales. The observed synchronicity of humpback whale adiposity and dietary markers, with climate patterns in the Southern Ocean, lends strength to the role of humpback whales as powerful Antarctic sea-ice ecosystem sentinels. The work carries significant potential to reform current ecosystem surveillance in the Antarctic region. PMID- 29284197 TI - The associations between psychotic experiences and substance use and substance use disorders: findings from the World Health Organization World Mental Health surveys. AB - BACKGROUND AND AIMS: Prior research has found bidirectional associations between psychotic experiences (PEs) and selected substance use disorders. We aimed to extend this research by examining the bidirectional association between PEs and various types of substance use (SU) and substance use disorders (SUDs), and the influence of antecedent mental disorders on these associations. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We used data from the World Health Organization World Mental Health surveys. A total of 30 902 adult respondents across 18 countries were assessed for (a) six types of life-time PEs, (b) a range of types of SU and DSM-IV SUDs and (c) mental disorders using the Composite International Diagnostic Interview. Discrete-time survival analyses based on retrospective age at-onset reports examined the bidirectional associations between PEs and SU/SUDs controlling for antecedent mental disorders. FINDINGS: After adjusting for demographics, comorbid SU/SUDs and antecedent mental disorders, those with prior alcohol use disorders [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2 2.0], extra-medical prescription drug use (OR = 1.5, 95% CI = 1.1-1.9), alcohol use (OR = 1.4, 95% CI = 1.1-1.7) and tobacco use (OR = 1.3, 95% CI = 1.0-1.8) had increased odds of subsequent first onset of PEs. In contrast, those with temporally prior PEs had increased odds of subsequent onset of tobacco use (OR = 1.5, 95% CI = 1.2-1.9), alcohol use (OR = 1.3, 95% CI = 1.1-1.6) or cannabis use (OR = 1.3, 95% CI = 1.0-1.5) as well as of all substance use disorders (ORs ranged between 1.4 and 1.5). There was a dose response relationship between both count and frequency of PEs and increased subsequent odds of selected SU/SUDs. CONCLUSIONS: Associations between psychotic experiences (PEs) and substance use/substance use disorders (SU/SUDs) are often bidirectional, but not all types of SU/SUDs are associated with PEs. These findings suggest that it is important to be aware of the presence of PEs within those with SUDs or at risk of SUDs, given the plausibility that they may each impact upon the other. PMID- 29284199 TI - Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin-mediated phosphoinositide 3-kinase/Akt/mammalian target of rapamycin. AB - Bone marrow mesenchymal stem cells (BMMSC) have been shown to be recruited to the tumor microenvironment and exert a tumor-promoting effect in a variety of cancers. However, the molecular mechanisms related to the tumor-promoting effect of BMMSC on head and neck cancer (HNC) are not clear. In this study, we investigated Periostin (POSTN) and its roles in the tumor-promoting effect of BMMSC on HNC. In vitro analysis of HNC cells cultured in BMMSC-conditioned media (MSC-CM) showed that MSC-CM significantly promoted cancer progression by enhancing cell proliferation, migration, epithelial-mesenchymal transformation (EMT), and altering expression of cell cycle regulatory proteins and inhibition of apoptosis. Moreover, MSC-CM promoted the expression of POSTN and POSTN promoted HNC progression through the activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. In a murine model of HNC, we found that BMMSC promoted tumor growth, invasion, metastasis and enhanced the expression of POSTN and EMT in tumor tissues. Clinical sample analysis further confirmed that the expression of POSTN and N-cadherin were correlated with pathological grade and lymph node metastasis of HNC. In conclusion, this study indicated that BMMSC promoted proliferation, invasion, survival, tumorigenicity and migration of head and neck cancer through POSTN mediated PI3K/Akt/mTOR activation. PMID- 29284200 TI - Betel and tobacco chewing habit and its relation to risk factors for periodontal disease. AB - OBJECTIVES: To comparatively assess periodontal status in patients who chew different products and patients who do not have this habit and to assess how this practice interacts with predisposing factors and risk indicators of disease. METHODS: Patients included in the dental care carried out in a rural community in India were considered for a cross-sectional study. The simplified oral hygiene index and the community periodontal index (CPI) were assessed. Furthermore, a validated survey with items concerning chewing habits was administered. Statistical analysis of the effects of age range, gender, chewing products and hygiene status on CPI was performed. RESULTS: In total, 1,023 patients met the inclusion criteria. The chewer patients (430) exhibited a significantly higher CPI than the non-chewers (593). The chewing habit increased the likelihood of a higher CPI by 6.76-fold, while excellent-good oral hygiene status decreased the probability of a higher CPI by approximately 45%. CPI did not differ significantly among chewers of different products. CONCLUSION: In the population studied, a chewing habit was associated with a worse periodontal status, and this association was not modified by gender and age as predisposing factors. Oral hygiene could decrease the effect of chewing habit on periodontal health. PMID- 29284201 TI - Australian wheat production expected to decrease by the late 21st century. AB - Climate change threatens global wheat production and food security, including the wheat industry in Australia. Many studies have examined the impacts of changes in local climate on wheat yield per hectare, but there has been no assessment of changes in land area available for production due to changing climate. It is also unclear how total wheat production would change under future climate when autonomous adaptation options are adopted. We applied species distribution models to investigate future changes in areas climatically suitable for growing wheat in Australia. A crop model was used to assess wheat yield per hectare in these areas. Our results show that there is an overall tendency for a decrease in the areas suitable for growing wheat and a decline in the yield of the northeast Australian wheat belt. This results in reduced national wheat production although future climate change may benefit South Australia and Victoria. These projected outcomes infer that similar wheat-growing regions of the globe might also experience decreases in wheat production. Some cropping adaptation measures increase wheat yield per hectare and provide significant mitigation of the negative effects of climate change on national wheat production by 2041-2060. However, any positive effects will be insufficient to prevent a likely decline in production under a high CO2 emission scenario by 2081-2100 due to increasing losses in suitable wheat-growing areas. Therefore, additional adaptation strategies along with investment in wheat production are needed to maintain Australian agricultural production and enhance global food security. This scenario analysis provides a foundation towards understanding changes in Australia's wheat cropping systems, which will assist in developing adaptation strategies to mitigate climate change impacts on global wheat production. PMID- 29284203 TI - Severe 5,10-methylenetetrahydrofolate reductase deficiency: a rare, treatable cause of complicated hereditary spastic paraplegia. AB - BACKGROUND AND PURPOSE: Juvenile- or adult-onset forms of severe 5,10 methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described. METHODS: Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies. RESULTS: Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 MUmol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by MTHFR direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features. CONCLUSIONS: Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders. PMID- 29284202 TI - Pembrolizumab in Asia-Pacific patients with advanced head and neck squamous cell carcinoma: Analyses from KEYNOTE-012. AB - KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (RECIST version 1.1), and ECOG performance status (PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co primary end-points were safety and overall response rate (RECIST version 1.1, central review). Secondary end-points included overall survival and response duration. Patients enrolled at any of the five centers throughout the Asia Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. The median age was 62 years, 65% of patients had ECOG PS 1, and 62% had received two or more prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment related adverse event of any grade, including two (8%) patients who experienced one or more events of grade 3 severity. No treatment-related deaths occurred. The overall response rate was 19% (95% confidence interval, 7%-39%). After a median follow-up of 12 months (range, 2-21 months), a median response duration was not reached (range, 6 to 17+ months); four of five responses lasted >=6 months. Median overall survival was 11.6 months (95% confidence interval, 4.7-17.7 months). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region. (Trial registration no. NCT01848834.). PMID- 29284204 TI - Rapid visual detection of Mycobacterium avium subsp. paratuberculosis by recombinase polymerase amplification combined with a lateral flow dipstick. AB - Paratuberculosis (Johne's disease) is a chronic debilitating disease of domestic and wild ruminants. However, widespread point-of-care testing is infrequent due to the lack of a robust method. The isothermal recombinase polymerase amplification (RPA) technique has applied for rapid diagnosis. Herein, RPA combined with a lateral flow dipstick (LFD) assay was developed to estimate DNA from Mycobacterium avium subsp. paratuberculosis. First, analytical specificity and sensitivity of the RPA-nfo primer and probe sets were assessed. The assay successfully detected M. paratuberculosis DNA in 30 min at 39 degrees C with a detection limit of up to eight copies per reaction, which was equivalent to that of the real-time quantitative polymerase chain reaction (qPCR) assay. The assay was specific, as it did not amplify genomes from five other Mycobacterium spp. or five pathogenic enteric bacteria. Six hundred-twelve clinical samples (320 fecal and 292 serum) were assessed by RPA-LFD, qPCR, and enzyme-linked immunosorbent assay, respectively. The RPA-LFD assay yielded 100% sensitivity, 97.63% specificity, and 98.44% concordance rate with the qPCR results. This is the first report utilizing an RPA-LFD assay to visualize and rapidly detect M. paratuberculosis. Our results show this assay should be a useful method for the diagnosis of paratuberculosis in resource-constrained settings. PMID- 29284206 TI - A two-component signal transduction system contributes to the virulence of Riemerella anatipestifer. AB - Similar to other studies of bacterial pathogens, current studies of the pathogenesis of Riemerella anatipestifer (RA) are focused mainly on in vitro culture conditions. To elucidate further the pathogenesis of RA in vivo, bacterial RNA was extracted from overnight tryptic soy broth cultures (in vitro) and from the blood of infected ducks (in vivo) for comparative RNA sequencing analysis. In total, 682 upregulated genes were identified in vivo. Among the upregulated genes, a signal transduction response regulator (ArsR) and a signal transduction histidine kinase (SthK) were predicted to be located on the same operon. A mutant was constructed by deletion of both of these genes. Duck infection tests showed that genes ArsR and SthK were related to the virulence of the pathogen in vivo. Differentially expressed genes identified by comparison of in vitro and in vivo conditions provided an insight into the physiological process of RA infection and provided an opportunity to identify additional virulence factors. PMID- 29284205 TI - Pathogenic and phylogenetic characteristics of non-O157 Shiga toxin-producing Escherichia coli isolates from retail meats in South Korea. AB - Herein, we report the pathogenic and phylogenetic characteristics of seven Shiga toxin (Stx)-producing Escherichia coli (STEC) isolates from 434 retail meats collected in Korea during 2006 to 2012. The experimental analyses revealed that all isolates (i) were identified as non-O157 STEC, including O91:H14 (3 isolates), O121:H10 (2 isolates), O91:H21 (1 isolate), and O18:H20 (1 isolate), (ii) carried diverse Stx subtype genes (stx1, stx2c, stx2e, or stx1 + stx2b) whose expression levels varied strain by strain, and (iii) lacked the locus of enterocyte effacement (LEE) pathogenicity island, a major virulence factor of STEC, but they possessed one or more alternative virulence genes encoding cytotoxins (Cdt and SubAB) and/or adhesins (Saa, Iha, and EcpA). Notably, a significant heterogeneity in glutamate-induced acid resistance was observed among the STEC isolates (p < 0.05). In addition, phylogenetic analyses demonstrated that all three STEC O91:H14 isolates were categorized into sequence type (ST) 33, of which two beef isolates were identical in their pulsotypes. Similar results were observed with two O121:H10 pork isolates (ST641; 88.2% similarity). Interestingly, 96.0% of the 100 human STEC isolates collected in Korea during 2003 to 2014 were serotyped as O91:H14, and the ST33 lineage was confirmed in approximately 72.2% (13/18 isolates) of human STEC O91:H14 isolates from diarrheal patients. PMID- 29284207 TI - Production of transgenic pigs using a pGFAP-CreERT2/EGFP LoxP inducible system for central nervous system disease models. AB - Transgenic (TG) pigs are important in biomedical research and are used in disease modeling, pharmaceutical toxicity testing, and regenerative medicine. In this study, we constructed two vector systems by using the promoter of the pig glial fibrillary acidic protein (pGFAP) gene, which is an astrocyte cell marker. We established donor TG fibroblasts with pGFAP-CreERT2/LCMV-EGFPLoxP and evaluated the effect of the transgenes on TG-somatic cell nuclear transfer (SCNT) embryo development. Cleavage rates were not significantly different between control and transgene-donor groups. Embryo transfer was performed thrice just before ovulation of the surrogate sows. One sow delivered 5 TG piglets at 115 days after pregnancy. Polymerase chain reaction (PCR) analysis with genomic DNA isolated from skin tissues of TG pigs revealed that all 5 TG pigs had the transgenes. EGFP expression in all organs tested was confirmed by immunofluorescence staining and PCR. Real-time PCR analysis showed that pGFAP promoter-driven Cre fused to the mutated human ligand-binding domain of the estrogen receptor (CreERT2) mRNA was highly expressed in the cerebrum. Semi-nested PCR analysis revealed that CreERT2 mediated recombination was induced in cerebrum and cerebellum but not in skin. Thus, we successfully generated a TG pig with a 4-hydroxytamoxifen (TM)-inducible pGFAP-CreERT2/EGFPLoxP recombination system via SCNT. PMID- 29284208 TI - Double filtration plasmapheresis in the treatment of hyperproteinemia in dogs affected by Leishmania infantum. AB - Three dogs were evaluated for severe hyperproteinemia and hyperglobulinemia secondary to Leishmania infantum. Double filtration plasmapheresis (DFPP) was performed in two dogs at days 1, 2, and 6 after presentation. The third dog received DFPP at days 1 and 3 after presentation and eleven hemodialysis treatments. Significant reduction in serum total protein (p < 0.0001), alpha-1 (p = 0.023), alpha-2 (p = 0.018), gamma globulins (p = 0.0105), and a significant increase in albumin/globulin ratio (p = 0.0018) were found. DFPP may be a promising therapeutic technique for rapid resolution of signs of hyperproteinemia in dogs affected by L. infantum. PMID- 29284209 TI - Calcium-sensing receptor-mediated L-tryptophan-induced secretion of cholecystokinin and glucose-dependent insulinotropic peptide in swine duodenum. AB - This study aimed to elucidate the effect of tryptophan (Trp) on gut hormone secretion as well as the roles of the calcium-sensing receptor (CaSR) and its downstream signaling pathway in gut hormone secretion by assessing swine duodenal perfusion in vitro. Swine duodenum was perfused with Krebs-Henseleit buffer as a basal solution. Various concentrations (0, 10, and 20 mM) of Trp were applied to investigate its effect on gut hormone secretion. A CaSR antagonist was used to detect the involvement of CaSR and its signal molecules. The 20 mM Trp concentration promoted the secretion of cholecystokinin (CCK) and glucose dependent insulinotropic peptide (GIP), elevated the mRNA level of CaSR, and upregulated the protein levels of CaSR, protein kinase C (PKC), and inositol trisphosphate receptor (IP3R). However, NPS 2143, an inhibitor of CaSR, attenuated the CCK and GIP release, reduced the mRNA level of CaSR, and decreased the protein levels of CaSR, PKC, and IP3R with 20 mM Trp perfusion. The results indicate that CCK and GIP secretion can be induced by Trp in swine duodenum in vitro, and the effect is mediated by CaSR and its downstream signal molecules PKC and IP3R. PMID- 29284210 TI - Genomic characterization and pathogenic study of two porcine reproductive and respiratory syndrome viruses with different virulence in Fujian, China. AB - Two strains of porcine reproductive and respiratory syndrome virus (PRRSV) were isolated in 2006 and 2016 and designated as FZ06A and FZ16A, respectively. Inoculation experiments showed that FZ06A caused 100% morbidity and 60% mortality, while FZ16A caused 100% morbidity without death. By using genomic sequence and phylogenetic analyses, close relationships between a Chinese highly pathogenic PRRSV strain and the FZ06A and FZ16A strains were observed. Based on the achieved results, multiple genomic variations in Nsp2, a unique N glycosylation site (N33->K33), and a K151 amino acid (AA) substitution for virulence in the GP5 of FZ16A were detected; except the 30 AA deletion in the Nsp2-coding region. Inoculation experiments were conducted and weaker virulence of FZ16A than FZ06A was observed. Based on our results, a 30 AA deletion in the Nsp2-coding region is an unreliable genomic indicator of a high virulence PRRSV strain. The Nsp2 and GP5 differences, in addition to the virulence difference between these two highly pathogenic PRRSV strains, have the potential to be used to establish a basis for further study of PRRSV virulence determinants and to provide data useful in the development of vaccines against this economically devastating disease. PMID- 29284211 TI - Ovary and vaginal epithelium dynamics during the estrous cycle in Dasyprocta prymnolopha Wagler, 1831: ultrasound and cytological examinations. AB - The objective of the present study was to monitor and characterize morphological alterations in ovaries of agouti (Dasyprocta prymnolopha), reared in captivity, by using abdominal ultrasonography. All animals underwent daily vaginal cytological examination to identify the current cycle phase. For each phase of the estrous cycle, ultrasound examinations were carried out to identify and describe the morphology of both ovaries. Topographic parameters in an ultrasound window were established to locate the ovaries. The agouti estrous cycle lasted an average of 29.94 +/- 6.77 days. During vaginal cytology examinations, all cell types were identified, and each phase of the estrous cycle was established by cell counts. No significant alterations were observed in the assessed ovarian morphometry measurements. In 75% of the animals examined, ovarian follicle presence was observed in the proestrus phase. PMID- 29284212 TI - Identification and characterization of atypical porcine pestivirus genomes in newborn piglets with congenital tremor in China. AB - Recently, a novel atypical porcine pestivirus (APPV) in pig was reported. In this study, two APPV strains, APPV-China/GZ01/2016 (GZ01) and APPV-China/GD-SD/2016 (GD-SD), were identified in two newborn piglet herds with congenital tremor from China. The open reading frame of the two strains shared an 83.5% nucleotide identity. Phylogenetically, the APPV strains were placed into two groups: GZ01 belonged to group I and GD-SD belonged to group II. A high viral load was detected in the cerebellum (quantification cycles < 26). Further studies should be carried out to thoroughly elucidate the development of congenital tremors caused by APPV. PMID- 29284213 TI - Pathologic and molecular characterization of Streptococcus dysgalactiae subsp. equisimilis infection in neonatal piglets. AB - Streptococcus dysgalactiae subspecies equisimilis (SDSE) is an emerging pathogen in animals and humans. Herein, we describe two clinical swine cases of SDSE infection presenting with lameness, neurological signs, or sudden death. Pathological examination indicated suppurative arthritis, encephalitis, and multifocal abscesses in kidney and heart. The beta-hemolytic colonies obtained from joint samples of each case were identified as SDSE. The two isolates had low minimum inhibitory concentrations for beta-lactams, and they presented the same virulence gene profile (slo-/sagA+/pSTKP8+). Molecular analysis by multilocus sequence typing identified the SDSE isolates from cases 1 and 2 as sequence types 315 and 252, respectively. PMID- 29284214 TI - Detection of hepatitis E virus genotypes 3 and 4 in pig farms in Korea. AB - Zoonotic transmission of hepatitis E virus (HEV) is mostly mediated by HEV-3 and HEV-4 genotypes, and domestic pigs are an important reservoir of these genotypes. A survey of 14 pig farms in Korea revealed HEV RNA in 30 of 148 (20.3%) fecal samples. HEV-3a and HEV-4c subtypes were identified in five pig farms (35.7%) and two pig farms (14.3%), respectively. Phylogenetic analysis indicated that the isolated HEV strains were closely related to previously reported zoonotic strains in Korea. The results of the genetic analysis partially explain the possible source of the zoonotic transmission of HEV to humans in Korea. PMID- 29284215 TI - Clinical assessment after human adipose stem cell transplantation into dogs. AB - Adipose tissue-derived stem cell (ASCs) are an attractive source of stem cells with therapeutic applicability in various fields for regenerating damaged tissues because of their stemness characteristics. However, little has reported on evaluating adverse responses caused by human ASC therapy. Therefore, in the present study, a clinical assessment after human ASC transplantation into dogs was undertaken. A total of 12 healthy male dogs were selected and divided into four groups: saline infusion, saline bolus, ASC infusion, and ASC bolus groups. Physical assessment and blood analysis were performed following ASC transplantation, and the concentrations of angiogenic factors, and pro- and anti inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). There were no adverse vital sign responses among the dogs. Blood analyses revealed no remarkable complete blood count or serum chemistry results. ELISA results for angiogenic and anti-inflammatory factors including matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and interleukin 10 (IL-10) were significantly higher in the two ASCs groups than in the controls. In conclusion, this study demonstrated that transplantation of human ASCs produced no adverse effects and could be used safely in dogs. In addition, human ASCs could be involved in modulating secretions of angiogenic factors including MMP9, VEGF, bFGF, and HGF and anti-inflammatory factor IL-10. PMID- 29284217 TI - Strengths, weaknesses, opportunities, and threats analysis of integrating the World Health Organization patient safety curriculum into undergraduate medical education in Pakistan: a qualitative case study. AB - PURPOSE: The purpose of this study was to conduct a strengths, weaknesses, opportunities, and threats (SWOT) analysis of integrating the World Health Organization (WHO) patient safety curriculum into undergraduate medical education in Pakistan. METHODS: A qualitative interpretive case study was conducted at Riphah International University, Islamabad, from October 2016 to June 2017. The study included 9 faculty members and 1 expert on patient safety. The interviews were audiotaped, and a thematic analysis of the transcripts was performed using NVivo software. RESULTS: Four themes were derived based on the need analysis model. The sub-themes derived from the collected data were arranged under the themes of strengths, weaknesses, opportunities, and threats, in accordance with the principles of SWOT analysis. The strengths identified were the need for a formal patient safety curriculum and its early integration into the undergraduate program. The weaknesses were faculty awareness and participation in development programs. The opportunities were an ongoing effort to develop an appropriate curriculum, to improve the current culture of healthcare, and to use the WHO curricular resource guide. The threats were attitudes towards patient safety in Pakistani culture, resistance to implementation from different levels, and the role of regulatory authorities. CONCLUSION: The theme of patient safety needs to be incorporated early into the formal medical education curriculum, with the main goals of striving to do no harm and seeing mistakes as opportunities to learn. Faculty development activities need to be organized, and faculty members should to be encouraged to participate in them. The lack of a patient safety culture was identified as the primary reason for resistance to this initiative at many levels. The WHO curriculum, amended according to local institutional culture, can be implemented appropriately with support from the corresponding regulatory bodies. PMID- 29284218 TI - Understanding Gastric Cancer Risk Factors: We Need to Close the Gap. PMID- 29284216 TI - Dembo polymerase chain reaction technique for detection of bovine abortion, diarrhea, and respiratory disease complex infectious agents in potential vectors and reservoirs. AB - Bovine abortion, diarrhea, and respiratory disease complexes, caused by infectious agents, result in high and significant economic losses for the cattle industry. These pathogens are likely transmitted by various vectors and reservoirs including insects, birds, and rodents. However, experimental data supporting this possibility are scarce. We collected 117 samples and screened them for 44 bovine abortive, diarrheal, and respiratory disease complex pathogens by using Dembo polymerase chain reaction (PCR), which is based on TaqMan real time PCR. Fifty-seven samples were positive for at least one pathogen, including bovine viral diarrhea virus, bovine enterovirus, Salmonella enterica ser. Dublin, Salmonella enterica ser. Typhimurium, and Neospora caninum; some samples were positive for multiple pathogens. Bovine viral diarrhea virus and bovine enterovirus were the most frequently detected pathogens, especially in flies, suggesting an important role of flies in the transmission of these viruses. Additionally, we detected the N. caninum genome from a cockroach sample for the first time. Our data suggest that insects (particularly flies), birds, and rodents are potential vectors and reservoirs of abortion, diarrhea, and respiratory infectious agents, and that they may transmit more than one pathogen at the same time. PMID- 29284219 TI - Crohn's Disease with Jejunal Involvement as a Predictor of Long-Term Clinical Outcomes. PMID- 29284220 TI - Can Umbilical Cord Mesenchymal Stem Cells Treatment Be a Hope for Patients with Refractory Crohn's Disease? PMID- 29284221 TI - Comparison of the AIMS65 Score with Other Risk Stratification Scores in Upper Variceal and Nonvariceal Gastrointestinal Bleeding. PMID- 29284222 TI - Primary and secondary prevention of breast cancer. AB - INTRODUCTION: Breast cancer is the most common cancer among women and is the second cancer frequently occurring worldwide of newly-diagnosed cancers. There is much evidence showing the influence of life style and environmental factors on the development of mammary gland cancer (high-fat diet, alcohol consumption, lack of physical exercise), the elimination of which (primary prevention) may contribute to a decrease in morbidity and mortality. Secondary prevention, comprising diagnostic tests (e.g. mammography, ultrasonography, magnetic resonance imaging, breast self-examination, as well as modern and more precise imaging methods) help the early detection of tumours or lesions predisposing to tumours. OBJECTIVE: The aim of this study paper is to review current knowledge and reports regarding primary and secondary prevention of breast cancer. STATE OF KNOWLEDGE: It is estimated that nearly 70% of malign tumours are caused by environmental factors, whereas in breast cancer this percentage reaches 90-95%. There are national programmes established in many countries to fight cancer, where both types of prevention are stressed as serving to decrease morbidity and mortality due to cancers. CONCLUSIONS: Cancer prevention is currently playing a key role in the fight against the disease. Behaviour modification, as well as greater awareness among women regarding breast cancer, may significantly contribute towards reducing the incidence of this cancer. Another important aspect is the number of women undergoing diagnostic tests, which still remains at an unsatisfactory level. PMID- 29284223 TI - Psychological consequences of IVF fertilization - Review of research. AB - INTRODUCTION AND OBJECTIVE: Due to the reported efficacy of in vitro fertilization (IVF) this method of dealing with infertility is increasing being used. Experiencing IVF can be a source of psychological and emotional difficulties for couples trying to have a child. A systematic review was performed to discuss IVF as a psychological issue that impacts on the functioning of individuals, couples and families. Ebsco, Science Direct and PsycARTICLES databases were searched using the keywords: IVF fertilization, IVF psychology, infertility, and IVF consequences, using published peer reviewed articles from 2006 onwards. Studies in the English and Polish languages, peer reviewed and investigating general IVF and infertility psychological issues were included. Data was collected by the authors between June 2015-January 2016. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Studies indicate that partners going through IVF may not have enough support from their closest social environments. It is argued that these unsupportive social interactions affect the well-being of couples, can hinder conception, and therefore are one of the reasons for attrition from IVF, the most effective assisted reproduction method. CONCLUSIONS: There is a need to conduct studies on the effect of supportive social interactions for the functioning of couples undergoing IVF. PMID- 29284224 TI - Application of dietetics in reproductive medicine. AB - In the light of up-to-date epidemiological data concerning the prevalence of infertility, and also considering the scale of the problem of obesity and proven cause-effect relationship between abnormal body weight and infertility, it is justifiable to undertake the task of systematization of the state of knowledge concerning nutritional correlates of infertility, in order to create a scientific basis for the formulation of the assumptions of a fertility diet. The study is an attempt to systematize the current state of knowledge concerning the importance of energy and structural (qualitative) aspects of nutrition in the prevention and treatment of infertility. PMID- 29284225 TI - Correlation between the single, high dose of ingested baclofen and clinical symptoms. AB - INTRODUCTION AND OBJECTIVES: Baclofen is a drug used mainly to treat muscle spasticity. Its overdose can lead to life-threatening clinical symptoms, including acute respiratory failure requiring mechanical ventilation. The aim of this study was to assess the prevalence of selected clinical symptoms associated with baclofen poisoning comparing to an ingested dose. MATERIAL AND METHODS: 60 cases of oral baclofen poisoning were analyzed. Gender, age distribution, and correlation between the dose of ingested baclofen were studied, as well as and following clinical parameters: degree of altered consciousness, heart rate, blood pressure, presence of acute respiratory failure, duration of mechanical ventilation, and presence of psychotic symptoms. RESULTS: The study found statistically significant correlations between dosage of ingested baclofen and presence of acute respiratory failure, as well as duration of mechanical ventilation. No statistically significant correlations were found between the dose of ingested baclofen and presence of hypertension, bradycardia, acute psychotic symptoms, or level of consciousness disturbance. However, it was found that patients who suffered from hypertension, bradycardia, and altered mental status ingested a larger dose of baclofen. CONCLUSIONS: There is a statistically significant correlation between the dose of ingested baclofen and the presence of acute respiratory failure, and duration of mechanical ventilation. Patients who have taken a single dose of baclofen of 200 mg, or higher, should be managed in centres able to provide continuous monitoring of life functions. Those with a higher level of a single dose of baclofen ingestion (>500 mg), should be hospitalized in a Toxicology Unit or Intensive Care Unit able to provide airway support and mechanical ventilation. PMID- 29284226 TI - Acrylamide in food products - eating habits and consumer awareness among Medical School students. AB - INTRODUCTION: Acrylamide is formed in several foods during high-temperature processing. In view of reports written about the neurotoxic, genotoxic and carcinogenic effects of acrylamide, it was considered that the presence of this substance in food products might pose a risk for human health. Currently, according to EU Commission recommendations, the content of acrylamide in food should be monitored. OBJECTIVE: The aim of this work was to analyze the food preferences of youth and students from medical schools in Radom, central-eastern Poland, as the most frequent precipitantsas in the field of food products that may be a significant source of acrylamide in the diet. Furthermore, an attempt was made to determine the level of knowledge of the population in the field of acrylamide. MATERIAL AND METHODS: The research was conducted by questionnaire. The study was based on the answers of 227 respondents. The survey was carried out by direct contact with an interviewer from February - June 2012. RESULTS: Analysis of the study population shows that women consume more coffee than men. In addition, adults over 25 years old consumed the largest quantity of coffee; it can therefore be assumed that it is a significant source of acrylamide in their bodies. However, even young people under 17 declared that they consume coffee every day (20%). CONCLUSIONS: Due to the adverse effects of this compound it is important to reduce the level of acrylamide in food products. A few people in the population (7%) had heard of acrylamide previously, but none of them had any knowledge of its occurrence and formation. It is necessary to take strong action to change attitudes towards acrylamide and attempt to introduce ways to reduce this compound in the diet, for example, by appropriate selection of products in the daily diet and appropriate means of thermal preparation of products at home. PMID- 29284227 TI - Overweight and obesity vs. simple carbohydrates consumption by elderly people suffering from diseases of the cardiovascular system. AB - INTRODUCTION: Overweight and obesity belong to the alarming and constantly increasing problems of the 21st century among all age groups. One of the major factors enhancing these problems are simple carbohydrates commonly found in popular sweet drinks. OBJECTIVE: The aim of the study was to estimate the nutritional patterns of elderly people with diagnosed cardiovascular system diseases, and analysis of the relationship between consumption of simple carbohydrates and prevalence of overweight and obesity. MATERIAL AND METHODS: From 233 individuals hospitalized in the Clinic of Cardiology and Hypertension in Krakow, Poland, a group of 128 elderly people was selected (66 women and 62 men). Actual food consumption for each individual was assessed using a 24-hour nutrition recall. BMI values was calculated for assessment of nutritional status. Statistical analysis was performed on two groups: one with BMI <25kg/m2 and other with BMI>=25kg/m2. RESULTS: Overweight was stated among 33.8% of women and 50% of men, obesity among 27.7% of women and 17.7% of men. Results indicated that consumption of products rich in sucrose was associated with overweight and obesity. People with overweight and obesity statistically more often ate sweet products comparing to those with proper weight: 46.2 g vs 33.8g. The growing world-wide epidemic of overweight and obesity is one of the main priorities of preventive medicine remains changing eating patterns As observed in this study, one additional spoon of sugar consumed daily increases the risk of being overweight or obese by about 14%. CONCLUSIONS: Overweight and obesity was found among 60% of the examined elderly people. Correlation was found between rise in risk of obesity or overweight by about 14% with each additional spoon of sugar (5g) eaten every day. PMID- 29284228 TI - Assessment of dietary habits and nutritional status of depressive patients, depending on place of residence. AB - INTRODUCTION AND OBJECTIVES: An increased incidence of depressive disorders observed in recent years in the Polish and world population is a serious health problem. The aim of the study was to compare dietary habits and nutritional status of patients with recurrent depressive disorders, depending on their place of residence. Their impact on selected metabolic parameters was also considered. MATERIAL AND METHODS: The study group comprised 96 women and 84 men reporting to the Outpatient Mental Health Clinic at the Department of Psychiatry, Medical University of Bialystok in north-eastern Poland. The average age of the women was 46.7+/-11.7 years, and of men 47.0+/-11.3 years. In the quantitative assessmentof diets, 24-hour food recall interviews were conducted. Assessment of the nutritional status of the respondents consisted of anthropometric measurements, body composition analysis and biochemical parameters. RESULTS: It was show that the diets of female urban inhabitants were characterized by a significantly lower energy value and total fat content, compared to their rural counterparts. The food rations of men living in the city had a significantly higher energy value, protein content and total FAT, compared to rural residents. It was also noted that urban residents of both genders were characterized by a lower percentage of body fat, both visceral and subcutaneous (women), and a higher water content than rural residents. CONCLUSIONS: The study showed dietary errors in all compared groups, regardless of place of residence, which was reflected in the nutritional status of the respondents. The results also indicated that during the declared change in dietary habits, the treatment of depressive patients should include dietary instructions in order to ensure an optimum supply of nutrients. PMID- 29284229 TI - Iron status in obese women. AB - INTRODUCTION AND OBJECTIVE: A decreased concentration of iron, and consecutively haemoglobin, ferritin and decreased level of saturated transferrin, were observed in obese individuals more often than in healthy subjects. The purpose of this study was to determine whether iron, ferritin, transferrin saturation are significantly diminished in obese female patients compared to non-obese counterparts, and whether excess adiposity and inflammation were associated with depleted iron. MATERIAL AND METHODS: Female patients (n=48) diagnosed with obesity (BMI > 30 kg/m2), aged 18-40 were accepted for the study. A control group (n=30) encompassed normal weight women, aged 18-30. All obese women obtained an individually adjusted dietary plan with an energy content of 1,500 kcal. Blood glucose, insulin, lipids, ferritin, TIBC and iron concentrations were assayed in serum twice, initially and after 8 weeks of dieting. RESULTS: The obese women at the initial evaluation, in comparison to non-obese control women, were characterized by a significantly lower mean red blood cell volume (MCV; 84.2+/-12.4 vs. 91.3+/-9.3 fL; p<0.0001), serum iron level (92.6+/-42.4 vs. 119.8+/-44.0 MUg/dL; p<0.01), and transferrin saturation (TSAT; 25.9+/-12.7 vs. 38.8+/-15.7%; p<0.01), but by higher plasma level of the C-reactive protein (CRP; 7.0+/-6.7 vs. 1.2+/-1.3 mg/L; p<0.01). The obese women after 8 weeks of diet decreased their mean total body weight from 104.1+/-21.3 to 99.2+/-20.7 kg (p<0.0001). CRP level decreased slightly but significantly from 6.9+/-7.1 to 6.2+/-7.5 (p<0.05). CONCLUSIONS: Obese women exhibit an increased level of CRP which may affect iron homeostasis. Weight loss leads to decrease in the CRP level, but it does not change haematologic parameters in the period of 8 weeks. PMID- 29284230 TI - New directions in cervical cancer prophylaxis worldwide and in Poland - Case study of the Polish rural female population. AB - INTRODUCTION: Cervical cancer is one of the most frequent malignant neoplasms in females. Such neoplasms can be almost completely eliminated by means of adequate primary and secondary prophylaxis. The most developed countries focus their attention on the improvement of prophylaxis systems, test quality, and efficacy improvement, as well as on the expansion of the primary prophylaxis. In Poland, the discussions focus on the improvement of the malfunctioning population programme. OBJECTIVE: Drawing on recent research findings, the article presents current Polish and global recommendations with regard to screening tests for cervical cancer. The results of the Population Programme of Prophylaxis and Early Detection of Cervical Cancer are discussed in the context of current trends of healthy behaviour among women inhabiting rural areas. DESCRIPTION OF THE STATE OF KNOWLEDGE: In the future, it will be relevant to increase the number of human papillary virus (HPV) tests as part of the prophylaxis programme, especially among the high risk patient group. In particular, there is a necessity to increase the number of vaccinations among young women, especially before the beginning of their sexual activity, as well as to establish new strategies of secondary prophylaxis in this group. At present, women who had been vaccinated should undergo routine screening. In Poland, the report based on SIMP registry (IT System of Prophylaxis Monitoring), shows that only 27% of the 3.3 million of invited women participated in the cytology tests. The data analysis shows that women living in rural areas more often respond and participate in the tests, compared to women living in the cities (39.3% vs. 16.8%). PMID- 29284231 TI - Assessment of the influence of jogging on the shape of female foot arches. AB - INTRODUCTION: Both walking and its faster, running, consist of cyclical subsequent phases of swing and support; however, they differ in their time proportions as well as magnitude of acting forces. There is a lack of studies concerning the long-term consequences of repeated jogging cycles on the function of feet and, above all, on their permanent impact on the shape of foot arches. OBJECTIVES: The objective of this study was to answer the question whether regular jogging changes the shape of the transverse and medial longitudinal arches of the feet. MATERIAL AND METHODS: The research material consisted of 96 women with an average age of 26.57, and included 50 actively jogging women, and 46 of non-joggers. The study was performed with the use of EMED-SF force platform. The plantar surface of the foot was divided into 10 regions according to Cavanagh, for which peak pressure and contact time were established. Two indicators were defined: metatarsal bone pressure distribution pattern acc. to Kantali, and longitudinal arch index acc. to Cavanagh. RESULTS: The data obtained revealed more frequent occurrence of the greatest pressure under the centrally located metatarsal heads (lack of functional foot transverse arch) among the female joggers, compared with the non-joggers. Moreover, the findings indicate the higher frequency of medial longitudinal foot arch flattening among female runners, with a great deal of consistency between both feet, whereas results for the control group show asymmetrical medial arch shapes with right foot propensity to normal arch shape and left foot tendency for excessive arch. CONCLUSIONS: The observed differences in feet arch shapes between female joggers and non-joggers indicate the influence of jogging on feet functional adaptations. PMID- 29284232 TI - Chromium in urothelial carcinoma of the bladder. AB - INTRODUCTION AND OBJECTIVES: Many epidemiological and experimental studies report a strong role of chemical carcinogens in the etiology of bladder cancer. However, the involvement of heavy metals in tumourigenesis of urothelial carcinoma of the bladder has been poorly investigated. Therefore, the aim of this study was to examine the relationship between chromium (Cr) and bladder cancer. MATERIAL AND METHODS: Chromium concentration in two 36-sample series of bladder cancer tissue and sera from patients with this neoplasm were matched with those of a control group. The amount of trace elements in every tissue sample was determined using atomic absorption spectrometry. This was correlated with tumour stage. RESULTS: While the median chromium concentration levels reached statistically higher values in the bladder cancer tissue, compared with the non-cancer tissue (99.632ng/g and 33.144ng/g, respectively; p<0.001), the median Cr levels in the sera of the patients with this carcinoma showed no statistical difference when compared to those of the control group (0.511MUg/l and 0.710MUg/l, respectively; p=0.408). The median levels of Cr in the bladder tissue, depending on the stage of the tumour, compared with the tissue without the neoplasm, observed the same relationship for both non-muscle invasive and muscle-invasive tumours (p<0.001 and p<0.01, respectively). CONCLUSIONS: This study shows that patients with urothelial carcinoma of the bladder had higher tissue Cr levels than people without tumour, while no difference was found in the Cr serum levels between the two groups of patients under investigation. PMID- 29284233 TI - Legal grounds for 'extending the scope or type of procedure'. AB - INTRODUCTION: The development of patient rights and increasing number of lawsuits based on medical malpractice make medical doctors constantly improve knowledge regarding the acceptability of changing the scope of operation. This is particularly important when patients have expressed their refusal to changing the scope and type of procedure (ESTP) or no informed consent (IC) has been obtained from the patient prior to the procedure. MATERIAL AND METHODS: The method of study comprised content analysis of existing legislation. The current jurisprudence and doctrine were confronted with existing regulations. An algorithm of correct formal procedures was elaborated. RESULTS: The doctor has right to realize ESTP when the patient has not given the consent to it or the refusal expressed by him was not fully conscious. Healthcare providers are absolutely prohibited from realizing ESTP when patient objected to any changes being thoroughly informed by the physician prior to the operation. When patient refuses possible ESTP, the doctor has the right to withdraw from performing surgery but should inform the patient about other places, where a similar procedure can be provided. PMID- 29284234 TI - Chemometric evaluation of concentrations of trace elements in intervertebral disc tissue in patient with degenerative disc disease. AB - BACKGROUND: The work is designed to uncover the pattern of mutual relation among trace elements and epidemiological data in the degenerated intervertebral disk tissue in humans. Hitherto the reason of the degenerative process is not fully understood. Trace elements are the basic components of the biological compound related both its metabolism as well as environmental exposure. The relation pattern among elements occurs gives new perspective in solving the cause of the disease. MATERIAL AND METHODS: We have analysed trace elements content in the 30 intervertebral disc from 22 patients with degenerative disc disease. The concentrations of Al, Cu, Cd, Mo, Ni and Pb were determined with Atomic Absorption Spectrometry. To analyse the multidimentional relation between trace element concentration and epidemiological data the chemometric analysis was applied. RESULTS: The similarity have been shown in occurrence of following pairs: Cd-Mo as well as Mg-Zn. The second pair was correlated with Pb concentration. Pb levels are observed to be competitive to Cu concentration. Cd concentration was related to Zn and Mg deficiency. No single but rather cluster of epidemiological data show observable influence on the TE tissue variance. Zn and Cu was related to the male sex. Operation with orthopedic implants were related to combined Al, Mo and Zn concentration. CONCLUSIONS: This is the first chemometric analysis of trace elements in disk tissue. It shows multidimentional relations that are missed by the classical statistic. The analysis shows significant relation. The nature of the relations is the basis for further metabolic and environmental research. PMID- 29284235 TI - Uncompleted polymerization and cytotoxicity of dental restorative materials as potential health risk factors. AB - INTRODUCTION: Composite materials used in dentistry indicate adverse biological effects in laboratory conditions. One reason for this activity is incomplete conversion of their polymer matrix, favoring chemical instability and release of biologically harmful components to the external environment. AIM: The aim of the study was to assess the degree of conversion of restorative materials commonly available on the European market and to examine the cytotoxic effects of their eluates in vitro. MATERIAL AND METHODS: Using the Fournier transform infrared spectroscopy (FTIR) technique of analysis, the degree of polymer matrix conversion of 6 restorative materials was examined: Gradia Direct, Arkon, Filtek Z550, Herculite XRV, Tetric Evo Ceram, Charisma, polymerized with LED light. In order to assess the cytotoxicity of eluates of the studied materials obtained after 1 hour , 24 hours and 7 days, the MTT assay was used in cultured 3T3 cells. The results were statistically analyzed at significance level of p=0.05. RESULTS: The conversion degree of the assessed polymers ranged from 31.56% for Tetric Evo Ceram to 75.84% for Arcon. The strongest (p=0.05) cytotoxic effect was demonstrated after 7-day observation of Tetric Evo Ceram eluates, reducing the metabolic activity of cells down to 56%. A positive correlation (r(x, y) = 0.62) between the degree of conversion of composite materials and cytotoxic effects of their eluates on cell cultures was confirmed. CONCLUSIONS: 1. Restorative dental materials are chemically unstable in the conditions of the present study. 2. Polymer-based restorative dental materials available on the European market demonstrate cytotoxic properties constituting a potential threat to the patients' health. PMID- 29284236 TI - Attitudes of women after the age of 50 towards preventive screening. AB - INTRODUCTION: Prevention is one of the major branches of the health sector. The National Health Programme encompasses main risk factors, elimination of which may lead to a reduced incidence of illnesses in the society. At the same time, the criteria of selecting people eligible for preventive screening are established according to risk groups determined by sex, as well as age in the population of women. The perimenopausal and menopausal period contributes to occurrence of numerous systemic diseases and to an increased risk of illnesses, especially cancers. OBJECTIVE: The objective of the research was to evaluate the performance of preventive screening tests of women after 50 aimed at early detection of cervical and breast cancer. Furthermore, the research estimated frequency of pathological lesions detected and regularity of their monitoring. MATERIALS AND METHODS: The research covered 150 women after 50 years of age. The database was statistically examined with STATISTICA software. RESULTS: A low percentage of the respondents, in comparison to the risk increasing with age, had a Pap test (61.3%) and mammography (51.3%) in the last two years. In the case of women whose latest Pap test or mammography showed abnormalities and was the basis for diagnosing pathological lesions, 69.2% of them were under regular medical supervision if abnormalities were identified by a Pap test and 68.7% if lesions were detected in breast structure. CONCLUSIONS: In the examined group we observed a small percentage of women undergo Pap tests and mammography. Furthermore, medical recommendations regarding early detection of cancers are frequently ignored and disregarded by patients. PMID- 29284237 TI - Effect of 3-year education in the Main Fire Service School on the fitness level of students. AB - INTRODUCTION AND OBJECTIVE: The aim of the study was to determine changes in the fitness level among students of the Main Fire Service School during 3-year's education. MATERIAL AND METHODS: A total of 75 male and 5 female students took part in the study. Fitness level measurements were carried out before beginning the studies (Measurement 0) and after the 1st, 2nd and 3rd years at the school (Measurement 1, 2, 3). The following tests were performed to estimate level of physical fitness for men: pull-ups on a bar, a 50 m sprint and 1,000 m run, and for women: sit-ups, medical ball (2 kg) throw from above the head and a 4 x10 m shuttle run. RESULTS: General fitness level (average number of points from 3 attempts) of the male and female students improved. Improvement of fitness level between Measurement 0 (male students 60.3p.+/-7.58; female students 61.60p.+/ 3.08), and Measurements 1, 2, 3 (men 64.59p.+/-6.87; 64.41p.+/-7.17; 64.03p.+/ 7.65 and women 68.40p.+/-1.99; 66.67p.+/-2.36; 68.87+/-1.87 respectively), was found. The same relationship was found while analysing results of individual competitions. Only speed endurance (anaerobic-aerobic) assessed during Measurement 0 at 64.03p.+/-10.23, decreased after the 1st year at the school (Measurement 1 - 59.29p.+/-14.14) and remained on the same level during Measurements 2 and 3 (60.25p.+/-11.20 and 58.56p. +/-12.80, respectively). CONCLUSIONS: Speed endurance (anaerobic-aerobic) is a capability which decreased among the students in the subsequent years. Because this capability highly correlates with activities that a fire-fighter will perform during rescue operations, it should be treated as a matter of priority during physical education classes in the Main Fire Service School. PMID- 29284238 TI - Adherence to physical activity guidelines and functional fitness of elderly women, using objective measurement. AB - INTRODUCTION AND OBJECTIVE: Physical activity is an important factor in maintaining the health and functional fitness of elderly people. The aim of the study was to determine the number of senior women meeting the physical activity guidelines, and their level of functional fitness in comparison to women who are not sufficiently physically active. MATERIAL AND METHODS: The study involved 61 women, aged 60-75. Physical activity was monitored on seven consecutive days of the week, using a triaxial accelerometer ActiGraph GT3X. Results of the assessment of physical activity were verified against the Global Recommendations of Physical Activity for Health. The Senior Fitness Test (Fullerton Test) was used to evaluate functional fitness. RESULTS: In the studied group, 36.1% achieved the recommended level of physical activity. All those examined mainly undertook physical activity of low intensity. Vigorous physical activity during the week was noted in only 6 seniors. Women who met the recommendations of physical activity achieved significantly better results in test trials, e.g. Chair Stands, Up and Go, Six Minute Step Test. CONCLUSIONS: Adherence to physical activity guidelines was associated with better functional fitness of older women. However, less than half of the examined seniors met the Global Recommendations on Physical Activity for Health. PMID- 29284239 TI - The potential impact of the hypovitaminosis D on metabolic complications in obese adolescents - Preliminary results. AB - INTRODUCTION AND OBJECTIVE: Vitamin D deficiency is common in obesity; however, its contribution in the development of metabolic complications remains uncertain. The aim of the study was to examine the relationships between vitamin D status and metabolic complications. MATERIAL AND METHODS: The results of blood pressure measurements, biochemical tests and ultrasound of the liver were compared in both groups. The study was conducted at the Children's University Hospital in Krakow, Poland. 30 obese adolescents (mean 13.23y.o.); 18 with 25OHD levels <20ng/mL, 12 with 25OHD>20 ng/mL. RESULTS: The vitamin D deficient group presented with significantly higher values of the diastolic blood pressure (125.9vs.115mmHg), uric acid level (384.7vs.301.5umol/L) and lower phosphorus level (1.4vs.1.65mmol/L), higher prevalence of arterial hypertension (44vs.8.3%), and liver steatosis (25vs.8.3%); lower, but not significantly, levels of fibroblast growth factor 23 and fibroblast growth factor 19. CONCLUSIONS: Hypovitaminosis D in obese adolescents is associated with higher prevalence of arterial hypertension, liver steatosis, elevated serum uric acid and low phosphorus levels. The potential contribution of the fibroblast growth factor 23 and fibroblast growth factor 19 in these complications development needs further investigation. PMID- 29284240 TI - Measuring physical activity during pregnancy - Cultural adaptation of the Pregnancy Physical Activity Questionnaire (PPAQ) and assessment of its reliability in Polish conditions. AB - INTRODUCTION AND OBJECTIVE: The assessment of physical activity during pregnancy is crucial in perinatal care and it is an important research topic. Unfortunately, in Poland there is a lack of one commonly accepted questionnaire of physical activity during pregnancy. The aim of this study was to adapt the Pregnancy Physical Activity Questionnaire (PPAQ) to Polish conditions and assess the reliability of its Polish version (PPAQ-PL). MATERIAL AND METHODS: The PPAQ was translated from English into Polish and its reliability tested. 64 correctly completed (twice, one week apart) questionnaires were qualified for analysis. Test-retest reliability was assessed using Intraclass Correlation Coefficient (ICC). RESULTS: As a result of the adaptation and psychometric assessment, in the Polish version of the questionnaire the number of questions was reduced from 36 to 35 by removing the question concerning 'mowing lawn while on a riding mower'. The ICC value for total activity was 0.75, which confirms a substantial level of reliability. The ICC values for subscales of intensity ranged from 0.53 (light) - 0.86 (vigorous). For subscales of type, ICC values ranged from 0.59 (transportation) - 0.89 (household/caregiving). CONCLUSIONS: The PPAQ-PL can be accepted as a reliable tool for the assessing physical activity of pregnant women in Poland. Information obtained using the questionnaire might be helpful in monitoring health behaviours, preventing obesity, as well as designing and promoting physical activity programmes for pregnant women. PMID- 29284241 TI - Psychosocial determinants of disease acceptance in selected mental disorders. AB - INTRODUCTION AND OBJECTIVE: Every mental disorder may cause a number of negative consequences in the personal lives of the patients and their families as well as in their social relations. Acceptance of the disease is a crucial factor in the process of coping with the problems resulting from it. Acceptance of the disease may significantly influence the reduction of negative emotional reactions it causes. Consequently, it may contribute to better adaptation of the patients and hence may facilitate the process of recovery. The study attempts to define the socio-psychological conditioning of the degree of disease acceptance among patients treated for psychical disorders. MATERIAL AND METHODS: Opinion surveys were carried out in 2013 among a group of 240 patients treated in Mental Health Clinic in Chelm, eastern Poland. The study applied Acceptance Illness Scale - AIS B. Felton, T. A. Revenson, G.A. Hinrichsen, adapted in Poland by Z. Juczynski, as well as a socio-demographic questionnaire. RESULTS: The analysis of the obtained results revealed a similar level of acceptance of such diseases as anxiety disorders (24.41+/-8.52), depression (22.80+/-7.51) and personality disorders (23.89+/-7.89). The medical records of all patients fitted among the low average. CONCLUSIONS: The greatest problem in the researched group related to the social consequences of the psychical disorders. Those questioned were afraid of the negative reactions of others and of being a burden to their families. The level of acceptance was not correlated with independent variables (age, gender, education, place of residence, general well-being). PMID- 29284242 TI - Lay beliefs on Polish oncology in the evaluation of healthy individuals. AB - INTRODUCTION: Poland is among the countries which reported the highest rates of mortality from cancer. The health behaviours of people are influenced, among other things, by their beliefs about cancer, but their evaluation of oncological institutions and specialists seems also to be of great importance. Objectives. 1. How the respondents evaluate Polish oncology: a) the conditions of treatment in oncology hospitals, b) access to oncological medical services, c) the competence of oncologists. 2. What are the socio-cultural factors of the assessment of Polish oncology? 3. What is the influence of the grade level of the assessment of Polish oncology on the degree of fear and the knowledge about cancer? MATERIAL AND METHODS: The study was carried out with a sample of 910 adult residents of Wroclaw in south-west Poland. Quota sampling was used. An interview questionnaire was used as the method. RESULTS: Analysis of the data showed a negative image of Polish oncology, according to the study participants: dissatisfaction with both treatment conditions and with access to medical services. Assessment of Polish oncology depends primarily on education, age and economic situation, as well as 'family history of cancer', and attitude towards doctors. The lower the rating of Polish oncology, the lower the medical knowledge, and the higher the level of fear of cancer. CONCLUSIONS: Negative assessment of Polish oncology perpetuates the fear of cancer in society. There is a need for constant improvement of the quality of medical oncology services, for building public trust in physicians, to fight inequalities in health, and to take into account the lay perspectives in developing strategies to combat cancer. PMID- 29284243 TI - Lower extremity and spine pain in cyclists. AB - INTRODUCTION: The number of cyclists increases each year. Some people treat cycling as a passion and practice it at every possible occasion, while for others it is a mean of transport or a form of relaxation at the weekend. However, very few people realize that cycling can also have a negative impact on their health. OBJECTIVE: To assess the prevalence of lower extremity and spine pain in cyclists, and evaluate the influence of various factors causing it. MATERIAL AND METHODS: The study was performed on 167 subjects during amateur cycling competitions in the Greater Poland and Kuyavian-Pomeranian Provinces. A specially prepared questionnaire was used in the study. The questions related to the pain caused by cycling, the character and the localization of the pain, and the presence of warm-up and stretching. RESULTS: Knee pain was reported in 40% of the study subjects (mostly anterior pain - 26%). Spine pain was reported in 41% of the studied athletes, where 26% was related with the lumbar spine. Variables, such as age, weight, age, BMI, training experience and number of hours devoted to training per week had no influence on the incidence and the localization of leg pain, but it had influence in the case of spine pain. Stretching after cycling was the factor which significantly distinguished the studied groups with regard to the incidence of knee pain. CONCLUSIONS: The most common type of leg pain was knee pain (anterior knee pain) whereas spine pain was most commonly reported in the lumbar spine. Statistical analysis showed that spine pain is more often reported by people who are older, have higher weight, and people who spend more time training per week. Warm-up and stretching after cycling are recommended to cyclists who experience pain. PMID- 29284244 TI - Melatonin reverses the enhanced oxidative damage to membrane lipids and improves skin biophysical characteristics in former-smokers - A study in postmenopausal women. AB - INTRODUCTION AND OBJECTIVE: Protective antioxidative effects of melatonin have been repeatedly documented in experimental and clinical studies. One of the most spectacular exogenous prooxidative agents is cigarette smoking. The aim of the study was to evaluate the level of oxidative damage to membrane lipids (lipid peroxidation; LPO) in blood serum, and in epidermis exfoliated during microdermabrasion collected from former-smokers who were treated with melatonin. MATERIAL AND METHODS: The study was performed in postmenopausal women. Ninety (90) female volunteers, aged 46-67 years, were enrolled. Two major groups, i.e. never-smokers (n=44) and former-smokers (n=46), were divided into: Control, melatonin topical skin application, Restructurer (containing antioxidants) topical skin application, and melatonin oral treatment. Microdermabrasion was performed at point '0', after 2 weeks, and after 4 weeks of treatment. The following parameters were measured: LPO in blood serum, LPO in epidermis exfoliated during microdermabrasion, and skin biophysical characteristics, such as sebum, moisture, elasticity, and pigmentation. Malondialdehyde+4 hydroxyalkenals level (LPO index) was measured spectrophotometrically. RESULTS: Melatonin oral treatment significantly reversed the increased serum LPO level in former-smokers already after 2 weeks of treatment. In a univariate regression model, LPO blood level constituted the only independent factor negatively associated with melatonin oral treatment. After 4 weeks of treatment, melatonin given orally increased skin sebum, moisture and elasticity levels, and melatonin applied topically increased sebum level. CONCLUSIONS: Exogenous melatonin reverses the enhanced oxidative damage to membrane lipids and improves skin biophysical characteristics in former-smokers. PMID- 29284245 TI - Concentrations of selected toxic elements in ewe living near an environmentally loaded area of eastern part of Slovakia. AB - INTRODUCTION AND OBJECTIVE: Research focused on the monitoring of selected heavy metals in ewes' blood. Concentrations of selected toxic elements, lead, cadmium and zinc, in ewes living near an environmentally-loaded area, concerned 15 ewes (aged 3-4 years) in good physical condition, during the spring of 2014 and 2015 in the eastern part of Slovakia. The aim of the research was to determine the concentration of selected heavy metals and state the correlations of selected heavy metals in ewes' blood. MATERIAL AND METHODS: Within the period of 2 years, 15 ewe were evaluated. Ewes' blood samples were collected twice during the spring season from a farm located in area Spis, eastern Slovakia, and then analysed for heavy metal contents. In the area under investigation, contamination with heavy metals was assumed as a result of intensive agricultural development and former mining activities. The level of selected heavy metals in the experimental group of animal blood was determined using an optical spectrophotometry. RESULTS: Statistical analyses were carried out using the Statistica programme. The significant differences between means were calculated by the statistical method of the non-parametric Mann-Whitney's U test. The statistical test experimental group of ewes in 2014 and 2015 confirmed the presence of selected heavy metals in ewes. The measured values of Cd (P=0.0003), Pb (P=0.0200) and Zn (P=0.0018) showed significant differences when comparing the years 2014 and 2015. CONCLUSIONS: The obtained and analysed blood samples confirmed the presence of selected heavy metals in ewes from area of Spis in eastern Slovakia, which belongs the sub-region or is among the localities environmentally burdened. The conclusions are centred on the population's interest and concern for the environment, as well as on the preoccupation with factors that affect the satisfaction of basic needs, the local agricultural development and former mining activities. PMID- 29284246 TI - Changes in leptospirosis etiology in animals and humans. AB - INTRODUCTION: Leptospirosis is endemic in Ternopil region. In Ukraine, the disease is registered in almost all regions, including the Ternopil region. The aim of the research is to study the regularities of epidemic and epizootic processes of leptospirosis, and the circulation of its pathogens among different sources (small mammals, animals) and humans. MATERIAL AND METHODS: Etiologic spectrum of leptospirosis registered in Ternopil region in 1972-2016 among small mammals, farm animals and sick people was studied. RESULTS: Due to the analysis of pathogens circulation among different sources (small mammals, animals), as well as the annual morbidity in humans, it was proved that new leptospira serovars are endemic and brought into the regions mostly by farm animals. Farm animals introduce the infection to humans through the environment, sometimes within 3-5-years. The spread was observed of pathogen serovars, which are new in certain areas, among all types of mouse-like small mammals and rats. It was established that livestock and small mammals are parallel reservoirs. CONCLUSIONS: In the regions with endemic species, the structural modification in the etiology of leptospirosis in humans is caused by additional reservoirs among animals, as well as the circulation of other pathogen serovars that were absent in the main natural reservoir, i.e. mouse-like small mammals and rats. The constant monitoring of the population, contamination and carrier state of mouse like small mammals, rats and farm animals, is required In order to predict the future epidemiological situation on leptospirosis among the population and to improve leptospirosis diagnosis. PMID- 29284247 TI - Large prospective validation and cultural adaptation of the Polish version of the Swiss Spinal Stenosis Questionnaire for patients with lumbar spinal stenosis. AB - OBJECTIVE: The aim of this prospective cohort study was to translate, validate and perform a cultural adaptation of the Polish version of the Swiss Spinal Stenosis Questionnaire (P-SSSQ), a disease-specific questionnaire for assessing symptom severity, physical function and satisfaction with treatment in patients with lumbar spinal stenosis (LSS). MATERIAL AND METHODS: Patients were prospectively recruited at two orthopedic centres in Krakow, Poland, between January 2011 - October 2016. During the interview, each patient completed the P SSSQ, SF-36 Health Survey, and a demographic data questionnaire. After translation, cross-cultural adaptation, and pilot testing, assessment was made of the internal consistency, test-retest reliability, construct validity, and responsiveness of the P-SSSQ subscales. RESULTS: Finally, 171 consecutive patients were included in the study. Cronbach's alpha and ICC values were above 0.8 for all three subscales of the P-SSSQ. The symptom severity domain was highly negatively correlated with physical functioning and bodily pain of SF-36, with Pearson correlation coefficients of -0.68 and -0.63, respectively. The physical function domain was highly negatively correlated with physical functioning (r = 0.62). The satisfaction subscale was also highly negatively correlated with the change in the symptom severity (r = -0.61) and physical function scale (r = 0.65). CONCLUSIONS: The proposed version of the P-SSSQ showed excellent measurement properties and can be considered validated for use in Polish. It is easy to understand, quick to complete, and the psychometric properties of the original version are maintained. PMID- 29284248 TI - Streptococcus suis: a re-emerging pathogen associated with occupational exposure to pigs or pork products. Part I - Epidemiology. AB - Streptococcus suis (ex Elliot 1966, Kilpper-Balz & Schleifer 1987) is a facultatively anaerobic Gram-positive ovoid or coccal bacterium surrounded by a polysaccharide capsule. Based on the antigenic diversity of the capsule, S. suis strains are classified serologically into 35 serotypes. Streptococcus suis is a commensal of pigs, commonly colonizing their tonsils and nasal cavities, mostly in weaning piglets between 4-10 weeks of age. This species occurs also in cattle and other mammals, in birds and in humans. Some strains, mostly those belonging to serotype 2, are also pathogenic for pigs, as well as for other animals and humans. Meningitis is the primary disease syndrome caused by S. suis, both in pigs and in humans. It is estimated that meningitis accounted for 68.0% of all cases of human disease reported until the end of 2012, followed by septicaemia (including life-threatening condition described as 'streptococcal toxic shock-like syndrome' - STSLS), arthritis, endocarditis, and endophthalmitis. Hearing loss and/or ves tibular dysfunction are the most common sequelae after recovery from meningitis caused by S. suis, occurring in more than 50% of patients. In the last two decades, the number of reported human cases due to S. suis has dramatically increased, mostly due to epidemics recorded in China in 1998 and 2005, and the fulminant increase in morbidity in the countries of south-eastern Asia, mostly Vietnam and Thailand. Out of 1,642 cases of S. suis infections identified between 2002-2013 worldwide in humans, 90.2% occurred in Asia, 8.5% in Europe and 1.3% in other parts of the globe. The human disease has mostly a zoonotic and occupational origin and occurs in pig breeders, abattoir workers, butchers and workers of meat processing facilities, veterinarians and meat inspectors. Bacteria are transmitted to workers by close contact with pigs or pig products, usually through contamination of minor cuts or abrasions on skin of hands and/or arms, or by pig bite. A different epidemiologic situation occurs in the Southeast Asian countries where most people become infected by habitual consumption of raw or undercooked pork, blood and offal products in the form of traditional dishes. Prevention of S. suis infections in pigs includes vaccination, improvement in pig-raising conditions, disinfection and/or fumigation of animal houses, and isolation of sick animals at the outbreak of disease. Prevention of human infections comprises: protection of skin from pig bite or injury with sharp tools by people occupationally exposed to pigs and pig products, prompt disinfection and dressing of wounds and abrasions at work, protection of the respiratory tract by wearing appropriate masks or repirators, consulting a doctor in the case of febrile illness after exposure to pigs or pork meat, avoidance of occupations associated with exposure to pigs and pork by immunocompomised people, avoidance of consumption of raw pork or pig blood, adequate cooking of pork, and health education. PMID- 29284249 TI - Design, construction and evaluation of multi-epitope antigens for diagnosis of Lyme disease. AB - INTRODUCTION: Introduction and objective. Lyme disease (LD) is the most common vector-borne disease in the temperate zone of the Northern Hemisphere. Diagnosis of LD is mainly based on clinical symptoms supported with serology (detection of anti-Borrelia antibodies) and is often misdiagnosed in areas of endemicity. MATERIAL AND METHODS: In this study, the chimeric proteins (A/C-2, A/C-4 and A/C-7.1) consisting of B-cell epitopes of outer surface proteins OspA and OspC from Borrelia genospecies prevalent in Eastern Slovakia, were designed, over-expressed in E. coli, and used to detect specific anti Borrelia antibodies in serologically characterized sera from patients with Lyme-like symptoms to evaluate their diagnostic potential. RESULTS: Results showed that chimeras vary in their immuno-reactivity when tested with human sera. Compared with the results obtained from a two-tier test, the application of recombinant multi-epitope chimeric proteins as diagnosis antigens, produced fair agreement in the case of A/C-2 (0.20Coxiella burnetii is an obligatory intracellular bacterial pathogen causing the zoonotic disease Q fever. The most common reservoirs of C. burnetii are wild mammals, birds and ticks. Pregnant domestic ruminants infected with this bacterium are also a major source of human infection. MATERIAL AND METHODS: The serological prevalence of C. burnetii in goats and sheep diagnosed with adverse pregnancy outcomes was assessed by undertaking a survey on 800 dairy goats and 800 dairy ewes reared in four different regions of Greece (Macedonia, Thrace, Thessaly, and Peloponnese). A stratified sampling was carried out, taking also as a criterion the age of the animals. Serum antibodies were analyzed by a commercial ELISA according to the manufacturer's recommendations. RESULTS: Generally, there was a statistically significantly higher serological prevalence of C. burnetii (14.4%) in goats compared to sheep (8%). Serological prevalence was higher in adults (15.5% in goats and 8.5% in sheep) compared to yearlings (7.4% in goats and 4.6% in sheep). The prevalence increased significantly with age only in goats. Finally, all animals reared in Peloponnese had a prevalence significantly higher (21% in goats and 18% in sheep) than animals reared in the other three regions. CONCLUSIONS: To the best of the authors' knowledge, this is the first report that associates C. burnetii with reproductive disturbances of domestic ruminants in Greece. However, considering the importance of coxiellosis for public health, further investigations are required on its epidemiology regarding abortion, premature delivery, stillbirth and weak offspring in small ruminants, as well as in other domestic and wild animal species. PMID- 29284251 TI - Dissatisfaction with work as a risk factor of musculoskeletal complaints among foresters in Poland. AB - INTRODUCTION: Researchers indicate an important relationship between the level of job satisfaction and the state of health of the employees. Some elements of work related with its character, organization, and interpersonal relationships may evoke strong stress, manifested by, among others, an increased musculoskeletal tension which, in turn, may lead to permanent dysfunction of this system. OBJECTIVE: The objective of the study was analysis of the relationship between the level of job satisfaction and occurrence of musculoskeletal disorders among employees of the State Forests. MATERIAL AND METHODS: The research material was collected using two instruments: the modified Nordic Questionnaire for assessment of musculoskeletal disorders, and a questionnaire concerning job satisfaction. The study was conducted in a group of 396 employees of the State Forests from 8 regions of Poland. RESULTS: The results of analysis confirmed a significant relationship between job satisfaction and the occurrence of musculoskeletal disorders. The lower the level of job satisfaction, the more frequent the experiencing of musculoskeletal disorders. CONCLUSIONS: Low level of job satisfaction is a risk factor for the occurrence of musculoskeletal disorders. Shaping of work conditions, which are the source of job satisfaction, should be considered as one of the main elements of prevention of musculoskeletal complaints. PMID- 29284252 TI - Diagnosis of cutaneous anthrax in resource-poor settings in West Arsi Province, Ethiopia. AB - INTRODUCTION: Cutaneous anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis, which typically presents with ulcers after contact with animals or animal products, and is rarely seen in high-income countries but is common in those with low- and middle-incomes. Objective. The aim of this study is to show the main clinical characteristics of cutaneous anthrax in endemic areas. MATERIAL AND METHODS: The study describes the main clinical characteristics of cutaneous anthrax in eight patients (six female and two male, age range 1 - 56 years) admitted to the rural General Hospital of Gambo, West Arsi Province of Ethiopia from 2010-2013. RESULTS: In all cases, lesions began as an erythematous papule located on exposed sites (n=7 head; n=1 thigh) and subsequently became a necrotic black eschar surrounded by an edematous halo. Two patients presented with painful ipsilateral adenopathy near the black eschar. Four patients developed a malignant pustule on the suborbital region of the face. Patients responded positively to treatment, and the lesions resolved, leaving eschars. However, one patient suffered the loss of an eyeball, and another died 12 hours after starting treatment. CONCLUSIONS: Physicians working in rural areas of resource-poor settings should be trained in the clinical identification of cutaneous anthrax. Early antibiotic treatment is essential for decreasing morbidity and mortality. PMID- 29284253 TI - Risk factors for work-related eczema and urticaria among vocational students of agriculture. AB - INTRODUCTION AND OBJECTIVE: Farmers are at high risk of occupational skin diseases which may start already during vocational training. This study was aimed at identification of risk factors for work-related skin diseases among vocational students of agriculture. MATERIAL AND METHODS: The study involved 440 students (245 males, 195 females aged 17-21 years) in 11 vocational schools which were at least 100 km from each other. The protocol included a physician-managed questionnaire and medical examination, skin prick tests, patch tests, total IgE and Phadiatop. Logistic regression model was used for the identification of relevant risk factors. RESULTS: Work-related dermatoses were diagnosed in 29 study participants (6.6%, 95%CI: 4.3-8.9%): eczema in 22, urticaria in 14, and co existence of both in 7 students. Significant risk factors for work-related eczema were: history of respiratory allergy (OR=10.10; p<0.001), history of eczema (itchy rash) provoked by wet work and detergents before entering the school (OR=5.85; p<0.001), as well as history of contact dermatitis to metals, rubber or cosmetics prior to inscription (OR=2.84; p=0.016), and family history of any skin disease (OR=2.99; p=0.013). Significant risk factors for work-related urticaria were: history of allergic rhinitis and asthma prior to inscription (OR=7.29; p=0.006), positive skin prick tests to work place allergens (OR=4.65; p=0.002) and to environmental allergens (OR=3.79; p=0.009), and positive Phadiatop test (OR=3.61; p=0.013). CONCLUSIONS: Work-related skin diseases are common among vocational students of agriculture. Atopy, past history of asthma, allergic rhinitis, and eczema (either atopic, allergic or irritant) are relevant risk factors for work-related eczema and urticaria in young farmers, along with family history of any skin disease. Positive skin prick tests seem relevant, especially in the case of urticaria. Asking simple, aimed questions during health checks while enrolling students into agricultural schools would suffice to identify students at risk for work-related eczema and urticaria, giving them the chance for selecting a safer profession, and hopefully avoiding an occupational disease in the future. PMID- 29284254 TI - Effects of heavy metal Cd pollution on microbial activities in soil. AB - Heavy metal contamination of soil occurs when heavy metals are introduced to soil through human activities, leading to the gradual deterioration of the ecology and environment. Microorganism activity reflects the intensity of various biochemical reactions in soil, and changes in it reflect the level of heavy metal pollution affecting the soil. The effects were studied of heavy metal Cd on the microbial activity of soil at different concentrations by investigating the respiratory intensity, urease activity, and catalase activity in forest soil and garden soil. The results showed that the respiratory intensity, urease and catalase activities in the garden soil were all higher than in the forest soil. Cd has obvious inhibitory effects on microbial activities. The three parameters exhibited a downward trend with increasing concentrations of Cd. Catalase activity increased when the mass concentration of Cd reached 1.0 mg/kg, indicating that low concentrations of Cd can promote the activity of some microorganisms. Respiratory intensity and urease activity also increased when the concentration reached 10.0 mg/kg, showing that respiratory intensity and urease activity have strong response mechanisms to adverse conditions. The effective state of Cd in soil, as well as inhibition of microbial activity, decreased with incubation time. PMID- 29284255 TI - Total phenolic content, FTIR analysis, and antiproliferative evaluation of lupin seeds harvest from western Romania. AB - INTRODUCTION: Lupinus spp. are herbaceous perennial flowering plants included in the Fabaceae family. Among the approximately 200 species belonging to this genre, Lupinus albus L., also known as white lupin, Lupinus angustifolius L., and narrow leafed lupin or blue lupin, represent two of the most studied species due to their intense culinary use and potential biological activity. The intention of the study was to characterize total phenolic content, perform FTIR analysis, and antiproliferative effects against A375 human melanoma cells extracts obtained from germinated and ungerminated seeds from Lupinus albus L. and Lupinus angustifolius L. MATERIAL AND METHODS: Total phenolic content was assessed using the Folin-Ciocalteu colorimetric method. FTIR spectra were carried out by a Shimadzu Prestige-21 spectrometer in the range 400-4000 cm-1, using KBr pellets and resolution of 4 cm-1. Antiproliferative capacity was screened by employing the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and scratch assay methods. RESULTS: The study showed increased values corresponding to total phenolic content for the germinated extracts. FTIR spectra confirmed the presence of genistein and main cinnamic acids derivatives (ferulic, caffeic, rosmarinic, and coumaric acids). All tested extracts showed weak antiproliferative potential against A375 human melanoma cells. CONCLUSIONS: Germination increased the amount of bioactive compounds in the seeds of the two studied species of lupin. FTIR analyses provided an important fingerprint of the chemical composition. PMID- 29284256 TI - Perception of preventive care and readiness for lifestyle change in rural and urban patients in Poland: a questionnaire study. AB - INTRODUCTION AND OBJECTIVE: The idiosyncrasies of rural health demand further research to instigate rural health initiatives and to monitor progress in rural health care. In 2008, a study examined health-related behaviour, perception of importance of preventive interventions, readiness to change lifestyle and willingness to receive support from GPs, according to gender and place of residence. MATERIAL AND METHODS: A cross-sectional survey was conducted among patients who visited any of ten randomly-selected general practices in Poland. RESULTS: Four hundred patients were enrolled: 50% from rural areas, 50.3% were females; 23.8% declared a primary level of education (35% rural vs. 12.5% urban) respondents; the median age was 50 years (IQR=18), The predicted means for prevention importance scores for rural residents were 0.623 and for urban residents - 0.682. Place of residence had a significant effect on the importance of prevention (p<0.05; ICC=0.048). Area and gender have a statistically significant effect on preventive behaviour importance scores (p<0.05; ICC=0.0526). Patient expectations of individual counselling by GPs were highest for eating habits - 35.5% rural vs. 16% urban residents (p<0.0001). CONCLUSIONS: Patient importance scores for prevention were associated with residence and gender. The villagers attached less importance to prevention. They also declared less willingness to change their lifestyle. Women had higher scores regarding prevention than men. More rural respondents would like to receive individual counselling from their GP regarding eating habits, physical activity, body weight, giving up smoking and safe alcohol use. Urban respondents were more likely to expect leaflets from their GPs on normalizing body weight. PMID- 29284257 TI - Self-Cleaning Microcavity Array for Photovoltaic Modules. AB - Development of self-cleaning coatings is of great interest for the photovoltaic (PV) industry, as soiling of the modules can significantly reduce their electrical output and increase operational costs. We fabricated flexible polymeric films with novel disordered microcavity array (MCA) topography from fluorinated ethylene propylene (FEP) by hot embossing. Because of their superhydrophobicity with water contact angles above 150 degrees and roll-off angles below 5 degrees , the films possess self-cleaning properties over a wide range of tilt angles, starting at 10 degrees , and contaminant sizes (30-900 MUm). Droplets that impact the FEP MCA surface with velocities of the same order of magnitude as that of rain bounce off the surface without impairing its wetting properties. Additionally, the disordered MCA topography of the films enhances the performance of PV devices by improving light incoupling. Optical coupling of the FEP MCA films to a glass-encapsulated multicrystalline silicon solar cell results in 4.6% enhancement of the electrical output compared to that of an uncoated device. PMID- 29284258 TI - pH-Sensitive Coiled-Coil Peptide-Cross-Linked Hyaluronic Acid Nanogels: Synthesis and Targeted Intracellular Protein Delivery to CD44 Positive Cancer Cells. AB - The clinical translation of protein drugs that act intracellularly is limited by the absence of safe and efficient intracellular protein delivery vehicles. Here, pH-sensitive coiled-coil peptide-cross-linked hyaluronic acid nanogels (HA-cNGs) were designed and investigated for targeted intracellular protein delivery to CD44 overexpressing MCF-7 breast cancer cells. HA-cNGs were obtained with a small size of 176 nm from an equivalent mixture of hyaluronic acid conjugates with GY(EIAALEK)3GC (E3) and GY(KIAALKE)3GC (K3) peptides, respectively, at pH 7.4 by nanoprecipitation. Circular dichroism (CD) proved the formation of coiled-coil structures between E3 and K3 peptides at pH 7.4 while fast uncoiling at pH 5.0. HA-cNGs showed facile loading of cytochrome C (CC) and greatly accelerated CC release under mild acidic conditions (18.4%, 76.8%, and 91.4% protein release in 24 h at pH 7.4, 6.0, and 5.0, respectively). Confocal microscopy and flow cytometry displayed efficient internalization of CC-loaded HA-cNGs and effective endosomal escape of CC in MCF-7 cancer cells. Remarkably, HA-cNGs loaded with saporin, a ribosome inactivating protein, exhibited significantly enhanced apoptotic activity to MCF-7 cells with a low IC50 of 12.2 nM. These coiled-coil peptide-cross-linked hyaluronic acid nanogels have appeared as a simple and multifunctional platform for efficient intracellular protein delivery. PMID- 29284259 TI - Cold and Hot Gelling of Alginate-graft-PNIPAM: a Schizophrenic Behavior Induced by Potassium Salts. AB - Recently, alginates (ALG) characterized by high mannuronic content (M blocks) have been shown to undergo a reversible sol/gel transition during cooling in the presence of potassium salts. Cold gelling takes place at low temperatures, just below 0 degrees C for a KCl concentration of 0.3 mol/kg, but the aggregation process can be easily shifted to higher temperatures by increasing the salt concentration. In the present paper, we take advantage of this peculiar behavior to design a copolymer with schizophrenic gelling properties. For this purpose, side chains of poly(N-isopropylacrylamide) (PNIPAM), characterized by a Lower Critical Solution Temperature (LCST) in water, were grafted on the alginate backbone. Working in semidilute solutions, we show by coupling DSC and viscoelastic measurements that ALG-g-PNIPAM solutions are able to form gels either by cooling or heating depending on the ionic environment. As the aggregation process of ALG and PNIPAM depends mainly and respectively on the nature of the cations and anions, the choice of the salt is then critical to control the self-assembly behavior and the gel properties. Moreover, as the gelation process of alginates driven by the aggregation of mannuronic sequences is characterized by a large hysteresis of 20-30 degrees C between gelling and melting, both ALG and ALG-g-PNIPAM polymers offer a large versatility not only in terms of salt (nature and concentration) but also in preparation history as different states (sol or gel) can be obtained at room temperature. PMID- 29284260 TI - Targeted, Stimuli-Responsive Delivery of Plasmid DNA and miRNAs Using a Facile Self-Assembled Supramolecular Nanoparticle System. AB - Gene therapy is rapidly regaining traction in terms of research activity and investment across the globe, with clear potential to revolutionize medicine and tissue regeneration. Viral vectors remain the most commonly utilized gene delivery vehicles, due to their high efficiency, however, they are acknowledged to have numerous drawbacks, including limited payload capacity, lack of cell-type specificity, and risk of possible mutations in vivo, hence, patient safety. Synthetic nanoparticle gene delivery systems can offer substantial advantages over viral vectors. They can be utilized as off-the-shelf components to package genetic material, display targeting ligands, and release payloads upon environmental triggers and enable the possibility of programmed cell-specific uptake and transfection. In this study, we have synthesized three functional polymeric building blocks that, in a rapid, facile, tailorable, and stage-wise manner, associate through both electrostatic and noncovalent hydrophobic "host guest" interactions to form monodisperse self-assembled nanoparticles (SaNP). We show that these SaNPs successfully package significant amounts of microRNA through to plasmid DNA, present desired ligands on their outer surface for targeted receptor-mediated cell-specific uptake and affect efficient translation of packaged plasmids. We confirm that these SaNPs outperform commercially available, gold standard transfection agents in terms of in vitro transfection efficiencies and have very low cytotoxicity. With facile self-assembly and tailorable composition, our SaNP gene delivery system has significant potential in targeted gene therapy applications. PMID- 29284261 TI - B(C6F5)3-Catalyzed C3-Selective C-H Borylation of Indoles: Synthesis, Intermediates, and Reaction Mechanism. AB - Without the addition of any additives and production of any small molecules, C3 borylated indoles and transfer hydrogenated indolines have been simultaneously achieved by a B(C6F5)3-catalyzed disproportionation reaction of a broad range of indoles with catecholborane. This catalyst system exhibits excellent catalytic performance for practical applications, such as easy scale-up under solvent-free conditions and long catalytic lifetime over ten sequential additions of starting materials. A combined mechanistic study, including isolation and characterization of key reaction intermediates, analysis of the disproportionation nature of the reaction, in situ NMR of the reaction, and analysis of detailed experimental data, has led to a possible reaction mechanism which illustrates pathways for the formation of both major products and byproducts. Understanding the reaction mechanism enables us to successfully suppress side reactions by choosing appropriate substrates and adjusting the amount of catecholborane needed. More importantly, with an elevated reaction temperature, we could achieve the convergent disproportionation reaction of indoles, in which indolines were continuously oxidized to indoles for the next disproportionation catalytic cycle. Near quantitative conversions and up to 98% yields of various C3-selective borylated indoles were achieved, without any additives or H2 acceptors. PMID- 29284262 TI - Atomic Origins of the Self-Healing Function in Cement-Polymer Composites. AB - Motivated by recent advances in self-healing cement and epoxy polymer composites, we present a combined ab initio molecular dynamics and sum frequency generation (SFG) vibrational spectroscopy study of a calcium-silicate-hydrate/polymer interface. On stable, low-defect surfaces, the polymer only weakly adheres through coordination and hydrogen bonding interactions and can be easily mobilized toward defected surfaces. Conversely, on fractured surfaces, the polymer strongly anchors through ionic Ca-O bonds resulting from the deprotonation of polymer hydroxyl groups. In addition, polymer S-S groups are turned away from the cement-polymer interface, allowing for the self-healing function within the polymer. The overall elasticity and healing properties of these composites stem from a flexible hydrogen bonding network that can readily adapt to surface morphology. The theoretical vibrational signals associated with the proposed cement-polymer interfacial chemistry were confirmed experimentally by SFG vibrational spectroscopy. PMID- 29284263 TI - Reticular Electronic Tuning of Porphyrin Active Sites in Covalent Organic Frameworks for Electrocatalytic Carbon Dioxide Reduction. AB - The electronic character of porphyrin active sites for electrocatalytic reduction of CO2 to CO in a two-dimensional covalent organic framework (COF) was tuned by modification of the reticular structure. Efficient charge transport along the COF backbone promotes electronic connectivity between remote functional groups and the active sites and enables the modulation of the catalytic properties of the system. A series of oriented thin films of these COFs was found to reduce CO2 to CO at low overpotential (550 mV) with high selectivity (faradaic efficiency of 87%) and at high current densities (65 mA/mg), a performance well beyond related molecular catalysts in regard to selectivity and efficiency. The catalysts are stable for more than 12 h without any loss in reactivity. X-ray absorption measurements on the cobalt L-edge for the modified COFs enable correlations between the inductive effects of the appended functionality and the electronic character of the reticulated molecular active sites. PMID- 29284264 TI - Formation of Single-Digit Nanometer Scale Silica Nanoparticles by Evaporation Induced Self-Assembly. AB - There are emerging demands for single-digit nanoscale particles in multidisciplinary fields, such as nanomedicine, optics, catalysis, and sensors, to create new functional materials. Here, we report a novel route to prepare silica nanoparticles less than 3 nm in size via the evaporation-induced self assembly of silicate species and quaternary trialkylmethylammonium surfactants, which usually form reverse micelles. The solvent evaporation induces a local concentration increase and simultaneous polycondensation of silicate species within the hydrophilic region of the surfactant mesophases. Extremely small silica nanoparticles in the silica-surfactant mesostructures can be stably dispersed in organic solvents by destroying the mesostructure, which is in clear contrast to the preparation of silica nanoparticles using the conventional reverse micelle method. The surface chemical modification of the formed silica nanoparticles is easily performed by trimethylsilylation. The particle size is adjustable by changing the ratio of the surfactants to the silica source because the hydrophobic/hydrophilic ratio determines the curvature and diameter of the resulting spherical silica-surfactant domains in the mesostructure. The versatility of this method is demonstrated by the fabrication of very small titania nanoparticles. These findings will increase the designability of oxide nanoparticles at the single-digit nanoscale because conventional methods based on the generation and growth of nuclei in a solution cannot produce such nanoparticles with highly regulated sizes. PMID- 29284265 TI - Wannier Koopmans Method Calculations of 2D Material Band Gaps. AB - A major drawback of the widely successful density functional theory is its underestimation of the material band gap. Various methods have been proposed to correct its band gap predictions. Wannier Koopmans method (WKM) is recently developed for this purpose to predict the band gap of extended 3D bulk systems. While the WKM has also been shown to be successful for isolated molecules, it is still a question whether it will work for 2D materials that are in between the 0D molecules and 3D bulk systems. We apply the WKM to 16 commonly known well studied 2D materials and find that the WKM predicted band gaps are on par with their GW calculated results. PMID- 29284266 TI - From Quasicrystals to Crystals with Interpenetrating Icosahedra in Ca-Au-Al: In Situ Variable-Temperature Transformation. AB - The irreversible transformation from an icosahedral quasicrystal (i-QC) CaAu4.39Al1.61 to its cubic 2/1 crystalline approximant (CA) Ca13Au56.31(3)Al21.69 (CaAu4.33(1)Al1.67, Pa3 (No. 205); Pearson symbol: cP728; a = 23.8934(4)), starting at ~570 degrees C and complete by ~650 degrees C, is discovered from in situ, high-energy, variable-temperature powder X-ray diffraction (PXRD), thereby providing direct experimental evidence for the relationship between QCs and their associated CAs. The new cubic phase crystallizes in a Tsai-type approximant structure under the broader classification of polar intermetallic compounds, in which atoms of different electronegativities, viz., electronegative Au + Al vs electropositive Ca, are arranged in concentric shells. From a structural chemical perspective, the outermost shell of this cubic approximant may be described as interpenetrating and edge-sharing icosahedra, a perspective that is obtained by splitting the traditional structural description of this shell as a 92-atom rhombic triacontahedron into an 80-vertex cage of primarily Au [Au59.86(2)Al17.14?3.00] and an icosahedral shell of only Al [Al10.5?1.5]. Following the proposal that the cubic 2/1 CA approximates the structure of the i-QC and on the basis of the observed transformation, an atomic site analysis of the 2/1 CA, which shows a preference to maximize the number of heteroatomic Au-Al nearest neighbor contacts over homoatomic Al-Al contacts, implies a similar outcome for the i-QC structure. Analysis of the most intense reflections in the diffraction pattern of the cubic 2/1 CA that changed during the phase transformation shows correlations with icosahedral symmetry, and the stability of this cubic phase is assessed using valence electron counts. According to electronic structure calculations, a cubic 1/1 CA, "Ca24Au88Al64" (CaAu3.67Al2.67) is proposed. PMID- 29284267 TI - Integrating Metal-Enhanced Fluorescence and Surface Acoustic Waves for Sensitive and Rapid Quantification of Cancer Biomarkers from Real Matrices. AB - Metal-enhanced fluorescence (MEF) is utilized to lower the detection limit of carcinoembryonic antigen (CEA), a prognostic biomarker for colorectal cancer among others, in immunofluorescence assays. In addition, Rayleigh surface acoustic waves (SAWs) were utilized to remove nonspecifically bound proteins, improve mixing, and reduce incubation times. Fluorescence intensity was plasmonically enhanced by incubating silver nanocubes (AgNCs) of 50 nm edge length on a SAW device. This increased sensor sensitivity by a factor of 6 and lowered the limit of detection to below 1 ng/mL in fluorescence detection of the antigen. Surface density of the AgNCs was optimized to produce the largest MEF, which increased the signal intensity by an order of magnitude. Acoustic streaming induced by Rayleigh SAWs was found to decrease antibody/antigen incubation times to 1/6th of the values without such micromixing, and to increase the fluorescence signal strength. Overall, the demonstrated results allow for construction of a sensor capable of detecting CEA rapidly in clinically relevant concentrations. Variables relevant for optimizing this sensor performance were identified, which will enable even better performance in immunofluorescence assays. PMID- 29284268 TI - Injectable Hydrogel with Slow Degradability Composed of Gelatin and Hyaluronic Acid Cross-Linked by Schiff's Base Formation. AB - We developed an injectable gelatin/hyaluronic acid hydrogel with slow degradability, which consisted of carbohydrazide-modified gelatin (Gel-CDH) and hyaluronic acid monoaldehyde (HA-mCHO). Gel-CDH/HA-mCHO hydrogels were degraded much more slowly in phosphate-buffered saline than the other Schiff's base cross linked gelatin/hyaluronic acid hydrogels that were comprised of native gelatin, adipic acid dihydrazide-modified gelatin, or hyaluronic acid dialdehyde because of stable Schiff's base formation between aldehyde and carbohydrazide groups, and suppression of ring-opening oxidation by monoaldehyde modification. This prolonged degradation would be suitable for inducing angiogenesis. Therefore, the Gel-CDH/HA-mCHO hydrogels were sufficiently stable during the angiogenesis process. In addition, the hydrogel had a pore size of 15-55 MUm and a shear storage modulus of 0.1-1 kPa, which were appropriate for scaffold application. Ex vivo rat aortic-ring assay demonstrated the concentration dependency of microvascular extension in the Gel-CDH/HA-mCHO hydrogel. These results demonstrated the potential usefulness of Gel-CDH/HA-mCHO hydrogel for tissue engineering scaffolds. PMID- 29284269 TI - RECALAD. Patient care at National Health System Digestive Care Units - A pilot study, 2015. AB - OBJECTIVES: To reach a situation diagnosis on the status of patient management at digestive care units (DCUs) in Spain. MATERIAL AND METHODS: A cross-sectional descriptive study across DCUs in general acute care hospitals within the Spanish National Health System (data referred to 2015). The study variables were collected with a questionnaire including items on structure, services portfolio, activity, education, research, and good practice. Hospital discharge rates for digestive diseases were also assessed using the minimum basic data set (2005 2014). RESULTS: Two hundred and nine hospitals invited, 55 responders (26.3%). Average discharges from hospital were 1,139 +/- 653 per DCU/year, and 100 +/- 66 per year per dedicated gastroenterologist. In 2014, admission rate to DCUs per 1,000 population and year was 280, with a mean stay of 7.4 days. The analysis of the MBDS for 2005-2014 reveals a progressive increase in the number of discharges (37% more in 2014 versus 2005), with a 28% decrease in hospital gross mortality rate (3.7% in 2014) and a slightly reduced (14%) mean stay (7.6 days in 2014). Considerable variability may be seen in structure, activity, and results indicators. Mortality and readmission rates, as well as mean stay, vary more than 100% amongst DCUs, and major dispersions also exist in frequentation and results amongst autonomous communities. CONCLUSIONS: The RECALAD 2015 survey unveiled relevant aspects related to DCUs organization, structure, and management. The notable variability encountered likely reflects relevant differences in efficiency and productivity, and thus points out there is ample room for improvement. PMID- 29284270 TI - Measuring health-related quality of life (HRQoL) in functional dyspepsia: is it really important? AB - Although health-related quality of life (HRQoL) measure instruments in functional dyspepsia (FD) have been available for many years, as in other functional gastrointestinal disorders, their real application in clinical practice, beyond therapeutic studies, is unknown. For first time, the new Rome IV diagnostic criteria include the consideration of symptom severity enough to impact on usual patients' activities. A new focus on the management of this entity is proposed, therefore we should carefully revise the HRQoL measures and define its real role in our clinical practice. PMID- 29284271 TI - A comparison of submucosal tunneling endoscopic resection and endoscopic full thickness resection for gastric fundus submucosal tumors. AB - AIM: Both submucosal tunneling endoscopic resection (STER) and endoscopic full thickness resection (EFTR) are effective methods for gastric fundus submucosal tumors (SMTs). However, there is little data that compares the two methods. The aim of this study was to compare the safety and efficacy of STER and EFTR for the treatment of SMTs in the gastric fundus. METHODS: Clinical data was retrospectively collected from patients with gastric fundus SMTs who underwent STER or EFTR at our hospital from April 2011 to May 2016. Epidemiological data (gender, age), tumor size, procedure-related parameters, complications, postoperative hospital stay, cost and follow-up data were compared. RESULTS: A total of 43 patients were enrolled: 15 underwent STER and the remaining 28 cases underwent EFTR. There were no significant differences between the two groups with regard to gender, age, tumor size, en bloc resection rate, operation time, pathohistological results and cost (p > 0.05). However, patients who underwent EFTR had a longer suture time, required a larger number of clips for closure and a prolonged postoperative hospital stay (p < 0.05). No recurrence was noted in either the STER or the EFTR group during a mean follow-up of 12.1 and 22.8 months, respectively. CONCLUSIONS: The treatment efficacy of STER and EFTR for the treatment of gastric fundus SMTs was comparable. However, STER has some advantages over EFTR in terms of suture time, the number of clips required for closure and postoperative hospital stay. PMID- 29284272 TI - On the centenary of The Spanish Journal of Gastroenterology (REED). AB - Editor-in Chief and Executive Editor summerize the recent evolution of The Spanish Journal of Gastroenterology. They tackle several questions regarding the internet impact on scientific journals. PMID- 29284273 TI - A double whammy! New baccalaureate registered nurses' transitions into rural acute care. AB - INTRODUCTION: Transitioning into the Canadian rural acute care environment can be challenging for new RNs, and so retention is of concern. Currently, few seasoned registered nurses (RNs) are available to support new RNs during transition because (a) the Canadian RN workforce countrywide is aging and significant numbers are retiring, and (b) the number of Canadian RNs working rurally has plummeted in the past 10 years. Investigations into the phenomenon of new RNs?' transitions into the workforce have been conducted, but little is known about this phenomenon as it relates to Canadian rural acute care hospitals. Most findings have been based on data from urban or mixed rural–urban samples. METHODS: An interpretive description research approach was used to understand new RNs?' transition experiences into the Alberta, Canada, rural acute care environment including supports and challenges specific to recruitment and retention. Face-to-face interviews were conducted with a convenience sample of 12 new RNs who had been employed in one or more Alberta rural acute care hospitals from 1 month to less than 2 years. RESULTS: In this study, participants experienced a double whammy consisting of learning I?'m a generalist! and managing the responsibility of I?'m it! Participants experienced contradictory emotions of exhilaration and shock that set them on an emotional roller coaster, a finding that differs from previously reported findings, wherein transition was frequently identified as only shocking. The few participants who were well supported by their colleagues and employersreportedexperiencing minor emotional fluctuations and described transition as exciting, good, and manageable. Thosewho were not experienced major fluctuations from exhilaration to shock. They described transition as exhilarating, but overwhelming, and unsafe. Notably, 9 of the 12 participants changed jobs within their first 2 years of practice. Other significant findings included problems with the outdated definitions of rural and rural acute care hospitals, which currently do not accurately address rural population growth and the services provided at rural acute care hospitals. Populations of some communities identified as rural by Alberta Health Services exceeded the upper limit of 10 000, the level long used to distinguish between rural and urban in the Canadian literature. As well, two different types of rural hospitals exist in Alberta: generalist types and urban types. The transition experience into these two different types of hospitals varied significantly. CONCLUSIONS: Whiledouble whammyoffers only one description of new RNs?' transition experiences into rural acute care, it may present readers with recognizable similarities about transition that resonate with their own learning and responsibilities. Transition supports and challenges learned from this study can assist rural healthcare providers, policymakers, and educators in developing strategies to support and retain new RNs in rural acute care environments. Additionally, researchers must consider a priori whether or not different types of rural acute care hospitals exist in their study locale and if rural population growth is a factor when conducting future investigations related to rural acute care. PMID- 29284274 TI - The Development of a Motor-Free Short-Form of the Wechsler Intelligence Scale for Children-Fifth Edition. AB - PURPOSE: This study aimed to develop a motor-free short-form of the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V) that allows clinicians to estimate the Full Scale Intelligence Quotients of youths with motor impairments. METHOD: Using the reliabilities and intercorrelations of six WISC-V motor-free subtests, psychometric methodologies were applied to develop look-up tables for four Motor-free Short-form indices: Verbal Comprehension Short-form, Perceptual Reasoning Short-form, Working Memory Short-form, and a Motor-free Intelligence Quotient. Index-level discrepancy tables were developed using the same methods to allow clinicians to statistically compare visual, verbal, and working memory abilities. RESULTS: The short-form indices had excellent reliabilities ( r = .92 .97) comparable to the original WISC-V. CONCLUSION: This motor-free short-form of the WISC-V is a reliable alternative for the assessment of intellectual functioning in youths with motor impairments. Clinicians are provided with user friendly look-up tables, index level discrepancy tables, and base rates, displayed similar to those in the WISC-V manuals to enable interpretation of assessment results. PMID- 29284275 TI - Alzheimer's Disease Assessment: A Review and Illustrations Focusing on Item Response Theory Techniques. AB - Alzheimer's disease (AD) affects neurological, cognitive, and behavioral processes. Thus, to accurately assess this disease, researchers and clinicians need to combine and incorporate data across these domains. This presents not only distinct methodological and statistical challenges but also unique opportunities for the development and advancement of psychometric techniques. In this article, we describe relatively recent research using item response theory (IRT) that has been used to make progress in assessing the disease across its various symptomatic and pathological manifestations. We focus on applications of IRT to improve scoring, test development (including cross-validation and adaptation), and linking and calibration. We conclude by describing potential future multidimensional applications of IRT techniques that may improve the precision with which AD is measured. PMID- 29284276 TI - A Psychometric Evaluation of the DSM-IV Criteria for Antisocial Personality Disorder: Dimensionality, Local Reliability, and Differential Item Functioning Across Gender. AB - This study aims at evaluating the psychometric properties of the antisocial personality disorder (ASPD) criteria in a large sample of patients, most of whom had one or more personality disorders (PD). PD diagnoses were assessed by experienced clinicians using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Axis II PDs. Analyses were performed within an item response theory framework. Results of the analyses indicated that ASPD is a unidimensional construct that can be measured reliably at the upper range of the latent trait scale. Differential item functioning across gender was restricted to two criteria and had little impact on the latent ASPD trait level. Patients fulfilling both the adult ASPD criteria and the conduct disorder criteria had similar latent trait distributions as patients fulfilling only the adult ASPD criteria. Overall, the ASPD items fit the purpose of a diagnostic instrument well, that is, distinguishing patients with moderate from those with high antisocial personality scores. PMID- 29284277 TI - "Life Within the Person Comes to The Fore": Pastoral Workers' Practice Wisdom on Using Arts in Palliative Care. AB - BACKGROUND: Pastoral care (also chaplaincy, spiritual care) assists people to find meaning, personal resources, and connection with self, others, and/or a higher power. Although essential in palliative care, there remains limited examination of what pastoral workers do. This study examined how pastoral workers use and consider the usefulness of art-based modalities. METHODS: Qualitative research was used to examine the practice wisdom (tacit practice knowledge) of pastoral workers experienced in using visual arts and music in palliative care. Two focus groups were conducted. Thematic analysis was informed by grounded theory. RESULTS: Six pastoral workers shared information. Three themes emerged. First, pastoral workers use arts as "another tool" to extend scope of practice by assisting patients and families to symbolically and more deeply contemplate what they find "sacred." Second, pastoral workers' art affinities inform their aims, assessments, and interactions. Third, pastoral workers perceive that art-based modalities can validate, enlighten, and transform patients and families through enabling them to "multisensorially" (through many senses) feel recognized, accepted, empowered, and/or close to God. Key elements involved in the work's transformative effects include enabling beauty, ritual, and the sense of "home" being heard, and legacy creation. DISCUSSION AND CONCLUSION: Pastoral workers interpret that offering art-based modalities in palliative care can help patients and families to symbolically deal with painful memories and experiences, creatively engage with that deemed significant, and/or encounter a sense of transcendence. Training in generalist art-based care needs to be offered in pastoral education. PMID- 29284278 TI - Implementation and Evaluation of the Early-Onset Sepsis Risk Calculator in a High Risk University Nursery. AB - There is growing interest in the Kaiser early-onset sepsis (EOS) risk calculator though institutions are hesitant to deviate from the Centers for Disease Control and Prevention guidelines and implement this in their hospitals. We describe the process of implementing routine use of the risk calculator in term and late preterm newborns delivered to mothers with chorioamnionitis in a level III neonatal intensive care unit (NICU). A retrospective chart review of infants delivered to mothers with chorioamnionitis from 2011 to 2014 was performed. Implementation of routine use of the calculator began in January 2015; preintervention and postintervention data were analyzed after a 9-month period of routine use. Following implementation, NICU admission rates, number of blood cultures drawn, and rates of antibiotic use dropped by 54%, 42%, and 59%, respectively ( P < .001). No negative outcomes were reported. In this article, we describe how the calculator was safely implemented in our NICU while decreasing the number of interventions. PMID- 29284279 TI - Sociodemographic factors influencing island foods consumption in the Pacific Islander Health Study. AB - OBJECTIVES: Pacific Islander Americans are a small, but quickly growing population that experiences alarming disparities in obesity and obesity-related chronic illnesses influenced by dietary patterns. This population also has a unique culinary heritage including traditional foods and more contemporary imports such as tinned meats and refined carbohydrates. This analysis is a novel attempt to understand the sociodemographic factors influencing island foods consumption. DESIGN: A sample of 240 Samoan and Tongan adults in California from the Pacific Islander Health Study was used. Following univariate and bivariate analyses, a series of four multivariable regression models were created to predict past week frequency of island foods consumption after sequential adjustment for demographic, socioeconomic, and cultural covariates. RESULTS: Participants reported consuming island foods an average of 2.93 times in the previous week, with the largest proportion of participants (20.42%) reporting eating island foods 6 or more times. Age and Samoan ethnicity were initially significant, positive predictors of island foods consumption, but their effect was attenuated after addition of cultural covariates. With the third model that adjusted for birthplace, financial insecurity and Tongan birthplace were positive predictors. Both lost significance in the fourth and final model upon addition of cultural affinity, which was positively associated with island foods. CONCLUSION: Understanding how sociodemographic factors are associated with island foods consumption is a first step in understanding the broad way in which an ethnically specific dietary pattern may be associated with obesity-related chronic illness risk among Pacific Islander Americans. PMID- 29284280 TI - Occupational therapy private practice workforce: Issues in the 21st century: La main-oeuvre en ergotherapie dans le secteur prive : Les enjeux du 21e siecle. AB - BACKGROUND: The number of occupational therapists working in the private sector in British Columbia (BC) has risen steadily since 2008, employing approximately 25.7% of occupational therapists by 2012. Processes used to determine workforce needs for occupational therapists in BC have previously overlooked this growing sector. PURPOSE: This study aims to describe the supply, demand, and workforce needs for occupational therapists in BC's private sector. METHOD: This exploratory study used a sample of occupational therapists and employers of occupational therapists in BC's private sector. Data collection included an online survey that collected information about the workplace and supply and demand needs. Descriptive data analysis was conducted on the survey data, and thematic analysis was used to organize participants' comments into categories. FINDINGS: In addition to identifying current supply, this study identifies barriers, facilitators, projected movement in and out of the sector, and current and future demand for occupational therapists. IMPLICATIONS: This study supports the need for an increase in supply of occupational therapists in the private sector to fulfill the current and future workforce demands. PMID- 29284281 TI - Implementation of a nutrition assessment, counseling and support program and its association with body mass index among people living with HIV in Accra, Ghana. AB - In spite of the important role nutrition plays in the management of HIV, access to nutrition services is inadequate, especially in resource limited settings. In addition, nutrition programs for people living with HIV (PLWH) have not been sufficiently evaluated for efficacy and this study was conducted to address this gap. This study aimed to evaluate the implementation of the nutrition assessment, counseling and support (NACS) program in Accra, Ghana, and to assess whether the level of implementation of NACS was associated with the body mass index (BMI) of PLWH. A cross-sectional study was conducted in six HIV clinics (3 NACS designated and 3 non-NACS). Study participants were 152 adult PLWH at least 6 months on antiretroviral therapy and not pregnant or breastfeeding. Using a NACS implementation scale developed for this study ranging from 0 to 8 (a higher score indicating better NACS implementation), median NACS implementation score was not different between NACS-designated, and non-NACS HIV clinics (5 vs 4, p = 0.14). Almost half (47%) of the respondents were overweight or obese. A higher score on the NACS implementation scale was not significantly associated with overweight or obesity (BMI >24.9 kg/m2) after adjusting for other covariates. It was concluded that, there was poor implementation of NACS in the NACS designated HIV clinics surveyed with no nutrition counseling offered nor food support available to those who might need it. PMID- 29284282 TI - Chronic Disease, Prescription Medications, and Food Purchases. AB - PURPOSE: Diet-related chronic diseases like diabetes can be dangerous and expensive to treat, especially for patients who do not follow a recommended diet. Meanwhile, prescription drugs can alleviate the symptoms of or control many diet related chronic diseases, but these drugs may also weaken the resolve to follow recommended diets (moral hazard). DESIGN: We measure the effect of a diagnosis of chronic disease and subsequent pharmacological treatment on the dietary quality of food purchases using a large panel data set of US consumers. We estimate the effect of prescription drug utilization on food purchases for the following chronic diseases: type 2 diabetes, high cholesterol, heart disease, and obesity. PARTICIPANTS: Panelists of the Information Resources, Inc consumer panel. MEASURES: Dietary quality is measured as purchases of (1) food groups (ie, fruit, vegetables, and sweets) and (2) nutrients (ie, saturated fat, fiber, sodium, sugar, and total calories). ANALYSIS: Linear regression with mixed effects on pooled panel (household random effects, city fixed effects). RESULTS/CONCLUSION: We do not find strong effects of either diagnosis or pharmacological treatment of diet-related disease on food purchases. PMID- 29284283 TI - Temporal Effects of Acute Walking Exercise on Learning and Memory Function. AB - PURPOSE: To evaluate the temporal effects of acute exercise on episodic memory. DESIGN: A quasi-experimental study. SAMPLE: Eighty-eight college students (N = 22 per group). MEASURES: Four experimental groups were evaluated, including a control group, exercising prior to memory encoding, exercising during encoding, and exercising during memory consolidation. The exercise stimulus consisted of a 15-minute moderate-intensity walk on a treadmill. Participants completed the Rey Auditory Verbal Learning Test (RAVLT) to assess learning and memory. Prospective memory was assessed via a Red Pen Task. Long-term memory (recognition and attribution) of the RAVLT was assessed 20 minutes and 24 hours after exercise. ANALYSIS: Repeated-measures analysis of variance (ANOVA) assessed the performance of RAVLT scores of trials 1 to 5 across groups. One-way ANOVA assessed the performance of individual trials across groups, whereas chi2 assessed the performance of the Red Pen Task across groups. RESULTS: Regarding learning, the interaction of groups * trial was marginally statistically significant ( F12,332 = 1.773, P = .05), indicating that the group which exercised before encoding did better than the group that exercised during encoding and consolidation. For both 24-hour recognition and attribution performance, the group that exercised before memory encoding performed significantly better than the group that exercised during consolidation ( P = .05 recognition, P = .006 attribution). DISCUSSION: Engaging in a 15-minute bout of moderate-intensity walking before a learning task was effective in influencing long-term episodic memory. PMID- 29284284 TI - Intimate ties of people living with HIV in France resulted both from social status and the experience of being HIV-infected: results from the ANRS-Vespa2 study, France. AB - Based on data from the ANRS-Vespa2 study, conducted among a representative sample of PLWHIV (France, 2011), we studied intimate ties with relatives and friends and their determinants. Six social network profiles were identified, with a clear association with socioepidemiological groups: the most surrounded individuals were MSM, and the most isolated ones were sub-Saharan African migrants (especially women). Social networks were shaped both by material socioeconomic status and HIV experience: involvement in PLWHIV organizations, disclosure of HIV infection, and the experience of discrimination. Among PLWHIV, intimate ties appeared to be shaped by both their multifaceted social position rooted in power relationships and by HIV-related stigma. Such a process nurtures social inequality in coping with HIV infection, since the most disadvantaged individuals appear to be the most isolated ones. A holistic approach to HIV care is still required to overcome the marginalization of PLWHIV . PMID- 29284285 TI - Barriers to contraceptive careseeking: the experience of Eritrean asylum-seeking women in Israel. AB - OBJECTIVES: In recent years, there has been a mass migration of Eritreans (many seeking political asylum) into Israel after precarious irregular movement across international borders. This study qualitatively explores the structural barriers to family planning (i.e. contraceptive services) for Eritrean women in Israel that are rooted in their temporary legal status and the patchwork of family planning services. DESIGN/METHODS: From December 2012 to September 2013, we interviewed 25 key informants (NGO workers, researchers, Eritrean community activists, International NGO representatives and Ministry of Health officials) and 12 Eritrean asylum seekers. We also conducted 8 focus groups with Eritrean asylum seekers. Data were analyzed using both inductive and deductive coding. RESULTS: We identified 7 main barriers to accessing family planning services: (1) distance to health facilities; (2) limited healthcare resources; (3) fragmentation of the healthcare system; (4) cost of contraceptive services; (5) low standard of care in private clinics; (6) discrimination; and (7) language barriers. CONCLUSION: The political, economic and social marginalization of Eritrean asylum-seeking women in Israel creates structural barriers to family planning services. Their marginalization complicates providers' efforts (NGO and governmental) to provide them with comprehensive healthcare, and hinders their ability to control their sexual and reproductive health. Failure to act on this evidence may perpetuate the pattern of unwanted pregnancies and social and economic disparities in this population. PMID- 29284286 TI - 10 years EU regulation of pediatric medicines - impact on cardiovascular drug formulations. AB - INTRODUCTION: Child-appropriate drug formulations are mandatory for an efficient and safe drug therapy in children. Since the implementation of supportive legislations development of novel drug formulations has significantly been enforced despite the fact that children are a heterogeneous group of patients with varying needs according to age, maturation and disease. Areas covered: In this review, recent advances and current strategies are evaluated how to overcome the specific hurdles in pediatric drug development. For cardiovascular diseases as an example, EMA's decisions on pediatric investigation plans (PIPs) have been evaluated. New developments with innovative platform technologies such as mini tablets and orodispersible preparations have been identified indicating a clear shift from liquid preparations to small-sized solid (multiparticulate) or orodispersible dosage forms. Reasons for this shift of paradigm are discussed. Expert opinion: Innovative platform technologies for solid drug dosage forms such as mini-tablets, orodispersible tablets or film preparations will continue to conquer the pharmaceutical market. Still, there are some major issues to be resolved, e.g. how to ensure quality of the new dosage forms and dose accuracy in flexible dosing, but the governmental incentives will continue to accelerate development of pediatric medicines and will bridge the still existing gaps in the near future. PMID- 29284288 TI - Traumatic brain injury among refugees and asylum seekers. AB - BACKGROUND: Refugees and asylum seekers face many challenges in their pursuit of a safe home. The journey for displaced individuals can be extremely dangerous and many do not survive or go missing. Survivors face significant risks of injury, abuse, and torture. Traumatic brain injury is one of the most common and disabling injuries sustained by these populations. This already complex condition can have profound implications on these groups and their families due to factors related to mental health, cultural perspectives, and their ability to navigate healthcare systems. METHODS: A literature review was performed to investigate the incidence and prevalence of torture and traumatic brain injury in displaced and fleeing populations. Impacts of traumatic brain injury and residency status on outcomes in these individuals were also examined. RESULTS: The incidence and prevalence of torture and traumatic brain injury among refugees and asylum seekers is significant. These populations may access healthcare systems differently than other groups and as a result may experience a unique health related outcomes following traumatic brain injury. CONCLUSIONS: This information should sensitize healthcare providers to a potential history of traumatic brain injury sustained by patients/clients who are refugees or asylum seekers and may serve to guide some clinical encounters. Implications for rehabilitation Traumatic brain injuries are commonly sustained by refugees and asylum seekers. Cultural factors may complicate how refugees and asylum seekers understand, report, and manage these injuries. The above may be worsened by cognitive, emotional, and behavioral changes following traumatic brain injury. Rehabilitation providers should be aware of potential traumatic brain injury history during encounters with refugee and asylum seeker populations, especially if a history of torture is suspected. PMID- 29284287 TI - Recombinant Adenovirus-p53 Gene Therapy for Advanced Unresectable Soft-Tissue Sarcomas. AB - Patients with unresectable advanced soft-tissue sarcomas (STS) receiving radiotherapy or/and chemotherapy still have a poor prognosis. This study aimed to evaluate retrospectively the efficacy and safety of recombinant adenovirus-p53 (rAd-p53) gene therapy combined with radiotherapy and hyperthermia for advanced STS. A total of 71 patients with advanced unresectable STS treated at the authors' center from April 2007 to November 2014 were included. Of these 71 patients, 36 cases received rAd-p53 therapy combined with radiotherapy and hyperthermia (p53 group), while 35 cases received radiotherapy and hyperthermia alone (control group). Short-term therapeutic efficacies, long-term survival outcomes, and adverse events were evaluated and compared between groups. Compared to the control group, the p53 group had a significantly higher disease control rate (83.33% vs. 54.29%; p = 0.008) and a lower progressive disease rate (16.67% vs. 45.71%; p = 0.018). In addition, rAd-p53 treatment significantly improved the progression-free survival and overall survival of STS patients. Cox regression indicated that rAd-p53 treatment significantly reduced the risks for disease progression or death event for STS patients. Furthermore, there was no significant difference in all adverse events, except for transient fever, which occurred in 89% of patients with rAd-p53 therapy. rAd-p53 combined with radiotherapy and hyperthermia can effectively improve the therapeutic efficacy and survival outcomes in patients with advanced unresectable STS, providing a new therapeutic strategy. PMID- 29284289 TI - Signaling and Regulation Through the NAD+ and NADP+ Networks. AB - SIGNIFICANCE: NAD+ and NADP+ are important cosubstrates in redox reactions and participate in regulatory networks operating in adjustment of metabolic pathways. Moreover, NAD+ is a cosubstrate in posttranslational modification of proteins and is involved in DNA repair. NADPH is indispensable for reductive syntheses and the redox chemistry involved in attaining and maintaining correct protein conformation. Recent Advances: Within a couple of decades, a wealth of information has been gathered on NAD(H)+/NADP(H) redox imaging, regulatory role of redox potential in assembly of spatial protein structures, and the role of ADP ribosylation of regulatory proteins affecting both gene expression and metabolism. All these have a bearing also on disease, healthy aging, and longevity. CRITICAL ISSUES: Knowledge of the signal propagation pathways of NAD+ dependent posttranslational modifications is still fragmentary for explaining the mechanism of cellular stress effects and nutritional state on these actions. Evaluation of the cosubstrate and regulator roles of NAD(H) and NADP(H) still suffers from some controversies in experimental data. FUTURE DIRECTIONS: Activating or inhibiting interventions in NAD+-dependent protein modifications for medical purposes has shown promise, but restraining tumor growth by inhibiting DNA repair in tumors by means of interference in sirtuins is still in the early stage. The same is true for the use of this technology in improving health and healthy aging. New genetically encoded specific NAD and NADP probes are expected to modernize the research on redox biology. Antioxid. Redox Signal. 00, 000-000. PMID- 29284290 TI - Occlusion Detection Time in Insulin Pumps at Two Different Basal Rates. AB - BACKGROUND: The detection of insulin infusion set (IIS) occlusions is an important feature of insulin pumps with regard to patient safety. However, there are no requirements for a time limit until an alarm has to be triggered after an occlusion occurred. The standard IEC 60601-2-24 is applicable for insulin pumps and describes test settings and procedures to determine occlusion detection time (ODT). METHODS: In this study, ODT of six different insulin pump models with different IIS (in total 10 different insulin pump systems) was tested for two basal rates (1.0 U/h and 0.1 U/h). RESULTS: Differences were seen between the tested pump systems. At a basal rate of 1.0 U/h all insulin pump systems showed an acceptable ODT of less than 5 hours. However, at a basal rate of 0.1 U/h, as often used in children, the median ODT ranged from approximately 4 hours to more than 40 hours. With the lower basal rate, median ODT was longer than 6-8 hours for 9 of the 10 systems. CONCLUSIONS: Insulin pump users should not blindly rely on occlusion alarms but perform regular glucose monitoring and manufacturers should develop mechanisms that allow an earlier detection at low basal rates. PMID- 29284292 TI - National Rare Diseases Registry System of China and Related Cohort Studies: Vision and Roadmap. AB - Rare diseases are major challenges in healthcare and medical research and are the basis of national development strategies in many countries. However, inadequate definition of rare diseases and lags in orphan drug development in China hinder rare disease research. In response, the first National Rare Diseases Registry System of China (NRDRS) was established, and various cohort studies have been launched since 2016. More than 20 top academic institutions in China are currently participating in this joint effort to carry out nationwide registration of rare diseases. The primary objectives are to establish standardization for the registration platform, build biobanks of genomic data, and create partnerships for data sharing and research collaboration. Innovative informatics technologies have been implemented to develop the NRDRS, including employment of ontological and knowledge bases to render standardization and support standard of care. Development of informatics analysis tools will facilitate accurate and more efficient diagnoses for rare diseases. Long-term research collaboration is encouraged to create additional national rare disease networks for research translation and to benefit patients with rare diseases. The NRDRS of China and related cohort studies are anticipated to enlighten rare disease research significantly in China. PMID- 29284291 TI - The Use of Quantitative EEG for Differentiating Frontotemporal Dementia From Late Onset Bipolar Disorder. AB - The behavioral variant frontotemporal dementia (bvFTD) usually emerges with behavioral changes similar to changes in late-life bipolar disorder (BD) especially in the early stages. According to the literature, a substantial number of bvFTD cases have been misdiagnosed as BD. Since the literature lacks studies comparing differential diagnosis ability of electrophysiological and neuroimaging findings in BD and bvFTD, we aimed to show their classification power using an artificial neural network and genetic algorithm based approach. Eighteen patients with the diagnosis of bvFTD and 20 patients with the diagnosis of late-life BD are included in the study. All patients' clinical magnetic resonance imaging (MRI) scan and electroencephalography recordings were assessed by a double-blind method to make diagnosis from MRI data. Classification of bvFTD and BD from total 38 participants was performed using feature selection and a neural network based on general algorithm. The artificial neural network method classified BD from bvFTD with 76% overall accuracy only by using on EEG power values. The radiological diagnosis classified BD from bvFTD with 79% overall accuracy. When the radiological diagnosis was added to the EEG analysis, the total classification performance raised to 87% overall accuracy. These results suggest that EEG and MRI combination has more powerful classification ability as compared with EEG and MRI alone. The findings may support the utility of neurophysiological and structural neuroimaging assessments for discriminating the 2 pathologies. PMID- 29284293 TI - Assessment of Needle Tip Deflection During Transrectal Guided Prostate Biopsy: Implications for Targeted Biopsies. AB - OBJECTIVES: To measure needle tip deflection during transrectal ultrasound (TRUS) prostate biopsy and evaluate predictors for needle tip deflection. MATERIALS AND METHODS: Analysis of 568 prostate biopsies obtained from 51 consecutive patients who underwent a standard 12-core TRUS guided prostate biopsy. TRUS guided prostate biopsies were performed using BK flex500, with a side-fire biplane probe. Each biopsy core image was captured and clinical data were recorded prospectively. The angle between the expected trajectory of the needle and actual needle course was measured using the longitudinal view of the captured image. The distance between expected and actual needle tip was calculated. We measured median and interquartile needle tip deflection rate stratified by side and location (apex, midgland, base). Univariable and multivariable linear regressions analysis were performed. RESULTS: The overall median needle tip deflection was 1.77 mm (IQR 1.35-2.47). Location did not significantly alter needle deflection measurements. On multivariable linear regression analysis, higher prostate volume (B = 0.007 95%, CI 0.004, 0.011; p < 0.001) and the right sided biopsy (B = 0.191 95%, CI 0.047, 0.336; p = 0.010) emerged as predictors of higher needle tip deflection. CONCLUSIONS: To the best of our knowledge this is the first study to measure needle tip deflection during TRUS guided prostate biopsies. We demonstrated that larger prostate size and biopsy side may affect the accuracy of biopsies. These results may have clinical implication to those performing targeted biopsies. PMID- 29284294 TI - Sex Ed to Go: A Content Analysis of Comprehensive Sexual Education Apps. AB - Mobile applications ("apps") designed for sexual health education have the potential to reach teens and young adults that are hard to reach through traditional platforms; however, little is known about availability of these apps and their adherence to existing guidelines. Following a search on the two major app stores, data from 2,693 apps were analyzed. Only 697 (25%) addressed sexual health, and only 15 (1%) of apps met inclusion criteria for comprehensive programs and their content was further analyzed. The content of most of these apps narrowly focused on sexually transmitted infections and pregnancy prevention and lacked information on puberty, sexual identity, and personal safety. Theoretically grounded strategies including self-efficacy and modeling behavior to strengthen behavior change efforts were largely absent. Last, we identified significant shortcomings in the literate design of these apps, including limited use of interactive features, such as videos, quizzes, or games. These findings indicate that the potential of apps as sexual health promotion tools has not yet been fully realized. We outline recommendations for developing theory- and evidence-based sexual education apps and provide suggestions for health educators on how to select relevant apps when working for youth. PMID- 29284295 TI - Perceptions of Cancer Risk/Efficacy and Cancer-Related Risk Behaviors: Results From the HCHS/SOL Sociocultural Ancillary Study. AB - This study evaluated the associations among perceived risk, perceived efficacy, and engagement in six cancer-related risk behaviors in a population-based Hispanic/Latino sample. Interviews were conducted with 5,313 Hispanic/Latino adults as part of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary Study. Participants were recruited from the study's four field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) between February 2010 and June 2011. Perceived risk and perceived efficacy were assessed with questions drawn from the Health Interview National Trends Survey. More than half of the sample endorsed perceived risk of cancer associated with the six evaluated behaviors, as well as general perceived efficacy for preventing cancer. Adjusted logistic regression analyses demonstrated significant differences across Hispanic/Latino background groups for perceived risk associated with high consumption of alcohol and saturated fat, low consumption of fruits and vegetables, and insufficient exercise but not with smoking or low consumption of fiber. Differences were also found for the belief, "It seems like everything causes cancer" but not for other perceived efficacy items. Perceived cancer risk and perceived efficacy for preventing cancer were neither independently nor interactively associated with engagement in cancer-related risk behaviors after controlling for sociodemographic covariates. Results suggest that perceptions of risk and efficacy with regard to cancer vary across Hispanic/Latino background groups, and therefore background group differences should be considered in prevention efforts. Perceived risk and perceived efficacy were not related to cancer-related risk behaviors among Hispanics/Latinos. Further work is needed to evaluate determinants of cancer-related risk in this population. PMID- 29284296 TI - Applications of Virus Vector-Mediated Gene Therapy in China. AB - Due to the increased safety and efficiency of virus vectors, virus vector mediated gene therapy is now widely used for various diseases, including monogenic diseases, complex disorders, and infectious diseases. Recent gene therapy trials have shown significant therapeutic benefits, and Chinese researchers have contributed significantly to this progress. This review highlights disease applications and strategies for virus vector-mediated gene therapy in preclinical studies and clinical trials in China. PMID- 29284297 TI - Editorial Comment on: Anatomic and Radiologic Study of Renal Avascular Plane (Brodel's Line) and Its Potential Relevance on Percutaneous and Surgical Approaches to the Kidney by Macchi et al. PMID- 29284298 TI - Originator of the hormesis concept: Rudolf Virchow or Hugo Schulz. AB - In 2006, Henschler disputed the claim of Calabrese and Baldwin that Hugo Schulz should be considered the originator of the hormesis concept. Henschler cited an 1854 paper by Rudolf Virchow on the effects of two agents on the beating of cilia, which showed a hormetic-biphasic dose response. The interpretation of Henschler became broadly accepted over the past decade based on citations in the literature. However, a recent translation of the Virchow paper from German into English reveals that the claims of Henschler are not supported by the article. PMID- 29284299 TI - A new phenanthrene and a new 9,10-dihydrophenanthren from Bulbophyllum retusiusculum. AB - A new phenanthrene, bobulretin A (1), and a new 9,10-dihydrophenanthrene, bobulretin B (2) along with four known bibenzyls (3-6) were isolated from the whole plants of Bulbophyllum retusiusculum. Their structures were elucidated by means of extensive spectroscopic analysis. Bobulretin B (2), isolated as enantiomer mixture with unequal proportions, was verified by analysis on a chiral OD-H HPLC column. Compounds 1, 3 and 4 were evaluated for their alpha-glucosidase inhibitory activity. Neither of them showed obvious activity. PMID- 29284300 TI - Stem-Cell Therapy Advances in China. AB - Stem-cell therapy is a promising method for treating patients with a wide range of diseases and injuries. Increasing government funding of scientific research has promoted rapid developments in stem-cell research in China, as evidenced by the substantial increase in the number and quality of publications in the past 5 years. Multiple high-quality studies have been performed in China that concern cell reprogramming, stem-cell homeostasis, gene modifications, and immunomodulation. The number of translation studies, including basic and preclinical investigations, has also increased. Around 100 stem-cell banks have been established in China, 10 stem-cell drugs are currently in the approval process, and >400 stem cell-based clinical trials are currently registered in China. With continued state funding, advanced biotechnical support, and the development of regulatory standards for the clinical application of stem cells, further innovations are expected that will lead to a boom in stem-cell therapies. This review highlights recent achievements in stem-cell research in China and discusses future prospects. PMID- 29284301 TI - John Smeaton and the vis viva controversy: Measuring waterwheel efficiency and the influence of industry on practical mechanics in Britain 1759-1808. AB - In this paper, I will examine John Smeaton's contribution to the vis viva controversy in Britain, focusing on how the hybridization of science, technology, and industry helped to establish vis viva, or mechanic power, as a measure of motive force. Smeaton, embodying the 'hybrid expert' who combined theoretical knowledge and practical knowhow, demonstrated that the notion of vis viva possessed a greater explanatory power than momentum, because it could be used to explain the difference in efficiency between overshot and undershot waterwheels. Smeaton's conclusions were correct since waterwheel efficiency was already measured in terms that were proportional to vis viva, not momentum, as a result of the industrial applications of waterwheel technology, which favored measuring efficiency by the product of mass and vertical displacement. Toward the end of the eighteenth century, the loss of motive force in the inelastic collision driving the undershot wheel began to be seen as equivalent to the expenditure of labor in the manufacture of commodities, further underlining how strictly scientific conclusions about motive force could have their origin in industrial practices. PMID- 29284302 TI - Long-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy. AB - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in TYMP, the gene encoding the enzyme thymidine phosphorylase (TP). TP dysfunction results in systemic accumulation of the noxious TP substrates thymidine and deoxyuridine. Gene therapy using either a lentiviral vector or adeno-associated vector (AAV) has proven to be a feasible strategy, as both vectors restore biochemical homeostasis in a murine model of the disease. This study shows that the effect of an AAV containing the TYMP coding sequence transcriptionally targeted to the liver persists long term in mice. Although the vector copy number was diluted and AAV-mediated liver TP activity eventually reduced or lost after 21 months at the lowest vector doses, the effect was sustained (with a negligible decrease in TP activity) and fully effective on nucleoside homeostasis for at least 21 months at a dose of 2 * 1012 vg/kg. Macroscopic visual inspection of the animals' organs at completion of the study showed no adverse effects associated with the treatment. These results further support the feasibility of gene therapy for MNGIE. PMID- 29284303 TI - 'I am free in my wheelchair but pain does have a say in it though': The meaning and experience of quality of life when living with paraplegia and chronic pain. AB - This study investigated how wheelchair-using individuals with paraplegia and chronic pain make sense of the factors associated with quality of life based on interviews using photo-elicitation and interpretative phenomenological analysis. Three superordinate themes emerged in the analysis: experiencing quality of life through the perception of self and identity, interpersonal relationships as facilitators and barriers to quality of life and life in a wheelchair: pain experience and management. Quality of life for those living with paraplegia and chronic pain is experienced as a complex interaction across several life domains. The use of photographs may improve the communication of pain-related experiences and understanding by healthcare staff. PMID- 29284304 TI - Altered Long Non-Coding RNA Transcriptomic Profiles in Ischemic Stroke. AB - A previous study described the important regulatory roles of microRNAs (miRNAs) in ischemic stroke. However, the functional significance of long non-coding RNA (lncRNAs) in ischemic stroke was largely unknown. This study aimed to identify lncRNA profiling and elucidate the regulatory mechanisms in the pathophysiology of stroke. RNA sequencing was performed on the blood of three ischemic stroke patients and three normal controls. Differential expression analysis was used to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). After further correlation and co-expression analysis, the corresponding co-expression networks and miRN-lncRNA-mRNA interaction network were then constructed. The expression of DElncRNAs and DEmRNAs was verified in Gene Expression Omnibus. RNA sequencing and subsequent bioinformatics analysis produced a total of 61 DElncRNAs (14 upregulated and 47 downregulated) and 673 DEmRNAs (432 upregulated and 241 downregulated). LOC105372881 and LOC101929707 were the most highly increased and decreased lncRNAs in ischemic stroke. LncRNA-mRNA co-expression networks were constructed according to 3,008 positively co-expressed and 607 negatively co-expressed lncRNA-mRNA pairs. The DElncRNAs may play roles in the pathways of glycolysis/gluconeogenesis, arrhythmogenic right ventricular cardiomyopathy, adherens junction, lysosome, and hematopoietic cell lineage by regulating their co-expressed mRNAs. Combined with previous data, a miRNA-lncRNA mRNA interaction network for ischemic stroke was constructed. Based on GSE22255, the expression of six DElncRNAs (CEBPA-AS1, LINC00884, HCG27, MATN1-AS1, HCG26, and LINC01184) and 11 DEmRNAs (TREML4, AHSP, PI3, TESC, ANXA3, OAS1, OAS2, IFI6, ISG15, IFI44L, and LY6E) was similar to the current sequencing data. This study is the first to identify blood lncRNAs in human ischemic stroke using RNA sequencing. The findings may be the foundation for understanding the potential role of lncRNAs in ischemic stroke. PMID- 29284305 TI - How Functional Is Moringa oleifera? A Review of Its Nutritive, Medicinal, and Socioeconomic Potential. AB - Moringa oleifera is an important tropical food plant that seems to have great nutritional, therapeutic, industrial, agricultural, and socioeconomic value. Dietary consumption of its parts and preparations is encouraged by several organizations, health food enthusiasts, and other specialists as a strategy of personal health preservation and self-medication in the treatment of various diseases. Studies extoling its ability to mitigate various degenerative ailments now exist in both the scientific and the popular literature. At face value, and considering the volume of reports available, much of this enthusiasm seems to be indeed justified. However, it is imperative to distinguish rigorous scientific evidence from anecdote. To achieve this, relevant experimental and review articles were sought and read critically to identify recent patterns and trends on this subject matter. Studies on the medicinal and functional properties of M. oleifera are available from various parts of the world, especially developing regions. Attempts have been made to parse the contemporary scientific data available supporting the claims regarding the phytochemical, nutritive, medicinal, environmental, agricultural, and socioeconomic capabilities of this plant. Studies reviewed provide compelling, albeit preliminary experimental evidence of therapeutic potential of the plant. It is important that M. oleifera products and preparations be properly chemically characterized and standardized before being administered. PMID- 29284306 TI - Coverage and Consumption of Micronutrient Powders, Fortified Staples, and Iodized Salt Among Children Aged 6 to 23 Months in Selected Neighborhoods of Nairobi County, Kenya. AB - BACKGROUND: Intake of micronutrient-rich foods among children aged 6 to 23 months in Nairobi is low. OBJECTIVE: This study aimed to assess existing coverage and utilization of micronutrient powders (MNPs), fortified staples, and iodized salt among children aged 6 to 23 months prior to implementation of an MNP program. METHODS: A cross-sectional survey among caregivers of children aged 6 to 23 months (n = 618) was implemented in 7 neighborhoods within Nairobi County, representing the implementation area of the new MNP program. RESULTS: Results for MNP coverage and utilization showed 28.5% of all caregivers were aware of MNP, 18.5% had ever received MNP for their child, and 10.8% had fed MNP to their child in the previous 7 days. Effective coverage (ie, the child had been given the MNP at least 3 times in the previous 7 days) was 5.8%. Effective coverage of infants and young children with poor feeding practices was significantly lower as compared to those with non-poor feeding practices (coverage ratio, 0.34; confidence interval, 0.12-0.70). Most households purchased iodized salt (96.9%), fortified oil (61.0%), and fortified maize flour (93.9%). An estimated 23.9% of vitamin A requirements of children (6-23 months) were provided from fortified oil and 50.7% of iron from fortified maize flour. Most households consumed processed milk (81%). CONCLUSION: Coverage of MNPs in the surveyed neighborhoods was low. Coverage of fortified salt, oil, and maize flour was high and provided significant amount of micronutrients to children. Processed milk has potential as a vehicle for food fortification. PMID- 29284307 TI - Diarylheptanoids from the fresh pericarps of Juglans sigillata. AB - One new diarylheptanoid (3S)-3', 4"-epoxy-1-(4'-hydroxylphenyl)-7-(3" hydroxylphenyl) heptane-3-hydroxy (1), together with eleven known ones (2-12), was isolated from the fresh pericarps of Juglans sigillata. Their structures were elucidated on the basis of extensive spectroscopic methods, including HR-ESI-MS, 1D and 2D-NMR. All isolates were evaluated for their cytotoxic activities in vitro against the growth of human cancer cells lines HT-29 and MCF-7 by MTT assay. PMID- 29284308 TI - Fighting Cancer with Viruses: Oncolytic Virus Therapy in China. AB - As part of oncolytic virotherapy to treat cancer, oncolytic viruses (OVs) can selectively infect tumor cells to promote oncolysis of cancer cells, local immunological reactions, and systemic antitumor immunity with minimal toxicity to normal tissues. The immunostimulatory properties of OVs provide enormous benefits for the treatment of cancer. A variety of OVs, including genetically engineered and natural viruses, have shown promise in preclinical models and clinical studies. In 2005, the China Food and Drug Administration approved its first OV drug, Oncorine (H101), for treatment of advanced head and neck cancer. To explore new treatment strategies, >200 recombinant or natural OVs are undergoing in-depth investigation in China, and >250 oncolytic virotherapy-related reports from the OV community in China have been published in the past 5 years. These studies investigated a variety of exogenous genes and combination therapeutic strategies to enhance the treatment effects of OVs. To date, five clinical trials covering four OV agents (Oncorine, OrienX010, KH901, and H103) are ongoing, and additional OV agents are awaiting approval for clinical trials in China. Overall, this research emphasizes that combination therapy, especially tumor immunotherapy coupled with effective system administration strategies, can promote the development of oncolytic virotherapies. This article focuses on studies that were carried out in China in order to give an overview of the past, present, and future of oncolytic virotherapy in China. PMID- 29284309 TI - Proteomics and metabolomics for analysis of the dynamics of microbiota. PMID- 29284310 TI - Does the novel delivery system for the STENTYS self-apposing coronary stent increase the risk of stent edge dissections? Optical coherence tomography post stent findings. AB - BACKGROUND: With optical coherence tomography (OCT), details of arterial injuries during percutaneous coronary intervention can be assessed accurately. There might be an increased risk of stent edge dissections with the novel delivery system for the STENTYS stent. We evaluated the prevalence of stent edge dissections using the novel Xposition delivery device as compared with the conventional delivery device. METHODS: A total of 38 patients who were treated with the self-apposing STENTYS stent and with OCT assessment at our center were retrospectively analysed. Twenty patients were treated using the Xposition- and 18 using the conventional delivery device. OCT was performed according to study protocol. Frames with poor quality were excluded. RESULTS: A total of 12(18%) dissections were detected, 7(20%) in the Xposition delivery device group, and 5(15%) in the conventional group (p = 1). Using the Xposition delivery device 4(33%) dissections were found proximally, using the conventional delivery device 3(25%) (p = ns). Mean longitudinal dissection length was 2.07 +/- 1.80mm, 8(67%) appeared as flaps, 4(33%) as cavities. Morphometric parameters were comparable in both groups. CONCLUSIONS: Detailed OCT assessment of stent edge dissections was possible, which revealed no large differences using the Xposition delivery device as compared with conventional delivery device, however large studies are warranted. PMID- 29284311 TI - "Keep All Thee 'Til the End": Reclaiming the Lifeworld for Patients in the Hospice Setting. AB - St Christopher's Hospice, London, was founded to provide specialist care to the incurably ill. We studied the dimensions of difference that set St Christopher's Hospice apart from hospital care of the dying, focusing on physical space and social organization. Material from 1953 to 1980 from the Cicely Saunders Archive was analyzed qualitatively. Through thematic analysis, quotes were found and analyzed using open coding. Five themes were developed. Themes identified were home/homelike, community, consideration of others, link with outside world, and privacy. The hospice philosophy functioned as the catalyst for the development of the physical environment of St Christopher's Hospice. Taking Habermas' concept of lifeworld, it seems that, in contrast to acute care, the need for hospice to formulate their own lifeworld to support and fully engage patients was central. As lifeworlds are culture sensitive, this underlines the need for variation in design and organization of hospices around the world. PMID- 29284312 TI - Exploring the Contemporary Stage and Scripts for the Enactment of Dying Roles: A Narrative Review of the Literature. AB - This narrative review explores the literature regarding the drama of dying from several academic perspectives. Three key themes were identified including "The impact of blurred boundaries on roles and transitions," "The orchestration of death and dying through time," and "Contemporary dying and new machinery of control." This review reveals the manner in which tightly scripted dying roles serve the needs of the living to a greater extent than those of the dying, by ensuring the depiction of both dying and death as phenomena which have been brought under the control of the living, thereby countering death anxiety. An incongruence between the actual experience of dying and contemporary dying scripts is also highlighted. The authors argue that this incongruence is hidden from the broader societal audience through the maintenance of a dying role that demands serenity and acceptance, thus downplaying or even hiding the actual end of-life experiences of the dying themselves. PMID- 29284313 TI - The Long Road to Farewell: The Needs of Families With Dying Children. AB - Families of dying children are profoundly impacted by numerous interactions with health-care providers before, during, and after their child's death. However, there is a dearth of research on these families' direct, qualitative experiences with health-care providers. This study presents findings from interviews with 18 family members, predominantly parents, regarding their experiences with health care providers during a child's terminal illness, from diagnosis to death. The importance of compassion emerged as a salient theme, manifested in myriad ways, and connected to participants' perception of caregiver presence in multiple domains. Families were likewise negatively affected by a wide variety of situations and behaviors that represented individual or institutional abandonment or nonpresence, and thus compounded the experience of loss. Specifics and implications for practice are explored. PMID- 29284314 TI - When Men Grieve: Widowers' Stories of Coping With Their Wives' Deaths. AB - To increase our understanding of the role gender plays in spousal loss, this qualitative study analyzes bereavement narratives of 33 recent widowers, aged 45 89 years, all of whom accessed the National Widowers' Organization website. In particular, we look at how these widowers' lives changed, the impact of changing gender norms, and coping strategies. To illuminate the temporal process evident in these narratives, we utilize Silverman's nonlinear characteristics of bereavement and the anthropological concept of liminality. In contrast to studies of widowers in earlier decades, our analysis reveals questioning and rejection of stereotypical masculine gender norms, a wide variety of creative responses to spousal loss, and the need for individualized support. PMID- 29284315 TI - Oxidation of proteins: is it a programmed process? AB - Proteins represent extremely susceptible targets for oxidants. Oxidative modifications of proteins may bring about violation of their structure and functionality. It implies that the structures of proteins are not infallible in terms of their antioxidant defence. The protection mechanisms in preventing oxidative damages for proteins within cells are mainly related to a large variety of antioxidant enzymatic systems. In contrast, plasma proteins are scarcely protected by these systems, so the mechanism that provides their functioning in the conditions of generating reactive oxygen species (ROS) seems to be much more complicated. Oxidation of many proteins was long considered as a random process. However, the highly site-specific oxidation processes was convincingly demonstrated for some proteins, indicating that protein structure could be adapted to oxidation. According to our hypothesis, some of the structural elements present in proteins are capable of scavenging ROS to protect other protein structures against ROS toxicity. Various antioxidant elements (distinct subdomains, domains, regions, and polypeptide chains) may act as ROS interceptors, thus mitigating the ROS action on functionally crucial amino acid residues of proteins. In the review, the oxidative modifications of certain plasma proteins, such as alpha2-macroglobulin, serum human albumin, fibrinogen, and fibrin-stabilising factor, which differ drastically in their spatial structures and functions, are analysed. The arguments that demonstrate the possibility of existing hypothetical antioxidant structures are presented. For the first time, the emphasis is being placed on the programmed mechanism of protein oxidation. PMID- 29284316 TI - Profile of GenMark's ePlex(r) blood culture identification fungal pathogen panel. AB - INTRODUCTION: Fungemia presents high morbi-mortality and thus rapid microbiological diagnosis may contribute to appropriate patient management. In the last decade, kits based on molecular technologies have become available and health care institutes are increasingly facing critical investment choices. Although all these tools aim to achieve rapid fungal detection and species identification, they display different inherent characteristics. Areas covered: Considering technologies allowing detection and identification of fungal species in a sepsis context, the market proposes either tests on positive blood culture or tests on patient's whole blood. In this review, the authors describe and compare the ePlex(r) Blood Culture Identification Fungal Pathogen (BCID-FP) test, a fully automated one-step single-use cartridge assay that has been designed to detect identify frequent or rare but emerging, fungal species, from positive blood culture. A comparison with the competing kits is provided. Expert commentaries: The ePlex BCID-FP test provides a diversified and rather relevant panel. Its easy-to-use cartridges allow flexible use around the clock. Nevertheless, prospective clinical studies assessing the time-to-result benefit on antifungal stewardship and on hospital length of stay are not available yet. New tools aim to benefit clinicians and patients, but they should be accompanied by supervision of result interpretation and adaptation of antifungal stewardship. PMID- 29284317 TI - Autonomic dysfunction in a patient with X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy is an inherited disease caused by abnormal accumulation of very long chain fatty acids. The diagnosis of X-linked adrenoleukodystrophy can be confirmed with the mutation of ABCD1 gene. The main symptom of the X-linked adrenoleukodystrophy is spastic paraparesis, and autonomic dysfunction is rare in X-linked adrenoleukodystrophy. Here, we presented an X-ALD case of a 46-year-old Asian male with severe autonomic dysfunction. Impairment of the autonomic nervous system may closely relate to mitochondrial defect. PMID- 29284318 TI - Pembrolizumab for the treatment of bladder cancer. AB - INTRODUCTION: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies. Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab. Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy. PMID- 29284319 TI - Next-generation sequencing: from conventional applications to breakthrough genomic analyses and precision oncology. PMID- 29284321 TI - Ral function in muscle is required for flight maintenance in Drosophila. AB - Ral is a small GTPase of the Ras superfamily that is important for a number of cellular functions. Recently, we found that expression of Ral is regulated by store-operated calcium entry (SOCE) in Drosophila neurons. In this study, through genetic and behavioural experiments, we show that Ral function is required in differentiated muscles for flight. Reducing Ral function in muscles, specifically reduced duration of flight bouts but not other motor functions, like climbing. Interestingly, unlike in the nervous system, Ral expression in the muscle is not regulated by SOCE. Moreover, either knockdown or genetic inhibition of SOCE in muscles does not affect flight. These findings demonstrate that a multiplicity of signalling mechanisms very likely regulate Ral expression in different tissues. PMID- 29284320 TI - Clinical and virologic effects of four neuraminidase inhibitors in influenza A virus-infected children (aged 4-12 years): an open-label, randomized study in Japan. AB - BACKGROUND: Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670). METHODS: Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint. RESULTS: Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups. CONCLUSIONS: The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation. PMID- 29284322 TI - Maximizing Nutrition Support Practice and Measuring Adherence to Nutrition Support Guidelines in a Canadian Tertiary Care ICU. AB - OBJECTIVE: New comprehensive guidelines for nutrition support (NS) in the intensive care unit (ICU) can be used to improve quality of care and benchmark current practice. The objective of this study was to (a) compare NS practices in our medical/surgical ICU (MSICU) to 18 recommendations described in the Canadian Clinical Practice Guidelines and Society of Critical Care Medicine/American Society of Parenteral and Enteral Nutrition guidelines, (b) determine the percentage of goal calories and protein delivered, and (c) identify the barriers to successful NS delivery. DESIGN: This was a prospective observation trial of up to 14 days duration. SETTING: A 24-bed MSICU in a tertiary teaching hospital in Toronto, Canada. PATIENTS: We studied 98 mechanically ventilated patients with any diagnosis who were expected to require either enteral nutrition (EN) or parenteral nutrition (PN) for >48 hours. MEASUREMENTS: We measured nutritional intake, barriers to nutritional intake, and parameters that allowed comparison of our practice to 18 guidelines. MAIN RESULTS: Mean delivery of protein and energy was 79.3% and 81.1% of goal, respectively. The average time to initiation of EN support was 29.5 +/- 23.7 hours. The 3 main reasons for interruption to enteral feeding were airway management issues, procedures, and gastrointestinal intolerance. Enteral feeding during vasopressor therapy was well tolerated. Ten of the 18 guidelines were followed for >=80% of the time. Protein goals for patients on renal replacement therapy and patients with liver disease were not reached. Head-of-bed positioning was also inadequate. The 13 patients requiring PN all had appropriate indications for this therapy, including gastrointestinal leaks, maldigestion, or malabsorption. CONCLUSIONS: Nutrition support delivery was successful for most patients in this study. However, only 10 of the 18 guidelines were adequately followed. This study helped identify NS practices that work well and others that require strategies for improvement. PMID- 29284323 TI - Receiving Spiritual Care: Experiences of Dying and Grieving Individuals. AB - The study examines the perceptions of interfaith spiritual care, received through a volunteer hospice organization, by 10 individuals facing death and dying. Qualitative methodology based on the Interpretive Phenomenological Analysis was used to collect and analyze the data. Four superordinate themes reflected meanings ascribed to spirituality and spiritual care in facing end of life: Vital Role of Spirituality in the End-of-Life Care, Definitions and Parameters of Spirituality and Interfaith Spiritual Care, Distinct Aspects of Interfaith Spiritual Care, and Unmet Spiritual Needs. The results expand an understanding of the role of spirituality and spiritual care as part of the hospice and palliative care through attention to individual perceptions and experiences, as well as to ways to expand attention to spirituality within the hospice care. PMID- 29284324 TI - Pre-existing diabetes mellitus and all-cause mortality in cancer patients: a register-based study in Latvia. AB - BACKGROUND: Most studies from high income countries consistently report that preexisting diabetes reduces overall survival of cancer patients. We examined this association in a retrospective cohort study using two nation-wide population based data sets in Latvia. MATERIAL AND METHODS: The Cancer Register, linked with the Diabetes Register and Causes of Death Database, was the first data source used to select 22,936 men and 25,338 women with cancer diagnosed from 2009 to 2013. The follow-up period ended on 28 February 2015. The National Health Service data served as a second data source, which was used to select 10,130 men and 13,236 women with cancer as the main diagnosis, who were discharged from oncology hospitals from 2009 to 2012. Prescriptions of reimbursed antidiabetic medications indicated prior diabetes status. The follow-up period started at the date of discharge and ended on 31 December 2013. A Cox proportional hazards model was used to assess association between preexisting diabetes and all-cause mortality, adjusted for age. RESULTS: Men with preexisting diabetes had better overall short term survival: the age-adjusted hazard ratios (95% CI) were 0.86 (0.79-0.93) for the first year and 0.89 (0.80-0.98) for the first two years after cancer diagnosis according to the disease register and health service data, respectively. After three full follow-up years, their relative mortality increased, with an age-adjusted hazard ratio of 1.60 (1.28-1.99). Among women, preexisting diabetes was associated with slightly higher all-cause mortality during the entire follow-up period, with age-adjusted hazard ratios of 1.17 (1.10 1.24) for the disease register data and 1.11 (1.02-1.21) for the health service data. CONCLUSION: Interestingly, we found better overall survival of diabetic men during the first years after cancer diagnosis. We hypothesize that access to health services may be advantageous to diabetic patients who are in close contact with the healthcare system. PMID- 29284325 TI - Fathers Raising Motherless Children: Widowed Men Give Voice to Their Lived Experiences. AB - Little is known about the experiences of widowed men with dependent children. With such limited knowledge it is not clear how mental health professionals can assist this population. In this qualitative case study the researcher describes the experiences of ten widowed fathers from the Southeastern United States as they struggle with their new parenting responsibilities after the death of their wives and their children's mothers. The researcher used an inductive constant comparative method to reveal themes. The interview data revealed three themes: Ways to Cope, Concerns, and Newfound Respect. These themes and their subcategories are presented together with suggestions on how to assist widowers with dependent children. PMID- 29284327 TI - The Influence of Supportive Supervisory Practices and Health Care Aides' Self Determination on the Provision of Person-Centered Care in Long-Term Care Facilities. AB - Person-centred care (PCC) is recognized as best practice in long-term care (LTC). Using a cross-sectional design, we examined the relationship between supportive supervisory practices and health care aides' (HCAs) self-determination on HCAs' perceived ability to provide PCC. A total of 131 HCAs from four LTC facilities participated in the study. There were strong, positive associations between HCAs' self-determination and their perceived ability to provide PCC, r = .59, p < .0001, and how supportive their supervisors were, r = .50, p < .0001. Mediation analysis using structural equation modeling found the direct effect of self determination on PCC was 73% of its total effect on PCC; its indirect effect mediated through supervisory support was 27% of its total effect on PCC. Improving supportive supervisory relationships that encourage and enable HCAs' self-determination in LTC settings may be an important and effective means by which to increase the provision of PCC. PMID- 29284330 TI - Clinical characterization of women with burning mouth syndrome in a case-control study. AB - OBJECTIVE: Burning mouth syndrome (BMS) is a chronic orofacial pain disorder that is defined by a burning sensation in the oral mucosa. The aim of this study was to investigate the underlying factors, clinical characteristics and self-reported oral and general health factors associated with BMS. MATERIAL AND METHODS: Fifty six women with BMS (mean age: 67.7) and their age-matched controls were included in the study. A general questionnaire, an OHRQL index and BMS-specific questionnaires were used. Each subject underwent an oral examination. RESULTS: The mean severity of the BMS symptoms (VAS, 0-100) was 66.2 (SD 19.7). Overall, 45% of the patients reported taste disturbances. More of the patients than the controls rated their general health, oral health and life situation as 'less satisfactory'. The patients also reported more frequently on-going medications, diseases/disorders, xerostomia, allergy and skin diseases. Except for more bruxofacets among the patients, there were no significant differences regarding signs of parafunction. In a multiple logistic regression analysis, xerostomia and skin diseases showed the strongest prediction for BMS and no significant effect was found for medication, allergy or bruxofacets. CONCLUSIONS: Skin diseases and xerostomia but not parafunction were strongly associated with BMS. Our findings provide the basis for additional studies to elucidate the causal factors of BMS. PMID- 29284329 TI - Drug release kinetics of temperature sensitive liposomes measured at high temporal resolution with a millifluidic device. AB - PURPOSE: Current release assays have inadequate temporal resolution ( ~ 10 s) to characterise temperature sensitive liposomes (TSL) designed for intravascular triggered drug release, where release within the first few seconds is relevant for drug delivery. MATERIALS AND METHODS: We developed a novel release assay based on a millifluidic device. A 500 um capillary tube was heated by a temperature-controlled Peltier element. A TSL solution encapsulating a fluorescent compound was pumped through the tube, producing a fluorescence gradient along the tube due to TSL release. Release kinetics were measured by analysing fluorescence images of the tube. We measured three TSL formulations: traditional TSL (DPPC:DSPC:DSPE-PEF2000,80:15:5), MSPC-LTSL (DPPC:MSPC:DSPE PEG2000,85:10:5) and MPPC-LTSL (DPPC:MMPC:PEF2000,86:10:4). TSL were loaded with either carboxyfluorescein (CF), Calcein, tetramethylrhodamine (TMR) or doxorubicin (Dox). TSL were diluted in one of the four buffers: phosphate buffered saline (PBS), 10% bovine serum albumin (BSA) solution, foetal bovine serum (FBS) or human plasma. Release was measured between 37-45 degrees C. RESULTS: The millifluidic device allowed measurement of release kinetics within the first few seconds at ~5 ms temporal resolution. Dox had the fastest release and highest release %, followed by CF, Calcein and TMR. Of the four buffers, release was fastest in human plasma, followed by FBS, BSA and PBS. CONCLUSIONS: The millifluidic device allows measurement of TSL release at unprecedented temporal resolution, thus allowing adequate characterisation of TSL release at time scales relevant for intravascular triggered drug release. The type of buffer and encapsulated compound significantly affect release kinetics and need to be considered when designing and evaluating novel TSL-drug combinations. PMID- 29284331 TI - Empathy Mind-Set Moderates the Association Between Low Empathy and Social Aggression. AB - Empathy plays an important role in creating and maintaining adaptive interpersonal relationships. Accordingly, existing studies often report a negative correlation between empathy and interpersonal aggression. However, findings are sometimes inconsistent, and concerns have been raised about the size of the overall effect. Here, we examined the potential moderating role of empathy mind-sets-beliefs about the malleability of empathy. We hypothesized that the association between low empathy and aggression would be especially strong if individuals also believed that their levels of empathy were unchangeable (i.e., they endorsed a fixed mind-set about empathy); in contrast, a belief that empathy was malleable may weaken the association. Results supported this hypothesis, such that individuals with low levels of empathy were less likely to report aggression social aggression in particular-if they also believed that empathy was changeable. These results point to a role for beliefs about the malleability of empathy as an important moderator and may point to ways to enhance empathy interventions by targeting mind-sets. PMID- 29284332 TI - Past Year Technology-Involved Peer Harassment Victimization and Recent Depressive Symptoms and Suicide Ideation Among a National Sample of Youth. AB - This article aims to better understand the complex role of technology in peer victimization events with recent depressive symptomatology and suicide ideation (SI). Telephone interviews were conducted with a national sample of 791 youth in the United States, aged 10 to 20 years, collected from December 2013 to March 2014. Rates of any peer harassment victimization varied by past month depressive symptomatology and SI -28% of youth with no/low depressive symptomatology reported past year peer harassment as did 43% of youth with high depressive symptomatology without SI, and 66% of youth with SI. When examining the role of technology in peer harassment, youth experiencing any mixed harassment (i.e., those incidents that occurred both in-person and through technology) were almost 4 times more likely to report past month depressive symptoms without SI (RRadj = 3.9, 95% confidence interval [CI] = [1.5, 10.0], p <= .01) and 7.5 times (95% CI = [1.9, 28.9], p <= .01) more likely to report past month SI compared with youth who had no past year peer harassment. Given the multilayered relationships among these variables, schools, medical, and mental health professionals might screen youth who are involved in higher risk peer victimization situations, for depressive symptoms and SI to improve their access to appropriate mental health services. PMID- 29284333 TI - Having another child without intellectual disabilities: Comparing mothers of a single child with disability and mothers of multiple children with and without disability. AB - To investigate how having a child without a disability is related to maternal mental health and its predictors, we compared mothers of a single child with intellectual disabilities (single-child group, n = 117) and mothers of children with and without intellectual disabilities (multiple-children group, n = 457), in Japan. Compared to the multiple-children group, the single-child group had lower hope and social capital and poorer mental health; furthermore, 42.5% of them had decided not to have another child, despite desiring one. Hope was the strongest predictor of mental health in both groups but was more positively related to mental health in the multiple-children group. The fear of the possibility of the next child having a disability and receiving inadequate support were the obstacles for mothers who had decided not to have another child. Thus, greater support and more opportunities for obtaining adequate information about the implications of having another child may be needed. PMID- 29284336 TI - Prenatal diagnosis of Seckel syndrome at 21 weeks' gestation and review of the literature. AB - BACKGROUND: The Seckel syndrome is an autosomal recessive inherited disorder that characterized severe pre- and post-natal growth restriction, microcephaly and a bird-like fetal head appearance. A few clinical reports revealed prenatal sonographic findings in the literature. CASE: A 29-year-old, Turkish, gravid 3, para 2, woman was referred to our center for further evaluation of a suspicion of microcephaly at 21 weeks' gestation. The couple was third degree consanguineous. Detailed 2- and 3-dimensional sonography scan revealed a bird-headed appearance, prominent eyes with hypotelorism, a severe microcephaly (bi-parietal diameter and head circumference were both < 1. Percentile for 21 weeks' gestation), a beaked nose, and increased nuchal fold thickness measurement (> 95th percentile), low set and prominent ears. All sonographic findings suggested Seckel syndrome and the couple elected termination of pregnancy in the present case. SUMMARY: Seckel syndrome should be kept in mind in the differential diagnosis of severe microcephaly, accompanied by fetal growth restriction. 3D ultrasound is a useful adjuvant to routine 2D sonography for prenatal diagnosis of the syndrome and can delineate abnormal fetal head appearance (a bird-headed profile). PMID- 29284337 TI - Evaluation of maternal serum ischemia modified albumin and total antioxidant status in ectopic pregnancy. AB - BACKGROUND: Ectopic pregnancies constitute about 2% of all pregnancies which are the leading cause of pregnancy-related deaths and a considerable cause of maternal morbidity. Oxidative stress can lead to a number of pregnancy related diseases including miscarriage, eclampsia and preterm labor. Ischemia modified albumin (IMA) which reflects the oxidative stress may be used as a marker for ectopic pregnancy. Our aim was to compare the levels of IMA and total antioxidant status (TAS) in ectopic and normal pregnancies and to understand if IMA can be used as a marker to diagnose ectopic pregnancy. MATERIALS AND METHODS: Our case control study consisted of 38 women with ectopic and 42 women with normal pregnancy. IMA and TAS levels were determined in serum samples with an albumin cobalt binding test and by commercially available kits, respectively. IMA levels were adjusted according to serum albumin levels. Index of oxidation (IOS) was calculated by dividing adjusted IMA (A-IMA) levels with TAS. A receiver operating characteristics (ROC) curve analysis was made and cut-off values for the biomarkers were investigated in SPSS 21.0 program (SPSS, Chicago, IL). Data were presented as mean +/- standard deviation and a p value < .05 was accepted as statistically significant. RESULTS: There was a statistically significant difference in IMA, A-IMA, and IOS levels between ectopic and normal pregnancies. Although TAS level was not different statistically, it was lower in ectopic pregnancy. According to ROC curve analysis, IOS had the largest area under curve. A cut-off value of 0.545 for IOS had 81.6% sensitivity and 59.5% specificity. CONCLUSIONS: According to our study, oxidative stress plays an important role in ectopic pregnancy and either A-IMA or IOS can be evaluated as a marker of ectopic pregnancy after further studies. PMID- 29284338 TI - Catastrophic antiphospholipid syndrome and pregnancy. Clinical report. AB - We have observed the development of a catastrophic antiphospholipid syndrome (CAPS) in a pregnant woman hospitalized at 28 weeks of gestation with a severe preeclampsia. On the same day, an eclampsia attack developed, and an emergency surgical delivery was performed. On the third day, multiorgan failure developed. Examination showed a persistent circulation of lupus anticoagulant, high level of antibodies to cardiolipin, b2-glycoprotein I, and prothrombin. The usual diagnosis of the severe preeclampsia masked a catastrophic antiphospholipid syndrome, exacerbated by the coincident presence of several types of antiphospholipid antibodies. The first pregnancy resulted in a premature birth at 25 weeks, possibly also due to the circulation of antiphospholipid antibodies. The trigger of the catastrophic form development was the pregnancy itself, surgical intervention, and hyperhomocysteinemia. CAPS is the most severe form of antiphospholipid syndrome, manifested in multiple microthrombosis of microcirculation of vital organs and in the development of multiorgan failure against the background of the high level of antiphospholipid antibodies. CAPS is characterized by renal, cerebral, gastrointestinal, adrenal, ovarian, skin, and other forms of microthrombosis. Thrombosis recurrence is typical. Thrombotic microvasculopathy lies at the heart of multiorgan failure and manifests clinically in central nervous system lesions, adrenal insufficiency, and ARDS development. CAPS is a life-threatening condition, therefore, requires an urgent treatment. Optimal treatment of CAPS is not developed. CAPS represent a general medical multidisciplinary problem. PMID- 29284340 TI - On the advantage of autobiographical memory pliability: implantation of positive self-defining memories reduces trait anxiety. AB - This paper is devoted to the mechanism of the positive construction of autobiographical memory. Positive construction consists of the spontaneous transformation of memories in the direction of the subjective enhancement of self competence in past activities to anticipate improvement over time. We speculated that trait anxiety may indicate a failure to exhibit this mechanism that results in a deficit of affirmative self-esteem. We hypothesised that the implantation of positive self-defining memories in anxiety-evoking domains would decrease trait anxiety. One hundred twenty adults recollected three negative self-defining memories. Then, half of the participants imagined episodes of desired behaviour that differed from the originally recollected ones either in discussion or in hypnosis. Thirty participants experienced a hypnotic state without any references to memories, and the rest formed the control group. Subjects from the "Memory Implantation in Hypnosis" group became unable to distinguish the originally reported memories from the imagined ones, exhibited decreased trait anxiety scores after a 4-month delay, and reported enhanced self-esteem. In contrast, the participants from the "Hypnosis with no reference to the past" group exhibited decreased scores at a short delay but later returned to their original scores. These findings highlight the power of cured episodic-like autobiographical memory for updating the self. PMID- 29284341 TI - Cerebral perfusion monitoring in adult patients following cardiac surgery: an observational study. AB - BACKGROUND: Following adult cardiac surgery, often difficult to detect fluctuations in regional cerebral perfusion can contribute to strokes. Optimal cerebral perfusion remains elusive and traditional monitoring strategies do not consistently identify acute changes. Non-invasive cerebral oximetry may detect perfusion variations. OBJECTIVE: To assess the feasibility of postoperative non invasive cerebral oximetry monitoring. METHODS: Non-invasive cerebral oximetry was performed on adult aortic valve surgery patients in a cardiac surgical intensive care unit. Monitoring feasibility was assessed using an investigator developed, data extraction tool. RESULTS: Non-invasive cerebral oximetry was completed in 94% of patients. Sixty percent had values that fell below pre-set ischemic threshold. Nurses reported monitoring was feasible, and they perceived identifying deleterious cerebral perfusion trends may improve patient care. CONCLUSIONS: Prevalence of low cerebral oximetry values underscores the importance of increasing sensitivity of monitoring tools. Further evaluation is required to assess this modality and the role of nurses in optimizing neurocognitive outcomes. Impact statement: Cerebral oximetry monitoring may help identify adult patients at risk of neurological complications after cardiac surgery, and as a consequence initiate definitive therapeutic strategies. PMID- 29284344 TI - Differential age-related effects on conjunctive and relational visual short-term memory binding. AB - An age-related associative deficit has been described in visual short-term binding memory tasks. However, separate studies have suggested that ageing disrupts relational binding (to associate distinct items or item and context) more than conjunctive binding (to integrate features within an object). The current study directly compared relational and conjunctive binding with a short term memory task for object-colour associations in 30 young and 30 older adults. Participants studied a number of object-colour associations corresponding to their individual object span level in a relational task in which objects were associated to colour patches and a conjunctive task where colour was integrated into the object. Memory for individual items and for associations was tested with a recognition memory test. Evidence for an age-related associative deficit was observed in the relational binding task, but not in the conjunctive binding task. This differential impact of ageing on relational and conjunctive short-term binding is discussed by reference to two underlying age-related cognitive difficulties: diminished hippocampally dependent binding and attentional resources. PMID- 29284343 TI - Evaluation of a medication intensity screening tool used in malignant hematology and bone marrow transplant services to identify patients at risk for medication related problems. AB - Background In 2014, a screening tool was implemented at Medical University of South Carolina (MUSC) Health to identify patients who are at risk for medication related events. Patients are classified as high-risk if they meet one of the following criteria: receiving anticoagulation therapy, taking more than 10 scheduled medications upon admission, or readmission within the past 30 days. The goal of this study was to determine risk criteria specific to the malignant hematology (MH) and bone marrow transplant (BMT) patients. Methods A retrospective chart review of 114 patients admitted and discharged from the MH/BMT services between 1 September 2015 and 31 October 2015 was performed. A pharmacist-conducted medication history was completed and documented, and all interventions at admission and throughout hospitalization were categorized by severity and by value of service. The primary objective was to evaluate if patients in the MH/BMT services have more medication-related interventions documented upon admission compared with patients who are not screened as high risk. The secondary objectives were to evaluate the different types and severities of interventions made by pharmacists during the entire hospital stay, and to determine if there are certain characteristics that can help identify hematology/oncology high-risk patients. Results More interventions documented upon admission in the high-risk group as a whole when compared with the not high risk group (73 vs. 31), but when normalized per patients in each group, there was an equal number of interventions (1.0). The most common interventions were to modify regimen (36%) and discontinue therapy (16%). The patient characteristics associated with high-risk included neutropenia, lower average platelet counts on admission, and longer length of stay. Conclusion The screening tool does not further differentiate an already complex MH/BMT patient population. Pharmacists may be more useful at capturing errors or changes during a patient's hospital stay instead of upon admission. Thrombocytopenia, neutropenia, and active infections may correlate with higher-risk status. PMID- 29284345 TI - From skin to spontaneous lysis: A case of spontaneous tumor lysis syndrome in metastatic melanoma. AB - Tumor lysis syndrome is a life-threatening complication that often occurs after administration of cytotoxic therapy, but rarely occurs spontaneously without chemotherapy. This vignette describes a 59-year-old male with known extensive metastatic melanoma who presented to the hospital with spontaneous tumor lysis syndrome. Most spontaneous tumor lysis cases occur in patients with acute leukemias and aggressive lymphomas; however, this rare case depicts a patient with melanoma developing tumor lysis before the administration of chemotherapy. PMID- 29284346 TI - Safe handling of monoclonal antibodies: Too large to be hazardous? AB - It has been argued that the larger molecular weight of hazardous monoclonal antibodies may prevent their dermal absorption via occupational exposure. However, this assertion does not seem to be supported by direct evidence. Although the larger molecular weight may render monoclonal antibodies less probable to achieve therapeutic systemic level through dermal absorption, the concern in occupational health is whether these drugs can possibly attain a detectable level through repeated dermal exposure. Currently, there is no direct evidence to support a particular molecular weight above which a drug cannot achieve a detectable level following repeated occupational exposure. Therefore, the precautionary principle would dictate that repeated exposure of healthcare workers to hazardous monoclonal antibodies should be kept to a minimum. PMID- 29284347 TI - Real world treatment patterns in chronic myeloid leukemia patients newly initiated on tyrosine kinase inhibitors in an U.S. integrated healthcare system. AB - Purpose To evaluate treatment patterns in patients diagnosed with incident chronic myelogenous leukemia (CML) newly initiating therapy with imatinib, dasatinib, or nilotinib. Patients were followed to determine switching and discontinuation rates. Factors associated with switching or discontinuation from index TKI therapy, reasons for discontinuation based on electronic chart notes, and frequency of laboratory monitoring were assessed during the follow-up period. Methods A retrospective cohort study was conducted in chronic myelogenous leukemia patients aged >= 18 years who were identified from the Kaiser Permanente Southern California (KPSC) Cancer Registry database during the study time period of 1 January 2007 to 12 December 2013. The index date was defined as the date of the first TKI prescription (imatinib, dasatinib, or nilotinib) identified during the study time period with no prior history of TKI use within 12 months. Patients had to have continuous membership with drug benefit eligibility and no prior history of stem cell transplant (SCT) or other cancers during the 12 months prior to the index date. Baseline characteristics were identified during 12 months prior to the index date and outcomes were identified during the follow-up period after the index date. All patients were followed from index TKI therapy until end of study time period (12 December 2014), death, stem cell transplant, or disenrollment from the health plan unless one of the following occurred first: a patient switched their index therapy, or a patient discontinued their index therapy. Forward stepwise selection multivariable logistic regression models were used to evaluate factors associated with patients who continued therapy compared to those who switched or discontinued therapy with the index TKI. Chart notes were reviewed 30 days prior and 30 days post index TKI discontinuation to evaluate reasons for discontinuation. Molecular and cytogenetic testing frequency was also assessed during the follow-up period among the different patient groups. Results Two hundred sixteen patients were identified with incident chronic myelogenous leukemia and use of TKI therapy: 189 (87.5%) received imatinib, 19 (8.8%) received dasatinib, and 8 (3.7%) received nilotinib. The mean age on index date was 53 years and 63% were male; 103 patients (48%) continued on their index therapy, while 62 patients (28%) switched, and 51 patients (24%) discontinued. PMID- 29284348 TI - Severe anaphylactic reaction following anti-thymocyte globulin administration in a pediatric stem cell transplantation patient. AB - We present a case of a severe reaction after anti-thymocyte administration despite premedication and strict adherence to administration guidelines during the conditioning regimen. Due to the severity of the adverse drug reaction, we believe that this case should be reported. PMID- 29284349 TI - Association of hypertension and treatment outcomes in advanced stage non-small cell lung cancer patients treated with bevacizumab or non-bevacizumab containing regimens. AB - Background Studies suggest that bevacizumab-induced hypertension is prognostic of better outcomes in bevacizumab-treated patients with metastatic colorectal, HER2 negative breast, kidney, and pancreatic cancer. Few have examined this correlation in metastatic non-small cell lung cancer and evaluated whether hypertension independent of bevacizumab can improve the treatment outcomes. Objectives The primary objective was to determine the effect of hypertension on the overall response of advanced non-small cell lung cancer patients from start of the first-line chemotherapy to maintenance therapy. Secondary objectives include the effect of hypertension on the overall survival in all patients and on the overall response in bevacizumab-treated patients. Methods A retrospective chart review for a single institution was conducted from 2008 to 2013 on all patients with advanced non-squamous non-small cell lung cancer who received >= 1 cycle of combination chemotherapy. Patients were divided into hypertension versus no hypertension and into bevacizumab versus non-bevacizumab groups. Results Of the 188 advanced non-small cell lung cancer patients evaluated, 62 were treated with bevacizumab-containing regimens. The mean age at diagnosis was 58 years in both the groups. Hypertension independent of bevacizumab did not lead to improved treatment outcomes. However, in the bevacizumab subgroup, hypertensive patients had significantly higher response rates versus non-hypertensive patients (36.7% vs. 12.5%; p = 0.02). There was no significant difference in the overall survival between hypertensive versus non-hypertensive patients. Conclusion While hypertension alone did not significantly improve the treatment outcomes, hypertension in bevacizumab-treated patients with metastatic non-small cell lung cancer led to significantly improved responses. Further prospective studies are needed to confirm the association of hypertension with improved treatment outcomes in metastatic NSCLC. PMID- 29284350 TI - A minimally invasive treatment of an asymptomatic case of mesh erosion into the caecum after total extraperitoneal inguinal hernia repair. AB - BACKGROUND: Mesh migration and erosion into adjacent viscera is a rare complication after laparoscopic inguinal hernia repair. We present a minimally invasive treatment of an asymptomatic case of mesh erosion into the caecum after total extraperitoneal inguinal hernia repair, including an overview of the relevant recent literature. METHODS: A male patient underwent a laparoscopic inguinal hernia repair at the age of 42. Two years after this procedure, a screening colonoscopy revealed erosion of the mesh into the caecum. A laparoscopy was performed with partial resection of the mesh and minimal resection of the involved colon. Results of a systematic review of English PubMed articles on mesh migration and erosion after inguinal hernia repair is presented. RESULTS: We report a first-time minimally invasive treatment of mesh erosion into the colon. A laparoscopic approach is feasible and provides an excellent exposure. Partial removal of the mesh is suggested in uncomplicated cases to avoid complications associated with complete mesh removal. PMID- 29284351 TI - Recurrence of malignancy-associated venous thromboembolism among patients treated with rivaroxaban compared to enoxaparin. AB - Purpose Although low-molecular-weight heparin (LMWH) remains the standard of care, factor Xa inhibitors such as rivaroxaban may serve as an alternative treatment for venous thromboembolism (VTE) in patients with active malignancy. The purpose of the analysis was to evaluate outcomes of VTE management in cancer patients treated with rivaroxaban compared to enoxaparin. Methods This single center retrospective analysis was conducted on patients with malignancy associated VTE initiated on treatment with either rivaroxaban or enoxaparin. The primary endpoint was the incidence of recurrent VTE. Secondary outcomes included a comparison in rates of bleeding, mean duration of treatment, and mean time to recurrence of VTE. Results A total of 45 patients were included in each group. The incidence of recurrent VTE was 8.9% in the rivaroxaban group versus 13.3% in the enoxaparin group ( p = 0.53). There were no statistically significant differences in the secondary outcomes with the exception of longer mean duration of treatment in the rivaroxaban group compared to the enoxaparin group (169 vs. 110 days, respectively; p = 0.04). Conclusions This study provides important preliminary information regarding the efficacy and safety of rivaroxaban for treatment of VTE in cancer patients. Although LMWH should remain the standard of care, these results provide initial reassurance that rivaroxaban serves as a viable alternative in the event that injectable anticoagulation is not an acceptable approach to VTE management. PMID- 29284352 TI - Pharmacological management of anticancer agent extravasation: A single institutional guideline. AB - Although the risk of extravasation of a chemotherapy (anticancer) medication is low, the complications associated with these events can have a significant impact on morbidity and health care costs. Institutions that administer anticancer agents should ideally have a current guideline on the proper management of the inadvertent administration of these toxic medications into tissues surrounding blood vessels. It is imperative that the health care team involved in administering drugs used to treat cancer be educated on the risk factors, preventative strategies and treatment of anticancer extravasations, as well as practice safe and proper administration techniques. Anticancer agents are generally divided into classes based on their ability to cause tissue damage. The review of current published guidelines and available literature reveals a lack of consensus on how these medications should be classified. In addition, many recently approved drugs for the treatment of cancer may lack data to support their classification and management of extravasation events. The treatment of the majority of extravasations of anticancer agents involves nonpharmacological measures, potentially in the ambulatory care setting. Antidotes are available for the extravasation of a minority of vesicant agents in order to mitigate tissue damage. Due to the limited data and lack of consensus in published guidelines, a working group was established to put forth an institutional guideline on the management of anticancer extravasations. PMID- 29284353 TI - "Going to the Gym Is Not Congolese's Culture": Examining Attitudes Toward Physical Activity and Risk for Type 2 Diabetes Among Congolese Immigrants. AB - Purpose The purpose of this study was to explore perceptions and attitudes around physical activity among immigrants from the Democratic Republic of Congo and examine the influence of Congolese cultural beliefs on physical activity practice. Methods In-depth interviews were conducted and augmented by photo elicitation among 20 Congolese immigrants, distributed equally by gender, aged 35 years or older. The PEN-3 model was used as the cultural conceptual framework. Results Using both the Relationships and Expectations dimension (Perceptions, Enablers, and Nurturers) and Cultural Empowerment dimension (Positive, Existential, and Negative) of the PEN-3 model, emergent themes were categorized around knowing the benefits of being physically active (perceptions), doctor encouragement to be more physically active (enablers), and the habit and local tradition of consuming beer after a soccer match (nurturers). Other emergent themes included Congolese loves to dance (positive), going to the gym is not Congolese culture (existential), and the challenge of increased physical activity (negative). Conclusions Congolese have their intrinsic cultural perceptions and attitudes around types of physical activity. The study disclosed a much more pronounced willingness to dance (as a potential source of increased physical activity) than to go to a gym. As such, if one wants to advocate a regimen of increased physical activity to offset the risk for type 2 diabetes, dance is an alternative to consider among some immigrants. PMID- 29284354 TI - Factors Associated With Medication Engagement Among Older Adults With Diabetes: Systematic Review and Meta-Analysis. AB - Purpose The purpose of this systematic review and meta-analysis is to explore the factors associated with medication engagement among older adults (>=60 years) with diabetes. Methods Five databases (PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Scopus) were systematically searched to identify studies examining the association between factors and medication engagement among older diabetes patients. A study met inclusion for meta-analysis if the prevalence of medication engagement or factor was reported in >=2 studies and the frequency or strength of association was either reported or able to be computed. Quality appraisal was performed with the Downs and Black tool. Results Of 538 retrieved studies, 33 (20 cohort and 13 cross-sectional) were included for systematic review; of these, 22 met criteria for meta-analysis. Findings from meta-analysis show that women (odds ratio [OR], 0.92; 95% CI, 0.86 0.97), those with depression (OR, 0.73; 95% CI, 0.62-0.87), and those with higher out-of-pocket spending for prescription drugs (OR, 0.87; 95% CI, 0.80-0.94) were less likely to take diabetes medication when compared with men, those without depression, and those with lower out-of-pocket costs, respectively. Older age (OR, 1.13; 95% CI, 1.00-1.27) was associated with better engagement to diabetes medication. Conclusions Of 4 identified factors, 2 are modifiable. Recent policy efforts to decrease the cost burden of prescribed medication for older adults, such as Medicare Part D, may remove this barrier to medication engagement. Routine screening for depression among older adults with diabetes should be included as part of usual care to facilitate an integrated treatment approach. PMID- 29284355 TI - Stability of sodium bicarbonate injection 8.4% in syringes over a six-week period in refrigerated temperature. AB - Background Dysfunctional central venous catheter prohibits the administration of potential life-saving chemotherapy and the delivery of essential supportive care needs to patients. Sodium bicarbonate injection has been shown to impede against fibrin clot formation and prolong prothrombin time and thrombin clotting time. Sodium bicarbonate injection has been tried as a second-line agent with good results in a small number of patients (internal data not published) when alteplase failed. We assessed whether the pre-filled sodium bicarbonate injection in 5 mL syringes would not only preserve sterility and retain its pH and concentration but also amount to the potential cost savings for future use when stored in a refrigerated environment. Methodology Twelve pre-filled 5 mL syringes were prepared aseptically, of which four each were tested for pH, sodium bicarbonate injection concentration and sterility when stored in refrigerated temperature over a six-week period. A standard pH meter, enzymatic carbon dioxide analyzer, and a 14-day incubation for microbial detection were employed for this study. Results Sodium bicarbonate concentration measured in the form of carbon dioxide ranged from 923 mmol/L or (1846 mosol/L) to 1006 mmol/L or (2012 mosmol/L), and pH ranged from (7.88 to 8.05) were reported over the duration of the study period. The 14-day incubation period resulted in no microbial growth. Conclusion Our study results have indicated that the pH and sodium bicarbonate injection concentration values were stable and within range, comparable to those reported by the manufacturer within the study period. The contents of the subdivided sodium bicarbonate injection 5 mL syringes retained sterility over a 14-day incubation period. PMID- 29284356 TI - Comparison of conditioning regimen toxicities among autologous stem cell transplantation eligible multiple myeloma patients: High-dose melphalan versus high-dose melphalan and bortezomib. AB - Background Autologous hematopoietic stem cell transplantation (AHSCT) remains the standard of care for younger patients with multiple myeloma (MM). Currently, high dose melphalan (HDM) is recommended as conditioning regimen before AHSCT. Preclinical data suggest that combining bortezomib and melphalan has synergistic effect against multiple myeloma cells. Bortezomib and HDM (Bor-HDM) combination as conditioning regimen has been investigated by many other investigators. Objective In this retrospective study, we aimed to compare transplant-related toxicities and hematologic recovery of HDM and Bor-HDM conditioning regimens. Method We retrospectively evaluated hematologic recovery and toxicity profile in patients with MM who received AHSCT with either HDM ( n = 114) or Bor-HDM ( n = 53) conditioning regimen. Results Nonhematologic toxicities were comparable between HDM and Bor-HDM conditioning regimen, except mucositis and diarrhea being more frequent in the Bor-HDM group. Neutrophil and platelet engraftment time and duration of hospital stay were significantly shorter for HDM regimen. Conclusions In this retrospective analysis, we observed engraftment kinetics and duration of hospitalization were significantly worse in Bor-HDM conditioning regimen with manageable toxicities. Randomized studies are needed to further compare Bor- HDM regimen to HDM in terms of response rates, toxicities, and transplant-related mortality. PMID- 29284357 TI - Experience with dasatinib and nilotinib use in pregnancy. AB - Pregnancy in a patient with chronic myeloid leukemia presents a therapeutic challenge. Both dasatinib and nilotinib are indicated for first-line treatment as well as for treatment-resistant chronic myeloid leukemia. Animal studies with dasatinib or nilotinib demonstrate fetal skeletal malformations as well as significant mortality during organogenesis. The goal of this article is to review the experience to date of dasatinib and nilotinib in human pregnancy, specifically dasatinib and nilotinib dose, length of exposure, trimester of use, as well as patient and fetal outcomes. Based on the limited data, both dasatinib and nilotinib may cause fetal harm. Additionally, thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose, length of exposure, trimester of use, and deleterious patient or fetal outcomes can be concluded. Therefore, health care professionals need to regularly counsel women of child bearing potential with chronic myeloid leukemia regarding the risks of taking dasatinib or nilotinib during pregnancy. The safest potential therapeutic options for the management of chronic myeloid leukemia in pregnancy include temporary discontinuation of the tyrosine kinase inhibitor followed by observation or intervention with interferon alfa and/or leukapheresis. PMID- 29284358 TI - Storage and transport of reconstituted omacetaxine mepesuccinate: Considerations for home administration. AB - Purpose Omacetaxine mepesuccinate ("omacetaxine") is approved by the US Food and Drug Administration for the treatment of adult patients with chronic- or accelerated-phase chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. In May 2014, the US Food and Drug Administration approved revisions to the packaging information that included directions for home administration of reconstituted omacetaxine by patients or caregivers using syringes filled at a healthcare facility. We developed recommendations for the transport, storage, and spill-clean procedure of reconstituted omacetaxine for home and clinic administration. Methods We conducted chemical stability and microbial growth studies of reconstituted omacetaxine solution stored in vials and syringes at room temperature or refrigerated for various durations. Several shipping configurations were tested in simulated transport conditions to evaluate their ability to contain solution leakage and maintain product quality during distribution. In addition, we evaluated cleaning products and procedures for their effectiveness in removing residual omacetaxine from household surfaces after mock spills. Results Reconstituted omacetaxine showed limited degradation when refrigerated for 14 days in vials and syringes, and no microbial growth was observed for 12 days after intentional inoculation. In shipping studies, the configurations maintained prepared syringes within the recommended storage temperature range throughout transport and could contain leaks if spills occurred. In the event of an accidental spill in a home environment, effective cleaning can be achieved using household cleaning products and defined procedures. Conclusion These data provide important information regarding the safe transportation and administration of reconstituted omacetaxine in the home and clinic. PMID- 29284359 TI - Rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel. AB - Tumor lysis syndrome is a serious and sometimes lethal complication of cancer treatment that is comprised of a set of metabolic disturbances along with clinical manifestations. Initiating chemotherapy in bulky, rapidly proliferating tumors causes rapid cell turnover that in turn releases metabolites into circulation that give rise to metabolic derangements that can be dangerous. This syndrome is usually seen in high-grade hematological malignancies. Less commonly, tumor lysis syndrome can present in solid tumors and even rarely in genitourinary tumors. In this report, the authors describe a specific case of tumor lysis syndrome in a patient with metastatic prostate cancer following treatment with docetaxel. PMID- 29284360 TI - The utility of routine pre-chemotherapy screening with cardiac gated blood pool scan for patients at low risk of anthracycline toxicity. AB - Background Anthracycline-based chemotherapy is used in many malignancies. Current recommendations by several groups suggest cardiac monitoring prior to and during anthracycline therapy. We aim to review the usefulness of baseline cardiac screening for left ventricular ejection fraction to assess if it had any impact on chemotherapy decisions in patients to be treated with anthracycline-based regimens or any beneficial effect upon outcomes. Methods We conducted a retrospective three-year audit of cancer patients who underwent GBPS prior to anthracycline (doxorubicin) chemotherapy. Subjects were identified via records from the Department of Nuclear Medicine. Pharmacy dispensing records identified those who received doxorubicin. Patient demographics, cancer type, cardiac risk factors, GBPS ejection fraction (EF), and cumulative anthracycline dose were collected. Results From 1 August 2009 to 31 July 2012, 179 patients underwent GBPS pre-doxorubicin chemotherapy. The mean age was 59 years (range 21-89 years), with 51% being males. Only two patients (1.1%) had an abnormal EF < 50%, while 33 patients (18%) had an EF 51-59% and 144 patients (80%) had EF >= 60%. The two patients with reduced baseline EF still received anthracycline-based chemotherapy. All 135 patients without any known cardiovascular risk factors had normal EFs. The total number of patients who received anthracycline chemotherapy during the same period was 207. Thus 28 patients (13%) commenced anthracycline without a prior GBPS. Conclusion Only 1.1% of the screened patients had EF < 50%. These two patients still received doxorubicin chemotherapy despite a compromised EF, as their treating clinicians believed that the benefits of chemotherapy outweighed the risk of potential cardiac toxicity. Our audit questions the practice of routine cardiac evaluation pre-anthracycline screening with GBPS. We propose that routine screening only be requested if cardiac risk factors are present. PMID- 29284361 TI - Green alga-mediated treatment process for removal of zinc from synthetic solution and industrial effluent. AB - The present work explored biosorption of Zn(II) ions from aqueous and zinc bearing factory effluent using marine seaweed Ulva lactuca. The batch pH edge experiments using aqueous zinc solution indicated that Zn(II) uptake by U. lactuca was found to be maximum at pH 4.5 and the batch isotherm trials performed at pH 4.5 resulted in maximum uptake capacity of 128.0 mg Zn(II)/g. With 0.1 M CaCl2 (pH 3.5, HCl) as elutant, the elution of Zn(II) ions from Zn(II)-laden U. lactuca biosorbent was effective with possible regeneration and reuse for three cycles. The zinc industrial effluent was found to comprise of 87.8 mg/L of zinc ions along with excess co-ions and high total dissolved solids (838.1 mg/L). Owing to this, Zn(II) uptake from electroplating effluent by U. lactuca was suppressed due to competition from other ions. Continuous-flow sorption trials were conducted at flow rate of 5 mL/min in an up-flow fixed column. The existence of surplus competing ions in zinc wastewater influenced the Zn(II) biosorption by U. lactuca. U. lactuca-loaded packed column exhibited uptakes of 78.3 and 70.8 mg Zn(II)/g for aqueous solution and effluent, respectively. The results of three continuous sorption-desorption cycles demonstrated that reuse of U. lactuca biosorbent in remediation of zinc-containing wastewaters was practical and economical. PMID- 29284363 TI - Preparation, mechanical properties and in vitro cytocompatibility of multi-walled carbon nanotubes/poly(etheretherketone) nanocomposites. AB - Desired bone repair material must have excellent biocompatibility and high bioactivity. Moreover, mechanical properties of biomaterial should be equivalent to those of human bones. For developing an alternative biocomposite for load bearing orthopedic application, combination of bioactive fillers with polymer matrix is a feasible approach. In this study, a series of multi-walled carbon nanotubes (MWCNTs)/poly(etheretherketone) (PEEK) bioactive nanocomposites were prepared by a novel coprecipitation-compounding and injection-molding process. Scanning electron microscope (SEM) images revealed that MWCNTs were adsorbed on the surface of PEEK particles during the coprecipitation-compounding process and dispersed homogeneously in the nanocomposite because the conjugated PEEK polymers stabilized MWCNTs by forming strong pi-pi stack interactions. The mechanical testing revealed that mechanical performance of PEEK was significantly improved by adding MWCNTs (2-8 wt%) and the experimental values obtained were close to or higher than that of human cortical bone. In addition, incorporation of MWCNTs into PEEK matrix also enhanced the roughness and hydrophilicity of the nanocomposite surface. In vitro cytocompatibility tests demonstrated that the MWCNTs/PEEK nanocomposite was in favor of cell adhesion and proliferation of MC3T3-E1 osteoblast cells, exhibiting excellent cytocompatibility and biocompatibility. Thus, this MWCNTs/PEEK nanocomposite may be used as a promising bone repair material in orthopedic implants application. PMID- 29284362 TI - A retrospective review of fall risk factors in the bone marrow transplant inpatient service. AB - Purpose The purpose of this study was to compare medications and potential risk factors between patients who experienced a fall during hospitalization compared to those who did not fall while admitted to the Blood and Marrow Transplant inpatient setting at The James Cancer Hospital. Secondary objectives included evaluation of transplant-related disease states and medications in the post transplant setting that may lead to an increased risk of falls, post-fall variables, and number of tests ordered after a fall. Methods This retrospective, case-control study matched patients in a 2:1 ratio of nonfallers to fallers. Data from The Ohio State University Wexner Medical Center (OSUWMC) reported fall events and patient electronic medical records were utilized. A total of 168 adult Blood and Marrow Transplant inpatients with a hematological malignancy diagnosis were evaluated from 1 January 2010 to 30 September 2012. Results Univariable and multivariable conditional logistic regression models were used to assess the relationship between potential predictor variables of interest and falls. Variables that were found to be significant predictors of falls from the univariable models include age group, incontinence, benzodiazepines, corticosteroids, anticonvulsants and antidepressants, and number of days status post transplant. When considered for a multivariable model age group, corticosteroids, and a cancer diagnosis of leukemia were significant in the final model. Conclusion Recent medication utilization such as benzodiazepines, anticonvulsants, corticosteroids, and antidepressants placed patients at a higher risk of experiencing a fall. Other significant factors identified from a multivariable analysis found were patients older than age 65, patients with recent corticosteroid administration and a cancer diagnosis of leukemia. PMID- 29284364 TI - Preoperative Computed Tomography-Determined Sarcopenia and Postoperative Outcome After Surgery for Non-Small Cell Lung Cancer. AB - BACKGROUND: Sarcopenia, reduced skeletal muscle mass, is associated with frailty, injuries, and mortality. The purpose of this study was to evaluate the impact of computed tomography-determined sarcopenia on surgical complications and outcomes after resection of non-small cell lung cancer. METHODS: For a total 272 non-small cell lung cancer patients that underwent surgery between 2011 and 2016, cross sectional area of muscle at the third lumbar vertebra (L3) was retrospectively measured using preoperative chest computed tomography images. Sarcopenia was defined as an L3 muscle index of <55 cm2/m2 for men and of <39 cm2/m2 for women. Clinical characteristics, postoperative complications, disease-free survival, and overall survival of patients with or without sarcopenia were compared. RESULTS: A total of 60.3% ( n = 164) were male, and mean patient age was 62.9 +/- 9.6 years. The prevalence of sarcopenia was 22.4% for all study subjects, 32.9% for men, and 6.5% for women. No significant difference was observed between patients with or without sarcopenia in terms of intensive care unit or hospital stay ( p = 0.502 and p = 0.378, respectively), and the presence of sarcopenia was not associated with postoperative complications. Furthermore, no significant difference was observed between the 3-year disease-free survival rate (74.3% vs 66.7%, p = 0.639) or 3-year overall survival rate (83.9% vs 87.7%, p = 0.563) of patients with or without sarcopenia. CONCLUSION: Sarcopenia as determined by preoperative computed tomography does not appear to have a negative impact on surgical outcome or overall survival for resected non-small cell lung cancer patients. PMID- 29284365 TI - Echocardiographic Guidance for Surgical Excision of the Intracardiac Component of a Pheochromocytoma. AB - Pheochromocytomas are rare neuroendocrine tumors, with published incidence of 2 to 8 cases per million patients per year. The extension of these tumors into the vena cava and right atrium is rarely seen. Transesophageal echocardiography may be invaluable to delineate tumor extent and characteristics, which in turn may provide a useful tool to guide intraoperative surgical approach to these uncommon masses. In the case presented in this article, we describe the role of transesophageal echocardiography in guiding a safe and complete, excision of an invasive pheochromocytoma without embolization of tumor components. PMID- 29284366 TI - Pepsi(r) or Coke(r)? Influence of acid on dasatinib absorption. AB - Dasatinib is a second generation ABL kinase inhibitor used in the management of chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Dasatinib's bioavailability is highly dependent on gastric pH. When proton-pump inhibitors (PPIs) are co-administered with dasatinib, absorption is significantly reduced. Cola intake at the time of drug administration has been demonstrated to lead to relevant increases in the bioavailability for other acid labile drugs during PPI treatment. This manuscript reviews the relevant literature supporting a strategy of temporarily lowering the gastric pH with a carbonated beverage at the time of drug administration. The use of cola provides an easy to implement way to significantly improve dasatinib bioavailability, especially during concomitant use of a PPI. PMID- 29284367 TI - Regulation of influent sulfide concentration on anaerobic denitrifying sulfide removal. AB - The objective of this study is to find a comprehensive regulation for sulfide removal and elemental sulfur transformation based on the denitrifying sulfide removal process. The experiment was performed based on several influent sulfide concentrations (150-600 mg/L) and nitrate-to-sulfur (N/S) molar ratios (0.5-2.0) at reaction times of 24 and 48 h. Sulfide and nitrate removals were mainly dependent on the influent sulfide concentration at sulfide concentrations of 150 200 and 400-600 mg/L, but on the N/S ratio at sulfide concentrations of 250-350 mg/L. Up to 99.7% and 93.8% of sulfide and nitrate were removed, respectively, with 26.5% of elemental sulfur formed at sulfide concentrations of 250-350 mg/L (N/S of 1.0). Only 4-9.4% of elemental sulfur was formed, with sulfide and nitrate removals of 99.9% and 98.7%, respectively, at sulfide concentrations of 150-200 mg/L. Meanwhile, 46.9-94.7% of sulfate was formed with a nitrogen gas conversion rate of 18.2-57.1%. Fewer microorganisms were detected by fluorescence in situ hybridization (FISH) at high sulfide concentrations of 400-600 mg/L, suggesting that the processes of anaerobic denitrification and desulfurization were inhibited. PMID- 29284368 TI - Estimation of the relative difference (or relative risk reduction) under the sequential parallel comparison design. AB - To increase power or reduce the number of patients needed in trials studying treatments for psychiatric or mental disorders with a high placebo response rate, we may consider use of the sequential parallel comparison design proposed elsewhere. Because statistical significance does not necessarily imply that the difference between treatment and placebo is of clinical importance, it is always of importance to quantify the treatment effect in clinical trials. When the patient responses are dichotomous, the treatment and other covariates effects are not likely additive. Thus, using a weighted average of the risk differences over two phases may not be a meaningful summary index to measure the treatment effect. To alleviate this concern, we consider use of the relative difference or relative risk reduction to measure the treatment effect. We derive both point and interval estimators for the relative difference by use of the weighted-least-squares estimator and Mantel-Haenszel type estimator. We employ Monte Carlo simulation to evaluate the finite-sample performance of these estimators in a variety of situations. We also include a procedure for testing the homogeneity of the relative difference between phases under the sequential parallel comparison design. We use the placebo-controlled study to assess the efficacy of a low dose of aripiprazole adjunctive to antidepressant therapy in the treatment of patients with major depressive disorder to illustrate the use of estimators developed here. PMID- 29284369 TI - Bayesian Phase II optimization for time-to-event data based on historical information. AB - After exploratory drug development, companies face the decision whether to initiate confirmatory trials based on limited efficacy information. This proof-of concept decision is typically performed after a Phase II trial studying a novel treatment versus either placebo or an active comparator. The article aims to optimize the design of such a proof-of-concept trial with respect to decision making. We incorporate historical information and develop pre-specified decision criteria accounting for the uncertainty of the observed treatment effect. We optimize these criteria based on sensitivity and specificity, given the historical information. Specifically, time-to-event data are considered in a randomized 2-arm trial with additional prior information on the control treatment. The proof-of-concept criterion uses treatment effect size, rather than significance. Criteria are defined on the posterior distribution of the hazard ratio given the Phase II data and the historical control information. Event times are exponentially modeled within groups, allowing for group-specific conjugate prior-to-posterior calculation. While a non-informative prior is placed on the investigational treatment, the control prior is constructed via the meta-analytic predictive approach. The design parameters including sample size and allocation ratio are then optimized, maximizing the probability of taking the right decision. The approach is illustrated with an example in lung cancer. PMID- 29284370 TI - A test of inflated zeros for Poisson regression models. AB - Excessive zeros are common in practice and may cause overdispersion and invalidate inference when fitting Poisson regression models. There is a large body of literature on zero-inflated Poisson models. However, methods for testing whether there are excessive zeros are less well developed. The Vuong test comparing a Poisson and a zero-inflated Poisson model is commonly applied in practice. However, the type I error of the test often deviates seriously from the nominal level, rendering serious doubts on the validity of the test in such applications. In this paper, we develop a new approach for testing inflated zeros under the Poisson model. Unlike the Vuong test for inflated zeros, our method does not require a zero-inflated Poisson model to perform the test. Simulation studies show that when compared with the Vuong test our approach not only better at controlling type I error rate, but also yield more power. PMID- 29284371 TI - Glyphosate residues in Swiss market foods: monitoring and risk evaluation. AB - A total of 243 samples of diverse foodstuffs were analysed for glyphosate and aminomethylphosphonic acid (AMPA) using a liquid chromatography triple quadrupole mass spectrometry (LC/MS/MS) method with a relatively low limit of quantification in the range of 0.0005-0.0025 mg kg-1. Main contributors for dietary glyphosate and AMPA intake were cereals and pulses. The results suggest that pasta is a very important foodstuff for dietary glyphosate residue intake in Switzerland. Interestingly all samples of wine, fruit juice and nearly all samples of honey tested positive for glyphosate although at very low levels. A dietary risk assessment was conducted. Food products for analysis were not selected purely at random, rather products were selected for which high levels of glyphosate residues were suspected. However, even in samples where high residue levels were expected, no exceedances of maximum residue levels were found. Consequently, human exposure did not exceed neither acceptable daily intake nor acute reference dose. Therefore, glyphosate residues found in the sampled foodstuffs from the Swiss market were of no concern for human health. PMID- 29284372 TI - Histologic Grade Does Not Predict Outcome in Dogs with Appendicular Osteosarcoma Receiving the Standard of Care. AB - Canine appendicular osteosarcoma is an aggressive bone neoplasm that imposes a short survival time. There are several published histologic grading systems for canine osteosarcoma but no universally accepted system. Location within the skeleton and therapy received are both correlated with survival time, but these factors were not always considered when the prognostic value of published grading systems was determined. Our objective was to compare 2 published histologic grading systems in a population of dogs with appendicular osteosarcoma treated with the standard of care for curative intent. Three evaluators graded 85 tumors using 2 histologic grading systems. The relationships between histologic grade as well as individual histologic features and outcome (survival time and disease free interval) were evaluated using Kaplan-Meier survival functions and a univariate Cox proportional hazards model. Histologic grade, as assigned by any evaluator, did not correlate with outcome. Increased number of mitotic figures per 3 randomly selected 400* microscope fields, as assessed by 1 evaluator, was correlated with both survival time and disease-free interval; this was the only individual histologic feature that was significantly correlated with outcome for any evaluator. These findings cast doubt on the predictive value of routine histologic grading in dogs with appendicular osteosarcoma who receive amputation followed by adjuvant chemotherapy and highlight the need for better tools to predict outcome in canine appendicular osteosarcoma. PMID- 29284373 TI - Chrysin isolated from Pyrus pashia fruit ameliorates convulsions in experimental animals. AB - OBJECTIVE: The traditional use of the ethanolic extract of the fruit of Pyrus pashia (EPP) as a potential anticonvulsant was validated using experimental animal models. Furthermore, the anticonvulsant activity of isolated chrysin was investigated against experimental animal models to draw a possible therapeutic mechanism of EPP. Additionally, the safety profile of chrysin was evaluated to explore the possible therapeutic alternative in the management of epilepsy. METHOD: The anticonvulsant activity in terms of duration of onset of hind limb tonic extension and convulsion of standardized EPP was evaluated against maximal electroshock (MES) and pentylenetetrazole (PTZ) model of experimental epilepsy respectively. Furthermore, the anticonvulsant activity and electrophysiological properties of chrysin was investigated in addition to antioxidant activity against PTZ-induced convulsion in experimental animals. Moreover, the neurotoxic profile of the chrysin was assessed in terms of duration of movement and running in photoactometer and rotarod apparatus, respectively. RESULTS: EPP (100, 200, and 400 mg/kg) exhibited significant anticonvulsant activity against an acute model of MES and PTZ-induced convulsions in experimental animals. Furthermore, chrysin (2.5, 5, and 10 mg/kg) also exhibited significant anticonvulsant activity against PTZ-induced convulsions in rats. In addition, chrysin did not exhibit sedative-like behavior in experimental rodents. DISCUSSION: EPP could be considered as a potential and alternative therapeutic option in the management of epilepsy. PMID- 29284374 TI - Safer sex practices among newly diagnosed HIV-positive men who have sex with men in China: results from an ethnographic study. AB - The study reported here sought to understand the rationales of safer sex practices adopted by newly diagnosed HIV-positive men who have sex with men (MSM). Guided by a socio-ecological framework, an ethnography was conducted among newly diagnosed HIV-positive MSM. In-depth interviews and participant observation were employed to produce an account of the social and cultural settings that was faithful to the perspectives of participants. A total of 31 participants with diverse backgrounds were recruited in a southern city of China. Participant observation was conducted in local healthcare settings, MSM venues, and NGO offices. Most participants (24/31) reported stopping unprotected anal intercourse (UAI) immediately after being diagnosed as HIV-positive. Factors associated with safer sex practices were identified at both individual and environmental levels, including self-protection, establishment of self-esteem, dignity, altruism and reciprocity, disease experience as a source of personal growth, and organizational culture and values. Newly diagnosed HIV-positive MSM navigate their sexual practices within the context of multiple competing factors. Implications for sustained behaviour change enabling safer sex practices include stimulating survival instinct, facilitating safer sex decision making, motivating and facilitating personal growth, and encouraging volunteerism to promote intentional activities for safer sex practices. PMID- 29284375 TI - One-week exposure to a free-choice high-fat high-sugar diet does not disrupt blood-brain barrier permeability in fed or overnight fasted rats. AB - OBJECTIVES: The hypothalamus lies adjacent to the third ventricle and is in close proximity with the median eminence (ME), a circumventricular organ with an incomplete blood-brain barrier (BBB) which controls direct entry of nutrients into the brain. The blood-CSF barrier of the hypothalamus shows dynamic changes upon neuroendocrine events and adjusts permeability with the tight junction (TJ) complex. It has been shown that chronic exposure to a high-fat diet (HFD) affects BBB permeability. HFD also induces leptin resistance and alters neuropeptide expression in the arcuate nucleus (Arc) of the hypothalamus starting early during overnutrition. We hypothesized altered integrity of the BBB to occur after exposing rats to a free-choice high-fat high-sugar (fcHFHS) diet for 1 week. METHODS: We measured diffusion of Evans blue dye over the ME and assessed expression of the TJ proteins ZO-1, claudin-5, and occludin in the tanycytic wall of the third ventricle. Furthermore, we assessed protein expression of glucose transporter 1 (GLUT-1), which is highly expressed in the Arc-ME complex and facilitates glucose transport over the BBB. RESULTS: fcHFHS-fed rats increased caloric intake compared to control, however, there was no effect of the fcHFHS diet on permeability of the BBB, nor changes in protein expression of tight TJ proteins or GLUT-1. Fasting acutely affects the BBB and we hypothesized that exposure to the fcHFHS diet affects the BBB differently compared to chow after fasting. We did not, however, find any differences in Evans blue diffusion nor protein expression between chow- and fcHFHS-fed rats when fasted overnight. CONCLUSIONS: We conclude that short-term consumption of a fcHFHS diet does not change permeability or diffusion in the hypothalamus barrier in ad libitum fed or fasted rats. PMID- 29284376 TI - The Limitations and Strengths of the Evidence-Based Practice Attitude Scale as a Measure of Correctional Employees' Attitudes: A Psychometric Evaluation. AB - Evidence-based practices (EBPs) hold tremendous potential for improving the outcomes of corrections interventions. The implementation of EBPs requires support from staff at all levels of an organization; however, the study of correctional staff attitudes toward organizational change and EBPs is in its infancy. The current study examines the psychometric properties of the Evidence Based Practice Attitude Scale (EBPAS), an instrument originally designed for mental health professionals, to measure correctional employees' readiness to implement EBPs. The results indicate mixed conclusions regarding the use of the EBPAS with correctional staff. We found that the total scale and subscales are reliable and exhibit high internal consistency. However, the results of an exploratory and confirmatory factor analysis failed to replicate the factor structure from previous research with mental health providers. The findings indicate potential drawbacks regarding the construct validity of the EBPAS for use with correctional personnel. PMID- 29284377 TI - Narratives of Young Men With Injecting Drug Use Histories Leaving Adult Prison. AB - This research focuses on an under-examined aspect of the post-release prison trajectory for a seldom-researched cohort. Narratives of the immediate days/weeks surrounding release were gathered from young men with histories of injecting drug use (IDU). Twenty-eight participants (aged 19-24) released from adult prisons in Victoria, Australia, participated in face-to-face in-depth qualitative interviews after release. Analysis of findings through the lens of a "risk environment" framework reveals how their experiences were compromised by risk factors embedded in the physical spaces and social situations they inhabited, as well as the multi sectoral policy environments under which they were governed. A complex interplay between these factors, young men's drug use and broader issues of structural vulnerability, including institutionalization and social disadvantage, combined to limit young men's chances of "success"1 on the outside. Narratives provide evidence for interventions that transform risk environments into enabling environments, thereby promoting a more successful transition from prison to community for young men with IDU histories. PMID- 29284378 TI - Assessing Protective Factors for Violence Risk in U.K. General Mental Health Services Using the Structured Assessment of Protective Factors. AB - Violence risk assessment and management are key tasks in mental health services and should be guided by validated instruments covering both risk and protective factors. This article is part of an international effort to validate the Structured Assessment of Protective Factors (SAPROF) for violence. The SAPROF, Historical, Clinical, Risk Management-20 (HCR-20) and the Psychopathy Checklist Screening Version (PCL-SV) were administered in a sample of 261 patients in U.K. forensic, general inpatient, and community mental health settings. There was significant variation between these groups on SAPROF scores with fewer protective factors in the forensic group. The prospective validity of the SAPROF for nonviolence in the general inpatient and community samples was moderate (area under the curve [AUC] = .60). Adoption of the SAPROF or similar instruments as a supplement to risk-focused assessments has the potential to improve awareness of protective factors and enhance therapeutic engagement in a range of mental health services. PMID- 29284379 TI - Sociodemographic Information, Aversive and Traumatic Events, Offence-Related Characteristics, and Mental Health of Delinquent Women in Forensic-Psychiatric Care in Switzerland. AB - The present study describes a much understudied group-namely, female prisoners under forensic-psychiatric care in the German-speaking part of Switzerland-to improve understanding of their risks and their needs. Data were derived from internal databases of a Forensic-Psychiatric Service. Data were collected in the form of their sociodemographic characteristics, prevalence of aversive and traumatic events, type of offence committed, and mental health conditions. Based on a full-sample approach, a total of 1,571 files were analysed. Results reveal that two thirds of the participants were not in a stable relationship, more than half did not complete a school degree, and three quarters were without stable employment prior to their incarceration. Two thirds were mothers and about one third did not grow up with their parents. Almost half grew up with an alcohol abusing parent, about half experienced violence and/or neglect in childhood, and about a quarter of the cases sexual abuse. About 95% had a mental health diagnosis according to International Classification of Diseases-Version 10 (ICD 10), and the most prevalent mental and behavioural disorder was due to psychoactive substance abuse. The most frequent offence type was drug-related crimes. Women convicted for drug-related crimes were more likely to have an ICD 10 F1 disorder compared with those convicted for other crimes. Conversely, women with violent offences were less likely to suffer from ICD-10 F1 disorder than those who had committed nonviolent offences. Findings have implications for practitioners and policy makers, and contribute to the cycle of violence theory discussion. In conclusion, future research areas are suggested. PMID- 29284380 TI - Potential cost savings by dose down-rounding of monoclonal antibodies in a community cancer center. AB - Purpose Increasing new cancer cases and approval of effective but expensive new drugs extending survival have led to unsustainable cancer care costs. Potential cost savings by a hypothetical dose down-rounding project of monoclonal antibodies at a community-based cancer center is presented. Methods From October 2014 through October 2015, metastatic cancer patients receiving monoclonal antibodies at CHI-Health St Francis Cancer Treatment Center in Grand Island, Nebraska, were identified through electronic health records. A total of 11 different types of monoclonal antibodies that were administered during the study period were identified. Trastuzumab, ofatumumab, and obinutuzumab did not require dose-rounding; thus, they were excluded from the analyses. Available vial size(s) and costs per milligram per average wholesale price for each monoclonal antibody were recorded. Costs of actual amounts prescribed were compared to the costs of theoretically reduced <=5% and <=10% doses rounded to the nearest vial sizes. Reduced doses resulting in a decreased number of opened vials qualified for meaningful dose down-rounding and were included in the analysis. Average actual dose reduction percentage resulting in cost savings for both groups was also calculated. Results A total of 728 doses of eight monoclonal antibodies suitable for dose down-rounding were identified. Vial sizes of pembrolizumab and ipilimumab did not allow for a meaningful dose down-rounding. At the <=5% dose down-rounding, 255 of 728 doses (35%) qualified with a potential annual cost savings of $220,793.80. At the <=10% dose down-rounding, 526 of 728 doses (72%) qualified with a potential annual cost savings of $454,461.00. The average actual dose reduction was 2.4% for the <=5% dose reduction group and 4.9% for the <=10% dose reduction group. Overall average cost savings per qualifying dose reduction was around $865.00. More doses qualified for cost savings in the <=10% dose reduction group. Significant differences between different monoclonal antibodies for dose rounding at either <=5% (p = 0.002) or <=10% (p < 0.001) were observed. Conclusion A practical dose down-rounding procedure may allow significant cost reduction in metastatic cancer setting, where the cure is not the goal. Drug waste can be avoided by convenient vial sizes or can even be eliminated by lyophilized forms like in trastuzumab. Our data reflect the monoclonal antibody use and potential cost savings with the proposed dose down-rounding approach in a community-based cancer program. PMID- 29284381 TI - Biphasic malignant melanoma adenocarcinoma in the digit of a dog. AB - A 7-y-old Black Russian Terrier dog was evaluated for chronic lameness of the right forelimb and concurrent weight loss. Clinical examination revealed a pigmented mass arising from digit 4 of the right forelimb; the digit was amputated and submitted for histologic evaluation. Histologically, the neoplasm was composed of ill-defined streams, sheets, and clusters of melanocytes admixed with a distinct population of malignant epithelial cells forming glands and nests. The diagnosis was a biphasic malignant melanoma adenocarcinoma, a rarely reported neoplasm in human medicine that has not been described in veterinary medicine, to our knowledge. PMID- 29284382 TI - Identification of Felis catus papillomavirus 3 in skin neoplasms from four cats. AB - Bowenoid in situ carcinomas (BISCs) are papillomavirus (PV)-induced skin neoplasms that are thought to be caused by Felis catus papillomavirus (FcaPV) 2. As BISCs are typically multiple and can become extensive, they can be difficult to treat. Herein we describe 4 cats that developed skin neoplasms that contained FcaPV-3 DNA. One cat developed multiple basal cell carcinomas (BCCs), 1 a BISC with unusual extension into hair follicles, and 2 developed a single typical appearing BISC. All neoplasms contained prominent PV-induced cell changes and intense p16CDKN2a protein immunostaining. Results from these 4 cats provide evidence that FcaPV-3 could cause a proportion of feline skin cancers, albeit less frequently than FcaPV-2. Excision of the typical BISCs and the BCCs appeared curative. Although the cat with the unusual BISC was euthanized because of the large size of the lesion, evidence from these 4 cats suggests that skin neoplasms that contain FcaPV-3 DNA may have a less aggressive clinical behavior than those associated with FcaPV-2. A consistent feature of the neoplasms in all 4 cats was the presence of prominent basophilic intracytoplasmic inclusion bodies; these inclusions have not been reported in lesions caused by FcaPV-2, to our knowledge, and their detection may allow differentiation between the different PV types and could therefore be a useful prognostic feature. PMID- 29284383 TI - Comparison of two methods for measurement of equine adrenocorticotropin. AB - Accurate measurement of equine adrenocorticotropin (ACTH) is important for the diagnosis of equine pituitary pars intermedia dysfunction (PPID). Several radioimmunoassays (RIAs) and chemiluminescent immunoassays (CIAs) are used for measurement of ACTH concentration in horses; whether these methods yield similar results across a range of concentrations is not determined. We evaluated agreement between a commercial RIA and CIA. Archived plasma samples ( n = 633) were measured with both assays. Correlation between the 2 methods was moderate ( r = 0.49, p < 0.001). Bland-Altman analysis revealed poor agreement, with a proportional bias and widening limits of agreement with increasing values. Poor agreement between assays was also observed when evaluating plasma samples with concentrations at or below the recommended diagnostic cutoff value for PPID testing. The lack of agreement suggests that measurements obtained should not be considered interchangeable between methods. PMID- 29284384 TI - Comparison of reverse-transcription real-time PCR and immunohistochemistry for the detection of canine distemper virus infection in raccoons in Ontario, Canada. AB - Canine distemper virus (CDV) is a widespread morbillivirus that causes subclinical to fatal infections in domestic and wild carnivores. Raccoons ( Procyon lotor) are CDV reservoirs and suffer from associated disease. Aspects of pathogenesis may lead to difficulty in the interpretation of commonly used testing modalities, such as reverse-transcription real-time (RT-rt)PCR and immunohistochemistry (IHC). The reliance upon such tests is greater for wildlife, which are often submitted as carcasses with no clinical history. We compared CDV RT-rtPCR results to immunohistochemistry (the gold standard) in tissues from 74 raccoons. These tests had high kappa agreement (lymph node: 0.9335; lung: 0.8671) and a negative correlation between IHC score and threshold cycle (Ct) value for lymph node and lung (Spearman rank correlation coefficient [ rs] = -0.8555 and 0.8179, respectively; p < 0.00001). An RT-rtPCR Ct value of 30 in lung and lymph node with sensitivity and specificity of 92.3 and 92.6% and 86.8 and 96.4%, respectively, was suitable for determining CDV involvement. Conjunctival swabs provide an alternative for distemper diagnosis, as there was a strong correlation between Ct values of conjunctival swabs and tissues ( rs = -0.8498, p < 0.00001, n = 46). This information will aid in more efficient and accurate diagnoses in individuals, small-scale outbreaks, and epidemiologic investigations in wildlife. PMID- 29284385 TI - Therapeutic Applications of Prostaglandins and Thromboxane A2 Inhibitors in Abdominal Aortic Aneurysms. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is one of the leading causes of death in western countries. Surgery is still, at the present time, the sole treatment that has however a significant mortality and cost rate. Many pharmacological agents are under investigation aiming to reduce growth and prevent AAA rupture. These drugs target different pathological pathways and, notably, the excessive production of prostanoids by cyclooxygenases (COX). Intra-aneurysmal thrombus plays an adverse key role in the progression of AAA, platelets being a primary source of prostanoids as thromboxane A2. OBJECTIVE: In this review, we summarize studies targeting prostanoids production and down-stream pathways in cardiovascular diseases, and more specifically in AAA. RESULTS AND CONCLUSION: Various inhibitors of COX or antagonists of prostanoids receptors have been investigated in AAA animal models with conflicting results. In human AAA, only a few number of studies focused on anti-platelet therapy mostly using acetylsalicylic acid (aspirin, ASA), a COX1 inhibitor. Finally, we report preliminary promising results of a model of AAA in rats receiving a thromboxane A2 inhibitor, BM-573 that induced a reduction of aneurysmal growth. PMID- 29284387 TI - Optimal Time for Pharmacological Treatment of Abdominal Aortic Aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA), if left untreated, poses the main risks of progressive expansion, rupture, and hemorrhage, leading to death. Large AAA with a risk of rupture is usually treated by graft replacement or endovascular aneurysm repair. Nonsurgical treatment is not an alternative for large AAA, but is potentially beneficial for small AAA which usually requires a watchful waiting approach with medication. OBJECTIVE: We introduce current clinical research regarding the pharmacological treatment of small AAA and assess the optimal time for starting the treatment. RESULTS: Data from current clinical researches on pharmacological treatment of AAA investigating the efficacy of pharmacological treatment to limit AAA growth were presented and introduced the medicines currently evaluated by randomized controlled trials for their efficacy for AAA. CONCLUSION: The optimal time to administer pharmacological treatment for AAA is during the stage wherein its diameter is still small. To detect early small-diameter AAA, screening tests are mandatory in high-risk patients. For pharmacological treatment, the drug that shows acceptable results in clinical tests and is the most effective for the patient's condition should be carefully selected. Lifestyle changes should also accompany pharmacological treatment. PMID- 29284386 TI - Current Status and Perspectives on Pharmacologic Therapy for Abdominal Aortic Aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA), a common disease involving the segmental expansion and rupture of the aorta, has a high mortality rate. Therapeutic options for AAA are currently limited to surgical repair to prevent catastrophic rupture. Non-surgical approaches, particularly pharmacotherapy, are lacking for the treatment of AAA. OBJECTIVE: We review both basic and clinical studies and discuss the current challenges to developing medical therapy that reduces AAA progression. RESULTS: Studies using animal models of AAA progression and human AAA explant cultures have identified several potential targets for preventing AAA growth. However, no clinical studies have convincingly confirmed the efficacy of any pharmacologic treatment against the growth of AAA. Thus, there is as yet no strong recommendation regarding pharmacotherapy to reduce the risk of AAA progression and rupture. CONCLUSION: This review identifies concerns that need to be addressed for the field to progress and discusses the challenges that must be overcome in order to develop effective pharmacotherapy to reduce AAA progression in the future. PMID- 29284388 TI - Fenofibrate and Telmisartan in the Management of Abdominal Aortic Aneurysm. AB - OBJECTIVE: This mini-review provides the rationale and updated progress for ongoing randomized controlled trials assessing fenofibrate and telmisartan efficacy to limit abdominal aortic aneurysm (AAA) growth. METHODS/RESULTS: There remains an urgent need to identify a drug therapy that will limit AAA growth. Data from preclinical and human studies indicate that fenofibrate and telmisartan have the potential to slow aortic destruction. Fenofibrate has been shown to reduce serum and tissue levels of the proinflammatory protein osteopontin, as well as reducing macrophage recruitment to the aortic wall, both of which are integral processes in the development and progression of AAAs. Telmisartan acts via blockade of the angiotensin II receptor, type 1, and also as a peroxisome proliferator-activated receptor gamma agonist. In turn, this inhibits the production of a range of biomarkers associated with AAA progression, including transforming growth factor-beta one, osteoprotegerin, osteopontin and matrix metalloproteinase- 9. Based on these findings, there are currently three randomized controlled trials assessing both fenofibrate and telmisartan as potential interventions to limit aneurysm growth in AAA patients. CONCLUSION: Fenofibrate and telmisartan have potential as repurposed medications to limit AAA growth, and randomized trials for further assessment in AAA patients are ongoing. PMID- 29284389 TI - Efficacy and Safety of Serotonin Receptor Ligands in the Treatment of Irritable Bowel Syndrome: A Review. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. OBJECTIVE: This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. RESULTS AND CONCLUSION: We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles. PMID- 29284390 TI - Imparting pharmaceutical applications to the surface of fabrics for wound and skin care by ultrasonic waves. AB - The review, reports on the functionalization of textiles for the treatment of wounds and skin diseases such as acne. In view of the growing demand for high quality textiles, much research is focused on the creation of antimicrobial finishings for fabrics, in order to protect customers from pathogenic or odor generating microorganisms. We present coatings from inorganic, organic and biochemical nanoparticles (NPs) on surfaces that impart the ability to kill bacteria, avoid biofilm formation and speed up the recovery of wounds. In all three cases, sonochemistry is used for immobilizing the nanoparticles on the surfaces. The Introduction broadly covers the progress of nanotechnology in the fields of wound and skin care. The first section of this review outlines the mechanism of the ultrasound-assisted deposition of nanoparticles on textiles. The coating can be performed by an in-situ process in which the nanoparticles are formed and subsequently thrown onto the surface of the fabrics at a very high speed. This approach was used in depositing metal-oxide NPs such as ZnO, CuO and Zn-CuO or the organic NPs of tannic acid, chitosan, etc. on textiles. In addition, the sonochemical process can be used as a "throwing stone" technique, namely, previously synthesized or commercially purchased NPs can be placed in the sonication bath and sonicated in the presence of the fabric. This section will also outline why sonochemical deposition on textiles is considered the best coating technique. The second section will discuss new applications of the sonochemically-coated textiles in killing bacteria, avoiding biofilm formation and more. PMID- 29284391 TI - Inorganic Nanoparticles for Cancer Therapy: a Transition from Lab to Clinic. AB - Inorganic nanoparticles (NPs) including those derived from metals (e.g., gold, silver), semiconductors (e.g., quantum dots), carbon dots, carbon nanotubes, or oxides (e.g., iron oxide), have been deeply investigated recently for diagnostic and therapeutic purposes in oncology. Compared to organic nanomaterials, inorganic NPs have advanced advantages and unique characteristics for better imaging and drug delivery. Still, only a limited number of inorganic NPs are translated into clinical practice. In this review, we discuss the progression of inorganic NPs for cancer therapy and imaging, focusing our attention on opportunities, limitations and challenges for the main constituting nanomaterials, including metallic and magnetic NPs. In particular, the pre clinical and clinical trials from the bench toward clinic are here investigated. PMID- 29284392 TI - MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine cAMP binding sites as a tool for drug design. AB - MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology. The first step in the long process of drug rational design is to identify the therapeutic target and characterize the mechanism by which it affects the given pathology. In order to develop a pharmacological agent with high specific activity, the second step is to systematically study the structure of the target and identify all the possible binding sites. Using available homology models and mutagenesis assays, in this review we recapitulate the up-to-date knowledge about MRP structure and aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides bind. We have also listed the most relevant MRP inhibitors studied to date, considering drug safety and specificity for MRP4 in particular. This metaanalysis platform may serve as a basis for the future development of inhibitors of MRP4 cAMP specific transport. PMID- 29284395 TI - Editorial: Current Challenges in Islet Transplantation and Stem Cell Therapies in Diabetes. PMID- 29284396 TI - Reactions of 3-Arylisocoumarins with N-Nucleophiles - A Route to Novel Azaheterocycles. AB - This review highlights the promising science that has arisen from the synthesis of novel azaheterocycles from isocoumarins. Specific topics include their synthesis and biological activity. Isocoumarins (1H-isochromen-1-ones) are promising synthons, in particular due to the presence of a deoxybenzoin fragment which opens up wide possibilities for synthetic transformations. The deoxybenzoin cycle is highly susceptible to the action of various nucleophilic agents; its oxygen atom participates in recyclization reactions under the action of N nucleophiles where it is replaced by a nitrogen atom, making it possible to obtain isoquinolones via a reaction with ammonia, primary amines, hydroxylamine and benzodiazepinones via a reaction with hydrazine. We systematize literature data, including patents (about 60 publications in all), demonstrate the routes of 3- arylisocoumarins modification under the action of N-nucleophiles - ammonia and primary amines, diamines, secondary amines, (het)arylamines, hydroxylamine, and hydrazines, and discuss the practical importance of these studies for medicinal chemistry. PMID- 29284393 TI - The interplay between G-quadruplex and Transcription. AB - G4 DNA is a non-canonical DNA structure consisting of a stacked array of G quartets held together by base pairing between guanine bases. The formation of G4 DNA requires a cluster of guanine-runs within a strand of DNA. Even though the chemistry of this remarkable DNA structure has been under investigation for decades, evidence supporting the biological relevance of G4 DNA has only begun to emerge and point to very important and conserved biological functions. This review will specifically focus on the interplay between transcription and G4 DNA and discuss two alternative but interconnected perspectives. The first part of the review will describe the evidence substantiating the intriguing idea that a shift in DNA structural conformation could be another layer of non-genetic or epigenetic regulator of gene expression and thereby an important determinant of cell fate. The second part will describe the recent genetic studies showing that those genomic loci containing G4 DNA-forming guanine-rich sequences are potential hotspots of genome instability and that the level and orientation of transcription is critical in the materialization of genome instability associated with these sequences. PMID- 29284397 TI - Stem/Progenitor Cells and Biodegradable Scaffolds in the Treatment of Retinal Degenerative Diseases. AB - BACKGROUND: Visual impairment caused by retinal degeneration is primarily attributed to the irreversible degradation of retinal neurons or the adjacent retinal pigment epithelium (RPE). No efficient clinical therapies to restore or improve visual ability are currently available. Cell therapy has been touted as a promising strategy to overcome this challenge. OBJECTIVE: This review aims to depict the effects and progresses of using stem/progenitor cells and biodegradable scaffolds in the treatment of retinal degenerative diseases, as well as discuss the challenges and opportunities of cell-based therapy for the future clinical application. RESULTS: Progenitor/stem cells may be obtained from both ocular and non-ocular tissues. The former mainly includes retinal progenitor cells (RPCs), whereas the latter comprises embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which have been utilized in stem cell replacement therapy studies ranging from proof-of-concept animal models to clinical trials in humans. Mesenchymal stem cells (MSCs), which represent another type of stem cells, secrete anti-inflammatory cytokines and neurotrophic factors that protect and nourish retinae. Although the origins of seed cells are diverse, the cell survival rate after transplantation in vivo is limited. Therefore, cell delivery techniques that combine seed cells with polymer scaffolds are applied to improve the cell survival rate. CONCLUSION: This review summarized the different resources of stem cells and the significant progresses in the treatment of retinal degeneration combined with seed cells and scaffolds, which may pave the way for future clinical therapies. PMID- 29284398 TI - Mechanisms of Radiation Bystander and Non-Targeted Effects: Implications to Radiation Carcinogenesis and Radiotherapy. AB - BACKGROUND: Knowledge of radiobiology is of paramount importance to be able to grasp and have an in-depth understanding of the consequences of ionizing radiation. One of the most important effects of this physical stressor's interaction to targeted and non-targeted cells, tissues and organs is on the late effects on the development of primary and secondary cancers. Thus, an in-depth understanding of the mechanisms of radiation carcinogenesis remains to be elucidated, and some studies have demonstrated or proposed a role of non-targeted effect in excess risk of cancer incidence. The non-targeted effect in radiobiology refers to a dynamic complex response in non-irradiated tissues caused by the release of presumably of clastogenic factors from irradiated cells. Although, most of these responses in non-targeted tissues have marked similarities to irradiated tissues, other studies have shown some differences. Also, the non-targeted effect has shown sex and tissue specificity that are seen in irradiated tissues too. So far, several studies have been conducted to depict mechanisms that may be involved in this phenomenon. Epigenetic dysfunctions, DNA damage and cell death are responsible for initiation of several signaling pathways that finally result in secretion of clastogenic factors. Moreover, studies have shown that damage to both nucleus and mitochondrial DNA, membrane and some organelles is involved. Oxidized DNA associated with other cell death factors stimulates secretion of inflammatory as well as some anti-inflammatory cytokines from irradiated area. Additionally, oxidative stress that results in damage to cellular structures to include cell membranes can affect secretion of exosomes and miRNAs. These bystander effect exogenous mediators migrate to distant tissues and stimulate various signaling pathways which can lead to changes in immune responses, epigenetic modulations and radiation carcinogenesis. CONCLUSION: In this review, we focus on descriptive and hierarchical events with emphasis on the molecular and functional interactions of ionizing radiation with cells to the mechanisms involved in cancer induction in non-targeted tissues. PMID- 29284399 TI - Profiling the onset of somatic embryogenesis in Arabidopsis. AB - BACKGROUND: Totipotency is the ability of a cell to regenerate a whole organism. Plant somatic embryogenesis (SE) is a remarkable example of totipotency because somatic cells reverse differentiation, respond to an appropriate stimulus and initiate embryo development. Although SE is an ideal system to investigate de differentiation and differentiation, we still lack a deep molecular understanding of the phenomenon due to experimental restraints. RESULTS: We applied the INTACT method to specifically isolate the nuclei of those cells undergoing SE among the majority of non-embryogenic cells that make up a callus. We compared the transcriptome of embryogenic cells to the one of proliferating callus cells. Our analyses revealed that embryogenic cells are transcriptionally rather than metabolically active. Embryogenic cells shut off biochemical pathways involved in carbohydrate and lipid metabolism and activate the transcriptional machinery. Furthermore, we show how early in SE, ground tissue and leaf primordia specification are switched on before the specification of a shoot apical meristem. CONCLUSIONS: This is the first attempt to specifically profile embryogenic cells among the different cell types that constitute plant in vitro tissue cultures. Our comparative analyses provide insights in the gene networks regulating SE and open new research avenues in the field of plant regeneration. PMID- 29284400 TI - Medium-term outcomes of 78,808 patients after heart valve surgery in a middle income country: a nationwide population-based study. AB - BACKGROUND: Heart valve surgery outcomes are unknown in middle-income countries and thus cannot be used in health system decision making processes. This study estimated in-hospital mortality and medium and long-term survival. METHODS: This was a retrospective study of 78,806 patients who underwent heart valve surgery between 2001 and 2007 in Brazil. Two national databases were used, the Hospital Information System and the Mortality Information System. Kaplan-Meier survival analysis and log-rank tests were performed. Maximum and median follow-up was 7.7 and 2.8 years, respectively (0.002-7.707). RESULTS: Valve replacement accounted for 69.1% of procedures performed. Mitral stenosis, the most common valve injury, represented 38.9% of the total. In 94.7% of mitral stenosis patients, aetiology was rheumatic heart disease. In-hospital mortality was 7.6% and was higher for women, for patients who had undergone concomitant coronary artery bypass grafting (CABG) and for the elderly. Overall survival was 69.9% at the end of follow-up. Survival was worst among elderly, male and concomitant CABG patients (P<0.001). CONCLUSIONS: Rheumatic heart disease is still a major public health problem in Brazil. In-hospital mortality and global survival rates of patients who have undergone heart valve surgery were less satisfactory than those reported in high income countries. The findings of this study can contribute to guiding decision making processes in middle-income countries similar to Brazil and others concerned with improving the quality of care. PMID- 29284401 TI - Mapping and screening of the tomato Stemphylium lycopersici resistance gene, Sm, based on bulked segregant analysis in combination with genome resequencing. AB - BACKGROUND: Tomato gray leaf spot disease caused by Stemphylium lycopersici (S. lycopersici) is considered one of the major diseases of cultivated tomatoes. The only S. lycopersici resistance gene, Sm, was derived from the wild tomato species S. pimpinellifolium. Sm has been identified as an effective source of gray leaf spot resistance in tomatoes and has been mapped to tomato chromosome 11. In this study, the first bulked segregant analysis (BSA) combined with genome resequencing for the mapping and screening of the Sm candidate gene was performed. RESULTS: Based on the resequencing results, we identified 50,968 Diff markers, most of which were distributed on chromosome 11. A total of 37 genes were located in the interval of 0.26-Mb. The gene loci of resistant and susceptible lines were sequenced successfully using PCR products. The relative expression levels of candidate genes in resistant and susceptible lines were confirmed via qRT-PCR, Solyc11g011870.1.1 and Solyc11g011880.1.1 were identified through qRT-PCR. A marker, D5, which was cosegregated with the resistant locus, was identified according to the mutation of the Solyc11g011880.1.1 trait in the resistant line. CONCLUSIONS: The Sm gene was mapped to the short arm of chromosome 11. The candidate genes Solyc11g011870.1.1 and Solyc11g011880.1.1 displayed expression patterns related to the resistance response. This study will be valuable for Sm cloning and Sm gene breeding in tomato. PMID- 29284402 TI - The utility of personal activity trackers (Fitbit Charge 2) on exercise capacity in patients post acute coronary syndrome [UP-STEP ACS Trial]: a randomised controlled trial protocol. AB - BACKGROUND: The benefits of physical activity and cardiovascular rehabilitation on the reduction of cardiovascular risk are well documented. Despite this, significant barriers and challenges remain in optimizing patient risk factors post acute coronary syndromes (ACS) and ensuring patient compliance. Consumer wearable personal activity trackers represent a cost effective and readily available technology that may aid in this endeavour. METHODS: UP-STEP ACS is a prospective single-blinded, two-arm, parallel, randomized control trial with an aim to enrol 200 patients all undertaking cardiac rehabilitation. It will assess the affect that personal activity monitors have on change in exercise capacity in patients post acute coronary syndromes primarily measured by a six-minute walk test (6MWT). Secondary end points will be the improvement in other cardiovascular risk factors, namely; blood lipid and glucose levels, weight, waist circumference, along with mood, quality of life and cardiac rehabilitation adherence. Patients will be randomized to either receive a personal activity tracker or standard post hospital care during their index event. After the 8- week intervention period, patients will return for a clinical review and repeat of baseline assessments including the 6MWT. DISCUSSION: The utility and impact on exercise capacity of personal activity trackers in patient's post-acute coronary syndrome has not been assessed. This study aims to add to the scientific evidence emerging regarding the clinical utility and validity of these devices in different patient population groups. If proven to be of benefit, these devices represent a cost effective, easily accessible technology that could aid in the reduction of cardiovascular events. TRIAL REGISTRATION: The trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). The registration number is ACTRN12617000312347 (28/02/2017). PMID- 29284403 TI - The emerging picture of the mitochondrial protein import complexes of Amoebozoa supergroup. AB - BACKGROUND: The existence of mitochondria-related organelles (MROs) is proposed for eukaryotic organisms. The Amoebozoa includes some organisms that are known to have mitosomes but also organisms that have aerobic mitochondria. However, the mitochondrial protein apparatus of this supergroup remains largely unsampled, except for the mitochondrial outer membrane import complexes studied recently. Therefore, in this study we investigated the mitochondrial inner membrane and intermembrane space complexes, using the available genome and transcriptome sequences. RESULTS: When compared with the canonical cognate complexes described for the yeast Saccharomyces cerevisiae, amoebozoans with aerobic mitochondria, display lower differences in the number of subunits predicted for these complexes than the mitochondrial outer membrane complexes, although the predicted subunits appear to display different levels of diversity in regard to phylogenetic position and isoform numbers. For the putative mitosome-bearing amoebozoans, the number of predicted subunits suggests the complex elimination distinctly more pronounced than in the case of the outer membrane ones. CONCLUSION: The results concern the problem of mitochondrial and mitosome protein import machinery structural variability and the reduction of their complexity within the currently defined supergroup of Amoebozoa. This results are crucial for better understanding of the Amoebozoa taxa of both biomedical and evolutionary importance. PMID- 29284404 TI - Multiple functions of CREB-binding protein during postembryonic development: identification of target genes. AB - BACKGROUND: Juvenile hormones (JH) and ecdysteroids control postembryonic development in insects. They serve as valuable targets for pest management. Hence, understanding the molecular mechanisms of their action is of crucial importance. CREB-binding protein (CBP) is a universal transcriptional co regulator. It controls the expression of several genes including those from hormone signaling pathways through co-activation of many transcription factors. However, the role of CBP during postembryonic development in insects is not well understood. Therefore, we have studied the role of CBP in postembryonic development in Tribolium, a model coleopteran insect. RESULTS: CBP is ubiquitously expressed in the red flour beetle, Tribolium castaneum. RNA interference (RNAi) mediated knockdown of CBP resulted in a decrease in JH induction of Kr-h1 gene expression in Tribolium larvae and led to a block in their development. Moreover, the injection of CBP double-stranded RNA (dsRNA) showed lethal phenotypes within 8 days of injection. RNA-seq and subsequent differential gene expression analysis identified CBP target genes in Tribolium. Knockdown of CBP caused a decrease in the expression of 1306 genes coding for transcription factors and other proteins associated with growth and development. Depletion of CBP impaired the expression of several JH response genes (e.g., Kr h1, Hairy, early trypsin) and ecdysone response genes (EcR, E74, E75, and broad complex). Further, GO enrichment analyses of the downregulated genes showed enrichment in different functions including developmental processes, pigmentation, anatomical structure development, regulation of biological and cellular processes, etc. CONCLUSION: These data suggest diverse but crucial roles for CBP during postembryonic development in the coleopteran model insect, Tribolium. It can serve as a target for RNAi mediated pest management of this stored product pest. PMID- 29284405 TI - Highly accurate sequence imputation enables precise QTL mapping in Brown Swiss cattle. AB - BACKGROUND: Within the last few years a large amount of genomic information has become available in cattle. Densities of genomic information vary from a few thousand variants up to whole genome sequence information. In order to combine genomic information from different sources and infer genotypes for a common set of variants, genotype imputation is required. RESULTS: In this study we evaluated the accuracy of imputation from high density chips to whole genome sequence data in Brown Swiss cattle. Using four popular imputation programs (Beagle, FImpute, Impute2, Minimac) and various compositions of reference panels, the accuracy of the imputed sequence variant genotypes was high and differences between the programs and scenarios were small. We imputed sequence variant genotypes for more than 1600 Brown Swiss bulls and performed genome-wide association studies for milk fat percentage at two stages of lactation. We found one and three quantitative trait loci for early and late lactation fat content, respectively. Known causal variants that were imputed from the sequenced reference panel were among the most significantly associated variants of the genome-wide association study. CONCLUSIONS: Our study demonstrates that whole-genome sequence information can be imputed at high accuracy in cattle populations. Using imputed sequence variant genotypes in genome-wide association studies may facilitate causal variant detection. PMID- 29284406 TI - An additive effect of leading role in the organization between social participation and dementia onset among Japanese older adults: the AGES cohort study. AB - BACKGROUND: Several previous studies reported social participation may reduce the incident of dementia; therefore, the type of positions held in the organization may relate to dementia onset. However, this hypothesis remains largely unknown. The purpose of the present study was to examine the additive effect of a leadership position in the organization on dementia onset and social participation among elderly people in a local community, according to data from a Japanese older adults cohort study. METHODS: Of 29,374 community-dwelling elderly, a total of 15,313 subjects responded to the baseline survey and were followed-up from November 2003 to March 2013. To evaluate the association between dementia onset and social participation as well as the role in the organization, we conducted Cox proportional hazard regression analysis with multiple imputation by age group (aged 75 years older or younger). The dependent variable was dementia onset, which was obtained from long-term care insurance data in Japan; independent variables were social participation and the role in the organization to which they belonged (head, manager, or treasurer). Covariates were sex, age, educational level, marriage status, job status, residence status, alcohol consumption, smoking status, and walking time, instrumental activities of daily living, depression, and medical history. RESULTS: During the follow-up period, 708 young-old elderly people (7.7%) and 1289 old-old elderly people (27.9%) developed dementia. In young-old elderly, relative to social non-participants, adjusted Hazard Ratio (HR) for dementia onset for participants (regular members + leadership positions) was 0.75 (95% confidence interval (CI), 0.64-0.88). Relative to regular members, adjusted HR for dementia onset for non-participants was 1.22 (95% CI, 1.02-1.46), for leadership positions 0.81 (95% CI, 0.65-0.99). The results for old-old elderly participants did not show that any significantly adjusted HR between dementia onset and social participation, the role in the organization. CONCLUSIONS: In young-old elderly people, social participation might have a positive effect on dementia onset, and holding leadership positions in organization could lead to a decrease in risk of dementia onset by almost 20% than regular members. PMID- 29284408 TI - Changes of the perceived quality of care for older patients with hypertension by community health centers in shanghai. AB - BACKGROUND: Monitoring and evaluating changes of quality of primary care for older adult hypertensive patients is part of effective delivery of primary care. This study aimed to investigate changes of older adult hypertensive patients' perceived quality of primary care over time in Shanghai. METHODS: Two rounds of cross-sectional questionnaire surveys were conducted in Shanghai in November 2011 and June 2013. A total of 437 patients participated in the first Round survey and 443 in the second. Primary care attributes were collected from Community Health Center users through on-site face-to-face interview surveys using the validated Primary Care Assessment Tool. Multiple linear regressions were used to determine whether there was any difference in primary quality of care scores between 2011 and 2013 surveys. RESULTS: Compared with those in the first Round, participants in the second Round reported higher scores in total primary care quality (28.73 vs. 27.75, P < 0.001), as well as primary care attributes including first-contact utilization (2.81 vs. 2.60, P < 0.001) and accessibility (2.48 vs. 2.44, P < 0.05), continuity of care (3.38 vs. 3.27, P < 0.001), coordination of information (3.82 vs. 3.67, P < 0.001), comprehensiveness of service availability (3.51 vs. 3.39, P < 0.001) and provision (2.69 vs. 2.43, P < 0.001), and cultural competence (2.67 vs. 2.49, P < 0.05), but a lower score in coordination of services (2.45 vs. 2.55, P < 0.05). CONCLUSION: Older adult hypertensive patients perceived better primary care quality from 2011 to 2013 in Shanghai. This may be associated with the general practitioner team service in Shanghai where hypertensive patients were targeted. PMID- 29284407 TI - Clinical drug trials in general practice: how well are external validity issues reported? AB - BACKGROUND: When reading a report of a clinical trial, it should be possible to judge whether the results are relevant for your patients. Issues affecting the external validity or generalizability of a trial should therefore be reported. Our aim was to determine whether articles with published results from a complete cohort of drug trials conducted entirely or partly in general practice reported sufficient information about the trials to consider the external validity. METHODS: A cohort of 196 drug trials in Norwegian general practice was previously identified from the Norwegian Medicines Agency archive with year of application for approval 1998-2007. After comprehensive literature searches, 134 journal articles reporting results published from 2000 to 2015 were identified. In these articles, we considered the reporting of the following issues relevant for external validity: reporting of the clinical setting; selection of patients before inclusion in a trial; reporting of patients' co-morbidity, co-medication or ethnicity; choice of primary outcome; and reporting of adverse events. RESULTS: Of these 134 articles, only 30 (22%) reported the clinical setting of the trial. The number of patients screened before enrolment was reported in 61 articles (46%). The primary outcome of the trial was a surrogate outcome for 60 trials (45%), a clinical outcome for 39 (29%) and a patient-reported outcome for 25 (19%). Clinical details of adverse events were reported in 124 (93%) articles. Co-morbidity of included participants was reported in 54 trials (40%), co medication in 27 (20%) and race/ethnicity in 78 (58%). CONCLUSIONS: The clinical setting of the trials, the selection of patients before enrolment, and co morbidity or co-medication of participants was most commonly not reported, limiting the possibility to consider the generalizability of a trial. It may therefore be difficult for readers to judge whether drug trial results are applicable to clinical decision-making in general practice or when developing clinical guidelines. PMID- 29284409 TI - Primary care multidisciplinary teams in practice: a qualitative study. AB - BACKGROUND: Current recommendations for strengthening the US healthcare system consider restructuring primary care into multidisciplinary teams as vital to improving quality and efficiency. Yet, approaches to the selection of team designs remain unclear. This project describes current primary care team designs, primary care professionals' perceptions of ideal team designs, and perceived facilitating factors and barriers to implementing ideal team-based care. METHODS: Qualitative study of 44 health care professionals at 6 primary care practices in North Carolina using focus group discussions and surveys. Data was analyzed using framework content analysis. RESULTS: Practices used a variety of multidisciplinary team designs with the specific design being influenced by the social and policy context in which practices were embedded. Practices overwhelmingly located barriers to adopting ideal multidisciplinary teams as being outside of their individual practices and outside of their control. Participants viewed internal organizational contexts as the major facilitators of multidisciplinary primary care teams. The majority of practices described their ideal team design as including a social worker to meet the needs of socially complex patients. CONCLUSIONS: Primary care multidisciplinary team designs vary across practices, shaped in part by contextual factors perceived as barriers outside of the practices' control. Facilitating factors within practices provide a culture of support to team members, but they are insufficient to overcome the perceived barriers. The common desire to add social workers to care teams reflects practices' struggles to meet the complex demands of patients and external agencies. Government or organizational policies should avoid one-size fits-all approaches to multidisciplinary care teams, and instead allow primary care practices to adapt to their specific contextual circumstances. PMID- 29284410 TI - Transcriptome analysis reveals key roles of AtLBR-2 in LPS-induced defense responses in plants. AB - BACKGROUND: Lipopolysaccharide (LPS) from Gram-negative bacteria cause innate immune responses in animals and plants. The molecules involved in LPS signaling in animals are well studied, whereas those in plants are not yet as well documented. Recently, we identified Arabidopsis AtLBR-2, which binds to LPS from Pseudomonas aeruginosa (pLPS) directly and regulates pLPS-induced defense responses, such as pathogenesis-related 1 (PR1) expression and reactive oxygen species (ROS) production. In this study, we investigated the pLPS-induced transcriptomic changes in wild-type (WT) and the atlbr-2 mutant Arabidopsis plants using RNA-Seq technology. RESULTS: RNA-Seq data analysis revealed that pLPS treatment significantly altered the expression of 2139 genes, with 605 up regulated and 1534 down-regulated genes in WT. Gene ontology (GO) analysis on these genes showed that GO terms, "response to bacterium", "response to salicylic acid (SA) stimulus", and "response to abscisic acid (ABA) stimulus" were enriched amongst only in up-regulated genes, as compared to the genes that were down regulated. Comparative analysis of differentially expressed genes between WT and the atlbr-2 mutant revealed that 65 genes were up-regulated in WT but not in the atlbr-2 after pLPS treatment. Furthermore, GO analysis on these 65 genes demonstrated their importance for the enrichment of several defense-related GO terms, including "response to bacterium", "response to SA stimulus", and "response to ABA stimulus". We also found reduced levels of pLPS-induced conjugated SA glucoside (SAG) accumulation in atlbr-2 mutants, and no differences were observed in the gene expression levels in SA-treated WT and the atlbr-2 mutants. CONCLUSION: These 65 AtLBR-2-dependent up-regulated genes appear to be important for the enrichment of some defense-related GO terms. Moreover, AtLBR-2 might be a key molecule that is indispensable for the up-regulation of defense related genes and for SA signaling pathway, which is involved in defense against pathogens containing LPS. PMID- 29284411 TI - Prediction of posthepatectomy liver failure using transient elastography in patients with hepatitis B related hepatocellular carcinoma. AB - BACKGROUND: It is essential to accurately predict Postoperative liver failure (PHLF) which is a life-threatening complication. Liver hardness measurement (LSM) is widely used in non-invasive assessment of liver fibrosis. The aims of this study were to explore the application of preoperative liver stiffness measurements (LSM) by transient elastography in predicting postoperative liver failure (PHLF) in patients with hepatitis B related hepatocellular carcinoma. METHODS: The study included 247 consecutive patients with hepatitis B related hepatocellular carcinoma who underwent hepatectomy between May 2015 and September 2015. Detailed preoperative examinations including LSM were performed before hepatectomy. The endpoint was the development of PHLF. RESULTS: All of the patients had chronic hepatitis B defined as the presence of hepatitis B surface antigen (HBsAg) for more than 6 months and 76 (30.8%) had cirrhosis. PHLF occurred in 37 (14.98%) patients. Preoperative LSM (odds ratio, OR, 1.21; 95% confidence interval, 95% CI: 1.13-1.29; P < 0.001) and international normalized ratio (INR) (OR, 1.07; 95% CI: 1.01-1.12; P < 0.05) were revealed to be independent risk factors for PHLF, and a new model was defined as LSM-INR index (LSM-INR index = 0.191*LSM + 6.317*INR-11.154). The optimal cutoff values of LSM and LSM-INR index for predicting PHLF were 14 kPa (AUC 0.86, 95% CI: 0.811-0.901, P < 0.001) and -1.92 (AUC 0.87, 95% CI: 0.822-0.909, P < 0.001), respectively. CONCLUSIONS: LSM can be helpful for surgeons to make therapeutic decisions in patients with hepatitis B related hepatocellular carcinoma. PMID- 29284412 TI - CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV. AB - BACKGROUND: Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1). METHODS: 60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-gamma, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response. RESULTS: Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p = 0.001; CXCL11: p < 0.001; CCL3: p = 0.006; CCL4: p = 0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p = 0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p = 0.039). CONCLUSIONS: IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype. PMID- 29284413 TI - Lower diastolic wall strain is associated with coronary revascularization in patients with stable angina. AB - BACKGROUND: Left ventricular (LV) diastolic dysfunction occurs earlier in the ischemic cascade than LV systolic dysfunction and electrocardiographic changes. Diastolic wall strain (DWS) has been proposed as a marker of LV diastolic stiffness. Therefore, the objectives of this study were to define the relationship between DWS and coronary revascularization and to evaluate other echocardiographic parameters in patients with stable angina who were undergoing coronary angiography (CAG). METHODS: Four hundred forty patients [mean age: 61 +/ 10; 249 (57%) men] undergoing CAG and with normal left ventricular systolic function without regional wall motion abnormalities were enrolled. Among them, 128 (29%) patients underwent revascularization (percutaneous intervention: 117, bypass surgery: 11). All patients underwent echocardiography before CAG and the DWS was defined using posterior wall thickness (PWT) measurements from standard echocardiographic images [DWS = PWT(systole)-PWT(diastole)/PWT(systole)]. RESULTS: Patients who underwent revascularization had a significantly lower DWS than those who did not (0.26 +/- 0.08 vs. 0.38 +/- 0.09, p < 0.001). Age was comparable between the two groups (61 +/- 9 vs. 60 +/- 11, p = 0.337), but the proportion of males was significantly higher among patients who underwent revascularization (69 vs. 52%, p = 0.001). The LV ejection fraction was similar but slightly decreased (60.9 +/- 5.7 vs. 62.4 +/- 6.2%, p = 0.019) and the E/E' ratio was elevated (10.3 +/- 4.0 vs. 9.0 +/- 3.1, p < 0.001) among patients who underwent revascularization. In multiple regression analysis, lower DWS was an independent predictor of revascularization (cut-off value: 0.34; sensitivity: 89%; AUC: 0.870; SE: 0.025; p < 0.001). CONCLUSION: DWS, a simple parameter that can be calculated from routine 2D echocardiography, is inversely associated with the presence of coronary artery disease and the need for revascularization. PMID- 29284414 TI - Can statistic adjustment of OR minimize the potential confounding bias for meta analysis of case-control study? A secondary data analysis. AB - BACKGROUND: Different confounder adjustment strategies were used to estimate odds ratios (ORs) in case-control study, i.e. how many confounders original studies adjusted and what the variables are. This secondary data analysis is aimed to detect whether there are potential biases caused by difference of confounding factor adjustment strategies in case-control study, and whether such bias would impact the summary effect size of meta-analysis. METHODS: We included all meta analyses that focused on the association between breast cancer and passive smoking among non-smoking women, as well as each original case-control studies included in these meta-analyses. The relative deviations (RDs) of each original study were calculated to detect how magnitude the adjustment would impact the estimation of ORs, compared with crude ORs. At the same time, a scatter diagram was sketched to describe the distribution of adjusted ORs with different number of adjusted confounders. RESULTS: Substantial inconsistency existed in meta analysis of case-control studies, which would influence the precision of the summary effect size. First, mixed unadjusted and adjusted ORs were used to combine individual OR in majority of meta-analysis. Second, original studies with different adjustment strategies of confounders were combined, i.e. the number of adjusted confounders and different factors being adjusted in each original study. Third, adjustment did not make the effect size of original studies trend to constringency, which suggested that model fitting might have failed to correct the systematic error caused by confounding. CONCLUSIONS: The heterogeneity of confounder adjustment strategies in case-control studies may lead to further bias for summary effect size in meta-analyses, especially for weak or medium associations so that the direction of causal inference would be even reversed. Therefore, further methodological researches are needed, referring to the assessment of confounder adjustment strategies, as well as how to take this kind of bias into consideration when drawing conclusion based on summary estimation of meta-analyses. PMID- 29284415 TI - Streptococcus agalactiae infective endocarditis complicated by multiple mycotic hepatic aneurysms and massive splenic infarction: a case report. AB - BACKGROUND: The burden of disease caused by Streptococcus agalactiae has increased significantly among older adults in the last decades. Group B streptococcus infection can be associated with invasive disease and severe clinical syndromes, such as meningitis and endocarditis. CASE PRESENTATION: We present the case of a 56-year-old man who developed multiple mycotic aneurysms of the right hepatic artery and massive splenic infarction as rare complications of Streptococcus agalactiae infective endocarditis. The patient underwent urgent right hepatic artery ligation and splenectomy. The postoperative course was complicated by an episode of hemobilia due to the rupture of a partially thrombosed mycotic aneurysm into the biliary tree. Thus, selective radiological embolization of the left hepatic artery branches was necessary. CONCLUSION: To our knowledge, this is the first case reported of infected aneurysms of visceral arteries caused by Group B streptococcus infection. Clinical and laboratory findings were non-specific, while imaging features with computed tomography scan and angiography were highly suggestive. In our case, early recognition, culture specific intravenous antibiotics and urgent surgical treatment combined with interventional radiology played a decisive role in the final result. PMID- 29284416 TI - Preoperative medication use and postoperative delirium: a systematic review. AB - BACKGROUND: Medications are frequently reported as both predisposing factors and inducers of delirium. This review evaluated the available evidence and determined the magnitude of risk of postoperative delirium associated with preoperative medication use. METHODS: A systematic search in Medline and EMBASE was conducted using MeSH terms and keywords for postoperative delirium and medication. Studies which included patients 18 years and older who underwent major surgery were included. The methodological quality of included studies was assessed independently by two authors using the Newcastle-Ottawa quality assessment scale for cohort studies. RESULTS: Twenty-nine studies; 25 prospective cohort, three retrospective cohort and one post hoc analysis of RCT data were included. Only four specifically aimed to assess medicines as an independent predictor of delirium, all other studies included medicines among a number of potential predictors of delirium. Of the studies specifically testing the association with a medication class, preoperative use of beta-blockers (OR = 2.06[1.18-3.60]) in vascular surgery and benzodiazepines RR 2.10 (1.23-3.59) prior to orthopedic surgery were significant. However, evidence is from single studies only. Where medicines were included as one possible factor among many, hypnotics had a similar risk estimate to the benzodiazepine study, with one significant and one non-significant result. Nifedipine use prior to cardiac surgery was found to be significantly associated with delirium. The non-specific grouping of psychoactive medication use preoperatively was generally higher with an associated two-to seven-fold higher risk of postoperative delirium, while only two studies included narcotics without other agents, with one significant and one non-significant result. CONCLUSIONS: There was a limited number of high quality studies in the literature quantifying the direct association between preoperative medication use and postsurgical delirium. More studies are required to evaluate the association of specific preoperative medications on the risk of postoperative delirium so that comprehensive guidelines for medicine use prior to surgery can be developed to aid delirium prevention. TRIAL REGISTRATION: This systematic review has been registered on PROSPERO International prospective register of systematic reviews (Registration number: CRD42016051245 ). PMID- 29284417 TI - Abstract analysis method facilitates filtering low-methodological quality and high-bias risk systematic reviews on psoriasis interventions. AB - BACKGROUND: Article summaries' information and structure may influence researchers/clinicians' decisions to conduct deeper full-text analyses. Specifically, abstracts of systematic reviews (SRs) and meta-analyses (MA) should provide structured summaries for quick assessment. This study explored a method for determining the methodological quality and bias risk of full-text reviews using abstract information alone. METHODS: Systematic literature searches for SRs and/or MA about psoriasis were undertaken on MEDLINE, EMBASE, and Cochrane database. For each review, quality, abstract-reporting completeness, full-text methodological quality, and bias risk were evaluated using Preferred Reporting Items for Systematic Reviews and Meta-analyses for abstracts (PRISMA-A), Assessing the Methodological Quality of Systematic Reviews (AMSTAR), and ROBIS tools, respectively. Article-, author-, and journal-derived metadata were systematically extracted from eligible studies using a piloted template, and explanatory variables concerning abstract-reporting quality were assessed using univariate and multivariate-regression models. Two classification models concerning SRs' methodological quality and bias risk were developed based on per item and total PRISMA-A scores and decision-tree algorithms. This work was supported, in part, by project ICI1400136 (JR). No funding was received from any pharmaceutical company. RESULTS: This study analysed 139 SRs on psoriasis interventions. On average, they featured 56.7% of PRISMA-A items. The mean total PRISMA-A score was significantly higher for high-methodological-quality SRs than for moderate- and low-methodological-quality reviews. SRs with low-bias risk showed higher total PRISMA-A values than reviews with high-bias risk. In the final model, only 'authors per review > 6' (OR: 1.098; 95%CI: 1.012-1.194), 'academic source of funding' (OR: 3.630; 95%CI: 1.788-7.542), and 'PRISMA endorsed journal' (OR: 4.370; 95%CI: 1.785-10.98) predicted PRISMA-A variability. Reviews with a total PRISMA-A score < 6, lacking identification as SR or MA in the title, and lacking explanation concerning bias risk assessment methods were classified as low-methodological quality. Abstracts with a total PRISMA-A score >= 9, including main outcomes results and explanation bias risk assessment method were classified as having low-bias risk. CONCLUSIONS: The methodological quality and bias risk of SRs may be determined by abstract's quality and completeness analyses. Our proposal aimed to facilitate synthesis of evidence evaluation by clinical professionals lacking methodological skills. External validation is necessary. PMID- 29284418 TI - The aetiologies of central nervous system infections in hospitalised Cambodian children. AB - BACKGROUND: Central nervous system (CNS) infections are an important cause of childhood morbidity and mortality. The aetiologies of these potentially vaccine preventable infections have not been well established in Cambodia. METHODS: We did a one year prospective study of children hospitalised with suspected CNS infection at Angkor Hospital for Children, Siem Reap. Cerebrospinal fluid specimens (CSF) samples underwent culture, multiplex PCR and serological analysis to identify a range of bacterial and viral pathogens. Viral metagenomics was performed on a subset of pathogen negative specimens. RESULTS: Between 1st October 2014 and 30th September 2015, 284 analysable patients were enrolled. The median patient age was 2.6 years; 62.0% were aged <5 years. CSF white blood cell count was >=10 cells/MUL in 116/272 (42.6%) cases. CNS infection was microbiologically confirmed in 55 children (19.3%). Enteroviruses (21/55), Japanese encephalitis virus (17/55), and Streptococcus pneumoniae (7/55) accounted for 45 (81.8%) of all pathogens identified. Of the pathogens detected, 74.5% (41/55) were viruses and 23.6% (13/55) were bacteria. The majority of patients were treated with ceftriaxone empirically. The case fatality rate was 2.5%. CONCLUSIONS: Enteroviruses, JEV and S. pneumoniae are the most frequently detected causes of CNS infection in hospitalised Cambodian children. PMID- 29284419 TI - Serotype distribution and antibiotic resistance of Streptococcus pneumoniae isolates from 17 Chinese cities from 2011 to 2016. AB - BACKGROUND: Streptococcus pneumoniae, the leading pathogen of bacterial infections in infants and the elderly, is responsible for pneumococcal diseases with severe morbidity and mortality. Emergence of drug-resistant strains presented new challenges for treatment and prevention. Vaccination has proven to be an effective means of preventing pneumococcal infection worldwide. Detailed epidemiological information of antibiotic susceptibilities and serotype distribution will be of great help to the management of pneumococcal infections. METHODS: A total of 881 S. pneumoniae isolates were collected from patients at 23 teaching hospitals in 17 different cities from 2011 to 2016. The main specimen types included sputum, blood, broncho-alveolar lavage fluid, pharyngeal swabs, and cerebrospinal fluid. Minimum inhibitory concentrations (MICs) were determined using the agar dilution method. Capsular serotypes were identified using latex agglutination and quellung reaction test. Molecular epidemiology was investigated using multilocus sequence typing. RESULTS: S. pneumoniae isolates were highly resistant to macrolides, tetracycline, and trimethoprim/sulfamethoxazole. The rate of resistance to penicillin was 51.6% (oral breakpoint). However, levofloxacin and moxifloxacin maintained excellent antimicrobial activity and all of the isolated strains were susceptible to vancomycin. Twenty-two serotypes were identified among the 881 isolates. Prevalent serotypes were 19F (25.7%), 19A (14.0%), 15 (6.8%), 6B (3.6%), 6A (3.0%), and 17 (2.8%). The overall vaccine coverage rates for 7- and 13-valent pneumococcal conjugate vaccines were 37.5% and 58.3%, respectively. Vaccine coverage rates in young children and economically underdeveloped regions were higher than those in older adults and developed regions. Vaccine-covered serotypes demonstrated higher resistance compared with uncovered serotypes. Molecular epidemiological typing demonstrated that S. pneumoniae showed significant clonal dissemination and that ST271 (120, 28.3%), ST320 (73, 17.2%) and ST81 (27, 6.6%) were the major STs. CONCLUSIONS: High resistance to clinical routine antibiotics was observed for all 881 S. pneumoniae strains. Drug resistance varied among different serotypes and age groups. Prevalent serotypes among the isolates were 19F, 19A, 15, 6B, 6A, and 17. Community-acquired strains should also be included in future studies to gain a better understanding of the prevalence and resistance of S. pneumoniae in China. PMID- 29284420 TI - An evaluation of a recombinant multiepitope based antigen for detection of Toxoplasma gondii specific antibodies. AB - BACKGROUND: The inefficiency of the current tachyzoite antigen-based serological assays for the serodiagnosis of Toxoplasma gondii infection mandates the need for acquirement of reliable and standard diagnostic reagents. Recently, epitope-based antigens have emerged as an alternative diagnostic marker for the achievement of highly sensitive and specific capture antigens. In this study, the diagnostic utility of a recombinant multiepitope antigen (USM.TOXO1) for the serodiagnosis of human toxoplasmosis was evaluated. METHODS: An indirect enzyme-linked immunosorbent assay (ELISA) was developed to evaluate the usefulness of USM.TOXO1 antigen for the detection of IgG antibodies against Toxoplasma gondii in human sera. Whereas the reactivity of the developed antigen against IgM antibody was evaluated by western blot and Dot enzyme immunoassay (dot-EIA) analysis. RESULTS: The diagnostic performance of the new antigens in IgG ELISA was achieved at the maximum values of 85.43% and 81.25% for diagnostic sensitivity and specificity respectively. The USM.TOXO1 was also proven to be reactive with anti- T. gondii IgM antibody. CONCLUSIONS: This finding makes the USM.TOXO1 antigen an attractive candidate for improving the toxoplasmosis serodiagnosis and demonstrates that multiepitope antigens could be a potential and promising diagnostic marker for the development of high sensitive and accurate assays. PMID- 29284421 TI - Improved performance of Xpert MTB/RIF assay on sputum sediment samples obtained from presumptive pulmonary tuberculosis cases at Kibong'oto infectious diseases hospital in Tanzania. AB - BACKGROUND: The introduction of Xpert MTB/RIF assay (Xpert) has significantly improved diagnosis of Tuberculosis (TB) in resource limited human immunodeficiency virus (HIV) endemic settings. We aimed to modify the Xpert protocol to improve the detection of Mycobacterium tuberculosis (MTB). METHODS: This cross sectional study was conducted among presumptive pulmonary tuberculosis (PTB) patients at Kibong'oto Infectious Diseases Hospital between August and November 2015. Each patient consented to provide 2 samples of raw sputa. One sputum sample was sedimented using the Petroff's method and divided into two portions. One portion of sediment was inoculated on Lowenstein-Jensen culture media and observed for any growth for up to 8 weeks. Both, raw sputum and the portions of sediments were tested separately using Xpert with a sample reagent ratio of 1:2. Mean age of patients, prevalence of MTB, Xpert sensitivity, specificity, positive and negative predictive value were calculated. An incremental sensitivity was determined. Pearson chi-square and either an independent T or Mann-Whitney U-test were used to compared categorical and continuous variables respectively. A p- value of <=0.05 was considered significant. RESULTS: Of the 270 presumptive PTB cases, 262 were eligible for analysis. Eight (3%) were excluded due to contaminated culture. Patients' mean age was 42.9 (+/-SD 15.1) years of which 173 (66%) were female. The overall prevalence of PTB was 112 (43%), of which the Xpert detected 105 (40%) in sediments and 98 (37%) in raw sputa as compared to culture which detected 85 (32%) cases of PTB. Sensitivity, specificity, positive and negative predictive values of Xpert on sputum sediments were 92%, 85%, 74% and 96% respectively. Overall, the incremental sensitivity of Xpert on sediment over raw sputum was 6%. In HIV infected Presumptive PTB, the incremental sensitivity was 12%. CONCLUSION: Lowering the sample reagent to sediment dilution ratio increases sensitivity of Xpert on MTB detection among presumptive PTB cases, especially in HIV infected individuals. PMID- 29284422 TI - Hepatitis B virus infection in hilly/mountainous regions of southeastern China: a locality-dependent epidemiology. AB - BACKGROUND: The overall prevalence of hepatitis B virus (HBV) infection in China is declining. The purpose of this study was to use a community-based epidemiological study to update the infection status of hepatitis B virus (HBV) in mountainous regions of China, and to evaluate the impact of the Expanded Program of Immunization (EPI) on HBV transmission. METHODS: In total, 10,383 participants were selected by multi-stage stratified random cluster sampling in two mountainous regions, Xianju and Anji, in Zhejiang province, China. RESULTS: The positive rates of hepatitis B virus surface antigen (HBsAg), anti-HBV core antigen (anti-HBc), and anti-HBV surface antigen (anti-HBs) were 9.5%, 33.9%, and 51.0%, respectively. Positive HBV markers were more frequently detected in males than in females (P < 0.01). The alanine aminotransferase (ALT) levels were elevated (>38 IU/L) in 15.3% of the HBsAg-positive and 6.3% of the HBsAg-negative subjects. The alpha-fetoprotein (AFP) level was elevated in 0.8% of the HBsAg positive participants who were older than 30 years old. CONCLUSIONS: The epidemiology of HBV infection is location dependent. The prevalence of HBV infection in the mountainous regions is higher than the national levels. Moreover, HBV infection in women of childbearing age is up to 10%, which represents a main factor for continuous HBV transmission. PMID- 29284423 TI - The relationship between lower limb muscle volume and body mass in ambulant individuals with bilateral cerebral palsy. AB - BACKGROUND: Individuals with cerebral palsy have smaller muscle volumes normalised to body mass than their typically developing peers. The aim of this study is to investigate the relationship between lower limb muscle volume and body mass in young people with bilateral cerebral palsy and their typically developing peers. METHODS: Twenty-five participants with bilateral cerebral palsy (aged 14.7+/-3.0 years, GMFCS level I-III) and 25 of their typically developing peers (aged 16.8+/-3.3 years) took part in this study. None of the participants had undergone orthopaedic surgery, botulinum toxin injections, or serial casting in the previous year. All participants underwent magnetic resonance imaging of both lower limbs. Nine major muscles of each lower limb were individually manually segmented and the muscle volumes calculated. RESULTS: Body mass and total lower limb muscle volume were significantly linearly related in both the cerebral palsy (R2 = 0.75, p<0.001) and typically developing (R2 = 0.77, p<0.001) groups. The slope of the relationship between muscle volume and body mass was significantly shallower in the cerebral palsy group compared to the typically developing group (p=0.007). CONCLUSIONS: This cross-sectional study suggests that the increase in size of lower limb muscles relative to body mass is reduced in adolescents and young adults with cerebral palsy. Longitudinal studies are required to further investigate altered muscle growth trajectories in this group and their impact on long-term mobility. PMID- 29284424 TI - The effect of whole-body cooling on renal function in post-cardiac arrest patients. PMID- 29284425 TI - MRI texture analysis in differentiating luminal A and luminal B breast cancer molecular subtypes - a feasibility study. AB - BACKGROUND: The aim of this study was to use texture analysis (TA) of breast magnetic resonance (MR) images to assist in differentiating estrogen receptor (ER) positive breast cancer molecular subtypes. METHODS: Twenty-seven patients with histopathologically proven invasive ductal breast cancer were selected in preliminary study. Tumors were classified into molecular subtypes: luminal A (ER positive and/or progesterone receptor (PR)-positive, human epidermal growth factor receptor type 2 (HER2) -negative, proliferation marker Ki-67 < 20 and low grade (I)) and luminal B (ER-positive and/or PR-positive, HER2-positive or HER2 negative with high Ki-67 >= 20 and higher grade (II or III)). Co-occurrence matrix -based texture features were extracted from each tumor on T1-weighted non fat saturated pre- and postcontrast MR images using TA software MaZda. Texture parameters and tumour volumes were correlated with tumour prognostic factors. RESULTS: Textural differences were observed mainly in precontrast images. The two most discriminative texture parameters to differentiate luminal A and luminal B subtypes were sum entropy and sum variance (p = 0.003). The AUCs were 0.828 for sum entropy (p = 0.004), and 0.833 for sum variance (p = 0.003), and 0.878 for the model combining texture features sum entropy, sum variance (p = 0.001). In the LOOCV, the AUC for model combining features sum entropy and sum variance was 0.876. Sum entropy and sum variance showed positive correlation with higher Ki-67 index. Luminal B types were larger in volume and moderate correlation between larger tumour volume and higher Ki-67 index was also observed (r = 0.499, p = 0.008). CONCLUSIONS: Texture features which measure randomness, heterogeneity or smoothness and homogeneity may either directly or indirectly reflect underlying growth patterns of breast tumours. TA and volumetric analysis may provide a way to evaluate the biologic aggressiveness of breast tumours and provide aid in decisions regarding therapeutic efficacy. PMID- 29284426 TI - The morphology of maxillary first and second molars analyzed by cone-beam computed tomography in a polish population. AB - BACKGROUND: The success of endodontic treatment is greatly affected by the location of the root canals. The purpose of this study was to evaluate the root and canal morphology of permanent maxillary first and second molars in a Polish population using cone-beam computed tomography scanning. METHODS: Cone-beam computed tomography (CBCT) scans of maxillary first and second molars the maxilla were examined. The number of roots and root canals, and the frequency of additional canals (MB2) in the mesiobuccal root canals were determined. The results were subjected to statistical analysis using the chi-square test or the chi-square test with Yates' correction. RESULTS: A total of 112 CBCT images of maxillary first (n = 185) and second molars (n = 207) from 112 patients were analyzed. All the maxillary first molars had three roots (100%). The majority of maxillary second molars had three roots (91.8%), 5.8% had two roots and 2.4% had one root. A statistically significant difference was observed between the numbers of roots in the maxillary first and second molars (p < 0.01). A statistically significant difference was also found in the distribution of the number of canals in the maxillary first and second molars (p < 0.001). The majority of maxillary first molars had four root canals (59.5%), while 40.5% had three root canals. Most maxillary second molars had three root canals (70%). Additional canals (MB2) in the mesiobuccal roots were detected significantly more frequently in the maxillary first molars than the second molars (p = 0.000) and more frequently in men than in women (p < 0.05). A higher prevalence of two canals in the mesiobuccal roots in maxillary second molars occurred in patients aged between 31 and 40 years than in patients aged between 21 and 30 years. In the maxillary first molars, the prevalence of the MB2 canal in the mesiobuccal root was almost equally distributed in the two age groups (21-30 and 31-40 years). CONCLUSION: Within the limitations of this study, it can be concluded that there are differences in the number and configuration of roots and root canals between maxillary first and second molars in the studied patients of a Polish population. PMID- 29284428 TI - Unilateral lateral rectus muscle advancement surgery based on one-fourth of the angle of consecutive esotropia. AB - BACKGROUND: To evaluate the efficacy of unilateral lateral rectus muscle advancement surgery based on one-fourth of the angle of consecutive esotropia within 25 prism diopters (PD) occurring after bilateral lateral rectus muscle recession for intermittent exotropia. METHODS: Medical records of 11 patients who underwent unilateral lateral rectus muscle advancement for consecutive esotropia from 2011 to 2014 and who were observed for at least 6 months after surgery were retrospectively reviewed. The change in angle of deviation from before to after consecutive esotropia surgery, as well as the success rate and surgical effect, were evaluated. RESULTS: Preoperative esodeviation was -19.6 +/- 4.7 PD [median - 20.0 PD, interquartile range (IQR) 9.0] at distance and -16.5 +/- 7.4 PD [median 18.0 PD, IQR 17.0] at near. The mean surgical amount of unilateral lateral rectus muscle advancement surgeries, based on one-fourth of the angle of consecutive esotropia, was 4.8 +/- 1.1 mm [median 5.0 mm, IQR 2.0]. Of the 11 patients, 10 (91%) recovered to orthotropia or exodeviation within 8 PD. The surgical effects of unilateral lateral rectus muscle advancement were 3.3 +/- 0.7 PD/mm [median 3.6 PD/mm, IQR 1.0] after 1 day, 3.7 +/- 0.6 PD/mm [median 3.8 PD/mm, IQR 1.0] after 1 week, and 3.8 +/- 0.7 PD/mm [median 3.8 PD/mm, IQR 1.5] after 6 months. CONCLUSIONS: Unilateral lateral rectus muscle advancement surgery based on one-fourth of the angle of consecutive esotropia within 25 PD was successful in all 11 patients. The surgical effect was significantly greater in unilateral lateral rectus muscle advancement than in primary lateral rectus muscle recession. Reduction in the amount of surgery should be considered carefully in unilateral lateral rectus muscle advancement for consecutive esotropia. PMID- 29284427 TI - Study design and baseline findings from the progression of ocular findings (PROOF) natural history study of dry eye. AB - BACKGROUND: The aim of this research is to initiate a 5-year natural history study of dry eye disease (DED) using objectively assessed and patient-reported outcomes, to explore the hypothesis that DED is a progressive condition that has substantive and measurable impacts not only on the ocular surface, but on quality of life and visual functioning. Our objective for this report is to examine the baseline data. METHODS: A multicenter, prospective, controlled, observational study of Level 2 (mild-to-moderate) DED patients based on International Task Force Delphi Panel severity grading, and controls, documented baseline measures (including tear film biomarkers and quality of life). Tear cytokine concentrations were also measured in the tear film. Patients were using artificial tears as needed. RESULTS: Two hundred seventeen DED patients and 67 gender- and age-matched controls were enrolled. A majority were females and Caucasian and groups did not differ significantly in terms of gender, race, or age. Differences between DED and matched controls, at baseline, included mean scores for Ocular Surface Disease Index (31.7 vs 4.1, P < 0.0001), Schirmer test (5.7 vs 15.3 mm, P < 0.0001), corneal staining (1.4 vs 0.2, P < 0.0001), conjunctival staining (1.4 vs 0.3, P < 0.0001), and tear break-up time (5.7 vs 8.5 s, P < 0.0001). Tear cytokines levels were determined and included interferon gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor alpha, epidermal growth factor, IL-13, IL-17, IL-1alpha, and inducible protein 10. The mean levels of IL-8 and IL-6 were slightly higher in the DED group at baseline. Blurred vision was reported as moderate/severe/very severe at baseline in 57.6% of DED patients vs.10.5% of normal controls (P < 0.0001). DED patients reported greater reductions in work and non-work productivity, as well as greater need for visits to ophthalmologists during the prior year. CONCLUSIONS: In this report of the baseline findings of a 5-year natural history study of DED, a striking disease burden is observed with regard to blurred vision, productivity, and visits to eye care practitioners in mild to moderate DED patients compared to normal subjects of similar ages and genders. TRIAL REGISTRATION: ClinicalTrials.gov NCT00833235 on January 30, 2009. PMID- 29284429 TI - Galectin 3 expression in primary oral squamous cell carcinomas. AB - BACKGROUND: Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens. METHODS: Preoperative diagnostic biopsies (n = 26) and tumor resection specimens (n = 34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed. RESULTS: In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p < 0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p < 0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p < 0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p < 0.05) with higher grading (G3) in tumor resection specimens. CONCLUSION: High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target. PMID- 29284430 TI - Successful anticoagulant therapy for disseminated intravascular coagulation during conservative management of placenta percreta: a case report and literature review. AB - BACKGROUND: Placenta percreta is a rare obstetric condition associated with the risk of massive intraoperative hemorrhage. Recently, conservative management of placenta percreta has been performed to reduce maternal morbidity. However, various complications have been reported during such management. Only a few cases of asymptomatic disseminated intravascular coagulation (DIC) or fever without infection have been reported. Here, we discuss such a case and review the related literature to understand this rare condition better. For this, we performed an electronic literature review. CASE PRESENTATION: We present the clinical course, results of blood tests, and serial magnetic resonance images of a 35-year-old female (gravida 5, para 2) with placenta percreta complicated by placenta previa that was managed conservatively. The patient successfully delivered a healthy baby by a cesarean delivery via a transverse uterine fundal incision at 36 weeks of gestation. We did not observe intraoperative complications during cesarean delivery, and the postoperative course remained uncomplicated until 47 days after the delivery. However, asymptomatic DIC developed after 47 days, and her serum fibrinogen level declined to 42 mg/dL, which was successfully treated with anticoagulant therapy by a therapeutic dose of intravenous heparin for 22 days (postoperative days 48-69). Although DIC resolved, subsequent fever persisted for approximately 1 month (postoperative days 67-103). Infection was ruled out, and conservative management was successfully continued. Literature review revealed that successful conservative management of a patient with asymptomatic DIC and subsequent fever without infection is extremely rare. CONCLUSIONS: Some patients with DIC and fever can continue conservative management of placenta percreta, although careful examination and monitoring are needed. PMID- 29284431 TI - The health and wellbeing needs of veterans: a rapid review. AB - BACKGROUND: For the majority of serving members, life in the military has a positive effect on wellbeing. However, the type, intensity and duration of service, along with the transition from fulltime military to civilian life, may have a negative effect on veterans' wellbeing. Such negative consequences, alongside the growing veteran population, indicate the need for greater exploration of veterans' physical, mental and social wellbeing. METHODS: The current paper reports on the findings of a rapid review of the literature on the health and wellbeing needs of veterans, commissioned by the Australian Department of Veterans' Affairs to inform future programs and services. The databases Embase, Medline, Cinahl, PubMed, Web of Science and Cochrane Database were searched for systematic reviews reporting on veterans' physical, mental and social wellbeing published in English in peer-reviewed journals. RESULTS: A total of 21 systematic reviews were included. The reviews reported on a range of mental, physical and social health problems affecting veterans. While there was limited information on prevalence rates of physical, mental and social health problems in veterans compared to civilian populations, the reviews demonstrated the interconnection between these domains and the effect of demographic and military service factors. CONCLUSIONS: A key finding of the review is the interconnection of the mental, physical, and social health of veterans, highlighting the importance that an integrated approach to veterans' wellbeing is adopted. It is suggested that understanding key factors, such as demographic factors and factors relating to military service, can support improved service provision for veterans. PMID- 29284432 TI - Mujeres Fuertes y Corazones Saludables: adaptation of the StrongWomen -healthy hearts program for rural Latinas using an intervention mapping approach. AB - OBJECTIVE: To describe our use of intervention mapping as a systematic method to adapt an evidence-based physical activity and nutrition program to reflect the needs of rural Latinas. METHODS: An intervention mapping process involving six steps guided the adaptation of an evidence based physical activity and nutrition program, using a community-based participatory research approach. We partnered with a community advisory board of rural Latinas throughout the adaptation process. RESULTS: A needs assessment and logic models were used to ascertain which program was the best fit for adaptation. Once identified, we collaborated with one of the developers of the original program (StrongWomen - Healthy Hearts) during the adaptation process. First, essential theoretical methods and program elements were identified, and additional elements were added or adapted. Next, we reviewed and made changes to reflect the community and cultural context of the practical applications, intervention strategies, program curriculum, materials, and participant information. Finally, we planned for the implementation and evaluation of the adapted program, Mujeres Fuertes y Corazones Saludables, within the context of the rural community. A pilot study will be conducted with overweight, sedentary, middle-aged, Spanish-speaking Latinas. Outcome measures will assess change in weight, physical fitness, physical activity, and nutrition behavior. CONCLUSIONS: The intervention mapping process was feasible and provided a systematic approach to balance fit and fidelity in the adaptation of an evidence-based program. Collaboration with community members ensured that the components of the curriculum that were adapted were culturally appropriate and relevant within the local community context. PMID- 29284433 TI - Adaptation of the WHO maternal near miss tool for use in sub-Saharan Africa: an International Delphi study. AB - BACKGROUND: Assessments of maternal near miss (MNM) are increasingly used in addition to those of maternal mortality measures. The World Health Organization (WHO) has introduced an MNM tool in 2009, but this tool was previously found to be of limited applicability in several low-resource settings. The aim of this study was to identify adaptations to enhance applicability of the WHO MNM tool in sub-Saharan Africa. METHODS: Using a Delphi consensus methodology, existing MNM tools were rated for applicability in sub-Saharan Africa over a series of three rounds. Maternal health experts from sub-Saharan Africa or with considerable knowledge of the context first rated importance of WHO MNM parameters using Likert scales, and were asked to suggest additional parameters. This was followed by two confirmation rounds. Parameters accepted by at least 70% of the panel members were accepted for use in the region. RESULTS: Of 58 experts who participated from study onset, 47 (81%) completed all three rounds. Out of the 25 WHO MNM parameters, all 11 clinical, four out of eight laboratory, and four out of six management-based parameters were accepted, while six parameters (PaO2/FiO2 < 200 mmHg, bilirubin >100 MUmol/l or >6.0 mg/dl, pH <7.1, lactate >5 MUmol/l, dialysis for acute renal failure and use of continuous vasoactive drugs) were deemed to not be applicable. An additional eight parameters (uterine rupture, sepsis/severe systemic infection, eclampsia, laparotomy other than caesarean section, pulmonary edema, severe malaria, severe complications of abortions and severe pre-eclampsia with ICU admission) were suggested for inclusion into an adapted sub-Saharan African MNM tool. CONCLUSIONS: All WHO clinical criteria were accepted for use in the region. Only few of the laboratory- and management based were rated applicable. This study brought forward important suggestions for adaptations in the WHO MNM criteria to enhance its applicability in sub-Saharan Africa and possibly other low-resource settings. PMID- 29284434 TI - Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer. AB - BACKGROUND: The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer. METHODS: The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy. RESULTS: Five-year disease-free survival (DFS) and disease specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p < 0.001) and extracapsular spread (p = 0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p = 0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p = 0.028) were significant factors associated with 5 year DFS. In univariate analysis, cervical lymph node metastasis (p = 0.048), lymphovascular invasion (p = 0.041), extracapsular spread (p = 0.015), and esophageal invasion (p = 0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p = 0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p = 0.005) remained significant factors associated with 5-year DSS. CONCLUSION: Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery. PMID- 29284436 TI - Health care use, drug treatment and comorbidity in patients with schizophrenia or non-affective psychosis in Sweden: a cross-sectional study. AB - BACKGROUND: This study investigated the prevalence of schizophrenia (ICD-10 F 20) and of other non-affective psychosis (NAP, ICD-10 F 21 - F 29) in Sweden. It further assessed health care use, comorbidity and medication for these patient groups. Most studies either have a study population of patients with strictly defined schizophrenia or a psychosis population of which strict schizophrenia cases form a smaller set. The present study permits comparison of the two mutually exclusive patient groups using data at the individual level in the diagnosis of non-affective psychosis, use of health care, medical treatment and comorbidity by diagnosis or medical treatment. METHODS: In 2012, data were extracted from a regional registry containing patient-level data on consultations, hospitalisations, diagnoses and dispensed drugs for the total population in the region of Stockholm (2.1 million inhabitants). The size of the total psychosis population was 18,769, of which 7284 had a diagnosis of schizophrenia. Crude prevalence rates and risk rates with 95% confidence intervals were calculated. RESULTS: In 2012, the prevalence of schizophrenia and NAP was 3.5/1000 and 5.5/1000, respectively. Schizophrenia was most common among patients aged 50-59 years and NAP most common among patients aged 40-49 years. Schizophrenia patients used psychiatric health care more often than the NAP patients but less overall inpatient care (78.6 vs. 60.0%). The most prevalent comorbidities were substance abuse/dependence (7.9% in the schizophrenia group vs. 11.7% in the NAP group), hypertension (7.9 vs. 9.7%) and diabetes (6.9 vs. 4.8%). The parenteral form of long-acting injectable antipsychotics was more often dispensed to patients with schizophrenia (10 vs. 2%). CONCLUSIONS: This study, analysing all diagnoses recorded in a large health region, confirmed prevalence rates found in previous studies. Schizophrenia patients use more psychiatric and less overall inpatient health care than NAP patients. Differences between the two patient groups in comorbidity and drug treatment were found. The registered rates of a substance abuse/dependence diagnosis were the most common comorbidity observed among the patients investigated. The observed differences between the schizophrenia and the NAP patients in health care consumption, comorbidity and drug treatment are relevant and warrant further studies. PMID- 29284435 TI - Influenza vaccine effectiveness against influenza-related hospitalization during a season with mixed outbreaks of four influenza viruses: a test-negative case control study in adults in Canada. AB - BACKGROUND: The Serious Outcomes Surveillance (SOS) Network was established to monitor seasonal influenza complications among hospitalized Canadian adults and to assess the effectiveness of influenza vaccination against severe outcomes. Here we report age- and strain-specific vaccine effectiveness (VE) in preventing severe outcomes during a season characterized by mixed outbreaks of four different influenza strains. METHODS: This prospective, multicentre, test negative case-control study evaluated the VE of trivalent influenza vaccine (TIV) in the prevention of laboratory-confirmed influenza-hospitalization in adults aged >=16 years (all adults) and adults aged 16-64 years (younger adults). The SOS Network identified hospitalized patients with diagnoses potentially attributable to influenza during the 2011/12 influenza season. Swabs collected at admission were tested by reverse transcriptase polymerase chain reaction (RT PCR) or viral culture to discriminate influenza cases (positive) from controls (negative). VE was calculated as 1-odds ratio (OR) of vaccination in cases versus controls * 100. RESULTS: Overall, in all adults, the unadjusted and adjusted VEs of TIV against influenza-hospitalization were 41.8% (95% Confidence Interval [CI]: 26.0, 54.3), and 42.8% (95% CI: 23.8, 57.0), respectively. In younger adults (16-64 years), the unadjusted and adjusted VEs of TIV against influenza hospitalization were 35.8% (95% CI: 4.5, 56.8) and 33.2% (95% CI: -6.7, 58.2), respectively. In the all adults group, adjusted VE against influenza A/H1N1 was 72.5% (95% CI: 30.5, 89.1), against A/H3N2 was 86.1% (95% CI: 40.1, 96.8), against B/Victoria was 40.5% (95% CI: -28.9, 72.6), and against B/Yamagata was 32.3% (95% CI: -8.3, 57.7). The adjusted estimate of early season VE (from November 1 to March 11) was 54.4% (95% CI: 29.7-70.4), which was higher than late season (from March 11 to May 25) VE estimate (VE: 29.7%, 95% CI: -5.3, 53.1). CONCLUSIONS: These results suggest that TIV was highly effective against A viruses and moderately effective against B viruses during a mild season characterised by co-circulation of four influenza strains in Canada. Findings underscore the need to provide VE assessment by subtype/lineage as well as the timing of vaccination (early season vs late season) to accurately evaluate vaccine performance and thus guide public health decision-making. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01517191. Registration was retrospective and the date of registration was January 17, 2012. PMID- 29284437 TI - Challenges in defining the rates of ADHD diagnosis and treatment: trends over the last decade. AB - BACKGROUND: There is a global trend of large increases in the prevalence and incidence of Attention Deficit Hyperactivity Disorder (ADHD). This study aimed to address potential causes of these major changes. METHODS: The authors used a large cohort to analyze data employing patients' electronic medical records, with physicians' diagnosis of ADHD, including records of medication purchases. RESULTS: The prevalence of ADHD diagnoses rose twofold from 6.8% to 14.4% between 2005 and 2014 (p < 0.001), while the ratio of males to females with ADHD decreased from 2.94 in 2005 to 1.86 in 2014 (p < 0.001). The incidence increased, peaking in 2011 before declining in 2014. ADHD medication usage by children and adolescents was 3.57% in 2005 and 8.51% by 2014 (p < 0.001). CONCLUSIONS: We report a dramatic increase in the rate of ADHD diagnoses. One of the leading factors to which we attribute this increase is the physicians' and parents' changed attitude towards diagnosing attention/hyperactivity problems, with more parents appear to consider ADHD diagnosis and treatment as a means to improve their child's academic achievements, commonly with the aid of medications. This change in attitude may also be associated with the dramatic increase in female ADHD diagnosis prevalence. PMID- 29284439 TI - Facility-imposed barriers to early utilization of focused antenatal care services in Mangochi District, Malawi - a mixed methods assessment. AB - BACKGROUND: Focused Antenatal Care (FANC) is advocated by the World Health Organization (WHO) as a key service approach to improving the health of pregnant women. Four targeted visits to antenatal clinics are recommended starting in the first trimester. First trimester attendance for FANC in Mangochi District, Malawi was low at 8%. FANC has mainly been promoted through health facility based communication activities with less emphasis on activities at community level. We developed and tested a community focused health communication approach "Community Driven Total FANC Attendance (CDTFA)" with the aim of increasing FANC clinic attendance. We included a research component in order to understand the context and responses of community members to this intervention. METHODS: CDTFA meetings were designed in parallel with data gathering with approval of the local research ethics committee and community stakeholders. Participants in both the CDTFA meetings and data gathering activities, undertaken from December, 2015 to June, 2016 were of reproductive age (15-49 years). Data were collected through flexible interactive processes from participants through recording on pre-designed forms. Quantitative data were processed and analyzed in Microsoft Excel, while qualitative data were manually analyzed to identify themes. RESULTS: In total, 403 CDTFA meetings were held. In the course of interactions with community members, some barriers that affected early utilization of FANC services were identified. Women who did not bring their partners and those who could not bring along with them cloth wraps for the newborn to clinics were not allowed to access FANC services. Payment for authorization letters from village heads for women who have no partners and user fees in non-governmental health facilities were also identified as barriers. CONCLUSIONS: Despite the benefits of FANC services, health authorities in the District should ensure that use and promotion of the approach does not inadvertently bar some pregnant women from accessing services. There is a need to explore strategies and redesign an approach to health promotion that will promote uptake of the integrated services in FANC clinics without infringing on women's rights to access health care. PMID- 29284438 TI - Randomised control trial of the effectiveness of an integrated psychosocial health promotion intervention aimed at improving health and reducing substance use in established psychosis (IMPaCT). AB - BACKGROUND: People with psychosis have a reduced life expectancy of 10-20 years, largely due to cardiovascular disease. This trial aimed to determine the effectiveness of a modular health promotion intervention (IMPaCT Therapy) in improving health and reducing cardiovascular risk in psychosis. METHODS: A multicentre, two arm, parallel cluster RCT was conducted across five UK mental health NHS trusts. Community care coordinators (CC) were randomly assigned to training and supervision in delivering IMPaCT Therapy or treatment as usual (TAU) to current patients with psychosis (cluster). The primary outcome was the physical and mental health subscales of the Short form-36 (SF-36) questionnaire. RESULTS: Of 104 care coordinators recruited, 52 (with 213 patients) were randomised to deliver IMPaCT therapy and 52 (with 193 patients) randomised to TAU. Of 406 patients, 318 (78%) and 301 (74%) attended 12- and 15-month follow-up respectively. IMPaCT therapy showed no significant effect on the physical or mental health component SF-36 scores versus TAU at 12 or 15 months. No effect was observed for cardiovascular risk indicators, except for HDL cholesterol, which improved more with IMPACT therapy than TAU (Treatment effect (95% CI); 0.085 (0.007 to 0.16); p = 0.034). The 22% of patients who received >180 min of IMPACT Therapy in addition to usual care achieved a greater reduction in waist circumference than did controls, which was clinically significant. CONCLUSION: Training and supervising community care coordinators to use IMPaCT therapy in patients with psychosis is insufficient to significantly improve physical or mental health quality of life. The search for effective, pragmatic interventions deliverable in health care services continues. TRIAL REGISTRATION: The trial was retrospectively registered with ISRCTN registry on 23/4/2010 at ISRCTN58667926 ; recruitment started on 01/03/2010 with first randomization on 09.08.2010 ISRCTN58667926 . PMID- 29284440 TI - Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells. AB - BACKGROUND: Glioma stem cells (GSCs) contribute to tumor recurrence and drug resistance. This study characterizes the tumorigenesis of CD133+ cells and their sensitivity to pharmacological inhibition. METHODS: GSCs from human U87 and rat C6 glioblastoma cell lines were isolated via magnetic cell sorting using CD133 as a cancer stem cell marker. Cell proliferation was determined using the WST-1 assay. An intracranial mouse model and bioluminescence imaging were used to assess the effects of drugs on tumor growth in vivo. RESULTS: CD133+ cells expressed stem cell markers and exhibited self-renewal and enhanced tumor formation. Minocycline (Mino) was more effective in reducing the survival rate of CD133+ cells, whereas CD133- cells were more sensitive to inhibition by the signal transducer and activator of transcription 3 (STAT3) inhibitor. Inhibition of STAT3 decreased the expression of CD133+ stem cell markers. The combination of Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells. Furthermore, this combination synergistically suppressed tumor growth in nude mice. CONCLUSION: The results suggest that concurrent targeting of different subpopulations of glioblastoma cells may be an effective therapeutic strategy for patients with malignant glioma. PMID- 29284441 TI - Expression of cannabinoid 1 and, 2 receptors and the effects of cannabinoid 1 and, 2 receptor agonists on detrusor overactivity associated with bladder outlet obstruction in rats. AB - BACKGROUND: This study investigated changes in the expression of cannabinoid (CB) receptors and the effects of CB1 and CB2 agonists on detrusor overactivity (DO) associated with bladder outlet obstruction (BOO) in rats. METHODS: Male Sprague Dawley rats were randomly assigned to four groups (n = 10) in each group. The control group comprised sham-operated rats. A animals in the BOO, CB1 agonist and CB2 agonist groups all underwent BOO surgery. Three weeks postoperatively, cystometrography (CMG) was performed on all rats. After confirming the presence of DO in the CB1 and CB2 agonist groups, a CB1 agonist (WIN 55,212-2) and a CB2 agonist (CB65) were instilled intravesically, and CMG was repeated. CMG parameters, including the contraction interval (CI) and contraction pressure (CP) were then analyzed. The bladders of rats in all four groups were excised following CMG. Immunofluorescence staining and Western blotting were performed to localize CB1 and CB2 and measure their expression levels in the urothelium and detrusor muscle. RESULTS: The CI was significantly longer and the CP was significantly lower in the CB1 agonist group than in the BOO group. CI and CP in the CB2 agonist group showed the same results. CB1 receptor immunofluorescence staining signals and immunoreactive bands in Western blotting were increased in the BOO group compared with results in the control group. Similarly, results for the CB2 receptor were also increased in the BOO group, although this difference was not significant. The CMG parameters in the BOO group were significantly improved by the inhibitory effects of CB1 and CB2 agonists on BOO-associated DO. The expression of CB1 was significantly increased in the urothelium and detrusor muscle in BOO-associated DO, but no significant change in CB2 expression was observed. CONCLUSIONS: CB1 and CB2 receptors, especially CB1, play a role in the pathophysiology of BOO-associated DO, and could serve as therapeutic targets. PMID- 29284442 TI - How to avoid unintended valgus alignment in distal femoral derotational osteotomy for treatment of femoral torsional malalignment - a concept study. AB - BACKGROUND: Defining the optimal cutting plane for derotational osteotomy at the distal femur for correction of torsion in cases of patellofemoral instability is still challenging. This preliminary study investigates changes of frontal alignment by a simplified trigonometrical model and demonstrates a surgical guidance technique with the use of femur cadavers. The hypothesis was that regardless of midshaft bowing, a cutting plane perpendicular to the virtual anatomic shaft axis avoids unintended valgus malalignment due to derotation. METHODS: A novel mathematical model, called the Pillar-Crane-Model, was developed to forecast changes on frontal alignment of the femur when a perpendicular cutting plane to the virtual anatomical shaft was chosen. As proof of concept, eight different torsion angles were assessed on two human cadaver femora (left and right). A single cut distal femoral osteotomy perpendicular to the virtual anatomical shaft was performed. Frontal plane alignment (mLDFA, aLDFA, AMA) was radiographically analyzed before and after rotation by 0 degrees , 10 degrees , 20 degrees , and 30 degrees . Measurements were compared to the model. RESULTS: The trigonometrical equation from the Pillar-Crane-Model provides mathematical proof that slight changes into varus occur, seen by an increase in AMA and mLDFA, when the cutting plane is perpendicular to the virtual anatomical shaft axis. A table with standardized values is provided. Exemplarily, the specimens showed a mean increase of AMA from 4.8 degrees to 6.3 degrees and mLDFA from 85.2 degrees to 86.7 after derotation by 30 degrees . Throughout the derotation procedure, aLDFA remained at 80.4 degrees +/- 0.4 degrees SD. CONCLUSIONS: With the use of this model for surgical guidance and anatomic reference, unintended valgus changes on frontal malalignment can be avoided. When the cutting plane is considered to be perpendicular to the virtual anatomical shaft from a frontal and lateral view, a slight increase of mLDFA results when a derotational osteotomy of the distal femur is performed. PMID- 29284444 TI - Comparison of efficacy between coaxial microincision and standard-incision phacoemulsification in patients with age-related cataracts: a meta-analysis. AB - BACKGROUND: Incision size plays a critical role in the efficacy of cataract surgery, but the available evidence on ideal incision size is inconsistent. In this study, we conducted a meta-analysis to evaluate the efficacy of coaxial microincisional phacoemulsification surgery (MICS) compared with that of standard incision phacoemulsification surgery (SICS) in patients with age-related cataracts. METHODS: The Cochrane Library (Wiley Online Library), PubMed, Medline, National Knowledge Infrastructure (CNKI), and VIP databases were searched to identify reports of clinical randomized controlled trials (RCTs) comparing MICS to SICS for the treatment of age-related cataracts. The outcomes of interest included surgically induced astigmatism (SIA), effective phacoemulsification time (EPT), central corneal thickness (CCT), endothelial cell count (ECC), endothelial cell count loss (ECC Loss %), and average ultrasonic energy (AVE). RESULTS: Eleven RCT studies were included in this meta-analysis. No statistically significant differences were observed in EPT (Z = 1.29, P > 0.05), CCT (1 day: Z = 1.37, P > 0.05; 7 days: Z = 0.75, P > 0.05; 30 days: Z = 0.38, P > 0.05; 90 days: Z = 0.29, P > 0.05), ECC (7 days: Z = 1.13, P > 0.05; 30 days: Z = 1.42, P > 0.05) or ECC Loss % (7 days: Z = 0.24, P > 0.05; 30 days: Z = 0.06, P > 0.05; 90 days: Z = 0.10, P > 0.05) between MICS and SICS. However, statistically significant differences were found in AVE (Z = 4.19, P < 0.0001) and SIA (1 day: Z = 10.33, P < 0.00001; 7 days: Z = 10.71, P < 0.00001; 30 days: Z = 10.95, P < 0.00001; 90 days: Z = 2.21,- P < 0.01) between MICS and SICS. CONCLUSION: Compared with SICS, MICS can reduce short-term and long-term SIA, but it does not differ in safety outcomes or in the time required for surgery. PMID- 29284443 TI - Readiness to change and therapy outcomes of an innovative psychotherapy program for surgical patients: results from a randomized controlled trial. AB - BACKGROUND: Readiness to change is a pivotal construct for psychotherapy research and a major target of motivational interventions. Our primary objective was to examine whether pre-treatment readiness to change moderated therapy effects of Bridging Intervention in Anesthesiology (BRIA), an innovative psychotherapy approach for surgical patients. This stepped care program aims at motivating and supporting surgical patients with mental disorders to engage in psychosocial mental health care. METHODS: The major steps of BRIA are two motivational interventions with different intensity. The first step of the program consists of preoperative computer-assisted psychosocial self-assessment including screening for psychological distress and automatically composed computerized brief written advice (BWA). In the second step, patients participate in postoperative psychotherapy sessions combining motivational interviewing with cognitive behavioural therapy (BRIA psychotherapy sessions). We performed regression-based moderator analyses on data from a recent randomized controlled trial published by our research group. The sample comprised 220 surgical patients with diverse comorbid mental disorders according to ICD-10. The most frequent disorders were mood, anxiety, substance use and adjustment disorders. The patients had a mean age of 43.31 years, and 60.90% were women. In a regression model adjusted for pre treatment psychological distress, we investigated whether readiness to change moderated outcome differences between (1) the BRIA psychotherapy sessions and (2) no psychotherapy / BWA only. RESULTS: Multiple regression analyses showed that readiness to change moderated treatment effects regarding the primary outcomes "Participation in psychosocial mental health care options at month 6" (p = 0.03) and "Having approached psychosocial mental health care options at month 6" (p = 0.048) but not regarding the secondary outcome "Change of general psychological distress between baseline assessment and month 6" (p = 0.329). Probing the moderation effect with the Johnson-Neyman technique revealed that BRIA psychotherapy sessions were superior to BWA in patients with low to moderate readiness, but not in those with high readiness. CONCLUSIONS: Readiness to change may act as moderator of the efficacy of psychosocial therapy. Combinations of motivational interviewing and cognitive behavioural therapy may be effective particularly in patients with a variety of mental disorders and low readiness to change. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01357694. PMID- 29284446 TI - Management of Whiplash Associated Disorders in Australian general practice. AB - BACKGROUND: Whiplash Associated Disorders (WAD) are common and costly, and are usually managed initially by general practitioners (GPs). How GPs manage WAD is largely unstudied, though there are clinical guidelines. Our aim was to ascertain the rate of management (percentage of encounters) of WAD among patients attending Australian general practice, and to review management of these problems, including imaging, medications and other treatments. METHODS: We analysed data from 2013 to 2016 collected by different random samples of approximately 1000 general practitioners (GPs) per year. Each GP collected data about 100 consecutive consultations for BEACH (Bettering the Evaluation and Care of Health), an Australian national study of general practice encounters. Main outcome measures were: the proportion of encounters involving management of WAD; management including imaging, medications and other treatments given; appropriateness of treatment assessed against published clinical guidelines. RESULTS: Of 291,100 encounters from 2919 GP participants (a nationally representative sample), WAD were managed at 137 encounters by 124 GPs (0.047%). Management rates were 0.050% (females) and 0.043% (males). For 63 new cases (46%), 19 imaging tests were ordered, most commonly neck/cervical spine x-ray (52.6% of tests for new cases), and neck/cervical spine CT scan (31.6%). One or more medications were prescribed/supplied for 53.3% of WAD. NSAIDs (11.7 per 100 WAD problems) and compound analgesics containing paracetamol and opioids (10.2 per 100 WAD problems) were the commonest medications used by GPs overall. Paracetamol alone was used in 8 per 100 WAD problems. The most frequent clinical/procedural treatments for WAD were physical medicine/rehabilitation (16.1 per 100 WAD problems), counselling (6.6), and general advice/education (5.8). CONCLUSIONS: GPs refer about 30% of new cases for imaging (possibly overutilising imaging), and prescribe a range of drugs, approximately 22% of which are outside clinical guidelines. These findings suggest a need for further education of GPs, including indications for imaging after whiplash injury, identification of those more likely to develop chronic WAD, and medication management guidelines. WAD carry a large personal and economic burden, so the impact of improvements in GP management is potentially significant. PMID- 29284445 TI - Mapping standard ophthalmic outcome sets to metrics currently reported in eight eye hospitals. AB - BACKGROUND: To determine alignment of proposed international standard outcomes sets for ophthalmic conditions to metrics currently reported by eye hospitals. METHODS: Mixed methods comparative benchmark study, including eight eye hospitals in Australia, India, Singapore, Sweden, U.K., and U.S. All are major international tertiary care and training centers in ophthalmology. Main outcome measure is consistency of ophthalmic outcomes measures reported. RESULTS: International agreed standard outcomes (ICHOM) sets are available for cataract surgery (10 metrics) and macular degeneration (7 metrics). The eight hospitals reported 22 different metrics for cataract surgery and 2 for macular degeneration, which showed only limited overlap with the proposed ICHOM metrics. None of the hospitals reported patient reported visual functioning or vision related quality of life outcomes measures (PROMs). Three hospitals (38%) reported rates for uncomplicated cataract surgeries only. There was marked variation in how and at what point postoperatively visual outcomes following cataract, cornea, glaucoma, strabismus and oculoplastics procedures were reported. Seven (87.5%) measured post-operative infections and four (50%) measured 30 day unplanned reoperation rates. CONCLUSIONS: Outcomes reporting for ophthalmic conditions currently widely varies across hospitals internationally and does not include patient-reported outcomes. Reaching consensus on measures and consistency in data collection will allow meaningful comparisons and provide an evidence base enabling improved sharing of "best practices" to improve eye care globally. Implementation of international standards is still a major challenge and practice based knowledge on measures should be one of the inputs of the international standardization process. PMID- 29284447 TI - Adjunctive corticosteroid therapy for inpatients with Mycoplasma pneumoniae pneumonia. AB - BACKGROUND: There is conflicting evidence regarding the benefit of adjunctive corticosteroid therapy in patients with Mycoplasma pneumoniae pneumonia. We hypothesised that corticosteroid therapy could reduce mortality and length of stay (LOS) in such patients. METHODS: Adult patients with M. pneumoniae pneumonia from January 2010 to December 2013 were identified from the Japanese Diagnosis Procedure Combination inpatient database. The effects of low-dose and high-dose corticosteroid therapies on mortality, LOS, drug costs and hyperglycaemia requiring insulin treatment were evaluated using propensity score analyses. RESULTS: Eligible patients (n = 2228) from 630 hospitals were divided into no corticosteroid (n = 1829), low-dose corticosteroid (n = 267) and high-dose corticosteroid (n = 132) groups. The propensity score-matched pairs were generated from no-corticoid and low-dose corticoid groups (251 pairs), or no corticoid and high-dose corticosteroid groups (120 pairs). Adjunctive corticosteroid therapy did not decrease 30-day mortality. In addition, both low dose and high-dose corticosteroid therapies were associated with increases in LOS. Furthermore, hyperglycaemia requiring insulin treatment and drug cost increased with corticosteroid use. CONCLUSIONS: Adjunctive treatment with low dose or high-dose corticosteroids may not be beneficial in M. pneumoniae pneumonia. PMID- 29284448 TI - Economic evaluation of an experience sampling method intervention in depression compared with treatment as usual using data from a randomized controlled trial. AB - BACKGROUND: Experience sampling, a method for real-time self-monitoring of affective experiences, holds opportunities for person-tailored treatment. By focussing on dynamic patterns of positive affect, experience sampling method interventions (ESM-I) accommodate strategies to enhance personalized treatment of depression-at potentially low-costs. This study aimed to investigate the cost effectiveness of an experience sampling method intervention in patients with depression, from a societal perspective. METHODS: Participants were recruited between January 2010 and February 2012 from out-patient mental health care facilities in or near the Dutch cities of Eindhoven and Maastricht, and through local advertisements. Out-patients diagnosed with major depression (n = 101) receiving pharmacotherapy were randomized into: (i) ESM-I consisting of six weeks of ESM combined with weekly feedback regarding the individual's positive affective experiences, (ii) six weeks of ESM without feedback, or (iii) treatment as usual only. Alongside this randomised controlled trial, an economic evaluation was conducted consisting of a cost-effectiveness and a cost-utility analysis, using Hamilton Depression Rating Scale (HDRS) and quality adjusted life years (QALYs) as outcome, with willingness-to-pay threshold for a QALY set at ?50,000 (based on Dutch guidelines for moderate severe to severe illnesses). RESULTS: The economic evaluation showed that ESM-I is an optimal strategy only when willingness to pay is around ?3000 per unit HDRS and around ?40,500 per QALY. ESM I was the least favourable treatment when willingness to pay was lower than ?30,000 per QALY. However, at the ?50,000 willingness-to-pay threshold, ESM-I was, with a 46% probability, the most favourable treatment (base-case analysis). Sensitivity analyses confirmed the robustness of these results. CONCLUSIONS: We may tentatively conclude that ESM-I is a cost-effective add-on intervention to pharmacotherapy in outpatients with major depression. TRIAL REGISTRATION: Netherlands Trial register, NTR1974 . PMID- 29284449 TI - Experimental research on the relationship between the stiffness and the expressions of fibronectin proteins and adaptor proteins of rat trabecular meshwork cells. AB - BACKGROUND: Trabecular meshwork (TM) plays an important role in maintaining normal intraocular pressure (IOP). Studies have shown that glaucomatous TM tissues are stiffer than those of normal tissue. The high expression of fibronectin protein (FN) and adaptor protein (LNK) may be related to high resistance to aqueous humor outflow as well as high IOP. Our concern is what factors lead to the variation of the stiffness of trabecular tissue/cells. METHODS: Atomic force microscope (AFM) and Western blot (WB) analysis were applied to test TM cells of rats cultured with different concentrations of dexamethasone (DEX) and mifepristone (MIF). Rat TM cells were randomly divided into 7 groups, marked as D1, D2, D3 and M1, M2 M3 for different concentrations of DEX and MIF, respectively, and C for blank control. RESULTS: The elastic modulus of the treated cells were 2.67 +/- 0.914 KPa, 2.92 +/- 0.986 KPa, 4.52 +/- 1.22 KPa for D1, D2, D3, 2.06 +/- 0.745 KPa, 1.23 +/- 0.462 KPa, 0.467 +/- 0.275 KPa for M1, M2, M3, and 2.43 +/- 0.713 KPa for C group, respectively. Expressions of FN and LNK increase (decrease) with the increase of the concentrations of DEX (MIF). DISCUSSION: We focus on the relationship between the stiffness and the expressions of FN and LNK of rat TM cells. We analyzed the correlation between cell stiffness and FN, LNK expression, discussed the relationship between cell stiffness and aqueous humor outflow resistance. CONCLUSIONS: The changes of TM cell stiffness and the expressions of FN and LNK are positively correlated. PMID- 29284450 TI - Cardiovascular magnetic resonance in the evaluation of heart valve disease. AB - BACKGROUND: Over the last 25 years, cardiovascular magnetic resonance imaging (CMR) has emerged as an alternative to echocardiography for assessment of valvular heart disease (VHD). Although echo remains the first-line imaging modality for the assessment of patients with VHD, CMR can now provide a comprehensive assessment in many instances. Using a combination of techniques, CMR provides information on valve anatomy and enables quantitative analysis of the severity of the valve lesion. MAIN TEXT: In this review, the fundamentals of CMR in assessment of VHD are described, together with its strengths and weaknesses. We detail the utility of CMR for studying all aspects of VHD, including valve anatomy, flow quantification as well as ventricular volumes and function. The optimisation of CMR for evaluating the commonest valve lesions (aortic stenosis, aortic regurgitation, mitral regurgitation, mitral stenosis) as well as in right-sided VHD and prosthetic valves is summarised. The focus of this review is to enable the reader to optimise the use of CMR in his or her own evaluation of heart valve lesions in clinical practice. CONCLUSIONS: CMR can be used for the comprehensive evaluation of VHD. This exciting, non-invasive imaging modality is likely to have increasing utility in the clinical evaluation of patients with VHD. PMID- 29284451 TI - Synovial inflammation plays a greater role in post-traumatic osteoarthritis compared to idiopathic osteoarthritis in the Hartley guinea pig knee. AB - BACKGROUND: The objective of this study was to evaluate the extent of stromal cell-derived factor-1's (SDF-1) involvement in the pathogenesis of idiopathic versus post-traumatic OA by comparing differences in synovial membrane morphology, SDF-1 synovial fluid (SF) concentrations, and matrix metalloproteinase-13 (MMP-13) SF concentrations. METHODS: Thirty-six 3-month-old Hartley guinea pigs were obtained and divided into 6 groups. Upon sacrifice, India Ink staining was used to evaluate gross morphology, Safranin O/Fast green staining was used to assess cartilage damage, H/E staining was employed to visualize the synovium, and SF samples were obtained for biochemical analyses. Sandwich ELISA was used to quantify the SF concentrations of SDF-1 and MMP-13. RESULTS: 12 month-old, idiopathic OA guinea pigs and 5.5 month-old ACLT animals had comparable cartilage damage when evaluated by the Modified Mankin Score. SDF 1 and MMP-13 concentrations were not statistically different between the two groups. The synovial membrane of the 5.5 month ACLT group had severe synovitis compared to the idiopathic OA group. CONCLUSION: In this study, it was found that synovial inflammation, independent of cartilage morphology, SDF-1 concentration, and MMP-13 concentration, was markedly different between idiopathic and post traumatic OA. These results highlight the differing morphological and biochemical profiles of post-traumatic versus idiopathic osteoarthritis and calls for a more thorough examination of the sole of the synovial membrane in the pathogenesis of post-traumatic osteoarthritis. PMID- 29284452 TI - Screw migration and oesophageal perforation after surgery for osteosarcoma of the cervical spine. AB - BACKGROUND: Even though internal fixation has expanded the indications for cervical spine surgery, it carries the risks of fracture or migration, with associated potential life threatening complications. Removal of metal work from the cervical spine is required in case of failure of internal fixation, but it can become challenging, especially when a great amount of scar tissue is present because of previous surgery and radiotherapy. CASE PRESENTATION: We report a 16 year old competitive basketball athlete who underwent a combined anterior and posterior approach for resection of an osteosarcoma of the sixth cervical vertebra. Fourteen years after the index procedure, the patient eliminated spontaneously one screw through the intestinal tract via an oesophageal perforation and developed a severe dysphagia. Three revision surgeries were performed to remove the anterior plate because of the great amount of post surgery and post-irradiation fibrosis. CONCLUSIONS: Screw migration and oesophageal perforation after cervical spine surgery are uncommon potentially life-threatening occurrences. Revision surgery may be challenging and it requires special skills. PMID- 29284453 TI - A pilot exploratory investigation on pregnant women's views regarding STan fetal monitoring technology. AB - BACKGROUND: Women's views are critical for informing the planning and delivery of maternity care services. ST segment analysis (STan) is a promising method to more accurately detect when unborn babies are at risk of brain damage or death during labour that is being trialled for the first time in Australia. This is the first study to examine women's views about STan monitoring in this context. METHODS: Semi-structured interviews were conducted with pregnant women recruited across a range of clinical locations at the study hospital. The interviews included hypothetical scenarios to assess women's prospective views about STan monitoring (as an adjunct to cardiotocography, (CTG)) compared to the existing fetal monitoring method of CTG alone. This article describes findings from an inductive and descriptive thematic analysis. RESULTS: Most women preferred the existing fetal monitoring method compared to STan monitoring; women's decision-making was multifaceted. Analysis yielded four themes relating to women's views towards fetal monitoring in labour: a) risk and labour b) mobility in labour c) autonomy and choice in labour d) trust in maternity care providers. CONCLUSIONS: Findings suggest that women's views towards CTG and STan monitoring are multifaceted, and appear to be influenced by individual labour preferences and the information being received and understood. This underlies the importance of clear communication between maternity care providers and women about technology use in intrapartum care. This research is now being used to inform the implementation of the first properly powered Australian randomised trial comparing STan and CTG monitoring. PMID- 29284454 TI - The effect of low intensity shockwave treatment (Li-SWT) on human myoblasts and mouse skeletal muscle. AB - BACKGROUND: Transplanting myogenic cells and scaffolds for tissue engineering in skeletal muscle have shown inconsistent results. One of the limiting factors is neovascularization at the recipient site. Low intensity shockwave therapy (Li SWT) has been linked to increased tissue regeneration and vascularization, both integral to survival and integration of transplanted cells. This study was conducted to demonstrate the response of myoblasts and skeletal muscle to Li-SWT. METHOD: Primary isolated human myoblasts and explants were treated with low intensity shockwaves and subsequently cell viability, proliferation and differentiation were tested. Cardiotoxin induced injury was created in tibialis anterior muscles of 28 mice, and two days later, the lesions were treated with 500 impulses of Li-SWT on one of the legs. The treatment was repeated every third day of the period and ended on day 14 after cardiotoxin injection.. The animals were followed up and documented up to 21 days after cardiotoxin injury. RESULTS: Li-SWT had no significant effect on cell death, proliferation, differentiation and migration, the explants however showed decreased adhesion. In the animal experiments, qPCR studies revealed a significantly increased expression of apoptotic, angiogenic and myogenic genes; expression of Bax, Bcl2, Casp3, eNOS, Pax7, Myf5 and Met was increased in the early phase of regeneration in the Li-SWT treated hind limbs. Furthermore, a late accumulative angiogenic effect was demonstrated in the Li-SWT treated limbs by a significantly increased expression of Angpt1, eNOS, iNOS, Vegfa, and Pecam1. CONCLUSION: Treatment was associated with an early upregulation in expression of selected apoptotic, pro-inflammatory, angiogenic and satellite cell activating genes after muscle injury. It also showed a late incremental effect on expression of pro-angiogenic genes. However, we found no changes in the number of PAX7 positive cells or blood vessel density in Li-SWT treated and control muscle. Furthermore, Li-SWT in the selected doses did not decrease survival, proliferation or differentiation of myoblasts in vitro. PMID- 29284455 TI - Visual rehabilitation in moderate keratoconus: combined corneal wavefront-guided transepithelial photorefractive keratectomy and high-fluence accelerated corneal collagen cross-linking after intracorneal ring segment implantation. AB - BACKGROUND: To investigate the effects of combined corneal wavefront-guided transepithelial photorefractive keratectomy (tPRK) and accelerated corneal collagen cross-linking (CXL) after intracorneal ring segment (ICRS) implantation in patients with moderate keratoconus. METHODS: Medical records of 23 eyes of 23 patients undergoing combined tPRK and CXL after ICRS implantation were retrospectively analyzed. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent (MRSE), corneal indices based on Scheimpflug tomography, higher-order aberrations (HOAs), and corneal biomechanical properties were evaluated before and after ICRS implantation, and at 1, 3, and 6 months after combined tPRK and CXL. RESULTS: There were significant improvements in final logMAR UDVA and logMAR CDVA, and reductions in sphere, MRSE, and all corneal indices from baseline. Significant improvements in logMAR UDVA and reductions in sphere, MRSE, maximal keratometry, keratometry at the apex, mean keratometry, and keratoconus index were noted after ICRS implantation. After tPRK and CXL, significant improvements in logMAR UDVA and logMAR CDVA, and reductions in cylinder and all corneal indices were observed. There were significant improvements in final root mean square HOAs and coma aberrations from baseline, but no changes from baseline after ICRS implantation. Significant reductions in final radius and deformation amplitude from baseline were noted. CONCLUSIONS: Combined tPRK and accelerated CXL after ICRS implantation in moderate keratoconus appears to be a safe and effective treatment, providing an improvement in visual acuity, corneal indices, and HOAs. TRIAL REGISTRATION: retrospectively registered (identification no. NCT03355430 ). Date registered: 28/11/2017. PMID- 29284456 TI - Blood pressure self-monitoring in pregnancy: examining feasibility in a prospective cohort study. AB - BACKGROUND: Raised blood pressure (BP) affects approximately 10% of pregnancies worldwide, and a high proportion of affected women develop pre-eclampsia. This study aimed to evaluate the feasibility of self-monitoring of BP in pregnancy in women at higher risk of pre-eclampsia. METHODS: This prospective cohort study of self-monitoring BP in pregnancy was carried out in two hospital trusts in Birmingham and Oxford and thirteen primary care practices in Oxfordshire. Eligible women were those defined by the UK National Institute for Health and Care Excellence (NICE) guidelines as at higher risk of pre-eclampsia. A total of 201 participants were recruited between 12 and 16 weeks of pregnancy and were asked to take two BP readings twice daily three times a week through their pregnancy. Primary outcomes were recruitment, retention and persistence of self monitoring. Study recruitment and retention were analysed with descriptive statistics. Survival analysis was used to evaluate the persistence of self monitoring and the performance of self-monitoring in the early detection of gestational hypertension, compared to clinic BP monitoring. Secondary outcomes were the mean clinic and self-monitored BP readings and the performance of self monitoring in the detection of gestational hypertension and pre-eclampsia compared to clinic BP. RESULTS: Of 201 women recruited, 161 (80%) remained in the study at 36 weeks or to the end of their pregnancy, 162 (81%) provided any home readings suitable for analysis, 148 (74%) continued to self-monitor at 20 weeks and 107 (66%) at 36 weeks. Self-monitored readings were similar in value to contemporaneous matched clinic readings for both systolic and diastolic BP. Of the 23 who developed gestational hypertension or pre-eclampsia and self monitored, 9 (39%) had a raised home BP prior to a raised clinic BP. CONCLUSIONS: Self-monitoring of BP in pregnancy is feasible and has potential to be useful in the early detection of gestational hypertensive disorders but maintaining self monitoring throughout pregnancy requires support and probably enhanced training. PMID- 29284457 TI - TRAIL gene 1595C/T polymorphisms contribute to the susceptibility and severity of intervertebral disc degeneration: a data synthesis. AB - BACKGROUND: Studies have investigated the correlation between tumor necrosis factor related apoptosis-inducing ligand (TRAIL) gene polymorphisms and the susceptibility and severity of intervertebral disc degeneration (IDD), but the results were inconsistent. To evaluate the specific relationship, we performed a meta-analysis to clarify the controversies. METHODS: Four databases were searched, and the pooled results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Three case-control studies from Han Chinese were included (565 cases and 427 controls). All the included studies reported TRAIL 1595C/T gene polymorphisms. The recessive model (CC vs. CT + TT) was the optimal model, which demonstrated a significant relationship between 1595C/T polymorphisms and increased IDD risk (OR = 2.18, 1.45 to 3.27, P = 0.000). No significant heterogeneity was found in the recessive model (I2 = 48.6%, P = 0.143). Patients with lower grade IDD had more genotypes or alleles including 1595TT genotype (grade II vs. grade III: OR = 2.12, 1.18 to 3.83, P = 0.012; grade III vs. grade IV: OR = 2.59, 1.29 to 5.22, P = 0.007) and 1595 T allele (grade II vs. grade III: OR = 1.91, 1.43 to 2.55, P = 0.000; grade II vs. grade IV: OR = 2.46, 0.94 to 1.76, P = 0.000). CONCLUSIONS: There is a significant relationship between 1595C/T polymorphisms and the susceptibility and severity of IDD in Han Chinese. Patients with lower grade IDD had higher frequency of the 1595TT genotype and 1595 T allele. PMID- 29284459 TI - Autotransplantation of mature and immature third molars in 23 Chinese patients: a clinical and radiological follow-up study. AB - BACKGROUND: We investigated the clinical and radiographic outcomes of autotransplanted teeth over a follow-up period of 2 to 8 years, and summarize the findings of other relevant studies with regard to the primary factors that influence a good prognosis in such patients. METHODS: Twenty-three patients (6 men, 17 women) who attended Tanggu Stomatological Hospital, Tianjin, China, from 2008 through 2013, were included in the study. These patients presented with a variety of dental problems, including tooth loss, residual crowns, missing first or second molars, dental trauma, tooth fracture, and unrestored teeth. A total of 26 third molars, including 2 immature molars, were autotransplanted in these patients. The success rate of autotransplantation was assessed on the basis of clinical and radiographic outcomes after follow-up periods ranging from 2 to 8 years. RESULTS: Clinical examination revealed stability of all 26 transplanted teeth, with satisfactory masticatory function and no patient discomfort. Radiographic examination revealed normal periapical tissues and an intact lamina dura surrounding the tooth root, indicating adequate healing of periodontal tissues. CONCLUSIONS: Autotransplantation achieved good results in the Chinese sample population investigated, and was associated with an excellent prognosis. Rigorous case selection, adequate protection of the periodontal ligament, and proper oral hygiene contribute significantly to the long-term success of the procedure. PMID- 29284460 TI - Correction to: Ficus sycomorus extract reversed behavioral impairment and brain oxidative stress induced by unpredictable chronic mild stress in rats. AB - CORRECTION: After the publication of this article [1] it came to our attention that Harquin Simplice Foyet was incorrectly included as Harquin Simplice Harquin Foyet. The corrected name is included in the author list. The original article was updated. PMID- 29284458 TI - Menthol cigarettes and the public health standard: a systematic review. AB - BACKGROUND: Although menthol was not banned under the Tobacco Control Act, the law made it clear that this did not prevent the Food and Drug Administration from issuing a product standard to ban menthol to protect public health. The purpose of this review was to update the evidence synthesis regarding the role of menthol in initiation, dependence and cessation. METHODS: A systematic review of the peer reviewed literature on menthol cigarettes via a PubMed search through May 9, 2017. The National Cancer Institute's Bibliography of Literature on Menthol and Tobacco and the FDA's 2011 report and 2013 addendum were reviewed for additional publications. Included articles addressing initiation, dependence, and cessation were synthesized based on study design and quality, consistency of evidence across populations and over time, coherence of findings across studies, and plausibility of the findings. RESULTS: Eighty-two studies on menthol cigarette initiation (n = 46), dependence (n = 14), and cessation (n = 34) were included. Large, representative studies show an association between menthol and youth smoking that is consistent in magnitude and direction. One longitudinal and eight cross-sectional studies demonstrate that menthol smokers report increased nicotine dependence compared to non-menthol smokers. Ten studies support the temporal relationship between menthol and reduced smoking cessation, as they measure cessation success at follow-up. CONCLUSIONS: The strength and consistency of the associations in these studies support that the removal of menthol from cigarettes is likely to reduce youth smoking initiation, improve smoking cessation outcomes in adult smokers, and in turn, benefit public health. PMID- 29284461 TI - Clinical validation and assessment of a modular fluorescent imaging system and algorithm for rapid detection and quantification of dental plaque. AB - BACKGROUND: Significant numbers of adults and children have untreated plaque due to poor oral hygiene and consequently suffer from associate dental and systemic diseases. METHODS: A handheld device equipped with 405 nm light-emitting diodes was constructed to examine the prevalence of red fluorescence signatures associated with dental plaque. This device was used for in vivo imaging of all four incisors and all four canines of twenty-eight consenting human subjects. The same areas were further imaged under white light illumination with a commercial image-processing based plaque-imaging device, and evaluated by a hygienist and dentist. A custom computer vision algorithm using pixel information was developed to calculate plaque coverage ratios ranging from 0 (no plaque) to 1 (complete plaque coverage) for images captured by both devices. RESULTS: The algorithm calculated red fluorescence-based plaque coverage ratios ranging from 0.011 to 0.211 for the subjects imaged. Clinical assessment and statistical analyses of associated plaque ratios of the 405 nm device images indicated high sensitivity and specificity in detecting dental plaque by the experimental device compared to the commercial reference device. CONCLUSIONS: The low-cost and open source 405 nm device and the associated computer vision algorithm successfully captured red fluorescence signatures associated with dental plaque and demonstrated comparable performance to a commercially available device. Therefore, a proof of concept validation was provided for the construction and application of a sensitive cost effective plaque-detecting device. A miniaturized mobile adaptable version of the device was also provided, together with and a step-by-step guide for device assembly and webhost the associated software, to facilitate open-source access to a cost-effective at-home, in-clinic oral care technology. TRIAL REGISTRATION: ClinicalTrials.gov NCT03379337, December 19 2017. Retrospectively registered. PMID- 29284463 TI - Clinical studies on core-carrier obturation: a systematic review and meta analysis. AB - BACKGROUND: This systematic review aimed to evaluate the clinical performance of core-carrier obturation in endodontic treatment. METHODS: Keywords of "(core carrier OR Thermafil) OR (cold lateral condensation OR lateral condensation) OR (warm vertical condensation OR vertical condensation) AND (obturation OR root canal filling) AND clinical study" were searched for all obtainable publications up to year 2017 in the databases of PubMed, ScienceDirect, EMBASE, Scopus and Web of Science. The success rate, short-term postoperative pain, overfilling and adaptation of core-carrier obturation from clinical studies were selected. Reviews, laboratory studies, animal studies and irrelevant reports were excluded. RESULTS: 1349 relevant articles were identified with 149 duplicated articles removed and 1173 irrelevant articles were excluded after screening. The titles and abstracts of the 19 identified articles were screened in the systematic review. The full texts of remaining articles were retrieved with data extracted for meta-analysis on the success rate, postoperative pain, overfilling and adaptation of obturation. The pooled success rate of core-carrier obturation was 83% (95% CI: 69%-91%). The pooled incidence of 1-day and 7-day short-term postoperative pain were 35% (95% CI: 15%-62%) and 6% (95% CI: 1-35%). The pooled proportion of teeth with overfilling and adequate adaptation of the obturation material were 31% (95% CI: 18%-50%) and 85% (95% CI: 75%-91%), respectively. CONCLUSIONS: The success rate of endodontic treatment using core-carrier obturation was 83%. Short-term postoperative pain was not uncommon (24%). Most teeth (85%) had adequate adaptation using core-carrier obturation material, but a considerable amount of teeth (31%) had overfilling. PMID- 29284462 TI - Estimating peer density effects on oral health for community-based older adults. AB - BACKGROUND: As part of a long-standing line of research regarding how peer density affects health, researchers have sought to understand the multifaceted ways that the density of contemporaries living and interacting in proximity to one another influence social networks and knowledge diffusion, and subsequently health and well-being. This study examined peer density effects on oral health for racial/ethnic minority older adults living in northern Manhattan and the Bronx, New York, NY. METHODS: Peer age-group density was estimated by smoothing US Census data with 4 kernel bandwidths ranging from 0.25 to 1.50 mile. Logistic regression models were developed using these spatial measures and data from the ElderSmile oral and general health screening program that serves predominantly racial/ethnic minority older adults at community centers in northern Manhattan and the Bronx. The oral health outcomes modeled as dependent variables were ordinal dentition status and binary self-rated oral health. After construction of kernel density surfaces and multiple imputation of missing data, logistic regression analyses were performed to estimate the effects of peer density and other sociodemographic characteristics on the oral health outcomes of dentition status and self-rated oral health. RESULTS: Overall, higher peer density was associated with better oral health for older adults when estimated using smaller bandwidths (0.25 and 0.50 mile). That is, statistically significant relationships (p < 0.01) between peer density and improved dentition status were found when peer density was measured assuming a more local social network. As with dentition status, a positive significant association was found between peer density and fair or better self-rated oral health when peer density was measured assuming a more local social network. CONCLUSIONS: This study provides novel evidence that the oral health of community-based older adults is affected by peer density in an urban environment. To the extent that peer density signifies the potential for social interaction and support, the positive significant effects of peer density on improved oral health point to the importance of place in promoting social interaction as a component of healthy aging. Proximity to peers and their knowledge of local resources may facilitate utilization of community-based oral health care. PMID- 29284464 TI - Potential use of telephone-based survey for non-communicable disease surveillance in Sri Lanka. AB - BACKGROUND: Telephone survey (TS) has been a popular tool for conducting health surveys, particularly in developed countries. However, the feasibility, and reliability of TS are not adequately explored in Sri Lanka. The main aim of this study is to assess the effectiveness of telephone-based survey in estimating the prevalence of common non-communicable diseases (NCDs) in Sri Lanka. METHODS: We carried out an observational cross-sectional study using telephone interview method in Galle district, Sri Lanka. The study participants were selected randomly from the residents living in the households with fixed land telephone lines. The prevalence of the main NCDs was estimated using descriptive statistics. RESULTS: Overall, 975 telephone numbers belonging to six main areas of Galle district were called, and 48% agreed to participate in the study. Of the non-respondents, 22% actively declined to participate. Data on NCDs were gathered from 1470 individuals. The most common self-reported NCD was hypertension (17.%), followed by diabetes (16.3%) and dyslipidaemia (15.6%). Smoking was exclusively seen in males (7.4%), and regular alcohol use was significantly more common in males (19.2%) than females (0.4%, P < .001). CONCLUSIONS: Our study revealed average response rate for telephone based interview in Sri Lankan setting. Overall prevalence of main NCDs in this study showed a comparable prevalence to studies used face to face interview method. This study supports the potential use of telephone-based survey to assess heath related information in Sri Lanka. PMID- 29284465 TI - Acupuncture for patients with mild to moderate Alzheimer's disease: a randomized controlled trial. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. However, none of medical treatment can stop or reverse the underlying neurodegenerative of AD at present. Acupuncture has attracted more and more attention in recent years due to its efficacy and very few side effects. Lately, a systematic review has thought that the evidence on the effectiveness of acupuncture in improving the cognitive function of AD patients was not powerful enough. Therefore, the aim of this study is to explore the efficacy and safety of acupuncture in patients with mild to moderate AD. METHODS: This was a randomized, controlled, parallel-group, exploratory study with 4-week baseline (T0), 12-week treatment phase (T1) and 12-week follow-up period (T2). Patients with mild to moderate AD meeting the included criteria were randomly allocated into either acupuncture or donepezil hydrochloride groups. The acupuncture group(AG) was given acupuncture treatment three times per week and the donepezil hydrochloride group(DG) group was administered donepezil hydrochloride once daily (5 mg/day for the first 4 weeks and 10 mg/day thereafter). Primary efficacy was measured using Alzheimer's disease Assessment Scale-Cognitive (ADAS-cog) and Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus). The second outcomes were measured with 23-Item Alzheimer's disease Cooperative Study Activities of Daily Living Scales (ADAS-ADL23) and Neuropsychiatric Index (NPI). RESULTS: Of 87 participants enrolled in the study, 79 patients finished their treatment and follow-up processes. The ADAS-cog scores for AG group showed obvious decreases at T2 and ?(T2-T0)when compared with DG group, and significant between-group differences were detected (all p < 0.05). The mean CIBIC-Plus values for the AG group at T1 and T2 were much lower than that for the DG group, and there were significant differences between the two groups (?<0.05). There were no significant between-group differences in the scores of ADAS-ADL23 and NPI during the study period. Treatment discontinuations due to adverse events were 0 (0%) and 4 (9.09%) for the AG and DG groups, respectively. CONCLUSIONS: Acupuncture is safe, well tolerated and effective in improving the cognitive function, global clinical status of AD. TRIAL REGISTRATION: ChiCTR-IOR-17010465 (Retroactively registered on 18 JAN 2017). PMID- 29284467 TI - Satisfaction of doctors with their training: evidence from UK. AB - BACKGROUND: This study considers the primary training environment factors affecting the satisfaction of doctors in training with their training. METHODS: An OLS multiple regression analysis was performed on responses given by doctors in training (trainees) to General Medical Council (UK) National Trainee Survey annually from 2012 to 2015. Two different research models investigate the determinant of trainee doctor satisfaction. The first model includes clinical supervision, feedback, workload, and gender as explanatory variables. The second model adds supportive environment to the first model. RESULTS: The GMC survey response rate is 97%. Our analysis shows the key factors that determine trainee satisfaction are strong clinical supervision, frequent and useful feedback meetings, an adequate workload and a supportive environment. CONCLUSIONS: It is suggested focus on clinical supervision, feedback, workload and supportive environment would increase trainee satisfaction, improve the quality of training and morale, and hopefully, therefore, the quality of care patients receive. PMID- 29284466 TI - Factors associated with sports-related dental injuries among young athletes: a cross-sectional study in Miyagi prefecture. AB - BACKGROUND: Sports-related dental injuries, such as tooth fracture, loosening, and avulsion, are a major concern among young athletes because they directly impair oral function. Although the preventive efficacy of mouthguards has been well established, the prevalence of sports-related dental injuries remains high among young athletes. The aim of this study is to identify the variables contributing to the risk of sports-related dental injuries by conducting a survey on large population of young athletes in Miyagi prefecture. METHODS: A cross sectional study was conducted with school-aged athletes (aged 6-15 years, n = 5735) using a self-reported questionnaire. The questionnaire examined general variables, including sex, age, and body mass index; sports-related variables, including sports-type, team level, activity schedule, break time, and verbal/physical abuse by coaches; and lifestyle variables related to free time, including screen-time and sleep duration. Their associations with sports-related dental injuries were examined using multivariate logistic regression models. RESULTS: The prevalence of sports-related dental injuries was 13.3% (763 of 5735 young athletes) and was higher in males (14.3%, 592 of 4132) than in females (10.7%, 171 of 1603; adjusted odds ratios [ORs] and 95% confidence intervals [CIs]: 1.48 [1.22-1.79], p < 0.001). After stratification according to sex, significant associations with the prevalence of sports-related dental injuries were evident for three variables-insufficient break time, verbal abuse, and physical punishment-in males (adjusted ORs [95% CI]: 1.35 [1.03-1.77], p = 0.032; 1.31 [1.05-1.62], p = 0.015; and 1.36 [1.06-1.75], p = 0.016, respectively) but not in females (adjusted ORs [95% CI]: 0.88 [0.53-1.47], p = 0.623; 1.29 [0.87 1.91], p = 0.206; and 0.97 [0.57-1.63], p = 0.894, respectively). CONCLUSIONS: Although our results might be based on the individual athlete's self-perception to the sports-related variables, our results suggest that insufficient break time, verbal abuse, and physical punishment from coaches are positively associated with the prevalence of sports-related dental injuries in young male athletes. PMID- 29284468 TI - Evaluation of the content quality of websites for recurrent aphthous ulcers and oral lichen planus. AB - BACKGROUND: The Internet is one of the most popular resources for people to obtain medical information; however, only a limited number of studies have reported the quality of the available health information related to oral mucosal diseases. The present study aimed to evaluate the quality of information on websites for recurrent aphthous ulcers (RAU) and oral lichen planus (OLP), in both Chinese and English. METHODS: Common search engines, BaiDu, Google, and Yahoo in Chinese; and Bing, Google, and Yahoo in English were used to identify websites providing content related to the oral mucosal diseases. The first 100 links for keywords "recurrent aphthous ulcers" and "oral lichen planus" were visited and content was downloaded within 24 h. Two separate trained researchers use the validated DISCERN rating instrument and JAMA benchmarks to evaluate the content. The rating scores were analyzed and the quality was assessed according to the scores and content of websites. RESULTS: A total of 145 websites for RAU and 128 of OLP were analyzed. Based on the DISCERN instrument, the quality of the content in websites for both diseases, whether in English or Chinese, was not high, generally scoring 2 to 3 (max. 5). Only 13 of the RAU websites and 21 of the OLP websites fulfilled the four criteria of the JAMA benchmarks. Generally, the scores of the English websites were higher than those of the Chinese websites. During the twelve searches, only four (Yahoo of RAU in Chinese, Bing and Yahoo of RAU in English, and Google of OLP in Chinese) showed moderate correlation between the website's ranking and their rating scores. People cannot obtain high quality medical information if they only look at the top ranked sites on the viewing lists. Websites belonging to universities or medical centers had relatively higher scores compared with the others. CONCLUSIONS: The quality of the content on websites relating to RAU and OLP in Chinese and English was moderate. More good quality websites and information are needed in the future. PMID- 29284470 TI - Improving equity in health care financing in China during the progression towards Universal Health Coverage. AB - BACKGROUND: China is reforming the way it finances health care as it moves towards Universal Health Coverage (UHC) after the failure of market-oriented mechanisms for health care. Improving financing equity is a major policy goal of health care system during the progression towards universal coverage. METHODS: We used progressivity analysis and dominance test to evaluate the financing channels of general taxation, pubic health insurance, and out-of-pocket (OOP) payments. In 2012 a survey of 8854 individuals in 3008 households recorded the socioeconomic and demographic status, and health care payments of those households. RESULTS: The overall Kakwani index (KI) of China's health care financing system is 0.0444. For general tax KI was -0.0241 (95% confidence interval (CI): -0.0315 to 0.0166). The indices for public health schemes (Urban Employee Basic Medical Insurance, Urban Resident's Basic Medical Insurance, New Rural Cooperative Medical Scheme) were respectively 0.1301 (95% CI: 0.1008 to 0.1594), -0.1737 (95% CI: -0.2166 to -0.1308), and -0.5598 (95% CI: -0.5830 to -0.5365); and for OOP payments KI was 0.0896 (95%CI: 0.0345 to 0.1447). OOP payments are still the dominant part of China's health care finance system. CONCLUSION: China's health care financing system is not really equitable. Reducing the proportion of indirect taxes would considerably improve health care financing equity. The flat rate contribution mechanism is not recommended for use in public health insurance schemes, and more attention should be given to optimizing benefit packages during China's progression towards UHC. PMID- 29284469 TI - Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children. AB - BACKGROUND: Young children are at greatest risk for malaria-associated morbidity and mortality. The immune response of young children differs in fundamental ways from that of adults, and these differences likely contribute to the increased susceptibility of children to severe malaria and to their delayed development of immunity. Elevated levels of pro-inflammatory cytokines and chemokines in the peripheral blood during acute infection contribute to the control of parasitaemia, but are also responsible for much of the immunopathology seen during symptomatic disease. Clinical immunity to malaria may depend upon the ability to regulate these pro-inflammatory responses, possibly through mechanisms of immunologic tolerance. In order to explore the effect of age on the immune response to malaria and the development of clinical immunity, cytokines and chemokines were measured in the plasma of children at day 0 of an acute malaria episode and during convalescence. RESULTS: Younger children presenting with acute malaria exhibited much higher levels of TNF, IL2, and IL6, as well as increased Th1 associated chemokines IP10, MIG, and MCP1, compared to older children with acute malaria. Additionally, the regulatory cytokines IL10 and TNFRI were dramatically elevated in younger children compared to older children during acute infection, indicating that regulatory as well as pro-inflammatory cytokine responses are dampened in later childhood. CONCLUSIONS: Together these data suggest that there is a profound blunting of the cytokine and chemokine response to malaria among older children residing in endemic settings, which may be due to repeated malaria exposure, intrinsic age-based differences in the immune response, or both. PMID- 29284471 TI - Prevalence of dental caries and associated factors among 12 years old students in Eritrea. AB - BACKGROUND: Dental caries is one of the most prevalent diseases of childhood in developing countries. However, there is a paucity of epidemiological data on the prevalence and associated factors of dental caries in Eritrea. The objective of this study was to assess the prevalence and associated factors of dental caries among 12 years old school children in Eritrea. METHODS: A school based cross sectional study was conducted among 225 twelve years old students in two selected schools. One school from randomly selected urban and rural subzones of the country were selected. WHO adopted questionnaire and a standard checklist were used to collect relevant data. To assess dental caries, two examiners were calibrated by a certified dentist and inter observer agreement was calculated using the Cohen's Kappa statistic (0.82). All data analysis was done using SPSS version 20. RESULTS: The prevalence of dental caries was 78%, without significant difference between males (78%) and females (79%).The mean DMFT value was 2.50 (+/ 2.21). The decayed component contributed 98.3% of the score as it had 2.44 (+/ 1.2) share to the mean DMFT value. The first molar was the most affected tooth with a DMFT value of 1.55 (+/-1.36). The mean significant caries index score (SiC) was 4.97 (+/-1.9) which is higher than the upper limit of SiC value of 3 set by the WHO as a global average. More than half of the respondents had never visited a dentist and out of the students who had utilized a dental health facility, 82% of visits were due to dental pain while visits for regular checkups were cited by only 6.6% of the respondents. CONCLUSION: Dental caries was found to be a common public health problem among 12 years old Eritrean students. The prevalence of dental caries, mean DMFT and SiC scores were higher than the average score of other developing countries. Gaps in dental health service utilization, dental health practices and suboptimal water fluoride levels contribute to poor dental health among school children in Eritrea. PMID- 29284472 TI - Differentiating early stage florid osseous dysplasia from periapical endodontic lesions: a radiological-based diagnostic algorithm. AB - BACKGROUND: Osseous dysplasia (OD) is the most common fibro-osseous lesion of the jaw affecting the periapical region. Early stages of OD can resemble periapical radiolucencies, thus mimicking the radiological aspects of an endodontic pathology. Such radiolucent lesions affecting previously decayed or treated teeth are even more complex to interpret. CASE PRESENTATION: The aim of this paper is to report a case-series of representative clinical situations describing the radiological features and illustrating the diagnostic workup of patients with florid osseous dysplasia (FOD). Emphasis is given to the endodontic implications of such periapical bone disease and the complexity of accurate diagnosis in the context of endodontic retreatment. We then propose a practical radiological-based diagnostic algorithm to assist the clinician in the diagnostic of OD periapical lesions. CONCLUSION: Periapical lesions may be confused with bone diseases such as osseous dysplasia, especially in the radiolucent initial stage. Knowledge of clinical features associated with a careful reading of cone beam CT images, such as fine opacities within the hypodense periapical lesion, may help determine the right diagnostic. PMID- 29284473 TI - Involvements of p38 MAPK and oxidative stress in the ozone-induced enhancement of AHR and pulmonary inflammation in an allergic asthma model. AB - BACKGROUND: Exposure to ambient ozone (O3) increases the susceptivity to allergens and triggers exacerbations in patients with asthma. However, the detailed mechanisms of action for O3 to trigger asthma exacerbations are still unclear. METHODS: An ovalbumin (OVA)-established asthmatic mouse model was selected to expose to filtered air (OVA-model) or 1.0 ppm O3 (OVA-O3 model) during the process of OVA challenge. Next, the possible involvements of p38 MAPK and oxidative stress in the ozone actions on the asthma exacerbations were investigated on the mice of OVA-O3 model by treating them with SB239063 (a p38 MAPK inhibitor), and/or the alpha-tocopherol (antioxidant). Biological measurements were conducted including airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL), inflammation in the airway lumen and lung parenchyma, the phosphorylation of p38 MAPK and heat shock protein (HSP) 27 in the tracheal tissues, and the malondialdehyde (MDA) content and the glutathione peroxidase (GSH-Px) activity in lung tissues. RESULTS: In OVA-allergic mice, O3 exposure deteriorated airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL) and pulmonary inflammation, accompanied by the increased oxidative stress in lung tissues and promoted p38 MAPK and HSP27 phosphorylation in tracheal tissues. Administration of SB239063 (a p38 MAPK inhibitor) on OVA-O3 model exclusively mitigated the Raw, the CL, and the BAL IL-13 content, while alpha-tocopherol (antioxidant) differentially reduced the BAL number of eosinophils and macrophages, the content of BAL hyaluronan, the peribronchial inflammation, as well as the mRNA expression of TNF-alpha and IL-5 in the lung tissues of OVA-O3 model. Administration of these two chemical inhibitors similarly inhibited the AHR, the BAL IFN-gamma and IL-6 production, the perivascular lung inflammation and the lung IL-17 mRNA expression of OVA-O3 model. Interestingly, the combined treatment of both compounds together synergistically inhibited neutrophil counts in the BALF and CXCL-1 gene expression in the lung. CONCLUSIONS: O3 exposure during the OVA challenge process promoted exacerbation in asthma. Both p38 MAPK and oxidative stress were found to play a critical role in this process and simultaneous inhibition of these two pathways significantly reduced the O3-elicited detrimental effects on the asthma exacerbation. PMID- 29284474 TI - A systematic review of the economic impact of rapid diagnostic tests for dengue. AB - BACKGROUND: Dengue fever is rapidly expanding geographically, with about half of the world's population now at risk. Among the various diagnostic options, rapid diagnostic tests (RDTs) are convenient and prompt, but limited in terms of accuracy and availability. METHODS: A systematic review was conducted of published data on the use of RDTs for dengue with respect to their economic impact. The search was conducted with combinations of key search terms, including "((Dengue[Title]) AND cost/economic)" and "rapid diagnostic test/assay (or point of-care)". Articles with insufficient report on cost/economic aspect of dengue RDTs, usually on comparison of different RDTs or assessment of novel rapid diagnostic tools, were excluded. This review has been registered in the PROSPERO International prospective register of systematic reviews (registry #: CRD42015017775). RESULTS: Eleven articles were found through advanced search on Pubmed. From Embase and Web of Science, two and 14 articles were obtained, respectively. After removal of duplicate items, title screening was done on 21 published works and 12 titles, including 2 meeting abstracts, were selected for abstract review. For full-text review, by two independent reviewers, 5 articles and 1 meeting abstract were selected. Among these, the abstract was referring to the same study results as one of the articles. After full text review, two studies (two articles and one abstract) were found to report on cost-wise or economic benefits of dengue RDTs and were selected for data extraction. One study found satisfactory performance of IgM-based Panbio RDT, concluding that it would be cost-effective in endemic settings. The second study was a modeling analysis and showed that a dengue RDT would not be advantageous in terms of cost and effectiveness compared to current practice of antibiotics prescription for acute febrile illness. CONCLUSIONS: Despite growing use of RDTs in research and clinical settings, there were limited data to demonstrate an economic impact. The available two studies reached different conclusions on the cost-effectiveness of dengue RDTs, although only one of the two studies reported outcomes from cost effectiveness analysis of dengue and the other was considering febrile illness more generally. Evidence of such an impact would require further quantitative economic studies. PMID- 29284475 TI - Existential decision-making in a fatal progressive disease: how much do legal and medical frameworks matter? AB - BACKGROUND: Healthcare legislation in European countries is similar in many respects. Most importantly, the framework of informed consent determines that physicians have the duty to provide detailed information about available therapeutic options and that patients have the right to refuse measures that contradict their personal values. However, when it comes to end-of-life decision making a number of differences exist in the more specific regulations of individual countries. These differences and how they might nevertheless impact patient's choices will be addressed in the current debate. MAIN TEXT: In this article we show how the legal and medical frameworks of Germany, Poland and Sweden differ with regard to end-of-life decisions for patients with a fatal progressive disease. Taking Amyotrophic Lateral Sclerosis (ALS) as an example, we systematically compare clinical guidelines and healthcare law, pointing out the country-specific differences most relevant for existential decision-making. A fictional case report discusses the implications of these differences for a patient with ALS living in either of the three countries. Patients with ALS in Germany, Poland and Sweden are confronted with a similar spectrum of treatment options. However, the analysis of the normative frameworks shows that the conditions for making existential decisions differ considerably in Germany, Poland and Sweden. Specifically, these differences concern (1) the legal status of advance directives, (2) the conditions under which life-sustaining therapies are started or withheld, and (3) the legal regulations on assisted dying. CONCLUSION: According to the presented data, regulations of terminating life sustaining treatments and the framework of "informed consent" are quite differently understood and implemented in the legal setting of the three countries. It is possible, and even likely, that these differences in the legal and medical frameworks have a considerable influence on existential decisions of patients with ALS. PMID- 29284476 TI - Why some sites are responding better to anti-malarial interventions? A case study from western Kenya. AB - BACKGROUND: In sub-Saharan Africa, malaria interventions over the last decades have been successful in reducing both mortality and morbidity. In western Kenya however some areas experience contrasting outcomes of the ongoing interventions while the causes for this observation remains not yet clearly known. METHODS: The WHO insecticide (deltamethrin) susceptibility test of the common malaria vectors was studied. Multiple surveys on household use and hospital prescriptions of antimalarial drugs from 2003 to 2015 were done. Along with this, cross sectional surveys on their availability in the local drug dispensing outlets were also done in 2015. Monthly precipitations and air temperature data was collected along with systematic review on abundance and composition of common malaria vectors in the study area before and during interventions. The above factors were used to explain the possible causes of contrasting outcome of malaria interventions between the three study sites. RESULTS: Areas with malaria resurgence or sustained high transmission (Kombewa and Marani) showed higher composition of Anopheles funestus sensu lato (s.l.) than the previously abundant Anopheles gambiae sensu stricto (s.s.) and the later had higher composition to an area with a sustained infection decline (Iguhu). Anopheles gambiae s.l. from Kombewa showed highest resistance (50% mortality) upon exposure to WHO deltamethrin discriminating dosage of 0.75% while those from Marani and Iguhu had reduced resistance status (both had a mean mortality of 91%). Sampled An. funestus s.l. from Marani were also highly resistant to deltamethrin as 57% of the exposed vectors survived. An increasing of mean air temperature by 2 degrees C was noted for Marani and Iguhu from 2013 to 2015 and was accompanied by an increased rainfall at Marani. Community drug use and availability in selling outlets along with prescription in hospitals were not linked to the struggling control of the disease. CONCLUSIONS: The malaria vector species composition shift, insecticide resistance and climatic warming were the likely cause of the contrasting outcome of malaria intervention in western Kenya. Surveillance of malaria parasite and vector dynamics along with insecticide resistance and vector biting behaviour monitoring are highly recommended in these areas. PMID- 29284477 TI - Disparities in the use of mobile phone for seeking childbirth services among women in the urban areas: Bangladesh Urban Health Survey. AB - BACKGROUND: In Bangladesh, similar to its other South Asian counterparts, shortage of health workers along with inadequate infrastructure constitute some of the major obstacles for the equitable provision of reproductive healthcare services, particularly among the marginalized and underserved neighbourhoods. However, given the rapidly expanding broadband communication and mobile phone market in the country, the application of eHealth and mHealth technologies offer a window of opportunities to minimise the impact of socioeconomic barriers and promote the utilization of maternal healthcare services thereby. In the present study we aimed to investigate 1) the prevalence of usage of mobile phones for seeking childbirth services, 2) neighbourhood and socioeconomic disparities in the use, and 3) association between using mobile phones and the uptake of postnatal care among mothers and neonates. METHODS: Data for the present study came from Bangladesh Urban Health Survey 2013. Study subjects were 9014 married women aged between 15 and 49 years. RESULTS: The overall rate of use of mobile phone was highest in City Corporation non-Slum areas (16.2%) and lowest in City Corporation Slum areas (7.4%). The odds of using mobile for seeking childbirth services were significantly higher among those who were living in non-slum areas, and lower among those who never attended school and lived in poorer households. Results also indicated that women in the slum areas who used mobile phone for childbirth service seeking, were 4.3 times [OR = 4.250;95% CI = 1.856-9.734] more likely to receive postnatal care for themselves, and those from outside the city corporation areas were 2.7 times [OR = 2.707;95% CI = 1.712-4.279] more likely to receive postnatal care for the newborn. CONCLUSION: Neighbourhood, educational and economic factors were significantly associated with the mobile phone utilization status among urban women. Promoting access to better education and sustainable income earning should be regarded as an integral part to the expansion of mHealth for maternal healthcare seeking behaviour. PMID- 29284479 TI - Acacia hydaspica R. Parker prevents doxorubicin-induced cardiac injury by attenuation of oxidative stress and structural Cardiomyocyte alterations in rats. AB - BACKGROUND: The use of doxorubicin (DOX) an anthracycline antineoplastic agent is withdrawn due to its cardio-toxic side effects. Oxidative stress has been recognized as the primary cause of DOX induced cardiotoxicity. We have investigated whether polyphenol rich ethyl acetate extract of Acacia hydaspica (AHE) can attenuate doxorubicin-induced cardiotoxicity via inhibition of oxidative stress. METHODS: AHE was administered orally to rats once daily for 6 weeks at doses of 200 and 400 mg/kg b.w. DOX (3 mg/kg b.w. i.p., single dose/week) was administered for 6 weeks (chronic model). The parameters studied to evaluate cardioprotective potential were the serum cardiac function biomarkers (CK, CKMB, AST and LDH), hematological parameters, cardiac tissue antioxidant enzymatic status and oxidative stress markers, and histopathological analysis to validate biochemical findings. RESULTS: Chronic 6 week treatment of DOX significantly deteriorated cardiac function biomarkers and decreased the activities of antioxidant enzymes, whereas significant increase in oxidative stress biomarkers was noticed in comparison to control group. AHE dose dependently protected DOX-induced leakage of cardiac enzymes in serum and ameliorated DOX-induced oxidative stress; as evidenced by decreasing lipid peroxidation, H2O2 and NO content with increase in phase I and phase II antioxidant enzymes. Doxorubicin treatment produced severe morphological lesions, leucopenia, decrease in red blood cell counts and hemoglobin concentrations. AHE co-treatment protected the heart and blood elements from the toxic effects of doxorubicin as indicated by the recovery of hematological parameters to normal values and prevention of myocardial injuries in a dose dependent way. The protective potency of AHE (400 mg/kg b.w) was equivalent to silymarin. CONCLUSION: Results revealed that AHE showed protective effects against DOX induce cardiotoxicity. The protective effect might attribute to its polyphenolic constituents and antioxidant properties. AHE might be helpful in combination therapies as safer and efficient. PMID- 29284478 TI - Phoyunnanin E inhibits migration of non-small cell lung cancer cells via suppression of epithelial-to-mesenchymal transition and integrin alphav and integrin beta3. AB - BACKGROUND: The conversion of the epithelial phenotype of cancer cells into cells with a mesenchymal phenotype-so-called epithelial-mesenchymal transition (EMT) has been shown to enhance the capacity of the cells to disseminate throughout the body. EMT is therefore becoming a potential target for anti-cancer drug discovery. Here, we showed that phoyunnanin E, a compound isolated from Dendrobium venustum, possesses anti-migration activity and addressed its mechanism of action. METHODS: The cytotoxic and proliferative effects of phoyunnanin E on human non-small cell lung cancer-derived H460, H292, and A549 cells and human keratinocyte HaCaT cells were investigated by MTT assay. The effect of phoyunnanin E on EMT was evaluated by determining the colony formation and EMT markers. The migration and invasion of H460, H292, A549 and HaCaT cells was evaluated by wound healing assay and transwell invasion assay, respectively. EMT markers, integrins and migration-associated proteins were examined by western blot analysis. RESULTS: Phoyunnanin E at the concentrations of 5 and 10 MUM, which are non-toxic to H460, H292, A549 and HaCaT cells showed good potential to inhibit the migratory activity of three types of human lung cancer cells. The anti-migration effect of phoyunnanin E was shown to relate to the suppressed EMT phenotypes, including growth in anchorage-independent condition, cell motility, and EMT-specific protein markers (N-cadherin, vimentin, slug, and snail). In addition to EMT suppression, we found that phoyunnanin E treatment with 5 and 10 MUM could decrease the cellular level of integrin alphav and integrin beta3, these integrins are frequently up-regulated in highly metastatic tumor cells. We further characterized the regulatory proteins in cell migration and found that the cells treated with phoyunnanin E exhibited a significantly lower level of phosphorylated focal adhesion kinase (p-FAK) and phosphorylated ATP-dependent tyrosine kinase (p-AKT), and their downstream effectors (including Ras-related C3 botulinum (Rac-GTP); Cell division cycle 42 (Cdc42); and Ras homolog gene family, member A (Rho-GTP)) in comparison to those of the non-treated control. CONCLUSIONS: We have determined for the first time that phoyunnanin E could inhibit the motility of lung cancer cells via the suppression of EMT and metastasis-related integrins. This new information could support further development of this compound for anti-metastasis approaches. PMID- 29284480 TI - Creating research and development awareness among dental care professionals by use of strategic communication: a 12-year intervention study. AB - BACKGROUND: Despite the availability of contemporary research advances, only a limited fraction is implemented into dental practice. One possible way to facilitate this process is to stimulate the research and development (R&D) awareness and interest with aid of strategic communication. METHODS: The aim of the study was to analyse the role of a strategic communication in R&D awareness and interest among dental care professionals (DCP) over a 12-year period. A second aim was to compare the findings with those from primary care professionals (PCP). The project had a prospective design and the intervention was conducted through established oral, written and digital channels. The outcome was captured by two validated questionnaires submitted after 7 and 12 years, respectively. An additional Questionnaire file shows the details [see Additional file 1]. The material consisted of 599 health care professionals (205 DCP; 394 PCP) that responded to the first questionnaire and 526 individuals (195 DCP; 331 PCP) who responded to the second. All were employed by the primary care organization of Region Halland located in southwest of Sweden. The majority were women (>= 85%) and the mean age at the first questionnaire was 49 years (SD 8.5). Longitudinal analyses were applied to those individuals that responded to both surveys after 7 and 12 years (n = 248). Comparisons between DCP's and PCP's were processed with Chi-square and Fischer's exact tests. RESULTS: Strategic communication contributed to increase the R&D awareness and interest among the dental personnel. The created interest was reported stronger among the DCP when compared with PCP at both surveys (p < 0.05). The longitudinal findings confirmed a long term interest among the DCP's. Direct and indirect communication facilitated R&D interest in both groups. The most powerful channels were the written "Research bulletin" and peer inspiration. CONCLUSION: Strategic communication can be employed as a scientific tool that may contribute to the creation of a long-term R&D awareness and interest among dental care professionals. PMID- 29284481 TI - Danshen extract circumvents drug resistance and represses cell growth in human oral cancer cells. AB - BACKGROUND: Danshen is a common traditional Chinese medicine used to treat neoplastic and chronic inflammatory diseases in China. However, the effects of Danshen on human oral cancer cells remain relatively unknown. This study investigated the antiproliferative effects of a Danshen extract on human oral cancer SAS, SCC25, OEC-M1, and KB drug-resistant cell lines and elucidated the possible underlying mechanism. METHODS: We investigated the anticancer potential of the Danshen extract in human oral cancer cell lines and an in vivo oral cancer xenograft mouse model. The expression of apoptosis-related molecules was evaluated through Western blotting, and the concentration of in vivo apoptotic markers was measured using immunohistochemical staining. The antitumor effects of 5-fluorouracil and the Danshen extract were compared. RESULTS: Cell proliferation assays revealed that the Danshen extract strongly inhibited oral cancer cell proliferation. Cell morphology studies revealed that the Danshen extract inhibited the growth of SAS, SCC25, and OEC-M1 cells by inducing apoptosis. The Flow cytometric analysis indicated that the Danshen extract induced cell cycle G0/G1 arrest. Immunoblotting analysis for the expression of active caspase-3 and X-linked inhibitor of apoptosis protein indicated that Danshen extract-induced apoptosis in human oral cancer SAS cells was mediated through the caspase pathway. Moreover, the Danshen extract significantly inhibited growth in the SAS xenograft mouse model. Furthermore, the Danshen extract circumvented drug resistance in KB drug-resistant oral cancer cells. CONCLUSION: The study results suggest that the Danshen extract could be a potential anticancer agent in oral cancer treatment. PMID- 29284482 TI - Outcomes of arthroscopic debridement of isolated Ligamentum Teres tears using the iHOT-33. AB - BACKGROUND: Tears of the Ligamentum Teres are a common cause of groin pain. Tears of the ligament frequently co-exist alongside other bony or labral intra articular hip lesions, which are also treated at the time of arthroscopy. For this reason, it is often difficult to assess the effect that debridement alone has on improving patient pain and function. This study aims to assess the short term outcomes of arthroscopic debridement of isolated Ligamentum Teres tears using a validated patient-reported outcome score - the International Hip Outcome Tool (iHOT-33). METHODS: A retrospective review was performed of 35 patients (37 hips) who had an isolated Ligamentum Teres tear treated with arthroscopic radiofrequency debridement between September 2012 and September 2015. Patients with concomitant intra-articular hip pathology (femoroacetabular impingement, labral lesions, hip dysplasia) were excluded from the study. All patients completed the iHOT-33 questionnaire pre-operatively and post-operatively. The mean age was 37.7 years (range 16-67 years) and patients were followed up for a mean period of 17.7 months (range 6-42 months). Thirty-one patients were female and 4 were male. RESULTS: Thirty-seven isolated partial tears were managed with arthroscopic radiofrequency debridement. At follow up, the mean iHOT-33 score improved from 26.9 pre-operatively to 48.0 post-operatively, representing a mean improvement of 21.1 (p < 0.001). The minimum clinically important difference of the iHOT-33 is 6.1 points. Significant improvements were noted in all four sub sections of the iHOT-33. CONCLUSION: Arthroscopic radiofrequency debridement of isolated Ligamentum Teres tears provides short-term benefit in the majority of patients, including significant improvement in sporting function. PMID- 29284483 TI - Bovine tuberculosis visible lesions in cattle culled during herd breakdowns: the effects of individual characteristics, trade movement and co-infection. AB - BACKGROUND: Bovine tuberculosis (bTB), caused by Mycobacterium bovis, remains a significant problem for livestock industries in many countries worldwide including Northern Ireland, where a test and slaughter regime has utilised the Single Intradermal Comparative Cervical Tuberculin (SICCT) test since 1959. We investigated the variation in post-mortem confirmation based on bTB visible lesion (VL) presence during herd breakdowns using two model suites. We investigated animal-level characteristics, while controlling for herd-level factors and clustering. We were interested in potential impacts of concurrent infection, and therefore we assessed whether animals with evidence of liver fluke infection (Fasciola hepatica; post-mortem inspection), M. avium reactors (animals with negative M. bovis-avium (b-a) tuberculin reactions) or Bovine Viral Diarrhoea Virus (BVDV; RT-PCR tested) were associated with bTB confirmation. RESULTS: The dataset included 6242 animals removed during the 14 month study period (2013-2015). bTB-VL presence was significantly increased in animals with greater b-a reaction size at the disclosing SICCT test (e.g. b-a = 5-9 mm vs. b-a = 0 mm, adjusted Odds ratio (aOR): 14.57; p < 0.001). M. avium reactor animals (b a < 0) were also significantly more likely to disclose VL than non-reactor animals (b-a = 0; aOR: 2.29; p = 0.023). Animals had a greater probability of exhibiting lesions with the increasing number of herds it had resided within (movement; log-herds: aOR: 2.27-2.42; p < 0.001), if it had an inconclusive penultimate test result (aOR: 2.84-3.89; p < 0.001), and with increasing time between tests (log-time; aOR: 1.23; p = 0.003). Animals were less likely to have VL if they were a dairy breed (aOR: 0.79; p = 0.015) or in an older age-class (e.g. age-quartile 2 vs. 4; aOR: 0.65; p < 0.001). Liver fluke or BVDV variables were not retained in either multivariable model as they were non-significantly associated with bTB-VL status (p > 0.1). CONCLUSIONS: Our results suggest that neither co-infection of liver fluke nor BVDV had a significant effect on the presence of VLs in this high-risk cohort. M. avium tuberculin reactors had a significantly increased risk of disclosing with a bTB lesion, which could be related to the impact of co-infection with M. avium subsp. paratuberculosis (MAP) affecting the performance of the SICCT however further research in this area is required. Movements, test history, breed and age were important factors influencing confirmation in high-risk animals. PMID- 29284484 TI - Platform-independent gene expression signature differentiates sessile serrated adenomas/polyps and hyperplastic polyps of the colon. AB - BACKGROUND: Sessile serrated adenomas/polyps are distinguished from hyperplastic colonic polyps subjectively by their endoscopic appearance and histological morphology. However, hyperplastic and sessile serrated polyps can have overlapping morphological features resulting in sessile serrated polyps diagnosed as hyperplastic. While sessile serrated polyps can progress into colon cancer, hyperplastic polyps have virtually no risk for colon cancer. Objective measures, differentiating these types of polyps would improve cancer prevention and treatment outcome. METHODS: RNA-seq training data set and Affimetrix, Illumina testing data sets were obtained from Gene Expression Omnibus (GEO). RNA-seq single-end reads were filtered with FastX toolkit. Read mapping to the human genome, gene abundance estimation, and differential expression analysis were performed with Tophat-Cufflinks pipeline. Background correction, normalization, and probe summarization steps for Affimetrix arrays were performed using the robust multi-array method (RMA). For Illumina arrays, log2-scale expression data was obtained from GEO. Pathway analysis was implemented using Bioconductor package GSAR. To build a platform-independent molecular classifier that accurately differentiates sessile serrated and hyperplastic polyps we developed a new feature selection step. We also developed a simple procedure to classify new samples as either sessile serrated or hyperplastic with a class probability assigned to the decision, estimated using Cantelli's inequality. RESULTS: The classifier trained on RNA-seq data and tested on two independent microarray data sets resulted in zero and three errors. The classifier was further tested using quantitative real-time PCR expression levels of 45 blinded independent formalin fixed paraffin-embedded specimens and was highly accurate. Pathway analyses have shown that sessile serrated polyps are distinguished from hyperplastic polyps and normal controls by: up-regulation of pathways implicated in proliferation, inflammation, cell-cell adhesion and down-regulation of serine threonine kinase signaling pathway; differential co-expression of pathways regulating cell division, protein trafficking and kinase activities. CONCLUSIONS: Most of the differentially expressed pathways are known as hallmarks of cancer and likely to explain why sessile serrated polyps are more prone to neoplastic transformation than hyperplastic. The new molecular classifier includes 13 genes and may facilitate objective differentiation between two polyps. PMID- 29284485 TI - Patient experiences of engagement with care plans and healthcare professionals' perceptions of that engagement. AB - BACKGROUND: Although patient engagement is internationally recognized as a core quality indicator of healthcare systems, no report has yet explored patient engagement in Saudi Arabia. Thus, we explored patients' experiences of engagement with healthcare services and assessed physicians' and nurses' perceptions of this engagement. METHODS: We performed a cross-sectional study on patients and their family members admitted to either the rehabilitation or neurology department of King Fahad Medical City, Riyadh, Saudi Arabia. We also studied physicians and nurses involved in direct patient care in these departments. Two self administered questionnaires were used to collect data on patients' experiences of engagement with healthcare services and physicians' and nurses' perceptions of that engagement. RESULTS: We recruited 36 patients and 46 family members, as well as 64 nurses and 36 physicians. About 73% of patients and family members felt that doctors and nurses engaged them in decision making regarding care plans; 80% felt that they were a partners in the treatment plans. Over one-third of physicians and nurses believed that patient engagement improved healthcare outcomes, and about 7% believed that patient engagement was unimportant or not extremely important. Responses of physicians and nurses differed significantly from those of patients and family members with regards to the extent of the patient-physician/nurse relationship, the perception of involvement, and the degree of partnership and shared leadership. CONCLUSION: We assessed patient experiences of engagement with health care service and physicians' and nurses' perceptions of that engagement. Most patients/family members reported good engagement. Although most physicians and nurses believed that patient engagement improved the healthcare outcomes, some believed that improving healthcare outcomes through patient engagement was not important or not extremely important. PMID- 29284486 TI - Use of transcriptomic data for extending a model of the AppA/PpsR system in Rhodobacter sphaeroides. AB - BACKGROUND: Photosynthetic (PS) gene expression in Rhodobacter sphaeroides is regulated in response to changes in light and redox conditions mainly by PrrB/A, FnrL and AppA/PpsR systems. The PrrB/A and FnrL systems activate the expression of them under anaerobic conditions while the AppA/PpsR system represses them under aerobic conditions. Recently, two mathematical models have been developed for the AppA/PpsR system and demonstrated how the interaction between AppA and PpsR could lead to a phenotype in which PS genes are repressed under semi-aerobic conditions. These models have also predicted that the transition from aerobic to anaerobic growth mode could occur via a bistable regime. However, they lack experimentally quantifiable inputs and outputs. Here, we extend one of them to include such quantities and combine all relevant micro-array data publically available for a PS gene of this bacterium and use that to parameterise the model. In addition, we hypothesise that the AppA/PpsR system alone might account for the observed trend of PS gene expression under semi-aerobic conditions. RESULTS: Our extended model of the AppA/PpsR system includes the biological input of atmospheric oxygen concentration and an output of photosynthetic gene expression. Following our hypothesis that the AppA/PpsR system alone is sufficient to describe the overall trend of PS gene expression we parameterise the model and suggest that the rate of AppA reduction in vivo should be faster than its oxidation. Also, we show that despite both the reduced and oxidised forms of PpsR binding to the PS gene promoters in vitro, binding of the oxidised form as a repressor alone is sufficient to reproduce the observed PS gene expression pattern. Finally, the combination of model parameters which fit the biological data well are broadly consistent with those which were previously determined to be required for the system to show (i) the repression of PS genes under semi aerobic conditions, and (ii) bistability. CONCLUSION: We found that despite at least three pathways being involved in the regulation of photosynthetic genes, the AppA/PpsR system alone is capable of accounting for the observed trends in photosynthetic gene expression seen at different oxygen levels. PMID- 29284489 TI - The ethical relevance of the unconscious. AB - BACKGROUND: Ethical analyses of disorders of consciousness traditionally focus on residual awareness. Going one step further, this paper explores the potential ethical relevance of the unawareness retained by patients with disorders of consciousness, focusing specifically on the ethical implications of the description of the unconscious provided by recent scientific research. METHODS: A conceptual methodology is used, based on the review and analysis of relevant scientific literature on the unconscious and the logical argumentation in favour of the ethical conclusions. RESULTS: Two conditions (experiential wellbeing and having interests) that are generally considered critical components in the ethical discussion of patients with disorders of consciousness might arguably be both conscious and unconscious. CONCLUSIONS: The unconscious, as well as consciousness, should be taken into account in the ethical discussions of patients with disorders of consciousness. PMID- 29284488 TI - Unexpected high circulation of Plasmodium vivax in asymptomatic children from Kedougou, southeastern Senegal. AB - BACKGROUND: Malaria in Senegal is due essentially to infections by Plasmodium falciparum and, to a lesser extent to Plasmodium malariae and Plasmodium ovale. By the use of molecular methods, detection of Plasmodium vivax has been recently reported in the region of Kedougou, raising the question of appraisal of its potential prevalence in this setting. METHODS: A retrospective serological study was carried out using 188 samples taken from 2010 to 2011 in a longitudinal school survey during which 48 asymptomatic children (9-11 years) were recruited. Four collections of samples collected during two successive dry and rainy seasons were analysed for antibody responses to P. vivax and P. falciparum. Recombinant P. falciparum and P. vivax MSP1 antigens and total P. falciparum schizont lysate from African 07/03 strain (adapted to culture) were used for ELISA. Nested PCR amplification was used for molecular detection of P. vivax. RESULTS: A surprising high prevalence of IgG responses against P. vivax MSP1 was evidenced with 53% of positive samples and 58% of the individuals that were found positive to this antigen. There was 77% of responders to P. falciparum outlined by 63% of positive samples. Prevalence of responders did not differ as function of seasons. Levels of antibodies to P. falciparum fluctuated with significant increasing between dry and rainy season (P < 0.05), contrary to responses to P. vivax. There was a significant reciprocal relationship (P < 10-3) between antibody responses to the different antigens, but with weak coefficient of correlation (Rho around 0.3) underlining a variable profile at the individual level. Clear molecular signature was found in positive IgG to P. vivax msp1 samples by PCR. CONCLUSION: This cross sectional longitudinal study highlights the unexpected high circulation of P. vivax in this endemic area. Sero-immunology and molecular methods are powerful additive tools to identify endemic sites where relevant control measures have to be settled and monitored. PMID- 29284487 TI - Review of Journal of Cardiovascular Magnetic Resonance (JCMR) 2015-2016 and transition of the JCMR office to Boston. AB - The Journal of Cardiovascular Magnetic Resonance (JCMR) is the official publication of the Society for Cardiovascular Magnetic Resonance (SCMR). In 2016, the JCMR published 93 manuscripts, including 80 research papers, 6 reviews, 5 technical notes, 1 protocol, and 1 case report. The number of manuscripts published was similar to 2015 though with a 12% increase in manuscript submissions to an all-time high of 369. This reflects a decrease in the overall acceptance rate to <25% (excluding solicited reviews). The quality of submissions to JCMR continues to be high. The 2016 JCMR Impact Factor (which is published in June 2016 by Thomson Reuters) was steady at 5.601 (vs. 5.71 for 2015; as published in June 2016), which is the second highest impact factor ever recorded for JCMR. The 2016 impact factor means that the JCMR papers that were published in 2014 and 2015 were on-average cited 5.71 times in 2016.In accordance with Open Access publishing of Biomed Central, the JCMR articles are published on-line in the order that they are accepted with no collating of the articles into sections or special thematic issues. For this reason, over the years, the Editors have felt that it is useful to annually summarize the publications into broad areas of interest or themes, so that readers can view areas of interest in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes with previously published JCMR papers to guide continuity of thought in the journal. In addition, I have elected to open this publication with information for the readership regarding the transition of the JCMR editorial office to the Beth Israel Deaconess Medical Center, Boston and the editorial process.Though there is an author publication charge (APC) associated with open-access to cover the publisher's expenses, this format provides a much wider distribution/availability of the author's work and greater manuscript citation. For SCMR members, there is a substantial discount in the APC. I hope that you will continue to send your high quality manuscripts to JCMR for consideration. Importantly, I also ask that you consider referencing recent JCMR publications in your submissions to the JCMR and elsewhere as these contribute to our impact factor. I also thank our dedicated Associate Editors, Guest Editors, and reviewers for their many efforts to ensure that the review process occurs in a timely and responsible manner and that the JCMR continues to be recognized as the leading publication in our field. PMID- 29284490 TI - What makes or mars the facility-based childbirth experience: thematic analysis of women's childbirth experiences in western Kenya. AB - BACKGROUND: Sub-Saharan Africa accounts for approximately 66% of global maternal deaths. Poor person-centered maternity care, which emphasizes the quality of patient experience, contributes both directly and indirectly to these poor outcomes. Yet, few studies in low resource settings have examined what is important to women during childbirth from their perspective. The aim of this study is to examine women's facility-based childbirth experiences in a rural county in Kenya, to identify aspects of care that contribute to a positive or negative birth experience. METHODS: Data are from eight focus group discussions conducted in a rural county in western Kenya in October and November 2016, with 58 mothers aged 15 to 49 years who gave birth in the preceding nine weeks. We recorded and transcribed the discussions and used a thematic approach for data analysis. RESULTS: The findings suggest four factors influence women's perceptions of quality of care: responsiveness, supportive care, dignified care, and effective communication. Women had a positive experience when they were received well at the health facility, treated with kindness and respect, and given sufficient information about their care. The reverse led to a negative experience. These experiences were influenced by the behavior of both clinical and support staff and the facility environment. CONCLUSIONS: This study extends the literature on person-centered maternity care in low resource settings. To improve person-centered maternity care, interventions need to address the responsiveness of health facilities, ensure women receive supportive and dignified care, and promote effective patient-provider communication. PMID- 29284491 TI - Dental care use in Ontario: the Canadian community health survey (CCHS). AB - BACKGROUND: Oral health is a significant measure of overall health, and regular dental visits are recommended for the maintenance of oral health. The purpose of this study is to determine the pattern (amount and type) of, and factors associated with dental care use among Ontarians. METHODS: Data from the 2014 cycle of the Canadian Community Health Survey was used and analysis was restricted to individuals aged 12 and above residing in Ontario. Dental care use was defined by two distinct outcomes: not visiting a dentist within the past year and visiting a dentist only for emergencies. Multivariable logistic regression was performed to examine the association between socio-demographic, health behavior, oral health, and other health-related factors and the two outcomes. RESULTS: More than a quarter of participants reported not visiting the dentist in the last year, and 19% reported usually visiting a dentist only for emergencies. Multivariable logistic regression analysis suggested that males, individuals of Aboriginal status, those with low educational attainment, low household income, no dental insurance, who smoked, less frequent teeth brushing, poor health of teeth and mouth, or had diabetes were at a significant increased likelihood of not visiting the dentist within the past year, and only visiting a dentist for emergency care. CONCLUSIONS: Socioeconomic status, self-reported oral health, and general health behaviors were associated with dental care use. These findings highlight the need for focusing efforts toward improving dental care use among Ontarians. PMID- 29284492 TI - Experiences and perceptions of online continuing professional development among clinicians in sub-Saharan Africa. AB - BACKGROUND: Limitations in healthcare worker (HCW) capacity compound the burden of dual TB and HIV epidemics in sub-Saharan Africa. To fill gaps in knowledge and skills, effective continuing profession development (CPD) initiatives are needed to support practicing HCWs reach high standards of care. e-learning opportunities can bring expert knowledge to HCWs in the field and provide a flexible learning option adaptable to local settings. Few studies provide insight into HCW experiences with online CPD in the developing country context. METHODS: An online survey using both close-ended and free response was conducted to HCWs in sub Saharan Africa who completed the University of Washington (UW) School of Medicine online graduate course, "Clinical Management of HIV." Associations between respondent characteristics (age, gender, rural/urban, job title) and learning preferences, course barriers, and facilitators with an emphasis on online courses were examined using chi-square. Covariates significant at the p < 0.05 were analyzed using multivariable logistic regression. Responses to open-ended comments were analyzed using simplified grounded theory. RESULTS: Of 2,299 former students, 464 (20%) HCWs completed surveys from 13 countries: about half were women. Physicians (33%), nurses (27%), and clinical officers (30%) responded mostly from urban areas (67%) and public institutions (69%). Sixty-two percent accessed the online course from work, noting that slow (55%) or limited (41%) internet as well as lack of time (53%) were barriers to course completion. Women (p < 0.001) and HCWs under age 40 (p = 0.007) were more likely to prefer learning through mentorship than men or older HCWs. Respondents favored group discussion (46%), case studies (42%), and self-paced Internet/computer-based learning (39%) and clinical mentorship (37%) when asked to choose 3 preferred learning modalities. Free-response comments offered additional positive insights into the appeal of online courses by noting the knowledge gains, the flexibility of format, a desire for recognition of course completion, and a request for additional online coursework. CONCLUSIONS: Online CPD opportunities were accepted across a diverse group of HCWs from sub-Saharan Africa and should be expanded to provide more flexible opportunities for self-initiated learning; however, these need to be responsive to the limited resources of those who seek these courses. PMID- 29284493 TI - Impact on healthcare resource utilization of multiple sclerosis in Spain. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic disease with a high socioeconomic impact. The aim of this study was to assess healthcare resources utilization and costs in a sample of patients with MS. METHODS: A retrospective, cohort study was conducted using electronic medical records from 19 primary care centres in Asturias and Catalonia, Spain. Adult patients diagnosed with MS were distributed into two groups according to the Expanded Disability Status Scale (EDSS) score: 0-3.5 (no-moderate disability) and 4-9.5 (severe disability). Healthcare (direct cost) and non-healthcare costs (work productivity losses) were analysed. An analysis of covariance (ANCOVA) was used for correction, p < 0.05. A multiple regression model was performed to obtain the variables associated with costs. RESULTS: A total of 222 patients were analyzed; mean (SD) age: 45.5 (12.5) years, 64.4% female, and 62.2% presented a diagnosis of relapsing-remitting MS. Median EDSS score was 2.5, with 68.5% of the patients with no to moderate disability. The mean annual cost per MS patient was ?25,103. For no-moderate and severe disability, the ANCOVA-adjusted mean annual cost was ?23,157 and ?29,242, respectively (p = 0.013). Direct costs and MS disease-modifying therapy accounted for 39.4% and 31.7% of the total costs, respectively. The total costs were associated with number of relapses (beta = 0.135, p = 0.001), time since diagnosis (beta = 0.281, p = 0.023), and age (beta = 0.198, p = 0.037). CONCLUSIONS: Multiple sclerosis imposes a substantial economic burden on the Spanish National Health System, patients and society as a whole. Costs significantly correlated with disease progression. PMID- 29284494 TI - Ferumoxytol enhanced black-blood cardiovascular magnetic resonance imaging. AB - BACKGROUND: Bright-blood and black-blood cardiovascular magnetic resonance (CMR) techniques are frequently employed together during a clinical exam because of their complementary features. While valuable, existing black-blood CMR approaches are flow dependent and prone to failure. We aim to assess the effectiveness and reliability of ferumoxytol enhanced (FE) Half-Fourier Single-shot Turbo Spin-echo (HASTE) imaging without magnetization preparation pulses to yield uniform intra luminal blood signal suppression by comparing FE-HASTE with pre-ferumoxytol HASTE imaging. METHODS: This study was IRB-approved and HIPAA compliant. Consecutive patients who were referred for FE-CMR between June 2013 and February 2017 were enrolled. Qualitative image scores reflecting the degree and reliability of blood signal suppression were based on a 3-point Likert scale, with 3 reflecting perfect suppression. For quantitative evaluation, homogeneity indices (defined as standard deviation of the left atrial signal intensity) and signal-to-noise ratios (SNR) for vascular lumens and cardiac chambers were measured. RESULTS: Of the 340 unique patients who underwent FE-CMR, HASTE was performed in 257. Ninety three patients had both pre-ferumoxytol HASTE and FE-HASTE, and were included in this analysis. Qualitative image scores reflecting the degree and reliability of blood signal suppression were significantly higher for FE-HASTE images (2.9 [IQR 2.8-3.0] vs 1.8 [IQR 1.6-2.1], p < 0.001). Inter-reader agreement was moderate (k = 0.50, 95% CI 0.45-0.55). Blood signal suppression was more complete on FE-HASTE images than on pre-ferumoxytol HASTE, as indicated by lower mean homogeneity indices (24.5 [IQR 18.0-32.8] vs 108.0 [IQR 65.0-170.4], p < 0.001) and lower blood pool SNR for all regions (5.6 [IQR 3.2-10.0] vs 21.5 [IQR 12.5-39.4], p < 0.001). CONCLUSION: FE-HASTE black-blood imaging offers an effective, reliable, and simple approach for flow independent blood signal suppression. The technique holds promise as a fast and routine complement to bright-blood cardiovascular imaging with ferumoxytol. PMID- 29284495 TI - Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. AB - BACKGROUND: Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity. METHODS: The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing gammaH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy). RESULTS: TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the "skin sparing effect". Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions. CONCLUSIONS: Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities. PMID- 29284496 TI - High CEA levels in a case of resected colorectal cancer: delayed diagnosis of metachronous medullary thyroid cancer. AB - BACKGROUND: Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers, and its value in the surveillance of post-operative colorectal cancer is well established. Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been clinically used in colorectal cancer imaging including preoperative staging, evaluation of therapeutic response, detection of disease recurrence, and investigation of unexplained rising tumor markers. CASE PRESENTATION: We report a case of resected colorectal cancer presented with rising CEA levels in 5 years, and FDG-PET revealed no definitive evidence of recurrence except abnormal focal FDG uptake in the right thyroid lobe. However, fine needle aspiration cytology (FNAC) of the thyroid nodule showed negative for malignancy. Progressively rising CEA levels were noted over the following 5 years, but serial follow-up examinations did not find evidence of recurrence. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed subsequently and again showed focal FDG uptake in the right thyroid lobe. This time, FNAC revealed positive for malignancy, in favor of medullary thyroid carcinoma (MTC). The patient underwent total thyroidectomy and modified radical neck dissection, and MTC with cervical nodal metastasis (pT3N1) was diagnosed. He had cervical lymph nodes recurrence 2 years later, which was resected. CONCLUSIONS: This case reminded us that FDG-PET/CT may detect occult tumors resulting in CEA elevation other than colorectal cancer. Moreover, FNA has a higher false negative rate in detecting MTC than other forms of thyroid cancer. Repeat FNAC for the initial negative cytology result and measure of serum calcitonin for the early MTC detection could be more helpful to avoid the delay in MTC diagnosis. PMID- 29284498 TI - Accelerated super-resolution imaging with FRET-PAINT. AB - Super-resolution fluorescence microscopy in the current form is hard to be used to image the neural connectivity of thick tissue samples due to problems such as slow imaging speed, severe photobleaching of fluorescent probes, and high background noise. Recently developed DNA-PAINT solved the photobleaching problem, but its imaging speed is extremely low. We report accelerated super-resolution fluorescence microscopy named FRET-PAINT. Compared to conventional DNA-PAINT, the imaging speed of the microscopy increases up to ~30-fold. As demonstrations, we show that 25-50 second imaging time is long enough to provide super-resolution reconstruction of microtubules and mitochondria of COS-7 cells. PMID- 29284499 TI - Left Atrial structure and function in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. AB - BACKGROUND: Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH). METHOD: Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15). RESULTS: LA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 +/- 8%) and overt HCM (59 +/- 10%), compared with controls (70 +/- 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 +/- 11%) compared with controls (47 +/- 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both). CONCLUSION: LA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis. PMID- 29284497 TI - Intergenic disease-associated regions are abundant in novel transcripts. AB - BACKGROUND: Genotyping of large populations through genome-wide association studies (GWAS) has successfully identified many genomic variants associated with traits or disease risk. Unexpectedly, a large proportion of GWAS single nucleotide polymorphisms (SNPs) and associated haplotype blocks are in intronic and intergenic regions, hindering their functional evaluation. While some of these risk-susceptibility regions encompass cis-regulatory sites, their transcriptional potential has never been systematically explored. RESULTS: To detect rare tissue-specific expression, we employed the transcript-enrichment method CaptureSeq on 21 human tissues to identify 1775 multi-exonic transcripts from 561 intronic and intergenic haploblocks associated with 392 traits and diseases, covering 73.9 Mb (2.2%) of the human genome. We show that a large proportion (85%) of disease-associated haploblocks express novel multi-exonic non coding transcripts that are tissue-specific and enriched for GWAS SNPs as well as epigenetic markers of active transcription and enhancer activity. Similarly, we captured transcriptomes from 13 melanomas, targeting nine melanoma-associated haploblocks, and characterized 31 novel melanoma-specific transcripts that include fusion proteins, novel exons and non-coding RNAs, one-third of which showed allelically imbalanced expression. CONCLUSIONS: This resource of previously unreported transcripts in disease-associated regions ( http://gwas captureseq.dingerlab.org ) should provide an important starting point for the translational community in search of novel biomarkers, disease mechanisms, and drug targets. PMID- 29284500 TI - Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment. AB - BACKGROUND: Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. METHODS: Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 MUL samples using a 'proximity extension assay' (PEA) based immunoassay. Since Transforming growth factor beta (TGF-beta) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA. RESULTS: In CFS/ME patients, the 'normalized protein expression' value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-beta did not differ between patients and controls. CONCLUSIONS: In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014. PMID- 29284501 TI - Nucleoli cytomorphology in cutaneous melanoma cells - a new prognostic approach to an old concept. AB - BACKGROUND: The nucleolus is an organelle that is an ultrastructural element of the cell nucleus observed in H&E staining as a roundish body stained with eosin due to its high protein content. Changes in the nucleoli cytomorphology were one of the first histopathological characteristics of malignant tumors. The aim of this study was to assess the relationship between the cytomorphological characteristics of nucleoli and detailed clinicopathological parameters of melanoma patients. Moreover, we analyzed the correlation between cytomorphological parameters of nucleoli and immunoreactivity of selected proteins responsible for, among others, regulation of epithelial-mesenchymal transition (SPARC, N-cadherin), cell adhesion and motility (ALCAM, ADAM-10), mitotic divisions (PLK1), cellular survival (FOXP1) and the functioning of Golgi apparatus (GOLPH3, GP73). METHODS: Three characteristics of nucleoli - presence, size and number - of cancer cells were assessed in H&E-stained slides of 96 formalin-fixed paraffin-embedded primary cutaneous melanoma tissue specimens. The results were correlated with classical clinicopathological features and patient survival. Immunohistochemical analysis of the above mentioned proteins was described in details in previous studies. RESULTS: Higher prevalence and size of nucleoli were associated with thicker and mitogenic tumors. All three nucleolar characteristics were related to the presence of ulceration. Moreover, microsatellitosis was strongly correlated with the presence of macronucleoli and polynucleolization (presence of two or more nucleoli). Lack of immunologic response manifested as no TILs in primary tumor was associated with high prevalence of melanoma cells with distinct nucleoli. Interestingly, in nodular melanoma a higher percentage of melanoma cells with prominent nucleoli was observed. In Kaplan-Meier analysis, increased prevalence and amount, but not size of nucleoli, were connected with shorter cancer-specific and disease-free survival. CONCLUSION: (1) High representation of cancer cells with distinct nucleoli, greater size and number of nucleoli per cell are characteristics of aggressive phenotype of melanoma; (2) higher prevalence and size of nucleoli are potential measures of cell kinetics that are strictly correlated with high mitotic rate; and (3) high prevalence of cancer cells with distinct nucleoli and presence of melanocytes with multiple nucleoli are features associated with unfavorable prognosis in patients with cutaneous melanoma. PMID- 29284502 TI - Reciprocal interactions between prostaglandin E2- and estradiol-dependent signaling pathways in the injured zebra finch brain. AB - BACKGROUND: Astrocytic aromatization and consequent increases in estradiol are neuroprotective in the injured brain. In zebra finches, cyclooxygenase-activity is necessary for injury-induced aromatase expression, and increased central estradiol lowers neuroinflammation. The mechanisms underlying these influences are unknown. Here, we document injury-induced, cyclooxygenase-dependent increases in glial aromatase expression and replicate previous work in our lab showing increases in central prostaglandin E2 and estradiol following brain damage. Further, we describe injury-dependent changes in E-prostanoid and estrogen receptor expression and reveal the necessity of E-prostanoid and estrogen receptors in the injury-dependent, reciprocal interactions of neuroinflammatory and neurosteroidogenic pathways. METHODS: Adult male and female birds were shams or received bilateral injections of the appropriate drug or vehicle into contralateral telencephalic lobes. RESULTS: Injuries sustained in the presence of indomethacin (a cyclooxygenase inhibitor) had fewer aromatase-expressing reactive astrocytes relative to injuries injected with vehicle suggesting that cyclooxygenase activity is necessary for the induction of glial aromatase around the site of damage. Injured hemispheres had higher prostaglandin E2 and estradiol content relative to shams. Importantly, injured hemispheres injected with E prostanoid- or estrogen receptor-antagonists showed elevated prostaglandin E2 and estradiol, respectively, but lower prostaglandin E2 or estradiol-dependent downstream activity (protein kinase A or phosphoinositide-3-kinase mRNA) suggesting that receptor antagonism did not affect injury-induced prostaglandin E2 or estradiol, but inhibited the effects of these ligands. Antagonism of E prostanoid receptors 3 or 4 prevented injury-induced increases in neural estradiol in males and females, respectively, albeit this apparent sex-difference needs to be tested more stringently. Further, estrogen receptor-alpha, but not estrogen receptor-beta antagonism, exaggerated neural prostaglandin E2 levels relative to the contralateral lobe in both sexes. CONCLUSION: These data suggest injury-induced, sex-specific prostaglandin E2-dependent estradiol synthesis, and estrogen receptor-alpha dependent decreases in neuroinflammation in the vertebrate brain. PMID- 29284503 TI - Bronchoscopy versus an endotracheal tube mounted camera for the peri interventional visualization of percutaneous dilatational tracheostomy - a prospective, randomized trial (VivaPDT). AB - BACKGROUND: Percutaneous dilatational tracheostomy (PDT) in critically ill patients often involves bronchoscopic optical guidance. However, this procedure is not without disadvantages. Therefore, we aimed to study a recently introduced endotracheal tube-mounted camera (VivaSightTM-SL tube [VST]; ETView, Misgav, Israel) for guiding PDT. METHODS: This was a randomized controlled trial involving 46 critically ill patients who received PDT using optical guidance with a VST or with bronchoscopy. The primary outcome measure was visualization of the tracheal structures (i.e., identification and monitoring of the thyroid, cricoid, and tracheal cartilage and the posterior wall) rated on 4-point Likert scales. Secondary measures were the quality of ventilation (before puncture and during the tracheostomy procedure rated on 4-point Likert scales) and blood gases sampled at standardized time points. RESULTS: The mean ratings for visualization (lower values better; values given for per-protocol analysis) were 5.4 (95% CI 4.5-6.3) for the VST group and 4.0 (95% CI 4.0-4.0) for the bronchoscopy group (p < 0.001). Mean ventilation ratings were 2.5 (95% CI 2.1-2.9) for VST and 5.0 (95% CI 4.4-5.7) for bronchoscopy (p < 0.001). Arterial carbon dioxide increased to 5.9 (95% CI 5.4-6.5) kPa in the VST group vs. 8.3 (95% CI 7.2-9.5) kPa in the bronchoscopy group (p < 0.001), and pH decreased to 7.40 (95% CI 7.36-7.43) in the VST group vs. 7.26 (95% CI 7.22-7.30) in the bronchoscopy group (p < 0.001), at the end of the intervention. CONCLUSIONS: Visualization of PDT with the VST is not noninferior to guidance by bronchoscopy. Ventilation is superior with less hypercarbia with the VST. Because visualization is not a prerequisite for PDT, patients requiring stable ventilation with normocarbia may benefit from PDT with the VST. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02861001 . Registered on 13 June 2016. PMID- 29284504 TI - Self-help and help-seeking for communication disability in Ghana: implications for the development of communication disability rehabilitation services. AB - BACKGROUND: In low and middle-income countries, such as Ghana, communication disability is poorly recognised and rehabilitation services for people with communication disability are limited. As rehabilitation services for communication disability develop, and the profession of speech-language pathology grows, it is important to consider how services can most appropriately respond to the needs and preferences of the community. Understanding the ways in which people currently self-help and seek help for communication disability is central to developing services that build on existing local practices and are relevant to the community. METHODS: A qualitative descriptive survey was used to explore likely self-help and help-seeking behaviours for communication disability, in Accra, Ghana. The survey required participants to describe responses to hypothetical scenarios related to communication disability. A mix of theoretical sampling and convenience sampling was used. Qualitative content analysis was used to analyse data and develop categories and subcategories of reported self-help behaviours and sources of help and advice for communication disability. RESULTS: One hundred and thirty-six participants completed the survey. Results indicated that community members would be likely to engage in a variety self-help strategies in response to communication disability. These included working directly with a person with a communication disability to attempt to remediate a communication impairment, altering physical and communication environments, changing attitudes or care practices, educating themselves about the communication disability, providing resources, and responding in spiritual ways. Participants indicated that they would seek help for communication disability across a range of sectors - including the Western healthcare, religious, and traditional sectors. CONCLUSIONS: Understanding existing community actions to self-help and help-seek may allow emerging communication rehabilitation services, including the profession of speech-language pathology, to build on existing community practices in resource-limited contexts such as Ghana. PMID- 29284505 TI - Factors related to healthy sexual and contraceptive behaviors in undergraduate students at university of Seville: a cross- sectional study. AB - BACKGROUND: Young people are a group of population with sexual risk-taking behaviors. Despite efforts to inform them it is common for them to adopt risk conducts during their stay at University. The aim of this research was to assess knowledge, attitudes and experiences on sexual health and contraceptives and factors related to risk behaviors in university students. METHODS: A cross- sectional analytical study was carried out from February to April 2014 among undergraduate students at University of Seville. A self-administered questionnaire was filled in by participants. Data analysis was performed using SPSS V22. Descriptive statistics were used to show data. A P-value of 5% (two tailed) was considered statistically significant. RESULTS: A total of 566 students responded to the questionnaire. 47.3% (267) were male and 52.6% (297) female. About sexual behavior: 93.3% of participants were sexually active last year. 58.3% had had sex under alcohol effect and 18% under drugs effect. About contraceptive behavior: 86.9% used a contraceptive method during their first sexual relation, the male condom being the most used (90.6%). Currently, the most used contraceptives are the male condom, and hormonal pills. The participants' answers about their knowledge on contraceptives and STIs (sexual transmission infections) showed weaknesses. Participants who had received sexual and contraceptive education showed more knowledge (p < 0.001). We did not find differences about knowledge on contraceptives and STIs by age (p = 0.056). Level of knowledge is less in young people who use coitus interruptus or none as a contraceptive method (p < 0.001). We observed differences by frequency of sex since young people who had sex more frequently showed more knowledge about contraceptives and STI (p < 0.001). There are more women that had a partner than men (p = 0.003) and their attitudes and experiences on sex are healthier. Females showed more knowledge about management of hormonal contraceptives and medical controls (p < 0.001). CONCLUSION: Factors that contribute to having a healthier behavior on sexuality and contraception are age, gender and background in health issues, showing greater knowledge and less risky behavior. Programing reproductive health programs at university should be continued. PMID- 29284506 TI - The long-term effects of adolescent pregnancies in a community in Northern Ghana on subsequent pregnancies and births of the young mothers. AB - BACKGROUND: In Ghana, adolescents represent 22% of the total population. The rates of adolescent pregnancies are high. Of all births registered in the country in 2014, 30% were by adolescents, and 14% of adolescents aged between 15 and 19 years had begun childbearing. Pregnancies and deliveries of adolescents are accompanied by more risks as compared to older women. The aim of the study was to explore the long-term effects of adolescent pregnancies on subsequent pregnancies and births and on the socioeconomic status of the women. METHOD: A cross sectional interviewer-performed survey of a purposive sample of 400 women in one community of Northern Ghana was conducted. Relationships between the age at first pregnancy and complications such as cesarean section, preterm or stillbirth and others were explored in 143 patients using the statistical program SPSS (Statistical Package for the Social Sciences). RESULT: Results show that adolescent women (<19 years at their first pregnancy) have an 80% higher risk for a cesarean section for the first and subsequent births as compared to older women (>= 19 years). Furthermore, younger mothers have a 45% higher risk of stillbirths and a 30% increased risk of losing their baby within the first 6 weeks after birth. There was no difference in the socioeconomic status between the two age groups. CONCLUSION: Adolescent pregnancies are risk factors for the outcome of subsequent pregnancies of these mothers. This study, for the first time, shows that not only the first pregnancy and birth of very young women are negatively influenced by the early pregnancy but also subsequent pregnancies and births. While this study is of a purposive sample of women in one community, the clinical relevance of this study should not only be interesting for healthcare practitioners in Northern Ghana and other African regions but also for prevention campaigns in these regions. PMID- 29284507 TI - A pediatric disease to keep in mind: diagnostic tools and management of bronchiectasis in pediatric age. AB - Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.The most common medical conditions leading to bronchial damage are previous pneumonia and recurrent lower airway infections followed by underlying diseases such as immune-deficiencies, congenital airway defects, recurrent aspirations and mucociliary clearance disorders.The most frequent symptom is chronic wet cough. The introduction of high-resolution computed tomography (HRCT) has improved the time of diagnosis allowing earlier treatment.However, the term "bronchiectasis" in pediatric age should be used with caution, since some lesions highlighted with HRCT may improve or regress. The use of chest magnetic resonance imaging (MRI) as a radiation-free technique for the assessment and follow-up of lung abnormalities in non-Cystic Fibrosis chronic lung disease is promising.Non-Cystic Fibrosis Bronchiectasis management needs a multi-disciplinary team. Antibiotics and airway clearance techniques (ACT) represent the pillars of treatment even though guidelines in children are lacking. The Azithromycin thanks to its antinflammatory and direct antimicrobial effect could be a new strategy to prevent exacerbations. PMID- 29284508 TI - Inflammatory dysregulation of monocytes in pediatric patients with obsessive compulsive disorder. AB - BACKGROUND: Although the exact etiology of obsessive-compulsive disorder (OCD) is unknown, there is growing evidence of a role for immune dysregulation in the pathophysiology of the disease, especially in the innate immune system including the microglia. To test this hypothesis, we studied inflammatory markers in monocytes from pediatric patients with OCD and from healthy controls. METHODS: We determined the percentages of total monocytes, CD16+ monocytes, and classical (CD14highCD16-), intermediate (CD14highCD16low), and non-classical (CD14lowCD16high) monocyte subsets in 102 patients with early-onset OCD and in 47 healthy controls. Moreover, proinflammatory cytokine production (GM-CSF, IL 1beta, IL-6, IL-8, and TNF-alpha) was measured by multiplex Luminex analysis in isolated monocyte cultures, in basal conditions, after exposure to lipopolysaccharide (LPS) to stimulate immune response or after exposure to LPS and the immunosuppressant dexamethasone. RESULTS: OCD patients had significantly higher percentages of total monocytes and CD16+ monocytes than healthy controls, mainly due to an increase in the intermediate subset but also in the non classical monocytes. Monocytes from OCD patients released higher amounts of GM CSF, IL-1beta, IL-6, IL-8, and TNF-alpha than healthy controls after exposure to LPS. However, there were no significant differences in basal cytokine production or the sensitivity of monocytes to dexamethasone treatment between both groups. Based on monocyte subset distribution and cytokine production after LPS stimulation, patients receiving psychoactive medications seem to have an intermediate inflammatory profile, that is, lower than non-medicated OCD individuals and higher than healthy controls. CONCLUSIONS: These results strongly support the involvement of an enhanced proinflammatory innate immune response in the etiopathogenesis of early-onset OCD. PMID- 29284509 TI - Should high risk patients with concomitant severe aortic stenosis and mitral valve disease undergo double valve surgery in the TAVR era? AB - BACKGROUND: Significant mitral regurgitation in patients undergoing transcatheter aortic valve replacement (TAVR) is associated with increased mortality. The aim of this study is to determine if surgical correction of both aortic and mitral valves in high risk patients with concomitant valvular disease would offer patients better outcomes than TAVR alone. METHODS: A retrospective analysis of 43 high-risk patients who underwent concomitant surgical aortic valve replacement and mitral valve surgery from 2008 to 2012 was performed. Immediate and long term survival were assessed. RESULTS: There were 43 high-risk patients with severe aortic stenosis undergoing concomitant surgical aortic valve replacement and mitral valve surgery. The average age was 80 +/- 6 years old. Nineteen (44%) patients had prior cardiac surgery, 15 (34.9%) patients had chronic obstructive lung disease, and 39 (91%) patients were in congestive heart failure. The mean Society of Thoracic Surgeons Predicted Risk of Mortality for isolated surgical aortic valve replacement for the cohort was 10.1% +/- 6.4%. Five patients (11.6%) died during the index admission and/or within thirty days of surgery. Mortality rate was 25% at six months, 35% at 1 year and 45% at 2 years. There was no correlation between individual preoperative risk factors and mortality. CONCLUSIONS: High-risk patients with severe aortic stenosis and mitral valve disease undergoing concomitant surgical aortic valve replacement and mitral valve surgery may have similar long term survival as that described for such patients undergoing TAVR. Surgical correction of double valvular disease in this patient population may not confer mortality benefit compared to TAVR alone. PMID- 29284510 TI - The NAPRESSIM trial: the use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine in elective hepatobiliary surgery: a study protocol and statistical analysis plan for a randomised controlled trial. AB - BACKGROUND: Intrathecally administered morphine is effective as part of a postoperative analgesia regimen following major hepatopancreaticobiliary surgery. However, the potential for postoperative respiratory depression at the doses required for effective analgesia currently limits its clinical use. The use of a low-dose, prophylactic naloxone infusion following intrathecally administered morphine may significantly reduce postoperative respiratory depression. The NAPRESSIM trial aims to answer this question. METHODS/DESIGN: 'The use of low dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine' trial is an investigator-led, single-centre, randomised, double-blind, placebo-controlled, double-arm comparator study. The trial will recruit 96 patients aged > 18 years, undergoing major open hepatopancreaticobiliary resections, who are receiving intrathecally administered morphine as part of a standard anaesthetic regimen. It aims to investigate whether the prophylactic administration of naloxone via intravenous infusion compared to placebo will reduce the proportion of episodes of respiratory depression in this cohort of patients. Trial patients will receive an infusion of naloxone or placebo, commenced within 1 h of postoperative extubation continued until the first postoperative morning. The primary outcome is the rate of respiratory depression in the intervention group as compared to the placebo group. Secondary outcomes include pain scores, rates of nausea and vomiting, pruritus, sedation scores and adverse outcomes. We will also employ a novel, non invasive, respiratory minute volume monitor (ExSpiron 1Xi, Respiratory Motion, Inc., 411 Waverley Oaks Road, Building 1, Suite 150, Waltham, MA, USA) to assess the monitor's accuracy for detecting respiratory depression. DISCUSSION: The trial aims to provide a clear management plan to prevent respiratory depression after the intrathecal administration of morphine, and thereby improve patient safety. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02885948 . Registered retrospectively on 4 July 2016. Protocol Version 2.0, 3 April 2017. Protocol identification (code or reference number): UCDCRC/15/006 EudraCT registration number: 2015-003504-22. Registered on 5 August 2015. PMID- 29284511 TI - Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number. AB - BACKGROUND: Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer specific survival (LCSS). METHODS: Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation. RESULTS: OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n <= 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n <= 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n <= 3). CONCLUSIONS: In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n <= 3). PMID- 29284512 TI - Quantifying the learning curve for pulmonary thromboendarterectomy. AB - BACKGROUND: Pulmonary thromboendarterectomy (PTE) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but is a technically challenging operation for cardiothoracic surgeons. Starting a new program allows an opportunity to define a learning curve for PTE. METHODS: A retrospective case review was performed of 134 consecutive PTEs performed from 1998 to 2016 at a single institution. Outcomes were compared using either a two-tailed t-test for continuous variables or a chi-squared test for categorical variables according to experience of the program by terciles (T). RESULTS: The 30-day mortality was 3.7%. The mean length of hospital stay, length of ICU stay, and duration on a ventilator were 12.6 days, 4.6 days, and 2.0 days, respectively. The mean decrease in systolic pulmonary artery pressure (sPAP) was 41.3 mmHg. Patients with Jamieson type 2 disease had a greater change in mean sPAP than those with type 3 disease (p = 0.039). The mean cardiopulmonary bypass time was 180 min (T1 198 min, T3-159 min, p = <0.001), and the mean circulatory arrest time was 37 min (T1-44 min, T3-31 min, p < 0.001). Plotting circulatory arrest times as a running sum compared to the mean demonstrated 2 inflection points, the first at 22 cases and the second at 95 cases. CONCLUSIONS: PTE is a challenging procedure to learn, and good outcomes are a result of a multi-disciplinary effort to optimize case selection, operative performance, and postoperative care. Approximately 20 cases are needed to become proficient in PTE, and nearly 100 cases are required for more efficient clearing of obstructed pulmonary arteries. PMID- 29284513 TI - Xeno- and feeder-free differentiation of human pluripotent stem cells to two distinct ocular epithelial cell types using simple modifications of one method. AB - BACKGROUND: Human pluripotent stem cells (hPSCs) provide a promising cell source for ocular cell replacement therapy, but often lack standardized and xenogeneic free culture and differentiation protocols. We aimed to develop a xeno- and feeder cell-free culture system for undifferentiated hPSCs along with efficient methods to derive ocular therapy target cells: retinal pigment epithelial (RPE) cells and corneal limbal epithelial stem cells (LESCs). METHODS: Multiple genetically distinct hPSC lines were adapted to a defined, xeno-, and feeder-free culture system of Essential 8TM medium and laminin-521 matrix. Thereafter, two stage differentiation methods toward ocular epithelial cells were established utilizing xeno-free media and a combination of extracellular matrix proteins. Both differentiation methods shared the same basal elements, using only minor inductive modifications during early differentiation towards desired cell lineages. The resulting RPE cells and LESCs were characterized after several independent differentiation experiments and recovery after xeno-free cryopreservation. RESULTS: The defined, xeno-, and feeder-free culture system provided a robust means to generate high-quality hPSCs with chromosomal stability limited to early passages. Inductive cues introduced during the first week of differentiation had a substantial effect on lineage specification, cell survival, and even mature RPE properties. Derivative RPE formed functional epithelial monolayers with mature tight junctions and expression of RPE genes and proteins, as well as phagocytosis and key growth factor secretion capacity after 9 weeks of maturation on inserts. Efficient LESC differentiation led to cell populations expressing LESC markers such as p40/p63alpha by day 24. Finally, we established xeno-free cryobanking protocols for pluripotent hPSCs, hPSC-RPE cells, and hPSC LESCs, and demonstrated successful recovery after thawing. CONCLUSIONS: We propose methods for efficient and scalable, directed differentiation of high quality RPE cells and LESCs. The two clinically relevant cell types are generated with simple inductive modification of the same basal method, followed by adherent culture, passaging, and cryobanking. PMID- 29284514 TI - 2-methyl butyramide, a previously identified urine biomarker for Ascaris lumbricoides, is not present in infected Indonesian individuals. AB - : ?: Previous reports suggest that the 2-methyl butyramide and 2-methyl valeramide metabolites of Ascaris lumbricoides in urine of infected individuals could be considered as urinary biomarkers for active infection. We have developed an LC-MS method with a detection limit of 10 ng/mL using synthetic chemicals as reference material. Urine samples (n = 21) of infected individuals were analyzed for the presence of these metabolites, but they were not detected in any of the samples. Furthermore, the recorded 1H-NMR spectrum for reference 2-methyl butyramide did not match with the spectrum that was described for the Ascaris metabolite. Based on these two observations, we concluded that the urinary biomarkers that were detected for A. lumbricoides infection are not 2-methyl butyramide nor 2-methylvaleramide. New discovery efforts will be required to identify the structure of these metabolite biomarkers in urine of infected individuals. TRIAL REGISTRATION: Urine samples used in this study were collected as part of a clinical trial with trial number ISRCTN75636394 (12 November 2013). PMID- 29284516 TI - Lack of SOCS3 increases LPS-induced murine acute lung injury through modulation of Ly6C(+) macrophages. AB - BACKGROUND: SOCS3 (suppressor of cytokine signaling 3) is a negative regulator of JAK/STAT3 signaling pathway and participates in the regulation of lung inflammation in a mouse model with acute lung injury (ALI). However, it is not well understood how SOCS3 regulates lung inflammation in the ALI mouse model. METHOD: In the present study, we investigated the effects of SOCS3 on modulation of Ly6C(+) monocyte phenotypes in a mouse model with lipopolysaccharide (LPS) induced ALI. Conditional SOCS3(Lyz2cre) mice with myeloid cell-restricted depletion of SOCS3 gene were created by breeding transgenic Lyz2Cre mice with SOCS3(fl/fl) mice. Wilde-type (WT) and SOCS3(Lyz2cre) mice were intratracheal instilled with 5 mg/kg LPS for 2 days. Lung, bronchoalveolar lavage (BAL) and blood were collected for analysis by flow cytometry, ELISA, qRT-PCR and Western blot analysis. RESULTS: The studies in the ALI mouse model revealed that myeloid cell-restricted SOCS3 deficiency exacerbated the severity of ALI as compared to the WT mice. The increased severity of ALI in SOCS3-deficient mice was associated with higher populations of neutrophils, T lymphocytes and Ly6C(+) monocytes in the inflamed lung tissues. In addition, CCR2 and CXCL15 were elevated, and accompanied by greater expression and activation of STAT3 in the lung of SOCS3 deficient mice. SOCS3-deficient bone marrow-derived macrophages (BMDMs) expressed a higher amount of TNF-alpha, and adoptive transfer of the SOCS3-deficient Ly6C(+) BMDMs into WT mice enhanced the severity of ALI than adoptive transfer of WT control BMDMs. However, depletion of Ly6C(+) circulating monocytes by anti Ly6C(+) neutralizing antibody moderately attenuated neutrophil infiltration and resulted in lower prevalence of Ly6C(+) cells in the lung of treated mice. CONCLUSION: Myeloid cell-restricted lack of SOCS3 induced more severe ALI through modulation of Ly6C(+) subtype macrophages. The results provide insight into a new role of SOCS3 in modulation of Ly6C(+) monocyte phenotypes and provide a novel therapeutic strategy for ALI by molecular intervention of macrophages subtypes. PMID- 29284515 TI - Adaptation of Arabidopsis thaliana to the Yangtze River basin. AB - BACKGROUND: Organisms need to adapt to keep pace with a changing environment. Examining recent range expansion aids our understanding of how organisms evolve to overcome environmental constraints. However, how organisms adapt to climate changes is a crucial biological question that is still largely unanswered. The plant Arabidopsis thaliana is an excellent system to study this fundamental question. Its origin is in the Iberian Peninsula and North Africa, but it has spread to the Far East, including the most south-eastern edge of its native habitats, the Yangtze River basin, where the climate is very different. RESULTS: We sequenced 118 A. thaliana strains from the region surrounding the Yangtze River basin. We found that the Yangtze River basin population is a unique population and diverged about 61,409 years ago, with gene flows occurring at two different time points, followed by a population dispersion into the Yangtze River basin in the last few thousands of years. Positive selection analyses revealed that biological regulation processes, such as flowering time, immune and defense response processes could be correlated with the adaptation event. In particular, we found that the flowering time gene SVP has contributed to A. thaliana adaptation to the Yangtze River basin based on genetic mapping. CONCLUSIONS: A. thaliana adapted to the Yangtze River basin habitat by promoting the onset of flowering, a finding that sheds light on how a species can adapt to locales with very different climates. PMID- 29284517 TI - Updates and reflections about the IJHPR, on the eve of its seventh year. AB - The Israel Journal of Health Policy Research (IJHPR) will soon be completing 6 years of publication. During this period, it has published well over 300 articles and has become a stable and vital part of Israeli health care. The number of IJHPR articles published annually has increased significantly over time, and the number of submissions has increased even more significantly. The journal is regularly drawing submissions from a very broad range of Israeli universities, hospitals, health plans, and other institutions, and from leading institutions abroad. The journal's articles cover a wide spectrum of subjects related to health policy, as reflected in the diversity of the article collections that the journal has launched to date. True to its mission statement, the IJHPR is promoting "intensive intellectual interactions among scholars and practitioners from Israel and other countries regarding all aspects of health policy".The journal has been indexed in all of the leading international academic databases and its current impact factor (1.36) puts it in the third quartile in two key Web of Science subject categories. Several IJHPR articles have been accessed over 10,000 times and the IJHPR has become the predominant vehicle in which Israeli scholars are publishing articles with a health policy orientation. IJHPR articles are also figuring prominently in many course syllabi in Israel, and Israeli universities have incorporated IJHPR publications into assessments of faculty members for promotion. The journal's success and progress are a part of a larger trend of greater reliance on data and analysis in health policymaking in Israel and the increasing prominence of health in the Israeli policy agenda and public discourse.During the journal's seventh year, its editors will be carrying out a serious assessment of the challenges and opportunities ahead and developing an updated plan for the journal's development. In doing so, they will draw on data presented in this editorial as well as on in-depth discussions with those who have contributed to the journal's success to date: it publisher, sponsor, and editorial board members, as well as a sample of authors, reviewers and readers. The expectation is that, by working together, it will be possible to take the journal to new heights. PMID- 29284519 TI - Self-efficacy moderates the relationship between health comparisons and social exclusion: results of the German ageing survey. AB - BACKGROUND: Little is known about the consequences of health comparisons. Negative health comparisons might, for example, result in emotions such as anger or frustration. These negative emotions might intensify feelings of social exclusion. Thus, the objective of the current study was to investigate whether health comparisons are associated with social exclusion. Moreover, it was examined whether the relation between health comparisons and social exclusion is moderated by self-efficacy. METHODS: We analyzed cross-sectional data of N = 7838 individuals from the German Ageing Survey. The German Ageing Survey is a representative sample of community-residing individuals aged 40 and over. An established social exclusion scale was used. The degree of self-efficacy was measured according to Schwarzer and Jerusalem. Health comparisons were measured with the question "How would you rate your health compared with other people your age" (Much better; somewhat better; the same; somewhat worse, much worse). RESULTS: Multiple linear regressions revealed that negative health comparisons were associated with feelings of social exclusion in men, but not women. Furthermore, positive health comparisons were weakly associated with decreased feelings of social exclusion in men. The association between negative as well as positive health comparisons and social exclusion in men was significantly moderated by self-efficacy. CONCLUSIONS: The findings of the present study suggests that negative health comparisons are associated with feelings of social exclusion in men. In conclusion, comparison effects are not symmetric and predominantly upwards among men in the second half of life. Strengthening self efficacy might be fruitful for attenuating this relationship. PMID- 29284518 TI - DE-kupl: exhaustive capture of biological variation in RNA-seq data through k-mer decomposition. AB - We introduce a k-mer-based computational protocol, DE-kupl, for capturing local RNA variation in a set of RNA-seq libraries, independently of a reference genome or transcriptome. DE-kupl extracts all k-mers with differential abundance directly from the raw data files. This enables the retrieval of virtually all variation present in an RNA-seq data set. This variation is subsequently assigned to biological events or entities such as differential long non-coding RNAs, splice and polyadenylation variants, introns, repeats, editing or mutation events, and exogenous RNA. Applying DE-kupl to human RNA-seq data sets identified multiple types of novel events, reproducibly across independent RNA-seq experiments. PMID- 29284520 TI - Chinese herbal medicine TangBi Formula treatment of patients with type 2 diabetic distal symmetric polyneuropathy disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Diabetic distal symmetric polyneuropathy (DSPN) is one of the most common microvascular complications of diabetes mellitus, and it has become a major public health problem worldwide because of its high and increasing prevalence, morbidity, and disability rate. The current medications for DSPN are not entirely satisfactory. Preliminary studies indicated that the Chinese herbal TangBi Formula may alleviate signs and symptoms and improve the velocity of nerve conduction in patients with DSPN. This study was designed to determine if Chinese herbal medicine used in combination with conventional treatment is more effective than conventional treatment alone. METHODS/DESIGN: We are conducting a multicenter, placebo-controlled, double-blind, randomized, controlled clinical trial as a means of assessing the therapeutic effects of traditional Chinese medicine (TCM) treatment. A total of 188 patients will be randomized in a 1:1 ratio to a treatment group (TangBi Formula plus mecobalamin) and a control group (placebo plus mecobalamin). The test period lasts 6 months, during which all of the patients will be given standard medical care as recommended by established guidelines. The primary outcome will be development of differences in changes in clinical symptoms and signs in patients and changes in Michigan Diabetic Neuropathy Score (MDNS) between the two groups before and after treatment. The secondary outcome will be changes in nerve conduction velocity and in single clinical signs and symptoms. Safety assessments and adverse events will also be evaluated. DISCUSSION: We postulate that patients with DSPN will benefit from therapy that includes TCM. If successful, this work will provide an evidence based complementary therapeutic approach for treatment of DSPN. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03010241 . Registered on 2 January 2017. PMID- 29284521 TI - Exercise intervention for unilateral amputees with low back pain: study protocol for a randomised, controlled trial. AB - BACKGROUND: Atraumatic lower limb amputation is a life-changing event for approximately 185,000 persons in the United States each year. A unilateral amputation is associated with rapid changes to the musculoskeletal system including leg and back muscle atrophy, strength loss, gait asymmetries, differential mechanical joint loading and leg length discrepancies. Even with high-quality medical care and prostheses, amputees still develop secondary musculoskeletal conditions such as chronic low back pain (LBP). Resistance training interventions that focus on core stabilization, lumbar strength and dynamic stability during loading have strong potential to reduce LBP and address amputation-related changes to the musculoskeletal system. Home-based resistance exercise programs may be attractive to patients to minimize travel and financial burdens. METHODS/DESIGN: This study will be a single-assessor-blinded, pre-post test randomised controlled trial involving 40 men and women aged 18-60 years with traumatic, unilateral transtibial amputation. Participants will be randomised to a home-based, resistance exercise group (HBRX) or a wait-list control group (CON). The HBRX will consist of 12 weeks of elastic resistance band and bodyweight training to improve core and lumbopelvic strength. Participants will be monitored via Skype or Facetime on a weekly basis. The primary outcome will be pain severity (11-point Numerical Pain Rating Scale; NRSpain). Secondary outcomes will include pain impact on quality of life (Medical Outcomes Short Form 36, Oswestry Disability Index and Roland Morris Disability Questionnaire), kinematics and kinetics of walking gait on an instrumented treadmill, muscle morphology (muscle thickness of multifidus, transversus abdominis, internal oblique), maximal muscle strength of key lumbar and core muscles, and daily step count. DISCUSSION: The study findings will determine whether a HBRX program can decrease pain severity and positively impact several physiological and mechanical factors that contribute to back pain in unilateral transtibial amputees with chronic LBP. We will determine the relative contribution of the exercise-induced changes in these factors on pain responsiveness in this population. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03300375 . Registered on 2 October 2017. PMID- 29284523 TI - Development of a core outcome set for studies involving patients undergoing major lower limb amputation for peripheral arterial disease: study protocol for a systematic review and identification of a core outcome set using a Delphi survey. AB - BACKGROUND: The development of a standardised reporting set is important to ensure that research is directed towards the most important outcomes and that data is comparable. To ensure validity, the set must be agreed by a consensus of stakeholders including patients, healthcare professionals and lay representatives. There is currently no agreed core outcome set for patients undergoing major lower limb amputation for peripheral arterial disease (PAD) for either short- or medium-term research outcomes. By developing these sets we aim to rationalise future trial outcomes, facilitate meta-analysis and improve the quality and applicability of amputation research. METHODS/DESIGN: We will undertake a comprehensive systematic review of studies of patients undergoing major lower limb amputation for PAD. Data regarding all primary and secondary outcomes reported in relevant studies will be extracted and summarised as outcome domains. We will then undertake focus groups with key stakeholders (patients, carers, health and social care workers) to collect qualitative data to identify the main short- and medium-term research outcomes for patients undergoing major lower limb amputation. Results of the systematic review and focus groups will be combined to create a comprehensive list of potential key outcomes. Stakeholders (patients, researchers and health and social care workers) will then be polled to determine which of the outcomes are considered to be important in a general context using a three-phase Delphi process. After preliminary analysis, results will be presented at a face-to-face meeting of key stakeholders for discussion and voting on the final set of core outcomes. This project is being run in parallel with a feasibility trial assessing perineural catheters in patients undergoing lower limb amputation (the PLACEMENT trial). Full ethical approval has been granted for the study (Wales REC 3 reference number 16/WA/0353). DISCUSSION: Core outcome sets will be developed for short- and medium-term outcomes of research involving patients undergoing major lower limb amputation for PAD. This will help with the design of future trials and facilitate meta-analyses of trial data. TRIAL REGISTRATION: PROSPERO: CRD42017059329 . Registered on 30 March 2017. COMET: 975 . Registered on 5 April 2017. PMID- 29284522 TI - Dengue and yellow fever virus vectors: seasonal abundance, diversity and resting preferences in three Kenyan cities. AB - BACKGROUND: The transmission patterns of dengue (DENV) and yellow fever (YFV) viruses, especially in urban settings, are influenced by Aedes (Stegomyia) mosquito abundance and behavior. Despite recurrent dengue outbreaks on the Kenyan coast, these parameters remain poorly defined in this and other areas of contrasting dengue endemicity in Kenya. In assessing the transmission risk of DENV/YFV in three Kenyan cities, we determined adult abundance and resting habits of potential Aedes (Stegomyia) vectors in Kilifi (dengue-outbreak prone), and Nairobi and Kisumu (no dengue outbreaks reported). In addition, mosquito diversity, an important consideration for changing mosquito-borne disease dynamics, was compared. METHODS: Between October 2014 and June 2016, host-seeking adult mosquitoes were sampled using CO2-baited BG-Sentinel traps (12 traps daily) placed in vegetation around homesteads, across study sites in the three major cities. Also, indoor and outdoor resting mosquitoes were sampled using Prokopack aspirators. Three samplings, each of five consecutive days, were conducted during the long-rains, short-rains and dry season for each city. Inter-city and seasonal variation in mosquito abundance and diversity was evaluated using general linear models while mosquito-resting preference (indoors vs outdoors) was compared using Chi-square test. RESULTS: Aedes aegypti, which comprised 60% (n = 7772) of the total 12,937 host-seeking mosquitoes collected, had comparable numbers in Kisumu (45.2%, n = 3513) and Kilifi (37.7%, n = 2932), both being significantly higher than Nairobi (17.1%, n = 1327). Aedes aegypti abundance was significantly lower in the short-rains and dry season relative to the long-rains (P < 0.0001). Aedes bromeliae, which occurred in low numbers, did not differ significantly between seasons or cities. Mosquito diversity was highest during the long-rains and in Nairobi. Only 10% (n = 43) of the 450 houses aspirated were found positive for resting Ae. aegypti, with overall low captures in all areas. Aedes aegypti densities were comparable indoors/outdoors in Kilifi; but with higher densities outdoors than indoors in Kisumu and Nairobi. CONCLUSIONS: The presence and abundance of Ae. aegypti near human habitations and dwellings, especially in Kilifi/Kisumu, is suggestive of increased DENV transmission risk due to higher prospects of human vector contact. Despite low abundance of Ae. bromeliae suggestive of low YFV transmission risk, its proximity to human habitation as well as the observed diversity of potential YFV vectors should be of public health concern and monitored closely for targeted control. The largely outdoor resting behavior for Ae. aegypti provides insights for targeted adult vector control especially during emergency outbreak situations. PMID- 29284524 TI - Bidirectional transcription initiation marks accessible chromatin and is not specific to enhancers. AB - BACKGROUND: Enhancers are modular regulatory elements that are central to the spatial and temporal regulation of gene expression. Bidirectional transcription initiating at enhancers has been proposed to mark active enhancers and as such has been utilized to experimentally identify active enhancers de novo. RESULTS: Here, we show that bidirectional transcription initiation is a pervasive feature of accessible chromatin, including at enhancers, promoters, and other DNase hypersensitive regions not marked with canonical histone modification profiles. Transcription is less predictive for enhancer activity than epigenetic modifications such as H3K4me1 or the accessibility of DNA when measured both in enhancer assays and at endogenous loci. The stability of enhancer initiated transcripts does not influence measures of enhancer activity and we cannot detect evidence of purifying selection on the resulting enhancer RNAs within the human population. CONCLUSIONS: Our results indicate that bidirectional transcription initiation from accessible chromatin is not sufficient for, nor specific to, enhancer activity. Transcription initiating at enhancers may be a frequent by product of promiscuous RNA polymerase initiation at accessible chromatin and is unlikely to generally play a functional role in enhancer activity. PMID- 29284525 TI - Disease-specific health related quality of life patient reported outcome measures in Genodermatoses: a systematic review and critical evaluation. AB - BACKGROUND: Health Related Quality of Life (HR-QoL) Patient reported outcome measures (PROMs) have high utility in evaluation of new interventions in genodermatoses, however inconsistent standards of development and validation have hampered widespread acceptance and adoption. OBJECTIVES: To identify all published HR-QoL PROMs in genodermatoses and critically evaluate their development and measurement properties. METHODS: This systematic review was registered with PROSPERO (CRD42016053301). Ovid Medline, Embase and PsycINFO databases were utilised for literature review using predefined inclusion and exclusion criteria. PROM development was assessed using the COSMIN Checklist and measurement properties were assessed against quality criteria for measurement properties of health standard questionnaires. RESULTS: 15 HRQoL PROMs in genodermatoses were identified. Major areas of deficiency in development were internal consistency, reliability and structural validity. No PROM satisfied measurement property standards for agreement, responsiveness or floor and ceiling effects. Four PROMs included Minimal Important Change scores for interpretability. Issues regarding the generalisability of the evaluated PROMs in culturally diverse and paediatric populations remain unresolved. CONCLUSIONS: The overall standards of development and measurement properties in PROMs in genodermatoses is fair, despite no single instrument meeting all requirements. None are perfectly validated according to COSMIN criteria but seven of the fifteen PROMs may be appropriate pending further validation. The development of culturally appropriate and child-specific variants of PROMs should be a priority in order to increase the utility of patient based outcome measures in genodermatoses in various patient populations. PMID- 29284526 TI - Postoperative extracranial metastasis from glioblastoma: a case report and review of the literature. AB - BACKGROUND: Glioblastoma is the most common primary malignant brain tumor. Extraneural metastases are rarely reported in the literature. CASE PRESENTATION: We report a case of a 38-year-old patient who was diagnosed with glioblastoma in 2015. Four months after surgery, local relapse was found and the patient received a second surgery. After another 4 months, we found a hard mass in the right posterior neck when she admitted to our department for fourth cycle of adjuvant chemotherapy. Immunohistochemical investigation supported the diagnosis of glioblastoma metastases to the neck after resection of the right neck mass. A few days later, spinal vertebral magnetic resonance imaging (MRI) confirmed multiple metastases in the thoracic, lumbar, sacral, and bilateral iliac bones. CONCLUSIONS: Glioblastoma is the most common primary malignant brain tumor. Whole tumor resection and early radiotherapy and chemotherapy can delay recurrence and prolong survival. Extracranial metastases are extremely rare. We report this case with the aim of bringing attention to extracranial metastasis of brain glioma. PMID- 29284527 TI - The evolving role of the renin-angiotensin system in ARDS. PMID- 29284529 TI - Use of the Hippocratic or other professional oaths in UK medical schools in 2017: practice, perception of benefit and principlism. AB - OBJECTIVE: This paper concerns the continued use of the Hippocratic Oath in United Kingdom (UK) medical schools. A survey of all UK medical schools looked at which schools use the Oath, which variants they use, and what they perceive to be the benefits of using the Oath. 27 schools participated in the study. RESULTS: Although some authors have deemed the Oath as out of date for the purposes of modern medicine [1], new variants of the Oath have been embraced and 19/27 (70%) of schools use an Oath, with some Universities asking student doctors to acknowledge this Oath on entry to and graduation from medical school. There is a renewed interest in use of the Oath, with use in some Schools on admission and graduation. Reasons for adopting the Oath include a desire to enhance good practice and to prevent unwanted behaviour. Variants of the Oath used were analysed according to which bioethical principles are contained within them and some do not accord with all principles. A new variant of the Oath is proposed which encompasses all four bioethical principles. PMID- 29284528 TI - Virus-like particles vaccine containing Clonorchis sinensis tegumental protein induces partial protection against Clonorchis sinensis infection. AB - BACKGROUND: Human clonorchiasis, caused by the infection of Clonorchis sinensis, is one of the major health problems in Southeast Asia. However, vaccine efficacy against C. sinensis infection remains largely unknown. METHODS: In this study, for the first time, we generated virus-like particles (VLPs) vaccine containing the C. sinensis tegumental protein 22.3 kDa (CsTP 22.3) and the influenza matrix protein (M1) as a core protein, and investigated the vaccine efficacy in Sprague Dawley rats. RESULTS: Intranasal immunization of VLPs vaccine induced C. sinensis specific IgG, IgG2a and IgG2c in the sera and IgA responses in the feces and intestines. Notably, upon challenge infection with C. sinensis metacercariae, significantly lower adult worm loads (70.2%) were measured in the liver of rats immunized with VLPs, compared to those of naive rats. Furthermore, VLPs immunization induced antibody secreting cells (ASC) responses and CD4+/CD8+ T cell responses in the spleen. CONCLUSIONS: Our results indicated that VLPs vaccine containing C. sinensis CsTP 22.3 kDa provided partial protection against C. sisnensis infection. Thus, VLPs could be a potential vaccine candidate against C. sinensis. PMID- 29284530 TI - FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC): study protocol for randomized controlled trial. AB - BACKGROUND: Fimasartan is the ninth angiotensin receptor blocker to be developed. However, it has not yet been evaluated for reno-protective effects in hypertensive diabetic chronic kidney disease (CKD). The target blood pressure (BP) for hypertensive diabetic CKD is also a controversial topic. This trial was designed to assess the reno-protective effects of fimasartan compared to those of losartan as a primary outcome. This study also compares the two drugs with regard to cardiovascular and renal outcomes in accordance with target systolic BP (SBP) (as secondary outcomes). METHODS: This study is a prospective, phase III, randomized, double-blind, active-controlled, non-inferiority, four-parallel group, dose-titration, multicenter trial. We recruit patients with hypertensive diabetic CKD with overt proteinuria. Participants will be randomized into four groups (1:1:1:1): fimasartan standard SBP control (SBP < 140 mmHg); fimasartan strict SBP control (SBP < 130 mmHg); losartan standard SBP control; and losartan strict SBP control. After 24 weeks, all individuals are treated with fimasartan for an additional 120 weeks in an open-label design, maintaining their assigned SBP control groups as randomized. The primary endpoint is the rate of change in proteinuria, which is assessed using the spot urine albumin-creatinine ratio at 24 weeks. The secondary endpoints are the cardiovascular and renal outcomes at 144 weeks compared between the strict SBP and standard SBP control groups. DISCUSSION: The FANTASTIC is a clinical study to provide: (1) the reno-protective effect of fimasartan; and (2) the target BP to reduce adverse outcomes in hypertensive diabetic CKD with overt proteinuria. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02620306. Registered on 1 December 2015. PMID- 29284531 TI - Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline. AB - BACKGROUND: Cerebrovascular disease (CVD) and amyloid-beta (Abeta) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Abeta on neurodegenerative markers and cognition in patients without dementia. METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Abeta1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Abeta and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Abeta and WMH. We investigated differences in phosphorylated tau, total tau (t tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. RESULTS: MTA and t-tau were elevated in the Abeta - WMH+, Abeta + WMH-, and Abeta + WMH+ groups. MTA was most severe in the Abeta + WMH+ group compared with the groups with a single pathology. Both WMH and Abeta were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. CONCLUSIONS: In the present study, we found an additive association of Abeta and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up. PMID- 29284532 TI - Abnormal elevation of myocardial necrosis biomarkers after coronary artery bypass grafting without established myocardial infarction assessed by cardiac magnetic resonance. AB - BACKGROUND: The diagnosis of peri-procedural myocardial infarction is complex, especially after the emergence of high-sensitivity markers of myocardial necrosis. METHODS: In this study, patients with normal baseline cardiac biomarkers and formal indication for elective on-pump coronary bypass surgery were evaluated. Electrocardiograms, cardiac biomarkers, and cardiac magnetic resonance imaging with late gadolinium enhancement were performed before and after procedures. Myocardial infarction was defined as more than ten times the upper reference limit of the 99th percentile for troponin I and for creatine kinase isoform (CK-MB) and by the findings of new late gadolinium enhancement on cardiac magnetic resonance. We assessed the release of cardiac biomarkers in patients with no evidence of myocardial infarction on cardiac magnetic resonance. RESULTS: Of 75 patients referred for on-pump coronary bypass surgery, 54 (100%) did not have evidence of myocardial infarction on cardiac magnetic resonance. However, all had a peak troponin I above the 99th percentile; 52 (96%) had an elevation 10 times higher than the 99th percentile. Regarding CK-MB, 54 (100%) patients had a peak CK-MB above the 99th percentile limit, and only 13 (24%) had an elevation greater than 10 times the 99th percentile. The median value of troponin I peak was 3.15 (1.2 to 3.9) ng/mL, which represented 78.7 times the 99th percentile. CONCLUSION: In this study, different from CK-MB findings, troponin was significantly increased in the absence of myocardial infarction on cardiac magnetic resonance. Thus, CK-MB was more accurate than troponin I for excluding procedure-related myocardial infarction. These data suggest a higher troponin cutoff for the diagnosis of coronary bypass surgery related myocardial infarction. CLINICAL TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN09454308 . Registered 08 May 2012. PMID- 29284533 TI - Hidden diversity of Nycteribiidae (Diptera) bat flies from the Malagasy region and insights on host-parasite interactions. AB - BACKGROUND: We present information on Nycteribiidae flies parasitizing the bat families Pteropodidae, Miniopteridae and Vespertilionidae from the Malagasy Region, contributing insight into their diversity and host preference. RESULTS: Our phylogenetic analysis identified nine clusters of nycteribiid bat flies on Madagascar and the neighbouring Comoros Archipelago. Bat flies sampled from frugivorous bats of the family Pteropodidae are monoxenous: Eucampsipoda madagascariensis, E. theodori and Cyclopodia dubia appear wholly restricted to Rousettus madagascariensis, R. obliviosus and Eidolon dupreanum, respectively. Two different host preference patterns occurred in nycteribiids infecting insectivorous bats. Flies parasitizing bats of the genera Miniopterus (Miniopteridae) and Myotis (Vespertilionidae), namely Penicillidia leptothrinax, Penicillidia sp. and Nycteribia stylidiopsis, are polyxenous and showed little host preference, while those parasitizing the genera Pipistrellus and Scotophilus (both Vespertilionidae) and referable to Basilia spp., are monoxenous. Lastly, the inferred Bayesian phylogeny revealed that the genus Basilia, as currently configured, is paraphyletic. CONCLUSION: This study provides new information on the differentiation of nycteribiid taxa, including undescribed species. Host preference is either strict as exemplified by flies parasitizing fruit bats, or more relaxed as found on some insectivorous bat species, possibly because of roost site sharing. Detailed taxonomic work is needed to address three undescribed nycteribiid taxa found on Pipistrellus and Scotophilus, tentatively allocated to the genus Basilia, but possibly warranting different generic allocation. PMID- 29284534 TI - Perineural local anaesthetic catheter after major lower limb amputation trial (PLACEMENT): study protocol for a randomised controlled pilot study. AB - BACKGROUND: Pain after major lower limb amputation for peripheral arterial disease (PAD) is a significant problem. A perineural catheter (PNC) can be placed adjacent to the major nerve at the time of amputation with a continuous local anaesthetic infusion given postoperatively to try and reduce pain. Although low quality observational data suggest that PNC usage reduces postoperative opioid requirements, there are limited data regarding its effect on pain. The aim of PLACEMENT is to explore the feasibility of running an effectiveness trial to assess the impact of a PNC with continuous local anaesthetic infusion, inserted at the time of amputation, on short and medium-term postoperative outcomes. METHODS/DESIGN: Fifty patients undergoing a major lower limb amputation (below or above the knee) for PAD will be recruited from two centres. Patients will be randomised in a 1:1 ratio to receive standard postoperative analgesia, with or without insertion of a PNC and local anaesthetic infusion for the first 5 postoperative days. Outcome data will be captured for the first 5 days, including pain scores (primary outcome, captured three times a day), opioid use, nausea or vomiting, itching, dizziness and complications. Patients will be contacted 2 and 6 months after surgery to assess quality of life, phantom limb pain, chronic stump pain and total healthcare costs. Semi-structured interviews will be conducted with at least 10 patients (dependent on saturation of analytic themes on preliminary coding) purposefully sampled to achieve variation in site and study arm. Interviews will explore patients' perception of post-amputation pain and its treatment, and experience of study processes. Semi-structured interviews with 5-10 health professionals will explore feasibility, fidelity, and acceptability of the study. Data from this pilot will be used to assess feasibility of, and estimate parameters to calculate the sample size for an effectiveness trial. Full ethical approval has been granted (Wales Research Ethics Committee 3 reference number 16/WA/0353). DISCUSSION: PLACEMENT will be the first study to explore the feasibility of running an effectiveness trial on PNC usage for postoperative pain in amputees, and provide parameters to calculate the appropriate sample size for this study. TRIAL REGISTRATION: ISRCTN.com, ISRCTN85710690 . Registered on 21 October 2016. European Clinical Trials Database (EudraCT), 2016-003544-37. Registered on 24 August 2016. PMID- 29284535 TI - Bacterial diversity of wild-caught Lutzomyia longipalpis (a vector of zoonotic visceral leishmaniasis in Brazil) under distinct physiological conditions by metagenomics analysis. AB - BACKGROUND: The leishmaniases are a group of diseases caused by protozoans of the genus Leishmania, which are transmitted by the bite of phlebotomine sand flies. In the New World, Lutzomyia longipalpis is the most important vector of visceral leishmaniasis and is a proven vector for Leishmania infantum chagasi in Brazil. During development within the vector, Leishmania can interact with a variety of microorganisms such as fungi and bacteria. The presence of bacteria in the midgut of sand flies can influence the development and survival of the parasite. RESULTS: The bacteria-targeted metagenomic analysis revealed different community compositions between the distinct physiological stages of those tested. The amplicon-oriented metagenomic profiling revealed 64 bacterial genera and 46 families. By crossing the taxa indices from each experimental condition a core composed of 6 genera was identified (Enterobacter, Serratia, Stenotrophomonas, Enhydrobacter, Pseudomonas and Chryseobacterium). CONCLUSIONS: The observed dynamic nature of the bacterial community expands the knowledge pertaining to the tripartite host-microbiota-pathogen interactions. Further studies addressing how laboratory and field collected communities differ are critical to successfully develop control strategies based on bacterial symbionts and paratransgenesis, as already tested in other arthropod vectors. PMID- 29284536 TI - Dental hygienists' perceptions of professionalism are multidimensional and context-dependent: a qualitative study in Japan. AB - BACKGROUND: Due to the declining birth rate and aging of Japanese society, the roles and responsibilities of dental hygienists are continuously expanding. Medical professionalism needs to be pursued continuously throughout one's career in order to improve dental care and treatment. Although conceptualising professionalism is essential to the education of health professionals, professionalism in the field of dental hygiene has not been defined or adequately examined in Japan. The purposes of this study are to investigate dental hygienists' perceptions of the constituent elements of professionalism and the factors affecting their perceptions. METHODS: Semi-structured interviews were conducted with 18 dental hygienists in Japan. Drawing on the conceptualisation of professionalism in medicine described by Van de Camp et al., the transcribed data were thematically analysed. RESULTS: The dental hygienists in this study perceived 70 constituent elements that were categorised into eight core competencies related to professionalism. These competencies were further classified into three main themes: intrapersonal, interpersonal, and public professionalism. There were three sociohistorical factors that affected their perceptions of the constituent elements, namely academic background (university or technical school), the contexts of any previously provided dental care (university hospital or dental clinic), and their social interactions with their colleagues during their engagement in dental practice (dental team or interprofessional team). Moreover, according to their sociohistorical backgrounds, the dental hygienists saw themselves variously as scholars (university graduates), facilitators (university hospital), skillful artisans (dental clinic), or collaborators (interprofessional team). CONCLUSIONS: Dental hygienists' perceptions of professionalism are multidimensional and context dependent, so culture- and professional-specific elements need to be included in educational curricula and continuing professional development programmes. In particular, the conceptualisation of professionalism in the field of dental hygiene as described in this study can be a springboard for enhancing undergraduate education and clinical training. PMID- 29284537 TI - The CogBIAS longitudinal study protocol: cognitive and genetic factors influencing psychological functioning in adolescence. AB - BACKGROUND: Optimal psychological development is dependent upon a complex interplay between individual and situational factors. Investigating the development of these factors in adolescence will help to improve understanding of emotional vulnerability and resilience. The CogBIAS longitudinal study (CogBIAS-L S) aims to combine cognitive and genetic approaches to investigate risk and protective factors associated with the development of mood and impulsivity related outcomes in an adolescent sample. METHODS: CogBIAS-L-S is a three-wave longitudinal study of typically developing adolescents conducted over 4 years, with data collection at age 12, 14 and 16. At each wave participants will undergo multiple assessments including a range of selective cognitive processing tasks (e.g. attention bias, interpretation bias, memory bias) and psychological self report measures (e.g. anxiety, depression, resilience). Saliva samples will also be collected at the baseline assessment for genetic analyses. Multilevel statistical analyses will be performed to investigate the developmental trajectory of cognitive biases on psychological functioning, as well as the influence of genetic moderation on these relationships. DISCUSSION: CogBIAS-L-S represents the first longitudinal study to assess multiple cognitive biases across adolescent development and the largest study of its kind to collect genetic data. It therefore provides a unique opportunity to understand how genes and the environment influence the development and maintenance of cognitive biases and provide insight into risk and protective factors that may be key targets for intervention. PMID- 29284538 TI - Use of programme theory to understand the differential effects of interventions across socio-economic groups in systematic reviews-a systematic methodology review. AB - BACKGROUND: Systematic review guidance recommends the use of programme theory to inform considerations of if and how healthcare interventions may work differently across socio-economic status (SES) groups. This study aimed to address the lack of detail on how reviewers operationalise this in practice. METHODS: A methodological systematic review was undertaken to assess if, how and the extent to which systematic reviewers operationalise the guidance on the use of programme theory in considerations of socio-economic inequalities in health. Multiple databases were searched from January 2013 to May 2016. Studies were included if they were systematic reviews assessing the effectiveness of an intervention and included data on SES. Two reviewers independently screened all studies, undertook quality assessment and extracted data. A narrative approach to synthesis was adopted. RESULTS: A total of 37 systematic reviews were included, 10 of which were explicit in the use of terminology for 'programme theory'. Twenty-nine studies used programme theory to inform both their a priori assumptions and explain their review findings. Of these, 22 incorporated considerations of both what and how interventions do/do not work in SES groups to both predict and explain their review findings. Thirteen studies acknowledged 24 unique theoretical references to support their assumptions of what or how interventions may have different effects in SES groups. Most reviewers used supplementary evidence to support their considerations of differential effectiveness. The majority of authors outlined a programme theory in the "Introduction" and "Discussion" sections of the review to inform their assumptions or provide explanations of what or how interventions may result in differential effects within or across SES groups. About a third of reviews used programme theory to inform the review analysis and/or synthesis. Few authors used programme theory to inform their inclusion criteria, data extraction or quality assessment. Twenty one studies tested their a priori programme theory. CONCLUSIONS: The use of programme theory to inform considerations of if, what and how interventions lead to differential effects on health in different SES groups in the systematic review process is not yet widely adopted, is used implicitly, is often fragmented and is not implemented in a systematic way. PMID- 29284539 TI - Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein-Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma. AB - BACKGROUND: According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients with N1 NPC are relatively under-researched, and the metastasis risk of this group is not well stratified. This study aimed to evaluate the prognostic values of gross tumor volume of metastatic regional lymph node (GTVnd) and pretreatment serum copy number of Epstein-Barr virus (EBV) DNA in predicting distant metastasis of patients with N1 NPC, and to develop an integrated prognostic model that incorporates GTVnd and EBV DNA copy number for this group of patients. METHODS: The medical records of 787 newly diagnosed patients with nonmetastatic, histologically proven N1 NPC who were treated at Sun Yat-sen University Cancer Center between November 2009 and February 2012 were analyzed. Computed tomography derived GTVnd was measured using the summation-of-area technique. Blood samples were collected before treatment to quantify plasma EBV DNA. The receiver operating characteristic (ROC) curve analysis was used to evaluate the cut-off point for GTVnd, and the area under the ROC curve was used to assess the predicted validity of GTVnd. The survival rates were assessed by Kaplan-Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model. RESULTS: The 5-year distant metastasis-free survival (DMFS) rates for patients with GTVnd > 18.9 vs. <= 18.9 mL were 82.2% vs. 93.2% (P < 0.001), and for patients with EBV DNA copy number > 4000 vs. <= 4000 copies/mL were 83.5% vs. 93.9% (P < 0.001). After adjusting for GTVnd, EBV DNA copy number, and T category in the Cox regression model, both GTVnd > 18.9 mL and EBV DNA copy number > 4000 copies/mL were significantly associated with poor prognosis (both P < 0.05). According to combination of GTVnd and EBV DNA copy number, all patients were divided into low-, moderate-, and high-risk groups, with the 5-year DMFS rates of 96.1, 87.4, and 73.8%, respectively (P < 0.001). Multivariate analysis confirmed the prognostic value of this model for distant metastatic risk stratification (hazard ratio [HR], 4.17; 95% confidence interval [CI] 2.34-7.59; P < 0.001). CONCLUSIONS: GTVnd and serum EBV DNA copy number are independent prognostic factors for predicting distant metastasis in NPC patients with N1 disease. The prognostic model incorporating GTVnd and EBV DNA copy number may improve metastatic risk stratification for this group of patients. PMID- 29284540 TI - PureCLIP: capturing target-specific protein-RNA interaction footprints from single-nucleotide CLIP-seq data. AB - The iCLIP and eCLIP techniques facilitate the detection of protein-RNA interaction sites at high resolution, based on diagnostic events at crosslink sites. However, previous methods do not explicitly model the specifics of iCLIP and eCLIP truncation patterns and possible biases. We developed PureCLIP ( https://github.com/skrakau/PureCLIP ), a hidden Markov model based approach, which simultaneously performs peak-calling and individual crosslink site detection. It explicitly incorporates a non-specific background signal and, for the first time, non-specific sequence biases. On both simulated and real data, PureCLIP is more accurate in calling crosslink sites than other state-of-the-art methods and has a higher agreement across replicates. PMID- 29284541 TI - DotAligner: identification and clustering of RNA structure motifs. AB - The diversity of processed transcripts in eukaryotic genomes poses a challenge for the classification of their biological functions. Sparse sequence conservation in non-coding sequences and the unreliable nature of RNA structure predictions further exacerbate this conundrum. Here, we describe a computational method, DotAligner, for the unsupervised discovery and classification of homologous RNA structure motifs from a set of sequences of interest. Our approach outperforms comparable algorithms at clustering known RNA structure families, both in speed and accuracy. It identifies clusters of known and novel structure motifs from ENCODE immunoprecipitation data for 44 RNA-binding proteins. PMID- 29284542 TI - A comparison of two emergency medical dispatch protocols with respect to accuracy. AB - BACKGROUND: Emergency medical dispatching should be as accurate as possible in order to ensure patient safety and optimize the use of ambulance resources. This study aimed to compare the accuracy, measured as priority level, between two Swedish dispatch protocols - the three-graded priority protocol Medical Index and a newly developed prototype, the four-graded priority protocol, RETTS-A. METHODS: A simulation study was carried out at the Emergency Medical Communication Centre (EMCC) in Stockholm, Sweden, between October and March 2016. Fifty-three voluntary telecommunicators working at SOS Alarm were recruited nationally. Each telecommunicator handled 26 emergency medical calls, simulated by experienced standard patients. Manuscripts for the scenarios were based on recorded real-life calls, representing the six most common complaints. A cross-over design with 13 + 13 calls was used. Priority level and medical condition for each scenario was set through expert consensus and used as gold standard in the study. RESULTS: A total of 1293 calls were included in the analysis. For priority level, n = 349 (54.0%) of the calls were assessed correctly with Medical Index and n = 309 (48.0%) with RETTS-A (p = 0.012). Sensitivity for the highest priority level was 82.6% (95% confidence interval: 76.6-87.3%) in the Medical Index and 54.0% (44.3-63.4%) in RETTS-A. Overtriage was 37.9% (34.2-41.7%) in the Medical Index and 28.6% (25.2 32.2%) in RETTS-A. The corresponding proportion of undertriage was 6.3% (4.7 8.5%) and 23.4% (20.3-26.9%) respectively. CONCLUSION: In this simulation study we demonstrate that Medical Index had a higher accuracy for priority level and less undertriage than the new prototype RETTS-A. The overall accuracy of both protocols is to be considered as low. Overtriage challenges resource utilization while undertriage threatens patient safety. The results suggest that in order to improve patient safety both protocols need revisions in order to guarantee safe emergency medical dispatching. PMID- 29284543 TI - External validation of type 2 diabetes computer simulation models: definitions, approaches, implications and room for improvement-a protocol for a systematic review. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM), a highly prevalent chronic disease, puts a large burden on individual health and health care systems. Computer simulation models, used to evaluate the clinical and economic effectiveness of various interventions to handle T2DM, have become a well-established tool in diabetes research. Despite the broad consensus about the general importance of validation, especially external validation, as a crucial instrument of assessing and controlling for the quality of these models, there are no systematic reviews comparing such validation of diabetes models. As a result, the main objectives of this systematic review are to identify and appraise the different approaches used for the external validation of existing models covering the development and progression of T2DM. METHODS: We will perform adapted searches by applying respective search strategies to identify suitable studies from 14 electronic databases. Retrieved study records will be included or excluded based on predefined eligibility criteria as defined in this protocol. Among others, a publication filter will exclude studies published before 1995. We will run abstract and full text screenings and then extract data from all selected studies by filling in a predefined data extraction spreadsheet. We will undertake a descriptive, narrative synthesis of findings to address the study objectives. We will pay special attention to aspects of quality of these models in regard to the external validation based upon ISPOR and ADA recommendations as well as Mount Hood Challenge reports. All critical stages within the screening, data extraction and synthesis processes will be conducted by at least two authors. This protocol adheres to PRISMA and PRISMA-P standards. DISCUSSION: The proposed systematic review will provide a broad overview of the current practice in the external validation of models with respect to T2DM incidence and progression in humans built on simulation techniques. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017069983 . PMID- 29284545 TI - Morphometric diagnosis of Glossina palpalis (Diptera: Glossinidae) population structure in Ghana. AB - OBJECTIVE: This study aimed to identify isolated population(s) of Glossina palpalis in Ghana using geometric morphometrics to evaluate variations in wing shape and size between populations of the fly from three regions. RESULTS: Wing shape of G. palpalis tsetse flies from the Northern, Western and Eastern Regions varied significantly between each other. Populations from the Northern and Western Regions varied the most (Mahalanobis Distance = 54.20). The least variation was noticed between populations from the Western and Eastern Regions (MD = 1.99). On morphospace, the Northern population clearly separated from the Eastern and Western populations both of which overlapped. Wing centroid size also significantly varied among populations. Reclassification scores were satisfactory reaching 100% for the Northern population. The Northern population of G. palpalis is possibly isolated from the Western and Eastern Region populations. Meanwhile, a panmictic relationship could be on-going between the Western and Eastern populations. We speculate that geographical distance and subspecific difference between populations are among factors responsible for observed pattern of wing shape variations among the studied populations. The implications of results regarding choice of control strategy and limitations of the study are discussed. PMID- 29284544 TI - Comprehensive measurement of stroke gait characteristics with a single accelerometer in the laboratory and community: a feasibility, validity and reliability study. AB - BACKGROUND: Application of objective measurement of stroke gait with accelerometer-based wearable technology and associated algorithms is increasing, despite reports questioning the accuracy of this technique in quantifying specific stroke-related gait impairments. The aim of this study is to determine the feasibility, validity and reliability of a low-cost open-source system incorporating algorithms and a single tri-axial accelerometer-based wearable to quantify gait characteristics in the laboratory and community post-stroke. METHODS: Twenty-five participants with stroke wore the wearable (AX3, Axivity) on the lower back during a laboratory 2 minute continuous walk (preferred pace) on two occasions a week apart and continuously in the community for two consecutive 7 day periods. Video, instrumented walkway (GaitRite) and an OPAL accelerometer based wearable were used as laboratory references. RESULTS: Feasibility of the proposed system was good. The system was valid for measuring step count (ICC 0.899). Inherent differences in gait quantification between algorithm and GaitRite resulted in difficulties comparing agreement between the different systems. Agreement was moderate-excellent (ICC 0.503-0.936) for mean and variability gait characteristics vs. OPAL. Agreement was moderate-poor between the system and OPAL for asymmetry characteristics. Moderate-excellent reliability (ICC 0.534-0.857) was demonstrated for 11/14 laboratory measured gait characteristics. Community test-retest reliability was good-excellent (ICC 0.867 0.983) for all except one (ICC 0.699) of the 19 gait characteristics. CONCLUSION: The proposed system is a low-cost, reliable tool for quantifying gait post-stroke with multiple potential applications. Further refinement to optimise gait quantification algorithms for certain gait characteristics including gait asymmetry is required. PMID- 29284546 TI - Medical Emergencies Related to Ethanol and Illicit Drugs at an Annual, Nocturnal, Indoor, Electronic Dance Music Event. AB - : Introduction Medical problems are frequently encountered during electronic dance music (EDM) events. Problem There are uncertainties about the frequencies and severity of intoxications with different types of recreational drugs: ethanol, "classical" illicit party drugs, and new psychoactive substances (NPS). METHODS: Statistical data on the medical problems encountered during two editions of an indoor electronic dance event with around 30,000 attendants were retrieved from the Belgian Red Cross (Mechelen, Belgium) database. Data on drug use were prospectively collected from the patient (or a bystander), the clinical presentation, and/or toxicological screening. RESULTS: In the on-site medical station, 487 patients were treated (265 in 2013 and 222 in 2014). The most frequent reasons were trauma (n=171), headache (n=36), gastro-intestinal problems (n=44), and intoxication (n=160). Sixty-nine patients were transferred to a hospital, including 53 with severe drug-related symptoms. Analysis of blood samples from 106 intoxicated patients detected ethanol in 91.5%, 3,4 methylenedioxymethamphetamine (MDMA) in 34.0%, cannabis in 30.2%, cocaine in 7.5%, amphetamine in 2.8%, and gamma-hydroxybutyric acid (GHB) in 0.9% of patients (alone or in combination). In only six of the MDMA-positive cases, MDMA was the sole substance found. In 2014, the neuroleptic drug clozapine was found in three cases and ketamine in one. Additional analyses for NPS were performed in 20 cases. Only in one agitated patient, the psychedelic phenethylamines 25B-NBOMe and 25C-NBOMe were found. CONCLUSIONS: At this particular event, recreational drug abuse necessitated on-site medical treatment in one out of 350 attendants and a hospital transfer in one out of 1,000. Ethanol remains the most frequently abused (legal) drug, yet classical illicit recreational drugs are also frequently (co-) ingested. The most worrying observation was high-risk poly-drug use, especially among MDMA users. Regarding NPS, the number of cases was low and the clinical presentations were rather mild. It should be stressed that these observations only apply to this particular event and cannot be generalized to other EDM events. Calle P , Sundahl N , Maudens K , Wille SMR , Van Sassenbroeck D , De Graeve K , Gogaert S , De Paepe P , Devriese D , Arno G , Blanckaert P . Medical emergencies related to ethanol and illicit drugs at an annual, nocturnal, indoor, electronic dance music event. Prehosp Disaster Med. 2018;33(1):71-76. PMID- 29284547 TI - Involving citizens in disinvestment decisions: what do health professionals think? Findings from a multi-method study in the English NHS. AB - Public involvement in disinvestment decision making in health care is widely advocated, and in some cases legally mandated. However, attempts to involve the public in other areas of health policy have been accused of tokenism and manipulation. This paper presents research into the views of local health care leaders in the English National Health Service (NHS) with regards to the involvement of citizens and local communities in disinvestment decision making. The research includes a Q study and follow-up interviews with a sample of health care clinicians and managers in senior roles in the English NHS. It finds that whilst initial responses suggest high levels of support for public involvement, further probing of attitudes and experiences shows higher levels of ambivalence and risk aversion and a far more cautious overall stance. This study has implications for the future of disinvestment activities and public involvement in health care systems faced with increased resource constraint. Recommendations are made for future research and practice. PMID- 29284548 TI - Validation of a photographic seafood portion guide to assess fish and shrimp intakes. AB - OBJECTIVE: To validate a novel photographic portion guide as a tool to estimate consumption of fish and shrimp. Application of such a validated tool can facilitate accurate individual and community seafood intake assessments and provide meaningful data relative to health benefits and hazard assessment, particularly in response to environmental contamination and disasters. DESIGN: A photographic fish and shrimp portion guide presenting a stepped range of cooked portion sizes was used by participants to estimate their typical portion sizes. Participants selected their typical portion size from the photographic guide and also from a selection of freshly cooked reference meals. Photographic portions selections were compared with plated reference portions for each participant. SETTING: Academic sensory testing laboratory in the USA. SUBJECTS: Separate groups of adults (25-64 years) contributed to fish (n 54) and shrimp (n 53) portion size comparison studies. RESULTS: In the fish study, there was no difference between photographic portion selections (6.59 (sd 2.65) oz (186.8 (sd 75.1) g)) and reference plate selections (7.04 (sd 2.63) oz (199.6 (sd 74.6) g); P=0.384). Similarly in the shrimp study, there was no difference between photographic portion selections (6.88 (sd 3.40) oz (195.0 (sd 96.4) g)) and reference plate selections (6.06 (sd 2.65) oz (171.8 (sd 75.1) g); P=0.159). Photographic portions predicted plated reference portions for both fish and shrimp based on linear regression (P<0.001). Bland-Altman plot analyses showed good agreement between the two methods, <1 oz (<28.3 g) bias, in both fish and shrimp studies. CONCLUSIONS: This validated photographic seafood portion guide provides a utilitarian tool for accurately assessing fish and shrimp intake in a community setting. PMID- 29284550 TI - Feasibility of Compliant Flooring in Long-Term Care: Results from a Stakeholder Symposium. AB - Compliant flooring aims to prevent fall-related injuries among high-risk older adults in long-term care, but uptake of compliant flooring in this setting is limited. We hosted a one-day stakeholder symposium to identify advantages and disadvantages of implementing compliant flooring in long-term care and the most pressing directions for future research from the perspective of key stakeholders. Twenty-three stakeholders representing health care, industry, and research attended the symposium. Attendees believed the most important advantages of compliant flooring were reducing injuries in residents who have fallen, potential benefits to care staff, and potential increases in quality of life for residents. Attendees perceived the most significant disadvantages of compliant flooring were financial considerations, lack of research evidence, and challenges with installation. Attendees indicated a need for additional research on cost effectiveness and clinical effectiveness. While stakeholders perceived compliant flooring to add value to long-term care, there are significant informational and financial barriers to uptake. PMID- 29284549 TI - The dietary impact of introducing new retailers of fruits and vegetables into a community: results from a systematic review. AB - OBJECTIVE: To investigate the potential dietary impact of the opening of new retailers of healthy foods. DESIGN: Systematic review of the peer-reviewed research literature. SETTING: References published before November 2015 were retrieved from MEDLINE, EMBASE and Web of Science databases using keyword searches. SUBJECTS: The outcome of the review was change in fruit and vegetable consumption among adults. RESULTS: Of 3514 references retrieved, ninety-two articles were reviewed in full text, and twenty-three articles representing fifteen studies were included. Studies used post-test only (n 4), repeated cross sectional (n 4) and repeated measures designs (n 7) to evaluate the dietary impact of supermarket (n 7), farmers' market (n 4), produce stand (n 2) or mobile market (n 2) openings. Evidence of increased fruit and vegetable consumption was most consistent among adults who began shopping at the new retailer. Three of four repeated measures studies found modest, albeit not always statistically significant, increases in fruit and vegetable consumption (range 0.23-0.54 servings/d) at 6-12 months after baseline. Dietary change among residents of the broader community where the new retailer opened was less consistent. CONCLUSIONS: The methodological quality of studies, including research designs, sampling methods, follow-up intervals and outcome measures, ranged widely. Future research should align methodologically with previous work to facilitate meta-analytic synthesis of results. Opening a new retailer may result in modest short-term increases in fruit and vegetable consumption among adults who choose to shop there, but the potential longer-term dietary impact on customers and its impact on the broader community remain unclear. PMID- 29284551 TI - Family care conferences in long-term care: Exploring content and processes in end of-life communication. AB - : ABSTRACTObjective:End-of-life (EoL) communication in long-term care (LTC) homes is often inadequate and delayed, leaving residents dying with unknown preferences or goals of care. Poor communication with staff contributes to families feeling unprepared, distressed, and dissatisfied with care. Family care conferences (FCCs) aim to increase structured systematic communication around goals and plans for the end of life. As part of the Strengthening a Palliative Approach to Care (SPA-LTC) project, FCCs were implemented in four LTC sites in Ontario, Canada. The purpose of this substudy was to examine FCC content and such guiding processes as documentation and multidisciplinary staff participation. METHOD: A total of 24 FCCs were held for residents with a Palliative Performance Scale score of 40% (nearing death). Data were collected from conference forms (i.e., Family Questionnaires, Care Plan Conference Summaries), site-specific electronic chart documents, and fieldnotes. Directed content analysis of data was informed by the Canadian Hospice Palliative Care Association's Square of Care Model, which describes eight domains of care: disease management, physical, psychological, social, practical, spiritual, EoL, and loss/bereavement. RESULTS: The FCCs addressed an average of 71% of the content domains, with physical and EoL care addressed most frequently and loss/bereavement addressed the least. Two goals and five interventions were documented and planned on average per FCC. Examination of the processes supporting EoL communication found: (1) advantages to using FCC forms versus electronic charts; and (2) high levels of multidisciplinary participation overall but limited participation of personal support workers (PSWs) and physicians. SIGNIFICANCE OF RESULTS: Communication around the end of life in LTC can be supported through the use of FCCs. Description of content and FCC processes provides guidance to persons implementing FCCs. Recommendations for tailoring conferences to optimize communication include use of specific conference forms, increased bereavement discussion, and further engagement of PSWs and physicians. PMID- 29284552 TI - Retrospective and Prospective Memory Among OEF/OIF/OND Veterans With a Self Reported History of Blast-Related mTBI. AB - OBJECTIVES: To evaluate prospective and retrospective memory abilities in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans with and without a self-reported history of blast-related mild traumatic brain injury (mTBI). METHODS: Sixty-one OEF/OIF/OND Veterans, including Veterans with a self-reported history of blast-related mTBI (mTBI group; n=42) and Veterans without a self-reported history of TBI (control group; n=19) completed the Memory for Intentions Test, a measure of prospective memory (PM), and two measures of retrospective memory (RM), the California Verbal Learning Test-II and the Brief Visuospatial Memory Test-Revised. RESULTS: Veterans in the mTBI group exhibited significantly lower PM performance than the control group, but the groups did not differ in their performance on RM measures. Further analysis revealed that Veterans in the mTBI group with current PTSD (mTBI/PTSD+) demonstrated significantly lower performance on the PM measure than Veterans in the control group. PM performance by Veterans in the mTBI group without current PTSD (mTBI/PTSD-) was intermediate between the mTBI/PTSD+ and control groups, and results for the mTBI/PTSD- group were not significantly different from either of the other two groups. CONCLUSIONS: Results suggest that PM performance may be a sensitive marker of cognitive dysfunction among OEF/OIF/OND Veterans with a history of self-reported blast-related mTBI and comorbid PTSD. Reduced PM may account, in part, for complaints of cognitive difficulties in this Veteran cohort, even years post-injury. (JINS, 2018, 24, 324 334). PMID- 29284553 TI - Nitrogen isotopic fractionation as a biomarker for nitrogen use efficiency in ruminants: a meta-analysis. AB - Animal proteins are naturally 15N enriched relative to the diet and the extent of this difference (Delta15Nanimal-diet or N isotopic fractionation) has been correlated to N use efficiency (NUE; N gain or milk N yield/N intake) in some recent ruminant studies. The present study used meta-analysis to investigate whether Delta15Nanimal-diet can be used as a predictor of NUE across a range of dietary conditions, particularly at the level of between-animal variation. An additional objective was to identify variables related to N partitioning explaining the link between NUE and Delta15Nanimal-diet. Individual values from eight publications reporting both NUE and Delta15Nanimal-diet for domestic ruminants were used to create a database comprising 11 experimental studies, 41 treatments and individual animal values for NUE (n=226) and Delta15Nanimal-diet (n=291). Data were analyzed by mixed-effect regression analysis taking into account experimental factors as random effects on both the intercept and slope of the model. Diets were characterized according to the INRA feeding system in terms of N utilization at the rumen, digestive and metabolic levels. These variables were used in a partial least squares regression analysis to predict separately NUE and Delta15Nanimal-diet variation, with the objective of identifying common variables linking NUE and Delta15Nanimal-diet. For individuals reared under similar conditions (within-study) and at the same time (within-period), the variance of NUE and Delta15Nanimal-diet not explained by dietary treatments (i.e. between-animal variation plus experimental error) was 35% and 55%, respectively. Mixed-effect regression analysis conducted with treatment means showed that Delta15Nanimal-diet was significantly and negatively correlated to NUE variation across diets (NUE=0.415 -0.055*Delta15Nanimal-diet). When using individual values and taking into account the random effects of study, period and diet, the relationship was also significant (NUE=0.358 -0.035*Delta15Nanimal-diet). However, there may be a biased prediction for animals close to zero, or in negative, N balance. When using a novel statistical approach, attempting to regress between-animal variation in NUE on between-animal variation in Delta15Nanimal-diet (without the influence of experimental factors), the negative relationship was still significant, highlighting the ability of Delta15Nanimal diet to capture individual variability. Among the studied variables related to N utilization, those concerning N efficiency use at the metabolic level contributed most to predict both Delta15Nanimal-diet and NUE variation, with rumen fermentation and digestion contributing to a lesser extent. This study confirmed that on average Delta15Nanimal-diet can predict NUE variation across diets and across individuals reared under similar conditions. PMID- 29284554 TI - Representation of time interval entrained by periodic stimuli in the visual thalamus of pigeons. AB - Animals use the temporal information from previously experienced periodic events to instruct their future behaviors. The retina and cortex are involved in such behavior, but it remains largely unknown how the thalamus, transferring visual information from the retina to the cortex, processes the periodic temporal patterns. Here we report that the luminance cells in the nucleus dorsolateralis anterior thalami (DLA) of pigeons exhibited oscillatory activities in a temporal pattern identical to the rhythmic luminance changes of repetitive light/dark (LD) stimuli with durations in the seconds-to-minutes range. Particularly, after LD stimulation, the DLA cells retained the entrained oscillatory activities with an interval closely matching the duration of the LD cycle. Furthermore, the post stimulus oscillatory activities of the DLA cells were sustained without feedback inputs from the pallium (equivalent to the mammalian cortex). Our study suggests that the experience-dependent representation of time interval in the brain might not be confined to the pallial/cortical level, but may occur as early as at the thalamic level. PMID- 29284555 TI - Investigation of Optimized Treatment Conditions for Acoustic-Transfection Technique for Intracellular Delivery of Macromolecules. AB - Manipulation of cellular functions and structures by introduction of genetic materials inside cells has been one of the most prominent research areas in biomedicine. High-frequency ultrasound acoustic-transfection has recently been developed and confirmed by intracellular delivery of small molecules into HeLa cells at the single-cell level with high cell viability. After we proved the concept underlying the acoustic-transfection technique, treatment conditions for different human cancer cell lines have been intensively investigated to further develop acoustic-transfection as a versatile and adaptable transfection method by satisfying the requirements of high-delivery efficiency and cell membrane permeability with minimal membrane disruption. To determine optimal treatment conditions for different cell lines, we developed a quantitative intracellular delivery score based on delivery efficiency, cell membrane permeability and cell viability after 4 and 20 h of treatment. The intracellular delivery of macromolecules and the simultaneous intracellular delivery of two molecules under optimal treatment conditions were successfully achieved. We found that DNA plasmid was delivered by acoustic-transfection technique into epiblast stem cells, which expressed transient mCherry fluorescence. PMID- 29284556 TI - Ultrasound Characterization of Bone Demineralization Using a Support Vector Machine. AB - We propose an ultrasound-guided remote measurement technique, utilizing an acoustic radiation force beam as our excitation source and a receiving hydrophone, to assess non-invasively a bone's mechanical properties. Features, such as velocity, were extracted from the acoustic pressure received from the bone surface. The typical velocity of an intact bone (3540 m/s) was higher in comparison to that of a demineralized bone (2231 m/s). According to the receiver operating characteristic curve, the optimal velocity cutoff value of >=3096 m/s yields 80% sensitivity and 82.61% specificity between intact and demineralized bone. Utilizing a support vector machine, the hours of bone demineralization were successfully classified with maximum accuracy >80% using 18% training data. The results indicate the potential application of our proposed technique and support vector machine for monitoring bone mechanical properties. PMID- 29284557 TI - Inter-Scan Reproducibility of Carotid Plaque Volume Measurements by 3-D Ultrasound. AB - We tested a novel 3-D matrix transducer with respect to inter-scan reproducibility of carotid maximum plaque thickness (MPT) and volume measurements. To improve reproducibility while focusing on the largest plaque/most diseased part of the carotid artery, we introduced a new partial plaque volume (PPV) measure centered on MPT. Total plaque volume (TPV), PPV from a 10-mm segment and MPT were measured using dedicated semi-automated software on 38 plaques from 26 patients. Inter-scan reproducibility was assessed using the t test, Bland-Altman plots and Pearson's correlation coefficient. There was a mean difference of 0.01 mm in MPT (limits of agreement: -0.45 to 0.42 mm, Pearson's correlation coefficient: 0.96). Both volume measurements exhibited high reproducibility, with PPV being superior (limits of agreement: -35.3 mm3 to 33.5 mm3, Pearson's correlation coefficient: 0.96) to TPV (limits of agreement: -88.2 to 61.5 mm3, Pearson's correlation coefficient: 0.91). The good reproducibility revealed by the present results encourages future studies on establishing plaque quantification as part of cardiovascular risk assessment and for follow-up of disease progression over time. PMID- 29284558 TI - Is the association between season of birth and schizophrenia due to neonatal cold exposure-induced permanent defects in skin functions? PMID- 29284559 TI - Validation of the Mandarin Chinese Version of the Pediatric Voice-Related Quality of Life (pVRQOL). AB - OBJECTIVES: The purposes of this study were to adapt and validate the English version of the pediatric Voice-Related Quality of Life questionnaire into Mandarin Chinese, and to determine the cutoff point for screening children with and without voice disorders. METHODS: A total of 377 parents were enrolled from May 2016 to June 2017, including 195 parents of children with voice disorder (patient group) and 182 parents of children without voice disorder (control group). The internal consistency, test-retest, contents and clinical validity, and sensitivity and specificity were analyzed. The clinical cutoff point was determined. RESULTS: The questionnaire showed strong internal consistency in the patient group (alpha = 0.89 for the total score, alpha = 0.88 for the social emotional domain, and alpha = 0.81 for the physical functioning domain) and good test-retest reliability (intra-class correlation coefficient = 0.93), as well as moderate to strong contents validity (r = 0.72-0.95). The total score and subscales scores in the patient group were significantly higher than the control group (P <0.001). The mean score of the physical functioning domain was lower than that of the social-emotional domain in the patient group. The clinical cutoff point was 96.25 (sensitivity = 78.0%, specificity = 100.0%). CONCLUSION: The Mandarin Chinese version of pediatric Voice-related Quality of Life questionnaire was a valid and reliable questionnaire, which can be used as a screening test for the pediatric population with and without voice disorders. PMID- 29284560 TI - The Vocal Fold Dysfunction Questionnaire: Validity and Reliability of the Persian Version. AB - OBJECTIVES: The aim of this study was to develop, validate, and assess the reliability of the Persian version of Vocal Cord Dysfunction Questionnaire (VCDQP). STUDY DESIGN: The study design was cross-sectional or cultural survey. MATERIALS AND METHODS: Forty-four patients with vocal fold dysfunction (VFD) and 40 healthy volunteers were recruited for the study. To assess the content validity, the prefinal questions were given to 15 experts to comment on its essential. Ten patients with VFD rated the importance of VCDQP in detecting face validity. Eighteen of the patients with VFD completed the VCDQ 1 week later for test-retest reliability. To detect absolute reliability, standard error of measurement and smallest detected change were calculated. Concurrent validity was assessed by completing the Persian Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) by 34 patients with VFD. Discriminant validity was measured from 34 participants. The VCDQ was further validated by administering the questionnaire to 40 healthy volunteers. Validation of the VCDQ as a treatment outcome tool was conducted in 18 patients with VFD using pre- and posttreatment scores. RESULTS: The internal consistency was confirmed (Cronbach alpha = 0.78). The test-retest reliability was excellent (intraclass correlation coefficient = 0.97). The standard error of measurement and smallest detected change values were acceptable (0.39 and 1.08, respectively). There was a significant correlation between the VCDQP and the CAT total scores (P < 0.05). Discriminative validity was significantly different. The VCDQ scores in patients with VFD before and after treatment was significantly different (P < 0.001). CONCLUSIONS: The VCDQ was cross-culturally adapted to Persian and demonstrated to be a valid and reliable self-administered questionnaire in Persian-speaking population. PMID- 29284561 TI - Does Type 2 Diabetes Mellitus Affect the Healing of Bell's Palsy in Adults? AB - OBJECTIVES: Bell's palsy (BP) is defined as an acute facial weakness of unknown cause. Many factors affecting the healing of BP have been identified; 1 factor commonly considered relevant is the presence of type 2 diabetes mellitus. Our aim was to investigate the effects of diabetes on the healing of BP. METHODS: Sixty patients with BP were followed up for 1 to 3 years and were divided into 2 groups, those with and those without type 2 diabetes. All were prescribed prednisone (initially 1 mg/kg per day, with a tapered dose reduction) and acyclovir (200 mg orally every 4 h, 5 times daily, for 5 days). Their recovery times were compared. RESULTS: The healing times of the patients with and without diabetes did not differ. CONCLUSIONS: Diabetes does not affect the severity, recovery rate from or healing of BP. PMID- 29284562 TI - Optimizing Glycemic Control in Adults With Type 1 or Type 2 Diabetes Attending a Multidisciplinary Foot Clinic. AB - OBJECTIVES: To determine the impact of a diabetes nurse educator (DNE) on glycemic control in a multidisciplinary diabetes foot (MDF) clinic. METHODS: A prospective cohort trial to measure the impact of a DNE on glycemic control was conducted in an MDF clinic. Change in glycated hemoglobin (A1C) levels over time was measured against the percentage of patient visits (PPVs) accompanied by a glucose meter and/or diary. RESULTS: Increasing PPVs were significantly associated with decline in A1C levels in females. Every 10% increase in PPVs resulted in a 0.18% decrease in A1C levels (p<0.0001). To achieve a clinically important decrease of 1% in A1C levels, a 56% increase in PPVs was required. Increased A1C levels were significantly associated with higher baseline A1C levels (p<0.001) and increased hospital days for foot complications (p<0.0052). CONCLUSIONS: Regular, face-to-face contact with a DNE in an MDF clinic has a positive impact on glycemic control in females. PMID- 29284563 TI - A novel Ehrlichia species in blood and Ixodes ornithorhynchi ticks from platypuses (Ornithorhynchus anatinus) in Queensland and Tasmania, Australia. AB - Worldwide, Ehrlichia spp. are emerging infectious organisms of domestic animals and people, however, most Ehrlichia spp. naturally infect wildlife reservoirs causing mainly asymptomatic infections. Australian ecosystems have been under explored for these potentially pathogenic organisms, and recent studies have identified a range of novel Ehrlichia, and their sister genera, Anaplasma and 'Candidatus Neoehrlichia' species, from native Australian ticks. We used bacterial 16S rRNA (16S) next-generation sequencing and genus-specific PCR to profile the bacterial communities in platypus (Ornithorhynchus anatinus) blood samples and platypus ticks (Ixodes ornithorhynchi), and identified a high prevalence of Ehrlichia sequences. We also observed Ehrlichia-like intra neutrophilic inclusions (morulae) in PCR-positive stained platypus blood films that were consistent in morphology with other Ehrlichia spp. Bayesian phylogenetic analysis of 16S (1343 bp), gltA (1004 bp), and groEL (1074 bp) gene sequences group the platypus Ehrlichia with 'Candidatus Ehrlichia khabarensis' from far-eastern Russia, and demonstrate that the platypus Ehrlichia is clearly distinct from all other Ehrlichia spp. Enough genetic divergence exists to delineate this platypus Ehrlichia as a separate species that we propose to designate 'Candidatus Ehrlichia ornithorhynchi'. There is no evidence that 'Candidatus Ehrlichia ornithorhynchi' causes disease in wild platypuses, however, the organism does seem to be widespread in Australia, being found in both Queensland and Tasmania. 'Candidatus Ehrlichia ornithorhynchi' is the second native Australian Ehrlichia described and adds to the rapidly growing diversity of recently described native Australian tick-borne bacteria. PMID- 29284564 TI - The folA gene from the Rickettsia endosymbiont of Ixodes pacificus encodes a functional dihydrofolate reductase enzyme. AB - Although nonpathogenic bacterial endosymbionts have been shown to contribute to their arthropod host's fitness by supplying them with essential vitamins and amino acids, little is known about the nutritional basis for the symbiotic relationship of endosymbionts in ticks. Our lab has previously reported that Rickettsia species phylotype G021 in Ixodes pacificus carries all five genes for de novo folate synthesis, and that these genes are monophyletic with homologs from other Rickettsia species. In this study, the rickettsial folate synthesis folA gene, coding for dihydrofolate reductase, was PCR amplified, cloned into an expression vector, and overexpressed in E. coli. Bioinformatic analysis identified that the FolA protein of phylotype G021 has the conserved DHFR domain, NADP binding sites, and substrate binding sites of bacterial dihydrofolate reductase. SDS-PAGE results showed that recombinant rickettsial FolA protein was overexpressed in BL21(DE3) E. coli in its soluble form. Affinity chromatography was used to purify the protein, and in vitro enzyme assays were performed to assess the biochemical activity of dihydrofolate reductase. The specific activity of recombinant FolA from phylotype G021 was determined to be 16.1 U/mg. This study has revealed that Rickettsia species phylotype G021 of I. pacificus is capable of producing a functional enzyme of the folate biosynthesis pathway, addressing the nutritional interactions behind the symbiosis between Rickettsia species phylotype G021 and its host. PMID- 29284565 TI - Bone Mineral Density of the Radius Predicts All-Cause Mortality in Patients With Type 2 Diabetes: Diabetes Heart Study. AB - This study aimed to determine the association between areal and volumetric bone mineral density (BMD) with all-cause mortality in patients with type 2 diabetes (T2D). Associations between BMD and all-cause mortality were examined in 576 women and 517 men with T2D in the Diabetes Heart Study. Volumetric BMD in the thoracic and lumbar spine was measured with quantitative computed tomography. Areal BMD (aBMD) in the lumbar spine, total hip, femoral neck, ultradistal radius, mid radius, and whole body was measured using dual X-ray absorptiometry. Association of BMD with all-cause mortality was determined using sequential models, stratified by sex: (1) unadjusted; (2) adjusted for age, race, smoking, alcohol, estrogen use; (3) model 2 plus history of cardiovascular disease, hypertension, and coronary artery calcification; (4) model 3 plus lean mass; and (5) model 3 plus fat mass. At baseline, mean age was 61.2 years for women and 62.7 years for men. At mean 11.0 +/- 3.7 years' follow-up, 221 (36.4%) women and 238 (43.6%) men were deceased. In women, BMD at all skeletal sites (except spine aBMD and whole body aBMD) was inversely associated with all-cause mortality in the unadjusted model. These associations remained significant in the mid radius (hazard ratio per standard deviation = 0.79; p = 0.0057) and distal radius (hazard ratio per standard deviation = 0.76; p = 0.0056) after adjusting for all covariates, including lean mass. In men, volumetric BMD measurements but not aBMD were inversely associated with mortality and only in the unadjusted model. In this longitudinal study, lower baseline aBMD in the radius was associated with increased all-cause mortality in women with T2D, but not men, independent of other risk factors for death. PMID- 29284567 TI - Determination of reference values for normal cranial morphology by using mid sagittal vector analysis in Japanese children. AB - Mid-Sagittal Vector Analysis (MSVA) is a method of measuring the distance from a defined central point on the skull surface in the entire mid-sagittal plane and provides a clear description of the lateral view of the skull. We used a series of images of normal skulls of Japanese children to determine normal MSVA values. For this cross-sectional study, we first constructed a database of head CT and MRI images of children aged 0-6 years (41.5 +/- 24.9 month (mean +/- SD)) who showed no abnormality of cranial development and growth at the time of imaging. Measurement errors due to lateral shifting of the sagittal plane during MSVA were examined, CT and MRI images taken in the same patients at the same time were compared, and measurement differences were examined. Finally, MSVA was carried out, and the mean of the measured values was calculated according to age group. Two hundred ninety-five images were included in the database. When the lateral shifting of the sagittal plane was within 4 mm from the true mid-sagittal plane, the mean errors were less than 1 mm at all measurement points. Between the CT and MRI images from the same patients, most differences in MSVA values were within +/ 1 mm. These differences were thus acceptable for use in clinical settings. After the above verifications, 220 images were extracted for determination of normal MSVA values. We established a normal dataset of MSVA for Japanese children that can be used effectively for preoperative diagnosis, surgery planning, and postoperative assessment of cranial deformities. PMID- 29284566 TI - Surviving Fournier's gangrene: Multivariable analysis and a novel scoring system to predict length of stay. AB - BACKGROUND: There is no contemporary scoring system to predict hospital length of stay and morbidity in Fournier's gangrene. A retrospective study was conducted to formulate a scoring system to predict duration of hospitalization, resource utilization, need for reconstruction, morbidity and mortality. METHODS: A retrospective chart review was performed on 54 patients treated for FG from 2010 2016 at LAC+USC Medical Center, the largest public hospital in Los Angeles County. Strobe guidelines were followed and the study was approved by the IRB. Predictors of LOS, morbidity, mortality and resource utilization were identified and univariate linear regressions performed to determine significance. Significant univariate predictors were used to develop a novel scoring system, the Combined Urology and Plastics Index (CUPI). The CUPI score was then compared to existing scoring systems for predicting length of stay. RESULTS: The mean patient age was 49.3, and the mean BMI was 28.6. Patients on average were hospitalized for 37.5 days, with a mean of 8.3 days in the ICU. Three patients (5.6%) died during their hospital stay, and 33 (61%) required reconstructive surgery. Multivariate logistic modeling showed that BMI (p = 0.001) and alkaline phosphatase (p < 0.001) correlated with decreasing length of stay, while age at admission was not significantly correlated (p = 0.369). Univariate analysis of existing scoring systems showed that FGSI, LRINEC, NLR, and CCI were not significantly correlated with length of stay, while the newly calculated CUPI score was shown to be a significant predictor of longer hospital stays (p = 0.001). DISCUSSION: Early emphasis on supportive care, nutrition, and involvement of reconstructive surgeons can decrease LOS in patients with Fournier's gangrene. The CUPI score on admission may be a useful tool for predicting LOS in this population. PMID- 29284568 TI - Clinical Characteristics of Subarachnoid Hemorrhage with an Intracerebral Hematoma and Prognostic Factors. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) with an intracerebral hematoma (ICH) shows an unfavorable prognosis. In the present study, we examined the characteristics of SAH with ICH and its prognosis. METHODS: Subjects comprised 218 patients with SAH who underwent surgery between January 2007 and December 2015. We compared age, sex, the location of the aneurysm, treatment procedures, medical history (hypertension, diabetes, and heart disease), the Glasgow Coma Scale (GCS) score on admission, rerupture rate, hydrocephalus, the diameter of the aneurysm, cerebral vasospasm, perioperative cardiopulmonary complications, and the Glasgow Outcome Scale (GOS) score after 2 months between patients with SAH with and without ICH. The interval from the onset of SAH until surgery, the location of ICH, and hematoma volume were investigated as prognostic factors for SAH with ICH. RESULTS: Among all subjects, 82 had SAH with ICH. GCS scores on admission were poorer in patients with SAH with ICH than in those without ICH (P < .001), and middle cerebral artery aneurysms were more likely to form hematomas (P < .001). GOS scores after 2 months were also poorer in patients with SAH with ICH (P < .01). The size of aneurysms was larger in the 82 patients with SAH with ICH than in those without ICH (P < .001), and the rerupture rate was higher (P < .001). The unfavorable prognosis of patients with SAH with ICH was associated with age and GCS score on admission. CONCLUSIONS: A young age and a favorable GCS score on admission may be associated with a favorable prognosis for patients with SAH with ICH, and SAH with ICH may easily rerupture. PMID- 29284569 TI - Epidemiology of Stroke in Costa Rica: A 7-Year Hospital-Based Acute Stroke Registry of 1319 Consecutive Patients. AB - BACKGROUND: Limited data on stroke exist for Costa Rica. Therefore, we created a stroke registry out of patients with stroke seen in the Acute Stroke Unit of the Hospital Calderon Guardia. METHODS: We analyzed 1319 patients enrolled over a 7 year period, which incorporated demographic, clinical, laboratory, and neuroimaging data. RESULTS: The mean age of patients with stroke was 68.0 +/- 15.5 years. Seven hundred twenty-five were men and the age range was 13-104 years. The most prevalent risk factors were hypertension (78.8%), dyslipidemia (36.3%), and diabetes (31.9%). Fifteen percent had atrial fibrillation and 24.7% had a previous stroke or transient ischemic attack. Prevalence of hypertension and atrial fibrillation increased with age; however, younger patients were more associated with thrombophilia. We documented 962 (72.9%) ischemic and 270 (20.5%) hemorrhagic strokes. Of the ischemic strokes, 174 (18.1%) were considered secondary to large-artery atherothrombosis, 175 (18.2%) were due to cardiac embolism, 19 (2.0%) were due to lacunar infarcts, and 25 (2.6%) were due to other determined causes. Five hundred sixty-nine (59.1%) remained undetermined. Atherothrombotic strokes were mostly associated with dyslipidemia, diabetes, metabolic syndrome, and obesity, whereas lacunar infarcts were associated with hypertension, smoking, sedentary lifestyle, and previous stroke or transient ischemic attack. Of our patients, 69.9% scored between 0 and 9 in the initial National Institutes of Health Stroke Scale (NIHSS). CONCLUSIONS: We found differences in sociodemographic features, risk factors, and stroke severity among stroke subtypes. Risk factor prevalence was similar to other registries involving Hispanic populations. PMID- 29284571 TI - Transorbital Sonography to Evaluate Optic Nerve in Hypertensive Encephalopathy. PMID- 29284570 TI - Prognosis of Midlife Stroke. AB - OBJECTIVE: To characterize stroke outcomes in a midlife population-based stroke cohort, and to describe comorbidities, quality of care, and risk of recurrence in this age group. MATERIALS AND METHODS: Ischemic strokes (ISs) were identified from the population-based Brain Attack Surveillance in Corpus Christi Project (2000-2012). Data were from medical records and patient interviews. Ninety-day outcomes (functional, neurologic, cognitive, quality of life [QOL]), prevalence of comorbidities, quality of care, and 1-year recurrence were estimated for those aged 45-64 (midlife) and compared with those aged >=65 using sex and race ethnicity adjusted regression models. RESULTS: Of 4858 ISs, 33% occurred in midlife. On average, the midlife group reported some difficulty with function, favorable neurologic and cognitive outcomes, and moderate QOL scores at 90 days. All outcomes except QOL were better in the midlife group. Prevalent comorbidities in midlife were hypertension (74%), diabetes (51%), hyperlipidemia (34%), heart disease (26%), prior stroke/transient ischemic attack (23%), smoking 37%, excess alcohol 10%, and atrial fibrillation 4%. Median body mass index (BMI) was 30 (interquartile range: 26-35). Diabetes, smoking, and alcohol were more prevalent and BMI higher in the midlife group. Quality of stroke care did not differ by age. One-year recurrence in midlife was 8% (95% confidence interval: 6%-9%) and did not differ by age. CONCLUSION: While 90-day outcomes were more favorable than in the elderly, midlife stroke survivors faced some disability and did not experience better QOL despite better outcomes. Additional research should identify targets to optimize secondary stroke prevention and improve outcomes in midlife stroke survivors-an understudied group with great potential disability and economic impact. PMID- 29284572 TI - Self-Perceived Participation and Autonomy at 1-Year Post Stroke: A Part of the Stroke Arm Longitudinal Study at the University of Gothenburg (SALGOT Study). AB - BACKGROUND: Identifying factors predicting the long-term outcome of participation and autonomy after stroke is essential for developing individualized rehabilitation interventions. The aim was to describe self-assessed participation and autonomy and to explore factors associated with the same at 1 year post stroke. METHODS: Participants consisted of 79 persons (mean age = 67) with a first-time stroke at the 1-year follow-up. To investigate perceived participation and autonomy at 1 year, a self-assessment questionnaire, the Impact on Participation and Autonomy-English version (IPA-E) was used. Multivariate logistic regression models were performed using age, gender, stroke severity, and functional dependency at discharge as potential contributors to the perceived level of participation and autonomy. RESULTS: A high percentage (70%-88%) evaluated their functions as fair to very good within all domains of the IPA-E at 1 year post stroke. However, around a fifth experienced their Family role as poor to very poor. Participants' functional dependency at discharge significantly influenced the outcome for the domains of Family role (odds ratio [OR] = 5.66, P < .01), Social relations (OR = 3.23, P < .03), and Autonomy indoors (OR = 3.44, P < .04) at 1 year post stroke. CONCLUSION AND IMPLICATIONS: Aspects of the Family role domain deserve further attention in interventions aimed at improving participation and autonomy at 1 year post stroke. The results also indicate that supporting indoor autonomy and social relations of persons with stroke during the acute rehabilitation is important to enhance participation and autonomy at 1 year post stroke. PMID- 29284574 TI - American College of Foot and Ankle Surgeons Clinical Consensus Statement: Diagnosis and Treatment of Adult Acquired Infracalcaneal Heel Pain. AB - Adult acquired inferior calcaneal heel pain is a common pathology seen in a foot and ankle practice. A literature review and expert panel discussion of the most common findings and treatment options are presented. Various diagnostic and treatment modalities are available to the practitioner. It is prudent to combine appropriate history and physical examination findings with patient-specific treatment modalities for optimum success. We present the most common diagnostic tools and treatment options, followed by a discussion of the appropriateness of each based on the published data and experience of the expert panel. PMID- 29284573 TI - Case Report: Late Reconstruction of the Land Mine-Injured Heel With an Osteomyocutaneous Composite Fibular Flap. AB - The heel comprises the epidermis, minimal subcutaneous tissue, a dense septum, and the calcaneus. Injury to any of these structures can impair the ability to walk. The soft tissue or calcaneal bone can be injured by trauma. Injuries incurred in war are usually high-energy traumas caused by weapons such as rifles, rockets, and land mines. Such injuries can be life threatening and involve the loss of tissue, including skin, soft tissue, bone, and neurovascular tissue. Two main treatment protocols are used for such injuries with large tissue defects: amputation and reconstruction. We describe a reconstruction with an osteomyocutaneous fibular flap for a heel injury. At the 2-year follow-up point, the patient had 30% loss of ankle range of motion. The visual analog scale score had dramatically decreased from 8 to 1, and the patient was satisfied with the result. In conclusion, patients with significant problems such as infection, pain, and anatomic deterioration of the calcaneus can be successfully treated using an osteomyocutaneous fibular flap in a single surgery. PMID- 29284575 TI - Does Weight Reduction Affect Foot Structure and the Strength of the Muscles That Move the Ankle in Obese Japanese Adults? AB - Obesity is considered a major influential factor of foot structure and function. It has been reported to result in detrimental alterations of foot structure indicators and a decrease in muscle strength, which can lower the quality of life and increase the morbidity of obesity. The purpose of the present study was to determine the effect of weight reduction on foot structure and the strength of the muscles that move the ankle in obese adults. A total of 33 obese Japanese participants (mean body mass index 28.49 +/- 2.87 kg/m2) without an exercise habit participated in a 12-week dietary modification program. Their foot structure indicators were measured using a 3-dimensional foot scanner, and the strength of the muscles that move the ankle was assessed using a dynamometer. After the dietary modification, the mean body weight reduction was 7.49 +/- 4.10 kg (9.38%; 77.82 +/- 13.26 kg before and 70.33 +/- 11.37 kg after; p <.001). The wide foot indicators, including the forefoot girth, rearfoot width, and instep girth, had decreased significantly (p <.05), and the decreases correlated positively with the weight reduction. Regarding the strength of the muscles that move the ankle, except for dorsiflexion, all the measured peak torque values per body weight had increased significantly (p <.01). These results suggest that the weight reduction induced by a 12-week dietary modification results in thinner feet and increased strength of the muscles that move the ankle. PMID- 29284576 TI - Effect of Obesity on Total Ankle Arthroplasty: A Systematic Review of Postoperative Complications Requiring Surgical Revision. AB - Total ankle arthroplasty has become an increasingly used alternative to ankle arthrodesis for the treatment of end-stage ankle arthritis. However, despite progressive technological advances and the advent of multiple commercial implant systems, some concern remains for the relatively high complication and failure rates. The objective of the present investigation was to perform a systematic review of the incidence of complications in obese patients undergoing total ankle arthroplasty. We performed a review of electronic databases with the inclusion criteria of retrospective case series, retrospective clinical cohort analyses, and prospective clinical trials with >=15 total participants, a mean follow-up period of >=12 months, >=1 defined cohort with a body mass index of >=30 kg/m2, and a reported incidence rate of complications requiring revisional surgery at the final follow-up point. Four studies met our inclusion criteria, with a total of 400 implants analyzed. Of these, >=71 (17.8%) developed a complication requiring a revisional surgical procedure. The most commonly reported surgeries were revision of the metallic components and ankle gutter debridement. It is our hope that our investigation will allow foot and ankle surgeons to more effectively communicate the perioperative risk to their patients during the education and consent process. PMID- 29284577 TI - Distinct Myocardial Targets for Diabetes Therapy in Heart Failure With Preserved or Reduced Ejection Fraction. AB - Noncardiac comorbidities such as diabetes mellitus (DM) have different outcomes in heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). These different outcomes are the result of distinct myocardial effects of DM on HFpEF and HFrEF, which relate to different mechanisms driving myocardial remodeling in each heart failure phenotype. Myocardial remodeling is driven by microvascular endothelial inflammation in HFpEF and by cardiomyocyte cell death in HFrEF. Evidence consists of: different biomarker profiles, in which inflammatory markers are prominent in HFpEF and markers of myocardial injury or wall stress are prominent in HFrEF; reduced coronary flow reserve with microvascular rarefaction in HFpEF; and upregulation of free radical-producing enzymes in endothelial cells in HFpEF and in cardiomyocytes in HFrEF. As biopsies from patients with diabetic cardiomyopathy reveal, DM affects failing myocardium by phenotype-specific mechanisms. In HFpEF, DM mainly increases cardiomyocyte hypertrophy and stiffness, probably because of hyperinsulinemia and microvascular endothelial inflammation. In HFrEF, DM augments replacement fibrosis because of cardiomyocyte cell death induced by lipotoxicity or advanced glycation end products. Because DM exerts distinct effects on myocardial remodeling in HFpEF and HFrEF, the heart failure phenotype is important for DM therapy. PMID- 29284578 TI - Sudden Cardiac Death in Athletes. AB - Sudden cardiac death is a tragedy at any age and under any circumstances but is perhaps most tragic when it claims the life of the athlete, the individual who epitomizes health and a healthy lifestyle. Sports cardiologists from around the world have worked to quantitate the incidence of sudden cardiac death (SCD) in the athlete, to identify risk factors, to develop pre-participation screening tools, and to formulate plans to deal with on-field SCD. Progress has been made, but much remains to be done in order to make both competitive and recreational sports safer for both patients with known cardiac disease and athletes without known or suspected cardiac abnormalities. PMID- 29284579 TI - Acute Heart Failure Is an Event Rather Than a Disease: Plea for a Radical Change in Thinking and in Therapeutic Drug Development. PMID- 29284580 TI - Acute Heart Failure Deserves a Log-Scale Boost in Research Support: Call for Multidisciplinary and Universal Actions. PMID- 29284581 TI - Greatness. PMID- 29284582 TI - I Don't Care How Low My BNP Is, I Want to Feel Good. PMID- 29284583 TI - Flosequinan: Morbidity and Mortality. PMID- 29284584 TI - Vitamin D as a Modifiable Risk Factor for Incident Heart Failure in Atrial Fibrillation. PMID- 29284586 TI - Paradigms and PARAGON-HF. PMID- 29284585 TI - Treatment of Hypertension to Prevent and Treat Heart Failure in Diabetic Patients Should Include Sodium Glucose Co-Transporter 2 Inhibitors. PMID- 29284587 TI - Current State of Knowledge About Cancer in Lesbians, Gay, Bisexual, and Transgender (LGBT) People. AB - OBJECTIVE: To review the current state of knowledge about cancer in lesbians, gay, bisexual, and transgender (LGBT) people by focusing on four major issues across the cancer continuum including: 1) lack of data collection on sexual orientation and gender identity; 2) need for a culturally competent workforce; 3) the need for a culturally competent health care system; and 4) creating LGBT tailored patient/client information and education. DATA SOURCES: Published literature. CONCLUSION: Oncology nurses and health care providers can work to improve the care of LGBT patients with cancer by following suggestions in this article. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses and other health care providers have many distinct occasions to improve overall cancer care for LGBT patients. PMID- 29284588 TI - The Personal Experience of LGBT Patients with Cancer. AB - OBJECTIVES: To capture the perspectives from lesbian, gay, bisexual and transgender (LGBT) individuals diagnosed treated for cancer. DATA SOURCES: Four LGBT individuals diagnosed and treated for cancer. CONCLUSION: Care for the LGBT patient is based on sensitivity and awareness to LGBT issues and concerns. IMPLICATIONS FOR NURSING PRACTICE: Nurses caring for the LGBT cancer patient provide that care in a context of awareness and sensitivity. The nurse's approach to LGBT patient and family care is based on open communication, establishing trusting relationships and honoring the patient's preferences. Excellent oncology nursing care for LGBT patients is excellent oncology nursing care. PMID- 29284589 TI - Serum alpha-fetoprotein level per total tumor volume as a predictor of recurrence of hepatocellular carcinoma after resection. AB - BACKGROUND: Alpha-fetoprotein has been used as a predictor of recurrence for hepatocellular carcinoma and disease-free survival post-resection. Studies in East Asia have shown that serum alpha-fetoprotein per total tumor volume ratio is a better prognostic indicator than alpha-fetoprotein alone. Similar studies in the United States evaluating serum alpha-fetoprotein to total tumor volume ratio have not been conducted. Its relevance is incompletely understood. METHODS: Consecutive patients undergoing resection for hepatocellular carcinoma at a single tertiary center between 2000 and 2013 were identified for inclusion in this retrospective cohort study. Patient demographics, associated liver disease, Child-Pugh and Model for End-Stage Liver Disease scores, preoperative imaging, surgical pathology, alpha-fetoprotein at diagnosis, last alpha-fetoprotein before surgery, and peak alpha-fetoprotein levels were recorded. Actual tumor volume by imaging volumetrics was used when available (n = 70). For the remaining cases, total tumor volume was calculated using the sum of the volumes of all the tumors ((4/3)pir3) where "r" is the mean radius of each lesion. Peak serum alpha fetoprotein was used to calculate the alpha-fetoprotein to total tumor volume ratio. RESULTS: A total of 124 patients resected for hepatocellular carcinoma between 2000 and 2013 were identified. Overall 1-, 3-, and 5-year survival post resection was 76%, 53%, and 35%, respectively. On multivariate analysis, peak alpha-fetoprotein to total tumor volume ratio > 20 (P < .001, HR = 3.72, 95% CI [1.82-7.58]) and lymphovascular space invasion (P = .002, HR = 3.30, 95% CI [1.57 6.94]) were found to affect hepatocellular carcinoma recurrence-free survival. CONCLUSION: A variety of prognostic values predict the recurrence of hepatocellular carcinoma postresection. Peak preoperative alpha-fetoprotein to total tumor volume > 20 and lymphovascular space invasion has been shown to predict recurrence of hepatocellular carcinoma. Our study confirms findings from East Asian studies. But larger series are needed to establish this correlation in patients with hepatocellular carcinoma not treated by resection. PMID- 29284590 TI - Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms. METHODS: The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow-up was 61 months. RESULTS: The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P=.047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P < .02). The incidence of nodal metastases at the time of resection was also less in the peptide receptor radionuclide therapy group (n= 9/23 vs 17/23; P<.02). Neither median disease-specific survival (not reached in either group; P=.411) nor progression-free survival (52 vs 37 months; P>.2) differed between groups, but progression-free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression-free survival not reached vs 36 months; P<.05). CONCLUSION: Neoadjuvant peptide receptor radionuclide therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms in patients with high-risk features of recurrence seems to be beneficial, but well-designed and much larger prospective trials are needed to confirm the safety and the oncologic value of this approach. PMID- 29284591 TI - Timing of parathyroidectomy in kidney transplant candidates with secondary hyperparathryroidism: effect of pretransplant versus early or late post transplant parathyroidectomy. AB - BACKGROUND: The timing of parathyroidectomy in kidney transplant candidates suffering from secondary hyperparathyroidism before versus early or late after transplantation remains controversial. METHODS: The short-term follow-up cohort comprised 66 patients with 1-year post-transplant follow-up, while the long-term follow-up cohort contained 123 patients. Risk-adjusted identification of independent risk factors for compromised renal graft function (KDIGO stage >= IV) was performed using multivariable regression analysis adjusted for propensity score logits for parathyroidectomy before versus after renal transplantation. Intra-individual matched-pairs analyses were used to identify significant effects of post-transplant parathyroidectomy on graft function as assessed by estimated glomerular filtration rate (eGFR) and paired t tests. RESULTS: Donor kidney function KDIGO stage III (P = .030; OR = 5.191, 95% CI: 1.100-24.508), donor blood group 0 (P = .005; OR = 0.176, 95% CI: 0.048-0.642), and post-transplant parathyroidectomy (P = .032; OR = 17.849, 95% CI: 1.086-293.268) were revealed as independent significant risk factors for compromised renal graft function in the short-term follow-up cohort using propensity score risk adjustment while post transplant parathyroidectomy had no independent influence in the long-term follow up cohort (P = .651). Parathyroidectomy after renal transplantation compromised graft function early after parathyroidectomy and at last follow-up in all post transplant parathyroidectomy cases (P <= .004). Parathyroidectomy within the first post-transplant year was associated with compromised renal graft function until last follow-up (P = .004), while parathyroidectomy late post-transplant was not. CONCLUSION: Parathyroidectomy should be conducted before transplantation or, if this is not possible, preferably after the first post-transplant year. PMID- 29284592 TI - Comparison of ethical issues in Indian and New Zealand prospective studies of cervical pre-cancer. AB - The aim was to compare the ethics of historical Indian and New Zealand prospective studies of cervical pre-cancer in terms of: scientific justification, potential harms and benefits to subjects, informed consent procedures, monitoring and stopping, and exploitation. The New Zealand study had poorer scientific justification, greater harm to subjects, absence of informed consent, and greater exploitation. Reasons proposed for on-going criticism of the Indian study are: semantic confusion, lack of consistent detail about informed consent procedures, and failure of a professional obligation to provide on-going medical care. Such criticisms might have been set on a firmer basis, or rejected, if there had been a public judicial inquiry, as happened in New Zealand. Current disagreement about the ethics of randomised trials of cervical screening in India might be resolved through a public inquiry. PMID- 29284593 TI - Antigen Analysis of Pre-Eclamptic Plasma Antibodies Using Escherichia Coli Proteome Chips. AB - Pre-eclampsia is one of the main causes of perinatal mortality and morbidity. Many biomarkers for diagnosing pre-eclampsia have been found but most have low accuracy. Therefore, a potential marker that can detect pre-eclampsia with high accuracy is required. Infection has been reported as a cause of pre-eclampsia. In recent years, protein microarray chips have been recognized as a strong and robust tool for profiling antibodies for infection diagnoses. The purpose of the present study was to profile antibodies in the human plasma of healthy and pre eclamptic pregnancies to identify suitable biomarkers. In this study, an Escherichia coli chip was probed with samples from 29 individuals (16 pre eclamptic women and 13 healthy pregnant women) to profile plasma antibodies. Bioinformatics tools were used to analyze the results, discover conserved motifs, compare against the entire human proteome, and perform protein functional analysis. An antibody classifier was identified using k-top scoring pairs and additional samples for a blinded test were collected. The findings indicated that compared with the healthy women, the pre-eclamptic women exhibited 108 and 130 differentially immunogenic proteins against human immunoglobulins G and M, respectively. In addition, pre-eclamptic women developed more immunoglobulin G but less immunoglobulin M against bacterial surface proteins compared with healthy women. The k-top scoring pairs identified five pairs of immunogenic proteins as classifiers with a high accuracy of 90% in the blind test. [AG] [ISV] GV [AE] L [LF] and [IV] [IV] RI [AG] [AD] E were the consensus motifs observed in immunogenic proteins in the immunoglobulin G and immunoglobulin M of pre eclamptic women, respectively, whereas GA [AG] [AL] L [LF] and [SRY] [IQML] [ILV] [ILV] [ACG] GI [GH] [AEF] [AK] [ATY] [RG] N [IV] were observed in the immunoglobulins G and immunoglobulin M of healthy women, respectively. PMID- 29284594 TI - Low dose CT screening for lung cancer. PMID- 29284595 TI - Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome. AB - To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1beta (IL-1beta) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) kappa paraprotein was detected in 86%; the remainder had IgM lambda or IgG kappa. Patients underwent searches for germ line and somatic mutations using next generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3, TNFRSF1A, NLRC4, or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients. PMID- 29284596 TI - Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. AB - Early response to induction chemotherapy is an important prognostic factor in B lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC. PMID- 29284598 TI - Noninvasive Assessment of Intracranial Pressure Status in Idiopathic Intracranial Hypertension Using Displacement Encoding with Stimulated Echoes (DENSE) MRI: A Prospective Patient Study with Contemporaneous CSF Pressure Correlation. AB - BACKGROUND AND PURPOSE: Intracranial pressure is estimated invasively by using lumbar puncture with CSF opening pressure measurement. This study evaluated displacement encoding with stimulated echoes (DENSE), an MR imaging technique highly sensitive to brain motion, as a noninvasive means of assessing intracranial pressure status. MATERIALS AND METHODS: Nine patients with suspected elevated intracranial pressure and 9 healthy control subjects were included in this prospective study. Controls underwent DENSE MR imaging through the midsagittal brain. Patients underwent DENSE MR imaging followed immediately by lumbar puncture with opening pressure measurement, CSF removal, closing pressure measurement, and immediate repeat DENSE MR imaging. Phase-reconstructed images were processed producing displacement maps, and pontine displacement was calculated. Patient data were analyzed to determine the effects of measured pressure on pontine displacement. Patient and control data were analyzed to assess the effects of clinical status (pre-lumbar puncture, post-lumbar puncture, or control) on pontine displacement. RESULTS: Patients demonstrated imaging findings suggesting chronically elevated intracranial pressure, whereas healthy control volunteers demonstrated no imaging abnormalities. All patients had elevated opening pressure (median, 36.0 cm water), decreased by the removal of CSF to a median closing pressure of 17.0 cm water. Patients pre-lumbar puncture had significantly smaller pontine displacement than they did post-lumbar puncture after CSF pressure reduction (P = .001) and compared with controls (P = .01). Post-lumbar puncture patients had statistically similar pontine displacements to controls. Measured CSF pressure in patients pre- and post-lumbar puncture correlated significantly with pontine displacement (r = 0.49; P = .04). CONCLUSIONS: This study establishes a relationship between pontine displacement from DENSE MR imaging and measured pressure obtained contemporaneously by lumbar puncture, providing a method to noninvasively assess intracranial pressure status in idiopathic intracranial hypertension. PMID- 29284597 TI - An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. AB - B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% +/- 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% +/- 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI- and BCMA-TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach. PMID- 29284599 TI - Spinal Arteriovenous Vascular Malformations in Patients with Neural Tube Defects. AB - BACKGROUND AND PURPOSE: Neural tube defects, such as tethered cord, intradural lipoma, or myelomeningocele may coexist with spinal vascular malformations. The coexistence of these 2 rare entities is suggestive of a causal relationship between them, which may lead to further understanding of their pathogenesis. We present a series of 6 patients with epidural spinal arteriovenous fistulas associated with neural tube defects. MATERIALS AND METHODS: We retrieved cases of spinal vascular malformations associated with neural tube defects seen at our institution. The clinical presentation, MR imaging/MRA and angiographic imaging, treatment outcomes, and long-term neurologic outcomes were analyzed. Descriptive statistical analyses are reported. RESULTS: Six patients with epidural arteriovenous fistulas and neural tube defects were included in this study. The mean age at presentation was 42 years, and the most common presenting symptoms were lower extremity weakness followed by sensory disturbances and bladder/bowel dysfunction. In most cases (5/6), the fistulas were located at the sacral level. All cases were fed by the lateral sacral artery (6/6). Four patients had prior spine surgery, but the fistula was in the operative bed in 2 cases. All fistulas were extradural with secondary intradural venous drainage. Five patients underwent transarterial embolization with Onyx, and 1 patient had a treatment related complication. CONCLUSIONS: It is conceivable that there is a pathophysiologic link between neural tube defects and development of spinal vascular malformations. Delayed neurologic deterioration or high conus signal in a patient with a neural tube defect should suggest the possibility of such an association. PMID- 29284600 TI - MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia. AB - BACKGROUND AND PURPOSE: MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia. MATERIALS AND METHODS: MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the chi2 test. RESULTS: The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas. CONCLUSIONS: MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases. PMID- 29284601 TI - Clinical and Radiologic Characteristics of Deep Lumbosacral Dural Arteriovenous Fistulas. AB - BACKGROUND AND PURPOSE: Spinal dural arteriovenous fistulas located in the deep lumbosacral region are rare and the most difficult to diagnose among spinal dural arteriovenous fistulas located elsewhere in the spinal dura. Specific clinical and radiologic features of these fistulas are still inadequately reported and are the subject of this study. MATERIALS AND METHODS: We retrospectively evaluated all data of patients with spinal dural arteriovenous fistulas treated and/or diagnosed in our institution between 1990 and 2017. Twenty patients with deep lumbosacral spinal dural arteriovenous fistulas were included in this study. RESULTS: The most common neurologic findings at the time of admission were paraparesis (85%), sphincter dysfunction (70%), and sensory disturbances (20%). Medullary T2 hyperintensity and contrast enhancement were present in most cases. The filum vein and/or lumbar veins were dilated in 19/20 (95%) patients. Time resolved contrast-enhanced dynamic MRA indicated a spinal dural arteriovenous fistula at or below the L5 vertebral level in 7/8 (88%) patients who received time-resolved contrast-enhanced dynamic MRA before DSA. A bilateral arterial supply of the fistula was detected via DSA in 5 (25%) patients. CONCLUSIONS: Clinical symptoms caused by deep lumbosacral spinal dural arteriovenous fistulas are comparable with those of spinal dural arteriovenous fistulas at other locations. Medullary congestion in association with an enlargement of the filum vein or other lumbar radicular veins is a characteristic finding in these patients. Spinal time-resolved contrast-enhanced dynamic MRA facilitates the detection of the drainage vein and helps to localize deep lumbosacral-located fistulas with a high sensitivity before DSA. Definite detection of these fistulas remains challenging and requires sufficient visualization of the fistula supplying arteries and draining veins by conventional spinal angiography. PMID- 29284602 TI - Cervical Cord Atrophy and Long-Term Disease Progression in Patients with Primary Progressive Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Cervical cord atrophy has been associated with clinical disability in multiple sclerosis and is proposed as an outcome measure of neurodegeneration. The aim of this study was to quantify the development of cervical cord atrophy and to evaluate its association with disability progression in patients with primary-progressive multiple sclerosis. MATERIALS AND METHODS: Thirty-one patients with primary-progressive multiple sclerosis underwent 1.5T brain and spinal cord MR imaging at baseline and 6-7 years later. The cervical spinal cord from C1 to C5 was segmented to evaluate the normalized overall cross sectional area and the cross-sectional area of C2-C3, C3-C4, and C4-C5. The annualized rates of normalized cross-sectional area loss were also evaluated. To estimate clinical progression, we determined the Expanded Disability Status Scale score at baseline and at 2 and 14 years after baseline to compute the normalized area under the curve of the Expanded Disability Status Scale and the Expanded Disability Status Scale changes from baseline to the follow-up time points. Associations between the cord cross-sectional area and brain MR imaging and clinical measures were also investigated. Finally, the value of all these measures for predicting long-term disability was evaluated. RESULTS: Some normalized cross-sectional area measurements showed moderate correlations with the normalized area under the curve of the Expanded Disability Status Scale, ranging from -0.439 to -0.359 (P < .05). Moreover, the annualized rate of the normalized mean cross-sectional area loss and the baseline Expanded Disability Status Scale were independent predictors of long-term disability progression. CONCLUSIONS: These data indicate that development of cervical cord atrophy is associated with progression of disability and is predictive of this event in patients with primary-progressive MS. PMID- 29284603 TI - Cerebrovascular Manifestations of Neurosarcoidosis: An Underrecognized Aspect of the Imaging Spectrum. AB - Involvement of the central nervous system by sarcoidosis, also referred to as neurosarcoidosis, is seen clinically in about 5% of patients with systemic disease. CNS involvement most frequently affects the leptomeninges and cranial nerves, though the ventricular system, brain parenchyma, and pachymeninges may also be involved. Even though the involvement of the intracranial vascular structures is well-known on postmortem studies, there is scant literature on imaging manifestations secondary to the vessel wall involvement, being confined mostly to isolated case reports and small series. The authors present a review of various cerebrovascular manifestations of neurosarcoidosis, along with a brief synopsis of the existing literature. PMID- 29284604 TI - Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor): Implications for the Efficacy of Evolocumab. AB - OBJECTIVE: Evolocumab, a PCSK9 (proprotein convertase subtilisin kexin type 9) neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemic (HoFH) patients with reduced LDLR (low density lipoprotein receptor) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition. APPROACH AND RESULTS: Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial (Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders). Ten patients were true homozygotes (FH1/FH1) and 5 identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9-neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased, whereas rPCSK9 reduced LDLR expression. The PCSK9-neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, before and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C on evolocumab treatment. CONCLUSIONS: Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab. PMID- 29284605 TI - Filamin A Modulates Store-Operated Ca2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets. AB - OBJECTIVE: Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE). APPROACH AND RESULTS: SOCE is a major mechanism for calcium influx controlled by the intracellular Ca2+ stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood. Our results demonstrate that STIM1 interacts with FLNA on calcium store depletion in human platelets. The interaction is dependent on the phosphorylation of FLNA at Ser2152 by the cAMP-dependent protein kinase. Impairment of FLNA phosphorylation and knockdown of FLNA expression using siRNA increased SOCE in platelets. Similarly, SOCE was significantly greater in FLNA deficient melanoma M2 cells than in the FLNA-expressing M2 subclone A7. Expression of FLNA in M2 cells attenuated SOCE, an effect prevented when the cells were transfected with the nonphosphorylatable FLNA S2152A mutant. Transfection of M2 cells with the STIM1(K684,685E) mutant reduced the STIM1-FLNA interaction. In platelets, attenuation of FLNA expression using siRNA resulted in enhanced association of STIM1 with the cytoskeleton, greater STIM1-Orai1 interaction, and SOCE. Introduction of an anti-FLNA (2597-2647) antibody attenuated the STIM1-FLNA interaction and enhanced thrombin-induced platelet aggregation. CONCLUSIONS: Our results indicate that FLNA modulates SOCE and then the correct platelet function, by fine-tuning the distribution of STIM1 in the cytoskeleton and the interaction with Orai1 channels. PMID- 29284606 TI - Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling. AB - OBJECTIVE: The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High vascular endothelial growth factor activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of prostabilization signals are still mostly unknown. Bone morphogenetic protein receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for growth differentiation factor 6 (GDF6; bone morphogenetic protein 13) in vascular integrity although GDF6's mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization. APPROACH AND RESULTS: We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured human umbilical vein endothelial cells in vitro. We report that GDF6 promotes vascular integrity by counteracting vascular endothelial growth factor activity. GDF6-deficient endothelium has increased vascular endothelial growth factor signaling, increased vascular endothelial-cadherin Y658 phosphorylation, vascular endothelial-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak. CONCLUSIONS: Our results suggest that GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans. PMID- 29284607 TI - Weight Loss and Exercise Alter the High-Density Lipoprotein Lipidome and Improve High-Density Lipoprotein Functionality in Metabolic Syndrome. AB - OBJECTIVE: High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. APPROACH AND RESULTS: Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. CONCLUSIONS: WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943. PMID- 29284608 TI - Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/ Mice. AB - OBJECTIVE: The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. APPROACH AND RESULTS: Apoe-/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1re/e) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe-/- Mc1re/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe-/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe-/- Mc1re/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6Chigh monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6Chigh monocytes, these cells had increased expression of L selectin and P-selectin glycoprotein ligand 1. CONCLUSIONS: The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. PMID- 29284610 TI - Initial Hodgkin treatment of the frail elderly. PMID- 29284609 TI - DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells. AB - OBJECTIVE: DKK3 (dickkopf 3), a 36-kD secreted glycoprotein, has been shown to be involved in the differentiation of partially reprogrammed cells and embryonic stem cells to smooth muscle cells (SMCs), but little is known about its involvement in vascular disease. This study aims to assess the effects of DKK3 on atherosclerotic plaque composition. APPROACH AND RESULTS: In the present study, we used a murine model of atherosclerosis (ApoE-/-) in conjunction with DKK3-/- and performed tandem stenosis of the carotid artery to evaluate atherosclerotic plaque development. We found that the absence of DKK3 leads to vulnerable atherosclerotic plaques, because of a reduced number of SMCs and reduced matrix protein deposition, as well as increased hemorrhage and macrophage infiltration. Further in vitro studies revealed that DKK3 can induce differentiation of Sca1+ (stem cells antigen 1) vascular progenitors and fibroblasts into SMCs via activation of the TGF-beta (transforming growth factor-beta)/ATF6 (activating transcription factor 6) and Wnt signaling pathways. Finally, we assessed the therapeutic potential of DKK3 in mouse and rabbit models and found that DKK3 altered the atherosclerotic plaque content via increasing SMC numbers and reducing vascular inflammation. CONCLUSIONS: Cumulatively, we provide the first evidence that DKK3 is a potent SMC differentiation factor, which might have a therapeutic effect in reducing intraplaque hemorrhage related to atherosclerotic plaque phenotype. PMID- 29284611 TI - DNA distress creates lethal opportunity in MPN. PMID- 29284612 TI - VAMP-3 mediates platelet endocytosis. PMID- 29284613 TI - Rapidly fatal Klebsiella pneumoniae sepsis in a patient with pyruvate kinase deficiency and asplenia. PMID- 29284614 TI - How Far to Babylon? PMID- 29284615 TI - The future of general practice: brave new dawn or dark skies ahead? PMID- 29284616 TI - Harnessing the power of intelligent machines to enhance primary care. PMID- 29284618 TI - Lifting the dead hand on general practice. PMID- 29284617 TI - Epigenetics and primary care. PMID- 29284619 TI - Ambulatory emergency care: how should acute generalists manage risk in undifferentiated illness? PMID- 29284620 TI - The future role of receptionists in primary care. PMID- 29284621 TI - 'Reception' teams. PMID- 29284622 TI - STPs: occupational therapists and physiotherapists can support GPs. PMID- 29284623 TI - It's time for GPs to be recognised as the specialists they are. PMID- 29284624 TI - Barriers and facilitators to integration of physician associates into the general practice workforce: a grounded theory approach. PMID- 29284626 TI - Viewpoint: A perfect example of a new-fashioned GP. PMID- 29284625 TI - Corrections. PMID- 29284627 TI - Viewpoint: Doctor daughter. PMID- 29284628 TI - Consultations start in the waiting room. PMID- 29284629 TI - Seeing double: expanding GP capacity through teamwork and redesign. PMID- 29284630 TI - My experience of being a doctor with psychosis. PMID- 29284631 TI - Worlds apart: a reflection on a Ugandan elective. PMID- 29284632 TI - Yonder: Health passports, online communities, sick leave, and emojis. PMID- 29284633 TI - Bad Medicine: You and the i-patient effect. PMID- 29284634 TI - Exhibition: Impressionists in London: French artists in exile 1870-1904: Mixed Impressions. PMID- 29284637 TI - Chaos. PMID- 29284638 TI - Primary care co-commissioning: challenges faced by clinical commissioning groups in England. PMID- 29284639 TI - Combining professional and lay knowledge to improve patient care. PMID- 29284640 TI - The IMPACT Q framework: teaching medical students how to gather a psychosocial history. PMID- 29284641 TI - Cervical radiculopathy and cervical myelopathy: diagnosis and management in primary care. PMID- 29284642 TI - Speech and language delay in children: a case to learn from. PMID- 29284643 TI - Corneal ulcers in general practice. PMID- 29284646 TI - A Drug Regimen for Progressive Familial Cholestasis Type 2. AB - Progressive familial cholestasis type 2 is caused by a genetically determined absence or reduction in the activity of the bile salt export pump (BSEP). Reduction or absence of BSEP activity causes a failure of bile salt excretion, leading to accumulation of bile salts in hepatocytes and subsequent hepatic damage. Clinically, patients are jaundiced, suffer from severe intractable pruritus, and evidence progressive liver dysfunction. A low level of serum gamma glutamyl transpeptidase, when associated with the described signs and symptoms, is often an early identifier of this condition. Treatment options to date include liver transplantation and the use of biliary diversion. We report a multidrug regimen of 4-phenylbutyrate, oxcarbazepine, and maralixibat (an experimental drug owned by Shire Pharmaceuticals, Dublin, Republic of Ireland) that completely controlled symptoms in 2 siblings with partial loss of BSEP activity. PMID- 29284647 TI - The new Neurology: Designed for reader engagement and increased depth of research reporting. PMID- 29284645 TI - Reading Aloud and Child Development: A Cluster-Randomized Trial in Brazil. AB - OBJECTIVES: Many children in low- and middle-income countries fail to reach their developmental potential. We sought to determine if a parenting program focused on the promotion of reading aloud enhanced parent-child interactions and child development among low-income families in northern Brazil. METHODS: This was a cluster-randomized study of educational child care centers randomly assigned to receive an additional parenting program (intervention) or standard child care without a parenting component (control). Parent-child dyads were enrolled at the beginning of the school year and were assessed at enrollment and at the end of the school year. Families in intervention centers could borrow children's books on a weekly basis and could participate in monthly parent workshops focused on reading aloud. We compared parents and children in intervention and control centers 9 months after the start of the intervention on measures of parent-child interaction and child language, cognitive, and social-emotional development. RESULTS: Five hundred and sixty-six parent-child dyads (279 intervention; 287 control) in 12 child care clusters (26-76 children per cluster) were assessed at enrollment; 464 (86%) contributed follow-up data. Parents in the intervention group engaged in significantly greater cognitive stimulation (Cohen's d = 0.43) and higher quantity and quality of reading interactions (d = 0.52-0.57) than controls; children in the intervention scored significantly higher than controls on receptive vocabulary (d = 0.33), working memory (d = 0.46), and IQ (d = 0.33). CONCLUSIONS: An innovative program focused on the promotion of parent-child reading aloud resulted in benefits to parent-child interactions and to child language and cognitive development that were greater than those provided by educational child care alone. This promising approach merits further evaluation at scale. PMID- 29284644 TI - COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin. AB - Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner. Mol Cancer Ther; 17(2); 474-83. (c)2017 AACR. PMID- 29284648 TI - Amyloid polyneuropathy in 2 patients after liver transplantation. PMID- 29284649 TI - Resident & Fellow Rounds. PMID- 29284650 TI - Residency Training: The Review Committee for Neurology: Revisions to the Common Program Requirements. PMID- 29284651 TI - Editors' note: Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage. PMID- 29284652 TI - Reader response: Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage. PMID- 29284654 TI - Editors' note: l-Dopa in dystonia: A modern perspective. PMID- 29284653 TI - Author response: Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage. PMID- 29284655 TI - Reader response: l-Dopa in dystonia: A modern perspective. PMID- 29284656 TI - Author response: l-Dopa in dystonia: A modern perspective. PMID- 29284657 TI - Clinical Reasoning: A 49-year-old man with progressive numbness, weakness, and evidence of leptomeningeal enhancement. PMID- 29284658 TI - Teaching NeuroImages: Leber hereditary optic neuropathy masquerading as neuromyelitis optica. PMID- 29284659 TI - A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP 1 Receptor Signaling in Pancreatic beta-Cells. AB - The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic beta-cells. We identify five (clathrin, dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) that increase and four (huntingtin-interacting protein 1 [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analog exendin-4. The roles of HIP1 and the endosomal SNX1 and SNX27 were further characterized in mouse and human beta-cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the SNXs were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation and, in doing so, determine the overall beta-cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D. PMID- 29284662 TI - Junctional trafficking and restoration of retrograde signaling by the cytoplasmic RyR1 domain. AB - The type 1 ryanodine receptor (RyR1) in skeletal muscle is a homotetrameric protein that releases Ca2+ from the sarcoplasmic reticulum (SR) in response to an "orthograde" signal from the dihydropyridine receptor (DHPR) in the plasma membrane (PM). Additionally, a "retrograde" signal from RyR1 increases the amplitude of the Ca2+ current produced by CaV1.1, the principle subunit of the DHPR. This bidirectional signaling is thought to depend on physical links, of unknown identity, between the DHPR and RyR1. Here, we investigate whether the isolated cytoplasmic domain of RyR1 can interact structurally or functionally with CaV1.1 by producing an N-terminal construct (RyR11:4300) that lacks the C terminal membrane domain. In CaV1.1-null (dysgenic) myotubes, RyR11:4300 is diffusely distributed, but in RyR1-null (dyspedic) myotubes it localizes in puncta at SR-PM junctions containing endogenous CaV1.1. Fluorescence recovery after photobleaching indicates that diffuse RyR11:4300 is mobile, whereas resistance to being washed out with a large-bore micropipette indicates that the punctate RyR11:4300 stably associates with PM-SR junctions. Strikingly, expression of RyR11:4300 in dyspedic myotubes causes an increased amplitude, and slowed activation, of Ca2+ current through CaV1.1, which is almost identical to the effects of full-length RyR1. Fast protein liquid chromatography indicates that ~25% of RyR11:4300 in diluted cytosolic lysate of transfected tsA201 cells is present in complexes larger in size than the monomer, and intermolecular fluorescence resonance energy transfer implies that RyR11:4300 is significantly oligomerized within intact tsA201 cells and dyspedic myotubes. A large fraction of these oligomers may be homotetramers because freeze-fracture electron micrographs reveal that the frequency of particles arranged like DHPR tetrads is substantially increased by transfecting RyR-null myotubes with RyR11:4300 In summary, the RyR1 cytoplasmic domain, separated from its SR membrane anchor, retains a tendency toward oligomerization/tetramerization, binds to SR-PM junctions in myotubes only if CaV1.1 is also present and is fully functional in retrograde signaling to CaV1.1. PMID- 29284660 TI - The ModERN Resource: Genome-Wide Binding Profiles for Hundreds of Drosophila and Caenorhabditis elegans Transcription Factors. AB - To develop a catalog of regulatory sites in two major model organisms, Drosophila melanogaster and Caenorhabditis elegans, the modERN (model organism Encyclopedia of Regulatory Networks) consortium has systematically assayed the binding sites of transcription factors (TFs). Combined with data produced by our predecessor, modENCODE (Model Organism ENCyclopedia Of DNA Elements), we now have data for 262 TFs identifying 1.23 M sites in the fly genome and 217 TFs identifying 0.67 M sites in the worm genome. Because sites from different TFs are often overlapping and tightly clustered, they fall into 91,011 and 59,150 regions in the fly and worm, respectively, and these binding sites span as little as 8.7 and 5.8 Mb in the two organisms. Clusters with large numbers of sites (so-called high occupancy target, or HOT regions) predominantly associate with broadly expressed genes, whereas clusters containing sites from just a few factors are associated with genes expressed in tissue-specific patterns. All of the strains expressing GFP tagged TFs are available at the stock centers, and the chromatin immunoprecipitation sequencing data are available through the ENCODE Data Coordinating Center and also through a simple interface (http://epic.gs.washington.edu/modERN/) that facilitates rapid accessibility of processed data sets. These data will facilitate a vast number of scientific inquiries into the function of individual TFs in key developmental, metabolic, and defense and homeostatic regulatory pathways, as well as provide a broader perspective on how individual TFs work together in local networks and globally across the life spans of these two key model organisms. PMID- 29284664 TI - LPAAT3 incorporates docosahexaenoic acid into skeletal muscle cell membranes and is upregulated by PPARdelta activation. AB - Adaption of skeletal muscle to endurance exercise includes PPARdelta- and AMP activated protein kinase (AMPK)/PPARgamma coactivator 1alpha-mediated transcriptional responses that result in increased oxidative capacity and conversion of glycolytic to more oxidative fiber types. These changes are associated with whole-body metabolic alterations including improved glucose handling and resistance to obesity. Increased DHA (22:6n-3) content in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is also reported in endurance exercise-trained glycolytic muscle; however, the DHA-metabolizing enzymes involved and the biological significance of the enhanced DHA content are unknown. In the present study, we identified lysophosphatidic acid acyltransferase (LPAAT)3 as an enzyme that was upregulated in myoblasts during in vitro differentiation and selectively incorporated DHA into PC and PE. LPAAT3 expression was increased by pharmacological activators of PPARdelta or AMPK, and combination treatment led to further increased LPAAT3 expression and enhanced incorporation of DHA into PC and PE. Our results indicate that LPAAT3 was upregulated by exercise-induced signaling pathways and suggest that LPAAT3 may also contribute to the enhanced phospholipid-DHA content of endurance-trained muscles. Identification of DHA-metabolizing enzymes in the skeletal muscle will help to elucidate broad metabolic effects of DHA. PMID- 29284665 TI - "Drunk tanks" are studied over festive period to see if they ease pressure on emergency departments. PMID- 29284661 TI - Effect of Ibuprofen on Skeletal Muscle of Dysferlin-Null Mice. AB - Ibuprofen, a nonsteroidal anti-inflammatory drug, and nitric oxide (NO) donors have been reported to reduce the severity of muscular dystrophies in mice associated with the absence of dystrophin or alpha-sarcoglycan, but their effects on mice that are dystrophic due to the absence of dysferlin have not been examined. We have tested ibuprofen, as well as isosorbide dinitrate (ISDN), a NO donor, to learn whether used alone or together they protect dysferlin-null muscle in A/J mice from large strain injury (LSI) induced by a series of high strain lengthening contractions. Mice were maintained on chow containing ibuprofen and ISDN for 4 weeks. They were then subjected to LSI and maintained on the drugs for 3 additional days. We measured loss of torque immediately following injury and at day 3 postinjury, fiber necrosis, and macrophage infiltration at day 3 postinjury, and serum levels of the drugs at the time of euthanasia. Loss of torque immediately after injury was not altered by the drugs. However, the torque on day 3 postinjury significantly decreased as a function of ibuprofen concentration in the serum (range, 0.67-8.2 ug/ml), independent of ISDN. The effects of ISDN on torque loss at day 3 postinjury were not significant. In long term studies of dysferlinopathic BlAJ mice, lower doses of ibuprofen had no effects on muscle morphology, but reduced treadmill running by 40%. Our results indicate that ibuprofen can have deleterious effects on dysferlin-null muscle and suggest that its use at pharmacological doses should be avoided by individuals with dysferlinopathies. PMID- 29284666 TI - Is the concept of clinical equipoise still relevant to research? PMID- 29284670 TI - NHS data don't confirm Labour's claim of 100 000 vacant posts in England. PMID- 29284668 TI - PARP1-dependent eviction of the linker histone H1 mediates immediate early gene expression during neuronal activation. AB - Neuronal stimulation leads to immediate early gene (IEG) expression through calcium-dependent mechanisms. In recent years, considerable attention has been devoted to the transcriptional responses after neuronal stimulation, but relatively little is known about the changes in chromatin dynamics that follow neuronal activation. Here, we use fluorescence recovery after photobleaching, biochemical fractionations, and chromatin immunoprecipitation to show that KCl induced depolarization in primary cultured cortical neurons causes a rapid release of the linker histone H1 from chromatin, concomitant with IEG expression. H1 release is repressed by PARP inhibition, PARP1 deletion, a non-PARylatable H1, as well as phosphorylation inhibitions and a nonphosphorylatable H1, leading to hindered IEG expression. Further, H1 is replaced by PARP1 on IEG promoters after neuronal stimulation, and PARP inhibition blocks this reciprocal binding response. Our results demonstrate the relationship between neuronal excitation and chromatin plasticity by identifying the roles of polyadenosine diphosphate ribosylation and phosphorylation of H1 in regulating H1 chromatin eviction and IEG expression in stimulated neurons. PMID- 29284671 TI - Dietary Energy Density, Glycemic Load, Glycemic Index, and Risk for Endometrial Cancer in the CPS-II Nutrition Cohort. AB - Background: The glycemic potential and energy density (ED) of diet may influence endometrial cancer risk. Although glycemic load (GL) is considered a probable risk factor for endometrial cancer, no studies have evaluated the association of total dietary ED with risk.Methods: We evaluated associations of ED, GL, and glycemic index (GI) with postmenopausal endometrial cancer incidence. Analyses included 30,997 postmenopausal women from the Cancer Prevention Study II Nutrition Cohort with no previous history of cancer or diabetes, who provided information on diet, lifestyle, and medical history in 1999 and were followed for cancer incidence through June 2013. Multivariable-adjusted HRs and 95% confidence intervals were estimated for quartiles (Q) of total dietary ED, GL, and GI in relation to endometrial cancer incidence using Cox proportional hazards regression models.Results: During a median follow-up time of 13.6 years, 425 endometrial cancer cases were identified. Median dietary ED was 1.5 kcal/g [interquartile range (IQR) = 1.3-1.7 kcal/g]. Median (IQR) GL and GI were 113.7 (100.5-126.8) and 52.5 (50.4-54.5), respectively. After adjustment for age, use of hormone replacement therapy, physical activity, and body mass index (kg/m2), neither ED, GL, nor GI were associated with endometrial cancer risk.Conclusions: We found no associations of ED, GL, or GI with endometrial cancer risk.Impact: These results do not support an association between total dietary ED, GL, or GI and risk of postmenopausal endometrial cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 113-5. (c)2017 AACR. PMID- 29284669 TI - MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification. AB - The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320-35. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 253. PMID- 29284672 TI - Hospice Admission and Survival After 18F-Fluoride PET Performed for Evaluation of Osseous Metastatic Disease in the National Oncologic PET Registry. AB - We have previously reported that PET using 18F-fluoride (NaF PET) for assessment of osseous metastatic disease was associated with substantial changes in intended management in Medicare beneficiaries participating in the National Oncologic PET Registry (NOPR). Here, we use Medicare administrative data to examine the association between NaF PET results and hospice claims within 180 d and 1-y survival. Methods: We classified NOPR NaF PET results linked to Medicare claims by imaging indication (initial staging [IS]; detection of suspected first osseous metastasis [FOM]; suspected progression of osseous metastasis [POM]; or treatment monitoring [TM]) and type of cancer (prostate, lung, breast, or other). Results were classified as definitely positive scan findings versus probably positive scan findings versus negative scan findings for osseous metastasis for IS and FOM; more extensive disease versus no change or less extensive disease for POM; and worse prognosis versus no change or better prognosis for TM, based on the postscan assessment. Our study included 21,167 scans obtained from 2011 to 2014 of consenting NOPR participants aged 65 y or older. Results: The relative risk of hospice claims within 180 d of a NaF PET scan was 2.0-7.5 times higher for patients with evidence of new or progressing osseous metastasis than for those without, depending on indication and cancer type (all P < 0.008). The percentage difference in hospice claims for those with a finding of new or more advanced osseous disease ranged from 3.9% for IS prostate patients to 28% for FOM lung patients. Six-month survival was also associated with evidence of new or increased osseous disease; risk of death was 1.8-5.1 times as likely (all P <= 0.0001), with percentage differences of approximately 30% comparing positive and negative scans in patients with lung cancer imaged for IS or FOM. Conclusion: Our analyses demonstrated that NaF PET scan results are highly associated with subsequent hospice claims and, ultimately, with patient survival. NaF PET provides important information on the presence of osseous metastasis and prognosis to assist patients and their physicians when making decisions on whether to select palliative care and transition to hospice or whether to continue treatment. PMID- 29284673 TI - Recent Advances in 18F Radiochemistry: A Focus on B-18F, Si-18F, Al-18F, and C 18F Radiofluorination via Spirocyclic Iodonium Ylides. AB - Straightforward radiosynthesis protocols for 18F-labeled radiopharmaceuticals are an indispensable but often overlooked prerequisite to successfully perform molecular imaging studies in vivo by PET. In recent years, thanks to the expansion of the 18F chemical toolbox, structurally diverse and novel clinically relevant radiopharmaceuticals have been synthesized with both high efficiency and ready implementation. This article provides an overview of recent 18F-labeling methodologies, specifically for B-18F, Si-18F, Al-18F, and iodine (III)-mediated radiofluorination via the spirocyclic iodonium ylide technology. PMID- 29284667 TI - Building the right centriole for each cell type. AB - The centriole is a multifunctional structure that organizes centrosomes and cilia and is important for cell signaling, cell cycle progression, polarity, and motility. Defects in centriole number and structure are associated with human diseases including cancer and ciliopathies. Discovery of the centriole dates back to the 19th century. However, recent advances in genetic and biochemical tools, development of high-resolution microscopy, and identification of centriole components have accelerated our understanding of its assembly, function, evolution, and its role in human disease. The centriole is an evolutionarily conserved structure built from highly conserved proteins and is present in all branches of the eukaryotic tree of life. However, centriole number, size, and organization varies among different organisms and even cell types within a single organism, reflecting its cell type-specialized functions. In this review, we provide an overview of our current understanding of centriole biogenesis and how variations around the same theme generate alternatives for centriole formation and function. PMID- 29284674 TI - Modeling the Effects of Age and Sex on Normal Pediatric Brain Metabolism Using 18F-FDG PET/CT. AB - Reference databases of pediatric brain metabolism are uncommon, because local brain metabolism evolves significantly with age throughout childhood, limiting their clinical applicability. The aim of this study was to develop mathematic models of regional relative brain metabolism using pediatric 18F-FDG PET with CT data of normal pediatric brains, accounting for sex and age. Methods: PET/CT brain acquisitions were obtained from 88 neurologically normal subjects, aged 6 mo to 18 y. Subjects were assigned to either a development group (n = 59) or a validation group (n = 29). For each subject, commercially available software was used to quantify the relative metabolism of 47 separate brain regions using whole brain-normalized (WBN) and pons-normalized (PN) activity. The effects of age on regional relative brain metabolism were modeled using multiple linear and nonlinear mathematic equations, and the significance of sex was assessed using the Student t test. Optimal models were selected using the Akaike information criterion. Mean predicted values and 95% prediction intervals were derived for all regions. Model predictions were compared with the validation dataset, and mean predicted error was calculated for all regions using both WBN and PN models. Results: As a function of age, optimal models of regional relative brain metabolism were linear for 9 regions, quadratic for 13, cubic for 6, logarithmic for 12, power law for 7, and modified power law for 2 using WBN data and were linear for 9, quadratic for 25, cubic for 2, logarithmic for 6, and power law for 4 using PN data. Sex differences were found to be statistically significant only in the posterior cingulate cortex for the WBN data. Comparing our models with the validation group resulted in 94.3% of regions falling within the 95% prediction interval for WBN and 94.1% for PN. For all brain regions in the validation group, the error in prediction was 3% +/- 0.96% using WBN data and 4.72% +/- 1.25% when compared with the PN data (P < 0.0001). Conclusion: Pediatric brain metabolism is a complex function of age and sex. We have developed mathematic models of brain activity that allow for accurate prediction of regional pediatric brain metabolism. PMID- 29284675 TI - Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F 18. AB - Alzheimer disease (AD) is characterized by beta-amyloid (Abeta) plaques and tau neurofibrillary tangles. There are several PET imaging biomarkers for Abeta including 11C-PiB and 18F-florbetapir. Recently, PET tracers for tau neurofibrillary tangles have become available and have shown utility in detection and monitoring of neurofibrillary pathology over time. Flortaucipir F 18 is one such tracer. Initial clinical studies indicated greater tau binding in AD and mild cognitive impairment patients than in controls in a pattern consistent with tau pathology observed at autopsy. However, little is known about the reproducibility of such findings. To our knowledge, this study reports the first data regarding test-retest reproducibility of flortaucipir F 18 PET. Methods: Twenty-one subjects who completed the study (5 healthy controls, 6 mild cognitive impairment, and 10 AD) received 370 MBq of flortaucipir F 18 and were imaged for 20 min beginning 80 min after injection and again at 110 min after injection. Follow-up (retest) imaging occurred between 48 h and 4 wk after initial imaging. Images were spatially normalized to Montreal Neurological Institute template space. SUVRs were calculated using AAL (Automated Anatomical Labeling atlas) volumes of interest (VOIs) for parietal, temporal, occipital, anterior, and posterior hippocampal, parahippocampal, and fusiform regions, as well as a posterior neocortical VOI composed of average values from parietal, temporal, and occipital areas. Further, a VOI derived by discriminant analysis that maximally separated diagnostic groups (multiblock barycentric discriminant analysis [MUBADA]) was used. All VOIs were referenced to a subsection of cerebellar gray matter (cere-crus) as well as a parametrically derived white matter-based reference region (parametric estimate of reference signal intensity [PERSI]). t test, correlation analyses, and intraclass correlation coefficient were used to explore test-retest performance. Results: Test-retest analyses demonstrated low variability in flortaucipir F 18 SUVR. The SD of mean percentage change between test and retest using the PERSI reference region was 2.22% for a large posterior neocortical VOI, 1.84% for MUBADA, 1.46% for frontal, 1.98% for temporal, 2.28% for parietal, and 3.27% for occipital VOIs. Further, significant correlations (R2 > 0.85; P < 0.001) were observed for all regions, and intraclass correlation coefficient values (test-retest consistency) were greater than 0.92 for all regions. Conclusion: Significant test-retest reproducibility for flortaucipir F 18 was found across neocortical and mesial temporal lobe structures. These preliminary data suggest that flortaucipir F 18 tau imaging could be used to examine changes in tau burden over time. PMID- 29284676 TI - Coordinated regulation of intracellular pH by two glucose-sensing pathways in yeast. AB - The yeast Saccharomyces cerevisiae employs multiple pathways to coordinate sugar availability and metabolism. Glucose and other sugars are detected by a G protein coupled receptor, Gpr1, as well as a pair of transporter-like proteins, Rgt2 and Snf3. When glucose is limiting, however, an ATP-driven proton pump (Pma1) is inactivated, leading to a marked decrease in cytoplasmic pH. Here we determine the relative contribution of the two sugar-sensing pathways to pH regulation. Whereas cytoplasmic pH is strongly dependent on glucose abundance and is regulated by both glucose-sensing pathways, ATP is largely unaffected and therefore cannot account for the changes in Pma1 activity. These data suggest that the pH is a second messenger of the glucose-sensing pathways. We show further that different sugars differ in their ability to control cellular acidification, in the manner of inverse agonists. We conclude that the sugar sensing pathways act via Pma1 to invoke coordinated changes in cellular pH and metabolism. More broadly, our findings support the emerging view that cellular systems have evolved the use of pH signals as a means of adapting to environmental stresses such as those caused by hypoxia, ischemia, and diabetes. PMID- 29284677 TI - Depletion of the membrane-fusion regulator Munc18c attenuates caerulein hyperstimulation-induced pancreatitis. AB - Epithelial pancreatic acinar cells perform crucial functions in food digestion, and acinar cell homeostasis required for secretion of digestive enzymes relies on SNARE-mediated exocytosis. The ubiquitously expressed Sec1/Munc18 protein mammalian uncoordinated-18c (Munc18c) regulates membrane fusion by activating syntaxin-4 (STX-4) to bind cognate SNARE proteins to form a SNARE complex that mediates exocytosis in many cell types. However, in the acinar cell, Munc18c's functions in exocytosis and homeostasis remain inconclusive. Here, we found that pancreatic acini from Munc18c-depleted mice (Munc18c+/-) and human pancreas (lenti-Munc18c-shRNA-treated) exhibit normal apical exocytosis of zymogen granules (ZGs) in response to physiologic stimulation with the intestinal hormone cholecystokinin (CCK-8). However, when stimulated with supraphysiologic CCK-8 levels to mimic pancreatitis, Munc18c-depleted (Munc18c+/-) mouse acini exhibited a reduction in pathological basolateral exocytosis of ZGs resulting from a decrease in fusogenic STX-4 SNARE complexes. This reduced basolateral exocytosis in part explained the less severe pancreatitis observed in Munc18c+/- mice after hyperstimulation with the CCK-8 analog caerulein. Likely as a result of this secretory blockade, Munc18c-depleted acini unexpectedly activated a component of the endoplasmic reticulum (ER) stress response that contributed to autophagy induction, resulting in downstream accumulation of autophagic vacuoles and autolysosomes. We conclude that Munc18c's role in mediating ectopic basolateral membrane fusion of ZGs contributes to the initiation of CCK-induced pancreatic injury, and that blockade of this secretory process could increase autophagy induction. PMID- 29284678 TI - The CUE1 domain of the SNF2-like chromatin remodeler SMARCAD1 mediates its association with KRAB-associated protein 1 (KAP1) and KAP1 target genes. AB - Chromatin in embryonic stem cells (ESCs) differs markedly from that in somatic cells, with ESCs exhibiting a more open chromatin configuration. Accordingly, ATP dependent chromatin remodeling complexes are important regulators of ESC homeostasis. Depletion of the remodeler SMARCAD1, an ATPase of the SNF2 family, has been shown to affect stem cell state, but the mechanistic explanation for this effect is unknown. Here, we set out to gain further insights into the function of SMARCAD1 in mouse ESCs. We identified KRAB-associated protein 1 (KAP1) as the stoichiometric binding partner of SMARCAD1 in ESCs. We found that this interaction occurs on chromatin and that SMARCAD1 binds to different classes of KAP1 target genes, including zinc finger protein (ZFP) and imprinted genes. We also found that the RING B-box coiled-coil (RBCC) domain in KAP1 and the proximal coupling of ubiquitin conjugation to ER degradation (CUE) domain in SMARCAD1 mediate their direct interaction. Of note, retention of SMARCAD1 in the nucleus depended on KAP1 in both mouse ESCs and human somatic cells. Mutations in the CUE1 domain of SMARCAD1 perturbed the binding to KAP1 in vitro and in vivo Accordingly, an intact CUE1 domain was required for tethering this remodeler to the nucleus. Moreover, mutation of the CUE1 domain compromised SMARCAD1 binding to KAP1 target genes. Taken together, our results reveal a mechanism that localizes SMARCAD1 to genomic sites through the interaction of SMARCAD1's CUE1 motif with KAP1. PMID- 29284681 TI - A novel AGGF1-PDGFRb fusion in pediatric T-cell acute lymphoblastic leukemia. PMID- 29284680 TI - CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting. AB - Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+ CD38+) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody-dependent cellular cytotoxicity. In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted and killed using an anti-CD36 antibody. PMID- 29284679 TI - Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid beta oligomers. AB - Alzheimer's disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-beta peptide (AbetaOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AbetaOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AbetaO induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Protection by MSCs entails three complementary mechanisms: 1) internalization and degradation of AbetaOs; 2) release of extracellular vesicles containing active catalase; and 3) selective secretion of interleukin-6, interleukin-10, and vascular endothelial growth factor to the medium. Results support the notion that MSCs may represent a promising alternative for cell-based therapies in AD. PMID- 29284682 TI - Glucocorticoids induce differentiation of monocytes towards macrophages that share functional and phenotypical aspects with erythroblastic island macrophages. AB - The classical central macrophage found in erythroblastic islands plays an important role in erythroblast differentiation, proliferation and enucleation in the bone marrow. Convenient human in vitro models to facilitate the study of erythroid-macrophage interactions are desired. Recently, we demonstrated that cultured monocytes/macrophages enhance in vitro erythropoiesis by supporting hematopoietic stem and progenitor cell survival. Herein, we describe that these specific macrophages also support erythropoiesis. Human monocytes cultured in serum-free media supplemented with stem cell factor, erythropoietin, lipids and dexamethasone differentiate towards macrophages expressing CD16, CD163, CD169, CD206, CXCR4 and the phagocytic TAM-receptor family. Phenotypically, they resemble both human bone marrow and fetal liver resident macrophages. This differentiation is dependent on glucocorticoid receptor activation. Proteomic studies confirm that glucocorticoid receptor activation differentiates monocytes to anti-inflammatory tissue macrophages with a M2 phenotype, termed GC macrophages. Proteins involved in migration, tissue residence and signal transduction/receptor activity are upregulated whilst lysosome and hydrolase activity GO-categories are downregulated. Functionally, we demonstrate that GC macrophages are highly mobile and can interact to form clusters with erythroid cells of all differentiation stages and phagocytose the expelled nuclei, recapitulating aspects of erythroblastic islands. In conclusion, glucocorticoid directed monocyte differentiation to macrophages represents a convenient model system to study erythroid-macrophage interactions. PMID- 29284683 TI - An informative intragenic microsatellite marker suggests the IL-1 receptor as a genetic modifier in cystic fibrosis. PMID- 29284684 TI - Chest physician-reported, work-related, long-latency respiratory disease in Great Britain. AB - Much of the current burden of long-latency respiratory disease (LLRD) in Great Britain is attributed to historical asbestos exposure. However, continuing exposure to other agents, notably silica, also contributes to disease burden. The aim of this study was to investigate the incidence of work-related LLRD reported by chest physicians in Great Britain, including variations by age, gender, occupation and suspected agent.LLRD incidence and incidence rate ratios by occupation were estimated (1996-2014). Mesothelioma cases by occupation were compared with proportional mortality ratios.Cases were predominantly in men (95%) and 92% of all cases were attributed to asbestos. Annual average incidence rates (males) per 100 000 were: benign pleural disease, 7.1 (95% CI 6.0-8.2); mesothelioma, 5.4 (4.8-6.0); pneumoconiosis, 1.9 (1.7-2.2); lung cancer, 0.8 (0.6 1.0); chronic obstructive pulmonary disease (COPD), 0.3 (0.2-0.4). Occupations with a particularly high incidence of LLRD were miners and quarrymen (COPD), plumbers and gas fitters (asbestosis), and shipyard and dock workers (all other categories). There was a clear concordance between cases of SWORD mesothelioma and proportional mortality ratios by occupation.Occupationally caused LLRD continues to contribute to a significant disease burden. Many cases are attributable to past exposure to agents such as asbestos and silica, but the potential for occupational exposures persists. PMID- 29284685 TI - Oxidative stress biomarkers and asthma characteristics in adults of the EGEA study. AB - Asthma is an oxidative stress related disease, but associations with asthma outcomes are poorly studied in adults. We aimed to study the associations between several biomarkers related to oxidative stress and various asthma outcomes.Cross sectional analyses were conducted in 1388 adults (mean age 43 years, 44% with asthma) from the Epidemiological Study of the Genetics and Environment of Asthma (EGEA2). Three blood antioxidant enzyme activities (biomarkers of response to oxidative stress) and exhaled breath condensate 8-isoprostanes and plasma fluorescent oxidation products (FlOPs) levels (two biomarkers of damage) were measured. Associations between biomarkers and 1) ever asthma and 2) asthma attacks, asthma control and lung function in participants with asthma were evaluated using regression models adjusted for age, sex and smoking.Biomarkers of response were unrelated to asthma outcomes. Higher 8-isoprostane levels were significantly associated with ever asthma (odds ratio for one interquartile range increase 1.28 (95% CI 1.06-1.67). Among participants with asthma, 8-isoprostane levels were negatively associated with adult-onset asthma (0.63, 0.41-0.97) and FlOPs levels were positively associated with asthma attacks (1.33, 1.07-1.65), poor asthma control (1.30, 1.02-1.66) and poor lung function (1.34, 1.04 1.74).Our results suggest that 8-isoprostanes are involved in childhood-onset asthma and FlOPs are linked to asthma expression. PMID- 29284686 TI - Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem. AB - Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data are lacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousal threshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep.21 individuals with and without OSA (18-65 years) completed 84 detailed sleep studies after receiving temazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind, placebo controlled, crossover trial (ACTRN12612001004853).The arousal threshold increased with zolpidem and zopiclone versus placebo (mean+/-sd -18.3+/-10 and -19.1+/-9 versus -14.6+/-7 cmH2O; p=0.02 and p<0.001) but not with temazepam (-16.8+/-9 cmH2O; p=0.17). Genioglossus muscle activity during stable non-REM sleep and responsiveness during airway narrowing was not different with temazepam and zopiclone versus placebo but, paradoxically, zolpidem increased median muscle responsiveness three-fold during airway narrowing (median -0.15 (interquartile range -1.01 to -0.04) versus -0.05 (-0.29 to -0.03)% maximum EMG per cmH2O epiglottic pressure; p=0.03). The upper airway critical closing pressure did not change with any of the hypnotics.These doses of common hypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airway muscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airway narrowing with zolpidem. PMID- 29284687 TI - A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis. AB - A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence.Raw genotype phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance.We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin.This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis. PMID- 29284689 TI - Genotypic and phenotypic M. tuberculosis resistance: guiding clinicians to prescribe the correct regimens. PMID- 29284688 TI - Renal Fanconi syndrome with meropenem/amoxicillin-clavulanate during treatment of extensively drug-resistant tuberculosis. PMID- 29284690 TI - AMPKalpha2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation. AB - RATIONALE: Mitochondrial dysfunction plays an important role in heart failure (HF). However, the molecular mechanisms regulating mitochondrial functions via selective mitochondrial autophagy (mitophagy) are poorly understood. OBJECTIVE: We sought to determine the role of AMPK (AMP-activated protein kinase) in selective mitophagy during HF. METHODS AND RESULTS: An isoform shift from AMPKalpha2 to AMPKalpha1 was observed in failing heart samples from HF patients and transverse aortic constriction-induced mice, accompanied by decreased mitophagy and mitochondrial function. The recombinant adeno-associated virus Serotype 9-mediated overexpression of AMPKalpha2 in mouse hearts prevented the development of transverse aortic constriction-induced chronic HF by increasing mitophagy and improving mitochondrial function. In contrast, AMPKalpha2-/- mutant mice exhibited an exacerbation of the early progression of transverse aortic constriction-induced HF via decreases in cardiac mitophagy. In isolated adult mouse cardiomyocytes, AMPKalpha2 overexpression mechanistically rescued the impairment of mitophagy after phenylephrine stimulation for 24 hours. Genetic knockdown of AMPKalpha2, but not AMPKalpha1, by short interfering RNA suppressed the early phase (6 hours) of phenylephrine-induced compensatory increases in mitophagy. Furthermore, AMPKalpha2 specifically interacted with phosphorylated PINK1 (PTEN-induced putative kinase 1) at Ser495 after phenylephrine stimulation. Subsequently, phosphorylated PINK1 recruited the E3 ubiquitin ligase, Parkin, to depolarized mitochondria, and then enhanced the role of the PINK1-Parkin-SQSTM1 (sequestosome-1) pathway involved in cardiac mitophagy. This increase in cardiac mitophagy was accompanied by the elimination of damaged mitochondria, improvement in mitochondrial function, decrease in reactive oxygen species production, and apoptosis of cardiomyocytes. Finally, Ala mutation of PINK1 at Ser495 partially suppressed AMPKalpha2 overexpression-induced mitophagy and improvement of mitochondrial function in phenylephrine-stimulated cardiomyocytes, whereas Asp (phosphorylation mimic) mutation promoted mitophagy after phenylephrine stimulation. CONCLUSIONS: In failing hearts, the dominant AMPKalpha isoform switched from AMPKalpha2 to AMPKalpha1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPKalpha2 was essential for efficient mitophagy to prevent the progression of HF. PMID- 29284691 TI - Adenosine-to-Inosine Editing of MicroRNA-487b Alters Target Gene Selection After Ischemia and Promotes Neovascularization. AB - RATIONALE: Adenosine-to-inosine editing of microRNAs has the potential to cause a shift in target site selection. 2'-O-ribose-methylation of adenosine residues, however, has been shown to inhibit adenosine-to-inosine editing. OBJECTIVE: To investigate whether angiomiR miR487b is subject to adenosine-to-inosine editing or 2'-O-ribose-methylation during neovascularization. METHODS AND RESULTS: Complementary DNA was prepared from C57BL/6-mice subjected to hindlimb ischemia. Using Sanger sequencing and endonuclease digestion, we identified and validated adenosine-to-inosine editing of the miR487b seed sequence. In the gastrocnemius muscle, pri-miR487b editing increased from 6.7+/-0.4% before to 11.7+/-1.6% (P=0.02) 1 day after ischemia. Edited pri-miR487b is processed into a novel microRNA, edited miR487b, which is also upregulated after ischemia. We confirmed editing of miR487b in multiple human primary vascular cell types. Short interfering RNA-mediated knockdown demonstrated that editing is adenosine deaminase acting on RNA 1 and 2 dependent. Using reverse-transcription at low dNTP concentrations followed by quantitative-PCR, we found that the same adenosine residue is methylated in mice and human primary cells. In the murine gastrocnemius, the estimated methylation fraction increased from 32.8+/-14% before to 53.6+/-12% 1 day after ischemia. Short interfering RNA knockdown confirmed that methylation is fibrillarin dependent. Although we could not confirm that methylation directly inhibits editing, we do show that adenosine deaminase acting on RNA 1 and 2 and fibrillarin negatively influence each other's expression. Using multiple luciferase reporter gene assays, we could demonstrate that editing results in a complete switch of target site selection. In human primary cells, we confirmed the shift in miR487b targeting after editing, resulting in a edited miR487b targetome that is enriched for multiple proangiogenic pathways. Furthermore, overexpression of edited miR487b, but not wild-type miR487b, stimulates angiogenesis in both in vitro and ex vivo assays. CONCLUSIONS: MiR487b is edited in the seed sequence in mice and humans, resulting in a novel, proangiogenic microRNA with a unique targetome. The rate of miR487b editing, as well as 2'-O-ribose-methylation, is increased in murine muscle tissue during postischemic neovascularization. Our findings suggest miR487b editing plays an intricate role in postischemic neovascularization. PMID- 29284692 TI - Modeling Outputs Can Be Valuable When Uncertainty Is Appropriately Acknowledged, but Misleading When Not. PMID- 29284693 TI - From Research to Policy: The WHO Experience With Developing Guidelines on the Potential Risk of HIV Acquisition and Progestogen-Only Contraception Use. PMID- 29284694 TI - Interventions for Preventing Unintended, Rapid Repeat Pregnancy Among Adolescents: A Review of the Evidence and Lessons From High-Quality Evaluations. AB - BACKGROUND: In 2017, of the 22.5 million parenting adolescents (ages 15-19) in 60 countries, approximately 4.1 million gave birth to a second or higher-order child. Adolescent pregnancy in general, and rapid repeat pregnancies specifically, expose young mothers and their children to multiple health and socioeconomic risks. The purpose of this article is to review the impact of interventions designed to prevent unintended, rapid repeat pregnancies among adolescents, including those aimed at changing norms to postpone "intended" closely spaced pregnancies to promote healthy spacing. METHODS: We searched PubMed and other databases for evaluations of interventions published in English from 1990 through 2016. We included evaluations that assessed a programmatic intervention specifically designed to prevent rapid repeat pregnancy (occurring less than 24 months after the index birth) or birth (occurring less than 33 months after the index birth), or that reported on contraceptive continuation for at least 2 years. We first assessed the quality of the evaluations, then ranked the interventions based on the quality of the evaluation and the level of impact on repeat pregnancy or birth (statistically significant impact, positive trends but not statistically significant, or no impact) to identify the most effective interventions. Finally, we extracted program design and implementation lessons from the interventions included in the high-quality evaluations. RESULTS: Our search identified 2,187 articles, of which 40 evaluations met the inclusion criteria (24=high quality, 14=moderate quality, 2=less rigorous). We found 14 high-quality evaluations in which the intervention achieved a statistically significant impact on repeat pregnancy or birth. These interventions fell into 5 broad categories: (1) contraceptive services and information, with proactive monitoring of contraceptive use and outreach to families; (2) postpartum contraceptive counseling and services provided soon after delivery; (3) activities that help adolescents improve planning skills, including preparing contraceptive plans; (4) social and behavioral change activities that help adolescents understand the role contraception can play in determining positive life outcomes, and the implications of their reproductive health decisions for their future; and (5) activities that provide mentoring, goal setting, and motivation. CONCLUSION: Effective interventions that prevent rapid adolescent childbearing link clinical contraceptive services with non-clinical activities that build planning skills, enhance understanding of the role that contraceptives can play in determining positive life outcomes, and provide mentoring and goal setting. Recognizing potentially synergistic effects, we recommend testing various combinations of these interventions, with access to contraception as the foundational activity. PMID- 29284695 TI - Maternal and Neonatal Directed Assessment of Technologies (MANDATE): Methods and Assumptions for a Predictive Model for Maternal, Fetal, and Neonatal Mortality Interventions. AB - Maternal, fetal, and neonatal mortality disproportionately impact low- and middle income countries, and many current interventions that can save lives are often not available nor appropriate for these settings. Maternal and Neonatal Directed Assessment of Technologies (MANDATE) is a mathematical model designed to evaluate which interventions have the greatest potential to save maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. The MANDATE decision support model includes interventions such as preventive interventions, diagnostics, treatments, and transfers to different care settings to compare the relative impact of different interventions on mortality outcomes. The model is calibrated and validated based on historical and current rates of disease in sub Saharan Africa and India. In addition, each maternal, fetal, or newborn condition included in MANDATE considers disease rates specific to sub-Saharan Africa and India projected to intervention rates similar to those seen in high-income countries. Limitations include variance in quality of data to inform the estimates and generalizability of findings of the effectiveness of the interventions. The model serves as a valuable resource to compare the potential impact of multiple interventions, which could help reduce maternal, fetal, and neonatal mortality in low-resource settings. The user should be aware of assumptions in evaluating the model and interpret results accordingly. PMID- 29284696 TI - Re-Evaluating the Possible Increased Risk of HIV Acquisition With Progestin-Only Injectables Versus Maternal Mortality and Life Expectancy in Africa: A Decision Analysis. AB - OBJECTIVE: The association between increased risk of HIV acquisition and use of progestin-only injectables (POIs) is controversial. We sought to compare the competing risks of maternal mortality and HIV acquisition with use of POIs using updated data on this association and considering an expanded number of African countries. METHODS: We designed a decision-analytic model to compare the benefits and risks of POIs on the competing risks of maternal mortality and HIV acquisition on life expectancy for women in 9 African countries. For the purposes of this analysis, we assumed that POIs were associated with an increased risk of HIV acquisition (hazards ratio of 1.4). Our primary outcome was life-years and the population was women of reproductive age (15-49 years) in these countries, who did not have HIV infection and were not currently planning a pregnancy. Probabilities for each variable included in the model, such as HIV incidence, access to antiretroviral therapy, and contraceptive prevalence, were obtained from the literature. Univariate and multivariate sensitivity analyses were performed to check model assumptions and explore how uncertainty in estimates would affect the model results. RESULTS: In all countries, discontinuation of POIs without replacement with an equally effective contraceptive method would result in decreased life expectancy due to a significant increase in maternal deaths. While the removal of POIs from the market would result in the prevention of some new cases of HIV, the life-years gained from this are mitigated due to the marked increase in neonatal HIV cases and maternal mortality with associated life-years lost. In all countries, except South Africa, typical-use contraceptive failure rates with POIs would need to exceed 39%, and more than half of women currently using POIs would have to switch to another effective method, for the removal of POIs to demonstrate an increase in total life-years. CONCLUSION: Women living in sub-Saharan Africa cope with both high rates of HIV infection and high rates of pregnancy-related maternal death relative to the rest of the world. Based on the most current estimates, our model suggests that removal of POI contraception from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality under a variety of scenarios. PMID- 29284697 TI - Jordan's 2002 to 2012 Fertility Stall and Parallel USAID Investments in Family Planning: Lessons From an Assessment to Guide Future Programming. AB - Health practitioners, researchers, and donors are stumped about Jordan's stalled fertility rate, which has stagnated between 3.7 and 3.5 children per woman from 2002 to 2012, above the national replacement level of 2.1. This stall paralleled United States Agency for International Development (USAID) funding investments in family planning in Jordan, triggering an assessment of USAID family planning programming in Jordan. This article describes the methods, results, and implications of the programmatic assessment. Methods included an extensive desk review of USAID programs in Jordan and 69 interviews with reproductive health stakeholders. We explored reasons for fertility stagnation in Jordan's total fertility rate (TFR) and assessed the effects of USAID programming on family planning outcomes over the same time period. The assessment results suggest that the increased use of less effective methods, in particular withdrawal and condoms, are contributing to Jordan's TFR stall. Jordan's limited method mix, combined with strong sociocultural determinants around reproduction and fertility desires, have contributed to low contraceptive effectiveness in Jordan. Over the same time period, USAID contributions toward increasing family planning access and use, largely focused on service delivery programs, were extensive. Examples of effective initiatives, among others, include task shifting of IUD insertion services to midwives due to a shortage of female physicians. However, key challenges to improved use of family planning services include limited government investments in family planning programs, influential service provider behaviors and biases that limit informed counseling and choice, pervasive strong social norms of family size and fertility, and limited availability of different contraceptive methods. In contexts where sociocultural norms and a limited method mix are the dominant barriers toward improved family planning use, increased national government investments toward synchronized service delivery and social and behavior change activities may be needed to catalyze national-level improvements in family planning outcomes. PMID- 29284698 TI - Food Security and Nutrition Outcomes of Farmer Field Schools in Eastern Democratic Republic of the Congo. AB - BACKGROUND: Food and nutrition security in eastern Democratic Republic of the Congo are threatened by political instability and chronic poverty. The Jenga Jamaa II project, implemented between 2011 and 2016 in South Kivu Province, aimed to improve household food security and child nutritional status using various intervention strategies, including farmer field school (FFS) programs. OBJECTIVE: To characterize the changes in agricultural production techniques, household food security, and child nutritional status associated with participation in FFS programs. METHODS: We used a community-matched design to select FFS intervention and control households from 3 health zones in which the project was operating. Data on food security (Household Dietary Diversity Score [HDDS] and Household Food Insecurity Access Scale [HFIAS]) and child anthropometry were collected semiannually for 3.5 years in both groups. Additional data on agricultural practices were collected annually in the FFS group only. Focus groups with FFS staff and beneficiaries were conducted in the final project year. Statistical analyses included basic descriptive statistics such as paired t tests and analysis of covariance; regression models using a bootstrap were applied to generate P values and confidence intervals while accounting for differences between groups. RESULTS: The study enrolled 388 FFS beneficiaries and their households in the intervention group and 324 non-FFS households in the control group. FFS participants reported increasing the number of different agricultural techniques they used by an average of 2.7 techniques over the project period, from 5.1 in 2013 to 7.9 in 2016 (P<.001). The mean HDDS and HFIAS improved more in the FFS group than in the control group (mean difference between intervention and control for HDDS was 0.9 points and for HFIAS was -4.6 points; P<.001). However, the prevalence of child stunting (60.2% intervention vs. 58.8% control) and underweight (22.3% intervention vs. 29.8% control) were similar in both groups at endline (P>.05). CONCLUSION: Although FFS participants diversified their agricultural production strategies and experienced improvements in household food security, there was not a positive impact on child nutritional status. In this food-insecure context, improvements in agricultural production alone are unlikely to significantly change child nutritional status-a health outcome with a complex, multilevel causal chain. PMID- 29284699 TI - What Factors Contribute to Postabortion Contraceptive Uptake By Young Women? A Program Evaluation in 10 Countries in Asia and sub-Saharan Africa. AB - BACKGROUND: Unintended pregnancy disproportionately affects young women and adolescents in developing countries. The abortion care setting offers a unique opportunity for adolescents and young women to access a full range of contraceptive services. This evaluation assesses the factors that influence contraceptive uptake among adolescents and young women seeking abortion care in health facilities. METHODS: Following provider training, we analyzed client log book data from 921,918 abortion care cases in 4,881 health facilities in 10 countries from July 2011 through June 2015. Log book data included client characteristics such as age, pregnancy gestation, type of service provided, and contraceptive method provision. Health facility characteristics were obtained through administration of a site baseline form prior to initiation of programmatic support by Ipas, an international NGO. Programmatic support included integration of postabortion contraceptive services with abortion care, improvements in commodities logistics, health worker training, upgraded recordkeeping, and post-training follow-up with providers and sites to solve problems and improve performance. We analyzed abortion cases by 3 age categories, <=19 years, 20-24 years, and >=25 years, and conducted unadjusted and adjusted analyses for the primary outcomes of interest: receipt of a contraceptive method at the time of care; type of contraceptive method selected; and the client, clinical care, and facility characteristics associated with contraceptive uptake. RESULTS: Overall, 77% of women left the facility with a contraceptive method. The majority (84%) of contraceptive acceptors selected a short-acting method, especially oral contraceptives. In the adjusted model, women <=19 were less likely to choose a method than women 25 years or older (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.79 to 0.96). Adolescents and young women were also significantly less likely to choose a long-acting, reversible contraceptive than those ages 25 or older (<=19 years: OR, 0.59; 95% CI, 0.52 to 0.67; 20-24 years: OR, 0.68; 95% CI, 0.63 to 0.73). Women treated by an Ipas-trained provider were significantly more likely to select postabortion contraception than women treated by non-Ipas-trained providers (OR, 1.37; 95% CI, 1.20 to 1.57). CONCLUSIONS: Programmatic support to health systems, including provider training in contraceptive counseling and provision, was associated with women's higher acceptance of postabortion contraception. However, gaps remained for young women, especially adolescents, who were significantly less likely than older women to accept postabortion contraception. Health systems and facilities should pay increased attention to meeting the contraceptive needs of young women and adolescents. PMID- 29284700 TI - An NGO-Implemented Community-Clinic Health Worker Approach to Providing Long-Term Care for Hypertension in a Remote Region of Southern India. AB - Poor blood pressure control results in tremendous morbidity and mortality in India where the leading cause of death among adults is from coronary heart disease. Despite having little formal education, community health workers (CHWs) are integral to successful public health interventions in India and other low- and middle-income countries that have a shortage of trained health professionals. Training CHWs to screen for and manage chronic hypertension, with support from trained clinicians, offers an excellent opportunity for effecting systemwide change in hypertension-related burden of disease. In this article, we describe the development of a program that trained CHWs between 2014 and 2015 in the tribal region of the Sittilingi Valley in southern India, to identify hypertensive patients in the community, refer them for diagnosis and initial management in a physician-staffed clinic, and provide them with sustained lifestyle interventions and medications over multiple visits. We found that after 2 years, the CHWs had screened 7,176 people over age 18 for hypertension, 1,184 (16.5%) of whom were screened as hypertensive. Of the 1,184 patients screened as hypertensive, 898 (75.8%) had achieved blood pressure control, defined as a systolic blood pressure less than 140 and a diastolic blood pressure less than 90 sustained over 3 consecutive visits. While all of the 24 trained CHWs reported confidence in checking blood pressure with a manual blood pressure cuff, 4 of the 24 CHWs reported occasional difficulty documenting blood pressure values because they were unable to write numbers properly. They compensated by asking other CHWs or members of their community to help with documentation. Our experience and findings suggest that a CHW blood pressure screening system linked to a central clinic can be a promising avenue for improving hypertension control rates in low- and middle-income countries. PMID- 29284701 TI - More Than Bar Codes: Integrating Global Standards-Based Bar Code Technology Into National Health Information Systems in Ethiopia and Pakistan to Increase End-to End Supply Chain Visibility. AB - The United Nations Population Fund (UNFPA) and the United States Agency for International Development (USAID) DELIVER PROJECT work together to strengthen public health commodity supply chains by standardizing bar coding under a single set of global standards. From 2015, UNFPA and USAID collaborated to pilot test how tracking and tracing of bar coded health products could be operationalized in the public health supply chains of Ethiopia and Pakistan and inform the ecosystem needed to begin full implementation. Pakistan had been using proprietary bar codes for inventory management of contraceptive supplies but transitioned to global standards-based bar codes during the pilot. The transition allowed Pakistan to leverage the original bar codes that were preprinted by global manufacturers as opposed to printing new bar codes at the central warehouse. However, barriers at lower service delivery levels prevented full realization of end-to-end data visibility. Key barriers at the district level were the lack of a digital inventory management system and absence of bar codes at the primary-level packaging level, such as single blister packs. The team in Ethiopia developed an open-sourced smartphone application that allowed the team to scan bar codes using the mobile phone's camera and to push the captured data to the country's data mart. Real-time tracking and tracing occurred from the central warehouse to the Addis Ababa distribution hub and to 2 health centers. These pilots demonstrated that standardized product identification and bar codes can significantly improve accuracy over manual stock counts while significantly streamlining the stock taking process, resulting in efficiencies. The pilots also showed that bar coding technology by itself is not sufficient to ensure data visibility. Rather, by using global standards for identification and data capture of pharmaceuticals and medical devices, and integrating the data captured into national and global tracking systems, countries are able to lay the foundation for interoperability and ensure a harmonized language between global health stakeholders. PMID- 29284702 TI - High Background Congenital Microcephaly in Rural Guatemala: Implications for Neonatal Congenital Zika Virus Infection Screening. AB - BACKGROUND: Congenital microcephaly is the result of a disturbance in early brain development and can have multiple etiologies. Establishing background prevalence of microcephaly in Zika virus (ZIKV)-affected areas is important for improving identification of ZIKV-affected newborns. However, to date, there is limited consistent guidance for the accurate identification of microcephaly in infants of unknown gestational age, a common concern in low- and middle-income countries. METHODS: Occipital frontal head circumference (OFC) obtained from infants (0-13 days) of unknown gestational age at enrollment in a pregnancy registry in rural Guatemala from August 2014 to March 2016 were retrospectively reviewed. Trained community health nurses recorded anthropometry in an online database. In April 2015, ZIKV was identified in this population. Gestational age was approximated in 2 ways: presumed term and estimated using z-score of zero for height on modified Fenton growth curves. After which, z-scores for OFC and weight were obtained. Microcephaly and microcephaly background prevalence were estimated using 7 established microcephaly case definitions from national and international organizations and 3 proposed definitions using Fenton growth curves. Independent associations with microcephaly and OFC, including relationship with date of birth, were assessed with prevalence ratios and linear regression. RESULTS: For 296 infants, the mean OFC was 33.1 cm (range, 29.5 to 37 cm) and the mean OFC z score was -0.68. Depending on case definition, 13 to 125 infants were classified as having microcephaly (background prevalence 439 to 4,223 per 10,000 live births), and 1 to 9 infants were classified as having severe microcephaly (<-3 standard deviation [SD]) (34 to 304 per 10,000 live births). Five (1.7%) infants met all the microcephaly case definitions. Weight <=-1 SD (prevalence rate [PR], 3.77; 95% confidence interval [CI]: 1.6 to 8.8; P=.002) and small for gestational age (PR, 4.68; 95% CI, 1.8 to 12.3; P=.002) were associated with microcephaly. Date of birth was not associated with OFC z-score or OFC after adjusting for gestational age and gender. CONCLUSIONS: Estimated background microcephaly is high in rural Guatemala compared with reported rates in Latin America prior to ZIKV epidemic, which has important implications for neonatal screening programs for congenital ZIKV infection. Fenton growth curves offer a standardized approach to the identification of microcephaly in infants of unknown gestational age. PMID- 29284703 TI - Authors' Response to Editorial: Maternal Death Surveillance and Response: A Tall Order for Effectiveness in Resource-Poor Settings. PMID- 29284704 TI - Corrigendum: Igras et al., Systems Approach to Monitoring and Evaluation Guides Scale Up of the Standard Days Method of Family Planning in Rwanda. PMID- 29284705 TI - Immunotherapy of Myelodysplastic Syndrome: You Can Run, but You Can't Hide. AB - The hypomethylating agent decitabine induces expression of the cancer/testis antigen NY-ESO-1 in the myeloid cells of patients with myelodysplastic syndrome (MDS). Patients with MDS treated with decitabine and an NY-ESO-1 vaccine developed NY-ESO-1-specific T-cell responses directed against their abnormal myeloid cells, raising hopes for combinatorial immunotherapy of this disease. Clin Cancer Res; 24(5); 991-3. (c)2017 AACRSee related article by Griffiths et al., p. 1019. PMID- 29284707 TI - Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. AB - Purpose: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models.Experimental Design: Patients were selected for treatment with crizotinib upon results of hybrid capture-based next generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations.Results: Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of KIF5B or STARD3NL and MET One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models.Conclusions: Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. Clin Cancer Res; 24(6); 1337-43. (c)2017 AACR. PMID- 29284706 TI - PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kalpha Inhibitors. AB - Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER+ breast cancer with an excellent response to the PI3Kalpha inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446-460 of the C2 domain, suggesting these residues are critical for p110alpha function.Experimental Design: A computational structural model of PIK3CAdelP447 L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and PIK3CAH450_P458del were used to understand the phenotype of C2 domain deletions.Results: Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110alpha. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor-independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment.Conclusions: C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426-35. (c)2017 AACR. PMID- 29284708 TI - ESR1 Methylation: A Liquid Biopsy-Based Epigenetic Assay for the Follow-up of Patients with Metastatic Breast Cancer Receiving Endocrine Treatment. AB - Purpose: Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma circulating tumor DNA (ctDNA). ESR1 epigenetic silencing potentially affects response to endocrine treatment. We evaluated ESR1 methylation in CTCs and paired plasma ctDNA. We evaluated ESR1 methylation in CTCs and paired plasma ctDNA as a potential biomarker for response to everolimus/exemestane treatment.Experimental Design: A highly sensitive and specific real-time MSP assay for ESR1 methylation was developed and validated in (i) 65 primary breast tumors formalin-fixed paraffin-embedded (FFPE), (ii) EpCAM+ CTC fractions (122 patients and 30 healthy donors; HD), (iii) plasma ctDNA (108 patients and 30HD), and (iv) in CTCs (CellSearch) and in paired plasma ctDNA for 58 patients with breast cancer. ESR1 methylation status was investigated in CTCs isolated from serial peripheral blood samples of 19 patients with ER+/HER2- advanced breast cancer receiving everolimus/exemestane.Results:ESR1 methylation was detected in: (i) 25/65 (38.5%) FFPEs, (ii) EpCAM+ CTC fractions: 26/112 (23.3%) patients and 1/30 (3.3%) HD, and (iii) plasma ctDNA: 8/108 (7.4%) patients and 1/30 (3.3%) HD. ESR1 methylation was highly concordant in 58 paired DNA samples, isolated from CTCs (CellSearch) and corresponding plasma. In serial peripheral blood samples of patients treated with everolimus/exemestane, ESR1 methylation was observed in 10/36 (27.8%) CTC positive samples, and was associated with lack of response to treatment (P = 0.023, Fisher exact test).Conclusions: We report for the first time the detection of ESR1 methylation in CTCs and a high concordance with paired plasma ctDNA. ESR1 methylation in CTCs was associated with lack of response to everolimus/exemestane regimen. ESR1 methylation should be further evaluated as a potential liquid biopsy-based biomarker. Clin Cancer Res; 24(6); 1500-10. (c)2017 AACR. PMID- 29284709 TI - Nup98 regulation of histone methylation promotes normal gene expression and may drive leukemogenesis. AB - Nuclear pore proteins (Nups) interact with chromosomes to regulate gene expression and chromatin structure. A new study by Franks and colleagues (pp. 2222-2234) provides new mechanistic insight into the molecular basis by which Nup98 promotes gene activation in normal hematopoietic cells and how that process is altered by translocations to cause excess expression of developmental genes in leukemia. PMID- 29284711 TI - Corrigendum: Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program. PMID- 29284712 TI - Quality assessment of nutrition coverage in the media: a 6-week survey of five popular UK newspapers. AB - OBJECTIVES: To investigate the quality of nutrition articles in popular national daily newspapers in the UK and to identify important predictors of article quality. SETTING: Newspapers are a primary source of nutrition information for the public. DESIGN: Newspaper articles were collected on 6 days of the week (excluding Sunday) for 6 weeks in summer 2014. Predictors included food type and health outcome, size of article, whether the journalist was named and day of the week. OUTCOME MEASURES: A validated quality assessment tool was used to assess each article, with a minimum possible score of -12 and a maximum score of 17. Newspapers were checked in duplicate for relevant articles. The association of each predictor on article quality score was analysed adjusting for remaining predictors. A logistic regression model was implemented with quality score as the binary outcome, categorised as poor (score less than zero) or satisfactory (score of zero or more). RESULTS: Over 6 weeks, 141 nutrition articles were included across the five newspapers. The median quality score was 2 (IQR -2-6), and 44 (31%) articles were poor quality. There was no substantial variation in quality of reporting between newspapers once other factors such as anonymous publishing, health outcome, aspect of diet covered and day of the week were taken into account. Particularly low-quality scores were obtained for anonymously published articles with no named journalist, articles that focused on obesity and articles that reported on high fat and processed foods. CONCLUSIONS: The general public are regularly exposed to poor quality information in newspapers about what to eat to promote health, particularly articles reporting on obesity. Journalists, researchers, university press officers and scientific journals need to work together more closely to ensure clear, consistent nutrition messages are communicated to the public in an engaging way. PMID- 29284710 TI - Chromatin and nucleosome dynamics in DNA damage and repair. AB - Chromatin is organized into higher-order structures that form subcompartments in interphase nuclei. Different categories of specialized enzymes act on chromatin and regulate its compaction and biophysical characteristics in response to physiological conditions. We present an overview of the function of chromatin structure and its dynamic changes in response to genotoxic stress, focusing on both subnuclear organization and the physical mobility of DNA. We review the requirements and mechanisms that cause chromatin relocation, enhanced mobility, and chromatin unfolding as a consequence of genotoxic lesions. An intriguing link has been established recently between enhanced chromatin dynamics and histone loss. PMID- 29284713 TI - Effects of parenting interventions for at-risk parents with infants: a systematic review and meta-analyses. AB - OBJECTIVES: Infancy is a critical stage of life, and a secure relationship with caring and responsive caregivers is crucial for healthy infant development. Early parenting interventions aim to support families in which infants are at risk of developmental harm. Our objective is to systematically review the effects of parenting interventions on child development and on parent-child relationship for at-risk families with infants aged 0-12 months. DESIGN: This is a systematic review and meta-analyses. We extracted publications from 10 databases in June 2013, January 2015 and June 2016, and supplemented with grey literature and hand search. We assessed risk of bias, calculated effect sizes and conducted meta analyses. INCLUSION CRITERIA: (1) Randomised controlled trials of structured psychosocial interventions offered to at-risk families with infants aged 0-12 months in Western Organisation for Economic Co-operation and Development (OECD) countries, (2) interventions with a minimum of three sessions and at least half of these delivered postnatally and (3) outcomes reported for child development or parent-child relationship. RESULTS: Sixteen studies were included. Meta-analyses were conducted on seven outcomes represented in 13 studies. Parenting interventions significantly improved child behaviour (d=0.14; 95% CI 0.03 to 0.26), parent-child relationship (d=0.44; 95% CI 0.09 to 0.80) and maternal sensitivity (d=0.46; 95% CI 0.26 to 0.65) postintervention. There were no significant effects on cognitive development (d=0.13; 95% CI -0.08 to 0.41), internalising behaviour (d=0.16; 95% CI -0.03 to 0.33) or externalising behaviour (d=0.16; 95% CI -0.01 to 0.30) post-intervention. At long-term follow-up we found no significant effect on child behaviour (d=0.15; 95% CI -0.03 to 0.31). CONCLUSIONS: Interventions offered to at-risk families in the first year of the child's life appear to improve child behaviour, parent-child relationship and maternal sensitivity post-intervention, but not child cognitive development and internalising or externalising behaviour. Future studies should incorporate follow-up assessments to examine long-term effects of early interventions. PMID- 29284715 TI - Pharmacy Diabetes Screening Trial: protocol for a pragmatic cluster-randomised controlled trial to compare three screening methods for undiagnosed type 2 diabetes in Australian community pharmacy. AB - INTRODUCTION: With the rising prevalence of type 2 diabetes in Australia, screening and earlier diagnosis is needed to provide opportunities to intervene with evidence-based lifestyle and treatment options to reduce the individual, social and economic impact of the disease. The objectives of the Pharmacy Diabetes Screening Trial are to compare the clinical effectiveness and cost effectiveness of three screening models for type 2 diabetes in a previously undiagnosed population. METHODS AND ANALYSIS: The Pharmacy Diabetes Screening Trial is a pragmatic cluster randomised controlled trial to be conducted in 363 community pharmacies across metropolitan, regional and remote areas of Australia, randomly allocated by geographical clusters to one of three groups, each with 121 pharmacies and 10 304 screening participants. The three groups are: group A: risk assessment using a validated tool (AUSDRISK); group B: AUSDRISK assessment followed by point-of-care glycated haemoglobin testing; and group C: AUSDRISK assessment followed by point-of-care blood glucose testing. The primary clinical outcome measure is the proportion of newly diagnosed cases of type 2 diabetes. Primary outcome comparisons will be conducted using the Cochran-Mantel-Haenszel test to account for clustering. The secondary clinical outcomes measures are the proportion of those who (1) are referred to the general practitioner (GP), (2) take up referral to the GP, (3) are diagnosed with pre-diabetes, that is, impaired glucose tolerance or impaired fasting glucose and (4) are newly diagnosed with either diabetes or pre-diabetes. The economic outcome measure is the average cost (direct and indirect) per confirmed new case of diagnosed type 2 diabetes based on the incremental net trial-based costs of service delivery and the associated incremental longer term health benefits from a health funder perspective. ETHICS AND DISSEMINATION: The protocol has been approved by the Human Research Ethics Committees at University of Sydney and Deakin University. Results will be available on the Sixth Community Pharmacy Agreement website and will be published in peer reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001240437; Pre-results. PMID- 29284714 TI - Development of a theoretical framework of factors affecting patient safety incident reporting: a theoretical review of the literature. AB - OBJECTIVES: The development and implementation of incident reporting systems within healthcare continues to be a fundamental strategy to reduce preventable patient harm and improve the quality and safety of healthcare. We sought to identify factors contributing to patient safety incident reporting. DESIGN: To facilitate improvements in incident reporting, a theoretical framework, encompassing factors that act as barriers and enablers ofreporting, was developed. Embase, Ovid MEDLINE(R) and PsycINFO were searched to identify relevant articles published between January 1980 and May 2014. A comprehensive search strategy including MeSH terms and keywords was developed to identify relevant articles. Data were extracted by three independent researchers; to ensure the accuracy of data extraction, all studies eligible for inclusion were rescreened by two reviewers. RESULTS: The literature search identified 3049 potentially eligible articles; of these, 110 articles, including >29 726 participants, met the inclusion criteria. In total, 748 barriers were identified (frequency count) across the 110 articles. In comparison, 372 facilitators to incident reporting and 118 negative cases were identified. The top two barriers cited were fear of adverse consequences (161, representing 21.52% of barriers) and process and systems of reporting (110, representing 14.71% of barriers). In comparison, the top two facilitators were organisational (97, representing 26.08% of facilitators) and process and systems of reporting (75, representing 20.16% of facilitators). CONCLUSION: A wide range of factors contributing to engagement in incident reporting exist. Efforts that address the current tendency to under report must consider the full range of factors in order to develop interventions as well as a strategic policy approach for improvement. PMID- 29284716 TI - Burden of early-term birth on adverse infant outcomes: a population-based cohort study in Brazil. AB - OBJECTIVES: To estimate the national rate of early-term live births in Brazil and to evaluate the effect of birth at 37 and 38 weeks' gestation, as compared with 39 and 40 weeks' gestation on infant outcomes according to precursors of birth and the existence of maternal/fetal medical conditions. DESIGN: National perinatal population-based cohort study. SETTING: 266 maternity services located in the five Brazilian macroregions. PARTICIPANTS: 18 652 singleton live newborns from 37 0/7 to 40 6/7 weeks of gestation. MAIN OUTCOME MEASURES: Resuscitation in delivery room, oxygen therapy, transient tachypnoea, admission to neonatal intensive care unit (NICU), hypoglycaemia, use of antibiotics, phototherapy, phototherapy after hospital discharge, neonatal death and breastfeeding. RESULTS: Early terms accounted for 35% (95% CI 33.4% to 36.7%) of all live births. Among provider-initiated births in women without medical conditions, infants of 37 and 38 weeks' gestation had higher odds of oxygen therapy (adjusted OR (AOR) 2.93, 95% CI 1.72 to 4.98 and AOR 1.92 95% CI 1.18 to 3.13), along with admission to NICU (AOR 2.01, 95% CI 1.18 to 3.41 and AOR 1.56, 95% CI 1.02 to 2.60), neonatal death (AOR 14.40, 95% CI 1.94 to 106.69 and AOR 13.76,95% CI 2.84 to 66.75), hypoglycaemia in the first 48 hours of life (AOR 7.86, 95% CI 1.95 to 31.71 and AOR 5.76, 95% CI 1.63 to 20.32), transient tachypnoea (AOR 2.98, 95% CI 1.57 to 5.65 and AOR 2.12, 95% CI 1.00 to 4.48) and the need for phototherapy within the first 72 hours of life (AOR 3.59, 95% CI 1.95 to 6.60 and AOR 2.29, 95% CI 1.49 to 3.53), yet lower odds of breastfeeding up to 1 hour after birth (AOR 0.67, 95% CI 0.53 to 0.86 and AOR 0.87, 95% CI 0.76 to 0.99) and exclusive breastfeeding during hospital stay (AOR 0.68, 95% CI 0.51 to 0.89 and AOR 0.84, 95% CI 0.71 to 0.99). CONCLUSION: Birth at 37 and 38 weeks' gestation increased the risk of most adverse infant outcomes analysed, especially among provider-initiated births and should be avoided before 39 weeks' gestation in healthy pregnancies. PMID- 29284717 TI - Association of professional identity, gender, team understanding, anxiety and workplace learning alignment with burnout in junior doctors: a longitudinal cohort study. AB - OBJECTIVES: To examine how burnout across medical student to junior doctor transition relates to: measures of professional identity, team understanding, anxiety, gender, age and workplace learning (assistantship) alignment to first post. DESIGN: A longitudinal 1-year cohort design. Two groups of final-year medical students: (1) those undertaking end-of-year assistantships aligned in location and specialty with their first post and (2) those undertaking assistantships non-aligned. An online questionnaire included: Professional Identity Scale, Team Understanding Scale, modified Hamilton Anxiety Rating Scale and modified Copenhagen Burnout Inventory. Data were collected on four occasions: (T1) prior to graduation; (T2) 1 month post-transition; (T3) 6 months post transition and (T4) 10 months post-transition. Questionnaires were analysed individually and using linear mixed-effect models. SETTING: Medical schools and postgraduate training in one UK country. PARTICIPANTS: All aligned assistantship (n=182) and non-aligned assistantship students (n=319) were contacted; n=281 (56%) responded: 68% (n=183) females, 73% (n=206) 22-30 years, 46% aligned (n=129). Completion rates: aligned 72% (93/129) and non-aligned 64% (98/152). RESULTS: Analyses of individual scales revealed that self-reported anxiety, professional identity and patient-related burnout were stable, while team understanding, personal and work-related burnout increased, all irrespective of alignment. Three linear mixed-effect models (personal, patient-related and work related burnout as outcome measures; age and gender as confounding variables) found that males self-reported significantly lower personal, but higher patient related burnout, than females. Age and team understanding had no effect. Anxiety was significantly positively related and professional identity was significantly negatively related to burnout. Participants experiencing non-aligned assistantships reported higher personal and work-related burnout over time. CONCLUSIONS: Implications for practice include medical schools' consideration of an end-of-year workplace alignment with first-post before graduation or an extended shadowing period immediately postgraduation. How best to support undergraduate students' early professional identity development should be examined. Support systems should be in place across the transition for individuals with a predisposition for anxiety. PMID- 29284719 TI - Cross-sectional analyses of participation in cancer screening and use of hormone replacement therapy and medications in meat eaters and vegetarians: the EPIC Oxford study. AB - OBJECTIVES: To examine differences in health-related behaviours such as screening or testing for cancer, use of hormone replacement therapy (HRT) and use of other medications in different diet groups. DESIGN: We studied 31 260 participants across four diet groups (18 155 meat eaters, 5012 fish eaters, 7179 vegetarians, 914 vegans) in the UK EPIC-Oxford cohort. Information was collected in 5-year (around 2000-2003) or 10-year (around 2007) follow-up questionnaires regarding participation in breast screening, cervical screening, prostate-specific antigen (PSA) testing, use of HRT and use of medications for the past 4 weeks. Using Poisson regression, we estimated the prevalence ratios (PR) for each behaviour across people of different diet groups, using meat eaters as the reference group. RESULTS: Compared with meat eaters, vegetarian (PR: 0.94, 95% CI 0.89 to 0.98) and vegan (PR: 0.82, 95% CI 0.71 to 0.95) women reported lower participation in breast screening, and vegetarian men were less likely to report PSA testing (PR: 0.82, 95% CI 0.71 to 0.96). No differences were observed among women for cervical screening. In women, all non-meat-eating groups reported lower use of HRT compared with meat eaters (P heterogeneity <0.0001). Lower reported use of any medication was observed for participants in all non-meat-eating groups with no (P<0.0001) or one (P=0.0002) self-reported illness. No heterogeneity was observed across the diet groups for the reported use of specific medication for high blood pressure, high blood cholesterol, asthma, diabetes and thyroid disease. CONCLUSIONS: Differences in self-reported breast screening, PSA testing, HRT use and overall medication use were observed across the diet groups. Whether such differences contribute to differential long-term disease risks requires further study. PMID- 29284718 TI - Cohort profile: Study of Transition, Outcomes and Gender (STRONG) to assess health status of transgender people. AB - PURPOSE: The Study of Transition, Outcomes and Gender (STRONG) was initiated to assess the health status of transgender people in general and following gender affirming treatments at Kaiser Permanente health plans in Georgia, Northern California and Southern California. The objectives of this communication are to describe methods of cohort ascertainment and data collection and to characterise the study population. PARTICIPANTS: A stepwise methodology involving computerised searches of electronic medical records and free-text validation of eligibility and gender identity was used to identify a cohort of 6456 members with first evidence of transgender status (index date) between 2006 and 2014. The cohort included 3475 (54%) transfeminine (TF), 2892 (45%) transmasculine (TM) and 89 (1%) members whose natal sex and gender identity remained undetermined from the records. The cohort was matched to 127 608 enrollees with no transgender evidence (63 825 women and 63 783 men) on year of birth, race/ethnicity, study site and membership year of the index date. Cohort follow-up extends through the end of 2016. FINDINGS TO DATE: About 58% of TF and 52% of TM cohort members received hormonal therapy at Kaiser Permanente. Chest surgery was more common among TM participants (12% vs 0.3%). The proportions of transgender participants who underwent genital reconstruction surgeries were similar (4%-5%) in the two transgender groups. Results indicate that there are sufficient numbers of events in the TF and TM cohorts to further examine mental health status, cardiovascular events, diabetes, HIV and most common cancers. FUTURE PLANS: STRONG is well positioned to fill existing knowledge gaps through comparisons of transgender and reference populations and through analyses of health status before and after gender affirmation treatment. Analyses will include incidence of cardiovascular disease, mental health, HIV and diabetes, as well as changes in laboratory-based endpoints (eg, polycythemia and bone density), overall and in relation to gender affirmation therapy. PMID- 29284720 TI - Overdiagnosis across medical disciplines: a scoping review. AB - OBJECTIVE: To provide insight into how and in what clinical fields overdiagnosis is studied and give directions for further applied and methodological research. DESIGN: Scoping review. DATA SOURCES: Medline up to August 2017. STUDY SELECTION: All English studies on humans, in which overdiagnosis was discussed as a dominant theme. DATA EXTRACTION: Studies were assessed on clinical field, study aim (ie, methodological or non-methodological), article type (eg, primary study, review), the type and role of diagnostic test(s) studied and the context in which these studies discussed overdiagnosis. RESULTS: From 4896 studies, 1851 were included for analysis. Half of all studies on overdiagnosis were performed in the field of oncology (50%). Other prevalent clinical fields included mental disorders, infectious diseases and cardiovascular diseases accounting for 9%, 8% and 6% of studies, respectively. Overdiagnosis was addressed from a methodological perspective in 20% of studies. Primary studies were the most common article type (58%). The type of diagnostic tests most commonly studied were imaging tests (32%), although these were predominantly seen in oncology and cardiovascular disease (84%). Diagnostic tests were studied in a screening setting in 43% of all studies, but as high as 75% of all oncological studies. The context in which studies addressed overdiagnosis related most frequently to its estimation, accounting for 53%. Methodology on overdiagnosis estimation and definition provided a source for extensive discussion. Other contexts of discussion included definition of disease, overdiagnosis communication, trends in increasing disease prevalence, drivers and consequences of overdiagnosis, incidental findings and genomics. CONCLUSIONS: Overdiagnosis is discussed across virtually all clinical fields and in different contexts. The variability in characteristics between studies and lack of consensus on overdiagnosis definition indicate the need for a uniform typology to improve coherence and comparability of studies on overdiagnosis. PMID- 29284722 TI - Comprehensive overview of computer-based health information tailoring: a scoping review protocol. AB - INTRODUCTION: Tailoring health information to the needs of individuals has become an important part of modern health communications. Tailoring has been addressed by researchers from different disciplines leading to the emergence of a wide range of approaches, making the newcomers confused. In order to address this, a comprehensive overview of the field with the indications of research gaps, tendencies and trends will be helpful. As a result, a systematic protocol was outlined to conduct a scoping review within the field of computer-based health information tailoring. METHODS AND ANALYSIS: This protocol is based on the York's five-stage framework outlined by Arksey and O'Malley. A field-specific structure was defined as a basis for undertaking each stage. The structure comprised three main aspects: system design, information communication and evaluation. Five leading databases were searched: PubMed, Scopus, Science Direct, EBSCO and IEEE and a broad search strategy was used with less strict inclusion criteria to cover the breadth of evidence. Theoretical frameworks were used to develop the data extraction form and a rigorous approach was introduced to identify the categories from data. Several explanatory-descriptive methods were considered to analyse the data, from which some were proposed to be employed for the first time in scoping studies. ETHICS AND DISSEMINATION: This study investigates the breadth and depth of existing literature on computer-tailoring and as a secondary analysis, does not require ethics approval. We anticipate that the results will identify research gaps and novel ideas for future studies and provide direction to combine methods from different disciplines. The research findings will be submitted for publication to relevant peer-reviewed journals and conferences targeting health promotion and patient education. PMID- 29284723 TI - Correction: National multicentre audit of pregnancy status in general surgery admissions in Scotland. PMID- 29284721 TI - Migraine and subsequent chronic kidney disease risk: a nationwide population based cohort study. AB - OBJECTIVE: We compared the incidence and risk of chronic kidney disease (CKD) between subjects with new-onset migraine and matched controls without migraine in this large-scale retrospective cohort study. DESIGN: Population-based cohort study. SETTING: 8880 subjects with migraine and 503 070 subjects without migraine were enrolled between January 1, 2000 and December 31, 2013, all diagnosed to be without kidney disease. All the participants were registered in the National Health Insurance Research Database. PARTICIPANTS: Finally, data from 7156 subjects with migraine and 7156 propensity-score-matched control subjects were analysed. PRIMARY OUTCOME MEASURE: We used Cox proportional hazards regression to estimate adjusted HRs for incident CKD; subgroup analyses were performed to assess the interactive effects of migraine with demographics, comorbidities and long-term medications. RESULTS: The incidence of CKD was higher in the migraine group than in the control group. The risk of developing CKD was significantly higher in subjects with migraine than without migraine (P=0.031). Subjects with migraine aged <65 years (age 40-64 (adjusted HR (aHR) 1.35; 95% CI 1.05 to 1.73); age <40 (aHR 1.55; 95% CI 1.02 to 2.36)), with >=1 comorbid diseases (1-2 diseases (aHR 1.30; 95% CI 1.01 to 1.68); >=3 diseases (aHR 1.45; 95% CI 1.01 to 2.07)), and not receiving anti-migraine agents (aHR 1.26; 95% CI 1.04 to 1.54) were at a higher risk of developing CKD compared with the control subjects. The interaction between migraine and comorbidities was not significant; age, male gender and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) were independent risk factors for CKD in subjects with migraine. CONCLUSION: Migraine may be an independent risk factor for CKD. Young subjects with migraine, and those with comorbid conditions or without medical control, are likely to be at higher risk for CKD. Ageing, male sex and NSAIDs tend to have an association with CKD in subjects with migraine. PMID- 29284724 TI - 'Dying': what medicine can learn from fiction. PMID- 29284726 TI - The LAST Word on Coaching as a Stroke Intervention? PMID- 29284725 TI - Carotid Intima-Media Thickness Is Associated With White Matter Hyperintensities: The Northern Manhattan Study. AB - BACKGROUND AND PURPOSE: Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort. METHODS: We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors. RESULTS: In a cohort of 1229 participants (mean age, 71+/-9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71+/-0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21-0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (beta=0.046 per SD cIMT; P=0.04). Age and race/ethnicity were significant modifiers (P for age, 0.02; and P for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (beta=0.088 per SD cIMT; P=0.01) and among Hispanics (beta=0.084 per SD cIMT; P=0.003). CONCLUSIONS: Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline. PMID- 29284727 TI - Letter by Shiue and Sands Regarding Article, "Incorporating Nonphysician Stroke Specialists Into the Stroke Team". PMID- 29284728 TI - Response by Miller to Letter Regarding Article, "Incorporating Nonphysician Stroke Specialists into the Stroke Team". PMID- 29284729 TI - Letter by Liu et al Regarding Article, "Thrombolysis in Postoperative Stroke". PMID- 29284730 TI - Richard Joel Traystman, PhD. PMID- 29284732 TI - Response by Voelkel and Hubert to Letter Regarding Article, "Thrombolysis in Postoperative Stroke". PMID- 29284733 TI - Cognitive and Mood Assessment Tools for Use in Stroke. PMID- 29284731 TI - Association Between Heart Rate and Subclinical Cerebrovascular Disease in the Elderly. AB - BACKGROUND AND PURPOSE: Although increased heart rate (HR) is a predictor of cardiovascular events and mortality, its possible association with subclinical cerebrovascular disease, which is prevalent in the elderly, has not been evaluated. This study aimed to investigate the association of daytime, nighttime, 24-hour HR, and HR variability with subclinical cerebrovascular disease in an elderly cohort without history of stroke. METHODS: The study cohort consisted of 680 participants (mean age, 73+/-7 years; 42% men) in sinus rhythm who underwent 24-hour ambulatory blood pressure and HR monitoring, 2-dimensional echocardiography, and brain magnetic resonance imaging as part of the CABL study (Cardiac Abnormalities and Brain Lesion). Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume (WMHV). The relationship of HR measures with the presence of silent brain infarct and upper quartile of log WMHV (log WMHV4) was analyzed. RESULTS: Presence of silent brain infarct was detected in 93 participants (13.7%); mean log WMHV was -0.92+/ 0.93 (median, -1.05; min, -5.88; max, 1.74). Multivariate analysis showed that only nighttime HR (adjusted odds ratio, 1.29 per 10 bpm; 95% confidence interval, 1.03-1.61; P=0.026) was significantly associated with log WMHV4, independent of traditional cardiovascular risk factors, ambulatory systolic blood pressure, and echocardiographic parameters. No similar association was observed for daytime HR and HR variability. There was no significant association between all HR measures and silent brain infarct. CONCLUSIONS: In a predominantly elderly cohort, elevated nighttime HR was associated with WMHV, suggesting an independent role of HR in subclinical cerebrovascular disease. PMID- 29284734 TI - Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. AB - BACKGROUND AND PURPOSE: Prehospital stroke severity scales may help to triage acute ischemic stroke patients with large vessel occlusion (LVO) for direct transportation to a comprehensive stroke center. The impact on resource use and time to reperfusion treatment for patients with and without LVO is unknown. METHODS: Based on empirical distributions of stroke symptom severity, prehospital delay times, and stroke symptom severity-dependent likelihood of LVO, we simulate prehospital incidents of stroke-like symptoms in abstract geographical environments to estimate the impact of prehospital triage strategies based on different cutoffs of the rapid arterial occlusion evaluation scale. RESULTS: Compared with transporting each patient to the nearest stroke center, implementation of a prehospital triage strategy based on a rapid arterial occlusion evaluation scale cutoff score >=5 is associated with more patients with suspected acute stroke at comprehensive stroke centers and less patients at primary stroke centers (+11.7% [95% confidence interval: +8.1% to +15.3%] and 18.4% [-19.1% to -17.7%], respectively). Mean time to groin puncture is reduced by 29.6 minutes (-35.2 to -24.7 minutes) while mean time to thrombolysis does not change significantly (+/-0.0 minutes [-0.3 to +0.3 minutes]). The total number of secondary transfers is reduced by 60.9% (-62.8% to -59.0%); mean time of ambulance use per patient is unchanged. Results are robust with regards to variation in model parameters. CONCLUSIONS: Implementation of prehospital triage based on stroke severity scales would have strong impact on patient flow and distribution. The benefit of earlier thrombectomy for patients with LVO may outweigh the harm associated with delayed access to thrombolysis for some patients without LVO. Randomized trials using clinical stroke severity scales as a triage tool are needed to confirm our findings. PMID- 29284736 TI - Carotid Atheroma From Men Has Significantly Higher Levels of Inflammation and Iron Metabolism Enabled by Macrophages. AB - BACKGROUND AND PURPOSE: Men differ from women in the manifestation of atherosclerosis and iron metabolism. Intraplaque hemorrhage and hemoglobin (Hb) catabolism by macrophages are associated with atherosclerotic lesion instability. The study aims were to investigate sex differences in (1) lesion severity in relation to blood Hb, (2) iron homeostasis in human carotid plaques, and (3) macrophage polarization within atheroma. METHODS: The carotid artery samples from 39 men and 23 women were immunostained with cell markers for macrophages, smooth muscle cells, ferritin, and TfR1 (transferrin receptor 1), which were further analyzed according to sex in relation to iron, Hb, and lipids in circulation. Additionally, samples of predefined regions from human carotid atherosclerotic lesions, including internal controls, were used for proteomic analysis by mass spectrometry. RESULTS: Male patients, compared with women, had larger necrotic cores and more plaque rupture, which were associated with higher levels of Hb. Atheroma of male patients had significantly higher levels of Hb in circulation and CD68 macrophages, ferritin, and TfR1 in lesions. CD68 macrophages were significantly correlated with ferritin and TfR1. Plaques from male patients comparatively possessed higher levels of inflammatory macrophage subsets, CD86 (M1) and CD163 (M2), but lower levels of STF (serotransferrin) and HPX (hemopexin). CONCLUSIONS: Male patients with carotid atheroma had more advanced and ruptured lesions associated with significantly higher levels of inflammatory macrophage infiltration and high iron stores in the blood and in their plaques. These findings help to understand sex differences and iron metabolism in atherosclerosis and factors related to atheroma progression. PMID- 29284735 TI - Contact Aspiration Versus Stent Retriever in Patients With Acute Ischemic Stroke With M2 Occlusion in the ASTER Randomized Trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). AB - BACKGROUND AND PURPOSE: Middle cerebral artery M2-segment occlusions represent an important subgroup of patients with acute stroke with large-vessel occlusion. The safety of mechanical thrombectomy, especially contact aspiration (CA), in such distal intracranial occlusions is still under debate. We compared reperfusion, adverse events, neurological recovery, and functional outcome of patients with isolated M2 occlusions according to the first-line strategy mechanical thrombectomy devices (CA versus stent retriever [SR]). METHODS: This is a post hoc analysis of the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). The primary outcome was successful reperfusion at the end of all endovascular procedures, defined as modified Thrombolysis in Cerebral Infarction (mTICI) scores 2b/3. Secondary outcomes were mTICI 2c/3 and mTICI 3, 90-day functional outcome, assessed with the modified Rankin Scale score. Safety outcomes included 90-day mortality and any symptomatic intracerebral hemorrhage. RESULTS: Seventy-nine patients were included: 48 were allocated to the CA group and 31 to the SR group. There were no significant differences between CA and SR groups in reperfusion after all endovascular procedures regarding mTICI 2b/3 (89.6% versus 83.9%; P=0.36), mTICI 2c/3 (54.2% versus 54.8%; P=0.90), and mTICI 3 (35.4% versus 41.9%; P=0.36) rates. There were no significant differences between CA and SR groups in 90-day modified Rankin Scale <=2 rate (54.4% versus 50.0%; P=0.84), 24-hour change in National Institutes of Health Stroke Scale (mean difference, -3.9; 95% confidence interval, -7.9 to 0.01), and Alberta Stroke Program Early Computed Tomography score (mean difference, 0.9; 95% confidence interval, -0.1 to 2.0) scores. Safety parameters were well balanced between the 2 groups except for a higher 90-day mortality rate in the CA group (19.6% versus 3.3%; P=0.078). CONCLUSIONS: First line mechanical thrombectomy with CA compared with SR did not result in an increased successful revascularization rate in patients with acute stroke with isolated M2 occlusion. PMID- 29284737 TI - Efficacy and Safety of Individualized Coaching After Stroke: the LAST Study (Life After Stroke): A Pragmatic Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: The evidence for interventions to prevent functional decline in the long term after stroke is lacking. The aim of this trial was to evaluate the efficacy and safety of an 18-month follow-up program of individualized regular coaching on physical activity and exercise. METHODS: This was a multicentre, pragmatic, single-blinded, randomized controlled trial. Adults (age >=18 years) with first-ever or recurrent stroke, community dwelling, with modified Rankin Scale <5, and no serious comorbidities were included 10 to 16 weeks poststroke. The intervention group received individualized regular coaching on physical activity and exercise every month for 18 consecutive months. The control group received standard care. Primary outcome was the Motor Assessment Scale at end of intervention (18-month follow-up). Secondary measures were Barthel index, modified Rankin Scale, item 14 from Berg Balance Scale, Timed Up and Go test, gait speed, 6-minute walk test, and Stroke Impact Scale. Other outcomes were adverse events and compliance to the intervention assessed by training diaries and the International Physical Activity Questionnaire. RESULTS: Three hundred and eighty consenting participants were randomly assigned to individualized coaching (n=186) or standard care (n=194). The mean estimated difference on Motor Assessment Scale in favor of control group was -0.70 points (95% confidence interval, -2.80, 1.39), P=0.512. There were no differences between the groups on Barthel index, modified Rankin Scale, or Berg Balance Scale. The frequency of adverse events was low in both groups. Results from International Physical Activity Questionnaire and training diaries showed increased activity levels but low intensity of the exercise in the intervention group. CONCLUSIONS: The regular individualized coaching did not improve maintenance of motor function or the secondary outcomes compared with standard care. The intervention should be regarded as safe. Despite the neutral results, the health costs related to the intervention should be investigated. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01467206. PMID- 29284738 TI - Comparison of Risk Factor Control in the Year After Discharge for Ischemic Stroke Versus Acute Myocardial Infarction. AB - BACKGROUND AND PURPOSE: The Veterans Health Administration has engaged in quality improvement to improve vascular risk factor control. We sought to examine blood pressure (<140/90 mm Hg), lipid (LDL [low-density lipoprotein] cholesterol <100 mg/dL), and glycemic control (hemoglobin A1c <9%), in the year post hospitalization for acute ischemic stroke or acute myocardial infarction (AMI). METHODS: We identified patients who were hospitalized (fiscal year 2011) with ischemic stroke, AMI, congestive heart failure, transient ischemic attack, or pneumonia/chronic obstructive pulmonary disease. The primary analysis compared risk factor control after incident ischemic stroke versus AMI. Facilities were included if they cared for >=25 ischemic stroke and >=25 AMI patients. A generalized linear mixed model including patient- and facility-level covariates compared risk factor control across diagnoses. RESULTS: Forty thousand two hundred thirty patients were hospitalized (n=75 facilities): 2127 with incident ischemic stroke and 4169 with incident AMI. Fewer stroke patients achieved blood pressure control than AMI patients (64%; 95% confidence interval, 0.62-0.67 versus 77%; 95% confidence interval, 0.75-0.78; P<0.0001). After adjusting for patient and facility covariates, the odds of blood pressure control were still higher for AMI than ischemic stroke patients (odds ratio, 1.39; 95% confidence interval, 1.21-1.51). There were no statistical differences for AMI versus stroke patients in hyperlipidemia (P=0.534). Among patients with diabetes mellitus, the odds of glycemic control were lower for AMI than ischemic stroke patients (odds ratio, 0.72; 95% confidence interval, 0.54-0.96). CONCLUSIONS: Given that hypertension control is a cornerstone of stroke prevention, interventions to improve poststroke hypertension management are needed. PMID- 29284739 TI - Letter by Cooper et al Regarding the Article, "Incorporating Nonphysician Stroke Specialists Into the Stroke Team". PMID- 29284740 TI - Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains. AB - Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein, ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry. We found that the BAP1-ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small-molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable.Significance: Combined computational and biochemical approaches demonstrate that the BAP1-ASXL2 interaction is direct and high affinity and that many BAP1 mutations act allosterically to inhibit BAP1-ASXL2 binding. Cancer Res; 78(5); 1200-13. (c)2017 AACR. PMID- 29284741 TI - Converging Light, Energy and Hormonal Signaling Control Meristem Activity, Leaf Initiation, and Growth. AB - The development of leaf primordia is subject to light control of meristematic activity. Light regulates the expression of thousands of genes with roles in cell proliferation, organ development, and differentiation of photosynthetic cells. Previous work has highlighted roles for hormone homeostasis and the energy dependent Target of Rapamycin (TOR) kinase in meristematic activity, yet a picture of how these two regulatory mechanisms depend on light perception and interact with each other has yet to emerge. Their relevance beyond leaf initiation also is unclear. Here, we report the discovery that the dark-arrested meristematic region of Arabidopsis (Arabidopsis thaliana) experiences a local energy deprivation state and confirm previous findings that the PIN1 auxin transporter is diffusely localized in the dark. Light triggers a rapid removal of the starvation state and the establishment of PIN1 polar membrane localization consistent with auxin export, both preceding the induction of cell cycle- and cytoplasmic growth-associated genes. We demonstrate that shoot meristematic activity can occur in the dark through the manipulation of auxin and cytokinin activity as well as through the activation of energy signaling, both targets of photomorphogenesis action, but the organ developmental outcomes differ: while TOR dependent energy signals alone stimulate cell proliferation, the development of a normal leaf lamina requires photomorphogenesis-like hormonal responses. We further show that energy signaling adjusts the extent of cell cycle activity and growth of young leaves non-cellautonomously to available photosynthates and leads to organs constituted of a greater number of cells developing under higher irradiance. This makes energy signaling perhaps the most important biomass growth determinant under natural, unstressed conditions. PMID- 29284742 TI - The Long Intergenic Noncoding RNA (LincRNA) Landscape of the Soybean Genome. AB - Long intergenic noncoding RNAs (lincRNAs) are emerging as important regulators of diverse biological processes. However, our understanding of lincRNA abundance and function remains very limited especially for agriculturally important plants. Soybean (Glycine max) is a major legume crop plant providing over a half of global oilseed production. Moreover, soybean can form symbiotic relationships with Rhizobium bacteria to fix atmospheric nitrogen. Soybean has a complex paleopolyploid genome and exhibits many vegetative and floral development complexities. Soybean cultivars have photoperiod requirements restricting its use and productivity. Molecular regulators of these legume-specific developmental processes remain enigmatic. Long noncoding RNAs may play important regulatory roles in soybean growth and development. In this study, over one billion RNA-seq read pairs from 37 samples representing nine tissues were used to discover 6,018 lincRNA loci. The lincRNAs were shorter than protein-coding transcripts and had lower expression levels and more sample specific expression. Few of the loci were found to be conserved in two other legume species (chickpea [Cicer arietinum] and Medicago truncatula), but almost 200 homeologous lincRNAs in the soybean genome were detected. Protein-coding gene-lincRNA coexpression analysis suggested an involvement of lincRNAs in stress response, signal transduction, and developmental processes. Positional analysis of lincRNA loci implicated involvement in transcriptional regulation. lincRNA expression from centromeric regions was observed especially in actively dividing tissues, suggesting possible roles in cell division. Integration of publicly available genome-wide association data with the lincRNA map of the soybean genome uncovered 23 lincRNAs potentially associated with agronomic traits. PMID- 29284743 TI - Mitochondria Affect Photosynthetic Electron Transport and Photosensitivity in a Green Alga. AB - Photosynthetic organisms use sunlight as the primary source of energy to support their metabolism. In eukaryotes, reactions responsible of the conversion of light into chemical energy occur in specific organelles, the chloroplasts. In this study, we showed that mitochondria also have a seminal influence on cells' energy metabolism and on photosynthetic reactions. This is illustrated by the observation that the strong photosensitivity of Chlamydomonas reinhardtii cells depleted of the chloroplast protein PGRL1 was rescued by the introduction of a mitochondrial mutation affecting respiratory complex I. Functional analysis showed that such a reduced respiratory activity influenced chloroplast electron transport with consequent overreduction of plastoquinone and donor-side limitation of photosystem I (PSI). As a consequence, damage due to excess light affected more photosystem II (PSII) rather than PSI. Double mutant cells are able to grow under excess illumination, while single pgrl1 are not, thanks to the presence of an efficient repair mechanism of PSII. These results also underline the seminal biological relevance of the regulation of electron transport reactions within the photosynthetic complexes. Photosynthetic organisms evolved a strategy to respond to excess light where damage is targeting preferentially to a specific complex, PSII. Cells are able to endure extensive damage targeting this complex thanks to an efficient repair mechanisms, while if PSI is affected, there are drastic consequences on growth. PMID- 29284744 TI - An Iron-Activated Citrate Transporter, MtMATE67, Is Required for Symbiotic Nitrogen Fixation. AB - Iron (Fe) is an essential micronutrient for symbiotic nitrogen fixation in legume nodules, where it is required for the activity of bacterial nitrogenase, plant leghemoglobin, respiratory oxidases, and other Fe proteins in both organisms. Fe solubility and transport within and between plant tissues is facilitated by organic chelators, such as nicotianamine and citrate. We have characterized a nodule-specific citrate transporter of the multidrug and toxic compound extrusion family, MtMATE67 of Medicago truncatula The MtMATE67 gene was induced early during nodule development and expressed primarily in the invasion zone of mature nodules. The MtMATE67 protein was localized to the plasma membrane of nodule cells and also the symbiosome membrane surrounding bacteroids in infected cells. In oocytes, MtMATE67 transported citrate out of cells in an Fe-activated manner. Loss of MtMATE67 gene function resulted in accumulation of Fe in the apoplasm of nodule cells and a substantial decrease in symbiotic nitrogen fixation and plant growth. Taken together, the results point to a primary role of MtMATE67 in citrate efflux from nodule cells in response to an Fe signal. This efflux is necessary to ensure Fe(III) solubility and mobility in the apoplasm and uptake into nodule cells. Likewise, MtMATE67-mediated citrate transport into the symbiosome space would increase the solubility and availability of Fe(III) for rhizobial bacteroids. PMID- 29284746 TI - Atmospheric escape from the TRAPPIST-1 planets and implications for habitability. AB - The presence of an atmosphere over sufficiently long timescales is widely perceived as one of the most prominent criteria associated with planetary surface habitability. We address the crucial question of whether the seven Earth-sized planets transiting the recently discovered ultracool dwarf star TRAPPIST-1 are capable of retaining their atmospheres. To this effect, we carry out numerical simulations to characterize the stellar wind of TRAPPIST-1 and the atmospheric ion escape rates for all of the seven planets. We also estimate the escape rates analytically and demonstrate that they are in good agreement with the numerical results. We conclude that the outer planets of the TRAPPIST-1 system are capable of retaining their atmospheres over billion-year timescales. The consequences arising from our results are also explored in the context of abiogenesis, biodiversity, and searches for future exoplanets. In light of the many unknowns and assumptions involved, we recommend that these conclusions must be interpreted with due caution. PMID- 29284745 TI - Localizing softness and stress along loops in 3D topological metamaterials. AB - Topological states can be used to control the mechanical properties of a material along an edge or around a localized defect. The rigidity of elastic networks is characterized by a topological invariant called the polarization; materials with a well-defined uniform polarization display a dramatic range of edge softness depending on the orientation of the polarization relative to the terminating surface. However, in all 3D mechanical metamaterials proposed to date, the topological modes are mixed with bulk soft modes, which organize themselves in Weyl loops. Here, we report the design of a 3D topological metamaterial without Weyl lines and with a uniform polarization that leads to an asymmetry between the number of soft modes on opposing surfaces. We then use this construction to localize topological soft modes in interior regions of the material by including defect lines-dislocation loops-that are unique to three dimensions. We derive a general formula that relates the difference in the number of soft modes and states of self-stress localized along the dislocation loop to the handedness of the vector triad formed by the lattice polarization, Burgers vector, and dislocation-line direction. Our findings suggest a strategy for preprogramming failure and softness localized along lines in 3D, while avoiding extended soft Weyl modes. PMID- 29284747 TI - Motor dexterity and strength depend upon integrity of the attention-control system. AB - Attention control (or executive control) is a higher cognitive function involved in response selection and inhibition, through close interactions with the motor system. Here, we tested whether influences of attention control are also seen on lower level motor functions of dexterity and strength-by examining relationships between attention control and motor performance in healthy-aged and hemiparetic stroke subjects (n = 93 and 167, respectively). Subjects undertook simple tracking, precision-hold, and maximum force-generation tasks, with each hand. Performance across all tasks correlated strongly with attention control (measured as distractor resistance), independently of factors such as baseline performance, hand use, lesion size, mood, fatigue, or whether distraction was tested during motor or nonmotor cognitive tasks. Critically, asymmetric dissociations occurred in all tasks, in that severe motor impairment coexisted with normal (or impaired) attention control whereas normal motor performance was never associated with impaired attention control (below a task-dependent threshold). This implies that dexterity and force generation require intact attention control. Subsequently, we examined how motor and attention-control performance mapped to lesion location and cerebral functional connectivity. One component of motor performance (common to both arms), as well as attention control, correlated with the anatomical and functional integrity of a cingulo-opercular "salience" network. Independently of this, motor performance difference between arms correlated negatively with the integrity of the primary sensorimotor network and corticospinal tract. These results suggest that the salience network, and its attention-control function, are necessary for virtually all volitional motor acts while its damage contributes significantly to the cardinal motor deficits of stroke. PMID- 29284748 TI - Aridity weakens population-level effects of multiple species interactions on Hibiscus meyeri. AB - Predicting how species' abundances and ranges will shift in response to climate change requires a mechanistic understanding of how multiple factors interact to limit population growth. Both abiotic stress and species interactions can limit populations and potentially set range boundaries, but we have a poor understanding of when and where each is most critical. A commonly cited hypothesis, first proposed by Darwin, posits that abiotic factors (e.g., temperature, precipitation) are stronger determinants of range boundaries in apparently abiotically stressful areas ("stress" indicates abiotic factors that reduce population growth), including desert, polar, or high-elevation environments, whereas species interactions (e.g., herbivory, competition) play a stronger role in apparently less stressful environments. We tested a core tenet of this hypothesis-that population growth rate is more strongly affected by species interactions in less stressful areas-using experimental manipulations of species interactions affecting a common herbaceous plant, Hibiscus meyeri (Malvaceae), across an aridity gradient in a semiarid African savanna. Population growth was more strongly affected by four distinct species interactions (competition with herbaceous and shrubby neighbors, herbivory, and pollination) in less stressful mesic areas than in more stressful arid sites. However, contrary to common assumptions, this effect did not arise because of greater density or diversity of interacting species in less stressful areas, but rather because aridity reduced sensitivity of population growth to these interactions. Our work supports classic predictions about the relative strength of factors regulating population growth across stress gradients, but suggests that this pattern results from a previously unappreciated mechanism that may apply to many species worldwide. PMID- 29284749 TI - Visualizing long-term single-molecule dynamics in vivo by stochastic protein labeling. AB - Our ability to unambiguously image and track individual molecules in live cells is limited by packing of multiple copies of labeled molecules within the resolution limit. Here we devise a universal genetic strategy to precisely control copy number of fluorescently labeled molecules in a cell. This system has a dynamic range of ~10,000-fold, enabling sparse labeling of proteins expressed at different abundance levels. Combined with photostable labels, this system extends the duration of automated single-molecule tracking by two orders of magnitude. We demonstrate long-term imaging of synaptic vesicle dynamics in cultured neurons as well as in intact zebrafish. We found axon initial segment utilizes a "waterfall" mechanism gating synaptic vesicle transport polarity by promoting anterograde transport processivity. Long-time observation also reveals that transcription factor hops between clustered binding sites in spatially restricted subnuclear regions, suggesting that topological structures in the nucleus shape local gene activities by a sequestering mechanism. This strategy thus greatly expands the spatiotemporal length scales of live-cell single molecule measurements, enabling new experiments to quantitatively understand complex control of molecular dynamics in vivo. PMID- 29284751 TI - Unraveling submicron-scale mechanical heterogeneity by three-dimensional X-ray microdiffraction. AB - Shear banding is a ubiquitous phenomenon of severe plastic deformation, and damage accumulation in shear bands often results in the catastrophic failure of a material. Despite extensive studies, the microscopic mechanisms of strain localization and deformation damage in shear bands remain elusive due to their spatial-temporal complexities embedded in bulk materials. Here we conducted synchrotron-based X-ray microdiffraction (MUXRD) experiments to map out the 3D lattice strain field with a submicron resolution around fatigue shear bands in a stainless steel. Both in situ and postmortem MUXRD results revealed large lattice strain gradients at intersections of the primary and secondary shear bands. Such strain gradients resulted in severe mechanical heterogeneities across the fatigue shear bands, leading to reduced fatigue limits in the high-cycle regime. The ability to spatially quantify the localized strain gradients with submicron resolution through MUXRD opens opportunities for understanding the microscopic mechanisms of damage and failure in bulk materials. PMID- 29284750 TI - Cyclic AMP-dependent plasticity underlies rapid changes in odor coding associated with reward learning. AB - Learning and memory rely on dopamine and downstream cAMP-dependent plasticity across diverse organisms. Despite the central role of cAMP signaling, it is not known how cAMP-dependent plasticity drives coherent changes in neuronal physiology that encode the memory trace, or engram. In Drosophila, the mushroom body (MB) is critically involved in olfactory classical conditioning, and cAMP signaling molecules are necessary and sufficient for normal memory in intrinsic MB neurons. To evaluate the role of cAMP-dependent plasticity in learning, we examined how cAMP manipulations and olfactory classical conditioning modulate olfactory responses in the MB with in vivo imaging. Elevating cAMP pharmacologically or optogenetically produced plasticity in MB neurons, altering their responses to odorants. Odor-evoked Ca2+ responses showed net facilitation across anatomical regions. At the single-cell level, neurons exhibited heterogeneous responses to cAMP elevation, suggesting that cAMP drives plasticity to discrete subsets of MB neurons. Olfactory appetitive conditioning enhanced MB odor responses, mimicking the cAMP-dependent plasticity in directionality and magnitude. Elevating cAMP to equivalent levels as appetitive conditioning also produced plasticity, suggesting that the cAMP generated during conditioning affects odor-evoked responses in the MB. Finally, we found that this plasticity was dependent on the Rutabaga type I adenylyl cyclase, linking cAMP-dependent plasticity to behavioral modification. Overall, these data demonstrate that learning produces robust cAMP-dependent plasticity in intrinsic MB neurons, which is biased toward naturalistic reward learning. This suggests that cAMP signaling may serve to modulate intrinsic MB responses toward salient stimuli. PMID- 29284752 TI - Role of enhanced receptor engagement in the evolution of a pandemic acute hemorrhagic conjunctivitis virus. AB - Acute hemorrhagic conjunctivitis (AHC) is a painful, contagious eye disease, with millions of cases in the last decades. Coxsackievirus A24 (CV-A24) was not originally associated with human disease, but in 1970 a pathogenic "variant" (CV A24v) emerged, which is now the main cause of AHC. Initially, this variant circulated only in Southeast Asia, but it later spread worldwide, accounting for numerous AHC outbreaks and two pandemics. While both CV-A24 variant and nonvariant strains still circulate in humans, only variant strains cause AHC for reasons that are yet unknown. Since receptors are important determinants of viral tropism, we set out to map the CV-A24 receptor repertoire and establish whether changes in receptor preference have led to the increased pathogenicity and rapid spread of CV-A24v. Here, we identify ICAM-1 as an essential receptor for both AHC causing and non-AHC strains. We provide a high-resolution cryo-EM structure of a virus-ICAM-1 complex, which revealed critical ICAM-1-binding residues. These data could help identify a possible conserved mode of receptor engagement among ICAM-1 binding enteroviruses and rhinoviruses. Moreover, we identify a single capsid substitution that has been adopted by all pandemic CV-A24v strains and we reveal that this adaptation enhances the capacity of CV-A24v to bind sialic acid. Our data elucidate the CV-A24v receptor repertoire and point to a role of enhanced receptor engagement in the adaptation to the eye, possibly enabling pandemic spread. PMID- 29284753 TI - Interplay of structure, elasticity, and dynamics in actin-based nematic materials. AB - Achieving control and tunability of lyotropic materials has been a long-standing goal of liquid crystal research. Here we show that the elasticity of a liquid crystal system consisting of a dense suspension of semiflexible biopolymers can be manipulated over a relatively wide range of elastic moduli. Specifically, thin films of actin filaments are assembled at an oil-water interface. At sufficiently high concentrations, one observes the formation of a nematic phase riddled with [Formula: see text] topological defects, characteristic of a two-dimensional nematic system. As the average filament length increases, the defect morphology transitions from a U shape into a V shape, indicating the relative increase of the material's bend over splay modulus. Furthermore, through the sparse addition of rigid microtubule filaments, one can gain additional control over the liquid crystal's elasticity. We show how the material's bend constant can be raised linearly as a function of microtubule filament density, and present a simple means to extract absolute values of the elastic moduli from purely optical observations. Finally, we demonstrate that it is possible to predict not only the static structure of the material, including its topological defects, but also the evolution of the system into dynamically arrested states. Despite the nonequilibrium nature of the system, our continuum model, which couples structure and hydrodynamics, is able to capture the annihilation and movement of defects over long time scales. Thus, we have experimentally realized a lyotropic liquid crystal system that can be truly engineered, with tunable mechanical properties, and a theoretical framework to capture its structure, mechanics, and dynamics. PMID- 29284755 TI - LAMOST telescope reveals that Neptunian cousins of hot Jupiters are mostly single offspring of stars that are rich in heavy elements. AB - We discover a population of short-period, Neptune-size planets sharing key similarities with hot Jupiters: both populations are preferentially hosted by metal-rich stars, and both are preferentially found in Kepler systems with single transiting planets. We use accurate Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) Data Release 4 (DR4) stellar parameters for main sequence stars to study the distributions of short-period [Formula: see text] Kepler planets as a function of host star metallicity. The radius distribution of planets around metal-rich stars is more "puffed up" compared with that around metal-poor hosts. In two period-radius regimes, planets preferentially reside around metal-rich stars, while there are hardly any planets around metal-poor stars. One is the well-known hot Jupiters, and the other one is a population of Neptune-size planets ([Formula: see text]), dubbed "Hoptunes." Also like hot Jupiters, Hoptunes occur more frequently in systems with single-transiting planets although the fraction of Hoptunes occurring in multiples is larger than that of hot Jupiters. About [Formula: see text] of solar-type stars host Hoptunes, and the frequencies of Hoptunes and hot Jupiters increase with consistent trends as a function of [Fe/H]. In the planet radius distribution, hot Jupiters and Hoptunes are separated by a "valley" at approximately Saturn size (in the range of [Formula: see text]), and this "hot-Saturn valley" represents approximately an order-of-magnitude decrease in planet frequency compared with hot Jupiters and Hoptunes. The empirical "kinship" between Hoptunes and hot Jupiters suggests likely common processes (migration and/or formation) responsible for their existence. PMID- 29284756 TI - Altered stoichiometry of an evolved RNA aptamer. AB - Inhibitory aptamers against a protein are promising as antagonistic reagents and repressive genetic components. Typically, improvement of such aptamers is achieved by acquiring higher binding affinity. Here, we report an alternative mechanism for the improvement of aptamer activity. Recently, we reported a transcriptional activator based on an inhibitory RNA aptamer against lambda cI repressor. We improved the aptamer through in vitro selection (SELEX) from a randomly mutagenized aptamer pool, followed by in vivo screening and truncation. Biochemical analyses indicated that the activity improvement was achieved by alteration of the complex formation stoichiometry, rather than by higher affinity or expression. Our results suggest an alternative strategy for improving aptamer activity. PMID- 29284754 TI - Viral discovery and diversity in trypanosomatid protozoa with a focus on relatives of the human parasite Leishmania. AB - Knowledge of viral diversity is expanding greatly, but many lineages remain underexplored. We surveyed RNA viruses in 52 cultured monoxenous relatives of the human parasite Leishmania (Crithidia and Leptomonas), as well as plant-infecting PhytomonasLeptomonas pyrrhocoris was a hotbed for viral discovery, carrying a virus (Leptomonas pyrrhocoris ostravirus 1) with a highly divergent RNA-dependent RNA polymerase missed by conventional BLAST searches, an emergent clade of tombus like viruses, and an example of viral endogenization. A deep-branching clade of trypanosomatid narnaviruses was found, notable as Leptomonas seymouri bearing Narna-like virus 1 (LepseyNLV1) have been reported in cultures recovered from patients with visceral leishmaniasis. A deep-branching trypanosomatid viral lineage showing strong affinities to bunyaviruses was termed "Leishbunyavirus" (LBV) and judged sufficiently distinct to warrant assignment within a proposed family termed "Leishbunyaviridae" Numerous relatives of trypanosomatid viruses were found in insect metatranscriptomic surveys, which likely arise from trypanosomatid microbiota. Despite extensive sampling we found no relatives of the totivirus Leishmaniavirus (LRV1/2), implying that it was acquired at about the same time the Leishmania became able to parasitize vertebrates. As viruses were found in over a quarter of isolates tested, many more are likely to be found in the >600 unsurveyed trypanosomatid species. Viral loss was occasionally observed in culture, providing potentially isogenic virus-free lines enabling studies probing the biological role of trypanosomatid viruses. These data shed important insights on the emergence of viruses within an important trypanosomatid clade relevant to human disease. PMID- 29284757 TI - Autologous Stem Cell Transplantation in Elderly Lymphoma Patients in Their 70s: Outcomes and Analysis. AB - BACKGROUND: High-dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high-risk lymphoma. However, elderly patients are often not considered ASCT candidates based on age alone. SUBJECTS, MATERIALS, AND METHODS: A retrospective analysis of patients >=70 years of age with a diagnosis of Hodgkin or non-Hodgkin lymphoma receiving ASCT between 2000 and 2016 at two partner institutions was performed. Clinical data were extracted from institutional databases and individual medical records. Multivariate analysis was performed to examine the association of clinical variables with transplant outcomes. RESULTS: One hundred seven patients were identified. Median age at transplant was 72 years (range, 70-79). The most common lymphoma subtype was diffuse large B-cell (n = 63, 59%). Median time to neutrophil and platelet engraftment were 10 and 12 days, respectively. With a median follow-up for survivors of 20 months following ASCT (range, 6 months to 13.1 years), estimates for 2-year progression-free survival and overall survival were 58% (95% confidence interval [CI], 48%-67%) and 65% (95% CI, 55%-74%), respectively. Two-year estimate for relapse was 34% (95% CI, 25%-44%) and nonrelapse mortality (NRM) was 7% (95% CI, 3%-14%). Multivariate analysis showed that more recent date of transplant was associated with lower NRM. The Hematopoietic Cell Transplantation-Comorbidity Index score was not predictive of NRM in this data set (high-risk vs. low-risk, hazard ratio 3.45, p = .065). CONCLUSION: Eligibility for ASCT should be an individualized decision, and age should not be an absolute contraindication to ASCT in healthy elderly patients with lymphoma. IMPLICATIONS FOR PRACTICE: Although high-dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high-risk lymphoma, elderly patients are often not considered candidates due to concern for excess toxicity and mortality. This retrospective study showed favorable transplant outcomes, including survival and toxicity, in a large cohort of lymphoma patients over 70 years of age who underwent ASCT. Eligibility for ASCT should be an individualized decision, and age should not be an absolute contraindication to ASCT in healthy elderly patients with lymphoma. PMID- 29284758 TI - Barriers and Explanatory Mechanisms of Delays in the Patient and Diagnosis Intervals of Care for Breast Cancer in Mexico. AB - BACKGROUND: Most breast cancer patients in low- and middle-income settings are diagnosed at advanced stages due to lengthy intervals of care. This study aimed to understand the mechanisms through which delays occur in the patient interval and diagnosis interval of care. MATERIALS AND METHODS: We conducted a cross sectional survey including 886 patients referred to four major public cancer hospitals in Mexico City. Based in a conceptual model of help-seeking behavior, a path analysis strategy was used to identify the relationships between explanatory factors of patient delay and diagnosis delay. RESULTS: The patient and the diagnosis intervals were greater than 3 months in 20% and 65% of participants, respectively. We present explanatory models for each interval and the interrelationship between the associated factors. The patient interval was longer among women who were single, interpreted their symptoms as not worrisome, concealed symptoms, and perceived a lack of financial resources and the difficulty of missing a day of work as barriers to seek care. These barriers were more commonly perceived among patients who were younger, had lower socioeconomic status, and lived outside of Mexico City. The diagnosis interval was longer among those who used several different health services prior to the cancer hospital and perceived medical errors in these services. More health services were used among those who perceived errors and long waiting times for appointments, and who first consulted private services. CONCLUSION: Our findings support the relevance of strengthening early cancer diagnosis strategies, especially the improvement of quality of primary care and expedited referral routes to cancer services. IMPLICATIONS FOR PRACTICE: This study's findings suggest that policy in low- and middle-income countries (LMICs) should be directed toward reducing delays in diagnosis, before the implementation of mammography screening programs. The results suggest several factors susceptible to early diagnosis interventions. To reduce patient delays, the usually proposed intervention of awareness promotion could better work in LMIC contexts if the message goes beyond the advertising of screening mammography to encourage the recognition of potential cancer symptoms and sharing of symptoms with significant others. To reduce diagnosis delay, efforts should focus on strengthening the quality of public primary care services and improving referral routes to cancer care centers. PMID- 29284760 TI - The Concept of Biosimilars: From Characterization to Evolution-A Narrative Review. AB - : Biologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small-molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords "biosimilars," "market," and "regulatory." In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the "pharmerging" economies. IMPLICATIONS FOR PRACTICE: This article highlights the importance of biosimilars, as a cost cutting strategy, in the delivery of state-of-the-art health care in developing countries, at a fraction of what a reference biological agent would cost. PMID- 29284759 TI - Portomesenteric Venous Stenting for Palliation of Ascites and Variceal Bleeding Caused by Prehepatic Portal Hypertension. AB - BACKGROUND: The purpose of this study was to evaluate percutaneous transhepatic portal vein stenting (PVS) for palliation of refractory ascites and/or variceal bleeding caused by extrahepatic portomesenteric venous stenosis in patients with pancreaticobiliary cancer. MATERIALS AND METHODS: A single-institution, retrospective review of patients who underwent PVS between January 2007 and July 2015 was performed. A total of 38 patients were identified, of whom 28 met the inclusion criterion of PVS performed primarily for refractory ascites or variceal bleeding. In addition to technical success and overall survival, clinical success was measured by fraction of remaining life palliated. The palliative effect of PVS was also quantified by measuring changes in liver and ascites volumes after the procedure. RESULTS: Technical success was 93% (26/28). Stent deployment involved more than one portomesenteric vessel in most patients (20/26). The cumulative probability of symptom recurrence at 6, 12, 18, and 24 months was 12%, 16%, 26%, and 40%, respectively. There was a significant difference (p < .001) in the probability of symptom recurrence, recurrence of abdominal ascites, and increase in liver volume between patients whose stents remained patent and those whose stents demonstrated partial or complete occlusion. The mean fraction of remaining life palliated was 87%. All but two patients were found to have improvement in clinical symptoms for the majority of their lives after the procedure. There were no major or minor complications. CONCLUSION: As a low-risk procedure with a high clinical success rate, PVS can play a substantial role in improving quality of life in patients with portomesenteric stenoses. IMPLICATIONS FOR PRACTICE: Portomesenteric venous stenosis is a challenging complication of pancreaticobiliary malignancy. Portomesenteric stenoses can lead to esophageal, gastric, and mesenteric variceal bleeding, as well as abdominal ascites. The purpose of this study was to evaluate the safety and efficacy of portal vein stenting (PVS) in patients with cancer who have symptomatic portal hypertension caused by portomesenteric venous compression. As a low-risk procedure with a high clinical success rate, PVS can play a substantial role in improving quality of life in patients with portomesenteric stenoses. PMID- 29284761 TI - Refugees in Conflict: Creating a Bridge Between Traditional and Conventional Health Belief Models. AB - : The recent wave of migration from Middle Eastern countries to Europe presents significant challenges to the European health profession. These include the inevitable communication gap created by differences in health care beliefs between European oncologists, health care practitioners, and refugee patients. This article presents the conclusions of a workshop attended by a group of clinicians and researchers affiliated with the Middle East Cancer Consortium, as well as four European-based health-related organizations. Workshop participants included leading clinicians and medical educators from the field of integrative medicine and supportive cancer care from Italy, Germany, Turkey, Israel, Palestine, Iran, Lebanon, Jordan, Egypt, and Sudan. The workshop illustrated the need for creating a dialogue between European health care professionals and the refugee population in order to overcome the communication barriers to create healing process. The affinity for complementary and traditional medicine (CTM) among many refugee populations was also addressed, directing participants to the mediating role that integrative medicine serves between CTM and conventional medicine health belief models. This is especially relevant to the use of herbal medicine among oncology patients, for whom an open and nonjudgmental (yet evidence-based) dialogue is of utmost importance. The workshop concluded with a recommendation for the creation of a comprehensive health care model, to include bio-psycho-social and cultural-spiritual elements, addressing both acute and chronic medical conditions. These models need to be codesigned by European and Middle Eastern clinicians and researchers, internalizing a culturally sensitive approach and ethical commitment to the refugee population, as well as indigenous groups originating from Middle Eastern and north African countries. IMPLICATIONS FOR PRACTICE: European oncologists face a communication gap with refugee patients who have recently immigrated from Middle Eastern and northern African countries, with their different health belief models and affinity for traditional and herbal medicine. A culturally sensitive approach to care will foster doctor-refugee communication, through the integration of evidence-based medicine within a nonjudgmental, bio-psycho-social-cultural-spiritual agenda, addressing patients' expectation within a supportive and palliative care context. Integrative physicians, who are conventional doctors trained in traditional/complementary medicine, can mediate between conventional and traditional/herbal paradigms of care, facilitating doctor-patient communication through education and by providing clinical consultations within conventional oncology centers. PMID- 29284763 TI - Rational use of drugs in dermatology: A paradigm lost? PMID- 29284762 TI - Medical Council of India's Amended Qualifications for Indian Medical Teachers: Well Intended, yet Half-hearted. PMID- 29284764 TI - Adalimumab as a successful treatment for acne fulminans and bilateral acute sacroiliitis with hip synovitis complicating isotretinoin therapy. PMID- 29284765 TI - Erratum: A noncancerous variant of xeroderma pigmentosum type D associated with novel heterozygous missense ERCC2 gene mutation. AB - [This corrects the article DOI: 10.4103/ijdvl.IJDVL_485_16.]. PMID- 29284766 TI - Interesting statistics regarding the papers published in Journal of Educational Evaluation for Health Professions in 2017. PMID- 29284767 TI - Establishment of an open data policy for Journal of Educational Evaluation for Health Professions, appreciation for invited reviewers, and acknowledgement of volunteers who made audio recordings. PMID- 29284768 TI - Fitz-Hugh-Curtis Syndrome Caused by Gonococcal Infection in a Patient with Systemic Lupus Erythematous: A Case Report and Literature Review. AB - BACKGROUND Fitz-Hugh-Curtis (FHC) syndrome is a perihepatitis linked to inflammatory pelvic disease. It can be caused by Neisseria gonorrhoeae or Chlamydia trachomatis infections. FHC syndrome usually presents with pain in the right hypochondrium and fever, associated with symptoms and signs of pelvic infection in women. CASE REPORT We present the case of a 22-year-old woman with systemic lupus erythematous (SLE) who presented with polyarthritis, cutaneous lesions, and abdominal pain. The diagnosis of FHC syndrome was based on the findings of abdominal computerized tomography (CT) and the isolation of Neisseria gonorrhoeae (NG) in blood cultures. The association of arthritis and cutaneous lesions was diagnosed as a syndrome of arthritis-dermatitis, also caused by systemic NG infection. The patient had a favorable outcome with antibiotic treatment. CONCLUSIONS FHC syndrome should be considered in sexually active young patients, mainly women, with pelvic infection and perihepatitis. It may be caused by disseminated gonococcal infection. An important risk factor is the serum complement deficit, which may predispose to severe forms. Low serum complement level is a frequent manifestation of active SLE. CT images showing the typical findings of perihepatitis allow making the correct diagnosis. PMID- 29284769 TI - Few Gender Differences in Attitudes and Experiences after Live Kidney Donation, with Minor Changes Over Time. AB - BACKGROUND We sought to study gender differences and differences over time with respect to demographics, relation to recipient, donor motives, and experiences of live kidney donation. MATERIAL AND METHODS In all, 455 consecutive live kidney donors, representing all of the donors at our center between 1974 and 2008 were considered for this study. There were 28 deceased donors and 14 donors who had moved abroad, leaving 413 donors; 387 (94%) agreed to participate in this study. A questionnaire was sent and the answers was analyzed for gender differences and, where relevant, for changes over time. RESULTS In all sub-periods, female donors made up the majority (55-62%), except for sibling donors (45%) and child-to parent donors (40%). No significant gender differences were seen in perceived information given before donation. For males, it was more common that the recipient took the initiative to donate. For females, the motivation for donating was more frequently to help the recipient and because others wanted them to donate. For males, it was more common to feel a moral obligation. Post operatively, females more frequently felt sad and experienced nausea, and more frequently felt that the donation had a positive impact on their lifes. With the introduction of minimally invasive surgical techniques, donors experienced fewer problems from the operation, with no gender difference. CONCLUSIONS Females donate more frequently than males, a difference that did not change over time. Only a few gender differences were seen in donor motives and the donation experience; however, these differences may be relevant to address the gender imbalance in kidney donations. PMID- 29284770 TI - Alternate-Nostril Yoga Breathing Reduced Blood Pressure While Increasing Performance in a Vigilance Test. AB - BACKGROUND Reports suggest that vigilance or sustained attention increases sympathetic activity. A persistent increase in sympathetic activity can lead to an increase in blood pressure. Alternate-nostril yoga breathing has been shown to be useful to (i) improve attention and (ii) decrease the systolic and diastolic blood pressure. Earlier studies did not report simultaneous recordings of the blood pressure and performance in vigilance tests after alternate-nostril yoga breathing. With this background, the present study was planned to determine if 15 minutes of alternate nostril yoga breathing could improve the performance in a vigilance test without an increase in blood pressure. MATERIAL AND METHODS Fifteen healthy male volunteers participated in the study (group mean age +/-SD, 22.4+/-2.4 years). Participants were assessed on 3 separate days in 3 different sessions. These were (i) alternate nostril yoga breathing, (ii) breath awareness, and (iii) sitting quietly as a control. Blood pressure and the digit vigilance test were simultaneously assessed before and after each session. RESULTS Systolic blood pressure (p<0.01), mean arterial blood pressure (p<0.05), and the time taken to complete the digit vigilance test (p<0.05) significantly decreased following alternate-nostril yoga breathing. The time taken to complete the digit vigilance test differed significantly between sessions (p<0.05). The time taken to complete the digit vigilance test was also significantly decreased after sitting quietly (p<0.01). CONCLUSIONS Alternate-nostril yoga breathing appears to improve performance in the digit vigilance test, along with a reduction in systolic blood pressure. This is suggestive of better vigilance without sympathetic activation. PMID- 29284771 TI - Changing Efficacy of Wet Cupping Therapy in Migraine with Lunar Phase: A Self Controlled Interventional Study. AB - BACKGROUND The aim of this study was to evaluate the effect of blood-letting with wet cupping therapy (WCT) in migraine treatment and to determine whether there was any difference according to the phase of the moon when the treatment was applied. MATERIAL AND METHODS This self-controlled study was conducted in Karabuk between 2014 and 2016. Patients who were diagnosed with migraine were enrolled in the study. Migraine disability assessment questionnaire (MIDAS), demographic characteristics, migraine attack frequency and duration, and family history was used to assess the severity of headache. WCT was applied in 3 sessions and the questionnaire was administered before and 3 months after the final WCT session. Wilcoxon signed-rank test was used in pre-and posttreatment measurements, and the Chi-square test was used to check independence in two-way categorical tables. RESULTS A total of 85 patients were included. The reduction in MIDAS scores and number of migraine attacks was significantly greater in the WCT applications made in the first half of the month compared to those in the second half of the month. Although the reduction in visual analog scale (VAS) scores was greater in the second half of the month, it was also significant in the applications made in the first half of the month. CONCLUSIONS WCT was found to be an effective treatment of migraine. The effect on MIDAS, VAS, and the number of attacks was significantly better when the application was made in the second half of the month compared to those made in the first half. PMID- 29284772 TI - Consumptive hypothyroidism: an unusual paraneoplastic manifestation of a gastric gastrointestinal stromal tumor. AB - A 42-year-old hypothyroid shepherd presented with a progressive abdominal lump accompanied by nausea and abdominal fullness. In addition, he had worsening hypothyroidism, despite supranormal doses of thyroxine. Computed tomography of the abdomen was suggestive of a mass lesion in relation to the stomach. A resection of the mass was done and the histopathology was suggestive of gastrointestinal stromal tumor. After surgery, the patient became euthyroid. We believe the patient had consumptive hypothyroidism due to the tumor. PMID- 29284773 TI - Phenotypic features of endometrial tumors in patients with family history of cancer. AB - AIM: To determine the peculiarities of expression of a number of proteins regulators of the cell cycle in endometrial cancer (EC) cells in patients with a family history of oncological pathologies. PATIENTS AND METHODS: 95 EC patients (stage I-II) were included into the study. Clinical-genealogical analysis was performed. 54 patients (group I) had healthy relatives, and in families of 41 patients (group II) an aggregation of malignant tumors of different genesis (mainly tumors of the gastrointestinal tract and the female reproductive system) was recorded. p53, p21WAF1/CIP1, p16INK4a, and Ki-67 were assessed immunohistochemically in the surgical samples. RESULTS: In the majority of patients, both from group I and II, moderately differentiated tumors were observed (in 38.9 and 46.3% of cases, respectively), mainly with deep myometrium invasion (64.8 and 58.5% of cases, respectively). In EC patients from group II, a significantly higher number of p16INK4a-positive cells (17.7 +/- 1.7%; p = 0.001) and lower number of p53-positive (30.9 +/- 3.2%; p = 0.05) and Ki-67-positive (26.9 +/- 2.7%; p = 0.048) cells was observed compared to those in tumors of patients from group I (12.0 +/- 1.6; 37.7 +/- 2.8 and 36.7 +/- 3.4%, respectively). CONCLUSION: Phenotypic features of the EC in the patients with family history of cancer differ from those in tumors of patients without such aggregation. The biological heterogeneity of EC seems to relate to the oncogenealogical history of patients. Also this biological heterogeneity is linked to the molecular features of EC cells, which affects cancer aggressiveness and the course of the disease. PMID- 29284774 TI - Volodymyr Serhiiovych Mosiienko (1934-2017). PMID- 29284775 TI - L-arginine is an effective medication for prevention of endothelial dysfunction, a predictor of anthracycline cardiotoxicity in patients with acute leukemia. AB - AIM: To evaluate the effectiveness of L-arginine in the prevention of endothelial dysfunction, which may be a predictor of anthracycline-induced myocardial injury, in patients with acute leukemia (AL) on the background of anthracycline antibiotics low cumulative doses from 100 to 200 mg/m2. MATERIALS AND METHODS: A total of 81 adult AL patients (38 males and 43 females with the age of 16-59 years) were studied. The patients were divided into two groups: group I (n = 34), AL patients treated with chemotherapy (CT) and L-arginine hydrochloride; group II (n = 47) - AL patients treated with CT only. Cardiac evaluation and endothelial function assessment were performed at baseline and after second CT. Electrocardiography (ECG) parameters, lipid peroxidation activity, antioxidant protection and NO system state were evaluated. RESULTS: The bioelectric activity abnormalities of the myocardium were observed in studied patients with low cardiac risk after induction CT. In case of L-arginine administration, only minimal daily ECG changes were recorded. A significant difference in the lipid peroxidation and antioxidant defense system activity in patients of groups I and II was determined. We noticed deepening of endothelial dysfunction on the background of cytostatic therapy with anthracycline antibiotics compared with baseline values in patients of group II. It was found that prophylactic L arginine increases superoxide dismutase level and reduces the total NOS activity due to its inducible isoform. CONCLUSION: The leading factor of anthracycline induced cardiotoxicity is the imbalance between free radical generation and their inactivation that leads to endothelial dysfunction development. L-arginine eliminates the prooxidant-antioxidant imbalance and improves the endothelial function. PMID- 29284776 TI - The TGF-beta - SMAD pathway is inactivated in cronic lymphocytic leukemia cells. AB - AIM: To study the status of the tumor growth factor beta (TGFB) pathway in chronic lymphocytic leukemia (CLL) cells and to uncover molecular details underlying CLL cell genesis. OBJECTS AND METHODS: The study was conducted on peripheral blood samples of patients with CLL using the following methods: RNA isolation, analysis of expression of transcription factors using RT2 profiler assay, bioinformatics analysis of publicly available data bases on expression. RESULTS: We have shown that the TGFB - SMAD canonical pathway is not active in CLL cells. SMAD-responsive genes, such as BCL2L1 (BCL-XL), CCND2 (Cyclin D2), and MYC, are down-regulated in CLL cells compared with peripheral blood B cells of healthy donors. CONCLUSIONS: The TGFB-mediated signaling is not active in CLL cells due to low (or absent) expression of SMAD1, -4, -5, -9, and ATF-3. Expression and phosphorylation status of SMAD2 and -3 should be further elucidated in the future studies. PMID- 29284777 TI - Assessment of the effect of wave device application on morphological changes in organs and cells of irradiated animals. AB - AIM: To study the effect of the Device for wave influence on biological objects on the prevention of the development of acute radiation sickness and chronic radiation syndrome in vivo. MATERIALS AND METHODS: The studies were performed on white rats irradiated at a dose of 8 Gy. The experimental group of irradiated rats was treated with a wave Device (Patent of Ukraine No. 53568) once, for 2.5 min, 1.5 h after irradiation. Their organs were processed by standard histologic methods. RESULTS: In the demagnetized rats, dystrophic changes in cells and tissues of liver, lungs, kidneys, brain, bone marrow and spleen were insignificant in 60 days compared to the control non-demagnetized group of animals. CONCLUSION: The Device reduced the magnetic charge of magneto-containing elements and their compounds in the organism of the irradiated animals, and decreased the formation of reactive oxygen species, which play a key role in the development of radiation-induced diseases. PMID- 29284778 TI - Alterations of antitumor and metabolic responses in L5178Y-R lymphoma-bearing mice after only 30-minute daily chronic stress exposure. AB - AIM: In stress research, reducing times of stress induction may contribute to improving the well-being of experimental animals, especially in cancer models, already under physiological distress. To support this idea, we evaluated the effects of a short-timed stress protocol on endocrine, metabolic and immune indicators in mice bearing the L5178Y-R lymphoma. MATERIALS AND METHODS: A 30 minute daily stress protocol was applied for 28 days to healthy and lymphoma bearing BALB/c mice; body weight, plasma levels of corticosterone, norepinephrine, Th1/Th2 cytokines, insulin, and leptin, were measured. RESULTS: We found a 12% significant decrease in body weight in non-tumor bearing mice under stress (p < 0.007). The disruption of weight evolution was accompanied by a stress induced 85% decrease in plasmatic leptin (p < 0.01) and total reduction of insulin. Tumor burden alone was associated to an increase in more than two-fold of plasmatic levels of norepinephrine (p < 0.008). Neither stress nor tumor or their combination, resulted in an elevation of systemic IL-6. IFN-gamma levels were 20 times higher in lymphoma-bearing animals when compared with non-tumor bearing mice (p < 0.01); however, under stress, this response was reduced by half, indicating a suppressing effect of chronic stress on the antitumor immune response. CONCLUSION: A short-timed stress induction is enough to cause significant alterations in the metabolism and immunity of healthy and tumor bearing mice, supporting the use of short-timed protocols as an efficient way to induce chronic stress that also considers concerns regarding the well-being of experimental animals in biomedical research. PMID- 29284779 TI - Adsorption-rheological properties of blood serum in lung cancer patients. AB - : The aim and objectives of the study were to investigate the state of adsorption rheological properties of blood (ARPB) in patients with different clinical course of lung cancer (LC), the detection of violations of surface-active, viscoelastic and relaxation properties of blood serum, their association with tumor markers, the evaluation of the prognostic value of initial indexes in the development of complications from radiochemotherapy. PATIENTS AND METHODS: The study included 115 patients with LC at the age from 24 to 80 years (average age 58 years), among whom there were 78% men and 22% women. The parameters of surface (interfacial) viscosity, elasticity, viscoelasticity module, tension and relaxation of blood serum were studied by the oscillating drop method using a computer tensiometer "PAT2-Sinterface", and its volumetric viscosity was investigated using a Low Shear-30 rotational viscometer. ARPB parameters were also studied in a control group composed from 50 healthy donors. RESULTS: Increased levels of volumetrical viscosity, surface tension, surface elasticity and the relaxation time of the blood are typical for patients with LC and depended on the localization of the tumor, its histological variant, differentiation grade, severity of the course of the disease, the number of metastases in the lymph nodes, distant organs and skeleton, involvement of the pleura and ribs, the development of compression pulmonary syndrome, metastasis into the spine, adrenals, brain, and pancreas. The surface-active, viscoelastic and relaxation properties of the blood correlated with the levels of tumor markers (TGFbeta1, VEGF, C-reactive protein, alpha2 macroglobulin). CONCLUSIONS: Integral changes of ARPB observed in every fifth patient with LC are involved in the pathogenesis of the disease, have predictive value in relation to the clinical course of disease (volumetric viscosity) and the development of complications from radiochemotherapy (surface viscosity). PMID- 29284780 TI - Stress during puberty facilitates precancerous prostate lesions in adult rats. AB - : Puberty can be a critical period for the long-term development of diseases, especially for stress-related disorders that depend on neuroendocrine and immune responses. Some organs like the prostate are prone to diseases that result from neuroendocrine or immune challenges, such as cancer. AIM: In the present study, we assessed the long-term effects of an acute pubertal stressor (immune challenge) on the development of precancerous lesions in adult rats, and compared them with testosterone-induced prostatic lesions. MATERIALS AND METHODS: Pubertal male rats received a single injection of lipopolysaccharide (LPS) or saline during puberty (5 weeks old). At adulthood (8 weeks old) males were subcutaneously implanted with either an empty capsule or filled with testosterone propionate (100 mg/kg). This resulted in a total of five groups: 1) intact untreated, 2) saline-treated and implanted with a blank capsule, 3) saline treated and implanted with a testosterone capsule, 4) LPS-treated and implanted with a blank capsule, 5) LPS-treated and implanted with a testosterone capsule. Four weeks later, the rats were sacrified and their prostates processed for histology (hematoxylin and eosin stain) and blood serum processed for hormone analysis (testosterone and corticosterone). RESULTS: Males treated with LPS (stressed during puberty via immune challenge) expressed epithelium dysplasia (specially in the ventral prostate), anisocytosis, presence of mononuclear cells, anisokariosis, non-basal polarity, abnormal nucleus-cytoplasm ratio, proplastic myoepithelium, and granular content in the lumen. These histological alterations were similar, but less severe than those observed in males implanted with testosterone during adulthood. CONCLUSION: These results indicate that pubertal exposure to an immune challenge (stress) facilitates the long-term development of prostatic lesions in adult male rats. PMID- 29284781 TI - DNA damage in tumor cells and peripheral blood lymphocytes of endometrial cancer patients assessed by the comet assay. AB - : To date, genome instability is considered to be a common feature not only of tumor cells, but also of non-malignant cells of cancer patients, including peripheral blood lymphocytes (PBLs). The issue of the association between genome instability in tumor cells and PBLs, as well as of its relationship with tumor progression remains poorly understood. AIM: To evaluate the level DNA damage in tumor cells and PBLs of endometrial cancer (EC) patients with regard to clinical and morphological characteristics of the patients. MATERIALS AND METHODS: DNA damage was assessed in 106 PBLs samples and 42 samples of tumor cell suspension from EC patients by comet assay. PBLs from 30 healthy women were used as control. The level of DNA damage was expressed as the percentage of DNA in the comet tails (% tail DNA). RESULTS: It was revealed that the amount of DNA damage in PBLs of EC patients was 2.2 times higher in comparison with that of healthy donors (8.3 +/- 0.7 and 3.7 +/- 0.4% tail DNA, respectively) (p < 0.05). In this study, no association between the levels of DNA damage in endometrial tumor cells and PBLs was observed (r = 0.11; p > 0.05). The amounts of DNA damage both in tumor cells and PBLs were not related to the degree of tumor differentiation as well as the depth of myometrial invasion, but depended on the body mass index (BMI) of EC patients: high level of lesions was observed in patients with elevated BMI values. Furthermore, the level of DNA damage in tumor cells was associated to familial aggregation of cancer and was significantly higher in endometrial cells from patients with family history of cancer vs that from EC patients with sporadic tumors (32.3 +/- 2.9 and 22.8 +/- 1.8% tail DNA, respectively) (p < 0.05). It was also found that for women who had high level of DNA damage in PBLs, the risk of EC was greater (odds ratio value of 3.5) compared to those with low level of such lesions. CONCLUSION: Genome instability that appears as an increased level of DNA damage in tumor cells and PBLs of EC patients is associated with BMI and family history of cancer and can reflect a predisposition to cancer. PMID- 29284782 TI - Cytotoxic activity of metformin in vitro does not correlate with its antitumor action in vivo. AB - : It is known that metformin is a hypoglycemic drug used to treat type II diabetes mellitus. Recently active studies of its antitumor activity in relation to different types of malignant cells are conducted. AIM: To determine the relationship between cytotoxic activity of metformin in vitro and its antitumor activity in vivo. MATERIALS AND METHODS: The rat C6 glioma cell line and mouse Lewis lung carcinoma cells (LLC) were used in this work. The number of living cells in the cytotoxic test was evaluated using sulforhodamine B. Parameters of tumor cell susceptibility to metformin activity in vitro were calculated using nonlinear and linear regression of experimental data. The antitumor action of metformin in vivo was evaluated routinely by the extension of survival time (ST) (in rats with intracerebral C6 glioma) and its effect on the volume of the primary tumor, the number and volume of metastases (in mice with LLC). RESULTS: In cultured LLC cells in vitro, the proportions of metformin-resistant (A1, %) and metformin-sensitive (A2, %) subpopulations were 10.0 +/- 2.2% and 92.0 +/- 3.5%, respectively, in terms of the total number of living cells. Parameter t, which characterizes the sensitivity of cancer cells to metformin action (the lower is the value of this parameter the higher is sensitivity of cells to metformin cytotoxicity), for metformin-resistant and metformin-sensitive subpopulations was: t1(mM) = infinity and t2(mM) = 2.9 +/- 0.3, correspondingly. For metformin-sensitive subpopulation of LLC cells IC50 (mM) = 2.42 +/- 0.34. The volume of the primary tumor, the amount and volume of metastases in mice receiving metformin at a dose of Dmin (0.15 g/kg) and Dmax (0.3 g/kg) values did not significantly differ from those in the control. However, in the case of Dmin, there was a tendency to increased volume of the primary tumor, in the case of Dmax, there was a tendency to increased volume of metastases. The analogical parameters (A1, A2, b1, b2, IC50 (1), IC50 (2)) characterizing cell sensitivity to the action of metformin in vitro were obtained in relation to C6 glioma cells. In metformin-resistant subpopulation, these parameters were: A1 (%) = 72.3 +/- 1.4; b1 (%/mM) = 0.43 +/- 0.005; IC50 (1) (mM) = 84.1 +/- 2.4. For metformin sensitive subpopulation, these parameters were: A2 (%) = 30.8 +/- 2.3; b2 (%/mM) = 2.87 +/- 0.4; IC50 (2) (mM) = 5.37 +/- 0.45. In vivo, a statistically significant anti-glioma effect of metformin was observed: at a dose of Dmax (5.2 g/kg) administration of this preparation resulted in a prolongation of the mean ST of tumor-bearing rats by 23% (p < 0.05) compared with that in the control. CONCLUSIONS: We found no correlation between the cytotoxic/cytostatic action of metformin in vitro and its antitumor activity in vivo on the two types of tumor cells; these results indicate a significant contribution of the tumor microenvironment to the implementation of the antitumor activity of the drug. PMID- 29284784 TI - TGF-beta1 expression by glioma C6 cells in vitro. AB - : The aim of the work was to study the impact of fetal rat brain cell supernatant (FRBCS) on the expression of transforming growth factor beta1 (TGF-beta1) and p53 in C6 cells of rat glioma in vitro. MATERIALS AND METHODS: FRBCS was obtained from suspensions of fetal rat brain cells on the 14th (E14) day of gestation. C6 glioma cells were cultured for 48 h in the presence of FRBCS or FRBCS + anti-TGF beta1 monoclonal antibody. Immunocytochemical staining for TGF-beta1 and p53 was performed. RESULTS: The proportion of TGF-beta1-immunopositive tumor cells in C6 glioma cultures was statistically significantly higher than in the control cell cultures of normal fetal rat brain. FRBCS reduced the proportion of TGF-beta1 immunopositive tumor cells and increased the proportion of p53-immunopositive cells in C6 glioma cultures. In cells cultured with FRBCS + anti-TGF-beta1 monoclonal antibody, the above effects of FRBCS were abrogated. CONCLUSION: The obtained results suggest that TGF-beta1 seems to be responsible for decrease in TGF-beta1 expression and increase in p53 expression in C6 glioma cells treated with FRBCS. PMID- 29284783 TI - CD150 and CD180 are involved in regulation of transcription factors expression in chronic lymphocytic leukemia cells. AB - BACKGROUND: Sequential stages of B-cell development is stringently coordinated by transcription factors (TFs) network that include B-lineage commitment TFs (Ikaros, Runx1/Cbfb, E2A, and FOXO1), B-lineage maintenance TFs (EBF1 and PAX5) and stage specific set of TFs (IRF4, IRF8, BCL6, BLIMP1). Deregulation of TFs expression and activity is often occurs in malignant B cells. The aim of this study was to evaluate TFs expression in chronic lymphocytic leukemia cells taking into consideration CD150 cell surface expression. From other side we attempted to regulate TFs expression via CD150 and CD180 cell surface receptors. MATERIALS AND METHODS: Studies were performed on normal peripheral blood B-cell subpopulations and chronic lymphocytic leukemia (CLL) cells isolated from peripheral blood of 67 primary untreated patients with CLL. Evaluation of TFs expression was performed on mRNA level using qRT-PCR and on protein level by western blot analysis. RESULTS: Median of PAX5 and EBF1 mRNA expression was higher in cell surface CD150 positive (csCD150+) compared to csCD150- CLL cases or normal CD19+ and CD19+CD5+ B-cell subsets. Differences in mRNA expression of IRF8, IRF4 and BLIMP1 between studied groups of CLL and normal B cells were not revealed. All CLL cases were characterized by downregulated expression of PU.1 and BCL6 mRNAs in comparison to normal B cells. At the same time elevated SPIB mRNA expression level was restricted to CLL cells. Protein expression of IRF4, IRF8 and BCL6 was uniformly distributed between csCD150- and csCD150+ CLL cases. PU.1 protein and CD20 that is direct PU.1 target gene positively correlated with CD150 cell surface expression on CLL cells. Ligation of CD150 and CD180 alone or in combination upregulated IRF8 and PU.1 while downregulated the IRF4 mRNA expression. Signaling via CD150 or CD180 alone elevated the level of BCL6 mRNA. Strong downregulation of IRF4 mRNA was observed after CD150, CD180 or CD150 andCD180 coligation on CLL cells. We found that in CLL cells CD150 is a negative regulator of SPIB while CD180 is involved in upregulation of EBF1 expression level. Moreover, CD180 ligation on CLL cells caused increase of CD150 mRNA level that is a one of the EBF1 target genes. CONCLUSIONS: Analysis of TFs expression profile revealed upregulated SPIB mRNA level and downregulated PU.1 in CLL cells. CD150 and CD180 receptors may modulate transcriptional program in CLL cells by regulating the TFs expression levels. PMID- 29284785 TI - Dose reconstruction in workers exposed to two major pyrethroid pesticides and determination of biological reference values using a toxicokinetic model. AB - A toxicokinetic model has been optimized to describe the time profiles of common biomarkers of exposure to permethrin and cypermethrin: trans-3-(2,2 dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acids (trans-DCCA) and 3 phenoxybenzoic acid (3-PBA). The model then served to reproduce urinary time courses in exposed agricultural workers and predict corresponding absorbed doses. It allowed for the prediction of the main routes of exposure in workers during the study period. Modeling showed that simulating exposure mostly by the oral route, during the 3-day biomonitoring period, provided best-fits to the urinary time courses of most workers. This is compatible with an inadvertent oral exposure during work. According to best-fit scenarios, absorbed doses in workers reconstructed with the model reached a maximum of 2.4 ug/kg bw/day and were below the absorbed dose limits associated with an exposure to the reference dose values established by the U.S. Environmental Protection Agency (0.06 and 0.25 mg/kg bw/day for cypermethrin and permethrin, respectively) and the Acceptable Operator Exposure Level set by the European Commission (0.06 mg/kg bw/day for cypermethrin). Modeling was further used to derive biological reference values for cypermethrin and permethrin exposure. Respective values of 7 and 29 nmol/kg bw/day of trans-DCCA, and 3 and 13 nmol/kg bw/day of 3-PBA were obtained. None of the workers presented values above these biological reference values. PMID- 29284787 TI - Endemic goiter and iodine deficiency status among Guinea-Bissau school-age children. AB - BACKGROUND/OBJECTIVES: Iodine deficiency disorders are estimated to affect 25% of all school-age children around the world. Current policies concerning iodine deficiency disorders in many countries are not based on robust or recent national data. Our objective was to evaluate the current status of iodine nutrition in Guinea-Bissau (West Africa). SUBJECT/METHODS: A cross-sectional survey including 299 school-age children, aged 6-14 years old, from four distinct regions of Guinea-Bissau across a coast-hinterland gradient (Bolama, Bissau, Cambaju-Bafata, and Gabu) was performed. Several iodine deficiency disorders indicators were used: total goiter rate, median urinary iodine concentration (UIC) and regional iodine content in household salt and drinking water samples. Data on the total goiter rate were obtained by thyroid ultrasound. RESULTS: Goiter was found in 73.5% (CI 95%, 68.5-78.2%) of the school-age children. We observed a median urinary iodine concentration of 110 mcg/l, with 7.3% of the studied population presenting urinary iodine concentration < 50 mcg/l. Only 12.5% of the household salt samples revealed iodine content >= 15 mg/kg. Median well water iodine concentration was 11.7 mcg/l. CONCLUSIONS: Guinea-Bissau presents high rates of goiter in school-age children despite satisfactory median urinary iodine concentration population levels. Salt and drinking water iodine median content cannot explain these findings. Further studies following the progress in iodine deficiency status and the presence of potential goitrogens in diet of this vulnerable population are in needed. PMID- 29284786 TI - Effect of omega-3 long-chain polyunsaturated fatty acid supplementation on heart rate: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Elevated resting heart rate (HR) has emerged as a new risk factor for all-cause and cardiovascular mortality. The effect of marine-derived omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFAs) supplementation on HR was investigated as an outcome in many clinical trials. The present study was to provide an updated meta-analysis on the HR-slowing effect of n-3 LCPUFAs, and to differentiate the chronotropic effect between eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). METHODS: PubMed and Cochrane databases were searched for relevant articles examining the effects of n-3 PUFAs on HR through May 2017. A random-effects model was used to generate the pooled effect sizes and 95% confidence intervals (CIs). The pooled effect sizes were presented as weighted mean differences (WMDs). RESULTS: A total of 51 randomized controlled trials (RCTs) with approximately 3000 participants were included in this meta-analysis. Compared to placebo, n-3 PUFA supplementation mildly but significantly reduced HR (-2.23 bpm; 95% CI: -3.07, -1.40 bpm). Moderate evidence of heterogeneity was observed among included trials (I 2 = 49.1%, P heterogeneity < 0.001). When DHA and EPA were separately administered, modest HR reduction was observed in trials that supplemented with DHA (-2.47 bpm; 95% CI: -3.47, -1.46 bpm), but not in trials with EPA. CONCLUSIONS: The present meta-analysis provides strong clinical evidence demonstrating the effect of heart rate reduction by n-3 LCPUFA supplementation. When DHA or EPA administered alone, heart rate was slowed by DHA rather than by EPA. PMID- 29284788 TI - Polyphenol-rich curry made with mixed spices and vegetables increases postprandial plasma GLP-1 concentration in a dose-dependent manner. AB - Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis. Evidence is emerging that dietary bioactive phytochemicals such as polyphenols can increase GLP-1 concentration in vivo. Spices are rich in polyphenols and have oro-sensory properties, both of which can increase GLP-1 secretion. We therefore investigated the effects of mixed spices intake on postprandial GLP-1 concentration. Using a randomised, controlled, dose-response crossover trial in 20 young, healthy, Chinese men, volunteers were served white rice with 3 doses of curry made with mixed spices and vegetables. These test meals were isocaloric and macronutrient matched. Plasma total GLP-1 concentrations were measured before (baseline) and for up to 3 h after the consumption of test meals. We found a significant dose dependent increase in total AUC of plasma GLP-1 concentrations, adjusted for baseline, with increasing mixed spice doses [adjusted mean (+/-SEM) of 10568.3 +/- 1267.9, 12391.8 +/- 1333.94, and 13905.1 +/- 1267.6 pg ml-1.min for Dose 0 Control, Dose 1 Curry and Dose 2 Curry respectively (p = 0.019)]. Consumption of polyphenol rich mixed spices and vegetables can therefore increase in vivo GLP-1 concentration. PMID- 29284789 TI - Activating and sustaining c-Myc by depletion of miR-144/451 gene locus contributes to B-lymphomagenesis. AB - Hyper activity of protooncogene c-Myc is one of the hallmarks of highly aggressive lymphomas. However, the mechanism of how c-Myc is subjected to activation and amplification is still not well defined. In this study, we use gene knockout strategy to show that targeted depletion of a well-conserved microRNA gene locus miR-144/451 initiates tumorigenesis including B-lymphoma development in aged mice. This is due, at least in part, to the direct activation of the c-Myc gene by loss of miR-144/451 expression in hematopoietic cells. Moreover, oncoprotein c-Myc inversely regulates miR-144/451 expression by directly binding to the miR-144/451 promoter region, forming a miRNA-Myc positive feedback loop to safeguard the high level of c-Myc in B-lymphocytes. We also demonstrate that this miRNA-Myc crosstalk is disrupted in human diffuse large B cell lymphomas with aberrant c-Myc expression. Therefore, our findings provide strong evidence, for the first time, that deficiency of miR-144/451 expression may play a bona fide role in derepression of silenced c-Myc, which contributes to tumor development including B-lymphomagenesis. PMID- 29284790 TI - Prostate-specific PTen deletion in mice activates inflammatory microRNA expression pathways in the epithelium early in hyperplasia development. AB - PTen loss is one of the most frequent events in prostate cancer both at the initiation stage and during late stage metastatic development. The mouse model of prostate-specific probasin-mediated Pten deletion leads to prostate intraepithelial neoplasia (PIN) leading to adenocarcinoma. Using this model, we analysed the miR and mRNA transcriptome profile of Pten -/- PIN versus wild type age-matched prostate tissues and analysed the effects of Pten loss on miR expression in the early neoplastic process. At the PIN stage, Pten loss significantly changed the expression of over 20 miRNAs and over 4000 genes. The observed miR expression indicated a strong immunological cohort, which is seen in many human and mouse cancers and is thought to derive from infiltrating B and T immune cells. However, upon in situ hybridisation, these immunologically related miRs did not correlate with immune cell location, and emanated from the prostate epithelium itself and not from the associated immune cells present. Growing Pten /- prostate cells in culture showed that the overexpressed miRNAs seen in Pten -/ were directly in response to the overactive PI3 kinase pathway and were in part responsible in reducing target gene expression levels. Inhibition of PI3 kinase downstream regulators, or re-introducing wild type Pten cDNA reduced miR overexpression resulting in increased miR target gene expression. MiR inhibitors also showed this pattern, and synergised with an mTORC1 inhibitor. Overall, Pten deletion in the prostate epithelium activated a cohort of inflammation-related miRs usually associated with immune responses from B and T cells. These oncomiRs may then accelerate carcinogenesis. PMID- 29284791 TI - Cadherin 6 is activated by Epstein-Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, which is notorious among head-and-neck cancers with its metastatic feature. Epstein-Barr virus (EBV) infection plays a fundamental role in NPC development with the mechanism is not well understood. Here we demonstrate that EBV oncoprotein LMP1 drives EMT and metastasis of NPC by reactivating the adhesion molecule, cadherin 6 (CDH6), which normally occurs in embryogenesis with unknown role in NPC. CDH6 was found to be upregulated in LMP1-positive NPC tissues, and was identified as a target of the epithelium-specific miR-203. LMP1-activated NF-kappaB transcriptionally repressed the miR-203 expression by binding to the promoter region of miR-203 gene. CDH6 activation in turn induced EMT and promoted metastasis in NPC. CDH6 depletion, NF kappaB inhibitor and miR-203 overexpression were able to impair the EMT effects. The miR-203 downregulation in NPC tissues was strongly associated with metastasis clinically. The CDH6 activator, Runt-related transcription factor 2 (RUNX2), was also activated by EBV in the event. For both CDH6 and RUNX2 are components at TGF beta downstream, CDH6 became a node protein for the interplay of multiple signalings including NF-kappaB and TGF-beta. Therefore, the switch-on of miR-203 was important for nasopharyngeal epithelial cells to maintain normal phenotype. This study demonstrates that EBV has evolved sophisticated strategies by driving epithelial cells to obtain malignant features, particularly in NPC metastasis, providing novel biomarkers for the therapy and prognosis of EBV-associated NPC. PMID- 29284792 TI - A systematic review of complications in thoracic spine surgery for ossification of ligamentum flavum. AB - STUDY DESIGN: Systematic review. OBJECTIVES: The aim of this systematic review is to summarize the incidence of complications, to relate complication incidence to procedures performed, to assess the impact of the year of study publication and follow-up duration on complication incidence. METHODS: The authors conducted the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE searches for relevant literatures. The incidence of complications was summarized. Correlation of the incidence with year of study publications, follow-up duration, and the surgical outcome was statistically evaluated. RESULTS: A total of 16 studies met our inclusion criteria, including 475 patients. All of these studies were retrospective case series. The mean age of patients ranged from 55 to 64 years. Average follow-up duration ranged from 26 to 65 months. Partial patients in four studies underwent surgeries and reserved posterior structure of the spinal canal. The others underwent operations removing posterior structure of spinal canal. The mean recovery rate from each individual study varied between 31 and 68% and the pooled neurologic function recovery rate was 53% (95% CI: 43-62%). The mean complication rate was 24%. Cerebrospinal fluid leakage was the most reported postoperative complication (19%), then neurologic deterioration (5%). Other complications included local infections, wound dehiscence, increased kyphotic deformity, an hematoma. CONCLUSIONS: Operations removing posterior structure of spinal canal are the main technique to decompress spinal cord. Cerebrospinal fluid leakage and postoperative neurologic deterioration were the most reported complications. PMID- 29284793 TI - Sensitivity and specificity of the 'knee-up test' for estimation of the American Spinal Injury Association Impairment Scale in patients with acute motor incomplete cervical spinal cord injury. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: Precise classification of the neurological state of patients with acute cervical spinal cord injury (CSCI) can be challenging. This study proposed a useful and simple clinical method to help classify patients with incomplete CSCI. SETTING: Spinal Injuries Centre, Japan. METHODS: The sensitivity and specificity of the 'knee-up test' were evaluated in patients with acute CSCI classified as American Spinal Injury Association Impairment Scale (AIS) C or D. The result is positive if the patient can lift the knee in one or both legs to an upright position, whereas the result is negative if the patient is unable to lift the knee in either leg to an upright position. The AIS of these patients was classified according to a strict computerised algorithm designed by Walden et al., and the knee-up test was tested by non expert examiners. RESULTS: Among the 200 patients, 95 and 105 were classified as AIS C and AIS D, respectively. Overall, 126 and 74 patients demonstrated positive and negative results, respectively, when evaluated using the knee-up test. A total of 104 patients with positive results and 73 patients with negative results were classified as AIS D and AIS C, respectively. The sensitivity, specificity, positive predictive and negative predictive values of this test for all patients were 99.1, 76.8, 82.5 and 98.7, respectively. CONCLUSIONS: The knee-up test may allow easy and highly accurate estimation, without the need for special skills, of AIS classification for patients with incomplete CSCI. PMID- 29284794 TI - Prevalence and factors associated with a higher risk of neck and back pain among permanent wheelchair users: a cross-sectional study. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To determine the prevalence of, and factors associated with, spinal pain among wheelchair users. SETTING: Four Spanish hospitals specialized in providing care for wheelchair users. METHODS: Persons who had used a wheelchair for a median (IRQ) of 10 (5;19) years, 27% of them due to reasons other than spinal cord injury, were recruited consecutively (n = 750). Data on 43 demographic, psychosocial, ergonomic, and clinical variables were collected, and analyzed. Main outcome measures were: point prevalence of neck (NP), thoracic (TP), low back pain (LBP), and pain at any spinal level (PASL); and factors associated with them. RESULTS: Point prevalence was 56% for NP, 54% for TP, 45% for LBP, and 76% for PSAL. PASL was associated with a lower quality of life (OR (95% CI) 0.91 (0.86; 0.97)). Multivariable regression models showed that the main factors associated with significant pain (>=1.5 VAS points) were: (a) For NP: cervical spinal injury and wheelchair seat cushion thickness, (b) For TP: thoracic spinal injury and sagittal index, (c) For LBP: thoracic or lumbar spinal injury, with some sensitivity remaining, (d) For PASL: being female, living alone, and using a non-power wheelchair. Discrimination (AUC) of these models ranged between 0.638 and 0.818. p-values in the Hosmer-Lemeshow test ranged between 0.420 and 0.701. CONCLUSIONS: Prevalence of spinal pain among wheelchair users is high. It is associated with a lower quality of life. Future studies should assess whether using a power wheelchair affects PASL, and if the thickness of seat cushion affects NP. SPONSORSHIP: Spanish Back Pain Research Network. PMID- 29284795 TI - Considerations and recommendations for selection and utilization of upper extremity clinical outcome assessments in human spinal cord injury trials. AB - STUDY DESIGN: This is a focused review article. OBJECTIVES: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified. METHODS: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review. RESULTS: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered. CONCLUSIONS: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor. PMID- 29284797 TI - Bedside quantification of fat-free mass in acute spinal cord injury using bioelectrical impedance analysis: a psychometric study. AB - STUDY DESIGN: Psychometric. OBJECTIVES: Assess the validity of bioimpedance-based measures of fat-free mass (FFM) in acute SCI and of current definitions of obesity based on body mass index (BMI). SETTING: Australia. METHODS: All admissions within eight weeks of a new traumatic SCI were screened. 29% were eligible. 71% of those consented. Twenty participants (18 male) completed deuterium dilution (DD) and bioimpedance-based measurements of FFM. Thirteen also underwent dual-energy x-ray absorptiometry. Strength of relationships and agreement were examined using Lin's concordance coefficient and limits of agreement analysis, respectively. Sensitivity and specificity were calculated for three BMI cutoffs for obesity, using percentage fat mass (%FM) obtained from DD as reference. RESULTS: Median time since injury was 41 days (IQR 28-48). FFM from DD and DXA were highly correlated but not identical. Concordance and agreement between DD and seven bioimpedance-based predictive equations are presented. The best-fitting equation demonstrated a low bias (+0.6 kg) and moderate dispersion (+/-5.2 kg). The cutoff for overweight in able-bodied people (BMI >=25 kg/m2) provided sensitivity of 43.8%, compared to 25% for the cut-off for obesity (BMI >=30 kg/m2). FM from bioimpedance gave the highest sensitivity (88.9%). CONCLUSIONS: BMI demonstrates poor specificity to classify obesity in acute SCI. Present findings support the utility of bioimpedance-based measurements for estimating FFM in acute SCI for group comparisons. These results are generalizable to traumatic SCI 4-8 weeks post injury; however, the present data reflect a high proportion of high cervical injuries. Further research is indicated to establish validity for assessment of individuals and for longitudinal monitoring. SPONSORSHIP: The present study was funded by a grant from the Institute for Safety, Compensation and Recovery Research (ISCRR Project #NGE-E-13-078). M Panisset was supported by an Australian Postgraduate Award. K Desneves was supported by the Austin Medical Research Foundation. PMID- 29284796 TI - Intermittent negative pressure applied to the lower limb increases foot macrocirculatory and microcirculatory blood flow pulsatility in people with spinal cord injury. AB - STUDY DESIGN: Experimental prestudy and poststudy. OBJECTIVES: Examine the acute effects of intermittent negative pressure (INP) applied to the lower limb on foot circulation in people with spinal cord injuries (SCIs). SETTING: Vascular laboratory, Oslo University Hospital. METHODS: Twenty-four people with SCI (median age 59 years, range 29-74) were exposed to lower leg INP (-40 mm Hg) using an air-tight pressure chamber connected to an INP generator. The contralateral leg was placed outside the pressure chamber. We continuously measured arterial blood flow velocity (ultrasound Doppler), skin blood flow (laser Doppler), skin temperature of the dorsum of the foot, heart rate (ECG) and systemic blood pressure (Finometer) during 5-min baseline (atmospheric pressure), followed by 10-min INP (alternating 10 s -40 mm Hg and 7 s atmospheric pressure), and 5-min post-INP (atmospheric pressure). Skin blood flow was measured on the foot placed outside the pressure chamber. A mixed effects regression model was applied to estimate the effect of INP on blood flow. To quantify flow fluctuations, we calculated cumulative up-and-down changes in arterial blood flow velocity per minute. RESULTS: Flow fluctuations increased during INP compared to baseline [32.3 cm/s/min (95% CI 26.9 to 37.7) vs. 15.2 cm/s/min (95% CI 9.8 to 20.6), P < 0.001]. Peak blood flow velocity and skin blood flow was reached 2-3 s after the onset of negative pressure and increased 33% (95% CI 16 to 46, P < 0.001) and 11% (95% CI -4.1 to 60, P = 0.14) above baseline, respectively. CONCLUSIONS: INP induced increased foot arterial blood flow fluctuations compared to baseline. SPONSORSHIPS: The Norwegian Research Council provided funding to Otivio (grant: 241589). PMID- 29284799 TI - On Sets Defining Few Ordinary Circles. AB - An ordinary circle of a set P of n points in the plane is defined as a circle that contains exactly three points of P. We show that if P is not contained in a line or a circle, then P spans at least [Formula: see text] ordinary circles. Moreover, we determine the exact minimum number of ordinary circles for all sufficiently large n and describe all point sets that come close to this minimum. We also consider the circle variant of the orchard problem. We prove that P spans at most [Formula: see text] circles passing through exactly four points of P. Here we determine the exact maximum and the extremal configurations for all sufficiently large n. These results are based on the following structure theorem. If n is sufficiently large depending on K, and P is a set of n points spanning at most [Formula: see text] ordinary circles, then all but O(K) points of P lie on an algebraic curve of degree at most four. Our proofs rely on a recent result of Green and Tao on ordinary lines, combined with circular inversion and some classical results regarding algebraic curves. PMID- 29284798 TI - High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response. AB - The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma. PMID- 29284800 TI - Immunoinflammatory Therapies in Psychiatry: Current Evidence Base. PMID- 29284801 TI - Comprehensive Management of Autism: Current Evidence. AB - Autism is a neurodevelopmental disorder characterized by impaired social interaction, verbal and nonverbal communication, and restricted repetitive behavior. The goals of treatment are to target core behaviors, improve social interactions and communication, and reduce disruptive behavior. The present paper discusses the role of applied behavioral analysis and pharmacotherapy. PMID- 29284802 TI - Being a Forensic Psychiatrist in India: Responsibilities, Difficulties, and Criticalities. AB - Forensic psychiatry is in its infancy in India. There is a clear module or a well structured training in the country except for recently opened few courses. Lack of trainer in the field might lead to compromised state when one has to take decision between the well-being of a person versus society. Starting from social contexts, such as marriage and mental illness, to the interpretation of criminal mind, there is a multitude of situations where forensic psychiatrist has a handful of jobs which suffer due to lack of infrastructure. In this article, we delineate the importance of a forensic psychiatrist in different civil as well as legal scenarios and difficulties often faced while handling it. PMID- 29284803 TI - Validation of a Screening Tool for Learning Disorder in Children. AB - Background: Learning disorder (LD) is a common cause for poor academic performance among school students. Poor detection of this may be due to lack of proper validated diagnostic and screening tools, leading to considerable difficulty for affected children and their families. This study aims to validate a screening tool developed by us among students with poor scholastic performance. It is an easy-to-use tool that can be used by parents or teachers. Preliminary validation was done earlier using case-control design among 100 students, and the results were encouraging. Materials and Methods: A tool with 26 items was applied in 365 schoolchildren with poor scholastic performance in Calicut district. Receiver operating characteristic curve analysis was done to find area under curve (AUC) and to obtain the sensitivity and specificity at the predefined cutoff score >=10. Results: ROC analysis showed AUC of 0.93 for differentiating LD cases against the normal children. The optimum cutoff was taken as score >=10 which has a sensitivity and specificity of 84.7% and 100%, respectively. Conclusions: The new tool showed promising validity. PMID- 29284804 TI - Anxiety and Depression in Irritable Bowel Syndrome. AB - Background: Psychological factors have been prominently implicated in the causation as well as maintenance of irritable bowel syndrome (IBS). Studies comparing psychiatric morbidity in IBS with healthy controls have reported contrasting findings. The current study was undertaken to assess the prevalence of anxiety and depression in patients with IBS in comparison to healthy controls and to explore the relationship, if any, of anxiety and depression with various subtypes of IBS. Materials and Methods: Fifty consecutive patients of IBS (diagnosed as per Rome III criteria) between 18 and 65 years of age and fifty age and sex-matched healthy controls were assessed for the presence of anxiety and depression using Hamilton Rating Scale for Anxiety (HAMA) and Hamilton Rating Scale for Depression (HAMD), respectively. Results: The patient group scored higher than controls (P < 0.001) in both HAMA and HAMD scores. The HAMA scores were significantly higher (P < 0.001) in the severe IBS group compared to those with moderate IBS. HAMA scores predicted 25.6% (R2 = 0.256) of variance in IBS severity scores. However, there was no significant difference between the two groups in terms of HAMD scores. Conclusion: The high prevalence of psychiatric comorbidities such as anxiety and depression in IBS samples in our study provides evidence in favor of proper screening for these disorders in gastrointestinal clinics. Recognition and treatment for these comorbidities can improve the quality of life as well as overall outcomes. PMID- 29284805 TI - Stigma and Attitudes toward Patients with Psychiatric Illness among Postgraduate Indian Physicians. AB - Background: Due to paucity of psychiatrists in India, psychiatric patients often present to other doctors. We aimed to study nonpsychiatric residents' attitude and stigma toward psychiatric patients. Methods: A total of 57 postgraduate trainees participated in a cross-sectional study in a tertiary hospital in New Delhi. Attitudes to psychiatric patients were assessed using the attitude to mental illness questionnaire (AMIQ) and the perceived stigma questionnaire. This was correlated with sociodemographic information. Results: Over 70% residents accepted mentally ill patients as friends and felt they were equally employable. However, AMIQ demonstrated a negative attitude towards patients with schizophrenia. Perceived competence in dealing with psychiatric patients was associated with adequate undergraduate exposure (Chi-square = 7.270, P = 0.026) and correlated with positive attitudes (t-test, P = 0.0008). Conclusions: While the questionnaires revealed some prejudice toward psychiatric patients with schizophrenia, the postgraduate trainees who felt competent to deal with the mentally ill had the most positive attitudes toward them. PMID- 29284806 TI - First 2 Years of Experience of "Residential Care" at "Sakalawara Rehabilitation Services," National Institute of Mental Health and Neurosciences, Bengaluru, India. AB - Introduction: There is an unmet need for continuity-of-care is well known for those with severe mental disorders (SMDs) after acute care at hospitals in India. The "Sakalawara Rehabilitation Services (SRS)" functioned from March 2014 at "Sakalawara Community Mental Health Centre" (SCMHC) of "National Institute of Mental Health and Neurosciences," Bengaluru, India in the concepts of residential care (half-way-home) with the aim to develop a replicable model. Aim: To review the inpatient records after the initial 2 years of experience in residential care at SCMHC. Methodology: Retrospective file review of inpatients at SCMHC from March 2014 to March 2016 in a semi-structured proforma designed for the study. Ethical committee of NIMHANS Bengaluru has approved the study. Results: The total number of inpatients during this period was 85. It was found that Schizophrenia spectrum disorders were the most common diagnosis among these patients. The activity of daily living and psycho-education were the most common individual interventions. The majority of families underwent structured family psycho educational interventions. This review also demonstrated the feasibility of tele aftercare in continuity of care after discharge of patients. Conclusion: SRS kind of residential set-up is feasible and demonstrated effectiveness in maintaining continuity of care of SMDs. There is a need for better structured and customized interventions. There is further a scope for tele (video) aftercare for those with SMDs. PMID- 29284807 TI - A Clinical Study of Opioid Substitution Therapy in a Tertiary Care Center of Eastern India. AB - Background: Opioid substitution therapy (OST) is an evidence-based intervention for opiate-dependent persons that replaces illicit drug use with medically prescribed, orally administered opiates such as buprenorphine and methadone. OST reduces HIV risk behaviors and harms associated with injecting opioid. Most of the evidence for OST effectiveness has been generated in middle- and high-income countries where programs are mostly located in dedicated health-care settings; evidence regarding the outcomes of OST programs in low-income countries where OST is often provided in grassroots settings such as drop-in centers is limited. Aims and Objectives: To study the sociodemographic variables, HIV ELISA status, HIV risk behavior, comorbid substance use pattern, and required dose of buprenorphine used for treatment of injection drug users (IDUs) attending oral substitution therapy (OST) center at a tertiary health care center. Methodology: A total of IDUs aged 18-60 years who attended the OST center during 1-year period at a government medical college are included in the study. Results: Majority of the IDUs are male with mean age of 32.8 years. The mean dose of buprenorphine used for the substitution was 4.6 mg/day at the start of therapy. Most of the IDUs are of lower educational status and educated up to primary or middle school. 32.50% of the participants who are unemployed are totally dependent on the family. Most common substance abuse among IDU users were tobacco (74.17%), followed by heroine (57.5%). High-risk behavior found among OST clients was unprotected sexual intercourse (19.17%), sharing needle (11.67%), and sexual intercourse with multiple partners (6.67%). HIV ELISA testing showed positive among 2 (1.67%). Conclusion: These findings have relevance to other parts of India and Asia, where injecting drug use is common and is a first step toward filling the gap in knowledge regarding the effectiveness of community-based OST programs delivered in resource-constrained settings. PMID- 29284808 TI - Functional Impairment and Quality of Life in Patients with Obsessive Compulsive Disorder. AB - Background: This study was carried out to enumerate the level of difference in functional impairment and quality of life (QOL) in obsessive-compulsive disorder (OCD) patients and normal control group to find out the relationship among ICD functional impairment and QOL. Methodology: Thirty patients diagnosed with OCD as per International Classification of Diseases Diagnostic Criteria for Research-10 were taken for study. The control group consists of 30 normal participants from the community. Functional impairment and QOL questionnaires were administered on both groups to measure functional impairment and QOL in OCD. Results: The mean age of onset of OCD was (23.8 +/- 7.25), mean duration of illness was (6.3 +/- 4.47), and mean duration of treatment was (2.56 +/- 2.47). It was also observed that total score as well as all the domains of the World Health Organization QOL BREF, OCD patients scored significantly less (P < 0.001) compared to normal controls. Dysfunctional Analysis Questionnaire (DAQ)-Social area and DAQ-Personal area had statistically significant positive correlation (P < 0.05) with an obsessive subscale of Yale-Brown Obsessive Compulsive Scale (Y-BOCS) whereas DAQ social area (P < 0.05), DAQ-Personal Area (P < 0.05) had statistically significant positive correlation with a total score of Y-BOCS. Conclusion: The presence of functional impairment leads to poor QOL in the persons with OCD. PMID- 29284809 TI - Evaluation of Endocrine Parameters as Predictor of Major Depressive Disorder. AB - Background: The diagnosis of the disease, major depressive disorder (MDD), entirely depends on the presence of some symptoms without any biochemical parameter to support it. Depletion of dopamine though is an established feature, is not the sole causative factor of MDD. Moreover, it has very little diagnostic value due to a short half-life. Other chemical messengers like hormones have also been found to get altered due to significant over activity of hypothalamo pituitary axis. Literature review suggests that cortisol, thyroid-stimulating hormone (TSH), and prolactin (PRL) are mostly altered in MDD, which can be utilized to diagnose the condition. Materials and Methods: A total of 101 patients suffering from MDD along with 106 age- and sex-matched controls were included in this study. Cortisol, TSH, and PRL were assayed in all the study participants by enzyme immunoassay. Student's t-test and linear discriminant analysis were used for statistical analysis. Results: All the three hormones were found to be significantly high in cases with MDD. When applied for classification purpose, the errors in training group were found to be 15% and 15.74% from test set. None of the normal population was wrongly diagnosed as a patient of depression. Conclusion: To the best of our knowledge, this is the first attempt to evaluate multiple biochemical parameters as diagnostic marker of MDD. The study is in progress to find out a cutoff value of the responsible parameter so that they can be optimally used to diagnose a case of MDD. PMID- 29284810 TI - Efficacy and Tolerability of Clozapine versus Quetiapine in Treatment-resistant Schizophrenia. AB - Objectives: To compare the efficacy and tolerability of clozapine and quetiapine in patients with treatment-resistant schizophrenia (TRS). Patients and Methods: In this prospective, randomized, open label study of 14 weeks, 53 patients with schizophrenia diagnosed as per ICD-10 and fulfilling the modified version of Conley and Kelly's criteria of TRS were randomly assigned to receive clozapine or quetiapine as per a computer-generated random table. After 2-weeks of dose titration phase, doses were fixed at minimum therapeutic dose and subsequently adjusted according to the clinical improvement. All patients received dosage of respective drug in therapeutic range. 13 patients were lost to follow up. Treatment efficacy and side effects were evaluated with standardized rating scales. Results: Clozapine group (reduction in total score: mean=14.45, SD=10.39) had significantly greater reductions (P=0.004; CI=3.541-17.059) in the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive subscale and PANSS general psychopathology subscale at 14 weeks in comparison to the quetiapine group (reduction in total score: mean=4.15, SD=10.71). Significant reduction in PANSS negative subscale was seen with both drugs but no significant difference was present between the two drugs. At 14 weeks, 30% patients in clozapine group and 15% patients in quetiapine group showed response. Clozapine led to significantly greater side effects (P< 0.001, CI=2.241-6.059) on Glassgow Antipsychotic Side-effect Scale (GASS) than quetiapine. Conclusions: Clozapine was found to be more efficacious than quetiapine in patients with TRS but was associated with greater side effects. Both the drugs were found to be equally effective in reducing the negative symptoms. PMID- 29284811 TI - Caregiver Burden in Medical versus Psychiatric Patients: A Cross-sectional Comparative Study. AB - Background: An informal care-giver is generally an unpaid individual who looks after the personal and medical needs of the patient. India being a country of traditions and family values, this informal care-giver is usually a family member. These care-givers, being untrained in this job undergo tremendous stress. Available research studies the burden individually in the relatives of chronically medically ill patients and those of psychiatrically ill patients. Furthermore the previous research targets the burden in individual diseases. This study stands out as it makes a comparison between the two broad groups, taking into account almost all possible chronic diseases in each group. Methods: This is a cross-sectional analytical descriptive study that was conducted on the family caregivers of chronically medically ill and psychiatrically ill patients, using the Caregiver's Burden Scale. Data were analyzed by SPSS 20 statistical software and Pearson correlation coefficient tests. Significant difference between area of caregiver burden of medicine and psychiatric patients was tested using relative deviate "Z" of SEDM test at 5% level of significance. Result: There is a significant difference between each category of Caregiver's Burden Scale among chronically medically ill and psychiatrically ill patients. (P < 0.05). Conclusion: The outcome of this study may help the health care providers in designing stress relief programs for primary care-givers. Overall this study may help better delivery systems of care for both the chronically medically ill as well as psychiatrically ill patients, by proper specific framing and psycho education programs for the caregivers of specific chronic illnesses. PMID- 29284812 TI - Quality of the Reviews Submitted by Attendees of a Workshop on Peer Review. AB - Objective: The objective of the study was to study the methodological quality and error detection of the review by the participants of a peer review workshop. Methods: All participants of the workshop were invited to peer review a randomized controlled trial. The manuscript was E-mailed to them after introducing eight deliberate errors to it. Specific instructions and a deadline were provided. All the reviews were analyzed using review quality instrument (RQI). Furthermore, the rate and the type of errors identified were recorded. Results: Of 25 participants, 16 (64%) returned the reviews. The mean total score on RQI was 4.12 (standard deviation 0.70, 95% confidence interval 3.74-4.50); the items which most reviewers did not discuss where the importance of research question and originality of the paper. The number of errors correctly identified varied from 0 to 6 (median 3), the most common being a wrong conclusion (87.5%), randomization procedure (50%), written informed consent (50%), ethics committee approval (42.8%), and masking (31.2%). Only 5 (31.2%) gave an overall recommendation on whether the manuscript should be accepted or not. Conclusions: Major errors were readily identified by the reviewers; however, the need for training was felt in some areas in which the review quality was modest. PMID- 29284813 TI - Prevalence and Factors associated with Depression among Clinically Stable People Living with HIV/AIDS on Antiretroviral Therapy. AB - Background: Individuals with HIV/AIDS are prone for psychiatric/psychological morbidities. Many studies have reported significantly higher prevalence of depression in people living with HIV/AIDS (PLWHA's) when compared to general population. However, there are only very few studies looking at the prevalence of depression in patients on antiretroviral therapy (ART). Objectives: To estimate the prevalance and factors associated with depression among clinically stable PLWHAs. Materials and Methods: We used a cross-sectional study design to estimate the prevalence of depression and factors associated with it among clinically stable PLWHAs with CD4 cell count >400 cells/mm3 and on ART for >2 years. We assessed 100 PLWHAs and diagnosed depression using ICD-10 diagnostic criteria. Results: The prevalence of depression was 30% in this sample. Female gender, lack of family support, and HIV-positive status of the spouse were associated with depression in this study. Multiple logistic regression analysis showed lack of family support significantly associated with depression. High prevalence of depression and its association with stressful life circumstances even in individuals stable on ART points toward need for psychosocial interventions to improve metal health and well-being of these patients. PMID- 29284814 TI - A Rare Presentation of a Case of Obsessive-compulsive Disorder Comorbid with Bipolar Affective Disorder. AB - Obsessive-compulsive disorder (OCD) is a chronic illness with waxing and waning course. OCD is not uncommonly found to be comorbid with bipolar affective disorder (BPAD). The course and prognosis of OCD have distinctive features in such cases. Only rarely symptoms of OCD emerge during mania in such individuals. We hereby report a very unusual case of OCD comorbid with BPAD in which obsession and compulsion symptoms occurred only during manic episodes with complete remission during periods between manic episodes (including during depressive episodes). PMID- 29284815 TI - Rehabilitation in Schizophrenia: A Brain-behavior and Psychosocial Perspective. AB - Cognitive deficits in patients with schizophrenia have been documented consistently. They are known to contribute to functional impairment in patients. Cognitive remediation has been found to be beneficial in symptoms reduction and functional recovery. CH was a 26/F, completed her graduation, currently pursuing a management course through correspondence, unmarried, currently living with her parents, from Bengaluru, right-handed, Middle socio economic status (MSES). A diagnosis of paranoid schizophrenia was referred for cognitive assessment and rehabilitation. Patient's cognitive assessment showed impairment in all the cognitive domains. She was given home-based and neurofeedback training along with family intervention. Significant improvement was seen in patients overall functioning. PMID- 29284816 TI - A Case Report of Gender Dysphoria with Morbid Jealousy in a Natal Female. AB - Gender dysphoria is a new entity introduced in the Diagnostic and Statistical Manual of Mental Disorder V to address the distress of the previously labeled gender identity disorder patients. It is less commonly seen in natal females, often starting in their childhood. Adults and adolescent natal females with early onset gender dysphoria are almost always gynephilic. This case report is presented to discuss the interesting evolution of the symptoms in gender dysphoria case with difficulties in adjusting to the assigned sexual role, relationship problems, morbid jealousy, and severe depressive features with suicidal ideations. PMID- 29284817 TI - A Case of Early Onset Subacute Sclerosing Panencephalitis Presented as Juvenile Myoclonic Epilepsy. AB - A 7.5 years girl presented with myoclonic jerks with prolonged duration coming progressively at shorter intervals for last six moinths. There was declining academic performances. The dystonic, dyskinetic movements and ataxia were there for last three months. The stages were progressing too rapidly. IgG antibody titre to measles virus was found to be positive with EEG changes which confirms diagnosis. SSPE at so early age with atypical presentation is unique in this indexed case. PMID- 29284818 TI - Risperidone-induced Erythema Multiforme Minor. AB - Antipsychotic agents are known to cause adverse cutaneous reactions. These are supposedly rare with atypical antipsychotic agents. Adverse dermatologic reactions due to antipsychotic agent risperidone are rarely reported. Here, we present a case of risperidone-induced erythema multiforme minor. PMID- 29284819 TI - Olanzapine-induced Psoriasis. AB - Olanzapine is a second-generation antipsychotic drug mainly used in the treatment of schizophrenia. It has several side effects including weight gain, hypercholesterolemia, and hyperglycemia, but dermatological side effects are rarely reported. We report a rare case of olanzapine-induced psoriasis. PMID- 29284821 TI - The Tale of the Storyteller and the Painter: The Paradoxes in Nature. AB - Introduction: Brain as the seat of behavior is acknowledged from the times of Charaka, however where neurology ends and philosophy begins remains an enigma. It is certainly every neurologist's observation that there is loss of function either region based or domain based in progressive diseases of the nervous system making it the seat of all useful activities. However, there are references to occurrence of new skills seen during various illnesses causing progressive cognitive dysfunction. This serves as a pharmaco-sparing agent in behavior management and therefore serves as a rehabilitatory tool. However, its pathomechanism is not clear. Patient and Methods: Two patients comprising one male and one female who were being evaluated for progressive cognitive dysfunction and were found to have interesting creative skills and are being described. Results: The first patient is a case of young onset behavioral variant frontotemporal dementia and the second patient is a case of neurosarcoidosis. Conclusion: The emergence of these skills could be due to disinhibition of some of the innate skills of the patients during degeneration or establishment of new data linking circuits with creative potential during attempted repair. PMID- 29284820 TI - Examining Discrepancy between Performance on Traditional Measures and Parent Report Measure of Executive Functioning in Autism Spectrum Disorder. AB - There is a growing concern amongst the researchers regarding the ecological validity of the neuropsychological tests used to assess EF in ASD. Traditional EF tests have been criticized for not being unable to tap real-life scenarios that are relevant to and representative of everyday behavior. The present study aimed to examine any potential discrepancy between performance on traditional measures of executive function and behavioural expressions of EF in case of an individual with High Functioning Autism (HFA). The findings highlight the importance of use of ecologically valid measures to gain a more valid assessment of executive functions. PMID- 29284822 TI - Right-sided Transcranial Direct Current Stimulation and Attentional Salience of Auditory Hallucinations in Schizophrenia. AB - Transcranial direct current stimulation (tDCS) is a safe, noninvasive technique demonstrated to reduce persistent auditory hallucinations in patients with schizophrenia. Here, we report the differential effect of tDCS on auditory hallucinations against other positive symptoms and also the use of right-sided tDCS in patients with increased attentional salience toward auditory hallucinations. PMID- 29284823 TI - Schizophrenia with Comorbid Idiopathic Parkinson's Disease: A Difficult Clinical Management Scenario. AB - Comorbidity of idiopathic Parkinson's disease (IPD) and schizophrenia is an uncommon and rare scenario, which often poses a difficult and challenging situation for management. Both the disorders have completely opposite pathophysiology and treatment of one disorder with available pharmacological agents can pose a threat to the other disorder. The situation becomes graver and risk of adverse side effects increases when an individual presents at a later age with both these disorders along with compromised physical and mental health. Of all the available psychopharmacological agents, clozapine has been found to be quite helpful for the management of psychosis without deterioration of existing movement problems of Parkinson's disease. In this case report, we present the case of a 60-year-old female with long-standing paranoid schizophrenia for the last 30 years, who later developed IPD and discuss the various management issues encountered during her treatment. PMID- 29284824 TI - Clozapine-induced Delayed Ejaculation. PMID- 29284825 TI - Twin Registries: The Neglected Population Resource. PMID- 29284826 TI - Antipsychotics and OCD: Boon or Bane? PMID- 29284827 TI - Overestimation of Depression Prevalence among Adolescent Students. PMID- 29284828 TI - Aggressive Behavior and Short-Long Polymorphisms of Monoamine Oxidase A: An Example of Effect of Genetic Molecular Mass Change in Psychological Medicine. PMID- 29284829 TI - If Depression may be Associated with Future Care Seeking of Activity-limiting Low Back Pain, We Must Properly Address the Depression as Well. PMID- 29284830 TI - Successful Use of Risperidone, Trihexyphenidyl, and Paroxetine in Pregnancy. PMID- 29284832 TI - Application of Discharge Criteria for Home Readiness Using Bispectral and Supraglottic Airway Devices in Day-care Surgery without Using Muscle Relaxants. AB - Introduction: The availability of rapid and short-acting intravenous and volatile anesthetics has facilitated early recovery that is why nowadays ambulatory surgery is becoming more common. If the criteria used to discharge patients from the Postanesthesia Care Unit (PACU) are met in the operating room (OR), it would be appropriate to consider bypassing the PACU and transferring the patient directly to the step-down unit. This process is known as "fast-tracking" after ambulatory surgery. Aims: To compare hemodynamic characteristics and recovery profile as per fast-track criteria (FTC) of recovery and postanesthesia discharge scoring system (PADSS) between sevoflurane and desflurane. Materials and Methods: One hundred American Society of Anesthesiologists Class I-II patients aged 20-50 years were randomly divided into two groups. Following anesthesia induction with injection propofol and injection dexmedetomidine airway was secured with i-gel, Group D (n = 50) received desflurane + dexmedetomidine + O2 + N2O and Group S (n = 50) received sevoflurane in place of desflurane. Emergence time was noted and FTC was evaluated in the OR, Score >12 is considered as shifting criteria for ambulatory surgery unit (ASU). PADSS was noted in ASU at an interval of 15 min for 3 h and Score >9 is considered as ready to discharge home. Results: Response to pain, verbal commands, and spontaneous eye opening in Group D was shorter than that in Group S (P = 0.001). Mean time to achieve FTC score >12 was 15 min in both the groups. Eighty-six percent of patients were ready to go home between 60 and 90 min using PADSS. Conclusion: We concluded that early recovery is faster for desflurane, and there is no difference in ready to go home time between desflurane and sevoflurane. PMID- 29284831 TI - Anesthesiologist in Cardiac Catheterization Laboratories; the Roles and Goals!! A Postgraduate Educational Review. AB - It is not uncommon to see in developing and underdeveloped countries, where the anesthesiologist who is untrained in cardiac specialty takes care of cardiac catheterization centers. The service in cardiac catheterization laboratories (CCL) in developed countries and some of the developing countries is mainly provided by the cardiac anesthesiologists. The scenario is not same in some part of developing countries or in underdeveloped countries which are mainly due to increase in number of CCL (catheterization laboratory) when compared to the number of cardiac anesthesiologists working outside the operation theater. It is also important for training the postgraduate in this field as to make them capable and competitive in managing such cases during emergency situation as it may save the life of a patient. Many a times, CCL is built as per the need of cardiologist ignoring the basic needs of cardiac anesthesiologist. It is important to note that anesthesiologist should be competent enough to provide complete, integrated anesthetic care outside the operation theater with available resources. It is challenging for the anesthesiologist to provide sedation or general anesthesia in such critical area where he/she will be dealing with life threatening situations. In the modern era, the interventional techniques are advancing and treating complex heart diseases is more often. Days are not far where the CCL procedures may reduce the requirement of major surgeries. A careful and dedicated approach by the anesthesiologist with thorough knowledge and skills decreases morbidity and mortality rate. This article helps both cardiac and noncardiac anesthesiologists to improve their knowledge and to approach the patient systematically. PMID- 29284833 TI - Preemptive Epidural Analgesia for Postoperative Pain Relief Revisited: Comparison of Combination of Buprenorphine and Neostigmine with Combination of Buprenorphine and Ketamine in Lower Abdominal Surgeries, A Double-blind Randomized Trial. AB - Context: Postoperative pain relief provides subjective comfort to patient in addition to blunting of autonomic and somatic reflex responses to pain, subsequently enhancing restoration of function by allowing the patient to breathe, cough, and move easily. Aims: The aim is to evaluate and compare the effects of neostigmine + buprenorphine and ketamine + buprenorphine for preemptive epidural analgesia for postoperative pain relief in patients undergoing abdominal surgeries under general anesthesia (GA). Settings and Design: A double-blind randomized trial. Subjects and Methods: A total of 60 American Society of Anesthesiologists physical status Classes I and II patients undergoing abdominal surgeries under GA were taken up for the study. They were randomly allocated into two groups, Group A and Group B of thirty patients each. Preemptive epidural analgesia for postoperative pain relief was provided by a combination of neostigmine 1 MUg/kg + buprenorphine 2 MUg/kg in Group A patients and ketamine 1 mg/kg + buprenorphine 2 MUg/kg in Group B patients after induction of GA but before surgical incision. Postoperatively, vital parameters, pain score, requirement of top up doses, and side effects in the two groups were observed and recorded at 2, 4, 6, 10, 18, and 22 h. Statistical Analysis Used: Mean values within each of the Group A and Group B were compared using one-way analysis of variance (one-way ANOVA). Mean values between Group A and Group B were compared using double analysis of variance (two-way ANOVA). Results: Group A patients had a significant analgesia (visual analog scale [VAS] pain scores reduced significantly from 54.6 +/- 6.3 at 2 h to 8.1 +/- 8.9 at 22 h postoperatively). Group B patients had significant analgesia too (VAS pain scores reduced significantly from 36 +/- 12.5 at 2 h to 5.3 +/- 10.9 at 22 h postoperatively). There was however no significant difference between the two groups with respect to the degree of postoperative analgesia on comparison of VAS scores, effect on vital parameters, and incidence of side effects. Conclusions: Either of the two combinations, neostigmine 1 MUg/kg + buprenorphine MUg/kg or ketamine 1 mg/kg + buprenorphine 2 MUg/kg can be safely used for preemptive epidural analgesia for postoperative pain relief in patients undergoing abdominal surgeries under GA. PMID- 29284834 TI - Comparison of Dexmedetomidine and Midazolam for Sedation in Mechanically Ventilated Patients Guided by Bispectral Index and Sedation-Agitation Scale. AB - Background: Mechanical ventilation and sedation are inextricably linked components of critical care that represent, what we do for the patients during their vulnerable course in Intensive Care Unit (ICU). Aims: The aim of this study is to compare the efficacy and safety of midazolam and dexmedetomidine in patients on mechanical ventilator with the help of Bispectral Index (BIS) monitoring and correlation of BIS with Sedation-Agitation Scale (SAS). Settings and Design: Prospective, observational, and comparative study. Materials and Methods: In this study, recruited patients were allocated into two groups of 14 patients each. Group A and Group B patients received injection dexmedetomidine and injection Midazolam, respectively. Hemodynamic parameters, time of extubation, duration of mechanical ventilation, and mortality were compared between two groups. Statistical Analysis: Mean and the standard deviation were calculated. Test of analysis between two groups was performed using unpaired t test. We applied correlation technique, that is, Pearson product-moment correlation coefficient (r) to assess the correlation between BIS and SAS. It varies from + 1-0 to -1. Results: Heart rate and blood pressure were more stable and less in Group A than Group B. Duration of mechanical ventilation was found extremely significant between Group A (77.86 +/- 5.71 h) and Group B (95.64 +/- 17.00 h) (P = 0.001). There was significant difference found in the time of extubation between Group A (21 +/- 6.44 h) and Group B (30.4 +/- 10.62 h) P = 0.008. Conclusion: It is concluded in this study that sedation with dexmedetomidine resulted in quick extubation and decreased the duration of mechanical ventilation in comparison to midazolam in ICU patients. There was found moderate to high correlation between BIS index and SAS. PMID- 29284836 TI - Cardiopulmonary Resuscitation: Evaluation of Knowledge, Efficacy, and Retention in Young Doctors Joining Postgraduation Program. AB - Background: High-quality cardiopulmonary resuscitation (CPR) and rapid defibrillation the cornerstone for resuscitation from cardiac arrest and increase the incidence of return of spontaneous circulation. Regular CPR training imparted to health-care personnel increases knowledge and helps in skill enhancing. Aims: The aim of this study is to evaluate background knowledge, percentage improvement in the skills, and residual knowledge after a period of 6 months of postgraduate (PG) students as well as the efficacy of the designed teaching program for CPR. Design: The study type was interventional, nonrandomized with end point classification as efficacy study. Study Interventional model was single group assignment. Methods: A questionnaire-based study was conducted on 41 first year PG students. Their educational qualification was Bachelor of Medicine and Bachelor of Surgery. The study was conducted; 3 months after, these PG students joined hospital for their PG studies. The questionnaire designed by the Department of Anesthesiology and Critical Care was given as the pretest (before the CPR training program was initiated), posttest (immediately after the CPR training program was concluded), and residual knowledge test (conducted after 6 months of the CPR training program). After collection of data, a descriptive analysis was performed to evaluate results. Statistical Analysis: Statistical analysis was conducted for determining the test of significance using two-tailed, paired t-test. Results: The average overall score was 25.58 (+/-5.605) marks out of a maximum of 40 marks in the pretest, i.e., 63.97%. It improved to 33.88 (+/ 3.38) marks in posttest, i.e., 84.74%. After 6 months in the residual knowledge test, the score declined to 26.96 (+/-6.09) marks, i.e., 67.4%. Conclusion: The CPR training program being conducted was adequately efficacious, but a refresher course after 6 months could help taking the knowledge and skills acquired by our PG students a long way. PMID- 29284835 TI - To Evaluate the Efficacy of Intravenous Infusion of Dexmedetomidine as Premedication in Attenuating the Rise of Intraocular Pressure Caused by Succinylcholine in Patients Undergoing Rapid Sequence Induction for General Anesthesia: A Randomized Study. AB - Context: Laryngoscopy and intubation performed during RSI lead to choroidal blood volume increase and an eventual rise in intraocular pressure (IOP). Use of succinylcholine (SCh) causes an undesirable rise in IOP which is further aggravated by laryngoscopy and endotracheal intubation. Dexmedetomidine is a highly selective centrally acting alpha2 adrenergic agonist that has IOP lowering properties. Aims: This study aims to evaluate the efficacy of intravenous (i.v.) infusion of dexmedetomidine (0.5 MUg/kg) as premedication in attenuating the rise of IOP and adverse effect if any caused by SCh in patients undergoing RSI for general anesthesia. Settings and Design: This was a double-blind, randomized trial. Subjects and Methods: Sixty adult patients in the age group of 20-50 years scheduled for elective surgeries under general anesthesia. Group I (dexmedetomidine group) (n = 30) received i.v. infusion of dexmedetomidine (0.5 MUg/kg) and Group II (control group) (n = 30) received i.v. infusion of 50 ml normal saline as premedication. Statistical Analysis Used: The analysis was done using Statistical Package for Social Sciences Version 15.0 statistical Analysis Software. Results: It was observed that Group I (dexmedetomidine group) had a better attenuating effect over the increases in IOP in patients undergoing RSI for general anesthesia using SCh. An increase in IOP was seen in Group II (control group) patients with RSI. Conclusions: The findings in the present study indicate that i.v. dexmedetomidine effectively attenuates the increases in IOP with an additional advantage of control on hemodynamic responses following RSI. PMID- 29284837 TI - To Compare the Effects of Different Doses of Dexmedetomidine on Intrathecal Bupivacaine in Infraumbilical Surgeries: A Prospective, Randomized, Double-blind Clinical Study. AB - Introduction: Spinal anesthesia is preferred technique of choice in infraumbalical surgeries. Limitation of this technique is shorter duration of analgesia, so various adjuvants have been used with intrathecal bupivacaine such as fentanyl, clonidine, and dexmedetomidine. Dexmedetomidine is a highly selective alpha 2 adrenergic agonist. The aim of our study was to know the effect of different doses of dexmedetomidine on intrathecal bupivacaine. Materials and Methods: The prospective, randomized, double-blind study was conducted in tertiary health care center, on ninety patients of the American Society of Anesthesiology Class I and II, of age group 18-60 years of either sex. They were randomly allocated into three groups. Group BD5 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 5 MUg (0.5 ml), Group BD10 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 10 MUg (0.5 ml), Group BD15 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 15 MUg (0.5 ml) administered intarthecally. The onset and maximum level of sensory block, time to reach maximum level of sensory block, time of two-segment sensory regression, the total duration analgesia, time of rescue analgesia, onset and duration of motor block and heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, respiratory rate, and oxygen saturation were recorded at various intervals. Moreover, any adverse effects such as bradycardia, hypotension, nausea, vomiting, and sedation were recorded. Results: The onset time of sensory block in Group D5-2.76 +/- 1.32, Group D10-2.45 +/- 1.50, and Group D15-1.86+/-0.93, which is statistically significant (P = 0.025). The time taken for two-segment sensory regression Group D5-96.66 +/- 33.67, Group D10 116.80 +/- 36.27, and Group D15 120.96 +/- 30.24, (P = 0.014). The time taken for complete sensory recovery in Group D5-319.83 +/- 61.41, Group D10-336.13 +/- 61.38, and Group D15-415.20 +/- 96.6, which is statistically highly significant (P = 0.000). Time for rescue analgesia in Group D5-377.46 +/- 60.05, in Group D10 401.60 +/- 61.11, and in Group D15-517.96 +/- 97.30, which is statistically highly significant (P < 0.000). Conclusion: We concluded that there was decrease in onset of sensory and motor blockade with the prolongation of duration of anesthesia and analgesia in a dose-dependent manner. PMID- 29284838 TI - Efficacy of Oral Transmucosal Fentanyl Citrate for Premedication in Patients for Surgery under General Anesthesia. AB - Background: Oral transmucosal fentanyl citrate (OTFC), a water soluble salt when mixed in saliva is 80% nonionized; making it the only opioid suitable for transmucosal absorption. OTFC has rapid onset of action (3-5 min) with peak effect at 20-40 min and total duration of activity is 2-3 h. Aims: This study aims to determine the efficacy of OTFC as premedicant in patients scheduled for surgery under general anesthesia (GA) and to assess the effects of OTFC on anxiety, sedation. Settings and Design: A prospective randomized study. Subjects and Methods: Patients between 21 and 60 years of age in American Society of Anesthesiologists physical status Classes I and II scheduled for elective surgery under GA were randomly assigned to three groups of 30 each: OTFC, placebo, and control. Mean arterial blood pressure (MAP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO2) along with anxiety and sedation scores were recorded as baseline and upon entering the operation theater. Adverse effects were also recorded. Statistical Analysis Used: Statistical analysis was done using Statistical Package for Social Sciences Version 15.0 Statistical Analysis Software. Results: No significant differences were found in MAP, HR, RR, or SpO2 among the groups. OTFC group demonstrated significantly higher levels of anxiolysis than the control group (P < 0.05). No significant difference in sedation score was found. No remarkable adverse effects were observed. Conclusions: OTFC is an effective anxiolytic in adult with minimal risks and side effects. It is readily acceptable by the patients in its given form. PMID- 29284839 TI - "Comparison of Nalbuphine Hydrochloride and Fentanyl as an Adjuvant to Bupivacaine for Spinal Anesthesia in Lower Abdominal Surgeries:" A Randomized, Double-blind Study. AB - Background and Aims: Opioids have been favored as adjuvants to local anesthetics during spinal anesthesia. Nalbuphine, a MU-receptor antagonist and K-receptor agonist, seems to be a suitable adjuvant to local anesthetics. The aim of this study was to compare postoperative analgesia and adverse effects of nalbuphine and fentanyl when used as an adjuvant to hyperbaric bupivacaine during spinal anesthesia. Materials and Methods: Sixty patients belonging to the American Society of Anesthesiologists Physical Status I and II were randomly allocated into two groups of thirty each. Patients in bupivacaine nalbuphine group (Group BN) received 0.8 mg (0.3 ml) of nalbuphine with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine diluted to 3 ml and bupivacaine-fentanyl group (Group BF) received 25 MUg (0.5 ml) of fentanyl with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine. Patients were assessed for hemodynamic changes, sensory and motor block, early postoperative analgesia, and adverse effects. Results: Onset, duration of sensory and motor block, and duration of effective analgesia were comparable between both groups. Postoperative visual analog scale score was 4.8 +/- 1.12 in Group BN, and in Group BF, it was 3.86 +/- 1.04 which was statistically highly significant (P = 0.0007). The number of patients demanding rescue analgesia in early postoperative period was 18 (60.0%) in Group BN and 7 (23.33%) in Group BF which was statistically significant (P = 0.004). Conclusion: Fentanyl was more efficient than nalbuphine in providing early postoperative analgesia when used as an adjuvant to hyperbaric bupivacaine. PMID- 29284840 TI - Effect of Clonidine as Adjuvant in Thoracic Paravertebral Block for Patients Undergoing Breast Cancer Surgery: A Prospective, Randomized, Placebo-controlled, Double-blind Study. AB - Background and Aims: Postoperative pain after breast cancer surgery is unavoidable. Thoracic paravertebral block (TPVB), a locoregional anesthetic technique, has been proven successful for postoperative pain management in different thoracic surgical procedures, such as thoracotomy, breast cancer surgeries. Clonidine, an adjuvant, in TPVB may enhance the quality and prolong the duration of analgesia. This prospective study was to evaluate the effectiveness of clonidine; administered with TPVB; in addition to conventional local anesthetic solution. Materials and Methods: Fifty-two patients (25-55 years) scheduled for breast cancer surgery under general anesthesia were randomly divided into Group A (n = 26) receiving preoperative TPVB at T3 with clonidine added to local anesthesia solution and Group B (n = 26) receiving identical TPVB with local anesthesia but without any adjuvant. This was followed by balanced general anesthesia. A visual analog scale was used to assess pain postoperatively up to 48 h. Meantime to administration of the first dose of rescue analgesic was noted. Total dose of fentanyl consumption, hemodynamic parameters, and side effects were all recorded for each patient. Results: The dosage of fentanyl required in the intraoperative period was significantly lower in Group A. Mean time to administration of rescue analgesic was found to be significantly longer in clonidine group. Hemodynamics and side effects were quite comparable among two groups. Conclusion: Clonidine as adjuvant in TPVB provided profound analgesia for up to 48 h postoperatively for patients undergoing breast cancer surgery without any appreciable side effects. PMID- 29284841 TI - A Retrospective Analysis on Anesthetic Management during Rigid Bronchoscopy in Children with Foreign Body Aspiration: Propofol and Sevoflurane with Controlled Ventilation. AB - Background: Bronchoscopic removal of foreign body in the airway is one of the important life-saving procedure and demands skill and expertise on the part of the surgeon and anesthesiologist. Aim: To study the outcome of controlled ventilation during rigid bronchoscopy in children with foreign body aspiration. Materials and Methods: A review of fifty cases of foreign body in the bronchi, from January 2014 to December 2015 was undertaken in Vittal Institute of Child Care Hospital, Dharwad, through patient case records. Patients between 6 months and 14 years were included in the study. Cases of foreign body in the larynx and trachea were excluded. Patients were induced with propofol and maintained on sevoflurane. The parameters observed were bronchoscopy attempts, succinylcholine requirement, episodes of laryngospasm, cough, bronchospasm and spontaneous recovery. Statistical analysis was done by Chi-square test using software OpenEpi version 7.3. Results: Of 45 patients with organic foreign body, 42 (94%) patients required one attempt of bronchoscopy and 3 (6%) patients required two attempts. Five (100%) patients with inorganic foreign body required single attempt (P = 0.66). Forty-three (96%) patients with organic foreign body required two repeat doses of succinylcholine and 2 (4%) patients required three repeat doses. All 5 (100%) patients with inorganic foreign body required two repeat doses (P = 0.7461). Two (4%) patients aspirated with organic foreign body had laryngospasm, and there was no cough or bronchospasm with either patient. Two (4%) patients with organic foreign body required tracheostomy. Inorganic foreign body group of patients had lesser complications. Conclusion: In our study, patients on controlled ventilation had few intraoperative complication and smooth early recovery. Controlled ventilation with relaxation should be preferred for any pediatric bronchoscopies. Eliciting history of type of foreign body helps in planning and management of procedure. PMID- 29284842 TI - Randomized Comparison of Isoflurane versus Sevoflurane and Desflurane for Maintenance of Ambulatory Anesthesia. AB - Background: Ambulatory surgeries demand safe anesthesia with faster recovery which makes it expensive due to the cost of inhalational anesthetic agents such as sevoflurane and desflurane. Isoflurane is inexpensive agent but can cause delayed recovery. The aim of this study was to evaluate cost-benefit ratio of all three agent with respect to recovery and safety profile. Materials and Methods: Patients posted for elective ambulatory surgeries were divided into three groups. Suitable size laryngeal mask airway was inserted following induction with propofol and vecuronium. Anesthesia was maintained on low-flow anesthesia with inhalational agent as isoflurane for Group I, sevoflurane for Group II and Group III received desflurane. Patients were monitored for recovery as per modified Aldrete score and as per postanesthesia discharge scoring system for discharge from hospital. Cost analysis was done by Dion's formula. Statistical analysis was done with analysis of variance for recovery profile, Chi-square test for safety profile and Kruskal Wallis test for cost comparison between groups. Results: Patient characteristics and duration of anesthesia were similar in all three groups. Time to eye-opening was significantly less with desflurane than sevoflurane and isoflurane (P = 0.001). Time to home readiness was similar in all three groups (P = 0.451). The incidence of airway irritation, pain, and nausea/vomiting was similar in all three groups. Cost of Group I was statistically lower than other two groups (P = 0.00). Conclusion: Home readiness and safety profile were comparable between agents; the cost involved was the least with isoflurane. PMID- 29284843 TI - Gastric Volume and Its Relationship to Underlying Pathology or Acid-suppressing Medication. AB - Background: Pulmonary aspiration during sedation is a major concern for sedation providers, making identifying high-risk patients a priority. Gastric fluid volume (GFV), an accepted risk factor for aspiration, has not been well characterized in fasting children. We hypothesized that GFV would increase with gastrointestinal (GI) pathology and decrease with regular acid-suppressor use. Aims: The primary objective was to determine baseline GFV in fasting children. The secondary objectives were to evaluate the effect of GI pathology and regular use of acid suppressing medications on GFV. Settings and Study Design: This was prospective, observational study. Materials and Methods: We endoscopically aspirated and measured GFV of 212 children fasting for >6 h who were sedated for esophagogastroduodenoscopy (EGD). Inclusion criteria were children up to 21 years of age, with the American Society of Anesthesiologists physical Status I and II presenting for elective EGD. After determining baseline GFV, the effect of GI pathology and effect of regular acid-suppressing medication use on GFV was analyzed. Statistical Analysis: Analysis of variance was used to compare the GFV among ages and pathology and medication groups. Student's t-test was used to compare GFV between genders and also to compare GFV in confounder analyses. Results: For the studied 212 children, average GFV was 0.469 +/- 0.448 mL/kg (0 2.663 mL/kg). We found no association between GI pathology and GFV (P = 0.147), or acid-suppressor use and GFV (P = 0.360). Conclusions: Average GFV in this study falls within the range of prior EGD-measured GFV in fasting children. Contrary to our hypothesis, we found no association between pathologies or regular acid-suppressor use on GFV. On the basis of GFV, children with GI disorders or those using acid-suppressors do not appear to pose an increased risk of aspiration. Future studies should discern differences in effects on GFV of immediate preprocedural versus the regular use of acid-suppressing medications. PMID- 29284844 TI - Comparative Effects of Buprenorphine and Dexmedetomidine as Adjuvants to Bupivacaine Spinal Anaesthesia in Elderly Male Patients Undergoing Transurethral Resection of Prostrate: A Randomized Prospective Study. AB - Background and Aims: Transurethral resection of the prostate is a commonly performed urological procedure in elderly men with spinal anaesthesia being the technique of choice. Use of low-dose spinal anesthetic drug with adjuvants is desirable. This study compares the sensorimotor effects of addition of buprenorphine or dexmedetomidine to low-dose bupivacaine. Methods: Sixty patients were randomly allocated to three different groups. All received 1.8 mL 0.5% hyperbaric bupivacaine intrathecally. Sterile water (0.2 mL) or buprenorphine (60 MUg) or dexmedetomidine (5 MUg) was added to control group (Group C), buprenorphine group (Group B), and dexmedetomidine group (Group D), respectively. Time to the first analgesic request was the primary objective, and other objectives included the level of sensory-motor block, time to two-segment regression, time to S1 sensory regression and time to complete motor recovery. ANOVA and post hoc test were used for statistical analysis. The value of P < 0.05 was considered statistically significant. Results: All sixty patients completed the study. Postoperative analgesia was not required in the first 24 h in a total of 10 (50%), 12 (60%) and 15 (75%) patients in groups C, B, and D, respectively. Time to S1 regression was 130 +/- 46 min (Group C), 144 +/- 51.3 min (Group B) and 164 +/- 55.99 min (Group D), P = 0.117. Time to complete motor recovery was 177 +/- 56.9 min (Group C), 236 +/- 60 min (Group B) and 234 +/- 61.71 min (Group D), P < 0.001. Conclusion: Addition of buprenorphine (60 MUg) or dexmedetomidine (5 MUg) to intrathecal bupivacaine for transurethral resection prolongs the time to the first analgesic request with comparable recovery profile. PMID- 29284845 TI - Comparison of Efficacy of Oral versus Regional Clonidine for Postoperative Analgesia following Ilioinguinal/iliohypogastric Block in Children: A Prospective, Randomized, Double-blinded, Placebo-controlled Study. AB - Background: Clonidine improves quality and prolongs the duration of analgesia in ilioinguinal/iliohypogastric nerve block when given along with local anesthetic and as well as premedication. The objective of this study was to compare the efficacy of oral and regional clonidine for postoperative analgesia in pediatric population after ilioinguinal/iliohypogastric block. Materials and Methods: Sixty children aged between 1 and 8 years scheduled for elective hernia surgery were randomly allocated to three groups. Group I received oral midazolam and regional bupivacaine, Group II received oral midazolam with oral clonidine and regional bupivacaine, and Group III received oral midazolam and regional clonidine with bupivacaine. Preoperative sedation and separation score and postoperative duration and quality of analgesia, analgesic need, sedation score, and side effects of clonidine were assessed up to 6 h, postoperatively. Results: Duration of analgesia was prolonged in Group II (2.83 +/- 2.01 h) and Group III (4.43 +/- 2.29 h) compared to Group I (3.98 +/- 2.58 h), but the difference was not statistically significant (P = 0.161). Analgesic requirement was comparable between all the groups intraoperatively (P = 0.708) and postoperatively (P = 0.644). Group II had better parental separation (P < 0.001) and sedation score (P < 0.001) compared to Group I and III. Postoperatively, patients of Group II and III were more sedated compared to Group I up to 120 min. Adverse effects of clonidine were equally distributed in all the groups. Conclusion: Both oral and regional clonidine was equally efficacious in prolongation of duration and quality of analgesia. Oral clonidine produces better preoperative sedation and parenteral separation which is an added advantage in pediatric population. PMID- 29284846 TI - Comparison of the Intravenous and Epidural Administration of Tumor Necrosis Factor-alpha Antagonists in an Experimental Rat Pain Model. AB - Introduction: Inflammatory cytokines secreted from the nucleus pulposus are thought to lead to lumbar nerve root compression-like symptoms. Tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine, likely plays an important role in lumbar disc hernia-related leg pain. In this experimental study, we compared the effectiveness of TNF-alpha antagonists administered through the intravenous or epidural route in lumbar spine pathologies. Materials and Methods: After ethics committee approval had been obtained, 24 Sprague Dawley male rats aged 70-90 days and weighing 250-300 g each were allocated to four groups. In Group I, only the surgical procedure was performed; in Group II, 1 ml of saline solution was administered into the epidural field; in Group III, 10 mg/kg of infliximab was administered into the coccygeal vein; and in Group IV (epidural group), 25 mg of etanercept was administered into the epidural region. Results: When the left leg pull values were analyzed on day 14, whereas there was not a significant difference among the three groups, a decreasing difference was observed in Group IV (P < 0.05). When the 21st and 28th day left leg pull values were compared between groups, the values from Groups II, III, and IV were significantly lower than those of Group I (P < 0.05). Conclusion: The absence of a difference between the baseline values and left leg pull values on days 14, 21, and 28 in Group IV indicates that recovery began on day 21 with the epidural administration of etanercept. There was no difference between intravenous saline administration and intravenous infliximab administration with regard to the start of the recovery. In the present study of rats with discopathy, TNF-alpha antagonists administered epidurally led to earlier recovery from radiculopathy related allodynia compared to intravenous administration. PMID- 29284847 TI - Evaluation of Preoperative Flupirtine in Ambulatory Functional Endoscopic Sinus Surgery: A Prospective, Double-Blind, Randomized Controlled Trial. AB - Background: Functional endoscopic sinus surgery (FESS) is the mainstay therapeutic management for nasal pathologies. We evaluated flupirtine, a centrally acting analgesic, for producing perfect perioperative conditions in FESS for adults in a day-care setting. Materials and Methods: Sixty-two patients (25-40 years) scheduled for FESS under general anesthesia were randomly divided into Group F (n = 31) receiving preoperative flupirtine (100 mg) and Group C (n = 31) receiving identical-looking placebo capsule per oral 60 min before induction of anesthesia. Perioperative Nasal bleeding and surgeon's satisfaction score during operation; amount and number of patients receiving fentanyl, propofol, and esmolol infusion for analgesia; maintenance of desired bispectral index (BIS) and deliberate hypotension, respectively. Postanesthesia Care Unit (PACU) and hospital stay, hemodynamic parameters, and side effects were all recorded for each patient. Results: Significantly, less number of patients and less dosage of esmolol were required (P = 0.0040 and 0.0001, respectively) in Group F as compared to that in Group C. Again, number of patients requiring fentanyl and dosage of the same drug was significantly lower in Group F. Dose of propofol for the maintenance of BIS was significantly lower in Group F. However, the duration of controlled hypotension was almost similar in both groups. Group F patients suffered significantly less nasal bleeding and surgeon's satisfaction score was also high in this group. Discharge time from PACU and hospital was similar between two groups without any appreciable side effects. Conclusion: Flupirtine as a premedication found to be providing more favorable perioperative hemodynamic conditions, analgesia and thus allowing less nasal bleeding as well as more surgeons' satisfaction score. PMID- 29284848 TI - Utility of Acute Normovolemic Hemodilution in Major Surgeries in Rural Area: A Prospective Comparative Study from North India. AB - Introduction: Easy availability of autologous blood is difficult in rural areas. Acute normovolemic hemodilution (ANH) has been found to be an effective alternative in major surgeries where we are expecting major blood loss. Patients and Methods: A prospective comparative study was designed to evaluate the utility of ANH patients (patients receiving autologous blood) during major operations done at MRA Medical College Ambedkar Nagar, Uttar Pradesh, India. during from September 2015 to September 2016. A total of 60 patients undergoing major surgeries were randomly assigned into two groups of thirty patients' each. Group I received homologous blood intraoperative only when required. In Group II ANH was initiated to a target hematocrit of 30% after induction of anesthesia. Various parameters such as demographic, biochemical, and hemodynamic were compared. Results: The mean value of blood withdrawn in ANH group was 650.5 +/- 228 ml and it was replaced with an equal volume of 6% hydroethyl starch. There was no statistically significant variation in mean hemocrits levels in both the groups at various stages of the study. Hematocrits decreased significantly in both the groups at various stages as compared to preoperative values. The heart rate and mean blood pressure were almost similar and without statistically significant differences in both groups. Surgical blood loss in Group I was 895.29 +/- 568.30 ml as compared to 765 +/- 506 ml in Group II. The difference was statistically insignificant (P >= 0.05). The mean volume of homologous blood transfused in Group I was 850.71 +/- 318.29 ml, as compared to nil in Group II which was statistically significant (P < 0.05). Conclusion: It concludes that ANH up to a target hematocrit of 30% is safe and effective in reducing the need for homologous blood in various major surgeries in institutes in rural areas. PMID- 29284849 TI - Comparison of the Efficacy and Safety of Morphine and Fentanyl as Adjuvants to Bupivacaine in Providing Operative Anesthesia and Postoperative Analgesia in Subumblical Surgeries Using Combined Spinal Epidural Technique. AB - Introduction: The combined spinal epidural (CSE) technique involves intentional subarachnoid blockade and epidural catheter placement during the same procedure to combine their individual best features, to reduce the total drug dosage and avoid their respective disadvantages. The addition of opioids to local anesthetics (bupivacaine) for CSE anesthesia (CSEA) is increasingly common to enhance the block. Neuraxial fentanyl is more potent and has shorter duration of action than morphine which provides prolonged anesthesia and analgesia, however at the cost of increased incidence of adverse effects like delayed respiratory depression. Aims and Objectives: The aim is to compare the efficacy and safety of morphine and fentanyl as adjuvants to bupivacaine in subumblical surgeries using CSE technique. The characteristics of sensory and motor block, intergroup variations in pain, cardiorespiratory parameters, and adverse effects were compared between the two groups. Materials and Methods: A total of 60 patients belonging to physical status American Society of Anesthesiologists Classes I and II, aged 18-60 years were randomized into two groups: Group A (n = 30) received intrathecal 0.5% heavy bupivacaine 12.5 mg and morphine 2.85 MUg/kg; Epidural Anesthetic bolus (when required/T11Regression) 8 ml 0.25% isobaric bupivacaine and 0.04 mg/kg morphine; Epidural Analgesic bolus (postoperative visual analog scale [VAS] score >30) 5 ml 0.125% isobaric bupivacaine and 0.04 mg/kg morphine and Group B (n = 30) received intrathecal 0.5% heavy bupivacaine 12.5 mg and fentanyl 0.35 MUg/kg; Epidural Anesthetic bolus (when required/T11Regression) 8 ml 0.25% isobaric bupivacaine and 0.7 MUg/kg fentanyl; Epidural Analgesic bolus (postoperative VAS score >30) 5 ml 0.125% isobaric bupivacaine and 0.7 MUg/kg fentanyl. Results and Conclusion: Group A had significantly prolonged two segment regression time, T11 regression time, lower mean VAS score, prolonged effective analgesia, and required lesser number of epidural boluses in 24 h as compared to Group B (P < 0.001). There were no significant differences between the groups considering onset of sensory block, duration of motor block, median maximum sensory block level achieved after spinal component (T6), median highest sensory block level achieved after epidural anesthetic bolus (T7-4seg enhancement after regression to T11), cardiorespiratory parameters and adverse effects. None of the patients had respiratory depression nor was there any failure of spinal/epidural component of CSEA. Thus, addition of morphine to bupivacaine in CSEA produced prolonged effective anesthesia and postoperative analgesia compared to addition of fentanyl to bupivacaine without producing undue adverse effects. PMID- 29284850 TI - A Comparative Study of Dexmedetomidine and Diltiazem for Attenuating Pressor Responses to Laryngoscopy and Endotracheal Intubation: A Double-blind, Randomized Study. AB - Context: Endotracheal intubation has been suggested to be one of the most invasive stimuli in anesthesia, particularly during induction and after tracheal intubation. The present study aims to evaluate the efficacy of dexmedetomidine as compared to diltiazem on hemodynamic response to laryngoscopy and intubation. Aims: To assess and compare the hemodynamic response of dexmedetomidine as compared to diltiazem in patients undergoing laryngoscopy and intubation and rate and type of side effects of the drugs if any. Settings and Design: This study design was a prospective, randomized, and double-blind trial. Subjects and Methods: The patients were randomly allocated into three groups: Group I (control), Group II (dexmedetomidine), and Group III (diltiazem) of 45 patients each. Group I (n = 45): 0.9% NaCl 10 ml was given to the patients over 10 min before intubation in Group I (control). Group II (n = 45): injection dexmedetomidine (0.5 MUg/kg) in 10 ml normal saline was given to the patients over 10 min before intubation. Group III (n = 45): injection diltiazem (0.3 mg/kg) in 10 ml normal saline was given to the patients over 10 min before intubation. Statistical Analysis Used: The data so collected were subjected to statistical analysis using Statistical Package for the Social Sciences version 15.0. Results: Mean percentage increase in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) following intubation was 17.90%, 19.96%, and 19.04%, respectively, in control group, 9.04%, 6.32%, and 7.53%, respectively, in dexmedetomidine group, and 12.30%, 10.32%, and 11.14%, respectively, in diltiazem groups. Statistically, there was a significant difference in postintubation SBP, DBP, and MAP of the three groups (P < 0.001). Dexmedetomidine at a dose of 0.5 MUg/kg showed to have a better attenuation of pressor response as compared to diltiazem at a dose of 0.3 MUg/kg. Conclusions: Both dexmedetomidine and diltiazem were safe and effective in attenuating the hemodynamic response following laryngoscopy and endotracheal intubation; however, between two trial drugs, dexmedetomidine had a better response. PMID- 29284851 TI - Comparison of I-gel versus Endotracheal Tube in Patients Undergoing Elective Cesarean Section: A Prospective Randomized Control Study. AB - Background and Aim: Physiological changes during pregnancy and the sympatho adrenalstimulation during larynoscopy and intubation leads to evaluation of safe devices to secure airway during cesarean section under general anesthesia. I-gel, recently emerging effective supra glottic device found safe during general anesthesia in cesarean section. Aim of the study is to compare the hemodynamic disturbances and airway related complications of I-gel and Endotracheal tube in patients undergoing cesarean section under general anesthesia. Material and Methods: Eighty ASA II pregnant patients posted for elective LSCS were randomly divided into two groups of 40 each (n = 40). According to the group they were inserted either I-gel (Group I) or ETT (Group E). Insertion time, ease of intubation, hemodynamics during insertion and Extubation, airway related complications like sore throat, blood on the device, dysphagia, regurgitation, nausea, vomiting, aspiration and laryngospasm were noted and compared. Statistical analysis was done by using unpaired t test, chi square test and fisher's test. P value of <0.05 was considered as significant. Results: The demographic parameters, ease of insertion, insertion times and adequacy of ventilation were comparable between the groups (P > 0.05). 8 out of 40 patients in Group E had difficult intubation (P < 0.01). More than 20% of rise in MAP and HR were found during intubation and Extubation in Group E (40 out of 40 patients) which was statistically significant when compared to Group I (P < 0.001). Post operative sore throat significantly high in Group E (30 out of 40) (P < 0.001) when compared to Group I (4 out of 40). Conclusion: Easier insertion with less hemodynamic disturbances and very low incidence of sore throat I-gel found to be safer device to secure the airway in patients undergoing LSCS under general anesthesia. PMID- 29284852 TI - A Comparative Study of Postoperative Analgesia Provided by Ultrasound-Guided Transversus Abdominis Plane Block Using Two Concentrations of Bupivacaine in Patients Undergoing Inguinal Hernia Repair. AB - Background: Pain after open inguinal hernia surgery can be moderate to severe and is known to prolong hospital stay and delay return to normal daily activities. Settings: A randomized controlled trial conducted in the Department of Anesthesiology in a tertiary care hospital. Aims and Objectives: To compare the efficacy of postoperative analgesia provided by equal volumes of 0.125% and 0.25% bupivacaine administered in an ultrasound (US)-guided transversus abdominis plane (TAP) block in patients undergoing unilateral inguinal hernia repair. Materials and Methods: After obtaining Institutional Ethics Committee approval and informed consent, sixty patients posted for inguinal hernia repair were recruited. Randomization was done using a sealed envelope technique. Patients were divided into two groups; Group 0.125 received 20 ml of 0.125% bupivacaine and Group 0.25 received 20 ml of 0.25% bupivacaine through US-guided TAP block at the end of surgery. Visual analog scale (VAS) scores and duration of analgesia were recorded. Results: There was no significant difference in the VAS scores among both groups. The duration of analgesia provided by 0.25% bupivacaine was significantly longer than that provided by 0.125% (Group 0.125 - 355.67 +/- 118.88 min and Group 0.25 - 635.73 +/- 195.58 min; P < 0.05). No complications were noted in both groups. Conclusion: The duration of analgesia provided by 0.25% bupivacaine was significantly longer than that provided by 0.125% bupivacaine through US-guided TAP block in inguinal hernia repair. PMID- 29284853 TI - Comparison of Local Wound Infiltration with Ropivacaine Alone or Ropivacaine Plus Dexmedetomidine for Postoperative Pain Relief after Lower Segment Cesarean Section. AB - Context: Dexmedetomidine, alpha2-adrenergic agonist, when coadministered with local anesthetics, improves the speed of onset, duration of analgesia and decreases the dose of local anesthetic used. Aims: The aim of this study was to compare the efficacy of local subcutaneous wound infiltration of ropivacaine alone with ropivacaine plus dexmedetomidine for postoperative pain relief following lower segment cesarean section (LSCS). Subjects and Methods: The study was a prospective, randomized control, double-blind study. Sixty female patients belonging to physical status American Society of Anesthesiologists Grade I or II scheduled for LSCS under spinal anesthesia were randomly allocated into two groups of thirty patients each. Group A: local subcutaneous wound infiltration of 0.75% ropivacaine (3 mg/kg) diluted with normal saline to 40 ml. Group B: local subcutaneous wound infiltration of 0.75% ropivacaine (3 mg/kg) plus dexmedetomidine (1.5 MUg/kg) of the body weight diluted with normal saline to 40 ml. Standard spinal anesthesia technique was used and LSCS was conducted. The allocated drug was administered by local subcutaneous wound infiltration before closure of the skin. In postoperative period, pain was assessed using visual analog scale (VAS) over a period of 24 h, time of giving first rescue analgesic consumption, mean analgesic consumption, patient satisfaction, and incidence of side effects in 24 h postoperative period was noted. Statistical Analysis Used: All observations were tabulated and statistically analyzed using Chi-square test and unpaired t-test. Results: A total number of patients requiring rescue analgesic, mean VAS each time rescue analgesic was given, and the mean analgesic required in 24 h postoperative period was lesser in Group B than in Group A. Conclusions: Dexmedetomidine added to ropivacaine for the surgical wound infiltration significantly reduces postoperative pain and rescue analgesic consumption in patients undergoing LSCS. No serious adverse effects were noted. PMID- 29284854 TI - Clinical Study to Determine the Efficacy of Clonidine as an Adjuvant to Intrathecal Bupivacaine in Patients Undergoing Cesarean Section. AB - Introduction: Spinal anesthesia with bupivacaine is associated with hypotension and inadequate postoperative analgesia. The addition of clonidine as an adjuvant to intrathecal bupivacaine is beneficial in reducing the dose of the local anesthetic and also provides prolonged postoperative analgesia. Methodology: One hundred and five American Society of Anesthesiologists physical status Classes 1 and 2 parturient women undergoing elective cesarean section were randomly divided into three groups. Patients in Group C (control) received 2 ml of 0.5% of heavy bupivacaine (10 mg) with 0.5 ml of 0.9% saline to a total volume of 2.5 ml, those in Group H (high dose of bupivacaine) received 2 ml of 0.5% of heavy bupivacaine (10 mg) with 1 MUg/kg of clonidine and 0.9% saline to make a total volume of 2.5 ml, and those in Group L (low dose of bupivacaine) received 1.5 ml of 0.5% of heavy bupivacaine (7.5 mg) with 1 MUg/kg clonidine and 0.9% saline to make a total volume of 2.5 ml. Patients were observed for onset and duration of sensory and motor block and for postoperative analgesia. Results: Patients who received clonidine as adjuvant had effective prolonged postoperative analgesia (Group H - 480 +/- 40 min, Group L - 480 +/- 34 min) as compared to control group (180 +/- 19 min). Conclusion: The dose of intrathecal bupivacaine 0.5% was effectively reduced to 7.5 mg by adding 1 MUg/kg of clonidine as adjuvant in patients undergoing elective cesarean section. PMID- 29284855 TI - Intrathecal Hyperbaric Bupivacaine with Varying Doses of Buprenorphine for Postoperative Analgesia after Cesarean Section: A Comparative Study. AB - Background: Postoperative analgesia after cesarean section poses unique clinical challenges to anesthesiologist. Intrathecal buprenorphine is a promising drug for postoperative analgesia. Aim: The aim of this study was to compare the efficacy of two doses of buprenorphine (45 MUg and 60 MUg) as an adjuvant to hyperbaric bupivacaine for postoperative analgesia in cesarean section. Setting and Design: Prospective randomized double-blind controlled study involving ninety parturients posted for elective cesarean section under subarachnoid block. Materials and Methods: Group A (n = 30) received 1.8 ml of 0.5% hyperbaric bupivacaine with 45 MUg buprenorphine, Group B (n = 30) received 1.8 ml 0.5% hyperbaric bupivacaine with 60 MUg buprenorphine, Group C (n = 30) received 1.8 ml of 0.5% hyperbaric bupivacaine with 0.2 ml normal saline, respectively. Following parameters were observed: onset and duration of sensory block, postoperative pain scores based on visual analog scale (VAS), rescue analgesic requirement, and maternal and neonatal side effects if any. Statistical Analysis: Unpaired t-test and Chi square test were used. Results: Duration of postoperative analgesia was significantly prolonged in Groups A and B in comparison to Group C and it was longest in Group B. Rescue analgesic requirement and VAS score were significantly lower in the buprenorphine groups. No major side effects were observed. Conclusion: Addition of buprenorphine to intrathecal bupivacaine prolonged the duration and quality of postoperative analgesia after cesarean section. Increasing the dose of buprenorphine from 45 MUg to 60 MUg provided longer duration of analgesia without increase in adverse effects. PMID- 29284856 TI - ProSeal Laryngeal Mask Airway versus Cuffed Endotracheal Tube for Laparoscopic Surgical Procedures under General Anesthesia: A Random Comparative Study. AB - Context: The Proseal LMA(PLMA), which has been designed especially for positive pressure ventilation and protection against aspiration can act as an alternative to Endotracheal Tube (ETT) as an effective airway device for patients undergoing elective Laparoscopic surgeries. Aims: To compare the efficacy and safety of PLMA with ETT in patients undergoing Laparoscopic surgeries under general anaesthesia. Settings and Design: A prospective, randomized study was conducted in a tertiary care teaching hospital with 60 patients of ASA grade I/II undergoing elective Laparoscopic surgery under general anaesthesia. Ethical committee clearance and written consent taken. The patients were randomly divided into two equal groups to the PLMA group (Group S) and to the ETT group (Group C) Heart rate (HR), mean blood pressure (MAP), ETCO2 values, intraoperative complications such as regurgitation- aspiration, and Postoperative complications such as nausea or vomiting, throat soreness and oral injuries were monitored. Results: There was no difference demographically. Insertion success rate was 100% for both the groups. The mean increase in HR was seen all throughout the duration of the surgery to 8 % above the baseline in Group C and to 3% above the baseline in Group S. On comparing the MAP in Group C, there was a increased by 2.5% to 78.300 +/- 14.2615 mmHg as compared to an increase by 5% to 76.233 +/- 6.2072 mmHg in Group S. EtCO2 showed a rise in both groups after pneumoperitoneum, which returned to baseline values after completion of surgery. Gastric aspirate values showed no difference in each group. Post op complications were seen mainly in Group C with statistical significance. Conclusions: A properly positioned PLMA is a suitable and safe alternative to ETT for airway management in adequately fasted, adult patients undergoing elective Laparoscopic surgeries. PMID- 29284857 TI - To Compare the Effect of Two Different Doses of Dexmedetomidine on the Attenuation of Airway and Pressor Response during Tracheostomy Tube Change in Traumatic Brain Injury Patients. AB - Background: Tracheostomy tube (TT) change is the common procedure in trauma Intensive Care Unit (ICU) and almost always associated with cough reflex, increase in blood pressure, and heart rate. Dexmedetomidine (DEX) is a selective alpha2-adrenergic receptor agonist well studied for the prevention of pressor response during laryngoscopy and extubation, but literature on prevention of pressor response during TT change is lacking. Aims: The aim of this study is to compare two doses (0.5 and 1.0 MUg/kg) of DEX for prevention of cough and pressor response during TT change in traumatic brain injury patients. Settings and Design: Prospective randomized, double-blind trial. Materials and Methods: Sixty tracheostomized traumatic brain injury patients in ICU scheduled for TT change were randomized to two equal groups: Group A to receive DEX 0.5 MUg/kg and Group B to receive DEX 1.0 MUg/kg. Calculated dose of studied drug was given by infusion pump over 10 min after dilution in 50 ml. Hemodynamic parameters, cough reflex, and adverse event were recorded and statistically analyzed. Statistical Analysis: Statistical analysis was done with nonpaired (two tailed, independent) Student's t-test for continuous data. Demographic data were compared using Pearson's chi2 test. P < 0.05 was considered to be statistically significant. Results: Both doses of DEX were able to attenuate the hemodynamic response of tracheal stimulation and cough reflex. Cough reflex was better controlled with 1.0 MUg/kg dose but associated with increased incidence of hypotension and bradycardia. Conclusions: We conclude that 0.5 MUg/kg dose provides desired attenuation of hemodynamic response during TT change without any significant adverse events. PMID- 29284859 TI - Transversus Abdominis Plane Block versus Ilioinguinal/Iliohypogastric Nerve Block with Wound Infiltration for Postoperative Analgesia in Inguinal Hernia Surgery: A Randomized Clinical Trial. AB - Background: Various analgesic modalities have been used for postoperative analgesia in patients undergoing inguinal hernia surgery. In this randomized clinical trial, we have compared the analgesic efficacy of transversus abdominis plane (TAP) block with that of ilioinguinal/iliohypogastric (IIIH) nerve block with wound infiltration in patients undergoing unilateral open inguinal hernia repair. Aim: The primary objective of this study was to compare the efficacy of postoperative analgesia of ultrasound-guided TAP block and IIIH block with wound infiltration (WI) in patients undergoing open inguinal hernia surgery. Settings and Design: This was a randomized clinical trial performed in a tertiary care hospital. Materials and Methods: Sixty patients scheduled for hernia repair were randomized into two groups, Group T and Group I. Postoperatively, under ultrasound guidance, Group T received 20 ml of 0.25% ropivacaine - TAP block and Group I received 10 ml of 0.25% ropivacaine - IIIH block + WI with 10 ml of 0.25% ropivacaine. The primary outcome measure was the time to rescue analgesia in the first 24 h postoperatively. Fentanyl along with diclofenac was given as first rescue analgesic when the patient complained of pain. Statistical Analysis: Statistical comparisons were performed using Student's t-test and Chi-square test. Results: Mean time to rescue analgesia was 5.900 +/- 1.881 h and 3.766 +/- 1.754 h (P < 0.001) and the mean pain scores were 5.73 +/- 0.784 and 6.03 +/- 0.850 for Group TAP and IIIH + WI, respectively. Hemodynamics were stable in both the groups. One-third of the patients received one dose of paracetamol in addition to the rescue analgesic in the first 24 h. There were no complications attributed to the block. Conclusion: As a multimodal analgesic regimen, definitely both TAP block and IIIH block with wound infiltration have a supporting role in providing analgesia in the postoperative period for adult inguinal hernia repair. In this study, ultrasound-guided TAP block provided longer pain control postoperatively than IIIH block with WI after inguinal hernia repair. There were no complications attributed to the blocks in either of the group. PMID- 29284858 TI - The Influence of Two Different Doses of Magnesium Sulfate on Intraocular Pressure Variations after Injection of Succinylcholine and Endotracheal Intubation: A Prospective, Randomized, Parallel Three-Arm, Double-blind, Placebo-controlled Clinical Trial. AB - Background: The use of succinylcholine for rapid sequence induction in patients with open globe injuries may be detrimental to the eye. Aim: The aim of this study is to determine if the premedication with magnesium sulfate (MgSO4) could attenuate the increase in intraocular pressure (IOP) associated with succinylcholine injection and intubation. Setting: Operation theaters in a tertiary care University Hospital between December 2014 and July 215. Design: This was a prospective, randomized, parallel three-arm, double-blind, placebo controlled clinical trial. Participants: One hundred and thirteen patients' physical status ASA Classes I and II underwent elective cataract surgery under general anesthesia. Patients and Methods: These patients allocated into three groups: Group C (control group) received 100 ml normal saline, Group M1 received 30 mg/kg MgSO4 in 100 ml normal saline, and Group M2 received 50 mg/kg MgSO4 in 100 ml normal saline. IOP, mean arterial pressure (MAP), and heart rate (HR) reported at 5-time points related to study drug administration. In addition, any adverse effects related to MgSO4 were recorded. Intragroup and between-groups differences were examined by analysis of variance test. Results: We noticed a significant decrease in IOP in M1 (n = 38) and M2 (n = 37) groups as compared with C group (n = 38) after study drugs infusion, 2 and 5 min after intubation, P < 0.001. While the difference between M1 and M2 groups was insignificant, P = 0.296 and P = 0.647, respectively. There was a significant decrease in MAP and HR in M1 and M2 groups as compared with C group 2 and 5 min after intubation, P = 0.01. While the difference between M1 and M2 groups was insignificant, P = 1. Conclusion: MgSO4 30 mg/kg as well as 50 mg/kg effectively prevented the rise in IOP, MAP, and HR associated with rapid sequence induction by succinylcholine and endotracheal intubation. PMID- 29284860 TI - Effect of Locally Administered Dexmedetomidine as Adjuvant to Levobupivacaine in Supraclavicular Brachial Plexus Block: Double-blind Controlled Study. AB - Context: Brachial plexus block is effective with good postoperative analgesia in upper limb surgery has gained importance as it safe, low cost, and maintains stable hemodynamics intraoperatively. To decrease the onset time and prolong the duration of nerve block bicarbonate, opioids (morphine, fentanyl, etc.), sympathomimetic agents (epinephrine, phenylephrine, etc.), alpha-2 agonists (clonidine and dexmedetomidine), calcium channel blocker (verapamil), magnesium sulfate, etc., were studied with local anesthetics and their isomers. For their sedative, analgesic, perioperative sympatholytic, and cardiovascular stabilizing effects with reduced anesthetic requirements, alpha-2 adrenergic receptor agonists, such as more potent and highly selective dexmedetomidine, have been the focus of interest for regional anesthesia. Intravenous dexmedetomidine infusion resulted in significant opioid-sparing effects as well as a decrease in inhalational anesthetic requirements. Animal studies proved that dexmedetomidine enhances sensory and motor blockade along with increased duration of analgesia. In humans, dexmedetomidine has also shown to prolong the duration of block and postoperative analgesia when added to local anesthetic in various regional blocks. Bupivacaine, the widely used local anesthetic in regional anesthesia, is available in a commercial preparation as a racemic mixture (50:50) of its two enantiomers: levobupivacaine, S (-) isomer and dextrobupivacaine, R (+) isomer. Severe central nervous system and cardiovascular adverse reactions reported in the literature after inadvertent intravascular injection or intravenous regional anesthesia have been linked to the R (+) isomer of bupivacaine. The levorotatory isomers were shown to have a safer pharmacological profile with less cardiac and neurotoxic adverse effects. The decreased toxicity of levobupivacaine is attributed to its faster protein binding rate. The pure S (-) enantiomers of bupivacaine, i.e., ropivacaine and levobupivacaine were thus introduced into the clinical anesthesia practice. Such an increased usage mandates the documentation of evidence-based literature with regard to risk and safety concerns as well as clinical issues related to levobupivacaine. This study is designed to assess the efficacy of adding dexmedetomidine to levobupivacaine during placement of supraclavicular brachial plexus blockade. Materials and Methods: This prospective observational double-blinded study was conducted over a 1-year period among randomly selected seventy (n = 35) American Society of Anesthesiologists Classes I and II patients of ages between 18 and 60 years of both sexes scheduled to undergo upper limb surgery. With nerve locator, levobupivacaine (0.5%) 28 ml and 2 ml normal saline for Group L and levobupivacaine (0.5%) 28 ml and 0.75 MUg/kg dexmedetomidine made up a solution of 2 ml, for Group D, a total 30 ml will be injected locally, in both the groups. Onset and duration of sensory and motor block will be assessed. Results and Discussion: One patient in Group L and two patients in Group D failed to achieve block within 30 min. Those three patients were then excluded from the analysis. Hence, the analysis was done by taking 34 patients in Group L and 33 patients in Group D. Onset of sensory and motor block was earlier in Group D (12.03 +/- 0.85 and 13.58 +/- 0.97) than Group L (14.32 +/ 1.15 and 15 +/- 0.98), and the difference is statistically significant (P < 0.0001). Duration of sensory and motor block was longer in Group D (563.94 +/- 15.60 and 495.15 +/- 10.34) than Group L (368.53 +/- 9.89 and 321.47 +/- 7.84), and the difference is also statistically significant (P < 0.0001). Duration of analgesia was longer in Group D (672.12 +/- 11.39) than Group L (506.47 +/- 9.497), and the difference is statistically significant (P < 0.0001). Heart rate and mean arterial pressure were well maintained within the presumed range of significant variation, i.e., 20% from baseline, though at some point of time, intergroup comparison was statistically significant. Visual analog scale score compared at the time for administration of rescue analgesic between the groups come out to be statistically significant. Conclusion: Addition of 0.75 MUg/kg dexmedetomidine to 0.5% levobupivacaine for supraclavicular plexus block shortens sensory and motor block onset time and extends sensory block, motor block, and analgesia duration. PMID- 29284861 TI - A Comparison of Intrathecal Dexmedetomidine and Neostigmine as Adjuvant to Ropivacaine for Lower Limb Surgeries: A Double-blind Randomized Controlled Study. AB - Objective: The primary objective of this study was to compare the analgesic effects of intrathecal ropivacaine with or without neostigmine or dexmedetomidine in lower limb surgeries. Secondary objectives were to study the characteristics of block, duration of analgesia, postoperative analgesic requirement, and associated side effects. Materials and Methods: Seventy-five patients posted for elective orthopedic lower limb surgeries under spinal anesthesia were randomly divided into three equal groups to receive intrathecal ropivacaine 0.5% alone (Group R), with adjuvant 5 MUg dexmedetomidine (Group R + D) or 50 MUg neostigmine (Group R + N). Time to achieve T10 sensory block, time to 2-segment regression, duration of regression to L4, maximum modified Bromage score and duration of analgesia were noted. The incidences of adverse events such as nausea, vomiting, hypotension, bradycardia, desaturation, shivering, and itching were also noted. Statistical analysis was performed using two sample t-test for normally distributed variables and Pearson's Chi-squared test for categorical data. The level of significance was set as P < 0.05. Results: Quality of motor and sensory blockage was significantly better in both Group R + D and Group R + N than Group R. Mean time to achieve T10 sensory block was lowest, time taken in regression of block by 2-segments and duration of regression to L4 was longest in Group R + D and was significant when compared to other groups. Adverse effects such as nausea and vomiting were highest in Group R + N and was statistically significant as compared to other groups. Conclusions: Dexmedetomidine is a better intrathecal adjuvant emerged as compared to neostigmine due to faster onset of anesthesia, better intra- and post-operative analgesia and prolonged duration of motor and sensory blockade without significant increase in adverse effects. PMID- 29284862 TI - Comparison of Enhancement of Analgesic Effect of Intrathecal Neostigmine by Intrathecal Clonidine and Transdermal Nitroglycerin Patch on Bupivacaine Spinal Anesthesia. AB - Background: Relief of pain is very important goal intraoperatively and postoperatively. Neostigmine has been used successfully intrathecally with other agents such as clonidine and opioids for pain relief. Aims: This study aims to compare and evaluate the efficacy and safety of combining intrathecal (IT) neostigmine with IT clonidine and transdermal nitroglycerin (tNTG) patch for the relief of pain in patients after surgery. Settings and Design: This was a randomized, prospective, and comparative study. Materials and Methods: In this study, recruited patients were randomly allocated into three groups. Groups I, II, and III received intrathecally 25 MUg of neostigmine + 15 mg hyperbaric 0.5% bupivacaine, 25 MUg of neostigmine + 25 MUg clonidine + 15 mg hyperbaric 0.5% bupivacaine, and 25 MUg of neostigmine + tNTG patch (3 cm * 5 cm, 5 mg/24 h) +15 mg hyperbaric 0.5% bupivacaine, respectively. Heart rate, mean arterial pressure, analgesic properties, and complications were assessed and compared among groups. Statistical Analysis: Mean and standard deviation were calculated. Test of analysis between two groups was done by t-test and among three groups by ANOVA, then P value was calculated. Results: Duration of analgesia was significantly longer in Group III in comparison to Group II (7.142 +/- 1.81 vs. 4.408 +/- 0.813 h) and was significantly longer in Group II in comparison to Group I (4.408 +/- 0.813 vs. 2.583 +/- 0.493 h). Analgesic requirement was significantly less in Group III in comparison to Group II (1.9 +/- 0.76 vs. 2.5 +/- 0.51) and was significantly less in Group II in comparison to Group I (2.5 +/- 0.51 vs. 3.1 +/- 0.48). Sedation score was found significantly high in Group II than other groups. Conclusion: Both IT clonidine and tNTG patch with bupivacaine + neostigmine spinal anesthesia were found effective in pain control. Results were found better with tNTG patch. PMID- 29284863 TI - Evaluation of Effectiveness of Dexmedetomidine and Fentanyl-midazolam Combination on Sedation and Safety during Awake Fiberoptic Intubation: A Randomized Comparative Study. AB - Background: Awake fiberoptic intubation (AFOI) is a recommended technique for anticipated difficult airway. An ideal regime should provide patient comfort, cooperation, amnesia, hemodynamic stability, and blunt airway reflexes and maintain a patent airway with spontaneous ventilation. The aim of our study was to compare intubation conditions between dexmedetomidine and fentanyl-midazolam combination during AFOI. Methods: This prospective, randomized study was conducted on a total of sixty patients of the American Society of Anesthesiologists physical status I and II of either sex, in the age group of 18 60 years having predicted difficult intubation undergoing elective surgeries and the patients were allocated to two groups of thirty patients each. After premedication and topicalization of airways, dexmedetomidine group (Group I, n = 30) received dexmedetomidine 1 MUg/kg over 10 min and midazolam-fentanyl group (Group II, n = 30) received fentanyl 2 MUg/kg plus midazolam 0.02 mg/kg over 10 min. Adequacy of intubation condition was evaluated by cough score and postintubation score. Incidence of desaturation, hemodynamic changes, and sedation using Ramsay sedation scale were noted and compared between two groups. Results: The demographic characteristics were comparable in the two groups (P > 0.05). The mean Ramsay sedation score in Group I was 3.13 +/- 0.937 and Group II was 3.16 +/- 0.949, and the comparison between two groups was statistically insignificant (P = 0.891). Cough scores and postintubation scores were favorable in dexmedetomidine group than midazolam-fentanyl group and were statistically significant with P < 0.001 and 0.0001, respectively. Group I also showed better hemodynamics and less episodes of desaturation than Group II. Conclusions: Dexmedetomidine is more effective than midazolam-fentanyl during AFOI, as it provides better intubation condition, hemodynamic stability, and preservation of airway and spontaneous ventilation. PMID- 29284864 TI - Effect of Intravenous Magnesium Sulfate on the Minimum Alveolar Concentrations of Desflurane Using Bispectral Index Monitoring: A Prospective Randomized Double blind Controlled Study. AB - Background: Magnesium sulfate has been implicated to influence the minimum alveolar concentration (MAC) of various volatile anesthetics, but its effect on desflurane remains unanswered so far. Aim: To study the effect of perioperative intravenous magnesium sulfate on MAC of desflurane using bispectral index (BIS) monitoring. Settings: Operating room of a tertiary care hospital. Design: A prospective, randomized, controlled, double-blind clinical trial. Methods: Sixty American Society of Anesthesiologists Physical Status I/II patients aged 18-65 years and scheduled for breast conservative surgeries were randomized into three groups of 20 each. Control group (Group 1) was administered 100 ml normal saline (NS) as bolus followed by NS infusion. Magnesium (Mg) was administered as bolus of 40 mg/kg in 100 ml NS followed by NS infusion in Group 2 and as bolus of 40 mg/kg followed by infusion of 10 mg/kg/h of Mg in NS in Group 3. Anesthesia was induced with propofol, fentanyl, and atracurium. Dial setting of desflurane was adjusted to target a BIS of 45-55. Time from cessation of desflurane to beginning of spontaneous movement, time taken to respond to verbal commands, time of extubation, and time taken to reach BIS value of 70 were recorded. Statistical Analysis: Statistics was done using SPSS program using ANOVA and the Chi-square test for variables and a P < 0.05 was taken to indicate a significant difference. Results: No significant difference was present in MAC, end-tidal desflurane, and cumulative consumption of morphine. Recovery was similar in Group 2 and Group 3, but time to eye opening (P = 0.011), time to respond to verbal commands (P < 0.001), and time to extubate (P < 0.001) were significantly delayed when compared with patients in Group 1. Hemodynamic changes were comparable among three groups. Conclusions: From this study, we conclude that MACs of desflurane using BIS as a guide remains unaffected by perioperative infusion of magnesium sulfate. PMID- 29284865 TI - Comparison of Analgesic Efficacy of Caudal Dexamethasone with Intravenous Dexamethasone as an Adjuvant to Caudal Block in Pediatric Patients Undergoing Urogenital Surgeries. AB - Context: Caudal block is one of the most common regional anesthetic techniques employed in pediatric urogenital surgeries. Adjuvants play an important role to improve postoperative analgesia. Aims: The aim of this study was to evaluate the analgesic effect of dexamethasone when given systemically as against caudally as an adjuvant to caudal block. Subjects and Methods: In this randomized controlled study, sixty American Society of Anesthesiologists Physical Status I and II patients aged 3-6 years were randomly allocated into two groups of thirty each. Group D received caudal block with local anesthetic solution and 0.1 mg/kg injection dexamethasone. Group I received a caudal block with local anesthetic solution. They received intravenous injection dexamethasone 0.1 mg/kg after the block. Both the groups were compared for the duration of postoperative analgesia and analgesic requirement. Statistical Analysis Used: Statistical analysis was done with unpaired t-test and Chi-square test as was appropriate. Results: Group D showed a significant prolongation of postoperative analgesia (626.33 +/- 59.39 min) as compared to Group I (194.67 +/- 27.76 min). Similarly, requirement of analgesic was reduced on 1st postoperative day in group receiving caudal dexamethasone. Conclusions: Dexamethasone significantly prolongs the duration of postoperative analgesia of a caudal block when given caudally than when given intravenously. PMID- 29284866 TI - Does Pulmonary Artery Systolic Pressure as Estimated by Transthoracic Echocardiography Alter the Effect of Positive End-Expiratory Pressure on Arterial Blood Gases and Hemodynamics in Morbidly Obese Patients? AB - Background: Positive end-expiratory pressure (PEEP) at the time of induction increases oxygenation by preventing lung atelectasis. However, PEEP may not prove beneficial in all cases. Factors affecting the action of PEEP have not been elucidated well and remain controversial. Pulmonary vasculature has direct bearing on the action of PEEP as has been proven in the previous studies. Thus, this prospective study was planned to evaluate the action of PEEP on the basis of pulmonary artery systolic pressure (PASP) which is noninvasive and easily measured by transthoracic echocardiography. Materials and Methods: Seventy morbidly obese patients, the American Society of Anesthesiologists Grade II, or III, aged 20-65 years with body mass index >40 kg/m2, scheduled for elective laparoscopic bariatric surgery were included. Patients who denied consent, those undergoing emergency and/or open surgery and those requiring >2 attempts for intubation were excluded from the study. Ten patients had to be excluded. Thus, a total of sixty patients participated in the study. Thirty patients received no PEEP at the time of induction while other thirty patients were given a PEEP of 10 cm of H2O. Serial ABG samples were taken preoperatively, at the time of intubation, 5 min after intubation, and 10 min after intubation. Patients were then divided into four groups on the basis of PASP value of <=30 mm Hg with and without PEEP or >30 mm Hg with and without PEEP. Primary Outcome: The primary outcome was the effect of PEEP of 10 cm of H2 O on ABG and hemodynamics in morbidly obese patients. Secondary Outcome: The secondary outcome was the effect of PASP on the action of PEEP in morbidly obese patients undergoing laparoscopic surgery. Results: Patients having PASP of >30 mm Hg had significant improvement in oxygenation on PEEP application (270.11 +/- 119.26 mm Hg) as compared to those without PEEP (157.57 +/- 109.29 mm Hg) just after intubation. The increase in oxygenation remained significant at all time intervals. Patients with PASP <=30 mm Hg did not show significant improvement in oxygenation with PEEP application (177.09 +/- 85.85 mm Hg as compared to 226.27 +/- 92.42 mm Hg without PEEP). Hemodynamic parameters did not show statistically significant alterations. Conclusion: Morbidly obese patients who have PASP >30 mm Hg benefit most from the PEEP. Thus, PASP which is an easily measurable noninvasive parameter can be used as a criterion for selecting patients who benefit from PEEP application. PMID- 29284867 TI - Short-term Outcome of Patients with Infective Endocarditis: A Single-center Prospective Study. AB - Objectives: To investigate the short-term outcome of patients with infective endocarditis (IE). Patients and Methods: We analyzed data from 42 patients with active endocarditis which underwent different cardiac surgeries. An active endocarditis was considered due to urine analysis and/or blood culture and acute inflammation Gram stains of sample tissue and/or blood culture and acute inflammation Gram stains of sample tissue. Design: Collecting data of 42 patients prospectively. Setting: University hospital single center. Participants: Patients with IE from July 2014 to June 2016. Interventions: None. Measurement and Main Results: We collected data of 42 patients in Imam Hospital which is a university based 1700-bed center. Twelve patients experienced a redo operation; in which, 2 of them have had the second redo. Five patients underwent an aortic valve replacement operation, 2 mitral valve repair, and only one patient had experienced a subaortic web resection. Seven cases were addict; in which, 5 of them were intravenous abusers. There was 1 porphyric patient which suffered from pethidine reliability. Most of our cases underwent Bentall or tricuspid valve repair operation, and multivalve operation was more scarce. Conclusions: We have presented the therapeutic strategies and outcome of patients with IE and evaluated their short-term outcome. PMID- 29284868 TI - Comparison of Three Different Concentrations 0.2%, 0.5%, and 0.75% Epidural Ropivacaine for Postoperative Analgesia in Lower Limb Orthopedic Surgery. AB - Introduction: Ropivacaine has been studied previously and holds promise as an agent that offers a safe, efficacious, and better recovery profile than other conventional agents such as bupivacaine. The aim of the present study was to compare the safety and efficacy of equal volume of different concentration of ropivacaine for epidural analgesia in patients undergoing major lower limb orthopedic surgery. Subjects and Methods: One hundred and fifty adult patients were randomized into three groups to receive single dose of equal volume of ropivacaine through epidural route in concentrations of 0.2%, 0.5%, and 0.75%, respectively. All the groups received equal dose of ropivacaine of same concentration for subarachnoid block using combined spinal-epidural technique. Results: Modified Bromage Scale and Numeric rating scale was used to assess motor block and analgesia. Data analysis was done using WINDOW SPSS Student Version 17 ANOVA test. Student's t-test was performed for comparison between two groups, and qualitative data were analyzed by applying Chi-square test. Conclusion: 0.5% and 0.75% ropivacaine were sufficient and effective for intrathecal subarachnoid block as well as for postoperative analgesia with epidural use. Shorter duration of motor blockade and analgesia was seen with ropivacaine 0.2%. PMID- 29284869 TI - Postoperative Ultrasound Guided Continuous Femoral Nerve Blockade for Unilateral Total Knee Arthroplasty: A Comparison of 0.125% Bupivacaine and 0.2% Ropivacaine. AB - Context: Total knee arthroplasty (TKA) is associated with severe postoperative pain which increases morbidity and mortality. Aims: The aim of the study was to compare the analgesic efficacy and motor blockade of continuous infusion of 0.125% bupivacaine and 0.2% ropivacaine in femoral nerve block following unilateral TKA and to assess the effectiveness of femoral nerve block. Settings and Design: One hundred and fifty patients undergoing unilateral total knee replacement surgery were included in this prospective observational comparative study. Subjects and Methods: Patients are divided into two groups of 75 each. Femoral nerve catheter was placed at the end of surgery using ultrasound. Postoperative analgesia and motor blockade were compared for the next 24 h using visual analog scale (VAS) score, additional analgesic requirement, and Bromage scale. Statistical Analysis: Student's t-test and Chi-square test were applied. Results: There was no statistically significant difference in pain between the two groups though VAS score (during rest and movement) and opioid consumption were lower in bupivacaine group. Nearly 28.6% patients experienced pain and required additional analgesics. Seventy-two percent among them complained of pain in the popliteal region supplied by sciatic nerve. Eight patients excluded from the study also had pain in the popliteal fossa. There was a statistically significant difference in motor blockade between the two groups at 12, 18, and 24 h after starting infusion. Bupivacaine group had a higher percentage of type three blocks compared to ropivacaine group. Conclusion: Continuous femoral nerve block (CFNB) with 0.125% bupivacaine infusion provided better analgesia with denser motor blockade compared to 0.2% ropivacaine infusion. CFNB alone is not sufficient to provide adequate analgesia following unilateral TKA. PMID- 29284870 TI - Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study. AB - Background: Clonidine, opioids, beta-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Subjects and Methods: Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. Results: The HR and MAP were found to be higher in Group A. The difference was statistically significant (P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant (P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant (P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Conclusions: Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B. PMID- 29284871 TI - Comparative Study of Clonidine with Ropivacaine versus Ropivacaine Alone in Epidural Anesthesia for Lower Limb Orthopedic Surgery. AB - Background: Epidural anesthesia has been well established as a safe and effective technique not only for perioperative anesthesia but also for postoperative analgesia. Various adjuvants have been added to local anesthetic agent in an effort to prolong this duration. Aims: The aim of this study was to compare and evaluate the anesthesia and analgesic property of ropivacaine to its combination with clonidine for lower limb orthopedic surgery under epidural. Materials and Methods: In a prospective, randomized, double-blind study, eighty adult patients undergoing lower limb surgeries received either 0.75% ropivacaine or 75 MUg clonidine with 0.75% ropivacaine through epidural route. Patients were compared for hemodynamic variability, quality of motor and sensory block, intra- and post operative analgesia, and the side effects associated. Statistical Analysis: Data analysis was done by Student's paired t-test, Chi-square test, and Mann-Whitney test. P < 0.05 was considered statistically significant. Results: The time taken for onset of the motor as well as the sensory block was significantly shorter in ropivacaine with clonidine group as compared to ropivacaine alone group. Mean duration of analgesia was significantly higher in patients who received clonidine as an adjunct (P < 0.001). There was no significant difference observed in the incidence of hemodynamic changes or side effects. Conclusion: The study demonstrated that use of clonidine as an adjuvant to ropivacaine through epidural route provides a hemodynamically stable, faster, and prolonged epidural block and a longer analgesic effect as compared to ropivacaine alone. PMID- 29284872 TI - Effects of Dexmedetomidine on Intraoperative Hemodynamics and Propofol Requirement in Patients Undergoing Laparoscopic Cholecystectomy. AB - Background: Despite multiple benefits, laparoscopic surgery always poses anesthetic challenge due to significant alteration of hemodynamics. Various pharmacological agents have been used for the same with variable response. Dexmedetomidine, in addition to sympatholytic effect, diminishes intraoperative requirement of anesthetics including propofol. The present study was conducted to evaluate the effects of intravenous dexmedetomidine on intraoperative hemodynamics and propofol requirement using bispectral index (BIS) in laparoscopic cholecystectomy. Methods: Forty patients undergoing laparoscopic cholecystectomy were randomly allocated to receive either dexmedetomidine (Group A; n = 20) or normal saline (Group B; n = 20). In Group A, dexmedetomidine was loaded (1 MUg/kg) before anesthesia induction and infused (0.6 MUg/kg/h) during surgery. Anesthesia was induced with propofol, and maintenance infusion rate was adjusted to a BIS of 55-60 in both groups. Mean arterial pressure (MAP) and heart rate (HR) were recorded at baseline and at various time points from loading of drugs to just after tracheal extubation. All infusions were stopped with removal of scope from abdominal cavity. Recovery time (time from end of all infusions to BIS = 80) and extubation time (time from end of all infusions to extubation) were noted. Results: After intubation, MAP and HR values in Group A were significantly lower than Group B at various time points of study. To achieve similar BIS values, significantly low doses of propofol were required in Group A during induction and intraoperatively. Doses were reduced by 36% and 31%, respectively. Mean recovery time and mean extubation time in Group A were also significantly less. Conclusion: During propofol-based anesthesia for laparoscopic cholecystectomy, dexmedetomidine provides stable intraoperative hemodynamics and reduces propofol requirement for induction as well as maintenance, without compromising recovery profile. PMID- 29284873 TI - Optimal Dose of Dexmedetomidine Retrobulbar Anesthesia during Phacoemulsification Cataract Surgery. AB - Background: The cataract surgery anesthesia should be to make the procedure as safe and as satisfactory as possible for all concerned. The recent progress in anesthesia and surgery now allow cataract extraction to be done with minimal physiological changes to the patient. We aimed in the study to compare between two different doses of dexmedetomidine combined with lidocaine and bupivacaine during retrobulbar anesthesia for cataract extraction by phacoemulsification. Materials and Methods: This study was done on forty patients with cataract. The patients were enrolled in two groups: Group (A):Twenty patients were received 1.5 ml 2% lidocaine + 1.5 ml 0.5% bupivacaine + 0.25 MUg/kg of dexmedetomidine and Group (B): Twenty patients were received 1.5 ml 2% lidocaine + 1.5 ml 0.5% bupivacaine + 0.5 MUg/kg of dexmedetomidine. Results: The globe anesthesia duration, globe, and lid akinesia were significantly longer in the Group B than in the Group A (P < 0.05). Intraocular pressure decreased through the first 15 min after anesthesia in the two groups, and the changes were not significant between the two groups but highly significant in every group when compared to its baseline reading. As regards the conscious level in the two groups, there was a significant difference (P < 0.001). Group A is higher regarding score 2 and 3, and Group B higher in score 4. Conclusions: We concluded that dexmedetomidine 0.25 MUg/kg, when added to retrobulbar block for cataract surgery, will significantly increase the duration of retrobulbar block and improve both the surgeon and the patient satisfaction. PMID- 29284874 TI - Low-dose Succinylcholine to Facilitate Laryngeal Mask Airway Insertion: A Comparison of Two Doses. AB - Background and Aims: Around the world, the use of the laryngeal mask airway (LMA) is becoming more common for different surgeries accounting for it being the dominant choice of airway in numerous surgeries. Although propofol is known to blunt the laryngeal reflexes often patient movement, coughing, and gagging occur on insertion. This study aims to identify the optimum dose of succinylcholine required to facilitate LMA insertion comparing placebo, 0.1 mg/kg and 0.25 mg/kg of succinylcholine. Further objectives were to compare (a) the overall insertion conditions of the LMA, (b) the number of insertion attempts, (c) the amount of propofol consumption, and (d) the hemodynamics in the three groups. Setting and Design: This is a prospective, double-blinded, randomized control trial of 283 patients randomized into three groups-placebo, 0.1 mg/kg and 0.25 mg/kg of succinylcholine. It was done in the day case theatres of a tertiary hospital in Southern India. Subjects and Methods: Patients were induced with 2 mg/kg of propofol, after 2 MUg/kg of fentanyl. The study drug was given after loss of consciousness. After 60 s, a classic LMA was inserted by the standard method by a single investigator. Jaw relaxation, coughing, gagging, movement, laryngospasm, ease of insertion, number of attempts, propofol usage, and hemodynamics were assessed. Statistical Analysis: Statistical methods used were analysis of variance with Bonferroni's t-test, Chi-square test, and Fisher's test. P < 0.05 was considered statistically significant. Results: Jaw relaxation was significantly better in the 0.25 mg/kg succinylcholine group. There was no significant difference in coughing and gagging in the groups, but patient movement was more in the placebo group. Two patients in the placebo group experienced partial laryngospasm. Overall insertion conditions were significantly better in the 0.25 mg/kg group compared to the other two groups. Propofol consumption was significantly more in the placebo group. Conclusions: The study concludes that 0.25 mg/kg succinylcholine facilitates insertion of the LMA. PMID- 29284875 TI - Efficacy and Safety of Using Air Versus Alkalinized 2% Lignocaine for Inflating Endotracheal Tube Cuff and Its Pressure Effects on Incidence of Postoperative Coughing and Sore Throat. AB - Background and Objective: We wished to compare the endotracheal tube (ETT) cuff pressure inflated with air or alkalinized lignocaine during anesthesia and evaluate clinical symptoms such as coughing and sore throat (postoperative sore throat [POST]) following tracheal extubation. Materials and Methods: This was a prospective randomized controlled study conducted in a tertiary care set up over a period of 1 year. We included 100 patients in age group of 18-65 years posted for elective surgeries of duration more than 90 min under general anesthesia with N2O-O2 mixture. Patients were randomized using computer-generated randomization table into air and lignocaine group. The ETT cuff was inflated with air or alkalinized lignocaine (2% lignocaine with 7.5% sodium bicarbonate, in the proportions of 19.0:1.0 ml) to the volume that prevented air leak using cuff pressure manometer. After extubation, an independent observer blinded to study group recorded the presence or absence of coughing and POST at immediately, 1 h and 24 h postoperatively. Results: Demographic data, baseline characteristics (American Society of Anesthesiologists grade, intracuff volume/cuff pressure at start of surgery), and duration of anesthesia were comparable among study groups (P > 0.05). Cuff pressure and volume achieved in the end of surgery were much higher in air group as compared to lignocaine group (P < 0.05). Incidence of coughing and POST at immediately, 1 h and 24 h postoperatively was significantly higher in air group compared to lignocaine group. Impact of duration of anesthesia on rise in cuff pressure was significantly higher in air group and its effect on cuff-induced laryngotracheal morbidity was significant in both air and lignocaine group. Conclusion: This study showed the significance of use of alkalinized 2% lignocaine in prevention of rise of cuff pressure and incidence of coughing and POST. Duration of anesthesia has also a significant effect on incidence of postoperative trachea-laryngeal morbidity. PMID- 29284876 TI - Dexmedetomidine versus Magnesium Sulfate in Anesthesia for Cochlear Implantation Surgery in Pediatric Patients. AB - Context: Cochlear implantation surgery represents a great advance in ENT surgeries. Special anesthetic managements were required to provide bloodless surgical field and monitoring of the facial nerve. Aims: We aimed to compare both dexmedetomidine and magnesium sulfate as regards their efficacy in inducing deliberate hypotension and providing better quality of the surgical field during cochlear implantation in pediatrics. Settings and Design: Prospective, randomized double-blinded study. Subjects and Methods: Forty-six pediatric patients aging 1.5-2.5 years of either sex with American Society of Anesthesiologists physical status classes I and II were randomized into dexmedetomidine (D) group (n = 23) and magnesium sulfate (M) group (n = 23). In the D group, after induction of anesthesia but before the surgery, a bolus dose of 0.4 MUg/kg slowly infused over 10 min, then continuous infusion by a rate of 0.4 MUg/kg/h until the end of surgery. In M group, after induction of anesthesia but before the surgery, magnesium sulfate 10% (50 mg/kg) was given slowly, then continuous infusion by a rate of 10 mg/kg/h during the whole surgery. Intraoperative hemodynamics, quality of surgical field, fentanyl consumption, blood loss, operative time, FLACC pain scores, and adverse effects were compared in both groups. Statistical Analysis Used: Data were presented as mean +/- standard deviation, ranges, numbers, and percentages as appropriate. Comparison of demographic data and time of surgery was done by Student's t-test. Two-way analysis of variance with correction for repeated measurements was used for heart rate and blood pressure comparison. Mann Whitney U-test was used for nonparametric measurements. Results: Surgical field score and blood loss were better in D group than M group. Fentanyl consumption was less in D group than M group. Heart rate and mean atrial blood pressure were lower in D group except in the initial times than M group. Conclusions: In our study, both drugs were effective in achieving hypotensive anesthesia in pediatrics; however, dexmedetomidine proved to have superior effect on the surgical field and blood loss compared to magnesium sulfate with no intra- and post-operative complications for cochlear implantation surgery. PMID- 29284877 TI - Intravenous Dexmedetomidine Infusion Compared with that of Fentanyl in Patients Undergoing Arthroscopic Shoulder Surgery under General Anesthesia. AB - Background: Anesthesia for arthroscopic shoulder surgery is challenging due to the need for oligaemic surgical field as well as a good postoperative recovery profile. Aim: The present study was prospective, randomized to evaluate the efficacy of dexmdetomidine infusion compared to that of fentanyl in patients undergoing arthroscopic shoulder surgery under general anesthesia. Patients and Methods: A total of 60 patients aged from thirty to fifty years, American Society of Anesthesiologists Class I/II of either sex for arthroscopic shoulder surgery, were included. The patients were divided into two groups of 30 patients each. Group I received dexmedetomidine loading 1 MUg/kg over 10 min followed by maintenance 0.5 MUg/kg/h and Group II Fentanyl loading 1 MUg/kg followed by maintenance 0.5 MUg/kg/h. Measurements: Hemodynamic readings (Heart rate HR, and mean arterial blood pressure MAP) were recorded after the start of the study drug infusion (T1), after intubation (T2), then every 15 minutes till the end of surgery (T15, T30, T45, T60, T75, T90). In the PACU, MAP, and HR were recorded on arrival, after 30 min, 1 hr, and 2 hrs (R0, R30, R1 hr, R2 hr) Postoperative analgesia was assessed by visual analogue scale (VAS), Modified Observers's Assessment of Alertness and Sedation OAA/S was recorded on arrival to PACU. Results: This study showed that in the dexmedatomidine group there was statistically significant decrease of MAP and HR after drug infusion up to two hours in the recovery period, more sedation, better control of pain and surgeon satisfaction. Conclusion: Iv infusion of dexamedatomidine may be an attractive option during arthroscopic shoulder surgery as it provided a better hypotensive anesthesia by lowering MAP and HR which leads to better surgical field and surgeon satisfaction than iv infusion fentanyl along with a better postoperative VAS. PMID- 29284878 TI - Role of Oral Prednisolone in the Management of Postdural Puncture Headache after Spinal Anesthesia in Urological Patients. AB - Background and Aims: Postdural puncture headache (PDPH) is a frequently encountered complication of spinal anesthesia and may be associated with significant morbidity in some patients. Parenteral corticosteroids have been used in the management of PDPH both prophylactically and after the occurrence of headache. The aim of this study was to evaluate the effect of oral prednisolone in the management of PDPH after spinal anesthesia in urological patients. Materials and Methods: Sixty adult patients who developed PDPH after spinal anesthesia for urological surgeries were randomly allocated to two groups. Group C patients (n = 30) were managed conservatively, and Group P patients (n = 30) were given 20 mg of oral prednisolone for 4 days in addition to the conventional treatment. The intensity of headache was measured using visual analog scale (VAS). VAS score was taken just before the start of treatment (0 h) and at 12, 24, 48, 72, and 96 h after the start of treatment. Statistical Analysis: Statistical analysis was performed using Statistical Packages for Social Science version 19 (SPSS, Inc., Chicago, IL, USA). Results: There was no statistically significant difference in the VAS score in patients before the start of treatment (0 h) and at 12 h after the start of treatment. The VAS scores were less and statistically significant in Group P at 24, 48, 72 and 96 h after the start of treatment (P < 0.05). Conclusion: The use of oral prednisolone is effective in reducing the severity and duration of PDPH. PMID- 29284879 TI - A Comparison of Dexmedetomidine and Clonidine in Attenuating the Hemodynamic Responses at Various Surgical Stages in Patients Undergoing Elective Transnasal Transsphenoidal Resection of Pituitary Tumors. AB - Background: Transsphenoidal approach to pituitary tumors is a commonly performed procedure with the advantage of a rapid midline access to the sella with minimal complications. It may be associated with wide fluctuations in hemodynamic parameters due to intense noxious stimulus at various stages of the surgery. As duration of the surgery is short and the patients have nasal packs, it is prudent to use an anesthestic technique with an early predictable recovery. Materials and Methods: A total of 60 patients of either sex between 18 and 65 years of age, belonging to the American Society of Anesthesiologists I and II who were undergoing elective transnasal transsphenoidal pituitary surgery were chosen for this study. Patients were randomly allocated into two groups, Group C (clonidine) and Group D (dexmedetomidine), with each group consisting of 30 patients. Patients in Group C received 200 MUg tablet of clonidine and those in Group D received a pantoprazole tablet as placebo at the same time. Patients in the Group D received an intravenous infusion of dexmedetomidine diluted in 50 ml saline (200 MUg in 50 ml saline) 10 min before induction and patients in Group C received 0.9% normal saline (50 ml) as placebo. The hemodynamic variables (heart rate, mean arterial pressure) were noted at various stages of the surgery. Statistical analysis of the data was performed. Results: A total of 60 patients were recruited. The mean age, sex, weight and duration of surgery among the two groups were comparable (P > 0.05). Both dexmedetomidine and clonidine failed to blunt the increase in hemodynamic responses (heart rate and blood pressure) during intubation, nasal packing, speculum insertion and extubation. However when the hemodynamic response was compared between the patients receiving dexmedetomidine and clonidine it was seen that patients who received dexmedetomidine had a lesser increase in heart rate and blood pressure (P < 0.05) when compared to clonidine. Conclusions: A continuous intravenous infusion of dexmedetomidine as compared to oral clonidine improved hemodynamic stability in patients undergoing transnasal transsphenoidal resection of pituitary tumors. PMID- 29284880 TI - Securing a Difficult Airway: Tracheal Intubation Achieved after Deliberate Placement of an Endotracheal Tube in Esophagus: A New Approach. AB - Enlarged thyroid gland with retrosternal extension has an increased incidence of difficult intubation, and it poses real airway challenge for the anesthesiologists. Here, we present a case of successful management of a difficult airway in a female patient of enlarged thyroid gland, planned for open reduction and internal fixation of the upper end of humerus. Endotracheal intubation was achieved after deliberate insertion of an endotracheal tube in esophagus. The patient was extubated over a ventilating bougie, with uneventful postoperative course. PMID- 29284881 TI - Postoperative Chylothorax of Unclear Etiology in a Patient with Right-sided Subclavian Central Venous Catheter Placement. AB - A young male underwent decompressive craniotomy for an intracerebral bleed. A right-sided subclavian central venous catheter was placed in the operating room after induction of anesthesia. Postoperatively, he was shifted to Intensive Care Unit (ICU) for mechanical ventilation due to low Glasgow coma scale. He had an episode of severe agitation and straining on the tracheal tube in the evening same day. On the 2nd postoperative day in ICU, his airway pressures were high, and chest X-ray revealed massive pleural effusion on right side. Under ultrasound guidance, 1400 milky white fluid was aspirated. It was sent for analysis (triglycerides) that confirmed chyle and hence, chylothorax was made as diagnosis. A duplex scan was done which ruled out thrombosis in subclavian vein. The catheter had normal pressure tracing with free aspiration of blood from all ports. Enteral feeding was continued as it is a controversial matter in the literature and he was monitored clinically and radiologically. PMID- 29284882 TI - GuideWire Migrating into Murphy's Eye of Endotracheal Tube: An Unusual Complication of Percutaneous Dilational Tracheostomy. AB - Percutaneous dilational tracheostomy (PDT) is a frequently carried out bedside procedure in a critical care setting. It is usually performed under fiberoptic endoscopic guidance. Studies with PDT performed with endoscopic guidance have reported lower complication rates than studies performed with "blind" PDT. We report a case where PDT was performed without endoscopic assistance and the j shaped guidewire got stuck in the Murphy's eye of endotracheal tube causing difficulty in railroading of tracheostomy tube (TT). PMID- 29284883 TI - Anesthetic issues and Difficult Airway Management in a Case of Grisel's Syndrome. AB - Grisel's syndrome is a nontraumatic subluxation of atlanto-axial joint which is associated with inflammatory conditions of head and neck and occurs primarily in children. Anesthetic management is such cases constitute a multitude of challenges, especially related to the airway management. We presented here a case of 16-year-old male child weighing 23 kg, came to our hospital for the treatment of torticollis who was previously treated with intravenous antibiotics for rhinopharyngitis and diagnosed as a case of Grisel's syndrome. The child was operated on for unilateral resection of sternocleidomastoid muscle under general anesthesia. This case report pertains to the successful airway and anesthetic management in the background of difficult airway. PMID- 29284884 TI - Airway Considerations in Case of a Large Multinodular Goiter. AB - Patients with large goiters pose a great challenge to the anesthesiologist regarding securing the airway without compromising the safety of the patient. The technique of intubation depends on the choice and expertise of anesthesiologist. Awake fiberoptic intubation (AFOI) is the preferred technique. We present the case of large multinodular goiter with difficult airway in which AFOI was successfully used to secure the airway. Proper assessment, planning, and preparation for airway management should be done preoperatively to ensure patient safety. PMID- 29284885 TI - Anesthetic Management for Prolonged Incidental Surgery in Advanced Liver Disease. AB - In spite of advances in perioperative management, operative procedures in patients with chronic liver disease pose a significant challenge for the anesthesiologist due to multisystem involvement, high risk of postoperative hepatic decompensation, and mortality. We describe the anesthetic management of an elderly patient with advanced liver disease (model for end-stage liver disease 16) for prolonged abdominal surgery. The use of invasive hemodynamic monitoring, point-of-care biochemical, and hematological surveillance coupled with prompt correction of all abnormalities was responsible for good outcome. The patient's inguinal swellings turned out to be extensions of a large peritoneal mesothelioma, necessitating a large abdominal incision and blood loss. Analgesia was provided by bilateral transversus abdominis plane blocks, which helped to reduce opioid use and rapid extubation. PMID- 29284887 TI - Difficult Airway in a Case of Gross Hydrocephalus for Shunt Surgery. AB - Children with gross hydrocephalus for emergency ventriculoperitoneal (VP) shunt present challenges to anesthesiologist due to increase in circumference of head, associated congenital anomalies. Here is a case report of child with gross hydrocephalus with Type 2 Arnold chiari malformation posted for emergency VP shunt placement possessed a difficult airway. PMID- 29284886 TI - Monitored Anesthesia Care for the Acute Ischemic Stroke Patient with End-stage Pulmonary Disease. AB - The majority of patients who suffer acute ischemic stroke (AIS) from large vessel occlusion are at a significant risk for disability or death. Because patients on veno-arterial extracorporeal membrane oxygenation (VA ECMO) are therapeutically anticoagulated, intravenous recombinant tissue plasminogen activator is contraindicated. For AIS management, these patients must undergo emergent intra arterial therapy. Presented is a patient on VA ECMO who subsequently suffered a large vessel embolic stroke requiring emergent surgical intervention. The decision by our anesthetic team to perform the procedure under monitored anesthesia care is discussed. PMID- 29284888 TI - Haemothorax Following Internal Jugular Vein Cannulation: A Rare Event. AB - Catheterization of central veins is a routine technique which is widely used in emergency department, operation theater, and intensive care units. Seldinger technique is widely used to place central venous and arterial catheters and is generally considered safe. The technique does have multiple potential risks. We describe a case of hemothorax following internal jugular venous cannulation. Measures which can be taken to prevent such complications are explained in detail as well as recommended steps to remedy errors should they occur. PMID- 29284889 TI - Anaesthetic Implications of Severe Hyperthyroidism Secondary to Molar Pregnancy: A Case Report and Review of Literature. AB - Pregnant women with gestational trophoblastic disease have an increased likelihood to develop hyperthyroidism secondary to increased secretion of human chorionic gonadotropin. Most of these cases of hyperthyroidism remain undiagnosed and may present as a thyrotoxic crisis during the perioperative period. Pregnant patients with gestational trophoblastic disease should be always evaluated for hyperthyroidism, and in cases of severe hyperthyroidism, antithyroid treatment should be initiated before evacuation of the mole. Anesthetic management of these cases is challenging in view of the emergency nature of the surgery and potential for thyroid crisis. Spinal anesthesia can be safely administered and has a protective role in preventing thyroid crisis. PMID- 29284890 TI - A Safe Regional Technique in a High-risk Patient: Cervical Plexus Blockage. AB - Regional anesthesia in the form of combined cervical plexus block is gaining popularity as a technique of choice for cervical spine surgeries, especially for urgent ones. An important advantage is that it allows continuous monitoring of patient's neurological status. The success of the block often depends on accurate placement of the local anesthetic. Landmarks for the block are therefore of great importance. In this case, we aimed to present a 74-year-old man with C4-5 odontoid fracture. We planned to perform a unilateral combined cervical plexus block for anterior cervical instrumentation and fusion (ACIF) operation because of his associated high-risk comorbid disorders. PMID- 29284891 TI - Anesthetic Management of a Patient with Dilated Cardiomyopathy and End-stage Renal Disease for Emergency Strangulated Hernia Repair Surgery. AB - Dilated cardiomyopathy (DCMP) is a myocardial disease associated with dilatation of one or both the ventricles, impaired myocardial contractility, decreased cardiac output, and increased ventricular filling pressures. Patients with end stage renal disease are dependent on renal replacement therapy to survive and often manifest with a variety of pathological organ dysfunction. We present a case of DCMP and chronic kidney disease posted for emergency reduction of strangulated umbilical hernia under general plus epidural anesthesia. PMID- 29284892 TI - Resuscitation of a Newborn with Right Hypoplastic Heart Syndrome: A Rare Confrontation for an Anesthesiologist. AB - According to newborn resuscitation guidelines, all referrals for neonates with suspected or confirmed duct-dependent congenital heart disease are to be discussed with pediatric cardiologist beforehand and are to be transferred immediately under their care for optimal management. However, in case of emergency, when there is not adequate time for preoperative consultations or a multidisciplinary approach, we should be able to manage these patients in the immediate perioperative period to decrease the likelihood of adverse outcome. We herewith describe a case where we as anesthesiologists successfully resuscitated a newborn with right hypoplastic heart in an emergency case of cesarean section till the baby was transferred to level III cardiac institution for further management. PMID- 29284893 TI - Anesthetic Management of a Parturient with Hemolysis, Elevated Liver Enzyme Levels, and Low Platelet Syndrome Complicated by Renal Insufficiency and Coagulopathy. AB - The objective of this study is to describe the anesthetic management of a parturient with hemolysis, elevated liver enzyme levels, and low platelet (HELLP) syndrome and renal insufficiency. A 28-year-old female patient, gestational age of 35 weeks, with hypertensive crisis (blood pressure 190/110 mmHg), was admitted for an emergency cesarean section after diagnosis of HELLP syndrome and renal insufficiency. We performed total intravenous general anesthesia with rapid sequence induction. During the surgical procedure, reduced urine output and coagulopathy were detected. After the treatments of transfusion, diuresis, and anticoagulation, the surgery finished uneventfully. The patient was taken to the Intensive Care Unit without extubation and discharged on the 6th postoperative day. This case report revealed a successful anesthetic management applied to a pregnant woman with HELLP syndrome complicated by renal insuffciency and coagulopathy. There are several case reports about HELLP syndrome, but the patient in this paper is complicated with renal insuffciency and coagulopathy which made the treatment diffcult to handle. PMID- 29284894 TI - Predatory Publishing - Experience with OMICS International. PMID- 29284895 TI - The Effects of Aloe Vera on TNF-a Levels, the Percentage of Nk Cells and Th 17 Cells in Rat That Received Izoniazid and Rifampycin. AB - Background: The present study was undertaken to investigate the hepatoprotective effect of Aloe vera against side effect of antituberculosis drug. Material and methods: Twenty-five rats will be divided into five groups, namely the control group (without any treatment), the group of rats treated with anti-tuberculosis drugs, and a group of rats were treated antituberculosis drugs and got Aloe vera extract at a dose of 40; 80; and 120 mg/kg body weight. Antituberculosis drugs are isoniazid and rifampicin a dose of 50 mg/kg body weight. Results: Antituberculosis treated group showed significantly increase levels of TNF-a, the percentage of NK cells and the number of Th17 cells compared with the control group (p < 0.05). All doses of Aloe vera reduce levels of TNF-a compared with the antituberculosis group (p < 0.05), although it has not yet reached levels comparable to the control group (p > 0.05). Aloe vera at first and the third dose lower the number of NK cells compared to the antituberculosis group, although it has not yet reached a significant difference (p > 0.05). The first dose of Aloe vera was significantly decreased the percentage of Th17 cells compared to the antituberculosis drug group (p < 0.05), although it has not yet reached levels comparable to the control group (p > 0.05). Conclusions: It was concluded that administration of Aloe vera can suppress the production of TNF-a and the percentage of Th17 cells as a result of antituberculosis drug administration. Thus, Aloe vera can be a useful alternative to natural materials in the successful treatment of tuberculosis through the inhibition of side effect. PMID- 29284896 TI - Neutrophil-to-lymphocyte Ratio and Its Relation with Markers of Inflammation and Myocardial Necrosis in Patients with Acute Coronary Syndrome. AB - Introduction: Inflammation plays an important role in atherosclerosis which is the primary cause of acute coronary syndrome (ACS) that encompasses acute myocardial infarction (AMI) and unstable angina (UA). Objective: To investigate and characterize white blood cells (WBC) count, differential blood count in peripheral blood and neutrophil to lymphocyte ratio (NLR) in patients by the type of ACS. Patients and methods: The cross-sectional study included 100 patients with ACS (50 males, 50 females), aged 41 to 91 years, classified into two groups: AMI group (n=50) and UA group (n=50). Patients were hospitalized at the Clinic for Heart Diseases, University Clinical Center of Sarajevo. From patients' medical histories the following data were obtained: WBC, neutrophil, eosinophil and basophil granulocytes count, monocyte and lymphocyte count, levels of high sensitive troponin I (hsTnI), creatine kinase MB (CK-MB) and C-reactive protein (CRP). The results were analyzed using software package SPSS, version 19.0. Results: Average WBC count, neutrophil granulocytes, and monocytes were significantly higher in AMI group than in UA group (p = 0.001, p < 0.0005, p = 0.03, respectively). Eosinophil count was significantly lower in patients with AMI (p = 0.022). NLR was significantly higher in AMI group in relation to patients with UA (p = 0.001). Significantly higher values of hsTnI and CK-MB were established in patients with AMI. NLR correlated significantly positive with the values of hsTnI, CK-MB, CRP, WBC and neutrophil count, and significantly negative with lymphocyte count. Conclusion: Average values of NLR were significantly higher in patients with AMI in relation to patients with UA, indicating the importance of this inflammatory marker in discrimination of clinical forms of ACS. A positive correlation was established between NLR and markers of myocardial necrosis, and between NLR and CRP, indicating the importance of NLR in the assessment of the extent of the myocardial lesion and in inflammation intensity assessment in ACS. PMID- 29284897 TI - The Cumulative Incidence of Stroke, Myocardial infarction, Heart Failure and Sudden Cardiac Death in Patients with Atrial Fibrillation. AB - Introduction: Atrial fibrillation represents the most common cardiac arrhythmia in clinical practice. By year 2030, 14-17 million AF patients are anticipated in the European Union. Atrial fibrillation remains one of the major causes of stroke, heart failure, sudden death all over the world. Research Objectives: The objective of our study is to determine the cardiac and cerebrovascular events (myocardial infarction, heart failure, stroke, sudden cardiac death) and their cumulative incidence during 11 years follow up period. Patients and methods: This study includes 2352 ambulant and hospitalized patients with atrial fibrillation (AF) who were enrolled during the follow up period. All patients underwent clinical evaluation in order to determine cardiac and cerebrovascular events (myocardial infarction, heart failure, stroke, sudden cardiac death) and their cumulative incidence. Results: The results of cumulative incidence for sudden cardiac death was 1.71%, for stroke 2.56%, for myocardial infarction 1.20% and for heart failure was 5.73%. In our study the age-adjusted incidence and prevalence of AF are slightly lower in women. The study shows that the risk of death is higher in females than in males with AF. Conclusion: Despite good progress in the management of patients with atrial fibrillation (AF), this arrhythmia remains one of the major causes of stroke, heart failure, sudden death. Effective treatment of patients with atrial fibrillation includes not only rate control, rhythm control, and prevention of stroke, but also management of cardiovascular risk factors and concomitant diseases. PMID- 29284898 TI - Complications After Ileal Urinary Derivations. AB - Introduction: The aim of the study was to determine the most frequent early and late complications in different types of ileal urinary diversions. Patients and methods: The study was conducted in a five-year period, on 106 patients who were diagnosed with invasive urinary bladder cancer and who had indication for radical cystectomy with one of the investigated types of urine derivation. They were divided into 2 groups, based on the type of ileal urinary diversions. Results: The colonization of bacteria was more prominently present in the ileal conduit urinary diversion group (97%) compared to Ghoneim (25%) and Hautmann (10%) group, Ureteral stenosis was slightly less represented in the conduit group (9.1%). Wound infections were significantly more represented in the conduit (21.2%) than in the Ghoneim group (5%) Nighttime incontinence was present in 20% of patients in both groups or 4 patients in each group. Daytime incontinence in the Ghoneim group was present in 3 patients (15%) and in the Hautmann group 2 patients (10%). Late complications correlate significantly negative with the type of surgery and slightly negative with the grade, and significantly positively with the examined group and T stage, and slightly correlate positively to the N and R stages. Early complications correlate slightly negative with the type of surgery, slightly negative with the grade, and significantly positively with T stage, and slightly positively correlates with the N and R stage. Conclusion: The most commonly reported complications in ileal conduit are: prolonged ileus, stoma infection, wound dehiscence and bacterial colonization, followed by peristomal skin complications and complications related only to the stoma, such as stenosis and stoma retraction, and prolaps of ileostoma and ileointestinal stenosis. The ileus rate in orthotopic derivation was significantly lower than that of the ileal conduit group, which led to the conclusion that the neomybladder position does not disturb the anatomic abdominal structure. PMID- 29284899 TI - Myometrium Invasion, Tumour Size and Lymphovascular Invasion as a Prognostic Factor in Dissemination of Pelvic Lymphatics at Endometrial Carcinoma. AB - Objective: The aim of this work is to show the importance of the depth of myometrium invasion, tumour size and lymphovascular invasion as prognostic factors in dissemination of lymphatic nodes at endometrial carcinoma (CE). Materials and methods: In the period from 2010 to 2015 at the University Clinic for Gynecology and Obstetrics in Banja Luka, 221 endometrial cancer surgeries were done (laparatomy 184-83%, laparascopy 37-16,74%). Patients who had uterus bleeding in peri/postmenopause or those whose endometrium thickness was bigger than 5 mm which was established by ultrasound, or those who had in their cavum uteri pathological (PH) diagnosis, underwent fractional curettage (FC) or hysteroscopy in order to obtain pathohistological endometrium diagnosis. Substances which were removed by fractional curettage, biopsy or by surgery were sent to patohystological analysis. We analysed the following factors: age (5 groups), histological grade (G) of tumour, depth of myometrial invasion (DIM), whether it is more or less than 50%, the size of the tumour (if it is bigger or smaller than 2 cm), positive or negative lymphovascular invasion (LVI), positive or negative pelvic lymph nodes (PLN). Results: Within histological type the endometrioid type CE 166 (75,11%) was most dominant. Adenocarcinoma of endometrium was present 25 (11,31%), serous CE 11 (4,97%) and clear cell KE 2 (0,90%). Dominant population with CE was over 60 years old 127 (57,46) of female patients. At G3 where DIM was <50% positive PLN were present 2 (3.92%), whereas if DIM was>50%, 6 (26,73%) patients with positive PLN were registred. Tumour size < 2 cm was found with 57 (25,79%) female patients with positive PLN 8 (14,03%), while 164 (74,20%) patients had tumours > 2 cm who had 21 (12,80) PLN metastases. At G1 when tumour was <2 cm, positive PLN had 3 patients (5,88), while when tumour was >2 cm, positive PLN were found at 6 patients (9,69%). At G3 whose size was <2 cm, positive PLN were found at 2 patients (16,66%), but when tumour was >2 cm, PLN metastases were more frequent, 6 (25,00%). Negative LVI was found with 168 patients (76,01%) whose PLN were positive 16 (9,52%), while positive LIV was with 53 patients (23,99%) of whom 14 had PLN metastases (26,41%). At G1 two patients had positive PLN (2,32%) with negative LVI, while with positive LVI, positive PLN were found at 3 patients (11,11%). At G3 having negative LVI positive PLN were found with 6 patients (24,00%), while if LIV was positive, the number of positive PLN were 6 (54,54%). Conclusions: With low risk for lymphatic spread (DIM less than 50%, tumour size smaller than 2 cm and lack of LVI at G1 CE) we also encounter low metastasis rate of PLN. Diagnoses of this kind have an aim to lower the number of pelvic lymphadenectomies. With patients who have a high risk of lymphatic spread (myometrium invasion >50%, tumour size > 2cm, LVI present at G2 and G3) metastasis rate of PLN is high, therefore it is necessary to perform pelvic and paraaortic lymphadenectomy which lowers the mortality rate for more than 50% and at the same time patients get an absolute chance of 5-year survival period. PMID- 29284900 TI - Impact of Preoperative Anxiety in Patients on Hemodynamic Changes and a Dose of Anesthetic During Induction of Anesthesia. AB - Objectives: Each surgical patient is preoperatively, intraoperatively and postoperatively exposed to stress. The aim of this study was to determine the existence of preoperative anxiety, and to determine its impact on hemodynamic parameters (blood pressure, heart rate) in patients and dose of anesthetics during induction of anesthesia. Methods: A prospective clinical study conducted at the Department of Anesthesiology and Reanimation and Surgery Clinic of University Clinical Center Tuzla (UCC) in the period May 2012. to January 2015. The 80 patients were analyzed which were planned for and done an elective cholecystectomy surgery or herniectomy surgical intervention. Preoperative anxiety was measured with the help of Spielberg test and evaluation of depth of anesthesia was performed with BIS monitoring. Results: The results showed that all patients had some degree of preoperative manifest anxiety. Average values of mean arterial pressure, preoperatively and after the induction of general anesthesia, differed for 15,4 mm/Hg, but were not observed significant association between Spielberg score and differences in blood pressure. Preoperative anxiety is a significant predictor of administered dose of anesthetic. Each additional score on Spielberg scale reduces the dose of anesthetic for 0,304 mg/kgTT. Conclusion: Adequate assessment of preoperative anxiety and undertaking of certain steps to reduce it can assist in accurately determining the required dosage of anesthetic for the introduction of general anesthesia. PMID- 29284901 TI - Risk Factors for the Surgical Field Infections After the Osteosynthes of Tibia Diaphysis. AB - Introduction: Infections occurring in the wound as a consequence of the surgery represent the surgical field infections (SFI). Tibia diaphysis fractures are common due to its exposure to the external force. Clinical signs include: pain, swelling, lower leg deformity and skin changes. Tibia in the lower extremities has an eccentric position - from the front inner side it is covered only with the skin and from the back and the outer by muscle mass. The most common pathogens are: Staphylococcus aureus, Coagulase negative Staphylococcoc aureus or S. Epidermitis, Escherichia coli, and other. For the fracture fusion process, it is important that the skin and subcutaneous tissue above the fracture are well supplied with the blood. The American Association of Anesthesiologists defined the so-called ASA score, based on which all patients are divided into five categories according to health status before surgery. Goal: The goal of the study is to demonstrate the influence of risk factors on the occurrence of infection following osteosynthesis of tibial diaphysis, comparing emergency surgical interventions with elective. Material and methods: The study was conducted at the Clinic for Orthopedics and Traumatology of the Clinical Center of Sarajevo University during 2015 and 2016, with a total of 68 patients. Results: The age of the patient as risk factor is evident in our study, because deeper infections have had patients at the age over 60 with accompanying diseases such as Diabetes mellitus. Most of the hospitalized patients had a good health status prior to surgery, or they had ASA 1 or ASA 2 score. Surgical field infections were more common in men than in women, but the difference was not statistically significant (p>0.05). Patients who are operated as an elective surgery have longer hospitalization and more frequent surgical field infection. Also, infections are more common among smokers. PMID- 29284902 TI - Elongated Miofascial Temporal Flap in Comparison with Standard Surgical Procedure of Temporal Muscle Reconstruction. AB - Introduction: Flap of the temporal muscle (m. temporalis) with its natural position, its mass and its length, compared with other bound and free microvascular flaps, is the method of choice for covering the middle part of the face after the removal of large tumor masses. Material: The study included a sample of 36 patients who were surgically treated due to malignant process at the middle face level with the performed partial, total or bilateral maxillectomy at the Clinic for Maxillofacial Surgery, University Clinical Center in Sarajevo. The sample is divided into three groups. Methods: The usual procedure of lifting the temporal flap in the first group, at the second extension of the coronoid processus. A group of three-elongated myofascial flap, which includes lifting the muscle along with deep temporal branches of maxillary artery with deep temporal fascia, its two layers and associated stem of thesuperficial temporal artery. Results: Statistical analysis of the length indicated that in group III the mean length was 9.83 cm, group II- 8.25, and group I- 6 cm. The longest segmental lobe in group three provides safer work and the length of the lifted lobe with double vascular stem. This provides coverage of defects that cross over the median line of the middle face. The results coincide with the comparative world studies. Conclusion: For large defects at the meddle part of the face that overlap the median line, an extraordinary solution is elongated myofascial flap with double vascular supply, with a larger flap mass and a length of about 9.83 cm. PMID- 29284903 TI - Correlation Between Quality of Life and Depression Among Persons Suffering from Psoriasis. AB - Introduction: Chronic dermatitis is a major sociomedical issue still being marginalized due to generally accepted view that skin diseases are less of a health problem than is the case with diseases of other organs and organ systems for they are not life-threatening. Measurement of quality of life of persons suffering from psoriasis could become an important factor in assessing the success of treatment and modern aspect of integration of the diseased into the planning of therapeutic procedures, monitoring of their outcomes and improving the quality of treatment. Aim: To determine the quality of life and the degree of depression of persons with psoriasis, as well as to make a correlation between the two. Patients and methods: A descriptive and analytical study of cross sectional character has been performed. The sample consisted of N = 56 respondents with medically verified diagnosis of psoriasis that was treated at the Clinic for Skin and Venereal Diseases of the Clinical Centre of the University of Sarajevo. Criteria for involvement of participants: respondents are to be over 18 years of age with verified medical diagnosis of psoriasis, and to voluntarily consent for inclusion in the research. The research instruments consisted of standardized questionnaires: the WHO-BREF Quality Questionnaire and the Beck Depression Inventory. Results: Median value of scores relating to quality of life of persons with psoriasis from our sample was highest in the domain of social interaction and amounted to 72 (51.50-81.00); the domain of physical health was 63 (39.50-75.00); the psychological condition was 63 (44.00 75.00); and the environmental domain was 63 (44.00-73.50). Depression of persons with psoriasis showed correlation with domains of quality of life. The depression proved correlated with the respondents': physical health (rho = -0.793 p = 0.0001); psychological health (rho = -0.842 p = 0.0001); social interactions (rho = -0.598 p = 0.0001); as well as with attitude towards the environment (rho = 0.709 p = 0.0001). Gender, age, education, marital or employment status did not prove statistically significant for influencing occurrence of the depression. Conclusion: Given that median scores of all four domains of the quality of life of persons suffering from psoriasis were in the higher half of classification scale, the quality of their life can be considered as satisfactory. The degree of depression and the domain of quality of life are in negative correlation with psoriasis. PMID- 29284904 TI - Blood Count of Eosinophil Polymorphonuclear Leucocytes and Bronchial Hyperreactivity in Chronic Obstructive Pulmonary Disease. AB - Introduction: Polymorphonuclear eosinophil leucocytes (eosinophils) are found in increased numbers in the circulation and sputum in asthma patients, usually in relation to the severity of asthma but it is the question whether they have a significant role in the development and level of bronchial hyperreactivity in patients with chronic obstructive pulmonary disease (COPD). Objective: to show the role of the eosinophils in the development and level of BHR in patients with COPD and so in the severity of illness. Material and methods: We observed 240 patients with COPD treated in Clinic for Pulmonary Diseases and TB "Podhrastovi" Sarajevo during five years: from 2012 to 2016. They were divided into groups and subgroups according to the first registration of BHR in the course of illness and to the number of exacerbations of the disease in one year. The number of blood eosinophils was measured at the onset of exacerbation of the disease before switching on any therapy, at the beginning and at the end of the research. Results: we did not find any significant difference in the eosinophil blood count between the COPD patients with and without BHR, nor according to the time of the first registration of BHR in the course of illness nor according to the number of exacerbations of illness per one year. There was not statistically significant difference in eosinophil count (increase-drop) within any of the groups or subgroups, or between the groups and subgroups between the first and last test. Conclusion: There is not significant correlation between the eosinophil blood count and the level of BHR, number of exacerbations and the severity of COPD. PMID- 29284905 TI - Application of Ethics for Providing Telemedicine Services and Information Technology. AB - Introduction: Advanced technology has increased the use of telemedicine and Information Technology (IT) in treating or rehabilitating diseases. An increased use of technology increases the importance of the ethical issues involved. The need for keeping patients' information confidential and secure, controlling a number of therapists' inefficiency as well as raising the quality of healthcare services necessitates adequate heed to ethical issues in telemedicine provision. Aim: The goal of this review is gathering all articles that are published through 5 years until now (2012-2017) for detecting ethical issues for providing telemedicine services and Information technology. The reason of this time is improvement of telemedicine and technology through these years. This article is important for clinical practice and also to world, because of knowing ethical issues in telemedicine and technology are always important factors for physician and health providers. Material and methods: the required data in this research were derived from published electronic sources and credible academic articles published in such databases as PubMed, Scopus and Science Direct. The following key words were searched for in separation and combination: tele-health, telemedicine, ethical issues in telemedicine. A total of 503 articles were found. After excluding the duplicates (n= 93), the titles and abstracts of 410 articles were skimmed according to the inclusion criteria. Finally, 64 articles remained. They were reviewed in full text and 36 articles were excluded. At the end, 28 articles were chosen which met our eligibility criteria and were included in this study. Results: Ethics has been of a great significance in IT and telemedicine especially the Internet since there are more chances provided for accessing information. It is, however, accompanied by a threat to patients' personal information. Therefore, suggestions are made to investigate ethics in technology, to offer standards and guidelines to therapists. Due to the advancement in technology, access to information has become simpler than the past. This has prompted hackers to seize the opportunity. Discussion: This research shows that the ethical issues in telemedicine can be investigated from several aspects like technology, doctor-patient relationship, data confidentiality and security, informed consent, patient's and family's satisfaction with telemedicine services. Following ethical issues in telemedicine is a primary aspect of high quality services. In other words, if therapists abide by ethical rules, they can provide better services for patients. Attention to ethical issues in telemedicine guarantees a safer use of the services. PMID- 29284906 TI - May Heading in Soccer Result in Traumatic Brain Injury? A Review of Literature. AB - Background: Globally, soccer is the most popular team sport, unifying many fans all around the world. The epidemiological studies so far have confirmed that head playing and hitting the ball with head may cause minor head injuries, which exert their effects in a cumulative way. Methods: Literature search for this review was conducted and data about traumatic brain injury collected from various sources. Results: The consequences of head injury are evident as chronic changes in cognition, including disturbances in concentration and slowing of mental and physical agility. Conclusion: Various recommendations have been issued for the prevention of chronic negative cumulative effects of soccer ball head playing. In addition, the professional soccer players are also exposed to more intense craniocerebral trauma, such as concussions and contusions. These patients require treatment of skilled sports physicians, neurologists and neurosurgeons and some may need long to return to the sport scene again. PMID- 29284907 TI - Pleomorphic Adenoma of Minor Salivary Glands in Child. AB - Introduction: Tumors of salivary glands are very rare in children overall, and rarely in minor salivary glands. Among them pleoomorphic adenoma (PA) is the most common benign tumor of salivary glands in children and it acounts 60% of all salivary neoplasms, frequently found in major salivary glands (85 %) and rarely in minor salivary glands (10-15%). PA appears as painless oval mass, elastic consistency and smooth surface. It characterized by slow evolution of growing. The diagnosis can be confirmed only by histopathological features, after total excision of the lesion. Case report: This case report present the uncommon case of the formation well circumscribed in upper lip region, nearby the frenulum labii oris superior in 10 years old school girl. After clinical intraoral examination of the formation approximately 2cm in size the surgical treatment has been done and histopathologic analysis resulted as PA. Conclusion: Long term follow-up examination is necessary due to possible recurence or malignancy alteration. PMID- 29284908 TI - Contribution of Arabic Medicine and Pharmacy to the Development of Health Care Protection in Bosnia and Herzegovina - the First Part. AB - The time interval from the 9th to the 13th century remained known as the "Golden period of the Arab science", and a significant place among the taught sciences are occupied by Medicine and Pharmacy. In the history of medicine, Islamic medicine, also known as Arabic medicine, refers to the science of medicine developed in the Islamic Golden Age, and written in Arabic Arabs were able to use their cultural and natural resources and trade links to contribute to the strong development of pharmacy. After the collapse of the Arab rule, the Arab territorial expanses and cultural heritage were taken over by the Turks. Although scientific progress in the Turkish period slowed down due to numerous unfavorable political-economic and other circumstances, thanks to the Turks, Arab culture and useful Islamic principles expanded to the territory of our homeland of Bosnia and Herzegovina. Significant role in the transfer of Arabic medical and pharmaceutical knowledge was also attributed to the Sephardic Jews who, with their arrival, continued to perform their attar activities, which were largely based on Arab achievements. However, insufficiently elaborated, rich funds of oriental medical and pharmaceutical handwriting testify that Oriental science has nurtured in these areas as well, and that the Arab component in a specific way was intertwined with other cultures and traditions of Bosnia and Herzegovina. PMID- 29284909 TI - Evaluation of Founding Members of the International Academy of Health Sciences Informatics (IAHSI) Based on Google Scholar and Scopus Parameters. AB - Introduction: The International Academy of Health Sciences Informatics (IAHSI) is established by International Medical Informatics Association (IMIA) which is the world body for health and biomedical informatics. The Academy will serve as an honor society that recognizes expertise in biomedical and health informatics internationally. Academy membership will be one of the highest honors in the international field of biomedical and health informatics. Aim: To present scientometric analysis of founding members of the International Academy of Health Sciences Informatics, to evaluate members and their scientific rating. Material and methods: The work has an analytical character and presents analysis of the data obtained from the Google Scholar and Scopus database. Results are shown through number of cases, percentage and graphically. Results: The analysis showed a significant correlation between the Academy and the country (continent) of origin of the academician. In IAHSI are mainly represented academics originating from Europe - 40 members (33,3%), North America - 39 members (32,5%), Asia - 20 members (16,6%), South America - 9 members (7,5%), Australia - 7 members (5,8%), while only 5 members or 4,16% come from Africa. Conclusion: Criteria for number of representatives of each continent to main academic communities are relatively questionable, as this analysis showed. Development of Health Sciences Informatics should be the main purpose, and it should be evenly distributed with slight deviations in number of representatives of each continent. PMID- 29284910 TI - Virtual Screening and Prediction of Binding of Caprine CSN1S2 Protein Tryptic Peptides to Glucokinase. AB - Introduction: Glucokinase (hexokinase D) is an enzyme that phosphorylates glucose in hepatocytes totrap it in the cell and prime it for conversion to other compounds, yet this enzyme has low affinity to bind with glucose. In Diabetes Mellituspatients, the blood glucose level is poorly controled. Material and Methods: This study explored the possibility to induce glucokinase activity with bioactive peptides derived from the goat milk protein CSN1S2 by in- silico docking approach. Two bioactive tryptic peptides, CSN1S2 residues 41-47 and 214 221, were successfully docked to glucokinase and found to bind to the activation site. Results: Amino acid residues Asn41, Ala43, His45 and Arg221 from these peptides provided the major contribution to docking to glucokinase. Asn41 made more interactions with glucokinase than the other residues in the peptide, including hydrogen bonds and salt-bridge These bioactive peptides appear to help glucokinase to bind glucose, since the number of hydrogen bonds between the protein and the glucose was higher and their distances shorter in the complex with the peptides without disturbing the glucose position for phosphorylation. Conclusion: Thus, the activation effect of the CSN1S2 derived bioactive peptides for glucokinase binding affinity of glucose is indicated by this study. PMID- 29284911 TI - The Most Common Smartphone Applications Used By Medical Students and Barriers of Using Them. AB - Introduction: Medical knowledge is rapidly expanding and updating. It is very important that students can timely access to information and the latest scientific evidence without any time and place limitation. The smartphone is one of ICT tools that adopted greatly by healthcare professionals. Today, the most medical sciences universities have provided smartphone as an educational aid tool and acquisition licenses for medical apps resources in training of their students. Aim: This research was conducted to determine common smartphone applications among medical students of Urmia University of medical sciences and to identify barriers in using them. Materials and Methods: This research was a descriptive type of study carried out in 2016. Population of the study included 530 medical students completing the clinical course in Urmia University of Medical Sciences. Data were collected using researcher-developed questionnaire. The validity of it determined based on the view of experts and the reliability of it obtained by calculating the value of Cronbach's alpha (alpha = 0.82). Results: 82.3% of the students had smartphone, which in terms of operating system the highest was related Andriod (53%) and iPhone (32%). The most common applications used often by medical students included Up to date, PubSearch, Calculate by QxMD, Epocrates and OMnio. Lack of accreditation of medical apps by valid health institutions (4.63), lack of support and update of applications by their developers (4.44), lack of adequate skill to use applications (4.25) are the most important barriers in using these applications among students. Conclusion: To assurance quality of medical apps, it seems very important that academic and healthcare organizations should be involved to develop and update the apps and also provided guidelines for accreditation of apps. It is recommended that for promotion of knowledge and skill of students provide essential educations. PMID- 29284912 TI - Lower Jaw Grip Strength in Healthy and Sick Population Measured by Special Force Transducer. AB - Introduction: One of the basic chronic diseases of the MFH domain that is treated on an outpatient basis is temporomandibular dysfunction (TMD). It represents a number of pathological conditions that lead to the dysfunction of the normal function of the stomatognatic system. Observing the etiologic factors of this condition, temporomandibular TM trauma, poor habits such as infantile type of swallowing, tongue depression, and tectogenic disturbance of the myofunctional squamous system are reported in order to reconstruct the defects of neighboring regions. Material and Methods: The study included 60 patients divided into 3 groups: Group I without predetermined temporomandibular dysfunction, Group II with TMD, and Group III where one of the muscles of the masticatory group was used during the reconstruction procedure. Results: Statistically obtained results show that in group III there is a large difference in postoperative measurement after 6 weeks. Discussion: In the mentioned patients divided into three groups, the measurement of the pressure strength expressed in N follows certain states with it measured values, which coincides with comparative studies. Conclusion: From the obtained results we conclude that the parameter used, the strength of the lower jaw bite is a significant indicator of the chewing system functioning. PMID- 29284914 TI - Relationship Between Cybernetics Management and Organizational Trust Among Librarians of Mazandaran University of Medical Sciences. AB - Background and purpose: Organization must keep current skills, abilities, and in the current field of competition, and move one step ahead of other competitors; for this purpose, must be a high degree of trust inside the organization. Cybernetic management is a new approach in management of organizations that its main task according to internal issues. This study aimed to investigate the relationship between cybernetics management and organizational trust among librarians of Mazandaran University of Medical Sciences. Materials and methods: This is applied and analytical survey. which its population included all librarians of Mazandaran University of Medical Sciences, amounting to 42 people which were selected by census and participated in this research. Results: There has no relationship between components of Cybernetics management (participative decision making, commitment, pay equity, Correct flow of information, develop a sense of ownership, online education) with organizational trust amongst librarians of Mazandaran University of Medical Sciences. And there has a significant relationship between flat Structure of cybernetics management and organizational trust. For data analysis was used Kolmogorov-Smirnov test and linear regression. Conclusion: There is no significant relationship between Cybernetic management and organizational trust amongst librarians of Mazandaran University of Medical Sciences. PMID- 29284913 TI - Telemental Health Care, an Effective Alternative to Conventional Mental Care: a Systematic Review. AB - Background and Objectives: Due to the high costs of conventional mental health care, there has been a rise in the application of web-based technologies in recent years, i.e., telemental health care. We conducted this systematic review in 2017, using high quality research articles on the applications, technologies, advantages and challenges associated with telemental health care published since year 2000. Methods: We used a combination of relevant key words to search four major databases, such as "Web of Sciences, Embase, PubMed and Science Direct". From among 156 articles, which had been published since 2000, twenty five articles met all of the inclusion criteria and were selected for the final review. The information extracted from these articles were used to construct Tables 1 and 2. Also, the materials derived from 55 credible articles were used as further support and complementary facts to substantiate the information presented in the Discussion section. Results: The findings revealed that telemental health care is an extended domain supportive of conventional mental health services. Currently, telemental health care has multiple capabilities and technologies for providing effective interventions to patients with various mental illnesses. It provides clinicians with a wide variety of innovative choices and strategies for mental interventions, in addition to significant future potentials. Conclusions: Telemental health care can provide effective and adaptable solutions to the care of mental illnesses universally. While being comparable to in-person services, telemental health care is particularly advantageous and inexpensive through the use of current technologies and adaptable designs, especially in isolated communities. PMID- 29284915 TI - An Evaluation Protocol for Picture Archiving and Communication System: a Systematic Review. AB - Introduction: Picture archiving and communication system (PACS) serves to store, transmit, communicate and manage medical images. A logical evaluation protocol assists to determine whether the system is technically, structurally and operationally fit. The purpose of this systematic review was to propose a logical evaluation protocol for PACS, particularly useful for new hospitals and other healthcare institutions in developing countries. Methods and Materials: We systematically reviewed 25 out of 267 full-length articles, published between 2000 and 2017, retrieved from four sources: Science Direct, Scopus, PubMed and Google Scholar. The extracted data were tabulated and reviewed successively by three independent panels of experts that oversaw the design of this study and the process by which the PACS evaluation protocol was systematically developed. Results: The outcome data were ranked by expert panels and analyzed statistically, with the reliability established at 0.82 based on the Pearson's correlation coefficient. The essential components and the best options to establish an optimal PACS were organized under nine main sections: system configuration;system network;data storage; datacompression;image input; image characteristics; image presentation; communication link; and system security, with a total of 20 components, each of which capable of working optimally with one or more program options. Conclusions: This systematic review presents an objective protocol that is an ideal tool for the evaluation of new or existing PACS at healthcare institutions, particularly in developing countries. Despite the significant advantages, the protocol may face minor limitations, largely due to lack of appropriate technical resources in various clinical settings and the host countries. PMID- 29284916 TI - Comparison of Basic and Ensemble Data Mining Methods in Predicting 5-Year Survival of Colorectal Cancer Patients. AB - Introduction: Colorectal cancer (CRC) is one of the most common malignancies and cause of cancer mortality worldwide. Given the importance of predicting the survival of CRC patients and the growing use of data mining methods, this study aims to compare the performance of models for predicting 5-year survival of CRC patients using variety of basic and ensemble data mining methods. Methods: The CRC dataset from The Shahid Beheshti University of Medical Sciences Research Center for Gastroenterology and Liver Diseases were used for prediction and comparative study of the base and ensemble data mining techniques. Feature selection methods were used to select predictor attributes for classification. The WEKA toolkit and MedCalc software were respectively utilized for creating and comparing the models. Results: The obtained results showed that the predictive performance of developed models was altogether high (all greater than 90%). Overall, the performance of ensemble models was higher than that of basic classifiers and the best result achieved by ensemble voting model in terms of area under the ROC curve (AUC= 0.96). Conclusion: AUC Comparison of models showed that the ensemble voting method significantly outperformed all models except for two methods of Random Forest (RF) and Bayesian Network (BN) considered the overlapping 95% confidence intervals. This result may indicate high predictive power of these two methods along with ensemble voting for predicting 5-year survival of CRC patients. PMID- 29284917 TI - Assessment of the Mental Foramen Location in a Sample of Fully Dentate Lebanese Adults Using Cone-beam Computed Tomography Technology. AB - Objective: The literature reports that the location of mental foramen shows differences among races. The aim of this study was to assess the mental foramen position in a sample of Lebanese population using cone-beam computed tomography (CBCT) technology. Materials and methods: In this study, we investigated CBCT images of 50 fully dentate Lebanese adults (23 males and 27 females). We assessed the horizontal position of the mental foramen in relation with the mandibular premolars in both right and left sides and the vertical position by measuring the distance from the upper border of the foramen to the inferior border of the body of the mandible. The data obtained were statistically analyzed using Chi-square test, and two-sided t-test. Statistical significance was set at p < 0.05. Results: In our sample, the mental foramen was mostly found in line with the second mandibular premolar in both sides and the mean distance from the superior border of the foramen to the inferior border of the body of the mandible was 13.0120 +/- 0.98487 mm on the right and 13.0728 +/- 0.96029 mm on the left. Conclusion: Within the limits of this study, we concluded that in our sample of Lebanese population, there was substantial variability in the mental foramen location. PMID- 29284918 TI - Telemedicine in Cardiology - Perspectives in Bosnia and Herzegovina. AB - Introduction: Aim of article was to present perspectives of telemedicine in the field of cardiology in Bosnia and Herzegovina. Material and methods: Article has descriptive character and present review of literature. Results: Information technology can have the application in the education of students, starting from basic medical sciences up to clinical subjects. Information technologies are used for ECG analysis, 24h ECG Holter monitoring, which detects different rhythm disorders. By developing software packages for electrocardiogram analysis, which can be divided and interpreted by mobile phones, and complete the whole of the patient in the ambulance, specialist, experienced specialists, or even consultations in various illnesses and cities. Image segmentation algorithms have significance in the quantization and diagnostics of anatomic and pathological structures, and 3D representation has an important role in education, topography and clinical anatomy, radiology, pathology, as well as in clinical cardiology itself, especially in the sphere of coronary arteries identification in the multislice computerized angiography of coronary arteries. Interactive video consultations with subspecialists from the state and the region in adult cardiology, adult interventional cardiology, cardiovascular surgery, pediatric invasive and non-invasive cardiology enable better access to heart specialists and subspecialist, accurate diagnosis, better treatment, reduction of mortality, and a significant reduction in costs. Conclusion: Telemedicine by slow steps in entering the soil of Bosnia and Herzegovina, but the potential exists. It is necessary to educate the medical staff, as well as to provide a tempting environment for software engineers. Investing in infrastructure and equipment is imperative, as well as a positive climate for the its implementation. PMID- 29284919 TI - Presenting an Evaluation Model for the Cancer Registry Software. AB - Objectives: As cancer is increasingly growing, cancer registry is of great importance as the main core of cancer control programs, and many different software has been designed for this purpose. Therefore, establishing a comprehensive evaluation model is essential to evaluate and compare a wide range of such software. Methods: In this study, the criteria of the cancer registry software have been determined by studying the documents and two functional software of this field. The evaluation tool was a checklist and in order to validate the model, this checklist was presented to experts in the form of a questionnaire. To analyze the results of validation, an agreed coefficient of %75 was determined in order to apply changes. Finally, when the model was approved, the final version of the evaluation model for the cancer registry software was presented. Results: The evaluation model of this study contains tool and method of evaluation. The evaluation tool is a checklist including the general and specific criteria of the cancer registry software along with their sub-criteria. The evaluation method of this study was chosen as a criteria-based evaluation method based on the findings. Conclusion: The model of this study encompasses various dimensions of cancer registry software and a proper method for evaluating it. The strong point of this evaluation model is the separation between general criteria and the specific ones, while trying to fulfill the comprehensiveness of the criteria. Since this model has been validated, it can be used as a standard to evaluate the cancer registry software. PMID- 29284920 TI - National Communicable Disease Surveillance System: A review on Information and Organizational Structures in Developed Countries. AB - Introduction: To obtain necessary information for managing communicable diseases, different countries have developed national communicable diseases surveillance systems (NCDSS). Exploiting the lesson learned from the leading countries in development of surveillance systems provides the foundation for developing these systems in other countries. In this study, the information and organizational structure of NCDSS in developed countries were reviewed. Methods: The study reviewed publications found on the organizational structure, content and data flow of NCDSS in the United States of America (USA), Australia and Germany that were published in English between 2000 and 2016. The publications were identified by searching the CINAHL, Science Direct, ProQuest, PubMed, Google Scholar databases and the related databases in selected countries. Results: Thirty-four studies were investigated. All of the reviewed countries have implemented the NCDSS. In majority of countries the department of health (DoH) is responsible for managing this system. The reviewed countries have created a minimum data set for reporting communicable diseases data and information. Conclusion: For developing NCDSS, establishing coordinator centers, setting the effective policies and procedures, providing appropriate communication infrastructures for data exchange and defining a communicable diseases minimum data set are essential. PMID- 29284921 TI - Splenic Localization of Primary Hydatid Cyst in a 27-Year-Old Sportsman Treated by PAIR Technique: Imaging Anatomy Assessment. AB - Introduction: In this paper, we report our experience with a case of primary hydatid cyst involving only the spleen in a 27-year-old sportsman treated by PAIR technique. Case Report: Five years before, a 27-year-old handball player being admitted to our hospital, it was detected the cyst in his spleen which size was 35 x 30 mm in diameter, by abdominal ultrasound during a systematic examination. There was no pain or any other symptoms at that time. Tests on the presence of echinococcus cysts were negative. After a period of 5 years, and regular check ups, the patient began to feel a dull pain in the left upper quadrant area. The Echinococcus test was again negative. Puncture and aspiration of content was performed and sent to cytological analysis that confirmed the presence of Echinococcus. The CT finding showed the spleen in a normal position, shape, enlarged, 185 mm in longitudinal diameter (splenomegaly), with inhomogeneous parenchyma on the expense of rounded area with hyperdense halo, which did not opacify after contrast, located in the dorsal area of the spleen, 100x98 mm in diameter and which corresponded to the echinococcal cyst in differential diagnosis-clean dense contents (protein / haemorrhagic). Conclusion: The reported case is very specific, considering that handball is contact sport, where it is almost impossible to avoid the physical contact between players, which is sometimes even rough. Due to rough contacts, spleen trauma is something we should be very aware about, especially in cases of splenomegaly with hydatid cyst, where the spleen rupture might lead to fatal outcome. According to all this, careful follow up of this patient is necessary. PMID- 29284922 TI - The Most Influential Scientists in the Development of Medical Informatics (19): John Bryden. PMID- 29284923 TI - A Prerequisite for Patient Centred Care is Empowering and Engaging Patients in the Digital Health: Report from EFMI Special Topic Conference (STC) 2017. AB - The European Federation for Medical Informatics (EFMI) held its Special Topic Conference (STC) in October 2017 in Israel. EFMI holds STC's to focus on a particular issue, whereas its major annual conference Medical Informatics Europe (MIE) has a much wider remit. This conference challenged the informatics community to engage patients in digital health. Examples of the gap in digital engagementfrom the conference contributions include: An app to connect parents to a paediatric emergency department was presented. We heard how comparisons between general practice and paediatrician led health systems were being compromised through the lack of available databases and that Europe needs a fit-for-purpose paediatric electronic health records (EHR). The public should be involved in shared EHR platform development. We were informedpatients preferred clinicians to use their mobile device and how the online community can be a source of research subjects. A visualisation tool is being developed to display data about attention deficit hyperactivity disorder (ADHD). On a more sombre note the conference remembered Assa Reichert, a long standing member of EFMI. Notwithstanding our reflections on Assa's service to EFMI and informatics, this conference provide a real opportunity to explore how digital health might empower patients. PMID- 29284925 TI - Systemic and Topical Steroids in the Management of Oral Mucosal Lesions. AB - From the time of its introduction in the 1040s, glucocorticoids have provided a panacea for many diseases. The therapeutic benefit of corticosteroids lies in their anti-inflammatory and immunosuppressive properties which makes them highly effective in the management of oral mucosal lesions. This article aims to present to the clinician, the plethora of options available as steroid therapy and enables one to choose based on the underlying disease and the properties of the drug. PMID- 29284926 TI - A Clinicopathological Study of Various Oral Cancer Diagnostic Techniques. AB - Oral cancer is one of the most commonly occurring malignant tumors in the head and neck regions with high incident rate and mortality rate in the developed countries than in the developing countries. Generally, the survival rate of cancer patients may increase when diagnosed at early stage, followed by prompt treatment and therapy. Recently, cancer diagnosis and therapy design for a specific cancer patient have been performed with the advanced computer-aided techniques. The responses of the cancer therapy could be continuously monitored to ensure the effectiveness of the treatment process that hardly requires diagnostic result as quick as possible to improve the quality and patient care. This paper gives an overview of oral cancer occurrence, different types, and various diagnostic techniques. In addition, a brief introduction is given to various stages of immunoanalysis including tissue image preparation, whole slide imaging, and microscopic image analysis. PMID- 29284924 TI - In defence of model-based inference in phylogeography. AB - Recent papers have promoted the view that model-based methods in general, and those based on Approximate Bayesian Computation (ABC) in particular, are flawed in a number of ways, and are therefore inappropriate for the analysis of phylogeographic data. These papers further argue that Nested Clade Phylogeographic Analysis (NCPA) offers the best approach in statistical phylogeography. In order to remove the confusion and misconceptions introduced by these papers, we justify and explain the reasoning behind model-based inference. We argue that ABC is a statistically valid approach, alongside other computational statistical techniques that have been successfully used to infer parameters and compare models in population genetics. We also examine the NCPA method and highlight numerous deficiencies, either when used with single or multiple loci. We further show that the ages of clades are carelessly used to infer ages of demographic events, that these ages are estimated under a simple model of panmixia and population stationarity but are then used under different and unspecified models to test hypotheses, a usage the invalidates these testing procedures. We conclude by encouraging researchers to study and use model-based inference in population genetics. PMID- 29284927 TI - Ancient Seed for Modern Cure - Pomegranate Review of Therapeutic Applications in Periodontics. AB - Punica granatum (pomegranate), the member of Punicaceae family, is used in the prevention and treatment of health disorders. P. granatum contains diverse range of phytochemicals including ellagic acid, punicalagin, pedunculagin, quercetin, rutin, tannic acid, polyphenol, anthocyanins, and catechins. This review aims at providing an overview of the chemical constituents, antibacterial, anti inflammatory, and antioxidant properties of P. granatum, and its role in the prevention and treatment of gingival and periodontal diseases. PMID- 29284929 TI - Oral Field Cancerization and Its Clinical Implications in the Management in Potentially Malignant Disorders. AB - Oral cancer is one of the common malignancies reported in India. Most of these cancers are preceded by potentially malignant disorders. Despite improvements in the management strategies of these cancers the posttreatment prognosis has remained poor. The 5-year survival rates of oral cancers in most countries are still below 50%. The poor outcomes in oral cancer prevention and treatment can be due to nature of the spread of genetically altered cells as fields within the epithelial compartment. The conventional management protocols need to be modified taking into consideration the field spread of genetically altered cells. PMID- 29284928 TI - Molecular Pathogenesis and Diagnostic Imaging of Metastatic Jaw Tumors. AB - Metastasis is the spread of malignant cells from a primary tumor to distant sites through lymphatics or blood vessels. Malignant lesions metastasizing to the oral and perioral region are a rarity indeed. Malignant lesions could metastasize to both soft tissue of oral cavity and the hard tissues of the jaws and recent meta analysis showed that metastasis is more common in the jaws than oral soft tissues because of rich vascular supply. The incidence is very low when compared to the incidence of primary oral cancers; nevertheless, one has to include in the diagnostic workup, metastatic malignant lesions, when an irregular ill-defined radiolucency or radiodensity with ragged edges in noted. It could be a challenging task for a diagnostician, in cases with the presence and location of the primary tumor is unknown. Advanced oral imaging technologies and biochemical markers play a vital role in diagnosing such lesions. PMID- 29284930 TI - Obstructive Sleep Apnea. AB - Obstructive sleep apnea syndrome (OSAS) is a potentially serious disorder attacking millions of people around the world. Many of these individuals are undiagnosed, and even though diagnosed often exhibit a poor compliance with the use of continuous positive airway pressure at nights, a very effective nonsurgical treatment. A variety of surgical procedures have been proposed to manage and treat OSA. This article throws insights into assessing the sites of obstruction and a number of surgical procedures designed to address OSA. The scope of this article is to provide information to dentists which enables them to identify the patients who have OSAS and to guide these patients in making informed decisions regarding treatment options. PMID- 29284931 TI - Are Tooth Prints a Hard Tissue Equivalence of Finger Print in Mass Disaster: A Rationalized Review. AB - Personal identification methods may not be efficient when bodies are decomposed, burned, in cases of mass disasters when soft tissue cannot provide reliable information or has been lost. Various methods currently employed in forensic odontology for personal identification include comparing with antemortem dental charts, rugoscopy, denture labeling, DNA analysis from dental pulp, bite mark analysis, etc., Recently, there is growing interest in the study of enamel rod end patterns. These enamel rod end patterns are termed as "Tooth prints" and the study of these prints is known as "Ameloglyphics" (amelo: Enamel, Glyphics: Carvings). This review encompasses about the basis of using enamel rod end patterns, methods of obtaining the patterns and further suggests these tooth prints as an analogy to finger print in personal identification in mass disasters. PMID- 29284932 TI - Partial Edentulousness in a Rural Population Based on Kennedy's Classification: Epidemiological Study. AB - Introduction: Edentulousness falls in a special category among the various conditions of dental origin. A simple estimation of the partial edentulous condition is a rough indication of the prevalence of dental diseases and success or failure of dental care. Methodology: In this study a cross sectional survey was carried out among 1000 patients of rural population in JKK Nataraja Dental College, Komarapalayam, Namakkal District, Tamilnadu, India. The aim of this study was to evaluate the epidemiological features of partial edentulous condition in the age group of 30-60 years in a rural Population based on the Kennedy classification. A pre tested questionnaire was Used in this study. Result: Chi-square test was conducted and results were obtained and P value <0.05 was considered stastically significant. Conclusion: The study revealed Kennedy Class III partially edentulous condition was more common than other conditions. There is significant correlation between lack of awareness, education and socio economic status in relation to loss of teeth among population. PMID- 29284933 TI - Evaluation of Efficiency of Different Decontamination Methods of Dental Burs: An In vivo Study. AB - Introduction: Infection control is very important in dentistry. Both dentist and patients are at risk of communicating diseases during treatment procedures. Dental burs have been identified as a source of cross-contamination between patient and dental personnel. Aim: The present study was done to quantitatively and qualitatively assess the pathogenic contamination of dental burs used for tooth preparation and to determine the effective method of sterilization(autoclave, glass bead sterilizer, hot air oven and surgical spirit immersion) of burs used for crown preparation. Methodology: Dental burs were assessed before and after tooth preparation, also after sterilization burs were evaluated. Conclusion: Findings of our study revealed that among the experimental groups used in the present study, Autoclave and Hot air oven was found to be the relatively best method to sterilize burs. Proper cleaning and sterilization of burs should be strictly employed to prevent cross contamination in clinical practice. PMID- 29284934 TI - Detection of Adherence of Enterococcus faecalis in Infected Dentin of Extracted Human Teeth Using Confocal Laser Scanning Microscope: An In vitro Study. AB - Aim: The aim of this study is to detect in vitro adherence of Enterococcus faecalis to the infected dentinal tubules of human extracted teeth using confocal laser scanning microscope. Subjects and Methods: Roots from human premolar teeth (n = 40) were infected with E. faecalis strain the American Type Culture Collection 29212 in brain heart infusion for 21 days. After the experimental period, specimens were divided into two groups, Group A (n = 20), Group B (n = 20), and Group A specimens were stained with fluorescein diacetate dye for the detection of viability and adherence Group B were stained with acridine orange dye for detection of metabolic activity and adherence. Samples were washed, thoroughly sectioned and examined by confocal laser scanning microscopy. Computer assisted determinants of fluorescence, bacterial viability, metabolic activity, and adherence were compared statistically. Results: E. faecalis was able to invade the dentinal tubules to a depth of 1-400 MUm and adhere to 1-200 MUm depth. Adherence (90%) was significantly higher in 1-100 MUm using fluorescein diacetate and acridine orange dye. Conclusion: Adherence of E. faecalis as evaluated by confocal laser scanning microscope was highest at the depth of 1-100 MUm which may have an impact on the shaping and cleaning procedures on the root canal. PMID- 29284935 TI - An Evaluation of Occlusal Relationship and Primate Space in Deciduous Dentition in Kancheepuram District, Tamil Nadu, India. AB - Aim: The objective of the study was to evaluate the occlusal characteristics of primary dentition in 3-5-year-old children in Kancheepuram district. Materials and Methods: A cross-sectional survey was carried out on children aged 3-5 year old in the Kancheepuram district. A total of 603 children were examined. Occlusal relationship was assessed separately on both right and left side and was classified as a flush terminal plane, mesial step, or distal step. Similarly, occlusal relationship of primary canine was examined and classified as Class I, II, or III. Primate space was measured in both the arches using digital Vernier caliper. Results: Pearson Chi-square test was used. Statistical significance was noted on both right and left side primary molar occlusion as well as in the canine occlusion across the three age groups. Primate spaces in both arches have been found to be significant across the three age groups. Mann-Whitney test between gender and occlusal relationship was found to be not significant. Conclusion: Flush terminal plane is the most common primary molar occlusion found in the present study which is statistically significant. Most of the children had primate space present in upper and lower teeth which is statistically significant. PMID- 29284936 TI - Maternal Risk Factors and Periodontal Disease: A Cross-sectional Study among Postpartum Mothers in Tamil Nadu. AB - Background and Aim: It is inconclusive that periodontitis is an independent risk factor for adverse pregnancy outcomes. This study aims to investigate the association between maternal periodontitis and preterm and/or low birth weight babies. Settings and Design: This was a prospective cross-sectional study. After prior informed consent, 3500 postpartum mothers were selected from various hospitals in Tamil Nadu and categorized into the following groups: group-1 - Normal term normal birth weight (n = 1100); Group-2 - Preterm normal birth weight (n = 400); Group-3 - preterm low birth weight (PTLBW) (n = 1000); and Group-4 - Normal term low birth weight (n = 1000). Periodontal examination was done, and risk factors were ascertained by means of questionnaire and medical records. Statistical Analysis: Comparison between case groups and control groups were done, odds ratio (OR) was calculated, and statistical significance were assessed by Chi-square tests. To control for the possible confounders, all variables with P < 0.05 were selected and entered into multivariate regression model, and OR and 95% confidence limits were again estimated. SPSS-15 software was used. Results: Periodontitis was diagnosed in 54.8%, 52.3%, 53.8%, 59.4%, respectively. On comparison between the groups, none of periodontal parameters showed significant association except for the crude association observed in Group-4 for mild periodontitis (OR - 1.561; P = 0.000) and PTLBW. Conclusion: Periodontitis is not a significant independent risk factor, and obstetric factors contribute a major risk for preterm and/or low birth weight babies. PMID- 29284937 TI - Prevalence of Oral Mucosal Lesions among Dental Patients with Mixed Habits in Salem District - A Study. AB - Background: The practice of betel nut chewing with or without tobacco is still practiced in south india, salem inspite of its harmful effects. Methodology: 200 Patients visiting the outpatient department, Oral medicine and radiology from Aug 2015 to Aug 2016. Result and Conclusion: In our study, 3 women were exclusively churut smokers. Thirty-eight percent of the dental patients were beedi smoker, 32% were tobacco chewers, 12% were both betel nut and tobacco chewers, 8% were exclusively betel nut chewers, 1% of the dental population were exclusively churut smokers. Mean age group of the study population is 50.2 (14.4). There are 28 females and 172 males in the study group. Chi-square test revealed a statistically significant difference (P = 0.001) between males and females based on soft-tissue findings and no statistically significant difference (P = 0.572) between males and females based on distribution of hard-tissue findings. PMID- 29284938 TI - Root Canal Configuration of Human Permanent Mandibular First Molars of an Indo Dravidian Population Based in Southern India: An In vitro Study. AB - Aim: This study aims to analyze root canal configuration of human permanent mandibular first molars of an indo-Dravidian population based in southern India. Materials and Methods: A total of 1147 mandibular first permanent molars were collected, cleansed, and stored. The number of roots was recorded, access preparations made, pattern of orifices recorded after pulpal floor debridement, dye injected into the canals using apical negative pressure and subjected to a clearing technique. They were then analyzed using a stereo microscope and the canal configurations recorded (Vertucci). The number of roots, the pattern of orifices and canal configuration were recorded. Results: The pattern of orifices was triangular (87.9%), rectangular (8.5%), C-shaped (3.0%), and two orifice pattern (0.6%). About 95.6% of teeth had two roots, and 4.4% had three roots. The most common canal system configuration in mesial root was Vertucci type IV (52.3%), followed by type II (35%). Root canal configuration of the distal root revealed type I configuration in 62.7%, followed by types II (14.5%) and IV (12.4%). The distolingual root had a type I configuration. Conclusion: Awareness of canal configuration, adequate clinical skills, use of specialized techniques of diagnosis, debridement and obturation will pave the way for successful treatment outcomes. PMID- 29284939 TI - A Comparative Evaluation of Intraradicular Smear Removal Efficacy of 2% Chitosan (Low Molecular Weight), 4% Chitosan Citrate, and 10% Citric Acid when Used as Final Rinse in Irrigation Protocols: A Field Emission Scanning Electron Microscopic Study. AB - Aim: This study aims to compare the smear layer removal efficacy of 2% chitosan (low molecular weight) (C-LMV), 4% chitosan citrate (CC), and 10% citric acid (CA) when used in specific irrigant protocols. Materials and Methods: A total of 60 single-rooted maxillary incisors and canines were decoronated, standardized to a root length of 15 mm, and prepared with rotary files up to protaper F3 size. Sodium hypochlorite was used as initial rinse [8 ml]. The samples were divided into experimental (Group III, IV, V, and VI) (n = 10) and control groups (I - 17% EDTA, II - normal saline) (n = 5) based on the type of final rinse solution (5 ml) used, that is, 2% C-LMV, 4% C-citrate, 10% CA, and 1% acetic acid. Samples were dehydrated, split buccolingually, gold sputter coated, and examined in field emission scanning electron microscope. Results: Overall, the Group IV, V, and III presented the least amounts of smear, debris, and erosion among the experimental groups at the apical, middle, and coronal one-thirds of the root canal with a mean value of 1.53 +/- 0.42, 1.33 +/- 0.42, and 1.60 +/- 0.46, respectively, and there was no statistically significant difference (P > 0.05). Conclusion: The use of CC as final rinse solution during biomechanical preparation seems promising. PMID- 29284940 TI - Recovery of Mercury from Dental Amalgam Scrap-Indian Perspective. AB - Aim: The aim is to recycle mercury from dental amalgam scrap using the vacuum distillation method. Materials and Methods: A total of 150 g of dental amalgam scrap was taken in a round bottom flask and was subjected to vacuum distillation at 398 degrees C. The vapor of mercury was collected in another round bottom flask. Observation: The procedure is carried out for mercury recovery using vacuum distillation apparatus, and mercury vapor are collected in a round bottom flask, and the silver is recovered using sucrose as reducing agent. Using 150 g of dental amalgam scrap 50%-80% of silver are recovered, and silver has a purity of 70%-80%. However, the total time required in the reduction process ranged between 303 and 600 min. Conclusion: Mercury could be recycled from dental amalgam scrap through vacuum distillation method at 398 degrees C and its implication of dental amalgam scrap in an Indian perspective. PMID- 29284941 TI - A Comparative Evaluation of Bifidobacteria Levels in Early Childhood Caries and Severe Early Childhood Caries. AB - Background: Bifidobacteria levels in saliva were found to be significantly correlated in adults with dental caries but less information available in the literature regarding its role in children. Aim: The aim is to compare the salivary levels of Bifidobacteria in children who are caries free with that of early childhood caries (ECC) and severe ECC (S-ECC). Materials and Methods: Saliva was collected using the tongue-loop method from a total of 60 children between the age group of 3-5 years and they were further divided into 3 groups. In addition, the age and gender of the children, sugar amount in diet, sugar frequency in diet, were recorded. Results: Bifidobacteria was isolated from all the three groups, but more were from S-ECC, followed by ECC and very few cases of caries-free children and was found to statistically significant (P < 0.001). Salivary levels of Bifidobacteria were significantly correlated with amount of sugar in the diet and frequency of sugar consumption. Conclusions: Salivary levels of Bifidobacteria were significantly associated with S-ECC and ECC, followed by caries free group. In future, it can be used as a salivary marker for caries risk assesment. PMID- 29284942 TI - Knowledge and Attitude about Early Childhood Caries among Pregnant Mothers from Low Socioeconomic Status: A Questionnaire Study. AB - Background: For health and well-being, oral health is an integral component. Unfortunately, many children are afflicted with dental caries at an early age, even those as young as 12 months. By imparting knowledge, awareness among parents about this disease can bring about reduction of early childhood caries (ECC) at an early stage. Aim: The aim of this study was to evaluate knowledge and attitude of expectant mothers about ECC and to reassess the level of knowledge after giving anticipatory guidance. Materials and Methods: The questionnaire consisted of 10 questions which were distributed to 100 participants after which anticipatory guidance was given to them. After 15 days, the same questionnaire was distributed among the participants with order of the questions interchanged. Chi-square test was used for statistical analysis. Results: There was a significant improvement in the knowledge and attitude about the disease after giving the anticipatory guidance among the participants. P < 0.01 and the result were statistically significant. Conclusion: Knowledge and attitude of mothers were found to increase on provision of anticipatory guidance, which was retained even after 15 days. PMID- 29284943 TI - Comparative Evaluation of Dental and Skeletal Fluorosis in an Endemic Fluorosed District, Salem, Tamil Nadu. AB - Background: High levels of fluoride in the drinking water, especially ground water, results in skeletal fluorosis which involves the bone and major joints. This study was conducted to assess the prevalence of skeletal fluorosis to compare with dental fluorosis in an endemically fluorosed population in the District of Salem, Tamil Nadu. Materials and Methods: Institutional ethical clearance was obtained. A total of 206 patients who reported to the Department of Hematology for blood investigations were the participants in this study. Age, sex, place, weight, height, dental fluorosis, and skeletal complaints were noted down. Body mass index was calculated, and statistical analysis was performed. Results: Dental fluorosis was present in 63.1% and absent in 36.9% of the samples reported. Skeletal fluorosis was present in 24.8% and was absent in 75.2%. A large number of the patients had knee pain and difficulty in bending. Chi-square test was used for statistical analysis. Skeletal fluorosis and age were compared and P value was 0.00 and was significant. Dental fluorosis and skeletal fluorosis were compared and P value was found to be 0.000 and significant. Discussion and Conclusion: There is a need to take measures to prevent dental and skeletal fluorosis among the residents of Salem district. Calcium balance should be maintained, and fluoride intake should be minimized to reduce the symptoms. The government should provide water with low fluoride level for drinking and cooking. Once the symptoms develop, treatment largely remains symptomatic, using analgesics and physiotherapy. PMID- 29284944 TI - Comparison of Orthopantomogram and Lateral Cephalogram for Mandibular Measurements. AB - Aim: The aim of the present study is to clarify the possible application of orthopantomogram (OPG) for evaluating craniofacial specifications such as angular and linear measurements of the mandible by comparing with lateral cephalogram. Materials and Methods: OPG and lateral cephalogram were taken from 100 patients of age group 16-35 years from Chettinad Dental College and Research Institute. Linear measurements (body length and ramus height) and angular measurement (gonial angle) were assessed both in lateral cephalogram and OPG. Independent t test was performed for comparison of OPG and lateral cephalogram using SPSS with a probability level of P < 0.05 considered to be statistically significant. Results: The results of the present study show that there is no statistically significant difference in ramus height and gonial angle when compared between OPG and lateral cephalogram while statistically significant difference exists for body length between OPG and lateral cephalogram. Conclusion: It may be concluded that panoramic radiography can be used to determine the gonial angle and ramus height as accurately as a lateral cephalogram. However, clinicians should be vigilant when predicting horizontal measurement from OPGs. PMID- 29284945 TI - Comparison of Marginal Periosteal Pedicle Graft and Bioactive Glass with Platelet rich Fibrin and Bioactive Glass in the Treatment of Intrabony Defects - A Clinicoradiographic Study. AB - Introduction and Objectives: The objective of the study was to compare clinically and radiographically the regenerative potential of marginal periosteal pedicle graft (MPPG) or platelet-rich fibrin (PRF) with a bioactive glass in the treatment of two- and three-wall intrabony defects. Methods: A total of 28 sites (bilateral or contralateral infrabony defects) from 14 patient were treated with MPPG (Experimental site A) and the other site was treated with PRF (Experimental site B). The clinical parameters, such as full-mouth plaque index (PI) and site PI, were recorded at baseline, 3, 6, and 9 months' postsurgery while sulcus bleeding index (SBI), probing pocket depth (PD), clinical attachment level (CAL), and gingival recession were recorded at baseline, 6, and 9 months. Radiographic evaluation was carried out to evaluate the defect fill, change in alveolar crest height, and percent defect fill at 6 and 9 months. Results: Results showed that both the experimental groups showed clinically and statistically significant reduction in mean PI, SBI, PD, radiographic defect depth, and gain in CAL. The percentage of defect fill at 6 months (70.55 +/- 15.99 vs. 55.30 +/- 11.87) and 9 months (84.55 +/- 11.74 vs. 72.2 +/- 9.91) was significantly greater in Site A compared to Site B. Conclusions: Within the limitations of this study, it can be concluded that both the treatment modalities showed the potential of enhancing bone regeneration. However, the use of marginal periosteal pedicle flap showed better improvement in clinical and radiographic parameters. PMID- 29284946 TI - To Compare and Evaluate the Sorption and Solubility of Four Luting Cements after Immersion in Artificial Saliva of Different pH Values. AB - Introduction: The word 'luting' is derived from a latin word 'Lutum' which means 'mud'. 'Luting' is a word that is often used to describe the use of a mouldable substance to seal a space or to cement two components together. Therefore in view of the clinical importance of dissolution of luting cements in the oral environment, an in vitro study was designed to compare the sorption and solubility of commercially available luting cements mainly zinc phosphate, Glass Ionomer cement, Resin Modified Glass Ionomer Cement and Resin Cement after immersion in artificial saliva of different ph values of 5 and 7. Aim: To Compare and Evaluate the sorption and solubility of four luting cements after immersion in artificial saliva of different pH values. Materials and Method: A total of 120 test samples were prepared of which 30 samples of each luting cement were prepared for the purpose of assessing the water solubility and sorptionThese luting cements were grouped as: GROUP- A (Zinc Phosphate cement), GROUP- B (Glass Ionomer Cement), GROUP-C (Resin Modified Cement), GROUP- D (Resin Cement) In these groups, based on immersion of artificial saliva of acidic pH 5 and neutral pH7, the luting cement specimens were subdivided into 2 groups of 15 samples each. The volume (V) of each specimen was calculated using mathematical formula. Conclusion: Resin cement had the highest resistance to solubility and sorption followed by resin modified GIC, Conventional GIC, and Zinc Phosphate which exhibited the least resistance to solubility in both artificial saliva of pH 5 and pH 7. PMID- 29284947 TI - An In vitro Comparison of Coconut Water, Milk, and Saline in Maintaining Periodontal Ligament Cell Viability. AB - Background and Objectives: Two of the most critical factors affecting the prognosis of an avulsed tooth after replantation are extraoral dry time and the storage media in which the tooth is placed before treatment is rendered. The present study is undertaken to evaluate the periodontal ligament (PDL) cell viability after storage of teeth in different storage media, namely, coconut water, milk, and saline. Materials and Methods: Forty sound human premolars undergoing extraction for orthodontic purpose were selected. The teeth were allowed to lie dry on sand/mud for 30 min followed by which they were randomly divided and stored in three different media, i.e., coconut water, milk, and saline. After 45-min storage in their respective media, the root surface was then scraped for PDL tissue. Results: The ANOVA and Newman-Keuls post hoc procedure for statistical analysis of viable cell count under a light microscope using hemocytometer demonstrated that coconut water preserved significantly more PDL cells viable (P < 0.05) compared with milk and saline. Conclusion: Storage media help in preserving the viability of PDL cells when immediate replantation is not possible. This study evaluated the posttraumatic PDL cells' viability following storage in three different storage media. Within the parameters of this study, it was found that coconut water is the most effective media for maintaining the viability of PDL. PMID- 29284948 TI - Effect of Fluoride Varnish and Dentifrices and Its Combination on Deciduous Enamel Demineralization: An In vitro Study. AB - Introduction: Dental caries remains the most important dental health problem in developing countries. Application of varnish on tooth surfaces is shown to promote the uptake of firmly bound fluoride by enamel, which is considered important. Along with the incorporation of fluoride into the crystalline lattice, there is formation of calcium fluoride compounds on enamel. Methodology: Seventy deciduous canines were covered with nail polish. A window measuring 4 mm * 4 mm was left on their buccal surface, These were randomly assigned to seven groups (n = 6): S: sound enamel not subjected to any regimen or treatment; N: negative control, subjected to the pH-cycling regimen without any treatment; D1 and D2: subjected to the pH-cycling regimen and treated two times daily with 1100 and 500 ppm F dentifrice, respectively; VF: fluoride varnish (subjected to F-varnish before and in the middle of the pH-cycling regimen); and VF + D1 and VF + D2. After a period of 10 days, sectioning of teeth was done, and enamel demineralization was measured. Results: The combination of dentifrice and varnish (groups VF + D1 and VF + D2) significantly reduced demineralization compared with the N group at all distances evaluated (P < 0.05), but the combination did not differ from the dentifrice groups at most distances from the surface (P > 0.05). Conclusion: The results of this study suggest that the combination of F-varnish with dentifrices containing 500 or 1100 ppm F is not more effective in reducing demineralization in primary teeth than the isolated effect of dentifrice containing 1100 ppm. PMID- 29284949 TI - Smoking Cessation Advice: Knowledge, Attitude, and Practice among Clinical Dental Students'. AB - Background: Smoking is the single most important public health challenge facing the National Health Service. The detrimental effects on the general health of tobacco smoking are well documented. Smoking is a primary risk factor for oral cancer and many oral diseases. Dental professional scan plays an important role in preventing adverse health effects by promoting smoking cessation. Objective: To assess the knowledge, attitude, and practice among clinical dental students in giving smoking cessation advice and to explore the barriers to this activity. Materials and Methods: A total of 262 clinical dental trainee of two dental colleges (College of Dental Sciences and Bapuji Dental College) of Davangere city were included in the survey. A self-administered questionnaire was administered to assess the knowledge, attitude, and practice toward Tobacco Cessation Advise. Results: Among the 262 participants in the study, around 51% said they know about Nicotine Replacement Therapy, and among them, only 4.6% were aware of the options available in the market. When asked about 5A's of tobacco cessation, only 35.5% were aware of it. Similarly, when asked about 5R's of tobacco cessation, 48.5% were unaware of it. Conclusions: The respondents did not have sufficient knowledge regarding tobacco cessation advice. With patient's disinterest and lack of time being quoted as the important barriers in providing tobacco cessation advice, it is highly recommended that there is need to incorporate few chapters on tobacco, its effect and cessation of habit in the undergraduate dental curriculum with simultaneous application of the same in clinical practice. PMID- 29284950 TI - Effect of Biomineralization Ability on Push-out Strength of Proroot Mineral Trioxide Aggregate, Mineral Trioxide Aggregate Branco, and Calcium Phosphate Cement on Dentin: An In vitro Evaluation. AB - Context: Biomineralization is a process which leads to the formation of an interfacial layer with tag-like structures at the cement-dentin interface. It is due to interaction of mineral trioxide aggregate (MTA) and Portland cement with dentin in phosphate-buffered solution (PBS). This study is aimed to evaluate the effect of influence of biomineralization process on push-out bond strength of ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK, USA), MTA Branco (Angelus Soluc o~es Odontolo'gicas, Londrina, PR, Brazil) and calcium phosphate cement (BioGraft CPC). Aim: The aim of this study was to evaluate the effect of biomineralization process on the push-out strength of ProRoot MTA, MTA Branco, and CPC after mixing with 0.2% chlorhexidine gluconate solution (0.2% CHX) and 2% lidocaine solution (2% LA) on the bond strength of MTA-dentin. Materials and Methods: Dentin discs with uniform cavities were restored with ProRoot MTA, MTA Branco, and calcium phosphate cement after mixing with 0.2% CHX solution and 2% lidocaine solution. The samples were uniformly distributed into two groups. Experimental group being immersed in PBS solution and control group being immersed in saline for 2 months. Instron testing machine (Model 4444; Instron Corp., Canton, MA, USA) was used to determine the bond strength. Statistical Analysis Used: A two-way analysis of variance and post hoc analysis by Bonferroni test. Results: All samples immersed in experimental group displayed a significantly greater resistance to displacement than that observed for the samples in control group (P < 0.05). MTAs displayed a significantly greater resistance to displacement than calcium phosphate cements. Conclusion: The main conclusion of this study was that the push-out bond strength of the cements, mainly the MTA groups, was positively influenced by the biomineralization process. PMID- 29284951 TI - An In Vivo Study to Compare and Evaluate the Correlation of the Facial Measurements with the Combined Mesiodistal Width of the Maxillary Anterior Teeth between Males and Females. AB - Aim: The aim of this study was to compare and evaluate the correlation of the facial measurements (interalar, intercommissural, intercanthal, and interpupillary distance) with the combined mesiodistal width of the maxillary anterior teeth between males and females. Objectives: The objectives of this study were: (a) To evaluate the correlation of the facial measurements (interalar, intercommissural, intercanthal, and interpupillary distance) and combined mesiodistal width of maxillary anterior teeth. (b) To compare the correlation of the facial measurements (interalar, intercommissural, intercanthal, and interpupillary distance) with the combined mesiodistal width of maxillary anterior teeth between males and females. Materials and Methods: This study was carried out on 120 dentate Subjects selected from Yenepoya Dental College, Mangalore. The vernier caliper was used to measure the interalar, intercommissural, intercanthal, and interpupillary distance. The mesiodistal width of maxillary anterior teeth was measured on the cast. For accuracy, every distance was measured three times and the mean taken. Results: Comparison of parameters between males and females was calculated using independent sample t test. The values obtained for each variables are interalar distance: for males 38.89 +/- 2.19 and for females 35.58 +/- 2.33. Intercommissural distance: for males 50.96 +/- 2.99 and for females 47.15 +/- 2.97. Intercanthal distance: for males 31.92 +/- 1.46 and for females 30.46 +/- 2.07. Interpupillary distance: for males 65.15 +/- 2.82 and for females 61.78 +/- 3.18. Mesiodistal width of maxillary anterior teeth: for males 52.55 +/- 1.82 and for females 51.33 +/- 2.50. Conclusion: Within the limitations of this study, the study concluded there is a significant correlation between interalar, intercommissural, intercanthal, interpupillary distance, and mesiodistal width of maxillary anterior teeth in total subjects. In females, there is a significant correlation between interalar, intercanthal, interpupillary distance, and mesiodistal width of maxillary anterior teeth. PMID- 29284952 TI - An Evaluation of the Effect of Various Gloves on Polymerization Inhibition of Elastomeric Impression Materials: An In vitro Study. AB - Background: Latex protective barriers such as gloves and rubber dam material have been used widely in restorative procedures for crown and bridge. However, the chemical used during latex glove fabrication is thought to inhibit the polymerization of elastomeric impression materials used for impression making which has a detrimental effect on the dimensional accuracy and surface definition of resultant casts used for restorative procedures. The objectives of the study were to examine the surface of different elastomeric impressions on contact with various gloves. Materials and Methods: This clinical study included a total of eighty specimens of two types of the putty elastomeric impression material were hand manipulated by wearing three different gloves materials and is placed on a marked area of a clean and alcohol-treated glass slab at room temperature. The specimens examined for any signs of polymerization inhibition. The specimen will be rated as being "inhibited" if any residue remains on the glass slab and absence of the above will result as "no inhibition." Results: The results showed no interference with the polymerization inhibition of the selected elastomers followed by the nitrile glove. The latex gloves showed inhibited set of the elastomeric impression material but set after sometime confirming time-dependent inhibition of the impression material. Conclusion: This study shows that the use of latex and sometime nitrile gloves during crown and bridge procedures should be contraindicated and the use of vinyl gloves should be stressed when working with elastomeric impression materials. PMID- 29284953 TI - Incidence and Pattern of Dental Erosion in Gastroesophageal Reflux Disease Patients. AB - Aim: Gastroesophageal reflux disease (GERD) is a very common condition whose consequences of are localized not only in the esophagus; extra-esophageal involvement has frequently been reported. The aim of the study is to examine the incidence and pattern of dental erosion in GERD patients. Methodology: A total of 50 patients were recruited in this study (control -25 and GERD -25). All participants diagnosed having GERD by the endoscopic examination by their gastroenterologist are included. The patients were examined for dental erosion and will be quantified using Basic erosive wear examination index. Results: The results showed that the incidence of dental erosion was 88% as compared to 32% in the control group which was found to be statistically significant. PMID- 29284954 TI - Effect of Transcutaneous Electrical Nerve Stimulation on Parotid Saliva Flow in Patients with Hyposalivation. AB - Context: In recent days, we have come across an increase incidence of dry mouth as a side effects of drugs and in order to bring an awareness about a simple non- invasive method to increase the salivary flow, we have used TENS which in many way is beneficial to patients with metabolic disorders. Aims and Objectives: The aim is to assess the effectiveness of transcutaneous electrical nerve stimulation on salivary gland function in patients with hyposalivation. Subjects and Methods: The present study included total of 25 subjects with complaint of hyposalivation. Written informed consent was obtained from all the participants. Subjects with pacemakers, autoimmune diseases, pregnancy, and history of salivary gland pathology were excluded from the study. Subjects were asked to refrain from eating, drinking, chewing gum, smoking, and oral hygiene procedures for at least 1 h before the appointment. Unstimulated saliva was collected using modified Carlson Crittenden cup placed over the Stenson's duct bilaterally for 5 min and measured. TENS pads were placed over the parotid region and were activated. The intensity control switch was adjusted for patient's comfort. The intensity was turned up 1 increment at a time at 5 s intervals until the optimal intensity level was reached and stimulated saliva was then collected for 5 min using the modified Carlson Crittenden cup and measured. Any increase in parotid salivary flow (SF) with electrostimulation was considered a positive finding. Statistical Analysis Used: A paired t-test, evaluating mean changes in stimulated versus unstimulated SF rates, was applied to look for statistically significant differences using PASW 18.0 for Windows. An independent sample t-test was performed to note difference between genders. Results: There was significant increase in parotid SF in 19 of 25 patients after transcutaneous electrical nerve stimulation. Males showed more salivary secretion when compared to females. Conclusions: From the results of the study and within limitations of the study, it can be concluded that TENS was effective in increasing the SF rate in hyposalivatory patients with residual saliva. TENS was less effective in patients who are under xerogenic drugs. Thus, TENS may be an ever-growing armamentarium in the management of salivary gland hypofunction when other therapies have failed or are contraindicated. PMID- 29284955 TI - Knowledge and Attitude of Dental Surgeons about Ocular Complications Due to Dental Infection. AB - Background: Ocular complications such as ophthalmia, defective vision, orbital cellulitis, and blindness (temporary or permanent) are rare complications due to dental infection. Currently, there is lack of guidelines in preventing and managing ocular problems. Hence, we assessed the dentist's knowledge and attitudes about ocular complications due to dental infection. Materials and Methods: A cross-sectional prospective survey selecting practicing dentists or academicians was carried out through e-mail using a standardized self administered questionnaire. The data were statistically analyzed using descriptive statistics (percentage). Results: Only 25% participants knew about ocular complications due to dental infection. Journals and internet were the key sources of information among dentists. Majority of participants responded that ocular complications are underreported in the literature. Large proportion (90%) of the participants advocated research on ocular complications due to dental infection. Many participants indicated the prevention of ocular complications. Conclusion: In our observation, dentist's knowledge about ocular complications due to dental infection was poor, and the awareness and practice of taking preventive measures were satisfactory. There is need for providing adequate information about ocular problems in the curriculum of dentistry. Dentists should be trained about prevention and initial management of ocular complications due to dental infection through special educations such as continuing dental educations, workshops, and symposium. PMID- 29284956 TI - Effect of Surface Modifications on the Retention of Cement-retained Implant Crowns under Fatigue Loads: An In vitro Study. AB - Background: Masticatory forces cause fatigue to the dental luting agents, adversely affecting the retention of these cement-retained crowns. Sandblasting (SB) and diamond abrading the abutment surface improves the bond strength of luting agents. However, the effect of acid etching (AE) on the implant abutment surface and the effect of other surface modifications under masticatory load are yet to be documented. Purpose: The aim of the study was to evaluate the effect of abutment surface modifications on the retention of cement-retained restorations subjected to cyclic fatigue loads. Materials and Methods: Forty Ni-Cr copings were made on Cp-titanium laboratory analogs. The specimens were divided into two groups as Group I: Uniaxial tensile loading (UTL) and Group II: Offaxial cyclic loading followed by uniaxial tensile loading [CTL]. Further subgrouped as, subgroup I: Control (C), subgroup II: SB, subgroup III: AE, and subgroup IV: SB + AE. The copings were luted with Zn2(PO4)3 and subjected to uniaxial tensile loading. Copings were recemented, and CTL was conducted. Two-way analysis of variance was used as the statistical test of significance. Results: In relation to the subgroups, the bond strength of Zn2(PO4)3 was higher in Group I than in Group II. The bond strength in subgroup IV was superior in both Group I and Group II (547.170 N +/- 5.752 and 531.975 N +/- 6.221 respectively). Conclusions: For both UTL and CTL, abutment SB + AE elicited maximum coping retention followed by AE. Off-axial cyclic loading adversely affected the retention irrespective of the surface modifications. PMID- 29284957 TI - Color Stability Assessment of Two Different Composite Resins with Variable Immersion Time Using Various Beverages: An In vitro Study. AB - Purpose of the Study: The aim of the study was to evaluate the difference in the color of microhybrid (MH) and nanofilled (NF) composite resins after 24 and 48 h in beverages such as red wine (RW), Coca-Cola, and distilled water. The specific objective of this study was to investigate the cumulative effect of the colorant solutions on the dental composites. Materials and Methods: MH and NF composite resins (A2 shade) were used in this current study. Sixty disk-shaped material specimens (10 mm in diameter * 2 mm in thickness) were prepared using a fiber mold (ring), with the desired dimensions. The specimen surfaces were polished using super-snap polishing system. Sixty specimens were divided into two groups of 30 each (Group I: MH resin composite; Group II: NF resin composite). Both the groups divided into six subgroups (Subgroup I: RW for 24 h [RW-24]; Subgroup II: RW for 48 h; Subgroup III: Coca-Cola for 24 h [CC-24]; Subgroup IV: Coca-Cola for 48 h [CC-48]; Subgroup V: Distilled water for 24 h [DW-24]; Subgroup VI: Distilled water for 48 h [DW-48]). All the samples were immersed in respective drinks for a period of 24 h, and color differences were measured using ultraviolet spectrophotometer. Once again, all the samples were immersed for another 24 h in the same drinks. After 48 h, the color change of the samples was measured. Measurements were made according to the CIE L * a * b * color space relative to the CIE standard illuminant D65. The color changes of the specimens were evaluated using the following formula: Statistical analysis was performed. The data were analyzed using the one-way ANOVA and t-test at a significance level of 0.05. Conclusion: Color stability of MH composite resin was found to be inferior than the NF resin composite irrespective of immersion medium and time. In RW, the color change observed was maximum for both composite resins followed by Coca-Cola. Immersing the resin composites in distilled water for 24 and 48 h had negligible color change. A 48-h immersion of both composite resins in all three immersion mediums showed greater color change than 24 h immersion. PMID- 29284959 TI - Platelet-rich Plasma and Incidence of Alveolar Osteitis in High-risk Patients Undergoing Extractions of Mandibular Molars: A Case-control Study. AB - Background: To evaluate the efficiency of platelet-rich plasma (PRP) on the incidence of alveolar osteitis (AO) in patients with potential risk factors for the development of AO. Materials and Methods: This study was conducted in 150 patients visiting the outpatient department of oral and maxillofacial surgery. Patients with potential risk factors for the development of AO which included smokers, alcoholics, postmenopausal women, patients on oral contraceptives, pericoronitis, and bruxism were included for the study. Patients were randomly divided into two groups. Group A consisted of 75 patients in which PRP was placed in the socket after extraction. Group B consisted of 75 patients in which sockets were left for normal healing without the placement of PRP. The patients were assessed for pain and dry socket on the 3rd and 5th postoperative day. Results: All the local signs and symptoms of inflammation were mild to moderate and subsided in normal course of time. Pain was less in Group A where the extraction sockets were treated with PRP. Soft-tissue healing was also statistically significant on the PRP treated site when compared to the other group where PRP was not placed into the socket after extraction. The incidence of AO among the patients who have the potential risk factor for the development of the same was significantly reduced in Group A. Conclusion: The study showed that autologous PRP is a biocompatible material and has significantly improved the process of soft-tissue healing, reduced pain, and decreased the incidence of AO in the extraction socket when treated with PRP. PMID- 29284958 TI - Evaluation of Microhardness of Residual Dentin in Primary Molars Following Caries Removal with Conventional and Chemomechanical Techniques: An In vitro Study. AB - Background: Many patients consider removal of caries to be a very unpleasant experience. Removal of caries with conventional drill is considered traumatic mainly due to fear and anxiety of children and their parents. Minimally invasive dentistry adopts a philosophy that integrates prevention, remineralization, and minimal intervention for the placement and replacement of restorations, thus reaching the treatment objective using the least invasive surgical approach, with the removal of the minimal amount of healthy tissues. Chemomechanical caries removal (CMCR) is a method for minimally invasive, gentle dentin caries removal based on biological principles which is an effective alternative to the traditional method. The present study was done to compare the microhardness of sound dentin before and after carious removal using a chemomechanical method and a conventional method. Materials and Methods: The present in vitro study was done on 28 proximal surfaces of fourteen extracted primary molars (with active caries on one proximal surface and sound side as control). The study was done to assess the Knoop microhardness of remaining dentinal surface after caries removal using a slow speed conventional bur and a chemomechanical method (Carie-CareTM). Results and. Conclusion: The rotary instrument group showed a consistent microhardness value with not much difference according to depth. The chemomechanical group showed a lesser microhardness value closer to the cavity floor than away from it. The microhardness values at all depths were significantly different for each treatment group with an increased value seen in the rotary group. The mean microhardness values of residual dentin in treated side were found to be insignificant when compared among each interval in each group. The microhardness of sound dentin had high significant difference from that of residual dentin in both the rotary group and the chemomechanical group. PMID- 29284960 TI - Assessment of Regeneration of Bone in the Extracted Third Molar Sockets Augmented Using Xenograft (CollaPlugTN Zimmer) in Comparison with the Normal Healing on the Contralateral Side. AB - Introduction: Alveolar bone resorption is a significant clinical problem. Bone loss in third molar region following extraction or surgical removal not only leads to periodontal problems in second molar region but also it may lead to some serious problems like increased incidence of angle fractures. In order to reduce the risks following third molar surgery, the socket should be augmented with bone grafts. In recent days guided tissue regeneration is the most accepted and successful technique followed many authors and its efficacy has been proved. Materials and Methods: Based upon our clinical experience, the use of bio absorbable collagen wound dressing such as CollaPlugTN has achieved quick healing and more primary wound coverage. Amongst the graft materials collagen is preferable due to its high biocompatibility and hemostatic ability. This study was done to assess the regeneration of bone in the extracted third molar sockets using xenograft (CollaPlugTN-Zimmer) which was compared with the normal healing on the contra lateral side. The assessment was done to analyze post-operative healing complications and to compare the bone density formed between control site and implant site radiologically. Conclusion: On this basis of this study, the use of collaplugTN appears to be beneficial to the patient in postoperative wound healing and also for better bone formation. The use of this material was advantageous because of its simplicity of application cost effectiveness and availability. There is enhanced wound healing and early bone formation. PMID- 29284961 TI - Comparison of Efficacy of Amoxicillin versus Ciprofloxacin in Postsurgical Management of Transalveolar Extraction. AB - Background: The transalveolar extraction and the use of pharmacological antibiotic therapy following the surgical procedure in management of postoperative infection go hand in hand in minor oral surgery. Attention has often been focused on antibiotic therapy administered at different time schedules (before or after surgery or both). This investigation reveals how the use of different molecules and dosages is critical in the postoperative period and has always provided positive result. Methodology: A prospective randomized study was carried out in 100 healthy controls of age group 20-50 years undergoing transalveolar extraction in the Department of Oral and Maxillofacial Surgery, Vivekanandha Dental College for Women. A 5-day regimen of amoxicillin or ciprofloxacin group of antibiotics along with regular analgesics was administered to the patients following transalveolar extraction. The patients were evaluated for postoperative infection, inflammation and wound care on postoperative days: day zero, day 2, day 5, day 7, day 15, day 30, and analyzed. A P < 0.05 was considered statistically significant. Results and Conclusion: A total of 100 patients aged 23-50 years (24.6-4.43) met the inclusion criteria. Male accounted for 44, while female were 55, giving male:female ratio 1:1.4. Postoperative infection was minimum with ciprofloxacin group as compared to amoxicillin group and was more significant (P < 0.005) on evaluation. A complete review has also been taken into an account, various strategies used such as surgical flaps, no traumatic osteotomy, and primary or secondary closure. PMID- 29284962 TI - Comparative Evaluation of Serum Lipid Profile in Patients with Oral Submucous Fibrosis and Oral Squamous Cell Carcinoma with that of Control Subjects: A Case Control Study. AB - Aim: The aim of the study was to evaluate the serum lipid profile among untreated oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSMF) patients. Materials and Methods: This study was done in three groups of patients - OSMF, OSCC, and control. There are twenty participants in each group. Calorimetric method using semi-autoanalyzer was used for analyzing the lipid levels (cholesterol, triglycerides [TGL], and high-density lipids [HDL]) after collecting 2 ml of fasting blood from these patients. Low-density lipid [LDL] values were obtained by calculator method. Results: There was a significant decrease in serum lipid levels of patients with OSMF and OSCC. Conclusion: The decrease in lipid levels in OSMF and OSCC patients is due to its utilization by the cells during the cancer process. PMID- 29284963 TI - Evaluation of Push out Bond Strength of Fiber Post after Treating the Intra Radicular Post Space with Different Post Space Treatment Techniques: A Randomized Controlled In vitro Trial. AB - Objective: The aim of this study was to evaluate the push out bond strength after treating the post space with different irrigation procedures. Study Design: The study sample comprised of 60 recently extracted premolars. These teeth were placed in 5.25% sodium hypochlorite solution for 5 min and then washed under tap water. De-coronated samples were biomechanically prepared until F3 ProTaper and obturated using AH-Plus and 30# (6%) gutta-percha. The specimens were allowed to set for 24 h and then post space was prepared. The teeth were randomly assigned into three experimental groups based on the treatment technique: Group A - control, Group B - sodium hypochlorite and ethylene diamine tetra acetic acid (EDTA) and Group C - diode laser and EDTA. The samples were sectioned horizontally and push out bond strength was evaluated. The stereomicroscopic examination was done for evaluating the failure mode. One-way ANOVA variance followed by Tukey's post-hoc test was used for statistical analysis using SPSS software. Results: Use of diode laser does not enhance the bond strength of fiber post. Conclusion: Diode laser at a very low pulse can be used as an irrigant adjuvant to vaporize the cement residues. Using diode laser does not enhance the bond strength. EDTA as final irrigant increases the bond strength of fiber post. PMID- 29284964 TI - Incidence of Risk and Complications Associated with Orthodontic Therapeutic Extraction. AB - Background: Extraction in orthodontics are carried out in the cases where there is space deficiency to align the teeth. The elective extraction of first or second premolars has been discussed in the literature for more than 50 years. In the 1940s and 1950s Nance, Dewel and Carey reviewed this as a useful option, and in the 1970s Logan and other leading orthodontists favoured the extraction as choice. It is not always the elective extraction of premolar is a smooth drive for the surgeon as well as to patient. Sometimes the elective extraction of premolar result in complications, which might be due to both anatomical and surgical factors. Methodology: The study sample consisted of 100 patients referred for one or more orthodontic extractions to the department of oral and maxillofacial surgery were included in this retrospective study at the vivekanandha dental college for women tiruchengode between November 2014 and May 2016. All referrals were from the department of orthodontics. A survey was carried out to record the intraoperative risks and correlated with its morbidity as when occured. All intraoperative morbities were managed appropriately as required. Result and Conclusion: Between November 2014 and May 2016, 100 patients had one or more premolar teeth removed by the oral surgeons. The sample size was 100 patients who had a total of 334 premolars removed. The sample's mean age was 11.4+?- 8.4 years, and 57.0% were male. The average number of teeth extracted per patient was 2.34 +?- 1.46, and 73.8% had complete root development. More than 93.4% of subjects had normal root and bone morphology, whereas 35.65% had variations in root forms and bone texture. The intra-operative and post operative complication rates were 7.4% and 1.9%, respectively. Complications were generally minor (91.9%) and were managed nonoperatively on an outpatient basis. There were no case of oral antral communication. PMID- 29284965 TI - Immunohistochemical Expression Of Ezrin In Oral Potentially Malignant Disorders-A Descriptive Study. AB - Introduction: Ezrin, also known as cytovillin, is a member of the ERM family of protein. Ezrin cross-links actin filament with the plasma membrane. They are involved in the formation of microvilli, cell-cell adhesion, maintenance of cell shape, cell motility, and membrane trafficking. Recent analysis reveals their involvement in signaling pathways. Ezrin is highly expressed in several types of human cancers, and correlation between its immunoreactivity and histopathological data as well as the patient outcome has previously been studied. Objective: The objective of the study was to analyze the immunohistochemical expression pattern of ezrin in oral potentially malignant disorders (OPMDs), namely, oral submucous fibrosis (OSMF) with different grades and clinically leucoplakia (hyperkeratosis with various degree of dysplasia) and its use as a predictive marker for malignant transformation. Subjects and Methods: Sample size n = 43, histopathologically confirmed cases of OPMDs (13 cases of OSMF with different grades and 30 cases of clinically leukoplakia) were retrieved from the Department of Oral and Maxillofacial Pathology. Immunohistochemistry was done using anti ezrin antibody, and the expression was graded in terms of proportion and intensity. Results: There was a significant expression of ezrin in OPMDs, and its cytoplasmic shift can be used as a predictive marker for malignant transformation. Conclusion: The findings of the current study revealed that the expression of ezrin in OPMDs may be related to the progression of the disease. PMID- 29284966 TI - A Study of Diabetes Associated Oral Manifestations. AB - Aim: The aim of this work was to determine the frequency of oral changes in diabetic patients and to study the relationship between periodontal disease and diabetes mellitus. Materials and Methods: The study sample consisted of 440 known diabetic patients between the age group of 20-80 years, of which 212 were males and 228 were females. One hundred and six patients were below 40 years, 138 patients between 41 and 50 years, 97 in 51-60 years, and 99 above 60 years of age. Data were statistically analyzed by Student's t-test. Results: Nearly 57% of the patients showed a Russell's Periodontal Index score of 2-4.9, which suggested an established periodontal disease. Risk factors for the people above the age of 40 years to develop diabetes were 76%. Conclusion: The frequency of oral manifestations in diabetic patients was significantly high, hence showing a relationship of gingival and periodontal diseases with diabetes mellitus. PMID- 29284967 TI - Evaluation of Antibacterial Activity of Three Selected Fruit Juices on Clinical Endodontic Bacterial Strains. AB - Introduction: The increasing problem of antibiotic drug resistance by pathogenic microorganisms in the past few decades has recently led to the continuous exploration of natural plant products for new antibiotic agents. Many consumable food materials have good as well as their bad effects, good effect includes their antibacterial effects on different microorganisms present in the oral cavity. Recently, natural products have been evaluated as source of antimicrobial agent with efficacies against a variety of microorganisms. Methodology: The present study describes the antibacterial activity of three selected fruit juices (Apple, Pomegranate and Grape) on endodontic bacterial strains. Antimicrobial activity of fruit juices were tested by wel l diffusion assay by an inhibition zone surrounding the well. The aim of the study was to evaluate the antibacterial activity of three fruit juises on different endodontic strains. Result: Agar well diffusion method was adopted for determining antibacterial potency. Antibacterial activity present on the plates was indicated by an inhibition zone surrounding the well containing the fruit juice. The zone of inhibition was measured by measuring scale in millimeter. Comparision between antibacterial efficacy of all three fruit juices against Enterococcus feacalis and Streptococcus mutans was observed with significant value of P <= 0.05. Conclusion: The results obtained in this study clearly demonstrated a significant antimicrobial effect of apple fruit juice against Enterococcus fecalis and Streptococcus mutans. However, preclinical and clinical trials are needed to evaluate biocompatibility & safety before apple can conclusively be recommended in endodontic therapy, but in vitro observation of apple effectiveness appears promising. PMID- 29284968 TI - Incidence of Trismus in Transalveolar Extraction of Lower Third Molar. AB - Background: Conventional mandibular third molar removal produces tissue trauma that induces an inflammatory reaction, leading to postoperative sequelae, the most common ones being trismus which influences the patient's quality of life in the postoperative period. Identifying the factors determining trismus after mandibular third molar extraction helps us to evaluate and correlate the incidence of trismus with morphological and surgical factors that are associated with its incidence in the postoperative period. Methodology: Patients referred to our institution for surgical removal of their impacted lower third molar between November 2014 and February 2015 were the participants of the study. Type of impaction, indication, and level of difficulty based on Pedersen criteria were obtained. Postoperative pain, swelling, and mouth opening (MO) limitations were evaluated at postoperative day (POD) 0, POD1, POD3, POD5, and POD7 and were analyzed. P < 0.05 was considered statistically significant. Result and Conclusion: In this study, out of fifty patients, only nine patients had experienced limited MO during postoperative period when the duration of procedure exceeded 30 min. However, it occurred as cumulative of pericoronitis and tooth sectioning done. The postoperative trismus was more significant in disto-angular impaction (P < 0.05) due to postoperative sequelae, swelling and pain. PMID- 29284969 TI - Musculoskeletal Disorders and Mental Health-related Issues as Occupational Hazards among Dental Practitioners in Salem City: A Cross-sectional Study. AB - Background: Like in any other profession, dental surgeons are also afflicted by many occupational health hazards such as Musculoskeletal disorders (MSD) and mental health related issues. Aims: To assess the distribution of MSD and mental health related issues amidst dentists in Salem City according to age, sex and number of working hours per week. Objectives: A survey was organized to check the rate of occurrence of these occupational health hazards among dental practitioners in Salem city. Materials and Methods: The study was conducted among one hundred and fifty dentists practicing in Salem City in the form of questionnaire. Dentists were asked about any occupational disease that they suffered related to a musculo-skeletal pain and its location whether in the back, upper limbs or lower limbs. In addition to this, dentists were asked about mental stress that they had experienced. Results: MSD showed higher rate of prevalence compared to mental health related issues. Conclusion: The application of preventive measures is necessary, in view of the high rate of these disorders in the society of dental practitioners. PMID- 29284970 TI - Prevalence, Characteristics, and Complications of Supernumerary Teeth in Nonsyndromic Pediatric Population of South India: A Clinical and Radiographic Study. AB - Introduction: Supernumerary teeth are the presence of more number of teeth over the normal dental formula and may occur in permanent as well as early mixed dentition. This study determined the prevalence, characteristics, and complications caused by supernumerary teeth in nonsyndromic South Indian pediatric population. Materials and Methods: Characteristics of supernumerary teeth determined by clinical and radiographic examination were recorded. The age, sex, number of supernumerary teeth, eruption status, morphology, position, orientation, and complications (if any) associated with supernumerary teeth were recorded for each patient who had supernumerary teeth. The data collected were statistically analyzed. Results: Supernumerary teeth were detected in 45 subjects (1.1%), of which 34 (75.6%) were male and 11 (24.4%) were female. There was no association between the number of supernumerary teeth and the gender of the patient. The total number of supernumerary teeth among the affected 45 patients was 54. The average number of supernumerary teeth per person was 1.2. The number of supernumerary teeth was one in 35 cases, two in 8 cases, and 3 in 1 case. Of the 45 patients, 8 patients with supernumerary teeth were in deciduous dentition stage, 29 patients were in mixed dentition stage, and 8 patients were in permanent dentition stage. Most supernumerary teeth presented in the anterior maxilla. Morphologically, conical-shaped supernumerary teeth were the most common finding. 68.5% of supernumerary teeth presented with straight orientation and inverted orientation was seen in 24.1%. Complications seen in patients with supernumerary teeth were delayed or noneruption of adjacent tooth malposition or rotation of adjacent teeth, diastema formation, and formation of dentigerous cyst. Conclusions: Supernumerary teeth have an incidence of 1.1% in South Indian population and can cause many complications that can harm the developing occlusion. Knowledge about supernumerary teeth may help the dentist in early diagnosis and early intervention. PMID- 29284971 TI - Assessment of Total Antioxidant Capacity and Antimicrobial Activity of Glycyrrhiza glabra in Saliva of HIV-Infected Patients. AB - Objectives: The objectives of this study were to evaluate the antimicrobial activity and total antioxidant capacity (TAC) of licorice in Saliva of HIV/AIDS patients. Materials and Methods: Saliva specimens were collected from 20 people living with HIV infection, with CD4 count <500 cells/mm3 from people infected with HIV/AIDS in Mangalore city, India. A combination of amoxicillin-clavulanic acid and nystatin was taken as the positive control and normal saline as negative control. Results were compared using one-way analysis of variance followed by Tukey's post hoc analysis in SPSS 19. Results: The TAC was evaluated spectrophotometrically at 695nm using the phosphomolybdenum method. Glycyrrhiza glabra showed a statistically significant reduction (P < 0.05) in total Candida count. The TAC of G. glabra was found to be 4.467 mM/L. Conclusions: G. glabra extracts showed good anticandidal activity and also high antioxidant property which reduces the oxidative stress of HIV-infected people. PMID- 29284972 TI - Efficacy of Denture Cleansers on Impact Strength of Heat polymerized Acrylic Resins. AB - Purpose: The study was aimed to compare and evaluate the changes in the impact strength of heat cure denture base resins when treated using denture cleansers. Methodology: Study was conducted with sample size of 40 and dimesion 65 mm length, 10 mm width, and 3 mm thickness as per the ISO 1567. Distilled water has been used as control group, in which 10 samples were immersed of 40 samples. Of remaining 30 samples, 10 were treated with Clinsodent, 10 were treated with VI Clean, and 10 were treated with Clanden denture cleansers. The impact strength of these specimens from each group was tested with the help of Charpy-type pendulum impact strength tester. The energy absorbed to fracture the specimens was recorded, and impact strength was calculated and was analyzed using Kruskal Wallis ANOVA and Mann-Whitney test. Results: Impact strength of samples was significantly reduced after immersion in denture cleansers Clinsodent, VI-Clean, and Clanden solutions when compared to control group. Conclusion: Clinsodent, VI Clean, and Clanden denture cleansers decrease the impact strength of heat cure denture base resin after immersion. Hence, the study concludes that denture cleansers should be used with caution and advised to follow manufacturer's instructions. PMID- 29284973 TI - Successful Nonsurgical Management of Periapical Lesions of Endodontic Origin: A Conservative Orthograde Approach. AB - Periapical lesions of endodontic origin are common pathological conditions affecting periradicular tissues. Microbial infection of pulpal tissues is primarily responsible for initiation and progression of apical periodontitis. The primary objective of endodontic therapy should be to restore involved teeth to a state of normalcy nonsurgically. Different nonsurgical management techniques, namely, conservative root canal therapy, decompression technique, method using calcium hydroxide, aspiration-irrigation technique, lesion sterilization and tissue repair therapy, active nonsurgical decompression technique, and the apexum procedure have been advocated. New techniques which use drug-loaded injectable scaffolds, simvastatin, and epigallocatechin-3-gallate have been tried. Surgical option should be considered when intra- or extra-radicular infections are persistent. Incidence of nonendodontic periapical lesions has also been reported. An accurate diagnosis of the periapical lesion whether it is of endodontic or nonendodontic origin has to be made. Surgical methods have many disadvantages, and hence should be considered as an option only in the case of failure of nonsurgical techniques. Assessment of healing of periapical lesions has to be done periodically which necessitates a long-term follow-up. Even large periapical lesions and retreatment cases where the lesion is of endodontic origin have been successfully managed nonsurgically with orthograde endodontic therapy. PMID- 29284974 TI - Case Presentation of Two Maxillectomy Patients Restored with Two-piece Hollow Bulb Obturator Retained using Two Different Types of Magnets. AB - Palatal defect can be repaired by reconstructive surgery and/or a dental prosthesis. We present prosthodontic rehabilitation of two partially edentulous patients, both with surgically induced palatal defect and explains how to achieve the goal for esthetics and phonetics. This also describes the fabrication of a hollow obturator by two piece method, which is simple and may be used as definitive obturator for maximum comfort of the patient. In both the above cases, since the mouth opening is restricted due to surgery, obturator prosthesis is given as two pieces retained with opposite poles of magnet, which facilitates the removal and insertion of the prosthesis. PMID- 29284975 TI - Dental Implants: A Remote Option in Case of Somatic Delusion Disorder. AB - A 29-year-old female was referred by a psychiatrist for dental implantation and prosthodontic rehabilitation, as she had all her healthy permanent teeth extracted within a span of 2-6 months, due to somatic delusional disorder. She presently refuses artificial dentures and implants with the fear of having worms in her teeth and the fear not yet allayed. The patient cannot be treated for her edentulous state until her psychiatric symptoms are treated. This is the limitation for the implant surgeon where service rendered is impaired in spite of advanced professional skills, ideal patient ridge, and other factors, just where the patient is not mentally prepared for the dental rehabilitation procedures. PMID- 29284976 TI - Pterygoid Implant for Atrophic Posterior Maxilla. AB - Replacement of missing teeth in the posterior maxilla is always a challenge for the treating implant surgeon as the posterior maxilla has several obstacles in the form of quality, quantity, the anatomy of the maxillary sinus, and inaccessibility. To overcome these deficiencies, several surgical procedures such as sinus lift, bone augmentation, tilted implants, short implants, and zygomatic implants were tried. Since these procedures have their own limitations, pterygomaxillary region provides us an excellent place for placement of implant and rehabilitation of posterior maxilla. This case report describes the usage of the pterygomaxillary region for placement of the implant to restore atrophic posterior maxilla, without any additional surgical procedures. PMID- 29284977 TI - Rehabilitation of Anterior Maxilla with Dental Implants in Periodontally Compromised Patient. AB - Although implant is the treatment of choice for rehabilitation of patients with aggressive periodontitis, it is also challenging for the dentists. There are various views about success of implant therapy for these patients. Few authors have proposed that aggressive periodontitis patients have less success rate of implant survival, while many authors have shown successful management of aggressive periodontitis patients with implants. For implants to be successful in these patient, it is important to control the periodontal disease before placement of implants. Thus a multidisciplinary approach is essential for successful rehabilitation of these patients. This case report aims at discussing the periodontal management and implant rehabilitation in a patient with aggressive periodontitis. PMID- 29284978 TI - Successful Surgical Management of Palatogingival Groove Using Platelet-rich Fibrin and Guided Tissue Regeneration: A Novel Approach. AB - Palatogingival groove also known as radicularlingual groove is a developmental anomaly involving the lingual surface of the maxillary incisors. They are inconspicuous, funnel-shaped, extend for varying distances on root surface and occur due to infolding of the hertwigs epithelial root sheath. This encourages adherence of microorganisms and plaque to levels significant for pathological changes resulting in endodontic and periodontal lesions. The variations in anatomy of the tooth as a cause of pulp necrosis in teeth of anterior maxillary segment should be considered by the clinician when other etiological factors are ruled out. Recognition of palatogingival groove is critical, especially because of its diagnostic complexity and the problems that may arise if it is not properly interpreted and treated. Regeneration is a new emerging approach in endodontics. Choukroun et al. were among the pioneers for using platelet-rich fibrin (PRF) to improve bone healing. PRF is rich in platelet cytokines and growth factors. Numerous techniques have been used to eliminate or seal the groove and regenerate endodontic and periodontal tissues. In this case report of two cases, a novel combination therapy involving ultrasonics, blend of PRF with bone graft, guided tissue regeneration membrane was used in the treatment of a palatogingival groove with an endoperio lesion to ensure arrest of disease progression and promote regeneration. The groove was cleaned and prepared ultrasonically and sealed with a bioactive dentin substitute. PMID- 29284979 TI - Evaluation of the Accuracy of Cone Beam Computed Tomography for Immediate Implant Placement- A Case Report. AB - Diagnostic imaging acts as a distinctive method in analyzing and drawing in the appropriate treatment protocol for any procedure. Pertaining to immediate implant placement, determining the bone width and height plays a vital role in the success of the implant therapy. This visualization of the measurements done preoperatively will enhance the treatment by reducing the overall time span of the procedure. Currently, cone beam computed tomography (CBCT) plays a significant role in the preoperative determination of the measurements of the tooth and the bone. This case report is regarding, a 27-year-old male patient reporting to the Department of Oral and Maxillofacial Surgery at Madha Dental College and Hospital, with a chief complaint of fractured crown in relation to the upper left front tooth region. On clinical examination, there was the presence of an endodontically failed and fractured crown in relation to 22. With the interpretation of clinical and radiographic examination, the tooth was categorized under unfavorable prognosis. The patient was given a detailed description of the various treatment procedures available pertaining to that present condition, along with immediate implant placement procedure. Since the patient was young and conscious about his esthetics and accuracy, he opted for placement of immediate implant followed by extraction of the tooth. To accurately determine the length and width, the tooth and socket measurements were preoperatively measured by CBCT. This article evaluates the accuracy of CBCT by comparing the clinical quantity of bone and dimensions of tooth to be extracted and alveolar socket. PMID- 29284980 TI - Esthetic Management of Compromised Ridge in the Anterior Maxilla, a Modified Prosthetic Approach. AB - Replacing a missing tooth with an implant, especially in the esthetic zone has been increasing demand for the patient. Placing dental implants in the esthetic zone, especially in the compromised ridge with thin gingival thin biotype is considered to be the ultimate challenge for many dentists. This case report illustrates the implant placement in the traumatic anterior maxilla with thin gingival biotype (Class IV) and a modified approach in prosthetic placement. PMID- 29284981 TI - Neurilemmoma of Maxillary Alveolus: A Rare Case Report and Review of Literature. AB - Schwannomas or neurilemmomas are benign, slow growing, usually solitary and encapsulated tumor, originating from Schwann cells of the nerve sheath. Intraoral schwannomas account for 1% of head and neck region and are commonly seen at the base of the tongue. Most of the literature, reports of schwannomas in the tongue region are common. In this article we report a rare occurrence of schwannoma in the maxillary alveolus region and its management. A 45 year old female patient reported to the department of oral and maxillofacial surgery with a complaint of swelling in the left maxillary alveolus in relation to molar teeth that had been present for more than 3 months. Apparently the swelling was small one initially, which gradually increased in size. Such a rare cas e of intraoral schwannoma should be followed up periodically to look for any malignant transformation and recurrences. An important conclusion that has evolved from the reviewed articles, is that the differential diagnosis of painless nodules in head and neck must include schwannomas. PMID- 29284982 TI - Erosion Infiltration Technique': A Novel Alternative for Masking Enamel White Spot Lesion. AB - Enamel White spot lesions are early signs of demineralization under the intact enamel, which may or may not lead to the development of caries. An inactive white spot lesion might act as an arrested dental caries and impair the esthetic appearance by displaying a milky white color from its interior opacity. The first choice of treatment is remineralization with various remineralizing agents such as fluoride and ACP-CCP. Caries infiltration is a less invasive and effective method for arresting the white spot lesions. It also improves the esthetics by masking the chalky white appearance by the process of optical adaptation to the adjacent healthy enamel. This is achieved by the hydrophobic resin, which has a similar refractive index to that of the healthy enamel. PMID- 29284983 TI - Biological Rehabilitation of Complex Oblique Crown-root Fracture Segment Reattachment. AB - Dental trauma can predominantly affect the maxillary anteriors. Trauma can occur to any age group due to accidents, assaults, or leisure activities. The goal of the treatment for traumatically injured teeth is to return the teeth to acceptable function and form. In this case presentation, the endodontic and esthetic treatment approach of crown fracture is presented. PMID- 29284984 TI - Management of Tooth Fractures Using Fiber Post and Fragment Reattachment: Report of Two Cases. AB - Reattachment of the tooth fragment is an ultraconservative technique for managing coronal tooth fractures when the tooth fragment is available, and there is minimal violation of the biological width. The advances in adhesive dentistry have allowed dentists to use the patient's own fragment to restore the fractured tooth which provides fast and esthetically pleasing results. This article reports fragment reattachment technique and presents two clinical cases of complicated crown fracture. PMID- 29284985 TI - A Conservative Method of Retaining an Interim Obturator for a Total Maxillectomy Patient. AB - Interim obturators are indicated during the postsurgical phases. It promotes surgical healing and serves as a temporary prosthesis to rehabilitate a patient with intra-oral surgical defect. Retention is gained by wiring, surgical suturing, and other noninvasive methods to enable functional rehabilitation and easy replacement with a permanent obturator. Interim obturators serve as an easy guide for replacing with definitive obturators by indicating prosthesis extensions and the required method of retention. A more conservative and noninvasive method of retaining an interim obturator for a maxillectomy patient is described in this case report. PMID- 29284986 TI - Management of Tooth Surface Loss of Varying Etiology with Full Mouth all Ceramic Computer-Aided Design/Computer-Aided Manufacture Restorations. AB - The anatomical form of a tooth can undergo changes leading to loss of tooth form. The loss of tooth surface can be due to varying etiology. Dental caries, attrition, abrasion, erosion, involving any surface of the tooth can lead to loss of tooth structure. The rate of tooth destruction may proceed to such an extent that the esthetics, function and comfort may be lost. The role of a practioner lies in identification and screening of such case and motivate for oral rehabilitation that includes habit cessation. Computerized dentistry has raised the bar as far as esthetic restorations are concerned. Demanding esthetics has made zirconia crowns as the material of choice in full mouth rehabilitations. However, appropriate treatment planning with scientific evidence and a recommended treatment protocol with careful implementation results in successful restorations and satisfied patients. PMID- 29284987 TI - Efficient regeneration system for rapid multiplication of clean planting material of Ensete ventricosum (Welw.) Cheesman. AB - Enset (Ensete ventricosum (Welw.) Cheesman) is an economically important staple food crop in Ethiopia, especially in the southern and southwestern regions. It is called "false banana" due to its resemblance to banana, but inability to produce any edible fruit. The crop is clonally propagated using field-grown suckers. This study reports the development of a robust regeneration technique to propagate large numbers of plantlets using corm discs containing intercalary meristematic tissues. Hundreds of shoot buds were induced from corm discs of enset cultivar 'Bedadeti' cultured on Murashige and Skoog (MS) medium supplemented with 1.5 mg L 1 2,4-dichlorophenoxyacetic acid, 0.216 mg L-1 zeatin, and 2 g L-1 activated charcoal. The shoot buds were regenerated into complete plantlets when transferred onto MS medium supplemented with 1 mg L-1 6-benzylaminopurine and 2 g L-1 activated charcoal. More than 100 plantlets were generated in 4 mo from corm discs isolated from a single in vitro mother plantlet. Well-rooted plantlets were acclimatized in soil with 100% success, and did not show any apparent phenotypic abnormalities under glasshouse conditions. This efficient regeneration system could be very useful for the rapid multiplication of clean pathogen-free planting material. PMID- 29284989 TI - An Editorial View on Authors' Malversations. PMID- 29284988 TI - Comparing on-road real-time simultaneous in-cabin and outdoor particulate and gaseous concentrations for a range of ventilation scenarios. AB - Advanced automobile technology, developed infrastructure, and changing economic markets have resulted in increasing commute times. Traffic is a major source of harmful pollutants and consequently daily peak exposures tend to occur near roadways or while traveling on them. The objective of this study was to measure simultaneous real-time particulate matter (particle numbers, lung-deposited surface area, PM2.5, particle number size distributions) and CO concentrations outside and in-cabin of an on-road car during regular commutes to and from work. Data was collected for different ventilation parameters (windows open or closed, fan on, AC on), whilst traveling along different road-types with varying traffic densities. Multiple predictor variables were examined using linear mixed-effects models. Ambient pollutants (NOx, PM2.5, CO) and meteorological variables (wind speed, temperature, relative humidity, dew point) explained 5-44% of outdoor pollutant variability, while the time spent travelling behind a bus was statistically significant for PM2.5, lung-deposited SA, and CO (adj-R2 values = 0.12, 0.10, 0.13). The geometric mean diameter (GMD) for outdoor aerosol was 34 nm. Larger cabin GMDs were observed when windows were closed compared to open (b = 4.3, p-value = <0.01). When windows were open, cabin total aerosol concentrations tracked those outdoors. With windows closed, the pollutants took longer to enter the vehicle cabin, but also longer to exit it. Concentrations of pollutants in cabin were influenced by outdoor concentrations, ambient temperature, and the window/ventilation parameters. As expected, particle number concentrations were impacted the most by changes to window position / ventilation, and PM2.5 the least. Car drivers can expect their highest exposures when driving with windows open or the fan on, and their lowest exposures during windows closed or the AC on. Final linear mixed-effects models could explain between 88-97% of cabin pollutant concentration variability. An individual may control their commuting exposure by applying dynamic behavior modification to adapt to changing pollutant scenarios. PMID- 29284991 TI - Relationship of Employees' Achievement Motivation and Quality of Working Life with Their Self-efficacy at Selected Hospitals with a Multi-group Analysis: Moderating Role of Organizational Ownership. AB - Introduction: Motivational deficiencies and the low quality of working life significantly reduce employees' work performance and consequently their efficacy (effectiveness and proper performance in doing a task or specific tasks). Aim: The aim of this study was to determine the relationship between achievement motivation and quality of working life with self-efficacy among staff working in Mazandaran hospitals, by taking organizational ownership as a mediator variable. Materials and Methods: This study was an applied descriptive-correlation. Research population consisted of all staff working in selected hospitals of Mazandaran Province, Iran. 341 employees were selected with randomly-stratified sampling as the statistical sample. Three valid questionnaires were used for data collection. Data were analysis based on structured equations and path analysis with SPSS19 and AMOS. Results: In private hospitals, there was a significant relationship between the quality of working life and self-efficacy (p<0.001). In relationship between achievement motivation and self-efficacy, there was no significant differences between university hospitals and social security hospitals, but relationship between the quality of working life and self-efficacy was significant (p <0. 05). Considering achievement motivation and self-efficacy in private hospitals and university hospitals, a significant differences was observed (p<0. 05). Conclusion: The hospital ownership has a moderating in relationship of achievement motivation and quality of working life with self efficacy. Staff's empowerment courses for university hospitals and improvement in the overall space of job, increase in job security, reducing salary differences is suggested for private hospitals. PMID- 29284990 TI - The Impact of Risk Factors and Comorbidities on The Incidence of Atrial Fibrillation. AB - Introduction: Atrial fibrillation (AF) is the most common form of cardiac arrhythmia in clinical practice and its prevalence increases with age. Patients who develop AF also have cardiovascular risk factors, structural heart disease, and comorbidities, all of which can increase mortality. AF causes a significant economic burden with the increasing trend in AF prevalence and hospitalizations. Research Objectives: The objective of our study is to evaluate the impact of the most common known risk factors on the incidence of atrial fibrillation as an important precursor of cardiac and cerebrovascular morbidity and mortality among our patients in Bosnia and Herzegovina during median follow up period (September 2006 - September 2016). The other objective is to estimate the CHA2DS2-VASc score among our patients based on clinical parameters. Patients and methods: This study includes 2352 ambulant and hospitalized patients with atrial fibrillation. All patients underwent clinical evaluation which includes thorough assessment for potential risk factors and concomitant conditions in order to determine which of them represent the most common among examinees with atrial fibrillation. Results: The results show that male gender has slightly more incidence of AF. Obesity and overweight with BMI >= 27, cigarettes smoking and sedentary life style are almost present in patients with AF. Arterial hypertension, coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease, chronic renal dysfunction, structural and valvular heart disease and peripheral vascular disease are the most common comorbidities among our patients. The mean CHA2DS2 VASc score was 3.2+/-1.4 and the mean HAS-BLED score was 2.1+/-1.2. Conclusion: Atrial fibrillation is the most common sustained cardiac rhythm disorder. The study shows that obesity, alcohol consumption, smoking cigarettes and dyslipidemia can be considered as triggers and predisposing factors for appearance of AF. Arterial hypertension, coronary artery disease, chronic obstructive pulmonary disease, diabetes mellitus, Peripheral vascular disease and chronic kidney disease are playing important role in developing of AF. PMID- 29284992 TI - Determining the Effectiveness of Acceptance and Commitment Therapy (ACT) on Life Expectancy and Anxiety Among Bereaved Patients. AB - Introduction: Acceptance and commitment therapy tries to increase one's psychological acceptance regarding subjective experiences (thoughts, feelings, etc.,) and in turn, decrease ineffective control actions. Aim: The current study was conducted with the aim to investigate the effect of acceptance and commitment therapy (ACT) on the amount of life expectancy and anxiety among bereaved patients. Material and Methods: This research was a quasi-experimental study with pretest-post-test control group design. The statistical population included all bereaved patients aged between 20-40 who referred to counseling and treatment centers and psychiatric clinics in Tehran in 2015. Bereaved patients were identified through convenient random sampling method amongst patients and based on clinical diagnosis of psychiatrist treating patients. Thirty four persons were chosen and were randomly assigned in two 17- persons experimental and control groups. Both groups were evaluated at two stages of pre-test and post-test through anxiety scale (Spielberger STAI-y 1970) and life expectancy (Schneider, 1991). Findings: Conducted investigation shows that the average life expectancy in the experimental group has increased from 12.40 to 23.30 after acceptance and commitment therapy. Moreover, the average of anxiety scores in the experimental group has decreased in post-test from 121.20 to 79.10 after acceptance and commitment therapy. Results of covariance analysis revealed that the experimental group subjects experienced a significant lower level of anxiety than those in control group (p<0.001). Furthermore, the life expectancy has significantly increased in the experimental group (p<0.001). Conclusion: Inefficient beliefs (illogical), intellectual faults and cognitive distortions have reduced, and these in turn cause a reduction in anxiety. In this way bereaved patients' life expectancy has increased. Conclusion: The acceptance and commitment therapy has led to the anxiety reduction and caused an increase in bereaved patients' life expectancy. PMID- 29284993 TI - The Relationship Between Research Anxiety and Self-Efficacy. AB - Aim of the study: The aim of this research was to study of the relationship between research anxiety and self-efficacy from viewpoints of students at the Islamic Azad University (Babol Branch). Methods: The present study is applied research which using a survey and has done by descriptive approach. The study sample included of MA and PhD Students of which 312 were selected Stratified randomness at Islamic Azad University (Babol Branch). The instrument used for data collection, including two standard questionnaires, General Self-Efficacy Questionnaire and research anxiety Inventory. For data analyzing used, Linear regression test and analysis of variance. Findings: Multiple correlation coefficient between the variables is equal to R=0.385, which represents the correlation between variables (self-efficacy and research anxiety). The significance level for research anxiety was calculated less than the error rate is calculated, therefore, it can be considered a good predictor for efficacy. Gender and education variables due to the attention of higher levels of predictive cannot be considered so significant for efficacy. Conclusion: There is a significant negative relationship between research anxiety and self-efficacy. There is no relationship between demographic characteristics and self-efficiency. PMID- 29284994 TI - The Role of Dual Tasking in the Assessment of Gait, Cognition and Community Reintegration of Veterans with Mild Traumatic Brain Injury. AB - Background: This study focussed on the effect of dual versus single tasking on balance, gait and cognition in veterans with mild traumatic brain injury (mTBI). We examined the correlation between these parameters, with responses to questions on community reintegration activities. Method: 22 male and female veterans (aged 19-65) walked along a narrow and 6.1-meter long path, both at their self-selected and fastest but safe pace under single and dual tasking conditions. For dual tasking, participants were required to recall and vocalize a 5-digit number at the end of the path. The outcome measures were the accuracy, velocity, cadence, stride length, and number of steps off the path. We calculated the reliability and correlation coefficient values for the walking time compared with the stride length, velocity, and percentage of swing and stance. Results: Under dual task, the participants demonstrated slower gait, recalled shorter digit span and stepped off the path 12.6% more often than under single task. The stride length decreased by about 20% and the stride velocity increased by over 2% in dual compared with single tasking. Conclusions: Dual tasking slows down the gait and reduces the attention span in patients with mTBI, which can negatively impact their community reintegration, at least early after their hospital discharge, hence the need for exercising caution with their community reintegration activities. Dual tasking may have the potential to improve balance, gait and attention span of the patients in the long-term, thus leading to safer community integration, if incorporated in the rehabilitation plans. PMID- 29284995 TI - Prevalence of Musculoskeletal Disorders among Dentists in Iran: A Systematic Review. AB - Introduction: Musculoskeletal disorders (MSD) have become significant problems for all health care workers especially dentists. This systematic review provides prevalence of MSD in dentists of Iran. Material and Methods: In this study all published literatures about MSD in Iranian dentists were selected without any time limits or other restrictions. However, it was found that the studies about MSD among Iranian dentist are very low. Results: The results of literatures investigations show that the prevalence was between 0.5% and 70%. The prevalence of pain in different regions includes; neck pain (0.7- 0.15), back pain (0.08 - 0.55), wrist pain (0.005-0.48), shoulder pain (0.08-0.5), knee pain (0.03- 0.25) and elbow pain (0.01- 0.2). The gender has no influence on the prevalence. Compare the results with other similar studies shows that the prevalence of MSD is an important issue in other area too. Conclusion: Results show that the prevalence of musculoskeletal problems is high in Iran. Therefore it is necessary conduct reliable and comprehensive epidemiological studies in this field to determine the causes of the problem more consciously; and propose appropriate solutions. PMID- 29284996 TI - Effect of Oral Health Care Program on Oral Health Status of Elderly People Living in Nursing Homes: a Quasi-experimental Study. AB - Background: Oral health of elderly people plays a major role in their overall health and quality of life, and is an integral part of personal care. Aim: The aim of this study was to evaluate the effect of implementing the oral health care program (OHCP) on oral health status of elderly people resident in nursing homes. Materials and Methods: This quasi-experimental study was carried out using a pretest-posttest design on 101 elderly people (46 in the intervention group and 55 in the control group) resident in two randomly selected nursing homes in Mashhad, Iran. In the intervention group, the OHCP was carried out by caregivers for 8 weeks. The control group received routine care. Using the oral health assessment tool, the oral health status of elderly people was assessed in both groups at three times; onset of the study, 4th, and 8th week after the start of the study. Results: The oral health status of the elderly people in both groups was not statistically significantly different at baseline, but it changed significantly at the 4th, and 8th weeks (p<.001). Conclusion: The implementation of the OHCP for elderly people resident in nursing homes may improve their oral health status after 4 weeks. It is recommended that OHCP be included in care plans of all nursing homes to improve the elderly people's oral health status. PMID- 29284997 TI - The Frequency of Multifactorial Syndromes in Geriatrics of Tuzla Canton Population. AB - Introduction: There are four main multifactorial syndromes in geriatrics the so called "4N", which specifically occur at elderly patients. Listed syndromes often occur related, and they can be the cause and the result of many other syndromes at geriatric patients. Objective: determine the difference in the assessment of the level of immobility, instability, dependence, urinary incontinence ("4N") in elderly groups. Materials and methods: The research included total 200 elderly respondents experimental group made of elderly persons (>65 years) living alone. Control group included elderly persons living in a family environment. Universal geriatric questionnaire was made for this research. For fast orientation the redone questionnaire was used for our conditions: examination in clinics for usual elderly problems "Short list for examination". For the assessment of the mental abilities reduction at elderly we used "Short portable mental status questionnaire" (SPMSQ). Results: In total sample the research included 200 elderly respondents, 45% in experimental group and 55% in control group. The average age (+/-SD) was 75,4+/-6,2 years in the experimental group, while in the control group the average age was 74,9+/-5,6 years. We notice nearly equal distribution of falling risk according to groups (50%, 47%). In total sample there were 62% mobile, 22,5% limited mobility, and 4% immobile. Dependence frequency was more represented at examination group respondents (p=0,002). Dependence chances (OR) were 2,05 times larger (95 %CI=1,12-3,75) in examination group than in control group respondents. Frequency of urinary incontinence problem is significantly represented at all our respondents (42,2% v.s. 35%). Conclusion: Permanent gerontology and geriatrics training is needed both family medicine doctors and other experts in the field of elderly health protection and preventive health measures, pharmacotherapy, palliative care, especially about four main geriatrics syndromes at elderly. PMID- 29284998 TI - Physical Therapy in Elderly Suffering from Degenerative Diseases. AB - Introduction: Osteoarthritis of the joints (osteoarthritis or arthritis) represents the largest group of rheumatic diseases. Within rheumatic diseases 50% are degenerative rheumatic diseases, 10% inflammatory and 40% extra-articular. Goal: To determine the modalities of physical therapy for elderly with degenerative diseases. Material and methods: The study is retrospective prospective and descriptive. The survey conducted included 25 patients with degenerative diseases of the musculoskeletal and nervous systems in Gerontology Center in Sarajevo, from May 1, 2014- April 30, 2015. As research instruments were used: Questionnaire for users of physical therapy in Gerontology Center in Sarajevo, self-developed, visual-analog scale to assess pain and patient records. Results: Of the total number of patients with degenerative diseases (25), 10 (40%) were male and 15 (60%) were female. The most common degenerative disease is knee osteoarthritis which had 11 patients (29%), 3 males and 8 females. From physical therapy modalities in the treatment of degenerative diseases at the Gerontology Center in Sarajevo, kinetic therapy was administered to all patients, followed by manual massage and TENS in 15 cases (60%). From twenty-two patients, who completed a questionnaire, 11 (50%, 2 male and 9 female) rated their health as poor. Seven patients (32%, 3 male and 4 female) assessed their health as good. Three patients (14%, 2 male and 1 female) rated their health as very poor, and one patient (4%, 1 male) rated its health as very good. Conclusion: The Research Physical therapy in elderly with degenerative diseases is a pilot project, which highlights the need for: Conducting research for a longer time period, with a larger sample; Quality of keeping health records; Implementation of a continuous evaluation of functional status and; Stricter control for optimal effectiveness of physical therapy in order to improve the quality of life of elderly patients. PMID- 29284999 TI - High Burden of Stroke Risk Factors in Developing Country: the Case Study of Bosnia-Herzegovina. AB - Introduction: The burden of stroke has been increasing worldwide, especially in developing countries. Very few data regarding epidemiology of stroke are available in Bosnia and Herzegovina (BH). Patients and methods: We undertook a retrospective hospital-based study in all hospitals existing in five cantons and one district of BH. The patients were recruited between January 1st, 2014, and December 31st, 2014, and only first-ever-in-lifetime strokes (FES) were included for evaluation. Results: A FES was diagnosed in 1479 patients (age 71.83 +/- 11.703 years) during the study period. FES occurred in 709 men (47.9%; age 69.64 +/-12.002 years) and 770 women (52.1%; age 73.85+/- 11.051 years). Stroke was categorized into ischemic stroke (IS), primary intracerebral hemorrhage (PICH), subarachnoid hemorrhage (SAH) and cerebral venous thrombosis (CVT), which was diagnosed in 84%, 12,2%, 3,4% and 0,4% cases respectively. Early 28-day case fatality was 18.5 % for all patients and both sexes combined. Short-term case fatality was significantly greater in women (P=0.007). Among all patients with FES, 87% had hypertension, 35% diabetes mellitus, 39% hypercholesterolemia and almost 25 % atrial fibrillation. Discussion: This is the first study that provides us with information on epidemiology of stroke in BH. More than 90% of patients had one or more modifiable risk factors and the number would be even higher if we included smoking. The early stroke case-fatality was lower than that observed in other low- to middle-income countries. Conclusion: All modifiable stroke risk factors, especially high blood pressure, should be understood as a major public health problem in BH and efforts should be focused on the primary prevention of stroke. Our emphasis is on the designing of a stroke register in BH for a better health planning. PMID- 29285000 TI - Exploring the Added Value of Women Health Care Managers in Poland. AB - Introduction: Female managers in the Polish health care system are seldom a subject of scientific investigation. Material and Methods: This study describes the share and profile of women in health care management positions and explores how and why Polish female health care managers add value to the leadership of health care organizations. Three data collection methods were used including: scoping review, analysis of data from governmental information bases and in-depth interviews with female health care managers. Results: Men comprise nearly twice the number of hospital directors in Poland as compared to women, or 67% of the total representation. Traits often attributed to women including strength, perseverance, multi-tasking, empathy, emotional intelligence and intuition add value in leadership roles. Polish women managers value the complementarity of genders in professional roles and their contribution to constructive collaboration. Conclusion: The study contributes to the scarce literature on Polish female health care managers. PMID- 29285001 TI - Analysis of Food Toxin Trends in the Federation of Bosnia and Herzegovina Over Five Years Period. AB - Introduction: Alimentary toxoinfections represent a significant public health problem. Globalization of the market and food production, significant impoverishment of a large part of the population, and traditional approach with food preparation and consumption, cause a significant increase in the rates of population infections around the world. The epidemiological surveillance of the illness occurrence plays a significant role in monitoring and controlling the population's burden of diseases caused by unhygienically prepared and stored food. Aim: The aim of the article is to determine the rates and trends of food related diseases in the Federation of Bosnia and Herzegovina. Results: The results of the analysis have shown that the rate of illness in the Federation of Bosnia and Herzegovina is declining but is still significantly higher than in developed western countries. Particularly great burden is on the population of the Zenica-Doboj Canton (ZDC), which can be due to the traditional relation to the preparation and storage of food, as well as to the relatively poorer economic situation in ZDC. Conclusion: We can conclude that the strengthening of the monitoring system, laboratory capacities, the availability of monitoring guides will enable responsible FBiH/Bosnia and Herzegovina institutions to better control and implement safer food practice. PMID- 29285002 TI - Historical Contribution of Pharmaceutics to Botany and Pharmacognosy Development. AB - Introduction: Pharmacy and medicine belong to the oldest human activities, so the development of these sciences is closely related to the socio-economic, cultural and religious opportunities of the nations within which they have been developing. Goals: To present the historical influence of pharmacy on the development of the human being from its very beginning; To present the historical link between pharmaceutical and medical activity, as well as early development of independent pharmaceutical activity; To present the historical influence of pharmacists on the development of botany and pharmacognosy and to present the historical influence of the first written herbarium and incunabula on the development of pharmacognosy. Material and Methods: The article has a descriptive character, and represents a systematic review of the literature dealing with this topic. Results: The roots of pharmacy started to the very beginning of human civilization, when people collected various medicinal herbs and try to alleviate their health problems, pain and suffering. The scientific foundations of the pharmacy were set up in the antique period by the books of Dioskurides and Galen, and its further development continued in the mid-century, at the beginning by rewriting famous parts of ancient literature, and later by writing new discoveries (the base of this development was represented by South Italy) so that in 1240, for the first time in history, came the separation of doctors and pharmacists, and at the beginning of the 13th century the opening of the first pharmacy. Conclusion: The effort to maintain knowledge of medicinal herbs and its practical application has led to the writing of a large number of recipes books, the forerunners of today's pharmacopeia, while the aspiration to classify medicinal herbs, and the desire to present medicinal herbs to ordinary people, has led to a large number of herbaria, making the knowledge and descriptions of plants available to many, not just the nobility. Descriptions of plants in herbaria and later in incunabula lead to the development of pharmacognosy, and to the opening of the first Department for pharmacognosy, 1545 in Padua. PMID- 29285003 TI - Elevated antibiotic resistance of Sudanese urinary tract infection bacteria. AB - This study determined the prevalence of urinary tract infections in the Sudanese state of Khartoum and antimicrobial susceptibility pattern of isolated bacterial species. 200 adult patient urine specimens were collected and cultivated to identify the growing bacteria and their susceptibility to antibiotics. 35 % of specimens had significant bacterial growth. The most frequent isolates in this study were E. coli, E. faecalis and S. aureus. Most of the isolates were resistant to many antibiotics; Gram-negative and Gram-positive isolates were resistant to 67 % and 44 % of the examined antibiotics, respectively. E. coli was the most frequent bacterium in the studied samples and it was highly resistant to first-line antibiotics. The most resistant bacteria isolated were Pseudomonas species and the lowest was for S. saprophyticus. The results highlighted the need for knowledge about antibiotic susceptibility profile of the bacteria causing UTI prior to antibiotic prescription in order to ensure optimal treatment. PMID- 29285004 TI - Troxerutin protects hippocampal neurons against amyloid beta-induced oxidative stress and apoptosis. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease linked with increased production and/or deposition of amyloid-beta (Abeta) in the brain. The aim of the present study was to investigate the possible neuroprotective effect of troxerutin on an animal model of Alzheimer's disease. Alzheimer model was induced by a single dose intracerebroventricular (ICV) injection of Abeta 1-42 (5 nmol/5 ul). Thereafter, troxerutin (300 mg/kg) was gavaged for 14 days. The hippocampal malondialdehyde (MDA) levels and enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and acetylcholinesterase (AChE) were measured using enzyme-linked immunosorbent assay (ELISA) method. In addition, the number of apoptotic cells in the dentate gyrus (DG) was assessed by TUNEL kit. The results showed that ICV microinjection of Abeta 1-42 increased MDA levels, reduced SOD and GPx, and increased AChE activities in the hippocampus. Chronic administration of troxerutin significantly attenuated MDA levels and AChE activity and increased SOD and GPx activities in the hippocampus. Moreover, the number of apoptotic cells was decreased by troxerutin treatment. Taken together, our study demonstrated that troxerutin could increase the resistance of hippocampal neurons against apoptosis, at least in part, by diminishing the activity of AChE and oxidative stress. Therefore, troxerutin may have beneficial effects in the management of Alzheimer's disease. PMID- 29285006 TI - Not only Iranian rise in science marred by fraud: Misconduct is a global problem. PMID- 29285005 TI - A novel medium size lactam ring analoges as antibacterial agents: Synthesis, biological evaluation and molecular docking studies. AB - A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H benzo[e][1,4]diazonine-2,5-dione (6a-f) analogues were synthesized from (E)-3-(2 nitrophenyl)acrylicacid (2) reacting with various amino acid esters using Di isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3-dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass, 1H-NMR and 13C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking studies. All final molecules were docked with enzyme peptide deformylase to determine the probable binding conformation. PMID- 29285007 TI - Anti-inflammatory effect and mechanism of action of Lindera erythrocarpa essential oil in lipopolysaccharide-stimulated RAW264.7 cells. AB - The aim of this study was to investigate the chemical constituents of Lindera erythrocarpa essential oil (LEO) by gas chromatography-mass spectrometry and evaluate their inhibitory effect on the expression of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Fifteen compounds, accounting for 63.7 % of the composition of LEO, were identified. The main compounds were nerolidol (18.73 %), caryophyllene (14.41 %), alpha-humulene (7.73 %), germacrene-D (4.82 %), and alpha-pinene (4.47 %). LEO significantly inhibited the expression of inducible nitric oxide (NO) synthase and cyclooxygenase-2, and subsequent production of NO and prostaglandin E2. In addition, it reduced the release of pro-inflammatory cytokines in LPS-activated RAW264.7 cells. The molecular mechanism underlying the effect of LEO was associated with inhibition of the phosphorylation of mitogen-activated protein kinase (MAPK). Furthermore, LEO inhibited LPS-induced phosphorylation and degradation of inhibitor of kappa B alpha, which is required for the activation of the p50 and p65 nuclear factor (NF)-kappaB subunits in RAW264.7 cells. Taken together, these data suggest that LEO exerted its anti-inflammatory effect by downregulating LPS-induced production of pro-inflammatory mediators through the inhibition of NF-kappaB and MAPK signaling in RAW264.7 cells. PMID- 29285008 TI - Microwave-assisted synthesis and antitumor evaluation of a new series of thiazolylcoumarin derivatives. AB - A new series of thiazolylcoumarin derivatives was synthesized. The designed strategy embraced a molecular hybridization approach which involves the combination of the thiazole and coumarin pharmacophores together. The new hybrid compounds were tested for in vitro antitumor efficacy over cervical (Hela) and kidney fibroblast (COS-7) cancer cells. Compounds 5f, 5h, 5m and 5r displayed promising efficacy toward Hela cell line. In addition, 5h and 5r were found to be the most active candidates toward COS-7 cell line. The four active analogs, 5f, 5h, 5m and 5r were screened for in vivo antitumor activity over EAC cells in mice, as well as in vitro cytotoxicity toward W138 normal cells. Results illustrated that 5r has the highest in vivo activity, and that the four analogs are less cytotoxic than 5-FU toward W138 normal cells. In this study, 3D pharmacophore analysis was performed to investigate the matching pharmacophoric features of the synthesized compounds with trichostatin A. In silico studies showed that the investigated compounds meet the optimal needs for good oral absorption with no expected toxicity hazards. PMID- 29285010 TI - Variant BCR-ABL1 fusion genes in adult Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. PMID- 29285009 TI - The relation between rice consumption, arsenic contamination, and prevalence of diabetes in South Asia. AB - Rice is the major staple food for about two billion people living in Asia. It has been reported to contain considerable amount of inorganic arsenic which is toxic to pancreatic beta cells and disrupt glucose homeostasis. Articles and conference papers published between 1992 and 2017, indexed in Scopus, PubMed, EMBASE, Google, and Google scholar were used. Arsenic exposure has been associated with increased blood glucose and insulin levels, or decreased sensitization of insulin cells to glucose uptake. Several studies have shown the association between inorganic arsenic exposure and incidence of diabetes mellitus. Considerable amounts of arsenic have been reported in different types of rice which may be affected by cultivation methods, processing, and country of production. Use of certain microbes, fertilizers, and enzymes may reduce arsenic uptake or accumulation in rice, which may reduce its risk of toxicity. Combined exposure to contaminated rice, other foods and drinking water may increase the risk of diabetes in these countries. Maximum tolerated daily intake of arsenic contaminated rice (2.1 ug/day kg body weight) has been set by WHO, which may be exceeded depending on its content in rice and amount consumed. Hence, increased prevalence of diabetes in South Asia may be related to the consumption of arsenic contaminated rice depending on its content in the rice and daily amount consumed. In this review, we have focused on the possible relation between rice consumption, arsenic contamination, and prevalence of diabetes in South Asia. PMID- 29285011 TI - Highlight report: The EDI3-GPAM axis in tumor cell migration. PMID- 29285012 TI - Evaluation of in vitro and in vivo anticancer potential of two 5-acetamido chalcones against breast cancer. AB - Two 5'acetamido chalcones, C1 and C2 were synthesized by Claisen-Schmidt condensation method and characterized by IR, LC-MS, 1H NMR and 13C NMR. These compounds were evaluated for anticancer activity in vitro in breast cancer cell lines (MCF-7 and MDA-MB-231) using MTT assay, anti-metastatic assay, apoptotic screening by AO/EB staining and in vivo in N-Methyl-N-nitrosourea (MNU) induced breast carcinoma model. Sprague-Dawley rats with developed tumors (50 mg/kg MNU i.p.) were grouped in four, namely MNU control (0.25 % of CMC p.o.), standard group (doxorubicin 2 mg/kg once in 4 days, i.p.), C1 and C2 groups (50 mg/kg p.o. each). After 21 days of treatments, tumor volume and weight were assessed. Excised tumors were subjected to DNA fragmentation study. MTT assay showed IC50 values of 62.56 and 37.8 uM by for C1 and C2. Both compounds increased apoptotic bodies more than 3 fold compared to normal control in AO/EB staining. Antimetastatic (scratch wound) assay showed a significant (p<0.05) reduction in cell migration after 24 h and 48 h treatments compared to normal control. In in vivo studies, tumor weight and tumor volume were significantly (p<0.05) reduced in the doxorubicin group as well as in test groups compared to MNU control. DNA fragmentation assay showed an increase in the number of bands formed in C1 and C2 compared to normal control. Results obtained from in vitro and in vivo studies demonstrated the significant anticancer potentials of C1 and C2. PMID- 29285014 TI - microRNA-503 contribute to pancreatic beta cell dysfunction by targeting the mTOR pathway in gestational diabetes mellitus. AB - Loss of pancreatic beta cells is involved in pathogenesis of gestational diabetes mellitus (GDM). Recently, several studies have elucidated the connection between microRNAs (miRNAs) and diabetes mellitus (DM), but the role of miRNAs in GDM remains unclear. The aim of this study was to evaluate the potential functions of miRNAs in GDM and to investigate the underlying mechanisms of action. First, we explored the expression profile of miRNAs in placenta tissue from GDM patients using microarray. Validation analysis was performed in peripheral blood specimens using quantitative reverse transcription PCR (qRT-PCR). Then the role and regulating mechanism of miR-503 in weaken the function of pancreatic beta cell was investigated. We found that miR-503 was markedly upregulated in placenta tissue from GDM patients, as elevated in peripheral blood specimens, and the high level was positively correlated to blood glucose concentration. Knockdown of miR 503 enhanced insulin secretion of pancreatic beta-cells, promoted cell proliferation and protected cells from apoptosis, whereas overexpression of miR 503 showed the opposite effects. Furthermore, mammalian target of rapamycin (mTOR) was identified as a direct target of miR-503 and mTOR silencing could reverse the improving effects of miR-503 knockdown on insulin secretion and pancreatic beta-cells proliferation. High expression of miR-503 in peripheral blood may be acted as a diagnosis biomarker of GDM. MiR-503 regulated functions of pancreatic beta-cells by targeting the mTOR pathway, suggesting that targeting miR-503/mTOR axis could serve as a novel therapeutic target for GDM. PMID- 29285013 TI - Knockdown of SLC39A7 suppresses cell proliferation, migration and invasion in cervical cancer. AB - Cervical cancer is the fourth leading cause of malignancy related mortality in women worldwide. SLC39A7 (ZIP7) is a zinc transporter that plays a key role in intestinal epithelial self-renewal. However, whether or not SLC39A7 is involved in human cervical cancer remains unclear. In this study, we investigated the effects of SLC39A7 in cervical cancer in vitro and elucidate related underlying mechanisms. Using Oncomine data analysis, we first found SLC39A7 is commonly upregulated in cervical cancer tissues in comparison with corresponding normal controls. The in vitro experiments indicated that silencing of SLC39A7 expression resulted in decreased cell proliferation, increased cell apoptosis, and attenuated migratory and invasive ability using CCK-8, colony formation, flow cytometry, transwell assays, respectively in cervical cancer cell lines, HeLa and ME-180 cells. In molecular levels, Western blot further demonstrated that silencing of SLC39A7 significantly upregulated the expression of Bax and E cadherin, downregulated the expression of Bcl-2 and MMP-2 in both HeLa and ME-180 cells. These findings provide evidence that SLC39A7 plays a positive role in the progression of cervical cancer and its knockdown might be as a potential therapeutic target for cervical cancer treatment. PMID- 29285015 TI - Evaluation of glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and susceptibility to type 2 diabetes mellitus, a meta-analysis. AB - It is well established that type 2 diabetes mellitus (T2DM) is associated with oxidative stress and glutathione S-transferases (GSTs) protect cells against oxidative stress. The missense substitution Ile105Val (rs1695) of the glutathione S-transferase P1 (GSTP1, OMIM: 134660) results from an A/G base substitution at nucleotide 313. Many studies have evaluated the correlation between the rs1695 polymorphism and T2DM, but the results remain inconclusive. The aim of the present meta-analysis was to investigate the association between GSTP1 Ile105Val polymorphism and the susceptibility risk of T2DM. Eligible studies (published before August 2017) were identified in several databases. The heterogeneity between studies was evaluated with the chi-square based Q test and the I2 test. The strengths of the association were assessed by pooled odds ratios (ORs) and the corresponding 95 % confidence interval (95 % CI) using either a fixed or random-effects models. Eighteen studies documenting a total of 2595 T2DM cases and 2888 controls were included in this meta-analysis. In the overall analysis there was no significant association between the rs1695 polymorphism and the risk of T2DM. The subgroup analyses stratified by ethnicity, publication year and sample size did not reveal significant association between the study polymorphism and the risk of T2DM and any sources contributing to the substantial heterogeneity between studies. The present meta-analysis suggested that there was significant heterogeneity between studies. Considering some limi tations of our meta-analysis, further large-scale studies should be done to reach a more comprehensive understanding. PMID- 29285016 TI - Higher risk of progressing breast cancer in Kurdish population associated to CDH1 -160 C/A polymorphism. AB - There is an increasing interest about studying possible effects of genetic polymorphisms and risk of cancer progression. E-cadherin (CDH1) involves in many important cellular processes including cell-cell interactions, cell development and genetic changes of this molecule has been associated with greater tumor metastasis. The present study was aimed to evaluate the possible role of CDH1 160 C/A polymorphism as a potential risk factor for breast cancer in Kurdish population. This case-control study consisted of 100 breast cancer patients and 200 healthy controls. Clinicopathological findings of all individuals were reported and immunohistochemistry staining was carried out on tissue samples. The CDH1 -160 C/A genotype was determined by polymerase chain reaction- restriction fragment length polymorphism method (PCR-RFLP). CDH1 -160 C/A polymorphism was differently distributed between patient and control groups. The A allele of CDH1 160 C/A polymorphism significantly increased in patients compared to controls. In addition we found that the A allele of this polymorphism might be a potential risk factor for progression of breast cancer in our studied population. Patients with A allele of CDH1 -160 C/A was in higher risk to progress invasive ductal carcinoma. The A allele was also correlated with high grade and stage IV and also with metastatic tumors in studied subjects. The CDH1 -160 C/A polymorphism is correlated with clinicopathologial findings of breast cancer patients. The A allele of CDH1 -160 C/A may be a risk factor for progression of breast cancer in Kurdish patients. PMID- 29285018 TI - Additional evidence for the 'wimp SNP' concept of carcinogenesis. PMID- 29285017 TI - Comparative proteomics analysis of Neisseria gonorrhoeae strains in response to extended-spectrum cephalosporins. AB - Neisseria gonorrhoeae strains displaying reduced susceptibility and resistance to extended-spectrum cephalosporins (ESCs) are major public health concerns. Although resistance mechanisms of ESCs have extensively been studied, the proteome-wide investigation on the biological response to the antibiotic stress is still limited. Herein, a proteomics approach based on two-dimensional gel electrophoresis and MALDI-TOF/TOF-MS analysis was applied to investigate the global protein expression under ESC stresses of ESC-susceptible and ESC-reduced susceptible N. gonorrhoeae strains. Upon exposure to ceftriaxone, 14 and 21 proteins of ESC-susceptible and ESC-reduced susceptible strains, respectively, were shown to be differentially expressed. In the meanwhile, differential expressions of 13 and 17 proteins were detected under cefixime stress for ESC susceptible and ESC-reduced susceptible strains, respectively. ESC antibiotics have been proven to trigger the expression of several proteins implicated in a variety of biological functions including transport system, energy metabolism, stress response and pathogenic virulence factors. Interestingly, macrophage infectivity potentiators (Ng-MIP) showed increased expression for ESC-reduced susceptible strain under ESC stress. The altered expression of Ng-MIP was found to be a unique response to ESC stresses. Our finding proposes a broad view on proteomic changes in N. gonorrhoeae in response to ESC antibiotics that provides further insights into the gonococcal antimicrobial resistance and physiological adaptation mechanism. PMID- 29285019 TI - Consolidation radiotherapy for advanced-stage aggressive B-cell non-Hodgkin lymphoma: A systematic review and meta-analysis. AB - Patients with advanced aggressive B-cell non-Hodgkin lymphomas (NHL) are usually treated with rituximab in combination with chemotherapy. However, disease relapse rates are high. Radiotherapy (RT) has been shown to be efficacious in treating early-stage NHL but its role in advanced stage diseases is unclear. We performed a systematic review of randomized controlled trials (RCTs) comparing chemotherapy with RT to chemotherapy alone in patients with newly diagnosed advanced aggressive NHL. We searched online databases and pooled similar outcome estimates. For time-to-event outcomes, we estimated hazard ratios (HR) for overall survival (OS) and event-free survival (EFS) using the fixed-effect model. Two RCTs involving 254 patients met inclusion criteria. The trials were single centre RCTs with follow-up period of five and ten years. Both trials were conducted in the pre-rituximab era. Patients treated with consolidation RT had better OS (HR for mortality 0.61; 95 % CI 0.38 to 0.97) and EFS (HR for mortality 0.67; 95 % CI 0.46 to 0.98) compared to those who received no RT. There was an apparent benefit of RT on local control (OR 0.09; 95 % CI 0.04 to 0.20); although this was estimated as a dichotomous rather than time-to-event outcome. Limited evidence shows benefits of consolidation RT in advanced aggressive NHL. However, we were not able to estimate the effect size with confidence due to small number of trials and sample size. We cannot recommend routine consolidation RT in advanced aggressive NHL. More RCTs with the inclusion of rituximab and PET-CT monitoring are needed. PMID- 29285020 TI - The relationship between serum levels of fibroblast growth factor 21 and diabetic retinopathy. AB - Fibroblast growth factor 21 (FGF21) is a major metabolic regulator that has been shown to be elevated in a number of metabolic disturbances including type 2 diabetes mellitus (T2DM) and the metabolic syndrome, but few studies about the relationship between serum FGF21 and the complications of diabetes have been done. Since the association between FGF21 and diabetic retinopathy is not clear, this study was conducted to investigate this relationship. In this cross sectional study, 61 subjects (14 healthy controls, 22 diabetic patients without retinopathy, and 25 patients with diabetic retinopathy) were evaluated. All patients in the study were examined for the presence of diabetic retinopathy. Various clinical and biochemical parameters including FGF21 were evaluated and analyzed and compared between the study groups. Serum levels of FGF21 showed a significant difference between the three groups (P=0.003) but the difference between diabetic patients with and without retinopathy was not significant (P=0.122). Regression model was used to evaluate the role of FGF21 in predicting diabetic retinopathy. In the multivariate logistic regression model after adjustment of systolic blood pressure and fasting blood glucose, the level of FGF21 was not associated with diabetic retinopathy. In the multivariate model, only fasting blood glucose was associated with diabetic retinopathy (P=0.009). According to the results of this study, serum levels of FGF21 in diabetic patients was higher than the control group but these raised levels could not predict the presence of diabetic retinopathy. PMID- 29285021 TI - Discovering urinary bladder cancer risk variants: Status quo after almost ten years of genome-wide association studies. PMID- 29285022 TI - Recommendations for the surgical treatment of endometriosis-part 1: ovarian endometrioma. AB - Study question: What does this document on the surgical treatment of endometriosis jointly prepared by the European Society for Gynaecological Endoscopy (ESGE), ESHRE, and the World Endometriosis Society (WES) provide? Summary answer: This document provides recommendations covering technical aspects of different methods of surgery for endometriomas in women of reproductive age. What is already known: Endometriomas (ovarian endometriotic cysts) are a commonly diagnosed form of endometriosis, owing to the relative ease and accuracy of ultrasound diagnosis. They frequently present a clinical dilemma as to whether and how to treat them when found during imaging or incidentally during surgery. Previously published guidelines have provided recommendations based on the best available evidence, but without technical details on the management of endometriosis. Study design size and duration: A working group of ESGE, ESHRE and WES collaborated on writing recommendations on the practical aspects of endometrioma surgery. Participants/materials setting and methods: This document focused on endometrioma surgery. Further documents in this series will provide recommendations for surgery of deep and peritoneal endometriosis. Main results and the role of chance: The document presents general recommendations for surgery of endometrioma and specific recommendations for cystectomy, ablation by laser or by plasma energy, electrocoagulation and a combination of these techniques applied together or with an interval between them. Limitations and reasons for caution: Owing to the limited evidence available, recommendations are mostly based on clinical expertise. Wider implications of the findings: These recommendations complement previous guidelines on the management of endometriosis. Study funding/competing interests: The meetings of the working group were funded by ESGE, ESHRE and WES. CB declares to be a member of the independent data monitoring committee for a clinical study by ObsEva and receiving research grants from Bayer, Roche Diagnostics, MDNA Life Sciences and Volition. ES received honoraria for provision of training to healthcare professionals from Ethicon, Olympus and Gedeon Richter. The other authors declare that they have no conflict of interest. PMID- 29285023 TI - Treating symptomatic uterine fibroids with myomectomy: current practice and views of UK consultants. PMID- 29285024 TI - Corrigendum: Intrinsic and Extrinsic Properties Affecting Innate Immune Responses to Nanoparticles: The Case of Cerium Oxide. AB - [This corrects the article on p. 970 in vol. 8, PMID: 28855907.]. PMID- 29285025 TI - Corrigendum: Shoot the Message, Not the Messenger-Combating Pathogenic Virulence in Plants by Inhibiting Quorum Sensing Mediated Signaling Molecules. AB - [This corrects the article on p. 556 in vol. 8, PMID: 28446917.]. PMID- 29285026 TI - Corrigendum: Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency. AB - [This corrects the article on p. 113 in vol. 8, PMID: 28919908.]. PMID- 29285027 TI - Comparison of the Level of Substance P and Neurokinin A in Gingival Crevicular Fluid of Sound and Symptomatic Carious Primary Teeth by ELISA. AB - Objectives: Pulpal inflammation is often associated with odontogenic pain. Dental pulp is abundantly innervated with sensory fibers encompassing neuropeptides. Neurokinin A (NKA) and substance P (SP) are important neuropeptides in the dental pulp that can cause neurogenic inflammation. Since no previous study has assessed dental pulp neuropeptides in children, this study aimed to compare the level of NKA and SP in gingival crevicular fluid (GCF) of sound and symptomatic carious primary teeth. Materials and Methods: Samples of GCF were obtained of 20 sound and 20 painful carious primary teeth. Enzyme-linked immunosorbent assay (ELISA) was used to quantify neuropeptides in GCF. Data were analyzed using paired t test, ANOVA, Kolmogorov-Smirnov test and correlation coefficient test. Results: A significant difference was noted in the level of NKA in GCF of painful and sound teeth (2.23 pg/ml in painful, and 1.84 pg/ml in sound teeth, P<0.05). The difference between the two groups regarding SP was not significant (2.23 pg/ml in painful, and 2.02 pg/ml in sound teeth, P>0.05). Conclusions: The results showed that the level of NKA and SP was higher in GCF of painful teeth compared to that of sound teeth. This difference was statistically significant with regard to NKA. Thus, these neuropeptides can serve as indicators for pathological activities in teeth with symptomatic irreversible pulpitis. PMID- 29285028 TI - Perception of Iranian Mothers About Oral Health of Their School-Children: A Qualitative Study. AB - Objectives: Oral health is an important aspect of general health and well-being for children. Understanding the viewpoint of mothers about children's oral health provides a basis for the development of interventions to improve oral care and disease prevention. The purpose of this study was to explore the perception of Iranian mothers regarding the oral health of their children. Materials and Methods: This descriptive qualitative study was the first phase of an exploratory mixed method design and collected data from April to May 2015 in Tehran, Iran. The qualitative data were collected through seven focus group discussions and three semi-structured interviews. The participants were 58 Iranian women who had a first grader. Data were analyzed using conventional content analysis. Results: The main themes identified from the data were: (I) the definition of oral health, (II) the importance of maintaining oral health and dental treatment, (III) the effect of nutrition on children's oral health, (IV) the role of oral health behaviors, (V) the causes of dental caries and malocclusion/crowding, (VI) the symptoms and causes of gum disease, (VII) the causes of halitosis. Conclusions: According to the mothers' perception, the main factors influencing children's oral health were: nutrition and oral health behaviors such as daily tooth brushing and flossing. The results of this study can be used to develop a model of oral health education and a prevention program for improving oral health among Iranian school-children. PMID- 29285029 TI - Establishment and Characterization of Primary Cultures from Iranian Oral Squamous Cell Carcinoma Patients by Enzymatic Method and Explant Culture. AB - Objectives: Oral Squamous Cell Carcinoma (OSCC) is the most frequent oral cancer worldwide. It is known as the eighth most common cancer in men and as the fifth most common cancer in women. Cytogenetic and biochemical studies in recent decades have emphasized the necessity of providing an appropriate tool for such researches. Cancer cell culture is a useful tool for investigations on biochemical, genetic, molecular and immunological characteristics of different cancers, including oral cancer. Here, we explain the establishment process of five primary oral cancer cells derived from an Iranian population. Materials and Methods: The specimens were obtained from five oral cancer patients. Enzymatic, explant culture and magnetic-activated cell sorting (MACS) methods were used for cell isolation. After quality control tests, characterization and authentication of primary oral cancer cells were performed by short tandem repeats (STR) profiling, chromosome analysis, species identification, and monitoring the growth, morphology and the expression of CD326 and CD133 markers. Results: Five primary oral cancer cells were established from an Iranian population. The flow cytometry results showed that the isolated cells were positive for CD326 and CD133 markers. Furthermore, the cells were free from mycoplasma, bacterial and fungal contamination. No misidentified or cross-contaminated cells were detected by STR analysis. Conclusions: Human primary oral cancer cells provide an extremely useful platform for studying carcinogenesis pathways of oral cancer in Iranian population. They may be helpful in explaining the ethnic differences in cancer biology and the individuality in anticancer drug response in future studies. PMID- 29285030 TI - Proliferative and Anti-Inflammatory Effects of Resveratrol and Silymarin on Human Gingival Fibroblasts: A View to the Future. AB - Objectives: It has been demonstrated that polyphenol components such as silymarin and resveratrol have anti-inflammatory properties. Periodontitis is a chronic inflammatory disease that leads to the breakdown of dental supporting tissues and tooth loss. The purpose of this study was to investigate the anti-inflammatory effects of silymarin and resveratrol on lipopolysaccharide (LPS)-induced inflammatory response in human gingival fibroblasts (HGFs). Materials and Methods: HGFs were treated with different concentrations of silymarin and/or resveratrol (25, 50, 100 and 200MUg/ml). The effects of silymarin and resveratrol on cell viability and proliferation were assessed by MTT assay and cell cycle analysis, respectively. Also, HGFs were treated with silymarin and/or resveratrol and were stimulated with LPS. The levels of Interleukin-6 (IL-6) and IL-8 were assessed by enzyme-linked immunosorbent assay (ELISA). Results: After treatment with silymarin, the viability of fibroblasts significantly increased, whereas treatment with resveratrol did not have any significant effect on cell viability. However, the combination of these flavonoids (50MUg/ml silymarin and 100MUg/ml resveratrol) significantly increased the viability of fibroblasts. Resveratrol significantly inhibited LPS-induced IL-6 and IL-8 secretion by HGFs, but silymarin did not show such a significant effect. Conclusions: The findings of the present study demonstrated the anti-inflammatory effects of resveratrol and its combination with silymarin. Therefore, the combination of silymarin and resveratrol may be useful as a therapeutic agent for treatment of periodontal diseases. PMID- 29285031 TI - Efficacy of Modified Bioactive Glass for Dentin Remineralization and Obstruction of Dentinal Tubules. AB - Objectives: This study assessed the efficacy of modified bioactive glass (MBG) for dentin remineralization and obstruction of dentinal tubules. Materials and Methods: Thirty-six dentin discs were made from 20 third molars and were stored in 12% lactic acid solution for two weeks to induce demineralization. The samples were divided into three groups (n=12): 1- BG, 2- BG modified with 5% strontium (Sr) and 3- BG modified with 10% Sr. After applying the BG, the samples were stored in artificial saliva for 7, 14 and 21 days. Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR), X-ray Diffraction (XRD) analysis, Scanning Electron Microscopy (SEM), and Energy-Dispersive X-ray (EDX) analysis were used to assess remineralization. Also, 6 dentin discs were divided into three groups of BG, BG modified with 5% Sr and BG modified with 10% Sr, to examine tubular occlusion. The discs were etched using 0.5M of EDTA for two minutes and were stored in artificial saliva for 7 days. Changes in dentin surface morphology were evaluated under SEM. Results: Group 3 showed high rates of remineralization at days 7 and 14, although the rate decreased at day 21. Group 2 exhibited high rates of remineralization at days 7, 14 and 21. Dentinal tubules were partially occluded by BG and BG modified with 5% Sr, while they were almost completely obstructed after the use of BG modified with 10% Sr. Conclusions: Strontium increases remineralization. Addition of 10% Sr to BG enhances apatite formation; however, the apatite dissolves over time. Addition of 5% Sr to BG stabilizes the apatite lattice and increases the remineralization. PMID- 29285032 TI - Effect of Filtration and Thickness of Cross-Sections of Cone Beam Computed Tomography Images on Detection of Proximal Caries. AB - Objectives: When a patient has cone beam computed tomography (CBCT) images based on the treatment plan, it is possible to use these images for evaluation of caries, and there is no need for new radiographs, according to the "as low as reasonably achievable" (ALARA) principle. The aim of this study was to determine the effect of filtration and thickness of CBCT cross-sections on detection of proximal caries. Materials and Methods: In this in-vitro study, 100 teeth were placed in the dental sockets of a dry skull, and were fixed in normal proximal contacts. CBCT images were taken and were evaluated by two observers on the panoramic view at 1-, 3- and 5-mm-thick cross-sections, with the use of filtrations 0, 1 and 2. Afterwards, the samples were sectioned and underwent a histological evaluation. McNemar's test was used to compare the findings on CBCT images and histological evaluation. Receiver operating characteristic (ROC) curves and logistic regression were used to evaluate the diagnostic accuracy of different cross-sections. Results: The maximum AZ-value was achieved at 3-mm thickness/filtration 2. However, the differences between 1-mm thickness/filtration 2 and 1-mm thickness/filtration 1 were not significant (P=0.728 and 0.868, respectively). The minimum AZ-value was achieved at 5-mm thickness/filtration 0. Conclusions: Although CBCT is not sufficiently effective in detecting caries, the best cross-sections for detection of proximal caries were achieved at 3-mm thickness/filtration 2, 1-mm thickness/filtration 2 and 1 mm thickness/filtration 1. PMID- 29285033 TI - Flexural Strength of Polymethyl Methacrylate Repaired with Fiberglass. AB - Objectives: The purpose of this experimental study was to discover a method to increase the strength of repaired polymethyl methacrylate (PMMA) samples. Materials and Methods: In this experimental study, 40 specimens with the dimensions of 65*10*2.5mm3 were fabricated using heat-curing acrylic resin. Sixteen specimens were repaired with fiberglass and self-curing PMMA, while 16 samples were repaired with self-curing PMMA. Eight specimens were left intact as the control group. Afterwards, the flexural strengths of the repaired and intact specimens were measured by three-point bending test in a universal testing machine. Data were analyzed with one-way analysis of variance (ANOVA) and Tukey's HSD and LSD tests. The level of significance was set at P<0.05. Results: The mean flexural strength of the samples repaired with fiberglass was higher than that of the other repaired samples. However, the difference was statistically significant only with respect to the Meliodent group (P=0.008). Conclusions: Impregnated fiberglass could be used in the repair of denture bases to improve the flexural strength. In terms of the fracture site, it can be concluded that the lower flexural strength of the auto-polymerizing acryl compared to that of the heat curing type was the main reason for the occurrence of fractures, rather than the weak bond between heat-curing and auto-polymerizing acrylic resins. PMID- 29285034 TI - Performance of Preschoolers' Mothers and Senior Dental Students After Receiving Training on Fluoride Varnish Administration. AB - Objectives: Fluoride varnish application is an effective way to prevent caries in children. We aimed to educate preschool children's mothers on how to apply fluoride varnish and compare their performance with dental students and to assess their self-reported competency six months later. Materials and Methods: Eighty eight 4-6-year-old children presenting to toy houses of six randomly selected health centers in a non-affluent district of Tehran in 2014 were divided into two groups to receive fluoride varnish by their mothers and students. Mothers and senior dental students participated in a session consisting of lecture, discussion, and demonstration of fluoride varnish application for a child. Then, in three centers, mothers and in others, students applied fluoride varnish for preschoolers and their performance was evaluated. Six months later, mothers were asked to apply fluoride varnish again. Mann-Whitney U test, t-test, one-way ANOVA and logistic regression model were used for statistical analyses. Results: The mean performance score was 9.74+/-0.22 (out of 10) for mothers and 9.71+/-0.15 for students (P=0.89). After six months, the mean performance score was 9.58 for mothers, which was not significantly different from that in the first session. The age and educational level of mothers were conversely correlated to their performance (P<0.05). Of mothers, 96% believed that they were competent to repeat fluoride varnish application for their children. Conclusions: Mothers' high performance score and the point that the majority of them felt competent to apply varnish for their children casts light on their potential key role in oral health promotion. PMID- 29285035 TI - Biomarkers of Everolimus Sensitivity in Hormone Receptor-Positive Breast Cancer. AB - Activation of the mammalian target of rapamycin (mTOR) signaling pathway is an important mechanism of resistance to endocrine therapy in breast cancer. Everolimus, an mTOR inhibitor, has been shown to increase the efficacy of endocrine therapy and overcome resistance to endocrine therapies. Clinical studies have suggested that everolimus combined with endocrine therapy prolongs progression-free survival in hormone receptor-positive breast cancer patients. However, because breast cancer includes a group of highly heterogeneous tumors, patients may have different responses to everolimus. Therefore, finding biomarkers that can predict a patient's positive response or resistance to everolimus is critical. Numerous preclinical studies have shown that PIK3CA/PTEN mutations are predictive of sensitivity to everolimus; however, clinical trials have not confirmed the correlation between mutation status and clinical response. KRAS or BRAF mutations can bypass the phosphatidylinositol 3-kinase pathway; therefore, mutations in KRAS or BRAF may lead to resistance to mTOR inhibitors, and preclinical studies have shown that PIK3CA mutant cells which also contain KRAS mutations are resistant to everolimus. However, there are no clinical data in breast cancer patients to support this conclusion. Therefore, large-scale clinical studies are needed to identify biomarkers of efficacy and resistance to everolimus. PMID- 29285036 TI - Selective Radiation Therapy for Ductal Carcinoma In Situ Following Breast Conserving Surgery According to Age and Margin Width: Korean Radiation Oncology Group 11-04 and 16-02 Studies. AB - Purpose: The optimal indications for omitting adjuvant radiation therapy (RT) after breast-conserving surgery are still controversial in ductal carcinoma in situ (DCIS) of the breast. The purpose of this study was to validate the role of postoperative RT in DCIS patients aged <=50 years and with tumor margin widths of <1 cm, both of which have been proven to be high-risk features for recurrence in cohorts not receiving RT. Methods: Using two multicenter retrospective studies on DCIS, a pooled analysis was performed among patients aged <=50 years and with margin widths <1 cm. All patients underwent breast-conserving surgery. Two hundred thirty-two patients received postoperative RT, while 54 did not. The median follow-up period was 77 months (range, 2-190 months) and 70 months (range, 5-166 months) in the patients who received RT and those who did not, respectively. Results: The patients who received RT had larger tumors (p<0.001), higher nuclear grade (p<0.001), closer margin width (p<0.001), and negative estrogen receptor expression (p=0.010) compared with those who did not receive RT. During the follow-up period, there were 17 ipsilateral breast tumor recurrences (IBTRs) as follows: invasive carcinoma in 10 patients and DCIS in seven. In the univariate analysis, the treatment with RT and human epidermal growth factor receptor 2 (HER2) status were significant risk factors for IBTR. The 7-year IBTR rates with and without postoperative RT were 3.6% and 13.1%, respectively (p=0.008). HER2-positive tumors had a higher IBTR rate than the HER2 negative tumors (7-year rate, 13.6% vs. 3.9%; p=0.003). Conclusion: Postoperative RT following breast-conserving surgery significantly reduced the 7-year IBTR rate in the DCIS patients aged <=50 years and with margin widths <1 cm. HER2 positivity was associated with increased IBTR in these patients. PMID- 29285037 TI - Interactions of Family History of Breast Cancer with Radiotherapy in Relation to the Risk of Breast Cancer Recurrence. AB - Purpose: We examined associations between a family history of breast cancer and the risk of breast cancer recurrence in women who received or did not receive radiotherapy. Methods: Our study included 2,440 women enrolled in the Breast Cancer Registry of Greater Cincinnati. Information on breast cancer risk factors, including detailed family history of breast cancer, characteristics of the primary tumor, treatment received, and recurrence status was collected at baseline and via updates. Associations between a family history of breast cancer and the risk of breast cancer recurrence were examined separately in women treated with and without radiotherapy using survival analysis. Results: Over an average follow-up time of 8.78 years, we found no associations between a family history of breast cancer and the risk of breast cancer recurrence among women with a history of radiotherapy (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.75-1.23). Among women who did not receive radiotherapy, the total number of relatives with breast cancer was positively associated with the risk of breast cancer recurrence (HR, 1.21; 95% CI, 1.00-1.47). We found no interactions of radiotherapy with family history (p-interaction >0.05). Conclusion: Radiotherapy for a primary breast cancer in women with a family history of breast cancer does not increase risk of breast cancer recurrence. If these findings are replicated in future studies, the results may translate into an important health message for breast cancer survivors with a family history of breast cancer. PMID- 29285038 TI - A Multicenter Phase II Trial of Neoadjuvant Chemotherapy with Docetaxel and Gemcitabine in Locally Advanced Breast Cancer. AB - Purpose: The current multicenter phase II study was conducted to evaluate the efficacy and safety of the combination of docetaxel and gemcitabine as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer. Methods: A total of 98 patients with stage II-III breast cancer were enrolled. The primary endpoint was pathological complete response (pCR) rate of invasive cancer after the completion of the fourth cycle of NAC. The secondary endpoints included response rate (RR), rate of breast-conserving surgery, toxicity, and disease-free survival (DFS). This study is registered with ClinicalTrials.gov (NCT01352494). Results: pCR in the breast and the axillary lymph node was observed in seven of the 98 enrolled patients (7.1%). The overall clinical RR, including partial responses, was 65.3%. Breast-conserving surgery was performed in 75 of the 98 assessable patients (76.5%). Neutropenia was frequent and was observed in 92 of the 98 patients (93.9%), including grade 3 and 4 in 24 patients (24.5%) and 63 patients (64.3%), respectively. Dose reductions were required for 30 of the 92 patients (32.6%). After a median follow-up of 24 months, the overall DFS of the group was 86.7%. Conclusion: The combination of docetaxel and gemcitabine did not improve pCR. However, this regimen has shown potential as a NAC by producing a reasonable rate of breast-conserving surgery and favorable responses in patients with locally advanced breast cancer. The therapeutic efficacy of this regimen will be determined in additional trials to overcome the limitations of the current study. PMID- 29285039 TI - Cyclophosphamide, Methotrexate, and 5-Fluorouracil as Palliative Treatment for Heavily Pretreated Patients with Metastatic Breast Cancer: A Multicenter Retrospective Analysis. AB - Purpose: This study aimed to evaluate the efficacy and safety of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy beyond standard treatment for anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Methods: We consecutively enrolled 158 MBC patients who underwent CMF chemotherapy in a palliative setting at two academic hospitals in Korea between 2002 and 2016. Results: The median age of the 158 enrolled patients was 51 years (range, 30-77 years). The enrolled patients were treated with a median of 5 lines of systemic treatment (range, 2-11) before CMF therapy, and the median time from diagnosis of MBC to CMF administration was 36.0 months (range, 7.1 146.7 months). The median number of cycles of CMF treatment was 3 (range, 1-19), and the relative dose intensity was 90.4%. The toxicity profile was mild, with an observed 3.1% of grade 2 and 5.0% of grade 3/4 neutropenia. Among 147 patients (93.0%) whose response to CMF was evaluated, the response rate was 10.9% (16/147), with complete response (CR) in one and partial response (PR) in 15. In addition, the disease control rate (calculated as CR+PR+stable disease) was 44.2% (65/147). The median progression-free survival and overall survival were 3.1 months (95% confidence interval [CI], 2.7-3.6) and 9.4 months (95% CI, 7.1-11.6), respectively. Conclusion: CMF therapy is effective and tolerable as salvage treatment for heavily pretreated MBC. PMID- 29285040 TI - Tamoxifen and the Risk of Parkinson's Disease in Female Patients with Breast Cancer in Asian People: A Nationwide Population-Based Study. AB - Purpose: Whether tamoxifen affects the risk of neurodegenerative disease is controversial. This nationwide population-based study investigated the risk of Parkinson's disease (PD) associated with tamoxifen treatment in female patients with breast cancer using Taiwan's National Health Insurance Research Database. Methods: A total of 5,185 and 5,592 female patients with breast cancer who did and did not, respectively, receive tamoxifen treatment between 2000 and 2009 were included in the study. Patients who subsequently developed PD were identified. A Cox proportional hazards model was used to compare the risk of PD between the aforementioned groups. Results: Tamoxifen did not significantly increase the crude rate of developing PD in female patients with breast cancer (tamoxifen group, 16/5,169; non-tamoxifen group, 11/5,581; p=0.246). Tamoxifen did not significantly increase the adjusted hazard ratio (aHR) for subsequently developing PD (aHR, 1.310; 95% confidence interval [CI], 0.605-2.837; p=0.494). However, tamoxifen significantly increased the risk of PD among patients followed up for more than 6 years (aHR, 2.435; 95% CI, 1.008-5.882; p=0.048). Conclusion: Tamoxifen treatment may increase the risk of PD in Taiwanese female patients with breast cancer more than 6 years after the initiation of treatment. PMID- 29285041 TI - Wnt7a Deficiency Could Predict Worse Disease-Free and Overall Survival in Estrogen Receptor-Positive Breast Cancer. AB - Purpose: Wnt7a is a glycoprotein involved in embryonic development and the progression of different types of malignant tumors. This study aimed to detect the level of Wnt7a expression in breast cancer and explore its role in the disease progression and prognosis. Methods: A total of 258 patients diagnosed with invasive ductal carcinoma of the breast were included in this study. Using tissue microarray and immunohistochemical staining, we evaluated the association between Wnt7a expression and clinicopathological parameters, and the prognostic value of Wnt7a. Results: Wnt7a expression was significantly correlated with estrogen receptor (ER) expression (odds ratio, 3.95; 95% confidence interval [CI], 1.99-7.80; p<0.001). On univariate and multivariate analyses, loss of Wnt7a expression was associated with poor disease-free survival (DFS) (multivariate hazard ratio [HR], 9.12; 95% CI, 1.80-46.09; p=0.008), but not with poor overall survival (OS). In the ER-positive group (n=114), loss of Wnt7a expression was an independent prognostic factor for shorter DFS (multivariate HR, 13.54; 95% CI, 1.11-165.73; p=0.042) and OS (multivariate HR, 4.76; 95% CI, 1.29-17.61; p=0.019) on univariate and multivariate analyses. However, in the ER-negative group, there was no significant difference in DFS and OS according to Wnt7a expression. Conclusion: The loss of Wnt7a expression might be a meaningful factor in assessing DFS and OS, especially in ER-positive breast cancer. PMID- 29285042 TI - Treatment Patterns and Outcomes in Elderly Patients with Metastatic Breast Cancer: A Multicenter Retrospective Study. AB - Purpose: Currently, there is little information regarding optimal treatment for metastatic breast cancer (MBC) in elderly patients. In this retrospective study, we examined a cohort of elderly patients with MBC receiving a range of treatments, in terms of demographic and clinicopathologic characteristics, treatment patterns, and outcomes. Methods: Patients aged 65 years and older, and diagnosed with MBC between 2003 and 2015, were identified from the databases of three academic hospitals in South Korea. A total of 161 cases were eligible for inclusion. We assessed clinicopathologic features, treatment patterns, and outcomes, using the available electronic medical records. Based on age at MBC diagnosis, patients were divided into three groups: 65 to 69, 70 to 74, and >=75 years. Results: Most patients had received active treatment according to biologic subtype as in younger patients, although frequent dose modifications were observed during chemotherapy. The median overall survival (OS) for all patients was 30.3 months; age (>=70 years), Eastern Cooperative Oncology Group (ECOG) performance status (PS) (>=2), triple-negative cancer, and number of metastatic sites (>=2) were significant poor prognostic factors for OS in multivariate analyses. All types of systemic treatments according to biologic subtype conferred more prolonged OS in patients receiving treatment. Patients aged >=75 years were more likely to have a poor ECOG PS and advanced comorbidity, and tended to receive less intensive treatments compared to the other age groups. Conclusion: Elderly patients with MBC should not be excluded from receiving standard treatments prescribed for younger patients. Future research plans for elderly patients, especially aged >=75 years with breast cancer, should include a geriatric assessment for identifying individuals at risk for treatment-related toxicity. Overall, this analysis will provide a better understanding of this population and help guide clinical care in real-world practice. PMID- 29285043 TI - Improved Model for Predicting Axillary Response to Neoadjuvant Chemotherapy in Patients with Clinically Node-Positive Breast Cancer. AB - Purpose: Pathological complete response (pCR) of axillary lymph node (LN) is frequently achieved in patients with clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC). Treatment of the axilla after NAC is not well established and the value of sentinel LN biopsy following NAC remains unclear. This study investigated the predictive value of axillary response following NAC and evaluated the predictive value of a model based on axillary response. Methods: Data prospectively collected on 201 patients with clinically node positive breast cancer who were treated with NAC and underwent axillary LN dissection (ALND) were retrieved. A model predictive of axillary pCR was developed based on clinicopathologic variables. The overall predictive ability between models was compared by receiver operating characteristic (ROC) curve analysis. Results: Of 201 patients who underwent ALND after NAC, 68 (33.8%) achieved axillary pCR. Multivariate analysis using axillary LN pCR after NAC as the dependent variable showed that higher histologic grade (p=0.031; odds ratio [OR], 2.537; 95% confidence interval [CI], 1.087-5.925) and tumor response rate >=47.1% (p=0.001; OR, 3.212; 95% CI, 1.584-6.515) were significantly associated with an increased probability of achieving axillary pCR. The area under the ROC curve for estimating axillary pCR was significantly higher in the model that included tumor response rate than in the model that excluded this rate (0.732 vs. 0.649, p=0.022). Conclusion: Tumor response rate was the most significant independent predictor of axillary pCR in response to NAC. The model that included tumor response rate was a significantly better predictor of axillary pCR than the model that excluded tumor response rate. PMID- 29285045 TI - Optimization of RNA Extraction from Formalin-Fixed Paraffin-Embedded Blocks for Targeted Next-Generation Sequencing. AB - Purpose: Breast cancer has a high prevalence in Korea. To achieve personalized therapy for breast cancer, long-term follow-up specimens are needed for next generation sequencing (NGS) and multigene analysis. Formalin-fixed paraffin embedded (FFPE) samples are easier to store than fresh frozen (FF) samples. The objective of this study was to optimize RNA extraction from FFPE blocks for NGS. Methods: RNA quality from FF and FFPE tissues (n=5), expected RNA amount per unit area, the relationship between archiving time and quantity/quality of FFPE extracted RNA (n=14), differences in quantitative real-time polymerase chain reaction (qRT-PCR) and NGS results, and comparisons of both techniques with tissue processing at different institutions (n=96) were determined in this study. Results: The quality of RNA did not show any statistically significant difference between paired FF and FFPE specimens (p=0.49). Analysis of tumor cellularity gave an expected RNA amount of 33.25 ng/mm2. Archiving time affected RNA quality, showing a negative correlation with RNA integrity number and a positive correlation with threshold cycle. However, RNA from samples as old as 10 years showed a 100% success rate in qRT-PCR using short primers, showing that the effect of archiving time can be overcome by proper experiment design. NGS showed a higher success rate than qRT-PCR. Specimens from institution B (n=46), which were often stored in a refrigerator for more than 6 hours and fixed without slicing, showed lower success rates and worse results than specimens from the other institutes. Conclusion: Archived FFPE tissues can be used to extract RNA for NGS if they are properly processed before fixation. The expected amount of RNA per unit size calculated in this study will be useful for other researchers. PMID- 29285044 TI - Metabolic Activity of Normal Glandular Tissue on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: Correlation with Menstrual Cycles and Parenchymal Enhancements. AB - Purpose: The aims of our study were to correlate the degree of metabolic activity in normal glandular tissue measured on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with qualitative background parenchymal enhancement (BPE) grades on magnetic resonance imaging (MRI), and to investigate the change in standardized uptake value (SUV) according to the patients' menstrual cycles. Methods: From January 2013 to December 2015, 298 consecutive premenopausal patients with breast cancer who underwent both breast MRI and 18F-FDG PET/CT were identified. BPE was evaluated in the contralateral breast of cancer patients and categorized as minimal, mild, moderate, or marked based on Breast Imaging Reporting and Data System criteria. We analyzed the correlation between BPE and maximum SUV (SUVmax) and mean SUV (SUVmean) values. We also analyzed the metabolic activity of normal glandular tissue according to the patients' menstrual cycles. Results: The mean SUVmax and SUVmean values differed significantly according to BPE grade (p<0001), with the lowest values occurring in the minimal group and the highest values occurring in the marked group. Spearman's correlation coefficients revealed moderate correlations between BPE grade and SUVmax (r=0.472, p<0.001) and BPE and SUVmean (r=0.498, p<0.001). The mean SUVmax and SUVmean values differed significantly according to the patients' menstrual cycles, with the highest values in the 3rd week and the lowest value in the 2nd week. Of 29 patients with low metabolic parenchyma (high BPE but low SUVmean values), 17 (58.6%) were in the 4th week of their menstrual cycle. Conclusion: The metabolic activity of normal breast parenchyma, which is highest in the 3rd week and lowest in the 2nd week of the menstrual cycle, correlates moderately with BPE on MRI. Metabolic activity tends to be lower than blood flow and vessel permeability in the 4th week of the menstrual cycle. PMID- 29285046 TI - The Practice Patterns and Perceptions of Korean Surgeons Regarding Margin Status after Breast-Conserving Surgery. AB - Two consecutive surveys for breast surgeons in Korea were conducted to comprehend the practice patterns and perceptions on margin status after breast-conserving surgery. The surveys were conducted online in 2014 (initial) and 2016 (follow up). A total of 126 and 88 responses were obtained in the initial and follow-up survey, respectively. More than 80% of the respondents replied to routinely apply frozen section biopsy for intraoperative margin assessment in both surveys. Re excision recommendations of the margin for invasive cancer significantly changed from a close margin to a positive margin over time (p=0.033). Most of the respondents (73.8%) defined a negative margin as "no ink on tumor" in invasive cancer, whereas more diverse responses were observed in ductal carcinoma in situ cases. The influence of guideline establishment for negative margins has been identified. A high uptake rate of intraoperative frozen section biopsy was noted and routine use needs reconsideration. PMID- 29285047 TI - Ectopic Male Breast Cancer in the Perineum: A Case Report. AB - Ectopic breast tissue and male breast cancer are both very rare diseases with only a few reports in the literature. Here, we present the first case of ectopic male breast cancer in the perineum. The patient was a 70-year-old man with a palpable mass in the perineum. A wide local excision and inguinal lymph node dissection revealed invasive breast carcinoma of no special type involving the skin and subcutis, and inguinal lymph node metastases. Immunohistochemical staining showed that the tumor cells were strongly positive for estrogen and progesterone receptors and negative for human epidermal growth factor receptor 2. Moreover, no p53 overexpression was observed. Herein, the clinical and pathologic features, as well as a review of ectopic male breast cancer are discussed. PMID- 29285048 TI - Erratum: Follow-up Outcomes of Benign Pathology Initially Assigned as Breast Imaging Reporting and Data System Category 4A and 3. AB - [This corrects the article on p. 304 in vol. 20, PMID: 28970857.]. PMID- 29285049 TI - Innate immune evasion strategies against Cryptococcal meningitis caused by Cryptococcus neoformans. AB - As an infectious fungus that affects the respiratory tract, Cryptococcus neoformans (C. neoformans) commonly causes asymptomatic pulmonary infection. C. neoformans may target the brain instead of the lungs and cross the blood-brain barrier (BBB) in the early phase of infection; however, this is dependent on successful evasion of the host innate immune system. During the initial stage of fungal infection, a complex network of innate immune factors are activated. C. neoformans utilizes a number of strategies to overcome the anti-fungal mechanisms of the host innate immune system and cross the BBB. In the present review, the defensive mechanisms of C. neoformans against the innate immune system and its ability to cross the BBB were discussed, with an emphasis on recent insights into the activities of anti-phagocytotic and anti-oxidative factors in C. neoformans. PMID- 29285051 TI - Combined effects of tumor necrosis factor-alpha and interleukin-1beta on lysyl oxidase and matrix metalloproteinase expression in human knee synovial fibroblasts in vitro. AB - Previous studies have demonstrated that inflammatory cytokines are associated with matrix metalloproteinases (MMPs) and/or lysyl oxidases (LOXs) produced by anterior cruciate ligament (ACL) fibroblasts, which may contribute to the poor healing ability of the ACL. To evaluate whether the synovium also participates in ACL healing, the inflammatory microenvironment of the knee joint cavity was mimicked following ACL injury, and the combined effects of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the expression of MMPs and LOXs in synovial fibroblasts were studied. Cell viability was evaluated using trypan blue staining in the presence of TNF-alpha and IL-1beta, and the expression of LOXs and MMPs was measured by reverse transcription-quantitative polymerase chain reaction. MMP-2 activity was also measured by zymography. The results indicated that the combined effects of TNF-alpha and IL-1beta inhibited LOX expression, while promoting MMP-1, -2 and -3 expression and MMP-2 activity in synovial fibroblasts. These changes may impede healing by altering the balance between the degradative and biosynthetic arms of the ligament tissue remodeling process. Collectively, the present results suggest that the poor healing ability of cruciate ligaments may be due to the sensitivity of the synovium to inflammatory factors. Therefore, the synovium potentially serves a key regulatory role in the joint cavity microenvironment and in the healing process of the ACL, and thus should be considered as a therapeutic target to aid in the treatment of patients with ACL trauma. PMID- 29285050 TI - Thalidomide and its analogues: A review of the potential for immunomodulation of fibrosis diseases and opthalmopathy. AB - The US Food and Drug Administration approved thalidomide and its analogues for the treatment of erythema nodosum leprosum, in spite of the notoriety of reports of severe birth defects in the middle of the last century. As immunomodulatory drugs, thalidomide and its analogues have been used to effectively treat various diseases. In the present review, preclinical data about the effects of thalidomide and its analogues on the immune system are integrated, including the effects of cytokines on transdifferentiation, the anti-inflammatory effect, immune cell function regulation and angiogenesis. The present review also investigates the latest developments of thalidomide as a therapeutic option for the treatment of idiopathic pulmonary fibrosis, skin fibrosis, and ophthalmopathies. PMID- 29285052 TI - Suppression of Alzheimer's disease-related phenotypes by the heat shock protein 70 inducer, geranylgeranylacetone, in APP/PS1 transgenic mice via the ERK/p38 MAPK signaling pathway. AB - HSP70 overexpression has a remedying effect in neurodegenerative diseases. In Alzheimer's disease (AD), the suppressive effects of HSP70 overexpression on AD related phenotypes and the underlying mechanisms are unknown. In the current study, the effect of geranylgeranylacetone (GGA), a non-toxic inducer of heat shock protein (HSP)-70 expression, on cognitive function and other pathological phenotypes were evaluated in APP/PS1 mice. It was observed that all doses of orally administered GGA (200, 400, and 800 mg/kg/day) improved cognitive deficit (P<0.05) and lowered the levels of amyloid-beta (Abeta) peptide (P<0.05) in APP/PS1 mice. GGA treatment also increased the levels of low density lipoprotein receptor-related protein 1 (LRP-1) (P<0.05), while the levels of p-glycoprotein and receptor for advanced glycation end products were unaltered. Significant decreases in the levels of inflammatory cytokines, namely tumor necrosis factor alpha, interleukin-1beta and cyclooxygenase-2, were also observed in the GGA treated mice (P<0.05). Subsequent treatment with the HSP70 inhibitor quercetin caused significant decreases in the levels of phosphorylated (p)-p38 mitogen activated protein kinase (p38 MAPK) and p-extracellular signal-regulated protein kinases (ERK; P<0.05), indicating that ERK/p38 MAPK signaling in AD-related phenotypes may be suppressed by oral administration of GGA. Finally, in APP/PS1 mice treated with GGA+SB-203580 (p38 inhibitor) and GGA+PD98059 (ERK inhibitor), it was observed that orally administered GGA led to the activation of ERK/p38 MAPK signaling (P<0.05) and increased LRP-1 expression (P<0.05), which subsequently aided the clearance of Abeta40 and Abeta42 (P<0.05) and alleviated AD-related phenotypes. These results indicate that oral administration of GGA in APP/PS1 mice alleviates AD-related phenotypes by regulation of the ERK/p38 MAPK signaling pathway. Thus, GGA may be a potential therapeutic for the treatment of AD. PMID- 29285053 TI - Establishment of a mouse model of lipopolysaccharide-induced neutrophilic nasal polyps. AB - Research has identified that gram-negative bacteria have an important role in refractory nasal polyps. In the present study, lipopolysaccharide (LPS) was used to establish a mouse model with neutrophilic nasal polyps in order to explore the effect and mechanism of LPS on the formation of neutrophilic nasal polyps in mice. A total of 5 or 10 ug of LPS was dropped into the nasal cavities of C57BL/6J mice in order to establish animal models with neutrophilic nasal polyps. Histological staining, toll-like receptor 4 (TLR4), cluster of differentiation 68 for macrophages and myeloperoxidase for neutrophil immunohistochemistry were used to observe histopathological changes in the nasal mucosa. The expression levels of cytokines, including interferon (IFN)-gamma, tumor necrosis factor (TNF) alpha, interleukin (IL)-4 and IL-17 in the nasal lavage fluid, were detected by ELISA. Compared with the control group, mice in the LPS groups exhibited significant mucosa epithelial cell damage and nasal polyp formation. Furthermore, TLR4+ cells, macrophages, neutrophils and significantly increased levels of IFN gamma, TNF-alpha, and IL-17 in the nasal lavage fluids were indicated (all P=0.008). These findings indicated that LPS is able to activate the TLR4 receptor pathway to induce the formation of neutrophilic nasal polyps in mice. Additionally, LPS administration was accompanied by a significant increase in the number of macrophages, T helper (Th) 1 and Th17-related cytokines (P=0.009, P=0.008 and P=0.008, respectively). Therefore, the present model is commensurate with the characteristics of primary nasal polyps that have been identified in the Asian population. PMID- 29285054 TI - Gene expression profiling analysis of keloids with and without hydrocortisone treatment. AB - The present study aimed to investigate the genetic effects of hydrocortisone (HC) treatment on keloids and screen medicines to be used in a combination therapy of keloids with HC. The dataset GSE7890 was downloaded from Gene Expression Omnibus. It contained data regarding 4 fibroblast samples from normal scar tissue and 5 samples from keloid tissue with HC treatment, as well as 5 samples from normal scar and 5 samples from keloids without HC treatment. Following the identification of differentially expressed genes (DEGs), the functions of these DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Furthermore, adverse effects of HC were identified using WebGestalt. Additionally, candidate small molecule drugs associated with keloids were selected from a connectivity map database. A total of 166 and 41 DEGs, with and without HC treatment respectively, were only present in dermal fibroblasts from keloids (termed genesets A and B, respectively). A set of 26 DEGs was present following both treatments (geneset C). A number of DEGs in geneset B (COL18A1 and JAG1) were associated with endothelial cell differentiation. However, in genesets A and C, certain genes (CCNB1 and CCNB2) were involved in the cell cycle and p53 signaling pathways, and a number of genes (IL1R1 and COL1A1) were associated with bone loss. Additionally, numerous small molecule drugs (including acemetacin) were associated with keloids. Thus, it has been determined that HC may treat keloids by targeting genes associated to endothelial cell differentiation (COL18A1 and JAG1). However, HC has a number of adverse effects, including bone loss. Acemetacin may be applied in a combination therapy, along with HC, to treat keloids. PMID- 29285055 TI - Restoration of orbicularis oculi muscle function in rabbits with peripheral facial paralysis via an implantable artificial facial nerve system. AB - The purpose of the present study was to restore orbicularis oculi muscle function using the implantable artificial facial nerve system (IAFNS). The in vivo part of the IAFNS was implanted into 12 rabbits that were facially paralyzed on the right side of the face to restore the function of the orbicularis oculi muscle, which was indicated by closure of the paralyzed eye when the contralateral side was closed. Wireless communication links were established between the in vivo part (the processing chip and microelectrode) and the external part (System Controller program) of the system, which were used to set the working parameters and indicate the working state of the processing chip and microelectrode implanted in the body. A disturbance field strength test of the IAFNS processing chip was performed in a magnetic field dark room to test its electromagnetic radiation safety. Test distances investigated were 0, 1, 3 and 10 m, and levels of radiation intensity were evaluated in the horizontal and vertical planes. Anti interference experiments were performed to test the stability of the processing chip under the interference of electromagnetic radiation. The fully implanted IAFNS was run for 5 h per day for 30 consecutive days to evaluate the accuracy and precision as well as the long-term stability and effectiveness of wireless communication. The stimulus intensity (range, 0-8 mA) was set every 3 days to confirm the minimum stimulation intensity which could indicate the movement of the paralyzed side was set. Effective stimulation rate was also tested by comparing the number of eye-close movements on both sides. The results of the present study indicated that the IAFNS could rebuild the reflex arc, inducing the experimental rabbits to close the eye of the paralyzed side. The System Controller program was able to reflect the in vivo part of the artificial facial nerve system in real-time and adjust the working pattern, stimulation intensity and frequency, range of wave and stimulation time. No significant differences in the stimulus intensities were observed during 30 days. The artificial facial nerve system chip operation stable in the anti-interference test, and the radiation field strength of the system was in a safe range according to the national standard. The IAFNS functioned without any interference and was able to restore functionality to facially paralyzed rabbits over the course of 30 days. PMID- 29285056 TI - Effects of yak-activated protein on hematopoiesis and related cytokines in radiation-induced injury in mice. AB - The aim of the present study was to investigate the protective effects of yak activated protein on hematopoiesis and cytokine function in radiation-induced injury in mice. A total of 180 Kunming mice were randomly divided into three groups (A, B and C). Of these, 60 were randomly divided into a normal control group, a radiation model group, a positive control group and 3 yak-activated protein groups (high, medium and low dose groups; 10, 5 and 2.5 mg/kg, respectively). The other 120 mice were used for the subsequent experiments on days 7 and 14 following radiation. Yak-activated protein was administered orally to mice in the treatment groups and an equal volume of saline was administered orally to mice in the normal control and radiation model groups for 14 days. The positive control group received amifostine (150 mg/kg) via intraperitoneal injection. With the exception of the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body once. Changes in the peripheral hemogram, thymus and spleen indices, DNA content in the bone marrow, interleukin (IL)-2 and IL-6 levels, and the expression levels of B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) following irradiation were assessed. The low dose of yak-activated protein significantly increased Spleen indices in mice 14 days after irradiation and the high and middle dose of yak activated protein significantly increased Thymus indices in mice 14 days after irradiation (P<0.05) compared with the control group. In addition, hemogram results increased gradually in the low-yak-activated protein dose group and were significantly higher 7 days after irradiation compared with the radiation model group (P<0.05). The DNA content in the bone marrow was markedly increased in the yak-activated protein groups, and increased significantly in the low dose group at 7 days post-irradiation compared with the radiation model group (P<0.05). The IL-2 content was significantly increased in the yak-activated protein groups (P<0.05). Furthermore, Bcl-2 expression was increased and Bax expression was decreased (P<0.05). These results suggest that yak-activated protein exerts protective effects against radiation-induced injury in mice. The optimal effects of yak-activated protein were observed in the medium dose group 14 days after irradiation. PMID- 29285057 TI - Chenodeoxycholic acid attenuates high-fat diet-induced obesity and hyperglycemia via the G protein-coupled bile acid receptor 1 and proliferator-activated receptor gamma pathway. AB - G protein-coupled bile acid receptor 1 (TGR5) serves a key function in regulating glycometabolism. TGR5 is highly expressed in the mitochondria of brown adipose tissue (BAT) and downregulates adenosine triphosphate synthesis via the bile acid TGR5-cyclic adenosine monophosphate-2-iodothyronine deiodinase (D2) triiodothyronine-uncoupling protein pathway, thus regulating energy homeostasis and reducing body weight. Chenodeoxycholic acid (CDCA), the primary bile acid, is a natural ligand of TGR5. The present study aimed to characterize the ability of CDCA to reduce high-fat diet-induced obesity and improve glucose tolerance. A mouse model of diet-induced obesity was constructed. The results demonstrated that a high-fat diet significantly increased the weight of mice after 10 weeks (P<0.05), but following the addition of CDCA and continued feeding for another 10 weeks, a decrease in weight was detected and no significant difference in final weight was observed between the high fat diet group treated with CDCA and the group fed a normal diet. Furthermore, CDCA treatment significantly increased glucose tolerance (P<0.001, P<0.01 and P<0.01 at 15, 40 and 60 min after glucose injection, respectively) and significantly decreased serum insulin levels compared with mice fed a high-fat diet alone. Staining of the liver with hematoxylin and eosin and oil red O revealed that the CDCA-treated group exhibited significantly lower fat accumulation in BAT and WAT compared with mice fed a high-fat diet alone (P<0.001). Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the expression of D2 activation system-related factors was significantly increased in BAT from mice treated with CDCA (P<0.001), confirming the role of TGR5 in modulating high-fat diet-induced obesity. In addition, CDCA inhibited adipocyte differentiation in 3T3-L1 cells and inhibited ligand-stimulated peroxisome proliferator-activated receptor gamma (PPARgamma) transcriptional activity. These results suggest that CDCA may prevent high-fat diet-induced obesity and hyperglycemia, and that these beneficial effects are mediated via the activation of TGR5 and inhibition of PPARgamma transcriptional activity. PMID- 29285058 TI - Birth weight and type 2 diabetes: A meta-analysis. AB - The prevalence of T2DM is increasing around the world on a yearly basis. A meta analysis was conducted to analyze the association between birth weight and incidence of type 2 diabetes mellitus (T2DM). A literature search was performed from January 1990 to June 2016 in PubMed, ScienceDirect, SpringerLink, China National Knowledge Infrastructure and Chinese Biomedical Literature Database. After reviewing characteristics of all the included studies systematically, a meta-analytical method was employed to calculate the pooled odds ratios (ORs) and associated 95% confidence intervals (CI) from random-effects models. Heterogeneity was assessed by Q-statistic test. Funnel plot, Begg's and Egger's linear regression tests were applied to evaluate publication bias. A sensitivity analysis was also performed to assess the robustness of results. According to inclusion and exclusion criteria, 8 studies were selected to be included in the meta-analysis. Compared with normal birth weight (2,500-4,000 g), low birth weight (<2,500 g) was associated with an increased risk of T2DM (OR, 1.55; 95% CI, 1.39-1.73; P<0.001). No significant difference was observed between high birth weight (>4,000 g) and normal birth weight in terms of the risk of T2DM (OR, 0.98; 95% CI, 0.79-1.22). Compared with high birth weight, low birth weight was associated with an increased risk of diabetes mellitus (OR, 1.58; 95% CI, 1.30 1.93; P<0.001). These findings indicated that there may be an inverse linear association between birth weight and T2DM. PMID- 29285059 TI - Long noncoding RNA HOTAIR promotes the proliferation and metastasis of osteosarcoma cells through the AKT/mTOR signaling pathway. AB - It has been proven that long non-coding (lnc)RNAs serve an important role in the tumorigenesis and development of several types of human malignancy. Previous studies have demonstrated that the lncRNA Hox transcript antisense intergenic RNA (HOTAIR) is involved in the development various types of cancer, including osteosarcoma (OS). However, the underlying mechanisms by which it has an affect are still largely unknown. In the present study, it was observed that the expression of HOTAIR was significantly upregulated in OS tissues compared to matched adjacent normal tissues, using reverse transcription-quantitative polymerase chain reaction analysis. HOTAIR was silenced using specific small interfering RNA (siRNA/siR), siR-HOTAIR, in order to investigate its role in regulating OS cell proliferation, apoptosis, migration and invasion. siR-HOTAIR inhibited the proliferation of MG-63 cells due to the induction of G1 phase arrest. In addition, the results of in vitro assays demonstrated that the suppression of HOTAIR in MG-63 OS cells significantly reduced migration and invasion. The silencing of HOTAIR also significantly decreased the expression of matrix metalloproteinase (MMP) 2 and MMP9, but increased E-cadherin expression through regulating the RAC alpha serine/threonine protein kinase-mammalian target of rapamycin signaling pathway. The results indicated that siR-HOTAIR may be a potential OS therapy. PMID- 29285060 TI - Inhibitory effect of oxidative damage on cardiomyocyte differentiation from Wharton's jelly-derived mesenchymal stem cells. AB - Ischemic heart diseases are a serious health problem worldwide. The transplantation of mesenchymal stem cells (MSCs) has been investigated in numerous clinical trials on various other diseases due to the self-renewal capacity of these cells and their potential to differentiate into a variety of cell types. The presence of excess reactive oxygen species in injured myocardium causes cardiac dysfunction and leads to inefficient repair of the heart. The poor outcomes of stem cell transplantation have been suggested to result from residual oxidative damage affecting the transplanted cells. The aim of the present study was to compare the effects of hydrogen peroxide (H2O2) on Wharton's jelly-derived MSCs (WJ-MSCs) and bone marrow-derived MSCs (BM-MSCs) in vitro, in order to provide information useful for the future selection of MSC types for cardiac differentiation and transplantation. H2O2 at concentrations of 200, 500 and 1,000 uM was applied to WJ-MSCs and BM-MSCs under cardiogenic differentiation conditions. The morphology of MSCs treated with H2O2 was similar to that of untreated cells, whereas the cell density decreased in direct association with the dose of H2O2. Cardiac differentiation markers were then evaluated by immunofluorescence analysis of GATA4 and cardiac troponin T (cTnT). The fluorescence intensity levels of the two markers were identified to be diminished by increasing doses of H2O2 from 500 to 1,000 uM. The expression levels of homeobox protein Nkx2.5, cTnT and cardiac alpha-actin were also examined, and were identified to be low in the WJ-MSCs treated with 1,000 uM H2O2, which was similar to the findings observed in BM-MSCs. These results suggested that oxidative stress affects cardiomyocyte differentiation via the downregulation of cardiac genes and cardiac proteins. Furthermore, it should be noted that there was a marked difference in the effect depending on the source of MSCs. This evidence provided supportive information for the use of stem cells in transplantation. PMID- 29285061 TI - Wnt6 influences the viability of mouse embryonic palatal mesenchymal cells via the beta-catenin pathway. AB - The embryological stages of palatal shelf elongation and elevation, mainly induced by the proliferation and extracellular matrix secretion of embryonic palatal mesenchymal (MEPM) cells, are essential for normal palatal development. Wingless-related MMTV integration site gene family (Wnt) signaling pathways serve key roles in craniofacial development and palate formation. Recent studies have indicated that Wnt6 participates in embryonic development of the palate, though its exact role in palate development remains unclear. In the present study, to investigate the role of Wnt6 during the stages of palatal shelves elongation and elevation, mouse MEPM cells were cultured from dissected palatal shelves at embryonic day 13.5. Results of an MTT assay and flow cytometric analysis demonstrated that treatment with recombinant Wnt6 increased the viability of MEPM cells (P<0.01) and the proportion of cells in the S and G2/M phases (P<0.01). Meanwhile, Wnt6 activated the beta-catenin signaling pathway as indicated by the dual luciferase assay result, and blockade of the WNT/beta-catenin pathway reduced the cytoactivity of Wnt6 in MEPM cells (P<0.01). Collectively, these findings indicate that Wnt6 promotes the vitality of MEPM cells by increasing the S + G2/M-phase cell population, potentially through activation of the beta catenin pathway during palatal shelf elongation and elevation. PMID- 29285063 TI - MicroRNA-208a-3p contributes to connexin40 remolding in human chronic atrial fibrillation. AB - Previous studies have demonstrated that connexin40 (Cx40) remolding is involved in atrial fibrillation (AF). GJA5 encoding Cx40 is a potential target mRNA of microRNA-208a-3p (miR-208a-3p), as indicated by preliminary bioinformatics analyses. However, the exact effect of miR-208a-3p on Cx40 in human chronic AF has remained elusive. The present study demonstrated the role of miR-208a-3p in human chronic AF and further investigated the effect of miR-208a-3p on Cx40 expression. A total of 19 patients with AF and 18 patients with sinus rhythm (SR) were enrolled. The AC16 cell line was treated with miR-208a-3p inhibitor or mimics. The miR-208a-3p in right atrial appendage (RAA) tissues of patients was measured by in situ hybridization and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, the expression of Cx40 in the RAA of patients and in AC16 cells treated with miR-208a-3p inhibitor or mimics were detected by RT-qPCR and western blot analysis. A luciferase assay was performed to confirm whether Cx40 was directly targeted by miR-208a-3p. The miR 208a-3p levels in patients with AF were significantly increased compared with those in patients with SR. Conversely, the Cx40 protein levels were significantly decreased and lateralization of Cx40 was observed in patients with AF. miR-208a 3p inhibitor led to a significant upregulation of the protein expression of Cx40 in AC16 cells, while miR-208a-3p mimics led to a significant downregulation. However, the luciferase assay demonstrated that GJA5 was not a direct target gene of miR-208a-3p. The findings still suggested that miR-208a-3p may be involved in human chronic AF by mediating atrial Cx40 remolding, and may represent a potential therapeutic target for AF. PMID- 29285062 TI - Effects of apigenin on the expression levels of B-cell lymphoma-2, Fas and Fas ligand in renal ischemia-reperfusion injury in rats. AB - The aim of the present study was to investigate the effect and possible mechanism of apigenin on renal ischemia-reperfusion (I/R) injury in rats, as well as in in vitro experiments. In total, 36 rats were subjected to 45 min of renal ischemia, with or without treatment prior to ischemia with different concentrations of apigenin (2, 10 and 50 mg/kg) administered intravenously. All rats were sacrificed at 24 h after I/R injury. The serum creatinine (Cr) and blood urea nitrogen (BUN) levels were analyzed, and histological examination was conducted. In addition, the expression levels of B-cell lymphoma 2 (Bcl-2) and Fas/Fas ligand (FasL) were detected by immunohistochemistry, reverse transcription quantitative polymerase chain reaction and western blot analysis. For in vitro experiments, the NRK-52E cell line was employed. The viability, apoptosis and expression levels of Fas, FasL and Bcl-2 were examined in the culture of NRK-52E cells following the I/R. The results indicated that apigenin significantly decreased the levels of serum Cr and BUN induced by renal I/R, demonstrating an improvement in renal function. The histological evidence of renal damage associated with I/R was also mitigated by apigenin in vivo. Furthermore, apigenin increased the cell viability and decreased cell apoptosis in the culture of NRK52E after I/R in vitro. Compared with the I/R group, the expression of Bcl-2 was upregulated and the expression levels of Fas and FasL were downregulated by apigenin at the mRNA and protein levels in vivo and in vitro. In conclusion, apigenin appeared to increase the expression of Bcl-2 and reduce Fas/FasL expression in renal I/R injury, providing evident protection against renal I/R injury in rats. PMID- 29285064 TI - Predictors for advanced liver fibrosis in chronic hepatitis B virus infection with persistently normal or mildly elevated alanine aminotransferase. AB - The aim of the present study was to evaluate the predictors for advanced liver fibrosis in patients with chronic hepatitis B virus (HBV) infection with persistently normal alanine aminotransferase (PNALT), or persistently or intermittently mildly elevated ALT (PIEALT). A total of 305 patients were included in the present study. Liver biopsies were evaluated using the METAVIR scoring system. Liver stiffness (LS) was measured using Fibroscan. Multivariate logistic regression and the area under the receiver operating characteristic curve (AUROC) were used to examine the diagnostic value of the predictors for advanced liver fibrosis. HBV DNA viral load in the PNALT group was significantly lower compared with the PIEALT group (4.57+/-1.68 vs. 5.71+/-1.69 log10 IU/ml; P<0.001). Body mass index and LS were also significantly lower in the PNALT group compared with the PIEALT group (P<0.001). The proportion of patients with liver fibrosis was significantly higher in the PIEALT group compared with the PNATL group (P=0.001). High ALT levels were an independent predictor for liver fibrosis, with an odds ratio (OR) of 2.69 (P=0.002). Male sex (OR=0.34, P=0.007), high ALT levels (OR=2.37, P=0.029) and a high HBV DNA load (OR=1.39, P=0.005) were independent predictors for advanced liver fibrosis. The AUROC was 0.65 (P=0.003) when using ALT levels to predict advanced liver fibrosis. ALT levels at >=0.88 upper limit of normal (ULN; 35 IU/l) were considered as positive for advanced liver fibrosis, the sensitivity and specificity were 87.8 and 47.4%, respectively. The AUROC was 0.64 (P=0.004) when using the HBV DNA value to predict advanced liver fibrosis. When an HBV DNA value of >=4.99 log10 IU/ml was considered as positive for advanced liver fibrosis, the sensitivity and specificity were 78.0 and 49.5%, respectively. The AUROC was 0.72 (P<0.001) when combining ALT, HBV DNA load and sex into a formulation to predict advanced liver fibrosis. When the formulation score at >-2.22 was considered as positive for advanced liver fibrosis, the sensitivity and specificity were 61.5 and 70.7%, respectively. Therefore, normal ALT levels do not always indicate the absence of hepatic fibrosis. A combination of ALT levels, sex and serum HBV DNA load may more effectively identify patients with CHB at high risk of developing fibrosis. These patients may benefit from liver biopsy. PMID- 29285066 TI - Hyperthermia exposure induces apoptosis and inhibits proliferation in HCT116 cells by upregulating miR-34a and causing transcriptional activation of p53. AB - Hyperthermia, as an anticancer therapeutic strategy, presents notable advantages in conjunction with irradiation and/or chemotherapy in the treatment of cancer by promoting apoptosis and inhibiting proliferation. A number of studies have documented that hyperthermia inhibits cancer progression through transcriptional activation of p53, which promotes cell cycle arrest and apoptosis. However, the underlying molecular mechanisms of hyperthermia-regulated apoptosis and proliferation dependent on p53 remain largely unknown. To investigate the effects and molecular mechanism of hyperthermia on the apoptosis and proliferation of colorectal carcinoma (CRC) HCT116 cells, the present study assessed cell apoptosis and proliferation following exposure to hyperthermia (42 degrees C for 2-4 h). The results indicated that, compared with the control group at 0 h, hyperthermia exposure for 2 and 4 h induced the apoptosis of HCT116 cells (P<0.05), inhibited cell proliferation by causing cell cycle arrest at G1/G0 phase (P<0.05), and significantly increased microRNA (miR)-34a expression (P<0.05), but not miR-34b, miR-34c, miR-215 and miR-504 expression. The transcriptional activity of p53 on its consensus sequence and downstream target genes, namely p21, B cell lymphoma 2-associated X protein, mouse double minute 2 homolog, p53 upregulated modulator of apoptosis and growth arrest and DNA-damage inducible 45alpha, was subsequently detected. The data indicated significantly higher transcriptional activity of p53 following hyperthermia exposure for 2 and 4 h (P<0.05), and these observations were similar to the effects of transfection with miR-34a mimics in HCT116 cells. Furthermore, transfection with miR-34a antagomiR supressed hyperthermia-induced apoptosis and promoted cell cycle progression following hyperthermia exposure when compared with transfection controls (P<0.05). Collectively, these findings indicate that miR-34a may serve an important role in hyperthermia-regulated apoptosis and proliferation in HCT116 cells by influencing the transcriptional activity of p53. PMID- 29285065 TI - Reliability and validity of CODA motion analysis system for measuring cervical range of motion in patients with cervical spondylosis and anterior cervical fusion. AB - The aim of the present study was to evaluate the reliability of the Cartesian Optoelectronic Dynamic Anthropometer (CODA) motion system in measuring the cervical range of motion (ROM) and verify the construct validity of the CODA motion system. A total of 26 patients with cervical spondylosis and 22 patients with anterior cervical fusion were enrolled and the CODA motion analysis system was used to measure the three-dimensional cervical ROM. Intra- and inter-rater reliability was assessed by interclass correlation coefficients (ICCs), standard error of measurement (SEm), Limits of Agreements (LOA) and minimal detectable change (MDC). Independent samples t-tests were performed to examine the differences of cervical ROM between cervical spondylosis and anterior cervical fusion patients. The results revealed that in the cervical spondylosis group, the reliability was almost perfect (intra-rater reliability: ICC, 0.87-0.95; LOA, 12.86-13.70; SEm, 2.97-4.58; inter-rater reliability: ICC, 0.84-0.95; LOA, -13.09 13.48; SEm, 3.13-4.32). In the anterior cervical fusion group, the reliability was high (intra-rater reliability: ICC, 0.88-0.97; LOA, -10.65-11.08; SEm, 2.10 3.77; inter-rater reliability: ICC, 0.86-0.96; LOA, -10.91-13.66; SEm, 2.20 4.45). The cervical ROM in the cervical spondylosis group was significantly higher than that in the anterior cervical fusion group in all directions except for left rotation. In conclusion, the CODA motion analysis system is highly reliable in measuring cervical ROM and the construct validity was verified, as the system was sufficiently sensitive to distinguish between the cervical spondylosis and anterior cervical fusion groups based on their ROM. PMID- 29285067 TI - Morphologic characteristics and clinical significance of the macular-sparing area in patients with retinitis pigmentosa as revealed by multicolor imaging. AB - Retinitis pigmentosa (RP) is an inherited retinal disease caused by the degeneration of photoreceptors and retinal pigment epithelium cells within the eye. The present study aimed to evaluate the effectiveness of multicolor imaging as a novel technique for the depiction of morphological features in the macular area of patients with RP. Additionally, the correlation between the size of the macular-sparing area and the best corrected visual acuity (BCVA), central visual field function and subfoveal choroidal thickness (SFCT) was analyzed. A total of 25 individuals with RP (n=50 eyes) and 35 healthy individuals (n=70 eyes) were enrolled in the current study. Images of the macular area were captured using multicolor imaging and traditional fundus photography, and their ability to depict retinal features was compared. The size of the macular-sparing area in patients with RP was measured using built-in measurement software programs. The correlations between the macular-sparing area and the BCVA, visual field and SFCT were analyzed using a Spearman's rank correlation test. The results demonstrated that multicolor imaging revealed clinical features of the macular area in greater detail than traditional fundus photography irrespective of whether the patient also had complications, including cataracts and epiretinal membranes. Multicolor imaging clearly defined the borders of the macular-sparing area corresponding to the relatively intact outer retinal structures on optical coherence tomography images, particularly the status of the ellipsoid zone and external limiting membrane. There was a significant positive correlation between the macular sparing area and BCVA (r=-0.631; P<0.001), and the visual field in terms of MD (r=0.402; P<0.05) and PSD (r=0.595; P<0.001), however, there was not a statistically significant correlation between the macular-sparing area and SFCT. The present study demonstrated that multicolor imaging is capable of detecting macular changes and complications in patients with RP. Multicolor imaging may be particularly useful in assessing the detailed characteristics of the macular sparing area, as this appears to be associated with visual function. PMID- 29285068 TI - Radix Cyathula officinalis Kuan inhibits arterial remodeling in spontaneously hypertensive rats. AB - There is still no resolution for arterial remodeling related with hypertension, though hypertension treatment has access to a number of pharmacological agents. The present study aimed at investigating the prevention of Cyathula officinalis Kuan's roots (C. officinalis Kuan) against in arterial remodeling in vitro. Spontaneously hypertensive rats (SHRs) were intragastrically administered 3, 6 or 12 g/kg C. officinalis Kuan or normal saline or enalapril (2.5 mg/kg) once a day for 8 weeks. Hematoxylin and eosin were used to measure blood pressure and stain carotid and arota. The serum concentration of nitric oxide (NO) was measured by NO assay kit (nitrate reductase method). The endothelin-1 transcriptional level, endothelial NO synthase of endothelium as well as angiotensin II receptor type 1 (AT1R) of aorta and carotid was tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and the protein level in aorta was also measured by western blotting. The blood pressure in SHR+enalapril, SHR+3 g/kg, SHR+6 g/kg and SHR+12 g/kg C. officinalis Kuan groups was significantly decreased at 4, 6 and 8 weeks post-treatment compared with SHR group. Different doses of C. officinalis Kuan and enalapril treatment showed aortic wall thinness and strengthened NO serum level, but made no impact on the transcriptional level of AT1R in aorta or endothelial NO synthase in carotid. It is suggested by such results that therapy by C. officinalis Kuan is able to fight against arterial remodeling, thus may provide a new means to treat arterial remodeling caused by hypertension. PMID- 29285069 TI - Correlation of hypertensive disorders in pregnancy with procedures of in vitro fertilization and pregnancy outcomes. AB - We investigated the correlation of hypertensive disorders in pregnancy with different procedures of in vitro fertilization, and analyzed pregnancy outcomes of patients with hypertensive disorders in pregnancy. A retrospective analysis was performed on the medical records of 658 maternity patients who conceived through in vitro fertilization in Maternal and Child Health Hospital of Wuxi. Patients were divided into two groups according to different fertilization procedures: i) the routine in vitro fertilization-embryo transfer group (IVF-ET group, 377 cases) and ii) intra-cytoplasmic sperm injection-embryo transfer group (ICSI-ET group, 281 cases). Consequently, patients were further divided into two groups according to different embryo transfer cycles: the fresh embryo transfer group (F-ET group, 446 cases) and the frozen-thawed embryo transfer group (T-ET group, 212 cases). Characteristics of patients in each group were evaluated, and incidence of hypertensive disorders in pregnancy resulting from different assisted reproductive technology was compared. Among patients who conceived through IVF, there were 56 cases of hypertensive disorders in pregnancy, including 21 cases of gestational hypertension, 34 cases of pre-eclampsia and 1 case of eclampsia. The odds ratio (OR) of gestational hypertension in the comparison between the ICSI-ET and IVF-ET groups was 2.01 (0.81-4.74), and was reduced to 1.69 (0.70-4.02) after correction. The difference of OR in twin-birth patients of the two groups was statistically significant, but the difference in single-birth patients was not statistically significant. The odds ratio (OR) of gestational hypertension in the comparison between the F-ET and T-ET groups was 0.44 (0.13-1.34), and became 0.49 (0.15-1.51) after correction. The odds ratio of pre-eclampsia in the comparison between the ICSI-ET and IVF-ET groups was 1.36 (0.42-4.18), and was reduced to 1.17 (0.36-3.62) after correction. The odds ratio of pre-eclampsia in the comparison between the F-ET and T-ET groups was 0.93 (0.42-1.96), and became 0.98 (0.44-2.12) after correction. The differences were not statistically significant. The risk of onset of hypertensive disorders in pregnancy has a certain correlation with the ICSI fertilization technology, but has no apparent correlation with embryo transfer cycles. PMID- 29285070 TI - Oxidized low-density lipoprotein-induced p62/SQSTM1 accumulation in THP-1-derived macrophages promotes IL-18 secretion and cell death. AB - Macrophage autophagy has a protective role in the development of atherosclerosis; however, it turns dysfunctional in advanced lesions with an increase in p62/sequestosome-1 protein. Little is known about the role and significance of p62 accumulation in atherosclerosis. The present study investigated the association between p62 expression and the process of foam cell formation. Foam cell models were established through incubation of THP-1-derived macrophages with oxidized low-density lipoprotein, and the process of foam cell formation was detected by Oil red O staining. Furthermore, the dynamic change of p62 expression was detected by western blotting and quantitative polymerase chain reaction. Additionally, using gene silencing techniques, the roles of p62 in foam cells were investigated with ELISA, MTT and flow cytometry. The results indicated that besides serving as a marker of autophagy deficiency, the p62 protein could also mediate inflammation and cytotoxicity in advanced foam cells. Additionally, the implication of p62 in autophagy inhibition and foam cell formation makes it a key atherogenic factor under autophagy-deficient conditions. PMID- 29285071 TI - BMP-7 accelerates the differentiation of rabbit mesenchymal stem cells into cartilage through the Wnt/beta-catenin pathway. AB - Mesenchymal stem cells (MSCs) are able to differentiate into adipocytes, chondroblasts or cartilage under different stimulation conditions. Identifying a mechanism that triggers the differentiation of MSCs into cartilage may help the development of novel therapeutic approaches for heterotopic ossification, the pathological formation of lamellar bone in soft tissue outside the skeleton that may lead to debilitating immobility. Bone morphogenetic proteins (BMPs), including BMP-7, are the most potent growth factors for enhancing bone formation. The current study aimed to understand the potential involvement of the Wnt/beta catenin signaling pathway in the BMP-7-induced growth of rabbit MSCs (rMSCs). Different concentrations of BMP-7 were applied to cultured rMSCs, and proliferation was evaluated by MTT assay. Changes in the phosphorylation state of glycogen synthase kinase (GSK)-3beta, in addition to the expression levels of alkaline phosphatase, beta-catenin and runt-related transcription factor 2 were observed by western blot analysis. Following treatment with BMP-7, the phosphorylation of GSK-3beta was stimulated and the expression of beta-catenin, ALP and Runx2 was increased. Furthermore, inhibiting beta-catenin signaling with XAV-939 suppressed the BMP-7-mediated changes. The results indicated that the BMP 7-induced differentiation of rMSCs into cartilage was promoted primarily by the Wnt/beta-catenin pathway. PMID- 29285072 TI - Changes in transcranial electrical motor-evoked potentials during the early and reversible stage of permanent spinal cord ischemia predict spinal cord injury in a rabbit animal model. AB - The present study examined changes in the transcranial electrical motor-evoked potentials (TceMEP) waveform to predict neurological deficits and histopathological changes during the early and reversible stage of different levels of permanent spinal cord ischemic injury in a rabbit animal model. A total of 24 New Zealand rabbits were randomly divided into four groups of 6 rabbits each. Group 1 underwent a ligation of the lumbar artery at three levels (L1-L3), group 2 underwent a ligation of the lumbar artery at four levels (L1-L4) and group 3 underwent a ligation of the lumbar artery at five levels (L1-L5). The sham group contained 6 rabbits and did not receive ligation. TceMEP was recorded within 5 min of ligation and, 2 days later, motor function was assessed and the spinal cords were removed for histological examination. Following spinal cord injury, the relationship between variations in the TceMEP waveform and motor function and pathological damage was analyzed. It was observed that the amplitude of TceMEP began to decrease within 1 min of lumbar artery ligation and that the amplitude stabilized within 5 min. These amplitude changes that occurred within 5 min of different levels of permanent spinal cord ischemic injury were positively related to changes in motor function following recovery from anesthesia and 2 days after ligation. The Pearson correlation coefficient was 0.980 and 0.923 for these two time points, respectively (P<0.001). In addition, the amplitude changes were positively related to pathological damage, with a Pearson correlation coefficient of 0.945 (P<0.001). The results of the present study suggested that amplitude changes in TceMEP are particularly sensitive to ischemia. Ischemia may be detected within 1 min and the amplitude changes begin to stabilize within 5 min following ligation of the lumbar artery. The use of intraoperative monitoring of TceMEP allows for the detection of spinal cord ischemic injury with no time delay, which may allow for protective measures to be taken to prevent the occurrence of irreversible spinal cord injury. PMID- 29285073 TI - The significance of magnetic resonance imaging in severe femoral trochlear dysplasia assessment. AB - The clinical diagnosis of femoral trochlear dysplasia primarily relies on imaging. In the past, plain imaging was the major source of diagnosis. The present study investigated the application of magnetic resonance imaging (MRI) in the objective assessment of severe femoral trochlear dysplasia. A retrospective analysis was performed on knee MRIs from 30 normal subjects (30 knees) and 59 patients (61 knees) with severe femoral trochlear dysplasia based on the Dejour morphological classification. Cartilage and subchondral bone landmarks were used to compare a series of measurements between patient and control groups. These measurements included the femoral trochlear groove depth, sulcus angle, the lateral trochlear inclination, trochlear facet asymmetry, the femoral medial and lateral condyle symmetry, and the ratios between the femoral medial/lateral condyles and the maximal trochlear width. The measurement values based on the two types of landmarks were also compared within the patient and control groups, separately. In addition, the femoral trochlear groove depth, sulcus angle, lateral trochlear inclination and trochlear facet asymmetry of patients with different Dejour types were compared. Significant differences were observed in the femoral trochlear groove depth, sulcus angle, lateral trochlear inclination and trochlear facet asymmetry between the patient and control groups (P<0.05). Based on the two types of landmark, all indexes were significantly different (P<0.05; with the exception of lateral trochlear inclination) between the patient and control groups. Among patients with various Dejour types, the femoral trochlear groove depth, sulcus angle, lateral trochlear inclination and trochlear facet asymmetry demonstrated no significant differences. MRI exhibited advantages in revealing articular cartilage over conventional radiography and computed tomography. Therefore, cartilage landmarks in MRI images may be utilized to objectively evaluate femoral trochlear dysplasia in patients with severe femoral trochlear dysplasia. PMID- 29285074 TI - Paeoniflorin inhibits proliferation of endometrial cancer cells via activating MAPK and NF-kappaB signaling pathways. AB - Paeoniflorin (PAE), a principal bioactive component of Paeonia lactiflora Pall., appears to have antitumor properties. However, the pharmacological activity of PAE in endometrial cancer and the specific mechanisms have remained largely elusive. The present study aimed to determine the antitumor activity of PAE in the human endometrial cancer cell line RL95-2 and explore the potential mechanisms. Cell proliferation was assessed to evaluate the antitumor effect of PAE towards RL95-2 cells via a Cell Counting Kit-8 assay. Protein expression was examined to investigate changes in the signaling pathways of p38 mitogen activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-kappaB in RL95-2 cells during PAE treatment by western blot analysis. The results revealed that PAE significantly and dose- and time-dependently inhibited the proliferation of RL95 2 cells. In addition, PAE activated MAPK signaling pathways (p38, JNK and ERK) and the NF-kappaB signaling pathway. Furthermore, p38 MAPK and NF-kappaB inhibitors (SB203580 and MG-132, respectively) prevented PAE-induced proliferative inhibition in RL95-2 cells. However, ERK and JNK inhibitors (PD98059 and BI-78D3, respectively) did not produce such an inhibition. In conclusion, the present study demonstrated that PAE exerts its anti-proliferative activity via activating p38 MAPK and NF-kappaB signaling pathways in endometrial cancer cells, providing a potential new drug of choice for endometrial cancer therapy. PMID- 29285075 TI - TAT-mediated si-hWAPL inhibits the invasion and metastasis of cervical cancer stem cells. AB - Human wings apart-like (hWAPL) is reported to have an association with cervical cancer. In the present study, the role of hWAPL in cervical cancer stem cells (CCSCs) was evaluated. Cervical tumorspheres were generated from cervical cancer tissues cultured in stem cell medium, and the expression of hWAPL by the tumorspheres was detected using immunohistochemistry. hWAPL expression levels in the tumorspheres were then upregulated using hWAPL adenoviral vectors or downregulated via the TAT-mediated knockdown of hWAPL and the effects on the tumorspheres were evaluated using colony formation, cell invasion and western blotting assays. The results demonstrated that the expression of hWAPL and human papillomavirus (HPV) was associated with the pluripotency of CCSCs, with hWAPL expression decreasing following the differentiation of cervical tumorspheres. Knockdown of hWAPL expression decreased HPV E6 expression and inhibited tumor invasion and colony formation. TAT-mediated knockdown of hWAPL with short interfering RNA significantly reduced tumor growth in nude mice. These results suggest that hWAPL is a marker of CCSC proliferation and is potentially a therapeutic target for cervical carcinoma through the downregulation of HPV E6. PMID- 29285076 TI - Niu-Huang-Shen suppresses hepatocellular carcinoma cell growth and metastasis by regulating Yap1 expression. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers types. Niu-Huang Shen (NHS), a Chinese medicine, has been reported to exert antipyretic, anti inflammatory and vasodilatation effects. However, whether NHS has inhibitory effects on HCC cell phenotypes has remained elusive. In the present study, Cell Counting Kit-8, colony formation, fluorescence-activated cell sorting and Transwell assays were used to evaluate the effect of NHS on cell proliferation, migration and invasion. The results indicated that NHS suppressed cell proliferation and invasion, inhibited cell apoptosis, and induced cell cycle arrest. In addition, NHS significantly suppressed the mRNA and protein expression of Yes-associated protein (YAP). It was concluded that NHS downregulated YAP expression and inhibited the Hippo signaling pathway as well as HCC cell growth and invasion. NHS may be a novel potential therapeutic for HCC patients. PMID- 29285077 TI - Identification of microRNAs in human circulating monocytes of postmenopausal osteoporotic Mexican-Mestizo women: A pilot study. AB - MicroRNAs (miRNAs or miRs) are a class of short non-coding RNAs that serve an important regulatory role in living organisms. These molecules are associated with multiple biological processes and are potential biomarkers in multiple diseases. The present study aimed to further identify miRNAs that are differentially expressed in circulating monocytes (CMCs) from postmenopausal Mexican-Mestizo women. Microarray analyses of monocytes using Affymetrix miRNA 4.0 and Human Genome U133 Plus 2.0 arrays were performed in 6 normal and 6 osteoporotic women, followed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) validation. The overexpression of miR-1270, miR-548*-3p and miR-8084 were detected in the osteoporosis compared with the normal group according to the microarray analysis; miR-1270, a miRNA with several target genes associated with bone remodeling, was validated by RT-qPCR. Bioinformatics analysis identified that interferon regulatory factor 8 (IRF8) is the most likely target gene of miR-1270, which is associated with osteoclastogenesis. Furthermore, the findings of the present study demonstrate that an upregulation of miR-1270 may reduce the gene expression of IRF8 in CMCs (osteoclast precursors), implicating its potential role in leading to low bone mineral density and contributing to osteoporosis development in postmenopausal women. PMID- 29285078 TI - Antiproliferative effect of double suicide gene delivery mediated by polyamidoamine dendrimers in human Tenon's capsule fibroblasts. AB - The aim of the present study was to investigate the therapeutic potential of a double suicide gene, thymidine kinase (TK) combined with cytosine deaminase (CD), mediated by generation of 5-polyamidoamine dendrimers (G5-PAMAM-D) on human Tenon's capsule fibroblasts (HTFs) as an anti-scarring agent. The pAcGFP1-Hyg-TK CD plasmid was transfected into HTFs, and reverse-transcription polymerase chain reaction (RT-PCR) was used to detect TK-CD expression. MTT cell proliferation assay was used to evaluate the cytotoxic effects of ganciclovir (GCV) and 5 flurocytosine (5-FC) on HTFs. The optimal concentration of GCV and 5-FC in TK-CD transfected HTFs (HTF-TK-CD) was selected by accessing the lowest and highest cytotoxicity caused, respectively. The morphological changes of transfected HTFs following treatment with GCV and 5-FC were observed by light and transmission electron microscopy. Results demonstrated that the double suicide gene TK-CD mediated by the G5-PAMAM-D delivery system was successfully expressed in HTFs as determined by RT-PCR. A concentration of 3 ug/ml GCV and 200 ug/ml 5-FC was identified as optimal for these prodrugs. The growth rate and number of HTF-TK-CD cells decreased following treatment with GCV and 5-FC as revealed by light microscopy. Additionally, the prodrugs GCV and 5-FC not only demonstrated toxicity on transfected HTFs but also exerted a 'bystander effect'. The present study illustrated that the double suicide gene TK-CD delivery mediated by G5 PAMAM-D was effective in reducing HTF proliferation and inducing cell apoptosis. Furthermore, TK-CD delivery mediated by G5-PAMAM-D may be used as an anti scarring agent and provide a therapeutic potential for patients requiring glaucoma filtration surgery. PMID- 29285079 TI - Effects of puerarin on the retina and STAT3 expression in diabetic rats. AB - The effects of puerarin on electroretinogram, oxidative stress and STAT3 expression were determined, in diabetic rat retina and serum. Forty Sprague Dawley rats were randomly divided into the normal control (NC), the diabetic model (DM), the low dose (250 mg/kg) puerarin (LP) or the high dose (500 mg/kg) puerarin group (HP). A diabetic rat model was induced by streptozotocin and animals were continuously treated for 4 weeks; fasting blood glucose was measured at 2 and 4 weeks after modeling. An electroretinogram and serum and tissue levels of glucose, insulin, superoxide dismutase (SOD), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) were measured; real-time PCR and ELISA were used to determine STAT3 mRNA and protein expression, respectively, from the retina. The blood glucose and insulin levels in the puerarin groups were significantly lower and higher, respectively than that in the DM group. The amplitude of b-wave of electroretinogram in the DM and the LP groups was significantly lower than that in the NC group; in the LP and HP groups it was significantly higher than the DM group. The serum and retinal tissue activity of SOD and MDA was significantly lower and higher, respectively, in the DM group compared to the NC group; both the LP and HP groups had significantly higher SOD and lower MDA than the DM group. The levels of STAT3 mRNA and protein levels in the DM, LP and HP groups were significantly higher than the NC group; and levels of STAT3 mRNA and protein expression were significantly lower in the LP and HP groups than the DM group. In summary, puerarin can reduce the oxidative stress damage of the retina, and its mechanism is related to the inhibition of STAT3 expression. PMID- 29285080 TI - Orally administered sodium 4-phenylbutyrate suppresses the development of dextran sulfate sodium-induced colitis in mice. AB - Sodium 4-phenylbutyrate (PBA) exerts therapeutic effects in a wide range of pathologies. A previous study by the present authors revealed that intraperitoneal administration of PBA suppresses the onset of dextran sulfate sodium (DSS)-induced colitis in mice. In the present study, the effects of orally administered PBA are investigated, as this route of administration is more clinically relevant. The therapeutic efficacy of PBA (10 mg/12 h) in mice with experimental colitis was assessed based on the disease activity index, production of inflammatory cytokines, colon length and histopathological investigations. The results of the present study demonstrated a significantly higher survival rate in the PBA-treated group compared with the PBA-untreated (DSS control) group (P=0.0156). PBA treatment improved pathological indices of experimental colitis (P<0.05). Furthermore, the oral administration of PBA significantly inhibited the DSS-induced shortening of the colon (P<0.05) and overproduction of interleukin (IL)-1beta and IL-6 (both P<0.05) as measured in colonic lavage fluids. A marked attenuation of the DSS-induced overproduction of tumor necrosis factor was also observed. For histopathological analysis, a marked decrease in mature goblet cells and increase in enlarged nuclei of the absorptive cells was observed in colon lesions of DSS control mice as compared with normal untreated mice. However, in the PBA-treated mice, no such lesions were observed and the mucosa resembled that of DSS-untreated mice. The results of the present study, combined with those results of a previous study, suggest that oral and intraperitoneal administration of PBA have similar preventative effects on DSS-induced colitis, achieved by suppressing its pathogenesis. PMID- 29285081 TI - Relevance of the clustered regularly interspaced short palindromic repeats of Enterococcus faecalis strains isolated from retreatment root canals on periapical lesions, resistance to irrigants and biofilms. AB - A high prevalence of Enterococcus faecalis (E. faecalis) is observed in teeth with root canal treatment failures. Clustered regularly interspaced short palindromic repeats (CRISPR) are widely distributed in prokaryotes that have adaptive immune systems against mobile elements, including pathogenic genes. The present study investigated the relevance of the CRISPR in E. faecalis strains isolated from retreated root canals on biofilms, periapical lesions and drug resistance. A total of 20 E. faecalis strains were extracted from the root canals of teeth referred for root canal retreatment. CRISPR-Cas loci were identified by two pairs of relevant primers and polymerase chain reaction. The susceptibility of the 20 isolated strains to intracanal irrigants was evaluated by 1- and 5 minute challenges with a mixture of a tetracycline isomer, an acid and a detergent (MTAD), 2% chlorhexidine (CHX) and 5.25% sodium hypochlorite (NaOCl). The microtiter plate assay and crystal violet staining were used to compare the biofilm formation of the E. faecalis isolate strains. Out of the 20 E. faecalis isolate strains, 5 strains that lacked CRISPR-cas determinants exhibited significant periapical lesions. Among the 15 strains containing CRISPR-cas determinants, 8 were isolated from root canals with inadequate fillings and 7 were isolated from root canals without any fillings. The five strains lacking CRISPR-cas loci were observed to be more resistant to MTAD and 2% CHX than the 15 strains that had CRISPR-cas loci. All of the strains exhibited the same susceptibility to 5.25% NaOCl. Furthermore, the 5 strains lacking CRISPR-cas determinants generated more biofilm than the other 15 strains. Thus, the results of the present study suggested that E. faecalis root canal isolates lacking CRISPR-cas exhibit higher resistance to intracanal irrigants, stronger biofilm formation and generate significant periapical lesions. PMID- 29285083 TI - Quercetin-loaded mixed micelles exhibit enhanced cytotoxic efficacy in non-small cell lung cancer in vitro. AB - In the present study, quercetin (QUR)-loaded mixed micelles (QUR-M) were prepared with the aim of improving the physicochemical and anticancer efficacy of QUR in lung cancer cells. The mixed micelles comprised tocopheryl polyethylene glycol 1000 succinate (TPGS) and a 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine derivative of polyethylene glycol. The nanosized QUR-M exhibited a pH-responsive and controlled release of QUR that is likely to be beneficial in cancer treatment. The results of an MTT assay clearly demonstrated that the anticancer effect of QUR-M in A549 cancer cells was stronger compared with that of free QUR at 24 and 48 h time points. The half-maximal inhibitory concentrations of QUR and QUR-M were observed to be 12.45 and 6.42 ug/ml, respectively. When stained with Hoechst 33342 and observed using a confocal laser scanning microscope, A549 cells treated with QUR-M exhibited severe chromatin condensation and apoptotic body formation of the nuclei. Overall, high intracellular uptake, sustained drug release and the presence of TPGS in the mixed micelles may result in an increased inhibitory effect against cell proliferation and improved therapeutic efficacy in lung cancers. PMID- 29285082 TI - Molecular mechanisms in vascular injury induced by hypertension: Expression and role of microRNA-34a. AB - The aim of the present study was to investigate the expression and function of microRNA (miR)-34a in patients with primary hypertension. The expression of miR 34a was measured in the peripheral blood of 50 patients with primary hypertension and 28 normal controls by reverse transcription quantitative polymerase chain reaction. In addition, human umbilical vein endothelial cells (HUVECs) were transfected with an miR-34a inhibitor to suppress the expression of miR-34a, and the proliferation, migration and cell cycle distribution of HUVECs were measured by Cell Counting Kit-8, Transwell and flow cytometry assays. The target of miR 34a was also predicted by bioinformatics analysis and verified by a dual luciferase reporter gene assay and western blot analysis. miR-34a was significantly upregulated in the peripheral blood of patients with hypertension when compared with controls (P<0.05), and upregulation of miR-34a was associated with a higher clinical stage of hypertension (phase III; P<0.05). In vitro experiments demonstrated that inhibition of miR-34a promoted the proliferation, migration and G1/S transition of HUVECs, relative to scramble-miR controls (P<0.05). Furthermore, transforming growth factor beta-induced factor homeobox 2 (TIGF2) was predicted and verified to be a direct target of miR-34a. Collectively, these data suggested that miR-34a was upregulated in the peripheral blood of patients with hypertension, and that upregulated miR-34a may promote vascular endothelial injury by targeting TIGF2. PMID- 29285084 TI - Pterostilbene attenuates myocardial ischemia-reperfusion injury via the phosphatidylinositol 3'-kinase-protein kinase B signaling pathway. AB - The current study aimed to evaluate the cardioprotective effects of pterostilbene (PTB) on myocardial ischemia-reperfusion (I/R) injury in rats and identify its possible underlying mechanisms of action. A rat I/R model was established by ligating the left anterior descending coronary artery for 30 min and releasing the ligature to induce reperfusion for 120 min. Serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) levels were measured using CK-MB and LDH assay kits and myeloperoxidase (MPO) activity in the myocardium was evaluated using an MPO assay kit. Tumor necrosis factor-alpha, interleukin (IL)-6 and IL-8 levels were assayed using ELISA kits. Cardiomyocyte apoptosis was measured using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Levels of protein kinase B (Akt) and phosphorylated Akt (p-Akt) were measured using western blotting. The results demonstrated that treatment with PTB significantly reduced cardiomyocyte apoptosis, significantly increased Bcl-2 and p-Akt levels and decreased Bax expression in the hearts of rats subjected to I/R injury. However, the protective effects induced by PTB were attenuated by LY294002, which inhibits Akt activation. The results of the current study suggest that PTB treatment may reduce the I/R injury-induced apoptosis of cardiomyocytes, which is mediated by the phosphoinositide 3-kinase/Akt signaling pathway. PMID- 29285085 TI - Unfractionated heparin protects the protein C system against lipopolysaccharide induced damage in vivo and in vitro. AB - Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis-associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)-induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR in vitro using human umbilical vein endothelial cells (HUVECs). The in vivo data indicated that UFH preconditioning attenuated the decline in circulating activated protein C following LPS administration, and also reduced LPS-induced shedding of TM and EPCR. In HUVECs, LPS stimulation led to the downregulation of TM and EPCR expression, and UFH dose-dependently restored the mRNA and protein levels of TM and EPCR. In addition, UFH inhibited the LPS-induced activation of mitogen-activated protein kinase 14, proto-oncogene tyrosine-protein kinase Src and nuclear factor kappaB signaling in HUVECs. In summary, these results suggest that UFH has a protective effect on the protein C system during sepsis. Thus, UFH may be a candidate therapeutic agent for the treatment of patients with sepsis. PMID- 29285086 TI - A bronchogenic cyst of the larynx: A case report. AB - A 12-year-old female presented with a 2-month history of dyspnea and a progressively worsening hoarseness lasting >10 years. The subsequently identified mass was completely resected from the patient's supraglottic area using a laser and suspension laryngoscope. The mass was diagnosed as a bronchogenic cyst using histopathology. While the prognosis for these cysts is good, long-term follow-up remains necessary for such patients because there are several reports in the literature indicating the potential for malignancy to develop. The patient in the present study experienced no complications or recurrence of the bronchogenic cyst 2 years following surgery. To the best of our knowledge, only 2 cases of bronchogenic cysts arising from the larynx have been reported in China, and the present study introduces the first case of a bronchogenic cyst of the larynx in a Chinese patient reported in English. PMID- 29285087 TI - Scutellaria barbata D. Don inhibits migration and invasion of colorectal cancer cells via suppression of PI3K/AKT and TGF-beta/Smad signaling pathways. AB - Metastasis is one of the most aberrant behaviors of cancer cells. Patients with cancers, including colorectal cancer (CRC), have a higher risk of tumor recurrence and cancer-related mortality once metastasis is diagnosed. Existing treatment strategies fail to cure cancer mostly due to the onset of metastasis. Therefore, metastasis remains a challenge in cancer treatment. Some complementary and alternative medical therapies using traditional Chinese medicine have been demonstrated to be clinically effective in cancer treatment. Scutellaria barbata D. Don (SB) is a promising medicinal herb. It was previously reported that the ethanol extract of SB (EESB) is able to promote apoptosis, and inhibit cell proliferation and angiogenesis in human colon cancer cells. However, the anticancer effect of SB and the underlying mechanism require further investigation, particularly its role against metastasis. To further elucidate the antimetastatic effect of SB, MTT and Transwell assays were used in the present study to evaluate the effect of EESB on the proliferation, migration and invasion of the CRC cell line HCT-8. In addition, western blot analysis was performed to detect the expression of matrix metalloproteinases (MMPs), cadherins and other metastasis-associated proteins. EESB significantly reduced HCT-8 cell viability and attenuated the migration and invasion ability of HCT-8 cells in a dose dependent manner. In addition, EESB decreased the expression of MMP-1, MMP-2, MMP 3/10, MMP-9 and MMP-13, and proteins in the phosphoinositide 3-kinase (PI3K)/AKT and transforming growth factor (TGF)-beta/Smad pathways, but not the epithelial mesenchymal transition (EMT)-related factors E-cadherin and N-cadherin. In conclusion, the results suggested that SB inhibits CRC cell metastasis via the suppression of PI3K/AKT and TGF-beta/Smad signaling pathways, which may represent a mechanism by which SB exerts an anticancer effect. PMID- 29285088 TI - Vascular corrosion casting of normal and pre-eclamptic placentas. AB - Pre-eclampsia is an important cause of maternal and fetal morbidity and mortality that is associated with decreased placental perfusion. In the present study, vascular corrosion casting was used to investigate the differences in structural changes of the fetoplacental vasculature between normal and pre-eclamptic placentas. An improved epoxy resin vascular casting technique was used in the present study. Casting media were infused into 40 normal and 40 pre-eclamptic placentas through umbilical arteries and veins in order to construct three dimensional fetoplacental vasculatures. The number of branches, diameter, morphology and peripheral artery-to-vein ratio were measured for each specimen. The results indicated that the venous system of normal placentas was divided into 5-7 grades of branches and the volume of the vascular bed was 155.5+/-45.3 ml. In severe pre-eclamptic placentas, the volume was 106.4+/-36.1 ml, which was significantly lower compared with normal placentas (P<0.01). The venous system of pre-eclamptic placentas was divided into 4-5 grades of branches, which was much more sparse compared with normal placentas. In additions, the diameters of grade 1-3 veins and grade 2-3 arteries were significantly smaller in severe pre eclampsia (P<0.05). In conclusion, pre-eclamptic placentas displayed a decreased volume of vascular bed, smaller diameters of grade 1-3 veins and grade 2-3 arteries, and an increased peripheral artery-to-vein ratio, which may be a cause of the placental dysfunction during severe pre-eclampsia. PMID- 29285089 TI - MALP-2, an agonist of TLR6, promotes the immune status without affecting the differentiation capacity of umbilical cord mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are increasingly used in cell-based therapy due to their multiple differentiation capacity, low expression of co-stimulatory factors and immunosuppressive effect. However, accumulating studies reported the recognition and rejection of engrafted MSCs, which eventually led to the fail of clinical trials. Toll-like receptors (TLRs) are important in mediating the immune response. In the present study, macrophage-activated lipopeptide-2 (MALP-2) was introduced to activate the TLR6 pathway in umbilical cord MSCs (UCMSCs). PBLs isolated from healthy volunteers were co-cultured with UCMSCs to measure whether activation of TLR6 of UCMSCs could stimulate immune responses. Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry were performed to detect pro-inflammatory molecules and differentiation status of UCMSCs, respectively. The results indicated that activation of TLR6 in UCMSCs increased the proliferation of peripheral blood leukocytes (PBLs) and enhanced the release of lactate dehydrogenase in damaged UCMSCs, which confirmed the role of TLR6 in promoting the immunogenicity of UCMSCs. Furthermore, quantitative polymerase chain reaction demonstrated that the expression of proinflammatory molecules (including IL-1beta, IL-6, IL-8, IL-10, CCL1 and CCL4) was induced, whereas the expression of stem cell markers (Klf4 and Nanog) was inhibited. The differentiation results indicated that activation of TLR6 had no effect on the differentiation capacity of UCMSCs. All these findings suggest that stimulation of TLR6 pathway may increase the immunogenicity of UCMSCs in in vitro detections. In conclusion, the results of the current study indicated a new role of TLR6 in regulating the biological function of UCMSCs. PMID- 29285090 TI - Application of silk fibroin/chitosan/nano-hydroxyapatite composite scaffold in the repair of rabbit radial bone defect. AB - Silk fibroin (SF), chitosan (CS) and nano-hydroxyapatite (nHA) possess excellent biocompatibility, thus, these were used to construct a SF/CS/nHA composite scaffold. Previously published results identified that this material exhibited satisfactory physical and chemical properties, and therefore qualified as a repair material in bone tissue engineering. The aim of the present study was to investigate the capacity and mechanism of this composite scaffold in repairing bone defects. In total, 45 New Zealand white rabbits were used to model defect in the right radial bone. A radial bone defect was induced, and rabbits were divided into the following treatment groups (n=15 in each): Group A, in which the SF/CS/nHA scaffold was implanted; group B, in which the SF/CS scaffold was implanted; and group C, in which rabbits did not receive subsequent treatment. X ray scanning, specimen observation and histopathological examination were implemented at 1, 2, 3 and 4 months after modeling, in order to evaluate the osteogenic capacity and mechanism. At 1 month after modeling, the bone density shadow in the X-ray scan was darker in group A as compared with that in group B. Observation of the pathological specimens indicated that normal bone tissues partially replaced the scaffold. At 2 months, the bone density shadow of group A was similar to normal bone tissues, and normal tissue began to replace the scaffold. At 3-4 months after modeling, the X-ray scan and histopathological observation indicated that the normal bone tissues completely replaced the scaffold in group A, with an unobstructed marrow cavity. However, the bone mass of group B was lower in comparison with that of group A. The bone defect induced in group C was filled with fibrous connective tissues. Therefore, it was concluded that the SF/CS/nHA composite scaffold may be a promising material for bone tissue engineering. PMID- 29285091 TI - Treatment of acute intermittent porphyria during pregnancy and posterior reversible encephalopathy syndrome after delivery: A case report. AB - Acute intermittent porphyria (AIP) is a rare inherited disorder of heme metabolism. It has the ability to trigger posterior reversible encephalopathy syndrome (PRES), a rare acute neurologic condition that is characterized by acute neurological symptoms. Pregnancy may induce AIP attacks. The present report describes the case of a pregnant woman with AIP. The patient was treated with heme-arginate during pregnancy and successfully delivered a healthy baby. Following delivery, the patient presented with PRES and experienced generalized seizures. Treatment including arginine hemoglobin, calcium gluconate and sodium chloride was administered. The symptoms of epilepsy did not recur. Magnetic resonance imaging of the head demonstrated that the bilateral occipital lobe lesions were significantly reduced in size following the treatment. In the present report, it was demonstrated that administration of heme-arginate for AIP during pregnancy is safe. Timely administration of arginine hemoglobin, calcium gluconate and sodium chloride may more efficiently improve the clinical status in AIP patients diagnosed with PRES who experience generalized seizures. PMID- 29285092 TI - Effects of CD44 and E-cadherin overexpression on the proliferation, adhesion and invasion of ovarian cancer cells. AB - CD44 is a prognostic indicator of shorter survival time in ovarian cancer. E cadherin fragmentation promotes the progression of ovarian cancer. However, the effects of CD44 and E-cadherin overexpression on ovarian cancer cells have remained elusive. The present study aimed to investigate the effects of overexpression of CD44 and E-cadherin on cell proliferation, adhesion and invasion of SKOV-3 and OVCAR-3 ovarian cancer cells. Overexpression of CD44 and E cadherin was achieved by transfecting SKOV-3 and OVCAR-3 cells with viruses carrying the CD44 or E-cadherin gene, respectively. Expression of CD44 and E cadherin was detected by western blot analysis. The proliferation of SKOV-3 and OVCAR-3 cells was measured by a Cell Counting Kit-8 at 0, 24 and 48 h after viral transfection. The adhesion ability of SKOV-3 and OVCAR-3 cells to the endothelial layer was detected. A Transwell invasion assay was utilized to assess the invasion ability of the cells. Overexpression of CD44 and E-cadherin in SKOV-3 and OVCAR-3 cells was confirmed by western blot. Compared with the blank or negative control groups, the CD44 overexpression groups of SKOV-3 and OVCAR-3 cells exhibited an increased cell proliferation rate at 24 and 48 h, whereas overexpression of E-cadherin did not alter the proliferation of these cells. Furthermore, compared with the blank and negative control groups, the cell adhesion and invasion ability in the CD44 overexpression groups of SKOV-3 and OVCAR-3 cells was markedly higher. There were no significant differences in adhesion ability between the E-cadherin overexpression group and the blank/negative control group. Of note, overexpression of E-cadherin decreased the invasive ability of SKOV-3 and OVCAR-3 cells. In conclusion, Overexpression of CD44 increased the proliferation, adhesion and invasion of ovarian cancer cells, while overexpression of E-cadherin decreased the invasion of ovarian cancer cells. PMID- 29285093 TI - Application of interconnected porous hydroxyapatite ceramic block for onlay block bone grafting in implant treatment: A case report. AB - Autogenous block bone grafting as treatment for alveolar ridge atrophy has various disadvantages, including a limited availability of sufficiently sized and shaped grafts, donor site morbidity and resorption of the grafted bone. As a result, interconnected porous hydroxyapatite ceramic (IP-CHA) materials with high porosity have been developed and used successfully in orthopedic cases. To the best of the author's knowledge, this is the first report of clinical application of an IP-CHA block for onlay grafting for implant treatment in a patient with horizontal alveolar atrophy. The present study performed onlay block grafting using an IP-CHA block to restore bone volume for implant placement in the alveolar ridge area without collecting autogenous bone. Dental X-ray findings revealed that the border of the IP-CHA block became increasingly vague over the 3 year period, whereas CT scanning revealed that the gap between the block and bone had a smooth transition, indicating that IP-CHA improved the process of integration with host bone. In follow-up examinations over a period of 5 years, the implants and superstructures had no problems. An IP-CHA block may be useful as a substitute for onlay block bone grafting in implant treatment. PMID- 29285094 TI - Neuroprotective effects of astragaloside IV on Parkinson disease models of mice and primary astrocytes. AB - Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Inflammation and neural degeneration are implicated in the pathogenesis of PD. Astragaloside IV (AS-IV) has been verified to attenuate inflammation. The current study aimed to investigate the role of AS-IV in PD and the possible molecular mechanisms. Pole, traction and swim tests were performed to examine the effects of AS-IV on 1 methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-generated behavioral deficiencies in vivo. Meanwhile, as for in vitro experiments, the influence of AS IV on cell viability was evaluated using the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5 diphenyl-2-H-tetrazolium bromide (MTT) assay, the effects of AS-IV on 1-methyl-4 phenylpyridnium ion (MPP+)-induced cell viability changes were tested using MTT assays, cell apoptosis rates were assessed using an Annexin-V Fluorescein isothiocyanate kit, and the expression levels of phosphorylated-Jun N-terminal kinase (p-JNK), Bcl-2-associated X protein (Bax)/Bcl-2 and caspase-3 activity were assessed using western blot analysis. Behavioral tests showed that pretreatment of AS-IV significantly alleviated MPTP-generated behavioral deficiencies in vivo. Meanwhile, AS-IV remarkably rescued MPP+-induced cell viability reduction, increase in cell apoptosis rate, and upregulation of p-JNK, Bax/Bcl-2 ratio and caspase-3 activity in vitro. In conclusion, AS-IV may be a promising neuroprotective agent for PD. PMID- 29285095 TI - Kaempferol targets estrogen-related receptor alpha and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions. AB - Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of new-onset blindness in the developed world. The present study aimed to examine the effect of kaempferol on high glucose-induced human retinal endothelial cells (HRECs) in vitro. The expression levels of various mRNAs and proteins were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. The target of kaempferol was determined using a luciferase reporter assay. In addition, HREC proliferation, migration and cell sprouting were determined using Cell Counting kit-8, wound scratch and tube formation assays, respectively. RT-qPCR and western blotting results showed that treatment with 30 mM glucose for 12, 24 and 48 h increased the expression level of estrogen-related receptor alpha (ERRalpha) mRNA and protein. The luciferase reporter assay demonstrated that kaempferol inhibited ERRalpha activity in HRECs. Compared with 5 mM normal glucose treatment, high (30 mM) glucose significantly promoted the proliferation, migration and tube formation of HRECs, which was antagonized by 10 and 30 uM kaempferol in a dose dependent manner. Treatment with 30 mM glucose also increased the expression of vascular endothelial growth factor (VEGF) mRNA and protein, and the expression levels of VEGF mRNA and protein were suppressed by kaempferol (10 and 30 uM). Kaempferol (30 uM) treatment also increased the expression levels of thrombospondin 1 (TSP-1) and a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS-1) mRNA; however, TSP-1 and ADAMTS-1 levels did not differ between high glucose and normal (5 mM) glucose conditions. The results of this study suggest that kaempferol targets ERRalpha and suppresses the angiogenesis of HRECs under high glucose conditions. Kaempferol may be a potential drug for use in controlling the progression of DR; however, in vivo studies are required to evaluate its efficacy and safety. PMID- 29285096 TI - Anti-inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model. AB - Delphinidin, a flavonoid polyphenolic compound, is widely found in nature and is used as a food supplement due to its pharmacological activity. The aims of the present study were to examine the anti-inflammatory effect of delphinidin in alleviating spinal cord injury (SCI)-induced inflammation in a rat model and to determine the underlying mechanisms in SCI. The Basso, Beattie, Bresnahan (BBB) scores of rats were assessed to evaluate the effect of delphinidin on the recovery of motor function. ELISA kits were also used to analyze the activities of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and caspase-3. In addition, the protein expression levels of nuclear factor (NF)-kappaB, activator protein 1 (AP-1) and p38-MAPK protein expression were measured using western blot analysis. Treatment with delphinidin significantly increased the BBB scores, as well as inhibited the intramedullary spinal pressure in SCI rats. Delphinidin treatment also significantly suppressed the levels of inflammatory factors and NF-kappaB protein expression in SCI rats. Finally, treatment with delphinidin significantly inhibited NF-kappaB stimulation, COX-2 activity, PGE2 production, and AP-1 and p38-MAPK protein expression in SCI rats. These results suggest that the anti inflammatory effect of delphinidin alleviated inflammation in the SCI rat model via alleviation of the intramedullary spinal pressure through the NF-kappaB and p38-MAPK signaling pathways. PMID- 29285097 TI - miR-34a and miR-125b are upregulated in peripheral blood mononuclear cells from patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a leading cause of blindness, non-traumatic amputation and end-stage renal disease, as well as a major cardiovascular risk factor. To determine whether miR-125b and miR-34a serve an important role in the development of T2DM, the current study investigated the expression profile of two microRNAs (miR-34a and miR-125b) and their relative genes in peripheral blood mononuclear cells from 73 patients with T2DM and 52 healthy donors by reverse transcription-quantitative polymerase chain reaction In addition, the association between miR-34a, miR-125b and their relevant genes expression profile were analyzed with respect to the pathogenesis of T2DM. The present study demonstrated that the expression levels of miR-125b and miR-34a were elevated in peripheral blood mononuclear cell samples from patients with T2DM. Furthermore, miR-34a and miR-125b were positively correlated with low-density lipoprotein/high-density lipoprotein (HDL) and Foxp3 and negatively related to triglyceride/HDL. However, no correlation among miR-34a, miR-125b and the value of homeostasis model assessment of insulin resistance, homeostasis model assessment of beta-cell function and the genes of B lymphocyte-induced maturation protein-1, interferon regulatory factor-4, P53 and retinoid-related orphan receptor gammat were observed. These results indicate that the alteration of miR-34a and miR-125b exists in patients with T2DM, which may be involved in the pathogenesis of T2DM, and could be a potential novel biomarker of T2DM. PMID- 29285098 TI - Aspirin suppresses TNF-alpha-induced MMP-9 expression via NF-kappaB and MAPK signaling pathways in RAW264.7 cells. AB - Numerous studies have indicated that the expression of matrix metalloproteinase-9 (MMP-9) contributes to the atherosclerotic plaque hemorrhage and rupture. Aspirin, a non-steroidal anti-inflammation drug, has been known for its anti platelet effect in the prevention of the vascular complications of atherosclerosis. The present study aimed to investigate the pharmacological effects of aspirin on tumor necrosis factor-alpha (TNF-alpha)-induced MMP-9 expression and the underlying molecular mechanisms in murine macrophage RAW264.7 cells. Western blot analysis indicated that the protein level of MMP-9 was reduced by aspirin in a dose-dependent manner. In addition, downregulation of MMP 9 mRNA and activity were detected in aspirin-treated cells using quantitative polymerase chain reaction and a gelatin zymography assay separately. It was also observed that aspirin has a suppressive effect on the activation of nuclear factor (NF)-kappaB and inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases 1/2, p38 and c Jun N-terminal kinase. Furthermore, subsequent to inhibition of the MAPK pathway by specific inhibitors (PD98059, SB203580 and SP600125), the expression of MMP-9 was reduced, indicating that the inhibitory effect of aspirin on MMP-9 in TNF alpha-treated RAW264.7 cells may be, at least in part, through suppression of NF kappaB activation and the MAPK pathway. These findings support the notion that aspirin has therapeutic potential application in the prevention and treatment of atherosclerosis disease. PMID- 29285099 TI - IL-35 may maintain homeostasis of the immune microenvironment in periodontitis. AB - T lymphocyte cells, including regulatory T (Treg) and T helper 17 cells, have important roles in the human periodontium. However, the basis for Treg cytokine expression in various compartments of the periodontium remains unclear. The aim of the present study was to investigate the expression of interleukin (IL)-35 in the peripheral blood mononuclear cells (PBMCs) and periodontal tissues of patients with chronic periodontitis (CP), with a view to understanding its role in this disease, and ultimately providing improved treatments. Peripheral blood, periodontal tissues and gingival crevicular fluids (GCFs) were collected from patients with CP or impacted teeth, the latter serving as healthy controls. The expression levels of IL-35 subunit mRNAs in PBMCs and periodontal tissues were determined using reverse transcription-quantitative polymerase chain reaction, while the IL-35 protein expression in GCFs and sera was quantified by ELISA. The relative expression of IL-35 subunit mRNAs in the affected tissues of patients with CP was significantly higher compared with that in samples from healthy controls (P<0.05). The mean concentration of IL-35 protein in the GCFs and sera of patients with periodontitis was also significantly higher compared with that in samples from healthy controls (P<0.001). IL-35 protein and periodontal clinical indicators were negatively correlated. It was hypothesized that the increased level of IL-35 plays a protective role in periodontal disease by maintaining immune system homeostasis and dampening the inflammatory response, and highlights IL-35 as a potential new therapy for the treatment of periodontitis. PMID- 29285100 TI - MicroRNA-34a directly targets high-mobility group box 1 and inhibits the cancer cell proliferation, migration and invasion in cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma (CSCC) is the second most common type of skin cancer with increasing incidence. In recent years, several microRNAs (miRs) have been demonstrated to serve an oncogenic or tumor suppressive role in CSCC. However, the exact role of miR-34a in CSCC and the underlying regulatory mechanism remain unclear. The present study aimed to investigate the regulatory mechanism of miR-34a in the malignant phenotypes of CSCC cells using MTT assay, wound healing assay and transwell assay. It was observed that miR-34a was significantly downregulated in CSCC tissues and cell lines, and low miR-34a expression was associated with the aggressive progression of CSCC. Restoration of miR-34a significantly suppressed the proliferation, migration and invasion of CSCC SCL-1 cells. High-mobility group box 1 (HMGB1) was then identified as a target gene of miR-34a in SCL-1 cells using bioinformatics prediction. The expression of HMGB1 was significantly upregulated in the CSCC tissues and cell lines. Furthermore, the protein expression of HMGB1 was negatively regulated by miR-34a in SCL-1 cells, while overexpression of HMGB1 impaired the inhibitory effects of miR-34a on SCL-1 cells. These findings suggest that miR-34a represses the malignant phenotypes of CSCC cells, at least partly, via the inhibition of HMGB1. Therefore, miR-34a may be used as a promising therapeutic candidate for CSCC. PMID- 29285102 TI - Protective effects of carnosic acid against mitochondria-mediated injury in H9c2 cardiomyocytes induced by hypoxia/reoxygenation. AB - Myocardial ischemia and reperfusion occurs in myocardial infarction. Timely reperfusion will exacerbate the injury through the mitochondria-mediated apoptosis in cardiomyocytes due to the accumulation of excessive reactive oxygen species (ROS). In order to identify novel therapeutic approaches, the cardioprotective effects of carnosic acid and the underlying mechanisms were investigated in the present study in H9c2 cardiomyocytes injured by hypoxia/reoxygenation in vitro. The viability of H9c2 cardiomyocytes was detected by MTT assay and further confirmed by the detection of intracellular lactate dehydrogenase (LDH) release. The mitochondrial function in H9c2 cardiomyocytes was evaluated using fluorescence methods. The proteins related to apoptosis, including caspase-3, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were analyzed by western blot analysis, and the activity of caspase-3 was determined using a colorimetric method. As a result, carnosic acid was demonstrated to improve the viability of H9c2 cardiomyocytes and suppress the leakage of cytosolic lactate dehydrogenase under hypoxia/reoxygenation. In addition, the overproduction of intracellular ROS and intracellular calcium overload were ameliorated in the presence of carnosic acid. The dysfunction of mitochondria in H9c2 cardiomyocytes was also attenuated by carnosic acid through blocking the collapse of mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening. Furthermore, the apoptosis of H9c2 cardiomyocytes resulted from hypoxia/reoxygenation was inhibited by carnosic acid through the upregulation of Bcl-2 and the downregulation of Bax and caspase-3 levels. These results provided evidence for further investigation that would assist in the development of novel therapeutic approaches for myocardial infarction. PMID- 29285101 TI - Proteomic changes of CD4+/CD25+/forkhead box p3+ regulatory T cells in a 30-day rat model of sepsis survival. AB - Sepsis is defined as life threatening organ dysfunction arising from a dysregulated host response to infection. The outcomes of sepsis include early mortality, delayed mortality and recovery, and depend on the inflammatory response. Previous studies have demonstrated that regulatory T cells (Tregs) are important in determining the outcome of sepsis, as their suppressive function serves a role in maintaining immune homeostasis. However, Treg-mediated immunosuppression during the course of sepsis remains unclear and little is known about the survival of patients following diagnosis. Studying the survivors of sepsis may explain the mechanisms of natural recovery. Therefore, a 30-day rat model of sepsis survival was established in the current study. Cluster of differentiation CD4+/CD25+/forkhead box p3+ Tregs were isolated from the blood and spleens of rats undergoing cecal ligation and puncture or sham surgery, using flow cytometry. Proteomic analysis was performed using nano high-performance liquid chromatography-mass spectrometry. Several different biological pathways associated with uncommon differentially-expressed proteins were identified in the blood and spleen survivor and sham groups. Extracellular-regulated kinase/mitogen activated protein kinase, as well as integrin and actin cytoskeletal pathway elements, including Ras-related protein 1b, talin 1 and filamin A, were associated with Tregs in the blood. Pathway elements associated with cell cycle regulators in the B-cell translocation gene family of proteins, tumor necrosis factor receptor superfamily member 4, Hippo signaling, P70-S6 kinase 1, phosphatidylinositol 3-kinase/protein kinase B signaling and 1,25 dihydroxyvitamin D3 biosynthesis were associated with Tregs from the spleen including phosphatase 2A activator regulatory factor 4, histone arginine methyltransferase, CD4, major histocompatibility complex class I antigens, 14-3-3 protein theta and nicotinamide adenine dinucleotide phosphate cytochrome P450 reductase. These results explain the mechanism by which Tregs naturally recover and indicates that Tregs in the blood and spleen vary. Differentially-expressed proteins serving a role in these pathways provide additional insight for the identification of new targets for the diagnosis and treatment of sepsis. PMID- 29285103 TI - Effects of sepsis on the metabolism of sphingomyelin and cholesterol in mice with liver dysfunction. AB - Sepsis is characterized by a severe inflammatory response to infection. With the spread of sepsis, various tissues, including the lungs, liver and kidney, may be damaged. This may finally develop into multiple organ dysfunction syndrome. Sphingomyelin and cholesterol are two main lipids involved in sepsis. The metabolism of sphingomyelin and cholesterol in the livers of mice with sepsis needs to be clarified. To achieve this, the present study intraperitoneally injected mice with PBS, lipopolysaccharide (LPS; 10 mg/kg) and LPS + pyrrolidine dithiocarbamate (PDTC; 30 mg/kg). Subsequently, sphingomyelin and cholesterol content were measured using kits, the sphingomyelin synthase (SMS) activity was measured using thin layer chromatography, and the expression levels of SMS1 and 2, hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), ATP binding cassette subfamily A member 1 (ABCA1), scavenger receptor class B member 1 (SR-B1) and apolipoprotein A1 (Apo A1) were determined by western blotting in the livers of mice. Results demonstrated that, in the LPS group, sphingomyelin and cholesterol content was significantly increased (P<0.001; n=6), the SMS activity significantly enhanced (P<0.001; n=6), the expression levels of SMS2, HMGCR, ABCA1 and SR-B1 were augmented (P<0.05; n=6), and the expression of Apo A1 was decreased (P<0.05; n=6), whereas SMS1 level only slightly increased with no statistical significance (P>0.05; n=6), compared to the levels in the control group. However, PDTC was able to attenuate these alterations. These results indicated that sphingomyelin and cholesterol content may increase in the liver dysfunction of sepsis by increasing the expression of SMS2, HMGCR, SR-B1 and ABCA1, and downregulating Apo A1. PMID- 29285104 TI - Carboxymethyl-chitosan attenuates inducible nitric oxide synthase and promotes interleukin-10 production in rat chondrocytes. AB - Osteoarthritis (OA) is a common age-related degenerative joint disease, which is caused by the breakdown of joint cartilage and the underlying bone. Carboxymethyl (CM)-chitosan is a soluble derivative of chitosan that has similar physicochemical properties to the extracellular proteoglycans identified in hyaline cartilage. Previous studies have demonstrated that CM-chitosan serves a protective role in a rabbit OA model. The aim of the present study was to investigate the effect of CM-chitosan on NO production and inflammation through its upregulation of interleukin (IL)-10, and the activation of the janus kinase (JAK)/signal transducer and activator of transcription (STAT)/suppressor of cytokine signaling (SOCS) signaling pathway. In the present study primary rat chondrocytes were induced to inflammation with 2 ug/ml lipopolysaccharide. The cells were subsequently subjected to increasing concentrations of CM-chitosan (50, 100 and 200 ug/ml) and the relative mRNA and protein expression of inducible nitric oxide synthase (iNOS), IL-10, JAK1, STAT3 and SOCS3 were measured by RT qPCR and western blot analysis respectively. The results revealed that CM chitosan attenuated inflammation by significantly reducing iNOS expression and upregulating the anti-inflammatory cytokine IL-10 in a dose-dependent manner (P<0.05). The expression of JAK1, STAT3 and SOCS3 were also significantly upregulated by CM-chitosan (all P<0.05). The protective role of CM-chitosan against NO production was due to its upregulation of IL-10 and its activation of the JAK/STAT/SOCS signaling pathway. PMID- 29285105 TI - Small interfering RNA-mediated knockdown of Twist attenuates the aggressive phenotypes of human endometrial carcinoma Ishikawa cells. AB - The present study aimed to determine the effect of Twist downregulation on the proliferation, apoptosis and migration of human endometrial carcinoma Ishikawa cells. Endogenous expression of the Twist transcription factor was knocked down by delivery of Twist-targeting small interfering RNA (siRNA). Changes in the expression of epithelial-mesenchymal transition biomarkers, namely epithelial (E) cadherin, neural (N)-cadherin and Twist, were determined by western blot analysis. Cell cycle distribution and apoptosis were evaluated by flow cytometry. Cell proliferation and migration were analyzed using cell-counting and wound healing assays, respectively. Transfection with Twist siRNA led to a significant reduction in the expression of Twist and N-cadherin (P<0.05), while significantly increasing the expression of E-cadherin, relative to negative control transfectants (all P<0.05). Proliferation was also significantly decreased in Ishikawa cells transfected with Twist siRNA (P<0.05), which was accompanied by an increased rate of apoptosis and cell cycle arrest at S-phase. In addition, Twist downregulation led to a significant reduction in cell migration (P<0.05). These data suggest that Twist serves a role in the regulation of cell proliferation and migration in Ishikawa cells and may represent a potential target for the treatment of human endometrial carcinoma. PMID- 29285107 TI - N,N-dimethylformamide-induced acute hepatic failure: A case report and literature review. AB - N,N-dimethylformamide (DMF) is a major solvent predominantly used in the chemical industry. The main toxic effects following exposure to DMF are gastric irritation, skin eruption and hepatotoxicity. However, hepatic failure induced by DMF is rare. In this report, we present a case of acute hepatic failure following exposure to a toxic dose of DMF via respiratory tract inhalation and skin absorption with detailed abdominal computed tomography scan, sequential laboratory data and polymorphisms. The patient recovered satisfactorily following artificial liver support therapy and pharmacological agents to protect the liver in addition to plasma, blood platelet and albumin transfusions. In view of the high mortality rate and rare occurrence rate of acute hepatic failure, the clinical characteristics, polymorphisms and therapeutic strategy of DMF poisoning are discussed. PMID- 29285106 TI - Pediatric Chiari malformation type I: long-term outcomes following small-bone window posterior fossa decompression with autologous-fascia duraplasty. AB - Chiari malformation type I (CM-I) is a common hindbrain disorder that is associated with deformity and elongation of the cerebellar tonsils. Although CM-I occurs in both pediatric and adult patients, its prevalence, clinical features and management in the pediatric population are not well defined. The current study evaluated a consecutive case series of 92 children (38 females and 54 males) who were diagnosed with congenital CM-I. All patients underwent small-bone window posterior fossa decompression with autologous-fascia duraplasty. Clinical and radiological features were analyzed and long-term follow-up data were recorded. Risk factors associated with clinical outcomes were investigated using comprehensive statistical methods. Out of the 92 children, 11 (12.0%) were asymptomatic. Associated ventricular dilation was observed in 24 children (26.1%) and concomitant syringomyelia was observed in 72 children (78.3%). A total of 44 children (47.8%) showed scoliosis on plain films. Follow-up data (mean duration, 88.6 months) were available for all patients. Syringomyelia was absent or markedly reduced in 56 patients (77.8%). Symptoms were alleviated in 66 patients, remained unchanged in 12 patients and progressed in 3 patients. Statistical analysis indicated that the cerebellar tonsillar descent (CTD) grade, basilar invagination and platybasia influenced the clinical outcome (P<0.05). In conclusion, early recognition and surgical treatment of CM-I in pediatric patients can lead to good outcomes. The current results suggested that small-bone window posterior fossa decompression with autologous-fascia duraplasty was an effective safe treatment option with a low complication rate. High CTD grade, basilar invagination and platybasia were indicated to be predictors of poor clinical prognosis. PMID- 29285108 TI - Elevation of arachidonoylethanolamide levels by activation of the endocannabinoid system protects against colitis and ameliorates remote organ lesions in mice. AB - The endocannabinoid system (ECS) is a potential pharmaceutical target for the treatment of inflammatory bowel diseases (IBDs). The aim of this study was to explore the effects of activation of the ECS on IBD and the associated neural inflammation-induced disruption of the blood-brain barrier (BBB). In a mouse model of trinitrobenzene sulfonic acid-induced colitis, the inhibition of fatty acid amide hydrolase with URB597 elevated the arachidonoylethanolamide concentration of the colon. Macroscopic alterations of the colons were evaluated, and the 7-day survival rate of mice was analyzed. BBB integrity was assessed using a dye tracer method, and the cognitive function of mice was examined using a fear-conditioning test. URB597 treatment significantly reduced macroscopic alterations of the colon, decreased the mortality rate, and protected the integrity of the BBB in the mice (P<0.05). No significant changes were observed in the cognitive functions of the mice (P>0.05); therefore, the neuroprotective effect of ECS in this colitis model requires further investigation. Activation of the ECS was efficient in ameliorating colitis and increasing the survival rate of the mice, and reducing remote organ changes induced by colitis. The results suggest that modulation of the ECS is a potential therapeutic approach for IBDs and the associated remote organ lesions. PMID- 29285109 TI - Acute kidney injury in cancer patients and impedance cardiography-assisted renal replacement therapy: Experience from the onconephrology unit of a Chinese tertiary hospital. AB - Acute kidney injury (AKI) in cancer patients may disrupt anticarcinogenic treatment and greatly increase associated mortality rates. The present study reported on the management of cancer patients with AKI and, from the nephrologic viewpoint, on the significance of fine volume control during the continuous renal replacement therapy (CRRT). The records of 117 cancer patients with AKI treated over three years were reviewed and their data were compared with those of 120 healthy controls. AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria with serum creatinine levels determined on initial admission and for the diagnosis of AKI. CRRT with concomitant impedance cardiography (ICG) monitoring was performed in 79 patients. On average, AKI manifested as a 1.68+/-0.38-fold increase in serum creatinine within 10.2+/-5.7 days. The causes of AKI were diverse, with the major ones being nephrotoxic agents, hypotension and obstructive nephropathy. Renal biopsy confirmed two cases of thrombotic microangiopathy, due to the use of interfon-alpha and sunitinib malate, respectively, and a third case of cast nephropathy caused by immunoglobulin D multiple myeloma. The patients were generally marantic and had compromised cardiac function compared with the healthy controls. The CRRT prescription was discriminatingly optimized by the ICG parameters effecting discreet fluid balance, as the thoracic fluid content was significantly correlated with the ultrafiltration rate. By considering the causative mechanisms and applying subtle ICG-assisted volume control, the present study may thus help to improve the safety and efficacy of CRRT in cancer patients with AKI. In addition, it provided information to bring advances in onconephrology, a novel nephrological subspecialty field. PMID- 29285110 TI - Large scale ex vivo expansion of clinical-grade effector cells for adoptive immunotherapy. AB - Cell-based adoptive immunotherapy for the treatment of various cancer types has attracted the attention of scientists. However, due to the absence of unitary standard protocols to produce large quantities of clinical-grade effector cells, it remains challenging to translate the experimental findings into clinical applications. The present study used methods complying with good manufacturing practice to induce effector cells from human peripheral blood mononuclear cells (PBMCs) of healthy donors by interleukin-2 and anti-Her-2 antibody with or without anti-CD3 antibodies (OKT3). The results indicated that the addition of OKT3 resulted in a greater expansion of the total cells and CD8+ T cells, and primarily induced the PBMCs to differentiate into CD3+ T cells. Regardless of the presence of OKT3, the expression of activating receptor of natural killer (NK) group 2, member D, and the inhibitory receptors of CD158a and CD158b on NK cells and NKT cells was increased, while the expression of NKp46 was inhibited on NK cells, but not on NKT cells. Furthermore, OKT3 did not affect the toxicity of the effector cells. Subgroup analysis indicated that although a variation of the composition of effector cells was present in different individuals under identical culture conditions, consistent marker expression on effector cells and target cell-killing effects were observed in different subgroups treated with or without OKT3. Furthermore, western blot analysis indicated that OKT3, apart from its involvement in cell cycle regulation, affects transcription and protein translation during processes of proliferation and differentiation. The present study provided experimental data regarding the production of effector cells for adoptive immunotherapy as a clinical application. PMID- 29285111 TI - Effects of Bambusa tulda on the proliferation of human stem cells. AB - To date, the effects of Bambusa tulda on stem cells have not been thoroughly assessed. The present study aimed to evaluate the effects of Bambusa tulda extract on the morphology and proliferative potential of human mesenchymal stem cells derived from the gingiva. The stem cells were cultured in a growth medium in the presence of Bambusa tulda methanolic extract (BBT) at concentrations ranging from 0.001 to 1%. Evaluation of cell morphology and cellular proliferation as well as immunofluorescent assays for collagen I were performed on days 1, 3, 5 and 7. Stem cells in the control group displayed a fibroblast like morphology, and BBT treatment did not produce any noticeable morphological changes. However, application of 1% BBT produced a significant increase in cell proliferation. BBT, particularly at the concentration of 1%, also caused a noticeable increase of collagen I expression at day 1 and day 3. Based on these findings, it was concluded that BBT exerted beneficial effects on the proliferation of mesenchymal stem cells and enhanced collagen I expression at early time points. PMID- 29285112 TI - Effects of dietary vitamin E on growth performance as well as intestinal structure and function of channel catfish (Ictalurus punctatus, Rafinesque 1818). AB - To evaluate the impact of dietary vitamin E supplementation on growth performance, the intestinal structure and function of channel catfish (Ictalurus punctatus, Rafinesque 1818) was investigated. A total of 900 healthy channel catfish (weight, 5.20+/-0.15 g) were divided into four groups, which received experimental diets with different vitamin E content (0, 50, 100 or 1,000 mg/kg). At the end of the feeding trial (after 15 weeks), the growth and gut performance of the animals was determined. The digestive enzyme activity in hepatopancreas and gut was also detected. In addition, the height of intestinal fold, the thickness of the mucous membrane and the number of somatostatin-positive cells was examined by histological analysis. Dietary vitamin E supplementation at 50 and 100 mg/kg significantly improved the growth and gut performance, which also increased the activity of several digestive enzymes compared to that in animals without vitamin E supplementation (P<0.05). In addition, vitamin E supplementation also significantly increased the height of intestinal fold and the thickness of the mucous membrane (P<0.05). Fish with dietary vitamin E supplementation at appropriate doses also had more somatostatin-positive cells in than those without vitamin E supplementation (P<0.05). In conclusion, dietary vitamin E supplementation at 50 and 100 mg/kg was shown to improve the growth performance as well as intestinal structure and function of channel catfish. PMID- 29285113 TI - Low dose irradiation increases adoptive cytotoxic T lymphocyte migration in gastric cancer. AB - Adoptive cellular immunotherapy (ACI) has been demonstrated to be a promising cancer therapeutic; however, the inefficient migration of adoptive immune cells to tumors is one of the rate-limiting factors of ACI. The present study investigated whether 2 Gy low dose irradiation (LDI) was able to increase the migration of adoptive lymphocytes to gastric cancer cells. Treatment with 2 Gy LDI resulted in marked chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 production from gastric cancer cell lines. A Transwell chamber migration assay demonstrated enhanced transmigration of cytotoxic T lymphocytes to gastric cancer cells following LDI treatment. After 2 Gy LDI application to established gastric carcinoma in nude mice, labeled immune cells were infused by intravenous injection and concentrated fluorescence signals were observed at the tumor sites within the mice, with a peak signal at 8-h LDI. Increased numbers of adoptive T cells at the tumor sites were also observed using flow cytometry. Furthermore, a case study of a patient with metastatic gastric cancer who had received ACI treatment combined with 2 Gy LDI provided further evidence that 2 Gy LDI is able to recruit antitumor effector T cells to tumor sites. Therefore, the ability of 2 Gy LDI to convert tumors into inflamed peripheral tissues may be exploited to overcome obstacles at the effector phase of the antitumor immune response and improve the therapeutic efficacy of immunotherapy. PMID- 29285114 TI - Severe erythema multiforme-type drug eruption controlled by tumor necrosis factor alpha antagonist: A case study. AB - Using a tumor necrosis factor-alpha antagonist, the present study successfully treated a case of severe erythema multiform-type drug eruption, which occurred following anti-Helicobacter pylori therapy. A 73-year-old female suffering from upper gastrointestinal bleeding and peptic-ulcer presented with an itchy rash, fever, an increase in leukocytes and eosinophils and lymphadenectasis following oral administration of amoxicillin. Following six subcutaneous injections of etanercept (initially 50 mg, then 25 mg every 3 days), the patient was deemed to have recovered. Following the first injection, the fever was under control. On day 2, the lesions were no longer expanding. On day 4, the rash was markedly less itchy, the swelling decreased, the erythema began to crust and mucosal secretions disappeared. On day 16, the patient was deemed to have recovered and was discharged from the hospital. Her peripheral blood eosinophil count continued to rise following the injection, peaking on day 9. Following this, the count declined slowly, but remained significantly higher than normal when the patient was discharged. The present case indicates that tumor necrosis factor-alpha antagonist is a safe, fast and effective treatment for severe drug eruption, but it is unable to prevent the rise of peripheral blood eosinophils. PMID- 29285115 TI - Quantification of ascites based on abdomino-pelvic computed tomography scans for predicting the in-hospital mortality of liver cirrhosis. AB - Ascites is among the most common complications of liver cirrhosis and is associated with a high mortality rate. The present retrospective study aimed to evaluate the potential correlation between in-hospital mortality of liver cirrhosis and volume of ascites. Patients with liver cirrhosis who were admitted to the General Hospital of Shenyang Military Region (Shenyang, China) between June 2012 and June 2014 and underwent axial abdomino-pelvic computed tomography (CT) scans were retrospectively reviewed. The volume of ascites was approximated using a five-point method, and diagnostic accuracy was expressed by the area under the receiver operating characteristic curves (AUROCs) with 95% confidence intervals (CIs). Of the 177 patients reviewed in the present study, 117 (61.10%) exhibited ascites on CT scans, and the in-hospital mortality rate was 4.52% (8/177). Child-Pugh and model for end-stage liver disease (MELD) scores were significantly increased in the presence of ascites (P<0.001). The in-hospital mortality rate did not differ significantly between patients with and without ascites (P=0.052). In patients with ascites >300 ml (n=72), the AUROCs of the Child-Pugh score, MELD score, and ascites volume for predicting in-hospital mortality were 0.939 (95% CI, 0.856-0982), 0.952 (95% CI, 0.873-0.988), and 0.782 (95% CI, 0.668-0.871), respectively. These AUROCs did not differ significantly. In conclusion, quantification of ascites may aid to predict the in-hospital mortality rate of cirrhotic patients. PMID- 29285116 TI - Effect of Hua Yu Xiao Zheng decoction on the expression levels of vascular endothelial growth factor and angiopoietin-2 in rats with endometriosis. AB - The aims of the present study were to investigate the effects of a traditional Chinese medicine, Hua Yu Xiao Zheng (HYXZ) decoction, on surgically induced endometriosis in a rat model and to determine the possible underlying regulatory mechanisms. A total of 108 female Sprague-Dawley rats were divided into the control group (n=12) and endometriosis group (EM group; n=96), in which endometriosis was surgically induced in model rats by autotransplantation of endometrial tissues and 72 rats survived. After 3 weeks, the EM model rats were randomly divided into four subgroups (n=18), including the untreated model group, and three groups administered 7, 14 or 21 g/kg HYXZ decoction. Following 28 days of treatment, the associated proteins and genes of ectopic endometrial tissues were analyzed using immunohistochemistry, western blotting and quantitative polymerase chain reaction to investigate the underlying mechanisms. Compared with the model group, the size of the endometriotic implants decreased significantly in the HYXZ-treated groups. Furthermore, the expression levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were significantly decreased in HYXZ-treated groups compared with the model group. These results indicate that HYXZ affected the inhibition of angiogenesis and decreased the endometriotic implant volumes and histopathological scores. The effectiveness of HYXZ may be partially attributed to the decrease of VEGF and Ang-2 expression levels in the ectopic endometrium. PMID- 29285117 TI - Increased expression of Myc-interacting zinc finger protein 1 in APP/PS1 mice. AB - Myc-interacting zinc-finger protein 1 (Miz1) is a member of the poxvirus and zinc finger domain/zinc finger transcription factor family. Its transcription activation and repression functions in the nucleus are well elucidated; however its cytoplasmic inflammation function is poorly understood and may be associated with the pathogenesis of Alzheimer's disease (AD). The aim of the present study was to investigate the association between AD and Miz1 expression. In the present study, the expression and distribution of Miz1 in wild-type (WT) and amyloid precursor protein/presenelin-1 (AD) mice was studied using reverse transcription quantitative polymerase chain reaction, western blot analysis, and immunohistochemical and immunofluorescence staining. The results indicated that Miz1 was significantly upregulated in the cortex of AD mice (P<0.05). Double immunofluorescence labeling revealed that Miz1 protein was predominantly expressed in neurons and astrocytes, as evidenced by co-localization with the dendritic markers microtubule associated protein 2 and glial fibrillary acidic protein, respectively. The results of the present study suggest that the expression of Miz1 in the brain tissue of AD mice may serve an important role in AD pathogenesis. PMID- 29285118 TI - Anti-epileptic effect of ifenprodil on neocortical pyramidal neurons in patients with malformations of cortical development. AB - Ifenprodil has been demonstrated to reduce spontaneous action potentials observed by local field potential in animal models. To investigate whether ifenprodil exerts an anti-epileptic effect on neuronal levels in humans, whole-cell patch clamp recordings were used to study the electrophysiological membrane properties of neocortical pyramidal neurons in human brain tissues. Electrophysiological membrane properties and spontaneous spikes of neocortical pyramidal neurons were investigated by using whole-cell patch clamp recordings, prior to and following the application of ifenprodil. In the present study, ifenprodil significantly decreased the membrane input resistance (P<0.01), membrane time constant (P<0.01), action potential amplitude (P<0.01), action potential rising rate (P<0.05) and falling rate (P<0.05) on neocortical pyramidal neurons in patients with epilepsy caused by malformations of cortical development (MCD). These results suggested that ifenprodil decreased neuronal excitability of neocortical pyramidal neurons in patients with epilepsy and MCD and demonstrated that ifenprodil may be a potentially specific treatment for refractory epilepsy caused by MCD. PMID- 29285119 TI - Trichosanthin enhances the antitumor effect of gemcitabine in non-small cell lung cancer via inhibition of the PI3K/AKT pathway. AB - Gemcitabine (GEMZ) is the first-line therapy used against non-small cell lung cancer (NSCLC), and studies have focused on investigating the potential effects of agents combined with GEMZ to enhance the anticancer efficacy in NSCLC. Previous studies have reported that trichosanthin (TCS) has various physiological and pharmacological effects, including anti-human influenza virus enzymes, inhibition of protein synthesis and antitumor activity. The purpose of the present study was to investigate if TCS enhanced the antitumor effects of GEMZ in NSCLC. MTT assay demonstrated that TCS significantly enhanced the cytotoxic effect of GEMZ (P>0.05). Furthermore, a propidium iodide/Alphannexin V staining assay revealed that TCS exerted its pharmacological effect by increasing the apoptotic population. In addition, western blot analysis demonstrated that the combination treatment of TCS with GEMZ further decreased the expression level of phosphoinositide 3-kinase (PI3K) and AKT via regulating the expression of insulin growth factor. The results of the present study demonstrated that TCS enhanced the cytotoxic and apoptotic effects of GEMZ in A549 cells via regulating the PI3K/AKT pathway. In conclusion, these observations may provide a potential rational basis for a combination strategy for chemotherapy treatment of NSCLC. PMID- 29285120 TI - Protective efficacy of inhaled quercetin for radiation pneumonitis. AB - Radiation pneumonitis is a clinical problem with a high incidence. Once the onset of radiation pneumonitis has occurred, the administration of antioxidants and anti-inflammatory agents is the most commonly used method of clinical treatment. Quercetin (Que) is a common flavonoid, with potent anti-inflammatory and anti oxidant activities. In the present study, the therapeutic effect of inhaled Que on radiation-induced radiation pneumonitis in rats was investigated. Treatment with Que via inhalation was shown to increase the number of leukocytes and erythrocytes in the blood, and reduce the number of inflammatory cells in bronchoalveolar lavage fluid. Histological examination of lung tissue indicated that inhaled Que reduced hemorrhaging and the infiltration of inflammatory cells, and suppressed the expression of the proinflammatory cytokines transforming growth factor-beta1 and interleukin-6. These results indicated that treatment with Que via inhalation ameliorates radiation pneumonitis by reducing the number of inflammatory cells, and attenuating the inflammatory response and pathological changes. This suggests that administration of Que via inhalation has the potential to become a novel treatment for radiation pneumonitis. PMID- 29285121 TI - Persistent Mullerian duct syndrome: A case report and review. AB - Persistent Mullerian duct syndrome (PMDS) is a rare type of male pseudohermaphroditism caused by a deficiency in anti-Mullerian hormone (AMH) or a defect in its type II receptor. The current study reports the clinical data and results of the genetic analysis of a 17-month-old male diagnosed with PMDS. The clinical manifestations of the patient included a left transverse testicular ectopia and bilateral cryptorchidism. Pelvic ultrasonography indicated two testes on the same left inguinal ring and left inguinal hernia and uterine tissue located at the left rear of the bladder. Karyotype analysis detected a 46,XY chromosome pattern and tests determined that the level of AMH was increased. Gene sequencing of AMHR-II indicated a compound heterozygous nucleotide variation and identified two novel mutations. The c.1184 (E9) to c.1185 (E9) CT deletion mutant gene originated from the father of the patient. This mutation causes a frameshift resulting in a truncated protein. The c.1388G>A (E10) mutant site was derived from the patient's mother and caused a change in p.463, R>H, resulting in the alteration of the structure of the protein, which subsequently induced a conformational change in AMHR-II. The results of the current study may help to further understanding of the PMDS genetic profile. PMID- 29285122 TI - Pathophysiological correlations between fundus fluorescein angiography and optical coherence tomography results in patients with idiopathic epiretinal membranes. AB - The aim of the current study was to determine the association between fundus fluorescein angiography (FFA) image results, optical coherence tomography (OCT) imaging results and visual functions in patients with idiopathic epiretinal membranes (ERMs). A total of 80 eyes from 40 patients diagnosed with ERM were analyzed. Best-corrected visual acuity (BCVA) and metamorphopsia were measured using the Early Treatment Diabetic Retinopathy Study eye chart and M-charts, respectively. Macular thickness and volume were determined using OCT. Macular vascular leakage and distortion, and foveal avascular zone (FAZ) diameters were assessed using FFA. BCVA and M-chart results confirmed macular degeneration in the affected eyes. The area of macular vascular leakage was positively correlated with macular volume (r=0.50; P=0.001). The ratio of FAZ diameters was negatively correlated with central macular thickness (r=-0.41; P=0.008). The grade of macular vascular distortion was positively correlated with macular thickness (all r>=0.47; P<0.01) and volume (r=0.53; P<0.001). The results of the current study demonstrated that FFA may effectively identify the degree of changes in retinal macular vasculature. Vascular distortion, measured by FFA, may reflect changes in macular structure and visual functions. These results suggest a potential application of FFA in the pre- and post-surgical evaluation of patients with ERMs. PMID- 29285123 TI - An in vitro endothelial cell protective effect of secretory leukocyte protease inhibitor against simulated ischaemia/reperfusion injury. AB - Endothelial dysfunction is an essential deleterious modulator of ischaemia/reperfusion (I/R) injury. Secretory leukocyte protease inhibitor (SLPI) has demonstrated myocardial protection in cardiac transplantation; however, the effect of SLPI in endothelial I/R injury remains unexplored. In the present study, the effect of recombinant human SLPI (rhSLPI) treatment against endothelial cells (ECs) subjected to simulated I/R injury and the effect of treatment at different time points were determined. Human umbilical vein ECs (HUVECs) were subjected to normoxic or simulated I/R (sI/R) conditions, and rhSLPI at concentrations of 1, 10, 100 and 1,000 ng/ml was added to the cells prior to ischaemia, during ischaemia or at the onset of reperfusion. Endothelial injury and cytoskeleton disruption were assessed, and western blot analysis was conducted. The results revealed that rhSLPI treatment at 1,000 ng/ml significantly increased the HUVEC viability under sI/R injury (P<0.05). In addition, treatment with rhSLPI prior to or during ischaemia markedly attenuated the activity of lactase dehydrogenase compared with that in the sI/R group. In addition, the H2O2-induced reactive oxygen species production was reduced by ~17% upon rhSLPI pretreatment. Endothelial cytoskeleton disruption was also preserved by rhSLPI added prior to the reperfusion period. Furthermore, pretreatment with rhSLPI promoted protein kinase B activation, as well as reduced p38 mitogen activated protein kinase phosphorylation and B-cell lymphoma 2-associated X protein expression in response to I/R injury. These findings indicated that rhSLPI possesses antioxidant and antiapoptotic properties against endothelial responses to I/R injury. Therefore, the cytoprotective effect of rhSLPI may provide a potential pharmaceutical target to limit endothelial-mediated I/R injury. PMID- 29285124 TI - Rhein lysinate protects renal function in diabetic nephropathy of KK/HlJ mice. AB - The purpose of the present study was to assess the protective effects of rhein lysinate (RHL) in a KK/HlJ mouse model of diabetic nephropathy (DN) and to explore its mechanism of action. A total of 4 groups were established: C57BL/J control, the KK/HlJ model and 25 and 50 mg/kg/day RHL-treated KK/HlJ groups. The KK/HlJ mouse model of DN was established by streptozotocin injection, followed by maintenance on a specific diet. The albumin-to-creatinine ratio (ACR) was determined at 5 weeks and at 16 weeks, the kidneys were harvested, and morphological examination and immunohistochemical analysis were performed. The levels of malondialdehyde (MDA), as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities in the kidneys were measured using appropriate assay kits. The expression of inflammatory factors and associated proteins was analyzed using western blot analysis. At 5 weeks, the levels of ACR in KK/HlJ mice were increased, which was inhibited by treatment with RHL. Treatment with RHL (50 mg/kg/day) decreased the body weight of KK/HlJ mice. Compared with the C57BL/J control, the KK/HlJ model mice had a significantly lower activity of SOD and GSH-px in the kidneys, but had significantly higher levels of MDA. Treatment of KK/HlJ mice with RHL significantly increased the activities SOD and GSH-px, and reduced the MAD level in the kidneys. Renal tubular epithelial cell edema was observed in KK/HlJ mice but not in C57BL/J mice. RHL decreased the incidence of renal tubular epithelial cell edema and significantly decreased the expression of TNF-alpha and IL-6 as well as the expression and phosphorylation of NF-kappaB in the kidneys. Therefore, DN is associated with the expression of inflammatory factors, renal tubular epithelial cell edema and renal dysfunction in KK/HlJ mice. RHL improves renal function by decreasing kidney inflammation. PMID- 29285125 TI - Anti-inflammatory effects of Daehwangmokdantang, a traditional herbal formulation, in lipopolysaccharide-stimulated RAW 264.7 macrophages. AB - Daehwangmokdantang (DHMDT) is a traditional polyherbal formulation that has known antidiarrheal and anti-inflammatory activities. However, the underlying mechanisms of these activities are poorly understood. In the present study, the inhibitory effects of DHMDT on the production of proinflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were investigated. The inhibitory effects of DHMDT on LPS-induced nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor (TNF)-alpha and interleukin (IL) 1beta production were examined using Griess reagent and ELISA detection kits. The effects of DHMDT on the expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, IL-1beta and TNF-alpha, and their upstream signal proteins, including nuclear factor (NF)-kappaB, mitogen-activated protein kinases (MAPKs) and RAC-alpha serine/threonine-protein kinase (Akt), a phosphatidylinositol 3-kinase (PI3K) downstream effector, were investigated using western blotting and immunofluorescence staining. The results revealed the pretreatment with DHMDT significantly inhibited the LPS-induced production of NO, PGE2, TNF-alpha, and IL-1beta, and expression of iNOS, COX-2 TNF-alpha, and IL 1beta, without any significant cytotoxicity. DHMDT also efficiently prevented the translocation of the NF-kappaB subunit p65 into the nucleus by interrupting the activation of the upstream mediator inhibitor of NF-kappaB kinase alpha/beta. Furthermore, the anti-inflammatory effects of DHMDT were associated with the suppression of LPS-induced phosphorylation of Akt and MAPKs in RAW 264.7 macrophages. Therefore, the results of the present study indicate that DHMDT exhibited anti-inflammatory activity via the inhibition of proinflammatory mediators and cytokines, in which the inactivation of NF-kappaB, PI3K/Akt, and MAPKs may be involved. These results suggest that DHMDT may be a potential anti inflammatory drug candidate. PMID- 29285126 TI - Analysis of human papilloma virus type 52 integration status in exfoliated cervical cells. AB - To explore the significance of human papilloma virus type 52 (HPV52) infection and its integration in cells within cervical lesions, the expression levels of HPV52 were detected using polymerase chain reaction (PCR). The copy numbers of HPV52 E2, HPV52 E6 and the reference gene beta-actin were determined by quantitative PCR to analyze the association between HPV52 integration and cervical lesions. HPV52 integration was analyzed by the amplification of papillomavirus oncogene transcripts. A total of 13 samples from 468 cases were positive for HPV52. Among the samples, 1 case with an E2/E6 ratio >1 was purely episomal, 3 cases with an E2/E6 ratio of 0 were purely integrated, and 9 cases with an E2/E6 ratio of between 0 and 1 were a mixture of integrated and episomal. With the progression of cervical disease, the prevalence of the episomal type decreased gradually, and the prevalence of the integrated (episomal and integrated) forms increased. The pure integration of HPV52 occurred in chromosomes 2, 5 and 8. These results indicate that HPV52 integration into the host genome may be a key factor in cervical lesions. Thus, patients at high risk for cervical lesions may potentially be identified by screening for HPV52 infection and integration. PMID- 29285127 TI - Glutamine ameliorates lipopolysaccharide-induced cardiac dysfunction by regulating the toll-like receptor 4/mitogen-activated protein kinase/nuclear factor-kB signaling pathway. AB - The inflammatory response of sepsis induced by lipopolysaccharide (LPS) may result in irreversible cardiac dysfunction. Glutamine (GLN) has a multitude of pharmacological effects, including anti-inflammatory abilities. Previous studies have reported that GLN attenuated LPS-induced acute lung injury and intestinal mucosal injury. The present study investigated whether GLN exerts potential protective effects on LPS-induced cardiac dysfunction. Male Sprague-Dawley rats were divided into three groups (15 rats per group), including the control (saline treated), LPS and LPS+GLN groups. Pretreatment with 1 g/kg GLN was provided via gavage for 5 days in the LPS+GLN group, while the control and LPS groups received the same volume of normal saline. On day 6, a cardiac dysfunction model was induced by administration of LPS (10 mg/kg). After 24 h, the cardiac functions of the rats that survived were detected by echocardiography and catheter-based measurements. The serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 were detected by enzyme-linked immunosorbent assay, while the mRNA levels of toll-like receptor (TLR)4, TNF-alpha, IL-1beta and IL-6 were examined by reverse transcription-quantitative polymerase chain reaction. The protein expression of TLR4, mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) were also determined by western blot analysis. The results of echocardiography and catheter-based measurements revealed that GLN treatment attenuated cardiac dysfunction. GLN treatment also attenuated the serum and mRNA levels of the pro-inflammatory cytokines. In addition, the protein levels of TLR4, phosphorylated (p-)extracellular signal regulated kinase, p-c-Jun N-terminal kinase and p-P38 were reduced upon GLN pretreatment. Furthermore, GLN pretreatment resulted in decreased activation of the NF-kappaB signaling pathway. In conclusion, GLN has a potential therapeutic effect in the protection against cardiac dysfunction mediated by sepsis through regulating the TLR4/MAPK/NF-kappaB signaling pathway. PMID- 29285128 TI - The relationship between inflammatory mediator expression in the aqueous humor and secondary glaucoma incidence after silicone oil tamponade. AB - The expression of inflammatory mediators in the aqueous humor and the incidence of secondary glaucoma after vitreous body resection combined with silicone oil tamponade for patients with retinal detachment were inestigated, and the roles of IL-17, IL-6 and TNF-alpha in secondary glaucoma after silicone oil tamponade were analyzed. Fifty-eight cases of retinal detachment treated by vitrectomy combined with silicone oil tamponade were examined at the time of silicone oil removal surgery. All patients underwent unilateral surgery. Patients were divided into observation (19 cases with) and control (39 cases without) groups depending on development of secondary glaucoma. Prior to silicone oil removal, expression levels of IL-17, IL-6 and TNF-alpha in the aqueous humor were examined. IL-17, IL 6 and TNF-alpha levels in the aqueous humor in the observation group were 204.2+/ 18.3, 351.1+/-28.4 and 850.0+/-51.7 pg/ml, respectively, vs. 152.3+/-22.2, 254.4+/-26.8 and 625.6+/-61.2 pg/ml, respectively in the control group (P<0.001). The expression of IL-17 was positively correlated with those of IL-6 and TNF alpha (r=0.687, 0.745; P<0.001). IL-17, IL-6 and TNF-alpha presented good diagnostic values for glaucoma. The receiver operating characteristic (ROC) areas were 0.957, 0.980 and 0.975, respectively (P<0.001). The expression of inflammatory mediators such as IL-17, IL-6 and TNF-alpha in the aqueous humor of patients with secondary glaucoma after silicone oil tamponade significantly increased relative to patients without secondary glaucoma. The resultant inflammation may be involved in the development of secondary glaucoma. PMID- 29285129 TI - Kushenin combined with adefovir dipivoxil affects the HBV-DNA load in serum, immune functions and liver functions of patients with chronic hepatitis B. AB - This study aimed to explore the effect of kushenin combined with adefovir dipivoxil on the load of hepatitis B virus DNA (HBV-DNA) in serum, in immune functions and in liver functions of patients with chronic hepatitis B. A sample of 80 patients with chronic hepatitis B was selected who were admitted to Weifang People's Hospital for treatment between January, 2013 and December, 2015. They were divided into the observation group (n=40) and the control group (n=40). The patients in both groups received adefovir dipivoxil, while those in the observation group additionally received the kushenin. Variations in HBV-DNA load and transforming growth factor-beta1 (TGF-beta1) in the two groups were detected before intervention, at 1 month, 3 months and 6 months after intervention. In addition, after intervention, we also observed the changes in CD4+, CD8+ and CD4+/CD8+, as well as the levels of immune globulin. Furthermore, in these two groups, we detected the changes in endotoxin in serum before and after intervention, the liver function after intervention, and the variations of hyaluronic acid (HA) and type III procollagen (PCIII) before and after intervention which were used to serve as the indicators for hepatic fibrosis. Results showed that at one month, 3 months and 6 months after intervention, HBV DNA load and the level of TGF-beta1 in the observation group were lower than those in the control group (P<0.05). In the observation group, the HBV-DNA load at 6 months after intervention was the lowest, sequentially followed by the levels at 3 months, at 1 month and before intervention (P<0.05). After intervention, the levels of CD4+ and CD8+ and CD4+/CD8+ in the observation group were higher than those in the control group (P<0.05). Moreover, the levels of immunoglobulin M (IgM), immunoglobulin G (IgG) and immunoglobulin A (IgA) were elevated in the observation group compared to the levels in the control group (P<0.05). Additionally, the level of endotoxin in serum, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil). Besides, after intervention, the levels of HA and PCIII in the observation group were found to be lower than those in the control group before and after intervention (P<0.05). This study concludes that, for patients with chronic hepatitis B, kushenin combined with adefovir dipivoxil can remarkably decrease the HBV-DNA load, improve their immunity, ameliorate the liver function and delay the onset of liver cirrhosis. PMID- 29285130 TI - Effects of hUCB-MSCs on recovery of neurological function and TERT expression in brain tissue of rats with cerebral ischemia-reperfusion injury. AB - The aim of this study was to investigate and analyze the effects of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) on the recovery of neurological function and telomerase reverse transcriptase (TERT) expression in brain tissue of rats with cerebral ischemia-reperfusion injury. A total of 100 healthy adult Wistar rats were randomly divided into two groups: The control group and the observation group according to the random number table method. After the model of cerebral ischemia-reperfusion injury was established, the rats in the observation group were treated with hUCB-MSCs (10 ml/kg), while the rats in the control group were treated with saline every day. The neurological deficit score and foot fault test were evaluated at 1, 7 and 14 days after treatment, and the rats were sacrificed at 14 days to detect the expression of TERT in brain tissue. There was no significant difference in the scores of mNSS between the two groups before the model establishment (P>0.05), but there was significant differences in two groups after the operation (P<0.05). At 1 day after the operation, the mNSS score of the two groups peaked, which was decreased in the groups with the progress of treatment. The degree of decline in the observation group was significantly greater than that in the control group (P<0.05). Similarly, there was no significant difference in the number of errors between the two groups before the model establishment (P>0.05), but there was significant difference in two groups after the operation (P<0.05). At 1 day after the operation, the number of errors also peaked, which was reduced in the groups with the progress of treatment. The degree of reduction in the observation group was significantly greater than that in the control group (P<0.05). The results of H&E staining showed it had positive reaction as nucleus or cytoplasm stained brown or yellowish brown in the observation group, while it showed neuronal shrinkage, cytoplasm and nucleus yellow dye deepening in the control group as the significant positive reaction. The gray level of the TERT protein in the brain tissue of the control group was 0.458+/-0.052 LOD, which was significantly lower than that in the observation group with 0.983+/-0.056 LOD (P<0.05). In conclusion, hUCB-MSCs can effectively improve the neurological function and the expression of TERT in brain tissue of rats with cerebral ischemia-reperfusion injury, which may be helpful to reduce the ischemia-reperfusion injury of brain tissue. PMID- 29285131 TI - Effects of water extracts of Rehmannia glutinosa on antioxidant system of Nrf2 in paraquat-induced insulin resistance diabetic rat model. AB - The objective of this study was to observe the effects of water extracts of Rehmannia glutinosa on the antioxidant system of Nrf-2 in diabetic mice induced by paraquat, and to provide the basis for its further development. Thirty male mice were randomly divided into the control group, model group and observation group. The mice in the model group and the observation group were treated with paraquat to induce insulin resistance, with the control group injected with the same volume saline. After the model establishment, the mice in observation group was given 1.2 g/kg.day with water extract of Rehmannia glutinosa, and the other groups were given equal volume of 1% hydroxymethyl cellulose sodium. After 7 days, the glucose tolerance was detected and the body weight was measured before and after the treatment. The body weight of the mice in the model group was significantly decreased (P<0.05), but the body weight of mice in the observation group was significantly higher than that in the model group (P<0.05). After 7 days of model establishment, the glucose tolerance of mice was damaged, with the blood sugar increased, but the level of blood sugar was significantly decreased when treated with water extracts of Rehmannia glutinosa. The water extract of Rehmannia glutinosa increased the level of phosphorylation of PKB significantly compared to the model group with the inhibition of PTEN. The level of malondialdehyde in mitochondria and muscle tissue was significantly increased after treated with water extracts of Rehmannia glutinosa (P<0.05). With decreased NQO-1 protein expression and the nuclear translocation of Nrf-2 in the model group, the water extract of Rehmannia glutinosa cloud reverse the injury effectively. Similarly, the water extract of Rehmannia glutinosa significantly increased the expression of IKBalpha, which was significantly decreased in the model group. In conclusion, water extracts of Rehmannia glutinosa effectively reversed the glucose metabolism disorder in insulin resistance mice induced by paraquat, and effectively activated the level of Nrf-2 to enhance the muscle insulin signal while alleviating the insulin resistance in mice. PMID- 29285132 TI - Effects of dexmedetomidine on H-FABP, CK-MB, cTnI levels, neurological function and near-term prognosis in patients undergoing heart valve replacement. AB - This study investigated the effects of dexmedetomidine on heart-type fatty acid binding protein (H-FABP), creatine kinase isoenzymes (CK-MB), and troponin I (cTnI) levels, neurological function and near-term prognosis in patients undergoing heart valve replacement. Patients undergoing heart valve replacement were randomly allocated to remifentanil anesthesia (control group, n=48) or dexmedetomidine anesthesia (observation group, n=48). Hemodynamic parameters were measured before anesthesia induction (T1), 1 min after intubation (T2), 10 min after start of surgery (T3), and on completion of surgery (T4). Levels of plasma H-FABP, CK-MB and cTnI were measured 10 min before anesthesia induction (C1), 10 min after start of surgery (C2), on completion of surgery (C3), 6 h after surgery (C4), and 24 h after surgery (C5). S100beta protein and serum neuron-specific enolase (NSE) were detected 10 min before anesthesia induction (C1), and 24 h after surgery (C5). Neurological and cardiac function was evaluated 24 h after surgery. Incidence of cardiovascular adverse events was recorded for 1 year of follow-up. There were no significant differences in the average heart rate between the two groups during the perioperative period. The mean arterial pressure in the observation group was significantly lower than control group (P<0.05). Levels of H-FABP, CK-MB and cTnI at C2, C3, C4 and C5, were significantly higher than C1, but significantly lower in the observation versus control group (P<0.05). Twenty-four hours after surgery, levels of S100beta and NSE in both groups were higher than those before induction (P<0.05), but significantly lower in the observation versus control group (P<0.05). Twenty-four hours after surgery, neurological function scores were better, and myocardial contractility and arrhythmia scores significantly lower in the observation versus control group (P<0.05 for all). After follow-up for 1 year, incidence of cardiovascular adverse events was significantly lower in the observation versus control group (P<0.05). Dexmedetomidine anesthesia can effectively maintain hemodynamic stability, reduce myocardial injury and the occurrence of cognitive dysfunction, and improve prognosis in patients undergoing heart valve replacement. PMID- 29285133 TI - Effects of Ginkgo biloba leaf extract on local renin-angiotensin system through TLR4/NF-kappaB pathway in cardiac myocyte. AB - The present study investigated the effects of Ginkgo biloba leaf extract (GBE50) on lipopolysaccharide (LPS) induced Toll-like receptor 4 (TLR4)/nuclear factor kappaB (NF-kappaB) signaling pathway and its effects on angiotensinogen (ATG) and AT1a receptor, so as to explore the mechanism of GBE50 in prevention and treatment of left ventricular remodeling. In vitro cultured neonatal rat ventricular myocytes (NRVMs) were divided into 4 groups including i) control group: DMEM medium; ii) LPS group: iii) LPS + GBE50 group; iv) LPS + caffeic acid phenethyl ester (CAPE, specific inhibitor of NF-kappaB) group. Nuclear translocation of NF-kappaB p65 was detected by immunocytochemical method after intervention for 24 h. Expression of TLR4, ATG, AT1a receptors and beta-myosin heavy chain (beta-MHC) mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). Protein content of cardiomyocytes was measured by Coomassie Brilliant Blue method. Under LPS stimulation, expression level of TLR4 mRNA in NRVMs was significantly increased (P<0.01), nuclear translocation of NF kappaB p65 was increased, expression levels of ATG, AT1a receptor and beta-MHC mRNA and the protein content in cells were also increased significantly (P<0.01). GBE50 and CAPE significantly inhibited nuclear translocation of NF-kappaB p65. GBE50 and CAPE treatments also reduced the increased mRNA levels of TLR4, ATG, AT1a receptor and beta-MHC and protein content in cell caused by LPS stimulation. We concluded that, GBE50 can inhibit the activation of local renin-angiotensin system by inhibiting the activation of TLR4/NF-kappaB and TLR4/NF-kappaB, signaling pathway inhibition may be one of the mechanisms of the role of Ginkgo biloba leaf extract in preventing myocardial remodeling. PMID- 29285134 TI - Sicyos angulatus ameliorates atherosclerosis through downregulation of aortic inflammatory responses in apolipoprotein E-deficient mice. AB - Sicyos angulatus (SA), a summer annual vine originating from Northeastern USA, is a widely distributed noxious invasive plant. However, the clinical application of SA has not been investigated previously. The purpose of present study was to determine the effects of SA on atherosclerosis and its underlying mechanism. Atherosclerosis was induced by feeding apolipoprotein E-deficient (apoE-/-) mice with an atherogenic diet for 8 weeks. SA was administered daily by oral gavage during induction of atherosclerosis. ApoE-/- mice treated with SA demonstrated a significant reduction in atherosclerotic plaque area in the whole aorta and aortic sinus compared with vehicle-treated mice. The plasma lipid profiles, including triglyceride, total cholesterol, high-density lipoprotein and low density lipoprotein, were not affected by SA administration. Of note, gene expression levels of proatherogenic cytokines including tumor necrosis factor alpha (Tnfalpha) and interleukin-6 (Il-6) were significantly decreased in the aorta of SA administered apoE-/- mice. In lipopolysaccharide-stimulated RAW 264.7 macrophage cells, SA also inhibited the induction Tnfa, Il-6 and Il-1beta in a dose-dependent manner. Furthermore, gene expression levels of endothelial cell adhesion molecules, including vascular cell adhesion protein 1 and intercellular adhesion molecule 1 were reduced in the aorta of apoE-/- mice treated with SA, which was followed by diminished aortic infiltration of monocytes/macrophages. In conclusion, to the best of our knowledge, this is the first study to demonstrate that SA is able to suppress the development of atherosclerosis by inhibiting the aortic expression of proinflammatory factors in atherogenic diet-fed apoE-/- mice. The present study may provide novel insights into the application of the environmentally problematic weed SA as a therapeutically effective natural product for preventing atherosclerosis. PMID- 29285135 TI - Omeprazole preserves the RER in chief cells and enhances re-epithelialization of parietal cells with SOD and AQP-4 up-regulation in ethanol-induced gastritis rats. AB - Gastric mucosal cells, particularly parietal and chief cells, are usually affected by exogenous, and endogenous stimuli-induced gastritis. The integrity of these cells and their alterations are involved in the pathogenesis of numerous gastric disorders. Omeprazole, a gastric acid secretion blocker, is commonly used for gastrointestinal diseases due to its antioxidative stress and anti inflammatory properties. Little is known regarding how omeprazole modulates the re-epithelialized effect on gastric mucosal cells associated with gastrointestinal disorders. The present study aimed to determine whether omeprazole attenuates parietal and chief cell damage in association with its antioxidative property. An in vivo ethanol-induced gastritis rat model was used. Histopathological, scanning and transmission electron microscopic, and immunohistochemical studies were performed. The results revealed that omeprazole improved the gastric mucosal surface, and reduced the severity of mucosal inflammation and hemorrhaging. Notably, ethanol-induced gastritis caused dysmorphic rough endoplasmic reticulum (RER) in chief cells, which was accompanied by mitochondrial swelling. This alteration was modulated by omeprazole due to its antioxidant effect characterized by upregulation of superoxide dismutase in gastric mucosal cells. In addition, expression of aquaporin-4 was increased in the omeprazole treatment group, which may be due to the expansion of regenerative parietal cells and acid suppression. The results of the present study suggest that omeprazole preserves the RER in chief cells and enhances parietal cell regeneration through its antioxidative property by exerting anti-inflammatory effects. PMID- 29285136 TI - Comparison of naturally aging and D-galactose induced aging model in beagle dogs. AB - Animal models have been used to study aging for decades. In numerous aging studies, beagles are the most commonly used breed of dog. However, few studies have compared between naturally aging models and experimentally induced aging models in beagle dogs. In the present study, a D-galactose induced aging model was compared with a naturally aging model, and young adult dogs were considered as the young control group. The level of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in serum, and brain tissue were measured. Histopathological comparisons of the liver, kidneys, heart, lungs and spleen were evaluated using hematoxylin and eosin (H&E) staining, in addition, the brain was evaluated by H&E staining, and Nissl staining. The expression levels of aging-associated factors in the hippocampus, including proliferating cell nuclear antigen (PCNA), P16 and P21 were also determined through reverse transcription quantitative-polymerase chain reaction, and western blot analysis. The results indicated that D-galactose induced aging significantly increased the MDA level, while the levels of SOD and GSH-Px were diminished when compared with the young control group, which was similar to the naturally aging group. Parallel histopathological features were observed in the D-galactose induced aging and naturally aging groups compared with the young control group. However, a reduced expression level of PCNA, and increased expression levels of P16 and P21 were observed in the naturally ageing and induced aging groups compared with the young control group. The results of the current study demonstrated that the beagle dogs in D-galactose induced aging model exhibited significant similarities with the naturally aging model, providing evidence to support that the D-galactose induced aging model may be applied to aging studies. PMID- 29285137 TI - Inhibition of chemotherapy-induced apoptosis of testicular cells by squid ink polysaccharide. AB - The aim of this study was to determine the mechanisms driving the protective effects of squid ink polysaccharide (SIP) against cyclophosphamide (CP)-induced testicular damage, focusing on germ cells. In the testes of mice exposed to CP and/or SIP, the present study examined the levels of reactive oxygen species (ROS) and malondialdehyde, activity of superoxide dismutase levels, protein expression levels of B-cell lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax), and total Caspase 3, activation of p-p38 and p-Akt proteins, and tissue morphology. The findings indicated that CP induced ROS production and oxidative stress, resulting in testicular damage. However, under administration of SIP, oxidative stress was impaired and the testicular toxicity induced by CP was weakened, which implied that SIP may have an important role in preventing chemotherapeutic damage to the male reproductive system via promoting antioxidant ability. Furthermore, the altered expression levels, including the upregulation of Bax and Caspase 3, downregulation of Bcl-2 and the increased Bax/Bcl-2 ratio, indicated that apoptosis occurred in CP exposed testes of mice; however, the alterations were reversed in mice treated with SIP. Moreover, in CP-exposed testes, p38 and Akt proteins were significantly phosphorylated (P<0.05), whereas in the testes of mice co-treated with SIP and CP, phosphorylation of the two proteins was inhibited, demonstrating that the two signalling pathways participated in the regulative processes of the deleterious effects caused by CP, and the preventive effects SIP mediated. PMID- 29285138 TI - Curcumin modulates covalent histone modification and TIMP1 gene activation to protect against vascular injury in a hypertension rat model. AB - Hypertension is a leading risk factor for morbidity and mortality. Previous studies have reported that curcumin has anti-oxidation and anti-aging effects and inhibits histone deacetylase activity. However, it is still unclear whether curcumin could protect against vascular injury induced by hypertension. Thus, the current study examined the therapeutic effects and mechanism of curcumin on vascular injury induced by hypertension in spontaneous hypertensive rats (SHRs). The present study revealed that curcumin may improve vascular structure and attenuate coronary artery pathology. Moderate doses (~50 mg) of curcumin were most effective in treating coronary artery injury in SHRs. Moreover, the results of immunohistochemical analysis indicated that the expression levels of histone deacetylase 1 (HDAC1), matrix metalloproteinase-2 (MMP-2) and transforming growth factor beta (TGFbeta) decreased in the curcumin treatment group, compared with the non-treated group or the negative control group. However, the expression of tissue inhibitor of metalloproteinase 1 (TIMP1) did not visibly decrease. Furthermore, chromatin immunoprecipitation results suggested that curcumin was capable of promoting the transcription activation of TIMP1 through suppressing HDAC1 expression and increasing histone H3 acetylation at the TIMP1 promoter region in SHRs. In conclusion, curcumin could relieve extracellular matrix degradation and interstitial fibrosis induced by hypertension, and lower blood pressure. It could also serve a function in improving vascular structure through inhibiting the expression of HDAC1, thereby promoting TIMP1 transcription activation and suppressing the expression of MMP-2 and TGFbeta. PMID- 29285139 TI - Ganoderma lucidum polysaccharide enhances radiosensitivity of hepatocellular carcinoma cell line HepG2 through Akt signaling pathway. AB - Ganoderma lucidum polysaccharide (GLP) is a well-known traditional Chinese medicine, known for its anti-cancer and immunomodulatory properties. The present study aims to investigate whether GLP has a therapeutic effect on hepatocellular carcinoma (HCC) cells exposed to radiation. Immunofluorescence was used to detect the nuclei, the protein expression was measured by western blot analysis and flow cytometry was used to detect the rate of cell apoptosis. GLP treatment was demonstrated to enhance radiation-induced growth inhibition and apoptotic death of HCC cells. At a molecular level, GLP suppressed the activities of DNA repair associated proteins including ataxia-telangiectasia mutated (ATM) and DNA dependent-protein kinase (DNA-PK) in liver cancer cells under radiation conditions. Furthermore, the addition of an Akt inhibitor elevated the activities of DNA-PK and ATM and attenuated the GLP-induced HepG2 cell injury under the radiation condition. In conclusion, the present study demonstrates that GLP enhances the radiosensitivity of HCC cells via the regulation of Akt signaling pathways, implying a potential therapeutic effect of GLP as a radiation sensitizer in HCC treatment. PMID- 29285140 TI - Bayesian network meta-analysis of the effects of single-incision laparoscopic surgery, conventional laparoscopic appendectomy and open appendectomy for the treatment of acute appendicitis. AB - The present study aimed to systematically evaluate the effectiveness of single incision laparoscopic surgery (SILS), conventional laparoscopic appendectomy (CLA) and open appendectomy (OA) for the treatment of acute appendicitis. PubMed and Embase databases were systematically searched to identify relevant studies comparing the effectiveness of different appendectomy methods for treating acute appendicitis published prior to April 2016. ADDIS 1.16.5 software was used for data analysis. Heterogeneity was assessed using I2 statistic. Odds ratios or standardized mean differences and 95% confidence intervals were calculated and pooled accordingly. Consistency was assessed using node-splitting analysis and inconsistency standard deviation. Convergence was assessed with the Brooks-Gelman Rubin method using Potential Scale Reduction Factor (PSRF). Surgical procedure duration, duration of hospital stay, wound infection and incidence of abscesses were compared. A total of 24 eligible studies were included in this meta analysis. A consistency model was used to pool data regarding the four outcomes. The PSRFs in each item were all <1.03. Pooled results showed that, compared with OA, SILS and CLA were associated with significantly shorter durations of hospital stay (all P<0.01) and lower risk of wound infection (SILS vs. OA P=0.02 and CLA vs. OA P<0.01, respectively), but no significant differences were identified between SILS and CLA. However, compared with OA, SILS exhibited a significantly longer surgical procedure duration (P=0.01) and lower incidence of abscesses (P=0.04), while no significant difference was observed between OA and CLA. This comprehensive network meta-analysis indicated that laparoscopic appendectomy, including SILS and CLA, may have more advantages for acute appendicitis compared with OA. Furthermore, SILS procedures require improvement and simplification to reduce the surgical procedure duration. PMID- 29285141 TI - Interferon-alpha inhibits cell migration and invasion and induces the expression of antiviral proteins in Huh-7 cells transfected with hepatitis B virus X gene expressing lentivirus. AB - Hepatitis B virus (HBV) X protein (HBx) serves an important role in HBV infection and the development of HBV-related liver cancer. Interferon-alpha (IFN-alpha) is used to treat patients with HBV; however, the role of IFN-alpha in the development of HBV-related liver cancer remains unclear. The present study established a new HBV-related liver cancer model (Huh-7-HBx) by transfecting the hepatoma cell line Huh-7, with HBx-expressing lentivirus. Following IFN-alpha treatment, cell viability, migration and invasion, as well as the expression of antiviral proteins in Huh-7-HBx, were subsequently determined. The results demonstrated that HBx-expressing lentivirus had no significant effect on cell viability but promoted the migration and invasion of Huh-7 cells. The expression of the antiviral genes IFN alpha and beta receptor subunit 1 (IFNAR1), IFNAR2, IFN-stimulated gene factor 3, double-stranded RNA-activated protein kinase and ribonuclease L, was also increased. Following treatment of Huh-7-HBx cells with IFN-alpha, the expression of antiviral genes was increased at the level of transcription and translation, whereas cell migration and invasion was decreased. The present study suggests that IFN-alpha may attenuate the development of HBV related liver cancer by reducing cell migration and invasion and promoting the expression of antiviral proteins. PMID- 29285142 TI - Increased levels of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells, and associated factors Bcl-6, CXCR5, IL-21 and IL-6 contribute to repeated implantation failure. AB - In vitro fertilization-embryo transfer (IVF-ET) can be used by infertile couples to assist with reproduction; however, failure of the embryo to implant into the endometrial lining results in failure of the IVF treatment. The present study investigated the expression of chemokine receptor 7 (CCR7)(lo) programmed death 1(PD-1)(hi) chemokine receptor type 5 (CXCR5)+ cluster of differentiation 4 (CD4)+ T cells and associated factors in patients with repeated implantation failure (RIF). A total of 30 females with RIF and 30 healthy females were enrolled in the current study. Flow cytometry was used to detect the proportion of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells in the peripheral blood. Cytokine bead arrays were performed to detect the levels of interleukin (IL)-6, -4 and -2 in the serum. ELISAs were used to detect the level of IL-21 in the serum. Quantitative real time polymerase chain reaction analysis and immunohistochemistry were used to investigate the expression of B-cell lymphoma 6 (Bcl-6), chemokine receptor type 5 (CXCR5) and IL-21 in the endometrium. The results revealed that the percentage of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells was increased in the RIF group compared with the control group during the mid luteal phase. The mRNA and protein levels of Bcl-6, IL-21 and CXCR5 in the endometrium and the concentrations of IL-21 and IL-6 in the serum were significantly increased in the RIF group; however, no significant difference was observed between the two groups in regards to the expression of IL-4 and IL-2. Furthermore, a significant positive correlation was identified between the percentage of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells and IL-21 and IL-6 levels. The expression of IL-21 also had a positive correlation with Bcl-6 and CXCR5 expression in the RIF group. These results suggest that increased levels of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells and associated factors contribute to RIF and could therefore be a potential therapeutic target. PMID- 29285143 TI - Combination treatment with quercetin and resveratrol attenuates high fat diet induced obesity and associated inflammation in rats via the AMPKalpha1/SIRT1 signaling pathway. AB - Diet-induced obesity is associated with systemic inflammation, which is considered to originate predominantly from the adipose tissue. Quercetin and resveratrol are two dietary polyphenols that exhibit anti-inflammatory properties and anti-insulin resistance when administered in isolation or combination (CQR). It remains unknown whether CQR reduces high fat diet (HFD)-induced obesity and inflammation in rats. In the current study, 46 male Wistar rats were divided into two groups, one of which was fed a normal diet (ND, 5.4% fat, w/w) and one of which was fed a HFD (45% fat, w/w) for 3 weeks. Following removal of the 12 most obesity-resistant rats from the HFD group, the remaining rats were divided into two sub-groups: A HFD group and a HFD+CQR group (administered 120 mg/kg/day resveratrol and 240 mg/kg/day quercetin). The results revealed that the HFD+CQR group had significantly lower body weights at 11 weeks compared with the HFD group and had significantly reduced visceral adipose tissue weights and adipocyte sizes. Serum lipid profiles were also significantly ameliorated in the HFD+CQR group. CQR attenuated the expression of systemic proinflammatory adipokines, including leptin, tumor necrosis factor-alpha, monocyte chemoattractant protein-1 and interleukin-6. It also reduced the recruitment of mast cells to the epididyotic adipose tissue (EAT). Furthermore, CQR reversed the HFD-induced suppression of 5'-adenosine monophosphate-activated protein kinase alpha1 (AMPKalpha1) phosphorylation and sirtuin 1 (SIRT1) expression in EAT. In conclusion, CQR may suppress obesity and associated inflammation via the AMPKalpha1/SIRT1 signaling pathway in rats fed a HFD. PMID- 29285144 TI - Icaritin inhibits decidualization of endometrial stromal cells. AB - The aim of the present study was to investigate the effects of Icaritin on the proliferation and decidualization of endometrial stromal cells (ESCs). A total of 20 specimens of endometrium were collected during hysterectomy at the Gynecology Department of Shenzhen Nanshan People's Hospital (Shenzhen, China) between August 2014 and December 2015. The endometrium was digested with high concentrations of collagenase and DNase and filtered with meshes, and then the glandular epithelial and stromal cells were separated by the adhesion purification method. The purity of stromal cells was identified by vimetin and cytokeratin 7 immunostaining. The estradiol + progesterone (E2+P4) and/or cyclic adenosine monophosphate (cAMP) were added to induce an in vitro decidualization model, which was used to analyze the effect of Icaritin on the decidualization ability of the human ESCs. The decidualization markers of human ESCs, prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP-1), was analyzed by reverse-transcription quantitative polymerase chain reaction measurements of the mRNA levels, PRL immunostaining and ELISA analysis of the IGFBP-1 protein levels in the cells or cell culture supernatant separately. The results demonstrated that treatment with E2+P4 and/or cAMP for 96 h was able to induce decidualization in ESCs, and that the cells demonstrated polygon-shaped epithelioid changes. The cell nuclei revealed multinuclear changes, and the cells were also observed to be large and round in shape. The PRL expression and upregulated IGFBP-1 mRNA and protein levels in the E2+P4+cAMP treatment group indicated successful decidualization of the in vitro model. However, the addition of Icaritin inhibited the expression of PRL and IGFBP-1 mRNA, as well as IGFBP-1 protein in the induced ESCs compared with groups without Icaritin. These results suggest that Icaritin was able to inhibit the expression of decidualization-related genes in ESCs in vitro. However, the exact mechanisms require further investigation. PMID- 29285145 TI - Comparison of bone marrow-vs. adipose tissue-derived mesenchymal stem cells for attenuating liver fibrosis. AB - Mesenchymal stem cell (MSC) therapy has emerged as a potential novel method of treating liver fibrosis. To date, bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) have not been analyzed with respect to their ability to combat liver fibrosis. The present study aimed to compare the capabilities of BM-MSCs and AD-MSCs in the treatment of liver fibrosis. BM-MSCs and AD-MSCs were taken from male Sprague-Dawley rats and cultured. Hepatic stellate cells (HSCs) were co-cultured with either BM-MSCs or AD-MSCs, and the effects of BM-MSCs or AD-MSCs on the proliferation, activation and apoptosis of HSCs were determined. The secretion of a selected group of cytokines by BM-MSCs and AD-MSCs was measured using enzyme-linked immunosorbent assays. Using a CCl4 induced liver fibrosis animal model, the anti-inflammatory and anti-fibrotic effects of BM-MSCs or AD-MSCs against liver fibrosis in vivo were evaluated. The morphological examination and analysis of specific surface markers confirmed the successful preparation of BM-MSCs and AD-MSCs. Furthermore, the proliferation, activation and apoptosis of HSCs were significantly inhibited by BM-MSCs and AD MSCs, with statistically greater reductions achieved by AD-MSCs compared with BM MSCs. Direct comparison of the secretion of selected cytokines by BM-MSCs and AD MSCs revealed that significantly higher levels of nerve growth factor and transforming growth factor-beta1 were secreted in the AD-MSC culture medium, whereas levels of vascular endothelial growth factor and interleukin-10 did not differ significantly between AD-MSCs and BM-MSCs. In vivo studies using a CCl4 induced liver fibrosis model demonstrated that inflammatory activity and fibrosis staging scores were significantly lower in the MSC-treated groups compared with controls. Although AD-MSCs improved anti-inflammatory and anti-fibrotic effects compared with BM-MSCs, these differences were not significant. Thus, the current study demonstrated that BM-MSCs and AD-MSCs are similarly effective at attenuating liver fibrosis by inhibiting the activation and proliferation of HSCs, as well as promoting the apoptosis of HSCs. PMID- 29285146 TI - Isoforskolin downregulates proinflammatory responses induced by Borrelia burgdorferi basic membrane protein A. AB - The plant Coleus forskohlii is distributed primarily in India, Thailand, China, Egypt and Brazil and has a history of use in the treatment of multiple diseases. Isoforskolin (ISOF) is the principle active component of C. forskohlii native to China and has previously been studied for its biological effects. The aim of the present study was to evaluate the effect of ISOF on the proinflammatory responses induced by recombinant Borrelia burgdorferi basic membrane protein A (rBmpA). In in vitro experiments, the proinflammatory effects of rBmpA and the anti inflammatory function of ISOF were evaluated in murine macrophages, human macrophages and dendritic cells by detecting the transcription and expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In in vivo experiments, mean arthritis index and X-ray and histopathological examinations were used to verify the role of ISOF in experimental Lyme arthritis in mice. The results indicated that rBmpA, which induced the transcription and expression of TNF-alpha and IL-6, activated proinflammatory responses in murine macrophages, human macrophages and dendritic cells. In turn, ISOF downregulated the transcription and expression of TNF-alpha and IL-6 induced by rBmpA. Additionally, the in vivo experiments demonstrated that ISOF could also inhibit the symptoms of experimental Lyme arthritis. These results suggest that ISOF may have a potential application as an anti-inflammatory agent for the treatment of Lyme arthritis. PMID- 29285148 TI - Correlation between CD64 and PCT levels in cerebrospinal fluid and degree of hearing impairment sequelae in neonates with purulent meningitis. AB - This study investigated the possible correlation between the degree of hearing impairment caused by neonatal purulent meningitis and the levels of CD64 and PCT in cerebrospinal fluid of patients, and assessed the prognostic value of such levels. We recorded data from 156 cases of neonatal purulent meningitis retrospectively. All the patients received brainstem response audiometry, and cerebrospinal fluid samples were collected within the first day after admission through lumbar puncture. Flow cytometry was used to detect CD64 levels and enzyme linked fluorescent assay was used to detect PCT levels. The children with hearing impairment were followed up for 1 year and brainstem response audiometry was performed again in them. We found that 43.59% of the children showed different degrees of hearing impairment, and 55% of them did not fully recover. The levels of PCT and CD64 in cerebrospinal fluid of children with hearing impairment were significantly higher than those of children with normal hearing (P<0.01). The levels of PCT and CD64 in mild, moderate and severe hearing impaired children increased gradually with higher degrees of impairment, and the differences between groups were significant (P<0.01). During the follow-up, it was found that the levels of PCT and CD64 in children correlated well with the degree of hearing recovery, and the differences between groups were significant (P<0.01). In our study, approximately 1/4 children with purulent meningitis showed long-term hearing impairment. Based on our analyses, the levels of CD64 and PCT in cerebrospinal fluid can be used to predict the degree and long-term prognosis of hearing impairment caused by purulent meningitis in children. PMID- 29285147 TI - Expression of the deubiquitinase cylindromatosis in articular cartilage and subchondral bone is associated with the severity of knee osteoarthritis. AB - Cylindromatosis (CYLD) is a deubiquitinating enzyme that regulates multiple key signaling pathways involved in the pathophysiology of knee osteoarthritis (KOA). Previous studies have indicated that the expression of CYLD in the articular cartilage of patients with KOA is significantly higher than in healthy controls. However, limited data are available regarding the association between CYLD expression and the severity of KOA. The aim of the present study was to investigate the association between CYLD expression in joint tissues and the severity of KOA. A total of 156 individual tibial plateau samples were obtained between January 2011 and January 2016 from patients that had undergone total knee arthroplasty due to KOA or from healthy controls. The severity of KOA was evaluated using the Kellgren Lawrence (KL) and Mankin scoring systems. Additionally, CYLD expression in the articular cartilage and subchondral bone was analyzed using immunohistochemistry. Compared with the healthy controls, patients with KOA exhibited significantly increased CYLD levels in the articular cartilage (6.53+/-2.01 vs. 28.69+/-13.23, P<0.001) and significantly decreased CYLD levels in the subchondral bone (11.46+/-2.34 vs. 3.50+/-2.54, P<0.001). Correlation analysis indicated that CYLD expression in the articular cartilage was positively correlated with the KL (r=0.837, P<0.001) and Mankin scores (r=0.925, P<0.001), while its expression in the subchondral bone was negatively correlated with the KL (r=-0.802, P<0.001) and Mankin scores (r=-0.844, P<0.001). The results of the present study demonstrate that CYLD levels in the articular cartilage and subchondral bone are associated with the severity of KOA. Thus, CYLD may be a potential diagnostic and predictive biomarker for KOA and a novel target in its treatment. PMID- 29285149 TI - The importance of pegaptanib sodium treatment for patients with vascular active vitreoretinopathy. AB - The aim of the present study was to report the importance of pegaptanib sodium (PGSD) injection treatment for vascular active vitreoretinopathy (VAVR). A total of 82 patients with VAVR diagnosed by increasing subretinal exudation were enrolled and received a single intravitreal injection of PGSD. The efficacies of PGSD for patients with VAVR were analyzed using photography, fluorescein angiography and optical coherence tomography. The pathological changes in vascular activity, amount of exudation and visual acuity between the PGSD, and placebo group were also compared. The results demonstrated that the PGSD injection significantly decreased subretinal exudation and leakage compared with the placebo when assessed using fluorescein angiography in a 12-month follow-up. It was observed that the PGSD injection inhibited inflammatory cytokines interleukin-1beta and tumor necrosis factor alpha for patients with VAVR compared with the placebo. Furthermore, results demonstrated that the average inflammation score and intraocular pressure was significantly decreased compared with the placebo. Visual acuity was improved from 1.3 to 0.7 in the majority of patients in the PGSD group. In conclusion, the outcomes of the present study indicate that the PGSD intravitreal injection is an efficient treatment option for patients with VAVR. PMID- 29285150 TI - Expression of PBMC apoptosis-related factors in patients with chronic hepatitis B and their relationships with clinical prognosis. AB - The present study was conducted to investigate the expression of apoptosis related factors in peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis B and their correlation to clinical prognosis. Sixty-two patients that were diagnosed with chronic hepatitis B were admitted to Xuzhou Hospital from March 2015 to February 2016 and were enrolled as the observation group, while 60 healthy subjects who were examined in the health examination center were selected as the control group. The PBMC of patients were collected, and mRNA expression levels of the apoptotic molecules (FAS, CASP3, CASP8 and CASP9) were measured using real-time fluorescence quantitative PCR. The protein expression levels of apoptosis-related genes in the plasma were detected using enzyme-linked immunosorbent assay (ELISA) and the serum HBV-DNA was quantitatively measured using real-time fluorescence quantitative PCR. The mRNA and protein expression levels of FAS, CASP3, CASP8 and CASP9 in the observation group were significantly higher than those in the control group (P<0.05). The positive rate and log value of the copy amount of HBV DNA in the observation group were significantly higher than those in the control group (P<0.05). The Pearson correlation coefficient analysis showed that FAS, CASP3, CASP8 and CASP9 were positively correlated with HBV DNA (P<0.05). The mRNA expression levels of FAS, CASP3, CASP8 and CASP9 in patients with negative HBV-DNA were significantly lower than those with positive HBV-DNA (P<0.05). Apoptosis of PBMCs play an important role in the occurrence and development of chronic hepatitis B, and is closely correlated to the level of serum virus replication and prognosis. PMID- 29285151 TI - Protective effects of notoginsenoside R1 on cerebral ischemia-reperfusion injury in rats. AB - The objective of this study was to investigate the protective effect of notoginsenoside R1 (NGR1) on cerebral ischemia-reperfusion injury (CIRI) in rats, and its molecular mechanism, to provide new insights into the diagnosis and treatment of CIRI. Sixty Sprague-Dawley rats were randomly divided into four groups including the sham-operation group (Sham), cerebral ischemia-reperfusion model group (CIR), NGR1 treatment group (NGR1), and nimodipine positive control group (NDC) with 15 rats each. Bilateral common carotid arteries occlusion was used to establish the rat CIRI model. The area of cerebral infarction at the end of reperfusion was calculated by triphenyl tetrazolium chloride staining. Apoptosis of hippocampal neurons in each group was detected by Annexin V/propidium iodide double staining. Hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA, and Bcl-2 and Bax protein at the end of reperfusion were measured by RT-qPCR and western blot analysis, respectively. Data were analyzed by SPSS software analysis to ensure statistical significance. At the end of reperfusion, the area of cerebral infarction in the NGR1 and NDC groups was significantly smaller than that of the CIR group. Apoptosis analysis showed that compared with the CIR group, the apoptosis rate of hippocampal neurons was significantly decreased in the NGR1 and NDC groups. RT-qPCR and western blot analysis showed that at the end of reperfusion, higher levels of BDNF mRNA and the anti-apoptotic factor, Bcl-2, and lower levels of the pro apoptotic factor, Bax, in the hippocampus were found in the NGR1 and NDC groups compared with the CIR group. The protective effect of NGR1 on CIRI was significantly stronger than that of nimodipine. In conclusion, NGR1 can reduce the area of cerebral infarction, reduce apoptosis of hippocampal neurons, and protect rats from CIRI. Those effects were achieved by activating the expression of BDNF and Bcl-2, and by inhibiting the expression of Bax. PMID- 29285152 TI - The single nucleotide polymorphism site of aquaporin-4 gene in patients with neuromyelitis optica. AB - The single nucleotide polymorphism (SNP) site within the aquaporin (AQP)-4 gene exons and its possible role in the pathogenesis of neuromyelitis optica (NMO) were studied. From March 2010 to June 2012, 72 patients with NMO from Xiangyang No. 1 People's Hospital, Hubei University of Medicine were enrolled in the NMO group. At the same time, 80 patients with multiple sclerosis (MS) were enrolled in our study as the MS group. Blood samples were collected and DNA was extracted for analysis of SNP sites of AQP4 gene. Specific site-directed mutagenesis method was used for site-directed mutagenesis on plasmid enhanced green fluorescence protein carrying AQP4 gene. Mutant plasmids were constructed and used for transfecting cell lines. The differences of anti-AQP4 antibody level in the cell line were analyzed. The possible correlation between AQP4 gene SNP sites and the pathogenesis of NMO were analyzed. In the NMO group, 6 SNP sites in AQP4 gene were located in exons 2 and 5. These included R108T, I110N, E280R, D281R, P295R and E317M. There was no SNP site in exons 1, 3 and 4. In the MS group, no SNP site was found in AQP4 gene. R108T, I110N, R108T/I110N, E280R/D281R, P295R and E317M cell lines were constructed in the NMO group, and anti-AQP4 antibody in the serum was compared between R108T/I110N, E280R/D281R and E317M cell lines and the original HEK293T cell line. The difference was statistically significant (P<0.05). The positive rate of anti-AQP4 antibody titer in serum was compared between R108T, I110N, R108T/I110N, E280R/D281R, P295R and E317M cell lines in the NMO group and the original cell line in the MS group. In conclusion, SNP sites in AQP4 gene in patients with NMO may lead to some conformational changes in AQP4 protein. This affects the antigenicity of AQP4 protein. The different intensity of antigen-antibody reaction may cause the differences of titer observed between the different mutant cell lines. PMID- 29285153 TI - Effects of quercetin on the expression of MCP-1, MMP-9 and VEGF in rats with diabetic retinopathy. AB - Diabetic retinopathy, a severe complication of diabetes, is the leading cause of blindness in the developed world. This study investigated the effects of quercetin on levels of monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in serum of rats with diabetic retinopathy, and explored the functional mechanisms of quercetin in the treatment of diabetic retinopathy. Twenty rats with induced diabetes were divided into a model group and a quercetin group, with 10 rats in each group. Ten healthy rats were also included to serve as a control group. Rats in the quercetin group were treated with an intragastric injection of quercetin (150 mg/kg), while the same amount of sodium carboxymethyl cellulose (CMCNa) was used for rats in the model group and the control group. The treatment was performed once per day and blood glucose was measured in each group at 0, 10 and 20 weeks after the first treatment. Blood glucose tests showed that quercetin did not reduce blood glucose in rats with diabetes. However, pathological examination showed that quercetin could relieve pathological changes caused by diabetes, such as retinal edema and vacuoles. ELISA results showed that, compared with the control group, levels of MCP-1, MMP-9 and VEGF in the model group were significantly increased (P<0.01). No significant difference in serum MCP-1 content was found between the model group and the quercetin group, but levels of MMP-9 and VEGF were significantly decreased in the quercetin group (P<0.01). Results of RT-PCR and western blot analysis showed that, compared with the control group, levels of MCP-1, MMP-9 and VEGF mRNA and protein in the retinal tissue of rats in the model group were significantly increased (P<0.01). No significant differences in expression levels of MCP-1 mRNA and protein were found between the model group and the quercetin group, but levels of MMP-9 and VEGF mRNA and protein were significantly decreased in the quercetin group (P<0.01). Quercetin has a certain therapeutic effect on rats with diabetic retinopathy and its effect may be achieved by reducing the expression of MMP-9 and VEGF, but not the inflammatory mediator, MCP-1. PMID- 29285154 TI - Impact of cusp inclinations on dental fractures in cracked tooth syndrome model and relevant risk evaluation. AB - We explored the impact of cusp inclinations on dental fractures in cracked tooth syndrome model and formulated corresponding risk scale. Forty maxillary premolars were randomized into four groups for cusp inclination measurements by digital radiovisiography (RVG). For cracked tooth models, buccal and palatal cusp inclinations were achieved by grinding in groups I (59 degrees -50 degrees ), II (64 degrees -55 degrees ) and III (69 degrees -60 degrees ), with group IV as blank control. All groups underwent compression loading test, with fracture levels recorded for statistical analysis. The fracture modes included a majority of crown root fractures and a minority of crown fractures in groups I and II, exclusive crown root fractures in group III, and exclusive crown fractures in group IV. Overall, palatal fractures were predominant versus buccal fractures, with exclusive palatal fractures in group IV, and oblique fractures were overwhelming versus the scanty vertical fractures. Fracture risk classification: grade III was prevalent in groups I and II, grade IV in group III, and grades I and II in group IV only. The fracture risk scores in groups III and IV had significant statistical differences versus groups I and II (P<0.05), with insignificant differences between groups I and II, respectively (P>0.05). Cracked teeth are more vulnerable to complex fractures, with increment of cusp inclinations contributable to complex fracture modes, involving deep roots and high risk scores. PMID- 29285155 TI - The level of urinary IL-18 in acute kidney injury after cardiopulmonary bypass. AB - This study investigated the diagnostic value of urinary interleukin-18 (uIL-18) in acute kidney injury (AKI) after cardiopulmonary bypass (CPB) in clinical practice. A total of 103 patients who underwent CPB were divided into the AKI group and non-AKI group according to the diagnostic criteria of AKI, and we collected the urine samples before and at 2, 4, 6, 8 and 12 h after CPB and the blood samples before and at 12, 24, 48 and 72 h after CPB for detection of the levels of uIL-18 and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in urine samples and the levels of serum creatinine (Scr) in blood samples, respectively. With the results of detection, we measured the sensitivity and specificity of uIL-18 and uNGAL levels at 2 h after CPB in early diagnosis of AKI using the receiver operating characteristic (ROC) curve and area under curve (AUC). There were a total of 22 patients (21.4%) with AKI. From 12 h after CPB, the level of Scr in the AKI group was significantly elevated, and this increasing trend lasted for 60 h; comparisons with the levels before CPB and in non-AKI group showed that the differences had statistical significance (P<0.05). In AKI group, uIL-18 attained the peak level at 2 h after CPB, and the high level lasted for 10 h; comparisons with the levels before CPB and in non-AKI group showed that the differences had statistical significance (P<0.05); 2 h after CPB, the AUC was 90.48, and when the critical value was set as 1.6 ug/l, the sensitivity and specificity was 90.91 and 91.36%, respectively. Although there was a significant elevation in uNGAL level at 2 h after CPB in the AKI group, the level was dramatically decreased as soon as the peak level was attained at 4 h, and the high level only lasted for 8 h; difference between the level at 2 h after CPB and the level before CPB as well as that in the non-AKI group had statistical significance (P<0.05); at 2 h after CPB, the AUC was 83.25, and when the critical value was set as 100 ug/l, the sensitivity and specificity was, respectively 90.91 and 93.83%. The results indicated that after CPB, the level of uIL-18 shows a more promising diagnostic value in clinical practice than Scr and uNGAL in early diagnosis of AKI. PMID- 29285156 TI - Curcumin suppresses AGEs induced apoptosis in tubular epithelial cells via protective autophagy. AB - Renal tubular cell apoptosis and tubular dysfunction is an important process underlying diabetic nephropathy (DN). Understanding the mechanisms underlying renal tubular epithelial cell survival is important for the prevention of kidney damage associated with glucotoxicity. Curcumin has been demonstrated to possess potent anti-apoptotic properties. However, the roles of curcumin in renal epithelial cells are yet to be defined. The present study investigated advanced glycation or glycoxidation end-product (AGE)-induced toxicity in renal tubular epithelial cells via several complementary assays, including cell viability, cell apoptosis and cell autophagy in the NRK-52E rat kidney tubular epithelial cell line. The extent of apoptosis was significantly increased in the NRK-52E cells following treatment with AGEs. The results also indicated that curcumin reversed this effect by promoting autophagy through the phosphoinositide 3-kinase/AKT serine/threonine kinase signaling pathway. These conclusions suggested that curcumin exerts a renoprotective effect in the presence of AGEs, at least in part by activating autophagy in NRK-52E cells. Collectively, these findings indicate that curcumin not only exerts renoprotective effects, however may also act as a novel therapeutic strategy for the treatment of diabetic nephropathy. PMID- 29285157 TI - Serum creatinine level and ESR values associated to clinical pathology types and prognosis of patients with renal injury caused by ANCA-associated vasculitis. AB - The correlation between serum creatinine and erythrocyte sedimentation rate (ESR) values and clinical pathology and prognosis in patients with renal injury caused by anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis were analyzed. Eighty-six patients with ANCA-associated vasculitis (AAV) treated in the Affiliated Hospital of Qingdao University were enrolled in the study. Patients were assigned into an elderly group (n=45) or a non-elderly group (n=41) according to age. The serum creatinine (Scr) level was measured via the sarcosine oxidase method, and the erythrocyte sedimentation rate (ESR) was measured using the full-automatic ESR analyzer; the relationship between Scr and ESR values and the pathology type of patients was statistically analyzed. The mean levels of Scr and ESR in the 86 patients were 406.87+/-12.37 umol/l and 83.83+/-7.64 mm/1 h, respectively. Importantly, the levels of Scr and the ESR in the elderly group were significantly higher than those in the non-elderly group (P<0.05). In addition, patients with high levels of Scr and accelerated ESR presented mainly the crescentic and sclerotic pathological types, while in the same patients the numbers of focal and mixed types were lower (P<0.05). Kaplan-Meier analysis showed that the survival rate in the elderly group was significantly lower than that in the non-elderly group, and likewise patients with high levels of Scr and accelerated ESR had significantly lower survival rates than those with low levels of Scr and normal ESR (P<0.05). The AUC of the Scr level was 0.901, the sensitivity 90.2%, the specificity 89.5% and the cut-off value was 392.5 umol/l; while the AUC of the ESR level was 0.864, the sensitivity 89.2%, the specificity 88.5% and the cut-off value 72.8 mm/1 h. Logistic regression analysis showed that the levels of Scr (OR=2.315, P<0.01) and ESR (OR=1.847, P<0.01) were independent factors affecting the prognosis of patients. Based on our findings, the seric Scr level and the ESR are closely related to the clinicopathological features of the disease in patients with renal injury caused by ANCA-associated vasculitis, and they can be used as prognosis and treatment evaluation markers. PMID- 29285158 TI - Clinical observation of ulinastatin combined with CRRT in the treatment of early cardiopulmonary resuscitation. AB - The clinical efficacy of ulinastatin (UTI) combined with continuous renal replacement therapy (CRRT) in the treatment after early cardiopulmonary resuscitation (CPR) was evaluated. A total of 70 patients who were successfully treated with CPR in Ganzhou People's Hospital from October 2016 to March 2017 were selected as the subjects. The patients were randomly divided into control group (35 cases, conventional treatment) and UTI combined with CRRT group (35 cases, UTI + CRRT). The whole blood of patients was collected at 0, 3, 6 and 12 h after CPR. Reverse transcription-polymerase chain reaction assay was used to detect the changes of toll-like receptor 4 (TLR4) gene in mRNA levels between the two groups, i-STAT system 300 was used to analyze pH level, SO2, HCO3- and lactic acid (LAC) concentration; Abbott AXSYM system was used to detect the expression of cardiac troponin I (cTnI) in serum; the concentration of plasma malondialdehyde (MDA) was examined by a special kit; interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients was determined by enzyme linked immunosorbent assay. The effect of UTI combined with CRRT in the early stage of CPR was analyzed. The levels of TLR4, cTnI, TNF-alpha, IL-6 and MDA in the plasma of patients in both groups were significantly increased (P<0.05), but the expression level in UTI + CRRT group was lower than that in control group (P<0.05). Compared with the control group, the HCO3- decreased significantly (P<0.05) in the UTI + CRRT group at 3 h, while the pH and SO2 did not change significantly. UTI + CRRT could significantly shorten the average recovery time of consciousness and the average recovery time of consciousness and spontaneous respiration in patients treated with CPR (P<0.05). Moreover, the score of APACHE II was significantly lower than that of control group (P<0.05). UTI combined with CRRT treatment can significantly improve the patient's condition after early CPR. PMID- 29285159 TI - Amelioration of the DSS-induced colitis in mice by pretreatment with 4,4' diaponeurosporene-producing Bacillus subtilis. AB - Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disorder of the gastrointestinal tract. Current IBD treatments have poor tolerability and insufficient therapeutic efficacy, thus, alternative therapeutic approaches are required. Recently, a number of dietary supplements have emerged as promising interventions. In the present study oral administration of a carotenoid (4,4' diaponeurosporene)-producing Bacillus subtilis markedly ameliorated dextran sulfate sodium salt-induced mouse colitis, as demonstrated by a reduction in weight loss and the severity of bleeding, which indicated that 4,4' diaponeurosporene may have beneficial effects on treatments for colitis. This preliminary study indicated that 4,4'-diaponeurosporene may function synergistically with probiotics to provide a novel and effective strategy to prevent colitis. PMID- 29285160 TI - Major pathogen microorganisms except yeasts can be detected from blood cultures within the first three days of incubation: A two-year study from a University Hospital. AB - The knowledge of the expected time-to-positivity (TTP) of blood cultures by major pathogens is essential both clinically and economically. To this end, we conducted the present two-year study in our Institution, aiming to assess the TTP of all the major microorganisms including Enterobacteriaceae, Pseudomonas aeruginosa, Acinetoacter baumannii, Enterococcii spp, Staphylococcus aureus and yeasts, to determine whether a 3-day interval is sufficient for their detection. The TTP for each case of strain isolation per patient was determined as the TTP of the first bottle among a set of bottles collected within the same period of time to be flagged as positive per patient. Based on our results, almost all major Gram-negative (99.30%), Gram-positive microbia (99.01%) and yeasts (98.85%) were detected within the first 5-days of incubation, leading to the solid conclusion that a 5-day period of incubation is adequate to detect almost all the major routine pathogens. By contrast, when a 3-day period was examined acceptable results were only found for Gram-negative (98.33%) and Gram-positive (98.51%) microbia. A significant proportion of yeasts (8.05%) could not be detected within this time frame. Therefore, regarding the yeasts, a 3-day incubation period cannot be considered as adequate and is not advocated. PMID- 29285161 TI - Hemorrhagic pleural effusion related to acquired coagulation factor VIII deficiency: A case report. AB - A patient with acquired hemophilia A (AHA) with hemorrhagic pericardial effusions was admitted to Xiamen Chang Gung Hospital (Xiamen, China) in August 2015. The patient had been experiencing progressive dyspnea for 1 week. Bloody effusion (~6.3 l) was drained from the membrane surrounding the heart over a period of 20 days. Biochemical, cytological and radiological examinations were unable to elucidate the reason for the effusion. Coincidentally, it was discovered that activated partial thromboplastin time prolongation could not be corrected by plasma mixing. Furthermore, immunologic and functional assays identified that the patient had factor VIII-deficient plasma. Finally, the coagulopathy was treated by infusion of cryoagglutinin and steroids to eradicate the coagulation inhibitor. The production of cardiac bloody effusions did not recur. Notably, the patient was diagnosed with AHA accompanied by the rare complication of pericardial effusions. The present case was the first to report AHA with the complication of pericardial effusions. PMID- 29285162 TI - Enhancing effects of basic fibroblast growth factor and fibronectin on osteoblast adhesion to bone scaffolds for bone tissue engineering through extracellular matrix-integrin pathway. AB - The present study aimed to investigate the effects of basic fibroblast growth factor (bFGF) and fibronectin (FN) on adhesion of osteoblasts seeded into bio derived bone scaffolds. Rat calvarial osteoblasts were separated and their osteogenic phenotypes were determined by staining for alkaline phosphatase as well as alizarin red staining. The bio-derived bone scaffolds were prepared from the metaphysis of porcine femur and their physicochemical properties were assessed by scanning electron microscopy (SEM) and X-ray diffraction analysis. An MTT assay was used to detect the effects of bFGF and FN on osteoblast adhesion or proliferation on cell/scaffold constructs through blocking the extracellular matrix FN-integrin pathway by the Gly-Arg-Gly-Asp-Ser (GRGDS) peptide. Western blot analysis was used to measure the beta1 integrin levels. Based on the adhesion of osteoblasts stimulated by various concentrations of bFGF (0.1, 1, 10 and 100 ng/ml) on bio-derived bone scaffolds modified by various concentrations of FN (0.1, 1, 10 and 100 ug/ml), the cell/scaffold constructs were divided into four groups: i) Control, non-stimulated and non-modified group; ii) 10 ug/ml FN modified group; iii) 100 ng/ml bFGF-stimulated group; iv) 10 ug/ml FN + 100 ng/ml bFGF group. Cell proliferation curves acquired by MTT assay and micrographs obtained by SEM showed that the combination of bFGF and FN significantly improved cell adhesion, particularly in the 10 ug/ml FN + 100 ng/ml bFGF group vs. the other groups, and the effect on cell adhesion was inhibited by 1 mmol/l GRGDS peptide through the FN-integrin pathway. Western blot results showed that the combination of bFGF and FN significantly enhanced beta1 integrin expression levels. These results suggested that osteoblasts stimulated by 100 ng/ml bFGF and bio-derived bone materials modified by 10 ug/ml FN should be combined to be applied in the bone tissue engineering. PMID- 29285163 TI - CDKN2A and CDKN2B methylation in coronary heart disease cases and controls. AB - The aim of the present study was to investigate the association between cyclin dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) methylation, and coronary heart disease (CHD), and to explore the interaction between methylation status and CHD clinical characteristics in Han Chinese patients. A total of 189 CHD (96 males, 93 females) and 190 well-matched non-CHD controls (96 males, 94 females) were recruited for the study. Methylation specific polymerase chain reaction technology was used to examine gene promoter methylation status. Comparisons of methylation frequencies between CHD and non CHD patients were carried out using the Chi-square test. Methylation levels of CDKN2A and CDKN2B genes were not found to be associated with the risk of CHD. However, the mean age of CDKN2A-hypermethylated participants was significantly lower than CDKN2A-unmethylated participants (58.73+/-5.88 vs. 62.62+/-5.36 years, adjusted P<0.001). Conversely, the mean age of CDKN2B-hypermethylated participants was significantly higher compared with CDKN2B-unmethylated participants (62.26+/-5.48 vs. 58.33+/-7.47 years, adjusted P=0.048). In addition, CDKN2B methylation frequencies were significantly increased in female participants compared with males (99.47 vs. 11.98%, P=0.032). In conclusion, the results indicated that CDKN2A and CDKN2B promoter methylation frequencies were significantly associated with age, and there was a gender dimorphism in CDKN2B methylation. PMID- 29285164 TI - Resveratrol alleviates Staphylococcus aureus pneumonia by inhibition of the NLRP3 inflammasome. AB - Staphylococcus aureus (S. aureus) causes a wide variety of infections, including S. aureus pneumonia. Resveratrol, a natural polyphenolic compound contained in several plant species, exerts various activities, including anti-bacterial and pulmonary protective activities. The aim of the present study was to evaluate the protective effect of resveratrol on a murine model of S. aureus pneumonia and to elucidate the underlying mechanisms. It was found that resveratrol significantly reduced S. aureus-induced mortality, ameliorated lung injury and decreased cytokine levels in the bronchoalveolar lavage fluid and lung tissue of S. aureus infected-mice. In addition, reverse-transcription quantitative polymerase chain reaction and western blot assays showed that resveratrol markedly decreased the mRNA and protein expression of nucleotide-binding domain and leucine-rich repeat containing gene family pyrin domain containing 3 protein (NLRP3), apoptosis associated speck-like protein containing a C-terminal caspase recruitment domain and caspase-1. These results demonstrated that resveratrol significantly alleviates S. aureus pneumonia in mice, the possible underlying mechanism of which is associated with the inhibition of the NLRP3 inflammasome. The present study suggested that resveratrol is a potentially useful agent for the treatment of S. aureus pneumonia and S. aureus-induced infectious diseases. PMID- 29285165 TI - MitoKATP channels promote the proliferation of hypoxic human pulmonary artery smooth muscle cells via the ROS/HIF/miR-210/ISCU signaling pathway. AB - Previous results have indicated that mitochondrial ATP-sensitive potassium (mitoKATP) channels are associated with the hypoxic proliferation of pulmonary artery smooth muscle cells (PASMCs). However, the mechanism underlying the promotive effects of mitoKATP channels on cell proliferation in response to hypoxia remains unknown. mitoKATP channel opening results in a collapse of mitochondrial membrane potential and generation of mitochondrial reactive oxygen species (ROS). As hypoxia-inducible factor-1alpha (HIF-1alpha) is a critical oxygen sensor and major transcriptional regulator of the hypoxic adaptive response, the current study assessed whether mitoKATP opening contributes to the chronic proliferation of human PASMCs (hPASMCs) in collaboration with HIF-1alpha and its downstream targets under hypoxic conditions. The present study demonstrated that there was crosstalk between mitoKATP channels and HIF-1alpha signaling in PASMCs under hypoxic conditions. The results suggest that mitoKATP channels are involved in the proliferation of PASMCs during hypoxia through upregulation of the ROS/HIF/microRNA-210/iron-sulfur cluster protein signaling pathway. PMID- 29285166 TI - Annexin A2 is an independent prognostic biomarker for evaluating the malignant progression of laryngeal cancer. AB - Due to the lack of a definite diagnosis, a frequent recurrence rate and resistance to chemotherapy or radiotherapy, the clinical outcome for patients with advanced laryngeal cancer has not improved over the last decade. Annexin A2 is associated with the invasion and metastasis of cancer cells. In the present study, it was demonstrated using differential proteomics analysis that Annexin A2 is highly expressed in laryngeal carcinoma tissues and this was confirmed using immunohistochemistry, which demonstrated that the expression of Annexin A2 in laryngeal carcinoma tissues was significantly higher than in healthy adjacent tissue. In addition, its potential predictive value in the prognosis of patients with laryngeal carcinoma was evaluated. The results demonstrated that Annexin A2 expression was significantly associated with tumor size, lymph node metastasis, distant metastasis and clinical stage. In addition, higher Annexin A2 expression was associated with a poor prognosis of patients with laryngeal cancer. Thus, the results of the present study indicate that Annexin A2 expression is an independent prognostic biomarker for evaluating the malignant progression of laryngeal cancer. PMID- 29285167 TI - Effectiveness of C5a aptamers in a TNBS-induced colitis mouse model. AB - The complement-activated product, complement component 5a (C5a), is a potent inflammatory peptide with a broad spectrum of functions. In vivo and in vitro studies have demonstrated that C5a serves an important role in inflammation; however, the role of C5a in the pathogenesis of inflammatory bowel disease (IBD) is not known. The purpose of the current study was to investigate the role of C5a in IBD using an experimental mouse model of colitis. Colitis was induced in mice using 2,4,6-trinitrobenzene sulfonic acid (TNBS), and C5a aptamers were subsequently administered via intraperitoneal injection. Clinical symptoms of the disease, histopathological analysis of the colon and the level of inflammatory components were examined. The symptoms of colitis, including changes in behavior, weight loss, colon damage and an increase in inflammatory cytokines, were attenuated following the treatment of mice with TNBS-induced colitis with C5a aptamers. The aptamer-treated mice exhibited a marked attenuation of colitis when compared with untreated mice, as demonstrated by the phenotypic observations, histological examinations and inflammatory cytokine levels. Colitis is characterized by an imbalance between pro-inflammatory and anti-inflammatory mediators. The results of the current study suggest that C5a may serve a critical role in inflammation in IBD. PMID- 29285168 TI - Berberine inhibits the LPS-induced proliferation and inflammatory response of stromal cells of adenomyosis tissues mediated by the LPS/TLR4 signaling pathway. AB - A previous study by our group has demonstrated that lipopolysaccharide (LPS) induces adenomyosis through stimulating inflammatory cell proliferation and invasive growth of stromal cells via Toll-like receptor 4 (TLR4) signaling. The present study aimed to investigate the effects of berberine (BBR) on LPS-induced ectopic endometrial stromal cells (EESCs) isolated from patients with adenomyosis. The viability of EESCs treated with LPS or LPS plus BBR was detected by a cell counting kit-8 assay, and the cell cycle distribution and apoptosis were evaluated by flow cytometry. The effect of BBR on the expression of key molecules of inflammatory proliferation and invasive growth of LPS-induced EESCs was also evaluated. BBR significantly inhibited the LPS-induced proliferation of EESCs in a dose- and time-dependent manner. BBR induced cell cycle arrest in G0/G1 phase and enhanced apoptosis of LPS-induced EESCs. Furthermore, BBR inhibited the expression of interleukin (IL)-6, IL-8, transforming growth factor beta, epithelial growth factor, vascular endothelial growth factor and matrix metalloproteinase 2 in LPS-induced EESCs. To the best of our knowledge, the present study was the first to demonstrate that BBR has a protective effect on ameliorating the LPS-induced progression of adenomyosis. This result may provide a novel therapeutic strategy for the clinical treatment of the disease. PMID- 29285169 TI - miR-30b regulates chondrogenic differentiation of mouse embryo-derived stem cells by targeting SOX9. AB - The present study aimed to investigate the mechanisms underlying microRNA (miRNA) mediated regulation of chondrogenic differentiation. Mouse embryo-derived stem cells C3H10T1/2 were cultured and chondrogenic differentiation was induced using transforming growth factor-beta3 (TGF-beta3). In addition, miRNA expression profiles were detected via miRNA array analysis, and quantitative polymerase chain reaction was performed to verify the differentially expressed miRNAs. Furthermore, bioinformatics software was used to predict the putative targets and the prediction was validated by dual-luciferase reporter assays and western blot analysis. In addition, cell proliferation and glycosaminoglycans were measured by a direct cell count method and alcian blue staining, respectively. Compared with the control group, 86 miRNAs were identified as differentially expressed in TGF beta3-induced cells and the expression levels of 28 miRNAs were increased while the remaining 58 miRNAs exhibited a decline in expression. Amongst the differentially expressed miRNAs, miR-30b expression was observed to have significantly decreased during chondrogenic differentiation. SOX9 is a target gene of miR-30b, and miR-30b inhibits SOX9 expression during chondrogenic differentiation. Furthermore, the alcian blue staining results demonstrated that miR-30b inhibited early chondrogenic differentiation. However, the data of the present study indicated that miR-30b had no influence on C3H10T1/2 cell line proliferation. In conclusion, miR-30b is a key negative regulator of TGF-beta3 induced C3H10T1/2 cell chondrogenic differentiation, which functions by directly targeting SOX9. PMID- 29285170 TI - HMGB1, TGF-beta and NF-kappaB are associated with chronic allograft nephropathy. AB - The present study aimed to investigate the association between high mobility group protein B1 (HMGB1), transforming growth factor-beta1 (TGF-beta1), nuclear factor-kappaB (NF-kappaB) and chronic allograft nephropathy (CAN) and to identify the clinical significance of HMGB1, TGF-beta1, NF-kappaB on patients with CAN. Between September 2012 and November 2014, 27 patients with CAN diagnosed by biopsy were enrolled in the present study and a further 30 patients that underwent nephrectomy following trauma were selected as the control group. Immunohistochemical staining with HMGB1, TGF-beta1 and NF-kappaB expression in the renal tissues, and western blot analysis were used to measure the relative expression of HMGB1, TGF-beta1 and NF-kappaB. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to estimate the relative expression of HMGB1, TGF-beta1 and NF-kappaB mRNA. Statistical analysis was used to calculate the association between HMGB1, TGF-beta1 and NF-kappaB expression and CAN grade. Immunohistochemical staining demonstrated that HMGB1, TGF-beta1 and NF kappaB had markedly positive expression rates in renal tubular epithelial cell cytoplasm and membranes in CAN renal tissues, and the positive rates of HMGB1, TGF-beta1 and NF-kappaB increased with the aggravation of CAN pathological grade (I, II and III). The results of western blot analysis indicated that the expression levels of HMGB1, TGF-beta1 and NF-kappaB were significantly higher in the CAN group, compared with the normal group (P<0.05), and the expression levels increased with the progression of CAN grade. A positive association among HMGB1, TGF-beta1 and NF-kappaB expression was identified. RT-qPCR analysis demonstrated that the expression of HMGB1, TGF-beta1 and NF-kappaB mRNA in the CAN group was significantly higher than in the normal group (P<0.05), and the relative expression level of HMGB1, TGF-beta1 and NF-kappaB mRNA not only increased with the aggravation of CAN grade, but was also positively associated with the expression of HMGB1, TGF-beta1 and NF-kappaB, respectively. The abnormal expression of HMGB1, TGF-beta1 and NF-kappaB is therefore, an important manifestation of CAN and the expression of HMGB1, TGF-beta1 and NF-kappaB mRNA in the renal tissues are significantly associated with CAN pathological progression. HMGB1, TGF-beta1 and NF-kappaB may form a signaling pathway that leads to the occurrence of CAN, which induces renal interstitial fibrosis. PMID- 29285171 TI - MicroRNA-10a-5p suppresses cancer proliferation and division in human cervical cancer by targeting BDNF. AB - The aim of the present study was to investigate the effect and mechanism of microRNA (miR)-10a-5p in human cervical cancer. The expression level of miR-10-5p in cervical cancer lines was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In cervical cancer HeLa and SiHa cells, miR 10-5p was ectopically overexpressed by lentiviral transduction. Brain-derived neurotrophic factor (BDNF) was then overexpressed in HeLa and SiHa cells to evaluate its selective effect on miR-10-5p in cervical cancer modulation. The targeting of miR-10-5p on its downstream gene, BDNF, was evaluated using RT-qPCR and western blot analysis. Cervical cancer cell viability and cell cycle was evaluated using an MTT assay and flow cytometry, respectively. The results indicated that miR-10-5p expression was significantly lower in cervical cancer cell lines compared with normal cells (P<0.05). Ectopic overexpression of miR-10 5p significantly inhibited cancer cell viability and induced cell cycle arrest in HeLa and SiHa cells (both P<0.05). miR-10-5p overexpression significantly reduced BDNF gene expression (P<0.05) and also reduced BDNF protein levels in cervical cancer cells compared with the control. In conclusion, the current study indicated that miR-10-5p is a cervical cancer suppressor, which regulates BDNF expression in cervical cancer. PMID- 29285172 TI - Omega-3 polyunsaturated fatty acids prevent murine dilated cardiomyopathy by reducing oxidative stress and cardiomyocyte apoptosis. AB - Mice that lacked manganese-superoxide dismutase (Mn-SOD) activity exhibited the typical pathology of dilated cardiomyopathy (DCM). The aim of the present study was to investigate the effect of supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA) on heart function and oxidative stress biomarkers in mice with DCM. In the present study, heart/muscle-specific Mn-SOD-deficient mice (H/M Sod2-/-) were treated with n-3 PUFA (30 mg/kg/day) for 10 weeks, and the reactive oxygen species (ROS) production in their heart mitochondria and cardiac function was subsequently assessed. n-3 PUFA treatment diminished ROS production and suppressed the progression of cardiac dysfunction. Furthermore, n-3 PUFA treatment effectively reversed the cardiac dysfunction and dilatation observed in symptomatic H/M-Sod2-/- mice. Notably, n-3 PUFA treatment ameliorated a molecular defect in connexin 43. Hematoxylin-eosin staining indicated that the phenotype of DCM was also ameliorated following n-3 PUFA treatment. Furthermore, echocardiography demonstrated that cardiac function was significantly improved in the mice treated with n-3 PUFA (P<0.05). Meanwhile, pre-treatment with n-3 PUFA significantly decreased cardiomyocyte apoptosis (P<0.001). In conclusion, n-3 PUFA treatment is able to prevent murine DCM, primarily by reducing ROS production and improving myocardial apoptosis. Therefore, the impairment of ROS production is proposed as a potential therapy for DCM. PMID- 29285173 TI - Rapamycin therapy for neonatal tuberous sclerosis complex with cardiac rhabdomyomas: A case report and review. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that varies greatly in its expression. The current study reports a novel case of TSC caused by a TSC2 mutation (TSC2c.1642_1643insA or TSC2p.K549fsX589), in which multiple cardiac rhabdomyomas were detected by fetal echocardiography in week 31 of pregnancy. The infant was delivered successfully; however, seizures began 16 days following birth. Subsequent genetic tests confirmed a diagnosis of TSC. Rapamycin treatment resulted in regression of cardiac rhabdomyomas and controlled seizures. The current study demonstrates the value of fetal echocardiography in the diagnosis of TSC and suggests that inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway may be considered as a potential antiepileptogenic therapy for neonatal TSC. In addition, it was demonstrated that rapamycin treatment was therapeutically beneficial for preventing disorders caused by abnormal mTOR signaling, such as cancer. According to the literature, cardiac rhabdomyomas, seizures and skin lesions are well established markers for TSC in neonates. MRI scans of the brain and genetic screening of TSC1 and TSC2 genes may facilitate an early diagnosis of TSC. PMID- 29285174 TI - Kasabach-Merritt syndrome combined with hypercalcemia: A case report. AB - The present case report presented the diagnosis and treatment course of an infant diagnosed with Kasabach-Merritt syndrome (KMS) combined with hypercalcemia (HC). A 35-day-old infant with swelling on the upper right arm for >1 month and thrombocytopenia for 1 day was admitted to Hunan Provincial People's Hospital (Changsha, China) and a series of treatments, including gamma-globulin impact, heparin anticoagulation, platelet transfusion, supplement of cryoprecipitate and fibrinogen following heparinization and inhabitation of vascular endothelial cell proliferation by propranolol, were performed. At 2 months after the initial admission to the hospital, surgery was conducted and the hemangioma was removed through pipeline arteriosclerosis embolization when the patient was hospitalized again with symptoms of vomiting and atrophy accompanied by HC. The level of blood calcium reduced to normal following surgery. Cases of KMS combined with HC are extremely rare and the most effective way to treat such cases is surgical resection of the hemangioma. PMID- 29285175 TI - Quercetin prevents alcohol-induced liver injury through targeting of PI3K/Akt/nuclear factor-kappaB and STAT3 signaling pathway. AB - Quercetin is a type of flavonoid compound, which has potent antioxidant and anti inflammatory activities, capable of treating a variety of diseases including neurodegenerative diseases, tumors, diabetes and obesity. The present study selected alcohol-induced liver injury model mice and aimed at studying the protective role of quercetin in preventing alcohol-induced liver injury. In alcohol-induced liver injury mice treated with quercetin, it was demonstrated that levels of aspartate transaminase, alanine transaminase, total bilirubin and triglyceride were reduced. In addition to this, the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were increased, malondialdehyde was inhibited, and interleukin (IL)-1beta, IL-6, IL-10 and inducible nitric oxide synthase were suppressed. Quercetin additionally suppressed the protein expression levels of B-cell lymphoma (Bcl)-2, Bcl-2 associated X apoptosis regulator, Caspase-3, poly ADP-ribose polymerase, and signal transducer and activator of transcription (STAT) 3 phosphorylation, nuclear factor (NF)-kappaB and protein kinase B (Akt) phosphorylation levels in alcohol-induced liver injured mice. These results suggested that the protective role of quercetin prevents alcohol-induced liver injury through the phosphoinositide 3-kinase/Akt/NF-kappaB and STAT3 pathway. PMID- 29285176 TI - Efficacy of continuous positive airway pressure treatment in treating obstructive sleep apnea hypopnea syndrome associated with carotid arteriosclerosis. AB - Sleep apnea negatively impacts patients' ability to oxygenate the bloodstream during sleep and has far-reaching, deleterious effects. The present study sought to assess the correlation between obstructive sleep apnea hypopnea syndrome (OSAHS), carotid atherosclerosis, and blood pressure variability (BPV), and to evaluate the therapeutic effects of continuous positive airway pressure (CPAP). Patients with OSAHS were classified as mild, moderate, or severe according to their condition and compared with healthy control participants. CPAP treatment was used to treat patients with OSAHS for 6 months. Prior to CPAP treatment, the apnea-hypopnea index (AHI), lowest blood oxygen saturation (LSaO2), carotid intima media thickness (IMT), and plasma levels of endothelin-1 (ET-1), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-alpha) were measured in all participants, along with the low frequency components of BPV (BPV LF). The results demonstrated that carotid IMT, AHI, plasma ET-1, and plasma TNF-alpha were significantly higher in patients with OSAHS than those in the control group (P<0.05); whereas LSaO2 and plasma NO levels were significantly higher in the control group (P<0.05). The degree to which these indices differed was associated with the severity of OSAHS. Furthermore, the carotid IMT of patients with OSAHS was significantly correlated with AHI (P=0.037), plasma ET-1 (P=0.001), plasma NO (P<0.001), BPV LF before retiring (P<0.001). Following CPAP treatment, the observation indices of patients with moderate or severe OSAHS improved significantly (P<0.01). These results support the use of CPAP to improve the significant vascular endothelial dysfunction, increased inflammatory response, and high blood pressure variability correlated with carotid atherosclerosis observed in patients with OSAHS. PMID- 29285178 TI - MicroRNA-520a suppresses the proliferation and mitosis of HaCaT cells by inactivating protein kinase B. AB - Psoriasis is a chronic inflammatory disease of the skin for which an effective treatment strategy remains to be developed. Characteristics of psoriasis include an altered differentiation of keratinocytes and hyperplasia of the skin. The present study aimed to investigate the role served by miR-520a in psoriasis. The results demonstrated that miR-520a inhibited the proliferation of HaCaT cells. miR-520a directly regulated the mRNA and protein expression of its target gene, protein kinase B (AKT). The siRNA silencing of AKT expression in these cells was also evaluated. miRNA-520a repressed the proliferation and mitotic entry of HaCaT cells, and promoted cell apoptosis. AKT silencing suppressed the proliferation of HaCaT cells. These results suggest that miRNA-520a regulates the survival of HaCaT cells by inhibiting AKT expression. miRNA-520a and AKT may therefore be novel targets for the treatment of patients with psoriasis. PMID- 29285177 TI - Anti-inflammatory effects of Simvastatin in patients with acute intracerebral hemorrhage in an intensive care unit. AB - Intracerebral hemorrhage is one of the most common types of cerebrovascular disease in humans and often causes paralysis, a vegetative state and even death. Patients with acute intracerebral hemorrhage are frequently monitored in intensive care units (ICUs). Spontaneous intracerebral hemorrhage is associated with a higher rate of mortality and morbidity than other intracephalic diseases. The expression levels of inflammatory factors have important roles in inflammatory responses indicative of changes in a patient's condition and are therefore important in the monitoring and treatment of affected patients at the ICU as well as the development of therapeutic strategies for acute cerebral hemorrhage. The present study investigated the anti-inflammatory effects of Simvastatin in patients with acute intracerebral hemorrhage at an ICU, and inflammatory factors and cellular changes were systematically analyzed. The plasma concentrations of inflammatory factors, including interleukin (IL)-4, IL 6, IL-8 and IL-10, were evaluated by ELISAs. The plasma concentrations of inflammatory cellular changes were detected by using flow cytometry. The results demonstrated that after Simvastatin treatment of patients with acute cerebral hemorrhage at the ICU, the plasma concentrations of IL-4, IL-6, IL-8 and IL-10 were downregulated compared with those in placebo-treated controls. In addition, Simvastatin treatment at the ICU decreased lymphocytes, granulocytes and mononuclear cells in patients with acute cerebral hemorrhage. The levels of inflammatory factors were associated with brain edema in patients with acute cerebral hemorrhage treated at the ICU. In addition, the amount of bleeding was reduced in parallel with the inflammatory cell plasma concentration of lymphocytes, granulocytes and mononuclear cells. Importantly, Simvastatin treatment produced beneficial outcomes by improving brain edema and reducing the amount of bleeding. In conclusion, the present study demonstrated the efficacy of Simvastatin in treating acute intracerebral hemorrhage and evidenced the association between inflammatory responses and the progress of affected patients at the ICU, thereby providing insight for applying effective therapies for patients with acute intracerebral hemorrhage. PMID- 29285179 TI - MicroRNA-219 exerts a tumor suppressive role in glioma via targeting Sal-like protein 4. AB - MicroRNAs (miRs) serve important roles in the development and progression of various human cancer types, including glioma. Recently, miR-219 has been suggested to function as a tumor suppressor in glioma; however, the underlying mechanism remains largely unknown. The aim of this study was to investigate the regulatory mechanism of miR-219 in the malignant phenotypes of glioma cells. Quantitative polymerase chain reaction (qPCR) and western blotting were conducted to examine the mRNA and protein expression. An MTT assay, wound healing assay and Transwell assay were used to study cell proliferation, migration and invasion. The qPCR data indicated that the expression of miR-219 was significantly decreased in glioma tissues compared with normal brain tissues. In addition, a low expression of miR-219 was identified to be associated with an advanced pathological grade. In vitro experiments demonstrated that miR-219 was also downregulated in several common glioma cell lines, including A172, U87, U251 and U373, when compared with that in normal astrocytes. Ectopic expression of miR-219 caused a significant decrease in U87 cell proliferation, migration and invasion. Luciferase reporter assay data indicated that Sal-like protein 4 (SALL4) was a direct target gene of miR-219, while the protein expression of SALL4 was negatively regulated by miR-219 in U87 cells. Furthermore, SALL4 was significantly upregulated in glioma tissues and cell lines, and upregulation of SALL4 was associated with a higher pathological grade. Furthermore, overexpression of SALL4 significantly attenuated the suppressive effects of miR 219 on U87 cell proliferation, migration and invasion, suggesting that miR-219 serves a suppressive role in glioma growth and metastasis via targeting SALL4. Therefore, the present study highlighted the clinical significance of the miR 219/SALL4 axis in glioma. PMID- 29285180 TI - Herpes zoster in patients with systemic lupus erythematosus: Clinical features, complications and risk factors. AB - Herpes Zoster (HZ) is reported as the most prevalent viral infection in patients with systemic lupus erythematosus (SLE). The aim of the present study was to investigate the clinical features, complications, and potential risk factors of HZ in patients with SLE from Southern China. A retrospective study was performed among patients with SLE admitted to the First Affiliated Hospital of Sun Yet-Sen University (Guangzhou, China) between 2009 and 2013. Demographic information, clinical and laboratory data, and medications used were collected and analyzed. A total of 48 instances of HZ from 46 individuals in a cohort of 1,265 SLE patients during the follow-up period were identified, with an overall prevalence of 3.6%. Complications occurred in 23.9% of patients with HZ (11/46). The risk of HZ was highest within 3-6 months following SLE diagnosis and reduced thereafter. The multivariate logistic regression analysis demonstrated that lymphopenia (OR=4.6; 95% CI=1.5-13.8; P=0.006) and treatment with high-dose glucocorticoids (GC; OR=4.3; 95% CI=1.6-11.7; P=0.004) were both significantly associated with occurrence of HZ. Lymphopenia was the only independent risk factor for the occurrence of complicated HZ (OR=15.2; 95% CI=2.7-85.1; P=0.002). There are some notable characteristics of HZ in patients with SLE in Southern China, such as the tendency to manifest in an early stage of SLE, and frequent complications with benign outcomes. The present data supported the role of lymphopenia and high-dose of GC therapy as risk factors for the occurrence of HZ. Lymphopenia was also shown to contribute to complicated HZ. PMID- 29285181 TI - Correlation between TSC1 gene polymorphism and epilepsy. AB - The correlation between tuberous sclerosis complex 1 (TSC1) gene polymorphism and epilepsy was studied. In total, 38 patients with epilepsy treated in People's Hospital of Rizhao from May 2015 to June 2016 were selected as study subjects, as the observation group, 38 healthy people in the same period were selected as the control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to study the polymorphism of TSC1 gene in the above study subjects. The mRNA expression of TSC1 gene in the observation group and the control group was measured by fluorescence quantitative PCR, the expression of TSC1 protein in the control and observation group was measured by western blotting and ELISA. The polymorphisms of TSC1 gene in control group and observation group were analyzed by PCR-RFLP. There were three genotypes of TCS1 gene locus 142 in healthy population: CC (79.3%), CA (13.9%) and AA (6.8%), there were also three genotypes at locus 142 in the observation group: CC (21.3%), CA (26.4%) and AA (52.3%), there was significant difference in the genotypes at locus 142 between healthy population and the patients with epilepsy (P<0.05). It was observed by fluorescence quantitative PCR that there was no significant difference in the mRNA expression of TSC1 gene between the control group and the observation group (P>0.05). The expression of TSC1 gene was detected by western blot method. Western blotting showed no significant difference in TSC1 protein expression between the two groups (P>0.05). However, by determining the activity of TSC1 protein in the observation group and the control group by ELISA, it was found that TSC1 activity in healthy human body (8.95+/-2.41 U/ml) was much lower than that in the patients with epilepsy (29.27+/-4.06 U/ml), the difference was statistically significant (P<0.05). It was found that locus 142 may be located at the active center of TSC1 enzyme by homology modeling of SWISS-MODEL, the mutation of locus 142 could lead to the change of TSC1 activity. The polymorphism of locus 142 in TSC1 gene is correlated with epilepsy, that is, the increase of CA and AA content in locus 142 leads to the occurrence of epilepsy. PMID- 29285182 TI - Effects of CASZI on bronchopulmonary development of neonatal rats. AB - The effect of CASZI on bronchopulmonary development in neonatal rats was investigated. Forty SD rats were randomly divided into the control group (n=20) and the experimental group (n=20) using a random number table. The experimental group was treated with hyperoxia to establish the bronchopulmonary dysplasia (BPD) model, while the control group received no treatment. At 14 days of experiment, rats in each group were treated, and lung tissues were taken for hematoxylin and eosin (H&E) staining. Radial alveolar count (RAC) and morphological changes in lung tissues were observed under a microscope, and the thickness of respiratory membrane was detected via IPP6 image. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect the expression levels of CASZI, Rho kinase, RhoA and ET-A receptor in lung tissues. There were no obviously pathological changes in lung tissues of neonatal rats in the control group, while BPD could be seen in lung tissue structures of neonatal rats in the experimental group. RAC in experimental group was significantly lower than that in the control group (P<0.05), and the thickness of respiratory membrane was significantly higher than that in the control group (P<0.05). CASZI mRNA expression level in the experimental group was significantly lower than that in control group (P<0.05), and Rho kinase, RhoA and ET-A receptor mRNA expression levels were significantly higher than those in the control group (P<0.05). CASZI protein expression level in the experimental group was significantly lower than that in the control group (P<0.05), and the Rho kinase, RhoA and ET-A receptor protein expression levels were significantly higher than those in the control group (P<0.05). In conclusion, CASZI expression was downregulated during the development of BPD. CASZI downregulation may have an effect on the pulmonary microvascular regeneration through RhoA/ROCK signaling pathway, thus participating in the pathogenesis of BPD. PMID- 29285183 TI - Targeting microRNA/UHRF1 pathways as a novel strategy for cancer therapy. AB - Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms. UHRF1 overexpression is observed in a number of solid tumors and hematological malignancies, and is considered a primary mechanism in inhibiting apoptosis. UHRF1 exerts its inhibitory activity on TSGs by binding to functional domains and therefore influences several epigenetic actors including DNA methyltransferase, histone deacetylase 1, histone acetyltransferase Tat interacting protein 60 and histone methyltransferases G9a and Suv39H1. UHRF1 is considered to control a large macromolecular protein complex termed epigenetic code replication machinery, in order to maintain epigenetic silencing of TSGs during cell division, thus enabling cancer cells to escape apoptosis. MicroRNAs (miRNAs) are able to regulate the expression of its target gene by functioning as either an oncogene or a tumor suppressor. In the present review, the role of tumor suppressive miRNAs in the regulation of UHRF1, and the importance of targeting the microRNA/UHRF1 pathways in order to induce the reactivation of silenced TSGs and subsequent apoptosis are discussed. PMID- 29285184 TI - Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer. AB - Human papillomaviruses (HPVs) are double stranded circular DNA viruses that infect cutaneous and mucosal epithelial cells. Almost 99% of cervical cancer has a HPV infection. The early oncoproteins E6 and E7 are important in this cellular transformation process. Epigenetic mechanisms have long been known to result in decisive alterations in DNA, leading to alterations in DNA-protein interactions, alterations in chromatin structure and compaction and significant alterations in gene expression. The enzymes responsible for these epigenetic modifications are DNA methyl transferases (DNMTs), histone acetylases and deacetylases. Epigenetics has an important role in cancer development by modifying the cellular micro environment. In this review, the authors discuss the role of HPV oncoproteins E6 and E7 in modulating the epigenetic mechanisms inside the host cell. The oncoproteins induce the expression of DNMTs which lead to aberrant DNA methylations and disruption of the normal epigenetic processes. The E7 oncoprotein may additionally directly bind and induce methyl transferase activity of the enzyme. These modulations lead to altered gene expression levels, particularly the genes involved in apoptosis, cell cycle and cell adhesion. In addition, the present review discusses how epigenetic mechanisms may be targeted for possible therapeutic interventions for HPV mediated cervical cancer. PMID- 29285185 TI - Crosstalk between the Notch signaling pathway and non-coding RNAs in gastrointestinal cancers. AB - The Notch signaling pathway is one of the main signaling pathways that mediates direct contact between cells, and is essential for normal development. It regulates various cellular processes, including cell proliferation, apoptosis, migration, invasion, angiogenesis and metastasis. It additionally serves an important function in tumor progression. Non-coding RNAs mainly include small microRNAs, long non-coding RNAs and circular RNAs. At present, a large body of literature supports the biological significance of non-coding RNAs in tumor progression. It is also becoming increasingly evident that cross-talk exists between Notch signaling and non-coding RNAs. The present review summarizes the current knowledge of Notch-mediated gastrointestinal cancer cell processes, and the effect of the crosstalk between the three major types of non-coding RNAs and the Notch signaling pathway on the fate of gastrointestinal cancer cells. PMID- 29285186 TI - Function of insulin-like growth factor 1 receptor in cancer resistance to chemotherapy. AB - Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options. PMID- 29285187 TI - Radiographic findings of hemolymphangioma in four patients: A case report. AB - Due to the rarity of hemolymphangioma, a limited number of cases of the disease have been reported in the literature thus far. The present case report describes the cases of 4 patients with hemolymphangioma that were diagnosed and treated at the Second Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China). All patients were female, with a mean age of 44.7 years and a mean duration of symptoms prior to diagnosis of 2.7 years. The diagnosis of hemolymphangioma was determined by postoperative histopathology in all patients. A total of 2 patients were diagnosed with tumors that exhibited cystic characteristics (one in the mediastinum and the other in the neck), which was determined by computed tomography and magnetic resonance imaging. Another of the patients' tumors was located in the left forearm, and 1 patient had multifocal hemolymphangioma in the mediastinum and spleen. All patients underwent surgery and were asymptomatic during the follow-up periods (range, 8-15 months). In the present case report, the radiographic findings of the 4 cases are presented, including the unusual imaging characteristics that were observed, and relevant reports in the literature are discussed. PMID- 29285188 TI - Nuclear expression of claudin-3 in human colorectal adenocarcinoma cell lines and tissues. AB - Claudins are members of a large family of transmembrane proteins, which are essential for the formation of tight junctions and have a significant effect on the biological behavior of tumor progression. Previous studies have demonstrated that several claudins show aberrant expression patterns in numerous types of cancer. The present study investigated the expression and localization of claudin 3 and claudin-7 in human colorectal adenocarcinoma cell lines and tissues. The protein expression levels of claudin-3 and claudin-7 were determined using immunocytochemical and immunohistochemical staining. Claudin-3, but not claudin 7, exhibited nuclear localization in the human colorectal adenocarcinoma Caco-2 and SW620 cell lines. Surgically resected colorectal adenocarcinoma tissue specimens were obtained, and the associations between the expression of claudin-3 or claudin-7 and various clinicopathological parameters were analyzed. The membranous expression rates of claudin-3 and claudin-7 were 58.0 and 50.0%, while their nuclear expression rates were 22.0 and 2.0%, respectively. The membranous expression of claudin-3 and claudin-7 was not associated with any clinicopathological factors, whereas the nuclear expression of claudin-3 was associated with histological type and was significantly increased in colorectal mucinous adenocarcinomas compared with that in well- to moderately-differentiated colorectal adenocarcinomas (P<0.01). However, no associations were observed between the nuclear expression of claudin-7 and any clinicopathological parameter. In conclusion, the nuclear expression of claudin-3 in colorectal mucinous adenocarcinoma may be involved in the biological transformation of tumors. The results from the present study indicated that claudin-3 is an important protein associated with histological type and has potential as a prognostic marker. Although the mechanisms underlying the nuclear localization of claudin-3 in tumorigenesis have not yet been elucidated in detail, the present results indicated the potential of claudin-3 as a histopathological biomarker for colorectal adenocarcinomas. PMID- 29285190 TI - Spontaneous remission of acute lymphoblastic leukemia: A case report. AB - Spontaneous remission (SR) in acute lymphoblastic leukemia (ALL) is a rare phenomenon, but the disease course and its underlying processes are of basic and clinical interest. Herein is reported the case of a pregnant, 31-year-old patient who developed ALL, followed by septic shock and SR of ALL. Information is summarized from earlier case reports and incidences of SR in ALL, to identify common patterns. Furthermore, the phenomenon of SR is compared with another disease variant of ALL, termed prodromal or preceding-ALL (pre-ALL). SR and the aleukemic phase in pre-ALL are associated with fever and/or sepsis and have similar kinetics and epidemiology. Therefore, pre-ALL not only closely resembles SR in ALL, but both conditions may represent a single disease entity. Production of pro-inflammatory cytokines and immune cell effects may induce temporary remission of ALL and the suppression of hematopoiesis. In contrast to SR in other types of cancer, all documented cases of SR in ALL were only transient. However, the disease can still be effectively treated with standard ALL therapies following relapse. PMID- 29285189 TI - Sulforaphane reverses gefitinib tolerance in human lung cancer cells via modulation of sonic hedgehog signaling. AB - Gefitinib is a targeted anticancer drug that was developed as an effective clinical therapy for lung cancer. Numerous patients develop gefitinib resistance in response to treatment. Sulforaphane (SFN) is present in cruciferous vegetables, and has been demonstrated to inhibit the malignant growth of various types of cancer cells. To investigate the role of SFN in gefitinib resistance, a gefitinib-tolerant PC9 (PC9GT) cell model was established by continually exposing PC9 cells to gefitinib. Cell viability was measured using a cell proliferation assay. Components of the sonic hedgehog (SHH) signaling pathway and markers of lung cancer stem cells were detected via western blotting. SFN markedly inhibited the proliferation of PC9GT and PC9 cells in a dose-dependent manner; combination SFN/gefitinib treatment also markedly decreased PC9GT cell proliferation, compared with SFN or gefitinib administered alone (P<0.05). Western blot analysis revealed that the expression of SHH, Smoothened (SMO), zinc finger protein GLI1 (GLI1), GLI2, CD133 and CD44 were upregulated in PC9GT cells, as compared with in PC9 cells. Furthermore, SFN markedly inhibited the expression of SHH, SMO and GLI1 in PC9GT and PC9 cells in a dose dependent manner, and SFN combined with gefitinib markedly inhibited the expression of SHH, SMO, GLI1, CD133 and CD44 in PC9GT cells when compared with SFN or gefitinib monotherapy. The results of the present study demonstrated that SFN inhibits the proliferation of gefitinib tolerant lung cancer cells via modulation of the SHH signaling pathway. Therefore, combined SFN and gefitinib therapy may be an effective approach for the treatment of lung cancer. PMID- 29285191 TI - CDKN1A-interacting zinc finger protein 1 is a novel biomarker for lung squamous cell carcinoma. AB - CDKN1A-interacting zinc finger protein 1 (CIZ1), a nuclear protein that participates in DNA replication, is involved in the pathogenesis of several types of cancer. However, the role of CIZ1 in lung squamous cell carcinoma (LSCC) is not fully understood. In the present study, the expression of CIZ1 in tissue microarrays and surgical samples of human LSCCs was examined. CIZ1 expression was found to be significantly increased in LSCC tissues compared with adjacent tissues or normal controls, whereas expression of a CIZ1-interacting protein, p21Cip1/Waf1, was decreased. CIZ1 staining intensity and CIZ1-positive vascular invasion were positively correlated with at least two categories of the Tumor Node-Metastasis (TNM) staging system (T stage, N stage or TNM stage). It was also observed that CIZ1 was specifically expressed in the vascular cells of LSCC tissues. These results indicate that overexpression of CIZ1 may contribute to the growth and angiogenesis of LSCC, thus CIZ1 could represent a biomarker for diagnosis and a target for therapeutic intervention. PMID- 29285192 TI - Ten-eleven translocation 1 dysfunction reduces 5-hydroxymethylcytosine expression levels in gastric cancer cells. AB - A sixth base, 5-hydroxymethylcytosine (5hmC), is formed by the oxidation of 5 methylcytosine (5mC) via the catalysis of the ten-eleven translocation (TET) protein family in cells. Expression levels of 5hmC are frequently depleted during carcinogenesis. However, the detailed mechanisms underlying the depletion of 5hmC expression in gastric cancer cells remains unclear, and further research is required. The present study examined the expression levels of 5mC and 5hmC and the expression levels of TET1 and TET2 in gastric cancer tissues using immunohistochemistry. The results revealed that 5hmC expression levels were markedly lower in gastric cancer tissues compared with corresponding adjacent normal tissues. Furthermore, a decrease in 5hmC expression levels was associated with a decrease in TET1 protein expression levels in gastric cancer tissues. The ectopic expression level of TET1 may increase the 5hmC expression level in gastric cancer cells. In addition, the results revealed that TET1 protein expression was markedly different in regards to subcellular localization, and mislocalization was significantly associated with the depletion of 5hmC expression levels in gastric cancer. Together, the results of the present study indicated that TET1 dysfunction reduces 5hmC expression levels, and this phenomenon may serve a crucial role in gastric cancer progression. PMID- 29285193 TI - Orbital alveolar soft part sarcoma: A report of 8 cases and review of the literature. AB - Alveolar soft part sarcoma (ASPS) is a rare soft tissue neoplasm. The incidence of orbital involvement is the highest in ASPS arising in the head and neck region. However, limited information is available regarding its clinical characteristics. The present study presents the clinical manifestations, imaging findings, pathological features, treatment strategies and prognosis records of 8 cases of orbital ASPS over the last 15 years in a single hospital, along with a review of the literature. Included were 3 male and 5 female patients, with the median age at presentation being 9.5 years. The mean average largest tumour diameter was 3.6 cm. A total of 5 patients underwent surgical excision of the tumour, with 2 undergoing orbital exenteration and 1 undergoing partial orbital exenteration. In total, 6 patients received postoperative radiotherapy and 2 received chemotherapy. Upon follow-up, 6 patients were doing well with no evidence of recurrence or metastasis. Local recurrence developed in 2 patients, of whom 1 succumbed following withdrawal from treatment. According to the present series and the cases mentioned in the literature, orbital alveolar soft part sarcoma has characteristics distinct from those of alveolar soft part sarcoma which arises in other locations. Orbital alveolar soft part sarcoma presents itself in a younger population with a shorter course of disease, smaller tumour size, improved prognosis, a marked association with the extraocular muscles and with the Ki-67 proliferation index possibly associated with prognosis of the disease. PMID- 29285194 TI - Combination of the neutrophil to lymphocyte ratio and the platelet to lymphocyte ratio as a useful predictor for recurrence following radiofrequency ablation of hepatocellular carcinoma. AB - The aim of the present study was to investigate the prognostic potential of a novel inflammation-based system, the combination of the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) (CNP), for predicting the survival time of patients with hepatocellular carcinoma (HCC) who had received radiofrequency ablation (RFA). A total of 287 HCC patients treated with RFA were enrolled in the study. Patients with an elevated NLR (>2.58) and an elevated PLR (>131.78) were allocated a score of 2, and patients exhibiting one or neither of these characteristics were allocated a score of 1 or 0, respectively. The association between the CNP and various HCC clinicopathological factors, patterns of recurrence and prognoses were analyzed. The CNP was associated with liver cirrhosis (P=0.015), Child-Pugh class (P=0.024), total bilirubin level (P=0.028), neutrophil count (P<0.001), lymphocyte count (P<0.001) and platelet count (P<0.001). Compared with their low-CNP counterparts, patients with an elevated CNP were more likely to develop distant intrahepatic recurrence [52.3% (CNP 2) vs. 33.9% (CNP 0) and 34.6% (CNP 1), P=0.015; CNP 0 vs. CNP 1, P=0.922; CNP 1 vs. CNP 2, P=0.020] and extrahepatic metastasis [25.0% (CNP 2) vs. 7.6% (CNP 0) and 18.5% (CNP 1), P=0.003; CNP 0 vs. CNP 1, P=0.020; CNP 1 vs. CNP 2, P=0.309], and had shorter overall survival (OS) time (CNP 0 vs. CNP 1, P<0.001; CNP 1 vs. CNP 2, P<0.001) and recurrence-free survival (RFS; CNP 0 vs. CNP 1, P=0.012; CNP 1 vs. CNP 2, P=0.004). Moreover, multivariate analysis revealed that the CNP was superior to the NLR and the PLR as an independent prognostic marker of OS and RFS. Therefore, it was concluded that the CNP may represent a useful predictor for recurrence and prognosis in patients with HCC treated with RFA. PMID- 29285195 TI - 14-3-3epsilon is a nuclear matrix protein, and its altered expression and localization are associated with curcumin-induced apoptosis of MG-63 cells. AB - The 14-3-3 protein family may regulates protein interaction, transportation and cellular localization. The regulatory role of 14-3-3epsilon is influenced by its altered localization. In the present study, human osteosarcoma MG-63 cells were treated with curcumin to induce apoptosis. Subsequently, the altered expression and localization of 14-3-3epsilon and its co-localization with other apoptosis associated proteins during apoptosis was investigated. Analysis of nuclear matrix proteins (NMPs), using two-dimensional gel electrophoresis with matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry, revealed that 14-3 3epsilon existed on the nuclear matrix of MG-63 cells, and its expression was decreased compared with that in control cells following curcumin treatment. In addition, western blot analysis validated that the expression level of 14-3 3epsilon was downregulated during curcumin-induced apoptosis of MG-63 cells compared with that in control cells. Using immunofluorescence labeling, it was observed that 14-3-3epsilon was located on the nuclear matrix of MG-63 cells and the distribution of 14-3-3epsilon on the nuclear matrix was decreased following treatment with curcumin, compared with that in control cells. Double immunofluorescence staining and laser-scanning confocal microscopy demonstrated that 14-3-3epsilon was co-localized with B-cell lymphoma-2 (Bcl-2), Bcl-2 associated-X protein, p53 and c-FOS transcription factor in MG-63 cells. Furthermore, following treatment with curcumin, these co-localization regions were decreased. The results of the present study revealed that 14-3-3epsilon is an NMP in MG-63 cells, and its altered expression and co-localization with apoptosis-associated proteins indicated an important function of 14-3-3epsilon in apoptosis of MG-63 cells. Additional studies are required to investigate the results of the present study. PMID- 29285196 TI - Identification of key miRNA-gene pairs in chronic lymphocytic leukemia through integrated analysis of mRNA and miRNA microarray. AB - The aim of the present study was to explore the miRNA-Gene regulatory mechanism in chronic lymphocytic leukemia (CLL), and identify new targets for the therapy of CLL. The miRNA expression dataset GSE62137 and mRNA expression dataset GSE22529 were downloaded from National Center of Biotechnology Information Gene Expression Omnibus database. In CLL samples compared with normal B cell samples, differentially expressed miRNAs (DEMs) were identified via the GEO2R instrument of GEO and differentially expressed genes (DEGs) were obtained via the limma package of R. Functional enrichment analysis of the DEGs was performed via the Database for Annotation, Visualization and Integrated Discovery. The targets of the DEMs were identified based on the miRNAWalk platform. The overlaps between the DEGs and the targets of the DEMs were selected, and the miRNA-Gene regulatory network was constructed based on the overlaps and the corresponding DEMs. A total of 63 DEMs and 504 DEGs were identified in CLL samples compared with normal B cell samples. Eleven enriched functional clusters of the DEGs were obtained. 405 miRNA-Gene regulatory pairs were identified. The miRNA-Gene regulatory pairs contained 351 target genes of the DEMs, including 9 overlaps with the DEGs. A miRNA-Gene regulatory network was constructed. Bioinformatics methods could help us develop a better understanding of the molecular mechanism of CLL. MiRNAs may play a critical role in regulating the process of CLL. They may affect CLL by regulating the processes of immunoreactivity and protein degradation. Genes such as Neurogenic Locus Notch Homolog Protein 2, PR/SET domain 4 and A-kinase anchoring protein 12 may be their regulating targets in CLL. PMID- 29285197 TI - Correlation of telomere length to malignancy potential in non-melanoma skin cancers. AB - Telomeres are associated with cell fate and aging through their role in the cellular response to stress and growth stimulation resulting from previous cell divisions and DNA damage. Telomere shortening has been observed in most human cancers, and is known to be a feature of malignancy. The aim of this study is to clarify whether telomere length is related to the malignant potential of non melanoma skin cancers. Telomere length was analyzed using tissue quantitative fluorescence in situ hybridization in 36 non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Bowen's disease (BD) and actinic keratosis (AK), and also in 26 samples of normal-appearing epidermal tissue surrounding or located close to each tumor. The fluorescence intensities of telomeres and centromeres within nuclei were determined, and the telomere centromere ratio (TCR) was then calculated in each sample. The resulting histograms suggested that the TCR values for each type of tumor cell were distributed in a lower range than those for epidermal cells located close to the corresponding tumor type, and that the TCR values for SCC and BCC cells were distributed in a lower range than those for BD and AK cells. These results were completely consistent with the potential for metastasis and invasion of each tumor type, suggesting that telomere length in non-melanoma skin cancer cells is intrinsically linked to their biological behavior. PMID- 29285198 TI - Total alkaloids of Corydalis saxicola bunting inhibits migration of A549 cells by suppressing Cdc42 or Vav1. AB - Cell division cycle 42 (Cdc42) is a critical regulator, which functions in cancer metastasis. Numerous previous studies have demonstrated that vav guanine nucleotide exchange factor 1 (Vav1) is ectopically expressed in numerous types of human malignancies and have suggested that Vav1 may efficiently promote the formation of invadopodia and matrix degradation by regulating the activation of Cdc42. Total alkaloids of Corydalis saxicola bunting (TAOCSB), a type of alkaloid compound extracted from the root of C. saxicola bunting, has been revealed to have anticancer properties. However, there is no available information to address the effects of TAOCSB on the metastasis of human lung cancer. In the present study, the anticancer effect on A549 non-small cell lung cancer cells induced by TAOCSB was investigated, as well as its underlying mechanisms. The results demonstrated that a low dose of TAOCSB exhibited anti-metastatic potential in suppressing the invasion and migration of A549 cells, and this action may be involved in TAOCSB-mediated inhibition of Cdc42 expression at the level of mRNA and protein in parallel with TAOCSB-mediated inhibition of matrix metalloproteinase (MMP)-2 and MMP-9 protein expression levels. Although the present study did not reveal the expression level of Vav1 protein in A549 cells, the expression level of Vav1 mRNA was investigated. The effect of Vav1 expression in A549 cells requires further study. Overall, the results of the present study revealed that TAOCSB may provide more information regarding lung cancer treatment. PMID- 29285199 TI - Overexpression of ADAM9 in oral squamous cell carcinoma. AB - Overexpression of a disintegrin and metalloproteinase 9 (ADAM9) has been shown in various types of cancer. Some studies have reported inconclusive findings regarding chromosomal aberrations in the ADAM9-containing region and ADAM9 expression in oral cancer. Therefore, in this study, ADAM9 protein expression was determined and compared between oral squamous cell carcinoma (OSCC) and normal oral tissues, and between oral cancer cell lines and human oral keratinocytes (HOKs). In total, 34 OSCC and 10 healthy paraffin-embedded tissue sections were probed with an anti-ADAM9 antibody, and the immunohistochemical score was determined by multiplying the percentage of positively stained cells with the intensity score. Four different oral cancer and eight independent HOK cell lines were cultured, and the expression of membrane ADAM9 and active ADAM9 at 84 kDa in these cell lines was assayed by flow cytometry and western blot hybridization, respectively. The results showed that the median immunohistochemical score of ADAM9 expression in OSCC tissues was significantly greater than that in normal tissues (P<0.001). Furthermore, among OSCC cases, intense staining of ADAM9 expression was detected in well-differentiated and in moderately-differentiated OSCC; ADAM9 expression was also correlated with an increased degree of cell differentiation (r=0.557; P=0.001). Expression of membrane ADAM9 was present in 3/4 cancer cell lines. Expression of active ADAM9 varied among all the tested cell lines, but significantly higher ADAM9 expression was present in certain cancer cell lines than those in HOKs (P<0.05). In summary, ADAM9 expression is enhanced in OSCC and oral cancer cell lines, suggesting its role in the pathogenesis of oral cancer. Similar to the overexpression of ADAM9 in well differentiated prostate cancer, high degrees of ADAM9 expression have also been observed in well-differentiated OSCC. PMID- 29285201 TI - Effects of HuR downregulation on anaplastic thyroid cancer cells. AB - Anaplastic thyroid cancer (ATC) constitutes one of the most aggressive types of human solid cancer, and is characterized by the absence of thyroid differentiation features and a marked degree of invasiveness. We have previously demonstrated that the RNA-binding protein Hu antigen R (HuR) is overexpressed in thyroid carcinoma; thus, the biological role of this RNA-binding protein was investigated in the present study using the ATC cell lines SW1736 and 8505C. In both cell lines, HuR protein levels were higher compared with in the non tumorigenic thyroid cell line Nthy-ori-3.1. HuR silencing by RNA interference in both ATC cell lines decreased cell viability, increased apoptosis rates and reduced the capability to form colonies in soft agar. Thus, HuR plays an important role in the proliferation and aggressiveness of ATC cells. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) was able to reduce the viability of ATC cells. The results demonstrated that SAHA was able to decrease HuR expression in SW1736 and 8505C cells. Furthermore, since it is known that the transcription factor nuclear factor (NF)-kappaB modulates HuR expression, whether SAHA affects the nuclear (active) fraction of NF-kappaB in ATC cells was investigated. The data suggested that SAHA decreases ATC cell viability by reducing the active form of NF-kappaB, which, in turn, modulates HuR expression. PMID- 29285200 TI - Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD-1 in infiltrating CD8+ T cells in patients with lung cancer. AB - The present study aimed to identify the level of programmed death-1 (PD-1) expression in infiltrating cluster of differentiation (CD)4+ and CD8+ T cells isolated from lung cancer tissues, and investigated whether the level of PD-1 expression may be directly regulated by lung cancer cells via prostaglandin E2 (PGE2)-associated signaling pathways in patients with lung cancer. A total of 75 patients with lung cancer were enrolled in the present study. The percentage of infiltrating CD4+ and CD8+ T cells was determined by flow cytometry. ELISA was performed to evaluate the concentration of PGE2 in lung cancer tissue homogenate. The correlation between PGE2 and PD-1 expression levels in CD8+ T cells was assessed by Spearman's rank correlation test. The expression levels of PD-1 and PGE2 receptors were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The level of PD-1 expression in infiltrating CD8+ T cells was gradually increased as the stage of lung cancer increased. The level of PD-1 expression was also positively associated with the concentration of PGE2 in lung cancer tissues. Furthermore, the level of PD-1 expression was closely associated with the PGE2/EP2 and PGE2/EP4 signaling pathways. The activation of PGE2-associated EP2- and EP4-pathways may positively regulate the level of PD-1 in infiltrating CD8+ T cells, which results in immune tolerance in the lung cancer microenvironment. PMID- 29285202 TI - Effective treatment of a patient with stage IV ovarian cancer: A case report. AB - The present case report describes a patient with stage IV ovarian cancer who survived for 9 years without achieving a complete remission since the first relapse. The patient's long-term survival may be ascribed to the slow growth of the cancer cells, limited metastasis and favorable responses to the treatments received. The patient manifested initially with malignant pleural effusion and was not able to tolerate surgical treatment. However, the disease was well controlled using various treatments, including neoadjuvant chemotherapy, interval cytoreductive surgery and post-operative long-term chemotherapy. Management of ovarian cancer is most effective when tailored to the individual needs of the patient, maximizing its efficacy and prolonging the patient's survival rate. The present case may offer useful insight into the clinical management of stage IV ovarian cancer. PMID- 29285203 TI - Anticancer effect of S-allyl-L-cysteine via induction of apoptosis in human bladder cancer cells. AB - To examine the anticancer effects of S-allyl-L-cysteine (SAC) in human bladder cancer cells and to identify possible molecular mechanisms, bladder cancer cell lines (HTB5, HTB9, JON, UMUC14, T24, and cisplatin resistant-T24R2) were incubated with SAC, and cell proliferation was measured using the Cell Counting Kit-8 assay and clonogenic assay. Cell cycle and apoptosis were evaluated by flow cytometry. Expression levels of apoptosis- and cell cycle-associated proteins were analyzed by western blotting. Proliferation and colony formation in bladder cancer cells was significantly inhibited by SAC treatment in a dose-dependent manner. SAC treatment significantly enhanced apoptosis and promoted a cell cycle arrest in the S phase. SAC also increased the expression of apoptosis-related genes, including caspases, poly (ADP-ribose) polymerase and cytochrome c. SAC had an anticancer effect on bladder cancer cells in vitro, at least partially, through the induction of apoptosis and a cell cycle arrest. SAC is a potential therapeutic agent for the treatment of bladder cancer. PMID- 29285204 TI - Surface Structure of TiO2 Rutile (011) Exposed to Liquid Water. AB - The rutile TiO2(011) surface exhibits a (2 * 1) reconstruction when prepared by standard techniques in ultrahigh vacuum (UHV). Here we report that a restructuring occurs upon exposing the surface to liquid water at room temperature. The experiment was performed in a dedicated UHV system, equipped for direct and clean transfer of samples between UHV and liquid environment. After exposure to liquid water, an overlayer with a (2 * 1) symmetry was observed containing two dissociated water molecules per unit cell. The two OH groups yield an apparent "c(2 * 1)" symmetry in scanning tunneling microscopy (STM) images. On the basis of STM analysis and density functional theory (DFT) calculations, this overlayer is attributed to dissociated water on top of the unreconstructed (1 * 1) surface. Investigation of possible adsorption structures and analysis of the domain boundaries in this structure provide strong evidence that the original (2 * 1) reconstruction is lifted. Unlike the (2 * 1) reconstruction, the (1 * 1) surface has an appropriate density and symmetry of adsorption sites. The possibility of contaminant-induced restructuring was excluded based on X-ray photoelectron spectroscopy (XPS) and low-energy He+ ion scattering (LEIS) measurements. PMID- 29285205 TI - Ion Pairing and Adsorption of Azo Dye/C16TAB Surfactants at the Air-Water Interface. AB - Mixed layers of 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonate (Sunset Yellow, SSY) and cetyltrimethylammonium bromide (C16TAB) at the air-water interface were studied using vibrational sum-frequency generation (SFG) and dynamic surface tension measurements. In the bulk, addition of C16TAB to SSY aqueous solution causes substantial changes in UV/vis absorption spectra, which originate from strong electrostatic interactions between the anionic SSY azo dye with the cationic C16TAB surfactant. These interactions are a driving force for the formation of SSY/C16TAB ion pairs. The latter are found to be highly surface active while free SSY molecules show no surface activity. Dynamic SFG as well as surface tension measurements at low SSY concentrations reveal that free C16TAB surfactants adsorb at the air-water interface on time scales <1 s where they initially form the dominating surface species, but on longer time scales free C16TAB is exchanged by SSY/C16TAB ion pairs. This causes a dramatic reduction of the surface tension to 35 mN/m but also in foam stability. These changes are accompanied by a substantial loss in SFG intensity from O-H stretching bands around 3200 and 3450 cm-1, which we relate to a decrease in surface charging due to adsorption of ion pairs with no or negligible net charges. For SSY/C16TAB molar ratios >0.5, the O-H bands in SFG spectra are reduced to very low intensities and are indicative to electrically neutral SSY/C16TAB ion pairs. This conclusion is corroborated by an analysis of macroscopic foams, which become highly instable in the presence of neutral SSY/C16TAB ion pairs. From an analysis of SFG spectra of air-water interfaces, we show that the electrostatic repulsion forces inside the ubiquitous foam films are reduced and thus remove the major stabilization mechanism within macroscopic foam. PMID- 29285206 TI - Targeting macrophages to treat intracranial aneurysm. PMID- 29285207 TI - Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer's disease. AB - Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer's Disease Neuroimaging Initiative (mean follow-up 50.5+/-30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss >= 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/ADelta42 ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2 year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/ADelta42 ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non cognitive manifestation of pre-clinical AD. PMID- 29285208 TI - Rab coupling protein mediated endosomal recycling of N-cadherin influences cell motility. AB - Rab coupling protein (RCP) is a Rab GTPase effector that functions in endosomal recycling. The RCP gene is frequently amplified in breast cancer, leading to increased cancer aggressiveness. Furthermore, RCP enhances the motility of ovarian cancer cells by coordinating the recycling of alpha5beta1 integrin and EGF receptor to the leading edge of migrating cells. Here we report that RCP also influences the motility of lung adenocarcinoma cells. Knockdown of RCP inhibits the motility of A549 cells in 2D and 3D migration assays, while its overexpression enhances migration in these assays. Depletion of RCP leads to a reduction in N-cadherin protein levels, which could be restored with lysosomal inhibitors. Trafficking assays revealed that RCP knockdown inhibits the return of endocytosed N-cadherin to the cell surface. We propose that RCP regulates the endosomal recycling of N-cadherin, and in its absence N-cadherin is diverted to the degradative pathway. The increased aggressiveness of tumour cells that overexpress RCP may be due to biased recycling of N-cadherin in metastatic cancer cells. PMID- 29285209 TI - Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells. AB - FOXP3+ regulatory T cell (Treg) based cellular therapies represent promising therapeutic options in autoimmunity, allergy, transplantation and prevention of Graft Versus Host (GVH) Disease. Among human FOXP3-expressing CD4+T cells, only the CD45RA+ naive Treg (nTreg) subset is suitable for in vitro expansion. However, FoxP3 expression decays in cells using currently described culture protocols. Rapamycin alone was not able to prevent FOXP3 loss in nTregs cells, as only a half of them maintained FOXP3 expression after 14 days of culture. In contrast we report a novel combined drug regimen that can drastically stabilize FOXP3 expression in cultured Tregs. IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors act in synergy to allow expansion of human regulatory T cells with sustained high expression of FOXP3 and CD15s with potent suppressive capacities in vitro and control of murine xeno-GVH reactions. Of note, an additional subsequent infusion of expanded nTreg cells did not improve survival of mice. Combination of IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors is optimal for the expansion in vitro of pure effective nTreg maintaining high levels of FOXP3 for therapeutic purposes. PMID- 29285210 TI - Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti angiogenic and anti-cancer agents. AB - Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR 2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents. Among them, QDAU5 displayed the most promising potency and selectivity. It significantly suppressed viability of EA.hy926 and proliferation of several cancer cells. Further investigations indicated that QDAU5 showed high affinity to VEGFR-2 and reduced the phosphorylation of VEGFR-2. We identified QDAU5 as a potent multiple RTKs inhibitor exhibiting prominent anti-angiogenic and anticancer potency both in vitro and in vivo. Moreover, quinazolin-4(3H)-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4. PMID- 29285211 TI - Molecular analyses of prostate tumors for diagnosis of malignancy on fine-needle aspiration biopsies. AB - Prostate cancer (PCa) is a common cancer and remains the second-leading cause of cancer-associated mortality in men, but diagnosis of PCa remains a main clinical challenge. To investigate the involvement of differentially expressing genes in PCa with deregulated pathways to allow earlier diagnosis of the disease, transcriptomic analyses of differential expression genes in fine-needle aspiration (FNA) biopsies helped to discriminate PCa from benign prostatic hyperplasia (BPH). We identified 255 genes that were deregulated in prostate tumors compared with BPH tissues. qRT-PCR was conducted to examine the expression levels of the four genes in FNA biopsies and confirmed that ITGBL1 was significantly up-regulated and HOXA7, KRT15 and TGM4 were down-regulated in the PCa compared to the BPH, with a sensitivity of 87.1% and a specificity of 87.8%; the area under the receiver operating characteristic curve was estimated at 0.94, which was significantly improved compared with PSA alone (AUC = 0.82). Moreover, the increased expression of ITGBL1 correlated with total cholesterol, triglyceride and PSA. Our results demonstrated that transcriptomic analyses in FNA biopsies could facilitate rapid identification of potential targets for therapy and diagnosis of PCa. PMID- 29285212 TI - Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity. AB - Chronic inflammation precedes the majority of hepatocellular carcinoma (HCC) cases. We investigated the chemopreventive potential of S-adenosylmethionine (SAM), an essential donor for all methylation reactions in the cell, at the late precancerous stage of HCC development using the Mdr2-knockout (Mdr2-KO, Abcb4-/-) mice, a model of inflammation-mediated hepatocarcinogenesis. Previously, we revealed down-regulation of the genes regulating SAM metabolism in the liver of these mice at the precancerous stages. Now, we have supplied Mdr2-KO mice at the late precancerous stage with SAM during either a short-term (17 days) or a long term (51 days) period and explored the effects of such supplementation on tumor development, DNA methylation and gene expression in the liver. The short-term SAM supplementation significantly decreased the number of small tumor nodules, proliferating hepatocytes and the total DNA methylation level, while it increased expression of the tumor suppressor proteins Mat1a and p21. Surprisingly, the long term SAM supplementation did not affect tumor growth and hepatocyte proliferation, while it increased the total liver DNA methylation. Our results demonstrate that the short-term SAM supplementation in the Mdr2-KO mice inhibited liver tumor development potentially by increasing multiple tumor suppressor mechanisms resulting in cell cycle arrest. The long-term SAM supplementation resulted in a bypass of the cell cycle arrest in this HCC model by a yet unknown mechanism. PMID- 29285213 TI - Clinicopathological features and prognosis of malignant peripheral nerve sheath tumor: a retrospective study of 159 cases from 1999 to 2016. AB - Objective: To investigate the clinicopathological features and prognosis of malignant peripheral nerve sheath tumors (MPNST). Results: A total of 159 patients with MPNST were enrolled in the study. The ratio of male to female was 1.04 to 1. The median age was 40 (range: 5-76) years at the time of diagnosis. The 3- and 5-year overall survival rates were 50.0% and 43.0%, respectively. The median follow-up period was 31.0 (range: 2.0-199.0) months. Multivariate analysis showed that AJCC stage and S-100 were independent factors affecting overall survival (p < 0.05 for both). 3- and 5-year tumor-free survival rates for 140 completely resected patients were 40.0% and 34.0%, respectively. Multivariate analysis showed that AJCC stage, S-100 and Ki67 staining were independent factors of tumor-free survival (p < 0.05 for all). Materials and Methods: The clinical data of MPNST patients who were treated at Cancer Institute and Hospital, Chinese Academy of Medical Science from January 1999 to January 2016 was retrospectively reviewed. Conclusions: MPSNT is a highly aggressive tumor with poor prognosis and this study may be useful for prognostic assessment and management decisions. This had been largest documented retrospective study of MPSNT among Chinese populations. Some characteristics were different from those of foreign populations which may suggest the specificity of Chinese patients. PMID- 29285214 TI - mRNA expression profiles obtained from microdissected pancreatic cancer cells can predict patient survival. AB - Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating malignancies in developed countries because of its very poor prognosis and high mortality rates. By the time PDAC is usually diagnosed only 20 25% of patients are candidates for surgery, and the rate of survival for this cancer is low even when a patient with PDAC does undergo surgery. Lymph node invasion is an extremely bad prognosis factor for this disease. Methods: We analyzed the mRNA expression profile in 30 PDAC samples from patients with resectable local disease (stages I and II). Neoplastic cells were isolated by laser-microdissection in order to avoid sample 'contamination' by non-tumor cells. Due to important differences in the prognoses of PDAC patients with and without lymph node involvement (stage IIB and stages I-IIA, respectively), we also analyzed the association between the mRNA expression profiles from these groups of patients and their survival. Results: We identified expression profiles associated with patient survival in the whole patient cohort and in each group (stage IIB samples or stage I-IIA samples). Our results indicate that survival associated genes are different in the groups with and without affected lymph nodes. Survival curves indicate that these expression profiles can help physicians to improve the prognostic classification of patients based on these profiles. PMID- 29285215 TI - Depression and its impact on health-related quality of life among Chinese inpatients with lung cancer. AB - Depression is of great concern for patients with cancer. A detailed epidemiological profile of depression in Chinese patients with lung cancer and whether depression impacts patients' health-related quality of life (HRQOL) remain unknown. This study examined the prevalence and socio-demographic and clinical correlates of depression and its effect on HRQOL in Chinese inpatients with lung cancer of two large general hospitals. A total of 148 inpatients were consecutively recruited, and administered with a standardized questionnaire to collect socio-demographic and clinical data. Depression and HRQOL were assessed with the Hospital Anxiety and Depression Scale and World Health Organization QOL Scale Brief Version, respectively. As high as 43.2% Chinese inpatients with lung cancer had clinically significant depressive symptoms. Multiple logistic regression found that depression was significantly associated with moderate-to severe pain (OR: 4.43), metastatic cancer (OR: 3.63), a short duration after cancer diagnosis (OR: 1.04), poor performance status (OR: 3.41), and small-cell cancer (OR: 4.52). Depressed patients had significantly poorer HRQOL than not depressed patients in terms of all four domains of HRQOL. After controlling for the potential confounding effects of socio-demographic and clinical factors with analysis of covariance, these group-differences in physical (F = 29.074, P < 0.001), psychological (F = 76.869, P < 0.001), social (F = 21.465, P < 0.001), and environmental (F = 27.685, P < 0.001) HRQOL remained statistically significant. Depression is prevalent in inpatients with lung cancer and independently associated with poor HRQOL. To address this serious issue, effective pain management, psycho-oncology services and, when necessary, psychiatric assessment and treatment, should be routinely provided in oncology departments of Chinese general hospitals. PMID- 29285216 TI - Lamin B2 binding to minichromosome maintenance complex component 7 promotes non small cell lung carcinogenesis. AB - We investigated the role of lamin B2 in non-small cell lung cancer (NSCLC). We detected higher lamin B2 expression in 20 NSCLC tumor tissues obtained from The Cancer Genome Atlas than in adjacent normal lung tissues. LMNB2-RNAi knockdown in A549 and H1299 NSCLC cells inhibited colony formation, cell proliferation and G1 S cell cycle progression while increasing apoptosis. LMNB2 overexpression had the opposite effects. Tumor xenograft experiments showed diminished tumor growth with LMNB2 knockdown H1299 cells than with controls. Yeast two-hybrid studies revealed minichromosome maintenance complex component 7 (MCM7) to be a binding partner of lamin B2, which was confirmed by co-immunoprecipitation and co-localization studies. Lamin B2 binding enhanced DNA binding and helicase activities of MCM7. Deletion analysis with MCM7-N, MCM7-M or MCM7-C mutant proteins showed that lamin B2 binds to the C-terminus of MCM7, and competes with the binding of the tumor suppressor retinoblastoma (RB) protein. Immunohistochemical analysis of 150 NSCLC patient samples revealed that both lamin B2 and MCM7 levels positively correlated with histological grade and tumor TNM stage. Moreover, high lamin B2 and MCM7 levels correlated with shorter overall survival of NSCLC patients. In sum, these results show that lamin B2 interaction with MCM7 promotes NSCLC progression. PMID- 29285217 TI - Identification of novel gene expression signature in lung adenocarcinoma by using next-generation sequencing data and bioinformatics analysis. AB - Lung adenocarcinoma is one of the leading causes of cancer-related death worldwide. We showed transcriptomic profiles in three pairs of tumors and adjacent non-tumor lung tissues using next-generation sequencing (NGS) to screen protein-coding RNAs and microRNAs. Combined with meta-analysis from the Oncomine and Gene Expression Omnibus (GEO) databases, we identified a representative genetic expression signature in lung adenocarcinoma. There were 9 upregulated genes, and 8 downregulated genes in lung adenocarcinoma. The analysis of the effects from each gene expression on survival outcome indicated that 6 genes (AGR2, SPDEF, CDKN2A, CLDN3, SFN, and PHLDA2) play oncogenic roles, and 7 genes (PDK4, FMO2, CPED1, GNG11, IL33, BTNL9, and FABP4) act as tumor suppressors in lung adenocarcinoma. In addition, we also identified putative genetic interactions, in which there were 5 upregulated microRNAs with specific targets - hsa-miR-183-5p-BTNL9, hsa-miR-33b-5p-CPED1, hsa-miR-429-CPED1, hsa-miR-182-5p FMO2, and hsa-miR-130b-5p-IL33. These 5 microRNAs have been shown to be associated with tumorigenesis in lung cancer. Our findings suggest that these genetic interactions play important roles in the progression of lung adenocarcinoma. We propose that this molecular change of genetic expression may represent a novel signature in lung adenocarcinoma, which may be developed for diagnostic and therapeutic strategies in the future. PMID- 29285218 TI - Doxycycline inhibits breast cancer EMT and metastasis through PAR-1/NF-kappaB/miR 17/E-cadherin pathway. AB - Doxycycline displays high efficiency for cancer therapy. However, the molecular mechanism is poorly understood. In our previous study, doxycycline was found to suppress tumor progression by directly targeting proteinase-activated receptor 1 (PAR1). In this study, microRNAs were found to be involved in PAR1-mediated anti tumor effects of doxycycline. Among these miRNAs, miR-17 was found to promote breast cancer cell metastasis both in vivo and in vitro. Moreover, miR-17 could reverse partial doxycycline inhibition effects on breast cancer. Employing luciferase and chromatin immunoprecipitation assays, nuclear factor-kappaB (NF kappaB) was found to bind miR-17 promoters. Furthermore, E-cadherin was identified as the target gene of miR-17. These results showed that miR-17 can resist the inhibitory effects of doxycycline on breast cancer epithelial mesenchymal transformation (EMT) by targeting E-cadherin. PMID- 29285219 TI - MicroRNA-200a activates Nrf2 signaling to protect osteoblasts from dexamethasone. AB - Treatment with dexamethasone in human osteoblasts leads to oxidative stress and cell injures. NF-E2-related factor 2 (Nrf2) is a key anti-oxidant signaling. We want to induce Nrf2 activation via microRNA-mediated silencing its suppressor Keap1. Our results show that microRNA-200a ("miR-200a") expression depleted Keap1, causing Nrf2 protein stabilization in OB-6 osteoblastic cells. Reversely, the miR-200a anti-sense led to Keap1 upregulation and Nrf2 degradation. miR-200a expression activated Nrf2 signaling, which inhibited dexamethasone-induced reactive oxygen species production and OB-6 cell death/apoptosis. Keap1 shRNA also activated Nrf2 and protected OB-6 cells from dexamethasone. Importantly, miR 200a was in-effective in Keap1-silenced (by shRNA) OB-6 cells. In the primary human osteoblasts, Keap1 silence by targeted-shRNA or miR-200a protected cells from dexamethasone. Significantly, miR-200a level was decreased in necrotic femoral head tissues, which was correlated with Keap1 mRNA upregulation. Together, miR-200a expression activates Nrf2 signaling and protects human osteoblasts from dexamethasone. PMID- 29285220 TI - Dietary polyphenols influence antimetabolite agents: methotrexate, 6 mercaptopurine and 5-fluorouracil in leukemia cell lines. AB - Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6 mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis. Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines. This was associated with reduced DNA damage and increased glutathione levels, greater than that seen following individual treatments alone. In contrast, 5-fluorouracil when combined with quercetin, apigenin and rhein caused synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis in some leukemia cell lines. However, antagonistic effects were observed when 5-fluorouracil was combined with rhein and cis-stilbene in myeloid cell lines. The effects were dependant on polyphenol type and chemotherapy agent investigated, and cell type treated. Interestingly treatment of non-tumor control cells with polyphenols protected cells from antimetabolite treatments. This suggests that polyphenols modulate the action of antimetabolite agents; more importantly they antagonized methotrexate and 6-mercaptopurine actions, thus suggesting the requirement of polyphenol exclusion during their use. PMID- 29285221 TI - A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib. AB - Triple negative breast cancers (TNBC) have poor prognosis compared to other breast cancer subtypes and represent 15-20% of breast cancers diagnosed. Unique targets and new molecularly-targeted therapies are urgently needed for this subtype. Despite high expression of Epidermal Growth Factor Receptor, inhibitors such as lapatinib have not shown therapeutic efficacy in TNBC patients. Herein, we report that treatment with the covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death, while these compounds as single agents have little effect. The combination significantly increases survival of mice bearing xenografts of MDA-MB-231 human TNBC cells. Our studies demonstrate that lapatinib treatment increases c-Jun and JNK phosphorylation indicating a mechanism of resistance. Combined, these compounds significantly reduce transcriptional activity of Nuclear Factor kappa B, Activating Protein 1, and Nuclear factor erythroid 2-Related Factor 2. As master regulators of antioxidant response, their decreased activity induces a 10-fold increase in reactive oxygen species that is cytotoxic, and is rescued by addition of exogenous antioxidants. Over expression of p65 or Nrf2 also significantly rescues viability during JNK-IN-8 and lapatinib treatment. Further studies combining JNK-IN-8 and lapatinib may reveal a benefit for patients with TNBC, fulfilling a critical medical need. PMID- 29285222 TI - A primary tumor gene expression signature identifies a crucial role played by tumor stroma myofibroblasts in lymph node involvement in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is the most common oral and pharyngeal cancer, and is responsible of approximately 3% of cancers in men and 2% in women in the Western World, with increasing incidence rates in developing countries. Early detection by screening is necessary to prevent fatal disease because early, curable lesions are rarely symptomatic. The overall 5-yr survival rate is approximately 50% when surgery, radiation, or both are employed as treatment options, but lymph node involvement greatly influences this estimate, by decreasing the survival rate by about 50%. Here, we aimed at finding genetic signatures associated with lymph node metastasis in OSCC patients. We addressed this issue by whole transcriptome analysis through microarray expression profiling of a set of OSSC specimens of patients without lymph node involvement (10 patients, mean age +/- SD 61.2+/-13.8, male 7, female 3) and with lymph node involvement (11 patients, mean age +/- SD 62.1+/-15.1, male 8, female 3). We evidenced a gene expression signature associated to muscle contraction-related genes in specimens obtained from OSCC patients with lymph node involvement. This gene signature suggests the presence of myofibroblasts in tumor stoma of patients with lymph node involvement and emphasizes the decisive role played by myofibroblasts probably through their secretome in determining OSCC invasiveness. PMID- 29285223 TI - A CARP-1 functional mimetic loaded vitamin E-TPGS micellar nano-formulation for inhibition of renal cell carcinoma. AB - Current treatments for Renal Cell Carcinoma (RCC) include a combination of surgery, targeted therapy, and immunotherapy. Emergence of resistant RCCs contributes to failure of drugs and poor prognosis, and thus warrants development of new and improved treatment options for RCCs. Here we generated and characterized RCC cells that are resistant to Everolimus, a frontline mToR targeted therapy, and tested whether our novel class of CARP-1 functional mimetic (CFM) compounds inhibit parental and Everolimus-resistant RCC cells. CFMs inhibited RCC cell viability in a dose-dependent manner that was comparable to Everolimus treatments. The GI50 dose of Everolimus for parental A498 cells was ~1.2MUM while it was <0.02MUM for the parental UOK262 and UOK268 cells. The GI50 dose for Everolimus-resistant A498, UOK262, and UOK268 cells were >=10.0MUM, 1.8 7.0MUM, and 7.0->=10.0MUM, respectively. CFM-4 and its novel analog CFM-4.16 inhibited viabilities of Everolimus resistant RCC cells albeit CFM-4.16 was more effective than CFM-4. CFM-dependent loss of RCC cell viabilities was due in part to reduced cyclin B1 levels, activation of pro-apoptotic, stress-activated protein kinases (SAPKs), and apoptosis. CFM-4.16 suppressed growth of resistant RCC cells in three-dimensional suspension cultures. However, CFMs are hydrophobic and their intravenous administration and dose escalation for in-vivo studies remain challenging. In this study, we encapsulated CFM-4.16 in Vitamin-E TPGS based- nanomicelles that resulted in its water-soluble formulation with higher CFM-4.16 loading (30% w/w). This CFM-4.16 formulation inhibited viability of parental and Everolimus-resistant RCC cells in vitro, and suppressed growth of parental A498 RCC-cell-derived xenografts in part by stimulating apoptosis. These findings portent promising therapeutic potential of CFM-4.16 for treatment of RCCs. PMID- 29285224 TI - Soluble chemokine (C-X-C motif) ligand 16 (CXCL16) in urine as a novel biomarker candidate to identify high grade and muscle invasive urothelial carcinomas. AB - Information on biomarkers of urothelial carcinomas (UC) for clinical decision making is limited. Here, we newly identified and verified CXCL16 as a promising novel biomarker in urine for high grade and muscle invasive UC in a cross sectional cohort of 308 UC patients, 126 urological hospital controls, and 50 population controls using antibody arrays and ELISA. Median CXCL16 levels in urine was significantly higher in UC patients (273.2 pg/mg creatinine) compared to hospital (148.1 pg/mg) and population controls (85.1 pg/mg) with a particular preference for high grade (460.8 pg/mg), muscle invasive (535.7 pg/mg) and primary UC (327.8 pg/mg) (all p<0.0001). Group differences were confirmed after adjusting or stratifying for potential clinical and individual characteristics, such as leukocyte counts, haematuria, age, gender, and smoking status. In contrast, CXCL16 showed less discriminating power in low grade (244.3 pg/mg), non muscle invasive (<=pT1, 251.2 pg/mg) and recurrent UC (203.9 pg/mg). In agreement with its function in immune defence, expression of CXCL16 in tissue samples of primary UC patients (n=53) showed only a weak or no immunoreactivity compared to urological hospital controls (n=32). Expression of CXCR6, the G-protein-coupled receptor of CXCL16, remained unchanged. Our findings suggest that evading the immune defence by shedding cell-surface CXCL16 and its increased elimination in urine is a molecular feature of high grade and muscle invasive UC. Therefore, urinary CXCL16 may serve as a useful, simple and non-invasive tool to identify high-risk UC with increased risk of progression at the molecular level. PMID- 29285225 TI - The protective value of miR-204-5p for prognosis and its potential gene network in various malignancies: a comprehensive exploration based on RNA-seq high throughput data and bioinformatics. AB - Purpose: The prognostic role of miR-204-5p (previous ID: miR-204) is varied and inconclusive in diverse types of malignant neoplasm. Therefore, the purposes of the study comprehensively explore the overall prognostic role of miR-204-5p based on high-throughput microRNA sequencing data, and to investigate the potential role of miR-204-5p via bioinformatics approaches. Materials and Methods: The data of microRNA sequencing and survival were downloaded from The Cancer Genome Atlas (TCGA), and the prognostic value of miR-204-5p was analyzed by using Kaplan-Meier and univariate cox regressions. Then a meta-analysis was conducted with all TCGA data and relevant studies collected from literature. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. The prospective molecular mechanism of miR-204-5p was also assessed at a functional level with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-to protein interactions (PPI) network. Results: From TCGA data, the prognostic value of miR-204-5p obviously varied among 20 types of cancers. The pooled HR was 0.928 (95% CI: 0.774-1.113, P = 0.386, 6203 cases of malignancies). For the meta analysis based on 15 studies from literature, the pooled HR was 0.420 (95% CI: 0.306-0.576, P < 0.001, 1783 cases of malignancies) for overall survival (OS). Furthermore, the combined HR from both TCGA and literature was 0.708 (95% CI: 0.600-0.834, P < 0.001, 7986 cases of malignancies). Subgroup analyses revealed that miR-204-5p could act as a prognostic marker in cancers of respiratory system and digestive system. Functional analysis was conducted on genes predicted as targets (n = 2057) after the overlay genes from six out of twelve software were extracted. Two significant KEGG pathways were enriched (hsa04360: Axon guidance and hsa04722: Neurotrophin signaling pathway). PPI network revealed some hub genes/proteins (CDC42, SOS1, PIK3R1, MAPK1, PLCG1, ESR1, MAPK11, and AR). Conclusions: The current study demonstrates that over-expression of miR-204-5p could be a protective factor for a certain group of cancers. Clinically, the low miR-204-5p level could gain a predictive value for a poor survival in cancers of respiratory system and digestive system. The detailed molecular mechanisms of miR 204-5p remain to be verified. PMID- 29285226 TI - Parity improves anti-tumor immunity in breast cancer patients. AB - Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy. To this end, we collected peripheral blood from healthy nulliparous, primigravid and parous women, as well as from breast cancer patients. IFN-gamma ELISpot assays were performed to measure the intensity and specificity of T cell responses against 11 different TAA. The impact of TAA-specific Treg cells on anti-TAA responses was assessed by performing the assay before and after depletion of CD4+CD25+ T cells. The antigenic specificities of these Treg cells were analyzed by the Treg specificity assay. Furthermore, we conducted flow cytometric analyses to determine the memory phenotype and cytokine secretion profile of TAA-specific T cells. Our results demonstrate that pregnancy induces functional and long-lived memory and effector T cells that react against multiple TAA. These persist for many decades in parous females, but are not found in age-matched females without children. We also detected TAA-specific Treg cells, which suppressed strong effector T cell responses after delivery. Nulliparous breast cancer patients displayed median TAA-specific effector T cell responses to be decreased threefold compared to parous patients, which could be restored in vitro after depletion of Treg cells. PMID- 29285227 TI - Effects of trimetazidine on periprocedural microRNA-21 expression by CD4+ T lymphocytes in patients with unstable angina pectoris. AB - Objective: Post-percutaneous coronary intervention (PCI) myocardial injury is related to the CD4+ T lymphocyte-mediated inflammatory response. microRNA-21 expression is associated with CD4+ T lymphocyte activation. The pre-PCI use of trimetazidine prevents periprocedural myocardial injury and reduces inflammatory cytokine levels. This study aimed to assess the effects of trimetazidine on periprocedural microRNA-21 expression by CD4+ T lymphocytes in patients with unstable angina pectoris. Methods: A total of 252 patients with unstable angina pectoris were randomized to the trimetazidine (60 mg/d, administered 3 days before PCI, n=128) and control (no trimetazidine, n=124) groups. Serum CK-MB, cTnI, and hs-CRP levels were tested pre-PCI and 16-24 h post-PCI. Peripheral blood CD4+ T lymphocytes were isolated by magnetic activated cell sorting. Quantitative polymerase chain reaction was used to assess microRNA-21 and PDCD4 mRNA expression levels in CD4+ T lymphocytes, and western blot was used to evaluate PDCD4 protein expression. Enzyme-linked immunosorbent assay was used to assess serum TNF-alpha and IL-10 levels. Results: Compared with the control group, the trimetazidine group had a lower frequency of patients with post-PCI serum CK-MB and cTnI levels higher than normal values; the trimetazidine group had also significantly lower serum hs-CRP and TNF-alpha levels, and higher IL-10 levels post-PCI. Finally, the trimetazidine group had significantly lower PDCD4 expression and higher microRNA-21 levels in CD4+ T lymphocytes post-PCI. Conclusions: Trimetazidine reduces the incidence of periprocedural myocardial injury, possibly by increasing microRNA-21 levels in CD4+ T lymphocytes and inhibiting PDCD4-mediated inflammatory response. PMID- 29285228 TI - Four-month course of adjuvant dabrafenib in patients with surgically resected stage IIIC melanoma characterized by a BRAFV600E/K mutation. AB - Background: We tested the hypothesis that a 4-month course of adjuvant dabrafenib in stage IIIC BRAF-mutated melanoma would improve 2 year RFS from 24% to 51%, and that tumor-derived cell free DNA (cfDNA) in plasma would correlate with and predict recurrence. Methods: Patients with stage IIIC BRAF V600E/K mutated melanoma who were free of disease after surgical resection received 4 months of adjuvant dabrafenib. Patients were evaluated with imaging at baseline, at the end of cycles 2, 4, 6, then every 3 months until disease relapse or 2 years, whichever came first. Serial blood samples were collected for evaluation of cfDNA at the same time. Results: 21/23 patients enrolled were evaluable; 2 patients withdrew consent during the first week of treatment. The 2 year RFS was 28.6% (95% CI 12-48%). The estimated overall survival at 2 years was 78% (95% CI 51 91%). cfDNA detection had a 53% sensitivity in relapsing patients but cfDNA detection did not provide lead-time advantage over CT scanning. Conclusion: A 4 month course of adjuvant dabrafenib did not result in a detectable improvement in 2-year RFS. cfDNA was less sensitive than standard CT imaging and did not provide a lead-time advantage in detecting relapse. PMID- 29285229 TI - Relationship of tumor size with pathological and prognostic factors for hilar cholangiocarcinoma. AB - Objective: To determine the correlation of different tumor-size cutoffs with prognostic factors and survival outcomes to provide a reference for the modification of the T-stage classification in the DeOliveira staging system for hilar cholangiocarcinoma (HCCA). Materials and Methods: We retrospectively analyzed 216 patients who underwent curative surgery for HCCA (mean tumor diameter, 2.8 cm) between 2000 and 2013. Univariate and multivariate logistic regression were used to assess the correlation of tumor-size cutoffs with various factors. Results: Tumor differentiation (odds ratio [OR]: 1.649, 95% confidence interval [CI]: 1.065-2.555, P = 0.025), node status (OR: 1.971, 95% CI: 1.060 3.664, P = 0.032), resection margin (OR: 2.465, 95% CI: 1.024-5.937, P = 0.044), and hepatectomy (OR: 2.373, 95% CI: 1.226-4.593, P = 0.01) were independently correlated with the 2-cm cutoff, while tumor differentiation (OR: 1.755, 95% CI: 1.062-2.091, P = 0.028), node status (OR: 2.166, 95% CI: 1.054-4.452, P = 0.035), and tumor margin (OR: 2.539, 95% CI: 1.089-5.919, P = 0.031) were independently associated with the 3-cm cutoff. Conclusions: The 2-cm and 3-cm cutoffs were strongly correlated with resection margin, node status, tumor differentiation and survival. The 2-cm cutoff may be added to the DeOliveira staging system. PMID- 29285230 TI - Gene editing of the extra domain A positive fibronectin in various tumors, amplified the effects of CRISPR/Cas system on the inhibition of tumor progression. AB - Background: The low efficiency of clustered, regularly interspaced, palindromic repeats-associated Cas (CRISPR/Cas) system editing genes in vivo limits the application. A components of the extracellular matrix (ECM), the extra domain A positive fibronectin (EDA+FN), may be a target for CRISPR/Cas system for the pro oncogenic effects. The exclusion of EDA exon would alter the microenvironment and inhibit tumor progression, even the frequency of gene editing is still limited. Results: The pro-oncogenic effects were confirmed by the exclusion of EDA exon from the fibronectin gene, as illustrated by the down-regulated proliferation, migration and invasion of CNE-2Z or SW480 cells (P<0.05). Furthermore, although the efficacy of EDA exon knockout through CRISPR/Cas system was shown to be low in vivo, the EDA+FN protein levels decrease obviously, inhibiting the tumor growth rate significantly (P<0.05), which was accompanied by a decrease in Ki-67 expression and microvessel numbers, and increased E-cadherin or decreased Vimentin expression (P<0.05). Methods and materials: Human nasopharyngeal carcinoma cell line CNE-2Z, and the colorectal carcinoma cell line SW480 were transfected with CRISPR/Cas9 plasmids targeting EDA exon. The effects of the exclusion of EDA on the cell proliferation, motility and epithelial-mesenchymal transition (EMT) were investigated, and the western blot and real-time PCR were performed to analyze the underlying mechanisms. Furthermore, CRISPR/Cas9 plasmids were injected into xenograft tumors to knockout EDA exon in vivo, and tumor growth, cell proliferation, EMT rate, or vascularization were investigated using western blot, PCR and immunohistochemistry. Conclusion: CRISPR/Cas system targeting ECM components was shown to be an effective method for the inhibition of tumor progression, as these paracrine or autocrine molecules are necessary for various tumor cells. This may represent a novel strategy for overcoming the drug evasion or resistance, in addition, circumventing the low efficiency of CRISPR/Cas system in vivo. PMID- 29285231 TI - Associations between TNFSF4, TNFSF8 and TNFSF15 and Behcet's disease but not VKH syndrome in Han Chinese. AB - The present study was designed to explore the interrelationship between single nucleotide polymorphisms (SNP) of the tumor necrosis factor superfamily (TNFSF) and its respective receptor superfamily (TNFRSF) genes and Behcet's disease (BD) and Vogt-Koyanagi-Harada syndrome (VKH) in Han Chinese. The study sample included 796 patients with BD, 792 patients with VKH syndrome, and 1604 healthy controls. The genotyping of 35 SNPs was performed by MassARRAY platform (Sequenom), iPLEX Gold Assay, PCR-restriction fragment length polymorphism assay and TaqMan SNP assay. The mRNA expression levels of TNFSF4, TNFSF8 and TNFSF15 were analyzed by real-time PCR. The IL-6 and TNF-alpha expression levels were measured by ELISA. The A allele and AA genotype frequencies of TNFSF4/rs1234313 were significantly increased, and the GG genotype frequency of rs1234313 was decreased in subjects with BD. Significantly lower frequencies of the C allele and the CC genotype and higher frequencies of the TT and CT genotypes of TNFSF15/rs4246905 were observed in BD patients. A decreased frequency of the A allele of TNFSF8/rs7028891 was observed in BD patients. The expression of TNFSF15 in CT carriers was significantly higher than that in CC/TT individuals. Increased IL-6 expression and TNF-alpha production were found in the TNFSF15 CT carriers compared with the CC/TT genotype carriers. No significant differences were observed between the VKH patients and controls. This study indicates that TNFSF4, TNFSF15 and TNFSF8 may participate in the susceptibility to BD among Han Chinese. PMID- 29285232 TI - Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a common and deadly cancer worldwide and is often refractory to chemotherapy due to the development of multidrug resistance. Lonafarnib is an orally active and potent non-peptidomimetic inhibitor of farnesyl transferase. Here, using in vitro HCC cell models, we demonstrated that lonafarnib inhibited tumor proliferation and reduced the activity of mitogen activated protein kinases pathways. In addition, lonafarnib caused G1 to S phase arrest through the downregulation of Cyclin D1, CDK6 and SKP2, while it induced cellular apoptosis by promoting the cleavage and activation of Caspase-3 and PARP. When combined with doxorubicin and sorafenib, lonafarnib was able to increase the sensitivity of HCC cells to chemotherapy. Furthermore, we also constructed ABCB1-overexpressing HCC cells and found that lonafarnib decreased chemoresistance by inhibiting ABCB1-mediated drug efflux activity. These results suggest that lonafarnib may be a promising synergistic agent for improving the treatment of drug-resistant HCC. PMID- 29285233 TI - AIO LQ-0110: a randomized phase II trial comparing oral doxycycline versus local administration of erythromycin as preemptive treatment strategies of panitumumab mediated skin toxicity in patients with metastatic colorectal cancer. AB - Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. Patients and methods: In this multicentre, randomized, open label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity >= grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). Results: In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade >= 2 versus 63% in the standard arm (P = n.s.). However, as per WoMo score significantly more patients in the erythromycin arm developed moderate or severe skin toxicity at earlier time points. Skin related and overall quality of life was comparable between both arms. Conclusions: Based on this data erythromycin cannot be regarded as an alternative to doxycycline as prevention of EGFR-related skin toxicity. PMID- 29285234 TI - Targeted next generation sequencing in Chinese colorectal cancer patients guided anti-EGFR treatment and facilitated precision cancer medicine. AB - Objective: Colorectal cancer (CRC) patients with both RAS and BRAF wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as PIK3CA or PTEN. In this study, a broad, hybrid capture-based NGS assay was used to identify RAS, BRAF and additional targetable genetic alterations from Chinese CRC tissues. Methods: Fifty-seven cases of CRC were enrolled, and all the patients signed the informed consent. In total, 7708 exons of 508 tumor-related genes and 78 introns of 19 frequently rearranged genes were assessed for base substitutions, INDELs, copy number alterations, and gene fusions. Results: The study found that 50.9% (29/57) of the tumors harbored KRAS mutations, 3.5% (2/57) harbored NRAS mutations and 3.5% (2/57) harbored BRAF mutations. More specifically, 89.7% (26/29) of RAS mutations were located in codon 12. Except for RAS and RAF, anti EGFR therapy response genetic mutations in PTEN (n=2) and PIK3CA (n=1) were found in 4.7% (3/64) of the samples. Actionable alterations were found in HER2 (n = 7), CCND2 (n = 2), NF1 (n = 1), and BRCA1 (n = 1). Conclusions: Our results illustrated that 82.5% (47/57) of the samples harbored at least one actionable genetic alteration identified by NGS. HER2 amplifications or mutations, which were identified in 12.3% of the tissues, defined a unique molecular subtype of CRC. The study suggests that high-throughput NGS testing in CRC tissues is a comprehensive and efficient genomic profiling assay to guide personalized therapy. PMID- 29285235 TI - Eyes absent gene (EYA1) is a pathogenic driver and a therapeutic target for melanoma. AB - EYA1 is a DNA repair enzyme that is induced after DNA damage and is upregulated in melanoma. However, its role in pathogenesis and therapeutic targeting of melanoma is unknown. Our objectives are (1) to study the relationship between EYA1 expression levels and melanoma patients' clinical pathologic parameters including survival; (2) to investigate its impact on cultured melanoma cells in vitro; and (3) to evaluate EYA1 inhibitors' potential as a treatment of melanoma. Melanoma tissue microarrays were used to assess EYA1 protein expression in 326 melanoma tissues, and to correlate the expression with patients' clinical pathological parameters. In addition, retroviral ShRNA vectors were used to silence expression of EYA1 in A375 melanoma cells, and the resultant cells examined for changes in growth, DNA synthesis, and tumor formation in vitro. Lastly, melanoma cells were treated with benzbromarone with or without the BRAF inhibitor vemurafenib. Our results showed that EYA1 protein is low in benign nevi, but is significantly up-regulated in melanoma in situ, and remains high in invasive and metastatic melanoma. In addition, silencing of EYA1 gene expression resulted in decreased proliferation and colony formation. These were associated with decreased cyclin D1 and increased phosphorylated histone protein gammaH2AX. Finally, treatment with benzbromarone, a specific inhibitor of EYA1, caused significant inhibition of melanoma cell proliferation, and increased sensitivity to the BRAF inhibitor vemurafenib. In conclusion, EYA1 gene is a pathogenic driver in melanoma pathogenesis. Targeting EYA1 may be a valuable strategy for treatment of melanoma. PMID- 29285236 TI - Intrapleural targeted therapies (anti-VEGF and anti-EGFR) in the model of malignant pleural effusion. AB - Rationale: Malignant pleural effusion has few options of treatment and drugs administrated by different routes can lead to a less permissive microenvironment for the development of malignant pleural disease. Objectives: To analyze therapies administered intrapleurally in malignant pleural disease and to study EGFR and KRAS mutations in adenocarcinoma. Methods: Mice received LLC cells and were treated intrapleurally with anti-VEGF, anti-EGFR, anti-VEGF+anti-EGFR or saline. Animal survival, weight and mobility, volume, biochemistry and immunology of fluid, gene expression, KRAS and EGFR mutation were evaluated. Results: All animals developed malignant effusion and presented progressive weight loss without difference between groups; however, groups treated with anti-EGFR were more active. No difference in mortality was observed. Temporal increase of volume and inflammatory markers was observed mainly in the untreated group. Gene expression in tumors was overexpressed in VEGF, EGFR and KRAS compared with normal tissue. Mutation in exon 2 of the KRAS gene was observed. Conclusions: Intrapleural Anti-VEGF and/or anti-EGFR reduced volume and inflammatory mediators in pleural fluid. Anti-EGFR and anti-VEGF+anti-EGFR decreased morbidity although without impact on survival. LLC tumors presented KRAS mutation, this could have influenced the action of these therapies. PMID- 29285237 TI - Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors. AB - Background: Several mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC have been described including the T790M mutation and MET amplification. Whereas T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, data are lacking on clinical features and outcome of MET-driven resistant EGFR-mutated NSCLC patients. Methods: Patients with metastatic EGFR-mutated NSCLC displaying high MET overexpression or MET amplification, detected on a biopsy performed after progression on EGFR TKI, were identified in 15 centers. Clinical and molecular data were retrospectively collected. Results: Forty two patients were included. The median overall survival (OS), and the median post EGFR TKI progression overall survival (PPOS) were 36.2 months [95%CI 27.3-66.5] and 18.5 months [95%CI 10.6-27.4] respectively. Nineteen out of 36 tumors tested for MET FISH had MET amplification. A T790M mutation was found in 11/41 (26.8%) patients. T790M-positive patients had a better OS than T790M-negative patients (p=0.0224). Nineteen patients received a MET TKI. Objective response was reported in 1 out of 12 evaluable patients treated with a MET inhibitor as a single agent and in 1 of 2 patients treated with a combination of MET and EGFR TKIs. Conclusion: MET-driven resistance to EGFR TKI defines a specific pattern of resistance characterized by low objective response rate to MET inhibitors given alone and overlapping with T790M mutations. Further studies are warranted to define adequate therapeutic strategies for MET-driven resistance to EGFR TKI. PMID- 29285239 TI - Low density lipoprotein - rosiglitazone - chitosan-calcium alginate/nanoparticles inhibition of human tenon's fibroblasts activation and proliferation. AB - Anti-fibrotic therapeutic methods with safety and efficiency after glaucoma filtration surgery (GFS) are desirable. In our previous study, by using Human Tenon's Fibroblasts (HTFs) as a model, we proved the expression of peroxisome proliferator activates receptor-gamma (PPAR-gamma) in HTFs; in addition, rosiglitazone (RSG), an agonist of PPAR-gamma, can inhibit transforming growth factorsbeta1 (TGF-beta1)-induced reactivation of HTFs, thus to inhibit specifically scarring after GFS through intervening TGF-beta/Smads signal pathway. However, a better drug delivery way of RSG, to prolong the duration of its function, and to reduce the toxicity of RSG to ocular tissue still remains challenges. Low density lipoprotein receptor (LDLr) is strongly expressed in hyper-proliferation HTFs after GFS. Therefore, we structured targeting LDL-RSG complexes and channel them into HTFs through LDL-LDLr pathway in order to promote anti-proliferation of HTFs and reduce the toxicity to ocular tissue. Meanwhile, in order to improve the release properties of LDL-RSG complexes, we structured slow release system of LDL-RSG/chitosan-calcium alginate - nanoparticles (CSNP), which effectively inhibited TGF-beta1-induced HTFs proliferation, synthesis of extracellular matrix and activation of TGF-beta1/SMAD pathway. These data suggested that LDL-RSG/CSNP can be a new anti-fibrotic therapeutic method on scarring after GFS and also a novelty administration of RSG. PMID- 29285238 TI - Hepatitis B virus (HBV) X gene mutations and their association with liver disease progression in HBV-infected patients. AB - Hepatitis B virus (HBV) is one of the most widespread human pathogens causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). This study investigated the clinical impact of single and combinational mutations in HBx gene on the pathogenesis of HCC during progressive stages of liver disease. The patients were categorized into inactive HBV carriers, active carriers, cirrhosis and HCC groups based on disease severity. Male sex, age > 50 years, and high serum alanine aminotransferase level were associated with risk of progressive liver disease. I127T, V131I, and F132Y/I/R mutations showed a significant increasing trend associated with the disease progression to HCC. H94Y and K130M mutations were also significantly associated with severe liver disease. One double mutation (K130M+V131I) and two triple mutations (I127T+K130M+V131L and K130M+V131I+F132Y) were observed, with significant rising prevalence through progressive clinical phases of liver disease to HCC. Several single and combinational mutations in HBx correlating with severity and progressive clinical phases of HBV infection were identified. The mutational combinations may have a synergistic effect in accelerating the progression to HCC. These specific patterns of HBx mutations can be useful in predicting the clinical outcome of HBV infected patients and may serve as early markers of high risk of developing HCC. PMID- 29285240 TI - Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7. AB - Anthrapyridazones, imino analogues of anthraquinone, constitute a family of compounds with remarkable anti-cancer activity. To date, over 20 derivatives were studied, of which most displayed nanomolar cytotoxicity towards broad spectrum of cancer cells, including breast, prostate and leukemic ones. BS-154, the most potent derivative, had IC50 values close to 1 nM, however, it was toxic in animal studies. Here, we characterize another anthrapyridazone, PDZ-7, which retains high cytotoxicity while being well tolerated in mice. PDZ-7 is also active in vivo against anthracycline-resistant tumor in a mouse xenograft model and induces DNA damage in proliferating cells, preferentially targeting cells in S and G2 phases of the cell cycle. Activation of Mre11-Rad50-Nbs1 (MRN) complex and phosphorylation of H2AX suggest double-stranded DNA breaks as a major consequence of PDZ-7 treatment. Consistent with this, PDZ-7 treatment blocked DNA synthesis and resulted in cell cycle arrest in late S and G2 phases. Analysis of topoisomerase IIalpha activity and isolation of the stabilized covalent topoisomerase IIalpha - DNA complex in the presence of PDZ-7 suggests that this compound is a topoisomerase IIalpha poison. Moreover, PDZ-7 interfered with actin polymerization, thereby implying its action as a dual inhibitor of processes critical for dividing cells. Using nuclear magnetic resonance (NMR) spectroscopy we show that PDZ-7 interacts with DNA double helix and quadruplex DNA structure. Taken together, our results suggest that PDZ-7 is a unique compound targeting actin cytoskeleton and DNA. PMID- 29285241 TI - GOLPH3: a novel biomarker that correlates with poor survival and resistance to chemotherapy in breast cancer. AB - The association between Golgi phosphoprotein 3 (GOLPH3) and clinical pathological characteristics, as well as the clinical outcomes of both neoadjuvant and adjuvant chemotherapies in breast cancer, remain largely unknown. In this study, we investigated the biological role and clinical significance of GOLPH3 in breast cancer. We found that GOLPH3 expression in tumor tissue was higher than that in adjacent noncancerous tissue (ANT) and fibroadenoma. GOLPH3 silencing reduced the migration, invasion, and proliferation of breast cancer cells and promoted apoptosis of the cells. Importantly, patients with high GOLPH3 expression had worse disease-free survival (DFS) and overall survival (OS), and GOLPH3 expression was correlated with clinical pathological characteristics such as molecular subtype, tumor-node-metastasis classification, and age but was not associated with surgery type. Patients with high GOLPH3 expression had poor DFS and OS in every molecular subtype, and an increase in tumor invasion and lymph node metastasis. The risk of recurrence increased with age in patients with high GOLPH3 expression, and surgery type had no influence on patient survival. This is the first study to investigate the correlation between GOLPH3 and response to chemotherapy in breast cancer. Patients with high GOLPH3 expression showed resistance to neoadjuvant and adjuvant chemotherapies, and GOLPH3 overexpression indicated a high risk of recurrence in patients who received adjuvant chemotherapy. These data suggest that GOLPH3 may be a novel biomarker that correlates with poor survival and resistance to chemotherapy in breast cancer. PMID- 29285242 TI - Roscovitine strongly enhances the effect of olaparib on radiosensitivity for HPV neg. but not for HPV pos. HNSCC cell lines. AB - At present, advanced stage human Papillomavirus (HPV) negative and positive head and neck squamous cell carcinoma (HNSCC) are treated by intense multimodal therapy that includes radiochemotherapy, which are associated with relevant side effects. Patients with HPV positive tumors possess a far better prognosis than those with HPV negative cancers. Therefore, new therapeutic strategies are needed to improve the outcome especially of the latter one as well as quality of life for all HNSCC patients. Here we tested whether roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), which hereby also blocks homologous recombination (HR), can be used to enhance the radiation sensitivity of HNSCC cell lines. In all five HPV negative and HPV positive cell lines tested, roscovitine caused inhibition of CDK1 and 2. Surprisingly, all HPV positive cell lines were found to be defective in HR. In contrast, HPV negative strains demonstrated efficient HR, which was completely suppressed by roscovitine. In line with this, for HPV negative but not for HPV positive cell lines, treatment with roscovitine resulted in a pronounced enhancement of the radiation-induced G2 arrest as well as a significant increase in radiosensitivity. Due to a defect in HR, all HPV positive cell lines were efficiently radiosensitized by the PARP-1 inhibitor olaparib. In contrast, in HPV negative cell lines a significant radiosensitization by olaparib was only achieved when combined with roscovitine. PMID- 29285243 TI - High visceral fat percentage is associated with poor outcome in endometrial cancer. AB - Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity on clinical and histological phenotype is poorly understood. This study explored abdominal fat volumes and fat distribution quantified by computed tomography (CT), in relation to tumor characteristics and outcome. 227 EC patients with preoperative abdominal CT scans were included. Total abdominal fat volume (TAV), subcutaneous abdominal fat volume (SAV) and visceral abdominal fat volume (VAV) were quantified, and visceral fat percentage calculated (VAV%=[VAV/TAV]x100). Waist circumference (WC) and liver density (LD) were measured, and body mass index (BMI) calculated. Data for estrogen, progesterone and androgen receptor (ERalpha/PR/AR) expression by immunohistochemistry were available for 149 tumors, and global gene expression data for 105 tumors. High BMI, TAV, SAV, VAV and WC, and low LD, were associated with low grade endometrioid tumors and PR and AR positivity (all p<=0.03). High VAV% was associated with high age (p<0.001), aneuploidy (p=0.01) and independently predicted reduced disease-specific survival (HR 1.05, 95% CI 1.00-1.11, p=0.041). Tumors from patients with low VAV% showed enrichment of gene sets related to immune activation and inflammation. In conclusion, high VAV% independently predicts reduced EC survival. Tumors arising in patients with low VAV% show enrichment of immune and inflammation related gene sets, suggesting that the global metabolic setting may be important for tumor immune response. PMID- 29285244 TI - Coordinated downregulation of Spinophilin and the catalytic subunits of PP1, PPP1CA/B/C, contributes to a worse prognosis in lung cancer. AB - The scaffold protein Spinophilin (Spinophilin, PPP1R9B) is one of the regulatory subunits of phosphatase-1 (PP1), directing it to distinct subcellular locations and targets. The loss of Spinophilin reduces PP1 targeting to pRb, thereby maintaining higher levels of phosphorylated pRb. Spinophilin is absent or reduced in approximately 40% of human lung tumors, correlating with the malignant grade. However, little is known about the relevance of the coordinated activity or presence of Spinophilin and its reported catalytic partners in the prognosis of lung cancer. In the present work, we show that the downregulation of Spinophilin, either by protein or mRNA, is related to a worse prognosis in lung tumors. This effect is more relevant in squamous cell carcinoma, SCC, than in adenocarcinoma. Downregulation of Spinophilin is related to a decrease in the levels of its partners PPP1CA/B/C, the catalytic subunits of PP1. A decrease in these subunits is also related to prognosis in SCC and, in combination with a decrease in Spinophilin, are markers of a poor prognosis in these tumors. The analysis of the genes that correlate to Spinophilin in lung tumors showed clear enrichment in ATP biosynthesis and protein degradation GO pathways. The analysis of the response to several common and pathway-related drugs indicates a direct correlation between the Spinophilin/PPP1Cs ratio and the response to oxaliplatin and bortezomib. This finding indicates that this ratio may be a good predictive biomarker for the activity of the drugs in these tumors with a poor prognosis. PMID- 29285245 TI - A population pharmacokinetic model for individualised dosage regimens of vancomycin in Chinese neonates and young infants. AB - Population pharmacokinetic (PPK) modelling is an easy and impartment method for estimating drug concentration for use inindividualized therapy, especially for young patients and to help protect drug-induced diseases. The purpose of this study was to develop a PPK model for effective dosing of vancomycin in Chinese neonates and young infants. The PPK modelling tool Phoenix(r) NLMETM was use to assess demographic and routine clinical pharmacokinetic (PK) data retrospectively collected for patients admitted to Children's Hospital of Chongqing Medical University between 2011 and 2016. Data of patients admitted to the hospital between January and June of 2017 were used in validation study, and the final model was also preliminary validated in 2 cases in another hospital. A total of 421 serum samples from 316 patients were included in the initial PPK analysis. A two-compartment PPK model was developed, and exponential-error model was used to describe inter-individual variability of clearance. Residual variability was described by an additive model. The final PPK model was demonstrated as valid by internal and external model evaluation. Of note, the clearance and volume of vancomycin in Chinese neonates and young infants may be greater than in Caucasians. Herein, we describe the establishment of an accurate PPK model of vancomycin for Chinese neonates and young infants, which may be useful as a dosing algorithm for this particular paediatric population. PMID- 29285246 TI - Gene function analysis and underlying mechanism of esophagus cancer based on microarray gene expression profiling. AB - Esophageal cancer (EC) is one of the most common digestive malignant tumors worldwide. Over the past decades, there have been minimal improvements in outcomes for patients with EC. New targets and novel therapies are needed to improve outcomes for these patients. This study aimed to explore the molecular mechanisms of EC by integrated bioinformatic analyses of the feature genes associated with EC and correlative gene functions which can distinguish cancerous tissues from non-cancerous tissues. Gene expression profile GSE20347 was downloaded from Gene Expression Omnibus (GEO) database, including 17 EC samples and their paired adjacent non-cancerous samples. The differentially expressed genes (DEGs) between EC and normal specimens were identified and then applied to analyze the GO enrichment on gene functions and KEGG pathways. Corresponding Pathway Relation Network (Pathway-net) and Gene Signal Network (signal-net) of DEGs were established based on the data collected from GCBI datasets. The results showed that DEGs mainly participated in the process of cell adhesion, cell proliferation, survival, invasion, metastasis and angiogenesis. Aberrant expression of PTK2, MAPK signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway and MET were closely associated with EC carcinogenesis. Importantly, Interleukin 8 (IL8) and C-X-C chemokine receptor type 7 (CXCR-7) were predicted to be significantly related to EC. These findings were further validated by analyzing both TCGA database and our clinical samples of EC. Our discovery provides a registry of genes and pathways that are disrupted in EC, which has the potential to be used in clinic for diagnosis and target therapy of EC in future. PMID- 29285247 TI - CTHRC1 activates pro-tumorigenic signaling pathways in hepatocellular carcinoma. AB - CTHRC1 expression is involved in invasion and metastasis in various tumors. However, the molecules involved in its signaling pathways in hepatocellular carcinoma (HCC) remain elusive. The migration and invasion abilities of HCC cells stably expressing CTHRC1 were assessed in vitro and in vivo with a mouse model. Moreover, signaling pathways involved in invasion and metastasis were analyzed. CTHRC1 was abundantly expressed in HCC cell lines and HCC tissues. CTHRC1 was also detectable in the serum of HCC patients, compared with non-tumor controls. CTHRC1 mRNA was positively correlated with large tumor size (p <0.003), Edmondson differentiation grade (p <0.0001), microvessel invasion (p <0.05), intrahepatic metastasis (p <0.005), and HCC stage (AJCC, p <0.0001). Ectopic expression of CTHRC1 in HepG2 cells promoted cell migration and invasiveness in vitro, and promoted tumor metastasis in a lung metastasis mouse model. Knockdown of CTHRC1 by short hairpin RNA (shRNA) in HCC cells suppressed migratory and invasive abilities. Growth factor-mediated CTHRC1 expression promoted cancer cell invasiveness and metastasis through activation of CREB/Snail signaling, which induced EMT change and MMPs expression. Therefore, CTHRC1 and its downstream molecules may be potential therapeutic targets for HCC invasion and metastasis. PMID- 29285248 TI - Super enhancer associated RAI14 is a new potential biomarker in lung adenocarcinoma. AB - Purpose: Tyrosine kinase inhibitors (TKIs) are widely used to treat lung adenocarcinoma patients with EGFR mutations or ALK-fusions. However, patients with wild-type genes or TKIs-resistant mutations lack effective therapeutic targets. Extensive studies reveal that super enhancer (SE), a large cis regulatory element, is associated with key oncogenes in a variety of cancers. By comparing the effect of SE on lung adenocarcinoma cell lines with normal cell line, this work attempts to find new biomarkers and potential therapeutic targets for lung adenocarcinoma. Experimental Design: Chromatin Immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) of H3K27ac (acetylation on lysine 27 of histone 3) was performed in lung adenocarcinoma cell lines SPC-A1 and SCH-1153. The differences in SE distribution were then analyzed among SPC-A1, SCH-1153, A549 and normal human lung fibroblasts (NHLF) to identify SE-associated oncogenes. The expression of SE-associated oncogenes was then detected by RNA-seq and further verified in 71 patients by real-time PCR. Results: SE associated with many new oncogenes in lung adenocarcinoma, among which, RAI14 was up-regulated in A549 and 31 of 71 patients. High expression of RAI14 could inhibit cell proliferation, indicating its potential as a new biomarker for lung adenocarcinoma. PMID- 29285249 TI - Retinol dehydrogenase-10 promotes development and progression of human glioma via the TWEAK-NF-kappaB axis. AB - Retinol dehydrogenase-10 (RDH10) is a member of the short-chain dehydrogenase/reductase family, which plays an important role in retinoic acid (RA) synthesis. Here, we show that RDH10 is highly expressed in human gliomas, and its expression correlates with tumor grade and patient survival times. In vitro, lentivirus-mediated shRNA knockdown of RDH10 suppressed glioma cell proliferation, survival, and invasiveness and cell cycle progression. In vivo, RDH10 knockdown reduced glioma growth in nude mice. Microarray analysis revealed that RDH10 silencing reduces expression of TNFRSF12A (Fn14), TNFSF12 (TWEAK), TRAF3, IKBKB (IKK-beta), and BMPR2, while it increases expression of TRAF1, NFKBIA (IkappaBalpha), NFKBIE (IkappaBepsilon), and TNFAIP3. This suggests that RDH10 promotes glioma cell proliferation and survival by regulating the TWEAK-NF kappaB axis, and that it could potentially serve as a novel target for human glioma treatment. PMID- 29285250 TI - SPC24 promotes osteosarcoma progression by increasing EGFR/MAPK signaling. AB - In this study, we investigated the role of the spindle checkpoint protein SPC24 in osteosarcoma progression. SPC24 knockdown in 143B and U2OS osteosarcoma cells decreased cell growth, survival and invasiveness. The SPC24 knockdown cells also exhibited low EGFR, Ras and phospho-ERK levels and high E-cadherin levels, suggesting inhibition of EGFR/Ras/ERK signaling and epithelial-to-mesenchymal transitioning. Xenografted SPC24 knockdown osteosarcoma cells showed reduced tumor growth in nude mice with decreased EGFR and phospho-ERK levels and increased E-cadherin levels. By contrast, human osteosarcoma tissue samples showed high SPC24 and phospho-ERK levels and low E-cadherin levels. These results suggest SPC24 promotes osteosarcoma progression by increasing EGFR/Ras/ERK signaling. PMID- 29285251 TI - Abnormally glycosylated MUC1 establishes a positive feedback circuit of inflammatory cytokines, mediated by NF-kappaB p65 and EzH2, in colitis-associated cancer. AB - The abnormal hypoglycosylated form of the epithelial mucin MUC1 is over-expressed in chronic inflammation and on human adenocarcinomas, suggesting its potential role in inflammation-driven tumorigenesis. The presence of human MUC1 aggravates colonic inflammation and increases tumor initiation and progression in an in vivo AOM/DSS mouse model of colitis-associated cancer (CAC). High expression levels of pro-inflammatory cytokines, including TNF-alpha and IL-6, were found in MUC1+ inflamed colon tissues. Exogenous TNF-alpha promoted the transcriptional activity of MUC1 as well as over-expression of its hypoglycosylated form in intestinal epithelial cells (IECs). In turn, hypoglycosylated MUC1 in IECs associated with p65 and up-regulated the expression of NF-kappaB-target genes encoding pro inflammatory cytokines. Intestinal chronic inflammation also increased the expression of histone methyltransferase Enhancer of Zeste protein-2 (EzH2) and its interaction with cytokine promoters. Consequently, EzH2 was a positive regulator of MUC1 and p65-mediated IL-6 and TNF-alpha gene expression, and this function was not dependent on its canonical histone H3K27 methyltransferase activity. Our findings provide a mechanistic basis for already known tumorigenic role of the hypoglycosylated MUC1 in CAC, involving a transcriptional positive feedback loop of pro-inflammatory cytokines. PMID- 29285252 TI - Immunological landscape of consensus clusters in colorectal cancer. AB - Recent, large-scale expression-based subtyping has advanced our understanding of the genomic landscape of colorectal cancer (CRC) and resulted in a consensus molecular classification that enables the categorization of most CRC tumors into one of four consensus molecular subtypes (CMS). Currently, major progress in characterization of immune landscape of tumor-associated microenvironment has been made especially with respect to microsatellite status of CRCs. While these studies profoundly improved the understanding of molecular and immunological profile of CRCs heterogeneity less is known about repertoire of the tumor infiltrating immune cells of each CMS. In order to comprehensively characterize the immune landscape of CRC we re-analyzed a total of 15 CRC genome-wide expression data sets encompassing 1597 tumors and 125 normal adjacent colon tissues. After quality filtering, CRC clusters were discovered using a combination of multiple clustering algorithms and multiple validity metrics. CIBERSORT algorithm was used to compute relative proportions of 22 human leukocyte subpopulations across CRC clusters and normal colon tissue. Subsequently, differential expression specific to tumor epithelial cells was calculated to characterize mechanisms of tumor escape from immune surveillance occurring in particular CRC clusters. Our results not only characterize the common and cluster-specific influx of immune cells into CRCs but also identify several deregulated gene targets that may contribute to improvement of immunotherapeutic strategies in CRC. PMID- 29285253 TI - Functional polymorphisms in NR3C1 are associated with gastric cancer risk in Chinese population. AB - Recently promoter of NR3C1 has been found to be high methylated in gastric cancer tissues which might be involved in the initiation of gastric carcinoma development. To test whether the variants in NR3C1 could modify the risk of gastric cancer, we evaluated the association between four SNPs (rs6194, rs12521436, rs33388 and rs4912913) in NR3C1 and gastric cancer risk in a case control study with 1,113 gastric cancer cases and 1,848 cancer-free controls in a Chinese population. We found a significant association between rs4912913 and gastric cancer risk (OR=1.18, 95%CI=1.05-1.33, P=5.49*10-3). We also observed that the A-allele of rs12521436 and rs33388 were significantly associated with a decreased risk of gastric cancer (OR=0.84, 95%CI=0.76-0.94, P=2.78*10-3; OR=0.85, 95%CI=0.75-0.97; P=0.018). Finally, we made a joint effect analysis of rs12521436, rs33388 and rs4912913 on risk of gastric cancer (PTrend =2.83*10-5). These findings indicate that the variants rs4912913, rs33388 and rs12521436 of NR3C1 may contribute to gastric cancer susceptibility. PMID- 29285254 TI - MicroRNA co-expression networks exhibit increased complexity in pancreatic ductal compared to Vater's papilla adenocarcinoma. AB - MiRNA expression abnormalities in adenocarcinoma arising from pancreatic ductal system (PDAC) and Vater's papilla (PVAC) could be associated with distinctive pathologic features and clinical cancer behaviours. Our previous miRNA expression profiling data on PDAC (n=9) and PVAC (n=4) were revaluated to define differences/similarities in miRNA expression patterns. Afterwards, in order to uncover target genes and core signalling pathways regulated by specific miRNAs in these two tumour entities, miRNA interaction networks were wired for each tumour entity, and experimentally validated target genes underwent pathways enrichment analysis. One hundred and one miRNAs were altered, mainly over-expressed, in PDAC samples. Twenty-six miRNAs were deregulated in PVAC samples, where more miRNAs were down-expressed in tumours compared to normal tissues. Four miRNAs were significantly altered in both subgroups of patients, while 27 miRNAs were differentially expressed between PDAC and PVAC. Although miRNA interaction networks were more complex and dense in PDAC than in PVAC, pathways enrichment analysis uncovered a functional overlapping between PDAC and PVAC. However, shared signalling events were influenced by different miRNA and/or genes in the two tumour entities. Overall, specific miRNA expression patterns were involved in the regulation of a limited core signalling pathways in the biology landscape of PDAC and PVAC. PMID- 29285255 TI - Agrin para-secreted by PDGF-activated human hepatic stellate cells promotes hepatocarcinogenesis in vitro and in vivo. AB - Evaluating the process and mechanism of fibrogenesis is essential in hepatocellular carcinoma (HCC), especially in hepatocyte transformation and oncogenic signaling. We evaluated the oncogenic role of agrin secreted by platelet-derived growth factor (PDGF)-induced hepatic stellate cell (HSC) in HCC. Cells were co-cultured to investigate the effect of activated HSC on hepatocytes. Liquid chromatography and protein profiling analysis were used to search the distinct proteins secreted in HSC supernatant. Sprague Dawley rats with Diethylnitrosamine (DEN)-induced HCC were used to simulate human liver cancer and sorafenib was administered to investigate its effect on hepatocarcinogenesis. A paired "two-tailed" Student t-test and chi-square tests was used for statistical analysis. PDGF acted as an activator of the HSC and sorafenib inhibits the activation by blocking the combination of PDGF and PDGF receptor. The supernatant of activated HSCs promoted the proliferation, metastasis, and invasion of HL-7702 and SMMC-7721, as well as epithelial-mesenchymal transition (EMT). Agrin found in the HSC supernatant showed the same effect on SMMC-7721 as to the supernatant of activated LX-2. Furthermore, downregulation of agrin by siRNA could decrease the proliferation, metastasis, and invasion of SMMC-7721, and promote MET. Sorafenib prevented DEN-induced hepatocarcinogenesis and could alleviate the liver inflammation and fibrosis. Sorafenib could improve the liver function of Sprague Dawley rats by decreasing the serum levels of ALT and AST. These results demonstrate thatPDGF is an effective activator of HSC and sorafenib could inhibit the activation. In vivo experiment suggested sorafenib could alleviate the hepatocarcinogenesis mediated through agrin secretion and could be potential candidate for treatment of cirrhosis. PMID- 29285256 TI - Investigation of RIP140 and LCoR as independent markers for poor prognosis in cervical cancer. AB - Introduction: RIP140 (Receptor Interacting Protein) is involved in the regulation of oncogenic signaling pathways and in the development of breast and colon cancers. The aim of the study was to analyze the expression of RIP140 and its partner LCoR in cervical cancers, to decipher their relationship with histone protein modifications and to identify a potential link with patient survival. Methods: Immunohistochemical analyses were carried out to quantify RIP140 and LCoR expression in formalin-fixed paraffin-embedded tissue sections cervical cancer samples. Correlations of RIP140 and LCoR expression with histopathological variables were determined by correlation analyses. Survival rates of patients expressing low or high levels of RIP140 and LCoR were compared by Kaplan-Meier curves. Results: RIP140 overexpression was associated with a significantly shorter overall survival of cervical cancer patients. This effect was significant in the squamous cell carcinoma subtype but not in adenocarcinomas. RIP140 is no longer a significant negative prognosticator for cervical cancer when LCoR expression is low. Discussion: RIP140 is an independent predictor of poor survival of patients with cervical cancer. Patients with tumors expressing low levels of both RIP140 and LCoR showed a better survival compared to patients expressing high levels of RIP140. Modulation of RIP140 and LCoR may represent a novel targeting strategy for cervical cancer prevention and therapy. PMID- 29285257 TI - Sensitization of lung cancer cells by altered dimerization of HSP27. AB - Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells. PMID- 29285259 TI - CD20 expression sub-stratifies standard-risk patients with B cell precursor acute lymphoblastic leukemia. AB - Patients with standard-risk adult acute lymphoblastic leukemia (ALL) treated with chemotherapy do not have satisfactory outcomes. To more precisely classify ALL patients and optimize treatment, we re-evaluated the risk stratification system by examining CD20 expression and other classic risk factors at diagnosis. We retrospectively analyzed response to induction chemotherapy of 217 consecutive patients with newly diagnosed Philadelphia-negative B cell precursor-ALL. Survival analyses were conducted for the 136 patients who were intended to be treated with chemotherapy alone. Among the 217 patients, 69 (31.8%) were considered standard risk based on age <35 years, white blood cell count <30 * 109/L, absence of central nervous system involvement, and high-risk cytogenetic abnormalities. Seventy-four patients (34.1%) expressed CD20 on >=20% of leukemia blasts and were considered CD20 positive. We found that fewer CD20-positive than CD20-negative patients achieved durable first complete responses (CR1 >=3 months) (81.1% vs. 94.9%, P=0.002). Within the standard-risk group, more CD20-negative than CD20-positive patients achieved CR (100% vs. 83.3%, P=0.003) and durable CR1 (100% vs. 82.4%, P=0.014). For patients in the CD20-negative standard-risk, CD20 positive standard-risk, CD20-negative high-risk, and CD20-positive high-risk groups, the 3-year cumulative incidence of relapse was 42.6%, 70.0%, 59.3%, and 69.5%, respectively (P=0.118); the 3-year disease-free survival rates were 52.1%, 0%, 20.7%, and 13.7%, respectively (P=0.006); and the 3-year overall survival rates were 55.8%, 13.8%, 23.6%, and 16.9%, respectively (P=0.006). Our results suggest that patients with CD20-negative standard-risk B cell precursor-ALL have favorable prognosis compared with CD20-positive standard-risk or CD20-negative or -positive high-risk patients. CD20-positive standard-risk ALL patients may need other therapeutic modalities bridging to allogeneic hematopoietic stem cell transplantation. PMID- 29285258 TI - Mek activity is required for ErbB2 expression in breast cancer cells detached from the extracellular matrix. AB - Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fraction of breast cancers and promotes anchorage independent tumor cell growth by poorly understood mechanisms. In an effort to understand them we found that in order to produce ErbB2, detached breast cancer cells require the activity of an ErbB2 effector protein kinase Mek and that Mek driven ErbB2 expression is neccesary for anchorage-independent growth of such cells. We observed that Mek inhibition does not alter ErbB2 mRNA levels in detached cancer cells and that ErbB2 protein loss induced by this inhibition can be blocked by a lysosomal inhibitor. We also noticed that an increase of the density of cancer cells detached from the ECM downregulates a Mek effector protein kinase Erk and causes ErbB2 loss. Those cells that survive after ErbB2 loss display resistance to trastuzumab, an anti-ErbB2 antibody used for ErbB2 positive breast cancer treatment. Thus, Mek-induced ErbB2 stabilization in detached breast cancer cells is critical for their ability to grow anchorage independently and their trastuzumab sensitivity. PMID- 29285260 TI - Genetic variations of NTCP are associated with susceptibility to HBV infection and related hepatocellular carcinoma. AB - Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC. PMID- 29285261 TI - Use of autoantibodies against tumor-associated antigens as serum biomarkers for primary screening of cervical cancer. AB - Serum autoantibodies against tumor-associated antigens (TAAs) have received much attention as potential biomarkers for early detection of cancers, since they can be detected in the early stages of cancers. Autoantibodies against Cancer Antigen 15-3 (CA15-3), carcinoembryonic antigen (CEA), Cancer Antigen 19-9 (CA19-9), c Myc, p53, heat shock protein (Hsp)27 and Hsp70 have been suggested as potential markers for detecting several types of cancer. In the present study, the seven types of antibody listed above were evaluated for detecting cervical lesions. Enzyme-linked immunosorbent assays (ELISAs) were used to measure IgG levels of the autoantibodies in women with normal cytology, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III and cervical cancer. The increases of anti CA15-3 and anti-CEA IgG in cervical cancer were more pronounced than the increases of the other markers, and the level of anti-CA19-9 IgG in CIN III stage was higher than in normal CIN I, CIN II or cervical cancer. A combination of ELISAs detecting anti-CA15-3, anti-CEA and anti-CA19-9 IgGs was found to reliably discriminate CINs from normal and to strongly differentiate cancer from normal (90.3% of sensitivity and 82.1% of specificity). We suggest that the combination of three ELISA may be useful for detecting cervical lesions. PMID- 29285263 TI - Predicting castration-resistant prostate cancer after combined androgen blockade. AB - This study analyzed 99Tcm-MDP bone scans and investigated factors influencing early-stage castration resistance in prostate cancer (CRPC) patients with bone metastasis. We retrospectively analyzed clinical data from 92 patients with bone metastatic prostate cancer treated with maximal androgen blockade. Patients were imaged with 99Tcm-MDP bone scan to detect metastases, and prostate specific antigen (PSA) values were measured regularly. Before treatment, 464 total bone metastases were detected in the 92 patients, with pelvic bone metastases accounting for about 30.6% of the total. After combined androgen blockade treatment, median CRPC occurrence time was 23 months. A longer time to reach the lowest PSA value was an independent predictor of early-onset CRPC (occurrence <1 year after treatment). Our findings suggest that 99Tcm-MDP bone scans are useful for diagnosing prostate cancer bone metastasis and grading. Patients with Gleason scores>8, higher PSA values after treatment, and shorter times to reach the lowest PSA value had poorer responses to combined androgen blockade treatment. PMID- 29285262 TI - Nuclear membrane-localised NOX4D generates pro-survival ROS in FLT3-ITD expressing AML. AB - Internal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) is the most prevalent genetic aberration present in 20-30% of acute myeloid leukaemia (AML) cases and is associated with a poor prognosis. FLT3 ITD expressing cells express elevated levels of NADPH oxidase 4 (NOX4)-generated pro-survival hydrogen peroxide (H2O2) contributing to increased levels of DNA oxidation and double strand breaks. NOX4 is constitutively active and has been found to have various isoforms expressed at multiple locations within a cell. The purpose of this study was to investigate the expression, localisation and regulation of NOX4 28 kDa splice variant, NOX4D. NOX4D has previously been shown to localise to the nucleus and nucleolus in various cell types and is implicated in the generation of reactive oxygen species (ROS) and DNA damage. Here, we demonstrate that FLT3-ITD expressing-AML patient samples as well as -cell lines express the NOX4D isoform resulting in elevated H2O2 levels compared to FLT3-WT expressing cells, as quantified by flow cytometry. Cell fractionation indicated that NOX4D is nuclear membrane-localised in FLT3-ITD expressing cells. Treatment of MV4-11 cells with receptor trafficking inhibitors, tunicamycin and brefeldin A, resulted in deglycosylation of NOX4 and NOX4D. Inhibition of the FLT3 receptor revealed that the FLT3-ITD oncogene is responsible for the production of NOX4D generated H2O2 in AML. We found that inhibition of the PI3K/AKT and STAT5 pathways resulted in down-regulation of NOX4D-generated pro-survival ROS. Taken together these findings indicate that nuclear membrane-localised NOX4D-generated pro-survival H2O2 may be contributing to genetic instability in FLT3-ITD expressing AML. PMID- 29285264 TI - Decreased incidence of glaucoma in children with asthma using inhaled corticosteroid: a cohort study. AB - Among the anti-inflammatory medications used for treating asthma, corticosteroids are the most effective. The effects of orally administered corticosteroids on intraocular pressure and lens opacity have been well defined, but the influence of inhaled corticosteroids (ICS) on children has yet to be clearly explained. Therefore, we used a nationwide cohort database to investigate glaucoma in childhood asthma patients using ICS. We analyzed a dataset of 1,000,000 randomly sampled individuals from Taiwan's 2000 National Health Insurance Research Database. The study cohort included 5,380 patients who were first diagnosed with asthma (ICD9: 493.X) diagnosis when they were six years old or younger. All subjects were followed through December 2011. We applied Cox's proportional hazard model to determine whether ICS use has a correlation with glaucoma. Of the 5,380 patients enrolled in this study, we identified 1,232 patients who had used ICS and 4,148 patients who had no history of ICS administration throughout the follow-up period. The prevalence of glaucoma was significantly lower in patients using ICS, with a 0.52-fold decreased risk of developing glaucoma in comparison to the control group [adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.28~0.96]. Among the evaluated comorbidities, cataract was positively associated with glaucoma in asthma children (adjusted HR 8.22; 95% CI = 2.59~26.12). This study provides not only the first but also strong evidence that the glaucoma incidence in the ICS group is lower than that in the non-ICS group in children with asthma. Further consultation with an ophthalmologist regarding the high-risk group of asthma children with cataracts is necessary. PMID- 29285266 TI - Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations. AB - Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to first- and second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with the EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFR-TKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs. The present study used this approach to characterize the efficacy of third-generation EGFR-TKIs and compare them with that of other EGFR TKIs. Treatment efficacy was examined using human lung cancer-derived cell lines and Ba/F3 cells, which were transduced with clinically relevant mutant EGFRs. Interestingly, mutation-related differences in EGFR-TKI sensitivity were observed. For classic EGFR mutations (exon 19 deletion and L858R, with or without T790M), osimertinib showed lower IC50 values and wider therapeutic windows than nazartinib. For less common EGFR mutations (G719S or L861Q), afatinib showed the lowest IC50 values. For G719S+T790M or L861Q+T790M, the IC50 values of osimertinib and nazartinib were around 100 nM, which was 10- to 100-fold higher than those for classic+T790M mutations. On the contrary, osimertinib and nazartinib showed similar efficacies in cells expressing EGFR exon 20 insertions. The findings highlight the diverse mutation-related sensitivity pattern of EGFR TKIs. These data may help in the selection of EGFR-TKIs for non-small cell lung cancer patients harboring EGFR mutations. PMID- 29285265 TI - Role of VEGFA gene polymorphisms in colorectal cancer patients who treated with bevacizumab. AB - Objectives: This study aimed to explore the effects of vascular endothelial growth factor A (VEGFA) gene polymorphisms (rs699947 and rs833061) on Bevacizumab (BEV) treatment in colorectal cancer (CRC) patients. Methods: 125 CRC cases receiving BEV plus FOLFIRI treatment were recruited in this study. VEGFA polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Correlation of VEGFA gene polymorphisms with the response rate and progression free survival (PFS) was evaluated. Multivariate analyses were performed to estimate the effects of VEGFA polymorphisms on the therapeutic effects of BEV treatment in CRC patients. Results: Rs699947 variants did not show significant association with BEV treatment. For rs833061 analysis, TT and TC genotype carriers had significantly higher ORR (objective response rate) than CC carriers (P=0.048 and P=0.021, respectively). Moreover, TT carriers underwent a well DCR (disease control rate) compared to CC carriers (P=0.002). PFS time also showed obvious correlation with rs833061 polymorphism (log rank test, P=0.002). Multivariate analyses demonstrated that TT and TC genotypes of rs833061 polymorphism were significantly correlated with enhanced therapeutic effects and prolonged PFS in CRC patients. Conclusion: VEGFA rs833061 polymorphism is significantly associated with the therapeutic efficiency of bevacizumab in CRC patients. PMID- 29285267 TI - A molecular signature of lung cancer: potential biomarkers for adenocarcinoma and squamous cell carcinoma. AB - Adenocarcinoma (AC) and squamous cell carcinoma (SCC), sub-types of non-small cell lung cancer (NSCLC), both present unique features at the genome, epigenome, transcriptome and proteome levels, as well as shared clinical and histopathological characteristics, but differ in terms of treatment. To ensure proper treatment, one must be able to distinguish between these sub-types. Here, we identify novel biomarker proteins in NSCLC, allowing for distinguishing between the AC and SCC sub-types. Proteomics analysis distinguished between healthy and tumor tissues, with the expression level of 1,494 proteins being altered, 378 of which showed a >=|100|-fold change. Enrichment of proteins related to protein synthesis and degradation, and of proteins associated with mitochondria, metabolism, and apoptosis, was found. Network analysis defined groups of proteins, such as those associated with cell metabolic processes or with fatty acid/lipid metabolism and transport. Several biomarkers that enable for distinguishing between AC and SCC were identified here for the first time, and together with previous reports confirmed here, led us to propose a list of proteins differentially expressed in SCC and AC. Some of these biomarkers are clear signatures for AC or SCC and four of them are secreted proteins. The presence of the mitochondrial protein SMAC/Diablo in the nucleus was found to be a signature for SCC. Precise diagnosis of AC and SCC is essential for selecting appropriate treatment and thus, increasing patient life expectancy. Finally, the search for drugs that target some of these biomarkers may lead to new treatments for lung cancer. PMID- 29285268 TI - Reactive oxygen species levels control NF-kappaB activation by low dose deferasirox in erythroid progenitors of low risk myelodysplastic syndromes. AB - Anemia is a frequent cytopenia in myelodysplastic syndromes (MDS) and most patients require red blood cell transfusion resulting in iron overload (IO). Deferasirox (DFX) has become the standard treatment of IO in MDS and it displays positive effects on erythropoiesis. In low risk MDS samples, mechanisms improving erythropoiesis after DFX treatment remain unclear. Herein, we addressed this question by using liquid cultures with iron overload of erythroid precursors treated with low dose of DFX (3MUM), which corresponds to DFX 5 mg/kg/day, an unusual dose used for iron chelation. We highlight a decreased apoptosis rate and an increased proportion of cycling cells, both leading to higher proliferation rates. The iron chelation properties of low dose DFX failed to activate the Iron Regulatory Proteins and to support iron depletion, but low dose DFX dampers intracellular reactive oxygen species. Furthermore low concentrations of DFX activate the NF-kappaB pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-kappaB modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-kappaB. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents. PMID- 29285270 TI - Metformin alleviates nickel-induced autophagy and apoptosis via inhibition of hexokinase-2, activating lipocalin-2, in human bronchial epithelial cells. AB - Autophagy is an intracellular recycling and degradation process for regulating tumor progression, survival and drug resistance. Nickel compounds have been identified as human carcinogens. However, the role of nickel-induced autophagy in lung carcinogenesis has not yet been fully elucidated. In this study, we determined that hexokinase 2 (HK2), which phosphorylates glucose and regulates autophagy, is the key mediator in nickel-induced autophagy in lung bronchial epithelial cells. We attempted to investigate the effects of the antidiabetic drug metformin on HK2 expression and lung cancer chemoprevention. Our results showed that metformin decreases nickel-induced autophagy and activation of apoptosis through inhibition of HK2 gene, protein and activity. Furthermore, we demonstrated that lipocalin 2 (LCN2), which is released by neutrophils at sites of infection and inflammation is involved in HK2-driven autophagy pathway. Knockdown of endogenous HK2 and LCN2 by shRNA reduced nickel-elicited autophagy and apoptosis, illustrating that metabolic alteration and inflammatory action are important in nickel-elicited carcinogenesis. We also determined the association between nickel-induced autophagy and apoptosis. Inhibition of nickel-induced autophagy abolished apoptotic cell death in chloroquine-treated, shLC3 Beas-2B cells and Atg5-/- MFFs. From TGCA database and immunohistochemistry analysis, HK2 and LCN2 expression increased in lung squamous cell carcinoma and their related adjacent normal tissues. Taken together, our results demonstrated that metformin alleviates NiCl2-induced autophagy and apoptosis via HK2-driven LCN2 activation in human bronchial epithelial cells. This novel mechanism provides a strategy for targeting nickel-elicited lung cancer progression, as well as for preventing HK2 cumulative damage triggered by environmental carcinogens. PMID- 29285269 TI - SphK2 over-expression promotes osteosarcoma cell growth. AB - It is needed to explore novel biological markers for early diagnosis and treatment of human osteosarcoma. Sphingosine kinase 2 (SphK2) expression and potential functions in osteosarcoma were studied. We demonstrate that SphK2 is over-expressed in multiple human osteosarcoma tissues and established human osteosarcoma cell lines. Silence of SphK2 by targeted-shRNAs inhibited osteosarcoma cell growth, and induced cell apoptosis. On the other hand, exogenous over-expression of SphK2 could further promote osteosarcoma cell growth. Notably, microRNA-19a-3p ("miR-19a-3p") targets the 3' UTR (untranslated region) of SphK2 mRNA. Remarkably, forced-expression of miR-19a-3p silenced SphK2 and inhibited osteosarcoma cell growth. In vivo, SphK2 silence, by targeted-shRNA or miR-19a-3p, inhibited U2OS tumor growth in nude mice. These results suggest that SphK2 could be a novel and key oncotarget protein for OS cell progression. PMID- 29285271 TI - Identification of a three miRNA signature as a novel potential prognostic biomarker in patients with bladder cancer. AB - There is not a good biomaker that is closely related to survival time for bladder cancer(BLCA), The aim of the study is to identify a miRNA signature that could predict prognosis in BLCA patients according to the data from The Cancer Genome Atlas (TCGA). a total of 377 BLCA patients were finally enrolled in the study. The three miRNA signature was identified by Multivariate Cox proportional hazards analyses that common clinical variables were controled. The three microRNA signature showed greater predicting prognosis capacity for predicting 5-year survival in BLCA with an AUC of 0.664, 0.681 and 0.668 in Train set, Test set and Total set respectively. Furthermore, there was a significant difference between high score and low score in Total set(P=3e-05), Test set(P=0.00435) and Train set(P=0.00143), respectively. Therefore, these results provided a new prospect for prognostic biomarker of BLCA. PMID- 29285272 TI - Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction. AB - Background: Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. Methods: PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. Results: The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERalpha, and GR. At a low concentration, 2.5 MUM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Conclusions: Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth. PMID- 29285273 TI - The meta and bioinformatics analysis of fascin expression in gastric cancer: a potential marker for aggressiveness and worse prognosis. AB - Fascin is a FSCN1-encoded actin bundling protein, and positively associated with proliferation, migration and metastasis of malignancies. Here, we performed a systematic meta and bioinformatics analysis through multiple online databases up to March 14, 2017. We found up-regulated fascin expression in gastric cancer, compared with normal mucosa (p<0.05). Fascin expression was positively with lymph node metastasis, TNM staging and worse prognosis of gastric cancer (p<0.05). According to bioinformatics database, FSCN1 mRNA expression was higher in gastric cancer than normal tissues (p<0.05). According to Kaplan-Meier plotter, we found that a higher FSCN1 expression was negatively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters (p<0.05). These findings indicated that fascin expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis. PMID- 29285275 TI - Apatinib is effective for treatment of advanced hepatocellular carcinoma. AB - As treatment options for hepatocellular carcinoma (HCC) are currently limited, we evaluated the efficacy and safety of oral apatinib, a VEGFR-2 inhibitor, on patients with advanced HCC. Twenty-two patients from Tianjin Medical University Cancer Institute and Hospital were enrolled for evaluation. Apatinib was administered at 500 mg/day or 250 mg/day continuously. Clinical endpoints were time to disease progression (TTP), overall survival (OS), and safety. The median TTP of treated patients was 10.4 months (95% CI 3.4 -17.5). At the last follow up, 50% patients had survived longer than 11.4 months from the first dose. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0%, 40.9%, 40.9%, and 18.2%, respectively. The most common apatinib-related adverse events were hand-foot skin reaction (HFSR) (81.8%) and diarrhea (77.3%). Hypertension (27.3%) and HFSR (13.6%) were the most frequent grade 3/4 adverse events. In summary, results of this small study indicate that apatinib is well tolerated and extremely effective for the treatment of advanced HCC. It is therefore imperative to design and carry out well-controlled clinical trials to confirm its efficacy. PMID- 29285274 TI - Lipopolysaccharide-coated CuS nanoparticles promoted anti-cancer and anti metastatic effect by immuno-photothermal therapy. AB - To meet the ultimate goal of cancer therapy, which is treating not only the primary tumor but also preventing metastatic cancer, the concept of combining immunotherapy with photothermal therapy (PTT) is gaining great interest. Here, we studied the new material, lipopolysaccharide (LPS) coated copper sulfide nanoparticles (LPS-CuS), for the immuno-photothermal therapy. We evaluated the effect of LPS-CuS for induction of apoptosis of CT26 cells and activation of dendritic cells. Moreover, the LPS-CuS and laser irradiation was examined anti metastasis effect by liver metastasis model mouse in vivo. Through PTT, LPS-CuS induced elimination of CT26 tumor in BALB/c mice, which produced cancer antigens. In addition, released LPS and cancer antigen by PTT promoted dendritic cell activation in tumor draining lymph node (drLN), and consequently, enhanced the tumor antigen-specific immune responses. Finally, the primary tumor cured mice by LPS-CuS-mediated PTT completely resisted secondary tumor injection in the spleen and also prevented liver metastasis. Our results demonstrated the potential usage of LPS-CuS for the immuno-photothermal therapy against various types of cancer by showing the clear elimination of primary colon carcinoma with complete prevention of spleen and liver metastasis. PMID- 29285276 TI - Pilot study: molecular risk factors for diagnosing sporadic Parkinson's disease based on gene expression in blood in MPTP-induced rhesus monkeys. AB - Clinical diagnosis of Parkinson's disease (PD) is characterized by the classical features of tremor, bradykinesia and rigidity, which are present only when more than 70%-80% degeneration of dopaminergic (DA) neurons in the substantia nigra. The lack of means for early diagnosis of PD has elicited interest in searching for its risk factors, which, by now, are almost obtained at a single time point in PD process, and little developing risk factors, obtained from completely normal situation to the onset or even advanced stage of PD in individual person which could monitor the progress of PD, are present. Here we have detected some potential factors in the blood of MPTP induced PD monkeys along with the progress of the disease. All the PD monkeys showed mild PD symptoms since the 9th week and gradually reached a classic and stable parkinsonism stage at the 18th week. Our results have found that the expression of Parkin, USP30, MUL1, PINK1, and LRRK2 significantly increased at 1st, 3th, 3th, 5th, and 8th week respectively and remained high till the end; The expression of UCHL1 and TRIM24 significantly increased at the 1st and 18th week, respectively, then gradually decreased and significantly lower than normal value; DJ-1 showed significantly decreased since the 12th week, while SNCA showed no significantly changed excepted at the 5th week. And, the terminal results of whole blood were highly consistent with those of in SN. These results support that these genes change may as biomarkers to monitor the progress of PD, and may facilitate the development of biomarkers for early diagnosis. PMID- 29285277 TI - Indirubin, a bisindole alkaloid from Isatis indigotica, reduces H1N1 susceptibility in stressed mice by regulating MAVS signaling. AB - Isatis indigotica has a long history in treating virus infection and related symptoms in China. Nevertheless, its antivirus evidence in animal studies is not satisfactory, which might be due to the lack of appropriate animal model. Previously, we had utilized restraint stress to establish mouse H1N1 susceptibility model which was helpful in evaluating the anti-virus effect of medicines targeting host factors, such as type I interferon production. In this study, this model was employed to investigate the effect and mechanism of indirubin, a natural bisindole alkaloid from Isatis indigotica, on influenza A virus susceptibility. In the in vitro study, the stress hormone corticosterone was used to simulate restraint stress. Our results demonstrated that indirubin decreased the susceptibility to influenza virus with lowered mortality and alleviated lung damage in restraint-stressed mice model. Moreover, indirubin promoted the expression of interferon-beta and interferon inducible transmembrane 3. In addition, indirubin maintained the morphology and function of mitochondria following influenza A virus infection. Further study revealed that indirubin promoted interferon-beta production through promoting mitochondrial antiviral signaling pathway. Our study indicated that indirubin could be a candidate for the therapy of influenza. PMID- 29285278 TI - Relationship between expression of cyclooxygenase 2 and neovascularization in human pterygia. AB - In present study, we are to test the relationship between cyclooxygenase 2 (COX 2) and angiogenesis in pterygium tissues from a group of Chinese patients. Here forty-five primary pterygium tissues and twenty-three normal bulbar conjunctival tissues were obtained during ophthalmologic surgeries. The primary pterygium samples were treated for the immunohistochemical evaluation of COX-2, CD31 and vascular endothelial growth factor (VEGF) antibodies for different tissues. In order to evaluate the relationship between COX-2 and neovascularization, a statistical analysis was performed using the SPSS 13.0 statistical software package. As results, in our study, 36 (80%) of the primary pterygia samples were found to be positive for COX-2 staining, which was not found in the normal conjunctivas. The density of the microvessels (MVD) was significantly increased in the COX-2 positive patients when compared to the COX-2 negative ones (19.06 +/ 1.84 vs.10.44 +/- 2.98, P=1.36*10-5) in the pterygia cases. In the group that was positive for COX-2, there were 39 (86.7%) samples with VEGF expression. Furthermore, the staining of both COX-2 and VEGF was localized to the lower and middle layers of the epithelium and the endothelial cells of the microvessels. When analyzed the relation between them, the expression of COX-2 showed a significant correlation with the MVD (P = 4.02*10-4) and VEGF (p = 2.72*10-4). In conclusion, the present study showed that COX-2 may play an important role in stimulating the angiogenesis of pterygium in concert with VEGF. PMID- 29285279 TI - Survivin overexpression is potentially associated with pituitary adenoma invasiveness. AB - Background and objective: Survivin is an inhibitor of apoptosis. Its role in guiding the treatment of neoplasms, making diagnosis and predicting prognosis has been reported. However, there is little information on the implications and uses of survivin in predicting pituitary adenoma (PA) invasiveness. Existing information is unclear and controversial. We thus conducted this meta-analysis to explore whether the surviving expression levels in invasive PAs (IPA) and regular PAs are different or not. We considered both non-secreting and secreting tumors together. Methods: A global search strategy was systematically applied among five databases including Cochrane Library, Embase, PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) up to June 18th, 2017. With a specially designed form including PAs' invasive features, etc., data was collected. The included studies should present the data representing the surviving levels in IPA groups and regular PA groups, respectively. Differences were expressed as standard mean differences (SMDs) or odds ratios (ORs) with 95% confidence interval (CI). To estimate the heterogeneities, I2 test, Cochran's Q-test and Galbr figure were all conducted. A sensitivity-analysis and potential-publication bias were also performed. Results: In the present meta-analysis, 9 studies containing 489 patients were included. Seven studies with dichotomous-data showed that survivin over-expression in PA tissue was closely associated with a high invasive tendency (OR 6.226, 95% CI 3.970, 9.765; P<0.001), but 2 continuous-data studies revealed that there was no significant association (SMD -5.043, 95% CI 10.965, 0.878; p=0.095). A sensitivity-analysis suggested a statistically stable result. We did not find publication bias. Conclusion: We suggest that survivin overexpression is potentially associated with PA invasiveness. More research based on medical big data is needed to confirm this finding. PMID- 29285280 TI - Altered network efficiency of functional brain networks in patients with breast cancer after chemotherapy. AB - Objective: To investigate the topological organization of functional brain networks in chemotherapy-treated breast cancer (BC) patients with source memory impairment. Methods: Twenty-eight patients with BCfollowingchemotherapyand40age and education-matched healthy controls (HCs) were recruited in the current study. All participants underwent source memory tests and resting-state functional MRI scans. Individual whole-brain functional brain networks were constructed and analyzed using graph-based network approaches. Results: Compared with the HCs, the BC patients showed lower scores in the source memory tests (P < 0.001).Graph based analyses revealed that the patients showed higher absolute global and local efficiency (both P < 0.01) but lower normalized global and normalized local efficiency (both P< 0.001) compared with the HCs. Locally, several prefrontal, occipital, and parietal regions exhibited higher nodal efficiency and functional connectivity in the patients(P< 0.05, corrected). Finally, positive correlations were observed between normalized global efficiency and Mini-Mental State Examination scores (r = 0.398, P = 0.036) and between normalized local efficiency and the source memory scores (r = 0.497, P = 0.01) in the patients. Conclusion: Chemotherapy-treated BC is associated with abnormal organization of large-scale functional brain networks, which could account for source memory dysfunction in patients with BC. PMID- 29285282 TI - A green and facile preparation approach, licochalcone A capped on hollow gold nanoparticles, for improving the solubility and dissolution of anticancer natural product. AB - This study described a valuable drug delivery system for poorly water-soluble anticancer naturalproduct, licochalcone A, isolated from Glycyrrhiza inflata, loaded on hollow gold nanoparticles by green method to improve solubility and dissolution and maintain its natural pharmacological property. Briefly, the formation of hollow gold nanoparticles involves three steps: preparing of silica nanospheres by Stober method, forming of a thick gold shell around the silica templates and etching of silica particles by HF solution. Hollow gold nanoparticles (HGNPs) and drug loaded hollow gold nanoparticles (L-HGNPs) displayed spherical structure and approximately 200nm in size observed by SEM, XRD, EDS and DSC analysis showed that HGNPs were gold hollow structure and crystalline form. The solubility in aqueous solution of licochalcone A was increased obviously to 488.9 MUg/ml, compared with free drugs of 136.1 MUg/ml. Another interesting finding is that near-infrared (NIR) irradiation increased the speed of solubility of licochalcone A in aqueous solutions, rather than quantity. In short, the method of nano-delivery system combined with poorly water-soluble drug to improve its solubility and dissolution is worth applying to other natural products in order to increase their opportunities in clinical applications. PMID- 29285281 TI - Activation of Nrf2 by MIND4-17 protects osteoblasts from hydrogen peroxide induced oxidative stress. AB - MIND4-17 is a recently developed NF-E2-related factor 2 (Nrf2) activator, which uniquely causes Nrf2 disassociation from Keap1. Here, we showed that pretreatment with MIND4-17 significantly inhibited hydrogen peroxide (H2O2)-induced viability reduction of primary osteoblasts and OB-6 osteoblastic cells. Meanwhile, MIND4-17 inhibited both apoptotic and non-apoptotic osteoblast cell death by H2O2. MIND4 17 treatment induced Keap1-Nrf2 disassociation, causing Nrf2 stabilization, accumulation and nuclear translocation in osteoblasts, leading to transcription of several Nrf2-dependent genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), gamma-glutamylcysteine synthetase modifier subunit (GCLM) and catalytic subunit (GCLC). Additionally, MIND4-17 largely attenuated H2O2-reactive oxygen species (ROS) production, lipid peroxidation and DNA damages. Nrf2 knockdown by targeted short hairpin RNA (shRNA) exacerbated H2O2-induced cytotoxicity in OB-6 osteoblastic cells, and nullified MIND4-17 mediated cytoprotection against H2O2. Meanwhile, Keap1 shRNA took over MIND4-17's actions and protected OB-6 cells from H2O2. Together, MIND4-17 activates Nrf2 signaling and protects osteoblasts from H2O2. PMID- 29285283 TI - Diffusion-weighted MRI-derived ADC values reflect collagen I content in PDX models of uterine cervical cancer. AB - Apparent diffusion coefficient (ADC) values derived from diffusion-weighted magnetic resonance imaging (DW-MRI) are known to reflect the cellular environment of biological tissues. However, emerging evidence accentuates the influence of stromal elements on ADC values. The current study sought to elucidate whether a correlation exists between ADC and the fraction of collagen I-positive tissue across different tumor models of uterine cervical cancer. Early and late generation tumors of four patient-derived xenograft (PDX) models of squamous cell carcinoma (BK-12, ED-15, HL-16, and LA-19) were included. DW-MRI was performed with diffusion encoding constants (b) of 200, 400, 700, and 1000 s/mm2 and diffusion gradient sensitization in three orthogonal directions. The fraction of collagen I-positive connective tissue was determined by immunohistochemistry. Mono-exponential decay curves, from which the ADC value of tumor voxels was calculated, yielded good fits to the diffusion data. A significant inverse correlation was detected between median tumor ADC and collagen I fraction across the four PDX models, indicating that collagen fibers in the extracellular space have the ability to inhibit the movement of water molecules in these xenografts. The results encourage further exploration of DW-MRI as a non-invasive imaging method for characterizing the stromal microenvironment of tumors. PMID- 29285284 TI - Activation of the NGF/TrkA signaling pathway attenuates diabetic erectile dysfunction. AB - Erectile dysfunction (ED) is a common complication of diabetes mellitus (DM). The exact role of the NGF/TrkA signaling pathway in the pathogenesis of diabetic ED is largely unknown. In the present study, we investigated the role of the NGF/TrkA signaling pathway in Sprague-Dawley rats with diabetic ED. Animals were divided into 2 groups: the normal group and the DM ED model group. The model group included the blank subgroup, the negative control (NC) subgroup, the TrkA subgroup and the TrkA + NGF subgroup. Erectile function, intracavernous pressure (ICP) and mean arterial pressure were measured respectively. Immunohistochemistry was used to examine the number of neuronal nitric oxide synthase (nNOS) expressing nerve fibers. The quantitative real-time polymerase chain reaction was applied to detect the mRNA expressions of NGF and TrkA in the cavernous tissue. Further, Western blotting was conducted to detect the expressions of NGF, TrkA and its downstream ERK pathway-related proteins. Higher erectile frequency, ICP values and diastolic function, more nNOS-positive nerve fibers, and decreased systolic function of the corpus cavernosum smooth muscle were found in the TrkA and TrkA+NGF groups when compared with the blank and the NC groups. Moreover, significantly higher mRNA expressions of NGF and TrkA, and upregulated protein expressions of NGF, TrkA, c-raf, ERK1/2 and CREB1 were found in the TrkA and the TrkA + NGF groups. In conclusion, downregulation in the NGF/TrkA signaling pathway may contribute to the pathogenesis of diabetic ED. PMID- 29285285 TI - Ginseng Rh2 protects endometrial cells from oxygen glucose deprivation/re oxygenation. AB - In this study, oxygen glucose deprivation/re-oxygenation (OGDR) was applied to cultured endometrial cells to mimic ischemic-reperfusion injuries. We also tested the potential effect of Ginseng Rh2 (GRh2) against the process. In established T HESC human endometrial cells and primary murine endometrial cells, GRh2 largely inhibited OGDR-induced viability reduction and cell death. Remarkably, OGDR induced programmed necrosis in the endometrial cells, evidenced by cyclophilin D p53-adenine nucleotide translocator 1 (ANT-1) mitochondrial association, mitochondrial depolarization, reactive oxygen species production, and lactate dehydrogenase release. Notably, such effects by OGDR were largely attenuated with co-treatment of GRh2. Further, cyclophilin D inhibition or knockdown also protected endometrial cells from OGDR. On the other hand, forced over-expression of cyclophilin D facilitated OGDR-induced T-HESC cell necrosis, which was dramatically inhibited by GRh2. Together, GRh2 protects endometrial cells from OGDR possibly via inhibiting CypD-dependent programmed necrosis pathway. PMID- 29285286 TI - MutT-related proteins are novel progression and prognostic markers for colorectal cancer. AB - Background: MutT-related proteins, including MTH1, MTH2, MTH3 and NUDT5, can effectively degrade 8-oxoGua-containing nucleotides. The MTH1 expression is elevated in many types of human tumors and MTH1 overexpression correlates with the tumor pathological stage and poor prognosis. However, the expression of other MutT-related proteins in human cancers remains unknown. The present study systematically investigated the expression of MTH1, MTH2, MTH3 and NUDT5 in human colorectal cancer to establish its clinical significance. Methods: Amounts of MutT-related mRNA and protein in CRC cell lines were assessed by qRT-PCR and Western blotting, respectively. Furthermore, the MutT-related protein expression was evaluated by immunohistochemical staining of tissue microarrays containing 87 paired CRC tissues and by Western blotting of 44 CRC tissue samples. Finally, the effect of knockdown of MutT-related proteins on CRC cell proliferation was investigated. Results: The expression of MTH1, MTH2, MTH3 and NUDT5 was significantly higher in CRC cells and CRC tissues than normal cells and tissues, and this phenomenon was significantly associated with AJCC stage and lymph node metastasis of CRC specimens. CRC patients with high expression of MTH1, MTH2 or NUDT5 had an extremely poor overall survival after surgical resection. Notably, NUDT5 was an independent prognostic factor of CRC patients. We found that knockdown of MutT-related proteins inhibited CRC cell proliferation. Conclusions: We showed for the first time that MutT-related proteins play an important role in CRC progression and prognosis. Further investigations are needed to elucidate the role of these proteins in CRC progression and their potential use for therapeutic targets. PMID- 29285287 TI - MerTK inhibition by RXDX-106 in MerTK activated gastric cancer cell lines. AB - RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment. We also investigated the effect of RXDX 106 in patient-derived cell lines to mimic the in vivo condition. The prevalence of MerTK protein overexpression was evaluated in 229 cancer tissue specimens. We have found that MerTK inhibitor treatment resulted in considerable inhibition of cell growth and downstream signaling. In addition, MerTK phosphorylation, not total MerTK expression, is likely more predictive of therapeutic success. p-MerTK protein overexpression by IHC was found in 18% (17/87) of GC patients. Lastly, RXDX-106 inhibited cell proliferation in MerTK activated gastric cancer cell line. These findings provide further evidence of oncogenic roles for MerTK in GC, and demonstrate the importance of kinase activity for MerTK tumorigeneicity and validate RXDX-106, a novel MerTK inhibitor, as a potential therapeutic agent for treatment of GC. PMID- 29285288 TI - Synthetic nickel-containing superoxide dismutase attenuates para-phenylenediamine induced bladder dysfunction in rats. AB - Para (p)-phenylenediamine and its toxic metabolites induce excess reactive oxygen species formation that results in bladder voiding dysfunction. We determined the effects of synthetic Ni-containing superoxide dismutase mimics and the role of oxidative stress in p-phenylenediamine-induced urinary bladder dysfunction. P phenylenediamine (60 MUg/kg/day) was intraperitoneally administered for 4 weeks to induce bladder injury in female Wistar rats. Synthetic Ni-containing superoxide dismutase mimics, WCT003 (1.5 mg/kg) and WCT006 (1.5 mg/kg), were then intraperitoneally administered for 2 weeks. Transcystometrograms were performed in urethane-anesthetized rats. The in vitro and in vivo reactive oxygen species levels and pathological changes in formalin-fixed bladder sections were evaluated. Western blotting and immunohistochemistry elucidated the pathophysiological mechanisms of oxidative stress-induced apoptosis, autophagy, and pyroptosis. P-phenylenediamine increased voiding frequency, blood and urinary bladder levels of reactive oxygen species, and neutrophil and mast cell infiltration. It also upregulated biomarkers of autophagy (LC3 II), apoptosis (poly (ADP-ribose) polymerase), and pyroptosis (Caspase 1). WCT003 and WCT006 ameliorated reactive oxygen species production, inflammation, apoptosis, autophagy, pyroptosis, and bladder hyperactivity. P-phenylenediamine increased oxidative stress, inflammatory leukocytosis, autophagy, apoptosis, and pyroptosis formation within the urinary bladder. Novel synthetic nickel-containing superoxide dismutase mimics relieved p-phenylenediamine-induced bladder inflammation and voiding dysfunction. PMID- 29285289 TI - Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306). AB - Purpose: To assess the impact of primary tumor sidedness on outcome of patients with metastatic colorectal cancer (mCRC) across treatment lines. Patients and Methods: Patients of the FIRE-3 trial (initial FOLFIRI plus either cetuximab or bevacizumab) were separately evaluated according to primary tumor site differentiating left-sided (LPT) from right-sided primary tumors (RPT). Efficacy (i.e. progression-free survival (PFS2nd) and overall survival (OS2nd) of second line therapy) was evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression analyses. All analyses were also reported according to drug sequences. Results: 411 of 592 patients (69%) with KRAS exon 2 wild-type tumors received 2nd-line therapy has and had available information on primary tumor location, of those 309 patients (75%) presented with LPT. In patients with LPT, PFS2nd was markedly longer than in patients with RPT (6.0 months [95% CI 5.5 6.5] versus 3.8 months [95% CI 2.5-5.2], hazard ratio: 0.61 [95% CI 0.47-0.78], P<0.001). Differences in PFS2nd between study-arms were evident in patients with LPT, but not in patients with RPT (Cox model interaction test, P=0.12). Consistent observations were also made for OS2nd. Conclusion: This retrospective analysis of FIRE-3 indicates that efficacy of second-line therapy was significantly greater in patients with left-sided tumors as compared to right sided tumors. This difference was driven by superior activity of second-line regimens of the initial cetuximab-arm as compared to the initial bevacizumab-arm in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in second-line therapy of mCRC. PMID- 29285290 TI - Preliminary quantitative proteomics analysis in chronic and latent Keshan disease by iTRAQ labeling approach. AB - Keshan disease is a congestive cardiomyopathy. Dietary selenium deficiency combined with additional stressors are recognized to cause the cardiomyopathies. In this study, clinical condition of individuals with different subtypes including chronic and latent were analyzed. ECG abnormalities, chest radiography, echocardiography and blood selenium concentration were assessed. Subsequently, in effort to uncover proteins that were reliably changed in patients, isobaric tags for absolute and relative quantitation technology was applied. Bioinformatics analysis of the differentially expressed proteins were performed by means of Gene Ontology classification, KEGG pathway, and Ingenuity Pathway Analysis. ELISA experiment was used to detect the interesting proteins. As a result, chronic patients showed more EGC abnormalities compared to Latent. All patients had low blood selenium level. Proteomics data revealed 28 differentially expressed proteins. By ELISA variation, LGALS3BP was increased in chronic patients. PZP was elevated specially in latent patients. The above results might be beneficial for further biomarkers discovery and Keshan disease pathological mechanism study. PMID- 29285291 TI - Serum SDF-1 levels are a reliable diagnostic marker of feline mammary carcinoma, discriminating HER2-overexpressing tumors from other subtypes. AB - The feline mammary carcinoma (FMC) is the third most common tumor in cat, sharing many clinicopathological features with human breast cancer and thus, considered a suitable model for comparative oncology. Due to its poor prognosis, further studies are required to improve the diagnostic accuracy and treatment of cats with spontaneous mammary carcinoma. Recently, it was reported that the overexpression of stromal cell-derived factor-1 (SDF-1) has great value in human breast cancer diagnosis, suggesting that diagnostic tools and therapies targeting the SDF-1 ligand can improve the clinical outcome. In this study, we aimed to evaluate if serum SDF-1 levels can also be used as a biomarker of mammary carcinoma in cats and to analyze if serum SDF-1 levels are associated with clinicopathological features, linked to a specific FMC subtype or correlated with the tumor expression of SDF-1 receptor, the chemokine C-X-C motif receptor 4 (CXCR4). Results showed that cats with mammary carcinoma had significantly higher serum SDF-1 levels than healthy controls (p=0.035) and ROC analysis revealed that the best cut-off value to differentiate sick from healthy animals was 2 ng/ml (specificity: 80%; sensitivity: 57%; AUC=0.715). Significant associations were also found between cats with elevated serum SDF-1 concentrations (>= 2 ng/ml) and HER2-overexpressing mammary carcinomas (Luminal B-like and HER2-positive subtypes, p<0.0001), CXCR4-negative mammary carcinomas (p=0.027), mammary carcinomas with small size (<3 cm, p=0.027) and tumors with low Ki-67 expression (p=0.012). No statistical associations were found between serum SDF-1 levels and overall or disease-free survival. In summary, our results show that serum SDF-1 levels can be used as a biomarker of feline mammary carcinoma, especially in cats with HER2-overexpressing mammary tumors. Data suggest that targeted therapies against the SDF-1 ligand and/or its CXC4 receptor may be effective for the treatment of FMC, as described for human breast cancer, strengthening the concept that spontaneous feline mammary carcinoma is a suitable model for comparative oncology. PMID- 29285292 TI - Development of a novel biomarker model for predicting preoperative lymph node metastatic extent in esophageal squamous cell carcinoma1. AB - The number and range of lymph node metastasis (LNM) are critical prognostic factors in esophageal squamous cell carcinoma (ESCC). Preoperative serum biomarkers are reported to be associated with LNM. However, whether these markers can precisely predict the extent of LNM is not known. The aim of this study was to evaluate the predictive value of preoperative serum SCC-Ag, Cyfra21-1, CEA, CA19-9 and CA72-4 for LNM number and range by retrospectively investigating 577 ESCC patients undergone esophagectomy from 2007-2010. In this study, the positive rate of SCC-Ag and CA19-9 were associated with pN stage. Significant differences were found in CEA and CA19-9 between pN0-1 stage patients and pN2-3 stage patients. However, in subgroup analysis (patients with pN0-1), significant difference was found only in SCC-Ag between pN0 and pN1 stage patients (P=0.003). Middle thoracic ESCC patients were Chosen to analyze the correlation between the range of LNM and biomarkers. SCC-Ag was correlated with paraesophageal and paracardial lymph nodes, but not correlated with subcarinal and left gastric artery lymph nodes. Interestingly, the results of CEA were opposite to that of SCC-Ag. CA19-9 was associated with subcarinal and paracardial LNM (P=0.000, P=0.038). Based on the results, a model incorporated SCC-Ag, CEA and CA19-9 was constructed. The rate of patients with pN2-3 stage was 15.4% and 54.4% in group 1 and 4 of our model. In summary, SCC-Ag was associated with early lymph node metastatic stage, and CEA and CA19-9 have a close relationship with advanced lymph node metastatic stage. The model combining SCC-Ag, CEA and CA19-9 might help identify the preoperative extent of LNM for a subgroup of ESCC patients that can be benefited from neoadjuvant therapy. PMID- 29285293 TI - Two new species of betatorqueviruses identified in a human melanoma that metastasized to the brain. AB - The role of viral infections in the etiology of brain cancer remains uncertain. Prior studies mostly focused on transcriptome or viral DNA integrated in tumor cells. To investigate for the presence of viral particles, we performed metagenomics sequencing on viral capsid-protected nucleic acids from 12 primary and 8 metastatic human brain tumors. One brain tumor metastasized from a skin melanoma harbored two new human anellovirus species, Torque teno mini virus Emory1 (TTMV Emory1) and Emory2 (TTMV Emory2), while the remaining 19 samples did not reveal any exogenous viral sequences. Their genomes share 63-67% identity with other TTMVs, and phylogenetic clustering supports their classification within the Betatorquevirus genus. This is the first identification of betatorqueviruses in brain tumors. The viral DNA was in its expected non integrated circular form, and it is unclear if the viruses contributed to tumor formation. Whether the viruses originated from blood, or the primary skin tumor could not be ascertained. Overall, our results demonstrate the usefulness of viral metagenomics to detect previously unknown exogenous virus in human brain tumors. They further suggest that active viral infections are rare events in brain tumors, but support a follow-up larger scale study to quantify their frequency in different brain tumor subtypes. PMID- 29285294 TI - Usefulness of plasma matrix metalloproteinase-9 levels in prediction of in hospital mortality in patients who received emergent percutaneous coronary artery intervention following myocardial infarction. AB - The aim of the present study was to investigate the predictive value of the plasma matrix metalloproteinase-9 (MMP-9) level at admission for in-hospital mortality in patients who received emergency percutaneous coronary intervention (PCI) following AMI. A single blood sample was collected at admission from 155 consecutive AMI patients who underwent emergent PCI. The plasma levels of MMP-9 value (528.9+/-191.6 ng/ml) were significantly higher in the patients who died (n=24) than in the survivors (385.4+/-236.0 ng/ml) during 14 days of hospitalization (P=0.005). The age, left ventricle wall motion score index (WMIS), Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) levels and GENSINI score at admission were significantly different between the patients who died and those who survived (P<0.001, P=0.004, P<0.001 and P<0.001, respectively). Cut-off concentrations for prediction of death was identified from receiver operator characteristic (ROC) curves. Using the cut-off value (MMP-9 level 398.2 ng/ml) to stratify the patients into two groups, the group with higher MMP-9 levels had a greater rate of in-hospital mortality than the lower level group (P<0.001). With the exception of the GRACE score, among all biomarkers measured, in stepwise multiple logistic regressions, only the MMP-9 level predicted the risk of in-hospital death after adjustment for all other risk factors (odds ratio 5.02, 95% CI 1.44 to 17.55). In conclusion, a higher MMP-9 level is an independent predictor of in-hospital death in AMI patients who received emergency PCI. PMID- 29285295 TI - NMR-based metabolomic techniques identify potential urinary biomarkers for early colorectal cancer detection. AB - Better early detection methods are needed to improve the outcomes of patients with colorectal cancer (CRC). Proton nuclear magnetic resonance spectroscopy (1H NMR), a potential non-invasive early tumor detection method, was used to profile urine metabolites from 55 CRC patients and 40 healthy controls (HCs). Pattern recognition through orthogonal partial least squares-discriminant analysis (OPLS DA) was applied to 1H-NMR processed data. Model specificity was confirmed by comparison with esophageal cancers (EC, n=18). Unique metabolomic profiles distinguished all CRC stages from HC urine samples. A total of 16 potential biomarker metabolites were identified in stage I/II CRC, indicating amino acid metabolism, glycolysis, tricarboxylic acid (TCA) cycle, urea cycle, choline metabolism, and gut microflora metabolism pathway disruptions. Metabolite profiles from early stage CRC and EC patients were also clearly distinguishable, suggesting that upper and lower gastrointestinal cancers have different metabolomic profiles. Our study assessed important metabolomic variations in CRC patient urine samples, provided information complementary to that collected from other biofluid-based metabolomics analyses, and elucidated potential underlying metabolic mechanisms driving CRC. Our results support the utility of NMR-based urinary metabolomics fingerprinting in early diagnosis of CRC. PMID- 29285296 TI - RNA-sequencing reveals genome-wide long non-coding RNAs profiling associated with early development of diabetic nephropathy. AB - Background: Diabetic nephropathy (DN) seriously threatens the lives of patients, and the mechanism of DN remains largely unknown because of the complex regulation between long non-coding RNA (lncRNA) and protein-coding genes. In early development of diabetic nephropathy (DN), pathogenesis remains largely unknown. Results: We used RNA-sequencing to profile protein-coding and lncRNA gene transcriptome of mouse kidney proximal tubular cells during early stage of DN at various time points. Over 7000 protein-coding and lncRNA genes were differentially expressed, and most of them were time-specific. Nearly 40% of lncRNA genes overlapped with functional element signals using CHIP-Seq data from ENCODE database. Disease progression was characterized by lncRNA expression patterns, rather than protein-coding genes, indicating that the lncRNA genes are potential biomarkers for DN. For gene ontologies related to kidney, enrichment was observed in protein-coding genes co-expressed with neighboring lncRNA genes. Based on protein-coding and lncRNA gene profiles, clustering analysis reveals dynamic expression patterns for kidney, suggesting that they are highly correlated during disease progression. To evaluate translation of mouse model to human conditions, we experimentally validated orthologous genes in human cells in vitro diabetic model. In mouse model, most gene expression patterns were repeated in human cell lines. Conclusions: These results define dynamic transcriptome and novel functional roles for lncRNAs in diabetic kidney cells; these roles may result in lncRNA-based diagnosis and therapies for DN. PMID- 29285297 TI - Identification of WT1 as determinant of heptatocellular carcinoma and its inhibition by Chinese herbal medicine Salvia chinensis Benth and its active ingredient protocatechualdehyde. AB - Candidates from Chinese herbal Medicine might be preferable in drug discovery as the abundant experiences of traditional use usually hint the clinical efficacy. In this study, we screened the anti-tumour effect of several commonly used Chinese herbal Medicines on human hepatocellular carcinoma cells (HCC). We identified that Salvia chinensia Benth. (Shijianchuan in Chinese, SJC) exhibited prominent in vitro inhibition of HCC cells and suppressed the orthotopic growth of HCC in the liver of mice and repressed the lung metastasis of tumour cells. Using a pathway-specific PCR array and Gene Ontology analysis, we identified that Wnt/beta-catenin pathway was associated with the suppressive effect of SJC on HCC cell proliferation and cell cycle progression. SJC repressed transcription activity of Wnt/beta-catenin pathway and reduced expression of beta-catenin in GSK-3beta-independent but promoter-specific transcription inhibition mechanism. The suppressive effect of SJC on beta-catenin expression and its transcription activity was associated with Wilms' tumor 1 (WT1) protein. WT1 was overexpressed in HCC tissues, and was negatively correlated to the overall survival of HCC patients. WT1 promoted proliferation and invasion of HCC cells, as well as beta catenin-dependent transcription activation of Wnt products, while knockdown of WT1 had the opposite effect. Docking experiment revealed that protocatechualdehyde (PCA) might be the active component of the herb. PCA suppressed transcription activity of Wnt/beta-catenin pathway in WT1-dependent manner. Our study sheds light on the potential of PCA from commonly used anti cancer Chinese herbal Medicine SJC as a lead compound targeting WT1 in the discovery of anti-HCC drugs. PMID- 29285298 TI - Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression. AB - Glioblastoma multiforme (GBM) can be a fatal tumor because of difficulties in treating the related metastasis. Andrographolide is the bioactive component of the Andrographis paniculata. Andrographolide possesses the anti-inflammatory activity and inhibits the growth of various cancers; however, its effect on GBM cancer motility remains largely unknown. In this study, we examined the antimetastatic properties of andrographolide in human GBM cells. Our results revealed that andrographolide inhibited the invasion and migration abilities of GBM8401 and U251 cells. Furthermore, andrographolide inhibited matrix metalloproteinase (MMP)-2 activity and expression. Real-time PCR and promoter activity assays indicated that andrographolide inhibited MMP-2 expression at the transcriptional level. Such inhibitory effects were associated with the suppression of CREB DNA-binding activity and CREB expression. Mechanistically, andrographolide inhibited the cell motility of GBM8401 cells through the extracellular-regulated kinase (ERK) 1/2 pathway, and the blocking of the ERK 1/2 pathway could reverse MMP-2-mediated cell motility. In conclusion, CREB is a crucial target of andrographolide for suppressing MMP-2-mediated cell motility in GBM cells. Therefore, a combination of andrographolide and an ERK inhibitor might be a good strategy for preventing GBM metastasis. PMID- 29285299 TI - MiR-20a-5p promotes radio-resistance by targeting NPAS2 in nasopharyngeal cancer cells. AB - MicroRNAs (miRNAs) are key players of gene expression involved in diverse biological processes including the cancer radio-resistance, which hinders the effective cancer therapy. Here we found that the miR-20a-5p level is significantly up-regulated in radio-resistant nasopharyngeal cancer (NPC) cells via an RNA-seq and miR-omic analysis. Moreover, we identified that the neuronal PAS domain protein 2 (NPAS2) gene is one of the targets of miR-20a-5p. The involvement of miR-20a-5p and NPAS2 with NPC radio-resistance was further validated by either down- or up-regulation of their levels in NPC cell lines. Taken together, these results not only reveal novel insights into the NPC radio resistance, but also provide hints for an effective therapeutic strategy to fight against NPC radio-resistance. PMID- 29285300 TI - Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione. AB - Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD+, NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor. PMID- 29285301 TI - GSTT1, GSTP1, and GSTM1 genetic variants are associated with survival in previously untreated metastatic breast cancer. AB - Purpose: The polymorphisms in genes including GSTM1, GSTP1 and GSTT1 have been found to predict development and therapeutic efficacy in various malignancies. Breast cancer is one of most common cancers among women. In this study, we evaluated the prognostic value of three functional polymorphisms of GSTs in patients with previously untreated metastatic breast cancer (MBC). Patients and Methods: The genotype of GSTT1, GSTP1, and GSTM1 in 170 patients with previously untreated MBC from one single center were assessed via PCR-based RFLP methods. The prognostic of polymorphisms on overall survival (OS) was examined using the Kaplan-Meier estimates and Cox proportional hazard ratio (HR) regression analyses. Results: The null genotypes of GSTT1 and GSTM1 were significantly correlated to poor OS compared with the present genotypes, respectively. After adjusting for clinic-pathologic factors, GSTT1 and GSTM1 genetic variants were still significantly associated with OS (HR, 1.92; 95% CI, 1.26-2.91 and HR, 1.53; 95% CI, 1.05-2.23). GSTT1 and GSTM1 were independent survival predictors and GSTP1 was not associated with overall survival of previous untreated MBC. Conclusion: This exploratory analysis suggests that in addition to clinic pathologic factors, the genetic variants in GSTT1 and GSTM1 might be predictive of survival outcome in patients with previously untreated MBC. PMID- 29285302 TI - Telomere length associated with the risks of high-risk and ischemic stroke in southern Chinese Han population. AB - Some previous studies suggested telomere length was associated with the risk of ischemic stroke (IS). The aim of this study was to further confirm the association between relative telomere length (RTL) and risk of IS and to especially explore its correlation with the risk of high-risk stroke population in southern Chinese Han. RTL was determined by using real-time quantitative polymerase chain reaction from 400 ischemic stroke patients, 409 high-risk stroke populations and 399 healthy controls. The correlations between the controls and the risk of high-risk and ischemic stroke were evaluated by using an unconditional logistic regression. IS patients have shown longer RTL than controls (median1.52vs1.11, p60 years) and gender suggested that the first and second tertile of RTL were correlated with the risk of IS in each group when the second tertile was used as a reference. However, the increased risk for high-risk stroke populations were only presented in the first tertile of RTL in the age<=60 years and female groups. the RTL was associated with an increased risk of ischemic stroke, while it elevated the risk of high-risk stroke in some specific subpopulations. PMID- 29285303 TI - Insulin receptor substrate-4 interacts with ubiquitin-specific protease 18 to activate the Jak/STAT signaling pathway. AB - Ubiquitin-specific protease 18 (USP18) as a negative regulator of the Jak/STAT signaling pathway plays an important role in the host innate immune response. USP18 has been shown to bind to the type I interferon receptor subunit 2 (IFNAR2) to down-regulate the Jak/STAT signaling. In this study, we showed that insulin receptor substrate (IRS)-4 functioned as a novel USP18-binding protein. Co precipitation assays revealed that two regions (amino acids 335-400 and 1094 1257) of IRS4 were related to bind to the C- terminal region of USP18. IRS4 binding to USP18 diminished the inhibitory effect of USP18 on Jak/STAT signaling. IRS4 over-expression enhanced while IRS4 knock-down suppressed the Jak/STAT signaling in the presence of IFN-a stimulation. As such, IRS4 increased IFN-a mediated anti-HCV activity. Mechanistically, IRS4 promoted the IFN-a-induced Jak/STAT signaling by interact with USP18. These results suggested that IRS4 binds to USP18 to diminish the blunting effect of USP18 on IFN-a-induced Jak/STAT signaling. Our findings indicated that IRS4 is a novel USP18-binding protein that can be used to boost the host innate immunity to control HCV, and potentially other viruses that are sensitive to IFN-a. PMID- 29285304 TI - Elevated CEA is associated with worse survival in recurrent rectal cancer. AB - This study investigated the prognostic impact of serum carcinoembryonic antigen (CEA) level in recurrent rectal cancer. We reviewed 745 patients who developed recurrence after curative treatment for rectal cancer between January 2000 and December 2012. Multivariate analyses for survival revealed that age > 60 years (p = 0.005), r-CEA >= 5 ng/ml (p < 0.001), disease free interval (DFI) < 12 months (p < 0.001), and palliative or conservative treatment (p < 0.001) were unfavorable factors. PMID- 29285305 TI - A premature stop codon within the tvb receptor gene results in decreased susceptibility to infection by avian leukosis virus subgroups B, D, and E. AB - Avian leukosis virus (ALV) is an oncogenic virus causing a variety of neoplasms in chickens. The group of avian leukosis virus in chickens contains six closely related subgroups, A to E and J. The prevalence of ALVs in hosts may have imposed strong selective pressure toward resistance to ALVs infection. The tvb gene encodes Tvb receptor and determines susceptibility or resistance to the subgroups B, D, and E ALV. In this study, we characterized a novel resistant allele of the tvb receptor gene, tvbr3, which carries a single-nucleotide substitution (c.298C>T) that constitutes a premature termination codon within the fourth exon and leads to the production of a truncated TvbR3 receptor protein. As a result, we observed decreased susceptibility to infection by ALV-B, ALV-D and ALV-E both in vitro and in vivo, and decreased the binding affinity of the TvbR3 receptor for the subgroups B, D, and E ALV envelope glycoproteins. Additionally, we found that the tvbr3 allele was prevalent in Chinese broiler lines. This study demonstrated that premature termination codon in the tvb receptor gene can confer genetic resistance to subgroups B, D, and E ALV in the host, and indicates that tvbr3 could potentially serve as a resistant target against ALV-B, ALV-D and ALV E infection. PMID- 29285306 TI - HLA-G+3027 polymorphism is associated with tumor relapse in pediatric Hodgkin's lymphoma. AB - In this study, we tested whether polymorphisms in human leukocyte antigen G (HLA G) were associated with event-free survival (EFS) in pediatric Hodgkin's lymphoma (HL). We evaluated the association of HLA-G 3'-UTR polymorphisms with EFS in 113 pediatric HL patients treated using the AIEOP LH-2004 protocol. Patients with the +3027-C/A genotype (rs17179101, UTR-7 haplotype) showed lower EFS than those with the +3027-C/C genotype (HR= 3.23, 95%CI: 0.99-10.54, P=0.012). Female patients and systemic B symptomatic patients with the HLA-G +3027 polymorphism showed lower EFS. Multivariate analysis showed that the +3027-A polymorphism (HR 3.17, 95%CI 1.16-8.66, P=0.025) was an independent prognostic factor. Immunohistochemical analysis showed that HL cells from patients with the +3027 C/A genotype did not express HLA-G. Moreover, HLA-G +3027 polymorphism improved EFS prediction when added to the algorithm for therapeutic group classification of pediatric HL patients. Our findings suggest HLA-G +3027 polymorphism is a prognostic marker in pediatric HL patients undergoing treatment according to LH 2004 protocol. PMID- 29285307 TI - Polymorphisms in matrix metalloproteinases 2, 3, and 8 increase recurrence and mortality risk by regulating enzyme activity in gastric adenocarcinoma. AB - The association of polymorphisms in matrix metalloproteinases (MMPs) with clinical outcomes of gastric adenocarcinoma has not been examined. Ten polymorphisms in MMP1, 2, 3, 7, 8, 9, 12, and 13 were genotyped and investigated, and patients were followed for an average of 58 months. The activities of MMP2, 3, and 8 were measured. Recurrence risk increased in patients with the MMP2 rs2285053 CC genotype (hazard ratio [HR], 1.85), MMP3 rs679620 AA genotype (HR, 2.15), and MMP8 rs1940475 TT genotype (HR, 2.22) on recurrence free survival (RFS). Co-presence of the unfavorable MMP2 rs2285053 CC and MMP8 rs1940475 TT genotypes resulted in an additional increased risk of recurrence (RFS: HR, 4.42; 95% confidence interval [CI], 2.15-9.09; p<0.0001) and risk of death (overall survival ( OS) : HR, 6.59; 95% CI, 3.15-13.19; p<0.0001). Theoretical survival tree analysis revealed that recurrence-free survival significantly varied from 15.5 to 87 months among patients with different polymorphisms in MMP2, 3, and 8. The enzymatic activities of MMP2 and MMP3 increased (MMP2 rs2285053 CC: 888.60 vs. CT: 392.00, p <0.0001; MMP3 rs679620 AA: 131.10 vs. GG: 107.74, p=0.015), whereas those of MMP8 decreased (MMP8 rs1940475 TT: 133.78 vs. CC: 147.54, p=0.011) in gastric cancer tissues. These results suggest that polymorphisms in MMP2, 3, and 8 may increase cancer recurrence and patient death by increasing or decreasing enzyme activity in patients with gastric adenocarcinoma. PMID- 29285308 TI - Decisive role of P42/44 mitogen-activated protein kinase in Delta9 tetrahydrocannabinol-induced migration of human mesenchymal stem cells. AB - In past years, medical interest in Delta9-tetrahydrocannabinol (THC), the major psychoactive ingredient of the Cannabis plant, has been renewed due to the elucidation of the endocannabinoid system and diverse other receptor targets involved in biological cannabinoid effects. The present study therefore investigates the impact of THC on the migration of mesenchymal stem cells (MSCs) which are known to be involved in various regenerative processes such as bone healing. Using Boyden chamber assays, THC was found to increase the migration of adipose-derived MSCs. Migration by THC was almost completely suppressed by the CB1 receptor antagonist AM-251 and to a lesser extent by the CB2 receptor antagonist AM-630. By contrast, the TRPV1 antagonist capsazepine as well as the G protein-coupled receptor 55 (GRP55) agonist O-1602 did not significantly interfere with the promigratory effect of THC. Furthermore, increased migration by THC was fully suppressed by PD98059, an inhibitor of p42/44 mitogen-activated protein kinase (MAPK) activation, and was accompanied by a time-dependent activation of this pathway accordingly. In line with the migration data, additional inhibitor experiments pointed towards a decisive role of the CB1 receptor in conferring THC-induced activation of p42/44 MAPK. Collectively, this study demonstrates THC to exert a promigratory effect on MSCs via a CB1 receptor dependent activation of p42/44 MAPK phosphorylation. This pathway may be involved in regenerative effects of THC and could be a target of pharmacological intervention. PMID- 29285309 TI - 1,8-cineole prevents UVB-induced skin carcinogenesis by targeting the aryl hydrocarbon receptor. AB - 1,8-cineole is a natural monoterpene cyclic ether present in Eucalyptus, and has been reported to exhibit anti-inflammatory and antioxidant effects. However, the preventive effect of 1,8-cineole on skin carcinogenesis and the molecular mechanism of action responsible remains unknown. In the present study, we investigated the effect of 1,8-cineole on UVB-induced skin carcinogenesis. 1,8 cineole inhibited UVB-induced cyclooxygenase-2 (COX-2) protein and mRNA expression and prostaglandin E2 (PGE2) generation in HaCaT cells. 1,8-cineole also inhibited phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and phosphorylation of its upstream kinases, c-Src and epidermal growth factor receptor (EGFR). Quantitative real-time RT-PCR (qRT-PCR) and drug affinity responsive target stability (DARTS) assay results showed that 1,8-cineole suppressed UVB-induced expression of a target gene of the aryl hydrocarbon receptor (AhR), cyp1a1, and directly binds to AhR. Knockdown of AhR suppressed COX-2 expression as well as phosphorylation of ERK1/2 in HaCaT cells. Furthermore, topical treatment of 1,8-cineole on mouse skin delayed tumor incidence and reduced tumor numbers, while inhibiting COX-2 expression in vivo. Taken together, these results suggest that 1,8-cineole is a potent chemopreventive agent that inhibits UVB-induced COX-2 expression by targeting AhR to suppress UVB-induced skin carcinogenesis. PMID- 29285310 TI - Role of preoperative magnetic resonance imaging and histological assessment in identifying patients with a low risk of endometrial cancer: a Korean Gynecologic Oncology Group ancillary study. AB - Preoperative identification of individuals at low risk of lymph node metastasis is key to the proper management of endometrial cancer. This study evaluated the role of preoperative assessment based on magnetic resonance imaging (MRI) and histological analysis in identifying a group having a low risk of lymph node metastasis. Data of 529 patients with endometrial cancer were obtained from a prospective multicenter database, between January 2012 and December 2014. Clinical staging, based on MRI and histological analysis, was compared with final pathology results after the surgical staging procedure. The preoperative low-risk criteria, based on current guidelines from Korea, France, and Canada, and criteria used for fertility-sparing therapies, were applied to our multicenter cohort and the accuracy of each set of criteria for identifying group at low risk of lymph node metastasis was evaluated. When considering grades or MR stages separately, the overall agreement between preoperative and postoperative findings was poor (Kappa 0.45 for grades; 0.41 for stages). However, when combining these two parameters, the low-risk group, as defined by any of the guidelines, had an acceptable rate of lymph node metastasis (below 3%). The French guidelines identified 249 patients (47.1%) as being in the low-risk group. Criteria used to define fertility-sparing therapy candidates identified 48 patients (9.1%) among the study population, only one of whom had extra-uterine disease. This study shows that the current guidelines, using preoperative assessment based on MRI and histological analysis, can identify low-risk patients, who may be candidates for omitting lymphadenectomy. PMID- 29285311 TI - Gene delivery and gene expression in vertebrate using baculovirus Bombyx mori nucleopolyhedrovirus vector. AB - The baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) has been investigated as a possible tool for gene therapy, but its inhibition by complement proteins in human serum limits its applicability. Here, we used the baculovirus Bombyx mori nucleopolyhedrovirus (BmNPV) to construct a gene delivery vector in which a reporter gene is driven by a cytomegalovirus IE promoter. Enhanced green fluorescent protein (EGFP) and luciferase reporter genes were used to test the efficiency of gene delivery. In vitro complement inactivation data showed that the recombinant BmNPV vector was more stable in human serum than the recombinant AcMNPV vector. The recombinant BmNPV vector successfully delivered the reporter genes into different tissues and organs in mice and chicks. These results demonstrate that the BmNPV vector is more stability against complement inactivation in human serum than the AcMNPV vector, and indicate that it may be useful as an effective gene delivery vector for gene therapy in vertebrates. PMID- 29285312 TI - RTL1 promotes melanoma proliferation by regulating Wnt/beta-catenin signalling. AB - Cutaneous melanoma is a highly malignant and metastatic skin cancer with high mortality. However, its underlying mechanisms remain largely unclear. Here, we found that retrotransposon-like 1 (RTL1) is highly enriched in melanoma tissue, especially in early and horizontal growth tissues. Knockdown of RTL1 in melanoma cells resulted in cell proliferation suppression; cell cycle arrest at G1 phase; and down-regulation of E2F1, CYCLIN D1, cyclin-dependent kinase 6 (CDK6) and c MYC. Moreover, overexpression of RTL1 in melanoma cells accelerated cell proliferation, promoted passage of the cell cycle beyond G1 phase, and increased the expression of cell cycle related genes. Mechanistically, we found that knockdown of RTL1 inhibited the Wnt/beta-Catenin pathway by regulating the expression of genes specifically involved in beta-CATENIN stabilization. Furthermore, the overexpression and knockdown of beta-CATENIN rescued the effects of RTL1 on melanoma cell proliferation and the cell cycle. These findings were also confirmed via tumour xenografts in nude mice. Together, our results demonstrated that RTL1 promotes melanoma cell proliferation by regulating the Wnt/beta-Catenin signalling pathway. PMID- 29285313 TI - FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice. AB - FAM3C, a member of FAM3 gene family, has been shown to improve insulin resistance and hyperglycemia in obese mice. This study further determined whether FAM3C functions as a hepatokine to suppress hepatic gluconeogenesis of type 1 diabetic mice. In STZ-induced type 1 diabetic mouse liver, the FAM3C-HSF1-CaM signaling axis was repressed. Hepatic FAM3C overexpression activated HSF1-CaM-Akt pathway to repress gluconeogenic gene expression and ameliorate hyperglycemia of type 1 diabetic mice. Moreover, hepatic HSF1 overexpression also activated CaM-Akt pathway to repress gluconeogenic gene expression and improve hyperglycemia of type 1 diabetic mice. Hepatic FAM3C and HSF1 overexpression had little effect on serum insulin levels in type 1 diabetic mice. In cultured hepatocytes, conditioned medium of Ad-FAM3C-infected cells induced Akt phosphorylation. Moreover, Akt activation and gluconeogenesis repression induced by FAM3C overexpression were reversed by the treatment with anti-FAM3C antibodies. Treatment with recombinant FAM3C protein induced Akt activation in a HSF1- and CaM-dependent manner in cultured hepatocytes. Furthermore, recombinant FAM3C protein repressed gluconeogenic gene expression and gluconeogenesis by inactivating FOXO1 in a HSF1-dependent manner in cultured hepatocytes. In conclusion, FAM3C is a new hepatokine that suppresses hepatic gluconeogenic gene expression and gluconeogenesis independent of insulin by activating HSF1-CaM-Akt pathway. PMID- 29285314 TI - TLR2/MyD88 pathway-dependent regulation of dendritic cells by dengue virus promotes antibody-dependent enhancement via Th2-biased immunity. AB - Possible risk mediators in primary dengue virus (DenV) infection that favor secondary DenV infection to life-threatening dengue hemorrhagic fever (DHF) and shock syndrome (DSS) via antibody-dependent enhancement (ADE) have not yet been described. Here, DenV infection enhanced the expression of inflammatory mediators and activation molecules in dendritic cells (DCs) through TLR2/MyD88 pathway. TLR2 appeared to facilitate DenV infection in DCs that were less permissive than macrophages for viral replication. In experiments using separate evaluations of DenV-infected and uninfected bystander DCs, infected DCs showed impaired maturation accompanied with TLR2-dependent production of inflammatory cytokines, by which uninfected bystander DCs showed increased expression of co-stimulatory molecules. Differential phosphorylation of MAPK and STAT3 was also detected between DenV-infected and uninfected DCs. Furthermore, DenV infection stimulated Th2-polarized humoral and cellular immunity against foreign and DenV Ag via TLR2/MyD88 pathway, and DenV-infected DCs were revealed to facilitate Th2-biased immune responses in TLR2-dependent manner. TLR2/MyD88-mediated Th2-biased Ab responses to primary DenV infection increased the infectivity of secondary homotypic or heterotypic DenV via ADE. Collectively, these results indicate that TLR2/MyD88 pathway in DC-priming receptors can drive Th2-biased immune responses during primary DenV infection, which could favor secondary DenV infection to DHF/DSS via ADE. PMID- 29285315 TI - CXCL8 derived from tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression by promoting migration and invasion of cancer cells. AB - Tumor-associated macrophages (TAMs) are involved in tumor progression and poor prognosis in several malignancies. We previously demonstrated the interaction between high numbers of infiltrating TAMs and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To investigate the significance of TAMs in ESCC, we conducted a cDNA microarray analysis of peripheral blood monocytes (PBMo)-derived macrophages and PBMo-derived macrophages stimulated with conditioned media of TE-series ESCC cell lines (TAM-like PBMo-derived macrophages). C-X-C motif chemokine ligand 8 (CXCL8) was up-regulated in the TAM like PBMo-derived macrophages. Here we confirmed a high expression level of CXCL8 in TAM-like PBMo-derived macrophages and the expression of CXCR1/2, known as CXCL8 receptors, in TE-series ESCC cell lines. Recombinant human CXCL8 induced the ESCC cell lines' migration and invasion by the phosphorylation of Akt and Erk1/2. In indirect co-cultures, not only signal pathway inhibitors but also neutralizing antibodies against CXCL8, CXCR1 and CXCR2 suppressed these phenotypes induced by TAM-like PBMo-derived macrophages. Immunohistochemical analysis of 70 resected ESCC samples showed that high expression levels of CXCL8 in ESCC tissues were significantly associated with lymph node metastasis and poor prognosis. These results suggest that CXCL8 up-regulated in the microenvironment may contribute to ESCC progression by promoting cancer cells' migration and invasion. PMID- 29285316 TI - Elevated pretreatment platelet distribution width and platelet count predict poor prognosis in nasopharyngeal carcinoma. AB - Background: Previous studies have demonstrated that platelets play a multifaceted role in cancer progression and metastasis. However, the value of platelet indices for predicting survival in nasopharyngeal carcinoma (NPC) patients remains unknown. The aim of this study was to evaluate the predictive significance of platelet indices in NPC cases. Materials and Methods: A total of 168 patients who were diagnosed with NPC between January 2011 and June 2012 were recruited. The optimal cut-off values for the platelet indices were determined using a receiver operating characteristic curve. The Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of the potential predictors. Results: Of the 168 patients, high platelet distribution width (PDW) and platelet count (PLT) levels were observed in 81 (48.21%) and 68 (40.48%) of the patients, respectively. An increased PDW was associated with the depth of invasion (T stage, P = 0.019), lymph node metastasis (N stage, P = 0.026), and clinical stage (P < 0.001). Moreover, the survival analysis showed that the overall survival of the patients with a PDW > 16.3 fL or platelet count > 266 * 109/L was associated with a poorer prognosis (both P < 0.001). In the multivariate Cox regression model, the PDW (P < 0.001), PLT (P = 0.001), T stage (P < 0.001), N stage (P = 0.006), clinical stage (P = 0.005), and Epstein-Barr virus DNA (P = 0.039) were independent prognostic factors for the overall survival. Conclusions: The PDW and PLT are easily available via a routine blood test, and our study showed that the PDW and PLT could be prognostic predictors in NPC patients. However, further studies are required to confirm this conclusion. PMID- 29285317 TI - Altered expression of differential gene and lncRNA in the lower thoracic spinal cord on different time courses of experimental obstructive jaundice model accompanied with altered peripheral nociception in rats. AB - The spinal origin of jaundice-induced altered peripheral nociceptive response poorly understood. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a jaundice model accompanied by altered peripheral nociceptive response, and then to analyze differential gene and lncRNA expression patterns in the lower thoracic spinal cord on different time courses after BDL operation by using high-throughput RNA sequencing. The differentially expressed genes (DEGs) identified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, followed by clustering analysis, Gene Ontology analysis and pathway analysis. As a result, a total of 2033 lncRNAs were differentially expressed 28d after BDL, in which 1545 probe sets were up regulated and 488 probe sets were down-regulated, whereas a total of 2800 mRNAs were differentially expressed, in which 1548 probe sets were up-regulated and 1252 probe sets were down-regulated. The RNAseq data of select mRNAs and lncRNAs was validated by RT-qPCR. 28d after BDL, the expressions of lncRNA NONRATT002335 and NONRATT018085 were significantly up-regulated whereas the expression of lncRNA NONRATT025415, NONRATT025388 and NONRATT025409 was significantly down regulated. 14d after BDL, the expressions of lncRNA NONRATT002335 and NONRATT018085 were significantly up-regulated; the expression of lncRNA NONRATT025415, NONRATT025388 and NONRATT025409 was significantly down-regulated. In conclusion, the present study showed that jaundice accompanied with decreased peripheral nociception involved in the changes of gene and lncRNA expression profiles in spinal cord. These findings extend current understanding of spinal mechanism for obstructive jaundice accompanied by decreased peripheral nociception. PMID- 29285318 TI - Comparison of hydrocortisone and prednisone in the glucocorticoid replacement therapy post-adrenalectomy of Cushing's Syndrome. AB - Cushing's syndrome requires glucocorticoid replacement following adrenalectomy. Based on a simplified glucocorticoid therapy scheme and the peri-operative observation, we investigated its efficacy and safety up to 6 months post adrenalectomy in this cohort study. We found the adrenocorticotropic hormone (ACTH) levels were normal post-adrenalectomy, and sufficient to stimulate the recovery of the dystrophic adrenal cortex, thus exogenous supplemental ACTH might not be necessary. Patients were grouped by oral reception of either hydrocortisone or prednisone since day 2 post-adrenalectomy. Both groups had similar baseline responses to adrenalectomy, regarding the correction of hypertension (10/15 vs.12/19), hyperglycemia (6/11 vs. 7/10), and hypokalemia (12/12 vs. 11/11). Most patients lost weight (17/20 vs. 20/22). Both groups reported significant improvement in a subjective evaluation questionnaire. Hydrocortisone showed advantages over prednisone in improving liver function (7/8 vs. 2/7, p = 0.035), but also caused significant lower extremety edema (p = 0.034). Both groups developed adrenal insufficiency (AI) during glucocorticoid withdrawal, with no significant difference regarding the incidence rate (7/20 vs. 10/22) or severity. Most AI symptoms were relieved by resuming the prior oral doses, while two severe cases were hospitalized. The withdrawal process may last longer time for hydrocortisone than prednisone. In conclusion, our data supports the use of both hydrocortisone and prednisone in the glucocorticoid replacement therapy post-adrenalectomy for patients of adrenal adenoma or Cushing's disease. Hydrocortisone showed advantages over prednisone in improving liver function, and prednisone exhibited significantly lower risk of edema. PMID- 29285319 TI - Impact of socioeconomic status on survival of colorectal cancer patients. AB - Socioeconomic status (SES) has an impact on the survival of various cancers, but it has not been fully understood in colorectal cancer (CRC). The Surveillance, Epidemiology and End Results database was adopted to detect the role of SES in the survival outcomes of CRC. A total of 184,322 eligible patients were included and SES status was analyzed. The multivariable analysis showed that Non-Hispanic Black (HR, 1.20; 95% CI, 1.15-1.24), being widowed (HR, 1.04; 95% CI, 1.01-1.07), any Medicaid (HR, 1.36; 95% CI, 1.33-1.39) and the lowest education level group patients had relative poorer prognosis. Besides, sex, tumor location, age, differentiation level and American Joint Committee on Cancer stage also had significant effects on overall survival of CRC. The individuals were further divided into five groups according to the number of survival-adverse factors. All of the four groups containing adverse factors showed impaired survival outcomes compared with the group containing no adverse factor. PMID- 29285320 TI - Immune system and melanoma biology: a balance between immunosurveillance and immune escape. AB - Melanoma is one of the most immunogenic tumors and its relationship with host immune system is currently under investigation. Many immunomodulatory mechanisms, favoring melanomagenesis and progression, have been described to interfere with the disablement of melanoma recognition and attack by immune cells resulting in immune resistance and immunosuppression. This knowledge produced therapeutic advantages, such as immunotherapy, aiming to overcome the immune evasion. Here, we review the current advances in cancer immunoediting and focus on melanoma immunology, which involves a dynamic interplay between melanoma and immune system, as well as on effects of "targeted therapies" on tumor microenvironment for combination strategies. PMID- 29285321 TI - Carcinogenesis-relevant biological events in the pathophysiology of the efferocytosis phenomenon. PMID- 29285323 TI - Cytology and molecular mechanisms of drug-induced gingival hypertrophy: a rewiew. AB - Introduction: Gingival hypertrophy is a frequent condition associated to the increased number of patients taking some categories of drugs. The goal of this work is to emphasize the importance of diagnosis to set a proper therapy. Material and methods: The plaque accumulation in patients having a poor oral hygiene damages the periodontium and requires the application of strict professional and home hygiene protocols. Results and conclusion: The drug-induced gingival proliferation knowledge is essential in order to succeed in working with the internist and in planning a precise therapy, without interfering with the metabolism of drugs, often necessary and irreplaceable for patients' health. PMID- 29285322 TI - HPV infection in the oral cavity: epidemiology, clinical manifestations and relationship with oral cancer. AB - Purpose: The aim of this paper is to describe epidemiology and clinical manifestations of oral infection by Human papillomavirus (HPV), with particular attention to potential malignant lesions. Materials and methods: A systematic review of the literature was conducted to describe the state of the art about HPV infection in oropharyngeal mucosa and its modalities of transmission, with particular attention to possible simultaneous infection in multiple anatomic sites. The aspects of prevention and control of infection by administering vaccines and the diffusion of sexual education campaigns are discussed also. Therapeutic protocols are also described where necessary. Results: In recent years there has been a growing interest in HPV oral medicine, suggesting a role of such a family of viruses in the development of neoplasms of the oropharyngeal district as well as of the uterine cervix. Even if the mass media have increasingly faced the problem, causing frequent alarming among patients, the dentist therefore needs a complete and up-to-date knowledge of this infectious condition that is one of the most common causes of sexually transmitted mucous membrane infections (e.g. genital, anal and oral). Conclusions: Recent studies about HPV infection are a basic requirement in order to promote the health of patients and provide them with the most exhaustive indications from dentists. PMID- 29285324 TI - Focus on periodontal disease and colorectal carcinoma. AB - Diagnosis of focal disease, the theory that the human oral microbial (HOM) could affect the onset and development of systemic diseases, was very popular in the past, but the lack of scientific evidence has led to the abandonment of this idea. Interestingly, increasing evidence over the past 3 or so decades suggests that HOM can indeed serve as a reservoir for systemic dissemination of pathogenic bacteria and their toxins in distant body sites, favouring the developments of malignant tumours. Malignant tumours are complex communities of oncogenically transformed cells with aberrant genomes, associated non-neoplastic cells including immune and stromal cells, and sometimes HOM, including bacteria and viruses. Recent data suggest that HOM and periodontal disease play an active role in the pathogenesis of colorectal cancer, in fact HOM has been found within the colorectal cancer microenvironment, and the composition of the HOM was different from that of adjacent non-neoplastic tissue. An association of fusobacterium nucleatum with the colonic mucosa of colorectal cancer has been proven. Several questions thus arise. Is periodontal disease a risk factor for colorectal carcinoma? Given the connectivity of the digestive tract, could fusubacterium nucleatum or other HOM be involved in additional gastrointestinal disorders? Furthermore, based on the "mobility" of Fusubacterium nucleatum and the omnipresence of cadherins, could this organism be involved in cancers beyond the gastrointestinal tract? Answers to these questions will shed new lights on the role of the HOM in onset of diseases. PMID- 29285326 TI - 3D X-ray microscopic analysys on a prosthetically loaded implant with platform switching and conical connection: a case report. AB - The histological and histomorphometrical examination were the gold standard in the qualitative and quantitative analyses of the peri-implant tissue around the implant. In recent years, the field of microscopy has witnessed a considerable enhancement of the performance of microscopes that have very high resolution performance and allowing very sophisticated analysis even larger than traditional preparations. The possibility to have an affordable analyses of whole implant with the surrounding different tissues (soft and hard tissues) without the traditional pre-treatment necessary for the histological analysis may represent a goal to describe material properties and behaviors or simply to visualize structural details. The aim of the present study were to evaluate a 3D X-ray microscopic analysis of peri-implant tissue compared to a traditional histological and histomorphometrical analysis of the peri-implant tissues around an implant with a conical connection associated with platform-switching in order to assess the validity of the new analysis technique. PMID- 29285325 TI - A new system of implant abutment connection: how to improve a two piece implant system sealing. AB - Purpose: Implant dentistry has become one of the most successful dentistry techniques for replacing missing teeth. The success rate of implant dentistry is above 80%. However, peri-implantitis is a later complication of implant dentistry that if untreated, can lead to implant loss. One of the hypotized causes of peri implantis is the bacterial leakage at the level of implant-abutment connection. Bacterial leakage is favored to the presence of a micro gap at the implant abutment interface, allowing microorganisms to penetrate and colonize the inner part of the implant leading to biofilm accumulation and consequently to peri implantitis development. Materials and methods: To identify the capability of the implant to protect the internal space from the external environment, the passage of genetically modified Escherichia coli across implant-abutment interface was evaluated. Implants were immerged in a bacterial culture for twenty-four hours and then bacteria amount was measured inside implant-abutment interface with Real time PCR. Results: Bacteria were detected inside all studied implants, with a median percentage of 9%. Conclusions: The reported results are better to those of previous studies carried out on different implant systems. Until now, none implant-abutment system has been proven to seal the gap between implant and abutment. PMID- 29285327 TI - Clinical protocol with digital cad/cam chairside workflow for the rehabilitation of severely worn dentition patients. AB - Objectives: The purpose of this paper is to investigate the effectiveness and to describe a clinical protocol with digital CAD CAM chairside workflow for the rehabilitation of severely compromised and worn dentitions. Methods: This article reports 4 consecutive cases, where a clinical digital chairside workflow is used for the rehabilitation of severely compromised and worn dentitions. Advantages and limitations of this method compared with the traditional prosthetic protocol are also described and discussed. Results: With all four patients treated with this protocol, we obtained a good aesthetic and functional result, improvement in chewing function, loss of cold sensitivity, better preservation of most of the left hard tissue and a good level of satisfaction. In a two-year follow-up, all patients also maintained the condition obtained with prosthetic chairside rehabilitation, resulting in almost 100% cumulative survival rate. Conclusion: Within the limitations of this study, we can assert that the aforementioned restorative treatment with digital CAD/CAM chairside workflow represents a valid alternative to rehabilitate this kind of patients, because it is a safe, predictable and personalized procedure but also it seems easier, faster and cheaper than traditional protocols. PMID- 29285328 TI - A new spiral dental implant: a tool for oral rehabilitation of difficult cases. AB - Spiral dental implant (SDI) is an implant with a conical internal helix that confers the characteristic of self-drilling, self-tapping, and self-bone condensing. These proprieties offer better control during insertion of SDI giving a high primary stabilization, even in poor quality bone. A shorter diameter of SDI results in reduced drilling during insertion and consequently less trauma and minimal bone loss. To address the research purpose, the investigators designed a retrospective cohort study. The study population was composed of 25 patients, 11 males and 14 females that have been treated by Dr. Balan with 187 SDI positioned in mandible and into maxilla bone. The implants were placed during the years 2013 to 2014 in Dr. Balan clinic. All patients underwent the same surgical protocol. Several variables are investigated: demographic (age and gender), anatomic (upper/lower jaws and tooth site), implant (length and diameter and type) variables, edentulism (partial or total), and comorbid status of health (i.e.: hypothyroidism, parodontitis, hypertension, diabetes, presence of cancer, heart disease, hepatitis and rheumatologic disease). Pearson Chi-Square test was used to investigate variables and p < 0.05 was considered statistically significant. Statistically it has been shown that females have a higher possibility of unsuccessful respect of male, with a "p value" of 0.014. Another important impact factor for success of implant insertion has been represented by concomitants pathologies: cancer represents the most negative high factor risk with a percentage of unsuccessful of 50%, followed by heart disease (15%), and diabetes (3.7%). SDIs are reliable tools for difficult cases of oral rehabilitation. They have a higher success and survival rate, which means stable results over time. No differences were detected among SDI lengths, implant/crown ratio. In addition, the insertion of SDIs in banked bone can be performed without adverse effects. Finally, flapless and computer tomography-planned surgery does not significantly increase the clinical outcome of SDIs in complex rehabilitation. Cancer represents the most important variable to consider when a patient wants to do oral rehabilitation because of its high risk of unsuccessful. PMID- 29285329 TI - The flap recovery on the impacted lower third molar surgery comparing 3 different flap designs: a clinical study. AB - Aim: The purpose of the study was to analyze the healing of the deep and superficial lower first and second molars periodontium, after the surgical extraction of the contiguous impacted third molar, comparing 3 mucoperiosteal flap designs. Materials and methods: 150 patients which had to undergo a impacted lower third molar surgery were enrolled in this study. They were checked from day 0 to day 90, in order to focus on the recovery quality of the soft tissues around the lower second molar, comparing 3 different flap designs. Results: No intraoperatory incident happened. The complete recovery of the periodontium around the second molar has been shown in each patient after 90 days from surgery and each adverse reaction happened within the sixth week after surgery. Only 2 slight gengival recessions 0,5 mm have been find out. Conclusions: The impacted third molar surgery is an operation that, if rightly programmed and performed, is relatively safe. Besides, the correct handling and management of periodontium around the second molar and the choice of the flap type to be used support a correct recovery on the second molar periodontium, avoiding any long-term damage. Clinical significance: This study wanted to analyze the healing of the deep and superficial lower second molar periodontium, after the impacted lower third molar surgery. In order to improve the surgical technique used for lower third molar germectomies, we wanted to compare 3 different kind of flap designs. PMID- 29285330 TI - Prosthetic management of patients with oro-maxillo-facial defects: a long-term follow-up retrospective study. AB - Introduction: The aim of this study is to determine the outcome of maxillofacial prosthetic rehabilitation after oncological resections, including both intra- and extra-oral prosthetic devices. Methods: In this study were included 72 patients, who have undergone an intra or extra-oral maxillofacial prosthetic rehabilitation after an oncologic resection. Tumors on the head and neck were analyzed and the defects of these resections have been divided in two different groups: intra and extra-oral defects. Results: 72 participants were treated with maxillofacial prosthesis, 3 of which with post-traumatic wounds and 69 with resections of tumors on the head and neck. Of the 69 treated for neoplastic disease, 43 received an intraoral prosthesis (palatal obturator) and 29 with an extraoral epithesis (18 with nasal prostheses, 8 with orbital implants and 3 with ear implants). The group included patients with different types of tumors. All the patients were evaluated in terms of aesthetic appearance after the construction of the prostheses and the results were satisfactory. Conclusion: Within the limitations of this study, after the use of maxillofacial protheses patients feel more confident and self-assured. Maxillofacial protheses are a good solution in order to improve the life's quality in patients with tumors resections: prostheses are easy to handle and provide a satisfying social interaction for the patients. PMID- 29285331 TI - Risk assessment of colonization of legionella spp. in dental unit waterlines. AB - The aerosol produced during the use of dental instruments can spread pathogens potentially harmful to health. Most of the pathogens found in hydraulic system are Gram-negative aerobic heterotrophic environmental bacterial species exhibiting very low pathogenicity, although they may be of concern in the treatment of vulnerable patients, such as immunocompromised, medically compromised individuals and dental team. Dental team can be exposed to pathogenic microorganisms including cytomegalovirus, hepatitis B virus, hepatitis C virus, herpes simplex virus and Legionella spp. Legionella spp. are ubiquitous in hydraulic system, in fact surveys have shown that the percentage of samples taken at different dental chairs that were positive for Legionella spp. and ranged from 0 to 100%. The concentration of Legionella spp. in hydraulic system may reach 1000 organisms per ml. The primary route of Legionella spp. transmission is inhalation or aspiration of environmentally contaminated aerosols. All dentists are required to conduct a statutory risk assessment of their hydraulic system, in fact to comply with their legal duties, dentists must identify and assess the sources of risk and prepare a scheme for preventing and controlling risks. Moreover, they must monitor the quality of their hydraulic system at least annually to ensure that they are "legionellae free". PMID- 29285332 TI - Correlations between dental malocclusions, ocular motility, and convergence disorders: a cross-sectional study in growing subjects. AB - Objective: The purpose of the study was to analyze the association between dento skeletal malocclusions, ocular motility, and convergence disorders in growing subjects. Materials and methods: 84 subjects (49 males, 35 females) with a mean age of 7.3+/-1.7 years were enrolled in a screening procedure for celiac disease at the Department of Gastroenterology of the University of Rome "Tor Vergata". Each child underwent an orthodontic, orthoptic, and ophtalmological examination. Pearson's Chi-Square test with Yates' correction and Fisher's exact test were conducted to assess the association between orthoptic defects and malocclusions (p<0.05). Results: Ocular motility disorders were present in 44.9% of males and in 57.1% of females, while convergence defects were present in 10.2% of males and in 2.9% of females. Ocular motility disorders were more frequent in subjects with Angle Class III malocclusion (66.7%) than in subjects with Angle Class II (59.1%) and Class I (45.8%) malocclusion. Convergence defects were equally frequent in Angle Class I and Class II malocclusion (5.1%), while none subject presenting with Angle Class III malocclusion exhibited convergence defects. A statistically significant correlations was found between ocular motility disorders and unilateral cross-bite with midline deviation. Conclusion: Ocular motility defects had a significant greater prevalence in subjects presenting with unilateral cross bite and midline deviation. The importance of role of orthodontic diagnosis among interdisciplinary treatment in growing children should be recognized. PMID- 29285333 TI - Obstructive site localization in patients with Obstructive Sleep Apnea Syndrome: a comparison between otolaryngologic data and cephalometric values. AB - Purpose: Obstructive Sleep Apnea Syndrome (OSAS) is a respiratory disorder characterized by repeated obstructive episodes affecting upper airways.This study aims at examining the anatomical craniofacial and pharyngeal characteristics of the patient as to identify the obstructive site which triggers the pathologic process.Correlations between otolaryngologic data observed in the patient and the cephalometric ones for the identification of the obstructive site were also highlighted. Materials and methods: We worked on a sample of 16 patients, 12 males and 4 females, attended to at the Otolaryngology Operative Unit of Bari University Hospital.The patients underwent an otolaryngologic (ORL) diagnostic procedure which provided for ApneaGraph (AG) recording, and a dental diagnostic procedure with cephalometric assessment. Results: The statistical analysis highlighted a strict correlation between the otolaryngologic value of AHI and the cephalometric values of the ANB angle, with the distance between the hyoid bone and the mandibular plane and with the distance between the hyoid bone and the plane passing between C3 and Me. Conclusions: We observed a concurrence between the ORL diagnosis of the obstruction level assessed with AG and the cephalometric values regarding respiratory tracts (IPAS and SAS). More precisely, we observed the correlation between the otolaryngologic value of AHI with cephalometric values of the ANB angle, with the distance between hyoid bone and mandibular plan, and with the distance between the hyoid bone and the plane passing between C3 and Me. Furthermore, the identification of the caudal position of the hyoid bone can be considered an alarm bell in the diagnosis of severe OSAS. PMID- 29285334 TI - Bisphosphonates therapy in children with Osteogenesis imperfecta: clinical experience in oral surgery. AB - Objectives: To define the possible complications of oral surgery in childhood in patients affected by type 1 Osteogenesis imperfecta (OI) and treated with bisphosphonates (BP). Methods: The study was conducted among 20 patients in childhood with an age range 8-14 (12 ? e 8 ?) affected by OI. Patients were initially evaluated at the Policlinico Umberto I, University Hospital of Rome, Rare Disease Center Skeletal Dysplasia-Bone Metabolic Pathologies and after at the Policlinico Umberto I, University Hospital of Rome, Head and Neck Department, UOC Pediatric Dentistry. Results: From this experience, we showed that a proper patient management from the medical and dental point of view can protect these patients from the risk of post-operative problems, such as onj, soft tissue flogos, intraoral and extraoral fistulas, failure to heal the post-extractive alveolus, infections, post-operative pain and pathological fractures. The follow up, ranging from a minimum of 2 years to a maximum of 5 years, have not demonstrated the presence of particular complications or healing defects. Conclusions: The clinical experiences observed in these patients are encouraging because no postoperative complications have been observed compared to patients non-affected by OI. PMID- 29285335 TI - Treatment of severe atrophic maxilla with zygomatic implants: a case series. AB - Treatment of severe maxillary atrophy with implants has achieved important successes in recent years. The limit of implant insertion is related to inadequate bone quantity (i.e. height and width). Alveolar bone grafting, sinus lifting and major grafting via Le Fort I osteotomy have used in the past to restore bone volume prior of implant insertion. However successes do not always occur and a second stage surgery is necessary in most cases. Immediate loading cannot be performed in all grafted bone. In recent years a new treatment approach has been proposed by using zygomatic implants. This new technique can provide a better stability to the prosthesis and less morbidity for patient. Here a cases series of eighteen patients rehabilitated with zygomatic together with standard implants and immediate loading is reported. PMID- 29285336 TI - Surgiplanner: a new method for one step oral rehabilitation of severe atrophic maxilla. AB - The implant-prosthetic rehabilitation of edentulous upper jaws has always been complex for surgeons and dentists. The lack of bone in both vertical and horizontal dimension does not allow the correct insertion of dental implants. In addition, patients with edentulous upper and lower arch have a loss of vertical dimension of the face and an aged expression. Many surgical techniques have been proposed to increase the bone volume, height and thickness, such as the Le Fort I osteotomy, the bone grafts and the placement of dental implants. Planning these surgical procedures is difficult, because it is not possible to reproduce the movements of osteotomized bone segments in three planes of space. This article describes the treatment of severe atrophy maxilla with a new approach using a new instrument named "Surgiplanner". Surgiplanner is a method that, only using a computerized axial tomography (CAT), allows to obtain a totally predetermined therapeutic result from both an aesthetic and functional point of view, with surgery of severe resorbed jaws. Surgiplanner allows repositioning of segment of the skeleton of the patient's face in a predetermined and controlled way for the best implant-supported oral rehabilitation. PMID- 29285337 TI - Management of the exposure of a dense PTFE (d-PTFE) membrane in guided bone regeneration (GBR): a case report. AB - Guided bone regeneration (GBR) is a well-established and generally predictable method for repairing alveolar ridge defects and preparing edentulous sites for implant placement. Standard GBR involves filling the space underneath a membrane with autogenous bone or a mixture composed of autogenous bone particles and allogeneic bone tissue or heterologous biomaterials. The use of a barrier membrane for GBR has sometimes been associated with complications, however - reportedly involving exposure, infection, and collapse - and the non-resorbable types of membrane seem to be involved more often than the resorbable solutions. Such complications may be severe enough to defeat the object of the GBR procedure. A non-resorbable high-density polytetrafluoroethylene (d-PTFE) membrane has recently been designed specifically for use in bone-augmentation procedures that seems to assure a good bone regeneration process even when the membrane is exposed to the oral cavity. This case report describes an exposure of a d-PTFE membrane occurring after a maxillary GBR procedure and how it was overcome successfully, enabling implants insertion. PMID- 29285338 TI - Treatment of maxillary retained canine with implants: new perspectives. AB - Purpose: The surgical-orthodontic treatment of impacted maxillary canine (IMC) remains a challenge to today's clinicians. The aim of the present paper is to describe an unconventional treatment of IMC with insertion of implant into the retained canine and 3 years follow-up. Case report: A 55-year-old female patient attended to rehabilitate her maxillary left canine site. An unconventional approach was proposed to the patient. A large diameter tapered implant (O 5 * 18 mm) was inserted (Nobel Active, Kolten, Swisse). An immediate loading prosthetic rehabilitation was performed. After checking for implant stability the prosthetic steps were carried out and a single crown was delivered with Procera system. Conclusion: The patient was happy of this kind of single non-invasive session for treating IMC. At the 3-year control, the implant did not show any mobility or signs of peri-implantitis clinically or radiographically. In addiction patient was satisfied of aesthetic results. PMID- 29285340 TI - 46,XY ovotesticular disorders of sex development: A therapeutic challenge. PMID- 29285339 TI - Medium chain acyl-CoA dehydrogenase deficiency in a premature infant. AB - Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is identified by newborn screening (NBS). The natural history of MCADD includes metabolic decompensation with hypoglycemia, hyperammonemia, seizures, coma, and death. NBS enables expectant management thus severe symptoms are rare in managed patients. We report premature birth of an MCADD affected infant and resultant management challenges. Nutritional support advanced from parenteral nutrition at 24 hours to enteral feeds. A NBS sample was collected day 2, positive results for MCADD was reported day six, and diagnostic tests were performed day seven. Lab results confirmed MCADD; however, representation of pathologic analytes was so extreme that ingestion of medium chain triglycerides was suspected and subsequently confirmed. Diet was adjusted and reflected in moderation of pathologic analytes. This case emphasizes the need for prompt review NBS results in premature infants. Implementing informatic intervention within electronic medical records, when a disorder requiring special nutritional intervention is identified, will protect premature infants in this vulnerable setting. Standard of care management provided premature infants may be contraindicated in the context of a comorbid inborn error of metabolism. PMID- 29285341 TI - Simulating a virtual population's sensitivity to salt and uninephrectomy. AB - Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt-sensitive hypertension for many individuals. Factors that are important in the condition of decreased renal mass and how they affect blood pressure (BP) or salt sensitivity are unclear. We used HumMod, an integrative mathematical model of human physiology, to create a heterogeneous population of 1000 virtual patients by randomly varying physiological parameters. We examined potential physiological mechanisms responsible for the change in BP in response to high-salt diet (8* change in salt intake for three weeks) with full kidney mass and again after the removal of one kidney in the same group of virtual patients. We used topological data analysis (TDA), a clustering algorithm tool, to analyse the large dataset and separate patient subpopulations. TDA distinguished five unique clusters of salt-sensitive individuals (more than 15 mmHg change in BP with increased salt). While these clusters had similar BP responses to salt, different collections of variables were responsible for their salt sensitivity, e.g. greater reductions in glomerular filtration rate (GFR) or impairments in the renin-angiotensin system. After simulating uninephrectomy in these virtual patients, the three most salt-sensitive clusters were associated with a blunted increase in renal blood flow (RBF) and higher increase in loop and distal sodium reabsorption when compared with the salt-resistant population. These data suggest that the suppression of sodium reabsorption and renin angiotensin system is key for salt resistance, and RBF in addition to GFR may be an important factor when considering criteria for kidney donors. Here, we show that in our model of human physiology, different derangements result in the same phenotype. While these concepts are known in the experimental community, they were derived here by considering only the data obtained from our virtual experiments. These methodologies could potentially be used to discover patterns in patient sensitivity to dietary change or interventions and could be a revolutionary tool in personalizing medicine. PMID- 29285342 TI - A study on the predictability of acute lymphoblastic leukaemia response to treatment using a hybrid oncosimulator. AB - Efficient use of Virtual Physiological Human (VPH)-type models for personalized treatment response prediction purposes requires a precise model parameterization. In the case where the available personalized data are not sufficient to fully determine the parameter values, an appropriate prediction task may be followed. This study, a hybrid combination of computational optimization and machine learning methods with an already developed mechanistic model called the acute lymphoblastic leukaemia (ALL) Oncosimulator which simulates ALL progression and treatment response is presented. These methods are used in order for the parameters of the model to be estimated for retrospective cases and to be predicted for prospective ones. The parameter value prediction is based on a regression model trained on retrospective cases. The proposed Hybrid ALL Oncosimulator system has been evaluated when predicting the pre-phase treatment outcome in ALL. This has been correctly achieved for a significant percentage of patient cases tested (approx. 70% of patients). Moreover, the system is capable of denying the classification of cases for which the results are not trustworthy enough. In that case, potentially misleading predictions for a number of patients are avoided, while the classification accuracy for the remaining patient cases further increases. The results obtained are particularly encouraging regarding the soundness of the proposed methodologies and their relevance to the process of achieving clinical applicability of the proposed Hybrid ALL Oncosimulator system and VPH models in general. PMID- 29285343 TI - Non-invasive assessment of patient-specific aortic haemodynamics from four dimensional flow MRI data. AB - We introduce a parameter estimation framework for automatically and robustly personalizing aortic haemodynamic computations from four-dimensional magnetic resonance imaging data. The framework is based on a reduced-order multiscale fluid-structure interaction blood flow model, and on two calibration procedures. First, Windkessel parameters of the outlet boundary conditions are personalized by solving a system of nonlinear equations. Second, the regional mechanical wall properties of the aorta are personalized by employing a nonlinear least-squares minimization method. The two calibration procedures are run sequentially and iteratively until both procedures have converged. The parameter estimation framework was successfully evaluated on 15 datasets from patients with aortic valve disease. On average, only 1.27 +/- 0.96 and 7.07 +/- 1.44 iterations were required to personalize the outlet boundary conditions and the regional mechanical wall properties, respectively. Overall, the computational model was in close agreement with the clinical measurements used as objectives (pressures, flow rates, cross-sectional areas), with a maximum error of less than 1%. Given its level of automation, robustness and the short execution time (6.2 +/- 1.2 min on a standard hardware configuration), the framework is potentially well suited for a clinical setting. PMID- 29285344 TI - A model for the optimization of anti-inflammatory treatment with chemerin. AB - Routine treatment of mild to moderate pain with a combination of non-steroidal anti-inflammatory drugs such as paracetamol in combination with corticoid opioids can lead to severe complications including death from gastrointestinal injury or to drug dependence. There is a need for the development of new safer drugs. Chemerin is a mediator promoting resolution of inflammation and it is then a promising candidate for a new treatment. A pilot experimental work using the zymosan-induced peritonitis model has found that injecting extra chemerin resulted in an approximately 1% reduction in the total number of inflammatory cells recruited. This paper combines and adapts existing mathematical models of inflammation to reproduce these results and to explore the therapeutic potential of chemerin through simulations. Analysis of the model predicts that the injection of chemerin at a concentration of 2000 ng ml-1 within the first 5 min of inflammation onset leads to maximal inflammation inhibition. The degree of inhibition is shown to be sensitive to data used for the fit with a mean inhibition of 22 +/- 3.7% for a series of remove-one bootstrap tests, whereas optimal chemerin injection parameters were not. Overall sensitivity analysis identifies parameters of the model that need to be measured more accurately or with increased sampling rate to improve model robustness and confirm chemerin's therapeutic potential. PMID- 29285345 TI - Intima heterogeneity in stress assessment of atherosclerotic plaques. AB - Atherosclerotic plaque rupture is recognized as the primary cause of cardiac and cerebral ischaemic events. High structural plaque stresses have been shown to strongly correlate with plaque rupture. Plaque stresses can be computed with finite-element (FE) models. Current FE models employ homogeneous material properties for the heterogeneous atherosclerotic intima. This study aimed to evaluate the influence of intima heterogeneity on plaque stress computations. Two dimensional FE models with homogeneous and heterogeneous intima were constructed from histological images of atherosclerotic human coronaries (n = 12). For homogeneous models, a single stiffness value was employed for the entire intima. For heterogeneous models, the intima was subdivided into four clusters based on the histological information and different stiffness values were assigned to the clusters. To cover the reported local intima stiffness range, 100 cluster stiffness combinations were simulated. Peak cap stresses (PCSs) from the homogeneous and heterogeneous models were analysed and compared. By using a global variance-based sensitivity analysis, the influence of the cluster stiffnesses on the PCS variation in the heterogeneous intima models was determined. Per plaque, the median PCS values of the heterogeneous models ranged from 27 to 160 kPa, and the PCS range varied between 43 and 218 kPa. On average, the homogeneous model PCS values differed from the median PCS values of heterogeneous models by 14%. A positive correlation (R2 = 0.72) was found between the homogeneous model PCS and the PCS range of the heterogeneous models. Sensitivity analysis showed that the highest main sensitivity index per plaque ranged from 0.26 to 0.83, and the average was 0.47. Intima heterogeneity resulted in substantial changes in PCS, warranting stress analyses with heterogeneous intima properties for plaque-specific, high accuracy stress assessment. Yet, computations with homogeneous intima assumption are still valuable to perform sensitivity analyses or parametric studies for testing the effect of plaque geometry on PCS. Moreover, homogeneous intima models can help identify low PCS, stable type plaques with thick caps. Yet, for thin cap plaques, accurate stiffness measurements of the clusters in the cap and stress analysis with heterogeneous cap properties are required to characterize the plaque stability. PMID- 29285347 TI - Patient-specific simulations for planning treatment in congenital heart disease. AB - Patient-specific computational models have been extensively developed over the last decades and applied to investigate a wide range of cardiovascular problems. However, translation of these technologies into clinical applications, such as planning of medical procedures, has been limited to a few single case reports. Hence, the use of patient-specific models is still far from becoming a standard of care in clinical practice. The aim of this study is to describe our experience with a modelling framework that allows patient-specific simulations to be used for prediction of clinical outcomes. A cohort of 12 patients with congenital heart disease who were referred for percutaneous pulmonary valve implantation, stenting of aortic coarctation and surgical repair of double-outlet right ventricle was included in this study. Image data routinely acquired for clinical assessment were post-processed to set up patient-specific models and test device implantation and surgery. Finite-element and computational fluid dynamics analyses were run to assess feasibility of each intervention and provide some guidance. Results showed good agreement between simulations and clinical decision including feasibility, device choice and fluid-dynamic parameters. The promising results of this pilot study support translation of computer simulations as tools for personalization of cardiovascular treatments. PMID- 29285346 TI - Subject-specific multi-poroelastic model for exploring the risk factors associated with the early stages of Alzheimer's disease. AB - There is emerging evidence suggesting that Alzheimer's disease is a vascular disorder, caused by impaired cerebral perfusion, which may be promoted by cardiovascular risk factors that are strongly influenced by lifestyle. In order to develop an understanding of the exact nature of such a hypothesis, a biomechanical understanding of the influence of lifestyle factors is pursued. An extended poroelastic model of perfused parenchymal tissue coupled with separate workflows concerning subject-specific meshes, permeability tensor maps and cerebral blood flow variability is used. The subject-specific datasets used in the modelling of this paper were collected as part of prospective data collection. Two cases were simulated involving male, non-smokers (control and mild cognitive impairment (MCI) case) during two states of activity (high and low). Results showed a marginally reduced clearance of cerebrospinal fluid (CSF)/interstitial fluid (ISF), elevated parenchymal tissue displacement and CSF/ISF accumulation and drainage in the MCI case. The peak perfusion remained at 8 mm s-1 between the two cases. PMID- 29285348 TI - Meeting the multiscale challenge: representing physiology processes over ApiNATOMY circuits using bond graphs. AB - We introduce, and provide examples of, the application of the bond graph formalism to explicitly represent biophysical processes between and within modular biological compartments in ApiNATOMY. In particular, we focus on modelling scenarios from acid-base physiology to link distinct process modalities as bond graphs over an ApiNATOMY circuit of multiscale compartments. The embedding of bond graphs onto ApiNATOMY compartments provides a semantically and mathematically explicit basis for the coherent representation, integration and visualisation of multiscale physiology processes together with the compartmental topology of those biological structures that convey these processes. PMID- 29285349 TI - Rhopalurus junceus scorpion venom induces apoptosis in the triple negative human breast cancer cell line MDA-MB-231. AB - Rhopalurus junceus scorpion venom has demonstrated high cytotoxic activity in epithelial cancer cells. In the present study, the effect of scorpion venom on cell viability and apoptosis was evaluated in the MDA-MB-231 human breast carcinoma cell line. Cell viability was analyzed using MTT assay. The cell death event was examined trough end-point RT-PCR to identify the expression of apoptosis-related genes, fluorescent microscopy and mitochondrial membrane potential (DeltaPsim) alteration. The results demonstrated that scorpion venom induced apoptosis in MDA-MB-231 cells in a time-dependent manner. Besides, scorpion venom treatment also resulted in p53, bax, noxa, puma, caspase 3 and p21 over-expression, while the expression of bcl-2 and bcl-xl was down-regulated. Apoptosis was associated with depolarization of DeltaPsim. The overall effect indicates that the selective cytotoxic effect of the scorpion venom is associated with its apoptosis-inducing effect through the mitochondrial pathway. Therefore, R. junceus scorpion venom may be an interesting natural extract for further investigation in breast cancer treatment strategies. PMID- 29285350 TI - Outcome determinants of snakebites in North Bihar, India: a prospective hospital based study. AB - Bihar is the state with the third largest number of snakebite deaths per year in India. This prospective, one-year study of 608 snakebites provides the first data from Bihar on determinants of unfavourable outcomes in snakebites. Any delay in reaching hospital raised the risk of a snakebite patient for an unfavourable outcome [OR 8.88, CI 2.04-38.8]. Attending a traditional practitioner prior to presenting to the hospital was the only specific, significant delay [OR 3.52, CI 1.26-9.7]. Prevention of unfavourable outcomes occurred by presenting to hospital in less than 1.5 hours [OR 0.23, CI 0.052-1.0]. Motorbike was the best mode of transport [OR 0.37, CI 0.12-1.1]. Other risk factors were patients aged under 15 years [OR 3.79, CI 1.57-9.12] and bites to the upper limb [OR 2.47, CI 1.01 6.04]. Patients who were envenomated had a higher risk of unfavourable outcome, if referred due to antivenom being unavailable [OR 12.2, CI 1.49-100]. To save lives, it is imperative that measures to reduce delays in getting patients to hospital must be included in snakebite management, alongside continued availability of antivenom and assisted ventilation. PMID- 29285351 TI - Application of phage display for the development of a novel inhibitor of PLA2 activity in Western cottonmouth venom. AB - Snakebite envenomation is an important global health concern. The current standard treatment approach for snakebite envenomation relies on antibody-based antisera, which are expensive, not universally available, and can lead to adverse physiological effects. Phage display techniques offer a powerful tool for the selection of phage-expressed peptides, which can bind with high specificity and affinity towards venom components. In this research, the amino acid sequences of Phospholipase A2 (PLA2) from multiple cottonmouth species were analyzed, and a consensus peptide synthesized. Three phage display libraries were panned against this consensus peptide, crosslinked to capillary tubes, followed by a modified surface panning procedure. This high throughput selection method identified four phage clones with anti-PLA2 activity against Western cottonmouth venom, and the amino acid sequences of the displayed peptides were identified. This is the first report identifying short peptide sequences capable of inhibiting PLA2 activity of Western cottonmouth venom in vitro, using a phage display technique. Additionally, this report utilizes synthetic panning targets, designed using venom proteomic data, to mimic epitope regions. M13 phages displaying circular 7 mer or linear 12-mer peptides with antivenom activity may offer a novel alternative to traditional antibody-based therapy. PMID- 29285352 TI - Evidence for in vitro antiophidian properties of aqueous buds extract of Eucalyptus against Montivipera bornmuelleri venom. AB - Because snake venoms are complex mixtures of bioactive molecules, snake bites produce a large panel of symptoms which cannot be totally prevented by current antivenoms. Thus investigating plant extracts for antivenomics therapy approaches seemed relevant. Here, we evaluated the potency of the aqueous Buds extract of Eucalyptus (ABEE) to counteract the main enzymatic activities of Montivipera bornmuelleri venom. We showed that ABEE efficiently counteracts the proteolytic, Phospholipases A2 (PLA2), and L-aminoacid oxidase activities (LAAO) of M. bornmuelleri venom. ABEE was found to inhibit Acetylcholine esterase (AChE) and to exhibit a potent antioxidant activity. In addition, M. bornmuelleri venom displays antibacterial properties against Staphylococcus aureus, which were not inhibited by ABEE. We also showed that of M. bornmuelleri venom lacks AChE, either anti-AChE activities. ABEE represents a promising natural source of antivenomics compounds against the deleterious effects of M. bornmuelleri or other Vipera species bites. PMID- 29285353 TI - Triple-negative breast cancer and its association with obesity. AB - Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks expression of the estrogen and progesterone receptor and does not overexpress human epidermal growth factor 2 receptor protein. TNBC is associated with special characteristics, including aggressiveness, poor prognosis and poor response to treatment, and has been attracting increasing attention worldwide. Obesity is a well-documented factor exerting a significant effect on the development of breast cancer, including TNBC. The purpose of the present review was to focus on the association between obesity and TNBC and provide a summary of novel research findings. The aim was to highlight the association between TNBC and obesity and provide an overview of novel outlooks on clinical issues, biological rationale, novel targeted therapies and prognosis, in order to draw attention to the significance of weight management, primary prevention, early diagnosis and treatment of this intractable disease. PMID- 29285354 TI - Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5-fluorouracil-based chemotherapy: A meta-analysis. AB - In the past decades, various studies have suggested a possible link between thymidine phosphorylase (TP) level and colorectal cancer (CRC) treated with 5 fluorouracil (5-FU)-based chemotherapy; however, they have arrived at inconsistent results. Therefore, the present meta-analysis aimed to disclose a more comprehensive evaluation of this relationship. PubMed, the Cochrane Library, Ovid MEDLINE, Embase and China National Knowledge Infrastructure were systematically searched for studies that evaluated the prognostic value of TP in CRC. Stata 12.0 software was used to test the heterogeneity and evaluate the overall test performance. A total of 15 studies, including 1,225 patients, were included. The summary estimates of TP for CRC treated with 5-FU-based chemotherapy indicated a moderately positive prognosis with a hazard ratio (HR) of 0.76 (P=0.031) for overall survival and a HR of 0.711 (P=0.022) for relapse free survival. On the basis of the present meta-analysis, TP could be promising and meaningful in the prognosis of CRC treated with 5-FU-based chemotherapy. PMID- 29285355 TI - Glioblastoma fed by middle meningeal artery and displaying cyst formation soon after repeated implantation of carmustine wafers: A case report. AB - The present study reported an unusual case of temporal lobe glioblastoma (GBM) fed from the middle meningeal artery that progressed rapidly. A 66-year-old male was admitted to the Department of Neurosurgery at Nihon University Itabashi Hosipital (Tokyo, Japan) with epilepsy. Magnetic resonance imaging disclosed a small well-enhanced right middle fossa mass lesion, which was relatively boundary clear and attached to the dura mater. An angiogram showed a stain fed from the right middle meningeal artery. The mass lesion was removed completely by surgery and diagnosed pathologically as GBM. Tumor recurrence was observed 6 months later and a second surgery was performed. Eight pieces of carmustine wafers were implanted in the tumor resection cavity at the first and second surgeries. The patient underwent a third surgery soon after the second surgery, as a cyst had formed in the resection cavity. The tumor became uncontrollable and the patient died at 11 months after the first surgery even though he had undergone multimodality treatment. Since GBM fed by the middle meningeal artery is rare, the timing of surgical treatment is difficult as it is easy to misdiagnose a case like the present one as a meningioma. Furthermore, repeated implantation of carmustine wafers should be considered carefully, since adverse events associated with such wafers may easily occur. PMID- 29285356 TI - Effect of paiteling on human papillomavirus infection of the cervix. AB - The aim of the present study was to investigate the effect of the traditional Chinese medicine paiteling on the outcome of high-risk human papillomavirus (HR HPV) infection of the cervix. A total of 321 patients were enrolled in this study and HPV subtypes were determined by the Hybribio HPV genotyping system. The patients were divided into the loop electrosurgical excision procedure (LEEP; n=82) and non-LEEP (n=239) groups, according to the cervical intraepithelial neoplasia classification. These two groups were further subdivided into the drug (paiteling) and control subgroups. Thin-prep cytology and HR-HPV tests were performed every 3 months for 1 year. In the non-LEEP group, the negative conversion rate of HR-HPV and the regression rate of the cervical lesions in drug subgroup were significantly higher compared with those in the control subgroup. In the LEEP group, the seroconversion rate of the drug subgroup, but not the regression rate of the lesions, was significantly higher compared with that in the control subgroup. The seroconversion rate of HPV16-infected patients at 12 months was 85.7%, whereas it reached 100% in all other HPV subtypes. Therefore, paiteling may accelerate the clearance of HPV infection and the regression of cervical lesions. PMID- 29285357 TI - Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma. AB - Definitive concomitant chemoradiotherapy (CRT) with high-dose cis-platinum (CDDP) is a current standard protocol for advanced laryngeal and hypopharyngeal cancer sparing surgery for salvage. However, this modality is associated with limited feasibility and frequent sever toxicities. In the present study, a 'chemoradioselection' protocol with minimal toxicity was developed using initial response to CRT as a biomarker for patient selection. Between 2000, March and 2012, September 123 patients with stage III (44), IV (79) laryngeal (64) and hypopharyngeal carcinoma (59) excluding T4 cases were enrolled to this protocol. Two cycles of split (15 mg/m2 *5 days, 2000-2008) or bolus (80 mg/m2, 2009 present) CDDP was concurrently administered. Tumor responses were evaluated after 40 Gy of CRT and 64 responders (chemoradioselected, CRS) received further CRT up to 70 Gy, while radical surgery was recommended for the 59 non-responders (N CRS), and 34 underwent surgery (N-CRS-ope). The remaining 25 patients who refused surgery (N-CRS-refu) were treated with continuous CRT. The 5-year overall survival (OS) and disease-specific survival (DSS) were 67, and 77%, respectively. The CRS demonstrated favorable 5-year OS (73%) and laryngo-esophageal dysfunction free survival (LEDFS, 69%) rates. In contrast, the N-CRS-refu showed significantly lower 5-year OS (47%) compared with CRS (73%) and N-CRS-ope (70%) (P=0.0193), and significantly lower 5-year LEDFS (20%) compared with the CRS (69%) (P<0.0001). On multivariate analyses, including T, N, primary site and planned treatment (CRS + N-CRS-ope) or not (N-CRS-refu), unplanned treatment alone showed a significant correlation with poor OS [hazard ratio (HR), 2.584; 95% confidence interval (CI), 1.313-4.354; P=0.007). Chemoradioselection reflects the biological aggressiveness of each tumor, and is able to segregate patients for functional laryngeal preservation with moderate intensity CRT (150-160 mg/m2 of CDDP) from those who would be better treated with surgery. This strategy may be useful for the optimization of the therapeutic intensity. PMID- 29285358 TI - Ameloblastic fibro-odontosarcoma of the mandible with active epithelial proliferation: A rare case report. AB - Ameloblastic fibro-odontosarcoma (AFOS) is an extremely rare subtype of odontogenic sarcoma, with no more than 19 cases reported in the English literature to date. AFOS is a biphasic neoplasm, with deposits of dentin and enamel matrix. We herein present a case of AFOS with active epithelial proliferation in a 31-year-old female patient. The patient was referred to the West China Hospital of Stomatology (Chengdu, China) due to a 6-month history of a swelling in the left mandible. Following clinical and radiological examination, the initial preoperative diagnosis was ameloblastoma, with local invasion and the possibility of malignant transformation. Left hemimandibular resection was subsequently performed. The postoperative histopathological diagnosis was AFOS, accompanied by active epithelial proliferation. Immunohistochemically, cytokeratin (CK)14 and CK19 were intensely positive in the epithelium, whereas the mesenchymal cells were strongly positive for vimentin. The Ki-67 labeling index was considerably higher in the mesenchymal component (mean, 40%) compared with that in the epithelial element (mean, 5-8%). Three months after the surgical procedure, the patient remained clinically and radiologically disease-free. PMID- 29285359 TI - Mucinous tubular and spindle cell carcinoma with a high nuclear grade and micropapillary pattern: A case report. AB - Mucinous tubular and spindle cell carcinoma (MTSCC) is rare in renal cell carcinoma (RCC) and usually demonstrates a low nuclear grade and a better prognosis compared with other RCCs. The authors present a case report of MTSCC containing an area of Fuhrman nuclear grade 3, in addition to an area with a micropapillary pattern. An 82-year-old man consulted a hospital due to macrohematuria, and a tumor in the right kidney was detected. The tumor was resected and histologically examined. The tumor consisted of various growth patterns: Elongated tubular structure, a papillary structure containing a micropapillary pattern and solid pattern with spindle cells. The tumor cells demonstrated Fuhrman nuclear grades 2 and 3. Invasion into the lymph vessel and metastasis into the regional lymph node were observed. Thus, the tumor was diagnosed as a high grade MTSCC. Five months following resection, a computed tomography scan suggested metastasis of the tumor into the para-aortic lymph nodes and liver, and the patient succumbed to brain metastasis. When MTSCC of kidney is observed, careful histological observation is important to avoid missing a high nuclear grade area. PMID- 29285361 TI - Response to nivolumab in metastatic collecting duct carcinoma expressing PD-L1: A case report. AB - The authors present a case report of collecting duct carcinoma (CDC) that responded to nivolumab, a programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, following the failure of systemic treatment with chemotherapy and targeted therapy. The patient underwent right radical nephrectomy and segmentectomy of the lung following chemotherapy. Fifteen months following the first surgery, segmentectomy and subsequent second-line chemotherapy were performed for recurrence in the lung. Targeted therapy with temsirolimus for recurrence of the lung and lymph node metastases was ultimately used for 30 months. However, the temsirolimus treatment failed to suppress the growth of metastatic lesions. Nivolumab resulted in complete response of the lung metastasis, and it stabilized the lymph node metastasis. PD-L1 was highly expressed in both primary tumor and the metastatic regions. Therapy with nivolumab is ongoing. These findings suggest that treatment with nivolumab may be considered for metastatic and treatment-failure CDC. PMID- 29285360 TI - Detection of epidermal growth factor receptor mutations in lung adenocarcinoma cytological specimens by immunocytochemistry. AB - Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) improve the survival of patients with lung adenocarcinoma, and determine the EGFR mutation status before treatment is necessary. In contrast to biopsy samples, cytological specimens are obtained less invasively and are useful for EGFR mutation analyses. Recently, novel antibodies against two major EGFR mutations were developed: SP111, which is specific for the E746-A750 deletion in exon 19; and SP125, which is specific for the L858R mutation. To the best of our knowledge, no study has evaluated cytological specimens using the two novel antibodies, thus their specificity and sensitivity were examined in surgical resection, and cytological lung adenocarcinoma samples in the present study. Previous screening for EGFR mutation status by molecular testing identified delE746-A750 in 3 cases and the L858R mutation in 7 cases; the other cases did not have the L858R or the delE746 A750 mutation. Using a four-grade scoring system (score 0 to 3+), the immunohistochemistry (IHC) and immunocytochemistry (ICC) results were compared with those of molecular testing. Using a score of >=2 as positive, IHC and ICC using SP111 demonstrated sensitivities of 100 and 33.3%, and specificities of 100 and 100%, respectively. IHC and ICC using SP125 revealed sensitivities of 100 and 71.4%, and specificities of 100 and 100%, respectively. Therefore, screening for EGFR mutations by ICC may facilitate therapeutic decision-making, particularly in medical centers that are unable to perform molecular testing. PMID- 29285362 TI - dTCApFs, a derivative of a novel human hormone peptide, induces apoptosis in cancer cells through a mechanism involving loss of Golgi function. AB - dTCApFs (NerofeTM) is a 14-amino acid derivative of a longer hormone peptide, tumor-cells apoptosis factor (TCApF), which enters the cells through the T1/ST2 receptor. In the present study, the mechanism of action (MOA) of dTCApFs as an anticancer agent was investigated. Experiments were performed in pancreatic cancer cell lines, and immunofluorescent staining demonstrated that dTCApFs is located in the Golgi apparatus of treated cells. It was also demonstrated in pancreatic, breast and ovarian cell lines that dTCApFs treatment led to Golgi structural changes, loss of Golgi function, and molecular effects associated with endoplasmic reticulum (ER) stress, such as increased levels of C/EBP homologous protein, binding immunoglobulin protein (BiP), phosphorylated inositol-requiring enzyme 1 (pIRE1), and increased phosphorylation of eukaryotic translation initiation factor 2alpha, and to the generation of reactive oxygen species, which was attenuated by ER stress inhibitors. Moreover, in these cell lines, long-term exposure to dTCApFs led to downregulation of spliced X-box-binding protein 1, which is an ER stress repair mechanism gene, downregulation of the Golgi anti apoptotic protein, and reduced cell viability. In vivo studies using murine xenograft models of human pancreatic cancer verified the cell culture findings by demonstrating structural changes in the ER/Golgi and increased levels of pIRE1and BiP in dTCApFs-treated mice vs. the controls. Finally, human tissue samples from a patient who received dTCApFs for 11 months in a clinical trial were analyzed, and an increase was observed in the number of cells expressing pIRE1 and BiP post treatment. In conclusion, we herein report a novel MOA for an anticancer agent involving triggering of apoptosis through induction of opposite effects: ER stress and downregulation of the ER stress repair mechanism. These findings provide the framework for the clinical evaluation of dTCApFs. PMID- 29285363 TI - Development of fever following first administration of zoledronate as a prognostic factor in advanced non-small cell lung cancer patients with bone metastases. AB - Nitrogen-containing bisphosphonates (N-BPs), which are usually used for the treatment of advanced cancer with bone metastasis, occasionally cause fever following the first administration. However, it is unclear as to how the development of fever following the first administration of N-BP is associated with clinical outcome. The aim of the present study was to determine the prognostic value of the development of fever following the first administration of N-BP in advanced non-small cell lung cancer patients with bone metastases. The present study reviewed the data of 46 patients with advanced non-small cell lung cancer who were administered zoledronate (ZOL), an N-BP, for bone metastasis, between March 2009 and March 2011 in the Department of Medical Respirology at Tottori University Hospital. Clinicopathological factors were evaluated using univariate and multivariate analyses, and these factors were compared between the fever and non-fever groups. Of the 46 patients, 15 (32.6%) developed fever following the first administration of ZOL. No significant differences were observed in the clinicopathological characteristics between the two groups. The overall survival in the fever group was significantly longer compared with the non-fever group (median survival time: 33.4 vs. 15.7 months, P=0.04), and the development of fever following the first ZOL administration was independently associated with longer overall survival. The development of fever following the first ZOL administration was an independent prognostic factor in advanced non small cell lung cancer patients with bone metastases. Thus, ZOL-associated fever may be a predictive factor for an undefined, survival-promoting effect of ZOL. PMID- 29285364 TI - Bilateral and multiple mixed epithelial and stromal tumors of the kidney: A case report. AB - Mixed epithelial and stromal tumor (MEST) of the kidney is a benign tumor occurring predominantly in older women. Histologically, MEST comprises tubuloglandular and cystic structures in an ovarian-like stroma. Bilateral and multiple cases are rare. We herein present a case of bilateral and multiple MEST in a 43-year-old woman. The patient presented with gross hematuria and was referred to a primary care physician. A computed tomography scan revealed 5 tumors in the right and 2 in the left kidney. Renal cell carcinoma was suspected, and left partial nephrectomy followed by right radical nephrectomy was planned. After the left partial nephrectomy, the histopathological diagnosis was MEST, which was consistent with the results obtained following needle biopsy. Therefore, the contralateral tumor was also suspected to be MEST, and needle biopsy was performed. The histopathological diagnosis was identical and the right kidney was spared. The patient is currently periodically monitored. As MEST is a benign tumor, preoperative diagnosis is crucial for avoiding overtreatment. PMID- 29285365 TI - Dedifferentiated endometrial carcinoma: A report of three cases and review of the literature. AB - Dedifferentiated endometrial carcinoma, which is defined microscopically as the co-existence of undifferentiated carcinoma and grade 1 or 2 endometrioid adenocarcinoma, is an aggressive type of cancer regardless of the percentage of undifferentiated components. It is reported that undifferentiated carcinoma comprises 9% of endometrial carcinoma. The percentage of dedifferentiated endometrial carcinoma has been hypothesized to be 40% of undifferentiated carcinoma. A precise pathological diagnosis is essential for defining the appropriate therapeutic approach and prognosis. Furthermore, since there is an association between dedifferentiated endometrial carcinoma and Lynch syndrome, it is important to identify the patient's genetic background. The current case report presents three cases of dedifferentiated endometrial carcinoma treated in our hospital. In immunohistochemical staining for DNA mismatch-repair (MMR) proteins in dedifferentiated endometrial carcinoma, the components of undifferentiated carcinoma demonstrated a loss of MMR protein expression, and it is suspected that there may be a germline mutation in these cases. Therefore, Lynch syndrome should be suspected and the appropriate genetic approaches in cases of dedifferentiated endometrial carcinoma should be considered. PMID- 29285366 TI - Clinical effects and safety of intra-arterial infusion therapy of cisplatin suspension in lipiodol combined with 5-fluorouracil versus sorafenib, for advanced hepatocellular carcinoma with macroscopic vascular invasion without extra-hepatic spread: A prospective cohort study. AB - Although sorafenib and hepatic arterial infusion chemotherapy (HAIC) have been proven to improve prognosis in hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion (MVI), the most appropriate approach remains unclear. The present multicenter, non-randomized, prospective cohort study aimed to compare the efficacy and safety of HAIC and sorafenib in patients with advanced HCC and MVI, without extra-hepatic spread (EHS) and Child-Pugh class A disease. The present study was performed between April 2008 and March 2014, and 64 HCC patients with MVI, without EHS and Child-Pugh class A disease were registered. Of these patients, 44 were treated with HAIC and 20 with sorafenib. HAIC involved cisplatin (50 mg fine powder in 5-10 ml lipiodol) and a continuous infusion of 5-fluorouracil (FU) (1,500 mg/5 days), which is referred to as new 5 FU and cisplatin therapy (NFP). The primary outcome was progression-free survival, and the secondary outcome was overall survival (OS). Clinical factors influencing OS and the therapeutic effect were identified using univariate and multivariate analyses. There were no differences in clinical factors between the two groups. The median progression-free survival was 5.1 and 9.5 months in the sorafenib and NFP groups, respectively (P=0.001). The complete response (CR) or partial response (PR) rates were 10 and 71% in the sorafenib and NFP groups, respectively (P<0.001). The median OS in the sorafenib and NFP groups was 13.2 and 30.4 months, respectively (P=0.013). Multivariate analysis revealed that the independent predictors of survival were Child-Pugh score (5, P=0.022, 95% CI, 0.191-0.892), grade of portal vein invasion (brunch, P=0.009, 95% CI, 0.220 0.752), and therapeutic effect (CR or PR, P<0.001, 95% CI, 0.220-0.752), and the independent predictor of therapeutic effect was therapeutic regimen (NFP, P<0.001, 95% CI, 0.006-0.199). NFP should be the first choice for patients with advanced HCC and MVI, without EHS and Child-Pugh A disease. PMID- 29285367 TI - Clinical study on collagen gel droplet-embedded culture drug sensitivity test for multidrug combination chemotherapy and super selective intra-arterial infusion chemoradiotherapy in oral squamous cell carcinoma. AB - Using trace three-dimensional culture, the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) can be tested even in cases with a small number of cells, including oral squamous cell carcinoma (OSCC), and evaluation of the antitumor effect with a drug concentration close to the in vivo level is possible. The present report aimed to evaluate the utility of the CD-DST in the assessment of the in vitro efficacy of single-agent and multidrug combination chemotherapy for OSCC in comparison with the clinical response rates and to examine the possible clinical application of CD-DST for such cases. A total of 33 OSCC patients from whom 33 samples were obtained from January 2010 to September 2015 were included. CD-DST was performed, individually and in combination, on the three drugs [i.e., cisplatin (CDDP), 5-fluorouracil (5-FU), and docetaxel (DOC)] and on super selective intra-arterial infusion chemoradiotherapy (IACRT). The overall evaluable rate of the CD-DST in OSCC was 81.8% (27 of 33 cases) and the sensitivity to each anticancer drug was evaluated. The in vitro efficacy rates of IACRT, cisplatin + 5-fluorouracil, and docetaxel + cisplatin + 5-fluorouracil (TPF) confirmed the estimated clinical response rates. In 14 of 33 patients, the results of CD-DST were compared with clinical efficacy, which was judged based on measurable lesions on imaging. For TPF therapy, the sensitivity test of the IACRT had a positive predictive value of 90.9% (10 of 11 cases) and a negative predictive value of 100% (3 of 3 cases); the accuracy of the susceptibility test for the anticancer agents was 92.8% (13 of 14 cases). The CD-DST may be useful in selecting multidrug combination chemotherapy and IACRT for OSCC, however, accumulation of further clinical data is required in the future. PMID- 29285368 TI - Role of endometriosis as a prognostic factor for post-progression survival in ovarian clear cell carcinoma. AB - The clinical significance of coexistence of endometriosis (EM) in ovarian clear cell carcinoma (CCC) has not yet been determined. The aim of the present study was to analyze the correlation of endometriosis with clinicopathological factors in CCC. The cases with CCC that received primary debulking surgery at the present hospital between 1990 and 2013 were identified. Retrospective analysis was conducted to evaluate the association between complications with EM and clinicopathological features in CCC. Of the 105 cases enrolled in the study, 45 cases were complicated with EM, and 60 cases did not have EM (non-EM). The patients with EM were diagnosed at a younger age (P=0.03), and at earlier stages (P<0.01) compared with non-EM cases. Although there was no significant difference of progression-free survival (P=0.36), complications with EM were identified as an independent prognostic factor for overall survival (OS; P<0.01) by multivariate analysis. A total of 48 patients (45.7%) developed recurrence: 18 patients in EM-group and 30 patients in non-EM group. There were no significant differences of clinicopathological factors in the treatment at recurrence between both groups. Recurrent cases in EM had significantly worse post-progression survival (PPS) compared with recurrent non-EM group (P<0.01). Multivariate analysis for PPS demonstrated that complications with EM (P<0.01) were identified as a worse prognostic factor. In CCC, the complication with EM was identified as a significant worse prognostic factor for PPS in recurrent cases. Additionally, EM was significantly associated with OS in all cases with CCC. Novel treatment strategies are therefore necessary for recurrent CCC, particularly for cases exhibiting EM. PMID- 29285369 TI - Clinical significance of atypical squamous cells of undetermined significance after treatment for cervical intraepithelial grade 3 neoplasia: A retrospective single-center cohort study. AB - The aim of the present study was to evaluate the clinical significance of atypical squamous cells of undetermined significance (ASC-US) following cervical conization for cervical intraepithelial neoplasia (CIN) grade 3. This study was a retrospective cohort analysis. The medical records of women treated with conization for CIN 2-3 were reviewed and 142 patients with CIN 3 who had been diagnosed using the conization specimens were selected. The mean follow-up period after conization was 41.8 months. Cytological abnormalities after conization were observed in 19.0% of the patients and consisted of ASC-US (13.4%) and worse than low-grade squamous intraepithelial lesion (LSIL; 5.6%). Recurrence was defined as a diagnosis worse than CIN 2, and the recurrence rate was 29.6% among patients with abnormal cytology. The recurrence rate was 15.7% in the ASC-US group and 71.4% in the worse than LSIL group. There was no significant difference in the time of initial identification of abnormal cytology after treatment between the worse than LSIL and the ASC-US groups (P=0.054). However, the ASC-US group had a significantly better cumulative recurrence-free rate compared with the worse than LSIL group (P<0.05). Women with ASC-US following treatment for CIN appear to be at a relatively high risk. Regarding the risk stratification of women following treatment for CIN, if surveillance cytology shows ASC-US, immediate colposcopy is recommended, along with long-term follow-up. PMID- 29285370 TI - Low uric acid level increases the risk of infectious mononucleosis and this effect is more pronounced in women. AB - Infectious mononucleosis (IM) due to Epstein-Barr virus infection is common. Uric acid (UA) is an important endogenous antioxidant. To the best of our knowledge, the association between UA and IM has not been comprehensively investigated to date. The aim of the present study was to investigate this association in Chinese patients. A total of 95 patients (47 men and 48 women) with IM were recruited, along with 95 healthy controls. Clinical data were classified by patient sex. Receiver operating characteristic (ROC) curve analysis was adopted to determine the cut-off values of UA for IM diagnosis and prediction. Crude and adjusted odds ratios (ORs) of UA for IM were analyzed by binary logistic regression. The UA levels were significantly lower in IM patients compared with those in controls. In addition, UA levels in men were significantly higher compared with those in women. The ROC curve demonstrated good diagnostic and predictive values of UA for IM in both sexes. The UA cut-off values were 326.00 and 243.50 umol/l for diagnosing IM in men and women, respectively, with a diagnostic accuracy of 76.596 and 80.208%, respectively. Binary logistic regression analysis revealed a significant risk of IM in the low UA quartiles in both sexes. Following adjustments, the ORs even increased. Women with low UA levels appeared to be more susceptible to IM. For example, the crude ORs in quartile 1 were 24.000 and 52.500 for men and women, respectively, and the respective adjusted ORs were 31.437 and 301.746 (all P<0.01). To the best of our knowledge, the present study is the first to demonstrate the inverse association between UA and IM, suggesting a progressive decrease of antioxidant reserve in IM. Moreover, low UA was suggestive of IM, particularly in women. PMID- 29285371 TI - En bloc resection, intraoperative extracorporeal irradiation and re-implantation of involved bone for the treatment of limb malignancies. AB - Reconstruction of the defect following limb-sparing resection of malignant bone tumors is controversial and extremely challenging. Extracorporeal irradiation (ECI) and re-implantation have been used for limb salvage surgery for patients, with major advantages, including biological reconstruction, ready availability and preservation of bone stock, over replacement with a megaprosthesis. The purpose of the present study was to present our experience and details of all patients treated with this surgery. Between June 2005 and December 2014, we followed-up 23 patients with limb malignancies who were treated with en bloc excision followed by 50-Gy single dose ECI and re-implantation of involved bone segments. All cases were evaluated based on clinical and radiological examinations, complications and Musculoskeletal Tumor Society (MSTS) score. Mean follow-up period was 77.6 months (range, 17-116 months). A total of 17 patients (73.9%) demonstrated no evidence of disease, 5 (21.7%) patients succumbed to the disease and 1 (4.3%) patient was alive with the disease at the final follow-up. Local recurrence occurred in 3 patients (recurrence rate, 13.0%) in the bed outside of the irradiated graft, and 4 of the 5 patients that lost their lives did so due to associated metastatic disease. The mean value of the MSTS score was 78.8% (50-93.3%). The majority of patients demonstrated solid bony union; however, 3 patients had non-union (13.0%) and 1 had a delayed union (4.3%). Early or late complications occurred in 11 patients (47.8%). Although the complication rate (47.8%) and re-operation rate (39.1%) were high, ECI and re-implantation may be a useful and cheap technique following en bloc resection for limb salvage in appropriately selected patients. PMID- 29285372 TI - Malignant mesothelioma of the tunica vaginalis testis: A case report and literature review. AB - Malignant mesothelioma of the tunica vaginalis testis is an extremely rare tumor without specific clinical manifestations, mainly including hydrocele formation and a painless mass. We herein present the case of a patient with hydrocele of the left testis, without any other complaints. Tunica vaginalis subinvolution was performed, and postoperative pathological examination revealed a malignant mesothelioma arising from the left tunica vaginalis testis. Whole-body positron emission tomography-computed tomography (PET-CT) and subsequent abdominal and pelvic magnetic resonance imaging (MRI) revealed no evidence of local lymphadenopathy. Radical left orchiectomy was performed after the pathological diagnosis. The pathological examination after the second surgery demonstrated that the tumor had invaded the adjacent periorchium and spermatic cord, but there was no evidence of local lymph node metastasis. Pemetrexed and cisplatin were administered at a dose of 900 and 130 mg, respectively, on the first day of a 28 day cycle. After 6 months of therapy, the disease had not progressed on abdominal and pelvic PET-CT and MRI. The patient was still followed up in our urology outpatient clinic at the time of the present report. Although testicular hydrocele is a common and easily diagnosed condition, detailed medical history and physical examination are required. Thus, when clinicians encounter patients with testicular hydrocele, a variety of possible causes must be considered, including testicular or paratesticular tumors, even rare tumors such as mesothelioma of the tunica vaginalis testis. PMID- 29285373 TI - Successful detection of SRY gene via fine needle biopsy: A case of extragenital gestational choriocarcinoma in the kidney. AB - The current report describes a case of extragenital gestational choriocarcinoma in the kidney. A 36-year-old woman with a history of two deliveries of male babies visited the present hospital due to secondary amenorrhea following a positive urinary pregnancy test. Despite a high serum level of human chorionic gonadotropin, at 51,800 mIU/ml, diagnostic imaging methods and pathological examination did not detect any conceptus in the genital tract. Positron emission tomography-computed tomography detected 18F-FDG-positive tumors in the left kidney and right lung. A fine needle biopsy of the renal lesion pathologically revealed the presence of choriocarcinoma and a subsequent polymerase chain reaction analysis verified the presence of a Y-chromosome-specific the sex determining region Y (SRY) gene, diagnosed as extragenital gestational choriocarcinoma. Clinically, 10 cycles of EMA/CO chemotherapy were administered and an optimal response was obtained. In conclusion, this is the first report of the diagnosis of extragenital gestational choriocarcinoma by the detection of the SRY gene with PCR using biopsy samples. PMID- 29285374 TI - Stereotactic body radiotherapy for oligo-recurrence in the liver in a patient with esophageal carcinoma: A case report. AB - Stereotactic body radiation therapy (SBRT) is a safe and effective treatment for solitary cancerous lesions. The present study reported a rare case of sustained remission after SBRT for oligorecurrence in the liver in a patient with esophageal carcinoma. A 60-year-old Japanese man presented with a chief complaint of dysphagia. On medical examination, the patient was diagnosed as having squamous cell carcinoma of the esophagus that was clinically staged as T4bN1M0. The patient received definitive concurrent chemoradiotherapy, consisting of four 28-day cycles of chemotherapy comprising nedaplatin 80 mg/m2 on day 1 and S-1 120 mg/body orally on days 1-14, with radiotherapy comprising a total of 50 Gy in daily fractions of 2 Gy. After a 9-month disease-free interval following the primary treatment, a solitary liver metastasis was identified. The patient underwent SBRT using a radiation dose of 48 Gy in 4 fractions and two 28-day cycles of adjuvant chemotherapy comprising nedaplatin 80 mg/m2 on day 1, and S-1 100 mg/body orally on days 1-14. The patient exhibited no signs of recurrence for 3 years with sustained local control. SBRT may be considered a treatment option for patients with relapsed esophageal cancer with oligo-recurrence in the liver. PMID- 29285375 TI - Expression of Topoisomerase II-alpha protein in salivary gland tumors. AB - Salivary glands give rise to approximately 30 histological distinct tumor types, which results in a diagnostic challenge for the pathologist. The present retrospective, immunohistochemical study aimed to evaluate the expression of Topoisomerase II-alpha, a nuclear enzyme, as a diagnostic and prognostic marker in benign and malignant salivary gland tumors, including leomorphic adenoma, mucoepidermoid carcinoma, acinic cell carcinoma and carcinoma ex-pleomorphic adenoma. A total of 59 cases of benign and malignant salivary gland tumors were included in the present study. Representative paraffin-embedded sections were immunostained for Topoisomerase II-alpha (Topo II-alpha). The expression level was semi-quantified for each case and then correlated with the histological diagnosis using hematoxylin and eosin-stained slides, grade of tumor and total survival. Significant differences were revealed between the expression level of Topo II-alpha in pleomorphic adenoma and mucoepidermoid carcinoma (P<0.001), carcinoma ex-pleomorphic adenoma (P<0.001), acinic cell carcinoma (P=0.005) and a group composed of all the malignant tumors (P<0.001). Cancer-specific survival rates were insignificantly increased in tumors expressing low levels of Topo II alpha (P=0.464). Thus, the present study demonstrated different expression levels of Topo II-alpha in benign and malignant salivary gland tumors. These differing expression levels may act as valuable biomarkers for the correct histological diagnosis. Further studies conducted on a larger scale may lead to even more conclusive results. PMID- 29285376 TI - Neoadjuvant treatment with cisplatin and S-1 in elderly patients with oesophagogastric adenocarcinoma and locoregional disease: Two case reports and review of the literature. AB - Perioperative platinum/fluoropyrimidine-based chemotherapy is the therapeutic standard for oesophagogastric cancer (OAC) patients with locoregional disease. The preoperative condition directly affects postoperative prognosis; thus, particularly for elderly patients, a perioperative regimen with a favourable side effect profile is highly desirable. In the palliative setting, the combination of cisplatin and S-1 (Cis/S-1) was found to be as effective as cisplatin/5 fluorouracil, but with a more favourable side effect profile. However, no data on this combination have been reported in the perioperative setting in Caucasian patients. To the best of our knowledge, this is the first report on the treatment outcome of two elderly Caucasian OAC patients with locoregional disease receiving two neoadjuvant 4-week cycles of intravenous Cis/S-1. Both patients tolerated the doublet therapy well. No treatment delay or dose reduction was required. In both cases, preoperative staging revealed a clear response and complete surgical resection could be performed without any complications. PMID- 29285377 TI - Elevated neutrophil-to-lymphocyte ratio is associated with nutritional impairment, immune suppression, resistance to S-1 plus cisplatin, and poor prognosis in patients with stage IV gastric cancer. AB - Gastric cancer continues to be a major cause of morbidity and mortality worldwide. Recently, there has been a growing interest in the host inflammatory response and there is increasing evidence that the neutrophil to lymphocyte ratio (NLR), which is a useful marker of systemic inflammation, can be an effective prognostic indicator in various types of malignant diseases. A total of 110 patients with stage IV gastric cancer who received chemotherapy of S-1 plus cisplatin were enrolled in this study. Eleven patients did not complete four cycles of the chemotherapy. The patients were divided into two groups with 3.0 of NLR. The percentage of patients with a partial response to chemotherapy was significantly higher in the group of patients with a lower NLR (<3) (19.1 vs. 38.5%, high vs. low NLR group, respectively; P<0.05). The percentage of patients with progressive disease was higher in the high vs. low NLR group (57.4 vs. 25.0%, respectively; P<0.05). NLR levels were significantly inversely correlated with serum levels of prealbumin (P<0.01) and retinol binding protein (P<0.05). NLR levels were also significantly correlated with c-reactive protein levels (P<0.05), white blood cell count (P<0.05) and inversely with the stimulation index (a marker of cell-mediated immune function; P<0.05). Overall survival was significantly longer in patients with a lower NLR (<= 3.0) than in those with a higher NLR (>3.0). The present study demonstrated that the NLR is a useful marker for resistance to chemotherapy, malnutrition, systemic inflammation and immune suppression. Moreover, the NLR was demonstrated to be a strong prognostic indicator in these patients. PMID- 29285378 TI - Phase II study of neoadjuvant anthracycline combined with nanoparticle albumin bound paclitaxel for human epidermal growth factor receptor 2-negative breast cancer. AB - Neoadjuvant chemotherapy (NAC) with anthracyclines followed by taxane chemotherapy has become the standard treatment for patients with locally advanced, operable breast cancer. Recently, the efficacy of nanoparticle albumin bound paclitaxel (nab-PTX) for metastatic breast cancer was reported. However, there are still few studies of a neoadjuvant regimen including nab-PTX. Thus, the present phase II study evaluated the efficacy and safety of 5-fluorouracil, epirubicin and cyclophosphamide (FEC regimen) followed by nab-PTX as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Women with operable HER2-negative breast cancer (clinical stage T1a-4N1-3) received 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days), followed by 4 cycles of nab PTX at 260 mg/m2 every 21 days. The patients then underwent mastectomy or breast conserving surgery (BCS). The primary endpoint was pathological complete response (pCR) rate. The secondary endpoints included clinical response rate, pathological response rate, BCS rate and safety. A total of 16 patients were evaluated and 3 patients (18%) achieved pCR (1 patient with estrogen receptor-positive cancer and 2 with estrogen receptor-negative cancer). The pCR rate was 12 and 25% in patients with estrogen receptor-positive and -negative cancers, respectively. The clinical response rate was 100% (clinical complete and partial response in 6 and 10 patients, respectively). The BCS rate was 31.25%. Three patients experienced grade 3 neutropenia during FEC therapy, and no grade 3/4 events occurred during nab-PTX therapy. Thus, neoadjuvant therapy with FEC followed by nab-PTX for operable HER2-negative breast cancer was found to be a safe and effective option. PMID- 29285379 TI - Patient age and cutaneous malignant melanoma: Elderly patients are likely to have more aggressive histological features and poorer survival. AB - Patient age has been reported as a highly significant and strong predictor of the outcome in patients with cutaneous melanoma. The aim of the present study was to determine the clinical significance of patient age in Turkish patients with cutaneous melanoma. A total of 1,169 patients with pathologically proven cutaneous melanoma were enrolled. Age of patients was classified as young (<40 years), middle-aged (40-59 years) and old (>=60 years). The median age of the patients was 51 years (range, 16-104 years). Non-superficial spreading histology was significantly more observed in old patients than in the other age groups (P<0.001). A lower Clark invasion level was significantly more observed in young patients compared with the other age groups (P=0.013) and higher levels were significantly more observed in older patients compared with the other age groups (P=0.002). Furthermore, the rate of thin Breslow depth was significantly higher in young patients compared with others (P=0.038). Although a lower mitotic rate was observed predominantly in young patients compared with others (P=0.007), ulceration was significantly more present in older patients (P<0.001) and absent in the young patients (P=0.003). Patient age was not significantly associated with relapse-free survival (P=0.327), whereas a significant correlation was demonstrated for overall survival (OS) (P=0.007). The old patients had poorer survival compared with the other ages (P=0.009 for young patients and P=0.012 for middle-aged patients). However, patient age did not remain significant for OS in multivariate analysis (P=0.768). In conclusion, although patient age does not have a significant predictive role on nodal involvement, recurrence and metastasis, an age of >=60 years may be associated with more aggressive histological features and poorer outcome in patients with cutaneous melanoma. PMID- 29285380 TI - Assessment of the use of latissimus dorsi restoration during modified radical mastectomy in breast cancer patients. AB - The incision area of modified radical mastectomy in breast cancer patients is associated with subcutaneous effusion and skin flap necrosis as the most common complications. The aim of the present study was to assess the effect of latissimus dorsi restoration during modified radical mastectomy in breast cancer patients by evaluating 365 cases. Among these cases, 185 received modified radical mastectomy combined with intraoperative latissimus dorsi restoration, while 180 received modified radical mastectomy alone. The flap tension, drainage fluid amount and extubation time were compared between the two methods. The flap tension in patients who received modified radical mastectomy combined with intraoperative latissimus dorsi restoration was significantly lower and the blood supply was better. After surgery, the drainage fluid amount was also significantly lower in these patients compared with the control group. Furthermore, the mean time to drainage tube removal was significantly shorter in these patients and the postoperative cosmetic outcome was superior. Thus, it was concluded that modified radical mastectomy combined with intraoperative latissimus dorsi restoration in breast cancer patients was associated with reduced drainage fluid effusion, shorter hospitalization time and decreased flap tension. Overall, this method appears to be potentially suitable for extensive application in the clinical setting. PMID- 29285381 TI - Effect of biology on the outcome of female melanoma patients. AB - The aim of the present study was to investigate plausible explanations for the favorable outcome of female melanoma patients and determine the effect of biology on this outcome. Data from 1,169 cutaneous melanoma patients were retrospectively analyzed. Cox proportional hazards models were used and the confounding factors on the survival difference were analyzed by a forward step multivariate modification method. The majority of the factors contributing to poor prognosis were significantly more pronounced in male melanoma patients. After the survival advantage of female patients (P=0.0001 on univariate analysis) was confounded (P=0.708 on multivariate analysis) following adjustment for the prognostic factors, two factors (neurotropism and vertical growth phase) were identified as the confounders, and this effect was attributed to the small number of patients in the groups of these two variables. The already known female advantage in melanoma survival was not affected by other prognostic factors, and female sex remained an independent predictor of good survival in melanoma. This sex-related independent survival advantage was attributed to a biological characteristic that has not yet been fully elucidated, but may be more closely associated with host related rather than melanoma-related factors. PMID- 29285382 TI - IL18 rs360719 A>G, IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G polymorphisms and risk of gastric cardiac adenocarcinoma. AB - The present study was conducted to investigate the association between gastric cardiac adenocarcinoma (GCA) and four functional single-nucleotide polymorphisms (SNPs), including interleukin 18 (IL18) rs360719 A>G, IL18 receptor 1 (IL18R1) rs13015714 G>T, IL18 receptor accessory protein (IL18RAP) rs917997 C>T and interleukin 28B (IL28B) rs8099917 T>G variants. A hospital-based case-control study was performed to evaluate the genetic effects of these SNPs. A total of 243 GCA cases and 476 controls were enrolled in this study. A custom-by-design 48 Plex SNPscanTM kit was used to determine the genotypes. When the IL18 rs360719 AA homozygote genotype was used as the reference group, the AG genotype was not associated with the risk for GCA; the GG genotype was also not associated with the risk for GCA. In the dominant model, the IL18 rs360719 AG/GG variants were not associated with the risk for GCA, compared with the IL18 rs360719 AA genotype. In the recessive model, when the IL18R1 rs13015714 AA/AG genotypes were used as the reference group, the GG homozygote genotype was not associated with risk for GCA. No association was observed between IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G polymorphisms and the risk for GCA. These results demonstrated that the functional polymorphisms IL18 rs360719 A>G, IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G do not contribute to GCA susceptibility. However, as the statistical power of our study was limited, large well-designed studies and further functional investigations are required to confirm our findings. PMID- 29285383 TI - Effect of O6-methylguanine-DNA methyltransferase methylation in medulloblastoma. AB - Medulloblastoma is a highly malignant brain tumor that predominately affects children and requires multimodal treatment, including chemotherapy with alkylating agents. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that plays an important role in tumor resistance to alkylating agents. Recent studies demonstrated that MGMT promoter methylation suppresses the expression of MGMT and is associated with favorable outcomes of malignant glioma patients. However, the MGMT methylation status and its prognostic impact on medulloblastoma have not been fully elucidated to date. The objective of the present study was to investigate the association between MGMT status and clinical outcomes of pediatric medulloblastoma patients. The records of 15 patients with medulloblastoma treated at our institution were reviewed, and the methylation status of 18 CpG sites in the MGMT promoter region was determined using bisulfite sequencing analysis. A larger number of methylated CpG sites was identified in 9 patients with complete remission (median, 5 sites; range, 2-9 sites) compared with that in 6 patients with relapse (median, 2 sites, range, 1-4 sites; P=0.041). These results suggest that a higher number of methylated CpG sites in the MGMT promoter region are associated with a favorable outcome of medulloblastoma. PMID- 29285384 TI - The combination of paclitaxel and carboplatin as second-line chemotherapy can be a preferred regimen for patients with urothelial carcinoma after the failure of gemcitabine and cisplatin chemotherapy. AB - There is no established standard second-line chemotherapy after the failure of the first-line cisplatin-based chemotherapy for patients with advanced or metastatic urothelial carcinoma. With regards to second-line chemotherapy, methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) was used from July 2009 onwards, and paclitaxel and carboplatin (TC) was introduced in April 2014 at the National Kyushu Cancer Center. The present study aimed to assess the prognostic factors for overall survival (OS) in second-line treatment that included best supportive care (BSC), and the tolerability and efficacy of TC chemotherapy. In total, 52 patients who were confirmed to have disease progression with first-line gemcitabine and cisplatin (GC) between June 2009 and November 2016 were enrolled in the current study. In addition, 28 patients selected BSC as second-line treatment, while 24 patients received second-line chemotherapy (MVAC, n=8; TC, n=16). The median OS for BSC, MVAC and TC was 2.8, 5.4, and 12.7 months, respectively. The difference between BSC and MVAC was not statistically significant (P=0.596). However, the difference between BSC and TC was statistically significant after Bonferroni correction (P=0.002). Multivariate analyses revealed that anemia [hazard ratio (HR), 7.047; 95% confidence interval (CI), 1.553-35.636; P=0.011], the presence of visceral metastasis (HR, 4.174; 95% CI, 1.506-13.429; P=0.005) and second-line treatment (TC HR, 0.296; 95% CI, 0.124 0.636; P=0.003) were independent prognostic factors. TC achieved an 18.7% overall response rate and a 56.2% disease control rate. Myelosuppression was the most common grade >=3 toxicity, but no treatment-associated mortalities occurred during the study period. TC was associated with favorable benefits and safety, and may be considered a preferred regimen after the failure of GC. PMID- 29285385 TI - MHC class II associated stomach cancer mutations correlate with lack of subsequent tumor development. AB - The role of tumor cell expression of major histocompatibility class II (MHCII) has been controversial, with evidence indicating that tumor cell expression of MHCII may lead to an anti-tumor immune response and to tumor cell apoptosis and that MHCII has pro-tumorigenic functions. The cancer genome atlas (TCGA) indicates numerous deleterious mutations for the highly specific, MHCII transcriptional activation proteins, RFX5, RFXAP, RFXANK and CIITA. Also, mutations in the non-polymorphic, human leukocyte antigen (HLA)-DRA gene, which encodes the heavy chain for the most prominent human MHCII molecule, HLA-DR, are common. For many, if not most TCGA cancer datasets, the MHCII specific mutations do not associate with clinical outcomes. However, stomach carcinoma represents an exception, where the data indicate that MHCII-specific mutations are associated with a more favorable outcome. These data raise the question of whether stomach cancer mutations represent effective haploinsufficiency or whether mutations that are associated with a favorable outcome occur with other stomach cancer molecular features that limit the function of the two alleles that represent these MHCII related proteins. PMID- 29285386 TI - Scalp recurrence of cholangiocarcinoma after curative hepatectomy: A report of two cases. AB - Cholangiocarcinomas are the second most common primary liver malignancies. The lymphatics are the common route of metastatic spread for cholangiocarcinomas. The most frequent sites of metastasis are the liver, abdominal lymph nodes, peritoneum and lungs. Cutaneous metastasis of cholangiocarcinoma is rare, and most commonly occurs following percutaneous biliary drainage. Brain or skull metastases from this tumor are uncommon. However, these rare metastatic lesions may occasionally be the first disease manifestation, although scalp recurrence following curative treatment is uncommon. We herein present the cases of two patients with cholangiocarcinoma, who were evaluated as resectable based on the criteria for cholangiocarcinoma resectability, and developed scalp recurrence following curative hepatectomy. Therefore, although scalp recurrence is a rare occurrence following curative treatment for cholangiocarcinoma, metastases should be included in the differential diagnosis. PMID- 29285387 TI - Breast cancer cases of female patients under 35 years of age in Togo: A series of 158 cases. AB - Breast cancer in young female patients represents a public health problem in developing countries. The objectives of the study were to study the epidemiological and histological characteristics of breast cancer in female patients under 35 years of age. This was a retrospective analytical study of a series of 158 cases of breast cancer in female patients under 35 years of age, conducted at the University Teaching Hospital of Lome between 2000 and 2015. A total of 158 cases were collected, representing 36.2% (436) of all breast cancer cases. The average age of the patients was 30.9 years (range, 16-35 years). A family history of breast cancer at the 1st or 2nd degree was identified in 13.9% of cases. Genetic mutation studies were carried out for 7 patients, 5 of which revealed mutations (4 BRCA1 and 1 BRCA2). According to the locus, the cancer was located preferentially in the left breast in 88 cases (55.7%). Malignant mammary lesions were epithelial tumors (n=144 cases, 91.1%), infiltrating (n=125 cases, 79.1%) and non-infiltrating (n=19 cases, 12.0%). The other histological groups consisted of 8 cases of sarcomas (5 cases of angiosarcoma, 2 cases of fibrosarcoma and 1 case of Kaposi's sarcoma), 5 cases of lymphomas and one case of melanoma. Not otherwise specified infiltrating ductal carcinomas were SBR II and III in 43.2 and 35.2% of cases, respectively. The tumors classified as T4 were the most frequent (30.4%). Regarding the lymph node status, lymph node metastasis was noted in 22.8% of cases. Studies of hormone receptors were carried out in 23 patients and were positive for 11 patients: Estrogen receptor (ER)+plus progesterone receptor (PR)+(7 patients), ER+PR-(4 patients). Of the aforementioned 8 cases of sarcoma, 5 were angiosarcoma. The lymphomas were predominantly Burkitt's type for 4 cases. Mammary ultrasonography was performed in 45.6% of the patients and 54.4% underwent the combined ultrasonography and mammography. Ultrasound identified one or more sign of malignancy in 67 patients (42.4%), and combined ultrasonography and mammography classified 51.9% of lesions in BIRADS 4 and 5. The incidence of breast cancer in young Togolese patients is high. It is a disease distinguished by a delay in diagnosis, which contributes to the high number of cases that initially diagnosed at an advanced stage, particularly the high histo-prognosis grades of infiltrating ductal carcinoma. These results indicate a genetic origin; therefore, a thorough investigation into genetic mutations should be carried. In addition, further collaborative studies are required to verify these results. PMID- 29285388 TI - Metronomic cyclophosphamide-induced long-term remission after recurrent high grade serous ovarian cancer: A case study. AB - Metronomic oral cyclophosphamide has gained increasing interest in recent years as a promising maintenance therapy in advanced, platinum-sensitive, high-grade serous ovarian cancer (HGSOC). Metronomic treatment with cyclophosphamide refers to the frequent, usually daily, administration of a low (oral) dose of cyclophosphamide with no prolonged drug-free breaks. Main advantages of this treatment are the effective reduction of tumour activity, oral administration in an outpatient setting, low cost and the low toxicity profile. Metronomic oral cyclophosphamide can benefit patients suffering from types of cancer known to be sensitive to alkylating agents, such as platinum-sensitive HGSOC. In recent years, several publications have underlined the advantage of this regimen and possible explanations were explored. We here present a patient with multiple recurrences of metastasized HGSOC, platinum-sensitive, with an on-going complete response to monotherapy with oral cyclophosphamide. This observation supports that patients with relapsing HGSOC who responded to platinum-based chemotherapy and cannot continue platinum-based chemotherapy because of toxicity, can be offered a course of metronomic cyclophosphamide. This case may serve as a reminder that old drugs can be used successfully even in the age of new upcoming therapy such as anti-angiogenic agents (VEGF inhibitors) and poly-ADP-ribose polymerase (PARP) inhibitors. PMID- 29285389 TI - Early sorafenib induction after transarterial chemoembolization for unresectable hepatocellular carcinoma: Can sorafenib after TACE improve loco-regional control? AB - This prospective study aimed to estimate the efficacy of sorafenib therapy after transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC). Between July 2011 and March 2013, 17 patients were enrolled, 11 of whom received sorafenib therapy. Patients who previously received TACE for HCC and whose disease progressed within a six-month period were given 400-800 mg sorafenib orally, once or twice daily, within the 3 weeks after a second TACE (sorafenib after TACE group). The response to treatment, time to progression (TTP), overall survival (OS), and adverse events (AEs) were recorded. Of the 113 patients who underwent initial TACE for unresectable HCC between January 1995 and January 2013, 23 patients were selected who were treated with TACE alone, and for whom the interval between the second and third TACE treatments was <6 months (TACE alone group). The interval (TTP) was calculated between the third and fourth TACE treatments, then TTP was compared among the three groups: Sorafenib after TACE for > or <4 months; and TACE alone. During a median follow-up period of 34.4 months (range, 5.9-51.7 months) in both groups receiving sorafenib after TACE, sorafenib prolonged TTP (3.9 months) and OS (34.4 months). It was demonstrated that sorafenib use for >4 months prolonged TTP (5.7 months) significantly compared with use for <4 months (3.0 months) (P=0.002). The OS of patients given sorafenib for >4 months (35.9 months) was longer than that of patients who received the drug for <4 months (17.2 months), but this difference was not significant. In the TACE alone group, the median TTP between the third and fourth TACE treatments was 4.3 months. TTP decreased among the groups in the following order: Sorafenib for >4 months, TACE alone, and sorafenib for <4 months. There were three AEs of grade 3 in the present study. Two patients demonstrated a decrease in liver reserve function following sorafenib treatment, but improved immediately after sorafenib administration was stopped. Sorafenib induction early after TACE for unresectable HCC was generally well tolerated and significantly improved TTP. Further studies are required to confirm the safety and efficacy of this combination therapy. PMID- 29285390 TI - Elevated erythrocyte sedimentation rate is associated with metastatic disease and worse survival in patients with cutaneous malignant melanoma. AB - Elevated erythrocyte sedimentation rate (ESR) is common in cancer patients and it may affect survival. However, its clinical role and prognostic significance remain unknown in melanoma patients. The objective of the present study was to determine the clinical significance of the ESR levels in cutaneous melanoma patients. A total of 139 cutaneous melanoma patients were enrolled in this study and were retrospectively investigated. The median age of the patients was 52 years (range, 16-88 years). The median ESR was 22 mm/h (range, 2-122 mm/h). Significant differences in ESR were found to be associated with sex, histology, blood hemoglobin level, lactate dehydrogenase (LDH) and metastatic disease. Female patients (P=0.006) and those with nodular histology (P=0.005), low hemoglobin concentration (P<0.001), higher LDH levels (P=0.003) and metastatic disease (P<0.001) were more likely to have elevated ESR levels. However, ESR was not found to be significantly associated with age, site of lesion, or pathological indicators, including Clark's level of invasion, Breslow's depth, mitotic rate, ulceration, vertical growth phase, tumor-infiltrating lymphocytes, regression, neurotropism, lymphovascular invasion and BRAF (V600E) mutation (P>0.05). ESR was also not associated with lymph node involvement (P=0.188) or responsiveness to chemotherapy (P=0.390). However, ESR was found to be significantly associated with outcome; patients with increased ESR had worse survival compared with those with normal values (hazard ratio=2.033; 95% confidence interval: 1.156-3.577; P=0.012). In conclusion, elevated ESR was found to be associated with metastatic disease and was also found to be a prognostic factor adversely affecting survival in patients with cutaneous melanoma. PMID- 29285391 TI - F18-fluorodeoxyglucose positron emission tomography/computed tomography for bone hemangiopericytoma. AB - Bone hemangiopericytoma (HPC) is extremely rare, and its clinical manifestations and radiographic features are nonspecific. There are few case reports about application of F18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in HPC. A total of four subjects with pathologically diagnosed bone HPC had FDG PET/CT for staging and/or restaging bone HPC. Medical records were retrospectively reviewed for radiological, pathological and follow up information. All primary bone and metastatic lesions demonstrated high FDG avidity on PET/CT, which also revealed the adjacent soft tissue involvement and synchronous lesion. PET/CT correctly detected metastatic lesions in 1 patient. Furthermore, 3/4 patients with available laboratory data had hypocalcemia, but normal phosphorus levels when HPC existed as primary lesions or metastatic disease; however, normalization of calcium levels when they were disease-free. The results suggested that FDG PET/CT could be effectively used for staging, surveillance and detection of recurrent/metastatic disease in HPC. There may be an association between bone HPC and hypocalcemia. PMID- 29285392 TI - Association between genetic polymorphisms of long non-coding RNA PRNCR1 and prostate cancer risk in a sample of the Iranian population. AB - The aim of the present study was to determine whether there is an association between the long non-coding RNA (lncRNA) prostate cancer-associated non-coding RNA 1 (PRNCR1) polymorphisms and prostate cancer (PCa) risk in a sample of the Iranian population. This case-control study was performed on 178 patients with PCa and 180 subjects with benign prostatic hyperplasia (BPH). Genotyping assay was performed by polymerase chain reaction-restriction fragment length polymorphism. The findings indicated that the GG genotype of the rs13252298 A>G variant significantly increased the risk of PCa (odds ratio=3.49, 95% confidence interval: 1.79-6.81, P=0.0001) compared with AA+AG. As regards the rs1456315 G>A polymorphism, the AG genotype and G allele significantly increased the risk of PCa. As regards the rs7841060 T>G variant, the findings demonstrated that this TG genotype and the G allele significantly increased the risk of PCa. The rs7007694 T>C variant was not found to be associated with the risk of PCa. Haplotype analysis indicated that GTGA and GTGG significantly increased the risk of PCa compared with rs1456315A/rs7007694T/rs7841060T/rs13252298G (ATTG). The PRNCR1 variants were not found to be significantly associated with the clinicopathological characteristics of PCa patients. In conclusion, our findings support an association between PRNCR1 variants and the risk of PCa in a sample of the Iranian population. PMID- 29285393 TI - Chronic myeloid leukemia following liver transplantation: A case report. AB - Long-term utilization of immunosuppression in organ transplant recipients leads to decreased immune-mediated tumor surveillance and increased risk of developing malignant tumors. However, chronic myeloid leukemia (CML) following living donor liver transplantation (LDLT) is rarely reported. The current case report presents a 42-year-old male patient who developed CML 14 months following LDLT. The patient achieved complete hematologic remission and early molecular response at 3 months imatinib treatment and major molecular response at 12 months imatinib treatment. The pathogenesis, risk factors, treatment and prognosis for CML following liver transplantation are unclear. Therefore, further analysis through accumulation of cases will be of great importance to prevent and treat this rare complication following liver transplantation. PMID- 29285395 TI - Paradoxical response to osimertinib therapy in a patient with T790M-mutated lung adenocarcinoma. AB - A 'paradoxical response' to cancer treatment is a term used to describe the emergence of unexpected new lesions and the progression of existing lesions, despite appropriate and effective therapy. 'Pseudo-progression' is a phenomenon in which lymphocytes activated by an immune checkpoint inhibitor accumulate in a tumor and expand its shadow, mimicking enlargement of the primary lesion or development of a new metastatic lesion. Patients receiving cancer chemotherapy may respond differently to treatment, by exhibiting a response, deterioration, or the simultaneous occurrence of both. These variations may be attributed to the heterogeneity of the cancer. However, differences in the temporary response to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment are rarely observed. If such a phenomenon is observed, it should not affect the evaluation of the therapeutic effect or be considered as an indication for the discontinuation of treatment. We herein report a rare case of a transient increase in carcinomatous pleural fluid as a paradoxical response to osimertinib treatment in a patient with T790M-mutated lung adenocarcinoma. The primary lesion and pulmonary metastases responded well to therapy. Although this paradoxical response is very rare, of non-malignant nature, and does not usually require treatment modification of, physicians must acknowledge that it is not a clinically discouraging characteristic when using EGFR-TKI to treat T790M-mutated lung adenocarcinoma. PMID- 29285396 TI - Multi-environment Nanocalorimeter with Electrical Contacts for Use in the Scanning Electron Microscope. AB - We have developed a versatile nanocalorimeter sensor which allows imaging and electrical measurements of samples under different gaseous environments using the scanning electron microscope (SEM) and can simultaneously measure the sample temperature and associated heat of reaction. This new sensor consists of four independent heating/sensing elements for nanocalorimetry and eight electrodes for electrical measurements, all mounted on a 50 nm thick, 250 MUm * 250 MUm suspended silicon nitride membrane. This membrane is highly electron transparent and mechanically robust enabling in situ SEM observation under realistic temperatures, environmental conditions and pressures up to one atmosphere. To demonstrate this new capability, we report here on 1) in situ SEM-nanocalorimetry study of melting and solidification of polyethylene oxide, 2) the temperature dependence of conductivity of a nanowire; 3) the electron beam induced current measurements (EBID) of a nanowire in vacuum and air. Furthermore, the sensor is easily adaptable to operate in liquid environment and is compatible with most existing SEM. This versatile platform couples nanocalorimetry with in situ SEM imaging under various gaseous and liquid environments and is applicable to materials research, nanotechnology, energy, catalysis and biomedical applications. PMID- 29285394 TI - C-C motif chemokine receptors in gastric cancer. AB - Gastric cancer is the fifth most common cancer and the third leading cause of cancer-associated mortality worldwide. Despite recent advances in molecular and clinical research, patients with gastric cancer at an advanced stage have a dismal prognosis and poor survival rates, and systemic treatment relies predominantly on traditional cytotoxic chemotherapy. To improve patients' quality of life and survival, an improved understanding of the complex molecular mechanisms involved in gastric cancer progression and treatment resistance, and of its clinical application in the development of novel targeted therapies, is urgently required. Chemokines are a group of small chemotactic cytokines that interact with seven-transmembrane G-protein-coupled receptors, and this interaction serves a crucial role in various physiological processes, including organ development and the host immune response, to recruit cells to specific sites in the body. There is also accumulating evidence that chemokines and chemokine receptors (CCRs) contribute to tumor development and progression, as well as metastasis. However, research regarding the functional roles of chemokines and their receptors in cancer is dynamic and context-dependent, and much remains to be elucidated, although various aspects have been explored extensively. In gastric cancer, C-C motif CCRs are involved in the biological behavior of tumor cells, including the processes of growth, invasion and survival, as well as the epithelial-mesenchymal transition. In the present review, attention is given to the clinical relevance of C-C motif CCRs in the development, progression, and metastasis of gastric cancer, particularly CCR7 and CCR5, which have been investigated extensively, as well as their potential therapeutic implications. PMID- 29285397 TI - Divergent evolutionary patterns of the MAPK cascade genes in Brassica rapa and plant phylogenetics. AB - Mitogen-activated protein kinase (MAPK) cascade signal transduction modules play crucial roles in regulating many biological processes in plants. These cascades are composed of three classes of hierarchically organized protein kinases, MAPKKKs, MAPKKs and MAPKs. Here, we analyzed gene retention, phylogenetic, evolution and expression patterns of MAPK cascade genes in Brassica rapa. We further found that the MAPK branches, classes III and IV, appeared after the split of bryophytes and green algae after analyzing the MAPK cascade genes in 8 species, and their rapid expansion led to the great size of the families of MAPKs. In contrast, the ancestral class I subfamily of MAPKK gene families have been highly conserved from algae to angiosperms. For the MAPKKK family, the MEKK and Raf subfamily share a common evolutionary origin, and Raf plays a major role in the expansion of the MAPKKK gene family. The cis-elements and interaction network analyses showed the important function of MAPK cascade genes in development and stress responses in B. rapa. This study provides a solid foundation for molecular evolution analyses of MAPK cascade genes. PMID- 29285398 TI - Combination of iTRAQ proteomics and RNA-seq transcriptomics reveals multiple levels of regulation in phytoplasma-infected Ziziphus jujuba Mill. AB - Jujube witches' broom (JWB) is caused by infection with a phytoplasma. A multi omics approach was taken during graft infection of jujube by JWB-infected scion through the analysis of the plant transcriptome, proteome and phytohormone levels. A high number of differentially expressed genes (DEGs) were identified 37 weeks after grafting (WAG), followed by observation of typical symptoms of JWB at 48 WAG. At 37 WAG, the majority of the upregulated DEGs and differentially expressed proteins (DEPs) were related to flavonoid biosynthesis, phenylalanine metabolism and phenylpropanoid biosynthesis. Two of the four upregulated proteins were similar to jasmonate-induced protein-like. Among the downregulated genes, the two most populated GO terms were plant-pathogen interaction and plant hormone signal transduction (mainly for tryptophan metabolism). Moreover, phytoplasma infection resulted in reduced auxin content and increased jasmonate content, indicating that auxin and jasmonic acid have important roles in regulating jujube responses during the first and second stages of phytoplasma infection. At 48 WAG, the two largest groups of upregulated genes were involved in phenylpropanoid biosynthesis and flavonoid biosynthesis. Both genes and proteins involved in carbon metabolism and carbon fixation in photosynthetic organisms were downregulated, indicating that photosynthesis was affected by the third stage of phytoplasma infection. PMID- 29285400 TI - Structural insight into the Ragulator complex which anchors mTORC1 to the lysosomal membrane. AB - The mechanistic target of rapamycin (mTOR) signal-transduction pathway plays a key role in regulating many aspects of metabolic processes. The central player of the mTOR signaling pathway, mTOR complex 1 (mTORC1), is recruited by the pentameric Ragulator complex and the heterodimeric Rag GTPase complex to the lysosomal membrane and thereafter activated. Here, we determined the crystal structure of the human Ragulator complex, which shows that Lamtor1 possesses a belt-like shape and wraps the other four subunits around. Extensive hydrophobic interactions occur between Lamtor1 and the Lamtor2-Lamtor3, Lamtor4-Lamtor5 roadblock domain protein pairs, while there is no substantial contact between Lamtor2-Lamtor3 and Lamtor4-Lamtor5 subcomplexes. Interestingly, an alpha-helix from Lamtor1 occupies each of the positions on Lamtor4 and Lamtor5 equivalent to the alpha3-helices of Lamtor2 and Lamtor3, thus stabilizing Lamtor4 and Lamtor5. Structural comparison between Ragulator and the yeast Ego1-Ego2-Ego3 ternary complex (Ego-TC) reveals that Ego-TC only corresponds to half of the Ragulator complex. Coupling with the fact that in the Ego-TC structure, Ego2 and Ego3 are lone roadblock domain proteins without another roadblock domain protein pairing with them, we suggest that additional components of the yeast Ego complex might exist. PMID- 29285399 TI - Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging. AB - The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research. In particular, it will be important to better understand how environmental factors, such as diet, physical activity, co morbidities, and pharmacological treatments, delay or contribute to the decline of the capability of the aging immune system to appropriately respond to infectious diseases and vaccination. Recent findings suggest that successful approaches specifically targeted to the older population can be developed, such as the high-dose and adjuvanted vaccines against seasonal influenza, the adjuvanted subunit vaccine against herpes zoster, as well as experimental interventions with immune-potentiators or immunostimulants. Learning from these first successes may pave the way to developing novel and improved vaccines for the older adults and immunocompromised. With an integrated, holistic vaccination strategy, society will offer the opportunity for an improved quality of life to the segment of the population that is going to increase most significantly in numbers and proportion over future decades. PMID- 29285401 TI - Multifunctional stimuli responsive polymer-gated iron and gold-embedded silica nano golf balls: Nanoshuttles for targeted on-demand theranostics. AB - Multi-functional nanoshuttles for remotely targeted and on-demand delivery of therapeutic molecules and imaging to defined tissues and organs hold great potentials in personalized medicine, including precise early diagnosis, efficient prevention and therapy without toxicity. Yet, in spite of 25 years of research, there are still no such shuttles available. To this end, we have designed magnetic and gold nanoparticles (NP)-embedded silica nanoshuttles (MGNSs) with nanopores on their surface. Fluorescently labeled Doxorubicin (DOX), a cancer drug, was loaded in the MGNSs as a payload. DOX loaded MGNSs were encapsulated in heat and pH sensitive polymer P(NIPAM-co-MAA) to enable controlled release of the payload. Magnetically-guided transport of MGNSs was examined in: (a) a glass capillary tube to simulate their delivery via blood vessels; and (b) porous hydrogels to simulate their transport in composite human tissues, including bone, cartilage, tendon, muscles and blood-brain barrier (BBB). The viscoelastic properties of hydrogels were examined by atomic force microscopy (AFM). Cellular uptake of DOX-loaded MGNSs and the subsequent pH and temperature-mediated release were demonstrated in differentiated human neurons derived from induced pluripotent stem cells (iPSCs) as well as epithelial HeLa cells. The presence of embedded iron and gold NPs in silica shells and polymer-coating are supported by SEM and TEM. Fluorescence spectroscopy and microscopy documented DOX loading in the MGNSs. Time-dependent transport of MGNSs guided by an external magnetic field was observed in both glass capillary tubes and in the porous hydrogel. AFM results affirmed that the stiffness of the hydrogels model the rigidity range from soft tissues to bone. pH and temperature-dependent drug release analysis showed stimuli responsive and gradual drug release. Cells' viability MTT assays showed that MGNSs are non-toxic. The cell death from on-demand DOX release was observed in both neurons and epithelial cells even though the drug release efficiency was higher in neurons. Therefore, development of smart nanoshuttles have significant translational potential for controlled delivery of theranostics' payloads and precisely guided transport in specified tissues and organs (for example, bone, cartilage, tendon, bone marrow, heart, lung, liver, kidney, and brain) for highly efficient personalized medicine applications. PMID- 29285403 TI - Sacroiliac stabilization for sacral metastasis: A case series. AB - Background: The sacrum is a rare location for spinal metastasis. These lesions are typically large and destructive by the time of diagnosis, making treatment difficult. When indicated, surgical stabilization offers pain relief and preserves independence in patients with impending and acute pathological sacral fractures. Case Description: Three consecutive patients presented with sacral metastases. After either failing radiation therapy or presenting with acute fracture and instability, the patients underwent intralesional excision, bilateral L4 to ilium fusion with instrumentation, and sacroiliac (SI) screw fixation. Pain improved after surgery, and there were no wound healing complications. Two patients could continue walking without any assistive device, while one patient required a walker. Conclusion: Stabilization with combined modified Galveston fixation and SI screw fixation relieves pain and allows maintenance of independence in patients with sacral metastasis. PMID- 29285404 TI - Cervicothoracic syringomyelia caused by cervical spinal stenosis: Case report and literature review. AB - Background: Syringomyelia is commonly associated with Chiari malformations, spinal trauma, arachnoiditis, or tumors. However, rarely, cervical canal stenosis is implicated in intramedullary cavitations. Case Discription: Here, we report the case of a 60-year-old male patient who presented with loss of pain and temperature sensation in upper extremities associated with a spastic tetraparesis. On magnetic resonance imaging, the patient was found to have syringomyelia extending from C1 to Th3. Following posterior decompressive surgery, the syrinx resolved along with the patient's neurological complaints. Conclusion: Here, the authors presented a case and reviewed the literature regarding how cervical spinal stenosis may contribute to cervical or thoracic syringomyelia. PMID- 29285405 TI - Prepontine arachnoid cyst presenting with headache and diplopia: A case report study. AB - Background: Arachnoid cysts are found everywhere in cerebrospinal axis, most often in the middle cranial fossa. They are very rare in prepontine location. Case Description: In this study, we report a 26-year-old female presenting with a 3-month history of headache and diplopia. On physical examination, she had clinical manifestations of sixth cranial nerve palsy. Magnetic resonance imaging revealed a prepontine arachnoid cyst with extension into interpeduncular and suprasellar cisterns. Computed tomography scan demonstrated no evidence of hydrocephalus. The patient was treated surgically by endoscopic fenestration of the cyst with endonasal transsphenoidal approach. The cyst was opened to prepontine, interpeduncular, and suprasellar cisterns. Conclusion: Endoscopic endonasal fenestration of the cyst to adjacent cistern may be safe in prepontine arachnoid cysts with sellar and suprasellar extension; it may be effective and less invasive compare to transcranial approach. PMID- 29285406 TI - Virtual autopsy to assess sacral anatomy: Conditions for a minimal invasive approach to the spinal canal through the hiatus sacralis. AB - Background: Despite multiple advantages of minimally invasive techniques in spinal surgery, the currently used approaches may lead to postoperative pain and spinal instability. As a natural orifice, the hiatus sacralis offers a nontransmuscular alternative entry point for endoscopic approaches. In this study, we collected data about the complex anatomical conditions of the sacral canal as a basis for the development of a sacral endoscope. Methods: We retrospectively evaluated 192 postmortem human cadaveric specimens with computed tomography (CT). The anatomical conditions of the sacrum and lumbar spine were analyzed, including assessment of the lateral and anteroposterior diameters, measurement of the cross-sectional area of the sacral canal at the lumbosacral transition, hiatus sacralis, and the narrowest point of the sacral canal. Results: The narrowest anteroposterior diameter was >2.3 mm in 95% of the cases; the width was >13 mm in 95% of the cases. The narrowest point was located at the hiatus in 72% of the cases. The angle of sacral kyphosis was less than 30 degrees and less than 50 degrees in lumbar lordosis in 95% of the cases. A length shorter than 288 mm was measured in 95% of the cases. Anatomical conditions in male and female sacra were comparable. Conclusions: The narrow anteroposterior diameter is the key limiting feature for using the canalis sacralis as a natural entry point into the spinal canal. Sacroscopy will require endoscopes with a flattened shape, with parallel arrangement of instruments and flexibility to accommodate the varied dorsal and ventral curvatures. PMID- 29285402 TI - Bone biomaterials and interactions with stem cells. AB - Bone biomaterials play a vital role in bone repair by providing the necessary substrate for cell adhesion, proliferation, and differentiation and by modulating cell activity and function. In past decades, extensive efforts have been devoted to developing bone biomaterials with a focus on the following issues: (1) developing ideal biomaterials with a combination of suitable biological and mechanical properties; (2) constructing a cell microenvironment with pores ranging in size from nanoscale to submicro- and microscale; and (3) inducing the oriented differentiation of stem cells for artificial-to-biological transformation. Here we present a comprehensive review of the state of the art of bone biomaterials and their interactions with stem cells. Typical bone biomaterials that have been developed, including bioactive ceramics, biodegradable polymers, and biodegradable metals, are reviewed, with an emphasis on their characteristics and applications. The necessary porous structure of bone biomaterials for the cell microenvironment is discussed, along with the corresponding fabrication methods. Additionally, the promising seed stem cells for bone repair are summarized, and their interaction mechanisms with bone biomaterials are discussed in detail. Special attention has been paid to the signaling pathways involved in the focal adhesion and osteogenic differentiation of stem cells on bone biomaterials. Finally, achievements regarding bone biomaterials are summarized, and future research directions are proposed. PMID- 29285408 TI - A technique for sequential, progressive clipping for a giant thrombosed distal anterior cerebral artery aneurysm: Technical note. AB - Background: Giant thrombosed aneurysms often present with thickened walls and a hard thrombus, including in the near-neck aneurysmal sac. These usually make it difficult to achieve complete neck clipping with preservation of local branch patency. Here, we demonstrate a simple but safe and effective technique to overcome these problems in a patient with a 6-cm giant thrombosed distal anterior cerebral artery aneurysm. Case Description: A 77-year-old-man suffered from loss of volitional activity due to the frontal mass effect. The aneurysm was exposed with unilateral paramedian craniotomy and an interhemispheric approach. The clip was applied to the aneurysmal neck but it slipped onto the parent artery, which caused branch artery occlusion. Intra-aneurysmal thrombectomy was immediately performed near the aneurysmal neck with ultrasonic aspiration. The next clip was added along the aneurysm side of the preceding clip, which was then removed. This procedure was repeated twice so that complete neck clipping was achieved while preserving the branch patency. All the residual thrombus and aneurysmal wall were subsequently removed. Postoperatively, there was no additional neurological deficit. The patient's mental function was significantly improved. Conclusions: We conclude that the sequential, progressive clipping technique is a robust option for successful neck clipping of giant thrombosed aneurysms. PMID- 29285409 TI - Massive lumbar spine hematoma post-spinal tap. AB - Background: Lumbar puncture is a well-known procedure. The indications for lumbar puncture vary among different medical and surgical disciplines, though obtaining a sample for cerebrospinal fluid analysis is the most common one. A normal coagulation profile is crucial prior to pursing the procedure. Occasionally, an urgent sample is needed to guide an appropriate treatment while the patient's coagulation status is suboptimum. In those specific critical situations, some may accept suboptimal correction owing to the urgency of the case. Case Description: We report a case for a patient with Burkitt lymphoma who presented with mild neuroaxial symptoms. An urgent cerebrospinal fluid sample was required which was taken after correcting his platelets count to 53.4 * 109/L. He developed a massive multi-compartmental thoracolumbar hematoma with acute cauda equine syndrome requiring surgical intervention. Despite aggressive management, he remained permanently paraplegic with functional status that negatively affected his overall outcome. Conclusion: Lumbar puncture is a useful diagnostic and treatment tool. Although serious events are seldom, they can be detrimental. A precaution not to underestimate such events in practicing lumbar, especially in patients with suboptimum coagulation state. Image-guided procedure can be useful and should be considered in appropriately selected patients. PMID- 29285407 TI - Designing a pain management protocol for craniotomy: A narrative review and consideration of promising practices. AB - Background: Craniotomy is a relatively common surgical procedure with a high incidence of postoperative pain. Development of standardized pain management and enhanced recovery after surgery (ERAS) protocols are necessary and crucial to optimize outcomes and patient satisfaction and reduce health care costs. Methods: This work is based upon a literature search of published manuscripts (between 1996 and 2017) from Pubmed, Cochrane Central Register, and Google Scholar. It seeks to both synthesize and review our current scientific understanding of postcraniotomy pain and its part in neurosurgical ERAS protocols. Results: Strategies to ameliorate craniotomy pain demand interventions during all phases of patient care: preoperative, intraoperative, and postoperative interventions. Pain management should begin in the perioperative period with risk assessment, patient education, and premedication. In the intraoperative period, modifications in anesthesia technique, choice of opioids, acetaminophen and nonsteroidal anti inflammatory drugs (NSAIDs), regional techniques, dexmedetomidine, ketamine, lidocaine, corticosteroids, and interdisciplinary communication are all strategies to consider and possibly deploy. Opioids remain the mainstay for pain relief, but patient-controlled analgesia, NSAIDs, standardization of pain management, bio/behavioral interventions, modification of head dressings as well as patient-centric management are useful opportunities that potentially improve patient care. Conclusions: Future research on mechanisms, predictors, treatments, and pain management pathways will help define the combinations of interventions that optimize pain outcomes. PMID- 29285410 TI - The clinical examination in the patient with subarachnoid hemorrhage is still the most reliable parameter for predicting pathophysiological changes. AB - Background: Macrovasospasms and delayed cerebral injury are factors which correlate with high morbidity in patients suffering a subarachnoid hemorrhage. Transcranial Doppler (TCD) ultrasonography and perfusion computed tomography (PCT) are diagnostic tools used to diagnose such pathologies. However, TCD is not very reliable and PCT exposes patients to radiation and cannot be performed daily. Case Description: We present the case of a 47-year-old female with subarachnoid hemorrhage caused by rupture of an intracranial aneurysm. The aneurysm was coil embolized, and the clinical course of the patient was uncomplicated. She was writing notes about her stay in the intensive care unit. Without having any other complaints, she noticed that her writing became abruptly unrecognizable. TCD failed to show pathological signs, although PCT revealed decreased brain perfusion. Conclusion: We rely more and more on our technical tools in medicine. However, clinical examination is and will stay the the first sign indicating cerebral pathologies and should remain the first priority to have an awake patient who can be examined routinely. In addition, we emphasize on the need of seeing the patient and not only the images. More than anything else, the patient is the first who shows signs of pathology and not the instruments (CT, TCD, etc.). The sentence "a fool with a tool is still a fool" should be present in every doctor's mind to avoid mistakes and react appropriately. PMID- 29285412 TI - Nontraumatic, posterior circulation pseudoaneurysm of the basilar artery summit with complete spontaneous resolution: Case Report and literature review. PMID- 29285411 TI - Simple training tricks for mastering and taming bypass procedures in neurosurgery. AB - Background: Neurosurgeons devoted to bypass neurosurgery or revascularization neurosurgery are becoming scarcer. From a practical point of view, "bypass neurosurgeons" are anastomosis makers, vessels technicians, and time-racing repairers of vessel walls. This requires understanding the key features and hidden tricks of bypass surgery. The goal of this paper is to provide simple and inexpensive tricks for taming the art of bypass neurosurgery. Most of these tricks and materials described can be borrowed, donated, or purchased inexpensively. Methods: We performed a review of relevant training materials and recorded videos for training bypass procedures for 3 years between June 2014 and July 2017. In total, 1,300 training bypass procedures were performed, of which 200 procedures were chosen for this paper. Results: A training laboratory bypass procedures is required to enable a neurosurgeon to develop the necessary skills. The important skills for training bypass procedures gained through meticulous practice to be as reflexes are coordination, speed, agility, flexibility, and reaction time. Bypassing requires synchronization between the surgeon's gross movements, fine motoric skills, and mental strength. The suturing rhythm must be timed in a brain-body-hand fashion. Conclusion: Bypass-training is a critical part of neurosurgical training and not for a selected few. Diligent and meticulous training can enable every neurosurgeon to tame the art of bypass neurosurgery. This requires understanding the key features and hidden tricks of bypass surgery, as well as uncountable hours of training. In bypass neurosurgery, quality and time goes hand in hand. PMID- 29285413 TI - Minimally invasive repair of a pseudomeningocele caused by a sheared intrathecal catheter following implantation of a drug delivery system. AB - Background: Shearing of an intrathecal catheter during implantation of a drug delivery system is an underreported complication that can be challenging to manage. Case Description: A 53-year-old man with refractory cancer pain had an intrathecal pump system implanted. The procedure was complicated with catheter shear and retention in the intrathecal space. A second catheter was successfully placed but formation of a painful pseudomeningocele and ineffective pain relief complicated the outcome. A minimally invasive approach through a tubular retractor was employed to access the spinal canal via a laminotomy, the sheared catheter was removed and the dural defect repaired. Complete resolution of the pseudomeningocele and efficient pain control were observed at follow-up. Conclusion: Minimally invasive approach to the spine is demonstrated as a safe and effective alternative in this case of retained catheter induced cerebrospinal fluid (CSF) leak. PMID- 29285414 TI - Deep brain stimulation for obsessive-compulsive disorder: Knowledge and concerns among psychiatrists, psychotherapists and patients. AB - Background: Deep brain stimulation (DBS) is under investigation for severe obsessive-compulsive disorder (OCD) resistant to other therapies. The number of implants worldwide is slowly increasing. Therefore, it is of importance to explore knowledge and concerns of this novel treatment among patients and their psychiatric healthcare contacts. This information is relevant for scientific professionals working with clinical studies for DBS for this indication. Especially, for future study designs and the creation of information targeting healthcare professionals and patients. The aim of this study was to explore the knowledge and concerns toward DBS among patients with OCD, psychiatrists, and cognitive behavioral therapists. Methods: The study was conducted through web based surveys for the aimed target groups -psychiatrist, patients, and cognitive behavioral therapists. The surveys contained questions regarding previous knowledge of DBS, source of knowledge, attitudes, and concerns towards the therapy. Results: The main source of information was from scientific sources among psychiatrists and psychotherapists. The patient's main source of information was the media. Common concerns among the groups included complications from surgery, anesthesia, stimulation side effects, and the novelty of the treatment. Specific concerns for the groups included; personality changes mentioned by patients and psychotherapists, and ethical concerns among psychiatrists. Conclusion: There are challenges for DBS in OCD as identified by the participants of this study; source and quality of information, efficacy, potential adverse effects, and eligibility. In all of which the current evidence base still is limited. A broad research agenda is needed for studies going forward. PMID- 29285415 TI - Preclinical Cancer Models and Biomarkers for Drug Development: New Technologies and Emerging Tools. AB - Background and purpose: Predicting the efficacy of anticancer therapy is the holy grail of drug development and treatment selection in the clinic. To achieve this goal, scientists require pre-clinical models that can reliably screen anticancer agents with robust clinical correlation. However, there is increasing challenge to develop models that can accurately capture the diversity of the tumor ecosystem, and therefore reliably predict how tumors respond or resistant to treatment. Indeed, tumors are made up of a heterogeneous landscape comprising malignant cells, normal and abnormal stroma, immune cells, and dynamic microenvironment containing chemokines, cytokines and growth factors. In this mini-review we present a focused, brief perspective on emerging preclinical models for anticancer therapy that attempt to address the challenge posed by tumor heterogeneity, highlighting biomarkers of response and resistance. Recent findings: Starting from 2-dimensional and 3-dimensional in-vitro models, we discuss how organoid co-cultures have led to accelerated efforts in anti-cancer drug screening, and advanced our fundamental understanding for mechanisms of action using high-throughput platforms that interrogate various biomarkers of 'clinical' efficacy. Then, mentioning the limitations that exist, we focus on in vivo and human explant technologies and models, which build-in intrinsic tumor heterogeneity using the native microenvironment as a scaffold. Importantly, we will address how these models can be harnessed to understand cancer immunotherapy, an emerging therapeutic strategy that seeks to recalibrate the body's own immune system to fight cancer. Conclusion: Over the past several decades, numerous model systems have emerged to address the exploding market of drug development for cancer. While all of the present models have contributed critical information about tumor biology, each one carries limitations. Harnessing pre-clinical models that incorporate cell heterogeneity is beginning to address some of the underlying challenges associated with predicting clinical efficacy of novel anticancer agents. PMID- 29285416 TI - Cancer Immunotherapy and Personalized Medicine: Emerging Technologies and Biomarker-Based Approaches. AB - Purpose of review: The vision and strategy for the 21st century treatment of cancer calls for a personalized approach in which therapy selection is designed for each individual patient. While genomics has led the field of personalized cancer medicine over the past several decades by connecting patient-specific DNA mutations with kinase-targeted drugs, the recent discovery that tumors evade immune surveillance has created unique challenges to personalize cancer immunotherapy. In this mini-review we will discuss how personalized medicine has evolved recently to accommodate the emerging era of cancer immunotherapy. Moreover, we will discuss novel platform technologies that have been engineered to address some of the persisting limitations. Recent finding: Beginning with early evidence in personalized medicine, we discuss how biomarker-driven approaches to predict clinical success have evolved to account for the heterogeneous tumor ecosystem. In the emerging field of cancer immunotherapy, this challenge requires the use of a novel set of tools, distinct from the classic approach of next-generation genomic sequencing-based strategies. We will introduce new techniques that seek to tailor immunotherapy by re-programming patient-autologous T-cells, and new technologies that are emerging to predict clinical efficacy by mapping infiltration of lymphocytes, and harnessing fully humanized platforms that reconstruct and interrogate immune checkpoint blockade, ex-vivo. Summary: While cancer immunotherapy is now leading to durable outcomes in difficult-to-treat cancers, success is highly variable. Developing novel approaches to study cancer immunotherapy, personalize treatment to each patient, and achieve greater outcomes is penultimate to developing sustainable cures in the future. Numerous techniques are now emerging to help guide treatment decisions, which go beyond simple biomarker-driven strategies, and are now we are seeking to interrogate the entirety of the dynamic tumor ecosystem. PMID- 29285417 TI - Agreement in Cone Density Derived from Gaze-Directed Single Images Versus Wide Field Montage Using Adaptive Optics Flood Illumination Ophthalmoscopy. AB - Purpose: We compared cone density measurements derived from the center of gaze directed single images with reconstructed wide-field montages using the rtx1 adaptive optics (AO) retinal camera. Methods: A total of 29 eyes from 29 healthy subjects were imaged with the rtx1 camera. Of 20 overlapping AO images acquired, 12 (at 3.2 degrees , 5 degrees , and 7 degrees ) were used for calculating gaze directed cone densities. Wide-field AO montages were reconstructed and cone densities were measured at the corresponding 12 loci as determined by field projection relative to the foveal center aligned to the foveal dip on optical coherence tomography. Limits of agreement in cone density measurement between single AO images and wide-field AO montages were calculated. Results: Cone density measurements failed in 1 or more gaze directions or retinal loci in up to 58% and 33% of the subjects using single AO images or wide-field AO montage, respectively. Although there were no significant overall differences between cone densities derived from single AO images and wide-field AO montages at any of the 12 gazes and locations (P = 0.01-0.65), the limits of agreement between the two methods ranged from as narrow as -2200 to +2600, to as wide as -4200 to +3800 cones/mm2. Conclusions: Cone density measurement using the rtx1 AO camera is feasible using both methods. Local variation in image quality and altered visibility of cones after generating montages may contribute to the discrepancies. Translational Relevance: Cone densities from single AO images are not interchangeable with wide-field montage derived-measurements. PMID- 29285418 TI - PDK4 Deficiency Induces Intrinsic Apoptosis in Response to Starvation in Fibroblasts from Doberman Pinschers with Dilated Cardiomyopathy. AB - The Doberman pinscher (DP) canine breed displays a high incidence of idiopathic, nonischemic dilated cardiomyopathy (DCM) with increased mortality. A common mutation in DPs is a splice site deletion in the pyruvate dehydrogenase kinase 4 (PDK4) gene that shows a positive correlation with DCM development. PDK4, a vital mitochondrial protein, controls the switch between glycolysis and oxidative phosphorylation based upon nutrient availability. It is likely, although unproven, that DPs with the PDK4 mutation are unable to switch to oxidative phosphorylation during periods of low nutrient availability, and thus are highly susceptible to mitochondrial-mediated apoptosis. This study investigated cell viability, mitochondrial stress, and activation of the intrinsic (mitochondrial mediated) apoptotic pathway in dermal fibroblasts from DPs that were healthy (PDK4wt/wt), heterozygous (PDK4wt/del), and homozygous (PDK4del/del) for the PDK4 mutation under conditions of high (unstarved) and low (starved) nutrient availability in vitro. As hypothesized, PDK4wt/del and PDK4del/del cells showed evidence of mitochondrial stress and activation of the intrinsic apoptotic pathway following starvation, while the PDK4wt/wt cells remained healthy and viable under these conditions. Adeno-associated virus (AAV) PDK4-mediated gene replacement experiments confirmed cause-effect relationships between PDK4 deficiency and apoptosis activation. The restoration of function observed following administration of AAV-PDK4 provides strong support for the translation of this gene therapy approach into the clinical realm for PDK4-affected Dobermans. PMID- 29285419 TI - Developing a Wireless, High Precision and Processing Speed Pulse Monitoring Headset Using Photoplethysmography. AB - In this paper, thorough improvement of pulse monitoring and analysis equipment with a headset structure is presented. In order to study the most suitable infrared wavelength for the acquisition of the pulse wave at the earlobe, Monte Carlo simulation was adapted. Both high frequency noise and baseline drift, generated in the signal acquisition process, are considered. To further optimize the system design and improve accuracy, for the sensor's dimensional drift, the corresponding compensation was carried on in the software. This paper introduced nonlinear quantization, especially in terms of very weak pulse signal, in the time domain analysis process. A quick extraction method named table look-up combing with interpolation was utilized to obtain frequency domain information whose processing speed can be increased by about 30 times compared with fast Fourier transformation setting the sampling point as 300. The results demonstrated the sensor's excellent performance in pulse signal acquisition whose maximum residual is less than 0.004 mV. The test on a random sample of 300 people indicates that the system had high correlation with reference, validating the system accuracy is extremely high. Overall, this paper provides a practical pulse monitoring and analysis system with high precision and processing speed that can be widely applied in the field of health management or medical measurement. PMID- 29285420 TI - Development of a Non-Invasive Blink Reflexometer. AB - Qualitative assessments of the blink reflex are used clinically to assess neurological status in critical care, operating room, and rehabilitative settings. Despite decades of literature supporting the use of quantitative measurements of the blink reflex in the evaluation of multiple neurological disorders, clinical adoption has failed. Thus, there remains an unmet clinical need for an objective, portable, non-invasive metric of neurological health that can be used in a variety of settings. We have developed a high-speed videography based device to trigger, record, and analyze a blink reflex. A pilot study was performed to compare the device's measurements to the published literature of electromyographic measurements, currently the gold standard. The study results indicate that the device is a viable tool to obtain fast, objective, and quantitative metrics of a blink reflex, and has promise as a non-invasive diagnostic assessment of neurological health. PMID- 29285421 TI - Epoxyeicosatrienoic acid activation moderates endothelial mesenchymal transition to reduce obstructive nephropathy. PMID- 29285422 TI - Serum uric acid and mortality risk among maintenance hemodialysis patients. PMID- 29285423 TI - Renal intercalated cells and blood pressure regulation. AB - Type B and non-A, non-B intercalated cells are found within the connecting tubule and the cortical collecting duct. Of these cell types, type B intercalated cells are known to mediate Cl- absorption and HCO3- secretion largely through pendrin dependent Cl-/HCO3- exchange. This exchange is stimulated by angiotensin II administration and is also stimulated in models of metabolic alkalosis, for instance after aldosterone or NaHCO3 administration. In some rodent models, pendrin-mediated HCO3- secretion modulates acid-base balance. However, the role of pendrin in blood pressure regulation is likely of more physiological or clinical significance. Pendrin regulates blood pressure not only by mediating aldosterone-sensitive Cl- absorption, but also by modulating the aldosterone response for epithelial Na+ channel (ENaC)-mediated Na+ absorption. Pendrin regulates ENaC through changes in open channel of probability, channel surface density, and channels subunit total protein abundance. Thus, aldosterone stimulates ENaC activity through both direct and indirect effects, the latter occurring through its stimulation of pendrin expression and function. Therefore, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contributory role of pendrin in distal nephron function and blood pressure. PMID- 29285424 TI - Maturation of arteriovenous fistula: Analysis of key factors. AB - The growing proportion of individuals suffering from chronic kidney disease has considerable repercussions for both kidney specialists and primary care. Progressive and permanent renal failure is most frequently treated with hemodialysis. The efficiency of hemodialysis treatment relies on the functional status of vascular access. Determining the type of vascular access has prime significance for maximizing successful maturation of a fistula and avoiding surgical revision. Despite the frequency of arteriovenous fistula procedures, there are no consistent criteria applied before creation of arteriovenous fistulae. Increased prevalence and use of arteriovenous fistulae would result if there were reliable criteria to assess which arteriovenous fistulae are more likely to reach maturity without additional procedures. Published studies assessing the predictive markers of fistula maturation vary to a great extent with regard to definitions, design, study size, patient sample, and clinical factors. As a result, surgeons and specialists must decide which possible risk factors are most likely to occur, as well as which parameters to employ when evaluating the success rate of fistula development in patients awaiting the creation of permanent access. The purpose of this literature review is to discuss the role of patient factors and blood markers in the development of arteriovenous fistulae. PMID- 29285425 TI - Active maintenance of endothelial cells prevents kidney fibrosis. AB - Background: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents. Methods: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. Results: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1 ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks. Treatment with AUDA significantly ameliorated tubulointerstitial fibrosis by reducing fibroblast mobilization and enhancing endothelial cell activity. In an in vitro model of endothelial-to-mesenchymal transition (EndMT) using human vascular endothelial cells (HUVECs), AUDA prevented the morphologic changes associated with EndMT and reduced expression of fibroblast-specific protein 1. Furthermore, HUVECs activated by AUDA prevented the epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in a co-culture system. Conclusion: Our findings suggest that regulation of sEH is a potential target for therapies aimed at delaying the progression of kidney fibrosis by inhibiting EndMT and EMT. PMID- 29285426 TI - Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations for estimating glomerular filtration rates in cancer patients receiving cisplatin-based chemotherapy. AB - Background: Although the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation has been recommended for accurate estimates of glomerular filtration rate (eGFR), there is little information regarding differences in GFR estimates obtained using the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) equations in East Asian cancer patients. We investigated discrepancies in GFR and toxicities in patients treated with cisplatin-based chemotherapy using three equations equations. Methods: A total of 229 patients were retrospectively recruited. We calculated eGFR using the three equations and separated patients into three categories based on GFR < 10 (group A), 10-50 (group B), and > 50 (group C) mL/min/1.73m2. We analyzed chemotherapy toxicities. Results: The mean eGFR calculated using the CG was the lowest of the values derived using the three equations. Estimates using the MDRD and CKD-EPI equations resulted in reclassifying 32 (71.1%) and 33 (73.3%) of 45 patients, originally placed in group B using the CG into group C. However, only 1 (7.7%) of 13 patients placed in group B using the MDRD were reclassified into group C using the CKD-EPI. Twenty-eight of 45 patients classified into group B using the CG equation were treated with reduced doses of cisplatin. However, these patients did not show significant differences in toxicities compared with other patients taking full doses of cisplatin. Conclusion: The CG equations underestimated GFR compared to the MDRD and CKD-EPI equations. Therefore, when GFR is estimated using CG equations, East Asian cancer patients may receive insufficient doses of chemotherapeutic agents, including cisplatin. PMID- 29285427 TI - Physician perceptions of blood pressure control in patients with chronic kidney disease and target blood pressure achievement rate. AB - Background: Blood pressure (BP) control is the most-established method for the prevention of chronic kidney disease (CKD) progression. However, the ideal BP target for CKD patients is still under debate. Methods: We performed a survey of regular registered members of the Korean Society of Nephrology to determine physician perceptions of BP control in patients with CKD. In addition, we evaluated the target BP achievement rate using data from the APrODiTe-2 study. Results: Two-thirds of physicians considered the target BP for CKD to be < 130/85 mmHg. The systolic BP (SBP) thresholds for diabetic CKD, proteinuria >= 300 mg/day, 30 <= glomerular filtration rate (GFR) < 60 mL/min/1.73 m2, age < 60 years, and the presence of atherosclerotic (ASO) complications were significantly lower than the SBP thresholds of the opposite parameters. The three major hurdles to controlling BP were non-compliance with lifestyle modification and medications, and self-report of well-controlled home BP. Most physicians prescribed home and ambulatory BP monitoring to less than 50% of their patients. The target BP achievement rates using the SBP thresholds in this survey were as follows: non-diabetic (69.3%); diabetic (29.5%); proteinuria < 300 mg/day (72.3%); proteinuria > 300 mg/day (33.7%); GFR >= 60 (76.4%); GFR < 30 (47.8%); no evidence of ASO (67.8%); and the presence of ASO (42.9%). Conclusion: The target BP was lower in patients with higher cerebro-cardiovascular risks. These patient groups also showed lower target BP achievement rates. We also found a relatively lower application and clinical reflection rate of home or ambulatory BP monitoring. PMID- 29285428 TI - Prognostic performance of combined use of high-sensitivity troponin T and creatine kinase MB isoenzyme in high cardiovascular risk patients with end-stage renal disease. AB - Background: The principal goal of this study was to determine the importance of high-sensitivity troponin T (hs-TnT) and creatine kinase MB isoenzyme (CK-MB) in predicting cardiovascular events in asymptomatic end-stage renal disease (ESRD) patients. Methods: This study included 110 participants; 54 ESRD patients undergoing hemodialysis and 56 healthy control participants. Biochemical parameters and cardiac markers were estimated. Comparative utilities were assessed through logistic regression and receiver operating characteristic (ROC) analyses. Results: We found that 96.3% of ESRD patients had an elevated level of hs-TnT (mean, 0.049 +/- 0.0324 MUg/L) compared to healthy participants. Among patients with ESRD, hs-TnT showed significant correlations with the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (HDL-C) (P = 0.042, r = 0.278) and total cholesterol/HDL-C (P = 0.044, r = 0.276) ratios. CK-MB (odds ratio [OR], 1.138; P = 0.04) and hs-TnT (OR, 2.153; P = 0.017) predicted cardiovascular events on logistic regression analysis, and the prediction was improved by the model that combined two cardiac markers. The diagnostic performance of hs-TnT and CK-MB alone and the combination of the two biomarkers was assessed by the area under the ROC curve (AUC). The highest AUC was produced by the combination of hs-TnT and CK-MB markers (0.920) compared to hs-TnT or CK MB alone. Conclusion: In asymptomatic patients with ESRD, hs-TnT appeared to be an important predictor for cardiovascular mortality, and its diagnostic accuracy improved with CK-MB. This study provides new insights into the predictive value of multiple biomarkers for identifying cardiovascular events in ESRD patients on hemodialysis. PMID- 29285429 TI - Relationship between serum uric acid and mortality among hemodialysis patients: Retrospective analysis of Korean end-stage renal disease registry data. AB - Background: It is thought that hyperuricemia might lower the risk of mortality among hemodialysis patients, unlike in the general population, but the evidence is controversial. The aim of the current study was to evaluate the impact of serum uric acid level on the long-term clinical outcomes of hemodialysis patients in Korea. Methods: Retrospective analysis was performed on data from the End Stage Renal Disease Registry of the Korean Society of Nephrology. This included data for 7,333 patients (mean age, 61 +/- 14 years; 61% male) who received hemodialysis from January 2001 through April 2015. Initial laboratory data were used in the analysis. Results: The mean serum uric acid level in this study was 7.1 +/- 1.7 mg/dL. Body mass index, normalized protein catabolic rate, albumin, and cholesterol were positively correlated with serum uric acid level after controlling for age and sex. After controlling for demographic data, comorbidities, and residual renal function, a higher uric acid level was independently associated with a significantly lower all-cause mortality (hazard ratio [HR], 0.90 per 1 mg/dL increase in uric acid level; 95% confidence interval [CI], 0.83-0.97; P = 0.008), but not cardiovascular mortality (HR, 0.90; 95% CI, 0.80-1.01; P = 0.078). Comparing uric acid levels in the highest and lowest quintiles, the HR for all-cause mortality was 0.65 (95% CI, 0.42-0.99; P = 0.046). Conclusion: Hyperuricemia was strongly associated with a lower risk of all-cause mortality, but there seems to be no significant association between serum uric acid level and cardiovascular mortality among Korean hemodialysis patients with end-stage renal disease. PMID- 29285430 TI - Changes in geriatric nutritional risk index and risk of major adverse cardiac and cerebrovascular events in incident peritoneal dialysis patients. AB - Background: Geriatric nutritional risk index (GNRI) is a validated nutritional assessment method, and lower GNRI values are closely associated with adverse clinical outcomes in dialysis patients. This study investigated the impact of changes in GNRI during the first year of dialysis on cardiovascular outcomes in incident peritoneal dialysis (PD) patients. Methods: We reviewed medical records in 133 incident PD patients to determine GNRI at the start of PD and after 12 months. Patients were categorized into improved (delta GNRI > 0) and worsening/stationary (delta GNRI <= 0) groups. The primary outcome was major adverse cardiac and cerebrovascular events (MACCEs). Results: During a mean follow-up of 51.1 months, the primary outcome was observed in 42 patients (31.6%). The baseline GNRI at PD initiation was not significantly associated with MACCEs (log-rank test, P = 0.40). However, the cumulative event-free rate was significantly lower in the worsening or stationary GNRI group than in the improved group (log-rank test, P = 0.004). Multivariate Cox analysis revealed that a worsening or stationary GNRI was independently associated with higher risk for MACCEs (hazard ratio, 2.47; 95% confidence interval, 1.15-5.29; P = 0.02). In subgroup analysis, patients with worsening or stationary GNRI were at significantly greater risk for MACCEs in both the lower (P = 0.04) and higher (P = 0.01) baseline GNRI groups. Conclusion: Baseline GNRI was not associated with MACCEs, but patients with deteriorating or stationary nutritional status were at significantly greater risk for MACCEs, suggesting that serial monitoring of nutritional status is important to stratify cardiovascular risk in incident PD patients. PMID- 29285432 TI - Type 1 primary hyperoxaluria in a male infant. PMID- 29285431 TI - Acute kidney injury aggravated by treatment initiation with apixaban: Another twist of anticoagulant-related nephropathy. AB - Anticoagulant-related nephropathy (ARN) was initially described in patients on warfarin (as warfarin-related nephropathy) and recently in those using dabigatran. Herein, we report clinical history and kidney biopsy findings in a patient on apixaban (Eliquis). Initiation of treatment with apixaban resulted in aggravation of preexisting mild acute kidney injury (AKI). A few days after apixaban therapy, the patient became oligoanuric, and kidney biopsy showed severe acute tubular necrosis with numerous occlusive red blood cell casts. Only one out of 68 glomeruli with open capillary loops had small segmental cellular crescent. Therefore, there was major discrepancy between the degree of glomerular injury and the glomerular hematuria. Considering that the onset of this AKI was associated with apixaban treatment initiation, we propose that this patient had ARN associated with factor Xa inhibitor (apixaban), which has not previously been described. Monitoring of kidney function is recommended after initiation of anticoagulant therapy. PMID- 29285433 TI - Unilateral renal atrophy associated with abdominal aortic aneurysm. PMID- 29285434 TI - Travel by public transit to mammography facilities in 6 US urban areas. AB - We examined lack of private vehicle access and 30 minutes or longer public transportation travel time to mammography facilities for women 40 years of age or older in the urban areas of Boston, Philadelphia, San Antonio, San Diego, Denver, and Seattle to identify transit marginalized populations - women for whom these travel characteristics may jointly present a barrier to clinic access. This ecological study used sex and race/ethnicity data from the 2010 US Census and household vehicle availability data from the American Community Survey 2008-2012, all at Census tract level. Using the public transportation option on Google Trip Planner we obtained the travel time from the centroid of each census tract to all local mammography facilities to determine the nearest mammography facility in each urban area. Median travel times by public transportation to the nearest facility for women with no household access to a private vehicle were obtained by ranking travel time by population group across all U.S. census tracts in each urban area and across the entire study area. The overall median travel times for each urban area for women without household access to a private vehicle ranged from a low of 15 minutes in Boston and Philadelphia to 27 minutes in San Diego. The numbers and percentages of transit marginalized women were then calculated for all urban areas by population group. While black women were less likely to have private vehicle access, and both Hispanic and black women were more likely to be transit marginalized, this outcome varied by urban area. White women constituted the largest number of transit marginalized. Our results indicate that mammography facilities are favorably located for the large majority of women, although there are still substantial numbers for whom travel may likely present a barrier to mammography facility access. PMID- 29285435 TI - Endocrinology and the Nudge Hypothesis. PMID- 29285436 TI - Pentads and Hexads in Diabetes Care: Numbers as Targets; Numbers as Tools. PMID- 29285437 TI - The Effect of Electromagnetic Radiation due to Mobile Phone Use on Thyroid Function in Medical Students Studying in a Medical College in South India. AB - Background: Enormous increase in mobile phone use throughout the world raises widespread concerns about its possible detrimental effect on human health. Radiofrequency waves are emitted by cell phones. They are non-ionising and the effect on the thyroid gland is part of their non thermal effects. The thyroid gland may be particularly vulnerable to this effect because of its normal anatomical position. Materials and Methods: The study was done to explore the association between radiation exposure and thyroid dysfunction among mobile phone users. It had an exploratory design and unit survey method to collect information from all medical students in a medical college in South India. Inclusion criteria included active use of mobile phone prior to and during the study period. Criteria for exclusion was presence of pre-existsting thyroid disease,thyroid nodule,thyroid goitre/nodule and altered thyroid function. Results: The sample size was 83 undergraduate students. 71% of respondents had no family history of thyroid illness. Among the remainder,20.5% had a first degree relative with thyroid dysfunction,8.4% had a second degree relative affected. Clinical examination revealed that 79.5% of the respondents were normal,13.6% had thyroid swelling,3.6% had symptoms of thyroid dysfunction and 3.6% had both thyroid swelling and symptoms of thyroid dysfunction. 53% of the respondents spent 0.5 hrs on an average talking on the phone daily,28.9% spent 1.5 hrs daily and 10.8% of respondents spent over 3.5 hours. We found there was a significant correlation between total radiation exposure and an increase in TSH among both groups -in those with and without family history of thyroid illness. Conclusion: In our study there was a significant correlation between total radiation exposure and increasing TSH values among both all respondents. PMID- 29285438 TI - Neck Circumference as a Marker of Overweight and Obesity and Cutoff Values for Bangladeshi Adults. AB - Objective: There are several methods of assessing overweight and obesity. Several studies conducted in different populations indicate that neck circumference (NC) can be used as a simple measure of overweight and obesity. This study was conducted to evaluate NC as a marker of overweight and obesity and to determine respective cutoff values for Bangladeshi male and female participants. Research Design/Materials and Methods: This cross-sectional observational study was conducted with during July 2013-June 2014 among randomly selected 871 Bangladeshi participants (male = 496 [56.9%], female = 375 [43.1%], aged >18 years) who visited Outpatient Department of United Hospital, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic disorders, primary health-care centers located in Dhaka, Savar, Gazipur. NC of participants was taken in centimeter to the nearest 1 mm, using plastic tape measure. Main outcome included NC, waist circumferences (WC), body mass index (BMI), and waist: hip ratio (WHR). Results: Pearson's correlation coefficients indicated a significant association between NC and height (men, r = 0.33; women, r = 0.28; P < 0.0001), weight (men, r = 0.61; women, r = 0.55; P < 0.0001), BMI (men, r = 0.51; women, r = 0.41; P < 0.0001), WC (men, r = 0.61; women, r = 0.46; P < 0.0001), hip circumference (men, r = 0.61; women, r = 0.44; P < 0.0001), WHR (men, r = 0.22; women, r = 0.18; P < 0.0001). Receiver operating characteristic curve analysis showed that NC >=34.75 cm in men (area under curve [AUC]: 0.77; P < 0.001) and >=31.75 cm in women (AUC: 0.62; P < 0.001) were the best cutoff value for BMI >=23 (overweight). NC >=35.25 cm in men (AUC: 0.82; P < 0.001) and NC >=34.25 cm in women (AUC: 0.76; P < 0.001) were the best cutoff value for BMI >=27.5 (obesity). NC >=35.25 cm in male (AUC: 0.83; P < 0.001) and NC >=31.25 cm in women (AUC: 0.65; P < 0.001) were the best cutoff value for WC >90 cm in men and > 80 cm in women, respectively. NC >=34.45 cm in male (AUC: 0.59; P = 0.001) and NC >=31.25 cm in women (AUC: 0.66; P = 0.008) were the best cutoff value for WHR >0.9 in men and >0.8 in women, respectively. Conclusion: NC measurement is a simple, convenient, inexpensive screening measure to identify overweight and obese participants. Men with NC >=34.75 cm and women with NC >=31.75 cm are to be considered overweight while men with NC >=35.25 cm and women with NC >=34.25 cm are to be considered obese. NC >=35.25 cm in male and NC >=31.25 cm in women were the best cutoff value for abdominal obesity. PMID- 29285439 TI - Incidence of Endocrine Disorders in Indian Adult Male Population. AB - Background: The comprehensive epidemiology of endocrine disorders is lacking from our country. Most of the available data pertain to the prevalence of diabetes and thyroid disorders only. We studied the incidence of endocrine disorders in a cohort of service personnel followed for a long duration. Materials and Methods: The data for this descriptive epidemiologic study were derived from the electronic medical records of the male service personnel enrolled between 1990 and 2015. They were recruited between the ages of 17 and 20 years in good health, and their morbidity data were derived from the medical records. We calculated the incidence rates as per person-years (py) using appropriate statistical methods. Results: Our analysis includes 51,217 participants (median: age 33 years, range: 17-54) with a mean follow-up of 12.5 years. Yearly evaluation of the data gave a cumulative follow-up duration of 613,925 py. The incidence of diabetes, obesity, and dyslipidemia was 0.41, 0.23, and 0.12 per 1000 py, respectively. The incidence of thyroid, parathyroid, pituitary, adrenal, and metabolic bone disorders was 3.9, 8.6, 1.6, 0.81, and 0.97 per 100,000 py, respectively. Conclusion: Our cohort had lower incidence rates of endocrine disorders when compared with the Western population. Long-term epidemiological studies are essential to identify the demographic trends of the endocrine disorders in India. PMID- 29285440 TI - Verbal Episodic Memory in Young Hypothyroid Patients. AB - Context: Hypothyroidism affects cognitive functions especially memory. However, most of the previous studies have generally evaluated older hypothyroid patients and sample size of these studies varied in terms of age range. Aims: To see whether hypothyroidism affects memory in young patients. Settings and Design: The sample consisted of 11 hypothyroid patients with an age of 18-49 and 8 healthy controls matched on age and education. Subjects and Methods: Verbal episodic memory was assessed using Hindi adaptation of Rey-Auditory Verbal Learning Test. Statistical Analysis Used: An independent t-test was used to see the difference between mean performance of the patient group and healthy control on memory measures. Results: Results indicated nonsignificant difference between verbal episodic memory of patient group and healthy controls. Conclusions: On the basis of these findings, it was concluded that hypothyroidism may not affect younger patients in terms of episodic verbal memory the same way as it does in the older patients. PMID- 29285441 TI - High-dose Vitamin D Supplementation Precipitating Hypercalcemic Crisis in Granulomatous Disorders. AB - Background: Vitamin D supplementation precipitating hypercalcemic crisis is often the first manifestation in patients with granulomatous disorders. Methods: We report our experience on patients presenting with hypercalcemic crisis due to granulomatous disorder and the role of Vitamin D supplementation in the precipitation of hypercalcemic crisis in them. Results: The study included five patients with granulomatous disorders who presented with hypercalcemic crisis. All patients initially presented with nonspecific constitutional symptoms to other health-care centers to receive high-dose Vitamin D supplementation (60,000 U/week or 600,000 U intramuscular single dose). All of these patients presented with hypercalcemic crisis (serum calcium: 16.04 +/- 0.3 mg/dl) to our centers after a period of 32.8 +/- 9.62 days. Three patients were diagnosed to have sarcoidosis, and two were diagnosed to have tuberculosis. All five patients had parathyroid hormone-independent hypercalcemia with elevated serum 1,25-dihydroxy Vitamin D. Serum angiotensin-converting enzyme level was elevated in all the three patients with sarcoidosis. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography was performed in two patients with sarcoidosis which demonstrated diffusely increased tracer uptake in liver. In these two patients, liver biopsy confirmed the diagnosis. Conclusions: High-dose Vitamin D supplementation is most often the underlying cause of hypercalcemic crisis in patients with granulomatous disorders. Hence, high-dose Vitamin D supplementation should be used judiciously. PMID- 29285442 TI - Prevalence and Etiological Profile of Short Stature among School Children in a South Indian Population. AB - Background and Objectives: Short stature (SS) is a common pediatric problem and it might be the first sign of underlying illness. Studies documenting the burden and etiological profile of SS are scarce from India and are mostly limited to data obtained from referral centers. Due to the lack of large-scale, community based studies utilizing a standard protocol, the present study aimed to assess the prevalence and etiological profile of SS in school children of a South Indian district. Materials and Methods: In this cross-sectional study, children aged 4 16 years from 23 schools in Madurai district, Tamil Nadu, underwent anthropometric measurements and height was plotted in Khadilkar et al. growth chart. The cause of SS was assessed using clinical and laboratory evaluations in assigned children with a height less than third centile. Results: A total of 15644 children belonging to 23 schools were evaluated, and 448 (2.86%) children had SS. Etiological evaluation was further performed in 87 randomly assigned children, and it is identified that familial SS or constitutional delay in growth was the most common cause of SS in the study population (66.67%). Hypothyroidism and growth hormone deficiency were the two most common pathological causes of SS seen in 12 (13.79%) and 8 (9.20%) children, respectively. Malnutrition was the cause of SS in 6 (6.9%) children and cardiac disorders, psychogenic SS, and skeletal dysplasia were other identified causes of SS in the study. Interpretation and Conclusions: The overall prevalence of SS in school children was 2.86% and familial SS or constitutional delay in growth was the most common cause of SS. As a significant percentage of children with SS had correctable causes, monitoring growth with a standard growth chart should be mandatory in all schools. PMID- 29285443 TI - Cardiovascular Risk Factors in Children and Adolescents with Subclinical Hypothyroidism. AB - Background: Subclinical hypothyroidism (SCH) is a commonly encountered entity in day-to-day clinical practice and has been associated with adverse cardiovascular risk profile in adults and children. Data on children and adolescents with SCH, from India, are limited. Materials and Methods: This study was a cross-sectional case-control study, conducted at a tertiary care center in Northeast India. Twenty-seven children and adolescents aged 11 +/- 2.4 years with SCH and thyroid stimulating hormone >7.5 mIU/L were included in the study along with 20 age-, gender-, and height-matched controls. Multiple clinical, biochemical, and radiological cardiovascular risk factors were assessed and compared between the two groups. Results: Body mass index (BMI) (P = 0.048), waist circumference (P = 0.008), waist to height ratio (P = 0.007), low-density lipoprotein cholesterol (P = 0.04), triglycerides (TGs) (P = 0.038), TGs to high-density lipoprotein (HDL) cholesterol ratio (P = 0.005), non-HDL cholesterol (P = 0.019), fasting insulin (P = 0.006), and homeostasis model assessment of insulin resistance (P = 0.007) were found to be significantly higher while free T4 (P = 0.002) and HDL cholesterol (P = 0.019) were found to be significantly lower in SCH subjects compared to controls. On multiple regression analysis, BMI was found to have significant association with multiple cardiovascular risk factors. Conclusion: Children and adolescents with SCH were found to have adverse cardiovascular risk profile. Long-term follow-up studies are required to assess the clinical significance of these findings and requirement for therapy. PMID- 29285444 TI - Optimal Levothyroxine Replacement Adequately Improves Symptoms of Hypothyroidism; Residual Symptoms Need Further Evaluation for Other than Hypothyroidism Causation. AB - Objectives: Many patients with hypothyroidism complain of persistent residual symptoms, despite optimal treatment, although the similar prevalence is seen in patients with documented absence of thyroid disorder in primary health-care setup. We aimed to investigate symptomatic relief in new cases of primary hypothyroidism and compare with controls with other chronic conditions. Methods: This prospective case-control follow-up study enrolled patients from July 2014 to May 2015 in an endocrine outpatient clinic of a tertiary hospital. Controls were age- and gender-matched ambulatory individuals with well-controlled other chronic diseases and no major comorbidity. Thyroid symptom questionnaire (TSQ) was administered at pretreatment to all the cases and then they were started on levothyroxine (LT). At euthyroidism, TSQ was readministered. For controls, TSQ was administered only once. TSQ was measured on Likert scale 1-4 for lack of energy, dry skin, constipation, aches and pains, cold intolerance, poor memory, depression, weight gain, tiredness after walking, and difficulty in getting up (DGU). P < 0.05 was considered statistically significant. Results: A total of 194 cases (147 females and 47 males) and 259 controls (187 females and 72 males) were analyzed. A significant difference in the symptoms prevalence was seen between controls and pretreatment cases, except for DGU, and between subclinical and overt hypothyroidism. Pretreatment serum thyroid-stimulating hormone in cases correlated significantly with all their pretreatment symptoms score. All symptoms prevalence decreased significantly posttreatment. At euthyroidism, the mean symptoms score in posttreatment cases was similar or lower than the controls. Conclusion: LT effectively improves the symptoms of hypothyroidism in newly diagnosed cases of primary hypothyroidism. The residual symptoms need an alternation explanation other than hypothyroidism. PMID- 29285445 TI - Comparison of Two Protocols in the Management of Glucocorticoid-induced Hyperglycemia among Hospitalized Patients. AB - Context: There is limited literature focusing on the management of glucocorticoid induced hyperglycemia (GCIH). Aims: The primary objective was to compare the mean blood glucose between the experimental group (new protocol) and the control group (standard protocol) in the management of GCIH. The secondary objective was to compare other parameters of glycemic efficacy, variability, and safety parameters. Methods: This was a randomized, open-labeled, parallel arm trial. Adult patients who were given glucocorticoid (minimum dose equivalent to prednisolone 10 mg) in the past 24 h and had 2 h postmeal plasma glucose >=200 mg/dl were included in the study. Patients randomized to control group received standard basal-bolus insulin. In the experimental group, a "correctional insulin" matching the glycemic profile of the glucocorticoid administered was provided with or without "background" basal-bolus insulin. The parameters of glycemic efficacy, variability, and safety were compared. P < 0.05 was considered statistically significant. Results: Data of 67 patients included in the study were analyzed, of which 33 patients were in the experimental group and 34 patients in the control group. The mean blood glucose in the experimental and the control group was 170.32 +/- 33.46 mg/dl and 221.05 +/- 49.72, respectively (P = 0.0001). The parameters for glycemic variability were all significantly lower in patients in the experimental group. The hypoglycemia event rate was low in both the groups. Conclusion: When compared to the standard basal-bolus insulin protocol, the new protocol showed lower mean blood glucose and lower glycemic variability. PMID- 29285446 TI - Correlation between the Cernea Classification of External Branch of Superior Laryngeal Nerve in Relation to the Ultrasound-based Volume of Thyroid Gland. AB - Introduction: Goiter is a very common problem dealt with by surgeons. Surgical treatment of thyroid requires removal of a part (hemi) or whole of the gland (total thyroidectomy). The external branch of the superior laryngeal nerve (EBSLN) is an important but less researched structure to be preserved during surgery. Various studies have described the incidence of different types of EBSLN, but have not described regarding the relationship between the change in volume of the gland to the nerve. Materials and Methods: A prospective analysis of 100 patients who underwent total thyroidectomy in our department was done. All patients underwent preoperative ultrasonography and the volume of the gland was calculated. Intraoperatively, the EBSLN was identified and preserved prior to ligating the superior thyroid vessels. The nerve was classified as per the Cernea classification. The gland was divided into high and low volume, taking 20 ml as the cutoff. The incidence of Type 2 nerve in a low-volume gland was compared with that of a high-volume gland. Results: In 100 patients (200 nerves), 191 nerves were identified. The nerve was type 1 in 56/200 (28%), Type 2a in 116/200 (58%), and Type 2b in 19/200 (9%) patients. In large-volume glands, Type 2 nerve was more common (87%). Conclusion: Dissection of thyroid gland requires expertise to preserve the EBSLN. Large volume glands pose a more difficult challenge, as the gland is more closer to the nerve. PMID- 29285447 TI - Role of Parathyroid Hormone in Determination of Fat Mass in Patients with Vitamin D Deficiency. AB - Background: Obesity has become a global epidemic and it is rising is Asia. Vitamin D deficiency (VDD) is widely prevalent in the Indian subcontinent. Studies have linked VDD to obesity and shown correlation between parathyroid hormone (PTH), 25-hydroxy Vitamin D (25(OH)D), and fat mass (FM). However, studies on the role of PTH among subjects with VDD are lacking. Objective: The objective of this study is to study the role of PTH in the determination of FM in participants with VDD. Subjects: Five hundred and fifty-one adults (m:247, f:304) were included in this study. Materials and Methods: Total and regional (trunk, arm, and leg) FM was assessed by dual X-ray absorptometry. Biochemical and hormonal parameters such as calcium, phosphorus, alkaline phosphatase, ionic calcium, 25(OH)D, and PTH were also analyzed. Results: The mean age of the study population was 58.8 +/- 15.8 years (Male: [63.3 +/- 13.1], Female: [55.2 +/- 16.9]). FM and body mass index were significantly lower in females with higher levels of serum 25(OH)D. Total FM was negatively correlated with serum 25(OH)D (r = -0.363, P < 0.0001) and positively correlated with serum PTH (r: 0.262, P < 0.0001) in females only. Females with VDD and secondary hyperparathyroidism had higher FM than those with normal PTH. Conclusions: Females with VDD had higher total and regional FM. However, this correlation was evident only in those with high serum PTH levels, suggesting a potential role of PTH in the accumulation of FM. PMID- 29285448 TI - Maternal and Neonatal Outcome in Mothers with Gestational Diabetes Mellitus. AB - Introduction: Gestational diabetes mellitus (GDM) is common and is accompanied with other comorbidities. Challenges to treatment exist at our institute as it serves women with low income. This study assessed the burden of comorbidities and the outcome of GDM. Methods: This was a prospective, observational study of women with gestational diabetes attending the obstetrics department from September 2012 to April 2014. GDM was diagnosed based on the International Association of Diabetes and Pregnancy Study Groups criteria. Medical comorbidities were noted, and lipid profile was done. All the women were followed up till delivery, and the complications were recorded. Age- and parity-matched pregnant women with normal oral glucose tolerance test were recruited as controls. Results: One hundred and thirty-nine women were followed up till delivery. The average age was 28 years. Eighteen percent had bad obstetric history. The average body mass index was 28.8. Twenty-five percent had gestational hypertension (HTN), and 6.4% had chronic HTN. Thirty percent had hypothyroidism. 65% women received insulin. The glucose values were within the recommended range in 60% of the women. Maternal hypoglycemia occurred in 7 (5%) women. Forty-four percent of the women required cesarean section and 34% had complications either during pregnancy or labor. Three neonates had macrosomia. Twenty-six neonates (20%) required admission to the Neonatal Intensive Care Unit. Four neonates (3%) died. Newborns of mothers whose GDM optimally treated had less complications. Conclusion: Gestational diabetes is associated with HTN, hypothyroidism, obesity, and lipid abnormalities. The majority of women required insulin for treatment and optimal control of blood glucose resulted in lower neonatal complications. PMID- 29285449 TI - Carotid Intima-medial Thickness and Glucose Homeostasis in Indian Obese Children and Adolescents. AB - Objective: To evaluate for subclinical atherosclerosis and its risk factors in Indian obese children. Materials and Methods: A cross-sectional, case-control study was conducted to recruit 80 children aged 6-17 years with constitutional obesity as cases and 23 age- and gender-matched controls with normal body mass index (BMI). Anthropometric and clinical evaluation was followed by biochemical analysis and body fat estimation by dual-energy X-ray absorptiometry in cases. Similar evaluation was performed for controls except laboratory parameters. Carotid intima-media thickness (CIMT) was measured with B-mode ultrasonography in both cases and controls to evaluate subclinical atherosclerosis. Results: The mean age of cases was 12.8 +/- 3 years, with mean BMI of 29.2 +/- 4.8 kg/m2. The mean CIMT was significantly higher in cases than controls (0.54 +/- 0.13 vs. 0.42 +/- 0.08; P < 0.001 across all ages). CIMT was significantly higher in participants who were hypertensive than nonhypertensive (0.6 +/- 0.11 vs. 0.53 +/ 0.11 mm; P = 0.04). CIMT showed a positive correlation with BMI (r = 0.23, P = 0.02), percentage body fat and fat mass index (r = 0.28 and 0.3 respectively; P < 0.001), but not with waist: hip ratio. CIMT showed significant positive correlation with blood glucose at 60 min (r = 0.22; P = 0.04), serum insulin at 60 min (r = 0.28; P = 0.01) while negative correlation with whole body insulin sensitivity (r = -0.27; P = 0.01). Conclusion: CIMT correlated significantly to blood pressure, insulin sensitivity, and body fat in Indian obese children. PMID- 29285451 TI - The Prevalence of New Onset Diabetes Mellitus after Renal Transplantation in Patients with Immediate Posttransplant Hyperglycemia in a Tertiary Care Centre. AB - Objectives: This study aimed to determine the prevalence of immediate posttransplant hyperglycemia and new onset diabetes after renal transplantation (NODAT). It also aims at answering whether posttransplant hyperglycemia per se is a risk factor for future development of NODAT. Methods: A retrospective study was conducted among patients undergoing kidney transplantation under a single surgical unit in a tertiary care hospital in the past 5 years. All known patients with diabetes were excluded from the study. Immediate postoperative hyperglycemia was defined as random blood sugar (RBS) >=200 mg/dl or requirement of insulin. NODAT was defined as fasting plasma glucose >=126 mg/dl or RBS >=200 mg/dl or if the patient is receiving therapy for glycemic control at 6 weeks or 3 months posttransplantation. Results: The study population included 191 patients. The overall prevalence of posttransplant hyperglycemia and NODAT was 31.4% and 26.7%, respectively. NODAT developed in 28 patients (46.7%) of those who had posttransplant hyperglycemia. Thus, posttransplant hyperglycemia was associated with a fourfold increased risk of NODAT (P = 0.000). Posttransplant hyperglycemia was associated with increased infections (P = 0.04) and prolonged hospital stay (P = 0.0001). Increased age was a significant risk factor for NODAT (P = 0.000), whereas gender, acute rejection episodes, cadaveric transplant, hepatitis C virus status, human leukocyte antigen mismatch, and high calcineurin levels were not significantly associated with the future development of NODAT. Conclusion: The significant risk of NODAT posed by posttransplant hyperglycemia makes it prudent to follow up these patients more diligently in a resource-limited setting wherein routine monitoring in all patients is cumbersome. PMID- 29285450 TI - Neutrophil-lymphocyte Ratio is a Novel Reliable Predictor of Nephropathy, Retinopathy, and Coronary Artery Disease in Indians with Type-2 Diabetes. AB - Background and Aims: Neutrophil-lymphocyte ratio (NLR) has been suggested to be a predictor of coronary artery disease (CAD), and end-organ damage in type-2 diabetes mellitus (T2DM). Similar data are lacking from Indians with T2DM. Hence, this study aimed to evaluate the role of NLR as a predictor of microvascular complications and CAD in T2DM. Subjects and Methods: Consecutive T2DM patients attending the outpatient services of 2 different hospitals, who gave consent, underwent clinical, anthropometric evaluation, and evaluation for the occurrence of retinopathy, nephropathy, neuropathy, and CAD. Results: A total of 298 patients were screened of which 265 patients' data were analyzed. Occurrence of hypertension, neuropathy, nephropathy, retinopathy, and CAD was 12.8%, 18.5%, 41.5%, 62.3%, and 3.8%, respectively. Patients in higher NLR quartiles had significantly higher diabetes duration, occurrence of nephropathy, albuminuria, retinopathy, CAD and lpwer glomerular filtration rate. Patients with more microvascular complications had significantly longer diabetes duration, blood pressure, NLR, creatinine, and urine albumin excretion. Binary logistic regression revealed NLR followed by body mass index were best predictors of microvascular complications. NLR had areas under the receiver operating characteristic curve (AUC) of 0.888 (95% CI: 0.848-0.929; P < 0.001), 0.708 (95% CI: 0.646-0.771; P < 0.001), and 0.768 (95% CI: 0.599-938; P = 0.004) in predicting albuminuria, retinopathy, and CAD, respectively. NLR of 2.00 had sensitivity and specificity of 86.4% and 69% in predicting albuminuria; sensitivity and specificity of 64.2% and 63% in predicting retinopathy; sensitivity and specificity of 80% and 47.1% in predicting CAD. Conclusion: NLR is inexpensive, easy to use, reliable predictor of nephropathy, retinopathy, and CAD in Indian T2DM. PMID- 29285452 TI - Validity of Madras Diabetes Research Foundation: Indian Diabetes Risk Score for Screening of Diabetes Mellitus among Adult Population of Urban Field Practice Area, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India. AB - Introduction: IDRS is based on four simple parameters derived from known risk factors for diabetes; two modifiable risk factors (waist circumference and physical inactivity) and two non-modifiable risk factors (age and family history of diabetes), which may be amenable to intervention. The present study has been planned as the region specific validation is important before it can be used for screening in this part of the country. Aims: The aim of the present study was to validate MDRF-IDRS for screening of diabetes mellitus among adult population of urban field practice area, IGMC, Shimla, Himachal Pradesh, India. Methods: The present community based cross sectional study was conducted among 417 adults fulfilling the eligibility criteria using a two stage sampling design. Results: In the present study IDRS value >=70 had an optimum sensitivity of 61.33% and specificity of 56.14% for detecting undiagnosed type 2 diabetes in the community. At an IDRS score of >=70, the PPV was 23.47%, NPV as 86.88%, the diagnostic accuracy as 57.07%, LR for positive test as 1.398, LR for negative test as 0.69 and Youden's index as 0.17. However Youden's index was 0.19 at a cut of >=60 i.e. higher than what was at >=70. Higher IDRS scores increased the specificity but the sensitivity dramatically decreased. Conversely, lower IDRS values increased the sensitivity but the specificity drastically decreased. Area under the curve = 0.630 and a P value < 0.001. Conclusions: MDRF IDRS is user friendly screening tool but the criteria of including the parameter of physical activity for the calculation of the risk score needs to be clearly defined. In the present study the maximum sensitivity of 100% was seen at a cut off of >=30. Hence we would recommend that all those in the medium and high risk group should be screened for type 2 Diabetes. PMID- 29285453 TI - Predisposition of Angiotensin-converting Enzyme Deletion/Deletion Genotype to Coronary Artery Disease with Type 2 Diabetes Mellitus in South India. AB - Background: Worldwide, South Asians contribute to a high proportion of coronary artery disease (CAD) burden, mainly attributed to a high prevalence of diabetes. Early identification of such high-risk individuals would enable aggressive disease modification and prevention of complications. Definition of susceptible genotypes early in the course of disease may be one such avenue for reduction in morbidity and mortality from CAD. Aim: Our study was aimed to investigate the insertion/deletion polymorphism of angiotensin-converting enzyme (ACE I/D) gene and susceptibility to CAD in patients with type 2 diabetes mellitus (T2DM) in a South Indian population. Subjects and Methods: ACE (I/D) genotyping was performed by polymerase chain reaction specific primer for 187 CAD patients and 185 age- and sex-matched controls. Results: We observed that the ACE"II" genotype was found to be significantly associated with CAD patients (odds ratio [OR] = 1.689; P = 0.028). However, multiple logistic regression analysis revealed that ACE "DD" genotype was found to be most predominant risk factor for CAD patients with T2DM (OR = 6.118; P = 0.001). Conclusion: Our results showed that ACE (I/D) genotypes and alleles presented functional dimorphism in the development of CAD and CAD with T2DM patients in South India. This finding may be extremely useful in identifying subsets of patients where early aggressive treatment of risk factors is warranted. PMID- 29285454 TI - Hypothyroidism and Depression: Are Cytokines the Link? AB - Context: Primary hypothyroidism has been thought of as an inflammatory condition characterized by raised levels of cytokines such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Depression is also well known to occur in hypothyroidism. Depression is also characterized by elevated inflammatory cytokines. We planned to study whether cytokines play an important part in linking these two conditions. Objectives: (1) To know the prevalence of depression in overt hypothyroidism due to autoimmune thyroid disease. (2) To correlate the levels of inflammatory markers with the occurrence of depression. (3) To study the effect of levothyroxine on inflammatory markers and depression. Materials and Methods: In this longitudinal, case-controlled study, 33 patients with autoimmune hypothyroidism (thyroid-stimulating hormone >10 uIU/ml) were included with 33 age-, sex-, and body max index-matched healthy controls. Individuals were tested for Serum TNF-alpha, IL-6, high-sensitivity-CRP (hs-CRP). They were assessed for depression using Montgomery Asberg Depression Rating Scale (MADRS) and World Health Organization Quality of Life (QOL) Scale. Patients received L Thyroxine titrated to achieve euthyroidism and were reassessed for inflammatory markers and cognitive dysfunction. Results: Nineteen patients (57%) had mild to moderate depression (MADRS >11). After 6 months of treatment, eight patients (42%) had remission of depression with significant improvement in QOL scores (P < 0.05). TNF-alpha, IL-6, and hs-CRP were significantly elevated in patients compared with controls and reduced with therapy but did not reach baseline as controls. The change in inflammatory markers correlated with improvement in QOL scores in social and environmental domains (P < 0.01). Conclusions: Primary autoimmune hypothyroidism is an inflammatory state characterized by elevated cytokines which decline with LT4 therapy. It is associated with depression and poor quality of life. Treatment of hypothyroidism results in alleviation of depression in the majority of patients. Similarly, patients with mild to moderate depression should be tested for hypothyroidism as simple treatment may ameliorate their depression and improves MADRS score and QOL. PMID- 29285456 TI - Gemigliptin: Newer Promising Gliptin for Type 2 Diabetes Mellitus. AB - The dipeptidyl peptidase-4 (DPP-4) inhibitors have facilitated the management of type 2 diabetes mellitus (T2DM) owing to their superior efficacy and safety with low incidence of adverse effects. Gemigliptin is a new member of this family of drugs, and studies have revealed certain advantages of gemigliptin use compared to its previous congeners. Besides, this drug has also been studied for the treatment of T2DM as monotherapy, in combination with metformin or other oral antidiabetic drugs and in T2DM with moderate-to-severe renal failure. In this review, we explore the published data highlighting the pharmacology, efficacy, and safety of gemigliptin along with its recommendations for use in patients with T2DM. PMID- 29285455 TI - Bhagavad Gita for the Physician. AB - This communication presents verses from the Bhagavad Gita which help define a good clinician's skills and behavior. Using the teachings of Lord Krishna, these curated verses suggest three essential skills that a physician must possess: Excellent knowledge, equanimity, and emotional attributes. Three good behaviors are listed (Pro-work ethics, Patient-centered care, and Preceptive leadership) and supported by thoughts written in the Gita. PMID- 29285457 TI - Osteogenesis Imperfecta. AB - Osteogenesis imperfecta is a common heritable connective tissue disorder. Nearly ninety percent are due to Type I collagen mutations. Type I-IV are autosomal dominant, and Type VI-XIII are autosomal recessive. They are Graded 1-5 based on severity. Genomic testing is done by collagen analysis from fibroblasts. The mainstay of treatment is bisphosphonate therapy. The prognosis is variable. PMID- 29285460 TI - Prevalence of Pharamcologically-treated Diabetes in Term Pregnancies in Haryana, India. AB - Gestational diabetes mellitus (GDM) is common in pregnancy. Epidemiological studies have described the prevalence of GDM in the antenatal period, but do not assess the number of women who require pharmacological therapy at term. This information is important for obstetric care providers and health planners. We reviewed indoor charts of all women admitted for delivery at a maternity center in Karnal, Haryana, India. Of the 569 participants, 0.87% had preexisting diabetes, while 1.93% were being treated with drugs for GDM (0.70% insulin, 1.23% metformin). The overall prevalence of diabetes needing drug therapy at time of delivery in pregnant women was 2.81%. PMID- 29285461 TI - Sulfonylureas: Scoring beyond START STUDY. PMID- 29285462 TI - Leptin Receptors can be an Alternative Target for New Anti-hypertensive Drug Development. PMID- 29285459 TI - The Heart of the Matter: Cardiac Manifestations of Endocrine Disease. AB - Endocrine disorders manifest as a disturbance in the milieu of multiple organ systems. The cardiovascular system may be directly affected or alter its function to maintain the state of homeostasis. In this article, we aim to review the pathophysiology, diagnosis, clinical features and management of cardiac manifestations of various endocrine disorders. PMID- 29285458 TI - Sodium-glucose Cotransporter-2 Inhibitors: Moving Beyond the Glycemic Treatment Goal. AB - Revelations of the multifactorial pathogenesis of type 2 diabetes mellitus (T2DM) that extend beyond the role of insulin and glucose utilization have been crucial in redefining the treatment paradigm. The focus of treatment is currently directed towards achieving wide-ranging targets encompassing the management of cardiovascular comorbidities that have been evidenced as indispensable aspects of T2DM. While most currently prescribed antihyperglycemic agents have little or no effect on reducing cardiovascular risks, some have been associated with undesirable effects on common risk factors such as weight gain and cardiovascular sequelae. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are newer additions to the array of therapeutic agents for T2DM that have demonstrated robust glycemic control as mono and add-on therapies. Their unique renal mode of action, independent of insulin modulation, confers complementary metabolic benefits. By virtue of these effects, SGLT2i may have a distinct role in the revised treatment recommendations by established working groups such as the American Diabetes Association and the American Association of Clinical Endocrinologists that advocate a more comprehensive management of T2DM, not restricting to glycemic targets. The current review gives an overview of the changing treatment needs for T2DM and discusses the nonglycemic effects of SGLT2i. It provides an updated summary on the efficacy of canagliflozin, dapagliflozin, and empagliflozin in promoting weight loss, stabilizing blood pressure, and other favorable metabolic effects. PMID- 29285463 TI - Karma and Diabetes Mellitus. PMID- 29285464 TI - Preservation of Thyrotroph Function in Sheehan's Syndrome. PMID- 29285465 TI - Primary Antiphospholipid Antibody Syndrome Presenting as Unilateral Adrenal Hemorrhage. PMID- 29285466 TI - Gestational Diabetes Mellitus Training: A Well-grounded Approach for Safeguarding Two Generations. PMID- 29285468 TI - Self-reported Knowledge, Attitude and Consumption of Sugar-sweetened Beverages among Undergraduate Oral Health Students at a University in South Africa. AB - Aims and Objectives: This study assessed the knowledge, attitude and consumption of sugar-sweetened beverages (SSBs) and its association with body mass index (BMI) among undergraduate oral health students. Materials and Methods: A cross sectional design was used and the study was conducted at a South African dental university. Undergraduate dental and oral hygiene students (n = 344) registered in 2015 were invited to participate. A self-administered questionnaire was used to elicit the necessary information. Data analysis included frequencies and correlations using Chi-square tests. Statistical significance was set at P < 0.05. Results: The response rate was 88% (301) and the mean age was 22.3 years (range: 17-42; standard deviation +/-3.2). The majority were female (72%) and 70% of respondents had an acceptable level of knowledge on the types of SSBs and possible health conditions if consumed excessively. Almost half (46%) had a positive attitude toward the consumption of SSBs. Clinical students had a significantly higher level of knowledge compared to nonclinical students (P = 0.03). Participants consumed an average of six teaspoons (+/-9.5) of sugar from SSBs daily. Those with poor knowledge and attitude consumed significantly more SSBs (P < 0.01) than those with higher levels of knowledge and attitude. Males were significantly more obese and overweight than females (P < 0.01). There was no association between the amount of sugar consumed from SSBs and the BMI. Conclusions: The knowledge and attitude toward SSBs was acceptable. Although sugar consumption from SSBs was relatively high, there was no significant correlation between the consumption of SSBs and the BMI. PMID- 29285467 TI - Role of Cone Beam Computed Tomography in Diagnosis and Treatment Planning in Dentistry: An Update. AB - Accurate diagnosis and treatment planning are the backbone of any medical therapy; for this reason, cone beam computed tomography (CBCT) was introduced and has been widely used. CBCT technology provides a three-dimensional image viewing, enabling exact location and extent of lesions or any anatomical region. For the very same reason, CBCT can not only be used for surgical fields but also for fields such as endodontics, prosthodontics, and orthodontics for appropriate treatment planning and effective dental care. The aim and clinical significance of this review are to update dental clinicians on the CBCT applications in each dental specialty for an appropriate diagnosis and more predictable treatment. PMID- 29285469 TI - Bonding System Choice and Practices among Senior Dental Students. AB - Aim and Objective: This survey investigated bonding system type and composite application rationale by senior dental students at a dental school in Saudi Arabia. Materials and Methods: Eighty-three questionnaires with 15 open and closed questions were randomly distributed to final year dental students about the use of etch and rinse versus self-etch adhesives and application techniques for posterior resin composite. Data were collected, and statistical analysis was done using Chi-square test (0.05) with two factors "question answer" and "gender." Results: For all questions, the impact of gender was statistically nonsignificant (P > 0.05). Etch and rinse adhesive was significantly (P > 0.05) favored by students with majority do not perform selective etching, use intermittent air for drying tooth structure, apply a single layer bonding agent and thin it by air, cure it for 20 s with the curing tip at close proximity to the cavity, use incremental application technique for composite restorations, cure it for 40 s, and neglect to do extra curing. Conclusion: Students showed good knowledge regarding the bonding and composite application steps but with some clear mispractices such as low frequency of selective etching, less etchant washing, and the preference of vertical layering. Moreover, results from the current investigation should direct curricular updates in the future. PMID- 29285470 TI - Oral Health Status among Children with Cerebral Palsy in Dubai, United Arab Emirates. AB - Objectives: The purpose of this study was to assess the oral health status of children with cerebral palsy (CP) in Dubai, United Arab Emirates (UAE). Materials and Methods: Eighty-four CP and 125 healthy children were recruited from special needs centers and private/public schools in Dubai. A dental examination for decayed-missing-filled teeth in primary dentition (dmft)/Decayed-Missing-Filled teeth in permanent dentition (DMFT) indices, simplified oral hygiene index, calculus index (CI), and oral debris index was conducted. In addition, assessments of occlusal, dentofacial, soft tissue anomalies and erosion were conducted. Statistical analysis was conducted using SPSS for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). Results: DMFT/dmft scores were comparable in both groups. CI was significantly higher among children with CP. CP patients had a significantly higher proportion of anterior open bite, anterior spacing, Class II molar Angle malocclusion, trauma, high-arched palate, tongue thrust, lymphadenopathy, angular cheilitis, macroglossia, drooling, and erosion as compared to controls. Conclusions: The study highlighted peculiar characteristics and needs for the CP patients in Dubai, UAE. PMID- 29285471 TI - BRCA1/2 Mutations in Salivary Pleomorphic Adenoma and Carcinoma-ex-Pleomorphic Adenoma. AB - Objectives: It is hypothesized that carcinoma-ex-pleomorphic adenoma (Ca-ex-PA) is malignant from the beginning or is a malignant transformation of a recurrent or a long-standing pleomorphic adenoma (PA). The accumulation of genetic instabilities is suggested to be the main reason for malignant transformation in PA. The aim of this study was to determine the prevalence of BRCA1/2 mutations in PA and Ca-ex-PA. Materials and Methods: A total of ninety salivary gland tumors (45 Ca ex-PA and 45 PA) were selected. Immunohistochemistry was performed for all samples. Analyses were conducted through SPSS software version 22.0 (SPSS, Inc., Chicago, IL, USA). Chi-square test was used to examine the differences between the variables. Significant level was set at 0.05. Results: In general, 93.3% of PA samples showed positive staining for BRCA1 (in myoepithelial cells); however, BRCA2 positivity was found in 60% of samples (in myoepithelial cells). Among 45 samples of Ca-ex-PA, 93.3% of showed positivity for BRCA1 and 80% of samples showed positivity for BRCA2. Chi-square test found differences between PAs and Ca ex-PAs regarding BRCA1/2 mutations in ductal cells and myoepithelial cells (P = 0.007, 0.000), respectively. Conclusions: The present study found a trend toward the presence of BRCA1/2 mutations in PA and Ca-ex-PA samples. Patients with BRCA1/2 mutation carriers are excellent cases for therapies, such as the poly (ADP) ribose polymerase inhibitor. PMID- 29285472 TI - Screening Projects for Oral Carcinoma in Relation to Health Education and Patients' Compliance: Study on 600 Participants. AB - Aims and Objectives: The lack of information among the population regarding the existence of oral squamous cell carcinoma (OSCC) and the lack of attention and expertise in examining the oral cavity of dentists and clinicians still remain very worrying and could explain the high incidence of OSCC. The aim of this study is to evaluate the level of awareness of OSCC among 600 participants from Southern Italy. Materials and Methods: A 13-question survey was prepared and distributed to 600 participants divided into two subgroups, the first one of 300 patients referring to the Department of Neuroscience, Reproductive, and Odontostomatological Sciences, University Federico II of Naples, for the treatment of dental pathologies, and the second one of 300 patients referring to the Department of Internal Medicine of the Second University of Naples for the diagnosis and treatment of cardiovascular diseases. Statistical analysis consisted in the calculation of percentages related to the answers given by patients. Comparison of percentages was after performed between the two subgroups. Result: Only 175 participants (29.1%) knew about the existence of pathologies which can affect the oral mucosa, and only 46 (7.6%) were aware that carcinoma can arise in the oral cavity; 345 (57,5%) stated that they had periodical dental visits, at least once a year but none of them stated they had a visit for the identification of oral carcinomas. Conclusion: The data acquired must be taken into consideration to outline essential socio-healthcare educational projects on carcinoma and its risk factors, training programs to increase dentists and clinicians' competences, and to evaluate the feasibility and effectiveness of oral carcinoma screening programs. PMID- 29285473 TI - Mother's Work Status on Children's Bruxism in a Subset of Saudi Population. AB - Aims and Objectives: The aims and objectives of this study were to determine if an association exists between mothers work status and her children's incidence of bruxism and habits related to bruxism. Materials and Methods: A cross-sectional study was conducted through data collection of a questionnaire answered by 561 mothers' about their working status and their child's habits and behaviors. The survey consisted of 5 parts with a total of 34 questions: mother's information, child's behavior, child's sleeping pattern, mother's knowledge about bruxism, and child's medical history. Odds ratios, Chi-square, and their corresponding 95% confidence intervals are reported. Statistical significance was set at P <= 0.05. Results: The work status of the mother was not statistically significant in increasing the incidence of a child to have bruxism. However, this study clearly elucidates that 7 of the 15 habits correlate significantly with a status of bruxism. According to this sample, a child, that is, reported to be aggressive is more than twice as likely to have nocturnal bruxism. Likewise, any child that bites their nails, complains of headaches, drools in their sleep, snores, complains of muscle cramps, and colic is more than twice as likely to be a nocturnal bruxer than a child that does not have these habits. Conclusion: The prevalence of children's bruxism in this convenient sample was 34.5% (n = 141). The concerning habits related to bruxism can serve the pediatric dentist, general dentist, general practitioner, and primary care provider of children having these red flags as indicators of bruxism. It is imperative that parents of these children be made aware these habits that may occur together, alone or even simultaneously with bruxism. PMID- 29285474 TI - An Assessment of Teaching and Learning Practices: A Questionnaire Study for Dental Educators of Karnataka. AB - Aims and Objectives: Faculty members of dental institutions are being asked to assume new academic duties for which they have received no formal training. To succeed in new teaching tasks, faculty development through assessment of teaching skills is essential. Materials and Methods: A Self-Assessment Questionnaire consisting 18 closed-ended questions was sent to various faculty members of dental colleges of Karnataka. A total of 210 faculty members volunteered to participate in the study. The response rate was 69.8%. Data gathered were statistically analyzed using SPSS software version 16, Chi-square test, and descriptive statistics. Results: In the present study, 27.3% of participants were unaware of andragogy, 33.3% were unaware of teachers development programs, 44.6% do not obtain student feedback after teaching, 52.6% were unaware of peer review of teaching skills, and 50% were unaware of interprofessional education initiatives. Conclusion: By incorporating teaching and learning skills, dental faculty could acquire competencies and academic credentials to become valuable contributors to the institution. This study emphasizes the areas of improvement in dental school learning environment, based on activation of prior knowledge, elaboration of new learning, learning in context, transfer of learning, and organization of knowledge toward learning. PMID- 29285475 TI - Impact of Oral Health Education on Oral Health Knowledge of Private School Children in Riyadh City, Saudi Arabia. AB - Aims and Objectives: To assess the early effect of oral health education on oral health knowledge of primary and intermediate school students of private schools by utilizing pre/post questionnaires data from oral health educational projects in Riyadh city, Saudi Arabia. Second, to examine topic-specific knowledge differences between genders, nationalities, and educational levels of the students. Materials and Methods: Cross-sectional oral health educational data of private school students (n = 1279) in primary and intermediate levels were extracted from the King Salman Centre for Children's Health (KSCCH) projects undertaken by Riyadh Colleges of Dentistry and Pharmacy. Student's pre- and post test data were analyzed for changes in oral health knowledge. Overall knowledge score and topic-specific knowledge scores were calculated and the differences between gender, nationality, and educational level were examined using Mann Whitney U-test. Pre/post change in the oral health knowledge was evaluated by Wilcoxon's sign rank test. Results: Immediately, after oral health educational session high knowledge score category showed an increase of 25.6%, medium and low knowledge score categories showed -3.2% and -22.3% decrease, and this change was statistically significant (P < 0.001). Comparison of correct responses between pre- and post-test showed statistically significant (P < 0.05) increase in all the questions except for the timing of tooth brushing. Females, non-Saudi nationals and students in primary level of education showed significantly high mean knowledge (P < 0.001) at posttest assessment. Conclusion: Primary and intermediate private school student's overall, and topic-specific oral health knowledge improved immediately after educational intervention provided by KSCCH. High knowledge gain was observed among female non-Saudi primary school students. PMID- 29285476 TI - Vitamin D Status in Small Vessel and Large Vessel Ischemic Stroke Patients: A Case-control Study. AB - Background: Vitamin D insufficiency is a globally widespread issue. Recent studies have reported a high prevalence of Vitamin D deficiency in Middle-East countries. Studies have shown negative effects of Vitamin D deficiency on endothelium and related diseases such as ischemic brain stroke. Here, we assessed Vitamin D status in patients with different types of ischemic brain stroke and control group. Materials and Methods: Seventy-five patients (49.3% small vessel, 50.7% large vessel) and 75 controls, matched for age (68.01 +/- 10.94 vs. 67.64 +/- 10.24) and sex (42 male and 33 female) were recruited. 25(OH) D levels were measured by Chemiluminescence immunoassay. 25(OH) D status was considered as severely, moderately, or mildly deficient and normal with 25(OH) D levels of less than 5, 5-10, 10-16, and >16 ng/ml, respectively. Results: Mean +/- standard error concentration of 25(OH) D in cases and controls were 17.7 +/- 1.5 and 26.9 +/- 1.6 (P = 0.0001), respectively. Mild, moderate, and severe Vitamin D deficiency were observed in 10.8%, 32.4%, 8.1% vs. 34.3%, 31.5%, 9.5% of small vessel and large vessel group, respectively. 21.7% of the controls were Vitamin D deficient. Vitamin D deficiency was significantly associated with higher risk for ischemic stroke, (P = 0.000, OR = 7.17, 95% confidence interval: 3.36-15.29). 25(OH) D levels were significantly higher in control group comparing to small vessel (26.9 +/- 1.6 vs. 20.59 +/- 2.6 P < 0.05) and large vessel (26.9 +/- 1.6 vs. 13.4 +/- 1.3 P < 0.001) stroke patients. Small vessel group had significantly higher levels of Vitamin D than large vessel (P < 0.05). Conclusion: Vitamin D deficiency significantly increases the risk of ischemic stroke, favoring the types with the pathogenesis of large vessel strokes. PMID- 29285478 TI - Multiple Intelligences Profiles of Children with Attention Deficit and Hyperactivity Disorder in Comparison with Nonattention Deficit and Hyperactivity Disorder. AB - Background: Attention deficit and hyperactivity disorder (ADHD) is a common psychological problem during childhood. This study aimed to evaluate multiple intelligences profiles of children with ADHD in comparison with non-ADHD. Materials and Methods: This cross-sectional descriptive analytical study was done on 50 children of 6-13 years old in two groups of with and without ADHD. Children with ADHD were referred to Clinics of Child and Adolescent Psychiatry, Isfahan University of Medical Sciences, in 2014. Samples were selected based on clinical interview (based on Diagnostic and Statistical Manual of Mental Disorders IV and parent-teacher strengths and difficulties questionnaire), which was done by psychiatrist and psychologist. Raven intelligence quotient (IQ) test was used, and the findings were compared to the results of multiple intelligences test. Data analysis was done using a multivariate analysis of covariance using SPSS20 software. Results: Comparing the profiles of multiple intelligence among two groups, there are more kinds of multiple intelligences in control group than ADHD group, a difference which has been more significant in logical, interpersonal, and intrapersonal intelligence (P < 0.05). There was no significant difference with the other kinds of multiple intelligences in two groups (P > 0.05). The IQ average score in the control group and ADHD group was 102.42 +/- 16.26 and 96.72 +/- 16.06, respectively, that reveals the negative effect of ADHD on IQ average value. There was an insignificance relationship between linguistic and naturalist intelligence (P > 0.05). However, in other kinds of multiple intelligences, direct and significant relationships were observed (P < 0.05). Conclusions: Since the levels of IQ (Raven test) and MI in control group were more significant than ADHD group, ADHD is likely to be associated with logical-mathematical, interpersonal, and intrapersonal profiles. PMID- 29285477 TI - Pseudomonas aeruginosa-producing Metallo-beta-lactamases (VIM, IMP, SME, and AIM) in the Clinical Isolates of Intensive Care Units, a University Hospital in Isfahan, Iran. AB - Background: Pseudomonas aeruginosa is a severe challenge for antimicrobial therapy, due to the chromosomal mutations or exhibition of intrinsic resistance to various antimicrobial agents such as most beta-lactams. We undertook this study to evaluate the existence of SME, IMP, AIM, and VIM metallo-beta-lactamases (MBL) encoding genes among P. aeruginosa strains isolated from Intensive Care Unit (ICU) patients in Al-Zahra Hospital in Isfahan, Iran. Materials and Methods: In a retrospective cross-sectional study that was conducted between March 2012 and April 2013, a total of 48 strains of P. aeruginosa were collected from clinical specimens of bedridden patients in ICU wards. Susceptibility test was performed by disc diffusion method. All of the meropenem-resistant strains were subjected to modified Hodge test for detection of carbapenemases. Multiplex polymerase chain reaction was performed for detection of blaVIM, blaIMP, blaAIM, and blaSME genes. Results: In disk diffusion method, imipenem and meropenem showed the most and colistin the least resistant antimicrobial agents against P. aeruginosa strains. Of the 48 isolates, 36 (75%) were multidrug resistant (MDR). Amplification of beta-lactamase genes showed the presence of blaVIM genes in 7 (%14.6) strains and blaIMP genes in 15 (31.3%) strains. All of the isolates were negative for blaSME and blaAIM genes. We could not find any statistically significant difference among the presence of this gene and MDR positive, age, or source of the specimen. Conclusion: As patients with infections caused by MBL producing bacteria are at an intensified risk of treatment failure, fast determination of these organisms is necessary. Our findings may provide useful insights in replace of the appropriate antibiotics and may also prevent MBLs mediated resistance problem. PMID- 29285479 TI - Comparison of Sub-Bowman Keratoplasty Laser In situ Keratomileusis Flap Properties between Microkeratome and Femtosecond Laser. AB - Background: Since thin and high-quality flaps produce more satisfactory surgical outcomes, flaps created by mechanical microkeratomes are more economical as compared with femtosecond lasers, and no Iranian study has concentrated laser in situ keratomileusis (LASIK) flap peculiarities between Moria Sub-Bowman keratoplasty (SBK) microkeratomes and LDV femtoseconds, the present study compares and contrasts them. Materials and Methods: This cross-sectional study was done on all patients who underwent LASIK surgery 1-month before this study. Thirty eyes were divided into per group. Flaps in the first group and second group were created, respectively, using Moria SBK microkeratome and LDV femtosecond laser. The other stages of LASIK were done equally in both groups. One month after surgery, the thickness of flaps was measured by anterior segment optical coherence tomography in five regions of flaps. Corneal anterior density was calculated and recorded 1-month after surgery using pentacam and by employing optical densitometry in a distance in the limit range of 0-6 mm from cornea center. Densitometry measurements were obtained and expressed in standardized grayscale units (GSUs). Results: Postsurgery densitometry results reveal that anterior densities of cornea in limit range of 0-2 mm in groups of LDV femtosecond laser and Moria microkeratome are 21.35 +/- 0.87 GSU and 22.85 +/- 1.25 GSU, respectively. Accordingly, these two groups are significantly different in this regard (P < 0.001). Moreover, anterior densities of the cornea in the limit range of 2-6 mm in these groups are 19.66 +/- 0.99 GSU and 20.73 +/- 1.24 GSU, respectively. Accordingly, these two groups are significantly different in this regard (P = 0.04). There is a lower mean of flap thickness in the case of LDV femtosecond laser. Conclusion: Femtosecond laser method is greatly preferred as compared with Moria microkeratome because of greater homogeneity in flap thickness, smaller thickness, and lower density in optical zone. PMID- 29285480 TI - Comparison Study on the Effect of Treatment Decision Based on Renal Biopsy and Clinical Symptoms in the Outcome of Patients with Recurrent Lupus Nephritis. AB - Background: Renal involvement in systemic lupus erythematous is one of the most serious complications. The aim of this study was to compare the effects of treatment decisions based on clinical symptoms and renal biopsy on the outcome of patients with recurrent lupus nephritis. Materials and Methods: This descriptive study was conducted in 2012-13 in the Alzahra hospital on patients with lupus nephritis who had referred to the rheumatology clinic of this center due to lupus nephritis relapse. All lupus nephritis patients were diagnosed with renal biopsy and had gone into remission by treatment but due to the discontinuation of treatment and other causes had relapsed. The patients were divided randomly into two groups of 26, the first group was treated without renal biopsy and based on clinical and laboratory symptoms and the second group was re-biopsied through considering the ethical points. Then their relationship with laboratory findings (BUN, Cr, ANA, ds-DNA, C3, C4, CH50, U/A, cast, and proteinuria), treatment and recurrence outcome were compared between the two groups. Results: The mean of SLEDAI-2K index before initial treatment, after the first round of treatment and after the second round of treatment in single biopsy group and twice biopsy group is not significantly different (P = 0.27). Conclusions: Treatment decisions based on clinical and laboratory findings or re-biopsy of the kidney in patients who relapsed after initial treatment had no significant effect on the recovery of patients. Adoption of a treatment plan in patients with lupus nephritis is recommended based on clinical and laboratory finding and the discretion of the physician and if possible, kidney re-biopsy should be avoided. PMID- 29285481 TI - Comparing the Frequency of Endometritis in Unexplained Infertility and Anovulatory Infertility. AB - Background: Acute pelvic inflammatory disease (PID) is a common reason for infertility. This study aimed to evaluate the frequency distribution of endometritis in women with unexplained infertility and comparison with frequency distribution of endometritis in anovulatory infertility to identify the importance of endometritis due to subacute PID evaluation in the case of infertility. Materials and Methods: This case-control study was done on 100 women with unexplained infertility and ovulatory infertility who referred to Shahid Beheshti clinic in 2013 in Isfahan, Iran. They were divided into two groups of unexplained infertility and anovulatory infertility. Endometrial samples were given from all the patients by Pipelle biopsy under sterile conditions, and then prepared samples were sent to the pathology laboratory to evaluate the existence of plasma cells by a pathologist to diagnose endometritis. Results: Frequency distribution of acute PID history among the patients in both groups showed a significant difference (P < 0.05). Prevalence of endometritis in unexplained infertility group was 34% and in anovulatory group was 21% (P < 0.05). Prevalence of vaginitis was 46% in unexplained group and 40% in anovulatory group (P < 0.05), and prevalence of PID was 4% in unexplained infertility group and 0% in anovulatory infertility group. Conclusion: The prevalence of endometritis and vaginitis was more in the unexplained infertility group rather than the anovulatory infertility group that may reveal the importance of endometritis evaluation in the cases of unexplained infertility. PMID- 29285482 TI - Analysis of Factors Affecting the Body Mass Index in a National Sample of Iranian Children and Adolescents: Bootstrapping Regression. AB - Background: This study aims to evaluate the effect of some factors, including birth weight, sex, age, waist circumference, family history of obesity, as well as some lifestyle factors as frequency of breakfast days and physical activity, on the body mass index among a nationally representative sample of Iranian children and adolescents by using bootstrapping regression. Materials and Methods: This study was conducted as the third survey of a school-based surveillance system (CASPIAN-III study). Total participants were 5570 school students, aged 10-18 years, selected by multistage random cluster sampling from urban and rural areas of 27 provinces of Iran. Multiple linear regressions was used to evaluate the effect of various factors on obesity, but in our data the assumptions of this model violated, and possible solutions were not appropriate, therefore the bootstrapping regression based on the observations and errors resampling approaches was used as an alternative. Results: The tests of significance showed that the effects of sex, age, waist circumference, family history obesity and frequency of breakfast days were clearly significant (P < 0.001). The effect of vigorous level of physical activity was significant in comparison to mild physical activity (P = 0.01). In comparison to low birth weight, medium and high birth weight had significant effect on obesity. Conclusions: Bootstrap method is preferable in linear regression because of some theoretical properties like having any distributional assumptions on the residuals and hence allows for inference even if the errors do not follow normal distribution or constant error variance. PMID- 29285483 TI - An Evaluation of Ultrasound Features of Breast Fibroadenoma. AB - Background: Breast cancer is among the most common cancers in the world. Ultrasound evaluations of breast have come into attention as an alternative route. Ultrasound features of benign lesions such as fibroadenoma can be overlapping with those in a malignant tumor. Here, we assessed the reports of breast ultrasound in patients with pathologic diagnosis of fibroadenoma. Materials and Methods: We conducted a cross-sectional study and enrolled female patients with confirmed histologic diagnosis of fibroadenoma. Ultrasound studies were performed on the participants to see which sonographic patterns are more frequent in such lesions. Results: In 92 patients with 40.4 +/- 9.2 years of age, all participants were classified as stage 4 on Breast Imaging-Reporting and Data System scale. The mean +/- standard deviation of size for the lesions was 167.4 +/- 101.4 mm2. Upper outer quadrants in the breasts had the most number of lesions. Almost lesions were round with only 2.2% were oval. When assessed for the margin definition, 57.8% were circumscribed. Noncircumscribed masses were reported in 21.7%. About 91.3% of cases were hypoechoic in the ultrasound evaluation. Lobulated masses were in 28.3% of the cases. 8.7% of the masses were spongy whereas 9.8% and 2.2% of them had calcification and heterogenic appearance, respectively. Conclusion: The most frequent features include a hypoechoic mass with a circumscribed border; however, complex presentations that overlap malignant masses are also detectable including noncircumscribed margin, lobulation, presence of a posterior shadow, heterogenicity, and micro calcification. PMID- 29285484 TI - Undesired Outcomes of the Catania Stent Compared to the Xience Stent in Patients Undergoing Angioplasty: A Double-Blind Randomized Controlled Trial. AB - Background: The present study tries to compare the unintended outcomes of the Catania stent versus Xience stent in patients undergoing angioplasty. Materials and Methods: In a three month, follow-up, double-blinded, randomized controlled trial, 83 patients undergoing angioplasty, who met the inclusion criteria were entered into the study. After randomization 43 patients were treated with the Xience stent and 40 patients with the Catania stent. Stent-related outcomes such as Cardiac and Non-Cardiovascular Death, Myocardial Infarction (MI), Target Lesion Revascularization (TLR), Stent Thrombosis (ST), Coronary Artery Bypass Grafting (CABG), Peripheral vasculopathy, and Cerebral Vascular Accident (CVA) were compared between the groups. Results: There was no statistically significant difference in the incidence rate of complications and clinical outcomes between the two treatment groups (P > 0.05). The incidence of MI, TLR, CABG operation, peripheral vasculopathy, or CVA was not observed in any patient and there was no statistically difference in mortality (4.7% vs. 2.5%; P = 0.527) and stent thrombosis (2.3% vs. 2.5%; P = 0.735). Conclusion: All in all, the present study could not find the significant differences between the Catania stent and Xience stent in terms of clinical outcomes during the follow-up period. PMID- 29285486 TI - Erratum: Distribution of the Strains of Multidrug-resistant, Extensively Drug resistant, and Pandrug-resistant Pseudomonas aeruginosa Isolates from Burn Patients. AB - [This corrects the article on p. 74 in vol. 6, PMID: 28706882.]. PMID- 29285485 TI - A Novel Prokaryotic Green Fluorescent Protein Expression System for Testing Gene Editing Tools Activity Like Zinc Finger Nuclease. AB - Background: Gene editing technology has created a revolution in the field of genome editing. The three of the most famous tools in gene editing technology are zinc finger nucleases (ZFNs), transcription activator-like effector nucleases, clustered regularly interspaced short palindromic repeats (CRISPR), and CRISPR associated systems. As their predictable nature, it is necessary to assess their efficiency. There are some methods for this purpose, but most of them are time labor and complicated. Here, we introduce a new prokaryotic reporter system, which makes it possible to evaluate the efficiency of gene editing tools faster, cheaper, and simpler than previous methods. Materials and Methods: At first, the target sites of a custom ZFN, which is designed against a segment of ampicillin resistance gene, were cloned on both sides of green fluorescent protein (GFP) gene to construct pPRO-GFP. Then pPRO-GFP was transformed into Escherichia coli TOP10F' that contains pZFN (contains expression cassette of a ZFN against ampicillin resistant gene), or p15A-KanaR as a negative control. The transformed bacteria were cultured on three separate media that contained ampicillin, kanamycin, and ampicillin + kanamycin; then the resulted colonies were assessed by flow cytometry. Results: The results of flow cytometry showed a significant difference between the case (bacteria contain pZFN) and control (bacteria contain p15A, KanaR) in MFI (Mean Fluorescence Intensity) (P < 0.0001). Conclusion: According to ZFN efficiency, it can bind and cut the target sites, the bilateral cutting can affect the intensity of GFP fluorescence. Our flow cytometry results showed that this ZFN could reduce the intensity of GFP color and colony count of bacteria in media containing amp + kana versus control sample. PMID- 29285487 TI - Corrigendum: SimAlba: A Spatial Microsimulation Approach to the Analysis of Health Inequalities. AB - [This corrects the article on p. 230 in vol. 4, PMID: 27818989.]. PMID- 29285489 TI - Masked hypertension. PMID- 29285488 TI - Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes. AB - Background: Based on a single placebo-controlled randomized clinical trial, empagliflozin is licensed to reduce cardiovascular death in diabetes and comorbid cardiovascular disease. Methods: We examined the comparative effectiveness of empagliflozin on mortality and cardiovascular morbidity in type 2 diabetes. We conducted random-effects direct frequentist meta-analyses of aggregate data and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to May 2017 identified 11 meta-analyses, multiple publications, and unpublished data from 29 randomized controlled trials (RCTs). Results: Empagliflozin reduces all cause mortality [relative risk (RR) of death, 0.69; 95% confidence interval (CI): 0.58-0.82; number needed to treat (NNT) to postpone mortality in one patient, 39; 95% CI: 26-79; 1 RCT of 7,020 patients) in patients with but not without (RR, 0.90; 95% CI: 0.36-2.23; 14 RCTs of 7,707 patients) established cardiovascular disease when compared with placebo. Empagliflozin reduces cardiovascular mortality (RR, 0.62; 95% CI: 0.50-0.78; NNT, 45; 95% CI: 30-90; 1 RCT of 7,020 patients) in patients with but not without (RR, 0.98; 95% CI: 0.29-3.33; 10 RCTs of 5,429 patients) established cardiovascular disease when compared with placebo. There are no differences in cardiovascular morbidity and mortality and all-cause mortality between empagliflozin and metformin (4 RCTs of 1,344 patients), glimepiride (1 RCT of 1,549 patients), linagliptin (2 RCTs of 1,348 patients), or sitagliptin (3 RCTs of 1,483 patients). Two network meta-analyses concluded that sodium-glucose cotransporter 2 (SGLT2) inhibitors, mostly due to empagliflozin, decrease all-cause and cardiovascular mortality but increase the risk of nonfatal stroke, genital infection, and volume depletion. Conclusions: We conclude that empagliflozin reduces all-cause and cardiovascular mortality in patients with established cardiovascular disease and type 2 diabetes. Sparse direct evidence suggests no difference in mortality between empagliflozin and metformin, glimepiride, linagliptin, or sitagliptin. Long-term comparative safety needs to be established. PMID- 29285490 TI - Hypertension associated with atrial fibrillation. PMID- 29285491 TI - Detection of MET amplification in gastroesophageal tumor specimens using IQFISH. AB - Background: The gene mesenchymal epithelial transition factor (MET) is a proto oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. MET is found to be amplified in several human cancers including gastroesophageal cancer. Methods: Here we report the MET amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, MET/CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay]. MET amplification was defined as a MET/CEN-7 ratio >=2.0. Furthermore, the link between the MET signal distribution and amplification status was investigated. Results: The prevalence of MET amplification was found to be 6.9%. The FISH assay demonstrated a high inter-observer reproducibility. The inter-observer results showed a 100% overall agreement with respect to the MET status (amplified/non amplified). The inter-observer CV was estimated to 11.8% (95% CI: 10.2-13.4). For the signal distribution, the inter-observer agreement was reported to be 98.7%. We also report an association of MET amplification and a unique signal distribution pattern in the G/GEJ/E tumor specimens. We found that the prevalence of MET amplification was markedly higher in tumors specimens with a heterogeneous (66.7%) versus homogeneous (2.0%) signal distribution. Furthermore, specimens with a heterogeneous signal distribution had a statically significantly higher median MET/CEN-7 ratio (2.35 versus 1.04; P<0.0001). Conclusions: The novel FISH assay showed a high inter-observer reproducibility both with respect to amplification status and signal distribution. Based on the finding in the study it is suggested that MET amplification mainly is associated with tumor cells that is represented by a heterogonous growth pattern. PMID- 29285492 TI - River blindness goes beyond the eye: autoimmune antibodies, cross-reactive with Onchocerca volvulus antigen, detected in brain of patients with Nodding syndrome. PMID- 29285493 TI - Alectinib in untreated anaplastic lymphoma kinase-positive non-small cell lung cancer. PMID- 29285494 TI - New evidence for nodding disease as an autoimmune reaction to Onchocerca volvulus. PMID- 29285495 TI - Antibody-drug conjugate targeting protein tyrosine kinase 7, a receptor tyrosine kinase-like molecule involved in WNT and vascular endothelial growth factor signaling: effects on cancer stem cells, tumor microenvironment and whole-body homeostasis. PMID- 29285496 TI - Creative technology advances tissue preservation. PMID- 29285497 TI - Drugs targeting protease-activated receptor-4 improve the anti-thrombotic therapeutic window. PMID- 29285498 TI - Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. PMID- 29285499 TI - Prediction models to advance individualized resuscitation in trauma hemorrhage and acute traumatic coagulopathy (ATC): even the longest journey starts with first steps-Lao-Tzu (Chinese philosopher). PMID- 29285500 TI - Novel regulators of PD-L1 expression in cancer: CMTM6 and CMTM4-a new avenue to enhance the therapeutic benefits of immune checkpoint inhibitors. PMID- 29285501 TI - Predictors of response and resistance to checkpoint inhibitors in solid tumors. PMID- 29285502 TI - Nrf2: a promising trove for diabetic wound healing. PMID- 29285503 TI - Sodium-glucose cotransporter 2 inhibitors and death and heart failure in type 2 diabetes. PMID- 29285504 TI - Lysosomal function in beta-cell survival during glucolipotoxicity. PMID- 29285505 TI - Telomeric zinc-finger associated protein (TZAP): a new player in telomere diseases? PMID- 29285506 TI - Canagliflozin lowers blood sugar, but does it also lower cardiovascular risk? Maybe not. PMID- 29285507 TI - Comparative effectiveness of cardiovascular outcomes in new users of sodium glucose cotransporter-2 inhibitors: SGLT2 inhibitors in the real world. PMID- 29285508 TI - Semaglutide-the "new kid on the block" in the field of glucagon-like peptide-1 receptor agonists? PMID- 29285509 TI - Cardiovascular outcome studies with glucagon-like peptide 1 receptor agonists what will REWIND add? PMID- 29285510 TI - The ODYSSEY DM-DYSLIPIDEMIA trial: confirming the benefits of alirocumab in diabetic mixed dyslipidemia. PMID- 29285511 TI - Empagliflozin reduces albuminuria-a promise for better cardiorenal protection from the EMPA-REG OUTCOME trial. PMID- 29285512 TI - Liquid biopsy for ctDNA to revolutionize the care of patients with early stage lung cancers. AB - The current standard of adjuvant therapies for patients with early stage non small-cell lung cancers largely depends on the stage of disease. Liquid biopsy for circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease, depict genomic evolution, guide precision medicine to individual patients and revolutionize the management of early stage lung cancers. In light of the seminal work published by Abbosh and colleagues, we discuss the potential paradigm changing clinical implications of ctDNA, the biological and technological challenges to consider, and the future of ctDNA driven therapeutic studies. PMID- 29285513 TI - Radiation risk from lung cancer screening. PMID- 29285514 TI - Clinicopathological and Prognostic Role of Long Noncoding RNA Linc00152 in Various Human Neoplasms: Evidence from Meta-Analysis. AB - Recent researches have demonstrated that long noncoding RNA linc00152 was aberrantly upregulated in multiple tumor types. High expression of linc00152 was associated with poor outcomes in cancer patients. Therefore, we conducted this meta-analysis to evaluate its potential value as a prognostic predictor in various human neoplasms. Eligible studies were searched through several electronic databases including PubMed, Embase, Web of Science, and the Cochrane Library. Eight original studies including 752 cancer patients were ultimately enrolled. Statistical analysis suggested that overexpression of linc00152 was significantly correlated with unfavorable overall survival (OS) (HR = 2.05, 95% CI: 1.59-2.64) and disease-free/progression-free survival (DFS/PFS) (HR = 3.52, 95% CI: 1.82-6.79) in cancer patients. In addition, a significant correlation was observed between aberrant linc000152 expression and lymph node metastasis (LNM) (OR = 2.49, 95% CI: 1.57-3.94) but not in vessel invasion (VI) (OR = 1.02, 95% CI: 0.54-1.93) and distant metastasis (DM) (OR = 0.600, 95% CI: 0.213-1.689). Our meta-analysis demonstrated that high linc00152 expression significantly predicted inferior OS and DFS/PFS in multiple neoplasms, as well as advanced LNM and VI. Linc00152 may serve as a potential indicator in predicting poor outcomes and metastases of diverse cancers. PMID- 29285516 TI - Semisupervised learning using denoising autoencoders for brain lesion detection and segmentation. AB - The work explores the use of denoising autoencoders (DAEs) for brain lesion detection, segmentation, and false-positive reduction. Stacked denoising autoencoders (SDAEs) were pretrained using a large number of unlabeled patient volumes and fine-tuned with patches drawn from a limited number of patients ([Formula: see text], 40, 65). The results show negligible loss in performance even when SDAE was fine-tuned using 20 labeled patients. Low grade glioma (LGG) segmentation was achieved using a transfer learning approach in which a network pretrained with high grade glioma data was fine-tuned using LGG image patches. The networks were also shown to generalize well and provide good segmentation on unseen BraTS 2013 and BraTS 2015 test data. The manuscript also includes the use of a single layer DAE, referred to as novelty detector (ND). ND was trained to accurately reconstruct nonlesion patches. The reconstruction error maps of test data were used to localize lesions. The error maps were shown to assign unique error distributions to various constituents of the glioma, enabling localization. The ND learns the nonlesion brain accurately as it was also shown to provide good segmentation performance on ischemic brain lesions in images from a different database. PMID- 29285515 TI - Area PEc Neurons Use a Multiphasic Pattern of Activity to Signal the Spatial Properties of Optic Flow. AB - The cortical representation of visual perception requires the integration of several-signal processing distributed across many cortical areas, but the neural substrates of such perception are largely unknown. The type of firing pattern exhibited by single neurons is an important indicator of dynamic circuitry within or across cortical areas. Neurons in area PEc are involved in the spatial mapping of the visual field; thus, we sought to analyze the firing pattern of activity of PEc optic flow neurons to shed some light on the cortical processing of visual signals. We quantified the firing activity of 152 optic flow neurons using a spline interpolation function, which allowed determining onset, end, and latency of each neuronal response. We found that many PEc neurons showed multiphasic activity, which is strictly related to the position of the eye and to the position of the focus of expansion (FOE) of the flow field. PEc neurons showed a multiphasic activity comprised of excitatory phases interspersed with inhibitory pauses. This phasic pattern seems to be a very efficient way to signal the spatial location of visual stimuli, given that the same neuron sends different firing patterns according to a specific combination of FOE/eye position. PMID- 29285517 TI - Context-aware stacked convolutional neural networks for classification of breast carcinomas in whole-slide histopathology images. AB - Currently, histopathological tissue examination by a pathologist represents the gold standard for breast lesion diagnostics. Automated classification of histopathological whole-slide images (WSIs) is challenging owing to the wide range of appearances of benign lesions and the visual similarity of ductal carcinoma in-situ (DCIS) to invasive lesions at the cellular level. Consequently, analysis of tissue at high resolutions with a large contextual area is necessary. We present context-aware stacked convolutional neural networks (CNN) for classification of breast WSIs into normal/benign, DCIS, and invasive ductal carcinoma (IDC). We first train a CNN using high pixel resolution to capture cellular level information. The feature responses generated by this model are then fed as input to a second CNN, stacked on top of the first. Training of this stacked architecture with large input patches enables learning of fine-grained (cellular) details and global tissue structures. Our system is trained and evaluated on a dataset containing 221 WSIs of hematoxylin and eosin stained breast tissue specimens. The system achieves an AUC of 0.962 for the binary classification of nonmalignant and malignant slides and obtains a three-class accuracy of 81.3% for classification of WSIs into normal/benign, DCIS, and IDC, demonstrating its potential for routine diagnostics. PMID- 29285518 TI - Accounting for reconstruction kernel-induced variability in CT radiomic features using noise power spectra. AB - Large variability in computed tomography (CT) radiomics feature values due to CT imaging parameters can have subsequent implications on the prognostic or predictive significance of these features. Here, we investigated the impact of pitch, dose, and reconstruction kernel on CT radiomic features. Moreover, we introduced correction factors to reduce feature variability introduced by reconstruction kernels. The credence cartridge radiomics and American College of Radiology (ACR) phantoms were scanned on five different scanners. ACR phantom was used for 3-D noise power spectrum (NPS) measurements to quantify correlated noise. The coefficient of variation (COV) was used as the variability assessment metric. The variability in texture features due to different kernels was reduced by applying the NPS peak frequency and region of interest (ROI) maximum intensity as correction factors. Most texture features were dose independent but were strongly kernel dependent, which is demonstrated by a significant shift in NPS peak frequency among kernels. Percentage improvement in robustness was calculated for each feature from original and corrected %COV values. Percentage improvements in robustness of 19 features were in the range of 30% to 78% after corrections. We show that NPS peak frequency and ROI maximum intensity can be used as correction factors to reduce variability in CT texture feature values due to reconstruction kernels. PMID- 29285519 TI - Characterization and correction of intraoperative soft tissue deformation in image-guided laparoscopic liver surgery. AB - Laparoscopic liver surgery is challenging to perform due to a compromised ability of the surgeon to localize subsurface anatomy in the constrained environment. While image guidance has the potential to address this barrier, intraoperative factors, such as insufflation and variable degrees of organ mobilization from supporting ligaments, may generate substantial deformation. The severity of laparoscopic deformation in humans has not been characterized, and current laparoscopic correction methods do not account for the mechanics of how intraoperative deformation is applied to the liver. We first measure the degree of laparoscopic deformation at two insufflation pressures over the course of laparoscopic-to-open conversion in 25 patients. With this clinical data alongside a mock laparoscopic phantom setup, we report a biomechanical correction approach that leverages anatomically load-bearing support surfaces from ligament attachments to iteratively reconstruct and account for intraoperative deformations. Laparoscopic deformations were significantly larger than deformations associated with open surgery, and our correction approach yielded subsurface target error of [Formula: see text] and surface error of [Formula: see text] using only sparse surface data with realistic surgical extent. Laparoscopic surface data extents were examined and found to impact registration accuracy. Finally, we demonstrate viability of the correction method with clinical data. PMID- 29285520 TI - The range of confidence scales does not affect the relationship between confidence and accuracy in recognition memory. AB - Researchers use a wide range of confidence scales when measuring the relationship between confidence and accuracy in reports from memory, with the highest number usually representing the greatest confidence (e.g., 4-point, 20-point, and 100 point scales). The assumption seems to be that the range of the scale has little bearing on the confidence-accuracy relationship. In two old/new recognition experiments, we directly investigated this assumption using word lists (Experiment 1) and faces (Experiment 2) by employing 4-, 5-, 20-, and 100-point scales. Using confidence-accuracy characteristic (CAC) plots, we asked whether confidence ratings would yield similar CAC plots, indicating comparability in use of the scales. For the comparisons, we divided 100-point and 20-point scales into bins of either four or five and asked, for example, whether confidence ratings of 4, 16-20, and 76-100 would yield similar values. The results show that, for both types of material, the different scales yield similar CAC plots. Notably, when subjects express high confidence, regardless of which scale they use, they are likely to be very accurate (even though they studied 100 words and 50 faces in each list in 2 experiments). The scales seem convertible from one to the other, and choice of scale range probably does not affect research into the relationship between confidence and accuracy. High confidence indicates high accuracy in recognition in the present experiments. PMID- 29285523 TI - Acknowledgment of Ad Hoc Reviewers. PMID- 29285521 TI - Enhanced Differentiation of Human Preosteoblasts on Electrospun Blend Fiber Mats of Polydioxanone and Anionic Sulfated Polysaccharides. AB - The viability and differentiation of SaOS-2 preosteoblasts on fiber mats of blends comprising of the biodegradable poly(ester-ether) polydioxanone (PDX) and the sulfate-containing anionic polysaccharides kappa-carrageenan (KCG) and fucoidan (FUC) were investigated for a range of different blend compositions. The detailed analysis of the blend nanofiber properties revealed a different degree of miscibility of PDX and the polysaccharide leading to a different enrichment at the surface of the blend nanofibers, which were observed to be stable in phosphate buffer solution (PBS) for up to 5 weeks. The fibrous mats of PDX/FUC led to the highest osteogenic differentiation with very good cell viability. The electrospun blend fibers also supported human-induced pluripotent stem (iPS) cells and iPS cell-derived embryoid bodies with high cell viability, which underlines the potential of these novel blend fiber systems for optimized performance in bone tissue engineering applications. PMID- 29285522 TI - Cannabidiol Does Not Convert to Delta9-Tetrahydrocannabinol in an In Vivo Animal Model. AB - Introduction: Cannabidiol (CBD) can convert to Delta9-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo. Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs (N=3) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liquid chromatography with tandem mass spectrometry analysis determined CBD, THC, and 11-hydroxy-THC (11-OH-THC) concentrations. Lower limits of quantification: plasma CBD=1 ng/mL, plasma THC and 11-OH-THC=0.5 ng/mL, GI tract CBD=2 ng/mL, and GI tract THC and 11-OH-THC=1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concentrations (Cmax) of CBD were observed between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean Cmax CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clinical studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h.ng/mL) and 5 (881 h.ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concentrations reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function. PMID- 29285524 TI - Analysis of the Genes Involved in Thiocyanate Oxidation during Growth in Continuous Culture of the Haloalkaliphilic Sulfur-Oxidizing Bacterium Thioalkalivibrio thiocyanoxidans ARh 2T Using Transcriptomics. AB - Thiocyanate (N=C-S-) is a moderately toxic, inorganic sulfur compound. It occurs naturally as a by-product of the degradation of glucosinolate-containing plants and is produced industrially in a number of mining processes. Currently, two pathways for the primary degradation of thiocyanate in bacteria are recognized, the carbonyl sulfide pathway and the cyanate pathway, of which only the former has been fully characterized. Use of the cyanate pathway has been shown in only 10 strains of Thioalkalivibrio, a genus of obligately haloalkaliphilic sulfur oxidizing Gammaproteobacteria found in soda lakes. So far, only the key enzyme in this reaction, thiocyanate dehydrogenase (TcDH), has been purified and studied. To gain a better understanding of the other genes involved in the cyanate pathway, we conducted a transcriptomics experiment comparing gene expression during the growth of Thioalkalivibrio thiocyanoxidans ARh 2T with thiosulfate with that during its growth with thiocyanate. Triplicate cultures were grown in continuous substrate-limited mode, followed by transcriptome sequencing (RNA-Seq) of the total mRNA. Differential expression analysis showed that a cluster of genes surrounding the gene for TcDH were strongly upregulated during growth with thiocyanate. This cluster includes genes for putative copper uptake systems (copCD, ABC-type transporters), a putative electron acceptor (fccAB), and a two component regulatory system (histidine kinase and a sigma54-responsive Fis family transcriptional regulator). Additionally, we observed the increased expression of RuBisCO and some carboxysome shell genes involved in inorganic carbon fixation, as well as of aprAB, genes involved in sulfite oxidation through the reverse sulfidogenesis pathway. IMPORTANCE Thiocyanate is a moderately toxic and chemically stable sulfur compound that is produced by both natural and industrial processes. Despite its significance as a pollutant, knowledge of the microbial degradation of thiocyanate is very limited. Therefore, investigation of thiocyanate oxidation in haloalkaliphiles such as the genus Thioalkalivibrio may lead to improved biotechnological applications in wastewater remediation. PMID- 29285525 TI - Postsynthesis Transformation of Insulating Cs4PbBr6 Nanocrystals into Bright Perovskite CsPbBr3 through Physical and Chemical Extraction of CsBr. AB - Perovskite-related Cs4PbBr6 nanocrystals present a "zero-dimensional" crystalline structure where adjacent [PbBr6]4- octahedra do not share any corners. We show in this work that these nanocrystals can be converted into "three-dimensional" CsPbBr3 perovskites by extraction of CsBr. This conversion drastically changes the optoelectronic properties of the nanocrystals that become highly photoluminescent. The extraction of CsBr can be achieved either by thermal annealing (physical approach) or by chemical reaction with Prussian Blue (chemical approach). The former approach can be simply carried out on a dried film without addition of any chemicals but does not yield a full transformation. Instead, reaction with Prussian Blue in solution achieves a full transformation into the perovskite phase. This transformation was also verified on the iodide counterpart (Cs4PbI6). PMID- 29285526 TI - Important Dental Fiber-Reinforced Composite Molding Compound Breakthroughs. PMID- 29285527 TI - Spatiotemporal Segmentation and Modeling of the Mitral Valve in Real-Time 3D Echocardiographic Images. AB - Transesophageal echocardiography is the primary imaging modality for preoperative assessment of mitral valves with ischemic mitral regurgitation (IMR). While there are well known echocardiographic insights into the 3D morphology of mitral valves with IMR, such as annular dilation and leaflet tethering, less is understood about how quantification of valve dynamics can inform surgical treatment of IMR or predict short-term recurrence of the disease. As a step towards filling this knowledge gap, we present a novel framework for 4D segmentation and geometric modeling of the mitral valve in real-time 3D echocardiography (rt-3DE). The framework integrates multi-atlas label fusion and template-based medial modeling to generate quantitatively descriptive models of valve dynamics. The novelty of this work is that temporal consistency in the rt-3DE segmentations is enforced during both the segmentation and modeling stages with the use of groupwise label fusion and Kalman filtering. The algorithm is evaluated on rt-3DE data series from 10 patients: five with normal mitral valve morphology and five with severe IMR. In these 10 data series that total 207 individual 3DE images, each 3DE segmentation is validated against manual tracing and temporal consistency between segmentations is demonstrated. The ultimate goal is to generate accurate and consistent representations of valve dynamics that can both visually and quantitatively provide insight into normal and pathological valve function. PMID- 29285528 TI - Considerations on the Role of Algorithm-Based Levator Aponeurectomy in Small Incision External Ptosis Surgery for Involutional Ptosis-Reply. PMID- 29285529 TI - Visual Field Assessment in Children. PMID- 29285530 TI - Lazy Pentagonal Wedge Resection of Eyelid Margin Lesions. PMID- 29285531 TI - Persistent Angiographic Abnormalities After Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity. PMID- 29285532 TI - Electronic Health Records Are Here to Stay. PMID- 29285533 TI - Scaffold-Assisted Artificial Hair Implantation in a Rat Model. AB - Importance: Current treatments for alopecia with autograft hair transplantation face limitations that may preclude complete hair restoration and leave patients with donor site scars. Scaffold assisted artificial hair implantation as demonstrated in a rat model may provide an adjunct for hair restoration without donor site morbidity. Objective: To design and create porous high-density polyethylene (PHDPE) and expanded polytetrafluoroethylene (ePTFE) hair-bearing scaffolds and evaluate their biocompatibility in a rat model. Design, Setting, and Participants: For this single-institution randomized prospective animal study, 34 Sprague Dawley rats were randomly selected into 2 groups: 24 rats for direct implantation and 10 rats for delayed implantation. The direct-implantation group was randomly divided into 3 subgroups of 8 rats, which were observed for 2, 12, and 24 week. Interventions: Each rat dorsum was implanted with 4 scaffolds PHDPE and ePTFE with and without hair-in a randomized 4-quadrant manner. The rats in the direct-implantation group were observed to their selected time points of 2, 12, and 24 weeks. The rats in the delayed-implantation group were observed for 4 weeks at which, all well-healed scaffolds without hair were then percutaneously implanted with 2 follicular units of hair. These rats were then observed for another 4 weeks. Main Outcomes and Measures: During the clinical observation period, scaffolds were observed for signs of infection, extrusion, and persistence of follicular units. Following sacrifice, sagittal sections of scaffold and surrounding skin were fixed in formalin, stained with hematoxylin eosin, and evaluated for degree of fibrovascular invasion and acute and chronic inflammation. Results: Overall 94.5% (86 of 91) of the scaffolds were well healed at time of evaluation (2 week, 100% [32 of 32]; 12 week, 96.3% [26 of 27]; 24 week, 87.5% [28 of 32]); while 85.6% of artificial hair follicular units were intact at time of evaluation (2 week, 93.8% [30 of 32]; 12 week, 86.7% [26 of 30]; 24 week, 75.0% [21 of 28]). Within the delayed implant group 100% (19 of 19) of the hair-implanted scaffolds were well healed at 8 weeks, with 94.7% (36 of 38) of the follicular units intact; 100% of the delayed-hair implant scaffolds were well healed with 86.1% (36 of 38) of the follicular units intact. Kaplan Meier log-rank analysis showed no significant difference in survival between ePTFE and PHDPE scaffolds, as well as scaffolds with hair and scaffolds without hair. Upon histological analysis, overall scaffolds with hair were noted to have greater chronic inflammation (95% CI, -0.81 to -1.10; P = .01), and PHDPE was noted to have significantly great fibrovascular integration (95% CI, -11.42 to 1.96; P = .01) compared with ePTFE. Conclusions and Relevance: Overall, PHDPE and ePTFE hair bearing scaffolds were well tolerated in a rat model. Progressive loss of artificial hair may be percutaneously implanted without significant increases in infection or extrusion. Level of Evidence: NA. PMID- 29285534 TI - Comparison of Quality and Output of Different Optimal Perimetric Testing Approaches in Children With Glaucoma. AB - Importance: There is limited evidence to support the development of guidance for visual field testing in children with glaucoma. Objective: To compare different static and combined static/kinetic perimetry approaches in children with glaucoma. Design, Setting, and Participants: Cross-sectional, observational study recruiting children prospectively between May 2013 and June 2015 at 2 tertiary specialist pediatric ophthalmology centers in London, England (Moorfields Eye Hospital and Great Ormond Street Hospital). The study included 65 children aged 5 to 15 years with glaucoma (108 affected eyes). Main Outcomes and Measures: A comparison of test quality and outcomes for static and combined static/kinetic techniques, with respect to ability to quantify glaucomatous loss. Children performed perimetric assessments using Humphrey static (Swedish Interactive Thresholding Algorithm 24-2 FAST) and Octopus combined static tendency-oriented perimetry/kinetic perimetry (isopter V4e, III4e, or I4e) in a single sitting, using standardized clinical protocols, administered by a single examiner. Information was collected about test duration, completion, and quality (using automated reliability indices and our qualitative Examiner-Based Assessment of Reliability score). Perimetry outputs were scored using the Aulhorn and Karmeyer classification. One affected eye in 19 participants was retested with Swedish Interactive Thresholding Algorithm 24-2 FAST and 24-2 standard algorithms. Results: Sixty-five children (33 girls [50.8%]), with a median age of 12 years (interquartile range, 9-14 years), were tested. Test quality (Examiner-Based Assessment of Reliability score) improved with increasing age for both Humphrey and Octopus strategies and were equivalent in children older than 10 years (McNemar test, chi2 = 0.33; P = .56), but better-quality tests with Humphrey perimetry were achieved in younger children (McNemar test, chi2 = 4.0; P = .05). Octopus and Humphrey static MD values worse than or equal to -6 dB showed disagreement (Bland-Altman, mean difference, -0.70; limit of agreement, -7.74 to 6.35) but were comparable when greater than this threshold (mean difference, 0.03; limit of agreement, -2.33 to 2.27). Visual field classification scores for static perimetry tests showed substantial agreement (linearly weighted kappa, 0.79; 95% CI, 0.65-0.93), although 25 of 80 (31%) were graded with a more severe defect for Octopus static perimetry. Of the 7 severe cases of visual field loss (grade 5), 5 had lower kinetic than static classification scores. Conclusions and Relevance: A simple static perimetry approach potentially yields high-quality results in children younger than 10 years. For children older than 10 years, without penalizing quality, the addition of kinetic perimetry enabled measurement of far-peripheral sensitivity, which is particularly useful in children with severe visual field restriction. PMID- 29285535 TI - Considerations on the Role of Algorithm-Based Levator Aponeurectomy in Small Incision External Ptosis Surgery for Involutional Ptosis. PMID- 29285536 TI - Language, Science, and Politics: The Politicization of Public Health. PMID- 29285537 TI - Primary Cancer vs Competing Causes of Death in Survivors of Head and Neck Cancer. PMID- 29285539 TI - Erratum. PMID- 29285538 TI - Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis. AB - Importance: Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE. Objective: To determine the incidence of carfilzomib associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies. Data Sources: PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017. Study Selection: Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis. Data Extraction and Synthesis: Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE. Main Outcomes and Measures: Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded. Results: A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively. Conclusions and Relevance: Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks. PMID- 29285540 TI - Improving Public Health Requires Inclusion of Underrepresented Populations in Research. PMID- 29285541 TI - Ascertainment Bias and Estimating Penetrance. PMID- 29285542 TI - Adoption of Electronic Health Records and Perceptions of Financial and Clinical Outcomes Among Ophthalmologists in the United States. AB - Importance: Assessing the rate of electronic health record (EHR) adoption and ophthalmologists' perceptions on financial and clinical productivity is important in understanding how to direct future design and health care policy. Objective: To assess adoption rate and perceptions of financial and clinical outcomes of EHRs among ophthalmologists in the United States. Design, Setting, and Participants: Population-based, cross-sectional study. A random sample of 2000 ophthalmologists was generated on the basis of mailing address zip codes from the 2015 American Academy of Ophthalmology US active membership database, which included more than 18 000 ophthalmologists. A survey was sent by email to assess adoption rate of EHRs, perceptions of financial and clinical productivity, and engagement with Medicare and Medicaid programs that incentivize the use of EHRs. The survey was conducted between 2015 and 2016. Main Outcomes and Measures: Adoption rate of EHRs and perceptions of financial and clinical productivity. Results: The adoption rate of EHRs among surveyed ophthalmologists (348 respondents) was 72.1%. The responding ophthalmologists perceived that their net revenues and productivity have declined and that practice costs are higher with EHR use. Of those who attested for stage 1 of the EHR incentive program, 83% had already or were planning to attest to stage 2, but 9% had no plans. Conclusions and Relevance: The adoption of EHRs by ophthalmologists has more than doubled since a 2011 survey and is similar to that of primary care physicians (79%). In comparison with 2 previous surveys of ophthalmologists, respondents had more negative perceptions of EHR productivity outcomes and effect on practice costs, although financial data were not collected in this survey to support these opinions. These negative perceptions suggest that more attention should be placed on improving the efficiency and usability of EHR systems. PMID- 29285543 TI - Are Value Frameworks Missing the Mark When Considering Long-term Benefits From Immuno-oncology Drugs? PMID- 29285544 TI - Cancer Drugs Approved Based on Biomarkers and Not Tumor Type-FDA Approval of Pembrolizumab for Mismatch Repair-Deficient Solid Cancers. PMID- 29285545 TI - Health Behavioral Models to Find Reasons for Low Rates of Lung Cancer Screening by Low-Dose Computed Tomography. PMID- 29285546 TI - Hormone Therapy-Related Hot Flashes and Their Management. PMID- 29285547 TI - Association of Immunotherapy With Durable Survival as Defined by Value Frameworks for Cancer Care. AB - Importance: Modern immuno-oncology agents have generated great excitement because of their potential to provide durable survival for some patients. However, there is concern regarding the cost of cancer care, and multiple frameworks have been developed to assess value. The American Society of Clinical Oncology (ASCO) framework awards bonus points if substantial durable survival is demonstrated. Objective: To assess whether modern immuno-oncology agents reach defined efficacy thresholds in value frameworks. Design, Setting, and Participants: In this analysis, all US Food and Drug Administration (FDA) approvals for immuno-oncology agents between March 2011 and August 2017 were reviewed. Data required for the ASCO framework were collected, specifically improvement in proportion of patients alive with the test regimen and survival rate with standard treatment. Main Outcomes and Measures: Awarding of bonus points for durable survival based on the ASCO criteria. Results: Twenty-three metastatic indications for 6 immuno-oncology agents (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab) were approved by the FDA from March 2011 to August 2017. Ten (43%) of the approvals were based on survival end points, while 13 (57%) were based on response rates. Only 3 drug indications fulfilled the threshold defined for the survival rate of patients receiving standard care (minimum 20%). Nine indications achieved the required level of improvement in proportion to patients alive in the test regimen compared with the standard (above 50%). There was overlap between these 2 criteria for 3 drug indications, allowing them to gain the durable survival bonus points awarded by the ASCO framework. Conclusions and Relevance: Durable survival and response rates of modern immuno-oncology agents are rarely recognized as significant by current oncology value frameworks. This may be due to insufficient demonstration of efficacy of such agents or inappropriately calibrated value frameworks. PMID- 29285549 TI - Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide. AB - Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities. PMID- 29285548 TI - Preclinical evaluation of an 18F-trifluoroborate methionine derivative for glioma imaging. AB - PURPOSE: 11C-methionine (MET) is one of the most commonly used amino acid tracers for PET imaging of brain tumors. In this study, we report an 18F-labeled boron derived methionine analogue, denoted as 18F-B-MET, as a potential substitute of 11C-MET for glioma PET imaging. METHODS: 19F-B-MET was synthesized from readily available chemicals according to our previous publication. For kit development, 19F-B-MET was aliquoted in quantities of 10 nmol for on-demand one-step labeling. The 18F-labeling was performed by 18F-19F isotope exchange, and quality control was performed by both HPLC and radio-TLC. Uptake of the tracer was determined in GL26, C6 and U87 tumor cells. PET imaging and the biodistribution assay were performed on mice bearing subcutaneous or orthotopic C6 and U87 tumor xenografts. RESULTS: Starting with 740-1110 MBq 18F-fluoride, >370 MBq of 18F-B-MET was obtained in 25 min (n = 5) with >99% purity and high specific activity (>37 GBq/MUmol). 18F-B-MET demonstrated excellent in vitro stability with <1% decomposition after incubation with plasma for 2 h. In vitro cell uptake assay showed that 18F-B-MET accumulated in tumor cells in a time dependent manner and could be competitively inhibited by natural methionine and other L-type transporter transported amino acids. In vivo biodistribution and imaging studies showed high tumor accumulation (2.99 +/- 0.23 %ID/g, n = 6) compared with low uptake of brain (0.262 +/- 0.05 %ID/g, n = 6) at 60 min after injection in a subcutaneous C6 tumor model. Orthotropic C6 and U87 tumors were clearly visualized with high tumor to brain ratios at 60 min post-injection, corroborating with tumor L-type amino acid transporter 1 (LAT-1) expression levels. CONCLUSION: 18F-B-MET was radiolabeled with high yield in a one-step labeling process, showed excellent pharmacokinetic properties in vivo, with high tumor-to-brain contrast. PMID- 29285550 TI - Symbiont-Mediated Host-Parasite Dynamics in a Fungus-Gardening Ant. AB - Group-living can promote the evolution of adaptive strategies to prevent and control disease. Fungus-gardening ants must cope with two sets of pathogens, those that afflict the ants themselves and those of their symbiotic fungal gardens. While much research has demonstrated the impact of specialized fungal pathogens that infect ant fungus gardens, most of these studies focused on the so called higher attine ants, which are thought to coevolve diffusely with two clades of leucocoprinaceous fungi. Relatively few studies have addressed disease ecology of lower Attini, which are thought to occasionally recruit (domesticate) novel leucocoprinaceous fungi from free-living populations; coevolution between lower-attine ants and their fungi is therefore likely weaker (or even absent) than in the higher Attini, which generally have many derived modifications. Toward understanding the disease ecology of lower-attine ants, this study (a) describes the diversity in the microfungal genus Escovopsis that naturally infect fungus gardens of the lower-attine ant Mycocepurus smithii and (b) experimentally determines the relative contributions of Escovopsis strain (a possible garden disease), M. smithii ant genotype, and fungal cultivar lineage to disease susceptibility and colony fitness. In controlled in-vivo infection laboratory experiments, we demonstrate that the susceptibility to Escovopsis infection was an outcome of ant-cultivar-Escovopsis interaction, rather than solely due to ant genotype or fungal cultivar lineage. The role of complex ant-cultivar-Escovopsis interactions suggests that switching M. smithii farmers onto novel fungus types might be a strategy to generate novel ant-fungus combinations resistant to most, but perhaps not all, Escovopsis strains circulating in a local population of this and other lower-attine ants. PMID- 29285551 TI - Analeptic agent from microbes upon cyanide degradation. AB - Microbes being the initial form of life and ubiquitous in occurrence, they adapt to the environment quickly. The microbial metabolism undergoes alteration to ensure conducive environment either by degrading the toxic substances or producing toxins to protect themselves. The presence of cyanide waste triggers the cyanide degrading enzymes in the microbes which facilitate the microbes to utilize the cyanide for its growth. To enable the degradation of cyanide, the microbes also produce the necessary cofactors and enhancers catalyzing the degradation pathways. Pterin, a cofactor of the enzyme cyanide monooxygenase catalyzing the oxidation of cyanide, is considered to be a potentially bioactive compound. Besides that, the pterins also act as cofactor for the enzymes involved in neurotransmitter metabolism. The therapeutic values of pterin as neuromodulating agent validate the necessity to pursue the commercial production of pterin. Even though chemical synthesis is possible, the non-toxic methods of pterin production need to be given greater attention in future. PMID- 29285552 TI - Focal cortical thinning in patients with stable relapsing-remitting multiple sclerosis: cross-sectional-based novel estimation of gray matter kinetics. AB - PURPOSE: The aim of our study is to identify radiological patterns of cortical gray matter atrophy (CGMA) that correlate with disease duration in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients were randomly selected from the Sheba Multiple Sclerosis (MS) center computerized data registry based on stratification of disease duration up to 10 years. Patients were scanned by 3.0 T (Signa, GE) MRI, using a T1 weighted 3D high resolution, FSPGR, MS protocol. Neurological disability was assessed by the Expanded Disability Status Scale (EDSS). FreeSurfer was used to obtain brain volumetric segmentation and to perform cortical thickness surface-based analysis. Clusters of change in cortical thickness with correlation to disease duration were produced. RESULTS: Two hundred seventy-one RRMS patients, mean +/- SD age 33.0 +/ 7.0 years, EDSS 1.6 +/- 1.2, disease duration 5.0 +/- 3.4 years. Cortical thickness analysis demonstrated focal areas of cerebral thinning that correlated with disease duration. Seven clusters accounting for 11.7% of the left hemisphere surface and eight clusters accounting for 10.6% of the right hemisphere surface were identified, with cluster-wise probability of p < 0.002 and p < 0.02, respectively.The clusters included bilateral involvement of areas within the cingulate, precentral, postcentral, paracentral, superior-parietal, superior frontal gyri and insular cortex. Mean and cluster-wise cortical thickness negatively correlated with EDSS score, p < 0.001, with stronger Spearman rho for cluster-wise measurements. CONCLUSIONS: We identified CGMA patterns in sensitive brain regions which give insight and better understanding of the progression of cortical gray matter loss in relation to dissemination in space and time. These patterns may serve as markers to modulate therapeutic interventions to improve the management of MS patients. PMID- 29285553 TI - Arthroscopic primary repair of the anterior cruciate ligament: what the radiologist needs to know. AB - Recently, there has been a renewed interest in primary repair of proximal anterior cruciate ligament (ACL) tears. Magnetic resonance imaging (MRI) plays an important role in preoperative patient selection and in postoperative ligament assessment. Knowledge of the imaging factors that make patients candidates for primary ACL repair, namely proximal tear location and good tissue quality, can help radiologists provide information that is meaningful for surgical decision making. Furthermore, an understanding of the surgical techniques can prevent misinterpretation of the postoperative MRI. This article reviews preoperative MRI characterization of ACL injuries, techniques of arthroscopic primary ACL repair surgery and examples of postoperative MRI findings. PMID- 29285554 TI - Hallux saltans due to stenosing tenosynovitis of flexor hallucis longus: dynamic sonography and arthroscopic findings. AB - Triggering of the toes is rare, with isolated cases reported in the literature involving predominantly the flexor hallucis longus (FHL) tendon, a condition known as "hallux saltans" (HS). We report the dynamic sonographic findings of a 42-year-old female with a 2-month history of ankle pain and triggering of right hallux, consistent with HS. Sonography demonstrated tenosynovitis and focal thickening of FHL at the level of hindfoot, with a fibrous band adjacent to the tendon. Dynamic ultrasound showed triggering and snapping of FHL tendon during hallux flexion and extension, respectively. We present comprehensive documentation of this rare entity, including sonographic still images and cine clips, as well as correlation with arthroscopic surgical findings. PMID- 29285556 TI - Mixotrophic cultivation of microalgae to enhance the quality of lipid for biodiesel application: effects of scale of cultivation and light spectrum on reduction of alpha-linolenic acid. AB - The research on microalgal biodiesel is focused not only on getting the highest lipid productivity but also desired quality of lipid. The experiments were initially conducted on flask scale (1L) using acetate carbon source at different concentrations viz. 0.5, 2, 3 and 4 g L-1. The optimum concentration of acetate was considered for further experiments in two airlift photobioreactors (10 L) equipped separately with red and white LED lights. The Feasibility Index (FI) was derived to analyze the scalability of mixotrophic cultivation based on net carbon fixation in biomass per consumption of total organic carbon. The experimental strategy under mixotrophic mode of cultivation lowered the alpha-linolenic acid content of lipid by 60-80% as compared to autotrophic cultivation for Scenedesmus abundans species and yielded the highest biomass and lipid productivities, 59 +/- 2 and 17 +/- 1.8 mg L-1 day-1, respectively. The TOC, nitrate, and phosphate reduction rates were 74.6 +/- 3.0, 11.5 +/- 1.4, 9.6 +/- 2.4 mg L-1 day-1, respectively. The significant change was observed in lipid compositions due to the scale, mode of cultivation, and light spectra. As compared to phototrophic cultivation, biodiesel obtained under mixotrophic cultivation only met standard biodiesel properties. The FI data showed that the mixotrophic cultivation was feasible on moderate concentrations of acetate (2-3 g L-1). PMID- 29285555 TI - Parent handling of typical infants varies segmentally across development of postural control. AB - Although trunk muscles extend across multiple vertebral joints, recent motor control studies have shown that a top-down progression of trunk control in typical infants occurs incrementally, one segment at a time, until independent sitting. The current study merges this surprising developmental pattern with parent behavior by exploring the relationship between how parents hold their infant and the segmental level for which the infant exhibits postural control. We measured trunk control of 60 infants (1-8 months) via the segmental assessment of trunk control. Spontaneous parental hold and variability was recorded during repeated sitting and standing conditions. Parent hold correlated with infant level of control in both sitting and standing, providing evidence for a positive interaction between parent behavior and segmental trunk development. PMID- 29285557 TI - Transfusion practices at end of life for hematopoietic stem cell transplant patients. AB - PURPOSE: Limited data exist regarding transfusion practices at end of life (EOL) for hematopoietic stem cell transplant (HSCT) patients. The purpose of this study was to examine red blood cell (RBC) and platelet transfusion practices in HSCT patients who enrolled or did not enroll in hospice. METHODS: This was a single center, retrospective chart review in deceased HSCT patients. The primary objective was to determine the mean difference between the last transfusion and death in HSCT patients (n = 116) who enrolled or did not enroll in hospice. RESULTS: Sixteen (14%) and 100 (86%) patients were enrolled in hospice and not enrolled in hospice, respectively. Hospice patients observed a larger mean difference between death and last transfusion (45.9 +/- 66.7 vs. 14.6 +/- 48.1 days, p < 0.0001). A higher amount of platelet, but not RBC, transfusions occurred in patients not enrolled in hospice (p = 0.04). The last transfusion that occurred more than 96 h before death was observed in 12 (75%) and 22 (22%) in hospice and non-hospice patients, respectively. For HSCT patients not enrolled in hospice, 17 patients received a transfusion on the same day of death and 31 patients received the last transfusion 24 h before death. CONCLUSIONS: Blood transfusion practices differed in HSCT patients enrolled and not enrolled in hospice. For most patients not enrolled in hospice, the last transfusion occurred 24 h before death. Future efforts should explore if limited access to blood products is a barrier to hospice enrollment for HSCT patients. PMID- 29285558 TI - Meta-ethnography of experiences of early discharge, with a focus on paediatric febrile neutropenia. AB - PURPOSE (STATING THE MAIN PURPOSES AND RESEARCH QUESTION): Many children have no significant sequelae of febrile neutropenia. A systematic review of clinical studies demonstrated patients at low risk of septic complications can be safely treated as outpatients using oral antibiotics with low rates of treatment failure. Introducing earlier discharge may improve quality of life, reduce hospital acquired infection and reduce healthcare service pressures. However, the review raised concerns that this might not be acceptable to patients, families and healthcare professionals. METHODS: This qualitative synthesis explored experiences of early discharge in paediatric febrile neutropenia, including reports from studies of adult febrile neutropenia and from other paediatric conditions. Systematic literature searching preceded meta-ethnographic analysis, including reading the studies and determining relationships between studies, translation of studies and synthesis of these translations. RESULTS: Nine papers were included. The overarching experience of early discharge is that decision making is complex and difficult and influenced by fear, timing and resources. From this background, we identified two distinct themes. First, participants struggled with practical consequences of treatment regimens, namely childcare, finances and follow-up. A second theme identified social and emotional issues, including isolation, relational and environmental challenges. Linking these, participants considered continuity of care and the need for information important. CONCLUSIONS: Trust and confidence appeared interdependent with resources available to families-both are required to manage early discharge. Socially informed resilience is relevant to facilitating successful discharge strategies. Interventions which foster resilience may mediate the ability and inclination of families to accept early discharge. Services have an important role in recognising and enhancing resilience. PMID- 29285559 TI - Pressure-induced end-plate fracture in the porcine spine: Is the annulus fibrosus susceptible to damage? AB - PURPOSE: To determine if the mechanical properties of the annulus fibrosus (AF) are altered following end-plate fracture. Vertebral fractures, particularly those in the growth plate, are relatively common among adolescents. What is unclear is whether or not these fractures are also associated with concomitant damage to the intervertebral disc (IVD), in particular the AF. METHODS: The current study employed a high-rate IVD pressurization model to create growth plate fractures in the porcine cervical spine. Posterior AF mechanical properties and laminate adhesion strength were quantified in fractured spines and compared to samples obtained from non-pressurized, un-fractured spines. RESULTS: AF laminate adhesion strength was 31% lower in the fractured spines compared to the un-fractured spines. CONCLUSION: This decrease in laminate adhesion strength suggests that growth plate fracture damage is not isolated to the vertebra and results in microdamage to the interlamellar matrix of the AF. This may increase in the risk of progressive delamination of the AF, which is associated with IVD herniation. These slides can be retrieved under Electronic Supplementary Material. PMID- 29285560 TI - Anterior controllable antidisplacement and fusion surgery for the treatment of multilevel severe ossification of the posterior longitudinal ligament with myelopathy: preliminary clinical results of a novel technique. AB - PURPOSE: Although anterior and posterior decompression surgery are both reported to treat patients with myelopathy caused by ossification of the posterior longitudinal ligament (OPLL). The surgical strategy of the disease is still controversial when the OPLL is multilevel and severe. This present study reports the preliminary clinical results of a novel technique named anterior controllable antidisplacement and fusion (ACAF) for the treatment of multilevel-severe OPLL with myelopathy. METHODS: A series of 15 patients with cervical myelopathy caused by compression of multilevel severe OPLL were enrolled. All the patients underwent ACAF after thorough surgical designing based on preoperative imaging. The patients were followed for a mean follow-up duration of 9 months in this study. The main surgical procedures include discectomy of the involved levels, thinning of the anterior part of the involved vertebrae, intervertebral cages, anterior plate and screws installation, bilateral osteotomies of the vertebrae, and antedisplacement of the vertebrae-OPLL complex (VOC). The Japanese Orthopaedic Association (JOA) scales, Visual Analog Scale (VAS) were studied. And the pre- and postoperative radiological parameters, and surgical complications were also investigated. RESULTS: Postoperative CT and MRI showed complete decompression of the cord by antidisplacement of the VOC. Restoration of neurological defects was confirmed at the last follow-up assessment. Bone fusion was confirmed by CT at 6 months follow-up. No specific complications were identified that were associated with this technique. CONCLUSIONS: The present study demonstrates that excellent postoperative outcome can be achieved with the use of the ACAF. Though further study is required to confirm the conclusion, this novel technique has the potential to serve as an alternative surgical technique for the treatment of cervical OPLL. These slides can be retrieved under Electronic Supplementary Material. PMID- 29285561 TI - Latitudinal variation in responses of a forest herbivore and its egg parasitoids to experimental warming. AB - Disrupted biotic interactions are a predicted consequence of anthropogenic climate change when interactants differ in the magnitude or direction of phenological responses. Here, we examined the responses to artificial warming of northern, southern and central populations of the eastern tent caterpillar and its hymenopteran egg parasitoids. We subjected egg masses from each region to the typical conditions they experience in their source locality or to a warmer temperature regime, to quantify the effects of simulated warming on their relative phenology, survival and neonate starvation endurance. In addition, we characterized spring heat accumulation and cloud cover at each collection site using 30 years of hourly weather station data. As predicted, degree-day accumulation rates decreased with latitude; however, the mid-latitude site experienced what we predict to be the harshest spring conditions for tent caterpillars: slow heat accumulation combined with thick cloud cover. Remarkably, caterpillars from this site exhibited the largest phenological plasticity, hatching a month earlier under warmer than under typical conditions and doubling caterpillar survival. Survival of caterpillars from all regions was enhanced at warmer temperatures, whereas parasitoid survival was unaffected. The starvation endurance of hatchlings increased under warmer conditions in the central and southern populations only. We show that phenological responses to warming differed between hosts and parasitoids, resulting in a 5-day reduction in the relative phenology of wasps and caterpillars in the northern population. Our findings caution that responses to global warming are likely to be population or region specific and cannot be readily generalized, particularly for wide-ranging organisms. PMID- 29285562 TI - Phenological cues intrinsic in indigenous knowledge systems for forecasting seasonal climate in the Delta State of Nigeria. AB - Shifts in the timing of phenological events in plants and animals are cited as one of the most robust bioindicators of climate change. Much effort has thus been placed on the collection of phenological datasets, the quantification of the rates of phenological shifts and the association of these shifts with recorded meteorological data. These outputs are of value both in tracking the severity of climate change and in facilitating more robust management approaches in forestry and agriculture to changing climatic conditions. However, such an approach requires meteorological and phenological records spanning multiple decades. For communities in the Delta State of Nigeria, small-scale farming communities do not have access to meteorological records, and the dissemination of government issued daily to seasonal forecasts has only taken place in recent years. Their ability to survive inter-annual to inter-decadal climatic variability and longer-term climatic change has thus relied on well-entrenched indigenous knowledge systems (IKS). An analysis of the environmental cues that are used to infer the timing and amount of rainfall by farmers from three communities in the Delta State reveals a reliance on phenological events, including the croaking of frogs, the appearance of red millipedes and the emergence of fresh rubber tree and cassava leaves. These represent the first recorded awareness of phenology within the Delta State of Nigeria, and a potentially valuable source of phenological data. However, the reliance of these indicators is of concern given the rapid phenological shifts occurring in response to climate change. PMID- 29285563 TI - Integrated analysis of transcriptomic and metabolomic data reveals critical metabolic pathways involved in rotenoid biosynthesis in the medicinal plant Mirabilis himalaica. AB - Mirabilis himalaica (Edgew.) Heimerl is among the most important genuine medicinal plants in Tibet. However, the biosynthesis mechanisms of the active compounds in this species are unclear, severely limiting its application. To clarify the molecular biosynthesis mechanism of the key representative active compounds, specifically rotenoid, which is of special medicinal value for M. himalaica, RNA sequencing and TOF-MS technologies were used to construct transcriptomic and metabolomic libraries from the roots, stems, and leaves of M. himalaica plants collected from their natural habitat. As a result, each of the transcriptomic libraries from the different tissues was sequenced, generating more than 10 Gb of clean data ultimately assembled into 147,142 unigenes. In the three tissues, metabolomic analysis identified 522 candidate compounds, of which 170 metabolites involved in 114 metabolic pathways were mapped to the KEGG. Of these genes, 61 encoding enzymes were identified to function at key steps of the pathways related to rotenoid biosynthesis, where 14 intermediate metabolites were also located. An integrated analysis of metabolic and transcriptomic data revealed that most of the intermediate metabolites and enzymes related to rotenoid biosynthesis were synthesized in the roots, stems and leaves of M. himalaica, which suggested that the use of non-medicinal tissues to extract compounds was feasible. In addition, the CHS and CHI genes were found to play important roles in rotenoid biosynthesis, especially, since CHS might be an important rate-limiting enzyme. This study provides a hypothetical basis for the screening of new active metabolites and the metabolic engineering of rotenoid in M. himalaica. PMID- 29285565 TI - Morphological and molecular characterization of a novel myxosporean parasite Myxobolus bejeranoi n. sp. (Cnidaria: Myxosporea) from hybrid tilapia in Israel. AB - Myxosporean infections can cause severe damage to commercially grown tilapia. Here, we report a novel myxosporean that was found in gills of Oreochromis aureus male * Oreochromis niloticus female, which is an important aquaculture tilapia hybrid in Israel. Three-month-old fish were found to have cysts located in gill muscle tissue, which were filled with both immature and mature spores. Affected fish displayed higher mortality rate. Spore dimensions (10.8 +/- 0.7 MUm length * 6.8 +/- 0.6 MUm width) and molecular characterization using 18S ribosomal DNA revealed that the unknown parasite belongs in the Myxobolus clade. Based on the infection site, spore morphology and molecular characterization, we describe this parasite as Myxobolus bejeranoi n. sp. (MF401455). Phylogenetic analysis showed that the new species is most closely related to two Myxobolus spp. from O. niloticus in Egypt and Ghana. PMID- 29285564 TI - The effects of CXCL10 polymorphisms on COPD susceptibility. AB - The polymorphisms of cytokine genes has been reported to modulate the individual's susceptibility to environmental stimuli in COPD development. C-X-C motif chemokine 10 (CXCL10) mediates recruitment inflammatory cells such as monocytes. Therefore, it may play a key role in COPD. Here, a case-control study was conducted to evaluate the association between CXCL10 tag-SNPs and COPD risk. Four tag-SNPs including rs4256246, rs4508917, rs56061981, and rs56316945 were identified based on the linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between these four tag-SNPs and COPD risk were further evaluated in 480 COPD cases and 488 controls. We found that the "T" allele of rs56061981 was significantly associated with reducing risk of COPD, while "G" allele of rs56316945 was significantly associated with increasing risk of COPD. SNP rs56316945 was significantly associated with increasing risk of COPD under different models except recessive model after adjusting the sex, age, pack year, and biomass. SNP rs56061981 was significantly associated with decreasing COPD risk under different models except recessive model after adjusting the sex, age, pack year, and biomass. Stratified analysis of smoking status and biomass with SNPs supported rs56061981 may interact with biomass and smoking thus modulate COPD susceptibility and rs56216945 was apparently associated with the severity of pulmonary function of COPD patients. This study suggests that rs56061981 and rs56216945 in CXCL10 gene promoter contribute COPD susceptibility. PMID- 29285566 TI - Suppression of aortic expansion and contractile recovery in a rat abdominal aortic aneurysm model by biodegradable gelatin hydrogel sheet incorporating basic fibroblast growth factor. AB - Biodegradable gelatin hydrogel sheet (BGHS) incorporating basic fibroblast growth factor (bFGF) may inhibit the progression of abdominal aortic aneurysm (AAA). We investigated whether AAA in a rat model treated with BGHS soaked with bFGF can suppress aortic expansion and recover the contractile response of aneurysmal aortic wall. Experimental AAA was induced in 10-week-old male Sprague-Dawley rats with intra-aortic elastase infusion. Aortas of these rats were assigned to 4 groups (n = 6 each) as follows: Control group, aortas infused with saline; Elastase only group, aortas infused with elastase; Hydrogel group, aortas wrapped with saline-soaked BGHS after elastase infusion; and bFGF group, aortas wrapped with bFGF (100 MUg)-soaked BGHS after elastase infusion. Preoperatively and on postoperative day (POD)7 and POD14, mean aortic maximal diameter was measured ultrasonographically. Aortic expansion ratio was calculated as: (post-infusion aortic diameter on POD14/pre-infusion aortic diameter * 100). Aortas were stained with Elastica van Gieson and alpha-smooth muscle actin to measure the ratio of elastic fibers and alpha-smooth muscle actin-positive cells area to the media area. Aortas on POD14 were cut into 2-mm rings and treated with contractile agent, then tension was recorded using myography. Maximum aorta diameters were significantly greater in Elastase only group, Hydrogel group, and bFGF group than in Control group (on POD14). Maximum diameter was significantly lower in bFGF group (3.52 +/- 0.4 mm) than in Elastase only group (6.21 +/- 1.4 mm on POD14, P < .05). On histological analysis, ratio of the area staining positively for elastic fibers was significantly greater in bFGF group (7.43 +/- 1.8%) than in Elastase only group (3.76 +/- 2.9%, P < .05). The ratio for alpha-smooth muscle actin-positive cells was significantly lower in Elastase only group (38.3 +/- 5.1%) than in Control group (49.8 +/- 6.7%, P < .05). No significant differences were seen between Elastase only group and bFGF group, but ratios tended to be increased in bFGF group. Consecutive mean contractile tensions were significantly higher in bFGF group than in Elastase only group. Maximum contractile tension was significantly higher in bFGF group (1.3 +/- 0.4 mN) than in Elastase only group (0.4 +/- 0.2 mN, P < .05). Aortic expansion can be suppressed and contractile responses of aneurysmal aortic wall recovered using BGHS incorporating bFGF. PMID- 29285567 TI - Management of symptomatic knee osteoarthritis in obesity: a survey of orthopaedic surgeons' opinions and practice. AB - INTRODUCTION: The aim of this survey was to explore knee surgeons' opinions and practices regarding the management of symptomatic knee osteoarthritis in obesity. METHODS: Questionnaires were sent electronically to all consultant members of the British Association for Surgery of the Knee. RESULTS: The response rate was 52%. The survey showed considerable practice variation and divided opinion on the evidence base. The majority stated that weight loss should be the first-line treatment. 53% (91/172) stated that such cases should ideally be assessed by a specialist multidisciplinary service; however, only 24% (41/169) would be interested in being the orthopaedic surgeon in such a service. DISCUSSION: The optimal pathway of care for the obese patient with symptomatic knee osteoarthritis remains unclear. Given recent debate around the rationing of knee arthroplasty surgery in obesity, we felt it was timely to survey knee surgeons' current practice. CONCLUSION: Our survey has shown considerable variation in the opinions and practice of surgeons on the management of symptomatic knee osteoarthritis in obesity, together with divided views on current literature. PMID- 29285568 TI - Characterization of migraineurs presenting interictal widespread pressure hyperalgesia identified using a tender point count: a cross-sectional study. AB - BACKGROUND: Migraineurs exhibit pain hypersensitivity throughout the body during and between migraine headaches. Migraine is classified as a central sensitivity syndrome, typified by fibromyalgia showing widespread pressure hyperalgesia determined by a tender point. This study was performed to examine whether: 1) there is a subgroup of episodic migraineurs with widespread pressure hyperalgesia during and between attacks; 2) if such a subgroup exists, what is the prevalence and what is the difference between groups with interictal widespread hyperalgesia and acute allodynia regarding the demographic and clinical characteristics of migraine. METHODS: This was a cross-sectional study. A total of 176 consecutive episodic migraineurs and 132 age- and sex-matched controls were recruited. The presence of widespread pressure hyperalgesia was investigated using manual tender point survey. To classify a subject's response as widespread pressure hyperalgesia, the cutoff value for responders was defined as the positive tender point count below which 95% of controls responded. RESULTS: Based on the number of positive tender points in controls, the cutoff value of tender point count for pressure hyperalgesia responders was 7. Of the 176 subjects, interictal widespread pressure hyperalgesia and acute allodynia were observed in 74 (42%) and 115 (65.3%) patients, respectively. Univariate analysis indicated that risk factors associated with interictal widespread pressure hyperalgesia were female gender, younger age at migraine onset, higher frequency of migraine attacks, severe headache impact, cutaneous allodynia and depression. Multivariate logistic regression analysis confirmed that independent risk factors associated with interictal widespread pressure hyperalgesia were female gender, higher frequency of migraine attack and younger age at onset. CONCLUSION: Interictal widespread pressure hyperalgesia was common (42%) in the episodic migraineurs and was associated with younger age at onset, female gender, and higher frequency of headache, but not duration of migraine illness. Presence of interictal widespread pressure hyperalgesia is assumed to be an indicator of genetic susceptibility to migraine attacks. We expect that a tender point count, as an alternative to quantitative sensory testing, will become useful as a diagnostic indicator of interictal hyperalgesia in migraineurs to predict susceptibility to migraine attacks and to permit tailored treatment. PMID- 29285569 TI - The enigma of site of action of migraine preventives: no effect of metoprolol on trigeminal pain processing in patients and healthy controls. AB - BACKGROUND: Beta-blockers are a first choice migraine preventive medication. So far it is unknown how they exert their therapeutic effect in migraine. To this end we examined the neural effect of metoprolol on trigeminal pain processing in 19 migraine patients and 26 healthy controls. All participants underwent functional magnetic resonance imaging (fMRI) during trigeminal pain twice: Healthy subjects took part in a placebo-controlled, randomized and double-blind study, receiving a single dose of metoprolol and placebo. Patients were examined with a baseline scan before starting the preventive medication and 3 months later whilst treated with metoprolol. RESULTS: Mean pain intensity ratings were not significantly altered under metoprolol. Functional imaging revealed no significant differences in nociceptive processing in both groups. Contrary to earlier findings from animal studies, we did not find an effect of metoprolol on the thalamus in either group. However, using a more liberal and exploratory threshold, hypothalamic activity was slightly increased under metoprolol in patients and migraineurs. CONCLUSIONS: No significant effect of metoprolol on trigeminal pain processing was observed, suggesting a peripheral effect of metoprolol. Exploratory analyses revealed slightly enhanced hypothalamic activity under metoprolol in both groups. Given the emerging role of the hypothalamus in migraine attack generation, these data need further examination. PMID- 29285570 TI - Experts' opinion about the primary headache diagnostic criteria of the ICHD-3rd edition beta in children and adolescents. AB - BACKGROUND: The 2013 International Classification of Headache Disorders-3 (ICHD 3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents. RESULTS: Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho social basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use with children. PMID- 29285572 TI - Characteristics and diagnoses of acute headache in pregnant women - a retrospective cross-sectional study. AB - BACKGROUND: Acute headache is one of the most frequent neurological symptoms in pregnant women. The early diagnosis of underlying secondary conditions has a major influence on patient outcome, especially in emergency settings. However, at the time being no well-established guideline for diagnostic evaluation of acute headache during pregnancy exists. In this study, we aimed to characterize acute headache in pregnant women concerning demographic, clinical, and diagnostic features, and to determine predictors of secondary headache. METHODS: We analysed retrospectively the data of 151 pregnant women receiving neurological consultation due to acute headache at the Charite Berlin between 2010 and 2016. To assess risk factors for secondary headache in these patients we compared multiple anamnestic and clinical features of the primary and secondary headache group. RESULTS: 57.6% of the patients were diagnosed with primary headache, most common migraine and tension type headache. Concerning secondary headaches, the most common aetiologies were infections (29.7%) and hypertensive disorders (22.0%). The primary and secondary headache group were similar in most anamnestic and clinical features. In multivariate logistic regression analysis, secondary headache history [OR 6.6; 95% CI 1.3-33.1], elevated blood pressure [OR 7.2; 95% CI 2.3-22.6], fever [OR 12.1; 95% CI 1.3-111.0] and abnormal neurological examination [OR 9.9; 95% CI 2.7-36.3] represented independent predictors for secondary headache. Regarding additional diagnostic procedures, abnormal thrombocytes, GOT, GPT and CRP, proteinuria, pathologic results of lumbar puncture and neuroimaging were associated with secondary headache. CONCLUSIONS: Secondary headache disorders are common during pregnancy, occurring in over one third of acute headache cases receiving neurological consultation. Most anamnestic and clinical features may not allow a clear distinction between primary and secondary headaches. Clinicians should pay attention to the presence of secondary headache history, elevated blood pressure, fever and abnormal findings in the neurological examination. Additional investigations, including laboratory tests and neuroimaging, are essential for the diagnostic process. PMID- 29285573 TI - Bacterial LPX motif-harboring virulence factors constitute a species-spanning family of cell-penetrating effectors. AB - Effector proteins are key virulence factors of pathogenic bacteria that target and subvert the functions of essential host defense mechanisms. Typically, these proteins are delivered into infected host cells via the type III secretion system (T3SS). Recently, however, several effector proteins have been found to enter host cells in a T3SS-independent manner thereby widening the potential range of these virulence factors. Prototypes of such bacteria-derived cell-penetrating effectors (CPEs) are the Yersinia enterocolitica-derived YopM as well as the Salmonella typhimurium effector SspH1. Here, we investigated specifically the group of bacterial LPX effector proteins comprising the Shigella IpaH proteins, which constitute a subtype of the leucine-rich repeat protein family and share significant homologies in sequence and structure. With particular emphasis on the Shigella-effector IpaH9.8, uptake into eukaryotic cell lines was shown. Recombinant IpaH9.8 (rIpaH9.8) is internalized via endocytic mechanisms and follows the endo-lysosomal pathway before escaping into the cytosol. The N terminal alpha-helical domain of IpaH9.8 was identified as the protein transduction domain required for its CPE ability as well as for being able to deliver other proteinaceous cargo. rIpaH9.8 is functional as an ubiquitin E3 ligase and targets NEMO for poly-ubiquitination upon cell penetration. Strikingly, we could also detect other recombinant LPX effector proteins from Shigella and Salmonella intracellularly when applied to eukaryotic cells. In this study, we provide further evidence for the general concept of T3SS-independent translocation by identifying novel cell-penetrating features of these LPX effectors revealing an abundant species-spanning family of CPE. PMID- 29285571 TI - Experts' opinion about the pediatric secondary headaches diagnostic criteria of the ICHD-3 beta. AB - BACKGROUND: The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0-18 years) and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD 3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. RESULTS: Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD 3 more appropriate for use in children. PMID- 29285574 TI - Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum? AB - Post-infectious irritable bowel syndrome is a well-defined pathological entity that develops in about one-third of subjects after an acute infection (bacterial, viral) or parasitic infestation. Only recently it has been documented that an high incidence of post-infectious irritable bowel syndrome occurs after Clostridium difficile infection. However, until now it is not known why in some patients recovered from this infection the gastrointestinal disturbances persist for months or years. Based on our in vitro studies on enteric glial cells exposed to the effects of C. difficile toxin B, we hypothesize that persistence of symptoms up to the development of irritable bowel syndrome might be due to a disturbance/impairment of the correct functions of the enteroglial intestinal network. PMID- 29285575 TI - Alteration of gray matter texture features over the whole brain in medication overuse headache using a 3-dimentional texture analysis. AB - BACKGROUND: Imaging studies have provided valuable information in understanding the headache neuromechanism for medication-overuse headache (MOH), and the aim of this study is to investigate altered texture features of MR structural images over the whole brain in MOH using a 3-dimentional texture analysis. METHODS: Brain three-dimensional T1-weighted structural images were obtained from 44 MOH patients and 32 normal controls (NC). The imaging processing included two steps: gray matter (gray images) segment and a 3-dimensional texture features mapping. Voxel-based gray-level co-occurrence matrix (VGLCM) was performed to measure the texture parameters mapping including Contrast, Correlation, Energy, Entropy and inverse difference moment (IDM). RESULTS: The texture parameters of increased Contrast and Entropy, decreased Energy and IDM were identified in cerebellar vermis of MOH patients compared to NCs. Increased Contrast and decreased Energy were found in left cerebellum. Increased Correlation located in left dorsolateral periaqueductal gray (L-dlPAG), right parahippocampal gyrus (R-PHG), and left middle frontal gyrus (L-MFG) and decreased Correlation located in right superior parietal lobule(R-SPL). Disease duration was positively correlated with Contrast of vermis and negatively correlated with Correlation of R-SPL.HAMD score was negatively correlated with Correlation of R-PHG. MoCA score was positively correlated with Correlation of R-SPL. CONCLUSION: The altered textures in gray matter related to pain discrimination and modulation, affective and cognitive processing were helpful in understanding the pathogenesis of MOH. Texture analysis using VGLCM is a sensitive and efficient method to detect subtle gray matter changes in MOH. PMID- 29285576 TI - Sphenopalatine ganglion: block, radiofrequency ablation and neurostimulation - a systematic review. AB - BACKGROUND: Sphenopalatine ganglion is the largest collection of neurons in the calvarium outside of the brain. Over the past century, it has been a target for interventional treatment of head and facial pain due to its ease of access. Block, radiofrequency ablation, and neurostimulation have all been applied to treat a myriad of painful syndromes. Despite the routine use of these interventions, the literature supporting their use has not been systematically summarized. This systematic review aims to collect and summarize the level of evidence supporting the use of sphenopalatine ganglion block, radiofrequency ablation and neurostimulation. METHODS: Medline, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were reviewed for studies on sphenopalatine ganglion block, radiofrequency ablation and neurostimulation. Studies included in this review were compiled and analyzed for their treated medical conditions, study design, outcomes and procedural details. Studies were graded using Oxford Center for Evidence-Based Medicine for level of evidence. Based on the level of evidence, grades of recommendations are provided for each intervention and its associated medical conditions. RESULTS: Eighty three publications were included in this review, of which 60 were studies on sphenopalatine ganglion block, 15 were on radiofrequency ablation, and 8 were on neurostimulation. Of all the studies, 23 have evidence level above case series. Of the 23 studies, 19 were on sphenopalatine ganglion block, 1 study on radiofrequency ablation, and 3 studies on neurostimulation. The rest of the available literature was case reports and case series. The strongest evidence lies in using sphenopalatine ganglion block, radiofrequency ablation and neurostimulation for cluster headache. Sphenopalatine ganglion block also has evidence in treating trigeminal neuralgia, migraines, reducing the needs of analgesics after endoscopic sinus surgery and reducing pain associated with nasal packing removal after nasal operations. CONCLUSIONS: Overall, sphenopalatine ganglion is a promising target for treating cluster headache using blocks, radiofrequency ablation and neurostimulation. Sphenopalatine ganglion block also has some evidence supporting its use in a few other conditions. However, most of the controlled studies were small and without replications. Further controlled studies are warranted to replicate and expand on these previous findings. PMID- 29285578 TI - Characterization of mercury(II)-induced inhibition of photochemistry in the reaction center of photosynthetic bacteria. AB - Mercuric contamination of aqueous cultures results in impairment of viability of photosynthetic bacteria primarily by inhibition of the photochemistry of the reaction center (RC) protein. Isolated reaction centers (RCs) from Rhodobacter sphaeroides were exposed to Hg2+ ions up to saturation concentration (~ 103 [Hg2+]/[RC]) and the gradual time- and concentration-dependent loss of the photochemical activity was monitored. The vast majority of Hg2+ ions (about 500 [Hg2+]/[RC]) had low affinity for the RC [binding constant Kb ~ 5 mM-1] and only a few (~ 1 [Hg2+]/[RC]) exhibited strong binding (Kb ~ 50 MUM-1). Neither type of binding site had specific and harmful effects on the photochemistry of the RC. The primary charge separation was preserved even at saturation mercury(II) concentration, but essential further steps of stabilization and utilization were blocked already in the 5 < [Hg2+]/[RC] < 50 range whose locations were revealed. (1) The proton gate at the cytoplasmic site had the highest affinity for Hg2+ binding (Kb ~ 0.2 MUM-1) and blocked the proton uptake. (2) Reduced affinity (Kb ~ 0.05 MUM-1) was measured for the mercury(II)-binding site close to the secondary quinone that resulted in inhibition of the interquinone electron transfer. (3) A similar affinity was observed close to the bacteriochlorophyll dimer causing slight energetic changes as evidenced by a ~ 30 nm blue shift of the red absorption band, a 47 meV increase in the redox midpoint potential, and a ~ 20 meV drop in free energy gap of the primary charge pair. The primary quinone was not perturbed upon mercury(II) treatment. Although the Hg2+ ions attack the RC in large number, the exertion of the harmful effect on photochemistry is not through mass action but rather a couple of well-defined targets. Bound to these sites, the Hg2+ ions can destroy H-bond structures, inhibit protein dynamics, block conformational gating mechanisms, and modify electrostatic profiles essential for electron and proton transfer. PMID- 29285577 TI - The burden of headache is associated to pain interference, depression and headache duration in chronic tension type headache: a 1-year longitudinal study. AB - BACKGROUND: To investigate variables associated at one year (longitudinal design) with the physical or emotional component of burden in chronic tension type headache (CTTH). METHODS: One hundred and thirty (n = 130) individuals with CTTH participated in this longitudinal study. Clinical features were collected with a 4-weeks headache diary at baseline and 1-year follow-up. The burden of headache was assessed at baseline and one -year follow-up with the Headache Disability Inventory (HDI), physical (HDI-P) or emotional (HDI-E) component. Sleep quality (Pittsburgh Sleep Quality Index), anxiety and depression (Hospital Anxiety and Depression Scale-HADS), and quality of life (SF-36) were also assessed at baseline. Hierarchical regression analyses were conducted to determine the associations between the baseline variables and the headache burden at 1-year. Simple mediation models were also applied to determine the potential mediation effect of any intermediary variable. RESULTS: Regression analyses revealed that baseline pain interference and depression explained 32% of the variance in the emotional burden of headache, whereas baseline emotional burden of the headache, pain interference, and headache duration explained 51% of the variance in the physical burden of headache (P < .01) at 1-year. The mediation models observed that the effect of baseline pain interference on emotional burden of headache at 1-year was mediated through baseline depression, whereas the effect of baseline pain interference on the physical burden of headache at 1-year was mediated through baseline emotional burden of headache (both P < .05). CONCLUSIONS: The current study found a longitudinal interaction between pain interference and depression with the burden of headache in individuals with CTTH. PMID- 29285579 TI - R132 mutations in canine isocitrate dehydrogenase 1 (IDH1) lead to functional changes. AB - Glioma is the second most common intracranial neoplasia in dogs, but the pathogenic mechanisms remain unclear. In humans, isocitrate dehydrogenase 1 (IDH1) is frequently mutated in gliomas. Although almost all human IDH1 mutations have been identified as involving the Arg132 codon, few studies have reported structural, functional, and mutational information for canine IDH1. Therefore, in this study, we cloned the canine IDH1 homologue and used PCR mutagenesis to substitute the wildtype (WT) Arg132 with His (R132H) or Ser (R132S). WT and mutated IDH1 were overexpressed in HeLa cells, and their presence was confirmed by immunoblotting and immunocytochemistry using mutation-specific antibodies. The IDH1 activity between WT, R132H, and R132S transfectants was compared by measuring the production of NADH and NADPH. NADPH production in R132H and R132S transfectants was lower than that in WT, but NADH levels were not significantly different. Finally, we detected increased expression of hypoxia inducible factor 1 alpha (HIF-1alpha) in the R132H and R132S transfectants. These results indicated that the canine IDH1 Arg132 mutation has the potential to induce carcinogenesis in canine somatic cells. PMID- 29285580 TI - Bone marrow findings in blast phase of polycythemia vera. AB - Approximately 10% of patients with polycythemia vera (PV) transform to acute leukemia (blast phase) at 10 years after initial diagnosis of PV. The bone marrow pathologic, cytogenetic, and molecular features of blast phase have not been well characterized. In this study, we reviewed 422 PV patients over a period of 11 years and identified 58 patients who developed acute myeloid leukemia (blast phase) during the course of disease. We found that blast phase of PV was characterized by overt myelodysplasia (n = 51, 88%); moderate to severe myelofibrosis (33 of 45, 73%); an abnormal karyotype (n = 51, 88%) that was often complex karyotype (n = 42, 72%); and gene mutations involving TP53 (55%), TET2 (27%), and DNMT3A (25%). Patients with blast phase of PV had an aggressive clinical course, with a median overall survival of 4 months after onset of blast phase. Eleven patients had close follow-up from polycythemic phase to blast phase: Four patients showed dysplastic changes in the polycythemic phase, and three of them transformed to blast phase without a "middle phase" of post-PV myelofibrosis.We conclude that blast phase of PV is characterized by myelodysplasia, moderate to severe fibrosis, a high frequency of an abnormal and often complex karyotype, and frequentTP53mutation. PMID- 29285582 TI - Low-virulent Babesia venatorum infection masquerading as hemophagocytic syndrome. PMID- 29285581 TI - MRD-negative complete remission in relapsed refractory hairy cell leukemia with bendamustine and obinutuzumab. PMID- 29285583 TI - Focus on paediatrics: 2017. PMID- 29285584 TI - Prevalence and predictors of severe grief reactions and desire for support following a death in the intensive care unit: a multicentre observational study. PMID- 29285585 TI - Discussion on Terminal weaning or immediate extubation for withdrawing mechanical ventilation in critically ill patients (the ARREVE observational study). PMID- 29285586 TI - Intracranial Ewing sarcoma: four pediatric examples. AB - BACKGROUND: Ewing sarcoma typically arises in bone and is unrelated to intraparenchymal small blue cell embryonal central nervous system (CNS) tumors previously designated primitive neuroectodermal tumors (PNETs). When the CNS is impacted, it is usually secondary to local extension from either the epidural space, skull, or intracranial or spinal metastases. Primary examples within the cranial vault are rare, usually dural-based, and are largely case reports in the literature. We detail four pediatric patients with solitary, primary intracranial Ewing sarcoma, all manifesting the archetypal EWRS1 gene rearrangement that confirms diagnosis. PROCEDURE: Neurosurgical Department records, spanning 21 years (1995-2016), were reviewed to identify patients. Demographics, clinical history, pathological/genetic features, and clinical course were retrieved from the medical record and personal files of the authors. RESULTS: Four patients, one male and three females, age 5 to 16 years, were identified. One presented in extremis from a large lesion, two with soft tissue masses, and the fourth as an incidental finding after being involved in a motor vehicle collision. Three had clear bony involvement: a 10-year-old girl with a large left temporal lesion had clear origin in the skull, with spiculated calcified striations throughout the mass; a 9-year-old girl presented with a bony left petrous apex mass; and a 16 year-old girl presented with a left temporal mass with extension to the dura and underlying bone erosion. Only the 5-year-old boy had a large left frontoparietal mass traversing the falx with no bony contact. All four tumors manifested the diagnostic EWSR1 mutation and were treated with an Ewing sarcoma regimen. Outcomes were variable, with one patient showing progressive metastatic disease and death 3 years after presentation, one patient with disease-free survival 10.5 years after completion of therapy, and one alive and well at the completion of therapy 1 year after diagnosis. One patient completed therapy recently with post therapy scans showing no evidence of disease. CONCLUSION: Testing for the EWSR1 mutation confirms the diagnosis of Ewing sarcoma and excludes other types of embryonal CNS tumors. Long-term disease-free survival is possible with adherence to the appropriate therapeutic regimen after gross surgical resection. PMID- 29285587 TI - The percutaneous pie-crusting medial release during arthroscopic procedures of the medial meniscus does neither affect valgus laxity nor clinical outcome. AB - PURPOSE: To analyze the effect of percutaneous pie-crusting medial release on valgus laxity before and after surgery and on clinical outcomes. METHODS: Eight hundred fourteen consecutive patients who underwent an arthroscopic procedure for the medial compartment of the knee were evaluated retrospectively. Sex, age, type of operation (meniscectomy, meniscal repair, and posterior root repair), type of accompanying surgery (none, cartilage procedure, ligament procedure and osteotomy) were documented. Sixty-four patients who underwent percutaneous pie crusting medial release (release group) and 64 who did not undergo medial release (non-release group) were matched using the propensity score method. Each patient was evaluated for the following variables: degree of valgus laxity on stress radiographs, Lysholm knee score, visual analog scale score, and International Knee Documentation Committee knee score and grade. RESULTS: At the 24-month follow-up, no significant increase in side-to-side differences in the valgus gap was observed in comparison to the preoperative value in the release group [preoperative, - 0.1 +/- 1.3 mm; follow-up, - 0.1 +/- 1.4 mm; (n.s.)]. The follow up Lysholm score, visual analog scale score and International Knee Documentation Committee knee score and grade were similar between the two groups. CONCLUSIONS: Percutaneous pie-crusting medial release is an additional procedure that can be performed during arthroscopic surgery for patients with a narrow medial joint space of the knee. Percutaneous pie-crusting medial release reduces iatrogenic injury to the cartilage and does not produce any residual valgus laxity of the knee. LEVEL OF EVIDENCE: IV. PMID- 29285588 TI - A Selective Fluorescence Sensor for Fe (III) Based on Phenanthroimidazole Imine Compound. AB - Experimental studies in the aqueous solution are crucial for the detection of metal cations in environmental and biological media. Polymer materials allow to work in aqueous media for fluorescent substances which are insoluble in water. Fluorescence sensor studies of the phenanthroimidazole imine compound (PI) synthesized previously by our group were performed in the polymer medium and the selective response to Fe (III) cation was obtained. The resulting sensor exhibited a selective fluorescence quenching effect to Fe (III). A logarithmic calibration graph was obtained in the range of 5.0 * 10- 5 and 1.0 * 10- 2 M. The interference effects of other ions besides Fe (III) have been examined and it has been observed that PI compound behaves selectively to Fe (III) ion in aqueous media. In addition, regeneration and reproducibility studies were carried out to determine the long-term usage of PI doped polymer film and reproducible results have been obtained for Fe (III) cation. PMID- 29285589 TI - Thiophene Appended Dual Fluorescent Sensor for Detection of Hg2+ and Cysteamine. AB - An efficient and highly selective pyrene-thiophene conjugate has been reported as a dual sensor for Hg2+ and cysteamine (an important drug for genetic disorder). The sensor displays a turn-on fluorescence response towards Hg2+ in a 2:1 stoichiometric ratio via excimer formation with a detection limit as low as of 30.6 nM. The excimer emission upon binding with Hg2+ has been rationalized by experimental as well as theoritical studies. Moreover, the [probe-Hg2+] adduct functions as an efficient sensor for cysteamine. This sensing process happens via the extraction of Hg2+ from the adduct. In this paper, change in emission properties of the receptor with varying pH and water content has also been explained. The sensing abilities of the sensor were examined in real water sample analysis. Therefore, the sensor can be used as an efficient and reusable fluorescent sensor for recognition of Hg2+ in water. PMID- 29285590 TI - In Silico Screening-Level Prioritization of 8468 Chemicals Produced in OECD Countries to Identify Potential Planetary Boundary Threats. AB - Legislation such as the Stockholm Convention and REACH aim to identify and regulate the production and use of chemicals that qualify as persistent organic pollutants (POPs) and very persistent and very bioaccumulative (vPvB) chemicals, respectively. Recently, a series of studies on planetary boundary threats proposed seven chemical hazard profiles that are distinct from the POP and vPvB profiles. We previously defined two exposure-based hazard profiles; airborne persistent contaminants (APCs) and waterborne persistent contaminants (WPCs) that correspond to two profiles of chemicals that are planetary boundary threats. Here, we extend our method to screen a database of chemicals consisting of 8648 substances produced within the OECD countries. We propose a new scoring scheme to disentangle the POP, vPvB, APC and WPC profiles by focusing on the spatial range of exposure potential, discuss the relationship between high exposure hazard and elemental composition of chemicals, and identify chemicals with high exposure hazard potential. PMID- 29285591 TI - Is a pretreatment radiological staging system feasible for suggesting the optimal extent of resection and predicting prognosis in glioblastoma? An observational study. AB - To assess the value of resection in glioblastoma based on pre-surgical tumor characteristics and a subsequent staging system. The lack of a staging system for glioblastoma hinders the analysis of treatment outcome. We classified 292 uniformly treated glioblastoma patients as stage I, II, or III based on tumor size, location, and eloquence and then analyzed the impact of the extent of resection. We classified 62% of patients as stage I, 25.3% as stage II, and 12.7% as stage III. Gross total resection (GTR) was performed mainly in stage I rather than stage II or III patients (79.2% vs. 14.6% vs. 6.3%; P < 0.001). Overall survival (OS) was 17.7, 14.6, and 10.8 months for stage I, II, and III patients, respectively (P = 0.005). Longer OS was significantly associated with greater extent of resection, younger age, KPS >= 70%, MGMT methylation, lower stage, and tumor <= 5 cm. In the subgroups of stage I (P = 0.04) and stage II (P < 0.001) but not stage III-patients, GTR and partial resection (PR) were associated with longer OS. We constructed several multivariable models including different variables, and greater extent of resection, smaller tumor size, and MGMT methylation consistently emerged as independent markers of longer OS. This staging system provides a feasible tool for comparison of results. We confirmed the value of partial resection in stage I and II patients, in contrast to some reports suggesting that biopsy only is sufficient when gross total resection cannot be safely achieved. PMID- 29285592 TI - On Modality Effects in Bilingual Emotional Language Processing: Evidence from Galvanic Skin Response. AB - Though previous research has shown a decreased sensitivity to emotionally-laden linguistic stimuli presented in the non-native (L2) compared to the native language (L1), studies conducted thus far have not examined how different modalities influence bilingual emotional language processing. The present experiment was therefore aimed at investigating how late proficient Polish (L1) English (L2) bilinguals process emotionally-laden narratives presented in L1 and L2, in the visual and auditory modality. To this aim, we employed the galvanic skin response (GSR) method and a self-report measure (Polish adaptation of the PANAS questionnaire). The GSR findings showed a reduced galvanic skin response to L2 relative to L1, thus suggesting a decreased reactivity to emotional stimuli in L2. Additionally, we observed a more pronounced skin conductance level to visual than auditory stimuli, yet only in L1, which might be accounted for by a self reference effect that may have been modulated by both language and modality. PMID- 29285593 TI - Klotho ameliorates hydrogen peroxide-induced oxidative injury in TCMK-1 cells. AB - PURPOSE: Defects in Klotho gene expression in mice result in a vulnerability to oxidative injuries. We aimed to identify the expression of Klotho in a mouse tubular epithelial (TCMK-1) cell line, and also to investigate changes in Klotho expression induced by oxidative stress and the potential role of intra- and extracellular Klotho protein. METHODS: During exposure to hydrogen peroxide (H2O2), an overexpression of the Klotho gene was induced and exogenous Klotho protein was added in TCMK-1 cells. The generation of reactive oxidative species (ROS) was examined by flow cytometry, and cell viability was assessed by Cell Counting Kit-8. Cellular apoptosis was determined by flow cytometry and Hoechst 33258 staining followed by Western blotting to evaluate the expression of Klotho, antioxidant enzymes, and apoptosis-associated proteins. RESULTS: While H2O2 significantly suppressed Klotho expression, cell viability, and the expression of antioxidant enzymes in a concentration-dependent manner, cellular apoptosis was increased and p38/MAPK and JNK/MAPK were activated. Intra- and extracellular Klotho remarkably ameliorated viability inhibition, ROS generation, and cellular apoptosis induced by H2O2. Intra- and extracellular Klotho also reversed the loss of antioxidant enzymes, the elevation of cleaved Caspase-3 and Bax/Bcl-2, and the phosphorylation of JNK/MAPK and p38/MAPK. CONCLUSIONS: Klotho has posed antioxidant and anti-apoptotic effects on oxidative injuries in TCMK-1 cells, which might be partially related to its inhibition of JNK/MAPK and p38/MAPK phosphorylation and subsequent elevation of antioxidant enzymes. Increasing Klotho expression has played a protective role against oxidative stress in tubular epithelial cells. PMID- 29285595 TI - Correction to: The relationship between childhood trauma and alcohol use initiation in Black and White adolescent girls: considering socioeconomic status and neighborhood factors. AB - In the original article, in Table 3, the sentence "Primary caregiver education <= 12 years" should be "Primary caregiver education < 12 years". The original article was corrected. PMID- 29285594 TI - Sleep quality, obstructive sleep apnea, and psychological distress in truck drivers: a cross-sectional study. AB - PURPOSE: Sleep disorders are highly prevalent in truck drivers. The aim of this study is to evaluate the prevalence of self-reported obstructive sleep apnea (OSA) and poor sleep quality in truck drivers, and to analyze the relationship between sleep problems and mental health. METHODS: A total of 526 male truck drivers (mean age 45.9; DS 9.4) responded to a questionnaire about risk factors for OSA (STOP-Bang), sleep quality perception (Pittsburg sleep questionnaire inventory, PSQI), excessive daytime sleepiness (Epworth sleepiness scale, ESS), and psychological disorders (general health questionnaire, GHQ-12). RESULTS: It was found that 51.1% of the drivers were at risk of OSA, 17.3% had bad sleep quality, and 8.9% had excessive daytime sleepiness (EDS). The association between psychological distress, OSA (OR = 1.67; CI 95% 0.99-2.83; p = 0.057), bad sleep quality (OR = 2.58; CI 95% 1.52-4.37; p < 0.001), and EDS (OR = 1.65; CI 95% 0.83 3.30; p = 0.151) was assessed. CONCLUSIONS: The high prevalence of sleep problems, especially suspected OSA, and low quality of sleep in truck drivers can worsen the general and psychological wellbeing of the workers. Educational programs focusing on sleep hygiene and behavioral interventions are needed to promote adequate sleep habits and improve individual and public health. PMID- 29285596 TI - Differential diagnostics of female "sexual" fluids: a narrative review. AB - INTRODUCTION AND HYPOTHESIS: Women expel various kinds of fluids during sexual activities. These are manifestations of sexual arousal and orgasm or coital incontinence. This study is aimed at suggesting a diagnostic scheme to differentiate among these phenomena. METHODS: Web of Science and Ovid (MEDLINE) databases were systematically searched from 1950 to 2017 for articles on various fluid expulsion phenomena in women during sexual activities, which contain relevant information on sources and composition of the expelled fluids. RESULTS: An ultra-filtrate of blood plasma of variable quantity, which is composed of transvaginal transudate at sexual stimulation, enables vaginal lubrication. Female ejaculation (FE) is the secretion of a few milliliters of thick, milky fluid by the female prostate (Skene's glands) during orgasm, which contains prostate-specific antigen. Squirting (SQ) is defined as the orgasmic transurethral expulsion of tenths of milliliters of a form of urine containing various concentrations of urea, creatinine, and uric acid. FE and SQ are two phenomena with different mechanisms. Coital incontinence (CI) could be classified into penetration and orgasm forms, which could be associated with stress urinary incontinence or detrusor hyperactivity. CONCLUSION: Squirting, FE, and CI are different phenomena with various mechanisms and could be differentiated according to source, quantity, expulsion mechanism, and subjective feelings during sexual activities. PMID- 29285598 TI - Diagnosis of Budd-Chiari syndrome. AB - Budd-Chiari syndrome (BCS) is defined by clinical and laboratory signs associated with partial or complete impairment of hepatic venous drainage in the absence of right heart failure or constrictive pericarditis. Primary BCS is the most frequent type and is a complication of hypercoagulable states, in particular myeloproliferative neoplasms. Secondary BCS involves tumor invasion or extrinsic compression. Most patients present with chronic BCS including a non-cirrhotic, dysmorphic, chronic liver disease with various degrees of fibrosis deposition. Acute BCS is rare, and patients present with hepatomegaly, ascites, and hepatic insufficiency. The diagnosis is based on imaging. Imaging features include (1) direct signs, in particular occlusion or compression of the hepatic veins and/or the inferior vena cava and venous collaterals and (2) indirect signs, in particular morphological changes in the liver with hypertrophy of the caudate lobe and delayed nodule formation. Ultrasound and magnetic resonance imaging are the gold standard for diagnosis. The aim of this review is to provide an overview of the role of imaging in the diagnosis of BCS. PMID- 29285599 TI - Computed tomography and magnetic resonance imaging of peripelvic and periureteric pathologies. AB - Peripelvic and periureteric areas are frequently overlooked in the imaging evaluations of the urinary system on computed tomography and magnetic resonance imaging. Several neoplastic and non-neoplastic disorders and diseases including lipomatosis, angiomyolipoma and angiolipomatous proliferation, vascular lesions, lymphangiomatosis, Rosai-Dorfman disease, Erdheim-Chester disease, extramedullary hematopoiesis, IgG4-related disease, lymphoma, mesenchymal tumors, trauma, and Antopol-Goldman lesion may involve these areas. Differentiation of these benign or malignant pathologies among themselves and from primary renal pathologies is of utmost importance to expedite the triage of patients for correct treatment approach. In this article, we aim to increase the awareness of the imaging specialists to the typical and atypical imaging features of the entities affecting these areas. PMID- 29285600 TI - Medical oncology and pancreatic cancer: what the radiologist needs to know. AB - The majority of PCs present as advanced disease, and treatment goals are for prolongation of life and palliation of the symptoms. Oncologists rely on our radiology colleagues to provide information on the extent of disease and the effectiveness of our treatment. The stakes rise in those patients where the disease has seemingly not spread and who might be treated with a goal of cure. For this subset of patients, medical oncologists and surgeons require as precise a radiologic description as possible in order to most accurately characterize the extent of the disease, in turn informing us as to the likelihood of a successful surgery and potential cure. In this paper, we review the fine points of imaging that distinguish resectable from borderline or unresectable patients, explain the principles of neoadjuvant and adjuvant therapy for pancreatic cancer, highlight some of the novel therapies now being pioneered in pancreatic cancer, and review radiologic features important for palliative care in patients with these tumors. PMID- 29285597 TI - Interspecific and intergeneric hybridization as a source of variation for wheat grain quality improvement. AB - KEY MESSAGE: The hybridization events with wild relatives and old varieties are an alternative source for enlarging the wheat quality variability. This review describes these process and their effects on the technological and nutritional quality. Wheat quality and its end-uses are mainly based on variation in three traits: grain hardness, gluten quality and starch. In recent times, the importance of nutritional quality and health-related aspects has increased the range of these traits with the inclusion of other grain components such as vitamins, fibre and micronutrients. One option to enlarge the genetic variability in wheat for all these components has been the use of wild relatives, together with underutilised or neglected wheat varieties or species. In the current review, we summarise the role of each grain component in relation to grain quality, their variation in modern wheat and the alternative sources in which wheat breeders have found novel variation. PMID- 29285602 TI - Triterpenoid Saponins from the Seeds of Aesculus chinensis and Their Cytotoxicities. AB - Six new triterpenoid saponins, aesculusosides A-F (1-6), together with 19 known ones, were isolated from the seeds of Aesculus chinensis. The new structures were elucidated through extensive spectroscopic analyses and by comparison with previously reported data. Some of the isolates were evaluated for their cytotoxic activities against MCF-7 cell line by an MTT assay, and compounds 15, 16, 19, and 23-25 exhibited inhibitory activities against MCF-7 with IC50 values ranging from 7.1 to 31.3 MUM. PMID- 29285601 TI - STOP-Bang questionnaire: the validation of a Portuguese version as a screening tool for obstructive sleep apnea (OSA) in primary care. AB - INTRODUCTION: The growing number of suspected patients diagnosed with obstructive sleep apnea (OSA) that are observed in sleep units has increased in the last decade. Therefore, screening methods have become important, especially in primary care (PC). AIM: This work aimed to test the performance of the STOP-Bang questionnaire for the suspicion/diagnosis of obstructive sleep apnea. METHODS: Eight-month prospective study; all patients referred from PC to the respective sleep clinic accompanied by a completed and translated version of the STOP-Bang questionnaire for a clinical evaluation. RESULTS: Two hundred fifty-nine observed patients were the study object. The age was 55.14 +/- 12.07 years, 71.03% were male patients with a neck circumference of 40.97 +/- 3.07 cm and BMI of 31.1 +/- 5.14 kg/m2. The diagnosis was confirmed in 82.6% of the patients: 34.6% having moderate and 36.8% severe disease. A STOP-Bang score of 3 or more resulted in positive predictive value (PPV) of 88.4% and a sensitivity for OSA of 98.6%. Has the questionnaire score raises, OSA's probability also raises in a proportional basis. For a STOP-Bang score of 6, the OSA probability reaches 98% and for a score of 8, it reaches 80% for severe OSA. Lower scores, 3 or 2, had a negative predictive value (NPV) for moderate-to-severe OSA of 86.96 and 87.5%, respectively. CONCLUSION: As much as we know, our study is the first that applied the STOP-Bang questionnaire in Portuguese PC. We demonstrate that these is a useful tool for the stratification of patients with suspicion and diagnosis of OSA, showing a high sensitivity and PPV. Besides that, the probability of severe OSA steadily increases along with its score and we show an excellent NPV with lower scores. PMID- 29285603 TI - Dual-task automatization: The key role of sensory-motor modality compatibility. AB - How do people automatize their dual-task performance through bottleneck bypassing (i.e., accomplish parallel processing of the central stages of two tasks)? In the present work we addressed this question, evaluating the impact of sensory-motor modality compatibility-the similarity in modality between the stimulus and the consequences of the response. We hypothesized that incompatible sensory-motor modalities (e.g., visual-vocal) create conflicts within modality-specific working memory subsystems, and therefore predicted that tasks producing such conflicts would be performed less automatically after practice. To probe for automaticity, we used a transfer psychological refractory period (PRP) procedure: Participants were first trained on a visual task (Exp. 1) or an auditory task (Exp. 2) by itself, which was later presented as Task 2, along with an unpracticed Task 1. The Task 1-Task 2 sensory-motor modality pairings were either compatible (visual manual and auditory-vocal) or incompatible (visual-vocal and auditory-manual). In both experiments we found converging indicators of bottleneck bypassing (small dual-task interference and a high rate of response reversals) for compatible sensory-motor modalities, but indicators of bottlenecking (large dual-task interference and few response reversals) for incompatible sensory-motor modalities. Relatedly, the proportion of individuals able to bypass the bottleneck was high for compatible modalities but very low for incompatible modalities. We propose that dual-task automatization is within reach when the tasks rely on codes that do not compete within a working memory subsystem. PMID- 29285604 TI - A new four-step hierarchy method for combined assessment of groundwater quality and pollution. AB - A new four-step hierarchy method was constructed and applied to evaluate the groundwater quality and pollution of the Dagujia River Basin. The assessment index system is divided into four types: field test indices, common inorganic chemical indices, inorganic toxicology indices, and trace organic indices. Background values of common inorganic chemical indices and inorganic toxicology indices were estimated with the cumulative-probability curve method, and the results showed that the background values of Mg2+ (51.1 mg L-1), total hardness (TH) (509.4 mg L-1), and NO3- (182.4 mg L-1) are all higher than the corresponding grade III values of Quality Standard for Groundwater, indicating that they were poor indicators and therefore were not included in the groundwater quality assessment. The quality assessment results displayed that the field test indices were mainly classified as grade II, accounting for 60.87% of wells sampled. The indices of common inorganic chemical and inorganic toxicology were both mostly in the range of grade III, whereas the trace organic indices were predominantly classified as grade I. The variabilities and excess ratios of the indices were also calculated and evaluated. Spatial distributions showed that the groundwater with poor quality indices was mainly located in the northeast of the basin, which was well-connected with seawater intrusion. Additionally, the pollution assessment revealed that groundwater in well 44 was classified as "moderately polluted," wells 5 and 8 were "lightly polluted," and other wells were classified as "unpolluted." PMID- 29285605 TI - Comparative effectiveness of abatacept, apremilast, secukinumab and ustekinumab treatment of psoriatic arthritis: a systematic review and network meta-analysis. AB - To assess the comparative effectiveness and safety of novel biologic therapies in psoriatic arthritis (PsA) and to establish the position of the non-anti-tumor necrosis factor alpha (TNF-alpha) biologic drugs in the treatment regimen of the disease. A systematic review and network meta-analysis (NMA) was conducted according to the preferred reporting items for systematic reviews and meta analyses (PRISMA) requirements. Two investigators identified the studies, abstracted data, and assessed the risk of bias independently. The NMA was conducted for efficacy [American College of Rheumatology (ACR) criteria, ACR20 and ACR50; psoriasis area and severity index (PASI), PASI75] and safety outcomes [any adverse events (AEs) and serious adverse events (SAEs)]; treatments were ranked using the P score for each outcome. The PROSPERO registration number was 42017072200. MEDLINE/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from the inception of each database to July 10, 2017. Randomized controlled trials (RCTs) for abatacept, apremilast, secukinumab or ustekinumab in adults with moderate and severe PsA were included. The overall PsA population and anti-TNF-alpha-naive, anti-TNF-alpha-failure, or anti-TNF-alpha-experienced subpopulations were considered. We identified eight eligible RCTs and included them in the systematic review and NMA. Significant differences in ACR20 response rate were revealed between secukinumab 150 mg and apremilast 20 mg [relative risk; RR = 2.55 (CI-confidence interval; 1.24, 5.23)] and between secukinumab 300 mg and apremilast 20 or 30 mg [RR = 3.57 CI (1.48, 8.64) and RR = 2.84 CI (1.18, 6.86), respectively]. Any AEs occurred more often in apremilast 20 and 30 mg compared with placebo [RR = 0.58 CI (0.45, 0.74) and RR = 0.58 CI (0.45, 0.75), respectively] but also compared with secukinumab 150 mg [RR = 0.54 CI (0.35, 0.81) and RR = 0.45 CI (0.35, 0.82), respectively]. No significant differences were revealed for SAEs among biologics and between biologics and placebo. In the overall population, as well as in the anti-TNF-alpha-naive subpopulation, secukinumab at a dose of 300 and 150 mg was ranked the highest for the ACR20 endpoint, while in the anti-TNF-alpha-experienced subpopulation, secukinumab 300 mg and apremilast 30 mg revealed the highest rank. Secukinumab 75 mg was the safest drug in terms of any AEs, but for SEAs the safest was ustekinumab 90 mg. Our study revealed no significant differences among non-anti-TNF-alpha biologics in the treatment of PsA in the comparisons performed with regards to the highest efficacy and safety. Both in the overall population and in the analyzed subpopulations, secukinumab 300 mg was ranked the highest for the ACR20 response rate. Secukinumab 300 mg was the safest drug in terms of any AEs, and ustekinumab 90 mg presented the lowest overall risk of SAEs. Head-to-head trials and evaluation of comparative efficacy and safety between non-TNF-alpha biologics are warranted to inform clinical decision making with a relevant treatment paradigm. PMID- 29285606 TI - The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes. AB - Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and SupersomesTM. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte(r) hepatocytes. The influence of 5 uM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4 hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions. PMID- 29285607 TI - A Nanocarrier Skin-Targeted Drug Delivery System using an Ascorbic Acid Derivative. AB - PURPOSE: As trisodium L-ascorbyl 2-phosphate 6-palmitate (APPS), an ascorbic acid derivative, is an amphiphilic substance, it forms micelles in aqueous solutions. Micelles are used as drug carriers and can emulsify drugs that are poorly soluble in water, such as nadifloxacin (NDFX). The purpose of this study was to prepare nanocarriers using APPS to carry NDFX into Yucatan micropig skin. METHODS: After synthesis of the NDFX nanoparticles by using the hydration method, physical evaluations were carried out that included assessments of particle size and zeta potential, encapsulation efficiency, particle structure by transmission electron microscopy, 31P-NMR spectra, and particle stability. Functional evaluations of the nanoparticles included 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays, skin penetration tests, and fluorescence microscopy observations. RESULTS: The encapsulation efficiency of NDFX in the nanoparticles was approximately 75%. With added magnesium chloride, the nanoparticles remained stably dispersed in aqueous solution for at least 14 days at 25 degrees C under protection from light. In addition, the nanoparticle formulation improved the skin permeability of NDFX. CONCLUSION: APPS-derived nanoparticles were shown to be useful as skin-targeting nanocarriers. PMID- 29285608 TI - Treatment Outcomes and Prognostic Factors After Recurrence of Esophageal Squamous Cell carcinoma. AB - BACKGROUND: The evaluation of treatment outcomes and detection of prognostic factors after recurrence are very important for tailoring optimal therapies for individual patients with recurrent esophageal cancer. METHODS: We reviewed 133 patients in whom esophageal squamous cell carcinoma (ESCC) recurred after curative surgery, and assessed recurrence patterns, treatment outcomes and prognostic factors. RESULTS: Recurrence in 57 (42.9%), 54 (40.6%) and 22 (16.5%) patients was locoregional, distant and combined, respectively. The median amounts of elapsed time until recurrence and median survival after recurrence for all patients were 9.1 and 8.3 months, respectively. Univariate and multivariate analyses selected time to recurrence (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.97-0.999; p = 0.04), recurrence location (locoregional vs. distant: HR, 1.63; 95% CI, 1.03-2.61; p = 0.04), number of organs with recurrence (1 vs. 3: HR, 3.49; 95% CI, 1.23-9.87; p = 0.02) and treatment after recurrence (best supportive care, [BSC] vs. chemotherapy [CT] or radiation therapy [RT]: HR, 0.37; 95% CI, 0.15-0.94; p = 0.04; BSC vs. CT and RT: HR, 0.50; 95% CI, 0.26 0.94; p = 0.03; BSC vs. surgery: HR, 0.47; 95% CI, 0.25-0.88; p = 0.02) as independent factors for survival after recurrence. Seventeen (12.8%) patients who had localized lymph node recurrence and lung oligometastasis and received multidisciplinary therapy after recurrence survived for >3 years thereafter. CONCLUSION: Despite the poor survival of patients with ESCC and early or distant recurrence or recurrence in >=3 recurrent organs, appropriate multimodal therapies should be tailored for individual patients with recurrent ESCC. PMID- 29285609 TI - Functional Compromise Cohort Study (FCCS): Sarcopenia is a Strong Predictor of Mortality in the Intensive Care Unit. AB - BACKGROUND: Functional compromise in elderly patients is considered to be a significant contributing factor in increased postoperative morbidity and mortality. It is described as a state of reduced physiologic reserves including, e.g., sarcopenia, cachexia, malnutrition and frailty with increased susceptibility to adverse health outcomes. Aim of this study was to investigate the association of sarcopenia with mortality in ICU patients. METHODS: A retrospective analysis of a total of 687 patients admitted to the ICU from January 2013 until December 2014 was performed. Indirect measurements of functional compromise in these patients were conducted. Sarcopenia was assessed using the L3 muscle index by using Osirix(c) on computed tomography scans. Groningen Frailty Indicator (GFI) and Short Nutritional Assessment Questionnaire (SNAQ) scores were extracted from the digital patient filing system and were used to assess frailty and nutritional status. These factors were analyzed using logistic regression analysis as predictor for in-hospital mortality and 6-month mortality, which was the primary endpoint along with other secondary outcome measures. RESULTS: Age was an independent predictor of in-hospital mortality, OR 1.043 (95% CI 1.030-1.057, p < 0.001). Analysis of sarcopenia showed OR 2.361 (95% CI 1.138-4.895, p = 0.021), for GFI OR 1.012 (95% CI 0.919-1.113, p = 0.811) and for SNAQ OR 1.262 (95% CI 1.091-1.460, p = 0.002). CONCLUSION: This study shows a promising role for the sarcopenia score as a predictor of mortality on the ICU, based upon CT imaging at L3 level and SNAQ score. Further research is necessary to test this in larger cohorts and to develop a possible instrument to predict mortality in the intensive care unit. PMID- 29285610 TI - A Pilot Study for a Better Visibility in the 3D Laparoscopic Right Colectomy Surgery. AB - OBJECTIVE: The aim of this study was to investigate the feasibility of digital defog technique in 3D laparoscopic surgery for right colon cancer. METHODS: Fifty patients with right colon cancer were divided into digital defogging group and control group. The intraoperative image clarity, the surgeon's anxiety, the time of operation and the time of fog nursing were compared. RESULTS: The clarity of the video screen of the digital defogging group was significantly higher than that of the control group, and the degree of anxiety was significantly lower than that of the control group. The operative time was (136.4 +/- 30.4) min in the digital defogging group, the operation time of the control group was (168.7 +/- 32.7) min, and the difference was statistically significant (P < 0.05). The time of dehumidification was (4.8 +/- 1.3) min in the digital defogging group and (16.3 +/- 4.6) min in the control group, and the difference was statistically significant (P < 0.05). CONCLUSION: Digital defogging technology in the 3D laparoscopic right colon cancer surgery significantly improves the clarity of video images, reduces the surgeon due to screen clarity caused by anxiety, reduces the operation of right colon cancer time and reduces the time to fog care. PMID- 29285611 TI - Process-induced degradation of bioresorbable PDLGA in bone tissue scaffold production. AB - Process-induced degradation of clinically relevant resorbable polymers was investigated for two thermal techniques, filament extrusion followed by fused deposition modelling (FDM). The aim was to develop a clear understanding of the relationship between temperature, processing time and resultant process-induced degradation. This acts to address the current knowledge gap in studies involving thermal processing of resorbable polymers. Poly(DL-lactide-co-glycolide) (PDLGA) was chosen for its clinically relevant resorption properties. Furthermore, a comparative study of controlled thermal exposure was conducted through compression moulding PDLGA at a selected range of temperatures (150-225 degrees C) and times (0.5-20 min). Differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) were used to characterise thermally induced degradation behaviour. DSC proved insensitive to degradation effects, whereas GPC demonstrated distinct reductions in molecular weight allowing for the quantification of degradation. A near-exponential pattern of degradation was identified. Through the application of statistical chain scission equations, a predictive plot of theoretical degradation was created. Thermal degradation was found to have a significant effect on the molecular weight with a reduction of up to 96% experienced in the controlled processing study. The proposed empirical model may assist prediction of changes in molecular weight, however, accuracy limitations are highlighted for twin-screw extrusion, accredited to high-shear mixing. The results from this study highlight the process sensitivity of PDLGA and proposes a methodology for quantification and prediction, which contributes to efforts in understanding the influence of manufacture on performance of degradable medical implants. PMID- 29285612 TI - Outcomes of operative and nonoperative treatment of 3- and 4-part proximal humeral fractures in elderly: a 10-year retrospective cohort study. AB - PURPOSE: Despite a rising incidence in proximal humeral fractures, there is still no evidence for the best treatment option, especially for elderly patients. The aim of this retrospective cohort study was to evaluate health-related quality of life (HRQoL), functional outcome, pain and social participation in elderly patients, after operative and nonoperative treatment of displaced 3- and 4-part proximal humeral fractures. METHODS: 150 patients aged >= 65, treated for a displaced 3- or 4-part proximal humeral fracture between 2004 and 2014, were invited to participate. Eventually 91 patients (61%) participated, of which 32 non-operatively treated patients were matched to 32 of the 59 operatively treated patients by propensity score matching. The EQ-5D, DASH, VAS for pain and WHODAS 2.0 Participation in Society domain were administered. Complications and reinterventions were registered. RESULTS: No significant difference was found between the two treatment groups in HRQoL (p = 0.43), function (p = 0.78) and pain (p = 0.19). A trend toward better social participation in the operative group (p = 0.09) was found. More complications and reinterventions occurred in the operative group than the nonoperative group, with 9 versus 5 complications (p = 0.37) and 8 versus 2 reinterventions (p = 0.08). CONCLUSIONS: In this study, we found no evidence of a difference in HRQoL, functional outcome or pain 1-10 years after operative or nonoperative treatment in patients of 65 and older with a displaced 3- or 4-part humeral fracture. Operatively treated patients showed a trend toward better social participation but also higher reintervention rates. PMID- 29285613 TI - Are large fracture trials really possible? What we have learned from the randomized controlled damage control study? AB - PURPOSE: Although they are considered the 'gold standard' of evidence-based medicine, randomized controlled trials are still a rarity in orthopedic surgery. In the management of patients with multiple trauma, there is a current trend toward 'damage control orthopedics', but to date, there is no proof of the superiority of this concept in terms of evidence-based medicine. The purpose of this article is to present unexpected difficulties we encountered in successfully completing our randomized controlled trial and to discuss the problematic differences between theoretically planning a trial and real-life practical experience of implementing the plan, with attention to published strategies. METHODS: The multicenter randomized controlled trial on risk adapted damage control orthopedic surgery of femur shaft fractures in multiple trauma patients (DCO study) was designed to determine whether 'risk adapted damage control orthopedics' of femoral shaft fractures is advantageous when treating multiple trauma patients. We compared our methods of study planning and realization point by point with published methods for conducting such trials. RESULTS: The study was methodically planned. We met the most prerequisites for successfully completing a large fracture trial, but experienced unexpected difficulties. After 2.5 years, the Deutsche Forschungsgemeinschaft suspended the financing because of low recruitment. The reasons were multifactorial. CONCLUSIONS: We believe it is much more difficult to perform a large fracture trial in reality than to plan it in theory. Even the theoretically best designed trial can prove unsuccessful in its implementation. The question remains: are large fracture trials even possible? Hopefully YES! TRIAL REGISTRATION: Current Controlled Trials ISRCTN10321620. Date assigned: 09/02/2007. LEVEL OF EVIDENCE: Level I. PMID- 29285614 TI - The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons. AB - Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5-200 MUM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation. PMID- 29285615 TI - Application of image recognition-based automatic hyphae detection in fungal keratitis. AB - The purpose of this study is to evaluate the accuracy of two methods in diagnosis of fungal keratitis, whereby one method is automatic hyphae detection based on images recognition and the other method is corneal smear. We evaluate the sensitivity and specificity of the method in diagnosis of fungal keratitis, which is automatic hyphae detection based on image recognition. We analyze the consistency of clinical symptoms and the density of hyphae, and perform quantification using the method of automatic hyphae detection based on image recognition. In our study, 56 cases with fungal keratitis (just single eye) and 23 cases with bacterial keratitis were included. All cases underwent the routine inspection of slit lamp biomicroscopy, corneal smear examination, microorganism culture and the assessment of in vivo confocal microscopy images before starting medical treatment. Then, we recognize the hyphae images of in vivo confocal microscopy by using automatic hyphae detection based on image recognition to evaluate its sensitivity and specificity and compare with the method of corneal smear. The next step is to use the index of density to assess the severity of infection, and then find the correlation with the patients' clinical symptoms and evaluate consistency between them. The accuracy of this technology was superior to corneal smear examination (p < 0.05). The sensitivity of the technology of automatic hyphae detection of image recognition was 89.29%, and the specificity was 95.65%. The area under the ROC curve was 0.946. The correlation coefficient between the grading of the severity in the fungal keratitis by the automatic hyphae detection based on image recognition and the clinical grading is 0.87. The technology of automatic hyphae detection based on image recognition was with high sensitivity and specificity, able to identify fungal keratitis, which is better than the method of corneal smear examination. This technology has the advantages when compared with the conventional artificial identification of confocal microscope corneal images, of being accurate, stable and does not rely on human expertise. It was the most useful to the medical experts who are not familiar with fungal keratitis. The technology of automatic hyphae detection based on image recognition can quantify the hyphae density and grade this property. Being noninvasive, it can provide an evaluation criterion to fungal keratitis in a timely, accurate, objective and quantitative manner. PMID- 29285616 TI - Correlation between the skeletal muscle index and surgical outcomes of pancreaticoduodenectomy. AB - PURPOSES: Sarcopenia is known to be associated with a worse prognosis following abdominal operations; however, the relationship between sarcopenia and the outcomes of pancreaticoduodenectomy remains unclear. MATERIALS: We measured body composition parameters, including total abdominal muscle area, using preoperative staging computed tomography (CT), in patients undergoing pancreaticoduodenectomy for periampullary cancer. The incidence of sarcopenia among these patients was evaluated and multivariable analysis was performed to identify independent predictors of postoperative pancreatic fistula. RESULTS: We identified 335 consecutive patients who were eligible for the study. Patients with sarcopenia had significantly poorer 5-year survival rates than those without sarcopenia (32.4 vs. 51.6%, respectively, P = 0.009). Interestingly, the incidence of Grade B/C pancreatic fistula was significantly lower in the sarcopenia group than in the non-sarcopenia group. Multivariate analysis identified high body mass index and soft pancreatic texture as independent predictors of postoperative pancreatic fistula. CONCLUSION: Sarcopenia may have an independent prognostic effect on the survival of patients with periampullary cancer. Preoperative nutritional intervention and rehabilitation may improve the postoperative outcomes of pancreaticoduodenectomy for periampullary cancer. PMID- 29285619 TI - Correction to: British Society of Interventional Radiology (BSIR) Inferior Vena Cava (IVC) Filter Registry. AB - On page 1553, the caption on Table 1 should read: Retrieval of filter by filter make/model and % retrievals within the manufacturer timescale. PMID- 29285618 TI - Oryza sativa salt-induced RING E3 ligase 2 (OsSIRP2) acts as a positive regulator of transketolase in plant response to salinity and osmotic stress. AB - MAIN CONCLUSION: A rice gene (OsSIRP2) encoding the RING Ub E3 ligase was highly induced under salinity stress and physically interacted with a transketolase (OsTKL1). Overexpression of OsSIRP2 conferred salinity and osmotic stress tolerance in plants. The RING E3 ligases play a vital role in post transitional modification through ubiquitination-mediated protein degradation that mediate plants responses during abiotic stresses and signal transduction. In this study, we report an Oryza sativa salt induced Really Interesting New Gene (RING) finger protein 2 gene (OsSIRP2) and elucidate its role under salinity and osmotic stress. The transcript levels of OsSIRP2 in rice leaves were induced in response to different abiotic stresses, such as salt, drought, heat, and abscisic acid (ABA) exposure. In vitro ubiquitination revealed that the OsSIRP2 protein formed poly-ubiquitin products, whereas a single amino acid substitution in OsSIRP2 (OsSIRP2C149A) in the RING domain did not form ubiquitinated substrates, supporting the hypothesis that E3 ligase activity requires the functional RING domain. Using the yeast two-hybrid (Y2H) assay, O. sativa transketolase 1 (OsTKL1) was identified as an interacting partner. OsSIRP2 was localized in the nucleus, whereas its interacting partner (OsTKL1) was localized in the cytosol and plastids in the rice protoplasts. Fluorescence signals between OsSIRP2 and OsTKL1 were observed in the cytosol. The pull-down assay confirmed the physical interaction between OsSIRP2 and OsTKL1. In vitro ubiquitination assay and in vitro protein degradation assay revealed that OsSIRP2 ubiquitinates OsTKL1 and enhances the degradation of OsTKL1 through the 26S proteasomal pathway. Heterogeneous overexpression of OsSIRP2 resulted in conferring tolerance against salinity and osmotic stress. Overall, our findings suggest that OsSIRP2 may be associated with plant responses to abiotic stresses and act as a positive regulator of salt and osmotic stress tolerance. PMID- 29285620 TI - Effect of the combined treatment of albumin with plasma synthesised pyrrole polymers on motor recovery after traumatic spinal cord injury in rats. AB - Traumatic spinal cord injury (TSCI) is a health problem for which there is currently no treatment or definitive therapy. Medicine has explored therapeutic options for patients with TSCI with the aim to improve their quality of life. One alternative has been the development of biomaterials that offer neuroprotection or neuroregeneration of damaged nerve tissue. The microinjection of iodine-doped polypyrrole particles synthesised by plasma (PPPy/I) has shown neuroprotective effects that favour motor function recovery in experimental animals with TSCI. However, their ability to migrate into the tissue has led to the need to test a suspension vehicle that enables the concentration of particles at the site of injury. To achieve this, two biomaterials of PPPy/I (P1 and P2) were studied. The superficial physicochemical characterisation of the polymers was performed by infrared spectroscopy, X-ray photoelectron spectroscopy and contact angle. The rheological performance under oscillatory shear rate of suspensions containing both polymers alone and in combination with bovine serum albumin was also studied. In vivo tests were performed on animals with and without TSCI that were microinjected with particles of P1 or P2 in suspension using a solution of rat serum albumin. Exposure to the protein solutions generates a protein multilayer on the surface of the biomaterials that can drastically change the behaviour of both P1 and P2, which led to severe repercussions in the in vivo assays. The results showed that surface chemistry plays an important role in the performance and that it is possible to treat TSCI with these materials. The interaction of the surface of materials PPPy/I.1 (P1) and PPPy/I.2 (P2) with bovine serum albumin (BSA) resulted in a series of changes in the surface chemistry of both biomaterials. The contact angle study (Fig. A) showed the presence of a critical BSA concentration ([BSA]c), in which a monolayer was formed on both polymers and then a stable protein multilayer, as evidenced by the establishment of a plateau in the determination of the contact angle. In vivo tests showed that this interaction may be beneficial in the treatment of traumatic spinal cord injury (TSCI), depending on the surface characteristics with or without rat serum albumin (RSA). The TSCI + P1 and TSCI + P2 + RSA groups obtained significant differences in functional recovery compared with the control group according to the Basso, Beattie and Bresnahan scale (BBB). PMID- 29285621 TI - Five-year clinical outcomes of visually guided laser balloon pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation. AB - BACKGROUND: Visually guided laser balloon (VGLB) ablation allows for pulmonary vein isolation (PVI) under direct endoscopic control. Short- and midterm clinical outcomes are in accordance with results of radiofrequency current (RFC) ablation for the treatment of paroxysmal atrial fibrillation (PAF). OBJECTIVE: The current study sought to assess the long-term clinical outcomes of VGLB-based PVI for PAF. METHODS: A total of 90 patients [60 +/- 10 years; 33 (37%) female, left atrial diameter 42 +/- 4 mm] with drug-refractory PAF underwent VGLB ablation. The median duration of PAF until VGLB ablation was 36 (interquartile range 12; 84) months. Follow-up was based on outpatient clinic visits including Holter ECGs and telephone interviews. Repeat ablation due to arrhythmia recurrences was performed using RFC ablation. RESULTS: After a single VGLB procedure, 5-year freedom from arrhythmia recurrence was 51% [95% confidence interval (CI) 39-62%]. Thirty-three patients underwent repeat RFC ablation procedures, resulting in multiple procedure freedom from arrhythmia recurrence of 78% (95% CI 68-88%). Major periprocedural complications occurred in four patients (4%). CONCLUSIONS: VGLB ablation for the treatment of drug-refractory PAF is safe and results in 5-year single and multiple procedure arrhythmia-free survival of 51 and 78%, respectively. PMID- 29285623 TI - Right versus left parasternal electrode position in the entirely subcutaneous ICD. AB - OBJECTIVES: The subcutaneous implantable cardioverter defibrillator (S-ICD(r)) has been established as an alternative to conventional transvenous ICD for the prevention of sudden cardiac death. Initial studies have shown safety and efficacy of the system with a left parasternal (LP) electrode. However, several case studies reported a right parasternal (RP) position. The purpose of this study was to analyze shock efficacy and safety of an RP electrode position. METHODS: Between June 2010 and May 2016, 120 S-ICD(r) were implanted at our institution. On the basis of the heart location on preoperative chest radiography (CXR), the investigators decided on an RP (n = 52) or LP electrode position (n = 68). All perioperative induced VF episodes, and spontaneous appropriate and inappropriate episodes during follow-up were analyzed. RESULTS: Patients with an RP electrode did not differ in terms of age, sex, or ejection fraction. A statistically significant difference in underlying cardiac disease was observed between the RP and LP electrode group, with more patients with channelopathies in the RP electrode group and more patients with non-ischemic cardiomyopathy in the LP electrode group. During a mean follow-up of 24.3 +/- 19.5 months, 27 appropriate (19 in the LP group and 8 in the RP group) and 28 inappropriate (18 LP and 10 RP) ICD shocks occurred (p value = NS). CONCLUSIONS: In the present study, an RP electrode position was chosen on the basis of chest radiographic characteristics and was efficient in terms of sensing and shock efficacy. Thus, a right-sided electrode implant might be an alternative if a left-sided electrode implant is inadequate. It might also be favorable for young patients with narrow heart silhouettes in the midsagittal position. PMID- 29285622 TI - Effects of the intensity of prehospital treatment on short-term outcomes in patients with acute heart failure: the SEMICA-2 study. AB - OBJECTIVE: Little is known about treatments provided by advanced life support (ALS) ambulance teams to patients with acute heart failure (AHF) during the prehospital phase, and their influence on short-term outcome. We evaluated the effect of prehospital care in consecutive patients diagnosed with AHF in Spanish emergency departments (EDs). METHODS: We selected patients from the EAHFE registry arriving at the ED by ALS ambulances with available follow-up data. We recorded specific prehospital ALS treatments (supplemental oxygen, diuretics, nitroglycerin, non-invasive ventilation) and patients were grouped according to whether they received low- (LIPHT; 0/1 treatments) or high-intensity prehospital therapy (HIPHT; > 1 treatment) for AHF. We also recorded 46 covariates. The primary endpoint was all-cause 7-day mortality, and secondary endpoints were prolonged hospitalisation (> 10 days) and in-hospital and 30-day mortality. Unadjusted and adjusted odds ratios were calculated to compare the groups. RESULTS: We included 1493 patients [mean age 80.7 (10) years; women 54.8%]. Prehospital treatment included supplemental oxygen in 71.2%, diuretics in 27.9%, nitroglycerin in 13.5%, and non-invasive ventilation in 5.3%. The LIPHT group included 1041 patients (70.0%) with an unadjusted OR for 7-day mortality of 1.770 (95% CI 1.115-2.811; p = 0.016), and 1.939 (95% CI 1.114-3.287, p = 0.014) after adjustment for 16 discordant covariables. The adjusted ORs for all secondary endpoints were always > 1 in the LIPHT group, but none reached statistical significance. CONCLUSIONS: Patients finally diagnosed with AHF at then ED that have received LIPHT by the ALS ambulance teams have a poorer short-term outcome, especially during the first 7 days. PMID- 29285625 TI - First confirmed case of chronic traumatic encephalopathy in a professional bull rider. PMID- 29285624 TI - Balloon dilatation of the Eustachian tube in adult patients with chronic dilatory tube dysfunction: a retrospective cohort study. AB - OBJECTIVES: The aim of this study is to assess the subjective and objective short term results and safety of transnasal balloon dilatation of the Eustachian tube (BET) in adult patients with chronic dilatory Eustachian tube dysfunction (ETD). DESIGN: Retrospective cohort study. Data collection was performed preoperatively, 1 and 3 months after BET. SETTING: Tertiary referral hospital. PARTICIPANTS: A cohort of 42 consecutive patients (66 ears). MAIN OUTCOME MEASURES: ETDQ-7 score, bone conduction threshold, air-bone gap, the ability to perform Valsalva's and/or Toynbee's manoeuvre, tympanic membrane and middle ear conditions were collected pre- and postoperatively. Subjective satisfaction and complications were collected postoperatively. RESULTS: The ETDQ-7 score improved significantly from 4.28 to 3.09 1 month postoperatively and from 4.10 to 2.96 3 months postoperatively. Bone conduction thresholds did not differ significantly postoperatively. A significant improvement of air-bone gap was found postoperatively. The tympanic membrane and middle ear condition showed improvement in 62%. Subjective satisfaction 1 and 3 months postoperatively was around 43 and 48%. A small number of minor (self-limiting) complications did occur. CONCLUSIONS: BET has shown to be a safe intervention, which may have a positive effect on objective and subjective indicators for chronic dilatory ETD in adult patients. We observed subjective positive effects in less than half of the patients. For certain indications, there was a measurable positive effect on the findings of the eardrum and ETDQ-7, whereas in other patients it seemed not to have any effect at all. Careful patient selection may improve this success rate. Randomized controlled trials with a prolonged follow-up are required to assess the value of BET in comparison to grommets. PMID- 29285627 TI - Fracture liaison services for osteoporosis in the Asia-Pacific region: current unmet needs and systematic literature review. AB - The analysis aimed to identify the treatment gaps in current fracture liaison services (FLS) and to provide recommendations for best practice establishment of future FLS across the Asia-Pacific region. The findings emphasize the unmet need for the implementation of new programs and provide recommendations for the refinement of existing ones. The study's objectives were to evaluate fracture liaison service (FLS) programs in the Asia-Pacific region and provide recommendations for establishment of future FLS programs. A systematic literature review (SLR) of Medline, PubMed, EMBASE, and Cochrane Library (2000-2017 inclusive) was performed using the following keywords: osteoporosis, fractures, liaison, and service. Inclusion criteria included the following: patients >= 50 years with osteoporosis-related fractures; randomized controlled trials or observational studies with control groups (prospective or retrospective), pre post, cross-sectional and economic evaluation studies. Success of direct or indirect interventions was assessed based on patients' understanding of risk, bone mineral density assessment, calcium intake, osteoporosis treatment, re fracture rates, adherence, and mortality, in addition to cost-effectiveness. Overall, 5663 unique citations were identified and the SLR identified 159 publications, reporting 37 studies in Asia-Pacific. These studies revealed the unmet need for public health education, adequate funding, and staff resourcing, along with greater cooperation between departments and physicians. These actions can help to overcome therapeutic inertia with sufficient follow-up to ensure adherence to recommendations and compliance with treatment. The findings also emphasize the importance of primary care physicians continuing to prescribe treatment and ensure service remains convenient. These findings highlight the limited evidence supporting FLS across the Asia-Pacific region, emphasizing the unmet need for new programs and/or refinement of existing ones to improve outcomes. With the continued increase in burden of fractures in Asia-Pacific, establishment of new FLS and assessment of existing services are warranted to determine the impact of FLS for healthcare professionals, patients, family/caregivers, and society. PMID- 29285628 TI - Diversity of activity participation determines bone mineral content in the lower limbs of pre-pubertal children with developmental coordination disorder. AB - : This study examined the relationships between activity participation and bone mineralization in children with developmental coordination disorder. Limited participation in physical, recreational, social, and skill-based and self improvement activities contributed to lower bone mineral content. For improved bone health, these children should participate in a variety of activities, not only physical activities. INTRODUCTION: Limited activity participation in children with developmental coordination disorder (DCD) may have a negative impact on bone mineral accrual. The objectives of this study were to compare bone mineralization and activity participation patterns of pre-pubertal children with DCD and those with typical development, and to determine the association between activity participation patterns and bone mineralization in children with DCD. METHODS: Fifty-two children with DCD (mean age = 7.51 years) and 61 children with typical development (mean age = 7.22 years) participated in the study. Appendicular and total body (less head) bone mineral content (BMC) and bone mineral density (BMD) were evaluated by a whole-body dual-energy X-ray absorptiometry scan. Activity participation patterns were assessed using the Children's Assessment of Participation and Enjoyment (CAPE) questionnaire. RESULTS: Children with DCD had lower appendicular and total body BMCs and BMDs than children with typical development overall (p < 0.05). They also had lower CAPE total activity and physical activity diversity scores (p < 0.05). After accounting for the effects of age, sex, height, lean mass, and fat mass, the total activity diversity score remained independently associated with leg BMC in children with DCD, explaining 5.1% of the variance (p = 0.030). However, the physical activity diversity score was no longer associated with leg BMC (p = 0.090). CONCLUSIONS: Diversity of activity participation and bone mineralization were lower in pre-pubertal children with DCD. Decreased total activity participation diversity was a contributing factor to lower BMC in the legs of children with DCD. PMID- 29285629 TI - Higher risk of gastric cancer among immigrants to Ontario: a population-based matched cohort study with over 2 million individuals. AB - BACKGROUND: The risk of gastric carcinoma (GC) varies around the world and between females and males. We aimed to compare the risk of GC among immigrants to Ontario, Canada, to the risk of GC in its general population. METHODS: This was a retrospective population-based matched cohort study from 1991 to 2014. We identified immigrants who were first eligible for the Ontario Health Insurance Plan at age 40 years or older, and matched 5 controls by year of birth and sex. We calculated crude rates and relative rates of GC stratified by sex. We modeled GC hazard using multivariable Cox proportional hazards regression, where a time varying coefficient was incorporated to examine changes in the association of immigrant status with GC hazard over time. RESULTS: Among females, 415 GC cases were identified among 209,843 immigrants and 1872 among 1,049,215 controls. Among males, 596 GC cases were identified among 191,792 immigrants and 2998 among 958,960 controls. Comparing immigrants from East Asia and Pacific with the controls, the crude relative rate of GC was 1.54 for females and 1.32 for males. The adjusted hazard ratio (HR) for GC among female immigrants was 1.29 [95% confidence interval (CI) 1.12, 1.48] within 10 years and 1.19 (1.01, 1.40) beyond 10 years; for males, the HR was 1.17 (1.04, 1.31) within 10 years and 1.00 (0.87, 1.15) beyond 10 years. CONCLUSION: The risk of GC among immigrants is elevated. Although high-risk immigrant populations in Ontario have been identified, further knowledge is required before a program of GC prevention that is targeted to them can be planned. PMID- 29285630 TI - Preeclampsia and Hypertension During Pregnancy in Areas with Relatively Low Levels of Traffic Air Pollution. AB - Objectives Air pollution exposure may contribute to the development of preeclampsia and hypertension during pregnancy. However, the evidence for such a relation is still limited. We investigated the associations between exposure for moderate to low levels of air pollution during pregnancy and preeclampsia and gestational hypertension in selected urban and county areas of Norway. Methods This study used a sub-group of 17,533 women in the Norwegian Mother and Child Cohort Study. Air pollution levels at residential addresses were estimated using land use regression models and back-extrapolated to the period of each pregnancy. Information on preeclampsia and gestational hypertension were obtained from the Medical Birth Registry of Norway and information on lifestyle factors was collected from questionnaires completed by the women during pregnancy. Results Moderate mean levels of NO2 (13.6 +/- 6.9 ug/m3) at residential address during pregnancy were not associated with preeclampsia and pregnancy hypertension. We found no statistically significant associations per 10 ug/m3 change in NO2 exposure and preeclampsia (adjusted OR 0.89, 95% CI 0.74, 1.08) or hypertension during pregnancy (adjusted OR 0.91, 95% CI 0.78, 1.06). Conclusions for Practice In this large Norwegian pregnancy cohort, we found no statistically significant associations for moderate to low levels of pregnancy NO2 exposure and preeclampsia or hypertension during pregnancy. PMID- 29285631 TI - Factors Associated with Vaccination Status of Children Aged 12-48 Months in India, 2012-2013. AB - Objectives India has more unvaccinated children than any other country despite provision of free vaccines through the government's Universal Immunization Program. In this study, we calculated the proportion of children aged 12-48 months who were fully vaccinated, under-vaccinated, or who had not received any vaccines. Childhood, household, and sociocultural factors associated with under vaccination and non-vaccination were evaluated. Methods Using data from India's 4th District-level Health and Facility Survey, 2012-2013 (DLHS-4) and the 2012 2013 Annual Health Survey (AHS), we calculated the proportion of children who were non-vaccinated, under-vaccinated, or fully vaccinated with 1 dose of Bacillus Calmette-Guerin, 3 doses of oral polio vaccine, 3 doses of diphtheria pertussis-tetanus, and 1 dose of measles-containing vaccine. The odds of full vaccination compared to non-vaccination and under-vaccination relative to various factors was assessed using a multivariable, multinomial logistic regression which accounted for survey design. Results Of 1,929,580 children aged 12-48 months, 59% were fully vaccinated, 34% were under-vaccinated, and 7% were non-vaccinated. Compared to children born in government institutions, children delivered in non institutional settings with a skilled birth attendant present had higher odds of non-vaccination (OR 1.66) and those without a skilled attendant present had still greater odds of non-vaccination (OR 2.39) and under-vaccination (OR 1.11). Conclusions for Practice India's vaccination rates among children aged 12-48 months remains unacceptably low. The Indian government should encourage institutional delivery or birthing with a skilled attendant to ensure women receive adequate health education through antenatal care that includes the importance of childhood vaccination. PMID- 29285632 TI - Infant Health and Future Childhood Adversity. AB - Objective To investigate the extent to which disabling infant health conditions are associated with adverse childhood experiences at age 5. Methods We conducted a secondary analysis of data from the Fragile Families and Child Wellbeing Study, a national urban birth cohort. We estimated logistic regression models of associations between the presence of a disabling infant health condition and the child's ACE exposures at age 5, controlling for factors that preceded the child's birth, including the mother's sociodemographic characteristics, physical health, mental illness, and substance abuse and the parents' criminal justice system involvement and domestic violence or sexual abuse. ACEs included 4 categories of child maltreatment (physical, sexual, psychological abuse, neglect) and 5 categories of household dysfunction (father absence, substance use, mental illness, caregiver treated violently, incarceration). Results 3.3% of the children were characterized as having a disabling health condition that was likely present at birth. Logistic regression estimates indicate that having a disabling infant health condition was associated with 83% higher odds of the child experiencing 2 or more ACEs (AOR 1.83, CI 1.14-2.94) and 73% higher odds of the child experiencing 3 or more ACEs (AOR 1.73, CI 1.07-2.77) at age 5. Conclusions for Practice The finding of strong links between disabling infant health conditions and ACEs at age 5 suggests that child health and ACEs play intertwining and mutually reinforcing roles during the early lifecourse and highlights the critical importance of investing in systems that simultaneously promote optimal child development and address childhood adversity. PMID- 29285635 TI - Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group. AB - An increasing number of manuscripts focus on the in vitro evaluation of established and novel anti-tumor agents in experimental models. Whilst the design of such in vitro assays is inherently flexible, some of these studies lack the minimum information necessary to critically evaluate their relevance or have been carried out under unsuitable conditions. The use of appropriate and robust methods and experimental design has important implications for generating results that are reliable, relevant, and reproducible. The Pharmacology and Molecular Mechanisms (PAMM) group of the European Organization for Research and Treatment of Cancer (EORTC) is the largest group of academic scientists working on drug development and bundle decades of expertise in this field. This position paper addresses all researchers with an interest in the preclinical and cellular pharmacology of anti-tumor agents and aims at generating basic recommendations for the correct use of compounds to be tested for anti-tumor activity using a range of preclinical cellular models of cancer. PMID- 29285633 TI - Release behavior of VAN from four types of CaP-ceramic granules using various loading methods at two different degrees of acidity. AB - The release behavior of vancomycin (VAN) from beta-tricalciumphosphate (betaTCP), hydroxyapatite (HA), glass ceramic (GC) and sponge-like collagen betaTCP granule composite (sponge) was studied. Vacuum and drip loading methods were compared. The influence of VAN concentration and pH on release behavior was analyzed with respect to a stable release level of VAN above the minimum inhibitory concentration over 14 days. Initially the morphology of the granule carrier systems was examined with ESEM, stereomicroscopy, uCT-imaging and Camsizer(r) regarding porosity, interconnecting pores and granule size. Drug release patterns following a vacuum and a drip loading method with VAN at concentrations of 5 and 50 mg/ml were compared. The influence of pH 7.4 compared to pH 5.0 on release behavior was studied. The drug was released in bidistilled water at 37 degrees C, the concentration determined by photometry at 220 nm. For statistical purposes, the mean and standard deviation were calculated and analyzed by Origin 9.1 Professional SR1 (OriginLab). Due to low interconnectivity and low porosity, the vacuum loading method was unable to attain complete drug loading of the ceramic granules. The sponge showed an inhomogeneous distribution of betaTCP granules. Drug release was high at pH 7.4, at pH 5.0 it practically did not occur. All samples except for the collagen-complex show an initial VAN burst release with a following steady release. Loading with 5 mg/ml concentrated VAN resulted in a higher percentage of available drug being released. However, when loaded with 50 mg/ml, the absolute amount of drug released was higher. PMID- 29285634 TI - Transient inactivation of the paraventricular nucleus of the thalamus enhances cue-induced reinstatement in goal-trackers, but not sign-trackers. AB - RATIONALE: The paraventricular nucleus of the thalamus (PVT) has been shown to mediate cue-motivated behaviors, such as sign- and goal-tracking, as well as reinstatement of drug-seeking behavior. However, the role of the PVT in mediating individual variation in cue-induced drug-seeking behavior remains unknown. OBJECTIVES: This study aimed to determine if inactivation of the PVT differentially mediates cue-induced drug-seeking behavior in sign-trackers and goal-trackers. METHODS: Rats were characterized as sign-trackers (STs) or goal trackers (GTs) based on their Pavlovian conditioned approach behavior. Rats were then exposed to 15 days of cocaine self-administration, followed by a 2-week forced abstinence period and then extinction training. Rats then underwent tests for cue-induced reinstatement and general locomotor activity, prior to which they received an infusion of either saline (control) or baclofen/muscimol (B/M) to inactivate the PVT. RESULTS: Relative to control animals of the same phenotype, GTs show a robust increase in cue-induced drug-seeking behavior following PVT inactivation, whereas the behavior of STs was not affected. PVT inactivation did not affect locomotor activity in either phenotype. CONCLUSION: In GTs, the PVT appears to inhibit the expression of drug-seeking, presumably by attenuating the incentive value of the drug cue. Thus, inactivation of the PVT releases this inhibition in GTs, resulting in an increase in cue-induced drug-seeking behavior. PVT inactivation did not affect cue-induced drug-seeking behavior in STs, suggesting that the role of the PVT in encoding the incentive motivational value of drug cues differs between STs and GTs. PMID- 29285636 TI - The effect of selective internal radiation therapy with yttrium-90 resin microspheres on lung carbon monoxide diffusion capacity. AB - BACKGROUND: Selective internal radiation therapy (SIRT) with embolization of branches of the hepatic artery is a valuable therapeutic tool for patients with hepatic malignancies; however, it is also associated with lung injury risk due to shunting. Diffusion capacity of the lungs for carbon monoxide (DLCO) is a clinically significant lung function test, and worsening in DLCO is suggested to reflect a limited gas exchange reserve caused by the potential toxicity of chemoradiotherapy or it may be a marker of related lung injury. This study aimed to examine the changes in DLCO during SIRT with resin microspheres in newly treated and retreated patients. Forty consecutive patients who received SIRT for a variety of malignant conditions were included. All subjects were treated with Yttrium-90 labelled resin microspheres. DLCO tests were performed after the procedures. In addition, patients were specifically followed for radiation pneumonitis. RESULTS: The mean DLCO did not significantly change after the first (82.8 +/- 19.4 vs. 83.1 +/- 20.9, p = 0.921) and the second treatments (87.4 +/- 19.7 vs. 88.6 +/- 23.2, p = 0.256). Proportion of patients with impaired DLCO at baseline was not altered significantly after the first (37.5 vs. 45.0%, p = 0.581) and the second treatments (27.3 vs. 27.3%, p = 1.000). Also, percent change in DLCO values did not correlate with radiation dose, lung shunt fraction, or lung exposure dose (p > 0.05 for all comparisons). None of the patients developed radiation pneumonitis. CONCLUSIONS: Our results suggest that no significant change in DLCO in association with SIRT occurs, both after the first or the second treatment sessions. Further larger studies possibly with different protocols are warranted to better delineate DLCO changes after SIRT in a larger spectrum of patients. PMID- 29285637 TI - Lymphomas in IgG4-related disease: clinicopathologic features in a Western population. AB - Lymphomas that occur in the setting of IgG4-related disease (IgG4-RD) are uncommon. Most reported cases derive from Asia and are MALT lymphomas occurring in orbital IgG4-RD. The spectrum of lymphomas among IgG4-RD patients in the Western world remains poorly defined. The aim of this study was to report our experience with lymphomas occurring in IgG4-RD. Eight cases were identified from the pathology and consultation files. The median age was 61 years (range 22-68) at IgG4-RD diagnosis and 63.5 years (range 33-79) at lymphoma diagnosis, with a M:F ratio of 4:4. The diagnosis of lymphoma and IgG4-RD was concurrent in three cases and asynchronous in five (interval 4.3-16.4 years). Concurrent cases included a MALT lymphoma and a diffuse large B cell lymphoma (DLBCL) occurring with IgG4-related sialadenitis and a follicular lymphoma occurring with orbital IgG4-RD. Asynchronous cases included a lymphoplasmacytic lymphoma with large cell transformation and intervening IgG4-related pancreatitis, a MALT lymphoma after lacrimal IgG4-RD, two DLBCLs after multiorgan IgG4-RD, and a DLBCL after IgG4 related sialadenitis. Our findings suggest that lymphomas in IgG4-RD are more varied in location and type than the experience reported from Asia to date. Pathologists should be aware of the potential for lymphoma to develop in patients with IgG4-RD and should have a high degree of suspicion when lymphadenopathy or extranodal masses persist despite appropriate therapy for IgG4-RD. The co occurrence of IgG4-RD and lymphoma that is reported here and previously suggests a possible etiologic association. PMID- 29285639 TI - Analysis of 3D spatial trajectories in Parkinsonian, essential and physiological tremors. AB - The clinical differentiation of the tremor in Parkinson's disease (PD) and essential tremor (ET) can sometimes be challenging, especially in the early stage of the disease. As different neural oscillators are involved in the generation of these two types of tremor, their trajectorial analysis could also be different. The goal of this study was to investigate whether some disease-specific patterns related to their tremor trajectories in fact exist. The three-axial accelerometer signals of the hand tremor obtained from a total of 369 participants [49 with PD, 25 with isolated resting tremor (iRT), 133 with ET, and finally 162 normal subjects with physiological tremor (Ph)] were subjected to vector analysis using a custom-made mathematical program. Subsequently, detailed trajectorial analysis was performed. The key discrimination ability between the PD and ET groups was represented by the ratio of the vector in the y-z plane and the spatial vector. The great majority of the patients with PD and iRT showed significantly higher values as compared to those with ET. The differences between the PD and iRT groups and between ET and Ph were not statistically significant. We suggest that the newly introduced three-axial accelerometry with analysis of tremor trajectories could be beneficial in differentiating between tremors in PD and ET. PMID- 29285638 TI - The Use of Online Posts to Identify Barriers to and Facilitators of HIV Pre exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men: A Comparison to a Systematic Review of the Peer-Reviewed Literature. AB - Pre-exposure prophylaxis (PrEP) remains an under-utilized HIV prevention tool among men who have sex with men (MSM). To more comprehensively elucidate barriers and facilitators to PrEP use among US MSM, we conducted a systematic review of peer-reviewed published articles and content analysis of online posts about PrEP. We searched peer-reviewed databases (Medline, Web of Science, Google Scholar) using MESH headings and keywords about PrEP and/or HIV prevention from 2005 to 2015. We included original studies among MSM in the US that reported on barriers, facilitators, or other factors related to PrEP use. We also searched online posts and associated comments (news articles, opinion pieces, blogs and other social media posts) in diverse venues (Facebook, Slate Outward, Huffington Post Gay Voices, Queerty, and My PrEP Experience blog) to identify posts about PrEP. We used content analysis to identify themes and compare potential differences between the peer-reviewed literature and online posts. We identified 25 peer reviewed articles and 28 online posts meeting inclusion criteria. We identified 48 unique barriers and 46 facilitators to using PrEP. These 94 themes fit into six overarching categories: (1) access (n = 14), (2) attitudes/beliefs (n = 24), (3) attributes of PrEP (n = 13), (4) behaviors (n = 11), (5) sociodemographic characteristics (n = 8), and (6) social network (n = 6). In all categories, analysis of online posts resulted in identification of a greater number of unique themes. Thirty-eight themes were identified in the online posts that were not identified in the peer-reviewed literature. We identified barriers and facilitators to PrEP in online posts that were not identified in a systematic review of the peer-reviewed literature. By incorporating data both from a systematic review of peer-reviewed articles and from online posts, we have identified salient and novel information about barriers to and facilitators of PrEP use. Traditional research approaches may not comprehensively capture current factors important for designing and implementing PrEP related interventions. PMID- 29285640 TI - Difference of clinical course between cases with bone union and those with delayed union following osteoporotic vertebral fractures. AB - : In this prospective multicenter study of osteoporotic vertebral fractures (OVFs), delayed union of OVF at 6-month follow-up caused prolonged pain, QOL impairment, ADL impairment, cognitive status deterioration, and vertebral collapse progression. PURPOSE: Delayed union following osteoporotic vertebral fracture displayed as an intravertebral cleft on plain X-rays was reported to be a factor for prolonged severe pain. However, the difference of clinical course between bone union and delayed union cases still remains unclear. The purpose of this study was to identify how OVF delayed union following conventional conservative treatment influences the clinical course with a prospective multicenter study. METHODS: A total of 324 OVF patients from 25 institutes in Osaka, Japan, were included in the study. At the 6-month follow-up after initial visit to each institute, the patients were classified into bone union and delayed union groups based on plain X-ray findings. The outcome assessments included a VAS for back pain, SF-36 for quality of life (QOL), severity of bed-ridden state for activities of daily living (ADL), MMSE for cognitive functions, and degree of vertebral collapse on plain X-rays. RESULTS: Overall, 280 patients were included into the union group and 44 into the delayed union group. The VAS score at 6 months was significantly worse in the delayed union group (p = 0.01). The scores for the SF-36 scales of physical functioning and bodily pain at 6 months were significantly lower in the delayed union group (p = 0.019, p = 0.01, respectively). The percentage of nearly or completely bed-ridden patients was significantly higher in the delayed union group. The percentage of newly developed cognitive impairment was significantly higher in the delayed union group (p = 0.02). Progression of vertebral collapse during the 6-month follow-up was more pronounced in the delayed union group (p < 0.01). CONCLUSION: The present results revealed that delayed union following OVF causes prolonged pain, QOL impairment, ADL impairment, cognitive status deterioration, and vertebral collapse progression. PMID- 29285641 TI - Core Body Temperature but Not Intraabdominal Pressure Predicts Postoperative Complications Following Closed-System Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Administration. AB - BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery (CRS), performed using closed-abdomen technique (CAT), may affect intraabdominal pressure (IAP). High IAP may increase postoperative complications due to decreased venous return and hypoperfusion to vital organs. Elevated core body temperature (CBT) may cause multiorgan dysfunction. Low IAP or CBT could result in suboptimal HIPEC and potentially translate into early disease recurrence. The aim of the present study is to identify possible correlations between IAP or CBT and postoperative complications. PATIENTS AND METHODS: Continuous intraabdominal pressure measurement was performed by intraabdominal catheter. Inflow temperature was set at 44 degrees C, and mean perfusate temperature was 42 degrees C. CBT was measured continuously in the distal esophagus. We compared the rate of postoperative complications between the low IAP group (2-10 mmHg, n = 28), target IAP group (10-20 mmHg, n = 71), and high IAP group (20-34 mmHg, n = 16) as well as with CBT as a continuous variable. RESULTS: 115 patients were included in the study. There was no difference between IAP groups in terms of age, gender, primary diagnosis, operative peritoneal cancer index, CBT, or operative time. There was no correlation between IAP and postoperative complications or with prolonged hospital stay. On multivariate analysis, elevated mean CBT was a positive predictor of postoperative complications (p = 0.035). CONCLUSIONS: IAP level during closed-abdomen technique HIPEC is not associated with postoperative complications. However, elevated CBT may increase postoperative complications. PMID- 29285643 TI - Correction to: Exploring the peptide retention mechanism in molecularly imprinted polymers. AB - The authors would like to call the reader's attention to the fact that unfortunately due to the file formatting during the exporting of the data matrix from the program Unscrambler (used for the development of the statistical model) to the Word office file. PMID- 29285642 TI - Association of Delivery System Integration and Outcomes for Major Cancer Surgery. AB - BACKGROUND: Integrated delivery systems (IDSs) are postulated to reduce spending and improve outcomes through successful coordination of care across multiple providers. Nonetheless, the actual impact of IDSs on outcomes for complex multidisciplinary care such as major cancer surgery is largely unknown. METHODS: Using 2011-2013 Medicare data, this study identified patients who underwent surgical resection for prostate, bladder, esophageal, pancreatic, lung, liver, kidney, colorectal, or ovarian cancer. Rates of readmission, 30-day mortality, surgical complications, failure to rescue, and prolonged hospital stay for cancer surgery were compared between patients receiving care at IDS hospitals and those receiving care at non-IDS hospitals. Generalized estimating equations were used to adjust results by cancer type and patient- and hospital-level characteristics while accounting for clustering of patients within hospitals. RESULTS: The study identified 380,053 patients who underwent major resection of cancer, with 38% receiving care at an IDS. Outcomes did not differ between IDS and non-IDS hospitals regarding readmission and surgical complication rates, whereas only minor differences were observed for 30-day mortality (3.5% vs 3.2% for IDS; p < 0.001) and prolonged hospital stay (9.9% vs 9.2% for IDS; p < 0.001). However, after adjustment for patient and hospital characteristics, the frequencies of adverse perioperative outcomes were not significantly associated with IDS status. CONCLUSIONS: The collective findings suggest that local delivery system integration alone does not necessarily have an impact on perioperative outcomes in surgical oncology. Moving forward, stakeholders may need to focus on surgical and oncology-specific methods of care coordination and quality improvement initiatives to improve outcomes for patients undergoing cancer surgery. PMID- 29285644 TI - Designation of fingerprint glycopeptides for targeted glycoproteomic analysis of serum haptoglobin: insights into gastric cancer biomarker discovery. AB - Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide, largely because of difficulties in early diagnosis. Despite accumulating evidence indicating that aberrant glycosylation is associated with GC, site-specific localization of the glycosylation to increase specificity and sensitivity for clinical use is still an analytical challenge. Here, we created an analytical platform with a targeted glycoproteomic approach for GC biomarker discovery. Unlike the conventional glycomic approach with untargeted mass spectrometric profiling of released glycan, our platform is characterized by three key features: it is a target-protein-specific, glycosylation-site-specific, and structure-specific platform with a one-shot enzyme reaction. Serum haptoglobin enriched by immunoaffinity chromatography was subjected to multispecific proteolysis to generate site-specific glycopeptides and to investigate the macroheterogeneity and microheterogeneity. Glycopeptides were identified and quantified by nano liquid chromatography-mass spectrometry and nano liquid chromatography-tandem mass spectrometry. Ninety-six glycopeptides, each corresponding to a unique glycan/glycosite pairing, were tracked across all cancer and control samples. Differences in abundance between the two groups were marked by particularly high magnitudes. Three glycopeptides exhibited exceptionally high control-to-cancer fold changes along with receiver operating characteristic curve areas of 1.0, indicating perfect discrimination between the two groups. From the results taken together, our platform, which provides biological information as well as high sensitivity and reproducibility, may be useful for GC biomarker discovery. Graphical abstract ?. PMID- 29285645 TI - Analysis of ibuprofen and its main metabolites in roots, shoots, and seeds of cowpea (Vigna unguiculata L. Walp) using liquid chromatography-quadrupole time-of flight mass spectrometry: uptake, metabolism, and translocation. AB - A liquid chromatography quadruple time-of-flight mass spectrometry (LC-QqTOF MS/MS) method was developed for simultaneous quantitative analysis of ibuprofen (IBU), 1- and 2-hydroxyibuprofen (1-OH IBU and 2-OH IBU), and carboxyibuprofen (CBX IBU) while preserving the ability of the instrument to get precursor and product ion mass spectra of non-target compounds. The trigger was the precursor ions reaching 100 cps intensity. Sample preparation was carried out by ultrasound solid-liquid extraction with methanol as extraction solvent at pH < 2 followed by solid-phase extraction (SPE) clean-up using STRATA-X cartridges and methanol as an eluent. Linearity was obtained in the range 50-10,000 ng mL-1 for IBU, each OH IBU and CBX IBU (r >= 0.99). The proposed method was satisfactorily validated showing absolute recoveries of > 70% for all target analytes at low and high concentration levels. The lowest limit of quantification was < 50 ng g-1 in plant. This method was applied to investigate IBP behavior in cowpea (Vigna unguiculata (L.) Walp) treated at high IBU concentrations and its presence in vegetables irrigated with treated water. Up to 46 metabolites, mostly hydroxylated metabolites and conjugates with hexosides and amino acids, were identified. The most abundant metabolites were also identified in an eggplant sample. Graphical Abstract ? Ibuprofen metabolite identification. PMID- 29285646 TI - Use of phenyl/tetrazolyl-functionalized magnetic microspheres and stable isotope labeled internal standards for significant reduction of matrix effect in determination of nine fluoroquinolones by liquid chromatography-quadrupole linear ion trap mass spectrometry. AB - In this study, the strategy of unique adsorbent combined with isotope labeled internal standards was used to significantly reduce the matrix effect for the enrichment and analysis of nine fluoroquinolones in a complex sample by liquid chromatography coupled to quadrupole linear ion trap mass spectrometry (LC-QqQLIT MS/MS). The adsorbent was prepared conveniently by functionalizing Fe3O4@SiO2 microspheres with phenyl and tetrazolyl groups, which could adsorb fluoroquinolones selectively via hydrophobic, electrostatic, and pi-pi interactions. The established magnetic solid-phase extraction (MSPE) method as well as using stable isotope labeled internal standards in the next MS/MS detection was able to reduce the matrix effect significantly. In the process of LC-QqQLIT-MS/MS analysis, the precursor and product ions of the analytes were monitored quantitatively and qualitatively on a QTrap system equipped simultaneously with the multiple reaction monitoring (MRM) and enhanced product ion (EPI) scan. Subsequently, the enrichment method combined with LC-QqQLIT-MS/MS demonstrated good analytical features in terms of linearity (7.5-100.0 ng mL-1, r > 0.9960), satisfactory recoveries (88.6%-118.3%) with RSDs < 12.0%, LODs = 0.5 MUg kg-1 and LOQs = 1.5 MUg kg-1 for all tested analytes. Finally, the developed MSPE-LC-QqQLIT-MS/MS method had been successfully applied to real pork samples for food-safety risk monitoring in Ningxia Province, China. Graphical abstract Mechanism of reducing matrix effect through the as-prepared adsorbent. PMID- 29285647 TI - Spatial and frequency specificity of the ventriloquism aftereffect revisited. AB - Exposure to audiovisual stimuli with a consistent spatial misalignment seems to result in a recalibration of unisensory auditory spatial representations. The previous studies have suggested that this so-called ventriloquism aftereffect is confined to the trained region of space, but yielded inconsistent results as to whether or not recalibration generalizes to untrained sound frequencies. Here, we reassessed the spatial and frequency specificity of the ventriloquism aftereffect by testing whether auditory spatial perception can be independently recalibrated for two different sound frequencies and/or at two different spatial locations. Recalibration was confined to locations within the trained hemifield, suggesting that spatial representations were independently adjusted for the two hemifields. The frequency specificity of the ventriloquism aftereffect depended on the presence or the absence of conflicting audiovisual adaptation stimuli within the same hemifield. Moreover, adaptation of two different sound frequencies in opposite directions (leftward vs. rightward) resulted in a selective suppression of leftward recalibration, even when the adapting stimuli were presented in different hemifields. Thus, instead of representing a fixed stimulus-driven process, cross-modal recalibration seems to critically depend on the sensory context and takes into account inconsistencies in the cross-modal input. PMID- 29285649 TI - Carboxyhemoglobin Levels Induced by Cigarette Smoking Outdoors in Smokers. AB - INTRODUCTION: Non-invasive screening of carboxyhemoglobin saturation (SpCO) in the emergency department to detect occult exposure is increasingly common. The SpCO threshold to consider exposure in smokers is up to 9%. The literature supporting this cutoff is inadequate, and the impact of active smoking on SpCO saturation remains unclear. The primary objective was to characterize baseline SpCO in a cohort of smokers outdoors. Secondary objectives were to explore the impact of active smoking on SpCO and to compare SpCO between smokers and non smokers. METHODS: This was a prospective cohort pilot study in two outdoor urban public areas in the USA, in a convenience sample of adult smokers. SpCO saturations were assessed non-invasively before, during, and 2 min after cigarette smoking with pulse CO-oximetry. Analyses included descriptive statistics, correlations, and a generalized estimating equation model. RESULTS: Eighty-five smokers had mean baseline SpCO of 2.7% (SD 2.6) and peak of 3.1% (SD 2.9), while 15 controls had SpCO 1.3% (SD 1.3). This was a significant difference. Time since last cigarette was associated with baseline SpCO, and active smoking increased mean SpCO. There was correlation among individual smokers' SpCO levels before, during, and 2 min after smoking, indicating smokers tended to maintain their baseline SpCO level. CONCLUSIONS: This study is the first to measure SpCO during active smoking in an uncontrolled environment. It suggests 80% of smokers have SpCO <= 5%, but potentially lends support for the current 9% as a threshold, depending on clinical context. PMID- 29285648 TI - Bacteria from bronchoalveolar lavage fluid from children with suspected chronic lower respiratory tract infection: results from a multi-center, cross-sectional study in Spain. AB - : This cross-sectional study assessed the prevalence of bacteria isolated from Spanish children with suspected chronic lower respiratory tract infection (LRTI) for whom bronchoalveolar lavage (BAL) was indicated. BAL fluid (BALF) was collected from 191 children (aged >= 6 months to < 6 years, with persistent or recurrent respiratory symptoms, non-responders to usual treatment) and cultured. Nasopharyngeal swabs (NPSs) were also obtained and cultured to assess concordance of BALF and NPS findings in the same patient. Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis were identified from BALF with a bacterial load indicative of infection (> 104 colony-forming units/mL) in 10.5, 8.9, and 6.3% of children, respectively. Clinical characteristics were similar among participants, regardless of positivity status for any of the bacteria. Approximately 26% of pneumococcal isolates were PCV13 serotypes, and 96% of H. influenzae isolates were non-typeable (NTHi). Concordance between BALF and NPS isolates was 51.0% for S. pneumoniae, 52.1% for H. influenzae, and 22.0% for M. catarrhalis. CONCLUSION: S. pneumoniae, NTHi, and M. catarrhalis were the main bacteria detected in BALF and NPS. Children with suspected chronic LRTI may benefit from a vaccine protecting against NTHi. What is Known: * Chronic lower respiratory tract infection (LRTI) in children can cause high morbidity and is a major use of healthcare resources worldwide. Despite this, their etiology or potential preventive measures are poorly assessed. * Bronchoalveolar lavage can be used to determine bacterial etiology of chronic LRTI. What is New: * We used conventional and molecular techniques to show that Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis were present in the LRT of Spanish children with suspected chronic LRTI * Concordance between isolates from bronchoalveolar lavage fluid and nasopharyngeal swabs was low, suggesting that samples from the upper respiratory tract could not reliably predict the bacterial etiology of suspected chronic LRTI. PMID- 29285650 TI - Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells. AB - PURPOSE: The influence of the dipeptidyl peptidase-IV inhibitor, gemigliptin alone or in combination with metformin on survival, proliferation, and migration of thyroid carcinoma cells was investigated. METHODS: SW1736 and TPC-1 human thyroid carcinoma cells were used. RESULTS: Gemigliptin and metformin caused cell death in a dose-dependent manner. In cells treated with both gemigliptin and metformin, compared with metformin alone, all of the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of two agents. Cell viability, the percentage of viable cells, ATP levels, and mitochondrial membrane potential decreased; however, cytotoxic activity, and the protein levels of cleaved PARP, phospho-Akt and phospho-AMP-activated protein kinase (AMPK) increased. Administration of wortmannin, but not compound C, further decreased cell viability, and further increased cytotoxic activity. Moreover, compared with control, cell proliferation and migration as well as the protein levels of p53, p21, vascular cell adhesion molecule-1 (VCAM-1), and phospho-extracellular signal regulated kinase (ERK) 1/2 decreased. The decrement of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein levels was cell specific. CONCLUSIONS: Our results demonstrate that gemigliptin induces cytotoxic activity, and has a synergistic activity with metformin in inducing cytotoxicity via regulation of Akt and AMPK in thyroid carcinoma cells. Furthermore, gemigliptin augments the inhibitory effect of metformin on proliferation and migration through involvement of matrix metalloproteinase-2, matrix metalloproteinase-9, p53, p21, VCAM-1, and ERK in thyroid carcinoma cells. PMID- 29285652 TI - Risk factors in Swedish young men for amyotrophic lateral sclerosis in adulthood. AB - Recent research suggests that the incidence of amyotrophic lateral sclerosis (ALS) may be on the rise. Since ALS becomes predominant in later life, most studies on causal factors are conducted in middle-aged or older populations where potentially important influences from early life can usually not be adequately captured. We aimed to investigate predictors in young Swedish men for ALS in adulthood. Therefore, we performed a prospective cohort study of young men (aged 16-25, n = 1,819,817) who enlisted 1968-2005 and took part in comprehensive conscription examinations. Incident cases of ALS (n = 526) during up to 46 years of follow-up were identified in the National Hospital Register and Swedish Cause of Death Register. Those who developed ALS had lower BMI (body mass index) at conscription than their peers (p = 0.03). The risk of ALS during follow-up was calculated with Cox proportional hazards models. No associations were found with physical fitness, erythrocyte sedimentation rate, or non-psychotic mental disorders. Low overall muscle strength compared to high overall muscle strength [hazard ratio (HR) 1.36; 95% confidence interval (CI) 1.01-1.83] and low BMI (a one-unit increase HR 0.96; 95% CI 0.93-0.99) and lower erythrocyte volume fraction (a one-unit increase HR 0.96; 95% CI 0.92-0.998) were the statistically significant predictors for ALS in adjusted models. These findings provide novel epidemiologic evidence of a prospective association between low overall muscle strength and erythrocyte volume fraction in young men and ALS risk. PMID- 29285651 TI - A long-term survival case treated with conversion surgery following chemotherapy after diagnostic metastasectomy for pancreatic cancer with synchronous liver metastasis. AB - BACKGROUND: Pancreatic cancer with distant metastases is classified as "unresectable," for which the standard treatment is systemic chemotherapy. The effectiveness of radical resection for pancreatic cancer with distant metastases is unknown. Here, we report a case of long term survival treated with conversion surgery following chemotherapy after diagnostic metastasectomy for pancreatic cancer with synchronous liver metastasis. CASE PRESENTATION: A 73-year-old man was referred to our hospital to examine and treat for cancer of the pancreatic body. Computed tomography (CT) scan revealed a 26-mm hypovascular tumor in contact with the common hepatic artery (CHA) (> 180 degrees ), the celiac artery (< 180 degrees ), and portal vein at the pancreatic body. Resectability was determined as "borderline resectable." Two courses of gemcitabine plus S-1 combination therapy (GS) were administered as neoadjuvant chemotherapy (NAC). CT scan showed tumor shrinkage (21 mm), determined as stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST). Although the abdomen was opened for radical resection, a small nodule on the liver was detected and removed. Since the nodule was diagnosed as adenocarcinoma by intraoperative frozen section, resection of the primary tumor was not performed. After three subsequent courses of GS therapy, no distant metastases were detected under radiological findings. Distal pancreatectomy with celiac artery resection (DP CAR) was performed as radical surgery 6 months after the initial diagnosis. Histological diagnosis was well-differentiated tubular adenocarcinoma, showing ypT1 ypN1 M1 stage IV, negative surgical margin (R0), and grade III in the Evans classification. S-1 was administered every other day from 6 months after resection up to the present. The patient has been alive with no recurrence for 5 years after the initial diagnosis and 4.5 years after the resection. CONCLUSION: There is a case that received survival benefits from conversion surgery following chemotherapy after diagnostic metastasectomy in pancreatic cancer with synchronous liver metastasis. PMID- 29285653 TI - Continuous subcutaneous apomorphine infusion does not impair the dynamics of cognitive action control in mild to moderate Parkinson's disease. AB - INTRODUCTION: Continuous subcutaneous apomorphine infusion (CSAI) is increasingly used in Parkinson's disease (PD), notably in patients contraindicated for subthalamic deep brain stimulation. Although it has been suggested that CSAI is safe regarding cognition, few studies have actually investigated its effect, especially on cognitive control which is a crucial process for goal-directed behavior. More specifically, its impact on the dynamics of cognitive action control, as reflected by the activation and suppression of impulsive responses, has yet to be investigated, which is the objective of the present study. METHODS: We compared cognitive action control between baseline (M0) and 6 months (M6) after the start of add-on CSAI by administering an oculomotor Simon task to 20 patients with mild to moderate PD. We used the activation-suppression model to determine whether CSAI had an effect on either the impulsive errors made in conflict situations or the suppression of these responses. RESULTS: We found no difference between M0 and M6 in the congruence effect regarding either reaction time or accuracy, indicating that overall conflict resolution was not influenced by CSAI. Furthermore, the rate of fast errors in the conflict situation and the last slope of the delta plots (reflecting the strength of impulsive response suppression) were unaffected by the treatment. The 95% confidence intervals calculated for the treatment effect on both of these measures fell below the range of usual meaningful effects. CONCLUSION: We found no difference between M0 and M6, which strongly suggests that CSAI does not impair the dynamics of cognitive action control. PMID- 29285655 TI - The Psychology of Gay Men's Cuckolding Fantasies. AB - Cuckolding (also known as troilism) is a sexual interest in which one obtains sexual arousal from the experience of a romantic partner engaging in sexual activity with someone else. The present study investigated fantasies about and experiences with cuckolding in a large and diverse sample of predominately gay identified men (N = 580). Compared to previous research focusing on heterosexual men's cuckolding fantasies, our results indicate that gay men's cuckolding fantasies share many common elements; however, they differ in some important ways. Most notably, interracial and BDSM themes do not appear to be as common in gay men's cuckolding fantasies as they are among heterosexual men. Our findings also indicate that frequent fantasies about cuckolding are linked to several overlapping sexual interests (e.g., voyeurism, group sex) and, further, the content of these fantasies is associated with a number of individual differences (e.g., agreeableness, sensation seeking, sociosexuality). Finally, this study also suggests that gay men who act on their cuckolding fantasies tend to report positive experiences; however, the likelihood of reporting positive outcomes appears to depend upon one's personality and attachment style. PMID- 29285654 TI - Time to consider integration of a formal robotic-assisted surgical training program into obstetrics/gynecology residency curricula. AB - The objectives of the study were to describe robotic-assisted surgery training programs currently being used by ACGME-accredited obstetrics and gynecology (OB/Gyn) residency programs and to explore residents' attitudes towards their robotic surgery training curricula to evaluate resident desire for robotics training. We conducted a cross-sectional study of OB/Gyn residents for the 2015 2016 academic year. Participants completed a 31-item online questionnaire regarding their robotic-assisted surgical training and associated perspectives. Analyses of these data were primarily descriptive. In total, 98.9% of included respondents (N = 177) reported availability of a surgical robot at their training institution, and 35.0% of participants reported not having any structured robotics training program at their institution. The most commonly used training modalities included online modules (62.2%), dual-assist console (55.1%) and virtual reality simulation (50.3%). The most commonly reported barriers to completing a robots training were a lack of personal time (56.2%) and availability of the virtual reality simulator or access to the robotic equipment (29.2%). OB/Gyn residents desire robotics training and are exposed to a wide variety of training modalities. The ACGME should consider recommending the incorporation of a standardized formal robotics training program as part of the OB/Gyn residency curriculum. PMID- 29285656 TI - Preface. PMID- 29285657 TI - Inter-individual variations and hemispheric asymmetries in structural connectivity patterns of the inferior fronto-occipital fascicle: a diffusion tensor imaging tractography study. AB - PURPOSE: Precise knowledge of the structural connectivity of white matter fascicles could yield new insights into function and is important for neurosurgical planning. Therefore, we aimed to provide a detailed map of the cortical terminations of the inferior fronto-occipital fascicle (IFOF), with special emphasis on putative inter-individual variations and hemispheric asymmetries. METHODS: Deterministic diffusion tensor imaging-based tractography was used to perform virtual dissection of the IFOF in 20 healthy subjects. The IFOF was probed from a single seed region of interest placed within the external/extreme capsule, i.e. the white matter region of "obligatory passage" along the known path of the IFOF. This enabled to reconstruct all the fibers belonging to the IFOF and to provide the complete map of their cortical terminations. RESULTS: We observed widespread projections over a total of 11 cortical territories within the occipital, parietal, temporal and frontal lobes. Importantly, compared to previous studies we consistently found some inter individual variability with several distinct patterns connecting subsets of the 11 cortical territories, and tangible differences between the two hemispheres. IFOF terminations within the superior parietal lobule were rightward lateralized, whereas terminations within the inferior frontal gyrus were leftward lateralized. CONCLUSIONS: Our results provide a clinically relevant map of IFOF's cortical terminations, including intra- and inter-individual variations. Right-left differences in connectivity patterns might be related to known functional asymmetries in the human brain, and reinforce the general evidence that the IFOF likely supports distinct clinical features and functional roles according to the (affected) hemisphere, such as language and spatial attention. PMID- 29285659 TI - Shoreline change and potential sea level rise impacts in a climate hazardous location in southeast coast of India. AB - Climate change impact on the environment makes the coastal areas vulnerable and demands the evaluation of such susceptibility. Historical changes in the shoreline positions and inundation based on projected sea-level scenarios of 0.5 and 1 m were assessed for Nagapattinam District, a low-lying coastal area in the southeast coast of India, using high-resolution Shuttle Radar Topography Mission data; multi-dated Landsat satellite images of 1978, 1991, 2003, and 2015; and census data of 2011. Image processing, geographical information system, and digital shoreline analysis system methods were used in the study. The shoreline variation indicated that erosion rate varied at different time scales. The end point rate indicated the highest mean erosion of - 3.12 m/year, occurred in 73% of coast between 1978 and 1991. Weighted linear regression analysis revealed that the coast length of 83% was under erosion at a mean rate of - 2.11 m/year from 1978 to 2015. Sea level rise (SLR) impact indicated that the coastal area of about 14,122 ha from 225 villages and 31,318 ha from 272 villages would be permanently inundated for the SLR of 0.5 and 1 m, respectively, which includes agriculture, mangroves, wetlands, aquaculture, and forest lands. The loss of coastal wetlands and its associated productivity will severely threaten more than half the coastal population. Adaptation measures in people participatory mode, integrated into coastal zone management with a focus on sub-regional coastal activities, are needed to respond to the consequences of climate change. PMID- 29285661 TI - Correction to: Cupriavidus malaysiensis sp. nov., a novel poly(3-hydroxybutyrate co-4-hydroxybutyrate) accumulating bacterium isolated from the Malaysian environment. AB - In the original publication of the article, it was noted that Fig. 1 present an image of Cupriavidus malaysiensis strain USMAHM13 and not of strain USMAA1020, as indicated in the figure legend. The image in the original version is thus noted to serve as a record of strain USMAHM13 and the corrected version of Fig. 1 is reprinted below. PMID- 29285660 TI - Effect of Blood Phenylalanine Levels on Oxidative Stress in Classical Phenylketonuric Patients. AB - Mental retardation, which occurs in phenylketonuric patients, is associated with increased levels of phenylalanine, increased oxidative stress, and an imbalance of amino acids in the brain. Recent studies have shown that oxidative stress plays a role in the pathogenesis of phenylketonuria. In this work, we aimed to compare the influence of blood phenylalanine levels on oxidative stress parameters in phenylketonuric patients who divided patients into groups according to blood Phe levels during follow-up visits and compared these groups with healthy controls. Results showed significant differences in glutathione peroxidase (GSHPx), coenzyme Q10 (Q10), Q10/cholesterol, and L-carnitine levels in phenylketonuria patients and the control group. GSHPx, Q10, and Q10/cholesterol levels were significantly lower in poor adherence patients than in the control groups. L-carnitine levels were significantly increased in good adherence patients than poor adherence patients and decreased in poor adherence patients than healthy controls. No correlations were observed between phenylalanine and L-carnitine concentrations in poor adherence group. No significant differences were observed in paraoxonase 1 (PON1), total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) levels. As a result, in this work, poor adherence patients are prone to oxidative stress. Although the patients may have the same diagnosis, patients have different clinical characteristics and different prognosis. Antioxidants can be used as an adjuvant therapy in order to avoid neurological damage in these patients. PMID- 29285662 TI - Heme-binding of bovine lactoferrin: the potential presence of a heme-binding capacity in an ancestral transferrin gene. AB - Lactoferrin (Lf) and transferrin (Tf) are iron-binding proteins that can bind various metal ions. This study demonstrates the heme-binding activity of bovine Lf and Tf using biotinylated hemin. When both proteins were coated on separate plate wells, each directly bound biotinylated hemin. On the other hand, when biotinylated hemin was immobilized on an avidin-coated plate, soluble native Lf bound to the immobilized biotinylated hemin whereas native Tf did not, suggesting that a conformational change triggered by coating on the plate allows the binding of denatured Tf with hemin. Incubation of Lf with hemin-agarose resulted in negligible binding of Lf with biotinylated hemin. Lf in bovine milk also bound to immobilized biotinylated hemin. These results demonstrate that bovine Lf has specific heme-binding activity, which is different from Tf, suggesting that either Tf lost heme-binding activity during its evolution or that Lf evolved heme binding activity from its Tf ancestral gene. Additionally, Lf in bovine milk may bind heme directly, but may also bind heme indirectly by interaction with other milk iron- and/or heme-binding proteins. PMID- 29285663 TI - Correlation between the concentrations of lactoferrin and neutrophil gelatinase associated lipocalin in meconium. AB - Neutrophil gelatinase-associated lipocalin (NGAL) and lactoferrin (Lf) are among the key components of the innate immune system due to their ability to bind iron with high affinity and thus control inflammation. The aim of this study was to test the use of NGAL and LF measurements in meconium for the assessment of the intrauterine homeostasis. NGAL and Lf concentrations were measured using ELISA kits in all serial meconium portions (n = 81) collected from 20 healthy neonates. Mean +/- SD meconium concentration of Lf was 45.07 +/- 78.53 ug/g and more than 1000-fold higher compared with that of NGAL at 1.93 +/- 2.46 ng/g. The correlation between the two proteins (r = 0.83, p < 0.0001) was found only for portions with Lf concentrations > 25 MUg/g. High variability of NGAL and Lf concentrations in meconium and their correlations prove their key role as biomarkers of the fetal condition in utero. NGAL and Lf measured in meconium are candidate biomarkers for fetal iron status. PMID- 29285664 TI - Pectoralis minor transfer for elbow flexion restoration in late obstetric brachial plexus palsy. AB - PURPOSE: Obstetric brachial plexus palsy (OBPP) may result in a severe impairment of upper limb function, especially when major motor functions do not recover with or without early microsurgical reconstruction. Various methods to restore elbow flexion have been described. The aim of this study was to report the results after pectoralis minor transfer for elbow flexion restoration in late OBPP. METHODS: Nineteen patients were included. Mean age at surgery was six years (range, 2.3-12.8). The mean follow-up period was four years (range, 1-15). Shoulder function was evaluated by the Mallet classification and hand function by the Raimondi scale. We used the "active movement scale" (AMS) to evaluate elbow flexion function. RESULTS: Eighteen of the 19 patients had improvement in their elbow active flexion. There was significant improvement in biceps muscle power according to the BMRC grading system, from an average grading of 1.7 (range, 1-3) pre-operatively to 3 (range, 1-4) post-operatively (P < 0.05). The average active elbow flexion was significantly improved from a mean of 81 degrees (range, 0 120; SD = 44) pre-operatively, most of them gravity eliminated, to a mean of 111 degrees (range, 0-140; SD = 33) post-operatively (P < 0.05). According to the AMS, 12 patients (63%) had a good result, 4 (21%) a fair result and 5 (26%) a poor result. Poor results were significantly correlated with a low pre-operative AMS score (P < 0.05). CONCLUSIONS: The pectoral minor transfer can be a reliable technique for elbow flexion improvement in late OBPP by strengthening an already existing but inadequate active flexion. LEVEL OF EVIDENCE: IV. PMID- 29285665 TI - Total hip arthroplasty performed with a tissue-preserving technique using superior capsulotomy. AB - PURPOSE: We present a minimally invasive tissue-sparing posterior superior (TSPS) approach that intends to protect the abductor muscles during total hip arthroplasty, prevents the release of the short rotator muscles, and provides the surgeon with the option to repair the posterior capsule. We hypothesized that the TSPS technique would produce a better clinical outcome, faster recovery, and lower complication rates, and that it would not jeopardize acetabular component position. METHODS: A retrospective, observational study was conducted in a consecutive series of patients. A cohort of 130 patients (130 hips) operated with a standard posterolateral approach were compared with a cohort of 132 patients (132 hips) operated with a TSPS approach. Patients were assessed with the Harris hip score (HHS) and Western Ontario and McMaster Universities index (WOMAC), which were carried out preoperatively, one month (HHS only), three months, one year, and at four years post-operatively. RESULTS: Compared with the standard group, patients in the TSPS group showed a faster return to ambulation as reflected in better post-operative HHS and WOMAC scores up until one year (p < 0.05). No significant differences in HHS (p = 0.564) and WOMAC (p = 0.796) scores were found at the four-year follow-up. No major adverse events were observed in either group. CONCLUSION: The TSPS approach yielded better early clinical outcomes and appears to be a safe and reliable technique. However, these early differences do not appear to be sustained over time, as comparable mid-term clinical outcomes with similar complications rates were observed. PMID- 29285666 TI - Acetabular index is the best predictor of late residual acetabular dysplasia after closed reduction in developmental dysplasia of the hip. AB - PURPOSE: Our objective was to find the best predictor of late residual acetabular dysplasia in developmental dysplasia of the hip (DDH) after closed reduction (CR) and discuss the indications for secondary surgery. METHODS: We retrospectively reviewed the records of 89 patients with DDH (mean age 16.1 +/- 4.6 months; 99 hips) who were treated by CR. Hips were divided into three groups according to final outcomes: satisfactory, unsatisfactory and operation. The changes in the acetabular index (AI), centre-edge angle of Wiberg (CEA), Reimer's index (RI) and centre-head distance discrepancy (CHDD) over time among groups were compared. The power of predictors for late residual acetabular dysplasia of AI, CEA, RI and CHDD at different time points was analysed by logistic regression analysis. Receiver operating characteristics (ROC) curve analysis was used to determine cutoff values and corresponding sensitivity, specificity and diagnostic accuracy for these parameters. RESULTS: Both AI and CEA improved in all groups of patients following CR. In the satisfactory group, AI progressively decreased until seven to eight years, while CEA increased until nine to ten years (P < 0.05). In the unsatisfactory group, AI and CEA ceased to improve three and two years after CR, respectively (P < 0.05). CEA and RI were significantly better in the satisfactory group compared with the unsatisfactory group at all time points (P < 0.05). Following CR, both RI and CHDD remained stable over time in all groups. Final outcome following CR could be predicted by AI, CEA and RI at all time points (P < 0.01). Cutoff values of AI, CEA and RI were 28.4 degrees , 13.9 degrees and 34.5%, respectively, at one year and 25 degrees , 20 degrees and 27%, respectively, at two to four years post-CR. A total of 80-88% of hips had an unsatisfactory outcome if AI > 28.4 degrees and >25 at one and two to four years following CR, respectively. However, if CEA was less than or RI was larger than the cutoff values at each time point, only 40-60% of hips had an unsatisfactory outcome. Mean sensitivity (0.889), specificity (0.933) and diagnostic accuracy (92.1%) of AI to predict an unsatisfactory outcome were significantly better compared with CEA (0.731; 0.904; 78.2%) and RI (0.8; 0.655; 70.8%) (P < 0.05). CONCLUSIONS: Satisfactory and unsatisfactory hips show different patterns of acetabular development after reduction. AI, CEA and RI are all predictors of final radiographic outcomes in DDH treated by CR, although AI showed the best results. AI continues to improve until seven years after CR in hips with satisfactory outcomes, while it ceases to improve three to four years after CR in hips with unsatisfactory outcomes. According to our results, surgery is indicated if AI >28 degrees 1 year following CR or AI >25 degrees two to four years after CR. CEA and RI should be used as a secondary index to aid in the selection of patients requiring surgery. PMID- 29285667 TI - Epigenetic Erasing and Pancreatic Differentiation of Dermal Fibroblasts into Insulin-Producing Cells are Boosted by the Use of Low-Stiffness Substrate. AB - Several studies have demonstrated the possibility to revert differentiation process, reactivating hypermethylated genes and facilitating cell transition to a different lineage. Beside the epigenetic mechanisms driving cell conversion processes, growing evidences highlight the importance of mechanical forces in supporting cell plasticity and boosting differentiation. Here, we describe epigenetic erasing and conversion of dermal fibroblasts into insulin-producing cells (EpiCC), and demonstrate that the use of a low-stiffness substrate positively influences these processes. Our results show a higher expression of pluripotency genes and a significant bigger decrease of DNA methylation levels in 5-azacytidine (5-aza-CR) treated cells plated on soft matrix, compared to those cultured on plastic dishes. Furthermore, the use of low-stiffness also induces a significant increased up-regulation of ten-eleven translocation 2 (Tet2) and histone acetyltransferase 1 (Hat1) genes, and more decreased histone deacetylase enzyme1 (Hdac1) transcription levels. The soft substrate also encourages morphological changes, actin cytoskeleton re-organization, and the activation of the Hippo signaling pathway, leading to yes-associated protein (YAP) phosphorylation and its cytoplasmic translocation. Altogether, this results in increased epigenetic conversion efficiency and in EpiCC acquisition of a mono hormonal phenotype. Our findings indicate that mechano-transduction related responsed influence cell plasticity induced by 5-aza-CR and improve fibroblast differentiation toward the pancreatic lineage. PMID- 29285669 TI - Identification of metolachlor mineralizing bacteria in aerobic and anaerobic soils using DNA-stable isotope probing. AB - The influence of soil environmental factors such as aeration on the ecology of microorganisms involved in the mineralization and degradation of the popular soil applied pre-emergent herbicide, metolachlor is unknown. To address this knowledge gap, we utilized DNA-based stable isotope probing (SIP) where soil microcosms were incubated aerobically or anaerobically and received herbicide treatments with unlabeled metolachlor or 13C-metolachlor. Mineralization of metolachlor was confirmed as noted from the evolution of 14CO2 from 14C-metolachlor-treated microcosms and clearly demonstrated the efficient utilization of the herbicide as a carbon source. Terminal restriction fragment length polymorphisms (T-RFLP) bacterial community profiling performed on soil DNA extracts indicated that fragment 307 bp from aerobic soil and 212 bp from anaerobic soil were detected only in the herbicide-treated (both unlabeled metolachlor and 13C-metolachlor) soils when compared to the untreated control microcosms. T-RFLP profiles from the ultracentrifugation fractions illustrated that these individual fragments experienced an increase in relative abundance at a higher buoyant density (BD) in the labeled fractions when compared to the unlabeled herbicide amendment fractions. The shift in BD of individual T-RFLP fragments in the density-resolved fractions suggested the incorporation of 13C from labeled herbicide into the bacterial DNA and enabled the identification of organisms responsible for metolachlor uptake from the soil. Subsequent cloning and 16S rRNA gene sequencing of the 13C-enriched fractions implicated the role of organisms closely related to Bacillus spp. in aerobic mineralization and members of Acidobacteria phylum in anaerobic mineralization of metolachlor in soil. PMID- 29285668 TI - CabaGast: multicentre, Phase II study with cabazitaxel in previously treated patients with advanced or metastatic adenocarcinoma of the esophagogastric junction and stomach. AB - INTRODUCTION: This is a single-arm study (NCT01956149) to determine the prolonged (>= 4 months) disease control rate with cabazitaxel administered in second-(or later) setting for patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (EGJ) and stomach. METHODS: 65 patients with advanced EGJ and stomach cancer were treated with 20 mg/m2 cabazitaxel every 3 weeks for a maximum of six cycles. The main objective of the study is a prolonged disease control rate (pDCR: CR, PR or SD lasting at least 4 months). Secondary outcome measures were overall survival, progression-free survival, response rate by subgroup (with vs without previous treatment with a taxane) and toxicity. Patients were assessed for tumor response every 6 weeks during therapy and during the follow-up (up to 12 months). RESULTS: 65 patients (median age: 63, range 31 86 years) were assigned to treatment. Median no. of prior therapies that had received prior taxane therapy was 2. 80%. Patients received a median of two cycles of cabazitaxel. Efficacy results are for the ITT population. The mDCR in n = 65 patients was 10.8% (95% CI 4.4-20.9%). There was a control of disease (CR + PR + SD) in n = 26 patients of n = 65, corresponding to a DCR of 40.0% (95% CI 28.0-52.9%). In patients without prior taxane use, it was 46.2% (95% CI 25.1 80.8%) and in patients with only one prior therapy, DCR was 50.0% (95% CI 31.3 68.7%). The median overall survival was 4.6 months (95% CI 3.16, 5.59) in the whole ITT population. In patients with only one prior therapy, median OS was 5.4 months (95% CI 2.60, 7.43) and in patients without taxane pretreatment, it was 6.4 months (95% CI 1.38, 14.17). The median progression-free survival time was 1.5 months (95% CI 1.32, 2.27) in the whole ITT population, 2.9 months (95% CI 0.72, 4.67) without prior taxane therapy and was 1.7 (95% CI 1.28, 3.35) months in patients with only one prior therapy median. CONCLUSIONS: Cabazitaxel is active in heavily pretreated patients with metastatic and advanced esophagogastric junction and gastric adenocarcinoma. Efficacy results in a classic second-line population are comparable to other second-line studies, therefore, under the limitations of this trial, (single arm, Phase II design) cabazitaxel might be an option especially in patients without prior taxane therapy, in second line and even further line therapy of metastatic and advanced esophagogastric junction and gastric adenocarcinoma. PMID- 29285670 TI - A 3-variable prognostic score (3-PS) for overall survival prediction in metastatic castration-resistant prostate cancer treated with 223Radium dichloride. AB - OBJECTIVE: In mCRPC patients treated with 223Ra, a major issue is the validation of reliable prognostic and predictive biomarkers to maximize clinical benefit and minimize toxicities and costs. Bearing in mind how changes in tALP did not meet statistical requirements as surrogate marker for survival, aim of this single center retrospective study was to characterize the prognostic and predictive role of baseline clinical variables associated with overall survival in patients receiving 223Ra treatment. METHODS: 92 consecutive CRPC patients with symptomatic bone metastases receiving 223Ra treatment were included. Available baseline clinical data relevant to the survival analysis were retrospectively collected. The primary end-point of the study was overall survival, which was established from the first 223Ra administration until date of death from any cause. RESULTS: Median follow-up time from the first 223Ra administration was 6 months (range 1 31 months). The univariate analysis evaluating the prognostic value of all baseline clinical variables showed that patients' weight, BMI, ECOG PS, Hb and tALP values were independently associated with OS. On multivariable analysis only baseline Hb value and ECOG PS remained significantly correlated with OS. To determine reliable baseline predictive factors for survival in patients receiving 223Ra treatment, we produced a predictive score. We tried all possible variable combinations, and found that the best score was obtained by combining baseline ECOG PS with Hb < 12 g/dl and PSA >= 20 ng/ml. This resulted in a score ranging from 0 to 4, with AUC 78.4% (p < 0.001). CONCLUSIONS: We propose a multidimensional clinical evaluation to select those mCRPC subjects suitable to receive the maximum benefit from 223Ra treatment. PMID- 29285671 TI - The Interleukin-33/ST2 Pathway Is Expressed in the Failing Human Heart and Associated with Pro-fibrotic Remodeling of the Myocardium. AB - The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway is a potential pathophysiological mediator of cardiac fibrosis. Soluble ST2 (sST2) is one of the main isoforms of ST2 with strong prognostic value in cardiac disease. The exact role of sST2 in cardiac fibrosis is unknown. The aim of this study was (1) to investigate myocardial expression of the IL-33/ST2 pathway in relation to myocardial fibrosis in end-stage heart failure patients and (2) to study whether plasma sST2 is associated with histologically determined cardiac fibrosis. In 38 patients undergoing left ventricular assist device implantation, mRNA expression of sST2, total ST2, and IL-33 was measured in cardiac tissue obtained during the implantation. In the same tissue, histological fibrosis was digitally quantified and mRNA expression of pro-fibrotic signaling molecules, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGFbeta1), was measured. In addition, plasma levels of sST2 were determined. Expression levels of IL-33/ST2 pathway factors in myocardial tissue were significantly associated with cardiac fibrosis and the expression levels of CTGF and TGFbeta1. Plasma levels of sST2 did not correlate with tissue expression of ST2, the amount of fibrosis or myocardial expression of pro-fibrotic signaling proteins. The interleukin-33/ST2 pathway is expressed in the failing human heart and its expression is associated with cardiac fibrosis and pro-fibrotic signaling proteins, suggesting a role in pro-fibrotic myocardial remodeling. Soluble ST2 levels in the circulation did not correlate with the amount of cardiac fibrosis or myocardial ST2 expression, however. Therefore, other pathophysiological processes such as inflammation might also substantially affect sST2 plasma levels. PMID- 29285672 TI - Stimulatory effect of dietary taurine on growth performance, digestive enzymes activity, antioxidant capacity, and tolerance of common carp, Cyprinus carpio L., fry to salinity stress. AB - The present study was carried out to evaluate the effect of dietary taurine (Tau) on performance, digestive enzymes, antioxidant activity, and resistance of common carp, Cyprinus carpio L., fry to salinity stress. Fish (0.97 +/- 0.033 g) were fed on different taurine levels of 0.0 (control), 5, 10, 15, or 20 g/kg diet up to satiation twice daily for 8 weeks. At the end of the feeding trial, fish were stressed by exposure to 10 ppt salinity for 3 days during which fish mortality was observed. Fish performance was significantly (P < 0.05) improved by dietary taurine up to 15 g Tau/kg diet after which fish growth and feed intake were almost the same. Also, taurine supplementation significantly (P < 0.05) elevated activities of intestinal amylase, lipase, and protease resulting in an improving in feed intake giving better performance. Furthermore, Tau-stimulated antioxidant activity of common carp was observed in a dose-related manner, where activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were significantly (P < 0.05) higher, but malondialdehyde (MDA) value was significantly (P < 0.05) lower in Tau-fed fish groups than those fed the control diet. In salinity stress experiment, highest survival rate was observed at fish fed Tau-supplemented diets without significant (P > 0.05) differences over fish fed the control diet. It appears that taurine could be used as a feed supplement to confer better growth and health of common carp fry with optimal level of 15 g/kg diet. PMID- 29285673 TI - Detection, isolation, and characterization of chikungunya viruses associated with the Pakistan outbreak of 2016-2017. AB - The chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus, which has infected millions of people in Africa, Asia, Americas, and Europe since it reemerged in India and Indian Ocean regions in 2005-2006. Starting in the middle of November 2016, CHIKV has been widely spread, and more than 4,000 cases of infections in humans were confirmed in Pakistan. Here, we report the first isolation and characterization of CHIKV from the Pakistan outbreak. Eight CHIKV strains were newly isolated from human serum samples using a cell culture procedure. A full-length genome sequence and eight complete envelope (E1) sequences of CHIKV from Pakistan were obtained in this study. Alignment of the CHIKV E1 sequences revealed that the eight new CHIKV isolates were highly homogeneous, with only two nonsynonymous substitutions found at generally conserved sites (E99 and Q235). Based on the comparison of 342 E1 sequences, the two nonsynonymous mutations were located in well-recognized domains associated with viral functions such as the cell fusion and vector specificity, suggesting their potential functional importance. Phylogenetic analysis indicated that the CHIKV strains from Pakistan originated from CHIKV circulating in the Indian region. This study helps elucidate the epidemics of CHIKV in Pakistan and also provides a foundation for studies of evolution and expansion of CHIKV in South Asia. PMID- 29285674 TI - HCV nonstructural protein 4 is associated with aggressiveness features of breast cancer. AB - BACKGROUND: Hepatitis C virus (HCV) has the lymphotropic feature that is supposed to be the reason of related extrahepatic manifestation. HCV viral oncoproteins may participate in the regulation of some gene expression that has been implicated in tumorigenesis. Our aim is to evaluate the HCV-NS4 circulating levels in breast cancer (BC) and to investigate its relation with BC tumor aggressiveness. METHODS: This study was performed among 158 Egyptian women (120 with BC and 38 with benign breast diseases). ELISA was used for detection of anti HCV antibodies, HCV-NS4, fibronectin, and CA 15-3. RESULTS: No association between HCV detection in this group of BC patients (27.5% in BC vs. 23.7% in breast benign diseases, P = 0.687). Among HCV-infected patients, the mean HCV-NS4 serum level in BC was significantly higher than benign group (61.7 MUg/mL vs. 33.9 MUg/mL, P = 0.0005). Fibronectin levels were higher (P = 0.014) in patients infected with HCV than noninfected BC patients. Elevated HCV-NS4 levels were associated with tumor severity features like large size, late stages, high grades, and infiltrated lymph nodes. The elevated levels of HCV-NS4 (> 40 MUg/mL) yielded an estimated odds ratio (95% confidence intervals) of 2.5 (0.98-6.36), 1.2 (0.44-3.33), 1.9 (0.53-7.00), and 2.5 (0.87-7.33) for developing large size, late stages, high grades, and infiltrated lymph nodes, respectively. Interestingly, HCV-NS4 levels significantly correlated with other BC tumor marker like CA15-3 (r = 0.535; P = 0.0009) and fibronectin (r = 0.432; P < 0.0001). CONCLUSIONS: HCV-NS4 appears to be associated with BC progression features. Oncologists treating such BC patients should consider HCV screening to enable the early identification and to prevent progression of the disease. PMID- 29285675 TI - Cloning and Characterization of the Gene Encoding Alpha-Pinene Oxide Lyase Enzyme (Pralpha-POL) from Pseudomonas rhodesiae CIP 107491 and Production of the Recombinant Protein in Escherichia coli. AB - The alpha-pinene oxide lyase (Pralpha-POL) from Pseudomonas rhodesiae CIP107491 belongs to catabolic alpha-pinene degradation pathway. In this study, the gene encoding Pralpha-POL has been identified using mapping approach combined to inverse PCR (iPCR) strategy. The Pralpha-POL gene included a 609-bp open reading frame encoding 202 amino acids and giving rise to a 23.7 kDa protein, with a theoretical isoelectric point (pI) of 5.23. The amino acids sequence analysis showed homologies with those of proteins with unknown function from GammaProteobacteria group. Identification of a conserved domain in amino acid in positions 18 to 190 permitted to classify Pralpha-POL among the nuclear transport factor 2 (NTF2) protein superfamily. Heterologous expression of Pralpha-POL, both under its native form and with a histidin tag, was successfully performed in Escherichia coli, and enzymatic kinetics were analyzed. Bioconversion assay using recombinant E. coli strain allowed to reach a rate of isonovalal production per gramme of biomass about 40-fold higher than the rate obtained with P. rhodesiae. PMID- 29285678 TI - Correction to: Pegvisomant in acromegaly: an update. AB - Unfortunately, in page 584, second column, the first sentence under the heading "Type of switch" has been published incorrectly. The complete correct sentence is given below. PMID- 29285676 TI - Speciation and quantification of Hg in sediments contaminated by artisanal gold mining in the Gualaxo do Norte River, Minas Gerais, SE, Brazil. AB - The Iron Quadrangle in SE Brazil was, in the eighteenth century, one of the most important Au producing regions of Brazil. In this region, gold is produced, even today, by artisanal methods that use Hg to increase the extraction efficiency with no control of Hg release to water systems and the atmosphere. In this context, the Gualaxo do Norte River is of particular interest; its springs are located in the Doce River basin, an important Brazilian basin that supplies water for 3.5 million people. The main goal of this work was to quantify and speciate the Hg in the sediments of the Gualaxo do Norte River using a direct mercury analyzer and gas chromatography-pyrolysis-atomic fluorescence detection system. Statistical analyses consisted of principal component analysis, aiming to assess interactions among elements and species and to group the variables in factors affecting the properties of sediment. The results show that total Hg (THg) and methylmercury (CH3Hg+) concentrations in samples ranged from 209 to 1207 MUg kg-1 and from 0.07 to 1.00 MUg kg-1, respectively (methylation percentages from 0.01 to 0.27%). Thermal desorption analysis showed that mercury is mainly present in the oxidized form, and correlation analyses pointed to a relationship between THg and MnO, indicating that manganese can oxidize and/or adsorb Hg. Together, MO and CH3Hg+ are important parameters in the third principal component, indicating the influence of OM on the methylation process. This first investigation on Hg methylation in this small-scale gold mining area points to the possibility of Hg bioaccumulation and to the need of better understanding the biogeochemical cycle of Hg in this area. Samples were collected in 2012, prior to the 2015 Fundao Dam disaster. The results are also a record of the characteristics of the sediment prior to that event. PMID- 29285680 TI - Single-stage total resection of giant dumbbell-shaped hypoglossal schwannoma: a case report. AB - Extensive large dumbbell-shaped hypoglossal schwannoma is extremely rare, and total resection is nearly impossible. We present a case of a 61-year-old male with a giant-size hypoglossal schwannoma with moderate tongue atrophy. The tumor extended from the enlarged hypoglossal canal to the brainstem intradurally and the high cervical region extradurally. Through the extreme lateral infrajugular transcondylar (ELITE) skull base approach, the tumor was totally removed in a single-stage operation. Single-stage total resection is feasible by an experienced skull base team utilizing transcondylar skull base techniques and high cervical dissection. PMID- 29285679 TI - Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model. AB - Over 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed in part to limited and isolated testing often solely in "young" rodent models and focusing on a single secondary injury mechanism. Here, extracellular vesicles (EVs), nanometer-sized cell signaling particles, were tested in a mouse thromboembolic (TE) stroke model. Neural stem cell (NSC) and mesenchymal stem cell (MSC) EVs derived from the same pluripotent stem cell (PSC) line were evaluated for changes in infarct volume as well as sensorimotor function. NSC EVs improved cellular, tissue, and functional outcomes in middle aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in 18-month-old aged rodents. NSC EV treatment has a positive effect on motor function in the aged rodent as indicated by beam walk, instances of foot faults, and strength evaluated by hanging wire test. Increased time with a novel object also indicated that NSC EVs improved episodic memory formation in the rodent. The therapeutic effect of NSC EVs appears to be mediated by altering the systemic immune response. These data strongly support further preclinical development of a NSC EV based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies. PMID- 29285681 TI - Outcomes of ileal pouch-anal anastomosis without primary diverting loop ileostomy if postoperative sepsis develops. AB - BACKGROUND: The aim of the present study was to assess the short-term and long term consequences of diverting loop ileostomy (DLI) omission in ileal pouch-anal anastomosis (IPAA) surgery complicated by postoperative pelvic sepsis. METHODS: This was a retrospective review of a prospectively maintained database. Of 4031 patients who underwent IPAA in 1983-2014, 357 developed IPAA-related pelvic sepsis with or without anastomotic dehiscence. Patients with Crohn's disease or cancer were excluded. The patient cohort was divided into two groups, depending on the presence or absence of DLI. Patient characteristics, short-term and long term outcomes were compared. Long-term pouch survival was estimated with the Kaplan-Meier method. Quality of life (QOL) in the groups was compared at the latest follow-up. RESULTS: Three hundred and twenty-six patients developing pelvic sepsis had diversion at the time of IPAA (D group) and in 31 who developed pelvic sepsis DLI had been omitted (O group). The length of hospital stay was significantly longer in the O group 11.5 (3-33) days versus 8 (2-59) days in the D group (p = 0.006). Forty-eight percent of patients from the O group with anastomotic leak underwent reoperation and had a DLI formed at this second procedure versus 12% in the D group requiring reoperation (p < 0.0001). In long term follow-up, there was no difference in pouch survival between the groups: 99 versus 97% after 5 years and 88 versus 87% after 10 years, in the O group and D group, respectively (p = 0.40). There was no difference in QOL observed between the groups. CONCLUSIONS: Omission of DLI in selected patients who had IPAA surgery did not increase pouch failure or adversely affect QOL in the long term, if pelvic sepsis occurred. PMID- 29285683 TI - A single-centre study on 1000 consecutive cases of transanal haemorrhoidal dearterialization. PMID- 29285682 TI - Efficacy of autologous fat graft injection in the treatment of anovaginal fistulas. AB - BACKGROUND: Injection of autologous fat is an established method within plastic surgery for soft tissue augmentation. The aim of the present study was to determine whether transperineal fat graft injection could promote healing of anovaginal fistulas. METHODS: The procedures were performed at the University Hospital of North Norway, Tromso, Norway, and at Aarhus University Hospital, Aarhus, Denmark, between May 2009 and September 2016. After abdominal liposuction, fat was injected around the fistula tract that was finally transected percutaneously with a sharp cannula and fat injected between the cut parts. The internal opening was closed with a suture. Patients had a minimum follow-up of 6 months after last fat graft injection. RESULTS: Twenty-seven women underwent 48 procedures. The cause of fistula was obstetric (n = 9), abscess (n = 9), Crohn's disease (n = 7), radiation for anal cancer (n = 1) and endoscopic surgery after radiation for rectal cancer (n = 1). The mean amount of injected fat was 73 ml (SD +/- 20 ml), and operating time was 63 min (SD +/- 21 min). At median follow-up of 20 months (range 6-87 months) after the last injection, fistulas were healed in 21 women (77%), in 8 women after just one procedure. Healing was achieved in 6 of 7 women (86%) with Crohn's disease and in both women who had undergone radiation therapy. One woman developed an abscess and additional trans-sphincteric fistula 8 weeks after injection. CONCLUSIONS: Fat graft injection for anovaginal fistulas is effective and safe. PMID- 29285684 TI - Socioeconomic Disparities and Metabolic Risk in Veterans with Serious Mental Illness. AB - Socioeconomic disparities were assessed in predicting metabolic risk among veterans with serious mental illness. Veterans with schizophrenia, schizoaffective, or bipolar disorders were identified in VISN 4 facilities from 10/1/2010 to 9/30/2012. Differences between patients with and without metabolic syndrome were compared using t-tests, Chi square tests and multivariate logistic regressions. Among 10,132 veterans with mental illness, 48.8% had metabolic syndrome. Multivariate logistic regression analysis confirmed that patients with metabolic syndrome were significantly more likely to be older, male, African American, married, and receiving disability pensions but less likely to be homeless. They were more likely to receive antipsychotics, antidepressants, or anticonvulsants. Bivariate cross-sectional analysis revealed that patients with metabolic syndrome had higher rates of coronary artery disease, cerebrovascular disease, and mortality, and that metabolic syndrome was more often associated with emergency visits and psychiatric or medical hospitalizations. Demographics, socioeconomic status and medications are independent predictors of metabolic syndrome and should be considered in broader screening of risk factors in order to provide preventive interventions for metabolic syndrome. PMID- 29285685 TI - Transcriptome profile and unique genetic evolution of positively selected genes in yak lungs. AB - The yak (Bos grunniens), which is a unique bovine breed that is distributed mainly in the Qinghai-Tibetan Plateau, is considered a good model for studying plateau adaptability in mammals. The lungs are important functional organs that enable animals to adapt to their external environment. However, the genetic mechanism underlying the adaptability of yak lungs to harsh plateau environments remains unknown. To explore the unique evolutionary process and genetic mechanism of yak adaptation to plateau environments, we performed transcriptome sequencing of yak and cattle (Bos taurus) lungs using RNA-Seq technology and a subsequent comparison analysis to identify the positively selected genes in the yak. After deep sequencing, a normal transcriptome profile of yak lung that containing a total of 16,815 expressed genes was obtained, and the characteristics of yak lungs transcriptome was described by functional analysis. Furthermore, Ka/Ks comparison statistics result showed that 39 strong positively selected genes are identified from yak lungs. Further GO and KEGG analysis was conducted for the functional annotation of these genes. The results of this study provide valuable data for further explorations of the unique evolutionary process of high-altitude hypoxia adaptation in yaks in the Tibetan Plateau and the genetic mechanism at the molecular level. PMID- 29285687 TI - Collaboration between interactive three-dimensional visualization and computer aided detection of pulmonary embolism on computed tomography pulmonary angiography views. AB - This paper explores the benefits of interactive three-dimensional (3D) visualization of stimuli using a computer aided detection (CAD) system of pulmonary embolisms (PEs), on computed tomography pulmonary angiography (CTPA) views. We designed a new CAD method that prompts the PE sites on CTPA views; we then utilized two interactive approaches of 3D visualization to assess CAD performance. This collaboration allows different methodologies to be used to assess PE-CAD performance, by comparison with the common method in which radiologists are prompted with CAD stimuli directly on the CTPA views. Both 3D approaches are based on the voxel size of the CTPA examination, and consider the acquisition settings. A set of ten retrospective CTPA cases were collected, with different acquisition parameters, in terms of voxel size and spatial resolution. 3D visualization CAD performance was examined by an experienced radiologist. Both 3D visualization methods proved to have a constructive impact on improving CAD performance. The rate of true positive (TP) responses increased by 27%; while the rate of false positive (FP) responses dropped by 31%. We concluded that evaluation of PE-CAD performance utilizing interactive 3D visualization could increase or ascertain the correct rate of TP stimuli, as well as noticeably reduce FP responses. PMID- 29285686 TI - Novel real-time tumor-contouring method using deep learning to prevent mistracking in X-ray fluoroscopy. AB - Robustness to obstacles is the most important factor necessary to achieve accurate tumor tracking without fiducial markers. Some high-density structures, such as bone, are enhanced on X-ray fluoroscopic images, which cause tumor mistracking. Tumor tracking should be performed by controlling "importance recognition": the understanding that soft-tissue is an important tracking feature and bone structure is unimportant. We propose a new real-time tumor-contouring method that uses deep learning with importance recognition control. The novelty of the proposed method is the combination of the devised random overlay method and supervised deep learning to induce the recognition of structures in tumor contouring as important or unimportant. This method can be used for tumor contouring because it uses deep learning to perform image segmentation. Our results from a simulated fluoroscopy model showed accurate tracking of a low visibility tumor with an error of approximately 1 mm, even if enhanced bone structure acted as an obstacle. A high similarity of approximately 0.95 on the Jaccard index was observed between the segmented and ground truth tumor regions. A short processing time of 25 ms was achieved. The results of this simulated fluoroscopy model support the feasibility of robust real-time tumor contouring with fluoroscopy. Further studies using clinical fluoroscopy are highly anticipated. PMID- 29285688 TI - Pancreatoblastoma: an unusual diagnosis in an adult patient. AB - The authors describe a 31-year-old man admitted due to progressive weight loss, diarrhea and massive hepatomegaly. Laboratory data showed anemia (haemoglobin 11.7 g/dl), abnormal liver tests (total bilirubin 1.4 g/dl, aspartate aminotransferase 70 U/l, alanine aminotransferase 37 U/l and alkaline phosphatase 520 U/l). Abdominal ultrasound (US) displayed a large heterogeneous liver with a segment IV 25 mm nodule. Magnetic resonance revealed a 4 cm pancreatic tail mass and several liver nodules consistent with metastasis. The patient underwent an endoscopic ultrasound (EUS) with fine needle aspiration (FNA) from the pancreatic mass and liver metastasis with cytological evaluation consistent with a pancreatoblastoma, later confirmed through a percutaneous US-guided liver biopsy. During the inpatient period, liver function deteriorated and acute kidney injury developed. Severe progressive cachexia was observed. The patient was discharged on renal replacement therapy and palliative care. Death occurred 3 months after diagnosis. Pancreatoblastoma is an uncommon pancreatic malignant epithelial cancer of the pancreas, typically occurring in the paediatric population. Adult pancreatoblastoma is extremely rare, with about 40 cases reported in the literature and generally presenting a more aggressive biologic and clinical behaviour. Surgical resection is the treatment of choice, but most cases are detected in advanced stages. This case underlines the ability to establish a pancreatoblastoma cytology-based diagnosis with EUS-FNA, and confirms the associated poor outcome. PMID- 29285692 TI - Diagnostic ultrasound widespread. PMID- 29285691 TI - Wallerian degeneration of the bilateral middle cerebellar peduncles secondary to pontine infarction. PMID- 29285690 TI - Using single-cell multiple omics approaches to resolve tumor heterogeneity. AB - It has become increasingly clear that both normal and cancer tissues are composed of heterogeneous populations. Genetic variation can be attributed to the downstream effects of inherited mutations, environmental factors, or inaccurately resolved errors in transcription and replication. When lesions occur in regions that confer a proliferative advantage, it can support clonal expansion, subclonal variation, and neoplastic progression. In this manner, the complex heterogeneous microenvironment of a tumour promotes the likelihood of angiogenesis and metastasis. Recent advances in next-generation sequencing and computational biology have utilized single-cell applications to build deep profiles of individual cells that are otherwise masked in bulk profiling. In addition, the development of new techniques for combining single-cell multi-omic strategies is providing a more precise understanding of factors contributing to cellular identity, function, and growth. Continuing advancements in single-cell technology and computational deconvolution of data will be critical for reconstructing patient specific intra-tumour features and developing more personalized cancer treatments. PMID- 29285689 TI - Gut microbiota in the pathogenesis of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic and relapsing inflammatory disorder of the intestine. Although its incidence is increasing globally, the precise etiology remains unclear and a cure for IBD has yet to be discovered. The most accepted hypothesis of IBD pathogenesis is that complex interactions between genetics, environmental factors, and the host immune system lead to aberrant immune responses and chronic intestinal inflammation. The human gut harbors a complex and abundant aggregation of microbes, collectively referred to as the gut microbiota. The gut microbiota has physiological functions associated with nutrition, the immune system, and defense of the host. Recent advances in next-generation sequencing technology have identified alteration of the composition and function of the gut microbiota, which is referred to as dysbiosis, in IBD. Clinical and experimental data suggest dysbiosis may play a pivotal role in the pathogenesis of IBD. This review is focused on the physiological function of the gut microbiota and the association between the gut microbiota and pathogenesis in IBD. In addition, we review the therapeutic options for manipulating the altered gut microbiota, such as probiotics and fecal microbiota transplantation. PMID- 29285693 TI - Barium concentrations and speciation in surface waters collected from an active barium mining area in Guizhou Province, southwestern China. AB - Barium (Ba) is a toxic element and can cause serious health effects. Humans have experienced increased exposure to Ba due to its intensive usage in industrial areas and daily life. Anthropogenic activities of Ba mining and the manufacture of Ba containing products introduce the element into surrounding areas, posing environmental concerns. Concentrations of total Ba (TBa) and dissolved Ba (DBa) in water samples collected from active Ba mines in Tianzhu, east Guizhou Province, southwestern China were measured to show the regional dispersion of Ba contamination. Aqueous Ba species in water were calculated using the PHREEQC program. The results showed that TBa and DBa concentrations ranged from 6.7 to 483.1 MUg/L and from 7.5 to 222.7 MUg/L, respectively. TBa concentrations presented a high average value of 126.6 MUg/L and greatly exceeded the reported common value of 10 MUg/L Ba in surface water set by the Ministry of Environment Protection of China. PHREEQC results indicated that Ba species in water were present as Ba2+, BaSO4, BaHCO3, BaCO3, and BaOH+. The distribution of Ba species in water is controlled by pH and total organic carbon (TOC), and the lower pH (pH < 7) the higher the dissolved fractions. The log K d values (K d , dissolved particulate distribution coefficients) varied from 2.41 to 6.32. Significant correlations were observed among Ba2+ and K+, Na+, Cl-, NO3-, with Pearson correlation coefficients of 0.425, 0.531, 0.853, 0.612, and 0.329, respectively (p < 0.01). Elevated Ba concentrations in water indicated that the Ba contamination and its distribution pattern in local aquatic ecosystems are derived from Ba mining sites in the Tianzhu area. PMID- 29285694 TI - Employing response surface methodology (RSM) to improve methane production from cotton stalk. AB - China is the largest cotton producer with the cotton output accounting for 25% of the total world's cotton production. A large quantity of cotton stalk (CS) waste is generated which is burned and causes environmental and ecological problems. This study investigated the anaerobic digestibility of CS by focusing on improving the methane yield by applying central composite design of response surface methodology (RSM). The purpose of this study was to determine the best level of factors to optimize the desired output of methane production from CS. Thus, it was necessary to describe the relationship of many individual variables with one or more response values for the effective utilization of CS. The influences of feed to inoculum (F/I) ratio and organic loading (OL) on methane production were investigated. Results showed that the experimental methane yield (EMY) and volatile solid (VS) removal were calculated to be 70.22 mL/gVS and 14.33% at F/I ratio of 0.79 and organic loading of 25.61 gVS/L, respectively. Characteristics of final effluent showed that the anaerobic system was stable. This research laid a foundation for future application of CS to alleviate the problems of waste pollution and energy output. PMID- 29285695 TI - Heavy metal enrichment in roadside soils in the eastern Tibetan Plateau. AB - The effects of human activities on heavy metal pollution in soil have been less investigated on the Tibetan Plateau. The present study was designed to assess the effects of highway traffic on Cu, Zn, Pb, and Cd enrichments in the 0-60-cm soil profile in the eastern Tibetan Plateau. Soils were sampled at four transects (with an altitude range of 2643-2911 m) across the G212 highway and five transects (3163-3563 m) across the G213 highway. Background concentrations of Cu, Zn, Pb, and Cd to the 60-cm soil depth (measured at each transect 400 m away from highways) varied greatly among transects and between highways. However, this spatial variation in the heavy metal concentrations was not related to the altitude of the investigated areas. On each the left and right sides of G212 or G213, Cu, Zn, and Pb concentrations to the 60-cm depth, at 5, 10, 20, and 50 m away from the highway, were all generally greater than the respective metal background concentrations. Cd concentrations to the 20 cm on G212 or 60-cm soil depth on G213 increased prominently within a distance of 20 m away from the highways, compared to background values in different depths. From the curb to 400 m away from highways, concentrations of Cu, Zn, Pb, and Cd were generally higher in the upper than in the lower soil layers. This may suggest that other factors such as atmospheric deposition were also contributable to the accumulation of heavy metals in soil. The contamination factor (C f ) calculation showed that roadside soils to the 60-cm depth, within a distance of 50 m from the curbs of both G212 and G213, were moderately (1 <= C f < 3) contaminated with Cu, Zn, and Pb. The contamination from Cd mainly occurred (1 <= C f < 8) in the top 20 cm soil with a closer distance from the highways. Our results indicated that traffic effects in enriching heavy metals reached 60-cm depth in roadside soils on the eastern Tibetan Plateau. For assessment of heavy metal pollutions in soil in mountainous areas, it is necessary to in situ identify the background values. PMID- 29285696 TI - Photocatalytic reduction of carbon dioxide over Cu/TiO2 photocatalysts. AB - The photocatalytic reduction of CO2 with H2O was investigated using Cu/TiO2 photocatalysts in aqueous solution. For this purpose, Cu/TiO2 photocatalysts (with 0.2, 0.9, 2, 4, and 6 wt.% of Cu) have been synthesized via sol-gel method. The photocatalysts were extensively characterized by means of inductively coupled plasma optical emission spectrometry (ICP-OES), N2 physisorption (BET), XRD, UV vis DRS, FT-IR, Raman spectroscopy, TEM-EDX, and photoelectrochemical measurements. The as-prepared photocatalysts contain anatase as a major crystalline phase with a crystallite size around 13 nm. By increasing the amount of Cu, specific surface area and band gap energy decreased in addition to the formation of large agglomeration of CuO. Results revealed that the photocatalytic reduction of CO2 decreased in the presence of Cu/TiO2 in comparison to pure TiO2, which might be associated to the formation of CuO phase acting as a recombination center of generated electron-hole pair. Decreasing of photoactivity can also be connected with a very low position of conduction band of photocatalysts with high Cu content, which makes H2 production necessary for CO2 reduction more difficult. PMID- 29285697 TI - Silicon alleviates cadmium toxicity in wheat seedlings (Triticum aestivum L.) by reducing cadmium ion uptake and enhancing antioxidative capacity. AB - Cadmium (Cd) is a toxic element that poses a great threat to human health, while silicon (Si) is a beneficial element and has been shown to have a mitigation effect on plants under Cd toxicity. However, the mechanisms underlying the role of Si in alleviating Cd toxicity are still poorly understood in wheat. Therefore, growth status, photosynthesis parameters, root morphology, antioxidant system, and Cd2+ uptake and flux under Cd toxicity were studied through hydroponic experiment, aiming to explore the mitigation of Si on Cd toxicity in wheat seedlings. The results showed that Si supply improved plant biomass as well as photosynthetic but had little effects on root morphology of seedlings under Cd stress. Si addition decreased Cd contents both in shoots and roots. In situ measurements of Cd2+ flux showed that Si significantly inhibited the net Cd2+ influx in roots of wheat. Si also mitigated the oxidative stress in wheat leaves by decreasing malondialdialdehyde (MDA) and hydrogen peroxide (H2O2) contents as well as by increasing superoxide dismutase (SOD) and guaiacol peroxidase (POD) activity. Overall, the results revealed that Si could alleviate Cd toxicity in wheat seedlings by improving plant growth and antioxidant capacity and by decreasing Cd uptake and lipid peroxidation. PMID- 29285698 TI - Dynamics and sources of pharmaceutically active compounds in a coastal Mediterranean river during heavy rains. AB - Concentrations of pharmaceutically active compounds (PACs) in freshwater systems depend on numerous factors such as land use and hydrometeorological conditions. In the Mediterranean, heavy rain events are of particular importance as they highly influence the concentration of micropollutants found in freshwater and are a source of recurrent first foul flushes due to combined sewer overflows (CSOs). In this study, we seek to assess the dynamics of pharmaceuticals during storm events in coastal Mediterranean rivers at a fine scale and to determine their contribution to multicontamination phenomena owing to CSOs. Our results showed that, while dissolved PACs followed the same trend as other contaminants, i.e., they increased significantly during CSOs, PACs in the total fraction did not peak yet maintained their already high concentrations for slightly longer due to their release via CSOs. Pharmaceutical concentrations for both the dissolved and the total fraction were dramatically diluted during the peak river flow. A fine-scale follow-up of PACs dynamics in the total fraction, including the differentiation of sewer overflows from both the right and left river banks, as well as the analyses of a large amount of PACs molecules, allowed us to clearly identify their major sources. While domestic inputs were dominated by nicotine and caffeine, the use of gadolinium (an MRI contrast agent) as a marker, attributed the main source of medical drugs such as tramadol, ibuprofen, and diclofenac to the major public hospital of the region. Thus, identifying major sources of PACs and implementing adapted water treatments directly at those sources would be the most cost-efficient alternative to cope with pharmaceutical drugs in coastal Mediterranean aquatic environments. Moreover, PACs behavior differed depending on the molecules considered and the source of these molecules, but we could not establish a direct link between their behavior and their chemical or physical properties. Our study highlights the importance of monitoring at strategic locations and with a high frequency sampling in order to better understand fate, sources, and behavior of pharmaceuticals in aquatic environments. PMID- 29285699 TI - Activated carbons from avocado seed: optimisation and application for removal of several emerging organic compounds. AB - In this study, avocado seed was successfully used as raw material for producing activated carbons by conventional pyrolysis. In order to determine the best condition to produce the activated carbons, a 22 full-factorial design of experiment (DOE) with three central points was employed by varying the temperature and time of pyrolysis. The two evaluated factors (temperature and time of pyrolysis) strongly influenced the SBET, pore volumes, hydrophobicity hydrophilicity ratio (HI) and functional groups values; both factors had a negative effect over SBET, pore volumes and functional groups which means that increasing the values of factors leads to decrease of these responses; on the other hand, with regards to HI, both factors caused a positive effect which means that increasing their values, the HI has an enhancement over its values. The produced activated carbon exhibited high specific surface areas in the range of 1122-1584 m2 g-1. Surface characterisation revealed that avocado seed activated carbons (ASACs) have hydrophilic surfaces and have predominantly acidic groups on their surfaces. The prepared ASACs were employed in the adsorption of 25 emerging organic compounds such as 10 pharmaceuticals and 15 phenolic compounds which presented high uptake values for all emerging pollutants. It was observed that the activated carbon prepared at higher temperature of pyrolysis (700 degrees C), which generated less total functional groups and presented higher HI, was the activated carbon with higher sorption capacity for uptaking emerging organic contaminants. Based on results of this work, it is possible to conclude that avocado seed can be employed as a raw material to produce high surface area and very efficient activated carbons in relation to treatment of polluted waters with emerging organic pollutants. PMID- 29285700 TI - Formation of a lead-insoluble phase, pyromorphite, by hydroxyapatite during lead migration through the water-unsaturated soils of different lead mobilities. AB - This study combined the original unsaturated-column-percolation test with X-ray diffraction (XRD) analysis to understand how lead is transformed into lead insoluble phase and immobilized by hydroxyapatite during lead migration in the water-unsaturated soil of different lead mobilities. The amounts of lead migrated from the soils without hydroxyapatite ranged from 4 to 46%, depending on the lead mobilities of soils. On the other hand, those of soils with hydroxyapatite were greatly suppressed by > 95% as compared with those without hydroxyapatite. The XRD analysis showed that the amounts of lead transformed into pyromorphite were compatible with those of lead migrated from the soil irrespective of the different lead mobilities. To the best of our knowledge, this study provides the first experimental evidence that lead migration can induce lead to transform into pyromorphite in the water-unsaturated soil. In addition, this study quantitatively demonstrates that the amount of lead migrated is almost equal to that of lead formed into pyromorphite. Thus, it was found that even if soluble lead remains after the application of immobilization material, it would be immobilized by the material during the lead migration as long as adequate material is applied to the soil. PMID- 29285701 TI - Effectiveness of narrow grass hedges in reducing atrazine runoff under different slope gradient conditions. AB - Atrazine is frequently detected in surface runoff and poses a potential threat to the environment. Grass hedges may minimize runoff loss of atrazine from crop fields. Therefore, the effectiveness of two grass hedges (Melilotus albus and Pennisetum alopecuroides) in controlling atrazine runoff was investigated using simulated rainfall on lands at different slope gradients (15 and 20%) in northern China. Results showed that a storm (40 mm in 1 h), occurring 4 h after atrazine application, caused a loss of 3% of the applied amount. Atrazine loss under 20% slope was significantly greater than that under 15% slope in control plots. Atrazine exports associated with the water fraction accounted for the majority of total loss. Pennisetum hedges were more efficient in controlling atrazine loss with runoff compared to Melilotus hedges. No significant difference in the capacity of grass hedges to reduce atrazine exports was observed between 15 and 20% slopes. These findings suggest grass hedges are effective in minimizing atrazine runoff in northern China, and Pennisetum hedges should be preferentially used on sloping croplands in similar climatic regions. PMID- 29285703 TI - Phthalate esters in surface water of Songhua River watershed associated with land use types, Northeast China. AB - The ubiquitous presence of phthalate esters (PAEs) in the environment and their potential role as endocrine disruptors of marine organisms has attracted much attention. The presence of PAEs in different water sources collected from the Songhua River mainstream and its tributaries has been determined in this study. The total concentration of the seven PAEs (?PAEs) detected was found to range from 1.153 to 7.867 MUg L-1, with di(2-ethylhexyl) phthalate (DEHP) present as the predominate PAE congener. Dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), and DEHP were present in all of the water samples analyzed. The concentration of ?PAEs in the Songhua River mainstream was shown to decrease initially, with a subsequent increase being detected due to inflow from branch tributaries contaminated with higher concentrations of PAEs. Analysis of land type usage, in this agriculture-dominated river watershed, also revealed an increase in ?PAE concentration in waters flowing through forested area. The concentration of ?PAEs in river waters also had a significant positive correlation with both agricultural and urban areas (p < 0.05); however, anthropogenic activities were not the only determining factor determining the ?PAE concentration in this river watershed. Ecological risk assessment revealed that the levels of DMP and DEP in all waters were generally low, representing a relatively low ecological risk to marine organisms; however, DBP was present at medium or high risk levels, whilst DEHP also displayed high risk levels. PMID- 29285704 TI - Direct perfusion of the carotid artery in patients with brain malperfusion secondary to acute aortic dissection. AB - OBJECTIVE: Presenting our experience of direct perfusion of the carotid artery in patients with brain malperfusion secondary to acute aortic dissection. PATIENTS: Among 381 patients who underwent aortic repair for acute type A aortic dissection from October 1999 to August 2017, brain malperfusion was recognized in 50 patients. Nine patients had direct perfusion of the right carotid artery in patients with brain malperfusion secondary to acute aortic dissection. Age at surgery was 65.7 +/- 13.5 years and three patients were male. Preoperative consciousness level was alert in one patients, drowsy in six, and coma in two. Five patients had preoperative hemiplegia. All patients showed a blood pressure difference between the upper extremities and eight patients showed more than 15% difference of rSO2. Seven patients had a temporary external active shunt from the femoral artery to the right common carotid artery preoperatively. Two patients had direct perfusion to the right common carotid artery during cardiopulmonary bypass or in the intensive care unit after surgery because of a sudden decrease of rSO2 and cessation of carotid artery flow. Antegrade cerebral perfusion was used in all patients. Total arch replacement was performed in six patients and hemiarch in three. RESULTS: The hospital mortality was 33% (3 patients). Causes of death were huge hemispheric brain infarction or anoxic brain damage in two patients and myocardial infarction in one. The postoperative neurological outcome was alert in four, hemiplegia in two, and coma in three, but five patients showed some improvement of neurological signs. CONCLUSION: Aggressive direct reperfusion of the carotid artery before the aortic repair may reduce neurological complications in patients with preoperative brain malperfusion secondary to acute aortic dissection. PMID- 29285702 TI - Pesticide dichorvos induces early solid Ehrlich tumoral development associated with a non-protective pro-inflammatory response. AB - Prolonged exposure to dichlorvos (DDVP), a common pesticide used for food crops, has been related to the development of infections and malignancies. Macrophages are used as bioindicators of immunotoxicity; thus, evaluation of their activity in solid Ehrlich tumor-bearing mice (TBM) may be useful to evaluate the influence of pesticides on human health. To investigate the effects of low DDVP doses, Swiss mice were divided into the following groups: the DDVP group, composed of mice fed diets containing 10 mg/kg of DDVP; the TBM group, consisting of mice subcutaneously inoculated with 107 tumor cells/100 MUl and fed a basal diet; the DDVP-TBM group, consisting of mice previously fed DDVP-containing diets for 28 days and then subcutaneously inoculated with tumor cells; and the control (CTRL) group, composed of mice fed a basal diet. After 7 and 21 days of tumor inoculation, the mice were euthanized; and after necroscopic examination, the neoplastic mass, organs, and intraperitoneal fluid were collected. Adherent peritoneal cells were cultivated to determine the production of H2O2 and TNF. Altogether, our results indicate that even at low doses, the intake of DDVP caused weight loss and increased tumor mass, which were associated with H2O2 production and high levels of TNF, a pro-inflammatory cytokine. These data are important as the exposure to pesticides, even at low doses, could potentially hinder the immune response against tumors and, consequently, create favorable conditions for their development. PMID- 29285705 TI - Bilateral Scheie's procedure with Ophthalmic Viscoelastic Device and 5 Fluorouracil. AB - INTRODUCTION: The surgical management of glaucoma has evolved over time. CASE REPORT: This report describes the first ever case, to our knowledge, of bilateral Scheie's procedures performed with retention of an ophthalmic viscoelastic device and intraoperative and post-operative 5-fluorouracil injections. DISCUSSION: These procedures have now successfully controlled the intraocular pressure in both of the patient's eyes for more than 17 years. PMID- 29285706 TI - Comparison of anterior segment parameters and axial lengths of myopic, emmetropic, and hyperopic children. AB - PURPOSE: To compare the anterior segment parameters of myopic, hyperopic, and emmetropic children by using optical biometry. METHODS: This prospective cross sectional study included 150 eyes of 150 children between 6 and 16 years old. The eyes were divided into three groups according to their spherical equivalent (SE) refractive error values as myopic [between - 1.0 and - 6.0 diopter (D)], emmetropic (between + 0.50 and - 0.50 D), and hyperopic (between + 1. 0 and + 3.0 D). Axial length (AL), central corneal thickness, anterior chamber depth (ACD), lens thickness (LT), and mean keratometry (K mean) measurements were obtained by an optical biometry (LenStar LS 900, Haag Streit Diagnostics) were compared between the groups. RESULTS: There were no statistically significant differences regarding the ages and genders of the participants between the groups (p > 0.05). The mean SE refractive error values were - 2.20 +/- 0.71 D in myopic, - 0.08 +/- 0.49 D in emmetropic, and + 2.06 +/- 0.53 D in hyperopic eyes. The mean AL values were 24.50 +/- 0.69, 23.41 +/- 0.61, and 22.33 +/- 0.61 mm, respectively, in myopic, emmetropic, and hyperopic eyes (p < 0.001). The mean ACD values were 3.94 +/- 0.22, 3.78 +/- 0.23, and 3.45 +/- 0.20 mm, respectively, in myopic, emmetropic, and hyperopic eyes (p < 0.001). The mean LT values were 3.56 +/- 0.20, 3.43 +/- 0.17, and 3.31 +/- 0.12 mm, respectively, in myopic, emmetropic, and hyperopic eyes (p < 0.001). There were no significant differences in the other parameters between the groups. CONCLUSIONS: Refractive errors are the main factors those affect anterior segment parameters and AL in children and the most severely affected parameters were found to be the AL, ACD, and LT values. PMID- 29285707 TI - An Emerging Treatment Alternative for Anemia in Chronic Kidney Disease Patients: A Review of Daprodustat. AB - This article reviews an emerging therapeutic agent, which is currently in phase III development for the treatment of anemia secondary to chronic kidney disease, covering promising phase II results, drug characteristics, and the current phase III trials, which, if approved, may significantly impact the management of anemia in this patient population. PMID- 29285708 TI - Intragastric Balloon Treatment for Obesity: FDA Safety Updates. AB - Over the past year, the FDA has issued two letters to healthcare providers alerting them to adverse events associated with ORBERA and ReShape intragastric balloons (IGBs), including several deaths. Both IGB devices were FDA-approved for use in the US in the summer of 2015. Although the adverse events cited in the two letters occurred following FDA approval, there was already evidence prior to FDA approval that the safety and efficacy of ReShape and ORBERA were highly questionable. Since January 1, 2006, ORBERA and Reshape IGB have been implicated in 33 deaths. Given the cited evidence, we recommend FDA withdrawal of these two devices. PMID- 29285709 TI - Effects of dried tofu supplementation during interval walking training on the methylation of the NFKB2 gene in the whole blood of older women. AB - Muscle atrophy with aging is closely associated with chronic systemic inflammation and lifestyle-related diseases. Here, we assessed whether dried tofu intake during 5-month interval walking training (IWT) enhanced increases in thigh muscle mass and strength and ameliorated susceptibility to inflammation in older women. Subjects (n = 32, ~ 65 years) who performed IWT for > 6 months participated in this study. They were randomly divided into 2 groups: IWT + placebo intake (PLG, n = 16; 108 kcal, 0.2 g protein, 5.5 g fat, and 14.4 g carbohydrate) and IWT + dried tofu intake (DTG, n = 16; 111 kcal, 9.6 g protein, 6.0 g fat, and 4.6 g carbohydrate). They were instructed to repeat >= 5 sets of fast and slow walking for 3 min each at >= 70 and 40% peak aerobic capacity for walking, respectively, per day for >= 4 days/week. Immediately after daily exercise, subjects were instructed to consume the supplements assigned to each group. In the DTG, after IWT, the methylation increased at 4/6 sites in the promoter region of the NFKB2 gene in the whole blood (all, P < 0.04), with an 18% increase in the average methylation of the 6 sites (P = 0.035). On the other hand, in the PLG, the increase occurred at only 2/6 sites, with no significant increase in the average methylation of the 6 sites. No significant differences were observed in increases in thigh muscle strength or cross-sectional area between the groups (all, P > 0.2). Altogether, dried tofu supplementation during IWT likely enhanced the methylation of the NFKB2 gene more than IWT alone, without detectably enhanced increases in thigh muscle strength or cross-sectional area. PMID- 29285710 TI - Newly characterized crystal structures: further insights into the architecture of GPCRs. PMID- 29285711 TI - Robust genome editing of CRISPR-Cas9 at NAG PAMs in rice. PMID- 29285712 TI - Enlightenment of blinding trachoma elimination in China. PMID- 29285713 TI - Genome sequencing brought Gossypium biology research into a new era. PMID- 29285714 TI - The triphibious warfare against viruses. PMID- 29285715 TI - Gene mutations and clinical phenotypes in 15 Chinese children with cryopyrin associated periodic syndrome (CAPS). AB - The aim of our study is to explore the features of clinical manifestations and genetic mutations in Chinese CAPS patients. Fifteen confirmed patients with CAPS were enrolled. The onset time ranges from 2 days after birth to 6 years and 1 month. Recurrent urticaria rash (93.3%) with fever (100%) were two dominant characteristics of these patients that were presented as either acute or chronic process. Systemic involvements were found in all patients except for one with only rash and fever. The top three symptoms were fever (100%), rash (93.3%) and myalgia (76%). Other clinical manifestations include arthritis (11 cases), lung involvement (seven cases), optical dysfunction (seven cases), nerve deafness (six cases), nervous system involvement (five cases), hepatomegaly, splenomegaly and lymphadenectasis (five cases). Also, four patients had heart involvement and one patient suffered kidney involvement. The laboratory inflammation index such as leukocyte counts, platelet counts, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), serum amyloid A (SAA) and fibrinogen (FIB) increased significantly at initial stage, but decreased after therapy. As for gene mutation detection, Twelve out of 15 patients were confirmed with mutation in NLRP3, including 11 mutant site: c1789A = 30 kg/m2, 10 female) and 23 lean control participants (BMI 18.5-24.9 kg/m2, 11 female) performed a probabilistic learning task during functional magnetic resonance imaging (fMRI), in which they learned to choose between advantageous and disadvantageous choice options in separate monetary gain, loss, and neutral conditions. During learning individuals with obesity made a significantly lower number of correct choices and accumulated a significantly lower overall monetary outcome than lean control participants. FMRI analyses revealed aberrant medial prefrontal cortex responses to monetary losses in individuals with obesity. There were no significant group differences in the regional representation of prediction errors. However, we found evidence for increased functional connectivity between the ventral striatum and insula in individuals with obesity. The present results suggest that obesity is associated with aberrant value representations for monetary losses, alterations in functional connectivity during the processing of learning outcomes, as well as a decresased reinforcement-based learning performance. This may affect how new information is incorporated to adjust dysfunctional behavior and could be a factor contributing to the maintenance of dysfunctional eating behavior in obesity. PMID- 29285722 TI - Determination of Heavy Metals in Almonds and Mistletoe as a Parasite Growing on the Almond Tree Using ICP-OES or ICP-MS. AB - In this study, the elements of Al, As, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Ni, Sr, Pb, Ti, and Zn were determined in the leaves, fruits, and branches of mistletoe, (Viscum album L.), used as a medicinal plant, and in the leaves, branches and barks of almond tree which mistletoe grows on. The aim of the study is to investigate whether the mistletoe are more absorbent than the almond tree in terms of the heavy metal contents and the determination of the amount of the elements penetrated into the mistletoe from the almond tree. ICP-MS (inductively coupled plasma-mass spectrometry) was used for the analysis of As, Cd, Mo, and Pb, whereas ICP-OES (inductively coupled plasma optical emission spectrometry) was used for the other elements. The results obtained were statistically evaluated at 95% confidence level. Within the results obtained in this study, it was determined whether there is a significant difference between metal elements in almond tree and mistletoe, or not. As a result, it was observed that there were higher contents of B, Ba, K, Mg, and Zn in the mistletoe than in the almond tree. K was found much higher than other elements in the mistletoe. On the other hand, Al, As, Ca, Cd, Cr, Cu, Fe, Mo, Ni, Sr, Pb, and Ti contents were determined to be more in almond tree than mistletoe. PMID- 29285723 TI - The Divalent Elements Changes in Early Stages of Chronic Kidney Disease. AB - As the glomerular filtration rate (GFR) decreases, it can cause imbalance in some divalent elements. These imbalances can cause increased oxidative stress in patients with renal impairment. The aim of present study was to investigate the changes of these divalent elements with CKD progression. One hundred and ninety four patients with chronic kidney diseases (CKD) were divided into five stages, stage 1, 2, 3a, 3b, 4, and were recruited into this study. The divalent elements, calcium, magnesium, phosphorus, as well as iron, zinc, and copper were determined in clinical chemistry analyzer. Higher CKD stages were found to be associated with increased levels of phosphorus and copper; Ptrend values were 0.002 and 0.004, respectively. Also, higher CKD stages were associated with decreased levels of zinc; Ptrend value was 0.002, after adjustment for age, gender, smoke, education, diabetes, hypertension, and BMI. Decreased levels of zinc and elevated levels of phosphorus and copper might increase the oxidative stress and complications in CKD patients. Future randomized studies are needed to show whether adjusting dietary intake of phosphorus, copper, and zinc might affect the progression of CKD. PMID- 29285724 TI - Management of Itch in Atopic Dermatitis. AB - Atopic dermatitis (AD) is the most common itchy dermatosis that affects millions of children and adults worldwide. Chronic itch in this condition has significant impact on measures of quality of life, such as sleep. Treating itch in AD has been challenging for decades, but new drugs have emerged in the last year with significant anti-pruritic effect. The optimal treatment regimen for atopic itch addresses barrier dysfunction, inflammation, neural hypersensitivity, and the itch-scratch cycle. Topical moisturizers remain the foundation of treatment and should be used by all patients with AD-associated pruritus. Step-wise therapy, from topical anti-inflammatory creams to systemic monoclonal antibodies and immunosuppressants, is recommended. There are multiple adjuvant therapies that can be used, especially to target itch in the setting of minimal skin inflammation. Finally, patient education, sleep management, and stress relief are important components to optimize outcomes. This review assesses the latest advances and treatment recommendations for pruritus in AD. Finally, suggested therapeutic ladders and emerging treatments are discussed. PMID- 29285726 TI - Myocardial perfusion in patients with non-ischaemic systolic heart failure and type 2 diabetes: a cross-sectional study using Rubidium-82 PET/CT. AB - Both patients with non-ischaemic systolic heart failure and patients with type 2 diabetes (T2DM) often have reduced myocardial blood flow without significant coronary atherosclerosis. However, the mechanisms are not fully understood. The aim of this study was to investigate whether perfusion is reduced additionally when the 2 are combined. In a cross-sectional study, we scanned patients with non ischaemic systolic heart failure with and without T2DM using Rubidium-82 positron emission tomography/computed tomography at rest and adenosine-induced stress, thereby obtaining the myocardial flow reserve (myocardial flow reserve (MFR) = stress flow/rest flow) as a measure of the myocardial vasomotor function; 28 patients with T2DM and 123 without T2DM were included. All patients received heart failure treatment according to guidelines. Multiple regression analysis was performed to assess the association between T2DM and MFR. Age [68 (60-75) years vs. 68 (62-72) years; P = 0.84] and female sex (21% vs. 33%; P = 0.26) were similar between patients with and without T2DM. Patients with T2DM had higher body mass index, (29.9 vs. 26.5 kg/m2; P = 0.02), higher blood glucose (6.2 vs. 5.7 mmol/L; P = 0.03), more often hypertension (50 vs. 27%; P = 0.02) and received more cholesterol lowering medication (61 vs. 35%; P = 0.02). Apart from this, the groups were similar. In a multivariable analysis, MFR was 16% lower in patients with T2DM compared with patients without [estimate - 16%; 95% confidence interval (CI) - 29 to - 0.7%; P = 0.04]. Patients with T2DM and systolic heart failure have lower myocardial flow reserve compared with heart failure patients without T2DM. PMID- 29285725 TI - Influence of iterative reconstruction on coronary calcium scores at multiple heart rates: a multivendor phantom study on state-of-the-art CT systems. AB - The objective of this study was to evaluate the influence of iterative reconstruction on coronary calcium scores (CCS) at different heart rates for four state-of-the-art CT systems. Within an anthropomorphic chest phantom, artificial coronary arteries were translated in a water-filled compartment. The arteries contained three different calcifications with low (38 mg), medium (80 mg) and high (157 mg) mass. Linear velocities were applied, corresponding to heart rates of 0, < 60, 60-75 and > 75 bpm. Data were acquired on four state-of-the-art CT systems (CT1-CT4) with routinely used CCS protocols. Filtered back projection (FBP) and three increasing levels of iterative reconstruction (L1-L3) were used for reconstruction. CCS were quantified as Agatston score and mass score. An iterative reconstruction susceptibility (IRS) index was used to assess susceptibility of Agatston score (IRSAS) and mass score (IRSMS) to iterative reconstruction. IRS values were compared between CT systems and between calcification masses. For each heart rate, differences in CCS of iterative reconstructed images were evaluated with CCS of FBP images as reference, and indicated as small (< 5%), medium (5-10%) or large (> 10%). Statistical analysis was performed with repeated measures ANOVA tests. While subtle differences were found for Agatston scores of low mass calcification, medium and high mass calcifications showed increased CCS up to 77% with increasing heart rates. IRSAS of CT1-T4 were 17, 41, 130 and 22% higher than IRSMS. Not only were IRS significantly different between all CT systems, but also between calcification masses. Up to a fourfold increase in IRS was found for the low mass calcification in comparison with the high mass calcification. With increasing iterative reconstruction strength, maximum decreases of 21 and 13% for Agatston and mass score were found. In total, 21 large differences between Agatston scores from FBP and iterative reconstruction were found, while only five large differences were found between FBP and iterative reconstruction mass scores. Iterative reconstruction results in reduced CCS. The effect of iterative reconstruction on CCS is more prominent with low-density calcifications, high heart rates and increasing iterative reconstruction strength. PMID- 29285727 TI - Influence of heart rate on coronary calcium scores: a multi-manufacturer phantom study. AB - To evaluate the influence of heart rate on coronary calcium scores (CCS) using a dynamic phantom on four high-end computed tomography (CT) systems from different manufacturers. Artificial coronary arteries were moved in an anthropomorphic chest phantom at linear velocities, corresponding to < 60, 60-75 and > 75 beats per minute (bpm). Data was acquired with routinely used clinical protocols for CCS on four high-end CT systems (CT1-CT4). CCS, quantified as Agatston and mass scores were compared to reference scores at < 60 bpm. Influence of heart rate was assessed for each system with the cardiac motion susceptibility (CMS) Index. At increased heart rates (> 75 bpm), Agatston scores of the low mass calcification were similar to the reference score, while Agatston scores of the medium and high mass calcification increased significantly up to 50% for all CT systems. Threefold CMS increases at > 75 bpm in comparison with < 60 bpm were shown. For medium and high mass calcifications, significant differences in CMS between CT systems were found. Heart rate substantially influences CCS for high-end CT systems of four major manufacturers, but CT systems differ in motion susceptibility. Follow-up CCS CT scans should be acquired on the same CT system and protocol, and preferably with comparable heart rates. PMID- 29285728 TI - Setting Standards for Pregnancy Registries. PMID- 29285729 TI - Are Randomized Control Trials the Best Method to Assess the Effectiveness of Community Treatment Orders? AB - Many jurisdictions have enacted community treatment order (CTO) legislation that requires a person, who suffers from a severe mental disorder, to follow a treatment plan when living in the community. CTOs have been a source of debate because of controversies on whether evidence of effectiveness should only be considered from randomized controlled trials (RCTs). RCTs are considered the "gold standard" method to evaluate effectiveness of simple therapeutic interventions such as medication, but they are problematic for evaluation of complex interventions because valid attribution of causation in complex interventions is not guaranteed with RCTs. CTOs are complex interventions that require the interaction of many individuals and organizations to achieve their effects and effectiveness research must measure these complexities of delivery and outcomes. This paper examines conceptual, methodological and analytical challenges of CTO research within the context of RCTs and other research designs. It also discusses the current state of knowledge on effectiveness of CTOs. Finally, we suggest a way forward by presenting alternative causal inference approaches and potential models for evaluation complex interventions, such as CTOs. We propose that these approaches should be used alongside other research designs in a nuanced approach that may involve using findings from initial studies to refine the intervention and/or its implementation. PMID- 29285730 TI - Adaptive Optimal Designs for Dose-Finding Studies with Time-to-Event Outcomes. AB - We consider optimal design problems for dose-finding studies with censored Weibull time-to-event outcomes. Locally D-optimal designs are investigated for a quadratic dose-response model for log-transformed data subject to right censoring. Two-stage adaptive D-optimal designs using maximum likelihood estimation (MLE) model updating are explored through simulation for a range of different dose-response scenarios and different amounts of censoring in the model. The adaptive optimal designs are found to be nearly as efficient as the locally D-optimal designs. A popular equal allocation design can be highly inefficient when the amount of censored data is high and when the Weibull model hazard is increasing. The issues of sample size planning/early stopping for an adaptive trial are investigated as well. The adaptive D-optimal design with early stopping can potentially reduce study size while achieving similar estimation precision as the fixed allocation design. PMID- 29285731 TI - Therapeutic Cancer Vaccines: How Much Closer Are We? AB - The promise of immune-based therapies to treat cancer has been realized over the last several years with several breakthrough therapies, including T-cell checkpoint inhibitors and chimeric antigen receptor (CAR)-T cell therapies. While cancer vaccines have been investigated for many decades, to date only one has been approved in the USA as a treatment for existing cancer. The failure of several anti-tumor vaccines in large phase III trials has led many to question their future role in cancer treatment. Trials to date have demonstrated that many cancer vaccines can elicit tumor-specific T cells, but these T cells may be insufficient to mediate substantial anti-tumor effects without concurrent blockade of tumor-resistance mechanisms. Emerging data from preclinical models and clinical trials demonstrate that cancer vaccines have greater activity in low volume disease and in combination with other immune-modulating therapies, including T-cell checkpoint blockade, targeting these resistance mechanisms. Because T-cell checkpoint therapies likely require the presence or activity of tumor-specific T cells, cancer vaccines may be optimal agents to use in combination to enable these therapies to work for greater numbers of patients. Future trials will explore optimal vaccine approaches and antigens that work best in combination treatment approaches and in earlier stages of disease. PMID- 29285732 TI - Emerging Approaches to Neurocircuits in PTSD and TBI: Imaging the Interplay of Neural and Emotional Trauma. AB - Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) commonly co occur in general and military populations and have a number of overlapping symptoms. While research suggests that TBI is risk factor for PTSD and that PTSD may mediate TBI-related outcomes, the mechanisms of these relationships are not well understood. Neuroimaging may help elucidate patterns of neurocircuitry both specific and common to PTSD and TBI and thus help define the nature of their interaction, refine diagnostic classification, and may potentially yield opportunities for targeted treatments. In this review, we provide a summary of some of the most common and the most innovative neuroimaging approaches used to characterize the neural circuits associated with PTSD, TBI, and their comorbidity. We summarize the state of the science for each disorder and describe the few studies that have explicitly attempted to characterize the neural substrates of their shared and dissociable influence. While some promising targets in the medial frontal lobes exist, there is not currently a comprehensive understanding of the neurocircuitry mediating the interaction of PTSD and TBI. Future studies should exploit innovative neuroimaging approaches and longitudinal designs to specifically target the neural mechanisms driving PTSD-TBI-related outcomes. PMID- 29285733 TI - Relationship between masticatory function and frailty in community-dwelling Japanese elderly. AB - BACKGROUND: Frailty likely results in impaired functioning, and frail individuals requiring long-term care have recently attracted the attention of researchers. In the oral health field, the number of elderly individuals who require intervention for retaining occlusion has been increasing, as has the number of remaining teeth and required prosthetic treatment. Additionally, the number of elderly with reduced masticatory function has also been increasing, and frailty is a suspected factor. AIMS: The aim of this study is to clarify the relationship between frailty and masticatory function decline. DESIGN: A cross-sectional study. METHODS: A total of 747 participants (total mean age 73.6 +/- 5.8 years old) underwent a comprehensive examination at the Tokyo Metropolitan Institute of Gerontology. Three masticatory functions were evaluated: maximum occlusal force, mixing ability, and self-reported chewing ability. Frailty was determined using all 25 questions of the Basic checklist developed by the Japanese Ministry of Health, Labour and Welfare, following the method reported by Satake et al. RESULTS: Binomial logistic analysis clarified the relationship between frailty and evaluation of each of the three masticatory functions. Significant correlations of pre-frailty or frailty with maximum occlusal force, mixing ability, and subjective chewing ability were observed. CONCLUSION: All three masticatory functions (maximum occlusal force, mixing ability, and self-reported chewing ability) were associated with pre-frailty or frailty in community dwelling Japanese elderly. PMID- 29285734 TI - Erratum to: The Positive Effects of Exercise in Chemotherapy-Related Cardiomyopathy. PMID- 29285735 TI - Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment. AB - The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a two-assay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars. PMID- 29285737 TI - Association between Polymorphisms of X-Ray Repair Cross Complementing Group 1 Gene and Pancreatic Cancer Risk: a Systematic Review with Meta-Analysis. AB - Emerging evidences have shown that common genetic polymorphisms in X-ray repair cross complementing group 1 (XRCC1) gene may be associated with the development of pancreatic cancer, but individually published studies and previous meta analyses revealed inconclusive results. The aim of our study was to investigate the association between polymorphisms in XRCC1 gene and pancreatic cancer risk. We conducted a search of PubMed, Embase, the Cochrane Library and Web of Science databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined as measures of the strength of association between polymorphisms of XRCC1 and pancreatic cancer risk. Sensitivity analysis and publication bias were evaluated. All analyses were undertaken using the STATA 13.0. A total of 10 studies were included in this systematic review. Five common functional single-nucleotide polymorphisms (SNPs) in XRCC1 gene were found, including Arg399Gln G > A (rs25487), Arg194Trp C > T (rs1799782), Arg280His G > A (rs25489), c.1517G > C, c.1471G > A. Results from our stratified analysis based on Hardy-Weinberg equilibrium (HWE) showed that there was a robust significant association between Arg280His polymorphism and pancreatic cancer risk (allelic model, OR 0.743, 95% CI 0.576-0.958, P = 0.022; heterozygous model, OR 0.701, 95% CI 0.525-0.936, P = 0.016; dominant model, OR 0.710, 95% CI 0.537-0.939, P = 0.016). We also found a statistically significant association between c.1517G > C polymorphism and pancreatic cancer risk (Allelic model, OR 1.252, 95% CI 1.064-1.473, P = 0.007). No significant results were obtained for Arg399Gln, Arg194Trp and c.1471G > A polymorphisms. The present meta-analysis suggested that Arg280His and c.1517G > C polymorphisms in XRCC1 gene were associated with pancreatic cancer risk. PMID- 29285736 TI - Beyond Conventional Medicine - a Look at Blueberry, a Cancer-Fighting Superfruit. AB - Nearly 40% of men and women will be diagnosed with cancer during their lifetime. Thus, there is a rapidly growing need for novel therapies to combat this deadly disease. One such method is the consumption of blueberries. Long coveted for their powerful antioxidant properties, more recent studies have demonstrated that blueberries also exhibit inherent abilities to prevent carcinogenesis, inhibit the proliferation of neoplastic cells, and reduce the risks of recurrence in patients in remission. This review will focus on the specific activities of blueberry derivatives in cancer cells across many different forms of cancer. Ultimately, such research could be helpful in the development of new strategies to treat cancer. PMID- 29285738 TI - Developmental Changes of Synaptic and Extrasynaptic NMDA Receptor Expression in Rat Cerebellar Neurons In Vitro. AB - Transient expression of different NMDA receptors (NMDARs) plays a role in development of the cerebellum. Whether similar processes undergo during neuronal differentiation in culture is not clearly understood. We studied NMDARs in cerebellar neurons in cultures of 7 and 21 days in vitro (DIV) using immunocytochemical and electrophysiological approaches. Whereas at 7 DIV, the vast majority of neurons were immunopositive for GluN2 subunits, further synaptoginesis was accompanied by the time-dependent loss of NMDARs. In contrast to GluN2B- and GluN2C-containing NMDARs, which at 7 DIV exhibited homogenous distribution in extrasynaptic regions, GluN2A-containing receptors were aggregated in spots both in cell bodies and dendrites. Double staining for GluN2A subunits and synaptophysin, a widely used marker for presynaptic terminals, revealed their co-localization in about 75% of dendrite GluN2A fluorescent spots, suggesting postsynaptic origin of GluN2A subunits. In agreement, diheteromeric GluN2A-containing NMDARs contributed to postsynaptic currents recorded in neurons throughout the timescale under study. Diheteromeric GluN2B-containing NMDARs escaped postsynaptic regions during differentiation. Finally, the developmental switch favored the expression of triheteromeric NMDARs assembled of 2 GluN1/1 GluN2B/1 GluN2C or GluN2D subunits in extrasynaptic regions. At 21 DIV, these receptors represented over 60% of the NMDAR population. Thus, cerebellar neurons in primary culture undergo transformations with respect to the expression of di- and triheteromeric NMDARs that should be taken into account when studying cellular aspects of their pharmacology and functions. PMID- 29285739 TI - Sonic Hedgehog Regulation of the Neural Precursor Cell Fate During Chicken Optic Tectum Development. AB - During nervous system development, neurons project axons over long distances to reach the appropriate targets for correct neural circuit formation. Sonic hedgehog (Shh) is a secreted protein and plays a key role in regulating vertebrate embryogenesis, especially in central nervous system (CNS) patterning, including neuronal migration and axonal projection in the brain and spinal cord. In the developing ventral midbrain, Shh is sufficient to specify a striped pattern of cell fates. Little is known about the molecular mechanisms underlying the Shh regulation of the neural precursor cell fate during the optic tectum development. Here, we aimed at studying how Shh might regulate chicken optic tectum patterning. In the present study, in ovo electroporation methods were employed to achieve the overexpression of Shh in the optic tectum during chicken embryo development. Besides, the study combined in ovo electroporation and neuron isolation culturing to study the function of Shh in vivo and in vitro. The fluorescent immunohistochemistry methods were used to check the related indicators. The results showed that Shh overexpression caused 87.8% of cells to be distributed to the stratum griseum central (SGC) layer, while only 39.3% of the GFP-transfected cells resided in the SGC layer in the control group. Shh overexpression also reduced the axon length in vivo and in vitro. In conclusion, we provide evidence that Shh regulates the neural precursor cell fate during chicken optic tectum development. Shh overexpression impairs neuronal migration and may affect the fate determination of transfected neurons. PMID- 29285740 TI - Grading system to categorize breast MRI using BI-RADS 5th edition: a statistical study of non-mass enhancement descriptors in terms of probability of malignancy. AB - PURPOSE: To analyze the association of breast non-mass enhancement descriptors in the BI-RADS 5th edition with malignancy, and to establish a grading system and categorization of descriptors. MATERIALS AND METHODS: This study was approved by our institutional review board. A total of 213 patients were enrolled. Breast MRI was performed with a 1.5-T MRI scanner using a 16-channel breast radiofrequency coil. Two radiologists determined internal enhancement and distribution of non mass enhancement by consensus. Corresponding pathologic diagnoses were obtained by either biopsy or surgery. The probability of malignancy by descriptor was analyzed using Fisher's exact test and multivariate logistic regression analysis. The probability of malignancy by category was analyzed using Fisher's exact and multi-group comparison tests. RESULTS: One hundred seventy-eight lesions were malignant. Multivariate model analysis showed that internal enhancement (homogeneous vs others, p < 0.001, heterogeneous and clumped vs clustered ring, p = 0.003) and distribution (focal and linear vs segmental, p < 0.001) were the significant explanatory variables. The descriptors were classified into three grades of suspicion, and the categorization (3, 4A, 4B, 4C, and 5) by sum-up grades showed an incremental increase in the probability of malignancy (p < 0.0001). CONCLUSION: The three-grade criteria and categorization by sum-up grades of descriptors appear valid for non-mass enhancement. PMID- 29285741 TI - Effects of Polygonum cuspidatum on AMPK-FOXO3alpha signaling pathway in a rat model of uric acid-induced renal damage. AB - OBJECTIVE: To observe the effects of Polygonum cuspidatum (PC) on adenosine 5' monophosphateactivated protein kinase (AMPK), forkhead box O3alpha (FOXO3alpha), Toll-like receptor-4 (TLR4), NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and monocyte chemoattractant protein-1 (MCP-1) expression in a rat model of uric acid-induced renal damage and to determine the molecular mechanism. METHODS: A rat model of uric acid-induced renal damage was established, and rats were randomly divided into a model group, a positive drug group, and high-, medium-, and low-dose Chinese medicine (CM) PC groups (n=12 per group). A normal group (n=6) was used as the control. Rats in the normal and model groups were administered distilled water (10 mL*kg-1) by intragastric infusion. Rats in the positive drug group and the high-, medium-, and low-dose CM Polygonum cuspidatum groups were administered allopurinol (23.33 mg*kg-1), and 7.46, 3.73, or 1.87 g*kg-1*d-1 Polygonum cuspidatum by intragastric infusion, respectively for 6 to 8 weeks. After the intervention, reverse transcription polymerase chain reaction, Western blotting, enzyme linked immunosorbent assay, and immunohistochemistry were used to detect AMPK, FOXO3alpha, TLR4, NLRP3, and MCP-1 mRNA and protein levels in renal tissue or serum. RESULTS: Compared with the normal group, the mRNA transcription levels of AMPK and FOXO3alpha in the model group were signififi cantly down-regulated, and protein levels of AMPKalpha1, pAMPKalpha1 and FOXO3alpha were signififi cantly down-regulated at 6th and 8th week (P<0.01, P<0.05). The mRNA transcription and protein levels of TLR4, NLRP3 and MCP-1 were signififi cantly up-regulated (P<0.01 or P<0.05). Compared with the model group, at the 6th week, the mRNA transcription levels of AMPK in the high- and medium dose groups, and protein expression levels of AMPKalpha1, pAMPKalpha1 and FOXO3alpha in the high-dose group, AMPKalpha1 and pAMPKalpha1 in the medium-dose group, and pAMPKalpha1 in the low-dose group were signififi cantly up-regulated (P<0.01 or P<0.05); the mRNA transcription and protein levels of TLR4 and NLRP3 in the 3 CM groups, and protein expression levels of MCP-1 in the medium- and low dose groups were down-regulated (P<0.01 or P<0.05). At the 8th week, the mRNA transcription levels of AMPK in the high- dose group and FOXO3alpha in the medium dose group, and protein levels of AMPKalpha1, pAMPKalpha1 and FOXO3alpha in the 3 CM groups were signififi cantly up-regulated (P<0.01 or P<0.05); the mRNA transcription levels of TLR4 in the medium- and low-dose groups, NLRP3 in the high- and low-dose groups and MCP-1 in the medium- and low-dose groups, and protein expression levels of TLR4, NLRP3 and MCP-1 in the 3 CM groups were down regulated (P<0.01 or P<0.05). CONCLUSION: PC up-regulated the expression of AMPK and its downstream molecule FOXO3alpha and inhibited the biological activity of TLR4, NLRP3, and MCP-1, key signal molecules in the immunoinflfl ammatory network pathway, which may be the molecular mechanism of PC to improve hyperuricemia mediated immunoinflammatory metabolic renal damage. PMID- 29285742 TI - Characterisation of Lactic Acid Bacteria Isolated from the Gut of Cyprinus carpio That May Be Effective Against Lead Toxicity. AB - The present study was conducted to isolate and characterise Pb-resistant lactic acid bacteria (LAB), and thus determine their potential for use as probiotics against Pb toxicity. A total of 107 Pb-resistant LAB strains were isolated from the gut content of Cyprinus carpio, of which 41 were established to be gram positive and catalase-negative. Investigation of the Pb-binding ability of these isolated LAB identified seven strains (P2, P6, P7, P9, P16, P19 and P22) with comparatively high Pb-binding activities. These were selected for further screening to establish their Pb tolerance, anti-oxidative capacity and in vitro probiotic characteristics. Strain P16 exhibited both the highest Pb-binding and a relatively good antioxidant capacity. Furthermore, P16 displayed a high survival rate during 4 h of exposure to both low-pH (2.5-3.5) conditions and 10.0% fish bile, and a strong capacity to adhere to fish intestinal mucus (62.4%). Furthermore, P16 showed strong antibacterial activities against all tested fish pathogens. Strains P6, P9, P16, P19 and P22 were susceptible to a range of tested antibiotics, but not to vancomycin. Thus, of the isolated lactobacilli, strain P16 exhibited the best Pb-binding ability, a high level of antioxidant activity and satisfactory in vitro probiotic properties. Biochemical and 16S-rRNA gene analyses identified P16 as Lactobacillus reuteri. Thus, the results of the conducted in vitro tests suggest that the fish-associated P16 Lact. reuteri strain is a promising candidate probiotic, which should undergo further investigation to assess its suitability for use in protecting against lead exposure-induced toxicities in aquaculture. PMID- 29285743 TI - Brazilian Kefir-Fermented Sheep's Milk, a Source of Antimicrobial and Antioxidant Peptides. AB - Fermented milks are a source of bioactive peptides and may be considered as functional foods. Among these, sheep's milk fermented with kefir has not been widely studied and its most relevant properties need to be more thoroughly characterized. This research study is set out to investigate and evaluate the antioxidant and antimicrobial properties of peptides from fermented sheep's milk in Brazil when produced by using kefir. For this, the chemical and microbiological composition of the sheep's milk before and after the fermentation was evaluated. The changes in the fermented milk and the peptides extracted before the fermentation and in the fermented milk during its shelf life were verified. The antimicrobial and antioxidant activities of the peptides from the fermented milk were evaluated and identified according to the literature. The physicochemical properties and mineral profile of the fermented milk were like those of fresh milk. The peptide extract presented antimicrobial activity and it was detected that 13 of the 46 peptides were able to inhibit the growth of pathogenic microorganisms. A high antioxidant activity was observed in the peptides extracted from fermented milk (3.125 mg/mL) on the 28th day of storage. Two fractions displayed efficient radical scavenging properties by DPPH and ABTS methods. At least 11 peptides distributed in the different fractions were identified by tandem mass spectrometry. This sheep's milk fermented by Brazilian kefir grains, which has antioxidant and antimicrobial activities and probiotic microorganisms, is a good candidate for further investigation as a source for bioactive peptides. The fermentation process was thus a means by which to produce potential bioactive peptides. PMID- 29285744 TI - Biases in attention and memory for body shape images in eating disorders. AB - PURPOSE: To investigate attentional and memorial biases towards body shape pictures among female patients with clinical eating disorders and healthy female controls. METHODS: A visual dot-probe task was used to assess attention towards pictures reflecting either a thin, normal, or obese female body shape. Pictures were presented in pairs; each pair depicted two different body shapes and were presented twice. Participant responses were compared across time and population. RESULTS: Overall, the eating disorder patients responded more slowly than controls, F(1,63) = 20.32, p < .001. Both groups showed an attentional bias towards the larger of two body shapes, F(1,63) = 4.30, p = .04, and responded more quickly the second time they viewed the picture pairs, F(1,63) = 33.80, p < .001. Upon second viewing of picture pairs, the eating disorder patients had a larger decrease in reaction time (86 ms) than the control sample (33 ms) only when both pictures included extreme body shapes (thin and obese); the decrease in reaction time when one of the pictures included a normal body shape was the same across groups upon second viewing (eating disorder: 37 ms; control: 32 ms), F(1,63) = 9.32, p = .003. CONCLUSIONS: These findings suggest that individuals with eating disorders may be biased towards recall of dichotomous and/or extreme body shape images. While it remains unclear whether attentional and/or memorial bias is a risk, maintenance, or causal factor in eating disorders, future studies should employ longitudinal, prospective research designs to address these questions. LEVEL OF EVIDENCE: Level II, comparative study. PMID- 29285745 TI - Reciprocal longitudinal relations between weight/shape concern and comorbid pathology among women at very high risk for eating disorder onset. AB - PURPOSE: Understanding how known eating disorder (ED) risk factors change in relating to one another over time may inform efficient intervention targets. We examined short-term (i.e., 1 month) reciprocal longitudinal relations between weight/shape concern and comorbid symptoms (i.e., depressed mood, anxiety) and behaviors (i.e., binge drinking) over the course of 24 months using cross-lagged panel models. METHODS: Participants were 185 women aged 18-25 years at very high risk for ED onset, randomized to an online ED preventive intervention or waitlist control. We also tested whether relations differed based on intervention receipt. RESULTS: Weight/shape concern in 1 month significantly predicted depressed mood the following month; depressed mood in 1 month also predicted weight/shape concern the following month, but the effect size was smaller. Likewise, weight/shape concern in 1 month significantly predicted anxiety the following month, but the reverse was not true. Results showed no temporal relations between weight/shape concern and binge drinking in either direction. Relations between weight/shape concern, and comorbid symptoms and behaviors did not differ based on intervention receipt. CONCLUSIONS: Results support focusing intervention on reducing weight/shape concern over reducing comorbid constructs for efficient short-term change. LEVEL OF EVIDENCE: Level I, evidence obtained from a properly designed randomized controlled trial. PMID- 29285746 TI - Influence of emotions evoked by life events on food choice. AB - PURPOSE: Considering the importance of replicating real-life experiences in studying emotional eating, this study investigated the influence of emotions evoked by life events on food choice in normal-weight and overweight women. METHODS: Normal-weight (n = 21) and overweight women (n = 23) aged 25-42 years were assigned to one of two different conditions: in one, they were shown a video with scenes of daily activities to elicit neutral responses; in the other, they were shown a video with scenes of common problems to evoke negative emotions. The participants were then offered a brunch containing sweet, salty, and healthy food items to evaluate their consumption and food choice. RESULTS: Exposure to negative emotions evoked by life problems increased energy intake in both groups, but they differed in terms of food choice. The normal-weight women increased only the consumption of sweet food (p = 0.044), whereas the overweight women significantly increased ingestion of sweet and salty foods (sweet food p = 0.031; salty food p = 0.008). CONCLUSIONS: The results show that common problems of life might trigger food consumption in the presence of high availability. Both groups increased food consumption after negative emotions and the normal-weight group had a higher increase than the overweight group. However, normal-weight women increased consumption of sweet foods, whereas overweight women consumed more salty, fried, and sweet foods. Healthy food was not chosen under these conditions. This should serve as a warning for the risks of excess exposure to high-sugar or high-fat food as everyday problems will not cease to exist. LEVEL OF EVIDENCE: Level II: evidence obtained from well-designed controlled trials without randomization. PMID- 29285748 TI - An Industry Perspective on the 2017 EMA Guideline on First-in-Human and Early Clinical Trials. AB - The European Medicines Agency (EMA) in 2017 issued a revised guideline on nonclinical and clinical aspects of first-in-human (FIH) and early clinical trials (CTs). External input was solicited during a draft comment phase, and although some industry suggestions were adopted, others were not. We agree that subject safety is of utmost priority, and believe that minimizing risk must be balanced with efficient and informative study designs to bring new medicines to patients. PMID- 29285747 TI - Potential role of NDRG2 in reprogramming cancer metabolism and epithelial-to mesenchymal transition. AB - Epithelial-to-mesenchymal transition (EMT) allows a cell with epithelial characteristics to transdifferentiate into a cell with mesenchymal characteristics, which is recognized as a key priming event for the initiation and evolvement of cancer metastasis. Accumulating data have shown that aberrant cancer metabolism contributes to the execution of EMT and cancer metastasis through multiple pathological pathways. Recently, the N-MYC downstream-regulated gene 2 (NDRG2), as a tumor suppressor and metabolism-related gene in various cancers, has been widely noted. NDGR2 is associated with energy metabolism, especially glycose metabolism. Hence, we propose a hypothesis that EMT is repressed by NDRG2 via cancer metabolic reprogramming, and summarize the pathological processes and molecular pathways related to the regulation of NDRG2. PMID- 29285749 TI - Prognostic Circulating MicroRNA Biomarkers in Early-Stage Non-Small Cell Lung Cancer: A Role for miR-150. AB - Circulating microRNA biomarkers can be indicators of early-stage non-small cell lung cancer (NSCLC) but may also hold prognostic value. The ability to predict prognosis of early-stage NSCLC is important, as it may potentially impact patient outcome. Studies to define these prognostic microRNA biomarkers are urgently needed. Also, insight into the biological significance of the microRNA biomarker in the cancer cell-and within the tumor-may reveal novel and therapeutically interesting signaling networks. PMID- 29285750 TI - The Use of Stem Cell Therapy to Reverse Opioid Tolerance. AB - Opioid tolerance (OT) and opioid-induced hyperalgesia (OIH) are major challenges in medicine. Here we report that transplantation of mesenchymal stem cells (MSCs) prevented and reversed OT and OIH in rats and mice. The preventive and therapeutic effects were long-lasting and consistent across different assessment schemes. Both intrathecal and intravenous transplantations were effective and safe. This emerging therapeutic strategy has thus shown promise to impact clinical practice and improve the efficacy and safety of opioid therapy. PMID- 29285751 TI - Endogenous Metabolites-Mediated Communication Between OAT1/OAT3 and OATP1B1 May Explain the Association Between SLCO1B1 SNPs and Methotrexate Toxicity. AB - Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients with hematological malignancies. Using a targeted urinary metabolomics approach, we identified 38 and 34 metabolites which were differentially excreted between wildtype and carriers of the c.388A>G or c.521T>C variant alleles, respectively, half of them being associated with methotrexate toxicity. These metabolites mainly consisted of fatty acid derivatives and microbiota catabolites, including glycine conjugates and other uremic toxins, all known OATs substrates. These results suggest that dysfunction of a transporter affects the excretion profile of endogenous or exogenous substrates, possibly through metabolite-mediated interactions involving other transport systems, even in distant organs. This opens the way for better comprehension of complex pharmacokinetics and transporter-mediated drug-drug or nutrient-drug interactions. PMID- 29285752 TI - Will a small randomly assembled community be feasible and stable? AB - How likely is it that few species can randomly assemble into a feasible and stable community? Some studies have answered that as long as the community is feasible, it will nearly always be stable. In contrast, other studies have answered that the likelihood is almost null. Here, we show that the origin of this debate has been the underestimation of the association of the parameter space of intrinsic growth rates with the feasibility and stability properties of small randomly-assembled communities. In particular, we demonstrate that not all parameterizations and sampling distributions of intrinsic growth rates lead to the same probabilities of stability and feasibility, which could mistakenly lead to under- or overestimate the stability properties of feasible communities. Additionally, we find that stability imposes a filtering of species abundances "towards" more even distributions in small feasible randomly-assembled communities. This indicates that the stability of feasible communities is inherently linked to the starting distribution of species abundances, a characteristic that many times has been ignored, but should be incorporated in manageable lab and field experiments. Overall, the return to this debate is a central reminder that a more systematic exploration of the feasible parameter space is necessary to derive general conclusions about the stability properties of ecological communities. PMID- 29285753 TI - Biobanks in the Era of Digital Medicine. AB - Digitalization is currently permeating virtually all sectors of modern societies, including biomedical research and medical care. At the same time, biobanks engaged in the long-term storage of biological samples that are fit for purpose have become key drivers in both fields. The present article highlights some of the challenges and opportunities that biobanking is facing in the current proverbial "era of digitalization." PMID- 29285754 TI - Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. AB - BACKGROUND: Oral anticoagulants may improve the survival of people with cancer through both an antitumor effect and antithrombotic effect, yet increase the risk of bleeding. OBJECTIVES: To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: We conducted a comprehensive literature search in February 2016 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (Ovid) and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; a search for ongoing studies; and using the 'related citation' feature in PubMed. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 December 2017. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) in ambulatory people with cancer. These participants are typically undergoing systemic anticancer therapy, possibly including chemotherapy, target therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form, we extracted data in duplicate on study design, participants, intervention outcomes of interest and risk of bias. Outcomes of interest included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook). MAIN RESULTS: Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta-analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low certainty evidence), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate certainty evidence) and minor bleeding (RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate certainty evidence).The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence). AUTHORS' CONCLUSIONS: The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for bleeding.Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. PMID- 29285755 TI - Pharmaceutical Benefits Scheme listing of adalimumab for hidradenitis suppurativa: Is hidradenitis suppurativa a life-changing drug or does lifestyle change the drug? PMID- 29285757 TI - Agency in advanced liberal services: grounding sociological knowledge in homeless people's accounts. AB - This paper aims to understand how people who are homeless respond to advanced liberal social services that endeavour to promote their autonomy and responsible actions. We prioritize the experiences and positions of people who are homeless, and what agentic action means to them. Sociological literature is selective about what accounts are deemed agentic. Agency is associated with accounts that resist or subvert dominant neoliberal framings of homelessness as failure of individuals. When people experiencing homelessness or poverty themselves foreground autonomy or responsibility, sociologists treat them as cultural dopes who have internalized neoliberal discourse. Our analysis is driven by an ethnographic study in an Australian homelessness shelter. We demonstrate how people who are homeless neither outright reject nor completely embrace advanced liberal practices to influence their actions and promote autonomy. People engaged in relational reasoning. Paternalist and advanced liberal social services were both lauded and rejected for their capacities and limitations to realize a good life. We contribute to the discussion for sociology to value people's accounts and experiences, rather than broader social process explaining their accounts. From the perspectives of people who are homeless, we show that just because something appears neoliberal does not mean it should be automatically rejected. PMID- 29285756 TI - Expression, distribution and function of kinin B1 receptor in the rat diabetic retina. AB - BACKGROUND AND PURPOSE: The kinin B1 receptor contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression, cellular localization and vascular inflammatory effect of B1 receptors in retina of streptozotocin diabetic rats. EXPERIMENTAL APPROACH: The distribution of B1 receptors on retinal cell types was investigated by immunocytochemistry. Effects of B1 receptor agonist, R-838, and antagonist, R-954, on retinal leukocyte adhesion, gene expression of kinin and VEGF systems, B1 receptor immunoreactivity, microgliosis and capillary leakage were measured. Effect of B1 receptor siRNA on gene expression was also assessed. KEY RESULTS: mRNA levels of the kinin and VEGF systems were significantly enhanced at 2 weeks in streptozotocin (STZ)-retina compared to control-retina and were further increased at 6 weeks. B1 receptor mRNA levels remained increased at 6 months. B1 receptor immunolabelling was detected in vascular layers of the retina, on glial and ganglion cells. Intravitreal R-838 amplified B1 and B2 receptor gene expression, B1 receptor levels (immunodetection), leukostasis and vascular permeability at 2 weeks in STZ-retina. Topical application (eye drops) of R-954 reversed these increases in B1 receptors, leukostasis and vascular permeability. Intravitreal B1 receptor siRNA inhibited gene expression of kinin and VEGF systems in STZ-retina. Microgliosis was unaffected by R-838 or R-954 in STZ-retina. CONCLUSION AND IMPLICATIONS: Our results support the detrimental role of B1 receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B1 receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR. PMID- 29285758 TI - Overwhelmed by Emotion: Pathways from Revictimization to Mothers' Negative Emotional Responsivity. AB - Maternal history of childhood abuse has consistently been linked to increased risk for poor emotional adjustment and parenting as an adult. The aim of this study was to examine a model that may explain the link between maternal history of childhood abuse and mothers' tendencies to respond negatively to their adolescent children's negative emotions. A community sample of 66 mothers with adolescent children participated. Path analysis supported associations between mothers with a history of high betrayal trauma revictimization (i.e., trauma perpetrated by someone close to the mother during childhood and again as a young adult) and increased difficulty regulating their emotions. In turn, mothers who struggled to regulate their own emotions were also more likely to respond negatively to their adolescent's negative emotions. Findings highlight effects of childhood trauma may be particularly problematic for mothers who are revictimized as young adults. These results provide the foundation for future research evaluating clinical interventions targeted at increasing maternal emotion regulation skills. PMID- 29285759 TI - The Trouble With Quantifiers: Exploring Children's Deficits in Scalar Implicature. AB - Adults routinely use the context of utterances to infer a meaning beyond the literal semantics of their words (e.g., inferring from "She ate some of the cookies" that she ate some, but not all). Contrasting children's (N = 209) comprehension of scalar implicatures using quantifiers with contextually derived ad hoc implicatures revealed that 4- to 5-year-olds reliably computed ad hoc, but not scalar, implicatures (Experiment 1). Unexpectedly, performance with "some" and "none" was correlated (Experiments 1 and 2). An individual differences study revealed a correlation between quantifier knowledge and implicature success (Experiment 3); a control study ruled out other factors (Experiment 4). These findings suggest that some failures with scalar implicatures may be rooted in a lack of semantic knowledge rather than general pragmatic or processing demands. PMID- 29285760 TI - Subthalamic deep brain stimulation and trunk posture in Parkinson's disease. AB - OBJECTIVES: We sought to assess the efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD)-associated trunk posture abnormalities retrospectively analyzing data from 101 patients reporting mild-to severe trunk posture abnormalities of a cohort of 216 PD patients treated with STN-DBS at our center. METHODS: Abnormal trunk posture was rated on a scale of 0 (normal) to 4 (marked flexion with an extreme abnormality of posture) as per the grading score reported in the Unified Parkinson's Disease Rating Scale. The independent effect of STN-DBS on trunk posture was assessed comparing Medication Off (presurgery) vs Stimulation-On/Medication-Off (post-surgery). The combined effect of STN-DBS plus levodopa was evaluated comparing Medication-On (presurgery) vs Stimulation-On/Medication-On (post-surgery). Analyses were conducted considering both the entire cohort of patients and the subgroup with camptocormia (CMC) and Pisa syndrome (PS). RESULTS: The independent effect of STN DBS resulted in a 41.4% improvement in abnormal trunk posture severity (P < .001), with 78.2% of patients (n = 79) reporting an improvement of at least 1 point. The combined effect of STN-DBS and levodopa resulted in a 30.9% improvement (P = .061), with 54.5% of patients (n = 55) reporting an improvement of at least 1 point. The subanalysis of patients with CMC (n = 23) and PS (n = 5) showed a 42.7% improvement in abnormal posture severity when considering the independent effect of STN-DBS (P < .001) and 30.5% when considering the combined effect of STN-DBS and levodopa (P < .001). CONCLUSIONS: STN-DBS may have the potential for improving posture in patients with advanced PD. PMID- 29285761 TI - Aire controls the recirculation of murine Foxp3+ regulatory T-cells back to the thymus. AB - In the thymus, medullary thymic epithelial cells (mTEC) determine the fate of newly selected CD4+ and CD8+ single positive (SP) thymocytes. For example, mTEC expression of Aire controls intrathymic self-antigen availability for negative selection. Interestingly, alterations in both Foxp3+ Regulatory T-cells (T-Reg) and conventional SP thymocytes in Aire-/- mice suggest additional, yet poorly understood, roles for Aire during intrathymic T-cell development. To examine this, we analysed thymocytes from Aire-/- mice using Rag2GFP and Foxp3 expression, and a recently described CD69/MHCI subset definition of post selection CD4+ conventional thymocytes. We show that while Aire is dispensable for de novo generation of conventional alphabetaT-cells, it plays a key role in controlling the intrathymic T-Reg pool. Surprisingly, a decline in intrathymic T Reg in Aire-/- mice maps to a reduction in mature recirculating Rag2GFP- T-Reg that express CCR6 and re-enter the thymus from the periphery. Furthermore, we show mTEC expression of the CCR6 ligand CCL20 is reduced in Aire-/- mice, and that CCR6 is required for T-Reg recirculation back to the thymus. Collectively, our study re-defines requirements for late stage intrathymic alphabetaT-cell development, and demonstrates that Aire controls a CCR6-CCL20 axis that determines the developmental makeup of the intrathymic T-Reg pool. PMID- 29285762 TI - The Necessary Return of Comprehensive Primary Health Care. PMID- 29285763 TI - GP Practices as a One-Stop Shop: How Do Patients Perceive the Quality of Care? A Cross-Sectional Study in Thirty-Four Countries. AB - OBJECTIVE: To contribute to the current knowledge on how a broad range of services offered by general practitioners (GPs) may contribute to the patient perceived quality and, hence, the potential benefits of primary care. STUDY SETTING: Between 2011 and 2013, primary care data were collected among GPs and their patients in 31 European countries, plus Australia, Canada, and New Zealand. In these countries, GPs are the main providers of primary care, mostly specialized in family medicine and working in the ambulatory setting. STUDY DESIGN: In this cross-sectional study, questionnaires were completed by 7,183 GPs and 61,931 visiting patients. Moreover, 7,270 patients answered questions about what they find important (their values). In the analyses of patient experiences, we adjusted for patients' values in each country to measure patient perceived quality. Perceived quality was measured regarding five areas: accessibility and continuity of care, doctor-patient communication, patient involvement in decision making, and comprehensiveness of care. The range of GP services was measured in relation to four areas: (1) to what extent they are the first contact to the health care system for patients in need of care, (2) their involvement in treatment and follow-up of acute and chronic conditions, in other words treatment of diseases, (3) their involvement in minor technical procedures, and (4) their involvement in preventive treatments. EXTRACTION METHODS: Data of the patients were linked to the data of the GPs. Multilevel modeling was used to construct scale scores for the experiences of patients in the five areas of quality and the range of services of GPs. In these four-level models, items were nested within patients, nested in GP practices, nested in countries. The relationship between the range of services and the experiences of patients was analyzed in three-level multilevel models, also taking into account the values of patients. PRINCIPAL FINDINGS: In countries where GPs offer a broader range of services patients perceive better accessibility, continuity, and comprehensiveness of care, and more involvement in decision making. No associations were found between the range of services and the patient perceived communication with their GP. The range of GP services mostly explained the variation between countries in the areas of patient perceived accessibility and continuity of care. CONCLUSIONS: This study showed that in countries where GP practices serve as a "one-stop shop," patients perceive better quality of care, especially in the areas of accessibility and continuity of care. Therefore, primary care in a country is expected to benefit from investments in a broader range of services of GPs or other primary care physicians. PMID- 29285764 TI - Paediatric amendment to adult BSH Guidelines for aplastic anaemia. PMID- 29285766 TI - Pulmonary arterial hypertension associated with connective tissue diseases: A review focusing on distinctive clinical aspects. AB - Recent studies have clarified that pulmonary arterial hypertension associated with connective tissue diseases (CTD-PAH) has some distinctive clinical aspects from other PAH, such as high prevalence, venous and cardiac involvement, less favourable outcome, helpfulness of detection algorithm, response to immunosuppression, pre-PAH conditions in borderline pulmonary arterial pressure and coexistence of interstitial lung disease. In this review, by focusing on these distinctive aspects, we discuss how to provide an efficacious and safe management of CTD-PAH and garner attention to areas where further evidence is desired. PMID- 29285767 TI - Opioid Neonatal Abstinence Syndrome: An Overview. AB - Opioid neonatal abstinence syndrome (NAS) refers to signs of withdrawal observed in infants experiencing intrauterine opioid exposures. Early identification of at risk infants allows for the prompt initiation of nonpharmacologic supportive care. When withdrawal symptoms are severe despite these interventions, pharmacologic therapy including opioid weaning is initiated. Consistency with standardized nonpharmacologic approaches as well as stringent weaning protocols are important in minimizing the length of stay and length of pharmacologic treatment for these vulnerable patients. PMID- 29285768 TI - Optimization of culture conditions for penicilazaphilone C production by a marine derived fungus Penicillium sclerotiorum M-22. AB - : The aim of this study was to optimize the culture conditions of a marine derived fungus Penicillium sclerotiorum M-22 for the production of penicilazaphilone C (PAC), a novel azaphilonidal derivative exhibiting broad cytotoxic and antibacterial effects. By single factor experiments, the effects to the production of PAC of aged seawater concentration, initial pH values, fermentation time, carbon sources, nitrogen sources and inorganic salt sources were investigated individually. Response surface methodology (RSM) analysis was adopted to investigate the interactions between variables and determine the optimal values for maximum PAC production. Evaluation of the experimental results signified that the optimum conditions for maximum production of PAC (19.85 mg l-1 ) in 250 ml Erlenmeyer flask were fermentation time 24.83 days, pH of 7.00, corn meal concentration of 10.72 g l-1 , yeast extract concentration of 4.58 g l-1 , crude sea salt concentration of 20.59 g l-1 . Production under optimized conditions increased to 1.344-fold comparing to its production prior to optimization. The higher PAC production and the penicilazaphilone C -producing marine fungus would be provide a promising alterative approach for industrial and commercial applications. SIGNIFICANCE AND IMPACT OF THE STUDY: Penicilazaphilone C (PAC) was a novel azaphilonidal derivative which had exhibited selective cytotoxicity and antibacterial activity. To further enhance production of PAC by optimizing fermentation conditions of Penicillium sclerotiorum M-22 would provide a promising alterative approach for industrial and commercial applications. We used the single factor test to determine the key factors which influence the PAC production. Then through the Response surface methodology and Box-Behnken design to determine the best fermentation condition for maximum production of PAC. Through these experimental designs and analysis will help us improve experimental efficiency and save time and materials. PMID- 29285769 TI - Polymorphisms in the porcine CD163 associated with response to PRRSV infection. PMID- 29285770 TI - Feeling out a link between feeling and infant sociomoral evaluation. AB - Recent research has shown that infants selectively approach prosocial versus antisocial characters, suggesting that foundations of sociomoral development may be present early in life. Despite this, to date, the mental processes involved in infants' prosocial preferences are poorly understood. To explore a possible role of emotions in early social evaluations, the current studies examined whether four samples of infants and toddlers express different emotional reactions after observing prosocial (giving) versus antisocial (taking) events. Experimentally blind coders rated infants' and toddlers' emotional reactions to prosocial and antisocial interactions from video using a 1- to 7-point Likert scale of negative to positive emotion; reactions were rated as more positive after viewing prosocial compared to antisocial interactions in three of four samples. While the observed effects were small, a single-paper meta-analysis suggests that the findings are robust and stable across age. These results support the possibility that emotional reactions play some role in infants' sociomoral evaluations. Statement of contribution What is already known Infants prefer prosocial to antisocial individuals from the first year of life. Emotion plays some role in the sociomoral judgments of children and adults. What this study adds Infants and toddlers express more positive reactions after observing prosocial giving versus antisocial taking acts, though observed effect sizes are small. Naive coders can predict at a better than chance rate what type of act an infant or toddler just viewed based on their facial expressions. Provides the first evidence that emotion plays some to-be-specified role in infants' and toddlers' sociomoral evaluations. PMID- 29285771 TI - Endotoxemia rocks sphingolipid metabolism at the blood-brain barrier: An Editorial Highlight for 'Alteration of sphingolipid metabolism as a putative mechanism underlying LPS-induced BBB disruption' on page 172. AB - In this issue of the Journal of Neurochemistry, Vutukuri et al. evaluate the impact of endotoxemia-induced encephalopathy on the sphingosine-1-phosphate (S1P) signaling pathway at the blood-brain barrier (BBB). Four hours after intraperitoneal administration of lipopolysaccharides (LPS, 4 mg/kg) to mice, they first demonstrate BBB dysfunction and then evaluate changes in sphingolipid metabolites in serum, isolated brain microvessels (MBMV), and whole brain. In parallel, they investigate the fate of indicated S1P generating and metabolizing enzymes and S1P receptors in brain and MBMV. S1P levels decreased in serum and brain and a similar tendency was observed in MBMV. Sphk2 expression was strongly reduced in MBMV together with an up-regulation of lipid phosphate and S1P phosphatases, resulting in a net decrease in S1P levels despite a compensatory increase in Sphk1 expression. The implications of disturbed sphingolipid metabolism for the pathogenesis of septic encephalopathy will depend on the net impact of these changes on S1P receptor signaling at the BBB and the importance of the S1P pathway in regulating vascular homeostasis in this context. PMID- 29285772 TI - Computational and experimental exploration of the structure-activity relationships of flavonoids as potent glyoxalase-I inhibitors. AB - Hit, Lead & Candidate Discovery Glyoxalase-I (Glo-I) enzyme has emerged as a potential target for cancer treatment. Several classes of natural products including coumarins and flavonoids have shown remarkable Glo-I inhibitory activity. In the present study, computational and experimental approaches were used to explore the structure-activity relationships of a panel of 24 flavonoids as inhibitors of the Glo-1 enzyme. Scutellarein with an IC50 value of 2.04 MUM was identified as the most potent inhibitor among the series studied. Di- or tri hydroxylation of the benzene rings A and B accompanied with a C2/C3 double bond in ring C were identified as essential structural features for enzyme inhibition. Moreover, the ketol system showed a minor role in the inhibitory power of these compounds. The structure-activity relationships revealed in this study had deepened our understanding of the Glo-I inhibitory activities of flavonoids and opened the door for further exploration of this promising compound class. PMID- 29285773 TI - Functional architecture of the somatosensory homunculus detected by electrostimulation. AB - KEY POINTS: We performed a prospective electrostimulation study, based on 50 operated intact patients, to acquire accurate MNI coordinates of the functional areas of the somatosensory homunculus. In the contralateral BA1, the hand representation displayed not only medial-to-lateral, little-finger-to-thumb, but also rostral-to-caudal discrete somatotopy, with the tip of each finger located more caudally than the proximal phalanx. The analysis of the MNI body coordinates showed rare inter-individual variations in the medial-to-lateral somatotopic organization in these patients with rather different intensity thresholds needed to elicit sensations in different body parts. We found some similarities but also substantial differences with the previous, seminal works of Penfield and his colleagues. We propose a new drawing of the human somatosensory homunculus according to MNI space. ABSTRACT: In this prospective electrostimulation study, based on 50 operated patients with no sensory deficit and no brain lesion in the postcentral gyrus, we acquired coordinates in the standard MNI space of the functional areas of the somatosensory homunculus. The 3D brain volume of each patient was normalized to that space to obtain the MNI coordinates of the stimulation site locations. For 647 sites stimulated on Brodmann Area 1 (and 1025 in gyri nearby), 258 positive points for somatosensory response (40%) were found in the postcentral gyrus. In the contralateral BA1, the hand representation displayed not only medial-to-lateral and little-finger-to-thumb somatotopy, but also rostral-to-caudal discrete somatotopy, with the tip of each finger located more caudally than the proximal phalanx. We detected a medial-to-lateral, tip-to base tongue organization but no rostral-to-caudal functional organization. The analysis of the MNI body coordinates showed rare inter-individual variations in the medial-to-lateral somatotopic organization in these patients with intact somatosensory cortex. Positive stimulations were detected through the 'on/off' outbreak effect and discriminative touch sensations were the sensations reported almost exclusively by all patients during stimulation. Mean hand (2.39 mA) and tongue (2.60 mA) positive intensity thresholds were lower (P < 0.05) than the intensities required to elicit sensations in the other parts of the body. Unlike the previous, seminal works of Penfield and colleagues, we detected no sensations such as sense of movement or desire to move, no somatosensory responses outside the postcentral gyrus, and no bilateral responses for face/tongue stimulations. We propose a rationalization of the standard drawing of the somatosensory homunculus according to MNI space. PMID- 29285774 TI - Widespread papular eruption in an infant. PMID- 29285775 TI - Systemic immune-inflammation index predicts the combined clinical outcome after sequential therapy with abiraterone and docetaxel for metastatic castration resistant prostate cancer patients. AB - OBJECTIVE: To compare the antitumor effect of abiraterone (AA) followed by docetaxel-prednisone (DP) or vice versa in metastatic castration-resistant prostate cancer (mCRPC) patients, and explored factors that might predict combined PSA-PFS, combined rPFS and OS. PATIENTS AND METHODS: We retrospectively analyzed mCRPC patients treated with sequential therapy using DP followed by AA or vice versa. Patients who had received enzalutamide or cabazitaxel were excluded. The primary outcome measure was overall survival (OS). The combined PSA progression-free survival (PSA-PFS), combined radiographic PFS (rPFS), and OS of AA-to-DP were compared to the reverse sequence using Kaplan-Meier curves with log rank statistics. Univariable and multivariable Cox regression analyses were performed to determine prognostic factors that were associated with combined PSA PFS, combined rPFS and OS. RESULTS: A total of 104 mCRPC patients who began treatment between 2013 and 2017 were identified: 42 were in the DP-to-AA group and 62 were in the AA-to-DP group. There was no significant difference of baseline clinical characteristics between AA-to-DP and DP-to-AA group. In addition, there was no significant difference in combined PSA-PFS (AA-to-DP: 12.5 [11.4-13.6] vs DP-to-AA: 13.2 [10.9-15.5] months [P = 0.127]), combined rPFS (AA to-DP: 12.2 [10.9-13.4] vs DP-to-AA: 11.2 [8.9-13.5] months [P = 0.183]) and OS (AA-to-DP: 23.3 [19.7-26.9] vs DP-to-AA: 22.9 [22.1-23.7] months [P = 0.213]) between the two treatment sequences in Kaplan-Meier analysis. In multivariate Cox regression analysis, high systematic Immune-Inflammation Index (SII) level, which was calculated by P (platelet) * N (neutrophil)/L(lymphocyte), remained significant predictors of OS, combined rPFS and combined PSA-PFS. CONCLUSION: In this study, we did not observe differences in clinical outcomes based on alternative sequencing of AA and DP in mCRPC patients. The ability to tolerate side effects and patient preference may be used to determine the treatment sequencing. In addition, high pretreatment SII level is a negative independent prognosticator of survival outcomes in mCRPC with sequential therapy using DP followed by AA or vice versa, which might guide clinicians select the best treatment. PMID- 29285776 TI - Association of the CYP17 MSP AI (T-34C) and CYP19 codon 39 (Trp/Arg) polymorphisms with susceptibility to acne vulgaris. AB - The aim of this study was to detect the association of the cytochrome P450 (CYP) 17 T-34C and CYP19 T 0.05), suggesting scaled eye growth during the last weeks before birth. Multivariate Gaussian analysis demonstrated that a statistical eye model can be defined that generates synthetic data that is significantly equal to the original data (non-parametric Mann-Whitney test for equality; all p < 0.05), with similar variability (non-parametric Levene test; all p > 0.05). CONCLUSION: The eye undergoes a scaled growth until birth, at which time male and female infants have similar values. The models presented may serve as an early biometry reference. PMID- 29285780 TI - Axially Decorated SiIV -phthalocyanines Bearing Mannose- or Ammonium-conjugated Siloxanes: Comparative Bacterial Labeling and Photodynamic Inactivation. AB - Herein, we present a comparative study about the photoinactivation of Staphylococcus aureus (Gram-positive model) and Escherichia coli (Gram-negative model) employing a neutral and a dicationic axially functionalized SiIV phthalocyanine. Depending on the charge of the siloxane moiety (neutral monosaccharide or cationic ammonium salt), different interactions with the bacteria were observed, and a differential photoinactivation was facilitated. The intensity of the fluorescence labeling correlated with the photoinactivation of the two types of bacteria: While the neutral species only significantly affected the Gram-positive cells, we observed that the positively charged photosensitizer interacted both with the Gram-positive and with the Gram-negative models. The dicationic photosensitizer labeled both models with a characteristic deep-red fluorescence and photoinactivated both classes of prokaryotes. In general, our study clearly demonstrates that axially ammoniumsiloxane-functionalized Si(IV) phthalocyaninates constitute excellent photosensitizers due to their weak aggregation in aqueous environments. In particular, we also show that charge based targeting with axial ammonium groups leads toward broad-spectrum SiIV phthalocyanines for photodynamic inactivation of bacteria. PMID- 29285781 TI - Non-water-suppressed 1 H FID-MRSI at 3T and 9.4T. AB - PURPOSE: This study investigates metabolite concentrations using metabolite cycled 1 H free induction decay (FID) magnetic resonance spectroscopic imaging (MRSI) at ultra-high fields. METHODS: A non-lipid-suppressed and slice-selective ultra-short echo time (TE) 1 H FID MRSI sequence was combined with a low-specific absorption rate (SAR) asymmetric inversion adiabatic pulse to enable non-water suppressed metabolite mapping using metabolite-cycling at 9.4T. The results were compared to a water-suppressed FID MRSI sequence, and the same study was performed at 3T for comparison. The scan times for performing single-slice metabolite mapping with a nominal voxel size of 0.4 mL were 14 and 17.5 min on 3T and 9.4T, respectively. RESULTS: The low-SAR asymmetric inversion adiabatic pulse enabled reliable non-water-suppressed metabolite mapping using metabolite cycling at both 3T and 9.4T. The spectra and maps showed good agreement with the water suppressed FID MRSI ones at both field strengths. A quantitative analysis of metabolite ratios with respect to N-acetyl aspartate (NAA) was performed. The difference in Cre/NAA was statistically significant, ~0.1 higher for the non water-suppressed case than for water suppression (from 0.73 to 0.64 at 3T and from 0.69 to 0.59 at 9.4T). The difference is likely because of chemical exchange effects of the water suppression pulses. Small differences in mI/NAA were also statistically significant, however, are they are less reliable because the metabolite peaks are close to the water peak that may be affected by the water suppression pulses or metabolite-cycling inversion pulse. CONCLUSION: We showed the first implementation of non-water-suppressed metabolite-cycled 1 H FID MRSI at ultra-high fields. An increase in Cre/NAA was seen for the metabolite-cycled case. The same methodology was further applied at 3T and similar results were observed. Magn Reson Med 80:442-451, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29285782 TI - Hyperpolarized 13 C,15 N2 -urea T2 relaxation changes in acute kidney injury. AB - PURPOSE: To investigate the correlation between renal ischemia and 13 C-urea T2 relaxation rate in an acute kidney injury (AKI) rat model. METHODS: Six rats subjected to unilateral renal ischemia were investigated. Creatinine clearance, urine output, plasma creatinine as well as blood-urea nitrogen (BUN) values were acquired before and after the procedure. 1 H T2* mapping was acquired using blood oxygenation level dependent (BOLD) MRI and hyperpolarized 13 C-urea T2 mapping was acquired using a 2D golden-angle radial approach. Kidney perfusion was estimated using noncontrast flow alternating inversion recovery arterial spin labeling. RESULTS: All rats showed clinical signs of AKI with increased plasma creatinine and increased BUN. Whole kidney 13 C-urea T2 significantly decreased 26% (P = 0.001) 24 h after reperfusion. A significantly different (3.7 times steeper; P = 0.008) osmolality gradient was observed in the contralateral kidney (P = 0.008; R2 = 0.86) compared with the postischemic kidney (P = 0.0004, R2 =0.97). Whole kidney T2* signal (P = 0.14) and T2* gradient (P = 0.26) was similar between the two kidneys. Oxygen availability dependency on 13 C-urea T2 was investigated by means of the correlation between the BOLD and T2 signals; a statistically significant difference (P = 0.03) was found in the contralateral kidney (P = 0.0001; R2 = 0.95), but not in the postischemic kidney (P = 0.31; R2 = 0.25). CONCLUSION: We demonstrate that hyperpolarized [13 C,15 N2 ]urea T2 relaxation correlates with renal oxygen tension ( T2*) in the healthy contralateral kidney, but not in the postischemic kidney. The whole kidney T2 relaxation difference between the postischemic and contralateral kidney may originate from altered blood volume in the postischemic kidney. Magn Reson Med 80:696-702, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29285783 TI - Simultaneous editing of GABA and glutathione at 7T using semi-LASER localization. AB - PURPOSE: To demonstrate simultaneous editing of the two most commonly edited and overlapping signals, gamma-aminobutyric acid (GABA), and glutathione (GSH), with Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) using sLASER localization at 7T. METHODS: Density matrix simulations of HERMES at 7T were carried out and compared with phantom experiments. Additional phantom experiments were performed to characterize the echo time (TE) -dependent modulation of GABA- and GSH-edited HERMES spectra at TE of 80-160 ms. In vivo experiments were performed in 10 healthy volunteers, comparing HERMES (11 min) to sequentially acquired MEGA-sLASER detection of GABA and GSH (2 * 11 min). RESULTS: Simulations of HERMES show GABA- and GSH-edited spectra with negligible levels of crosstalk, and give modest agreement with phantom spectra. The TE series of GABA- and GSH-edited HERMES spectra modulate as a result of T2 relaxation and coupling evolution, with GABA showing a stronger TE-dependence. In vivo HERMES experiments show well-edited GABA and GSH signals. Measured concentrations are not statistically different between HERMES and MEGA-sLASER for GABA (1. 051 +/- 0.254 i.u. and 1.053 +/- 0.248 i.u; P > 0.985) or GSH (0.300 +/- 0.091 i.u. and 0.302 +/- 0.093 i.u; P > 0.940). CONCLUSION: Simulated, phantom and in vivo measurements of HERMES show excellent segregation of GABA- and GSH edited signals, and excellent agreement with separately acquired MEGA-sLASER data. HERMES allows two-fold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-sLASER measurements. Magn Reson Med 80:474-479, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29285784 TI - Staff's reactions towards partnered sexual expressions involving people with dementia living in long-term care facilities. AB - AIMS: To explore staff responses, in terms of common practices, towards partnered sexual relationships in long-term care facilities where one or both people involved have dementia. It also tries to determine personal and institutional factors influencing these responses. BACKGROUND: Although some studies, mostly qualitative, have focused on reactions to residents' sexual expressions so far the issue has not been assessed in a study using large and diverse samples. DESIGN: Cross-sectional quantitative study using vignette technique. METHODS: Participants were 2,295 staff members at 152 Spanish long-term care facilities. Data were collected during 2016. A vignette describing sexual situations involving people with dementia was presented to participants. After the vignette, participants had to answer the question: "What do you think most of your colleagues would do in this situation?" with nine possible responses. RESULTS: Results showed that relationships involving persons with dementia were perceived as potentially problematic by staff. In both conditions, discussing the case with a colleague or supervisor was the most frequently chosen reaction. More restrictive reactions were mentioned when only one person with dementia was involved in the relationship. Factors such as participants" age and years of experience, professional post and commitment to person-centred care practices were related with the frequency of common restriction practices. CONCLUSION: Results highlight the importance of providing staff with clear guidelines regarding the management of specific sexual situations to avoid stereotyped restrictive reactions. PMID- 29285785 TI - Associations between health literacy, HIV-related knowledge, and information behavior among persons living with HIV in the Dominican Republic. AB - OBJECTIVES: To determine the health literacy levels of persons living with human immunodeficiency virus (HIV) (PLWH) at a health clinic in the Dominican Republic (DR) and assess associations between health literacy, HIV-related knowledge, and health information behavior (how patients need, seek, receive, and use information). DESIGN AND SAMPLE: Cross-sectional, descriptive. Participants were 107 PLWH attending the Clinic. MEASURES: A theoretically based, 64-item survey assessing information behavior and HIV-related knowledge was administered in Spanish through individual interviews. Health literacy was assessed using the Short Assessment of Health Literacy-Spanish and English. RESULTS: On average, participants were 40.8 years old and had lived with HIV for 7.7 years. The majority (69.2%) had low health literacy. HIV-related knowledge and information behavior varied by health literacy level and uncertainty regarding a main indicator of disease progression, viral load, was demonstrated regardless of health literacy level. Participants with low health literacy were less likely to answer questions or answer questions correctly and many participants (39.2%) indicated viral transmission can occur through supernatural means. CONCLUSIONS: Findings demonstrate unmet information need and that information received may not always be understood. Methods to improve health education are needed to ensure patients receive health information in an understandable way. PMID- 29285786 TI - An industrial design solution for integrating NMR magnetic field sensors into an MRI scanner. AB - PURPOSE: Neuroimaging research relies on the skills of increasingly multidisciplinary individuals and often requires the installation and use of additional home-built or third-party equipment. The purpose of the present work was the safe, ergonomic, durable, and aesthetically pleasing installation of magnetic field monitoring equipment into a scanner, while keeping the setup compatible with standard operating procedures. METHODS: An extensive set of steps was required to design a 3D printed solution to install a magnetic field camera into the eight-channel head coil of a 3T MRI scanner. First, the outer surface of the plastic coil housing was recreated into a 3D model, and the installation of the magnetic field sensors around this 3D model was performed in a virtual environment. The 3D printed solution was then assembled and tested for safety, reproducible performance, and image quality. RESULTS: The 3D printed solution holds the probes in stable positions and guides the necessary cables in an organized fashion and away from the volunteer. Assembly is easy and the solution is ergonomic, durable, and safe. We did not find excessive heating in the 3D printed parts, nor in the electronics, that they help to incorporate. The material used interferes minimally with transmit B1+ field. CONCLUSION: The design met all of the boundary conditions for a durable, safe, cost-effective, attractive, and functional installation. This work will provide the basis for installing the magnetic field sensors into other available head coils, and for designing the experimental setup for projects with varying experimental requirements. Magn Reson Med 80:833-839, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29285787 TI - Artifact-reduced imaging of biopsy needles with 2D multispectral imaging. AB - PURPOSE: Magnetic resonance (MR) guidance for biopsy procedures requires high intrinsic soft-tissue contrast. However, artifacts induced by the metallic needle can reduce its localization and require low-susceptibility needle materials with poorer cutting performance. In a proof of concept, we demonstrate the feasibility of 2D multispectral imaging (2DMSI) for both needle tracking and for needle artifact reduction for more precise needle localization and to enable the usage of needle materials with higher susceptibility. METHOD: We applied 2DMSI for imaging of MR-compatible biopsy needles, conventional stainless-steel needles, and mixed-material needles and compared it to conventional techniques. In addition, we exploited intrinsic off-resonance information for passive needle tracking. RESULTS: 2DMSI achieved a stronger reduction of the needle artifact compared to conventional techniques. For the mixed-material needles, the artifact was reduced to a level below that for MR-compatible needles with conventional imaging. The passive tracking also improved the ability to pinpoint the needle. CONCLUSION: 2DMSI is promising for both needle tracking and artifact-reduced imaging of biopsy needles for a more precise needle localization. 2DMSI may be particularly promising for needles inducing large distortions or for targeting of small lesions. In addition, it may enable the use of needle materials with higher susceptibility and potentially better sampling performance. Magn Reson Med 80:655 661, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29285788 TI - FLT3 inhibitors in acute myeloid leukemia: Choosing the best when the optimal does not exist. AB - Despite significant advances in deciphering the molecular and cytogenetic pathways governing acute myeloid leukemia, improvements in treatment strategies and clinical outcomes have been limited. The discovery of FLT3 pathway and its potential role in leukemogenesis has generated excitement in the field and has provided a potential target for drug development. Despite setbacks encountered with first-generation inhibitors, we are witnessing an outbreak of novel agents with potent activity and improved pharmacodynamics which continue to generate promising results. The disease, however, remains a challenge to both patients and physicians with rapid emergence of resistance and subsequent treatment failure. Multiple unanswered questions remain as to which are the optimal FLT3-inhibitors and which strategies and combinations are likely to overcome resistance. This review revisits the development of FLT3-inhibitors, the pathways incriminated in their failure and summarizes available molecularly-designed strategies to design better clinical trials. PMID- 29285789 TI - Intraoperative objective evaluation of venous congestion in deep epigastric artery perforator flap breast reconstruction: A pilot study. AB - BACKGROUND: In a deep epigastric artery perforator (DIEP) flap breast reconstruction, the necessity of additional anastomosis of the superficial inferior epigastric vein (SIEV) should be determined intraoperatively. The purpose of this pilot study is to propose a method to detect venous congestion intraoperatively using the blood glucose measurement index (BGMI). METHODS: In 70 DIEP flaps of 67 patients for breast reconstruction, the ratio of blood glucose content in the flap to systemic blood glucose (BGMI) was measured immediately after wound closure. Eight flaps in which BGMI was less than 0.8 were categorized into the low BGMI group, and additional venous anastomosis using SIEV was conducted. The other 62 flaps were categorized into the normal BGMI group. Perioperative objective color difference of the flap calculated using the L*a*b* color coordinate scale was recorded simultaneously. Correlation between BGMI and color difference was analyzed. RESULTS: In all flaps in the low BGMI group, SIEV diameter was increased; after additional anastomosis, the BGMI significantly improved (from 0.71 +/- 0.05 to 0.94 +/- 0.05, P < .01). There was a significant correlation between BGMI and color difference (P = .04). The determination coefficient was 0.265. When a BGMI of less than 0.8 was assumed to be a true positive, the area under the curve of color difference in the receiver operating characteristic curve was 0.82. CONCLUSION: BGMI immediately after wound closure may be useful to detect initial signs of venous congestion. Intraoperative objective color difference also reflects venous congestion; however, it is not highly accurate. PMID- 29285790 TI - Drug eluting stents are superior to bare metal stents to reduce clinical outcome and stent-related complications in CKD patients, a systematic review, meta analysis and network meta-analysis. AB - Aims To compare clinical outcome in Chronic kidney disease (CKD) patients receiving coronary stents according to stent type BMS versus DES and 1st generation versus 2nd generation DES. Methods and Results PubMed, Cinhal, Cochrane, Embase, and Web of Science were searched for studies including CKD patients. CKD was defined as eGFR < 60 mL/min. We selected n = 35 articles leading to 376 169 patients, of which 76 557 CKD patients receiving BMS n = 35,807, 1st generation DES n = 37,650, or 2nd generation DES n = 3100. Patient receiving DES, compared to BMS, had a 18% lower all-cause mortality (RR 0.82, 95%CI 0.71-0.94). The composite of death or myocardial infarction (MI) was lower in DES patients (RR 0.78, 95%CI 0.67-0.91), as was stent thrombosis (ST) (RR 0.57, 95%CI 0.34-0.95), target vessel/lesion revascularization (TVR/TLR) (RR 0.69, 95%CI 0.57-0.84) and death for cardiovascular cause (RR 0.43, 95%CI 0.25 0.74). We also found a gradient between 1st and 2nd generation DES, through BMS. Second, compared to 1st generation DES, were associated with further relative risk (RR) reduction of -18% in of all-cause death, and lower incidence of stent related clinical events: -39% RR of ST risk; -27 RR of TVR/TLR risk. Conclusions DES in CKD patients undergoing PCI were superior to BMS in reducing major adverse clinical events. This was possibly explained, by a lower risk of stent-related events as ST and TVR or TLR. Second, compared to 1st generation DES may furtherly reduce clinical events. PMID- 29285791 TI - Genotoxicity associated with the use of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. PMID- 29285792 TI - Kernel machine methods for integrative analysis of genome-wide methylation and genotyping studies. AB - Many large GWAS consortia are expanding to simultaneously examine the joint role of DNA methylation in addition to genotype in the same subjects. However, integrating information from both data types is challenging. In this paper, we propose a composite kernel machine regression model to test the joint epigenetic and genetic effect. Our approach works at the gene level, which allows for a common unit of analysis across different data types. The model compares the pairwise similarities in the phenotype to the pairwise similarities in the genotype and methylation values; and high correspondence is suggestive of association. A composite kernel is constructed to measure the similarities in the genotype and methylation values between pairs of samples. We demonstrate through simulations and real data applications that the proposed approach can correctly control type I error, and is more robust and powerful than using only the genotype or methylation data in detecting trait-associated genes. We applied our method to investigate the genetic and epigenetic regulation of gene expression in response to stressful life events using data that are collected from the Grady Trauma Project. Within the kernel machine testing framework, our methods allow for heterogeneity in effect sizes, nonlinear, and interactive effects, as well as rapid P-value computation. PMID- 29285793 TI - Application of a modified diabetes prevention program with adolescents. AB - OBJECTIVE: The purpose of this study was to increase type 2 diabetes (T2DM) awareness and decrease T2DM risk factors by examining effectiveness of a modified version of the Centers for Disease Control and Prevention (CDC) Diabetes Prevention Program (DPP) with adolescents. DESIGN AND SAMPLE: A quasi experimental one-group, pretest/posttest design was used to determine impact of the modified DPP on adolescents. Study intervention was incorporated into the health education curriculum at a public charter school and implemented over 11 weeks. Study sample included primarily African-American and Hispanic adolescents (N = 101) aged 13-18 attending the public charter school in a New Jersey urban community. MEASURES: Instrumentation included valid, reliable measures of self efficacy for healthy eating, physical activity, food knowledge, and healthy food choices. Participants' pretest/posttest waist circumference and body mass index (BMI) were collected. RESULTS: Outcomes revealed significant (p < .001) increase in participants' food knowledge, self-efficacy for choosing healthy foods and performing physical activity, healthy food choices, and amount of weekly aerobic exercise. Reductions in BMI and waist circumference were statistically significant (p < .05). CONCLUSIONS: A modified DPP adapted for adolescents' learning needs lowered risk for T2DM. Implications for clinical practice, education, and research are posed. PMID- 29285794 TI - Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency. AB - Mitochondrial defects associated with respiratory chain complex I deficiency lead to heterogeneous fatal syndromes. While the role of NDUFS8, an essential subunit of the core assembly of the complex I, is established in mitochondrial diseases, the mechanisms underlying neuropathology are poorly understood. We developed a Drosophila model of NDUFS8 deficiency by knocking down the expression of its fly homologue in neurons or in glial cells. Downregulating ND23 in neurons resulted in shortened lifespan, and decreased locomotion. Although total brain ATP levels were decreased, histological analysis did not reveal any signs of neurodegeneration except for photoreceptors of the retina. Interestingly, ND23 deficiency-associated phenotypes were rescued by overexpressing the glucose transporter hGluT3 demonstrating that boosting glucose metabolism in neurons was sufficient to bypass altered mitochondrial functions and to confer neuroprotection. We then analyzed the consequences of ND23 knockdown in glial cells. In contrast to neuronal knockdown, loss of ND23 in glia did not lead to significant behavioral defects nor to reduced lifespan, but induced brain degeneration, as visualized by numerous vacuoles found all over the nervous tissue. This phenotype was accompanied by the massive accumulation of lipid droplets at the cortex-neuropile boundaries, suggesting an alteration of lipid metabolism in glia. These results demonstrate that complex I deficiency triggers metabolic alterations both in neurons and glial cells which may contribute to the neuropathology. PMID- 29285795 TI - Ataluren-driven restoration of Shwachman-Bodian-Diamond syndrome protein function in Shwachman-Diamond syndrome bone marrow cells. AB - Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well-characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably, we show that ataluren treatment readily restores SBDS protein expression in different cell types, particularly bone marrow stem cells. Furthermore, ataluren promotes myeloid differentiation in hematopoietic progenitors, reduces apoptotic rate in primary PBMCs, and brings mammalian target of rapamycin phosphorylation levels back to normal in both lymphoblasts and bone marrow mesenchymal stromal cells (BM-MSCs). Since a specific therapy against SDS is currently lacking, these results provide the rationale for ataluren repurposing clinical trials. PMID- 29285796 TI - Weight-based carbohydrate treatment of hypoglycaemia in people with Type 1 diabetes using insulin pump therapy: a randomized crossover clinical trial. AB - AIM: To test whether weight-based treatment is more effective than usual care in people with Type 1 diabetes receiving continuous subcutaneous insulin infusion therapy with regard to both hypoglycaemia and avoiding excessive rebound hyperglycaemia. METHODS: Children and adults on continuous subcutaneous insulin infusion were enrolled into a study with a crossover design. Each episode of hypoglycaemia (defined as capillary glucose <4.0 mmol/l) was randomly assigned one of two treatment protocols using glucose tablets: either 0.3 g/kg body weight or usual treatment with 15 g (adults) or 10 g (children) for capillary glucose levels 3-3.9 mmol/l or twice these doses for capillary glucose levels <3 mmol/l. All participants received each treatment in random order for up to 10 hypoglycaemic episodes. Glucose levels were re-tested 10 min after treatment, with a repeat dose if still <4 mmol/l. RESULTS: Of the 37 participants enrolled, 35 (aged 6-68 years) completed the study. Twenty-four participants completed all treatment episodes, while 10 participants had <10 hypoglycaemic episodes and two withdrew without data. The mean glucose difference between weight-based and usual treatment after 10 min was 0.33 mmol/l (95% CI 0.005 to 0.66; P=0.047) in adults and 0.45 (95% CI 0.18 to 0.72; P=0.001) in children. The odds ratios for resolution of hypoglycaemia at 10 min with a single treatment using weight-based compared with usual treatment were 3.12 (95% CI 1.38 to 7.02; P=0.0070) in adults and 2.61 (95% CI 1.19 to 5.74; P=0.017) in children. CONCLUSIONS: Weight-based treatment using 0.3 g/kg glucose was more effective for symptomatic hypoglycaemia in children and adults with Type 1 diabetes who were using continuous subcutaneous insulin infusion than treatment based on current international recommendations. PMID- 29285797 TI - Sodium fluoride disturbs DNA methylation of NNAT and declines oocyte quality by impairing glucose transport in porcine oocytes. AB - Sodium fluoride (NaF) is used as a medicine to prevent tooth decay; however, excessive NaF could cause a pathological damage to the health. Recent studies showed that NaF impaired mouse oocyte maturation, included of abnormal spindle configuration, actin cap formation, cortical granule-free domain formation, and the following development after fertilization. However, few studies used large animals as models to study the toxicology of NaF on oocytes maturation. We proposed a hypothesis that NaF would affect the nuclear and cytoplasmic maturation of porcine oocytes and DNA methylation pattern of imprinted genes in oocytes. Our results showed that NaF affected cumulus expansion, polar body emission, spindle morphology, cortical granule distribution, early apoptosis, and the following development after parthenogenetic activation during porcine oocyte maturation. Moreover, NaF increased the DNA methylation of NNAT and decreased its expression, which disturbed the glucose transport in oocytes. These results suggest that NaF impairs the porcine oocytes maturation epigenetically, which provides a new toxicological mechanism of NaF on the oocyte maturation. Environ. Mol. Mutagen. 59:223-233, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29285798 TI - Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter. AB - Leukodystrophies are often devastating diseases, presented with progressive clinical signs as spasticity, ataxia and cognitive decline, and lack proper treatment options. New therapy strategies for leukodystrophies mostly focus on oligodendrocyte replacement to rescue lack of myelin in the brain, even though disease pathology also often involves other glial cells and the spinal cord. In this study we investigated spinal cord pathology in a mouse model for Vanishing White Matter disease (VWM) and show that astrocytes in the white matter are severely affected. Astrocyte pathology starts postnatally in the sensory tracts, followed by changes in the astrocytic populations in the motor tracts. Studies in post-mortem tissue of two VWM patients, a 13-year-old boy and a 6-year-old girl, confirmed astrocyte abnormalities in the spinal cord. For proper development of new treatment options for VWM and, possibly, other leukodystrophies, future studies should investigate spinal cord involvement. PMID- 29285800 TI - Translation and validation of the Canadian diabetes risk assessment questionnaire in China. AB - OBJECTIVES: To adapt the Canadian Diabetes Risk Assessment Questionnaire for the Chinese population and to evaluate its psychometric properties. DESIGN AND SAMPLE: A cross-sectional study was conducted with a convenience sample of 194 individuals aged 35-74 years from October 2014 to April 2015. METHODS: The Canadian Diabetes Risk Assessment Questionnaire was adapted and translated for the Chinese population. Test-retest reliability was conducted to measure stability. Criterion and convergent validity of the adapted questionnaire were assessed using 2-hr 75 g oral glucose tolerance tests and the Finnish Diabetes Risk Scores, respectively. Sensitivity and specificity were evaluated to establish its predictive validity. RESULTS: The test-retest reliability was 0.988. Adequate validity of the adapted questionnaire was demonstrated by positive correlations found between the scores and 2-hr 75 g oral glucose tolerance tests (r = .343, p < .001) and with the Finnish Diabetes Risk Scores (r = .738, p < .001). The area under receiver operating characteristic curve was 0.705 (95% CI .632, .778), demonstrating moderate diagnostic value at a cutoff score of 30. The sensitivity was 73%, with a positive predictive value of 57% and negative predictive value of 78%. CONCLUSIONS: Our results provided evidence supporting the translation consistency, content validity, convergent validity, criterion validity, sensitivity, and specificity of the translated Canadian Diabetes Risk Assessment Questionnaire with minor modifications. This paper provides clinical, practical, and methodological information on how to adapt a diabetes risk calculator between cultures for public health nurses. PMID- 29285799 TI - Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. AB - The Melatonin Osteoporosis Prevention Study (MOPS) demonstrated that nightly melatonin resulted in a time-dependent decrease in equilibrium ratios of serum osteoclasts and osteoblasts in perimenopausal women. This study examines mechanisms related to the ratios of osteoblasts and osteoclasts using coculture models (transwell or layered) of human mesenchymal stem cell (MSC) and human peripheral blood monocytes (PBMCs). Human MSC/PBMC cocultures exposed to melatonin in osteogenic (OS+) medium for 21 days induced osteoblast differentiation and mineralization; however, only in layered cocultures did melatonin inhibit osteoclastogenesis. Melatonin effects were mediated through MT2 melatonin receptors, MEK1/2, and MEK5. In layered but not transwell cocultures, melatonin increased OPG:RANKL ratios by inhibiting RANKL, suggesting that contact with osteoclasts during osteoblastogenesis inhibits RANKL secretion. Melatonin modulated expression of ERK1/2, ERK5, beta1 integrin, GLUT4, and IRbeta that was dependent upon the type of coculture; however, in both cultures, melatonin increased RUNX2 and decreased PPARgamma expression, indicating a role for metabolic processes that control osteogenic vs adipogenic cell fates of MSCs. Furthermore, melatonin also has osteoblast-inducing effects on human adipose derived MSCs. In vivo, one-year nightly melatonin (15 mg/L) given to neu female mice in their drinking water increased pErk1/2, pErk5, Runx2, and Opg and Rankl levels in bone consistent with melatonin's already reported bone-enhancing effects. Finally, analysis of daily logs from the MOPS demonstrated a significant improvement in mood and perhaps sleep quality in women receiving melatonin vs placebo. The osteoblast-inducing, bone-enhancing effects of melatonin and improvement in quality of life suggest that melatonin is a safe and effective bone loss therapy. PMID- 29285801 TI - Tinea faciei in a central Portuguese hospital: A 9-year survey. AB - Tinea faciei is a relatively uncommon dermatophytosis that affects the glabrous skin of the face. The aim of this study was to analyse the epidemiologic, clinical and mycological features of tinea faciei cases diagnosed at the Dermatology and Venereology Department of Hospital Santo Antonio dos Capuchos (Lisbon, Portugal). Consecutive cases diagnosed between 2008 and 2016 were studied retrospectively. A total of 72 tinea faciei cases have been diagnosed, involving 37 male and 35 female, aged between 8 months and 86 years. The majority were observed in patients younger than 12 years of age (59.72%). Anthropophilic isolates (mainly Microsporum audouinii, Trichophyton soudanense and Trichophyton rubrum) accounted for 75.7% of the identified dermatophytes. One quarter of the patients were also affected by dermatophytosis in other areas, such as the scalp. Only 10 cases were previously treated with topical steroids due to misdiagnosis. Most patients were treated with topical and systemic antifungal therapy with total resolution of skin lesions, without relapse or side effects. In contrast to other European studies, anthropophilic dermatophytes were the main causative agents of tinea faciei. As previously described to tinea capitis, this result is probably due to changes in the epidemiology of dermatophytes worldwide. PMID- 29285802 TI - First Principles Calculation of the Reaction Rates for Ligand Binding to Myoglobin: The Cases of NO and CO. AB - Ligand binding by proteins is among the most fundamental processes in nature. Among these processes the binding of small gas molecules, such as O2 , CO and NO to heme proteins has traditionally received vivid interest, which was further boosted by their recently recognized significant role in gas sensing in the body. At the heart of the binding of these ligands to the heme group is the spinforbidden reaction between high-spin iron(II) and the ligand yielding a low spin adduct. We use computational means to address the complete mechanism of CO and NO binding by myoglobin. Considering that it involves several steps occurring on different time scales, molecular dynamics simulations were performed to address the diffusion of the ligand through the enzyme, and DFT calculations in combination with statistical rate calculation to investigate the spin-forbidden reaction. The calculations yielded rate constants in qualitative agreement with experiments and revealed that the bottleneck of NO and CO binding is different; for NO, diffusion was found to be rate-limiting, whereas for CO, the spin forbidden step is the slowest. PMID- 29285803 TI - Balloon aortic valvuloplasty to improve candidacy of patients evaluated for transcatheter aortic valve replacement. AB - OBJECTIVES: Evaluate the role of balloon aortic valvuloplasty (BAV) in improving candidacy of patients for transcatheter aortic valve replacement (TAVR). BACKGROUND: Patients who are not candidates for TAVR may undergo BAV to improve functional and clinical status. METHODS: 117 inoperable or high-risk patients with critical aortic stenosis underwent BAV as a bridge-to-decision for TAVR. Frailty measures including gait speed, serum albumin, hand grip, activities of daily living (ADL); and NYHA functional class before and after BAV were compared. RESULTS: Mean age was 81.6 +/- 8.5 years and the mean Society of Thoracic Surgeons predicted risk of mortality was 9.57 +/- 5.51, with 19/117 (16.2%) patients non-ambulatory. There was no significant change in mean GS post-BAV, but all non-ambulatory patients completed GS testing at follow-up. Albumin and hand grip did not change after BAV, but there was a significant improvement in mean ADL score (4.85 +/- 1.41 baseline to 5.20 +/- 1.17, P = 0.021). The number of patients with Class IV congestive heart failure (CHF) was significantly lower post BAV (71/117 [60.7%] baseline versus 18/117 [15.4%], P = 0.008). 78/117 (66.7%) of patients were referred to definitive valve therapy after BAV. CONCLUSIONS: When evaluating frailty measures post BAV, we saw no significant improvement in mean GS, however, we observed a significant improvement in non ambulatory patients and ADL scores. We also describe improved Class IV CHF symptoms. With this improved health status, the majority of patients underwent subsequent valve therapy, demonstrating that BAV may improve candidacy of patients for TAVR. PMID- 29285804 TI - Centrifugation-free washing: A novel approach for removing immunoglobulin A from stored red blood cells. AB - Washed red blood cells (RBCs) are indicated for immunoglobulin A (IgA) deficient recipients. Centrifugation-based cell processors commonly used by hospital blood banks cannot consistently reduce IgA below the recommended levels, hence double washing is frequently required. Here, we describe a prototype of a simple, portable, disposable system capable of washing stored RBCs without centrifugation, while reducing IgA below 0.05 mg/dL in a single run. Samples from RBC units (n = 8, leukoreduced, 4-6 weeks storage duration) were diluted with normal saline to a hematocrit of 10%, and then washed using either the prototype washing system, or via conventional centrifugation. The efficiency of the two washing methods was quantified and compared by measuring several key in vitro quality metrics. The prototype of the washing system was able to process stored RBCs at a rate of 300 mL/hour, producing a suspension of washed RBCs with 43 +/- 3% hematocrit and 86 +/- 7% cell recovery. Overall, the two washing methods performed similarly for most measured parameters, lowering the concentration of free hemoglobin by >4-fold and total free protein by >10-fold. Importantly, the new washing system reduced the IgA level to 0.02 +/- 0.01 mg/mL, a concentration 5-fold lower than that produced by conventional centrifugation. This proof-of concept study showed that centrifugation may be unnecessary for washing stored RBCs. A simple, disposable, centrifugation-free washing system could be particularly useful in smaller medical facilities and resource limited settings that may lack access to centrifugation-based cell processors. PMID- 29285805 TI - Atmospheric ammonia alters lipid metabolism-related genes in the livers of broilers (Gallus gallus). AB - Atmospheric ammonia in animal housing is reported to have adverse effects on livestock performance and animal health. Previous experiments have found that 75 ppm ammonia reduced the production performance and altered body fat distribution quality of broilers. In this study, we examined the body fat distribution, serum metabolites and lipid metabolism gene expression of broiler exposed to ammonia. A total of 400 chickens were randomly allocated to four groups with four replicates and received ammonia treatments at 0, 25, 50 and 75 ppm, respectively, for 3 weeks. The average daily feed intake and weight gain were decreased when broiler was exposed to ammonia concentration exceeding 50 ppm (p < .05). The increased abdominal fat and reduced thickness of subcutaneous adipose were found in broilers of 75 ppm group (p < .05). When ammonia exceeded 50 ppm, the content of fat in breast muscle of broiler was increased, and when ammonia was higher than 25 ppm, the fat in liver was increased (p < .05). It showed that the fat content in liver was a sensitive index for broilers exposed to ammonia. Furthermore, ammonia exposure had no significant effect on total cholesterol and triglyceride in serum, but significantly increased the relative mRNA expression of acetyl-CoA carboxylase (p = .046) and malic enzyme in liver (p = .038), which indicated that ammonia exposure may increase the de novo fat synthesis in liver. In addition, ammonia increased the high-density lipoprotein cholesterol (p = .02) and activity of hepatic lipase in serum (p < .001), which indicated that ammonia exposure may improve the transportation of cholesterol to liver. To conclude, our results indicated that ammonia exposure might increase the de novo fat synthesis in liver and increased the transportation of cholesterol to liver. In addition, the concentration of ammonia in poultry house should be limited lower than 25 ppm based on the variation of hepatic fat content. PMID- 29285806 TI - Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies. AB - OBJECTIVE: Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B lymphocytes as well as other kinases including interleukin-2-inducible T cell kinase (ITK) in CD4+ Th2 regulatory T cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated. METHODS: The published literature and conference abstracts of prospective clinical trials using ibrutinib in hematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc.org per PRISMA guidelines. Infectious events with a focus on pneumonia were collated per the Common Terminology Criteria for Adverse Events Version 4.03 grading. RESULTS: Infectious complications are common, occurring in 56% of patients taking single-agent ibrutinib and 52% of those on combination therapy. Approximately one in 5 patients developed pneumonia, which was the major contributor to a 2% rate of death from infections. Many of the cases of pneumonia were due to opportunistic pathogens. CONCLUSIONS: Ibrutinib use requires prudent consideration of the impacts on host immunity. We identified a high rate of serious adverse infectious events within prospective clinical trials. Data suggest a role of both BTK and ITK inhibition for the increased events. There was considerable variability in the reporting of adverse events between trials, journals, and conference reports. PMID- 29285807 TI - Doramectin in the treatment of generalized demodicosis. AB - BACKGROUND: Generalized demodicosis is a common disease in dogs and doramectin has been reported as a successful treatment. Different treatment protocols using doramectin have not been previously evaluated. OBJECTIVE: To evaluate whether oral administration of doramectin twice a week is more effective than administration by subcutaneous injection once a week. ANIMALS: Twenty nine privately owned dogs affected with generalized demodicosis. METHODS: Dogs randomly received one of two treatments. Sixteen dogs were treated with 600 MUg/kg doramectin by subcutaneous injection once a week and 13 dogs received 600 MUg/kg doramectin by oral administration twice a week. RESULTS: The mean age of affected dogs was 2.8 and 2.6 years (P = 0.587) and the mean mite number detected at the initial evaluation was 201 and 287 (P = 0.04), respectively, for each group. The mean time to achieve negative skin scrapings was 13 and 12 weeks, respectively (P = 0.955). Adult-onset demodicosis affected five of 16 and two of 13 dogs, respectively (P = 0.662). The success rate for treatment was 13 of 16 (81%) of dogs receiving subcutaneous injections once a week and 12 of 13 (92%) dogs receiving oral dosaging twice a week. (P = 0.691). Four dogs did not achieve disease remission. In the 12 month follow-up period, one dog that had received the once a week protocol relapsed after eight weeks of treatment withdrawal. Adverse effects were not observed in any dog. CONCLUSION: Based on the results of this study, oral administration of doramectin twice a week does not achieve a more rapid resolution of canine generalized demodicosis than administration by subcutaneous injection once a week. The treatment success rate was the same for both protocols. PMID- 29285808 TI - Is prolonged cold ischemia a contraindication to using kidneys from acute kidney injury donors? AB - To determine the impact of prolonged cold ischemia time (CIT) on the outcome of acute kidney injury (AKI) renal grafts, we therefore performed a single-center retrospective analysis in adult patients receiving kidney transplantation (KT) from AKI donors. Outcomes were stratified according to duration of CIT. A total of 118 patients receiving AKI grafts were enrolled. Based on CIT, patients were stratified as follows: (i) <20 hours, 27 patients; (ii) 20-30 hours, 52 patients; (iii) 30-40 hours, 30 patients; (iv) >=40 hours, nine patients. The overall incidence of delayed graft function DGF was 41.5%. According to increasing CIT category, DGF rates were 30%, 42%, 40%, and 78%, respectively (P = .03). With a mean follow-up of 48 months, overall patient and graft survival rates were 91% and 81%. Death-censored graft survival (DCGS) rates were 84% and 88% for patients with and without DGF (P = NS). DCGS rates were 92% in patients with CIT <20 hours compared to 85% with CIT >20 hours (P = NS). In the nine patients with CIT >40 hours, the 4-year DCGS rate was 100%. We conclude that prolonged CIT in AKI grafts may not adversely influence outcomes and so discard of AKI kidneys because of projected long CIT is not warranted when donors are wisely triaged. PMID- 29285809 TI - Investigation of the BOLD and CBV fMRI responses to somatosensory stimulation in awake marmosets (Callithrix jacchus). AB - Understanding the spatiotemporal features of the hemodynamic response function (HRF) to brain stimulation is essential for the correct application of neuroimaging methods to study brain function. Here, we investigated the spatiotemporal evolution of the blood oxygen level-dependent (BOLD) and cerebral blood volume (CBV) HRF in conscious, awake marmosets (Callithrix jacchus), a New World non-human primate with a lissencephalic brain and with growing use in biomedical research. The marmosets were acclimatized to head fixation and placed in a 7-T magnetic resonance imaging (MRI) scanner. Somatosensory stimulation (333 MUs pulses; amplitude, 2 mA; 64 Hz) was delivered bilaterally via pairs of contact electrodes. A block design paradigm was used in which the stimulus duration increased in pseudo-random order from a single pulse up to 256 electrical pulses (4 s). For CBV measurements, 30 mg/kg of ultrasmall superparamagnetic ironoxide particles (USPIO) injected intravenously, were used. Robust BOLD and CBV HRFs were obtained in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2) and caudate at all stimulus conditions. In particular, BOLD and CBV responses to a single 333-MUs-long stimulus were reliably measured, and the CBV HRF presented shorter onset time and time to peak than the BOLD HRF. Both the size of the regions of activation and the peak amplitude of the HRFs grew quickly with increasing stimulus duration, and saturated for stimulus durations greater than 1 s. Onset times in S1 and S2 were faster than in caudate. Finally, the fine spatiotemporal features of the HRF in awake marmosets were similar to those obtained in humans, indicating that the continued refinement of awake non-human primate models is essential to maximize the applicability of animal functional MRI studies to the investigation of human brain function. PMID- 29285810 TI - Von Willebrand factor revisited. AB - Degenerative aortic valve stenosis is the most common valvular heart disease seen in developed countries. Since the implementation of transcatheter aortic valve replacement, there has been a surge of efforts to improve procedural technique as well as reduce mortality. Until recently, the mainstay method of assessment of valve implantation as well as paravalvular regurgitation has relied heavily on imaging techniques including transesophageal echocardiography and aortic root angiography. There has been a lot of scientific inquiry to identify biomarkers in the management of patients with aortic stenosis. von Willebrand factor activity and high molecular weight multimer level assessment has emerged as an excellent biomarker with intraoperative, point of care potential. These implications can both supplement imaging modalities as well as potentially serve as a more accurate assessment TAVR complications. PMID- 29285811 TI - EZH2 overexpression in head and neck cancer is related to lymph node metastasis. AB - BACKGROUND: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2, plays an important role in tumor development and progression by interacting with histone and non-histone proteins. EZH2 represents a putative therapeutic target and has been suggested as a prognostic marker in several cancer types. MATERIAL AND METHODS: This study investigates the prognostic relevance of immunohistochemical EZH2 expression in head and neck squamous cell carcinoma. Tissue microarray sections with 667 cancers of oral cavity, oro- and hypopharynx and larynx were analyzed for EZH2 expression. RESULTS: Nuclear EZH2 staining was recorded in 322 (81.8%) of 394 cases. Staining was weak in 33 (10.2%), moderate in 128 (39.6%), and strong in 103 (32.0%) cancers. The prevalence of EZH2 expression in tumors of the oral cavity and the orohypopharynx was higher as compared to cancers of the larynx (P = .0023). EZH2 expression was correlated to presence of lymph node metastasis (P = .0089) but was unrelated to histological grade, tumor stage, surgical margin, or distant metastasis. EZH2 expression had no impact on patient survival. CONCLUSION: The high prevalence of EZH2 expression in head and neck squamous cell carcinoma stresses its capability as a therapeutic target. PMID- 29285812 TI - Are government-approved products containing new psychoactive substances perceived to be safer and more socially acceptable than alcohol, tobacco and illegal drugs? Findings from a survey of police arrestees in New Zealand. AB - INTRODUCTION AND AIMS: In July 2013, New Zealand passed the Psychoactive Substances Act (PSA), which established a legal regulated market for government approved products containing new psychoactive substances (NPS). One of the aims of the PSA was to separate the market for approved NPS products from unapproved products and illegal drugs. The aim of this study was to explore perceived health risks and social acceptability of government-approved NPS compared to unapproved NPS and other drugs. DESIGN AND METHODS: About 834 police arrestees were surveyed about the health risks and social acceptability of regularly using nine drug types, including approved and unapproved synthetic cannabinoids (SC) and 'party pills' (PP) under the interim PSA regime. Statistical analyses included fitted analysis of variance and logistic ordinal regression models. RESULTS: Approved SC were considered riskier to health than (natural) cannabis, alcohol, approved and unapproved PP, tobacco and ecstasy, but safer than unapproved SC and methamphetamine. Younger participants (16-29 years) were more likely than older participants (30+ years) to give approved SC a high health-risk score. Approved SC were considered less socially acceptable than alcohol, tobacco and cannabis, but more socially acceptable than methamphetamine, unapproved SC and unapproved PP. Frequent SC users were more likely to rate the social acceptability of approved legal SC higher than other drug users. Approved PP received more positive health and social acceptability scores than approved SC. DISCUSSION AND CONCLUSIONS: The PSA was partially successful at separating approved NPS from other drugs. High health-risk and low social acceptability scores for approved SC may reflect the absence of product testing during the interim PSA market. PMID- 29285814 TI - Altered motor plasticity in an acute relapse of multiple sclerosis. AB - In relapsing-remitting MS (RRMS), the symptoms of a clinical relapse subside over time. Neuroplasticity is believed to play an important compensatory role. In this study, we assessed excitability-decreasing plasticity during an acute relapse of MS and 12 weeks afterwards. Motor plasticity was examined in 19 patients with clinically isolated syndrome or RRMS during a steroid-treated relapse (t1) and 12 weeks afterwards (t2) using paired-associative stimulation (PAS10). This method combines repetitive electric nerve stimulation with transcranial magnetic stimulation of the contralateral motor cortex to model long-term synaptic depression in the human cortex. Additionally, 19 age-matched healthy controls were assessed. Motor-evoked potentials of the abductor pollicis brevis muscle were recorded before and after intervention. Clinical disability was assessed by the multiple sclerosis functional composite and the subscore of the nine-hole peg test taken as a measure of hand function. The effect of PAS10 was significantly different between controls and patients; at t1, but not at t2, baseline normalized postinterventional amplitudes were significantly higher in patients (106 [IQR 98-137] % post10-15 and 111 [IQR 88-133] % post20-25) compared to controls (92 [IQR 85-111] % and 90 [IQR 75-102] %). Additional exploratory analysis indicated a potentially excitability-enhancing effect of PAS10 in patients as opposed to controls. Significant clinical improvement between t1 and t2 was not correlated with PAS10 effects. Our results indicate an alteration of PAS10-induced synaptic plasticity during relapse, presumably reflecting a polarity shift due to metaplastic processes within the motor cortex. Further studies will need to elucidate the functional significance of such changes for the clinical course of MS. PMID- 29285815 TI - Formal models and quantitative measures of multisensory integration: a selective overview. AB - Multisensory integration (MI) is defined as the neural process by which unisensory signals are combined to form a new product that is significantly different from the responses evoked by the modality-specific component stimuli. In recent years, MI research has seen exponential growth in the number of empirical and theoretical studies. This study presents a selective overview of formal modeling approaches to MI. Emphasis is on models and measures for behavioral paradigms, such as localization, judgment of temporal order or simultaneity, and reaction times, but some concepts for the modeling of single cell spike rates are treated as well. We identify a number of essential concepts underlying most model classes, such as Bayesian causal inference, probability summation, coactivation, and time window of integration. Quantitative indexes for measuring and comparing the strength of MI across different paradigms are also discussed. Whereas progress over the last years is remarkable, we point out some strengths and weaknesses of the modeling approaches and discuss some obstacles toward a unified theory of MI. PMID- 29285813 TI - Resveratrol attenuates reproductive alterations in type 1 diabetes-induced rats. AB - The progression of diabetes mellitus leads to several complications including overproduction of reactive oxygen species and reproductive alterations. As resveratrol (RES) is a powerful anti-oxidant and an anti-apoptotic compound, we hypothesized that side effects of type-1 diabetes (DM1) on male reproduction could be reduced by the RES treatment. Eighty-four prepubertal male rats were distributed into seven groups: sham-control (SC), RES-treated (R), resveratrol vehicle-treated (RV), diabetic (D), diabetic-insulin-treated (DI), diabetic-RES treated (DR), diabetic-insulin and RES-treated (DIR). DM1 was induced by a single intraperitoneal streptozotocin (STZ) injection (65 mg/kg) on the 30th day postpartum (dpp). Animals of DR, DIR and R groups received 150 mg/day of RES by gavage for 43 consecutive days (from the 33 to 75 dpp). DI and DIR rats received subcutaneous injections of insulin (1 U/100 g b.w./day) from 5th day after the DM1 induction. The blood glucose level was monitored. At 75 dpp, the euthanasia was performed for morphometric and biometric testicular analyses, spermatic evaluation and hormonal doses. In the D group, the blood glucose level was higher than in the DR, DI and DIR groups. Besides morphometric testicular measurements, testosterone and estradiol doses were lower in D group than in DR and DIR groups; LH dose was also lower than in DR. The preputial separation age was delayed in diabetes-induced groups. The DR and DIR groups showed an improvement in sperm mitochondrial activity, epididymal sperm counts and the frequency of morphologically normal sperms. RES treatment improved glycaemic level, sperm quantitative and qualitative parameters and the hormonal profile in DM1-induced rats and seems to be a good reproductive protector. PMID- 29285816 TI - Arterialized collateral capillaries progress from nonreactive to capable of increasing perfusion in an ischemic arteriolar tree. AB - OBJECTIVE: CCA, outward remodeling of capillaries that anastomose 2 arteriolar trees with different parent feed arteries, may represent a therapeutic target for patients who lack collaterals. ACCs can reperfuse an ischemic tree, but their functional capacity is unknown. Therefore, we determined whether ACCs mature into resistance vessels that regulate blood flow following arterial occlusion. METHODS: We ligated the lateral spinotrapezius feed artery in Balb/C mice, which induces CCA. At days 7 and 21 following occlusion, we measured vasodilation of ACCs using intravital microscopy and blood flow in the ischemic tree using LSF. We determined the presence of ACCs and neurovascular alignment with immunofluorescence. RESULTS: At day 7, ACCs do not vasodilate following muscle contraction and have reduced responses to endothelial- and smooth muscle dependent agents. By day 21, ACCs exhibit normal vasodilation, accompanied by normalized increases in relative blood flow to the ischemic zone. Although functioning as resistance vessels by regulating blood flow, ACCs do not appear to be innervated. CONCLUSIONS: ACCs mature into resistance vessels that regulate blood flow to the downstream tissue. Therefore, induction of mature ACCs may be a target for reducing ischemia in patients who lack collateral networks. PMID- 29285818 TI - Software ion scan functions in analysis of glycomic and lipidomic MS/MS datasets. AB - Hardware ion scan functions unique to tandem mass spectrometry (MS/MS) mode of data acquisition, such as precursor ion scan (PIS) and neutral loss scan (NLS), are important for selective extraction of key structural data from complex MS/MS spectra. However, their software counterparts, software ion scan (SIS) functions, are still not regularly available. Software ion scan functions can be easily coded for additional functionalities, such as software multiple precursor ion scan, software no ion scan, and software variable ion scan functions. These are often necessary, since they allow more efficient analysis of complex MS/MS datasets, often encountered in glycomics and lipidomics. Software ion scan functions can be easily coded by using modern script languages and can be independent of instrument manufacturer. Here we demonstrate the utility of SIS functions on a medium-size glycomic MS/MS dataset. Knowledge of sample properties, as well as of diagnostic and conditional diagnostic ions crucial for data analysis, was needed. Based on the tables constructed with the output data from the SIS functions performed, a detailed analysis of a complex MS/MS glycomic dataset could be carried out in a quick, accurate, and efficient manner. Glycomic research is progressing slowly, and with respect to the MS experiments, one of the key obstacles for moving forward is the lack of appropriate bioinformatic tools necessary for fast analysis of glycomic MS/MS datasets. Adding novel SIS functionalities to the glycomic MS/MS toolbox has a potential to significantly speed up the glycomic data analysis process. Similar tools are useful for analysis of lipidomic MS/MS datasets as well, as will be discussed briefly. PMID- 29285817 TI - Predicting delinquency by self-reported impulsivity in adolescents in Ghana. AB - BACKGROUND: Impulsivity is one of several variables associated with delinquent and criminal acts, but its utility depends on the psychometric properties of the measure used. AIM: To investigate the latent structure of the abbreviated Barratt Impulsivity Scale (ABIS) and its convergent validity with measures of aggression and psychopathy in a Ghanaian sample. METHODS: In a cross-sectional survey, high school students were recruited from two randomly selected schools in Ghana and asked to respond to the ABIS and measures of delinquency, aggression and psychopathy. RESULTS: Three hundred and sixty-three young people, aged 15-19 were recruited, 149 (41%) boys. Findings supported a three-factor (attention, motor and non-planning) structure of impulsivity, which did not differ by sex. Motor and attentional impulsivity were associated with both violent and general delinquent behaviours. Impulsivity scores also correlated with aggression and psychopathy scores, thus providing evidence of convergent validity. CONCLUSION: The ABIS was shown to have sound psychometrics in a standard Ghanaian secondary school sample. Even in this group, where delinquency and antisocial behaviours were of low frequency, its motor and attention impulsivity scores were shown to have some relationship with violent and general delinquent behaviours, suggesting that the ABIS could be a useful tool across cultures for identifying adolescents at high risk of such problems and intervening early to limit damage. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29285819 TI - The Xanthomonas effector XopL uncovers the role of microtubules in stromule extension and dynamics in Nicotiana benthamiana. AB - Xanthomonas campestris pv. vesicatoria type III-secreted effectors were screened for candidates influencing plant cell processes relevant to the formation and maintenance of stromules in Nicotiana benthamiana lower leaf epidermis. Transient expression of XopL, a unique type of E3 ubiquitin ligase, led to a nearly complete elimination of stromules and the relocation of plastids to the nucleus. Further characterization of XopL revealed that the E3 ligase activity is essential for the two plastid phenotypes. In contrast to the XopL wild type, a mutant XopL lacking E3 ligase activity specifically localized to microtubules. Interestingly, mutant XopL-labeled filaments frequently aligned with stromules, suggesting an important, yet unexplored, microtubule-stromule relationship. High time-resolution movies confirmed that microtubules provide a scaffold for stromule movement and contribute to stromule shape. Taken together, this study has defined two populations of stromules: microtubule-dependent stromules, which were found to move slower and persist longer, and microtubule-independent stromules, which move faster and are transient. Our results provide the basis for a new model of stromule dynamics including interactions with both actin and microtubules. PMID- 29285820 TI - MALDI imaging detects endogenous digoxin in glioblastoma cells infected by Zika virus-Would it be the oncolytic key? PMID- 29285822 TI - Rapid qualitative analysis of 2 flavonoids, rutin and silybin, in medical pills by direct analysis in real-time mass spectrometry (DART-MS) combined with in situ derivatization. AB - Direct analysis in real-time mass spectrometry (DART-MS) with in situ silylation was used for the rapid analysis of the flavonoids silybin ((2R,3R)-3,5,7 trihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-2,3 dihydrobenzo[1,4]dioxin-6-yl]chroman-4-one) and rutin (quercetin-3-O-rutinoside). Three different derivatization reagents, hexamethyldisilazane/trimethylchlorosilane/pyridine (HMDS/TMCS/pyridine), N,O bis(trimethylsilyl)acetamide/trimethylchlorosilane/N-trimethylsilyimidazole (BSA/TMCS/TMSI), and N,O bis(trimethylsilyl)trifluoroacetamide/trimethylchlorosilane (BSTFA/TMCS), were applied. Silybin and rutin were detected with various degrees of silylation, and the formation of dimers with pyridine and imidazole was also observed. HMDS/TMCS/pyridine was the best choice for the DART-MS analysis of silybin, and BSA/TMCS/TMSI was the most effective for the detection of rutin. The effects of the DART source temperature on desorption, ionization, in-source fragmentation, dimer formation, and hydrolysis of the trimethylsilyl groups were also studied. In addition, the collision-induced dissociation properties of the derivatized silybin and rutin were explored. With our in situ silylation method, the derivatized bioactive compounds in intact medical pills could also be detected by DART-MS. PMID- 29285823 TI - Provision of oral hygiene services as a potential method for preventing periodontal disease and control hypertension and diabetes in a community health centre in Korea. AB - This study aimed to evaluate the effects of a community-based oral hygiene service on general and periodontal health indicators of patients with hypertension and type 2 diabetes mellitus visiting a community health centre in Korea. The study used a one-group pretest-posttest and interrupted time-series design. A total of 151 participants (45% male), with a mean age of 63 +/- 8.4 years, were included in the study; these included patients with hypertension (62%), diabetes (12%) and both hypertension and diabetes (26%). Two dental hygienists dedicated 2 days per week to this project, providing oral hygiene services to 10-13 participants per day. Four oral hygiene service sessions were provided per patient. The objective oral hygiene status and subjective self reported periodontal status were compared before and after the service. The changes in blood pressure and glycosylated haemoglobin levels were also assessed. A lower frequency of subjective swelling was reported at the fourth session (37.9%) compared to the first (55.6%) session. Further, significantly fewer cases of calculus and bleeding were observed (p < .05), and significantly more patients reported having no gum problems at the fourth session (43.1% vs. 27.2%; p < .05) than at the first session. Finally, the participants maintained stable blood pressures at each of the four sessions, and their glycosylated haemoglobin levels were significantly lower at the fourth session. In conclusion, the findings of this study suggest that community oral hygiene services provided by dental hygienists can promote objective oral hygiene and subjective periodontal status in the local community, and may help in the control of hypertension and diabetes. PMID- 29285824 TI - Graves' disease presenting as life-threatening hypokalaemic periodic paralysis. PMID- 29285825 TI - Targeted copy number screening highlights an intragenic deletion of WDR63 as the likely cause of human occipital encephalocele and abnormal CNS development in zebrafish. AB - Congenital malformations affecting the neural tube can present as isolated malformations or occur in association with other developmental abnormalities and syndromes. Using high-resolution copy number screening in 66 fetuses with neural tube defects, we identified six fetuses with likely pathogenic mutations, three aneuploidies (one trisomy 13 and two trisomy 18) and three deletions previously reported in NTDs (one 22q11.2 deletion and two 1p36 deletions) corresponding to 9% of the cohort. In addition, we identified five rare deletions and two duplications of uncertain significance including a rare intragenic heterozygous in-frame WDR63 deletion in a fetus with occipital encephalocele. Whole genome sequencing verified the deletion and excluded known pathogenic variants. The deletion spans exons 14-17 resulting in the expression of a protein missing the third and fourth WD-repeat domains. These findings were supported by CRISPR/Cas9 mediated somatic deletions in zebrafish. Injection of two different sgRNA-pairs targeting relevant intronic regions resulted in a deletion mimicking the human deletion and a concomitant increase of abnormal embryos with body and brain malformations (41%, n = 161 and 62%, n = 224, respectively), including a sac-like brain protrusion (7% and 9%, P < 0.01). Similar results were seen with overexpression of RNA encoding the deleted variant in zebrafish (total abnormal; 46%, n = 255, P < 0.001) compared with the overexpression of an equivalent amount of wild-type RNA (total abnormal; 3%, n = 177). We predict the in-frame WDR63 deletion to result in a dominant negative or gain-of-function form of WDR63. These are the first findings supporting a role for WDR63 in encephalocele formation. PMID- 29285826 TI - A cone-beam computed tomography study of the anatomical relationships between mandibular teeth and the mandibular canal, with a review of the current literature. AB - The purpose of this study was to evaluate age- and sex-related changes in the anatomical relationships between the roots of the molars and premolars and the mandibular canal using cone-beam computed tomography (CBCT) images. A total of 243 patients (116 males, 127 females) aged 16-83 years for whom previous CBCT scans were available were enrolled in this study. The patients were subcategorized by sex and age (Group I, <21 years; Group II, 21-40 years; and Group III, >40 years). The distances between the mandibular canal and the molars and premolars were measured. The mandibular canal was significantly closer to the root apices of the second and third molars than to the apices of other evaluated teeth (p < 0.05). All measurements were significantly higher in male than in female subjects (p < 0.05). Group I subjects exhibited significantly shorter distances between the mandibular canal and root apices of the first and second premolars, and the molars, than those of Group II and III subjects (p < 0.05). Direct contact relationships were found in 1.6%, 3.3%, 3.3%, 16%, and 32.2% of teeth (running from the first premolar to the third molar, respectively). Age and sex influenced the anatomical relationships between mandibular teeth and the mandibular canal, and these should be considered when planning endodontic and surgical procedures to avoid potential nerve injury. PMID- 29285827 TI - Comparing fishers' and scientific estimates of size at maturity and maximum body size as indicators for overfishing. AB - We tested whether fishers' local ecological knowledge (LEK) of two fish life history parameters, size at maturity (SAM) at maximum body size (MS), was comparable to scientific estimates (SEK) of the same parameters, and whether LEK influenced fishers' perceptions of sustainability. Local ecological knowledge was documented for 82 fishers from a small-scale fishery in Samana Bay, Dominican Republic, whereas SEK was compiled from the scientific literature. Size at maturity estimates derived from LEK and SEK overlapped for most of the 15 commonly harvested species (10 of 15). In contrast, fishers' maximum size estimates were usually lower than (eight species), or overlapped with (five species) scientific estimates. Fishers' size-based estimates of catch composition indicate greater potential for overfishing than estimates based on SEK. Fishers' estimates of size at capture relative to size at maturity suggest routine inclusion of juveniles in the catch (9 of 15 species), and fishers' estimates suggest that harvested fish are substantially smaller than maximum body size for most species (11 of 15 species). Scientific estimates also suggest that harvested fish are generally smaller than maximum body size (13 of 15), but suggest that the catch is dominated by adults for most species (9 of 15 species), and that juveniles are present in the catch for fewer species (6 of 15). Most Samana fishers characterized the current state of their fishery as poor (73%) and as having changed for the worse over the past 20 yr (60%). Fishers stated that concern about overfishing, catching small fish, and catching immature fish contributed to these perceptions, indicating a possible influence of catch-size composition on their perceptions. Future work should test this link more explicitly because we found no evidence that the minority of fishers with more positive perceptions of their fishery reported systematically different estimates of catch-size composition than those with the more negative majority view. Although fishers' and scientific estimates of size at maturity and maximum size parameters sometimes differed, the fact that fishers make routine quantitative assessments of maturity and body size suggests potential for future collaborative monitoring efforts to generate estimates usable by scientists and meaningful to fishers. PMID- 29285828 TI - Mixed evidence for early bursts of morphological evolution in extant clades. AB - Macroevolutionary theory predicts high rates of evolution should occur early in a clade's history as species exploit ecological opportunity. Evidence from the fossil record has shown a high prevalence of early bursts in morphological evolution, but recent work has provided little evidence for early high rates in the evolution of extant clades. Here, I test the prevalence of early bursts in extant data using phylogenetic comparative methods. Existing models are extended to allow a shift from a background Brownian motion (BM) process to an early burst process within subclades of phylogenies, rather than an early burst being applied to an entire phylogenetic tree. This nested early burst model is compared to other modes of evolution that can occur within subclades, such as evolution with a constraint (Ornstein-Uhlenbeck model) and nested BM rate shift models. These relaxed models are validated using simulations and then are applied to body size evolution of three major clades of amniotes (mammals, squamates and aves) at different levels of taxonomic organization (order, family). Applying these unconstrained models greatly increases the support for early bursts within nested subclades, and so early bursts are the most common model of evolution when only one shift is analysed. However, the relative fit of early burst models is worse than models that allow for multiple shifts of the BM or OU process. No single shift or homogenous model is superior to models of multiple shifts in BM or OU evolution, but the patterns shown by these multirate models are generally congruent with patterns expected from early bursts. PMID- 29285829 TI - Fixed-effect variance and the estimation of repeatabilities and heritabilities: issues and solutions. AB - Linear mixed-effects models are frequently used for estimating quantitative genetic parameters, including the heritability, as well as the repeatability, of traits. Heritability acts as a filter that determines how efficiently phenotypic selection translates into evolutionary change, whereas repeatability informs us about the individual consistency of phenotypic traits. As quantities of biological interest, it is important that the denominator, the phenotypic variance in both cases, reflects the amount of phenotypic variance in the relevant ecological setting. The current practice of quantifying heritabilities and repeatabilities from mixed-effects models frequently deprives their denominator of variance explained by fixed effects (often leading to upward bias of heritabilities and repeatabilities), and it has been suggested to omit fixed effects when estimating heritabilities in particular. We advocate an alternative option of fitting models incorporating all relevant effects, while including the variance explained by fixed effects into the estimation of the phenotypic variance. The approach is easily implemented and allows optimizing the estimation of phenotypic variance, for example by the exclusion of variance arising from experimental design effects while still including all biologically relevant sources of variation. We address the estimation and interpretation of heritabilities in situations in which potential covariates are themselves heritable traits of the organism. Furthermore, we discuss complications that arise in generalized and nonlinear mixed models with fixed effects. In these cases, the variance parameters on the data scale depend on the location of the intercept and hence on the scaling of the fixed effects. Integration over the biologically relevant range of fixed effects offers a preferred solution in those situations. PMID- 29285830 TI - Relevance of Tongue Force on Mandibular Denture Stabilization during Mastication. AB - PURPOSE: Tongue activity, involving stereognosis of denture position, food bolus distribution, and direct denture pressing, can affect the stability of removable mandibular dentures. Knowledge of details of tongue activity in patients with removable dentures could contribute to the development of training methods to improve bilateral mastication. The hypothesis of this study was that tongue force improves mandibular complete denture stabilization on the atrophied foundation during mastication load transfer with a typical balanced occlusion. MATERIALS AND METHODS: Finite element analysis was used to assess the effect of tongue activity on denture stability, which was evaluated with objective biomechanical criteria. Denture movement (displacement), sliding distance on the mucosal surface, and pressure on the foundation during occlusal load transfer were considered with and without additional tongue forces. RESULTS: Tongue force in the canine zone of the balancing flange contributed to a slight reduction in the sliding distance. An adverse effect of tongue force on the working side and in the posterior zone of the balancing side was found. CONCLUSIONS: Despite the lack of substantial improvement in stability with the addition of tongue forces, tongue action that contributes to a slight reduction in sliding may help reduce common frictional trauma resulting from cyclic movement during chewing. The beneficial impact of tongue force shown in earlier work under conditions of complete adherence of dentures to the foundation indicates a benefit of using adhesives. PMID- 29285831 TI - Proposal for reclassification of N staging system in penile cancer patients, based on number of positive lymph nodes. AB - In the present study, we aim to compare the rationality of proposed N classification based on the number of metastatic lymph nodes (LNs) with the current one. A total of 509 penile cancer patients at our institute were analyzed. Univariable and multivariable statistical analyses were used to assess cancer-specific survival (CSS) in 2 staging systems. Harrell's concordance index was applied to evaluate predictive accuracy of the current and proposed N classification in predicting CSS. We propose a new classification: pN1 (metastasis in 1-2 regional LNs), pN2 (metastasis in 3 regional LNs, or 3 or fewer regional lymph nodes with extranodal extension), and pN3 (metastasis in 4 or more regional LNs). According to the current and proposed N classification, the 5-year CSS of penile cancer patients with pN1, pN2 and pN3 was 85.8%, 39.0%, and 19.7%; and with pN1, pN2 and pN3 was 79.8%, 39.3% and 15.3%, which almost all showed significant difference (P < .001, P = .259) (P < .001, P < .001). Multivariable predictive accuracy of the proposed and current N staging was 76.48% and 70.92% (5.56% gain; P < .001). With a multivariable model of clinical features, both current (hazard ratio [HR], 7.761, 10.612; P < .001, P < .001) and proposed N stages (HR, 3.792, 3.971; P < .001, P < .001) exhibited independent effects on survival. The proposed N classification is superior to the current one, which is simpler and provides more accurate prognosis. PMID- 29285832 TI - Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: A phase I study. AB - Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m2 on day 1) and fluorouracil (1000 mg/m2 on days 1-4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum-tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade >=3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade >=3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer. PMID- 29285834 TI - Evidence for increased use of the Society of Pediatric Anesthesia Critical Events Checklist in resource-limited environments: A retrospective observational study of app data. AB - BACKGROUND: Electronic decision support tools in anesthesiology practice have great value, including the potential for mobile applications to simplify delivery of best-practice guidelines. AIMS: We sought to combine demographics with usage information to elucidate important patterns in the rate of use of the Society of Pediatric Anesthesia Critical Events Checklist, as measured by in-app accesses of the checklist via the freely available anesthesia calculator app anesthesiologist. METHODS: We performed a retrospective analytic observational case-control study using analytics and survey data collected from the app. Users of the app were classified on the basis of whether or not they had accessed the checklist. This classification was used to perform logistic regression against a number of independent variables, including frequency of app use, country income level, professional role, rating of app importance, length of time in practice, group size, practice model, community served, and primary practice environment. RESULTS: Individual app users practicing in low- and middle-income countries have a significantly higher rate of Society for Pediatric Anesthesia Critical Events Checklist utilization as compared with high-income countries. Rural practitioners had higher utilization of the checklist. Practice size did not affect the utilization of the checklist. The checklist was used for both provider learning and for just-in-time patient care. CONCLUSION: mHealth apps are invaluable resource in everyday clinical practice. Mobile app analytics and in-app survey data reveal variable penetration and applicability of such technology worldwide. mHealth apps may be particularly impactful in limited-resource areas, such as lower-income environments and rural communities. PMID- 29285833 TI - Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. AB - Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF 1alpha) was first reported in 1997. Since then, accumulating evidence has shown that HIF-1alpha may become stable and active even under normoxic conditions; for example, when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms. PMID- 29285835 TI - The boy with the ruddy face: An approach to polycythaemia presenting in childhood. PMID- 29285836 TI - Disease and treatment characteristics of polycythemia vera patients in Belgium: Results from a scientific survey. AB - OBJECTIVE: The current survey aimed to gather predefined disease parameters and treatment strategies to characterize the polycythemia vera (PV) patient population in Belgium. METHODS: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analyzed descriptively and quantitatively. RESULTS: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were >=60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased hematological parameters (hematocrit > 45% [31.2%], leukocytes > 10 * 109 /L [33.3%], and platelet > 400 * 109 /L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low-dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea (HU) as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to HU. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials. CONCLUSION: This survey provides better insight into the characteristics of Belgian PV patients and currently used treatment strategies. It shows that 232 (67.6%) PV patients continue to receive HU despite being potentially HU resistant. PMID- 29285838 TI - Vasomotor, urogenital, psychological, and somatic symptoms in association with CYP1B1 polymorphisms in Slovak women of different menopausal status. AB - OBJECTIVES: The aim of this study was to examine if the Arg48Gly, Ala119Ser, Leu432Val, and Asn453Ser polymorphisms in the CYP1B1 estrogen-metabolizing gene are associated with menopausal symptom experience in healthy Slovak women aged 40 60 years. We also investigated the possible association of other factors with menopausal symptoms, including health status, physical activity, reproductive history, psychological status, and smoking. METHODS: The total sample consisted of 367 women (mean age 49.11 +/- 5.86 years), encompassing 180 premenopausal (mean age 45.06 +/- 3.81 years), 29 peri-menopausal (mean age 49.41 +/- 3.94 years), and 158 postmenopausal (mean age 53.71 +/- 4.54 years) women. The research comprised anthropometric and bioelectrical impedance analysis measurements (BIA), blood or saliva samples collected for DNA analysis, and a specific menopausal questionnaire. RESULTS: CYP1B1 Arg48Gly is significantly associated with vasomotor, psychological, and somatic symptoms. It appears that the Gly/Gly genotype is a risk factor during the postmenopause and protective in the pre- and peri-menopause. CYP1B1 Ala119Ser was associated with all menopausal symptoms, with the Ser/Ser genotype increasing risk in the premenopause and offering protection in the peri- and postmenopause. Polymorphisms Leu432Val and Asn453Ser gave unequivocal results; independent of menopausal status, the Leu/Leu genotype was associated with increasing risk of vasomotor, urogenital, and psychological symptoms and the Asn/Asn genotype provided a protective effect against psychological symptoms. CONCLUSIONS: Our results suggest possible associations of CYP1B1 polymorphisms with the occurrence and manifestation of particular menopausal symptoms in healthy mid-life Slovak women. PMID- 29285837 TI - New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways. AB - Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of the present study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose-dependent way. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) levels and apoptotic cells with caspase-3 and -9 activation. HL156A inhibited the expression and activation of insulin-like growth factor (IGF)-1 and its downstream proteins, AKT, mammalian target of rapamycin (mTOR), and ERK1/2. In addition, HL156A activated AMP-activated protein kinase/nuclear factor kappa B (AMPK-NF-kappaB) signaling of FaDu and YD-10B cells. A xenograft mouse model further showed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by down-regulated p-IGF-1, p-mTOR, proliferating cell nuclear antigen (PCNA) and promoted p-AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer. PMID- 29285839 TI - Role of ultrasound guided epidural anesthesia for lower limb surgery in children with previously repaired meningomyelocele. AB - BACKGROUND: Children that have had a meningomyelocele repair often present for hip and bilateral lower limb surgeries. Due to vertebral, epidural, and nerve root abnormalities, placement of epidural catheter is difficult. AIMS: We aim to describe the potential role of ultrasound in delineating the most appropriate intervertebral space for central neuroaxial blocks in these patients. METHODS: Twelve children with previous meningomyelocele repair, in the age group of 6-12 years posted for hip or bilateral lower limb surgeries were included. After induction of anesthesia, an ultrasound scan was done with the patient in the left lateral position. The central neuroaxial block was performed in the most appropriate intervertebral space seen on transverse scan of spine. These patients were studied with regard to visibility of the osseous framework of the spine, the anterior and posterior dural complexes, ease of insertion of catheter, evidence of dural puncture, and possibility of identification of the extent of peri incisional fibrosis. RESULTS: One case required 2 attempts. There was no evidence of dural puncture. We could confirm the soft tissue shadow, the osseous framework, and the anterior and posterior dural complexes in all 12 patients. Ultrasonography guided in selecting the most appropriate space for epidural catheter placement. CONCLUSION: Ultrasound guidance aids in identification of normal intervertebral space and explicitly shows the abnormal space. It can be used as an aid to differentiate between normal and abnormal space in post meningomyelocele repair. PMID- 29285840 TI - Methods for time-varying exposure related problems in pharmacoepidemiology: An overview. AB - PURPOSE: Lack of control for time-varying exposures can lead to substantial bias in estimates of treatment effects. The aim of this study is to provide an overview and guidance on some of the available methodologies used to address problems related to time-varying exposure and confounding in pharmacoepidemiology and other observational studies. The methods are explored from a conceptual rather than an analytical perspective. METHODS: The methods described in this study have been identified exploring the literature concerning to the time varying exposure concept and basing the search on four fundamental pharmacoepidemiological problems, construction of treatment episodes, time varying confounders, cumulative exposure and latency, and treatment switching. RESULTS: A correct treatment episodes construction is fundamental to avoid bias in treatment effect estimates. Several methods exist to address time-varying covariates, but the complexity of the most advanced approaches-eg, marginal structural models or structural nested failure time models-and the lack of user friendly statistical packages have prevented broader adoption of these methods. Consequently, simpler methods are most commonly used, including, for example, methods without any adjustment strategy and models with time-varying covariates. The magnitude of exposure needs to be considered and properly modelled. CONCLUSIONS: Further research on the application and implementation of the most complex methods is needed. Because different methods can lead to substantial differences in the treatment effect estimates, the application of several methods and comparison of the results is recommended. Treatment episodes estimation and exposure quantification are key parts in the estimation of treatment effects or associations of interest. PMID- 29285842 TI - Accelerating Membrane-based CO2 Separation by Soluble Nanoporous Polymer Networks Produced by Mechanochemical Oxidative Coupling. AB - Achieving homogeneous dispersion of nanoporous fillers within membrane architectures remains a great challenge for mixed-matrix membrane (MMMs) technology. Imparting solution processability of nanoporous materials would help advance the development of MMMs for membrane-based gas separations. A mechanochemically assisted oxidative coupling polymerization strategy was used to create a new family of soluble nanoporous polymer networks. The solid-state ball milling method affords inherent molecular weight control over polymer growth and therefore provides unexpected solubility for the resulting nanoporous frameworks. MMM-based CO2 /CH4 separation performance was significantly accelerated by these new soluble fillers. We anticipate this facile method will facilitate new possibilities for the rational design and synthesis of soluble nanoporous polymer networks and promote their applications in membrane-based gas separations. PMID- 29285841 TI - Cancer immunotherapy-targeted glypican-3 or neoantigens. AB - Immune checkpoint inhibitors have ushered in a new era in cancer therapy, although other therapies or combinations thereof are still needed for many patients for whom these drugs are ineffective. In this light, we have identified glypican-3 an HLA-24, HLA-A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials showing that glypican-3 peptide vaccines induce specific CTLs in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, and UMIN000006357). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy. PMID- 29285844 TI - "Mummy, keep it steady": phonetic variation shapes word learning at 15 and 17 months. AB - Fifteen-month-olds have difficulty detecting differences between novel words differing in a single vowel. Previous work showed that Australian English (AusE) infants habituated to the word-object pair DEET detected an auditory switch to DIT and DOOT in Canadian English (CanE) but not in their native AusE (Escudero et al., ). The authors speculated that this may be because the vowel inherent spectral change variation (VISC) in AusE DEET is larger than in CanE DEET. We investigated whether VISC leads to difficulty in encoding phonetic detail during early word learning, and whether this difficulty dissipates with age. In Experiment 1, we familiarized AusE-learning 15-month-olds to AusE DIT, which contains smaller VISC than AusE DEET. Unlike infants familiarized with AusE DEET (Escudero et al., ), infants detected a switch to DEET and DOOT. In Experiment 2, we familiarized AusE-learning 17-month-olds to AusE DEET. This time, infants detected a switch to DOOT, and marginally detected a switch to DIT. Our acoustic analysis showed that AusE DEET and DOOT are differentiated by the second vowel formant, while DEET and DIT can only be distinguished by their changing dynamic properties throughout the vowel trajectory. Thus, by 17 months, AusE infants can encode highly dynamic acoustic properties, enabling them to learn the novel vowel minimal pairs that are difficult at 15 months. These findings suggest that the development of word learning is shaped by the phonetic properties of the specific word minimal pair. PMID- 29285843 TI - Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA. AB - Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA. PMID- 29285845 TI - A Terminal Fluoride Ligand Generates Axial Magnetic Anisotropy in Dysprosium Complexes. AB - The first dysprosium complexes with a terminal fluoride ligand are obtained as air-stable compounds. The strong, highly electrostatic dysprosium-fluoride bond generates a large axial crystal-field splitting of the J=15/2 ground state, as evidenced by high-resolution luminescence spectroscopy and correlated with the single-molecule magnet behavior through experimental magnetic susceptibility data and ab initio calculations. PMID- 29285846 TI - Development of a modified swallowing screening tool to manage post-extubation dysphagia. AB - Post-extubation dysphagia is a condition that is becoming a growing concern. The condition occurs in 3-62% of extubated patients and can be related to mixed aetiologies, such as neuromuscular impairment, critical illness and laryngeal damage. The risk factors for developing dysphagia in critically ill patients are under-diagnosed and perhaps underestimated. Recent studies recommend the implementation of a standardized swallowing screen to prevent aspiration and decrease pneumonia rate and mortality. The aim of this quality improvement initiative was the development of a bedside swallowing screening tool to assess effective swallowing post-endotracheal extubation. Post-extubation dysphagia can result in a delay in re-feeding, with the potential for malnutrition as well as overt and covert aspiration if swallowing is not effectively screened. It is apparent that ICU nurses commence the initial screen for swallowing in the absence of an evidence base of care. A review of current local and international practice guidelines excludes the process of an effective swallowing screen of the extubated patient. Previously, a referral to speech and language therapists would be required to assess swallowing only after an initial review by the ICU medical team. This often leads to delays if the referral is made outside normal working practice, such as weekends or evenings. The initial development of a swallowing screening tool is the first step to promoting a nurse-led/-initiated bedside swallow screening tool that will enhance patient care and patient safety. There is growing body of evidence regarding the incidence of post-extubation dysphagia. Currently, there are very few recognized bedside swallowing screening tools to identify patients at risk. The most serious complication associated with post extubation dysphagia is aspiration pneumonia, which is the leading cause of nosocomial infection in the critically ill patient. PMID- 29285847 TI - 2-anilino-4-amino-5-aroylthiazole-type compound AS7128 inhibits lung cancer growth through decreased iASPP and p53 interaction. AB - Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents has become critical for lung cancer treatment. In this study, compound AS7128 was selected from a 2-million entry chemical library screening and identified as a candidate drug against non-small cell lung cancer in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and, thus, increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs through disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insight for using iASPP as a therapeutic target for non small cell lung cancer treatment. PMID- 29285848 TI - Implementation of "clinical sequencing" in cancer genome medicine in Japan. AB - In oncology, actionable mutations (alterations) in cancer-associated genes are critical in terms of the selection of therapeutic approaches. Next-generation sequencing of tumor sample DNA (ie, clinical sequencing) can guide clinical management by providing diagnostic or prognostic data, and facilitating the identification of potential treatment regimens, such as molecular-targeted and immune checkpoint blockade therapies. In the USA, a variety of tumor-profiling multiplex gene panels have been developed and implemented for this purpose. In Japan, several academic institutions have now carried out detailed investigations of the feasibility and value of clinical sequencing, and cancer societies have issued consensus clinical practice guidance for next-generation sequencing-based gene panel tests. These efforts will facilitate the implementation of cancer genome medicine in Japan. PMID- 29285850 TI - Resilience. PMID- 29285849 TI - Failure Mode and Effect Analysis (FMEA) may enhance implementation of clinical practice guidelines: An experience from the Middle East. AB - RATIONALE, AIMS, AND OBJECTIVES: Implementation of clinical practice guidelines (CPGs) has been shown to reduce variation in practice and improve health care quality and patients' safety. There is a limited experience of CPG implementation (CPGI) in the Middle East. The CPG program in our institution was launched in 2009. The Quality Management department conducted a Failure Mode and Effect Analysis (FMEA) for further improvement of CPGI. METHODS: This is a prospective study of a qualitative/quantitative design. Our FMEA included (1) process review and recording of the steps and activities of CPGI; (2) hazard analysis by recording activity-related failure modes and their effects, identification of actions required, assigned severity, occurrence, and detection scores for each failure mode and calculated the risk priority number (RPN) by using an online interactive FMEA tool; (3) planning: RPNs were prioritized, recommendations, and further planning for new interventions were identified; and (4) monitoring: after reduction or elimination of the failure mode. The calculated RPN will be compared with subsequent analysis in post-implementation phase. RESULTS: The data were scrutinized from a feedback of quality team members using a FMEA framework to enhance the implementation of 29 adapted CPGs. The identified potential common failure modes with the highest RPN (>= 80) included awareness/training activities, accessibility of CPGs, fewer advocates from clinical champions, and CPGs auditing. Actions included (1) organizing regular awareness activities, (2) making CPGs printed and electronic copies accessible, (3) encouraging senior practitioners to get involved in CPGI, and (4) enhancing CPGs auditing as part of the quality sustainability plan. CONCLUSION: In our experience, FMEA could be a useful tool to enhance CPGI. It helped us to identify potential barriers and prepare relevant solutions. PMID- 29285851 TI - von Willebrand factor propeptide to antigen ratio identifies platelet activation and reduced von Willebrand factor survival phenotype in mice. AB - : Essentials Reduced survival of von Willebrand factor (VWF) in plasma causes type 1C von Willebrand disease. Blood was collected from mouse strains by various methods and VWF propeptide and antigen assayed. VWF propeptide to antigen ratio identifies a reduced VWF survival phenotype in mice. This ratio validates the acceptability of murine blood samples for coagulation studies. SUMMARY: Background Reduced plasma survival of von Willebrand factor (VWF) is characteristic of patients with type 1C von Willebrand disease (VWD). These subjects can be identified by an increased steady-state ratio of plasma VWF propeptide (VWFpp) to VWF antigen (VWF:Ag). A similar phenotype occurs in mice with the Mvwf1 allele. Objectives To (i) determine if the VWFpp/VWF:Ag ratio can be used to identify a 'type 1C' phenotype in mice, (ii) determine the most reliable method for murine blood sampling, and (iii) identify the source of VWF released during problematic blood collection. Methods 'Platelet-VWF' and 'endothelial-VWF' mice were generated by bone marrow transplantation between C57BL/6J and VWF-/- mice. Several blood sampling methods were used and murine VWFpp and VWF:Ag levels determined. Plasma and platelet VWF:Ag and VWFpp, VWF multimers and VWF half-life were examined in mouse strains with and without Mvwf1. Results A single retro-orbital bleed and vena cava collection were found to be the optimal methods of blood collection. Problematic collection resulted in release of VWF from platelets and endothelium. The VWFpp/VWF:Ag ratio identified strains of mice with reduced VWF survival. Conclusion Assay of murine VWFpp and VWF:Ag has utility in determining the acceptability of murine blood samples for coagulation testing and in identification of a reduced VWF survival phenotype in mice. PMID- 29285852 TI - CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion. PMID- 29285853 TI - Development and validation of a new condition-specific instrument for evaluation of smile esthetics-related quality of life. AB - OBJECTIVE: Orofacial esthetics raises psychosocial issues. The purpose was to create and validate new short instrument for psychosocial impacts of altered smile esthetics. MATERIALS AND METHODS: A team of an orthodontist, two prosthodontists, psychologist, and a dental student generated items that could draw up specific hypothetical psychosocial dimensions (69 items initially, 39 in final analysis). The sample consisted of 261 Caucasian subjects attending local high schools and university (26% male) aged 14 to 28 years that have self administrated the designed questionnaire. Factorial analysis, Cronbach's alpha, Pearson correlation, paired samples t-test and analysis of variance were used for analyses of internal consistency, construct validity, responsiveness, and test retest. RESULTS: Three dimensions of psychosocial impacts of altered smile esthetics were identified: dental self-consciousness, dental self-confidence and social contacts that can be best fitted by 12 items, 4 items in each dimension. Internal consistency was good (alpha in range 0.85-0.89). Good stability in test retest was confirmed. In responsiveness testing, tooth whitening induced increase in dental self-confidence (P = 0.002), but no significant changes in other dimensions. CONCLUSION: The new instrument, Smile Esthetics-Related Quality of Life (SERQoL), is short and has proven to be a good indicator of psychosocial dimensions related to perception of smile esthetics. CLINICAL SIGNIFICANCE: Smile Esthetics-Related Quality of Life questionnaire might have practical validity when applied in esthetic dental clinical procedures. PMID- 29285855 TI - Esthetics and smile-related characteristics assessed by laypersons. AB - PURPOSE: This study aimed to identify the characteristics of full-smile images assessed by laypersons using visual analog scale measurement. MATERIALS AND METHODS: A total of 176 young Chinese subjects (88 males and 88 females; 20-35 years of age) with healthy dentogingival tissue were recruited to have their dynamic smiles captured using digital technology. A full-smile frame image of each subject was selected and evaluated by 22 laypersons (11 males and 11 females; 20-35 years of age) using visual analog scale measurement. Unattractive and attractive groups were designated according to the 25th percentile and 75th percentile of average visual analog scale score for the subjects, respectively. Eight smile variables were used to measure the characteristics of the full-smile images. Pearson's Chi-square test and unpaired t tests were used to analyze the data with significance level alpha = 0.05. RESULTS: The visual analog scale measurement scores of unattractive and attractive subgroups, respectively, were 37.89 +/- 2.12 and 50.67 +/- 2.75 (male subjects), and 37.14 +/- 2.80 and 51.92 +/- 1.99 (female subjects). VAS scores were significantly different between subgroups for both male and female subjects (P < .001). No significant differences were observed between male and female subjects (P > .05). CONCLUSIONS: Attractive full-smiles in young Chinese subjects demonstrated higher frequencies of average or low anterior smile line, average or low posterior smile line, upward upper lip curvature, and "broad and short" smile with high smile index. CLINICAL SIGNIFICANCE: The smile variables of anterior smile line, posterior smile line, upper lip curvature, and smile index are predominant factors of smile attractiveness, which should be given priority to consider and manage in the anterior esthetic treatment plan. PMID- 29285857 TI - Update on research and application of problem-based learning in medical science education. AB - Problem-based learning (PBL) is a unique form of pedagogy dedicated to developing students' self-learning and clinical practice skills. After several decades of development, although applications vary, PBL has been recognized all over the world and implemented by many medical schools. This review summarizes and updates the application and study of PBL in medical education through the literature published between 1993 and early 2017. It focuses on understanding real medical PBL courses and ways to improve PBL to achieve better learning outcomes. PBL aims to develop lifelong skills to solve practical problems rather than limiting learning to theoretical knowledge. To achieve this goal, strict and reasonable procedures need to be designed and implemented. Rigorous monitoring and timely feedback and evaluation are indispensable to constant improvements and perfecting of the process. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):186-194, 2018. PMID- 29285854 TI - C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma. AB - In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1alpha (HIF 1alpha) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN. PMID- 29285856 TI - Estimation of dietary threonine requirement using plasma amino acid concentrations in mature thoroughbreds. AB - The experiment was conducted to estimate dietary threonine (Thr) requirement using plasma amino acid concentrations as a criterion in mature thoroughbreds. Four adult thoroughbreds were used, and a 4 * 4 Latin square design was used for four dietary Thr levels. Plasma Thr concentration was constant until 0.41%, and then increased rapidly with increasing dietary Thr levels. The Thr requirement was estimated to be 67% of lysine with plasma Thr concentration at four Thr levels. PMID- 29285859 TI - Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population. AB - : Essentials Why venous thrombosis is more prevalent in chronic kidney disease is unclear. We investigated whether renal and vascular function are associated with hypercoagulability. Coagulation factors showed a procoagulant shift with impaired renal and vascular function. This suggests that renal and vascular function play a role in the etiology of thrombosis. SUMMARY: Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50th [reference] to < 1st) and UACR (< 50th [reference] to > 99th), and per four categories (< 50th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m- 2 and median UACR 0.4 mg mmol-1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL-1 (95% CI, 13-32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL-1 (95% CI, 3-22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL-1 (95% CI, 0.70-3.2) higher. Conclusions Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis. PMID- 29285858 TI - Hypothalamic POMC expression is required for peripheral insulin action on hepatic gluconeogenesis through regulating STAT3 in sepsis rats. AB - Liver injury and dysregulated glucose homoeostasis are common manifestations during sepsis. Although plenty of studies reported insulin could protect against multiple organ injuries caused by critical infections among patients, little was known about the precise mechanism. We investigated whether liver inflammatory pathway and central neuropeptides were involved in the process. In sepsis rats, hepatic IKK/NF-kappaB pathway and STAT3 were strongly activated, along with reduced body weight, blood glucose and suppressed hepatic gluconeogenesis (GNG). Peripheral insulin administration efficiently attenuated liver dysfunction and glucose metabolic disorders by suppressing hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC) expression, hepatic NF-kappaB pathway and STAT3 phosphorylation. Furthermore, knockdown of hypothalamic POMC significantly diminished protective effect of insulin on hepatic GNG and insulin-induced STAT3 inactivation, but not inflammation or IKK/NF-kappaB pathway. These results suggest that hepatic IKK/NF-kappaB pathway mediates the anti-inflammatory effect of insulin in septic rats, and peripheral insulin treatment may improve hepatic GNG by inhibiting STAT3 phosphorylation dependent on hypothalamic POMC expression. PMID- 29285860 TI - Tattoos: Evaluation of knowledge about health complications and their prevention among students of Tricity universities. AB - INTRODUCTION: Tattooing is a very popular form of body modification among young people. However, this kind of procedure entails the risk of various health complications. The objective of the study was to evaluate the students' knowledge about contraindications, complications, and health risks that skin tattooing may cause. Additionally, the purpose of the study was to assess how the profile of education (medical vs nonmedical) impacts on the knowledge of the respondents. METHODS: We surveyed a group of 1199 people, of which 326 (27%) had tattoos. The base of the study is an anonymously filled, author's online survey consisting of 25 questions. RESULTS: Eighty six percent of the students from the Medical University of Gdansk indicated the risk of HCV virus infection during tattooing, while only 34% of students from other Tricity universities were aware of this danger. Sixty seven percent of people with tattoos felt that having them does not affect any diagnostic and therapeutic procedures. Most of respondents mentioned the tattoo artist (79%) and the Internet (73%) as a source of information before having a tattoo, while only 5% and 8% respondents asked a doctor or read medical literature about it. Fourty nine percent of respondents reported that before the procedure, tattooist failed to ask them about their health condition and medications. CONCLUSIONS: Knowledge of students about safety, contraindications, and complications associated with the performance of tattooing is insufficient. As a result, a need for a better education on the topic for both people who are getting tattoos and tattooists appears evident. PMID- 29285861 TI - Biliary vs thyroid-like: A tale of two morphologies. PMID- 29285862 TI - Grade distribution digests: A novel tool to enhance teaching and student learning in laboratory practicals. AB - Assessment is a central component of course curriculums and is used to certify student learning, but it can also be used as a tool to improve teaching and learning. Many laboratory courses are structured such that there is only a grade for a particular laboratory, which limits the insights that can be gained in student learning. We developed a laboratory program that incorporates assessments designed to probe student understanding of different components of the individual modules making up the program. The challenge was to analyze and present grades from these assessment tasks in a format that was readily interpretable by academics. We show that a simplified synthesis of grade distributions (grade distribution digests) provides sufficient information to make decisions about changes in course components. The main feature of the digests is its data visualization approach, where student grades for individual laboratory practicals, individual assessment tasks or individual assessment items are graphically presented as an overall average grade, an average top quartile grade and an average bottom quartile grade, and relative averages across all assessments. This ability to visualize student grades in variety of contexts enables academics with many other demands on their time (e.g. research and administration) to more efficiently identify ways to improve teaching delivery and learning outcomes. Examples are presented of the use of such data to identify and improve deficiencies in both student skills and teaching practice, resulting in improved learning outcomes. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):130-140, 2018. PMID- 29285863 TI - Microfocused ultrasound in combination with diluted calcium hydroxylapatite for improving skin laxity and the appearance of lines in the neck and decolletage. AB - BACKGROUND: Skin laxity and wrinkling on the neck and decolletage reveal age as reliably as the face. OBJECTIVE: To evaluate the combined use of microfocused ultrasound with visualization (MFU-V; Ultherapy(r) ) and diluted calcium hydroxylapatite (CaHA; Radiesse(r) ) for treating the neck and decolletage. METHODS: Subjects with moderate-to-severe lines on the neck and/or decolletage were retrospectively enrolled. MFU-V was applied using 7 and 10 MHz transducers followed by subdermal injection of CaHA diluted 1:1 with lidocaine solution. Photographs at baseline and 90 days were assessed by two independent, blinded evaluators using three scales: Merz Aesthetics decollete wrinkles, Fabi-Bolton chest wrinkle, and Allergan transverse neck lines scales. RESULTS: A total of 47 subjects were treated as follows: 29 (neck only), five (decolletage only), and 13 (both areas). Mean neckline score improved from 2.6 (moderate-to-severe lines) at baseline to 1.3 (mild lines) 90 days after treatment (P < .001). Mean decolletage scores improved from 2.6 and 3.3 (moderate-to-severe wrinkles) on the Merz Aesthetics and Fabi-Bolton scales, respectively, to 1.1 and 1.8 (mild wrinkles), respectively, after treatment (both P < .001). Both procedures were well tolerated with high subject satisfaction. CONCLUSIONS: Combining MFU-V with 1:1 diluted CaHA is effective for improving the appearance of neck and decolletage lines and wrinkles. PMID- 29285864 TI - Proximodistal exploration in motor learning as an emergent property of optimization. AB - To harness the complexity of their high-dimensional bodies during sensorimotor development, infants are guided by patterns of freezing and freeing of degrees of freedom. For instance, when learning to reach, infants free the degrees of freedom in their arm proximodistally, that is, from joints that are closer to the body to those that are more distant. Here, we formulate and study computationally the hypothesis that such patterns can emerge spontaneously as the result of a family of stochastic optimization processes, without an innate encoding of a maturational schedule. In particular, we present simulated experiments with an arm where a computational learner progressively acquires reaching skills through adaptive exploration, and we show that a proximodistal organization appears spontaneously, which we denote PDFF (Proximo Distal Freezing and Freeing of degrees of freedom). We also compare this emergent organization between different arm morphologies-from human-like to quite unnatural ones-to study the effect of different kinematic structures on the emergence of PDFF. PMID- 29285865 TI - Sorting into payment schemes and medical treatment: A laboratory experiment. AB - In this study, we introduce the opportunity for physicians to sort into capitation or fee-for-service payment. Using a controlled medically framed laboratory experiment with a sequential within-subject design allows isolating sorting from incentive effects. We observe a strong preference for fee-for service payment, which does not depend on subjects' prior experience with one of the two payment schemes. Further, we identify a significant sorting effect. Subjects choosing capitation deviate ex ante less from patient-optimal medical treatment than subjects who sort into fee-for-service payment. Particularly the latter become even less patient-oriented after introducing the choice option. Consequently, the opportunity to choose between fee-for-service and capitation payment worsens patient treatment, if at all. Our results hold for medical and for nonmedical students. PMID- 29285866 TI - Separation of prescription and treatment in health care markets: A laboratory experiment. AB - Health care is a credence good, and its market is plagued by asymmetric information. In this paper, we use a laboratory experiment to test the performance of a potential remedy discussed in the applied literature, the separation of prescription and treatment activities. We observe a significant amount of overtreatment (and a smaller nonpredicted amount of undertreatment) in our baseline environment. Requiring a different than the treating physician to provide diagnosis and prescription for free is an effective way to reduce overtreatment in our laboratory setting. This effect, however, is partially offset by an increased frequency of undertreatment. Allowing prescription and treatment physicians to independently set prices for their services reduces efficiency due to coordination failures: In sum, prices are often higher than expected benefit of patients, who in turn do not attend to the physician. Also contrary to theory, bargaining power does not play a significant role for the distribution of profits between physicians. PMID- 29285867 TI - Quality competition and hospital mergers-An experiment. AB - On the basis of a Salop model with regulated prices, we investigate quality provision behaviour of competing hospitals before and after a merger. For this, we use a controlled laboratory experiment where subjects decided on the level of treatment quality as head of a hospital. We find that the post-merger average quality is significantly lower than the average pre-merger quality. However, for merger insiders and outsiders, average quality choices are significantly higher than predicted for pure profit-maximising hospitals. This upward deviation is potentially driven by altruistic behaviour towards patients. Furthermore, we find that in the case where sufficient cost synergies are realised by the merged hospitals, there is a significant increase in average quality choices compared to the scenario without synergies. Finally, we find that our results do not change when comparing individual decisions to team decisions. PMID- 29285868 TI - Behavioral responses to surveys about nicotine dependence. AB - Behavioral responses to surveys can significantly affect inferences about population prevalence unless correctly modeled statistically. An important case study is the prevalence of nicotine dependence, a formal psychiatric disorder satisfying clinical criteria. Data from the National Epidemiologic Survey on Alcohol and Related Conditions in the United States are used, along with a flexible semi-nonparametric sample selection model. Corrections for sample selection responses to "gateway" survey questions lead to significantly higher estimates of the prevalence of nicotine dependence among current daily smokers. These corrections also imply even higher levels of the decades-long and lifetime long persistence of nicotine dependence after the onset of smoking. PMID- 29285869 TI - Behavioural consequences of vaccination recommendations: An experimental analysis. AB - Annual vaccination is the most effective way to prevent seasonal influenza. However, globally, the recommendations vary from country to country, ranging from universal recommendations, risk-group-specific recommendations, to no recommendation at all. Due to high diversity both in recommendation practice and country-specific preconditions, it is difficult to determine the effect of different recommendations on vaccine uptake. This incentivised laboratory experiment (N = 288) tests the behavioural consequences of different recommendations in a repeated interactive vaccination game. The participants are part of heterogeneous groups, comprised of low- and high-risk type of players. They receive either a universal, risk-group-specific or no recommendation prior to their vaccination decisions. Results show that individuals are sensitive to the recommendations. In detail, a risk-group-specific recommendation increases vaccine uptake of high-risk types. However, at the same time, it decreases vaccine uptake of low-risk types. The results imply that when the proportion of low-risk types in a population is considerably larger than the high-risk group, a risk-group-specific (vs. universal) recommendation comes at the cost of decreased social benefit of vaccination due to the overall lower vaccine uptake. Policy decision-making should therefore complement epidemiological considerations with potential positive and negative behavioural consequences of vaccination recommendations. PMID- 29285870 TI - Behavioural experiments in health: An introduction. PMID- 29285871 TI - Risk-taking in vaccination, surgery, and gambling environments: Evidence from a framed laboratory experiment. AB - Vaccination involves a tradeoff between two risky alternatives, namely, susceptibility and immunization. By designing a controlled laboratory experiment, we investigate the association between risk preferences and immunization decisions. To contrast the role of risk preferences in vaccination decisions with other domains, we implemented four frames: vaccination, surgery, complex neutral, and simple neutral. We found direct framing effects for females but not for males. For the former, the demand for the safer alternative is significantly larger in the surgery frame than in all other frames. For male subjects, we found a significant association between stated risk preferences and choice behavior in the simple neutral frame but not in the other three frames. For female subjects, we observed the exact opposite. Although the complexity of the decision problem matters, there is no indication of differential roles of risk preferences for a given complexity. We found that the share of consistent choices is significantly larger in the surgery frame as compared to the two neutral frames, that is, context improves decision making. This does not apply to the vaccination frame, so there is something about vaccinations that prevents individuals from better understanding the decision problem at hand. PMID- 29285872 TI - The effects of competition on medical service provision. AB - We explore how competition between physicians affects medical service provision. Previous research has shown that, without competition, physicians deviate from patient-optimal treatment under payment systems like capitation and fee-for service. Although competition might reduce these distortions, physicians usually interact with each other repeatedly over time and only a fraction of patients switches providers at all. Both patterns might prevent competition to work in the desired direction. To analyze the behavioral effects of competition, we develop a theoretical benchmark that is then tested in a controlled laboratory experiment. Experimental conditions vary physician payment and patient characteristics. Real patients benefit from provision decisions made in the experiment. Our results reveal that, in line with the theoretical prediction, introducing competition can reduce overprovision and underprovision, respectively. The observed effects depend on patient characteristics and the payment system, though. Tacit collusion is observed and particularly pronounced with fee-for-service payment, but it appears to be less frequent than in related experimental research on price competition. PMID- 29285873 TI - Risk attitudes in medical decisions for others: An experimental approach. AB - The aim of this paper is to investigate how risk attitudes in medical decisions for others vary across health contexts. A lab experiment was designed to elicit the risk attitudes of 257 medical and nonmedical students by assigning them the role of a physician who must decide between treatments for patients. An interval regression model was used to estimate individual coefficients of relative risk aversion, and an estimation model was used to test for the effect of type of medical decision and experimental design characteristics on elicited risk aversion. We find that (a) risk attitudes vary across different health contexts, but risk aversion prevails in all of them; (b) students enrolled in health related degrees show a higher degree of risk aversion; and (c) real rewards for third parties (patients) make subjects less risk-averse. The results underline the importance of accounting for attitudes towards risk in medical decision making. PMID- 29285874 TI - Early cellular interactions and immune transcriptome profiles in human factor VIII-exposed hemophilia A mice. AB - : Essentials Initial immune cell interactions leading to factor (F) VIII immunity are not well characterized. We assessed cellular interactions and expression profiles in hemophilia A mice. MARCO+, followed by SIGLEC1+ and SIGNR1+ macrophages co-localize most with human FVIII. The splenic transcriptome highlights potential therapeutic targets to prevent inhibitors. SUMMARY: Background Developing factor VIII (FVIII) inhibitory antibodies is the most serious complication in hemophilia A treatment, representing a significant health and economic burden. A better understanding of the early events in an immune response leading to this outcome may provide insight into inhibitor development. Objective To identify early mediators of FVIII immunity and to detail immune expression profiles in the spleen and liver. Methods C57Bl/6 F8 E16 knockout mice were infused with 5-20 MUg (2000-8000 IU kg-1 ) of recombinant FVIII. Spleens were frozen at various time-points post-infusion and stained for FVIII and cellular markers. Splenic and liver RNA expression analysis was performed 3 h post-infusion of 0.6 MUg (240 IU kg-1 ) FVIII by nCounter technology using a 561 gene immunology panel. Results FVIII localization in the spleen did not change over 2.5 h. We observed significantly higher co-localization of FVIII with MARCO+ cells compared with SIGLEC1+ and SIGNR1+ in the splenic marginal zone. FVIII exhibited little co-localization with CD11c+ dendritic cells and the macrophage mannose receptor, CD206. Following FVIII infusion, the splenic mRNA profiling identified genes such as Tnfaip6 and Il23r, which are implicated in chemotaxis and a proinflammatory Th17 response, respectively. In contrast, an upregulation of Gfi1 in the liver suggests an anti-inflammatory environment. Conclusions FVIII co-localizes predominantly with marginal zone macrophages (MARCO+ ) in the murine spleen following intravenous infusion. Targeting pathways that are implicated in the early FVIII innate immune response in the spleen may lead to therapeutic interventions to prevent inhibitor formation. PMID- 29285875 TI - Photochemically and Thermally Driven Full-Color Reflection in a Self-Organized Helical Superstructure Enabled by a Halogen-Bonded Chiral Molecular Switch. AB - Supramolecular approaches toward the fabrication of functional materials and systems have been an enabling endeavor. Recently, halogen bonding has been harnessed as a promising supramolecular tool. Herein we report the synthesis and characterization of a novel halogen-bonded light-driven axially chiral molecular switch. The photoactive halogen-bonded chiral switch is able to induce a self organized, tunable helical superstructure, that is, cholesteric liquid crystal (CLC), when doped into an achiral liquid crystal (LC) host. The halogen-bonded switch as a chiral dopant has a high helical twisting power (HTP) and shows a large change of its HTP upon photoisomerization. This light-driven dynamic modulation enables reversible selective reflection color tuning across the entire visible spectrum. The chiral switch also displays a temperature-dependent HTP change that enables thermally driven red, green, and blue (RGB) reflection colors in the self-organized helical superstructure. PMID- 29285877 TI - RNA Isolation from Plant Tissues: A Hands-on Laboratory Experimental Experience for Undergraduates. AB - The practice of RNA isolation in undergraduate experimental courses is rare because of the existence of robust, ubiquitous and stable ribonucleases. We reported here modifications to our original protocol for RNA isolation from plant tissues, including the recovery of nucleic acids by ethanol precipitation at 0 degrees C for 10 min and the assessment of RNA quality by visualizing the banding profile of the separated RNAs on a standard nondenaturing agarose gel to shorten the duration of the whole procedure and simplify the operation. As a result, the modified procedure, including RNA isolation and quality control analysis could be finished in 4 hr and divided into two sessions. Because endogenous ribonucleases released upon disruption of the organelles and vacuoles were effectively and quickly inactivated, measures were taken to protect RNA integrity throughout the whole procedure so that total RNA with high purity and integrity as well as an appropriate yield could be obtained by students. The RNA isolation protocol described here was simple, efficient, flexible, and low cost. Therefore, it is an ideal approach for undergraduates to learn about RNA techniques. The pedagogical approach of the correlation of experimental work with the rationale for the whole protocol described in this report is an effective way for undergraduates to improve their learning of the techniques of RNA isolation and analysis and the theories behind them, as well as experimental design and data analysis. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(3):253-261, 2018. PMID- 29285876 TI - Metabolomic analysis of 92 pulmonary embolism patients from a nested case-control study identifies metabolites associated with adverse clinical outcomes. AB - : Essentials Risk-stratification often fails to predict clinical deterioration in pulmonary embolism (PE). First-ever high-throughput metabolomics analysis of risk stratified PE patients. Changes in circulating metabolites reflect a compromised energy metabolism in PE. Metabolites play a key role in the pathophysiology and risk stratification of PE. SUMMARY: Background Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. Objectives To improve our understanding of the physiology differentiating low risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. Patients/methods We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. Results When we compared 46 low-risk with 46 intermediate/high-risk PEs, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid (TCA) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk with 18 high-risk PE patients, 41 metabolites differed at a nominal P-value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism. Conclusion Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE. PMID- 29285878 TI - A Comparison of the Effectiveness of Silibinin and Resveratrol in Preventing Alpha-Amanitin-Induced Hepatotoxicity. AB - Amanita phalloides species mushrooms containing alpha-amanitin (alpha-AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of alpha-AMA-induced hepatotoxicity. We investigated the effects of resveratrol on alpha-AMA-induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with alpha-AMA (alpha-AMA + SR) or 12 (alpha-AMA + 12R) or 24 (alpha-AMA + 24R) hr after alpha AMA administration. Silibinin (5 mg/kg) (alpha-AMA + Sil) and normal saline (alpha-AMA + NS) were given simultaneously with alpha-AMA. We found that liver transaminase levels in alpha-AMA + SR and alpha-AMA + 12R groups and histomorphologic injury score in the alpha-AMA + SR, alpha-AMA + 12R, alpha-AMA + 24R and alpha-AMA + Sil groups were significantly lower than that of the alpha AMA + NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase-3 immunopositivity in the liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in a reduction in cell viability induced by alpha-AMA in THLE-2 and THLE-3 hepatocytes. Neither resveratrol nor silibinin was found to be effective in increasing cell viability decreased by alpha-AMA + NS. As a conclusion, resveratrol was found to be effective in alpha-AMA-induced hepatotoxicity with its anti-inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings. PMID- 29285879 TI - Autonomic and subjective responsivity to emotional images in people with dissociative seizures. AB - People with dissociative seizures (DS) report a range of difficulties in emotional functioning and exhibit altered responding to emotional facial expressions in experimental tasks. We extended this research by investigating subjective and autonomic reactivity (ratings of emotional valence, arousal and skin conductance responses [SCRs]) to general emotional images in 39 people with DS relative to 42 healthy control participants, whilst controlling for anxiety, depression, cognitive functioning and, where relevant, medication use. It was predicted that greater subjective negativity and arousal and increased SCRs in response to the affective pictures would be observed in the DS group. The DS group as a whole did not differ from controls in their subjective responses of valence and arousal. However, SCR amplitudes were greater in 'autonomic responders' with DS relative to 'autonomic responders' in the control group. A positive correlation was also observed between SCRs for highly arousing negative pictures and self-reported ictal autonomic arousal, in DS 'autonomic responders'. In the DS subgroup of autonomic 'non-responders', differences in subjective responses were observed for some conditions, compared to control 'non responders'. The findings indicate unaffected subjective responses to emotional images in people with DS overall. However, within the group of people with DS, there may be subgroups characterized by differences in emotional responding. One subgroup (i.e., 'autonomic responders') exhibit heightened autonomic responses but intact subjective emotional experience, whilst another subgroup (i.e., 'autonomic non-responders') seem to experience greater subjective negativity and arousal for some emotional stimuli, despite less frequent autonomic reactions. The current results suggest that therapeutic interventions targeting awareness and regulation of physiological arousal and subjective emotional experience could be of value in some people with this disorder. PMID- 29285880 TI - Melasma, a photoaging disorder. AB - Melasma is a common hyperpigmentary disorder. The impact on the quality of life of affected individuals is well demonstrated, demanding new therapeutic strategies. However, the treatment of melasma remains highly challenging. Melasma is often considered as the main consequence of female hormone stimulation on a predisposed genetic background. Although these two factors do contribute to this acquired pigmentary disorder, the last decade has revealed several other key players and brought new pieces to the complex puzzle of the pathophysiology of melasma. Here, we summarize the latest evidence on the pathophysiology of melasma, and we suggest that melasma might be a photoaging skin disorder affecting genetically predisposed individuals. Such data must be taken into consideration by clinicians as they could have a profound impact on the treatment and the prevention of melasma. PMID- 29285881 TI - Every Woman, Every Child's 'Progress in Partnership' for stillbirths: a commentary by the stillbirth advocacy working group. PMID- 29285882 TI - Systemic RNAi of V-ATPase subunit B causes molting defect and developmental abnormalities in Periplaneta fuliginosa. AB - The vacuolar (H+ )-ATPases (V-ATPases) are ATP-driven proton pumps with multiple functions in many organisms. In this study, we performed structural and functional analysis of vha55 gene that encodes V-ATPase subunit B in the smokybrown cockroach Periplaneta fuliginosa (Blattodea). We observed a high homology score of the deduced amino acid sequences between 10 species in seven orders. RNAi of the vha55 gene in P. fuliginosa caused nymphal/nymphal molting defects with incomplete shedding of old cuticles, growth inhibition, as well as bent and wrinkled cuticles of thoraxes and abdominal segments. Since growth inhibition caused by vha55 RNAi did not interfere in the commencement of cockroach molting, molting timing and body growth might be controlled by independent mechanism. Our study suggested V-ATPases might be a good candidate molecule for evolutionary and developmental studies of insect molting. PMID- 29285884 TI - Two-year observational study of deferiprone in superficial siderosis. AB - INTRODUCTION: Superficial siderosis is a rare, neurodegenerative disease caused by toxic accumulation of hemosiderin on the surface of the brain and the spinal cord, most commonly from chronic subarachnoid hemorrhage. AIMS: The aim of this study was to assess the clinical and radiological outcomes of superficial siderosis patients using deferiprone, a cell permeant iron chelator. Subjects obtained pre- and post-treatment brain MRIs and weekly laboratory tests. Osirix software was used to develop a method of quantifying hemosiderin deposition. Three-dimensional whole brain images of gradient echo images were rendered and compared by dividing the mean T2 hyperintensity to the maximal cerebrospinal fluid signal. RESULTS: A total of 38 subjects completed the study, of which clinical and radiological data were available for 30. The average age was 64 years (range 37-86), 53% were male, 94% were white. Nineteen subjects (63%) reported either no progression of disease or an improvement in at least one neurological domain, with 40% of patients reporting a stabilization in hearing function and 30% reporting stable or improved coordination and walking. By MRI, there was an overall mean increase in T2 hyperintensity of the whole brain of 1% 13% over the 2-year time period in half of patients, indicating a reduction hemosiderosis. There were no cases of agranulocytosis, and declines of white blood cells counts and neutrophils averaged <10%. Fatigue was the most common side effect. CONCLUSION: This is the first long-term prospective study of superficial siderosis on the iron chelator, deferiprone. MRI quantification of hemosiderin appears to demonstrate a measurable reduction in half of patients and this correlated with a stabilized or improving disease course. A future placebo controlled trial is necessary to determine whether deferiprone is an effective therapy for superficial siderosis. PMID- 29285883 TI - Associations between friendship characteristics and HIV and HSV-2 status amongst young South African women in HPTN-068. AB - INTRODUCTION: Prevalence of HIV among young women in South Africa remains extremely high. Adolescent peer groups have been found to be an important influence on a range of health behaviours. The characteristics of young women's friendships might influence their sexual health and HIV risk via connections to sexual partners, norms around sexual initiation and condom use, or provision of social support. We investigated associations between young women's friendships and their Herpes Simplex Virus Type 2 (HSV-2) and HIV infection status in rural South Africa. METHODS: Our study is a cross-sectional, egocentric network analysis. In 2011 to 2012, we tested 13- to 20-year-old young women for HIV and HSV-2, and collected descriptions of five friendships for each. We generated summary measures describing friend socio-demographic characteristics and the number of friends perceived to have had sex. We used logistic regression to analyse associations between friend characteristics and participant HIV and HSV-2 infection, excluding likely perinatal HIV infections. RESULTS: There were 2326 participants included in the study sample, among whom HIV and HSV-2 prevalence were 3.3% and 4.6% respectively. Adjusted for participant and friend socio demographic characteristics, each additional friend at least one year older than the participant was associated with raised odds of HIV (odds ratio (OR) = 1.37, 95% CI 1.03 to 1.82) and HSV-2 (adjusted OR=1.41, 95% CI 1.18 to 1.69). Each additional friend perceived to have ever had sex also raised the odds of HIV (OR = 1.29, 95% CI 1.03 to 1.63) and HSV-2 (OR=1.18, 95% CI 1.03 to 1.35). DISCUSSION: We found good evidence that a greater number of older friends and friends perceived to have had sex were associated with increased risk for HSV-2 and HIV infection among young women. CONCLUSIONS: The characteristics of young women's friendships could contribute to their risk of HIV infection. The extent to which policies or programmes influence age-mixing and young women's normative environments should be considered. PMID- 29285885 TI - A mutation in the progesterone receptor predisposes to HEV infection in HIV positive patients. AB - BACKGROUND AND AIMS: Infection with Hepatitis E virus (HEV) can cause chronic liver disease in immunocompromised hosts. In transplant recipients, the use of certain immunosuppressants and food habits has been proposed as risk factors for HEV. In individuals infected with the human immunodeficiency virus (HIV), risk factors for HEV infection are less clear. We aimed to study the association between a mutation in the progesterone receptor (PR) named PROGINS and HEV infected in HIV-positive individuals. METHODS: We evaluated the presence of the SNP PROGINS via KASP in serum samples of 64 HIV-positive individuals and 187 healthy controls. We performed ELISA tests to address the serum levels of IL-10 and IL-12, as well as T-cell stimulation assays in peripheral blood to address immune response in individuals with PROGINS. RESULTS: We found a significant association between the presence of PROGINS mutation and HEV seroprevalence in individuals infected with HIV (30% in HIV+/HEV+ versus 2% in HIV+/HEV, respectively, P = .009). Moreover, we found that HIV+/HEV+ individuals expressing the PROGINS mutation had lower serum levels of IL-10 and higher levels of IL-12. The presence of the mutation led to a reduced response upon stimulation of CD4+ and CD8+ T cells compared to those without the mutation, suggesting an immune modulation associated with PROGINS. CONCLUSIONS: Our study identified a mutation in the PR that provides significant insights into mechanisms of HEV infection in immunosuppressed individuals. PMID- 29285886 TI - Poly(ethylene glycol)-[60]Fullerene-Based Materials for Perovskite Solar Cells with Improved Moisture Resistance and Reduced Hysteresis. AB - A series of [60]fullerenes covalently functionalized with the polymer poly(ethylene glycol) is presented. These new [60]fullerene-based materials have been incorporated as additives in CH3 NH3 PbI3 (MAPbI3 ), the most common organic inorganic perovskite used in perovskite solar cells. The extensive photovoltaic study performed by using these materials shows several beneficial effects on the performance of these cells, including a reduction in hysteresis and an increased stability against moisture, whereby the solar cells retain up to 97 % of their initial power conversion efficiency in an ambient atmosphere. PMID- 29285887 TI - Hit Dexter: A Machine-Learning Model for the Prediction of Frequent Hitters. AB - False-positive assay readouts caused by badly behaving compounds-frequent hitters, pan-assay interference compounds (PAINS), aggregators, and others continue to pose a major challenge to experimental screening. There are only a few in silico methods that allow the prediction of such problematic compounds. We report the development of Hit Dexter, two extremely randomized trees classifiers for the prediction of compounds likely to trigger positive assay readouts either by true promiscuity or by assay interference. The models were trained on a well prepared dataset extracted from the PubChem Bioassay database, consisting of approximately 311 000 compounds tested for activity on at least 50 proteins. Hit Dexter reached MCC and AUC values of up to 0.67 and 0.96 on an independent test set, respectively. The models are expected to be of high value, in particular to medicinal chemists and biochemists who can use Hit Dexter to identify compounds for which extra caution should be exercised with positive assay readouts. Hit Dexter is available as a free web service at http://hitdexter.zbh. uni hamburg.de. PMID- 29285888 TI - Presence of Torque teno sus virus 1 and 2 in porcine circovirus 3-positive pigs. AB - In this study, the co-infection of Torque teno sus virus (TTSuV) and porcine circovirus type 3 (PCV3) was reported. One hundred and ten of 132 (83.3%) PCV3 positive samples were co-infected with Torque teno sus virus 1 (TTSuV1). Ninety four of 132 (71.2%) PCV3-positive samples were co-infected with Torque teno sus virus 2 (TTSuV2). Sixty-six of 132 (50.0%) of PCV3-positive samples were co infected with both TTSuV1 and TTSuV2. There were no clinical signs of infection in pigs that were both PCV3-positive and PCV2-negative, in either multiparous sows or live-born infants. The high co-infection rate provides valuable information for the further study of the pathological correlation between PCV3 and TTSuVs. PMID- 29285889 TI - Evaluation of topical liposome incorporated clove oil in the treatment of idiopathic palmar hyperhidrosis: Single-blinded placebo-controlled study. AB - INTRODUCTION: Palmar hyperhidrosis is of great concern to patients because of its physical, occupational, and psychological impact on quality of life. Topical clove oil has been used in many conditions due to its major component Eugenol that exerts blocking effect on nerve transmission. AIM OF THE WORK: To assess the efficacy of topical liposome incorporated clove oil in decreasing the rate of sweating among patients with idiopathic palmar hyperhidrosis. PATIENTS AND METHOD: Forty patients with palmar hyperhidrosis were treated with clove oil 45% in liposome and another twenty patients were treated as a control group with 0.9% saline solution and evaluation was carried out before and after treatment through gravimetry testing and hyperhidrosis disease severity scale (HDSS). RESULT: The gravimetry testing among clove oil-treated group showed that the mean sweating rate before treatment was 80.5 +/- 41.85 (SD) mg/min which decreased significantly after treatment to 52.98 +/- 37.94(SD) mg/min (P value < .001). On the other hand, the placebo-treated group,(control) the mean sweating rate before treatment was 77.40 +/- 29.29(SD) which did not show significant improvement after placebo application 77.35 +/- 28.29(SD; P value = .957). CONCLUSION: The topical application of 45% clove oil in liposome twice daily for 2 weeks showing promising result evidenced by declining in the rate of palmar sweating among patients with idiopathic palmar hyperhidrosis. PMID- 29285890 TI - Flower-like Vanadium Suflide/Reduced Graphene Oxide Composite: An Energy Storage Material for Aluminum-Ion Batteries. AB - A flower-like vanadium sulfide/reduced graphene oxide (VS4 /rGO) composite was prepared by a typical hydrothermal method and it was investigated as cathode for aluminum-ion batteries with non-inflammable and non-explosive ionic-liquid electrolytes. The charge/discharge performance measurements were performed in a voltage range of 0.1-2.0 V versus Al/AlCl4- , which gave an initial charge/discharge specific capacity af approximately 491.57 and 406.94 mA h g-1 , respectively, at a current density of 100 mA g-1 . Additionally, in the cycling performance, the discharge capacity was observed to remain over 80, 70, and 60 mA h g-1 at current densities of 100, 200, and 300 mA g-1 after 100 cycles, respectively. The result of a coulombic efficiency over 90 % after 100 cycles and high retained capacity indicate that the composite is a favorable cathode material for new rechargeable aluminum-ion batteries. PMID- 29285891 TI - High-throughput analysis of anammox bacteria in wetland and dryland soils along the altitudinal gradient in Qinghai-Tibet Plateau. AB - This study investigated the diversity, community composition, and abundance of anaerobic ammonium oxidation (anammox) bacteria along the altitudinal gradient in Qinghai-Tibet Plateau. Two types of soil samples (wetland and dryland soils, n = 123) were collected from 641 m to 5,033 m altitudes. Polymerase chain reaction (PCR) screening showed that anammox were not widespread, and were only detected in 9 sampling sites of the 50 sites tested by amplifying the 16S rRNA genes. Then, only samples collected from Linzhi (2,715 m), Rikaze (4,030 m), and Naqu (5,011 m), which were positive for the presence of anammox, were further processed to explore the biogeography of anammox bacteria in Qinghai-Tibet Plateau. Results of high-throughput sequencing targeting the hydrazine synthesis beta-subunit (hzsB) gene revealed the presence of three known anammox genera (Candidatus Brocadia, Candidatus Jettenia, and Candidatus Kuenenia) in both soil types. Their diversity, community composition, and abundance did not show significant variation with altitude at large scale. However, it was the small scale environmental heterogeneities between wetland and dryland soils that determined their biogeographical distribution. Specifically, the dryland soils had higher diversity of anammox bacteria than the wetland soils, but their abundance patterns varied. The community composition of anammox bacteria were found to be influenced by soil nitrate content. PMID- 29285892 TI - Cytopathologic features of papillary glioneuronal tumor. PMID- 29285893 TI - Cerebellar microglia are dynamically unique and survey Purkinje neurons in vivo. AB - Microglia are the innate immune cells of the central nervous system and are also important participants in normal development and synaptic plasticity. Here, we demonstrate that the microglia of the mouse cerebellum represent a unique population compared to cortical microglia. Microglia are more sparsely distributed within the cerebellum and have a markedly less ramified morphology compared to their cortical counterparts. Using time-lapse in vivo imaging, we found that these differences in distribution and morphology ultimately lead to decreased parenchymal surveillance by cerebellar microglia. We also observed a novel form of somal motility in cerebellar microglia in vivo, which has not been described in cortical populations. We captured microglial interactions with Purkinje neurons in vivo. Cerebellar microglia interact dynamically with both the dendritic arbors and somas of Purkinje neurons. These findings suggest that cerebellar microglia are physiologically distinct from cortical populations and that these differences may ultimately alter how they could contribute to plasticity and disease processes in the cerebellum. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 627-644, 2018. PMID- 29285894 TI - The effect of a single injection of irinotecan on the development of enamel in the Wistar rats. AB - Cancer is the second most frequent cause of death in children. Because the prognosis for childhood malignancies has improved, attention has now focused on long-term consequences of cancer treatment. The immediate effects of chemotherapy on soft tissues have been well described; however, there is less information about long-term effects of chemotherapy on the development of dental tissues. To test the association between the effect of chemotherapy on enamel development, we examined two groups of rats: one that had received an intraperitoneal dose of 200 mg/kg of irinotecan, whereas the other (control) group had received vehicle only. Rats were killed at 6, 48 and 96 hr post-injection; the mandibles dissected out, fixed for histological evaluation and scanned for mineralization defects by Micro CT. Our results showed structural changes in the ameloblast layer along with a significant reduction in mineralization and thickness of enamel at 96 hr after chemotherapy. These data demonstrate that irinotecan induces structural changes in forming enamel that become apparent after anticancer chemotherapy treatment. PMID- 29285895 TI - Hydrothermally Induced Oxygen Doping of Graphitic Carbon Nitride with a Highly Ordered Architecture and Enhanced Photocatalytic Activity. AB - As an amorphous or semicrystalline material, graphitic carbon nitride (g-C3 N4 ) displays poor photocatalytic activity owing to rapid recombination of the photogenerated charge carriers, which is mainly caused by a high density of defects in the graphitic structure. In this work, a porous O-doped g-C3 N4 (P CNO) nanosheet with a highly ordered architecture is fabricated by introducing a novel hydrothermal treatment to the precursor before the final thermal condensation. The photocatalytic hydrogen evolution rate (HER) and HER per surface area of P-CNO are 13.9 and 1.7 times higher than that of bulk g-C3 N4 . The improved photocatalytic activity is ascribed to a synergistic effect of O doping, a porous sheet-like morphology, and increased crystallinity. This work also provides a new approach for the synthesis of other polymer-based photocatalysts with high crystallinity and excellent performance. PMID- 29285896 TI - Increase in the number of admissions to psychiatric hospitals immediately after the Great East Japan Earthquake. AB - INTRODUCTION: Major natural disasters have a significant impact on the mental health of survivors in affected communities. Although it has been speculated that the number of survivors requiring admission to psychiatric hospital increases immediately after a major disaster, few studies have examined the issue. METHODS: On March 11, 2011, the Great East Japan Earthquake and subsequent tsunami devastated the relatively isolated city of Kesennuma. We therefore compared the weekly number of patients admitted to 2 psychiatric hospitals in Kesennuma in the 4 weeks immediately after the earthquake with those in the 4 weeks immediately preceding the earthquake. We also made comparisons between this 8-week period and the corresponding 8-week periods in 2009, 2010, and 2012. RESULTS: The number of patients admitted to the 2 psychiatric hospitals increased in 4 weeks after the disaster in 2011, with a weekly median (range) of 13 (9-16), compared with 6 (5 9) in the preceding 4 weeks in 2011. The corresponding figures were 5.5 (2-10) in 2009, 6.5 (5-9) in 2010, and 4 (3-7) in 2012 (P = .01, H = 13.05). By diagnostic category, admissions for schizophrenia spectrum disorder and neurotic stress related disorder increased significantly following the disaster. DISCUSSION: Demands for inpatient psychiatric treatment increased immediately after the Great East Japan Earthquake. Government officials and mental health professionals must strengthen support for survivors with mental illness, especially those with schizophrenia spectrum disorder. This should include support for mental health authorities and medical staff in the affected community. PMID- 29285897 TI - Impact of a 'stent for life' initiative on post-ST elevation myocardial infarction heart failure: a 15 year heart failure clinic experience. AB - AIMS: Multidisciplinary heart failure (HF) clinics are a cornerstone of contemporary HF management. The stent-for-life (SFL) initiative improves mortality after ST elevation myocardial infarction (STEMI), but its impact in post-STEMI HF is not well characterized. Here we assessed the impact of SFL among patients referred to a multidisciplinary HF clinic over a 15 year time period. METHODS AND RESULTS: Between 2001 and 2015, 1921 patients were admitted to our HF clinic. In 2009, Catalonia established the Codi IAM network, a regional STEMI network that prioritizes primary percutaneous coronary intervention in STEMI. Patients admitted during the study period were divided into two groups based on admission date: pre-SFL (2001-June 2009; n = 1031) and post-SFL (July 2009-2015; n = 890). Compared with those in the pre-SFL group, patients admitted in the post SFL period had better New York Heart Association (NYHA) functional class (22.1 vs. 38.7 NYHA classes III-IV; P < 0.001) and higher left ventricular ejection fraction (LVEF) (36.1 +/- 19.6 vs. 32.6 +/- 13.4; P < 0.001). Among STEMI survivors, 101 (6.7%) pre-SFL patients and 40 (2%) post-SFL patients (P < 0.001) fulfilled the criteria for HF clinic referral (Killip-Kimball class >= 2 during index admission and/or LVEF of <40%). Furthermore, among patients admitted to the HF clinic, post-STEMI HF with reduced ejection fraction patients comprised 8.9% of the pre-SFL group and only 4.2% of the post-SFL group (P < 0.001). CONCLUSIONS: Among patients treated at our multidisciplinary HF clinic, the adoption of an SFL network has decreased the prevalence of post-STEMI HF with reduced ejection fraction. PMID- 29285898 TI - Upconversion in Nanostructured Materials: From Optical Tuning to Biomedical Applications. AB - Photon upconversion that is characterized by high-energy photon emission followed by lower-energy excitation has been conventionally studied in bulk materials for several decades. This unique nonlinear luminescence process has become a subject of great attention since 2000 when upconverted emission was demonstrated in nanostructured crystals. In comparison with their bulk counterparts, nanostructured materials provide more room for optical fine-tuning by allowing flexible compositional integration and structural engineering. Moreover, the high colloidal stability of nanoparticles coupled with high amenability to surface functionalization opens up a number of new applications for upconversion, especially in the fields of biology and life science. In this focus review, we discuss recent developments in upconversion materials through nanostructural design and review emerging biomedical applications that involve these nanostructured upconversion materials. We also attempt to highlight challenging problems of these nanomaterials that constrain further progress in utilizing upconversion processes. PMID- 29285899 TI - Design of Polymeric Culture Substrates to Promote Proangiogenic Potential of Stem Cells. AB - Stem cells are a promising cell source for regenerative medicine due to their differentiation and self-renewal capacities. In the field of regenerative medicine and tissue engineering, a variety of biomedical technologies have been tested to improve proangiogenic activities of stem cells. However, their therapeutic effect is found to be limited in the clinic because of cell loss, senescence, and insufficient therapeutic activities. To address this type of issue, advanced techniques for biomaterial synthesis and fabrication have been approached to mimic proangiogenic microenvironment and to direct proangiogenic activities. This review highlights the types of polymers and design strategies that have been studied to promote proangiogenic activities of stem cells. In particular, scaffolds, hydrogels, and surface topographies, as well as insight into their underlying mechanisms to improve proangiogenic activities are the focuses. The strategy to promote angiogenic activities of hMSCs by controlling substrate repellency is introduced, and the future direction is proposed. PMID- 29285900 TI - Design Nitrogen (N) and Sulfur (S) Co-Doped 3D Graphene Network Architectures for High-Performance Sodium Storage. AB - To develop high-performance sodium-ion batteries (NIBs), electrodes should possess well-defined pathways for efficient electronic/ionic transport. In this work, high-performance NIBs are demonstrated by designing a 3D interconnected porous structure that consists of N, S co-doped 3D porous graphene frameworks (3DPGFs-NS). The most typical electrode materials (i.e., Na3 V2 (PO4 )3 (NVP), MoS2 , and TiO2 ) are anchored onto the 3DPGFs-NS matrix (denoted as NVP@C@3DPGFs NS; MoS2 @C@3DPGFs-NS and TiO2 @C@3DPGFs-NS) to demonstrate its general process to boost the energy density of NIBs. The N, S co-doped porous graphene structure with a large surface area offers fast ionic transport within the electrode and facilitates efficient electron transport, and thus endows the 3DPGFs-NS-based composite electrodes with excellent sodium storage performance. The resulting NVP@C@3DPGFs-NS displays excellent electrochemical performance as both cathode and anode for NIBs. The MoS2 @C@3DPGFs-NS and TiO2 @C@3DPGFs-NS deliver capacities of 317 mAhg-1 at 5 Ag-1 after 1000 cycles and 185 mAhg-1 at 1 Ag-1 after 2000 cycles, respectively. The excellent long cycle life is attributed to the 3D porous structure that could greatly release mechanical stress from repeated Na+ extraction/insertion. The novel structure 3D PGFs-NS provides a general approach to modify electrodes of NIBs and holds great potential applications in other energy storage fields. PMID- 29285901 TI - Characterization of porcine sapelovirus isolated from Japanese swine with PLC/PRF/5 cells. AB - Porcine sapelovirus (PSV) is a causative agent of neurological disorders, fertility disorders and dermal lesions of swine. In this study, we isolated two PSV strains, Jpsv477 and Jpsv1315, from swine faecal specimens using a PLC/PRF/5 cell culture system. The PSV infection of PLC/PRF/5 cells induced a cytopathic effect (CPE). Two types of virus particles with identical diameter (~35 nm) but different densities (1.300 and 1.285 g/cm3 ) were observed in the cell culture supernatants. Analysis of the entire genome sequence of Jpsv477 and Jpsv1315 revealed that both strains possess 7,558 nucleotides and the poly (A) tail and have a typical PSV genome organization consisting of a 5' terminal untranslated region (5'UTR), a large open reading frame (ORF), and a 3' terminal untranslated region (3'UTR). The ORF encodes a single polyprotein that is subsequently processed into a leader protein (L), four structural proteins (VP1, VP2, VP3 and VP4) and seven functional proteins (2A, 2B, 2C, 3A, 3B, 3C and 3D). The structural proteins VP1, VP2, VP3 and VP4 have molecular masses of ~35, ~26, ~25 and ~6 kDa. The N-terminal amino acid sequence analysis of VP1, VP2, VP3 and VP4 confirmed that the cleavage sites between VP4 and VP2, VP2 and VP3, and VP3 and VP1 are K/A, Q/G and Q/G, respectively. We further confirmed that HepG2/C3A, Vero E6 and primary green monkey kidney cells (PGMKC) were also susceptible to PSV infection. The stability assay demonstrated that PSV was inactivated by heating at 60 degrees C for 10 min or 65 degrees C for 5 min. The virus also lost infectivity by incubation with 62.5 ppm of NaClO for 30 min. PMID- 29285902 TI - [Clinical classification and treatment status of atlantoaxial dislocation]. PMID- 29285903 TI - [Clinical observation on the treatment of atlantoaxial dislocation based on the classification]. AB - OBJECTIVE: To retrospectively analyze the surgical methods and its clinical effects and explore a clinical classification and treatment strategy for atlantoaxial dislocation(AAD). METHODS: The clinical data of 89 patients with atlantoaxial dislocation were analyzed from September 2005 to September 2013. There were 49 males and 40 females, aged from 13 to 67 years with an average of 48.1 years. According to the reductive effects with preoperative cervical dynamic radiograph and high weight skeletal traction under general anesthesia, the dislocations were classified into three types:easy reduction type, hard reduction type and irreducible type. The patients with easy reduction type were treated with posterior screw rod internal fixation after manual reduction, while the patients with hard reduction type were treated with posterior screw rod fixation after high weight skeletal traction reduction under general anesthesia. The patients with irreducible type were treated with transoral atlantoaxial joint release or depression and posterior internal fixation and fusion. According to JOA scores to evaluate the neurological status and treatment outcome. RESULTS: Thirty patients were classified as easy reduction type, 55 patients as hard reduction type, and 4 patients as irreducible type. The preoperative JOA score was 8.2+/-3.1 on average, while the postoperative score was 14.2+/-2.4. The improvement rate was 40.1% to 82.5% with an average of 62.5%. Eighty nine patients were followed up from 6 to 37 months with a mean of 17.3 months. Eighty two cases obtained anatomical reduction and 85 cases obtained bony fusion. One case complicated with hyponatremia after operation and 1 case combined with Guillain-Barre syndrome, 4 cases complicated with delayed union wounds, 1 case died of for respiratory failure 2 years after operation. No wound infections were found in the patients approach for transoral operation. CONCLUSIONS: According to the cervical dynamic radiograph and high weight skeletal traction under general anesthesia to classify for atlantoaxial dislocation, and adopting well strategies to treat the patients, can achieve satisfactory effects. PMID- 29285904 TI - [Clinical analysis of the self made needle guide for the treatment of odontoid fracture]. AB - OBJECTIVE: To analyze the curative effects and feasibility of the self regulating simple localizer through anterior approach for the treatment of odontoid fracture in adults. METHODS: From June 2010 and December 2012, 6 patients with odontoid fracture underwent an anterior operation using a single hollow screw located by the self regulating simple localizer. There were 4 males and 2 females, aged from 28 to 55 years old with an average of 39.1 years. The injuries were caused by traffic accidents in 4 cases and falling injury from high in 2 cases. According to the classification of Anderson, 4 cases were type II and 2 cases were simple type III. All the patients underwent operations in 5 to7 days after injury with the mean of 5.9 days. None of the patients had a spinal cord injury. The safety and feasibility of the self made localizer were observed in follow up for fracture healing and clinical effects. RESULTS: All the operations were successful with an average time of 50 min (ranged from 45 to 55 min) and the mean bleeding volume was 25 ml(ranged from 20 to 30 ml). No injuries of esophagus, trachea or nerve were found. All the patients were followed up from 8 to 16 months and all fractures were obtained bone healing. The flexion extension radiograph showed a well stability of atlantoaxial joint in last followed up. CONCLUSIONS: The self regulating simple localizer is a minimally invasive, short time and safe method in treating odontoid fractures through anterior operation with hollow screw. It may be a reliable choice while without a professional localizer. PMID- 29285905 TI - [Analysis of clinical characteristics and image for sternum tumor]. AB - OBJECTIVE: To analyze the clinical characteristics and imaging features of sternum tumor, in order to improve the knowledge of the diseases. METHODS: The clinical data and imaging data of 18 patients with sternum tumor were retrospectively analyzed. There were 13 males and 5 females, aged from 24 to 73 years old with an average of 58.3 years. Eleven patients were treated by conservative treatment and 7 patients were treated by surgery. The course of disease ranged from 2 months to 6 years. One patient had no obvious symptoms and 1 patient had a history of chest trauma. Lesion location, pattern of bone destruction, cortical bone abnormality, MRI signal characteristics and contrast enhancement were observed in the patients. RESULTS: Eighteen cases included malignant bone tumor in 16 cases and benign tumor in 2 cases;and 7 cases located in sternal manubrium, 9 cases located in sternal body, and 2 cases located in both. On the imaging, sternal tumor had expansively developing tendency, and the bone destruction zone boundary continuity or partial disruption occurred in 15 cases, the border of cortical bone thinning in 2 cases, the cortical bone increased thickness in 1 case. No bone marrow edema around tumor was found in 7 cases by MRI and soft tissues was encroached in 2 cases; in T1WI of MRI, 4 cases showed the hypointense signal and 3 cases showed the iso or hyper intensity signal; in T2WI of MRI, 6 cases showed the iso or hyper intensity signal and 1 case showed confounding signal. Enhancement scanning in MRI, premodinantly tumors showed obviously strengthening. CONCLUSIONS: The types of the sternum tumors are various and the most tumors are malignant. The images of the mostly sternum tumor absented same charactiristic, and it must combine with clinical manifestation to analyze the X rays, CT scanning and MRI, it will conduce to improve the diagonstic accuracy of the sternum tumors. PMID- 29285906 TI - [Surgical treatment with cable dragged reduction and cantilever beam internal fixation by posterior approach for odontoid fracture associated with atlantoaxial dislocation]. AB - OBJECTIVE: To explore the clinical effects of surgical treatment with cable dragged reduction and cantilever beam internal fixation by posterior approach for odontoid fracture associated with atlantoaxial dislocation. METHODS: The clinical data of 12 patients with odontoid fracture associated with atlantoaxial dislocation from January 2008 to December 2013 were retrospectively analyzed. There were 8 males and 4 females, ranging in age from 21 to 53 years with an average of 37.2 years. Eleven cases were fresh fracture and 1 case was old fracture, all patients complicated with atlantoaxial anterior dislocation. According to Anderson-D' Alonzo typing method modified by Grauer, 3 cases were type IIA, 5 cases were type IIB, 3 cases were type IIC, and 1 case was type IIIA. All patients underwent surgical treatment with cable dragged reduction and cantilever beam internal fixation by posterior approach. JOA score and ADI method were respectively used to evaluate the nerve function and reductive condition of atlantoaxial dislocation. RESULTS: All patients were followed up from 6 months to 2 years with an average of 1 year and 3 months. At 1 week, 6 months after operation, and final follow up, JOA scores were 13.2+/-1.3, 13.5+/-1.4, 14.3+/ 1.5, respectively, and these data were obviously better than that of preoperative 8.3+/-1.4(P<0.05). Postoperative X rays and CT showed satisfactory reduction of atlantoaxial dislocation. At 1 week, 6 months after operation, and final follow up, ADI were (2.2+/-0.4), (2.4+/-0.6), (2.3+/-0.5) mm, respectively, and these data were obviously better than that of preoperative.(5.8+/-1.2) mm(P<0.05). All screws and cables had good location without looseness and breakage, and bone graft got fusion. CONCLUSIONS: Surgical treatment with cable dragged reduction and cantilever beam internal fixation by posterior approach for odontoid fracture associated with atlantoaxial dislocation is a good method, with advantage of firm fixation and high safety. It could obtain good clinical effects. PMID- 29285907 TI - [Study on the clinical value of cervical spondylosis with articulatio atlantoepistrophica sublaxation]. AB - OBJECTIVE: To explore the effect of articulatio atlantoepistrophica sublaxation on the pathogenesis of cervical spondylosis, and provide a thread for diagnosis and treatment of cervical spondylosis with manipulation. METHODS: There were two groups in the study, which were non cervical spondylosis group and cervical spondylosis group. There were 333 patients in cervical spondylosis group, included 119 males and 214 females with the mean age of(48.11+/-12.21) years old. The patients were recruited from clinic service of orthopaedics in Shuguang Hospital between March 2006 and December 2008. There were 73 subjects in non cervical spondylosis group, included 18 males and 55 females with the mean of(45.99+/-11.47) years old. The subjects were recruited from undergraduate students, postgraduate, advanced study persons, and community personnel. The position relation of the atlanto axial joint was observed by cervical X rays with opening position, and the incidence rate of articulatio atlantoepistrophica sublaxation was compared between two groups, and their clinical characteristics were analyzed. RESULTS: The incidence of articulatio atlantoepistrophica sublaxation in cervical spondylosis group was 81.38%(271/333)and was more than non cervical spondylosis group(P<0.01). Furthermore, the pattern of the articulatio atlantoepistrophica sublaxation in cervical spondylosis group was complicated and diversified, which was 50.55% (137/271)with single moving sublaxation, 7.01%(19/271) with revolving sublaxation, 42.44%(115/271) with single moving and revolving sublaxation. CONCLUSIONS: The articulatio atlantoepistrophica sublaxation may be a X ray diagnostic indication to the cervical spondylosis, which should be grouping studied in clinic. It will provide guidance for the diagnosis and treatment of cervical spondylosis. PMID- 29285908 TI - [Pedicle exposure technique for atlas screw fixation:a radiological research]. AB - OBJECTIVE: To investigate the meaning of pedicle exposure technique for screw fixation on atlas with the vertebral groove height less than 4 mm by using reconstructive computed tomography. METHODS: From April 2015 to June 2015, 84 pedicles of 51 patients with groove heights less than 4 mm were studied by digital reconstruction respectively. Parameters of atlas pedicle screw fixation were measured. RESULTS: Among the 51 cases, the vertebral groove height was (3.28+/-0.51) mm. Lateral mass heights, lateral mass widths and the transition area heights between lateral mass and posterior arch were fit for 3.5 mm screw implanting. Ideal pedicle screw trajectory lengths from 0 degrees to 15 degrees (0 degrees , 5 degrees , 10 degrees , 15 degrees ) were (27.36+/-1.81), (27.01+/ 1.68), (27.07+/-1.75), (27.48+/-1.72) mm, exposed trajectory lengths from 0 degrees to 15 degrees (0 degrees , 5 degrees , 10 degrees , 15 degrees ) were(23.44+/-1.79), (23.87+/-1.84), (24.58+/-1.89), (25.56+/-2.01) mm, trajectory length of lateral mass was (20.78+/-2.05) mm. The mean CT values on 5 sections through pedicle trajectory and lateral mass trajectory were (701.89+/-141.48) HU and (599.11+/-137.33) HU, respectively. There were no significant differences between ideal pedicle trajectory lengths from 0 degrees to 15 degrees (P>0.05). Exposed trajectory lengths was significantly increased accompanying with medial angles increasing (P<0.05), and was longer than trajectory lengths of lateral mass (P<0.05). CT value of pedicle screws was higher than CT value of lateral mass screws significantly (P<0.01). CONCLUSIONS: Screws can be implanted in atlas with vertebral groove height less than 4 mm by using pedicle exposure technique. Few trajectory lengths will be sacrificed with favorable pull out strength due to adequate bone mass purchased. PMID- 29285909 TI - [The preliminary clinical study about the effectiveness of selective treatment for traumatic cervical disc herniation with stand alone RIO-C]. AB - OBJECTIVE: To discuss the efficacy of a new double plate self locking interbody fusion device(ROI-C) in the anterior cervical discectomy and fusion(ACDF) to treat traumatic cervical disc herniation(TCDH) without segmental instability, fracture or dislocation. METHODS: ACDF with stand alone ROI-C was performed in 17 selective TCDH patients between December 2011 and December 2013. There were 12 males and 5 females, aged from 24 to 41 years old with a mean of 32.9 years, including 11 patients with single segment, 4 patients with double segments and 2 patients with three segments. Japanese Orthopaedics Assiciation (JOA), visual analogue scale(VAS) score and the Neck Disability Index(NDI) were recorded before and after operation in order to evaluate the clinical outcome, meanwhile, the preoperative and postoperative X ray films were collected to measure the intervertebral space height and whole cervical curvature. According to Vaccraro criteria to observe the bone fusion. The clinical effects were assessed according to Odom criteria. RESULTS: All patients were followed up from 12 to 33 months with an average of 18.5 months. JOA score was increased significantly from preoperative 4.3+/-3.8 to 13.9+/-2.5 at final follow up (P<0.05). VAS, NDI were decreased from preoperative (6.5+/-2.2) scores and (38.2+/-11.7) % to (1.0+/-0.9) scores and (8.7+/-3.4) % in final follow up, respectively (P<0.05). Intervertebral space height and cervical curvature were increased from preoperative (5.2+/-1.7) mm and (5.1+/-7.5) degrees to (7.8+/-0.6) mm and (10.5+/-5.1) degrees , respectively(P<0.05). Hoarseness occurred in one patient and dysphagia occurred in 2 patients and they recovered spontaneously in 2 weeks and 3 months after operation, respectively. All the segments (25 levels) of the 17 cases achieved bony fusion in 6 months after operation. No displacement, subsidence and failure of ROI-C were found during follow up. According to Odom's criteria to evaluate clinical effects at the last follow up, 13 cases got excellent results, 3 good, and 1 fair. CONCLUSIONS: ACDF with stand alone ROI-C is an effective, minimally invasive and reliable method in treating TCDH without segmental instability, fracture or dislocation, it can obtain satisfactory clinical outcomes and has advantage of less complications, high fusion rate. PMID- 29285910 TI - [Comparison of short term curative effects of open door laminoplasty with different plate density for the treatment of multi segment cervical spondylotic myelopathy]. AB - OBJECTIVE: To compare the short term curative effect of posterior open door laminoplasty between continuous placement of shaping plate and intermittent placement in treating multilevel cervical spondylotic myelopathy. METHODS: From January 2012 to March 2015, 43 patients with multi segment cervical spondylotic cervical were treated with posterior open door laminoplasty, 21 patients with continuous placement of shaping plate(continuous group), 22 patients with intermittent placement of shaping plate(intermittent group). Operative time, intraoperative blood loss, JOA score, VAS score, postoperative spinal sagittal diameter and cervical curvature, postoperative cervical activity, complications, hospitalization expenses etc. were observed. RESULTS: The patients of two groups were followed up with an average of (23.2+/-8.1) months and (23.3+/-8.0) months in continuous group and intermittent group, respectively. There was no significant difference in operative time, intraoperative blood loss, hospitalization time between two groups(P>0.05). JOA and VAS scores of all patients at final follow up were obviously improved than preoperative(P<0.05). Postoperative spinal sagittal diameter at 3 days and final follow up were obviously improved(P<0.05), and there was no significant difference between postoperative at 3 days and final follow up(P>0.05). Cervical activity of all patients at final follow up was decreased than preoperative(P<0.05), but there was no significant difference between two groups(P>0.05). There was no significant difference in postoperative complication and there was significant difference in hospitalization expenses between two groups. CONCLUSIONS: Posterior open door laminoplasty with continuous or intermittent placement of shaping plate have similar clinical effects in ameliorating nerve function for the treatment of multilevel cervical spondylotic myelopahty. However, the hospitalization expenses of intermittent group is obviously reduced, and the medical resources can be saved. PMID- 29285911 TI - [Analysis of clinical characteristics of 20 patients with pyogenic spondylitis]. AB - OBJECTIVE: To investigate the diagnostic value of clinical manifestation, laboratory examination and imaging changes for pyogenic spondylitis and to summarize the clinical characteristics of patients with pyogenic spondylitis. METHODS: The clinical data, of 20 patients with pyogenic spondylitis were diagnosed by histopathological examination from March 2012 to March 2015, were retrospectively analyzed. There were 9 males and 11 females, aged from 43 to 72 years old with an average of 58.9 years. Included 3 cases of cervical vertebrae, 7 cases of thoracic vertebrae, 10 cases of lumbar vertebrae. Patients of blood analysis, erythrocyte sedimentation rate(ESR), C reactive protein(CRP), X rays, CT and MRI were performed before treatment. Visual analogue scale (VAS) was used to evaluate the pain of patients suffering from vertebral pain. RESULTS: All the patients had suffered from vertebral pain before treatment. VAS was 9 points in 4 cases, 8 points in 6 cases, 7 points in 1 case, 3 points in 6 cases, and 2 points in 3 cases. Among them, 7 patients complicated with neurological symptoms, 11 with aggravating night pain, 10 with fever. WBC and Neutrophil count (NEU) of 5 cases were increased and other 15 cases were normal;CRP of 19 cases were increased and 1 case was normal;ESR of all 20 cases were increased. X rays showed the intervertebral space narrowing in all 20 cases, 13 cases complicated with destruction of vertebral body; CT showed the lesions of vertebral body in the 20 cases and complicated with destruction, sclerosis of sclerotin; MRI showed that the lesions of the vertebral body in the T1 image had uneven medium low signal, in the T2 image of the 16 cases had uneven high signal and 2 cases had uniform and high signal, 2 cases had main high signal compliated with mixed signal. Thirteen patients underwent surgical treatment and 7 patients received conservative treatment, and the patients left hospital while VAS had significantly improved after treatment. CONCLUSIONS: Pyogenic spondylitis is easy to be misdiagnosed or missed in clinic. It can be combined with the clinical manifestations, laboratory examination and imaging characteristics in order to make a definite diagnosis for purulent spondylitis in early. PMID- 29285913 TI - [Fibrous dysplasia complicated with severe kyphosis:a case report]. PMID- 29285912 TI - [Study of olfactory ensheathing cells transplantation and treadmill training on improving hindlimb motor function of spinal cord injury rats]. AB - OBJECTIVE: To investigate the effects of olfactory ensheathing cells (OECs) transplantation and treadmill training in improving hindlimb motor function of spinal cord injury(SCI) rats and explore its possible mechanism. METHODS: A total of 80 male SD rats were randomly divided into four groups: media untrained (group A), OECs untrained (group B), media trained (group C) and OECs trained(group D). Each group had 20 rats and all rats were made the model of spinal cord injury. The rats of group C and D underwent treadmill exercise in 3 days after operation, the rats of group B and D underwent OECs transplantation in 7 days after operation (each rat was injected a total of 4 MUl, cell concentration was 1.0*106/MUl), at the same time, the rats of group A received the corresponding dose of saline. Then observed was continued for 4 weeks totally. BBB scores in each group were measured weekly. The expression of Bax, Bcl-2, NF-200 were observed by immunohistochemisty staining. Mallory staining was used to the regeneration of nerve fibers and TUNEL staining was used to observe neuronal apoptosis. RESULTS: (1)The BBB scores in group D in the 4th week was significantly higher than of other three groups(P<0.05). (2)On the Bcl-2 protein expression, there was interaction between OECs and treadmill training, the two mutually reinforcing;while OECs transplantation can significantly reduce the Bax protein expression without significant interaction with treadmill training(P>0.05). TUNEL staining showed that OECs transplantation, treadmill training, the time factor had an interaction and significantly inhibited the apoptosis(P<0.05). (3)It was showed in immunohistochemisty staining of NF-200 and Mallory staining that OECs transplantation, treadmill training with the time factor were an interaction among the three with significant regeneration of nerve fibers(P<0.05). CONCLUSIONS: OECs transplantation combined with treadmill training can significantly improve hindlimb motor function of SCI rats, which may be achieved by the following ways. OECs transplantation and treadmill training can collaborate with each other, significantly increasing the expression of Bcl-2 gene, which significantly inhibit neuronal apoptosis;at the same time it can promote neuronal axonal regeneration, increase the number of nerve fibers, and this effect may be more remarkable with time. PMID- 29285914 TI - [Cervical single open door laminoplasty with lateral mass screw fixation for the treatment of cervical spondylotic myelopathy with cervical instability]. AB - OBJECTIVE: To evaluate the outcomes of single open door laminoplasty with lateral mass screw fixation in treating cervical spondylotic myelopathy (CSM) with cervical instability. METHODS: From March 2010 to October 2012, 25 patients with spondylotic myelopathy and cervical instability underwent single open door laminoplasty with lateral mass screw fixation. There were 18 males and 7 females, aged from 57 to 68 years with the mean of 57 years. Japanese Orthopaedic Association (JOA) scores were used to evaluate clinical effects before operation and final follow up. Radiographical measures were made in change of Cobb angle by sagittal plane from C2 to C7, and cervical range of motion. RESULTS: All the patients were followed up from 18 to 36 months with an average of 25.6 months. Cerebrospinal fluid leakage occurred in 1 case, incision fat necrosis in 1 case, C5 nerve root palsy in 4 cases. JOA scores was improved from preoperative 5.2+/ 2.1 to 11.3+/-2.4 final follow up. Cobb angle was changed from preoperative (6.5+/-3.4) degrees to (13.2+/-4.9) degrees final follow up. Cervical range of motion was changed from preoperative (30.4+/-9.2) degrees to (26.5+/-8.4) degrees final follow up. CONCLUSIONS: As an effective treatment to CSM with cervical instability, single open door laminoplasty with lateral mass screw fixation has the advantage of extensive application scope, safety and steady, but the incidence rate of complication must be reduced. PMID- 29285915 TI - [Anterior slip phenomenon of the vertebrae after corpectomy surgery and its clinical significance]. AB - OBJECTIVE: To investigate the anterior slip phenomenon of the vertebrae after corpectomy surgery and its clinical significance. METHODS: The clinical data of 164 patients with cervical spondylotic myelopathy treated from January 2010 to April 2013 were retrospectively analyzed. There were 88 males and 76 females, aged from 38 to 74 years old with the mean of 56.2 years. Among them, 31 cases for C4 corpectomy, 87 cases for C5 corpectomy, 46 cases for C6 corpectomy. Preoperative and postoperative distance of posterior wall of vertebral canal to the line of adjacent upper vertebral bodies anterosuperior border and lower vertebral bodies anteroinferior border was measured by CT in cervical sagittal middle layer scanning as the center, anterior slip degree of the vertebrae after operation was evaluated. The fast clustering method was used, the vertebral shift distance as variable, according to the size of the forward distance, 90 cases classified as group 1(forward greatly group), and the 74 cases classified as group 2(forwad short group). The relationships on the anterior slip of the vertebrae and cervical curvature, surgical segment were analyzed. Japanese Orthopaedic Association (JOA) scores and its improvement rate were observed before and after operation, and the relationships on the anterior slip of the vertebrae and sagittal plane diagonal diameter of spinal canal, clinical effect were analyzed. RESULTS: All the patients were followed up from 12 to 48 months with an average of 29.5 months. All operative vertebrae occurred anterior slip with different degree after corpectomy surgery, the maximum was 3.52 mm and minimum was 1.12 mm, with an average of (2.14+/-1.02) mm. According to the clustering method, the anterior slip distance with (3.07+/-0.21) mm classified as forward greatly group(90 cases, 54.9%) and the anterior slip distance with (1.55+/-0.32) mm classified as forwad short group(74 cases, 45.1%). There was no significant difference between anterior slip distance and operation segments(chi2=0.01, P=0.996). Cervical curvature index and anterior slip distance of operated vertebra had a positive correlation (r=0.724). The incidence of reduction of the diagonal diameter of cervical spinal canal in forward greatly group was higher than that of forwad short group(chi2=4.45, P=0.035). The patients with unsatisfactory efficacy appeared obvious anterior slip of the vertebrae after corpectomy than the patients with satisfactory efficacy(P<0.05). CONCLUSIONS: Corpectomy of the cervical spine can result in vertebral forward displacement trend, and obvious displacement may cause the secondary compression of the spinal cord. PMID- 29285916 TI - [Unilateral versus bilateral pedicle screw fixation in minimally invasive transforaminal lumbar interbody fusion(MIS-TLIF): a Meta analysis]. AB - OBJECTIVE: To compare the clinical outcome between unilateral and bilateral pedicle screw fixation in minimally invasive transforaminal lumbar interbody fusion(MIS-TLIF) for the treatment of lumbar degenerative diseases. METHODS: The studies concerning unilateral or bilateral pedicle screw fixation in MIS-TLIF for the treatment of lumbar degenerative diseases from January 2000 to October 2015 were searched from Medline, Embase, The Cochrane Library, China Biology Medicinedisc and Wanfang database, China National Knowledge Internet (CNKI). The data of the studies were collected, risk of bias of the included RCTs were assessed according to Cochrane handbook 5.1.0, risk of bias of the included retrospective or prospective studies were assessed according to MINORS. The Oswestry Disability Index (ODI), visual analogue scale(VAS), lumbar lordosis angle, segmental lordosis angle, lumbar scoliosis angle, segmental scoliosis angle, fusion rate, complication rate, hospitalization time, operative time and blood loss data were Meta analyzed by RevMan 5.2.0 software. RESULTS: Nine studies were included, containing 4 randomized controlled trials (RCT), 2 prospective studies and 3 retrospective studies, there were 451 patients in total. The results showed that there was no significant difference between the two methods in VAS of back pain, VAS of leg pain, ODI, lumbar lordosis angle, segmental lordosis angle, lumbar scoliosis angle, segmental scoliosis angle, fusion rate, complication rate, hospitalization time. There was significant difference in operative time and blood loss between unilateral and bilateral pedicle screw fixation. CONCLUSIONS: Using unilateral or bilateral pedicle screw fixation in MIS-TLIF for lumbar degenerative diseases can achieve the same clinical effects, and there was no significant difference in complication rate. Unilateral pedicle screw fixation is safer than bilateral fixation because of less operative time and blood loss. However, the number and quality of the literatures may result in low reliability, so greater sample size and high quality RCTs are needed in future. PMID- 29285917 TI - [Research progress on tranexamic acid application strategy in total knee arthroplasty]. AB - Tranexamic acid(TXA) as an antifibrinolytic drugs used to reduce the total knee arthroplasty(TKA) postoperative blood loss is a hot issue in recent years. Such as blood loss, hemoglobin, transfusion rate and other relevant indexs effected by the impact of total knee replacement have been studied and investigated by many scholars. There is no a gold standard about how to safely and effectively apply the TXA. Depending on the dose, TXA may be used by body weight or using 1.5 g or 3.0 g directly. Depending on the different route of administration, TXA may be intravenous infusion, topical application and oral medication. Depending on the using opportunity, TXA can be used preoperative, intraoperative, postoperative or combined application with different times. Without any increase in the chances of thrombosis after TKA, choosing the more scientific instructions to play the greatest utility TXA is a hot issue recently. PMID- 29285918 TI - [Research progress on wear particles and periprosthetic osteolysis after artificial joint replacement]. AB - It is an important influencing factor that the generated wear particles lead to periprosthetic osteolysis after artificial joint replacement. Current research suggests that the primary cause of wear particles results in periprosthetic osteolysis is relate to the prosthetic materials and the stimulations because of these materials generated wear particles to relevant cells such as macrophage, osteoblast, osteoclast. Induced a variety of inflammatory cytokines, activating and openning the cell signal and channels, producing the long term chronic inflammation leads to periprosthetic osteolysis. Therefor, the paper mainly studies the different types of wear particles influence on periprosthetic osteolysis, and the wear particles around the periprosthetic osteolysis mechanism in the process of progress, moreover, to explore how to reduce the occurrence of wear particles and blocking its role in the periprosthetic osteolysis, in order to achieve the purpose of prevention and treatment of periprosthetic osteolysis. PMID- 29285919 TI - Ultrasensitive Flexible Proximity Sensor Based on Organic Crystal for Location Detection. AB - A new type of flexible proximity sensor that uses a microsized organic crystal as the sensing element is demonstrated. The two-terminal organic sensor can accurately perceive the external objects, such as the human finger, fiber, and even atomic force microscopy tip. The proximity sensor shows an unprecedented distance resolution of 0.05 mm, which is 2 orders of magnitude higher than that of the previously reported conventional capacitor proximity sensors. A novel method has been proposed to realize the location detection of the approaching unknown-charge object by changing the distance between the stimulus and the sensor. Our results open a new route to realize an ultrasensitive perception of objects, making it a promising candidate for applications in artificial intelligence, healthcare systems, and high-precision robots. PMID- 29285920 TI - Fragment Molecular Orbital Based Parametrization Procedure for Mesoscopic Structure Prediction of Polymeric Materials. AB - In the analyses of miscibility behaviors of macromolecules and polymers, dissipative particle dynamics (DPD) simulations are generally performed. In these simulations, the so-called chi parameters describing the effective interactions among particles are crucial. It has been known that such parameters can be obtained within the classical or empirical force field frameworks. However, there is a potential problem that charge transfer and polarization occasionally occur. Additionally, satisfactory reference parameters are not available for some cases. Therefore, we developed a new procedure to evaluate the set of parameters by using the ab initio fragment molecular orbital (FMO) method which can provide the set of interaction energies among segments as polymer units. Moreover, we evaluated the anisotropy of molecules by using the FMO-based effective interaction parameters for three standard binary mixture systems (hexane nitrobenzene, polyisobutylene-diisobutyl ketone, and polyisoprene-polystyrene). The calculated values showed good agreement with the experimental values with about 10% errors. PMID- 29285922 TI - Perovskite Light-Emitting Diodes via Laser Crystallization: Systematic Investigation on Grain Size Effects for Device Performance. AB - Owing to unique potential for high color purity luminance based on low-cost solution processes, organic/inorganic hybrid perovskite light-emitting diodes (PeLEDs) are attracting a great deal of research attention. For high performance PeLEDs, optimum control of the perovskite film morphology is a critical parameter. Here, we introduce a reliable and well-controllable PeLED crystallization process based on beam-damage-free near-infrared laser (lambda = 808 nm) irradiation. Morphology of the CH3NH3PbBr3 films can be precisely controlled by laser irradiation condition parameters: power density and beam scan rate. We systematically investigate the perovskite film morphology and device performance of the PeLEDs under different processing conditions. In the optimum power density and high beam scan rate (30 W cm-2, 0.1 mm s-1), a dense and smooth perovskite film is attained with a small crystal grain size. The critical relationship between the crystal grain size and LED efficiency is established while attaining the device performance of 0.95 cd A-1 efficiency and 1784 cd m-2. PMID- 29285921 TI - Incorporating C60 as Nucleation Sites Optimizing PbI2 Films To Achieve Perovskite Solar Cells Showing Excellent Efficiency and Stability via Vapor-Assisted Deposition Method. AB - To achieve high-quality perovskite solar cells (PSCs), the morphology and carrier transportation of perovskite films need to be optimized. Herein, C60 is employed as nucleation sites in PbI2 precursor solution to optimize the morphology of perovskite films via vapor-assisted deposition process. Accompanying the homogeneous nucleation of PbI2, the incorporation of C60 as heterogeneous nucleation sites can lower the nucleation free energy of PbI2, which facilitates the diffusion and reaction between PbI2 and organic source. Meanwhile, C60 could enhance carrier transportation and reduce charge recombination in the perovskite layer due to its high electron mobility and conductivity. In addition, the grain sizes of perovskite get larger with C60 optimizing, which can reduce the grain boundaries and voids in perovskite and prevent the corrosion because of moisture. As a result, we obtain PSCs with a power conversion efficiency (PCE) of 18.33% and excellent stability. The PCEs of unsealed devices drop less than 10% in a dehumidification cabinet after 100 days and remain at 75% of the initial PCE during exposure to ambient air (humidity > 60% RH, temperature > 30 degrees C) for 30 days. PMID- 29285923 TI - Single-Molecule Mechanochemical pH Sensing Revealing the Proximity Effect of Hydroniums Generated by an Alkaline Phosphatase. AB - Due to the fast diffusion, small molecules such as hydronium ions (H3O+) are expected to be homogeneously distributed, even close to the site-of-origin. Given the importance of H3O+ in numerous processes, it is surprising that H3O+ concentration ([H3O+]) has yet to be profiled near its generation site with nanometer resolution. Here, we innovated a single-molecule method to probe [H3O+] in nanometer proximity of individual alkaline phosphatases. We designed a mechanophore with cytosine (C)-C mismatch pairs in a DNA hairpin. Binding of H3O+ to these C-C pairs changes mechanical properties, such as stability and transition distance, of the mechanophore. These changes are recorded in optical tweezers and analyzed in a multivariate fashion to reduce the stochastic noise of individual mechanophores. With this method, we found [H3O+] increases in the nanometer vicinity of an active alkaline phosphatase, which supports that the proximity effect is the cause for increased rates in cascade enzymatic reactions. PMID- 29285924 TI - Self-Catalyzing Chemiluminescence of Luminol-Diazonium Ion and Its Application for Catalyst-Free Hydrogen Peroxide Detection and Rat Arthritis Imaging. AB - We report the unique self-catalyzing chemiluminescence (CL) of luminol-diazonium ion (N2+-luminol) and its analytical potential. Visual CL emission was initially observed when N2+-luminol was subjected to alkaline aqueous H2O2 without the aid of any catalysts. Further experimental investigations found peroxidase-like activity of N2+-luminol on the cleavage of H2O2 into OH* radical. Together with other experimental evidence, the CL mechanism is suggested as the activation of N2+-luminol and its dediazotization product 3-hydroxyl luminol by OH* radical into corresponding intermediate radicals, and then further oxidation to excited state 3-N2+-phthalic acid and 3-hydroxyphthalic acid, which finally produce 415 nm CL. The self-catalyzing CL of N2+-luminol provides us an opportunity to achieve the attractive catalyst-free CL detection of H2O2. Experiments demonstrated the 10-8 M level detection sensitivity to H2O2 as well as to glucose or uric acid if presubjected to glucose oxidase or uricase. With the exampled determination of serum glucose and uric acid, N2+-luminol shows its analytical potential for other analytes linking the production or consumption of H2O2. Under physiological condition, N2+-luminol exhibits highly selective and sensitive CL toward 1O2 among the common reactive oxygen species. This capacity supports the significant application of N2+-luminol for detecting 1O2 in live animals. By imaging the arthritis in LEW rats, N2+-luminol CL is demonstrated as a potential tool for mapping the inflammation-relevant biological events in a live body. PMID- 29285925 TI - Yeast beta-Glucan Suppresses the Chronic Inflammation and Improves the Microenvironment in Adipose Tissues of ob/ob Mice. AB - Inflammation in visceral adipose tissues (VATs) contributes to the pathology of diabetes. This study focused on the inflammatory regulation in VATs by a yeast beta-1,3-glucan (BYG) orally administered to ob/ob mice. BYG decreased pro inflammatory modulators of TNF-alpha, IL-6, IL-1beta, CCL2, and SAA3, and increased anti-inflammatory factors of Azgp1 (2.53 +/- 0.02-fold change) at protein and/or mRNA levels (p < 0.05). Remarkably, BYG decreased the degree of adipose tissue macrophages (ATMs) infiltration to 82.5 +/- 8.3%, especially the newly recruited ATMs. Interestingly, BYG increased the protective Th2 cell regulator GATA3 (7.72 +/- 0.04-fold change) and decreased immunosuppressors IL-10 and IL-1ra, suggesting that BYG elicited inflammation inhibition via stimulating immune responses. Additionally, BYG increased the gut microbiota proportion of Akkermansia from 0.07% to 4.85% and improved the microenvironment of VATs through decreasing fibrosis and angiogenesis. These findings suggest that BYG has anti inflammatory effect in diabetic mice, which can be used as a food component and/or therapeutic agent for diabetes. PMID- 29285926 TI - Synthesis of Oligosaccharide Components of the Outer Core Domain of P. aeruginosa Lipopolysaccharide Using a Multifunctional Hydroquinone-Derived Reducing-End Capping Group. AB - The synthesis of a trisaccharide (common to glycoform I and II) and a tetrasaccharide (common to glycoform I) from the outer core domain of Pseudomonas aeruginosa lipopolysaccharide (LPS) using a novel hydroquinone-based reducing-end capping group is reported. This multifunctional capping group was utilized as purification handle and was stable toward many common transformations in oligosaccharide synthesis. The access to outer-core LPS antigens with a TBDPS protected hydroquinone (TPH) at the reducing end will be useful for glycan array and therapeutic glycoconjugate synthesis. PMID- 29285927 TI - Crystalline Dipeptide Nanobelts Based on Solid-Solid Phase Transformation Self Assembly and Their Polarization Imaging of Cells. AB - Controlled phase transformation involving biomolecular organization to generate dynamic biomimetic self-assembly systems and functional materials is currently an appealing topic of research on molecular materials. Herein, we achieve by ultrasonic irradiation the direct solid-solid transition of bioinspired dipeptide organization from triclinic structured aggregates to nanofibers and eventually to monoclinic nanobelts with strong polarized luminescence. It is suggested that the locally high temperature and pressure produced by cavitation effects cleaves the hydrophobic, pi-pi stacking or self-locked intramolecular interactions involved in one phase state and then rearranges the molecular packing to form another well-ordered aromatic dipeptide crystalline structure. Such a sonication modulated solid-solid phase transition evolution is governed by distinct molecular interactions at different stages of structural organization. The resulting crystalline nanobelts are for the first time applied for polarization imaging of cells, which can be advantageous to directly inspect the uptake and fate of nanoscale delivery platforms without labeling of fluorescent dyes. This finding provides a new perspective to comprehend the dynamic evolution of biomolecular self-organization with energy supply by an external field and open up a facile and versatile approach of using anisotropic nanostructures for polarization imaging of cells and even live organisms in future. PMID- 29285928 TI - Isolation, Synthesis, and Radical-Scavenging Activity of Rhodomelin A, a Ureidobromophenol from the Marine Red Alga Rhodomela confervoides. AB - A novel ureidobromophenol, rhodomelin A (1), was characterized from Rhodomela confervoides. Its structure was elucidated by spectroscopic analysis. Both enantiomers of 1 were synthesized using a convergent strategy starting from d/l pyroglutamic acids, respectively, allowing assignment of the R-configuration for the naturally occurring isomer by chiral HPLC analysis. Rhodomelin A represents the first example of a naturally occurring ureidopyrrolidone alkaloid incorporating a gamma-aminobutyric acid unit. The scavenging activity of 1 toward DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonate)) radicals was assayed. PMID- 29285930 TI - Improving the Sensitivity of Solid-Phase Microextraction by Reducing the Volume of Off-Line Elution Solvent. AB - Solid-phase microextraction (SPME) coupled with liquid chromatograph (LC) is widely used to detect polar and ionic organic compounds, including various pharmaceuticals and endogenous bioactive compounds. In this study, a small-sized insert tube for use in the commercial autosampler vial was designed for eluting the extracted analytes from SPME fibers for LC analysis. By using this custom made insert tube as an alternative to the commercial insert tube, the volume of the elution solvent was reduced by four-fifths. Even though smaller fractions of the analytes were eluted from the fiber coatings, the analyte concentrations in the elution solutions were substantially increased by using the custom-made insert tube. Therefore, larger amounts of the analytes could be injected to LC and higher signal-to-noise ratios could be achieved, even at smaller injection volumes. Since the elution in the custom-made insert tube was nonexhaustive, four strategies were developed to figure out the extracted amounts in the fiber coatings. In combination with the sampling-rate calibration method, these strategies were successfully used to determine the concentrations of fluoxetine in living tilapias. This study provides a simple but effect way for improving the analytical sensitivity when coupling SPME with LC. PMID- 29285929 TI - Application of Electrochemical Devices to Characterize the Dynamic Actions of Helicases on DNA. AB - Much remains to be understood about the kinetics and thermodynamics of DNA helicase binding and activity. Here, we utilize probe-modified DNA monolayers on multiplexed gold electrodes as a sensitive recognition element and morphologically responsive transducer of helicase-DNA interactions. The electrochemical signals from these devices are highly sensitive to structural distortion of the DNA produced by the helicases. We used this DNA electrochemistry to distinguish the details of the DNA interactions of three distinct XPB helicases, which belong to the superfamily-2 of helicases. Clear changes in DNA melting temperature and duplex stability were observed upon helicase binding, shifts that could not be observed with conventional UV-visible absorption measurements. Binding dissociation constants were estimated in the range from 10 to 50 nM and correlated with observations of activity. ATP stimulated DNA unwinding activity was also followed, revealing exponential time scales and distinct time constants associated with conventional and molecular wrench modes of operation further confirmed by crystal structures. These devices thus provide a sensitive measure of the structural thermodynamics and kinetics of helicase-DNA interactions. PMID- 29285932 TI - Superposed Redox Chemistry of Fused Carbon Rings in Cyclooctatetraene-Based Organic Molecules for High-Voltage and High-Capacity Cathodes. AB - Even though many organic cathodes have been developed and have made a significant improvement in energy density and reversibility, some organic materials always generate relatively low voltage and limited discharge capacity because their energy storage mechanism is solely based on redox reactions of limited functional groups [N-O, C?X (X = O, N, S)] linking to aromatic rings. Here, a series of cyclooctatetraene-based (C8H8) organic molecules were demonstrated to have electrochemical activity of high-capacity and high-voltage from carbon rings by means of first-principles calculations and electronic structure analysis. Fused molecules of C8-C4-C8 (C16H12) and C8-C4-C8-C4-C8 (C24H16) contain, respectively, four and eight electron-deficient carbons, generating high-capacity by their multiple redox reactions. Our sodiation calculations predict that C16H12 and C24H16 exhibit discharge capacities of 525.3 and 357.2 mA h g-1 at the voltage change from 3.5 to 1.0 V and 3.7 to 1.3 V versus Na+/Na, respectively. Electronic structure analysis reveals that the high voltages are attributed to superposed electron stabilization mechanisms, including double-bond reformation and aromatization from carbon rings. High thermodynamic stability of these C24H16 based systems strongly suggests feasibility of experimental realization. The present work provides evidence that cyclooctatetraene-based organic molecules fused with the C4 ring are promising in designing high-capacity and high-voltage organic rechargeable cathodes. PMID- 29285931 TI - Enzymes as Immunotherapeutics. AB - Enzymes are attractive as immunotherapeutics because they can catalyze shifts in the local availability of immunostimulatory and immunosuppressive signals. Clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales. The time scale and location of biocatalysis are often dictated by the location of the substrate. For example, therapeutic enzymes that convert substrates distributed systemically are typically designed to have a long half-life in circulation, whereas enzymes that convert substrates localized to a specific tissue or cell population can be more effective when designed to accumulate at the target site. This Topical Review surveys approaches to improve enzyme immunotherapeutic efficacy via chemical modification, encapsulation, and immobilization that increases enzyme accumulation at target sites or extends enzyme half-life in circulation. Examples provided illustrate "replacement therapies" to restore deficient enzyme function, as well as "enhancement therapies" that augment native enzyme function via supraphysiologic doses. Existing FDA-approved enzyme immunotherapies are highlighted, followed by discussion of emerging experimental strategies such as those designed to enhance antitumor immunity or resolve inflammation. PMID- 29285933 TI - QM/MM and MM MD Simulations on the Pyrimidine-Specific Nucleoside Hydrolase: A Comprehensive Understanding of Enzymatic Hydrolysis of Uridine. AB - The pyrimidine-specific nucleoside hydrolase Yeik (CU-NH) from Escherichia coli cleaves the N-glycosidic bond of uridine and cytidine with a 102-104-fold faster rate than that of purine nucleoside substrates, such as inosine. Such a remarkable substrate specificity and the plausible hydrolytic mechanisms of uridine have been explored by using QM/MM and MM MD simulations. The present calculations show that the relatively stronger hydrogen-bond interactions between uridine and the active-site residues Gln227 and Tyr231 in CU-NH play an important role in enhancing the substrate binding and thus promoting the N-glycosidic bond cleavage, in comparison with inosine. The estimated energy barrier of 30 kcal/mol for the hydrolysis of inosine is much higher than 22 kcal/mol for uridine. Extensive MM MD simulations on the transportation of substrates to the active site of CU-NH indicate that the uridine binding is exothermic by ~23 kcal/mol, more remarkable than inosine (~12 kcal/mol). All of these arise from the noncovalent interactions between the substrate and the active site featured in CU NH, which account for the substrate specificity. Quite differing from other nucleoside hydrolases, here the enzymatic N-glycosidic bond cleavage of uridine is less influenced by its protonation. PMID- 29285934 TI - Synthetic Polymeric Mixed Micelles Targeting Lymph Nodes Trigger Enhanced Cellular and Humoral Immune Responses. AB - It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines because antigen presentation and initiation of T-cell-mediated immune responses occur primarily at these locations. In this study, amphiphilic diblock copolymer poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) combined with carboxylterminated-Pluronic F127 was used to construct mixed micelles [carboxylated-nanoparticles (NPs)] for codelivery of antigen ovalbumin (OVA) and Toll-like receptor-7 agonist CL264 (carboxylated-NPs/OVA/CL264) to the LN resident dendritic cells (DCs). The results showed that the small, sub-60 nm size of the self-assembled mixed micelles enables them to rapidly penetrate into lymphatic vessels and reach draining lymph nodes after subcutaneous injection. Furthermore, the surface modification with carboxylic groups imparted the carboxylated-NPs with endocytic receptor-targeting ability, allowing for DC internalization of carboxylated-NPs/OVA/CL264 via the scavenger receptor-mediated pathway. Because stimulation of CL264 in early endosomes will lead to a more effective immune response than that in late endo/lysosomes, the mass ratio of PEOz-PLA to carboxylated-Pluronic F127 in the mixed micelles was adjusted to release the encapsulated CL264 to the early endosome, resulting in increased expression of costimulatory molecules and secretion of stimulated cytokines by DCs. Moreover, the incorporation of PEOz outside the micellar shell effectively augmented MHC I antigen presentation through facilitating endosome escape and cytosolic release of antigens. This in turn evoked potent immune responses in vivo, including activation of antigen-specific T-cell responses, production of antigen-specific IgG antibodies, and generation of cytotoxic T-lymphocyte responses. Finally, immunization with the codelivery system in E.G7-OVA tumor bearing mice could not only significantly inhibit tumor growth but also markedly prolong the survival of tumor-bearing mice. Taken together, carboxylated NPs/OVA/CL264 have demonstrated great potential for clinical applications as an effective antitumor vaccine for further immunotherapy. PMID- 29285935 TI - Stability of Illicit Drugs as Biomarkers in Sewers: From Lab to Reality. AB - Systematic sampling and analysis of wastewater samples are increasingly adopted for estimating drug consumption in communities. An understanding of the in-sewer transportation and transformation of illicit drug biomarkers is critical for reducing the uncertainty of this evidence-based estimation method. In this study, biomarkers stability was investigated in lab-scale sewer reactors with typical sewer conditions. Kinetic models using the Bayesian statistics method were developed to simulate biomarkers transformation in reactors. Furthermore, a field scale study was conducted in a real pressure sewer pipe with the systematical spiking and sampling of biomarkers and flow tracers. In-sewer degradation was observed for some spiked biomarkers over typical hydraulic retention time (i.e., a few hours). Results indicated that sewer biofilms prominently influenced biomarker stability with the retention time in wastewater. The fits between the measured and the simulated biomarkers transformation demonstrated that the lab based model could be extended to estimate the changes of biomarkers in real sewers. Results also suggested that the variabilities of biotransformation and analytical accuracy are the two major contributors to the overall estimation uncertainty. Built upon many previous lab-scale studies, this study is one critical step forward in realizing wastewater-based epidemiology by extending biomarker stability investigations from laboratory reactors to real sewers. PMID- 29285936 TI - Visible-Light-Mediated Decarboxylative Alkylation Cascade Cyano Insertion/Cyclization of N-Arylacrylamides under Transition-Metal-Free Conditions. AB - The visible-light-mediated decarboxylative functionalization of aliphatic carboxylic acids using organocatalysts has rarely been reported. This study represented an environmentally benign decarboxylation method involving the combination of eosin Y and (NH4)2S2O8. This system converted aliphatic carboxylic acids to alkyl radicals, followed by their addition to the carbon-carbon double bond of the N-arylacrylamide cascade cyano insertion/cyclization to construct alkylated phenanthridines in moderate to good yields under photoredox catalysis. PMID- 29285937 TI - Organocatalytic Synthesis of 4-Aryl-1,2,3,4-tetrahydropyridines from Morita Baylis-Hillman Carbonates through a One-Pot Three-Component Cyclization. AB - An efficient DABCO-catalyzed three-component formal [3 + 2 + 1] annulation, involving a Morita-Baylis-Hillman carbonate, a 1,3-ketoester, and a primary amine, leading to one-pot synthesis of substituted 4-aryl-1,2,3,4 tetrahydropyridines, has been developed. The densely functionalized products were generally obtained in good to excellent yields under mild conditions. The structures including the relative stereoconfigurations of the representative products were confirmed by X-ray diffraction analysis. PMID- 29285939 TI - Development of a Highly Efficient Hybrid White Organic-Light-Emitting Diode with a Single Emission Layer by Solution Processing. AB - We use a mixed host, 2,6-bis[3-(carbazol-9-yl)phenyl]pyridine blended with 20 wt % tris(4-carbazoyl-9-ylphenyl)amine, to lower the hole-injection barrier, along with the bipolar and high-photoluminescence-quantum-yield (Phip= 84%), blue thermally activated delay fluorescence (TADF) material of 9,9-dimethyl-9,10 dihydroacridine-2,4,6-triphenyl-1,3,5-triazine (DMAC-TRZ) as a blue dopant to compose the emission layer for the fabrication of a TADF blue organic-light emitting diode (BOLED). The device is highly efficient with the following performance parameters: maximum brightness (Bmax) = 57586 cd/m2, maximum current efficiency (CEmax) = 35.3 cd/A, maximum power efficiency (PEmax) = 21.4 lm/W, maximum external quantum efficiency (EQEmax) = 14.1%, and CIE coordinates (0.18, 0.42). This device has the best performance recorded among the reported solution processed TADF BOLEDs and has a low efficiency roll-off: at brightness values of 1000 and 5000 cd/m2, its CEs are close, being 35.1 and 30.1 cd/A, respectively. Upon further doping of the red phosphor Ir(dpm)PQ2 (emission peak lambdamax = 595 nm) into the blue emission layer, we obtained a TADF-phosphor hybrid white organic-light-emitting diode (T-P hybrid WOLED) with high performance: Bmax = 43594 cd/m2, CEmax = 28.8 cd/A, PEmax = 18.1 lm/W, and CIE coordinates (0.38, 0.44). This Bmax = 43594 cd/m2 is better than that of the vacuum-deposited WOLED with a blue TADF emitter, 10000 cd/m2. This is also the first report on a T-P hybrid WOLED with a solution-processed emitting layer. PMID- 29285938 TI - Novel Kunitz-like Peptides Discovered in the Zoanthid Palythoa caribaeorum through Transcriptome Sequencing. AB - Palythoa caribaeorum (class Anthozoa) is a zoanthid that together jellyfishes, hydra, and sea anemones, which are venomous and predatory, belongs to the Phyllum Cnidaria. The distinguished feature in these marine animals is the cnidocytes in the body tissues, responsible for toxin production and injection that are used majorly for prey capture and defense. With exception for other anthozoans, the toxin cocktails of zoanthids have been scarcely studied and are poorly known. Here, on the basis of the analysis of P. caribaeorum transcriptome, numerous predicted venom-featured polypeptides were identified including allergens, neurotoxins, membrane-active, and Kunitz-like peptides (PcKuz). The three predicted PcKuz isotoxins (1-3) were selected for functional studies. Through computational processing comprising structural phylogenetic analysis, molecular docking, and dynamics simulation, PcKuz3 was shown to be a potential voltage gated potassium-channel inhibitor. PcKuz3 fitted well as new functional Kunitz type toxins with strong antilocomotor activity as in vivo assessed in zebrafish larvae, with weak inhibitory effect toward proteases, as evaluated in vitro. Notably, PcKuz3 can suppress, at low concentration, the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish, which indicated PcKuz3 may have a neuroprotective effect. Taken together, PcKuz3 figures as a novel neurotoxin structure, which differs from known homologous peptides expressed in sea anemone. Moreover, the novel PcKuz3 provides an insightful hint for biodrug development for prospective neurodegenerative disease treatment. PMID- 29285940 TI - [Characteristics and determinants of informal care in chronic diseases in Hungary: a comparative analysis]. AB - INTRODUCTION: Informal care plays an important role in ageing societies. AIM: To analyse informal care use and its determinants among patients with chronic diseases in Hungary. METHOD: Patient level data from previous studies in 14 diagnoses were analysed including patients' EQ-5D-3L health status. Descriptive statistics were performed and a linear regression model was built to analyse determinants of informal care time. RESULTS: 2047 patients (female: 58%) with mean age of 58.9 (SD = 16.3) years and EQ-5D-3L index score of 0.64 (SD = 0.33) were involved. 27% received informal care, the average time of care was 7.54 (SD = 26.36) hours/week. Both the rate of informal care use and its time differed significantly between the diagnoses (p<0.05), the highest were in dementia, Parkinsons' disease and in chronic inflammatory immunological diseases. Significant determinants were age, EQ-5D-3L scores, gender and certain diagnosis dummys (R2 = 0.111). CONCLUSIONS: Informal care use is significant in chronic debilitating conditions. Future studies are encouraged to reveal unmet needs, preferences and further explanatory factors. Orv Hetil. 2017; 158(52): 2068-2078. PMID- 29285941 TI - [Proposal for the modernization of cervical screening procedure in Hungary]. AB - Two main considerations played roles in creation of new cervical screening system. One was the proven fact that high-risk human papilloma virus infection plays a role in the development of cervical cancer and pre-cancerous lesions. The other was the implementation of the HPV infection's biological behavior in the new screening strategy. The new screening procedure faithfully reflects the cervical carcinogenesis. An organised, population-based and age differentiated screening method could increase attendance of screening and could decrease the possibility of interval cancer rate due to increased sensitivity. Orv Hetil. 2017; 158(52): 2062-2067. PMID- 29285942 TI - [Non-alcoholic fatty liver disease, as a component of the metabolic syndrome, and its causal correlations with other extrahepatic diseases]. AB - Non-alcoholic fatty liver disease is the most common non-infectious chronic liver disease in our age, and is a spectrum of all the diseases associated with increased fat accumulation in the hepatocytes. Its development is promoted by sedentary life-style, over-feeding, and certain genetic predisposition. Prevalence in the adult population, even in Hungary is ~30%. In a part of cases, this disease may pass into non-alcoholic steatohepatitis, later into fibrosis, rarely into primary hepatocellular cancer. Fatty liver is closely and bidirectionally related to the metabolic syndrome and type 2 diabetes, and nowadays there is a general consensus that fatty liver is the hepatic manifestation of the metabolic sycndrome. The importance of the fatty liver has been highly emphasized recently. In addition to the progression into steatohepatitis, its causal relationship with numerous extrahepatic disorders has been discovered. In our overview, we deal with the epidemiology, pathomechanism of the disease, discuss the possibilities of diagnosis, its relationship with the intestinal microbiota, its recently recognized correlations with bile acids and their receptors, and its supposed correlations with the circadian CLOCK system. Hereinafter, we overview those extrahepatic disorders, which have been shown to be causal link with the non-alcoholic fatty liver disease. Among these, we emphasize the metabolic syndrome/type 2 diabetes, cardiovascular disorders, chronic kidney disease, sleep apnea/hypoventilation syndrome, inflammatory bowel disease, Alzheimer's disease, osteoporosis, and psoriasis, as well. Based on the above, it can be stated, that high risk individuals with non-alcoholic fatty liver disease need systemic care, and require the detection of other components of this systemic pathological condition. While currently specific therapy for the disease is not yet known, life-style changes, adequate use of available medicines can prevent disease progression. Promising research is under way, including drugs, manipulation of the intestinal flora or the possibility of therapeutic use of bile acid receptors, and also bariatric surgery. Orv Hetil. 2017; 158(52): 2051-2061. PMID- 29285943 TI - [Assessment of sacroiliacal joint mobility in patients with low back pain]. AB - INTRODUCTION: Sagittal alignment of the pelvis is typically characterized using three fundamental parameters. Among these, pelvic incidence is traditionally considered to be anatomically 'constant'. AIM: We aimed to analyze the pelvic parameters of low back pain patients with suspected sacroiliac joint laxity. METHOD: Pelvic parameters were assessed in standing and seated EOS 2D/3D radiographs of 48 cases of persistent low back pain, and compared to upper body position using cluster analysis and t-test. RESULTS: Median pelvic incidence did not differ statistically between standing and sitting (47.8 degrees -47.7 degrees ). However, in individual analysis 7 cases (15%) exhibited a forward tilt in their upper body with an increased pelvic incidence, and 7 cases (15%) showed a backward upper body tilt. No change was found in 34 cases. CONCLUSION: Our results indicate the pelvis should not be regarded as a rigid unit, as in some cases significant appreciable sacroiliac joint laxity can occur. Orv Hetil. 2017; 158(52): 2079-2085. PMID- 29285944 TI - [Sandor Miksa Kocsis MD who established the first Oncology Department out of Budapest (Hungary), was born one hundred years ago]. PMID- 29285945 TI - [Dr. Tibor Vizkelety (1929-2017)]. PMID- 29285946 TI - Implementation of a metastatic malignancy of unknown primary origin service led by a palliative physician. AB - BACKGROUND: Cancer of unknown primary is the fourth most common cause of cancer death in the United Kingdom. National guidance in 2010 recommended the establishment of a dedicated unknown primary team to facilitate targeted investigation and symptom control. A service development project was undertaken to identify those affected by malignancy of unknown origin and institute a pathway for coordinating their care led by a palliative physician. METHOD: In order to describe the patient population and illness trajectory and to assess the effect of the new pathway on the clinical outcomes we used a retrospective and prospective comparative case notes survey to identify the pre- and post-pathway population. This took place in secondary care. Inclusion criteria were patients with metastatic disease with no known primary; exclusion criteria were where the site of metastasis was so suggestive of a primary that it would be managed as per that disease process. 88 patients were included. RESULTS: Mean age was 72.5 years. The mean survival time from presentation was 81.8 days. There was no difference pre or during pathway implementation in age, performance status or survival time. There was no reduction in the numbers referred for tumour directed therapy. There was a non-statistically significant reduction in the number who died in hospital during the pathway implementation. CONCLUSIONS: This study suggests having a metastatic malignancy of unknown primary origin service led by a palliative physician does not reduce the number referred for tumour directed therapy. It also adds evidence of the poor prognosis and thus the need for early palliative care input. PMID- 29285947 TI - Eslicarbazepine acetate in epilepsies with focal and secondary generalised seizures: systematic review of current evidence. AB - INTRODUCTION: Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug (AED) approved for adjunctive treatment in adults, children, and adolescents with focal-onset seizures. Recently ESL was approved for initial monotherapy in adults. The intention of this article is to review current evidence for ESL and to summarise its pharmacological profile in comparison to other AEDs of the dibenzazepine group. Areas covered: We performed a systematic literature search in electronic databases (MEDLINE database, Cochrane Central Register of Controlled Trials, Excerpta Medica dataBASE) using a combined search strategy including the following keywords: eslicarbazepine, epilepsy and seizure. The search was performed from 2000 until December 2017. Using a standardised assessment form, information on the study design, methodological framework, data sources and efficacy and adverse events attributed to ESL were extracted from each publication and systematically reported. Expert commentary: ESL is an effective, safe and well tolerated third-generation AED for the treatment of focal epilepsies. During therapy, especially serum sodium levels and possible interactions with other substances have to be monitored. As of yet, long-term experience is still needed to make severe late-occurring adverse events unlikely and to obtain data regarding its use in pregnancy. PMID- 29285950 TI - PRRT2 mutations in a cohort of Chinese families with paroxysmal kinesigenic dyskinesia and genotype-phenotype correlation reanalysis in literatures. AB - PURPOSE OF THE STUDY: Though rare, children are susceptible to paroxysmal dyskinesias such as paroxysmal kinesigenic dyskinesia, and infantile convulsions and choreoathetosis. Recent studies showed that the cause of paroxysmal kinesigenic dyskinesia or infantile convulsions and choreoathetosis could be proline-rich transmembrane protein 2 (PRRT2) gene mutations. MATERIAL AND METHODS: This study analysed PRRT2 gene mutations in 51 families with paroxysmal kinesigenic dyskinesia or infantile convulsions and choreoathetosis by direct sequencing. In particular, we characterize the genotype-phenotype correlation between age at onset and the types of PRRT2 mutations in all published cases. RESULTS: Direct sequencing showed that 12 out of the 51 families had three different pathogenic mutations (c.649dupC, c.776dupG, c.649C>T) in the PRRT2 gene. No significant difference of age at onset between the patients with and without PRRT2 mutations was found in this cohort of patients. A total of 97 different PRRT2 mutations have been reported in 87 studies till now. The PRRT2 mutation classes are wide, and most mutations are frameshift mutations but the most common mutation remains c.649dupC. Comparisons of the age at onset in paroxysmal kinesigenic dyskinesia or infantile convulsions patients with different types of mutations showed no significant difference. CONCLUSIONS: This study expands the clinical and genetic spectrums of Chinese patients with paroxysmal kinesigenic dyskinesia and infantile convulsions and choreoathetosis. No clear genotype-phenotype correlation between the age at onset and the types of mutations has been determined. PMID- 29285948 TI - Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook. AB - The concept of nanomedicine is not new. For instance, some nanocrystals and colloidal drug molecules are marketed that improve pharmacokinetic characteristics of single-agent therapeutics. For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited. Chronic diseases such as cancer and HIV/AIDS require drug combinations, not single agents, for durable therapeutic responses. Therefore, development and clinical translation of drug combination nanoformulations could play a significant role in improving human health. Successful translation of promising concepts into pre-clinical and clinical studies requires early considerations of the physical compatibility, pharmacological synergy, as well as pharmaceutical characteristics (e.g. stability, scalability and pharmacokinetics). With this approach and robust manufacturing processes in place, some drug-combination nanoparticles have progressed to non-human primate and human studies. In this article, we discuss the rationale and role of drug-combination nanoparticles, the pre-clinical and clinical research progress made to date and the key challenges for successful clinical translation. Finally, we offer insight to accelerate clinical translation through leveraging robust nanoplatform technologies to enable implementation of personalised and precision medicine. PMID- 29285949 TI - Proteomic analysis of the cardiac extracellular matrix: clinical research applications. AB - INTRODUCTION: The cardiac extracellular matrix (ECM) provides anatomical, biochemical, and physiological support to the left ventricle. ECM proteins are difficult to detect using unbiased proteomic approaches due to solubility issues and a relatively low abundance compared to cytoplasmic and mitochondrial proteins present in highly prevalent cardiomyocytes. Areas covered: Proteomic capabilities have dramatically improved over the past 20 years, due to enhanced sample preparation protocols and increased capabilities in mass spectrometry (MS), database searching, and bioinformatics analysis. This review summarizes technological advancements made in proteomic applications that make ECM proteomics highly feasible. Expert commentary: Proteomic analysis of the ECM provides an important contribution to our understanding of the molecular and cellular processes associated with cardiovascular disease. Using results generated from proteomics approaches in basic science applications and integrating proteomics templates into clinical research protocols will aid in efforts to personalize medicine. PMID- 29285952 TI - When Bailout Stenting Is the Only Option, the Difference Lies in the Details. PMID- 29285951 TI - SEIFEM 2017: from real life to an agreement on the use of granulocyte transfusions and colony-stimulating factors for prophylaxis and treatment of infectious complications in patients with hematologic malignant disorders. AB - INTRODUCTION: The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 * 108 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders. PMID- 29285954 TI - Clinical implications of myelin regeneration in the central nervous system. AB - INTRODUCTION: Amongst strategies to repair the brain, myelin repair offers genuine cause for optimism. Myelin, which sheaths most axons in the central nervous system (CNS), is vital for normal neurological function, as demonstrated by the functional deficits that accrue when it is absent in a range of debilitating myelin diseases. Following demyelination, post-mortem and imaging studies have shown that extensive regeneration of myelin is possible in the human brain. Over recent decades preclinical research has given us a strong understanding of the biology of myelin regeneration, opening up several exciting therapeutic opportunities that are on the cusp of clinical translation. Areas covered: This review discusses diseases that compromise the function of myelin, the endogenous capacity of the CNS to regenerate myelin, and why this sometimes fails. We then outline the extensive progress that has been made towards therapies that promote the regeneration of myelin. Expert commentary: Finally, a commentary on the first examples of these therapies to reach human patients and the evidence base that supports them, giving our opinion on where attention should be focused going forward is provided. PMID- 29285953 TI - Incidence, characteristics and prognosis of acute kidney injury in Cameroon: a prospective study at the Douala General Hospital. AB - OBJECTIVE: There are limited data on AKI in sub-Saharan Africa. We aim to determine the incidence, characteristics and prognosis of AKI in Cameroon. PATIENTS AND METHODS: A prospective study including all consenting acute admissions in the internal medicine and the ICU of a tertiary referral hospital in Cameroon from January 2015 to June 2016. Serum creatinine assay was done on admission, days 2 and 7 to diagnose AKI. For patients with AKI, serum creatinine was done on discharge, days 30, 60 and 90. AKI was defined according to the modified KDIGO 2012 criteria as an increase or decrease in serum creatinine of 3 mg/l or greater, or an increase of 50% or more from the reference value obtained at admission or the known baseline value. AKI severity was graded using KDIGO2012 criteria. Outcome measures were renal recovery, mortality and causes of death. Renal recovery was complete if serum creatinine between the first 90 days was less than baseline or reference, partial if less than diagnosis but not baseline or reference, no-recovery if creatinine did not decrease or if the patient remained on dialysis. RESULTS: Of the 2402 patients included, 536 developed AKI giving a global incidence of 22.3% and annual incidence of 15 per 100 patients years. Of the 536 patients with AKI, 43.3% were at stage 3, 54.7% were males, median age was 56 years. Pre-renal AKI (61.4%) and acute tubular necrosis (28.9%) were the most frequent forms. Main etiologies were sepsis (50.4%) and volume depletion (31.6%). Renal outcome was unknown in 34% of patients. Of the 354 patients with known renal function at 3 months, 84.2% recovered completely, 14.7% partially and 1.1% progressed to CKD. Global mortality rate was 36.9% mainly due to sepsis. CONCLUSIONS: AKI is frequent in our setting, mainly due to sepsis and hypovolemia. It carries a poor prognosis. PMID- 29285956 TI - Self-management programs for Aboriginal and Torres Strait Islander Peoples with chronic conditions: A rapid review. AB - Objectives Review the evidence for the effectiveness of chronic condition self management programs applied to Aboriginal and Torres Strait Islander Peoples. Methods A rapid review methodology was followed to develop an evidence summary from peer-reviewed and grey literature. Results Only seven peer-reviewed studies were identified. The evidence indicated that group programs, particularly the Stanford Program, and structured individual chronic condition self-management programs were of good quality for Aboriginal and Torres Strait Islander Peoples, although these need to be integrated into practice in order to see the greatest benefits. The Flinders Program showed promise as a standardised program with content designed specifically with and for these populations. Numerous grey literature sources were identified, many using strong participatory approaches developed locally within Aboriginal and Torres Strait Islander Peoples. However, few of these programs have been subject to rigorous evaluation. Discussion Despite the significant focus on chronic condition self-management programs to help address the burden of disease for Aboriginal and Torres Strait Islander Peoples, few studies exist that have been properly evaluated. The Closing the Gap Principles developed by the Australian Institute of Health and Welfare offer important guidance for how to proceed to maximise engagement, cultural appropriateness and ownership of program initiatives. PMID- 29285955 TI - Novel Nitinol Stent for Lesions up to 24 cm in the Superficial Femoral and Proximal Popliteal Arteries: 24-Month Results From the TIGRIS Randomized Trial. AB - PURPOSE: To evaluate the safety and effectiveness of the TIGRIS stent for lesions up to 24 cm in the superficial femoral and proximal popliteal arteries (SFA/PPA). METHODS: This prospective, multicenter, randomized study enrolled 274 subjects at 36 sites in the United States and Europe. Subjects were randomly assigned in a 3:1 ratio to treatment with the TIGRIS stent (n=197; mean age 66.7+/-9.28 years; 141 men) or LifeStent (n=70; mean age 67.9+/-8.87 years; 49 men). The primary safety endpoint was 30-day freedom from major adverse events (MAE). The primary efficacy endpoint was primary patency at 12 months. Secondary endpoints included target lesion revascularization (TLR) and stent fracture. Clinical success and quality of life were also assessed. RESULTS: Mean lesion length (107.6 vs 117.9 mm, p=0.29), procedure success (99.5% vs 97.1%, p=0.17), and freedom from MAE (99.5% vs 100%, p>0.99) were similar for the TIGRIS and control groups, respectively. Likewise, there was no difference in primary patency at 12 months (60.6% vs 63.2%, p=0.73) or 24 months (56.3% vs 50.2%, p=0.60) or in TLR at the same time points (76.6% vs 80.6%, p=0.49; 70.5% vs 67.2%, p=0.85). There were no differences in the changes in Rutherford category or the ankle/brachial index through 24 months. The rate of stent fracture was lower for TIGRIS compared with LifeStent (0% vs 32.7%, p<0.001). CONCLUSION: The TIGRIS stent and LifeStent were similarly effective for the treatment of lesions in the SFA and PPA. The high flexibility and zero fracture rate associated with the TIGRIS stent make this device favorable for use in high-flexion arteries. PMID- 29285957 TI - Human disease glycomics: technology advances enabling protein glycosylation analysis - part 1. AB - INTRODUCTION: Protein glycosylation is recognized as an important post translational modification, with specific substructures having significant effects on protein folding, conformation, distribution, stability and activity. However, due to the structural complexity of glycans, elucidating glycan structure-function relationships is demanding. The fine detail of glycan structures attached to proteins (including sequence, branching, linkage and anomericity) is still best analysed after the glycans are released from the purified or mixture of glycoproteins (glycomics). The technologies currently available for glycomics are becoming streamlined and standardized and many features of protein glycosylation can now be determined using instruments available in most protein analytical laboratories. Areas covered: This review focuses on the current glycomics technologies being commonly used for the analysis of the microheterogeneity of monosaccharide composition, sequence, branching and linkage of released N- and O-linked glycans that enable the determination of precise glycan structural determinants presented on secreted proteins and on the surface of all cells. Expert commentary: Several emerging advances in these technologies enabling glycomics analysis are discussed. The technological and bioinformatics requirements to be able to accurately assign these precise glycan features at biological levels in a disease context are assessed. PMID- 29285958 TI - Maintaining consistent quality and clinical performance of biopharmaceuticals. AB - INTRODUCTION: Biopharmaceuticals are large protein based drugs which are heterogeneous by nature due to post translational modifications resulting from cellular production, processing and storage. Changes in the abundance of different variants over time are inherent to biopharmaceuticals due to their sensitivity to subtle process differences and the necessity for regular manufacturing changes. Product variability must thus be carefully controlled to ensure that it does not result in changes in safety or efficacy. Areas covered: The focus of this manuscript is to provide improved understanding of the science and strategies used to maintain the quality and clinical performance of biopharmaceuticals, including biosimilars, throughout their lifecycle. This review summarizes rare historical instances where clinically relevant changes have occurred, defined here as clinical drift, and discusses modern tools used to prevent such changes, including improved analytics, quality systems and regulatory frameworks. Expert opinion: Despite their size complexity and heterogeneity, modern analytics, manufacturing quality systems and comparability requirements for the evaluation of manufacturing changes cumulatively help to ensure the consistent quality and clinical performance of biopharmaceuticals throughout their product lifecycle. Physicians and patients can expect the same safety and efficacy from biopharmaceuticals and their respective biosimilars irrespective of batch or production history. PMID- 29285959 TI - Kyrle's disease effectively treated with oral isotretinoin. AB - BACKGROUND: Kyrle's disease (KD) is a primary perforating dermatosis that affects more commonly 30-50 year old females, and clinically characterized by pruritic hyperkeratotic and ulcerated nodules, papules and plaques, localized on extensor surface of upper and lower limbs, and on the trunk. OBJECTIVE: To determine the effectiveness of the treatment with oral isotretinoin in KD. METHODS: We present the case of a 63-year-old woman with hyperkeratotic, erythematous-brown nodules and plaques localized on arms and legs, intensely itching; some lesions were ulcerated and discharging. Histology showed hyperplastic epidermis, cup-shaped invagination, degenerative basophilic material with plug formation. In the upper dermis, there was a dense lympho-histiocytic infiltrate. Narrow-band UVB and low dose oral corticosteroids were ineffective. Treatment with isotretinoin 20 mg/day was started with an excellent response in two months, and complete remission in the next four months. Isotretinoin was reduced to 10 mg/day for additional four months. In the next 9-month follow up, no recurrence of the disease was observed. CONCLUSIONS: Low-dose isotretinoin was very effective and well tolerated in our patient. One previous case treated with isotretinoin has been published. PMID- 29285960 TI - Targeting oxidative stress through antioxidants in diabetes mellitus. AB - The myriad of complications associated with diabetes is closely linked with the generation of reactive species or free radicals leading to oxidative and nitrosative stress. Increased oxidative stress is an important cause and result of diabetes and it is thought to underlie the cellular changes that lead to diabetic complications. The whole cause and effect form a vicious circle, underlying many layers of potential therapeutics in its research. In this regards, this review outlines the briefs about the correlation of type 2 diabetes and oxidative (or nitrosative) stress and also compiles the potentiality of various antioxidants that are being or can be used for alleviating the oxidative stress. Since the complications are like a knit matrix of numerous deteriorating mechanisms, a single antioxidant therapeutic approach cannot be an answer. Therefore, it is important to develop new fixed-dose combinations of effective antioxidants that target key reactive oxygen (or nitrogen)-producing sources, mimic endogenous antioxidants and scavenge the reactive species generated balancing the pro and antioxidant cycle. This review focuses on the preclinical and clinical trial data with therapeutic antioxidants in type 2 diabetes along with a brief focus on success and failures of antioxidant-based therapy. PMID- 29285961 TI - Immunogenicity and safety of WHO-approved TRC-ID regimen with a chromatographically purified Vero cell rabies vaccine with or without rabies immunoglobulin in children. AB - INTRODUCTION: Children are at risk of rabies exposure in many Asian countries. The safety and immunogenicity profile of the WHO-approved two-site intradermal Thai Red Cross regimen (modified TRC-ID regimen; 2-2-2-0-2) with a new chromatographically purified Vero-cell rabies vaccine (CPRV) is lacking. Area covered: We studied the safety and immunogenicity of the TRC-ID regimen with a new CPRV in non-immunized Thai children with possible or proven rabies exposure. Thirty-nine seronegative patients (age range 2-14 years) with rabies exposure (WHO categories II or III) received two 0.1-mL intradermal doses of CPRV at both deltoid regions on days 0, 3, 7, and 28. Twenty-five patients (64.1%) received rabies immunoglobulin due to having rabies exposure, according to WHO category III. All serum samples were tested for rabies neutralizing antibody (Nab) by the rapid fluorescent focus inhibition test (RFFIT) before vaccination, and on days 14 and 90 after vaccination. All patients had an adequate immune response (Nab titers >= 0.5 IU/mL) on days 14 and 90. No patients died of rabies infection. No serious adverse reactions were observed. Expert commentary: CPRV is economic, safe, and immunogenic if given as the modified TRC-ID regimen in children. PMID- 29285963 TI - Femoropopliteal In-Stent Restenosis: Gaining Ground With Excimer Laser and Drug Coated Balloons. PMID- 29285962 TI - Cellular and molecular mechanisms driving neuropathic pain: recent advancements and challenges. AB - INTRODUCTION: Current pharmacotherapeutics for neuropathic pain offer only symptomatic relief without treating the underlying pathophysiology. Additionally, they are associated with various dose-limiting side effects. Pain research in the past few decades has revolved around the role of oxidative-nitrosative stress, protein kinases, glial cell activation, and inflammatory signaling cascades but has failed to produce specific and effective therapies. Areas covered: This review focuses on recent advances in cellular and molecular mechanisms of neuropathic pain that may be translated into future therapies. We discuss emerging targets such as WNT signaling mechanisms, the tetrahydrobiopterin pathway, Mrg receptors, endogenous lipid mediators, micro-RNAs and their roles in pain regulation. Recent evidence is also presented regarding genetic and epigenetic mechanisms of pain modulation. Expert opinion: During chronic neuropathic pain, maladaptation occurs in the peripheral and central nervous systems, including a shift in microglial phenotype from a surveillance state to an activated state. Microglial activation leads to an altered expression of cell surface proteins, growth factors, and intracellular signaling molecules that contribute to development of a neuroinflammatory cascade and chronic pain sensitization. Specific targeting of these cellular and molecular mechanisms may provide the key to development of effective neuropathic pain therapies that have minimal side effects. PMID- 29285965 TI - Admixture and Ancestry Inference from Ancient and Modern Samples through Measures of Population Genetic Drift. AB - Methods that leverage the information about population history contained within the increasingly abundant genetic sequences of extant and extinct hominid populations are diverse in form and versatile in application. Here, we review key methods recently developed to detect and quantify admixture and ancestry in modern human populations. We begin with an overview of the f- and D-statistics, covering their conceptual principles and important applications, as well as any extensions developed for them. We then cover a combination of more recent and more complex methods for admixture and ancestry inference, discussing tests for direct ancestry between two populations, quantification of admixture in large data sets, and determination of admixture dates. These methods have revolutionized our understanding of human population history and highlight its complexity. Therefore, we emphasize that current methods may not capture this population history in its entirety but nonetheless provide a reasonable picture that is supported by data from multiple methods and from the historical record. PMID- 29285966 TI - Infectious Disease and the Diversification of the Human Genome. AB - The human immune system is under great pathogen-mediated selective pressure. Divergent infectious disease pathogenesis across human populations combined with the overrepresentation of "immune genes" in genomic regions with signatures of positive selection suggests that pathogens have significantly altered the human genome. However, important features of the human immune system can confound searches for and interpretations of signatures of pathogen-mediated evolution. Immune system redundancy, immune gene pleiotropy, host ability to acquire immunity and alter the immune repertoire of offspring through "priming," and host microbiome complicate evolutionary interpretations of host-pathogen interactions. The overall promiscuity and sensitivity of the immune system to local environments can also muddy assumptions about the origins of a selective pressure on a given set of genes. This review addresses (a) how features of the immune system, the primary buffer between a pathogen and the human genome, affect evolutionary signal and (b) the considerations that must be made when assessing how pathogens have contributed to human diversification. PMID- 29285964 TI - The assessment of P-wave dispersion and myocardial repolarization parameters in patients with chronic kidney disease. AB - OBJECTIVE: The risks of sudden death and cardiac arrhythmia are increased in patients with chronic kidney disease (CKD). Here, we aimed to evaluate the indicators of arrhythmias, such as p-wave dispersion (P-WD), QTc dispersion, Tp-e and Tp-e/QT ratio in patients with CKD stages 3-5 on no renal replacement therapy (RRT). MATERIAL AND METHODS: One-hundred and thirty three patients with CKD stages 3-5 and 32 healthy controls were enrolled into the study. No patients received RRT. QTc dispersion, P-WD and Tp-e interval were measured using electrocardiogram and Tp-e/QT ratio was also calculated. RESULTS: Mean age rates were found similar in patients and controls (60.8 +/- 14.2 and 61 +/- 12.9 y, p = .937, respectively). Compared patients with controls, P-WD (45.85 +/- 12.42 vs. 21.17 +/- 6.6 msec, p < .001), QTc-min (366.99 +/- 42.31 vs. 387.15 +/- 20.5 msec, p < .001), QTc dispersion (71.13 +/- 27.95 vs. 41.25 +/- 14.55 msec, p < .001), Tp-e maximum (81.04 +/- 10.34 vs. 75.49 +/- 10.9 msec, p < .001), Tp-e minimum (62.25 +/- 7.58 vs. 54.8 +/- 6.72 msec, p < .001) and Tp-e/QTc ratio (0.19 +/- 0.02 vs. 0.18 +/- 0.01, p = .001) were found to be different. QTc-max and Tp-e interval were found to be similar in both groups. CONCLUSION: P-WD and QTc dispersion, Tp-e interval and Tp-e/QTc ratio were found to be increased in with CKD stages 3-5 on no RRT. PMID- 29285967 TI - The Genomic Health of Ancient Hominins. AB - The genomes of ancient humans, Neandertals, and Denisovans contain many alleles that influence disease risks. Using genotypes at 3,180 disease-associated loci, we estimated the disease burden of 147 ancient genomes. After correcting for missing data, genetic risk scores (GRS) were generated for nine disease categories and the set of all combined diseases. We used these genetic risk scores to examine the effects of different types of subsistence, geography, and sample age on the number of risk alleles in each ancient genome. On a broad scale, hereditary disease risks are similar for ancient hominins and modern-day humans, and the GRS percentiles of ancient individuals span the full range of what is observed in present-day individuals. In addition, there is evidence that ancient pastoralists may have had healthier genomes than hunter-gatherers and agriculturalists. We also observed a temporal trend whereby genomes from the recent past are more likely to be healthier than genomes from the deep past. This calls into question the idea that modern lifestyles have caused genetic load to increase over time. Focusing on individual genomes, we found that the overall genomic health of the Altai Neandertal is worse than 97% of present-day humans and that Otzi, the Tyrolean Iceman, had a genetic predisposition for gastrointestinal and cardiovascular diseases. As demonstrated by this work, ancient genomes afford us new opportunities to diagnose past human health, which has previously been limited by the quality and completeness of remains. PMID- 29285968 TI - Evolution, Function, and Deconstructing Histories: A New Generation of Anthropological Genetics. PMID- 29285969 TI - Minutes of the Business Meeting of the American Association of Anthropological Genetics. PMID- 29285970 TI - Introgression Makes Waves in Inferred Histories of Effective Population Size. AB - Human populations have a complex history of introgression and of changing population size. Human genetic variation has been affected by both these processes, so inference of past population size depends upon the pattern of gene flow and introgression among past populations. One remarkable aspect of human population history as inferred from genetics is a consistent "wave" of larger effective population sizes, found in both African and non-African populations, that appears to reflect events prior to the last 100,000 years. I carried out a series of simulations to investigate how introgression and gene flow from genetically divergent ancestral populations affect the inference of ancestral effective population size. Both introgression and gene flow from an extinct, genetically divergent population consistently produce a wave in the history of inferred effective population size. The time and amplitude of the wave reflect the time of origin of the genetically divergent ancestral populations and the strength of introgression or gene flow. These results demonstrate that even small fractions of introgression or gene flow from ancient populations may have visible effects on the inference of effective population size. PMID- 29285971 TI - Leveraging Multiple Populations across Time Helps Define Accurate Models of Human Evolution: A Reanalysis of the Lactase Persistence Adaptation. AB - Access to a geographically diverse set of modern human samples from the present time and from ancient remains, combined with archaic hominin samples, provides an unprecedented level of resolution to study both human history and adaptation. The amount and quality of ancient human data continue to improve and enable tracking the trajectory of genetic variation over time. These data have the potential to help us redefine or generate new hypotheses of how human evolution occurred and to revise previous conjectures. In this article, we argue that leveraging all these data will help us better detail adaptive histories in humans. As a case in point, we focus on one of the most celebrated examples of human adaptation: the evolution of lactase persistence. We briefly review this dietary adaptation and argue that, effectively, the evolutionary history of lactase persistence is still not fully resolved. We propose that, by leveraging data from multiple populations across time and space, we will find evidence of a more nuanced history than just a simple selective sweep. We support our hypotheses with simulation results and make some cautionary notes regarding the use of haplotype-based summary statistics to estimate evolutionary parameters. PMID- 29285975 TI - The Significance of a Fast-Track EVAR Procedure: It's Not the Years in Your Life That Count, It's the Life in Your Years. PMID- 29285972 TI - Incidence, patterns and risk factors for injuries among Ugandan children. AB - There is limited epidemiological data on childhood injuries in developing countries. This study assessed the incidence, patterns and risk factors for injuries among children aged 0-5 years in Wakiso District, Uganda. To determine differences, chi-square and Wilcoxon rank sum tests were used. Risk factors were assessed using Poisson regression. Overall, information from 359 children of mean age 32 months (SD: 18.4) was collected. Annual incidence of injuries was 69.8 per 1000 children/year (95% CI 58.8-80.8). One fatal injury due to burns was reported. Incidence of injuries was less associated with being female (IRR: 0.56, 95% CI 0.34-0.90) and increasing age of the caretaker (IRR: 0.96, 95% CI 0.92 0.99). The high incidence of childhood injuries necessitates the need for interventions to reduce injuries among children. PMID- 29285976 TI - Partial Recovery of Proprioception in Rats with Dorsal Root Injury after Human Olfactory Bulb Cell Transplantation. AB - Transplanted human olfactory ensheathing cells (hOECs) were mixed with collagen into a unilateral transection of four dorsal roots (C6-T1) in a rat model. By mixing with collagen, the limited numbers of hOEC were maximized from an olfactory bulb biopsy and optimize cavity filling. Cyclosporine was administered daily to prevent immune rejection. Forelimb proprioception was assessed weekly in a vertical climb task. Half of the rats receiving hOEC transplants showed some functional improvement ("responders") over six weeks of the study while the other half did not ("nonresponders") and performed similarly to "injured only" rats. Transplanted cells were seen at both one week and six weeks after the surgical procedure; many were concentrated within the lesion cavity, but others were found with elongated processes in the overlying connective tissue. There were some fibers in the injury area associated with transplanted cells that were immunostained for neurofilament and TUJ1. Responder and nonresponder rats were compared with regard to microglial activation within the deep dorsal horn of cervical levels C7, C8 and also axon loss within the cuneate fasciculus at cervical level C3. Little difference was seen in microglial activation or axonal loss that could account for the improved proprioception in the responders group. This preliminary study is the first to transplant human olfactory bulb cells into a rat model of dorsal root injury; by refining each component part of the procedure, the repair potential of OECs can be maximized in a clinical setting. PMID- 29285978 TI - ONC201 shows promise in AML treatment. PMID- 29285977 TI - A Practitioner's Guide to End-of-Life Intimacy: Suggestions for Conceptualization and Intervention in Palliative Care. AB - Sexuality and intimacy, including contact, tenderness, and love, are important at every life stage. Intimate expression is especially vital at the end of life, when relationships with loved ones are time limited. Unfortunately, care providers often ignore the potential need for sexual expression, especially at the end of life. In this article, we consider current research on sexuality and end-of-life care and situate these two fields in an ecological framework. We explore how end-of-life sexuality and intimacy can be supported by practitioners in multiple nested contexts and provide suggestions for theoretically-driven interventions. We also provide reflexive considerations for practitioners. PMID- 29285980 TI - Xenon Protects against Blast-Induced Traumatic Brain Injury in an In Vitro Model. AB - The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for patients with blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (p < 0.01) injury that increased with peak-overpressure and impulse of the shockwave, and which exhibited a secondary injury development up to 72 h after trauma. Blast-induced propidium iodide fluorescence overlapped with cleaved caspase-3 immunofluorescence, indicating that shock-wave-induced cell death involves apoptosis. Xenon (50% atm) applied 1 h after blast exposure reduced injury 24 h (p < 0.01), 48 h (p < 0.05), and 72 h (p < 0.001) later, compared with untreated control injury. Xenon-treated injured slices were not significantly different from uninjured sham slices at 24 h and 72 h. We demonstrate for the first time that xenon treatment after blast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for those with blast induced traumatic brain injury. PMID- 29285981 TI - Keeping care connected: e-Consultation program improves access to nephrology care. AB - Introduction Health systems are seeking innovative solutions to improve specialty care access. Electronic consultations (eConsults) allow specialists to provide formal clinical recommendations to primary care providers (PCPs) based on patient chart review, without a face-to-face visit. Methods We implemented a nephrology eConsult pilot program within a large, academic primary care practice to facilitate timely communication between nephrologists and PCPs. We used primary care referral data to compare wait times and completion rates between traditional referrals and eConsults. We surveyed PCPs to assess satisfaction with the program. Results For traditional nephrology referrals placed during the study period (July 2016-March 2017), there was a 51-day median appointment wait time and a 40.9% referral completion rate. For eConsults, there was a median nephrologist response time of one day and a 100% completion rate; 67.5% of eConsults did not require a subsequent face-to-face specialty appointment. For eConsults that were converted to an in-person visit, the median wait time and completion rate were 40 days and 73.1%, respectively. Compared to traditional referrals placed during the study period, eConsults converted to in-person visits were more likely to be completed ( p = 0.001). Survey responses revealed that PCPs were highly satisfied with the program and consider the quick turnaround time as the greatest benefit. Discussion Our eConsult pilot program reduced nephrology wait times and significantly increased referral completion rates. In large integrated health systems, eConsults have considerable potential to improve access to specialty care, reduce unnecessary appointments, and optimize the patient population being seen by specialists. PMID- 29285982 TI - Effects of veliparib on microglial activation and functional outcomes following traumatic brain injury in the rat and pig. AB - The inflammation response induced by brain trauma can impair recovery. This response requires several hours to fully develop, and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. Here we evaluated delayed treatment with veliparib, a poly(ADP ribose) polymerase inhibitor currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI). In rats, CCI induced a robust inflammatory response at the lesion margins, scattered cell death in the dentate gyrus, and a delayed, progressive loss of corpus callosum axons. Pre-determined measures of cognitive and motor function showed evidence of attentional deficits that resolved after 3 weeks, and motor deficits that only partially recovered over 8 weeks. Veliparib was administered beginning 2 or 24 hours after CCI and continued for up to 12 days. Veliparib suppressed CCI induced microglial activation at doses of 3 mg/kg or higher and reduced reactive astrocytosis and cell death in the dentate gyrus, but had no significant effect on delayed axonal loss or functional recovery. In pigs, CCI similarly induced a peri-lesional microglial activation that was attenuated by veliparib. CCI in the pig did not, however, induce detectable persisting cognitive or motor impairment. Our results showed veliparib suppression of CCI-induced microglial activation with a delay-to-treatment interval of at least 24 hours in both rats and pigs, but with no associated functional improvement. The lack of improvement in long term recovery underscores the complexities in translating anti-inflammatory effects to clinically relevant outcomes. PMID- 29285984 TI - Tetrandrine enhances radiosensitivity through the CDC25C/CDK1/cyclin B1 pathway in nasopharyngeal carcinoma cells. AB - The increasing resistance of nasopharyngeal carcinoma to irradiation makes the exploration of effective radiosensitizers necessary. Tetrandrine is known to be an antitumor drug, but little is known regarding its radiosensitization effect on nasopharyngeal carcinoma. We investigated the effect of combined treatment of irradiation and maximum non-cytotoxic doses of tetrandrine on the nasopharyngeal carcinoma cell lines CNE1 and CNE2. The maximum non-cytotoxic doses of tetrandrine in CNE1 and CNE2 cells were assessed using the MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The radiosensitization of cells receiving the maximum non-cytotoxic doses of tetrandrine was assessed by evaluating cell proliferation and DNA damage repair using MTT, clonogenic, comet assays and detection of caspase-3 and phosphorylated histone H2AX (gamma-H2AX). The cell cycle was assessed by flow cytometry, and protein expression was detected by western blot analysis. The maximum non cytotoxic doses of tetrandrine in CNE1 and CNE2 cells were 1.5 MUmol/L and 1.8 MUmol/L, respectively. When cells were exposed to irradiation and the maximum non cytotoxic doses of tetrandrine, the survival fraction was decreased. DNA damage and gamma-H2AX levels markedly increased. Moreover, tetrandrine abrogated the G2/M phase arrest caused by irradiation. Combined treatment with the maximum non cytotoxic dose of tetrandrine and irradiation caused suppression of the phosphorylation of CDK1 and CDC25C and increase in the expression of cyclin B1. The study in vivo also showed that the maximum non-cytotoxic dose of tetrandrine could reduce tumor growth in xenograft tumor model. Our results suggest that the maximum non-cytotoxic dose of tetrandrine can enhance the radiosensitivity of CNE1 and CNE2 cells and that the underlying mechanism could be associated with abrogation of radiation-induced G2/M arrest via activation of the CDC25C/CDK1/Cyclin B1 pathway. PMID- 29285986 TI - Monoclonal antibody-based enzyme immunoassay for detection of porcine plasma in fish surimi. AB - Detection of porcine plasma using indirect ELISA was developed using mAb B4E1 for the prevention of their usage in human food that creates religious and health conflicts. The immunoassay has a CV < 20% and did not cross-react to other meat and non-meat proteins. The sensitivity of the assay is 0.25% (w/w) of porcine plasma in spiked raw and cooked fish surimi. The assay did not produce a false positive result for any of the commercial fish surimi tested that were not contain porcine plasma. Determination of a 60-kDa antigenic protein of porcine blood using Western blot confirmed its presence in the plasma fraction of the porcine blood. Further proteomic analysis involving liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the 60-kDa protein to be porcine serum albumin. PMID- 29285987 TI - Anticancer efficacy of tannic acid is dependent on the stiffness of the underlying matrix. AB - Tannic acid (TA) has been previously shown to have anticancer potential for breast cancer but its effects on melanoma have not yet been investigated. Similarly, stiffness of the tumor microenvironment is known to have a profound effect on breast cancer metastasis, but little is known about its role on melanoma. The goal of the current study is to investigate the synergistic effects of TA and matrix stiffness on melanoma progression. A375 melanoma cells with metastatic potential were cultured on TA crosslinked uncompacted (UC; soft) and electrochemically compacted (ECC; stiff) collagen gels and the effects of TA on gel morphology, mechanical properties, and cellular response (i.e. morphology and proliferation) were evaluated. SEM results showed that TA crosslinking induced merging of collagen fibrils that resulted in decrease in pore size of both UC and ECC collagen gels. Tensile testing showed that TA crosslinking significantly (p < 0.05) improved the mechanical properties of ECC collagen gels. Results from Alamar blue assay showed that TA preferentially inhibited the proliferation of A375 melanoma cells compared to the non-cancerous NIH 3T3 fibroblasts on UC collagen gels. However, on ECC collagen gels, preferential effect of TA was not prevalent as proliferation of both cell types was inhibited to a similar extent. When comparing the two gel types, inhibition of A375 melanoma cell proliferation was more pronounced on TA crosslinked UC collagen gels compared to TA crosslinked ECC collagen gels. Overall, these results suggest that TA incorporated into UC collagen gels may more selectively inhibit the proliferation of melanoma cells, and that matrix stiffness is an important driver of tumor proliferation and progression. PMID- 29285985 TI - Discontinuous transcription. AB - Numerous studies based on new single-cell and single-gene techniques show that individual genes can be transcribed in short bursts or pulses accompanied by changes in pulsing frequencies. Since so many examples of such discontinuous or fluctuating transcription have been found from prokaryotes to mammals, it now seems to be a common mode of gene expression. In this review we discuss the occurrence of the transcriptional fluctuations, the techniques used for their detection, their putative causes, kinetic characteristics, and probable physiological significance. PMID- 29285988 TI - Characterization and Differentiation of Sorted Human Fetal Pancreatic ALDHhi and ALDHhi/CD133+ Cells Toward Insulin-Expressing Cells. AB - The enzyme aldehyde dehydrogenase (ALDH) is found in developing and multipotent cell populations, and is important for the production and regulation of retinoic acid, which controls beta-cell differentiation in the pancreas. The role of ALDH expressing cells in the formation of endocrine-like cells and co-localization with the putative stem cell marker CD133 has not been examined during human pancreatic development. This study focuses on the co-expression of CD133 on ALDH+ cells from the human fetal pancreas (18-22 weeks of fetal age) with transcription factors (TFs) central to endocrine cell development. Fluorescence-activated cell sorting demonstrated that cells with high ALDH activity (ALDHhi) had increased co expression of CD133 and endocrine-lineage TFs when compared with cells with low ALDH (ALDHlo) expression. Hormone-expressing (insulin, somatostatin) and ductal cells (CK19) were noted in the ALDHhi population, while mesenchymal (vimentin) and endothelial (CD31) markers were predominantly found in ALDHlo cells. Culture of sorted ALDHhi or ALDHhi/CD133+ cells resulted in loss of endocrine TF, insulin, and CK19 expression. The formation of cell clusters from cultured ALDHhi or ALDHhi/CD133+ cells led to restored CK19 expression and showed endocrine TFs and insulin expression. In summary, pancreatic ALDHhi cells contain a heterogeneous CD133-enriched population with a subset of beta-cell associated markers in the developing human pancreas. PMID- 29285989 TI - Synthesis and functionalization of chitosan built hydrogel with induced hydrophilicity for extended release of sparingly soluble drugs. AB - Addressing the functional biomaterials as next-generation therapeutics, chitosan and alginic acid were copolymerized in the form of chemically crosslinked interpenetrating networks (IPNs). The native hydrogel was functionalized via carbodiimide (EDC), catalyzed coupling of soft ligand (1,2-Ethylenediamine) and hard ligand (4-aminophenol) to replace -OH groups in alginic acid units for extended hydrogel- interfaces with the aqueous and sparingly soluble drug solutions. The chemical structure, Lower solution critical temperature (LCST ~ 37.88 degrees C), particle size (Zh,app ~ 150-200 nm), grain size (160-360 nm), surface roughness (85-250 nm), conductivity (37-74 mv) and zeta potential (16-32 mv) of native and functionalized hydrogel were investigated by using FT-IR, solid state-13C-NMR, TGA, DSC, FESEM, AFM and dynamic light scattering (DLS) measurements. The effective swelling, drug loading (47-78%) and drug release (53 86%) profiles were adjusted based on selective functionalization of hydrophobic IPNs due to electrostatic complexation and extended interactions of hydrophilic ligands with the aqueous and drug solutions. Drug release from the hydrogel matrices with diffusion coefficient n ~ 0.7 was established by Non- Fickian diffusion mechanism. In vitro degradation trials of the hydrogel with a 20% loss of wet mass in simulated gastric fluid (SGF) and 38% loss of wet mass in simulated intestinal fluid (SIF), were investigated for 400 h through bulk erosion. Consequently, a slower rate of drug loading and release was observed for native hydrogel, due to stronger H-bonding, interlocking and entanglement within the IPNs, which was finely tuned and extended by the induced hydrophilic and functional ligands. In the light of induced hydrophilicity, such functional hydrogel could be highly attractive for extended release of sparingly soluble drugs. PMID- 29285990 TI - Application of Fenton process to remove organic matter and PCBs from waste (fuller's earth) contaminated with insulating oil. AB - Polychlorinated biphenyls (PCBs) are carcinogenic to humans and can be found in fuller's earth used for the treatment of used transformer oil. This work describes an optimization of the Fenton process for the removal of contaminants from fuller's earth. The effects of pH (2.5 and 4.0), [H2O2] (1.47 and 2.07 mol L 1), and [Fe2+] (1.7 and 40 mmol L-1) were studied. The Fenton process efficiency was monitored using the decreases in the chemical oxygen demand (COD) and the concentrations of oil and grease, total carbon (TC), PCBs, and H2O2. The fuller's earth contaminated with insulating oil presented 35% (w/w) of TC, 34% (w/w) of oil and grease, 297.0 g L-1 COD, and 64 mg of PCBs per kg. The material could therefore be considered a dangerous waste. After Fenton treatment, using a slurry mode, there was a removal of 55% of COD, 20% of oil and grease, and 20% of TC, achieved at pH 2.5 using 2.07 mol L-1 of H2O2 and 40.0 mmol L-1 of Fe2+. No PCBs were detected in the samples after the Fenton treatment, even using smaller amounts of Fenton reagents (1.47 mol L-1 of H2O2, 1.7 mmol L-1 of Fe2+, pH 2.5). The results indicated that the treated fuller's earth was free from PCB residues and could be disposed of in a simple landfill, in accordance with Brazilian PCB regulations. PMID- 29285991 TI - Evaluating the antioxidant effects of human hair protein extracts. AB - The intrinsically high cysteine content in human hair keratins and keratin associated proteins confer hair its outstanding mechanical strength through the formation of strong intermolecular disulfide bonds. In addition, these proteins offer the potential to be exploited as potent antioxidants. This report presents our findings on the antioxidant effects of human hair protein extracts and their consequent protective role against oxidative stress in human dermal fibroblast (HDF) cultures. Protein extracts were obtained from human hair using sodium sulfide as the reducing agent, and characterized using SDS-PAGE, Western blotting, MALDI-ToF mass spectrometry and amino acid analysis. Cysteine was found to account for 11.2 mol % in the extracted fractions. By measuring 2,2-diphenyl-1 picryl-hydrazyl-hydrate (DPPH) radical scavenging activity, the hair protein fractions were shown to possess significant antioxidant ability (IC50 = 16.22 MUM). As a supplement in cell culture media, the extracts protected HDFs from H2O2 induced oxidative stress, which was demonstrated by the maintenance of cell viability and reduced reactive oxygen species production. Besides offering mechanical support as a scaffolding material, the unique antioxidizing ability of human hair protein extracts may also be exploited in biomedical applications. PMID- 29285992 TI - Family cumulative risk and at-risk kindergarteners' social competence: the mediating role of parent representations of the attachment relationship. AB - Secure attachment relationships have been linked to social competence in at-risk children. In the current study, we examined the role of parent secure base scripts in predicting at-risk kindergarteners' social competence. Parent representations of secure attachment were hypothesized to mediate the relationship between lower family cumulative risk and children's social competence. Participants included 106 kindergarteners and their primary caregivers recruited from three urban charter schools serving low-income families as a part of a longitudinal study. Lower levels of cumulative risk predicted greater secure attachment representations in parents, and scores on the secure base script assessment predicted children's social competence. An indirect relationship between lower cumulative risk and kindergarteners' social competence via parent secure base script scores was also supported. Parent script-based representations of the attachment relationship appear to be an important link between lower levels of cumulative risk and low-income kindergarteners' social competence. Implications of these findings for future interventions are discussed. PMID- 29285993 TI - Figure-Ground Processing: A Reassessment of Gelb and Granit. AB - In 1923, Adhemar Gelb and Ragnar Granit, two prominent researchers in early Gestalt perceptual theory, reported a lower threshold for detection of a target (a small colored dot) on the ground region of an image than on an adjacent figural region. Although their results had a wide influence on the understanding of figure-ground perception, they are at odds with more recent investigations in which figural regions appear to have a processing advantage over ground regions. The two present studies replicated Gelb and Granit's experiment using a similar figure-ground stimulus albeit with a two-alternative forced choice procedure rather than their original method of adjustment. Experiment 1 found that, contrary to Gelb and Granit's findings, a detection advantage was found for the figural over the ground region. Experiment 2 indicated that explicit contours might have played a role in detection. PMID- 29285994 TI - A biomechanical comparison of countermovement performance after short-term traditional and daily-undulated loaded vertical jump training. AB - In order to assess lower extremity muscle mechanical properties in athletes, power-load characteristics during multi-joint tasks are frequently examined. This work compared 6 weeks of traditional (TP) and daily-undulated (DUP) periodized loaded countermovement jumping (CMJ). 20 amateur athletes (age: 24.2 +/- 2.6 years, height: 175.6 +/- 7.1 cm, body mass: 71.5 +/- 7.7 kg, 10 males/10 females) exercised three times weekly using maximal CMJs with loads corresponding to 0%, 15% and 30% of body mass. Prior to the training period, subjects were once-only assigned by random to either the TP or DUP training scheme. Pre-to-post training, maximal center of mass (COM) -height, -take-off velocity, -power output and impulse were compared during CMJ with additional loads corresponding to 0-30% of body mass. ANOVA (time * group) with repeated measures revealed significant (P < 0.05) temporal gains of maximal COM-height (2-11%), -take-off velocity (1-7%), power (2-8%) and -impulse (3-9%) over most loading conditions for TP and DUP. However, ANOVA indicated no group effects for any outcome. Independent from the periodization model, maximal power output remained statistically unchanged with increased testing loads. For short-term conditioning periods, TP and DUP were equally effective in enhancing biomechanical jumping variables under varying loading conditions. PMID- 29285995 TI - The challenges of treating aspergillus abdominal aneurysm after hematopoietic cell transplant: Rapid voriconazole metabolizer. AB - Mycotic aneurysms are a fatal manifestation of disseminated fungal infections in immunocompromised hosts. We present a patient with an Aspergillus mycotic aneurysm after hematopoietic cell transplant. Due to CYP2C19 rapid metabolizer phenotype (*1/*17), therapeutic levels of voriconazole were unobtainable. Successful therapy was achieved with posaconazole salvage therapy and early, aggressive surgery. This case demonstrates the consequences of voriconazole rapid metabolism and the potential impact of genetic variants. PMID- 29285996 TI - Scope of practice and supervision of orthodontic therapists in the United Kingdom: Part 2: a national cross-sectional survey of orthodontic therapists. AB - BACKGROUND: Orthodontic therapists (OTs) are the most recent addition to the orthodontic clinical team. The General Dental Council (GDC) and the British Orthodontic Society have formulated guidance and guidelines relating to their scope of practice and level of supervision, however there has been no contemporary UK-based research investigating practice and supervision of OTs. The aim of this study was to investigate the scope of practice and level of supervision of OTs working in the UK. METHOD: Ethical approval was received from the University of Manchester Research Ethics Committee. An anonymous postal questionnaire was dispatched using postal details acquired through the British Orthodontic Societies mailing list. Three mailings of the questionnaire were conducted. RESULTS: A 74% response rate was achieved. OTs routinely conducted 16 of the 20 procedures from their scope of practice. Uncommon procedures included fitting headgear (24%), lingual appliances (27%), inserting or removing temporary anchorage devices (20%), and taking facebow record (18%). A total of 62% of OTs took patient consent for treatment. 59% were supervised through a written prescription with no direct supervision. OTs were directly supervised for only a quarter of their clinical practice. Orthodontists viewing frequency for OTs varied significantly, and was found to be the following: every 2-4 visits (36%), every other visit (35%), and every visit (26%). CONCLUSIONS: OTs mostly carried out the scope of practice as permitted by the GDC. Procedures uncommon to routine orthodontic practice were also uncommon to Orthodontic therapist clinical practice. OTs work mostly through written prescription with no direct supervision. PMID- 29285997 TI - Evaluation of different adsorbents for acidity reduction in residual oils. AB - This work aims to evaluate the adsorption potential of bentonite and sugarcane bagasse clay for the reduction of free fatty acids in cooking oil through batch technique, experimental planning with different operating conditions (temperature, adsorbent mass and agitation). After were carried out kinetic studies and thermodynamic studies. Thus, both adsorbents were characterized by nitrogen dispersion, scanning electron microscopy with coupled energy dispersion spectroscopy. The sugarcane bagasse provided higher reductions compared to the bentonite clay, 58 and 50%, respectively. In the kinetic studies, it was observed that the pseudo-secunda model for both materials. Among the isotherms studied, the Langmuir model was better adjusted for sugarcane bagasse and Freundlich for bentonite clay. Thermodynamic parameters indicated spontaneous and endothermic adsorption at temperatures of 18 degrees C, 20 degrees C and 25 degrees C. Both materials showed an advantageous result with the reduction to the adsorption of free fatty acids in the residual oil, considering that they are low-cost materials, their pre-treatment is simple from the operational point of view and their physical and chemical characteristics are favorable to the adsorption process, sugarcane bagasse contains about 42% hemicellulose, which is a hydroxyl rich material that attracts the H+ ions from the medium. PMID- 29285998 TI - Structure-function Evaluation of Stem Cell Therapies for Spinal Cord Injury. AB - BACKGROUND: Spinal cord injuries (SCI) are prevalent, devastating for quality and expectancy of life, and cause heavy economic burdens. Stem cell therapies hold promise in complete structural and functional restoration of SCI. OBJECTIVE: This review focuses on the methods currently used to evaluate the stem cell therapies for SCI. RESULTS: Various kinds of stem cells involving embryonic stem cells (ESCs), bone marrow stromal cells (BMSCs), neural stem cells (NSCs) and induced pluripotent stem cells (iPSCs) are extensively used in regenerative research of SCI. For evaluation, the survival and integration of transplanted cells, spinal cord reconstruction and functional recovery all should be considered. Histological and histochemistrical, microscopic, and colorimetric assays, and real-time RT-PCR techniques are applied to determine the outcome. From the three main aspects-transplanted cells, spinal cord structure, and functional recovery we summarize and discuss these methods with certain instances of applications in SCI models. Importantly, for the evaluations of function, neuronal transmitting, electrophysiological analysis and behavioral score are included. CONCLUSION: Wider conjunction of established technologies, as well as the further development of nondestructive methods might make a big difference in testing stem cell therapies. PMID- 29286000 TI - Optimising care in an age of austerity: patient-reported outcome measures in paediatric ENT, journal bias, tonsillectomy and endoscopic ear surgery. PMID- 29285999 TI - The clinical characteristics and surgical approach of scar endometriosis: A case series of 14 women. AB - Scar endometriosis, also referred to as abdominal wall endometriosis (AWE), is a rare form of endometriosis that usually develops in the scar after obstetric or gynecological surgeries, including cesarean section (CS). Recently, the occurrence of scar endometriosis has been increasing together with the increase of CS incidence. Scar endometriosis can be clinically misdiagnosed as hernia, lipoma, or hematoma. Here we retrospectively analyzed the clinical aspects of scar endometriosis and surgical approach in 14 patients from a tertiary hospital, who were treated by surgery, between 2012 and 2017. The mean age was 32.71 +/- 8.61 years (range: 19-45). Palpable mass and cyclic pain at the scar site were the most common complaints. Twelve patients had previously undergone CS, and two patients had undergone a surgery of ovarian endometrioma. The preoperative diagnosis was determined with ultrasonography (US), magnetic resonance imaging (MRI), or computed tomography (CT). Preoperatively, scar endometriosis was diagnosed in 12/14 patients (85.7%), while 2 patients (14.3%) were diagnosed with inguinal hernia. The treatment was surgical excision in all patients; in addition, mesh repair surgery was performed in 1 patient with recurrent scar endometriosis. Postoperatively, endometriosis was confirmed by histology in all patients. The average size of endometriomas was 24.71 +/- 6.67 mm (range: 11-35). No woman had concurrent pelvic endometriosis. In the follow-up period (mean: 9 months) the recurrence of endometriosis was not observed. Scar endometriosis should be considered in all women of reproductive age presenting with cyclic pain and swelling in their abdominal incision sites. PMID- 29286002 TI - Cell-accurate optical mapping across the entire developing heart. AB - Organogenesis depends on orchestrated interactions between individual cells and morphogenetically relevant cues at the tissue level. This is true for the heart, whose function critically relies on well-ordered communication between neighboring cells, which is established and fine-tuned during embryonic development. For an integrated understanding of the development of structure and function, we need to move from isolated snap-shot observations of either microscopic or macroscopic parameters to simultaneous and, ideally continuous, cell-to-organ scale imaging. We introduce cell-accurate three-dimensional Ca2+ mapping of all cells in the entire electro-mechanically uncoupled heart during the looping stage of live embryonic zebrafish, using high-speed light sheet microscopy and tailored image processing and analysis. We show how myocardial region-specific heterogeneity in cell function emerges during early development and how structural patterning goes hand-in-hand with functional maturation of the entire heart. Our method opens the way to systematic, scale-bridging, in vivo studies of vertebrate organogenesis by cell-accurate structure-function mapping across entire organs. PMID- 29286001 TI - Environmental stimuli shape microglial plasticity in glioma. AB - In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-gamma produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-gamma, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b+ cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain. PMID- 29286003 TI - 135La as an Auger-electron emitter for targeted internal radiotherapy. AB - 135La has favorable nuclear and chemical properties for Auger-based targeted internal radiotherapy. Here we present detailed investigations of the production, emissions, and dosimetry related to 135La therapy. 135La was produced by 16.5 MeV proton irradiation of metallic natBa on a medical cyclotron, and was isolated and purified by trap-and-release on weak cation-exchange resin. The average production rate was 407 +/- 19 MBq uA-1 (saturation activity), and the radionuclidic purity was 98% at 20 h post irradiation. Chemical separation recovered > 98 % of the 135La with an effective molar activity of 70 +/- 20 GBq umol-1. To better assess cellular and organ dosimetry of this nuclide, we have calculated the x-ray and Auger emission spectra using a Monte Carlo model accounting for effects of multiple vacancies during the Auger cascade. The generated Auger spectrum was used to calculate cellular S-factors. 135La was produced with high specific activity, reactivity, radionuclidic purity, and yield. The emission spectrum and the dosimetry are favorable for internal radionuclide therapy. PMID- 29286004 TI - Areas under peripheral pulse waves: a potential marker of atherosclerotic changes. AB - OBJECTIVE: In this study, we propose a method for finding atherosclerotic changes based on the ratios of areas under peripheral arterial pulse wave (PW) contours and analyze its performance. APPROACH: The PW signals were recorded with force sensors and photoplethysmographic sensors from ankle, wrist, cubital fossa, index finger and second toe from 30 atherosclerotic patients and 52 control subjects. In addition, the day-to-day repeatability of the method was studied with 10 test subjects examined on three different days. The ratios of areas under the PWs were computed and the results were evaluated by means of receiver operating characteristic (ROC) analysis, intra-class correlation (ICC) coefficient and multiple linear regression analysis. MAIN RESULTS: Areas under ROC curves of 0.802-0.906 were found for different area ratios having statistically significant differences between the atheroslerotic group and control groups. ICCs over 0.80 were found widely for the beat-by-beat analyzed data and over 0.95 for the data based on the averages over different numbers of PWs. Multiple linear regression analysis showed linear dependence between the area ratios and age and the diagnosis of atherosclerosis. SIGNIFICANCE: Our findings may facilitate development of novel diagnostic approaches and preventive strategies against cardiovascular disorders. However, further studies are needed to confirm the results. The presented study demonstrates the potential of arterial PW analysis in finding vascular abnormalities. PMID- 29286005 TI - Current concepts and trends in the treatment of bone metastases in patients with advanced prostate cancer. AB - Bone metastases have a major impact on quality of life and survival of patients with advanced prostate cancer. In the last decade, the development and approval of substances inhibiting the vicious cycle of bone metastases have enabled the reduction of complications caused by bone metastases in patients with castration resistant prostate cancer. These drugs have raised awareness of the importance of skeletal-related events which in the meantime represent an important end point also in trials using agents not specifically designed for bone lesions. Second generation antihormonal drugs such as enzalutamide or abiraterone have been shown to have a positive impact on the incidence of skeletal complications and therefore provide an important tool in the armamentarium used for treating bone metastases. Radiopharmaceuticals such as radium-223 dichloride ([223Ra]) have been demonstrated not only to reduce skeletal-related events and bone-related pain, but also to prolong overall survival, thereby being the first bone targeting agent showing a survival benefit. As previous studies have not provided an obvious benefit of bone-targeted lesions in castration-sensitive disease, the use of these agents is not recommended. In oligometastatic prostate cancer, the role of local treatment of metastases using stereotactic radiation or radiosurgery is a matter of intense debates and may play an increasing role in the future. PMID- 29286006 TI - Altered PIWI-LIKE 1 and PIWI-LIKE 2 mRNA expression in ejaculated spermatozoa of men with impaired sperm characteristics. AB - In about half the cases of involuntary childlessness, a male infertility factor is involved. The PIWI-LIKE genes, a subclade of the Argonaute protein family, are involved in RNA silencing and transposon control in the germline. Knockout of murine Piwi-like 1 and 2 homologs results in complete infertility in males. The aim of this study was to analyze whether the mRNA expression of human PIWI-LIKE 1 4 genes is altered in ejaculated spermatozoa of men with impaired sperm characteristics. Ninety male participants were included in the study, among which 47 were with normozoospermia, 36 with impaired semen characteristics according to the World Health Organization (WHO) manual, 5th edition, and 7 with azoospermia serving as negative control for the PIWI-LIKE 1-4 mRNA expression in somatic cells in the ejaculate. PIWI-LIKE 1-4 mRNA expression in the ejaculated spermatozoa of the participants was measured by quantitative real-time PCR. In nonazoospermic men, PIWI-LIKE 1-4 mRNA was measurable in ejaculated spermatozoa in different proportions. PIWI-LIKE 1 (100.0%) and PIWI-LIKE 2 (49.4%) were more frequently expressed than PIWI-LIKE 3 (9.6%) and PIWI-LIKE 4 (15.7%). Furthermore, a decreased PIWI-LIKE 2 mRNA expression showed a significant correlation with a decreased sperm count (P = 0.022) and an increased PIWI-LIKE 1 mRNA expression with a decreased progressive motility (P = 0.048). PIWI-LIKE 1 and PIWI-LIKE 2 mRNA expression exhibited a significant association with impaired sperm characteristics and may be a useful candidate for the evaluation of the impact of PIWI-LIKE 1-4 mRNA expression on male infertility. PMID- 29286007 TI - Histological subtype is a significant predictor for inguinal lymph node metastasis in patients with penile squamous cell carcinoma. AB - The present study aimed to investigate the relationship between histopathological subtype and the probability of inguinal lymph node metastasis (ILNM) in patients with penile squamous cell carcinoma (PSCC). The clinical records of 198 consecutive patients with PSCC were analyzed retrospectively. Primary lesions were reevaluated according to the 2016 World Health Organization (WHO) histopathological classification. We retrieved the clinicopathological factors from the medical records including age, clinical lymph node stage, pathological tumor stage, lymphatic invasion, and nerve invasion. Uni- and multivariate logistic regression analyses were used to explore the risk factors of ILNM. Multivariate analyses identified clinical lymph node stage (P = 0.000), pathological tumor stage (P = 0.016), histologic grade (P = 0.000), and risk group of histological subtypes (P = 0.029) as independent predictors for ILNM. Compared with the low-risk group of PSCC subtypes, the intermediate- (HR: 3.66, 95% CI: 1.30-10.37, P = 0.021) and high-risk groups (HR: 28.74, 95% CI: 2.37 348.54, P = 0.008) were significantly associated with ILNM. In conclusion, the histopathological subtype of the primary lesion is a significant predictor for ILNM in patients with PSCC. PMID- 29286008 TI - Update on the main MDR pathogens: prevalence and treatment options. AB - In recent years the proportion of multi-drug resistance (MDR) among the bacterial pathogens causing infections, particularly those acquired in healthcare settings, has risen worryingly worldwide. It poses a serious public health threat as the multiple patterns of resistance limit the effective treatment options for such infections. Although many bacterial species have developed reduced susceptibility to a wide array of antimicrobial molecules, a particular group of pathogens acronymically referred to as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) plays a clinically relevant role in the aetiology of life threatening nosocomial infections. In this review, we represent the rise of MDR among the ESKAPE pathogens over the decades and report studies from each continent showing the current prevalence and burden of such infections worldwide. PMID- 29286009 TI - Efficacy of loading dose of colistin in Acinetobacter baumannii ventilator associated pneumonia. AB - Colistin loading dose (LD) has been postulated as an advance in therapy. The clinical, microbiological effectiveness and nephrotoxicity of adding an LD to systemic colistin in ventilator-associated pneumonia (VAP) caused by multidrug resistant (MDR) Acinetobacter baumannii remain unknown. In this quasi experimental study, the efficacy, outcomes and nephrotoxicity in 30 adults who received intravenous colistin with LD for MDR A. baumannii ventilator associated pneumonia were compared with 22 in absence of LD. Adding LD, the clinical cure rate at 14 days of therapy increased from 47.6% to 56.7% (p>0.397). No significant differences in bacteriological clearance (80 vs 81%), ICU mortality (50% vs 54.2%) or ICU length of stay (median: 32 vs 36 days) were identified. Mortality increased (76.2% vs 35.5%, p=0.004) in patients with nephrotoxicity, with age (median 67.0 vs. 50.0 years, p=0.002) being the only risk factor for nephrotoxicity. The nephrotoxicity rate increased from 27.3% in absence of LD to 35.3% with LD and SOFA <8, and 69.2% (p= 0.065) with LD and SOFA >7. Overall, nephrotoxicity was more severe in the LD group according to RIFLE criteria (p=0.015). Adding LD to systemic colistin for MDR A. baumannii VAP had no significant effect on clinical cure rates, bacteriologic clearance or pre-defined outcomes. However, the nephrotoxicity rate increased with LD, with special risk in adults with high organ failure development or advanced age. Further evidence regarding the risks and benefits of LD is required. The development of newer agents and strategies is urgently needed. PMID- 29286010 TI - Blood-Brain Barrier and Intrathecal Immune Response in patients with neuroinfections. AB - Cerebrospinal fluid/serum albumin ratio is one of the most informative parameters for blood-brain barrier (BBB) integrity in cases of central nervous system (CNS) infectious diseases. Normally, CNS albumin concentration is a function of diffusion processes along with CSF drainage and resorption. In pathological processes CSF albumin levels are dependent only on the rate of CSF drainage resulting in non-linear reciprocal changes of albumin quotient (Qalb). IgG, IgA and IgM concentrations both in CSF and serum can be compared to Qalb, thus determining the intrathecal immune response. The aim of the study was to detect BBB permeability impairment and the intrathecal immune response in patients with CNS infections with various etiologies. CSF/serum ratios were calculated and related to IgG IgA and IgM concentrations in CSF and blood serum. The results were integrated and presented by Reibergrams. The results demonstrated typical patterns which prove albumin to be the main modulator of protein dynamics and at the same time explicates the complex pathophysiological mechanisms involved in BBB disruption and intrathecal immune response in CNS infections. The diagnostic model presented in our study seeks to explain the observations of meningitis and meningoencephalitis pathophysiology and points out the mandatory cooperation between clinicians and laboratory for accurate diagnosis and proper treatment. PMID- 29286011 TI - Prevalence of zoonotic and non-zoonotic genotypes of Giardia intestinalis in cats: a systematic review and meta-analysis. AB - There are no meta-analyses specifically describing the prevalence of zoonotic and non-zoonotic genotypes of Giardia intestinalis in cats, which would be useful in defining the importance of cats as a source of zoonotic transmission. We performed a systematic review of the literature in three databases (PubMed, Scopus and SciELO) to assess the proportion of cats that were infected with specific G. intestinalis genotypes. A meta-analysis using a random effects model was performed to calculate the pooled prevalence and 95% confidence intervals (95%CI). A 2-tailed alpha level of 5% was used for hypothesis testing. Measures of heterogeneity, including Cochran's Q statistic, the I2 index, and the tau squared test, were estimated and reported. Subgroup analyses were conducted by geographic area and animal origin, as well as coinfection. Publication bias was assessed using a funnel-plot. Up to November 1, 2015, the literature search yielded 780 articles, of which 29 studies were valid for analysis. The pooled prevalence rate was higher for genotype F (19 studies, n=368 cats) with 55.8% [95%CI (42.8%-68.7%), tau2=0.0463]. For genotype A (21 n=409) it was 38.7% [95%CI (29.0%-48.4%), tau2=0.0527], for genotype D (7, n=276) 8.9% [95%CI (2.1%-15.8%), tau2=0.0024], for genotype C (2, n=212) 3.1% [95%CI (2.5%-3.5%), tau2=0.0001], for genotype E (3, n=187) 2.9% [95%CI (0.0%-8.1%), tau2=0.0009], and for genotype B (4, n=230) it was 2.8% [95%CI (0.0%-5.7%), tau2=0.0002]. Genotypes A and B of G. intestinalis are present in a wide range of hosts, including humans and cats, whilst genotype E has been reported in bovines, ovines, caprine and porcine animals, as well as in dogs and cats; and genotype F is almost exclusive to cats. Thus genotypes A and B are the most important for zoonotic transmission. In this study, after genotype F (55.5%), genotype A yielded more than 38% in cats (95%CI 29-48). This has interesting possible implications in zoonotic transmission of giardiasis between cats and humans. PMID- 29286012 TI - Hepatitis A, B, C and HIV seroprevalence among Syrian refugee children admitted to outpatient clinics. AB - Viral hepatitis is the most common cause of serious health problems such as liver cirrhosis and hepatocellular carcinoma (HCC). Leading to immunodeficiency disorders through different mechanisms, Human Immunodeficiency Virus (HIV) causes the development of severe secondary infections. Hepatitis A (HAV) is thought to spread by the faecal-oral route, while Hepatitis B (HBV), Hepatitis C (HCV) and HIV are mostly transmitted vertically during childhood. In our study, we aimed to determine the seroprevalence of HAV, HBV, HCV and HIV among Syrian refugee children who were admitted to outpatient clinics. We conducted a retrospective review of data concerning 171 Syrian children aged between 0-18 years admitted between April 2014 and December 2015 to the outpatient infectious disease clinic of ?zmir Tepecik Training and Research Hospital and the social welfare outpatient clinic for Syrian refugees for reasons other than jaundice. Serum samples from patients were studied for HAV antibody IgG (anti-HAV IgG), HBV surface antigen (HBsAg), antibodies against HBV surface antigen (anti-HBs), antibodies against HBV core antigen (anti-HBc total), HCV antibody (anti-HCV) (anti-HIV) with the ELISA (Enzyme-Linked Immunosorbent Assay) method. In this study 51% of patients were female, with a mean age of 6.52 years among all patients. Six of the 140 patients (4.2%) scanned for HBV among the patients enrolled in the study were HBsAg and anti-HBc total positive and anti-HBs negative. Three patients (2.1%) were HBsAg negative, and anti-HBc total and anti-HBs positive, which indicated they had previously recovered from an HBV infection. HBsAg, anti-HBs, anti-HBc total data for 140 patients (81.9%), anti-HCV data for 109 patients (63.8%), anti HIV data for 88 patients (51.5%) and HAV IgG data for 86 patients (50.3%) were obtained. Due to migration from regions in Syria where there is no regular follow up of HBV vaccination in children, HBsAg seroprevalence of refugee children is thought to be higher than in other children in Turkey and anti-HBs positivity is thought to be lower. We expected to see a higher seroprevalence of anti-HCV and anti-HIV in Syria due to the lack of health facilities such as non-regular anti HCV and anti-HIV screening before blood transfusions and during pregnancy in all regions of Syria. Yet in this study, the anti-HCV, anti-HIV seroprevalence of Syrian refugee children was similar to that in Turkey. According to the results, if the children of asylum seekers are admitted to the national HAV and HBV vaccination schedule, hepatitis infections and their complications may be prevented. PMID- 29286013 TI - Outbreak of severe Hepatitis A in Eastern Piedmont, Italy. AB - Hepatitis A (HA) is caused by a hepatovirus from the family Picornaviridae (Hepatitis A Virus, HAV). Transmission occurs mainly by the orofaecal route through food or water contaminated by faeces. Sexual transmission has also been reported among men who have sex with men (MSM). From February to May 2017, 14 patients with HA were hospitalized at the University Hospital "Maggiore della Carita", Novara (Eastern Piedmont), Italy. One patient was two years old and was therefore admitted to the Paediatric Unit, the remaining 13 to the Infectious Disease Unit. Two of the adults were female and the rest (11) were male. The male patients were MSM, and contracted the infection sexually; three of them were known to be HIV positive, while two had a new diagnosis of syphilis infection. Women contracted the infection from contaminated food. PMID- 29286014 TI - Symptomatic congenital Cytomegalovirus deafness: the impact of a six-week course of antiviral treatment on hearing improvement. AB - Congenital Cytomegalovirus infection is the leading non-genetic cause of neurosensory deafness. We compared the outcomes of a treated group of children to an untreated group. The effect of antiviral therapy on hearing improvement between baseline and 2-year follow-up was statistically significant. These results suggest that the benefit of 6-week therapy is not limited to preventing further hearing deterioration. PMID- 29286015 TI - Prevalence of class 1 integrons and plasmid-mediated qnr-genes among Enterobacter isolates obtained from hospitalized patients in Ahvaz, Iran. AB - Quinolones are frequently used classes of antimicrobials in hospitals, crucial for the treatment of infections caused by Gram-negative bacteria. The inappropriate use of quinolones and other antimicrobial agents for the treatment of bacterial infections leads to a significant increase of resistant isolates. The acquisition of antimicrobial resistance may be related to achievement of resistance determinant genes mediated by plasmids, transposons and gene cassettes in integrons. The objective of this cross-sectional study, conducted from December 2015 to July 2016 at two teaching hospitals in Ahvaz, southern Iran, was to screen for the presence of class 1 integrons and quinolone resistance genes in clinical isolates of Enterobacter spp. In all, 152 non-duplicated Enterobacter isolates were collected from clinical specimens and identified as Enterobacter spp. using standard microbiological methods. Antimicrobial susceptibility test was determined using the disc diffusion method according to the CLSI recommendation. Determination of class 1 integrons and PMQR genes was assessed by PCR. Analysis of antibiotic susceptibility tests showed that the highest antibiotic resistance was toward ciprofloxacin (55.3%), while the lowest level was observed against meropenem (34.9%). Moreover, 47.4% (72/152) and 29% (44/152) of isolates were positive for class 1 integron and quinolone resistance genes, respectively. The relative frequencies of antibiotic resistance were significantly higher among class 1 integron-positive isolates. In summary, our results highlight the importance of PMQR genes in the emergence of quinolone resistant Enterobacter isolates. Moreover, it seems that class 1 integrons have a widespread distribution among Enterobacter isolates and have clinical relevance to multiple-drug-resistant isolates. PMID- 29286016 TI - Granulated sugar for adjuvant treatment of surgical wound infection due to multi drug-resistant pathogens in a child with sarcoma: a case report and literature review. AB - The use of sugar for treating wounds which are difficult to heal and positive to resistant pathogens has already been documented. The authors describe the successful treatment by direct instillation of granular sugar in the antibiotic resistant infected surgical site wound of a child with sarcoma. Sugar instillation in the extended spectrum beta-lactamase (ESBL)-producing Enterobacter cloacae positive wound, in addition to systemic treatment with meropenem and levofloxacin, allowed culture negativization in six days and complete wound healing in 30 days. These results make the use of sugar an attractive option for wounds which are difficult to treat, even in an immunocompromised child. PMID- 29286017 TI - A case of invasive infection caused by a highly virulent strain of Klebsiella pneumoniae displaying hypermucoviscosity in a patient with hepatic involvement without liver abscess. AB - Klebsiella pneumoniae is an opportunistic nosocomial pathogen belonging to the Enterobacteriaceae family that is associated with a wide range of infections. In the 1980s a new hypervirulent (hypermucoviscous) variant of Klebsiella pneumoniae (hvKP) emerged in southeast Asia and is now increasingly spreading to Western countries due to an invasive syndrome. hvKP isolates can cause serious, life threatening community-acquired infections in younger healthy hosts, including liver abscess, pneumonia, meningitis and endophthalmitis. We present a case of an 83-year-old man who was examined in the Medicine Department of San Camillo Hospital in Treviso for dehydration in gastroenteritis. Since he presented fever on admission, microbiological investigations were performed and empiric antibiotic therapy with cefotaxime was started. Blood analysis showed a high level of cholestasis indexes and transaminases. Blood cultures were found positive for K. pneumoniae that showed hypermucoviscosity. The hypermucoviscous phenotype of this K. pneumoniae isolate was easily identified by the "string test". Abdominal computed tomography and ultrasonography did not show presence of liver abscesses. After a few days of antibiotic therapy the patient's clinical condition improved. Correct microbiology identification of this kind of strain was essential for appropriate clinical management. PMID- 29286018 TI - Miliary pulmonary infection after BCG intravesical instillation: a rare, misdiagnosed and mistreated complication. AB - Intravesical Bacillus Calmette-Guerin (BCG) immunotherapy decreases the progression risk of non-muscle-invasive bladder cancer, but potentially yields a broad spectrum of side effects. We report the case of a 73-year-old man affected by miliary pulmonary BCG infection, whose microbiological diagnosis was probably hindered by empiric fluoroquinolones, focusing on imaging and clinical work-up. PMID- 29286019 TI - Rothia mucilaginosa bacteraemia in an immunocompetent paediatric patient: a new pathogen to take into account. A case report. AB - Rothia mucilaginosa, previously known as Stomatococcus mucilaginosus, is a Gram positive coccus that is part of the oropharyngeal microbiota and upper respiratory tract. It is mainly related to infections in immunosuppressed patients. Given its complex microbiological identification, its prevalence may be underestimated. We describe in this article a case of bacteraemia by Rothia in an immunocompetent paediatric patient without epidemiological or medical relevant history. In the available literature no cases of bacteraemia by Rothia mucilaginosa in immunocompetent paediatric patients have been reported. Given the characteristics of our patient, the publication of this case is of interest. Once the diagnosis of Rothia mucilaginosa has been made, the correct functioning of the immune system of the patient should be checked. PMID- 29286020 TI - A case of Candida septic arthritis with rice body formation in a 2-month-old infant. AB - We present a case of rice body formation in the left knee joint of a 2-month-old infant affected by Candida albicans septic arthritis which has never been reported before. Rice body formation has been described in association with rheumatoid or tuberculous arthritis and is very rare in Candida arthritis. After three weeks of therapy with amphotericin B administered intravenously, the infant recovered fully from infection. Septic arthritis is a serious cause of morbidity and for proper evaluation and treatment fungal septic arthritis should be included in the differential diagnosis. PMID- 29286021 TI - Toenail onychomycosis by Trichophyton rubrum and concurrent infestation with Tyrophagus putrescentiae. AB - A remarkable case of onychomycosis by Trichophyton (T.) rubrum combined with nail infestation by Tyrophagus (T.) putrescentiae in an elderly diabetic farmer is described and discussed. Large numbers of eggs and mites in all development stages were present in nail debris, reflecting active reproduction on site. Treatment with ivermectin 0.1% cream and environmental decontamination cleared the mite infestation, while onychomycosis responded well to oral terbinafine and ciclopirox 8% nail lacquer. Such a combination of onychomycosis and mite infestation of the same nail is an exceptional finding reported only twice in the literature. PMID- 29286022 TI - Italian prisoners with tuberculosis in the early nineteenth century: the experience in the Pianosa prison hospital. AB - In the late nineteenth century, with industrial growth and the resulting mass urbanisation, tuberculosis represented a plague mainly among the poor social classes. The outdated and crowded Italian prisons (formerly old monasteries) during the early 1900s were insufficient to "host" the multitude of inmates condemned or waiting for judgment. Italian prisoners were beset by hunger and poor hygiene facilities. Clothes did not differ between winter and summer. The Criminal Sanatorium of Pianosa was officially inaugurated in 1907, but from the 1860s it had been set up to host an agricultural penal colony. Here we report the excellent results obtained between 1907 and 1909 in the management of tuberculosis among prisoners in Pianosa, where surgery was also available. In those times, climate therapy with an enriched and varied nutrition was the only effective treatment for tuberculosis. Overall, of the 913 prisoners housed in Pianosa in that period and according to the acknowledged scientific criteria, the following results were achieved: complete cure in 182, improvement in 416, mild amelioration in 94, worsening in 80, no change in 20. The number of prisoners who died or were transferred to another prison is unknown. The case series of the prison hospital in Pianosa may be reconstructed thanks to data published by the Director Roberto Passini. The better outcome of the prisoners in Pianosa, in comparison with inmates of other Italian institutions, was due both to treatment standards (climate, nutritional, hygienic, and surgical) and to the proportionally longer period of stay in Pianosa for prisoners with already confirmed detention periods. PMID- 29286023 TI - Preventing syphilis in the 16th century: the distinguished Italian anatomist Gabriele Falloppio (1523-1562) and the invention of the condom. AB - By the end of the 15th century, syphilis had reached epidemic proportions in Europe. Unable to ascertain its causes, physicians resorted to superstition. At the beginning of the 16th century, the sexual transmission of the disease was established. Initially, the principal measure of infection control was sexual abstinence and mutual fidelity. However, during the same period the Italian anatomist Gabriele Falloppio (1523-1562) proposed a method of preventing syphilis transmission: the medication-soaked linen sheath. Thus was born the idea of a mechanical barrier against sexually transmitted diseases: the condom. PMID- 29286025 TI - [The outcomes of different surgical procedures for thoracic injuries]. AB - AIM: To assess the outcomes of video-assisted techniques compared with conventional procedures. MATERIAL AND METHODS: 596 victims with thoracic injuries were enrolled. Video-assisted techniques were applied in 236 cases, conventional procedures - 360 patients. Groups were standardized by the type of surgery. Morbidity, hospital-stay and mortality according to Clavien-Dindo classification have been analyzed. RESULTS: There was similar incidence of complications in both groups. However, severe adverse events followed by redo surgery under general anesthesia occurred in 1.2% and 7.1% of cases respectively (p<0.05). Hospital stay was 11.3+/-3.6 and 14.5+/-5.3 days respectively (p<0.05). Mortality was 0.58% vs. 1.08% respectively (p>0.05). CONCLUSION: In victims with thoracic injuries and no need for urgent thoracotomy video-assisted techniques are preferable for diagnosis and treatment. PMID- 29286024 TI - [Subclavian-carotid replacement in chronic cerebrovascular insufficiency management]. AB - AIM: To present own experience of subclavian-carotid replacement for chronic cerebrovascular insufficiency management. MATERIAL AND METHODS: For 12 years 7 subclavian-carotid reconstructions were performed that was 1.2% of all carotid repairs during this period. Great saphenous vein was always used as a graft. Carotid endarterectomy from proximal internal carotid artery was additionally performed if it was necessary. Patients had severe advanced lesion of supra aortic vessels including bilateral carotid lesion and significant stenosis of ipsilateral proximal common carotid artery. The vast majority of them had cerebrovascular insufficiency grade 3-4. RESULTS: All patients underwent surgery without significant complications despite initially severe state due to advanced lesion of brachiocephalic arteries. Long-term postoperative patency of the grafts was satisfactory within the period from 12 years to 1.5 months. There were no neurological impairment and stroke. CONCLUSION: Subclavian-carotid grafting is an effective alternative for carotid endarterectomy in patients with advanced atherosclerotic lesion of common and internal carotid arteries. PMID- 29286026 TI - [Quality of life of patients with complicated reflux-esophagitis followed antireflux surgery]. AB - AIM: To analyze quality of life of patients with complicated reflux-esophagitis followed antireflux surgery. MATERIAL AND METHODS: The trial enrolled 200 patients who underwent surgical treatment at the Burdenko Faculty Surgery Clinic of Sechenov First Moscow State Medical University for complicated reflux esophagitis from 2008 to 2015. Inclusion criteria were long-standing reflux esophagitis irresistible to conservative treatment, hiatal hernia with shortening of the esophagus and/or peptic stricture and/or Barrett's esophagus. Patients were divided into 2 groups according to the degree of esophagus shortening: group I - 98 patients with esophagus shortening degree I; group II - 102 patients with shortening grade II. Men/women ratio was 87(43.5%)/113(56.5%). Mean age was 56.0+/-13.9 years (16-83 years). We performed fundoplication in A.F. Chernousov modification in the first group and modified valvular gastroplication in the second group. All patients underwent survey within 6 months - 10 years after surgery to assess long-term outcomes. X-ray examination, upper GI endoscopy, standard laboratory tests were performed with pH-impedance and computed tomography if it was necessary. Quality of life was estimated by RAND SF-36 and GSRS (Gastrointestinal Symptom Rating Scale) questionnaires. RESULTS: SF-36 questionnaire revealed postoperative changes of physical, psychological and social values and was able to compare them with those in general population. Postoperative overall health was significantly higher in both groups compared with preoperative level and comparable with general population. GSRS questionnaire have also revealed positive changes. Overall postoperative GSRS score was 1.6+/-0.5 and 1.6+/-0.6 points in groups I and II respectively that corresponds to minor concern after surgery. PMID- 29286027 TI - [Gastrointestinal stromal tumors: surgical treatment and targeted therapy]. AB - AIM: To improve surgical and complex treatment of patients with gastrointestinal stromal tumors (GIST). MATERIAL AND METHODS: Our analysis included 97 GIST patients who were at Petrovsky Russian Research Center of Surgery and Moscow City Oncological Hospital #62 from January 2006 to September 2016. RESULTS: Advisability of surgery for GIST patients was confirmed. We have assessed surgical outcomes, defined the indications for adjuvant targeted therapy depending on GIST prognostic risk and additional factors for unfavorable course of disease. CONCLUSION: It was concluded that surgical treatment is preferred for patients with resectable GISTs. Adjuvant therapy is indicated in patients with high risk of progression if mutations indicating tumor sensitivity to the drugs are revealed. Adjuvant targeted therapy is not indicated in patients with low and very low risk of progression. PMID- 29286028 TI - [Isolated pancreatic metastases of renal cell carcinoma]. AB - AIM: To present own experience of surgical treatment of isolated pancreatic metastases of renal cell carcinoma. MATERIAL AND METHODS: There are 3 cases of pancreatic metastases of renal cell carcinoma. They were diagnosed in women aged 55, 66 and 67 years in 9, 11 and 23 years after nephrectomy respectively. RESULTS: The tumors were placed in head (60 mm), body (10 and 5 mm) and tail (30 mm) of the pancreas. There were 2 distal pancreatectomy with splenectomy and 1 pancreatoduodenectomy. All patients are alive within 39, 49 and 8 months after surgery respectively. One woman has been diagnosed pulmonary metastases after 19 months. 20-month sunitinib administration contributes to regression of the disease. There was no recurrent disease in other two patients. CONCLUSION: Isolated pancreatic metastases of renal cell carcinoma can occur in decades after nephrectomy. Therefore, lifelong follow-up is necessary. Pancreatectomy for focal lesion is associated with good long-term outcome. PMID- 29286029 TI - [Surgical technique in patients with chronic pancreatitis]. AB - AIM: To justify ligation of vascular branches of anterior pancreateroduodenal arterial arch or gastroduodenal artery prior to bifurcation. MATERIAL AND METHODS: This method was tested on sufficient clinical material: 147 patients with recurrent chronic pancreatitis. The interventions are presented by Frey, Beger procedures and its Berne variant. RESULTS: Comparative analysis showed reliable advantages of vascular ligation during pancreatectomy. PMID- 29286030 TI - [Urgent surgical care for patients with colon cancer complicated by hemorrhage]. AB - AIM: To evaluate an effectiveness of various hemostatic methods in patients with colon and rectal cancer. MATERIAL AND METHODS: 77 urgent patients with colon and rectal cancer complicated by bleeding were enrolled. Medication was effective in 11 patients (group 1), endoscopic hemostasis in 47 patients (group 2), vascular embolization in 2 cases (group 3), internal iliac arteries ligation in 2 patients (group 4), 15 patients underwent emergency resection (group 5). Twenty out of 62 patients in groups 1-4 underwent elective radical procedures and radio- or chemotherapy in 7-10 days after hemostasis and normalization of hemoglobin. 3 year Kaplan-Meier survival was assessed after emergency (group 5) and elective surgery (groups 1-4) in 31 patients. RESULTS: Effectiveness of various hemostatic methods was 14.3% in group 1, 79.7% in group 2, 28.6% in group 3 and 100% in groups 4 and 5. Postoperative morbidity and mortality were higher after emergency (group 5) compared with elective (groups 1-4) procedures: 33.3 and 20%; 15 and 5% respectively. 3-year survival was better after elective than emergency operations - 0.78 and 0.57, respectively. CONCLUSION: Management of bleeding should be carried out by highly qualified specialist at multi-field emergency care hospital. Endoscopy and arterial embolization are the most effective methods of hemostasis with minimal risk of complications. In hemorrhage patients endoscopy and embolization ("bridge to surgery") are an alternative to conditionally radical operations, since they allow to reduce mortality. PMID- 29286031 TI - [Increase of reparative potential of fabrics in sugar diabetes]. AB - AIM: The purpose of the study was to study the effectiveness of the domestic drug Remaxol in reparative processes of laparotomic wound tissues in acute surgical abdominal pathology in patients with diabetes mellitus. MATERIAL AND METHODS: Clinical and laboratory studies were performed in 86 patients with acute surgical pathology of the abdominal cavity, 56 patients with type 1 diabetes mellitus, including 26 patients who received Remaxol in the early postoperative period (daily intravenous infusions of 400.0 ml for 5 days). RESULTS: It was established that diabetes mellitus is an important aggravating factor in the reparative process of tissue structures of a laparotomic wound. Undoubtedly, a significant factor in reducing the reparative potential of tissues is a significant activation of factors leading to membrane-destabilizing phenomena - oxidative stress, activation of phospholipases, hypoxia. The inclusion of Remaxol, which has antioxidant and antihypoxic effects, allows to significantly correct these pathogenetic components, which is the basis for optimization of the reparative process against the background of diabetes mellitus. There was a significant decrease in wound complications in the early postoperative period, a significant reduction in the stay of patients in the hospital. PMID- 29286033 TI - [Minimally invasive aortic valve replacement]. PMID- 29286032 TI - [Bidirectional knotless barbed sutures during primary total knee arthroplasty: effective solution or new problem?] AB - THE HYPOTHESIS OF THE STUDY: The use of bidirectional knotless barbed sutures for closure of capsule and subcutaneous fat tissue in primary total knee arthroplasty (TKA) is safe and time-saving. MATERIAL AND METHODS: 302 patients with end-stage osteoarthritis scheduled for primary non-complex TKA were randomly divided into two prospective groups: in group I (N=102) the capsule of the knee joint and subcutaneous fat tissues were closed by continuous braided suture while in group II (N=200) by bidirectional knotless barbed sutures. The skin in both groups was closed by non-absorbable monofilament polycaproamide uninterrupted suture. RESULTS: The time of the surgery was significantly shorter in group II (65,25+/ 11,9 min) than in group I (72,5+/-14,7 min) (p<0.05). The volume of hidden blood loss was similar in both groups. The number of patients with superficial infection during the first two week after surgery did not differ significantly (1,9% (I) and 1% (II)): they all healed successfully after skin debridement and additional closure. There were no cases of deep periprosthetic infection (PPI). At 3-month follow-up no difference found regarding pain level and knee function (Knee Society Score). CONCLUSION: The use of bidirectional knotless barbed sutures in TKA reduces the time of surgery, does not affect the volume of hidden blood loss or PPI occurrence. PMID- 29286034 TI - [Surgical treatment of hepatoblastoma PRETEXT/POST-TEXT III and IV]. PMID- 29286035 TI - [Postoperative sternomediastinitis management]. PMID- 29286036 TI - [Perforated chronic gastric ulcer in sliding hiatus hernia]. PMID- 29286037 TI - [Endoscopic treatment of complicated primary-multiple synchronous cancer of the ascending colon in elderly patients]. PMID- 29286038 TI - [Surgical treatment of extravasal compression of the celiac trunk]. PMID- 29286039 TI - [Principles and modern trends in liver echinococcosis treatment]. PMID- 29286040 TI - [Venous acute disturbance of mesenteric circulation: diagnosis and treatment]. PMID- 29286041 TI - [The use of aceclofenac (airtal) in the outpatient practice of the orthopedic traumatologist]. PMID- 29286042 TI - Growth and growth disorders in 2017: Genetic and epigenetic regulation of childhood growth. PMID- 29286043 TI - The artificial pancreas in 2017: The year of transition from research to clinical practice. PMID- 29286045 TI - Therapy: Achieving T2DM remission in primary care. PMID- 29286044 TI - Thyroid function: Thyroid hormone therapy resolves pulmonary fibrosis in mice. PMID- 29286046 TI - Neuropsychiatric disorders: Side effects of olanzapine worsened by metabolic dysfunction. PMID- 29286047 TI - Nutraceuticals in 2017: Nutraceuticals in endocrine disorders. PMID- 29286049 TI - Technology watch: AI can diagnose diabetic retinopathy. PMID- 29286048 TI - Immunometabolism in 2017: Metabolism and the inflammasome in health and ageing. PMID- 29286051 TI - Gut microbiota: Fibre restores healthy gut microbiota. PMID- 29286050 TI - Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. AB - Nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus are common diseases that often coexist and might act synergistically to increase the risk of hepatic and extra-hepatic clinical outcomes. NAFLD affects up to 70-80% of patients with type 2 diabetes mellitus and up to 30-40% of adults with type 1 diabetes mellitus. The coexistence of NAFLD and diabetes mellitus increases the risk of developing not only the more severe forms of NAFLD but also chronic vascular complications of diabetes mellitus. Indeed, substantial evidence links NAFLD with an increased risk of developing cardiovascular disease and other cardiac and arrhythmic complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus. NAFLD is also associated with an increased risk of developing microvascular diabetic complications, especially chronic kidney disease. This Review focuses on the strong association between NAFLD and the risk of chronic vascular complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus, thereby promoting an increased awareness of the extra hepatic implications of this increasingly prevalent and burdensome liver disease. We also discuss the putative underlying mechanisms by which NAFLD contributes to vascular diseases, as well as the emerging role of changes in the gut microbiota (dysbiosis) in the pathogenesis of NAFLD and associated vascular diseases. PMID- 29286053 TI - Erratum: Anesthesiologist in Catheterization Laboratory; the Roles and Goals!! a Postgraduate Educational Review. AB - [This corrects the article DOI: 10.4103/0259-1162.186866.]. PMID- 29286052 TI - Practical Challenges of Current Video Rate OCT Elastography: Accounting for Dynamic and Static Tissue Properties. AB - Optical coherence tomography (OCT) elastography (OCTE) has the potential to be an important diagnostic tool for pathologies including coronary artery disease, osteoarthritis, malignancies, and even dental caries. Many groups have performed OCTE, including our own, using a wide range of approaches. However, we will demonstrate current OCTE approaches are not scalable to real-time, in vivo imaging. As will be discussed, among the most important reasons is current designs focus on the system and not the target. Specifically, tissue dynamic responses are not accounted, with examples being the tissue strain response time, preload variability, and conditioning variability. Tissue dynamic responses, and to a lesser degree static tissue properties, prevent accurate video rate modulus assessments for current embodiments. Accounting for them is the focus of this paper. A top-down approach will be presented to overcome these challenges to real time in vivo tissue characterization. Discussed first is an example clinical scenario where OTCE would be of substantial relevance, the prevention of acute myocardial infarction or heart attacks. Then the principles behind OCTE are examined. Next, constrains on in vivo application of current OCTE are evaluated, focusing on dynamic tissue responses. An example is the tissue strain response, where it takes about 20 msec after a stress is applied to reach plateau. This response delay is not an issue at slow acquisition rates, as most current OCTE approaches are preformed, but it is for video rate OCTE. Since at video rate each frame is only 30 msec, for essentially all current approaches this means the strain for a given stress is changing constantly during the B-scan. Therefore the modulus can't be accurately assessed. This serious issue is an even greater problem for pulsed techniques as it means the strain/modulus for a given stress (at a location) is unpredictably changing over a B-scan. The paper concludes by introducing a novel video rate approach to overcome these challenges. PMID- 29286054 TI - Meropenem/vaborbactam fixed combination for the treatment of patients with complicated urinary tract infections. AB - On August 29, 2017, the United States Food and Drug Administration (FDA) approved meropenem/ vaborbactam fixed combination for the treatment of adults with complicated urinary tract infections (cUTI). The decision was based on substantial preclinical and clinical data, including two recent trials involving hundreds of adults with cUTI. Meropenem/ vaborbactam represents a powerful new treatment option to address antibiotic-resistant pathogens, including Klebsiella pneumoniae carbapenemase-producing bacteria. In this paper, we examine the work that led to FDA approval, with special emphasis on molecular pharmacology, pharmacokinetics, metabolism, efficacy and drug safety. We also look ahead, to explore how this promising new antimicrobial agent might be used in the near future to confront other drug-resistant infections.. PMID- 29286055 TI - Midostaurin for the treatment of adult patients with newly diagnosed acute myeloid leukemia that is FLT3 mutation-positive. AB - Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits activated fms-related tyrosine kinase 3 (FLT3) in the nanomolar range and other kinases including platelet-derived growth factor receptors alpha (PDGFR alpha) and beta (PDGFR- beta), cyclin-dependent kinase, proto-oncogene tyrosine protein kinase Src, tyrosine-protein kinase Fgr, spleen tyrosine kinase (Syk), KIT proto-oncogene receptor tyrosine kinase and the major vascular endothelial growth factor receptor (VEGFR). Activating mutations in FLT3, which is one of the more common acute myeloid leukemia (AML) mutations, particularly those that result in an FLT3-ITD (internal tandem duplication) mutation, confer poor prognosis and represent a therapeutic target. Small molecule TKIs that vary in potency and selectivity for FLT3 are under investigation. Here, we provide a comprehensive review of the preclinical and clinical activity of midostaurin, a recently approved drug indicated to be used in combination with cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy for the treatment of AML featuring an FLT3 mutation. PMID- 29286056 TI - Sacubitril and valsartan fixed combination to reduce heart failure events in post acute myocardial infarction patients. AB - Heart failure is a term used to define a constellation of symptoms and signs that are commonly attributed to the inability of the heart to produce a cardiac output that meets the demands of the body. It remains a deadly disease, affecting between 1-2% of the population, and is more common in the elderly, with around 6 10% of patients over 65 suffering from the condition. Sacubitril/valsartan (LCZ 696) is a combined neprilysin inhibitor and angiotensin AT1 receptor blocker approved in recent years for the treatment of chronic heart failure with reduced ejection fraction. In an area where there have been limited pharmacological advances in the last 10 years, this drug was a game changer and a much welcomed addition to contemporary heart failure therapy. It is currently being studied in patients with heart failure with preserved ejection fraction and for the reduction of heart failure events post-acute myocardial infarction. Results from the ongoing PARADISE-MI study are awaited by the global cardiology community with great interest. PMID- 29286057 TI - Notable licensing deals in the biopharma industry in the third quarter of 2017. AB - During the third quarter of 2017, Cortellis Competitive Intelligence registered 949 new deals (excluding mergers and acquisitions) added as part of its ongoing coverage of pharmaceutical licensing activity compared to 1,007 in Q2 this year and 1,023 in Q3 the previous year. PMID- 29286058 TI - European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) - 7th Joint Triennial Congress (October 25-28, 2017 - Paris, France). AB - The 7th Triennial Joint conference of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) was held in Paris, France. The meeting brought together attendees from a wide range of disciplines involved in multiple sclerosis (MS) research to explore an extensive program of teaching courses, plenary lectures, oral and poster sessions from approximately 2,000 abstracts submitted, and hot topic and young investigator presentations. These presentations covered topics including diagnostics, therapeutics and biomarkers, as well as a special section for MS nurses. Industry-sponsored symposia were also held. The report from this conference covers the latest developments in MS treatments. PMID- 29286059 TI - Functional anatomy of the nasal bones and adjacent structures. Consequences for nasal surgery. AB - The periosteum of the nasal bones, the periosteal-perichondrial nasal envelope, and the cartilaginous support of the bony vault were studied in serial coronal sections of four human cadaver noses. To differentiate between the various tissue components, the sections were stained according to Mallory-Cason and Verhoeff-Van Gieson stain. The results demonstrated: 1. the presence of clearly distinguishable layers of the periosteum covering the nasal bones; 2. the presence of a continuous periosteal-perichondrial covering of the bony and cartilaginous nasal vaults; 3. the way the cartilaginous support of the bony vault is constructed. The findings described in the present study may have clinical relevance in nasal surgery. PMID- 29286060 TI - Evodiamine promotes differentiation and inhibits proliferation of C2C12 muscle cells. AB - Evodiamine is a botanical alkaloid compound extracted from Tetradium plants. Previous studies have reported that evodiamine (Evo) treatment can reduce food uptake and improve insulin resistance in animals . The skeletal muscle comprises about 40% of the body mass of adults and has a vital role in regulating whole body glucose metabolism and energy metabolism. However, the effect of Evo on skeletal muscle is unclear. The main aim of the present study was to investigate the effect of Evo on the differentiation and proliferation of the mouse C2C12 muscle cell line. The results demonstrated that Evo promoted the expression of myogenic marker genes (Myogenin and muscle myosin heavy chain) and increased myoblast differentiation, potentially via activation of the Wnt/beta-catenin pathway. Furthermore, Evo increased mRNA expression of p21, reduced mRNA expression of Cyclin B, Cyclin D and Cyclin E and reduced the percentage of proliferating cells. Also, phosphorylation of ERK1/2 was decreased by Evo treatment during cell proliferation. In conclusion, these findings indicated that Evo has marked effects on skeletal muscle development. PMID- 29286061 TI - Cardioprotection by exenatide: A novel mechanism via improving mitochondrial function involving the GLP-1 receptor/cAMP/PKA pathway. AB - Accumulating evidence suggests that glucagon-like peptide-1 (GLP-1) and its analogues exert cardioprotective effects via modulating cardiomyocyte metabolism. Mitochondria play a pivotal role in the regulation of cell metabolism. It was hypothesized that treatment with exenatide, a GLP-1 analogue, may exert cardioprotective effects by improving mitochondrial function in an in vitro model of hypoxia/reoxygenation (H/R). H9c2 cells were employed to establish an in vitro model of H/R. Exenatide was added to the cells for 30 min prior to exposure to hypoxia. The GLP-1 receptor antagonist exendin-(9-39), the cyclic adenosine monophosphate (cAMP) inhibitor Rp-cAMPS and the protein kinase A (PKA) inhibitor H-89 were added to the cells for 10 min prior to treatment with exenatide. The release of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) and cardiomyocyte apoptosis were evaluated. The characteristics of mitochondrial morphology and functions, including ATP synthesis, membrane potential (DeltaPsim), mitochondrial permeability transition pore (mPTP), mitochondrial ATPase activity and oxidative stress, were determined. the mitochondrial uncoupling protein-3 (UCP-3) and nuclear respiratory factor-1 (Nrf-1) were also investigated by western blot analysis. Exenatide pretreatment significantly decreased LDH and CK-MB release and cardiomyocyte apoptosis in H9c2 cells subjected to H/R. More importantly, to the best of our knowledge, this is the first report of exenatide pretreatment decreasing mitochondrial abnormalities and reducing oxidative stress, while enhancing ATP synthesis, mitochondrial ATPase activity and DeltaPsim in H9c2 cells subjected to H/R. Exenatide pretreatment also decreased mitochondrial calcium overload and inhibited the opening of mPTP in H9c2 cells subjected to H/R. Furthermore, exenatide pretreatment upregulated UCP-3 and Nrf-1 expression in H9c2 cells subjected to H/R. However, the abovementioned observed effects of exenatide were all abolished when exenatide was co-administered with exendin-(9-39), Rp-cAMPS andor H-89. Therefore, the GLP 1 analogue exenatide was found to exert cardioprotective effects in an in vitro model of H/R, and this cardioprotection may be attributed to the improvement of mitochondrial function. These effects are most likely associated with the activation of the GLP-1 receptor/cAMP/PKA signaling pathway. PMID- 29286062 TI - miR-200c regulates the proliferation, apoptosis and invasion of gastric carcinoma cells through the downregulation of EDNRA expression. AB - This study aimed to investigate the regulatory effects of microRNA (miR)-200c on the proliferation, apoptosis and invasion of gastric carcinoma cells and to elucidate the underlying mechanisms involving the possible role of endothelin receptor A (EDNRA). The expression levels of miR-200c and EDNRA in the gastric carcinoma cell lines, BGC-823, SGC-7901 and HGC-27, and in GES-1 normal gastric cells were evaluated by RT-PCR and western blot analysis. The gastric carcinoma cells, particularly the BGC-823 cells, expressed significantly lower levels of miR-200c than the normal gastric cells (P<0.01). Thus, the BGC-823 cells were employed as model cells. In comparison to the normal gastric cells, EDNRA was overexpressed in the gastric carcinoma cells (P<0.01). Following the transfection of the gastric carcinoma cells with miR-200c mimics, or negative control vector (miR-200c NC), or with siRNA targeting EDNRA (siRNA EDNRA) or negatvie control siRNA (siRNA NC), the expression levels were assessed again by RT-PCR and western blot analysis. The successful transfection of miR-200c mimics was observed and this markedly elevated the expression of miR-200c (P<0.01). The transfection of miR-200c mimics or siRNA EDNRA notably decreased the EDNRA mRNA and protein expression levels (both P<0.01). In additoin, dual-luciferase reporter gene analysis was performed to reveal the targeting relationship between miR-200c and EDNRA. EDNRA was found to be the downstream target gene of miR-200c. Moreover, methyl thiazolyl tetrazolium (MTT) assay, Hoechst staining and Transwell assay were conducted to demonstrate the effects of miR-200c mimics or siRNA EDNRA on the proliferation, apoptosis and invasion of the gastric carcinoma cells, respectively. We found that transfection with miR-200c mimics and siRNA EDNRA were able to markedly suppress the proliferation and invasive capacity, and to promote the apoptosis of the gastric carcinoma cells (all P<0.01). On the whole, our data indicate that miR-200c regulates the proliferation, apoptosis and invasion of gastric carcinoma cells through the downregulation of EDNRA expression. PMID- 29286063 TI - MicroRNA-137 regulates hypoxia-induced retinal ganglion cell apoptosis through Notch1. AB - The apoptosis of retinal ganglion cells (RGCs) is a hallmark of several optic neuropathies. MicroRNAs (miRNAs) are recently identified regulators of various biological processes. However, the role of miRNAs in regulating RGC apoptosis remains largely unknown. We herein aimed to demonstrate that miR-137 acts as a hypoxia-responsive gene in RGCs that is downregulated under hypoxic conditions. It was observed that overexpression of miR-137 markedly aggravated hypoxia induced cell apoptosis, whereas inhibition of miR-137 effectively protected RGCs against hypoxia-induced apoptosis. Hypoxia induced Notch1 expression and signaling activation, while blocking Notch signaling significantly aggravated hypoxia-induced cell apoptosis. Further data revealed that the pro-survival Akt signaling pathway was involved in miR-137-Notch signaling pathway-mediated RGC protection. Knockdown of Notch significantly reversed the effect of anti-miR-137 on RGC protection and Akt signaling activation. In addition, blocking Akt signaling also significantly abrogated the protective effect of anti-miR-137 on hypoxia-induced cell injury. Overall, the results of the present study demonstrated that miR-137 targets Notch1 expression, revealing a novel link between miR-137 and Notch signaling, and suggesting that a miR-137/Notch1 axis may serve as a potential molecular target for the treatment of hypoxia-induced retinal diseases. PMID- 29286064 TI - miR-152 is involved in the proliferation and metastasis of ovarian cancer through repression of ERBB3. AB - MicroRNAs (miRNAs) participate in post-transcriptional regulation by targeting the 3' untranslated region of target genes that are involved in diverse biological processes. To the best of our knowledge, the association between miR 152 and ERBB3 in ovarian cancer remains unclear. In the present study, a negative correlation between miR-152 and ERBB3 in ovarian cancer was observed. The luciferase reporter gene assay results demonstrated that miR-152 negatively regulated ERBB3 in SKOV3 and OVCAR3 ovarian cancer cells. Furthermore, our results revealed that miR-152 suppressed the ability of ovarian cancer cell proliferation, migration and invasion, and promoted apoptosis through inhibiting ERBB3 in vitro. Therefore, in the present study, miR-152 was found to be involved in the proliferation and metastasis of ovarian cancer cells through repression of ERBB3 expression. Therefore, miR-152 may be a potential therapeutic target for the treatment of ovarian cancer. PMID- 29286066 TI - Effects of ERK1/2 S-nitrosylation on ERK1/2 phosphorylation and cell survival in glioma cells. AB - Aberrant activation of extracellular signal-regulated kinase 1/2 (ERK1/2) by phosphorylation modification can trigger tumor cell development in glioma. S nitrosylation, which refers to the covalent addition of a nitric oxide (NO) group to a cysteine (Cys) thiol, is an important post-translational modification that occurs on numerous cancer-associated proteins. Protein S-nitrosylation can increase or decrease protein activity and stability, and subsequent signal transduction and cellular processes. However, the association between ERK1/2 S nitrosylation and ERK1/2 phosphorylation, and the effects of ERK1 S-nitrosylation on glioma cell survival are currently unknown. U251 glioma cells were treated with NO donors sodium nitroprusside (SNP) or S-nitrosoglutathione (GSNO). CCK8 assay was used to assess the cell viability. NO levels in the medium were detected by Griess assay. Western blot analysis and biotin switch assay were employed to detect the ERK1/2 phosphorylation and S-nitrosylation. ERK1 wild-type and mutant plasmids were constructed, and used to transfect the U251 cells. Caspase-3 western blot analysis and flow cytometry were employed to assess cell apoptosis. The present study demonstrated that treatment with the NO donors SNP or GSNO led to an increase in ERK1/2 S-nitrosylation, and a reduction in ERK1/2 phosphorylation, which was accompanied by growth inhibition of U251 glioma cells. Mutational analysis demonstrated that Cys183 was vital for S-nitrosylation of ERK1, and that preventing ERK1 S-nitrosylation by replacing Cys183 with alanine partially reversed GSNO-induced cell apoptosis, and reductions in cell viability and ERK1/2 phosphorylation. In addition, increased ERK1/2 phosphorylation was associated with decreased ERK1/2 S-nitrosylation in human glioma tissues. These findings identified the relationship between ERK1/2 S-nitrosylation and phosphorylation in vitro and in vivo, and revealed a novel mechanism of ERK1/2 underlying tumor cell development and apoptotic resistance of glioma. PMID- 29286065 TI - Anti-inflammatory effects of Lefty-1 in renal tubulointerstitial inflammation via regulation of the NF-kappaB pathway. AB - Renal tubulointerstitial inflammation has an important role in fibrosis, which is the main pathogenetic alteration associated with chronic kidney disease (CKD). The left-right determination factor 1 (Lefty-1) gene pleiotropically and biologically regulates transforming growth factor, mitogen-activated protein kinase and other signaling pathways, and is considered to have a potential anti inflammatory function. However, its role in renal tubulointerstitial inflammation, which is often a long-term consequence of renal fibrosis, is currently unknown. In the present study, the effects of adenovirus-mediated overexpression of Lefty-1 (Ad-Lefty-1-flag) on renal tubulointerstitial inflammation were determined using a mouse model of unilateral ureteral obstruction (UUO) and a rat renal tubular duct epithelial cell line (NRK-52E), which was treated with lipopolysaccharide (LPS). In vivo results indicated that the inflammatory response was increased in UUO mice, as evidenced by the increase in inflammatory cytokines and chemokines. Conversely, Lefty-1 significantly reversed the effects of UUO. Furthermore, the results of the in vitro study demonstrated that Lefty-1 significantly inhibited LPS-induced inflammatory marker expression in cultured NRK-52E cells via the nuclear factor (NF)-kappaB signaling pathway. These results suggested that Lefty-1 may ameliorate renal tubulointerstitial inflammation by suppressing NF-kappaB signaling. In conclusion, the findings of the present study indicated that Lefty-1 may be considered a potential novel therapeutic agent for inhibiting renal tubulointerstitial inflammation or even reversing the CKD process. PMID- 29286067 TI - Changes in microRNA expression in the brachial plexus avulsion model of neuropathic pain. AB - The present study aimed to perform microRNA (miRNA/miR) expression profiling of the thalamus (T), the anterior cingulate (AC), the dorsal horn of the spinal cord (DHSC) and the blood (B) in post-complete brachial plexus avulsion (CBPA) pain model, and analyze biological functions. Neuropathic pain was induced in Sprague Dawley rats by CBPA. Animal behavioral tests were performed to differentiate the pain and control groups. DHSC, T, AC and B tissues were collected from the two groups for miRNA array analysis. The predicted mRNA targets were investigated by Gene Ontology analysis and pathway analysis. The results revealed that in the post-CBPA pain model, there were 10 differentially expressed miRNAs revealed among 4 different tissues. A total of 4 microRNAs in the AC and 3 microRNAs in the T were shown to be significantly upregulated. The functions of the differentially expressed miRNAs in the AC and T were synergetic in the aspect of positive regulation of neuron apoptotic process, inhibition of long-term potentiation and formation of synapse plasticity. miR-30c-1-3p and its predicted genes [calcium/calmodulin dependent protein kinase IIbeta (Camk2b) and protein kinase Cgamma (Prkcg)] existed in the AC and T groups with significant changes in expression. There were 2 miRNAs in the DHSC and B groups, respectively, with significant downregulation. The function of the change in miRNAs in the DHSC group was opposite to that in the AC and T groups. The differentially expressed microRNAs in the B group were revealed to be negative for the regulation of cell apoptosis. In conclusion, the central nerve groups (AC and T) and the peripheral nerve group (DHSC) exhibited contrasting effects on synapse plasticity and neuron apoptosis. miR-30c-1-3p and its predicted genes (Camk2b and Prkcg) existed in the AC and T groups with significant changes in expression. PMID- 29286068 TI - Protective effect of angiotensin-(1-7) against hyperglycaemia-induced injury in H9c2 cardiomyoblast cells via the PI3KAkt signaling pathway. AB - Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide mainly generated from cleavage of AngI and AngII, possesses physiological and pharmacological properties, including anti-inflammatory and antidiabetic properties. Activation of the phosphoinositide 3-kinase and protein kinase B (PI3KAkt) signaling pathway has been confirmed to participate in cardioprotection against hyperglycaemia-induced injury. The aim of the present study was to test the hypothesis that Ang-(1-7) protects H9c2 cardiomyoblast cells against high glucose (HG)-induced injury by activating the PI3KAkt pathway. To examine this hypothesis, H9c2 cells were treated with 35 mmol/l (mM) glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. The cells were co-treated with 1 umol/l (uM) Ang-(1-7) and 35 mM glucose. The findings of the present study demonstrated that exposure of H9c2 cells to HG for 24 h markedly induced injury, as evidenced by an increase in the percentage of apoptotic cells, generation of reactive oxygen species and level of inflammatory cytokines, as well as a decline in cell viability and mitochondrial luminosity. These injuries were significantly attenuated by co-treatment of the cells with Ang-(1-7) and HG. In addition, PI3KAkt phosphorylation was suppressed by HG treatment, but this effect was abolished when the H9c2 cells were co treated with Ang-(1-7) and HG. Furthermore, the cardioprotection of Ang-(1-7) against HG-induced injury in H9c2 cardiomyoblasts was highly attenuated in the presence of either D-Ala7-Ang-(1-7) (A-779, an antagonist of the Mas receptor) or LY294002 (an inhibitor of PI3KAkt). In conclusion, the present study provided new evidence that Ang-(1-7) protects H9c2 cardiomyoblasts against HG-induced injury by activating the PI3KAkt signaling pathway. PMID- 29286069 TI - A 16-gene expression signature to distinguish stage I from stage II lung squamous carcinoma. AB - The present study aimed to perform screening of a gene signature for the discrimination and prognostic prediction of stage I and II lung squamous carcinoma. A microarray meta-analysis was performed to identify differentially expressed genes (DEGs) between stage I and II lung squamous carcinoma samples in seven microarray datasets collected from the Gene Expression Omnibus database via the MetaQC and MetaDE package in R. The important DEGs were selected according to the betweenness centrality value of the protein-protein interaction (PPI) network. Support vector machine (SVM) analysis was performed to screen the feature genes for discrimination and prognosis. One independent dataset downloaded from The Cancer Genome Atlas was used to validate the reliability. Pathway enrichment analysis was also performed for the feature genes. A total of 924 DEGs were identified to construct a PPI network consisting of 392 nodes and 686 edges. The top 100 of the 392 nodes were selected as crucial genes to construct an SVM classifier, and a 16-gene signature (caveolin 1, eukaryotic translation elongation factor 1gamma, casein kinase 2alpha1, tyrosine 3 monooxygenase/tryptophan 5-monooxygenase activation eta, tyrosine 3 monooxygenase/tryptophan 5-monooxygenase activation theta, pleiotrophin, insulin receptor, insulin receptor substrate 1, 3-phosphoinositide-dependent protein kinase-1, specificity protein 1, COP9 signalosome subunit 6, N-myc downstream regulated gene 1, retinoid X receptor alpha, heat shock protein 90alpha A1, karyopherin subunit beta1 and erythrocyte membrane protein band 4.1) with high discrimination accuracy was identified. This 16-gene signature had significant prognostic value, and patients with stage II lung squamous carcinoma exhibited shorter survival rates, compared with those with stage I disease. Seven DEGs of the 16-gene signature were significantly involved in the phosphoinositide 3 kinase-Akt signaling pathway. The 16-gene signature identified in the present study may be useful for stratifying the patients with stage I or II lung squamous carcinoma and predicting prognosis. PMID- 29286070 TI - NPPB modulates apoptosis, proliferation, migration and extracellular matrix synthesis of conjunctival fibroblasts by inhibiting PI3K/AKT signaling. AB - When treating glaucoma, excessive scar tissue reactions reduce the postoperative survival rate of the filtering bleb. Accumulating evidence has demonstrated that the proliferation, migration and extracellular matrix (ECM) synthesis of fibroblasts are important molecular mechanisms underlying scar formation. Recent evidence has demonstrated that chloride channels play an important role in controlling cell proliferation, apoptosis, migration and the cell cycle process in several cell types, but the effects of chloride channels on conjunctival fibroblasts have not be studied. The aim of the present study was to investigate the effects of the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) on cell proliferation, apoptosis, migration, cell cycle progression and ECM synthesis in human conjunctival fibroblasts (HConFs), and to further investigate the mechanism of resistance to scar formation following glaucoma filtration surgery. HConFs were exposed to NPPB or lubiprostone. Cell proliferation and viability was evaluated using the Cell Counting Kit-8. Cell migration was measured using Transwell migration and scratch-wound assays. Flow cytometry was used to study apoptosis and cell cycle progression. Quantitative polymerase chain reaction and western blot analyses were performed to determine mRNA and protein expression levels, respectively. Following NPPB treatment, HConFs exhibited reduced proliferation and migration, along with increased apoptosis. NPPB also inhibited cell cycle progression by arresting cells in the G0G1 phase and reducing collagen I and fibronectin expression, as well as the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT). However, lubiprostone treatment exerted the opposite effects on HConFs. Therefore, NPPB treatment inhibited proliferation, migration, cell cycle progression and synthesis of the ECM, while promoting apoptosis in HConFs, by inhibiting the PI3KAKT signaling pathway. PMID- 29286072 TI - 3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition. AB - Adipose tissue-derived stem cells (ADSCs) are considered promising candidates for stem cell therapy; however, the tumorigenicity of ADSCs remains controversial. The present study aimed to investigate the association between ADSCs and liver cancer cells, and to determine whether culture methods could influence the effects of ADSCs on liver cancer cell growth in vitro. Liver cancer cells were treated with ADSCs-conditioned medium (CM) that was collected using the two dimensional (2D) culture method, sphere culture method, or three-dimensional (3D) culture method. After that, cell viability and apoptosis were measured using CCK 8 and Annexin V-FITC assay, respectively; the cell motility and adhesive capacity were analyzed by scratch wound healing and cell adhesion assay, respectively; the cell migration and invasion were examined by Transwell units; and the molecular mechanisms of ADSCs on effecting epithelial mesenchymal transition signaling pathway were further analyzed. The results demonstrated that ADSCs-CM was able to inhibit the growth of liver cancer cells by inhibiting cell proliferation and promoting cell apoptosis, as well as by suppressing cell motility, adhesive capacity, migration and invasion. In addition, ADSCs-CM was able to suppress cell growth via the downregulation of epithelial-mesenchymal transition signaling. Notably, the enhanced inhibitory effects of ADSCs on liver cancer cell growth could be achieved after cultu-ring using a 3D approach. These findings suggested that ADSCs may provide a novel promising therapeutic approach for the treatment of patients with liver cancer, and the 3D culture method may provide a novel approach to explore the association between ADSCs and cancer. PMID- 29286073 TI - Proteasome inhibition protects against diet-induced gallstone formation through modulation of cholesterol and bile acid homeostasis. AB - Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks. After 12 weeks of the lithogenic diet, 8 out of the 10 mice in the control group had developed gallstones, whereas none of the mice who received proteasome inhibitors had developed gallstones. Notably, the expression of genes associated with cholesterol synthesis (sterol regulatory element-binding protein-2 and 3-hydroxy 3-methylglutaryl-CoA reductase), cholesterol secretion [ATP-binding cassette subfamily G member 5 (ABCG5) and ABCG8] and bile acid synthesis [cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), Cyp7b1, Cyp27a1 and Cyp8b1] was reduced in the livers of mice injected with BT or CF. Cyp7a1 encodes cholesterol 7alpha hydroxylase, the rate-limiting enzyme in the synthesis of bile acid from cholesterol. The present study therefore measured the expression levels of transcription factors that are known to inhibit Cyp7a1 expression, namely farnesoid X receptor (FXR), pregnane X receptor (PXR) and small heterodimer partner (SHP). Although FXR, PXR and SHP expression was predicted to increase in the presence of proteasome inhibitors, the expression levels were actually reduced; thus, it was concluded that they were not involved in the proteasome inhibition-induced regulation of Cyp7a1. Further investigation of the mitogen activated protein kinase and protein kinase A (PKA) signaling pathways in human hepatoma cells revealed that proteasome inhibition-induced c-Jun N-terminal kinase (JNK) phosphorylation reduced CYP7A1 and CYP27A1 expression. In addition, reduced PKA phosphorylation as a result of proteasome inhibition regulated ABCG5 and ABCG8 expression. In conclusion, these findings suggest that proteasome inhibition regulates cholesterol and biliary metabolism via the JNK and PKA pathways, and is a promising therapeutic strategy to prevent gallstone disease. PMID- 29286071 TI - Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis (Review). AB - Numerous studies over the past two decades have focused on the epithelial-to mesenchymal transition (EMT) and its role in the development of metastasis. Certain studies highlighted the importance of EMT in the dissemination of tumor cells and metastasis of epithelium-derived carcinomas. Tumor metastasis is a multistep process during which tumor cells change their morphology, and start to migrate and invade distant sites. The present review discusses the current understanding of the molecular mechanisms contributing to EMT in embryogenesis, fibrosis and tumorigenesis. Additionally, the signaling pathways that initiate EMT through transcriptional factors responsible for the activation and suppression of various genes associated with cancer cell migration were investigated. Furthermore, the important role of the epigenetic modifications that regulate EMT and the reverse process, mesenchymal-to-epithelial transition (MET) are discussed. MicroRNAs are key regulators of various intracellular processes and current knowledge of EMT has significantly improved due to microRNA characterization. Their effect on signaling pathways and the ensuing events that occur during EMT at the molecular level is becoming increasingly recognized. The current review also highlights the role of circulating tumor cells (CTCs) and CTC clusters, and their ability to form metastases. In addition, the biological properties of different types of circulating cells based on their tumor-forming potential are compared. PMID- 29286074 TI - Codonopis bulleynana Forest ex Diels inhibits autophagy and induces apoptosis of colon cancer cells by activating the NF-kappaB signaling pathway. AB - Despite its favorable clinical efficacy, oxaliplatin-based chemotherapy frequently results in treatment withdrawal and induces liver damage in colon cancer. Therefore, it is important to develop novel drugs, which can safely and effectively complement or replace the therapeutic effects of oxaliplatin. Codonopis bulleynana Forest ex Diels (cbFeD) has wide range of pharmacological effects, including anticancer effects. In the present study, the anticancer activity of cbFeD and its potential molecular mechanisms were investigated. In vitro, cell counting kit-8 assays and flow cytometry were used to assess the anti proliferation and apoptosis-promoting activities of cbFeD. Transmission electron microscopy was used to monitor the autophagic vesicles. Immunofluorescence staining was performed to observe the nuclear translocation of p65 and the fluorescence of microtubule-associated protein 1 light chain 3 (LC3) B-II. The protein expression levels of p65, inhibitor of nuclear factor (NF)-kappaB (IkappaB) a, LC3B-I, LC3B-II and Beclin-1 were detected using western blot analysis. In vivo, the antitumor effect of cbFeD was assessed in colon cancer bearing nude mice as a model. H&E staining and immunohistochemistry (IHC) were performed, with oxaliplatin set as a positive control. The results showed that cbFeD inhibited cell proliferation and promoted cell apoptosis in a dose dependent manner. The effects of a high dose of cbFeD on colon cancer cells were similar to those of oxaliplatin. In HCT116 and SW480 cells, cbFeD inhibited the expression of IkappaBalpha, LC3B-I/II and Beclin-1, and the results of western blot analysis and immunofluorescence showed that, in the cells treated with cbFeD, p65 gradually entered nuclei in a dose-dependent manner, and the expression of LC3B-II was gradually reduced. The results of the acridine orangestaining and electron microscopy demonstrated fewer autophagic vesicles in the high-dose cbFeD group and the oxaliplatin group. The high dose of cbFeD reversed the effect of pyrrolidine dithiocarbamate, a p65-inhibitor, on the expression of p65, LC3B-I, LC3B-II and Beclin-1, and on the production of autophagic vacuoles. The high dose of cbFeD and oxaliplatin also suppressed tumorigenicity in vivo. The results of the H&E and IHC staining confirmed the inhibition of autophagy (LC3 and Beclin-1) and activation of p65 by treatment with the high dose of cbFeD and oxaliplatin. Taken together, cbFeD exhibited an antitumor effect in colon cancer cells by inhibiting autophagy through activation of the NF-kappaB pathway. Therefore, cbFeD may be a promising Chinese herbal compound for development for use in cancer therapy. PMID- 29286075 TI - Genome expression profiling predicts the molecular mechanism of peripheral myelination. AB - The present study aimed to explore the molecular mechanism of myelination in the peripheral nervous system (PNS) based on genome expression profiles. Microarray data (GSE60345) was acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were integrated and subsequently subjected to pathway and term enrichment analysis. A protein-protein interaction network was constructed and the top 200 DEGs according to their degree value were further subjected to pathway enrichment analysis. A microRNA (miR)-target gene regulatory network was constructed to explore the role of miRs associated with PNS myelination. A total of 783 upregulated genes and 307 downregulated genes were identified. The upregulated DEGs were significantly enriched in the biological function of complement and coagulation cascades, cytokine-cytokine receptor interactions and cell adhesion molecules. Pathways significantly enriched by the downregulated DEGs included the cell cycle, oocyte meiosis and the p53 signaling pathway. In addition, the upregulated DEGs among the top 200 DEGs were significantly enriched in natural killer (NK) cell mediated cytotoxicity and the B cell receptor (BCR) signaling pathway, in which Fc gamma receptor (FCGR), ras related C3 botulinum toxin substrate 2 (RAC2) and 1-phosphatidylinositol-4,5 bisphosphate phosphodiesterase gamma-2 (PLCG2) were involved. miR-339-5p, miR-10a 5p and miR-10b-5p were identified as having a high degree value and may regulate the target genes TOX high mobility group box family member 4 (Tox4), DNA repair protein XRCC2 (Xrcc2) and C5a anaphylatoxin chemotactic receptor C5a2 (C5ar2). NK cell mediated cytotoxicity and the BCR pathway may be involved in peripheral myelination by targeting FCGR, RAC2 and PLCG2. The downregulation of oocyte meiosis, the cell cycle and the cellular tumor antigen p53 signaling pathway suggests decreasing schwann cell proliferation following the initiation of myelination. miR-339-5p, miR-10a-5p and miR-10b-5p may play important roles in PNS myelination by regulating Tox4, Xrcc2 and C5ar2. PMID- 29286076 TI - Activation of transient receptor potential vanilloid 1 protects the heart against apoptosis in ischemia/reperfusion injury through upregulating the PI3K/Akt signaling pathway. AB - Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel and a molecular integrator of noxious stimuli. TRPV1 activation confers cardiac protection against ischemia/reperfusion (I/R) injury. The present study aimed to investigate whether the cardioprotective effects of TRPV1 were associated with the inhibition of apoptosis via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling pathways. Briefly, the hearts of TRPV1 knockout (TRPV1-/-) or wild-type (WT) mice were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion in a Langendorff apparatus in the presence or absence of the PI3K inhibitor, LY294002. At the end of reperfusion, infarct size was measured using 2,3,5-triphenyltetrazolium chloride staining and myocardial apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), and phosphorylated Akt and ERK1/2 were determined by western blot analysis. There was a significant increase in the extent of infarction and the percentage of TUNEL-positive cells, and a decrease in the Bcl 2/Bax ratio, and Akt and ERK1/2 phosphorylation in TRPV1-/- hearts. In addition, treatment with LY294002 increased infarct size and the percentage of TUNEL positive cells, and reduced Bcl-2/Bax expression and Akt phosphorylation in WT hearts, but not in TRPV1-/- hearts, following I/R. Taken together, these data suggested that TRPV1 serves a protective role against myocardial apoptosis during I/R via the PI3K/Akt signaling pathway. In conclusion, activating TRPV1 may be considered a potential approach to protect the heart against I/R injury. PMID- 29286077 TI - Analysis of the oncogene BRAF mutation and the correlation of the expression of wild-type BRAF and CREB1 in endometriosis. AB - B-Raf proto-oncogene, serine/threonine kinase (BRAF) has previously been identified as a candidate target gene in endometriosis. Wild-type and mutated BRAF serve important roles in different diseases. The aim of the present study was to explore BRAF mutation, the mRNA and protein expression of wild-type BRAF (wtBRAF) in endometriosis, and the association between the expression levels of wtBRAF and the predicted transcription factor cAMP responsive element binding protein 1 (CREB1). In the present study, BRAF mutation was detected using Sanger sequencing among 30 ectopic and matched eutopic endometrium samples of patients with endometriosis as well as 25 normal endometrium samples, and no BRAF mutation was detected in exons 11 or 15. A region of ~2,000 bp upstream of the BRAF gene was then screened using NCBI and UCSC databases, and CREB1 was identified as a potential transcription factor of BRAF by analysis with the JASPAR and the TRANSFAC databases. Quantitative polymerase chain reaction was used to analysis the mRNA expression levels of wtBRAF and CREB1, and the corresponding protein expression levels were evaluated using immunohistochemistry and western blot analysis. The results revealed that the mRNA and protein expression levels of wtBRAF and CREB1 were significantly upregulated in the eutopic endometrial tissues of patients with endometriosis compared with normal endometrial tissues (P<0.05) and no significant difference in wtBRAF and CREB1 levels was detected between the ectopic and eutopic endometrium (P>0.05). In addition, correlation analysis revealed that the protein expression of CREB1 was positively correlated with the transcript level and protein expression of wtBRAF. It is reasonable to speculate that CREB1 may activate the transcription of wtBRAF through directly binding to its promoter, increasing BRAF expression and regulating the cell proliferation, migration and invasion of endometriosis. PMID- 29286078 TI - Direct binding of Toll-like receptor 4 to ionotropic glutamate receptor N-methyl D-aspartate subunit 1 induced by lipopolysaccharide in microglial cells N9 and EOC 20. AB - Microglia, the primary immune cells in the brain, are the predominant cells regulating inflammation-mediated neuronal damage. In response to immunological challenges, such as lipopolysaccharide (LPS), microglia are activated and the inflammatory process is subsequently initiated. The aim of the present study was to determine whether LPS induces interactions between the Toll-like receptor 4 (TLR4) and the ionotropic glutamate receptor N-methyl-D-aspartate subunit 1 (GluN1) in N9 and EOC 20 microglial cells. Immunocytochemistry demonstrated co localization of TLR4 and GluN1 in response to LPS, and the direct binding of TLR4 and GluN1 was further validated by antibody-based Fluorescence Resonance Energy Transfer technology. Inhibition of the group I metabotropic glutamate receptor 5 with its selective antagonist, MTEP, abolished LPS-induced direct binding of TLR4 to GluN1. Therefore, these data demonstrated that GluN1 and TLR4 act reciprocally in response to LPS in N9 and EOC 20 microglial cells. PMID- 29286079 TI - Exogenous hydrogen sulfide protects human umbilical vein endothelial cells against high glucose-induced injury by inhibiting the necroptosis pathway. AB - Hyperglycemia is a key factor in the development of diabetic complications, including the processes of atherosclerosis. Receptor-interacting protein 3 (RIP3), a mediator of necroptosis, is implicated in atherosclerosis development. Additionally, hydrogen sulfide (H2S) protects the vascular endothelium against hyperglycemia-induced injury and attenuates atherosclerosis. On the basis of these findings, the present study aimed to confirm the hypothesis that necroptosis mediates high glucose (HG)-induced injury in human umbilical vein endothelial cells (HUVECs), and that the inhibition of necroptosis contributes to the protective effect of exogenous H2S against this injury. The results revealed that exposure of HUVECs to 40 mM HG markedly enhanced the expression level of RIP3, along with multiple injuries, including a decrease in cell viability, an increase in the number of apoptotic cells, an increase in the expression level of cleaved caspase-3, generation of reactive oxygen species (ROS), as well as dissipation of the mitochondrial membrane potential (MMP). Treatment of the cells with sodium hydrogen sulfide (NaHS; a donor of H2S) prior to exposure to HG significantly attenuated the increased RIP3 expression and the aforementioned injuries by HG. Notably, treatment of cells with necrostatin-1 (Nec-1), an inhibitor of necroptosis, prior to exposure to HG ameliorated the HG-induced injuries, leading to a decrease in ROS generation and a loss of MMP. However, pre treatment of the cells with Nec-1 enhanced the HG-induced increase in the expression levels of cleaved caspases-3 and -9. By contrast, pre-treatment with Z VAD-FMK, a pan -caspase inhibitor, promoted the increased expression of RIP3 by HG. Taken together, the findings of the present study have demonstrated, to the best of our knowledge for the first time, that exogenous H2S protects HUVECs against HG-induced injury through inhibiting necroptosis. The present study has also provided novel evidence that there is a negative interaction between necroptosis and apoptosis in the HG-treated HUVECs. PMID- 29286080 TI - A murine model of dry eye induced by topical administration of erlotinib eye drops. AB - In the present study, the effects of erlotinib on mouse tear function and corneal epithelial tissue structure were investigated. Throughout the 3 weeks of treatment, no notable differences were observed in the body, eye or lacrimal gland weights of the control and experimental mice. However, in the experimental group, the tear volume and break-up times of tear film were significantly lower following treatment with erlotinib compared with the control group. Corneal fluorescein staining in the experimental group revealed patchy staining, and the Lissamine green staining and inflammatory index were significantly higher in the experimental group at 3 weeks than in the control group. In the experimental group, the number of corneal epithelium layers increased significantly following treatment with erlotinib for 3 weeks and a significant increase in the number of vacuoles was observed compared with the control group. Treatment with erlotinib significantly increased the corneal epithelial cell apoptosis, and led to a significantly increased number of epithelial cell layers and increased keratin 10 expression. It also significantly reduced the number of conjunctival goblet cells. Transmission electron microscopy and scanning electron microscopy revealed that the corneal epithelial surface was irregular and there was a substantial reduction and partial loss of the microvilli in the experimental group. Mice treated with erlotinib also exhibited an increased protein expression of tumor necrosis factor-alpha and decreased protein expression of phosphorylated epidermal growth factor receptor in the corneal epithelial cells. The topical application of erlotinib eye drops was revealed to induce dry eyes in mice. This is a novel method of developing a model of dry eyes in mice. PMID- 29286081 TI - Aryl hydrocarbon receptor activation maintained the intestinal epithelial barrier function through Notch1 dependent signaling pathway. AB - Intestinal ischemia/reperfusion (I/R) induces disruption of the intestinal barrier function. Aryl hydrocarbon receptor (AhR) has a vital role in maintaining the intestinal barrier function. However, the precise mechanism by which AhR maintains intestinal barrier function remains unclear. Notch1 signaling is downstream of AhR, and has also been reported to have a role in the development of tight junctions (TJs) and maintenance of intestinal homeostasis. Therefore, we hypothesized that AhR activation may attenuate the intestinal barrier dysfunction through increased activation of Notch1 signaling. Adult C57BL/6J mice were divided into three groups: Sham, I/R and I/R + 6-formylindolo(3,2-b)carbazole (Ficz) groups. Mice were sacrificed after I/R for 6 h and the intestine was harvested for histological examination, mRNA and protein content analysis, and mucosal permeability investigation. Additionally, a hypoxic Caco-2 cell culture model was used to evaluate the role of AhR-Notch1 signaling in the development of TJs and epithelial permeability in vitro. The AhR-Notch1 signaling components and TJ proteins were assessed by reverse transcription-quantitative polymerase chain reaction, western blotting, immunohistochemistry or immunofluorescence staining. Epithelial permeability was detected by transepithelium electrical resistance. The data demonstrated that Ficz significantly attenuated the intestinal tissue damage and the disrupted distribution of TJs, increased the expression of TJ proteins, reversed the decrease in TER and upregulated epithelial Notch1 signaling following intestinal I/R in vivo and hypoxia in vitro. Furthermore, inhibition of Notch1 signaling by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S phenylglycine t-butyl ester (inhibitor of Notch signaling) counteracted the effects of Ficz on the development of TJs in hypoxic Caco-2 cells. In conclusion, AhR activation ameliorated epithelial barrier dysfunction following intestinal I/R and hypoxia through upregulation of Notch1 signaling, which suggests that AhR may be a potential pharmaceutical agent to combat this condition. PMID- 29286082 TI - CCN1/Cyr61 enhances the function of hepatic stellate cells in promoting the progression of hepatocellular carcinoma. AB - Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in liver fibrosis. Activated HSCs stimulate the proliferation and migration of hepatocellular carcinoma (HCC) cells. Cysteine-rich 61 (CCN1/Cyr61) is an ECM protein. Our previous studies demonstrated that the expression of CCN1 was significantly higher in benign hepatic cirrhosis tissue and cancer-adjacent hepatic cirrhosis tissues. CCN1 is a target gene of beta-catenin in HCC and promotes the proliferation of HCC cells. The present study aimed to examine whether CCN1 can activate HSCs and affect the function of activated HSCs in promoting the progression of HCC. CCN1 expression was determined during the progression of liver fibrosis in a mouse model. LX-2 cells, which were infected with adenoviruses AdCCN1 or AdRFP, and HepG2 cells were co-cultured or subcutaneously co-implanted into in nude mice. MTT assay, Crystal Violet staining, Boyden chamber, matrigel invasion and monolayer scratch assays were used to analyze the proliferation, migration and invasion capability of HepG2 cells. Xenograft sizes were measured and histological analyses were performed by hematoxylin and eosin, immunohistochemical, immunefluorescence and Sirius Red staining. It was demonstrated that the expression of CCN1 was continually increased in liver fibrosis and the that expression may be correlated with the progression of liver fibrosis. CCN1 affected the function of LX-2 and enhanced the effect of LX-2 on promoting the viability, migration and invasion of HepG2 cells in vitro. CCN1 enhanced the effect of LX-2 on promoting the growth of HepG2 xenografts in vivo. CCN1 also affected the function of activated HSCs and regulated the formation of the xenograft microenvironment, including fibrogenesis and angiogenesis, which are beneficial for the progression of HCC. These findings demonstrated that CCN1 may be involved in the progression of the hepatic cirrhosis-HCC axis through regulating HSCs. PMID- 29286083 TI - KDM3A inhibition attenuates high concentration insulin-induced vascular smooth muscle cell injury by suppressing MAPK/NF-kappaB pathways. AB - Previous studies have indicated that lysine (K)-specific demethylase 3A (KDM3A) is associated with diverse diabetes-associated cardiovascular complications in response to high glucose levels. However, the effects of KDM3A on the pathological progression of cardiovascular injuries in response to high insulin levels remain unknown. The present study aimed to explore whether KDM3A knockdown may attenuate high insulin-induced vascular smooth muscle cell (VSMC) dysfunction, and to further investigate the underlying mechanisms. Primary VSMCs were isolated from the thoracic aorta of Sprague-Dawley rats. Lentiviral vectors encoding control-small interfering (si)RNA or KDM3A-siRNA were transduced into VSMCs for 72 h, and cells were subsequently incubated in medium containing 100 nM insulin for a further 5 days. Cellular proli-feration, migration and apoptosis were measured by Cell Counting kit-8, Transwell chamber assay and flow cytometry, respectively. Reactive oxygen species (ROS) were detected using the dihydroethidium fluorescent probe. The mRNA expression levels of interleukin-6 and monocyte chemotactic protein-1 were measured by reverse transcription quantitative polymerase chain reaction. Furthermore, the protein expression levels of KDM3A, mitogen-activated protein kinases (MAPKs), nuclear factor (NF) kappaB/p65, B-cell lymphoma 2 (Bcl-2)-associated X protein and Bcl-2 were evaluated by west-ern blotting. Lentivirus transduction with KDM3A-siRNA markedly reduced the elevated expression of KDM3A induced by high insulin stimulation in VSMCs. In addition, inhibition of KDM3A significantly ameliorated insulin-induced VSMC proliferation and migration, which was accompanied by decreased ROS levels, cell apoptosis and inflammatory cytokine levels. Furthermore, KDM3A gene silencing mitigated phosphorylation of MAPKs and NF-kappaB/p65 activation. In conclusion, KDM3A inhibition may exert numerous protective effects on high insulin-stimulated VSMCs, and the underlying mechanisms may be partly associated with inactivation of MAPK/NF-kappaB signaling pathways. PMID- 29286084 TI - Petasites japonicus bakkenolide B inhibits lipopolysaccharide-induced pro inflammatory cytokines via AMPK/Nrf2 induction in microglia. AB - Abnormal neuroinflammatory responses have diverse roles in neuronal death, oxidative stress and neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Microglia regulate these responses via molecular signaling cascades that involve inflammatory cytokines and complement proteins. Bakkenolide B from Petasites japonicus exhibits significant anti-inflammatory and anti allergic bioactivities. The present study investigated the anti-neuroinflammatory effects and underlying molecular mechanisms of bakkenolide B on the lipopolysaccharide (LPS)-mediated neuroinflammatory response in microglia. The results indicated that bakkenolide B pretreatment significantly reduced microglial production of interleukin (IL)-1beta, IL-6, IL-12, and tumor necrosis factor (TNF)-alpha. Furthermore, this effect was associated with reduced production of reactive oxygen species. The role of bakkenolide B was then evaluated in the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathways. The results suggested that bakkenolide B significantly upregulated Nrf2/ARE pathway-related downstream factors, such as NADPH dehydrogenase quinone-1 (NQO-1) and heme oxygenase-1 (HO-1). Silencing of Nrf2, HO-1 and NQO-1 diminished the anti neuroinflammatory properties of bakkenolide B. AMP-activated protein kinase (AMPK) activates the Nrf2/ARE signaling pathway, and the results of the present study demonstrated that bakkenolide B increased AMPK phosphorylation in microglia. In addition, an AMPK inhibitor abolished the bakkenolide B-induced increase in nuclear Nrf2, NQO-1 and HO-1 protein expression. Finally, an AMPK inhibitor diminished the bakkenolide B-mediated inhibition of LPS-stimulated TNF alpha production. Taken together, the present results demonstrate that bakkenolide B may be an effective and therapeutically relevant AMPK/Nrf2 pathway activator for suppressing abnormal neuro-inflammation in neurodegenerative diseases. PMID- 29286085 TI - Estrogen receptor-beta-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation. AB - Saikosaponin-d (SSd) is one of the major triterpenoid saponins derived from Bupleurum falcatum L., which has been reported to possess antifibrotic activity. At present, there is little information regarding the potential target of SSd in hepatic stellate cells (HSCs), which serve an important role in excessive extracellular matrix (ECM) deposition during the pathogenesis of hepatic fibrosis. Our recent study indicated that SSd may be considered a novel type of phytoestrogen with estrogen-like actions. Therefore, the present study aimed to investigate the effects of SSd on the proliferation and activation of HSCs, and the underlying mechanisms associated with estrogen receptors. In the present study, a rat HSC line (HSC-T6) was used and cultured with dimethyl sulfoxide, SSd, or estradiol (E2; positive control), in the presence or absence of three estrogen receptor (ER) antagonists [ICI-182780, methylpiperidinopyrazole (MPP) or (R,R)-tetrahydrochrysene (THC)], for 24 h as pretreatment. Oxidative stress was induced by exposure to hydrogen peroxide for 4 h. Cell proliferation was assessed by MTT growth assay. Malondialdehyde (MDA), CuZn-superoxide dismutase (CuZn-SOD), tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), transforming growth factor-beta1 (TGF-beta1), hydroxyproline (Hyp) and collagen-1 (COL1) levels in cell culture supernatants were determined by ELISA. Reactive oxygen species (ROS) was detected by flow cytometry. Total and phosphorylated mitogen-activated protein kinases (MAPKs) and alpha-smooth muscle actin (alpha-SMA) were examined by western blot analysis. TGF-beta1 mRNA expression was determined by RT-quantitative (q)PCR. SSd and E2 were able to significantly suppress oxidative stress-induced proliferation and activation of HSC-T6 cells. Furthermore, SSd and E2 were able to reduce ECM deposition, as demonstrated by the decrease in transforming growth factor-beta1, hydroxyproline, collagen-1 and tissue inhibitor of metalloproteinases-1, and by the increase in matrix metalloproteinase-1. These results suggested that the possible molecular mechanism could involve downregulation of the reactive oxygen species/mitogen activated protein kinases signaling pathway. Finally, the effects of SSd and E2 could be blocked by co-incubation with ICI-182780 or THC, but not MPP, thus indicating that ERbeta may be the potential target of SSd in HSC-T6 cells. In conclusion, these findings suggested that SSd may suppress oxidative stress induced activation of HSCs, which relied on modulation of ERbeta. PMID- 29286086 TI - MicroRNA-107 prevents amyloid-beta-induced neurotoxicity and memory impairment in mice. AB - The pathogenesis of Alzheimer's disease (AD) has still not been fully elucidated, however it is thought that the build up of amyloid plaque at least partially causes the symptoms of AD. MicroRNAs (miRNAs) are endogenous non-coding small RNA molecules that regulate the expression and degradation of proteins. The present study induced symptoms of AD in mice via intraventricular injection of amyloid beta 1-42 (Abeta1-42), which decreased levels of miR-107. However, miR-107 levels increased following administration of miR-107 mimic, a double-stranded RNA molecule designed to imitate the native miRNA. Intraventricular injection of Abeta1-42 aggregates led to spatial memory impairments, inhibited hippocampal long-term potentiation (LTP) and resulted in the loss of pyramidal cells in the CA1 region of the hippocampus. The miR-107 mimic reversed the impairments of spatial memory and LTP and the loss of pyramidal neurons caused by Abeta neurotoxicity. Furthermore, the miR-107 mimic reversed the Abeta-induced increase in Abeta1-42 and phosphorylated Tau levels. Critically, Abeta1-42 injection decreased levels of brain-derived neurotrophic factor and reduced the phosphorylation of tyrosine receptor kinase B and protein kinase B; these changes were reversed following treatment with the miR-107 mimic. Collectively, these results demonstrated that miR-107 may be a potential target for the treatment of AD. PMID- 29286087 TI - Growth differentiation factor-5 induces tenomodulin expression via phosphorylation of p38 and promotes viability of murine mesenchymal stem cells from compact bone. AB - Growth differentiation factor (GDF)-5 serves a role in tissue development and tenomodulin serves an important role in the development of tendons. The effects of GDF-5 on mesenchymal stem cells (MSCs), particularly with regards to tendon bioengineering, are poorly understood. The present study aimed to investigate the effects of GDF-5 on cell viability and tenomodulin expression in MSCs from murine compact bone. MSCs were isolated from murine compact bones and confirmed by flow cytometric analysis. In addition, the adipogenic, osteoblastic and chondrocyte differentiation capabilities of the MSCs were determined. MSCs were treated with GDF-5 and the effects of GDF-5 on MSC viability were determined. The mRNA and protein expression levels of tenomodulin were detected by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. MSCs from murine compact bone were successfully isolated. GDF-5 had optimal effects on cell viability at 100 ng/ml (+36.9% of control group without GDF-5 treatment, P<0.01) and its effects peaked after 6 days of treatment (+56.6% of control group, P<0.001). Compared with the control group, treatment with 100 ng/ml GDF-5 for 4 days enhanced the mRNA expression levels of tenomodulin (3.56+/-0.94 vs. 1.02+/-0.25; P<0.05). In addition, p38 was activated by GDF-5, as determined by enhanced expression levels of phosphorylated p38 (p-p38). The GDF-5-induced protein expression levels of p-p38 and tenomodulin were markedly inhibited following treatment with SB203580, an inhibitor of p38 mitogen-activated protein kinase. These results suggested that GDF-5 treatment may increase tenomodulin protein expression via phosphorylation of p38 in MSCs from murine compact bone. These findings may aid the future development of tendon bioengineering. PMID- 29286088 TI - Arkadia protein expression is reduced in the liver during the progression of hepatic fibrosis. AB - Arkadia is able to degrade key signaling molecules in the transforming growth factor (TGF)-beta1 signaling pathway; however, the expression of Arkadia in the liver during development and progression of TGF-beta1/Smad signaling-regulated hepatic fibrosis remains to be elucidated. The present study aimed to examine Arkadia expression in the livers of two rat models of hepatic fibrosis induced by bile duct ligation and carbon tetrachloride intoxication, and in human liver samples from patients with hepatic fibrosis. Expression was analyzed by quantitative polymerase chain reaction, immunohistochemistry and western blot analysis. The results indicated that Arkadia was predominantly expressed in the cytoplasm of cholangiocytes and hepatocytes. The protein expression levels of Arkadia were significantly decreased in fibrotic livers, whereas the mRNA expression levels of Arkadia were significantly increased in fibrotic livers compared with in nonfibrotic livers. In conclusion, these data indicated that Arkadia may regulate the pathogenesis and progression of hepatic fibrosis. PMID- 29286090 TI - Therapeutic inhibition of galectin-3 improves cardiomyocyte apoptosis and survival during heart failure. AB - Galectin-3 is an important mediator of cardiac fibrosis and heart failure. Cell viability of cardiomyocytes was measured using a CCK-8 assay; flow cytometry was employed for the detection of the cell cycle and cardiomyocytes apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting was performed to examine the expression of associated genes and proteins. The present study demonstrated that overexpression of galectin-3 significantly decreased the viability of cardiomyocytes in a time-dependent manner, with simultaneous arrest of the cell cycle and induction of apoptosis. The expression levels of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma 2 (Bcl-2) were decreased and Bcl-2-associated X protein (Bax) was increased in cardiomyocytes with galectin-3 overexpression. However, inhibition of galectin-3 by intravenous tail vein injection of a galectin-3-targeting short hairpin RNA expressing vector during hypertension-induced heart failure in Dahl hypertensive rats increased rat survival and body weight. Inhibition of galectin-3 also increased the expression of PCNA and Bcl-2 and reduced the expression of Bax in the cardiac tissue of hypertensive rats. These results demonstrate the therapeutic potential of targetinggalectin-3 for the treatment of cardiac disease. PMID- 29286089 TI - BCSG1 siRNA delivered by lentiviral vector suppressed proliferation and migration of MDA-MB-231 cells. AB - Breast cancer-specific gene 1 (BCSG1), also referred to as gamma-synuclein (SNCG), is highly expressed in human infiltrating breast carcinomas, but not in normal or benign breast tissue. The present study aimed to evaluate the effects of BCSG1 siRNA delivered by lentiviral vector on breast cancer cells and investigate the underlying mechanisms. BCSG1 RNAi lentiviral vector was constructed and transfected into MDA-MB-231 cells. BCSG1 mRNA levels were determined by quantitative polymerase chain reaction analysis. Cell proliferation, migration and apoptosis were evaluated by using the cell counting kit-8, Transwell assay and flow cytometry, respectively, followed by western blotting to determine the relative levels of AKT, extracellular signal-regulated kinase (ERK), p-AKT and p-ERK expression. BCSG1 mRNA levels were significantly reduced in MDA-MB-231 cells following transfection of BCSG1 siRNA delivered by lentiviral vector. Cell migration and proliferation were significantly decreased and the cell cycle was arrested. Western blot analysis indicated that the protein levels of p-AKT and p-ERK were significantly lower in the BCSG1 siRNA-treated groups compared with the control and negative control groups. Therefore, BCSG1 siRNA delivered by lentiviral vector was able to significantly reduce BCSG1 expression, suppress cell migration and proliferation, possibly through the reduction of the protein levels of p-AKT and p-ERK. PMID- 29286091 TI - Identifying heterogeneous subtypes of gastric cancer and subtype-specific subpaths of microRNA-target pathways. AB - The present study aimed to classify gastric cancer (GC) into subtypes and to screen the subtype-specific genes, their targeted microRNAs (miRNAs) and enriched pathways to explore the putative mechanism of each GC subtypes. The GSE13861 data set was downloaded from the Gene Expression Omnibus and used to screen differential expression genes (DEGs) in GC samples based on the detection of imbalanced differential signal algorithm. The specific genes in each subtype were identified with the cut-off criterion of U>0.04, pathway enrichment analysis was performed and the subtype-specific subpaths of miRNA-target pathway were determined. A total of 1,263 DEGs were identified in the primary gastric adenocarcinoma (PGD) samples, which were subsequently divided into four subtypes, according to the hierarchy cluster analysis. Identification of the subpaths of each subtype indicated that the subpath related to subtype 1 was miRNA (miR) 202/calcium voltage-gated channel subunit alpha1 (CACNA1E)/type II diabetes mellitus. The nuclear factor-kappaB signaling pathway was the most significantly specific pathway and subpath identified for subtype 2, which was regulated by miR 338-targeted suppression of C-C motif chemokine ligand 21 (CCL21). For subtype 3, significant related pathways included ubiquitin-mediated proteolysis and proteasome, and the important subpath was miR-146B/proteasome 26S subunit, non ATPase 3 (PSMD3)/proteasome; focal adhesion was the significant pathway indicated for subtype 4, and the subpaths were miR-34A/vinculin (VCL)/focal adhesion and miR-34C/VCL/focal adhesion. In addition, Helicobacter pylori infection was higher in GC subtype 1 than in other subtypes. Specific genes, such as CACNA1E, CCL21, PSMD3 and VCL, may be used as potential feature genes to identify different subtypes of GC, and their associated subpaths may partially explain the pathogenetic mechanism of each GC subtype. PMID- 29286092 TI - 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside inhibits septic serum-induced inflammatory injury via interfering with the ROS-MAPK-NF-kappaB signaling pathway in pulmonary aortic endothelial cells. AB - Sepsis is characterized by injury to the microvasculature and the microvascular endothelial cells, leading to barrier dysfunction. However, the specific role of injury in septic endothelial barrier dysfunction remains to be elucidated. In the present study, it was hypothesized that endothelial cell inflammatory injury is likely required for barrier dysfunction under septic conditions in vitro. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), a compound extracted from Chinese herbs, is able to inhibit the inflammatory injury of septic-serum in endothelial cells. In the present study, cell viability was assayed by CCK-8 method; mRNA and protein expression was identified by RT-qPCR, western blot or Elisa, respectively and the production of reactive oxygen species was observed by a fluorescence microscope. The present study indicated that septic serum significantly decreased the cell viability of pulmonary aortic endothelial cells (PAECs) following co-cultivation for 6 h, which occurred in a time-dependent manner. TSG notably increased the viability of PAECs in a time- and concentration dependent manner. Further investigations revealed that septic serum increased the secretion of interleukin (IL)-1beta, IL-6 and C-reactive protein in PAECs, whereas pretreatment with TSG significantly decreased the secretion of these inflammatory factors. These data indicated that septic serum increased inflammatory injury to the PAECs, and TSG decreased this injury via the reactive oxygen species-mitogen-activated protein kinase-nuclear factor-kappaB signaling pathway. PMID- 29286094 TI - Sphingosine-1-phosphate ameliorates the cardiac hypertrophic response through inhibiting the activity of histone deacetylase-2. AB - Inhibition of histone deacetylase-2 (HDAC2), which is a prohypertrophic factor in the heart, can functionally attenuate cardiac hypertrophy. The present study aimed to investigate whether sphingosine-1-phosphate (S1P), which has recently been reported to suppress HDAC2 activity, could ameliorate the cardiac hypertrophic response and improve cardiac function in mice with transverse aortic constriction (TAC), as well as to determine the underlying mechanisms. Briefly, 8 week-old male C57BL/6 mice were randomly divided into sham, TAC and TAC + S1P groups; the results indicated that S1P treatment attenuated TAC-induced cardiac dysfunction. In addition, heart size and the expression levels of fetal cardiac genes were reduced in the TAC + S1P group compared with in the TAC group. Furthermore, in cultured H9c2 cells exposed to phenylephrine, S1P was revealed to decrease cardiomyocyte size and the exaggerated expression of fetal cardiac genes. The present study also demonstrated that S1P had no effect on HDAC2 expression, but it did suppress its activity and increase acetylation of histone H3 in vivo and in vitro. Kruppel-like factor 4 (KLF4) is an antihypertrophic transcriptional regulator, which mediates HDAC inhibitor-induced prevention of cardiac hypertrophy; in the present study, KLF4 was upregulated by S1P. Finally, the results indicated that S1P receptor 2 (S1PR2) may be involved in the antihypertrophic effects, whereas the suppressive effects of S1P on HDAC2 activity were independent of S1PR2. In conclusion, the present study demonstrated that S1P treatment may ameliorate the cardiac hypertrophic response, which may be partly mediated by the suppression of HDAC2 activity and the upregulation of KLF4; it was suggested that S1PR2 may also be involved. Therefore, S1P may be considered a potential therapy for the treatment of heart diseases caused by cardiac hypertrophy. PMID- 29286093 TI - Identifying hub genes and potential mechanisms associated with senescence in human annulus cells by gene expression profiling and bioinformatics analysis. AB - The aim of the present study was to reveal the potential hub genes and regulatory mechanisms associated with senescence in human annulus cells by analyzing microarray data using bioinformatics. The gene expression dataset GSE17077, of senescent and non-senescent annulus cells obtained from patients with disc degenerative diseases (DDD), was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified. Functional and pathway annotations were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms, respectively. Web-based Gene Set Analysis Toolkit and Chip Enrichment Analysis were used to identify key transcription factors (TFs). A protein-protein interaction (PPI) network was constructed to analyze the hub genes associated with senescence in DDD. A total of 667 DEGs were screened, including 368 up- and 299 down-regulated genes. These DEGs were enriched in phosphorylation, regulation of apoptosis and regulation of programmed cell death. In addition, DEGs were involved in axon guidance, natural killer cell-mediated cytotoxicity, purine metabolism and the mitogen-activated protein kinase (MAPK) signaling pathway. The TFs activator protein 1 (AP1), specificity protein 1 and aryl hydrocarbon receptor may serve regulatory roles in gene expression in senescent cells. Certain key target genes of TFs, including heat shock protein 90 (HSP90) and C-X-C motif chemokine 5 (CXCL5), within the DEGs were revealed to have a high connectivity degree by PPI analysis. The results of the present study indicated that the MAPK-regulated AP1 pathway may contribute to senescence associated disc degeneration. The DEGs, including HSP90 and CXCL5, with a high degree of connectivity may be potential targets for future investigations into molecular biomarkers. PMID- 29286095 TI - Structural and functional failure of fibrillin-1 in human diseases (Review). AB - Fibrillins (FBNs) are key relay molecules that form the backbone of microfibrils in elastic and non-elastic tissues. Interacting with other components of the extracellular matrix (ECM), these ubiquitous glycoproteins exert pivotal roles in tissue development, homeostasis and repair. In addition to mechanical support, FBN networks also exhibit regulatory activities on growth factor signalling, ECM formation, cell behaviour and the immune response. Consequently, mutations affecting the structure, assembly and stability of FBN microfibrils have been associated with impaired biomechanical tissue properties, altered cell-matrix interactions, uncontrolled growth factor or cytokine activation, and the development of fibrillinopathies and associated severe complications in multiple organs. Beyond a panoramic overview of structural cues of the FBN network, the present review will also describe the pathological implications of FBN disorders in the development of inflammatory and fibrotic conditions. PMID- 29286096 TI - Downregulation of microRNA-9 increases matrix metalloproteinase-13 expression levels and facilitates osteoarthritis onset. AB - Matrix metalloproteinase-13 (MMP-13) degrades collagen and other matrix components, thus playing a critical role in the development of osteoarthritis (OA). The expression level of microRNA-9 (miR-9) is significantly depressed in cartilage tissues of OA patients. Furthermore, bioinformatics analysis demonstrated complementary binding sites between miR-9 and MMP-13. The current study, therefore, investigated whether miR-9 is involved in regulating MMP-13 expression levels and OA onset. Cartilage tissues from OA patients and healthy individuals were compared for miR-9, MMP-13 and collagen type II alpha1 chain (Col2A1) expression levels. A dual luciferase gene reporter assay was performed to evaluate the association between miR-9 and MMP-13. Sodium iodoacetate was injected into the knee joint cartilage tissues to generate the rat OA model. The expression levels of miR-9, MMP-13 and Col2A1 were compared between the model and control rats. In addition, the OA model rats received miR-9 agomir for further expressional assay. Cartilage tissue samples from the OA patients exhibited significantly lower miR-9 and Col2A1 expression levels when compared with the control rats, whilst the expression level of MMP-13 was upregulated. As the target gene of miR-9, MMP-13 is under the targeted regulation of miR-9. The injection of miR-9 agomir into the knee joint cavity significantly depressed MMP 13 expression in the cartilage tissues of OA rats, with reduced collagen degradation and enhanced COL2A1. OA cartilage tissues have lower miR-9 expression and higher MMP-13 expression levels. Thus, miR-9 inhibits the expression level of MMP-13, decreases its inhibitory effects on COL2A1, and therefore contributes to antagonizing OA. PMID- 29286097 TI - Identification of key genes associated with congenital heart defects in embryos of diabetic mice. AB - Maternal diabetes has been reported to be a critical factor for congenital heart defects (CHD) in offspring. The present study aimed to screen the key genes that may be involved in CHD in offspring of diabetic mothers. The present study obtained the gene expression profile of GSE32078, including three embryonic heart tissue samples at embryonic day 13.5 (E13.5), three embryonic heart tissue samples at embryonic day 15.5 (E15.5) from diabetic mice and their respective controls from normal mice. The cut-off criterion of P<0.08 was set to screen differentially expressed genes (DEGs). Their enrichment functions were predicted by Gene Ontology. The enriched pathways were forecasted by Kyoto Encyclopedia of Genes and Genomes and Reactome analysis. Protein-protein interaction (PPI) networks for DEGs were constructed using Cytoscape. The present study identified 869 and 802 DEGs in E13.5 group and E15.5 group, respectively and 182 DEGs were shared by the two developmental stages. The pathway enrichment analysis results revealed that DEGs including intercellular adhesion molecule 1 (Icam1) and H2-M9 were enriched in cell adhesion molecules; DEGs including bone morphogenetic protein receptor type 1A, transforming growth factor beta receptor 1 and SMAD specific E3 ubiquitin protein ligase 1 were enriched in the tumor growth factor beta signaling pathway. In addition, DEGs including Icam1, C1s and Fc fragment of IgG receptor IIb were enriched in Staphylococcus aureus infection. Furthermore, the shared DEGs including Icam1, nuclear receptor corepressor 1 (Ncor1) and AKT serine/threonine kinase 3 (Akt3) had high connectivity degrees in the PPI network. The shared DEGs including Icam1, Ncor1 and Akt3 may be important in the cardiogenesis of embryos. These genes may be involved in the development of CHD in the offspring of diabetic mothers. PMID- 29286099 TI - Downregulation of matrix metalloproteinase 14 by the antitumor miRNA, miR-150-5p, inhibits the aggressiveness of lung squamous cell carcinoma cells. AB - In the present study, in order to elucidate the aggressive nature of lung squamous cell carcinoma (LUSQ), we investigated the oncogenic RNA networks regulated by antitumor microRNAs (miRNAs or miRs) in LUSQ cells. The analysis of our original miRNA expression signatures of human cancers revealed that microRNA 150-5p (miR-150-5p) was downregulated in various types of cancer, indicating that miR-150-5p acts as an antitumor miRNA by targeting several oncogenic genes. Thus, the aims of this study were to investigate the antitumor roles of miR-150-5p in LUSQ cells and to identify oncogenes regulated by miR-150-5p that are involved in the aggressive behavior of LUSQ. The downregulation of miR-150-5p was validated in clinical samples of LUSQ and cell lines (SK-MES-1 and EBC-1). The ectopic overexpression of miR-150-5p significantly suppressed cancer cell aggressiveness. Comprehensive gene expression analyses revealed that miR-150-5p regulated 9 genes in the LUSQ cells. Among these, matrix metalloproteinase 14 (MMP14) was found to be a direct target of miR-150-5p, as shown by luciferase reporter assay. The knockdown of MMP14 using siRNA against MMP14 (si-MMP14) significantly inhibited cancer cell migration and invasion. The overexpression of MMP14 was detected in clinical specimens of LUSQ by immunohistochemistry. On the whole, these findings suggest that the downregulation of miR-150-5p and the overexpression of MMP14 may be deeply involved in the pathogenesis of LUSQ. PMID- 29286098 TI - Luteolin inhibits pancreatitis-induced acinar-ductal metaplasia, proliferation and epithelial-mesenchymal transition of acinar cells. AB - Luteolin, a flavone, has been demonstrated to have anti-cancer properties. In the current study, the effects of luteolin on certain carcinogenesis-associated changes induced by pancreatitis, which are significant risk factors for pancreatic cancer, were investigated. Male six-week-old C57BL6 mice used in the current study were divided into three groups; the control group, acute pancreatitis group and luteolin group. Intra-peritoneal injection of cearulein was performed in the acute pancreatitis group and luteolin group to induce acute pancreatitis whereas the luteolin group received intra-peritoneal injection of luteolin. The control group received intra-peritoneal injection of normal saline. Then, the expression of SOX9, phosphorylated (p-) STAT3, p-EGFR, cytokeratin-19, Ki67 and N-cadherin were determined by immunohistochemistry. Morphological changes of acinar cells were determined by hematoxylin and eosin staining. The mRNA expression of the epithelial-mesenchymal transition markers CDH1, CDH2, Slug, Zeb1, EpCAM, ZO1, Vimentin, Snail and Twist was determined by reverse transcription-quantitative polymerase chain reaction. It was identified that luteolin inhibits the formation of tubular complexes and ectopic expression of cytokeratin-19 and luteolin also decreased proteins of SOX9, p-STAT3 and p-EGFR. In addition, luteolin inhibits proliferation and epithelial-mesenchymal transition of acinar cells induced by acute pancreatitis. As tubular complex formation and ectopic expression of cytokeratin-19 were two prominent characters of acinar-ductal metaplasia, it was concluded that luteolin inhibits acinar ductal metaplasia induced by pancreatitis and also inhibits pancreatitis-induced proliferation and epithelial-mesenchymal transition of acinar cells. Acinar ductal metaplasia and proliferation have close associations with pancreatic carcinogenesis. It is suggested that luteolin has potential anti-pancreatic carcinogenesis effects and merits further investigation. PMID- 29286100 TI - Effects of icariside II ameliorates diabetic cardiomyopathy in streptozotocin induced diabetic rats by activating Akt/NOS/NF-kappaB signaling. AB - Icariside II is a flavonoid extracted from Epimedium that has antioxidant, anti inflammatory and antiapoptotic effects. The aim of the present study was to evaluate the effects icariside II on diabetic cardiomyopathy in streptozotocin induced diabetic rats. Icariside II treatment improved body weight, heart/body weight ratio and fasting blood glucose in diabetic model rats. Icariside II was demonstrated to reduce the expression levels of creatine kinase and lactate dehydrogenase in serum, and to lower cardiac oxidative stress, inflammation and apoptosis levels in diabetic rats. Icariside II treatment induced phosphoinositide 3-kinase and phosphorylated-Akt expression, and suppressed inducible nitric oxide synthase (iNOS) and nuclear factor (NF)-kappaB protein expression in diabetic rat. Results from the present study suggested that treatment with icariside II improved diabetic cardiomyopathy in streptozotocin induced diabetic rats by activating the Akt/NOS/NF-kappaB pathway. PMID- 29286101 TI - [Corrigendum] Insights into the pathogenesis of Mycoplasma pneumoniae (Review). AB - Following the publication of this review, an interested reader alerted us to the fact that a couple of figures had been reproduced from a pair of previous publications without proper acknowledgement of the original source/authors. Figs. 2 and 3, as featured in our review, had originally appeared (with only minor modifications) as Figs. 2 and 4, respectively, in the following articles: Rottem S: Interaction of mycoplasmas with host cells. Physiol Rev 83: 417-32, 2003; and Pilo P, Vilei EM, Peterhans E, Bonvin-Klotz L, Stoffel MH, Dobbelaere D and Frey J: A metabolic enzyme as a primary virulence factor of Mycoplasma mycoides subsp. mycoides small colony. J Bacteriol 187: 6824-6831, 2005. Permission to publish these figures was sought retrospectively from the publishers [The American Physiological Society (Fig. 2) and The American Society of Microbiology (Fig 3)]. Subsequently, Figs. 2 and 3 are reprinted in this Corrigendum, together with strap-lines that properly acknowledge the source articles. In addition, we omitted to explain that the glycerol metabolism causing injury in host cells refers to Mycoplasma mycoides subsp. mycoides. Consequently, this information has also been inserted into the corrected legend for Fig. 3 (opposite), with a pair of supporting references. We profusely apologize to the authors of the previous publications (Dr Joachim Frey and colleagues) for our having failed to include a proper acknowledgement of their figure, or to have credited their work appropriately. [the original article was published in the Molecular Medicine Reports 14: 4030-4036, 2016; DOI: 10.3892/mmr.2016.5765]. PMID- 29286102 TI - Pin1 facilitates isoproterenol-induced cardiac fibrosis and collagen deposition by promoting oxidative stress and activating the MEK1/2-ERK1/2 signal transduction pathway in rats. AB - Peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1 (Pin1) is a member of a large superfamily of phosphorylation-dependent peptidyl-prolyl cis/trans isomerases, which not only regulates multiple targets at various stages of cellular processes, but is also involved in the pathogenesis of several diseases, including microbial infection, cancer, asthma and Alzheimer's disease. However, the role of Pin1 in cardiac fibrosis remains to be fully elucidated. The present study investigated the potential mechanism of Pin1 in isoprenaline (ISO)-induced myocardial fibrosis in rats. The rats were randomly divided into three groups. Echocardiography was used to evaluate changes in the size, shape and function of the heart, and histological staining was performed to visualize inflammatory cell infiltration and fibrosis. Reverse transcription-quantitative polymerase chain reaction analysis, immunohistochemistry and Picrosirius red staining were used to differentiate collagen subtypes. Additionally, cardiac-specific phosphorylation of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and extracellular-signal regulated protein kinase 1/2 (ERK1/2), and the activities of Pin1 and alpha smooth muscle actin (alpha-SMA) and other oxidative stress parameters were estimated in the heart. The administration of ISO resulted in an increase in cardiac parameters and elevated the heart-to-body weight ratio. Histopathological examination of heart tissues revealed interstitial inflammatory cellular infiltrate and disorganized collagen fiber deposition. In addition, lipid peroxidation products and oxidative stress marker activity in plasma and tissues were significantly increased in the ISO-treated rats. Western blot analysis showed significantly elevated protein levels of phosphorylated Pin1, MEK1/2, ERK1/2 and alpha-SMA in remodeling hearts. Treatment with juglone following intraperitoneal injection of ISO significantly prevented inflammatory cell infiltration, improved cardiac function, and suppressed oxidative stresses and fibrotic alterations. In conclusion, the results of the present study suggested that the activation of Pin1 promoted cardiac extracellular matrix deposition and oxidative stress damage by regulating the phosphorylation of the MEK1/2-ERK1/2 signaling pathway and the expression of alpha-SMA. By contrast, the inhibition of Pin1 alleviated cardiac damage and fibrosis in the experimental models, suggesting that Pin1 contributed to the development of cardiac remodeling in ISO administered rats, and that the inactivation of Pin1 may be a novel therapeutic candidate for the treatment of cardiovascular disease and heart failure. PMID- 29286104 TI - Treatment with Shuyu capsule increases 5-HT1AR level and activation of cAMP-PKA CREB pathway in hippocampal neurons treated with serum from a rat model of depression. AB - Depressive disorder (DD) is one of the typical affective disorders with a high morbidity, high suicide rate and high recurrence rate. Dysfunction of the 5 hydroxytryptamine 1A receptor (5-HT1AR) in the brain may serve an important role in the pathogenesis of DD. Currently, selective serotonin reuptake inhibitors are the first line antidepressants with 60-70% efficacy and severe adverse effects. Previous studies have demonstrated that Chinese herbal medicines, including the Shuyu capsule (SYC), are effective antidepressants with few side effects. However, the mechanism remains unclear. In the present study, the effects of the SYC on the 5-HT1AR level and the activation of adenylyl cyclase-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding (CREB) signaling pathway that 5-HT1AR mediates in the cells of hippocampal neurons were investigated in vitro. The SYC demonstrated an antidepressant effect similar to that of fluoxetine in a rat depression model. Treatment of hippocampal neurons with the serum of depressive rats resulted in a decrease in the 5-HT1AR protein level and the activation of the cAMP-PKA-CREB signaling pathway in hippocampal neurons. Exposure to the serum of rats that received chronic mild stress plus SYC treatment led to no alterations in the 5-HT1AR level or the activation of the cAMP-PKA-CREB signaling pathway compared with those of cells exposed to normal rat serum. This effect is similar to the effects of 5-HT1AR antagonist WAY 100635. In addition, the 5-HT1A agonist 8-hydroxy-(dipropylamino) tetralin did not antagonize the effects of the SYC. Furthermore, the SYC exhibited an increased effect compared with fluoxetine on 5-HT1AR levels and CREB activation. The present study suggested that the SYC functions by increasing 5-HT1AR protein levels and the activation of the 5-HT1AR-mediated cAMP-PKA-CREB signaling pathway in hippocampal neurons. PMID- 29286103 TI - Gene expression profiling of acute myeloid leukemia samples from adult patients with AML-M1 and -M2 through boutique microarrays, real-time PCR and droplet digital PCR. AB - Acute myeloid leukemia (AML) is the most common and severe form of acute leukemia diagnosed in adults. Owing to its heterogeneity, AML is divided into classes associated with different treatment outcomes and specific gene expression profiles. Based on previous studies on AML, in this study, we designed and generated an AML-array containing 900 oligonucleotide probes complementary to human genes implicated in hematopoietic cell differentiation and maturation, proliferation, apoptosis and leukemic transformation. The AML-array was used to hybridize 118 samples from 33 patients with AML of the M1 and M2 subtypes of the French-American-British (FAB) classification and 15 healthy volunteers (HV). Rigorous analysis of the microarray data revealed that 83 genes were differentially expressed between the patients with AML and the HV, including genes not yet discussed in the context of AML pathogenesis. The most overexpressed genes in AML were STMN1, KITLG, CDK6, MCM5, KRAS, CEBPA, MYC, ANGPT1, SRGN, RPLP0, ENO1 and SET, whereas the most underexpressed genes were IFITM1, LTB, FCN1, BIRC3, LYZ, ADD3, S100A9, FCER1G, PTRPE, CD74 and TMSB4X. The overexpression of the CPA3 gene was specific for AML with mutated NPM1 and FLT3. Although the microarray-based method was insufficient to differentiate between any other AML subgroups, quantitative PCR approaches enabled us to identify 3 genes (ANXA3, S100A9 and WT1) whose expression can be used to discriminate between the 2 studied AML FAB subtypes. The expression levels of the ANXA3 and S100A9 genes were increased, whereas those of WT1 were decreased in the AML-M2 compared to the AML-M1 group. We also examined the association between the STMN1, CAT and ABL1 genes, and the FLT3 and NPM1 mutation status. FLT3+/NPM1- AML was associated with the highest expression of STMN1, and ABL1 was upregulated in FLT3+ AML and CAT in FLT3- AML, irrespectively of the NPM1 mutation status. Moreover, our results indicated that CAT and WT1 gene expression levels correlated with the response to therapy. CAT expression was highest in patients who remained longer under complete remission, whereas WT1 expression increased with treatment resistance. On the whole, this study demonstrates that the AML array can potentially serve as a first-line screening tool, and may be helpful for the diagnosis of AML, whereas the differentiation between AML subgroups can be more successfully performed with PCR-based analysis of a few marker genes. PMID- 29286105 TI - Tsoong induces apoptosis and inhibits proliferation, migration and invasion of pancreatic ductal adenocarcinoma cells. AB - The roots of Codonopsis cordifolioidea (classified as campanulaceae cordifolioidea), locally known as Tsoong, have been used as a tonic food. The major components isolated from Tsoong have been demonstrated to present anti human immunodeficiency virus-1 activities and cytotoxicity against various tumor cell lines. However, the possible effects of the novel compound isolated from Tsoong, cordifoliketones A, on pancreatic ductal adenocarcinoma (PDAC) cells, are still unknown. In the present study, cordifoliketones A extractions were prepared from Tsoong, and the possible effects on PDAC cell growth, apoptosis, migration and invasion in vitro and in vivo were exlored. The cytotoxicity assay, apoptosis assay, western blotting, migration and invasion assay, and a PDAC cell (AsPC-1, BxPC-3 and PANC-1) xenograft mice model were employed. The results demonstrated that treatment with cordifoliketones A: i) inhibited proliferation and promoted apoptosis of PDAC cells; ii) significantly induced apoptosis and altered expression of apoptosis-associated proteins in a dose-dependent manner; iii) suppressed migration and invasion of PDAC cells in a dose-dependent manner; and iv) restrained the growth of PDAC neoplasm in nude mice. Furthermore, cordifoliketones A demonstrated non-cytotoxic activity in a panel of normal human cells, including hTERT-HPNE, 293, hepatocyte HL-7702 and HL-1 cells. Therefore, these data indicated that cordifoliketones A may be a potential candidate compound for the prevention of PDAC cell proliferation and metastasis, presumably by induction apoptosis and inhibiting viability, invasion and migration of PDAC cells. PMID- 29286106 TI - Integrative analysis of long non-coding RNAs and messenger RNA expression profiles in systemic lupus erythematosus. AB - Thousands of long noncoding RNAs (lncRNAs) have been reported and represent an important subset of pervasive genes associated with a broad range of biological functions. Abnormal expression levels of lncRNAs have been demonstrated in multiple types of human disease. However, the role of lncRNAs in systemic lupus erythematosus (SLE) remains poorly understood. In the present study, the expression patterns of lncRNAs and messenger RNAs (mRNAs) were investigated in peripheral blood mononuclear cells (PBMCs) in SLE using Human lncRNA Array v3.0 (8x60 K; Arraystar, Inc., Rockville, MD, USA). The microarray results indicated that 8,868 lncRNAs (3,657 upregulated and 5,211 downregulated) and 6,876 mRNAs (2,862 upregulated and 4,014 downregulated) were highly differentially expressed in SLE samples compared with the healthy group. Gene ontology (GO) analysis of lncRNA target prediction indicated the presence of 474 matched lncRNA-mRNA pairs for 293 differentially expressed lncRNAs (fold change, >=3.0) and 381 differentially expressed mRNAs (fold change, >=3.0). The most enriched pathways were 'Transcriptional misregulation in cancer' and 'Valine, leucine and isoleucine degradation'. Furthermore, reverse transcription-quantitative polymerase chain reaction data verified six abnormal lncRNAs and mRNAs in SLE. The results indicate that the lncRNA expression profile in SLE was significantly changed. In addition, a range of SLE-associated lncRNAs were identified. Thus, the present results provide important insights regarding lncRNAs in the pathogenesis of SLE. PMID- 29286107 TI - Kinetic alterations of collagen and elastic fibres and their association with cardiac function in acute myocardial infarction. AB - The present study aimed to investigate kinetic alterations of collagen and elastic fibres and their association with cardiac function in the acute myocardial infarction (AMI) heart. AMI was generated in Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Cardiac function was determined using B-ultrasonography, AMI was verified using histopathology. The kinetics of collagen type I/III and elastic fibre were evaluated using immunohistochemistry and western blotting at 1 week (1 w), 2 weeks (2 w), 3 weeks (3 w) and 4 weeks (4 w) post-AMI. Cardiac function was decreased by 78, 70, 50 and 38% at weeks 1, 2, 3 or 4 post-AMI, respectively, compared with the normal heart. Elastic fibre was decreased gradually, demonstrating alterations of 2, 77, 86 or 97% reduction, respectively, at weeks 1, 2, 3 or 4 in the AMI heart. Collagen I fibre was increased 1.4-, 1.5-, 2.9- or 3.9-fold at weeks 1, 2, 3 or 4 respectively, compared with the normal heart. Similarly, collagen III was increased 1.2-, 1.7-, 2.8- or 3.9-fold, following AMI. Kinetics of increased collagen I/III, in combination with decreased elastic fibre in infarcted area following AMI, provided evidence that compromised cardiac function following AMI was due to graduate wound healing/scar formation in the infarcted zone, increased stiffness and reduced flexibility of the heart. PMID- 29286108 TI - miR-197-3p-induced downregulation of lysine 63 deubiquitinase promotes cell proliferation and inhibits cell apoptosis in lung adenocarcinoma cell lines. AB - Lung adenocarcinoma (LUAD) is a common cause of cancer-associated mortality. The dysregulation of microRNA (miR) expression has been reported to induce lung carcinogenesis. In the present study, miR-197-3p upregulation was detected within LUAD tissues compared with in adjacent noncancerous tissues. The suppression of miR-197-3p expression was confirmed to inhibit proliferative ability and induce apoptosis of LUAD cell lines; miR-197-3p overexpression within the HBE cell line exhibited opposing effects. Via in silico modeling, western blot analyses and dual-luciferase assays, it was confirmed that miR-197-3p directly targets the lysine 63 deubiquitinase (CYLD) gene. In the present study, the expression of miR 197-3p was negatively associated with CYLD mRNA expression within LUAD cell lines. In conclusion, the findings of the present study have provided novel insight into the association of miR-197-3p with LUAD proliferation and apoptotic regulation; the miR-197-3p/CYLD axis may serve as a novel potential therapeutic target for the treatment of LUAD. PMID- 29286109 TI - The protective effects of magnolol on acute trinitrobenzene sulfonic acid-induced colitis in rats. AB - The present study aimed to investigate the protective effects of magnolol on acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, and its underlying mechanisms. Experimental colitis was induced by intracolonic administration of TNBS/ethanol into rats. The model rats were randomly assigned into groups: TNBS, magnolol (high, medium and low doses), and salazosulfapyridine (positive control). All intervention regimens were administered by oral gavage, once a day for 7 consecutive days, 24 h after colitis induction. Histological and biochemical changes in colonic inflammation were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. Rats treated with all doses of magnolol exhibited decreased colonic myeloperoxidase activity (P<0.05 vs. TNBS), reduced serum levels of proinflammatory cytokines [including interleukin (IL)-6 and IL-17], and downregulated Toll-like receptor-4 (TLR-4) mRNA expression. Histological analysis revealed that medium and high doses of magnolol conferred an anti-inflammatory effect, which was indicated by a decrease in disease activity index, an increase in thymus index, and downregulation of nuclear factor (NF)-kappaB p65 mRNA and TLR-4 protein expression. However, only high-dose magnolol significantly ameliorated the elevated colon weight/length ratio. The results of the present study indicate that magnolol exerts protective effects against acute TNBS-induced colitis in rats, and the TLR-4/NF-kappaB signaling pathway-mediated inhibitory effect on inflammatory cascades may contribute to the protective activity of magnolol. PMID- 29286110 TI - Tumor necrosis factor-alpha acts reciprocally with solute carrier family 26, member 3, (downregulated-in-adenoma) and reduces its expression, leading to intestinal inflammation. AB - Solute carrier family 26, member 3 (Slc26a3), also termed downregulated-in adenoma (DRA) is a member of the Slc26 family of anion transporters and is mutated in congenital chloride diarrhea. Our previous study demonstrated that DRA deficiency is associated with severely reduced colonic HCO3- secretion, a loss of colonic fluid absorption, a lack of a firmly adherent mucus layer and a severely reduced colonic mucosal resistance to dextran sodium sulfate (DSS) damage. However, the direct effect of mediators that trigger intestinal inflammatory factors on DRA has not been fully investigated. Tumor necrosis factor (TNF)-alpha is a central mediator of intestinal inflammation in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease. However, to the best of our knowledge, whether TNF-alpha acts reciprocally with DRA leading to the development of gut inflammation in IBD has not been reported. The present study identified that the expression level of DRA was reduced in active UC patients and DSS-induced colitis mice with high expression levels of TNF-alpha identified in the peripheral blood serum. In addition, TNF-alpha may affect the expression level of DRA in human colonic Caco2BBE cells in a dose-dependent manner, including in DRA overexpressed Caco2BBE cells. Furthermore, knockdown of TNF-alpha in Caco2BBE cells led to a higher expression level of DRA and a markedly reduced secretion of TNF-alpha in the culture media. In addition, knockdown of DRA in Caco2BBE cells led to a higher secretion of TNF-alpha in the culture media compared with the control cells, which could be reversed by overexpression of DRA. Overall, these results indicate that TNF-alpha may act reciprocally with DRA, leading to the development of intestinal inflammation. Based on the pivotal position of TNF-alpha in IBD, DRA is hypothesized to have therapeutic potential against colitis serving as an important target. PMID- 29286111 TI - MiR-31a-5p protects myocardial cells against apoptosis by targeting Tp53. AB - The pathogenesis and progression of heart failure (HF) involves multiple mechanisms, including the increased activity of the renin-angiotensin-aldosterone system, apoptosis and differential expression of microRNAs (miRNAs/miRs). Our previous study revealed an increase in miR-31a-5p levels in the failing hearts of a rat HF model. In the present study, whether and how miR-31a-5p mediates angiotensin II (AngII)-induced apoptosis in the cardiac H9C2 cell line, was investigated using molecular biological approaches, including reverse transcription followed by quantitative polymerase chain reaction, western blotting, RNA arrays, and mutagenesis. It was demonstrated that AngII stimulation increased apoptosis and decreased miR-31a-5p expression, which coincided with increased tumor protein p53 (Tp53) levels. Overexpression of miR-31a-5p significantly suppressed the AngII-induced apoptotic rate and caspase-3 activity, while suppression of miR-31a-5p did the opposite. A total of 16 proapoptotic genes that were downregulated and 4 antiapoptotic genes that were upregulated in the miR-31a-5p-overexpressed cells were identified. It was also revealed that Tp53 mRNA contained the seed sequence in its 3'-untranslated region for miR-31a 5p binding. The luciferase reporter analysis showed that miR-31a-5p repressed the luciferase activity of the wild-type seed sequence, but not the mutated seed sequence fused to a reporter construct. Thus, it was demonstrated that miR-31a-5p mediated AngII-triggered apoptosis in myocardial cells at least partially through targeting Tp53. These findings advance the understanding of the functional interaction between miRNAs and Tp53 in the setting of cardiac diseases. Further work is required to explore whether miR-31a-5p can serve as a therapeutic target for HF treatment in vivo. PMID- 29286112 TI - Upregulation of BAG3 with apoptotic and autophagic activities in maggot extract promoted rat skin wound healing. AB - Maggot extract (ME) accelerates rat skin wound healing, however its effect on cell maintenance in wound tissues remains unclear. B-cell lymphoma (Bcl) 2 associated athanogene (BAG)3 inhibits apoptosis and promotes autophagy by associating with Bcl-2 or Beclin 1. Bcl-2, the downstream effector of signal transducer and activator of transcription 3 signaling, is enhanced in ME-treated wound tissues, which may reinforce the Bcl-2 anti-apoptotic activity and/or cooperate with Beclin 1 to regulate autophagy during wound healing. The present study investigated expression levels of BAG3, Bcl-2, Beclin 1 and light chain (LC)3 levels in rat skin wound tissues in the presence and absence of ME treatment. The results revealed frequent TUNEL-negative cell death in the wound tissues in the early three days following injury, irrespective to ME treatment. TUNEL-positive cells appeared in the wound tissues following 4 days of injury and 150 ug/ml ME efficiently reduced apoptotic rate and enhanced BAG3 and Bcl-2 expression. Elevated Beclin 1 and LC3 levels and an increased LC3 II ratio were revealed in the ME-treated tissues during the wound healing. The results of the present study demonstrate the anti-apoptotic effects of BAG3 and Bcl-2 in ME promoted wound healing. Beclin 1/LC3 mediated autophagy may be favorable in maintaining cell survival in the damaged tissues and ME-upregulated BAG3 may enhance its activity. PMID- 29286113 TI - Synergistic effect of nutlin-3 combined with aspirin in hepatocellular carcinoma HepG2 cells through activation of Bcl-2/Bax signaling pathway. AB - Aspirin as an antitumor drug has been studied in various malignancies with regards to its effects on apoptosis, proliferation, metastasis and senescence of tumor cells. However, the clinical application is limited by its side effects. Nutlin-3 is a novel antitumor compound, which has not been clinically approved. The present study investigated the value of combining aspirin and nutlin-3 on hepatocellular carcinoma (HCC) cells. MTT was performed to detect the proliferation of HepG2 cells treated with aspirin or/and nutlin-3. Transwell invasion assays were performed to estimate the invasion ability of HepG2 cells treated with aspirin or/and nutlin-3. Then the apoptotic analysis of HepG2 cells evaluated the synergistic effect of aspirin and nutlin-3. Apoptosis markers, including B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, caspase-8 and caspase-9 were estimated by western blot analysis at various time points. In addition, a Xenograft mouse model was established by infection with HepG2 cells, and aspirin and/or nutlin-3 was administrated to verify the anti apoptotic effect of the two drugs in vivo. A high dose of aspirin and nutlin-3 inhibit the proliferation and apoptosis of HepG2 cells. The antitumor effect was enhanced with the combined treatment of the two drugs, particularly in the group with a low concentration of aspirin and nutlin-3. Nutlin-3 was able to increase the level of Bax in HepG2 cells treated with aspirin significantly after treatment for 8 h. When treated with a low concentration of aspirin and nutlin-3, the level of Bax in HepG2 cells was enhanced for 2 h. In the animal model, tumor volume and tumor angiogenesis were significantly decreased in combination group compared with other groups (P<0.01). Although there were side effects in the group treated with aspirin alone, no side effects were observed in the combination group. Nutlin-3 enhanced the apoptotic effect of a low dose of aspirin by upregulating Bax expression in the HepG2 cell line and in vivo. The synergistic effect of nutlin-3 in aspirin antitumor therapy contributed to diminishing the dose of aspirin required and decreased the occurrence of adverse drug events in HCC through targeting the Bcl-2/Bax signaling pathway. PMID- 29286114 TI - Cigarette smoke-induced EGFR activation promotes epithelial mesenchymal migration of human retinal pigment epithelial cells through regulation of the FAK-mediated Syk/Src pathway. AB - Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is inevitable change of age-related macular degeneration (AMD). Smoking is a major risk factor for the development of EMT in several diseases, including lung cancer. Cigarette smoke-induced stress promotes the production of epidermal growth factor (EGF) in RPE cells. However, the underlying signaling pathways induced by aberrant EGF receptor (EGFR) expression in cigarette smoke-exposed RPE cells remain largely unknown. In the present study, the morphological transformation and production of EMT-associated cytokines were investigated to analyze the effect of smoking on the retina. Furthermore, EGF-treated or cigarette smoke-exposed RPE cells, as well as the downstream targets of EGFR, were investigated to identify the key molecules involved in EMT of cigarette smoke-stimulated RPE cells via immunoblotting. Exposure of RPE cells to cigarette smoke extract (CSE) induced secretion of VEGF and TGF-beta1, and increased the expression of EMT markers. CSE-mediated focal adhesion kinase (FAK) activation resulted in the phosphorylation and activation of spleen associated tyrosine kinase (Syk)/Src proto-oncogene, non-receptor tyrosine kinase (Src), leading to migration and invasion of RPE cells. Knockdown of FAK or pharmacological inhibition of Syk/Src abrogated CSE-mediated VEGF and TGF-beta1 production and blocked the phosphorylation of Smad2/3 in CSE-stimulated RPE cells. Erlotinib (an EGFR inhibitor) suppressed EGF and CSE-mediated switch from an epithelial to mesenchymal phenotype. Baicalein, an inhi-bitor of 12/15-lipooxygenase, also efficiently suppressed CSE-induced EMT processes by inhibiting EGFR-associated downstream signaling transduction. The results identified a novel signaling pathway mediated by EGFR in CSE-activated RPE cells, and suggest baicalein as a potential new therapeutic drug for CSE-associated retinopathy. PMID- 29286115 TI - MicroRNA-379 inhibits cell proliferation and invasion in glioma via targeting metadherin and regulating PTEN/AKT pathway. AB - Numerous microRNAs (miRNAs) are aberrantly expressed in glioma, and implicated in glioma occurrence and development. Therefore, the development of miRNAs as potential therapeutic targets for the treatment of patients with glioma has been proposed. miR-379 has been shown to be aberrantly expressed in the progression of malignant tumours. However, the expression, biological functions and mechanism of miR-379 in glioma are yet to be fully understood. Hence, the present study aimed to detect miR-379 expression, investigate its functional relevance and explore its associated molecular mechanism in glioma. In this study, miR-379 expression was significantly downregulated in glioma tissues and cell lines. Enforced miR 379 expression markedly suppressed the cell proliferation and invasion of glioma. Metadherin (MTDH) was identified as a direct target of miR-379 in glioma. The miR 379 expression and MTDH mRNA levels exhibited an inverse association in glioma tissues. The restoration of the MTDH expression partially rescued the inhibitory effects of miR-379 overexpression on glioma cell proliferation and invasion, and the upregulation of miR-379 inhibited the activation of phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase (AKT) signaling pathway. Overall, these findings demonstrated that miR-379 may play tumour-suppressing roles in glioma through downregulation of MTDH and regulation of the PTEN/AKT signaling pathway, suggesting that miR-379 might be a possible target for the treatment of patients with this malignancy. PMID- 29286116 TI - BAMBI promotes macrophage proliferation and differentiation in gliomas. AB - The present study investigated the capacity of Bone morphogenic protein and activin membrane-bound inhibitor homolog (BAMBI) to regulate the migration and differentiation of macrophages in gliomas. Using a migration assay, it was determined that BAMBI stimulated monocytes migration in a dose-dependent effect. When induced by phorbol myristate acetate (PMA) the monocytes differentiated into macrophages, and BAMBI also increased the migration of PMA-induced macrophages compared with control cells. The expression of CD68 and BAMBI protein and mRNA in glioma and normal specimens were detected using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction, respectively. The localization of BAMBI was primarily in macrophages, as demonstrated by staining for the macrophage marker CD68, and the mRNA expression of CD68 and BAMBI were higher in gliomas compared to normal tissues. In addition, the mRNA expression of CD68 and BAMBI were positively correlated (R2=0.64). After treatment with 50 nM PMA and 10 nM BAMBI for 48 h, RAW 264.7 macrophages were exhibited dendrite-like morphology, indicating that the co-treatment promoted the differentiation of monocytes to macrophages. The expression of specific markers of M1 [inducible nitric oxide synthase (iNOS) and interleukin (IL)-12] and M2 (IL-10 and arginase 1) type macrophages was determined following 10 nM BAMBI treatment. BAMBI promoted the expression of M1 markers, whereas the M2 markers were not affected, which indicated that BAMBI induced differentiation of M1 type macrophages. These results indicate that BAMBI may be involved in macrophage differentiation in gliomas. PMID- 29286117 TI - Angiotensin 1-7 ameliorates caerulein-induced inflammation in pancreatic acinar cells by downregulating Toll-like receptor 4/nuclear factor-kappaB expression. AB - The present study aimed to investigate the effects of angiotensin (Ang) 1-7 on caerulein (CAE)-stimulated nuclear factor (NF)-kappaB, Toll-like receptor (TLR4) and cytokine expression using pancreatic acinar AR42J cells. AR42J cells were treated with 10 nmol/l CAE for various durations. In addition, cells were pretreated with various concentrations of Ang 1-7 or A779, a specific antagonist of Ang 1-7, and were stimulated with CAE for 12 h. Control cells were treated with vehicle (F-12K complete medium with 2% fetal bovine serum, 10 U/ml penicillin and 100 mg/ml streptomycin) alone. The mRNA and protein expression levels of TLR4, NF-kappaB, interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor-alpha (TNF-alpha) were determined by western blotting, immunofluorescence and reverse transcription-quantitative polymerase chain reaction. CAE treatment stimulated TLR4 and NF-kappaB expression within AR42J cells. Immunofluorescence indicated that TLR4 was expressed on the membranes and in the cytoplasm of AR42J cells, whereas NF-kappaB expression accumulated in the cytoplasm and nuclei. CAE induced expression of TLR4 and NF-kappaB within AR42J cells was abrogated by 10-5 mmol/l Ang 1-7; however, TLR4 and NF-kappaB expression was enhanced with the addition of A779, particularly 10-5 mmol/l. In addition, treatment with 10-6 and 10-5 mmol/l Ang 1-7 significantly mitigated CAE-induced expression of IL-6, IL-8 and TNF-alpha, whereas it enhanced IL-10 expression. Conversely, A779 treatment enhanced the CAE-induced expression of IL-6, IL-8 and TNF-alpha, and reduced IL 10 expression in AR42J cells. In conclusion, these results suggested that Ang 1-7 may attenuate CAE-induced inflammation by downregulating TLR4, NF-kappaB and proinflammatory cytokine expression within AR42J cells. Therefore, Ang 1-7 may exert protective effects against the pathological progression of AP in a cell model of AP induced by CAE and may be considered in the development of treatments for this disease. PMID- 29286119 TI - Perioperative oral supplementation with fish oil promotes liver regeneration following partial hepatectomy in mice via AMPK activation. AB - The present study aimed to observe the effects of perioperative oral supplementation with fish oil (FO) on liver regeneration in mice and examine the potential mechanism. A total of 120 male ICR mice were randomly divided into 5 groups: Sham, Control, fish oil (FO), Compound C [the AMP-activated protein kinase (AMPK) inhibitor dorsomorphin], and Compound C + FO. Changes in liver function, alterations in hepatocyte proliferation and in the expression of polarization markers, and activation of AMPK signaling were examined following partial hepatectomy (PH). The results demonstrated that restoration of serum alanine aminotransferase (ALT) and total bilirubin (TBIL) levels were significantly faster in FO-treated mice compared with Control mice, and this effect was suppressed by treatment with Compound C. FO-treated mice exhibited increased numbers of Ki-67 positive hepatocytes and their postoperative liver-to body weight ratio was significantly increased compared with the Control mice, which was also suppressed by co-treatment with the AMPK inhibitor. Furthermore, protein expression of Occludin, Claudin-3, tight junction protein 1 and bile salt export pump was gradually increased in FO-treated mice compared with Control, whereas Compound C treatment reversed this effect. Therefore, the present study revealed that perioperative oral supplementation with FO may promote liver regeneration and improved liver function in mice following PH through AMPK activation. PMID- 29286120 TI - Influence of static magnetic fields on human myoblast/mesenchymal stem cell co cultures. AB - The results of surgical repair of extensive muscle tissue defects are still of primary concern, leaving patients with residual cosmetic and functional impairments. Therefore, skeletal muscle tissue engineering attempts to grow functional neo-tissue from human stem cells to promote tissue regeneration and support defect closure. Despite intensive research efforts, the goal of stable induction of myogenic differentiation in expanded human stem cells by using clinically feasible stimuli, has not yet been reached to a sufficient extent. Therefore, the present study investigated the differentiation potential of static magnetic fields (SMFs), using co-cultures of human satellite cells and human mesenchymal stem cells (MSCs). It has previously been demonstrated that SMFs may act as a promising myogenic stimulus. Tests were performed on co-cultures with and without SMF exposure, using growth medium [high growth factor concentrations (GM)] and differentiation medium [low growth factors concentrations (DM)]. AlamarBlue(r) assay-based cell proliferation analysis revealed no significant difference between co-cultures with, vs. without SMF stimulation, regardless of growth factor concentrations in the cell culture medium. To determine the degree of differentiation in co-cultures under stimulation with SMFs, semi-quantitative gene expression measurements of the following marker genes were performed: Desmin, myogenic factor 5, myogenic differentiation antigen 1, myogenin, adult myosin heavy chain 1 and skeletal muscle alpha1 actin. In neither GM nor DM was a steady, significant increase in marker gene expression detected. Verifying the gene expression findings, immunohistochemical antibody staining against differentiation markers revealed that SMF exposure did not enhance myogenic maturation. Therefore, SMF treatment of human satellite cell/MSC co-cultures did not result in the desired increase in myogenic differentiation. Further studies are required to identify a suitable stimulus for skeletal muscle tissue engineering. PMID- 29286118 TI - Amelioration of streptozotocin-induced pancreatic beta cell damage by morin: Involvement of the AMPK-FOXO3-catalase signaling pathway. AB - Pancreatic beta cells are sensitive to oxidative stress, which is one of the predominant causes of cell damage and the emergence of diabetes. The identification of effective therapeutic strategies to protect pancreatic cells from oxidative stress has increased interest in the screening of antioxidants from natural products. The present study aimed to investigate the protective effects of morin against streptozotocin (STZ)-induced cell damage in a rat insulinoma cell line (RINm5F pancreatic beta cells) and to identify the underlying mechanisms. The results indicated that morin inhibited the increase in intracellular reactive oxygen species, attenuated the activity of poly (ADP ribose) polymerase, restored intracellular nicotinamide adenine dinucleotide levels and reduced the apoptotic cell death of STZ-treated pancreatic beta cells. Treatment with morin significantly upregulated catalase in pancreatic beta cells, and ameliorated the STZ-induced loss of catalase at the genetic, protein and enzymatic level. In further experiments, morin induced the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK), which subsequently promoted the translocation of forkhead box O3 (FOXO3) to the nucleus. Specific small interfering RNAs (siRNAs) against AMPK and FOXO3 suppressed morin-induced catalase expression. Furthermore, catalase-specific siRNA abolished the protective effects of morin against STZ-stimulated cell death. Taken together, these results indicated that morin protected RINm5F cells from STZ-induced cell damage by triggering the phosphorylation of AMPK, thus resulting in subsequent activation of FOXO3 and induction of catalase. PMID- 29286121 TI - Effects of epidermal growth factor receptor fusion protein on the cytotoxic activity of SOCS1-silenced dendritic cells in vitro. AB - The aim of the present study was to observe the effects of cytokine signaling suppressor 1 (SOCS1)-silenced dendritic cells (DCs) pulsed with epidermal growth factor receptor (EGFR) fusion protein on the activation of T lymphocyte and cytotoxic T-lymphocyte (CTL) activity against Hep-2 cells. DCs were derived from the medullary cells of mice and authenticated by flow cytometry (FCM). Recombinant glutathione-S-transferase (GST)-EGFR fusion protein was produced and purified. After being pulsed with it, DCs were modified by recombinant SOCS1 siRNA adenoviral to silence SOCS1 gene expression. The maturation of DCs was evaluated by FCM. The effects of modified DCs on T-cell proliferation were assessed by MTT assay. The killing effects against Hep-2 cells of CTL were assessed by lactate dehydrogenase (LDH) release assay. High-purity DCs from the medullary cells of mice were obtained. Compared with the control, EGFR-pulsed DCs displayed higher expression of cell surface molecules, including CD83, CD860 and HLA-DR. The MTT assay revealed that all of the EGFR-pulsed, SOCS1-silenced and EGFR-pulsed plus SOCS1-silenced DCs had an enhanced capacity to stimulate T lymphocyte proliferation. As expected, EGFR-pulsed plus SOCS1-silenced DCs had the strongest effects on T-cell proliferation. The splenic T cells isolated from both EGFR-pulsed DC-immunized mice and EGFR-pulsed plus SOCS1-silenced DC immunized mice enhanced the cytotoxicity against Hep-2 cells, while T cells from EGFR-pulsed plus SOCS1-silenced DC-immunized mice exhibited significantly higher cytotoxicity than those from EGFR-DC-immunized mice. The EGFR-pulsed SOCS1-siRNA silenced DCs had the strongest effects on activation of T-cell proliferation and the CTL activity against Hep-2 cells. PMID- 29286122 TI - Overexpression of interleukin-32alpha promotes invasion by modulating VEGF in hepatocellular carcinoma. AB - Interleukin-32alpha (IL-32alpha) was reported to exhibit pluripotent pro inflammatory properties. Recent studies indicate that it promotes the migration and invasion of cancers. We detected the expression of IL-32 in hepatocellular carcinoma (HCC) tissues and investigated its role in tumor angiogenesis and invasion. IL-32alpha expression in HCC was evaluated by real-time PCR, western blot analysis and immunohistochemical (IHC) staining. Secreted serum IL-32alpha and VEGF concentrations were detected using a custom-made sandwich ELISA. Furthermore, IL-32alpha was knocked down in HCC cell lines using siRNA and the cell migration and invasion abilities were assessed. IHC staining showed that IL32alpha-positive particles were mainly located in the cytoplasm of cancer cells, and it was significantly upregulated in the tumor tissues compared with that in peritumoral tissues. Notably, IL-32alpha was strongly expressed in perivascular areas. The mean serum concentration of IL-32alpha in HCC patients was significantly higher than that in the control group (571.45+/-102.28 vs. 144.60+/-51.172 pg/ml; P<0.01). Real-time RT-PCR showed that IL-32alpha mRNA was significantly overexpressed in HCC tumor tissues (IL-32/beta-actin, 15.59+/-7.8 vs. 3.37+/-0.47; P<0.01). The in vitro results indicated that IL-32alpha knockdown inhibited the activation of VEGF-STAT3 signaling in HCC tumor cell lines. IL-32alpha expression was correlated with clinical relevance in HCC tumor tissues. It is strongly suggested that IL-32alpha may be a potential predictor of anti-angiogenesis therapy and prognosis of HCC. PMID- 29286123 TI - [Retracted] FOXO1 is crucial in glioblastoma cell tumorigenesis and regulates the expression of SIRT1 to suppress senescence in the brain. AB - The first author, Han Yan, wishes to retract the above article entitled 'FOXO1 is crucial in glioblastoma cell tumorigenesis and regulates the expression of SIRT1 to suppress senescence in the brain' to be published in Molecular Medicine Reports 17: 2535-2542, 2018. The article was submitted by the first author without the prior knowledge or authorization of the corresponding author, Anhua Wu, who did not participate in the design, preparation or the writing of the paper. The first author apologizes for the inconvenience caused in this regard. [The original article was published in Molecular Medicine Reports 17: 2535-2542, 2018; DOI: 10.3892/mmr.2017.8146]. PMID- 29286124 TI - MicroRNA-454 inhibits non-small cell lung cancer cells growth and metastasis via targeting signal transducer and activator of transcription-3. AB - Lung cancer is one of the most common type of cancers and the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases. Emerging studies have suggested that microRNAs are dysregulated in NSCLC and serve important roles in NSCLC initiation and development. However, to the best of our knowledge, the expression, roles and molecular mechanism of microRNA-454 (miR-454) have not been investigated in NSCLC. In the present study, miR-454 was demonstrated to be significantly downregulated in NSCLC tissues and cell lines, as assessed by western blot analysis and reverse transcription-quantitative polymerase chain reaction. Reduced miR-454 expression was significantly correlated with aggressive clinicopathological features in NSCLC. In addition, upregulation of miR-454 suppressed proliferation, migration and invasion NSCLC cells, as assessed by Cell Counting Kit-8 and in vitro migration and invasion assays, respectively. Furthermore, bioinformatics analysis identified STAT3 as a direct target gene of miR-454, and STAT3 knockdown was demonstrated to simulate the effects of miR-454 overexpression in NSCLC. In conclusion, the present study provided convincing evidence that miR-454 is downregulated in NSCLC, and regulates growth and metastasis by directly targeting STAT3, which suggests that miR-454 may be an efficient therapeutic target for NSCLC. PMID- 29286125 TI - Goserelin promotes the apoptosis of epithelial ovarian cancer cells by upregulating forkhead box O1 through the PI3K/AKT signaling pathway. AB - Gonadotropins, including luteinizing hormone (LH) and follicle stimulating hormone (FSH), are conducive to the growth of ovarian cancer based on the 'gonadotropin theory' and are regulated by gonadotropin-releasing hormone (GnRH). The present study was carried out to investigate the effect of goserelin, a GnRH agonist, on the apoptosis of epithelial ovarian cancer (EOC) cells and the underlying in vitro and in vivo mechanisms. Through flow cytometry, Hoechst staining and TUNEL staining, we demonstrated that goserelin promoted the apoptosis of EOC cells both in vitro and in vivo. Through human apoptosis gene PCR array, we verified that the promotion of EOC cell apoptosis by goserelin was linked to the upregulation of members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, which have been identified as downstream targets of forkhead box O1 (FOXO1). Goserelin enhanced FOXO1 expression, and siRNA-mediated knockdown of FOXO1 abrogated the induction of apoptosis by goserelin. Moreover, goserelin decreased AKT activity, and FOXO1 upregulation by goserelin was dependent on the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vivo, the expression of key factors in the PI3K/AKT/FOXO1 pathway was consistent with that observed in vitro. In conclusion, our data suggested that goserelin may promote EOC cell apoptosis by upregulating FOXO1 through the PI3K/AKT signaling pathway. We believe that GnRH agonists may be potential antitumor agents, and key factors in the PI3K/AKT-FOXO1 pathway may also be novel therapeutic targets for the treatment of EOC. PMID- 29286126 TI - Bcl-2 overexpression reduces cisplatin cytotoxicity by decreasing ER mitochondrial Ca2+ signaling in SKOV3 cells. AB - Recent studies have revealed that a small amount of cisplatin can penetrate into the nucleus and induce intranuclear DNA damage. Specifically, most cisplatin accumulates in and stresses different organelles, including mitochondria, endoplasmic reticulum (ER) and the cytosol, where apoptosis signaling is activated and magnified. Bcl-2, which is mainly localized to ER and mitochondria, is identified as a key regulator of survival and apoptosis. Bcl-2 is reported to block cisplatin-induced apoptosis via regulating Ca2+ signaling in a variety of cancer cell lines. However, its target molecule and the mechanism responsible for its inhibitory effect in ovarian cancer are undefined. The present study revealed that Bcl-2 overexpression reduced cisplatin-induced growth inhibition and apoptosis in SKOV3 human ovarian cancer cells. Furthermore, Bcl-2 inhibited cisplatin-induced Ca2+ release from the ER to the cytoplasm and mitochondria, which reduced cisplatin-induced ER stress-mediated apoptosis through the mitochondrial apoptotic pathway. The overexpression of Bcl-2 inhibited the cisplatin-induced increase in the number of ER-mitochondrial contact sites in SKOV3 human ovarian cancer cells. In addition, the present study provided evidence that Bcl-2 reduced the anticancer activity of cisplatin towards ovarian cancer cells in vivo. These results revealed that Bcl-2 attenuates cisplatin cytotoxicity via downregulating ER-mitochondrial Ca2+ signaling transduction. Thus, Bcl-2 which may be a potential therapeutic target for ovarian cancer. PMID- 29286128 TI - Protection against monocrotaline-induced pulmonary arterial hypertension and caveolin-1 downregulation by fluvastatin in rats. AB - Statins are Hydroxymethylglutaryl-coenzyme A reductase inhibitors, which are typically used to lower blood cholesterol. Additional beneficial effects, including improvement to pulmonary arterial hypertension (PAH), have also been confirmed. However, the mechanisms underlying this improvement have not yet been clarified. The present study was conducted to determine if fluvastatin was protective against experimental PAH development and to investigate the potential effects of fluvastatin on caveolin-1 (cav-1) expression. Rats were randomized to either receive a single subcutaneous injection of monocrotaline (MCT; 60 mg/kg; MCT group) or a single subcutaneous injection of MCT (60 mg/kg) followed by an oral gavage of fluvastatin (10 mg/kg) once daily until day 42 (M + F group). Rats in the MCT group received an equivalent volume of saline following the MCT injection. Six additional rats were given an equivalent volume of saline throughout as a control measure. PAH associated variables and cav-1 protein expression were measured in each group at various times during the experimental period. Hemodynamic and morphometric analysis revealed that M + F rats developed moderate, delayed PAH. Cav-1 western blot analysis demonstrated that cav-1 expression was not significantly different in fluvastatin treated rats; however, MCT injured rats given saline had markedly reduced cav-1 expression. It was concluded that fluvastatin may protect against PAH development and ameliorate MCT induced inhibition of cav-1 expression in rats. PMID- 29286127 TI - Autophagy regulates TGF-beta2-induced epithelial-mesenchymal transition in human retinal pigment epithelium cells. AB - Transforming growth factor (TGF)-beta2-induced epithelial-mesenchymal transition (EMT) in human retinal pigment epithelium (RPE) cells has an important role in the pathophysiology of intraocular fibrotic disorders, which may cause vision impairment and blindness. Autophagy, an intracellular homeostatic pathway, contributes to the physiological and pathological processes of RPE. Furthermore, autophagy has previously been reported to function in the EMT process in numerous tissue and cell types. However, the association between autophagy and the EMT process in RPE cells has not yet been fully determined. The present study demonstrated that TGF-beta2-treated human RPE cells (ARPE-19 cell line) exhibited a significantly increased autophagic flux compared with control cells, as determined by western blot analysis of the protein levels of microtubule associated protein 1 light chain 3-II and p62 (also termed sequestosome 1). Furthermore, it was demonstrated that autophagy activation enhanced the TGF-beta2 induced EMT process in ARPE-19 cells, and inhibition of autophagy by chloroquine administration attenuated TGF-beta2-induced EMT, which was determined by analyzing the expression of mesenchymal and epithelial markers by reverse transcription-quantitative polymerase chain reaction and/or western blotting. A transwell migration and invasion assays was also performed that demonstrated that autophagy activation by rapamycin enhanced TGF-beta2-stimulated RPE cell migration and invasion, and inhibition of autophagy reduced TGF-beta2-stimulated RPE cell migration and invasion. These results also demonstrated that autophagy activation enhanced the TGF-beta2-induced EMT process in ARPE-19 cells, and inhibition of autophagy attenuated TGF-beta2-induced EMT. Overall, the results of the present study demonstrated that TGF-beta2-induced EMT may be regulated by autophagy, thus indicating that autophagy may serve as a potential therapeutic target for the attenuation of EMT in intraocular fibrotic disorders. PMID- 29286129 TI - Knockdown of elF3a inhibits TGF-beta1-induced extracellular matrix protein expression in keloid fibroblasts. AB - Keloid formation is characterized by hyperproliferation of secretory and responsive keloid fibroblasts (KFs) and overproduction of extracellular matrix (ECM). Eukaryotic translation initiation factor 3 subunit A (eIF3a) one of the core subunits of the translation initiation complex, eIF3, has previously been reported to possess an anti-fibrogenic effect. However, the role of eIF3a in keloid formation has not yet been investigated. Therefore, the present study examined the effect of eIF3a on transforming growth factor-beta1 (TGF-beta1) mediated ECM expression in KFs. The expression levels of eIF3a in human keloid tissues was evaluated using reverse transcription-quantitative polymerase chain reaction and western blotting. KFs were incubated with siRNA-eIF3a or siRNA-mock for 48 h. The cells were then treated with TGF-beta1 (10 ng/ml) for 72 h. Cell proliferation was evaluated using the CCK-8 assay. The expression levels of alpha SMA, collagen type I, TGF-beta receptor I (RI), TGF-beta RII, phosphorylated (p) mothers against decapentaplegic homolog (Smad2), Smad2, p-Smad3 and Smad3 were detected western blotting. The present study identified significant upregulation of eIF3a mRNA and protein and in human keloid tissues compared with in normal tissues. Knockdown of eIF3a inhibited KF proliferation induced by TGF-beta1. In addition, eIF3a silencing significantly suppressed the TGF-beta1-induced expression of alpha-smooth muscle actin, collagen I, TGF-beta RI and TGF-beta RII in KFs. Furthermore, eIF3a silencing inhibited the phosphorylation levels of Smad2 and Smad3 in TGF-beta1-induced KFs. To the best of our knowledge, the current study is the first to demonstrate that siRNA-eIF3a inhibits the expression ECM proteins via the TGF-beta1/Smad signaling pathway in KFs. Therefore, eIF3a may be a potential, novel target for treatment of keloids. PMID- 29286130 TI - Salidroside inhibits steroid-induced avascular necrosis of the femoral head via the PI3K/Akt signaling pathway: In vitro and in vivo studies. AB - Dexamethasone (Dex) and other glucocorticoids are widely used to treat serious infections and immunological diseases, however they may cause steroid-induced avascular necrosis of the femoral head (SANFH). Salidroside (Sal) has demonstrated an anti-apoptotic effect on neurocytes by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. In the present study, primary osteoblasts were used in vitro and in rats in vivo to determine the anti-apoptotic effect of Sal on SANFH. The result of the present study demonstrated that pretreatment with Sal increased the cell survival rate while decreasing the cell apoptosis and lactate dehydrogenase release rate. Additionally, Sal also caused the reduction of TUNEL positive cells in TUNEL staining assay. Sal decreased the expression of cleaved caspase-3, cleaved caspase-9, apoptosis regulator BAX and cytochrome C, while it increased the expression of B cell lymphoma-2 and phosphorylated-Akt in Dex-induced osteoblasts. In vivo Sal protected against SANFH in rats by decreasing the percentage of empty lacunae. The present study demonstrated that Sal alleviated Dex-induced osteoblast apoptosis by activating the PI3K/Akt signaling pathway and downregulating caspase-3 expression in osteoblasts. Sal also protected against SANFH in a rat model of SANFH by decreasing the percentage of empty lacunae. The inhibition of the mitochondrial apoptosis pathway was also involved. Further research is required to determine the full underlying mechanisms by which Sal has an effect. PMID- 29286131 TI - Targeting the overexpressed CREB inhibits esophageal squamous cell carcinoma cell growth. AB - Although several studies highlight the important role of cAMP-responsive element binding protein (CREB) in tumor progression, little is known concerning the expression and function of CREB in esophageal cancer. In the present study, the expression of CREB was evaluated using a human esophageal squamous cell carcinoma tissue array by immunohistochemical analysis, which was confirmed by western blot analysis of tissues from esophageal cancer, and adjacent esophageal tissue. The role of CREB on esophageal cancer cell growth was analyzed in vitro and in vivo. Results showed that CREB was overexpressed in esophageal squamous cell carcinomas tissues, which was positively correlated with lymph node metastasis and tumor node-metastasis (TNM) stage of esophageal cancer patients. Downregulating the expression of CREB effectively reduced esophageal cell growth in vitro and in vivo, induced S phase cell cycle arrest, triggered apoptosis and inhibited cell migration and invasion. These findings suggested CREB as an attractive drug target for esophageal cancer. PMID- 29286132 TI - EZH2 enhances the invasive capability of renal cell carcinoma cells via activation of STAT3. AB - The enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) gene has been recognized to be a proto-oncogene and to be linked to human malignancies. However, the additional functions of EZH2 in renal cell carcinoma (RCC) are not completely understood. In the present study, a possible role of EZH2 in RCC was identified. EZH2 was demonstrated to promote the cell proliferation and invasion potential of 769-P cells, and inhibition of EZH2 was demonstrated to prevent these two processes in 786-O cells. Mechanically, EZH2 was demonstrated to increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and upregulate 72 kDa type IV collagenase (MMP-2) expression. When cells were treated with small interfering RNA targeting STAT3 or Stattic, a specific inhibitor of STAT3, the invasive ability of the cells was decreased and downregulation of MMP-2 was observed. Based on these results, in the present study it was hypothesized that EZH2 may serve a critical role in the progression of RCC. Its ability to facilitate invasion makes EZH2 a promising target for the management of advanced RCC. PMID- 29286133 TI - Hydroxytyrosol inhibits the inflammatory response of osteoarthritis chondrocytes via SIRT6-mediated autophagy. AB - Osteoarthritis (OA) is a common degenerative joint disease. Inflammation may exaggerate the catabolism and degeneration in the pathogenesis of OA. Hydroxytyrosol (HT) has been used in the management of inflammatory diseases. In addition, reports have revealed that autophagy was a therapeutic target of diseases caused by inflammation. Sirtuin 6 (SIRT6) has also been demonstrated to prevent OA development by reducing both the inflammatory response and chondrocyte senescence. However, the roles of SIRT6 and autophagy in cartilage and its underlying anti-inflammatory mechanism are unknown. Therefore, the present study aimed to determine the effects of HT on autophagy and inflammation in chondrocytes, and clarify whether HT regulates the inflammatory response through SIRT6-mediated autophagy. The expression of protein and mRNA were determined by western blot analysis and reverse transcription-quantitative polymerase chain reaction. The production of cytokines was detected by ELISA. It was demonstrated that HT inhibited the levels of interleukin (IL)-1beta and IL-6 in tumor necrosis factor (TNF)-alpha-stimulated chondrocytes in a concentration-dependent manner. In addition, HT promoted cell autophagy and increased the mRNA and protein expression levels of SIRT6 in chondrocytes stimulated with TNF-alpha. Autophagy inhibitor 3-methyladenine or knockdown of SIRT6 decreased the inhibitory effects of HT on the inflammatory response in chondrocytes. In addition, knockdown of SIRT6 attenuated the expression of microtubule-associated protein 1A/1B-light chain 3 and Beclin1 in chondrocytes. Overall, these findings suggested that HT inhibits the inflammatory response of chondrocytes through SIRT6-mediated autophagy. The present study provided a new drug target for the clinical treatment of inflammatory diseases. PMID- 29286134 TI - YAP knockdown inhibits proliferation and induces apoptosis of human prostate cancer DU145 cells. AB - The role of yes-associated protein (YAP) in human prostate cancer DU145 cells and its underlying molecular mechanisms were explored in the present study. Initially, the expression levels of YAP were detected in DU145 cells, which revealed that YAP was highly expressed in these cells. To investigate the role of YAP in DU145 cells, a stable YAP-silenced DU145 cell line was generated using YAP small interfering RNA. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed for mRNA and protein detection, respectively. An MTT assay and flow cytometry were performed to investigate the proliferation and apoptosis of DU145 cells. The results demonstrated that YAP knockdown significantly decreased the proliferative ability of DU145 cells, whereas the percentage of apoptotic cells was markedly increased, compared with the control. In addition, the mRNA and protein expression levels of connective tissue growth factor and cysteine-rich angiogenic factor 61 were notably decreased, the ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) was significantly reduced, and the expression levels of caspase 3 were significantly decreased within YAP-silenced DU145 cells. In conclusion, YAP knockdown reduced the proliferation and induced apoptosis of DU145 cells. Therefore, the gene transcription and protein expression of YAP may be involved in the development of prostate cancer and may be considered a potential target for the treatment of such cancers. PMID- 29286135 TI - Characterization of different osteoclast phenotypes in the progression of bone invasion by oral squamous cell carcinoma. AB - The present study aimed to characterize different phenotypes of osteoclasts in the progression of bone invasion by oral squamous cell carcinoma (OSCC). A local bone invasion model of OSCC was established by injecting SCC25 human OSCC cells into the center of calvariae in nude mice, and all mice were found to have a typical bone resorption area. Staining for tartrate-resistant acid phosphatase (TRAP) revealed various types of giant osteoclasts in the tumour-bone interface. Bone marrow cells (BMCs) were isolated from the nude mice for primary osteoclast culture, but only a few giant osteoclasts were generated. Additionally, special blood centrifuge tubes were utilized to obtain large numbers of peripheral blood mononuclear cells (PBMCs). Using magnetic activated cell sorting (MACS) and the cytokines colony-stimulating factor (CSF) and receptor activator of nuclear factor-kappab ligand (RANKL), we differentiated human osteoclasts from CD14+ monocytes of PBMCs. Bone resorption was further confirmed by a bone resorption assay. Finally, Transwell inserts were used for indirect cell co-culture of SCC25 cells and CD14+ monocytes. Expression of specific osteoclast markers was detected by real-time PCR and western blotting. After co-culture for 3 and 6 days, conditioned medium (CM) of SCC25 cells stimulated the expression of osteoclast markers, and additional osteoclasts were detected through staining of TRAP and F actin. In the present study distinct osteoclast phenotypes were observed in the established bone invasion animal model, and were confirmed using various primary osteoclast cultures. CM of OSCC cells may promote the expression of osteoclast markers and induce the differentiation of monocytes to mature osteoclasts, which can resorb adjacent bone tissue. PMID- 29286136 TI - Proteomic investigation of the effects of preimplantation factor on human embryo implantation. AB - Despite the use of adjuvant therapies, the cumulative proportion of live births remains at ~40%. Accumulating data show that low pregnancy rates, even in the presence of high fertility rates, are due to implantation failure. The present study aimed to identify and construct a profile of proteins that react with preimplantation factor (PIF) and to provide an understanding into the molecular mechanisms by which PIF promotes trophoblast invasion. Cytoplasmic proteins were immunoprecipitated with biotin-labeled synthetic PIF or intralipid and scrambled PIF (PIFscr). The protein profiles were analyzed using isobaric tags for relative and absolute quantification coupled with mass spectrometry. Immunoprecipitation and western blot analyses were used to assess the interactions between PIF and myosin heavy chain 10 (MYH10) and heat shock protein family D1. Small interfering RNA-based silencing was performed to examine the function of MYH10. In the results of the present study, 21 proteins were identified with interactions with PIF. The immunoprecipitation and western blot analyses revealed an interaction between PIF and MYH10. Silencing of the expression of MYH10 in HEC-1-B cells significantly attenuated cell migration and invasion capacities. These data support the conclusion that MYH10-mediated cell migration and invasion act in conjunction with PIF to promote the trophoblast invasion procedure. PMID- 29286137 TI - MicroRNA-124a inhibits cell proliferation and migration in liver cancer by regulating interleukin-11. AB - Liver cancer is the sixth most common malignant tumour and ranks in the top three cancers with regard to mortality due to metastasis and postsurgical recurrence. It is significant to understand the mechanisms underlying liver cancer for diagnosis and treatment. Cumulative evidence suggests that the abnormal regulation of microRNAs (miRNAs/miRs) may contribute to the development and metastasis of cancer. miR-124a acts as a tumour suppressor in osteosarcoma, endometrial carcinoma, prostate cancer, and glioblastoma. However, the effects of miR-124a in liver cancer and its biological mechanism are not fully understood. It has been demonstrated that miR-124a is downregulated and interleukin (IL)-11 is upregulated in the liver cancer tissues. In the present study, miR-124a upregulation inhibited cell proliferation, migration and promoted cell apoptosis. Through a dual-luciferase reporter assay, it was verified that IL-11 is a direct target of miR-124a. Furthermore, the overexpression of miR-124a repressed the secretion of IL-11 from hepatoma cells. Finally, it was identified that mimics of miR-124a increased the expression of tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) and Caspase-3 and decreased the expression levels of matrix metalloproteinase 2 (MMP2), MMP9, B-cell lymphoma 2, signal transducer and activator of transcription 3 (STAT3), and phosphorylated-STAT3. In conclusion, the results indicated that miR-124a has an important role as a tumour suppressor gene by targeting IL-11. These findings may provide novel insights for clinical treatments to prevent the development of liver cancer. PMID- 29286138 TI - shRNA-induced silencing of Ras-related C3 botulinum toxin substrate 1 inhibits the proliferation of colon cancer cells through upregulation of BAD and downregulation of cyclin D1. AB - Ras-related C3 botulinum toxin substrate 1 (RAC1) is a member of the Rho family of small GTPases. Recent studies have reported that RAC1 serves an important role in colon cancer cell proliferation. The present study aimed to investigate the effects of RAC1 knockdown on cell proliferation, cell cycle progression and apoptosis of colon cancer cells. Lentivirus-mediated short hairpin RNA (shRNA) was used to knockdown RAC1 expression in colon cancer cell lines, and cell proliferation, apoptosis, cell cycle progression were evaluated by MTT assays and flow cytometry. The differences in mRNAs expression were identified between RAC1 knockdown cells and control cells using a mRNA microarray, following which quantitative PCR (qPCR) and western blot were employed to confirm the results of the mRNA microarray. The proliferative ability of colon cancer cells was significantly decreased following RAC1 knockdown, and RAC1 knockdown increased the apoptotic rate and enhanced cell cycle arrest at G1 phase in colon cancer cells. In addition, >1,200 known genes were demonstrated to be involved in RAC1 associated tumorigenic functions in SW620 colon cancer cells, as determined by gene chip analysis; these genes were associated with cell proliferation, cell cycle, apoptosis and metastasis. Furthermore, western blot analysis indicated that cyclin D1 was downregulated, whereas B-cell lymphoma 2-associated agonist of cell death (BAD) was upregulated following RAC1 knockdown in colon cancer cells. In conclusion, RAC1 silencing may suppress the proliferation of colon cancer cells by inducing apoptosis and cell cycle arrest. In addition, a large number of genes were revealed to be involved in the process, including BAD, which was upregulated and cyclin D1, which was downregulated. Further studies on these differentially expressed genes may provide a better understanding of the potential roles of RAC1 in colon carcinogenesis. PMID- 29286139 TI - Paeoniflorin exerts antitumor effects by inactivating S phase kinase-associated protein 2 in glioma cells. AB - Paeoniflorin (PF), a natural compound isolated from Paeoniae radix, has been shown to exert antitumor effects in various types of human cancers including glioma. However, the mechanism of action is not well understood. S-phase kinase associated protein (Skp)2 functions as an oncogene in many cancers. In the present study, we investigated whether Skp2 mediates the anti-glioma activity of PF. We found that PF inhibited glioma cell proliferation, migration and invasion, and induced G2/M arrest and apoptosis. Skp2 expression was downregulated in glioma cells treated with PF. PF-induced antitumor effects in glioma cells were abolished by Skp2 overexpression but were enhanced by RNA interference of Skp2. Moreover, PF treatment inhibited U87 cell-derived tumor growth in a xenograft mouse model. These results demonstrate that PF exerts its antitumor effects in part by inhibiting Skp2 expression in glioma cells and could be a promising therapeutic agent for glioma therapy. PMID- 29286141 TI - CircDOCK1 suppresses cell apoptosis via inhibition of miR-196a-5p by targeting BIRC3 in OSCC. AB - Oral squamous cell carcinoma (OSCC) is the most frequent oral cancer in the world, accounting for more than 90% of all oral cancer diagnosis. Circular RNAs (circRNAs) are large types of non-coding RNAs, demonstrating a great capacity of regulating the expression of genes. However, most of the functions of circRNAs are still unknown. Recent research revealed that circRNAs could serve as a miRNA sponge, consequently regulating the expression of target genes indirectly, including oncogenes. In this study, we built an apoptotic model with TNF-alpha, and then we confirmed a circRNA associated with the apoptosis of OSCC cells, circDOCK1 by comparing the expression profile of circRNAs in an apoptotic model with that in untreated OSCC cells. We ascertained the presence of circDOCK1 with qRT-PCR and circRNA sequencing. The knockdown of the expression of circDOCK1 led to the increase of apoptosis. Utilizing multiple bioinformatics methods, we predicted the interactions among circRNAs, miRNAs and genes, and built the circDOCK1/miR-196a-5p/BIRC3 axis. Both the silencing of circDOCK1 with small interfering RNA and the upregulation of the expression of miR-196a-5p with mimics led OSCC cells to increase apoptosis and decrease BIRC3 formation. We further confirmed this outcome by comparing the expression of circDOCK1, miR-196a-5p and BIRC3 in oral squamous carcinoma tissue with those in para-carcinoma tissue, and examining the expression profile of circRNAs in oral squamous carcinoma tissue and para-carcinoma tissue with microarray. Our results demonstrated that circDOCK1 regulated BIRC3 expression by functioning as a competing endogenous RNA (ceRNA) and participated in the process of OSCC apoptosis. Thus, we propose that circDOCK1 could represent a novel potential biomarker and therapeutic target of OSCC. PMID- 29286142 TI - 2-Phenyl-4-quinolone (YT-1) induces G2/M phase arrest and an intrinsic apoptotic mechanism in human leukemia cells. AB - The present study aimed to investigate the biological effects of the new compound 2-phenyl-4-quinolone (YT-1) on human leukemia cells. Cell viability was determined by propidium iodide (PI) exclusion method followed by flow cytometry. Our results showed that YT-1 inhibited the cell viability and resulted in morphologic changes to the U937, HL-60 and K562 cells, respectively. Among them, U937 cells were the most sensitive cell line. On the contrary, YT-1 had no cytotoxic effects on human fetal skin fibroblast WS1 cells. Flow cytometric analysis indicated that YT-1 induced G2/M phase arrest and apoptosis (sub-G1 population) in U937 cells. The presence of apoptotic bodies evidenced by DAPI staining and DNA fragmentation detected by agarose gel electrophoresis further supported the induction of apoptosis in the YT-1-treated U937 cells. Annexin V/PI staining of U937 cells confirmed that the early apoptotic event occurred after YT 1 exposure. YT-1 disrupted the mitochondrial membrane potential (DeltaPsim) in a time-dependent manner. YT-1 increased the protein levels of Bax and Bak but decreased Bcl-2 and Bid protein levels in U937 cells in a time-dependent manner. In addition, YT-1 stimulated the expression of cytochrome c and proteolytic activation of caspase-3 and caspase-9 after exposure to YT-1 in U937 cells. In summary, YT-1 suppressed the viability of U937 leukemia cells through the intrinsic apoptosis pathway. YT-1 is a potential chemotherapeutic candidate for the treatment of leukemia. PMID- 29286140 TI - Identification of key genes implicated in the suppressive function of human FOXP3+CD25+CD4+ regulatory T cells through the analysis of time-series data. AB - Human forkhead box P3 (FOXP3)+ cluster of differentiation (CD)25+CD4+ regulatory T cells (Tregs) are a type of T cell that express CD4, CD25 and FOXP3, which are critical for maintaining immune homeostasis. The present study aimed to determine the mechanisms underlying Treg function. The GSE11292 dataset was downloaded from the Gene Expression Omnibus, which included data from Treg cells at 19 time points (0-360 min) with an equal interval of 20 min, and corresponding repeated samples. However, data for Treg cells at time point 120 min were missing. Using the Mfuzz package, the key genes were identified by clustering analysis. Subsequently, regulatory networks and protein-protein interaction (PPI) networks were constructed and merged into integrated networks using Cytoscape software. Using Database for Annotation, Visualization and Integrated Discover software, enrichment analyses were performed for the genes involved in the PPI networks. Cluster 1 (including 292 genes), cluster 2 (including 111 genes), cluster 3 (including 194 genes) and cluster 4 (including 103 genes) were obtained from the clustering analysis. GAPDH (degree, 40) in cluster 1, Janus kinase 2 (JAK2) (degree, 10) and signal transducer and activator of transcription 5A (STAT5A) (degree, 9) in cluster 3, and tumor necrosis factor (TNF) (degree, 26) and interleukin 2 (IL2) (degree, 22) in cluster 4 had higher degrees in the PPI networks. In addition, it was indicated that several genes may have a role in Treg function by targeting other genes [e.g. microRNA (miR)-146b-3p->TNF, miR 146b-5p->TNF, miR-142-5p->TNF and tripartite motif containing 28 (TRIM28) >GAPDH]. Enrichment analyses indicated that IL2 and TNF were enriched in the immune response and T cell receptor signaling pathway. In conclusion, GAPDH targeted by TRIM28, TNF targeted by miR-146b-3p, miR-146b-5p and miR-142-5p, in addition to JAK2, IL2, and STAT5A may serve important roles in Treg function. PMID- 29286143 TI - Epithelial mesenchymal transition induced by the CXCL9/CXCR3 axis through AKT activation promotes invasion and metastasis in tongue squamous cell carcinoma. AB - The present study aimed to assess the induction of epithelial-mesenchymal transition (EMT), invasion, and metastasis by the chemokine CXCL9/receptor CXCR3 axis in tongue squamous cell carcinoma (TSCC), unveiling the underlying mechanisms and providing new insights into the prevention and treatment of oral cancer metastasis. The expression levels of CXCL9 and CXCR3 in TSCC tissue specimens were determined by immunohistochemistry, assessing differences between samples with cervical lymph node metastasis and those without. Moreover, protein expression or activity in the TSCC Cal-27 cell line was controlled by neutralizing antibodies, gene transfection, or knock-out. Then, alterations of cell proliferation, migration, invasion, and the cytoskeleton were analyzed by CCK-8, cell scratch, Transwell, and cyto-skeleton staining assays, respectively. Alterations of EMT markers (E-cadherin and vimentin) in Cal-27 cells were detected by immunofluorescence and western blotting. In addition, western blotting was utilized to detect protein expression levels of Akt2, p-Akt2, eIF4E and p-eIF4E, and to explore the regulatory roles and mechanisms of the CXCL9/CXCR3 axis in invasion and metastasis. Significantly increased expression levels of CXCL9 and CXCR3 were detected in tissue specimens with lymph node metastasis compared with those without (P<0.01). Overexpression of CXCL9/CXCR3 in Cal-27 cells resulted in cytoskeleton alterations, decreased E-cadherin expression, increased vimentin levels, enhanced migration and invasion (P<0.05), and increased phosphorylated Akt2 and eIF4E levels (P<0.05). These results revealed that in TSCC, the CXCL9/CXCR3 axis could activate the Akt signaling pathway, with EMT and cytoskeleton rearrangement, promoting invasion and metastasis. PMID- 29286144 TI - Effect of long non-coding RNA PVT1 on cell proliferation and migration in melanoma. AB - The present study aimed to investigate the potential role of the long non-coding RNA (lncRNA) Pvt1 oncogene (non-protein coding) (PVT1) in the progression and metastasis of malignant melanoma, and to reveal its possible molecular mechanisms. The expression of lncRNA PVT1 in melanoma tissues and adjacent normal skin from patients with melanoma, and in the melanoma A-375 and sk-mel-5 cell lines, was analyzed using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The effects of PVT1 expression on cell proliferation, the cell cycle, cell migration and cell invasion were analyzed using MTT assay, flow cytometry, Transwell and scratch assays, respectively. The interaction between PVT1 and enhancer of zeste homolog 2 (EZH2) in melanoma cells was analyzed using RNA immunoprecipitation (RIP) assay. The effect of PVT1 on microRNA-200c (miR-200c) expression was analyzed by chromatin immunoprecipitation (ChIP) assay. PVT1 was highly expressed in the melanoma tissues and cells. Silencing of PVT1 significantly inhibited cell proliferation, migration and invasion, and arrested the cell cycle at the G0/G1 stage. Additionally, PVT1 silencing significantly decreased the cyclin D1 expression in the melanoma cells. The expression of E-cadherin was significantly increased and the expression of N cadherin and vimentin was significantly decreased in the PVT1-silenced group. The RIP assay found that endogenous PVT1 was highly enriched by EZH2 RIP compared with that of the negative control. The ChIP assay revealed that the expression of miR-200c was decreased significantly in the PVT1-silenced group compared with the controls. Overall, the present study demonstrated that the lncRNA PVT1 may contribute to the tumorigenesis and metastasis of melanoma through binding to EZH2 and regulating the expression of miR-200c. lncRNA PVT1 may serve as a potential target for the therapy of melanoma. PMID- 29286145 TI - Antitumor activity of Notch-1 inhibition in human colorectal carcinoma cells. AB - This study investigated the roles of Notch-1 in colorectal carcinoma, to assess the mechanisms. The expression of Notch-1 and its ligand-Jagged1 was detected in human colorectal carcinoma, colorectal adenoma, paracancerous tissue and normal colorectal tissue by immunohistochemistry. Colorectal carcinoma cell lines were utilized to confirm the expression of Notch-1 in colorectal carcinoma cells. Lentiviral- encoding Notch-1-siRNA, as well as Notch-1 inhibitor was employed to silence Notch-1 expression and to inhibit Notch-1 activity in HT29 cells, respectively. As evidenced, Notch-1 and Jagged1 were highly expressed in colorectal carcinoma and colorectal adenoma tissues, compared with those in paracancerous tissue and normal colorectal tissue. However, the expression of Notch-1 and Jagged1 was comparable in colorectal carcinoma and colorectal adenoma tissues, and in paracancerous and normal colorectal tissues. After screening colorectal carcinoma cell lines, Notch-1 was extensively expressed in COLO 205, HT29, SW480 and SW1116 cells, but slightly expressed in LoVo cells. Subsequently, HT29 cell line was selected to investigate the roles of Notch-1 in tumor cell growth and apoptosis. Lenti-viral encoding Notch-1 siRNA significantly decreased Notch-1 expression, inhibited cell growth, arrested the cell cycle at G1 phase and promoted apoptosis. These effects were further confirmed by the Notch-1 inhibitor DAPT. Additionally, we evidenced that Notch-1 silence promoted P21 and PUMA expression in HT29 cells. Taken together, Notch-1 is an oncogene in colorectal carcinoma and the inhibition of Notch-1 could delay the cell growth and promote apoptosis in colorectal cancer. PMID- 29286146 TI - Immune response-associated gene profiling in Japanese melanoma patients using multi-omics analysis. AB - Project High-tech Omics-based Patient Evaluation (HOPE), including comprehensive whole-exome sequencing (WES) and gene expression profiling (GEP) using freshly resected tumor specimens, has been in progress since its implementation in 2014. Among a total of 1,685 cancer patients, 13 melanoma patients were registered in the HOPE Project and were characterized using multi-omics analyses. Among the 13 melanoma patients, 4 were deceased, and 9 were alive. The mean overall survival (OS) and relapse-free survival (RFS) times of the melanoma patients were 16.9 and 14.7 months, respectively. Previously, we developed an immune response-associated gene list, which consisted of 164 genes in Project HOPE, for evaluating the immunological status. In the present study, the association of immune response associated gene expression with immunological parameters, such as programmed death-ligand 1 (PD-L1) and CD8 expression levels, single nucleotide variant (SNV) number, and Vogelstein driver gene mutation number, was investigated. With respect to PD-L1 expression, both immuno-suppression and immuno-stimulation related genes were upregulated in PD-L1-positive melanomas. In contrast, regarding Vogelstein driver mutations, several T-cell activation-related genes were significantly downregulated in the high driver gene mutation group. In addition, many T-cell activation-related genes were upregulated in the CD8 positive melanomas. The correlation of immune response-associated gene expression with the survival time of the melanoma patients was investigated. Eight specific genes were commonly identified as genes that were significantly correlated for both the overall OS and RFS time, which could be possible prognostic factors for melanoma patients. These results revealed that an immune response-associated gene panel could be an informative tool for evaluating the immunological status prior to clinical immunotherapy in the upcoming era of genomic cancer medicine. PMID- 29286148 TI - DL-3-n-butylphthalide reduces microglial activation in lipopolysaccharide-induced Parkinson's disease model mice. AB - As microglial activation is a key factor in the pathogenesis of Parkinson's disease (PD), drugs that target this process may help to prevent or delay the development of PD. The present study investigated the effects of dl-3-n butylphthalide (NBP) on microglia in a lipopolysaccharide (LPS)-induced PD mouse model. The mice were randomly divided into a blank control group, LPS control group and NBP + LPS treatment group. Mice in the treatment group were given an intragastric infusion of 120 mg/kg NBP daily for 30 days during the establishment of the PD mouse model. At 4 and 28 weeks post-treatment, the motor behaviours of the mice in each group were observed using the rotarod test and the open field test. In addition, immunohistochemical staining was performed to determine the levels of activated microglia, tumour necrosis factor-alpha and alpha-synuclein, and the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra. NBP significantly improved dyskinesia, reduced microglial activation, decreased nuclear alpha-synuclein deposition and increased the survival of TH positive cells in the substantia nigra of LPS-induced PD model mice. These findings suggested that NBP may exert its therapeutic effect by reducing microglial activation in a mouse model of PD. PMID- 29286149 TI - Inhibition effect of triptolide on human epithelial ovarian cancer via adjusting cellular immunity and angiogenesis. AB - Chemotherapy resistance of advanced ovarian cancers is responsible for death of most cancer patients, so it is necessary to seek safe and effective natural ingredients to lower the chemotherapy resistance of ovarian cancer. In the present study, we studied the anticancer effects of triptolide (TPL) and TPL + cisplatin (DDP) in vitro and in vivo using SKOV3/DDP cell line and a mouse model. In vitro results showed that TPL and TPL + DDP inhibited cellular invasion and migration of SKOV3/DDP cells (P<0.05), and significantly reduced the expression of adhesion-related proteins integrin beta1 (ITGbeta1) and apoptosis-inhibiting proteins survivin, matrix metalloproteinase 2 (MMP-2) and MMP-9 (P<0.05). Animal results demonstrated that TPL and TPL + DDP had significantly enhanced the inflammatory factor-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) in serum of mice, and significantly increased the NK cell-related protein levels of CD16 and CD56, while significantly inhibited the production of vascular endothelial growth factor (VEGF) related protein clusters of differentiation 31 (CD31) and CD105. Collectively, the combination of TPL and DDP may produce a synergistic anticancer effect on epithelial ovarian cancer (EOC). PMID- 29286147 TI - Mutual regulation of the Hippo/Wnt/LPA/TGF-beta signaling pathways and their roles in glaucoma (Review). AB - Glaucoma is the leading cause of irreversible blindness worldwide and there is no effective treatment thus far. The trabecular meshwork has been identified as the major pathological area involved. Certain signaling pathways in the trabecular meshwork, including the Wnt, lysophosphatidic acid and transforming growth factor beta pathways, have been identified as novel therapeutic targets in glaucoma treatment. Meanwhile, it has been reported that key proteins in these pathways, particularly the primary transcription regulator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), exhibit interactions with the Hippo pathway. The Hippo pathway, which was first identified in Drosophila, has drawn great focus with regard to various aspects of studies in recent years. One role of the Hippo pathway in the regulation of organ size was indicated by more recent evidence. Defining the relevant physiological function of the Hippo pathway has proven to be extremely complicated. Studies have ascribed a role for the Hippo pathway in an overwhelming number of processes, including cell proliferation, cell death and cell differentiation. Therefore, the present review aimed to unravel the roles of YAP and TAZ in the Hippo pathway and the pathogenesis of glaucoma. Furthermore, a new and creative study for the treatment of glaucoma is provided. PMID- 29286150 TI - Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is known to have a high malignant potential. Because of its high recurrence rate, ICC has a poor prognosis even after complete tumor resection. Compared with normal differentiated cells, cancer cells have an altered metabolism for supporting their survival in severe conditions. Cancer cells acquire additional malignant potential as a result of this metabolic alteration. Thus, the molecules known to be involved in cancer metabolism, could be novel therapeutic targets. The mitochondrial pyruvate carrier (MPC) is a recently discovered pyruvate transporter, which is located in the mitochondrial inner membrane. Although MPC is composed of two subunits, it has been reported that the MPC1 subunit is specifically associated with poor prognosis in several cancers, including colorectal and prostate cancer. However, only a few studies have assessed the clinical significance of MPC1 and the molecular mechanisms underlying its influence on cancer progression are not well understood. This study aimed to clarify the function of MPC1 that affects the malignant potential of ICC. The expression of MPC1 in ICC clinical specimens was determined by immunohistochemistry. In addition, the correlations between MPC1 expression and the survival rate, as well as various clinicopathological parameters were assessed. Low MPC1 expression correlated with poor ICC prognosis and was correlated with tumor invasion and distant metastasis. Both these phenomena are closely associated with the epithelial-mesenchymal transition (EMT). Therefore, we investigated the impact of altering the MPC1 gene expression on the malignant potential of cancer cells using biliary tract cancer cell lines in vitro. The expression of MPC1 was downregulated in the cells induced to undergo EMT following treatment with TGF-beta. Furthermore, the inhibition of MPC1 expression induced EMT in cancer cells, and the overexpression of MPC1 suppressed the migration of tumor cells. These results indicated that MPC1 could be a novel therapeutic target in some cancers. PMID- 29286151 TI - Polysaccharide sulphated derivative from Aconitum coreanum induces cell apoptosis in the human brain glioblastoma U87MG cell line via the NF-kappaB/Bcl-2 cell apoptotic signaling pathway. AB - In a previous study, our team preliminarily investigated the bioefficacy of an extracted polysaccharide from the medicinal plant Aconitum coreanum (ACP1). In the present study, we further evaluated the antitumor efficacy of an ACP1 sulphated derivative (ACP1-s) in the human brain glioblastoma U87MG cell line. Cell viability assay and flow cytometry results demonstrated that 400, 800 and 1,600 ug/ml ACP1-s induced cell growth inhibition and cell apoptosis. We then investigated the underlying molecular mechanism of the ACP1-s induced cell apoptosis and found that the NF-kappaB/Bcl-2 cell apoptotic signaling pathway was involved. Following treatment with ACP1-s, the expression of IkappaB in U87MG cells was significantly upregulated, whereas the level of NF-kappaB and the ratio of Bcl-2/Bax was significantly decreased. The level of cleaved caspase-3 was increased accordingly. When we introduced exogenous p65 protein into the U87MG cells, the ACP1-s-induced cell growth inhibition and cell apoptosis were partially neutralized, and the expression of the anti-apoptotic gene Bcl-2 was recovered accordingly. These findings suggest the potential value of ACP1-s as a novel therapeutic agent for the treatment of glioblastoma. PMID- 29286153 TI - CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation. AB - Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0.89 to 2.75 uM, but limited cell death. Importantly, treatment of pancreatic cancer cell lines with LY2603618 reduced the levels of pCDC25C, pCDK1, and pCDK2, accompanied by DNA damage and RRM1/2 downregulation. Furthermore, LY2603618 synergized with gemcitabine treatment to induce growth inhibition and apoptosis in pancreatic cancer cells. Mechanistic investigations showed that gemcitabine sensitization by CHK1 inhibition was associated with CDK-dependent RRM1/2 downregulation and DNA damage enhancement. These findings provide a basis for further development of combining CHK1 inhibitors and gemcitabine to treat pancreatic cancer. PMID- 29286152 TI - A promising novel formulation for articular cartilage regeneration: Preclinical evaluation of a treatment that produces SOX9 overexpression in human synovial fluid cells. AB - Osteoarthritis (OA) is a chronic disorder of synovial joints, in which there is progressive softening and disintegration of the articular cartilage. OA is the most common form of arthritis, and is the primary cause of disability and impaired quality of life in the elderly. Despite considerable medical necessity, no treatment has yet been proven to act as a disease-modifying agent that may halt or reverse the structural progression of OA. The replacement of the joint with a prosthesis appears to be the best option in the advanced stages of the disease. A formulation (BIOF2) for cartilage regeneration has been recently developed. The present study evaluated the effects of BIOF2 on gene expression in human cell cultures, followed by efficacy trials in three OA animal models. Human synovial fluid cells that were exposed to the formulation exhibited increased transcription factor SOX-9 (SOX9; chondrogenic factor) expression, and decreased mimecan (mineralization inducer) and macrophage-stimulating protein receptor (osteoclastogenic factor) expression. The intra-articular application of BIOF2 in the animal models significantly increased cartilage thickness from 12 to 31% at 28 days, compared with articular cartilage treated with saline solution. The articular area and number of chondrocytes additionally increased significantly, maintaining an unaltered chondrocyte/mm2 proportion. Evaluation of the histological architecture additionally displayed a decrease in the grade of articular damage in the groups treated with BIOF2. In conclusion, BIOF2 has proven to be effective for treating OA in animal models, most likely due to SOX9 overexpression in articular cells. PMID- 29286154 TI - Possible role of miR-204 in optic nerve injury through the regulation of GAP-43. AB - Optic nerve injury is a common disease. The present study aimed to examine the possible role of microRNA-204 (miR-204) in optic nerve injury through the regulation of growth-associated protein-43 (GAP-43). Initially, optic nerve injury models were established in Sprague-Dawley (SD) rats, and the function of miR-204 was either enhanced or inhibited through injection of miR-204 mimic and inhibitor, respectively. Subsequently, the mRNA and protein levels of miR-204, GAP-43, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor-kappaB (NF-kappaB) were examined in retinal tissues using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The apoptosis of retinal tissue cells was also detected using a terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. There was a significant increase in the level of miR-204 in retinal blood vessels of the model SD rats, compared with that in the normal SD rats (P<0.05), and the expression of GAP-43 was significantly decreased (P<0.05). The results confirmed that the expression of GAP-43 was significantly reduced, compared with that in the normal control group when the rats were treated with miR-204 mimic (P<0.05), which was similar to the result in the model group. By contrast, its expression of GAP-43 was significantly increased when treated with the miR-204 inhibitor (P<0.05). Compared with the normal control group, the expression levels of TLR4, MyD88 and NF-kappaB were significantly increased in the miR-204 mimic group and model group (P<0.05), whereas the same three factors in the miR-204 inhibitor group were effectively inhibited, compared with those in the model group, and showed similar results to the normal control group. The apoptotic rates of retinal cells in the miR-204 mimic group and model group were significantly increased, compared with that in the normal control group (P<0.05), whereas miR 204 inhibitor effectively reversed the effects on apoptotic rate observed in the model group, showing similar results to those in the normal control group. Taken together, miR-204 promoted the apoptosis of retinal cells through inhibiting GAP 43, providing theoretical guidance for the function of GAP-43 in retinal injury. PMID- 29286155 TI - Mesenchymal stem cells reverse high-fat diet-induced non-alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice. AB - Although the multipotency of mesenchymal stem cells (MSCs) makes them an attractive choice for clinical applications, immune modulation is an important factor affecting MSC transplantation. At present, the effect of treatment with MSCs on non-alcoholic fatty liver disease (NAFLD) has received little attention. In the present study, a compact bone-derived method was used to isolate mouse MSCs (mMSCs) and a high-fat diet was used to establish a mouse model of NAFLD. Immunophenotypic features of mMSCs were analyzed using flow cytometry. Paraffin sections were stained with hematoxylin and eosin to assess inflammation and steatosis, and with picrosirius red to assess fibrosis. Spleen leukocytes were analyzed by flow cytometry. The results demonstrated that compact bone-derived MSC transplantation decreased high-fat diet-induced weight gain, expansion of subcutaneous adipose tissue, steatosis, lobular inflammation and liver fibrogenesis. Flow cytometry analysis of spleen leukocytes demonstrated that compact bone-derived MSC transplantation suppressed the proliferation of cluster of differentiation (CD) 4+ T lymphocytes in the spleen, which had been induced by the high-fat diet. In conclusion, compact bone-derived MSCs may exhibit clinical value in the treatment of NAFLD through their capacity to suppress the activation of CD4+ T cells. PMID- 29286157 TI - hsa-miR-212 modulates the radiosensitivity of glioma cells by targeting BRCA1. AB - Radioresistance remains a major challenge in the treatment of glioma, and the response of patients to radio-therapy varies considerably. MicroRNAs (miRNAs) are involved in various biological processes. The purpose of the present study was to investigate miRNAs involved in the response to radiation in glioma cell lines. Total RNA was isolated from human glioma U251 cells 30 min after gamma-ray exposure and hybridized to an miRNA chip array. miRNA expression profiles were analyzed by quantitative real-time PCR. pcDNA3/EGFP-miR-212 mimic transfection was used to verify the function of miR-212 in colony formation tests, and the effect of miR-212 overexpression on U251 cells was examined by western blot analysis of apoptosis-related proteins (Bcl-2, Bax, caspase-3 and cytochrome c). The target genes of miR-212 were predicted using bioinformatic tools including miRNA databases, and breast cancer susceptibility gene 1 (BRCA1) was selected for further confirmation by EGFP fluorescence reporter and loss- and gain-of-function assays. Of the 16 candidate miRNAs showing altered expression, five were assessed by real-time PCR; miR-212 was identified as contributing to the radioresistance of glioma cells and was shown to attenuate radiation-induced apoptosis. miR-212 negatively regulated BRCA1 expression by interacting with its 3'-untranslated region, suggesting a correlation between BRCA1 expression and radiosensitivity in glioma cells. U-118MG and SHG-44 cell lines were used to confirm these observations. The response of glioma cells to radiation involves the miR-212 mediated modulation of BRCA1 gene expression, suggesting that the miR-212/BRCA1 axis may play a potential role in the radiotherapy of gliomas. PMID- 29286156 TI - Metformin-induced activation of AMPK inhibits the proliferation and migration of human aortic smooth muscle cells through upregulation of p53 and IFI16. AB - The proliferation and migration of vascular smooth muscle cells are significant in the development and progression of atherosclerosis and plaque rupture. Metformin is a widely used antidiabetic drug, which has been reported to inhibit cell growth and migration. The antiproliferative and antimigratory effects of metformin have been attributed to 5' adenosine monophosphate-activated protein kinase (AMPK) activation. The purpose of the present study was to investigate the effects of metformin on primary human aortic muscle cells (HASMCs) in vitro and to clarify the underlying mechanism. We investigated the effectiveness of metformin in inhibiting the proliferation and migration of HASMCs in vitro using RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), cell number counting, cell viability assay, cell cycle assay and cell migration assay. Through transfection with small interfering (si)RNA targeting p53 and interferon-inducible protein 16 (IFI16), the roles of p53 and IFI16 in these processes were evaluated. The present study demonstrated that p53, IFI16 and AMPK were upregulated in senescent primary HASMCs, which exhibited a decrease in proliferation and migration. In addition, metformin was able to activate p53, IFI16 and AMPK, in order to inhibit proliferation and migration of HASMCs. Furthermore, siRNA-mediated knockdown of p53 and IFI16 attenuated AMPK activation and reversed the suppressive effects of metformin. Notably, in response to metformin, the activation of AMPK was not observed in p53- and IFI16-silenced HASMCs. These results indicated that metformin-induced activation of AMPK suppresses the proliferation and migration of HASMCs by upregulating p53 and IFI16. These findings suggested that metformin may have potential use in the treatment of atherosclerosis. PMID- 29286158 TI - Metformin inhibits HaCaT cell viability via the miR-21/PTEN/Akt signaling pathway. AB - Substantial preclinical evidence has indicated out a direct anti-proliferation effect of metformin on various solid tumors; however, further and more detailed exploration into its molecular mechanism remains to be performed. The present study aimed to investigate the effect of metformin on cell viability and its underlying mechanism, in the cultured human skin keratinocyte cell line, HaCaT. In addition, it aimed to clarify the role of the microRNA-21(miR-21)/phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase 1 (Akt) signaling pathway, which has been hypothesized to be involved in the molecular mechanism of this drug. Cell Counting Kit-8 assays were used to assess the impact of metformin on cell viability; reverse transcription-quantitative polymerase chain reaction was used to quantify the expression of miR-21; western blotting was used to monitor the expression level of PTEN and Akt proteins. In addition, miR-21 expression levels were artificially manipulated in HaCaT cells using a miR-21 inhibitor in order to observe the subsequent expression changes of miR-21 targets and alterations in cell viability. The results indicated that metformin suppressed HaCaT cell growth in a dose- and time-dependent manner (P<0.05). Metformin treatment downregulated miR-21 expression (t=-8.903, P<0.05). Following transfection with the miR-21 inhibitor, HaCaT cell growth was significantly slower than in the control groups (P<0.05). In addition, reduced miR-21 levels results in significantly increased PTEN protein expression levels and reduced Akt protein expression levels compared with control (P<0.05). Metformin was, therefore, concluded to inhibit HaCaT cell growth in a time-and dose-dependent manner, and the miR-21/PTEN/Akt signaling pathway may serve a crucial role in the molecular mechanism of metformin's effect on HaCaT cells. Therefore the present study presents an advanced insight into the potential inhibitory effect of metformin on tumor cells. PMID- 29286159 TI - Maternal chromium restriction induces insulin resistance in adult mice offspring through miRNA. AB - Increasing evidence suggests that undernutrition during the fetal period may lead to glucose intolerance, impair the insulin response and induce insulin resistance (IR). Considering the importance of chromium (Cr) in maintaining carbohydrate metabolism, the present study aimed to determine the effects of maternal low Cr (LC) on glucose metabolism in C57BL mice offspring, and the involved mechanisms. Weaned C57BL mice were born from mothers fed a control diet or LC diet, and were then fed a control or LC diet for 13 weeks. Subsequently, the liver microRNA (miRNA/miR) expression profile was analyzed by miRNA array analysis. A maternal LC diet increased fasting serum glucose (P<0.05) and insulin levels (P<0.05), homeostasis model assessment of IR index (P<0.01), and the area under curve for glucose concentration during oral glucose tolerance test (P<0.01). In addition, 8 upregulated and 6 downregulated miRNAs were identified in the maternal LC group (fold change >=2, P<0.05). miRNA-gene networks, Kyoto Encyclopedia of Genes and Genomes pathway analysis of differentially expressed miRNAs, and miRNA overexpression in HepG2 cells revealed the critical role of insulin signaling, via miR-327, miR-466f-3p and miR-223-3p, in the effects of early life Cr restriction on glucose metabolism. In conclusion, maternal Cr restriction may irreversibly increase IR, which may involve a specific miRNA affecting the insulin signaling pathway. PMID- 29286160 TI - Identification and characterization of epitopes from influenza A virus hemagglutinin that induce broadly cross-reactive antibodies. AB - Influenza is the most common infectious disease and is caused by influenza A virus (IAV) infection. Hemagglutinin (HA) is an important viral protein of influenza A and is a major component of current IAV vaccines. The side effects associated with IAV vaccination are well studied; however, the HA-induced immunopathological changes have remained largely elusive. The primary objective of the present study was to determine the tissue cross-reactive epitopes of HA proteins. Monoclonal antibodies (McAbs) were generated according to traditional methods using purified HA proteins from influenza vaccine lysates. The specificity of these McAbs was analyzed using western blot analysis and ELISA. Human tissue microarrays were employed for immunohistochemical staining to screen these McAbs. Rat brain tissues were subjected to immunohistochemical staining and electron microscopy to demonstrate the subcellular localization of antibodies targeting specific antigens. A total of 67 hybridoma cell lines positive for McAb against HA antigen were obtained. Three cross-reactive McAbs (H1-13, H1-15 and A1 10) were discovered through tissue screening. Based on the 3 cross-reactive McAbs and the amino acid sequence of HA, the presence of two broadly cross-reactive HA epitopes, 194-WGIHH-198 and 365-WYGYHH-370, was assumed. McAbs against these synthetic epitope peptides were obtained. They reacted with porphyrin ring containing molecules, including hemoglobin (Hb) and protoporphyrin, and with numerous types of normal tissue. In conclusion, the present study identified two broadly cross-reactive epitopes on HA (194-WGIHH-198 and 365-WYGYHH-370). Antibodies against these epitopes react with Hb and numerous types of important normal tissues/organs. These newly identified cross-reactive epitopes from IAV HA may provide crucial information for influenza research. PMID- 29286161 TI - Astilbin emulsion improves guinea pig lesions in a psoriasis-like model by suppressing IL-6 and IL-22 via p38 MAPK. AB - Astilbin has anti-inflammatory and immunoregulatory effects, and is frequently used in prescriptions treating psoriasis; however, the mechanism remains to be fully elucidated. In the present study, the effect of an astilbin microemulsion on a psoriasis-like model in guinea pigs was examined, and the underlying mechanism was investigated. The levels of interkeukin (IL)-6, IL-17A and IL-22 were determined using fluorescent reverse transcription-quantitative polymerase chain reaction analysis and enzyme-linked immunosorbent assays. The phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 was detected using western blot analysis. Compared with the untreated control, astilbin significantly ameliorated the lesions induced by propranolol hydrochloride. The effect of astilbin on cytokine levels were cytokine- and drug concentration-dependent. At a concentration of 2.22 uM, astilbin decreased the mRNA expression levels of IL-6, IL-17A and IL-22 in lipopolysaccharide (LPS) induced HaCaT cells by 89, 69.1 and 69.3%, respectively. However, 2.22 uM astilbin had no effect on the protein expression of IL-17A, and decreased the protein expression levels of IL-6 and IL-22 by 79.2 and 49.5%, respectively (P<0.05). At a concentration of 11.10 uM, astilbin decreased the mRNA expression of IL-6, which was significantly induced by LPS, and significantly (P<0.05) decreased the protein expression levels of IL-6 and IL-22. Additionally, astilbin inhibited the LPS-induced activation of phosphorylated p38. These results suggested that astilbin has the potential to be developed into a topical drug for the treatment of psoriasis via the inhibition of inflammatory cytokines. PMID- 29286162 TI - GC7 enhances cisplatin sensitivity via STAT3 signaling pathway inhibition and eIF5A2 inactivation in mesenchymal phenotype oral cancer cells. AB - Eukaryotic initiation factor 5A2 (eIF5A2), a newly identified oncogene, promotes cell survival, proliferation and motility in tumorigenesis. Drug resistance and dose-related adverse side-effects greatly reduce the efficiency and safety of cisplatin-based chemotherapy in advanced or recurrent oral squamous cell carcinoma (OSCC) patients. The present study investigated the effect of eIF5A2 combined with N1-guanyl-1,7-diaminoheptane (GC7, a novel eIF5A2 inhibitor) or siRNA. We found that low concentrations of GC7 (<=5 uM) had little effect on OSCC cell viability, but significantly enhanced cisplatin cytotoxicity. Compared with cisplatin, GC7/cisplatin had little effect on cisplatin-promoted mesenchymal epithelial transition in mesenchymal phenotype Tca8113 and HN30 cells, or on cisplatin-induced epithelial-mesenchymal transition (EMT) in epithelial phenotype Cal27 and HN4 cells. Further research revealed that the upregulation of p-STAT3 and c-Myc which was induced by the single treatment with either cisplatin or GC7 was significantly reversed by the GC7/cisplatin combination in mesenchymal phenotype Tca8113 and HN30 cells. In in vivo treatment, we revealed that the GC7/cisplatin combination presented significant tumor volume reduction without distinct body weight loss. In conclusion, our data indicated that eIF5A2 is a potent therapeutic target in OSCC treatment. Our results revealed a novel mechanism by which GC7/cisplatin combination therapy may offer an efficient and safe therapeutic alternative to advanced or recurrent OSCC patients. PMID- 29286163 TI - Using IFN-gamma antibodies to identify the pathogens of fungal rhinosinusitis: A novel immunohistochemical approach. AB - Fungal rhinosinusitis (FRS) is commonly caused by various Aspergillus species (spp) and Mucorales fungi, and the treatment and prognosis of cases differ depending on the causative fungus. The present study describes a novel immunohistochemical method that has high sensitivity and specificity for distinguishing between these two types of fungi in patients with FRS. Three groups were included in the study. Group A included formalin-fixed paraffin embedded blocks of 51 nasal tissue specimens of patients with FRS (27 Aspergillus spp and 24 Mucorales) that were continuously obtained from the Department of Pathology of Tongren Hospital in Beijing as the experimental group and 34 cultures (26 Aspergillus spp and 8 Mucorales) of FRS that were randomly selected from the bacterial laboratory of Tongren Hospital in Beijing to verify the staining results of the paraffin-embedded blocks. Formalin-fixed paraffin embedded blocks of 10 esophageal cancer specimens were included in Group B as the positive control group. All specimens in Groups A and B were stained with interferon-gamma (IFN-gamma) antibody. Group C consisted of the same specimens as described in Group A, however, when performing the immunohistochemical assay, IFN gamma antibody was replaced by PBS and this served as the negative control group. The differences in IFN-gamma immunohistochemical staining between Aspergillus spp and Mucorales were analyzed. Staining of IFN-gamma in paraffin-embedded samples was positive in 92.6% (25/27) of specimens in which Aspergillus spp were the causative pathogen, which was significantly higher compared with specimens in which Mucorales was causative (P<0.001), with only 4.2% (1/24) of specimens staining positive for IFN-gamma. Immunohistochemical staining of cell cultures was 100% positive for Aspergillus spp, whereas all Mucorales were negative. Thus, the results of the current study indicated that IFN-gamma antibody immunohistochemical staining may be used as a novel diagnostic tool to distinguish between Aspergillus spp and Mucorales when identifying the causative agent in FRS, providing a useful supplementary test to the current immunohistochemical methods in the clinical diagnosis of FRS. PMID- 29286164 TI - Differential effects of Wnt5a on the proliferation, differentiation and inflammatory response of keratinocytes. AB - The predominant role of Wnt family member 5A (Wnt5a) is to induce non-canonical Wnt signalling pathways, including the Wnt-Ca2+ and Wnt-planar cell polarity pathways. Enhanced Wnt5a expression is involved in the formation of psoriatic plaques; however, its mechanistic role remains to be determined. In the present study, the effects of Wnt5a expression on HaCaT keratinocytes were investigated. HaCaT cells were cultured in medium supplemented with 0, 40 or 80 ng/ml Wnt5a for 24 h. Cell proliferation, the cell cycle, gene expression and inflammatory responses were investigated using Cell-Counting Kit-8 assays, flow cytometry analyses, reverse transcription-quantitative polymerase chain reaction analyses and enzyme-linked immunosorbent assays, respectively. Wnt5a treatment was revealed to suppress cell proliferation in HaCaT cells. Furthermore, Wnt5a was also demonstrated to increase the proportion of HaCaT cells arrested at the G2/M phase of the cell cycle, but reduce the proportion of HaCaT cells arrested at G0/G1 phase cells. In addition, the expression levels of the differentiation markers, including filaggrin, keratin 1 and keratin 10 were revealed to be downregulated in HaCaT cells. Expression of the canonical Wnt signalling genes (beta-catenin and cyclin D1) and proliferation markers, such as Ki-67 and proliferating cell nuclear antigen in HaCaT cells were also revealed to be downregulated. However, the expression levels of inflammatory response markers (interferon-gamma, interleukin-8 and interleukin-17A) were revealed to be upregulated in HaCaT cells following Wnt5a treatment. These findings suggest that Wnt5a expression may be involved in the inhibition of cell differentiation and the induction of an inflammatory response in patients with psoriasis. PMID- 29286165 TI - Effects of cell-cell crosstalk on gene expression patterns in a cell model of renal cell carcinoma lung metastasis. AB - The median survival rate of patients with metastatic renal carcinoma is approximately 10 to 12 months, with up to 50% of patients developing metastases in the lung parenchyma. The molecular basis for metastatic development remains unclear. In the present study, we used renal cell carcinoma (RCC) cells and bronchial epithelial cells, representing metastasis target organ cells, conditioned medium and co-culture models to identify specific gene expression changes responsible for cancer cell viability in a metastatic microenvironment. RCC cell proliferation and migration increased when the culture was supplemented with conditioned medium from lung fibroblasts or pleural epithelial cells. Healthy epithelial cells were, in turn, also stimulated with conditioned medium from RCC cell lines. The mitogen-activated protein kinase (MAPK), interleukin (IL)-6, and phosphatidylinositol 4,5-bisphosphate (PIP2) signaling pathways were identified as deregulated upon cell-cell interaction. Thus, cell-cell communication may contribute to the development of the metastatic niche. The identified deregulated signaling pathways may be considered as potential therapeutic targets in metastatic renal carcinoma. PMID- 29286166 TI - Leucine and glycine dipeptides of porcine placenta ameliorate physical fatigue through enhancing dopaminergic systems. AB - Fatigue is a common and serious health problem, and various dietary interventions have previously been employed to ameliorate fatigue. The aim of the current study was to investigate the anti-fatigue effects of Danish porcine placenta (DPP) and its major dipeptides, including leucine-glycine (LG) and glycine-leucine (GL). The anti-fatigue effects of orally administered DPP, LG and GL were determined using a treadmill exercise test and a forced swimming test (FST) in mice. Additionally, the anti-inflammatory effects of DPP, LG and GL were investigated in activated splenocytes. The results demonstrated that oral treatment of mice with DPP, LG and GL increased the time to exhaustion during treadmill exercise. Furthermore, DPP, LG and GL enhanced the levels of dopamine, brain-derived neurotrophic factor and phosphorylated-extracellular signal-regulated kinase in the brains of mice with treadmill exercise-induced exhaustive fatigue, and decreased levels of certain proinflammatory cytokines in the serum and spleen, as determined by ELISA and western blot analysis. Following treadmill exercise, commercial kits were employed to demonstrate that DPP, LG and GL reduced the levels of lactate dehydrogenase, lactate, creatine kinase, blood urea nitrogen, alanine transaminase and aspartate transaminase in the muscle and/or serum of mice. In addition, DPP, LG and GL enhanced the muscle and liver glycogen levels, catalase activity in the liver and serum superoxide dismutase activity. DPP, LG and GL also increased the proliferation of splenocytes and inhibited proinflammatory cytokine production by reducing the activation of caspase-1 and nuclear factor-kappaB in activated splenocytes, as determined by MTT assays, ELISA and western blotting, respectively. Furthermore, DPP, LG and GL reduced immobility time in the FST in mice. In conclusion, DPP may limit intensive exercise-induced fatigue by increasing dopaminergic systems and inhibiting inflammatory responses. PMID- 29286167 TI - Serum microRNA panel excavated by machine learning as a potential biomarker for the detection of gastric cancer. AB - Early detection of gastric cancer (GC) is crucial to improve the therapeutic effect and prolong the survival of patients. MicroRNAs (miRNAs) are a group of small non-protein-coding RNAs that function as repressors of diverse genes. We aimed to identify a microRNA panel in the serum of patients to predict GC non invasively with high accuracy and sensitivity. Using six types of classifiers, we selected three markers (miR-21-5p, miR-22-3p and miR-29c-3p) from a published miRNA profiling study (GSE23739) which was treated as a training set. The values of the area under the receiver operating characteristic (ROC) curves (AUCs) were 0.9437, 0.9456 and 0.9563 in the three classifiers [Compound covariate classifier, Diagonal linear discriminant analysis (DLDA) classifier and Support vector machine classifier], respectively. Then the panel was validated further in another two miRNA profiles in GEO (Gene Expression Omnibus) databases (GSE26595, GSE28700) with high AUC values as well. Next, we found that the serum levels of miR-21 were significantly higher in GC patients than levels in healthy controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for confirmation, which was opposite to the serum levels of miR-22 and miR-29c (all P<0.0001). Finally, using bioinformatic tools, their biological mechanisms were elucidated by their predicted targets: Sp1 (miR-21) and PTEN (miR-22 and miR 29c). This miRNA panel is a non-invasive and potential biomarker for GC. PMID- 29286168 TI - Age-dependent alteration in the expression of oligodendrocyte-specific protein in the gerbil hippocampus. AB - Oligodendrocytes are myelin-forming cells in the central nervous system. Research into the effects of aging on oligodendrocyte protein expression remains limited. The present study aimed to determine the alterations in oligodendrocyte-specific protein (OSP) expression in the gerbil hippocampus at 1, 2, 3, 4, 6 and 24 months of age with western blot and immunohistochemistry analyses. OSP expression levels in the hippocampus were highest at 6 months of age. OSP immunoreactivity was identified in numerous cell bodies at 1 month, although the number of OSP immunoreactive cells was different according to hippocampal subregion. The number of OSP immunoreactive cells significantly decreased at 2 months and, thereafter, numbers decreased gradually. The detection of OSP immunoreactive fibers was negligible in all layers in the hippocampal subregions until 4 months. OSP immunoreactive fibers were abundant at 6 and 24 months, although the fiber distribution patterns in the CA1-3 areas and dentate gyrus were different. The results demonstrated that OSP expression in the gerbil hippocampus was age dependent. The detection of OSP immunoreactive cell bodies and fibers was significantly different according to the layers of hippocampal subregions, indicating that myelination may be continuously altered in the hippocampus during normal aging. PMID- 29286169 TI - Function of miR-152 as tumor suppressor in oral squamous cell carcinoma cells by targeting c-MET. AB - MicroRNA-152 (miR-152) has been reported to be involved in tumor development and progression in multiple cancers. However, the expression level, biological function and regulatory mechanisms of miR-152 in oral squamous cell carcinoma cells (OSCC) remain unclear. The aims of this study were therefore to investigate the role of miR-152 in OSCC and the relevant mechanism. It was found that miR-152 was downregulated in OSCC cell lines and tissues, and that decreased miR-152 was closely associated with lymph node metastasis, and patient survival rate. In vitro restoration of miR-152 significantly repressed cell proliferation, colony formation, migration and invasion of OSCC cells. Notably, cellular-mesenchymal to epithelial transition factor (c-MET) and its downstream signaling pathway (PI3K/AKT) was downregulated in OSCC cells by miR-152 through direct interactions with its 3' untranslated region. Restoring c-MET expression attenuated miR-152 induced inhibitory effects in OSCC cells. In vivo study confirmed that restoration of miR-152 suppressed tumor growth in xenograft nude mice by repressing c-MET. In summary, the present study highlight miR-152 as a tumor suppressor in OSCC through direct targeting c-MET, rendering miR-152 a promising therapeutic target for oral squamous cell carcinoma. PMID- 29286170 TI - Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway. AB - Licochalcone A (LicA) is a chalcone extracted from liquorice which has been used as a traditional Chinese medicine for many generations. Increased glucose consumption and glycolytic activity are important hallmarks of cancer cells, and hexokinase 2 (HK2) upregulation is a major contributor to the elevation of glycolysis. Recently, the antitumor activities of LicA have been reported in various cancers; however, its effect on tumor glycolysis in gastric cancer and the underlying mechanisms are completely unknown. In vitro, cell proliferation and clonogenic survival were substantially inhibited after LicA treatment. LicA reduced HK2 expression, and both glucose consumption and lactate production in gastric cancer cells were significantly suppressed. Mechanistic investigations revealed that multiple signaling pathways including Akt, ERK and NF-kappaB were suppressed by LicA. Further studies demonstrated that the inhibition of glycolysis by LicA was mainly attributed to the blockade of the Akt signaling pathway, and the suppression of glycolysis was substantially attenuated when Akt was exogenously overexpressed. In addition to the role in the inhibition of glycolysis, reduction in HK2 was confirmed to be involved in the induction of cell apoptosis. The apoptosis induced by LicA was substantially impaired after HK2 overexpression in gastric cancer cells. The in vivo experiment showed that MKN45 xenograft growth was markedly delayed after LicA treatment and HK2 expression in LicA-treated tissues was markedly decreased. All of these data demonstrated that blockade of the Akt/HK2 pathway was the underlying mechanism required for LicA to exert its biological activities in glycolysis inhibition and apoptosis induction. PMID- 29286172 TI - MicroRNA-454 inhibits the malignant biological behaviours of gastric cancer cells by directly targeting mitogen-activated protein kinase 1. AB - Gastric cancer (GC) is the fifth most commonly diagnosed malignant disease and the third leading cause of cancer-related deaths worldwide. Recently, numerous microRNAs (miRNAs) have been determined to contribute to GC initiation and progression, suggesting that miRNAs may be developed as effective diagnostic and prognostic molecular biomarkers and can be investigated as therapeutic targets for patients with this disease. Therefore, further investigation of the miRNAs involved in GC development represents an opportunity to improve the prognosis of GC patients. miRNA-454 (miR-454) is abnormally expressed in multiple types of human cancer. However, the expression pattern, biological roles and underlying mechanism of miR-454 in GC remain unclear and require further investigation. In the present study, we assessed miR-454 expression in GC tissues and cell lines. We also explored the effects of miR-454 on the biological behaviours of tumour cells and the underlying molecular mechanisms of miR-454. The results revealed that miR-454 was significantly downregulated in GC tissues and cell lines. Low miR-454 expression was positively associated with lymph node metastasis, invasive depth and TNM stage. Additionally, upregulation of miR-454 inhibited cell proliferation and invasion and induced the apoptosis of the GC cells. Subsequently, mitogen-activated protein kinase 1 (MAPK1) was identified as a direct target of miR-454. MAPK1 was upregulated in GC tissues and was found to be negatively correlated with the miR-454 expression level. Downregulation of MAPK1 also suppressed GC cell proliferation and invasion and increased apoptosis, thereby resembling the suppressive effects of miR-454 overexpression in GC. Moreover, upregulation of MAPK1 reversed the tumour-suppressive effects of miR 454 in GC. Collectively, our data demonstrated that miR-454 may play tumour suppressing roles in GC through the regulation of MAPK1, suggesting that miR-454 may be a novel biomarker and therapeutic target for patients with this disease. PMID- 29286171 TI - Au-poly(lactic-co-glycolic) acid complex nanoparticles as ultrasound contrast agents: Preparation, characterization and in vitro study. AB - The present study aimed to prepare and characterize an Au-poly(lactic-co glycolic) acid (PLGA) complex, surfaced with gold nanoparticles (GNPs), and to assess its use as an ultrasound contrast agent for in vitro imaging. PLGA nanoparticles (NPs) were prepared by a modified double-emulsion solvent evaporation method. GNPs were prepared via reduction with sodium citrate. Au-PLGA complexes were created through the binding of polyethylene glycosylated GNPs to the surface of PLGA NPs. Various physical characteristics of PLGA NPs, GNPs and Au-PLGA complexes, including morphology, size, dispersion, zeta potential and stability were observed and measured. The study of the in vitro imaging capability of the Au-PLGA complex was conducted by setting multi-parameter imaging conditions. The average sizes of PLGA NPs, GNPs and the Au-PLGA complex were 144.5+/-30.28, 21.42+/-1.56 and 359.4+/-67.94 nm, respectively. Transmission electron microscopy (TEM) revealed that PLGA NPs and GNPs were spherically shaped, but GNPs had smooth surface while PLGA NPs had a capsular morphology with a wrinkled surface and large voids. The maximum absorption peak of 20 nm GNPs was 508 nm while that of the Au-PLGA complex was 515 nm on an ultraviolet-visible absorption spectrum curve. The results of TEM and the redshift spectrum demonstrated that GNPs successfully bound to the surface of the PLGA NPs. The complex demonstrated good stability and its size changed little over time. In vitro imaging experiments revealed that the Au-PLGA complex had a good imaging ability. The present study demonstrated that the Au-PLGA complex is a promising novel ultrasound contrast agent. PMID- 29286173 TI - IPF and CPFE - the two different entities or two different presentations of the same disease? AB - In this article the co-existence of pulmonary emphysema with lung fibrosis of typical pattern and distribution for usual interstitial pneumonia (UIP) was compared with idiopathic pulmonary fibrosis (IPF) alone. Author discusses the etiopathogenesis of these diseases, differences in signaling pathways and the role of senescent cells. Moreover, clinical course, pulmonary function tests as well as main complications are reviewed. However, the lack of well-established diagnostic criteria for CPFE along with mainly retrospective character of the studies make current knowledge about this entity rather deficient. PMID- 29286174 TI - Domino Ring Expansion: Regioselective Access to 9-Membered Lactones with a Fused Indole Unit from 2-Nitrophenyl-1,3-cyclohexanediones. AB - The domino anionic fragmentation of 2-nitrophenyl-1,3-cyclohexanediones containing an electrophilic appendage such as aldehyde and epoxide is disclosed. This reaction, initiated by a series of nucleophiles, involves the generation of an intermediate hydroxylate followed by the regioselective formation and fragmentation of an intermediate lactolate into enolate. This strategy, devoid of any protecting group, enlarges the initial ring and provides an original access to decorated 9-membered lactones with a fused indole unit. PMID- 29286175 TI - Hyperbaric oxygen therapy: An alternative treatment for radiation-induced cutaneous ulcers. AB - Radiotherapy is a widely recognised treatment for non-melanoma skin cancer. We report three cases of radiation-induced skin ulcers in which hyperbaric oxygen therapy was administered in 90-min sessions, 5 days a week at 2.4 absolute atmospheres in a multiplace hyperbaric chamber. Hyperbaric oxygen therapy is an outpatient treatment that does not displace other classical treatments and may be used as an adjunct therapy. PMID- 29286176 TI - "Be kind to the mother": A celebration of the life of Marshall Klaus, 1927-2017. PMID- 29286177 TI - Kinetics of solutes and particles of different size in the digestive tract of cattle of 0.5-10 years of age, and relationships with methane production. AB - The digestive physiology of cattle is characterised by comparatively long digesta mean retention times (MRTs), a particle sorting mechanism (difference in MRTs of large vs. small particles) and a distinct digesta washing (difference in MRTs between particles and fluids) in the reticulorumen (RR). How these processes mature during ontogeny, and how they link to other digestion characteristics and methane production, is largely unknown. We used a set of passage markers (Co-EDTA for fluids and hay particles of 2, 5 and 8 mm length mordanted with Cr, La and Ce, respectively) to measure MRTs in 12 heifers (0.5-2.1 years; hay only) and two groups of 15 lactating cows (2.4-10.0 years; forage-only vs. forage-concentrate diet). The MRTs differed between markers (Co < Cr < La < Ce) and were longer in heifers than cows, consistent with the lower feed intake in heifers. MRTs were mostly similar between cow groups and increased with age. Digesta washing was not affected by group, age, feed intake and number of chews per unit of feed. The degree of digesta washing was not related to CH4 measures. Particle sorting was more prominent in cows than heifers but did not differ between cow groups or change with age in cows. This could be the consequence of the abrupt increase in intake from heifers to cows at a time when gut capacity is not yet fully developed; particle sorting might then clear smaller particles from the RR sooner allowing a higher intake. Surprisingly, CH4 yield per ingested feed did not correlate with MRTs, and CH4 yield per unit of digested fibre decreased with increasing MRTs and with increasing fibre digestibility. As this pattern occurred in heifers and both cow groups, it appeared independent of age, indicating a mechanism that has not been described in the literature so far and requires further investigation. PMID- 29286179 TI - Localized cyclical variations in immunoproteins in the female genital tract and the implications on the design and assessment of mucosal infection and therapies. AB - PROBLEM: Fluctuating hormones regulate reproductive processes in the female genital tract. Consequent changes in the local immunological environment are likely to affect cellular interaction with infectious agents and the assessment of therapies that target mucosal infections. METHOD OF STUDY: We compared Softcup and Weck-Cel sampling protocols and assessed the changes in the concentrations of 39 soluble proteins with menstrual cycle progression in the mucosal and peripheral compartments. RESULTS: We demonstrate that the mucosal immunological profile is distinct from serum with inflammatory and migratory signatures that are localized throughout the cycle. The analytes highlighted in the mucosal compartment were generally highest at the follicular phase with a tendency to fall as the cycle progressed through ovulation to the luteal phase. CONCLUSION: Our results underscore the need to consider these localized cyclical differences in studies aimed at assessing the outcome of disease and the efficacy of mucosal vaccines and other therapies. PMID- 29286180 TI - Computer-aided system for diagnosing thyroid nodules on ultrasound: A comparison with radiologist-based clinical assessments. AB - BACKGROUND: The purpose of this study was to compare the diagnostic efficiency of a thyroid ultrasound computer-aided diagnosis (CAD) system with that of 1 radiologist. METHODS: This study retrospectively reviewed 342 surgically resected thyroid nodules from July 2013 to December 2013 at our center. The nodules were assessed on typical ultrasound images using the CAD system and reviewed by 1 experienced radiologist. The radiologist stratified the risk of malignancy using the Thyroid Imaging Reporting and Data Systems (TIRADS) and the American Thyroid Association (ATA) guidelines. RESULTS: The radiologist, using TI-RADS and ATA guidelines, performed better than the CAD system (P < .01). The sensitivity of the CAD system was similar to that of an experienced radiologist (P > .05; P < .01; and P > .05). However, we found that the CAD system had lower specificity (P < .01). CONCLUSION: The sensitivity of a thyroid ultrasound CAD system in differentiating nodules was similar to that of an experienced radiologist. However, the CAD system had lower specificity. PMID- 29286178 TI - Toll-like receptor variants and cervical Atopobium vaginae infection in women with pelvic inflammatory disease. AB - PROBLEM: Toll-like (TLR) receptor genetic variants have been implicated in bacterial vaginosis (BV). We determined whether TLR variants are associated with fastidious BV-associated microbes that are linked with infertility following pelvic inflammatory disease (PID). METHOD OF STUDY: Sneathia spp., Atopobium vaginae, BVAB1, and Ureaplasma urealyticum were measured in 250 women from the PID Evaluation and Clinical Health (PEACH) study. Relative risk (RR) and 95% confidence intervals (CI) were calculated adjusting for chlamydia and gonorrhea. Principal component analysis was used to adjust for population stratification. A false discovery rate q-value of 0.05 was significant. RESULTS: TLR2-1733C>A (P = .003) and TLR2-616A>G (P = .004) were associated with cervical A. vaginae. TLR2 1733C>A and TLR6-438C>T were associated with A. vaginae detection in the endometrium, but this was not significant after adjustment for multiple comparisons (FDR q-value = 0.06). CONCLUSION: Host gene variants in TLR2 signaling pathways were modestly associated with cervical A. vaginae in women with clinical PID. PMID- 29286181 TI - Accuracy of Different Implant Impression Techniques: Evaluation of New Tray Design Concept. AB - PURPOSE: To evaluate implant impression accuracy with a new tray design concept in comparison to nonsplinted and splinted impression techniques for a 2-implant situation. MATERIALS AND METHODS: A reference bar titanium framework was fabricated to fit on 2 parallel implants. The framework was used to generate a resin master model with 2 implants that fit precisely against the framework. Three impression techniques were evaluated: (1) nonsplinted, (2) splinted, and (3) nonsplinted with modified tray impressions. All the trays were fabricated from light-cured acrylic resin material with openings that corresponded to the implant impression copings. Ten impressions were taken for each technique using poly(vinyl siloxane) impression material. The impressions were poured with type IV dental stone to generate the test casts. A rosette strain gauge was bonded to the middle of the framework. As the framework retaining screws were tightened on each test cast, the developed strains were recorded until the completion of the tightening to 35 Ncm. The generated strains of the rosette strain gauge were used to calculate the maximum principal strain. RESULTS: A statistically significant difference was observed among the different impression techniques. The modified tray design impression technique was associated with the least framework strains, which indicates greater accuracy compared with the other techniques. There was no significant difference between the splinted and the nonsplinted impression techniques. CONCLUSIONS: The new tray design concept appeared to produce more accurate implant impressions than the other techniques. Despite the statistical difference among the impression techniques, the clinical significance of this difference is yet to be determined. PMID- 29286182 TI - Knockdown of pseudogene derived from lncRNA DUXAP10 inhibits cell proliferation, migration, invasion, and promotes apoptosis in pancreatic cancer. AB - Current evidence suggests that pseudogene derived lncRNAs may be important players in human cancer progression. Our previous study showed that DUXAP10 could promote cell proliferation in colorectal cancer. However, the clinical significance and potential role of DUXAP10 in human pancreatic cancer (PC) has not been uncovered. In this study, we found that DUXAP10 was overexpressed in PC tissues compared with normal tissues. DUXAP10 expression was significantly higher in patients with an advanced TNM stage and positive lymph node metastasis. Bioinformatic analysis showed that cell cycle progression was increased in patients with high DUXAP10 expression. In vitro and in vivo assays of DUXAP10 alterations revealed a complex integrated phenotype affecting cell growth, apoptosis, migration, and invasion. Mechanistic studies revealed that DUXAP10 has a crucial role in G2/M arrest. We further showed that DUXAP10 regulated PC cell proliferation through interact with RNA-binding protein EZH2 and LSD1. Overall, our findings indicates that DUXAP10 is an oncogenic lncRNA that promotes PC proliferation and metastasis. PMID- 29286183 TI - Leiomyosarcoma of the head and neck: A 17-year single institution experience and review of the National Cancer Data Base. AB - BACKGROUND: Leiomyosarcoma is a rare neoplasm of the head and neck. The purpose of this study was to present our single-institution case series of head and neck leiomyosarcoma and a review of cases in the National Cancer Data Base (NCDB). METHODS: Patients with head and neck leiomyosarcoma at the University of Pennsylvania and in the NCDB were identified. Demographic characteristics, tumor factors, treatment paradigms, and outcomes were evaluated for prognostic significance. RESULTS: Nine patients with head and neck leiomyosarcoma from the institution were identified; a majority had high-grade disease and cutaneous leiomyosarcoma, with a 5-year survival rate of 50%. Two hundred fifty-nine patients with leiomyosarcoma were found in the NCDB; macroscopic positive margins and high-grade disease were associated with poor prognosis (P < .01), and positive surgical margins were related to adjuvant radiation (P < .001). CONCLUSION: Head and neck leiomyosarcoma presents at a high grade and is preferentially treated with surgery. Several demographic and tumor-specific factors are associated with outcomes and prognosis. PMID- 29286184 TI - In vitro biofilm growth on modern voice prostheses. AB - BACKGROUND: Biofilm formation on voice prostheses in laryngectomized patients usually limits the lifetime of the device. The purpose of this study was to compare the biofilm resistance of different valve flaps of modern voice prostheses in an in vitro simulation of an oropharyngeal biofilm. METHODS: Growth of biofilm deposits on valve flaps (n = 12) removed from Provox 2, Provox Vega, Provox ActiValve, Blom Singer Advantage, and Phonax voice prostheses was evaluated and compared to medical-grade silicone (n = 12) in an in vitro biofilm model (22 days) after incubation with a multispecies bacterial-fungal biofilm composition. RESULTS: The Provox ActiValve and the Blom Singer Advantage prostheses showed significantly less surface biofilm formation than the other prostheses and then silicone. CONCLUSION: The use of silver oxide and Teflon as valve flap materials proves to reduce long-term biofilm formation in vitro. The applied model allows rapid screening for novel biofilm-inhibitive materials and durable coatings designated for more biofilm resistant medical devices. PMID- 29286185 TI - The relationships between fluoride intake levels and fluorosis of late-erupting permanent teeth. AB - OBJECTIVES: To examine the relationships between fluoride intake levels and fluorosis of late-erupting permanent teeth. METHODS: The current study used information collected from 437 children in the longitudinal Iowa Fluoride Study. Participants' fluoride intake information was collected using questionnaires from birth to age 10 years. Estimated mean daily fluoride intake was categorized into low, moderate, and high intake tertiles for each age interval (2-5, 5-8, and 2-8 years). Bivariate analyses were performed to study the relationships between self reported fluoride intake levels during three age intervals and dental fluorosis. RESULTS: For canines and second molars, the prevalence of mostly mild fluorosis was less than 10% in the lowest fluoride intake tertile and more than 25% in the highest intake tertile. For both first and second premolars, the prevalence in the low and high intake tertiles was approximately 10-15% and 25-40%, respectively. When estimated total daily fluoride intake was 0.04 mg/kg BW during ages 2-8 years, the predicted probability of fluorosis was 16.0%, 20.5%, 21.8%, and 15.4% for canines, 1st and 2nd and premolars and 2nd molars, respectively. We found that an incremental increase in fluoride intake during the age 5- to 8-year interval led to greater odds for development of mostly mild dental fluorosis in late-erupting teeth compared to increases in fluoride intake during other age intervals. CONCLUSIONS: Our results clearly show that dental fluorosis prevalence is closely related to fluoride intake levels and that teeth have greater susceptibility to fluoride intake during certain age intervals. PMID- 29286186 TI - Improved pulp bleaching potential of Bacillus subtilis WB800 through overexpression of three lignolytic enzymes from various bacteria. AB - A chemical bleaching process of paper pulps gives off excessive amount of chlorinated organic wastes mostly released to environment without exposing complete bioremediaton. Recent alternative and eco-friendly approaches toward pulp bleaching appear more responsive to environmental awareness. Here we report, direct use of a recombinant Bacillus subtilis bacterium for pulp bleaching, endowed with three ligninolytic enzymes from various bacteria. In addition, efficient bleaching performance from glutathione-S-transferase (GST) biocatalyst tested for the first time in pulp bleaching applications was also achieved. Simultaneous and extracellular overproduction of highly active GST, laccase, and lignin peroxidase catalysts were also performed by Bacillus cells. Both enhanced bleaching success and improved delignification rates were identified when enzyme combinations tested on both pine kraft and waste paper pulps, ranging from 69.75% to 79.18% and 60.89% to 74.65%, respectively. Furthermore, when triple enzyme combination applied onto the papers from pine kraft and waste pulps, the best ISO brightness values were identified as 66.45% and 64.67%, respectively. The delignification rates of pulp fibers exposed to various enzymatic bleaching sequences were comparatively examined under SEM. In conclusion, the current study points out that in near future, a more fined-tuned engineering of pulp-colonizing bacteria may become a cost-effective and environmentally friendly alternative to chemical bleaching. PMID- 29286187 TI - Mitochondrial ATAD3A regulates milk biosynthesis and proliferation of mammary epithelial cells from dairy cow via the mTOR pathway. AB - ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein, which is essential for cell growth and metabolism. The mechanism by which ATAD3A acts is still not fully understood. In this study, we explored the regulatory role of ATAD3A on milk biosynthesis and proliferation of bovine mammary epithelial cell. We showed that ATAD3A is localized in mitochondria and the expression of ATAD3A was up-regulated in response to extracellular stimuli such as amino acids and hormones. We observed that ATAD3A positively regulated milk protein, fat, and lactose biosynthesis, and cell proliferation. We further revealed that ATAD3A promoted the expressions of mTOR, SREBP-1c, and Cyclin D1, and triggers mTOR phosphorylation. In summary, our data reveal that ATAD3A regulates the mTOR, SREBP-1c, and Cyclin D1 signaling pathways for milk biosynthesis and cell proliferation. PMID- 29286189 TI - Adverse Maternal and Birth Outcomes in Women Hospitalised due to Hyperemesis gravidarum. PMID- 29286188 TI - The mitochondrial calcium uniporter complex in trypanosomes. AB - The presence of a conserved mechanism for mitochondrial calcium uptake in trypanosomatids was crucial for the molecular identification of the mitochondrial calcium uniporter (MCU), a long-sought channel present in most eukaryotic organisms. Since then, research efforts to elucidate the role of MCU and its regulatory elements in different biological models have multiplied. MCU is the pore-forming subunit of a multimeric complex (the MCU complex or MCUC) and its predicted structure in trypanosomes is simpler than in mammalian cells, lacking two of its subunits and probably possessing other unidentified components. MCU protein has been characterized in Trypanosoma brucei and Trypanosoma cruzi, the causative agents of African and American trypanosomiasis, respectively. Contrary to its mammalian homolog, TbMCU was found to be essential for cell growth and survival, while its paralog MCUb is an essential protein in T. cruzi. These findings could be further exploited for chemotherapeutic purposes. The emergence of new molecular tools for the genetic manipulation of trypanosomatids has been determinant for the functional characterization of the MCUC components in these organisms. However, further research has to be done to determine the role of each component in intracellular calcium signaling and cell bioenergetics. In this mini review we summarize the original results on mitochondrial calcium uptake in trypanosomes, how did they contribute to the molecular identification of the MCU, and the functional characterization of the MCUC subunits that has so far been studied in these peculiar eukaryotes. PMID- 29286190 TI - Impact of alcohol dehydrogenase-aldehyde dehydrogenase polymorphism on clinical outcome in patients with hypopharyngeal cancer. AB - BACKGROUND: The purpose of this research was to investigate the association between alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms and hypopharyngeal squamous cell carcinoma (SCC) survival. METHODS: We genotyped ADH1B (rs1229984) and ALDH2 (rs671) single nucleotide polymorphisms (SNPs) in 85 Japanese male patients with hypopharyngeal SCC. The independent prognostic values of ADH1B-ALDH2 genotypes were analyzed by univariate and multivariate proportional hazard Cox regression, taking well-known clinical risk factors into account. RESULTS: Heavy drinkers with ALDH2*2 allele resulted in significantly worse overall survival (OS; P = .028) and disease-free survival (DFS; P = .029) compared with other patients. Heavy drinkers with ALDH2*2 allele remained statistically significant in multivariate analysis for OS and DFS, indicating independent poor prognostic factor (hazard ratio [HR] 2.251; 95% confidence interval [CI] 1.018-4.975 and HR 2.261; 95% CI 1.021-5.006, respectively). CONCLUSION: We conclude that heavy drinkers with the ALDH2*2 allele are associated with poor outcome in hypopharyngeal SCC. PMID- 29286191 TI - Development of a nomogram to predict the clinical impact of a postexcision preirradiation mammogram. AB - We aimed to better quantify the impact of a postexcision preirradiation mammogram (PPM), first by identifying factors associated with abnormal results and then incorporating these findings into a nomogram. Beginning February 2011, our institution made a practice change to obtain a PPM on all patients with any calcifications identified. A total of 530 patients underwent a PPM. Suspicious abnormalities were reported in 61 patients (11.5%), with the PPM leading to a change in management in 47 instances (8.9%). A nomogram was created based on patient and tumor characteristics to identify patients most likely to have an abnormal PPM. PMID- 29286192 TI - Combination of pegylated liposomal doxorubicin plus gemcitabine in heavily pretreated metastatic breast cancer patients: Long-term results from a single institution experience. AB - The combination of Pegylated Liposomal Doxorubicin (PLD) plus Gemcitabine (GEM) has been previously investigated in the treatment of metastatic breast cancer (MBC). PLD is a doxorubicin formulation with prolonged circulation time and better tissue distribution. GEM is a nucleoside analog with nonoverlapping toxicity compared to PLD. The aim of our study was to assess efficacy, toxicity, and long-term outcome of this combination. Patients with heavily treated MBC were retrospectively analyzed. Chemotherapy consisted of PLD 25 mg/m2 and GEM 800 mg/m2 day 1, on a three-week schedule. Cardiac function was evaluated baseline and during treatment. Radiological response was graded according to RECIST criteria v1.1. Toxicity was scored according to CTCAE v4.0. Progression-free survival (PFS) and overall survival (OS) were evaluated. From 2001 to 2014, 122 pts were included. Median age was 55 (range: 28-84). Median previous treatment schedules in the metastatic scenario were 3 (range: 1-15). Most patients received prior anthracyclines (85%). Median number of metastatic sites was 2 (range: 1-7). Median number of cycles delivered was 5 (range: 1-36). Overall response rate was 31% (5% complete responses; 26% partial responses). Stable and progressive diseases were observed in 32% and 26% of patients. Grade >=3 neutropenia was observed in 29 patients (24%). Grade >=3 hand-foot syndrome was detected in 17 patients (14%), mostly since cycle 3 (88%). Median cumulative PLD dose was 125 mg/m2 . At a median follow-up of 101 months, median PFS and OS were 7 and 22 months, respectively. PLD-GEM combination achieves remarkable long-term outcomes with an acceptable toxicity profile in patients with MBC. PMID- 29286193 TI - Eligibility of patients for minimally invasive breast cancer therapy based on MRI analysis of tumor proximity to skin and pectoral muscle. AB - There is growing interest in minimally invasive breast cancer therapy. Eligibility of patients is, however, dependent on several factors related to the tumor and treatment technology. The aim of this study is to assess the proportion of patients eligible for minimally invasive breast cancer therapy for different safety and treatment margins based on breast tumor location. Patients with invasive ductal cancer were selected from the MARGINS cohort. Semiautomatic segmentation of tumor, skin, and pectoral muscle was performed in Magnetic Resonance images. Shortest distances of tumors to critical organs (ie, skin and pectoral muscle) were calculated. Proportions of eligible patients were determined for different safety and treatment margins. Three-hundred-forty-eight patients with 351 tumors were included. If a 10 mm safety margin to skin and pectoral muscle is required without treatment margin, 72.3% of patients would be eligible for minimally invasive treatment. This proportion decreases to 45.9% for an additional treatment margin of 5 mm. Shortest distances between tumors and critical organs are larger in older patients and in patients with less aggressive tumor subtypes. If a 10 mm safety margin to skin and pectoral muscle is required, more than two-thirds of patients would be eligible for minimally invasive breast cancer therapy. PMID- 29286194 TI - Antidiarrheal effect of sodium hydrosulfide in diabetic rats: In vitro and in vivo studies. AB - BACKGROUND: The inhibitory effects of H2 S on spontaneous contractions of smooth muscles of small, and large intestines well-established but its role in the pathophysiology of diarrhea has not been identified. Therefore, this study evaluated the role of exogenous H2 S (NaHS) on diabetic-induced diarrhea and determined mRNA expression of cystathionine beta-lyase (CSE) and cystathionine gamma-synthase (CBS) in diabetic rats. METHODS: In order to evaluate antidiarrheal effect of H2 S, normal and diabetic rats received NaHS and L Cysteine and the total number of fecal pellets (FP) determined. The effect of NaHS on intestinal transit ratio (ITR) was also evaluated in diabetic rats. The level of mRNA expressions of CBS and CSE determined in smooth muscles of jejunum, ileum, and colon in normal, and diabetic rats. The effect of NaHS on frequency and tension of spontaneous contractions of smooth muscle strips of colon, ileum, and jejunum were investigated. KEY RESULTS: NaHS decreased ITR, total number of FP, frequency and tension of spontaneous contractions of colon, ileum, and jejunum muscle strips in diabetic rats. The level of mRNA expression of CSE and CBS in diabetic rats were lower than in normal rats. NaHS, and L-Cysteine decreased the number of FP in normal rats. CONCLUSIONS & INFERENCES: These findings showed NaHS effectively controlled diarrhea in diabetic rats through decreasing the frequency, and tension of spontaneous contraction of smooth muscles of large, and small intestines. The increased frequency and tension of spontaneous contractions of smooth muscles in diabetic rats may be due to down regulation of H2 S biosynthesis enzymes. PMID- 29286195 TI - Starting hormone therapy immediately after histological diagnosis of breast cancer. PMID- 29286196 TI - Breast cancer in a patient with neurofibromatosis type 1. PMID- 29286197 TI - Sepiolite as a New Nanocarrier for DNA Transfer into Mammalian Cells: Proof of Concept, Issues and Perspectives. AB - Sepiolite is a nanofibrous natural silicate that can be used as a nanocarrier for DNA transfer thanks to its strong interaction with DNA molecules and its ability to be naturally internalized into mammalian cells through both non-endocytic and endocytic pathways. Sepiolite, due to its ability to bind various biomolecules, could be a good candidate for use as a nanocarrier for the simultaneous vectorization of diverse biological molecules. In this paper, we review our recent work, issued from a starting collaboration with Prof. Ruiz-Hitzky, that includes diverse aspects on the characterization and main features of sepiolite/DNA nanohybrids, and we present an outlook for the further development of sepiolite for DNA transfer. PMID- 29286198 TI - The Taming of the Maleimide: Fabrication of Maleimide-Containing 'Clickable' Polymeric Materials. AB - Functional polymers are widely employed in various areas of biomedical sciences. In order to tailor them for desired applications, facile and efficient functionalization of these polymeric materials under mild and benign conditions is important. Polymers containing reactive maleimide groups can be employed for such applications since they provide an excellent handle for conjugation of thiol and diene-containing molecules and biomolecules. Until recently, fabrication of maleimide containing polymeric materials has been challenging due to the interference from the highly reactive double bond. A Diels-Alder/retro Diels Alder reaction sequence based strategy to transiently mask the maleimide group provides access to such polymeric materials. In this personal account, we summarize contributions from our group towards the fabrication and functionalization of maleimide-containing polymeric materials over the past decade. PMID- 29286199 TI - Design and Synthesis of Cobalt-Based Electrocatalysts for Oxygen Reduction Reaction. AB - Oxygen reduction reaction (ORR) is the crucial step of various renewable energy conversion and storage technologies such as fuel cells and air-batteries. Cobalt based electrocatalysts including oxides/chalcogenides and Co-Nx /C, one kind of non-precious metal electrocatalysts with competitive activity, enhanced durability, and acceptable cost, have been proposed as the potentially interesting alternatives to Pt-based electrocatalysts. In this account, we summarized the synthesis methods and the corresponding main impact factors including ligand effect, particle size effect, crystal structure, nanostructure, defects and active centers related to the ORR performance on both of oxides/chalcogenides and Co-Nx /C. Some special points have been discussed on design and synthesis of low-cost and high-performance cobalt-based electrocatalysts with enhanced electrocatalytic activity. Also, the current challenges and future trends are proposed for improving the performance of Co involving electrocatalysts. PMID- 29286200 TI - Relevance of megalin receptor injury with nuclear factor-kappa B upregulation in acute kidney injury induced in rats. AB - Proximal tubule protein take-up is interceded by 2 receptors, megalin and cubilin. These receptors rescue an assortment of filtered ligands including fundamental vitamins and hormones. The objective of this study was to investigate the potential relation of megalin receptor injury with nuclear factor-kappa B (NF kappaB) upregulation in acute kidney injury rat model. Twenty four rats were allocated into two groups: control group received saline, while the second group was intoxicated with cadmium chloride (2.4 mg Cd/kg/day i.p) for 30 days. Blood urea nitrogen, serum creatinine, tissue oxidant-antioxidant parameters (malondialdehyde [MDA] and reduced glutathione [GSH]) and expression levels for NF-kappaB, toll like receptor-2 (TLR2), toll like receptor-4 (TLR4), and megalin receptor were estimated. Noticeable downregulation of megalin receptor versus upregulation of NF-kappaB, TLR2, and TLR4 were observed in AKI rat model together with significant elevation in MDA as well as significant reduction in GSH. The study concluded that the oxidative stress in kidney tissue leads to megalin receptor damage, which indeed motivates upregulation of NF-kappaB through TLRs 2 and 4 pathways. PMID- 29286201 TI - The role of molecular breast imaging for diagnosis of nonpalpable lesions in dense breasts. PMID- 29286202 TI - Direct Crystallization of Layered Silicates on the Surface of Amorphous Silica. AB - We overview the entire surface coverage of amorphous silica with layered silicates (smectite-like) using the direct crystallization technique under hydrothermal conditions. Various shapes (e. g., microspheres, fibers, microcapsules) have been available as the silica substrates, which involve partial dissolution triggered by the hydrolysis of urea for supplying a source of the layered silicates. Other sources (e. g., Li+ , Mg2+ , Al3+ ) have been supplied from aqueous solutions, participating the heterogeneous nucleation of the layered silicates. Because of partial dissolution of the silica substrates, the original shape has been preserved after the hydrothermal reactions. Cation exchange reactions, usually observed for conventional smectite systems, occurred by replacing the interlayer cations in the silicates with metal (a rare-earth ion) and organic (a quaternary long-chain alkylammonium, methylene blue, and a tris-chelated complex) cations. We have discussed the mechanism of the crystallization and displayed some applications of the hybrids (e. g., chiral discrimination, filtering, and magnetic recovery). PMID- 29286203 TI - Docetaxel/cyclophosphamide chemotherapy in older patients with breast cancer. PMID- 29286204 TI - Genetic variation and potential coinfection of Wolbachia among widespread Asian citrus psyllid (Diaphorina citri Kuwayama) populations. AB - Wolbachia can profoundly influence the survival, reproduction, and defenses of insect hosts. These interactions could potentially be harnessed for managing pests or insect-transmitted diseases. Diaphorina citri Kuwayama is a phloem feeding pest capable of transmitting the putative causal agent of citrus greening, Candidatus Liberibacter asiaticus (CLas). Like many insects, D. citri is also infected with Wolbachia (wDi). Recent studies indicate that the relative abundance of wDi could be associated with the abundance of CLas, and that wDi may contribute to regulating expression of phage lytic cycle genes in CLas, suggesting the need for better understanding of wDi biology in general. This study investigated the genetic diversity of wDi among D. citri in populations spanning eleven countries and two U.S. territories. Six Wolbachia genes, wsp, coxA, fbpA, ftsZ, gatB, and hcpA, were sequenced and compared across samples. Two prevalent wDi strains were identified across the samples, and screening of clone libraries revealed possible coinfection of wDi strains in specific populations. D. citri mitochondrial cytochrome oxidase subunit I gene (mtCOI) were more divergent between D. citri populations that were infected with different wDi strains or had different infection statuses (single infection vs. coinfection). While we could not eliminate the possibility that maternal transmission may contribute to such patterns, it is also possible that wDi may induce cytoplasmic incompatibility in their host. These findings should contribute to the understanding of wDi population ecology, which may facilitate manipulation of this endosymbiont for management of citrus greening disease worldwide. PMID- 29286205 TI - Uptake of risk-reducing surgery in BRCA gene carriers in Wales, UK. AB - Women who inherit a mutated copy of the BRCA gene have a higher lifetime risk of developing breast cancer. No large epidemiological studies exist looking at BRCA mutation carriers in UK populations. All patients with BRCA1/BRCA2 mutation identified between 1995 and 2015 were included. Individuals were identified from a prospectively gathered data base. Genetics case-notes were obtained and retrospective analysis performed. 581 female BRCA mutation carriers were identified with a median age of 34 (18-81) at the time of testing. Of the 301 women who underwent diagnostic testing (symptomatic) 246 had been diagnosed with breast cancer, 89 with ovarian cancer and 37 had both at time of testing. Median age at diagnostic test was 51 (25-81). 33% of women underwent risk-reducing mastectomies (RRM); median age at surgery 45. This compares with 37% of women in this diagnostic group who underwent Risk-reducing bilateral salpingo oopherectomies (RRBSO) at a median age of 46. Two hundred and eighty women underwent predictive testing (family history, asymptomatic), median age 36 (18 81). 34% of women in this predictive group underwent RRM, median age 37. There was a 29% uptake of RRBSO (median age 44 years). Fifteen women (5%) developed breast cancer after being tested; none of these had undergone RRS. This unique study of all BRCA mutation carriers in Wales shows considerable variation in uptake of RRS. The decision to undergo RRS is complex and involves a number of factors, including a woman's age and life stage. As BRCA testing becomes more frequent and more gene mutation carriers are identified there will be significant implications for service allocation, screening demands, and provision of risk reducing surgery for this high-risk patient group. PMID- 29286206 TI - High resolution vs conventional esophageal manometry in the assessment of esophageal motor disorders in patients with non-cardiac chest pain. AB - BACKGROUND: High-resolution esophageal manometry (HREM) has become a leading tool in the assessment of esophageal motor disorders, replacing conventional manometry. However, there is limited data about the contribution of HREM as compared with conventional manometry to the assessment of esophageal motor disorders in patients with non-cardiac chest pain (NCCP). The aim of the study was to compare the distribution of esophageal motor disorders in patients with NCCP using HREM as compared with conventional manometry and to determine if HREM improved diagnosis of these disorders. METHODS: In this study, we included 300 consecutive patients with NCCP who underwent either HREM or conventional manometry over a period of 10 years. A total of 150 patients had conventional manometry and the other 150 patients HREM. The Chicago 3.0 classification and the Castell and Spechler classification were used to determine the esophageal motor disorder of NCCP patients undergoing HREM and conventional manometry, respectively. KEY RESULTS: In both HREM and the conventional manometry groups, normal esophageal motility was the most frequent finding (47% and 36%; respectively, P = .054). Hypotensive lower esophageal sphincter was the most common motility disorder identified by conventional manometry (27.3%), while ineffective esophageal motility was the most common esophageal motor disorder identified by HREM (25.3%). CONCLUSIONS & INFERENCES: There is a discrepancy in the type of esophageal motor disorders identified by HREM as compared with conventional manometry in NCCP patients. Hypotensive motility disorders are the most commonly diagnosed by both manometric techniques. PMID- 29286207 TI - Microcalcifications in the breast secondary to augmentation by filler injections. PMID- 29286208 TI - Diffuse liver infiltration by lobular breast carcinoma: Shear wave elastography as gold standard imaging study. PMID- 29286209 TI - Precision of DXA-Derived Visceral Fat Measurements in a Large Sample of Adults of Varying Body Size. AB - OBJECTIVE: The aim of this study was to determine the precision of GE Lunar's CoreScan tool (GE Healthcare, Madison, Wisconsin) for measuring visceral adipose tissue (VAT) in adults of varying body size. METHODS: Two consecutive dual-energy x-ray absorptiometry (DXA) scans with repositioning were undertaken in 233 participants (110 male, 123 female) aged 18 to 70 years; 38% (n = 89) had normal weight, 34% (n = 80) had overweight, and 27% (n = 64) had obesity. The coefficient of variation (CV), the root-mean-square standard deviation (RMS SD), and the corresponding 95% least significant change (LSC) were calculated for VAT, total fat, total lean, bone mineral density, and bone mineral content. RESULTS: VAT precision error in the total group was 28.9% (percent CV), with a RMS SD of 47.1 g. Bland-Altman plots demonstrated a mean precision bias of 2.4 g (95% CI: 6.2 to 11.0 g), giving an LSC of 130.6 g. BMI subgroup analyses revealed that precision errors (RMS SD) for VAT mass were 32.9 g in the group with normal weight, 33.5 g in the group with overweight, and 51.0 g in the group with obesity. Precision errors (percent CV) for total body fat, lean, and bone were significantly lower, ranging from 0.7% to 2.6%. CONCLUSIONS: The precision of DXA VAT mass measurements increase with BMI, and caution should be used with estimates in adults with obesity. PMID- 29286210 TI - N-Annulated Perylene-Based Hole Transporters for Perovskite Solar Cells: The Significant Influence of Lateral Substituents. AB - Perylene derivatives are a family of well-known organic electron-transporting materials with excellent photochemical and thermal stabilities, and have been widely used in various optoelectronic devices. In this work, two diphenylamine functionalized N-annulated perylenes are reported as hole-transporting materials (HTMs) for perovskite solar cells. Through joint theoretical and experimental studies, the HTM employing a methoxyphenyl lateral substituent is found to feature a closer stacking distance and better aggregate connectivity in the solid film than its analogue with the bulky 2-hexyldecyl lateral substituent, contributing to a higher hole mobility and a remarkably enhanced device performance of perovskite solar cells. This work demonstrates the significant influence of lateral substituents of HTMs on the intermolecular packing and solid microstructure, giving a clear insight on the molecular design of high performance organic semiconductors. PMID- 29286211 TI - Characterization of costal cartilage and its suitability as a cell source for articular cartilage tissue engineering. AB - Costal cartilage is a promising donor source of chondrocytes to alleviate cell scarcity in articular cartilage tissue engineering. Limited knowledge exists, however, on costal cartilage characteristics. This study describes the characterization of costal cartilage and articular cartilage properties and compares neocartilage engineered with costal chondrocytes to native articular cartilage, all within a sheep model. Specifically, we (a) quantitatively characterized the properties of costal cartilage in comparison to patellofemoral articular cartilage, and (b) evaluated the quality of neocartilage derived from costal chondrocytes for potential use in articular cartilage regeneration. Ovine costal and articular cartilages from various topographical locations were characterized mechanically, biochemically, and histologically. Costal cartilage was stiffer in compression but softer and weaker in tension than articular cartilage. These differences were attributed to high amounts of glycosaminoglycans and mineralization and a low amount of collagen in costal cartilage. Compared to articular cartilage, costal cartilage was more densely populated with chondrocytes, rendering it an excellent chondrocyte source. In terms of tissue engineering, using the self-assembling process, costal chondrocytes formed articular cartilage-like neocartilage. Quantitatively compared via a functionality index, neocartilage achieved 55% of the medial condyle cartilage mechanical and biochemical properties. This characterization study highlighted the differences between costal and articular cartilages in native forms and demonstrated that costal cartilage is a valuable source of chondrocytes suitable for articular cartilage regeneration strategies. PMID- 29286212 TI - Knockdown of CPEB4 expression suppresses cell migration and invasion via Akt pathway in non-small cell lung cancer. AB - Cytoplasmic polyadenylation element binding protein 4 (CPEB4) could be an important regulator in variety of cancers. However, the biological function and the underlying molecular mechanism of CPEB4 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the metastasis role of CPEB4 in NSCLC cells, we knocked down CPEB4 using siRNA. Transwell migration assay and cell invasion assay on Matrigel were presented, and cell migration was also determined by scratch-healing assay. ROS generation were determined by fluorescence probe DCFH2-DA. The protein expression was assessed by ELISA and Western blot analysis. LY294002 were used to inhibit PI3 K/Akt signaling. The data showed that knockdown of CPEB4 inhibited the migration and invasion of NSCLC. Moreover, silencing of CPEB4 reduced Snail and MMP-3 expression in vitro. We also indicated that CPEB4 knockdown increased the ROS expression. Furthermore, we found that silencing of CPEB4 decreased pAkt expression. Taken all together, our data demonstrated that silencing of CPEB4 induces ROS generation, thus suppressing the Akt expression, which finally prevents NSCLC cells invasion and migration. Therefore, CPEB4 may regard as a target to inhibit NSCLC invasion and metastasis through Akt pathway. PMID- 29286213 TI - Risk Factors for Invasive Fungal Infection among Thai Oncologic Patients with Febrile Neutropenia and Cutaneous Presentation: A 5-Year Retrospective Study in Southern Thailand AB - Background: Febrile neutropenia (FNP) is a condition defined by fever and neutropenia. There are current onlylimited data on related cutaneous manifestations. This study aimed to assess cutaneous lesions and their etiologies in aThai group of FNP patients. Methods: A retrospective analysis was conducted on 43 non-transplant febrile neutropenicpatients with concurrent cutaneous lesions, as determined by dermatopathologic studies at Songklanagarind Hospitalin Thailand over a five-year period. Results: The mean age was 39 years (SD: 18.8). Approximately 60% were male.The most common underlying disease was a hematologic neoplasm. Twenty-one of the participants had developed FNPwithin 7.5+/-8.7 days after presenting with skin lesions. Twenty-two participants had skin lesions 9.0+/-11.1 days after FNPdiagnosis. Cutaneous manifestations were mostly in the form of multiple lesions (67.4%), of which the most commonwere nodular skin lesions (37.2%) presenting on the lower extremities of the body (58.1%). The dermatopathologicdiagnoses included infections which were almost all fungal and leukemia cutis. The development of skin lesions afterFNP proved to be a statistically significant risk factor for fungal infection (OR 8.13, P = 0.009), whereas age (over 40years) proved to be a statistically significant protective factor (OR 0.20, P = 0.04). Conclusions: There are a varietyof cutaneous manifestations in FNP, of which the most common were cutaneous nodular skin lesions in the lowerextremities. The most frequent infection was fungal in patients under 40 who had developed skin lesions after FNP. PMID- 29286214 TI - Lack of Associations between TLR9 and MYD88 Gene Polymorphisms and Risk of Chronic Lymphocytic Leukemia AB - Background: Genetic factors like single nucleotide polymorphisms (SNPs) may play an important role in the etiologyof chronic lymphocytic leukemia (CLL). Mutations in Toll like receptor 9 (TLR9) and myeloid differentiation primaryresponse 88 (MYD88) genes may lead to an abnormal immune response that may cause greater cell proliferation andthus alter an individual's susceptibility to haematological malignancies including CLL. Objective: This work wasdesigned to study any association of the TLR9 (rs2066807C/G and rs187084T/C) and MYD88 (L265P) single nucleotidepolymorphism (SNPs) with risk of CLL in Egyptians. Materials and methods: One hundred patients with CLL and 100healthy controls from the Egyptian population were genotyped by the polymerase chain reaction/restriction fragmentlength polymorphism (PCR/RFLP) method. Results: With TLR9 rs2066807C/G the CC genotype was more frequentin both control and patient groups while for TLR9 rs187084T/C the TT genotype was most common. There were nosignificant associations with CLL risk. With MYD88 (L265P) only the TT genotype was detected. Conclusion: Ourpreliminary data suggest that polymorphisms in the TLR9 and MYD88 genes may not contribute to CLL susceptibility.To the best of our knowledge, this study is the first dealing with TLR9 and MYD88 gene polymorphisms in CLLpatients. Further studies with larger sample size should be conducted to validate these results in the Egyptian population. PMID- 29286215 TI - Inter- and Intra-Observer Variability in Diagnosis of Oral Dysplasia AB - Background: Oral potentially malignant disorders (OPMDs) are lesions from which malignancy is more likelyto develop that from other tissues. The potential for malignant transformation of OPMDs is estimated by determiningthe degree of dysplastic changes in the epithelium. Dysplasia grading has been criticized for lack of reproducibilityand poor predictive value but is still considered the gold standard for diagnosing OPMDs. Since grading of dysplasiais based on architectural and cytological changes, there can be considerable inter- and intra observer variability dueto subjective impressions. This aim in this study was to assess the degree of agreement between two pathologistsgrading dysplasia in the same patients and review the existing grading system. Materials and Methods: In thishospital-based cross-sectional study, 100 patients with clinically diagnosed OPMDs were subjected to biopsy followedby histopathological examination. The slides were examined by two pathologists using WHO and binary systems ofclassification and both were blinded to the clinical and each other's histological diagnosis. For statistical analysis theChi square test was applied. Results: Statistical analysis showed poor inter-observer variability with P values of 0.8using the WHO classification and 0.3 using the binary classification. Conclusion: Our study provides evidence thatthe existing systems for grading dysplasia are not competent to rule out subjectivity. There is a need for a classificationsystem that can overcome this drawback. PMID- 29286216 TI - Phosphorylated Akt Protein at Ser473 Enables HeLa Cells to Tolerate Nutrient Deprived Conditions AB - Background: Despite angiogenesis, many tumours remain hypovascular and starved of nutrients while continuingto grow rapidly. The specific biochemical mechanisms associated with starvation resistance, austerity, may be newbiological characters of cancer that are critical for cancer progression. Objective: This study aim was to investigatethe effect of nutrient starvation on HeLa cells and the possible mechanism by which the cells are able to toleratenutrient-deprived conditions. Methods: Nutrient starvation was achieved by culturing HeLa cells in nutrient deprivedmedium (NDM) and cell survival was estimated by using cell counting kit 8. The effect of starvation on cell cycledistribution and the quantitative analysis of apoptotic cells were investigated by flow cytometry using propidiumiodide staining. Western blotting was used to detect the expression levels of Akt and phosphorylated Akt at Ser473(Ser473p-Akt) proteins. Results: HeLa cells displayed extremely long survival when cultured in NDM. The percentageof apoptotic HeLa cells was significantly increased by starvation in a time-dependent manner. A significant increase inthe expression of Ser473p-Akt protein after starvation was also observed. Furthermore, it was found that Akt inhibitorIII molecule inhibited the cells proliferation in a concentration- and time-dependent manner. Conclusion: Results ofthe present study provide evidence that Akt activation may be implicated in the tolerance of HeLa cells for nutrientstarvation and may help to suggest new therapeutic strategies designed to prevent austerity of cervical cancer cellsthrough inhibition of Akt activation. PMID- 29286217 TI - Knowledge and Perceptions about Cancer Treatment-associated Infertility among Young Patients at a Tertiary Care Hospital in Pakistan AB - Introduction: Infertility after cancer treatment can cause significant emotional stress and grief for cancer survivors.In this study we assessed knowledge and perceptions among young cancer patients regarding the topic of cancer andinfertility related to different treatment options. Material and Methods: This cross-sectional study was conducted onyoung cancer patients in the Clinical Oncology Department, JPMC, Karachi, from January to August 2013. Patients wererequested to fill in questionnaires. Comparisons between gender and age groups were performed using the Student'st test and Pearson's Chi-squared. Significance was concluded with a two tailed p-value less than 0.05. Results: Thesurvey included 368 cancer patients, 194 males and 174 females. Ninety percent of respondents of either gender werenot aware that cancer or cancer treatment can cause infertility, this being age dependent (P=0.06). However, on beingmade aware, 98% of males and 91% of females wanted their oncologist to discuss treatment-related infertility prior toinitiating cancer treatment (P=0.005) and 92% and 78%, respectively, wanted to consider fertility preservation techniquesprior to treatment (P<0.0001). Of age groups 15-30 years and 31-50 years, 91 % and 81% wanted to consider FPprior to cancer treatment (P =0.011). Among 226 married individuals, 89% males and 79% females underestimatedthat effects that infertility issues might have on their relationships with their spouses. Conclusions: We recommendphysicians and oncology care givers to initiate discussion of the topic of cancer and treatment-related infertility withyoung cancer patients during their initial management planning. PMID- 29286218 TI - Seroepidemiological Study of Hepatitis B, C and HIV among Blood Donors in Kerman AB - Background: Infections transmitted through blood transfusions are the most important issue associated with blooddonation. We aimed to provide an assessment of the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV) andhuman immunodeficiency virus (HIV) among blood donors in Kerman province of Iran. Methods: Between 2014-2016,99,187 samples were examined in a retrospective study in five blood transfusion centers in Kerman province. Serologicscreening for HBsAg, anti-HCV and anti-HIV1/2 was conducted for all samples and positive cases were confirmed.Result: The positives with the initial serological screening tests for HBsAg , anti-HCV and HIV 1/2 numbered 524,409 and 285, respectively, and based on confirmation tests, final results were 196 , 72 and 1. The highest prevalences ofHBV and HCV were reported as 0.36% in Jiroft city and 0.1% in Rafsanjan city. Co- infection with HBV and HCV wasobserved in the city of Sirjan. Conclusion: Blood-borne viral infections in people with low education levels were morecommon. The prevalence in Kerman province was low as compared to previous studies carried out in other regions ofIran. Application of standard operating procedures, with updated equipment, as well as planning for the use of molecularmethods are necessary for the Iranian Blood Transfusion Organization, to monitor blood-transmitted infections. PMID- 29286219 TI - Aloe-Emodin Influence on the Lysosomal Compartment of Hela Cells AB - Background: Aloe-emodin belongs to the group of anthraquinones having extremely high biological activity.The aim of this study was to evaluate the range of morphological and biochemical changes in HeLa cells treated withaloe-emodin, especially with regard to the lysosomal compartment. Methods: Marking of lysosomes was performedwith neutral red staining for conventional light microscopy and acridine orange staining for confocal microscopy. Toevaluate ctivity of lysosomal enzymes and permeability of the lysosomal membrane, spectrophotometric techniqueswere employed. Results: Aloe-emodin caused increased permeability of lysosomal membranes in HeLa cells, expressedinter alia by extinction of the orange color of acridine orange (lysosomal marker) and in reduction of neutral red uptakeby lysosomes. These changes are accompanied by release of cathepsins from the interior of the lysosomes with asimultaneous highly significant increase in their activity in the cytoplasm. Conclusion: The results indicate that aloeemodincan activate lysosomal pathway-dependent apoptosis in HeLa cells. PMID- 29286220 TI - The Correlates of Kidney Dysfunction - Tumour Nephrectomy Database (CKD-TUNED) Study: Protocol for a Prospective Observational Study AB - Background: Tumour nephrectomy conveys a significant risk of adverse renal functional outcomes postoperatively,however there are limited strategies for predicting patients at increased risk of these outcomes. The Correlates of KidneyDysfunction - Tumour Nephrectomy Database (CKD-TUNED) study is a prospective observational study evaluatingthe risk of chronic kidney disease and end-stage kidney disease in tumour nephrectomy patients. Methods: The CKDTUNEDstudy involves analysis of clinical data and collection of tissue, urine and blood samples for the purposes offorming a tissue repository resource for future investigation. Recruitment began in 2013 and is expected to continueuntil 2023, with a projected sample size between 700-1000 subjects. Results: All relevant ethics and site-specificapprovals have been granted and all relevant infrastructure is in place. Study methods are undergoing validation andrefinement. As of June 2017 there are 267 participants enrolled in the study. Conclusion: It is anticipated that this studywill have the potential to identify risk factors for adverse renal functional outcomes following tumour nephrectomy,which can be used in the development of predictive models with clinical utility, and in turn improve patient outcomes. PMID- 29286221 TI - Prognostic Significance of Indicators of Systemic Inflammatory Responses in Glioblastoma Patients AB - Background: High-grade gliomas, with glioblastomas as the most frequently observed histologic subtype, arethe most common primary brain tumours in adults. It is considered that inflammatory responses play a major role inmalignancies, including tumour progression. This study aimed to determine the prognostic significance of the neutrophilto lymphocyte ratio (NLR) and the thrombocyte to lymphocyte ratio (PLR) as indicators of systemic inflammatoryresponse (SIR) in glioblastoma patients. Methods: A total of 90 patients treated for glioblastoma were retrospectivelyevaluated. Absolute counts were used to generate NLR and PLR. A SIR was considered to be present with an NLR >=5and/or PLR >=150. Results: Median follow-up time was 11.3 months (range: 1-70 months). The 1-year and 2 yearoverall survival rates were 55.2% and 19.5%, respectively. Univariate analysis showed that there was no correlationbetween overall survival and gender (p=0.184), comorbid disease (p = 0.30), clinical presentation (p = 0.884), or tumourlateralization (p = 0.159). Multivariate analysis showed that overall survival was significantly correlated with SIR basedon NLR (HR: 2.41), and ECOG performance status (HR: 1.53). The prognostic factors that affected survival, otherthan SIR, were Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.003), and tumour localization(p = 0.006). Conclusion: The present findings confirm that NLR based on peripheral blood counts prior to treatment canbe used as a prognostic factor in patients with glioblastoma. Since tumour aggression increases and survival decreasesas the NLR value rises, choice of treatment modality is facilitated for glioblastoma patients. PMID- 29286222 TI - BRCA1 Promoter Methylation and Expression - Associations with ER+, PR+ and HER2+ Subtypes of Breast Carcinoma AB - Introduction: Considering the increasing trend in incidence rates, morbidity and mortality of breast cancer, there isan urgent need to identify and validate new biomarkers for early detection and better management. The purpose of thestudy was to investigate BRCA1 protein expression and promoter methylation of the BRCA1 gene and their associationwith molecular subtypes based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growthfactor receptor 2 (HER2) positivity. Materials and Methods: A total of 114 breast cancer tissue biopsies were collectedfor methylation specific PCR (MSP) and immunohistochemical (IHC) analysis. Results: Seven tissue microarrays wereconstructed. BRCA1 protein expression was reduced in 55/114 (48.2%) and in the majority of ER-negative tumors(73.3%) (p<0.001). Similarly BRCA1 expression was reduced in the majority of PR-negative tumors (69.2%) butwithout statistical significance (p value=0.083). BRCA1 methylation was positive in 59.6% cases. A subset regardingER+, PR+ and HER2+ was identified which consisted of 31.6% in which an inverse relationship between BRCA1methylation and protein expression was noted. Conclusion: Reduced expression was associated with ER and PRnegative status which is linked with a poor prognosis. BRCA1 protein expression might thus be used as a prognosticindicator to predict treatment response to hormone therapy. PMID- 29286223 TI - Astrocyte Elevated Gene 1 (AEG-1): A Promising Candidate for Molecular Targeted Therapy in Oral Squamous Cell Carcinomas AB - Background: Astrocyte elevated gene 1 (AEG-1), also known as metadherin, is an oncogene which is overexpressedin various types of cancer, playing important roles in invasion, metastasis, angiogenesis and chemotherapy resistance.Hence it might be used as a therapeutic target. The aim of this study was to evaluate the expression of AEG-1 as a novelmolecular marker in oral squamous cell carcinomas and establish correlations with clinicopathologic factors. Materialsand Methods: Thirty formalin fixed paraffin-embedded blocks of OSCC cases and 30 samples of normal oral mucosawith minimal inflammation were selected and stained immunohistochemically for AEG-1. Staining intensity andpercentage of stained cells were scored according to nuclear and cytoplasmic staining of epithelial cells. Relationshipbetween immunoreactivity and clinicopathologic factors were examined by T-test and Mann-Whitney. Results: AEG-1expression in OSCCs was greater than in normal oral mucosa (P<0.05). However, nuclear and cytoplasmic expressionof AEG-1 was not associated with any of the clinicopathologic factors, age and gender of patients, tumor location,smoking history, tumor staging and grading, metastasis to lymph nodes and distant metastasis ( P>0.05). Conclusion:The current results support some role of AEG-1 in genesis of oral squamous cell carcinomas. PMID- 29286224 TI - Utility of 5-Methylcytosine Immunohistochemical Staining to Assess Global DNA Methylation and Its Prognostic Impact in MDS Patients AB - Background: DNA methylation plays a vital role in the pathogenesis of the myelodysplastic syndrome (MDS),a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders. It is reported to be an independentprognostic factor affecting overall survival (OS). Our aim was to analyze the role of global DNA methylation using ananti-5-methylcytosine (5-MC) antibody by immunohistochemistry (IHC) of bone marrow biopsy (BM Bx) specimensin MDS patients, assessing correlations with various clinical and biological prognostic factors. Material and methods:A total of 59 MDS cases, classified as per the World Health Organization (WHO) 2008 guidelines, were evaluatedover a period of 4 years. Clinical data were retrieved from departmental case records and anti-5-MC expression wasanalyzed with formalin fixed paraffin embedded sections of BM Bx specimens of MDS patients and controls. Results:The median age at diagnosis was 52 years (15-85years). Patients were categorized into low risk (59%) and high risk(41%) according to International Prognostic Scoring System (IPSS). The median follow-up time was 10 months (1 to37 months). We generated a methylation score (M score) using anti-5-MC and with the derived cut-off of 30.5 from thereceiver operator curve (ROC), there was a significant difference between the two groups in the percentage of BM blasts(p=0.01), WHO sub-type (p=0.01), IPSS (p=0.004), progression to AML (p=0.04) on univariate analysis. Interestingly,patients showing a high M-score (M-score >= 30.5) demonstrated a significantly shorter OS and progression to AML.However, on multivariate analysis, only BM blasts (p=0.01) and IPSS (p=0.02) remained independent variables forprogression to AML and OS respectively. Conclusion: Immunostaining with anti-5-MC antibody with BM Bx samplesis a simple and cost effective technique to detect global methylation, a powerful tool to predict overall survival inpatients with MDS. PMID- 29286225 TI - Comparison of Salivary Antioxidants in Children with Primary Tooth Abscesses before and after Treatment in Comparison with Healthy Subjects AB - Aim: The aim of this study was to compare the total antioxidant capacity (TAC) of children with primary molarabscesses before and two weeks after extraction of the infected tooth. Materials and methods: Forty one children agedbetween 3-6 years participatesd in this cross sectional study. The antioxidant activity of saliva was investigated in 20patients with tooth abscesses affecting one of the first primary molars before and after tooth extraction in the case groupand once in 21 children with no caries or dental problems in the control group. The FRAP (ferric reduction antioxidantpower) method was used to measure the antioxidant power of salivary samples and TAC values were calculated.Data were analyzed with SPSS Version 16 using the paired t-test at a significance level of 0.05. Results: The meanantioxidant index increased in children after (509.2 +/- 138.4) treatment (before 483.4 +/- 183.6), but this difference wasnot significant (P=0.61). Also, there was no difference in the mean antioxidant index in control group (494.5+/ 147.9)compared the study group before (P=0.83) and after (P=0.75) treatment. Conclusion: Under the conditions of thisstudy the total antioxidant capacity of saliva was not compromised in children with abscessed teeth. PMID- 29286226 TI - Almost Complete Lack of Human Cytomegalovirus and Human papillomaviruses Genome in Benign and Malignant Breast Lesions in Shiraz, Southwest of Iran AB - Breast cancer ranks as the most common cancer among women worldwide. There have been controversial reportsregarding contributions of human papillomaviruses (HPVs) and human cytomegalovirus (HCMV) to its development.The aim of this study was to determine the frequency of HPV and HCMV positivity in benign and malignant breasttumors. Materials and Methods: Formalin fixed paraffin-embedded tissue specimens of 150 breast cancers (invasiveductal and lobular carcinomas) and 150 non-malignant breast lesions (fibroadenomas, fibrocystic disease and adenosis)were examined. All samples were first deparafinized then subjected to commercial DNA extraction. The beta-globin genefragment was amplified using polymerase chain reaction (PCR) to confirm the quality of extracted DNA. The presenceof HPV and HCMV genomic DNA was determined using PCR and Real time PCR techniques, respectively. Results:The mean ages of the test and control groups were 35.2 and 45 years, respectively. For HCMV, none of the malignantlesions were positive and only 2 of the 150 benign samples demonstrated presence of the virus. No HPV genomicDNA was found in either malignant or benign cases. Conclusion: The results of this study indicated no relationshipbetween HCMV or HPV infection with breast cancer development. Whether investigations in larger populations withlonger follow-up might demonstrate any role remains unclear. PMID- 29286227 TI - Quality of Life Determinants in Breast Cancer Patients in Central Rural India AB - Introduction: Breast cancer is the most frequently diagnosed cancer among women throughout world, with incidencerates increasing in India. Improved survival in breast cancer patients has resulted in their quality of life (QOL) becomingan important issue. Identifying determinants for QOL may provide insights into how to improve their living conditions.This study aimed to assess socio-demographic and clinical factors, as well as the role of self-efficacy, in relation to QOLamong women with breast cancer in rural India. Methods: A total of 208 female patients with infiltrating carcinomaof the breast participated in the study. A questionnaire was administered that included sections for socio demographiccharacteristics, clinical stage of the cancer and patient delay in seeking health care. A standardized instrument to measureself-efficacy was applied. To assess QOL, the WHOQOL - BREF instrument was used. Results: The overall meanscore for QOL was 59.3. For domain 1 (physical health) the mean score across all groups was 55.5, for psychologicalhealth 58.2, for social relationships 63.2 and for environmental factors, 60.4. The environmental domain in QOL wasnegatively associated with lower education. Being divorced/widowed/unmarried had a negative association with thepsychological health and social relationship dimensions, whereas higher income was positively associated with QOLparameters such as psychology, social relationships and environmental factors. Self-efficacy was positively associatedwith all four domains of QOL. Conclusions: The present study demonstrated a moderate QOL in women with breastcancer in rural India. Young age, lack of education and being without a partner were negatively related to QOL, andemployment as casual and industrial workers, high monthly family income and higher self-efficacy were positivelyassociated with QOL. A comprehensive public health initiative is required, including social, financial and environmentalsupport, that can provide better QOL for breast cancer survivors. PMID- 29286228 TI - Effects of Damnacanthal and Nordamnacanthal on Proliferation, Apoptosis, and Migration of Oral Squamous Cell Carcinoma Cells AB - Cancer is one of the most common causes of death in the developed world, with one third of people diagnosed withcancer during their lifetime. Oral cancer commonly occurs involving the buccal mucosa (cheeks), tongue, floor of themouth and lip. It is one of the most devastating and disfiguring of malignancies. Morinda citrifolia L., commonly knownas 'noni', belongs to the Rubiaceae family. It is native to the Pacific islands, Hawaii, Caribbean, Asia and Australia.The plant displays broad curative effects in pharmacological studies. Damnacanthal (DAM) and Nordamnacanthal(NDAM), anthraquinone compounds isolated from the roots of Morinda citrifolia L., has been used for the treatmentof several chronic diseases including cancer. The objectives of this study were to evaluate cytotoxicity, morphologicalchanges, cell death mode (apoptosis/necrosis), and cell migration induced by DAM and NDAM on the most commontype of oral cancer, oral squamous cell carcinoma (OSCC)cells. Anti-proliferative effects of these compounds againstOSCC cell lines were determined by MTT assay. The mode of cell death was analysed by phase contrast and fluorescentmicroscopy as well as flow cytometry. In addition, cell migration was assessed. The results showed that DAM andNDAM exerted cytotoxicity against OSCC cells with IC50 values of 1.9 to >30 MUg/ml after 72 h treatment. Maximumgrowth inhibition among the tested cell lines for both compounds was observed in H400 cells, and thus it was selectedfor further study. The study demonstrated inhibition of H400 OSCC cell proliferation, marked apoptotic morphologicalchanges, induction of early apoptosis, and inhibition of cell migration by DAM and NDAM. Therefore, this informationsuggests that these compounds from noni have potential for used as anti tumor agents for oral cancer therapy. PMID- 29286229 TI - Synergistic Effect of Forbesione From Garcinia hanburyi in Combination with 5 Fluorouracil on Cholangiocarcinoma AB - Background: Chemotherapy for advanced cholangiocarcinoma (CCA) is largely ineffective; thus innovativecombinations of chemotherapeutic agents and natural compounds represent a promising strategy. This study aimed toinvestigate the synergistic effects of forbesione combined with 5-fluorouracil (5-FU) in hamster cholangiocarcinoma(Ham-1) cells both in vitro and in vivo. The anti-tumor effects of 5-FU combined with forbesione in vitro were determinedusing the Sulforhodamine B (SRB) assay and the effects in vivo were assessed in transplanted Ham-1 allographmodels. Using ethidium bromide/acridine orange (EB/AO) staining, the morphological changes of apoptotic cellswas investigated. The expressions of apoptosis-related molecules after combined treatment with forbesione and 5-FUwere determined using real-time RT-PCR and western blot analysis. Forbesione or 5-FU alone inhibited proliferationof Ham-1 cells in a dose-dependent manner and their combination showed a synergistic proliferation inhibitory effectin vitro. In vivo studies, forbesione in combination with 5-FU exhibited greater inhibition of the tumor in the hamstermodel compared with treatment using either drug alone. Forbesione combined with 5-FU exerted stronger apoptoticinduction in Ham-1 cells than did single drug treatment. The combination of drugs strongly suppressed the expressionof B-cell lymphoma 2 (Bcl-2) and procaspase-3 while enhancing the expression of p53, Bcl-2-associated X protein(Bax), apoptotic protease activating factor-1 (Apaf-1), caspase-9 and caspase-3, compared with single drug treatments.These results explained the decreased expression of cytokeratin 19 (CK19) positive cells and proliferation cell nuclearantigen (PCNA) positive cells in Ham-1 cell tumor tissues of the treated hamsters. There was no apparent systemictoxicity observed in the treated animals compared with the control groups. Forbesione combined with 5-FU stronglyinduced apoptosis in Ham-1 cells. The growth inhibitory effect of combined treatment using these two drugs was muchgreater than treatment with either drug alone, both in vitro and in vivo. PMID- 29286230 TI - Enhanced Photocatalytic Activity of Diamond Thin Films Using Embedded Ag Nanoparticles. AB - Silver nanoparticles embedded into the diamond thin films enhance the optical absorption and the photocatalytic activity toward the solvated electron-initiated reduction of N2 to NH3 in water. Here, we demonstrate the formation of diamond films with embedded Ag nanoparticles <100 nm in diameter. Cross-sectional scanning electron microscopy (SEM), energy-dependent SEM, and energy-dispersive X ray analysis demonstrate the formation of encapsulated nanoparticles. Optical absorption measurements in the visible and ultraviolet region show that the resulting films exhibit plasmonic resonances in the visible and near-ultraviolet region. Measurements of photocatalytic activity using supraband gap (lambda < 225 nm) and sub-band gap (lambda > 225 nm) excitation show significantly enhanced ability to convert N2 to NH3. Incorporation of Ag nanoparticles induces a nearly 5-fold increase in activity using a sub-band gap excitation with lambda > 225 nm. Our results suggest that internal photoemission, in which electrons are excited from Ag into diamond's conduction band, is an important process that extends the wavelength region beyond diamond's band gap. Other factors, including Ag-induced optical scattering and formation of graphitic impurities are also discussed. PMID- 29286231 TI - Electrochemical Investigation of the Interaction between Catecholamines and ATP. AB - The study of the colligative properties of adenosine 5'-triphosphate (ATP) and catecholamines has received the attention of scientists for decades, as they could explain the capabilities of secretory vesicles (SVs) to accumulate neurotransmitters. In this Article, we have applied electrochemical methods to detect such interactions in vitro, at the acidic pH of SVs (pH 5.5) and examined the effect of compounds having structural similarities that correlate with functional groups of ATP (adenosine, phosphoric acid and sodium phosphate salts) and catecholamines (catechol). Chronoamperometry and fast scan cyclic voltammetry (FSCV) provide evidence compatible with an interaction of the catechol and adenine rings. This interaction is also reinforced by an electrostatic interaction between the phosphate group of ATP and the protonated ammonium group of catecholamines. Furthermore, chronoamperometry data suggest that the presence of ATP subtlety reduces the apparent diffusion coefficient of epinephrine in aqueous media that adds an additional factor leading to a slower rate of catecholamine exocytosis. This adds another plausible mechanism to regulate individual exocytosis events to alter communication. PMID- 29286232 TI - Development of Cationic Quaternary Ammonium Sulfonamide Amino Lipids for Nucleic Acid Delivery. AB - Lipid nanoparticles (LNPs) currently comprise the most effective carrier class for the delivery of small RNAs. Among lipid carriers, charge-unbalanced lipids are relatively unexplored synthetically. Herein, we developed and evaluated a novel collection of compounds for small interfering RNA (siRNA) delivery, termed cationic quaternary ammonium sulfonamide amino lipids (CSALs). The formulated CSAL LNPs containing cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine, and lipid poly(ethylene glycol) exhibited biophysical property trends directly related to the CSAL chemical structure. Lead CSAL LNPs were identified using an siRNA delivery screen. Further chemical synthesis using a rational structure guided design showed that the head group structure could alter the pKa and other physical properties that modulated delivery efficacy. Shorter-chained dimethylamino head groups, acetate side chains, and higher tail carbon numbers were favorable for delivery. This led to a further study of A3-OAc-C2Me LNPs, which enabled in vivo delivery to normal mouse lungs and subcutaneous and orthotopic lung tumors. Incorporation of CSALs into liver-targeting formulations shifted the in vivo delivery of these carriers to the lungs. This study highlights the importance of the cationic lipid structure in LNPs and provides further design guidelines for nucleic acid carriers. PMID- 29286233 TI - Open-Framework Chalcogenide Showing Both Intrinsic Anhydrous and Water-Assisted High Proton Conductivity. AB - Proton-conducting materials have attracted increasing interest because of the promising technological applications as key components in various electrochemical devices. It is of great significance for technique application to seek superior proton-conducting materials, operating under both anhydrous and humidified conditions in a wide temperature range. Herein we demonstrate the proton conductance of an open-framework chalcogenide, (CH3NH3)2Ag4Sn3S8 (1), and the postsynthesis product 2 achieved by doping hydrochloric acid into 1. Hybrid 2 displays both intrinsic anhydrous and water-assisted high proton conductance, with sigma = 1.87 * 10-4 S.cm-1 at 463 K under N2 atmosphere and 1.14 * 10-3 S.cm 1 at 340 K and 99% relative humidity, and these conductivities are comparable to that in the efficient metal-organic frameworks-based proton-conducting materials. Moreover, hybrid 2 shows excellent thermal stability and long-term stability of proton conduction. PMID- 29286234 TI - Observation of Superconductivity in the LaNiO3/La0.7Sr0.3MnO3 Superlattice. AB - In the pursuit of high-temperature superconductivity like that in cuprates, artificial heterostructures or interfaces have attracted tremendous interest. It has been a long-sought goal to find similar unconventional superconductivity in nickelates. However, as far as we know, this has not yet been experimentally realized. To approach this objective, we synthesized a prototypical superlattice that consists of ultrathin LaNiO3 and La0.7Sr0.3MnO3 layers. Both zero resistance and the Meissner effect are observed using resistive and magnetic measurements of the superlattice. These are experimental indicators for superconductivity in new superconductors. X-ray linear dichroism causes the NiO2 planes to develop electron-occupied x2-y2 orbital order similar to that of cuprate-based superconductors. Our findings demonstrate that artificial interface engineering is suitable for investigating novel physical phenomena, such as superconductivity. PMID- 29286235 TI - Dual-Function Metal-Organic Framework-Based Wearable Fibers for Gas Probing and Energy Storage. AB - Metal-organic frameworks (MOFs) coupled with multiwalled carbon nanotubes (MWCNTs) have been developed with an ultrahigh sensitivity for hazardous gas monitoring. Both the MOF/MWCNT and as-derived metal oxides (MOs)/MWCNTs hybrid fibers deliver an ultralow detection limit for NO2 down to 0.1 ppm without external heating, and they can be further bent into different angles without loss of sensing performance. Also, a high specific capacitance of 110 F cm-3 can also be obtained for MO/MWCNT hybrid fibers, demonstrating promising application for integrated wearable devices. PMID- 29286236 TI - Enrichment and Recovery of Mammalian Cells from Contaminated Cultures Using Aqueous Two-Phase Systems. AB - This Article describes a density-based method for removing contaminants, including microorganisms and nonviable cells, from mammalian cell cultures using an aqueous two-phase system (ATPS). The properties of a 7% w/w polyethylene glycol (PEG)-11% w/w Ficoll ATPS can be tuned to prepare a biocompatible system that removes contaminants with little to no adverse effects on the viability or growth of the cultured cells after treatment. This system can be used to enrich cell culture populations for viable cells and to reduce the number of microorganism contaminants in a culture, which increases the chances of subsequent antibiotic treatments being successful. We test the effectiveness of our method in model contaminated cultures of both adherent (HeLa) and suspension (HL-60 II) mammalian cells contaminated with bacteria (E. coli) and yeast (S. cerevisiae). An average of 70.2 +/- 4.6% of HeLa cells added to the system are subsequently recovered, and 55.9 +/- 2.1% of HL-60 II cells are recovered. After sedimenting to the interface of the ATPS, these cells have an average viability of 98.0 +/- 0.2% and 95.3 +/- 2.2%, respectively. By removing unwanted cells, desired cell populations can be recovered, and cultures that would otherwise need to be discarded can continue to be used. PMID- 29286238 TI - 125Te NMR Probes of Tellurium Oxide Crystals: Shielding-Structure Correlations. AB - The local environments around tellurium atoms in a series of tellurium oxide crystals were probed by 125Te solid-state NMR spectroscopy. Crystals with distinct TeOn units (n from 3 to 6), including Na2TeO3, alpha-TeO2 and gamma TeO2, Te2O(PO4)2, K3LaTe2O9, BaZnTe2O7, and CsYTe3O8 were studied. The latter four were synthesized through a solid-state process. X-ray diffraction was used to confirm the successful syntheses. The 125Te chemical shift was found to exhibit a strong linear correlation with the Te coordination number. The 125Te chemical-shift components (delta11, delta22, and delta33) of the TeO4 units were further correlated to the O-Te-O-bond angles. With the aid of 125Te NMR, it is likely that these relations can be used to estimate the coordination states of Te atoms in unknown Te crystals and glasses. PMID- 29286239 TI - Suppression of Tumor Energy Supply by Liposomal Nanoparticle-Mediated Inhibition of Aerobic Glycolysis. AB - Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, and lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit the adenosine 5'-triphosphate (ATP) yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects because of their nonspecific delivery and distribution to nondiseased organs, low bioavailability, and a narrow therapeutic window. New strategies to enhance the biosafety and efficacy of these inhibitors are needed for moving them into clinical applications. To address this need, we developed a liposomal nanocarrier functionalized with a well-validated tumor-targeting peptide to specifically deliver the aerobic glycolysis inhibitor 3-bromopyruvate (3-BP) into the tumor tissue. The nanoparticles effectively targeted tumors after systemic administration into tumor-bearing mice and suppressed tumor growth by locally releasing 3-BP to inhibit the ATP production of the tumor cells. No overt side effects were observed in the major organs. This report demonstrates the potential utility of the nanoparticle-enabled delivery of an aerobic glycolysis inhibitor as an anticancer therapeutic agent. PMID- 29286237 TI - Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas. AB - The intracellular delivery of synthetic nucleic acids represents a major challenge in biotechnology and in biomedicine. Methods to deliver short, double stranded RNA to living cells are of particular interest because of the potential to engage the RNA interference machinery and to regulate mRNA expression. In this work, we describe novel RNA-polymer amphiphiles that assemble into spherical micellar nanoparticles with diameters of ca. 15-30 nm and efficiently enter live cells without transfection reagents. Each micelle consists of approximately 100 RNA strands forming a densely packed corona around a polymeric core. Importantly, the surface-displayed RNA remains accessible for hybridization with complementary RNA. Chemical modification of the termini of hybridized RNA strands enabled the display of small organic moieties on the outer surface of the micelle corona. We found that some of these modifications can have a tremendous impact on cellular internalization efficiencies. The display of hydrophobic dabcyl or stilbene units dramatically increased cell uptake, whereas hydrophilic neutral hydroxy or anionic phosphate residues were ineffective. Interestingly, neither of these modifications mediated noticeable uptake of free RNA oligonucleotides. We infer that their high density display on micellar nanoparticle surfaces is key for the observed effect; achieved with local effective surface concentrations in the millimolar range. We speculate that weak interactions with cell surface receptors that are amplified by the multivalent presentation of such modifications may be responsible. The installation of small molecule ligands on nanomaterial surfaces via hybridization of chemically modified oligonucleotides offers a simple and straightforward way to modulate cellular uptake of nanoparticles. Biological functionality of micellar RNA was demonstrated through the sequence-specific regulation of mRNA expression in HeLa cells. PMID- 29286241 TI - Multiplexed Detection of Tumor Markers with Multicolor Polymer Dot-Based Immunochromatography Test Strip. AB - There have been ongoing efforts to develop more sensitive and fast quantitative screening of cancer markers by use of fluorometric immunochromatographic test strips (ICTS) since the remarkable advances in fluorescent nanomaterials. Semiconducting polymer dots (Pdots) have recently emerged as a new type of biocompatible fluorescent probe with extraordinary brightness which is suitable for biological and clinical use. Here, we developed Pdot-based ICTS for quantitative rapid screening of prostate-specific antigen (PSA), alpha fetoprotein (AFP), and carcinoembryonic antigen (CEA) in 10 min. Through use of the ultrahigh fluorescence brightness of Pdots, this immunosensor enabled much better detection sensitivity (2.05, 3.30, and 4.92 pg/mL for PSA, AFP, and CEA, respectively), in which the detection limit is at least 2 orders of magnitude lower than that of conventional fluorometric ICTS. Furthermore, we performed proof-of-concept experiments for simultaneous determination of multiple tumor markers in a single test strip. These results demonstrated that this Pdot-based ICTS platform is a promising candidate for developing new generations of point-of care diagnostics. To the best of our knowledge, this is the first example of Pdot based ICTS with multiplexing capability. PMID- 29286242 TI - Photoelectrochemical Stripping Analysis. AB - Electrochemical stripping analysis (ECSA) is a promising method for metal ions detection. However, the low sensitivity and poor reproducibility limits its practical applications. The combination with other powerful detection techniques to address these concerns is highly desirable. Herein, the anodic stripping method and photoelectrochemical (PEC) technique are integrated into a new detection platform of PEC stripping analysis (PECSA) with bismuth vanadate (BiVO4) as both optoelectronic material and an electrochemical enrichment candidate. The new PECSA strategy presents high sensitivity and excellent reproducibility; in addition, inherited from the ECSA, this strategy also offers new selectivity dimensions through the potential-dependent response and thus implements reproducible, sensitive, and selective detection of silver ion (Ag+) in real biological and environmental samples. The success of PECAS strategy shed light on the rational combination of various analysis techniques for versatile applications. PMID- 29286243 TI - Effects of Resin Architecture and Protein Size on Nanoscale Protein Distribution in Ion-Exchange Media. AB - Knowledge of the nanoscale distribution of proteins in chromatographic resins is critical to our mechanistic understanding of separations performance. However, the nano- to mesoscale architecture of these materials is challenging to characterize using conventional techniques. Small-angle neutron scattering was used to probe (1) the nano- to mesoscale structure of chromatographic media and (2) protein sorption in these media in situ with protein-scale resolution. In particular, we characterize the effect of the architecture of cellulose-based and traditional and dextran-modified agarose-based ion-exchange resins on the nanoscale distribution of a relatively small protein (lysozyme) and two larger proteins (lactoferrin and a monoclonal antibody) at different protein loadings. Traditional agarose-based resins (SP Sepharose FF) can be envisioned as comprising long, thin strands of helical resin material around which the proteins adsorb, while higher static capacities are achieved in dextran-modified resins (SP Sepharose XL and Capto S) due to protein partitioning into the increased effective binding volume provided by the dextran. While protein size is shown not to affect the underlying sorption behavior in agarose-based resins such as SP Sepharose FF and XL, it plays an important role in the cellulose-based S HyperCel and the more highly cross-linked agarose-based Capto S, where size-exclusion effects prevent larger proteins from binding to the base matrix resin strands. Based on the data, we propose that entropic partitioning effects such as depletion forces may drive the observed protein crowding. In general, these observations elucidate the structure and point to the mechanism of protein partitioning in different classes of chromatographic materials, providing guidance for optimizing their performance. PMID- 29286244 TI - Kinetics of the Reactions between the Criegee Intermediate CH2OO and Alcohols. AB - Reactions of the simplest Criegee intermediate (CH2OO) with a series of alcohols have been studied in a flash photolysis flow reactor. Laser photolysis of diiodomethane at 355 nm in the presence of molecular oxygen was used to produce CH2OO, and the absolute number densities were determined as a function of delay time from analysis of broadband transient absorption spectra obtained using a pulsed LED. The kinetics for the reactions of CH2OO with methanol, ethanol, and 2 propanol were measured under pseudo-first-order conditions at 295 K, yielding rate constants of (1.4 +/- 0.4) * 10-13 cm3 s-1, (2.3 +/- 0.6) * 10-13 cm3 s-1, and (1.9 +/- 0.5) * 10-13 cm3 s-1, respectively. Complementary ab initio calculations were performed at the CCSD(T)/aug-cc-pVTZ//CCSD/cc-pVDZ level of theory to characterize stationary points on the reaction enthalpy and free energy surfaces and to elucidate the thermochemistry and mechanisms. The reactions proceed over free energy barriers of ~8 kcal mol-1 to form geminal alkoxymethyl hydroperoxides: methoxymethyl hydroperoxide (MMHP), ethoxymethyl hydroperoxide (EMHP), and isopropoxymethyl hydroperoxide (PMHP). The experimental and theoretical results are compared to reactions of CH2OO with other hydroxylic compounds, such as water and carboxylic acids, and trends in reactivity are discussed. PMID- 29286246 TI - Tactoid Annealing Improves Order in Self-Assembled Cellulose Nanocrystal Films with Chiral Nematic Structures. AB - The self-assembly process in cellulose nanocrystal (CNC) film formation was studied as a function of evaporation time. It is known that the total evaporation time of CNC dispersions affects the structure of the film obtained, but the extension of different phases of the evaporation has not been explored. By extending the evaporation time of CNC suspensions after the onset of liquid crystallinity, the homogeneity of the resulting films could be improved as observed by polarized optical microscopy and scanning electron microscopy. Here, we show that an intermediate stage of self-assembly, between phase separation and gel vitrification, called tactoid annealing, helps explain the discrepancies in order for chiral nematic CNC films dried at varying evaporation times. This intermediate stage of self-assembly may be useful for designing highly ordered and homogenous CNC-based materials. PMID- 29286245 TI - Corymbulosins I-W, Cytotoxic Clerodane Diterpenes from the Bark of Laetia corymbulosa. AB - The isolation studies of a crude MeOH/CH2Cl2 (1:1) extract (N005829) of the bark of Laetia corymbulosa yielded 15 new clerodane diterpenes, designated corymbulosins I-W (1-15), as well as four known diterpenes, 16-19. The structures of 1-15 were characterized on the basis of extensive 1D and 2D NMR and HRMS analyses. The absolute configurations of newly isolated compounds 1-15, as well as known 16-19, which were reported previously with only relative configurations, were determined through ECD experiments, X-ray analysis, chemical methods, including Mosher esterification, and comparison of their spectroscopic data. The isolated compounds were evaluated for cytotoxicity against human cancer cell lines. Flow cytometric and immunocytochemical observations of cells treated with cytotoxic clerodanes demonstrated that the chromatin was fragmented and dispersed with formation of apoptotic microtubules. PMID- 29286247 TI - Organocatalytic Asymmetric Vinylogous Aldol Reaction of Allyl Aryl Ketones to Silyl Glyoxylates. AB - A direct organocatalytic asymmetric vinylogous aldol reaction of allyl aryl ketones to silyl glyoxylates has been developed through the bifunctional catalyst, giving the alpha-hydroxysilanes with excellent enantioselectivity (up to 95% ee) and in high yields (up to 96%). The success of this catalytic methodology offers an opportunity to tackle the problems in the nucleophilic addition to acylsilanes. To activate both allyl aryl ketones and acylsilanes, the utilized bifunctional catalyst was an ideal organocatalyst in this unprecedented transformation. PMID- 29286248 TI - Triple Nucleophilic Attack of Nitromethane on (2-Iminoaryl)divinyl Ketones: A Domino Synthetic Strategy for Hexahydrophenanthridinones. AB - A novel domino reaction of (2-iminoaryl)divinyl ketones with nitromethane was developed for the efficient synthesis of hexahydrophenanthridin-9(5H)-ones. The reaction proceeded smoothly from readily available starting materials under mild reaction conditions to construct three new bonds and two rings with high diastereoselectivities in good to excellent yields in a single step. A mechanism is proposed, involving a stepwise double Michael addition/aza-Henry reaction cascade, and in this transformation, nitromethane acts as a trinucleophile. PMID- 29286249 TI - Destabilization of DNA G-Quadruplexes by Chemical Environment Changes during Tumor Progression Facilitates Transcription. AB - DNA G-quadruplex formation is highly responsive to surrounding conditions, particularly K+ concentration. Malignant cancer cells have a much lower K+ concentration than normal cells because of overexpression of a K+ channel; thus, G-quadruplexes may be unstable in cancer cells. Here, we physicochemically investigated how changes in intracellular chemical environments in vitro and in cells influence G-quadruplex formation and transcription during tumor progression. In vitro, the stable G-quadruplex formation inhibits transcription in a solution containing 150 mM KCl (normal condition). As K+ concentration decreases, which decreases G-quadruplex stability, transcript production from templates with G-quadruplex-forming potential increases. In normal cells, the trend in transcript productions was similar to that in in vitro experiments, with transcription efficiency inversely correlated with G-quadruplex stability. Interestingly, higher transcript levels were produced from templates with G quadruplex-forming potential in Ras-transformed and highly metastatic breast cancer cells (MDA-MB-231) than in nontransformed and control MCF-7 cells. Moreover, the amount of transcript produced from G-quadruplex-forming templates decreased upon addition of siRNA targeting KCNH1 mRNA, which encodes a potassium voltage-gated channel subfamily H member 1 (KV10.1). Importantly, G-quadruplex dissociation during tumor progression was observed by immunofluorescence using a G-quadruplex-binding antibody in cells. These results suggest that in normal cells, K+ ions attenuate the transcription of certain oncogenes by stabilizing G quadruplex structures. Our findings provide insight into the novel mechanism of overexpression of certain G-rich genes during tumor progression. PMID- 29286250 TI - 7alpha,20-Epoxy-ent-kaurane Diterpenoids from the Aerial Parts of Isodon pharicus. AB - A phytochemical investigation of an ethyl acetate extract of the aerial parts of Isodon pharicus led to the isolation of 21 new 7alpha,20-epoxy-ent-kaurane diterpenoids, pharicins C-W (1-21), and 29 known (22-50) analogues. The structural characterization of 1-21 and assignment of their relative configurations were accomplished by spectroscopic data interpretation, while the structures of 1 and 16 were confirmed by X-ray crystallography. The absolute stereostructure of 1 was confirmed by electronic circular dichroism data analysis. Twenty-five of the diterpenoids were screened for their cytotoxic activities against a panel of tumor cell lines, including HL-60, SMMC-7721, A 549, MCF-7, and SW-480. Compounds 11, 16, 38, and 48 exhibited inhibitory activities against these tumor cell lines with IC50 values ranging from 1.01 to 9.62 MUM, while 2, 15, 29, and 47 exhibited moderate cytotoxic potency. PMID- 29286251 TI - Arylsulfonyl Radical Triggered 1,6-Enyne Cyclization: Synthesis of gamma-Lactams Containing Alkenyl C-X Bonds. AB - Cascade radical cyclization of 1,6-enynes for the synthesis of biologically important gamma-lactams containing alkenyl C-X bonds is reported. In these radical cascade processes, three new chemical bonds, including C-S, C-C, and C-X bonds, are formed in one step. The method is attractive and valuable due to its mild reaction conditions, broad substrate scope, and the importance of the corresponding gamma-lactam products. PMID- 29286252 TI - Addition of N-Heterocyclic Carbene Catalyst to Aryl Esters Induces Remote C-Si Bond Activation and Benzylic Carbon Functionalization. AB - Through the incorporation of a silicon atom to an aryl carboxylic ester substrate, the resulting C-Si bond can be activated via the addition of a carbene catalyst on a remote site. This strategy allows for efficient functionalization of the benzylic sp3-carbons of aryl carboxylic esters. PMID- 29286253 TI - Quantitative Analysis of Situation Awareness (QASA): modelling and measuring situation awareness using signal detection theory. AB - This paper presents a model of situation awareness (SA) that emphasises that SA is necessarily built using a subset of available information. A technique (Quantitative Analysis of Situation Awareness - QASA), based around signal detection theory, has been developed from this model that provides separate measures of actual SA (ASA) and perceived SA (PSA), together with a feature unique to QASA, a measure of bias (information acceptance). These measures allow the exploration of the relationship between actual SA, perceived SA and information acceptance. QASA can also be used for the measurement of dynamic ASA, PSA and bias. Example studies are presented and full details of the implementation of the QASA technique are provided. Practitioner Summary: This paper presents a new model of situation awareness (SA) together with an associated tool (Quantitative Analysis of Situation Awareness - QASA) that employs signal detection theory to measure several aspects of SA, including actual and perceived SA and information acceptance. Full details are given of the implementation of the tool. PMID- 29286254 TI - Patterns of Circulating Corticosterone in a Population of Rattlesnakes Afflicted with Snake Fungal Disease: Stress Hormones as a Potential Mediator of Seasonal Cycles in Disease Severity and Outcomes. AB - Snake fungal disease (SFD) is an emerging threat to snake populations in the United States. Fungal pathogens are often associated with a physiological stress response mediated by the hypothalamo-pituitary-adrenal axis (HPA), and afflicted individuals may incur steep coping costs. The severity of SFD can vary seasonally; however, little is known regarding (1) how SFD infection relates to HPA activity and (2) how seasonal shifts in environment, life history, or HPA activity may interact to drive seasonal patterns of infection severity and outcomes. To test the hypothesis that SFD is associated with increased HPA activity and to identify potential environmental or physiological drivers of seasonal infection, we monitored baseline corticosterone, SFD infection severity, foraging success, body condition, and reproductive status in a field-active population of pigmy rattlesnakes. Both plasma corticosterone and the severity of clinical signs of SFD peaked in the winter. Corticosterone levels were also elevated in the fall before the seasonal rise in SFD severity. Severely symptomatic snakes were in low body condition and had elevated corticosterone levels compared to moderately infected and uninfected snakes. The monthly mean severity of SFD in the population was negatively related to population-wide estimates of body condition and temperature measured in the precedent month and positively correlated with corticosterone levels measured in the precedent month. Symptomatic females were less likely to enter reproductive bouts compared to asymptomatic females. We propose the hypothesis that the seasonal interplay among environment, host energetics, and HPA activity initiates trade-offs in the fall that drive the increase in SFD prevalence, symptom severity, and decline in condition observed in the population through winter. PMID- 29286256 TI - The Sequence Preference of Gamma-Radiation-Induced Damage in End-Labeled DNA after Heat Treatment. AB - In this work, we examined the DNA sequence preference of gamma-radiation-induced DNA damage in purified DNA sequences after heat treatment. DNA was fluorescently end-labeled and gamma-radiation-induced DNA cleavage was examined using capillary electrophoresis with laser-induced fluorescence detection. Our findings provide evidence that gamma-radiation-induced DNA damage to end-labeled DNA is nonrandom and has a sequence preference. The degree of cleavage was quantified at each nucleotide, and we observed that preferential cleavage occurred at C nucleotides with lesser cleavage at G nucleotides, while being very low at T nucleotides. The differences in percentage cleavage at individual nucleotides ranged up to sixfold. The DNA sequences surrounding the most intense radiation-induced DNA cleavage sites were examined and a consensus sequence 5'-AGGC*C (where C* is the cleavage site) was found. The highest intensity gamma-radiation-induced DNA cleavage sites were found at the dinucleotides, 5'-GG*, 5'-GC*, 5'-C*C and 5'-G*G and at the trinucleotides, 5'-GG*C, 5'-TC*A, 5'-GG*G and 5'-GC*C. These findings have implications for our understanding of ionizing radiation-induced DNA damage. PMID- 29286255 TI - miR-106b-responsive gene landscape identifies regulation of Kruppel-like factor family. AB - MicroRNA dysregulation is a common feature of cancer and due to the promiscuity of microRNA binding this can result in a wide array of genes whose expression is altered. miR-106b is an oncomiR overexpressed in cholangiocarcinoma and its upregulation in this and other cancers often leads to repression of anti tumorigenic targets. The goal of this study was to identify the miR-106b regulated gene landscape in cholangiocarcinoma cells using a genome-wide, unbiased mRNA analysis. Through RNA-Seq we found 112 mRNAs significantly repressed by miR-106b. The majority of these genes contain the specific miR-106b seed-binding site. We have validated 11 genes from this set at the mRNA level and demonstrated regulation by miR-106b of 7 proteins. Combined analysis of our miR 106b-regulated mRNA data set plus published reports indicate that miR-106b binding is anchored by G:C pairing in and near the seed. Novel targets Kruppel like factor 2 (KLF2) and KLF6 were verified both at the mRNA and at the protein level. Further investigation showed regulation of four other KLF family members by miR-106b. We have discovered coordinated repression of multiple members of the KLF family by miR-106b that may play a role in cholangiocarcinoma tumor biology. PMID- 29286257 TI - Synergy Theory in Radiobiology. AB - Customized open-source software is used to characterize, exemplify, compare and critically evaluate mathematical/computational synergy analysis methods currently used in biology, and used or potentially applicable in radiobiology. As examples, we reanalyze some published results on murine Harderian gland tumors and on in vitro chromosome aberrations induced by exposure to single-ion radiations that simulate components of the galactic cosmic ray field. Baseline no-synergy/no antagonism-mixture dose-effect relationships are calculated for corresponding mixed fields. No new experimental results are presented. Synergy analysis of effects due to a mixed radiation field whose components' individual dose-effect relationships are highly curvilinear should not consist of simply comparing to the sum of the components' effects. Such curvilinearity must often be allowed for in current radiobiology, especially when studying possible non-targeted ("bystander") effects. Consequently, many different synergy analysis theories are currently used in biology to replace simple effect additivity. We give evidence that for most synergy experiments and observations, incremental effect additivity is the most appropriate replacement. It has a large domain of applicability, being useful even when pronounced individual dose-effect relationship curvilinearity is a confounding factor. It allows calculation of 95% confidence intervals for baseline mixture dose-effect relationships taking into account parameter correlations; if non-targeted effects are important this gives much tighter intervals than neglecting the correlations. It always obeys two consistency conditions that simple effect additivity usually fails to obey: a "mixture of mixtures principle" and the standard "sham mixture principle". The mixture of mixtures principle is important in radiobiology because even nominally single-ion radiations are usually mixtures when they strike the biological target, due to intervening material. It is not yet clear whether mixing galactic cosmic ray components sometimes leads to statistically significant synergy for animal tumorigenesis. The substantial limitations of synergy theories are sometimes overlooked, and they warrant further study. PMID- 29286258 TI - A Survey of Tick Species in a Recently Reintroduced Elk ( Cervus canadensis) Population in Southeastern Kentucky, USA, with Potential Implications for Interstate Translocation of Zoonotic Disease Vectors. AB - In the late 20th century, elk ( Cervus canadensis) were reintroduced into southeastern Kentucky, US. This population has since been used as a stock population for additional elk reintroductions in other eastern states. Although reintroduction and translocation practices are effective, they can disseminate vectors and pathogens. Therefore, we surveyed tick species residing on elk hosts a decade after elk reintroduction in Kentucky by examining 263 captured individuals (female=86; male=177) from 2011 to 2013. A total of 1,617 ticks were collected from 255 elk. We found five tick species: American dog ( Dermacentor variabilis), Gulf Coast ( Amblyomma maculatum), winter ( Dermacentor albipictus), deer ( Ixodes scapularis), and Lone Star ( Amblyomma americanum). The most prevalent ticks were winter tick (52.3%) and American dog tick (42.1%). We found no difference between female and male elk in mean intensity of American dog tick (mean=2.6, 95% confidence limits: -2.6, 2.7; P=0.701) or winter tick (mean=3.28, 95% confidence limits: -2.21, 2.07; P=0.274). Our findings demonstrated that the elk population acts as host to a diversity of tick species, suggested a broader distribution of tick species than previously reported in Kentucky, and highlighted the potential for inadvertent spread of ticks through translocation and reintroduction efforts, even on a local scale. PMID- 29286260 TI - Molecular Characterization of Avian Paramyxovirus Types 4 and 8 Isolated from Wild Migratory Waterfowl in Mongolia. AB - Avian paramyxoviruses (APMVs) constitute some of the most globally prevalent avian viruses and are frequently isolated from wild migratory bird species. Using 1,907 fresh fecal samples collected during the 2012 avian influenza surveillance program, we identified two serotypes of APMV: APMV-4 ( n=10) and APMV-8 ( n=1). Sequences for these isolates phylogenetically clustered with Asian APMV-4 and APMV-8 recently isolated from wild birds in Korea, Japan, China, and Kazakhstan. Analysis by DNA barcoding indicated that the Mongolian APMV-4 and APMV-8 strains were isolated from Anseriformes species including Mallards ( Anas platyrhynchos) and Whooper Swans ( Cygnus cygnus). The close genetic relatedness to Asian isolates, and to similar host species, suggested that wild bird species in the Anatidae family might play an important role as a natural reservoir in the spread of APMV-4 and APMV-8. However, we did not find conclusive evidence to support this hypothesis owing to the limited number of strains that could be isolated. Enhanced surveillance of poultry and wild bird populations in Asia is therefore crucial for the understanding of global AMPV transmission, ecology, evolution, and epidemiology. PMID- 29286261 TI - Molecular Detection of Mycobacterium avium avium and Mycobacterium genavense in Feces of Free-living Scarlet Macaws ( Ara macao) in Costa Rica. AB - We conducted a study of the two main populations of free-living Scarlet Macaws ( Ara macao) in Costa Rica to detect the causal agents of avian tuberculosis using noninvasive techniques. We analyzed 83 fecal samples collected between February and May 2016 from the central and southern Pacific areas in the country. Using PCR, we first amplified the 16S region of the ribosomal RNA, common to all Mycobacterium species. Then, products from the insertion sequence IS901 and from a 155-base pair DNA fragment evidenced the presence of the avian pathogenic Mycobacterium avium subsp. avium strain and a Mycobacterium genavense strain, respectively. Seven of 38 (18%) samples collected in the central Pacific area were positive for Mycobacterium spp. and 3 of 38 (8%) were positive for M. genavense, with one sample amplifying regions for both. Two of the 45 (4%) samples collected in the south Pacific area of Costa Rica were positive to M. a. avium. Our detection of avian tuberculosis pathogens in free-living Scarlet Macaws suggests that free-living macaws could excrete in their feces M. genavense, bird-pathogenic M. a. avium, and possibly other Mycobacteria (not detected in our study). PMID- 29286262 TI - Plague in a Colony of Gunnison's Prairie Dogs ( Cynomys gunnisoni) Despite Three Years of Infusions of Burrows with 0.05% Deltamethrin to Kill Fleas. AB - At Valles Caldera National Preserve in New Mexico, US, infusing Gunnison's prairie dog ( Cynomys gunnisoni) burrows with an insecticide dust containing 0.05% deltamethrin killed fleas which transmit bubonic plague. The reduction in the number of fleas per prairie dog was significant and dramatic immediately after infusions, with a suggestion that the reduction persisted for as long as 12 mo. Despite the lower flea counts, however, a plague epizootic killed >95% of prairie dogs after 3 yr of infusions (once per year). More research is necessary for a better understanding of the efficacy of insecticide dusts at lowering flea counts and protecting prairie dogs from plague. PMID- 29286264 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: week in review - ambulatory pediatric cardiology. AB - The Seventh World Congress of Pediatric Cardiology was held in Barcelona in July, 2017. The central philosophy of the congress was "bridging together" all major specialties in the field. This article summarises the highlights of the meeting as it relates to ambulatory paediatric cardiology. There is a now a more unified approach to children with CHD, including assessment of neuro-developmental outcomes. The new World Heart Foundation criteria for the diagnosis of rheumatic fever remain controversial. PMID- 29286263 TI - Bridging together: teamwork in caring for the family touched by CHD. AB - In the opening plenary address of the 2017 7th World Congress of Pediatric Cardiology and Cardiac Surgery the author, who represented the World Society for Pediatric and Congenital Heart Surgery at the Congress and is currently the Society's president, described the history of the formation of the World Society. He listed accomplishments of the World Society including publication of the only journal devoted to congenital cardiac surgery, development of a global database, and convening several international conferences dating back to the inaugural conference in Washington, DC in 2007. The general theme of the presentation is the importance of teamwork in managing patients and families with CHD. Challenges facing congenital heart teams are discussed including the fragility of cardiac programmes, that can be heavily influenced by the administrative structure of a paediatric hospital; the difficulty of recruiting skilled surgeons into the field as training in general cardiothoracic surgery contracts and general surgery becomes predominantly laparoscopic with few open procedures; and increasing barriers to the international movement of surgeons including the opportunities for United States of America-based surgeons to acquire international experience at leading global centres. Finally, the author focusses on the danger that the team approach poses to maintaining empathy and emotional support for the family with CHD undergoing a stressful hospitalisation. He discusses strategies to optimise holistic support of the child and family. PMID- 29286265 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: Week in Review: heart failure, transplantation, and pulmonary hypertension. AB - The heart failure, heart transplantation, and pulmonary hypertension workgroups of the Scientific Committee were honoured to be asked to plan a full slate of sessions at the 2017 World Congress of Pediatric Cardiology and Cardiac Surgery. In all there were 35 oral platform presentations, a further 14 oral platform presentations in "Bridging Together" sessions with other workgroups/specialties, a terrific debate about transplant listing in adult CHD patients, and a further 23 oral abstract presentations. The speakers were clear and concise, the research presented was ground-breaking, and the global representation was evident. PMID- 29286267 TI - Landmark lecture on cardiology: the quest for the ultimate team in health care - what we can learn from musicians about leadership, innovation, and teambuilding? AB - The importance of teamwork is being increasingly recognised in healthcare. Nonetheless, it is equally recognised that teamwork is difficult. In this article, I explore whether we can learn lessons from musicians, orchestras, and conductors as we build our teams. The evolution of the role of the conductor provides useful lessons on leadership and the evolving role of the members of the orchestra on how team members can contribute to a shared outcome. The uncertainty of jazz provides useful lessons for innovation in an increasingly turbulent healthcare environment. PMID- 29286266 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: week in review - adults with CHD. AB - For the first time in 2017 adults with CHD was included in the World Congress of Pediatric Cardiology & Cardiac Surgery. With growing numbers and more complex patients reaching adulthood, there is a growing need for more attention to this subspecialty. Although survival is excellent and now over 90% of patients reach adulthood, many have residual problems and complications. Heart failure and arrhythmias are most commonly encountered. Life-expectancy is nearly normal for mild lesions, but remains reduced in moderate-complex lesions and re interventions are often needed. As most patients want to live a normal life, sports participation and pregnancy become very important issues. Finally, although innovative treatments are being developed, including for end-stage heart failure, we have to refine strategies for optimal care, including during the end stage lives of our patients. This article provides an overview of a selection of topics in the field of adults with CHD presented during the 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery (WCPCCS) in Barcelona. PMID- 29286268 TI - Landmark lecture in nursing: a life-cycle perspective on CHD: What happens beyond your clinic? AB - Over the past decades, survival of patients with CHD improved significantly, making it a life-cycle disease. Hence, there is a need for a workforce that can take up the care for afflicted individuals in the different phases of the life spectrum. Each life phase is associated with specific challenges. Topics that should receive more attention in clinical care or in CHD research are parenting styles of parents of children, transfer and transition of adolescents, cumulative burden of injury in the brain in adults, and geriatric care for older persons with CHD. Nurses, along with other healthcare professionals, will play a pivotal role in building up expertise in these areas and taking up these challenges. PMID- 29286269 TI - Landmark lecture: Perloff lecture: Tribute to Professor Joseph Kayle Perloff and lessons learned from him: aortopathy in adults with CHD. AB - Marfan syndrome, bicuspid aortic valve, and/or coarctation of the aorta are associated with medial abnormalities of the ascending aortic or para-coarctation aorta. Medial abnormalities in the ascending aorta are prevalent in other type of patients with a variety of CHDs such as single ventricle, persistent truncus arteriosus, transposition of the great arteries, hypoplastic left heart syndrome, and tetralogy of Fallot, encompassing a wide age range and may predispose to dilatation, aneurysm, and rapture necessitating aortic valve and root surgery. These CHDs exhibit ongoing dilatation of the aortic root and reduced aortic elasticity and increased aortic stiffness that may relate to intrinsic properties of the aortic root. These aortic dilatation and increased stiffness can induce aortic aneurysm, rapture of the aorta, and aortic regurgitation, but also provoke left ventricular hypertrophy, reduced coronary artery flow, and left ventricular failure. Therefore, a new clinical entity can be used to call this association of aortic pathophysiological abnormality, aortic dilation, and aorto-left ventricular interaction - "aortopathy". PMID- 29286270 TI - Landmark lecture on cardiac intensive care and anaesthesia: continuum and conundrums. AB - Cardiac anesthesia and critical care provide an important continuum of care for patients with congenital heart disease. Clinicians in both areas work in complex environments in which the interactions between humans and technology is critical. Understanding our contributions to outcomes (modifiable risk) and our ability to perceive and predict an evolving clinical state (low failure-to-predict rate) are important performance metrics. Improved methods for capturing continuous physiologic signals will allow for new and interactive approaches to data visualization, and for sophisticated and iterative data modeling that will help define a patient's phenotype and response to treatment (precision physiology). PMID- 29286271 TI - Landmark lecture on interventional cardiology: interventional cardiac catheterisation for CHD: the past, present, and the future. AB - CHD affects millions of patients worldwide. Interventional therapies for CHD goes back to the mid-1960s when Bill Rashkind performed balloon atrial septostomy on a cyanotic baby with transposition of the great vessels. This was followed by development of balloon catheters to perform balloon valvuloplasties and angioplasties in the early to late 1980s. Although King and Mills performed the first transcatheter closure of secundum atrial septal defect in the mid-1970s, this procedure was better realised in the mid-1990s. More intracardiac defect closures were performed in the late 1990s and early 2000. This brings us to the current era of percutaneous valve implantation as developed by Bonhoeffer. In this paper, we will discuss the past, present, and future of interventional cardiac catheterisation for CHD patients. PMID- 29286272 TI - Landmark lecture on surgery: paediatric cardiothoracic surgery - training the next generation of congenital heart surgeons. AB - : Introduction Recent changes in surgical education have had an impact on our congenital training programmes. The mandate of the 8-hour workweek, a rapidly expanding knowledge base, and a host of other mandates has had an impact on the readiness of the fellows who are entering congenital programmes. To understand these issues completely, we interviewed the top congenital experts in the United States of America. The purpose of this paper is to share their insight and offer suggestions to address these challenges. METHODS: We used a qualitative thematic analysis approach and performed phone interviews with the top five congenital experts in the United States of America. RESULTS: Experts unanimously felt that duty-hour restrictions have negatively affected congenital training programmes in the following ways: current fellows do not seem as conditioned as fellows in the past, patient handoffs are not consistent with excellent performance, the mentor mentee relationship has been affected by duty-hour restrictions, and fellows may be less prepared for real-world practice. Three positive themes emerged in response to duty-hour restrictions: fellows appear to be doing less menial task work, fellows are now better rested for learning, and we are attracting more individuals into the speciality. Experts agreed that congenital fellowships should be increased to 2 years. There was support for both the traditional and integrated residency pathways. Discussion We are in a new era of education and must work together to overcome the challenges that have arisen in recent years. PMID- 29286273 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: week in review: imaging. AB - The Imaging Program at the 7th World Congress highlighted the versatility and diagnostic power of the current and upcoming imaging tools in Pediatric Cardiology and Cardiac Surgery. Several experts presented interesting as well as practical data on the use of 2D and 3D Echocardiography, magnetic resonance imaging and computed tomography in the fetus, child, and adult with congenital heart disease. Bridging sessions coupled use of these imaging modalities and screening practices in patients with acquired heart disease. Hot topics included nomenclature of ventricular septal defects, the challenging diagnosis of double outlet right ventricle, cardiac tumors, and imaging of aortapathies. Several talks concentrated on the quantitative assessment of ventricular function and reviewed numerous exciting new modalities that currently serve as research tools. In summary, Imaging Sessions truly represented how far we have advanced the field of Imaging in Pediatric Cardiology and Cardiovascular Surgery. PMID- 29286274 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: week in review - interventional cardiology. AB - The interventional cardiology track at the 7th World Congress of Pediatric Cardiology and Cardiac Surgery reflects the pivotal position of transcatheter interventions in the future of our speciality. The highlights of the week are outlined in this review. PMID- 29286275 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: week in review: congenital cardiac anaesthesia. AB - The seventh meeting of the World Congress of Pediatric Cardiology and Cardiac Surgery was an opportunity for healthcare professionals from around the world to meet and discuss current issues affecting patients with acquired and CHD. A dedicated anaesthesia track facilitated the exchange of ideas and fostered many new friendships. This review highlights the congenital cardiac anaesthesia track and the involvement of the Congenital Cardiac Anesthesia Society in the congress. PMID- 29286276 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: week in review - cardiac surgery. AB - The 2017 Seventh World Congress was held in Barcelona, Spain, 16-21 July. The week in review for this meeting is presented in the current issue of Cardiology in the Young, and herein we discuss the surgical highlights of the programme. PMID- 29286278 TI - The 2017 Seventh World Congress of Paediatric Cardiology and Cardiac Surgery: "The Olympics of our Profession". AB - The 1st World Congress of Paediatric Cardiology was held in London, United Kingdom, in 1980, organised by Dr Jane Somerville and Prof. Fergus Macartney. The idea was that of Jane Somerville, who worked with enormous energy and enthusiasm to bring together paediatric cardiologists and surgeons from around the world. The 2nd World Congress of Paediatric Cardiology took place in New York in 1985, organised by Bill Rashkind, Mary Ellen Engle, and Eugene Doyle. The 3rd World Congress of Paediatric Cardiology was held in Bangkok, Thailand, in 1989, organised by Chompol Vongraprateep. Although cardiac surgeons were heavily involved in these early meetings, a separate World Congress of Paediatric Cardiac Surgery was held in Bergamo, Italy, in 1988, organised by Lucio Parenzan. Thereafter, it was recognised that surgeons and cardiologists working on the same problems and driven by a desire to help children would really rather meet together. A momentous decision was taken to initiate a Joint World Congress of Paediatric Cardiology and Cardiac Surgery. A steering committee was established with membership comprising the main organisers of the four separate previous Congresses and additional members were recruited in an effort to achieve numerical equality of cardiologists and surgeons and a broad geographical representation. The historic 1st "World Congress of Paediatric Cardiology and Cardiac Surgery" took place in Paris in June, 1993, organised by Jean Kachaner. The next was to be held in Japan, but the catastrophic Kobe earthquake in 1995 forced relocation to Hawaii in 1997. Then followed Toronto, Canada, 2001, organised by Bill Williams and Lee Benson; Buenos Aires, Argentina, 2005, organised by Horatio Capelli and Guillermo Kreutzer; Cairns, Australia, 2009, organised by Jim Wilkinson; Cape Town, South Africa, 2013, organised by Christopher Hugo-Hamman; and Barcelona, Spain, 2017, organised by Sertac Cicek. With stops in Europe (1993), Asia-Pacific (1997), North America (2001), South America (2005), Australia (2009), Africa (2013), and Europe again (2017), in 2021, The World Congress of Paediatric Cardiology and Cardiac Surgery will be held for the first time in the continental United States. 1 The 8th World Congress of Paediatric Cardiology and Cardiac Surgery will be held in Washington DC, United States of America, 19-24 September, 2021, and will be organised by Jeffrey P. Jacobs and Gil Wernovsky. Mitchell I. Cohen served as the Scientific Program Co-Chair for the 2017 World Congress of Paediatric Cardiology and Cardiac Surgery, and he will again serve as the Scientific Program Co-Chair for the 2021 World Congress of Paediatric Cardiology and Cardiac Surgery along with Kathyrn Dodds RN, MSN, CRNP. Information about the upcoming 8th World Congress of Paediatric Cardiology and Cardiac Surgery can be found at www.WCPCCS2021.org. PMID- 29286277 TI - Nomenclature for congenital and paediatric cardiac disease: the International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Iteration of the International Classification of Diseases (ICD-11). AB - An internationally approved and globally used classification scheme for the diagnosis of CHD has long been sought. The International Paediatric and Congenital Cardiac Code (IPCCC), which was produced and has been maintained by the International Society for Nomenclature of Paediatric and Congenital Heart Disease (the International Nomenclature Society), is used widely, but has spawned many "short list" versions that differ in content depending on the user. Thus, efforts to have a uniform identification of patients with CHD using a single up to-date and coordinated nomenclature system continue to be thwarted, even if a common nomenclature has been used as a basis for composing various "short lists". In an attempt to solve this problem, the International Nomenclature Society has linked its efforts with those of the World Health Organization to obtain a globally accepted nomenclature tree for CHD within the 11th iteration of the International Classification of Diseases (ICD-11). The International Nomenclature Society has submitted a hierarchical nomenclature tree for CHD to the World Health Organization that is expected to serve increasingly as the "short list" for all communities interested in coding for congenital cardiology. This article reviews the history of the International Classification of Diseases and of the IPCCC, and outlines the process used in developing the ICD-11 congenital cardiac disease diagnostic list and the definitions for each term on the list. An overview of the content of the congenital heart anomaly section of the Foundation Component of ICD-11, published herein in its entirety, is also included. Future plans for the International Nomenclature Society include linking again with the World Health Organization to tackle procedural nomenclature as it relates to cardiac malformations. By doing so, the Society will continue its role in standardising nomenclature for CHD across the globe, thereby promoting research and better outcomes for fetuses, children, and adults with congenital heart anomalies. PMID- 29286279 TI - Key events in the history of cardiac surgery and paediatric cardiology. AB - In this report, the authors prepared an opinion poll regarding the most important people, events, technologies, concepts, discoveries, and therapies in paediatric cardiology and cardiac surgery. The results were presented in continuous slide show format at the 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery (WCPCCS 2017), Barcelona, Spain. The presentation (under international copyright) is made available herein for educational purposes. PMID- 29286280 TI - The 2017 Seventh World Congress of Pediatric Cardiology & Cardiac Surgery: Week in review: electrophysiology. PMID- 29286281 TI - Molecular structure of human KATP in complex with ATP and ADP. AB - In many excitable cells, KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward rectifier K+ channel Kir6.2, in the presence of Mg2+ and nucleotides. These structures, referred to as quatrefoil and propeller forms, were determined by single-particle cryo-EM at 3.9 A and 5.6 A, respectively. In both forms, ATP occupies the inhibitory site in Kir6.2. The nucleotide-binding domains of SUR1 are dimerized with Mg2+-ATP in the degenerate site and Mg2+-ADP in the consensus site. A lasso extension forms an interface between SUR1 and Kir6.2 adjacent to the ATP site in the propeller form and is disrupted in the quatrefoil form. These structures support the role of SUR1 as an ADP sensor and highlight the lasso extension as a key regulatory element in ADP's ability to override ATP inhibition. PMID- 29286283 TI - Optoelectronic figure of merit of a metal nanoparticle - quantum dot (MNP-QD) hybrid molecule for assessing its suitability for sensing applications. AB - Recently, many have studied various configurations of metal nanoparticle-quantum dot (MNP-QD) hybrid molecules based on different metals and tunable parameters. In this paper, we aim to incite the interest in using MNP-QD nanohybrids, which possess sensing capabilities superior to those of the individual constituents, for sensing applications that rely on scattered light. When assessing whether a given MNP-QD configuration is suited for an application, sometimes it is hard to assess the pros and cons of a given configuration against other candidates. Here we propose a simple, elegant relative figure of merit (RFoM), which focuses on maximizing the scattered intensity and the refractive index sensitivity of the nanohybrid, to rank the suitability of viable MNP-QD configurations for a particular sensing application. We use the proposed RFoM to analyse the optical spectra of noble, transition, post transition and alkali metal based MNP-QD nanohybrids using the representative metals Au, Ag, Cu, Al and Na, adopting a generalized nonlocal optical response (GNOR) method based cavity QED approach. Based on our observations, we suggest how the usage of MNP-QD nanohybrids could improve the conventionally studied tumour targeting applications. Moreover, we propose potential substitutes for noble metals conventionally considered for MNP QD nanohybrids. PMID- 29286282 TI - An assessment of emotional intelligence in emergency medicine resident physicians. AB - Objectives: To define the emotional intelligence (EI) profile of emergency medicine (EM) residents, and identify resident EI strengths and weaknesses. Methods: First-, second-, and third-year residents (post-graduate years [PGY] 1, 2, and 3, respectively) of Thomas Jefferson University Hospital's EM Program completed the Emotional Quotient Inventory (EQ-i 2.0), a validated instrument offered by Multi-Health Systems. Reported scores included total mean EI, 5 composite scores, and 15 subscales of EI. Scores are reported as means with 95% CIs. The unpaired, two-sample t-test was used to evaluate differences in means. Results: Thirty-five residents completed the assessment (response rate 97.2%). Scores were normed to the general population (mean 100, SD 15). Total mean EI for the cohort was 103 (95%CI,100-108). EI was higher in female (107) than male (101) residents. PGY-2s demonstrated the lowest mean EI (95) versus PGY-1s (104) and PGY-3s (110). The difference in PGY-3 EI (110; 95%CI,103-116) and PGY-1 EI (95, 95%CI,87-104) was statistically significant (unpaired t-test, p<0.01). Highest composite scores were in interpersonal skills (107; 95%CI,100-108) and stress management (105; 95%CI,101-109). Subscale cohort strengths included self actualization (107); empathy (107); interpersonal relationships (106); impulse control (106); and stress tolerance (106). Lowest subscale score was in assertiveness (98). Self-regard (89), assertiveness (88), and independence (90) were areas in which PGY-2s attained relatively lower scores (unpaired t-test, p<0.05) compared to their peers and the general population. PGY-3's scored highest in nearly all subscales. Conclusions: The EQ-i offers insight into training that may assist in developing EM residents, specifically in self-regard, assertiveness, and self-expression. Further study is required to ascertain if patterns in level of training are idiosyncratic or relate to the natural maturation of residents. PMID- 29286284 TI - Spatial and thickness dependence of coupling interaction of surface states and influence on transport and optical properties of few-layer Bi2Se3. AB - Coupling interaction between the bottom and top surface electronic states and the influence on transport and optical properties of Bi2Se3 thin films with 1-8 quintuple layers (QLs) have been investigated by first principles calculations. Obvious spatial and thickness dependences of coupling interaction are found by analyzing hybridization of two surface states. In the thin film with a certain thickness, from the outer to inner atomic layers, the coupling interaction exhibits an increasing trend. On the other hand, as thickness increases, the coupling interaction shows a disproportionate decrease trend. Moreover, the system with 3 QLs exhibits stronger interaction than that with 2 QLs. The presence of coupling interaction would suppress destructive interference of surface states and enhance resistance in various degrees. In view of the inversely proportional relation to transport channel width, the resistance of thin films should show disproportionate thickness dependence. This prediction is qualitatively consistent with the transport measurements at low temperature. Furthermore, the optical properties also exhibit obvious thickness dependence. Especially as the thickness increases, the coupling interaction results in red and blue shifts of the multiple-peak structures in low and high energy regions of imaginary dielectric function, respectively. The red shift trend is in agreement with the recent experimental observation and the blue shift is firstly predicted by the present calculation. The present results give a concrete understanding of transport and optical properties in devices based on Bi2Se3 thin films with few QLs. PMID- 29286285 TI - Room temperature synthesis of ReS2 through aqueous perrhenate sulfidation. AB - In this study, a direct sulfidation reaction of ammonium perrhenate (NH4ReO4) leading to a synthesis of rhenium disulfide (ReS2) is demonstrated. These finding reveal the first example of a simplistic bottom-up approach to the chemical synthesis of crystalline ReS2. The reaction presented here takes place at room temperature, in an ambient and solvent-free environment and without the necessity of a catalyst. The atomic composition and structure of the as-synthesized product were characterized using several analysis techniques including energy dispersive X-ray (EDX) spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), transmission electron microscopy (TEM), Raman spectroscopy, thermogravimetric analysis (TGA) and differential scannig calorimetry (DSC). The results indicated the formation of a lower symmetry (1Td) ReS2 with a low degree of layer stacking. PMID- 29286286 TI - Accelerating the discovery of hidden two-dimensional magnets using machine learning and first principle calculations. AB - Two-dimensional (2D) magnets are explored in terms of data science and first principle calculations. Machine learning determines four descriptors for predicting the magnetic moments of 2D materials within reported 216 2D materials data. With the trained machine, 254 2D materials are predicted to have high magnetic moments. First principle calculations are performed to evaluate the predicted 254 2D materials where eight undiscovered stable 2D materials with high magnetic moments are revealed. The approach taken in this work indicates that undiscovered materials can be surfaced by utilizing data science and materials data, leading to an innovative way of discovering hidden materials. PMID- 29286287 TI - Nonperturbative theory of atom-surface interaction: corrections at short separations. AB - The nonperturbative expressions for the free energy and force of interaction between a ground-state atom and a real-material surface at any temperature are presented. The transition to the Matsubara representation is performed, whereupon the comparison is made with the commonly used perturbative results based on the standard Lifshitz theory. It is shown that the Lifshitz formulas for the free energy and force of an atom-surface interaction follow from the nonperturbative ones in the lowest order of the small parameter. Numerical computations of the free energy and force for the atoms of He[Formula: see text] and Na interacting with a surface of an Au plate have been performed using the frequency-dependent dielectric permittivity of Au and highly accurate dynamic atomic polarizabilities in the framework of both the nonperturbative and perturbative theories. According to our results, the maximum deviations between the two theories are reached at the shortest atom-surface separations of about 1 nm. Simple analytic expressions for the atom-surface free energy are derived in the classical limit and for an ideal-metal plane. In the lowest order of the small parameter, they are found in agreement with the perturbative ones following from the standard Lifshitz theory. Possible applications of the obtained results in the theory of van der Waals adsorption are discussed. PMID- 29286288 TI - Frequency-domain modelling of gain in pump-probe experiment by an inhomogeneous medium. AB - Introduction of a gain medium in lossy plasmonic metamaterials reduces and compensates losses or even amplifies an incident light often with nonlinear optical effect. Here, optical gain in a pump-probe experimental setup is effectively calculated in the frequency-domain by approximating a gain material as an inhomogeneous medium. Spatially varying local field amplitudes of the pump and probe beams are included in the model to reproduce the inhomogeneous gain effect, in which population inversion occurs most strongly near the surface and decays along the propagation direction. We demonstrate that transmission spectra calculated by this method agree well with finite-difference time-domain simulation results. This simplified approach of gain modelling offers an easy and reliable way to analyze wave propagation in a gain medium without nonlinear time domain calculation. PMID- 29286289 TI - Evolution of nanomechanical properties and crystallinity of individual titanium dioxide nanotube resonators. AB - Herein a complete characterization of single TiO2 nanotube resonator was reported for the first time. The modal vibration response analysis allows a non-invasive indirect evaluation of the mechanical properties of the TiO2 nanotube. The effect of post-grown thermal treatments on nanotube mechanical properties was investigated and carefully correlated to the chemico-physical parameters evolution. The Young's modulus of TiO2 nanotube rises linearly from 57 GPa up to 105 GPa for annealing at 600 degrees C depending on the compositional and crystallographic evolution of the nanostructure. Considering the growing interest in single nanostructure devices, the reported findings allow a deeper understanding of the properties of individual titanium dioxide nanotubes extrapolated from their standard arrayed architecture. PMID- 29286290 TI - Ovarian Cancer Screening: Lessons about Effectiveness. AB - Ovarian cancer screening has been described in scientific reports [1-4], as well as in reviews and summaries[...]. PMID- 29286291 TI - Transcriptomic Profiling and Physiological Analysis of Haloxylon ammodendron in Response to Osmotic Stress. AB - Haloxylon ammodendron, a perennial xero-halophyte, is an essential species for investigating the effects of drought on desert tree. To gain a comprehensive knowledge on the responses of H. ammodendron to drought stress, we specially performed the molecular and physiological analysis of H. ammodendron in response to -0.75 MPa osmotic stress for six and 24 h in lab condition via RNA-seq and digital gene expression (DGE). In total, 87,109 unigenes with a mean length of 680 bp and 13,486 potential simple sequence repeats (SSRs) were generated, and 3353 differentially expressed genes (DEGs) in shoots and 4564 in roots were identified under stress. These DEGs were mainly related to ion transporters, signal transduction, ROS-scavenging, photosynthesis, cell wall organization, membrane stabilization and hormones. Moreover, the physiological changes of inorganic ions and organic solute content, peroxidase (POD) activity and osmotic potential were in accordance with dynamic transcript profiles of the relevant genes. In this study, a detailed investigation of the pathways and candidate genes identified promote the research on the molecular mechanisms of abiotic stress tolerance in the xero-halophytic species. Our data provides valuable genetic resources for future improvement of forage and crop species for better adaptation to abiotic stresses. PMID- 29286292 TI - The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis. AB - Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions. PMID- 29286293 TI - Pinnatifidenyne-Derived Ethynyl Oxirane Acetogenins from Laurencia viridis. AB - Red algae of Laurencia continue to provide wide structural diversity and complexity of halogenated C15 acetogenin medium-ring ethers. Here, we described the isolation of three new C15 acetogenins (3-5), and one truncated derivative (6) from Laurencia viridis collected on the Canary Islands. These compounds are interesting variations on the pinnatifidenyne structure that included the first examples of ethynyl oxirane derivatives (3-4). The structures were elucidated by extensive study of NMR (Nuclear Magnetic Resonance) data, J-based configuration analysis and DFT (Density Functional Theory) calculations. Their antiproliferative activity against six human solid tumor cell lines was evaluated. PMID- 29286294 TI - Real-Time Detection of Sporadic Meteors in the Intensified TV Imaging Systems. AB - The automatic observation of the night sky through wide-angle video systems with the aim of detecting meteor and fireballs is currently among routine astronomical observations. The observation is usually done in multi-station or network mode, so it is possible to estimate the direction and the speed of the body flight. The high velocity of the meteorite flying through the atmosphere determines the important features of the camera systems, namely the high frame rate. Thanks to high frame rates, such imaging systems produce a large amount of data, of which only a small fragment has scientific potential. This paper focuses on methods for the real-time detection of fast moving objects in the video sequences recorded by intensified TV systems with frame rates of about 60 frames per second. The goal of our effort is to remove all unnecessary data during the daytime and make free hard-drive capacity for the next observation. The processing of data from the MAIA (Meteor Automatic Imager and Analyzer) system is demonstrated in the paper. PMID- 29286295 TI - Determination of Tangeretin in Rat Plasma: Assessment of Its Clearance and Absolute Oral Bioavailability. AB - Tangeretin (TAN) is a dietary polymethoxylated flavone that possesses a broad scope of pharmacological activities. A simple high-performance liquid chromatography (HPLC) method was developed and validated in this study to quantify TAN in plasma of Sprague-Dawley rats. The lower limit of quantification (LLOQ) was 15 ng/mL; the intra- and inter-day assay variations expressed in the form of relative standard deviation (RSD) were all less than 10%; and the assay accuracy was within 100 +/- 15%. Subsequently, pharmacokinetic profiles of TAN were explored and established. Upon single intravenous administration (10 mg/kg), TAN had rapid clearance (Cl = 94.1 +/- 20.2 mL/min/kg) and moderate terminal elimination half-life (t1/2 lambdaz = 166 +/- 42 min). When TAN was given as a suspension (50 mg/kg), poor but erratic absolute oral bioavailability (mean value < 3.05%) was observed; however, when TAN was given in a solution prepared with randomly methylated-beta-cyclodextrin (50 mg/kg), its plasma exposure was at least doubled (mean bioavailability: 6.02%). It was obvious that aqueous solubility hindered the oral absorption of TAN and acted as a barrier to its oral bioavailability. This study will facilitate further investigations on the medicinal potentials of TAN. PMID- 29286296 TI - Anti-Helicobacter pylori Properties of the Ant-Venom Peptide Bicarinalin. AB - The venom peptide bicarinalin, previously isolated from the ant Tetramorium bicarinatum, is an antimicrobial agent with a broad spectrum of activity. In this study, we investigate the potential of bicarinalin as a novel agent against Helicobacter pylori, which causes several gastric diseases. First, the effects of synthetic bicarinalin have been tested against Helicobacter pylori: one ATCC strain, and forty-four isolated from stomach ulcer biopsies of Peruvian patients. Then the cytoxicity of bicarinalin on human gastric cells and murine peritoneal macrophages was measured using XTT and MTT assays, respectively. Finally, the preventive effect of bicarinalin was evaluated by scanning electron microscopy using an adherence assay of H. pylori on human gastric cells treated with bicarinalin. This peptide has a potent antibacterial activity at the same magnitude as four antibiotics currently used in therapies against H. pylori. Bicarinalin also inhibited adherence of H. pylori to gastric cells with an IC50 of 0.12 MUg.mL-1 and had low toxicity for human cells. Scanning electron microscopy confirmed that bicarinalin can significantly decrease the density of H. pylori on gastric cells. We conclude that Bicarinalin is a promising compound for the development of a novel and effective anti-H. pylori agent for both curative and preventive use. PMID- 29286297 TI - Spatiotemporal Risk of Bacillary Dysentery and Sensitivity to Meteorological Factors in Hunan Province, China. AB - Bacillary dysentery remains a public health concern in the world. Hunan Province is one of the provinces having the highest risk of bacillary dysentery in China, however, the spatial-temporal distribution, variation of bacillary dysentery and sensitivity to meteorological factors in there are unclear. In this paper, a Bayesian space-time hierarchical model (BSTHM) was used to detect space-time variation, and effects of meteorological factors between 2010 and 2015. The risk of bacillary dysentery showed apparent spatial-temporal heterogeneity. The highest risk occurred in the summer season. Economically undeveloped mountainous areas in the west and south of the province had the highest incidence rates. Twenty three (18.9%) and 20 (16.4%) counties were identified as hot and cold spots, respectively. Among the hotspots, 11 counties (47.8%) exhibited a rapidly decreasing trend, suggesting they may become low-risk areas in the future. Of the cold spot counties, six (30%) showed a slowly decreasing trend, and may have a higher risk in the future. Among meteorological factors, air temperature, relative humidity, and wind speed all played a significant role in the spatial temporal distribution of bacillary dysentery risk. These findings can contribute to the implementation of an early warning system for controlling and preventing bacillary dysentery. PMID- 29286298 TI - Simple Purification of Nicotiana benthamiana-Produced Recombinant Colicins: High Yield Recovery of Purified Proteins with Minimum Alkaloid Content Supports the Suitability of the Host for Manufacturing Food Additives. AB - Colicins are natural non-antibiotic bacterial proteins with a narrow spectrum but an extremely high antibacterial activity. These proteins are promising food additives for the control of major pathogenic Shiga toxin-producing E. coli serovars in meats and produce. In the USA, colicins produced in edible plants such as spinach and leafy beets have already been accepted by the U. S. Food and Drug Administration (FDA) and U. S. Department of Agriculture (USDA) as food processing antibacterials through the GRAS (generally recognized as safe) regulatory review process. Nicotiana benthamiana, a wild relative of tobacco, N. tabacum, has become the preferred production host plant for manufacturing recombinant proteins-including biopharmaceuticals, vaccines, and biomaterials-but the purification procedures that have been employed thus far are highly complex and costly. We describe a simple and inexpensive purification method based on specific acidic extraction followed by one chromatography step. The method provides for a high recovery yield of purified colicins, as well as a drastic reduction of nicotine to levels that could enable the final products to be used on food. The described purification method allows production of the colicin products at a commercially viable cost of goods and might be broadly applicable to other cost-sensitive proteins. PMID- 29286299 TI - Evolution and Virulence of Influenza A Virus Protein PB1-F2. AB - PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in immune and epithelial cells, altering inflammatory responses, and promoting secondary bacterial pneumonia. The effects of PB1-F2 differ between virus strains and host species. This can at least partially be explained by the presence of multiple PB1-F2 sequence variants, including premature stop codons that lead to the expression of truncated PB1-F2 proteins of different lengths and specific virulence-associated residues that enhance susceptibility to bacterial superinfection. Although there has been a tendency for human seasonal IAV to gradually reduce the number of virulence associated residues, zoonotic IAVs contain a reservoir of PB1-F2 proteins with full length, virulence-associated sequences. Here, we review the molecular mechanisms by which PB1-F2 may affect influenza virulence, and factors associated with the evolution and selection of this protein. PMID- 29286300 TI - A Peptide Nucleic Acid against MicroRNA miR-145-5p Enhances the Expression of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Calu-3 Cells. AB - Peptide nucleic acids (PNAs) are very useful tools for gene regulation at different levels, but in particular in the last years their use for targeting microRNA (anti-miR PNAs) has provided impressive advancements. In this respect, microRNAs related to the repression of cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is defective in cystic fibrosis, are of great importance in the development of new type of treatments. In this paper we propose the use of an anti-miR PNA for targeting miR-145, a microRNA reported to suppress CFTR expression. Octaarginine-anti-miR PNA conjugates were delivered to Calu-3 cells, exerting sequence dependent targeting of miR-145-5p. This allowed to enhance expression of the miR-145 regulated CFTR gene, analyzed at mRNA (RT-qPCR, Reverse Transcription quantitative Polymerase Chain Reaction) and CFTR protein (Western blotting) level. PMID- 29286301 TI - Using Markov Chains and Multi-Objective Optimization for Energy-Efficient Context Recognition. AB - The recognition of the user's context with wearable sensing systems is a common problem in ubiquitous computing. However, the typically small battery of such systems often makes continuous recognition impractical. The strain on the battery can be reduced if the sensor setting is adapted to each context. We propose a method that efficiently finds near-optimal sensor settings for each context. It uses Markov chains to simulate the behavior of the system in different configurations and the multi-objective genetic algorithm to find a set of good non-dominated configurations. The method was evaluated on three real-life datasets and found good trade-offs between the system's energy expenditure and the system's accuracy. One of the solutions, for example, consumed five-times less energy than the default one, while sacrificing only two percentage points of accuracy. PMID- 29286302 TI - MicroRNA-27b Depletion Enhances Endotrophic and Intravascular Lipid Accumulation and Induces Adipocyte Hyperplasia in Zebrafish. AB - : miR-27b has emerged as a regulatory hub in cholesterol and lipid metabolism, and as a potential therapeutic target for treating atherosclerosis and obesity. However, the impact of miR-27b on lipid levels in vivo remains to be determined. Zebrafish lipids are normally stored as triacylglycerols (TGs) and their main storage sites are visceral, intramuscular, and subcutaneous lipid depots, and not blood vessels and liver. In this study, we applied microRNA-sponge (miR-SP) technology and generated zebrafish expressing transgenic miR-27b-SP (C27bSPs), which disrupted endogenous miR-27b activity and induced intravascular lipid accumulation (hyperlipidemia) and the early onset of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Oil Red O staining predominantly increased in the blood vessels and livers of larvae and juvenile C27bSPs, indicating that miR-27b depletion functionally promoted lipid accumulation. C27bSPs also showed an increased weight gain with larger fat pads, resulting from adipocyte hyperplasia. Molecular analysis revealed that miR-27b depletion increased the expression of genes that are associated with lipogenesis and the endoplasmic reticulum (ER). Moreover, miR-27b-SP increased peroxisome proliferator-activated receptor gamma (PPAR-gamma), CCAAT enhancer binding protein-alpha (C/EBP-alpha, and sterol regulatory element binding transcription factor 1c (SREBP-1c) expression and contributed to lipogenesis and adipogenesis. CONCLUSION: Our results suggest that miR-27b-SP acts as a lipid enhancer by directly increasing the expression of several lipogenic/adipogenic transcriptional factors, resulting in increased lipogenesis and adipogenesis. In this study, miR-27b expression improved lipid metabolism in C27bSPs, which suggests that miR-27b is an important lipogenic factor in regulating early onset of hyperlipidemia and adipogenesis in zebrafish. PMID- 29286304 TI - Natural Nanoparticles: A Particular Matter Inspired by Nature. AB - During the last couple of decades, the rapidly advancing field of nanotechnology has produced a wide palette of nanomaterials, most of which are considered as "synthetic" and, among the wider public, are often met with a certain suspicion. Despite the technological sophistication behind many of these materials, "nano" does not always equate with "artificial". Indeed, nature itself is an excellent nanotechnologist. It provides us with a range of fine particles, from inorganic ash, soot, sulfur and mineral particles found in the air or in wells, to sulfur and selenium nanoparticles produced by many bacteria and yeasts. These nanomaterials are entirely natural, and, not surprisingly, there is a growing interest in the development of natural nanoproducts, for instance in the emerging fields of phyto- and phyco-nanotechnology. This review will highlight some of the most recent-and sometimes unexpected-advances in this exciting and diverse field of research and development. Naturally occurring nanomaterials, artificially produced nanomaterials of natural products as well as naturally occurring or produced nanomaterials of natural products all show their own, particular chemical and physical properties, biological activities and promise for applications, especially in the fields of medicine, nutrition, cosmetics and agriculture. In the future, such natural nanoparticles will not only stimulate research and add a greener outlook to a traditionally high-tech field, they will also provide solutions-pardon-suspensions for a range of problems. Here, we may anticipate specific biogenic factories, valuable new materials based on waste, the effective removal of contaminants as part of nano-bioremediation, and the conversion of poorly soluble substances and materials to biologically available forms for practical uses. PMID- 29286305 TI - Muscle Selection for Focal Limb Dystonia. AB - Selection of muscles for botulinum toxin injection for limb dystonia is particularly challenging. Limb dystonias vary more widely in the pattern of dystonic movement and involved muscles than cervical dystonia or blepharospasm. The large variation in how healthy individuals perform skilled hand movements, the large number of muscles in the hand and forearm, and the presence of compensatory actions in patients with dystonia add to the complexity of choosing muscles for injection. In this article, we discuss approaches to selecting upper and lower extremity muscles for chemodenervation treatment of limb dystonia. PMID- 29286303 TI - Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD). AB - Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A's functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 MUmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true "vitamin A deficiency", but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites. PMID- 29286306 TI - InSiDDe: A Server for Designing Artificial Disordered Proteins. AB - InSiDDe (In Silico Disorder Design) is a program for the in silico design of intrinsically disordered proteins of desired length and disorder probability. The latter is assessed using IUPred and spans values ranging from 0.55 to 0.95 with 0.05 increments. One to ten artificial sequences per query, each made of 50 to 200 residues, can be generated by InSiDDe. We describe the rationale used to set up InSiDDe and show that an artificial sequence of 100 residues with an IUPred score of 0.6 designed by InSiDDe could be recombinantly expressed in E. coli at high levels without degradation when fused to a natural molecular recognition element (MoRE). In addition, the artificial fusion protein exhibited the expected behavior in terms of binding modulation of the specific partner recognized by the MoRE. To the best of our knowledge, InSiDDe is the first publicly available software for the design of intrinsically disordered protein (IDP) sequences. InSiDDE is publicly available online. PMID- 29286308 TI - Selenoprotein K Increases Efficiency of DHHC6 Catalyzed Protein Palmitoylation by Stabilizing the Acyl-DHHC6 Intermediate. AB - Selenoprotein K (SELENOK) is a selenocysteine (Sec)-containing protein localized in the endoplasmic reticulum (ER) membrane where it interacts with the DHHC6 (where single letter symbols represent Asp-His-His-Cys amino acids) enzyme to promote protein acyl transferase (PAT) reactions. PAT reactions involve the DHHC enzymatic capture of palmitate via a thioester bond to cysteine (Cys) residues that form an unstable palmitoyl-DHHC intermediate, followed by transfer of palmitate to Cys residues of target proteins. How SELENOK facilitates this reaction has not been determined. Splenocyte microsomal preparations from wild type mice versus SELENOK knockout mice were used to establish PAT assays and showed decreased PAT activity (~50%) under conditions of SELENOK deficiency. Using recombinant, soluble versions of DHHC6 along with SELENOK containing Sec92, Cys92, or alanine (Ala92), we evaluated the stability of the acyl-DHHC6 intermediate and its capacity to transfer the palmitate residue to Cys residues on target peptides. Versions of SELENOK containing either Ala or Cys residues in place of Sec were equivalently less effective than Sec at stabilizing the acyl DHHC6 intermediate or promoting PAT activity. These data suggest that Sec92 in SELENOK serves to stabilize the palmitoyl-DHHC6 intermediate by reducing hydrolyzation of the thioester bond until transfer of the palmitoyl group to the Cys residue on the target protein can occur. PMID- 29286307 TI - Signaling Pathways Driving Aberrant Splicing in Cancer Cells. AB - Aberrant profiles of pre-mRNA splicing are frequently observed in cancer. At the molecular level, an altered profile results from a complex interplay between chromatin modifications, the transcriptional elongation rate of RNA polymerase, and effective binding of the spliceosome to the generated transcripts. Key players in this interplay are regulatory splicing factors (SFs) that bind to gene specific splice-regulatory sequence elements. Although mutations in genes of some SFs were described, a major driver of aberrant splicing profiles is oncogenic signal transduction pathways. Signaling can affect either the transcriptional expression levels of SFs or the post-translational modification of SF proteins, and both modulate the ratio of nuclear versus cytoplasmic SFs in a given cell. Here, we will review currently known mechanisms by which cancer cell signaling, including the mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 (PI3)-kinase pathway (PI3K) and wingless (Wnt) pathways but also signals from the tumor microenvironment, modulate the activity or subcellular localization of the Ser/Arg rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) families of SFs. PMID- 29286310 TI - Formation Mechanism and Dispersion of Pseudo-Tetragonal BaTiO3-PVP Nanoparticles from Different Titanium Precursors: TiCl4 and TiO2. AB - Nano-sized tetragonal BaTiO3 (BT) particles that are well dispersed in solution are essential for the dielectric layer in multilayer ceramic capacitor technology. A hydrothermal process using TiCl4 and BaCl2, as source of Ti and Ba, respectively, or the precursor TiO2 as seed for the formation of BT, and poly(vinylpyrrolidone) (PVP) as a surfactant, was employed in this study to enhance both the dispersibility and tetragonality (c/a) simultaneously in a single reaction process. The process parameters, i.e., the ratio of TiO2 substitution of TiCl4, the reaction time, and PVP content were systematically studied, and the growth mechanism and relation between the tetragonality and the particle size are discussed. Dynamic light scattering (DLS) analysis was used to show that truncated pseudo-tetragonal BT-PVP particles with an average size of 100 nm, having a narrow size distribution and a coefficient of variation (CV) as low as 20% and being mono-dispersed in water, were produced. The narrow particle size distribution is attributed to the ability of PVP to inhibit the growth of BT particles, and the high c/a of BT-PVP to heterogeneous particle growth using TiO2 seeds. PMID- 29286309 TI - Lowering Low-Density Lipoprotein Particles in Plasma Using Dextran Sulphate Co Precipitates Procoagulant Extracellular Vesicles. AB - Plasma extracellular vesicles (EVs) are lipid membrane vesicles involved in several biological processes including coagulation. Both coagulation and lipid metabolism are strongly associated with cardiovascular events. Lowering very-low- and low-density lipoprotein ((V)LDL) particles via dextran sulphate LDL apheresis also removes coagulation proteins. It remains unknown, however, how coagulation proteins are removed in apheresis. We hypothesize that plasma EVs that contain high levels of coagulation proteins are concomitantly removed with (V)LDL particles by dextran sulphate apheresis. For this, we precipitated (V)LDL particles from human plasma with dextran sulphate and analyzed the abundance of coagulation proteins and EVs in the precipitate. Coagulation pathway proteins, as demonstrated by proteomics and a bead-based immunoassay, were over-represented in the (V)LDL precipitate. In this precipitate, both bilayer EVs and monolayer (V)LDL particles were observed by electron microscopy. Separation of EVs from (V)LDL particles using density gradient centrifugation revealed that almost all coagulation proteins were present in the EVs and not in the (V)LDL particles. These EVs also showed a strong procoagulant activity. Our study suggests that dextran sulphate used in LDL apheresis may remove procoagulant EVs concomitantly with (V)LDL particles, leading to a loss of coagulation proteins from the blood. PMID- 29286311 TI - Comparative Proteomics Analysis of Urine Reveals Down-Regulation of Acute Phase Response Signaling and LXR/RXR Activation Pathways in Prostate Cancer. AB - Detecting prostate cancer (PCa) using non-invasive diagnostic markers still remains a challenge. The aim of this study was the identification of urine proteins that are sufficiently sensitive and specific to detect PCa in the early stages. Comparative proteomics profiling of urine from patients with PCa, benign prostate hyperplasia, bladder cancer, and renal cancer, coupled with bioinformatics analysis, were performed. Statistically significant difference in abundance showed 20 and 85 proteins in the 2-D DIGE/MS and label-free LC-MS/MS experiments, respectively. In silico analysis indicated activation, binding, and cell movement of subset of immune cells as the top affected cellular functions in PCa, together with the down-regulation of Acute Phase Response Signaling and Liver X Receptor/ Retinoid X Receptor (LXR/RXR) activation pathways. The most promising biomarkers were 35, altered in PCa when compared to more than one group. Half of these have confirmed localization in normal or PCa tissues. Twenty proteins (CD14, AHSG, ENO1, ANXA1, CLU, COL6A1, C3, FGA, FGG, HPX, PTGDS, S100A9, LMAN2, ITIH4, ACTA2, GRN, HBB, PEBP1, CTSB, SPP1) are oncogenes, tumor suppressors, and multifunctional proteins with highly confirmed involvement in PCa, while 9 (AZU1, IGHG1, RNASE2, PZP, REG1A, AMY1A, AMY2A, ACTG2, COL18A1) have been associated with different cancers, but not with PCa so far, and may represent novel findings. LC-MS/MS data are available via ProteomeXchange with identifier PXD008407. PMID- 29286313 TI - Power Spectral Density Evaluation of Laser Milled Surfaces. AB - Ablating surfaces with a pulsed laser system in milling processes often leads to surface changes depending on the milling depth. Especially if a constant surface roughness and evenness is essential to the process, structural degradation may advance until the process fails. The process investigated is the generation of precise thrust by laser ablation. Here, it is essential to predict or rather control the evolution of the surfaces roughness. Laser ablative milling with a short pulse laser system in vacuum (~1 Pa) were performed over depths of several 10 um documenting the evolution of surface roughness and unevenness with a white light interference microscope. Power spectral density analysis of the generated surface data reveals a strong influence of the crystalline structure of the solid. Furthermore, it was possible to demonstrate that this effect could be suppressed for gold. PMID- 29286312 TI - A Triple-Mode Flexible E-Skin Sensor Interface for Multi-Purpose Wearable Applications. AB - This study presents a flexible wireless electronic skin (e-skin) sensor system that includes a multi-functional sensor device, a triple-mode reconfigurable readout integrated circuit (ROIC), and a mobile monitoring interface. The e-skin device's multi-functionality is achieved by an interlocked micro-dome array structure that uses a polyvinylidene fluoride and reduced graphene oxide (PVDF/RGO) composite material that is inspired by the structure and functions of the human fingertip. For multi-functional implementation, the proposed triple mode ROIC is reconfigured to support piezoelectric, piezoresistance, and pyroelectric interfaces through single-type e-skin sensor devices. A flexible system prototype was developed and experimentally verified to provide various wireless wearable sensing functions-including pulse wave, voice, chewing/swallowing, breathing, knee movements, and temperature-while their real time sensed data are displayed on a smartphone. PMID- 29286314 TI - Integration of Distributed Services and Hybrid Models Based on Process Choreography to Predict and Detect Type 2 Diabetes. AB - Life expectancy is increasing and, so, the years that patients have to live with chronic diseases and co-morbidities. Type 2 diabetes is one of the most prevalent chronic diseases, specifically linked to being overweight and ages over sixty. Recent studies have demonstrated the effectiveness of new strategies to delay and even prevent the onset of type 2 diabetes by a combination of active and healthy lifestyle on cohorts of mid to high risk subjects. Prospective research has been driven on large groups of the population to build risk scores that aim to obtain a rule for the classification of patients according to the odds for developing the disease. Currently, there are more than two hundred models and risk scores for doing this, but a few have been properly evaluated in external groups and integrated into a clinical application for decision support. In this paper, we present a novel system architecture based on service choreography and hybrid modeling, which enables a distributed integration of clinical databases, statistical and mathematical engines and web interfaces to be deployed in a clinical setting. The system was assessed during an eight-week continuous period with eight endocrinologists of a hospital who evaluated up to 8080 patients with seven different type 2 diabetes risk models implemented in two mathematical engines. Throughput was assessed as a matter of technical key performance indicators, confirming the reliability and efficiency of the proposed architecture to integrate hybrid artificial intelligence tools into daily clinical routine to identify high risk subjects. PMID- 29286315 TI - Structural and Electrochemical Characterization of Zn1-xFexO-Effect of Aliovalent Doping on the Li+ Storage Mechanism. AB - In order to further improve the energy and power density of state-of-the-art lithium-ion batteries (LIBs), new cell chemistries and, therefore, new active materials with alternative storage mechanisms are needed. Herein, we report on the structural and electrochemical characterization of Fe-doped ZnO samples with varying dopant concentrations, potentially serving as anode for LIBs (Rechargeable lithium-ion batteries). The wurtzite structure of the Zn1-xFexO samples (with x ranging from 0 to 0.12) has been refined via the Rietveld method. Cell parameters change only slightly with the Fe content, whereas the crystallinity is strongly affected, presumably due to the presence of defects induced by the Fe3+ substitution for Zn2+. XANES (X-ray absorption near edge structure) data recorded ex situ for Zn0.9Fe0.1O electrodes at different states of charge indicated that Fe, dominantly trivalent in the pristine anode, partially reduces to Fe2+ upon discharge. This finding was supported by a detailed galvanostatic and potentiodynamic investigation of Zn1-xFexO-based electrodes, confirming such an initial reduction of Fe3+ to Fe2+ at potentials higher than 1.2 V (vs. Li+/Li) upon the initial lithiation, i.e., discharge. Both structural and electrochemical data strongly suggest the presence of cationic vacancies at the tetrahedral sites, induced by the presence of Fe3+ (i.e., one cationic vacancy for every two Fe3+ present in the sample), allowing for the initial Li+ insertion into the ZnO lattice prior to the subsequent conversion and alloying reaction. PMID- 29286316 TI - Development and Validation of an UPLC-MS/MS Method for Pharmacokinetic Comparison of Five Alkaloids from JinQi Jiangtang Tablets and Its Monarch Drug Coptidis Rhizoma. AB - JinQi Jiangtang (JQJT) tablets, a Chinese patent medicine approved by the State Food and Drug Administration, are composed of Coptidis Rhizoma, Astragali Radix, and Lonicerae Japonicae Flos, and have a significant effect on diabetes. Coptidis Rhizoma is monarch drug in the prescription. The aim of the present study was to investigate and compare the pharmacokinetics of multiple ingredients from JQJT tablets and Coptidis Rhizoma extract (CRE) following oral administration in rats. Five alkaloids: coptisine chloride, epiberberine chloride, berberine chloride, jatrorrhizine chloride, and palmatine chloride, were simultaneously determined in rat plasma using established and validated ultra-high performance liquid chromatography mass spectrometry (UPLC-MS/MS). Significant pharmacokinetic differences were observed for the five alkaloids after a single administration of CRE and JQJT tablets. Compared with CRE, the Cmax values of palmatine chloride and jatrorrhizine chloride were decreased significantly, the AUC0-t values of four alkaloids (all except jatrorrhizine chloride) were notably decreased, and the mean residence times of all five alkaloids were significantly decreased after administration of JQJT tablets. The results indicated that the absorption characteristics of the five alkaloids from Coptidis Rhizoma would be influenced by the compatibility of Astragali Radix or Lonicerae Japonicae Flos from JQJT tablets, such that absorption was inhibited and elimination was accelerated. In conclusion, the developed strategy was suitable for the comparison of five alkaloids from JinQi Jiangtang tablets and its monarch drug, which could be valuable for compatibility studies of traditional Chinese medicines. PMID- 29286317 TI - Motor, Somatosensory, Viscerosensory and Metabolic Impairments in a Heterozygous Female Rat Model of Rett Syndrome. AB - Rett Syndrome (RTT), an autism-related disorder caused by mutation of the X linked Methyl CpG-binding Protein 2 (MECP2) gene, is characterized by severe cognitive and intellectual deficits. While cognitive deficits are well-documented in humans and rodent models, impairments of sensory, motor and metabolic functions also occur but remain poorly understood. To better understand non cognitive deficits in RTT, we studied female rats heterozygous for Mecp2 mutation (Mecp2-/x); unlike commonly used male Mecp2-/y rodent models, this more closely approximates human RTT where males rarely survive. Mecp2-/x rats showed rapid, progressive decline of motor coordination through six months of age as assessed by rotarod performance, accompanied by deficits in gait and posture. Mecp2-/x rats were hyper-responsive to noxious pressure and cold, but showed visceral hyposensitivity when tested by colorectal distension. Mecp2-/x rats ate less, drank more, and had more body fat resulting in increased weight gain. Our findings reveal an array of progressive non-cognitive deficits in this rat model that are likely to contribute to the compromised quality of life that characterizes RTT. PMID- 29286318 TI - Cytomegaloviruses in a Community of Wild Nonhuman Primates in Tai National Park, Cote D'Ivoire. AB - Cytomegaloviruses (CMVs) are known to infect many mammals, including a number of nonhuman primates (NHPs). However, most data available arose from studies led on captive individuals and little is known about CMV diversity in wild NHPs. Here, we analyzed a community of wild nonhuman primates (seven species) in Tai National Park (TNP), Cote d'Ivoire, with two PCR systems targeting betaherpesviruses. CMV DNA was detected in 17/87 primates (4/7 species). Six novel CMVs were identified in sooty mangabeys, Campbell's monkeys and Diana monkeys, respectively. In 3/17 positive individuals (from three NHP species), different CMVs were co-detected. A major part of the glycoprotein B coding sequences of the novel viruses was amplified and sequenced, and phylogenetic analyses were performed that included three previously discovered CMVs of western red colobus from TNP and published CMVs from other NHP species and geographic locations. We find that, despite this locally intensified sampling, NHP CMVs from TNP are completely host-specific, pinpointing the absence or rarity of cross-species transmission. We also show that on longer timescales the evolution of CMVs is characterized by frequent co divergence with their hosts, although other processes, including lineage duplication and host switching, also have to be invoked to fully explain their evolutionary relationships. PMID- 29286320 TI - Fog-Based Two-Phase Event Monitoring and Data Gathering in Vehicular Sensor Networks. AB - Vehicular nodes are equipped with more and more sensing units, and a large amount of sensing data is generated. Recently, more and more research considers cooperative urban sensing as the heart of intelligent and green city traffic management. The key components of the platform will be a combination of a pervasive vehicular sensing system, as well as a central control and analysis system, where data-gathering is a fundamental component. However, the data gathering and monitoring are also challenging issues in vehicular sensor networks because of the large amount of data and the dynamic nature of the network. In this paper, we propose an efficient continuous event-monitoring and data gathering framework based on fog nodes in vehicular sensor networks. A fog-based two-level threshold strategy is adopted to suppress unnecessary data upload and transmissions. In the monitoring phase, nodes sense the environment in low cost sensing mode and generate sensed data. When the probability of the event is high and exceeds some threshold, nodes transfer to the event-checking phase, and some nodes would be selected to transfer to the deep sensing mode to generate more accurate data of the environment. Furthermore, it adaptively adjusts the threshold to upload a suitable amount of data for decision making, while at the same time suppressing unnecessary message transmissions. Simulation results showed that the proposed scheme could reduce more than 84 percent of the data transmissions compared with other existing algorithms, while it detects the events and gathers the event data. PMID- 29286321 TI - Proton Conduction in Grain-Boundary-Free Oxygen-Deficient BaFeO2.5+delta Thin Films. AB - Reduction of the operating temperature to an intermediate temperature range between 350 degrees C and 600 degrees C is a necessity for Solid Oxide Fuel/Electrolysis Cells (SOFC/SOECs). In this respect the application of proton conducting oxides has become a broad area of research. Materials that can conduct protons and electrons at the same time, to be used as electrode catalysts on the air electrode, are especially rare. In this article we report on the proton conduction in expitaxially grown BaFeO2.5+delta (BFO) thin films deposited by pulsed laser deposition on Nb:SrTiO3 substrates. By using Electrochemical Impedance Spectroscopy (EIS) measurements under different wet and dry atmospheres, the bulk proton conductivity of BFO (between 200 degrees C and 300 degrees C) could be estimated for the first time (3.6 * 10-6 S cm-1 at 300 degrees C). The influence of oxidizing measurement atmosphere and hydration revealed a strong dependence of the conductivity, most notably at temperatures above 300 degrees C, which is in good agreement with the hydration behavior of BaFeO2.5 reported previously. PMID- 29286319 TI - Cellular and Molecular Mechanisms Underlying Non-Pharmaceutical Ischemic Stroke Therapy in Aged Subjects. AB - : The incidence of ischemic stroke in humans increases exponentially above 70 years both in men and women. Comorbidities like diabetes, arterial hypertension or co-morbidity factors such as hypercholesterolemia, obesity and body fat distribution as well as fat-rich diet and physical inactivity are common in elderly persons and are associated with higher risk of stroke, increased mortality and disability. Obesity could represent a state of chronic inflammation that can be prevented to some extent by non-pharmaceutical interventions such as calorie restriction and hypothermia. Indeed, recent results suggest that H2S induced hypothermia in aged, overweight rats could have a higher probability of success in treating stroke as compared to other monotherapies, by reducing post stroke brain inflammation. Likewise, it was recently reported that weight reduction prior to stroke, in aged, overweight rats induced by caloric restriction, led to an early re-gain of weight and a significant improvement in recovery of complex sensorimotor skills, cutaneous sensitivity, or spatial memory. CONCLUSION: animal models of stroke done in young animals ignore age associated comorbidities and may explain, at least in part, the unsuccessful bench-to-bedside translation of neuroprotective strategies for ischemic stroke in aged subjects. PMID- 29286322 TI - Harvesting Environmental Microalgal Blooms for Remediation and Resource Recovery: A Laboratory Scale Investigation with Economic and Microbial Community Impact Assessment. AB - A laboratory based microflotation rig termed efficient FLOtation of Algae Technology (eFLOAT) was used to optimise parameters for harvesting microalgal biomass from eutrophic water systems. This was performed for the dual objectives of remediation (nutrient removal) and resource recovery. Preliminary experiments demonstrated that chitosan was more efficient than alum for flocculation of biomass and the presence of bacteria could play a positive role and reduce flocculant application rates under the natural conditions tested. Maximum biomass removal from a hyper-eutrophic water retention pond sample was achieved with 5 mg.L-1 chitosan (90% Chlorophyll a removal). Harvesting at maximum rates showed that after 10 days, the bacterial diversity is significantly increased with reduced cyanobacteria, indicating improved ecosystem functioning. The resource potential within the biomass was characterized by 9.02 MUg phosphate, 0.36 mg protein, and 103.7 MUg lipid per mg of biomass. Fatty acid methyl ester composition was comparable to pure cultures of microalgae, dominated by C16 and C18 chain lengths with saturated, monounsaturated, and polyunsaturated fatty acids. Finally, the laboratory data was translated into a full-size and modular eFLOAT system, with estimated costs as a novel eco-technology for efficient algal bloom harvesting. PMID- 29286324 TI - PEG 400-Based Phase Change Materials Nano-Enhanced with Functionalized Graphene Nanoplatelets. AB - This study presents new Nano-enhanced Phase Change Materials, NePCMs, formulated as dispersions of functionalized graphene nanoplatelets in a poly(ethylene glycol) with a mass-average molecular mass of 400 g.mol-1 for possible use in Thermal Energy Storage. Morphology, functionalization, purity, molecular mass and thermal stability of the graphene nanomaterial and/or the poly(ethylene glycol) were characterized. Design parameters of NePCMs were defined on the basis of a temporal stability study of nanoplatelet dispersions using dynamic light scattering. Influence of graphene loading on solid-liquid phase change transition temperature, latent heat of fusion, isobaric heat capacity, thermal conductivity, density, isobaric thermal expansivity, thermal diffusivity and dynamic viscosity were also investigated for designed dispersions. Graphene nanoplatelet loading leads to thermal conductivity enhancements up to 23% while the crystallization temperature reduces up to in 4 K. Finally, the heat storage capacities of base fluid and new designed NePCMs were examined by means of the thermophysical properties through Stefan and Rayleigh numbers. Functionalized graphene nanoplatelets leads to a slight increase in the Stefan number. PMID- 29286325 TI - High-Cycle, Push-Pull Fatigue Fracture Behavior of High-C, Si-Al-Rich Nanostructured Bainite Steel. AB - The high-cycle, push-pull fatigue fracture behavior of high-C, Si-Al-rich nanostructured bainitic steel was studied through the measurement of fatigue limits, a morphology examination and phase composition analysis of the fatigue fracture surface, as well as fractography of the fatigue crack propagation. The results demonstrated that the push-pull fatigue limits at 107 cycles were estimated as 710-889 MPa, for the samples isothermally transformed at the temperature range of 220-260 degrees C through data extrapolation, measured under the maximum cycle number of 105. Both the interior inclusion and the sample surface constituted the fatigue crack origins. During the fatigue crack propagation, a high amount of secondary cracks were formed in almost parallel arrangements. The apparent plastic deformation occurred in the fracture surface layer, which induced approximately all retained austenite to transform into martensite. PMID- 29286323 TI - Fibrocytes: A Novel Stromal Cells to Regulate Resistance to Anti-Angiogenic Therapy and Cancer Progression. AB - An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic drugs improved the response rate and prolonged the survival of patients with various types of cancer; however, it is also true that the effect was mostly limited. Currently, the disappointing clinical results are explained by the existence of intrinsic or acquired resistance to the therapy mediated by both tumor cells and stromal cells. This article reviews the mechanisms of resistance mediated by stromal cells such as endothelial cells, pericytes, fibroblasts and myeloid cells, with an emphasis on fibrocytes, which were recently identified as the cell type responsible for regulating acquired resistance to anti-angiogenic therapy. In addition, the other emerging role of fibrocytes as mediator-producing cells in tumor progression is discussed. PMID- 29286326 TI - Role of RDW in Prediction of Burn after Caustic Substance Ingestion. AB - A quantifiable, quick, inexpensive and reproducible predictor is needed to decide if caustic substance ingestion results in burn regardless of the symptoms. A multicenter cohort study was conducted to investigate the predictive value of red cell distribution width (RDW) in detecting the esophageal burns. The data of 174 patients were retrospectively analyzed. Eleven patients were excluded due to inability to define the substance ingested. Complete blood count (CBC) was taken at admission, and an esophagogastroduodenoscopy was performed within the first 12 24 h in all patients, regardless of their symptoms. The age and gender of the patients, the types of substances ingested, the parameters in the CBC and the severity of the esophageal injury were correlated. Esophageal burns were diagnosed in 38 of 163 patients (23.3%). The risk of esophageal burn with RDW values below 12.20 was significantly lower. Multivariate analysis showed that RDW was the most significant predictor of esophageal burn (p = 0.000, odds ratio (OR) 7.74 (95% confidence interval (CI), 3.02-19.9)). Receiver operating characteristic (ROC) curve analysis demonstrated 84.2% sensitivity at a cut-off value of 12.20 for RDW. The results showed that CBC parameters could avoid unnecessary esophagogastroduodenoscopy. The RDW values regardless of the symptomatology is a good predictor of esophageal burns, and an RDW value over 12.20 shows the increased risk of esophageal burn. PMID- 29286327 TI - Assessment of the Possibility of Using Unmanned Aerial Vehicles (UAVs) for the Documentation of Hiking Trails in Alpine Areas. AB - The research described in this paper deals with the documentation of hiking trails in alpine areas. The study presents a novel research topic, applying up-to date survey techniques and top quality equipment with practical applications in nature conservation. The research presents the initial part of the process capturing imagery, photogrammetric processing, quality checking, and a discussion on possibilities of the further data analysis. The research described in this article was conducted in the Tatra National Park (TNP) in Poland, which is considered as one of the most-visited national parks in Europe. The exceptional popularity of this place is responsible for intensification of morphogenetic processes, resulting in the development of numerous forms of erosion. This article presents the outcomes of research, whose purpose was to verify the usability of UAVs to check the condition of hiking trails in alpine areas. An octocopter equipped with a non-metric camera was used for measurements. Unlike traditional methods of measuring landscape features, such a solution facilitates acquisition of quasi-continuous data that has uniform resolution throughout the study area and high spatial accuracy. It is also a relatively cheap technology, which is its main advantage over equally popular laser scanning. The paper presents the complete methodology of data acquisition in harsh conditions and demanding locations of hiking trails on steep Tatra slopes. The paper also describes stages that lead to the elaboration of basic photogrammetric products relying on structure from motion (SfM) technology and evaluates the accuracy of the materials obtained. Finally, it shows the applicability of the prepared products to the evaluation of the spatial reach and intensity of erosion along hiking trails, and to the study of plant succession or tree stand condition in the area located next to hiking trails. PMID- 29286328 TI - Microstructure and Mechanical Properties Evolution of the Al, C-Containing CoCrFeNiMn-Type High-Entropy Alloy during Cold Rolling. AB - The effect of cold rolling on the microstructure and mechanical properties of an Al- and C-containing CoCrFeNiMn-type high-entropy alloy was reported. The alloy with a chemical composition (at %) of (20-23) Co, Cr, Fe, and Ni; 8.82 Mn; 3.37 Al; and 0.69 C was produced by self-propagating high-temperature synthesis with subsequent induction. In the initial as-cast condition the alloy had an face centered cubic single-phase coarse-grained structure. Microstructure evolution was mostly associated with either planar dislocation glide at relatively low deformation during rolling (up to 20%) or deformation twinning and shear banding at higher strain. After 80% reduction, a heavily deformed twinned/subgrained structure was observed. A comparison with the equiatomic CoCrFeNiMn alloy revealed higher dislocation density at all stages of cold rolling and later onset of deformation twinning that was attributed to a stacking fault energy increase in the program alloy; this assumption was confirmed by calculations. In the initial as-cast condition the alloy had low yield strength of 210 MPa with yet very high uniform elongation of 74%. After 80% rolling, yield strength approached 1310 MPa while uniform elongation decreased to 1.3%. Substructure strengthening was found to be dominated at low rolling reductions (<40%), while grain (twin) boundary strengthening prevailed at higher strains. PMID- 29286330 TI - Control of Silver Diffusion in Low-Temperature Co-Fired Diopside Glass-Ceramic Microwave Dielectrics. AB - Electrode material for low-temperature co-fired diopside glass-ceramic used for microwave dielectrics was investigated in the present work. Diffusion of silver from the electrode to diopside glass-ceramics degrades the performance of the microwave dielectrics. Two approaches were adopted to resolve the problem of silver diffusion. Firstly, silicon-oxide (SiO2) powder was employed and secondly crystalline phases were chosen to modify the sintering behavior and inhibit silver ions diffusion. Nanoscale amorphous SiO2 powder turns to the quartz phase uniformly in dielectric material during the sintering process, and prevents the silver from diffusion. The chosen crystalline phase mixing into the glass ceramics enhances crystallinity of the material and inhibits silver diffusion as well. The result provides a method to decrease the diffusivity of silver ions by adding the appropriate amount of SiO2 and appropriate crystalline ceramics in diopside glass-ceramic dielectric materials. Finally, we used IEEE 802.11a 5.8 GHz as target specification to manufacture LTCC antenna and the results show that a good broadband antenna was made using CaMgSi2O6 with 4 wt % silicon oxide. PMID- 29286329 TI - Amyloid Biomarkers in Conformational Diseases at Face Value: A Systematic Review. AB - Conformational diseases represent a new aspect of proteomic medicine where diagnostic and therapeutic paradigms are evolving. In this context, the early biomarkers for target cell failure (neurons, beta-cells, etc.) represent a challenge to translational medicine and play a multidimensional role as biomarkers and potential therapeutic targets. This systematic review, which follows the PICO and Prisma methods, analyses this new-fangled multidimensionality, its strengths and limitations, and presents the future possibilities it opens up. The nuclear diagnosis methods are immunoassays: ELISA, immunodot, western blot, etc., while the therapeutic approach is focused on pharmaco- and molecular chaperones. PMID- 29286331 TI - Chemical Constituents of the Ethyl Acetate Extract from Diaphragma juglandis Fructus and Their Inhibitory Activity on Nitric Oxide Production In Vitro. AB - Diaphragma juglandis fructus contains various bioactive constituents. Fourteen compounds were isolated from Diaphragma juglandis fructus by preparative high performance liquid chromatography (pre-HPLC) and high-speed counter-current chromatography (HSCCC). Their structures were identified by nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS). Compounds (+)-dehydrovomifoliol (12), (6R,9R)-9-hydroxymegastigman-4-en-3-one (13) and (6R,9S)-9-hydroxymegastigman-4-en-3-one (14) are found from Juglans regia L. for the first time. Compounds dihydrophaseic acid (2), blumenol B (3) and (4S)-4 hydroxy-1-tetralone (11) are isolated from Diaphragma juglandis fructus for the first time. The anti-inflammatory effects of isolated compounds were evaluated by an in vitro model of lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds gallic acid (1), ethyl gallate (9) and (+)-dehydrovomifoliol (12) exhibited inhibitory activity on the nitric oxide production of RAW 264.7 at a concentration of 25 MUM. The result indicated that the combination HSCCC with pre HPLC is an effective way for compound separation and purification. And Diaphragma juglandis fructus constituents have the potential for the treatment of inflammatory-related diseases. PMID- 29286332 TI - Genome-Wide Analysis of Long Non-Coding RNAs in Potato and Their Potential Role in Tuber Sprouting Process. AB - Sprouting is a key factor affecting the quality of potato tubers. The present study aimed to compare the differential expression of long non-coding RNAs (lncRNAs) in the apical meristem during the dormancy release and sprouting stages by using lncRNA sequencing. Microscopic observations and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed the changes in the morphology and expression of lncRNAs in potato tubers during sprouting. Meristematic cells of potato tuber apical buds divided continuously and exhibited vegetative cone bulging and vascularisation. In all, 3175 lncRNAs were identified from the apical buds of potato tubers, among which 383 lncRNAs were up-regulated and 340 were down-regulated during sprouting. The GO enrichment analysis revealed that sprouting mainly influenced the expression of lncRNAs related to the cellular components of potato apical buds (e.g., cytoplasm and organelles) and cellular metabolic processes. The KEGG enrichment analysis also showed significant enrichment of specific metabolic pathways. In addition, 386 differentially expressed lncRNAs during sprouting were identified as putative targets of 235 potato miRNAs. Quantitative real-time polymerase chain reaction results agreed with the sequencing data. Our study provides the first systematic study of numerous lncRNAs involved in the potato tuber sprouting process and lays the foundation for further studies to elucidate their precise functions. PMID- 29286333 TI - Phytoestrogenic Activity of Blackcurrant Anthocyanins Is Partially Mediated through Estrogen Receptor Beta. AB - Phytoestrogens are plant compounds with estrogenic effects found in many foods. We have previously reported phytoestrogen activity of blackcurrant anthocyanins (cyanidin-3-glucoside, cyanidin-3-rutinoside, delphinidin-3-glucoside, and delphinidin-3-rutinoside) via the estrogen receptor (ER)alpha. In this study, we investigated the participation of ERbeta in the phytoestrogen activity of these anthocyanins. Blackcurrant anthocyanin induced ERbeta-mediated transcriptional activity, and the IC50 of ERbeta was lower than that of ERalpha, indicating that blackcurrant anthocyanins have a higher binding affinity to ERbeta. In silico docking analysis of cyanidin and delphinidin, the core portions of the compound that fits within the ligand-binding pocket of ERbeta, showed that similarly to 17beta-estradiol, hydrogen bonds formed with the ERbeta residues Glu305, Arg346, and His475. No fitting placement of glucoside or rutinoside sugar chains within the ligand-binding pocket of ERbeta-estradiol complex was detected. However, as the conformation of helices 3 and 12 in ERbeta varies depending on the ligand, we suggest that the surrounding structure, including these helices, adopts a conformation capable of accommodating glucoside or rutinoside. Comparison of ERalpha and ERbeta docking structures revealed that the selectivity for ERbeta is higher than that for ERalpha, similar to genistein. These results show that blackcurrant anthocyanins exert phytoestrogen activity via ERbeta. PMID- 29286334 TI - A Single Neonatal Exposure to BMAA in a Rat Model Produces Neuropathology Consistent with Neurodegenerative Diseases. AB - Although cyanobacterial beta-N-methylamino-l-alanine (BMAA) has been implicated in the development of Alzheimer's Disease (AD), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS), no BMAA animal model has reproduced all the neuropathology typically associated with these neurodegenerative diseases. We present here a neonatal BMAA model that causes beta-amyloid deposition, neurofibrillary tangles of hyper-phosphorylated tau, TDP-43 inclusions, Lewy bodies, microbleeds and microgliosis as well as severe neuronal loss in the hippocampus, striatum, substantia nigra pars compacta, and ventral horn of the spinal cord in rats following a single BMAA exposure. We also report here that BMAA exposure on particularly PND3, but also PND4 and 5, the critical period of neurogenesis in the rodent brain, is substantially more toxic than exposure to BMAA on G14, PND6, 7 and 10 which suggests that BMAA could potentially interfere with neonatal neurogenesis in rats. The observed selective toxicity of BMAA during neurogenesis and, in particular, the observed pattern of neuronal loss observed in BMAA-exposed rats suggest that BMAA elicits its effect by altering dopamine and/or serotonin signaling in rats. PMID- 29286335 TI - Estimating the Excess Mortality Risk during Two Red Alert Periods in Beijing, China. AB - The magnitude of excess mortality risk due to exposures to heavy air pollution during the red alert periods in Beijing remains unknown. A health impact assessment tool combined with the PM2.5-mortality relationship was applied to estimate the number of excess deaths due to high air pollution exposure during two red alert periods in Beijing, China in December 2015. Daily PM2.5 concentration increased from 80.2 ug/m3 to 159.8 ug/m3 during the first red alert period and from 61.9 ug/m3 to 226 ug/m3 during the second period in 2015 when compared to daily PM2.5 concentrations during the same calendar date of 2013 and 2014. It was estimated that 26 to 42 excessive deaths (including 14 to 34 cardiovascular deaths, and four to 16 respiratory deaths) occurred during the first period, and 40 to 65 excessive deaths (22 to 53 cardiovascular deaths, and six to 13 respiratory deaths) occurred during the second period. The results show that heavy smog may have substantially increased the mortality risk in Beijing, suggesting more stringent air pollution controlling measures should be implemented to protect the public health. PMID- 29286336 TI - A Field-Portable Cell Analyzer without a Microscope and Reagents. AB - This paper demonstrates a commercial-level field-portable lens-free cell analyzer called the NaviCell (No-stain and Automated Versatile Innovative cell analyzer) capable of automatically analyzing cell count and viability without employing an optical microscope and reagents. Based on the lens-free shadow imaging technique, the NaviCell (162 * 135 * 138 mm3 and 1.02 kg) has the advantage of providing analysis results with improved standard deviation between measurement results, owing to its large field of view. Importantly, the cell counting and viability testing can be analyzed without the use of any reagent, thereby simplifying the measurement procedure and reducing potential errors during sample preparation. In this study, the performance of the NaviCell for cell counting and viability testing was demonstrated using 13 and six cell lines, respectively. Based on the results of the hemocytometer (de facto standard), the error rate (ER) and coefficient of variation (CV) of the NaviCell are approximately 3.27 and 2.16 times better than the commercial cell counter, respectively. The cell viability testing of the NaviCell also showed an ER and CV performance improvement of 5.09 and 1.8 times, respectively, demonstrating sufficient potential in the field of cell analysis. PMID- 29286337 TI - Identification of Two Novel Fibrinogen Bbeta Chain Mutations in Two Slovak Families with Quantitative Fibrinogen Disorders. AB - Congenital fibrinogen disorders are caused by mutations in one of the three fibrinogen genes that affect the synthesis, assembly, intracellular processing, stability or secretion of fibrinogen. Functional studies of mutant Bbeta-chains revealed the importance of individual residues as well as three-dimensional structures for fibrinogen assembly and secretion. This study describes two novel homozygous fibrinogen Bbeta chain mutations in two Slovak families with afibrinogenemia and hypofibrinogenemia. Peripheral blood samples were collected from all subjects with the aim of identifying the causative mutation. Coagulation related tests and rotational thromboelastometry were performed. All exons and exon-intron boundaries of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR followed by direct sequencing. Sequence analysis of the three fibrinogen genes allowed us to identify two novel homozygous mutations in the FGB gene. A novel Bbeta chain truncation (BbetaGln180Stop) was detected in a 28-year-old afibrinogenemic man with bleeding episodes including repeated haemorrhaging into muscles, joints, and soft tissues, and mucocutaneous bleeding and a novel Bbeta missense mutation (BbetaTyr368His) was found in a 62-year-old hypofibrinogenemic man with recurrent deep and superficial venous thromboses of the lower extremities. The novel missense mutation was confirmed by molecular modelling. Both studying the molecular anomalies and the modelling of fibrinogenic mutants help us to understand the extremely complex machinery of fibrinogen biosynthesis and finally better assess its correlation with the patient's clinical course. PMID- 29286339 TI - Simplified Antenna Group Determination of RS Overhead Reduced Massive MIMO for Wireless Sensor Networks. AB - Massive multiple-input multiple-output (MIMO) systems can be applied to support numerous internet of things (IoT) devices using its excessive amount of transmitter (TX) antennas. However, one of the big obstacles for the realization of the massive MIMO system is the overhead of reference signal (RS), because the number of RS is proportional to the number of TX antennas and/or related user equipments (UEs). It has been already reported that antenna group-based RS overhead reduction can be very effective to the efficient operation of massive MIMO, but the method of deciding the number of antennas needed in each group is at question. In this paper, we propose a simplified determination scheme of the number of antennas needed in each group for RS overhead reduced massive MIMO to support many IoT devices. Supporting many distributed IoT devices is a framework to configure wireless sensor networks. Our contribution can be divided into two parts. First, we derive simple closed-form approximations of the achievable spectral efficiency (SE) by using zero-forcing (ZF) and matched filtering (MF) precoding for the RS overhead reduced massive MIMO systems with channel estimation error. The closed-form approximations include a channel error factor that can be adjusted according to the method of the channel estimation. Second, based on the closed-form approximation, we present an efficient algorithm determining the number of antennas needed in each group for the group-based RS overhead reduction scheme. The algorithm depends on the exact inverse functions of the derived closed-form approximations of SE. It is verified with theoretical analysis and simulation that the proposed algorithm works well, and thus can be used as an important tool for massive MIMO systems to support many distributed IoT devices. PMID- 29286338 TI - The Vulnerability of People to Damaging Hydrogeological Events in the Calabria Region (Southern Italy). AB - Background: Damaging Hydrogeological Events (DHEs) are severe weather periods during which floods, landslides, lightning, windstorms, hail or storm surges can harm people. Climate change is expected to increase the frequency/intensity of DHEs and, consequently, the potential harm to people. Method: We investigated the impacts of DHEs on people in Calabria (Italy) over 37 years (1980-2016). Data on 7288 people physically affected by DHEs were gathered from the systematic analysis of regional newspapers and collected in the database named PEOPLE. The damage was codified in three severity levels as follows: fatalities (people who were killed), injured (people who suffered physical harm) and involved (people who were present at the place where an accident occurred but survived and were not harmed). During the study period, we recorded 68 fatalities, 566 injured and 6654 people involved in the events. Results: Males were more frequently killed, injured and involved than females, and females who suffered fatalities were older than males who suffered fatalities, perhaps indicating that younger females tended to be more cautious than same-aged males, while older females showed an intrinsic greater vulnerability. Involved people were younger than injured people and fatalities, suggesting that younger people show greater promptness in reacting to dangerous situations. Floods caused the majority of the fatalities, injured and involved people, followed by landslides. Lightning was the most dangerous phenomenon, and it affected a relatively low number of people, killing 11.63% of them and causing injuries to 37.2%. Fatalities and injuries mainly occurred outdoors, largely along roads. In contrast, people indoors, essentially in public or private buildings, were more frequently involved without suffering harm. Being "dragged by water/mud" and "surrounded by water/mud", respectively, represented the two extremes of dynamic dangerousness. The dragging effect of rapid-flowing water totally or partially obstructed the attempts of people to save their lives. In contrast, people surrounded by steady water/mud encountered difficulties but ultimately could survive. Conclusions: The study outcomes can be used in informational campaigns to increase risk awareness among both administrators and citizens and to improve community resilience, particularly in promoting self-protective behaviors and avoiding the underestimation of hazardous situations. PMID- 29286341 TI - Fabrication of Glass Microchannel via Glass Imprinting using a Vitreous Carbon Stamp for Flow Focusing Droplet Generator. AB - This study reports a cost-effective method of replicating glass microfluidic chips using a vitreous carbon (VC) stamp. A glass replica with the required microfluidic microstructures was synthesized without etching. The replication method uses a VC stamp fabricated by combining thermal replication using a furan based, thermally-curable polymer with carbonization. To test the feasibility of this method, a flow focusing droplet generator with flow-focusing and channel widths of 50 um and 100 um, respectively, was successfully fabricated in a soda lime glass substrate. Deviation between the geometries of the initial shape and the vitreous carbon mold occurred because of shrinkage during the carbonization process, however this effect could be predicted and compensated for. Finally, the monodispersity of the droplets generated by the fabricated microfluidic device was evaluated. PMID- 29286340 TI - SLC9A3 Protein Is Critical for Acrosomal Formation in Postmeiotic Male Germ Cells. AB - Solute carrier family 9 isoform 3 (SLC9A3), a Na+/H+ exchanger, regulates the transepithelial absorption of Na+ and water and is primarily expressed on the apical membranes of the intestinal epithelium, renal proximal tubule, epididymis, and vas deferens. Loss of the Slc9a3 allele in mice enhances intestinal fluid and causes diarrhoea as a consequence of diminished Na+ and HCO3- absorption. Hence, the loss also causes male infertility and reveals the abnormal dilated lumen of the rete testis and calcification in efferent ductules. However, whether loss of Slc9a3 alleles also disrupts mammalian spermatogenesis remains unknown. First, through immunoblotting, we determined that SLC9A3 is highly expressed in the murine testis compared with the small intestine, epididymis, and vas deferens. During murine spermatogenesis, SLC9A3 is specifically expressed in the acrosome region of round, elongating, and elongated spermatids through immunostaining. Furthermore, SLC9A3 signals are enriched in the acrosome of mature sperm isolated from the vas deferens. In Slc9a3 knockout (KO) mice, compared with the same-aged controls, the number of spermatids on the testicular section of the mice progressively worsened in mice aged 20, 35, and 60 days. Sperm isolated from the epididymis of Slc9a3 KO mice revealed severe acrosomal defects. Our data indicated that SLC9A3 has a vital role in acrosomal formation during spermiogenesis. PMID- 29286342 TI - Impact of Interprofessional Relationships from Nurses' Perspective on the Decision-Making Capacity of Patients in a Clinical Setting. AB - Interprofessional relationships may impact the decision making of patients in a clinical setting. The objective of this study was to analyse the decision-making capabilities of patients from nurses' perspectives of interprofessional relationships using Foucauldian ethics. This qualitative study was based on poststructuralist Foucault references with in-depth interviews of nurses working in internal medicine and specialties in a general hospital. The patients constantly appeared in the definition of teamwork, but also as a passive element used by every professional to communicate with others. Nurses continue modelling a type of patient passivity, or what Foucault called passive subjectivity in relation to oneself, because the patient is guided and directed to take charge of a truth provided by professionals. Nurses must break the rigid design of sections or professional skills, and adopt a model of teamwork that meets the needs of the patient and increases their decision-making power. The quality of care will increase to the extent that professionals establish a relationship of equality with the patient, allowing the patient to make real decisions about their care. An egalitarian model of teamwork is beneficial to the patient, abandoning the idea of a team where the patient and family are constantly excluded from decisions about their care. PMID- 29286344 TI - Measuring Outcomes of Psychological Well-Being within Paediatric Health Settings. AB - There are many widely used, validated patient reported outcome measures for physical and mental health. However, capturing outcomes from young people living with chronic health conditions presents a challenge, needing to take the complex interplay of physical and mental health into consideration. The authors found that regularly used outcome measures for child and adolescent emotional well being in paediatric settings largely fall into two groups: paediatric quality of life and child and adolescent mental health measures. The applicability and potential for use of these measures within this context is discussed. Whilst offering some utility, neither approach leaves sufficient space for young people's individual experiences of illness and treatment. The scope of using alternative qualitative approaches that capture the rich stories and experiences of young people living with chronic illnesses is considered. PMID- 29286343 TI - Microbial Regulation of Glucose Metabolism and Insulin Resistance. AB - Type 2 diabetes is a combined disease, resulting from a hyperglycemia and peripheral and hepatic insulin resistance. Recent data suggest that the gut microbiota is involved in diabetes development, altering metabolic processes including glucose and fatty acid metabolism. Thus, type 2 diabetes patients show a microbial dysbiosis, with reduced butyrate-producing bacteria and elevated potential pathogens compared to metabolically healthy individuals. Furthermore, probiotics are a known tool to modulate the microbiota, having a therapeutic potential. Current literature will be discussed to elucidate the complex interaction of gut microbiota, intestinal permeability and inflammation leading to peripheral and hepatic insulin resistance. Therefore, this review aims to generate a deeper understanding of the underlying mechanism of potential microbial strains, which can be used as probiotics. PMID- 29286345 TI - A Tuned-RF Duty-Cycled Wake-Up Receiver with -90 dBm Sensitivity. AB - A novel wake-up receiver for wireless sensor networks is introduced. It operates with a modified medium access protocol (MAC), allowing low-energy consumption and practical latency. The ultra-low-power wake-up receiver operates with enhanced duty-cycled listening. The analysis of energy models of the duty-cycle-based communication is presented. All the WuRx blocks are studied to obey the duty cycle operation. For a mean interval time for the data exchange cycle between a transmitter and a receiver over 1.7 s and a 64-bit wake-up packet detection latency of 32 ms, the average power consumption of the wake-up receiver (WuRx) reaches down to 3 MU W . It also features scalable addressing of more than 512 bit at a data rate of 128 k bit / s -1. At a wake-up packet error rate of 10 - 2 , the detection sensitivity reaches a minimum of - 90 dBm . The combination of the MAC protocol and the WuRx eases the adoption of different kinds of wireless sensor networks. In low traffic communication, the WuRx dramatically saves more energy than that of a network that is implementing conventional duty-cycling. In this work, a prototype was realized to evaluate the intended performance. PMID- 29286346 TI - Hydrazone Derivatives Enhance Antileishmanial Activity of Thiochroman-4-ones. AB - Cutaneous leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, and toxicity or reduced effectiveness of available drugs in addition to complex and prolonged treatments, there is an urgent need to develop alternatives for the treatment for CL with different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antileishmanial activity against the intracellular amastigote form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Our results show that derivatization of the thiochroman-4-ones with acyl hydrazones significantly enhances the antileishmanial activity. Among the compounds tested semicarbazone and thiosemicarbazone derivatives of thioflavanone 19 and 20 displayed the highest antileishmanial activities, with EC50 values of 5.4 and 5.1 uM and low cytotoxicities (100.2 and 50.1 uM respectively), resulting in higher indexes of selectivity (IS). PMID- 29286347 TI - Anticonvulsant Activity of Halogen-Substituted Cinnamic Acid Derivatives and Their Effects on Glycosylation of PTZ-Induced Chronic Epilepsy in Mice. AB - Epilepsy is a common chronic neurological disorder disease, and there is an urgent need for the development of novel anticonvulsant drugs. In this study, the anticonvulsant activities and neurotoxicity of 12 cinnamic acid derivatives substituted by fluorine, chlorine, bromine, and trifluoromethyl groups were screened by the maximal electroshock seizure (MES) and rotarod tests (Tox). Three of the tested compounds (compounds 3, 6 and 12) showed better anticonvulsant effects and lower neurotoxicity. They showed respective median effective dose (ED50) of 47.36, 75.72 and 70.65 mg/kg, and median toxic dose (TD50) of them was greater than 500 mg/kg, providing better protective indices. Meanwhile, they showed a pentylenetetrazol (PTZ) ED50 value of 245.2, >300 and 285.2 mg/kg in mice, respectively. Especially, the most active compound 3 displayed a prominent anticonvulsant profile and had lower toxicity. Therefore, the antiepileptic mechanism of 3 on glycosylation changes in chronic epilepsy in mice was further investigated by using glycomics techniques. Lectin microarrays results showed that epilepsy was closely related to abnormal glycosylation, and 3 could reverse the abnormal glycosylation in scPTZ-induced epilepsy in mice. This work can provide new ideas for future discovery of potential biomarkers for evaluation of antiepileptic drugs based on the precise alterations of glycopatterns in epilepsy. PMID- 29286348 TI - Plant-Based Beverages as Good Sources of Free and Glycosidic Plant Sterols. AB - To address the ever-growing group of health-conscious consumers, more and more nutritional and health claims are being used on food products. Nevertheless, only very few food constituents, including plant sterols, have been appointed an approved health claim (European Commission and Food and Drugs Administration). Plant sterols are part of those limited lists of approved compounds for their cholesterol-lowering properties but have been praised for their anti-inflammatory and anti-carcinogenic properties as well. Despite this indisputable reputation, direct quantitative data is still lacking for naturally present (conjugated) plant sterols in beverages. This study aimed to fill this gap by applying a validated extraction and UPLC-MS/MS detection method to a diverse range of everyday plant-based beverages. beta-sitosterol-beta-d-glucoside (BSSG) showed to be by far the most abundant sterol in all beverages studied, with concentrations up to 60-90 mg per 100 mL in plant-based milk alternatives and fresh fruit juices. Ergosterol (provitamin D2) could be found in beers (0.8-6.1 ug per 100 mL, from the yeast) and occasionally in juices (17-29 ug per 100 mL). Overall, the results demonstrated that the concentrations of water-soluble sterol conjugates have been underestimated significantly and that specific plant-based beverages can be good, low-fat sources of these plant sterols. PMID- 29286349 TI - Compressional-Puffing Pretreatment Enhances Neuroprotective Effects of Fucoidans from the Brown Seaweed Sargassum hemiphyllum on 6-Hydroxydopamine-Induced Apoptosis in SH-SY5Y Cells. AB - In this study, a compressional-puffing process (CPP) was used to pretreat Sargassum hemiphyllum (SH) and then fucoidan was extracted from SH by hot water. Three fucoidan extracts, namely SH1 (puffing at 0 kg/cm2); SH2 (puffing at 1.7 kg/cm2); and SH3 (puffing at 10.0 kg/cm2) were obtained, and their compositions and biological activities were evaluated. The results indicate that CPP increased the extraction yield, total sugar content, and molar ratios of sulfate/fucose of fucoidan and decreased molecular weight and impurities of fucoidan. The SH1-SH3 extracts exhibited characteristics of fucoidan as demonstrated by the analyses of composition, FTIR spectroscopy, NMR spectroscopy, and molecular weight. All SH1 SH3 extracts showed antioxidant activities. The SH1-SH3 extracts protected SH SY5Y cells from 6-hydroxydopamine (6-OHDA)-induced apoptosis as illustrated by cell cycle distribution, cytochrome c release, activation of caspase-8, -9, and 3, and DNA fragmentation analyses. Additional experiments revealed that phosphorylation of Akt is involved in the opposing effects of SH1-SH3 on 6-OHDA induced neurotoxicity. SH3 exhibited a relatively high extraction yield, the lowest levels of impurities, and was the most effective at reversing the 6-OHDA induced neurotoxicity of SH-SY5Y cells among SH1-SH3, which taken together indicate that it may have potential as a candidate therapeutic agent for the preventive therapy of neurodegenerative diseases. PMID- 29286350 TI - Low Body Mass Index Is an Independent Predictive Factor after Surgical Resection in Patients with Non-Small Cell Lung Cancer AB - Background: The effect of body mass index (BMI) on postoperative survival in non small cell lung cancer (NSCLC)has been controversial. We retrospectively analysed the effect of preoperative BMI on postoperative outcomes of NSCLCsurgery. Methods: Consecutive 384 NSCLC patients were enrolled. Patients were subdivided into 3 groups: low BMIgroup (BMI<18.5 kg/m2), normal BMI group (BMI=18.5-24.0 kg/m2) and high BMI group (BMI>24.0 kg/m2). Theprognostic significance of BMI was examined retrospectively. Results: The 5-year survival of patients with low, normaland high BMI groups were 46.3%, 74.3% and 84.3%, respectively. The low BMI group had a poorer prognosis than theother groups (p<0.001). The survival of high BMI group had a more favorable trend than that of normal BMI group, butthis did not reach statistical significance (p=0.057). On multivariate analysis, significant risk factors for cancer-specificsurvival were male gender (p=0.0061), non-adenocarcinoma histology (p=0.0003), pN1-2 status (p=0.0007), high serumCEA level (p<0.0001) and low BMI (low vs. others: p <0.0001). Conclusions: Preoperative BMI is an independentprognostic factor for NSCLC patients after surgical resection, with low BMI patients having an unfavorable prognosis. PMID- 29286351 TI - Is pulsed ultrasound an alternative for osteoarthritis? AB - INTRODUCTION: Many osteoarthritis patients persist symptomatic despite nonsurgical treatment. Pulsed ultrasound might be a viable alternative for such cases, but its real clinical relevance remains unclear. METHODS: A literature review was conducted in Epistemonikos, the largest database for sys-tematic reviews in health that compiles multiple sources, including MEDLINE, EMBASE, and Cochrane, among others. Relevant data were extracted, and infor-mation from the primary studies was reanalyzed. A subsequent meta-analysis was conducted, and summary of findings tables were constructed using the GRADE methodology. RESULTS AND CONCLUSIONS: Six systematic reviews including eight randomized trials were identified. In conclusion, it is not clear whether pulsed ultrasound improves functionality, and it might slightly decrease pain but the certainty of the evidence is low. PMID- 29286352 TI - Are systemic corticosteroids useful for the management of acute pharyngitis? AB - INTRODUCTION: Pain associated to acute pharyngitis is a frequent cause of consultation. Usual care includes non-steroidal anti-inflammatories and antibiotics in selected cases, but pain relief is not always quick enough. The use of corticosteroids has been proposed as a therapeutic alternative, but its actual efficacy is matter of debate. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified eight systematic reviews including 11 studies overall, of which 10 were randomized trials. We concluded a short course of systemic corticosteroids reduces pain related to acute pharyngitis, without increasing the risk of adverse effects. PMID- 29286353 TI - Is perioperative pregabalin effective for reducing postoperative pain in major surgery? AB - INTRODUCTION: Pregabalin is a structural analog of gamma-aminobutyric acid that may have a role in acute pain management. It has been used in the perioperative context, but there is controversy regarding its real clinical utility. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 21 systematic reviews including 77 randomized trials. We concluded the use of perioperative pregabalin in major surgeries probably does not produce a clinically important decrease in acute postoperative pain. Although it could decrease nausea, postoperative vomiting and opioid requirements, it also produces an increase in sedation. PMID- 29286354 TI - Is pre-exposure prophylaxis effective for preventing HIV infection in men who have sex with men? AB - INTRODUCTION: Increasing rates of HIV infection remain of concern, especially for high-risk groups such as men who have sex with men. Oral pre-exposure prophylaxis has emerged as an alternative to prevention. However, doubts persist in patients and physicians about its effectiveness. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified six systematic reviews including twelve studies overall, of which six were randomized trials. We concluded the use of oral pre-exposure prophylaxis reduces the probability of HIV infection in men who have sex with men, has few or no adverse effects, and is a measure with a good balance between benefits, risks and costs. PMID- 29286356 TI - Is flumazenil an alternative for the treatment of hepatic encephalopathy? AB - INTRODUCTION: Flumazenil is an antagonist of the GABA/benzodiazepines receptor complex that might play a role in the treatment of hepatic encephalopathy. However, its efficacy and safety are a matter of debate. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews including fourteen randomized trials. We concluded flumazenil does not reduce mortality in patients with hepatic encephalopathy and it is not clear whether it leads to any clinical improvement because the certainty of the evidence is very low. PMID- 29286355 TI - Are cannabinoids effective for the management of chemotherapy induced nausea and vomiting? AB - INTRODUCTION: Nausea and vomiting are common side effects in cancer patients treated with chemotherapy. Proper control of these symptoms might improve quality of life in these patients. Addition of cannabinoids to standard antiemetic treatment has been proposed in order to improve control of these symptoms. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 16 systematic reviews that include 61 primary studies. Out of these, four were randomized trials that answered our question. At present, given that the certainty of the evidence is very low, it is unclear whether the addition of cannabinoids to standard antiemetic regimes benefits patients with chemotherapy induced nausea and vomiting. Cannabinoids probably increase adverse effects substantively. PMID- 29286357 TI - Are cannabinoids an alternative for cachexia-anorexia syndrome in patients with advanced cancer? AB - INTRODUCTION: Cachexia and anorexia are among the most frequent symptoms in patients with cancer. Cannabinoids have been used in patients with advanced cancer; however, their role is still controversial. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified ten systematic reviews including three studies overall, of which two were randomized trials. We concluded it is not clear whether cannabinoids have any positive effect on increasing weight because the certainty of the evidence is very low. They might not have any effect on appetite, and are probably associated to frequent adverse effects. PMID- 29286358 TI - Is wrist splint more effective than forearm band for lateral epicondylitis? AB - INTRODUCTION: Lateral epicondylitis is a common cause of lateral elbow pain. There are many treatments able to improvement symptoms, including orthotic devices. The main available orthosis are wrist splint and forearm band. However, it is not clear which one constitutes the best alternative for symptomatic treatment. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including four studies overall, all of them randomized trials. With this evidence, we concluded there might be no difference in global measure of improvement and pain free grip strength between the forearm band and wrist splint, and it is not clear whether using a wrist splint decreases pain in comparison with a forearm band, because the certainty of the evidence is very low. PMID- 29286359 TI - Is intravenous lidocaine effective for decreasing pain and speeding up recovery after surgery? AB - INTRODUCTION: Lidocaine is widely used in anesthesia due to its multiple properties, including its role as analgesic. However, it is not entirely clear which are the real benefits of its use in the perioperative setting. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 15 systematic reviews including 53 studies overall, all of them randomized controlled trials. We concluded the use of intravenous perioperative lidocaine probably results in a clinically irrelevant difference in pain and length of hospital stay, but it probably prevents postoperative nausea and vomiting. PMID- 29286360 TI - Conditional Knockdown of Gene Expression in Cancer Cell Lines to Study the Recruitment of Monocytes/Macrophages to the Tumor Microenvironment. AB - siRNA and shRNA-mediated knock down (KD) methods of regulating gene expression are invaluable tools for understanding gene and protein function. However, in the case that the KD of the protein of interest has a lethal effect on cells or the anticipated effect of the KD is time-dependent, unconditional KD methods are not appropriate. Conditional systems are more suitable in these cases and have been the subject of much interest. These include Ecdysone-inducible overexpression systems, Cytochrome P-450 induction system1, and the tetracycline regulated gene expression systems. The tetracycline regulated gene expression system enables reversible control over protein expression by induction of shRNA expression in the presence of tetracycline. In this protocol, we present an experimental design using functional Tet-ON system in human cancer cell lines for conditional regulation of gene expression. We then demonstrate the use of this system in the study of tumor cell-monocyte interaction. PMID- 29286361 TI - In Vivo Assay for Detection of Antigen-specific T-cell Cytolytic Function Using a Vaccination Model. AB - Current methodologies for antigen-specific killing are limited to in vitro use or utilized in infectious disease models. However, there is not a protocol specifically intended to measure antigen-specific killing without an infection. This protocol is designed and describes methods to overcome these limitations by allowing for the detection of antigen-specific killing of a target cell by CD8+ T cells in vivo. This is accomplished by merging a vaccination model with a traditional CFSE-labeled target killing assay. This combination allows the researcher to assess the antigen-specific CTL potential directly and quickly as the assay is not dependent upon tumor growth or infection. In addition, the readout is based on flow cytometry and so should be readily accessible to most researchers. The major limitation of the study is identifying the timeline in vivo that is appropriate to the hypothesis being tested. Variations in antigen strength and mutations in the T cells that may result in differential cytolytic function need to be carefully assessed to determine the optimal time for cell harvest and assessment. The appropriate concentration of peptide for vaccination has been optimized for hgp10025-33 and OVA257-264, but further validation would be needed for other peptides that may be more appropriate to a given study. Overall, this protocol allows a quick assessment of killing function in vivo and can be adapted to any given antigen. PMID- 29286362 TI - Dissection and Coronal Slice Preparation of Developing Mouse Pituitary Gland. AB - The pituitary gland or hypophysis is an important endocrine organ secreting hormones essential for homeostasis. It consists of two glands with separate embryonic origins and functions - the neurohypophysis and the adenohypophysis. The developing mouse pituitary gland is tiny and delicate with an elongated oval shape. A coronal section is preferred to display both the adenohypophysis and neurohypophysis in a single slice of the mouse pituitary. The goal of this protocol is to achieve proper pituitary coronal sections with well-preserved tissue architectures from developing mice. In this protocol, we describe in detail how to dissect and process pituitary glands properly from developing mice. First, mice are fixed by transcardial perfusion of formaldehyde prior to dissection. Then three different dissecting techniques are applied to obtain intact pituitary glands depending on the age of mice. For fetal mice aged embryonic days (E) 17.5 - 18.5 and neonates up to 4 days, the entire sella regions including the sphenoid bone, gland, and trigeminal nerves are dissected. For pups aged postnatal days (P) 5 - 14, the pituitary glands connected with trigeminal nerves are dissected as a whole. For mice over 3 weeks old, the pituitary glands are carefully dissected free from the surrounding tissues. We also display how to embed the pituitary glands in a proper orientation by using the surrounding tissues as landmarks to obtain satisfying coronal sections. These methods are useful in analyzing histological and developmental features of pituitary glands in developing mice. PMID- 29286363 TI - Mammalian Cell Division in 3D Matrices via Quantitative Confocal Reflection Microscopy. AB - The study of how mammalian cell division is regulated in a 3D environment remains largely unexplored despite its physiological relevance and therapeutic significance. Possible reasons for the lack of exploration are the experimental limitations and technical challenges that render the study of cell division in 3D culture inefficient. Here, we describe an imaging-based method to efficiently study mammalian cell division and cell-matrix interactions in 3D collagen matrices. Cells labeled with fluorescent H2B are synchronized using the combination of thymidine blocking and nocodazole treatment, followed by a mechanical shake-off technique. Synchronized cells are then embedded into a 3D collagen matrix. Cell division is monitored using live-cell microscopy. The deformation of collagen fibers during and after cell division, which is an indicator of cell-matrix interaction, can be monitored and quantified using quantitative confocal reflection microscopy. The method provides an efficient and general approach to study mammalian cell division and cell-matrix interactions in a physiologically relevant 3D environment. This approach not only provides novel insights into the molecular basis of the development of normal tissue and diseases, but also allows for the design of novel diagnostic and therapeutic approaches. PMID- 29286364 TI - Techniques for Investigating the Anatomy of the Ant Visual System. AB - This article outlines a suite of techniques in light microscopy (LM) and electron microscopy (EM) which can be used to study the internal and external eye anatomy of insects. These include traditional histological techniques optimized for work on ant eyes and adapted to work in concert with other techniques such as transmission electron microscopy (TEM) and scanning electron microscopy (SEM). These techniques, although vastly useful, can be difficult for the novice microscopist, so great emphasis has been placed in this article on troubleshooting and optimization for different specimens. We provide information on imaging techniques for the entire specimen (photo-microscopy and SEM) and discuss their advantages and disadvantages. We highlight the technique used in determining lens diameters for the entire eye and discuss new techniques for improvement. Lastly, we discuss techniques involved in preparing samples for LM and TEM, sectioning, staining, and imaging these samples. We discuss the hurdles that one might come across when preparing samples and how best to navigate around them. PMID- 29286365 TI - Proper Positioning and Restraint of a Rat Hind Limb for Focused High Resolution Imaging of Bone Micro-architecture Using In Vivo Micro-computed Tomography. AB - The use of in vivo micro-computed tomography (uCT) is a powerful tool which involves the non-destructive imaging of internal structures at high resolutions in live animal models. This allows for repeated imaging of the same rodent over time. This feature not only reduces the total number of rodents required in an experimental design and thereby reduces the inter-subject variation that can arise, but also allows researchers to assess longitudinal or life-long responses to an intervention. To acquire high quality images that can be processed and analyzed to more accurately quantify outcomes of bone micro-architecture, users of in vivo uCT scanners must properly anesthetize the rat, and position and restrain the hind limb. To do this, it is imperative that the rat be anesthetized to a level of complete relaxation, and that pedal reflexes are lost. These guidelines may be modified for each individual rat, as the rate of isoflurane metabolism can vary depending on strain and body size. Proper technique for in vivo uCT image acquisition enables accurate and consistent measurement of bone micro-architecture within and across studies. PMID- 29286366 TI - High-resolution Confocal Imaging of the Blood-brain Barrier: Imaging, 3D Reconstruction, and Quantification of Transcytosis. AB - The blood-brain barrier (BBB) is a dynamic multicellular interface that regulates the transport of molecules between the circulation and the brain. Transcytosis across the BBB regulates the delivery of hormones, metabolites, and therapeutic antibodies to the brain parenchyma. Here, we present a protocol that combines immunofluorescence of free-floating sections with laser scanning confocal microscopy and image analysis to visualize subcellular organelles within endothelial cells at the BBB. Combining this data-set with 3D image analysis software allows for the semi-automated segmentation and quantification of capillary volume and surface area, as well as the number and intensity of intracellular organelles at the BBB. The detection of mouse endogenous immunoglobulin (IgG) within intracellular vesicles and their quantification at the BBB is used to illustrate the method. This protocol can potentially be applied to the investigation of the mechanisms controlling BBB transcytosis of different molecules in vivo. PMID- 29286367 TI - Monitoring Colony-level Effects of Sublethal Pesticide Exposure on Honey Bees. AB - The effects of sublethal pesticide exposure to honey bee colonies may be significant but difficult to detect in the field using standard visual assessment methods. Here we describe methods to measure the quantities of adult bees, brood, and food resources by weighing hives and hive parts, by photographing frames, and by installing hives on scales and with internal sensors. Data from these periodic evaluations are then combined with running average and daily detrended data on hive weight and internal hive temperature. The resulting datasets have been used to detect colony-level effects of imidacloprid applied in a sugar syrup as low as 5 parts per billion. The methods are objective, require little training, and provide permanent records in the form of sensor output and photographs. PMID- 29286368 TI - Visualizing Multiciliated Cells in the Zebrafish Through a Combined Protocol of Whole Mount Fluorescent In Situ Hybridization and Immunofluorescence. AB - In recent years, the zebrafish embryo has emerged as a popular model to study developmental biology due to traits such as ex utero embryo development and optical transparency. In particular, the zebrafish embryo has become an important organism to study vertebrate kidney organogenesis as well as multiciliated cell (MCC) development. To visualize MCCs in the embryonic zebrafish kidney, we have developed a combined protocol of whole-mount fluorescent in situ hybridization (FISH) and whole mount immunofluorescence (IF) that enables high resolution imaging. This manuscript describes our technique for co-localizing RNA transcripts and protein as a tool to better understand the regulation of developmental programs through the expression of various lineage factors. PMID- 29286369 TI - Detecting the Water-soluble Chloride Distribution of Cement Paste in a High precision Way. AB - To improve the accuracy of the chloride distribution along the depth of cement paste under cyclic wet-dry conditions, a new method is proposed to obtain a high precision chloride profile. Firstly, paste specimens are molded, cured, and exposed to cyclic wet-dry conditions. Then, powder samples at different specimen depths are grinded when the exposure age is reached. Finally, the water-soluble chloride content is detected using a silver nitrate titration method, and chloride profiles are plotted. The key to improving the accuracy of the chloride distribution along the depth is to exclude the error in the powderization, which is the most critical step for testing the distribution of chloride. Based on the above concept, the grinding method in this protocol can be used to grind powder samples automatically layer by layer from the surface inward, and it should be noted that a very thin grinding thickness (less than 0.5 mm) with a minimum error less than 0.04 mm can be obtained. The chloride profile obtained by this method better reflects the chloride distribution in specimens, which helps researchers to capture the distribution features that are often overlooked. Furthermore, this method can be applied to studies in the field of cement-based materials, which require high chloride distribution accuracy. PMID- 29286370 TI - Continuous Flow Chemistry: Reaction of Diphenyldiazomethane with p-Nitrobenzoic Acid. AB - Continuous flow technology has been identified as instrumental for its environmental and economic advantages leveraging superior mixing, heat transfer and cost savings through the "scaling out" strategy as opposed to the traditional "scaling up". Herein, we report the reaction of diphenyldiazomethane with p nitrobenzoic acid in both batch and flow modes. To effectively transfer the reaction from batch to flow mode, it is essential to first conduct the reaction in batch. As a consequence, the reaction of diphenyldiazomethane was first studied in batch as a function of temperature, reaction time, and concentration to obtain kinetic information and process parameters. The glass flow reactor set up is described and combines two types of reaction modules with "mixing" and "linear" microstructures. Finally, the reaction of diphenyldiazomethane with p nitrobenzoic acid was successfully conducted in the flow reactor, with up to 95% conversion of the diphenyldiazomethane in 11 min. This proof of concept reaction aims to provide insight for scientists to consider flow technology's competitiveness, sustainability, and versatility in their research. PMID- 29286371 TI - Preparation of Keratin Hydrolysate from Chicken Feathers and Its Application in Cosmetics. AB - Keratin hydrolysates (KHs) are established standard components in hair cosmetics. Understanding the moisturizing effects of KH is advantageous for skin-care cosmetics. The goals of the protocol are: (1) to process chicken feathers into KH by alkaline-enzymatic hydrolysis and purify it by dialysis, and (2) to test if adding KH into an ointment base (OB) increases hydration of the skin and improves skin barrier function by diminishing transepidermal water loss (TEWL). During alkaline-enzymatic hydrolysis feathers are first incubated at a higher temperature in an alkaline environment and then, under mild conditions, hydrolyzed with proteolytic enzyme. The solution of KH is dialyzed, vacuum dried, and milled to a fine powder. Cosmetic formulations comprising from oil in water emulsion (O/W) containing 2, 4, and 6 weight% of KH (based on the weight of the OB) are prepared. Testing the moisturizing properties of KH is carried out on 10 men and 10 women at time intervals of 1, 2, 3, 4, 24, and 48 h. Tested formulations are spread at degreased volar forearm sites. The skin hydration of stratum corneum (SC) is assessed by measuring capacitance of the skin, which is one of the most world-wide used and simple methods. TEWL is based on measuring the quantity of water transported per a defined area and period of time from the skin. Both methods are fully non-invasive. KH makes for an excellent occlusive; depending on the addition of KH into OB, it brings about a 30% reduction in TEWL after application. KH also functions as a humectant, as it binds water from the lower layers of the epidermis to the SC; at the optimum KH addition in the OB, up to 19% rise in hydration in men and 22% rise in women occurs. PMID- 29286372 TI - Procedures of Laboratory Fumigation for Pest Control with Nitric Oxide Gas. AB - Nitric oxide (NO) is a newly discovered fumigant for postharvest pest control. This paper provides detailed protocols for conducting NO fumigation on fresh products and procedures for residue analysis and product quality evaluation. An airtight fumigation chamber containing fresh fruit and vegetables is first flushed with nitrogen (N2) to establish an ultralow oxygen (ULO) environment followed by injection of NO. The fumigation chamber is then kept at a low temperature of 2 - 5 degrees C for a specified time period necessary to kill a target pest to complete a fumigation treatment. At the end of a fumigation treatment, the fumigation chamber is flushed with N2 to dilute NO prior to opening the chamber to ambient air to prevent the reaction between NO and O2, which produces NO2 and may damage delicate fresh products. At different times after NO fumigation, NO2 in headspace and nitrate and nitrite in liquid samples were measured as residues. Product quality was evaluated after 2 weeks of post treatment cold storage to determine effects of NO fumigation on product quality. Keeping O2 from reacting with NO is critical to NO fumigation and is an important part of the protocols. Measuring NO levels is challenging and a practical solution is provided. Possible protocol modifications are also suggested for measuring NO levels in the fumigation chambers as well as residues. NO fumigation has the potential to be a practical alternative to methyl bromide fumigation for postharvest pest control on fresh and stored products. This publication is intended to assist other researchers in conducting NO fumigation research for postharvest pest control and accelerating the development of NO fumigation for practical applications. PMID- 29286373 TI - Central and Divided Visual Field Presentation of Emotional Images to Measure Hemispheric Differences in Motivated Attention. AB - Two dominant theories on lateralized processing of emotional information exist in the literature. One theory posits that unpleasant emotions are processed by right frontal regions, while pleasant emotions are processed by left frontal regions. The other theory posits that the right hemisphere is more specialized for the processing of emotional information overall, particularly in posterior regions. Assessing the different roles of the cerebral hemispheres in processing emotional information can be difficult without the use of neuroimaging methodologies, which are not accessible or affordable to all scientists. Divided visual field presentation of stimuli can allow for the investigation of lateralized processing of information without the use of neuroimaging technology. This study compared central versus divided visual field presentations of emotional images to assess differences in motivated attention between the two hemispheres. The late positive potential (LPP) was recorded using electroencephalography (EEG) and event-related potentials (ERPs) methodologies to assess motivated attention. Future work will pair this paradigm with a more active behavioral task to explore the behavioral impacts on the attentional differences found. PMID- 29286374 TI - Optical Screening of Novel Bacteria-specific Probes on Ex Vivo Human Lung Tissue by Confocal Laser Endomicroscopy. AB - Improving the speed and accuracy of bacterial detection is important for patient stratification and to ensure the appropriate use of antimicrobials. To achieve this goal, the development of diagnostic techniques to recognize bacterial presence in real-time at the point-of-care is required. Optical imaging for direct identification of bacteria within the host is an attractive approach. Several attempts at chemical probe design and validation have been investigated, however none have yet been successfully translated into the clinic. Here we describe a method for ex vivo validation of bacteria-specific probes for identification of bacteria within the distal lung, imaged by fibered confocal fluorescence microscopy (FCFM). Our model used ex vivo human lung tissue and a clinically approved confocal laser endomicroscopy (CLE) platform to screen novel bacteria-specific imaging compounds, closely mimicking imaging conditions expected to be encountered with patients. Therefore, screening compounds by this technique provides confidence of potential clinical tractability. PMID- 29286375 TI - Inducing Cre-lox Recombination in Mouse Cerebral Cortex Through In Utero Electroporation. AB - Cell-autonomous neuronal functions of genes can be revealed by causing loss or gain of function of a gene in a small and sparse population of neurons. To do so requires generating a mosaic in which neurons with loss or gain of function of a gene are surrounded by genetically unperturbed tissue. Here, we combine the Cre lox recombination system with in utero electroporation in order to generate mosaic brain tissue that can be used to study the cell-autonomous function of genes in neurons. DNA constructs (available through repositories), coding for a fluorescent label and Cre recombinase, are introduced into developing cortical neurons containing genes flanked with loxP sites in the brains of mouse embryos using in utero electroporation. Additionally, we describe various adaptations to the in utero electroporation method that increase survivability and reproducibility. This method also involves establishing a titer for Cre-mediated recombination in a sparse or dense population of neurons. Histological preparations of labeled brain tissue do not require (but can be adapted to) immunohistochemistry. The constructs used guarantee that fluorescently labeled neurons carry the gene for Cre recombinase. Histological preparations allow morphological analysis of neurons through confocal imaging of dendritic and axonal arbors and dendritic spines. Because loss or gain of function is achieved in sparse mosaic tissue, this method permits the study of cell-autonomous necessity and sufficiency of gene products in vivo. PMID- 29286376 TI - In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice. AB - Mitochondria are the powerhouses of cells and produce cellular energy in the form of ATP. Mitochondrial dysfunction contributes to biological aging and a wide variety of disorders including metabolic diseases, premature aging syndromes, and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Maintenance of mitochondrial health depends on mitochondrial biogenesis and the efficient clearance of dysfunctional mitochondria through mitophagy. Experimental methods to accurately detect autophagy/mitophagy, especially in animal models, have been challenging to develop. Recent progress towards the understanding of the molecular mechanisms of mitophagy has enabled the development of novel mitophagy detection techniques. Here, we introduce several versatile techniques to monitor mitophagy in human cells, Caenorhabditis elegans (e.g., Rosella and DCT-1/ LGG-1 strains), and mice (mt-Keima). A combination of these mitophagy detection techniques, including cross-species evaluation, will improve the accuracy of mitophagy measurements and lead to a better understanding of the role of mitophagy in health and disease. PMID- 29286377 TI - The Organoid Reconstitution Assay (ORA) for the Functional Analysis of Intestinal Stem and Niche Cells. AB - The intestinal epithelium is characterized by an extremely rapid turnover rate. In mammals, the entire epithelial lining is renewed within 4 - 5 days. Adult intestinal stem cells reside at the bottom of the crypts of Lieberkuhn, are earmarked by expression of the Lgr5 gene, and preserve homeostasis through their characteristic high proliferative rate1. Throughout the small intestine, Lgr5+ stem cells are intermingled with specialized secretory cells called Paneth cells. Paneth cells secrete antibacterial compounds (i.e., lysozyme and cryptdins/defensins) and exert a controlling role on the intestinal flora. More recently, a novel function has been discovered for Paneth cells, namely their capacity to provide niche support to Lgr5+ stem cells through several key ligands as Wnt3, EGF, and Dll12. When isolated ex vivo and cultured in the presence of specific growth factors and extracellular matrix components, whole intestinal crypts give rise to long-lived and self-renewing 3D structures called organoids that highly resemble the crypt-villus epithelial architecture of the adult small intestine3. Organoid cultures, when established from whole crypts, allow the study of self-renewal and differentiation of the intestinal stem cell niche, though without addressing the contribution of its individual components, namely the Lgr5+ and Paneth cells. Here, we describe a novel approach to the organoid assay that takes advantage of the ability of Paneth and Lgr5+ cells to associate and form organoids when co-cultured. This approach, here referred to as "organoid reconstitution assay" (ORA), allows the genetic and biochemical modification of Paneth or Lgr5+ stem cells, followed by reconstitution into organoids. As such, it allows the functional analysis of the two main components of the intestinal stem cell niche. PMID- 29286378 TI - Combining Chemical Cross-linking and Mass Spectrometry of Intact Protein Complexes to Study the Architecture of Multi-subunit Protein Assemblies. AB - Proteins interact with their ligands to form active and dynamic assemblies which carry out various cellular functions. Elucidating these interactions is therefore fundamental for the understanding of cellular processes. However, many protein complexes are dynamic assemblies and are not accessible by conventional structural techniques. Mass spectrometry contributes to the structural investigation of these assemblies, and particularly the combination of various mass spectrometric techniques delivers valuable insights into their structural arrangement. In this article, we describe the application and combination of two complementary mass spectrometric techniques, namely chemical cross-linking coupled with mass spectrometry and native mass spectrometry. Chemical cross linking involves the covalent linkage of amino acids in close proximity by using chemical reagents. After digestion with proteases, cross-linked di-peptides are identified by mass spectrometry and protein interactions sites are uncovered. Native mass spectrometry on the other hand is the analysis of intact protein assemblies in the gas phase of a mass spectrometer. It reveals protein stoichiometries as well as protein and ligand interactions. Both techniques therefore deliver complementary information on the structure of protein-ligand assemblies and their combination proved powerful in previous studies. PMID- 29286379 TI - Automated Robotic Liquid Handling Assembly of Modular DNA Devices. AB - Recent advances in modular DNA assembly techniques have enabled synthetic biologists to test significantly more of the available "design space" represented by "devices" created as combinations of individual genetic components. However, manual assembly of such large numbers of devices is time-intensive, error-prone, and costly. The increasing sophistication and scale of synthetic biology research necessitates an efficient, reproducible way to accommodate large-scale, complex, and high throughput device construction. Here, a DNA assembly protocol using the Type-IIS restriction endonuclease based Modular Cloning (MoClo) technique is automated on two liquid-handling robotic platforms. Automated liquid-handling robots require careful, often times tedious optimization of pipetting parameters for liquids of different viscosities (e.g. enzymes, DNA, water, buffers), as well as explicit programming to ensure correct aspiration and dispensing of DNA parts and reagents. This makes manual script writing for complex assemblies just as problematic as manual DNA assembly, and necessitates a software tool that can automate script generation. To this end, we have developed a web-based software tool, http://mocloassembly.com, for generating combinatorial DNA device libraries from basic DNA parts uploaded as Genbank files. We provide access to the tool, and an export file from our liquid handler software which includes optimized liquid classes, labware parameters, and deck layout. All DNA parts used are available through Addgene, and their digital maps can be accessed via the Boston University BDC ICE Registry. Together, these elements provide a foundation for other organizations to automate modular cloning experiments and similar protocols. The automated DNA assembly workflow presented here enables the repeatable, automated, high-throughput production of DNA devices, and reduces the risk of human error arising from repetitive manual pipetting. Sequencing data show the automated DNA assembly reactions generated from this workflow are ~95% correct and require as little as 4% as much hands-on time, compared to manual reaction preparation. PMID- 29286380 TI - Urinary Tract Infection in a Small Animal Model: Transurethral Catheterization of Male and Female Mice. AB - Urinary tract infections (UTI) are extremely common worldwide, incurring significant morbidity and healthcare-associated expenses. Small animal models, which accurately reflect disease establishment and progression, permit dissection of host-pathogen interactions and generation of immunity to infection. In mice, intravesical instillation of uropathogenic E. coli, the causative agent in more than 85% of community acquired UTI, recapitulates many of the stages of infection observed in humans. Until recently, however, UTI could only be modeled in female animals. This limitation has hindered the study of sex-related differences in UTI, as well as other bladder pathologies, such as cancer. Here, we describe a method to instill male mice that allows direct comparison between female and male animals and provide a detailed protocol to assess bladder tissue by flow cytometry as a means to better understand host responses to infection. Together, these approaches will aid in the identification of host factors that contribute to sex biases observed in UTI and other bladder-associated diseases. PMID- 29286382 TI - Laser-heating and Radiance Spectrometry for the Study of Nuclear Materials in Conditions Simulating a Nuclear Power Plant Accident. AB - Major and severe accidents have occurred three times in nuclear power plants (NPPs), at Three Mile Island (USA, 1979), Chernobyl (former USSR, 1986) and Fukushima (Japan, 2011). Research on the causes, dynamics, and consequences of these mishaps has been performed in a few laboratories worldwide in the last three decades. Common goals of such research activities are: the prevention of these kinds of accidents, both in existing and potential new nuclear power plants; the minimization of their eventual consequences; and ultimately, a full understanding of the real risks connected with NPPs. At the European Commission Joint Research Centre's Institute for Transuranium Elements, a laser-heating and fast radiance spectro-pyrometry facility is used for the laboratory simulation, on a small scale, of NPP core meltdown, the most common type of severe accident (SA) that can occur in a nuclear reactor as a consequence of a failure of the cooling system. This simulation tool permits fast and effective high-temperature measurements on real nuclear materials, such as plutonium and minor actinide containing fission fuel samples. In this respect, and in its capability to produce large amount of data concerning materials under extreme conditions, the current experimental approach is certainly unique. For current and future concepts of NPP, example results are presented on the melting behavior of some different types of nuclear fuels: uranium-plutonium oxides, carbides, and nitrides. Results on the high-temperature interaction of oxide fuels with containment materials are also briefly shown. PMID- 29286381 TI - Development of an In Vitro Assay to Quantitate Hematopoietic Stem and Progenitor Cells (HSPCs) in Developing Zebrafish Embryos. AB - Hematopoiesis is an essential cellular process in which hematopoietic stem and progenitor cells (HSPCs) differentiate into the multitude of different cell lineages that comprise mature blood. Isolation and identification of these HSPCs is difficult because they are defined ex post facto; they can only be defined after their differentiation into specific cell lineages. Over the past few decades, the zebrafish (Danio rerio) has become a model organism to study hematopoiesis. Zebrafish embryos develop ex utero, and by 48 h post-fertilization (hpf) have generated definitive HSPCs. Assays to assess HSPC differentiation and proliferation capabilities have been developed, utilizing transplantation and subsequent reconstitution of the hematopoietic system in addition to visualizing specialized transgenic lines with confocal microscopy. However, these assays are cost prohibitive, technically difficult, and time consuming for many laboratories. Development of an in vitro model to assess HSPCs would be cost effective, quicker, and present fewer difficulties compared to previously described methods, allowing laboratories to quickly assess mutagenesis and drug screens that affect HSPC biology. This novel in vitro assay to assess HSPCs is performed by plating dissociated whole zebrafish embryos and adding exogenous factors that promote only HSPC differentiation and proliferation. Embryos are dissociated into single cells and plated with HSPC-supportive colony stimulating factors that cause them to generate colony forming units (CFUs) that arise from a single progenitor cell. These assays should allow more careful examination of the molecular pathways responsible for HSPC proliferation, differentiation, and regulation, which will allow researchers to understand the underpinnings of vertebrate hematopoiesis and its dysregulation during disease. PMID- 29286383 TI - Visual Detection of Multiple Nucleic Acids in a Capillary Array. AB - Multi-target, short time, and resource-affordable methodologies for the detection of multiple nucleic acids in a single, easy to operate test are urgently needed in disease diagnosis, microbial monitoring, genetically modified organism (GMO) detection, and forensic analysis. We have previously described the platform called CALM (Capillary Array-based Loop-mediated isothermal amplification for Multiplex visual detection of nucleic acids). Herein, we describe improved fabrication and performance processes for this platform. Here, we apply a small, ready-to-use cassette assembled by capillary array for multiplex visual detection of nucleic acids. The capillary array is pre-treated into a hydrophobic and hydrophilic pattern before fixing loop-mediated isothermal amplification (LAMP) primer sets in capillaries. After assembly of the loading adaptor, LAMP reaction mixture is loaded and isolated into each capillary, due to capillary force by a single pipetting step. The LAMP reactions are performed in parallel in the capillaries. The results are visually read out by illumination with a hand-held UV flashlight. Using this platform, we demonstrate monitoring of 8 frequently appearing elements and genes in GMO samples with high specificity and sensitivity. In summary, the platform described herein is intended to facilitate the detection of multiple nucleic acids. We believe it will be widely applicable in fields where high-throughput nucleic acid analysis is required. PMID- 29286384 TI - Synthesis of Monocyte-targeting Peptide Amphiphile Micelles for Imaging of Atherosclerosis. AB - Atherosclerosis is a major contributor to cardiovascular disease, the leading cause of death worldwide, which claims 17.3 million lives annually. Atherosclerosis is also the leading cause of sudden death and myocardial infarction, instigated by unstable plaques that rupture and occlude the blood vessel without warning. Current imaging modalities cannot differentiate between stable and unstable plaques that rupture. Peptide amphiphiles micelles (PAMs) can overcome this drawback as they can be modified with a variety of targeting moieties that bind specifically to diseased tissue. Monocytes have been shown to be early markers of atherosclerosis, while large accumulation of monocytes is associated with plaques prone to rupture. Hence, nanoparticles that can target monocytes can be used to discriminate different stages of atherosclerosis. To that end, here, we describe a protocol for the preparation of monocyte-targeting PAMs (monocyte chemoattractant protein-1 (MCP-1) PAMs). MCP-1 PAMs are self assembled through synthesis under mild conditions to form nanoparticles of 15 nm in diameter with near neutral surface charge. In vitro, PAMs were found to be biocompatible and had a high binding affinity for monocytes. The methods described herein show promise for a wide range of applications in atherosclerosis as well as other inflammatory diseases. PMID- 29286385 TI - Luciferase Complementation Imaging Assay in Nicotiana benthamiana Leaves for Transiently Determining Protein-protein Interaction Dynamics. AB - Protein-protein interactions are fundamental mechanisms for relaying signal transduction in most cellular processes; therefore, identification of novel protein-protein interaction pairs and monitoring protein interaction dynamics are of particular interest for revealing how plants respond to environmental factors and/or developmental signals. A plethora of approaches have been developed to examine protein-protein interactions, either in vitro or in vivo. Among them, the recently established luciferase complementation imaging (LCI) assay is the simplest and fastest method for demonstrating in vivo protein-protein interactions. In this assay, protein A or protein B is fused with the amino terminal or carboxyl-terminal half of luciferase, respectively. When protein A interacts with protein B, the two halves of luciferase will be reconstituted to form a functional and active luciferase enzyme. Luciferase activity can be recorded with a luminometer or CCD-camera. Compared with other approaches, the LCI assay shows protein-protein interactions both qualitatively and quantitatively. Agrobacterium infiltration in Nicotiana benthamiana leaves is a widely used system for transient protein expression. With the combination of LCI and transient expression, these approaches show that the physical interaction between COP1 and SPA1 was gradually reduced after jasmonate treatment. PMID- 29286386 TI - Investigating the Detrimental Effects of Low Pressure Plasma Sterilization on the Survival of Bacillus subtilis Spores Using Live Cell Microscopy. AB - Plasma sterilization is a promising alternative to conventional sterilization methods for industrial, clinical, and spaceflight purposes. Low pressure plasma (LPP) discharges contain a broad spectrum of active species, which lead to rapid microbial inactivation. To study the efficiency and mechanisms of sterilization by LPP, we use spores of the test organism Bacillus subtilis because of their extraordinary resistance against conventional sterilization procedures. We describe the production of B. subtilis spore monolayers, the sterilization process by low pressure plasma in a double inductively coupled plasma reactor, the characterization of spore morphology using scanning electron microscopy (SEM), and the analysis of germination and outgrowth of spores by live cell microscopy. A major target of plasma species is genomic material (DNA) and repair of plasma-induced DNA lesions upon spore revival is crucial for survival of the organism. Here, we study the germination capacity of spores and the role of DNA repair during spore germination and outgrowth after treatment with LPP by tracking fluorescently-labelled DNA repair proteins (RecA) with time-resolved confocal fluorescence microscopy. Treated and untreated spore monolayers are activated for germination and visualized with an inverted confocal live cell microscope over time to follow the reaction of individual spores. Our observations reveal that the fraction of germinating and outgrowing spores is dependent on the duration of LPP-treatment reaching a minimum after 120 s. RecA YFP (yellow fluorescence protein) fluorescence was detected only in few spores and developed in all outgrowing cells with a slight elevation in LPP-treated spores. Moreover, some of the vegetative bacteria derived from LPP-treated spores showed an increase in cytoplasm and tended to lyse. The described methods for analysis of individual spores could be exemplary for the study of other aspects of spore germination and outgrowth. PMID- 29286387 TI - Establishment of an Extracellular Acidic pH Culture System. AB - Conditions of the tumor microenvironment, such as hypoxia or nutrient starvation, play critical roles in cancer progression and malignancy. However, the role of acidic extracellular pH in tumor aggressiveness and its underlying mechanism has not been extensively studied compared to hypoxic or nutrient starvation conditions. In addition, a well-defined culture method to mimic the acidic extracellular tumor microenvironment has not been fully reported. Here we present a simple in vitro culture method to maintain acidic extracellular pH using reduced bicarbonate and increased lactate or HCl concentrations in the culture medium. The medium pH was sustained for at least 24 h and gradually decreased by 72 h following culture of PANC-1 and AsPC-1 pancreatic cancer cells. Three distinct acidic media conditions in this study highly upregulated pH-responsive genes such as MSMO1, INSIG1, and IDI1 compared to hypoxia or nutrient starvation. The upregulation of these genes can be used as a marker of acidic pH. These simple techniques are beneficial to elucidate underlying mechanisms of tumor malignancy under acidic tumor microenvironment. Therefore, our extracellular acidic pH culture system enables discovery of cellular acidic pH responses not only in cancer cells but also in primary cells, such as renal tubular cells, in relation to the other acidic disorders including, diabetic ketoacidosis, lactic acidosis, renal tubular acidosis, and respiratory acidosis. PMID- 29286388 TI - Controlled Photoredox Ring-Opening Polymerization of O-Carboxyanhydrides Mediated by Ni/Zn Complexes. AB - Here, we describe an effective protocol that combines photoredox Ni/Ir catalysis with the use of a Zn-alkoxide for efficient ring-opening polymerization, allowing for the synthesis of isotactic poly(alpha-hydroxy acids) with expected molecular weights (>140 kDa) and narrow molecular weight distributions (Mw/Mn < 1.1). This ring-opening polymerization is mediated by Ni and Zn complexes in the presence of an alcohol initiator and a photoredox Ir catalyst, irradiated by a blue LED (400 500 nm). The polymerization is performed at a low temperature (-15 degrees C) to avoid undesired side reactions. The complete monomer consumption can be achieved within 4 - 8 hours, providing a polymer close to the expected molecular weight with narrow molecular weight distribution. The resulted number-average molecular weight shows a linear correlation with the degree of polymerization up to 1000. The homodecoupling 1H NMR study confirms that the obtained polymer is isotactic without epimerization. This polymerization reported herein offers a strategy for achieving rapid, controlled O-carboxyanhydrides polymerization to prepare stereoregular poly(alpha-hydroxy acids) and its copolymers bearing various functional side-chain groups. PMID- 29286389 TI - Differentiation of Mouse Embryonic Stem Cells into Cortical Interneuron Precursors. AB - GABAergic cortical interneurons are a heterogeneous population of cells that play critical roles in regulating the output of excitatory pyramidal neurons as well as synchronizing the outputs of pyramidal neuron ensembles. Deficits in interneuron function have been implicated in a variety of neuropsychiatric disorders, including schizophrenia, autism, and epilepsy. The derivation of cortical interneurons from embryonic stem cells not only allows for the study of their development and function, but provides insight into the molecular mechanisms underlying the pathogenesis of cortical interneuron-related disorders. Interneurons also have the remarkable capacity to survive, migrate, and integrate into host cortical circuitry post-transplantation, making them ideal candidates for use in cell-based therapies. Here, we present a scalable, highly efficient, modified embryoid body-to-monolayer method for the derivation of Nkx2.1 expressing interneuron progenitors and their progeny from mouse embryonic stem cells (mESCs). Using a Nkx2.1::mCherry:Lhx6::GFP dual reporter mESC line, Nkx2.1 progenitors or their Lhx6-expressing post-mitotic progeny can be isolated via fluorescence-activated cell sorting (FACS) and subsequently used in a number of downstream applications. We also provide methods to enrich for parvalbumin (PV) or somatostatin (SST) interneuron subgroups, which may be helpful for studying aspects of fate determination or for use in therapeutic applications that would benefit from interneuron subgroup-enriched transplantations. PMID- 29286391 TI - Development of New Methods for Quantifying Fish Density Using Underwater Stereo video Tools. AB - The use of video camera systems in ecological studies of fish continues to gain traction as a viable, non-extractive method of measuring fish lengths and estimating fish abundance. We developed and implemented a rotating stereo-video camera tool that covers a full 360 degrees of sampling, which maximizes sampling effort compared to stationary camera tools. A variety of studies have detailed the ability of static, stereo-camera systems to obtain highly accurate and precise measurements of fish; the focus here was on the development of methodological approaches to quantify fish density using rotating camera systems. The first approach was to develop a modification of the metric MaxN, which typically is a conservative count of the minimum number of fish observed on a given camera survey. We redefine MaxN to be the maximum number of fish observed in any given rotation of the camera system. When precautions are taken to avoid double counting, this method for MaxN may more accurately reflect true abundance than that obtained from a fixed camera. Secondly, because stereo-video allows fish to be mapped in three-dimensional space, precise estimates of the distance from-camera can be obtained for each fish. By using the 95% percentile of the observed distance from camera to establish species-specific areas surveyed, we account for differences in detectability among species while avoiding diluting density estimates by using the maximum distance a species was observed. Accounting for this range of detectability is critical to accurately estimate fish abundances. This methodology will facilitate the integration of rotating stereo-video tools in both applied science and management contexts. PMID- 29286392 TI - Overlapping Peptide Library to Map Qa-1 Epitopes in a Protein. AB - Qa-1 (HLA-E in human) belongs to a group of non-classical major histocompatibility complex 1b (MHC-Ib) molecules. Recent data suggest that Qa-1 molecules play important roles in surveying cells for structural and functional integrity, inducing immune regulation, and limiting immune responses to viral infections. Additionally, functional augmentation of Qa-1-restricted CD8+ T cells through epitope immunization has shown therapeutic effects in several autoimmune disease animal models, e.g. experimental allergic encephalomyelitis, collagen induced arthritis, and non-obese diabetes. Therefore, there is an urgent need for a method that can efficiently and quickly identify functional Qa-1 epitopes in a protein. Here, we describe a protocol that utilizes Qa-1-restricted CD8+ T cell lines specific for an overlapping peptide (OLP) library for determining Qa-1 epitopes in a protein. This OLP library contains 15-mer overlapping peptides that cover the whole length of a protein, and adjacent peptides overlap by 11 amino acids. Using this protocol, we recently identified a 9-mer Qa-1 epitope in myelin oligodendrocyte glycoprotein (MOG). This newly mapped MOG Qa-1 epitope was shown to induce epitope-specific, Qa-1-restricted CD8+ T cells that enhanced myelin specific immune regulation. Therefore, this protocol is useful for future investigation of novel targets and functions of Qa-1-restricted CD8+ T cells. PMID- 29286390 TI - A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations. AB - Birth defects that involve the cerebral cortex - also known as malformations of cortical development (MCD) - are important causes of intellectual disability and account for 20-40% of drug-resistant epilepsy in childhood. High-resolution brain imaging has facilitated in vivo identification of a large group of MCD phenotypes. Despite the advances in brain imaging, genomic analysis and generation of animal models, a straightforward workflow to systematically prioritize candidate genes and to test functional effects of putative mutations is missing. To overcome this problem, an experimental strategy enabling the identification of novel causative genes for MCD was developed and validated. This strategy is based on identifying candidate genomic regions or genes via array-CGH or whole-exome sequencing and characterizing the effects of their inactivation or of overexpression of specific mutations in developing rodent brains via in utero electroporation. This approach led to the identification of the C6orf70 gene, encoding for a putative vesicular protein, to the pathogenesis of periventricular nodular heterotopia, a MCD caused by defective neuronal migration. PMID- 29286393 TI - Three-dimensional Reconstruction of the Vascular Architecture of the Passive CLARITY-cleared Mouse Ovary. AB - The ovary is the main organ of the female reproductive system and is essential for the production of female gametes and for controlling the endocrine system, but the complex structural relationships and three-dimensional (3D) vasculature architectures of the ovary are not well described. In order to visualize the 3D connections and architecture of blood vessels in the intact ovary, the first important step is to make the ovary optically clear. In order to avoid tissue shrinkage, we used the hydrogel fixation-based passive CLARITY (Clear Lipid exchanged Acrylamide-hybridized Rigid Imaging/ Immunostaining/In situ hybridization-compatible Tissue Hydrogel) protocol method to clear an intact ovary. Immunostaining, advanced multiphoton confocal microscopy, and 3D image reconstructions were then used for the visualization of ovarian vessels and follicular capillaries. Using this approach, we showed a significant positive correlation (P <0.01) between the length of the follicular capillaries and volume of the follicular wall. PMID- 29286394 TI - Processing of Human Cardiac Tissue Toward Extracellular Matrix Self-assembling Hydrogel for In Vitro and In Vivo Applications. AB - Acellular extracellular matrix preparations are useful for studying cell-matrix interactions and facilitate regenerative cell therapy applications. Several commercial extracellular matrix products are available as hydrogels or membranes, but these do not possess tissue-specific biological activity. Because perfusion decellularization is usually not possible with human heart tissue, we developed a 3-step immersion decellularization process. Human myocardial slices procured during surgery are first treated with detergent-free hyperosmolar lysis buffer, followed by incubation with the ionic detergent, sodium dodecyl sulfate, and the process is completed by exploiting the intrinsic DNase activity of fetal bovine serum. This technique results in cell-free sheets of cardiac extracellular matrix with largely preserved fibrous tissue architecture and biopolymer composition, which were shown to provide specific environmental cues to cardiac cell populations and pluripotent stem cells. Cardiac extracellular matrix sheets can then be further processed into a microparticle powder without further chemical modification, or, via short-term pepsin digestion, into a self-assembling cardiac extracellular matrix hydrogel with preserved bioactivity. PMID- 29286395 TI - Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing. AB - It is now well recognized that heart failure (HF) patients with left bundle branch block (LBBB) derive substantial clinical benefits from cardiac resynchronization therapy (CRT), and LBBB has become one of the important predictors for CRT response. The conventional tachypacing-induced HF model has several major limitations, including absence of stable LBBB and rapid reversal of left ventricular (LV) dysfunction after cessation of pacing. Hence, it is essential to establish an optimal model of chronic HF with isolated LBBB for studying CRT benefits. In the present study, a canine model of asynchronous HF induced by left bundle branch (LBB) ablation and 4 weeks of rapid right ventricular (RV) pacing is established. The RV and right atrial (RA) pacing electrodes via the jugular vein approach, together with an epicardial LV pacing electrode, were implanted for CRT performance. Presented here are the detailed protocols of radiofrequency (RF) catheter ablation, pacing leads implantation, and rapid pacing strategy. Intracardiac and surface electrograms during operation were also provided for a better understanding of LBB ablation. Two-dimensional speckle tracking imaging and aortic velocity time integral (aVTI) were acquired to validate the chronic stable HF model with LV asynchrony and CRT benefits. By coordinating ventricular activation and contraction, CRT uniformed the LV mechanical work and restored LV pump function, which was followed by reversal of LV dilation. Moreover, the histopathological study revealed a significant restoration of cardiomyocyte diameter and collagen volume fraction (CVF) after CRT performance, indicating a histologic and cellular reverse remodeling elicited by CRT. In this report, we described a feasible and valid method to develop a chronic asynchronous HF model, which was suitable for studying structural and biologic reverse remodeling following CRT. PMID- 29286396 TI - Fabrication of Fine Electrodes on the Tip of Hypodermic Needle Using Photoresist Spray Coating and Flexible Photomask for Biomedical Applications. AB - We have introduced a fabrication method for electrical impedance spectroscopy (EIS)-on-a-needle (EoN: EIS-on-a-needle) to locate target tissues in the body by measuring and analyzing differences in the electrical impedance between dissimilar biotissues. This paper describes the fabrication method of fine interdigitated electrodes (IDEs) at the tip of a hypodermic needle using a photoresist spray coating and flexible film photomask in the photolithography process. A polyethylene terephthalate (PET) heat shrink tube (HST) with a wall thickness of 25 um is employed as the insulation and passivation layer. The PET HST shows a higher mechanical durability compared with poly(p-xylylene) polymers, which have been widely used as a dielectric coating material. Furthermore, the HST shows good chemical resistance to most acids and bases, which is advantageous for limiting chemical damage to the EoN. The use of the EoN is especially preferred for the characterization of chemicals/biomaterials or fabrication using acidic/basic chemicals. The fabricated gap and width of the IDEs are as small as 20 um, and the overall width and length of the IDEs are 400 um and 860 um, respectively. The fabrication margin from the tip (distance between the tip of hypodermic needle and starting point of the IDEs) of the hypodermic needle is as small as 680 um, which indicates that unnecessarily excessive invasion into biotissues can be avoided during the electrical impedance measurement. The EoN has a high potential for clinical use, such as for thyroid biopsies and anesthesia drug delivery in a spinal space. Further, even in surgery that involves the partial resection of tumors, the EoN can be employed to preserve as much normal tissue as possible by detecting the surgical margin (normal tissue that is removed with the surgical excision of a tumor) between the normal and lesion tissues. PMID- 29286397 TI - Flow-assisted Dielectrophoresis: A Low Cost Method for the Fabrication of High Performance Solution-processable Nanowire Devices. AB - Flow-assisted dielectrophoresis (DEP) is an efficient self-assembly method for the controllable and reproducible positioning, alignment, and selection of nanowires. DEP is used for nanowire analysis, characterization, and for solution based fabrication of semiconducting devices. The method works by applying an alternating electric field between metallic electrodes. The nanowire formulation is then dropped onto the electrodes which are on an inclined surface to create a flow of the formulation using gravity. The nanowires then align along the gradient of the electric field and in the direction of the liquid flow. The frequency of the field can be adjusted to select nanowires with superior conductivity and lower trap density. In this work, flow-assisted DEP is used to create nanowire field effect transistors. Flow-assisted DEP has several advantages: it allows selection of nanowire electrical properties; control of nanowire length; placement of nanowires in specific areas; control of orientation of nanowires; and control of nanowire density in the device. The technique can be expanded to many other applications such as gas sensors and microwave switches. The technique is efficient, quick, reproducible, and it uses a minimal amount of dilute solution making it ideal for the testing of novel nanomaterials. Wafer scale assembly of nanowire devices can also be achieved using this technique, allowing large numbers of samples for testing and large-area electronic applications. PMID- 29286398 TI - Evaluation of Vascular Control Mechanisms Utilizing Video Microscopy of Isolated Resistance Arteries of Rats. AB - This protocol describes the use of in vitro television microscopy to evaluate vascular function in isolated cerebral resistance arteries (and other vessels), and describes techniques for evaluating tissue perfusion using Laser Doppler Flowmetry (LDF) and microvessel density utilizing fluorescently labeled Griffonia simplicifolia (GS1) lectin. Current methods for studying isolated resistance arteries at transmural pressures encountered in vivo and in the absence of parenchymal cell influences provide a critical link between in vivo studies and information gained from molecular reductionist approaches that provide limited insight into integrative responses at the whole animal level. LDF and techniques to selectively identify arterioles and capillaries with fluorescently-labeled GS1 lectin provide practical solutions to enable investigators to extend the knowledge gained from studies of isolated resistance arteries. This paper describes the application of these techniques to gain fundamental knowledge of vascular physiology and pathology in the rat as a general experimental model, and in a variety of specialized genetically engineered "designer" rat strains that can provide important insight into the influence of specific genes on important vascular phenotypes. Utilizing these valuable experimental approaches in rat strains developed by selective breeding strategies and new technologies for producing gene knockout models in the rat, will expand the rigor of scientific premises developed in knockout mouse models and extend that knowledge to a more relevant animal model, with a well understood physiological background and suitability for physiological studies because of its larger size. PMID- 29286399 TI - Live-imaging of Breast Epithelial Cell Migration After the Transient Depletion of TIP60. AB - The wound-healing assay is efficient and one of the most economical ways to study cell migration in vitro. Conventionally, images are taken at the beginning and end of an experiment using a phase-contrast microscope, and the migration abilities of cells are evaluated by the closure of wounds. However, cell movement is a dynamic phenomenon, and a conventional method does not allow for tracking single-cell movement. To improve current wound-healing assays, we use live-cell imaging techniques to monitor cell migration in real time. This method allows us to determine the cell migration rate based on a cell tracking system and provides a clearer distinction between cell migration and cell proliferation. Here, we demonstrate the use of live-cell imaging in wound-healing assays to study the different migration abilities of breast epithelial cells influenced by the presence of TIP60. As cell motility is highly dynamic, our method provides more insights into the processes of wound healing than a snapshot of wound closure taken with the traditional imaging techniques used for wound-healing assays. PMID- 29286400 TI - Experimental Column Setup for Studying Anaerobic Biogeochemical Interactions Between Iron (Oxy)Hydroxides, Trace Elements, and Bacteria. AB - Fate and speciation of trace elements (TEs), such as arsenic (As) and mercury (Hg), in aquifers are closely related to physio-chemical conditions, such as redox potential (Eh) and pH, but also to microbial activities that can play a direct or indirect role on speciation and/or mobility. Indeed, some bacteria can directly oxidize As(III) to As(V) or reduce As(V) to As(III). Likewise, bacteria are strongly involved in Hg cycling, either through its methylation, forming the neurotoxin monomethyl mercury, or through its reduction to elemental Hg degrees . The fates of both As and Hg are also strongly linked to soil or aquifer composition; indeed, As and Hg can bind to organic compounds or (oxy)hydroxides, which will influence their mobility. In turn, bacterial activities such as iron (oxy)hydroxide reduction or organic matter mineralization can indirectly influence As and Hg sequestration. The presence of sulfate/sulfide can also strongly impact these particular elements through the formation of complexes such as thio-arsenates with As or metacinnabar with Hg. Consequently, many important questions have been raised on the fate and speciation of As and Hg in the environment and how to limit their toxicity. However, due to their reactivity towards aquifer components, it is difficult to clearly dissociate the biogeochemical processes that occur and their different impacts on the fate of these TE. To do so, we developed an original, experimental, column setup that mimics an aquifer with As- or Hg-iron-oxide rich areas versus iron depleted areas, enabling a better understanding of TE biogeochemistry in anoxic conditions. The following protocol gives step by step instructions for the column set-up either for As or Hg, as well as an example with As under iron and sulfate reducing conditions. PMID- 29286401 TI - Sample Preparation for Endopeptidomic Analysis in Human Cerebrospinal Fluid. AB - This protocol describes a method developed to identify endogenous peptides in human cerebrospinal fluid (CSF). For this purpose, a previously developed method based on molecular weight cut-off (MWCO) filtration and mass spectrometric analysis was combined with an offline high-pH reverse phase HPLC pre fractionation step. Secretion into CSF is the main pathway for removal of molecules shed by cells of the central nervous system. Thus, many processes in the central nervous system are reflected in the CSF, rendering it a valuable diagnostic fluid. CSF has a complex composition, containing proteins that span a concentration range of 8 - 9 orders of magnitude. Besides proteins, previous studies have also demonstrated the presence of a large number of endogenous peptides. While less extensively studied than proteins, these may also hold potential interest as biomarkers. Endogenous peptides were separated from the CSF protein content through MWCO filtration. By removing a majority of the protein content from the sample, it is possible to increase the sample volume studied and thereby also the total amount of the endogenous peptides. The complexity of the filtrated peptide mixture was addressed by including a reverse phase (RP) HPLC pre-fractionation step at alkaline pH prior to LC-MS analysis. The fractionation was combined with a simple concatenation scheme where 60 fractions were pooled into 12, analysis time consumption could thereby be reduced while still largely avoiding co-elution. Automated peptide identification was performed by using three different peptide/protein identification software programs and subsequently combining the results. The different programs were complementary rather than comparable with less than 15% of the identifications overlapped between the three. PMID- 29286402 TI - Reversible Cooling-induced Deactivations to Study Cortical Contributions to Obstacle Memory in the Walking Cat. AB - On complex, naturalistic terrain, sensory information about an environmental obstacle can be used to rapidly adjust locomotor movements for avoidance. For example, in the cat, visual information about an impending obstacle can modulate stepping for avoidance. Locomotor adaptation can also occur independent of vision, as sudden tactile inputs to the leg by an expected obstacle can modify the stepping of all four legs for avoidance. Such complex locomotor coordination involves supraspinal structures, such as the parietal cortex. This protocol describes the use of reversible, cooling-induced cortical deactivation to assess parietal cortex contributions to memory-guided obstacle locomotion in the cat. Small cooling loops, known as cryoloops, are specially shaped to deactivate discrete regions of interest to assess their contributions to an overt behavior. Such methods have been used to elucidate the role of parietal area 5 in memory guided obstacle avoidance in the cat. PMID- 29286403 TI - A Universal Protocol for Large-scale gRNA Library Production from any DNA Source. AB - The popularity of the CRISPR/Cas9 system for both genome and epigenome engineering stems from its simplicity and adaptability. An effector (the Cas9 nuclease or a nuclease-dead dCas9 fusion protein) is targeted to a specific site in the genome by a small synthetic RNA known as the guide RNA, or gRNA. The bipartite nature of the CRISPR system enables its use in screening approaches since plasmid libraries containing expression cassettes of thousands of individual gRNAs can be used to interrogate many different sites in a single experiment. To date, gRNA sequences for the construction of libraries have been almost exclusively generated by oligonucleotide synthesis, which limits the achievable complexity of sequences in the library and is relatively cost intensive. Here, a detailed protocol for CORALINA (comprehensive gRNA library generation through controlled nuclease activity), a simple and cost-effective method for the generation of highly complex gRNA libraries based on enzymatic digestion of input DNA, is described. Since CORALINA libraries can be generated from any source of DNA, plenty of options for customization exist, enabling a large variety of CRISPR-based screens. PMID- 29286404 TI - Zika Virus Specific Diagnostic Epitope Discovery. AB - High-density peptide microarrays allow screening of more than six thousand peptides on a single standard microscopy slide. This method can be applied for drug discovery, therapeutic target identification, and developing of diagnostics. Here, we present a protocol to discover specific Zika virus (ZIKV) diagnostic peptides using a high-density peptide microarray. A human serum sample validated for ZIKV infection was incubated with a high-density peptide microarray containing the entire ZIKV protein translated into 3,423 unique 15 linear amino acid (aa) residues with a 14-aa residue overlap printed in duplicate. Staining with different secondary antibodies within the same array, we detected peptides that bind to Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies present in serum. These peptides were selected for further validation experiments. In this protocol, we describe the strategy followed to design, process, and analyze a high-density peptide microarray. PMID- 29286405 TI - Live Images of GLUT4 Protein Trafficking in Mouse Primary Hypothalamic Neurons Using Deconvolution Microscopy. AB - Type 2 diabetes mellitus (T2DM) is a global health crisis which is characterized by insulin signaling impairment and chronic inflammation in peripheral tissues. The hypothalamus in the central nervous system (CNS) is the control center for energy and insulin signal response regulation. Chronic inflammation in peripheral tissues and imbalances of certain chemokines (such as CCL5, TNFalpha, and IL-6) contribute to diabetes and obesity. However, the functional mechanism(s) connecting chemokines and hypothalamic insulin signal regulation still remain unclear. In vitro primary neuron culture models are convenient and simple models which can be used to investigate insulin signal regulation in hypothalamic neurons. In this study, we introduced exogeneous GLUT4 protein conjugated with GFP (GFP-GLUT4) into primary hypothalamic neurons to track GLUT4 membrane translocation upon insulin stimulation. Time-lapse images of GFP-GLUT4 protein trafficking were recorded by deconvolution microscopy, which allowed users to generate high-speed, high-resolution images without damaging the neurons significantly while conducting the experiment. The contribution of CCR5 in insulin regulated GLUT4 translocation was observed in CCR5 deficient hypothalamic neurons, which were isolated and cultured from CCR5 knockout mice. Our results demonstrated that the GLUT4 membrane translocation efficiency was reduced in CCR5 deficient hypothalamic neurons after insulin stimulation. PMID- 29286406 TI - High-throughput Parallel Sequencing to Measure Fitness of Leptospira interrogans Transposon Insertion Mutants During Golden Syrian Hamster Infection. AB - In this manuscript, we describe a transposon sequencing (Tn-Seq) technique to identify and quantify Leptospira interrogans mutants altered in fitness during infection of Golden Syrian hamsters. Tn-Seq combines random transposon mutagenesis with the power of high-throughput sequencing technology. Animals are challenged with a pool of transposon mutants (input pool), followed by harvesting of blood and tissues a few days later to identify and quantify the number of mutants in each organ (output pools). The output pools are compared to the input pool to evaluate the in vivo fitness of each mutant. This approach enables screening of a large pool of mutants in a limited number of animals. With minor modifications, this protocol can be performed with any animal model of leptospirosis, reservoir host models such as rats and acute infection models such as hamsters, as well as in vitro studies. Tn-Seq provides a powerful tool to screen for mutants with in vivo and in vitro fitness defects. PMID- 29286408 TI - Diffuse Reflectance Spectroscopy: Getting the Capillary Refill Test Under One's Thumb. AB - The capillary refill test was introduced in 1947 to help estimate circulatory status in critically ill patients. Guidelines commonly state that refill should occur within 2 s after releasing 5 s of firm pressure (e.g., by the physician's finger) in the normal healthy supine patient. A slower refill time indicates poor skin perfusion, which can be caused by conditions including sepsis, blood loss, hypoperfusion, and hypothermia. Since its introduction, the clinical usefulness of the test has been debated. Advocates point out its feasibility and simplicity and claim that it can indicate changes in vascular status earlier than changes in vital signs such as heart rate. Critics, on the other hand, stress that the lack of standardization in how the test is performed and the highly subjective nature of the naked eye assessment, as well as the test's susceptibility to ambient factors, markedly lowers the clinical value. The aim of the present work is to describe in detail the course of the refill event and to suggest potentially more objective and exact endpoint values for the capillary refill test using diffuse polarization spectroscopy. PMID- 29286407 TI - Generic Protocol for Optimization of Heterologous Protein Production Using Automated Microbioreactor Technology. AB - A core business in industrial biotechnology using microbial production cell factories is the iterative process of strain engineering and optimization of bioprocess conditions. One important aspect is the improvement of cultivation medium to provide an optimal environment for microbial formation of the product of interest. It is well accepted that the media composition can dramatically influence overall bioprocess performance. Nutrition medium optimization is known to improve recombinant protein production with microbial systems and thus, this is a rewarding step in bioprocess development. However, very often standard media recipes are taken from literature, since tailor-made design of the cultivation medium is a tedious task that demands microbioreactor technology for sufficient cultivation throughput, fast product analytics, as well as support by lab robotics to enable reliability in liquid handling steps. Furthermore, advanced mathematical methods are required for rationally analyzing measurement data and efficiently designing parallel experiments such as to achieve optimal information content. The generic nature of the presented protocol allows for easy adaption to different lab equipment, other expression hosts, and target proteins of interest, as well as further bioprocess parameters. Moreover, other optimization objectives like protein production rate, specific yield, or product quality can be chosen to fit the scope of other optimization studies. The applied Kriging Toolbox (KriKit) is a general tool for Design of Experiments (DOE) that contributes to improved holistic bioprocess optimization. It also supports multi-objective optimization which can be important in optimizing both upstream and downstream processes. PMID- 29286409 TI - The Ingestion of Fluorescent, Magnetic Nanoparticles for Determining Fluid-uptake Abilities in Insects. AB - Fluid-feeding insects ingest a variety of liquids, which are present in the environment as pools, films, or confined to small pores. Studies of liquid acquisition require assessing mouthpart structure and function relationships; however, fluid uptake mechanisms are historically inferred from observations of structural architecture, sometimes unaccompanied with experimental evidence. Here, we report a novel method for assessing fluid-uptake abilities with butterflies (Lepidoptera) and flies (Diptera) using small amounts of liquids. Insects are fed with a 20% sucrose solution mixed with fluorescent, magnetic nanoparticles from filter papers of specific pore sizes. The crop (internal structure used for storing fluids) is removed from the insect and placed on a confocal microscope. A magnet is waved by the crop to determine the presence of nanoparticles, which indicate if the insects are able to ingest fluids. This methodology is used to reveal a widespread feeding mechanism (capillary action and liquid bridge formation) that is potentially shared among Lepidoptera and Diptera when feeding from porous surfaces. In addition, this method can be used for studies of feeding mechanisms among a variety of fluid-feeding insects, including those important in disease transmission and biomimetics, and potentially other studies that involve nano- or micro-sized conduits where liquid transport requires verification. PMID- 29286410 TI - An Engineered Split-TET2 Enzyme for Chemical-inducible DNA Hydroxymethylation and Epigenetic Remodeling. AB - DNA methylation is a stable and heritable epigenetic modification in the mammalian genome and is involved in regulating gene expression to control cellular functions. The reversal of DNA methylation, or DNA demethylation, is mediated by the ten-eleven translocation (TET) protein family of dioxygenases. Although it has been widely reported that aberrant DNA methylation and demethylation are associated with developmental defects and cancer, how these epigenetic changes directly contribute to the subsequent alteration in gene expression or disease progression remains unclear, largely owing to the lack of reliable tools to accurately add or remove DNA modifications in the genome at defined temporal and spatial resolution. To overcome this hurdle, we designed a split-TET2 enzyme to enable temporal control of 5-methylcytosine (5mC) oxidation and subsequent remodeling of epigenetic states in mammalian cells by simply adding chemicals. Here, we describe methods for introducing a chemical-inducible epigenome remodeling tool (CiDER), based on an engineered split-TET2 enzyme, into mammalian cells and quantifying the chemical inducible production of 5 hydroxymethylcytosine (5hmC) with immunostaining, flow cytometry or a dot-blot assay. This chemical-inducible epigenome remodeling tool will find broad use in interrogating cellular systems without altering the genetic code, as well as in probing the epigenotype-phenotype relations in various biological systems. PMID- 29286411 TI - Monitoring the Effects of Illumination on the Structure of Conjugated Polymer Gels Using Neutron Scattering. AB - We demonstrate a protocol to effectively monitor the gelation process of a high concentration solution of conjugated polymer both in the presence and absence of white light exposure. By instituting a controlled temperature ramp, the gelation of these materials can be precisely monitored as they proceed through this structural evolution, which effectively mirrors the conditions experienced during the solution deposition phase of organic electronic device fabrication. Using small angle neutron scattering (SANS) and ultra-small angle neutron scattering (USANS) along with appropriate fitting protocols we quantify the evolution of select structural parameters throughout this process. Thorough analysis indicates that continued light exposure throughout the gelation process significantly alters the structure of the ultimately formed gel. Specifically, the aggregation process of poly(3-hexylthiophene-2,5-diyl) (P3HT) nano-scale aggregates is negatively affected by the presence of illumination, ultimately resulting in the retardation of growth in conjugated polymer microstructures and the formation of smaller scale macro-aggregate clusters. PMID- 29286412 TI - Basic Research in Plasma Medicine - A Throughput Approach from Liquids to Cells. AB - In plasma medicine, ionized gases with temperatures close to that of vertebrate systems are applied to cells and tissues. Cold plasmas generate reactive species known to redox regulate biological processes in health and disease. Pre-clinical and clinical evidence points to beneficial effects of plasma treatment in the healing of chronic ulcer of the skin. Other emerging topics, such as plasma cancer treatment, are receiving increasing attention. Plasma medical research requires interdisciplinary expertise in physics, chemistry, and biomedicine. One goal of plasma research is to characterize plasma-treated cells in a variety of specific applications. This includes, for example, cell count and viability, cellular oxidation, mitochondrial activity, cytotoxicity and mode of cell death, cell cycle analysis, cell surface marker expression, and cytokine release. This study describes the essential equipment and workflows required for such research in plasma biomedicine. It describes the proper operation of an atmospheric pressure argon plasma jet, specifically monitoring its basic emission spectra and feed gas settings to modulate reactive species output. Using a high-precision xyz table and computer software, the jet is hovered in millisecond-precision over the cavities of 96-well plates in micrometer-precision for maximal reproducibility. Downstream assays for liquid analysis of redox-active molecules are shown, and target cells are plasma-treated. Specifically, melanoma cells are analyzed in an efficient sequence of different consecutive assays but using the same cells: measurement of metabolic activity, total cell area, and surface marker expression of calreticulin, a molecule important for the immunogenic cell death of cancer cells. These assays retrieve content-rich biological information about plasma effects from a single plate. Altogether, this study describes the essential steps and protocols for plasma medical research. PMID- 29286413 TI - Standardized Technique of Aortic Valve Re-implantation for Valve-sparing Aortic Root Replacement. AB - Despite the obvious advantages of the preservation of a normal aortic valve during aortic root replacement, the complexity of valve sparing procedures prevents a number of cardiac surgeons from incorporating them into their practice. The aim of this protocol is to describe a simplified and user-friendly technique of an aortic valve-sparing root replacement (VSRR) procedure by re implantation of the aortic valve. Proper selection of patients and limitations of the technique are discussed. In 54 consecutive patients, normal appearing aortic valves were re-implanted in a commercially available polyester prosthesis with pre-shaped sinuses by a simplified and standardized technique. Placement of the first row of the proximal suture line, choice of the prosthesis size, and adjustment of the height of the commissures of the patient to the fixed height of the sinus portion of the prosthesis were slightly modified from the reference techniques with the aim of increasing its feasibility for use by other cardiac surgeons. Early mortality and morbidity as well as 5-year survival, freedom from aortic valve reoperation, and freedom from recurrent moderate regurgitation were collected in all patients. Thirty-day mortality, re-sternotomy for bleeding, re sternotomy for mediastinitis, and the incidence of stroke were very low, 1.8% for each (1 of 54). No patient required permanent pace-maker implantation. At 5 years, survival, freedom from aortic valve reoperation, and freedom from recurrent moderate regurgitation were 97.5%, 95.2%, and 91.6%, respectively. Mid term results of our standardized technique of re-implantation of the aortic valve for valve-sparing aortic root replacement are very good and compare with more complex techniques reported by experienced surgeons. By following the present protocol of the standardized re-implantation technique, a greater number of cardiac surgeons can perform this procedure with comparable good results. PMID- 29286414 TI - Genome-wide Quantification of Translation in Budding Yeast by Ribosome Profiling. AB - Translation of mRNA into proteins is a complex process involving several layers of regulation. It is often assumed that changes in mRNA transcription reflect changes in protein synthesis, but many exceptions have been observed. Recently, a technique called ribosome profiling (or Ribo-Seq) has emerged as a powerful method that allows identification, with high accuracy, which regions of mRNA are translated into proteins and quantification of translation at the genome-wide level. Here, we present a generalized protocol for genome-wide quantification of translation using Ribo-Seq in budding yeast. In addition, combining Ribo-Seq data with mRNA abundance measurements allows us to simultaneously quantify translation efficiency of thousands of mRNA transcripts in the same sample and compare changes in these parameters in response to experimental manipulations or in different physiological states. We describe a detailed protocol for generation of ribosome footprints using nuclease digestion, isolation of intact ribosome footprint complexes via sucrose gradient fractionation, and preparation of DNA libraries for deep sequencing along with appropriate quality controls necessary to ensure accurate analysis of in vivo translation. PMID- 29286415 TI - Improved 3D Hydrogel Cultures of Primary Glial Cells for In Vitro Modelling of Neuroinflammation. AB - In the central nervous system, numerous acute injuries and neurodegenerative disorders, as well as implanted devices or biomaterials engineered to enhance function result in the same outcome: excess inflammation leads to gliosis, cytotoxicity, and/or formation of a glial scar that collectively exacerbate injury or prevent healthy recovery. With the intent of creating a system to model glial scar formation and study inflammatory processes, we have generated a 3D cell scaffold capable of housing primary cultured glial cells: microglia that regulate the foreign body response and initiate the inflammatory event, astrocytes that respond to form a fibrous scar, and oligodendrocytes that are typically vulnerable to inflammatory injury. The present work provides a detailed step-by-step method for the fabrication, culture, and microscopic characterization of a hyaluronic acid-based 3D hydrogel scaffold with encapsulated rat brain-derived glial cells. Further, protocols for characterization of cell encapsulation and the hydrogel scaffold by confocal immunofluorescence and scanning electron microscopy are demonstrated, as well as the capacity to modify the scaffold with bioactive substrates, with incorporation of a commercial basal lamina mixture to improved cell integration. PMID- 29286416 TI - Immuno-fluorescent Labeling of Microtubules and Centrosomal Proteins in Ex Vivo Intestinal Tissue and 3D In Vitro Intestinal Organoids. AB - The advent of 3D in vitro organoids that mimic the in vivo tissue architecture and morphogenesis has greatly advanced the ability to study key biological questions in cell and developmental biology. In addition, organoids together with recent technical advances in gene editing and viral gene delivery promises to advance medical research and development of new drugs for treatment of diseases. Organoids grown in vitro in basement matrix provide powerful model systems for studying the behavior and function of various proteins and are well suited for live-imaging of fluorescent-tagged proteins. However, establishing the expression and localization of the endogenous proteins in ex vivo tissue and in in vitro organoids is important to verify the behavior of the tagged proteins. To this end we have developed and modified tissue isolation, fixation, and immuno-labeling protocols for localization of microtubules, centrosomal, and associated proteins in ex vivo intestinal tissue and in in vitro intestinal organoids. The aim was for the fixative to preserve the 3D architecture of the organoids/tissue while also preserving antibody antigenicity and enabling good penetration and clearance of fixative and antibodies. Exposure to cold depolymerizes all but stable microtubules and this was a key factor when modifying the various protocols. We found that increasing the ethylenediaminetetraacetic acid (EDTA) concentration from 3 mM to 30 mM gave efficient detachment of villi and crypts in the small intestine while 3 mM EDTA was sufficient for colonic crypts. The developed formaldehyde/methanol fixation protocol gave very good structural preservation while also preserving antigenicity for effective labeling of microtubules, actin, and the end-binding (EB) proteins. It also worked for the centrosomal protein ninein although the methanol protocol worked more consistently. We further established that fixation and immuno-labeling of microtubules and associated proteins could be achieved with organoids isolated from or remaining within the basement matrix. PMID- 29286417 TI - Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers. AB - Targeted therapies against the human epidermal growth factor receptor 2 (HER2) have radically changed the outcome of patients with HER2-positive breast cancers. However, a minority of cases displays a heterogeneous distribution of HER2 positive cells, which generates major clinical challenges. To date, no reliable and standardized protocols for the characterization and quantification of HER2 heterogeneous gene amplification in large cohorts have been proposed. Here, we present a high-throughput methodology to simultaneously assess the HER2 status across different topographic areas of multiple breast cancers. In particular, we illustrate the laboratory procedure to construct enhanced tissue microarrays (TMAs) incorporating a targeted mapping of the tumors. All TMA parameters have been specifically optimized for the silver in situ hybridization (SISH) of formalin-fixed paraffin-embedded (FFPE) breast tissues. Immunohistochemical analysis of the prognostic and predictive biomarkers (i.e., ER, PR, Ki67, and HER2) should be performed using automated procedures. A customized SISH protocol has been implemented to allow a high-quality molecular analysis across multiple tissues that underwent different fixation, processing, and storage procedures. In this study, we provide a proof-of-principle that specific DNA sequences could be localized simultaneously in distinct topographic areas of multiple and heterogeneously processed breast cancers using an efficient and cost-effective method. PMID- 29286418 TI - Using Fluorescence In Situ Hybridization (FISH) to Monitor the State of Arm Cohesion in Prometaphase and Metaphase I Drosophila Oocytes. AB - In humans, chromosome segregation errors in oocytes are responsible for the majority of miscarriages and birth defects. Moreover, as women age, their risk of conceiving an aneuploid fetus increases dramatically and this phenomenon is known as the maternal age effect. One requirement for accurate chromosome segregation during the meiotic divisions is maintenance of sister chromatid cohesion during the extended prophase period that oocytes experience. Cytological evidence in both humans and model organisms suggests that meiotic cohesion deteriorates during the aging process. In addition, segregation errors in human oocytes are most prevalent during meiosis I, consistent with premature loss of arm cohesion. The use of model organisms is critical for unraveling the mechanisms that underlie age-dependent loss of cohesion. Drosophila melanogaster offers several advantages for studying the regulation of meiotic cohesion in oocytes. However, until recently, only genetic tests were available to assay for loss of arm cohesion in oocytes of different genotypes or under different experimental conditions. Here, a detailed protocol is provided for using fluorescence in situ hybridization (FISH) to directly visualize defects in arm cohesion in prometaphase I and metaphase I arrested Drosophila oocytes. By generating a FISH probe that hybridizes to the distal arm of the X chromosome and collecting confocal Z stacks, a researcher can visualize the number of individual FISH signals in three dimensions and determine whether sister chromatid arms are separated. The procedure outlined makes it possible to quantify arm cohesion defects in hundreds of Drosophila oocytes. As such, this method provides an important tool for investigating the mechanisms that contribute to cohesion maintenance as well as the factors that lead to its demise during the aging process. PMID- 29286419 TI - Generation and Culturing of Primary Human Keratinocytes from Adult Skin. AB - The main function of keratinocytes is to provide the structural integrity of the epidermis, thereby maintaining a mechanical barrier to the outside world. In addition, keratinocytes play an essential role in the initiation, maintenance, and regulation of epidermal immune responses by being part of the innate immune system responding to antigenic stimuli in a fast, nonspecific manner. Here, we describe a protocol for isolation of primary human keratinocytes from adult skin, and demonstrate that these cells respond to calcium-induced terminal differentiation, as measured by an increased expression of the differentiation marker involucrin. In addition, we show that the isolated keratinocytes are responsive to IL-1beta-induced activation of intracellular signaling pathways as measured by the activation of the p38 MAPK pathway. Taken together, we describe a method for isolation and culturing of primary human keratinocytes from adult skin. Because the keratinocytes are the predominant cell type in the epidermis, this method is useful to study molecular mechanisms in cutaneous biology in vitro. PMID- 29286420 TI - Comprehensive Workflow for the Genome-wide Identification and Expression Meta analysis of the ATL E3 Ubiquitin Ligase Gene Family in Grapevine. AB - Classification and nomenclature of genes in a family can significantly contribute to the description of the diversity of encoded proteins and to the prediction of family functions based on several features, such as the presence of sequence motifs or of particular sites for post-translational modification and the expression profile of family members in different conditions. This work describes a detailed protocol for gene family characterization. Here, the procedure is applied to the characterization of the Arabidopsis Toxicos in Levadura (ATL) E3 ubiquitin ligase family in grapevine. The methods include the genome-wide identification of family members, the characterization of gene localization, structure, and duplication, the analysis of conserved protein motifs, the prediction of protein localization and phosphorylation sites as well as gene expression profiling across the family in different datasets. Such procedure, which could be extended to further analyses depending on experimental purposes, could be applied to any gene family in any plant species for which genomic data are available, and it provides valuable information to identify interesting candidates for functional studies, giving insights into the molecular mechanisms of plant adaptation to their environment. PMID- 29286421 TI - Flexible Measurement of Bioluminescent Reporters Using an Automated Longitudinal Luciferase Imaging Gas- and Temperature-optimized Recorder (ALLIGATOR). AB - Luciferase-based reporters of cellular gene expression are in widespread use for both longitudinal and end-point assays of biological activity. In circadian rhythms research, for example, clock gene fusions with firefly luciferase give rise to robust rhythms in cellular bioluminescence that persist over many days. Technical limitations associated with photomultiplier tubes (PMT) or conventional microscopy-based methods for bioluminescence quantification have typically demanded that cells and tissues be maintained under quite non-physiological conditions during recording, with a trade-off between sensitivity and throughput. Here, we report a refinement of prior methods that allows long-term bioluminescence imaging with high sensitivity and throughput which supports a broad range of culture conditions, including variable gas and humidity control, and that accepts many different tissue culture plates and dishes. This automated longitudinal luciferase imaging gas- and temperature-optimized recorder (ALLIGATOR) also allows the observation of spatial variations in luciferase expression across a cell monolayer or tissue, which cannot readily be observed by traditional methods. We highlight how the ALLIGATOR provides vastly increased flexibility for the detection of luciferase activity when compared with existing methods. PMID- 29286422 TI - Methodology for Biomimetic Chemical Neuromodulation of Rat Retinas with the Neurotransmitter Glutamate In Vitro. AB - Photoreceptor degenerative diseases cause irreparable blindness through the progressive loss of photoreceptor cells in the retina. Retinal prostheses are an emerging treatment for photoreceptor degenerative diseases that seek to restore vision by artificially stimulating the surviving retinal neurons in the hope of eliciting comprehensible visual perception in patients. Current retinal prostheses have demonstrated success in restoring limited vision to patients using an array of electrodes to electrically stimulate the retina but face substantial physical barriers in restoring high acuity, natural vision to patients. Chemical neurostimulation using native neurotransmitters is a biomimetic alternative to electrical stimulation and could bypass the fundamental limitations associated with retinal prostheses using electrical neurostimulation. Specifically, chemical neurostimulation has the potential to restore more natural vision with comparable or better visual acuities to patients by injecting very small quantities of neurotransmitters, the same natural agents of communication used by retinal chemical synapses, at much finer resolution than current electrical prostheses. However, as a relatively unexplored stimulation paradigm, there is no established protocol for achieving chemical stimulation of the retina in vitro. The purpose of this work is to provide a detailed framework for accomplishing chemical stimulation of the retina for investigators who wish to study the potential of chemical neuromodulation of the retina or similar neural tissues in vitro. In this work, we describe the experimental setup and methodology for eliciting retinal ganglion cell (RGC) spike responses similar to visual light responses in wild-type and photoreceptor-degenerated wholemount rat retinas by injecting controlled volumes of the neurotransmitter glutamate into the subretinal space using glass micropipettes and a custom multiport microfluidic device. This methodology and protocol are general enough to be adapted for neuromodulation using other neurotransmitters or even other neural tissues. PMID- 29286423 TI - An Analog Macroscopic Technique for Studying Molecular Hydrodynamic Processes in Dense Gases and Liquids. AB - An analog, macroscopic method for studying molecular-scale hydrodynamic processes in dense gases and liquids is described. The technique applies a standard fluid dynamic diagnostic, particle image velocimetry (PIV), to measure: i) velocities of individual particles (grains), extant on short, grain-collision time-scales, ii) velocities of systems of particles, on both short collision-time- and long, continuum-flow-time-scales, iii) collective hydrodynamic modes known to exist in dense molecular fluids, and iv) short- and long-time-scale velocity autocorrelation functions, central to understanding particle-scale dynamics in strongly interacting, dense fluid systems. The basic system is composed of an imaging system, light source, vibrational sensors, vibrational system with a known media, and PIV and analysis software. Required experimental measurements and an outline of the theoretical tools needed when using the analog technique to study molecular-scale hydrodynamic processes are highlighted. The proposed technique provides a relatively straightforward alternative to photonic and neutron beam scattering methods traditionally used in molecular hydrodynamic studies. PMID- 29286424 TI - Collection of Post-mating Semen from the Female Reproductive Tract and Measurement of Semen Liquefaction in Mice. AB - In mice, ejaculated semen is deposited in the uterus. After ejaculation, the semen changes consistency from gel-like to watery, a process called liquefaction. In this study, we show how to collect the post-ejaculated semen from the female reproductive tract in a mouse model. First, adult female mice in the estrus stage were housed in a male's cage overnight. The next morning, copulation was confirmed by the presence of copulatory plug at the vaginal opening. Female mice with copulatory plugs were euthanized, and each reproductive tract was collected as a whole (vagina, uterus, oviducts, ovaries), ensuring a closed system to contain the semen. The reproductive tract was placed in a 1.5 mL microcentrifuge tube, and the vagina was cut off to release the semen into the tube. To ensure maximum semen volume for analysis, toothless forceps were used to squeeze the uterine horns from ovarian end to vaginal end expelling remaining semen. The whole reproductive tract was then discarded. The semen-containing tube was briefly spun down. A 25 MUL capillary pipette was placed into the tube at a 180 degrees angle (parallel to the tube wall). The amount of time used to fill the capillary tube to the 25 MUL line was recorded. Semen from a proven male breeder usually takes approximately 60-180 s to fill a 25 MUL capillary tube. This semen collection technique can also be used in other downstream applications such as sperm imaging and motility analysis. PMID- 29286425 TI - Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate binding Tag. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) have been shown to be linked with familial Parkinson's disease (FPD). Since abnormal activation of the kinase activity of LRRK2 has been implicated in the pathogenesis of PD, it is essential to establish a method to evaluate the physiological levels of the kinase activity of LRRK2. Recent studies revealed that LRRK2 phosphorylates members of the Rab GTPase family, including Rab10, under physiological conditions. Although the phosphorylation of endogenous Rab10 by LRRK2 in cultured cells could be detected by mass spectrometry, it has been difficult to detect it by immunoblotting due to the poor sensitivity of currently available phosphorylation-specific antibodies for Rab10. Here, we describe a simple method of detecting the endogenous levels of Rab10 phosphorylation by LRRK2 based on immunoblotting utilizing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) combined with a phosphate-binding tag (P-tag), which is N-(5-(2-aminoethylcarbamoyl)pyridin-2 ylmetyl)-N,N',N'-tris(pyridin-2-yl-methyl)-1,3-diaminopropan-2-ol. The present protocol not only provides an example of the methodology utilizing the P-tag but also enables the assessment of how mutations as well as inhibitor treatment/administration or any other factors alter the downstream signaling of LRRK2 in cells and tissues. PMID- 29286426 TI - AFM and Microrheology in the Zebrafish Embryo Yolk Cell. AB - Elucidating the factors that direct the spatio-temporal organization of evolving tissues is one of the primary purposes in the study of development. Various propositions claim to have been important contributions to the understanding of the mechanical properties of cells and tissues in their spatiotemporal organization in different developmental and morphogenetic processes. However, due to the lack of reliable and accessible tools to measure material properties and tensional parameters in vivo, validating these hypotheses has been difficult. Here we present methods employing atomic force microscopy (AFM) and particle tracking with the aim of quantifying the mechanical properties of the intact zebrafish embryo yolk cell during epiboly. Epiboly is an early conserved developmental process whose study is facilitated by the transparency of the embryo. These methods are simple to implement, reliable, and widely applicable since they overcome intrusive interventions that could affect tissue mechanics. A simple strategy was applied for the mounting of specimens, AFM recording, and nanoparticle injections and tracking. This approach makes these methods easily adaptable to other developmental times or organisms. PMID- 29286427 TI - Live Imaging Followed by Single Cell Tracking to Monitor Cell Biology and the Lineage Progression of Multiple Neural Populations. AB - Understanding the mechanisms that control critical biological events of neural cell populations, such as proliferation, differentiation, or cell fate decisions, will be crucial to design therapeutic strategies for many diseases affecting the nervous system. Current methods to track cell populations rely on their final outcomes in still images and they generally fail to provide sufficient temporal resolution to identify behavioral features in single cells. Moreover, variations in cell death, behavioral heterogeneity within a cell population, dilution, spreading, or the low efficiency of the markers used to analyze cells are all important handicaps that will lead to incomplete or incorrect read-outs of the results. Conversely, performing live imaging and single cell tracking under appropriate conditions represents a powerful tool to monitor each of these events. Here, a time-lapse video-microscopy protocol, followed by post processing, is described to track neural populations with single cell resolution, employing specific software. The methods described enable researchers to address essential questions regarding the cell biology and lineage progression of distinct neural populations. PMID- 29286428 TI - Stenosis of the Inferior Vena Cava: A Murine Model of Deep Vein Thrombosis. AB - Deep vein thrombosis (DVT) and its devastating complication, pulmonary embolism, are a severe health problem with high mortality. Mechanisms of thrombus formation in veins remain obscure. Lack of mobility (e.g., after surgery or long-haul flights) is one of the main factors leading to DVT. The pathophysiological consequence of the lack of mobility is blood flow stagnation in venous valves. Here, a model is described that mimics such flow disturbance as a thrombosis driving factor. In this model, partial flow restriction (stenosis) in the inferior vena cava (IVC) is created. Closure of about 90% of the IVC lumen for 48 h results in development of thrombi structurally similar to those in humans. The similarities are: i) most of the thrombus volume is red, i.e., consists of red blood cells and fibrin, ii) presence of a white part (lines of Zahn), iii) non denuded endothelial monolayer, iv) elevated plasma D-Dimer levels, and v) possibility to prevent thrombosis by low molecular weight heparin. Limitations include variable size of thrombi and the fact that a certain percentage of wild type mice (0 - 35%) may not produce a thrombus. In addition to visual observation and measurement, thrombi may be visualized by non-invasive technologies, such as ultrasonography, which allows for monitoring the dynamics of thrombus development. At shorter time points (1 - 6 h), intravital microscopy may be applied to directly observe events (e.g., recruitment of cells to the vessel wall) preceding thrombus formation. Use of this method by several teams around the world has made it possible to uncover basic mechanisms of DVT initiation and identify potential targets that might be beneficial for its prevention. PMID- 29286429 TI - Evaluation of the Cell Invasion and Migration Process: A Comparison of the Video Microscope-based Scratch Wound Assay and the Boyden Chamber Assay. AB - The invasion and migration abilities of tumor cells are main contributors to cancer progression and recurrence. Many studies have explored the migration and invasion abilities to understand how cancer cells disseminate, with the aim of developing new treatment strategies. Analysis of the cellular and molecular basis of these abilities has led to the characterization of cell mobility and the physicochemical properties of the cytoskeleton and cellular microenvironment. For many years, the Boyden chamber assay and the scratch wound assay have been the standard techniques to study cell invasion and migration. However, these two techniques have limitations. The Boyden chamber assay is difficult and time consuming, and the scratch wound assay has low reproducibility. Development of modern technologies, especially in microscopy, has increased the reproducibility of the scratch wound assay. Using powerful analysis systems, an "in-incubator" video microscope can be used to provide automatic and real-time analysis of cell migration and invasion. The aim of this paper is to report and compare the two assays used to study cell invasion and migration: the Boyden chamber assay and an optimized in vitro video microscope-based scratch wound assay. PMID- 29286430 TI - Wind Tunnel Experiments to Study Chaparral Crown Fires. AB - The present protocol presents a laboratory technique designed to study chaparral crown fire ignition and spread. Experiments were conducted in a low velocity fire wind tunnel where two distinct layers of fuel were constructed to represent surface and crown fuels in chaparral. Chamise, a common chaparral shrub, comprised the live crown layer. The dead fuel surface layer was constructed with excelsior (shredded wood). We developed a methodology to measure mass loss, temperature, and flame height for both fuel layers. Thermocouples placed in each layer estimated temperature. A video camera captured the visible flame. Post processing of digital imagery yielded flame characteristics including height and flame tilt. A custom crown mass loss instrument developed in-house measured the evolution of the mass of the crown layer during the burn. Mass loss and temperature trends obtained using the technique matched theory and other empirical studies. In this study, we present detailed experimental procedures and information about the instrumentation used. The representative results for the fuel mass loss rate and temperature filed within the fuel bed are also included and discussed. PMID- 29286431 TI - Pulling Membrane Nanotubes from Giant Unilamellar Vesicles. AB - The reshaping of the cell membrane is an integral part of many cellular phenomena, such as endocytosis, trafficking, the formation of filopodia, etc. Many different proteins associate with curved membranes because of their ability to sense or induce membrane curvature. Typically, these processes involve a multitude of proteins making them too complex to study quantitatively in the cell. We describe a protocol to reconstitute a curved membrane in vitro, mimicking a curved cellular structure, such as the endocytic neck. A giant unilamellar vesicle (GUV) is used as a model of a cell membrane, whose internal pressure and surface tension are controlled with micropipette aspiration. Applying a point pulling force on the GUV using optical tweezers creates a nanotube of high curvature connected to a flat membrane. This method has traditionally been used to measure the fundamental mechanical properties of lipid membranes, such as bending rigidity. In recent years, it has been expanded to study how proteins interact with membrane curvature and the way they affect the shape and the mechanics of membranes. A system combining micromanipulation, microinjection, optical tweezers, and confocal microscopy allows measurement of membrane curvature, membrane tension, and the surface density of proteins, concurrently. From these measurements, many important mechanical and morphological properties of the protein-membrane system can be inferred. In addition, we lay out a protocol of creating GUVs in the presence of physiological salt concentration, and a method of quantifying the surface density of proteins on the membrane from fluorescence intensities of labeled proteins and lipids. PMID- 29286432 TI - In Vivo Evaluation of Fracture Callus Development During Bone Healing in Mice Using an MRI-compatible Osteosynthesis Device for the Mouse Femur. AB - Endochondral fracture healing is a complex process involving the development of fibrous, cartilaginous, and osseous tissue in the fracture callus. The amount of the different tissues in the callus provides important information on the fracture healing progress. Available in vivo techniques to longitudinally monitor the callus tissue development in preclinical fracture-healing studies using small animals include digital radiography and uCT imaging. However, both techniques are only able to distinguish between mineralized and non-mineralized tissue. Consequently, it is impossible to discriminate cartilage from fibrous tissue. In contrast, magnetic resonance imaging (MRI) visualizes anatomical structures based on their water content and might therefore be able to noninvasively identify soft tissue and cartilage in the fracture callus. Here, we report the use of an MRI compatible external fixator for the mouse femur to allow MRI scans during bone regeneration in mice. The experiments demonstrated that the fixator and a custom made mounting device allow repetitive MRI scans, thus enabling longitudinal analysis of fracture-callus tissue development. PMID- 29286433 TI - Methodology for Sputum Induction and Laboratory Processing. AB - The technique of sputum induction and processing is a recognized non-invasive method allowing the collection and analysis of cells from the airways, which is interesting in various respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), chronic cough, or idiopathic pulmonary fibrosis. This technique is well tolerated, safe and non-invasive, but is currently limited to research services and specialized centers in clinical practice because it is technically demanding, time-consuming, and requires trained staff. The success rate of sputum induction and analysis is about 80%. Here, we describe the induction and laboratory processing of sputum samples. Sputum is induced by inhalation of hypertonic or isotonic saline with salbutamol. For the processing, we use the whole sputum technique. Dithiothreitol (DTT) is used to allow mucolysis of sputum samples. The primary aim of sputum processing is to obtain a differential cell count to study the cell types present in the airway lumen. Additional analyses may also be performed on sputum supernatant and sputum cells, which may allow further investigation into inflammatory processes and immune mechanisms. Examples include studying mediators in sputum supernatant and performing a large spectrum of analysis on sputum cells such as flow cytometry, genomics, or proteomics. Finally, representative results of sputum analysis in healthy controls, asthmatics, and COPD patients are presented. PMID- 29286434 TI - MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor. AB - Essential tremor (ET) is the most common type of tremor in adults. While ET does not result in decreased life expectancy, the disabilities associated with ET can have a significant impact on quality of life, mood, functional activities, and socialization. Patients suffering from ET not sufficiently treated with first line medications may be eligible for alternative strategies such as deep brain stimulation, radiofrequency ablation, and MRI guided focused ultrasound (MRgFUS). High-intensity MRgFUS is an emerging modality to treat ET, its attraction for patients being that it is noninvasive and associated with short recovery time, as patients are home the day after treatment. While MRgFUS centers are still limited, it will become important for clinicians to consider MRgFUS as a treatment alternative, particularly in the case of a patient for whom open surgery is contraindicated. This article outlines the steps of patient selection, equipment setup, sonication, and post-treatment follow-up, as well as critical steps to be aware of when performing a MRgFUS procedure. PMID- 29286435 TI - Visualization of Biofilm Formation in Candida albicans Using an Automated Microfluidic Device. AB - Candida albicans is the most common fungal pathogen of humans, causing about 15% of hospital-acquired sepsis cases. A major virulence attribute of C. albicans is its ability to form biofilms, structured communities of cells attached to biotic and abiotic surfaces. C. albicans biofilms can form on host tissues, such as mucosal layers, and on medical devices, such as catheters, pacemakers, dentures, and joint prostheses. Biofilms pose significant clinical challenges because they are highly resistant to physical and chemical perturbations, and can act as reservoirs to seed disseminated infections. Various in vitro assays have been utilized to study C. albicans biofilm formation, such as microtiter plate assays, dry weight measurements, cell viability assays, and confocal scanning laser microscopy. All of these assays are single end-point assays, where biofilm formation is assessed at a specific time point. Here, we describe a protocol to study biofilm formation in real-time using an automated microfluidic device under laminar flow conditions. This method allows for the observation of biofilm formation as the biofilm develops over time, using customizable conditions that mimic those of the host, such as those encountered in vascular catheters. This protocol can be used to assess the biofilm defects of genetic mutants as well as the inhibitory effects of antimicrobial agents on biofilm development in real time. PMID- 29286436 TI - Stromal Vascular Fraction-enriched Fat Grafting for the Treatment of Symptomatic End-neuromata. AB - The purpose of this study was to methodically illustrate and highlight the crucial steps of stromal vascular fraction (SVF)-enriched fat grafting as a novel treatment of symptomatic end-neuromata of peripheral sensory nerves, and in this study, specifically of the superficial branch of the radial nerve (SBRN). Despite a multitude of existing treatments, persistent postoperative pain and common pain relapse are still very common, independent of the procedure assessed. The neuroma is microsurgically excised accordingly to standardized protocol. Instead of the relocation of the regenerating nerve stump in neighboring anatomical structures, such as muscle or bone, a fat graft is applied perifocally and acts as a mechanical barrier. In order to reduce the fat resorption rate and boost the regenerative potential of the graft, the highly concentrated SVF is integrated in the grafting. The SVF is isolated from subcutaneous fat by enzymatic and mechanic separation of the lipoaspirate by a specific commercial isolation system. The SVF enriched fat graft provides both a mechanical barrier and various biological effects at the cellular level, including improving angiogenesis, inflammation, and fibrosis. Both mechanical and biologic effects help to reduce the disorganized axonal outgrowth of the nerve stump during nerve regeneration and hence prevent the recurrence of painful end-neuromata. PMID- 29286437 TI - Metabolic Glycoengineering of Sialic Acid Using N-acyl-modified Mannosamines. AB - Sialic acid (Sia) is a highly important constituent of glycoconjugates, such as N and O-glycans or glycolipids. Due to its position at the non-reducing termini of oligo- and polysaccharides, as well as its unique chemical characteristics, sialic acid is involved in a multitude of different receptor-ligand interactions. By modifying the expression of sialic acid on the cell surface, sialic acid dependent interactions will consequently be influenced. This can be helpful to investigate sialic acid-dependent interactions and has the potential to influence certain diseases in a beneficial way. Via metabolic glycoengineering (MGE), the expression of sialic acid on the cell surface can be modulated. Herein, cells, tissues, or even entire animals are treated with C2-modified derivatives of N acetylmannosamine (ManNAc). These amino sugars act as sialic acid precursor molecules and therefore are metabolized to the corresponding sialic acid species and expressed on glycoconjugates. Applying this method produces intriguing effects on various biological processes. For example, it can drastically reduce the expression of polysialic acid (polySia) in treated neuronal cells and thus affects neuronal growth and differentiation. Here, we show the chemical synthesis of two of the most common C2-modified N-acylmannosamine derivatives, N propionylmannosamine (ManNProp) as well as N-butanoylmannosamine (ManNBut), and further show how these non-natural amino sugars can be applied in cell culture experiments. The expression of modified sialic acid species is quantified by high performance liquid chromatography (HPLC) and further analyzed via mass spectrometry. The effects on polysialic acid expression are elucidated via Western blot using a commercially available polysialic acid antibody. PMID- 29286438 TI - Hemi-laryngeal Setup for Studying Vocal Fold Vibration in Three Dimensions. AB - The voice of humans and most non-human mammals is generated in the larynx through self-sustaining oscillation of the vocal folds. Direct visual documentation of vocal fold vibration is challenging, particularly in non-human mammals. As an alternative, excised larynx experiments provide the opportunity to investigate vocal fold vibration under controlled physiological and physical conditions. However, the use of a full larynx merely provides a top view of the vocal folds, excluding crucial portions of the oscillating structures from observation during their interaction with aerodynamic forces. This limitation can be overcome by utilizing a hemi-larynx setup where one half of the larynx is mid-sagittally removed, providing both a superior and a lateral view of the remaining vocal fold during self-sustained oscillation. Here, a step-by-step guide for the anatomical preparation of hemi-laryngeal structures and their mounting on the laboratory bench is given. Exemplary phonation of the hemi-larynx preparation is documented with high-speed video data captured by two synchronized cameras (superior and lateral views), showing three-dimensional vocal fold motion and corresponding time-varying contact area. The documentation of the hemi-larynx setup in this publication will facilitate application and reliable repeatability in experimental research, providing voice scientists with the potential to better understand the biomechanics of voice production. PMID- 29286439 TI - Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification. AB - Calcific aortic valve disease (CAVD) is characterized by the progressive thickening of the aortic valve leaflets. It is a condition frequently found in the elderly and end-stage renal disease (ESRD) patients, who commonly suffer from hyperphosphatemia and hypercalcemia. At present, there are no medication therapies that can stop its progression. The mechanisms that underlie this pathological process remain unclear. The aortic valve leaflet is composed of a thin layer of valve endothelial cells (VECs) on the outer surfaces of the aortic cusps, with valve interstitial cells (VICs) sandwiched between the VECs. The use of a rat model enables the in vitro study of ectopic calcification based on the in vivo physiopathological serum phosphate (Pi) and calcium (Ca) levels of patients who suffer from hyperphosphatemia and hypercalcemia. The described protocol details the isolation of a pure rat VIC population as shown by the expression of VIC markers: alpha-smooth muscle actin (alpha-SMA) vimentin and tissue growth factor beta (TGFbeta) 1 and 2, and the absence of cluster of differentiation (CD) 31, a VEC marker. By expanding these VICs, biochemical, genetic, and imaging studies can be performed to study and unravel the key mediators underpinning CAVD. PMID- 29286440 TI - Preparation of Meiotic Chromosome Spreads from Mouse Spermatocytes. AB - Mammalian meiosis is a dynamic developmental process that occurs in germ cells and can be studied and characterized. Using a method to spread nuclei on the surface of slides (rather than dropping them from a height), we demonstrate an optimized technique on mouse spermatocytes that was first described in 1997. This method is widely used in laboratories to study mammalian meiosis because it yields a plethora of high quality nuclei undergoing substages of prophase I. Seminiferous tubules are first placed in a hypotonic solution to swell spermatocytes. Then spermatocytes are released into a sucrose solution to create a cell suspension, and nuclei are spread onto fixative-soaked glass slides. Following immunostaining, a diversity of proteins germane to meiotic processes can be examined. For example, proteins of the synaptonemal complex, a tripartite structure that connects the chromosome axes/cores of homologs together can be easily visualized. Meiotic recombination proteins, which are involved in repair of DNA double-strand breaks by homologous recombination, can also be immunostained to evaluate progression of prophase I. Here we describe and demonstrate in detail a technique widely used to study mammalian meiosis in spermatocytes from juvenile or adult male mice. PMID- 29286441 TI - Measuring Biomolecular DSC Profiles with Thermolabile Ligands to Rapidly Characterize Folding and Binding Interactions. AB - Differential scanning calorimetry (DSC) is a powerful technique for quantifying thermodynamic parameters governing biomolecular folding and binding interactions. This information is critical in the design of new pharmaceutical compounds. However, many pharmaceutically relevant ligands are chemically unstable at the high temperatures used in DSC analyses. Thus, measuring binding interactions is challenging because the concentrations of ligands and thermally-converted products are constantly changing within the calorimeter cell. Here, we present a protocol using thermolabile ligands and DSC for rapidly obtaining thermodynamic and kinetic information on the folding, binding, and ligand conversion processes. We have applied our method to the DNA aptamer MN4 that binds to the thermolabile ligand cocaine. Using a new global fitting analysis that accounts for thermolabile ligand conversion, the complete set of folding and binding parameters are obtained from a pair of DSC experiments. In addition, we show that the rate constant for thermolabile ligand conversion may be obtained with only one supplementary DSC dataset. The guidelines for identifying and analyzing data from several more complicated scenarios are presented, including irreversible aggregation of the biomolecule, slow folding, slow binding, and rapid depletion of the thermolabile ligand. PMID- 29286442 TI - Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury. AB - We performed unilateral carotid artery occlusion on CD-1 mice to create a neonatal hypoxic-ischemic (HI) model and investigated the effects of neonatal HI brain injury by studying neurobehavioral functions in these mice compared to non operated (i.e., normal) mice. During the study, Rice-Vannucci's method was used to induce neonatal HI brain damage in postnatal day 7-10 (P7-10) mice. The HI operation was performed on the pups by unilateral carotid artery ligation and exposure to hypoxia (8% O2 and 92% N2 for 90 min). One week after the operation, the damaged brains were evaluated with the naked eye through the semi-transparent skull and were categorized into subgroups based on the absence ("no cortical injury" group) or presence ("cortical injury" group) of cortical injury, such as a lesion in the right hemisphere. On week 6, the following neurobehavioral tests were performed to evaluate the cognitive and motor functions: passive avoidance task (PAT), ladder walking test, and grip strength test. These behavioral tests are helpful in determining the effects of neonatal HI brain injury and are used in other mouse models of neurodegenerative diseases. In this study, neonatal HI brain injury mice showed motor deficits that corresponded to right hemisphere damage. The behavioral test results are relevant to the deficits observed in human neonatal HI patients, such as cerebral palsy or neonatal stroke patients. In this study, a mouse model of neonatal HI brain injury was established and showed different degrees of motor deficits and cognitive impairment compared to non-operated mice. This work provides basic information on the HI mouse model. MRI images demonstrate the different phenotypes, separated according to the severity of brain damage by motor and cognitive tests. PMID- 29286443 TI - Reprogramming Primary Amniotic Fluid and Membrane Cells to Pluripotency in Xeno free Conditions. AB - Autologous cell-based therapies got a step closer to reality with the introduction of induced pluripotent stem cells. Fetal stem cells, such as amniotic fluid and membrane mesenchymal stem cells, represent a unique type of undifferentiated cells with promise in tissue engineering and for reprogramming into iPSC for future pediatric interventions and stem cell banking. The protocol presented here describes an optimized procedure for extracting and culturing primary amniotic fluid and membrane mesenchymal stem cells and generating episomal induced pluripotent stem cells from these cells in fully chemically defined culture conditions utilizing human recombinant vitronectin and the E8 medium. Characterization of the new lines by applying stringent methods - flow cytometry, confocal imaging, teratoma formation and transcriptional profiling - is also described. The newly generated lines express markers of embryonic stem cells - Oct3/4A, Nanog, Sox2, TRA-1-60, TRA-1-81, SSEA-4 - while being negative for the SSEA-1 marker. The stem cell lines form teratomas in scid-beige mice in 6 8 weeks and the teratomas contain tissues representative of all three germ layers. Transcriptional profiling of the lines by submitting global expression microarray data to a bioinformatic pluripotency assessment algorithm deemed all lines pluripotent and therefore, this approach is an attractive alternative to animal testing. The new iPSC lines can readily be used in downstream experiments involving the optimization of differentiation and tissue engineering. PMID- 29286444 TI - Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease. AB - In neuroimaging, functional magnetic resonance imaging (fMRI) measures the blood oxygenation-level dependent (BOLD) signal in the brain. The degree of correlation of the BOLD signal in spatially independent regions of the brain defines the functional connectivity of those regions. During a cognitive fMRI task, a psychophysiological interaction (PPI) analysis can be used to examine changes in the functional connectivity during specific contexts defined by the cognitive task. An example of such a task is one that engages the memory system, asking participants to learn pairs of unrelated words (encoding) and recall the second word in a pair when presented with the first word (retrieval). In the present study, we used this type of associative memory task and a generalized PPI (gPPI) analysis to compare changes in hippocampal connectivity in older adults who are carriers of the Alzheimer's disease (AD) genetic risk factor apolipoprotein-E epsilon-4 (APOEepsilon4). Specifically, we show that the functional connectivity of subregions of the hippocampus changes during encoding and retrieval, the two active phases of the associative memory task. Context-dependent changes in functional connectivity of the hippocampus were significantly different in carriers of APOEepsilon4 compared to non-carriers. PPI analyses make it possible to examine changes in functional connectivity, distinct from univariate main effects, and to compare these changes across groups. Thus, a PPI analysis may reveal complex task effects in specific cohorts that traditional univariate methods do not capture. PPI analyses cannot, however, determine directionality or causality between functionally connected regions. Nevertheless, PPI analyses provide powerful means for generating specific hypotheses regarding functional relationships, which can be tested using causal models. As the brain is increasingly described in terms of connectivity and networks, PPI is an important method for analyzing fMRI task data that is in line with the current conception of the human brain. PMID- 29286446 TI - Measuring Influenza Neutralizing Antibody Responses to A(H3N2) Viruses in Human Sera by Microneutralization Assays Using MDCK-SIAT1 Cells. AB - Neutralizing antibodies against hemagglutinin (HA) of influenza viruses are considered the main immune mechanism that correlates with protection for influenza infections. Microneutralization (MN) assays are often used to measure neutralizing antibody responses in human sera after influenza vaccination or infection. Madine Darby Canine Kidney (MDCK) cells are the commonly used cell substrate for MN assays. However, currently circulating 3C.2a and 3C.3a A(H3N2) influenza viruses have acquired altered receptor binding specificity. The MDCK SIAT1 cell line with increased alpha-2,6 sialic galactose moieties on the surface has proven to provide improved infectivity and more faithful replications than conventional MDCK cells for these contemporary A(H3N2) viruses. Here, we describe a MN assay using MDCK-SIAT1 cells that has been optimized to quantify neutralizing antibody titers to these contemporary A(H3N2) viruses. In this protocol, heat inactivated sera containing neutralizing antibodies are first serially diluted, then incubated with 100 TCID50/well of influenza A(H3N2) viruses to allow antibodies in the sera to bind to the viruses. MDCK-SIAT1 cells are then added to the virus-antibody mixture, and incubated for 18 - 20 h at 37 degrees C, 5% CO2 to allow A(H3N2) viruses to infect MDCK-SIAT1 cells. After overnight incubation, plates are fixed and the amount of virus in each well is quantified by an enzyme-linked immunosorbent assay (ELISA) using anti-influenza A nucleoprotein (NP) monoclonal antibodies. Neutralizing antibody titer is defined as the reciprocal of the highest serum dilution that provides >=50% inhibition of virus infectivity. PMID- 29286445 TI - 3D Ultrasound Imaging: Fast and Cost-effective Morphometry of Musculoskeletal Tissue. AB - The developmental goal of 3D ultrasound imaging (3DUS) is to engineer a modality to perform 3D morphological ultrasound analysis of human muscles. 3DUS images are constructed from calibrated freehand 2D B-mode ultrasound images, which are positioned into a voxel array. Ultrasound (US) imaging allows quantification of muscle size, fascicle length, and angle of pennation. These morphological variables are important determinants of muscle force and length range of force exertion. The presented protocol describes an approach to determine volume and fascicle length of m. vastus lateralis and m. gastrocnemius medialis. 3DUS facilitates standardization using 3D anatomical references. This approach provides a fast and cost-effective approach for quantifying 3D morphology in skeletal muscles. In healthcare and sports, information on the morphometry of muscles is very valuable in diagnostics and/or follow-up evaluations after treatment or training. PMID- 29286447 TI - Simultaneous Mapping and Quantitation of Ribonucleotides in Human Mitochondrial DNA. AB - Established approaches to estimate the number of ribonucleotides present in a genome are limited to the quantitation of incorporated ribonucleotides using short synthetic DNA fragments or plasmids as templates and then extrapolating the results to the whole genome. Alternatively, the number of ribonucleotides present in a genome may be estimated using alkaline gels or Southern blots. More recent in vivo approaches employ Next-generation sequencing allowing genome-wide mapping of ribonucleotides, providing the position and identity of embedded ribonucleotides. However, they do not allow quantitation of the number of ribonucleotides which are incorporated into a genome. Here we describe how to simultaneously map and quantitate the number of ribonucleotides which are incorporated into human mitochondrial DNA in vivo by Next-generation sequencing. We use highly intact DNA and introduce sequence specific double strand breaks by digesting it with an endonuclease, subsequently hydrolyzing incorporated ribonucleotides with alkali. The generated ends are ligated with adapters and these ends are sequenced on a Next-generation sequencing machine. The absolute number of ribonucleotides can be calculated as the number of reads outside the recognition site per average number of reads at the recognition site for the sequence specific endonuclease. This protocol may also be utilized to map and quantitate free nicks in DNA and allows adaption to map other DNA lesions that can be processed to 5'-OH ends or 5'-phosphate ends. Furthermore, this method can be applied to any organism, given that a suitable reference genome is available. This protocol therefore provides an important tool to study DNA replication, 5' end processing, DNA damage, and DNA repair. PMID- 29286448 TI - Concurrent Recording of Co-localized Electroencephalography and Local Field Potential in Rodent. AB - Although electroencephalography (EEG) is widely used as a non-invasive technique for recording neural activities of the brain, our understanding of the neurogenesis of EEG is still very limited. Local field potentials (LFPs) recorded via a multi-laminar microelectrode can provide a more detailed account of simultaneous neural activity across different cortical layers in the neocortex, but the technique is invasive. Combining EEG and LFP measurements in a pre clinical model can greatly enhance understanding of the neural mechanisms involved in the generation of EEG signals, and facilitate the derivation of a more realistic and biologically accurate mathematical model of EEG. A simple procedure for acquiring concurrent and co-localized EEG and multi-laminar LFP signals in the anesthetized rodent is presented here. We also investigated whether EEG signals were significantly affected by a burr hole drilled in the skull for the insertion of a microelectrode. Our results suggest that the burr hole has a negligible impact on EEG recordings. PMID- 29286449 TI - The Madagascar Hissing Cockroach as an Alternative Non-mammalian Animal Model to Investigate Virulence, Pathogenesis, and Drug Efficacy. AB - Many aspects of innate immunity are conserved between mammals and insects. An insect, the Madagascar hissing cockroach from the genus Gromphadorhina, can be utilized as an alternative animal model for the study of virulence, host-pathogen interaction, innate immune response, and drug efficacy. Details for the rearing, care and breeding of the hissing cockroach are provided. We also illustrate how it can be infected with bacteria such as the intracellular pathogens Burkholderia mallei, B. pseudomallei, and B. thailandensis. Use of the hissing cockroach is inexpensive and overcomes regulatory issues dealing with the use of mammals in research. In addition, results found using the hissing cockroach model are reproducible and similar to those obtained using mammalian models. Thus, the Madagascar hissing cockroach represents an attractive surrogate host that should be explored when conducting animal studies. PMID- 29286450 TI - Deep Proteome Profiling by Isobaric Labeling, Extensive Liquid Chromatography, Mass Spectrometry, and Software-assisted Quantification. AB - Many exceptional advances have been made in mass spectrometry (MS)-based proteomics, with particular technical progress in liquid chromatography (LC) coupled to tandem mass spectrometry (LC-MS/MS) and isobaric labeling multiplexing capacity. Here, we introduce a deep-proteomics profiling protocol that combines 10-plex tandem mass tag (TMT) labeling with an extensive LC/LC-MS/MS platform, and post-MS computational interference correction to accurately quantitate whole proteomes. This protocol includes the following main steps: protein extraction and digestion, TMT labeling, 2-dimensional (2D) LC, high-resolution mass spectrometry, and computational data processing. Quality control steps are included for troubleshooting and evaluating experimental variation. More than 10,000 proteins in mammalian samples can be confidently quantitated with this protocol. This protocol can also be applied to the quantitation of post translational modifications with minor changes. This multiplexed, robust method provides a powerful tool for proteomic analysis in a variety of complex samples, including cell culture, animal tissues, and human clinical specimens. PMID- 29286451 TI - Preparation of Large-area Vertical 2D Crystal Hetero-structures Through the Sulfurization of Transition Metal Films for Device Fabrication. AB - We have demonstrated that through the sulfurization of transition metal films such as molybdenum (Mo) and tungsten (W), large-area and uniform transition metal dichalcogenides (TMDs) MoS2 and WS2 can be prepared on sapphire substrates. By controlling the metal film thicknesses, good layer number controllability, down to a single layer of TMDs, can be obtained using this growth technique. Based on the results obtained from the Mo film sulfurized under the sulfur deficient condition, there are two mechanisms of (a) planar MoS2 growth and (b) Mo oxide segregation observed during the sulfurization procedure. When the background sulfur is sufficient, planar TMD growth is the dominant growth mechanism, which will result in a uniform MoS2 film after the sulfurization procedure. If the background sulfur is deficient, Mo oxide segregation will be the dominant growth mechanism at the initial stage of the sulfurization procedure. In this case, the sample with Mo oxide clusters covered with few-layer MoS2 will be obtained. After sequential Mo deposition/sulfurization and W deposition/sulfurization procedures, vertical WS2/MoS2 hetero-structures are established using this growth technique. Raman peaks corresponding to WS2 and MoS2, respectively, and the identical layer number of the hetero-structure with the summation of individual 2D materials have confirmed the successful establishment of the vertical 2D crystal hetero structure. After transferring the WS2/MoS2 film onto a SiO2/Si substrate with pre patterned source/drain electrodes, a bottom-gate transistor is fabricated. Compared with the transistor with only MoS2 channels, the higher drain currents of the device with the WS2/MoS2 hetero-structure have exhibited that with the introduction of 2D crystal hetero-structures, superior device performance can be obtained. The results have revealed the potential of this growth technique for the practical application of 2D crystals. PMID- 29286452 TI - Esophageal Heat Transfer for Patient Temperature Control and Targeted Temperature Management. AB - Controlling patient temperature is important for a wide variety of clinical conditions. Cooling to normal or below normal body temperature is often performed for neuroprotection after ischemic insult (e.g. hemorrhagic stroke, subarachnoid hemorrhage, cardiac arrest, or other hypoxic injury). Cooling from febrile states treats fever and reduces the negative effects of hyperthermia on injured neurons. Patients are warmed in the operating room to prevent inadvertent perioperative hypothermia, which is known to cause increased blood loss, wound infections, and myocardial injury, while also prolonging recovery time. There are many reported approaches for temperature management, including improvised methods that repurpose standard supplies (e.g., ice, chilled saline, fans, blankets) but more sophisticated technologies designed for temperature management are typically more successful in delivering an optimized protocol. Over the last decade, advanced technologies have developed around two heat transfer methods: surface devices (water blankets, forced-air warmers) or intravascular devices (sterile catheters requiring vascular placement). Recently, a novel device became available that is placed in the esophagus, analogous to a standard orogastric tube, that provides efficient heat transfer through the patient's core. The device connects to existing heat exchange units to allow automatic patient temperature management via a servo mechanism, using patient temperature from standard temperature sensors (rectal, Foley, or other core temperature sensors) as the input variable. This approach eliminates vascular placement complications (deep venous thrombosis, central line associated bloodstream infection), reduces obstruction to patient access, and causes less shivering when compared to surface approaches. Published data have also shown a high degree of accuracy and maintenance of target temperature using the esophageal approach to temperature management. Therefore, the purpose of this method is to provide a low-risk alternative method for controlling patient temperature in critical care settings. PMID- 29286453 TI - Alternative In Vitro Methods for the Determination of Viral Capsid Structural Integrity. AB - Human norovirus exacts considerable public health and economic losses worldwide. Emerging in vitro cultivation advances are not yet applicable for routine detection of the virus. The current detection and quantification techniques, which rely primarily on nucleic acid amplification, do not discriminate infectious from non-infectious viral particles. The purpose of this article is to present specific details on recent advances in techniques used together in order to acquire further information on the infectivity status of viral particles. One technique involves assessing binding of a norovirus ssDNA aptamer to capsids. Aptamers have the advantage of being easily synthesized and modified, and are inexpensive and stable. Another technique, dynamic light scattering (DLS), has the advantage of observing capsid behavior in solution. Electron microscopy allows for visualization of the structural integrity of the viral capsids. Although promising, there are some drawbacks to each technique, such as non specific aptamer binding to positively-charged molecules from sample matrices, requirement of purified capsid for DLS, and poor sensitivity for electron microscopy. Nonetheless, when these techniques are used in combination, the body of data produced provides more comprehensive information on norovirus capsid integrity that can be used to infer infectivity, information which is essential for accurate evaluation of inactivation methods or interpretation of virus detection. This article provides protocols for using these methods to discriminate infectious human norovirus particles. PMID- 29286455 TI - Fragility Assessment of Bovine Cortical Bone Using Scratch Tests. AB - Bone is a complex hierarchical material with five distinct levels of organization. Factors like aging and diseases like osteoporosis increase the fragility of bone, making it fracture-prone. Owing to the large socio-economic impact of bone fracture in our society, there is a need for novel ways to assess the mechanical performance of each hierarchical level of bone. Although stiffness and strength can be probed at all scales - nano-, micro-, meso-, and macroscopic fracture assessment has so far been confined to macroscopic testing. This limitation restricts our understanding of bone fracture and constrains the scope of laboratory and clinical studies. In this research, we investigate the fracture resistance of bone from the microscopic to the mesoscopic length scales using micro scratch tests combined with nonlinear fracture mechanics. The tests are performed in the short longitudinal orientation on bovine cortical bone specimens. A meticulous experimental protocol is developed and a large number (102) of tests are conducted to assess the fracture toughness of cortical bone specimens while accounting for the heterogeneity associated with bone microstructure. PMID- 29286454 TI - Live Cell Fluorescence Microscopy to Observe Essential Processes During Microbial Cell Growth. AB - Core cellular processes such as DNA replication and segregation, protein synthesis, cell wall biosynthesis, and cell division rely on the function of proteins which are essential for bacterial survival. A series of target-specific dyes can be used as probes to better understand these processes. Staining with lipophilic dyes enables the observation of membrane structure, visualization of lipid microdomains, and detection of membrane blebs. Use of fluorescent-d-amino acids (FDAAs) to probe the sites of peptidoglycan biosynthesis can indicate potential defects in cell wall biogenesis or cell growth patterning. Finally, nucleic acid stains can indicate possible defects in DNA replication or chromosome segregation. Cyanine DNA stains label living cells and are suitable for time-lapse microscopy enabling real-time observations of nucleoid morphology during cell growth. Protocols for cell labeling can be applied to protein depletion mutants to identify defects in membrane structure, cell wall biogenesis, or chromosome segregation. Furthermore, time-lapse microscopy can be used to monitor morphological changes as an essential protein is removed and can provide additional insights into protein function. For example, the depletion of essential cell division proteins results in filamentation or branching, whereas the depletion of cell growth proteins may cause cells to become shorter or rounder. Here, protocols for cell growth, target-specific labeling, and time lapse microscopy are provided for the bacterial plant pathogen Agrobacterium tumefaciens. Together, target-specific dyes and time-lapse microscopy enable characterization of essential processes in A. tumefaciens. Finally, the protocols provided can be readily modified to probe essential processes in other bacteria. PMID- 29286456 TI - Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography. AB - Pain is an unpleasant sensory and emotional experience. In non-verbal patients, it is very difficult to measure pain, even with pain assessment tools. Those tools are subjective or determine secondary physiological indicators which also have certain limitations particularly when exploring the effectiveness of analgesia. As cortical processing is essential for pain perception, brain activity measures may provide a useful approach to assess pain in infants. Here we present a method to assess nociception with electrophysiological brain activity recordings optimized for the use in newborn infants. To produce highly standardized and reproducible noxious stimuli we applied mechanical stimulation with a flat-tip probe, e.g., PinPrick, which is not skin-breaking and does not cause behavioral distress. The noxious-evoked potential allows the objective measurement of nociception in non-verbal patients. This method can be used in newborn infants as early as 34 weeks of gestational age. Moreover, it could be applied in different situations such as measuring the efficacy of analgesic or anesthetic drugs. PMID- 29286457 TI - Methods to Study Changes in Inherent Protein Aggregation with Age in Caenorhabditis elegans. AB - In the last decades, the prevalence of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), has grown. These age associated disorders are characterized by the appearance of protein aggregates with fibrillary structure in the brains of these patients. Exactly why normally soluble proteins undergo an aggregation process remains poorly understood. The discovery that protein aggregation is not limited to disease processes and instead part of the normal aging process enables the study of the molecular and cellular mechanisms that regulate protein aggregation, without using ectopically expressed human disease-associated proteins. Here we describe methodologies to examine inherent protein aggregation in Caenorhabditis elegans through complementary approaches. First, we examine how to grow large numbers of age synchronized C. elegans to obtain aged animals and we present the biochemical procedures to isolate highly-insoluble-large aggregates. In combination with a targeted genetic knockdown, it is possible to dissect the role of a gene of interest in promoting or preventing age-dependent protein aggregation by using either a comprehensive analysis with quantitative mass spectrometry or a candidate-based analysis with antibodies. These findings are then confirmed by in vivo analysis with transgenic animals expressing fluorescent-tagged aggregation prone proteins. These methods should help clarify why certain proteins are prone to aggregate with age and ultimately how to keep these proteins fully functional. PMID- 29286458 TI - Surgical Training for the Implantation of Neocortical Microelectrode Arrays Using a Formaldehyde-fixed Human Cadaver Model. AB - This protocol describes a procedure to assist surgeons in training for the implantation of microelectrode arrays into the neocortex of the human brain. Recent technological progress has enabled the fabrication of microelectrode arrays that allow recording the activity of multiple individual neurons in the neocortex of the human brain. These arrays have the potential to bring unique insight onto the neuronal correlates of cerebral function in health and disease. Furthermore, the identification and decoding of volitional neuronal activity opens the possibility to establish brain-computer interfaces, and thus might help restore lost neurological functions. The implantation of neocortical microelectrode arrays is an invasive procedure requiring a supra-centimetric craniotomy and the exposure of the cortical surface; thus, the procedure must be performed by an adequately trained neurosurgeon. In order to provide an opportunity for surgical training, we designed a procedure based on a human cadaver model. The use of a formaldehyde-fixed human cadaver bypasses the practical, ethical and financial difficulties of surgical practice on animals (especially non-human primates) while preserving the macroscopic structure of the head, skull, meninges and cerebral surface and allowing realistic, operating room like positioning and instrumentation. Furthermore, the use of a human cadaver is closer to clinical daily practice than any non-human model. The major drawbacks of the cadaveric simulation are the absence of cerebral pulsation and of blood and cerebrospinal fluid circulation. We suggest that a formaldehyde-fixed human cadaver model is an adequate, practical and cost-effective approach to ensure proper surgical training before implanting microelectrode arrays in the living human neocortex. PMID- 29286459 TI - Environmental Screening of Aeromonas hydrophila, Mycobacterium spp., and Pseudocapillaria tomentosa in Zebrafish Systems. AB - Health monitoring systems are developed and used in zebrafish research facilities because pathogens of Danio rerio such as Aeromonas hydrophila, Mycobacterium spp., and Pseudocapillaria tomentosa have the potential to impair animal welfare and research. The fish are typically analyzed post mortem to detect microbes. The use of sentinels is a suggested way to improve the sensitivity of the surveillance and to reduce the number of animals to sample. The setting of a pre filtration sentinel tank out of a recirculating system is described. The technique is developed to prevent water pollution and to represent the fish population by a careful selection of age, gender, and strains. In order to use the minimum number of animals, techniques to screen the environment are also detailed. Polymerase Chain Reaction (PCR) on surface sump swabs is used to significantly improve the detection of some prevalent and pathogenic mycobacterial species such as Mycobacterium fortuitum, Mycobacterium haemophilum, and Mycobacterium chelonae. Another environmental method consists of processing the sludge at the bottom of a holding tank or sump to look for P. tomentosa eggs. This is a cheap and fast technique that can be applied in quarantine where a breeding device is submerged into the holding tank of imported animals. Finally, PCR is applied to the sludge sample and A. hydrophila is detected at the sump's bottom and surface. Generally, these environmental screening techniques applied to these specific pathogens have led to an increased sensitivity compared to the testing of pre-filtration sentinels. PMID- 29286460 TI - Novel Diagnostics in Revision Arthroplasty: Implant Sonication and Multiplex Polymerase Chain Reaction. AB - In orthopedic patients, foreign body-associated infections, especially periprosthetic joint infections (PJIs), are a devastating complication of arthroplasty. Infection requires complex treatment, may result in long hospitalization and causes considerable costs. Multiple surgical revisions can be necessary in these patients, with a loss in function as well as in quality of life. The routine preoperative diagnostics include blood examination for C reactive protein (CRP) and other biomarkers, as well as joint aspirate analysis for cell count, differentiation, and culture. Intraoperative specimens for histology and microbiology are also standard procedure. The microbiological examination of removed implants with sonication, in combination with the implementation of molecular biology techniques in microbiology, represent two novel techniques currently employed to enhance the differential diagnostics of PJI. We present here the step-wise procedure of analyzing joint aspirate and sonication fluid, using a cartridge-based multiplex polymerase chain reaction (PCR) system. Results were matched against conventional cultures and consensus criteria for PJI. Conventional microbiological cultures from tissue biopsies, joint aspirate and sonication fluid showed a sensitivity of 66.7%, 66.7%, and 88.9%, respectively, and a specificity of 82.3%, 54.6%, and 61.5%, respectively. The PCR diagnostic of the sonication fluid and the joint fluid showed a sensitivity of 50.0% and 55.6%, respectively, and both a specificity of 100.0%. Both PCR diagnostics combined had a sensitivity of 66.7% and a specificity of 100.0%. The multiplex PCR therefore presents a rapid diagnostic tool with moderate sensitivity but high specificity in diagnosing PJI. PMID- 29286461 TI - Ultrasonography in Experimental Reproductive Investigations on Rats. AB - With the development of assisted reproductive technology and the ethical limitations of research on humans, rat animal models have been widely used in reproductive medicine. In the past, the study of reproductive system development in rodents has been based on one-time histological examination of excised tissues. Recently, with the development of high-resolution transabdominal ultrasound, high-quality sonography can now be performed to evaluate the reproductive organs of rats, allowing a new method for studying the reproductive system. Images were obtained using a high-resolution ultrasonographic system. Gynecological ultrasonography was performed on 28 eight-week-old non-pregnant rats and 5 pregnant Sprague-Dawley rats. We describe how to recognize organs of the reproductive system and associated structures in typical views during different phases of the estrus cycle. Color flow Doppler was used to measure uterine artery blood flow and evaluate uterine blood flow pattern changes during different stages of pregnancy. We have demonstrated that ultrasound exploration is a useful method for evaluating changes in internal reproductive organs. Its use raises the possibility of conducting additional experiments, including medical or surgical procedures, and provides the ability to monitor sonographic changes to internal organs without sacrificing animals. PMID- 29286462 TI - Repeated Blood Collection from Tail Vein of Non-Anesthetized Rats with a Vacuum Blood Collection System. AB - Blood can be collected from rats in a number of sampling locations. For instance, the tail vein is a superior location for blood sampling. However, the tail vein is thin so that it is sometimes hard to puncture. In addition, the tail vein has low blood flow and requires a long sampling time to get sufficient blood. The present report describes a simple blood sampling method, the vacuum blood collection method, which is usually used to obtain blood samples from patients, here used for non-anesthetized rats. The 22 G butterfly needle tip was inserted into one of the lateral tail veins approximately 2-3 cm from the tip of the tail at an angle of approximately 20 degrees , and blood was collected in the vacuum collection tube by inserting the rubber end of the butterfly needle into the vacuum blood collection tube. The present experimental results show that the success rate was 95% in the experimental group and 90% in the beginner group. The success rate and puncture times were similar between two groups. The sampling duration was significantly shorter in the experimental group compared to beginner group. In conclusion, this vacuum blood collection method for sequential blood sampling from the tail vein of non- anesthetized rats is feasible and easy-to learn, which might serve as a reliable alternative to other conventionally used blood sampling techniques for rats. PMID- 29286463 TI - In Vitro Growth of Mouse Preantral Follicles Under Simulated Microgravity. AB - 14 day-old mouse ovarian tissue and preantral follicles isolated from same-aged mice were incubated in a simulated microgravity culture system. We quantitatively assessed follicle survival, measured follicle and oocyte diameters, and examined ultrastructure of the oocytes produced from the system. We observed decreased follicle survival, downregulation of expressions of proliferating cell nuclear antigen and growth differentiation factor 9, as indicators for the development of granulosa cells and oocytes, respectively, and oocyte ultrastructural abnormalities under the simulated microgravity condition. The simulated microgravity experimental setup needs to be optimized to provide a model for investigation of the mechanisms involved in the oocyte/follicle in vitro development. PMID- 29286464 TI - Protein Film Infrared Electrochemistry Demonstrated for Study of H2 Oxidation by a [NiFe] Hydrogenase. AB - Understanding the chemistry of redox proteins demands methods that provide precise control over redox centers within the protein. The technique of protein film electrochemistry, in which a protein is immobilized on an electrode surface such that the electrode replaces physiological electron donors or acceptors, has provided functional insight into the redox reactions of a range of different proteins. Full chemical understanding requires electrochemical control to be combined with other techniques that can add additional structural and mechanistic insight. Here we demonstrate a technique, protein film infrared electrochemistry, which combines protein film electrochemistry with infrared spectroscopic sampling of redox proteins. The technique uses a multiple-reflection attenuated total reflectance geometry to probe a redox protein immobilized on a high surface area carbon black electrode. Incorporation of this electrode into a flow cell allows solution pH or solute concentrations to be changed during measurements. This is particularly powerful in addressing redox enzymes, where rapid catalytic turnover can be sustained and controlled at the electrode allowing spectroscopic observation of long-lived intermediate species in the catalytic mechanism. We demonstrate the technique with experiments on E. coli hydrogenase 1 under turnover (H2 oxidation) and non-turnover conditions. PMID- 29286465 TI - Semi-automated Biopanning of Bacterial Display Libraries for Peptide Affinity Reagent Discovery and Analysis of Resulting Isolates. AB - Biopanning bacterial display libraries is a proven technique for peptide affinity reagent discovery for recognition of both biotic and abiotic targets. Peptide affinity reagents can be used for similar applications to antibodies, including sensing and therapeutics, but are more robust and able to perform in more extreme environments. Specific enrichment of peptide capture agents to a protein target of interest is enhanced using semi-automated sorting methods which improve binding and wash steps and therefore decrease the occurrence of false positive binders. A semi-automated sorting method is described herein for use with a commercial automated magnetic-activated cell sorting device with an unconstrained bacterial display sorting library expressing random 15-mer peptides. With slight modifications, these methods are extendable to other automated devices, other sorting libraries, and other organisms. A primary goal of this work is to provide a comprehensive methodology and expound the thought process applied in analyzing and minimizing the resulting pool of candidates. These techniques include analysis of on-cell binding using fluorescence-activated cell sorting (FACS), to assess affinity and specificity during sorting and in comparing individual candidates, and the analysis of peptide sequences to identify trends and consensus sequences for understanding and potentially improving the affinity to and specificity for the target of interest. PMID- 29286466 TI - An Optimized Hemagglutination Inhibition (HI) Assay to Quantify Influenza specific Antibody Titers. AB - Antibody titers are commonly used as surrogate markers for serological protection against influenza and other pathogens. Detailed knowledge of antibody production pre- and post-vaccination is required to understand vaccine-induced immunity. This article describes a reliable point-by-point protocol to determine influenza specific antibody titers. The first protocol describes a method to specify the antigen amounts required for hemagglutination, which standardizes the concentrations for subsequent usage in the second protocol (hemagglutination assay, HA assay). The second protocol describes the quantification of influenza specific antibody titers against different viral strains by using a serial dilution of human serum or cell culture supernatants (hemagglutination inhibition assay, HI assay). As an applied example, we show the antibody response of a healthy cohort, which received a trivalent inactivated influenza vaccine. Additionally, the cross-reactivity between the different influenza viruses is shown and methods to minimize cross-reactivity by using different types of animal red blood cells (RBCs) are explained. The discussion highlights advantages and disadvantages of the presented assays and how the determination of influenza specific antibody titers can improve the understanding of vaccine-related immunity. PMID- 29286467 TI - Fluorescence-mediated Tomography for the Detection and Quantification of Macrophage-related Murine Intestinal Inflammation. AB - Murine models of disease are indispensable to scientific research. However, many diagnostic tools such as endoscopy or tomographic imaging are not routinely employed in animal models. Conventional experimental readouts often rely on post mortem and ex vivo analyses, which prevent intra-individual follow-up examinations and increase the number of study animals needed. Fluorescence mediated tomography enables the non-invasive, repetitive, quantitative, three dimensional assessment of fluorescent probes. It is highly sensitive and permits the use of molecular makers, which allows for the specific detection and characterization of distinct molecular targets. In particular, targeted probes represent an innovative tool for analyzing gene activation and protein expression in inflammation, autoimmune disease, infection, vascular disease, cell migration, tumorigenesis, etc. In this article, we provide step-by-step instructions on this sophisticated imaging technology for the in vivo detection and characterization of inflammation (i.e., F4/80-positive macrophage infiltration) in a widely used murine model of intestinal inflammation. This technique might also be used in other research areas, such as immune cell or stem cell tracking. PMID- 29286468 TI - Analysis of Immune Cells in Single Sciatic Nerves and Dorsal Root Ganglion from a Single Mouse Using Flow Cytometry. AB - Nerve-resident immune cells in the peripheral nervous system (PNS) are essential to maintaining neuronal integrity in a healthy nerve. The immune cells of the PNS are affected by injury and disease, affecting the nerve function and the capacity for regeneration. Neuronal immune cells are commonly analyzed by immunofluorescence (IF). While IF is essential for determining the location of the immune cells in the nerve, IF is only semi-quantitative and the method is limited to the number of markers that can be analyzed simultaneously and the degree of surface expression. In this study, flow cytometry was used for quantitative analysis of leukocyte infiltration into sciatic nerves or dorsal root ganglions (DRGs) of individual mice. Single cell analysis was performed using DAPI and several proteins were analyzed simultaneously for either surface or intracellular expression. Both sciatic nerves from one mouse that were treated according to this protocol generated >= 30,000 single nucleated events. The proportion of leukocytes in the sciatic nerves, determined by expression of CD45, was approximately 5% of total cell content in the sciatic nerve and approximately 5-10% in the DRG. Although this protocol focuses primarily on the immune cell population within the PNS, the flexibility of flow cytometry to measure a number of markers simultaneously means that the other cells populations present within the nerve, such as Schwann cells, pericytes, fibroblasts, and endothelial cells, can also be analyzed using this method. This method therefore provides a new means for studying systemic effects on the PNS, such as neurotoxicology and genetic models of neuropathy or in chronic diseases, such as diabetes. PMID- 29286469 TI - Generation of Native Chromatin Immunoprecipitation Sequencing Libraries for Nucleosome Density Analysis. AB - We present a modified native chromatin immunoprecipitation sequencing (ChIP-seq) experimental protocol compatible with a Gaussian mixture distribution based analysis methodology (nucleosome density ChIP-seq; ndChIP-seq) that enables the generation of combined measurements of micrococcal nuclease (MNase) accessibility with histone modification genome-wide. Nucleosome position and local density, and the posttranslational modification of their histone subunits, act in concert to regulate local transcription states. Combinatorial measurements of nucleosome accessibility with histone modification generated by ndChIP-seq allows for the simultaneous interrogation of these features. The ndChIP-seq methodology is applicable to small numbers of primary cells inaccessible to cross-linking based ChIP-seq protocols. Taken together, ndChIP-seq enables the measurement of histone modification in combination with local nucleosome density to obtain new insights into shared mechanisms that regulate RNA transcription within rare primary cell populations. PMID- 29286470 TI - Nanopore DNA Sequencing for Metagenomic Soil Analysis. AB - This article describes the steps for construction of a DNA library from soil, preparation and use of the nanopore flow cell, and analysis of the DNA sequences identified using computer software. Nanopore DNA sequencing is a flexible technique that allows for rapid microbial genome sequencing to identify bacterial and viral species, to characterize bacterial strains, and to detect genetic mutations that confer resistance to antibiotics. The advantages of nanopore sequencing (NS) for life sciences include its low complexity, reduced cost, and rapid real-time sequencing of purified genomic DNA, PCR amplicons, cDNA samples, or RNA. NS is an example of "strand sequencing" which involves sequencing DNA by guiding a single stranded DNA molecule through a nanopore that is inserted into a synthetic polymer membrane. The membrane has an electrical current applied across it, so as the individual bases pass through the nanopore the electrical current is disrupted to varying degrees by the four nucleotide bases. The identification of each nucleotide occurs by detecting the characteristic modulation of the electrical current by the different bases as they pass through the nanopore. The NS system consists of a handheld, USB powered portable device and a disposable flow cell that contains a nanopore array. The portable device plugs into a standard laptop computer that reads and records the DNA sequence using computer software. PMID- 29286471 TI - In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease. AB - The use of personalized medicine to treat rare monogenic diseases like lysosomal storage disorders (LSDs) is challenged by complex clinical trial designs, high costs, and low patient numbers. Hundreds of mutant alleles are implicated in most of the LSDs. The diseases are typically classified into 2 to 3 different clinical types according to severity. Moreover, molecular characterization of the genotype can help predict clinical outcomes and inform patient care. Therefore, we developed a simple cell culture assay based on HEK293H cells heterologously over expressing the mutations identified in Fabry and Pompe disease. A similar assay has recently been introduced as a preclinical test to identify amenable mutations for Pharmacological Chaperone Therapy (PCT) in Fabry disease. This manuscript describes an amended cell culture assay which enables rapid phenotypic assessment of allelic variants in Fabry and Pompe disease to identify eligible patients for PCT and may aid in the development of novel pharmacochaperones. PMID- 29286472 TI - Combining Mitotic Cell Synchronization and High Resolution Confocal Microscopy to Study the Role of Multifunctional Cell Cycle Proteins During Mitosis. AB - Study of the various regulatory events of the cell cycle in a phase-dependent manner provides a clear understanding about cell growth and division. The synchronization of cell populations at specific stages of the cell cycle has been found to be very useful in such experimental endeavors. Synchronization of cells by treatment with chemicals that are relatively less toxic can be advantageous over the use of pharmacological inhibitory drugs for the study of consequent cell cycle events and to obtain specific enrichment of selected mitotic stages. Here, we describe the protocol for synchronizing human cells at different stages of the cell cycle, including both in S phase and M phase with a double thymidine block and release procedure for studying the functionality of mitotic proteins in chromosome alignment and segregation. This protocol has been extremely useful for studying the mitotic roles of multifunctional proteins which possess established interphase functions. In our case, the mitotic role of Cdt1, a protein critical for replication origin licensing in G1 phase, can be studied effectively only when G2/M-specific Cdt1 can be depleted. We describe the detailed protocol for depletion of G2/M-specific Cdt1 using double thymidine synchronization. We also explain the protocol of cell fixation, and live cell imaging using high resolution confocal microscopy after thymidine release. The method is also useful for analyzing the function of mitotic proteins under both physiological and perturbed conditions such as for Hec1, a component of the Ndc80 complex, as it enables one to obtain large sample sizes of mitotic cells for fixed and live cell analysis as we show here. PMID- 29286473 TI - A Simple Fluorescence-based Reporter Assay to Identify Cellular Components Required for Ricin Toxin A Chain (RTA) Trafficking in Yeast. AB - Bacterial and plant A/B toxins exploit the natural trafficking pathways in eukaryotic cells to reach their intracellular target(s) in the cytosol and to ultimately kill. Such A/B toxins generally consist of an enzymatically active Asubunit (e.g., ricin toxin A (RTA)) and one or more cell binding Bsubunit(s), which are responsible for toxin binding to specific cell surface receptors. Our current knowledge of how A/B toxins are capable of efficiently intoxicating cells helped scientists to understand fundamental cellular mechanisms, like endocytosis and intracellular protein sorting in higher eukaryotic cells. From a medical point of view, it is likewise important to identify the major toxin trafficking routes to find adequate treatment solutions for patients or to eventually develop therapeutic toxin-based applications for cancer therapy. Since genome-wide analyses of A/B toxin trafficking in mammalian cells is complex, time-consuming, and expensive, several studies on A/B toxin transport have been performed in the yeast model organism Saccharomyces cerevisiae. Despite being less complex, fundamental cellular processes in yeast and higher eukaryotic cells are similar and very often results obtained in yeast can be transferred to the mammalian situation. Here, we describe a fast and easy to use reporter assay to analyze the intracellular trafficking of RTA in yeast. An essential advantage of the new assay is the opportunity to investigate not only RTA retro-translocation from the endoplasmic reticulum (ER) into the cytosol, but rather endocytosis and retrograde toxin transport from the plasma membrane into the ER. The assay makes use of a reporter plasmid that allows indirect measurement of RTA toxicity through fluorescence emission of the green fluorescent protein (GFP) after in vivo translation. Since RTA efficiently prevents the initiation of protein biosynthesis by 28S rRNA depurination, this assay allows the identification of host cell proteins involved in intracellular RTA transport through the detection of changes in fluorescence emission. PMID- 29286474 TI - Mouse Model for Pancreas Transplantation Using a Modified Cuff Technique. AB - Mouse models have several advantages in transplantation research, including easy handling, a variety of genetically well-defined strains, and the availability of the widest range of molecular probes and reagents to perform in vivo as well as in vitro studies. Based on our experience with various murine transplantation models, we developed a heterotopic pancreas transplantation model in mice with the intent to analyze mechanisms underlying severe ischemia reperfusion injury associated early graft damage. In contrast to previously described techniques using suture techniques, herein we describe a new procedure using a non-suture cuff technique. In recent years, we have performed more than 300 pancreas transplantations in mice with an overall success rate of >90%, a success rate never described before in mouse pancreas transplantation. The backbone of this non-suture cuff technique for graft revascularization consists of two major steps: (I) pulling the recipient vessel over a polyethylene/polyamide cuff and fixing it with a circumferential ligature, and (II) placing the donor vessel over the everted recipient vessel and fixing it with a second circumferential ligature. The resultant continuity of the endothelial layer results in less thrombogenic lesions with high patency rates and, finally, high success rates. In this model, arterial anastomosis is achieved by pulling the abdominal aorta of the donor graft over the everted common carotid artery of the recipient animal. Venous drainage of the graft is achieved by pulling the portal vein of the graft over the everted external jugular vein of the recipient. This manuscript provides details and crucial steps of the organ recovery and organ implantation procedures, which will allow researchers with microsurgical skills to perform the transplantation successfully in their laboratories. PMID- 29286475 TI - Microstructured Devices for Optimized Microinjection and Imaging of Zebrafish Larvae. AB - Zebrafish have emerged as a powerful model of various human diseases and a useful tool for an increasing range of experimental studies, spanning fundamental developmental biology through to large-scale genetic and chemical screens. However, many experiments, especially those related to infection and xenograft models, rely on microinjection and imaging of embryos and larvae, which are laborious techniques that require skill and expertise. To improve the precision and throughput of current microinjection techniques, we developed a series of microstructured devices to orient and stabilize zebrafish embryos at 2 days post fertilization (dpf) in ventral, dorsal, or lateral orientation prior to the procedure. To aid in the imaging of embryos, we also designed a simple device with channels that orient 4 zebrafish laterally in parallel against a glass cover slip. Together, the tools that we present here demonstrate the effectiveness of photolithographic approaches to generate useful devices for the optimization of zebrafish techniques. PMID- 29286476 TI - Using Extraordinary Optical Transmission to Quantify Cardiac Biomarkers in Human Serum. AB - For a biosensing platform to have clinical relevance in point-of-care (POC) settings, assay sensitivity, reproducibility, and ability to reliably monitor analytes against the background of human serum are crucial. Nanoimprinting lithography (NIL) was used to fabricate, at a low cost, sensing areas as large as 1.5 mm x 1.5 mm. The sensing surface was made of high-fidelity arrays of nanoholes, each with an area of about 140 nm2. The great reproducibility of NIL made it possible to employ a one-chip, one-measurement strategy on 12 individually manufactured surfaces, with minimal chip-to-chip variation. These nanoimprinted localized surface plasmon resonance (LSPR) chips were extensively tested on their ability to reliably measure a bioanalyte at concentrations varying from 2.5 to 75 ng/mL amidst the background of a complex biofluid-in this case, human serum. The high fidelity of NIL enables the generation of large sensing areas, which in turn eliminates the need for a microscope, as this biosensor can be easily interfaced with a commonly available laboratory light source. These biosensors can detect cardiac troponin in serum with a high sensitivity, at a limit of detection (LOD) of 0.55 ng/mL, which is clinically relevant. They also show low chip-to-chip variance (due to the high quality of the fabrication process). The results are commensurable with widely used enzyme linked immunosorbent assay (ELISA)-based assays, but the technique retains the advantages of an LSPR-based sensing platform (i.e., amenability to miniaturization and multiplexing, making it more feasible for POC applications). PMID- 29286477 TI - Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions. AB - Here we present a protocol to study intracellular protein-protein interactions that is based on the widely used biotin-avidin pull-down system. The modification presented includes the combination of this technique with cell-penetrating sequences. We propose to design cell-penetrating baits that can be incubated with living cells instead of cell lysates and therefore the interactions found will reflect those that occur within the intracellular context. Connexin43 (Cx43), a protein that forms gap junction channels and hemichannels is down-regulated in high-grade gliomas. The Cx43 region comprising amino acids 266-283 is responsible for the inhibition of the oncogenic activity of c-Src in glioma cells. Here we use TAT as the cell-penetrating sequence, biotin as the pull-down tag and the region of Cx43 comprised between amino acids 266-283 as the target to find intracellular interactions in the hard-to-transfect human glioma stem cells. One of the limitations of the proposed method is that the molecule used as bait could fail to fold properly and, consequently, the interactions found could not be associated with the effect. However, this method can be especially interesting for the interactions involved in signal transduction pathways because they are usually carried out by intrinsically disordered regions and, therefore, they do not require an ordered folding. In addition, one of the advantages of the proposed method is that the relevance of each residue on the interaction can be easily studied. This is a modular system; therefore, other cell-penetrating sequences, other tags, and other intracellular targets can be employed. Finally, the scope of this protocol is far beyond protein-protein interaction because this system can be applied to other bioactive cargoes such as RNA sequences, nanoparticles, viruses or any molecule that can be transduced with cell penetrating sequences and fused to pull-down tags to study their intracellular mechanism of action. PMID- 29286478 TI - A Murine Model of Vertical Sleeve Gastrectomy. AB - Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is a surgery of the gastrointestinal tract that is performed for the purpose of weight loss. Bariatric surgery is currently the most effective long-term treatment for obesity. In addition to weight loss, bariatric surgery produces additional health benefits such as remission of type 2 diabetes, remission of hypertension, and decreased risk of developing certain types of cancer. The mechanisms beyond weight loss for these benefits remain incompletely defined. Therefore, animal models of bariatric surgery are being developed and validated to identify the mechanisms leading to these benefits, with the goal of improving understanding of gastrointestinal physiology and identifying new therapeutic targets. VSG has become the most commonly performed bariatric procedure in the clinic in the United States because it is highly effective at producing weight loss and metabolic improvement, and is simpler to perform than other bariatric procedures. Therefore, we have developed and validated a murine model of VSG. This murine VSG model recapitulates many of the effects of VSG seen in humans, including improved glucose and blood pressure regulation. The method is based on isolation of the stomach, ligation of gastric vessels, and removal of 70% of the stomach by transecting along the greater curvature of the stomach. We have successfully applied this surgical protocol to various genetically modified mouse lines to define the mechanistic contributors to the benefits of VSG. Furthermore, this murine VSG model has been combined with other surgical techniques, to achieve deeper mechanistic insight. Therefore, this is a simple and versatile model for studying gastrointestinal physiology and the health benefits of bariatric surgery. PMID- 29286479 TI - Method for Labeling Transcripts in Individual Escherichia coli Cells for Single molecule Fluorescence In Situ Hybridization Experiments. AB - A method is described for labeling individual messenger RNA (mRNA) transcripts in fixed bacteria for use in single-molecule fluorescence in situ hybridization (smFISH) experiments in E. coli. smFISH allows the measurement of cell-to-cell variability in mRNA copy number of genes of interest, as well as the subcellular location of the transcripts. The main steps involved are fixation of the bacterial cell culture, permeabilization of cell membranes, and hybridization of the target transcripts with sets of commercially available short fluorescently labeled oligonucleotide probes. smFISH can allow the imaging of the transcripts of multiple genes in the same cell, with limitations imposed by the spectral overlap between different fluorescent markers. Following completion of the protocol illustrated below, cells can be readily imaged using a microscope coupled with a camera suitable for low-intensity fluorescence. These images, together with cell contours obtained from segmentation of phase contrast frames, or from cell membrane staining, allow the calculation of the mRNA copy number distribution of a sample of cells using open-source or custom-written software. The labeling method described here can also be applied to image transcripts with stochastic optical reconstruction microscopy (STORM). PMID- 29286480 TI - 3D Mitochondrial Ultrastructure of Drosophila Indirect Flight Muscle Revealed by Serial-section Electron Tomography. AB - Mitochondria are cellular powerhouses that produce ATP, lipids, and metabolites, as well as regulate calcium homeostasis and cell death. The unique cristae-rich double membrane ultrastructure of this organelle is elegantly arranged to carry out multiple functions by partitioning biomolecules. Mitochondrial ultrastructure is intimately linked with various functions; however, the fine details of these structure-function relationships are only beginning to be described. Here, we demonstrate the application of serial-section electron tomography to elucidate mitochondrial structure in Drosophila indirect flight muscle. Serial-section electron tomography may be adapted to study any cellular structure in three dimensions. PMID- 29286481 TI - Method for Efficient Refolding and Purification of Chemoreceptor Ligand Binding Domain. AB - Identification of natural ligands of chemoreceptors and structural studies aimed at elucidation of the molecular basis of the ligand specificity can be greatly facilitated by the production of milligram amounts of pure, folded ligand binding domains. Attempts to heterologously express periplasmic ligand binding domains of bacterial chemoreceptors in Escherichia coli (E. coli) often result in their targeting into inclusion bodies. Here, a method is presented for protein recovery from inclusion bodies, its refolding and purification, using the periplasmic dCACHE ligand binding domain of Campylobacter jejuni (C. jejuni) chemoreceptor Tlp3 as an example. The approach involves expression of the protein of interest with a cleavable His6-tag, isolation and urea-mediated solubilisation of inclusion bodies, protein refolding by urea depletion, and purification by means of affinity chromatography, followed by tag removal and size-exclusion chromatography. The circular dichroism spectroscopy is used to confirm the folded state of the pure protein. It has been demonstrated that this protocol is generally useful for production of milligram amounts of dCACHE periplasmic ligand binding domains of other bacterial chemoreceptors in a soluble and crystallisable form. PMID- 29286482 TI - Real-time Measurement of Epithelial Barrier Permeability in Human Intestinal Organoids. AB - Advances in 3D culture of intestinal tissues obtained through biopsy or generated from pluripotent stem cells via directed differentiation, have resulted in sophisticated in vitro models of the intestinal mucosa. Leveraging these emerging model systems will require adaptation of tools and techniques developed for 2D culture systems and animals. Here, we describe a technique for measuring epithelial barrier permeability in human intestinal organoids in real-time. This is accomplished by microinjection of fluorescently-labeled dextran and imaging on an inverted microscope fitted with epifluorescent filters. Real-time measurement of the barrier permeability in intestinal organoids facilitates the generation of high-resolution temporal data in human intestinal epithelial tissue, although this technique can also be applied to fixed timepoint imaging approaches. This protocol is readily adaptable for the measurement of epithelial barrier permeability following exposure to pharmacologic agents, bacterial products or toxins, or live microorganisms. With minor modifications, this protocol can also serve as a general primer on microinjection of intestinal organoids and users may choose to supplement this protocol with additional or alternative downstream applications following microinjection. PMID- 29286483 TI - Serum and Plasma Copy Number Detection Using Real-time PCR. AB - Serum and plasma cell free DNA (cfDNA) has been shown as an informative, non invasive source of biomarkers for cancer diagnosis, prognosis, monitoring, and prediction of treatment resistance. Starting from the hypothesis that androgen receptor (AR) gene copy number (CN) gain is a frequent event in metastatic castration resistance prostate cancer (mCRPC), we propose to analyze this event in cfDNA as a potential predictive biomarker. We evaluated AR CN in cfDNA using 2 different real-time PCR assays and 2 reference genes (RNaseP and AGO1). DNA amount of 60 ng was used for each assay combination. AR CN gain was confirmed using Digital PCR as a more accurate method. CN variation analysis has already been demonstrated to be informative for the prediction of treatment resistance in the setting of mCRPC, but it could be useful also for other purposes in different patient settings. CN analysis on cfDNA has several advantages: it is non invasive, rapid and easy to perform, and it starts from a small volume of serum or plasma material. PMID- 29286485 TI - Characterization of Tumor Cells Using a Medical Wire for Capturing Circulating Tumor Cells: A 3D Approach Based on Immunofluorescence and DNA FISH. AB - Circulating tumor cells (CTCs) are associated with poor survival in metastatic cancer. Their identification, phenotyping, and genotyping could lead to a better understanding of tumor heterogeneity and thus facilitate the selection of patients for personalized treatment. However, this is hampered because of the rarity of CTCs. We present an innovative approach for sampling a high volume of the patient blood and obtaining information about presence, phenotype, and gene translocation of CTCs. The method combines immunofluorescence staining and DNA fluorescent-in-situ-hybridization (DNA FISH) and is based on a functionalized medical wire. This wire is an innovative device that permits the in vivo isolation of CTCs from a large volume of peripheral blood. The blood volume screened by a 30-min administration of the wire is approximately 1.5-3 L. To demonstrate the feasibility of this approach, epithelial cell adhesion molecule (EpCAM) expression and the chromosomal translocation of the ALK gene were determined in non-small-cell lung cancer (NSCLC) cell lines captured by the functionalized wire and stained with an immuno-DNA FISH approach. Our main challenge was to perform the assay on a 3D structure, the functionalized wire, and to determine immuno-phenotype and FISH signals on this support using a conventional fluorescence microscope. The results obtained indicate that catching CTCs and analyzing their phenotype and chromosomal rearrangement could potentially represent a new companion diagnostic approach and provide an innovative strategy for improving personalized cancer treatments. PMID- 29286484 TI - A Protocol for the Production of Integrase-deficient Lentiviral Vectors for CRISPR/Cas9-mediated Gene Knockout in Dividing Cells. AB - Lentiviral vectors are an ideal choice for delivering gene-editing components to cells due to their capacity for stably transducing a broad range of cells and mediating high levels of gene expression. However, their ability to integrate into the host cell genome enhances the risk of insertional mutagenicity and thus raises safety concerns and limits their usage in clinical settings. Further, the persistent expression of gene-editing components delivered by these integration competent lentiviral vectors (ICLVs) increases the probability of promiscuous gene targeting. As an alternative, a new generation of integrase-deficient lentiviral vectors (IDLVs) has been developed that addresses many of these concerns. Here the production protocol of a new and improved IDLV platform for CRISPR-mediated gene editing and list the steps involved in the purification and concentration of such vectors is described and their transduction and gene editing efficiency using HEK-293T cells was demonstrated. This protocol is easily scalable and can be used to generate high titer IDLVs that are capable of transducing cells in vitro and in vivo. Moreover, this protocol can be easily adapted for the production of ICLVs. PMID- 29286486 TI - Whole-body PET/MRI of Pediatric Patients: The Details That Matter. AB - Integrated PET/MRI is a hybrid imaging technique enabling clinicians to acquire diagnostic images for tumor assessment and treatment monitoring with both high soft tissue contrast and added metabolic information. Integrated PET/MRI has shown to be valuable in the clinical setting and has many promising future applications. The protocol presented here will provide step-by-step instructions for the acquisition of whole-body 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/MRI data in children with cancer. It also provides instructions on how to combine a whole-body staging scan with a local tumor scan for evaluation of the primary tumor. The focus of this protocol is to be both comprehensive and time efficient, which are two ubiquitous needs for clinical applications. This protocol was originally developed for children above 6 years, or old enough to comply with breath-hold instructions, but can also be applied to patients under general anesthesia. Similarly, this protocol can be modified to fit institutional preferences in terms of choice of MRI pulse sequences for both the whole-body scan and local tumor assessment. PMID- 29286487 TI - Using the Dot Assay to Analyze Migration of Cell Sheets. AB - Although complex organisms appear static, their tissues are under a continuous turnover. As cells age, die, and are replaced by new cells, cells move within tissues in a tightly orchestrated manner. During tumor development, this equilibrium is disturbed, and tumor cells leave the epithelium of origin to invade the local microenvironment, to travel to distant sites, and to ultimately form metastatic tumors at distant sites. The dot assay is a simple, two dimensional unconstrained migration assay, to assess the net movement of cell sheets into a cell-free area, and to analyze parameters of cell migration using time-lapse imaging. Here, the dot assay is demonstrated using a human invasive, lung colony forming breast cancer cell line, MCF10CA1a, to analyze the cells' migratory response to epidermal growth factor (EGF), which is known to increase malignant potential of breast cancer cells and to alter the migratory phenotype of cells. PMID- 29286488 TI - Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down. AB - The past two decades have seen a shift from cytotoxic drugs to targeted therapy in medical oncology. Although targeted therapeutic agents have shown more impressive clinical efficacy and minimized adverse effects than traditional treatments, drug resistance has become the main limitation to their benefits. Several preclinical in vitro/in vivo models of acquired resistance to targeted agents in clinical practice have been developed mainly by using two strategies: i) genetic manipulation for modeling genotypes of acquired resistance, and ii) in vitro/in vivo selection of resistant models. In the present work, we propose a unifying framework, for investigating the underlying mechanisms responsible for acquired resistance to targeted therapeutic agents, starting from the generation of drug-resistant cellular subclones to the description of silencing procedures used for restoring the sensitivity to the inhibitor. This simple time- and cost effective approach is widely applicable, and could be easily extended to investigate resistance mechanisms to other targeted therapeutic drugs in different tumor histotypes. PMID- 29286489 TI - Detection and Removal of Nuclease Contamination During Purification of Recombinant Prototype Foamy Virus Integrase. AB - The integrase (IN) protein of the retrovirus prototype foamy virus (PFV) is a model enzyme for studying the mechanism of retroviral integration. Compared to IN from other retroviruses, PFV IN is more soluble and more amenable to experimental manipulation. Additionally, it is sensitive to clinically relevant human immunodeficiency virus (HIV-1) IN inhibitors, suggesting that the catalytic mechanism of PFV IN is similar to that of HIV-1 IN. IN catalyzes the covalent joining of viral complementary DNA (cDNA) to target DNA in a process called strand transfer. This strand transfer reaction introduces nicks to the target DNA. Analysis of integration reaction products can be confounded by the presence of nucleases that similarly nick DNA. A bacterial nuclease has been shown to co purify with recombinant PFV IN expressed in Escherichia coli (E. coli). Here we describe a method to isolate PFV IN from the contaminating nuclease by heparin affinity chromatography. Fractions are easily screened for nuclease contamination with a supercoiled plasmid and agarose gel electrophoresis. PFV IN and the contaminating nuclease display alternative affinities for heparin sepharose allowing a nuclease-free preparation of recombinant PFV IN suitable for bulk biochemical or single molecule analysis of integration. PMID- 29286490 TI - A Facile Protocol to Generate Site-Specifically Acetylated Proteins in Escherichia Coli. AB - Post-translational modifications that occur at specific positions of proteins have been shown to play important roles in a variety of cellular processes. Among them, reversible lysine acetylation is one of the most widely distributed in all domains of life. Although numerous mass spectrometry-based acetylome studies have been performed, further characterization of these putative acetylation targets has been limited. One possible reason is that it is difficult to generate purely acetylated proteins at desired positions by most classic biochemical approaches. To overcome this challenge, the genetic code expansion technique has been applied to use the pair of an engineered pyrrolysyl-tRNA synthetase variant, and its cognate tRNA from Methanosarcinaceae species, to direct the cotranslational incorporation of acetyllysine at the specific site in the protein of interest. After first application in the study of histone acetylation, this approach has facilitated acetylation studies on a variety of proteins. In this work, we demonstrated a facile protocol to produce site-specifically acetylated proteins by using the model bacterium Escherichia coli as the host. Malate dehydrogenase was used as a demonstration example in this work. PMID- 29286492 TI - Streamlined 3D Cerebellar Differentiation Protocol with Optional 2D Modification. AB - Reducing the complexity and cost of differentiation protocols is important for researchers. This interest fits with concerns about possible unintended effects that extrinsic patterning factors might introduce into human pluripotent stem cell (hPSC) models of brain development or pathophysiology, such as masking disease phenotype. Here, we present two cerebellar differentiation protocols for hPSCs, designed with simpler startup method, fewer patterning factors, and less material requirements than previous protocols. Recently, we developed culture procedures, which generate free-floating 3-dimensional (3D) products consistent with other brain "organoid" protocols, including morphologies relevant to modeling brain development such as sub/ventricular zone- and rhombic lip-like structures. The second uses an adherent, 2D monolayer procedure to complete differentiation, which is shown capable of generating functional cerebellar neurons, as products are positive for cerebellar-associated markers, and exhibit neuron-like calcium influxes. Together, these protocols offer scientists a choice of options suited to different research purposes, as well as a basic model for testing other types of streamlined neural differentiations. PMID- 29286491 TI - Microprobe Capillary Electrophoresis Mass Spectrometry for Single-cell Metabolomics in Live Frog (Xenopus laevis) Embryos. AB - The quantification of small molecules in single cells raises new potentials for better understanding the basic processes that underlie embryonic development. To enable single-cell investigations directly in live embryos, new analytical approaches are needed, particularly those that are sensitive, selective, quantitative, robust, and scalable to different cell sizes. Here, we present a protocol that enables the in situ analysis of metabolism in single cells in freely developing embryos of the South African clawed frog (Xenopus laevis), a powerful model in cell and developmental biology. This approach uses a capillary microprobe to aspirate a defined portion from single identified cells in the embryo, leaving neighboring cells intact for subsequent analysis. The collected cell content is analyzed by a microscale capillary electrophoresis electrospray ionization (CE-ESI) interface coupled to a high-resolution tandem mass spectrometer. This approach is scalable to various cell sizes and compatible with the complex three-dimensional structure of the developing embryo. As an example, we demonstrate that microprobe single-cell CE-ESI-MS enables the elucidation of metabolic cell heterogeneity that unfolds as a progenitor cell gives rise to descendants during development of the embryo. Besides cell and developmental biology, the single-cell analysis protocols described here are amenable to other cell sizes, cell types, or animal models. PMID- 29286493 TI - Twenty five years of the National Academy of Medical Sciences of Ukraine - progress and priorities for future of radiation medicine and biology. AB - After the creation of the Academy of Medical Sciences of Ukraine in 1993 the Research Center for Radiation Medicine was among the first institutions to join the Academy (fig. 1). Estab lishing the Academy was among the first steps of the independent Ukrainian government and aimed to provide a high level health care for population. It was extremely needed for the minimization of Chornobyl medical consequences. This choice was related to a growing recognition of the scientific research in fulfilling the Senter's mission - study of the effects of low dose radiation on human body and radiation protection of the exposed population.The Center entered the Academy as a potent insti tution. Director General Dr. Anatoly Romanenko and his first deputy prof. Oles Pyatak were lucky to concentrate in three institutes of the Center a talent ed workforce including director of the Institute of Clinical Radiology prof Volodymyr Bebeshko, director of the Institute of Epidemiology and Prophylaxis of radiation Injuries prof. Volodymyr Buzunov, director of the Institute of Experimental Radiology prof. Mikhail Rudnev. Drs. T. Azaren kova, S. Galkina, V. Boer, T. Treskunova were appointed as scientific secretaries. Dosimetry divi sion was headed by brilliant prof Ilya Likhtarev and his staff Drs. I. Los, V. Korzun, V. Repin, O. Pere voznikov, O. Bondarenko, V. Chumak and others.The Center met creation of the Academy with expe rienced research and clinical staff encountering 1587 members, including 272 research staff, 28 doctors of science and 98 PhDs, modern diagnostic and labo ratory equipment, 300 beds in clinical departments and construction of hospital and out patient hospi tal in Svyatoshin. Scientific staff included experi enced prof. I. Khomaziuk, prof. B. Prevarsky, prof. V. Zamostian, prof. P. Chayalo, prof. M. Omelya nets, prof. A. Prysyazhnyuk. Dr. A. Niagu, Dr. E. Stepanova, Dr. A.Chumak, Dr. V. Klymenko, Dr. D. Komarenko, M. Pilinska, L.Ovsiannikova, O. Pi rogova. were among the first academic supervisors in studies of Chornobyl health effects and got professor certificates in this new area. First PhD theses were successfully passed by Dr. E. Gorbov, and Dr. of Sciences - by Dr. D. Bazyka. Basics of future aca demic research directions were elaborated that time by Drs. O. Kovalenko, Zh. Minchenko, V. Talko, I. Holyavka, D. Belyi, D. Yakimenko, E. Mikhai lovska, V. Malyzhev, V. Sushko, A. Cheban, K. Lo ganovsky, K. Bruslova, I. Dyagil, T. Liubarets, O. Kucher, G. Chobotko, and others. Later the major ity of these studies formed a background for Chornobyl legislation, regulatory directives, pre sented as dissertations.A quarter of century passed. The Center as a part of the National Academy of Medical Sciences resisted the challenges and moved forward, was recognized worldwide and fulfilled its main mission - providing highly qualified health care to radiation exposed. Staff numbers decreased (1,091), but work amount has increased. Since 2000, new premises were installed - a hospital with the biggest in Ukraine outpatient clin ic, new laboratory facilities, the last of which was in troduced in 2013. The Academy became a national one and since 2011 the Center was recognized as a national research institution (NRCRM), staff mem bers received 3 State Awards of Ukraine in the Field of Science and Technology, numerous personal awards.During this period, NRCRM staff conducted and published priority research data on radiation risks and molecular mechanisms of leukemia, including chronic lymphocytic, myelodysplastic syndrome, multiple myeloma, thyroid cancer, breast cancer in Chornobyl accident cleanup workers. Studies of the mechanisms of non tumor pathology - cardio vascular, cerebrovascular, cognitive disorders are in process. Of high importance are studies of possible transgenerational effects of radiation. The devel oped new technologies and protocols for the advanced care of radiation exposed were intro duced to the general health care system, the addi tional departments of oncology and chemotherapy were equipped and started activities, databases of cancer cases in exposed population and separate groups of exposed were introduced, as well as an international database of radiation injuries. The Clinical and Epidemiological registry of the NRCRM is in function and developed. An adapta tion of research directions with a respect to the pathomorphosis of radiation induced diseases in the remote period after irradiation will continue.Performed complex studies of the effects of incorporation of 131I on the fetus and the next gen eration of experimental animals became important for understanding the mechanisms of formation of radiation effects. Introduction of new foodstuffs and supplements with radiation protective proper ties was of positive effect for population protection during the first years.In the area of dosimetry a substantial progress has been achieved in reconstruction of thyroid doses in the Ukrainian population, dosimetric passportisation of settlements, radiochemistry, the creation of new methods for reconstructive dosimetry for cleanup workers - SEAD, RADRUE, and ROCKVILLE. All developments are implemented to practice, tens of thousands of doses have been restored. International recognition has received for the method of in utero doses reconstruction. As editor in chief, I regard it successful to incorporate our bilingual edition "Problems of Radiation Medicine and Radiobiology" into the NCBI MedLine, SCOPUS and other data bases, that creates an unique opportunity to widely disseminate results of the Center's research.Strategies for the future. Ukraine belongs to countries with a priority development of nuclear energy. Even with the increase in the production of clean energy, there is no other way than the further deployment of a complete nuclear fuel cycle and energy industrial complex, the expansion of the nuclear technologies to all sectors of the economy.The main potential threats to radiation safety include the aging of the material base of the NPPs with the prolongation of the working life for nuclear reactors with the expired terms of exploitation; the existence of a "nuclear legacy" sites of the former USSR in the territories of enterprises for the extrac tion and processing of uranium ores. About 5,000 institutions and enterprises use more than 25,000 sources of ionizing radiation in general. The use of radiological technologies and sources of ionizing radiation in medicine is increasing, in particular the burden on patients and staff in invasive cardiac sur gery. This will require significant efforts from the NRCRM to ensure an adequate radiation protec tion of the population, taking into account the experience collected during the mitigation of health effects of Chornobyl. Radiological threats of malev olent use of nuclear technology hasn't be forgotten.The mission of the NRCRM is to expand basic research of the health effects of ionizing radiation, elaboration and implementation of the care and radiation protection of population. Background for future is paved by a successful implementation of a special program of medical and biophysical control of personnel during transformation of the Shelter object into an environmentally safe sys tem, the State social program of increasing safty, labor hygiene and environment for 2014-2018; many years of successful cooperation with the State Nuclear Regulatory Inspectorate, the Natio nal Commission for Radiation Protection, "Ener goatom" company, the relevant departments of the Ministry of Health, international organizations such as WHO, UNSCEAR, IAEA, IARC, the US National Cancer Institute, IRSN, Nagasaki, Hiroshima, Fukushima universities and others.From the editorial board I congratulate the staff of the Center with the twenty fifth anniversary of the Academy. I would like also to wish the National Academy of Medical Sciences of Ukraine new ad vances in medical science and practice, sustainabil ity, unity, development and worldwide recognition. PMID- 29286494 TI - State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" - research activities and scientific advance in 2016. AB - Research activities and scientific advance achieved in 2016 at the State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" (NRCRM) concerning medical problems of the Chornobyl disaster, radiation medicine, radiobiology, radiation hygiene and epidemiology in collaboration with the WHO network of medical preparedness and assistance in radiation accidents are outlined in the annual report. The report presents the results of fundamental and applied research works of the study of radiation effects and health effects of the Chornobyl accident; fulfillment of tasks of "State social program for improving safety, occupational health and working environment in 2014-2018 years".The report also shows the results of scientific organizational and health care work, staff training. The NRCRM Annual Report was approved at the Scientific Council meeting of NAMS on March 17, 2016. PMID- 29286495 TI - Early and late radiation effects in healthy tissues of oncologic patients under therapeutic irradiations. AB - The objective of the article is summarize the literature regarding on the patterns and mechanisms of the formation of early and distant radiation reactions of healthy cells due to the therapeutic irradiation of cancer patients. Particular attention is given to the modern views on the molecular mechanisms of the processes of various repair systems (DDR, BER, NER, MMR, etc.) whose ineffectiveness is associated with radiation induced instability of the genome of healthy cells and the etiology of secondary tumours of radiation genesis in cancer patients as a result of radiation therapy. Solving the problem of individual radiation sensitivity of an organism of cancer patients will help to reduce the frequency of early and late radiation complications. PMID- 29286496 TI - Evoked bioelectrical brain activity following exposure to ionizing radiation. AB - The article provides an overview of modern physiological evidence to support the hypothesis on cortico limbic sys tem dysfunction due to the hippocampal neurogenesis impairment as a basis of the brain interhemispheric asym metry and neurocognitive deficit after radiation exposure. The importance of the research of both evoked poten tials and fields as a highly sensitive and informative method is emphasized.Particular attention is paid to cerebral sensor systems dysfunction as a typical effect of ionizing radiation. Changes in functioning of the central parts of sensory analyzers of different modalities as well as the violation of brain integrative information processes under the influence of small doses of ionizing radiation can be critical when determining the radiation risks of space flight. The possible long term prospects for manned flights into space, including to Mars, given the effects identified are discussed. Potential risks to the central nervous system during space travel comprise cognitive functions impairment, including the volume of short term memory short ening, impaired motor functions, behavioral changes that could affect human performance and health. The remote risks for CNS are considered to be the following possible neuropsychiatric disorders: accelerated brain aging, Alzheimer's disease and other types of dementia. The new radiocerebral dose dependent effect, when applied cog nitive auditory evoked potentials P300 technique with a possible threshold dose of 0.05 Gy, manifesting in a form of disruption of information processing in the Wernicke's area is under discussion. In order to identify neurophys iological biological markers of ionizing radiation further international researches with adequate dosimetry support are necessary. PMID- 29286497 TI - A modern view on the effect of ionizing radiation on patients with diagnosis of nuclei cell cancer and its dischariationn. AB - One of the effects of the ionizing radiation on the cell is the emergence of genetic mutations which may lead to cancer development. The patients' exposure dose during diagnostics of renal cell carcinoma (RCC) by means of ordinary CT amounts to 5 mGy (5 mSv) and it can rise up to 50 mGy (5mSV) in the setting of multiphase scan. Until recent times, the evaluation of a risk for the cancer development caused by such relatively small doses of radiation exposure has been considered unnecessary. Nowadays, the influence of ionizing radiation during diagnostic pro cedures has been proved to increase the risk of cancer development significantly. The multiphase CT, routinely used in RCC diagnostics, results in 1 case of radiation induced cancer per 250 (180-370) scans in female and per 330 (240-490) scans in male individuals. There is a proved association between CN scans in dose > 7,5 mSv and patients' DNA damage. Thus, one of the ways to avoid radiation exposure of the patients with RCC is wider appli cation of MRI and X ray tubes of decreased voltage, however, further investigations in this field are still required. PMID- 29286498 TI - Psychosocial state of the adult evacuees and risk factors of negative change. AB - : Numerous scientific studies have been carried out since the ChNPP accident indicating that the last one has caused a severe psychosocial stress in survivors. Population of radioactively contaminated territories, people migrated from the areas of strict radiation control, and accident consequences clean up participants in 1986 1987 were covered by the conducted research projects. Nature of the stress herewith is polygenic and includes factors directly related to the Chernobyl catastrophe, and factors being a result of social and economic circumstances. This report is devot ed to the results of research on psychosocial state of population evacuated from the 30 km zone of the ChNPP. OBJECTIVE: Study and evaluation of psychosocial state of population evacuated from the 30 km ChNPP zone at the age of 18 years and older; identification of potential psychosocial risk factors for the health loss. MATERIALS AND METHODS: The sampling epidemiological study of psychosocial state of population aged 18-50 years evacuated from the 30 km zone of ChNPP was conducted at the NRCRM Radiation Registry Outpatient Clinic and Radiation Psychoneurology Department. The study subjects (n=258) were mostly (98%) females. Study was con ducted from October 2013 till May 2015. All the sample members were registered since 1992 in the system of life long health monitoring, i.e. the NRCRM Clinical and Epidemiological Registry. Study subjects were interviewed through the method using an original "Questioning Inventory". Mathematical processing of study results was held using the Epi Info 7 software package. RESULTS: According to the study results, a nuclear accident at the Chornobyl NPP has become a powerful psychoso cial stress for evacuated people. Psychosocial state of the evacuees, formed during the post accident period, with full reason can be defined as a state of stable, chronic psychosocial stress. Nature of factors that caused the stress development is polygenic. Block of stressors directly related to the accident was determined, namely there were "change of radiation and ecological situation", "ionizing irradiation", "evacuation", and "radical breaking of dynamic stereotype of behavior and life". In parallel there was selected a block of stress factors generated by that background, i.e. psychological, social, economic, and cultural, on which a nuclear disaster was imposed upon. The effects of stress have manifested as a persistent syndrome of "anxiety" for the personal health and health of fami ly members, primarily the children, and as a stable state of "dissatisfaction" with fullness and quality of life. CONCLUSIONS: The nuclear accident at the ChNPP has been the cause of a strong psychosocial stress in adult evacu ated population, especially in women. Further in a remote period the stress was transformed into a stable, chronic form. Nature of stress is polygenic and includes stressors directly related to the accident, and stressors that are not directly related to the accident consequences, but are due to the level of social, economic, medical, and informa tional protection of survivors. Data presented in the paper are rather enough important for the formation of strate gies and measures for social and psychological protection of population in an event of nuclear accidents and incidents. PMID- 29286499 TI - Doses from radon 222 irradiation for workers of the granite mining industry. AB - OBJECTIVE: determining the integral value of annual effective dose from 222Rn for workers of the granite mining industry and assessment for the expected life effective dose from 222Rn. MATERIALS: Materials were the results of measurements of external exposure dose of radiation measurements equiv alent equilibrium volume activity of 222Rn in workrooms and workplaces of major groups of granite quarry workers Mykolaiv region, studies EROA 222Rn air premises of these workers, research content 222Rn in drinking water. RESULTS AND CONCLUSIONS: Granite quarry workers receive double radiation exposure of 222Rn due to exposure in the workplace and at home. The load in the workplace due to inhalation of 222Rn the air was (2.1 +/- 0.2) mSv / year (vari ation 0.9-5.9) in a residential area - (4,1 +/- 0,2) mSv/year (variation 1.8-5.9). The total annual effective dose from internal exposure from air flow and working premises and drinking water was on average (6,5 +/- 0,2) mSv/year, equal to a maximum value of 20 mSv/year. The expected life for the chronic exposure dose of technological naturally occurring radioactive sources for people who work in the granite quarries and, while living in high risk from radon is in the range of 0.16-1.12 Sv. The research results indicate that in assessing the effects associated with exposure due to radon 222 contingents persons such surveys must take into account all sources of this radionuclide dose. PMID- 29286500 TI - Information and statistical support for retrospective study of mortality among people exposed in childhood as a result of the Chornobyl accident and living in contaminated areas of Ukraine: assessment of feasibility. AB - OBJECTIVE: Analysis of information from various sources for its use in epidemiological study on mortality of people (born in 1968-1986) who were children and adolescents at the time of the Chornobyl accident. OBJECT OF STUDY: Information and statistical sources for 1986-2011 on mortality among people who were children and adolescents at the time of the Chornobyl accident and lived on the most radioactive contaminated territories (RCT) of Ukraine (Ivankiv and Polisske regions of Kyiv oblast, Narodychi and Ovruch regions of Zhytomyr oblast). RESEARCH METHODS: theoretical, general scientific, documentary analysis, demographic. RESULTS AND CONCLUSIONS: The study is to determine the suitability of available information and statistical support for measuring and assessing mortality of people exposed in childhood as a result of the Chornobyl accident and liv ing in contaminated areas of Ukraine. A combination of information and statistical data provided by SRU, Ministry of Justice of Ukraine, State Statistics Service (SSS) of Ukraine and NNCRM makes it possible to successfully conduct retrospective cohort studies in any area and for any period. PMID- 29286501 TI - Reconstruction of individualized doses of subjects from the Ukrainian State Register - of Persons that Affected due to Chornobyl accident and reside in Korosten raion of Zhytomyr oblast. AB - STUDY OBJECTIVE: To elaborate an ecological dosimetric model of reconstruction individualized exposure doses of subjects from the State Register of Ukraine (SRU) - of persons, affected due to Chornobyl accident and reside at the radioactive contaminated territory of Korosten raion of Zhytomyr Oblast, and to calculate exposure doses for those persons. MATERIALS AND METHODS: In the paper, an ecological dosimetric model is presented which is elaborated in order to individualize exposure doses of people who reside in Korosten raion of Zhytomyr Oblast and are registered in SRU. The model is based on the results of radio ecological and dosimetric monitoring held in the period of 1986-2013 at the territory of northern oblasts of Ukraine. Annual dose over each post accidental year consists of the two compo nents: (a) annual effective dose of external gamma exposure (due to radioactive fallout on the ground), and (b) internal exposure of the whole body (due to consumption of meal contaminated by radioactive isotopes). For 1986, the dose of internal exposure is evaluated out of all main radionuclides of radioactive accidental fallout, and after 1987 only for radioisotopes of caesium (134Cs and 137Cs). The parameterization of the model is based on the pre vious experience in working out a complex of ecological dosimetric models for estimation of referent exposure doses of Ukrainian population. RESULTS AND CONCLUSIONS: Individualized doses of external and internal exposure (annual and accumulated) are estimated for the population of various age groups that resides in the settlements of Korosten raion (totally about 100 settlements). Separately the doses are presented for rural settlements of the raion and for the city of Korosten for each year of the post accidental period of 1986-2016. Estimates of doses are given that were accumulated: (a) during 15 years just after the accident, (b) for the period of 2000-2016, and (c) for 30 year period after the acci dent. Mean dose accumulated for 30 years after the Chornobyl accident by residents of rural settlements of Korosten raion is estimated as 19.8 mSv, and for inhabitants of the Korosten city as 20.9 mSv. On condition of permanent res idence in the raion, residents of about 66 % settlements of Korosten raion accumulated the doses in the interval 5 20 mSv during 30 years after the accident. For the residents of about 25 % settlements the accumulated dose is in the interval 20-50 mSv, and for 7 % of settlements it exceeds 50 mSv. PMID- 29286502 TI - Social safety and medical maintenance of the labour pool in surveillance areas of the nuclear power plants. AB - OBJECTIVE: To study the contentment of population of NPP surveillance areas i.e. monitoring zones with specific components of quality of life, namely the social security, medical care, and socio economic compensation of risk. MATERIALS AND METHODS: A sociological study of public opinion about the specific components of quality of life has been conducted in population of the NPP monitoring zone. A questionnaire with independent question blocks was developed. A non repeatable probabilistic selection was applied in population opinion poll. The sampled population was calculated on the basis of the total population living in the NPP monitoring zone. Sample error not exceeded 7.0%. A comparative assessment of the responses of various groups of the able bodied population on issues of social security, medical care, socio economic compensation of risk and analysis of statistical data for 2011-2015 on the resource potential of medical facility of the nuclear power plant overspill town has been conducted. RESULTS: The safety and security status is rated at below the average. Documents regulating the life safety of pop ulation of NPP monitoring zone provide them no confidence in their security. Probability estimates of man made accidents are higher in urban population and depend on education level. The socialized health care is assessed on low and average levels according to the studied parameters. Among the types of medical care the providing of nec essary medical goods, preventive examinations, scheduled medical examination service, ambulance activity, and medical psychological aid need to be improved. There was no significant change in resource potential of special ized healthcare infirmary of NPP overspill town for the last 5 years. CONCLUSION: Low rating by the monitoring zone population of work efficiency of health facilities is determined by a set of factors, some of which lies in the plane of state socio economic problems. Choice priority of the direct sub ventions in population of monitoring zone depends on the place of residence and occupation. Provisions on social security, protection and medical care of population of the NPP monitoring zones in Ukraine do not correspond to European standards and require a revision. PMID- 29286503 TI - Population morbidity in the Zaporizhzhia Nuclear Power Plant observation zone as an integral part of public health. AB - OBJECTIVE: To evaluate the health status of adult population living in the Ukrainian nuclear power industry obser vation zone on the example of Zaporizhzhia Nuclear Power Plant. MATERIALS AND METHODS: System review, analytic, sociological survey and statistical methods. RESULTS: There was established an increase in the incidence of digestive diseases among adult population in Nikopol of Dnipropetrovsk region, which is included in the Zaporizhzhia NPP observation zone. The highest increase was observed in the incidence of peptic ulcer, gastritis and duodenitis, cholecystitis and cholangitis by 340 %, 305 % and 83 %, respectively. CONCLUSIONS: In connection with the residence in industrially developed region and NPP life extension in Ukraine, the possible influence of harmful factors on health status of the population of observation zones, an increase in the incidence of digestive diseases among adult population, there is required continuous monitoring and detailed study of public health. PMID- 29286504 TI - Features of morfological changes in primary thyroid gland CTLL cultures of rats descendants prenatally exposed by radioisotopes of iodine-131. AB - OBJECTIVE: to investigate morphological changes in the primary thyroid cell culture of rat infants whose parents were prenatally exposed by radioisotope iodine 131. MATERIALS AND METHODS: obtaining and culturing of thyroid tissue primary cell cultures of newborn rats, cytological (receipt and analysis of cell cultures agents for optical microscopy), biophysical (flow cytometry), statistics. RESULTS: It was shown that cells in thyroid primary culture of offspring rats prenatally exposed by radioisotopes of iodine 131 signs of destructive degenerative changes were observed mostly when animals of both sexes were irra diated. Increased number of two and three nuclear cells and induction of ring like cells is an evidence of signifi cant genotoxic violation and points to the genome instability in offspring of animals exposed by radioisotope iodine 131. CONCLUSIONS: Analysis and quantitative morphological parameters of cells in thyroid primary culture of newborn rats whose parents were exposed prenatally by radioisotopes of iodine 131 showed that upon exposure to radiation thy roid undergoes destructive changes at the cellular level and, even in the second generation of offspring, leads to disruption of its functions. PMID- 29286505 TI - Peculiarities of ultrastructural organization and metabolism of reactive forms of oxygen and nitrogen in a cardiovascular system for permanent effects of ionizing radiation in low doses. AB - OBJECTIVE: Determination of the peculiarities of ultrastructural changes and metabolism of reactive forms of oxy gen and nitrogen in the tissues of the myocardium, aorta and portal vein of the radiosensitive BALB/c mice due long term exposure to the complex of radionuclides of Chornobyl fallout (ejection) and low intensity low dose gamma irradiation. MATERIALS AND METHODS: Experimental studies were performed on 60 mice female radiosensitive lines BALB/c with a body weight of 20-22 g, which were divided into 3 groups: I group (control) animals age 6-9 months which were born and lived their lives in Kyiv vivarium under conditions natural radioactive background; II - animals age 6 months, which were born and lived in the Chornobyl exclusion zone throughout their lives; III - animals, which from 3 months of age for 6 months were constantly located in cages with flat ionizing radiation sources and exposed to external gamma irradiation in a total dose of 0.43 Sv. Animals of II and III groups were kept in the vivarium of the Institute for Safety Problems of Nuclear Power Plants of the National Academy of Sciences of Ukraine (Chornobyl). Mice of the BALB/c lines are sensitive to radiation: for males LD 50/30 < 5.7 Gy, for females - 5.85 Gy. RESULTS AND CONCLUSIONS: The peculiarities of structural and functional changes in the organs of the cardiovascular system (CVS) and mechanisms of the development of oxidative and nitrosatitative stress due long term exposure to the complex of radionuclides of the Chornobyl fallout (ejection) and low intensity low dose gamma radiation based on the study of ultrastructural organization and metabolism of reactive oxygen species (ROS) and nitrogen (NRS) of the atri al cardiomyocytes (CMC), the aortic endothelium and portal vein of the BALB/c mice. Found that the permanent expo sure to low doses of radiation changes occur, including the dominant mechanism is to run a CMC apoptosis and endothelial cells of the aorta and portal vein. It is shown that the development of oxidative stress accompanied by increased activity of ROS metabolism that occurs due to activation of nucleotide and lipid superoxide generators. Found that under these conditions the development of nitrosative stress is due to the activation of inducible NO syn thesis enzyme iNOS and inhibit its synthesis constitutive eNOS enzyme. High levels of simultaneous generation of superoxide and NO, bindting, lead to the formation of toxic peroxynitrite, which initiates the process of apoptosis. PMID- 29286506 TI - Photodynamic therapy effect on healing of radiation skin ulcer infected with pseudomonas aeruginosa. AB - OBJECTIVE: To reveal the effect of photodynamic therapy on the healing of experimental radiation skin ulcers infect ed with Pseudomonas aeruginosa. MATERIALS AND METHODS: The infected radionuclide was modeled by local X ray irradiation of the rat's hip skin at a dose of 85.0 Gy, followed by the application of Pseudomonas aeruginosa bacterial suspension to the surface of the ulcer. Photodynamic therapy (CTD) was performed with the help of a photon apparatus "Barva LED/630" and a photosen sitizer of methylene blue. The effect of PDT on the rate and quality of healing of an infected radionuclide was deter mined by comparing the histological and morphometric study of skin from the region of ulcer in animals from the control and treated groups of PDT. RESULTS AND CONCLUSIONS: The presence of Pseudomonas aeruginosa in the radiation sickness caused an increase in the area of the wound cavity compared with the non infected radionuclide and to a significant inhibition of its healing processes. The addition of the infection factor reduced the activity of the reparative processes in the radiation sick ness by 20 % compared with the uninfected. The effect of photodynamic therapy contributed to complete healing on average one month earlier than in control groups. PMID- 29286507 TI - Study the impact of astaxanthin on developing of genomic instability in human peripheral blood lymphocytes irradiated in vitro on G2 phase of cell cycle. AB - OBJECTIVE: To identify the possibility of modification by astaxanthin the level of genome damages induced by gamma quanta in the culture of human peripheral blood lymphocytes exposed in vitro on postsynthetic (G2) phase of the first mitotic cycle. MATERIALS AND METHODS: Peripheral blood lymphocytes from four apparently healthy volunteers 35-51 years old were cultivated using modified micromethod. To obtain genomic damages in G2 phase of the first mitotic cycle the part of cultures was irradiated by gamma quanta in dose 1.0 Gy through 46 hours of cultivation. Astaxanthin in final con centration 20 MUg/ml was exposed to lymphocytes' cultures before the irradiation. Cytogenetic analysis the uniform ly stained slides of metaphase chromosomes was carried out to determine the frequencies of chromosome and chro matid types of aberrations. Using the method of individual cells electrophoresis (Comet assay) the relative level of DNA damages (Tail Moment index) and the frequency of apoptotic cells with high level of DNA fragmentation were evaluated. RESULTS: Mean group frequencies of chromosome aberrations after gamma irradiation of lymphocytes in vitro exceed ed those without radiation exposure and were 72.35 +/- 1.17 and 2.46 +/- 0.30 per 100 metaphases, respectively (p < 0.001), mainly due to chromatid type of aberrations (58.32 +/- 1.29 per 100 metaphases). Adding of astaxanthin into culture medium before the irradiation did not result in changes as in the frequency of chromosomal damages (71.54 +/- 1.34 per 100 metaphases) as in the spectrum of aberrations - also prevailed chromatid type of aberrations (58.47 +/- 1.47 per 100 metaphases). The increase of Tail Moment index after radiation exposure (from 3.84 +/- 0.36 to 12.06 +/- 1.88, respectively, p < 0.001) and lack of significant impact of astaxanthin on this index in the irradiated lym phocytes (8.96 +/- 2.39, p > 0.05) was established, ie astaxanthin didn't change the relative level of radiation induced DNA damages. Also apoptogenic effect of astaxanthin was not found: frequency of apoptotic cells were (2.25 +/- 1.49) % in cultures of intact lymphocytes, (2.08 +/- 1.54) % in irradiated cultures and (1.78 +/- 1.25) % under joint action of gamma radiation and astaxanthin (p > 0.05). CONCLUSIONS: Noimpactofastaxanthinongenomicinstabilityinducedbygammairradiation invitroinculturesof human peripheral blood lymphocytes on postsynthetic (G2) phase of first mitotic cycle had been established. PMID- 29286508 TI - Tissue breathing and topology of rats thymocytes surface under acute total gamma irradiation. AB - OBJECTIVE: Assessment of the effect of single total gamma irradiation to the parameters of mitochondrial oxidation and the topology of the thymocyte surface. MATERIALS AND METHODS: The study was performed in sexually mature white outbreeding male rats divided into three groups: two experimental and one control. The states of energy metabolism were determined by the rate of oxygen consumption by the thymus tissues on endogenous substrates at the presence of 2,4 dinitrophenol, uncoupler of a tissue breathing (TB) and oxidative phosphorylation (OP) after a single total gamma irradiation at a dose of 1.0 Gy at 3, 10, 40 and 60 days. The topology of thymus cells was assessed using atomic force microscopy (AFM) and scanning electron microscopy (SEM). RESULTS: On the 3rd and 10th days after total gamma irradiation at a dose of 1.0 Gy, a significant decrease in respira tory activity was determined in thymus tissues on endogenous substrates. Simultaneously, on the 3rd day, pro nounced changes in the morphological parameters of thymocytes (height, volume, area of contact with the sub strate) and the topology of their surface were also observed. On the 10th day after irradiation, most of the morpho logical parameters of thymocytes, except for their volume, were characterized by restoration to normal. In the long term (on the 30th and 60th days after exposure), a gradual but not complete recovery of the respiratory activity of thymocytes was observed, accompanied by an increase in the degree of dissociation of TD and OP. CONCLUSIONS: The obtained data reflect and refine mechanisms of post radiation repair of lymphopoiesis, showing the presence of conjugated changes in the parameters of aerobic energy metabolism of thymocytes, morphology and topology of their surface. The synchronism of changes in the parameters under study is a reflection of the state of the cytoskeleton, the functional activity of which largely depends on the level and efficiency of mitochondrial oxidation. PMID- 29286509 TI - Mesenchymal stem and progenitor cells of rats' bone marrow under chronic action of ionizing radiation. AB - : Under the influence of ionizing radiation on hematopoietic system, the level of its injury is determined not only by the radiosensitivity of hematopoietic stem cells, but also by radiation induced changes in microenvironment func tioning, in particular, mesenchymal stem cells as its components. OBJECTIVE: to define functioning characteristics of mesenchymal stem and progenitor cells of rats' bone marrow under prolonged action of ionizing radiation as a result of 90Sr incorporation. MATERIALS AND METHODS: We applied the model of Wistar rats' internal irradiation with 90Sr radionuclide and per formed the in vitro cultivation of their bone marrow mesenchymal cells. Colony forming efficiency in the in vitro cell culture was determined, as well as the possibility of these cells to form feeder layers and to support rat bone mar row hematopoietic cells in the culture of diffusion chambers in vitro. RESULTS AND CONCLUSIONS: We established that chronic action of incorporated 90Sr radionuclide induced considerable decrease in proliferative activity of mesenchymal stem cells comparing to control, as well as the inhibition of the capability to prolonged support of hematopoietic processes in vitro by their feeder layers.Thus, bone marrow mesenchymal stem cells and their closest progeny - progenitor cells were characterized by rather high radiosensitivity under the influence of ionizing radiation, which was revealed in considerable decline of their functional activity in cell culture in vitro comparing to control indices as a result of irradiation. PMID- 29286510 TI - Comparative analysis the frequency and spectrum of chromosome aberrations in irradiated in vitro peripheral blood lymphocytes of the elderly and centenarians from Kyiv. AB - OBJECTIVE: To establish and compare the frequency and spectrum of chromosome aberrations under X radiation exposure in vitro in dose 0.25 Gy peripheral blood lymphocytes of the elderly and centenarians. MATERIAL AND METHODS: Material of cytogenetic research were peripheral blood lymphocytes from 11 elderly and 10 centenarians, which were irradiated in vitro in dose 0.25 Gy and cultured by generally accepted semi micromethod; slides of metaphase chromosomes were GTG stained and analyzed under the microscope with magnification x 1000. RESULTS: Under irradiation of blood in vitro the mean group frequencies of chromosome aberrations exceeded such without irradiation (r < 0.001) and were 11.60 +/- 0.95 and 6.82 +/- 0.63 per 100 cells in the elderly and the centenar ians, accordingly. Radiation induced increase in the frequency of chromosomal injuries occurred due to chromo some type aberrations which are markers of radiation exposure. In the elderly the elevated frequency of chromatid type aberrations also was registered what is considered a sign of chromosome instability. CONCLUSIONS: The results indicate increased sensitivity the blood lymphocytes from the elderly to radiation expo sure in low doses and allow to assume the advantage of persons with hereditary determined chromosomal stability in achieving longevity. PMID- 29286511 TI - Cerebral impact of prenatal irradiation by 131I: an experimental model of clinical neuroradioembryological effects. AB - : Human brain in prenatal period is a most vulnerable to ionizing radiation body structure. Unlike atomic bombings or radiological interventions in healthcare leading at most to external irradiation the intensive internal exposure may occur upon nuclear reactor accidents followed by substantial release and fallout of radioactive 131I. The latter can lead to specific neuroradioembryological effects. OBJECTIVE: To create an experimental model of prenatal cerebral radiation effects of 131I in human and to determine the experimental and clinical neuroradioembryological effects.Study object. The neuroradioembryological effects in Vistar rats exposed to 131I in prenatal period. Nervous system status and mental status in 104 persons exposed to ionizing radiation in utero due to the ChNPP accident and the same in 78 not exposed subjects. METHODS: Experimental i.e. behavioral techniques, including the spontaneous locomotive, exploratory activity and learning ability assessment, clinical i.e. neuropsychiatric, neuro and psychometric, neuropsychological, neurophys iological methods, both with dosimetric and statistical methods were applied. RESULTS: Intrauterine irradiation of Wistar rats by 131I was simulated on a model of one time oral 27.5 kBq radionu clide administration in the mid gestation period (0.72+/-0.14 Gy fetal thyroid dose), which provides extrapolation of neuroradioembryological effects in rats to that in humans exposed to intrauterine radiation as a result of the Chornobyl catastrophe. Abnormalities in behavioral reactions and decreased output of conditioned reflex reactions identified in the 10 month old rats suggest a deterioration of cerebral cognition in exposed animals. Specific cog nitive deficit featuring a disharmonic intellectual development through the relatively decreased verbal intelligence versus relative increase of nonverbal one is remained in prenatally exposed persons. This can indicate to dysfunc tion of cortical limbic system with especial involvement of a dominant hemisphere hippocampus. Decreased theta band spectral power (4-7 Hz range) of cerebral bioelectrical activity in the left frontotemporal area is suggestive of hippocampal dysfunction mainly in dominant hemisphere of prenatally irradiated persons. Disorders of hippocam pal neurogenesis due to prenatal exposure by radioactive iodine can be a biologic basis here. Innovative approach es in social adaptation, psychoprophylaxis and psychorehabilitation involve the maximum effective application and development of just the most developed psychological and cognitive abilities in survivors. PMID- 29286512 TI - Transgeneration effects of N-stearoylethanolamine in irradiated rats. AB - OBJECTIVE: to explore possible transgeneration effects in the rats offspring of the first generation of parents subject ed to the combined effects of N stearoylethanolamine (NSE) and external exposure.Materials and metods. In the first generation rats of both sexes born to parents who have experienced the combined influence of ionizing radiation at a dose of 2.0 Gy and NSE a daily dose of 50.0 mg/kg, administered before or after exposure indicators of pro and antioxidant systems (the concentration of TBA reactive products, catalase and glu tathione peroxidase activity in plasma) were defined, concentrations of sex hormones testosterone and estradiol and nitrite anion were studied. RESULTS: Irradiation of parents caused a three fold reduction of testosterone in the blood plasma of males progeny, increased activity of catalase in plasma of female offsprings, as well as significantly increased the concentration of protein in the offsprings' blood plasma of both sexes. Introduction of NSE to parents before exposure caused the acti vation of lipid peroxidation in plasma of both sexes offsprings' against the background of a trustworthy decrease in activity of antioxidant enzymes (catalase and glutathione peroxidase), however, prevented a sharp reduction of testosterone content in the blood plasma of males offsprings, conditioned by the influence of radiation on the body of their parents. NSE introduction to parents after exposure caused no significant violations of pro/ antioxidant bal ance in the body of both sexes progeny, but did not eliminate the negative impact of parental exposure to testos terone levels in male offsprings. CONCLUSION: The transgeneration impact of NSE is manifested by radio sensitizing properties in the first generation offsprings in case of application to parents before irradiation. PMID- 29286513 TI - Influence of polymorphic variants of the SLC6A4 gene on the frequency of detection of depressive states in the group of the clean up workers of consequences of Chornobyl accident in the remote period after the Chornobyl catastrophe. AB - : Mental disorders of the victims are one of the important medical consequences of the Chornobyl accident. It is also known that in the implementation of the pathogenesis of depressive states a significant role belongs to the sero tonin transporter gene (SLC6A4). OBJECTIVE: To determine the effect of polymorphic variants of the SLC6A4 gene on the frequency of detection of depression in a group of clean up workers in the remote period after the Chornobyl catastrophe. METHODS: The study was conducted in a group of 59 victims of the Chornobyl NPP accident, divided into two groups (without depression and with depressive symptoms). The diagnosis of depressive disorders was based on a compre hensive assessment of the complaints of the surveyed, the clinical and psychopathological data, the values of the Zung Self Rating Depression Scale (SDS), the Brief Psychiatric Rating Scale (BPRS), the General Health Questionnaire (GHQ 28). DNA from the peripheral blood mononuclear cells was isolated, and the 5 HTTLPR polymorphism was determined by polymerase chain reaction (PCR). RESULTS: Depressive symptoms were more often found among reconvalescents of acute radiation sickness (ARS) than in the clean up workers without ARS: (p = 0.006). The tendencies of the association of the received dose of exter nal exposure with the number of points on the SDS scale (r = 0.284; p = 0.043), the sum of scores on the BPRS scale (r = 0.686; p = 0.001), depression (r = 0.323, p = 0.017) and its severity (r = 0.273; p = 0.051) were found. Among the examined clean up workers, in comparison with a large group of Europeans without mental disorders, an increase in the number of carriers of the genotype S/S SLC6A4 was found (p = 0.03). Only for the carriers of the S/S genotype, the reciprocal association between the development of depression and the age of the patient was found: r = 0.503 (p = 0.033), between the development of depression and the time from the ChNPP accident: r = 0.581 (p = 0.011), as well as positive correlation of development of depression with dose of irradiation: r = 0.515 (p = 0.025). Among people aged 55 and older, the development of depression was associated with a decrease in the frequency of high ly functional genotype LA/LA to 4.76% versus 31.25% in the absence of depressed symptoms (p = 0.042). In the group of younger patients, the distribution of genotypes did not differ depending on the signs of depression (p = 0.476). CONCLUSION: The pilot analysis of the distribution of genotypes of the SLC6A4 gene for polymorphisms of 5 HTTLPR and rs25531 in the clean up workers group showed the promise of further studies of the contribution of LA/LA i S/S genotypes to the development of depressive states in combination with the action of the radiation factor. PMID- 29286514 TI - Cardiovascular diseases and systolic function of left ventricle in clean up workers of Chernobyl accident (based on 30 years follow up). AB - OBJECTIVE: To study the dynamics of circulatory system diseases during the 30 year period after irradiation, changes in the status of systolic function of heart left ventricle (LV) and the features of its remodeling in clean up workers (CW) of the accident at the Chernobyl nuclear power plant (ChNPP). MATERIAL AND METHODS: It was examined 144 CW at ChNPP, including 52 patients, who survived acute radiation sick ness (ARS) grade of severity 1-3, and 105 non irradiated persons (control group - CG). CW have been divided into two subgroups: without signs of ARS (ARS0) and those who suffered from ARS. CW and CG patients were male who had no signs of cardiovascular, nervous, pulmonary or endocrine pathology prior to the Chernobyl accident. Their average age at the beginning of the accident was 33.9-37.7 years. The study program included clinical examina tion, echocardiography, retrospective and statistical analysis. RESULTS: Hypertensive heart disease (HHD) has developed in the CW, including the ARS convalescents, by 12 years, and ischemic heart disease (CHD) at 9-11 years is believed to be earlier than in comparable non irradiated patients. In the post accident period, there was an increased mean value of LV posterior wall (PW) thickness, interventricular septum (IVS), myocardium mass and myocardium mass normalized by body surface area. These indices grew with the increase of HHD duration. Over the 30 year follow up period, between CW and CG from 14.3 to 28.6 % of patients with LV increased volumes it was found a decreased ejection fraction (EF), what indicated the development of sys tolic LV dysfunction with the phenomena of left ventricular heart failure (HF). Reduction of EF correlated with increase of end systolic volume (ESV) having the highest statistical strength. In CW and persons of CG there was from 77.3 to 84.8 % of patients had clinical signs of HF with preserved EF. From this number, 56-63.6 % of patients had concentric and 18.8 26.7 % had eccentric LV hypertrophy (LVH), and in 6.1 to 15.6% of patients, normal LV geom etry or its concentric remodeling was observed. CONCLUSIONS: The CW and non irradiated persons differed significantly by the onset of HHD and CHD, which previ ously developed in the CW, including the ARS survivors. Changes in the structural and functional state of myocardi um during long term follow up did not have any probable differences between CW and non irradiated persons and consisted of BW and IVS thickening, which predetermined the development of LVH. In CW and CG concentric LVH was dominant. The LV systolic dysfunction with decreased EF and increased ESV was characterized by clinical symptoms of left ventricular HF. More than half of patients with clinical symptoms of HF and preserved EF had signs of concen tric hypertrophy. PMID- 29286515 TI - Cortisol level as risk factor for malignant hematologic pathology in children exposed to ionizing radiation after Chornobyl accident. AB - OBJECTIVE: Determination of serum cortisol level in the initial period of acute leukemia in children, who exposed to ion izing radiation and other factors of Chornobyl accident, depending on their age and prognosis of disease. MATERIALS AND METHODS: The study involved 283 children residents of Kyiv, Zhytomyr and Chernihiv regions. There were 90 acute leukemia patients(AL) (ALL - 56, AML - 34), and 193 people of comparison group with anemia, leukemoid reactions and lymphadenopathy. We analyzed the type of comorbid somatic pathology, diseases in the genealogy, hematological parameters, cortisol levels in blood serum and irradiation doses in all children. In patients with AL expected median survival was calculated. RESULTS: In 28.9 % of AL children the initial cortisol content was below 200 nmol/l, in 7.8 % - higher than 500 nmol/l (in the comparison group 10.4 % and 17.1 % respectively). Among AL patients with cortisol levels below 200 nmol/l were significantly less amount of persons with chronic bacterial infections and persistent viral infections (CMV, EBV) and in the genealogy of these children allergic reactions, endocrine pathology diagnosed more often compared with patients, whose hormone levels was higher than 200 nmol/l (p < 0.05). Distribution of children from control group by gradations of cortisol, age groups, defined somatic pathology and diseases in genealogy had no difference. It is shown, that lower initial blood serum cortisol level in ALL children correlates to a greater probability of relapse (Rs = -0,67). In patients with AML a direct correlation between cortisol level and median survival was detected (Rs = 0,79). Children radiation doses were ranging from 0.08 mSv to 14.9 mSv, and there were slightly higher among residents of Zhytomyr region (8.4 +/- 1.2 mSv) compared to other regions. However, these doses did not affect blood serum cortisol levels in children and the course of AL. CONCLUSIONS: These data suggest the need for correction and individualization of corticosteroid doses for optimization of AL patients treatment. Children, who have lower than normative serum cortisol levels are at increased risk of hema tologic pathology and they need for hematologic monitoring. PMID- 29286516 TI - Cases of the staff unaccounted exposure during the construction of the protective shell for a new confinement at the ChNPP site. AB - OBJECTIVE: cytogenetic control of the staff radiation exposure level during the construction of the protective shell for a new confinement at the ChNPP site. MATERIALS AND METHODS: A cytogenetic examination was carried out for 32 staff persons from the contracting organ izations involved into construction of the protective shell for a new confinement. Additionally, for the goal of com parison, 28 persons who did not have professional contacts with the radiation factors were inspected. The analyti cal method of the aberrations on preparations of uniformly stained chromosomes of the peripheral blood lympho cytes has been used. The frequency has been determined for the dicentrics and centric rings with an accompanying pair fragment for 100 analyzed metaphases. The staff chronic exposure absorbed doses are estimated by means of the linear part of the linear quadratic equations, which describe the calibration dose dependence of the unstable chromosomal exchanges yield in the acute irradiated blood samples in vitro. RESULTS: Six staff persons from 32 investigated ones have the individual frequency of the recent exposure specific markers (unstable chromosomal exchanges with accompanying pair fragments) significantly higher than those for the comparison group and the population average spontaneous level. It indicates on the possibility of their exces sive irradiation during the work execution in the ChNPP zone. Single cells with two chromosomal exchanges were registered for three persons, while such cells were absent in the comparison group. This is the result of the incorpo ration of radionuclides, which are available in the air at the workplaces. The calculated averaged individual absorbed doses caused by the recent exposure of six staff persons lies in the range from 102.5 to 371.0 mGy. CONCLUSION: The doses calculated from the frequency of unstable chromosomal exchanges with the accompanying pair fragment caused by the recent exposure of six staff persons are exceeding significantly the doses determined by the methods of physical dosimetry and the occupational exposure dose limits. PMID- 29286517 TI - Distribution of rs2124594 genotypes in chronic lymphocytic leukemia patients depending on radiation anamnesis. AB - OBJECTIVE: to test the method of polymerase chain reaction with following fragments' length restriction to deter mine the rs2124594 polymorphism and to study its contribution in the development of chronic lymphocytic leukemia (CLL) in the post Chornobyl period. METHODS: Genotypes of rs2124594 were determined in 109 patients with CLL of B cell origin including 53 patients irradiated due to the Chornobyl NPP accident. Genotypes distribution among CLL patients was compared with healthy persons of European origin (the 1000 Genomes Project data set was used as a reference). RESULTS: Validity of the tested method was confirmed by direct sequencing. Associations between CLL risks and C allele (OR = 2.37; 95 % CI 1.50-3.73; r = 0.003), CLL risks and CT genotype (OR = 2.10; 95 % CI 1.38-3.21; r = 0.0012) were found. Distributions of rs2124594 genotypes in exposed and non exposed to ionizing radiation CLL patients did not differ. CONCLUSIONS: The association of single nucleotide polymorphisms across the 8q24 chromosome region (positioned at 127180736 and 127183014 near s MYC gene) with CLL risks was confirmed. Modified influence of ionizing radia tion on genetic susceptibility associated with rs2124594 was not found in this pilot study. PMID- 29286518 TI - Radiation induced violations of blood circulation in the ciliary body and changes of the anterior chamber angle in the pathogenesis of glaucoma in clean up workers of the Chornobyl NPP accident and residents of contaminated areas. AB - OBJECTIVE: Estimate changes blood filling of the ciliary body and changes of the anterior chamber angle; study their influence to glaucoma pathogenesis in irradiated persons. MATERIALS AND METHODS: Used the results of a randomly selected group survey of 41 clean up workers of the Chornobyl NPP accident (clean up workers), and 18 inhabitants of the zone of guaranteed voluntary resettlement; age at the time of the survey was 45-50 years. The control group consisted of 41 persons of the same age had not radiation exposure. State of the anterior chamber angle studied by gonioscopy, which was conducted 35 clean up workers and 35 persons of the control group. Changes of the blood circulation in the ciliary body examine by the ophtalmoreog raphy, what was done on 12 eyes of 6 clean up workers, control was 12 eyes of 6 persons had not radiation exposure. RESULTS: Detection revealed of the blood circulation in the ciliary body in all clean up workers, reography coefficient was probably lower (p < 0.05), than in the control group. The research of the state of the anterior chamber angle revealed a higher relative risk of appearance of involution changes of the anterior chamber angle in clean up work ers of ChNPP accident, in comparison with the control group was 3.5 (1.27; 9.5) chi2 = 7.48, p = 0.031. The same changes are characteristic for inhabitants of radiation polluted territories. CONCLUSIONS: Influence ionizing radiation causes a blood circulation decrease in the ciliary body and development changes of the angle of the anterior chamber. Presence of these changes can explain the features of the pathogene sis of glaucoma in irradiated late manifestation and, at the same time, severe course. PMID- 29286519 TI - Comparative characteristics of hepatoprotectors used for the treatment of non alcoholic steatohepatitis associated with herpesvirus infection in sufferers of the Chornobyl accident. AB - : Objective of the study was to determine the effectiveness of various groups of hepatoprotectors in the treatment of patients with nonalcoholic steatohepatitis (NASH) sufferers of the accident at the Chornobyl NPP following the assessment of metabolic changes and control of persistent infections. MATERIALS AND METHODS: The study included 104 males with NASH, who were sufferers of the Chornobyl disaster and underwent examination and treatment in the conditions of the clinics of the National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine. Analysis of the course of the functional state of the liver before and after treatment with hepatoprotectors was carried out using laboratory methods of investiga tion. RESULTS: Hepatoprotectors of different groups used for the treatment of patients affected by the Chornobyl accident with NASH, differed in their effect on various chains in the pathogenesis of disease. Ursodeoxycholic acid (UDCA) drugs and preparations of holy thistle normalized the functional state of the liver and disorders of fat metabolism. Treatment with essential phospholipids eliminated cytolytic syndrome with a significant decrease in alanine amino transferase (p < 0.05), but increased alkaline phosphatase (p < 0.001), beta lipoproteins (p < 0.05), triglycerides (p < 0.05), the total cholesterol level remained elevated to (7.0 +/- 0.8) mmol/L. Amino acid (AA) preparations normal ized the level of aminotransferases, eliminated the symptoms of cholestasis with a significant decrease in bilirubin (p < 0.001) and alkaline phosphatase (p < 0.001), positively influenced on fat and carbohydrate metabolism decreasing levels of beta lipoproteins (p < 0.05), triglycerides and glucose. Treatment with hepatoprotectors posi tively influenced on the state of antioxidant protection (AOP) - decreased before treatment in 56.5 % of patients, after treatment it reduced to 28.6 % (p < 0.05), the number of patients with elevated lipid peroxidation indices decreased from 39.1 % to 21.4 %. Titres of antibodies to persistent herpes virus infections, elevated before treat ment, under the influence of hepatoprotectors did not decrease to reference values. CONCLUSION: The most effective were drugs on the basis of AA, when applied they normalized the functional state of the, fat and carbohydrate metabolism, decreased lipoperoxidation and improved AOP state. Effect of drugs AA and UDCA on the level of antibodies to herpesvirus infection requires further study. PMID- 29286520 TI - Serum content of total adipionectin in the ChNPP accident clean up workers of the "iodine period" suffering from type 2 diabetes mellitus (literature review and research data). AB - OBJECTIVE: assay of the total adiponectin level in the ChNPP accident clean up workers (ACUW) of the "iodine peri od" exposed to ionizing radiation in a young age and suffering now from type 2 diabetes mellitusMaterials and methods. The Chernobyl Nuclear Power Plant accident clean up workers (ACUW) of the iodine period (n=111) exposed to ionizing radiation at a young age (18-35 years) were examined in two groups: Group I (main study group, n=66) of persons with type 2 diabetes mellitus (DM) and Group II (comparison group, n=45) of persons with normal glucose challenge test results. Total radiation doses varied in the range of 10.0-860.0 mSv. Group III (nosological control group, n=20) included persons suffering type 2 DM but not exposed to ionizing radiation (IR) and Group IV were apparently healthy. All study groups were representative by the age. Anthropometric data and parameters of glycemic control were assayed. Index of the homeostatic model for assessing insulin resistance (HOMA IR) was calculated. Level of total adiponectin was assayed by the immune enzyme method. Statistical pro cessing of the data was carried out using Missrosoft(r) Exxel 2002 software. RESULTS AND CONCLUSIONS: Serum concentration of total adiponectin in the Chornobyl NPP ACUW of the iodine peri od and suffering type 2 DM despite having normal body weight or overweight or any degree of obesity was signifi cantly lower compared to apparently healthy persons ACUW with and normal glycemic control. Moderate negative correlation was found between the level of total adiponectin and degree of obesity in the ACUW suffering type 2 DM (t = 0.367, p <0.05). With an increase in the duration of the disease there was a decrease in serum concentration of total adiponectin in the Chornobyl NPP ACUW of iodine period suffering type 2 DM and in the group of nosologi cal control. The most favorable type of glycemic profile was peculiar for patients in the main group with higher lev els of total serum adiponectin and the lowest body mass index (up to 25 kg/m2). An increase in the body mass index was accompanied by an adverse combination of abnormalities in glycemic metabolism (increased glucose concen tration, IRI, and HbA1c), insulin resistance (a significant increase in HOMA) against the background of a decrease in concentration of total adiponectin. No significant differences were found in adiponectin levels in dose subgroups. At the same time, the reliable differences between the main group and comparison group were found in the 2-5th dose subgroups, which are due to differences in numbers of people with metabolic syndrome (obesity) in the groups. PMID- 29286521 TI - Impact of chronic blood viral infection on lymphocyte telomere length in Chornobyl clean-up workers in a remote period after radiation exposure. AB - OBJECTIVE: To assess whether telomere length in lymphocytes of Chornobyl clean up workers at a late period 30 years after the exposure to ionizing radiation is influenced by a chronic blood viral infection and to determine role of viral carriage in cellular senescence. PATIENTS AND METHODS: Study group included 70 Chornobyl cleanup male workers 30 years after exposure {doses of external exposure (602.67 +/- 114.19) mSv (M +/- m); age (59.75 +/- 0.82) yrs}. Relative telomere length (RTL) was analysed by fluorescence in situ hybridization and flow cytometry, immune cell subsets by standard combinations of monoclonal antibodies (CD45/14, CD3/19, CD4/8, CD3/HLADR, CD3/16/56, TCRgammadelta) and flow cytometry; antiviral immunity was performed determining the chronic phase antibodies to viruses: Hepatitis C (HCV), Cytomegalovirus (CMV), Toxoplasma gondii (TOX), Herpes simplex (HSV) and Epstein Barr virus (EBV VCA IgG and EBV NA IgG). The object of the study was peripheral blood (PB) of clean up workers. RESULTS: RTL changes were associated at the group level with the carrier state of the viral infection. RTL shortening was demonstrated as a significant difference between the groups (M +/- SD) (HCV negative 15.27 +/- 3.35, HCV posi tive 13.09 +/- 3.05, p < 0.08, n = 12/52) or as a tendency (CMV negative 15.99 +/- 5.41, CMV positive 14.86 +/- 3.46 (M +/- SD), p < 0.57, n = 11/53; HSV negative 17.01 +/- 1.35, HSV positive 14.79 +/- 3.80, p < 0.33, n = 13/51; TOX neg ative 15.94 +/- 3.41, TOX positive 14.30 +/- 3.81(M +/- SD), p < 0.23, n = 27/37). These unidirectional changes can be associated with premature early cell aging of immune cells. To the contrary the significant RTL elongation was demonstrated in the group of EBV NA chronic carriers (EBV NA negative 11.25 +/- 3.02 (M +/- SD), EBV NA positive 16.15 +/- 3.08 (M +/- SD), p < 0.001, n = 15/49). CONCLUSION: The study confirmed the assumption on a relationship existing between the telomere length, chronic viral infection and late effects in immune cells. The changes of telomeres length on the background of immune dys function may be a sign of cellular aging, and concomitant chronic blood viral infection such as Hepatitis C, Epstein Barr viruses carriage could form a background for an error prone DNA reparation system as a factor of accumulation of pathological conditions, including malignant transformation. PMID- 29286522 TI - Pilot study of parathyroid glands in adult and pediatric subjects exposed to ionizing radiation after the ChNPP accident, methodology of parathyroid diagnostic ultrasound. AB - OBJECTIVE: Estimation of the parathyroid hyperplasia prevalence after the ChNPP accident in adults exposed to ion izing radiation and their descendants using the diagnostic ultrasound and its methodology elaboration. MATERIALS AND METHODS: The pilot prospective study of the prevalence of parathyroid hyperplasia among the Chornobyl Nuclear Power Plant (ChNPP) accident adult survivors (n=686) and their descendants (54 children) was performed using diagnostic ultrasound examination of thyroid and parathyroids. Among the study subjects there were 339 ChNPP accident clean up workers (ACUW), 32 persons were evacuated from the 30 km exclusion zone and 224 ones were included to the control group. Diagnostic ultrasound of thyroid and parathyroids was performed according to the standard method. Additionally, in children with parathyroid hyperplasia an additional assay of 25 hydroxyvitamin D levels in serum was performed. In calculating the statistical significance, its level p < 0.05 was considered statistically significant. RESULTS: Parathyroids are a few small but critically important endocrine glands that synthesize parathyroid hormone, regulating mainly phosphoric calcium metabolism. Insufficient (hypoparathyroidism) or excessive (hyperparathy roidism) function of parathyroids is harmful to the patients affecting the state of nervous and cardiovascular sys tem. Parathyroidss can accumulate isotopes of cesium, strontium and radioactive iodine. The available data testify to an increased incidence of clinically significant hyperplasia of parthyroids (more than 9 mm in adults and more than 5 mm in children) among persons exposed toionizng radiation as a result of the accident at the ChNPP (28.64%) and their descendants (23.8-70.6%). First of all are concerned those adults who live in contaminated areas in comparison with the control group (24.15% in not irradiated). Evacuees from the 30 km exclusion zone being the category of people who were exposed to the absorbed iodine isotopes in the first days of the Chernobyl accident are the another risk group. These data demonstrate sensitivity of parathyroidss to the impact of incorpo rated isotopes (iodine, cesium and strontium), which in the long term exposure create conditions for structural and functional changes in regulation of phosphorous calcium metabolism being the basis for a significant prevalence of osteopenia and osteoporosis in irradiated individuals and their descendants. A number of further studies are required to clarify the findings and to disclose the hormonal mechanisms of radiation effects on parathyroids. CONCLUSIONS: Parathyroid glands are radiosensitive and susceptible to effects of strontium, cesium and iodine iso topes, which cause parathyroid irradiation and subsequent structural and functional changes, being a prerequisite for development of osteopenia and osteoporosis in the ChNPP accident survivors and their descendants. High inci dence of parathyroid hypertrophy is found in the inhabitants of the radiation contaminated territories (long term irradiation by cesium isotopes), as well as in evacuated from the 30 km exclusion zone (irradiation by iodine iso topes in the early days of the accident). PMID- 29286523 TI - Myastenia and small doses of ionizing radiation: experience of successful use of rituximab for treatment of an irradiated with myasthenia gravis. AB - A clinical case of the rituximab ("Rituksim", "Mabthera") use to treat a man affected by the Chornobyl NPP acci dent with malignant resistant form of myasthenia gravis in conjunction with chronic mixed infection by Toxoplasma, Epstein Barr virus, Cytomegalovirus and Herpes simplex virus is described. In the dynamics of two year's observa tion the clinical efficacy of monoclonal antibodies was shown as the main symptoms stabilization and reducing doses of glucocorticoid and anticholinergic therapy. The positive effect was marked in the nearest and remote peri ods. Taking to account the efficacy, safety and good tolerability of rituximab, it is advisable to recommend treat ment for people exposed to ionizing radiation and developing myasthenia associated with chronic mixed infection by Toxoplasma, Epstein Barr, Cytomegalovirus and Herpes simplex virus. PMID- 29286524 TI - Psychophysiological characteristics in the ChNPP accident clean-up workers, exclusion zone evacuees and anti-terrorist operation servicemen. AB - OBJECTIVE: Evaluation of interdependencies between psychometric parameters and spontaneous cerebral electric activity in the ChNPP accident clean up workers, evacuees from exclusion zone, and anti terrorist operation service men. OBJECT AND METHODS: Psychometric and neurophysiological parameters were reviewed in the study subjects retro spectively and in comparison. Study population included the ChNPP accident clean up workers (ACUW), evacuees from the 30 kilometer exclusion zone, specifically in a sample from a cohort of the NRCRM Clinical Epidemiological Register (n=316), and anti terrorist operation servicemen (n=81) undergoing rehabilitation in the NRCRM Radiation psychoneurology department. A control group of persons (n=84) was also involved in the study. Diagnostic method ology for the characteristic personality features, namely the personality test of character accentuation by G. Shmishek and K. Leonhard, and Eysenck Personality Inventory (by H. J. Eysenck) were applied. Computer EEGs were registered and analyzed on the 16 channel electroencephalograph DX 4000 (Kharkiv, Ukraine). RESULTS: In the aftermath of the emergency period, a personality deformation occurs in the clean up workers and survivors of the ChNPP accident, which is characterized by aggravation of such personality traits as jam (fixedness), emotiveness, pedantry, anxiety, cyclothymia, excitability and disthymia, with diminished hyperthymia and ostenta tion (demonstrability). Increased incidence of fixedness, pedantry, cyclothymia, affectability and disthymia with decreased hyperthymia were revealed in the group of ATO participants. Cerebral bioelectrical activity in the ChNPP ACUW was characterized by an increased delta activity power with decreased beta and theta activity power and dom inant frequency in comparison with all groups of survivors and control group. The ATO group was different from groups of survivors and control group with a lower power of delta, theta and beta activity, and a higher dominant frequency. Introversion featured a negative correlation with delta and theta activity index along with positive cor relation with alpha activity index. The absolute spectral power of beta, alpha and theta bands positively correlated with introversion. Increase in neuroticism featured a decrease in theta activity index and an increase in beta activ ity index along with decreased theta and delta band absolute spectral power. CONCLUSIONS: There is a deformation of personality in the group of ChNPP ACUW, evacuees from the 30 kilometer zone and ATO servicemen. Deformation of personality correlates with abnormal cerebral bioelectrical activity. PMID- 29286525 TI - The incidence of hematological neoplasms morbidity on radiation-contaminated territories in Cherkasy region. AB - OBJECTIVE: The main goal was to analyze the incidence of the morbidity in 1980, 1989, 2001, 2014 years and the structures of the absolute number of hematopoietic and lymphoid neoplasms cases during the period 1980-2014 on radiation contaminated and not contaminated territories in Cherkasy region. MATERIALS AND METHODS: The epidemiological indecies of hematological neoplasms were analyzed on radiation con taminated and not contaminated territories in Cherkasy region during the period from 1980 to 2014. Referring the territory in Cherkasy region to radiation contaminated is based on settlements dosimetry certification of Ukraine after the Chornobyl accident. 63 settlements were enrolled to radiation contaminated areas in Cherkasy region and 11 settlements assigned as not contaminated areas. RESULTS: The first positions in the list of the hematological neoplasms structure and frequency among new cases during 1980-2014 on not contaminated territories in Cherkasy region occupied by lymphoid leukemia, Hodgkin's lymphoma and myeloid leukemia and on the radiation contaminated territories - chronic, acute lymphoid and myeloid leukemia and lymphoma, diffuse large cell lymphoma. In the structure of hematological neoplasms record ed on the contaminated territories in Cherkasy region, there is a smaller proportion of Hodgkin's lymphoma cases (C81) than 0.84 fold (RR = 0.84; 95 % CI = 0.75-0.93) and more than 1.15 times (RR = 1.15; 95 % CI = 1.02-1.30) other unspecified malignant lymphoid and hematopoietic neoplasms. In 2001 on the radiation contaminated terri tories in Cherkasy region increase the incidence of acute and chronic myeloid leukemia in 2.46 times (p = 0.024) observed compared to non contaminated areas there (5.30 per 100 000, 95% CI = 3.03-8.33 versus 2.15 per 100,000, 95 % CI = 0.66-3.64). It was calculated that RR of acute and chronic myeloid leukemia (C92) in 2001 on radiation contaminated areas in Cherkasy region is 1.40 (95 % CI = 1.12-1.17) and Hodgkin's lymphoma (C81) on condition ally clean areas Cherkasy region - 1.70 (95 % CI = 1.36-2.12). PMID- 29286526 TI - Reserch of the gene polymorphism TOX3 / LOC643714 and the risk of breast cancer development in persons exposed to ionizing radiation after Chornobyl disaster. AB - OBJECTIVE: The objective of this work was to identify and compare the polymorphism of the rs3803662 polymorphism of the TOX3/LOC643714 gene in breast cancer patients who have undergone ionizing radiation due to the Chornobyl accident and in patients without ionizing radiation (IR) in the history. MATERIALS AND METHODS: The determination of the rs3803662 polymorphism of the TOX3/LOC643714 gene was per formed by polymerase chain reaction (PCR) in 83 patients with breast cancer: 42 subjects who were exposed to ion izing radiation due to the Chornobyl accident, 41 people without ionizing radiation in history and 17 controls in Ukraine without cancer pathology. In order to compare the obtained data on spontaneous and radiation associated breast cancer and to calculate the differences in the frequencies of alleles and the risk of oncopathology, data from literature on control groups of the populations of the Russian Federation, Sweden, and the United Kingdom were used. RESULTS: Comparing with the literature data and the group of exposed subjects, the homozygous carriers of the minor alleles of the TOX3/LOC643714 TT gene revealed an increased risk of developing breast cancer: OR = 2.89, p = 0.02 (CI 95% 1.17 7,16). In subjects without the influence of IR in history, the carrier of homozygous minor axis of the gene TOX3/LOC643714 TT is also associated with the risk of breast cancer: OR = 3.83, p = 0.0002 (CI 95% 0.82-14.14). In the homozygous carriers of the minor alleles of the TOX3 / LOC643714 gene exposed to IR, there was no increase in the risk of developing breast cancer (OR = 0.65, p = 0.46, CI 95% 0.21-2.04) compared with the con trol group of Ukrainian population. CONCLUSIONS: The carrier of homozygous minor alleles of the TOX3/LOC643714 gene is not a risk factor for the devel opment of breast cancer under conditions of exposure to ionizing radiation in the study group of the Ukrainian population. PMID- 29286527 TI - Experience of correcting endothelial dysfunction in children-residents of radioactively contaminated areas by nitric oxide potential donator citrulline. AB - OBJECTIVE: to determine the effectiveness of citrulline use for correcting endothelial dysfunction in children resi dents of radioactively contaminated areas. MATERIALS AND METHODS: A group of children residents of radioactively contaminated areas with the presence of clinical and paraclinical signs of endothelial dysfunction was selected to assess the effectiveness of correcting endothelial dysfunction by the usage of NO potential donator - citrulline according to the data of selective screen ing. There were determined the biochemical parameters of the content of NO stable metabolites, L arginine, lipid peroxidation, antioxidant enzymes in the blood serum; the indices of cellular and humoral immunity; the instrumen tal indices of vascular endothelium dependent reaction on occlusion test, the lung ventilation capacity, the bioelec tric activity of the myocardium, the autonomic regulation of the cardiovascular system.Examined children were received a course of citrulline malate. RESULTS AND CONCLUSIONS: An increased content of serum L arginine, nitrite, and amounts of NO metabolites was established in children with endothelial dysfunction who were received a course of citrulline malate. Bronchospasm elimination was noted in the significant part of examined patients after the drug use. Decreased recovery period and increased period of hypercompensation for thermographic circulation index in the test with post occlusion reac tive hyperemia were detected by an evaluation of indicators for vascular endothelium dependent vasodilatation using thermographic method indicating an increased endothelial vasomotor capacity. There was tendency to improve the processes of autonomic regulation of the heart rhythm and repolarization of the heart muscle. The antioxidant effect of used citrulline malate course was determined as: decreased content of serum LPO end products that react with thiobarbituric acid under elevated activity of antioxidant - catalase. An increase in the percentage of T lymphocyte, normalization of their subpopulation composition was noted in dynamics of citrulline malate application. PMID- 29286528 TI - The role of three phase bone scintigraphy in arthroplasty of hip and knee joints of clean-up workers of Chornobyl accident. AB - OBJECTIVE: The objective of the work to determine the diagnostic role of the three phase bone scintigraphy (3 F BS) in the early prediction of paraendoprosthetic complications of the hip and knee joints of the participants in clean up workers of Chornobyl accident. MATERIAL AND METHODS: The 3 F BS method were investigated the radionuclide kinetic parameters of the inclusion and distribution of radiopharmaceuticals (RF) in damaged joints in the 75 male clean up workers. RESULTS: It was established that calculating the quantitative indices of kinetics of the drug at various stages of the 3 F BS allowed to determine statistically significant differences in metabolic changes in focal lesions in articular structures. Thus, the differential diagnostic capabilities of the radionuclide method of examination of patients with arthroplasty of the hip and knee joints are elevated. CONCLUSIONS: The kinetics of osteotropic RF in the foci of fixing the damaged hip and knee joints in the infectious and inflammatory processes is characterized by the predominance of retention and specific accumulation of the drug in the early static phase and the delayed static phase of the 3 F BS compared with the centers of fixation of RF in deforming osteoarthroses, which correlates with the differences in destructive reparative processes in them. PMID- 29286529 TI - Unanticipated difficult airway management in children - the consensus statement of the Paediatric Anaesthesiology and Intensive Care Section and the Airway Management Section of the Polish Society of Anaesthesiology and Intensive Therapy and the Polish So. AB - Tracheal intubation may be defined as an artificial airway established in order to provide mechanical ventilation of the lungs during surgical procedures under general anaesthesia, treatment in an intensive care unit, as well as in emergency situations. Difficulties encountered during intubation may cause hypoxia, hypoxic brain injury and, in extreme situations, may result in the patient's death. There may be unanticipated and anticipated difficult airway. Children form a specific group of patients as there are significant differences in both anatomy and physiology. There are some limitations in equipment used for the airway management in children. There are only few paediatric difficult airway guidelines available, some of which have significant limitations. The presented algorithm was created by a group of specialists who represent the Polish Society of Anaesthesiology and Intensive Therapy, as well as the Polish Neonatology Society. This algorithm is intended for the unanticipated difficult airway in children and can be used in all age groups. It covers both elective intubation, as well as rescue techniques. A guide forms an integral part of the algorithm. It describes in detail all stages of the algorithm considering some modifications in a specific age group, e.g. neonates. The main aim of Stage I is to optimise conditions for face mask ventilation, laryngoscopy and intubation. Stage IIA focuses on maximising the chances of successful intubation when face mask ventilation is possible. Stage IIB outlines actions aimed at improving face mask ventilation. Stage IIIA describes the use of a SAD (Supraglottic Airway Device) during effective face mask ventilation or in a CICV (Cannot Intubate, Cannot Ventilate) situation. Stage IIIB outlines intubation through a SAD. Stage IV describes rescue techniques and outlines possible options of either proceeding with surgery or postponing it, depending on clinical situation. PMID- 29286530 TI - Molecular mechanisms of bacterial infections of the central nervous system. AB - Central nervous system (CNS) infections may involve the meninges, brain and/or spinal cord. The most common etiologic agents are Streptococcus pneumoniae, group B Streptococci, Neisseria meningitidis, Haemophilus influenzae, and Listeria monocytogenes. CNS is characterized by specific structure and function. Despite a unique system of brain barriers and autonomous immune system, CNS is very susceptible to microorganisms which may invade directly, via the blood, or less frequently by reverse axonal transport. The complex process of bacteria and activated polymorphonuclear leukocyte transfer to the subarachnoid space, which is devoid of natural immune defence mechanisms, initiates an inflammatory response that subsequently spreads to the brain tissue. Consequences of these changes include damage to the blood-brain barrier, development of vasogenic cerebral oedema, and intracranial pressurevolume disturbances leading to impaired CNS perfusion. PMID- 29286531 TI - Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. AB - Although genetic revolution of recent years has vastly expanded a list of genes implicated in epilepsies, complex architecture of epilepsy genetics is still largely unknown, consequently, universally accepted workflows for epilepsy genetic testing in a clinical practice are missing. We present a comprehensive NGS-based diagnostic approach addressing both the clinical and genetic heterogeneity of disorders involving epilepsy or seizures. A bioinformatic panel of 862 epilepsy- or seizure-associated genes was applied to Mendeliome (4813 genes) or whole-exome sequencing data as a first stage, while the second stage included untargeted variant interpretation. Eighty-six consecutive patients with epilepsy or seizures associated with neurodevelopmental disorders and/or congenital malformations were investigated. Of the 86 probands, 42 harbored pathogenic and likely pathogenic variants, giving a diagnostic yield of 49%. Two patients were diagnosed with pathogenic copy number variations and 2 had causative mitochondrial DNA variants. Eleven patients (13%) were diagnosed with diseases with specific treatments. Besides, genomic approach in diagnostics had multiple additional benefits due to mostly non-specific, overlapping, not full blown phenotypes and abilities to diagnose novel and ultra rare epilepsy associated diseases. Likely pathogenic variants were identified in SOX5 gene, not previously associated with epilepsy, and UBA5, a recently associated with epilepsy gene. PMID- 29286532 TI - Semiparametric estimation of the accelerated mean model with panel count data under informative examination times. AB - Panel count data arise when the number of recurrent events experienced by each subject is observed intermittently at discrete examination times. The examination time process can be informative about the underlying recurrent event process even after conditioning on covariates. We consider a semiparametric accelerated mean model for the recurrent event process and allow the two processes to be correlated through a shared frailty. The regression parameters have a simple marginal interpretation of modifying the time scale of the cumulative mean function of the event process. A novel estimation procedure for the regression parameters and the baseline rate function is proposed based on a conditioning technique. In contrast to existing methods, the proposed method is robust in the sense that it requires neither the strong Poisson-type assumption for the underlying recurrent event process nor a parametric assumption on the distribution of the unobserved frailty. Moreover, the distribution of the examination time process is left unspecified, allowing for arbitrary dependence between the two processes. Asymptotic consistency of the estimator is established, and the variance of the estimator is estimated by a model-based smoothed bootstrap procedure. Numerical studies demonstrated that the proposed point estimator and variance estimator perform well with practical sample sizes. The methods are applied to data from a skin cancer chemoprevention trial. PMID- 29286533 TI - Regression analysis for secondary response variable in a case-cohort study. AB - Case-cohort study design has been widely used for its cost-effectiveness. In any real study, there are always other important outcomes of interest beside the failure time that the original case-cohort study is based on. How to utilize the available case-cohort data to study the relationship of a secondary outcome with the primary exposure obtained through the case-cohort study is not well studied. In this article, we propose a non-parametric estimated likelihood approach for analyzing a secondary outcome in a case-cohort study. The estimation is based on maximizing a semiparametric likelihood function that is built jointly on both time-to-failure outcome and the secondary outcome. The proposed estimator is shown to be consistent, efficient, and asymptotically normal. Finite sample performance is evaluated via simulation studies. Data from the Sister Study is analyzed to illustrate our method. PMID- 29286534 TI - Fitness training for cardiorespiratory conditioning after traumatic brain injury. AB - BACKGROUND: Reduced cardiorespiratory fitness (cardiorespiratory deconditioning) is a common consequence of traumatic brain injury (TBI). Fitness training may be implemented to address this impairment. OBJECTIVES: The primary objective of this updated review was to evaluate whether fitness training improves cardiorespiratory fitness in people who have sustained a TBI. The secondary objectives were to evaluate whether fitness training improves body function and structure (physical and cognitive impairments, psychological responses resulting from the injury), activity limitations and participation restrictions in people who have sustained a TBI as well as to evaluate its safety, acceptance, feasibility and suitability. SEARCH METHODS: We searched 10 electronic databases (the Cochrane Injuries Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Embase; PubMed (MEDLINE); CINAHL; AMED; SPORTDiscus; PsycINFO; PEDro and PsycBITE) and the International Clinical Trials Registry Platform for relevant trials. In addition we screened reference lists from systematic reviews related to the topic that we identified from our search, and from the included studies, and contacted trialists to identify further studies. The search was run in August 2017. SELECTION CRITERIA: Randomised controlled studies with TBI participants were eligible if they compared an exercise programme incorporating cardiorespiratory fitness training to usual care, a non exercise intervention, or no intervention. DATA COLLECTION AND ANALYSIS: Two authors independently screened the search results, extracted data and assessed bias. We contacted all trialists for additional information. We calculated mean difference (MD) or standardised mean difference (SMD) and 95% confidence intervals (CI) for continuous data, and odds ratio with 95% CI for dichotomous data. We pooled data when there were sufficient studies with homogeneity. MAIN RESULTS: Two new studies incorporating 96 participants were identified in this update and were added to the six previously included studies. A total of eight studies incorporating 399 participants are included in the updated review. The participants were primarily men aged in their mid-thirties who had sustained a severe TBI. No studies included children. The studies were clinically diverse with regard to the interventions, time postinjury and the outcome measures used. At the end of intervention, the mean difference in peak power output was 35.47 watts (W) in favour of fitness training (MD 35.47 W, 95% CI 2.53 to 68.41 W; 3 studies, 67 participants; low-quality evidence). The CIs include both a possible clinically important effect and a possible negligible effect, and there was moderate heterogeneity among the studies.Five of the secondary outcomes had sufficient data at the end of intervention to enable meta-analysis: body composition (SMD 0.29 standard deviations (favouring control), 95% CI -0.22 to 0.79; 2 studies, 61 participants; low-quality evidence), strength (SMD -0.02 (favouring control), 95% CI -0.86 to 0.83; 2 studies, 23 participants; very low quality evidence), fatigue (SMD -0.32 (favouring fitness training), 95% CI -0.90 to 0.26; 3 studies, 130 participants; very low-quality evidence), depression (SMD -0.43 (favouring fitness training), 95% CI -0.92 to 0.06; 4 studies, 220 participants; very low-quality evidence), and neuromotor function (MD 0.01 m (favouring fitness training), 95% CI -0.25 to 0.27; 2 studies, 109 participants; moderate-quality evidence). It was uncertain whether fitness training was more or less effective at improving these secondary outcomes compared to the control interventions. Quality of life was assessed in three trials, but we did not pool the data because of substantial heterogeneity. Five of the eight included studies had no dropouts from their intervention group and no adverse events were reported in any study. AUTHORS' CONCLUSIONS: There is low-quality evidence that fitness training is effective at improving cardiorespiratory deconditioning after TBI; there is insufficient evidence to draw any definitive conclusions about the other outcomes. Whilst the intervention appears to be accepted by people with TBI, and there is no evidence of harm, more adequately powered and well-designed studies are required to determine a more precise estimate of the effect on cardiorespiratory fitness, as well as the effects across a range of important outcome measures and in people with different characteristics (e.g. children). In the absence of high quality evidence, clinicians may be guided by pre-exercise screening checklists to ensure the person with traumatic brain injury is safe to exercise, and set training parameters using guidelines established by the American College of Sports Medicine for people who have suffered a brain injury. PMID- 29286536 TI - Optimal Remediation Scheme for a Wastewater Recharge Site: Contaminants Fate and Transport Model. AB - A 3-dimensional hydrologic groundwater flow and contaminant transport model was developed to address the feasibility and relevant time-scales for remediation of a large soil aquifer treatment (SAT) site for domestic wastewater. The model accounted for a range of organic pollutant retardation factors and biodegradation kinetics. In order to detect the effect of the most retained and the most refracted/recalcitrant pollutants, it was crucial to model fractions of different properties rather than with average set properties. Four aquifer remediation scenarios, including two active washing procedures and two involving natural attenuation, were evaluated. The remediation efficiencies, in terms of residual plume size and mass of pollutant washout, were compared to each other and to the current operation scheme. According to the results, remediation mainly via natural attenuation rather than some form of intense pump and treat technology, is feasible, unlike the situation with hazardous waste sites. Enforced washout becomes less efficient with time due to increasing retardation of the residual pollutants. Therefore, pollution containment with natural biodegradation, which removed 95% of the emerging contaminants within 30 to 40 years was found to be the most valuable remediation scheme. PMID- 29286535 TI - The changing landscape of Lynch syndrome due to PMS2 mutations. AB - DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is a autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers. In this review, we discuss the role of PMS2 in the MMR pathway, the evolving testing criteria used to identify variants in the PMS2 gene, the LS phenotype as well as the autosomal recessive condition called constitutional mismatch repair deficiency syndrome, and current methods used to elucidate the clinical impact of PMS2 mutations. PMID- 29286537 TI - Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis. AB - BACKGROUND: In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination. METHODS: We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1beta in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines. RESULTS: A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1beta. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users. CONCLUSIONS: These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets. PMID- 29286539 TI - Implications of the galactosidase activity of yieldin in the regulatory mechanism of yield threshold that is fundamental to cell wall extension. AB - To understand the action mechanism of yieldin (YLD) on the regulation of the yield threshold (Y), one of the critical parameters of cell wall extension, YLD was extracted from the cell walls of cowpea (Vigna unguiculata L.) hypocotyls and the hemagglutinin activity (HA) as well as the glycosidase activity of the protein was measured. Sedimentation assays using trypsinated rabbit erythrocytes showed that YLD possessed HA at pH 7. The digestion assays using 4-nitrophenyl (pNP) glycopyranosides as artificial substrates showed that YLD liberated galactose residues from pNP alpha-d-galactopyranoside mainly at pH 4.0, i.e. the pH level where Y was decreased at most. These results show that YLD is a bifunctional protein that switches between the HA and the galactosidase activities depending on the surrounding pH. Since D-galactose at concentration of 0.03 g l-1 perfectly inhibited the HA, YLD was suggested to associate with galactose residues. However, the galactose application ten times concentrated was necessary to inhibit both the galactosidase activity of YLD and the acid-induced shift of Y regulated by YLD. In addition, the specific inhibitor of alpha-d galactosidase (deoxygalactonojirimycin) inhibited both the galactosidase activity of YLD and the shift of Y at the same concentration, but not the HA. On the basis of these results, it is suggested the galactosidase activity of YLD plays a central role in the mechanism of Y-regulation at acidic pH. PMID- 29286540 TI - Facilitators and Barriers to the Adoption of Pharmacogenetic Testing in an Inner City Population. AB - OBJECTIVES: To examine the knowledge, attitudes, and interest of an inner-city population toward pharmacogenetic testing, with the primary objective of identifying facilitators and barriers toward pharmacogenetic testing; and secondary objectives of determining predictors of patient interest in pharmacogenetic testing and how much patients would pay for the test. METHODS: Patients were recruited from an Antithrombosis Clinic from March to April 2014. A cross-sectional 19-question survey was administered in person to determine patients' knowledge and awareness of pharmacogenetic testing and collect demographic information. After explaining pharmacogenetics, patients ranked their interest toward the test and answered open-ended questions that elicited facilitators and barriers toward pharmacogenetic testing and elucidated how much patients would pay for testing. RESULTS: A total of 120 patients (mean age 55.0 +/- 14.0 years, 39.2% male, 69.2% African American) were surveyed. Facilitators included providing further information about pharmacogenetic testing; elaborating on benefits of testing to predict treatment efficacy; patients' trust in their providers to make correct genotype-guided prescribing decisions; and insurance coverage and test affordability. Barriers to testing included concerns about the negative consequences associated with test results; burden of the testing process; perceived lack of utility among elderly and those whose medications were working; privacy issues; and concerns regarding insurance coverage and test affordability. Women had 4.2 times higher adjusted odds of being interested in pharmacogenetic testing. Almost half (44.4%) of the patients with high interest in the test were willing to pay $20 or more, whereas 76.2% of patients with low interest wanted testing at no cost. CONCLUSION: This study identified facilitators, such as providing additional pharmacogenetic test information, and barriers, such as perceived negative impact of the results and test utility, as issues to address when engaging an urban, largely minority population in pharmacogenetic testing. Female sex was a predictor of interest toward pharmacogenetic testing. These facilitators and barriers should be taken into consideration as pharmacogenetic testing gains widespread utility among inner city populations. PMID- 29286538 TI - Effect of Gabapentin on Sleep and Event-Related Oscillations (EROs) in Rats Exposed to Chronic Intermittent Ethanol Vapor and Protracted Withdrawal. AB - BACKGROUND: Disturbances in sleep architecture, especially reductions in slow wave sleep (SWS), are symptoms commonly observed in individuals with alcohol use disorders. Recent clinical trials have demonstrated that the anticonvulsant and analgesic drug gabapentin may have therapeutic value in normalizing sleep quality in recovering alcoholics. However, the brain mechanisms underlying this improvement in sleep following gabapentin treatment remain unknown. METHODS: In this study, adult Wistar rats were exposed to 8 weeks of chronic intermittent ethanol [EtOH] vapor (blood EtOH concentrations averaged 128.2 +/- 17.4 mg/dl) or control conditions and then withdrawn. Sleep electroencephalograms [EEGs] and event-related oscillations (EROs) were evaluated at baseline prior to EtOH exposure and 24 hours following EtOH withdrawal. Four weeks following EtOH withdrawal the effects of saline and 2 doses of gabapentin (30, 120 mg/kg), on EROs and sleep EEGs, were evaluated. RESULTS: As compared to baseline, 24 hours following alcohol withdrawal SWS became fragmented as indexed by a significant increase in the number and a decrease in the duration of SWS episodes. Compared to controls, the EtOH-exposed group had more ERO energy in the beta frequency band in the parietal cortex. Gabapentin induced a dose-dependent decrease in the latency to the first SWS episode, and a reduction in sleep fragmentation. Gabapentin also produced a dose-dependent increase in ERO energy in the control group that was significantly attenuated in the EtOH-exposed group in the theta, and beta frequency bands. CONCLUSIONS: Taken together, these studies suggest that gabapentin can reverse some of the alcohol-induced sleep and EEG deficits but does not eliminate all of the enduring brain effects of EtOH exposure. PMID- 29286541 TI - STRONG MILITARY FAMILIES INTERVENTION ENHANCES PARENTING REFLECTIVITY AND REPRESENTATIONS IN FAMILIES WITH YOUNG CHILDREN. AB - Military families face many challenges due to deployment and parental separation, and this can be especially difficult for families with young children. The Strong Military Families (SMF) intervention is for military families with young children, and consists of two versions: the Multifamily Group, and a Home-based psychoeducational written materials program. The Multifamily Group was designed to enhance positive parenting through both educational components and in vivo feedback and support during separations and reunions between parents and children (n = 78 parents). In the present study, we examine parenting reflectivity and mental representations in mothers versus fathers in military families, service members versus civilian spouses/parenting partners, and before versus after participation in the SMF Multifamily Group and Home-based interventions. Parenting reflectivity and mental representations were coded from the Working Model of the Child Interview (WMCI; C.H. Zeanah & D. Benoit, 1995). Results suggest that neither parenting reflectivity nor WMCI typology differs between mothers and fathers in military families, or between service members and civilian parenting partners. Furthermore, there was substantial stability in parenting reflectivity and WMCI typology from baseline to posttest, but participation in the Multifamily Group, relative to Home-based, was associated with improvements in both parenting reflectivity and WMCI ratings from baseline to postintervention. PMID- 29286543 TI - Detecting Deception in Our Research Participants: Are Your Participants Who You Think They Are? AB - There is increasing awareness of the potential negative impacts of participant deception on research, including possibly undermining reliability and reproducibility of study findings. These deceptive individuals set their personal interests above the rules of study participation, thereby jeopardizing data quality as well as placing themselves and others at risk. The costs of participant deception are numerous. Overall, it reduces statistical power and may even result in false conclusions about efficacy and safety. To date, most studies have not utilized sufficient methods to detect rule-breaking subjects. The purpose of this article is to bring to the attention of alcohol and other drug researchers issues involving deceptive participants. The review will suggest alcohol-specific as well as more general strategies to identify and thereby minimize enrollment of these deceptive participants. Specifically, we will identify strategies that are employed in different phases of human alcohol research and advance approaches that may be helpful to the field in reducing these contaminants. As a field, we need to be more proactive in identifying the deceptive participant even at the cost of more burdensome study enrollment. In light of the systemic nature and multipronged damage that this emerging pattern of deception inflicts on clinical research, it is imperative that we each assume greater responsibility for our role in mitigating this source of research contamination. PMID- 29286542 TI - Effects of Initiating Abstinence from Alcohol on Daily Craving and Negative Affect: Results from a Pharmacotherapy Clinical Trial. AB - BACKGROUND: Craving and negative affect are distressing and commonly experienced during alcohol use disorder (AUD) treatment. Patients may assume that initiating abstinence will intensify their cravings and negative affect despite limited empirical data to support this assumption. This study extends and replicates, under improved methodological conditions, previous work that found reductions in daily craving associated with initiating abstinence. METHODS: Seventy-eight adults (80.8% male, 57.1% Caucasian) in a clinical trial testing prazosin for AUD provided daily reports of drinking, craving, and negative affect for up to 12 weeks (mean = 64.77 daily reports). Participants were classified into 3 subgroups based on whether and when they initiated 14 days of continuous abstinence, including (i) "abstinence initiators" who quit drinking during treatment (n = 17), (ii) "already abstainers" who were abstinent at the start of treatment (n = 20), and (iii) "continued drinkers" who never initiated abstinence (n = 41). The timing and degree of change in craving and negative affect were compared across these groups using multivariate growth curve modeling. RESULTS: All participant subgroups reported gradual reductions in craving over the course of treatment, with "abstinence initiators" reporting additional sudden reductions in craving upon initiating abstinence from alcohol. "Continued drinkers" reported higher levels of craving than "already abstainers" throughout the full course of treatment. Negative affect followed a different pattern of change, with "abstinence initiators" experiencing gradual reductions in negative affect after initiating abstinence but no changes prior to or immediately upon initiating abstinence, and with "already abstainers" and "continued drinkers" experiencing no changes in negative affect over time. CONCLUSIONS: Initiating abstinence is associated with immediate reductions in craving, followed by gradual reductions in both craving and negative affect. Results provide insight into the timing and magnitude of changes in theoretically and clinically important variables and may help patients anticipate when to expect improvement in craving and negative effect. PMID- 29286544 TI - Direct analysis by time-of-flight secondary ion mass spectrometry reveals action of bacterial laccase-mediator systems on both hardwood and softwood samples. AB - The modification and degradation of lignin play a vital role in carbon cycling as well as production of biofuels and bioproducts. The possibility of using bacterial laccases for the oxidation of lignin offers a route to utilize existing industrial protein expression techniques. However, bacterial laccases are most frequently studied on small model compounds that do not capture the complexity of lignocellulosic materials. This work studied the action of laccases from Bacillus subtilis and Salmonella typhimurium (EC 1.10.3.2) on ground wood samples from yellow birch (Betula alleghaniensis) and red spruce (Picea rubens). The ability of bacterial laccases to modify wood can be facilitated by small molecule mediators. Herein, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), gallic acid and sinapic acid mediators were tested. Direct analysis of the wood samples was achieved by time-of-flight secondary ion mass spectrometry (ToF-SIMS), a surface sensitive mass spectrometry technique that has characteristic peaks for H, G and S lignin. The action of the bacterial laccases on both wood samples was demonstrated and revealed a strong mediator influence. The ABTS mediator led to delignification, evident in an overall increase of polysaccharide peaks in the residual solid, along with equal loss of G and S lignin peaks. The gallic acid mediator demonstrated minimal laccase activity. Meanwhile, the sinapic acid mediator altered the S/G peak ratio consistent with mediator attaching to the wood solids. The current investigation demonstrates the action of bacterial laccase-mediator systems directly on woody materials, and the potential of using ToF-SIMS to uncover the fundamental and applied role of bacterial enzymes in lignocellulose conversion. PMID- 29286545 TI - One-Year Effectiveness Study of Intravitreous Ranibizumab in Wet (Neovascular) Age-Related Macular Degeneration: A Meta-Analysis. AB - PURPOSE: The clinical efficacy of ranibizumab has been examined by a large number of prospective and retrospective studies to date. This meta-analysis was conducted to summarize the current body of evidence on visual acuity (VA) changes with use of ranibizumab in the treatment of wet (neovascular) age-related macular degeneration (wAMD). METHODS: A literature review of multiple electronic databases (EMBASE, MEDLINE, MedMEME) was conducted to find randomized controlled trials (RCTs) and observational studies that reported changes in VA while patients with wAMD were on ranibizumab. Study factors analyzed were baseline patient characteristics, study type, sample size, and 12-month change in VA. Data were pooled in a meta-analysis with VA change as the main outcome. Data were then stratified by study design and a meta-regression was conducted to assess 12-month VA change against baseline VA and age. RESULTS: A total of 42 studies were included for analysis. An overall increase of 5.58 letters (95% confidence interval [CI]: 4.42-6.75; p heterogeneity, < 0.001) was shown with use of ranibizumab compared to baseline. Improvements in VA were larger for RCTs, at 7.71 letters (95% CI: 6.66-8.76; p heterogeneity, 0.013), compared to observational studies, at 4.85 letters (95% CI: 3.32-6.38; p heterogeneity, < 0.001). The meta-regression showed a significant decrease in effect size between baseline VA and 12-month VA change. CONCLUSION: This meta-analysis suggests visual improvements at 12 months of 0.5-mg ranibizumab use in patients with wAMD. A higher gain in VA was observed when pooling results from RCTs compared to those in observational studies. PMID- 29286546 TI - Serious Liver Injury Associated with Macitentan: A Case Report. AB - Several endothelin receptor antagonists (ERAs) that were developed for the treatment of pulmonary arterial hypertension (PAH), including bosentan and sitaxentan, have been linked to clinically significant hepatocellular injury, as well as liver failure. We describe the first case of fulminant hepatitis to be reported in association with the ERA macitentan. This case was recently identified within the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and describes liver transplantation occurring 13 months after macitentan initiation in a young patient (23 years old) with idiopathic PAH New York Heart Association (NYHA) functional class III. PMID- 29286547 TI - Explaining the Origin of Three-Membrane-Bound Plastids in Dinoflagellates and Euglenophytes: Kleptoplastidy via Myzocytosis? PMID- 29286549 TI - Musculoskeletal complications following total body irradiation in hematopoietic stem cell transplant patients. AB - Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI. PMID- 29286550 TI - Reduced translocation in 2,4-D-resistant oriental mustard populations (Sisymbrium orientale L.) from Australia. AB - BACKGROUND: Two oriental mustard populations (P2 and P13) collected from Port Broughton, South Australia were identified as resistant to 2,4-D. The level of resistance, mechanism and the mode of inheritance for 2,4-D resistance in these populations were investigated. RESULTS: Populations P2 and P13 were confirmed to be resistant to 2,4-D at the field rate (600 g a.e. ha-1 ). P2 and P13 were 81- and 67-fold more resistant than the susceptible populations (S1 and S2) at the dose required for 50% mortality (LD50 ), respectively. No predicted amino acid modification was detected in sequences of potential target-site genes (ABP, TIR1 and AFB5). Resistant populations had reduced 2,4-D translocation compared with the susceptible populations, with 77% of [14 C]2,4-D retained in the treated leaf versus 32% at 72 h after treatment. Resistance to 2,4-D is encoded on the nuclear genome and is dominant, as the response to 2,4-D of all F2 individuals were similar to the resistant biotypes. The segregation of F2 phenotypes fitted a 3: 1 (R: S) inheritance model. CONCLUSION: Resistance to 2,4-D in oriental mustard is likely due to reduced translocation of 2,4-D out of the treated leaf. Inheritance of 2,4-D resistance is conferred by a single gene with a high level of dominance. (c) 2017 Society of Chemical Industry. PMID- 29286551 TI - Thiocarbamate fungicides: reliable tools in resistance management and future outlook. AB - Among contact fungicides, dithiocarbamates have remained successful and are used worldwide. These organic sulfur fungicides, viz. mancozeb, maneb, zineb, ziram, thiram, metiram and propineb, have helped growers manage several economically important plant diseases. Their multi-site mode of action and broad-spectrum disease control make them some of the most common partners in mixtures of a number of single-site fungicides as part of resistance management strategies. Indeed, it was the part played by ethylene-bis-dithiocarbamates such as mancozeb in delaying the evolution of phenylamide resistance in several oomycete phytopathogens that laid the groundwork for mixture strategies to become a cornerstone of anti-resistance management in plant disease control. Dithiocarbamates, however, do not have systemic action, are only surface protectants and have to be applied prior to pathogen infection. Dithiocarbamates will likely continue play a key role as reliable resistance management tools to prolong the efficacy of single-site fungicides. The primary metabolite ethylene thiourea produced by some of these fungicides is considered a reproductive and endocrine disrupter in animals. Therefore, dithiocarbamates need to be used at reduced rates or in slow-release formulations. (c) 2017 Society of Chemical Industry. PMID- 29286552 TI - The SMS, Phone, and medical Examination sports injury surveillance system is a feasible and valid approach to measuring handball exposure, injury occurrence, and consequences in elite youth sport. AB - Current methods of sports injury surveillance are limited by lack of medical validation of self-reported injuries and/or incomplete information about injury consequences beyond time loss from sport. The aims of this study were to (a) evaluate the feasibility of the SMS, Phone, and medical Examination injury surveillance (SPEx) system (b) to evaluate the proportion of injuries and injury consequences reported by SPEx when compared to outcomes from a modified version of the Oslo Sports Trauma Research Centre (OSTRC) Overuse Injury Questionnaire. We followed 679 elite adolescent handball players over 31 weeks using the SPEx system. During the last 7 weeks, we also implemented a modified OSTRC questionnaire in a subgroup of 271 players via telephone interviews. The weekly response proportions to the primary SPEx questions ranged from 85% to 96% (mean 92%). SMS responses were received from 79% of the participants within 1 day. 95% of reported injuries were classified through the telephone interview within a week, and 67% were diagnosed by medical personnel. Comparisons between reported injuries from SPEx and OSTRC demonstrated fair (kappa = 39.5% [25.1%-54.0%]) to substantial prevalence-adjusted bias-adjusted kappa (PABAK = 66.8% [95% CI 58.0% 75.6%]) agreement. The average injury severity score difference between SPEx and the OSTRC approach was -0.2 (95% CI -3.69-3.29) of possible 100 with 95% limits of agreement from(-14.81-14.41). These results support the feasibility and validity of the SPEx injury surveillance system in elite youth sport. Future studies should evaluate the external validity of SPEx system in different cohorts of athletes. PMID- 29286553 TI - Relationship between anxious temperament and harm avoidance in medical students and staff. AB - AIM: In order to resolve the equivocal relationship between anxious temperament rated by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) and harm avoidance rated by the Temperament and Character Inventory (TCI), the present study aimed to investigate whether the anxious temperament scale and the harm avoidance scale are significantly associated with adjustment of relevant factors. Our hypothesis was that anxious temperament might be associated with harm avoidance. METHODS: From the database of our previous studies, the data of 111 healthy subjects who had both TCI and TEMPS-A scores were extracted for the present study. Two multiple regression analyses were performed: one to predict variance in anxious temperament scores without and with harm avoidance scores, and relevant factors; and another to predict variance in harm avoidance scores without and with anxious temperament scores, and relevant factors. RESULTS: Anxious temperament was significantly and positively associated with depressive temperament, irritable temperament, and Hamilton Rating Scale for Depression whereas harm avoidance was significantly and negatively associated with hyperthymic temperament, novelty seeking, persistence, and self-directedness, although both were significantly and positively associated with each other. CONCLUSION: These findings support our hypothesis and suggest that anxious temperament may have 'depressive proneness' whereas harm avoidance may have 'passive proneness.' PMID- 29286554 TI - Effect of Intravenous Administration of Cobalt Chloride to Horses on Clinical and Hemodynamic Variables. AB - BACKGROUND: Cobalt chloride (CoCl2 ) is administered to racehorses to enhance performance. The purpose of this study was to evaluate the clinical, cardiovascular, and endocrine effects of parenterally administered CoCl2 . OBJECTIVES: To describe the effects of weekly intravenous doses of CoCl2 on Standardbred horses. ANIMALS: Five, healthy Standardbred mares. METHODS: Prospective, randomized, experimental dose-escalation pilot. Five Standardbred mares were assigned to receive 1 of 5 doses of CoCl2 (4, 2, 1, 0.5, or 0.25 mg/kg) weekly IV for 5 weeks. Physical examination, blood pressure, cardiac output, and electrocardiography (ECG) were evaluated for 4 hours after administration of the first and fifth doses. Blood and urine samples were collected for evaluation of cobalt concentration, CBC and clinical chemistry, and hormone concentrations. RESULTS: All mares displayed pawing, nostril flaring, muscle tremors, and straining after CoCl2 infusion. Mares receiving 4, 2, or 1 mg/kg doses developed tachycardia after dosing (HR 60-126 bpm). Ventricular tachycardia was noted for 10 minutes after administration of the 4 mg/kg dose. Increases in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) occurred after administration of all doses (4, 2, 1, 0.5, and 0.25 mg/kg). Profound hypertension was observed after the 4 mg/kg dose (SAP/DAP, MAP [mmHg] = 291-300/163-213, 218-279). Hemodynamics normalized by 1-2 hours after administration. ACTH and cortisol concentrations increased within 30 minutes of administration of all CoCl2 doses, and cardiac troponin I concentration increased after administration of the 4 and 2 mg/kg doses. CONCLUSIONS AND CLINICAL IMPORTANCE: The degree of hypertension and arrhythmia observed after IV CoCl2 administration raises animal welfare and human safety concerns. PMID- 29286555 TI - Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study. AB - PURPOSE: In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. PATIENTS AND METHODS: Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). RESULTS: Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). CONCLUSION: Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen. PMID- 29286556 TI - Total Synthesis of (+/-)-Phomoidride D. AB - Described herein is a synthetic strategy for the total synthesis of (+/-) phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels-Alder cycloaddition. A subsequent SmI2 -mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion. PMID- 29286557 TI - Enzymatic Electrosynthesis of Alkanes by Bioelectrocatalytic Decarbonylation of Fatty Aldehydes. AB - An enzymatic electrosynthesis system was created by combining an aldehyde deformylating oxygenase (ADO) from cyanobacteria that catalyzes the decarbonylation of fatty aldehydes to alkanes and formic acid with an electrochemical interface. This system is able to produce a range of alkanes (octane to propane) from aldehydes and alcohols. The combination of this bioelectrochemical system with a hydrogenase bioanode yields a H2 /heptanal enzymatic fuel cell (EFC) able to simultaneously generate electrical energy with a maximum current density of 25 MUA cm-2 at 0.6 V and produce hexane with a faradaic efficiency of 24 %. PMID- 29286558 TI - Family history-taking practices and genetic confidence in primary and tertiary care providers for childhood cancer survivors. AB - BACKGROUND: There is growing impetus for increased genetic screening in childhood cancer survivors. Family history-taking is a critical first step in determining survivors' suitability. However, the family history-taking practices of providers of pediatric oncology survivorship care and the confidence of these providers to discuss cancer risks to relatives are unknown. PROCEDURE: Fifty-four providers completed semistructured interviews in total, which included eight tertiary providers representing nine hospitals across two countries (63% male, 63% oncologists, 37% nurses) and 46 primary care providers (PCPs) nominated by a survivor (59% male, 35% regional practice). We used content analysis and descriptive statistics/regression to analyze the data. RESULTS: Few tertiary (38%) or primary (35%) providers regularly collected survivors' family histories, often relying on survivors/parents to initiate discussions. Providers mostly took two-generation pedigrees (63% tertiary and 81% primary). Primary providers focused on adult cancers. Lack of time, alternative priorities, and perceived lack of relevance were common barriers. Half of all tertiary providers felt moderately comfortable discussing genetic cancer risk to children of survivors (88% felt similarly discussing risks to other relatives). Most primary providers lacked confidence: 41% felt confident regarding risks to survivors' children and 48% regarding risks to other relatives. CONCLUSIONS: While family history-taking will not identify all survivors suitable for genetics assessment, recommendations for regular history-taking are not being implemented in tertiary or primary care. Additional PCP-targeted genetic education is warranted given that they are well placed to review family histories of pediatric cancer survivors. PMID- 29286559 TI - High incidence of acute kidney injury during chemotherapy for childhood acute myeloid leukemia. AB - BACKGROUND/OBJECTIVES: Childhood acute myeloid leukemia (AML) is a rare and heterogeneous disease. Pediatric data on the epidemiology of acute kidney injury (AKI) in AML are limited. We report on the incidence of AKI in childhood AML and the risk factors associated with AKI episodes. METHODS: A retrospective cohort of 53 patients (<=18 years), with de novo AML, receiving chemotherapy over a 10-year period. All serum creatinine (SCr) levels during therapy-related hospitalizations were assessed to stage AKI episodes as per Kidney Disease: Improving Global Outcomes criteria. Severe AKI was defined as AKI stages 2 or 3 and urine output criteria were not used. AKI risk factors were assessed independently in both cycle 1 alone and combining all chemotherapy cycles. RESULTS: AKI developed in 34 patients (64%) with multiple AKI episodes in 10 patients (46 total episodes). Twenty-four severe AKI episodes occurred in 23 patients (43.4%) with a mean duration of 26.1 days (SD 7.3). In cycle 1, hyperleukocytosis was not predictive of AKI, but severe sepsis was an independent risk factor of severe AKI (odds ratio [OR]: 13.4; 95% CI 1.9-94.9). With cycles combined, all subjects with AKI had severe sepsis and older age (>=10 years) was associated with severe AKI (OR: 20.8; 95% CI 3.8-112.2). CONCLUSION: There was a high incidence of AKI in our AML cohort with a strong association with older age (>=10 years) and severe sepsis. Larger prospective studies are needed to confirm the high burden of AKI and risk factors in this susceptible population. PMID- 29286561 TI - Intracranial metastasis in fibrolamellar hepatocellular carcinoma. AB - Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease. PMID- 29286560 TI - Modifying bone mineral density, physical function, and quality of life in children with acute lymphoblastic leukemia. AB - BACKGROUND: The early effects of childhood acute lymphoblastic leukemia (ALL) include decreased physical function, bone mineral density (BMD/g/cm2 ), and health-related quality of life (HRQL). We assessed the capacity of a physical therapy and motivation-based intervention, beginning after diagnosis and continuing through the end of treatment, to positively modify these factors. PROCEDURE: A 2.5-year randomized controlled trial of 73 patients aged 4-18.99 years within 10 days of ALL diagnosis assessed BMD at baseline (T0 ) and end of therapy (T3 ), strength, range of motion, endurance, motor skills, and HRQL at baseline (T0 ), 8 (T1 ), 15 (T2 ), and 135 (T3 ) weeks. RESULTS: There were no significant changes between groups (intervention, n = 33; usual care, n = 40) in BMD (P = 0.059) at T3 or physical function and HRQL at T0 -T3 . While BMD declined in both the intervention (T0 = -0.21, T3 = -0.55) and usual care (T0 = -0.62, T3 = -0.78) groups, rates of decline did not differ between groups (P = 0.56). Univariate analysis (n = 73) showed associations of higher T3 bone density with body mass index T1 (P = 0.01), T2 (P = <0.0001), T3 (P = 0.01), T3 ankle flexibility/strength (P = 0.001), and T2 parent (P = 0.02)/T0 child (P = 0.03) perceptions of less bodily pain. CONCLUSIONS: The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship. PMID- 29286563 TI - ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study. AB - BACKGROUND: Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome. PROCEDURE: In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR. RESULTS: All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6-NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%). CONCLUSION: The majority of cellular MNs harbor the ETV6-NTKR3 gene fusion, whereas all classic- and mixed type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS. PMID- 29286562 TI - Isolated late testicular relapse of B-cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response-based testicular radiation: A Children's Oncology Group study. AB - BACKGROUND: The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5-year overall survival (OS). This study aimed to improve outcome in patients with ITR of B-cell ALL (B-ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long-term sequelae by limiting use of testicular radiation. PROCEDURE: Forty patients in first ITR of B-ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high-dose methotrexate (MTX, 5 g/m2 ). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy-proven disease and received bilateral testicular radiation (24 Gy), whereas twenty-nine did not. RESULTS: Overall 5-year event-free survival (EFS)/OS was 65.0 +/- 8.8%/73.1 +/- 8.3%, with 5-year EFS 62.1 +/- 11.0% vs. 72.7 +/- 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5-year OS was similar for patients who did not receive XRT (72.6 +/- 10.2%) compared with those who did (72.7 +/- 14.4%) (P = 0.85). CONCLUSIONS: A 5-year OS rate of 73.1 +/- 8.3% was obtained in children with first ITR of B-ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation. PMID- 29286564 TI - Denosumab treatment in aneurysmal bone cyst: Evaluation of nine cases. AB - BACKGROUND: Aneurysmal bone cyst (ABC) is a benign bone tumor. Curettage and bone grafting is the common treatment. Here, we retrospectively evaluate nine patients treated with denosumab. PROCEDURE: Nine patients with ABC, mostly pelvic and vertebral, treated with denosumab were analyzed retrospectively. A 70 mg/m2 denosumab dose was used weekly in the first month, and then monthly. Clinical and radiological responses to treatment were evaluated. RESULTS: In all patients, clinical symptoms including pain and limping regressed completely within 3 months. Radiological evaluation revealed changes in lesion size and content. In six patients, overall volume reduction in the range of 18-82% was detected. Decreases in the size and number of cysts were detected in eight patients. In five patients, fat signal appeared on follow-up imaging. No major side effects were observed during treatment. Median follow-up time after treatment was 15 months. At 5 months, severe hypercalcemia was observed in two patients due to rebound increase in osteoclastic activity. Subsequent to denosumab treatment, three patients underwent surgery for clinical or radiological recurrence. CONCLUSIONS: Our results showed that denosumab provided a meaningful clinical and radiological improvement in ABC. It may be a treatment option, especially in spinal and pelvic tumors with potentially high surgical morbidity. However, late rebound hypercalcemia may restrict its use. Studies with more cases are required for routine use of denosumab in ABC. PMID- 29286565 TI - Children and adolescents with marginal zone lymphoma have an excellent prognosis with limited chemotherapy or a watch-and-wait strategy after complete resection. AB - Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty-four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty-three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 +/- 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only. PMID- 29286566 TI - Comment on: "Successful use of nitrous oxide during lumbar punctures: A call for nitrous oxide in pediatric oncology clinics". PMID- 29286567 TI - Crizotinib in ALK+ inflammatory myofibroblastic tumors-Current experience and future perspectives. AB - Inflammatory myofibroblastic tumor (IMT) and its subtype epithelioid inflammatory myofibroblastic sarcoma (EIMS) are rare soft-tissue tumors. As about 50% of IMT and 100% of EIMS contain activating rearrangements of the anaplastic lymphoma kinase (ALK) gene, targeted kinase inhibition of ALK by compounds such as crizotinib is a potential treatment option. We performed a literature review and analyzed a total of 30 patients with IMT/EIMS treated with crizotinib. A total of 12 patients achieved complete or partial remission. As preliminary data are promising, a prospective study evaluating crizotinib treatment in patients with unresectable/multifocal ALK+ IMT/EIMS is warranted. PMID- 29286568 TI - Utilization of frozen plasma, cryoprecipitate, and recombinant factor VIIa for children with hemostatic impairments: An audit of transfusion appropriateness. AB - BACKGROUND: Blood transfusions and fractionated products are not without risk and may lead to acute and long-term adverse events. The objective of this study was to evaluate the appropriateness of usage of frozen plasma (FP), cryoprecipitate (CRYO), and recombinant factor VIIa (rVIIa) in a pediatric setting. METHODS: All orders for FP, CRYO, and rVIIa were prospectively audited over 6 weeks. Data collected included demographics, laboratory values, indication, and adverse reactions. The appropriateness of each order was independently evaluated using adjudication criteria rated by two hematologists. RESULTS: Two hundred sixty-five products were ordered; 67% of the orders were issued to operating rooms or intensive care units. The most common indication for all products was cardiac surgery. FP was ordered as fluid replacement (15/215; 7%) to correct abnormal coagulation tests (23/215; 11%) and for patients with minor or no bleeding (111/242; 46%). FP was more likely to alter the international normalized ratio (INR) if the INR was over 2.0 (P < 0.0001). The rate of inappropriate products was judged as FP 19%, CRYO 21%, and rVIIa 91%. CONCLUSION: FP, CRYO, and rVIIa are most commonly used in the operating room and intensive care units. FP was often used for fluid resuscitation and for patients with mild to no bleeding. FP was only effective in lowering the INR when the INR was over 2.0. Use of rVIIa was rarely ordered for an appropriate indication. Results of this study inform its readers where trials of pediatric transfusion should be performed to clarify how these products should be used in clinical practice. PMID- 29286569 TI - Patterns of kidney injury in pediatric nonkidney solid organ transplant recipients. AB - The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty-three children (8%) developed CKD after a median follow-up of 3.4 years. Less than 5 children developed end-stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13-6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney-sparing strategies to decrease risk for progression to CKD. PMID- 29286571 TI - Irinotecan-induced muscular contractions. PMID- 29286570 TI - Identifying patient- and family-centered outcomes relevant to inpatient versus at home management of neutropenia in children with acute myeloid leukemia. AB - Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children >=8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial. PMID- 29286572 TI - Predicting bacterial infections among pediatric cancer patients with febrile neutropenia: External validation of the PICNICC model. AB - INTRODUCTION: The Predicting Infectious Complications in Neutropenic Children and Young People with Cancer (PICNICC) model was recently developed for antibiotic stewardship among pediatric cancer patients, but limited information is available about its clinical usefulness. We aimed to assess the performance of the PICNICC model for predicting microbiologically documented bacterial infections among pediatric cancer patients with febrile neutropenia. MATERIALS AND METHODS: We used data for febrile neutropenia episodes at a pediatric cancer center in Aarhus, Denmark between 2000 and 2016. We assessed the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness (i.e., net benefit). We also recalibrated the model using statistical updating methods. RESULTS: We observed 306 microbiologically documented bacterial infections among 1,892 episodes of febrile neutropenia. The AUC of the model was 0.73 (95% confidence limits [CL]: 0.71-0.75). The calibration intercept (calibration-in-the large) was -0.69 (95% CL: -0.86 to -0.51) and the slope was 0.77 (95% CL: 0.65 0.89). Modest net benefit was observed at a decision threshold of 5%. Recalibration improved calibration but did not improve net benefit. CONCLUSIONS: The PICNICC model has potential for reducing unnecessary antibiotic exposure for pediatric cancer patients with febrile neutropenia, but continued validation and refinement is necessary to optimize clinical usefulness. PMID- 29286573 TI - Hypothalamic involvement in craniopharyngioma-Implications for surgical, radiooncological, and molecularly targeted treatment strategies. PMID- 29286574 TI - Internal rulers to assess fluorescent protein photoactivation efficiency. AB - Photoactivatable fluorescent proteins (PA-FPs) have been widely used to assess the dynamics of cell biological processes. In addition, PA-FPs enabled single molecule based super-resolution imaging (photoactivated localization microscopy) and thereby provided unprecedented structural insight. For the lack of tools, however, the fraction of PA-FPs that is, actually being switched on to fluoresce, that is, the photoactivation efficiency, has been difficult to assess. Uncertainty about photoactivation efficiency has hampered an understanding of the absolute amount of PA-FPs, that is, being examined. Here, we present internal rulers to assess photoactivation efficiencies of photoactivatable proteins. These internal rulers comprise a PA-FP that is genetically directly coupled to a spectrally distinct always-on fluorescent protein. Thus, these fluorescent proteins will be expressed in the bacterial and mammalian cell in a one-to-one ratio. With these tools, we describe photoactivation efficiencies of PA-GFP and PA-Cherry in intensity-based ratiometric ensemble studies and on the single molecule level. In ratiometric ensemble studies, we show that photoactivation efficiency depends on how the PA-FPs are exposed to 405 nm light. Using a laser scanning microscope, hundreds of iterative low-level exposures are up to four times more efficient than a short high-power exposure. Using wide-field illumination, photoactivation was similarly efficient and instantaneous. These findings suggest that the repetitive or stochastic exposure to photons of 405 nm light results in more efficient photoactivation than a continuous flow of photons. Because of the differential photoactivation efficiency, it is crucial to assess photoactivation efficiency for any given experimental set-up. The tools we provide can be applied to any genetically encoded photoactivatable protein. Determination of photoactivation efficiency is essential for an understanding of absolute molecule numbers in ensemble studies and, most importantly, quantitative superresolution imaging. (c) 2017 International Society for Advancement of Cytometry. PMID- 29286575 TI - MYH9-macrothrombocytopenia caused by a novel variant (E1421K) initially presenting as apparent neonatal alloimmune thrombocytopenia. AB - MYH9-related disease is a rare cause of thrombocytopenia. We report an infant girl who presented with severe thrombocytopenia at birth and was initially diagnosed with and treated for neonatal alloimmune thrombocytopenia. However, persistent thrombocytopenia led to the suspicion of congenital thrombocytopenia and subsequent identification of a novel variant in MYH9 (E1421K). In silico analysis strongly predicts that this is a disruptive substitution. Immunofluorescent analysis of neutrophils demonstrates abnormal aggregates of MYH9 protein. This case also suggests that a very high immature platelet fraction (>=40%) may be useful for rapidly differentiating MYH9-related disease from other causes of neonatal thrombocytopenia. PMID- 29286577 TI - OMIP-043: Identification of human antibody secreting cell subsets. PMID- 29286576 TI - Cytoreductive surgery and hyperthermic intraperitoneal perfusion with chemotherapy in children with peritoneal tumor spread: A French nationwide study over 14 years. AB - BACKGROUND: Efficacy and role of cytoreductive surgery (CRS) and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) remain poorly documented in pediatric tumors. METHODS: This retrospective national study analyzed all pediatric patients with peritoneal tumor spread treated by CRS and HIPEC as part of a multimodal therapy in France from 2001 to 2015. RESULTS: Twenty-two patients (nine males and 13 females) were selected. The median age at diagnosis was 14.8 years (4.2-17.6). Seven had peritoneal mesotheliomas; seven, desmoplastic small round cells tumors (DSRCT); and eight, other histologic types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 (73%) cases. Incomplete resections were classified as CC-1 in four (18%) cases and CC-2 in two (9%) cases. Fourteen (64%) patients had complications within 30 days from HIPEC, requiring an urgent laparotomy in eight (36%) cases. Thirteen (59%) patients received adjuvant chemotherapy and four (18%) received total abdominal radiotherapy after surgery. Sixteen (72%) patients had relapse after a median time of 9.6 months (1.4-86.4) and nine (41%) eventually died after a median time of 5.3 months (0.1-36.1) from relapse. Six (27%) patients (four mesotheliomas, one pseudopapillary pancreatic tumor, and one DSRCT) were alive and in complete remission after a median follow-up of 25.0 months (5.3-78.2). The mean overall survival (OS) and disease-free survival (DFS) were 57.5 months (95% CI [38.59-76.32]) and 30.9 months (95% CI [14.96-46.77]). Patients with a peritoneal mesothelioma had a significantly better OS (p = 0.015) and DFS (p = 0.028) than other histologic type. CONCLUSIONS: In this national series, outcomes of HIPEC are encouraging for the treatment of peritoneal mesothelioma in children. PMID- 29286578 TI - RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. AB - RNA transcript expression estimates are a promising method to study the mechanisms and classification of renal allograft rejections. Here we use the Nanostring platform to profile RNA expression in renal allografts in a nonhuman primate (NHP), the Cynomolgus monkey. We analyzed protocol and indication 278 archival renal allograft samples, both protocol and indication from 76 animals with diagnoses of chronic antibody-mediated rejection (CAMR), acute cellular rejection (TCMR), and MIXED (both CAMR and TCMR), plus normals and samples with no pathological rejection using a Cynomolgus-specific probe set of 67 genes. Analysis identified RNA expression heterogeneity of endothelial and NK genes within CAMR and TCMR, including the stages of CAMR. Three factors were partitioned into additional groups. One group with the longest allograft survival time is pure CAMR without NK or CD3. Three mixed groups show variation in NK and CD3. TCMR was split into 2 groups with variation in NK genes. Additional validation of the complete gene-set correlated many of the genes with diagnoses of CAMR, MIXED, and TCMR rejections and with Banff histologic criteria defined in human subjects. These NHP data demonstrate the utility of RNA expression profiling to identify additional heterogeneity of endothelial and NK RNA gene expressions. PMID- 29286579 TI - Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients. AB - Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area. PMID- 29286580 TI - Optimization for imaging through scattering media for confocal microscopes with divided elliptical apertures. AB - We develop a confocal system equipped with optimal elliptical apertures to improve axial point spread function and signal-to-background ratio (SBR) for different detector sizes. By adjusting the parameters of the elliptical apertures, the axial half width at half-maximum can be reduced to 4.986 (described in optical coordinates) and SBR can be improved to 0.176. We evaluate this system with the 1951 USAF resolution test chart and the primary cultured neuron from SD rat stained by Map-2, and observe better imaging performance, which indicates the potential applications in biological science. PMID- 29286581 TI - Bone marrow features in Pearson syndrome with neonatal onset: A case report and review of the literature. AB - Pearson syndrome (PS) is a rare mitochondrial disorder that usually presents with transfusion-dependent macrocytic anemia, exocrine pancreatic dysfunction, and lactic acidosis. Typical bone marrow (BM) features are vacuolization in hematopoietic progenitors, hypocellularity, and ringed sideroblasts. At the neonatal age, PS may have a variable clinical onset. Moreover, there is little information about BM features at this age and the timing of their presentation. We report a neonatal case of PS that presented with refractory anemia and atypical BM features. We reviewed the BM findings in neonatal-onset PS cases to stress the importance and limitations of BM evaluation at this age. PMID- 29286582 TI - Alveolar soft part sarcoma in children and adolescents: The European Paediatric Soft Tissue Sarcoma study group prospective trial (EpSSG NRSTS 2005). AB - BACKGROUND: As alveolar soft part sarcomas (ASPS) are rare with no prospective series within pediatric sarcoma trials, the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) examined the clinical data and outcomes of ASPS enrolled in a multinational study of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). PATIENTS AND METHODS: Twenty-two patients with ASPS were enrolled into the EpSSG NRSTS 2005 study. After surgical resection, subsequent treatment depended on the stratification of patients for completeness of resection and Intergroup Rhabdomyosarcoma Study (IRS) stage, size, and French Federation of Cancer Centres Sarcoma Group (FNCLCC) grade. Chemotherapy using ifosfamide and doxorubicin was performed in IRS group III. Radiotherapy was performed in IRS groups II and III, and FNCLCC grades 2 and 3 tumors. RESULTS: The median age at diagnosis was 11.5 years (range 2.7-17.5 years). The majority in the series had localized disease (20), with small IRS I tumors (12), and in total 19 had surgical resection upfront. Of the four patients who received conventional chemotherapy, there were no responses. Three of 20 patients with localized tumors and all metastatic patients developed metastases. The median follow up of patients with localized disease is 61.7 months (range 25.7-135.5 months) from diagnosis. The 5-year event-free survival is 94.7% (95% confidence interval: 68.1 99.2), and therefore the overall survival (OS) is 100%. CONCLUSION: This report demonstrates the ability to run prospective pediatric studies in NRSTS in multiple European countries, despite the small numbers of ASPS patients. We can conclude that for the majority with small resected tumors, there were few events and no deaths. PMID- 29286583 TI - Chemical Valence-Dependent Electrocatalytic Activity for Oxygen Evolution Reaction: A Case of Nickel Sulfides Hybridized with N and S Co-Doped Carbon Nanoparticles. AB - Exploration of the relationship between electrocatalytic activities and their chemical valence is very important in rational design of high-efficient electrocatalysts. A series of porous nickel sulfides hybridized with N and S co doped carbon nanoparticles (Nix Sy -NSCs) with different chemical valences of Ni, Ni9 S8 -NSCs, Ni9 S8 -NiS1.03 -NSCs, and NiS1.03 -NSCs are successfully fabricated, and their electrocatalytic performances as oxygen evolution reaction electrocatalysts are systematically investigated. The Nix Sy -NSCs are obtained via a two-step reaction including a low-temperature synthesis of Ni-Cys precursor followed by thermal decomposing of the precursor in Ar atmosphere. By controlling the sulfidation process during the formation of Nix Sy -NSCs, Ni9 S8 -NSCs, Ni9 S8 -NiS1.03 -NSCs, and NiS1.03 -NSCs are obtained, respectively, giving rise to the increase of high-valence Ni component, and resulting in gradually enhanced oxygen evolution reaction electrocatalytic activities. In particular, the NiS1.03 -NSCs show an exceptional low overpotential of ~270 mV versus reversible hydrogen electrode at a current density of 10 mA cm-2 and a small Tafel slope of 68.9 mV dec-1 with mass loading of 0.25 mg cm-2 in 1 m KOH and their catalytic activities remained for at least 10 h, which surpass the state-of-the-art IrO2 , RuO2 , and Ni-based electrocatalysts. PMID- 29286584 TI - Selective Hydrodeoxygenation of Alkyl Lactates to Alkyl Propionates with Fe-based Bimetallic Supported Catalysts. AB - Hydrodeoxygenation (HDO) of methyl lactate (ML) to methyl propionate (MP) was performed with various base-metal supported catalysts. A high yield of 77 % MP was obtained with bimetallic Fe-Ni/ZrO2 in methanol at 220 degrees C and 50 bar H2 . A synergistic effect of Ni increased the yield of MP significantly when using Fe-Ni/ZrO2 instead of Fe/ZrO2 alone. Moreover, the ZrO2 support contributed to improve the yield as a phase transition of ZrO2 from tetragonal to monoclinic occurred after metal doping giving rise to fine dispersion of the Fe and Ni on the ZrO2 , resulting in a higher catalytic activity of the material. Interestingly, it was observed that Fe-Ni/ZrO2 also effectively catalyzed methanol reforming to produce H2 in situ, followed by HDO of ML, yielding 60 % MP at 220 degrees C with 50 bar N2 instead of H2 . Fe-Ni/ZrO2 also catalyzed HDO of other short-chain alkyl lactates to the corresponding alkyl propionates in high yields around 70 %. No loss of activity of Fe-Ni/ZrO2 occurred in five consecutive reaction runs demonstrating the high durability of the catalyst system. PMID- 29286585 TI - Blocking transferrin receptor inhibits the growth of lung adenocarcinoma cells in vitro. AB - BACKGROUND: Transferrin receptor (TfR) is expressed in most lung cancers and is an indicator of poor prognosis in certain groups of patients. In this study, we blocked cell surface TfR to inhibit lung adenocarcinoma (LAC) cell growth in vitro and investigated the associated molecular mechanisms to determine a potential therapeutic target in human LAC. METHODS: RNA interference and antibody blocking techniques were used to block the function of TfR in LAC cells, and cell proliferation assays were used to detect the results. Affymetrix microarray analysis was conducted using H1299 cells in which TfR was blocked with an antibody to investigate the molecular mechanisms involved. RESULTS: The cell proliferation assay demonstrated that H1299 cell proliferation was significantly inhibited after small interfering RNA knockdown or blocking of TfR. Mechanistic studies found that 100 genes were altered more than two-fold after TfR was blocked and that blocking TfR was accompanied by decreased expression of the oncogene KRAS. CONCLUSION: Our data provide evidence that blocking TfR could significantly inhibit LAC proliferation by targeting the oncogene KRAS; therefore, TfR may be a therapeutic target for LAC. In addition, our results suggest a new method for blocking the signal from the oncogene KRAS by targeting TfR in LAC. PMID- 29286586 TI - Cognitive enhancement therapy for adult autism spectrum disorder: Results of an 18-month randomized clinical trial. AB - : Cognitive remediation is a promising approach to treating core cognitive deficits in adults with autism, but rigorously controlled trials of comprehensive interventions that target both social and non-social cognition over a sufficient period of time to impact functioning are lacking. This study examined the efficacy of cognitive enhancement therapy (CET) for improving core cognitive and employment outcomes in adult autism. Verbal adult outpatients with autism spectrum disorder (N = 54) were randomized to an 18-month, single-blind trial of CET, a cognitive remediation approach that integrates computer-based neurocognitive training with group-based training in social cognition, or an active enriched supportive therapy (EST) comparison focused on psychoeducation and condition management. Primary outcomes were composite indexes of neurocognitive and social-cognitive change. Competitive employment was a secondary outcome. Intent-to-treat analyses indicated that CET produced significant differential increases in neurocognitive function relative to EST (d = .46, P = .013). Both CET and EST were associated with large social-cognitive improvements, with CET demonstrating an advantage at 9 (d = .58, P = 0.020), but not 18 months (d = .27, P = 0.298). Effects on employment indicated that participants treated with CET were significantly more likely to gain competitive employment than those in EST, OR = 6.21, P = 0.023, which was mediated by cognitive improvement. CET is a feasible and potentially effective treatment for core cognitive deficits in adult autism spectrum disorder. The treatment of cognitive impairments in this population can contribute to meaningful improvements in adult outcomes. Autism Res 2018, 11: 519-530. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Cognitive enhancement therapy (CET), an 18-month cognitive remediation intervention designed to improve thinking and social understanding, was found to be more effective than supportive therapy at improving mental quickness, attention, and employment in adults living with autism. Social understanding was equally improved in CET and supportive therapy. Cognitive remediation interventions are feasible and may confer significant functional benefits to adults with autism. PMID- 29286588 TI - Epidemiology and Economic Burden of Serotonin Syndrome With Concomitant Use of Serotonergic Agents: A Retrospective Study Utilizing Two Large US Claims Databases. AB - Objective: Serotonin syndrome (SS) is an adverse drug reaction occurring among patients receiving serotonergic agents (SAs), and although SAs are commonly prescribed, the epidemiology and economic burden of SS with concomitant SA use have not been comprehensively examined. The objective of this study was to investigate the prevalence, incidence, and economic burden of SS with SA use. Methods: A retrospective cohort study was conducted using Veterans Health Administration (VHA) records (identification period: October 1, 2008-September 30, 2012) and commercially insured patient records (Intercontinental Marketing Services PharMetrics Plus; identification period: January 1, 2010-December 31, 2013). Cohorts were based on drug classification and exposure: single monoamine oxidase inhibitor (MAOI), MAOIs in combination with SAs, single non-MAOI SA, and multiple non-MAOI SAs (2, 3, 4, >= 5). Participants were aged >= 18 years with continuous health plan enrollment for 12 months prior to the first SA claim. Outcomes were SS events (ICD-9-CM: 333.99), annual incidence and prevalence, related health care utilization and costs, and SS incidence relative risk. Results: Over 15 million patients were identified and categorized by SA prescription type. SS incidence in both populations decreased: 0.19%-0.07% (VHA) and 0.17%-0.09% (commercially insured). Overall SS prevalence decreased during the study period. Compared to single non-MAOI SA patients, SS incidence relative risk was highest among patients prescribed >= 5 non-MAOI SAs. Inpatient stays accounted for 4.35% (VHA) and 0.88% (commercially insured) of all SS events. Of SS-related inpatient stays, median costs were $8,765 (VHA) and $10,792 (commercially insured). Conclusions: SS incidence and prevalence and SS-related hospitalization risk among patients prescribed SAs were low in both populations. This study provides additional information regarding SS risk associated with SA use. PMID- 29286587 TI - Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death. AB - In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2-HDAC binding agents. Compound 3 [(E)-N-hydroxy-5-(3-(4 (3-oxo-3-(pyridin-3-yl)prop-1-en-1-yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC50 =13.3+/-1.5 MUm, HDAC1 IC50 =3.38+/-0.14 MUm, HDAC6 IC50 =4.10+/ 0.13 MUm) and in cell-based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 MUm and protects neurons against toxic insults induced by glutamate (5 mm) with an EC50 value of 3.7+/-0.5 MUm. PMID- 29286589 TI - Are Psychiatric Inpatients at Risk of Developing Wernicke's Encephalopathy Being Identified and Adequately Treated? AB - Objective: Wernicke's encephalopathy is caused by thiamine deficiency and occurs predominantly in alcohol-dependent individuals but also develops in those who are malnourished due to other reasons including medical and psychiatric disorders. This study examined the frequency rate and management of Wernicke's encephalopathy in alcohol-dependent and non-alcohol-dependent patients admitted to a psychiatric hospital. Methods: Data were retrospectively collected from electronic medical records of psychiatric inpatients admitted to a teaching hospital located in Texas between September 2013 and March 2014. The diagnostic criteria of Caine and colleagues and thiamine dosing strategies were used to identify cases of suboptimal management. Results: A total of 486 charts were reviewed. Nine patients (1.85%) had clinical signs of Wernicke's encephalopathy, and 36 (7%, n = 486) were at a high risk for developing the disorder. None of these patients received adequate doses of parenteral thiamine, and of those who were prescribed thiamine, the majority, including high-risk patients, were prescribed oral thiamine at the traditional dose of 100 mg/d. Conclusions: The findings suggest that Wernicke's encephalopathy is underdiagnosed and undertreated. Our study also highlights the need for clarifying diagnostic criteria, identifying the risk factors for thiamine deficiency, and improving awareness among physicians about diagnosis, prevention, and adequate treatment of Wernicke's encephalopathy in alcohol-dependent and non-alcohol-dependent patients. PMID- 29286590 TI - The Association Between Sleep Apnea and Suicidal Thought and Behavior: An Analysis of National Survey Data. AB - OBJECTIVE: Sleep disturbances have been associated with increased risk for suicidal thought and behavior. The literature in regard to sleep and suicide, however, has focused predominantly on generalized sleep disturbance or insomnia. The purpose of the current study is to examine relationships among sleep apnea and suicidal thought and behavior using a nationally representative sample. METHODS: We conducted a secondary analysis of 2014 data from the National Survey on Drug Use and Health. Respondents from a random sample of US households who were 18 years or older (N = 40,149) completed an interview including items assessing past-year sleep apnea, suicidal ideation, suicide planning, and suicide attempt. RESULTS: Among respondents with sleep apnea (2.9%; n = 1,155), prevalence of suicidality was reported to be 9.7% for suicidal ideation, 3.4% for suicide planning, and 1.0% for suicide attempt compared with 4.9%, 1.4%, and 0.7%, respectively, for those without sleep apnea. Multiple logistic regression analyses revealed that sleep apnea was significantly associated with both suicidal ideation (OR = 1.50; 95% CI, 1.18-1.91) and suicide planning (OR = 1.56; 95% CI, 1.08-2.26) after controlling for age, sex, ethnicity, past-year substance use disorder, self-rated overall health, past-year sedative-hypnotic misuse, past year depressive episode, heart disease, high blood pressure, stroke, diabetes, and body mass index. Sleep apnea was not significantly associated with report of past-year suicide attempt (OR = 1.22; 95% CI, 0.66-2.26). CONCLUSIONS: Suicidal ideation and suicide planning were more likely to be endorsed by respondents with sleep apnea compared to those without after accounting for key covariates. Diagnosis of sleep apnea may represent an early opportunity for providers to discuss suicide and mental health with their patients. PMID- 29286591 TI - Repeated Low-Grade Infections Predict Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study. AB - BACKGROUND: The relationship between severe inflammation and clinical depression in the context of major medical illnesses has been addressed, but the relationship between inflammation caused by mild infections and clinical depression is unclear. We aimed to examine whether a history of repeated low grade infections (RLGI) in medically healthy subjects (MHS) could increase their vulnerability to major depressive disorder (MDD) (ICD-9-CM) and whether RLGI could be associated with higher resistance to antidepressants in those developing MDD. METHOD: A nationwide, population-based cohort study (January 1996 to December 2011) was conducted for MHS with and without a history of RLGI. The rates of MDD during an up to 8-year follow-up period were compared between the 2 groups in 2 independent cohorts. The stratified responses to adequate antidepressant trials, including easy-to-treat (ETT) and difficult-to-treat (DTT) responses, were also compared in the MDD patients. RESULTS: During the follow-up, the 2 cohorts consistently revealed that the RLGI(+) (ie, high-inflammation; n = 727) group had a significantly higher chance of developing MDD over time than the RLGI(-) (ie, low-inflammation; n = 443) group: Cox proportional hazards regression models showed that the hazard ratio associated with a history of RLGI was 1.369 to 1.911 (P < .001), after adjusting for confounding factors. The RLGI(+) group was consistently associated with a higher likelihood of DTT responses than was the RLGI(-) group (Cohort-2002: 11.5% vs 7.6%; Cohort-2004: 11.8% vs 4.3%; P < .05 by Wald chi2 tests in both cohorts). CONCLUSIONS: This is the first large-scale retrospective cohort study to report a reliable temporal association between a history of RLGI and subsequent diagnosis of MDD and poor responses to antidepressants in 2 independent cohorts. Our data support the view that repeated mild infections play a role in the pathophysiology of MDD and antidepressant-resistant depression. PMID- 29286592 TI - Duty to Warn When There Is Accidental Exposure of a Psychiatrist's Residential Address to a Patient With Homicidal Ideation. PMID- 29286593 TI - Circadian Rhythm Sleep-Wake Disorders Predict Shorter Time to Relapse of Mood Episodes in Euthymic Patients With Bipolar Disorder: A Prospective 48-Week Study. AB - OBJECTIVE: Circadian rhythm dysfunction has been considered to be common in bipolar disorder (BD) and plays an important role in mood dysregulation in this disorder. However, no study has investigated whether circadian rhythm dysfunction would affect the clinical course of BD. The aim of this study was to test the hypothesis that circadian rhythm dysfunction could be a predictor of relapse in euthymic BD patients. METHODS: One hundred four euthymic outpatients with BD diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), participated in this prospective follow up study from August 2014 to April 2015. At baseline, data on demographic variables and clinical descriptive variables of bipolar disorder were ascertained via clinical interviews. The diagnoses of circadian rhythm sleep-wake disorders (CRSWDs) were made based on participants' sleep logs for 4 weeks and according to the International Classification of Sleep Disorders, Third Edition (ICSD-3). The BD symptoms of the subjects were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores every 4 weeks throughout the 48-week study period. Relapse of BD was defined as scores higher than the cutoff points (MADRS score >= 13 and YMRS score >= 7). The primary outcome was time to relapse of mood episodes. RESULTS: Thirty-four subjects met criteria for CRSWD at baseline, most frequently delayed sleep-wake phase disorder (n = 27). Of the total 104 subjects, 51 (49.0%) experienced relapse during the 48 week follow-up period. Multivariate Cox hazard regression analyses revealed that 2 or more previous mood episodes within the past year and comorbidity of CRSWD were significantly associated with the time to relapse of mood episodes (P < .001). CONCLUSIONS: Comorbid CRSWD, mainly delayed sleep-wake phase disorder, could be a significant predictor of relapse in BD patients. PMID- 29286594 TI - Circadian Rhythm and the Prediction of Relapse in Bipolar Disorder. PMID- 29286597 TI - Due Diligience for Independent Practice: an introductory overview. PMID- 29286596 TI - Physician Sexual Misconduct: Regulations and ramifications in the state of New Jersey. PMID- 29286598 TI - A Case Note Regarding Force-Feeding of Anorexic Patients and the Right to Die. PMID- 29286595 TI - Galantamine and Computerized Cognitive Behavioral Therapy for Cocaine Dependence: A Randomized Clinical Trial. AB - OBJECTIVE: To examine whether galantamine, a cognitive-enhancing medication that is both acetylcholinesterase inhibitor and agonist at nicotinic acetylcholine receptors, is effective at improving cocaine use outcomes and cognitive functioning, alone and in combination with computerized cognitive behavioral therapy (CBT). METHOD: A 12-week, randomized 2 * 2, factorial trial was conducted to evaluate galantamine versus placebo (double-blind) and computerized CBT plus standard methadone treatment versus standard methadone treatment alone in a community-based methadone maintenance program (September 2009-April 2015). One hundred twenty individuals diagnosed with DSM-IV cocaine use disorder were randomly assigned to the following conditions: (1) galantamine (8 mg/d) plus standard methadone maintenance treatment (treatment as usual [TAU]), (2) placebo plus TAU, (3) galantamine plus computerized CBT plus TAU, or (4) placebo plus computerized CBT plus TAU; medication administration was supervised at the time of daily methadone dosing. The primary cocaine use outcome was change in percent days of abstinence over time. Number of cocaine-negative urine toxicology screens submitted and cognitive function were secondary outcomes. RESULTS: Random effect regression analysis indicated significant reductions in frequency of cocaine use over time, with significant treatment-by-time effects for both galantamine over placebo (F = 5.3, P = .02, d = 0.34) and computerized CBT over standard methadone treatment (F = 4.2, P = .04, d = 0.30) but no evidence of significant benefit of the combination over either treatment alone. Pretreatment to posttreatment comparisons of multiple indices of cognitive functioning, including sustained attention, indicated no benefit of galantamine over placebo. CONCLUSIONS: Findings suggest benefits of galantamine and computerized CBT for reducing cocaine use in this sample. Although galantamine did not improve measures of cognitive function in this sample, multiple measures of cognitive function were associated with cocaine use outcomes, underlining the significance of cognitive function in cocaine treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00809835. PMID- 29286599 TI - Legislative UpdateL new jersey election preview and recent healthcare legislation. PMID- 29286600 TI - Looking Back: Timeless communication and leadership tips. PMID- 29286601 TI - Identifying and Treating Sepsis Early Can Save Lives. PMID- 29286602 TI - An Interview with David B. Nash, MD, MBA: a perspective on population health and the future direction of healthcare. PMID- 29286603 TI - Getting the Ring(Worm): how a nightclub experience taught me the importance of interprofessional communication in healthcare. PMID- 29286605 TI - Treatment-Related Quality of Life in Nepalese Women with Breast Cancer AB - Objective: To identify the level of quality of life and its predictors in Nepalese women with breast cancer whilereceiving chemotherapy. Methods: This cross-sectional study with a predictive design was conducted for a convenientlyselected sample of 85 Nepalese women with primary breast cancer receiving chemotherapy at outpatient clinics of threecancer hospitals of Kathmandu, Nepal. Data were collected during December 2016 and February 2017 using demographicsheets, the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire and themodified Medical Outcomes Study Social Support Survey. Descriptive and inferential statistics were employed fordata analysis. Results: The mean age of the sample was 50.2 years (SD = 11.50). Study participants reported moderateto poor quality of life (M = 33.5, SD = 23.5). Multiple regression analysis showed that age, years of education, stage,past breast surgery, overall symptom severity, and social support significantly explained 56.8% of the variance inquality of life (R2 = .568, F (8,76) = 12.469, p = .000). However, overall symptom severity (beta = -.477, p= .000) andsocial support (beta = .183, p = .050) were the most important predictors. Conclusions: As Nepalese women reporteddecreased quality of life, nurses should provide preventive and supportive services to improve the quality of life oftheir patients during chemotherapy. PMID- 29286604 TI - Protein-Protein Interaction Network Analysis for a Biomarker Panel Related to Human Esophageal Adenocarcinoma AB - Background: Esophageal adenocarcinoma (EAC) is one of the mostlethal cancers in the world with a very poorprognosis. Identification of molecular diagnostic methods is an important goal. Since protein-protein interaction (PPI)network analysis is a suitable method for molecular assessment, in the present research a PPI network related to EACwas targeted. Material and Method: Cytoscape software and its applications including STRING DB, Cluster ONEand ClueGO were applied to analyze the PPI network. Result: Among 182 EAC-related proteins which were identified,129 were included in a main connected component. Proteins based on centrality analysis of characteristics such asdegree, betweenness, closeness and stress were screened and key nodes were introduced. Two clusters were determinedof which only one was significant statistically. Gene ontology revealed 50 terms in three groups associated with EAC.Conclusion: The findings indicate nine crucial proteins could form a candidate biomarker panel for EAC. Furthermore,an important cluster with 27 proteins related to the disease was identified. Gene ontology analysis of this cluster showedmain related terms to closely correspond with those for colorectal cancer. PMID- 29286607 TI - Limited Understanding of Pap Smear Testing among Women, a Barrier to Cervical Cancer Screening in the United Arab Emirates AB - Global data indicate that cervical cancer is the fourth most common cancer among women worldwide. Importantfactors that affect interventions for early diagnosis of cervical cancer include social beliefs and values and poorknowledge. These may contribute to women's participation in screening for cervical cancer and have a significantimpact on decisions to take preventive action. The present study was conducted with 599 women in the UAE betweenSeptember 2016 and March 2017. A cross sectional survey was conducted to determine knowledge about cervical cancerand screening, demographic characteristics and perceived barriers. Knowledge about the Pap smear test was limited,and awareness that they should undergo the Pap smear test every three years even with an initial negative/normal Papsmear result was abysmal. In spite of the positive attitude of the women towards the Pap smear test, almost 80% ofthe women surveyed had no knowledge of precancerous lesions. Having higher income (21/29, 72%, p=0.027) andmore miscarriages were associated with better practice of Pap smears (19/26, 73%, p=0.010). Knowledge levels weresignificantly higher (66.3+/-22.2,) that values for attitude (60.5+/-20.9, p= 0.03, 95% CI {0.22-11.3}, Chi-square 4.38) andpractice (53.7 24.1, p= 0.001, 95% CI {6.9-18.1}, Chi-square 19.7). A well-designed health education programme oncervical cancer and benefits of screening should increase the awareness among women in UAE. One point to stress isthat better communication with health professionals and improvement of access to health care services should increasethe rate of cervical cancer screening. PMID- 29286606 TI - Human Papilloma Virus Genotype Distribution in Cervical lesions in Zanjan, Iran AB - Objective: Cervical cancer is one of the most common cancers among women all over the world, and main causeis persistent infection with high risk human papillomavirus (HPV) strains. It has been reported that the distributionand prevalence of HPV types varies by geographical region, so that this is important for prevention by type-specificvaccines. The aim of current study was to determine the genotype distribution of HPV using the INNO-LiPA genotypingassay in Zanjan province, North West Iran. Methods: A total of 112 formalin-fixed paraffin embedded (FFPE) tissuesamples from cases of low-grade intraepithelial lesion (LSIL), high-grade intraepithelial lesion (HSIL) and squamouscell carcinoma (SCC) were collected. The polymerase chain reaction (PCR) was used to amplify DNA for genotyping.Results: Among the 112 samples from females (ranging from 20 to 69 years, mean age 43.8 +/- 10.1) tested for HPVDNA, 50 samples were positive. Based on results of genotyping, most common HPV genotypes were HPV18 (48%)followed by HPV-6 (24%), HPV73 (16%), HPV-51(8%), HPV-31(8%), HPV-16 (8%), HPV-56 (4%), HPV 44 (4%).Conclusion: While HPV infection is the major etiological factor for cervical cancer, presence was relatively low inour survey. In the positive cases, however, HPV18 was the most common in line with many other populations. The factthat types vary among different populations must clearly be taken into account in design of vaccines for our country. PMID- 29286608 TI - Cox Regression and Parametric Models: Comparison of How They Determine Factors Influencing Survival of Patients with Non-Small Cell Lung Carcinoma AB - Background and objectives: The present study of survival rate of patients with non-small cell carcinoma (NSCLC)compared the efficiency of Cox semi-parametric vs. parametric models in determination of influencing factors. Methods:In this retrospective cohort study, data were gathered from 190 patients with a confirmed diagnosis of NSCLC referredto Shahid Sadoughi and Shohadaye Kargar Hospitals in Yazd, Iran during 2005 to 2014. To identify and compare factorsinfluencing the survival rate, a Cox semi-parametric model was fitted to the data. Data analysis was performed usingthe R software version R3.3.1, and the significance level was set at 0.05. Results: The average age was 64.5 years.About 40% of patients had stage 4 disease. The median survival was 8 months. After comparing the models, the moreefficient was the log-normal distribution (AIC=889.3829), with which disease stage, type of therapy, and age weresignificant factors. Among the different types of therapy, chemotherapy and radiotherapy yielded higher survival rates,and increased age was associated with lower survival. Conclusion: The most efficient model was a log-normal model.Implementation of optimal therapies at early stages can improve the survival of patients. PMID- 29286609 TI - Lung Lesion Detection in CT Scan Images Using the Fuzzy Local Information Cluster Means (FLICM) Automatic Segmentation Algorithm and Back Propagation Network Classification AB - Lung cancer is a frequently lethal disease often causing death of human beings at an early age because of uncontrolledcell growth in the lung tissues. The diagnostic methods available are less than effective for detection of cancer. Thereforean automatic lesion segmentation method with computed tomography (CT) scans has been developed. However it isvery difficult to perform automatic identification and segmentation of lung tumours with good accuracy because ofthe existence of variation in lesions. This paper describes the application of a robust lesion detection and segmentationtechnique to segment every individual cell from pathological images to extract the essential features. The proposedtechnique based on the FLICM (Fuzzy Local Information Cluster Means) algorithm used for segmentation, withreduced false positives in detecting lung cancers. The back propagation network used to classify cancer cells is basedon computer aided diagnosis (CAD). PMID- 29286610 TI - Cancer Mortality, Early Detection and Treatment among Adult New Zealanders: Changes in Perceptions between 2001 and 2014/5 AB - Background: Beliefs about cancer risk and experience of early detection and treatment can impact on willingnessto engage with these initiatives. This study describes changes in perceptions of cancer mortality, early detection andtreatment among adult New Zealanders (NZ) between two cross-sectional studies conducted in 2001 and 2014/5.Methods: Data was collected via telephone interviews conducted by trained interviewers in 2001 (231 females and207 males, 64% response rate) and 2014/5 (588 females and 476 males, 64% response rate). Participants were askedto identify the most common three causes of cancer mortality among women and then men. They were also asked tonote their agreement or otherwise with statements about early detection and treatment of cancer. Results: There was anincrease in proportions of men who correctly identified prostate cancer as one of the top three causes of cancer mortalityamong men, and also an increase among women who correctly identified bowel cancer as one of the top three. Mostparticipants agreed that there were benefits from early detection for cancer outcomes. Over time, there was a significantdecline in proportions which felt that most cancer treatment is "so terrible it is worse than death" and that alternativetherapy has an "equal or better chance of curing cancer." Conclusion: Internationally, there is little information availableabout changes in cancer perceptions over time, these findings suggest some changes in perceptions of treatment andawareness of types of cancer with the highest mortality in NZ, which should support timely engagement with earlydetection and treatment services. PMID- 29286611 TI - Descriptive Epidemiology of Cancers in Togo from 2009 to 2016 AB - Background: Cancer is a global public health problem. According to World Report on Cancer in 2000, developingcountries are becoming increasingly affected. Methods: This retrospective and descriptive 8-year study of all histologicalconfirmed cancers was conducted using data from the anatomical pathology laboratory registry of Togo's only laboratory.The parameters were frequency, site and histological type as well as age and gender. Results: We found 1,738 cancers inpatients aged from 4 months to 109 years (mean, 50.4 +/- 4. The sex ratio (M/F) was 1.3. The most frequent localizationsof the cancers were the prostate (10.3%) followed by the breast (9.9%), the stomach (8.4%) and the cervix (7.2%). Inwomen, the median age was 47.4 +/- 2.9 years, and the most common cancers were breast cancer (21.2%), followedby cervical cancer (16.3%). In men, the median age was 53.2 +/- 7.3 years and the most frequent cancers were prostatecancer (18.5%), non-Hodgkin's lymphoma (13.2%) and stomach cancer (10.7%). In children, Burkitt's lymphoma(41.8%), retinoblastoma (11.6%) and nephroblastoma (9.6%) were the most important cancers. Conclusion: Cancersare frequent in Togo, those of the prostate, breast and cervix being most important with a worse prognosis. Emphasisshould be placed on early detection and diagnosis. PMID- 29286612 TI - Unexpected Lower Expression of Oncoprotein Gankyrin in Drug Resistant ABCG2 Overexpressing Breast Cancer Cell Lines AB - Background: Development of a multidrug resistance (MDR) phenotype to chemotherapy remains a major barrier inthe treatment of cancer. Gankyrin (p28, p28GANK or PSMD10) is an oncoprotein overexpressed in different carcinomacell lines. The aim of this study was to compare Gankyrin expression level in MDR cells (MCF-7/ADR and MCF-7/MX) and non-MDR counterparts (MCF-7). Methods: Gankyrin, MDR1 (also known as ABCB1; the ATP-bindingcassette sub-family B member 1) and ABCG2 (also known as BCRP; the human breast cancer resistance protein)mRNA levels were analyzed by real-time RT-PCR. Western blot analysis was used to detect the protein expressionlevels of Gankyrin. Results: The PCR results showed that the expression of Gankyrin was significantly lower in theABCG2 overexpressing cell line MCF-7/MX than in non-resistanct MCF-7 cells. In contrast, there were no significantdifferences in mRNA expression of Gankyrin in the MDR1 overexpressing cell line MCF-7/ADR in comparison withMCF-7 cells. Similarly, Western blot analysis confirmed lower expression of Gankyrin protein in the MCF-7/MX cellline (26% compared to controls) but not in MCF-7/ADR cells. Conclusion: These findings showed that there may bea relation between down-regulation of Gankyrin and overexpression of ABCG2 but without any clear relationship withMDR1 expression in breast cancer cell lines. PMID- 29286613 TI - Vitamin D Deficiency Associated with Differentiated Thyroid Carcinoma: A Case- Control Study AB - Objective: In recent decades, the incidence of thyroid cancer has increased throughout the world. It is unclearwhether factors such as vitamin D deficiency may have been involved in this increase. The present case-control studywas conducted to examine any association between Vitamin D deficiency and thyroid cancers. Methods: The studywas conducted on 85 patients with differentiated thyroid cancer diagnosed based on fine needle aspiration biopsy as thecase group and 85 healthy controls. Serum levels of vitamin D were evaluated before thyroidectomy. For each patient inthe case group, one healthy euthyroid person without any thyroid nodules from the general population matched basedon season, sex, age (+/- 1 year) and BMI (+/- 1) was selected. Finally, 85 pairs were obtained considering inclusion andexclusion criteria. Thyroid function, thyroid antibodies and serum vitamin D were assessed and thyroid sonographywas performed in all participants. Results: In the patient group, 72 (85%) were female and 13 (15%) were male. Themean (SD) serum vitamin D level was 8.00 (+/-3.7) in patient group, as compared to 13.4 (+/-7.90) in the control group,the difference being significant (OR: 6, 95 % CI: 1.02-113.3; P=0.046). Conclusion: A significant association wasnoted between vitamin D deficiency and differentiated thyroid cancer. Further studies with a prospective design arenecessary to further define the roles of this factor. PMID- 29286614 TI - TP53 Gene Pro72Arg (rs1042522) Single Nucleotide Polymorphism as Not a Risk Factor for Colorectal Cancer in the Iranian Azari Population AB - Background: The p53 protein participates critically in several cellular functions such as cell growth and DNArepair. Polymorphisms in the TP53 locus have repeatedly been implicated in the pathogenesis of cancers all over theworld. Over 200 single nucleotide polymorphisms (SNPs) have been characterized, but one well known example at atcodon 72, Pro72Arg (rs1042522), has the displayed inconsistent results with regard to cancer risk. Herein, we aimedto evaluate whether Pro72Arg (rs1042522) single nucleotide polymorphism (SNP) in TP53 gene might be associatedwith risk of colorectal cancer in the Iranian Azari population. Methods: Blood samples were taken from 100 healthycontrols and 100 colorectal cancer patients with Iranian-Azeri ethnicity. Genotyping was performed with Tetra ARMSPCR. Results: The alleles of the TP53 gene Pro72Arg SNP did not significantly differ in prevalence between patientsand controls (P>0.05). Additionally, genotypes of Pro72Arg SNP were not significantly associated with colorectalcancer risk in the studied population. Conclusions: Pro72Arg SNP of TP53 gene may not be involved in the diseasepathogenesis in Iranian Azari patients with colorectal cancer. PMID- 29286615 TI - EpCAM-based Flow Cytometric Detection of Circulating Tumor Cells in Gallbladder Carcinoma Cases AB - Purpose: Liquid biopsy has entered the arena of cancer diagnostics in the past decade and detection of circulatingtumor cells (CTC) is one diagnostic component. CTCs in gallbladder cancer (GBC) have hitherto not beencomprehensively analysed. Methods and Results: The current study focused on the diagnostic role of CTCs in 27cases of treatment-naive GBC and 6 normal controls as well as 6 cases of cholecystitis. An EasySep kit featuringnegative immunomagnetic bead separation and flow cytometric detection of EpCAM positive and CD45 negative cellsrevealed CTCs in 25 of the 27 cases. At a cut-off point of >=1, the CTC count discriminated GBC from controls with asensitivity, specificity and diagnostic accuracy of 92.6%, 91.7% and 92.3%, respectively. CTC levels in turn correlatedsignificantly with clinico-pathological parameters of cases in terms of known prognostic indicators, with significantdiagnostic potential at a cut-off point of >4, to discriminate disease stage I and II vs. III and IV GBC. With a cut-off of>3, the CTC count discriminated tumor stages I and II vs. III and IV and at >6 CTCs could discriminate metastatic vs.non metastatic GBCs with a sensitivity, specificity and diagnostic accuracy of 55. 6%, 100.0% and 85.2, respectively.A review of CTC in pancreatico-biliary malignancies is included. Conclusion: Detection and quantification of CTCsmay serve as a non-invasive biomarker for GBC diagnosis in correlation with radiological studies. PMID- 29286616 TI - Dosimetric Validation of Volumetric Modulated Arc Therapy with Three 6MV Beam Matched Linear Accelerators AB - Background: To avoid inconvenience to patients due to linear accelerator down time in busy radio-therapydepartments, treatment plans can be switched between linear accelerators provided that all exhibit the same samedosimetric characteristics. In other words linear accelerators should be beam-matched. Aim: The aim of this studywas to evaluate the clinical significance of beam-matching using VMAT plans. Materials and Methods: Dosimetricdata with a 6MV beam from am Clinac 2100CD were taken as baseline values and other two units, a 2300CD and aUnique Performance, were factory tuned in accordance. An analysis of PDD data was performed for different fieldsizes to evaluate energy matching. Beam profiles for field sizes of 10*10 cm2 and 40 * 40 cm2 at depths of 1.5 cm and10 cm were analyzed. The relative output factor and MLC dosimetric properties were compared with each machine todetermine variability among the different models. Thirty patients from our database were selected, ten each for headand neck, thorax and pelvis sites. VMAT plans were created in the Eclipse treatment planning system for a Clinac 2100CD for reference. and verification plans were created for each to compare point dose measurements. Results: The TPR20/10 for 10 * 10 cm2 was well matched, showing no energy differences. Deviation of all point dose measurements fellwithin +/-3%. Planar dose maps all showed greater than 95% of points with a passed area gamma-value less than 1. Conclusion:Our study evaluation of beam matching with treatment planning modeling showed good agreement fior 6 MV beamsacross all three linear accelerators used in our clinical environment. PMID- 29286618 TI - Cancer Detection in Microarray Data Using a Modified Cat Swarm Optimization Clustering Approach AB - Objective: A better understanding of functional genomics can be obtained by extracting patterns hidden in geneexpression data. This could have paramount implications for cancer diagnosis, gene treatments and other domains.Clustering may reveal natural structures and identify interesting patterns in underlying data. The main objective ofthis research was to derive a heuristic approach to detection of highly co-expressed genes related to cancer from geneexpression data with minimum Mean Squared Error (MSE). Methods: A modified CSO algorithm using HarmonySearch (MCSO-HS) for clustering cancer gene expression data was applied. Experiment results are analyzed usingtwo cancer gene expression benchmark datasets, namely for leukaemia and for breast cancer. Result: The resultsindicated MCSO-HS to be better than HS and CSO, 13% and 9% with the leukaemia dataset. For breast cancer datasetimprovement was by 22% and 17%, respectively, in terms of MSE. Conclusion: The results showed MCSO-HS tooutperform HS and CSO with both benchmark datasets. To validate the clustering results, this work was tested withinternal and external cluster validation indices. Also this work points to biological validation of clusters with geneontology in terms of function, process and component. PMID- 29286617 TI - Genistein and Trichostatin A Induction of Estrogen Receptor Alpha Gene Expression, Apoptosis and Cell Growth Inhibition in Hepatocellular Carcinoma HepG 2 Cells AB - Epigenetic changes such as DNA methylation and histone acetylation play important roles in determining geneexpression. Hypermethylation of CpG islands of the promoter region of tumor suppressor genes can greatly influencecarcinogenesis through transcriptional silencing. Acetylation of lysine in histone tails causes relaxation of chromatin,which facilitates gene transcription, while deacetylation is associated with condensed chromatin resulting in genesilencing. DNA demethylating agents such as genistein (GE) and histone deacetylase inhibitors (HDACIs) such astrichostatin A (TSA) may strongly reactivate silenced genes and exposure to these two agents in combination is reportedto enhance estrogen receptor alpha (ERalpha) reactivation and induction of apoptosis. The present study was designed toevaluate the effect of these compounds on ERalpha gene expression, cell viability and apoptosis in hepatocellular carcinoma(HCC) Hep G2 cells. GE exerted biphasic effects; it stimulated cell growth at a low concentration (1 MUM) but inhibitoryinfluence was noted with high concentrations (10, 20 and 40 MUM). In contrast, TSA demonstrated inhibitory effects ongrowth at all of concentrations tested. Furthermore, GE and GE/TSA significantly induced apoptosis at all concentrations,but TSA only after 72 h. GE induced ERalpha re expression and this was maximal in combined treatment groups treatedwith GE/TSA for 72 h. Discussion: Our finding clearly indicates that GE and TSA have an inhibitory cell growth,induce apoptosis and reactivate the ERalpha gene expression. Conclusion: GE and TSA can significantly inhibit the growthof HCC cells and play a significant role in apoptosis and reactivation of ERalpha gene. PMID- 29286619 TI - Comparison of Diagnostic Yield of a FISH Panel Against Conventional Cytogenetic Studies for Hematological Malignancies: A South Indian Referral Laboratory Analysis Of 201 Cases AB - Objectives: Genetic markers are crucial fort diagnostic and prognostic investigation of hematological malignancies(HM). The conventional cytogenetic study (CCS) has been the gold standard for more than five decades. However,FISH (Fluorescence in Situ Hybridization) testing has become a popular modality owing to its targeted approach andthe ability to detect abnormalities in non-mitotic cells. We here aimed to compare the diagnostic yields of a FISHpanel against CCS in HMs. Methods: Samples of bone marrow and peripheral blood for a total of 201 HMs weretested for specific gene rearrangements using multi-target FISH and the results were compared with those from CCS.Results: Exhibited a greater diagnostic yield with a positive result in 39.8% of the cases, as compared to 17.9% of casesdetected by CCS. Cases of chronic lymphocytic leukaemia (CLL) benefited the most by FISH testing, which identifiedchromosomal aberrations beyond the capacity of CCS. FISH was least beneficial in myelodysplastic syndrome (MDS)where the highest concordance with CCS was exhibited. Acute lymphocytic leukaemia (ALL) demonstrated greaterbenefit with CCS. In addition, we found the following abnormalities to be most prevalent in HMs by FISH panel testing:RUNX1 (21q22) amplification in ALL, deletion of D13S319/LAMP1 (13q14) in CLL, CKS1B (1q21) amplificationin multiple myeloma and deletion of EGR1/RPS14 (5q31/5q32) in MDS, consistent with the literature. Conclusions:In conclusion, FISH was found to be advantageous in only a subset of HMs and cannot completely replace CCS.Utilization of the two modalities in conjunction or independently should depend on the indicated HM for an optimalapproach to detecting chromosomal aberrations. PMID- 29286620 TI - Highly Conductive and Transparent Reduced Graphene Oxide Nanoscale Films via Thermal Conversion of Polymer-Encapsulated Graphene Oxide Sheets. AB - Despite noteworthy progress in the fabrication of large-area graphene sheetlike nanomaterials, the vapor-based processing still requires sophisticated equipment and a multistage handling of the material. An alternative approach to manufacturing functional graphene-based films includes the employment of graphene oxide (GO) micrometer-scale sheets as precursors. However, search for a scalable manufacturing technique for the production of high-quality GO nanoscale films with high uniformity and high electrical conductivity is still continuing. Here we show that conventional dip-coating technique can offer fabrication of high quality mono- and bilayered films made of GO sheets. The method is based on our recent discovery that encapsulating individual GO sheets in a nanometer thick molecular brush copolymer layer allows for the nearly perfect formation of the GO layers via dip coating from water. By thermal reduction the bilayers (cemented by a carbon-forming polymer linker) are converted into highly conductive and transparent reduced GO films with a high conductivity up to 104 S/cm and optical transparency on the level of 90%. The value is the highest electrical conductivity reported for thermally reduced nanoscale GO films and is close to the conductivity of indium tin oxide currently in use for transparent electronic devices, thus making these layers intriguing candidates for replacement of ITO films. PMID- 29286621 TI - Quasi-Stem Cells Derived from Human Somatic Cells by Chemically Modified Carbon Nanotubes. AB - Surface modification of micro- and nanotopography was employed to alter the surface properties of scaffolds for controlling cell attachment, proliferation, and differentiation. This study reports a method for generating multinucleated colonies as evidenced by spherical colony formation through nanotopography induced expression of reprogramming factors in human dermal fibroblasts. Colony formation was achieved by subjecting the cells to specific environments such as culturing with single-walled carbon nanotubes and poly-l-lysine (PLL-SWCNTs). We obtained encouraging results showing that PLL-SWCNT treatment transformed fibroblast cells, and the transformed cells expressed the pluripotency-associated factors OCT4, NANOG, and SOX2 in addition to TRA-1-60 and SSEA-4, which are characteristic stem cell markers. Downregulation of lamin A/C, HDAC1, HDAC6, Bcl2, cytochrome c, p-FAK, p-ERK, and p-JNK and upregulation of H3K4me3 and p-p38 were confirmed in the generated colonies, indicating reprogramming of cells. This protocol increases the possibility of successfully reprogramming somatic cells into induced pluripotent stem cells (iPSCs), thereby overcoming the difficulties in iPSC generation such as genetic mutations, carcinogenesis, and undetermined risk factors. PMID- 29286622 TI - Drug Target Discovery Methods In Targeting Neurotropic Parasitic Amoebae. AB - Neurotropic parasitic amoebal infections have imposed an enormous challenge to chemotherapy in patients who fall victims to the infections caused by them. Conventional antibiotics that are given to treat these infections have a low patient compliance because of the serious adverse effects that are associated with their use. Additionally, the growing incidence of the development of drug resistance by the neurotropic parasites like Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp has made the drug therapy more challenging. Recent studies have reported some cellular targets in the neurotropic parasitic Acanthamoeba that are used as receptors by human neurotransmitters like acetylcholine. This Viewpoint attempts to highlight the novel methodologies that use drug assays and structural modeling to uncover cellular targets of diverse groups of drugs and the safety issues of the drugs proposed for their use in brain infections caused by the neurotropic parasitic amoebae. PMID- 29286623 TI - Microwave-Activated Mn-Doped Zirconium Metal-Organic Framework Nanocubes for Highly Effective Combination of Microwave Dynamic and Thermal Therapies Against Cancer. AB - Developing functional nanoagents for achieving the combination of microwave dynamic therapy (MDT) and microwave thermal therapy (MTT) is highly desirable due to the advantages of improving the therapeutic effect on tumors and minimizing the side effects. Metal-organic frameworks (MOFs), as emerging porous materials, exhibit many intriguing properties for application in biomedicine. Herein, new style flexible Mn-doped zirconium metal-organic framework (Mn-ZrMOF) nanocubes (NCs) with the average size of about 60 nm were prepared easily by a one-pot hydrothermal method. Due to the strong inelastic collision of ions confined in a large number of micropores, the Mn-ZrMOF NCs were demonstrated to be an effective microwave-sensitive agent with a high thermal conversion efficiency up to 28.7%, which is the highest one of the recently reported microwave-sensitive agents. This is the first report of determining the microwave thermal conversion efficiency, which can be used to evaluate, compare, and predict the microwave sensitivity of different microwave-sensitive agents. More importantly, such Mn ZrMOF NCs generate abundant reactive oxygen species (ROS) of hydroxyl radicals under microwave irradiation. As such, the Mn-ZrMOF NCs efficiently suppress the tumor cell growth in vivo and in vitro under mild microwave irradiation for the synergic effect of MTT and MDT. This work paves the way for developing nanoagents that are responsive to microwave irradiation, producing ROS and improving thermal effects to realize the noninvasive MTT and MDT treatment in clinics. PMID- 29286624 TI - Cationic Zn-Porphyrin Polymer Coated onto CNTs as a Cooperative Catalyst for the Synthesis of Cyclic Carbonates. AB - The development of solid catalysts containing multiple active sites that work cooperatively is very attractive for biomimetic catalysis. Herein, we report the synthesis of bifunctional catalysts by supporting cationic porphyrin-based polymers on carbon nanotubes (CNTs) using the direct reaction of 5,10,15,20 tetrakis(4-pyridyl)porphyrin zinc(II), di(1H-imidazol-1-yl)methane, and 1,4 bis(bromomethyl)benzene in the presence of CNTs. The bifunctional catalysts could efficiently catalyze the cycloaddition reaction of epoxides and CO2 under solvent free conditions with porphyrin zinc(II) as the Lewis acid site and a bromine anion as a nucleophilic agent working in a cooperative way. Furthermore, a relative amount of porphyrin zinc(II) and quaternary ammonium bromide could be facilely adjusted for facilitating cooperative behavior. The bifunctional catalyst with a TOF up to 2602 h-1 is much more active than the corresponding homogeneous counterpart and is one of the most active heterogeneous catalysts ever reported under cocatalyst-free conditions. The high activity is mainly attributed to the enhanced cooperation effect of the bifunctional catalyst. With a wide substrate scope, the bifunctional catalyst could be stably recycled. This work demonstrates a new approach for the generation of a cooperative activation effect for solid catalysts. PMID- 29286625 TI - MOF Nanoparticles with Encapsulated Autophagy Inhibitor in Controlled Drug Delivery System for Antitumor. AB - High porosities, large surface areas, and tunable functionalities made metal organic frameworks (MOFs) as effective carriers for drug delivery. One of the most promising MOFs is the zeolitic imidazolate framework (ZIF-8) crystal, an advanced functional material for small-molecule delivery, due to its high loading ability and pH-sensitive degradation. As a novel carrier, ZIF-8 nanoparticles were used in this work to control the release of an autophagy inhibitor, 3 methyladenine (3-MA), and prevent it from dissipating in a large quantity before reaching the target. The cellular uptake in HeLa cells of 3-MA encapsulated in ZIF-8 (3-MA@ZIF-8 NPs) is facilitated through the nanoparticle internalization with reference to TEM observations and the quantitative analyses of zinc by ICP MS. The autophagy-related proteins and autophagy flux in HeLa cells treated with 3-MA@ZIF-8 NPs show that the autophagosome formation is significantly blocked, which reveals that the pH-sensitive dissociation increases the efficiency of autophagy inhibition at the equivalent concentration of 3-MA. In vivo experiments, when compared to free 3-MA, 3-MA@ZIF-8 NPs show a higher antitumor efficacy and repress the expression of autophagy-related markers, Beclin 1 and LC3. It follows that ZIF-8 is an efficient drug delivery vehicle in antitumor therapy, especially in inhibiting autophagy of cancer cells. PMID- 29286626 TI - Heat Treatment for Regenerating Degraded Low-Dimensional Perovskite Solar Cells. AB - Organolead halide perovskite devices are reported to be susceptible to thermal degradation, which results from heat-induced fast ion diffusion and structural decomposition. In this work, it is found that the performances of degraded low dimensional perovskite solar cells can be considerably improved (e.g., power conversion efficiency shows ~10% increase over the fresh device) by a short-time heat treatment (85 degrees C, 3 min). Capacitance-frequency, X-ray diffraction, and ionic diffusion calculation results suggest that heat treatment can enhance the crystallinity of the degraded low-dimensional perovskite and minimize the detrimental effects caused by water molecules, leading to improved performances. Our results indicate that the heat treatment does not necessarily lead to the accelerated degradation but can also regenerate the degraded low-dimensional perovskite. PMID- 29286627 TI - Incorporating Electron-Deficient Bipyridinium Chromorphores to Make Multiresponsive Metal-organic Frameworks. AB - Metal-organic frameworks (MOFs) are versatile platforms to design switchable and sensory materials responsive to external stimulus. Copuling the electron deficient bipyridinium chromorphore with the pore structures of MOFs is a nice strategy to design multiresponsive MOFs. Here we present a proof-of-concept study. Postsynthetic N,N'-cycloalkylation of UiO-67-bpy (bpy = 2,2'-bipyridyl) leads to a novel ionic MOF (UiO-67-DQ) functionalized by the electron-deficient diquat (DQ) chromophore. The combination of porosity, cationic character and electron deficiency imparts UiO-67-DQ with versatile responsive properties. It readily undergoes anion exchange, with selective ionochromism associated with charge-transfer (CT) complexation; it is electrochemically active and shows anion dependent photochromism associated with radical formation through electron transfer (ET); the iono- and photochromism cause efficient luminescence quenching because of energy transfer (EnT) to CT complexes or radicals. The properties of UiO-67-MQ (MQ = N,N'-dimethyl-2,2'-bipyridylium) are also presented for comparison. The CT and ET effects and consequently the EnT efficiency in UiO-67 MQ are weaker than those in UiO-67-DQ because the electron-deficient character is weakened by the severe interannular twist in MQ2+. On the basis of the rich responsive properties, the MOFs are used as sensory and switching materials for facile discrimination of a range of anions, for quantitative detection of I-, and for mimicking of logic operations ranging from simple logic gates to complex integrated logic circuits. PMID- 29286628 TI - Energy Dissipation in Fluid Coupled Nanoresonators: The Effect of Phonon-Fluid Coupling. AB - Resonant nanomechanical systems find numerous sensing applications both in the vacuum and in the fluid environment but their performance is degraded by different dissipation mechanisms. In this work, we study dissipation mechanisms associated with high frequency axial excitation of a single-walled carbon nanotube (CNT) filled with argon, which is a representative fluid coupled resonator system. By performing molecular dynamics simulations, we identify two dissipative processes associated with the axial excitation of the resonator: (i) perturbation of the resonator phonons and their relaxation and (ii) oscillatory fluid flow developed by the resonator motion. Dissipation due to the first process, a form of "intrinsic" dissipation, is found to be governed by the Akhiezer mechanism and is verified for an empty CNT in vacuum. To estimate the dissipation due to the second process, which is the conventional "fluid" dissipation, we formulate an approach based on the response of the hydrodynamic force on the resonator. Our analysis of the coupled system reveals that phonon relaxations associated with the Akhiezer dissipation are significantly modified in the presence of fluidic interactions, which have been ignored in all previous dissipation studies of fluid-resonator systems. We show that an important consequence of this phonon-fluid interaction is inverse scaling of dissipation with density at low excitation frequencies. PMID- 29286629 TI - Environmentally Benign Production of Stretchable and Robust Superhydrophobic Silicone Monoliths. AB - Superhydrophobic materials hold an enormous potential in sectors as important as aerospace, food industries, or biomedicine. Despite this great promise, the lack of environmentally friendly production methods and limited robustness remain the two most pertinent barriers to the scalability, large-area production, and widespread use of superhydrophobic materials. In this work, highly robust superhydrophobic silicone monoliths are produced through a scalable and environmentally friendly emulsion technique. It is first found that stable and surfactantless water-in-polydimethylsiloxane (PDMS) emulsions can be formed through mechanical mixing. Increasing the internal phase fraction of the precursor emulsion is found to increase porosity and microtexture of the final monoliths, rendering them superhydrophobic. Silica nanoparticles can also be dispersed in the aqueous internal phase to create micro/nanotextured monoliths, giving further improvements in superhydrophobicity. Due to the elastomeric nature of PDMS, superhydrophobicity can be maintained even while the material is mechanically strained or compressed. In addition, because of their self similarity, the monoliths show outstanding robustness to knife-scratch, tape peel, and finger-wipe tests, as well as rigorous sandpaper abrasion. Superhydrophobicity was also unchanged when exposed to adverse environmental conditions including corrosive solutions, UV light, extreme temperatures, and high-energy droplet impact. Finally, important properties for eventual adoption in real-world applications including self-cleaning, stain-repellence, and blood repellence are demonstrated. PMID- 29286630 TI - Impact of Ultrathin C60 on Perovskite Photovoltaic Devices. AB - Halide perovskite solar cells have seen dramatic progress in performance over the past several years. Certified efficiencies of inverted structure (p-i-n) devices have now exceeded 20%. In these p-i-n devices, fullerene compounds are the most popular electron-transfer materials. However, the full function of fullerenes in perovskite solar cells is still under investigation, and the mechanism of photocurrent hysteresis suppression by fullerene remains unclear. In previous reports, thick fullerene layers (>20 nm) were necessary to fully cover the perovskite film surface to make good contact with perovskite film and avoid large leakage currents. In addition, the solution-processed fullerene layer has been broadly thought to infiltrate into the perovskite film to passivate traps on grain boundary surfaces, causing suppressed photocurrent hysteresis. In this work, we demonstrate an efficient perovskite photovoltaic device with only 1 nm C60 deposited by vapor deposition as the electron-selective material. Utilizing a combination of fluorescence microscopy and impedance spectroscopy, we show that the ultrathin C60 predominately acts to extract electrons from the perovskite film while concomitantly suppressing the photocurrent hysteresis by reducing space charge accumulation at the interface. This work ultimately helps to clarify the dominant role of fullerenes in perovskite solar cells while simplifying perovskite solar cell design to reduce manufacturing costs. PMID- 29286631 TI - Insights into the Electrochemical Reaction Mechanism of a Novel Cathode Material CuNi2(PO4)2/C for Li-Ion Batteries. AB - In this work, we first report the composite of CuNi2(PO4)2/C (CNP/C) can be employed as the high-capacity conversion-type cathode material for rechargeable Li-ion batteries (LIBs), delivering a reversible capacity as high as 306 mA h g-1 at a current density of 20 mA g-1. Furthermore, CNP/C also presents good rate performance and reasonable cycling stability based on a nontraditional conversion reaction mode. X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM) characterizations show that CNP is reduced to form Cu/Ni and Li3PO4 during the discharging process, which is reversed in the following charging process, demonstrating that a reversible conversion reaction mechanism occurs. X-ray absorption spectroscopy (XAS) discloses that Ni2+/Ni0 exhibits a better reversibility compared to Cu2+/Cu during the conversion reaction process, while Cu0 is more difficult to be reoxidized during the recharge process, leading to capacity loss as a consequence. The fundamental understanding obtained in this work provides some important clues to explore the high-capacity conversion-type cathode materials for rechargeable LIBs. PMID- 29286632 TI - g-C3N4/NiAl-LDH 2D/2D Hybrid Heterojunction for High-Performance Photocatalytic Reduction of CO2 into Renewable Fuels. AB - 2D/2D interface heterostructures of g-C3N4 and NiAl-LDH are synthesized utilizing strong electrostatic interactions between positively charged 2D NiAl-LDH sheets and negatively charged 2D g-C3N4 nanosheets. This new 2D/2D interface heterojunction showed remarkable performance for photocatalytic CO2 reduction to produce renewable fuels such as CO and H2 under visible-light irradiation, far superior to that of either single phase g-C3N4 or NiAl-LDH nanosheets. The enhancement of photocatalytic activity could be attributed mainly to the excellent interfacial contact at the heterojunction of g-C3N4/NiAl-LDH, which subsequently results in suppressed recombination, and improved transfer and separation of photogenerated charge carriers. In addition, the optimal g C3N4/NiAl-LDH nanocomposite possessed high photostability after successive experimental runs with no obvious change in the production of CO from CO2 reduction. Our findings regarding the design, fabrication and photophysical properties of 2D/2D heterostructure systems may find use in other photocatalytic applications including H2 production and water purification. PMID- 29286633 TI - Photodoping and Transient Spectroscopies of Copper-Doped CdSe/CdS Nanocrystals. AB - Colloidal Cu+-doped CdSe/CdS core/shell semiconductor nanocrystals (NCs) are investigated in their as-prepared and degenerately n-doped forms using time resolved photoluminescence and transient-absorption spectroscopies. Photoluminescence from Cu+:CdSe/CdS NCs is dominated by recombination of delocalized conduction-band (CB) electrons with copper-localized holes. In addition to prominent bleaching of the first excitonic absorption feature, transient-absorption measurements show bleaching of the sub-bandgap copper-to-CB charge-transfer (MLCBCT) absorption band and also reveal a photoinduced midgap valence-band (VB)-to-copper charge-transfer (LVBMCT) absorption band that extends into the near-infrared, as predicted by recent computations. The photoluminescence of these NCs is substantially diminished upon introduction of excess CB electrons via photodoping. Time-resolved photoluminescence measurements reveal that the MLCBCT excited state is still formed upon photoexcitation of the n-doped Cu+:CdSe/CdS NCs, but its luminescence is quenched by a fast (picosecond) three-carrier trap-assisted Auger recombination process involving two CB electrons and one copper-bound hole. PMID- 29286634 TI - High-Throughput Screening Raman Spectroscopy Platform for Label-Free Cellomics. AB - We present a high-throughput screening Raman spectroscopy (HTS-RS) platform for a rapid and label-free macromolecular fingerprinting of tens of thousands eukaryotic cells. The newly proposed label-free HTS-RS platform combines automated imaging microscopy with Raman spectroscopy to enable a rapid label-free screening of cells and can be applied to a large number of biomedical and clinical applications. The potential of the new approach is illustrated by two applications. (1) HTS-RS-based differential white blood cell count. A classification model was trained using Raman spectra of 52 218 lymphocytes, 48 220 neutrophils, and 7 294 monocytes from four volunteers. The model was applied to determine a WBC differential for two volunteers and three patients, producing comparable results between HTS-RS and machine counting. (2) HTS-RS-based identification of circulating tumor cells (CTCs) in 1:1, 1:9, and 1:99 mixtures of Panc1 cells and leukocytes yielded ratios of 55:45, 10:90, and 3:97, respectively. Because the newly developed HTS-RS platform can be transferred to many existing Raman devices in all laboratories, the proposed implementation will lead to a significant expansion of Raman spectroscopy as a standard tool in biomedical cell research and clinical diagnostics. PMID- 29286636 TI - Topology of Intermetallic Structures: From Statistics to Rational Design. AB - More than 38 000 substances made only of metal atoms are collected in modern structural databases; we may call them intermetallic compounds. They have important industrial applications, and yet they are terra incognita for most of our undergraduate students. Their structural complexity and synthesis are not easily adaptable to first years laboratories, keeping them away from the standard curricula. They have been described over the years following alternative and complementary views such as coordination polyhedra, atomic layers, and polyatomic clusters. All of these descriptions, albeit relying on grounded principles, have been applied on a subjective basis and never implemented as a strict computational algorithm. Sometimes, the authors generated multiple views of the same structure reported with beautifully drawn figures and/or photos of hand crafted models in seminal works of the precomputer age. With the use of our multipurpose crystallochemical program package ToposPro, we explored the structural chemistry of intermetallics with objective and reproducible topological methods that allow us to reconcile different structure descriptions. After computing the connectivity patterns between the metal atoms on the basis of Voronoi partitioning of the crystal space, we were able to group the 38 000 intermetallic compounds into 3700 sets of crystal structures with the same topology of atomic net. We have described the different views used in the literature and shown that 12-vertex polyhedra are the most frequent (33%) and that almost half of them are icosahedron-like (46%), followed by cuboctahedron (25%) and, unexpectedly, by bicapped pentagonal prism (13%). Looking for layers, we have found that the hexagonal lattice, which corresponds to the closest packing of spheres on a plane, exists in more than 11 000 crystal structures, confirming the close-packed nature of intermetallics. We have also applied the nanocluster approach, which goes beyond the first coordination sphere and looks for structural units as multishell clusters that assemble the whole structure. This approach shows that 41% of intermetallics can be assembled with a single nanocluster and that 22.4% of these are packed according to the face-centered cubic motif of the closest packing of spheres in three-dimensional space. We have shown that our approach can easily adopt any other building model and hence could become a platform for a universal predictive scheme. Within this scheme, all of the structural descriptors can be related to experimental data and theoretical modeling results and then can be used to synthesize new intermetallic compounds and to foresee novel materials. PMID- 29286637 TI - In Situ Self-Template Synthesis of Fe-N-Doped Double-Shelled Hollow Carbon Microspheres for Oxygen Reduction Reaction. AB - Herein, we reported a special Fe-N-doped double-shelled hollow carbon microsphere (Fe-N-DSC) which was prepared by a facile, in situ polymerization followed by pyrolysis. With porous ferroferric oxide (Fe3O4) hollow microspheres as the templates, where pyrrole monomers were dispersed around the outer surface and prefilled the interior space. By adding hydrochloric acid, Fe3+ ions were released to initiate polymerization of pyrrole on both the outer and inner surfaces of Fe3O4 microspheres until they were completely dissolved, resulting in the Fe-containing polypyrrole double-shelled hollow carbon microspheres (Fe-PPY DSC). The Fe-PPY-DSC was then pyrolyzed to generate the Fe-N-DSC. The Fe3O4 hollow microspheres played trifunctional roles, i.e., the template to prepare a double-shelled hollow spherical structure, the initiator (i.e., Fe3+ ions) for the polymerization of pyrrole, and the Fe source for doping. The Fe-N-DSC exhibited a superior catalytic activity for oxygen reduction as comparable to commercial Pt/C catalysts in both alkaline and acidic media. The high catalytic performance was ascribed to the special porous double-shelled hollow spherical structure, which provided more active sites and was beneficial to a high-flux mass transportation. PMID- 29286635 TI - Multiplexed Profiling of Single Extracellular Vesicles. AB - Extracellular vesicles (EV) are a family of cell-originating, membrane-enveloped nanoparticles with diverse biological function, diagnostic potential, and therapeutic applications. While EV can be abundant in circulation, their small size (~4 order of magnitude smaller than cells) has necessitated bulk analyses, making many more nuanced biological explorations, cell of origin questions, or heterogeneity investigations impossible. Here we describe a single EV analysis (SEA) technique which is simple, sensitive, multiplexable, and practical. We profiled glioblastoma EV and discovered surprising variations in putative pan-EV as well as tumor cell markers on EV. These analyses shed light on the heterogeneous biomarker profiles of EV. The SEA technology has the potential to address fundamental questions in vesicle biology and clinical applications. PMID- 29286638 TI - 3D Network and 2D Paper of Reduced Graphene Oxide/Cu2O Composite for Electrochemical Sensing of Hydrogen Peroxide. AB - In this study, two-dimensional (2D) and three-dimensional (3D) freestanding reduced graphene oxide-supported Cu2O composites (Cu2O-rGO) were synthesized via simple and cost-efficient hydrothermal and filtration strategies. The structural characterizations clearly showed that highly porous 3D graphene aerogel-supported Cu2O microcrystals (3D Cu2O-GA) have been successfully synthesized, and the Cu2O microcrystals are uniformly assembled in the 3D GA. Meanwhile, paper-like 2D reduced graphene oxide-supported Cu2O nanocrystals (2D Cu2O-rGO-P) have also been prepared by a filtration process. It was found that the products prepared from different precursors and methods exhibited different sensing performances for H2O2 detection. The electrochemical measurements demonstrated that the 3D Cu2O-GA has high electrocatalytic activity for the H2O2 reduction and excellent sensing performance for the electrochemical detection of H2O2 with a detection limit of 0.37 MUM and a linear detection range from 1.0 MUM to 1.47 mM. Meanwhile, the 2D Cu2O-rGO-P structure also showed good electrochemical sensing performance toward H2O2 detection with a much wider linear response over the concentration range from 5.0 MUM to 10.56 mM. Compared to the previously reported sensing materials, the as-obtained 2D and 3D Cu2O-rGO materials exhibited higher electrochemical sensing properties toward the detection of H2O2 with high sensitivity and selectivity. The 2D and 3D Cu2O-rGO composites also exhibited high sensing performance for the real-time detection of H2O2 in human serum. The present study indicates that 2D and 3D graphene-Cu2O composites have promising applications in the fabrication of nonenzymatic electrochemical sensing devices. PMID- 29286639 TI - Live Imaging of Label-Free Graphene Oxide Reveals Critical Factors Causing Oxidative-Stress-Mediated Cellular Responses. AB - The interest in graphene and its translation into commercial products has been expanding at a high pace. Based on previously described pulmonary safety concerns for carbon nanomaterials, there is a great need to define parameters guiding interactions between graphene-based materials and the pulmonary system. The aim of the present study was to determine the importance of two critical parameters: lateral dimensions of the material and coating with proteins in relation to each other and their pulmonary impact. Endotoxin-free materials with distinct lateral dimensions, s-GO (50-200 nm) and l-GO (5-15 MUm), were produced and thoroughly characterized. Exploiting intrinsic fluorescence of graphene oxide (GO) and using confocal live-cell imaging, the behavior of the cells in response to the material was visualized in real time. Although BEAS-2B cells internalized GO efficiently, l-GO was linked to higher plasma membrane interactions correlated with elevated reactive oxygen species (ROS) levels, pro-inflammatory response, and greater cytotoxicity, in agreement with the oxidative stress paradigm. For both GO types, the presence of serum alleviated lipid peroxidation of plasma membrane and decreased intracellular ROS levels. However, protein coating was not enough to entirely mitigate toxicity and inflammatory response induced by l-GO. In vitro results were validated in vivo, as l-GO was more prone to induce pulmonary granulomatous response in mice compared to s-GO. In conclusion, the lateral dimension of GO played a more important role than serum protein coating in determining biological responses to the material. It was also demonstrated that time-lapse imaging of live cells interacting with label-free GO sheets can be used as a tool to assess GO-induced cytotoxicity. PMID- 29286640 TI - Separation of Methylated Histone Peptides via Host-Assisted Capillary Electrophoresis. AB - Lysine methylation in protein is one important epigenetic mechanism that regulates diverse biological processes but is challenging to study due to the large variability in methylation levels and sites. Here, we show that supramolecular hosts such as calixarenes and cucurbiturils can be applied in the background electrolyte (BGE) of capillary electrophoresis (CE) for highly effective separation of post-translationally methylated histone peptides. The molecular recognition event causes a shift in the electrophoretic mobility of the peptide, allowing affinity measurement for binding between the synthetic receptor and various methylated lysine species. Successful separation of the H3 peptides carrying different methylation levels at the K9 position can be achieved using CX4 and CX6 as the BGE additives in CE, enabling monitoring of the activity of the histone lysine demethylase JMJD2E. This reveals the power of combining high resolution CE with synthetic hosts for study of protein methylation, and the method should be capable of analyzing complex biological samples for better understanding of the functions of histone methylation. PMID- 29286641 TI - Distinguishing Linkage Position and Anomeric Configuration of Glucose-Glucose Disaccharides by Water Adduction to Lithiated Molecules. AB - A method was developed to distinguish both the linkage position and the anomericity of all reducing and two nonreducing glucopyransosyl-glucose disaccharides using only electrospray ionization-mass spectrometry/mass spectrometry (ESI-MS/MS). Carbohydrates are well-known to form complexes with metal cations during electrospray ionization. Addition of a lithium salt to a solution containing a disaccharide, M, results in [M + Li]+ after ESI. Collision induced dissociation of these ions creates product ions at m/z 187 and m/z 169 from cleavage of the glycosidic bond and are present for all disaccharides studied. Both of these product ions were found to adduct water after their formation in a quadrupole ion trap. The kinetics of this water adduction can be measured by isolating either of the product ions and waiting a short time (<1 s) before mass analysis. Additionally, for both product ions, only a fraction of the ions were able to adduct water. This unreactive fraction was measured along with the reaction rate, and the combination of these two values was found to be unique for each disaccharide. Additionally, after CID, a 1000 ms delay can be added, and the ratios of the resulting products ions of m/z 169, 187, and 205 can be used to distinguish linkage position and anomericity with a single tandem mass spectrometry experiment. PMID- 29286642 TI - Atomistic Insights into FeF3 Nanosheet: An Ultrahigh-Rate and Long-Life Cathode Material for Li-Ion Batteries. AB - Iron fluoride with high operating voltage and theoretical energy density has been proposed as a high-performance cathode material for Li-ion batteries. However, the inertness of pristine bulk FeF3 results in poor Li kinetics and cycling life. Developing nanosheet-based electrode materials is a feasible strategy to solve these problems. Herein, on the basis of first-principles calculations, first the stability of FeF3 (012) nanosheet with different atomic terminations under different environmental conditions was systematically studied, then the Li-ion adsorption and diffusion kinetics were thoroughly probed, and finally the voltages for different Li concentrations were given. We found that F-terminated nanosheet is energetically favorable in a wide range of chemical potential, which provide a vehicle for lithium ion diffusion. Our Li-ion adsorption and diffusion kinetics study revealed that (1) the formation of Li dimer is the most preferred, (2) the Li diffusion energy barrier of Li dimer is lower than isolated Li atom (0.17 eV for Li dimer vs 0.22 eV for Li atom), and (3) the diffusion coefficient of Li is 1.06 * 10-6 cm2.s-1, which is orders of magnitude greater than that of Li diffusion in bulk FeF3 (10-13-10-11 cm2.s-1). Thus, FeF3 nanosheet can act as an ultrahigh-rate cathode material for Li-ion batteries. More importantly, the calculated voltage and specific capacity of Li on the FeF3 (012) nanosheet demonstrate that it has a much more stable voltage profile than bulk FeF3 for a wide range of Li concentration. So, few layers FeF3 nanosheet provides the desired long-life energy density in Li-ion batteries. These above findings in the current study shed new light on the design of ultrahigh-rate and long-life FeF3 cathode material for Li-ion batteries. PMID- 29286643 TI - Design of an Activity-Based Probe for Human Neutrophil Elastase: Implementation of the Lossen Rearrangement To Induce Forster Resonance Energy Transfers. AB - Human neutrophil elastase is an important regulator of the immune response and plays a role in host defense mechanisms and further physiological processes. The uncontrolled activity of this serine protease may cause severe tissue alterations and impair inflammatory states. The design of an activity-based probe for human neutrophil elastase reported herein relies on a sulfonyloxyphthalimide moiety as a new type of warhead that is linker-connected to a coumarin fluorophore. The inhibitory potency of the activity-based probe was assessed against several serine and cysteine proteases, and the selectivity for human neutrophil elastase (Ki = 6.85 nM) was determined. The adequate fluorescent tag of the probe allowed for the in-gel fluorescence detection of human neutrophil elastase in the low nanomolar range. The coumarin moiety and the anthranilic acid function of the probe, produced in the course of a Lossen rearrangement, were part of two different Forster resonance energy transfers. PMID- 29286644 TI - Complexation of NAC-Derived Peptide Ligands with the C-Terminus of alpha Synuclein Accelerates Its Aggregation. AB - Aggregation of alpha-synuclein (alpha-Syn) into neurotoxic oligomers and amyloid fibrils is suggested to be the pathogenic mechanism for Parkinson's disease (PD). Recent studies have indicated that oligomeric species of alpha-Syn are more cytotoxic than their mature fibrillar counterparts, which are responsible for dopaminergic neuronal cell death in PD. Therefore, the effective therapeutic strategies for tackling aggregation-associated diseases would be either to prevent aggregation or to modulate the aggregation process to minimize the formation of toxic oligomers during aggregation. In this work, we showed that arginine-substituted alpha-Syn ligands, based on the most aggregation-prone sequence of alpha-Syn, accelerate the protein aggregation in a concentration dependent manner. To elucidate the mechanism by which Arg-substituted peptides could modulate alpha-Syn aggregation kinetics, we performed surface plasmon resonance (SPR) spectroscopy, nuclear magnetic resonance (NMR) studies, and all atom molecular dynamics (MD) simulation. The SPR analysis showed a high binding potency of these peptides with alpha-Syn but one that was nonspecific in nature. The two-dimensional NMR studies suggest that a large stretch within the C terminus of alpha-Syn displays a chemical shift perturbation upon interacting with Arg-substituted peptides, indicating C-terminal residues of alpha-Syn might be responsible for this class of peptide binding. This is further supported by MD simulation studies in which the Arg-substituted peptide showed the strongest interaction with the C-terminus of alpha-Syn. Overall, our results suggest that the binding of Arg-substituted ligands to the highly acidic C-terminus of alpha Syn leads to reduced charge density and flexibility, resulting in accelerated aggregation kinetics. This may be a potentially useful strategy while designing peptides, which act as alpha-Syn aggregation modulators. PMID- 29286647 TI - Dehydropolymerization of H3B.NMeH2 To Form Polyaminoboranes Using [Rh(Xantphos alkyl)] Catalysts. AB - A systematic study of the catalyst structure and overall charge for the dehydropolymerization of H3B.NMeH2 to form N-methyl polyaminoborane is reported using catalysts based upon neutral and cationic {Rh(Xantphos-R)} fragments in which PR2 groups are selected from Et, iPr, and tBu. The most efficient systems are based upon {Rh(Xantphos-iPr)}, i.e., [Rh(kappa3-P,O,P-Xantphos-iPr)(H)2(eta1 H3B.NMe3)][BArF4], 6, and Rh(kappa3-P,O,P-Xantphos-iPr)H, 11. While H2 evolution kinetics show both are fast catalysts (ToF ~ 1500 h-1) and polymer growth kinetics for dehydropolymerization suggest a classical chain growth process for both, neutral 11 (Mn = 28 000 g mol-1, D = 1.9) promotes significantly higher degrees of polymerization than cationic 6 (Mn = 9000 g mol-1, D = 2.9). For 6 isotopic labeling studies suggest a rate-determining NH activation, while speciation studies, coupled with DFT calculations, show the formation of a dimetalloborylene [{Rh(kappa3-P,O,P-Xantphos-iPr)}2B]+ as the, likely dormant, end product of catalysis. A dual mechanism is proposed for dehydropolymerization in which neutral hydrides (formed by hydride transfer in cationic 6 to form a boronium coproduct) are the active catalysts for dehydrogenation to form aminoborane. Contemporaneous chain-growth polymer propagation is suggested to occur on a separate metal center via head-to-tail end chain B-N bond formation of the aminoborane monomer, templated by an aminoborohydride motif on the metal. PMID- 29286646 TI - Fast Calculation of Protein-Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model. AB - Determination of protein-protein binding affinity values is key to understanding various underlying biological phenomena, such as how missense variations change protein-protein binding. Most existing non-rigorous (fast) and rigorous (slow) methods that rely on all-atom representation of the proteins force the user to choose between speed and accuracy. In an attempt to achieve balance between speed and accuracy, we have combined rigorous umbrella sampling molecular dynamics simulation with a coarse-grained protein model. We predicted the effect of missense variations on binding affinity by selecting three protein-protein systems and comparing results to empirical relative binding affinity values and to non-rigorous modeling approaches. We obtained significant improvement both in our ability to discern stabilizing from destabilizing missense variations and in the correlation between predicted and experimental values compared to non rigorous approaches. Overall our results suggest that using a rigorous affinity calculation method with coarse-grained protein models could offer fast and reliable predictions of protein-protein binding free energies. PMID- 29286648 TI - Substituted Diphenylamine Antioxidants and Benzotriazole UV Stabilizers in Aquatic Organisms in the Great Lakes of North America: Terrestrial Exposure and Biodilution. AB - Substituted diphenylamine antioxidants (SDPAs) and benzotriazole UV stabilizers (BZT-UVs) are industrial additives of emerging environmental concern. However, the bioaccumulation, biomagnification, and spatial distribution of these contaminants in the Great Lakes of North America are unknown. The present study addresses these knowledge gaps by reporting SDPAs and BZT-UVs in herring gull (Larus argentatus) eggs, lake trout (Salvelinus namaycush), and their food web in the Great Lakes for the first time. Herring gull eggs showed much higher detection frequency and concentrations of target SDPAs and 2-(2H-benzotriazol-2 yl)-4,6-di-tert-pentylphenol (UV328) than that of the whole body fish homogenate. For herring gull eggs, the samples from upper Great Lakes contained significantly greater levels of SDPAs than those eggs from lower lakes, possibly due to the differences in terrestrial food in diet. Interestingly, the predominant SDPAs in herring gull eggs were dinonyl- (C9C9) and monononyl-diphenylamine (C9) which were previously shown to be less bioaccumulative than other SDPAs in fish. In contrast, dioctyl-diphenylamine (C8C8) was the major SDPA in lake trout, and biodilution of C8C8 was observed in a Lake Superior lake trout food web. Such variations in herring gull eggs and fish indicate the differences in accumulation and elimination pathways of SDPAs and BZT-UVs and require further elucidation of these mechanisms. PMID- 29286649 TI - Wavelength- and Temperature-Dependent Apparent Quantum Yields for Photochemical Production of Carbonyl Compounds in the North Pacific Ocean. AB - Photolysis of dissolved organic matter is the main source of carbonyl compounds in sunlit seawater, but rates and photoefficiences are poorly constrained. Wavelength- and temperature-dependent apparent quantum yields (AQYs) were determined for photochemical production of acetaldehyde, glyoxal, and methylglyoxal in North Pacific Ocean seawater. Wavelength-dependent AQYs at 20 degrees C decreased exponentially with increasing wavelength between 290 and 380 nm, from 1.29 * 10-4 to 4.12 * 10-6, 2.52 * 10-5 to 6.89 * 10-7, and 4.37 * 10-6 to 1.25 * 10-7 mol (mol quanta)-1 for acetaldehyde, glyoxal, and methylglyoxal, respectively. AQYs decreased after 6 h irradiation at 310 nm, possibly due to depletion of photochemical precursors or carbonyl photolysis. Average activation energies (95% CI) for photochemical production at 320 nm were 9.31 (+/-9.3), 26.0 (+/-7.5), and 34.7 (+/-12.8) kJ mol-1 for acetaldehyde, glyoxal, and methylglyoxal, respectively. The peak response for photochemical production rates in surface seawater was ~325 nm, with ~30% contribution from UV-B and ~70% from UV-A. Computed noontime wavelength-integrated photoproduction rates were 0.5-0.8, 0.04-0.2, and 0.03-0.06 nmol L-1 h-1 for acetaldehyde, glyoxal, and methylglyoxal, respectively, under cloudless conditions in August. Results can be used to determine regional-scale photochemical production rates for these compounds in the surface ocean. PMID- 29286650 TI - Functional Synthetic Model for the Lanthanide-Dependent Quinoid Alcohol Dehydrogenase Active Site. AB - The oxidation of methanol by dehydrogenase enzymes is an essential part of the bacterial methane metabolism cycle. The recent discovery of a lanthanide (Ln) cation in the active site of the XoxF dehydrogenase represents the only example of a rare-earth element in a physiological role. Herein, we report the first synthetic, functional model of Ln-dependent dehydrogenase and its stoichiometric and catalytic dehydrogenation of a benzyl alcohol. Density functional theory calculations implicate a hydride transfer mechanism for these reactions. PMID- 29286651 TI - Predictive Power of Different Types of Experimental Restraints in Small Molecule Docking: A Review. AB - Incorporating experimental restraints is a powerful method of increasing accuracy in computational protein small molecule docking simulations. Different algorithms integrate distinct forms of biochemical data during the docking and/or scoring stages. These so-called hybrid methods make use of receptor-based information such as nuclear magnetic resonance (NMR) restraints or small molecule-based information such as structure-activity relationships (SARs). A third class of methods directly interrogates contacts between the protein receptor and the small molecule. This work reviews the current state of using such restraints in docking simulations, evaluates their feasibility across broad systems, and identifies potential areas of algorithm development. PMID- 29286652 TI - Semisynthetic Phenol Derivatives Obtained from Natural Phenols: Antimicrobial Activity and Molecular Properties. AB - Semisynthetic phenol derivatives were obtained from the natural phenols: thymol, carvacrol, eugenol, and guaiacol through catalytic oxychlorination, Williamson synthesis, and aromatic Claisen rearrangement. The compounds characterization was carried out by 1H NMR, 13C NMR, and mass spectrometry. The natural phenols and their semisynthetic derivatives were tested for their antimicrobial activity against the bacteria: Staphylococcus aureus, Escherichia coli, Listeria innocua, Pseudomonas aeruginosa, Salmonella enterica Typhimurium, Salmonella enterica ssp. enterica, and Bacillus cereus. Minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values were determined using concentrations from 220 to 3.44 MUg mL-1. Most of the tested compounds presented MIC values <=220 MUg mL-1 for all the bacteria used in the assays. The molecular properties of the compounds were computed with the PM6 method. Through principle components analysis, the natural phenols and their semisynthetic derivatives with higher antimicrobial potential were grouped. PMID- 29286653 TI - Are Peptides Absorbable Compounds? PMID- 29286654 TI - Exhaustive Conversion of Inorganic Nitrogen to Nitrogen Gas Based on a Photoelectro-Chlorine Cycle Reaction and a Highly Selective Nitrogen Gas Generation Cathode. AB - A novel method for the exhaustive conversion of inorganic nitrogen to nitrogen gas is proposed in this paper. The key properties of the system design included an exhaustive photoelectrochemical cycle reaction in the presence of Cl-, in which Cl. generated from oxidation of Cl- by photoholes selectively converted NH4+ to nitrogen gas and some NO3- or NO2-. The NO3- or NO2- was finally reduced to nitrogen gas on a highly selective Pd-Cu-modified Ni foam (Pd-Cu/NF) cathode to achieve exhaustive conversion of inorganic nitrogen to nitrogen gas. The results indicated total nitrogen removal efficiencies of 30 mg L-1 inorganic nitrogen (NO3-, NH4+, NO3-/NH4+ = 1:1 and NO2-/NO3-/NH4+ = 1:1:1) in 90 min were 98.2%, 97.4%, 93.1%, and 98.4%, respectively, and the remaining nitrogen was completely removed by prolonging the reaction time. The rapid reduction of nitrate was ascribed to the capacitor characteristics of Pd-Cu/NF that promoted nitrate adsorption in the presence of an electric double layer, eliminating repulsion between the cathode and the anion. Nitrate was effectively removed with a rate constant of 0.050 min-1, which was 33 times larger than that of Pt cathode. This system shows great potential for inorganic nitrogen treatment due to the high rate, low cost, and clean energy source. PMID- 29286655 TI - Thallium Adsorption onto Illite. AB - We investigated the adsorption of Tl+ onto purified Illite du Puy (IdP). Distribution coefficients (Kd) for trace Tl adsorption indicated a moderate pH dependence from pH 2.5 to 11. Adsorption isotherms measured at Tl+ concentrations from 10-9 to 10-2 M at near-neutral pH on illite saturated with Na+ (100 mM), K+ (1 and 10 mM), NH4+ (10 mM) or Ca2+ (5 mM) revealed a high adsorption affinity of Tl+ in Na+- and Ca2+-electrolytes and strong competition with K+ and NH4+. Cation exchange selectivity coefficients for Tl+ with respect to Na+, K+, NH4+, and Ca2+ were derived using a 3-site sorption model. They confirmed the strong adsorption of Tl+ at the frayed edges of illite, with Tl selectivity coefficients between those reported for Rb+ and Cs+. X-ray absorption spectra of Tl adsorbed onto Na exchanged IdP indicated a shift from adsorption of (dehydrated) Tl+ at the frayed edges at low loadings to adsorption of (hydrated) Tl+ on planar sites at the highest loadings. Our results suggest that illite is an important adsorbent for Tl in soils and sediments, considering its often high abundance and its stability relative to other potential adsorbents and the selective nature of Tl+ uptake by illite. PMID- 29286656 TI - Physical and Chemical Properties of 3-Methyl-1,2,3-butanetricarboxylic Acid (MBTCA) Aerosol. AB - The properties and the chemical fate of later generation products of the oxidation of biogenic organic compounds are mostly unknown. The properties of fresh MBTCA aerosol, a later generation product of the oxidation of monoterpenes in the atmosphere, were determined combining an aerosol mass spectrometer (AMS), a thermodenuder, and a scanning mobility particle sizer. Based on its AMS spectrum m/z 141.055 (C7H9O3+) could be used as an MBTCA signature. The MBTCA particle density was 1.43 +/- 0.04 g cm-3, its saturation concentration was (1.8 +/- 1.3) * 10-3 MUg m-3 at 298 K, and its vaporization enthalpy was 150 +/- 15 kJ mol-1. After OH radical exposure (~1.2 days) and UV illumination the average aerosol O:C ratio decreased from 0.72 to 0.58-0.64 suggesting net fragmentation. Our findings suggest that the reactions of MBTCA with OH lead to CO2 loss with or without an oxygen addition. PMID- 29286645 TI - Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins. AB - As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal-oxygen intermediates. These reactive intermediates, including metal-superoxo, (hydro)peroxo, and high-valent metal-oxo species, are the basis for the various biological functions of O2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O2 activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron-oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs. PMID- 29286657 TI - The Transferability from Animal Models to Humans: Challenges Regarding Aggregation and Protein Corona Formation of Nanoparticles. AB - Nanomaterials are interesting candidates for applications in medicine as drug delivery or diagnostic agents. For safe application, they have to be evaluated in in vitro and in vivo models to finally be translated to human clinical trials. However, often those transfer processes fail, and it is not completely understood whether in vitro models leading to these animal models can reliably be compared to the situation in humans. In particular, the interaction of nanomaterials with components from different blood plasma sources is difficult to compare, and the outcomes of those interactions with respect to body distribution and cell uptake are unclear. Therefore, we investigated the interactions of differently functionalized polymeric and inorganic nanoparticles with human, mouse, rabbit, and sheep plasma. The focus was put on the determination of aggregation events of the nanoparticles occurring in concentrated plasma and the correlation with the respectively formed protein coronas. Both the stability in plasma as well as the types of adsorbed proteins were found to strongly depend on the plasma source. Thus, we suggest evaluating the potential use of nanocarriers always in the plasma source of the chosen animal model for in vitro studies as well as in human plasma to pin down differences and eventually enable transfer into clinical trials in humans. PMID- 29286659 TI - Control of Luminescence in Eu2+-Doped Orthosilicate-Orthophosphate Phosphors by Chainlike Polyhedra and Electronic Structures. AB - A series of Eu2+-doped orthosilicate-orthophosphate solid-solution phosphors, KxBa1.97-x(Si1-xPx)O4:0.03Eu2+, have been synthesized via the conventional solid state reaction. Using varying compositions, the lowest-energy excitation can be tuned from 470 to 405 nm, with an emission from 515 to 423 nm. We determined how chainlike cation polyhedra controlled excitation- and emission-band features by introducing in-chain characteristic length d22 and outside-chain characteristic length d12 and that there was a nearly linear relationship between the lowest energy-excitation position and the ratio of d22 to d12. This influence of chainlike polyhedra on luminescence can be understood through the inductive effect. Luminescent thermal properties are improved remarkably by the cosubstitution of K+ and P5+ ions for Ba2+ and Si4+ ions with a T1/2 over 200 degrees C. We have established the host-referred-binding-energy (HRBE) and vacuum referred-binding-energy (VRBE) schemes for the electronic structure of the series of lanthanide-doped phosphors according to the Dorenbos model and given a thermal quenching mechanism for this series of phosphors. PMID- 29286660 TI - Ophiobolins from the Mangrove Fungus Aspergillus ustus. AB - Seven new ophiobolins (1-5, 12, and 14) along with the 11 known analogues (6-11, 13, 15-18) were isolated from the ethyl acetate extracts of the liquid and solid cultures of the mangrove fungus Aspergillus ustus 094102. The structures including the absolute configurations of the seven new compounds were elucidated by spectroscopic analysis, chemical methods, and quantum ECD calculations. Compounds 4-8 and 11-15 showed cytotoxicities against the G3K, MCF-7, MD-MBA-231, MCF/Adr, A549, and HL-60 human cancer cell lines with the IC50 values ranging from 0.6 to 9.5 MUM. PMID- 29286661 TI - Controllable Monobromination of Perylene Ring System: Synthesis of Bay Functionalized Perylene Dyes. AB - Practical synthesis of bay-monofunctionalized perylene dyes has been developed based on controllable NBS bromination of tetrabenzyl perylene-3,4,9,10 tetracarboxylate. The ability to perform the convenient and high-yielding synthesis highlights the potential utility of our multifunctional approach to access a diverse range of new perylene systems. PMID- 29286658 TI - Predicting Displaceable Water Sites Using Mixed-Solvent Molecular Dynamics. AB - Water molecules are an important factor in protein-ligand binding. Upon binding of a ligand with a protein's surface, waters can either be displaced by the ligand or may be conserved and possibly bridge interactions between the protein and ligand. Depending on the specific interactions made by the ligand, displacing waters can yield a gain in binding affinity. The extent to which binding affinity may increase is difficult to predict, as the favorable displacement of a water molecule is dependent on the site-specific interactions made by the water and the potential ligand. Several methods have been developed to predict the location of water sites on a protein's surface, but the majority of methods are not able to take into account both protein dynamics and the interactions made by specific functional groups. Mixed-solvent molecular dynamics (MixMD) is a cosolvent simulation technique that explicitly accounts for the interaction of both water and small molecule probes with a protein's surface, allowing for their direct competition. This method has previously been shown to identify both active and allosteric sites on a protein's surface. Using a test set of eight systems, we have developed a method using MixMD to identify conserved and displaceable water sites. Conserved sites can be determined by an occupancy-based metric to identify sites which are consistently occupied by water even in the presence of probe molecules. Conversely, displaceable water sites can be found by considering the sites which preferentially bind probe molecules. Furthermore, the inclusion of six probe types allows the MixMD method to predict which functional groups are capable of displacing which water sites. The MixMD method consistently identifies sites which are likely to be nondisplaceable and predicts the favorable displacement of water sites that are known to be displaced upon ligand binding. PMID- 29286662 TI - Strain and Bond Length Dynamics upon Growth and Transfer of Graphene by NEXAFS Spectroscopy from First-Principles and Experiment. AB - As the quest toward novel materials proceeds, improved characterization technologies are needed. In particular, the atomic thickness in graphene and other 2D materials renders some conventional technologies obsolete. Characterization technologies at wafer level are needed with enough sensitivity to detect strain in order to inform fabrication. In this work, NEXAFS spectroscopy was combined with simulations to predict lattice parameters of graphene grown on copper and further transferred to a variety of substrates. The strains associated with the predicted lattice parameters are in agreement with experimental findings. The approach presented here holds promise to effectively measure strain in graphene and other 2D systems at wafer levels to inform manufacturing environments. PMID- 29286663 TI - Self-Assembly of Lysine-Based Dendritic Surfactants Modeled by the Self Consistent Field Approach. AB - Implementing a united atom model, we apply self-consistent field theory to study structure and thermodynamic properties of spherical micelles composed of surfactants that combine an alkyl tail with a charged lysine-based dendritic headgroup. Following experiments, the focus was on dendron surfactants with varying tail length and dendron generations G0, G1, G2. The heads are subject to acetylation modification which reduces the charge and hydrophilicity. We establish a reasonable parameter set which results in semiquantitative agreement with the available experiments. The critical micellization concentration, aggregation number, and micelle size are discussed. The strongly charged dendronic surfactants micelles are stable for generation numbers G0 and G1, for progressively higher ionic strengths. Associates of G2 surfactants are very small and can only be found at extreme surfactant concentration and salt strengths. Micelles of corresponding weaker charged acetylated variants exist up to G2, tolerate significantly lower salt concentrations, but lose the spherical micelle topology for G0 at high ionic strengths. PMID- 29286664 TI - Wisely Designed Phthalocyanine Derivative for Convenient Molecular Fabrication on a Substrate. AB - An axial-substituted silicon phthalocyanine derivative, SiPc(OR)2 (R = C4H9), that is soluble in organic solvent is conveniently synthesized. This silicon phthalocyanine derivative reacts with a hydroxyl group on a substrate and then with another phthalocyanine derivative under mild conditions. The accumulation number of the phthalocyanine molecules on the substrates is easily controlled by the immersion time. On the basis of AFM (atomic force microscopy) images, the surface of the phthalocyanine-modified glass substrate has uneven structures on the nanometer scale. ITO electrodes modified with the composition of the phthalocyanine derivative and PCBM show stable cathodic photocurrent generation upon light irradiation. PMID- 29286665 TI - Sodium-Periodate-Mediated Harringtonine Derivatives and Their Antiproliferative Activity against HL-60 Acute Leukemia Cells. AB - Harringtonine (HT) is a naturally occurring alkaloid isolated from the plant genus Cephalotaxus. It possesses antileukemic activity and has been clinically utilized for the treatment of acute leukemia and lymphoma. Sodium periodate (NaIO4) was reacted with HT to produce five HT derivatives including four novel compounds. Their antiproliferative activity against HL-60 acute promyelocytic leukemia cells revealed that the presence of the C-5' methyl group enhances the antiproliferative activity because the IC50 values of the HT derivatives, including HT1 (5'-de-O-methylharringtonine), were at least 2000 times higher (>100 MUM) than that of HT (~47 nM). In addition, an indirect competitive enzyme linked immunosorbent assay (icELISA) using a monoclonal antibody against HT (mAb 1D2) revealed that these antiproliferative activities were related to their cellular uptake. These results indicated that esterification of HT1 at the C-4' carboxylic acid group may enhance the antiproliferative activity of HT. PMID- 29286666 TI - Ultrafast Electron Injection from Photoexcited Perovskite CsPbI3 QDs into TiO2 Nanoparticles with Injection Efficiency near 99. AB - Photoexcited electron injection dynamics from CsPbI3 quantum dots (QDs) to wide gap metal oxides are studied by transient absorption spectroscopy. Experimental results show under a low excitation intensity that ~99% of the photoexcited electrons in CsPbI3 QDs can be injected into TiO2 with a size-dependent rate ranging from 1.30 * 1010 to 2.10 * 1010 s-1, which is also ~2.5 times faster than that in the case of ZnO. A demonstration QD-sensitized solar cell based on a CsPbI3/TiO2 electrode is fabricated that delivers a power conversion efficiency of 5%. PMID- 29286668 TI - Electrostatically Induced Quantum Point Contacts in Bilayer Graphene. AB - We report the fabrication of electrostatically defined nanostructures in encapsulated bilayer graphene, with leakage resistances below depletion gates as high as R ~ 10 GOmega. This exceeds previously reported values of R = 10-100 kOmega.1-3 We attribute this improvement to the use of a graphite back gate. We realize two split gate devices which define an electronic channel on the scale of the Fermi-wavelength. A channel gate covering the gap between the split gates varies the charge carrier density in the channel. We observe device-dependent conductance quantization of DeltaG = 2e2/h and DeltaG = 4e2/h. In quantizing magnetic fields normal to the sample plane, we recover the four-fold Landau level degeneracy of bilayer graphene. Unexpected mode crossings appear at the crossover between zero magnetic field and the quantum Hall regime. PMID- 29286669 TI - Star-Like CBe5Au5+ Cluster: Planar Pentacoordinate Carbon, Superalkali Cation, and Multifold (pi and sigma) Aromaticity. AB - We report on the computational design of star-like CBe5Au5+ cluster with planar pentacoordinate carbon (ppC), which is also classified as a superalkali cation. Relevant isovalent CBe5Aunn-4 (n = 2-4), BBe5Au5, and NBe5Au52+ clusters with ppC/B/N are studied as well. Global-minimum structures of the clusters are established via computer global searches. The species feature a pentacoordinate pentagonal XBe5 (X = C, B, N) core, with Au occupying outer bridging positions. Molecular dynamics simulations indicate that they are dynamically stable. Bonding analysis reveals 3-fold (pi and sigma) aromaticity in CBe5Au5+, a key concept that overrides the 18-electron rule and should be applicable for (or help revisit existing models of) other planar hypercoordinate systems. Vertical electron affinities of CBe5Au5+ and its lighter counterparts (CBe5Cu5+ and CBe5Ag5+) are calculated to be unusually low, which are below 3.89 eV, the smallest atomic ionization potential of any element in the periodic table. Thus, these three clusters belong to superalkali cations. The merge of ppC and superalkali characters makes them unique chemical species. PMID- 29286670 TI - Monochromatic Photocathodes from Graphene-Stabilized Diamondoids. AB - The monochromatic photoemission from diamondoid monolayers provides a new strategy to create electron sources with low energy dispersion and enables compact electron guns with high brightness and low beam emittance for aberration free imaging, lithography, and accelerators. However, these potential applications are hindered by degradation of diamondoid monolayers under photon irradiation and electron bombardment. Here, we report a graphene-protected diamondoid monolayer photocathode with 4-fold enhancement of stability compared to the bare diamondoid counterpart. The single-layer graphene overcoating preserves the monochromaticity of the photoelectrons, showing 12.5 meV ful width at half-maximum distribution of kinetic energy. Importantly, the graphene coating effectively suppresses desorption of the diamondoid monolayer, enhancing its thermal stability by at least 100 K. Furthermore, by comparing the decay rate at different photon energies, we identify electron bombardment as the principle decay pathway for diamondoids under graphene protection. This provides a generic approach for stabilizing volatile species on photocathode surfaces, which could greatly improve performance of electron emitters. PMID- 29286671 TI - Theoretical Investigation of the Reaction Mechanism of Photodeamination Induced by Excited-State Intramolecular Proton Transfer of Cresol Derivatives. AB - The novel photodeamination process of cresol derivatives 1 and 3 has been reported experimentally ( J. Org. Chem . 2015 , 80 , 10817 ). However, a full theoretical interpretation of the mechanism is still lacking. In the present study, we aim to provide insight into the factors that promote the deamination reaction through density functional theory (DFT) and time-dependent DFT methods. Calculated absorption and emission spectra are in good agreement with the experimental results. Hydrogen-bond strengthening in the excited state has been verified by analyzing relevant bond parameters and vibrational frequencies as well as frontier molecular orbitals (FMOs), implying that hydrogen-bond interaction acts as the important parameter for the excited-state intramolecular proton-transfer (ESIPT) reaction. The proton-transfer and deamination reactions have been qualitatively analyzed through Gibbs free-energy reaction profiles in different electronic states. It can be concluded that the ESIPT and photodeamination reactions occur in the excited state. To further illustrate the photodeamination mechanism, the constructed 2D potential-energy surface indicates that the photodeamination reaction is infeasible without the ESIPT reaction. This work provides the first theoretical rationale for ESIPT-induced photodeamination occurring spontaneously because of protonation of a basic nitrogen atom. PMID- 29286672 TI - Application of the CC(P;Q) Hierarchy of Coupled-Cluster Methods to the Beryllium Dimer. AB - The performance of coupled-cluster approaches with higher-than-doubly excited clusters, including the CCSD(T), CCSD(2)T, CR-CC(2,3), CCSD(TQ), and CR-CC(2,4) corrections to CCSD, the active-space CCSDt, CCSDtq, and CCSDTq methods, and the CC(t;3), CC(t,q;3), CC(t,q;3,4), and CC(q;4) corrections to CCSDt, CCSDtq, and CCSDTq resulting from the CC(P;Q) formalism, in reproducing the CCSDT and CCSDTQ potential energy curves and vibrational term values characterizing Be2 in its electronic ground state is assessed. The correlation-consistent aug-cc-pVnZ and aug-cc-pCVnZ (n = T and Q) basis sets are employed. Among the CCSD-based corrections, the completely renormalized CR-CC(2,3) and CR-CC(2,4) approaches perform the best. The CC(t;3), CC(t,q;3), CC(t,q;3,4), and CC(q;4) methods, especially CC(t;3) and CC(q;4), outperform other employed approaches in reproducing the CCSDT and CCSDTQ data. Composite schemes combining the all electron CCSDT calculations extrapolated to the complete basis set limit with the frozen-core CC(q;4) and CCSDTQ computations using the aug-cc-pVTZ basis to account for connected quadruple excitations reproduce the latest experimental vibrational spectrum of Be2 to within 4-5 cm-1, when the vibrational spacings are examined, with typical errors being below 1-2 cm-1. The resulting binding energies and equilibrium bond lengths agree with their experimentally derived counterparts to within ~10 cm-1 and 0.01 A. PMID- 29286673 TI - Can Supported Reduced Vanadium Oxides form H2 from CH3OH? A Computational Gas Phase Mechanistic Study. AB - A detailed density functional theory study is presented to clarify the mechanistic aspects of the methanol (CH3OH) dehydrogenation process to yield hydrogen (H2) and formaldehyde (CH2O). A gas-phase vanadium oxide cluster is used as a model system to represent reduced V(III) oxides supported on TiO2 catalyst. The theoretical results provide a complete scenario, involving several reaction pathways in which different methanol adsorption sites are considered, with presence of hydride and methoxide intermediates. Methanol dissociative adsorption process is both kinetically and thermodynamically feasible on V-O-Ti and V?O sites, and it might lead to form hydride species with interesting catalytic reactivity. The formation of H2 and CH2O on reduced vanadium sites, V(III), is found to be more favorable than for oxidized vanadium species, V(V), taking place along energy barriers of 29.9 and 41.0 kcal/mol, respectively. PMID- 29286674 TI - A Lubricant-Sandwiched Coating with Long-Term Stable Anticorrosion Performance. AB - Lubricant-infused surface(s) (LIS) bioinspired by the Nepenthes pitcher plant are receiving enormous attention owing to their excellent hydrophobicity as well as their self-healing ability. Thus, they have been applied as anticorrosion coatings. However, the loss of lubricant mediated by vapor or other liquids deteriorates their functions. Herein, we introduce a lubricant-inserted (sandwiched) microporous triple-layered surface (LIMITS) that prevents the sudden loss of lubricant. The sandwiched lubricant gradually self-secretes toward the surface, resulting in long-term stability even under water. The LIMITS prevented the corrosion of the Fe plate for at least 45 days, which is much superior to a conventional LIS coating. This work opens an avenue for the application of slippery coating materials that are stable under water and will also promote the development of anticorrosion coating in various industries. PMID- 29286675 TI - Roles of Textural and Surface Properties of Nanoparticles in Ultrasound Responsive Systems. AB - Acoustic inertial cavitation (IC) is a crucial phenomenon for many ultrasound (US)-related applications. This study aimed to investigate the roles of textural and surface properties of NPs in IC generation by combining typical IC detection methods with various types of silica model NPs. Acoustic passive cavitation detection, optical high-speed photography, and US imaging have been used to quantify IC activities (referred to as the IC dose, ICD) and describe the physical characteristics of IC activities from NPs. The results showed that the ICDs from NPs were positively correlated to their surface hydrophobicity and that their external surface hydrophobicity plays a much more crucial role than do the textural properties. The high-speed photography revealed that the sizes of IC generated bubbles from superhydrophobic NPs ranged from 20-40 MUm at 4-6 MPa and collapsed in several microseconds. Bubble clouds monitored with US imaging showed that IC from NPs was consistent with the surface hydrophobicity. The simulation results based on the crevice model of cavitation nuclei correlated well with the experimental results. This study has demonstrated that the surface property, instead of the textural property, of NPs dominated the IC generation, and surface nanobubbles adsorbed on the NP surface have been proposed to be cavitation nuclei. PMID- 29286676 TI - Enhancing Coherent Light-Matter Interactions through Microcavity-Engineered Plasmonic Resonances. AB - Quantum manipulation is challenging in localized-surface plasmon resonances (LSPRs) due to strong dissipations. To enhance quantum coherence, here we propose to engineer the electromagnetic environment of LSPRs by placing metallic nanoparticles (MNPs) in optical microcavities. An analytical quantum model is first built to describe the LSPR-microcavity interaction, revealing the significantly enhanced coherent radiation and the reduced incoherent dissipation. Furthermore, when a quantum emitter interacts with the LSPRs in the cavity engineered environment, its quantum yield is enhanced over 40 times and the radiative power over one order of magnitude, compared to those in the vacuum environment. Importantly, the cavity-engineered MNP-emitter system can enter the strong coupling regime of cavity quantum electrodynamics, providing a promising platform for the study of quantum plasmonics, quantum information processing, precise sensing, and spectroscopy. PMID- 29286677 TI - Melde's Experiment on a Vibrating Liquid Foam Microchannel. AB - We subject a single Plateau border channel to a transverse harmonic excitation, in an experiment reminiscent of the historical one by Melde on vibrating strings, to study foam stability and wave properties. At low driving amplitudes, the liquid string exhibits regular oscillations. At large ones, a nonlinear regime appears and the acoustic radiation splits the channel into two zones of different cross section area, vibration amplitude, and phase difference with the neighboring soap films. The channel experiences an inertial dilatancy that is accounted for by a new Bernoulli-like relation. PMID- 29286679 TI - Full Counting Statistics for Interacting Fermions with Determinantal Quantum Monte Carlo Simulations. AB - We present a method for computing the full probability distribution function of quadratic observables such as particle number or magnetization for the Fermi Hubbard model within the framework of determinantal quantum Monte Carlo calculations. Especially in cold atom experiments with single-site resolution, such a full counting statistics can be obtained from repeated projective measurements. We demonstrate that the full counting statistics can provide important information on the size of preformed pairs. Furthermore, we compute the full counting statistics of the staggered magnetization in the repulsive Hubbard model at half filling and find excellent agreement with recent experimental results. We show that current experiments are capable of probing the difference between the Hubbard model and the limiting Heisenberg model. PMID- 29286681 TI - Spin-Mechanical Scheme with Color Centers in Hexagonal Boron Nitride Membranes. AB - Recently observed quantum emitters in hexagonal boron nitride (hBN) membranes have a potential for achieving high accessibility and controllability thanks to the lower spatial dimension. Moreover, these objects naturally have a high sensitivity to vibrations of the hosting membrane due to its low mass density and high elasticity modulus. Here, we propose and analyze a spin-mechanical system based on color centers in a suspended hBN mechanical resonator. Through group theoretical analyses and ab initio calculation of the electronic and spin properties of such a system, we identify a spin doublet ground state and demonstrate that a spin-motion interaction can be engineered, which enables ground-state cooling of the mechanical resonator. We also present a toolbox for initialization, rotation, and readout of the defect spin qubit. As a result, the proposed setup presents the possibility for studying a wide range of physics. To illustrate its assets, we show that a fast and noise-resilient preparation of a multicomponent cat state and a squeezed state of the mechanical resonator is possible; the latter is achieved by realizing the extremely detuned, ultrastrong coupling regime of the Rabi model, where a phonon superradiant phase transition is expected to occur. PMID- 29286680 TI - Switching Molecular Conformation with the Torque on a Single Magnetic Moment. AB - For the endohedral fullerene molecule HoLu_{2}N@C_{80}, it is shown that the endohedral HoLu_{2}N unit may be oriented in a magnetic field. The Ho magnetic moment is fixed in the strong ligand field and aligns along the holmium-nitrogen axis. The torque of a magnetic field on the Ho magnetic moment leads to a hopping bias of the endohedral unit inclining to an orientation parallel to the externally applied field. This endohedral cluster distribution remains frozen below the onset of thermally induced rotation of the endohedral units. We derive an analytical statistical model for the description of the effect that scales below 7 T with the square of the external field strength, and that allows us to resolve the freezing temperature of the endohedral hopping motion. The freezing temperature is around 55 K and depends on the cooling rate, which in turn determines an activation energy for the hopping motion of 185 meV and a prefactor of 1.8*10^{14} s^{-1}. For TbSc_{2}N@C_{80} we find the same behavior with a 3.5% higher freezing temperature. PMID- 29286682 TI - Doublon-Holon Origin of the Subpeaks at the Hubbard Band Edges. AB - Dynamical mean-field theory (DMFT) studies frequently observe a fine structure in the local spectral function of the SU(2) Fermi-Hubbard model at half filling: In the metallic phase close to the Mott transition, subpeaks emerge at the inner edges of the Hubbard bands. Here we demonstrate that these subpeaks originate from the low-energy effective interaction of doublon-holon pairs, by investigating how the correlation functions of doublon and holon operators contribute to the subpeaks. A mean-field analysis of the low-energy effective Hamiltonian provides results consistent with our DMFT calculation using the numerical renormalization group as an impurity solver. In the SU(3) and SU(4) Hubbard models, the subpeaks become more pronounced due to the increased degeneracy of doublon-holon pair excitations. PMID- 29286683 TI - Anisotropic Superattenuation of Capillary Waves on Driven Glass Interfaces. AB - Metrological atomic force microscopy measurements are performed on the silica glass interfaces of photonic band-gap fibers and hollow capillaries. The freezing of attenuated out-of-equilibrium capillary waves during the drawing process is shown to result in a reduced surface roughness. The roughness attenuation with respect to the expected thermodynamical limit is determined to vary with the drawing stress following a power law. A striking anisotropic character of the height correlation is observed: glass surfaces thus retain a structural record of the direction of the flow to which the liquid was submitted. PMID- 29286684 TI - Three-Dimensional General-Relativistic Magnetohydrodynamic Simulations of Remnant Accretion Disks from Neutron Star Mergers: Outflows and r-Process Nucleosynthesis. AB - The merger of binary neutron stars, or of a neutron star and a stellar-mass black hole, can result in the formation of a massive rotating torus around a spinning black hole. In addition to providing collimating media for gamma-ray burst jets, unbound outflows from these disks are an important source of mass ejection and rapid neutron capture (r-process) nucleosynthesis. We present the first three dimensional general-relativistic magnetohydrodynamic (GRMHD) simulations of neutrino-cooled accretion disks in neutron star mergers, including a realistic equation of state valid at low densities and temperatures, self-consistent evolution of the electron fraction, and neutrino cooling through an approximate leakage scheme. After initial magnetic field amplification by magnetic winding, we witness the vigorous onset of turbulence driven by the magnetorotational instability (MRI). The disk quickly reaches a balance between heating from MRI driven turbulence and neutrino cooling, which regulates the midplane electron fraction to a low equilibrium value Y_{e}~0.1. Over the 380-ms duration of the simulation, we find that a fraction ~20% of the initial torus mass is unbound in powerful outflows with asymptotic velocities v~0.1c and electron fractions Y_{e}~0.1-0.25. Postprocessing the outflows through a nuclear reaction network shows the production of a robust second- and third-peak r process. Though broadly consistent with the results of previous axisymmetric hydrodynamical simulations, extrapolation of our results to late times suggests that the total ejecta mass from GRMHD disks is significantly higher. Our results provide strong evidence that postmerger disk outflows are an important site for the r process. PMID- 29286685 TI - Link between the Superconducting Dome and Spin-Orbit Interaction in the (111) LaAlO_{3}/SrTiO_{3} Interface. AB - We measure the gate voltage (V_{g}) dependence of the superconducting properties and the spin-orbit interaction in the (111)-oriented LaAlO_{3}/SrTiO_{3} interface. Superconductivity is observed in a dome-shaped region in the carrier density-temperature phase diagram with the maxima of superconducting transition temperature T_{c} and the upper critical fields lying at the same V_{g}. The spin orbit interaction determined from the superconducting parameters and confirmed by weak-antilocalization measurements follows the same gate voltage dependence as T_{c}. The correlation between the superconductivity and spin-orbit interaction as well as the enhancement of the parallel upper critical field, well beyond the Chandrasekhar-Clogston limit, suggest that superconductivity and the spin-orbit interaction are linked in a nontrivial fashion. We propose possible scenarios to explain this unconventional behavior. PMID- 29286686 TI - Chemical Continuous Time Random Walks. AB - Kinetic Monte Carlo methods such as the Gillespie algorithm model chemical reactions as random walks in particle number space. The interreaction times are exponentially distributed under the assumption that the system is well mixed. We introduce an arbitrary interreaction time distribution, which may account for the impact of incomplete mixing on chemical reactions, and in general stochastic reaction delay, which may represent the impact of extrinsic noise. This process defines an inhomogeneous continuous time random walk in particle number space, from which we derive a generalized chemical master equation. This leads naturally to a generalization of the Gillespie algorithm. Based on this formalism, we determine the modified chemical rate laws for different interreaction time distributions. This framework traces Michaelis-Menten-type kinetics back to finite-mean delay times, and predicts time-nonlocal macroscopic reaction kinetics as a consequence of broadly distributed delays. Non-Markovian kinetics exhibit weak ergodicity breaking and show key features of reactions under local nonequilibrium. PMID- 29286687 TI - Fate of the Hoop Conjecture in Quantum Gravity. AB - We consider a closed region R of 3D quantum space described via SU(2) spin networks. Using the concentration of measure phenomenon we prove that, whenever the ratio between the boundary ?R and the bulk edges of the graph overcomes a finite threshold, the state of the boundary is always thermal, with an entropy proportional to its area. The emergence of a thermal state of the boundary can be traced back to a large amount of entanglement between boundary and bulk degrees of freedom. Using the dual geometric interpretation provided by loop quantum gravity, we interpret such phenomenon as a pregeometric analogue of Thorne's "hoop conjecture," at the core of the formation of a horizon in general relativity. PMID- 29286688 TI - Large Longitudinal Spin Alignment of Excited Projectiles in Intermediate Energy Inelastic Scattering. AB - We study the sequential breakup of E/A=24.0 MeV ^{7}Li projectiles excited through inelastic interactions with C, Be, and Al target nuclei. For peripheral events that do not excite the target, we find very large spin alignment of the excited ^{7}Li projectiles longitudinal to the beam axis. This spin alignment is independent of the target used, and we propose a simple alignment mechanism that arises from an angular-momentum-excitation-energy mismatch. This mechanism is independent of the potential used for scattering and should be present in many scattering experiments. PMID- 29286689 TI - Efimov States of Strongly Interacting Photons. AB - We demonstrate the emergence of universal Efimov physics for interacting photons in cold gases of Rydberg atoms. We consider the behavior of three photons injected into the gas in their propagating frame, where a paraxial approximation allows us to consider them as massive particles. In contrast to atoms and nuclei, the photons have a large anisotropy between their longitudinal mass, arising from dispersion, and their transverse mass, arising from diffraction. Nevertheless, we show that, in suitably rescaled coordinates, the effective interactions become dominated by s-wave scattering near threshold and, as a result, give rise to an Efimov effect near unitarity. We show that the three-body loss of these Efimov trimers can be strongly suppressed and determine conditions under which these states are observable in current experiments. These effects can be naturally extended to probe few-body universality beyond three bodies, as well as the role of Efimov physics in the nonequilibrium, many-body regime. PMID- 29286690 TI - Resource Theory of Superposition. AB - The superposition principle lies at the heart of many nonclassical properties of quantum mechanics. Motivated by this, we introduce a rigorous resource theory framework for the quantification of superposition of a finite number of linear independent states. This theory is a generalization of resource theories of coherence. We determine the general structure of operations which do not create superposition, find a fundamental connection to unambiguous state discrimination, and propose several quantitative superposition measures. Using this theory, we show that trace decreasing operations can be completed for free which, when specialized to the theory of coherence, resolves an outstanding open question and is used to address the free probabilistic transformation between pure states. Finally, we prove that linearly independent superposition is a necessary and sufficient condition for the faithful creation of entanglement in discrete settings, establishing a strong structural connection between our theory of superposition and entanglement theory. PMID- 29286691 TI - Neel-Type Skyrmion Lattice in the Tetragonal Polar Magnet VOSe_{2}O_{5}. AB - The formation of the triangular Skyrmion lattice is found in a tetragonal polar magnet VOSe_{2}O_{5}. By magnetization and small-angle neutron scattering measurements on the single crystals, we identify a cycloidal spin state at zero field and a Neel-type Skyrmion-lattice phase under a magnetic field along the polar axis. Adjacent to this phase, another magnetic phase of an incommensurate spin texture is identified at lower temperatures, tentatively assigned to a square Skyrmion-lattice phase. These findings exemplify the versatile features of Neel-type Skyrmions in bulk materials, and provide a further opportunity to explore the physics of topological spin textures in polar magnets. PMID- 29286692 TI - Three-Dimensional Localized-Delocalized Anderson Transition in the Time Domain. AB - Systems which can spontaneously reveal periodic evolution are dubbed time crystals. This is in analogy with space crystals that display periodic behavior in configuration space. While space crystals are modeled with the help of space periodic potentials, crystalline phenomena in time can be modeled by periodically driven systems. Disorder in the periodic driving can lead to Anderson localization in time: the probability for detecting a system at a fixed point of configuration space becomes exponentially localized around a certain moment in time. We here show that a three-dimensional system exposed to a properly disordered pseudoperiodic driving may display a localized-delocalized Anderson transition in the time domain, in strong analogy with the usual three-dimensional Anderson transition in disordered systems. Such a transition could be experimentally observed with ultracold atomic gases. PMID- 29286693 TI - Dynamo Enhancement and Mode Selection Triggered by High Magnetic Permeability. AB - We present results from consistent dynamo simulations, where the electrically conducting and incompressible flow inside a cylinder vessel is forced by moving impellers numerically implemented by a penalization method. The numerical scheme models jumps of magnetic permeability for the solid impellers, resembling various configurations tested experimentally in the von Karman sodium experiment. The most striking experimental observations are reproduced in our set of simulations. In particular, we report on the existence of a time-averaged axisymmetric dynamo mode, self-consistently generated when the magnetic permeability of the impellers exceeds a threshold. We describe a possible scenario involving both the turbulent flow in the vicinity of the impellers and the high magnetic permeability of the impellers. PMID- 29286694 TI - Observation of a Degenerate Fermi Gas Trapped by a Bose-Einstein Condensate. AB - We report on the formation of a stable quantum degenerate mixture of fermionic ^{6}Li and bosonic ^{133}Cs in an optical trap by sympathetic cooling near an interspecies Feshbach resonance. New regimes of quantum degenerate Bose-Fermi mixtures are identified. With moderate attractive interspecies interactions, we show that a degenerate Fermi gas of Li can be fully confined in a Cs Bose Einstein condensate without external potentials. For stronger attraction where mean-field collapse is expected, no such instability is observed. Potential mechanisms to explain this phenomenon are discussed. PMID- 29286695 TI - Bounding the Set of Classical Correlations of a Many-Body System. AB - We present a method to certify the presence of Bell correlations in experimentally observed statistics, and to obtain new Bell inequalities. Our approach is based on relaxing the conditions defining the set of correlations obeying a local hidden variable model, yielding a convergent hierarchy of semidefinite programs (SDP's). Because the size of these SDP's is independent of the number of parties involved, this technique allows us to characterize correlations in many-body systems. As an example, we illustrate our method with the experimental data presented in Science 352, 441 (2016)SCIEAS0036 807510.1126/science.aad8665. PMID- 29286696 TI - Observation of Caroli-de Gennes-Matricon Vortex States in YBa_{2}Cu_{3}O_{7 delta}. AB - The copper oxides present the highest superconducting temperature and properties at odds with other compounds, suggestive of a fundamentally different superconductivity. In particular, the Abrikosov vortices fail to exhibit localized states expected and observed in all clean superconductors. We have explored the possibility that the elusive vortex-core signatures are actually present but weak. Combining local tunneling measurements with large-scale theoretical modeling, we positively identify the vortex states in YBa_{2}Cu_{3}O_{7-delta}. We explain their spectrum and the observed variations thereof from one vortex to the next by considering the effects of nearby vortices and disorder in the vortex lattice. We argue that the superconductivity of copper oxides is conventional, but the spectroscopic signature does not look so because the superconducting carriers are a minority. PMID- 29286697 TI - Observation of Terahertz Radiation via the Two-Color Laser Scheme with Uncommon Frequency Ratios. AB - In the widely studied two-color laser scheme for terahertz (THz) radiation from a gas, the frequency ratio of the two lasers is usually fixed at omega_{2}/omega_{1}=1:2. We investigate THz generation with uncommon frequency ratios. Our experiments show, for the first time, efficient THz generation with new ratios of omega_{2}/omega_{1}=1:4 and 2?3. We observe that the THz polarization can be adjusted by rotating the longer-wavelength laser polarization and the polarization adjustment becomes inefficient by rotating the other laser polarization; the THz energy shows similar scaling laws with different frequency ratios. These observations are inconsistent with multiwave mixing theory, but support the gas-ionization or plasma-current model. This study pushes the development of the two-color scheme and provides a new dimension to explore the long-standing problem of the THz generation mechanism. PMID- 29286698 TI - Helimagnon Resonances in an Intrinsic Chiral Magnonic Crystal. AB - We experimentally study magnetic resonances in the helical and conical magnetic phases of the chiral magnetic insulator Cu_{2}OSeO_{3} at the temperature T=5 K. Using a broadband microwave spectroscopy technique based on vector network analysis, we identify three distinct sets of helimagnon resonances in the frequency range 2 GHz<=f<=20 GHz with low magnetic damping alpha<=0.003. The extracted resonance frequencies are in accordance with calculations of the helimagnon band structure found in an intrinsic chiral magnonic crystal. The periodic modulation of the equilibrium spin direction that leads to the formation of the magnonic crystal is a direct consequence of the chiral magnetic ordering caused by the Dzyaloshinskii-Moriya interaction. The mode coupling in the magnonic crystal allows excitation of helimagnons with wave vectors that are multiples of the spiral wave vector. PMID- 29286699 TI - Destabilization of Magnetic Order in a Dilute Kitaev Spin Liquid Candidate. AB - The insulating honeycomb magnet alpha-RuCl_{3} exhibits fractionalized excitations that signal its proximity to a Kitaev quantum spin liquid state; however, at T=0, fragile long-range magnetic order arises from non-Kitaev terms in the Hamiltonian. Spin vacancies in the form of Ir^{3+} substituted for Ru are found to destabilize this long-range order. Neutron diffraction and bulk characterization of Ru_{1-x}Ir_{x}Cl_{3} show that the magnetic ordering temperature is suppressed with increasing x, and evidence of zizag magnetic order is absent for x>0.3. Inelastic neutron scattering demonstrates that the signature of fractionalized excitations is maintained over the full range of x investigated. The depleted lattice without magnetic order thus hosts a spin liquid-like ground state that may indicate the relevance of Kitaev physics in the magnetically dilute limit of RuCl_{3}. PMID- 29286700 TI - Nanoscale Particle Motion in Attractive Polymer Nanocomposites. AB - Using x-ray photon correlation spectroscopy, we examined the slow nanoscale motion of silica nanoparticles individually dispersed in an entangled poly (ethylene oxide) melt at particle volume fractions up to 42%. The nanoparticles, therefore, serve as both fillers for the resulting attractive polymer nanocomposites and probes for the network dynamics therein. The results show that the particle relaxation closely follows the mechanical reinforcement in the nanocomposites only at the intermediate concentrations below the critical value for the chain confinement. Quite unexpectedly, the relaxation time of the particles does not further slow down at higher volume fractions-when all chains are practically on the nanoparticle interface-and decouples from the elastic modulus of the nanocomposites that further increases orders of magnitude. PMID- 29286701 TI - Probing the Bond Order Wave Phase Transitions of the Ionic Hubbard Model by Superlattice Modulation Spectroscopy. AB - An exotic phase, the bond order wave, characterized by the spontaneous dimerization of the hopping, has been predicted to exist sandwiched between the band and Mott insulators in systems described by the ionic Hubbard model. Despite growing theoretical evidence, this phase still evades experimental detection. Given the recent realization of the ionic Hubbard model in ultracold atomic gases, we propose here to detect the bond order wave using superlattice modulation spectroscopy. We demonstrate, with the help of time-dependent density matrix renormalization group and bosonization, that this spectroscopic approach reveals characteristics of both the Ising and Kosterlitz-Thouless transitions signaling the presence of the bond order wave phase. This scheme also provides insights into the excitation spectra of both the band and Mott insulators. PMID- 29286702 TI - Phase Stochastic Resonance in a Forced Nanoelectromechanical Membrane. AB - Stochastic resonance is a general phenomenon usually observed in one-dimensional, amplitude modulated, bistable systems. We show experimentally the emergence of phase stochastic resonance in the bidimensional response of a forced nanoelectromechanical membrane by evidencing the enhancement of a weak phase modulated signal thanks to the addition of phase noise. Based on a general forced Duffing oscillator model, we demonstrate experimentally and theoretically that phase noise acts multiplicatively, inducing important physical consequences. These results may open interesting prospects for phase noise metrology or coherent signal transmission applications in nanomechanical oscillators. Moreover, our approach, due to its general character, may apply to various systems. PMID- 29286703 TI - Emergence of Non-Abelian Magnetic Monopoles in a Quantum Impurity Problem. AB - Recently, it was shown that molecules rotating in superfluid helium can be described in terms of the angulon quasiparticles [Phys. Rev. Lett. 118, 095301 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.095301]. Here, we demonstrate that in the experimentally realized regime the angulon can be seen as a point charge on a two-sphere interacting with a gauge field of a non-Abelian magnetic monopole. Unlike in several other settings, the gauge fields of the angulon problem emerge in the real coordinate space, as opposed to the momentum space or some effective parameter space. Furthermore, we find a topological transition associated with making the monopole Abelian, which takes place in the vicinity of the previously reported angulon instabilities. These results pave the way for studying topological phenomena in experiments on molecules trapped in superfluid helium nanodroplets, as well as on other realizations of orbital impurity problems. PMID- 29286704 TI - Demonstration of Two-Atom Entanglement with Ultrafast Optical Pulses. AB - We demonstrate quantum entanglement of two trapped atomic ion qubits using a sequence of ultrafast laser pulses. Unlike previous demonstrations of entanglement mediated by the Coulomb interaction, this scheme does not require confinement to the Lamb-Dicke regime and can be less sensitive to ambient noise due to its speed. To elucidate the physics of an ultrafast phase gate, we generate a high entanglement rate using just ten pulses, each of ~20 ps duration, and demonstrate an entangled Bell state with (76+/-1)% fidelity. These results pave the way for entanglement operations within a large collection of qubits by exciting only local modes of motion. PMID- 29286707 TI - Cascading Failures as Continuous Phase-Space Transitions. AB - In network systems, a local perturbation can amplify as it propagates, potentially leading to a large-scale cascading failure. Here we derive a continuous model to advance our understanding of cascading failures in power-grid networks. The model accounts for both the failure of transmission lines and the desynchronization of power generators and incorporates the transient dynamics between successive steps of the cascade. In this framework, we show that a cascade event is a phase-space transition from an equilibrium state with high energy to an equilibrium state with lower energy, which can be suitably described in a closed form using a global Hamiltonian-like function. From this function, we show that a perturbed system cannot always reach the equilibrium state predicted by quasi-steady-state cascade models, which would correspond to a reduced number of failures, and may instead undergo a larger cascade. We also show that, in the presence of two or more perturbations, the outcome depends strongly on the order and timing of the individual perturbations. These results offer new insights into the current understanding of cascading dynamics, with potential implications for control interventions. PMID- 29286706 TI - Melting Curve and Liquid Structure of Nitrogen Probed by X-ray Diffraction to 120 GPa. AB - Synchrotron x-ray diffraction measurements of nitrogen are performed up to 120 GPa to determine the melting curve and the structural changes of the solid and liquid phases along it. The melting temperature exhibits a monotonic increase up to the triple point where the epsilon molecular solid, the cubic gauche covalent solid, and the fluid meet at 116 GPa, 2080 K. Above, the stability of the cubic gauche phase induces a sharp increase of the melting curve. The structural data on liquid nitrogen show that the latter remains molecular over the whole probed domain, which contradicts the prediction of a liquid-liquid transition at 88 GPa, 2000 K. These findings thus largely revisit the phase diagram of hot dense nitrogen and challenge the current understanding of this model system. PMID- 29286705 TI - MICROSCOPE Mission: First Results of a Space Test of the Equivalence Principle. AB - According to the weak equivalence principle, all bodies should fall at the same rate in a gravitational field. The MICROSCOPE satellite, launched in April 2016, aims to test its validity at the 10^{-15} precision level, by measuring the force required to maintain two test masses (of titanium and platinum alloys) exactly in the same orbit. A nonvanishing result would correspond to a violation of the equivalence principle, or to the discovery of a new long-range force. Analysis of the first data gives delta(Ti,Pt)=[-1+/-9(stat)+/-9(syst)]*10^{-15} (1sigma statistical uncertainty) for the titanium-platinum Eotvos parameter characterizing the relative difference in their free-fall accelerations. PMID- 29286708 TI - Indications for a High-Rigidity Break in the Cosmic-Ray Diffusion Coefficient. AB - Using cosmic-ray boron to carbon ratio (B/C) data recently released by the Ams-02 experiment, we find indications (decisive evidence, in Bayesian terms) in favor of a diffusive propagation origin for the broken power-law spectra found in protons (p) and helium nuclei (He). The result is robust with respect to currently estimated uncertainties in the cross sections, and in the presence of a small component of primary boron, expected because of spallation at the acceleration site. Reduced errors at high energy as well as further cosmic ray nuclei data (as absolute spectra of C, N, O, Li, Be) may definitively confirm this scenario. PMID- 29286710 TI - Generic Primary Mechanical Response of Viscous Liquids. AB - Four decades ago a seminal review by Jonscher [Nature (London) 267, 673 (1977)NATUAS0028-083610.1038/267673a0] revealed that the dielectric response of conducting materials is characterized by a "remarkable universality". Demonstrating that the same response pattern is exhibited also by shear rheological spectra of nonpolymeric viscous liquids, the present contribution connects two branches of condensed matter physics: Concepts developed for charge transport can be employed for the description of mass flow and vice versa. Based on the virtual equivalence of the two dynamics a connection is established between microscopic and macroscopic viscoelastic characteristics of liquids, resembling the Barton-Nakajima-Namikawa relation for conductivity. PMID- 29286709 TI - Diffraction-Limited Plenoptic Imaging with Correlated Light. AB - Traditional optical imaging faces an unavoidable trade-off between resolution and depth of field (DOF). To increase resolution, high numerical apertures (NAs) are needed, but the associated large angular uncertainty results in a limited range of depths that can be put in sharp focus. Plenoptic imaging was introduced a few years ago to remedy this trade-off. To this aim, plenoptic imaging reconstructs the path of light rays from the lens to the sensor. However, the improvement offered by standard plenoptic imaging is practical and not fundamental: The increased DOF leads to a proportional reduction of the resolution well above the diffraction limit imposed by the lens NA. In this Letter, we demonstrate that correlation measurements enable pushing plenoptic imaging to its fundamental limits of both resolution and DOF. Namely, we demonstrate maintaining the imaging resolution at the diffraction limit while increasing the depth of field by a factor of 7. Our results represent the theoretical and experimental basis for the effective development of promising applications of plenoptic imaging. PMID- 29286711 TI - Spin Entanglement Witness for Quantum Gravity. AB - Understanding gravity in the framework of quantum mechanics is one of the great challenges in modern physics. However, the lack of empirical evidence has lead to a debate on whether gravity is a quantum entity. Despite varied proposed probes for quantum gravity, it is fair to say that there are no feasible ideas yet to test its quantum coherent behavior directly in a laboratory experiment. Here, we introduce an idea for such a test based on the principle that two objects cannot be entangled without a quantum mediator. We show that despite the weakness of gravity, the phase evolution induced by the gravitational interaction of two micron size test masses in adjacent matter-wave interferometers can detectably entangle them even when they are placed far apart enough to keep Casimir-Polder forces at bay. We provide a prescription for witnessing this entanglement, which certifies gravity as a quantum coherent mediator, through simple spin correlation measurements. PMID- 29286713 TI - High-Q Supercavity Modes in Subwavelength Dielectric Resonators. AB - Recent progress in nanoscale optical physics is associated with the development of a new branch of nanophotonics exploring strong Mie resonances in dielectric nanoparticles with a high refractive index. The high-index resonant dielectric nanostructures form building blocks for novel photonic metadevices with low losses and advanced functionalities. However, unlike extensively studied cavities in photonic crystals, such dielectric resonators demonstrate low quality factors (Q factors). Here, we uncover a novel mechanism for achieving giant Q factors of subwavelength nanoscale resonators by realizing the regime of bound states in the continuum. In contrast to the previously suggested multilayer structures with zero permittivity, we reveal strong mode coupling and Fano resonances in homogeneous high-index dielectric finite-length nanorods resulting in high-Q factors at the nanoscale. Thus, high-index dielectric resonators represent the simplest example of nanophotonic supercavities, expanding substantially the range of applications of all-dielectric resonant nanophotonics and meta-optics. PMID- 29286712 TI - Real-Space Imaging of the Tailored Plasmons in Twisted Bilayer Graphene. AB - We report a systematic plasmonic study of twisted bilayer graphene (TBLG)-two graphene layers stacked with a twist angle. Through real-space nanoimaging of TBLG single crystals with a wide distribution of twist angles, we find that TBLG supports confined infrared plasmons that are sensitively dependent on the twist angle. At small twist angles, TBLG has a plasmon wavelength comparable to that of single-layer graphene. At larger twist angles, the plasmon wavelength of TBLG increases significantly with apparently lower damping. Further analysis and modeling indicate that the observed twist-angle dependence of TBLG plasmons in the Dirac linear regime is mainly due to the Fermi-velocity renormalization, a direct consequence of interlayer electronic coupling. Our work unveils the tailored plasmonic characteristics of TBLG and deepens our understanding of the intriguing nano-optical physics in novel van der Waals coupled two-dimensional materials. PMID- 29286714 TI - Nonlinear Stimulated Raman Exact Passage by Resonance-Locked Inverse Engineering. AB - We derive an exact and robust stimulated Raman process for nonlinear quantum systems driven by pulsed external fields. The external fields are designed with closed-form expressions from the inverse engineering of a given efficient and stable dynamics. This technique allows one to induce a controlled population inversion which surpasses the usual nonlinear stimulated Raman adiabatic passage efficiency. PMID- 29286715 TI - Effective Thermodynamics for a Marginal Observer. AB - Thermodynamics is usually formulated on the presumption that the observer has complete information about the system he or she deals with: no parasitic current, exact evaluation of the forces that drive the system. For example, the acclaimed fluctuation relation (FR), relating the probability of time-forward and time reversed trajectories, assumes that the measurable transitions suffice to characterize the process as Markovian (in our case, a continuous-time jump process). However, most often the observer only measures a marginal current. We show that he or she will nonetheless produce an effective description that does not dispense with the fundamentals of thermodynamics, including the FR and the 2nd law. Our results stand on the mathematical construction of a hidden time reversal of the dynamics, and on the physical requirement that the observed current only accounts for a single transition in the configuration space of the system. We employ a simple abstract example to illustrate our results and to discuss the feasibility of generalizations. PMID- 29286716 TI - Estimating the Error of an Analog Quantum Simulator by Additional Measurements. AB - We study an analog quantum simulator coupled to a reservoir with a known spectral density. The reservoir perturbs the quantum simulation by causing decoherence. The simulator is used to measure an operator average, which cannot be calculated using any classical means. Since we cannot predict the result, it is difficult to estimate the effect of the environment. Especially, it is difficult to resolve whether the perturbation is small or if the actual result of the simulation is in fact very different from the ideal system we intend to study. Here, we show that in specific systems a measurement of additional correlators can be used to verify the reliability of the quantum simulation. The procedure only requires additional measurements on the quantum simulator itself. We demonstrate the method theoretically in the case of a single spin connected to a bosonic environment. PMID- 29286717 TI - Harmonic Quantum Coherence of Multiple Excitons in PbS/CdS Core-Shell Nanocrystals. AB - The generation and recombination dynamics of multiple excitons in nanocrystals (NCs) have attracted much attention from the viewpoints of fundamental physics and device applications. However, the quantum coherence of multiple exciton states in NCs still remains unclear due to a lack of experimental support. Here, we report the first observation of harmonic dipole oscillations in PbS/CdS core shell NCs using a phase-locked interference detection method for transient absorption. From the ultrafast coherent dynamics and excitation-photon-fluence dependence of the oscillations, we found that multiple excitons cause the harmonic dipole oscillations with omega, 2omega, and 3omega oscillations, even though the excitation pulse energy is set to the exciton resonance frequency, omega. This observation is closely related to the quantum coherence of multiple exciton states in NCs, providing important insights into multiple exciton generation mechanisms. PMID- 29286718 TI - Jammed Spin Liquid in the Bond-Disordered Kagome Antiferromagnet. AB - We study a class of continuous spin models with bond disorder including the kagome Heisenberg antiferromagnet. For weak disorder strength, we find discrete ground states whose number grows exponentially with system size. These states do not exhibit zero-energy excitations characteristic of highly frustrated magnets but instead are local minima of the energy landscape. This represents a spin liquid version of the phenomenon of jamming familiar from granular media and structural glasses. Correlations of this jammed spin liquid, which upon increasing the disorder strength gives way to a conventional spin glass, may be algebraic (Coulomb type) or exponential. PMID- 29286719 TI - Essentially Entropic Lattice Boltzmann Model. AB - The entropic lattice Boltzmann model (ELBM), a discrete space-time kinetic theory for hydrodynamics, ensures nonlinear stability via the discrete time version of the second law of thermodynamics (the H theorem). Compliance with the H theorem is numerically enforced in this methodology and involves a search for the maximal discrete path length corresponding to the zero dissipation state by iteratively solving a nonlinear equation. We demonstrate that an exact solution for the path length can be obtained by assuming a natural criterion of negative entropy change, thereby reducing the problem to solving an inequality. This inequality is solved by creating a new framework for construction of Pade approximants via quadrature on appropriate convex function. This exact solution also resolves the issue of indeterminacy in case of nonexistence of the entropic involution step. Since our formulation is devoid of complex mathematical library functions, the computational cost is drastically reduced. To illustrate this, we have simulated a model setup of flow over the NACA-0012 airfoil at a Reynolds number of 2.88*10^{6}. PMID- 29286720 TI - Laser-Induced Inelastic Diffraction from Strong-Field Double Ionization. AB - In this Letter, we propose a novel laser-induced inelastic diffraction (LIID) scheme based on the intense-field-driven atomic nonsequential double ionization (NSDI) process and demonstrate that, with this LIID approach, the doubly differential cross sections (DDCSs) of the target ions, e.g., Ar^{+} and Xe^{+}, can be accurately extracted from the two-dimensional photoelectron momentum distributions in the NSDI process of the corresponding atoms. The extracted DDCSs exhibit a strong dependence on both the target and the laser intensity, in good agreement with calculated DDCSs from the scattering of free electrons. The LIID scheme may be extended to molecular systems and provides a promising approach for imaging of the gas-phase molecular dynamics induced by a strong laser field with unprecedented spatial and temporal resolution. PMID- 29286721 TI - Ultrastable Silicon Cavity in a Continuously Operating Closed-Cycle Cryostat at 4 K. AB - We report on a laser locked to a silicon cavity operating continuously at 4 K with 1*10^{-16} instability and a median linewidth of 17 mHz at 1542 nm. This is a tenfold improvement in short-term instability, and a 10^{4} improvement in linewidth, over previous sub-10-K systems. Operating at low temperatures reduces the thermal noise floor and, thus, is advantageous toward reaching an instability of 10^{-18}, a long-sought goal of the optical clock community. The performance of this system demonstrates the technical readiness for the development of the next generation of ultrastable lasers that operate with an ultranarrow linewidth and long-term stability without user intervention. PMID- 29286678 TI - First Observation of the Rare Purely Baryonic Decay B^{0}->pp[over -]. AB - The first observation of the decay of a B^{0} meson to a purely baryonic final state, B^{0}->pp[over -], is reported. The proton-proton collision data sample used was collected with the LHCb experiment at center-of-mass energies of 7 and 8 TeV and corresponds to an integrated luminosity of 3.0 fb^{-1}. The branching fraction is determined to be B(B^{0}->pp[over -])=(1.25+/-0.27+/-0.18)*10^{-8}, where the first uncertainty is statistical and the second systematic. The decay mode B^{0}->pp[over -] is the rarest decay of the B^{0} meson observed to date. The decay B_{s}^{0}->pp[over -] is also investigated. No signal is seen and the upper limit B(B_{s}^{0}->pp[over -])<1.5*10^{-8} at 90% confidence level is set on the branching fraction. PMID- 29286722 TI - Extensional Strain Hardening Induced by pi-pi Interactions in Barely Entangled Polymer Chains: The Curious Case of Poly(4-vinylbiphenyl). AB - Aromatic pi-pi interactions between phenyl groups of adjacent chains in poly(4 vinylbiphenyl) (PVBP) have profound effects on the dynamics of this polymer. We report two unexpected nonlinear viscoelastic responses of PVBP when subjected to uniaxial flow. One is the unprecedented observation of extensional strain hardening (SH) in a barely entangled polymer melt. An even more intriguing finding is that SH of lightly (or even barely) entangled melts occurs at strain rates one order of magnitude below the coil-stretch transition predicted by Rouse theory (epsilon[over ]_{H}=0.5/tau_{R}).We postulate that this behavior is due to a molecular rearrangement mechanism (supported by x-ray diffraction measurements) that involves flow-induced pi-pi stacking of the phenyl groups, which results in an enhancement of the friction coefficient between polymer chains. PMID- 29286723 TI - Saturation of the Hosing Instability in Quasilinear Plasma Accelerators. AB - The beam hosing instability is analyzed theoretically for a witness beam in the quasilinear regime of plasma accelerators. In this regime, the hosing instability saturates, even for a monoenergetic bunch, at a level much less than standard scalings predict. Analytic expressions are derived for the saturation distance and amplitude and are in agreement with numerical results. Saturation is due to the natural head-to-tail variations in the focusing force, including the self consistent transverse beam loading. PMID- 29286725 TI - Symmetry Breaking and Strong Persistent Plasma Currents via Resonant Destabilization of Atoms. AB - The ionization rate of an atom in a strong optical field can be resonantly enhanced by the presence of long-living atomic levels (so-called Freeman resonances). This process is most prominent in the multiphoton ionization regime, meaning that the ionization event takes many optical cycles. Nevertheless, here, we show that these resonances can lead to rapid subcycle-scale plasma buildup at the resonant values of the intensity in the pump pulse. The fast buildup can break the cycle-to-cycle symmetry of the ionization process, resulting in the generation of persistent macroscopic plasma currents which remain after the end of the pulse. This, in turn, gives rise to a broadband radiation of unusual spectral structure, forming a comb from terahertz to visible. This radiation contains fingerprints of the attosecond electron dynamics in Rydberg states during ionization. PMID- 29286724 TI - Clogging Transition of Vibration-Driven Vehicles Passing through Constrictions. AB - We report experimental results on the competitive passage of elongated self propelled vehicles rushing through a constriction. For the chosen experimental conditions, we observe the emergence of intermittencies similar to those reported previously for active matter passing through narrow doors. Noteworthy, we find that, when the number of individuals crowding in front of the bottleneck increases, there is a transition from an unclogged to a clogged state characterized by a lack of convergence of the mean clog duration as the measuring time increases. It is demonstrated that this transition-which was reported previously only for externally vibrated systems such as colloids or granulars appears also for self-propelled agents. This suggests that the transition should also occur for the flow through constrictions of living agents (e.g., humans and sheep), an issue that has been elusive so far in experiments due to safety risks. PMID- 29286726 TI - Scattering by Finite Periodic PT-Symmetric Structures. AB - In this work, we study the transmission properties of one-dimensional finite periodic systems with PT symmetry. A simple closed-form expression is obtained for the total transmittance from a lattice of N cells, that allows us to describe the transmission minima (maxima) when the system is in the PT-unbroken (broken) phase. Utilizing this expression, we provide the necessary conditions, independent of the number of cells, for the occurrence of a coherent perfect absorber and laser for any finite PT-symmetric periodic potential. Under these conditions, we provide a recipe for building finite periodic structures with near perfect absorption and extremely large amplification. PMID- 29286727 TI - Extracellular Processing of Molecular Gradients by Eukaryotic Cells Can Improve Gradient Detection Accuracy. AB - Eukaryotic cells sense molecular gradients by measuring spatial concentration variation through the difference in the number of occupied receptors to which molecules can bind. They also secrete enzymes that degrade these molecules, and it is presently not well understood how this affects the local gradient perceived by cells. Numerical and analytical results show that these enzymes can substantially increase the signal-to-noise ratio of the receptor difference and allow cells to respond to a much broader range of molecular concentrations and gradients than they would without these enzymes. PMID- 29286728 TI - Magnetic Monopole Mass Bounds from Heavy-Ion Collisions and Neutron Stars. AB - Magnetic monopoles, if they exist, would be produced amply in strong magnetic fields and high temperatures via the thermal Schwinger process. Such circumstances arise in heavy-ion collisions and in neutron stars, both of which imply lower bounds on the mass of possible magnetic monopoles. In showing this, we construct the cross section for pair production of magnetic monopoles in heavy ion collisions, which indicates that they are particularly promising for experimental searches such as MoEDAL. PMID- 29286729 TI - Dirac and Nodal Line Magnons in Three-Dimensional Antiferromagnets. AB - We study the topological properties of magnon excitations in three-dimensional antiferromagnets, where the ground state configuration is invariant under time reversal followed by space inversion (PT symmetry). We prove that Dirac points and nodal lines, the former being the limiting case of the latter, are the generic forms of symmetry-protected band crossings between magnon branches. As a concrete example, we study a Heisenberg spin model for a "spin-web" compound, Cu_{3}TeO_{6}, and show the presence of the magnon Dirac points assuming a collinear magnetic structure. Upon turning on symmetry-allowed Dzyaloshinsky Moriya interactions, which introduce a small noncollinearity in the ground state configuration, we find that the Dirac points expand into nodal lines with nontrivial Z_{2}-topological charge, a new type of nodal line not predicted in any materials so far. PMID- 29286730 TI - Instability of Insulators near Quantum Phase Transitions. AB - Thin films of amorphous indium oxide undergo a magnetic field driven superconducting to insulator quantum phase transition. In the insulating phase, the current-voltage characteristics show large current discontinuities due to overheating of electrons. We show that the onset voltage for the discontinuities vanishes as we approach the quantum critical point. As a result, the insulating phase becomes unstable with respect to any applied voltage making it, at least experimentally, immeasurable. We emphasize that unlike previous reports of the absence of linear response near quantum phase transitions, in our system, the departure from equilibrium is discontinuous. Because the conditions for these discontinuities are satisfied in most insulators at low temperatures, and due to the decay of all characteristic energy scales near quantum phase transitions, we believe that this instability is general and should occur in various systems while approaching their quantum critical point. Accounting for this instability is crucial for determining the critical behavior of systems near the transition. PMID- 29286731 TI - Chiral Spin Order in Kondo-Heisenberg Systems. AB - We demonstrate that low dimensional Kondo-Heisenberg systems, consisting of itinerant electrons and localized magnetic moments (Kondo impurities), can be used as a principally new platform to realize scalar chiral spin order. The underlying physics is governed by a competition of the Ruderman-Kittel-Kosuya Yosida (RKKY) indirect exchange interaction between the local moments with the direct Heisenberg one. When the direct exchange is weak and RKKY dominates, the isotropic system is in the disordered phase. A moderately large direct exchange leads to an Ising-type phase transition to the phase with chiral spin order. Our finding paves the way towards pioneering experimental realizations of the chiral spin liquid in systems with spontaneously broken time-reversal symmetry. PMID- 29286732 TI - Quantum Experiments and Graphs: Multiparty States as Coherent Superpositions of Perfect Matchings. AB - We show a surprising link between experimental setups to realize high-dimensional multipartite quantum states and graph theory. In these setups, the paths of photons are identified such that the photon-source information is never created. We find that each of these setups corresponds to an undirected graph, and every undirected graph corresponds to an experimental setup. Every term in the emerging quantum superposition corresponds to a perfect matching in the graph. Calculating the final quantum state is in the #P-complete complexity class, thus it cannot be done efficiently. To strengthen the link further, theorems from graph theory-such as Hall's marriage problem-are rephrased in the language of pair creation in quantum experiments. We show explicitly how this link allows one to answer questions about quantum experiments (such as which classes of entangled states can be created) with graph theoretical methods, and how to potentially simulate properties of graphs and networks with quantum experiments (such as critical exponents and phase transitions). PMID- 29286733 TI - Identifying the Tunneling Site in Strong-Field Ionization of H_{2}^{+}. AB - The tunneling site of the electron in a molecule exposed to a strong laser field determines the initial position of the ionizing electron and, as a result, has a large impact on the subsequent ultrafast electron dynamics on the polyatomic Coulomb potential. Here, the tunneling site of the electron of H_{2}^{+} ionized by a strong circularly polarized (CP) laser pulse is studied by numerically solving the time-dependent Schrodinger equation. We show that the electron removed from the down-field site is directly driven away by the CP field and the lateral photoelectron momentum distribution (LPMD) exhibits a Gaussian-like distribution, whereas the corresponding LPMD of the electron removed from the up field site differs from the Gaussian shape due to the Coulomb focusing and scattering by the down-field core. Our current study presents the direct evidence clarifying a long-standing controversy over the tunneling site in H_{2}^{+} and raises the important role of the tunneling site in strong-field molecular ionization. PMID- 29286734 TI - Muon Creation in Supernova Matter Facilitates Neutrino-Driven Explosions. AB - Muons can be created in nascent neutron stars (NSs) due to the high electron chemical potentials and the high temperatures. Because of their relatively lower abundance compared to electrons, their role has so far been ignored in numerical simulations of stellar core collapse and NS formation. However, the appearance of muons softens the NS equation of state, triggers faster NS contraction, and thus leads to higher luminosities and mean energies of the emitted neutrinos. This strengthens the postshock heating by neutrinos and can facilitate explosions by the neutrino-driven mechanism. PMID- 29286737 TI - Equation of Motion for a Grain Boundary. AB - Grain boundary (GB) migration controls many forms of microstructural evolution in polycrystalline materials. Recent theory, simulations, and experiments demonstrate that GB migration is controlled by the motion of discrete line defects or disconnections. We present a continuum equation of motion for grain boundary derived from the underlying discrete disconnection mechanism. We also present an equation of motion for the junctions where multiple grain boundaries meet-as is always the case in a polycrystal. The resulting equation of motion naturally exhibits junction drag-a widely observed phenomena in junction dynamics in solids and liquids. PMID- 29286738 TI - Manipulating Twisted Electron Beams. AB - A theoretical description of twisted (vortex) electrons interacting with electric and magnetic fields is presented, based on Lorentz transformations. The general dynamical equations of motion of a twisted electron with an intrinsic orbital angular momentum in an external field are derived. Methods for the extraction of an electron vortex beam with a given orbital polarization and for the manipulation of such a beam are developed. PMID- 29286740 TI - Epi-Two-Dimensional Fluid Flow: A New Topological Paradigm for Dimensionality. AB - While a variety of fundamental differences are known to separate two-dimensional (2D) and three-dimensional (3D) fluid flows, it is not well understood how they are related. Conventionally, dimensional reduction is justified by an a priori geometrical framework; i.e., 2D flows occur under some geometrical constraint such as shallowness. However, deeper inquiry into 3D flow often finds the presence of local 2D-like structures without such a constraint, where 2D-like behavior may be identified by the integrability of vortex lines or vanishing local helicity. Here we propose a new paradigm of flow structure by introducing an intermediate class, termed epi-two-dimensional flow, and thereby build a topological bridge between 2D and 3D flows. The epi-2D property is local and is preserved in fluid elements obeying ideal (inviscid and barotropic) mechanics; a local epi-2D flow may be regarded as a "particle" carrying a generalized enstrophy as its charge. A finite viscosity may cause "fusion" of two epi-2D particles, generating helicity from their charges giving rise to 3D flow. PMID- 29286739 TI - Direct Measurement of the Key E_{c.m.}=456 keV Resonance in the Astrophysical ^{19}Ne(p,gamma)^{20}Na Reaction and Its Relevance for Explosive Binary Systems. AB - We have performed a direct measurement of the ^{19}Ne(p,gamma)^{20}Na reaction in inverse kinematics using a beam of radioactive ^{19}Ne. The key astrophysical resonance in the ^{19}Ne+p system has been definitely measured for the first time at E_{c.m.}=456_{-2}^{+5} keV with an associated strength of 17_{-5}^{+7} meV. The present results are in agreement with resonance strength upper limits set by previous direct measurements, as well as resonance energies inferred from precision (^{3}He, t) charge exchange reactions. However, both the energy and strength of the 456 keV resonance disagree with a recent indirect study of the ^{19}Ne(d, n)^{20}Na reaction. In particular, the new ^{19}Ne(p,gamma)^{20}Na reaction rate is found to be factors of ~8 and ~5 lower than the most recent evaluation over the temperature range of oxygen-neon novae and astrophysical x ray bursts, respectively. Nevertheless, we find that the ^{19}Ne(p,gamma)^{20}Na reaction is likely to proceed fast enough to significantly reduce the flux of ^{19}F in nova ejecta and does not create a bottleneck in the breakout from the hot CNO cycles into the rp process. PMID- 29286741 TI - SU(5) Unification without Proton Decay. AB - We construct a four-dimensional SU(5) grand unified theory in which the proton is stable. The standard model leptons reside in the 5 and 10 irreps of SU(5), whereas the quarks live in the 40 and 50 irreps. The SU(5) gauge symmetry is broken by the vacuum expectation values of the scalar 24 and 75 irreps. All fields that are not part of the standard model are heavy. Stability of the proton requires three relations between the parameters of the model to hold. However, abandoning the requirement of absolute proton stability, the model fulfills current experimental constraints without fine-tuning. PMID- 29286742 TI - Distribution of Off-Diagonal Cross Sections in Quantum Chaotic Scattering: Exact Results and Data Comparison. AB - The recently derived distributions for the scattering-matrix elements in quantum chaotic systems are not accessible in the majority of experiments, whereas the cross sections are. We analytically compute distributions for the off-diagonal cross sections in the Heidelberg approach, which is applicable to a wide range of quantum chaotic systems. Thus, eventually, we fully solve a problem that already arose more than half a century ago in compound-nucleus scattering. We compare our results with data from microwave and compound-nucleus experiments, particularly addressing the transition from isolated resonances towards the Ericson regime of strongly overlapping ones. PMID- 29286743 TI - Disentangling Intracycle Interferences in Photoelectron Momentum Distributions Using Orthogonal Two-Color Laser Fields. AB - We use orthogonally polarized two-color (OTC) laser pulses to separate quantum paths in the multiphoton ionization of Ar atoms. Our OTC pulses consist of 400 and 800 nm light at a relative intensity ratio of 10?1. We find a hitherto unobserved interference in the photoelectron momentum distribution, which exhibits a strong dependence on the relative phase of the OTC pulse. Analysis of model calculations reveals that the interference is caused by quantum pathways from nonadjacent quarter cycles. PMID- 29286744 TI - Reflection-Symmetric Second-Order Topological Insulators and Superconductors. AB - Second-order topological insulators are crystalline insulators with a gapped bulk and gapped crystalline boundaries, but with topologically protected gapless states at the intersection of two boundaries. Without further spatial symmetries, five of the ten Altland-Zirnbauer symmetry classes allow for the existence of such second-order topological insulators in two and three dimensions. We show that reflection symmetry can be employed to systematically generate examples of second-order topological insulators and superconductors, although the topologically protected states at corners (in two dimensions) or at crystal edges (in three dimensions) continue to exist if reflection symmetry is broken. A three dimensional second-order topological insulator with broken time-reversal symmetry shows a Hall conductance quantized in units of e^{2}/h. PMID- 29286745 TI - (d-2)-Dimensional Edge States of Rotation Symmetry Protected Topological States. AB - We study fourfold rotation-invariant gapped topological systems with time reversal symmetry in two and three dimensions (d=2, 3). We show that in both cases nontrivial topology is manifested by the presence of the (d-2)-dimensional edge states, existing at a point in 2D or along a line in 3D. For fermion systems without interaction, the bulk topological invariants are given in terms of the Wannier centers of filled bands and can be readily calculated using a Fu-Kane like formula when inversion symmetry is also present. The theory is extended to strongly interacting systems through the explicit construction of microscopic models having robust (d-2)-dimensional edge states. PMID- 29286746 TI - Covariant Conservation Laws and the Spin Hall Effect in Dirac-Rashba Systems. AB - We present a theoretical analysis of two-dimensional Dirac-Rashba systems in the presence of disorder and external perturbations. We unveil a set of exact symmetry relations (Ward identities) that impose strong constraints on the spin dynamics of Dirac fermions subject to proximity-induced interactions. This allows us to demonstrate that an arbitrary dilute concentration of scalar impurities results in the total suppression of nonequilibrium spin Hall currents when only Rashba spin-orbit coupling is present. Remarkably, a finite spin Hall conductivity is restored when the minimal Dirac-Rashba model is supplemented with a spin-valley interaction. The Ward identities provide a systematic way to predict the emergence of the spin Hall effect in a wider class of Dirac-Rashba systems of experimental relevance and represent an important benchmark for testing the validity of numerical methodologies. PMID- 29286747 TI - Navigating at Will on the Water Phase Diagram. AB - Despite the simplicity of its molecular unit, water is a challenging system because of its uniquely rich polymorphism and predicted but yet unconfirmed features. Introducing a novel space of generalized coordinates that capture changes in the topology of the interatomic network, we are able to systematically track transitions among liquid, amorphous, and crystalline forms throughout the whole phase diagram of water, including the nucleation of crystals above and below the melting point. Our approach, based on molecular dynamics and enhanced sampling or free energy calculation techniques, is not specific to water and could be applied to very different structural phase transitions, paving the way towards the prediction of kinetic routes connecting polymorphic structures in a range of materials. PMID- 29286748 TI - Structural Origin of Enhanced Dynamics at the Surface of a Glassy Alloy. AB - The enhancement of mobility at the surface of an amorphous alloy is studied using a combination of molecular dynamic simulations and normal mode analysis of the nonuniform distribution of Debye-Waller factors. The increased mobility at the surface is found to be associated with the appearance of Arrhenius temperature dependence. We show that the transverse Debye-Waller factor exhibits a peak at the surface. Over the accessible temperature range, we find that the bulk and surface diffusion coefficients obey the same empirical relationship with the respective Debye-Waller factors. Extrapolating this relationship to lower T, we argue that the observed decrease in the constraint at the surface is sufficient to account for the experimentally observed surface enhancement of mobility. PMID- 29286749 TI - Realization of a Quantum Random Generator Certified with the Kochen-Specker Theorem. AB - Random numbers are required for a variety of applications from secure communications to Monte Carlo simulation. Yet randomness is an asymptotic property, and no output string generated by a physical device can be strictly proven to be random. We report an experimental realization of a quantum random number generator (QRNG) with randomness certified by quantum contextuality and the Kochen-Specker theorem. The certification is not performed in a device independent way but through a rigorous theoretical proof of each outcome being value indefinite even in the presence of experimental imperfections. The analysis of the generated data confirms the incomputable nature of our QRNG. PMID- 29286750 TI - Complete Many-Body Localization in the t-J Model Caused by a Random Magnetic Field. AB - The many body localization (MBL) of spin-1/2 fermions poses a challenging problem. It is known that the disorder in the charge sector may be insufficient to cause full MBL. Here, we study dynamics of a single hole in one dimensional t J model subject to a random magnetic field. We show that strong disorder that couples only to the spin sector localizes both spin and charge degrees of freedom. Charge localization is confirmed also for a finite concentration of holes. While we cannot precisely pinpoint the threshold disorder, we conjecture that there are two distinct transitions. Weaker disorder first causes localization in the spin sector. Carriers become localized for somewhat stronger disorder, when the spin localization length is of the order of a single lattice spacing. PMID- 29286751 TI - Chimera States in Continuous Media: Existence and Distinctness. AB - The defining property of chimera states is the coexistence of coherent and incoherent domains in systems that are structurally and spatially homogeneous. The recent realization that such states might be common in oscillator networks raises the question of whether an analogous phenomenon can occur in continuous media. Here, we show that chimera states can exist in continuous systems even when the coupling is strictly local, as in many fluid and pattern forming media. Using the complex Ginzburg-Landau equation as a model system, we characterize chimera states consisting of a coherent domain of a frozen spiral structure and an incoherent domain of amplitude turbulence. We show that in this case, in contrast with discrete network systems, fluctuations in the local coupling field play a crucial role in limiting the coherent regions. We suggest these findings shed light on new possible forms of coexisting order and disorder in fluid systems. PMID- 29286752 TI - Gravitationally Induced Entanglement between Two Massive Particles is Sufficient Evidence of Quantum Effects in Gravity. AB - All existing quantum-gravity proposals are extremely hard to test in practice. Quantum effects in the gravitational field are exceptionally small, unlike those in the electromagnetic field. The fundamental reason is that the gravitational coupling constant is about 43 orders of magnitude smaller than the fine structure constant, which governs light-matter interactions. For example, detecting gravitons-the hypothetical quanta of the gravitational field predicted by certain quantum-gravity proposals-is deemed to be practically impossible. Here we adopt a radically different, quantum-information-theoretic approach to testing quantum gravity. We propose witnessing quantumlike features in the gravitational field, by probing it with two masses each in a superposition of two locations. First, we prove that any system (e.g., a field) mediating entanglement between two quantum systems must be quantum. This argument is general and does not rely on any specific dynamics. Then, we propose an experiment to detect the entanglement generated between two masses via gravitational interaction. By our argument, the degree of entanglement between the masses is a witness of the field quantization. This experiment does not require any quantum control over gravity. It is also closer to realization than detecting gravitons or detecting quantum gravitational vacuum fluctuations. PMID- 29286753 TI - Hartree and Exchange in Ensemble Density Functional Theory: Avoiding the Nonuniqueness Disaster. AB - Ensemble density functional theory is a promising method for the efficient and accurate calculation of excitations of quantum systems, at least if useful functionals can be developed to broaden its domain of practical applicability. Here, we introduce a guaranteed single-valued "Hartree-exchange" ensemble density functional, E_{Hx}[n], in terms of the right derivative of the universal ensemble density functional with respect to the coupling constant at vanishing interaction. We show that E_{Hx}[n] is straightforwardly expressible using block eigenvalues of a simple matrix [Eq. (14)]. Specialized expressions for E_{Hx}[n] from the literature, including those involving superpositions of Slater determinants, can now be regarded as originating from the unifying picture presented here. We thus establish a clear and practical description for Hartree and exchange in ensemble systems. PMID- 29286754 TI - Light-Induced Fractional Quantum Hall Phases in Graphene. AB - We show how to realize two-component fractional quantum Hall phases in monolayer graphene by optically driving the system. A laser is tuned into resonance between two Landau levels, giving rise to an effective tunneling between these two synthetic layers. Remarkably, because of this coupling, the interlayer interaction at nonzero relative angular momentum can become dominant, resembling a hollow-core pseudopotential. In the weak tunneling regime, this interaction favors the formation of singlet states, as we explicitly show by numerical diagonalization, at fillings nu=1/2 and nu=2/3. We discuss possible candidate phases, including the Haldane-Rezayi phase, the interlayer Pfaffian phase, and a Fibonacci phase. This demonstrates that our method may pave the way towards the realization of non-Abelian phases, as well as the control of topological phase transitions, in graphene quantum Hall systems using optical fields and integrated photonic structures. PMID- 29286755 TI - Photoinduced Enhancement of Excitonic Order. AB - We study the dynamics of excitonic insulators coupled to phonons using the time dependent mean-field theory. Without phonon couplings, the linear response is given by the damped amplitude oscillations of the order parameter with a frequency equal to the minimum band gap. A phonon coupling to the interband transfer integral induces two types of long-lived collective oscillations of the amplitude, one originating from the phonon dynamics and the other from the phase mode, which becomes massive. We show that, even for small phonon coupling, a photoinduced enhancement of the exciton condensation and the gap can be realized. Using the Anderson pseudospin picture, we argue that the origin of the enhancement is a cooperative effect of the massive phase mode and the Hartree shift induced by the photoexcitation. We also discuss how the enhancement of the order and the collective modes can be observed with time-resolved photoemission spectroscopy. PMID- 29286756 TI - Irreversible Local Markov Chains with Rapid Convergence towards Equilibrium. AB - We study the continuous one-dimensional hard-sphere model and present irreversible local Markov chains that mix on faster time scales than the reversible heat bath or Metropolis algorithms. The mixing time scales appear to fall into two distinct universality classes, both faster than for reversible local Markov chains. The event-chain algorithm, the infinitesimal limit of one of these Markov chains, belongs to the class presenting the fastest decay. For the lattice-gas limit of the hard-sphere model, reversible local Markov chains correspond to the symmetric simple exclusion process (SEP) with periodic boundary conditions. The two universality classes for irreversible Markov chains are realized by the totally asymmetric SEP (TASEP), and by a faster variant (lifted TASEP) that we propose here. We discuss how our irreversible hard-sphere Markov chains generalize to arbitrary repulsive pair interactions and carry over to higher dimensions through the concept of lifted Markov chains and the recently introduced factorized Metropolis acceptance rule. PMID- 29286757 TI - Dissociation of One-Dimensional Matter-Wave Breathers due to Quantum Many-Body Effects. AB - We use the ab initio Bethe ansatz dynamics to predict the dissociation of one dimensional cold-atom breathers that are created by a quench from a fundamental soliton. We find that the dissociation is a robust quantum many-body effect, while in the mean-field (MF) limit the dissociation is forbidden by the integrability of the underlying nonlinear Schrodinger equation. The analysis demonstrates the possibility to observe quantum many-body effects without leaving the MF range of experimental parameters. We find that the dissociation time is of the order of a few seconds for a typical atomic-soliton setting. PMID- 29286758 TI - Coherent Control of a Single Trapped Rydberg Ion. AB - Trapped Rydberg ions are a promising novel approach to quantum computing and simulations. They are envisaged to combine the exquisite control of trapped ion qubits with the fast two-qubit Rydberg gates already demonstrated in neutral atom experiments. Coherent Rydberg excitation is a key requirement for these gates. Here, we carry out the first coherent Rydberg excitation of an ion and perform a single-qubit Rydberg gate, thus demonstrating basic elements of a trapped Rydberg ion quantum computer. PMID- 29286759 TI - Pressure-Induced Ferromagnetism due to an Anisotropic Electronic Topological Transition in Fe_{1.08}Te. AB - A rapid and anisotropic modification of the Fermi-surface shape can be associated with abrupt changes in crystalline lattice geometry or in the magnetic state of a material. We show that such an electronic topological transition is at the basis of the formation of an unusual pressure-induced tetragonal ferromagnetic phase in Fe_{1.08}Te. Around 2 GPa, the orthorhombic and incommensurate antiferromagnetic ground state of Fe_{1.08}Te is transformed upon increasing pressure into a tetragonal ferromagnetic state via a conventional first-order transition. On the other hand, an isostructural transition takes place from the paramagnetic high temperature state into the ferromagnetic phase as a rare case of a "type-0" transformation with anisotropic properties. Electronic-structure calculations in combination with electrical resistivity, magnetization, and x-ray diffraction experiments show that the electronic system of Fe_{1.08}Te is instable with respect to profound topological transitions that can drive fundamental changes of the lattice anisotropy and the associated magnetic order. PMID- 29286760 TI - Quantitative Disentanglement of the Spin Seebeck, Proximity-Induced, and Ferromagnetic-Induced Anomalous Nernst Effect in Normal-Metal-Ferromagnet Bilayers. AB - We identify and investigate thermal spin transport phenomena in sputter-deposited Pt/NiFe_{2}O_{x} (4>=x>=0) bilayers. We separate the voltage generated by the spin Seebeck effect from the anomalous Nernst effect (ANE) contributions and even disentangle the ANE in the ferromagnet (FM) from the ANE produced by the Pt that is spin polarized due to its proximity to the FM. Further, we probe the dependence of these effects on the electrical conductivity and the band gap energy of the FM film varying from nearly insulating NiFe_{2}O_{4} to metallic Ni_{33}Fe_{67}. A proximity-induced ANE could only be identified in the metallic Pt/Ni_{33}Fe_{67} bilayer in contrast to Pt/NiFe_{2}O_{x} (x>0) samples. This is verified by the investigation of static magnetic proximity effects via x-ray resonant magnetic reflectivity. PMID- 29286761 TI - Transport Signatures of the Hall Viscosity. AB - Hall viscosity is a nondissipative response function describing momentum transport in two-dimensional systems with broken parity. It is quantized in the quantum Hall regime, and contains information about the topological order of the quantum Hall state. Hall viscosity can distinguish different quantum Hall states with identical Hall conductances, but different topological order. To date, an experimentally accessible signature of Hall viscosity is lacking. We exploit the fact that Hall viscosity contributes to charge transport at finite wavelengths, and can therefore be extracted from nonlocal resistance measurements in inhomogeneous charge flows. We explain how to determine the Hall viscosity from such a transport experiment. In particular, we show that the profile of the electrochemical potential close to contacts where current is injected is sensitive to the value of the Hall viscosity. PMID- 29286762 TI - Exit-Channel Suppression in Statistical Reaction Theory. AB - Statistical reaction theories such as the Hauser-Feshbach theory assume that branching ratios follow Bohr's compound nucleus hypothesis by factorizing into independent probabilities for different channels. Corrections to the factorization hypothesis are known in both nuclear theory and quantum transport theory, particularly an enhanced memory of the entrance channel. We apply the Gaussian orthogonal ensemble to study a complementary suppression of exit channel branching ratios. The combined effect of the width fluctuation and the limitation on the transmission coefficient can provide a lower bound on the number of exit channels. The bound is demonstrated for the branching ratio in neutron-induced reactions on a ^{235}U target. PMID- 29286763 TI - Fast Dynamical Decoupling of the Molmer-Sorensen Entangling Gate. AB - Engineering entanglement between quantum systems often involves coupling through a bosonic mediator, which should be disentangled from the systems at the operation's end. The quality of such an operation is generally limited by environmental and control noise. One of the prime techniques for suppressing noise is by dynamical decoupling, where one actively applies pulses at a rate that is faster than the typical time scale of the noise. However, for boson mediated gates, current dynamical decoupling schemes require executing the pulses only when the boson and the quantum systems are disentangled. This restriction implies an increase of the gate time by a factor of sqrt[N], with N being the number of pulses applied. Here we propose and realize a method that enables dynamical decoupling in a boson-mediated system where the pulses can be applied while spin-boson entanglement persists, resulting in an increase in time that is at most a factor of pi/2, independently of the number of pulses applied. We experimentally demonstrate the robustness of our entangling gate with fast dynamical decoupling to sigma_{z} noise using ions in a Paul trap. PMID- 29286764 TI - Experimental Detection of Information Deficit in a Photonic Contextuality Scenario. AB - Contextuality is an essential characteristic of quantum theory, and supplies the power for many quantum information processes. Previous tests of contextuality focus mainly on the probability distribution of measurement results. However, a test of contextuality can be formulated in terms of entropic inequalities whose violations imply information deficit in the studied system. This information deficit has not been observed on a single local system. Here we report the first experimental detection of information deficit in an entropic test of quantum contextuality based on photonic setup. The corresponding inequality is violated with more than 13 standard deviations. PMID- 29286766 TI - Converging High-Level Coupled-Cluster Energetics by Monte Carlo Sampling and Moment Expansions. AB - We propose a new approach to the determination of accurate electronic energies that are equivalent to the results of high-level coupled-cluster (CC) calculations. The approach is based on merging the CC(P;Q) formalism, which corrects energies obtained with an arbitrary truncation in the cluster operator, with the stochastic configuration interaction and CC ideas. The advantages of the proposed methodology are illustrated by molecular examples, where the goal is to recover the energetics obtained in the CC calculations with a full treatment of singly, doubly, and triply excited clusters. PMID- 29286765 TI - Ab initio Calculations of the Isotopic Dependence of Nuclear Clustering. AB - Nuclear clustering describes the appearance of structures resembling smaller nuclei such as alpha particles (^{4}He nuclei) within the interior of a larger nucleus. In this Letter, we present lattice Monte Carlo calculations based on chiral effective field theory for the ground states of helium, beryllium, carbon, and oxygen isotopes. By computing model-independent measures that probe three- and four-nucleon correlations at short distances, we determine the shape of the alpha clusters and the entanglement of nucleons comprising each alpha cluster with the outside medium. We also introduce a new computational approach called the pinhole algorithm, which solves a long-standing deficiency of auxiliary-field Monte Carlo simulations in computing density correlations relative to the center of mass. We use the pinhole algorithm to determine the proton and neutron density distributions and the geometry of cluster correlations in ^{12}C, ^{14}C, and ^{16}C. The structural similarities among the carbon isotopes suggest that ^{14}C and ^{16}C have excitations analogous to the well-known Hoyle state resonance in ^{12}C. PMID- 29286767 TI - Acid Dissociation in HCl-Water Clusters is Temperature Dependent and Cannot be Detected Based on Dipole Moments. AB - The dissociation of acids in aqueous environments at low temperatures in the presence of a limited amount of water is underlying a wealth of processes from atmospheric to interstellar science. For the paradigmatic case of HCl(H_{2}O)_{n} clusters, our extensive ab initio path integral simulations quantify in terms of free energy differences and barriers that n=4 water molecules are indeed required to dissociate HCl at low temperatures. Increasing the temperature, however, reverses the process and thus counteracts dissociation by fluctuation-driven recombination. The size of the electric dipole moment is shown to not correlate with the acid being in its dissociated or molecular state, thus rendering its measurement as a function of n unable to detect the dissociation transition. PMID- 29286768 TI - Steady-State Magneto-Optical Trap with 100-Fold Improved Phase-Space Density. AB - We demonstrate a continuously loaded ^{88}Sr magneto-optical trap (MOT) with a steady-state phase-space density of 1.3(2)*10^{-3}. This is 2 orders of magnitude higher than reported in previous steady-state MOTs. Our approach is to flow atoms through a series of spatially separated laser cooling stages before capturing them in a MOT operated on the 7.4-kHz linewidth Sr intercombination line using a hybrid slower+MOT configuration. We also demonstrate producing a Bose-Einstein condensate at the MOT location, despite the presence of laser cooling light on resonance with the 30-MHz linewidth transition used to initially slow atoms in a separate chamber. Our steady-state high phase-space density MOT is an excellent starting point for a continuous atom laser and dead-time free atom interferometers or clocks. PMID- 29286769 TI - Generic Local Hamiltonians are Gapless. AB - We prove that generic quantum local Hamiltonians are gapless. In fact, we prove that there is a continuous density of states above the ground state. The Hamiltonian can be on a lattice in any spatial dimension or on a graph with a bounded maximum vertex degree. The type of interactions allowed for include translational invariance in a disorder (i.e., probabilistic) sense with some assumptions on the local distributions. Examples include many-body localization and random spin models. We calculate the scaling of the gap with the system's size when the local terms are distributed according to a Gaussian beta orthogonal random matrix ensemble. As a corollary, there exist finite size partitions with respect to which the ground state is arbitrarily close to a product state. When the local eigenvalue distribution is discrete, in addition to the lack of an energy gap in the limit, we prove that the ground state has finite size degeneracies. The proofs are simple and constructive. This work excludes the important class of truly translationally invariant Hamiltonians where the local terms are all equal. PMID- 29286770 TI - Communication Games Reveal Preparation Contextuality. AB - A communication game consists of distributed parties attempting to jointly complete a task with restricted communication. Such games are useful tools for studying limitations of physical theories. A theory exhibits preparation contextuality whenever its predictions cannot be explained by a preparation noncontextual model. Here, we show that communication games performed in operational theories reveal the preparation contextuality of that theory. For statistics obtained in a particular family of communication games, we show a direct correspondence with correlations in spacelike separated events obeying the no-signaling principle. Using this, we prove that all mixed quantum states of any finite dimension are preparation contextual. We report on an experimental realization of a communication game involving three-level quantum systems from which we observe a strong violation of the constraints of preparation noncontextuality. PMID- 29286771 TI - Quantifying Complexity in Quantum Phase Transitions via Mutual Information Complex Networks. AB - We quantify the emergent complexity of quantum states near quantum critical points on regular 1D lattices, via complex network measures based on quantum mutual information as the adjacency matrix, in direct analogy to quantifying the complexity of electroencephalogram or functional magnetic resonance imaging measurements of the brain. Using matrix product state methods, we show that network density, clustering, disparity, and Pearson's correlation obtain the critical point for both quantum Ising and Bose-Hubbard models to a high degree of accuracy in finite-size scaling for three classes of quantum phase transitions, Z_{2}, mean field superfluid to Mott insulator, and a Berzinskii-Kosterlitz Thouless crossover. PMID- 29286772 TI - Multivalent-Ion-Activated Protein Adsorption Reflecting Bulk Reentrant Behavior. AB - Protein adsorption at the solid-liquid interface is an important phenomenon that often can be observed as a first step in biological processes. Despite its inherent importance, still relatively little is known about the underlying microscopic mechanisms. Here, using multivalent ions, we demonstrate the control of the interactions and the corresponding adsorption of net-negatively charged proteins (bovine serum albumin) at a solid-liquid interface. This is demonstrated by ellipsometry and corroborated by neutron reflectivity and quartz-crystal microbalance experiments. We show that the reentrant condensation observed within the rich bulk phase behavior of the system featuring a nonmonotonic dependence of the second virial coefficient on salt concentration c_{s} is reflected in an intriguing way in the protein adsorption d(c_{s}) at the interface. Our findings are successfully described and understood by a model of ion-activated patchy interactions within the framework of the classical density functional theory. In addition to the general challenge of connecting bulk and interface behavior, our work has implications for, inter alia, nucleation at interfaces. PMID- 29286774 TI - Cavity-Enhanced Transport of Charge. AB - We theoretically investigate charge transport through electronic bands of a mesoscopic one-dimensional system, where interband transitions are coupled to a confined cavity mode, initially prepared close to its vacuum. This coupling leads to light-matter hybridization where the dressed fermionic bands interact via absorption and emission of dressed cavity photons. Using a self-consistent nonequilibrium Green's function method, we compute electronic transmissions and cavity photon spectra and demonstrate how light-matter coupling can lead to an enhancement of charge conductivity in the steady state. We find that depending on cavity loss rate, electronic bandwidth, and coupling strength, the dynamics involves either an individual or a collective response of Bloch states, and we explain how this affects the current enhancement. We show that the charge conductivity enhancement can reach orders of magnitudes under experimentally relevant conditions. PMID- 29286775 TI - Evidence for the Role of Proton Shell Closure in Quasifission Reactions from X Ray Fluorescence of Mass-Identified Fragments. AB - The atomic numbers and the masses of fragments formed in quasifission reactions are simultaneously measured at scission in ^{48}Ti+^{238}U reactions at a laboratory energy of 286 MeV. The atomic numbers are determined from measured characteristic fluorescence x rays, whereas the masses are obtained from the emission angles and times of flight of the two emerging fragments. For the first time, thanks to this full identification of the quasifission fragments on a broad angular range, the important role of the proton shell closure at Z=82 is evidenced by the associated maximum production yield, a maximum predicted by time dependent Hartree-Fock calculations. This new experimental approach gives now access to precise studies of the time dependence of the N/Z (neutron over proton ratios of the fragments) evolution in quasifission reactions. PMID- 29286776 TI - Universal Extensions of Restricted Classes of Quantum Operations. AB - For numerous applications of quantum theory it is desirable to be able to apply arbitrary unitary operations on a given quantum system. However, in particular situations only a subset of unitary operations is easily accessible. This raises the question of what additional unitary gates should be added to a given gate set in order to attain physical universality, i.e., to be able to perform arbitrary unitary transformation on the relevant Hilbert space. In this work, we study this problem for three paradigmatic cases of naturally occurring restricted gate sets: (A) particle-number preserving bosonic linear optics, (B) particle-number preserving fermionic linear optics, and (C) general (not necessarily particle number preserving) fermionic linear optics. Using tools from group theory and control theory, we classify, in each of these scenarios, what sets of gates are generated, if an additional gate is added to the set of allowed transformations. This allows us to solve the universality problem completely for arbitrary number of particles and for arbitrary dimensions of the single-particle Hilbert space. PMID- 29286777 TI - Variational Approach to Monte Carlo Renormalization Group. AB - We present a Monte Carlo method for computing the renormalized coupling constants and the critical exponents within renormalization theory. The scheme, which derives from a variational principle, overcomes critical slowing down, by means of a bias potential that renders the coarse grained variables uncorrelated. The two-dimensional Ising model is used to illustrate the method. PMID- 29286736 TI - J/psi Elliptic Flow in Pb-Pb Collisions at sqrt[s_{NN}]=5.02 TeV. AB - We report a precise measurement of the J/psi elliptic flow in Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV with the ALICE detector at the LHC. The J/psi mesons are reconstructed at midrapidity (|y|<0.9) in the dielectron decay channel and at forward rapidity (2.51. These theories have a Z_{d} color-flavor center symmetry arising from intertwined color center transformations and cyclic flavor permutations. The symmetry realization depends on the temperature, baryon chemical potential, and value of n_{f}/N, with implications for conformal window studies and dense quark matter. PMID- 29286781 TI - Phase Memory Preserving Harmonics from Abruptly Autofocusing Beams. AB - We demonstrate both theoretically and experimentally that the harmonics from abruptly autofocusing ring-Airy beams present a surprising property: They preserve the phase distribution of the fundamental beam. Consequently, this "phase memory" imparts to the harmonics the abrupt autofocusing behavior, while, under certain conditions, their foci coincide in space with the one of the fundamental. Experiments agree well with our theoretical estimates and detailed numerical calculations. Our findings open the way for the use of such beams and their harmonics in strong field science. PMID- 29286782 TI - Proton Spectra from ^{3}He+T and ^{3}He+^{3}He Fusion at Low Center-of-Mass Energy, with Potential Implications for Solar Fusion Cross Sections. AB - Few-body nuclear physics often relies upon phenomenological models, with new efforts at the ab initio theory reported recently; both need high-quality benchmark data, particularly at low center-of-mass energies. We use high-energy density plasmas to measure the proton spectra from ^{3}He+T and ^{3}He+^{3}He fusion. The data disagree with R-matrix predictions constrained by neutron spectra from T+T fusion. We present a new analysis of the ^{3}He+^{3}He proton spectrum; these benchmarked spectral shapes should be used for interpreting low resolution data, such as solar fusion cross-section measurements. PMID- 29286779 TI - Sequence-Dependent Persistence Length of Long DNA. AB - Using a high-throughput genome-mapping approach, we obtained circa 50 million measurements of the extension of internal human DNA segments in a 41 nm*41 nm nanochannel. The underlying DNA sequences, obtained by mapping to the reference human genome, are 2.5-393 kilobase pairs long and contain percent GC contents between 32.5% and 60%. Using Odijk's theory for a channel-confined wormlike chain, these data reveal that the DNA persistence length increases by almost 20% as the percent GC content increases. The increased persistence length is rationalized by a model, containing no adjustable parameters, that treats the DNA as a statistical terpolymer with a sequence-dependent intrinsic persistence length and a sequence-independent electrostatic persistence length. PMID- 29286786 TI - Intertwining Topological Order and Broken Symmetry in a Theory of Fluctuating Spin-Density Waves. AB - The pseudogap metal phase of the hole-doped cuprate superconductors has two seemingly unrelated characteristics: a gap in the electronic spectrum in the "antinodal" region of the square lattice Brillouin zone and discrete broken symmetries. We present a SU(2) gauge theory of quantum fluctuations of magnetically ordered states which appear in a classical theory of square lattice antiferromagnets, in a spin-density wave mean field theory of the square lattice Hubbard model, and in a CP^{1} theory of spinons. This theory leads to metals with an antinodal gap and topological order which intertwines with the observed broken symmetries. PMID- 29286785 TI - Experimental Study of Ordering of Hard Cubes by Shearing. AB - We experimentally analyze the compaction dynamics of an ensemble of cubic particles submitted to a novel type of excitation. Instead of the standard tapping procedure used in granular materials we apply alternative twists to the cylindrical container. Under this agitation, the development of shear forces among the different layers of cubes leads to particle alignment. As a result, the packing fraction grows monotonically with the number of twists. If the intensity of the excitations is sufficiently large, an ordered final state is reached where the volume fraction is the densest possible compatible with the boundary condition. This ordered final state resembles the tetratic or cubatic phases observed in colloids. PMID- 29286784 TI - Factorization and Criticality in Finite XXZ Systems of Arbitrary Spin. AB - We analyze ground state (GS) factorization in general arrays of spins s_{i} with XXZ couplings immersed in nonuniform fields. It is shown that an exceptionally degenerate set of completely separable symmetry-breaking GSs can arise for a wide range of field configurations, at a quantum critical point where all GS magnetization plateaus merge. Such configurations include alternating fields as well as zero-bulk field solutions with edge fields only and intermediate solutions with zero field at specific sites, valid for d-dimensional arrays. The definite magnetization-projected GSs at factorization can be analytically determined and depend only on the exchange anisotropies, exhibiting critical entanglement properties. We also show that some factorization-compatible field configurations may result in field-induced frustration and nontrivial behavior at strong fields. PMID- 29286787 TI - Coupling between a Charge Density Wave and Magnetism in an Heusler Material. AB - The prototypical magnetic memory shape alloy Ni_{2}MnGa undergoes various phase transitions as a function of the temperature, pressure, and doping. In the low temperature phases below 260 K, an incommensurate structural modulation occurs along the [110] direction which is thought to arise from the softening of a phonon mode. It is not at present clear how this phenomenon is related, if at all, to the magnetic memory effect. Here we report time-resolved measurements which track both the structural and magnetic components of the phase transition from the modulated cubic phase as it is brought into the high-symmetry phase. The results suggest that the photoinduced demagnetization modifies the Fermi surface in regions that couple strongly to the periodicity of the structural modulation through the nesting vector. The amplitude of the periodic lattice distortion, however, appears to be less affected by the demagnetization. PMID- 29286788 TI - Anomalous Spin Precession under a Geometrical Torque. AB - Precession and relaxation predominantly characterize the real-time dynamics of a spin driven by a magnetic field and coupled to a large Fermi sea of conduction electrons. We demonstrate an anomalous precession with frequency higher than the Larmor frequency or with inverted orientation in the limit where the electronic motion adiabatically follows the spin dynamics. For a classical spin, the effect is traced back to a geometrical torque resulting from a finite spin Berry curvature. PMID- 29286789 TI - Beyond the Boost: Measuring the Intrinsic Dipole of the Cosmic Microwave Background Using the Spectral Distortions of the Monopole and Quadrupole. AB - We present a general framework for the accurate spectral modeling of the low multipoles of the cosmic microwave background (CMB) as observed in a boosted frame. In particular, we demonstrate how spectral measurements of the low multipoles can be used to separate the motion-induced dipole of the CMB from a possible intrinsic dipole component. In a moving frame, the leakage of an intrinsic dipole moment into the CMB monopole and quadrupole induces spectral distortions with distinct frequency functions that, respectively, peak at 337 and 276 GHz. The leakage into the quadrupole moment also induces a geometrical distortion to the spatial morphology of this mode. The combination of these effects can be used to lift the degeneracy between the motion-induced dipole and any intrinsic dipole that the CMB might possess. Assuming the current peculiar velocity measurements, the leakage of an intrinsic dipole with an amplitude of DeltaT=30 MUK into the monopole and quadrupole moments will be detectable by a PIXIE-like experiment at ~40 nK (2.5sigma) and ~130 nK (11sigma) level at their respective peak frequencies. PMID- 29286790 TI - Antiferromagnetic Resonance and Terahertz Continuum in alpha-RuCl_{3}. AB - We report measurements of optical absorption in the zigzag antiferromagnet alpha RuCl_{3} as a function of temperature T, magnetic field B, and photon energy homega in the range ~0.3-8.3 meV, using time-domain terahertz spectroscopy. Polarized measurements show that threefold rotational symmetry is broken in the honeycomb plane from 2 to 300 K. We find a sharp absorption peak at 2.56 meV upon cooling below the Neel temperature of 7 K at B=0 that we identify as the magnetic dipole excitation of a zero-wave-vector magnon, or antiferromagnetic resonance (AFMR). With the application of B, the AFMR broadens and shifts to a lower frequency as long-range magnetic order is lost in a manner consistent with transitioning to a spin-disordered phase. From a direct, internally calibrated measurement of the AFMR spectral weight, we place an upper bound on the contribution to the dc susceptibility from a magnetic excitation continuum. PMID- 29286792 TI - Entanglement Entropy of Eigenstates of Quantum Chaotic Hamiltonians. AB - In quantum statistical mechanics, it is of fundamental interest to understand how close the bipartite entanglement entropy of eigenstates of quantum chaotic Hamiltonians is to maximal. For random pure states in the Hilbert space, the average entanglement entropy is known to be nearly maximal, with a deviation that is, at most, a constant. Here we prove that, in a system that is away from half filling and divided in two equal halves, an upper bound for the average entanglement entropy of random pure states with a fixed particle number and normally distributed real coefficients exhibits a deviation from the maximal value that grows with the square root of the volume of the system. Exact numerical results for highly excited eigenstates of a particle number conserving quantum chaotic model indicate that the bound is saturated with increasing system size. PMID- 29286791 TI - Optimal Quantum Spatial Search on Random Temporal Networks. AB - To investigate the performance of quantum information tasks on networks whose topology changes in time, we study the spatial search algorithm by continuous time quantum walk to find a marked node on a random temporal network. We consider a network of n nodes constituted by a time-ordered sequence of Erdos-Renyi random graphs G(n,p), where p is the probability that any two given nodes are connected: After every time interval tau, a new graph G(n,p) replaces the previous one. We prove analytically that, for any given p, there is always a range of values of tau for which the running time of the algorithm is optimal, i.e., O(sqrt[n]), even when search on the individual static graphs constituting the temporal network is suboptimal. On the other hand, there are regimes of tau where the algorithm is suboptimal even when each of the underlying static graphs are sufficiently connected to perform optimal search on them. From this first study of quantum spatial search on a time-dependent network, it emerges that the nontrivial interplay between temporality and connectivity is key to the algorithmic performance. Moreover, our work can be extended to establish high fidelity qubit transfer between any two nodes of the network. Overall, our findings show that one can exploit temporality to achieve optimal quantum information tasks on dynamical random networks. PMID- 29286793 TI - Neutron Skin Thickness of ^{48}Ca from a Nonlocal Dispersive Optical-Model Analysis. AB - A nonlocal dispersive optical-model analysis has been carried out for neutrons and protons in ^{48}Ca. Elastic-scattering angular distributions, total and reaction cross sections, single-particle energies, the neutron and proton numbers, and the charge distribution have been fitted to extract the neutron and proton self-energies both above and below the Fermi energy. From the single particle propagator resulting from these self-energies, we have determined the charge and neutron matter distributions in ^{48}Ca. A best fit neutron skin of 0.249+/-0.023 fm is deduced, but values up to 0.33 fm are still consistent. The energy dependence of the total neutron cross sections is shown to have a strong sensitivity to the skin thickness. PMID- 29286794 TI - Ground-State Properties of Unitary Bosons: From Clusters to Matter. AB - The properties of cold Bose gases at unitarity have been extensively investigated in the last few years both theoretically and experimentally. In this Letter we use a family of interactions tuned to two-body unitarity and very weak three-body binding to demonstrate the universal properties of both clusters and matter. We determine the universal properties of finite clusters up to 60 particles and, for the first time, explicitly demonstrate the saturation of energy and density with particle number and compare with bulk properties. At saturation in the bulk we determine the energy, density, two- and three-body contacts, and the condensate fraction. We find that uniform matter is more bound than three-body clusters by nearly 2 orders of magnitude, the two-body contact is very large in absolute terms, and yet the condensate fraction is also very large, greater than 90%. Equilibrium properties of these systems may be experimentally accessible through rapid quenching of weakly interacting boson superfluids. PMID- 29286795 TI - Symmetry Protected Dynamical Symmetry in the Generalized Hubbard Models. AB - In this Letter we present a theorem on the dynamics of the generalized Hubbard models. This theorem shows that the symmetry of the single-particle Hamiltonian can protect a kind of dynamical symmetry driven by the interactions. Here the dynamical symmetry refers to the phenomenon that time evolution of certain observables are symmetric between the repulsive and attractive Hubbard models. We demonstrate our theorem with three different examples in which the symmetry involves bipartite lattice symmetry, reflection symmetry, and translation symmetry, respectively. Each of these examples relates to one recent cold atom experiment on the dynamics in the optical lattices where such a dynamical symmetry is manifested. These experiments include expansion dynamics of cold atoms, chirality of atomic motion within a synthetic magnetic field, and melting of charge-density-wave order. Therefore, our theorem provides a unified view of these seemingly disparate phenomena. PMID- 29286796 TI - Buckling Instability Causes Inertial Thrust for Spherical Swimmers at All Scales. AB - Microswimmers, and among them aspirant microrobots, generally have to cope with flows where viscous forces are dominant, characterized by a low Reynolds number (Re). This implies constraints on the possible sequences of body motion, which have to be nonreciprocal. Furthermore, the presence of a strong drag limits the range of resulting velocities. Here, we propose a swimming mechanism which uses the buckling instability triggered by pressure waves to propel a spherical, hollow shell. With a macroscopic experimental model, we show that a net displacement is produced at all Re regimes. An optimal displacement caused by nontrivial history effects is reached at intermediate Re. We show that, due to the fast activation induced by the instability, this regime is reachable by microscopic shells. The rapid dynamics would also allow high-frequency excitation with standard traveling ultrasonic waves. Scale considerations predict a swimming velocity of order 1 cm/s for a remote-controlled microrobot, a suitable value for biological applications such as drug delivery. PMID- 29286797 TI - Group Theoretical Route to Deterministic Weyl Points in Chiral Photonic Lattices. AB - Topological phases derived from point degeneracies in photonic band structures show intriguing and unique behavior. Previously identified band degeneracies are based on accidental degeneracies and subject to engineering on a case-by-case basis. Here we show that deterministic pseudo Weyl points with nontrivial topology and hyperconic dispersion exist at the Brillouin zone center of chiral cubic symmetries. This conceivably allows realization of topologically protected frequency isolated surface bands in 3D and n=0 properties as demonstrated for a nanoplasmonic system and a photonic crystal. PMID- 29286773 TI - chi_{c1} and chi_{c2} Resonance Parameters with the Decays chi_{c1,c2} >J/psiMU^{+}MU^{-}. AB - The decays chi_{c1}->J/psiMU^{+}MU^{-} and chi_{c2}->J/psiMU^{+}MU^{-} are observed and used to study the resonance parameters of the chi_{c1} and chi_{c2} mesons. The masses of these states are measured to be m(chi_{c1})=3510.71+/ 0.04(stat)+/-0.09(syst) MeV and m(chi_{c2})=3556.10+/-0.06(stat)+/-0.11(syst) MeV, where the knowledge of the momentum scale for charged particles dominates the systematic uncertainty. The momentum-scale uncertainties largely cancel in the mass difference m(chi_{c2})-m(chi_{c1})=45.39+/-0.07(stat)+/-0.03(syst) MeV. The natural width of the chi_{c2} meson is measured to be Gamma(chi_{c2})=2.10+/ 0.20(stat)+/-0.02(syst) MeV. These results are in good agreement with and have comparable precision to the current world averages. PMID- 29286798 TI - Asymmetric Splitting of an Antiferromagnetic Resonance via Quartic Exchange Interactions in Multiferroic Hexagonal HoMnO_{3}. AB - The symmetric splitting of two spin-wave branches in an antiferromagnetic resonance (AFR) experiment has been an essential measurement of antiferromagnets for over half a century. In this work, circularly polarized time-domain THz spectroscopy experiments performed on the low symmetry multiferroic hexagonal HoMnO_{3} reveal an AFR of the Mn sublattice to split asymmetrically in an applied magnetic field, with an ~50% difference in g factors between the high and low energy branches of this excitation. The temperature dependence of the g factors, including a drastic renormalization at the Ho spin ordering temperature, reveals this asymmetry to unambiguously stem from Ho-Mn interactions. Theoretical calculations demonstrate that the AFR asymmetry is not explained by conventional Ho-Mn exchange mechanisms alone and is only reproduced if quartic spin interactions are also included in the spin Hamiltonian. Our results provide a paradigm for the optical study of such novel interactions in hexagonal manganites and low symmetry antiferromagnets in general. PMID- 29286799 TI - Arrow of Time for Continuous Quantum Measurement. AB - We investigate the statistical arrow of time for a quantum system being monitored by a sequence of measurements. For a continuous qubit measurement example, we demonstrate that time-reversed evolution is always physically possible, provided that the measurement record is also negated. Despite this restoration of dynamical reversibility, a statistical arrow of time emerges, and may be quantified by the log-likelihood difference between forward and backward propagation hypotheses. We then show that such reversibility is a universal feature of nonprojective measurements, with forward or backward Janus measurement sequences that are time-reversed inverses of each other. PMID- 29286800 TI - Private States, Quantum Data Hiding, and the Swapping of Perfect Secrecy. AB - An important contribution to the understanding of quantum key distribution has been the discovery of entangled states from which secret bits, but no maximally entangled states, can be extracted [Horodecki et al., Phys. Rev. Lett. 94, 200501 (2005)PRLTAO0031-900710.1103/PhysRevLett.94.200501]. The construction of those states was based on an intuition that the quantum mechanical phenomena of data hiding and privacy might be related. In this Letter we firmly connect these two phenomena and highlight three aspects of this result. First, we simplify the definition of the secret key rate. Second, we give a formula for the one-way distillable entanglement of certain private states. Third, we consider the problem of extending the distance of quantum key distribution with help of intermediate stations, a setting called the quantum key repeater. We show that for protocols that first distill private states, it is essentially optimal to use the standard quantum repeater protocol based on entanglement distillation and entanglement swapping. PMID- 29286801 TI - Probing Low-Mass Vector Bosons with Parity Nonconservation and Nuclear Anapole Moment Measurements in Atoms and Molecules. AB - In the presence of P-violating interactions, the exchange of vector bosons between electrons and nucleons induces parity-nonconserving (PNC) effects in atoms and molecules, while the exchange of vector bosons between nucleons induces anapole moments of nuclei. We perform calculations of such vector-mediated PNC effects in Cs, Ba^{+}, Yb, Tl, Fr, and Ra^{+} using the same relativistic many body approaches as in earlier calculations of standard-model PNC effects, but with the long-range operator of the weak interaction. We calculate nuclear anapole moments due to vector-boson exchange using a simple nuclear model. From measured and predicted (within the standard model) values for the PNC amplitudes in Cs, Yb, and Tl, as well as the nuclear anapole moment of ^{133}Cs, we constrain the P-violating vector-pseudovector nucleon-electron and nucleon-proton interactions mediated by a generic vector boson of arbitrary mass. Our limits improve on existing bounds from other experiments by many orders of magnitude over a very large range of vector-boson masses. PMID- 29286802 TI - Maximum Redshift of Gravitational Wave Merger Events. AB - Future generations of gravitational wave detectors will have the sensitivity to detect gravitational wave events at redshifts far beyond any detectable electromagnetic sources. We show that if the observed event rate is greater than one event per year at redshifts z>=40, then the probability distribution of primordial density fluctuations must be significantly non-Gaussian or the events originate from primordial black holes. The nature of the excess events can be determined from the redshift distribution of the merger rate. PMID- 29286803 TI - Quantum Phase Transition in Few-Layer NbSe_{2} Probed through Quantized Conductance Fluctuations. AB - We present the first observation of dynamically modulated quantum phase transition between two distinct charge density wave (CDW) phases in two dimensional 2H-NbSe_{2}. There is recent spectroscopic evidence for the presence of these two quantum phases, but its evidence in bulk measurements remained elusive. We studied suspended, ultrathin 2H-NbSe_{2} devices fabricated on piezoelectric substrates-with tunable flakes thickness, disorder level, and strain. We find a surprising evolution of the conductance fluctuation spectra across the CDW temperature: the conductance fluctuates between two precise values, separated by a quantum of conductance. These quantized fluctuations disappear for disordered and on-substrate devices. With the help of mean-field calculations, these observations can be explained as to arise from dynamical phase transition between the two CDW states. To affirm this idea, we vary the lateral strain across the device via piezoelectric medium and map out the phase diagram near the quantum critical point. The results resolve a long-standing mystery of the anomalously large spectroscopic gap in NbSe_{2}. PMID- 29286804 TI - Multiphoton Effects Enhanced due to Ultrafast Photon-Number Fluctuations. AB - The rate of an n-photon effect generally scales as the nth order autocorrelation function of the incident light, which is high for light with strong photon-number fluctuations. Therefore, "noisy" light sources are much more efficient for multiphoton effects than coherent sources with the same mean power, pulse duration, and repetition rate. Here we generate optical harmonics of the order of 2-4 from a bright squeezed vacuum, a state of light consisting of only quantum noise with no coherent component. We observe up to 2 orders of magnitude enhancement in the generation of optical harmonics due to ultrafast photon-number fluctuations. This feature is especially important for the nonlinear optics of fragile structures, where the use of a noisy pump can considerably increase the effect without overcoming the damage threshold. PMID- 29286805 TI - Interplay of Chiral and Helical States in a Quantum Spin Hall Insulator Lateral Junction. AB - We study the electronic transport across an electrostatically gated lateral junction in a HgTe quantum well, a canonical 2D topological insulator, with and without an applied magnetic field. We control the carrier density inside and outside a junction region independently and hence tune the number and nature of 1D edge modes propagating in each of those regions. Outside the bulk gap, the magnetic field drives the system to the quantum Hall regime, and chiral states propagate at the edge. In this regime, we observe fractional plateaus that reflect the equilibration between 1D chiral modes across the junction. As the carrier density approaches zero in the central region and at moderate fields, we observe oscillations in the resistance that we attribute to Fabry-Perot interference in the helical states, enabled by the broken time reversal symmetry. At higher fields, those oscillations disappear, in agreement with the expected absence of helical states when band inversion is lifted. PMID- 29286806 TI - Role of Multichance Fission in the Description of Fission-Fragment Mass Distributions at High Energies. AB - Fission-fragment mass distributions were measured for ^{237-240}U, ^{239-242}Np, and ^{241-244}Pu populated in the excitation-energy range from 10 to 60 MeV by multinucleon transfer channels in the reaction ^{18}O+^{238}U at the Japan Atomic Energy Agency tandem facility. Among them, the data for ^{240}U and ^{240,241,242}Np were observed for the first time. It was found that the mass distributions for all the studied nuclides maintain a double-humped shape up to the highest measured energy in contrast to expectations of predominantly symmetric fission due to the washing out of nuclear shell effects. From a comparison with the dynamical calculation based on the fluctuation-dissipation model, this behavior of the mass distributions was unambiguously attributed to the effect of multichance fission. PMID- 29286807 TI - Detection Loss Tolerant Supersensitive Phase Measurement with an SU(1,1) Interferometer. AB - In an unseeded SU(1,1) interferometer composed of two cascaded degenerate parametric amplifiers, with direct detection at the output, we demonstrate a phase sensitivity overcoming the shot noise limit by 2.3 dB. The interferometer is strongly unbalanced, with the parametric gain of the second amplifier exceeding the gain of the first one by a factor of 2, which makes the scheme extremely tolerant to detection losses. We show that by increasing the gain of the second amplifier, the phase supersensitivity of the interferometer can be preserved even with detection losses as high as 80%. This finding can considerably improve the state-of-the-art interferometry, enable sub-shot-noise phase sensitivity in spectral ranges with inefficient detection, and allow extension to quantum imaging. PMID- 29286808 TI - Stability Landscape of Shell Buckling. AB - We measure the response of cylindrical shells to poking and identify a stability landscape, which fully characterizes the stability of perfect shells and imperfect ones in the case where a single defect dominates. We show that the landscape of stability is independent of the loading protocol and the poker geometry. Our results suggest that the complex stability of shells reduces to a low dimensional description. Tracking ridges and valleys of this landscape defines a natural phase-space coordinates for describing the stability of shells. PMID- 29286809 TI - Two-Dimensional Dirac Fermions Protected by Space-Time Inversion Symmetry in Black Phosphorus. AB - We report the realization of novel symmetry-protected Dirac fermions in a surface doped two-dimensional (2D) semiconductor, black phosphorus. The widely tunable band gap of black phosphorus by the surface Stark effect is employed to achieve a surprisingly large band inversion up to ~0.6 eV. High-resolution angle-resolved photoemission spectra directly reveal the pair creation of Dirac points and their movement along the axis of the glide-mirror symmetry. Unlike graphene, the Dirac point of black phosphorus is stable, as protected by space-time inversion symmetry, even in the presence of spin-orbit coupling. Our results establish black phosphorus in the inverted regime as a simple model system of 2D symmetry protected (topological) Dirac semimetals, offering an unprecedented opportunity for the discovery of 2D Weyl semimetals. PMID- 29286810 TI - Gapless Spin Excitations in the Field-Induced Quantum Spin Liquid Phase of alpha RuCl_{3}. AB - alpha-RuCl_{3} is a leading candidate material for the observation of physics related to the Kitaev quantum spin liquid (QSL). By combined susceptibility, specific-heat, and nuclear-magnetic-resonance measurements, we demonstrate that alpha-RuCl_{3} undergoes a quantum phase transition to a QSL in a magnetic field of 7.5 T applied in the ab plane. We show further that this high-field QSL phase has gapless spin excitations over a field range up to 16 T. This highly unconventional result, unknown in either Heisenberg or Kitaev magnets, offers insight essential to establishing the physics of alpha-RuCl_{3}. PMID- 29286811 TI - Engineering the Eigenstates of Coupled Spin-1/2 Atoms on a Surface. AB - Quantum spin networks having engineered geometries and interactions are eagerly pursued for quantum simulation and access to emergent quantum phenomena such as spin liquids. Spin-1/2 centers are particularly desirable, because they readily manifest coherent quantum fluctuations. Here we introduce a controllable spin-1/2 architecture consisting of titanium atoms on a magnesium oxide surface. We tailor the spin interactions by atomic-precision positioning using a scanning tunneling microscope (STM) and subsequently perform electron spin resonance on individual atoms to drive transitions into and out of quantum eigenstates of the coupled spin system. Interactions between the atoms are mapped over a range of distances extending from highly anisotropic dipole coupling to strong exchange coupling. The local magnetic field of the magnetic STM tip serves to precisely tune the superposition states of a pair of spins. The precise control of the spin-spin interactions and ability to probe the states of the coupled-spin network by addressing individual spins will enable the exploration of quantum many-body systems based on networks of spin-1/2 atoms on surfaces. PMID- 29286812 TI - Solvable Hydrodynamics of Quantum Integrable Systems. AB - The conventional theory of hydrodynamics describes the evolution in time of chaotic many-particle systems from local to global equilibrium. In a quantum integrable system, local equilibrium is characterized by a local generalized Gibbs ensemble or equivalently a local distribution of pseudomomenta. We study time evolution from local equilibria in such models by solving a certain kinetic equation, the "Bethe-Boltzmann" equation satisfied by the local pseudomomentum density. Explicit comparison with density matrix renormalization group time evolution of a thermal expansion in the XXZ model shows that hydrodynamical predictions from smooth initial conditions can be remarkably accurate, even for small system sizes. Solutions are also obtained in the Lieb-Liniger model for free expansion into vacuum and collisions between clouds of particles, which model experiments on ultracold one-dimensional Bose gases. PMID- 29286813 TI - Turbulence of Weak Gravitational Waves in the Early Universe. AB - We study the statistical properties of an ensemble of weak gravitational waves interacting nonlinearly in a flat space-time. We show that the resonant three wave interactions are absent and develop a theory for four-wave interactions in the reduced case of a 2.5+1 diagonal metric tensor. In this limit, where only plus-polarized gravitational waves are present, we derive the interaction Hamiltonian and consider the asymptotic regime of weak gravitational wave turbulence. Both direct and inverse cascades are found for the energy and the wave action, respectively, and the corresponding wave spectra are derived. The inverse cascade is characterized by a finite-time propagation of the metric excitations-a process similar to an explosive nonequilibrium Bose-Einstein condensation, which provides an efficient mechanism to ironing out small-scale inhomogeneities. The direct cascade leads to an accumulation of the radiation energy in the system. These processes might be important for understanding the early Universe where a background of weak nonlinear gravitational waves is expected. PMID- 29286814 TI - Free Surface Relaxations of Star-Shaped Polymer Films. AB - The surface relaxation dynamics of supported star-shaped polymer thin films are shown to be slower than the bulk, persisting up to temperatures at least 50 K above the bulk glass transition temperature T_{g}^{bulk}. This behavior, exhibited by star-shaped polystyrenes with functionality f=8 arms and molecular weights per arm M_{arm}1 spins, where we expose the same effective parameters, scaling properties, and phase diagram. Thus, a stronger form of universality is established, valid from N=1 up to the thermodynamic limit. PMID- 29286819 TI - Silicon-Vacancy Spin Qubit in Diamond: A Quantum Memory Exceeding 10 ms with Single-Shot State Readout. AB - The negatively charged silicon-vacancy (SiV^{-}) color center in diamond has recently emerged as a promising system for quantum photonics. Its symmetry protected optical transitions enable the creation of indistinguishable emitter arrays and deterministic coupling to nanophotonic devices. Despite this, the longest coherence time associated with its electronic spin achieved to date (~250 ns) has been limited by coupling to acoustic phonons. We demonstrate coherent control and suppression of phonon-induced dephasing of the SiV^{-} electronic spin coherence by 5 orders of magnitude by operating at temperatures below 500 mK. By aligning the magnetic field along the SiV^{-} symmetry axis, we demonstrate spin-conserving optical transitions and single-shot readout of the SiV^{-} spin with 89% fidelity. Coherent control of the SiV^{-} spin with microwave fields is used to demonstrate a spin coherence time T_{2} of 13 ms and a spin relaxation time T_{1} exceeding 1 s at 100 mK. These results establish the SiV^{-} as a promising solid-state candidate for the realization of quantum networks. PMID- 29286820 TI - Recognizing Axionic Dark Matter by Compton and de Broglie Scale Modulation of Pulsar Timing. AB - Light axionic dark matter, motivated by string theory, is increasingly favored for the "no weakly interacting massive particle era". Galaxy formation is suppressed below a Jeans scale of ?10^{8} M_{?} by setting the axion mass to m_{B}~10^{-22} eV, and the large dark cores of dwarf galaxies are explained as solitons on the de Broglie scale. This is persuasive, but detection of the inherent scalar field oscillation at the Compton frequency omega_{B}=(2.5 months)^{-1}(m_{B}/10^{-22} eV) would be definitive. By evolving the coupled Schrodinger-Poisson equation for a Bose-Einstein condensate, we predict the dark matter is fully modulated by de Broglie interference, with a dense soliton core of size ?150 pc, at the Galactic center. The oscillating field pressure induces general relativistic time dilation in proportion to the local dark matter density and pulsars within this dense core have detectably large timing residuals of ?400 nsec/(m_{B}/10^{-22} eV). This is encouraging as many new pulsars should be discovered near the Galactic center with planned radio surveys. More generally, over the whole Galaxy, differences in dark matter density between pairs of pulsars imprints a pairwise Galactocentric signature that can be distinguished from an isotropic gravitational wave background. PMID- 29286821 TI - Photoexcited Muon Spin Spectroscopy: A New Method for Measuring Excess Carrier Lifetime in Bulk Silicon. AB - We have measured excess carrier lifetime in silicon using photoexcited muon spin spectroscopy. Positive muons implanted deep in a wafer can interact with the optically injected excess carriers and directly probe the bulk carrier lifetime while minimizing the effect from surface recombination. The method is based on the relaxation rate of muon spin asymmetry, which depends on the excess carrier density. The underlying microscopic mechanism has been understood by simulating the four-state muonium model in Si under illumination. We apply the technique to different injection levels and temperatures, and demonstrate its ability for injection- and temperature-dependent lifetime spectroscopy. PMID- 29286822 TI - Microscopic Marangoni Flows Cannot Be Predicted on the Basis of Pressure Gradients. AB - A concentration gradient along a fluid-fluid interface can cause flow. On a microscopic level, this so-called Marangoni effect can be viewed as being caused by a gradient in the pressures acting on the fluid elements or as the chemical potential gradients acting on the excess densities of different species at the interface. If the interface thickness can be ignored, all approaches should result in the same flow profile away from the interface. However, on a more microscopic scale, the different expressions result in different flow profiles, only one of which can be correct. Here we compare the results of direct nonequilibrium molecular dynamics simulations with the flows that are generated by pressure and chemical-potential gradients. We find that the approach based on the chemical-potential gradients agrees with the direct simulations, whereas the calculations based on the pressure gradients do not. PMID- 29286823 TI - Switching Magnetism and Superconductivity with Spin-Polarized Current in Iron Based Superconductor. AB - We explore a new mechanism for switching magnetism and superconductivity in a magnetically frustrated iron-based superconductor using spin-polarized scanning tunneling microscopy (SPSTM). Our SPSTM study on single-crystal Sr_{2}VO_{3}FeAs shows that a spin-polarized tunneling current can switch the Fe-layer magnetism into a nontrivial C_{4} (2*2) order, which cannot be achieved by thermal excitation with an unpolarized current. Our tunneling spectroscopy study shows that the induced C_{4} (2*2) order has characteristics of plaquette antiferromagnetic order in the Fe layer and strongly suppresses superconductivity. Also, thermal agitation beyond the bulk Fe spin ordering temperature erases the C_{4} state. These results suggest a new possibility of switching local superconductivity by changing the symmetry of magnetic order with spin-polarized and unpolarized tunneling currents in iron-based superconductors. PMID- 29286824 TI - Accurate Measurement of the Optical Constants n and k for a Series of 57 Inorganic and Organic Liquids for Optical Modeling and Detection. AB - For optical modeling and other purposes, we have created a library of 57 liquids for which we have measured the complex optical constants n and k. These liquids vary in their nature, ranging in properties that include chemical structure, optical band strength, volatility, and viscosity. By obtaining the optical constants, one can model most optical phenomena in media and at interfaces including reflection, refraction, and dispersion. Based on the works of others, we have developed improved protocols using multiple path lengths to determine the optical constants n/k for dozens of liquids, including inorganic, organic, and organophosphorus compounds. Detailed descriptions of the measurement and data reduction protocols are discussed; agreement of the derived optical constant n and k values with literature values are presented. We also present results using the n/k values as applied to an optical modeling scenario whereby the derived data are presented and tested for models of 1 um and 100 um layers for dimethyl methylphosphonate (DMMP) on both metal (aluminum) and dielectric (soda lime glass) substrates to show substantial differences between the reflected signal from highly reflective substrates and less-reflective substrates. PMID- 29286825 TI - Is Treatment of Segond Fracture Necessary With Combined Anterior Cruciate Ligament Reconstruction? AB - BACKGROUND: There is a paucity of clinical information to guide the treatment of a combined anterior cruciate ligament (ACL) tear and Segond fracture. PURPOSE: To compare clinical outcomes, graft failure rates, and activity levels between patients undergoing ACL reconstruction (ACLR) with and without an untreated Segond fracture at a minimum 2-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study included a group of patients with a combined ACL tear/untreated Segond fracture that was matched based on age, sex, body mass index, and graft type to a control group of patients with an ACL tear and no Segond fracture. All patients were treated with ACLR alone between the years of 2000 and 2015. The diagnosis of a Segond fracture, or bony avulsion of the anterolateral complex, was made by radiographic analysis. Data regarding the initial injury, surgical intervention, and physical examination findings were recorded. Clinical and functional outcomes were obtained using physical examination results, International Knee Documentation Committee (IKDC) subjective scores, and Tegner activity levels. RESULTS: Twenty patients (16 male, 4 female) with a combined ACL tear/untreated Segond fracture with a mean age of 26.3 years (range, 13-44 years) were matched to a control group of 40 patients (32 male, 8 female) with an ACL tear and no Segond fracture with a mean age of 26.4 years (range, 13-47 years). The study group was followed for a mean of 59.1 months (range, 24-180 months) and the control group for a mean of 55.5 months (range, 24 120 months). The mean IKDC score was 86.5 (range, 54-100) for the study group compared with 93.0 (range, 54-100) for the control group ( P = .03). The graft rupture rate was 10% for both groups ( P = .97). The mean time to rupture was 33.0 months (range, 21-45 months) in the study group and 63.5 months (range, 39 88 months) in the control group ( P = .24). Patients in the study group had significantly more anteroposterior instability by preoperative Lachman testing than those in the control group (control group: 0 normal, 3 grade 1+, 37 grade 2+, 0 grade 3+; study group: 0 normal, 1 grade 1+, 10 grade 2+, 9 grade 3+; P = .0001). There was no significant difference between the 2 groups in regard to postoperative Lachman testing (control group: 35 normal, 3 grade 1+, 2 grade 2+, 0 grade 3+; study group: 17 normal, 3 grade 1+, 0 grade 2+, 0 grade 3+; P = .31). Patients in the study group had significantly more instability by preoperative pivot-shift testing than those in the control group (control group: 0 normal, 7 grade 1+, 33 grade 2+, 0 grade 3+; study group: 1 normal, 1 grade 1+, 11 grade 2+, 7 grade 3+; P = .0003). No significant difference was found between the 2 groups for postoperative pivot-shift testing (control group: 36 normal, 2 grade 1+, 2 grade 2+, 0 grade 3+; study group: 18 normal, 1 grade 1+, 1 grade 2+, 0 grade 3+; P = .61) or final Tegner activity level (median, 6). CONCLUSION: At midterm follow-up, patients undergoing ACLR with and without a Segond fracture had similar pivot-shift test results, graft failure rates, and activity levels. The IKDC score was statistically worse in the patients with a combined ACL tear/untreated Segond fracture, but the difference was less than the minimal clinically important difference for the IKDC score. These findings suggest that patients with a combined ACL tear/untreated Segond fracture can have comparable outcomes to patients with an ACL tear and no Segond fracture when treated with ACLR alone. PMID- 29286826 TI - Systematic review of low-level laser therapy for adult androgenic alopecia. AB - Alopecia is a common disorder affecting over half of the world's population. Within this condition, androgenic alopecia (AA) is the most common type, affecting 50% of males over 40 and 75% of females over 65. Anecdotal paradoxical hypertrichosis noted during laser epilation has generated interest in the possibility of using laser to stimulate hair growth. In this study, we aimed to critically appraise the application of low-level laser therapy for the treatment of AA in adults. A systematic review was performed on studies identified on Medline, EMBASE, Cochrane database, and clinicaltrials.org. Double-blinded randomized controlled trials were selected and analyzed quantitatively (meta analysis) and qualitatively (quality of evidence, risk of bias). Low-level laser therapy appears to be a promising noninvasive treatment for AA in adults that is safe for self-administration in the home setting. Although shown to effectively stimulate hair growth when compared to sham devices, these results must be interpreted with caution. Further studies with larger samples, longer follow-up, and independent funding sources are necessary to determine the clinical effectiveness of this novel therapy. PMID- 29286828 TI - Invited Commentary on "The Role of Anxiety in Simulation-Based Dexterity and Overall Performance: Does It Really Matter?" PMID- 29286827 TI - The Role of Anxiety in Simulation-Based Dexterity and Overall Performance: Does It Really Matter? AB - BACKGROUND: Essential Skills in the Management of Surgical Cases (ESMSC) is an international undergraduate surgical masterclass which combines ex vivo, dry lab and high fidelity in vivo simulation-based learning (SBL). It consists of 32 stations of skills-based learning, including open reduction internal fixation (ORIF) of fractures. Current literature suggests early involvement in skills based learning at the undergraduate level is vital. AIMS: To compare students' dexterity and skills-based performance with demographic and educational background parameters. METHODS: 112 medical students from European Union countries including the United Kingdom, Germany, Greece, Cyprus, Germany, and Bulgaria were selected from a competitive pool of candidates to attend the course. Students undertook ORIF in an ex vivo swine model, and in a simulated fracture on a bamboo rod. Skills-based performance was assessed by two consultant surgeons with validated direct observation of procedural skills (DOPS) forms. Anxiety was self-assessed using the Westside Anxiety Scale prior to the ORIF stations. Dexterity was measured with the O'Connor tweezer dexterity test. RESULTS: Female students had significantly higher dexterity scores (median difference 7, p =.003). Right-handed students achieved higher dexterity than left handed students (median difference 7, p =.043). There was no difference in students' performance across different medical schools, and across year groups (p <.05 for any correlation). Self-reported anxiety was not correlated with high fidelity skills-based performance (r = 0.032, p =.74). CONCLUSION: Anxiety does not seem to play a significant role in Simulation Skills-Based learning. Undergraduate surgical curricula should incorporate SBL-based modules to enhance practical skills learning and motivate future orthopedic surgeons. PMID- 29286829 TI - Method for Identifying Maize Haploid Seeds by Applying Diffuse Transmission Near Infrared Spectroscopy. AB - The identification for haploid seeds is an important process in maize haploid breeding. Thanks to the diffuse transmission (DT) technology of near-infrared (NIR) spectroscopy, maize haploid seeds can be selected automatically using NIR spectrum features. However, the NIR spectra of maize seeds contain a large number of redundant features and noise that will degrade the identification performance. We resolved this problem by designing a low dimension and uniform space of seed spectrum features to improve the collected spectra. The zero-phase component analysis (ZCA) method was utilized to uniform the feature space and the partial least squares regression (PLSR) was employed to design the low dimension space. Then, by using the classifier of back propagation neural network (BPNN), a high qualitative identification method was developed for selecting maize haploid seeds. The study results demonstrate that the average accuracy of the proposed method is outstanding (96.16%) with a minor standard deviation (SD) compared with other methods. Therefore, our proposed method is potentially useful for automatically identifying maize haploid seeds. PMID- 29286830 TI - Suicidality in Young Men Who Have Sex with Men: A Systematic Review of the Literature. AB - This systematic literature review addresses risk and protective factors associated with suicidal ideation and attempts in young men who have sex with men (YMSM). The Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, PsychArticles, and PsychInfo yielded 14 articles. Risk factors included (1) not being enrolled in school, (2) earlier sexual debut, (3) substance use/abuse, (4) homelessness, (5) bullying and victimization, (6) fear of community violence, (7) and parental abuse. Protective factors included (1) positive sexual minority LGBT stereotypes, (2) family acceptance, (3) school and peer support, (4) high self-esteem, and (5) adaptive coping mechanisms. PMID- 29286831 TI - Bisexual Mental Health: A Call to Action. AB - Over the past two decades research has consistently found that bisexual people experience poorer mental health than their gay, lesbian or heterosexual counterparts. The reasons behind this high prevalence of poor mental health remain under-researched and largely unknown. In order to improve these outcomes, more research is critically needed with the aim of providing new knowledge upon which health care provision and policy development can be based. This article presents an analysis of the literature to date relating to bisexuality broadly and bisexual mental health specifically, with the aim of providing direction for future research projects. PMID- 29286832 TI - Avascular Necrosis of the Femoral Head. AB - About 250000 patients are operated on annually for hip arthroplasty in the USA alone. Of this number, about 10% the cause of their osteoarthritis is the avascular necrosis of the femoral head. But the causes of necrosis are multiple and many of them are still unknown. That is why small advances in etiopathogenesis, diagnosis and treatment of different causes are very important in order to reduce the number of affected patients. It may seem that small changes, studies focused on the details of different diseases do not bring great changes to science, but it is these small changes that end up adding great evolutions in our knowledge. In addition, the changes of recent years, are not focused on our specialty in technical or anatomical evolutions exclusively, but are often based on biological bases, which is the branch that evolves more within trauma and orthopedics. That is why open and constant minds are what help us move forward. PMID- 29286834 TI - Recombinant Film and Opportunity. PMID- 29286833 TI - Liver X Receptors Activation Attenuates Ischemia Reperfusion Injury of Liver Graft in Rats. AB - PURPOSE: Suppression of the Toll like receptor 4 (TLR4)-nuclear factor-kappaB (NF kappaB) signaling was critical in protection against liver IRI. Previous studies revealed that Liver X receptors (LXRs) activation could antagonize TLR4-NF-kappaB signaling. The purpose of this study is to determine whether LXRs agonist GW3965 can suppress the TLR4-NF-kappaB signaling during liver transplantation and protect ischemia-reperfusion injury (IRI). MATERIALS AND METHODS: Sprague Dawley (SD) rats were used to perform orthotropic liver transplantation. Donors were pretreatment with GW3965 (0.3 mg/kg) through caudal vein injection 30 min before the surgery. The followings were analyzed after transplantation: alanine aminotransferase (ALT), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha) level in serum, ATP binding cassette transporter A1 (Abca1) expression, NF kappaB transcriptional activity, apoptosis and histological injury. RESULTS: GW3965 pretreatment significantly ameliorated the degree of IRI associated with the effects of upregulating Abca1 expression, inhibiting NF-kappaB transcriptional activity, and downregulating TNF-alpha and IL-6 level. CONCLUSION: LXRs activation attenuated hepatic IRI by preventing TLR4-NF-kappaB signaling. PMID- 29286835 TI - Drug use patterns and predictors among homeless youth: Results of an ecological momentary assessment. AB - BACKGROUND: Alcohol and drug use is associated with significant morbidity and mortality and is highly prevalent among homeless youth. Ecological Momentary Assessments (EMA) have been used to examine the effect of urges on drug use, though not among homeless youth. OBJECTIVES: We assessed the patterns of drug use and the correlation between real-time contextual factors and drug use using EMA collected daily. We identified predictors of drug use among a sample of homeless youth 18-25 years old in Houston, Texas. METHODS: Homeless youth (n = 66, 62% male) were recruited from a drop-in center between September 2015 and May 2016. We used generalized linear mixed models and cross-validation methods to determine the best predictive model of drug use. RESULTS: The overall drug use was high: 61% and 32% of participants reported using drugs or alcohol at least one day, respectively. Marijuana and synthetic marijuana use (i.e., Kush, K2, incense packs) were reported most frequently; 86% and 13% of the total drug use EMAs, respectfully. Drug use urge was reported on 26% of days and was the highest on drug use days. Drug use was predicted by discrimination, pornography use, alcohol use, and urges for drugs, alcohol, and to steal. CONCLUSIONS: EMA can be used to predict drug use among homeless youth. Drug use treatment among homeless youth should address the role of experiencing discrimination, pornography and alcohol use, and urge management strategies on drug use. Research is needed to determine if EMA informed just-in-time interventions targeting these predictors can reduce use. PMID- 29286836 TI - Are Contact Lens Discomfort or Soft Contact Lens Material Properties Associated with Alterations in the Corneal Sub-Basal Nerve Plexus? AB - PURPOSE: To study whether contact lens (CL) discomfort and some properties of soft CL materials are associated with alterations in the nerve fibers morphology and density of dendritic cells of the corneal sub-basal nerve plexus. MATERIALS AND METHODS: Forty soft CL wearers and 20 non-CL wearers were included. The Contact Lens Dry Eye Questionnaire-short form was administered to divide CL wearers based on their symptoms (20 symptomatic and 20 asymptomatic CL wearers were included). The CL material properties considered were the CL material type (16 hydrogel and 24 silicone hydrogel CL wearers were included), water content, oxygen transmissibility, and modulus of elasticity. Confocal microscopy was performed, and the number and density of corneal nerves, density of nerve branches, grade of nerve tortuosity, and density of dendritic cells were analyzed. The effects of CL discomfort and CL material properties on the confocal microscopy parameters were analyzed. RESULTS: No significant differences were found among symptomatic and asymptomatic CL wearers and non-CL wearers in any of the confocal microscopy parameters evaluated. The density of dendritic cells was higher in the hydrogel CL wearers compared to the silicone hydrogel CL wearers and non-CL wearers (p = 0.002). The density of dendritic cells tended to be higher as the oxygen transmissibility decreased (beta = -0.40, p = 0.07). CONCLUSIONS: CL discomfort appears not to be associated with alterations in the corneal sub-basal nerve plexus. Hydrogel CL wear might be involved in the recruitment of dendritic cells into the cornea, being a possible origin its lower oxygen permeability compared to silicone hydrogel materials. Future studies are required to confirm these results. PMID- 29286837 TI - Self-Stigma Experiences Among Older Adults with Mental Health Problems Residing in Long-Term Care Facilities: A Qualitative Study. AB - Self-stigma is linked with a variety of deleterious consequences for the stigmatised individual. Much of the past research on self-stigma focuses on younger adults; however, little is known about the self-stigma experience among institutionalised older adults with mental health problems. This study aims to explore experiences of self-stigma among older adults with mental health problems in long-term care facilities. Ten semi-structured interviews were conducted. Insight into mental illness was identified as having a key influence upon the self-stigma experiences among this group. Participants shared common understandings, views, and behavioural reactions towards mental health problems. Lacking control, public stigma, sympathy, disinterest, avoidance, and fear were key themes among them. Re-conceptualising self-stigma theories and implementing interventions that aim at reducing stigmatising attitudes among this group are essential. PMID- 29286838 TI - Patients' self-esteem before and after chemical peeling procedure. AB - INTRODUCTION: Chemical peeling is a safe method, widely used to treat a variety of skin conditions and reduce the aging effects. This study aims to evaluate self esteem among adolescents who undergo chemical peelings. MATERIAL AND METHODS: One hundred and twenty six patients constituted the study group. Sixty seven individuals had undergone chemical peeling for therapeutic reasons and 59 individuals for cosmetic reasons. To assess patients' self-esteem, the Rosenberg's Self-esteem Scale (RSES) was used before and after treatment. The control group included 71 healthy, age- and sex-matched volunteers from the general population. They were also asked to complete the RSES, after the same time interval as the patients. RESULTS: The healthy controls (23.01 +/- 3.12) presented statistically significantly higher self-esteem than both the groups of individuals who would be submitted to chemical peeling. Furthermore, patients who would undergo peeling for therapeutic reasons (21.58 +/- 3.20) had statistically significantly higher self-esteem than those who would undergo the procedure for cosmetic reasons (18.97 +/- 3.36). After the chemical peeling sessions, the self esteem of patients treated for therapeutic reasons (23.48 +/- 2.43) and of patients treated for cosmetic reasons (22.83 +/- 3.34) improved statistically significantly, while the self-esteem of the healthy controls remained stable, as expected. CONCLUSION: Patients who undergo chemical peelings tend to have low levels of self-esteem. Although facial lesions in skin diseases such as acne, acne scars, rosacea, and melasma seem to have negative effect on individuals' self-consciousness, patients who would be submitted to chemical peeling in order to treat wrinkles, loss of radiance, and skin tone clarity have even lower self esteem. Chemical peelings were shown to favorably affect patient's self-esteem since all patients showed an increase in self-esteem after treatment, while the control group experienced no change. PMID- 29286839 TI - A Prechop Technique Using a Reverse Chopper. AB - PURPOSE: To describe a manual prechop technique for splitting the nucleus of the lens using a recently developed reverse chopper. METHODS: During the process, the reverse chopper and the Nagahara chopper are placed diagonally in the peripheral area of the nucleus of the lens after capsulorhexis. The reverse chopper and the Nagahara chopper then are pushed horizontally toward each other so they meet at the center of the lens to split the nucleus of lens into 2 parts. RESULTS: In all cases, the reverse chopper was effective during the prechop procedure for hard nuclei, the nucleus of the lens remained in situ during the chopping process, and the reverse chopper did not retract the suspensory ligament in patients in whom the ligament was fragile. During the prechop procedure, no capsule breakage occurred, and the time and energy required for effective phacoemulsification were reduced significantly. CONCLUSIONS: The prechop technique using the reverse chopper can be applied for cases with grade III-V nuclei, overripe nuclei, and fragile suspensory ligaments. The procedure is simple, and the learning curve is not steep. PMID- 29286840 TI - Effect of Different Processing Methods on Antihypertensive Property and Antioxidant Activity of Sandpaper Leaf (Ficus exasperata) Extracts. AB - Sandpaper leaf (Ficus exasperata) is commonly used in folk medicine to manage high blood pressure. However, different methods such as soaking, boiling, hand maceration, and blending have been employed for preparing sandpaper leaf extracts for hypertensive patients. This study sought to investigate and compare the influence of different processing methods on the antihypertensive properties of sandpaper leaf as well as its effect on Fe2+ and sodium nitroprusside- (SNP-) induced lipid peroxidation in rat heart in vitro. Sandpaper leaf extracts were prepared using different methods and the resulting solutions were freeze-dried. Effect of the extracts on angiotensin-1-converting enzymes (ACE) and arginase activity was assessed. Thereafter, antioxidant activities of the extracts were determined using in vitro antioxidant assays, and the total phenolic content and flavonoid content of the extracts were determined. The results revealed that sandpaper leaf extracts from different processing methods inhibited ACE and arginase activity in a dose-dependent manner. However, the soaking method had significantly (p < .05) higher inhibitory effect on angiotensin converting (ACE) and arginase activity than hand maceration, boiling, and blending methods. Sandpaper leaf extracts also exhibited high antioxidant activities as typified by their iron-chelating ability, 2, 2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical-scavenging and iron-chelating ability as well as inhibition of Fe2+- and SNP-induced lipid peroxidation in rat heart in vitro. Processing methods alter the inhibitory effect of sandpaper leaf extracts on ACE and arginase activities. Thus, inhibition of ACE and arginase coupled with antioxidant properties could offer protective mechanisms against hypertension. However, the soaking method appears to be the most promising among methods considered. PMID- 29286841 TI - Vulnerability and Psychosocial Risk Factors Regarding People who Identify as Transgender. A Systematic Review of the Research Evidence. AB - The aim of this systematic review was to identify the issues related to the vulnerability and psychosocial risk factors of people who identify as transgender. A search of relevant electronic databases from 2007 to 2017 was conducted. Included studies involved transgender people, vulnerability, and risk factors. Following the application of rigorous inclusion and exclusion criteria, a total of 21 papers were considered suitable for the review. The identified themes included sexual risks, substance use, psychological vulnerability risk factors, and protective factors and behaviors. Nurses are in a strong position to address pertinent concerns and to provide the necessary psychosocial supports to this population. PMID- 29286842 TI - Defining Moments and Healing Emplotment: "I Have Cancer; It Doesn't Have Me". AB - Whereas illness, sickness, and disease are dark clouds on the horizon of our lives, the complex process of healing is our sunrise. In this essay, I introduce the concept of healing emplotment, a lived process of knowingly bringing together strategies for self-awareness, the creation of hope, and the management of risk to overcome psychosocial peril. This results in a purposeful re-authoring of the self in society, personhood, in the face of life-threatening events. Rather than only bringing threats to which the stricken must respond, serious illness can also present opportunities for narrative re-authoring of our biopsychosocial self. PMID- 29286843 TI - Where Does the Transplanted Fat is Located in the Gluteal Region? Research Letter. AB - INTRODUCTION: Liposuction is one of the most popular plastic surgery procedures. As in any surgery, there are risks and complications, especially when combined with fat injection. Case reports of fat embolism have been reported. A possible explanation is the puncture and tearing of gluteal vessels during the procedure, especially when a deep injection is planned. OBJECTIVE: To identify the places where fat can be located after injection during a fat graft in the gluteus. METHODS: An experimental study was done in which colorant was injected in four directions using four different quadrants of the gluteus. We Injected 10 cc six times following clock hands until 60 cc were injected, and the cutaneous flap and the muscles were then elevated. Our main purpose was to describe where the colorant went and if it was in contact with the vessels (superior and inferior gluteal vessels). In total, four gluteus muscles were injected and dissected. RESULTS: Injection in the lower lateral quadrant was mainly into the muscle, and colorant was observed in the hypogastric vessels. The injection in the upper quadrants stayed mainly in the subcutaneous tissue. CONCLUSIONS: During surgery, it is important to identify the location of the perforators and to avoid a deep injection, especially from the lower lateral quadrant to the superior medial quadrant (Q4 to Q1), as the probability of puncturing and injecting fat into the main vessels from this direction is higher. PMID- 29286844 TI - Performance validity testing in children and adolescents: A descriptive study comparing direct and embedded measures. AB - Effort testing is a standard element in adult neuropsychological assessment. Research examining performance validity tests (PVTs) has focused on adults. The purpose of this descriptive study was to examine direct and embedded PVTs in children and adolescents. The Test of Memory Malingering (TOMM), a stand-alone PVT, was compared to two embedded measures of effort: California Verbal Learning Test-Children's Version/Second Edition (CVLT-C/II) Recognition Discriminability and Reliable Digit Span (RDS). The sample consisted of 119 children and adolescents referred for outpatient assessment. Cut-off scores used for PVTs were based on previous studies. Results revealed 3/119 failures on the TOMM, 14/119 failures on the RDS, and 34/119 failures on the CVLT-C/II. There was a significant difference between failures on the TOMM and the RDS, as well as between failures on the TOMM and the CVLT-C/II and the RDS and the CVLT-C/II. The results of this study demonstrate that PVTs commonly used with adults may require modifications, including adjusted cut-off scores, to be appropriate with children and adolescents. Results of this study also suggest that relying on more than one measure likely provides the most utility. PMID- 29286845 TI - State-of-the-Art Health Information Technology Meets Patient-centered Care. PMID- 29286846 TI - Mind the Gap: Addressing Provider-Level Barriers to Lung Cancer Screening. PMID- 29286847 TI - Combined Pulmonary Fibrosis and Emphysema. PMID- 29286848 TI - Fitting Positive Airway Pressure Adherence into Teenage Life: Don't Push It! PMID- 29286850 TI - Out of One, Many: Moving beyond a Single Guideline toward Personalized Asthma Care for Obese Children. PMID- 29286849 TI - Severe Airflow Obstruction in a Man with Stomatitis and Lymphadenopathy. PMID- 29286851 TI - Subacute Respiratory Illness with Peripheral Pulmonary Opacities. PMID- 29286852 TI - Long-Term Oxygen Therapy: The Three Big Questions. PMID- 29286853 TI - Is Asthma Paying the Toll? PMID- 29286855 TI - Monocyte-derived Alveolar Macrophages: The Dark Side of Lung Repair? PMID- 29286856 TI - High-Mobility Group Box 1 Upregulates MUC5AC and MUC5B Expression in Primary Airway Epithelial Cells. PMID- 29286857 TI - Chlorine Countermeasures: Supplemental Oxygen Equals Supplemental Lung Injury? PMID- 29286858 TI - beta2-Agonists Enhance Asthma-Relevant Inflammatory Mediators in Human Airway Epithelial Cells. PMID- 29286859 TI - Hypercapnic Acidosis Regulates Mer Tyrosine Kinase Receptor Shedding and Activity. PMID- 29286860 TI - Biomarkers in Sarcoidosis: Can microRNAs Fill the Gap? PMID- 29286861 TI - Regulators of G-Protein Signaling as Asthma Therapy? PMID- 29286863 TI - Readability Assessment of Online Uveitis Patient Education Materials. AB - PURPOSE: To evaluate the readability of online uveitis patient education materials. METHODS: A Google search in November 2016 was completed using search term "uveitis" and "uveitis inflammation." The top 50 websites with patient centered information were selected and analyzed for readability using the Flesch Kincaid Grade Level (FKGL), Flesch Reading Ease Score (FRES), Gunning FOG Index (GFI), and Simple Measure of Gobbledygook (SMOG). Statistical analysis was performed with two-tailed t-tests. RESULTS: The mean word count of the top 50 websites was 1162.7 words, and averaged 16.2 words per sentence. For these websites, the mean FRES was 38.0 (range 4-66, SD = 12.0), mean FKGL was 12.3 (range 6.8-19, SD = 2.4), mean SMOG score was 14.4 (range 9.8-19, SD = 1.8), and the mean Gunning FOG index was 14.0 (range 8.6-19, SD = 2.0). CONCLUSIONS: The majority of online patient directed uveitis materials are at a higher reading level than that of the average American adult. PMID- 29286864 TI - A Study on Ocular Morbidity among Patients with Psoriasis Visiting a Tertiary Care Hospital in Karnataka, Southern India. AB - INTRODUCTION: Psoriasis is a chronic immune-mediated disorder with predominantly dermatological manifestations and varying prevalence in different parts of the world. Data on the ocular features of this disease are limited. Hence, we aimed to estimate the burden of ocular disease in psoriatic patients in the Indian population. MATERIALS AND METHODS: An interdisciplinary cross-sectional hospital based observational study was conducted in South India, wherein an ophthalmological evaluation was performed for the patients with Psoriasis. The ocular features were recorded and compared with the severity of psoriasis using the Psoriasis Area Severity Index (PASI) score. RESULTS: Ocular morbidity was observed in 80% of the patients with psoriasis which increased with increasing duration (p = 0.004) and increasing PASI score (p < 0.001). Blepharitis and dry eye disease were common in our patients with psoriasis. CONCLUSION: It is important to screen patients with psoriasis for ocular comorbidities so as to prevent sight-threatening complications. PMID- 29286865 TI - Randomized Controlled Study to Evaluate the Efficacy of Adalimumab in Patients with Different Forms of Refractory Uveitis. AB - PURPOSE: TNF alpha inhibitors have revolutionized the care of vision-threatening uveitis. This study evaluated the efficacy of adalimumab (ADA) for the treatment of refractory noninfectious uveitis. DESIGN: Randomized, prospective, controlled, two-center clinical trial Methods: Patients with active uveitis despite combined oral low-dose prednisolone and immunosuppression were randomized for additional ADA with corticosteroids in a fixed tapering regime, or corticosteroids only. Primary outcome measure at three months was improved best-corrected visual acuity (BCVA; >2 lines). In case of treatment failure, switch to the other arm was possible. RESULTS: Twenty-five patients (10 ADA, 15 controls) were included. BCVA increased with ADA by > 2 lines in 6/10 patients (60%; mean increase of 0.23 logMAR), but in only 2/15 from controls (13%, mean increase of 0.04 logMAR, Fisher's exact test p = 0.00221). CONCLUSIONS: The results show superiority of ADA over controls in severe ocular inflammation including anterior uveitis. PMID- 29286866 TI - Omega-3 fatty acid deficiency impairs frontostriatal recruitment following repeated amphetamine treatment in rats: A 7 Tesla in vivo phMRI study. AB - Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (n = 20) from P21 to P90. During adolescence (P40-60), one-half of each diet group received daily AMPH injections escalated weekly (0.5, 1.0, 2.5, 5.0 mg/kg/d) or drug vehicle. Following a 30-d abstinence period blood oxygen level dependent (BOLD) responses were determined in a 7 T Bruker Biospec system following an AMPH challenge (7.5 mg/kg, i.v). Postmortem erythrocyte and forebrain DHA composition were determined by gas chromatography. Compared with control rats, forebrain and erythrocyte DHA levels were significantly lower in DEF rats and significantly higher in FO rats. Across AMPH doses DEF rats exhibited greater locomotor activity compared to control and FO rats. In AMPH-naive rats, the AMPH challenge increased BOLD activity in the substantia nigra and basal forebrain and no diet group differences were observed. In AMPH-pretreated control and FO rats, the AMPH challenge similarly increased BOLD activation in the bilateral caudate putamen, thalamus, and motor and cingulate cortices. In contrast, BOLD activation in AMPH pretreated DEF rats was similar to AMPH-naive DEF animals, and AMPH-pretreated DEF rats exhibited attenuated frontostriatal BOLD activation compared with AMPH pretreated control and FO rats. These findings demonstrate that chronic escalating AMPH treatment induces enduring frontostriatal recruitment and that peri-adolescent deficits in brain DHA accrual impair this response. PMID- 29286867 TI - Lack of correlation between age at diagnosis and RB1 mutations for unilateral retinoblastoma: the importance of genetic testing. PMID- 29286735 TI - Observation of Top Quark Production in Proton-Nucleus Collisions. AB - The first observation of top quark production in proton-nucleus collisions is reported using proton-lead data collected by the CMS experiment at the CERN LHC at a nucleon-nucleon center-of-mass energy of sqrt[s_{NN}]=8.16 TeV. The measurement is performed using events with exactly one isolated electron or muon candidate and at least four jets. The data sample corresponds to an integrated luminosity of 174 nb^{-1}. The significance of the tt[over -] signal against the background-only hypothesis is above 5 standard deviations. The measured cross section is sigma_{tt[over -]}=45+/-8 nb, consistent with predictions from perturbative quantum chromodynamics. PMID- 29286868 TI - Elongator promotes germination and early post-germination growth. AB - The Elongator complex interacts with RNA polymerase II and via histone acetylation and DNA demethylation facilitates epigenetically the transcription of genes involved in diverse processes in plants, including growth, development, and immune response. Recently, we have shown that the Elongator complex promotes hypocotyl elongation and photomorphogenesis in Arabidopsis thaliana by regulating the photomorphogenesis and growth-related gene network that converges on genes implicated in cell wall biogenesis and hormone signaling. Here, we report that germination in the elo mutant was delayed by 6 h in the dark when compared to the wild type in a time lapse and germination assay. A number of germination correlated genes were down-regulated in the elo transcriptome, suggesting a transcriptional regulation by Elongator. We also show that the hypocotyl elongation defect observed in the elo mutants in darkness originates very early in the post-germination development and is independent from the germination delay. PMID- 29286872 TI - Drug-induced immune thrombocytopenia: Mapping of the drug binding site to the membrane-proximal region of platelet GPIX. AB - Drug-induced Immune thrombocytopenia (DIT) is a common complication of several medications, including commonly used antibiotics. The most widely studied DIT is caused by quinine. In DIT, antibodies predominantly bind to the platelet membrane glycoprotein (GP) IX in a drug-dependent fashion resulting in increased platelet clearance. Binding of the sensitizing drug, such as quinine, to GPIX has been proposed but is yet to be established. This work demonstrates that quinine is retained specifically by human GPIX. Quinine binding was first analyzed in wild type mouse platelets and in transgenic mouse platelet expressing human GPIX using high performance liquid chromatography. Binding of quinine to GPIX was then measured in Chinese hamster ovary (CHO) cells expressing a combination of wild type, human or mouse, three human/mouse chimeric constructs and six mutant GPIX proteins. Quinine was retained by human GPIX. No detectable absorption was observed with mouse GPIX or human GPIbalpha. The quinine binding site was mapped to residues 110-115 of human GPIX suggesting that quinine interacts with specific residues of the GP. These findings provide further insights into the molecular mechanisms of DIT. PMID- 29286869 TI - Enhancement of apple coloration using jasmonate treatment without sacrificing storage potential. AB - Apple coloration is very important for most cultivars. The application of jasmonate can effectively enhance the coloration of apple fruit, but it might ruin the fruit's storage potential. Here, we report that applying methyl jasmonate on apple fruit 3 weeks before commercial harvest not only enhanced the fruit coloration but also did not affect its storage potential. Our findings provide important information for enhancing apple coloration using jasmonate. PMID- 29286873 TI - Leaching and sorption of neonicotinoid insecticides and fungicides from seed coatings. AB - Seed coatings are a treatment used on a variety of crops to improve production and offer protection against pests and fungal outbreaks. The leaching of the active ingredients associated with the seed coatings and the sorption to soil was evaluated under laboratory conditions using commercially available corn and soybean seeds to study the fate and transport of these pesticides under controlled conditions. The active ingredients (AI) included one neonicotinoid insecticide (thiamethoxam) and five fungicides (azoxystrobin, fludioxonil, metalaxyl, sedaxane thiabendazole). An aqueous leaching experiment was conducted with treated corn and soybean seeds. Leaching potential was a function of solubility and seed type. The leaching of fludioxonil, was dependent on seed type with a shorter time to equilibrium on the corn compared to the soybean seeds. Sorption experiments with the treated seeds and a solution of the AIs were conducted using three different soil types. Sorption behavior was a function of soil organic matter as well as seed type. For most AIs, a negative relationship was observed between the aqueous concentration and the log Koc. Sorption to all soils tested was limited for the hydrophilic pesticides thiamethoxam and metalaxyl. However, partitioning for the more hydrophobic fungicides was dependent on both seed type and soil properties. The mobility of fludioxonil in the sorption experiment varied by seed type indicating that the adjuvants associated with the seed coating could potentially play a role in the environmental fate of fludioxonil. This is the first study to assess, under laboratory conditions, the fate of pesticides associated with seed coatings using commercially available treated seeds. This information can be used to understand how alterations in agricultural practices (e.g., increasing use of seed treatments) can impact the exposure (concentration and duration) and potential effects of these chemicals to aquatic and terrestrial organisms. PMID- 29286870 TI - A task-based analysis of black carbon exposure in Iowa farmers during harvest. AB - Diesel exhaust has been associated with adverse human health effects. Farmers are often exposed to diesel exhaust; however, their diesel exposure has not been well characterized. In this descriptive study, we measured black carbon concentrations as a proxy for diesel exhaust exposure in 16 farmers over 20 sampling days during harvest in southeast Iowa. Farmers wore a personal aethalometer which measured real-time black carbon levels throughout the working day, and their activities were recorded by a field researcher. Black carbon concentrations were characterized for each farmer, and by activity, vehicle fuel type, and microenvironment. Overall, 574 discrete tasks were monitored with a median task duration of 5.5 min. Of these tasks, 39% involved the presence of a diesel vehicle. Farmers' daily black carbon geometric mean exposures ranged from 0.1-2.3 ug/m3, with a median daily geometric mean of 0.3 ug/m3. The highest black carbon concentrations were measured on farmers who used or worked near diesel vehicles (geometric mean ranged from 0.5 ug/m3 while harvesting to 4.9 ug/m3 during animal work). Higher geometric means were found for near vs. far proximity to diesel fueled vehicles and equipment (2.9 vs. 0.3 ug/m3). Indoor, bystander proximity to diesel-operated vehicles resulted in the highest geometric mean black carbon concentrations (18 ug/m3). Use of vehicles with open cabs had higher mean black carbon concentrations than closed cabs (2.1-3.2 vs. 0.4-0.9 ug/m3). In summary, our study provided evidence that farmers were frequently exposed to black carbon associated with diesel-related activities at levels above urban ambient concentrations in their daily work during harvest. PMID- 29286874 TI - Malignant peripheral nerve sheath tumor in children: A single-institute retrospective analysis. AB - Malignant peripheral nerve sheath tumors are rare tumors that originate from Schwann cells. Patients with neurofibromatosis type 1 are prone to develop these tumors. Due to their rarity and lack of established treatment, the prognosis of malignant peripheral nerve sheath tumors is poor. A retrospective study was conducted on children treated for malignant peripheral nerve sheath tumors at the Seoul National University Children's Hospital between 2007 and 2016. Eleven patients were diagnosed with malignant nerve sheath tumors at a median age of 12 years, eight of whom had neurofibromatosis type 1. All the patients underwent chemotherapy and received surgical resection, and 5 patients relapsed. The 2-year overall survival rate was 72.7%, and the 2-year event-free survival rate was 58.2%. Univariate analysis was performed to assess the correlations between the clinical factors. There was no statistically significant difference in the overall survival rate according to the patients' clinical factors. However, there was a decreasing trend in the relationship between the event-free survival rate and the prevalence of neurofibromatosis type 1. Regular follow up of neurofibromatosis type 1. Regular follow-up of neurofibromatosis type 1 patients may identify detection of early relapse of malignant peripheral nerve sheath tumors. Genetic studies of these patients and tumors may identify opportunities for targeted therapy. PMID- 29286875 TI - Growth and cortical microtubule dynamics in shoot organs under microgravity and hypergravity conditions. AB - The body shape of plants varied in proportion to the logarithm of the magnitude of gravity in the range from microgravity to hypergravity to resist the gravitational force. Here we discuss the roles of cortical microtubule and 65 kDa microtubule-associated protein-1 (MAP65-1) in gravity-induced modification of growth anisotropy. Microgravity stimulated elongation growth and suppressed lateral expansion in shoot organs, such as hypocotyls and epicotyls. On the other hand, hypergravity inhibited elongation growth and promoted lateral expansion in shoot organs. The number of cells with transverse microtubules was increased by microgravity, but decreased by hypergravity. Furthermore, the levels of MAP65-1, which is involved in the maintenance of the transverse microtubule orientation, were increased by microgravity, but decreased by hypergravity. Therefore, the regulation of orientation of cortical microtubules via changes in the levels of MAP65-1 may contribute to the modification of the body shape of plants to resist the gravitational force. PMID- 29286871 TI - In vivo modeling of docosahexaenoic acid and eicosapentaenoic acid-mediated inhibition of both platelet function and accumulation in arterial thrombi. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with a variety of cellular alterations that mitigate cardiovascular disease. However, pinpointing the positive therapeutic effects is challenging due to inconsistent clinical trial results and overly simplistic in vitro studies. Here we aimed to develop realistic models of n-3 PUFA effects on platelet function so that preclinical results can better align with and predict clinical outcomes. Human platelets incubated with the n-3 PUFAs docosahexaenoic acid and eicosapentaenoic acid were stimulated with agonist combinations mirroring distinct regions of a growing thrombus. Platelet responses were then monitored in a number of ex-vivo functional assays. Furthermore, intravital microscopy was used to monitor arterial thrombosis and fibrin deposition in mice fed an n-3 PUFA-enriched diet. We found that n-3 PUFA treatment had minimal effects on many basic ex-vivo measures of platelet function using agonist combinations. However, n-3 PUFA treatment delayed platelet-derived thrombin generation in both humans and mice. This impaired thrombin production paralleled a reduced platelet accumulation within thrombi formed in either small arterioles or larger arteries of mice fed an n-3 PUFA-enriched diet, without impacting P-selectin exposure. Despite an apparent lack of robust effects in many ex-vivo assays of platelet function, increased exposure to n-3 PUFAs reduces platelet-mediated thrombin generation and attenuates elements of thrombus formation. These data support the cardioprotective value of-3 PUFAs and strongly suggest that they modify elements of platelet function in vivo. PMID- 29286877 TI - Where the rubber hits the road: Neuroscience and social work. AB - Multidisciplinary scholarly dialogue can bring academics and researchers together and open up new areas of inquiry. This paper is a case study about how two scholars, one in social work and the other in science, have found common ground. It discusses their respective research projects and how 'the rubber hits the road' by exploring why the knowledge of science/neuroscience is important to non science majors like social workers in their practice, using childhood trauma, to illustrate that. Finally, it makes recommendations regarding the inclusion of science education in social work curricula and offers some ideas for future research. PMID- 29286876 TI - Proton-induced accelerated decay of the fungicide, vinclozolin, on TiO2 surface under solar irradiation: Experimental and DFT study. AB - The photochemical degradation of vinclozolin by addition of titanium dioxide on silica support has been examined both experimental and quantum-chemically. Solar irradiation of vinclozolin on silica with and without addition of titanium dioxide for 6 h resulted in 21% and 97.8% vinclozolin residues, respectively. In both these cases, phototransformation leads to the formation of (3,5 dichlorophenyl isocyanate) and (3,5-dichloroaniline). The presence of the intermediary product resulted from opening of the 2,4-oxazolidine-dione ring is also confirmed by GS-MS and LC-MS chromatography. The proton-induced mechanism of vinclozolin decay at the above experimental conditions is clarified on the base of DFT calculations. PMID- 29286878 TI - Urrets-Zavalia like Syndrome, as a Complication of Sickle Cell Disease. AB - INTRODUCTION: We present a case of a sickle cell patient who presented with Urrets-Zavalia Syndrome (UZS) like characteristics without having undergone any surgical procedures. CASE REPORT: A 41-year-old woman diagnosed with sickle cell thalassemia presented with glaucoma of the both eyes. Visual acuity was decreased in both eyes. Epithelial edema was observed in corneas of both eyes, most prominently in the left eye. Peripheral anterior synechiae were present bilaterally. Intraocular pressure was measured to be 26 mmHg in the right eye and 36 mmHg in the left eye. Fixed dilated pupils were observed in both eyes. Fluorescein angiography revealed ischemia of the iris in the right eye. CONCLUSION: Physicians should keep a high suspicion of UZS in all patients with fixed dilated pupils, especially in sickle cell disease, regardless of having undergone ophthalmic surgeries or not. PMID- 29286879 TI - Capture efficiency of portable high-efficiency air filtration devices used during building construction activities. AB - The portable high-efficiency air filtration (PHEAF) device is used to control particulate matter (PM) generated from construction-type activities occurring within the built environment. Examples of activities where PHEAF devices are mobilized include building renovation, asbestos abatement, remediation of microbial contamination, and lead-based paint projects. Designed for use on short term, temporary projects the PHEAF device captures airborne PM using a high efficiency particulate air (HEPA) filter. This study sought to evaluate the capture efficiency of the PHEAF device in a field setting. An aerosol generator and photometer were used to measure particle penetration through 85 PHEAF devices. Average overall capture efficiency ranged from 41.78% to >=99.97% with more than 88% of the tests failing to achieve 99.97% capture efficiency. Approximately 73% of the PHEAF device sample population failed to demonstrate HEPA performance criteria during any test round. A higher occurrence of PM concentrations measured around the perimeter of the filter suggested the presence of bypass leakage. While PHEAF devices were effective in capturing a significant quantity of aerosol test agent, these findings suggest that routine testing of the PHEAF device should be conducted to validate performance. PMID- 29286880 TI - Awareness and barriers to adoption of assistive technologies among visually impaired people in Nigeria. AB - Assistive technology (AT), broadly defined as specialist equipment designed to promote computer access for people with disabilities, is increasingly becoming popular among people with vision impairment as computer use becomes commonplace in society. In developing and emerging economies, however, the adoption of ATs continues to lag behind the developed countries. This study explored barriers to adoption of assistive technologies among visually impaired people in five southern states in Nigeria. A mixed-method approach that employed qualitative interviews with 20 participants and structured questionnaires among 423 participants aged between 20 and 92 was employed. Participants were categorized into two groups: Visually Impaired Adults (VIAs, age range: 20-59 years) and Visually Impaired Older Adults (VIOAs, age range: 60 years and over). The findings show that while 36% of VIA had good awareness of the existence of ACTs, only 17.4% of them had good knowledge of usage. Among VIOA, 20% of them were aware of the existence of ACTs while only 8.07% had a good knowledge of how to use them. Implications of findings for interventions promoting barrier-free digital environment as well as strategies that could foster development of locally specific interventions for digital inclusion are discussed. PMID- 29286881 TI - Daurichromenic acid and grifolic acid: Phytotoxic meroterpenoids that induce cell death in cell culture of their producer Rhododendron dauricum. AB - Daurichromenic acid (DCA) is a meroterpenoid with anti-HIV activities that is isolated from Rhododendron dauricum L. We recently reported that DCA is biosynthesized and accumulated in the apoplast of glandular scales attached on the surface of young leaves of R. dauricum. In the present study, we confirmed that a cell suspension culture of R. dauricum could not produce DCA and its precursor grifolic acid even after elicitation with methyl jasmonate and beta cyclodextrin. In addition, exogenous supplementation of DCA and grifolic acid effectively induced cell death in the same culture, with apoptosis-associated phenomena such as cytoplasmic shrinkage, chromatin condensation, and genomic DNA degradation. These findings suggested that DCA and grifolic acid are phytotoxic metabolites that have to be sequestered in the apoplast to avoid self-poisoning. PMID- 29286882 TI - Acute effects of static stretching on passive stiffness and postural balance in healthy, elderly men. AB - OBJECTIVES: This study aimed to examine the acute effects of straight-leg raise (SLR) static stretching on passive stiffness and postural balance in healthy, elderly men. An additional aim of this study was to examine the relationships between stiffness and balance at baseline (prior to stretching) and the relationships between the stretch-induced changes in these variables. METHODS: Eleven elderly men (age = 69 +/- 6 years; height = 177 +/- 7 cm; mass = 83 +/- 13 kg) underwent postural balance and passive stiffness assessments before and after: 1) a stretching treatment consisting of four, 15-s SLR static stretches performed by the primary investigator and 2) a control treatment consisting of no static stretching. Passive stiffness was calculated from the slopes of the initial (phase 1) and final (phase 2) portions of the angle-torque curve. Unilateral postural balance was assessed on the right leg using a commercially designed balance testing device, which provides a measurement of static stability based on the overall stability index (OSI). RESULTS: The slope coefficients and OSI values decreased from pre- to post-treatment for the stretching intervention (P = 0.015 and 0.018, respectively); however, there were no changes for the control (P = 0.654 and 0.920). For the stretching intervention, a significant positive relationship was observed between OSI and the slope coefficient of phase 1 at baseline (r = 0.619; P = 0.042). A significant positive relationship was also observed between the stretched-induced changes in OSI and the slope coefficient of phase 1 (r = 0.731; P = 0.011). No relationship was observed between OSI and the slope coefficient of phase 2 at baseline (r = 0.262; P = 0.437) nor was there a relationship between the changes in these variables (r = 0.419; P = 0.200). CONCLUSION: A short, practical bout of SLR static stretching may be an effective intervention for reducing passive stiffness and improving postural balance in healthy, elderly men. PMID- 29286883 TI - Antifungal activities against toxigenic Fusarium specie and deoxynivalenol adsorption capacity of ion-exchanged zeolites. AB - Zeolites are often used as adsorbents materials and their loaded cations can be exchanged with metal ions in order to add antimicrobial properties. The aim of this study was to use the 4A zeolite and its derived ion-exchanged forms with Zn2+, Li+, Cu2+ and Co2+ in order to evaluate their antifungal properties against Fusarium graminearum, including their capacity in terms of metal ions release, conidia germination and the deoxynivalenol (DON) adsorption. The zeolites ion exchanged with Li+, Cu2+, and Co2+ showed an excellent antifungal activity against F. graminearum, using an agar diffusion method, with a zone of inhibition observed around the samples of 45.3 +/- 0.6 mm, 25.7 +/- 1.5 mm, and 24.7 +/- 0.6 mm, respectively. Similar results using agar dilution method were found showing significant growth inhibition of F. graminearum for ion-exchanged zeolites with Zn2+, Li+, Cu2+, and Co2+. The fungi growth inhibition decreased as zeolite Cu2+>zeolite-Li+>zeolite-Co2+>zeolite-Zn2+. In addition, the conidia germination was strongly affected by ion-exchanged zeolites. With regard to adsorption capacity, results indicate that only zeolite-Li+ were capable of DON adsorption significantly (P < 0.001) with 37% at 2 mg mL-1 concentration. The antifungal effects of the ion-exchanged zeolites can be ascribed to the interactions of the metal ions released from the zeolite structure, especially for zeolite-Li+, which showed to be a promising agent against F. graminearum and its toxin. PMID- 29286884 TI - Antigenotoxicity properties of Copaifera multijuga oleoresin and its chemical marker, the diterpene (-)-copalic acid. AB - : In view of the biological activities and growing therapeutic interest in oleoresin obtained from Copaifera multijuga, this study aimed to determine the genotoxic and antigenotoxic potential of this oleoresin (CMO) and its chemical marker, diterpene (-)-copalic acid (CA). The micronucleus (MN) assay in V79 cell cultures and the Ames test were used for in vitro analyses, as well as MN and comet assays in Swiss mice for in vivo analyses. The in vitro genotoxicity/mutagenicity results showed that either CMO (30, 60, or 120 ug/ml-MN assay; 0.39-3.12 mg/plate-Ames test) or CA (2.42; 4.84, or 9.7 ug/ml-MN assay; 0.39-3.12 mg/plate-Ames test) did not induce a significant effect on the frequency of MN and number of revertants, demonstrating an absence of genotoxic and mutagenic activities, respectively, in vitro. In contrast, these natural products significantly reduced the frequency of MN induced by methyl methanesulfonate (MMS), and exerted a marked inhibitory effect against indirect acting mutagens in the Ames test. In the in vivo test system, animals treated with CMO (6.25 mg/kg b.w.) exhibited a significant decrease in rate of MN occurrence compared to those treated only with MMS. An antigenotoxic effect of CA was noted in the MN test (1 and 2 mg/kg b.w.) and the comet assay (0.5 mg/kg b.w.). Data suggest that the chemical marker of the genus Copaifera, CA, may partially be responsible for the observed chemopreventive effect attributed to CMO exposure. ABBREVIATIONS: 2-AA, 2-anthramine; 2-AF, 2-aminofluorene; AFB1, aflatoxin B1; B[a]P, benzo[a]pyrene; BOD, biological oxygen demand; BPDE, benzo[a]pyrene-7,8-diol-9,10-epoxide; CA, (-)-copalic acid; CMO, oleoresin of Copaifera multijuga, DMEM, Dulbecco's Modified Eagles's Medium; DMSO, dimethylsulfoxide; EMBRAPA, Brazilian agricultural research corporation; GC-MS, gas chromatography-mass spectrometry; HAM-F10, nutrient mixture F-10 Ham; HPLC, high performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry; MI, mutagenic index; MMC, mitomycin C; MMS, methyl methanesulfonate; MN, micronucleus; MNPCE, micronucleated polychromatic erythrocyte; NCE, normochromatic erythrocyte; NDI, nuclear division index; NMR, nuclear magnetic resonance; NPD, 4-nitro-o-phenylenediamine; PBS, phosphate buffered saline; PCE, polychromatic erythrocyte; SA, sodium azide; V79, Chinese hamster lung fibroblast. PMID- 29286885 TI - Stability of pentobarbital in soil. AB - Intravenous injection of barbiturates, particularly pentobarbital (5-ethyl-5 pentan-2-yl-1,3-diazinane-2,4,5-trione), is a widely used method to euthanize large animals such as horses. However, one concern with this method is the fate of pentobarbital after the disposal of the carcass. As tissues decompose, pentobarbital may leach into the soil and from there migrate to groundwater. A method using methanol extraction, solid phase concentration, and liquid chromatography (LC/MS) has been developed to measure pentobarbital in soils. Recovery of pentobarbital from soil averaged approximately 85% from different soil types including topsoil, potting soil, sand, stall sweepings, and loam. The method was capable of detecting pentobarbital levels of 0.1 ppm. A calibration curve was constructed with a linear range of 1 ppm to 100 ppm. The limit of quantification was 0.5 ppm. The rate of degradation of pentobarbital in sand, topsoil, and potting soil was measured over a 17-week period. At the end of week 17, approximately 17% of the pentobarbital remained in the sand, 19% remained in the topsoil, and 10% remained in the potting soil. While there was a significant decrease in the pentobarbital recovered from the soil, there were still detectable amounts of pentobarbital present in the soil after 17 weeks. To determine the importance of bacterial degradation, the three soil types were autoclaved before addition of pentobarbital. After autoclaving, no degradation of pentobarbital was observed in sand and one topsoil sample, while there was no difference in the degradation of pentobarbital in autoclaved potting soil versus potting soil that had not undergone autoclaving. PMID- 29286886 TI - Rice reduces Mn uptake in response to Mn stress. AB - Rice (Oryza sativa L) is one of the most Mn-tolerant crops that can grow in submerged paddy fields, where the Mn concentration in soil solution is very high due to reduction. Although a large part of Mn is transferred from the roots to the shoot in rice, the roots are constantly exposed to high Mn concentrations in submerged paddies. Thus, mechanisms for preventing Mn overaccumulation in the cytoplasm of root cells are necessary. Recently, we showed that two cation diffusion facilitators, MTP8.1 and MTP8.2, play a crucial role in Mn tolerance in rice roots by sequestering Mn in vacuoles. Moreover, we observed that disruption of MTP8.1 and MTP8.2 resulted in reduced Mn accumulation under excess Mn. In the present study, we examined the effects of disruption of MTP8.1 and MTP8.2 on Mn uptake and determined that this phenotype is caused by a rapid and significant reduction of Mn uptake in response to excess Mn. Previously, we showed that Mn export from root cells through MTP9 was promoted by high Mn. Together, these findings suggest that optimal Mn concentration in rice roots is maintained by reduced uptake, vacuolar sequestration, and extrusion by cation diffusion facilitators. PMID- 29286887 TI - Roles of auxin and ethylene in aerenchyma formation in sugarcane roots. AB - Although the cross-talk between auxin and ethylene has been described during plant development, the role played by auxin upon gene expression during aerenchyma formation is poorly understood. Root aerenchyma formation results from the opening of gas spaces in the cortex. It is part of a developmental program (constitutive) or due to ethylene treatment or abiotic stress (induced) such as flooding and nutrient starvation. This process relies on programmed cell death and cell wall modifications. Here we followed development of aerenchyma formation in sugarcane along 5 cm from the root apex. As a constitutive process, the aerenchyma formation was observed in the cortex from the 3rd cm onwards. This occurred despite 1-methylcyclepropene (1-MCP) treatment, an inhibitor of ethylene perception. However, this process occurred while ethylene (and auxin) levels decreased. Within the aerenchyma formation zone, the concentration of ethylene is lower in comparison to the concentration in maize. Besides, the ratio between both hormones (ethylene and auxin) was around 1:1. These pieces of evidence suggest that ethylene sensitivity and ethylene-auxin balance may play a role in the formation of aerenchyma. Furthermore, the transcriptional analysis showed that genes related to cell expansion are up-regulated due to 1-MCP treatment. Our results help explaining the regulation of the formation constitutive aerenchyma in sugarcane. PMID- 29286889 TI - When Sciatica Is Not Disk Disease. AB - In brief Piriformis muscle syndrome is an often unrecognized cause of sciatic pain. The sciatic nerve, which normally passes beneath the piriformis muscle deep in the midbuttock, can be compressed when the muscle goes into spasm or is injured. The resultant pain is often confused with discogenic disease, but a thorough history and physical exam can pinpoint the true cause. Conservative treatment of piriformis syndrome-with a focus on stretching-is often successful. PMID- 29286888 TI - A Study of Sexual Relationship Power among Young Women Who Inject Drugs and Their Sexual Partners. AB - BACKGROUND: To date, research applying the Sexual Relationship Power Scale (SRPS) has been limited to sexual risk behaviors. OBJECTIVE: We measured levels of sexual relationship power and examined associations between sexual relationship power and injecting and sexual behaviors that place women at increased risk for blood borne infections. METHODS: Using data from a cross-sectional study of young women who inject drugs (WWID) in San Francisco, USA, logistic regression analysis identified independent associations between SRPS and subscale scores (relationship control [RC] and decision making dominance [DMD]) and injecting and sexual behaviors. RESULTS: Of the 68 young WWID, 24 (34%) reported receptive syringe sharing, 38 (56%) reused/shared a cooker to prepare drugs, and 25 (37%) injected someone else's drug residue during the three-months prior to enrollment. Most (60, 88%) reported condomless sex with main sex-partner, 8 (12%) reported transactional sex, and 36 (53%) had two or more recent sex partners. The median SRPS score was 2.98 (IQR: 2.65, 3.18), 3.23 (IQR: 3.23, 3.57) for RC and 2.40 (IQR: 2.20, 2.60) for DMD. No significant associations were detected between SRPS or DMD and injecting or sexual risk behaviors. After adjusting for gender and years injecting, for every one-point increase in RC, women had a 6.70 lower odds of recent condomless sex (95%CI: 0.92, 50.00, p = 0.06), and a 3.90 lower odds of recent transactional sex (95%CI: 1.22, 12.50, p = 0.02). CONCLUSION: Our study findings suggest that some components of sexual relationship power may play a role in sexual risk, but not in injecting risk. PMID- 29286890 TI - Reconditioning After Exertional Rhabdomyolysis. AB - In brief Prompt recognition and treatment of rhabdomyolysis may prevent further muscle damage and serious renal complications. The patient presented here, an unconditioned rugby player with moderately severe exertional rhabdomyolysis, had thigh pain, thigh and knee swelling, and myoglobinuria. His rehabilitation focused on a well-monitored, progressive exercise program after his muscle injury resolved. PMID- 29286891 TI - Rough Riders. AB - In brief The medical team at the International Finals Rodeo has kept records for the last 6 years on all injuries sustained by the riders. Eighty-six of the 738 participants sustained a total of 90 injuries. Most of these injuries occurred during rough-stock riding events. Comparing this injury data with previous data on intercollegiate and state competitions suggests that the injury rate at elite competitions is much lower. PMID- 29286892 TI - Screening for Heart Murmurs. AB - In brief In preparticipation screening, auscultation is a key component of a rapid but thorough cardiovascular exam. A systematic approach allows an examiner to identify the normal murmurs that occur among young athletes as well as the sounds that might signify underlying cardiac pathology. Keeping in mind the factors that influence murmur audibility helps ensure accurate differentiation between normal and pathologic murmurs. The goals are to identify athletes at risk for sudden death, to flag those who may need treatment for other cardiac conditions, and to allow athletes who have normal murmurs to remain active. PMID- 29286894 TI - Recovering From Shoulder Pain. PMID- 29286893 TI - Overcoming Runner's Diarrhea. AB - In brief Many people experience bowel dysfunction related to running, ranging from prerace 'nervous diarrhea' to bloody diarrhea after an exhausting run. Potential causes vary. Diagnosis rests on an accurate history and selective investigation to exclude disease. Treatment may include explanation, reassurance, defecation before running, dietary changes, adequate hydration, and, occasionally, antidiarrheals. PMID- 29286896 TI - Physical Activity and Psychological Benefits. PMID- 29286895 TI - NBA Play-Off Panic. PMID- 29286898 TI - Managing Fibromyalgia With Exercise. AB - Although its cause remains obscure and no laboratory test confirms its diagnosis, fibromyalgia is a well-defined condition, more common than rheumatoid arthritis. Exercise is an essential component of treatment, helping patients cope with this painful disease. PMID- 29286900 TI - Emergencies in the Backcountry. AB - Sports events in wilderness or remote areas are increasingly popular, attracting more and more participants every year. The long duration of many of the outdoor activities and the unique demands of the wilderness environment call for special medical care, organization, and staffing. PMID- 29286899 TI - Pearls. PMID- 29286901 TI - Football: A Painful Legacy for Players? AB - Do the cheers, salaries, fame, and challenges of professional football make up for the injuries players often cope with long after their football careers are over? Though pro players must come to their own conclusions, high school athletes and their parents often look to their family physician for answers about whether this game is worth the risks. PMID- 29286902 TI - Five-Step Treatment for Overuse Injuries. AB - In brief Overuse injuries can be particularly challenging to manage. An athlete's premature return to athletic activity often results in recurrent and recalcitrant injury. A five-step management plan that includes establishing a pathoanatomic diagnosis, controlling inflammation, promoting healing, increasing fitness, and controlling abusive activity offers athletes optimal opportunity to return successfully to athletic performance. PMID- 29286903 TI - Stopping the Spread of Herpes Simplex. AB - In brief Herpes simplex is readily spread through contact sports like wrestling, and sun exposure, emotional stress, and fever can trigger a recurrence. Ruling out other skin disorders is an important part of the diagnosis. Although acyclovir helps reduce recurrent episodes, physicians need to identify infected athletes early and remove them from sports when contagion is likely. PMID- 29286905 TI - The Beef on Food Myths. PMID- 29286904 TI - Scanning sports. PMID- 29286907 TI - QuikQuiz. PMID- 29286908 TI - Heart Murmurs and the Preparticipation Exam. PMID- 29286909 TI - Why OR.NET? Requirements and perspectives from a medical user's, clinical operator's and device manufacturer's points of view. AB - In the past decades, modern medicine has been undergoing a change in the direction of digitalisation and automation. Not only the integration of new digital technologies, but also the interconnection of all components can simplify clinical processes and allow progress and development of new innovations. The integration and interconnection of medical devices with each other and with information technology (IT) systems was addressed within the framework of the Federal Ministry of Education and Research (BMBF)-funded lighthouse project OR.NET ("Secure dynamic networking in the operating room and clinic".) (OR.net Forschungskonsortium (OR.net Research Syndicate.) OR.net - Sichere dynamische Vernetzung in Operationssaal und Klinik [Online]. Available: www.ornet.org. [last accessed 22 March 2017]). In this project the standards and concepts for interdisciplinary networking in the operating room (OR) were developed. In this paper, the diverse advantages of the OR.NET concept are presented and explained by the OR.NET "Medical Board". This board represents the forum of clinical users and includes clinicians and experts from various specialties. Furthermore, the opinion from the viewpoint of operators is presented. In a concluding comment of the "Operator Board", clinical user needs are aligned with technical requirements. PMID- 29286910 TI - Selective IUGR in dichorionic twins: what can Doppler assessment and growth discordancy say about neonatal outcomes? AB - OBJECTIVE: The aim of the present study was to assess, in a population of dichorionic twin pregnancies with selective growth restriction, the effect of inter-twin differences by use of Doppler velocimetry and fetal growth discordancy on perinatal outcomes. METHODS: This was a retrospective study including dichorionic twin pregnancies from January 2008 to December 2015 at the Department of Obstetrics and Gynecology of Fondazione MBBM. Only dichorionic twin pregnancies affected by selective intrauterine growth restriction (IUGR) delivering at >=24 weeks were included in the study. RESULTS: We found that twin pregnancies with inter-twin estimated fetal weight (EFW) discordance >=15% were significantly associated with a higher risk of preterm delivery before 32 (P=0.004) and 34 weeks (P=0.04). Similarly, twin pregnancies with inter-twin abdominal circumference (AC) discordance >=30 degrees centiles were associated with a higher rate of neonatal intensive care unit (NICU) admission (P=0.02), neonatal resuscitation (P=0.02) and adverse neonatal composite outcome (P=0.04). Of interest, when comparing twin pregnancies according to Doppler study, growth restricted twins had a higher rate of composite neonatal outcome and in multivariate analysis, an abnormal Doppler was an independent risk factor for this outcome. CONCLUSIONS: Our study associated growth discrepancy with specific pregnancy outcomes, according to defined cut-offs. In addition, we demonstrated that an abnormal umbilical artery Doppler is independently associated with a composite neonatal adverse outcome in growth restricted fetuses. PMID- 29286911 TI - Primary breast angiosarcoma - a single institution experience from a tertiary cancer center in South India. AB - INTRODUCTION: Primary angiosarcoma of the breast is a rare entity with incidence of less than 0.05% of all malignant breast neoplasms. It occurs in young females without any associated risk factors. The tumor behaves aggressively and has a poor prognosis compared to invasive ductal carcinoma. METHOD: It was a retrospective observational study done at a tertiary cancer center from January 2012 to December 2016. The medical records of patients diagnosed with primary breast angiosarcoma were reviewed for the study. Clinicopathological profile, treatment, and the outcomes were analyzed. RESULTS: Four patients were diagnosed with primary breast angiosarcoma out of 2560 breast cancer patients seen over a period of 5 years. Two had metastatic disease at presentation. Among four patients, two underwent surgery of the primary tumor, whereas, all received chemotherapy either as adjuvant or palliative setting. One patient received adjuvant radiation therapy. Three patients received 2nd line and one received 3rd line chemotherapy on disease progression. After a median follow-up of 18 months one patient was surviving on 3rd line chemotherapy with trabectedin. Other three succumbed to disease after progression. CONCLUSION: Due to a small number of this malignancy randomized studies are difficult to perform and optimum treatment strategy still need to be defined. PMID- 29286912 TI - Cytological diagnosis of crystallizing galactocele - report of an unusual case. AB - Crystallizing galactocele is a very rare entity which yields a viscous, chalky material on Fine Needle Aspiration Cytology (FNAC). FNAC is used both for diagnosis as well as treatment of this condition. We present here a case of 26 years old lactating female who presented with swelling in the right breast for 8 months. The swelling was firm, discrete, non-tender and mobile involving the upper inner quadrant of right breast. A diagnosis of benign breast disease, possibly fibroadenoma was made clinically. FNAC of the lesion yielded thick, milky and chalky material. Cytological smears showed numerous semitransparent crystals of varying size and shapes with angulated borders in a background of granular and amorphous debris along with frothy appearing micelles. These crystals show positive birefringence. Based on clinical history of lactation and typical cytological findings, a diagnosis of crystallizing galactocele was made. We report this case because of rarity of this condition and to the best of our knowledge, till date only five cases of crystallizing galactocele has been reported in medical literature. PMID- 29286913 TI - Rule of changes in serum GGT levels and GGT/ALT and AST/ALT ratios in primary hepatic carcinoma patients with different AFP levels. AB - OBJECTIVE: This study aims to explore the rule of changes in serum GGT activity, as well as GGT/ALT and AST/ALT ratios, in primary hepatic carcinoma (PHC) patients with different alpha-fetal protein (AFP) levels. METHODS: GGT, AST and ALT were detected in 370 PHC patients with positive HBs-Ag using a automatic biochemical analyzer, and AFP was detected using a Roche E170 modular analytics immunoassay analyzer. GGT level, as well as AST/ALT and GGT/ALT, ratios were compared among PHC patients with different AFP levels. RESULTS: As shown in Table 1, GGT levels were 109.59 +/- 111.06, 151.13 +/- 190.43, 135.86 +/- 107.62, 151.36 +/- 176.59 and 172.58 +/- 188.84, respectively, in the groups of primary PHC patients with AFP levels of ? 10, 10-100, 100-200, 200-400 and ? 400 ng/ml; and the differences among these groups were not statistically significant (P> 0.05). AST/ALT ratios were 1.55 +/- 1.02, 1.30 +/- 0.81, 2.02 +/- 1.89, 2.12 +/- 1.11 and 1.73 +/- 1.25, respectively; and the differences among these groups were not statistically significant (P> 0.05). GGT/ALT ratios were 3.43 +/- 3.12, 3.57 +/- 5.70, 3.57 +/- 2.94, 3.89 +/- 4.58 and 3.43 +/- 3.61, respectively; and the differences among these groups were not statistically significant (P> 0.05). CONCLUSION: For patients with chronic hepatitis B and cirrhosis after hepatitis B, no matter how AFP level is, when liver function report reveals increased GGT, AST/ALT > 1 and GGT/ALT > 1 (that is, AST > ALT and GGT > ALT), even if AFP is negative, we should also be alert to the existence of PHC. PMID- 29286914 TI - TP53 p.R72P genotype is a marker of poor prognosis in lung cancer. AB - BACKGROUND: Lung cancer is a leading cause of death worldwide, with poor survival rates despite diagnostic and therapeutic advances. Markers are needed in order to improve clinical patient management and survival. TP53 is frequently involved in lung cancer development with polymorphic sites potentially having a role in it. This study aims to determine the value of codon 72 missense polymorphic variant genotyping, TP53 R72P, as a prognostic factor in NSCLC patients. METHODS: One hundred and fifteen NSCLC samples from patients exposed to tobacco smoke and silica dust from Asturias (Northern Spain) were genotyped by direct sequencing. RESULTS: Seventy-five percent tumour samples alleles coded for Arg. The R72P genotype was an independent predictor of lymph node status (HR = 3.6). The heterozygous genotype was associated to a reduced 5-year survival rate (28% vs 51% for homozygotes). Importantly, this result was specifically observed in these subsets of patients: those over 67 years, patients with silicosis, current smokers, patients with squamous cell carcinomas and, notably, with tumour free lymph nodes. CONCLUSION: Our results indicate a remarkable application of R72P genotyping in the clinical setting: refine patient subclassification to identify those with an adverse clinical course despite tumour free lymph node status. PMID- 29286915 TI - Upregulation of the long noncoding RNA FOXD2-AS1 predicts poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND: The long non-coding RNA FOXD2-AS1 is highly expressed in non-small cell lung cancer and promotes malignant progression. However, the role of FOXD2 AS1 in esophageal squamous cell carcinoma (ESCC) is still unclear. OBJECTIVE: In this study, we examined the relationships between the expression level of FOXD2 AS1 and the outcome of ESCC patients. METHODS: Expression of FOXD2-AS1 was evaluated in cancer tissue and adjacent non-tumor tissue samples from 147 ESCC patients who received radical surgical resection using qRT-PCR. The correlations between the expression level of FOXD2-AS1 and patients' overall (OS) and disease free survival (DFS) were analyzed. RESULTS: FOXD2-AS1 expression was upregulated in ESCC tissue than that in adjacent non-tumor tissue samples (P< 0.001). Kaplan Meier analysis showed that high FOXD2-AS1 expression was correlated with poor prognosis in ESCC patients. Patients with a high level of FOXD2-AS1 had a shorter OS and DFS than those with a low level of FOXD2-AS1 (P= 0.005 and 0.0001, respectively). On multivariate analysis, the hazard ratio of FOXD2-AS1 expression was 1.66 (95% CI = 1.04-2.64, P= 0.033) for OS and 2.68 (95% CI = 1.49-4.82, P= 0.001) for DFS. CONCLUSIONS: Overall, our results provided convinced evidence that FOXD2-AS1 may serve as a predictive marker for ESCC patients' survival. PMID- 29286916 TI - Upregulation of serum miR-494 predicts poor prognosis in non-small cell lung cancer patients. AB - OBJECTIVE: Emerging studies show that microRNAs (miRNAs) play a essential role in tumorigenesis. Deregulation of miR-494 is frequently observed in various human cancers including non-small cell lung cancer (NSCLC). However, little is known about the clinical significance of serum miR-494. The aim of this study was to investigate the diagnostic and prognostic value of serum miR-494 for NSCLC. METHODS: We first compared miR-494 levels between NSCLC cell lines and lung bronchus epithelial cell line. A total of 90 NSCLC patients and 50 healthy controls were included in this study. MiR-494 levels were examined in serum samples by using real-time quantitative reverse transcription polymerase chain reactions. Association between serum miR-494 levels and the prognosis of NSCLC was further analyzed. RESULTS: Our results showed that miR-494 was elevated in NSCLC cell lines. Serum miR-494 levels were significantly increased in patients with NSCLC compared to healthy controls. Area under receiver operating characteristic (ROC) curve was 85.4%. In addition, serum miR-494 levels decreased remarkably when patients received effective therapy. High serummiR-494 levels were significantly associated with higher incidence of lymph node metastasis, advanced clinical stage and higher histological grade. Moreover, survival analysis demonstrated that patients in the high serum miR-494 group had a poorer 5 year overall survival and disease free survival compared with the patients in the low serum miR-494 group. Multivariate analysis showed that serum miR-494 was an independent risk factor. CONCLUSIONS: In conclusion, serum miR-494 was significantly elevated in NSCLC patients and closely correlated with poor clinical outcome, indicating that serum miR-494 might be a useful diagnostic and prognostic marker for NSCLC. PMID- 29286917 TI - Protein and DNA evidences of HCMV infection in primary breast cancer tissues and metastatic sentinel lymph nodes. AB - BACKGROUND AND OBJECTIVE: Breast cancer is the leading cause of death in women worldwide. There are evidences that human cytomegalovirus (HCMV) infection is associated with several malignant tumors. This study aims to investigate the infection of human cytomegalovirus (HCMV) in a large sample of breast cancer patients, and conduct a correlation analysis of clinical and pathological factors, to provide evidence for whether HCMV infection is associated with breast cancer development, progression and metastasis. MATERIALS AND METHODS: A total of 438 tissue samples (including breast cancer tissue, paracancerous tissue and sentinel lymph node [SLN] tissue) obtained from 146 patients who were diagnosed with breast cancer and intraoperatively underwent unilateral axillary SLN biopsy at the Affiliated Hospital of Qingdao University from June 2013 to June 2014 were included into this study. These tissue samples were divided into two groups: SLN positive group and SLN negative group. The clinical information is collated and numbered. Normal breast tissues of 40 patients with cyclomastopathy were taken as controls. The expressions of HCMV immediate-early (IE) and late antigen (LA) proteins of breast cancer tissues, paracancerous tissues, SLN tissues and normal breast tissues were analyzed by immunohistochemistry, and HCMV infection of the samples was graded according to the percentage of the positive cells, and HCMV IE2 mRNA expression was detected by reverse transcription polymerase chain reaction. The clinical data were collated and statistically analyzed. RESULTS: HCMV IE and LA proteins were highly expressed in all breast cancer tissue samples. IE proteins were detected in 47.9% (70/146) of paracancerous tissue samples, and LA proteins were detected in 53.4% (78/146) of paracancerous tissue samples. IE and LA proteins were expressed in 92.6% of metastatic SLN samples (62/68) and in most of the tumor cells. Inflammatory cells in 60% (42/70) of non metastatic samples were positive for HCMV. HCMV DNA was present in 100% of breast cancer tissue samples, 50% of paracancerous tissue samples, and 91% of metastatic SLN samples; but this was not present in HCMV negative and non-metastatic SLN samples. Differences in HCMV infection, and estrogen receptor-alpha, progesterone receptor, Elston classification, Ki67 percentage, Her-2 and Luminal type and other clinical indicators were not statistically significant. CONCLUSION: HCMV infection is common in breast cancer tissues, paracancerous tissues and SLN tissues. The severity of HCMV infection varied markedly with tissue type. HCMV infection might be associated with metastasis and invasion of breast cancer. The expression of HCMV IE2 was associated to breast cancer and lymph node metastasis. The expression level of estrogen receptor-alpha was related to HCMV infection. PMID- 29286918 TI - CD9 expression indicates a poor outcome in acute lymphoblastic leukemia. AB - OBJECTIVE: We undertook a single-center retrospective study to determine the relationship between CD9 and acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: In total, 112 newly diagnosed patients in our center were enrolled in the study. Their clinical information was collected and the patients werefollowed over the course of the study. Flow cytometry was used to detect the expression of CD9. RESULTS: CD9 expression was more common in B cell acute lymphoblastic leukemia (B-ALL) and patients > 40 years old. CD9-positive patients exhibited a higher BCR-ABL fusion gene positive rate and higher neutrophil counts than CD9 negative patients (P= 0.004 and P= 0.004, respectively). Response to induction chemotherapy was not dependent on CD9 expression. CD9-positive patients had a lower 2-year overall survival rate than CD9-negative patients. CONCLUSION: CD9 expression predicts some clinical characteristics and indicates an unfavorable prognosis in ALL patients. PMID- 29286919 TI - Knockdown of lncRNA GHET1 suppresses cell proliferation, invasion and LATS1/YAP pathway in non small cell lung cancer. AB - BACKGROUND: The aim in this study was to explore the role of long non-coding RNA GHET1 in development of non small cell lung cancer (NSCLC). METHODS: LncRNA GHET1 expression levels were analyzed by qRT-PCR in tumor tissues and adjacent normal tissues in NSCLC. Measuring the cell proliferation and invasion abilities by CCK8, cell colony formation and transwell invasion assays. Relative protein expression was analyzed by western blot assays. RESULTS: Expression of lncRNA GHET1 was notably higher in NSCLC tissues compared with adjacent normal tissues by using qRT-PCR analyses. Higher lncRNA GHET1 expression associated with lymph node metastasis, TNM stage and showed poor outcome in NSCLC patients. Knockdown of lncRNA GHET1 suppressed cell proliferation and invasion capacity and Epithelial-Mesenchymal Transition (EMT) phenomenon of NSCLC cells. Moreover, we demonstrated that knockdown of lncRNA GHET1 suppresses LATS1/YAP pathway signaling pathway by downregulating YAP1 expression in NSCLC cells. CONCLUSIONS: GHET1 predicted a poor outcome and acted as a tumor-promoting gene in NSCLC. Thus, inhibition of GHET1 may be a potential target of NSCLC treatment. PMID- 29286920 TI - Resveratrol enhances the effects of ALA-PDT on skin squamous cells A431 through p38/ MAPK signaling pathway. AB - AIMS AND BACKGROUND: Squamous cell carcinoma (SCC) is one of the most common skin cancers. Photodynamic therapy (PDT) is a non-invasive treatment for SCC, but it is usually effective only on tumors just under the skin. Resveratrol (Res) is a polyphenolic compound, which is capable of promoting apoptosis of a variety of cancer cells. Res administration is non-invasive and effective on SCC, thus it may be used as an adjuvant for PDT. So far, there is no published study investigating the combination use of PDT with Res to improve clinical outcome of SCC. So in this study, we will examine the effectiveness of combined treatment of PDT and Res as well as its underlying mechanism. METHODS: The human HaCaT keratinocytes and human A431 epidermoid carcinoma cells were treated with ALA-PDT or/and Res, and cell proliferation and apoptosis were evaluated by MTT and flow cytometry respectively afterwards. p-ERK, p38, p53 and caspase-3 protein expression was examined by western blot. Then a p38 inhibitor was added to test the involvement of p38 pathway in A431 cells responding to ALA-PDT and Res treatments. RESULTS: The results showed that Res could enhance the effect of ALA PDT on cell proliferation and apoptosis in A431 cells. We also found that the expression of p-ERK, p-p38, p53 and caspase-3 was increased. However, inhibition of p38 pathway attenuated the effect of Res. CONCLUSION: Our study demonstrated that Res could enhance the effect of ALA-PDT against skin cancer cells through p38/ MAPK pathway. PMID- 29286922 TI - lncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related hepatocellular carcinoma. AB - BACKGROUND: Chronic hepatitis C (CHC) is a contagious liver disease that results from infection with the hepatitis C virus (HCV). The most serious consequence of CHC is HCV-related hepatocellular carcinoma (HCC). OBJECTIVE: To illustrate the clinical significance of lncRNA HEIH expression in serum and exosomes in the development of HCV-related HCC. METHODS: Thirty-five CHC, twenty-two HCV-induced cirrhosis and ten HCV-related HCC patients in Huzhou Central Hospital from January 2016 to September 2016 were recruited in the present study. Basic patient information, clinical serological indicators, and clinical imaging data were investigated and analyzed. Serum samples were collected from patients after receiving informed consent. Exosomes were extracted from the serum, and electron microscopy was used to observe the ultrastructure of exosomes. Quantitative PCR was used to detect lncRNA HEIH gene expression in serum and exosomes. RESULTS: The changes in the ALT, GGT, HDL, INR, Alb and AFP levels in the patients with HCV-induced cirrhosis and HCV-related HCC were statistically significant. In patients with HCV-related HCC, lncRNA-HEIH expression in serum and exosomes was increased, but the ratio of lncRNA-HEIH expression in serum versus exosomes was decreased compared to patients with CHC. PMID- 29286921 TI - Tumor-infiltrating lymphocytes are associated with beta-catenin overexpression in breast cancer. AB - BACKGROUND: Inhibition of lymphocytes infiltration and activity may impair antitumor immune response and limit treatment responsiveness. Wnt/beta-catenin pathway has been suggested to contribute to immune evasion in tumor by suppressing the function of immune cells and excluding T cell infiltration. However, the effects of Wnt/beta-catenin on TILs recruitment remain controversial. OBJECTIVE: We aimed to investigate whether intratumoral Wnt/beta catenin signaling could affect the lymphocyte infiltration in breast cancer. METHODS: The distribution of stromal TILs, CD8+ and FOXP3+ TIL subsets, and the expression of beta-catenin were separately assessed on consecutive sections of 96 breast cancer specimens. RESULTS: Both stromal infiltrated TILs and beta-catenin expression were upregulated in hormone receptor negative HER2-enriched and TNBC subtypes. Furthermore, high levels of stromal TILs as well as CD8+ or FOXP3+ TIL subsets were associated with beta-catenin overexpression by breast cancer, respectively. CONCLUSIONS: For the first time, we demonstrated that rather than excluding lymphocytes infiltration as reported in mela-noma, high levels of TILs were associated with beta-catenin overexpression in BC. Wnt/beta-catenin signaling may play a critical role in BC immunity, particularly in HER2-enriched and triple negative BC, and may serve as a potential target for regulating immune infiltrates in breast cancer. PMID- 29286923 TI - Platelet indices in laryngeal cancer. AB - BACKGROUND: Laryngeal cancer is one of the most common malignancies in the head and neck. Activated platelets play a critical role in cancer development and progression. Altered mean platelet volume (MPV) and platelet distribution width (PDW) have been found in various types of cancer. The purpose of the current study was to investigate the association of platelet indices with laryngeal cancer. STUDY DESIGN: The study included 216 patients with laryngeal cancer, 189 subjects with benign laryngeal disease, and 213 control subjects between January 2015 and December 2015. All participants' clinical and laboratory characteristics at initial diagnosis were collected. RESULT: MPV was significantly lower and PDW was markedly higher in laryngeal cancer patients compared with control subjects and patients with benign laryngeal disease. A significant correlation between MPV and lymph node metastasis was found. The prevalence of laryngeal cancer increased as MPV quartiles decreased and PDW quartiles increased. Furthermore, MPV and PDW were independent risk factors for distinguishing laryngeal cancer from benign laryngeal disease. CONCLUSIONS: The patients with laryngeal cancer have reduced MPV and increased PDW compared to the subjects without laryngeal cancer. In addition, MPV and PDW play different roles in laryngeal cancer from benign laryngeal disease. PMID- 29286924 TI - Expression of CD105 cancer stem cell marker in three subtypes of renal cell carcinoma. AB - BACKGROUND: CD105 is recently described as a cancer stem cell (CSC) marker. OBJECTIVE: The present study was aimed to investigate the expression and prognostic significance of the CSC marker CD105 in different histological subtypes of renal cell carcinoma (RCC). METHODS: Expression of CD105 was evaluated using immunohistochemistry in RCC samples on tissue microarrays including clear cell RCCs (ccRCCs), papillary, and chromophobe RCCs. The association between CD105 expression and clinicopathological features as well as survival outcomes was determined. RESULTS: In ccRCC, increased tumoral cytoplasmic and endothelial expression of CD105 were significantly associated with advanced stage, renal vein invasion, and microvascular invasion (MVI). In addition, MVI was associated with a worse overall survival (OS). Moreover, in multivariate analysis tumor stage and nuclear grade were independent prognostic factors for OS both in case of tumoral cytoplasmic and endothelial CD105 expression. Additionally, CD105 expression was found to be a predictor of worse OS in univariate analysis. However, in papillary and chromophobe RCC, no significant association was found between CD105 expression and clinicopathological parameters or prognosis. CONCLUSIONS: We showed that CD105 expression was associated with more aggressive tumor behavior, more advanced disease, and worse prognosis in ccRCC but not in the other RCC subtypes. PMID- 29286925 TI - Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. AB - BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF). OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF. METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death. RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment. CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible. PMID- 29286926 TI - Effects of in-utero exposure to selective serotonin reuptake inhibitors and venlafaxine on term and preterm infants. AB - OBJECTIVE: We hypothesized that in-utero SSRI exposure affects Apgar scores and immediate post-delivery oxygen requirements. STUDY DESIGN: SSRI in-utero exposure was assessed retrospectively in preterm neonates >= 28 weeks gestation and term neonates. Primary outcome was Apgar <7 at five minutes and delivery room oxygen requirements. Secondary endpoints included one-minute Apgar, length of stay, birth weight, and NICU admission. RESULTS: Fifty-one preterm and 117 term neonates were exposed to a SSRI; mostly to sertraline. Pre-term SSRI-exposed neonates had 4.1 times higher delivery room oxygen requirements. One minute Apgar <7 was 3.5 times higher and NICU admission 5 times higher 95% CI (1.3-19) in SSRI exposed term neonates. Higher doses of sertraline had associated adverse outcomes. CONCLUSION: In-utero SSRI exposure was associated with increased neonatal care at birth, differences in Apgar scores compared with controls, and increased NICU admissions. Higher sertraline doses were associated with poorer outcomes. PMID- 29286927 TI - Carnitine deficiency in preterm infants: A national survey of knowledge and practices. AB - OBJECTIVE: Lipid supplementation improves developmental outcomes in preterm infants. Carnitine is essential for lipid metabolism; however, despite high risk for carnitine deficiency, there are no standards for carnitine supplementation in preterm infants receiving total parenteral nutrition (TPN). Our objective was to assess knowledge, beliefs and practices regarding preterm carnitine deficiency and supplementation among neonatal practitioners. METHODS: Cross-sectional electronic survey administered via a nationally representative listserv of neonatal practitioners. RESULTS: 492 respondents participated in the survey. Only 21% of respondents were aware that carnitine is secreted by the placenta. 72% believed that carnitine deficiency was common, and 60% believed deficiency could have serious consequences. Five percent routinely screened for deficiency, and 40% routinely provided carnitine supplementation. Respondents with >5 years' experience were more likely to report using carnitine supplementation (50% vs. 38%). CONCLUSIONS: Although most respondents believed that carnitine deficiency is common and could have serious consequences, few screened for deficiency and fewer than half routinely supplemented. Thus, many preterm infants remain at risk for carnitine deficiency. Further research is needed to elucidate the risks of carnitine deficiency in these vulnerable infants. PMID- 29286928 TI - Long-term neurodevelopment outcome of caffeine versus aminophylline therapy for apnea of prematurity. AB - OBJECTIVE: Methylxanthines are the most commonly prescribed drug in neonatal setups. However, Clinicians show indecision in choosing the right agent for Apnea of Prematurity in most of the developing countries. Present study aimed to compare rate of mortality and survival with normal neurodevelopment outcome at 18 to 24 months of corrected age, between Caffeine- and Aminophylline-treated infants for apnea of prematurity. METHODS: 240 infants were randomly allocated to caffeine and aminophylline for apnea of prematurity during February 2012 to January 2015. Long-term neurodevelopmental assessment was done only from children who had attained corrected age of 18 to 24 months during April 2014 to February 2016. Cognitive, language and motor deficits were assessed by Bayley Scale of infant and toddler development (BSID - III). Postnatal characteristics such as hearing and visual impairments during NICU stay were noted and same were followed up. RESULTS: Infants allocated to caffeine group showed 83% less risk of getting cognitive impairment (RR 0.16; CI 95% range 0.02 to 1.36), 50% less risk of developing motor deficits (RR 0.50; CI 95% range 0.12 to 1.95) and 24% less risk of developing language problems (RR 0.76; CI 95% range 0.36 to 1.58). However in all the neurodevelopment domains the difference between groups was not statistically significant. Risk of mortality in caffeine group was 9% less over aminophylline group which was statistically non-significant (RR - 0.92; CI 95% range - 0.45 to 1.84; p = 0.81). Physical growth parameters were found to be similar in both the groups. Risk of developing visual abnormality and hearing impairments was also statistically non-significant between the groups. CONCLUSION: Caffeine and aminophylline showed similar effects in reducing the rate of mortality and improving the survival without neurodevelopment delays; though the clinical significance of caffeine over aminophylline cannot be undermined. PMID- 29286929 TI - Correlation of hematocrit and Apgar scores in newborns of women with hypertensive disorders in pregnancy. AB - OBJECTIVES: To compare the incidence of polycythemia in newborns of women with hypertensive disorders in pregnancy (HDP) with those of normotensive mothers, to determine the incidence of perinatal stress using Apgar scores and to correlate hematocrit with Apgar scores in these newborn. STUDY DESIGN: This was a hospital based comparative study conducted in the University of Port Harcourt Teaching Hospital, Nigeria. MAIN OUTCOME MEASURES: Apgar scores of 200 newborns- 100 from mothers with HDP (case group) and 100 from normotensive mothers (control group)- were taken at 1st and 5th minute of birth and cord blood samples collected to determine hematocrit. The subjects were categorized into polycythemic and non polycythemic using a hematocrit >=65%. RESULTS: Eight percent of newborns of women with HDP had polycythemia while none of the controls did. Apgar scores in the case group with and without polycythemia at one-minute were 4.1+/-1.8 and 6.6+/-2.1, respectively and at 5 minutes were 6.9+/-1.7 and 8.5+/-1.4 respectively. Hematocrit correlated positively with Apgar scores (both at one and five minutes) in cases without polycythemia (r = 0.221, p = 0.034 and r = 0.255, p = 0.014). Hematocrit of polycythemic newborns did not correlate with Apgar scores (r = -0.287, p = 0.491 and r = -0.436, p = 0.281). CONCLUSION: The incidence of polycythemia is significantly higher in newborns of women with HDP and these polycythemic neonates had a significantly higher incidence of birth asphyxia. Therefore, birth outcome as determined by Apgar score is influenced by hematocrit. PMID- 29286930 TI - Hypoxic-ischemic brain injury: Planned delivery before intrapartum events. AB - BACKGROUND: Mothers are increasingly given greater control over many of the choices around birth, although there is little robust evidence to inform these choices. After an infant is born with HIE the question of whether it was predictable, or preventable, is often raised. Intrapartum 'sentinel' events and antenatal predictors of HIE have been well described, however there is little evidence how antenatal and intrapartum factors interact. This is particularly important when elective delivery by lower segment caesarean section (LSCS) has been shown to be beneficial in high risk groups. AIM: To develop a clinical risk score to identify women with a higher risk of having an infant with HIE. PATIENTS AND METHODS: This study is based on the Avon Longitudinal Study of Parents and Children (ALSPAC). This dataset was split into two halves: with each infant being randomly allocated to either cohort one or two. The first cohort was used for the derivation of the model, while it was tested exclusively on the second. Logistic regression modelling was then performed to develop a predictive model. The final model was used to predict the outcome of infants in the second cohort and infants divided into four risk quartiles. To give some indication of possible avoidable disease, the proportion of infants with HIE, potentially avoided by earlier delivery, was estimated by assuming that medicalized delivery by elective LSCS at 37 weeks would remove intrapartum risk of HIE for those infants undelivered at this point. RESULTS: In the final model seven covariates remained (parity, preeclampsia, polyhydramnios, prelabor rupture of membranes, gender, concerns over fetal growth and prematurity). When applied to the second cohort, a ROC curve for the prediction of developing HIE in the newborn period showed good evidence for association (AUC 0.68 (0.60 to 0.77)) and the risk score derived was strongly associated with the risk of HIE, resuscitation and stillbirth, and neonatal death (all p < 0.05). Elective delivery of high risk infants at 37 weeks gestation could prevent 14% of all HIE, with a NNT of 41. CONCLUSION: It is possible to combine routine antenatal findings to identify infants at higher risk of neonatal HIE, thereby recognizing those infants who may benefit most from delivery by elective caesarean section. This work suggests a clinical risk score permits antenatal identification of high-risk infants whose outcome may be amenable to changes in clinical practice to potentially reduce HIE rates, and its devastating consequences. PMID- 29286931 TI - Newborn drug testing practices in Iowa birthing hospitals. AB - OBJECTIVES: Federal law mandates states to have policies and procedures to identify newborns exposed to maternal substance use during pregnancy. National guidelines for newborn drug testing are lacking; therefore, procedures are variable and determined by state law and local practices. In Iowa, maternal substance use during pregnancy is considered child abuse and must be reported.The objective of this study was to identify newborn drug testing policies and procedures among birthing hospitals in Iowa. METHODS: This was a cross sectional survey of all birthing hospitals in Iowa identified via the Statewide Perinatal Care Program. An electronic survey was sent to the representative at each affiliated hospital. RESULTS: Sixty-nine of 76 hospitals completed the survey for a 90.8% response rate. Newborn drug testing is ordered in 97.1% of responding hospitals with most testing 25% or less of newborns annually. The majority utilized a risk assessment tool (89.6%), although many (62.7%) also allowed for provider discretion. No hospital performed universal testing of all newborns. 86.6% of hospitals reported all positive newborn drug test results including illicit and/or prescription drugs to child protective services. 35.0% of hospitals notified mothers of the report and 45.5% offered substance abuse services and/or treatment to the mothers. CONCLUSIONS: Most Iowa birthing hospitals perform newborn drug testing and report all positive test results to child protective services. The majority use risk assessment tools. Maternal notification practices and referral for substance use disorder treatment are suboptimal and represent an area for future improvement. PMID- 29286932 TI - Dexamethasone effect on heart rate variability in preterm infants on mechanical ventilation. AB - BACKGROUND: Dexamethasone is administered to some preterm infants with chronic lung disease to facilitate weaning from mechanical ventilation. Heart rate characteristics (HRC), including heart rate variability (HRV), may be impacted by glucocorticoids and may predict extubation readiness. A commercially available monitor developed for sepsis detection continuously calculates HRV and an HRC index, which are inversely related. OBJECTIVES: Determine the impact of dexamethasone on HRV and the HRC index, in relation to extubation success. METHODS: We identified 109 preterm infants who received dexamethasone while on mechanical ventilation and had HRC index monitoring data available. Average hourly HRV and HRC index were compared the day before and the day after initiation of dexamethasone in three groups: infants who remained on mechanical ventilation, those who were successfully extubated, and those who were extubated and required reintubation in < 3 days. RESULTS: There was a significant increase in HRV and decrease in the HRC index the day after dexamethasone was started (HRV 16.2+/-0.5 vs 27.6+/-1.1 ms; HRC index 1.51+/-0.11 vs. 0.79+/-0.06 mean SE, p < 0.001). The 63 infants who were extubated within a day of starting dexamethasone had significantly higher HRV compared to those who remained on mechanical ventilation. There was no difference in HRV or its change with dexamethasone in the 45 infants who remained successfully extubated compared to the 18 infants who required reintubation within 3 days. CONCLUSION: Dexamethasone improves HRV and lowers the HRC index in preterm infants with chronic lung disease on mechanical ventilation. PMID- 29286933 TI - Clinical and nutritional outcomes of two liquid human milk fortifiers for premature infants. AB - BACKGROUND: In preterm infants fortification of human milk with human milk fortifiers (HMF) to optimize nutrition and growth is standard practice. We compared clinical, nutrition and growth outcomes in infants receiving two types of liquid HMF (LHMF). METHODS: Clinical, nutrition and growth outcomes were compared between infants admitted to a level IV NICU, and born with birth weight less than or equal to 1800 grams, between 10/1/2014-12/31/2014 and received human milk with acidified LHMF (ALHMF) and between 1/1/2015-4/31/2015 and received human milk with heat treated LHMF (HTLHMF). RESULTS: Of the 85 qualifying infants, 67 received human milk and LHMF. ALHMF group had significantly higher incidence of metabolic acidosis and lower bicarbonate and base excess levels relative to infants receiving HTLHMF (P < 0.001). There were no significant differences by LHMF status in other clinical outcomes and nutrition and growth outcomes. In multivariate analyses, ALHMF use was associated with metabolic acidosis, and lower base excess and bicarbonate levels. CONCLUSION: In our study, the clinical, nutrition and growth outcomes between the two LHMF groups were similar. However, use of ALHMF in preterm infants was associated with increased incidence of metabolic acidosis in our cohort. Further randomized control trials are warranted to evaluate these findings. PMID- 29286934 TI - Use of prophylactic antibiotics in women with previable prelabor rupture of membranes. AB - OBJECTIVE: To measure the effect of prophylactic antibiotics given at time of previable prelabor rupture of membranes (PROM) on latency. METHODS: Single center, retrospective cohort study of singleton pregnancies with previable (<23 0/7weeks) PROM. Antibiotics were given at clinician discretion. The primary outcome was latency, defined as duration of time between previable PROM and delivery. Secondary outcomes included delivery at >= 23weeks, infant survival, and maternal morbidity. Bivariate analysis compared maternal covariates between women who did and did not receive antibiotics. Antibiotic effect on latency was modeled using a Cox proportional hazards ratio. RESULTS: 213 women with previable PROM were identified; 77 (36%) remained pregnant and thus were included in this analysis. Forty (52%) of 77 received antibiotics. Compared to women who did not receive antibiotics, those who did had PROM at a later median (IQR) estimated gestational age, EGA, (22.2weeks [20.7, 22.5] vs. 19.3weeks [18, 20.7], p < 0.01). Median (IQR) latency was not different between women who did and did not receive antibiotics (2.2 [0.7, 3.9] vs. 1.5 [0.5, 4.6] weeks, p = 0.49). More infants survived to discharge among women who received antibiotics compared to those who did not [17(43%) vs. 3(8%), p < 0.01]. When adjusted for EGA at PROM, antibiotics were associated with longer latency (HR 0.57 [95% CI 0.33, 0.97], p = 0.01). Antibiotic use was not associated with differences in maternal morbidity. CONCLUSION: After adjusting for EGA at PROM, antibiotic receipt was associated with longer latency. Larger prospective studies are needed to define the utility of prophylactic antibiotics in previable PROM. PMID- 29286935 TI - Neonatal methicillin-resistant Staphylococcus aureus colonization and infection. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a common etiological agent of a life-threatening infection in neonatal intensive care units (NICUs). Neonates with very low birth weight and patients with serious diseases are more likely to be exposed to invasive procedures which make them at a high risk of MRSA colonization and infection. Since MRSA colonization is a risk factor for MRSA infection, prevention of MRSA transmission is an important issue in NICUs. NICUs in Japan practice standard contact precautions and active surveillance cultures (ASC) to prevent MRSA transmission. In this report, we analyzed the clinical characteristics of MRSA colonization and infection between January 2010 and December 2015 in our perinatal care center. METHODS: We conducted retrospective analysis of 1716 neonates hospitalized in our perinatal care center. RESULTS: 120 cases had MRSA colonization (6.99%) and among them 33 neonates were infected. The duration of stay (P<=0.001) and the birth weight (P<=0.001) showed statistically significant differences between MRSA-colonized neonates and non-MRSA-colonized neonates. The number of central venous catheterization showed statistically significant differences (P = 0.001) and the number of digestive system diseases showed marginally significant differences (P = 0.072) between MRSA-colonized non-infected neonates and MRSA-infected neonates. CONCLUSIONS: As previous reports have shown, we present that the neonates with central venous catheterization were more likely to be infected with MRSA. We also need to pay attention to neonates with digestive system diseases, showing signs of infection, because they may be potentially infected with MRSA. PMID- 29286936 TI - Haddad syndrome novel association with BRAF mutation. AB - This is a report of a 36 week male infant who suffered abdominal distension and difficulty opening bowels within first few days of life and showed a pattern of hypoventilation and apnea associated with sleep. His diagnostic studies confirmed the diagnosis of congenital central hypoventilation syndrome CCHS (PHOX2B mutation) and Hirschsprung's disease and later found a further mutation of BRAF oncogene. This describes a novel association between these mutations and the shared qualities of tumorigenesis between BRAF and PHOX2B. PMID- 29286937 TI - Hemoperitoneum in peripartum: A case-series. AB - Hemorrhages are the first cause of perinatal deaths in French women. Thirteen percent of these deaths are not linked to obstetrical problems but rather to hemoperitoneum. These incidents are under-diagnosed and as a result, treatment is delayed and fetal and maternal mortality increases. We report three cases of patients, all White female in their last trimester of a non-problematic pregnancy presenting with hemoperitoneum and resulting in different outcomes. The analysis of published materials and of our cases leads us to infer that a diagnosis of hemoperitoneum must be considered in pregnant women when abdominal pain, symptoms of shock and a decrease in hemoglobin are associated. An immediate response and intensive care followed by hemostatic surgery give these patients the best chance to survive. PMID- 29286938 TI - The relationship between body weight, cystatin C and serum creatinine in neonates. AB - BACKGROUND: Serum creatinine (SCr) measurement to determine glomerular filtration rate (GFR) in neonates has many pitfalls. Cystatin C (CysC) appears to be a more reliable biomarker. METHODS: We investigated the effect of birth weight on SCr and CysC measurements in a cohort of 74 infants, consisting of both term and ex premature infants at term postmenstrual age. SCr and Cys C measurements were carried out at the same time. RESULTS: Eighty six infants were recruited into this study out of which complete data were available in 80 infants. The cohort consists of both term and premature infants at term PMA (31 terms and 49 preterms). The median SCr level was 17 [12-26] umol/L and mean CysC level was 1.64 [0.27] mg/L. SCr had a significant correlation with weight (r = 0.3; P = 0.011), whereas serum CysC had no correlation with the infant's weight (r = 0.01; P = 0.95). There were no statistically significant difference in SCr and CysC between male and female infants. CONCLUSION: Unlike CysC, SCr had a significant correlation with birth weight. SCr based GFR measurement may cause a delay in diagnosis of acute kidney injury in smaller neonates. PMID- 29286939 TI - Clinical profile and pattern of congenital heart disease in infants of diabetic mother and infants of non-diabetic mother at a tertiary care hospital. AB - OBJECTIVES: To assess the clinical manifestations and pattern of congenital heart diseases (CHD) in infants of diabetic mothers (IDMs) and infants of non-diabetic mothers. METHODS: A prospective cross sectional study was carried out at tertiary care center over a period of thirty months. All neonates were included in this study if CHD were identified by echocardiography within this study period. Chi square test and Fisher's exact test were used to compare between groups. RESULT: Out of 62 neonates, IDMs and non-IDMs were equal in number, male and female ratio was 3 : 2, and majority were delivered by cesarean section (85.5%). Mean gestational age was 35 weeks, 62.3% were preterm, and 37.7% were term. Common clinical presentations were cardiac murmur (61%), and respiratory distress (43.5%). Less common presentations were low SaO2 (27.4%), tachycardia (24.2%), and cyanosis (24.2%). Common combination of presentations were murmur and tachypnea (38.7%); cyanosis and low SaO2 (24.19%); and low SaO2 and tachypnea 15(24.19). The common echocardiographic findings were atrial septal defect (ASD; 72.6%), patent ductus arteriosus (PDA; 45.2%), and ventricular septal defect (VSD; 25.8%). ASD (77.4% vs 67.7%) and VSD (35.5% vs 16.1%) were more in IDMs, and PDA (48.4% vs 41.9%) was more in non-IDMs. These differences were not significant between groups. CONCLUSION: Clinical presentation and echocardiographic findings of CHD were similar in IDMs and non-IDMs. PMID- 29286940 TI - Sustained lung inflation at birth for preterm infants at risk of respiratory distress syndrome: The proper pressure and duration. AB - BACKGROUND: Variations exist among the administered pressure and duration of sustained lung inflation (SLI) in the delivery room (DR). We aimed to evaluate the appropriate pressure and duration needed for SLI in preterm infants with respiratory distress syndrome. METHODS: We prospectively randomized 100 preterm (<32 weeks) infants to receive either conventional therapy of continuous positive airway pressure (CPAP) at 5 cm H2O, or four groups of CPAP plus a single maneuver of SLI at four regimens based on administered pressures and durations; P20D20 (Pressure of 20 cm H2O for a duration of 20 seconds), P20D10 (20 cm H2O for 10 seconds), P15D20 (15 cm H2O for 20 seconds), and P15D10 (15 cm H2O for 10 seconds) using a T-piece ventilator. The primary outcome was the need for endotracheal intubation (ETT) in the DR. Broncho-alveolar lavage (BAL) was obtained from intubated infants for interleukin-10 (IL-10) assessment. RESULTS: SLI decreased the need for ETT in the DR (21% versus 55%, p < 0.01) compared to conventional therapy. ETT requirement was significantly lower in P20D10 (20%), P15D20 (20%), and P15D10 (20%) groups, but not P20D20 (25%) compared to the conventional group (55%, p < 0.05). Group P20D20 had significant higher BAL levels of IL-10 [713.8 (IQR 611-874) versus 535.4 (IQR 480-563) pg/ml, p < 0.05] compared to the conventional group, and to other SLI groups. Pneumothorax was not significantly different among studied groups. CONCLUSION: SLI for a pressure and duration >=20 cm H2O for 20 seconds is not superior to lower pressures for shorter duration and may be injurious to lungs. PMID- 29286941 TI - Thermic effect on metal body piercing by electrosurgery: An ex vivo study on pig skin and bovine liver. AB - BACKGROUND: Piercings are placed at different body sites often invisible to medical staff. They may cause additional injuries in trauma and emergency surgery by electro-cautery. OBJECTIVE: To clarify whether electrosurgery will have a direct damaging effect to the skin around a pierced skin area. METHODS: Metallic piercings were fixed at defined distances from the neutral and active electrode on abdominal pig skin. The distance of the active electrode was reduced by 5 mm increments to 0. The respective increases in temperature were determined with a thermal camera. A macroscopic and histological analysis of the area around the piercing to detect thermal damage was carried out. RESULTS: Significant increases in temperature and visible changes in the tissue around the piercing only occurred when the active electrode was in direct contact with the piercing (increase of 47.3?C). Electro-cautery in distance of 5 to 10 mm to the piercing showed only temperature increases of less than 5?C. CONCLUSIONS: If metallic piercings are not directly touched by the active electrode and the distance is more than 5-10 mm, no clinically relevant effect is created on the tissue in direct proximity to the piercings by electro-cautery. In an emergency surgery situation, a piercing not fixed in direct proximity to the surgical field may likely be ignored. PMID- 29286942 TI - Novel approach for automating medical emergency protocol in military environment. AB - BACKGROUND AND OBJECTIVES: Categorization of the casualties in accordance with medical care priorities is crucial in a military environment. Automation of the triage process is still a challenging task. The goal of the paper is to propose a novel algorithm for automation of medical emergency protocol in the military environment by the creation of classifiers that can provide accurate prioritization of injured soldier cases. It is a part of a complex military telemedicine system that provides continuous monitoring of soldiers' vital data gathered on-site using an unobtrusive set of sensors. METHODS: After pre processing the collected raw physiological data and eliminating the outliers using Naive Bayesian Classifier, the system is capable of calculating the risk level and categorizing the victims based on Markov Decision Process. The NBC has been trained with a dataset that has contained labels and 6 features. Training set has held 8000 randomly chosen samples. Twenty percent of the determined dataset has been used for the validation set. RESULTS: For algorithm verification, several evaluation scenarios have been created. In each scenario, randomly generated vital sign data describing the hypothetical health condition of soldiers was contemporarily assessed by the system as well as by 50 experienced military medical physicians. CONCLUSION: The obtained correlation result of the proposed algorithm and medical physicians' classifications is strong evidence that the system can be implemented in warfare emergency medicine. PMID- 29286943 TI - Integrating simulation based learning into nursing education programs: Hybrid simulation. AB - BACKGROUND: Hybrid simulation can be developed with mannequins of any fidelity and tabletop simulators with a standardized patient to create a complex, high level learning activity. OBJECTIVE: The aim of this study is to analyze the effects of a hybrid simulation technique used with nursing students in a scenario about the emergency setting. METHODS: This one-group pre-test post-test model quasi-experimental study was carried out with 39 students in Ankara, Turkey, from October 2014 to July 2015. RESULTS: Nearly all participants reported that the simulation improved their critical thinking, decision-making skills, and self confidence before the clinical activity and that they felt as though they were real nurses during the activity (94.7%, 97.3%, 84.2%, and 92.1%, respectively). CONCLUSION: The results of this study support the integration of hybrid simulation experiences throughout the nursing curriculum, as evidenced by positive responses from students through the simulation evaluation questionnaire. PMID- 29286944 TI - Update of a Systematic Review of Autoresuscitation After Cardiac Arrest. AB - OBJECTIVES: There has been a growth in publications focusing on the phenomena of autoresuscitation in recent years. In 2010, we systematically reviewed the medical literature with the primary objective of summarizing the evidence on the timing of autoresuscitation. Healthcare professionals have continued to voice concerns regarding the potential for autoresuscitation. With this in mind, the objective of this brief report is to update the results of our original review of autoresuscitation. DATA SOURCES: We applied the same search strategy described in our original article to update our findings to include articles published from January 2009 to September 2016. STUDY SELECTION AND DATA EXTRACTION: We screened an additional 1,859 citations, after duplicates were removed, and then assessed 46 full-text articles for eligibility, from which 15 studies were included for data extraction. DATA SYNTHESIS: During the time period of this review, there have been 1) 10 additional adult and three pediatric case reports of autoresuscitation in patients after cessation of cardiopulmonary resuscitation; in those cases with continuous monitoring and confirmation of circulation, the longest events are reported to be 10 and 2 minutes, respectively for adults and children; 2) six adults (4%, total n = 162) with autoresuscitation events reported from two observational studies and one chart review of patients undergoing withdrawal of life-sustaining therapy; the longest time reported to be 89 seconds with electrocardiogram and invasive arterial blood pressure monitoring and 3 minutes with electrocardiogram monitoring only; 3) 12 pediatric patients studied with vital sign monitoring during withdrawal of life-sustaining therapy without any reports of autoresuscitation. CONCLUSIONS: Although case reports of autoresuscitation are hampered by variability in observation and monitoring techniques, autoresuscitation has now been reported in adults and children, and there appears to be a distinction in timing between failed cardiopulmonary resuscitation and withdrawal of life-sustaining therapy. Although additional prospective studies are required to clarify the frequency and predisposing factors associated with this phenomenon, clinical decision-making regarding patient management under uncertainty is required nonetheless. Both adult and pediatric healthcare professionals should be aware of the possibility of autoresuscitation and monitor their patients accordingly before diagnosing death. PMID- 29286945 TI - An Interpretable Machine Learning Model for Accurate Prediction of Sepsis in the ICU. AB - OBJECTIVES: Sepsis is among the leading causes of morbidity, mortality, and cost overruns in critically ill patients. Early intervention with antibiotics improves survival in septic patients. However, no clinically validated system exists for real-time prediction of sepsis onset. We aimed to develop and validate an Artificial Intelligence Sepsis Expert algorithm for early prediction of sepsis. DESIGN: Observational cohort study. SETTING: Academic medical center from January 2013 to December 2015. PATIENTS: Over 31,000 admissions to the ICUs at two Emory University hospitals (development cohort), in addition to over 52,000 ICU patients from the publicly available Medical Information Mart for Intensive Care III ICU database (validation cohort). Patients who met the Third International Consensus Definitions for Sepsis (Sepsis-3) prior to or within 4 hours of their ICU admission were excluded, resulting in roughly 27,000 and 42,000 patients within our development and validation cohorts, respectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High-resolution vital signs time series and electronic medical record data were extracted. A set of 65 features (variables) were calculated on hourly basis and passed to the Artificial Intelligence Sepsis Expert algorithm to predict onset of sepsis in the proceeding T hours (where T = 12, 8, 6, or 4). Artificial Intelligence Sepsis Expert was used to predict onset of sepsis in the proceeding T hours and to produce a list of the most significant contributing factors. For the 12-, 8-, 6-, and 4-hour ahead prediction of sepsis, Artificial Intelligence Sepsis Expert achieved area under the receiver operating characteristic in the range of 0.83-0.85. Performance of the Artificial Intelligence Sepsis Expert on the development and validation cohorts was indistinguishable. CONCLUSIONS: Using data available in the ICU in real-time, Artificial Intelligence Sepsis Expert can accurately predict the onset of sepsis in an ICU patient 4-12 hours prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed sepsis prediction model. PMID- 29286946 TI - Using a K-W-L Chart to Bridge the Theory-Practice Gap. AB - As nursing is a practice discipline, theory and practice cannot be separated. Yet nursing education is traditionally divided into two components: classroom or theory-based learning and clinical or practice-based learning. The theory practice gap is one of the most significant issues in nursing today, given the emphasis on evidence-based practice. This article describes the use of a K-W-L chart as an approach to bridge the theory-practice gap and encourage students to become self-directed and take ownership of their knowledge. PMID- 29286947 TI - The Student Experience With Varying Immersion Levels of Virtual Reality Simulation. AB - With increasing use of virtual reality simulation (VRS) in nursing education and given the vast array of technologies available, a variety of levels of immersion and experiences can be provided to students. This study explored two different levels of immersive VRS capability. Study participants included baccalaureate nursing students from three universities across four campuses. Students were trained in the skill of decontamination using traditional methods or with VRS options of mouse and keyboard or head-mounted display technology. Results of focus group interviews reflect the student experience and satisfaction with two different immersive levels of VRS. PMID- 29286783 TI - Search for Evidence of the Type-III Seesaw Mechanism in Multilepton Final States in Proton-Proton Collisions at sqrt[s]=13 TeV. AB - A search for a signal consistent with the type-III seesaw mechanism in events with three or more electrons or muons is presented. The data sample consists of proton-proton collisions at sqrt[s]=13 TeV collected by the CMS experiment at the LHC in 2016 and corresponds to an integrated luminosity of 35.9 fb^{-1}. Selection criteria based on the number of leptons and the invariant mass of oppositely charged lepton pairs are used to distinguish the signal from the standard model background. The observations are consistent with the expectations from standard model processes. The results are used to place limits on the production of heavy fermions of the type-III seesaw model as a function of the branching ratio to each lepton flavor. In the scenario of equal branching fractions to each lepton flavor, heavy fermions with masses below 840 GeV are excluded. This is the most sensitive probe to date of the type-III seesaw mechanism. PMID- 29286948 TI - A Profile of Neuro-Ophthalmic Practice Around the World. AB - BACKGROUND: To compare contrast neuro-ophthalmic practice in various countries, an 18-question survey was sent to the international North American Neuro Ophthalmology Society (NANOS) members in the spring of 2016. METHODS: At least 1 NANOS member was contacted for each non-US nation in the NANOS membership roster. If there were multiple NANOS members from 1 country, multiple were contacted. If responses were received from more than 1 person from a single country, the first response received was used as the source data. The survey (in English) was emailed to 47 NANOS members from 31 countries. Twenty responses were received representing members from 15 nations. RESULTS: In all 15 nations, at least half of the neuro-ophthalmologists were trained as ophthalmologists. In 60% of nations, at least half of the neuro-ophthalmologists were trained internally, whereas in 33% of countries, at least half were trained in the United States. The number of physicians who practiced a significant amount of neuro-ophthalmology ranged from low (0.08/million, India) to high (3.10/million, Israel). Countries having the highest percentage of neuro-ophthalmologists exclusively practicing neuro-ophthalmology also were those with better patient access to neuro ophthalmic care. Requirement of approval to see a neuro-ophthalmologist or for imaging studies requested by neuro-ophthalmologists was not typical. In most nations, academic neuro-ophthalmologists were paid a straight salary. In no nation were neuro-ophthalmologists paid more than another ophthalmic subspecialty. CONCLUSIONS: Individual national health care system designs and compensation models have had a profound influence on the rewards and challenges that face neuro-ophthalmologists. There seems to have been a connection between recognition of the discipline, financial rewards of neuro-ophthalmic practice, conditions that permit full-time neuro-ophthalmic practice, and patient access to care. A higher percentage of gross national product for health care did not seem to insure an adequate supply of neuro-ophthalmologists. PMID- 29286949 TI - Rating Scale for Ocular Myasthenia Gravis: A Call to Action! PMID- 29286953 TI - Co-management Strategies for Hospitals and Orthopedic and Neurosurgery Practices. AB - Co-management arrangements can be a very effective means of aligning physicians and their hospitals to gain care delivery efficiencies, control costs, and reduce variation in practices. In an era of value-based care delivery all aspects must be examined and the appropriate incentives put in place to reduce waste and optimize asset and resource utilization. This article will review legal considerations, define basic co-management structure and goals, and suggest examples of metrics used to achieve success. PMID- 29286951 TI - Response to Recent Commentary. PMID- 29286950 TI - Psychometric Properties of the Chinese Version of the Occupational Fatigue Exhaustion/Recovery Scale: A Test in a Nursing Population. AB - BACKGROUND: The Occupational Fatigue Exhaustion/Recovery Scale (OFER) was designed to assess occupational fatigue in nurses. Although the original English version of this instrument has shown high degrees of reliability and validity, a Chinese version of this scale has yet to be verified. PURPOSE: The aim of this study was to evaluate the psychometric properties of the OFER in a population of Chinese nurses. METHODS: The scale was translated using translation and back translation. The validities and reliabilities were evaluated on 923 qualified participants using content validity index, concurrent validity, factorial validity, internal consistency reliability, and test-retest reliability. RESULTS: The content validity index for the OFER was .92. The correlation coefficients between the scores of the OFER subscales and the criteria in this study (varying from -.498 to .705) verified that the OFER has acceptable concurrent validity. Principal component analysis and confirmatory factor analysis revealed that three factors correspond to the structure of the original instrument and that recovery mediates the relationship between acute and chronic fatigue. The Cronbach's alpha for the chronic fatigue, acute fatigue, and intershift recovery subscales were .83, .85, and .86, respectively. Test-retest reliabilities with correlation coefficients from .61 to .78 were found in the three subscales. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: OFER is a reliable and valid instrument for assessing work-related fatigue in Chinese nurses. However, further improvement of the acute fatigue subscale is recommended. The OFER has the potential to elicit information that is useful for assessing fatigue in nurses in China. Furthermore, as it differentiates between acute and chronic fatigue, OFER may be an effective tool for guiding the development and implementation of various, related intervention measures. PMID- 29286952 TI - Prevalence of Meibomian Gland Atrophy in a Pediatric Population. AB - PURPOSE: To report the prevalence of meibomian gland atrophy and gland tortuosity in a pediatric population. METHODS: Participants who presented with no history of dry eye disease or meibomian gland dysfunction were recruited from the Duke University Eye Center. Meibography was performed and subjective symptoms were assessed through the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire. Grading of images was assessed by a masked rater using a previously validated 5-point meiboscale (0-4) for gland atrophy and a 3-point scale for gland tortuosity (0-2). RESULTS: Ninety-nine eyes of 99 participants (50 females) aged 4 to 17 years (mean 9.6 years) were imaged. The mean meiboscore was 0.58 +/- 0.80 (mean +/- SD) for gland atrophy and 0.45 +/- 0.64 for tortuosity. In all subjects, 42% (n = 42) had any evidence of meibomian gland atrophy (meiboscore >0) and 37% (n = 37) had any evidence of meibomian gland tortuosity. The majority of subjects had mild gland atrophy. No significant association was found between age, sex, or race and presence of gland atrophy. Males were significantly more likely to have gland tortuosity (P = 0.0124, odds ratio 3.36). CONCLUSIONS: This study reveals a relatively high level of mild meibomian gland atrophy in the pediatric population, though moderate-severe gland atrophy was also present in this young population. This calls into question our current understanding of baseline gland architecture and suggests that perhaps clinicians should be examining young patients for meibomian gland atrophy and dysfunction because it may have implications for future development of dry eye disease. PMID- 29286954 TI - Selective beta1-Blockers Are Not Associated With New-onset Diabetes Mellitus in Hypertensive Patients. AB - BACKGROUND: Although beta-blockers are known to increase new-onset diabetes mellitus (DM), previous evidence have been controversial. It has been suggested that newer vasodilatory beta-blockers yield better glycemic control than older nonselective agents. The aim of this study was to evaluate the diabetogenicity of currently used newer beta-blockers based on beta1 receptor selectivity in a series of Asian population. METHODS: We investigated a total of 65,686 hypertensive patients without DM from 2004 to 2014. Patients with hemoglobin (Hb) A1c <=6.0%, fasting blood glucose <=110 mg/dL, and no history of diabetes or diabetic treatment were enrolled for analysis. Patients were divided into the beta-blockers group and non-beta-blockers group. Propensity score matching (PSM) analysis using a logistic regression model was performed to adjust for potential confounders. The primary end point was the cumulative incidence of new-onset DM, defined as a fasting blood glucose >=126 mg/dL or HbA1c >=6.5%, and major adverse cardiac and cerebral events (MACCE), defined as a composite of total death, nonfatal myocardial infarction, and cerebrovascular accidents. We investigated predictors of new-onset DM and MACCE based on 2 models, including clinical risk factors and co-medications, respectively. RESULTS: Mean follow-up duration was 30.91 +/- 23.14 months in the entire group before adjustment. The beta-blockers group had a significantly higher incidence of new-onset DM and MACCE than the non beta-blockers group. After PSM, analysis of a total of 2284 patients (1142 pairs, C-statistic = 0.752) showed no difference between the 2 groups in new-onset DM or MACCE. In multivariate analysis after PSM, baseline HbA1c, stroke, heart failure, nonselective beta-blockers, and age were independent predictors of new-onset DM. Selective beta1-blockers did not increase new-onset DM after adjustment for other antihypertensive medication and statins. CONCLUSIONS: In the era of newer beta blockers, selective beta1-blockers were not associated with new-onset DM. More evidence is needed to verify this relationship and the underlying mechanisms. PMID- 29286955 TI - INVISIBLE, HONEYCOMB-LIKE, CAVITARY RETINAL ASTROCYTIC HAMARTOMA. AB - PURPOSE: To report a patient with clinically invisible retinal astrocytic hamartomas (RAHs) detected on optical coherence tomography (OCT) and studied with OCT angiography (OCTA). METHOD: Case report. RESULTS: An 11-year-old healthy girl was evaluated for reduced visual acuity in the right eye. On examination, best corrected visual acuity was 20/50 in the right eye and 20/20 in the left eye. Fundus examination revealed blunted foveal reflex in the right eye and normal findings in the left eye. Optical coherence tomography disclosed an abruptly elevated, honeycomb-like macular mass with thin filamentous walls in the right eye, limited to the nerve fiber layer and measuring 756 MUm in thickness. The numerous intralesional cavities (optically empty spaces) displayed no calcification. These findings were consistent with Type IV RAH. Optical coherence tomography of the left eye revealed intact foveola and focal nerve fiber layer thickening inferiorly without cavity, measuring 136 MUm in thickness, consistent with Type I RAH. En face OCTA detected microvascular flow within the walls of the cavitary RAH in the right eye. Bilateral RAH in a child with no systemic evidence of tuberous sclerosis syndrome was established. CONCLUSION: Multimodal imaging is important in revealing causes of visual loss and in the detection of subclinical fundus tumors. In this case, clinically invisible RAHs were detected only by OCT and surrounding vascular flow by OCTA. PMID- 29286956 TI - FIVE-YEAR INCIDENCE AND RISK FACTORS FOR IDIOPATHIC EPIRETINAL MEMBRANES. AB - PURPOSE: The aim of this was to determine the 5-year incidence of idiopathic epiretinal membrane (ERM) and its risk factors in Korean adults. METHODS: A total of 2,152 participants aged 50 years or older enrolled in a health screening program. All participants underwent baseline ophthalmic and systemic examinations in 2006, and were reexamined after 5 years. Epiretinal membranes were diagnosed using fundus photographs taken at baseline and at the 5-year follow-up. The incidence of idiopathic ERM was calculated in this study cohort, and then age standardized to the 2010 Korean Census. Epiretinal membranes were classified as preretinal macular fibrosis with prominent retinal folds or cellophane macular reflex without retinal folds. Associated risk factors for idiopathic ERM were also analyzed. RESULTS: Idiopathic ERM developed in 82 of 2,152 participants who had no previous ERM in either eye at baseline. The overall age-standardized incidence was 3.8% (95% confidence interval, 2.8-4.8), including 2.3% with cellophane macular reflex and 1.5% with preretinal macular fibrosis. Multivariate logistic regression analyses revealed that the factors related to the development of idiopathic ERM were age (adjusted odds ratio, 1.04; 95% confidence interval, 1.00-1.08) and hypertriglyceridemia (250 mg/dL or more; adjusted odds ratio, 3.16; 95% confidence interval, 1.54-6.49) after adjusting for confounding factors. CONCLUSION: Our results suggest that the 5-year incidence of idiopathic ERM in Korean adults is relatively similar to that in similar-aged white persons. Age and hypertriglyceridemia may increase the risk of developing idiopathic ERM. PMID- 29286957 TI - Uncommon Metastases to and from the Musculoskeletal System. PMID- 29286958 TI - Chronic Nocardia cyriacigeorgica Periprosthetic Knee Infection Successfully Treated with a Two-Stage Revision: A Case Report. AB - CASE: We report the successful treatment of a Nocardia cyriacigeorgica periprosthetic joint infection (PJI) that occurred at the site of a total knee arthroplasty. To our knowledge, this organism has not previously been reported in the literature as a cause of PJI. Given the need for a prolonged duration of treatment for this organism (a minimum of 6 to 12 months), modifications to the standard 2-stage revision were made in consultation with infectious-disease specialists. CONCLUSION: PJI is a devastating complication that leads to substantial patient morbidity and utilization of health-care resources. As the number of PJIs continues to rise, new and increasingly challenging infections are being encountered more frequently. In the case described here, the second stage of the revision was delayed for 6 months and antibiotics were continued for 7 months after the second operation, for a total of 13 months of antibiotic treatment. The present report provides a possible treatment plan for patients infected with durable bacteria similar to N. cyriacigeorgica. PMID- 29286959 TI - Congenital Quintus Valgus: An Extremely Rare Anomaly: A Case Report. AB - CASE: We present an unusual case of unilateral congenital quintus valgus of the left foot (congenital lateral deviation of the fifth [little] toe) in a 1.5-year old boy. The child had no other congenital malformations. Radiographs revealed the abnormal presence of 2 accessory phalangeal ossicles in the fourth web space, leading to lateral deviation of the fifth toe. Remarkably, the ossicles of the middle and distal phalanges of the fifth toe were absent. Surgical excision of the accessory ossicles was performed, and correction of the deformity was achieved. CONCLUSION: Congenital quintus valgus, to the best of our knowledge, has not been reported in the medical literature. Physicians must be aware of the possibility of such a condition while treating congenital malformations of the foot. PMID- 29286960 TI - Osseointegration as Treatment for a Knee Disarticulation Because of a Congenital Femoral Deficiency: A Case Report. AB - CASE: A 25-year-old woman underwent osseointegration surgery as treatment for an amputation that had been performed because of congenital femoral deficiency. The undersized custom-designed implant for the congenitally hypoplastic femur subsequently loosened, causing substantial pain and loss of function. The patient underwent revision surgery with a larger standard-sized osseointegration implant, and experienced no additional complications. CONCLUSION: This case demonstrates the possibility of stimulating a hypertrophic response in underdeveloped bone, which allows the subsequent insertion of a larger implant with greater stability. Similar procedures can be considered for the treatment of patients who had amputations because of congenital deficiencies, in order to produce improved outcomes and reduce the risk of additional complications. PMID- 29286961 TI - Regeneration of a Completely Transected Sciatic Nerve with Use of a Bioabsorbable Nerve Conduit Filled with Collagen with a 14-Year Follow-up: A Case Report. AB - CASE: A 65-year-old man with a completely transected left sciatic nerve at the buttock received an implant with a bioabsorbable nerve conduit over a 20-mm gap. The conduit was filled with collagen to facilitate nerve regeneration. At 4 years after implantation, reinnervation potentials were detected in the muscles, and there was sensory recovery in the reinnervated areas. Thereafter, motor and sensory function recovered gradually over a 14-year period. CONCLUSION: Mixed nerve regeneration after conduit-based reconstruction was demonstrated objectively. Although it took >4 years for motor and sensory functions to be regained, the nerve connection between the buttock and the foot was restored. PMID- 29286962 TI - Fractures of the Bilateral C2 Neurocentral and Lateral Dental Synchondroses with Kyphotic C1-C2 Subluxation in a 3-Year-Old Girl: A Description of a Rare Fracture Pattern and Its Treatment: A Case Report. AB - CASE: Spinal fractures are rare in young children. Because spinal anatomy and biomechanics differ in children and adults, knowledge of the deviations of the juvenile spine is necessary for adequate treatment. We present the case of a young girl with an unusual C2 fracture that included rupture of both of the neurocentral and lateral dental synchondroses, with an opening of the synchondroses and a caudal dislocation of both vertebral arches following a head on motor vehicle collision. The whole body and apex of the dens was displaced anteriorly and cranially with a kyphotic angulation of 34 degrees . We describe the treatment and clinical and radiographic outcome after 1 year. CONCLUSION: Using passive hyperextension and distraction of the head, a closed open-mouth digital reduction was performed under continuous fluoroscopy. At the 1-year follow-up, the patient had full range of motion of the head without pain or neurologic dysfunction. PMID- 29286963 TI - Restricted Range of Motion and a Cold Upper Extremity in a Two-Year-Old Boy: Kaposiform Hemangioendothelioma of the Bone and the Brachial Plexus: A Case Report. AB - CASE: We report a case of kaposiform hemangioendothelioma (KHE) of the scapula in a 2-year-old boy with motor and sensory abnormalities of the left upper extremity, suggesting brachial plexus involvement. The locally invasive nature prevented resection; sirolimus therapy resulted in improvement of the motor and sensory impairment, as well as decreased tumor size on imaging. CONCLUSION: Osseous infiltration of KHE is known to occur, but its primary presentation in bone without skin involvement is rare and diagnostically challenging. Awareness of rare presentations of KHE, along with accurate histopathologic interpretation, is important to achieve a diagnosis and to differentiate KHE from more common vascular lesions (e.g., infantile hemangioma). Sirolimus therapy is emerging as a promising treatment for unresectable KHE. PMID- 29286964 TI - Lymphaticovenous Anastomoses for Lymphedema Complicated by Severe Lymphorrhea Following Resection of Soft-Tissue Sarcomas of the Adductor Compartment: A Report of Two Cases. AB - CASE: Lymphedema and lymphorrhea are major causes of wound complications after the resection of soft-tissue sarcomas in the adductor compartment of the thigh. We report 2 cases of successful treatment of lymphedema and lymphorrhea, which had been refractory to nonoperative treatment, with use of lymphaticovenous anastomosis (LVA) and intraoperative indocyanine green lymphography after the resection of a sarcoma in the adductor compartment. CONCLUSION: These 2 cases highlight that LVA can be a useful and minimally invasive alternative to myocutaneous flaps for the treatment of wound complications caused by lymphedema and lymphorrhea after surgery for soft-tissue sarcomas in the adductor compartment of the thigh. PMID- 29286965 TI - Return to National Basketball Association Competition Following Anterior Cruciate Ligament and Fibular Collateral Ligament Injuries: A Case Report. AB - CASE: Numerous outcome studies regarding anterior cruciate ligament (ACL) reconstruction demonstrate the ability of athletes to return to a high level of play. However, to our knowledge, there is limited literature regarding return to play following injury to both the ACL and the fibular collateral ligament (FCL). We describe the case of a National Basketball Association (NBA) player who sustained a combined ACL and FCL knee injury and subsequently underwent surgical reconstruction of both affected ligaments. He was able to return to a preinjury level of competition at 9 months postoperatively. CONCLUSION: It is possible for athletes to return to competitive basketball and maintain a high production level following a single-staged reconstruction of both the ACL and the FCL. PMID- 29286966 TI - Isolated Scapular Metastasis in a Patient with Malignant Struma Ovarii: A Case Report. AB - CASE: We report the case of a 38-year-old woman who presented with a lytic bone lesion in the left scapula. A biopsy showed a tumor with the histologic appearance of thyroid tissue. She also was found to have a thyroid nodule and an enlarged ovary, both of which were excised. The thyroid nodule turned out to be a benign colloid nodule, and the ovary contained a monodermal teratoma composed of thyroid tissue (struma ovarii). The lesion in the scapula eventually was proven to be metastatic malignant struma ovarii. CONCLUSION: Malignant struma ovarii with bone metastases is very rare, and its diagnosis is a challenge. There are some documented cases with bone metastases, mostly to the thoracic and lumbar spine. The optimal treatment of choice for the bone lesion is unknown because of the rarity of its presentation. PMID- 29286967 TI - Failure of a Polyaryletheretherketone-Cobalt-Chromium Composite Femoral Stem Due to Coating Separation and Subsidence: A Case Report. AB - CASE: A 52-year-old man who previously had undergone total hip arthroplasty with use of an Epoch (Zimmer) extensively porous-coated femoral stem presented with hip pain after a high-energy motor-vehicle accident. Radiographs demonstrated delamination at the polyaryletheretherketone-cobalt-chromium (PEEK-CoCr) core interface, which led to loosening. At revision, the implant demonstrated gross evidence of debonding at the PEEK-CoCr interface. CONCLUSION: We demonstrate clinical and tribologic evidence of a rare failure mode involving the PEEK-metal interface in a composite femoral stem, which surgeons should be aware of when evaluating patients with this type of implant. PMID- 29286969 TI - Simultaneous Ipsilateral Dislocation of the Hip and the Knee: A Case Report. AB - CASE: A patient was struck by an agricultural vehicle and sustained ipsilateral hip and knee dislocations. Closed reduction of the hip was accomplished in the emergency department; the patient required general anesthesia in the operating room to reduce the knee dislocation. Nonoperative treatment was used for both injuries, with a good long-term outcome. CONCLUSION: Simultaneous ipsilateral hip and knee dislocations are rare and complex injuries that usually result from high energy trauma. In order to avoid severe neurovascular complications, they need prompt management. Nonoperative treatment followed by an intensive rehabilitation program should be considered as an alternative treatment to surgery in older patients with a low-demand lifestyle. PMID- 29286968 TI - Arthroscopically Assisted Reduction and Internal Fixation of a Displaced Posterior Glenoid Fracture: A Case Report. AB - CASE: We report the successful use of arthroscopy for reduction and internal fixation of a posterior glenoid fracture in a 62-year-old man 5 days following a skiing accident. Additionally, we review the technique utilized for successful fixation of this rare fracture, and we report the postoperative return of function. CONCLUSION: Arthroscopically facilitated fixation of glenoid fractures has been reported in the literature with excellent clinical outcomes. However, arthroscopic reduction and screw fixation of a posterior intra-articular glenoid fracture (Ideberg type Ib), to our knowledge, has not been previously published. The unique benefits of arthroscopic screw fixation are discussed. PMID- 29286970 TI - A Child with a Rare Extraosseous Extension and Pathologic Fracture from a Vertebral Hemangioma: A Case Report. AB - CASE: We present a case of a pathologic vertebral fracture and encroachment into the spinal canal from a vertebral hemangioma in a 13-year-old boy. The original approach of embolization followed by an anterior-posterior resection and stabilization through a costotransversectomy had to be converted intraoperatively to a combined anterior and posterior approach secondary to excessive bleeding. CONCLUSION: Because of the hypervascularity and the extensive nature of aggressive vertebral hemangiomas, surgeons attempting procedures similar to the case described herein must be prepared to adapt to the circumstances when preoperative embolization is not totally effective. Surgical technique, proper anesthesia, and patient clotting capacity are important factors to consider. PMID- 29286971 TI - Limitation of Knee Flexion by a Fibrotic Band of a Fifth Component of the Quadriceps Muscle in a Child: A Case Report. AB - CASE: We describe the case of a 3-year-old boy who presented with limited flexion in the left knee. High-resolution magnetic resonance imaging allowed visualization of a fibrotic muscle band in the anatomic position of the fifth component of the quadriceps muscle, which was confirmed by surgical findings. After surgical resection, the patient achieved full recovery of range of motion of the knee. CONCLUSION: To our knowledge, this is the first reported case of a fibrotic muscle band in the anatomic position of a previously described fifth accessory component of the quadriceps muscle that caused limited knee flexion in a child. PMID- 29286972 TI - Delayed Bone Infarct in the Ilium Following a Pelvic Crush Injury and Embolization: A Case Report. AB - CASE: We present a case of delayed osteonecrosis of the ilium. After receiving embolization and multiple orthopaedic procedures following a complex pelvic crush injury, the patient subsequently developed posterior pelvic pain and tenderness over the posterior superior iliac spine, along with pain on sacroiliac joint compression. Magnetic resonance imaging of the pelvis demonstrated a bone infarction in the left ilium adjacent to the sacroiliac joint. CONCLUSION: The symptoms from osteonecrosis of the ilium may simulate sacroiliitis or other conditions. It is important to keep the differential diagnosis in mind when considering additional management for posterior pelvic pain in the setting of prior trauma and preexisting hardware. PMID- 29286973 TI - A Collision Tumor Involving a Primary Leiomyosarcoma of the Lower Extremity and a Metastatic Medullary Thyroid Carcinoma: A Case Report. AB - CASE: A 49-year-old man presented with a rapidly growing thigh mass. Histologic analyses demonstrated separate regions that were consistent with a collision tumor composed of a primary leiomyosarcoma and a metastatic medullary thyroid carcinoma. After responding to chemotherapy, the patient underwent resection of the tumor and a total thyroidectomy; he was disease-free 9 years after the diagnosis. CONCLUSION: A wide diagnostic differential and thorough histologic analysis are necessary in patients presenting with neoplasms of the extremities. A leiomyosarcoma may be a hospitable location for metastatic disease, and the presence of a collision tumor should be considered when pathology findings are equivocal. PMID- 29286974 TI - A Combined Distal Tibial Turn-up Plasty and Intercalary Calcaneal Osteocutaneous Fillet Flap for Salvage of a Transtibial Amputation: A Case Report. AB - CASE: This case demonstrates the successful attempt at a combined distal tibial turn-up plasty and intercalary calcaneal osteocutaneous fillet flap to increase functional limb length in order to salvage a transtibial amputation following a high-energy blast injury. CONCLUSION: A transtibial amputation is preferred over more proximal levels of amputation because of the decreased energy expenditure that is required for ambulation. In cases where there is not enough viable tibia to allow for a transtibial level of amputation, combining a calcaneal osteocutaneous fillet flap with a distal tibial turn-up plasty can be utilized to optimize residual limb length for a transtibial amputation. PMID- 29286975 TI - A 75-Year-Old Man with Progressive Generalized Erythroderma and History of Anaplastic Large Cell Lymphoma: Answer. PMID- 29286976 TI - Palpable Purpura in a Boy With Abdominal Pain: Answer. PMID- 29286977 TI - Multiple Hybrid Cysts in a Child: Answer. PMID- 29286978 TI - Multiple Scattered Purpuric Vesicles: Challenge. PMID- 29286979 TI - Palpable Purpura in a Boy With Abdominal Pain: Challenge. PMID- 29286980 TI - Multiple Hybrid Cysts in a Child: Challenge. PMID- 29286981 TI - Age-Related Changes in Postural Control in Physically Inactive Older Women. AB - BACKGROUND AND PURPOSE: The maintenance of postural control is influenced by the complexity of a given task. Tasks that require greater attention and cognitive involvement increase the risk of falls among older adults. The aim of the present study was to evaluate the adaptation of the postural control system to different levels of task complexity in physically inactive young and older women. METHODS: A cross-sectional study was conducted with adult women classified as physically inactive based on the results of the International Physical Activity Questionnaire. The participants were 27 young (20-30 years of age) and 27 older (60-80 years of age) women. Sway velocity of the center of pressure in the anterior-posterior and medial-lateral directions was calculated using a force plate under 6 conditions: standing directly on the force plate or on a foam placed over the force plate, eyes open or closed, and task complexity with and without the foam. RESULTS AND DISCUSSION: A 2-way analysis of variance revealed that sway velocity increased in both groups when the task conditions were altered. The older women exhibited significantly greater sway velocity compared with the young women on all tasks. However, the patterns of postural control adaptation to the different levels of complexity were similar among all participants. CONCLUSIONS: In this study, the adaption of the postural control system to different levels of task complexity did not differ between physically inactive young and physically inactive older women. However, the physically inactive older women exhibited greater sway velocity compared with the young women. PMID- 29286982 TI - Concurrent Validity of the Zeno Walkway for Measuring Spatiotemporal Gait Parameters in Older Adults. AB - BACKGROUND AND PURPOSE: Previous studies have shown that older adults at high fall risk exhibit altered spatiotemporal gait parameters such as lesser gait speed, shorter step length, and greater step width compared with their healthy counterparts. Measurement of these gait parameters for older adults can play a pivotal role in clinical evaluation. While the GAITRite walkway has been previously validated and used extensively for research purposes, the Zeno walkway validity has not been established. Although both walkways use pressure sensor based technology, comparison of the spatiotemporal gait measurements between the systems for older adults is unknown. Our purpose was to determine the concurrent validity of the Zeno walkway with the gold-standard GAITRite walkway among healthy older adults and those at high fall risk using a cross-sectional study design. METHODS: Thirty healthy older adults and 17 older adults at high fall risk performed 5 walking trials barefoot on a 16' * 4' Zeno walkway and a 14' * 2' GAITRite walkway in a quasirandomized order. Testing on the Zeno walkway was performed in a continuous manner while testing on the GAITRite walkway was performed using 5 discrete trials. Walking trials were done at self-selected comfortable and fast pace conditions. Data from the Zeno walkway were processed using the PKMAS software. Data from the GAITRite were processed using the GAITRite software. For each group and condition, spatiotemporal gait parameters common to both walkways' footfall processing software were compared using a Wilcoxon signed rank test. Concurrent validity was estimated using intraclass correlation coefficient (ICC(2,5)) and Bland-Altman plots. RESULTS AND DISCUSSION: Both groups had significantly greater stride width on the GAITRite walkway during both conditions. During the fast pace condition, both groups walked with greater gait speed, cadence, and stride velocity, lesser step time, stance time, and double-support time, greater percentage of gait cycle spent in single-support phase, and lesser percentage of gait cycle spent in double-support phase on the GAITRite walkway. Differences observed could be attributed to surface textures, software used to process the footfalls, dimensions of the walkways, or the continuous versus discrete protocols used in the current study. The ranges of ICC(2,5) values for healthy older adults and adults at high fall risk walking at a comfortable pace were 0.449 to 0.918 and 0.854 to 0.969 and at a fast pace were 0.784 to 0.964 and 0.850 to 0.976, respectively. These values imply that the concurrent validity was moderate for most temporal parameters when healthy older adults walked at comfortable pace and excellent otherwise. Overall, the concurrent validity between both walkways was acceptable. CONCLUSION: Concurrent validity for spatiotemporal parameters between the GAITRite walkway and the Zeno walkway was moderate to excellent for older adults dependent on the specific parameter (spatial vs temporal), population (healthy or fall risk), and walking pace (comfortable or fast). PMID- 29286984 TI - Mental Health Service Use Among Youth with Autism Spectrum Disorder: A Comparison of Two Age Groups. AB - OBJECTIVE: Although youth with autism have elevated rates of mental health problems compared to typically developing youth, little is known about the mental health services that they receive. The current study examines predisposing, enabling, and clinical need factors as they relate to mental health service use in youth with autism. METHODS: The current study surveyed parents of 2337 children and adolescents with autism, compared their access to behavioral management and mental health treatment (MHT), and isolated the correlates of such receipt. RESULTS: Children used behavioral management more than adolescents, whereas the opposite was true for MHT. Mental health treatment receipt was associated with caregiver-related and mental health problems in both age groups, with routine health service use in children and with behavioral problems in adolescents. Behavioral management was correlated with caregiver-related services and behavioral problems in both age groups, and with sex and intellectual disability in adolescents. CONCLUSION: Clinical needs and caregiver service use are consistently associated with mental health care across ages, whereas the role of youth characteristics is particularly relevant when considering service use for adolescents. PMID- 29286983 TI - Aerobic Exercise Sustains Performance of Instrumental Activities of Daily Living in Early-Stage Alzheimer Disease. AB - BACKGROUND AND PURPOSE: Individuals with Alzheimer disease (AD) experience progressive loss of independence-performing activities of daily living. Identifying interventions to support independence and reduce the economic and psychosocial burden of caregiving for individuals with AD is imperative. The purpose of this analysis was to examine functional disability and caregiver time in individuals with early-stage AD. METHODS: This was a secondary analysis of a randomized controlled trial of 26 weeks of aerobic exercise (AEx) versus stretching and toning (ST). We measured functional dependence using the Disability Assessment for Dementia, informal caregiver time required using the Resources Utilization in Dementia Lite, and cognition using a standard cognitive battery. RESULTS: We saw a stable function in the AEx group compared with a significant decline in the ST group (4%; F = 4.2, P = .04). This was especially evident in more complex, instrumental activities of daily living, with individuals in the AEx group increasing 1% compared with an 8% loss in the ST group over 26 weeks (F = 8.3, P = .006). Change in memory was a significant predictor of declining instrumental activities of daily living performance (r = 0.28, 95% confidence interval = 0.08 infinity, P = .01). Informal caregiver time was not different between the AEx and ST groups. CONCLUSIONS: Our analysis extends recent work by revealing specific benefits for instrumental activities of daily living for individuals in the early stages of AD and supports the value of exercise for individuals with cognitive impairment. PMID- 29286985 TI - Trends in oral and vaginally administered estrogen use among US women 50 years of age or older with commercial health insurance. AB - OBJECTIVE: We aimed to provide information through 2015 about use in the United States of estrogen products, including orally and vaginally administered products, in postmenopausal women. METHODS: We used prescription claims for US commercial health insurance to calculate, in women 50 years of age or older (n = 12,007,364), the age-standardized and age-specific annual prevalence of estrogen use, by formulation and route of administration, for the period 2006 through 2015. RESULTS: The age-standardized annual prevalence of a prescription claim for oral estrogens declined over time, from 83 per 1,000 women in 2007 to 42 per 1,000 women in 2015. The age-standardized annual prevalence of a prescription claim for vaginal estrogens peaked in 2011, at 42 per 1,000 women, before declining to 35 per 1,000 women in 2015. The age-standardized annual prevalence of a prescription claim for transdermal estrogen fluctuated between 15 and 17 per 1,000 women. In age groups under 65 years of age, annual prevalence rates for vaginal rings and inserts declined over the latter half of the study period. CONCLUSIONS: Analyses of US prescription claims data between 2006 and 2015 for women 50 years of age or older showed declining use of oral estrogen generally and vaginally administered estrogen products specifically in age groups less than 65 years of age. PMID- 29286986 TI - Fractional microablative CO2 laser in breast cancer survivors affected by iatrogenic vulvovaginal atrophy after failure of nonestrogenic local treatments: a retrospective study. AB - OBJECTIVE: Vulvovaginal atrophy (VVA) is a condition frequently observed in menopause. Its symptoms can significantly affect the quality of life of patients. Since VVA is related to estrogen deficiency, chemotherapy and hormone therapy for breast cancer (BC) might cause VVA by inducing menopause. Given the lack of effective treatment for VVA in BC survivors, we retrospectively evaluated the efficacy and tolerability of fractional microablative CO2 laser therapy in these patients. METHODS: We treated 82 BC survivors with three cycles of CO2 laser after failure of topical nonestrogenic therapy. The severity of symptoms was assessed with a visual analog scale (VAS) at baseline and after completion of laser therapy. Differences in mean VAS scores of each symptom before and after treatment were assessed with multiple t tests for pairwise comparisons. Multivariate analyses were used to adjust the final mean scores for the main confounding factors. RESULTS: Pre versus post-treatment differences in mean VAS scores were significant for sensitivity during sexual intercourse, vaginal dryness, itching/stinging, dyspareunia and dysuria (P < 0.001 for all), bleeding (P = 0.001), probe insertion (P = 0.001), and movement-related pain (P = 0.011). Multivariate analyses confirmed that results were significant, irrespective of patients' age and type of adjuvant therapy. CONCLUSION: This study shows that CO2 laser treatment is effective and safe in BC patients with iatrogenic menopause. However, the optimal number of cycles to administer and the need for retreatment remain to be defined. Prospective trials are needed to compare CO2 laser therapy with therapeutic alternatives. PMID- 29286987 TI - A systematic review of intravaginal testosterone for the treatment of vulvovaginal atrophy. AB - OBJECTIVES: Intravaginal testosterone has emerged as a potential treatment for vulvovaginal atrophy (VVA) in women, in general, and women taking an aromatase inhibitor (AI). A systematic review of the literature was undertaken to determine whether available clinical trial data support efficacy and safety of intravaginal testosterone for the treatment of VVA. METHODS: Scopus, MEDLINE, EMBASE, and the Cochrane Library databases were systematically searched on July 26, 2017, for human studies published in English of clinical trials of intravaginal testosterone. RESULTS: Six separate clinical trials were identified that ranged in size from 10 to 80 participants, with either single dose, or durations of 4 to 12 weeks. Only one study incorporated a double-blind design. Three studies were of women taking an AI.Taken together, the studies suggest that intravaginal testosterone may lower vaginal pH, increase the proportion of vaginal lactobacilli, and possibly improve the vaginal maturation index. The lack of a placebo treatment in four studies, and failure to adjust for baseline differences, resulted in uncertainty of the effect on sexual function. Safety remains uncertain because of the small number of women exposed, short study durations, and inconsistent and incomplete outcome reporting for sex steroid levels. CONCLUSION: Adequately powered double-blind, placebo-controlled clinical trials of intravaginal testosterone therapy are needed to establish both efficacy and safety. PMID- 29286989 TI - Effects of a Cognitive Behavioral-Based Stress Management Program on Stress Management Competency, Self-efficacy and Self-esteem Experienced by Nursing Students. AB - Nursing students' exposure to stress negatively affects both academic and clinical performance and potentially their future as professional nurses. This pilot study measured the effects of a 10-week cognitive behavioral therapy-based stress management program, using a quasi-experimental design. Independent t tests showed positive effects of the training program compared with a control group. Students' perceived stress management competency, self-efficacy, and self-esteem were higher 1 year after the intervention. PMID- 29286988 TI - Cardiovascular and metabolic morbidity after hysterectomy with ovarian conservation: a cohort study. AB - OBJECTIVE: The aim of the study was to determine the long-term risk of cardiovascular disease and metabolic conditions in women undergoing hysterectomy with bilateral ovarian conservation compared with age-matched referent women. METHODS: Using the Rochester Epidemiology Project records-linkage system, we identified 2,094 women who underwent hysterectomy with ovarian conservation for benign indications between 1980 and 2002 in Olmsted County, Minnesota. Each woman was age-matched (+/-1 y) to a referent woman residing in the same county who had not undergone prior hysterectomy or any oophorectomy. These two cohorts were followed historically to identify de novo cardiovascular or metabolic diagnoses. We estimated hazard ratios (HRs) and 95% CIs using Cox proportional hazards models adjusted for 20 preexisting chronic conditions and other potential confounders. We also calculated absolute risk increases and reductions from Kaplan-Meier estimates. RESULTS: Over a median follow-up of 21.9 years, women who underwent hysterectomy experienced increased risks of de novo hyperlipidemia (HR 1.14; 95% CI, 1.05-1.25), hypertension (HR 1.13; 95% CI, 1.03-1.25), obesity (HR 1.18; 95% CI, 1.04-1.35), cardiac arrhythmias (HR 1.17; 95% CI, 1.05-1.32), and coronary artery disease (HR 1.33; 95% CI, 1.12-1.58). Women who underwent hysterectomy at age <=35 years had a 4.6-fold increased risk of congestive heart failure and a 2.5-fold increased risk of coronary artery disease. CONCLUSIONS: Even with ovarian conservation, hysterectomy is associated with an increased long term risk of cardiovascular and metabolic conditions, especially in women who undergo hysterectomy at age <=35 years. If these associations are causal, alternatives to hysterectomy should be considered to treat benign gynecologic conditions. PMID- 29286990 TI - Self-directed Learning Readiness Is Independent of Teaching and Learning Approach in Undergraduate Nursing Education. AB - Selecting appropriate teaching and learning strategies within an overarching teaching philosophy is 1 way of influencing nursing students' self-directedness. We conducted research to compare the self-directed learning readiness and learning attributes in different years of study of undergraduate nursing students who are exposed to traditional, lecture-based learning and problem-based learning strategies. We found that readiness for self-directed learning is not dependent on the dominant teaching-learning strategy used in the nursing program. PMID- 29286991 TI - Making Connections: An Innovative Seminar to Foster Integrative Learning. PMID- 29286992 TI - Preceptorship in a Nurse Practitioner Program: The Student Perspective. AB - Preceptorship has been identified as an effective strategy for facilitating clinical learning among diverse health care professionals. The benefits of preceptored experiences are well documented; however, the preceptorship model is also vulnerable to challenges. There has been limited evaluation of preceptorship with nurse practitioner (NP) students. This article describes an evaluation of the preceptorship experience from the perspective of NP students. In particular, the facilitators and barriers to clinical learning are described. PMID- 29286993 TI - Three-Dimensional Bioprinting Can Help Bone. PMID- 29286994 TI - The Effect of Midface Advancement Surgery on Obstructive Sleep Apnoea in Syndromic Craniosynostosis. AB - BACKGROUND: Children with syndromic craniosynostosis frequently suffer from obstructive sleep apnoea (OSA). The aim of the authors' study was to investigate if midface advancement surgery for patients with SC improved the severity of OSA by examining the results of sleep studies before and after surgery. METHODS: A retrospective comparison of the pre and postoperative sleep study data of children undergoing midface advancement surgery at Great Ormond Street Hospital between 2007 and 2016. RESULTS: A total of 65 children underwent midface advancement surgery between 2007 and 2016 at Great Ormond Street Hospital and had recorded pre- and postoperative sleep studies. Thirteen patients were excluded from the analysis as their sleep study techniques before and after surgery were not comparable (e.g., different conditions with prong/continuous positive airway pressure use). Fifty-six percent of the patients were treated by monobloc surgery and the remainder with bipartition surgery. A greater proportion of patients had a normal OSA grading following midface advancement (42.3% postoperatively vs. 23.1% preoperatively, P = 0.059) although no statistically significant categorical changes in OSA grade were observed. Seventy-one percent of the patients had a decrease in Apnoea-Hypopnoea Index after surgery (21 patients 2011 onward). Similarly, there was no significant change in median oxygen desaturation index or in oxygen saturation nadir following surgery. CONCLUSION: The authors report one of the largest reviews of the effects of midface advancement surgery on sleep study parameters. Most patients showed improvements in Apnoea-Hypopnoea Index and OSA grading, although measures of oxygenation showed no consistent change. PMID- 29286995 TI - The Americleft Project: Comparison of Ratings Using Two-Dimensional Versus Three Dimensional Images for Evaluation of Nasolabial Appearance in Patients With Unilateral Cleft Lip and Palate. AB - This study was conducted to determine if nasolabial appearance is rated with comparable results and reliability on 3-dimensional stereophotogrammetric facial images versus standard clinical photographs (2-dimensional). Twenty-seven consecutively treated patients with repaired complete unilateral cleft lip and palate were selected. Six trained and calibrated raters assessed cropped 2- and 3 dimensional facial images. Nasolabial profile, nasolabial frontal, and vermillion border esthetics were rated with the 5-point scale described by Asher-McDade using the modified Q-sort method. Cropped 3-dimensional images were available for viewing by each rater, allowing for complete rotational control for viewing the images from all aspects. Two- and three-dimensional ratings were done separately and repeated the next day.Interrater reliability scores were good for 2 dimensional (kappa = 0.607-0.710) and fair to good for 3-dimensional imaging (kappa = 0.374-0.769). Intrarater reliability was good to very good for 2 dimensional (kappa = 0.749-0.836) and moderate to good for 3-dimensional imaging (kappa = 0.554-0.855). Bland-Altman analysis showed satisfactory agreement of 2- and 3-dimensional scores for nasolabial profile and nasolabial frontal, but more systematic error occurred in the assessment of vermillion border.Although 3 dimensional images may be perceived as more representative of a direct clinical facial evaluation, their use for subjective rating of nasolabial aesthetics was not more reliable than 2-dimensional images in this study. Conventional 2 dimensional images provide acceptable reliability while being readily accessible for most cleft palate centers. PMID- 29286996 TI - Computer-Aided Freehand Maxillary Repositioning. AB - The authors aimed to test the hypothesis that in orthognathic surgery the maxilla could be repositioned using spatial distances from Glabella to 3 maxillary dental landmarks as references. An asymmetric skeletal Class 3 malocclusion patient was involved and bimaxillary orthognathic surgery was planned. Virtual surgery was simulated and spatial distances from Glabella to midpoint of the upper dentition (U0) and bilateral medial-buccal cusp of the first molar (6L and 6R) were measured. These distances were used as the repositioning references and were imported intraoperatively into a digital caliper after the maxilla was mobilized, the repositioning of maxilla was manipulated till all the true spatial distances reached the references. Postoperative computed tomography head model were superimposed onto the planned head model, the maxillary repositioning error was assessed using spatial distances between the pre- and postoperative dental landmarks. The asymmetric skeletal Class 3 malocclusion was corrected through bimaxillary surgery and the errors at U0, 6R and 6L was 1.37, 1.79, and 1.45 mm. The maxilla could be repositioned using spatial distances from Glabella to 3 maxillary dental landmarks as references. PMID- 29286997 TI - Microvascular Decompression for Trigeminal Neuralgia Due to Venous Compression Alone. AB - Microvascular decompression (MVD) has been confirmed as an effective treatment of trigeminal neuralgia (TN); however, most previous reports just focused on MVD for TN caused by arterial conflict, there is a paucity of information about its use in venous compression causing TN. In the present study, the authors summarize 5 year experience of MVD for primary TN due to venous compression alone. Thirty four patients with primary TN caused solely by veins underwent MVD. The presenting symptoms, key operative notes, surgical outcomes together with complications were reviewed. Of all the 34 patients, 19 (55.9%) patients occurred as typical TN. The V2 division was the most commonly affected area. Most of the venous conflicts were grade III (20/34, 58.8%). Deep superior petrosal venous system was the most frequent offending vessel (21/34, 61.8%). The venous conflicts were located at the trigeminal root entry zone in 10 (29.4%) patients, the mid cisternal zone in 18 (52.9%) patients, and the porus of Meckel's cave in 11 (32.4%) patients. At the last follow-up, excellent outcome was obtained in 26 (76.5%) patients, 7 (20.6%) patients got good outcome, fair outcome was achieved in 7 (20.6%) patients, and 1 patient unimproved (2.9%). Cerebrospinal fluid leakage was the most common complication (5.9%). In conclusion, MVD is a safe and effective surgical option for TN due to venous compression alone. It is noteworthy to explore the entire nerve and to protect veins as much as possible. PMID- 29286998 TI - Endoscopic Repairs of Sinonasal Cerebrospinal Leaks: Outcome and Prognostic Factors. AB - OBJECTIVE: The aim of this study was to review the management of sinonasal cerebrospinal fluid (CSF) leaks and outcome of endoscopic repairs and to provide experience regarding leaks at the lateral wall of sphenoid sinus and the posterior wall of frontal sinus. METHODS: Patients who underwent endoscopic repairs of CSF leaks were reviewed. Characteristics of different etiologies were compared, and prognostic factors were analyzed. RESULTS: The study included 144 patients with 150 CSF leaks, in which spontaneous leaks account for 55%. Patients with traumatic leaks were significantly younger than those with spontaneous leaks (P = 0.012), and most traumatic leaks occurred in men (P < 0.001). The computed tomography scan showed an overall accuracy of 86.7%. For 17 leaks at the lateral wall of sphenoid sinus, transnasal (29%), transethmoid (24%), and transpterygoid (47%) approaches were used, with a success rate of 75%. For 11 defects at the posterior wall of the frontal sinus, 2 were managed by draf III surgery, and 3 by trephination-assisted procedure successfully. Success rate for primary repair was 95.6%, reaching 100% after a second repairing. Six leaks failed to be repaired included 4 spontaneous leaks, and 3 occurred at the lateral wall of the sphenoid sinus, 4 occurred in patients with elevated body mass index (BMI), 4 had evidence of raised intracranial pressure (ICP). CONCLUSION: Repair of leaks at lateral sphenoid sinus and posterior frontal sinus could achieve favorable results via selected endoscopic approaches. The failure of repair was associated with inaccessible leak sites, spontaneous leaks, raised ICP, and elevated BMI. PMID- 29286999 TI - Comprehensive Evaluation of Visual Function in Patients With Orbital Fracture by Visual Electrophysiology and Visual Field Examination. AB - OBJECTIVE: At present, the effect of the visual electrophysiology and vision field examination in patients with orbital blowout fracture is rarely studied. So, the authors investigate the value of visual electrophysiology and vision field examination in the diagnosis of ocular contusion. METHODS: The position and range of fracture of 81 patients were determined by computed tomography (CT) scanning. Visual evoked potential (VEP), electroretinogram (ERG), and mfERG were vision field examination detected in 81 patients and the results were compared with those of contralateral healthy eyes. In addition, visual electrophysiology and vision field examination in diagnosis of eye contusion was analyzed and the correlation of the VEP, ERG, mfERG injury duration, and visual acuity was further analyzed. RESULTS: The visual acuity of orbital fractures was significantly decreased compared with that in the uninjured eyes (t = 2.181, P = 0.032). Compared injured eyes and normal eyes in 54 patients, b wave of Max-ERG and Cone ERG implied value extension (t = -2.426, P = 0.025; t = -2.942, P = 0.014), P-VEP P100 Peak duration and amplitude significantly extended (t = 3.162, P = 0.007; t = 9.314, P = 0.000), and F-VEP P1 amplitude decreased significantly (t = 3.362, P = 0.004). mfERG showed that the injured eye central reaction was significantly decreased (t = 8.727, P = 0.000). There was a significant correlation between P VEP P100 amplitude and visual acuity (r = 0.067, P = 0.000). But there was no significant correlation between the P100 peak value, amplitude of P-VEP, mfERG central reaction, and injured days, respectively. There was significant difference between 2 groups with average visual acuity and mean defect value (t = 3.253, 3.461, P = 0.006, 0.003). There was statistical means the difference in P VEP abnormal group, visual field abnormal group, and combined detection abnormal groups, the abnormal rate increased significantly (chi = 3.931, P < 0.01). CONCLUSION: Orbital floor fracture can lead to optic nerve damage and also may be associated with decreased macular function. The combination analysis of visual electrophysiology and vision field examination is beneficial to early diagnosis of ocular trauma and can improve the positive rate in clinic practice. PMID- 29287000 TI - An Applied Anatomical Study of the Ethmoidal Arteries: Computed Tomographic and Direct Measurements in Human Cadavers. AB - Computed tomography (CT) images have been used in very few studies on distances to the ethmoidal arteries in the orbit. Most other studies have included direct measurements on cadavers and frequently quote the 24-12-6 mm rule to describe distances from the anterior lacrimal crest to the anterior and posterior ethmoidal foramina (AEF and PEF), optic canal (OC), respectively. However, the large interindividual variation of distances renders absolute values less applicable in a clinical setting. Preoperative measurements on CT images may provide more precise distances than absolute rules and thus lead to safer orbital surgery. The authors hypothesize that the distances to the ethmoidal arteries and the length of the medial wall are positively correlated and that measurements of the distances from the posterior lacrimal crest (PLC) on CT images are feasible with a low intra- and interobserver variability.Fifty intact orbits from 25 Caucasian cadavers were exenterated and examined. In additional, high-resolution CT scans of 48 orbits from 24 other Caucasian nonexenterated cadavers were examined. Distances were measured from 4 different anterior landmarks to the AEF and PEF and the OC.Distances from the most anterior landmarks to the arteries were positively correlated with the length of the medial wall. Measurements of the distances from the PLC to the ethmoidal arteries on CT images were feasible with a low intra- and interobserver variability. In conclusion, iatrogenic damage to the ethmoidal arteries in the orbit may be best avoided by using CT measurements in presurgical planning. PMID- 29287001 TI - Optimal Conditions for Absorbable Fixation of Hydroxyapatite Ceramic Implants. AB - Synthetic hydroxyapatite (HAP) implants are common in craniofacial surgery; the major problem with HAP implants is fixation instability. An ultrasound-assisted pinned resorbable fixation system has recently been introduced. The authors hypothesized that this resorbable system could be used to fix HAP implants. The authors evaluated the optimal HAP porosity and resorbable pin using the pull-out test and microscopic analysis. Hydroxyapatite blocks were synthesized with 0% (dense type), 35% (fine pore type), and 50% (large pore type) porosity. Bioabsorbable pins of 4 sizes were tested: diameters of 1.6 or 2.1 mm and lengths of 4 or 7 mm. Among the 1.6 mm diameter pins, the 7-mm length pins showed higher pull-out strength (large pore, 6.5 +/- 1.2 kgf; fine pore, 4.1 +/- 0.7 kgf; dense, 2.4 +/- 0.4 kgf) than the 4-mm length pins (large pore, 2.1 +/- 1.0 kgf; fine pore, 1.3 +/- 0.4 kgf; dense, 1.5 +/- 0.9 kgf) with all 3 HAP types (P < 0.01). Among 2.1-mm diameter pins, all were removed from the large and fine pore HAP types without any resistance. Only three of seven 2.1 * 7 mm pins inserted into the dense type HAP showed pull-out strength (3.9 +/- 2.1 kgf). Among all conditions, the 7-mm length, 1.6-mm diameter pin in large pore type HAP showed the highest pull-out strength. Microscopically, the large pore type HAP showed the liquefying pin flowing into the large pore adjacent to the pilot hole. By contrast, the fine pore and dense pore types of HAP did not allow flow, and the pins did not change in structure 3-dimensionally. The authors found that pull-out strength depends on HAP porosity, and pin length and diameter. PMID- 29287004 TI - Non-invasive Markers of Portal Hypertension: Appraisal of Adult Experience and Potential Utilisation in Children. AB - Portal hypertension (PHT) is a significant cause of morbidity and mortality in children with chronic liver disease and portal vein obstruction. Increased portal pressure results in variceal formation along the gastrointestinal (GI) tract resulting in major bleeding. Identifying children with significant PHT who are more likely to suffer GI bleeding has been challenging and the role of surveillance upper GI endoscopy has been debated. This review analyses research done on serum biomarkers and imaging techniques as possible predictors of significant PHT. We evaluated the research performed on adult population, as well as the limited work done on children, to identify promising areas for future research. A literature search was conducted on "PubMed." Several search terms were used including "portal hypertension," "paediatric portal hypertension," "non invasive markers of portal hypertension," "spleen stiffness," "liver stiffness," "elastography," and "endothelial damage." The articles included were selected based on their relevance to the purpose of our review. The research suggests a combination of several biomarkers, in addition to an imaging technique such as transient elastography or magnetic resonance elastography, would allow for the best prediction of significant varices. The most promising indicators would be those that are applicable in both intra- and extra-hepatic causes of PHT. Further research on these predictors in children with PHT is required to determine their potential role as selection criteria for PHT and stratification of surveillance GI endoscopies. PMID- 29287003 TI - Magnetic Resonance Imaging Findings in Neonatal Hemochromatosis. AB - BACKGROUND: There are limited data on utility of magnetic resonance imaging (MRI) in the assessment of suspected neonatal hemochromatosis (NH). OBJECTIVES: The aim of the study was to present our experience with utilization of multi-echo sequence MRI technique in the evaluation of NH and to compare MRI findings in infants with and without NH. METHODS: MRI performed for suspected NH were retrospectively reviewed to note the presence and severity of iron deposition (ID) in liver, spleen, pancreas, and kidneys on multi-echo sequences. Findings were compared in infants with and without NH. RESULTS: Of 20 infants (9 boys and 11 girls; median age of 12.5 days) included in the study, 7 of 20 had NH and 13 of 20 were assigned to the non-NH group. Higher degree of pancreatic ID was seen in the NH group (P = 0.001) with 4 of 7 evaluable pancreas showing moderate-to severe degree and 1 of 7 showing mild degree of ID whereas none of the 13 infants in non-NH group showed moderate or severe degree of pancreatic ID. Even though the severity of hepatic ID was higher in NH group (P = 0.033), variable severity of hepatic ID was seen in both groups with most infants in both groups showing moderate-to-severe degree of ID. The severity of splenic ID was not particularly associated with any group (P = 0.774) but there was no moderate or severe degree of ID in NH. Renal ID was seen in two infants in non-NH group. CONCLUSIONS: A moderate-to-severe degree of pancreatic ID seen on MRI tends to be associated with NH and should be sought to establish a timely diagnosis of NH. Presence and severity of hepatic ID cannot be used for differentiation of NH from other causes of neonatal liver failure. PMID- 29287005 TI - Polycystic Pancreas Disease. PMID- 29287006 TI - Hyperadiponectinemia During Infliximab Induction Therapy in Pediatric Crohn Disease. AB - OBJECTIVES: The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD. METHODS: Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (MUg/mL) were assessed by enzyme linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 +/ 1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 +/- 1.6 years). RESULTS: At baseline, CD patients (mean age 15.0 +/ 1.5 years, 10 of 18 boys) compared with HC (13.4 +/- 1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5 14.5); P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6; P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2; P = 0.0156) and 17.2 ng/mL (10.8- 26.8; P = 0.1953) at weeks 0, 2, and 14 respectively; with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6; P = 0.0840) and 3.3 (1.3-4.6; P = 0.1309). Adiponectin peaked initially from 7.8 MUg/mL (4.6-11.9) at week 0 to 9.2 MUg/mL (4.1-20.7; P = 0.0005) at week 2 and thereafter fell to 6.5 MUg/mL (3.0 12.7; P = 0.0182) at week 14. CONCLUSIONS: TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti inflammatory adiponectin may contribute to the rapid response to IFX in CD. PMID- 29287007 TI - Bone Mineral Density of Very Long-term Survivors After Childhood Liver Transplantation. AB - OBJECTIVES: Liver transplant patients are at risk of osteopenia and fractures but limited information is available in long-term survivors after childhood transplantation. This study aimed to assess bone mineral density (BMD) of very long-term, >5 years, survivors after liver transplantation in childhood. METHODS: Patients aged <18 years at transplant, having survived >5 years after transplant were potentially eligible but only those with ongoing review in our state were included. Dual-energy x-ray absorptiometry (DXA) was used to measure BMD. Patients aged <20 years had lumbar spine (LS) and total body (TB) measurements whereas those aged 20 years or more had LS and femoral neck but not TB. BMD z scores for LS and TB, if available, were used in this study. BMD z-score <=-2.0 was considered reduced. Pre-pubertal children had radiologic bone age assessment. RESULTS: Forty-two patients, 17 boys, participated of whom 64% had biliary atresia. Median age at transplant was 2.22 (range 0.38-14.25) years; time since transplant 10.10 (5.01-25.98) years; and age at DXA 14.64 (6.59-38.07) years. Mean BMD z-scores were LS -0.15 +/- 1.07, and TB -0.76 +/- 1.14, with no sex difference noted. Four (9.5%) patients had reduced LS BMD, and although ongoing steroid use was more frequent in these patients, other comorbidities were likely important. Age at transplant, time since transplant, height, weight, and body mass index at DXA did not predict LS BMD. Pathologic fractures occurred in 2 of 42 (5%) patients; all within 18 months of transplant. CONCLUSIONS: Very long-term survivors after childhood liver transplant have LS BMD within the normal range. PMID- 29287008 TI - Prevalence of Anti-tissue Transglutaminase Antibodies and Celiac Disease in Children With Inflammatory Bowel Disease. AB - OBJECTIVES: Celiac disease can occur in children with inflammatory bowel disease (IBD) and poses a diagnostic challenge. We evaluated the presence of anti-tissue transglutaminase (tTG) antibodies and celiac disease among children with IBD. METHODS: In a retrospective chart review, we assessed the prevalence of tTG antibodies and celiac disease and compared with a control group of children with gastrointestinal symptoms without IBD. RESULTS: Study population included 130 children with IBD and 257 in the control group. Abnormal tTG levels were found in 6 and 20 patients, respectively (4.6% vs 7.8%, P = 0.24). One patient with IBD and 12 in the control group had celiac disease (0.8% vs 4.7%, P = 0.07). CONCLUSIONS: False-positive tTG can occur in children with IBD. The prevalence of celiac disease is not increased in children with IBD compared with non-IBD children with gastrointestinal symptoms and is similar to that in the general population. PMID- 29287009 TI - Adherence to the Gluten-free Diet and Health-related Quality of Life in an Ethnically Diverse Pediatric Population With Celiac Disease. AB - OBJECTIVES: Celiac disease (CD) is an autoimmune disease that requires lifelong adherence to a gluten-free diet (GFD). Adherence to the GFD in childhood may be poor and adversely influence health-related quality of life (HRQOL). The study purpose was to determine sociodemographic and socioeconomic factors influencing adherence to the GFD and HRQOL in a multiethnic cohort of youth with CD. METHODS: A multisite (Edmonton, Hamilton, Toronto) study examining child-parent HRQOL in youth with CD (n = 243) and/or mild gastrointestinal complaints (GI-CON; n = 148) was conducted. Sociodemographic (age, child-parental age/education/ethnicity/place of birth), anthropometric (weight, height, body mass index), disease (diagnosis, age at diagnosis, duration, Marsh score, serology), household characteristics (income, family size, region, number of children/total household size), HRQOL (Peds TM/KINDL and Celiac Disease DUX), GI Complaints (PedsQL: Gastrointestinal Symptom Scale) and gluten intake were measured. RESULTS: Younger age (<10 years), non-Caucasian ethnicity (parent/child), and presence of GI symptoms were associated with the highest rates of adherence to the GFD in CD children (P < 0.05). CD children (parent/child) had higher HRQOL (average, composite domains) than GI-CON (P < 0.05), but CD children were comparable to healthy children. Lack of GI symptoms, non-Caucasian ethnicity and age (<10 years) were associated with increased HRQOL in composite/average domains for CD (P < 0.05). CONCLUSIONS: Child-parent perceptions of HRQOL in a multiethnic population with CD are comparable to healthy reference populations, but significantly higher than in parent/child GI CON. Adherence to the GFD in ethnically diverse youth with CD was related to GI symptoms, age of the child, and ethnicity of the parent-child. PMID- 29287011 TI - Endoscopic Transesophageal Drainage of Mediastinal Pseudocyst in a Child. PMID- 29287010 TI - Electrogastrography, Near-infrared Spectroscopy, and Acoustics to Measure Gastrointestinal Development in Preterm Babies. AB - OBJECTIVES: The aim of the study was to obtain objective measures indicative of gastrointestinal maturity using 3 noninvasive technologies. METHODS: Electrogastrography (EGG), abdominal near-infrared spectroscopy (NIRS), and bowel sound/acoustics (AC) monitoring were used simultaneously to obtain physiologic measures of the gastrointestinal system of 18 preterm and 5 term neonates who were tolerating enteral feedings. Measures of EGG slow wave voltage (EGG dominant power) and AC signal amplitude (AC dominant power) were obtained after spectral density analysis. Mean abdominal regional saturations (A-rSO2) were obtained directly from NIRS. The relationship of these 3 measures with postmenstrual age (PMA) was assessed. RESULTS: The results of the 3 methods differed depending on whether the measurements were pre- or postprandial. Postprandial EGG dominant power increases with PMA (r = 0.67, P = 0.003), both pre- and postprandial abdominal NIRS mean regional saturation increase with PMA (r = 0.73, P < 0.001 and r = 0.55, P = 0.009), and postprandial AC dominant power (at 300-500 Hz) increases with PMA (r = -0.48, P = 0.025). CONCLUSIONS: EGG, abdominal NIRS, and AC, whenever used simultaneously, can provide objective and synergistic measures that correlate with PMA. These findings may be helpful in the assessment of feeding readiness because they reveal quantitative measures suggestive of the developmental process of the gut. PMID- 29287012 TI - Magnetic Resonance Enterography Cannot Replace Upper Endoscopy in Pediatric Crohn Disease: An Imagekids Sub-study. AB - OBJECTIVES: Although magnetic resonance enterography (MRE) can accurately reflect ileal inflammation in pediatric Crohn disease (CD), there are no pediatric data on the accuracy of MRE to detect upper gastrointestinal tract (UGI) lesions. We aimed to compare MRE and esophagogastroduodenoscopy (EGD) in detecting the spectrum and severity of UGI disease in children. METHODS: This is an ancillary study of the prospective multi-center ImageKids study focusing on pediatric MRE. EGD was performed within 2 weeks of MRE (at disease onset or thereafter) and explicitly scored by SES-CD modified for the UGI and physician global assessment. Local and central radiologists scored the UGI region of the MRE blinded to the EGD. Accuracy of MRE compared with EGD was examined using correlational coefficients (r) and area under receiver operating characteristic curves (AUC). RESULTS: One hundred and eighty-eight patients were reviewed (mean age 14 +/- 1 years, 103 [55%] boys); 66 of 188 (35%) children had macroscopic ulcerations on EGD (esophagus, 13 [7%]; stomach, 34 [18%]; duodenum, 45 [24%]). Most children had aphthous ulcers, but 10 (5%) had larger ulcers (stomach, 2 [1%]; duodenum, 8 [4%]). There was no agreement between local and central radiologists on the presence or absence of UGI inflammation on MRE (Kappa = -0.02, P = 0.71). EGD findings were not accurately detected by MRE, read locally or centrally (r = 0.03 to 0.11, P = 0.18-0.88; AUC = 0.47-0.55, P = 0.53-1.00).No fistulae or narrowings were identified on either EGD or MRE. CONCLUSIONS: MRE cannot reliably assess the UGI in pediatric CD and cannot replace EGD for this purpose. PMID- 29287013 TI - Non-invasive Assessment of Significant Dehydration in Infants Using the Inferior Vena Cava to Aortic Ratio: Is it Useful? AB - OBJECTIVES: The aim of the study was to assess the accuracy of the inferior vena cava to aorta (IVC/Ao) diameter ratio for predicting significant dehydration in infants relative to their percentage weight change and the clinical diagnosis by a physician. METHODS: A prospective observational study was performed on 200 infants presented with acute diarrhea and clinical evidence of significant dehydration whose treatment required intravenous (IV) fluids as determined by the attending physician at the pediatric emergency department of Tanta University Hospital. Weight was recorded at admission before IV fluid treatment and at hospital discharge. The percentage of dehydration was determined using the following formula: (discharge weight - admission weight)/discharge weight * 100%. Patients with a percentage weight change of <5% were considered to be nonsignificantly dehydrated, whereas patients with a percentage weight change >5% were considered significantly dehydrated. The IVC/Ao diameter ratio was measured for all patients before IV fluid rehydration and again at discharge. RESULTS: Only 134 out of 200 dehydrated infants were found to be significantly dehydrated using the gold standard, percentage weight change. Receiver operating characteristics (ROC) curve analysis of the prehydration IVC/Ao ratio showed a sensitivity of 82%, a specificity of 91%, and an accuracy of 87% for predicting significant dehydration in infants at a cut-off point of less than 0.75. In contrast, physician clinical diagnosis showed a sensitivity of 70%, a specificity of 63%, and an accuracy of 73%. CONCLUSIONS: The IVC/Ao diameter ratio can be used as a reliable predictor for diagnosing significant dehydration in infants. PMID- 29287014 TI - Treatment of Chronic Hepatitis C Virus Infection in Children: A Position Paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. AB - OBJECTIVES: In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12-17 years or weighing >35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children. METHODS: A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique. RESULTS: The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin. CONCLUSIONS: This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection. PMID- 29287015 TI - Diagnostic Tests in Pediatric Constipation. AB - Constipation is one of the most common gastrointestinal symptoms in children. With a median reported prevalence of 12%, it accounts for about 25% of all pediatric gastroenterology consultations. The majority of children experiences functional constipation and do not usually require any diagnostic testing. For those children not responding to conventional medical treatment or in the presence of a more significant clinical picture, however, an accurate instrumental assessment is usually recommended to evaluate either the underlying pathophysiologic mechanisms or a possible organic etiology. The present review analyzes the possible diagnostic investigations for severely constipated children, focusing on their actual indications and their utility in clinical practice. During the last decade, there has been a remarkable increase in our knowledge of normal and abnormal colonic and anorectal motility in children, and a number of different techniques to measure transit and motility have been developed and are discussed in this narrative review. PMID- 29287017 TI - Seroimmunity to Hepatitis B Virus in Children With Inflammatory Bowel Disease: Effects of Booster Vaccination. PMID- 29287016 TI - Seasonal Association of Pediatric Functional Abdominal Pain Disorders and Anxiety. AB - OBJECTIVES: Abdominal pain-related pediatric functional gastrointestinal disorders (AP-FGIDs) are defined by abdominal discomfort or pain that may provide obstacles to everyday activities, such as school attendance. It has been reported that AP-FGID symptoms may be reduced in summer, but it is unclear what drives this seasonal variation. This pilot study aimed to explore whether the seasonal variation in AP-FGID symptoms could be explained by various psychological and behavioral factors. METHODS: Parents of children with AP-FGID symptoms completed online questionnaires on symptoms, anxiety, parental responses to pain, sleep, diet, and physical activity once during spring months and again in the summer months. RESULTS: In a sample of 34 participants who completed both questionnaires, 22 reported improvements during the summer months. These participants reported a significantly higher seasonal decrease in anxiety than participants whose children's symptoms did not improve from spring to summer (mean decrease 2.21 vs 0.08, P = 0.017). Both groups reported equal improvements in sleep and decreased stress from spring to summer. Neither group experienced statistically significant seasonal change in physical activity or fruit, vegetables, dairy, or caffeine consumption. CONCLUSIONS: This study suggests that amelioration of gastrointestinal symptoms in pediatric patients with AP-FGID during summer months is associated with amelioration of anxiety in the same time period. It is not yet clear whether decreased anxiety is the cause or effect of decreased AP-FGID symptoms. PMID- 29287018 TI - Hypercoagulation and Pediatric Inflammatory Bowel Disease: A Case Report. PMID- 29287019 TI - Preliminary Results of High-Precision Computed Diffusion Weighted Imaging for the Diagnosis of Hepatocellular Carcinoma at 3 Tesla. AB - OBJECTIVE: To compare the utility of high-precision computed diffusion-weighted imaging (hc-DWI) and conventional computed DWI (cc-DWI) for the diagnosis of hepatocellular carcinoma (HCC) at 3 T. METHODS: We subjected 75 HCC patients to DWI (b-value 150 and 600 s/mm). To generate hc-DWI we applied non-rigid image registration to avoid the mis-registration of images obtained with different b values. We defined c-DWI with a b-value of 1500 s/mm using DWI with b-value 150 and 600 s/mm as cc-DWI, and c-DWI with b-value 1500 s/mm using registered DWI with b-value 150 and 600 s/mm as hc-DWI. A radiologist recorded the contrast ratio (CR) between HCC and the surrounding hepatic parenchyma. RESULTS: The CR for HCC was significantly higher on hc- than cc-DWIs (median 2.0 vs. 1.8, P < 0.01). CONCLUSION: The CR of HCC can be improved with image registration, indicating that hc-DWI is more useful than cc-DWI for the diagnosis of HCC. PMID- 29287020 TI - State-of-the-Art Diagnosis and Treatment of Melanoma: Optimal Multidetector Computed Tomographic Practice to Identify Metastatic Disease and Review of Innovative Therapeutic Agents. AB - The incidence of melanoma has risen dramatically over the past several decades. Oncologists rely on the ability of radiologists to identify subtle radiographic changes representing metastatic and recurrent melanoma in uncommon locations on multidetector computed tomography (MDCT) as the front-line imaging surveillance tool. To accomplish this goal, MDCT acquisition and display must be optimized and radiologist interpretation and search patterns must be tailored to identify the unique and often subtle metastatic lesions of melanoma. This article describes MDCT acquisition and display techniques that optimize the visibility of melanoma lesions, such as high-contrast display windows and multiplanar reconstructions. In addition, innovative therapies for melanoma, such as immunotherapy and small molecule therapy, have altered clinical management and outcomes and have also changed the spectrum of therapeutic complications that can be detected on MDCT. Recent advances in melanoma therapy and potential complications that the radiologist can identify on MDCT are reviewed. PMID- 29287021 TI - Does Computed Tomography Have the Ability to Differentiate Aggressive From Nonaggressive Solid Pseudopapillary Neoplasm? AB - OBJECTIVE: The aim of the study was to assess the ability of contrast-enhanced computed tomography (CECT) to differentiate aggressive from nonaggressive solid pseudopapillary neoplasms (SPNs). MATERIALS AND METHODS: Forty treatment-naive patients with pathologically proven pancreatic SPNs were included. Imaging characteristics were determined by consensus of 3 radiologists blinded to histopathologic aggressiveness. All patients underwent 4-phase CECT using a pancreatic protocol. The regions of interest of the tumor and the normal pancreas were documented on all phases. Lymph nodes were considered metastatic if greater than 1.0 cm in short-axis diameter.Fisher exact and Wilcoxon rank-sum tests were used to compare between aggressive and nonaggressive tumors. RESULTS: No significant difference was noted between imaging covariates, such as internal hemorrhage, calcification, wall thickness perceptibility, vascular invasion, margins, cystic component, and pancreatic and biliary ductal dilation. Tumors with greater than 62.5 Hounsfield units and progressive enhancement during the delayed phase had aggressive characteristics (P = 0.03). CONCLUSIONS: On delayed phase CECT, pathologically aggressive SPNs may show greater enhancement than nonaggressive SPNs. PMID- 29287022 TI - Inflammatory Pseudotumor-Like Follicular Dendritic Cell Sarcoma of the Spleen: Computed Tomography Imaging Characteristics in 5 Patients. AB - OBJECTIVES: The purpose of this study was to retrospectively review the computed tomography (CT) and clinicopathological characteristics of inflammatory pseudotumor (IPT)-like follicular dendritic cell sarcoma (FDCS) of the spleen in 5 patients. METHODS: Clinical, pathologic, and CT imaging findings of 5 patients with IPT-like FDCS of the spleen were reviewed and analyzed. Computed tomography imaging and pathologic features were compared. RESULTS: Abdominal unenhanced CT revealed a well-defined hypodense mass in the spleen with complex internal architecture with focal necrosis and/or speckle-strip calcification. On postcontrast CT, slightly delayed enhancement was observed in 5 cases. Four patients had a normalized spleen. The fourth patient had lung metastasis. The fifth patient had 2 relatively small lesions as well as metastases to the spine. CONCLUSIONS: Computed tomography imaging features of IPT-like FDCS of the spleen are distinctly different from other hypovascular splenic neoplasm; however, the definitive diagnosis requires further confirmation with needle biopsy or surgery. Inflammatory pseudotumor-like FDCS of the spleen should be suggested by using the CT imaging features of the splenic mass with evidence of metastatic disease. PMID- 29287023 TI - Single-Shot Version of FLAIR Sequence in the Detection of Intraventricular Anomalies: Preliminary Experience in Fetal MR Imaging. AB - OBJECTIVE: To evaluate single-shot (ss) FLAIR sequence in the detection of intraventricular anomalies in a series of fetuses showing mild-moderate ventriculomegaly at ultrasound. SUBJECTS AND METHODS: Fetuses with mild-moderate isolated ventriculomegaly, which underwent MR imaging between 2003 and 2014 were considered eligible. Fetuses were examined by standard MR protocol and ss-FLAIR sequence, tailored for snapshot imaging. Two paediatric neuroradiologists evaluated MR images. RESULTS: 542 cases were selected. MR imaging was performed at mean 26 weeks of gestation. ss-FLAIR sequence detected intraventricular findings, consistent with cysts in 10 cases. In 3/10 intraventricular cysts were also evident on ss-FSE T2 and FSE T1-weighted images. In no case diffusion weighted imaging was able to detect cyst. No cyst was highlighted on ss-FSE-T2 and FSE-T1-weighted images, without being visible also on ss-FLAIR. CONCLUSION: ss-FLAIR sequence may be useful to detect intraventricular anomalies especially when fetal position or maternal obesity prevents adequate visualization by ultrasound. PMID- 29287024 TI - Low-Dose Noncontrast Examination of the Paranasal Sinuses Using Volumetric Computed Tomography. AB - OBJECTIVES: The objective of this study was to evaluate image quality of low dose in noncontrast paranasal sinus computed tomography (CT) using single volumetric 320-row multidetector CT technique. METHODS: The low-dose protocol including tube voltage of 135 kV and tube current of 5 mAs was chosen based on results of the present phantom study. Forty-six patients were assigned to control group with factory standard settings (120 kVp, 75 mAs), and 46 patients were assigned to study group and underwent noncontrast CT of paranasal sinus with low-dose protocol using single volumetric 320-row multidetector CT device. Objective and subjective image qualities were performed. RESULTS: Effective radiation dose calculated for control group scans was 0.45 (SD, 0.39) mSv. It was 0.038 (SD, 0.004) mSv for study group scans. The effective radiation dose of study group was statistically significant lower than control group (P < 0.001). CONCLUSIONS: Noncontrast paranasal sinus CT imaging can be performed at very low radiation exposure maintaining high image quality with 135 kVp and 5 mAs. PMID- 29287025 TI - 2-Hydroxyglutarate Detection by Short Echo Time Magnetic Resonance Spectroscopy in Routine Imaging Study of Brain Glioma at 3.0 T. AB - OBJECTIVE: The objective of this study was to assess the effective performance of short echo time magnetic resonance spectroscopy (short TE MRS) for 2HG detection as biomarker of isocitrate dehydrogenase (IDH) status in all grade glioma (GL). METHODS: A total of 82 GL patients were prospectively investigated by short TE MRS at 3.0 T as part of a multimodal magnetic resonance imaging study protocol. Spectral analysis was performed using linear combination model. Tumor specimens were diagnosed as IDH mutant or wild type according to the 2016 World Health Organization (WHO) classification of brain tumors. Spectra were analyzed for the presence of 2HG. The performance of short TE MRS was evaluated in terms of sensitivity, specificity, and positive and negative likelihood ratio on the overall sample and on GL WHO grades II and III and glioblastoma separately. RESULTS: The specificity and sensitivity estimated on the overall sample were 88% and 77%, respectively. In GL WHO grades II and III, 100% specificity and 75% sensitivity were estimated. CONCLUSIONS: We reiterate the feasibility to identify IDH status of brain GL using short TE MRS at 3.0 T. The method can correctly detect 2HG as expression of IDH mutation in WHO grades II and III GL with a 100% specificity but a 75% sensitivity. In the evaluation of glioblastoma, short TE MRS performs poorly having a 17% false positive rate. PMID- 29287026 TI - Presence of Intratumoral Calcifications and Vasculature Is Associated With Poor Overall Survival in Clear Cell Renal Cell Carcinoma. AB - PURPOSE: The objective of this study was to explore the prognostic significance of the preoperative computed tomography (CT) features in clear cell renal cell carcinoma. PATIENTS AND METHODS: The clinical data and CT data from 210 patients (1 grade 1, 84 grade 2, 92 grade 3, and 32 grade 4) generated with The Cancer Imaging Archive were reviewed. Overall survival was assessed using Kaplan-Meyer analysis. The relationship between CT features and survivals were evaluated using univariate and multivariable Cox regression analysis. RESULTS: The follow-up occurred between 13 and 3989 days (median, 1405 days; mean, 1434 days).On univariate Cox regressions, 4 preoperative CT features (intratumoral calcifications: yes vs no hazard ratio [HR], 2.054; 95% confidence interval [CI], 1.231-3.428; renal vein invasion: yes vs no HR, 2.013; 95% CI, 1.218-3.328; collecting system invasion: yes vs no HR, 2.139; 95% CI, 1.286-3.558; gross appearance of intratumoral vasculature: yes vs no HR, 2.385; 95% CI, 1.454-3.915) were significantly associated with overall survival (all P < 0.05). On multivariable Cox regression analysis, predictors of mortality in clear cell renal cell carcinoma were the presence of intratumoral calcifications (HR, 1.718; 95% CI, 1.014-2.911; P = 0.044) and gross appearance of intratumoral vasculature (HR, 2.137; 95% CI, 1.284-3.557; P = 0.003). CONCLUSIONS: Presence of intratumoral calcifications and vasculature can be potential prognostic features to screen patients for unfavorable prognosis. PMID- 29287028 TI - HBV or HCV Coinfection in HIV-1-Infected Pregnant Women in France: Prevalence and Pregnancy Outcomes. AB - BACKGROUND: Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is frequent in HIV-infected persons but their impact on pregnant HIV-infected women is understudied. We explored whether these coinfections are associated with adverse pregnancy outcomes and lower response to antiretroviral therapy (ART). METHODS: Pregnancies in HIV-1-infected women included in the ANRS French Perinatal Cohort between 2005 and 2013 were analyzed if HBV and HCV infection statuses were available. RESULTS: Among 4236 women, the prevalence of HBV (HBs Ag+) and HCV (RNA+) were 6.2% (95% confidence interval: 5.4 to 6.8) and 1.7% (1.3 to 2.1), respectively. HCV coinfection was strongly associated with a history of drug use; HBV coinfection was 6 times more frequent in women born in Sub-Saharan Africa than in European France. Baseline HIV viral load, CD4 count, and HIV care during pregnancy were similar in coinfected and monoinfected HIV mothers, except that 90% of HBV/HIV women were receiving tenofovir and/or lamivudine or emtricitabine. HCV coinfection was significantly associated with cholestasis [adjusted odds ratio: 4.1 (1.5-10.8), P = 0.005], preterm delivery [3.0 (1.6 5.7), P < 0.001], lower CD4 [2.6 (1.0-6.4), P < 0.001], and detectable viral load [2.3 (1.0-5.5), P = 0.06] at the end of pregnancy. HBV coinfection was not associated with any of these outcomes. CONCLUSIONS: In HIV-infected women, chronic HBV infection, mostly treated using targeted ART, had no major impact on the course of pregnancy. By contrast, chronic HCV infection was associated with a higher risk of obstetrical complications and a poorer immune-virological response to ART. It is yet unknown whether cure of HCV infection before conception can limit these adverse outcomes. PMID- 29287031 TI - A Follow-Up Study on Return to Work in the Year After Reporting an Occupational Injury Stratified by Outcome of the Workers' Compensation System. AB - OBJECTIVE: The aim of this study was to compare return rates to work between different groups according to the decision from the workers' compensation. METHOD: Register data on disability benefits were used to describe return rates to work in Kaplan-Meier curves and association with decision on compensation claims. Disability benefits were granted by the municipalities independently of any compensation claim if sick-listed. RESULTS: Claimants with ongoing claims were the group with the largest proportion remaining on disability benefits. Claimants with rejected claims returned to work at the same rate (occupational disease) or slower (industrial accident) than claimants with recognized claim without compensation the subsequent year and at a faster rate after decision. CONCLUSION: Compensation claims and proceedings of the workers' compensation system probably increase time to return to work; other factors such as health and social difficulties, however, may explain some of these differences. PMID- 29287032 TI - The "Total Worker Health" Concept: A Case Study in a Rural Workplace. AB - OBJECTIVE: This case study was conducted to identify barriers of integration of health protection and health promotion in rural workplaces with tailored interventions that address the identified barriers. METHODS: Data on a workplace's ability to integrate wellness programs and health protection programs were collected through a questionnaire along with a seven-question interview. Descriptive statistics were used to analyze the quantitative data. Qualitative measures were assessed using thematic analysis. Based off the results of the assessments, the company received tailored training sessions. RESULTS: The largest hindrance to organizational support was time. However, improved knowledge about the need and importance of integration helped the participants to conceptualize and plan for more collaboration between departments. CONCLUSIONS: New ways to increase integration at workplaces, especially rural workplaces are needed. More comprehensive interventions that include management are also needed. PMID- 29287029 TI - Retention in HIV Care During Pregnancy and the Postpartum Period in the Option B+ Era: Systematic Review and Meta-Analysis of Studies in Africa. AB - BACKGROUND: Under Option B+ guidelines for prevention of mother-to-child transmission of HIV, pregnant and breastfeeding women initiate antiretroviral therapy for lifelong use. The objectives of this study were: (1) to synthesize data on retention in care over time in option B+ programs in Africa, and (2) to identify factors associated with retention in care. METHODS: PubMed, EMBASE, and African Index Medicus were systematically searched from January 2012 to June 2017. Pooled estimates of the proportion of women retained were generated and factors associated with retention were analyzed thematically. RESULTS: Thirty five articles were included in the final review; 22 reported retention rates (n = 60,890) and 25 reported factors associated with retention. Pooled estimates of retention were 72.9% (95% confidence interval: 66.4% to 78.9%) at 6 months for studies reporting <12 months of follow-up and 76.4% (95% confidence interval: 69.0% to 83.1%) at 12 months for studies reporting >=12 months of follow-up. Data on undocumented clinic transfers were largely absent. Risk factors for poor retention included younger age, initiating antiretroviral therapy on the same day as diagnosis, initiating during pregnancy versus breastfeeding, and initiating late in the pregnancy. Retention was compromised by stigma, fear of disclosure, and lack of social support. CONCLUSIONS: Retention rates in prevention of mother to-child transmission under option B+ were below those of the general adult population, necessitating interventions targeting the complex circumstances of women initiating care under option B+. Improved and standardized procedures to track and report retention are needed to accurately represent care engagement and capture undocumented transfers within the health system. PMID- 29287033 TI - Impact of New Medications and $4 Generic Programs on Overactive Bladder Treatment Among Older Adults in the United States, 2000-2015. AB - BACKGROUND: Despite several new medications being Food and Drug Administration approved for overactive bladder (OAB) and new prescription drug payment programs, there are limited population-based data regarding OAB medication use among older adults. OBJECTIVES: To examine: (1) impacts of new medications and $4 generic programs on time trends for OAB-related medication dispensing for older adults in the United States; (2) differences by age and sex; and (3) temporal changes in OAB-related medication payments. METHODS: Using Truven Health Analytics' Medicare Supplemental Database (2000-2015), we analyzed OAB-related medication claims for 9,477,061 Medigap beneficiaries age 65-104. We estimated dispensing rates (per 1000 person-months), assessed dispensing trends using interrupted time-series methods, compared dispensing rates by age and sex, and summarized payment trends. RESULTS: From 2000 to 2015, 771,609 individuals filled 13,863,998 OAB-related prescriptions. During 2000-2007, 3 new extended-release medications became available (tolterodine, darifenacin, solifenacin), leading to increases in overall OAB-related dispensing rates by 19.1 (99% confidence interval, 17.0 21.2), a 92% increase since 2000; overall rates remained stable during 2008-2015. By 2015, the most common medications were oxybutynin (38%), solifenacin (20%), tolterodine (19%), and mirabegron (12%). Dispensing rates peaked at age 90 (rate, 53.4; 99% confidence interval, 53.1-53.7). Women had higher rates than men at all ages (average ratewomen-ratemen, 22.0). The gap between upper and lower percentiles of medication payments widened between 2008-2015; by 2015, 25% of reimbursed dispensed prescriptions had total payments exceeding $250. CONCLUSIONS: Medication-specific dispensing rates for OAB changed when new alternatives became available. Recent changes in utilization and cost of OAB medications have implications for clinical guidelines, pharmacoepidemiologic studies, and payment policies. PMID- 29287034 TI - Electronic Medical Record Alert Associated With Reduced Opioid and Benzodiazepine Coprescribing in High-risk Veteran Patients. AB - BACKGROUND: Over the past decade, overdoses involving opioids and benzodiazepines have risen at alarming rates, making reductions in coprescribing of these medications a priority, particularly among patients who may be susceptible to adverse events due to high-risk conditions. OBJECTIVES: This quality improvement project evaluated the effectiveness of a medication alert designed to reduce opioid and benzodiazepine coprescribing among Veterans with known high-risk conditions (substance use, sleep apnea, suicide-risk, age 65 and above) at 1 Veterans Affairs (VA) health care system. METHODS: Prescribers were exposed to the point-of-prescribing alert for 12 months. For each high-risk cohort we used interrupted time series design to examine population trends in coprescribing 12 months after alert launch adjusting for coprescribing 12 months before launch, demographics and clinical covariates. Trends at the alert site were compared with those of a similar VA health care system without the alert. Secondary analyses examined population trends in opioid and benzodiazepine prescribing separately. RESULTS: Over 12 months, the alert activated for 1332 patients. Proportions of patients with concurrent prescriptions decreased significantly postalert launch among substance use [adjusted odds ratio (AOR)=0.97; 95% confidence interval (CI)=0.96-0.99; 12-month decrease=25.0%], sleep apnea (AOR=0.97, 95% CI=0.95 0.98, 12-month decrease=38.5%), and suicide-risk (AOR=0.94, 95% CI=0.91-0.98, 12 month decrease=61.5%) cohorts at the alert site. Decreases in coprescribing were significantly different from the comparison site among suicide-risk (AOR=0.92, 95% CI=0.86-0.97) and sleep apnea (AOR=0.98, 95% CI=0.96-1.00) cohorts. Significant decreases in benzodiazepine prescribing trends were observed at the alert site only. CONCLUSIONS: Medication alerts hold promise as a means of reducing opioid and benzodiazepine coprescribing among certain high-risk groups. PMID- 29287036 TI - Benign Paroxysmal Positional Vertigo (BPPV) in Children and Adolescents: Clinical Features and Response to Therapy in 110 Pediatric Patients. AB - OBJECTIVE: This study aimed to characterize the clinical features and outcomes of benign paroxysmal positional vertigo (BPPV) in the pediatric population. STUDY DESIGN: Retrospective case review. SETTING: Tertiary care center. PATIENTS: One hundred ten patients, aged 5 to 19 years old, diagnosed with BPPV. MAIN OUTCOME MEASURES: Patient demographics, comorbidities, canal involvement, response to treatment, and incidence of recurrence. RESULTS: BPPV was diagnosed in 19.8% of patients seen for dizziness during the study period. Patient age ranged 5 to 19 years old (mean =13.4 +/- 3.4 yr). Female:male ratio was 3:2. The most prevalent comorbidities were concussion (n = 42, 38.2%) and migraine disorders (n = 33, 30.0%). Average time to diagnosis from symptom onset was 178.2 +/- 190.8 days. The posterior canal was most frequently affected (n = 80, 72.7%), followed by the lateral canal (n = 37, 33.6%) and superior canal (n = 21, 19.1%), and 36.4% (n = 40) of patients had multiple canals affected. Treatment requiring more than or equal to five maneuvers to achieve resolution was observed in 11.8% of cases (n = 13). Recurrence was observed in 18.2% of cases. A logistic regression analysis demonstrated that patients with vestibular migraine or benign paroxysmal vertigo of childhood had five times higher odds of recurrence of BPPV, p = 0.003, 95% [1.735, 15.342], than those who did not have either. CONCLUSIONS: BPPV is a relatively common cause of dizziness in the pediatric population. Children and adolescents with BPPV can be successfully treated with repositioning maneuvers but may be at risk for treatment resistance and recurrence. Increased awareness of BPPV in pediatric patients may reduce delays in identification and treatment. PMID- 29287035 TI - The Differential Effects of Insurance Mandates on Health Care Spending for Children's Autism Spectrum Disorder. AB - OBJECTIVES: There is substantial variation in treatment intensity among children with autism spectrum disorder (ASD). This study asks whether policies that target health care utilization for ASD affect children differentially based on this variation. Specifically, we examine the impact of state-level insurance mandates that require commercial insurers to cover certain treatments for ASD for any fully-insured plan. METHODS: Using insurance claims between 2008 and 2012 from three national insurers, we used a difference-in-differences approach to compare children with ASD who were subject to mandates to children with ASD who were not. To allow for differential effects, we estimated quantile regressions that evaluate the impact of mandates across the spending distributions of three outcomes: (1) monthly spending on ASD-specific outpatient services; (2) monthly spending on ASD-specific inpatient services; and (3) quarterly spending on psychotropic medications. RESULTS: The change in spending on ASD-specific outpatient services attributable to mandates varied based on the child's level of spending. For those children with ASD who were subject to the mandate, monthly spending for a child in the 95th percentile of the ASD-specific outpatient spending distribution increased by $1460 (P<0.001). In contrast, the effect was only $2 per month for a child in the fifth percentile (P<0.001). Mandates did not significantly affect spending on ASD-specific inpatient services or psychotropic medications. CONCLUSIONS: State-level insurance mandates have larger effects for those children with higher levels of spending. To the extent that spending approximates treatment intensity and the underlying severity of ASD, these results suggest that mandates target children with greater service needs. PMID- 29287037 TI - Correlations Between the Degree of Endolymphatic Hydrops and Symptoms and Audiological Test Results in Patients With Meniere's Disease: A Reevaluation. AB - OBJECTIVE: This study was performed to reevaluate the diagnostic significance of clinically well-accepted audiological tests in indicating endolymphatic hydrops (EH) in Meniere's disease (MD). STUDY DESIGN: Retrospective case review. SETTINGS: Hospital. PATIENTS: Fifty patients (52 affected ears) diagnosed with MD were enrolled. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: To analyze the correlations between endolymphatic hydrops and results of audiological test including the pure-tone audiometry threshold, suprathreshold function tests, electrocochleogram, and glycerol test. RESULTS: Three-dimensional fluid attenuated inversion recovery magnetic resonance imaging demonstrated EH in either the vestibule or cochlea to various degrees in all of the MD patients, 24 hours after intratympanic gadolinium chelate injection. Both vestibular and cochlear EH were significantly correlated with PTA threshold. However, EH was not associated with alternate binaural loudness balance or the tone decay test, although a correlation was observed with the short-increment sensitivity index. There was also a correlation between vestibular EH, but not cochlear EH, and the negative summating potential/action potential (-SP/AP) ratio. Neither vestibular EH nor cochlear EH was correlated with the glycerol test results. In addition, the frequency of vertigo attacks, the existence of tinnitus, and aural fullness did not correlate with EH. CONCLUSIONS: Disrupted ionic homeostasis in the inner ear, but not the EH, may contribute to changes in the -SP/AP ratio. The relevance of glycerol test in identifying EH through detection of hearing changes needs further investigation in the future. PMID- 29287039 TI - Effect of Blast Injury on Auditory Localization in Military Service Members. AB - OBJECTIVES: Among the many advantages of binaural hearing are the abilities to localize sounds in space and to attend to one sound in the presence of many sounds. Binaural hearing provides benefits for all listeners, but it may be especially critical for military personnel who must maintain situational awareness in complex tactical environments with multiple speech and noise sources. There is concern that Military Service Members who have been exposed to one or more high-intensity blasts during their tour of duty may have difficulty with binaural and spatial ability due to degradation in auditory and cognitive processes. The primary objective of this study was to assess the ability of blast exposed Military Service Members to localize speech sounds in quiet and in multisource environments with one or two competing talkers. DESIGN: Participants were presented with one, two, or three topic-related (e.g., sports, food, travel) sentences under headphones and required to attend to, and then locate the source of, the sentence pertaining to a prespecified target topic within a virtual space. The listener's head position was monitored by a head-mounted tracking device that continuously updated the apparent spatial location of the target and competing speech sounds as the subject turned within the virtual space. Measurements of auditory localization ability included mean absolute error in locating the source of the target sentence, the time it took to locate the target sentence within 30 degrees, target/competitor confusion errors, response time, and cumulative head motion. Twenty-one blast-exposed Active-Duty or Veteran Military Service Members (blast-exposed group) and 33 non-blast-exposed Service Members and beneficiaries (control group) were evaluated. RESULTS: In general, the blast-exposed group performed as well as the control group if the task involved localizing the source of a single speech target. However, if the task involved two or three simultaneous talkers, localization ability was compromised for some participants in the blast-exposed group. Blast-exposed participants were less accurate in their localization responses and required more exploratory head movements to find the location of the target talker. CONCLUSIONS: Results suggest that blast-exposed participants have more difficulty than non-blast-exposed participants in localizing sounds in complex acoustic environments. This apparent deficit in spatial hearing ability highlights the need to develop new diagnostic tests using complex listening tasks that involve multiple sound sources that require speech segregation and comprehension. PMID- 29287038 TI - Effects of Amplification on Neural Phase Locking, Amplitude, and Latency to a Speech Syllable. AB - OBJECTIVE: Older adults often have trouble adjusting to hearing aids when they start wearing them for the first time. Probe microphone measurements verify appropriate levels of amplification up to the tympanic membrane. Little is known, however, about the effects of amplification on auditory-evoked responses to speech stimuli during initial hearing aid use. The present study assesses the effects of amplification on neural encoding of a speech signal in older adults using hearing aids for the first time. It was hypothesized that amplification results in improved stimulus encoding (higher amplitudes, improved phase locking, and earlier latencies), with greater effects for the regions of the signal that are less audible. DESIGN: Thirty-seven adults, aged 60 to 85 years with mild to severe sensorineural hearing loss and no prior hearing aid use, were bilaterally fit with Widex Dream 440 receiver-in-the-ear hearing aids. Probe microphone measures were used to adjust the gain of the hearing aids and verify the fitting. Unaided and aided frequency-following responses and cortical auditory-evoked potentials to the stimulus /ga/ were recorded in sound field over the course of 2 days for three conditions: 65 dB SPL and 80 dB SPL in quiet, and 80 dB SPL in six talker babble (+10 signal to noise ratio). RESULTS: Responses from midbrain were analyzed in the time regions corresponding to the consonant transition (18 to 68 ms) and the steady state vowel (68 to 170 ms). Generally, amplification increased phase locking and amplitude and decreased latency for the region and presentation conditions that had lower stimulus amplitudes-the transition region and 65 dB SPL level. Responses from cortex showed decreased latency for P1, but an unexpected decrease in N1 amplitude. Previous studies have demonstrated an exaggerated cortical representation of speech in older adults compared to younger adults, possibly because of an increase in neural resources necessary to encode the signal. Therefore, a decrease in N1 amplitude with amplification and with increased presentation level may suggest that amplification decreases the neural resources necessary for cortical encoding. CONCLUSION: Increased phase locking and amplitude and decreased latency in midbrain suggest that amplification may improve neural representation of the speech signal in new hearing aid users. The improvement with amplification was also found in cortex, and, in particular, decreased P1 latencies and lower N1 amplitudes may indicate greater neural efficiency. Further investigations will evaluate changes in subcortical and cortical responses during the first 6 months of hearing aid use. PMID- 29287041 TI - Using our voices. PMID- 29287042 TI - Helping employees stay. PMID- 29287043 TI - The social media conundrum. PMID- 29287044 TI - Internships: A recruitment tool for rural healthcare organizations. PMID- 29287045 TI - Post hospitalization management of patients with COPD. PMID- 29287046 TI - 2017 Visionary Leader: Maureen Maurano. AB - The following manuscript is the winning 2017 Richard Hader Visionary Leader Award entry submitted to Nursing Management in recognition of Maureen Maurano, BSN, RN, nurse manager of the neonatal intensive care unit at Children's National Health System in Washington, D.C. Ms. Maurano was formally recognized for her achievements before the Keynote Address at Congress2017, October 4, in Las Vegas, Nev. There, she received the award, sponsored by Hackensack Meridian Health. PMID- 29287047 TI - Improving real-time vital signs documentation. PMID- 29287048 TI - Academic-practice partnerships and patient outcomes. PMID- 29287049 TI - Nurse coordinators and ERAS programs. PMID- 29287050 TI - Development of an England-wide nursing director talent pipeline. PMID- 29287051 TI - Energize yourself. PMID- 29287053 TI - Diagnostic Performance of One-off Flexible Sigmoidoscopy with Fecal Immunochemical Testing in a Large Screening Population. AB - BACKGROUND: Flexible sigmoidoscopy and fecal immunochemical tests are established diagnostic tests for colorectal cancer (CRC) screening and less invasive, less expensive, and easier to conduct than colonoscopy. However, little is known about their joint diagnostic performance compared with colonoscopy. We aimed to assess the expected diagnostic performance of joint use of flexible sigmoidoscopy and fecal immunochemical test. METHODS: We assessed the overall and site-specific prevalences of colorectal neoplasms and the overall sensitivity, specificity, area under the receiver operating characteristics curve of a quantitative fecal immunochemical test (FOB Gold, Sentinel Diagnostics, Milano, Italy) among 3,466 participants in screening colonoscopy in Germany. Results were used to model the expected diagnostic performance of joint use of flexible sigmoidoscopy and fecal immunochemical testing. RESULTS: CRC and advanced adenomas were found in 29 (1%) and 354 (10%) participants, respectively. The area under the curve of fecal immunochemical testing for these outcomes could be raised from 96% to 100% and from 70% to 89%, respectively, by combining it with flexible sigmoidoscopy. At 90% specificity, sensitivity of fecal immunochemical testing would increase from 97% to 100% for CRC and from 40% to 79% for advanced adenomas. CONCLUSIONS: Combining flexible sigmoidoscopy and fecal immunochemical testing might strongly enhance diagnostic performance of each single test to a level close to the diagnostic performance of screening colonoscopy while avoiding many unnecessary colonoscopies. PMID- 29287057 TI - Early diagnosis using canonical discriminant analysis of innate immune receptor gene expression profiles in a murine infectious or sterile systemic inflammation model. AB - BACKGROUND: Infection in patients with systemic inflammation is difficult to diagnose with a single biomarker. We aimed to clarify the time course of change in the gene expression profile of innate immune receptors in infectious or sterile inflammation and to establish an early diagnostic method using canonical discriminant analysis (CDA) of the gene expression profile. METHODS: To compare infectious and sterile inflammation, we used cecal ligation and puncture (CLP) and 20% full-thickness burn injury (Burn) models. C57BL/6 mice underwent sham treatment (n = 9 * three groups), CLP (n = 12 * three groups), or Burn (n = 12 * three groups) injury. Mice were killed at 6, 12, and 24 hours after injury, and total RNA was extracted from whole blood. We used quantitative real-time polymerase chain reaction to investigate gene expression of innate immune receptors Toll-like receptor 2 (TLR2), TLR4, TLR9, NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3), and retinoic acid-inducible gene I. To evaluate all gene expression together as patterns, each value was standardized, and CDA was performed at each time point. RESULTS: Gene expression of TLR2 and TLR4 was already significantly increased in both CLP and Burn compared with sham mice at 6 hours after injury (p < 0.05). Gene expression of TLR9 was significantly decreased in CLP compared with sham and Burn mice at 12 hours and 24 hours after injury (p < 0.05) but not at 6 hours. Gene expression of NLRP3 was significantly increased in CLP and Burn compared with sham mice at 6 hours and 24 hours after injury (p < 0.05). In the CDA, each group showed distinctive gene expression patterns at only 6 hours after injury. Each group was clearly classified, and the classification error rates were 0% at all of the time points. CONCLUSIONS: Canonical discriminant analysis of the gene expression profile of innate immune receptors could be a novel approach for diagnosing the pathophysiology of complicated systemic inflammation from the early stage of injury. PMID- 29287058 TI - Activities of the THOR-AABB Working Party. AB - The AABB (formerly the American Association of Blood Banks) is an international authority on transfusion medicine and tissue banking. The Trauma, Hemostasis and Oxygenation Research (THOR) Network is an international multidisciplinary network of civilian and military providers ranging from first responders and medics to critical care physicians and from basic scientists to clinical trialists. The THOR Network's vision is to improve outcomes from traumatic hemorrhagic shock by optimizing the acute phase of resuscitation. Its mission is to develop and implement best practices for prehospital care through to the completion of the acute phase of hemorrhagic shock resuscitation. Thus, there is significant overlap between the missions of these two groups. To this end, the joint THOR AABB Working Party (WP) was created in the summer of 2016 with a view to improving patient outcomes by the establishment of a formal collaboration between these two groups. The WP has been engaged in many different endeavors, from successfully changing the AABB's standards for the administration of whole blood, to writing commentaries on the safety of unncrossmatched red blood cells and antibody titer methods and thresholds in potentially incompatible plasma products, to hosting a daylong symposium on blood product resuscitation of massively bleeding patients in conjunction with the AABB annual meeting. This review details the activities of the WP and indicates some future activities. PMID- 29287059 TI - Microfluidics: A high-throughput system for the assessment of the endotheliopathy of trauma and the effect of timing of plasma administration on ameliorating shock associated endothelial dysfunction. AB - BACKGROUND: Early resuscitation after trauma-hemorrhagic shock with plasma rather than crystalloid may ameliorate systemic endothelial cell (EC) injury and dysfunction (endotheliopathy of trauma). We postulated that endothelial-lined microfluidic networks would be a useful platform to study the EC activation/injury under flow conditions to mimic trauma-hemorrhagic shock. We then used the microfluidic system to further characterize the protective effects and optimal timing of plasma infusion on the development of "endotheliopathy of trauma" in our model. METHODS: Human umbilical vein ECs were added to microfluidic flow channels, and after overnight perfusion, the cells were subsequently treated with epinephrine and exposed to hypoxia reoxygenation. Media alone or 5% human plasma was perfused either immediately following treatment (early plasma) or after a 3-hour delay (late plasma). Glycocalyx injury was indexed by fluorescent microscopy and shedding of syndecan 1 and hyaluronic acid. Endothelial markers of activation/injury were also measured and included soluble thrombomodulin, tissue plasminogen activator, plasminogen activator inhibitor 1, and angiopoietins 1 and 2. Sheddase activity was indexed by ADAM metallopeptidase domain 17. RESULTS: Endothelial cell and glycocalyx barrier function studies using microfluidic devices are a more realistic model of the glycocalyx endothelial vascular barrier than studies performed on ECs using static (no flow) conditions. Conditions that mimic the internal milieu following hemorrhagic shock result in glycocalyx degradation and an inflammatory prothrombotic response by the endothelium. "Early" use of plasma in the microfluidic channel perfusate mitigated against these effects. Later perfusion with plasma had no protective effect. CONCLUSIONS: A temporal effect to plasma administration was noted in our biomimetic model of the endothelial vascular barrier following shock. This suggests a protective role to "early" plasma administration in the severely injured patient. PMID- 29287060 TI - Clinical Outcome of Total Knee Arthroplasty Performed Using Patient-Specific Cutting Guides. AB - BACKGROUND Patient-specific instruments have recently gained attention for ensuring the accuracy of osteotomy and correct alignment in total knee arthroplasty (TKA). We aimed to report our experience with TKA performed by using CT-based 3D model of cutting guides in our clinic. MATERIAL AND METHODS A total of 36 patients (mean age, 67.58+/-8.46 years; 24 females, 12 males) who underwent TKA with 3D patient-specific cutting guides in our clinic were included in the study. Differences between preoperatively planned bone resections and actual bone resections were calculated. Femoral and tibial component angles were measured on radiographs of the knee. The change in knee pain was evaluated by patients on a 10-point visual analog scale (VAS). Patients were followed up for 6 months postoperatively. RESULTS The actual bone resection was 0.5-1.5 mm higher than the planned resection for all sides, being statistically significant for posterior lateral and distal medial sides (1.1+/-1.3 mm and 1.5+/-0.9 mm, respectively; p<0.05). On postoperative radiographs, coronal tibial component angle was 88.8 degrees +/-0.9 degrees and coronal femoral component angle was 95.2 degrees +/ 1.6 degrees , showing good postoperative alignment. The VAS pain score of patients significantly decreased from preoperative 3.9+/-0.8 to 1.1+/-0.9 at 6 months after the operation. One patient developed superficial tissue infection on postoperative follow-up, which was effectively treated. No other pathology was detected in the postoperative period. CONCLUSIONS Patient-specific cutting guides can provide intraoperative guidance for better placement of the implant in TKA and increase the accuracy of osteotomy and postoperative alignment. PMID- 29287061 TI - The effects of interrupting prolonged sitting with intermittent activity on appetite sensations and subsequent food intake in preadolescent children. AB - BACKGROUND: Short-term and long-term exposure to prolonged sitting is associated with excess food intake and weight gain in children. Interrupting prolonged sitting with low-intensity activity has been shown to not alter hunger, satiety, or food consumption in children, however it is unclear whether interrupting sitting with high-intensity activity will alter appetite regulation in children. PURPOSE: The purpose of this study was to examine the acute effects of interrupting prolonged sitting with intermittent activity performed at varying intensities on hunger, satiety, prospective food consumption (PFC), and food intake in preadolescent children. METHODS: Thirty-nine children (ages 7-11 years, 54% female, 33% overweight/obese) completed four experimental conditions in random order: 8 hours of sitting interrupted with 20, 2-minute low-, moderate-, or high-intensity activity breaks or 20, 2-minute sedentary screen time breaks. Exercise intensity corresponded with 25%, 50% and 75% of heart rate reserve, respectively. Hunger, satiety, and PFC were assessed using the Visual Analog Scale, at five time points (pre- and post-breakfast, pre- and post-lunch, and pre dinner) during each experimental condition. Dietary compensation was assessed as total caloric intake during a post-condition dinner standardized to provide 70% of estimated daily energy requirements. RESULTS: There was a significant effect of time on hunger, satiety, and PFC throughout each condition day (p< 0.001). There were no differences across conditions for hunger (sedentary: 4.9+/-0.3 cm, low: 5.0+/-0.3 cm, moderate: 5.1+/-0.3 cm, high: 5.1+/-0.3 cm, p>0.05), satiety (sedentary: 4.7+/-0.3 cm, low: 4.4+/-0.3 cm, moderate: 4.6+/-0.3 cm, high: 4.2+/ 0.3 cm, p>0.05), and PFC (sedentary: 4.9+/-0.3 cm, low: 4.7+/-0.3 cm, moderate: 4.9+/-0.3 cm, high: 5.0+/-0.3 cm, p>0.05). There were no significant differences in post-activity food intake across conditions (sedentary: 1071.9+/-53.6 kcals; low: 1092.6+/-43.4kcals; moderate: 996.2+/-54.6kcals; high: 1138.7+/-62.8kcals, p>0.05). However, there was a significant effect of condition on energy balance (sedentary: +61.4+/-65.9 kcals, low: +74.9+/-57.6 kcals, moderate: -58.3+/-62.8 kcals, high: -391.2+/-77.9 kcals; p<0.001). There were no significant effects of weight status on hunger, satiety, PFC, post-activity food intake, and mean energy balance across conditions (all p's>0.05). CONCLUSIONS: Interrupting prolonged sitting with physical activity of any intensity does not alter appetite sensations and subsequent food consumption in children. These data suggest that interventions targeting prolonged sitting with high-intensity intermittent activity may be an effective strategy to increase physical activity energy expenditure without increasing food intake, allowing for a short-term energy deficit in both healthy weight and overweight/obese children. Future studies should examine the long-term effects of interrupting prolonged sitting with activity on food consumption and weight status in preadolescent children. PMID- 29287062 TI - The influence of conjugation variables on the design and immunogenicity of a glycoconjugate vaccine against Salmonella Typhi. AB - In recent years there have been major efforts to develop glycoconjugate vaccines based on the Vi polysaccharide that will protect against Salmonella enterica Typhi infections, particularly typhoid fever, which remains a major public health concern in low-income countries. The design of glycoconjugate vaccines influences the immune responses they elicit. Here we systematically test the response in mice to Vi glycoconjugates that differ in Vi chain length (full-length and fragmented), carrier protein, conjugation chemistry, saccharide to protein ratio and size. We show that the length of Vi chains, but not the ultimate size of the conjugate, has an impact on the anti-Vi IgG immune response induced. Full-length Vi conjugates, independent of the carrier protein, induce peak IgG responses rapidly after just one immunization, and secondary immunization does not enhance the magnitude of these responses. Fragmented Vi linked to CRM197 and diphtheria toxoid, but not to tetanus toxoid, gives lower anti-Vi antibody responses after the first immunization than full-length Vi conjugates, but antibody titres are similar to those induced by full-length Vi conjugates following a second dose. The chemistry to conjugate Vi to the carrier protein, the linker used, and the saccharide to protein ratio do not significantly alter the response. We conclude that Vi length and carrier protein are the variables that influence the anti-Vi IgG response to immunization the most, while other parameters are of lesser importance. PMID- 29287063 TI - Reference data on reaction time and aging using the Nintendo Wii Balance Board: A cross-sectional study of 354 subjects from 20 to 99 years of age. AB - BACKGROUND: Falls among older adults is one of the major public health challenges facing the rapidly changing demography. The valid assessment of reaction time (RT) and other well-documented risk factors for falls are mainly restricted to specialized clinics due to the equipment needed. The Nintendo Wii Balance Board has the potential to be a multi-modal test and intervention instrument for these risk factors, however, reference data are lacking. OBJECTIVE: To provide RT reference data and to characterize the age-related changes in RT measured by the Nintendo Wii Balance Board. METHOD: Healthy participants were recruited at various locations and their RT in hands and feet were tested by six assessors using the Nintendo Wii Balance Board. Reference data were analysed and presented in age-groups, while the age-related change in RT was tested and characterized with linear regression models. RESULTS: 354 participants between 20 and 99 years of age were tested. For both hands and feet, mean RT and its variation increased with age. There was a statistically significant non-linear increase in RT with age. The averaged difference between male and female was significant, with males being faster than females for both hands and feet. The averaged difference between dominant and non-dominant side was non-significant. CONCLUSION: This study reported reference data with percentiles for a new promising method for reliably testing RT. The RT data were consistent with previously known effects of age and gender on RT. PMID- 29287064 TI - Human behaviours associated with dominance in elite amateur boxing bouts: A comparison of winners and losers under the Ten Point Must System. AB - Humans commonly ascertain physical dominance through non-lethal fighting by participating in combat sports. However, the behaviours that achieve fight dominance are not fully understood. Amateur boxing competition, which is judged using the subjective "Ten Point Must-System", provides insight into fight dominance behaviours. Notational analysis was performed on 26 elite male competitors in a national boxing championship. Behavioural (guard-drop time; movement style [stepping/bouncing time]; clinch-time; interaction-time) and technical (total punches; punches landed [%Hit]; air punches [%Air]; defence) measures were recorded. Participants reported effort required (0-100%) and perceived effect of fatigue on their own performance (5-point Likert scale) following bouts. Differences between winners and losers, and changes across the duration of the bout were examined. Winners punched more accurately than losers (greater %Hit [33% vs. 23%] and lower %Air [17% vs. 27%]) but total punches, defence and interaction-time were similar. From rounds 1-2, clinch-time and guard drops increased whilst bouncing decreased. Perceived effect of fatigue increased throughout the bout while perceived effort increased only from rounds 2-3. %Hit and movement index together in regression analysis correctly classified 85% of bout outcomes, indicating that judges (subjectively) chose winning (dominant) boxers according to punch accuracy and style, rather than assertiveness (more punches thrown). Boxers appear to use tactical strategies throughout the bout to pace their effort and minimise fatigue (increased guard drops, reduced bouncing), but these did not influence perceived dominance or bout outcome. These results show that judges use several performance indicators not including the total number of successful punches thrown to assess fight dominance and superiority between fighters. These results provide valuable information as to how experienced fight observers subjectively rate superiority and dominance during one-on-one human fighting. PMID- 29287065 TI - Calmodulin fishing with a structurally disordered bait triggers CyaA catalysis. AB - Once translocated into the cytosol of target cells, the catalytic domain (AC) of the adenylate cyclase toxin (CyaA), a major virulence factor of Bordetella pertussis, is potently activated by binding calmodulin (CaM) to produce supraphysiological levels of cAMP, inducing cell death. Using a combination of small-angle X-ray scattering (SAXS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), and synchrotron radiation circular dichroism (SR-CD), we show that, in the absence of CaM, AC exhibits significant structural disorder, and a 75-residue-long stretch within AC undergoes a disorder-to-order transition upon CaM binding. Beyond this local folding, CaM binding induces long-range allosteric effects that stabilize the distant catalytic site, whilst preserving catalytic loop flexibility. We propose that the high enzymatic activity of AC is due to a tight balance between the CaM-induced decrease of structural flexibility around the catalytic site and the preservation of catalytic loop flexibility, allowing for fast substrate binding and product release. The CaM-induced dampening of AC conformational disorder is likely relevant to other CaM-activated enzymes. PMID- 29287066 TI - Variance components associated with long-echo-time MR spectroscopic imaging in human brain at 1.5T and 3T. AB - OBJECT: Magnetic resonance spectroscopic imaging (MRSI) is increasingly used in medicine and clinical research. Previous reliability studies have used small samples and focussed on limited aspects of variability; information regarding 1.5T versus 3T performance is lacking. The aim of the present work was to measure the inter-session, intra-session, inter-subject, within-brain and residual variance components using both 1.5T and 3T MR scanners. MATERIALS AND METHODS: Eleven healthy volunteers were invited for MRSI scanning on three occasions at both 1.5T and 3T, with four scans acquired at each visit. We measured variance components, correcting for grey matter and white matter content of voxels, of metabolite peak areas and peak area ratios. RESULTS: Residual variance was in general the largest component at 1.5T (8.6-24.6%), while within-brain variation was the largest component at 3T (12.0-24.7%). Inter-subject variation was around 5%, while inter- and intra-session variance were both generally small. CONCLUSION: Multiple variance contributions associated with MRSI measurements were quantified and the performance of 1.5T and 3T MRI scanners compared using data from the same group of subjects. Residual error is much lower at 3T, but other variance components remain important. PMID- 29287067 TI - How to determine leg dominance: The agreement between self-reported and observed performance in healthy adults. AB - CONTEXT: Since decades leg dominance is suggested to be important in rehabilitation and return to play in athletes with anterior cruciate ligament injuries. However, an ideal method to determine leg dominance in relation to task performance is still lacking. OBJECTIVE: To test the agreement between self reported and observed leg dominance in bilateral mobilizing and unilateral stabilizing tasks, and to assess whether the dominant leg switches between bilateral mobilizing tasks and unilateral stabilizing tasks. DESIGN: Cross sectional study. PARTICIPANTS: Forty-one healthy adults: 21 men aged 36 +/- 17 years old and 20 women aged 36 +/-15 years old. MEASUREMENT AND ANALYSIS: Participants self-reported leg dominance in the Waterloo Footedness Questionnaire Revised (WFQ-R), and leg dominance was observed during performance of four bilateral mobilizing tasks and two unilateral stabilizing tasks. Descriptive statistics and crosstabs were used to report the percentages of agreement. RESULTS: The leg used to kick a ball had 100% agreement between the self-reported and observed dominant leg for both men and women. The dominant leg in kicking a ball and standing on one leg was the same in 66.7% of the men and 85.0% of the women. The agreement with jumping with one leg was lower: 47.6% for men and 70.0% for women. CONCLUSIONS: It is appropriate to ask healthy adults: "If you would shoot a ball on a target, which leg would you use to shoot the ball?" to determine leg dominance in bilateral mobilizing tasks. However, a considerable number of the participants switched the dominant leg in a unilateral stabilizing task. PMID- 29287068 TI - Mutations in hepatitis B virus polymerase are associated with the postoperative survival of hepatocellular carcinoma patients. AB - Proofreading deficiencies of hepatitis B virus polymerase result in frequent DNA mutations in the hepatitis B virus genome. Here, we performed sequencing analysis of the hepatitis B virus polymerase gene to assess its association with the postoperative survival in 92 patients with HBV-related hepatocellular carcinoma by using the Kaplan-Meier method. The 2525, 2733, 2738, 2768, 2946, 3063, 3066, 3109, 31, 529, 735, 939, 1078, 1137, 1383, 1461, 1485, 1544, and 1613 mutation sites were identified as being associated with HCC outcomes by the log-rank test. After adjusting for clinical characteristics by using the Cox hazard model, site 31 (relative risk, 8.929; 95% confidence interval, 3.433-23.22; P = 0.000) in the spacer domain and sites 529 (relative risk, 5.656; 95% confidence interval, 1.599 19.999; P = 0.007) and 1078 (relative risk, 3.442; 95% confidence interval, 1.070 11.068; P = 0.038) in the reverse transcriptase domain of hepatitis B virus polymerase were identified as independent predictors of postoperative survival in hepatitis B virus related hepatocellular carcinoma. The mutations at the 31 (Ser314Pro), 529 (Asp480Asn), and 1078 (Ser663Ala) sites all resulted in amino acid changes in hepatitis B virus polymerase and were associated with shortened life-span. The 31 and 529 sites were located in the overlapping region for the PreS and S genes but did not induce amino acid substitution in these two regions. Our finding of the correlation between hepatitis B virus DNA polymerase mutations and hepatocellular carcinoma survival will help identify the patients subgroup with poor prognosis, and help the clinicians to refine the therapeutic decision individualized. PMID- 29287069 TI - On the prediction of DNA-binding proteins only from primary sequences: A deep learning approach. AB - DNA-binding proteins play pivotal roles in alternative splicing, RNA editing, methylating and many other biological functions for both eukaryotic and prokaryotic proteomes. Predicting the functions of these proteins from primary amino acids sequences is becoming one of the major challenges in functional annotations of genomes. Traditional prediction methods often devote themselves to extracting physiochemical features from sequences but ignoring motif information and location information between motifs. Meanwhile, the small scale of data volumes and large noises in training data result in lower accuracy and reliability of predictions. In this paper, we propose a deep learning based method to identify DNA-binding proteins from primary sequences alone. It utilizes two stages of convolutional neutral network to detect the function domains of protein sequences, and the long short-term memory neural network to identify their long term dependencies, an binary cross entropy to evaluate the quality of the neural networks. When the proposed method is tested with a realistic DNA binding protein dataset, it achieves a prediction accuracy of 94.2% at the Matthew's correlation coefficient of 0.961. Compared with the LibSVM on the arabidopsis and yeast datasets via independent tests, the accuracy raises by 9% and 4% respectively. Comparative experiments using different feature extraction methods show that our model performs similar accuracy with the best of others, but its values of sensitivity, specificity and AUC increase by 27.83%, 1.31% and 16.21% respectively. Those results suggest that our method is a promising tool for identifying DNA-binding proteins. PMID- 29287070 TI - A diagnostic and epidemiologic investigation of acute febrile illness (AFI) in Kilombero, Tanzania. AB - INTRODUCTION: In low-resource settings, empiric case management of febrile illness is routine as a result of limited access to laboratory diagnostics. The use of comprehensive fever syndromic surveillance, with enhanced clinical microbiology, advanced diagnostics and more robust epidemiologic investigation, could enable healthcare providers to offer a differential diagnosis of fever syndrome and more appropriate care and treatment. METHODS: We conducted a year long exploratory study of fever syndrome among patients >= 1 year if age, presenting to clinical settings with an axillary temperature of >=37.5 degrees C and symptomatic onset of <=5 days. Blood and naso-pharyngeal/oral-pharyngeal (NP/OP) specimens were collected and analyzed, respectively, using AFI and respiratory TaqMan Array Cards (TAC) for multi-pathogen detection of 57 potential causative agents. Furthermore, we examined numerous epidemiologic correlates of febrile illness, and conducted demographic, clinical, and behavioral domain specific multivariate regression to statistically establish associations with agent detection. RESULTS: From 15 September 2014-13 September 2015, 1007 febrile patients were enrolled, and 997 contributed an epidemiologic survey, including: 14% (n = 139) 1<5yrs, 19% (n = 186) 5-14yrs, and 67% (n = 672) >=15yrs. AFI TAC and respiratory TAC were performed on 842 whole blood specimens and 385 NP/OP specimens, respectively. Of the 57 agents surveyed, Plasmodium was the most common agent detected. AFI TAC detected nucleic acid for one or more of seven microbial agents in 49% of AFI blood samples, including: Plasmodium (47%), Leptospira (3%), Bartonella (1%), Salmonella enterica (1%), Coxiella burnetii (1%), Rickettsia (1%), and West Nile virus (1%). Respiratory TAC detected nucleic acid for 24 different microbial agents, including 12 viruses and 12 bacteria. The most common agents detected among our surveyed population were: Haemophilus influenzae (67%), Streptococcus pneumoniae (55%), Moraxella catarrhalis (39%), Staphylococcus aureus (37%), Pseudomonas aeruginosa (36%), Human Rhinovirus (25%), influenza A (24%), Klebsiella pneumoniae (14%), Enterovirus (15%) and group A Streptococcus (12%). Our epidemiologic investigation demonstrated both age and symptomatic presentation to be associated with a number of detected agents, including, but not limited to, influenza A and Plasmodium. Linear regression of fully-adjusted mean cycle threshold (Ct) values for Plasmodium also identified statistically significant lower mean Ct values for older children (20.8), patients presenting with severe fever (21.1) and headache (21.5), as well as patients admitted for in-patient care and treatment (22.4). CONCLUSIONS: This study is the first to employ two syndromic TaqMan Array Cards for the simultaneous survey of 57 different organisms to better characterize the type and prevalence of detected agents among febrile patients. Additionally, we provide an analysis of the association between adjusted mean Ct values for Plasmodium and key clinical and demographic variables, which may further inform clinical decision-making based upon intensity of infection, as observed across endemic settings of sub-Saharan Africa. PMID- 29287073 TI - Correction: Orienting the causal relationship between imprecisely measured traits using GWAS summary data. AB - [This corrects the article DOI: 10.1371/journal.pgen.1007081.]. PMID- 29287071 TI - Uptake of polyphosphate microparticles in vitro (SaOS-2 and HUVEC cells) followed by an increase of the intracellular ATP pool size. AB - Recently two approaches were reported that addressed a vitally important problem in regenerative medicine, i. e. the successful treatment of wounds even under diabetic conditions. Accordingly, these studies with diabetic rabbits [Sarojini et al. PLoS One 2017, 12(4):e0174899] and diabetic mice [Muller et al. Polymers 2017, 9, 300] identified a novel (potential) target for the acceleration of wound healing in diabetes. Both studies propose a raise of the intracellular metabolic energy status via exogenous administration either of ATP, encapsulated into lipid vesicles, or of polyphosphate (polyP) micro-/nanoparticles. Recently this physiological polymer, polyP, was found to release metabolic energy in form of ATP into both the extra- and also intra-cellular space. In the present work the uptake mechanism of the amorphous polyP microparticles "Ca-polyP-MP" has been described and found to be a clathrin-dependent endocytosis import, based on inhibition studies with the inhibitor trifluoperazine, which blocks the clathrin dependent endocytosis import. The experiments had been performed with SaOS-2 cells, by studying the uptake and distribution of the electron-dense particles into the cells, and with HUVEC cells, for analysis of the intracellular accumulation of polyP, visualized by fluorescent staining of polyP. Concurrently with the uptake of particular polyP the intracellular ATP level increased as well. In contrast to "Ca-polyP-MP" the soluble polyP, administered as "Na polyP[Ca2+]", did not cause an increase in the intracellular Ca2+ level, suggesting a different mode of action of these two forms of polyP. Based on existing data on the effect of polyP and ATP on the induction of vascularization during wound repair, both groups (Sarojini et al. and Muller et al.) propose that the acceleration of wound repair is based on an increased metabolic energy supply directly to the regenerating wound area. PMID- 29287072 TI - A highly stable blood meal alternative for rearing Aedes and Anopheles mosquitoes. AB - We investigated alternatives to whole blood for blood feeding of mosquitoes with a focus on improved stability and compatibility with mass rearing programs. In contrast to whole blood, an artificial blood diet of ATP-supplemented plasma was effective in maintaining mosquito populations and was compatible with storage for extended periods refrigerated, frozen, and as a lyophilized powder. The plasma ATP diet supported rearing of both Anopheles and Aedes mosquitoes. It was also effective in rearing Wolbachia-infected Aedes mosquitoes, suggesting compatibility with vector control efforts. PMID- 29287074 TI - Coronary angiography is related to improved clinical outcome of out-of-hospital cardiac arrest with initial non-shockable rhythm. AB - OBJECTIVE: Coronary angiography (CAG) for survivors of out-of-hospital cardiac arrest (OHCA) enables early identification of coronary artery disease and revascularization, which might improve clinical outcome. However, little is known for the role of CAG in patients with initial non-shockable cardiac rhythm. METHODS: We investigated clinical outcomes of successfully resuscitated 670 adult OHCA patients who were transferred to 27 hospitals in Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance (CAPTURES), a Korean nationwide multicenter registry. The primary outcome was 30-day survival with good neurological outcome. Propensity score matching and inverse probability of treatment weighting analyses were performed to account for indication bias. RESULTS: A total of 401 (60%) patients showed initial non-shockable rhythm. CAG was performed only in 13% of patients with non-shockable rhythm (53 out of 401 patients), whereas more than half of patients with shockable rhythm (149 out of 269 patients, 55%). Clinical outcome of patients who underwent CAG was superior to patients without CAG in both non-shockable (hazard ratio (HR) = 3.6, 95% confidence interval (CI) = 2.5-5.2) and shockable rhythm (HR = 3.7, 95% CI = 2.5 5.4, p < 0.001, all). Further analysis after propensity score matching or inverse probability of treatment weighting showed consistent findings (HR ranged from 2.0 to 3.2, p < 0.001, all). CONCLUSIONS: Performing CAG was related to better survival with good neurological outcome of OHCA patients with initial non shockable rhythms as well as shockable rhythms. PMID- 29287075 TI - Association of serum brain derived neurotropic factor with duration of drug-naive period and positive-negative symptom scores in drug naive schizophrenia. AB - INTRODUCTION: The aim of this study was to compare the serum brain derived neurotropic factor (BNDF) levels of patients with schizophrenia who had never received an antipsychotic treatment with those of a control group. Also, to analyze the relationship between the Positive and Negative Symptom Scale (PANSS) scores and BDNF levels of the patients during the period they were drug-naive. MATERIALS AND METHODS: The sample of the study comprised patients who presentedto the Psychiatry Clinic and were admitted after a distinctive schizophrenia diagnosis was made in accordance with the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) diagnosis classification and who were not using and never had any antipsychotic medicine. A total of 160 participants were included in the study, 80 of whom had schizophrenia patients and 80 constituted the age- and sex-matched healthy control group. Before the start of the treatment, the serum samples to be checked for the BDNF levels were collected from the patients. RESULTS: The difference between the average BDNF levels of the groups were statistically significant (t = -5.25; p?.001). An analysis as to whether there was a relation between the BDNF levels and the drug naive duration indicated no correlations. An examination of the relationship between PANSS scores and BDNF levels of the patients yielded no correlations. DISCUSSION: Serum BDNF levels seem to be one of the indicators of schizophrenia and its progress; nevertheless, we still do not have sufficient information about this neurotropic factor. In light of our study, the neurodevelopmental changes that occur at disease onset of the illness prominently affect the progress of the illness, which highlights the importance of the treatment in the early stages. PMID- 29287076 TI - Do neural nets learn statistical laws behind natural language? AB - The performance of deep learning in natural language processing has been spectacular, but the reasons for this success remain unclear because of the inherent complexity of deep learning. This paper provides empirical evidence of its effectiveness and of a limitation of neural networks for language engineering. Precisely, we demonstrate that a neural language model based on long short-term memory (LSTM) effectively reproduces Zipf's law and Heaps' law, two representative statistical properties underlying natural language. We discuss the quality of reproducibility and the emergence of Zipf's law and Heaps' law as training progresses. We also point out that the neural language model has a limitation in reproducing long-range correlation, another statistical property of natural language. This understanding could provide a direction for improving the architectures of neural networks. PMID- 29287078 TI - Reactive navigation in extremely dense and highly intricate environments. AB - Reactive navigation is a well-known paradigm for controlling an autonomous mobile robot, which suggests making all control decisions through some light processing of the current/recent sensor data. Among the many advantages of this paradigm are: 1) the possibility to apply it to robots with limited and low-priced hardware resources, and 2) the fact of being able to safely navigate a robot in completely unknown environments containing unpredictable moving obstacles. As a major disadvantage, nevertheless, the reactive paradigm may occasionally cause robots to get trapped in certain areas of the environment-typically, these conflicting areas have a large concave shape and/or are full of closely-spaced obstacles. In this last respect, an enormous effort has been devoted to overcome such a serious drawback during the last two decades. As a result of this effort, a substantial number of new approaches for reactive navigation have been put forward. Some of these approaches have clearly improved the way how a reactively controlled robot can move among densely cluttered obstacles; some other approaches have essentially focused on increasing the variety of obstacle shapes and sizes that could be successfully circumnavigated; etc. In this paper, as a starting point, we choose the best existing reactive approach to move in densely cluttered environments, and we also choose the existing reactive approach with the greatest ability to circumvent large intricate-shaped obstacles. Then, we combine these two approaches in a way that makes the most of them. From the experimental point of view, we use both simulated and real scenarios of challenging complexity for testing purposes. In such scenarios, we demonstrate that the combined approach herein proposed clearly outperforms the two individual approaches on which it is built. PMID- 29287077 TI - Ribotype 078 Clostridium difficile infection incidence in Dutch hospitals is not associated with provincial pig farming: Results from a national sentinel surveillance, 2009-2015. AB - BACKGROUND: It has been suggested that the high incidence of ribotype 078 Clostridium difficile infections (CDI) in the Netherlands is related to pig farming. METHODS: We used data of hospitalised CDI patients (>2yrs of age) diagnosed between May 2009 and May 2015 in 26 hospitals participating in a national sentinel surveillance. We compared clinical and geographical characteristics of 078 CDI to other CDI. We investigated the association between 078 CDI incidence and four indicators of pig farming (piglet, pig, piglet farm and pig farm density) by mixed-effects Poisson regression. We used a space-time permutation model to search for community-onset 078 CDI clusters (using SaTScan). RESULTS: A total of 4,691 CDI were identified. Ribotype 078 was isolated in 493 of 3,756 patients (13.1%) including a typing result. These patients had slightly higher community-onset disease and a 35% increase of 30-day mortality compared to non-078 CDI patients. The pooled overall and 078 incidence rates were 2.82 (95% CI, 2.42-3.29) and 0.26 (95% CI, 0.21-0.31) CDI per 10,000 patients-days respectively. Hospital 078 CDI incidence was not associated with provincial pig (IRR, 0.98; 95% CI, 0.89-1.08), piglet (IRR, 0.95; 95% CI, 0.75-1.19), pig farm (IRR, 1.08; 95% CI, 0.84-1.39), or piglet farm density (IRR, 1.00; 95% CI, 0.56 1.79). No clusters of community-onset ribotype 078 CDI were found. CONCLUSIONS: Our results do not indicate that the ribotype 078 CDI incidence in hospitals is related to pig (farm) or piglet (farm) density. However, transmission beyond provincial borders or in non-hospitalised patients cannot be excluded. PMID- 29287079 TI - Numerical modeling of nanodrug distribution in tumors with heterogeneous vasculature. AB - The distribution and accumulation of nanoparticle dosage in a tumor are important in evaluating the effectiveness of cancer treatment. The cell survival rate can quantify the therapeutic effect, and the survival rates after multiple treatments are helpful to evaluate the efficacy of a chemotherapy plan. We developed a mathematical tumor model based on the governing equations describing the fluid flow and particle transport to investigate the drug transportation in a tumor and computed the resulting cumulative concentrations. The cell survival rate was calculated based on the cumulative concentration. The model was applied to a subcutaneous tumor with heterogeneous vascular distributions. Various sized dextrans and doxorubicin were respectively chosen as the nanodrug carrier and the traditional chemotherapeutic agent for comparison. The results showed that: 1) the largest nanoparticle drug in the current simulations yielded the highest cumulative concentration in the well vascular region, but second lowest in the surrounding normal tissues, which implies it has the best therapeutic effect to tumor and at the same time little harmful to normal tissue; 2) on the contrary, molecular chemotherapeutic agent produced the second lowest cumulative concentration in the well vascular tumor region, but highest in the surrounding normal tissue; 3) all drugs have very small cumulative concentrations in the tumor necrotic region, where drug transport is solely through diffusion. This might mean that it is hard to kill tumor stem cells hiding in it. The current model indicated that the effectiveness of the anti-tumor drug delivery was determined by the interplay of the vascular density and nanoparticle size, which governs the drug transport properties. The use of nanoparticles as anti-tumor drug carriers is generally a better choice than molecular chemotherapeutic agent because of its high treatment efficiency on tumor cells and less damage to normal tissues. PMID- 29287080 TI - Serum apolipoprotein A1 and haptoglobin, in patients with suspected drug-induced liver injury (DILI) as biomarkers of recovery. AB - BACKGROUND: There is a clear need for better biomarkers of drug-induced-liver injury (DILI). AIMS: We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2 macroglobulin, in patients with DILI. METHODS: We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT <2x the upper limit of normal (ULN), and BILI <2x ULN. RESULTS: After adjudication, 154 patients were considered to have DILI and 22 were considered to have acute liver injury without DILI. A multivariate regression analysis (ActiTest-DILI patent pending) combining the ActiTest components without BILI and ALT (used as references), apolipoprotein-A1, haptoglobin, alpha-2 macroglobulin and GGT, age and gender, resulted in a significant prediction of recovery with 67.0% accuracy (77/115) and an AUROC of 0.724 (P<0.001 vs. no prediction 0.500). Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65) versus those that did not (n = 16), at inclusion, at 4-8 weeks and at 8-12 weeks. The same results were observed after stratification on APAP cases and non-APAP cases. CONCLUSIONS: We identified that apolipoprotein-A1 and haptoglobin had significant predictive values for the prediction of recovery at 12 weeks in DILI, enabling the construction of a new prognostic panel, the DILI-ActiTest, which needs to be independently validated. PMID- 29287081 TI - Firing rate equations require a spike synchrony mechanism to correctly describe fast oscillations in inhibitory networks. AB - Recurrently coupled networks of inhibitory neurons robustly generate oscillations in the gamma band. Nonetheless, the corresponding Wilson-Cowan type firing rate equation for such an inhibitory population does not generate such oscillations without an explicit time delay. We show that this discrepancy is due to a voltage dependent spike-synchronization mechanism inherent in networks of spiking neurons which is not captured by standard firing rate equations. Here we investigate an exact low-dimensional description for a network of heterogeneous canonical Class 1 inhibitory neurons which includes the sub-threshold dynamics crucial for generating synchronous states. In the limit of slow synaptic kinetics the spike synchrony mechanism is suppressed and the standard Wilson-Cowan equations are formally recovered as long as external inputs are also slow. However, even in this limit synchronous spiking can be elicited by inputs which fluctuate on a time-scale of the membrane time-constant of the neurons. Our meanfield equations therefore represent an extension of the standard Wilson-Cowan equations in which spike synchrony is also correctly described. PMID- 29287082 TI - Risk factors for mortality of children with zoonotic visceral leishmaniasis in Central Tunisia. AB - BACKGROUND: Zoonotic visceral leishmaniasis (ZVL) caused by Leishmania infantum is endemic with an epidemiological profile of a paediatric disease in Tunisia. In the context of a high fatality rate, identifying risk factors for in-hospital mortality in children treated for ZVL is of major epidemiological importance. DESIGN: A retrospective (case-control) study included 230 immuno-competent children diagnosed and confirmed with primary ZVL in the paediatric department of the University Hospital of Kairouan between 2004 and 2014. Forty-seven per cent (47%) were children under 18 months of age, and with a male / female ratio of 1.01:1. RESULTS: The overall case-fatality was 6% (n = 14). The risk factors for in-hospital death identified by a multivariate analysis were: bleeding at admission (OR = 25.5, 95% CI: 2.26-287.4; p = 0.009), white cell count less than 4000/mm3 (OR = 5.66, 95% CI: 1.16-27.6; p = 0.032), cytolysis (OR = 28.13, 95% CI: 4.55-173.6; p < 0.001), and delay between onset of symptoms and admission >= 15 days (OR = 11, 95% CI: 1.68-72; p = 0.012). CONCLUSION: The results strongly suggest that paediatric patients admitted 15 days after onset of symptoms, with bleeding, white cell counts below 4,000/mm3, and cytolysis at admission should be considered severe cases and subsequently, they are at high risk of mortality. A better understanding of factors associated with death of children from ZVL may contribute to decrease mortality. PMID- 29287084 TI - Differentiation and cell density upregulate cytochrome c levels in megakaryoblastic cell lines: Implications for analysis of CYCS-associated thrombocytopenia. AB - Mutations in the cytochrome c gene (CYCS) cause autosomal dominant thrombocytopenia by an unknown mechanism. While attempting to generate megakaryoblastic cell lines exogenously expressing cytochrome c variants, we discovered that endogenous cytochrome c expression increased both upon induction of differentiation with the phorbol ester phorbol 12-myristate 13-acetate (PMA), and as cell density increased. A concomitant increase in cytochrome c oxidase subunit II in response to PMA, but not cell higher cell density, suggests upregulation of the mitochondrial respiratory chain may be a specific feature of differentiation. These results highlight the likely importance of cytochrome c in both differentiating and proliferating cells, and illustrate the unsuitability of megakaryoblastic lines for modeling CYCS-associated thrombocytopenia. PMID- 29287083 TI - Molecular cloning, bioinformatics analysis, and expression of small heat shock protein beta-1 from Camelus dromedarius, Arabian camel. AB - Small heat shock protein beta-1 (HSPB-1) plays an essential role in the protection of cells against environmental stress.Elucidation of its molecular, structural, and biological characteristics in a naturally wild-type model is essential. Although the sequence information of the HSPB-1 gene is available for many mammalian species, the HSPB-1 gene of Arabian camel (Arabian camel HSPB-1) has not yet been structurally characterized. We cloned and functionally characterized a full-length of Arabian camel HSPB-1 cDNA. It is 791 bp long, with a 5'-untranslated region (UTR) of 34 bp, a 3'-UTR of 151 bp with a poly(A) tail, and an open reading frame (ORF) of 606 bp encoding a protein of 201 amino acids (accession number: MF278354). The tissue-specific expression analysis of Arabian camel HSPB-1 mRNA was examined using quantitative real-time PCR (qRT-PCR); which suggested that Arabian camel HSPB-1 mRNA was constitutionally expressed in all examined tissues of Arabian camel, with the predominately level in the esophagus tissue. Peptide mass fingerprint-mass spectrometry (PMF-MS) analysis of the purified Arabian camel HSPB-1 protein confirmed the identity of this protein. Phylogenetic analysis showed that the HSPB-1 protein of Arabian camel is grouped together with those of Bactrian camel and Alpaca. Comparing the modelled 3D structure of Arabian camel HSPB-1 protein with the available protein 3D structure of HSPB-1 from human confirmed the presence of alpha-crystallin domain, and high similarities were noted between the two structures by using super secondary structure prediction. PMID- 29287085 TI - Loss of TLR4 in mouse Muller cells inhibits both MyD88-dependent and -independent signaling. AB - Muller cells are key to metabolic and ionic regulation in the retina. They also produce a number of inflammatory mediators and are significantly affected in diabetic retinopathy. To investigate the role of toll-like receptor 4 (TLR4) in retinal Muller cells, we crossed TLR4 floxed with PDGFRalpha-Cre mice to eliminate TLR4 in retinal Muller cells. We performed Western blotting and ELISA analyses to determine whether loss of TLR4 affected myeloid differentiation primary response protein (MyD88)-dependent or -independent signaling, leading to reduced levels of tumor necrosis factor alpha (TNFalpha) and interleukin 1 beta (IL1beta) in whole retinal lysates from the TLR4 floxed and TLR4-PDGFRalpha-Cre mice. Data show that TLR4-PDGFRalpha-Cre mice have reduced levels of both the MyD88-dependent and -independent signaling pathways. These studies confirm successful development of a Muller cell-specific TLR4 knockout mouse colony. These mice have reduced MyD88-dependent and -independent signaling pathway proteins, as well as reduced TNFalpha and IL1beta levels. These mice can be used to dissect TLR4 signaling in disorders affecting retinal Muller cells. PMID- 29287086 TI - Dose-Duration Reciprocity for G protein activation: Modulation of kinase to substrate ratio alters cell signaling. AB - In animal cells, activation of heterotrimeric G protein signaling generally occurs when the system's cognate signal exceeds a threshold, whereas in plant cells, both the amount and the exposure time of at least one signal, D-glucose, are used toward activation. This unusual signaling property called Dose-Duration Reciprocity, first elucidated in the genetic model Arabidopsis thaliana, is achieved by a complex that is comprised of a 7-transmembrane REGULATOR OF G SIGNALING (RGS) protein (AtRGS1), a Galpha subunit that binds and hydrolyzes nucleotide, a Gbetagamma dimer, and three WITH NO LYSINE (WNK) kinases. D-glucose is one of several signals such as salt and pathogen-derived molecular patterns that operates through this protein complex to activate G protein signaling by WNK kinase transphosphorylation of AtRGS1. Because WNK kinases compete for the same substrate, AtRGS1, we hypothesize that activation is sensitive to the AtRGS1 amount and that modulation of the AtRGS1 pool affects the response to the stimulant. Mathematical simulation revealed that the ratio of AtRGS1 to the kinase affects system sensitivity to D-glucose, and therefore illustrates how modulation of the cellular AtRGS1 level is a means to change signal-induced activation. AtRGS1 levels change under tested conditions that mimic physiological conditions therefore, we propose a previously-unknown mechanism by which plants react to changes in their environment. PMID- 29287087 TI - Transition probabilities between changing sensitization levels, waitlist activity status and competing-risk kidney transplant outcomes using multi-state modeling. AB - BACKGROUND: Sensitization and activity status are associated with kidney transplant waitlist mortality. Unknown is how changes in these covariates after listing impact transplant outcomes. METHODS: Two cohorts were created from the OPTN (Organ Procurement and Transplantation Network) database, one pre-KAS (new kidney allocation system) (10/01/2009-12/04/2013, n = 97,793) and one post-KAS (12/04/2014-06/17/2015, n = 13,113). Multi-state modeling provides transition probabilities between intermediate states (CPRA category/activity status combinations) and competing-risk outcomes: transplant (living), transplant (deceased), death, or other/well. RESULTS: Transition probabilities show chances of converting between intermediate states prior to a competing-risk outcome. One year transplant probabilities for post-KAS candidates with a CPRA of 0%(P, 0.123[95% CI, 0.117,0.129]), 1-79%(P, 0.125 [95% CI, 0.112,0.139]), 95-98%(P, 0.242[95% CI, 0.188, 0.295]) and 99-100%(P, 0.252 [95% CI, 0.195, 0.308]) were significantly higher than the pre-KAS cohort; they were lower for CPRA 80-89%(P, 0.152 [95% CI, 0.116,0.189]) and not statistically different for CPRA 90-94%(P, 0.180 [95% CI, 0.137,0.223]) candidates. Post-KAS, Whites had a statistically higher transplant probability only at a CPRA of 99-100%. CONCLUSION: Multi-state modeling provides transition probabilities between CPRA/activity status combinations, giving estimates on how changing patient characteristic's after listing impact outcomes. Preliminarily, across most CPRA categories, there was no statistical difference in transplant probabilities between Whites, Blacks and Hispanics following KAS implementation, however, this finding requires longer follow-up for validation. PMID- 29287088 TI - Higher retention and viral suppression with adolescent-focused HIV clinic in South Africa. AB - OBJECTIVE: To determine retention in care and virologic suppression among HIV infected adolescents and young adults attending an adolescent-friendly clinic compared to those attending the standard pediatric clinic at the same site. DESIGN: Retrospective cohort analysis. SETTING: Government supported, hospital based antiretroviral clinic in KwaZulu-Natal, South Africa. PARTICIPANTS: Two hundred forty-one perinatally HIV-infected adolescents and young adults aged 13 to 24 years attending an adolescent-friendly clinic or the standard pediatric clinic from April 2007 to November 2015. INTERVENTION: Attendance in an adolescent-friendly clinic compared to a standard pediatric clinic. OUTCOMES MEASURES: Retention in care defined as one clinic visit or pharmacy refill in the prior 6 months; HIV-1 viral suppression defined as < 400 copies/ml. RESULTS: Overall, among 241 adolescents and young adults, retention was 89% (214/241) and viral suppression was 81% (196/241). Retention was higher among those attending adolescent clinic (95%) versus standard pediatric clinic (85%; OR 3.7; 95% confidence interval (CI) 1.2-11.1; p = 0.018). Multivariable logistic regression adjusted for age at ART initiation, gender, pre-ART CD4 count, months on ART, and tuberculosis history indicated higher odds of retention in adolescents and young adults attending adolescent compared to standard clinic (AOR = 8.5; 95% CI 2.3 32.4; p = 0.002). Viral suppression was higher among adolescents and young adults attending adolescent (91%) versus standard pediatric clinic (80%; OR 2.5; 95% CI 1.1-5.8; p = 0.028). A similar multivariable logistic regression model indicated higher odds of viral suppression in adolescents and young adults attending adolescent versus standard pediatric clinic (AOR = 3.8; 95% CI 1.5-9.7; p = 0.005). CONCLUSION: Adolescents and young adults attending an adolescent-friendly clinic had higher retention in care and viral suppression compared to adolescents attending the standard pediatric clinic. Further studies are needed to prospectively assess the impact of adolescent-friendly services on these outcomes. PMID- 29287089 TI - Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. AB - Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 MUM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug. PMID- 29287090 TI - Immune activation despite preserved CD4 T cells in perinatally HIV-infected children and adolescents. AB - BACKGROUND: HIV disease progresses more rapidly in children than adults with mortality rates exceeding 50% by 2 years of age without antiretroviral therapy (ART) in sub-Saharan Africa. Recent World Health Organization (WHO) guidelines recommend universal treatment for all living persons with HIV, yet there is limited supporting evidence in pediatric populations. The objective of this study was to determine whether CD4 cell counts reflect immunological markers associated with disease progression in ART naive perinatally-infected HIV+ children and adolescents and their response to ART. METHODS: PBMC and plasma samples were collected from 71 HIV negative and 132 HIV+ children (65 ART naive and 67 on ART) between ages 1-19 years from Mombasa, Kenya. Untreated HIV+ subjects were sub categorized by high or low CD4 T cell counts. Immune activation markers CD38, HLA DR and Ki67 were analyzed by flow cytometry. Plasma soluble CD14 (sCD14) was quantified by ELISA. RESULTS: HIV-infected children and adolescents with preserved CD4 cell counts had depleted CD4 percentages and CD4:CD8 ratios, and high immune activation levels. ART initiation rapidly and persistently reversed T cell activation, but failed to normalize CD4:CD8 ratios and plasma sCD14 levels. CONCLUSIONS: Diminished CD4 percentages and CD4:CD8 ratios along with profound immune activation occur independent of CD4 cell count thresholds in ART naive HIV+ children and adolescents. Immediate ART initiation, as recommended in the most recent WHO guidelines may protect them from pathologic sequelae associated with persistent inflammation. PMID- 29287091 TI - Grammatical verb aspect and event roles in sentence processing. AB - Two experiments examine how grammatical verb aspect constrains our understanding of events. According to linguistic theory, an event described in the perfect aspect (John had opened the bottle) should evoke a mental representation of a finished event with focus on the resulting object, whereas an event described in the imperfective aspect (John was opening the bottle) should evoke a representation of the event as ongoing, including all stages of the event, and focusing all entities relevant to the ongoing action (instruments, objects, agents, locations, etc.). To test this idea, participants saw rebus sentences in the perfect and imperfective aspect, presented one word at a time, self-paced. In each sentence, the instrument and the recipient of the action were replaced by pictures (John was using/had used a *corkscrew* to open the *bottle* at the restaurant). Time to process the two images as well as speed and accuracy on sensibility judgments were measured. Although experimental sentences always made sense, half of the object and instrument pictures did not match the temporal constraints of the verb. For instance, in perfect sentences aspect-congruent trials presented an image of the corkscrew closed (no longer in-use) and the wine bottle fully open. The aspect-incongruent yet still sensible versions either replaced the corkscrew with an in-use corkscrew (open, in-hand) or the bottle image with a half-opened bottle. In this case, the participant would still respond "yes", but with longer expected response times. A three-way interaction among Verb Aspect, Sentence Role, and Temporal Match on image processing times showed that participants were faster to process images that matched rather than mismatched the aspect of the verb, especially for resulting objects in perfect sentences. A second experiment replicated and extended the results to confirm that this was not due to the placement of the object in the sentence. These two experiments extend previous research, showing how verb aspect drives not only the temporal structure of event representation, but also the focus on specific roles of the event. More generally, the findings of visual match during online sentence picture processing are consistent with theories of perceptual simulation. PMID- 29287092 TI - Connective tissue growth factor dependent collagen gene expression induced by MAS agonist AR234960 in human cardiac fibroblasts. AB - Perspectives on whether the functions of MAS, a G protein-coupled receptor, are beneficial or deleterious in the heart remain controversial. MAS gene knockout reduces coronary vasodilatation leading to ischemic injury. G protein signaling activated by MAS has been implicated in progression of adaptive cardiac hypertrophy to heart failure and fibrosis. In the present study, we observed increased expression of MAS, connective tissue growth factor (CTGF) and collagen genes in failing (HF) human heart samples when compared to non-failing (NF). Expression levels of MAS are correlated with CTGF in HF and NF leading to our hypothesis that MAS controls CTGF production and the ensuing expression of collagen genes. In support of this hypothesis we show that the non-peptide MAS agonist AR234960 increases both mRNA and protein levels of CTGF via ERK1/2 signaling in HEK293-MAS cells and adult human cardiac fibroblasts. MAS-mediated CTGF expression can be specifically blocked by MAS inverse agonist AR244555 and also by MEK1 inhibition. Expression of CTGF gene was essential for MAS-mediated up-regulation of different collagen subtype genes in HEK293-MAS cells and human cardiac fibroblasts. Knockdown of CTGF by RNAi disrupted collagen gene regulation by the MAS-agonist. Our data indicate that CTGF mediates the profibrotic effects of MAS in cardiac fibroblasts. Blocking MAS-CTGF-collagen pathway should be considered for pharmacological intervention for HF. PMID- 29287094 TI - Validation of a novel automatic deposition of bacteria and yeasts on MALDI target for MALDI-TOF MS-based identification using MALDI Colonyst robot. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) -based identification of bacteria and fungi significantly changed the diagnostic process in clinical microbiology. We describe here a novel technique for bacterial and yeast deposition on MALDI target using an automated workflow resulting in an increase of the microbes' score of MALDI identification. We also provide a comparison of four different sample preparation methods. In the first step of the study, 100 Gram-negative bacteria, 100 Gram-positive bacteria, 20 anaerobic bacteria and 20 yeasts were spotted on the MALDI target using manual deposition, semi-extraction, wet deposition onto 70% formic acid and by automatic deposition using MALDI Colonyst. The lowest scores were obtained by manual toothpick spotting which significantly differ from other methods. Identification score of semi-extraction, wet deposition and automatic wet deposition did not significantly differ using calculated relative standard deviation (RSD). Nevertheless, the best results with low error rate have been observed using MALDI Colonyst robot. The second step of validation included processing of 542 clinical isolates in routine microbiological laboratory by a toothpick direct spotting, on plate formic acid extraction (for yeasts) and automatic deposition using MALDI Colonyst. Validation in routine laboratory process showed significantly higher identification scores obtained using automated process compared with standard manual deposition in all tested microbial groups (Gram-positive, Gram-negative, anaerobes, and yeasts). As shown by our data, automatic colony deposition on MALDI target results in an increase of MALDI-TOF MS identification scores and reproducibility. PMID- 29287095 TI - Probabilistic inversion of expert assessments to inform projections about Antarctic ice sheet responses. AB - The response of the Antarctic ice sheet (AIS) to changing global temperatures is a key component of sea-level projections. Current projections of the AIS contribution to sea-level changes are deeply uncertain. This deep uncertainty stems, in part, from (i) the inability of current models to fully resolve key processes and scales, (ii) the relatively sparse available data, and (iii) divergent expert assessments. One promising approach to characterizing the deep uncertainty stemming from divergent expert assessments is to combine expert assessments, observations, and simple models by coupling probabilistic inversion and Bayesian inversion. Here, we present a proof-of-concept study that uses probabilistic inversion to fuse a simple AIS model and diverse expert assessments. We demonstrate the ability of probabilistic inversion to infer joint prior probability distributions of model parameters that are consistent with expert assessments. We then confront these inferred expert priors with instrumental and paleoclimatic observational data in a Bayesian inversion. These additional constraints yield tighter hindcasts and projections. We use this approach to quantify how the deep uncertainty surrounding expert assessments affects the joint probability distributions of model parameters and future projections. PMID- 29287093 TI - Direct exposure to mild heat promotes proliferation and neuronal differentiation of neural stem/progenitor cells in vitro. AB - Heat acclimation in rats is associated with enhanced neurogenesis in thermoregulatory centers of the hypothalamus. To elucidate the mechanisms for heat acclimation, we investigated the effects of direct mild heat exposure on the proliferation and differentiation of neural stem/progenitor cells (NSCs/NPCs). The NSCs/NPCs isolated from forebrain cortices of 14.5-day-old rat fetuses were propagated as neurospheres at either 37.0 degrees C (control) or 38.5 degrees C (mild heat exposure) for four days, and the effects on proliferation were investigated by MTS cell viability assay, measurement of neurosphere diameter, and counting the total number of cells. The mRNA expressions of heat shock proteins (HSPs) and brain-derived neurotrophic factor (BDNF), cAMP response element-binding (CREB) protein and Akt phosphorylation levels, and intracellular reactive oxygen species (ROS) levels were analyzed using real time PCR, Western blotting and CM-H2DCFDA assay respectively. Heat exposure under proliferation condition increased NSC/NPC viability, neurosphere diameter, and cell count. BDNF mRNA expression, CREB phosphorylation, and ROS level were also increased by heat exposure. Heat exposure increased HSP27 mRNA expression concomitant with enhanced p-Akt level. Moreover, treatment with LY294002 (a PI3K inhibitor) abolished the effects of heat exposure on NSC/NPC proliferation. Furthermore, heat exposure under differentiation conditions increased the proportion of cells positive for Tuj1 (a neuronal marker). These findings suggest that mild heat exposure increases NSC/NPC proliferation, possibly through activation of the Akt pathway, and also enhances neuronal differentiation. Direct effects of temperature on NSCs/NPCs may be one of the mechanisms involved in hypothalamic neurogenesis in heat-acclimated rats. Such heat-induced neurogenesis could also be an effective therapeutic strategy for neurodegenerative diseases. PMID- 29287096 TI - Preference in place of delivery among rural Indian women. AB - India accounts for the highest number of maternal and child deaths globally. A large body of empirical research suggests that improvement in the coverage of institutional delivery is essential to reduce the burden of maternal and child death. However the dynamics of choice of place of delivery is poorly understood. Using qualitative survey data consisting of twelve focus group discussions, conducted in a rural setting of West Bengal, India, this study aims to understand the reasons behind preferring home or institution for delivery. Findings reveal that some women who underwent an institutional delivery preferred to deliver their baby at home. On the other hand, of women who delivered their baby at home, 60% wanted to deliver their babies in institutions but could not do so, primarily due to the unwillingness of family members and misreporting of the onset of true labour pain. With the help of Accredited Social Health Activists, the village level health workers, there is need for an intervention that focuses on educating household members (essentially targeting husbands and mother-in-laws) about birth preparedness, and identification of true labour pain. PMID- 29287097 TI - Standardization and validation of real time PCR assays for the diagnosis of histoplasmosis using three molecular targets in an animal model. AB - Histoplasmosis is considered one of the most important endemic and systemic mycoses worldwide. Until now few molecular techniques have been developed for its diagnosis. The aim of this study was to develop and evaluate three real time PCR (qPCR) protocols for different protein-coding genes (100-kDa, H and M antigens) using an animal model. Fresh and formalin-fixed and paraffin-embedded (FFPE) lung tissues from BALB/c mice inoculated i.n. with 2.5x106 Histoplasma capsulatum yeast or PBS were obtained at 1, 2, 3, 4, 8, 12 and 16 weeks post-infection. A collection of DNA from cultures representing different clades of H. capsulatum (30 strains) and other medically relevant pathogens (36 strains of related fungi and Mycobacterium tuberculosis) were used to analyze sensitivity and specificity. Analytical sensitivity and specificity were 100% when DNAs from the different strains were tested. The highest fungal burden occurred at first week post infection and complete fungal clearance was observed after the third week; similar results were obtained when the presence of H. capsulatum yeast cells was demonstrated in histopathological analysis. In the first week post-infection, all fresh and FFPE lung tissues from H. capsulatum-infected animals were positive for the qPCR protocols tested except for the M antigen protocol, which gave variable results when fresh lung tissue samples were analyzed. In the second week, all qPCR protocols showed variable results for both fresh and FFPE tissues. Samples from the infected mice at the remaining times post-infection and uninfected mice (controls) were negative for all protocols. Good agreement was observed between CFUs, histopathological analysis and qPCR results for the 100-kDa and H antigen protocols. We successfully standardized and validated three qPCR assays for detecting H. capsulatum DNA in fresh and FFPE tissues, and conclude that the 100 kDa and H antigen molecular assays are promising tests for diagnosing this mycosis. PMID- 29287098 TI - Future changes in hydro-climatic extremes in the Upper Indus, Ganges, and Brahmaputra River basins. AB - Future hydrological extremes, such as floods and droughts, may pose serious threats for the livelihoods in the upstream domains of the Indus, Ganges, Brahmaputra. For this reason, the impacts of climate change on future hydrological extremes is investigated in these river basins. We use a fully distributed cryospheric-hydrological model to simulate current and future hydrological fluxes and force the model with an ensemble of 8 downscaled General Circulation Models (GCMs) that are selected from the RCP4.5 and RCP8.5 scenarios. The model is calibrated on observed daily discharge and geodetic mass balances. The climate forcing and the outputs of the hydrological model are used to evaluate future changes in climatic extremes, and hydrological extremes by focusing on high and low flows. The outcomes show an increase in the magnitude of climatic means and extremes towards the end of the 21st century where climatic extremes tend to increase stronger than climatic means. Future mean discharge and high flow conditions will very likely increase. These increases might mainly be the result of increasing precipitation extremes. To some extent temperature extremes might also contribute to increasing discharge extremes, although this is highly dependent on magnitude of change in temperature extremes. Low flow conditions may occur less frequently, although the uncertainties in low flow projections can be high. The results of this study may contribute to improved understanding on the implications of climate change for the occurrence of future hydrological extremes in the Hindu Kush-Himalayan region. PMID- 29287099 TI - The impact of an extreme climatic disturbance and different fertilization treatments on plant development, phenology, and yield of two cultivar groups of Solanum betaceum Cav. AB - Changing climatic conditions impose a challenge both to biodiversity and food security. The effects of climate change affect different aspects of the plant or crop, such as morphological and phenological aspects, as well as yield. The effects of greenhouse conditions might be comparable in some cases to a permanent extreme disturbance in climate and weather, thus, contributing to our knowledge on climate change impacts on plant species. We have investigated the differences for 23 traits in two cultivar groups of an Andean traditional crop, Solanum betaceum, under two different environmental conditions that correspond to the traditional practices in the open field and three cultural managements under greenhouse conditions (no fertilization or control, organic, and mineral). We found that traditional practices in the open field are the less productive. Moreover, in warmer and drier conditions the treatment with organic fertilization was the most productive. Greenhouse conditions, however, delay production. We further identified traits that differentiate both cultivar groups and traits that are linked to either the new climate conditions or the fertilization treatments. Fruit characteristics were quite homogeneous between the two cultivar groups. Overall, our results provide insight on the consequences that climate change effects might exert on crops such as tree tomato, reveal that greenhouses can be a robust alternative for tree tomato production, and highlight the need to understand how different managements are linked to different solutions to fulfil the farmers' demands. PMID- 29287100 TI - Phylogenetic inference of Coxiella burnetii by 16S rRNA gene sequencing. AB - Coxiella burnetii is a human pathogen that causes the serious zoonotic disease Q fever. It is ubiquitous in the environment and due to its wide host range, long range dispersal potential and classification as a bioterrorism agent, this microorganism is considered an HHS Select Agent. In the event of an outbreak or intentional release, laboratory strain typing methods can contribute to epidemiological investigations, law enforcement investigation and the public health response by providing critical information about the relatedness between C. burnetii isolates collected from different sources. Laboratory cultivation of C. burnetii is both time-consuming and challenging. Availability of strain collections is often limited and while several strain typing methods have been described over the years, a true gold-standard method is still elusive. Building upon epidemiological knowledge from limited, historical strain collections and typing data is essential to more accurately infer C. burnetii phylogeny. Harmonization of auspicious high-resolution laboratory typing techniques is critical to support epidemiological and law enforcement investigation. The single nucleotide polymorphism (SNP) -based genotyping approach offers simplicity, rapidity and robustness. Herein, we demonstrate SNPs identified within 16S rRNA gene sequences can differentiate C. burnetii strains. Using this method, 55 isolates were assigned to six groups based on six polymorphisms. These 16S rRNA SNP-based genotyping results were largely congruent with those obtained by analyzing restriction-endonuclease (RE)-digested DNA separated by SDS-PAGE and by the high-resolution approach based on SNPs within multispacer sequence typing (MST) loci. The SNPs identified within the 16S rRNA gene can be used as targets for the development of additional SNP-based genotyping assays for C. burnetii. PMID- 29287101 TI - Cancer risk in Korean patients with Behcet's disease: A nationwide population based study. AB - BACKGROUND: Various immune-mediated diseases are associated with increased malignancy risks. However, the relationship between Behcet's disease (BD) and cancer remains unclear. We conducted a nationwide, population-based study to determine the risk of cancer in patients with BD. METHODS: Using National Health Insurance claims records, we collected data from 2402 patients diagnosed with BD between 2013 and 2014. Standardized incidence ratios (SIRs) of overall and site specific cancers in patients with BD in comparison with the general population were calculated. RESULTS: The risks of overall cancer (SIR, 3.54; 95% confidence interval, 2.35-5.11 in men and 2.17; 1.58-2.92 in women) and solid cancer (3.10; 1.94-4.69 in men and 2.13; 1.52-2.90 in women) were greater in patients with BD than in the general population. There were significantly increased risks for these solid cancers: colorectal (4.26; 1.38-9.94), liver (4.00; 1.09-10.25), bone/articular cartilage (55.66; 1.41-310.14), prostate (7.05; 1.45-20.60), and brain/central nervous system (28.32; 3.43-102.31) in men; and the lips/oral cavity/pharynx (13.97, 1.69-50.47), liver (12.78; 5.14-26.33), lungs (4.35; 1.18 11.13), other female genital organs (53.57; 1.36-298.49), and eyes (128.26; 3.24 714.59) in women. Patients with BD had a greater risk of myelodysplastic syndrome (MDS) than the general population did (65.72; 7.96-237.41 in men and 53.86; 11.11 157.40 in women), but not of hematological cancer. CONCLUSIONS: Compared to the general population, Korean patients with BD had greater risks of overall cancer, some solid cancers, and MDS, but not of hematological cancer. PMID- 29287102 TI - The influence of the social and cultural environment on maternal mortality in Nigeria: Evidence from the 2013 demographic and health survey. AB - INTRODUCTION: Reducing maternal mortality remains a priority for global health. One in five maternal deaths, globally, are from Nigeria. OBJECTIVE: This study aimed to assess the sociocultural correlates of maternal mortality in Nigeria. METHODS: We conducted a retrospective analysis of nationally representative data from the 2013 Nigeria Demographic and Health Survey. The analysis was based on responses from the core women's questionnaire. Maternal mortality was categorized as 'yes' for any death while pregnant, during delivery or two months after delivery (as reported by the sibling), and 'no' for deaths of other or unknown causes. Multilevel logistic regression analysis was conducted to test for association between maternal mortality and predictor variables of sociocultural status (educational attainment, community women's education, region, type of residence, religion, and women's empowerment). RESULTS: Region, Religion, and the level of community women's education were independently associated with maternal mortality. Women in the North West were more than twice as likely to report maternal mortality (OR: 2.14; 95% CI: 1.42-3.23) compared to those in the North Central region. Muslim women were 52% more likely to report maternal deaths (OR: 1.52; 95% CI: 1.10-2.11) compared to Christian women. Respondents living in communities where a significant proportion of women have at least secondary schooling were 33% less likely to report that their sisters died of pregnancy related causes (OR: 0.67; 95% CI: 0.48-0.95). CONCLUSION: Efforts to reduce maternal mortality should implement tailored programs that address barriers to health-seeking behavior influenced by cultural beliefs and attitudes, and low educational attainment. Strategies to improve women's agency should be at the core of these programs; they are essential for reducing maternal mortality and achieving sustainable development goals towards gender equality. Future studies should develop empirically evaluated measures which assess, and further investigate the association between women's empowerment and maternal health status and outcomes. PMID- 29287103 TI - History vs. legend: Retracing invasion and spread of Oxalis pes-caprae L. in Europe and the Mediterranean area. AB - Oxalis pes-caprae L. is a South African geophyte that behaves as an invasive in the eurimediterranean area. According to a long-established hypothesis, O. pes caprae may have invaded Europe and the Mediterranean area starting from a single plant introduced in the Botanical Garden of Malta at the beginning of the 19th century. The aim of this work was to test this hypothesis, to track the arrival of O. pes-caprae in different countries of the Euro-Mediterranean area and to understand the pathways of spreading and particularly its starting point(s). Historical data attesting the presence of the plant in the whole Euro Mediterranean region were collected from different sources: herbarium specimens, Floras and other botanical papers, plant lists of gardens, catalogs of plant nurseries and plant dealers. First records of the plant (both cultivated and wild) for each Territorial Unit (3rd level of NUTS) were selected and used to draw up a diachronic map and an animated graphic. Both documents clearly show that oldest records are scattered throughout the whole area, proving that the plant arrived in Europe and in the Mediterranean region more times independently and that its spreading started in different times from several different centers of invasion. Botanical gardens and other public or private gardens, nurseries and plant dealers, and above all seaside towns and harbors seemingly played a strategic role as a source of either intentional and unintentional introduction or spread. A geographic profiling analysis was performed to analyse the data. We used also techniques (Silhouette, Kmeans and Voronoi tessellation) capable of verifying the presence of more than one independent clusters of data on the basis of their geographical distribution. Microsatellites were employed for a preliminary analysis of genetic variation in the Mediterranean. Even if the sampling was insufficient, particularly among the populations of the original area, our data supported three main groups of populations, one of them corresponding to the central group of populations identified by GP analysis, and the other two corresponding, respectively, to the western and the eastern cluster of data. The most probable areas of origin of the invasion in the three clusters of observations are characterized by the presence of localities where the invasive plant was cultivated, with the exception of the Iberian cluster of observation where the observations in the field predate the data about known cultivation localities. Alternative possible reasons are also suggested, to explain the current prevalence of pentaploid short-styled plants in the Euro Mediterranean area. PMID- 29287104 TI - Fetal head size and effect of manual perineal protection. AB - OBJECTIVE: The aim of this study was to evaluate whether a previously identified modification of Viennese method of perineal protection remains most effective for reduction of perineal tension in cases with substantially smaller or larger fetal heads. METHODS: A previously designed finite element model was used to compare perineal tension of different modifications of the Viennese method of perineal protection to "hands-off" technique for three different sizes of the fetal head. Quantity and extent of tension throughout the perineal body during vaginal delivery at the time when the suboccipito-bregmatic circumference passes between the fourchette and the lower margin of the pubis was determined. RESULTS: The order of effectiveness of different modifications of manual perineal protection was similar for all three sizes of fetal head. The reduction of perineal tension was most significant in delivery simulations with larger heads. The final position of fingers 2cm anteriorly from the fourchette (y = +2) consistently remains most effective in reducing the tension. The extent of finger movement along the anterior-posterior (y-axis) contributes to the effectiveness of manual perineal protection. CONCLUSION: Appropriately performed Viennese manual perineal protection seems to reduce the perineal tension regardless of the fetal head size, and thus the method seems to be applicable to reduce risk of perineal trauma for all parturients. PMID- 29287106 TI - Life expectancy with and without cognitive impairment by diabetes status among older Americans. AB - Diabetes affects mortality and cognitive functioning. It is not known how diabetes influences life expectancy (LE) with and without cognitive impairment. We seek to examine age at onset of cognitive impairment and life expectancy (LE) with and without cognitive impairment by diabetes status among middle- and older aged Americans. Data come from the U.S. Health and Retirement Study 2000-2012 linked to the National Death Index (N = 13,687). We use multinomial regression models stratified by gender and controlling for age, education and race/ethnicity to estimate diabetes-status specific transition probabilities, then use a Markov chain matrix population model to calculate age at onset of cognitive impairment and LE with and without cognitive impairment by diabetes status at age 50. LE at age 50 was 27.6 (men) and 32.1 (women). From age 50, those with diabetes had a first incidence of cognitive impairment 3 (men) and 4 (women) years earlier than those without. Diabetes reduced total LE by 5-7 years and cognitively healthy LE by 4-6 years. Those with diabetes lived one year less in a cognitively impaired state than those without. Over 80% of the lower LE associated with diabetes is attributable to the loss of cognitively-healthy years. Those with diabetes have a shorter LE with cognitive impairment because of higher mortality. In analyses by educational attainment, education was strongly protective of cognitive health, yet diabetes was associated with lower age of cognitive impairment onset and fewer cognitive healthy years lived in all educational groups. The excess mortality because of diabetes may be decreasing. If the mortality decline is not coupled with a comparable decline in the risk of cognitive impairment, the population level burden of impaired cognition may grow larger. PMID- 29287105 TI - Effect of intra-articular administration of superparamagnetic iron oxide nanoparticles (SPIONs) for MRI assessment of the cartilage barrier in a large animal model. AB - Early diagnosis of cartilage disease at a time when changes are limited to depletion of extracellular matrix components represents an important diagnostic target to reduce patient morbidity. This report is to present proof of concept for nanoparticle dependent cartilage barrier imaging in a large animal model including the use of clinical magnetic resonance imaging (MRI). Conditioned (following matrix depletion) and unconditioned porcine metacarpophalangeal cartilage was evaluated on the basis of fluorophore conjugated 30 nm and 80 nm spherical gold nanoparticle permeation and multiphoton laser scanning and bright field microscopy after autometallographic particle enhancement. Consequently, conditioned and unconditioned joints underwent MRI pre- and post-injection with 12 nm superparamagnetic iron oxide nanoparticles (SPIONs) to evaluate particle permeation in the context of matrix depletion and use of a clinical 1.5 Tesla MRI scanner. To gauge the potential pro-inflammatory effect of intra-articular nanoparticle delivery co-cultures of equine synovium and cartilage tissue were exposed to an escalating dose of SPIONs and IL-6, IL-10, IFN-gamma and PGE2 were assessed in culture media. The chemotactic potential of growth media samples was subsequently assessed in transwell migration assays on isolated equine neutrophils. Results demonstrate an increase in MRI signal following conditioning of porcine joints which suggests that nanoparticle dependent compositional cartilage imaging is feasible. Tissue culture and neutrophil migration assays highlight a dose dependent inflammatory response following SPION exposure which at the imaging dose investigated was not different from controls. The preliminary safety and imaging data support the continued investigation of nanoparticle dependent compositional cartilage imaging. To our knowledge, this is the first report in using SPIONs as intra-articular MRI contrast agent for studying cartilage barrier function, which could potentially lead to a new diagnostic technique for early detection of cartilage disease. PMID- 29287107 TI - Correction: Molecular characterization and multi-locus genotypes of Enterocytozoon bieneusi from captive red kangaroos (Macropus Rfus) in Jiangsu province, China. AB - [This corrects the article DOI: 10.1371/journal.pone.0183249.]. PMID- 29287108 TI - Antennal olfactory responses of adult meadow spittlebug, Philaenus spumarius, to volatile organic compounds (VOCs). AB - The meadow spittlebug, Philaenus spumarius L. (Hemiptera, Aphrophoridae) is a commonly found vector of Xylella fastidiosa Wells et al. (1987) strain subspecies pauca associated with the "Olive Quick Decline Syndrome" in Italy. To contribute to the knowledge of the adult P. spumarius chemoreceptivity, electroantennographic (EAG) responses of both sexes to 50 volatile organic compounds (VOCs) including aliphatic aldehydes, alcohols, esters, and ketones, terpenoids, and aromatics were recorded. Measurable EAG responses were elicited by all compounds tested. In both sexes, octanal, 2-octanol, 2-decanone, (E)-2 hexenyl acetate, and vanillin elicited the strongest antennal amplitude within the chemical groups of aliphatic saturated aldehydes, aliphatic alcohols, aliphatic acetates and aromatics, respectively. Male and female EAG responses to sulcatol, (+/-)linalool, and sulcatone were higher than those to other terpenoinds. In both sexes, the weakest antennal stimulants were phenethyl alcohol and 2-pentanone. Sexual differences in the EAG amplitude were found only for four of test compounds suggesting a general similarity between males and females in antennal sensitivity. The olfactory system of both sexes proved to be sensitive to changes in stimulus concentration, carbon chain length, and compound structure. Compounds with short carbon chain length (C5-C6) elicited lower EAG amplitudes than compounds with higher carbon chain length (C9-C10) in all classes of aliphatic hydrocarbons with different functional groups. The elucidation of the sensitivity profile of P. spumarius to a variety of VOCs provides a basis for future identification of behaviorally-active compounds useful for developing semiochemical-based control strategies of this pest. PMID- 29287109 TI - Biogenesis of the mitochondrial DNA inheritance machinery in the mitochondrial outer membrane of Trypanosoma brucei. AB - Mitochondria cannot form de novo but require mechanisms that mediate their inheritance to daughter cells. The parasitic protozoan Trypanosoma brucei has a single mitochondrion with a single-unit genome that is physically connected across the two mitochondrial membranes with the basal body of the flagellum. This connection, termed the tripartite attachment complex (TAC), is essential for the segregation of the replicated mitochondrial genomes prior to cytokinesis. Here we identify a protein complex consisting of three integral mitochondrial outer membrane proteins-TAC60, TAC42 and TAC40-which are essential subunits of the TAC. TAC60 contains separable mitochondrial import and TAC-sorting signals and its biogenesis depends on the main outer membrane protein translocase. TAC40 is a member of the mitochondrial porin family, whereas TAC42 represents a novel class of mitochondrial outer membrane beta-barrel proteins. Consequently TAC40 and TAC42 contain C-terminal beta-signals. Thus in trypanosomes the highly conserved beta-barrel protein assembly machinery plays a major role in the biogenesis of its unique mitochondrial genome segregation system. PMID- 29287110 TI - The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. AB - Hepadnavirus covalently closed circular (ccc) DNA is the bona fide viral transcription template, which plays a pivotal role in viral infection and persistence. Upon infection, the non-replicative cccDNA is converted from the incoming and de novo synthesized viral genomic relaxed circular (rc) DNA, presumably through employment of the host cell's DNA repair mechanisms in the nucleus. The conversion of rcDNA into cccDNA requires preparation of the extremities at the nick/gap regions of rcDNA for strand ligation. After screening 107 cellular DNA repair genes, we herein report that the cellular DNA ligase (LIG) 1 and 3 play a critical role in cccDNA formation. Ligase inhibitors or functional knock down/out of LIG1/3 significantly reduced cccDNA production in an in vitro cccDNA formation assay, and in cccDNA-producing cells without direct effect on viral core DNA replication. In addition, transcomplementation of LIG1/3 in the corresponding knock-out or knock-down cells was able to restore cccDNA formation. Furthermore, LIG4, a component in non-homologous end joining DNA repair apparatus, was found to be responsible for cccDNA formation from the viral double stranded linear (dsl) DNA, but not rcDNA. In conclusion, we demonstrate that hepadnaviruses utilize the whole spectrum of host DNA ligases for cccDNA formation, which sheds light on a coherent molecular pathway of cccDNA biosynthesis, as well as the development of novel antiviral strategies for treatment of hepatitis B. PMID- 29287111 TI - The impact of pre-existing anxiety on affective and cognitive processing of a Virtual Reality analogue trauma. AB - Dysfunctional processing of traumatic events may be in particular related to high trait anxiety as a pre-traumatic risk factor for the development of post traumatic stress disorder (PTSD). However, as this has rarely been investigated in prospective, experimental studies, we aimed to analyse the association between high trait anxiety and affective as well as cognitive processing of stress using a new prospective Virtual Reality analogue trauma paradigm to overcome limitations of retrospective or current analogue designs. Individuals with high and low trait anxiety (N = 80) were exposed to a multi-sensory Virtual Reality emergency scenario while psychophysiological stress response, emotion regulation and intrusive memories were assessed. Our results showed that high trait anxiety individuals display increased (i) subjective stress responses, (ii) emotion dysregulation and (iii) intrusive memories upon VR analogue trauma exposure. In particular, our sample of high trait anxiety individuals displayed limited access to different emotion regulation strategies as well as increased worry and rumination regarding perceived intrusive memories. Considering the complex interplay of multiple risk factors, our findings suggests that peri-traumatic affective processing seems to mediate high trait anxiety and post-traumatic intrusive memories thereby pointing out the central role of peri-traumatic processes for intrusion development. In addition, HA as a modulating pre traumatic risk factor might further increase the risk of later dysfunctional processing of an analogue trauma by interacting with factors of affective processing during analogue trauma exposure. Implications of these findings which may contribute to a higher risk to develop PTSD are discussed. PMID- 29287113 TI - Diffusion-weighted MRI distinguishes Parkinson disease from the parkinsonian variant of multiple system atrophy: A systematic review and meta-analysis. AB - BACKGROUND: Putaminal diffusivity in brain magnetic resonance diffusion-weighted imaging (DWI) is increased in patients with the parkinsonian variant of multiple system atrophy (MSA-P) compared to Parkinson disease (PD) patients. PURPOSE: We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of DWI to distinguish MSA-P from PD. METHODS: Studies on DWI were identified through a systematic PubMed and Clarivate Analytics(r) Web of Science(r) Core Collection search. Papers were selected based on stringent inclusion criteria; minimum requirement was the inclusion of MSA-P and PD patients and documented true positive, true negative, false positive and false negative rates or overall sample size and reported sensitivity and specificity. Meta-analysis was performed using the hierarchical summary receiver operating characteristics curve approach. RESULTS: The database search yielded 1678 results of which 9 studies were deemed relevant. Diagnostic accuracy of putaminal diffusivity measurements were reported in all of these 9 studies, whereas results of other regions of interest were only reported irregularly. Therefore, a meta analysis could only be performed for putaminal diffusivity measurements: 127 patients with MSA-P, 262 patients with PD and 70 healthy controls were included in the quantitative synthesis. The meta-analysis showed an overall sensitivity of 90% (95% confidence interval (CI): 76.7%-95.8%) and an overall specificity of 93% (95% CI: 80.0%-97.7%) to distinguish MSA-P from PD based on putaminal diffusivity. CONCLUSION: Putaminal diffusivity yields high sensitivity and specificity to distinguish clinically diagnosed patients with MSA-P from PD. The confidence intervals indicate substantial variability. Further multicenter studies with harmonized protocols are warranted particularly in early disease stages when clinical diagnosis is less certain. PMID- 29287112 TI - Mitochondrial DNA depletion by ethidium bromide decreases neuronal mitochondrial creatine kinase: Implications for striatal energy metabolism. AB - Mitochondrial DNA (mtDNA), the discrete genome which encodes subunits of the mitochondrial respiratory chain, is present at highly variable copy numbers across cell types. Though severe mtDNA depletion dramatically reduces mitochondrial function, the impact of tissue-specific mtDNA reduction remains debated. Previously, our lab identified reduced mtDNA quantity in the putamen of Parkinson's Disease (PD) patients who had developed L-DOPA Induced Dyskinesia (LID), compared to PD patients who had not developed LID and healthy subjects. Here, we present the consequences of mtDNA depletion by ethidium bromide (EtBr) treatment on the bioenergetic function of primary cultured neurons, astrocytes and neuron-enriched cocultures from rat striatum. We report that EtBr inhibition of mtDNA replication and transcription consistently reduces mitochondrial oxygen consumption, and that neurons are significantly more sensitive to EtBr than astrocytes. EtBr also increases glycolytic activity in astrocytes, whereas in neurons it reduces the expression of mitochondrial creatine kinase mRNA and levels of phosphocreatine. Further, we show that mitochondrial creatine kinase mRNA is similarly downregulated in dyskinetic PD patients, compared to both non dyskinetic PD patients and healthy subjects. Our data support a hypothesis that reduced striatal mtDNA contributes to energetic dysregulation in the dyskinetic striatum by destabilizing the energy buffering system of the phosphocreatine/creatine shuttle. PMID- 29287115 TI - Effects of precipitation and clipping intensity on net primary productivity and composition of a Leymus chinensis temperate grassland steppe. AB - Leymus chinensis (Trin.) is the dominant vegetation type in eastern Eurasian temperate grasslands but is decreasing due to the combined pressure of reduced precipitation and overgrazing. This study evaluated the separate and combined effects of precipitation and defoliation on net primary productivity (NPP) and composition of a L. chinensis steppe to promote the sustainable development of temperate grasslands through improved management practices. The effects of three precipitation gradients (precipitation unchanged, reduced by 50%, and increased by 50%) and two clipping intensities (clipping once or twice per year) were examined on NPP and composition of the L. chinensis community using a 7-year in situ controlled trial at the Guyuan State Key Monitoring and Research Station of Grassland Ecosystem in China. The results showed that: (1) a 50% reduction in natural precipitation significantly decreased NPP; a 50% increase in precipitation did not significantly increase NPP, but it decreased the importance value of L. chinensis because more water promoted the growth of competing species. (2) Clipping twice per year increased NPP, but the increase was from the dry matter of other species (DMO) component, and not from the dry matter of L. chinensis. (3) The standardized coefficients of a regression model (beta) for DMO, NPP, and the importance value of L. chinensis were 0.685, 0.532, and -0.608 for precipitation, and 0.369, 0.419, and -0.276 for clipping mode, respectively. This study demonstrated that variation in precipitationis the key driver of NPP and composition of a L. chinensis steppe under the precipitation range and clipping intensities evaluated. This improved understanding of the effects of precipitation and clipping on NPP and composition will allow for improved, sustainable management of L. chinensis temperate grassland steppes. PMID- 29287114 TI - Postnatal lethality and chondrodysplasia in mice lacking both chondroitin sulfate N-acetylgalactosaminyltransferase-1 and -2. AB - Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) chain. In cartilage, CS plays important roles as the main component of the extracellular matrix (ECM), existing as side chains of the major cartilage proteoglycan, aggrecan. Six glycosyltransferases are known to coordinately synthesize the backbone structure of CS; however, their in vivo synthetic mechanism remains unknown. Previous studies have suggested that two glycosyltransferases, Csgalnact1 (t1) and Csgalnact2 (t2), are critical for initiation of CS synthesis in vitro. Indeed, t1 single knockout mice (t1 KO) exhibit slight dwarfism and a reduction in CS content in cartilage compared with wild-type (WT) mice. To reveal the synergetic roles of t1 and t2 in CS synthesis in vivo, we generated systemic single and double knockout (DKO) mice and cartilage-specific t1 and t2 double knockout (Col2-DKO) mice. DKO mice exhibited postnatal lethality, whereas t2 KO mice showed normal size and skeletal development. Col2-DKO mice survived to adulthood and showed severe dwarfism compared with t1 KO mice. Histological analysis of epiphyseal cartilage from Col2-DKO mice revealed disrupted endochondral ossification, characterized by drastic GAG reduction in the ECM. Moreover, DKO cartilage had reduced chondrocyte proliferation and an increased number of apoptotic chondrocytes compared with WT cartilage. Conversely, primary chondrocyte cultures from Col2-DKO knee cartilage had the same proliferation rate as WT chondrocytes and low GAG expression levels, indicating that the chondrocytes themselves had an intact proliferative ability. Quantitative RT-PCR analysis of E18.5 cartilage showed that the expression levels of Col2a1 and Ptch1 transcripts tended to decrease in DKO compared with those in WT mice. The CS content in DKO cartilage was decreased compared with that in t1 KO cartilage but was not completely absent. These results suggest that aberrant ECM caused by CS reduction disrupted endochondral ossification. Overall, we propose that both t1 and t2 are necessary for CS synthesis and normal chondrocyte differentiation but are not sufficient for all CS synthesis in cartilage. PMID- 29287116 TI - Lung microRNA deregulation associated with impaired alveolarization in rats after intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) was recently described as an independent risk factor of bronchopulmonary dysplasia, the main respiratory sequelae of preterm birth. We previously showed impaired alveolarization in rat pups born with IUGR induced by a low-protein diet (LPD) during gestation. We conducted a genome-wide analysis of gene expression and found the involvement of several pathways such as cell adhesion. Here, we describe our unbiased microRNA (miRNA) profiling by microarray assay and validation by qPCR at postnatal days 10 and 21 (P10 and P21) in lungs of rat pups with LPD-induced lung-alveolarization disorder after IUGR. We identified 13 miRNAs with more than two-fold differential expression between control lungs and LPD-induced IUGR lungs. Validated and predicted target genes of these miRNAs were related to "tissue repair" at P10 and "cellular communication regulation" at P21. We predicted the deregulation of several genes associated with these pathways. Especially, E2F3, a transcription factor involved in cell cycle control, was expressed in developing alveoli, and its mRNA and protein levels were significantly increased at P21 after IUGR. Hence, IUGR affects the expression of selected miRNAs during lung alveolarization. These results provide a basis for deciphering the mechanistic contributions of IUGR to impaired alveolarization. PMID- 29287118 TI - Serum N-propeptide of collagen IIA (PIIANP) as a marker of radiographic osteoarthritis burden. AB - OBJECTIVE: Cartilage homeostasis relies on a balance of catabolism and anabolism of cartilage matrix. Our goal was to evaluate the burden of radiographic osteoarthritis and serum levels of type IIA procollagen amino terminal propeptide (sPIIANP), a biomarker representing type II collagen synthesis, in osteoarthritis. METHODS: OA burden was quantified on the basis of radiographic features as total joint faces with an osteophyte, joint space narrowing, or in the spine, disc space narrowing. sPIIANP was measured in 1,235 participants from the Genetics of Generalized Osteoarthritis study using a competitive enzyme linked immunosorbent assay. Separate multivariable linear regression models, adjusted for age, sex, and body mass index and additionally for ipsilateral osteophytes or joint/disc space narrowing, were used to assess the independent association of sPIIANP with osteophytes and with joint/disc space narrowing burden in knees, hips, hands and spine, individually and together. RESULTS: After full adjustment, sPIIANP was significantly associated with a lesser burden of hip joint space narrowing and knee osteophytes. sPIIANP was associated with a lesser burden of hand joint space narrowing but a greater burden of hand osteophytes; these results were only evident upon adjustment for osteoarthritic features in all other joints. There were no associations of sPIIANP and features of spine osteoarthritis. CONCLUSIONS: Higher cartilage collagen synthesis, as reflected in systemic PIIANP concentrations, was associated with lesser burden of osteoarthritic features in lower extremity joints (knees and hips), even accounting for osteoarthritis burden in hands and spine, age, sex and body mass index. These results suggest that pro-anabolic agents may be appropriate for early treatment to prevent severe lower extremity large joint osteoarthritis. PMID- 29287117 TI - Metastatic spinal cord compression (MSCC) treated with palliative decompression: Surgical timing and survival rate. AB - BACKGROUND: Metastatic spinal cord compression (MSCC) treatment depends on life expectancies. Data regarding palliative decompression outcomes is scarce. We demonstrate that surgical timing has a significant impact on survival in MSCC patients treated with palliative decompression. METHODS: Eighty-nine consecutive MSCC patients at a tertiary referral medical center were enrolled between January 2012 and February 2016. Wide laminectomy was performed for tumors invading the vertebral body. Debulking surgery was done for tumors damaging the posterior column of the spine. Patient records were retrospectively analyzed. RESULTS: Better survival was observed in patients with preoperative intact motor function (Group A, n = 37) than in those with motor deficit (Group B, n = 52, p = 0.0031). In Group B, survival was better in those who underwent surgery within 7 days of motor deficit onset than in those who underwent surgery 7 days after onset (p = 0.0444) and in postoperative ambulant patients than in nonambulant patients (p = 0.0120). In Group B, Frankel grade improved in patients who underwent surgery within 48 h than in those who underwent surgery after 48 h (p = 0.0992). Group A patients had a shorter hospital stay and higher revised Tokuhashi score than Group B patients. Overall survival was better in patients with a lower Tomita score (<=5, p = 0.0012), higher revised Tokuhashi score (>=9, p = 0.0009), better preoperative Frankel grade (p < 0.0001), and younger age (<=55 years, p = 0.0179). There were no significant differences in age, sex, tumor type, involved vertebrae level, Tomita score, intraoperative blood loss, operation time, incidence of infection, and postoperative complications between groups. CONCLUSION: We can improve the survival of MSCC patients with palliative decompression before motor deficits occur. After motor deficit onset, survival can still be improved with surgery within 7 days. Overall survival was better in patients aged <=55 years. PMID- 29287119 TI - Effectiveness of atrial fibrillation rotor ablation is dependent on conduction velocity: An in-silico 3-dimensional modeling study. AB - BACKGROUND: We previously reported that stable rotors are observed in in-silico human atrial fibrillation (AF) models, and are well represented by a dominant frequency (DF). In the current study, we hypothesized that the outcome of DF ablation is affected by conduction velocity (CV) conditions and examined this hypothesis using in-silico 3D-AF modeling. METHODS: We integrated 3D CT images of left atrium obtained from 10 patients with persistent AF (80% male, 61.8+/-13.5 years old) into in-silico AF model. We compared AF maintenance durations (max 300s), spatiotemporal stabilities of DF, phase singularity (PS) number, life-span of PS, and AF termination or defragmentation rates after virtual DF ablation with 5 different CV conditions (0.2, 0.3, 0.4, 0.5, and 0.6m/s). RESULTS: 1. AF maintenance duration (p<0.001), spatiotemporal mean variance of DF (p<0.001), and the number of PS (p = 0.023) showed CV dependent bimodal patterns (highest at CV0.4m/s and lowest at CV0.6m/s) consistently. 2. After 10% highest DF ablation, AF defragmentation rates were the lowest at CV0.4m/s (37.8%), but highest at CV0.5 and 0.6m/s (all 100%, p<0.001). 3. In the episodes with AF termination or defragmentation followed by 10% highest DF ablation, baseline AF maintenance duration was shorter (p<0.001), spatiotemporal mean variance of DF was lower (p = 0.014), and the number of PS was lower (p = 0.004) than those with failed AF defragmentation after DF ablation. CONCLUSION: Virtual ablation of DF, which may indicate AF driver, was more likely to terminate or defragment AF with spatiotemporally stable DF, but not likely to do so in long-lasting and sustained AF conditions, depending on CV. PMID- 29287120 TI - Improving public transportation systems with self-organization: A headway-based model and regulation of passenger alighting and boarding. AB - The equal headway instability-the fact that a configuration with regular time intervals between vehicles tends to be volatile-is a common regulation problem in public transportation systems. An unsatisfactory regulation results in low efficiency and possible collapses of the service. Computational simulations have shown that self-organizing methods can regulate the headway adaptively beyond the theoretical optimum. In this work, we develop a computer simulation for metro systems fed with real data from the Mexico City Metro to test the current regulatory method with a novel self-organizing approach. The current model considers overall system's data such as minimum and maximum waiting times at stations, while the self-organizing method regulates the headway in a decentralized manner using local information such as the passenger's inflow and the positions of neighboring trains. The simulation shows that the self organizing method improves the performance over the current one as it adapts to environmental changes at the timescale they occur. The correlation between the simulation of the current model and empirical observations carried out in the Mexico City Metro provides a base to calculate the expected performance of the self-organizing method in case it is implemented in the real system. We also performed a pilot study at the Balderas station to regulate the alighting and boarding of passengers through guide signs on platforms. The analysis of empirical data shows a delay reduction of the waiting time of trains at stations. Finally, we provide recommendations to improve public transportation systems. PMID- 29287121 TI - High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity. AB - The contribution of high fructose corn syrup (HFCS) to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high fat diets are widely accepted as a rodent model of diet-induced obesity (DIO) and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6) received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets. PMID- 29287122 TI - Estimating the incidence of rotavirus infection in children from India and Malawi from serial anti-rotavirus IgA titres. AB - Accurate estimates of rotavirus incidence in infants are crucial given disparities in rotavirus vaccine effectiveness from low-income settings. Sero surveys are a pragmatic means of estimating incidence however serological data is prone to misclassification. This study used mixture models to estimate incidence of rotavirus infection from anti-rotavirus immunoglobulin A (IgA) titres in infants from Vellore, India, and Karonga, Malawi. IgA titres were measured using serum samples collected at 6 month intervals for 36 months from 373 infants from Vellore and 12 months from 66 infants from Karonga. Mixture models (two component Gaussian mixture distributions) were fit to the difference in titres between time points to estimate risk of sero-positivity and derive incidence estimates. A peak incidence of 1.05(95% confidence interval [CI]: 0.64, 1.64) infections per child year was observed in the first 6 months of life in Vellore. This declined incrementally with each subsequent time interval. Contrastingly in Karonga incidence was greatest in the second 6 months of life (1.41 infections per child year [95% CI: 0.79, 2.29]). This study demonstrates that infants from Vellore experience peak rotavirus incidence earlier than those from Karonga. Identifying such differences in transmission patterns is important in informing vaccine strategy, particularly where vaccine effectiveness is modest. PMID- 29287123 TI - Interventions to improve the outcomes of frail people having surgery: A systematic review. AB - BACKGROUND: Frailty is an important prognostic factor for adverse outcomes and increased resource use in the growing population of older surgical patients. We identified and appraised studies that tested interventions in populations of frail surgical patients to improve perioperative outcomes. METHODS: We systematically searched Cochrane, CINAHL, EMBASE and Medline to identify studies that tested interventions in populations of frail patients having surgery. All phases of study selection, data extraction, and risk of bias assessment were done in duplicate. Results were synthesized qualitatively per a prespecified protocol (CRD42016039909). RESULTS: We identified 2 593 titles; 11 were included for final analysis, representing 1 668 participants in orthopedic, general, cardiac, and mixed surgical populations. Only one study was multicenter and risk of bias was moderate to high in all studies. Interventions were applied pre- and postoperatively, and included exercise therapy (n = 4), multicomponent geriatric care protocols (n = 5), and blood transfusion triggers (n = 1); no specific surgical techniques were compared. Exercise therapy, applied pre-, or post operatively, was associated with significant improvements in functional outcomes and improved quality of life. Multicomponent protocols suffered from poor compliance and difficulties in implementation. Transfusion triggers had no significant impact on mortality or other outcomes. CONCLUSIONS: Despite a growing literature that demonstrates strong independent associations between frailty and adverse outcomes, few interventions have been tested to improve the outcomes of frail surgical patients, and most available studies are at substantial risk of bias. Multicenter, low risk of bias, studies of perioperative exercise are needed, while substantial efforts are required to develop and test other interventions to improve the outcomes of frail people having surgery. PMID- 29287124 TI - Impact of delirium on postoperative frailty and long term cardiovascular events after cardiac surgery. AB - BACKGROUND: Postoperative delirium (POD) is a common and critical complication after cardiac surgery. However, the relationship between POD and postoperative physical frailty and the effect of both on long-term clinical outcomes have not been fully explored. OBJECTIVE: We aimed to examine the associations among POD, postoperative frailty, and major adverse cardiac events (MACE). DESIGN: This was a prospective cohort study. METHODS: We studied 329 consecutive patients undergoing elective cardiac surgery. The intensive care delirium screening checklist was used to assess POD. Postoperative frailty was defined by handgrip strength and walking speed. Patients were subsequently followed-up to detect MACE. RESULTS: POD was present in 13.2%, while the incidence of postoperative frailty was 27.0%. POD was independently associated with development of postoperative frailty (adjusted odds ratio = 2.98). During follow-up, MACE occurred in 14.1% of all participants. On multivariate Cox proportional hazard analysis, POD (adjusted hazard ratio (HR) = 3.36), postoperative frailty (HR = 2.21), postoperative complications (HR = 1.54), and left ventricular ejection fraction (HR = 0.95) were independently associated with increased risk of MACE. LIMITATIONS: It is a single-center study with a risk of bias. We did not investigate follow up cognitive function. CONCLUSIONS: POD was a predictor of postoperative frailty after cardiac surgery. Both postoperative frailty and POD were associated with the incidence of MACE, while POD was the stronger predictor of MACE. Thus, POD and frailty play critical roles in the risk stratification of patients undergoing cardiac surgery. PMID- 29287125 TI - Correction: Effect of cervical cancer education and provider recommendation for screening on screening rates: A systematic review and meta-analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0183924.]. PMID- 29287126 TI - Comparison of Changes in the Lipid Profiles of Eastern Chinese Postmenopausal Women With Early-Stage Breast Cancer Treated With Different Aromatase Inhibitors: A Retrospective Study. AB - Cardiovascular morbidity is closely associated with serum lipid level. We aimed to investigate the effects of different aromatase inhibitors, including letrozole, anastrozole, and exemestane, on the lipid profile of eastern Chinese breast cancer patients. We evaluated a retrospective cohort of eastern Chinese postmenopausal women with early-stage breast cancer who received aromatase inhibitors. A total of 116 postmenopausal women with early-stage breast cancer without prior cardiovascular disease were included. Lipid changes at 3, 6, 12, and 24 months were compared across the endocrine therapy categories. Our data demonstrated that exemestane treatment significantly decreased triglyceride level compared with letrozole after 24 months. However, the aromatase inhibitors had almost equivalent impacts on high-density liportein cholesterol, low-density lipoprotein cholesterol, and triglyceride after long-term aromatase inhibitor treatment. As a small-size retrospective study, our data do not support a judgment about whether one AI or another carries more or less risk in terms of lipid disorders in eastern Chinese breast cancer patients. The exact effects need further randomized, controlled trials to investigate. PMID- 29287127 TI - Cytochrome c Catalyzes the Hydrogen Peroxide-Assisted Oxidative Desulfuration of 2-Thiouridines in Transfer RNAs. AB - The 5-substituted 2-thiouridines (R5S2Us) present in the first (wobble) position of the anticodon of transfer RNAs (tRNAs) contribute to accuracy in reading mRNA codons and tuning protein synthesis. Previously, we showed that, under oxidative stress conditions in vitro, R5S2Us were sensitive to hydrogen peroxide (H2 O2 ) and that their oxidative desulfuration produced 5-substituted uridines (R5Us) and 4-pyrimidinone nucleosides (R5H2Us) at a ratio that depended on the pH and an R5 substituent. Here, we demonstrate that the desulfuration of 2-thiouridines, either alone or within an RNA/tRNA chain, is catalyzed by cytochrome c (cyt c). Its kinetics are similar to those of Fenton-type catalytic 2-thiouridine (S2U) desulfuration. Cyt c/H2 O2 - and FeII -mediated reactions deliver predominantly 4 pyrimidinone nucleoside (H2U)-type products. The pathway of the cyt c/H2 O2 peroxidase-mediated S2U->H2U transformation through uridine sulfenic (U-SOH), sulfinic (U-SO2 H), and sulfonic (U-SO3 H) intermediates is confirmed by LC-MS. The cyt c/H2 O2 -mediated oxidative damage of S2U-tRNA may have biological relevance through alteration of the cellular functions of transfer RNA. PMID- 29287128 TI - Digest: Ontogenesis and evolutionary allometry shape divergent evolution of genitalia in female cetaceans. PMID- 29287129 TI - New advances in fetal cardiovascular magnetic resonance imaging for quantifying the distribution of blood flow and oxygen transport: Potential applications in fetal cardiovascular disease diagnosis and therapy. AB - Until recently, our modern understanding of fetal circulatory physiology has been largely based on invasive measurements made in fetal sheep. However, new MRI technology developed by our group has provided equivalent information about the distribution of blood flow and oxygen transport noninvasively. The initial findings largely confirm prior estimates about the human fetal circulation extrapolated from fetal sheep data and human ultrasound data. Here we describe the hemodynamics of the normal late gestation human fetal circulation by MRI and speculate about what the advent of this technology might mean in terms of the management of fetuses affected by placental insufficiency and congenital heart disease. PMID- 29287130 TI - A brief history of fetal echocardiography and its impact on the management of congenital heart disease. AB - Congenital heart disease (CHD), the most common congenital malformation, is associated with adverse outcome. Development of fetal echocardiography has made prenatal diagnosis of CHD a reality, and in the process revolutionized its management. This historical review briefly narrates this development over the decades focusing on the emergence of the primary modalities of fetal echocardiography comprised of the time-motion mode, two-dimensional B-mode, spectral Doppler, color Doppler, and three- and four-dimensional cardiac imaging. Collaboration between clinicians and engineers has been central to these advances. Also discussed are the accuracy and impact of fetal echocardiography on the management of CHD, and especially its role in the prenatal diagnosis of critical CHD in individualizing the management and improving the outcome. Despite these advances, most cases of CHD are not identified prenatally, emphasizing the continuing need for further technological and educational innovation and improvement. PMID- 29287133 TI - Cardiac function and dysfunction in the fetus. AB - Evaluation of fetal cardiac function is one of the most important components of fetal echocardiography. Fetal cardiac dysfunction is closely linked to risk of intrauterine fetal demise, in many, but not all cases is indicative of worse postnatal prognosis and may prompt the use of medications or interventions to optimize outcomes. There may be implications for termination versus continuation of pregnancy, an indication for early delivery, a change in location and even mode of delivery. In extreme cases, fetal cardiac dysfunction may prompt prenatal or early neonatal listing for cardiac transplantation. There are several important differences between the fetal and postnatal circulatory physiology which affect echocardiographic assessment of cardiac dysfunction. In this review, we examine the echocardiographic findings according to their underlying pathophysiology with reference to common causes. PMID- 29287132 TI - Fetal echocardiography for planning perinatal and delivery room care of neonates with congenital heart disease. AB - Fetal echocardiography facilitates the prenatal diagnosis of infants with congenital heart disease (CHD) and through sequential examinations, allows assessment of fetal hemodynamics and cardiovascular status from the time of diagnosis to delivery. Fetal cardiologists have created diagnostic protocols aimed at risk stratifying severity and potential postnatal compromise in fetuses with CHD, and identifying those who may require special intervention at birth or within the first days of life. In this article, we review fetal cardiovascular physiology, the progression of CHD in utero and fetal echocardiographic findings used for risk stratification of newborns with CHD, as well as some of the basic principles of planning for the neonatal resuscitation and initial transitional care of these complex newborns. PMID- 29287134 TI - Prenatal diagnosis of total anomalous pulmonary venous connection by 2D and 3D fetal echocardiography. AB - OBJECTIVE: Prenatal diagnosis of total anomalous pulmonary venous connection (TAPVC) by fetal echocardiography (FE) remains a challenge. We sought to ascertain the diagnostic accuracy of 2D and 3D spatiotemporal image correlation (STIC) FE and the potential incremental value of 3D STIC FE for prenatal diagnosis and assessment of TAPVC. METHODS: This study was conducted retrospectively in a single tertiary referral center. The study population consisted of 74 TAPVC from 17 063 fetuses by FE from August 2010 to April 2016. The 3D volume acquisition was also performed by STIC. RESULTS: A total of 17 063 fetal echocardiograms in our institution were queried and 74 (0.4%) were identified with TAPVC. In the TAPVC group, 11 had postnatal echocardiographic study, 25 had autopsies, 36 declined autopsy and 2 lost for follow-up. The sensitivity of FE for diagnosis of TAPVC was 97.14%, specificity 99.98%, respectively. In our cohort, 31 fetuses were evaluated by both 2D and 3D STIC and were confirmed by postnatal echocardiography or autopsies. TAPVC was diagnosed in all 31 patients (100%) by both 2D FE and 3D STIC. Furthermore, the classification of subtypes of TAPVC and accurate diagnosis of the drainage pathway was correct in 26 (83.9%) and 24 (77.4%) cases by 2D FE, respectively; but in 31 (100%) and 31 (100%) cases by 3D STIC. CONCLUSION: 2D and 3D STIC FE provide accurate diagnosis of TAPVC with excellent sensitivity and specificity. 3D STIC FE has incremental value in further evaluation of classification of TAPVC types and drainage pathways. PMID- 29287135 TI - Pulmonary hypoplasia in fetuses with congenital conotruncal defects. AB - OBJECTIVES: We sought to investigate pulmonary hypoplasia (PH) and associated risk factors in fetuses with congenital conotruncal defect (CTD). METHODS: A total of 75 fetuses with CTD (gestational age (GA): 22-32 weeks) and 150 normal GA-matched fetuses as the control group were studied. We measured diameters of aorta (Ao); main, left, and right pulmonary artery (PA); and their Z-scores by fetal echocardiography (FE). We also measured the lung area, lung area/chest area ratio (LCR), lung-to-head circumference ratio (LHR), right lung area/head circumference2 (quantitative lung index, QLI), and Z-scores. RESULTS: The PA, left pulmonary artery (LPA), RPA, and their Z-scores and the lung area measurements (except for QLI) were significantly smaller in the CTD group, compared with the normal control group. Subgroup analysis showed the following: (1) CTD with right ventricular outflow tract obstruction (RVOTO) had smaller main and branch PA dimensions and small lung areas in contrast to CTD without RVOTO. (2) CTD with pulmonary atresia had smaller LPA and RPA dimensions but no difference in lung areas. (3) In the common types of CTD, lung area variables were mostly smaller in double outlet right ventricle (DORV) and tetralogy of Fallot (TOF), but there was no difference in transposition of the great arteries (TGA). CONCLUSIONS: CTD is associated with hypoplastic main and branch pulmonary arteries as well as PH. Risk factors for PH included defect types (DORV and TOF but not TGA) and RVOTO. It is plausible that pulmonary blood flow, rather than the type of CTD, RVOTO, or pulmonary artery dimensions, plays a key role in PH. PMID- 29287136 TI - Cerebrovascular hemodynamics in fetuses with congenital heart disease. AB - BACKGROUND AND OBJECTIVE: It is hypothesized that diminished cerebral vascular resistance or the "brain sparing effect" is associated with fetuses with complex congenital heart defects (CHD) and may affect their neurodevelopmental outcome. An alternative explanation is that it is related to the location, cardiac output, pressure, and resistance in left heart obstructive CHDs. We sought to determine the effects of various left and right heart obstructive defects on the cerebral and placental hemodynamics and to evaluate the utility of these variables for the assessment and prognosis of CHDs. METHODS: A total of 290 fetal echocardiograms were reviewed, including 91 fetuses with CHD and 199 normal ones. The CHD fetuses were divided into four groups, that is, left-sided obstructive lesions (LSOL), hypoplastic left heart syndrome (HLHS), right-sided obstructive lesions (RSOL), and hypoplastic right heart syndrome (HRHS). The pulsatility index of middle cerebral artery (MCA-PI) and umbilical artery (UA-PI) were measured by pulse-wave Doppler, and their Z scores were also derived. Cerebroplacental ratio (CPR) was calculated as: CPR=MCA-PI/UA-PI. RESULTS: There was no significant difference in MCA-PI between the 4 CHD and normal control groups (P>.05). However, MCA-PI and Z score decreased in aortic stenosis but not in interrupted aortic arch or coarctation subgroups, whereas they increased in pulmonary atresia but not pulmonary stenosis or tetralogy of Fallot subgroups compared with normal group (P<.05). There was no significant difference in CPR between any study group or subgroup and normal control group. CONCLUSIONS: Our study suggests MCA-PI is lower in aortic stenosis and high in pulmonary atresia but not significantly different in other LSOL, HLHS, RSOL, and HRHS. MCA-PI regulation in CHD is probably more associated with left and right outflow obstruction, location of the obstruction, and hemodynamics rather than "brain sparing effect" or preferential shunting of blood to the fetal brain, heart, and adrenals in the stressed fetus (eg, IUGR). CPR may not be a sensitive measure for the effect of CHDs and their severity on cerebral and placental circulation. PMID- 29287137 TI - Maternal hyperoxygenation: A potential therapy for congenital heart disease in the fetuses? A systematic review of the current literature. AB - OBJECTIVES: To assess efficacy, safety, outcomes, and intrauterine complications following maternal hyperoxygenation (MH) therapy in fetuses with congenital heart disease (CHD). METHODS: A systematic review was performed following an electronic search of databases. Articles were published before January 1, 2017, in an English-language and non-English-language journals (with English translations), and included human fetuses and expectant mothers with a fetal diagnosis of CHD who received MH. RESULTS: Ninety-six articles were identified; 72 were excluded and 24 full-text articles were reviewed. Only 9 articles met inclusion criteria and were analyzed. A total of 270 fetuses underwent MH therapy: 169 had CHD, and 101 had normal heart anatomies. Seven studies used fetal echocardiography, while 2 studies used cardiac magnetic resonance imaging (CMR). The mean gestational age at therapy was 33.4 weeks (26-38 weeks). Majority of MH protocols used 100% FiO2 with non-rebreather face mask at 8 L of flow, achieving 60%-70% FiO2 , or maternal PaO2 goal of 250 mm Hg. No significant adverse events were reported. Four studies reported increased size of the hypoplastic cardiac structures after MH. Three studies utilized acute MH to risk stratify hypoplastic left heart syndrome fetuses. Two studies assessed acute MH in the setting of CMR. CONCLUSION: The current evidence for MH therapy suggests an increase in pulmonary blood flow, and venous return, ductal flow, and heart dimensions in fetuses. MH has potential as a diagnostic and therapeutic tool in fetuses with CHD. Further randomized controlled trials are needed to ascertain whether MH therapy provides improved outcomes on fetuses with certain types of CHD. PMID- 29287138 TI - 4D fetal echocardiography-An update. AB - With the introduction of the electronic 4-dimensional and spatial-temporal image Correlation (e-STIC), it is now possible to obtain large volume datasets of the fetal heart that are virtually free of artifact. This allows the examiner to use a number of imaging modalities when recording the volumes that include two dimensional real time, power and color Doppler, and B-flow images. Once the volumes are obtained, manipulation of the volume dataset allows the examiner to recreate views of the fetal heart that enable examination of cardiac anatomy. The value of this technology is that a volume of the fetal heart can be obtained, irrespective of the position of the fetus in utero, and manipulated to render images for interpretation and diagnosis. This article presents a summary of the various imaging techniques and provides clinical examples of its application used for prenatal diagnosis of congenital heart defects and abnormal cardiac function. PMID- 29287139 TI - Fetal interventions for structural heart disease. AB - Fetal cardiac intervention (FCI) offers the potential to alter in utero anatomy and physiology. For aortic stenosis with evolving hypoplastic left heart syndrome and pulmonary atresia with intact ventricular septum with evolving hypoplastic right heart syndrome, FCI may result in maintenance of a biventricular circulation, thus avoiding single-ventricle palliation and its attendant complications. In the case of hypoplastic left heart syndrome with intact atrial septum, FCI may ameliorate in utero pathophysiology and portend a more favorable postnatal prognosis. In all cases, a detailed fetal echocardiographic assessment to identify the appropriate FCI candidate is essential. This article reviews the three aforementioned lesions for which FCI can be considered. The pathophysiology and rationale for intervention, echocardiographic assessment, patient selection criteria, and outcomes for each lesion will be reviewed. A primary focus will be the echocardiographic evaluation of each lesion. PMID- 29287140 TI - Introduction: From fetal echocardiography to fetal cardiology: A journey of over half a century. AB - In this Special Issue of the Journal, 8 review articles that represent the new developments and applications of fetal echocardiography and fetal cardiology for diagnosis, prognosis, and treatment of fetal cardiovascular disease are included. The goal was to provide an updated review of the evidence for the current and emerging use of fetal echocardiography and cardiac magnetic resonance, improved diagnosis of challenging congenital heart disease, new tools for evaluation of fetal systolic and diastolic function, better prognosis and risk stratification of newborns with congenital heart diseases, and new and promising therapies for fetuses with cardiovascular disease. PMID- 29287141 TI - Isolated coarctation of the aorta in the fetus: A diagnostic challenge. AB - Isolated coarctation of the aorta (CoA) is estimated by the Centers for Disease Control and Prevention to account for 4%-6% of all congenital heart disease (CHD) in the United States, with a reported prevalence of ~4 per 10 000 live births. Prenatal recognition of coarctation is important as it may improve neonatal survival and reduce morbidity. However, despite advances in imaging and the trend toward detailed aortic arch assessment as part of a comprehensive fetal echocardiogram, isolated CoA may still elude prenatal detection, with potentially lethal consequences if the diagnosis is not suspected and the patent ductus arteriosus (PDA) closes spontaneously in postnatal life. The purpose of this review is to outline the methods of antenatal aortic arch evaluation in the current era, discuss "red flags" that raise the suspicion for CoA, including associated anomalies and serve as a repository of the most up to date information regarding its diagnosis in utero and its perinatal management. Other aortic arch abnormalities, such as interrupted aortic arch, or CoA associated with complex single ventricles, are not included in this review. PMID- 29287142 TI - Silver Nanocube and Nanobar Growth via Anisotropic Monomer Addition and Particle Attachment Processes. AB - Understanding the growth mechanism of noble metal nanocrystals during solution synthesis is of significant importance for shape and property control. However, much remains unknown about the growth pathways of metal nanoparticles due to the lack of direct observation. Using an in situ transmission electron microscopy technique, we directly observed Ag nanocube and nanobar growth in an aqueous solution through both classical monomer-by-monomer addition and nonclassical particle attachment processes. During the particle attachment process, Ag nanocubes and nanobars were formed via both oriented and nonoriented attachment. Our calculations, along with the dynamics of the observed attachment, showed that the van der Waals force overcomes hydrodynamic and friction forces and drives the particles toward each other at separations of 10-100 nm in our experiments. During classical growth, anisotropic growth was also revealed, and the resulting unsymmetrical shape constituted an intermediate state for Ag nanocube growth. We hypothesized that the temporary symmetry breaking resulted from different growth rates on (001) surfaces due to a local surface concentration variation caused by the imbalance between the consumption of Ag+ near the surface and the diffusion of Ag+ from the bulk to the surface. PMID- 29287143 TI - Diacetylene Functionalized Covalent Organic Framework (COF) for Photocatalytic Hydrogen Generation. AB - Covalent organic frameworks (COFs) are crystalline, highly porous, two- or three dimensional polymers with tunable topology and functionalities. Because of their higher chemical stabilities in comparison to their boron-linked counterparts, imine or beta-ketoenamine linked COFs have been utilized for a broad range of applications, including gas storage, heterogeneous catalysis, energy storage devices, or proton-conductive membranes. Herein, we report the synthesis of highly porous and chemically stable acetylene (-C=C-) and diacetylene (-C=C-C=C-) functionalized beta-ketoenamine COFs, which have been applied as photocatalyst for hydrogen generation from water. It is shown that the diacetylene moieties have a profound effect as the diacetylene-based COF largely outperforms the acetylene-based COF in terms of photocatalytic activity. As a combined effect of high porosity, easily accessible diacetylene (-C=C-C=C-) functionalities and considerable chemical stability, an efficient and recyclable heterogeneous photocatalytic hydrogen generation is achieved. PMID- 29287144 TI - Enhanced Biopharmaceutical Performance of Rivaroxaban through Polymeric Amorphous Solid Dispersion. AB - Rivaroxaban (RXB) is an orally active direct inhibitor of the activated serine protease Factor Xa, given as monotherapy in the treatment of venous thromboembolism (VTE). It has been characterized in vitro as a substrate for the active, nonsaturable efflux via P-gp transporter, limiting its high permeability. Therefore, the role of P-gp inhibiting polymers in enhancing the biopharmaceutical performance of RXB by preparing polymeric amorphous solid dispersion and subsequent improvement in solubility and permeability was investigated. Initially, solubility parameter and Flory-Huggins interaction parameter were determined for miscibility studies between drug and polymers. Binary dispersions were prepared by dissolving drug with polymers eudragit S100, eudragit L100, and soluplus in common solvent (5% v/v water in tetrahydrofuran) using spray dryer. Prepared binary dispersions were analyzed by differential scanning calorimetry (DSC), microscopy, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), dynamic vapor sorption (DVS), and solution nuclear magnetic resonance (NMR) spectroscopy. Superior performance of binary dispersions was observed upon dissolution and solubility studies over micronized active pharmaceutical ingredient. Amorphous solid dispersion (ASD) prepared with soluplus showed 10-fold increase in apparent solubility and maintenance of supersaturation for 24 h compared to the crystalline RXB. Further, pharmacokinetic study performed in animals was in good correlation with the solubility data. Increases of 5.7- and 6.7-fold were observed in AUC and Cmax, respectively, for ASDs prepared with soluplus compared to those with crystalline RXB. FTIR and NMR spectroscopy unveiled the involvement of N-H group of RXB with C?O group of polymers in intermolecular interactions. The decreased drug efflux ratio was observed for ASDs prepared with eudragit S100 and soluplus in Caco-2 transport study suggesting improvement in the absorption of RXB. Hence, the present study demonstrates ASD using soluplus as a promising formulation strategy for enhancing the biopharmaceutical performance of RXB by increasing the solubility and circumventing the P-gp activity. PMID- 29287145 TI - Chaperonin-GroEL as a Smart Hydrophobic Drug Delivery and Tumor Targeting Molecular Machine for Tumor Therapy. AB - The targeted delivery of hydrophobic therapeutic drugs to tumors is one of the major challenges in drug development. The use of natural proteins as drug delivery vehicles holds great promise due to various functionalities of proteins. In the current study, we exploited a natural protein, GroEL, which possesses a double layer cage structure, as a hydrophobic drug container, which is switchable by ATP binding to a hydrophilic status, to design a novel and intelligent hydrophobic drug delivery molecular machine with a controlled drug release profile. When loaded with the hydrophobic antitumor drug, Doxorubicin (Dox), GroEL was able to shield the drug from the aqueous phase of blood, releasing the drug once in the presence of a critical concentration of ATP at the tumor site. Unexpectedly, we found that GroEL has a specific affinity for the cell structural protein, plectin, which is expressed at abnormally elevated levels on the membranes of tumor cells but not in normal cells. This finding, in combination with the ATP sensitivity, makes GroEL a superior natural tumor targeting nanocarrier. Our data show that GroEL-Dox is able to effectively, and highly selectively, deliver the hydrophobic drug to fast growing tumors without overt adverse effects on the major organs. GroEL is therefore a promising drug delivery platform that can overcome the obstacles to hydrophobic drug targeting and delivery. PMID- 29287146 TI - Effects of Mineral Compositions on Matrix Diffusion and Sorption of 75Se(IV) in Granite. AB - Exploring the migration behaviors of selenium in granite is critical for the safe disposal of radioactive waste. The matrix diffusion and sorption of 75Se(IV) (analogue for 79Se) in granite were systematically studied to set reliable parameters in this work. Through-diffusion and batch sorption experiments were conduct with four types of Beishan granite. The magnitudes of the obtained apparent diffusion coefficient (Da) values are of the following order: monzogranite > granodiorite-2 > granodiorite-1, which is opposite to the sequence of the Kd values obtained from both the diffusion model and batch sorption experiments. The EPMA results of the granitic flakes showed that there was no obvious enrichment of Se(IV) on quartz, microcline and albite. Only biotite showed a weak affinity for Se(IV). Macroscopic sorption behaviors of Se(IV) on the four types of granite were identical with the sequence of the granitic biotite contents. Quantitative fitting results were also provided. XPS and XANES spectroscopy data revealed that bidentate inner-sphere complexes were formed between Se(IV) and Fe(III). Our results indicate that biotite can be representative of the Se(IV) sorption in complex mineral assemblages such as granite, and the biotite contents are critically important to evaluate Se(IV) transport in granite. PMID- 29287147 TI - Intratumoral Visualization of Oxaliplatin within a Liposomal Formulation Using X ray Fluorescence Spectrometry. AB - Microsynchrotron radiation X-ray fluorescence spectrometry (MU-SR-XRF) is an X ray procedure that utilizes synchrotron radiation as an excitation source. MU-SR XRF is a rapid, nondestructive technique that allows mapping and quantification of metals and biologically important elements in cell or tissue samples. Generally, the intratumor distribution of nanocarrier-based therapeutics is assessed by tracing the distribution of a labeled nanocarrier within tumor tissue, rather than by tracing the encapsulated drug. Instead of targeting the delivery vehicle, we employed MU-SR-XRF to visualize the intratumoral microdistribution of oxaliplatin (l-OHP) encapsulated within PEGylated liposomes. Tumor-bearing mice were intravenously injected with either l-OHP-containing PEGylated liposomes (l-OHP liposomes) or free l-OHP. The intratumor distribution of l-OHP within tumor sections was determined by detecting the fluorescence of platinum atoms, which are the main elemental components of l-OHP. The l-OHP in the liposomal formulation was localized near the tumor vessels and accumulated in tumors at concentrations greater than those seen with the free form, which is consistent with the results of our previous study that focused on fluorescent labeling of PEGylated liposomes. In addition, repeated administration of l-OHP liposomes substantially enhanced the tumor accumulation and/or intratumor distribution of a subsequent dose of l-OHP liposomes, presumably via improvements in tumor vascular permeability, which is also consistent with our previous results. In conclusion, MU-SR-XRF imaging efficiently and directly traced the intratumor distribution of the active pharmaceutical ingredient l-OHP encapsulated in liposomes within tumor tissue. MU-SR-XRF imaging could be a powerful means for estimating tissue distribution and even predicting the pharmacological effect of nanocarrier-based anticancer metal compounds. PMID- 29287148 TI - Validation and Comparison of Force Fields for Native Cyclodextrins in Aqueous Solution. AB - Molecular dynamics simulations of native alpha-, beta-, and gamma-cyclodextrin in aqueous solution have been conducted with the goal to investigate the performance of the CHARMM36 force field, the AMBER-compatible q4md-CD force field, and five variants of the GROMOS force field. The properties analyzed are structural parameters derived from X-ray diffraction and NMR experiments as well as hydrogen bonds and hydration patterns, including hydration free enthalpies. Recent revisions of the torsional-angle parameters for carbohydrate systems within the GROMOS family of force fields lead to a significant improvement of the agreement between simulated and experimental NMR data. Therefore, we recommend using the variant 53A6GLYC instead of 53A6 and 56A6CARBO_R or 2016H66 instead of 56A6CARBO to simulate cyclodextrins in solution. The CHARMM36 and q4md-CD force fields show a similar performance as the three recommended GROMOS parameter sets. A significant difference is the more flexible nature of the cyclodextrins modeled with the CHARMM36 and q4md-CD force fields compared to the three recommended GROMOS parameter sets. PMID- 29287149 TI - Shear-Induced Migration of Rigid Particles near an Interface between a Newtonian and a Viscoelastic Fluid. AB - Simulations of rigid particles suspended in two-phase shear flow are presented, where one of the suspending fluids is viscoelastic, whereas the other is Newtonian. The Cahn-Hilliard diffuse-interface model is employed for the fluid fluid interface, which can naturally describe the interactions between the particle and the interface (e.g., particle adsorption). It is shown that particles can migrate across streamlines of the base flow, which is due to the surface tension of the fluid-fluid interface and a difference in normal stresses between the two fluids. The particle is initially located in the viscoelastic fluid, and its migration is investigated in terms of the Weissenberg number Wi (shear rate times relaxation time) and capillary number Ca (viscous stress over capillary stress). Four regimes of particle migration are observed, which can roughly be described by migration away from the interface for Wi = 0, halted migration toward the interface for low Wi and low Ca, particle adsorption at the interface for high Wi and low Ca, and penetration into the Newtonian fluid for high Wi and high Ca. It is found that the angular velocity of the particle plays a large role in determining the final location of the particle, especially for high Wi. From morphology plots, it is deduced that the different dynamics can be described well by considering a balance in the first-normal stress difference and Laplace pressure. However, it is shown that other parameters, such as the equilibrium contact angle and diffusion of the fluid, are also important in determining the final location of the particle. PMID- 29287150 TI - Diverse Chromosomal Locations of Quantitative Trait Loci for Tolerance to Maize chlorotic mottle virus in Five Maize Populations. AB - The recent rapid emergence of maize lethal necrosis (MLN), caused by coinfection of maize with Maize chlorotic mottle virus (MCMV) and a second virus usually from the family Potyviridae, is causing extensive losses for farmers in East Africa, Southeast Asia, and South America. Although the genetic basis of resistance to potyviruses is well understood in maize, little was known about resistance to MCMV. The responses of five maize inbred lines (KS23-5, KS23-6, N211, DR, and Oh1VI) to inoculation with MCMV, Sugarcane mosaic virus, and MLN were characterized. All five lines developed fewer symptoms than susceptible controls after inoculation with MCMV; however, the virus was detected in systemic leaf tissue from each of the lines similarly to susceptible controls, indicating that the lines were tolerant of MCMV rather than resistant to it. Except for KS23-5, the inbred lines also developed fewer symptoms after inoculation with MLN than susceptible controls. To identify genetic loci associated with MCMV tolerance, large F2 or recombinant inbred populations were evaluated for their phenotypic responses to MCMV, and the most resistant and susceptible plants were genotyped by sequencing. One to four quantitative trait loci (QTL) were identified in each tolerant population using recombination frequency and positional mapping strategies. In contrast to previous studies of virus resistance in maize, the chromosomal positions and genetic character of the QTL were unique to each population. The results suggest that different, genotype-specific mechanisms are associated with MCMV tolerance in maize. These results will allow for the development of markers for marker-assisted selection of MCMV- and MLN-tolerant maize hybrids for disease control. PMID- 29287151 TI - Effects of stacked wedge pads and chains applied to the forefeet of Tennessee Walking Horses for a five-day period on behavioral and biochemical indicators of pain, stress, and inflammation. AB - OBJECTIVE To determine the effects of stacked wedge pads and chains applied to the forefeet of Tennessee Walking Horses on behavioral and biochemical indicators of pain, stress, and inflamation. ANIMALS 20 Tennessee Walking Horses. PROCEDURES Horses were randomly assigned to 2 treatment groups: keg shoes (control; n = 10) or stacked wedge pads and exercise with chains (10). Ten days before treatment application, an accelerometer was attached at the left metatarsus of each horse to record daily activity. Horses were exercised for 20 minutes daily, beginning on day -7. On day 0, exercise ceased, the forefeet were trimmed, and the assigned treatment was applied. From days 1 through 5, horses were exercised as before. Blood samples for measurement of plasma cortisol, substance P, and fibrinogen concentrations were collected on days -5, 1, and 5 before and after exercise and every 30 minutes thereafter for 6 hours. RESULTS No significant differences in plasma concentrations of cortisol, substance P, and fibrinogen were detected between groups. Although lying behaviors changed after shoes were applied, these behaviors did not differ significantly between groups. Shoeing appeared to have altered behavior to a greater extent than did the type of treatment applied. CONCLUSIONS AND CLINICAL RELEVANCE Application of stacked wedge pads and chains to the forefeet of horses for a 5-day period as performed in this study evoked no acute or subacute stress or nociceptive response as measured. Although these findings should not be extrapolated to the long-term use of such devices in Tennessee Walking Horses performing the running walk, the data should be considered when making evidence-based decisions relating to animal welfare and the use of stacked wedge pads and chains. PMID- 29287153 TI - Evaluation of the diagnostic yield of dental radiography and cone-beam computed tomography for the identification of anatomic landmarks in small to medium-sized brachycephalic dogs. AB - OBJECTIVE To evaluate the diagnostic yield of dental radiography (Rad method) and 3 cone-beam CT (CBCT) methods for the identification of predefined anatomic landmarks in brachycephalic dogs. ANIMALS 19 client-owned brachycephalic dogs admitted for evaluation and treatment of dental disease. PROCEDURES 26 predefined anatomic landmarks were evaluated separately by use of the RAD method and 3 CBCT software modules (serial CBCT slices and custom cross sections, tridimensional rendering, and reconstructed panoramic views). A semiquantitative scoring system was used, and mean scores were calculated for each anatomic landmark and imaging method. The Friedman test was used to evaluate values for significant differences in diagnostic yield. For values that were significant, the Wilcoxon signed rank test was used with the Bonferroni-Holm multiple comparison adjustment to determine significant differences among each of the 6 possible pairs of diagnostic methods. RESULTS Differences of diagnostic yield among the Rad and 3 CBCT methods were significant for 19 of 26 anatomic landmarks. For these landmarks, Rad scores were significantly higher than scores for reconstructed panoramic views for 4 of 19 anatomic landmarks, but Rad scores were significantly lower than scores for reconstructed panoramic views for 8 anatomic landmarks, tridimensional rendering for 18 anatomic landmarks, and serial CBCT slices and custom cross sections for all 19 anatomic landmarks. CONCLUSIONS AND CLINICAL RELEVANCE CBCT methods were better suited than dental radiography for the identification of anatomic landmarks in brachycephalic dogs. Results of this study can serve as a basis for CBCT evaluation of dental disorders in brachycephalic dogs. PMID- 29287154 TI - Evaluation of ADAMTS17 in Chinese Shar-Pei with primary open-angle glaucoma, primary lens luxation, or both. AB - OBJECTIVE To evaluate the coding regions of ADAMTS17 for potential mutations in Chinese Shar-Pei with a diagnosis of primary open-angle glaucoma (POAG), primary lens luxation (PLL), or both. ANIMALS 63 Shar-Pei and 96 dogs of other breeds. PROCEDURES ADAMTS17 exon resequencing was performed on buccal mucosal DNA from 10 Shar-Pei with a diagnosis of POAG, PLL, or both (affected dogs). A candidate causal variant sequence was identified, and additional dogs (53 Shar-Pei [11 affected and 42 unaffected] and 95 dogs of other breeds) were genotyped for the variant sequence by amplified fragment length polymorphism analysis. Total RNA was extracted from ocular tissues of 1 affected Shar-Pei and 1 ophthalmologically normal Golden Retriever; ADAMTS17 cDNA was reverse transcribed and sequenced, and ADAMTS17 expression was evaluated by quantitative reverse-transcription PCR assay. RESULTS All affected Shar-Pei were homozygous for a 6-bp deletion in exon 22 of ADAMTS17 predicted to affect the resultant protein. All unaffected Shar-Pei were heterozygous or homozygous for the wild-type allele. The variant sequence was significantly associated with affected status (diagnosis of POAG, PLL, or both). All dogs of other breeds were homozygous for the wild-type allele. The cDNA sequencing confirmed presence of the expected variant mRNA sequence in ocular tissue from the affected dog only. Gene expression analysis revealed a 4.24-fold decrease in the expression of ADAMTS17 in ocular tissue from the affected dog. CONCLUSIONS AND CLINICAL RELEVANCE Results supported that the phenotype (diagnosis of POAG, PLL, or both) is an autosomal recessive trait in Shar-Pei significantly associated with the identified mutation in ADAMTS17. PMID- 29287155 TI - Comparison of three computed tomographic angiography protocols to assess diameters of major arteries in African grey parrots (Psittacus erithacus). AB - OBJECTIVE To evaluate 3 contrast medium infusion (CMI) protocols for CT angiography (CTA) and measurement of major artery diameters in African grey parrots (Psittacus erithacus). ANIMALS 9 African grey parrots with no detectable cardiovascular disease. PROCEDURES Each bird was anesthetized and underwent placement of an IV catheter in the left basilic vein and 16-slice CTA scanning (started at peak aortic enhancement) with each of 3 CMI protocols at >= 1-month intervals. Protocol 1 involved catheter flushing with saline (0.9% NaCl) solution and IV infusion of iopamidol (2 mL) followed by saline solution (0.2 mL; total infused volume, 5 mL). Protocol 2 involved IV infusion of iopamidol (2 mL) followed by saline solution (0.4 mL; total infused volume, 2.4 mL). Protocol 3 involved catheter flushing with saline solution and IV administration of iopamidol (2 mL; total infused volume, 4.8 mL). The diameters of 6 major arteries were measured by 2 observers, and intra- and interobserver agreement, time enhancement variables, and patient factors affecting contrast medium enhancement were assessed. RESULTS Among the 3 CMI protocols, CTA-derived arterial diameters differed significantly. Measurements obtained with protocol 2 were significantly larger than those obtained with the other protocols. Uniformity of the time enhancement variables differed among CMI protocols. Patient factors had nonsignificant effects on contrast medium enhancement. CONCLUSIONS AND CLINICAL RELEVANCE Of the CMI protocols assessed, a 2-phase CMI protocol with a post-CMI saline solution flush was the most reliable for CTA-derived measurements of the major thoracic and abdominal arteries in African grey parrots. However, further technique modification is needed. PMID- 29287156 TI - Evaluation of the diagnostic yield of dental radiography and cone-beam computed tomography for the identification of dental disorders in small to medium-sized brachycephalic dogs. AB - OBJECTIVE To evaluate the diagnostic yield of dental radiography (Rad method) and cone-beam CT (CBCT) methods for the identification of 31 predefined dental disorders in brachycephalic dogs. ANIMALS 19 client-owned brachycephalic dogs admitted for evaluation and treatment of dental disease. PROCEDURES 31 predefined dental disorders were evaluated separately and scored by use of dental radiography and 3 CBCT software modules (serial CBCT slices and custom cross sections, tridimensional rendering, and reconstructed panoramic views). A qualitative scoring system was used. Dental disorders were grouped into 10 categories for statistical analysis. Point of reference for presence or absence of a dental disorder was determined as the method that could be used to clearly identify the disorder as being present. Accuracy, sensitivity, specificity, and positive and negative predictive values were calculated with the McNemar chi2 test of marginal homogeneity of paired data. RESULTS When all 3 CBCT methods were used in combination, the diagnostic yield of CBCT was significantly higher than that of dental radiography for 4 of 10 categories (abnormal eruption, abnormally shaped roots, periodontitis, and tooth resorption) and higher, although not significantly so, for all categories, except for 1 (loss of tooth integrity). CONCLUSIONS AND CLINICAL RELEVANCE CBCT provided more detailed information than did dental radiography. Therefore, CBCT would be better suited for use in diagnosing dental disorders in brachycephalic dogs. PMID- 29287157 TI - Pharmacokinetic evaluation of novel midazolam gel formulations following buccal administration to healthy dogs. AB - OBJECTIVE To determine the physiochemical properties and pharmacokinetics of 3 midazolam gel formulations following buccal administration to dogs. ANIMALS 5 healthy adult hounds. PROCEDURES In phase 1 of a 2-phase study, 2 gel formulations were developed that contained 1% midazolam in a poloxamer 407 (P1) or hydroxypropyl methylcellulose (H1) base and underwent rheological and in vitro release analyses. Each formulation was buccally administered to 5 dogs such that 0.3 mg of midazolam/kg was delivered. Each dog also received midazolam hydrochloride (0.3 mg/kg, IV). There was a 3-day interval between treatments. Blood samples were collected immediately before and at predetermined times for 8 hours after drug administration for determination of plasma midazolam concentration and pharmacokinetic analysis. During phase 2, a gel containing 2% midazolam in a hydroxypropyl methylcellulose base (H2) was developed on the basis of phase 1 results. That gel was buccally administered such that midazolam doses of 0.3 and 0.6 mg/kg were delivered. Each dog also received midazolam (0.3 mg/kg, IV). All posttreatment procedures were the same as those for phase 1. RESULTS The H1 and H2 formulations had lower viscosity, greater bioavailability, and peak plasma midazolam concentrations that were approximately 2-fold as high, compared with those for the P1 formulation. The mean peak plasma midazolam concentration for the H2 formulation was 187.0 and 106.3 ng/mL when the midazolam dose administered was 0.6 and 0.3 mg/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that buccal administration of gel formulations might be a viable alternative for midazolam administration to dogs. PMID- 29287158 TI - Pharmacokinetics of a concentrated buprenorphine formulation in red-tailed hawks (Buteo jamaicensis). AB - OBJECTIVE To determine the pharmacokinetics and sedative effects of 2 doses of a concentrated buprenorphine formulation after SC administration to red-tailed hawks (Buteo jamaicensis). ANIMALS 6 adult red-tailed hawks. PROCEDURES Concentrated buprenorphine (0.3 mg/kg, SC) was administered to all birds. Blood samples were collected at 10 time points over 24 hours after drug administration to determine plasma buprenorphine concentrations. After a 4-week washout period, the same birds received the same formulation at a higher dose (1.8 mg/kg, SC), and blood samples were collected at 13 time points over 96 hours. Hawks were monitored for adverse effects and assigned agitation-sedation scores at each sample collection time. Plasma buprenorphine concentrations were quantified by liquid chromatography-tandem mass spectrometry. RESULTS Mean time to maximum plasma buprenorphine concentration was 7.2 minutes and 26.1 minutes after administration of the 0.3-mg/kg and 1.8-mg/kg doses, respectively. Plasma buprenorphine concentrations were > 1 ng/mL for mean durations of 24 and 48 hours after low- and high-dose administration, respectively. Mean elimination half-life was 6.23 hours for the low dose and 7.84 hours for the high dose. Mean agitation sedation scores were higher (indicating some degree of sedation) than the baseline values for 24 hours at both doses. No clinically important adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Concentrated buprenorphine was rapidly absorbed, and plasma drug concentrations considered to have analgesic effects in other raptor species were maintained for extended periods. Most birds had mild to moderate sedation. Additional studies are needed to evaluate the pharmacodynamics of these doses of concentrated buprenorphine in red-tailed hawks. PMID- 29287160 TI - Kinematic analysis of the thoracic limb of healthy dogs during descending stair and ramp exercises. AB - OBJECTIVE To compare the kinematics of the thoracic limb of healthy dogs during descent of stairs and a ramp with those during a trot across a flat surface (control). ANIMALS 8 privately owned dogs. PROCEDURES For each dog, the left thoracic limb was instrumented with 5 anatomic markers to facilitate collection of 2-D kinematic data during each of 3 exercises (descending stairs, descending a ramp, and trotting over a flat surface). The stair exercise consisted of 4 steps with a 35 degrees slope. For the ramp exercise, a solid plank was placed over the steps to create a ramp with a 35 degrees slope. For the flat exercise, dogs were trotted across a flat surface for 2 m. Mean peak extension, peak flexion, and range of movement (ROM) of the shoulder, elbow, and carpal joints were compared among the 3 exercises. RESULTS Mean ROM for the shoulder and elbow joints during the stair exercise were significantly greater than during the flat exercise. Mean peak extension of the elbow joint during the flat exercise was significantly greater than that during both the stair and ramp exercises. Mean peak flexion of the elbow joint during the stair exercise was significantly greater than that during the flat exercise. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that descending stairs may be beneficial for increasing the ROM of the shoulder and elbow joints of dogs. Descending stair exercises may increase elbow joint flexion, whereas flat exercises may be better for targeting elbow joint extension. PMID- 29287161 TI - Evaluation of equine synovial-derived extracellular matrix scaffolds seeded with equine synovial-derived mesenchymal stem cells. AB - OBJECTIVE To create a bioactive synovium scaffold by infusing decellularized synovial-derived extracellular matrix (synECM) with synovial-derived mesenchymal stem cells (synMSCs). SAMPLE Synovium from the femoropatellar and medial femorotibial joints of equine cadavers. PROCEDURES The synMSCs were cultured in monolayer and not treated or cotransduced to enhance expression of green fluorescent protein (GFP) and human bone morphogenetic protein (BMP)-2. The synECM was decellularized with 0.1% peracetic acid and then seeded with synMSCs (0.5 * 106 cells/0.5 mL) by use of a 30% serum gradient. Samples were evaluated on days 0, 3, 7, and 14. Cell migration, differentiation, and distribution into the synECMs were determined by cell surface marker CD90, viability, histologic morphology, and fluorescence microscopy results and expression of GFP, BMP-2, hyaluronan (HA), and proteoglycan (PG). RESULTS At day 14, synMSCs were viable and had multiplied 2.5-fold in the synECMs. The synECMs seeded with synMSCs had a significant decrease in CD90 expression and significant increases in HA and PG expression. The synECMs seeded with synMSCs cotransduced with GFP, or BMP-2 had a significant increase in BMP-2 expression. CONCLUSIONS AND CLINICAL RELEVANCE The synECM seeded with synMSCs or synMSCs cotransduced with GFP, or BMP-2 yielded a bioactive synovial scaffold. Expression of BMP-2 by synMSCs cotransduced to enhance expression of BMP-2 or GFP and an accompanying increase in both HA and PG expression indicated production of anabolic agents and synoviocyte differentiation in the scaffold. Because BMP-2 can promote repair of damaged cartilage, such a bioactive scaffold could be useful for treatment of injured cartilage. PMID- 29287162 TI - Comparative pharmacokinetics of two florfenicol formulations following intramuscular and subcutaneous administration to sheep. AB - OBJECTIVE To compare the pharmacokinetics of 2 commercial florfenicol formulations following IM and SC administration to sheep. ANIMALS 16 healthy adult mixed-breed sheep. PROCEDURES In a crossover study, sheep were randomly assigned to receive florfenicol formulation A or B at a single dose of 20 mg/kg, IM, or 40 mg/kg, SC. After a 2-week washout period, each sheep was administered the opposite formulation at the same dose and administration route as the initial formulation. Blood samples were collected immediately before and at predetermined times for 24 hours after each florfenicol administration. Plasma florfenicol concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were estimated by noncompartmental methods and compared between the 2 formulations at each dose and route of administration. RESULTS Median maximum plasma concentration, elimination half-life, and area under the concentration-time curve from time 0 to the last quantifiable measurement for florfenicol were 3.76 MUg/mL, 13.44 hours, and 24.88 MUg*h/mL, respectively, for formulation A and 7.72 MUg/mL, 5.98 hours, and 41.53 MUg*h/mL, respectively, for formulation B following administration of 20 mg of florfenicol/kg, IM, and 2.63 MUg/mL, 12.48 hours, and 31.63 MUg*h/mL, respectively, for formulation A and 4.70 MUg/mL, 16.60 hours, and 48.32 MUg*h/mL, respectively, for formulation B following administration of 40 mg of florfenicol/kg, SC. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that both formulations achieved plasma florfenicol concentrations expected to be therapeutic for respiratory tract disease caused by Mannheimia haemolytica or Pasteurella spp at both doses and administration routes evaluated. PMID- 29287163 TI - Comparison of tensile strength and time to closure between an intermittent Aberdeen suture pattern and conventional methods of closure for the body wall of dogs. AB - OBJECTIVE To compare tensile strength and time to completion of body wall closure among 3 suture patterns. SAMPLE Eighteen 5 * 5-cm leather specimens and sixty eight 5 * 5-cm full-thickness tissue specimens from the ventral portion of the abdominal body wall of 17 canine cadavers. PROCEDURES During experiment 1 of a 2 experiment study, each leather specimen was cut in half and sutured with a simple interrupted or simple continuous pattern or continuous pattern with intermittent Aberdeen knots (intermittent Aberdeen pattern). During experiment 2, 4 tissue specimens were obtained from each cadaver; the linea alba of 3 specimens was incised and closed with 1 of the 3 suture patterns evaluated in experiment 1, and the fourth specimen was left intact as a control. All leather and tissue specimens underwent mechanical testing. Time to completion, mode of failure, and maximum force at failure (Fmax) were compared among the suture patterns. RESULTS In experiment 1, the mean Fmax for the simple continuous and intermittent Aberdeen patterns was significantly greater than that for the simple interrupted pattern. In experiment 2, the mean Fmax for specimens obtained cranial to the umbilicus was greater than that for specimens obtained caudal to the umbilicus, and the mean time to completion for both continuous suture patterns was significantly less than that for the simple interrupted pattern. Most (34/51) sutured tissue specimens failed because the suture cut through the tissue at the suture-tissue interface. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the intermittent Aberdeen pattern may be an alternative for body wall closure in dogs. PMID- 29287164 TI - Cyclooxygenase-2 expression in the eyes of cats with and without uveitis. AB - OBJECTIVE To characterize the distribution and intensity of cyclooxygenase (COX) 2 expression in the eyes of cats with and without uveitis and to determine whether COX-2 expression is correlated with severity of inflammation. SAMPLES Archived ocular tissue specimens from 51 cats with and 10 cats without ocular disease. PROCEDURES Specimens from only 1 eye were evaluated for each cat. Specimens were stained with H&E stain or immunohistochemical stain for detection of COX-2 and reviewed. For each eye, the type, severity, and distribution of inflammation and the distribution and intensity of COX-2 expression were determined for the uvea and other ocular tissues. Correlation between COX-2 expression and inflammation severity was also assessed. RESULTS COX-2 was not expressed in any nondiseased eye. Of the 51 diseased eyes, 20 had histologic evidence of lymphocytic-plasmacytic uveitis, 13 had neutrophilic uveitis, 11 had diffuse iris melanoma with uveitis, and 7 had diffuse iris melanoma without uveitis. Of the 44 eyes with uveitis, COX-2 was detected in the uvea of 16, including 11 eyes with lymphocytic-plasmacytic uveitis, 4 with neutrophilic uveitis, and 1 with diffuse iris melanoma-induced uveitis. Inflammation was severe, moderate, or mild in 10, 5, and 1 of those eyes, respectively. Cyclooxygenase-2 was detected in the cornea of 21 eyes with uveitis and 1 eye with diffuse iris melanoma without uveitis. Uveitis severity was positively correlated with COX-2 expression in both the uvea and cornea. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that COX-2 is an inflammatory mediator in feline uveitis but not diffuse iris melanoma. PMID- 29287165 TI - Comparison of the percentage of the C3-C7 vertebral canal occupied by the spinal cord in small-breed dogs with that in Doberman Pinschers and Great Danes with and without cervical spondylomyelopathy. AB - OBJECTIVE To compare the percentage of the C3-C7 vertebral canal occupied by the spinal cord in small-breed dogs with that in Doberman Pinschers and Great Danes with and without cervical spondylomyelopathy (CSM). ANIMALS 30 small-breed dogs (body weight, < 15 kg), 15 clinically normal Doberman Pinschers, 15 Doberman Pinschers with CSM, 15 clinically normal Great Danes, and 15 Great Danes with CSM. PROCEDURES In a retrospective study, sagittal and transverse T2-weighted MRI images of the cervical (C3 to C7) vertebral column obtained from dogs that met study criteria and were free of extensive abnormalities that could affect the spinal cord diameter between January 2005 and February 2015 were reviewed. The area and height of the vertebral column and spinal cord were measured at the cranial and caudal aspect of each vertebra from C3 to C7, and the percentage of the vertebral canal occupied by the spinal cord at each location was calculated and compared among groups of dogs. RESULTS Mean percentage of the vertebral canal occupied by the spinal cord was greatest for small-breed dogs and lowest for Great Danes, but did not differ between Doberman Pinschers and small-breed dogs at approximately half of the locations evaluated or between Doberman Pinschers with and without CSM or between Great Danes with and without CSM. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the percentage of the vertebral canal occupied by the spinal cord, although expected to increase with vertebral canal stenosis, may not have a primary role in the pathogenesis of CSM. PMID- 29287166 TI - Intraoperative optical coherence tomography of the human thyroid: Feasibility for surgical assessment. AB - Thyroid nodules assessed with ultrasound and fine-needle aspiration biopsy are diagnosed as "suspicious" or "indeterminate" in 15%-20% of the cases. Typically, total thyroidectomy is performed in such cases; however, only 25%-50% are found to be cancerous upon final histopathologic analysis. Here we demonstrate optical coherence tomography (OCT) imaging of the human thyroid as a potential intraoperative imaging tool for providing tissue assessment in real time during surgical procedures. Fresh excised tissue specimens from 28 patients undergoing thyroid surgery were imaged in the laboratory using a benchtop OCT system. Three dimensional OCT images showed different microstructural features in normal, benign, and malignant thyroid tissues. A similar portable OCT system was then designed and constructed for use in the operating room, and intraoperative imaging of excised thyroid tissue from 6 patients was performed during the surgical procedure. The results demonstrate the potential of OCT to provide real time imaging guidance during thyroid surgeries. PMID- 29287168 TI - Editorial Comment. PMID- 29287169 TI - Reply by Authors. PMID- 29287167 TI - A longitudinal analysis of the impact of child custody loss on drug use and crime among a sample of African American mothers. AB - : This study examines the influence of child custody loss on drug use and crime among a sample of African American mothers. Two types of custody loss are examined: informal custody loss (child living apart from mother but courts not involved), and official loss (child removed from mother's care by authorities). METHODS: Using data from 339 African American women, longitudinal random coefficient models analyzed the effects of each type of custody loss on subsequent drug use and crime. RESULTS: indicated that both informal and official custody loss predicted increased drug use, and informal loss predicted increased criminal involvement. Findings demonstrate that child custody loss has negative health implications for African American mothers, potentially reducing their likelihood of regaining or retaining custody of their children. CONCLUSIONS: This study highlights the need to integrate drug treatment and other types of assistance into family case plans to improve reunification rates and outcomes among mothers, children, and families. Additionally, the finding that informal loss predicts increased drug use suggests that community-based efforts within the mother's social network could be implemented to intervene before child welfare system involvement becomes necessary. PMID- 29287171 TI - No effect of conventional vs. minimally invasive surgical approach on clinical outcome and migration of a short stem total hip prosthesis at 2-year follow-up: A randomized controlled study. PMID- 29287170 TI - Outcomes Associated With Type of Milk Supplementation Among Late Preterm Infants. AB - OBJECTIVE: To assess whether type of milk supplementation provided to breastfeeding late preterm infants was associated with hospital length of stay (LOS) or breastfeeding status at discharge. DESIGN: Retrospective chart review. SETTING: Tertiary care teaching hospital in the southern United States. PARTICIPANTS: Late preterm infants 35 0/7 to 36 6/7 weeks gestational age (N = 183) admitted to the mother-baby unit between November 1, 2014, and October 31, 2016. METHODS: The exposure of interest was type of milk supplementation, for example, expressed human milk, pasteurized donor human milk, and formula. Outcomes measured were LOS and breastfeeding status at discharge. Generalized Poisson regression models were used to compare LOS by type of milk supplementation. Modified Poisson regression models were used to estimate risk ratios and 95% confidence intervals for associations with breastfeeding status at discharge. RESULTS: The LOS for breastfed infants supplemented with expressed human milk and/or pasteurized donor human milk did not differ significantly from exclusively breastfed infants who received no supplement. Exclusively formula-fed infants had longer LOS of 3.2 days compared with 2.6 days for exclusively breastfed infants (p = .001). Breastfed infants who received any formula supplementation were 16% less likely to continue breastfeeding until day of discharge compared with breastfed infants who received human milk supplementation (risk ratio = .84, 95% confidence interval [.77, .92]). CONCLUSION: The high prevalence of supplementation among breastfeeding late preterm infants underscores the potential effect of type of milk supplementation on LOS and breastfeeding outcomes. Our findings suggest that human milk supplementation discourages transition to formula feeding before hospital discharge without increasing LOS. PMID- 29287172 TI - Upper torso pain and musculoskeletal structure and function in women with and without large breasts: A cross sectional study. AB - BACKGROUND: Women with large breasts frequently experience upper torso pain secondary to their breast size. Evidence is lacking on the underlying causes of this pain. This study investigated whether upper torso pain and musculoskeletal structure and function differed between women with large breasts and women with small breasts. METHODS: A linear regression, adjusting for body mass, compared the upper torso pain, thoracic flexion torque due to breast mass, thoracic kyphosis, shoulder active range-of-motion, and scapular retraction muscle strength of 27 women with large breasts (bilateral breast volume>1200ml, age 45.9y SD 9.9y, BMI 29.0kg/m2 SD 3.8kg/m2) and 26 women with small breasts (bilateral breast volume <800ml, age 43.8y SD10.9y, BMI 23.3kg/m2 SD 2.9kg/m2). FINDINGS: Women with large breasts reported a higher upper torso pain score (46.6, 95%CI 33.3-58.0 versus 24.1, 95%CI 12.5-37.8), accompanied by a larger flexion torque (5.9Nm, 95%CI 4.5-5.8Nm versus 0.9Nm, 95%CI 0.8-2.4Nm), greater thoracic kyphosis (34 degrees , 95%CI 31-38 degrees versus 27 degrees , 95% CI 24-31 degrees ), decreased shoulder elevation range-of-motion (160 degrees , 95%CI 158-163 degrees versus 169 degrees , 95%CI 166-172 degrees ), and decreased scapular retraction endurance-strength (511.4s, 95%CI 362.2-691.3s versus 875.8s, 95%CI 691.5-1028.4s) compared to the women with small breasts. INTERPRETATION: Differences in the upper torso posture, range-of-motion, and muscle strength of women with large breasts provides insight into underlying causes of their musculoskeletal pain. This information can be used to develop evidence-based assessment and treatment strategies to relieve and prevent symptom progression. PMID- 29287173 TI - Microplastics cause neurotoxicity, oxidative damage and energy-related changes and interact with the bioaccumulation of mercury in the European seabass, Dicentrarchus labrax (Linnaeus, 1758). AB - Microplastics pollution is a global paradigm that raises concern in relation to environmental and human health. This study investigated toxic effects of microplastics and mercury in the European seabass (Dicentrarchus labrax), a marine fish widely used as food for humans. A short-term (96 h) laboratory bioassay was done by exposing juvenile fish to microplastics (0.26 and 0.69 mg/L), mercury (0.010 and 0.016 mg/L) and binary mixtures of the two substances using the same concentrations, through test media. Microplastics alone and mercury alone caused neurotoxicity through acetylcholinesterase (AChE) inhibition, increased lipid oxidation (LPO) in brain and muscle, and changed the activities of the energy-related enzymes lactate dehydrogenase (LDH) and isocitrate dehydrogenase (IDH). All the mixtures caused significant inhibition of brain AChE activity (64-76%), and significant increase of LPO levels in brain (2.9-3.4 fold) and muscle (2.2-2.9 fold) but not in a concentration-dependent manner; mixtures containing low and high concentrations of microplastics caused different effects on IDH and LDH activity. Mercury was found to accumulate in the brain and muscle, with bioaccumulation factors of 4-7 and 25-40, respectively. Moreover, in the analysis of mercury concentrations in both tissues, a significant interaction between mercury and microplastics was found. The decay of mercury in the water increased with microplastics concentration, and was higher in the presence of fish than in their absence. Overall, these results indicate that: microplastics influence the bioaccumulation of mercury by D. labrax juveniles; microplastics, mercury and their mixtures (ppb range concentrations) cause neurotoxicity, oxidative stress and damage, and changes in the activities of energy-related enzymes in juveniles of this species; mixtures with the lowest and highest concentrations of their components induced different effects on some biomarkers. These findings and other published in the literature raise concern regarding high level predators and humans consuming fish being exposed to microplastics and heavy metals, and highlight the need of more research on the topic. PMID- 29287174 TI - Effects of triphenyl phosphate on growth, reproduction and transcription of genes of Daphnia magna. AB - The additive flame retardant triphenyl phosphate (TPHP) has been frequently detected in environments and biota. Evidences indicate that TPHP has potential risks to aquatic organisms. Seldom has been reported about its chronic effects to aquatic organism at low trophic levels, such as Cladocera. In the present study, <12 h old Daphnia magna (D. magna) were exposed to 0, 5, 50 or 500 MUg/L TPHP for 21 days to investigate the chronic effects of TPHP on body length, fecundity and survival. Meanwhile, D. magna PCR arrays were used to evaluate the transcriptional responses of 155 genes involved in 40 pathways. Exposure to 500 MUg/L TPHP for 21 days significantly decreased the body lengths of both F0 and F1 generation and inhibited the fecundity of F0 generation. Results of RT-qPCR showed that the expressions of 76 genes involved in 15 pathways were significantly altered after exposure to 500 MUg/L TPHP for 21 days. The significantly altered pathways related to genetic information processing, cellular process and metabolism might be responsible for the observed effects of TPHP. Overall, our results showed that chronic exposure to TPHP caused developmental and reproductive toxicities to D. magna. PMID- 29287175 TI - Novel biochar-impregnated calcium alginate beads with improved water holding and nutrient retention properties. AB - Drought conditions and nutrients loss have serious impacts on soil quality as well as crop yields in agroecosystems. New techniques are needed to carry out effective soil water and nutrient conservation and fertilizer application tools. Here, calcium alginate (CA) beads impregnated with ball-milled biochar (BMB) were investigated as a new type of water/nutrients retention agent. Both CA and Ca alginate/ball milled biochar composite (CA-BMB) beads showed high kinetic swelling ratios in KNO3 solution and low kinetic swelling ratios in water, indicating that CA-BMB beads have the potential to retain mineral nitrogen and nutrients by ion exchange. Pseudo-second-order kinetic model well-described the swelling kinetics of both beads in KNO3 solution. Over a range of temperatures, the characteristics of dehydration suggested that impregnation with BMB improved the water holding capacity and postponed the dehydration time of Ca-alginate. The cumulative swelling and release characteristics of water, K+, and NO3- indicated that CA-BMB beads have great potential as a soil amendment to improve its nutrient retention and water holding capacity. PMID- 29287176 TI - Removal of Pb(II) from water using a bio-composite adsorbent-A systematic approach of optimizing synthesis and process parameters by response surface methodology. AB - The synthesis parameters for preparing a novel bio-composite adsorbent by integrating a copolymer of 2-hydroxyethyl methacrylate (HEMA), acrylamide (AM) and crosslinker N, N'-methylene bis acrylamide (MBA), polyethylene glycol (PEG) and Azadirachta Indica or Neem leaf (NL) and the process parameters for its subsequent use for adsorption of Pb(II) ion from water were optimized with central composite design (CCD) of response surface methodology (RSM). The structure of the bio-composite was characterized by FTIR, XRD, TGA, DMA, FESEM EDX and PZC analysis. The optimized adsorbent prepared with a AM: HEMA molar ratio of 5:1, MBA, PEG and NL wt% of 0.75, 4 and 2.5, respectively showed 182.85 mg/g (92.5%) adsorption of Pb(II) from water containing low concentration of 50 mg/L of Pb(II) ion and 911 mg/L (57%) adsorption of the same metal ion for a high feed concentration of 400 mg/L in a solution pH of 6, adsorbent dose of 0.25 g/L and a feed temperature of 30 degrees C. This functional bio-composite may also be suitably used for separation of other metal ions and polar molecules from water. PMID- 29287177 TI - Nuclear energy: Between global electricity demand, worldwide decarbonisation imperativeness, and planetary environmental implications. AB - For decades, nuclear energy has been considered an important option for ensuring global energy security, and it has recently started being promoted as a solution for climate change mitigation. However, nuclear power remains highly controversial due to its associated risks - nuclear accidents and problematic radioactive waste management. This review aims to assess the viability of global nuclear energy economically (energy-wise), climatically and environmentally. To this end, the nuclear sector's energy- and climate-related advantages were explored alongside the downsides that mainly relate to radioactive pollution. Economically, it was found that nuclear energy is still an important power source in many countries around the world. Climatically, nuclear power is a low-carbon technology and can therefore be a viable option for the decarbonization of the world's major economies over the following decades, if coupled with other large scale strategies such as renewable energies. These benefits are however outweighed by the radioactive danger associated to nuclear power plants, either in the context of the nuclear accidents that have already occurred or in that of the large amounts of long-lived nuclear waste that have been growing for decades and that represent a significant environmental and societal threat. PMID- 29287178 TI - The socioeconomic factors that facilitate or constrain restoration management: Watershed rehabilitation and wet meadow (bofedal) restoration in the Bolivian Andes. AB - Restoration ecology holds promise for addressing land degradation in impoverished rural environments, provided the approach is adapted to rural development settings. While there is a need for increased integration of social dynamics in land restoration, few systematic studies exist. We explored the socioeconomic factors that influence restoration management, including local motives and perceived benefits, incentives, land tenancy, institutional factors, conflict resolution, accessibility, off-farm labor, and outmigration. The study area is a successful watershed rehabilitation and wet meadow restoration project in the Bolivian Andes that began in 1992. We used household survey methods (n = 237) to compare the communities that had conducted the most restoration management with those that had conducted the least. Results suggest that several factors facilitate investments in land restoration, including aligning restoration objectives with local motives and perceived benefits, ensuring incentives are in place to stimulate long-term investments, conflict resolution, private land tenancy, and accessibility. However, higher levels of organization and active leadership can facilitate land restoration on communal lands. Increased livelihood benefits from land restoration helped slow the rate of rural to urban migration, with 24.5% outmigration in the highest restoration management communities compared to 62.1% in the lowest restoration management communities. Results suggest that land restoration projects that integrate community development into project planning and implementation will achieve greater success. PMID- 29287179 TI - Exposure to DDT and hypertensive disorders of pregnancy among South African women from an indoor residual spraying region: The VHEMBE study. AB - Indoor Residual Spraying (IRS), the use of insecticides inside residences for malaria control, may cause elevated exposure to insecticides such as dichlorodiphenyl trichloroethane (DDT). Evidence suggests that DDT exposure may increase blood pressure but no study has investigated associations with hypertensive disorders of pregnancy (HDP) in an IRS area. We measured the serum concentration of DDT and its breakdown product dichlorodiphenyl trichloroethylene (DDE) at the time of delivery among 733 rural South African women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE). We also collected data on HDP diagnosis through questionnaires administered to participants and medical record abstraction. We used multiple logistic regression models to examine the relation between DDT/E and HDP. p,p' DDT and p,p'-DDE serum concentrations were associated with HDP based on self report (OR = 1.50; 95%CI = 1.10, 2.03 for p,p'-DDT and OR = 1.58; 95%CI = 1.09, 2.28 for p,p'-DDE) and medical records (OR = 1.32; 95%CI = 0.99, 1.75 for p,p' DDT and OR = 1.47; 95%CI = 1.03, 2.09 for p,p'-DDE). p,p'-DDE was also associated with gestational hypertension (OR = 1.44; 95% CI = 1.00, 2.07). Exposure to DDT and DDE may be associated with elevated risks of HDP in South African women residing in an area sprayed for malaria control. PMID- 29287181 TI - What's hot about mercury? Examining the influence of climate on mercury levels in Ontario top predator fishes. AB - Mercury (Hg) levels in Ontario top predator fishes have been increasing in recent decades. These increases may be a result of many additive factors, including global climate change. Only recently has research been conducted on how climate change may impact Hg levels in freshwater fishes at large-scales. We examined the relationship between Hg trends and (1) local weather, (2) large-scale climate drivers, and (3) anthropogenic Hg emissions, in native cool water (walleye and northern pike) and warm water (smallmouth bass and largemouth bass) predatory fishes in Ontario, Canada, for historical (1970-1992) and recent (1993-2014) time periods. For each fish species studied, > 25% of Ontario's secondary watersheds shifted from historically declining to recently increasing fish Hg trends, and >= 50% of watersheds experienced increasing trends between 1993 and 2014. Recent fish Hg increased at up to 0.20ug/g/decade; which were significant (p < 0.05) for walleye, northern pike and smallmouth bass. Multiple linear regressions revealed a complex interplay of local weather, large-scale climate drivers, and anthropogenic Hg emissions influencing fish Hg levels. Recent Hg levels for walleye and largemouth bass increased with changes in global climate drivers, while higher precipitation influenced smallmouth bass Hg levels the most. Walleye Hg levels increased during the positive phases of global climate drivers, reflecting the local influence of local temperatures and precipitation indirectly. Differentiating the effects of climate-related parameters and emissions is increasingly crucial to assess how changing multiple environmental stressors may impact health of wildlife and humans consuming fish. PMID- 29287180 TI - Neurocognitive and physical functioning in the Seveso Women's Health Study. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is neurotoxic in animals but few studies have investigated its effects on the human brain. Related dioxin-like compounds have been linked to poorer cognitive and motor function in older adults, with effects more pronounced in women, perhaps due to the loss of neuro protective estrogen in menopause. On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in one of the highest known residential exposures to TCDD. In 1996, we initiated the Seveso Women's Health Study, a retrospective cohort study of the health of the women who were newborn to 40 years old in 1976. Here, we investigate whether TCDD exposure is associated with physical functioning and working memory more than 20 years later. Individual TCDD concentration (ppt) was measured in archived serum collected soon after the explosion. In 1996 and 2008, we measured physical functioning (n=154) and working memory (n=459), respectively. We examined associations between serum TCDD and motor and cognitive outcomes with multivariate linear regression and semi parametric estimators. A 10-fold increase in serum TCDD was not associated with walking speed (adjusted beta=0.0006ft/s, 95% Confidence Interval (CI): -0.13, 0.13), upper body mobility (adjusted beta=-0.06, 95% CI: -0.36, 0.23), or manual dexterity (adjusted beta=0.34, 95% CI: -0.65, 1.33). We observed an inverted U shaped association in grip strength, with poorer strength in the lowest and highest TCDD exposure levels. There was no association between TCDD and the Wechsler digit and spatial span tests. Neither menopause status at assessment nor developmental timing of exposure modified associations between TCDD and working memory. Our findings, in one of the only studies of TCDD's effects on neuropsychological and physical functioning in women, do not indicate an adverse effect on these domains, with the exception of a U-shaped relationship with grip strength. Given the limited assessment and relative youth of the women at this follow-up, future work examining additional neuropsychological outcomes is warranted. PMID- 29287182 TI - Persistent organic pollutants, skull size and bone density of polar bears (Ursus maritimus) from East Greenland 1892-2015 and Svalbard 1964-2004. AB - We investigated skull size (condylobasal length; CBL) and bone mineral density (BMD) in polar bears (Ursus maritimus) from East Greenland (n = 307) and Svalbard (n = 173) sampled during the period 1892-2015 in East Greenland and 1964-2004 at Svalbard. Adult males from East Greenland showed a continuous decrease in BMD from 1892 to 2015 (linear regression: p < 0.01) indicating that adult male skulls collected in the early pre-pollution period had the highest BMD. A similar decrease in BMD over time was not found for the East Greenland adult females. However, there was a non-significant trend that the skull size of adult East Greenland females was negatively correlated with collection year 1892-2015 (linear regression: p = 0.06). No temporal change was found for BMD or skull size in Svalbard polar bears (ANOVA: all p > 0.05) nor was there any significant difference in BMD between Svalbard and East Greenland subpopulations. Skull size was larger in polar bears from Svalbard than from East Greenland (two-way ANOVA: p = 0.003). T-scores reflecting risk of osteoporosis showed that adult males from both East Greenland and Svalbard are at risk of developing osteopenia. Finally, when correcting for age and sex, BMD in East Greenland polar bears increased with increasing concentrations of persistent organic pollutants (POPs) i.e. SigmaPCB (polychlorinated biphenyls), SigmaHCH (hexachlorohexane), HCB (hexachlorobenzene) and SigmaPBDE (polybrominated diphenyl ethers) while skull size increased with SigmaHCH concentrations all in the period 1999-2014 (multiple linear regression: all p < 0.05, n = 175). The results suggest that environmental changes over time, including exposure to POPs, may affect bone density and size of polar bears. PMID- 29287183 TI - Electronic properties of DNA: Description of weak interactions in TATA-box-like chains. AB - DNA is one of the most important biomolecules since it contains all the genetic information about an organism. The tridimensional structure of DNA is a determinant factor that influences the physiological and biochemical mechanisms by which this molecule carries out its biological functions. It is believed that hydrogen bonds and pi-pi stacking are the most relevant non-covalent interactions regarding DNA stability. Due to its importance, several theoretical works have been made to describe these interactions, however, most of them often consider only the presence of two nitrogenous bases, having a limited overview of the participation of these in B-DNA stabilization. Furthermore, due to the complexity of the system, there are discrepancies between which involved interaction is more important in duplex stability. Therefore, in this project we describe these interactions considering the effect of chain length on the energy related to both hydrogen bonds and pi-pi stacking, using as model TATA-box-like chains with n base pairs (n=1 to 14) and taking into consideration two different models: ideal and optimized B-DNA. We have found that there is a cooperative effect on hydrogen bond and pi-pi stacking mean energies when the presence of other base pairs is considered. In addition, it was found that hydrogen bonds contribute more importantly than pi-pi stacking to B-DNA stability; nevertheless, the participation of pi-pi stacking is not negligible: when B-DNA looks for a conformation of lower energy, pi-pi stacking interaction are the first to be optimized. All work was realized under the framework of DFT using the DMol3 code (M06-L/DNP). PMID- 29287184 TI - Photosystem I, when excited in the chlorophyll Qy absorption band, feeds on negative entropy. AB - It is often suggested that Life may lay outside the normal laws of Physics and particularly of Thermodynamics, though this point of view is refuted by many. As the Living State may be thought of as an open system, often far from equilibrium, most attempts at placing Life under the umbrella of the laws of Physics have been based, particularly in recent years, on non-equilibrium Thermodynamics and particularly the Maximum Entropy Production Principle. In this view it is the dissipation of entropy (heat) which permits the ever increasing complexity of Living Systems in biological evolution and the maintenance of this complexity. However, these studies usually consider such biological entities as whole cells, organs, whole organisms and even Life itself at the entire terrestrial level. This requires making assumptions concerning the Living State, which are often not soundly based on observation and lack a defined model structure. The present study is based on an entirely different approach, in which a classical thermodynamic analysis of a well-defined biological nanoparticle, plant Photosystem I, is performed. This photosynthetic structure, which absorbs light and performs primary and secondary charge separation, operates with a quantum efficiency close to one. It is demonstrated that when monochromatic light is absorbed by the lowest lying electronic transition, the chlorophyll Qy transition, entropy production in the system bath plus entropy changes internal to the system are numerically less than the entropy decrease of the light field. A Second Law violation is therefore suggested for these experimental conditions. This conclusion, while at first sight is supportive of the famous and much discussed statement of Schroedinger, that "Life feeds on negentropy", is analysed and the conditions in which this statement may be considered valid for a Plant Photosystem are defined and delimited. The remarkably high quantum efficiency, leading to minimal entropy production (energy wastage), seems to suggest that evolution of Photosystem I has gone down the road of maximal energy efficiency as distinct from maximal entropy production. Photosystem I cannot be considered a maximum entropy dissipation structure. PMID- 29287185 TI - Insufficient efficacy of vagus nerve stimulation for epileptic spasms and tonic spasms in children with refractory epilepsy. AB - BACKGROUND: Vagus nerve stimulation (VNS) leads to palliation of refractory seizures. Epileptic spasms (ES) and tonic spasms (TS) appear in children with West syndrome and symptomatic generalized epilepsy. Both types of spasms are often characterized by truncal muscular contractions and ictal electroencephalography (EEG) findings comprising the contiguous phases: phase 1) 15-20 Hz, spindle-like fast activity (occur in 70%), 2) diffuse polyphasic delta/theta waves (100%), and 3) electrodecremental activity (70%). Here, we examined the effect of VNS on these spasms that are uniformly associated with the EEG and electromyogram changes. METHODS: A consecutive series of 32 patients satisfied the inclusion criteria consisting of 1) medically refractory epilepsy, 2) VNS implantation between 2010 and 2015, 3) implantation of VNS before the age of 20 years, and 4) follow-up >2 years. From this cohort, 16 patients had spasms (ES/TS group), whereas the remaining 16 had partial seizures with or without secondary generalization (PS/SG group). We compared seizure outcomes between the two groups, and also determined the factors predicting these outcomes within the ES/TS group. RESULTS: The outcomes after 2 years of implantation, defined using the McHugh classification, were as follows: II (for 2 patients), III (5), and V (9) in the ES/TS group; and I (3 patients), II (6), III (2), IV (1), and V (4) in the PS/SG group. The ES/TS group had significantly worse outcomes than the PS/SG group (p = 0.024, Mann-Whitney U test). Multivariate ordinal logistic regression analysis revealed that shorter mean durations of ictal events were associated with better seizure outcomes following VNS implantation (p = 0.007). SIGNIFICANCE: Only 13% of the patients in the ES/TS group had seizure reductions of greater than 50%. VNS was less effective for the treatment of patients with ES/TS than for those with PS/SG and those described in previous studies. PMID- 29287186 TI - Transitions into young adulthood: Extent to which alcohol use, perceived drinking norms, and consequences vary by education and work statuses among 18-20year olds. AB - INTRODUCTION: With many young adults pursuing post-secondary education and many working, understanding the importance of education and work roles on alcohol use are of developmental and clinical importance. Utilizing a sample of 18-20year olds transitioning from adolescence to young adulthood, the current study examined how social role statuses in education (i.e., not in school, 2-year students, 4-year students) and work status (i.e., unemployed, employed part-time, employed full-time) were associated with alcohol use, alcohol-related consequences, and perceived drinking norms. METHOD: Participants were 18-20year old young adults (54% female) participating in a one-time online survey about alcohol use and sexual behavior. Regression models were conducted to examine associations between school status and work status with alcohol related outcomes. RESULTS: Individuals who were unemployed had a significantly lower likelihood of any heavy episodic drinking (HED) in the past month, consumed fewer drinks per week, and experienced fewer alcohol-related consequences compared to individuals who worked full-time. Individuals who worked part-time consumed fewer drinks per week and had lower perceived drinking norms compared to individuals who worked full-time. No significant associations were found for alcohol use and consequences by education status. DISCUSSION: Working full-time is a risk factor for HED, greater weekly drinking and negative alcohol-related consequences when compared to young adults who are unemployed, and to a lesser extent with young adults working part-time. Workplace interventions may be one approach to reach heavy drinking young adults. PMID- 29287187 TI - Evaluation of oral sugar test response for detection of equine metabolic syndrome in obese Crioulo horses. AB - Owing to the high prevalence of obesity in Crioulo horses, information allowing early diagnosis of equine metabolic syndrome (EMS) and prevention of the associated laminitis is of great value. The aim of this study was to evaluate the occurrence of EMS and the response to an oral sugar test (OST) in obese Crioulo horses. Twenty-two Crioulo horses were allocated into 3 groups according to their body condition score (BCS out of 9) and presence or absence of laminitis as follows: CON (6/22), BCS < 7; OB (8/22), BCS >= 7; and LAM (8/22), BCS >=7 with clinical and/or radiographic signs of laminitis. A complete clinical history was obtained, followed by a physical examination, morphometric measurements, radiographic evaluation of front feet, and ultrasonography measurements of subcutaneous body fat. For the OST, animals were fasted overnight, and blood samples were collected for glucose and insulin concentration before and after sugar administration. Morphometric and metabolic differences (P < 0.05) were observed between CON animals and obese ones, with horses from the LAM group presenting the highest morphometric measurements and insulin plasma concentrations. A delayed peak glucose response for OST was observed in the majority of obese animals, indicating that sampling between 60 and 90 min after sugar administration without glycemic curve follow-up, as previously used for hyperinsulinism detection, can be inadequate. The observed delay in the return to glucose baseline levels, combined with high insulin levels, supports the diagnosis of insulin dysregulation. These results indicate that there are clear obesity-related differences in the glucose and insulin responses of Crioulo horses to an OST. PMID- 29287188 TI - Standard representation and unified stability analysis for dynamic artificial neural network models. AB - An overview is provided of dynamic artificial neural network models (DANNs) for nonlinear dynamical system identification and control problems, and convex stability conditions are proposed that are less conservative than past results. The three most popular classes of dynamic artificial neural network models are described, with their mathematical representations and architectures followed by transformations based on their block diagrams that are convenient for stability and performance analyses. Classes of nonlinear dynamical systems that are universally approximated by such models are characterized, which include rigorous upper bounds on the approximation errors. A unified framework and linear matrix inequality-based stability conditions are described for different classes of dynamic artificial neural network models that take additional information into account such as local slope restrictions and whether the nonlinearities within the DANNs are odd. A theoretical example shows reduced conservatism obtained by the conditions. PMID- 29287189 TI - Human epidermal growth factor receptor 2 dual blockade with trastuzumab and pertuzumab in real life: Italian clinical practice versus the CLEOPATRA trial results. AB - OBJECTIVES: Given their inclusion and exclusion criteria, randomized clinical trials (RCT) might not include a population that truly mirrors real life (RL). This raises concerns about the applicability of RCT results in clinical practice. We evaluated the efficacy of anti-HER2 treatment with pertuzumab combined with trastuzumab and a taxane as first-line treatment for HER2-positive metastatic breast cancer in a RL setting, and compared the safety results obtained in our population versus the experimental cohort of the CLEOPATRA RCT, which led to the approval of this therapy. MATERIALS AND METHODS: Patients treated with trastuzumab, pertuzumab and a taxane were enrolled in this retrospective study. We compared the tumor features and the patients' characteristics of the RL cohort to those of the CLEOPATRA cohort. We also compared the median progression-free survival (PFS) in the RL population versus specific patients' subgroups. RESULTS: RL patients were more frequently HR-positive, less likely to have visceral metastases (P < .001 for both) and had more frequently received (neo)adjuvant hormone therapy or trastuzumab than CLEOPATRA patients (P = .004 and P < .001, respectively). The median number of anti-HER2 cycles was 8 vs 24 and the median number of cycles was 7 vs 8 for docetaxel in the RL versus CLEOPATRA population, respectively. Adverse reactions of all grades were less frequent in RL. Median PFS was 27.8 months in the RL population and the treatment was equally effective in all patients' subgroups. CONCLUSION: This study provides compelling evidence that pertuzumab, trastuzumab and a taxane are effective and safe also in a clinical scenario. PMID- 29287190 TI - A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy. AB - INTRODUCTION: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations. PMID- 29287191 TI - A compromised maternal vitamin D status is associated with congenital heart defects in offspring. AB - BACKGROUND: Interactions between genetic and environmental factors, including modifiable maternal nutrition and lifestyle, play a significant role in the pathogenesis of most congenital heart defects (CHD). The aim of this study was to investigate associations between periconceptional maternal vitamin D status and the prevalence of CHD in offspring. METHODS: A case-control study was performed in 345 mothers of a child with CHD and 432 mothers of a child without CHD from four tertiary hospitals in the Netherlands between 2003 and 2005. Approximately 15months after pregnancy mothers filled out questionnaires regarding general characteristics and periconceptional lifestyle. Maternal blood was obtained to determine serum 25-hydroxyvitamin D and lipid concentrations. The 25 hydroxyvitamin D concentration was stratified into a deficient <50nmol/l, moderate 50-75nmol/l and adequate >75nmol/l status. Logistic regression was performed to study associations between vitamin D status and CHD risk, adjusted for maternal age, body mass index, ethnicity, smoking and total cholesterol concentration. RESULTS: Case mothers less often had an adequate vitamin D status compared with controls (27% vs. 38%; p=0.002). The use of multivitamin supplements, ethnicity, season and body mass index were associated with vitamin D concentrations. A moderate (odds ratio 1.58, [95%CI 1.08, 2.32]) and deficient (odds ratio 2.15, [95%CI 1.44-3.19]) vitamin D status were associated with CHD in offspring. CONCLUSION: A compromised maternal vitamin D status is associated with an approximately two-fold increased prevalence of CHD in offspring. Therefore, improvement of the periconceptional maternal vitamin D status is recommended. PMID- 29287192 TI - Multiple mechanistic action of Rosmarinus officinalis L. extract against ethanol effects in an acute model of intestinal damage. AB - The high levels of oxidative stress and inflammation can be present in the etiology of degenerative intestinal pathologies associated with ethanol ingestion. The Rosmarinus officinalis L. has exhibited several physiological and medicinal activities. In this investigation, we intended to clarify, for the first time, the antioxidant and anti-inflammatory effects of ethanolic extract of Rosmarinus officinalis L. (eeRo) against an acute damage induced by ethanol, specifically in the small intestine of rats. The rats were treated three times, at every 24 h, with eeRo at 500-1000 mg/kg or vehicle, oral gavage. All groups got a single dose of ethanol (2 ml/kg), oral gavage, after 36 h of fasting and 1 h after the last dose of eeRo or vehicle administration. We performed the mensuration of oxidative stress profile in lipid peroxidation in serum and intestine; Na+/K+ ATPase, catalase, and superoxide dismutase activities assays only in intestine; and anti-inflammatory evidences of eeRo in myeloperoxidase activity assay only in the intestine. The eeRo was able to protect the animals against the lipid peroxidation in serum and intestine. It prevented the reduction in Na+/K+ ATPase and catalase levels induced by ethanol in the intestine. In addition, eeRo increased the superoxide dismutase activity when compared to control and protected the intestine against elevations in myeloperoxidase activity caused by ethanol. Our results suggested that eeRo exerted a significant intestinal protective effect by antioxidant and anti-inflammatory mechanisms. Thus, the eeRo represented a promising agent against intestinal lesions induced by ethanol. PMID- 29287193 TI - Autophagy induction by hispidulin provides protection against sevoflurane-induced neuronal apoptosis in aged rats. AB - AIM: Sevoflurane is a general anesthetic, which has been found to cause cognitive and memory deficit in elderly. This study is designed to explore the neuroprotective effect of hispidulin, a natural flavone compound, against sevoflurane-induced cognitive dysfunction in aged rats. MATERIALS AND METHODS: Human neuroglioma cell line H4 was used as cellular model in our study. The apoptosis of H4 cells was determined by DNA fragmentation and flow cytometry. The autophagy of H4 cells was determined by observing GFP-LC3 II puncta and flow cytometry. The levels of marker proteins for apoptosis and autophagy were determined by western blot. The neuroprotective effect of hispidulin was also examined in aged rat model. The impairment of cognitive function by sevoflurane exposure was evaluated by Morris water maze. The apoptotic cell death in hippocampus was measured by TUNEL assay. RESULTS: Our results showed that hispidulin significantly induced autophagy in H4 cells, which contributed to its protective activity against sevoflurane-induced apoptosis. In addition, our results showed that hispidulin triggered autophagy in AMPK-dependent way. Moreover, the neuroprotective effect hispidulin was verified in aged rat model, which showed that pretreatment with hispidulin significantly attenuated sevoflurane-induced cognitive dysfunction. Meanwhile, our findings revealed that the neuroprotectionin rat model by hispidulin was associated with activation of autophagy and AMPK signaling pathway. CONCLUSION: The findings in this present study highlight that hispidulin offers neuroprotection against sevoflurane induced cognitive dysfunction, which is mediated by autophagy induction through activating AMPK signaling. The present study provides novel information about the underlying mechanism for the neuroprotective activity of hispidulin. PMID- 29287194 TI - Potential role of propolis in wound healing: Biological properties and therapeutic activities. AB - Propolis is a resinous mixture that honey bees collect from the tree buds, sap flows, or other botanical sources. The chemical composition of propolis varies and depends on the geographical area, time of collection, seasonality, illumination, altitude, and food availability during propolis exploitation. The goal of this review is to discuss important concepts including mechanisms of action and therapeutic activities of propolis. The PubMed, ScienceDirect, and Cochrane Library databases were searched for the literature published from January the 1st 2000 to October the 1st 2017. Sixteen animals and three clinical studies were included. A quantitative and qualitative review was performed on the clinical trials and the animal studies were comprehensively overviewed. In this study, the clinical trials have been combined and the results were provided as meta-analysis. Propolis is a non-toxic natural product; however some cases of allergy and contact dermatitis to this compound have been described mainly among beekeepers. An important factor in impaired wound healing is biofilm formation; propolis as an anti-microbial agent can reduce biofilm generation and result in accelerated healing processes. Most of the in vivo studies on various wound models suggested the beneficial roles of propolis on experimental wound healing and this has also been approved in the clinical trial studies. However, there is a lack of information concerning, dose, side effects and clinical effectiveness of propolis on wounds. As the effectiveness of propolis between different products is variable, more characterizations should be done and future investigations comparing different propolis based products and characterization of their specific roles on different models of wounds are highly appreciated. PMID- 29287195 TI - [6]-Shogaol attenuates inflammation, cell proliferation via modulate NF-kappaB and AP-1 oncogenic signaling in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis. AB - Nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) is a major transcription factor which regulates many biological and pathological processes such as inflammation and cell proliferation, which are major implicates in cancer progression. [6]-Shogaol ([6]-SHO) is a major constituent of ginger, exhibits various biological properties such as anti-oxidants, anti-inflammation and anti tumor. Recently, we proven that [6]-SHO prevents oral squamous cell carcinoma by activating proapoptotic factors in in vitro and in vivo experimental model. However, the preventive efficacy of [6]-SHO in 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis (HBP) has not been fully elucidated, so far. Hence, we aimed to investigate the effect of [6]-SHO on inflammation and cell proliferation by inhibiting the translocation of NF-kappaB and AP-1 in DMBA induced HBP carcinogenesis. In this study, we observed upregulation of inflammatory markers (COX-2, iNOS, TNF-alpha, interleukin-1 and 6), cell proliferative markers (Cyclin D1, PCNA and Ki-67) and aberrant activation of NF-kappaB, AP-1, IKKbeta, c-jun, c-fos and decreased IkappaB-alpha in DMBA induced hamsters. Conversely, oral administration of [6]-SHO strongly inhibited constitutive phosphorylation and degradation of IkappaB and inhibit phosphorylation of c-jun, c-fos, resulting in inhibition of nuclear translocation of NF-kappaBp65 and AP-1. Thus, inhibition of NF-kappaB and AP-1 activation by [6]-SHO attenuates inflammation and cell proliferative response in DMBA induced hamsters. Our finding suggested that [6]-SHO is a novel functional agent capable of preventing DMBA induced inflammation and cell proliferation associated tumorigenesis by modulating multiple signalling molecules. PMID- 29287196 TI - The prophylactic and therapeutic effects of Momordica charantia methanol extract through controlling different hallmarks of the hepatocarcinogenesis. AB - Inspite of the wide facilities for controlling cancer growth, there are little drugs to inhibit its metastasis or prevent its angiogenesis. Discovering such natural or synthetic multi-targeted agent that might strike different targets is considered as a vital goal for tumor controlling. In a previous study, the chemoprotective effect of methanol extract of Momordicacharantia (MEMC) on albino western rats bearing hepatocarcinogenesis was evaluated. The mechanism by which MEMC exert its anticancer properties was unknown. Therefore, we aimed in this study to investigate the possible role of MEMC as anti-proliferative, anti angiogenic and anti-metastatic agent to exert its chemoprotective effect. The study was conducted on sixty albino western rats divided into six groups, 10 rats each. Diethylnitrosamine (DENA) was injected intraperitoneally (i.p.) at a dose of 200 mg/kg body weight once, 2 weeks later rats were received carbon tetrachloride (CCl4) subcutaneously (3 ml/kg/week) continued for 10 weeks. MEMC was orally produced to rats (40 mg/kg) alone, as well as before, at the same time and after DENA injection. Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), caspase-3,-8 (Casp-3,-8), histone deacetylase (HDAC) and matrixmetalloproteinases-2,-9 (MMP-2,-9) were evaluated. MEMC treatment significantly decreased Cox-2, VEGF, HDAC and MMP-2,-9 and increased Casp-3,-8 as compared to DENAgroup,which demonstrated that the anticancer effect of MEMC may be through the inhibition of angiogenesis, proliferation and metastasis and the activation of apoptosis. The improvement in before-treated group was more pronounced than that in after- and simultaneous-treated groups, indicating thatMEMC may act as a prophylactic agent more than being a therapeutic agent. PMID- 29287197 TI - Breast cancer: Lesser-known facets and hypotheses. AB - Breast cancer is the most common cancer in females. The deteriorating environment, and lifestyle flaws are raising the frequency of this cancer. Existing therapies are not universally-effective, and they cause side effects, relapses, and high mortality rate. Alternative medications may be milder, but are less effective or are inadequate for a complex disease like the breast cancer. So, it requires the understanding that drugs are not the solution of this cancer, but prevention is the sustainable solution. In the past decades, an enormous quantum of insights on this disease has been obtained. A lifestyle based on the template of estrogenic compounds and, the resultant endocrine disruption, and acidosis, is elevating aromatase level, promoting the deleterious forms of estrogen, and inducing epithelial proliferation. This review provids a holistic account of breast cancer as a inflammatory endocrinopathy, and how it can be curbed by discipline, and awareness. PMID- 29287198 TI - Upregulation of peroxisome proliferator activated receptor alpha by fenofibrate in induced testicular ischemia reperfusion. AB - Torsion of the spermatic cord is a common urological emergency among infants and adolescents that can lead to testicular necrosis and infertility. We investigated the effect of fenofibrate (FEN) on induced testicular ischemia reperfusion (testicular (I-R). FEN (100, 300 mg/kg/day) was administered orally in presence or absence of testicular (I-R). We measured testicular weight changes and serum testosterone level. In addition; Testicular tissue reduced glutathione (GSH), malondialdehyde (MDA), total nitrites (NOx) and superoxide dismutase (SOD) activity were measured. Moreover; tumor necrosis factor alpha (TNF-alpha), nuclear factor kappa B (NF-kappaB) immunoexpressions and histopathology were evaluated. Testicular (I-R) induced group showed significant decrease in serum testosterone level and testicular weight with increase in testicular tissue MDA and NOx levels. Testicular (I-R) induced group showed the histopathological changes of marked testicular damage according to Johnsen's score. In addition, there was significant reduction in GSH and SOD testicular tissue levels but significant increase in TNF-alpha and NF-kappaB immunoexpressions. FEN was able to markedly improve testicular (I-R) induced changes through its action on peroxisome proliferator activated receptor alpha (PPARalpha), anti-oxidant, anti inflammatory and anti-apoptotic effects. PMID- 29287200 TI - Gramine attenuates EGFR-mediated inflammation and cell proliferation in oral carcinogenesis via regulation of NF-kappaB and STAT3 signaling. AB - Gramine, a natural indole alkaloid found in Hordeum vulgare has been possesses anti-mutagenic properties. The aim of the present study was to evaluate the effect of gramine on inflammation and proliferation in 7,12 dimethylbenz[a]anthracene(DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Epidermal growth factor receptor (EGFR) tyrosine kinase phosphorylation trigged PI3K/Akt/mTOR and JAK signaling that activates NF-kappaB and STAT3. In contrast, gramine suppressed EGFR tyrosine kinase phosphorylation and simultaneously inhibiting PI3K/Akt/mTOR and JAK phosphorylation, thereby blockage NF-kappaB and STAT3 nuclear translocation. Attenuation of these oncogenic signals leads to downregulated iNOS, COX-2, TNF-alpha, IL-6, cyclin D1 and PCNA protein expressions. In addition, gramine enhanced the expression of the tumor suppressors p53, p21(WAF1/CIP1) and Gsk-3beta by inhibiting MDM2. These results suggested that gramine exhibited anti-inflammation and anti-proliferation effects via suppressed EGFR/PI3K/Akt/mTOR/ IKK/NF-kappaB and JAK/STAT3 signaling pathways. PMID- 29287199 TI - Trillium tschonoskii maxim saponin mitigates D-galactose-induced brain aging of rats through rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway. AB - During the expansion of aging population, the study correlated with brain aging is one of the important research topics. Developing novel and effective strategies for delaying brain aging is highly desired. Brain aging is characteristics of impaired cognitive capacity due to dysfunctional autophagy regulated by Rheb-mTOR signal pathway in hippocampal tissues. In the present study, we have established a rat model with brain aging through subcutaneous injection of D-galactose (D-gal). Upon the intervention of Trillium tschonoskii Maxim (TTM) saponin, one of bioactive components from local natural herbs in China, the learning and memory capacity of D-gal-induced aging rats was evaluated through Morris water maze test, and the regulation of Rheb-mTOR signal pathway and functional status of autophagy in hippocampal tissues of D-gal-induced aging rats was explored by Western blot. TTM saponin revealed an obvious function to improve learning and memory capacity of D-gal-induced aging rats through up regulating Rheb and down-regulating mTOR, thereby rescuing dysfunctional autophagy to execute anti-aging role. Meanwhile, this study confirmed the function of TTM saponin for preventing and treating brain aging, and provided a reference for the development and utilization of natural products in health promotion and aging-associated disease treatment. PMID- 29287201 TI - miR-365 functions as a tumor suppressor by directly targeting CYR61 in osteosarcoma. AB - Increasing evidence indicates that microRNAs(miRNAs) are often aberrantly expressed in osteosarcoma (OS) and play critical roles in OS tumorigenesis. Therefore, the discovery of miRNAs may provide a new and powerful tool for understanding the mechanismof OS initiation and development. The aim of this study was to investigate the functional significance of miR-365 and identify its possible mechanism in OS cells. Here, wefound that the expression level of miR 365 is significantly downregulated in OS tissues and cell lines, and its expression isassociated with the clinical stage, distant metastasis, tumor grade, and poor overall survival rate. The overexpression of miR-365 is able to inhibit cell proliferation, migration, and invasion in Saos-2 and MG-63 cells. Moreover, the cysteine-rich angiogenic inducer 61 (CYR61) has been identified as a target of miR-365 in OS cells, and its expression is found to be significantly increased in OS tissues, which is negatively correlated with miR-365. Furthermore, CYR61 overexpression significantly attenuated the suppressive effects of miR-365 on the proliferation, migration, and invasion of Saos-2 and MG-63 cells. Therefore, we consider that miR-365 acts as a tumor suppressor in OS, partly, by targeting CYR61 expression. PMID- 29287202 TI - microRNA-381 suppresses the growth and increases cisplatin sensitivity in non small cell lung cancer cells through inhibition of nuclear factor-kappaB signaling. AB - microRNA (miR)-381 is downregulated and exhibits anti-invasive activity in non small cell lung cancer (NSCLC). In this study, we investigated the role of miR 381 in proliferation, tumorigenesis, and cisplatin resistance of NSCLC cells. The effects of miR-381 overexpression on proliferation, tumorigenesis, cell cycle progression, and cisplatin sensitivity were examined. Overexpression of miR-381 significantly inhibited cell proliferation and colony formation in vitro and tumorigenesis in vivo. Ectopic expression of miR-381 arrested NSCLC cells at G0/G1 phase, which was accompanied by increased expression of p21 and p27 and decreased expression of cyclin D1 and CDK4. Compared to A549 parental cells, cisplatin-resistant equivalents (A549/CDDP) had reduced levels of miR-381. miR 381 re-sensitized A549/CDDP cells to cisplatin and potentiated cisplatin-induced apoptosis. Mechanistically, miR-381 interfered with the activation of nuclear factor (NF)-kappaB through repression of inhibitor of differentiation 1 (ID1). Co expression of ID1 reversed the suppression of proliferation and enhancement of cisplatin cytotoxicity by miR-381. Taken together, miR-381 can induce growth suppression and chemosensitization in NSCLC, largely through inactivation of NF kappaB via downregulation of ID1. Restoration of miR-381 represents a potential therapeutic strategy for NSCLC. PMID- 29287203 TI - DJ-1 preserving mitochondrial complex I activity plays a critical role in resveratrol-mediated cardioprotection against hypoxia/reoxygenation-induced oxidative stress. AB - Resveratrol has been demonstrated to have cardioprotective effects by attenuating ischemia/reperfusion (I/R)-induced oxidative stress injury, but its in-depth molecular mechanisms against I/R-induced oxidative stress is not fully elaborated. DJ-1 plays a role in maintenance of mitochondrial complex I activity and is closely associated with oxidative stress. Therefore, this study sought to determine the contribution of DJ-1-mediated maintenance of mitochondrial complex I activity to the anti-oxidative stress effect of Resveratrol in the H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R). The results showed that Resveratrol significantly attenuated the H/R-induced viability loss and lactate dehydrogenase leakage, accompanied by decreases in intracellular reactive oxygen species (ROS) and malondialdehyde contents and increases in the reduced glutathione/oxidized glutathione ratio. Furthermore, Resveratrol increased the expression and mitochondrial translocation of DJ-1 and promoted the direct binding of DJ-1 with complex I subunits ND1 and NDUFS4, which in turn improved mitochondrial complex I activity and inhibited mitochondria-derived ROS production after H/R. Intriguingly, the anti-oxidative stress effect of Resveratrol could be partially blocked by DJ-1 siRNA and Complex I inhibitor Rotenone, respectively. Conclusively, these results indicated that DJ-1 is necessary for Resveratrol-mediated cardioprotective effects against H/R-induced oxidative stress damage, at least in part, through preserving mitochondrial complex I activity, and subsequently decreasing mitochondrial ROS generation. PMID- 29287204 TI - Toddlers' comprehension of adult and child talkers: Adult targets versus vocal tract similarity. AB - How do children represent words? If lexical representations are based on encoding the indexical characteristics of frequently-heard speakers, this predicts that speakers like a child's own mother should be best understood. Alternatively, if they are based on the child's own motor productions, this predicts an own-voice advantage in word recognition. Here, we address this question by presenting 2.5 year-olds with recordings of their own voice, another child's voice, their own mother's voice, and another mother's voice in a child-friendly eye-tracking procedure. No own-voice or own-mother advantage was observed. Rather, children uniformly performed better on adult voices than child voices, even performing better for unfamiliar adult voices than own voices. We conclude that children represent words not in the form of own-voice motor codes or frequently heard speakers, but on the basis of adult speech targets. PMID- 29287207 TI - Further evidence for functional differences between guessing versus choosing an upcoming task. AB - We replicated and extended previous evidence regarding functional differences between guessing versus choosing an upcoming task. Participants switched among four tasks and were asked to predict the upcoming task on each trial. These predictions were instructed to participants as either 'guessing' or 'choosing'. Furthermore, we varied the proportion of trials in which the presented task conformed to participants' predictions on three levels. Whereas with choosing instructions unexpectedness affected task switches and repetitions similarly, leaving switch costs unchanged, with guessing instructions switch costs were reduced, that is, task switches were affected less than repetitions. This interaction was unaffected by the proportion of expected tasks. We propose that with choosing, the impact of a mismatch between chosen and presented tasks is reduced by explicit knowledge regarding the proportion of denied choices. With guessing, task unexpectedness mainly increases task difficulty, which is compensated by an increase of cognitive control that reduces switch costs. PMID- 29287205 TI - Novel names extend for how long preschool children sample visual information. AB - Known words can guide visual attention, affecting how information is sampled. How do novel words, those that do not provide any top-down information, affect preschoolers' visual sampling in a conceptual task? We proposed that novel names can also change visual sampling by influencing how long children look. We investigated this possibility by analyzing how children sample visual information when they hear a sentence with a novel name versus without a novel name. Children completed a match-to-sample task while their moment-to-moment eye movements were recorded using eye-tracking technology. Our analyses were designed to provide specific information on the properties of visual sampling that novel names may change. Overall, we found that novel words prolonged the duration of each sampling event but did not affect sampling allocation (which objects children looked at) or sampling organization (how children transitioned from one object to the next). These results demonstrate that novel words change one important dynamic property of gaze: Novel words can entrain the cognitive system toward longer periods of sustained attention early in development. PMID- 29287206 TI - Effect of lumbar spinal fusion surgery on the association of self-report measures with objective measures of physical function. AB - BACKGROUND: Self-report measures are used to evaluate surgery outcome but are not necessarily indicative of actual disabilities. RESEARCH QUESTION: The aim of the present study was to determine the association between self-report assessments of quality of life and objective measures of function in patients with symptomatic lumbar degenerative disease. Additionally, we evaluated the effect of lumbar spinal fusion surgery on this relationship. METHODS: Before and 6 month after surgery 26 patients completed self-report questionnaires and assessments of 3D gait analysis and trunk range of motion (ROM) during standing. RESULTS: Before surgery, questionnaires were not correlated with any of the gait parameters and with only 2 trunk ROM parameters. Six month after surgery, the questionnaires showed 12 significant correlations with gait parameters and 19 with trunk ROM parameters. A better Oswestry Disability Index (ODI) (r = 0.464, p = .026), EQ-5D (r = -0.440, p = .036), and EQ VAS (r = -0.472, p = .023) score were correlated with a reduced anterior thorax tilt during walking. Maximum forward flexion of the trunk during standing was correlated with a better EQ-5D (r = 0.684, p = .001) and ODI (r = -0.560, p = .008) score as well as with reduced pain scores. SIGNIFICANCE: The lack of association between self-reported questionnaires and objective measures of function before surgery was likely due to psychological distress, correlating with emotional and cognitive function rather than true functional capacities. The influence of these psychological factors might be reduced after surgery due to a reduction of low back pain. To obtain an accurate assessment of impairment, there is a need to evaluate function by measuring objective physiologic parameters that are unsusceptible to voluntary or affective influences. PMID- 29287208 TI - Diminishing covariation bias in women with a negative body evaluation and the potential roles of outcome aversiveness and interpretation of social feedback. AB - Women with a more negative body evaluation perceive that their body is associated with more negative social feedback. This covariation bias could reinforce negative body evaluation. We investigated whether covariation bias could be diminished and explored the potential roles of outcome aversiveness and interpretation of negative social feedback associated with one's body. Ninety seven undergraduate women completed a computer task wherein photos of their body, a control woman's body, and a neutral object were followed by negative social feedback or nothing. When the relation between each category and the negative feedback was random, women with a more negative body evaluation perceived more negative feedback following their body. They also experienced negative feedback following their body and the control woman's body as more aversive. After a manipulation block, women with a more negative body evaluation no longer perceived more negative feedback for their body. These effects coincided with improvements in state body evaluation. PMID- 29287209 TI - Total and fraction content of elements in volcanic soil: Natural or anthropogenic derivation. AB - Soil element composition derives from parent material disaggregation during pedogenesis and weathering processes but also by anthropogenic inputs. Elements are present in soils in different chemical forms that affect their availability and mobility. The aim of the study was to evaluate the main derivation, natural or anthropogenic, of elements in the soils of the Vesuvius National Park (a natural environment strongly affected by human impacts). Besides, the effects of age of the lava from which soils derive, different vegetation covers, traffic fluxes along the two roads connecting the Vesuvius crater and altitudes of the sites on the pseudo-total element concentrations and on their contents in different fraction of soil were investigated. To reach the aims, BCR (Bureau Commun de Reference) sequential extraction was performed in order to determine the distribution of elements into: acid-soluble, reducible, oxidizable and residual fractions. The relationship between the main environmental media and distribution of elements was discussed using non-metric multidimensional scaling (NMDS). The findings showed that, with the exception of Cd, Cu, Pb and Zn that would seem to derive also from human activities, the other investigated elements (Al, As, B, Ba, Ca, Cd, Cr, Cu, Fe, K, La, Mg, Mn, Na, Ni, P, Pb, Si, Ti, V, W and Zn) mainly had a natural derivation. Among the investigated elements, only Cd could represent a potential high risk for the studied andosols. The highest element accumulations in the soils at low altitude could be attributable to an integrated effect of plant cover, vicinity of downtowns and traffic flux. The acid-soluble fraction of elements appeared more linked to lava age; the reducible and oxidizable ones to plant cover; the residual one to the chemical composition of the parent material that gave origin to the soils. PMID- 29287210 TI - Combined use of radiocarbon and stable carbon isotope to constrain the sources and cycling of particulate organic carbon in a large freshwater lake, China. AB - The concentrations and isotopic compositions of dissolved inorganic carbon (DIC) and particulate organic carbon (POC) were measured in order to better constrain the sources and cycling of POC in Lake Fuxian, the largest deep freshwater lake in China. Model results based on the combined delta13C and Delta14C, showed that the average lake-wide contributions of autochthonous POC, terrestrial POC, and resuspended sediment POC to the bulk POC in Lake Fuxian were 61%, 22%, and 17%, respectively. This indicated autochthonous POC might play a dominant role in sustaining large oligotrophic lake ecosystem. A mean 17% contribution of resuspended sediment POC to the bulk POC implied that sediment might have more significant influence on aquatic environment and ecosystem than previously recognized in large deep lakes. The contributions of different sources POC to the water-column POC were a function of the initial composition of the source materials, photosynthesis, physical regime of the lake, sediment resuspension, respiration and degradation of organic matter, and were affected indirectly by environmental factors such as light, temperature, DO, wind speed, turbidity, and nutrient concentration. This study is not only the first systematic investigation on the radiocarbon and stable isotope compositions of POC in large deep freshwater lake in China, but also one of the most extensive radiocarbon studies on the ecosystem of any great lakes in the world. The unique data constrain relative influences of autochthonous POC, terrestrial POC, and resuspended sediment POC, and deepen the understanding of the POC cycling in large freshwater lakes. This study is far from comprehensive, but it serves to highlight the potential of combined radiocarbon and stable carbon isotope for constraining the sources and cycling of POC in large lake system. More radiocarbon investigations on the water-column POC and the aquatic food webs are necessary to illuminate further the fate of autochthonous POC, terrestrial POC, and resuspended sediment POC, and their eco-environmental effects. PMID- 29287211 TI - Chemical and microbiological evaluation of novel chemical treatment methods for acid sulfate soils. AB - Naturally occurring sulfide rich deposits are common along the northern Baltic Sea coast that when exposed to air, release large amounts of acid and metals into receiving water bodies. This causes severe environmental implications for agriculture, forestry, and building of infrastructure. In this study, we investigated the efficiency of ultrafine-grained calcium carbonate and peat (both separately and in combination) to mitigate acid and metal release. The experiments were carried out aerobically that mimicked summer conditions when the groundwater level is low and acid sulfate soils are exposed to oxygen, and anaerobically that is similar to autumn to spring conditions. The ultrafine grained calcium carbonate dissipated well in the soil and its effect alone and when mixed with peat raised the pH and reduced pyrite dissolution while peat alone was similar to the controls and did not halt metal and acid release. High throughput 16S rRNA gene sequencing identified populations most similar to characterized acidophiles in the control and peat treated incubations while the acidophilic like populations were altered in the calcium carbonate alone and calcium carbonate plus peat treated acid sulfate soils. Coupled with the geochemistry data, it was suggested that the acidophiles were inactivated by the high pH in the presence of calcium carbonate but catalyzed pyrite dissolution in the controls and peat incubations. In conclusion, the anaerobic conditions during winter would likely be sufficient to mitigate acid production and metal release from acid sulfate soils and in the summer, treatment with calcium carbonate was the best mitigation method. PMID- 29287212 TI - Application of biochar to sewage sludge reduces toxicity and improve organisms growth in sewage sludge-amended soil in long term field experiment. AB - The aim of the present study was to determine changes in the physicochemical properties and toxicity of soil amended with sewage sludge (10tdw/ha) or sewage sludge (10tdw/ha) with biochar addition (2.5, 5 or 10% of sewage sludge). The study was carried out as a field experiment over a period of 18months. Samples for analysis were taken at the beginning of the experiment as well as after 6, 12 and 18months. The study investigated toxicity of the unamended soil, sewage sludge-amended soil and sewage sludge-amended soil with biochar addition towards Folsomia candida (collembolan test) and Lepidium sativum (Phytotoxkit F). Moreover, toxicity of aqueous extracts obtained from the tested soils towards Vibrio fischeri (Microtox(r)) and Lepidium sativum (elongation test) was determined. The study showed that addition of biochar to the sewage sludge and soil reduced leaching of nutrients (mainly phosphorus and potassium) from the amended soil. Biochar significantly reduced sewage sludge toxicity, exhibiting a stimulating effect on the tested organisms. The stimulating effect of biochar addition to the sewage sludge persisted throughout the entire experiment. Apart from the remediatory character of biochar, this is also evidence of its fertilizing character. In the tests with L. sativum (leachates and solid phase) and V. fischeri (leachates), increasing the rate of biochar in the sewage sludge increased root growth stimulation (L. sativum) and bacteria luminescence (V. fischeri). However, increasing biochar rate decreased F. candida reproduction stimulation, which could have been an effect of reduced nutrient bioavailability due to the biochar. PMID- 29287213 TI - Using visual thinking strategies with nursing students to enhance nursing assessment skills: A qualitative design. AB - This qualitative design study addressed the enhancement of nursing assessment skills through the use of Visual Thinking Strategies and reflection. This study advances understanding of the use of Visual Thinking Strategies and reflection as ways to explore new methods of thinking and observing patient situations relating to health care. Sixty nursing students in a licensed practical nursing program made up the sample of participants who attended an art gallery as part of a class assignment. Participants replied to a survey of interest for participation at the art gallery. Participants reviewed artwork at the gallery and shared observations with the larger group during a post-conference session in a gathering area of the museum at the end of the visit. A reflective exercise on the art gallery experience exhibited further thoughts about the art gallery experience and demonstrated the connections made to clinical practice by the student. The findings of this study support the use of Visual Thinking Strategies and reflection as effective teaching and learning tools for enhancing nursing skills. PMID- 29287214 TI - Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model. AB - Levetiracetam (LEV), and its newer selective analog brivaracetam (BRV), are two seizure medications that share an innovative mechanism of action targeting the Synaptic Vesicle Protein 2A (SV2A), altering neurotransmitter release and decreasing seizure frequency. Behavioral changes are the most significant adverse effects reported by patients taking LEV. We hypothesize that BRV, the more potent SV2A analog, could exert less behavioral side effects, as it requires lower doses than LEV. Using Kainic Acid (KA)-treated and control rats, we measured adverse behavioral effect profiles of LEV, BRV, or Saline, on social and nonsocial behaviors. Our data indicate that both tested drugs had no effect on locomotion, anxiety levels, fear learning, depression-like behavior, and memory retention in rats. However, when considering social interactions, we first confirmed the epilepsy-induced strong increase in aggressive behaviors and specific hippocampal neuronal loss. We furthermore observed, in Sham rats, that LEV-treated animals were 2 times faster to attack at first encounter, had 5 times more aggressive behaviors, and had significantly less social behaviors than control rats. In all circumstances, BRV rats behaved like Saline rats, suggesting that BRV treatment in rats leads to significantly less aggressive behaviors than LEV treatment at the doses used, while there are limited differential effects between these two drugs on other types of behaviors. Since increased aggressiveness has been reported in patients well controlled on LEV, this study indicates based on our findings, that BRV could represent an effective alternative to LEV to limit aggressiveness problems due to this antiepileptic drug (AED) therapy. PMID- 29287215 TI - Impact of vagus nerve stimulation on sleep-related breathing disorders in adults with epilepsy. AB - BACKGROUND: Vagus nerve stimulation (VNS) can induce a sleep apnea syndrome (SAS), which in turn can worsen seizure control and represents a cardiovascular risk factor. Epidemiology of VNS-induced SAS has received little attention to date. The purpose of this study was to estimate the VNS-induced SAS prevalence and to explore clinical variables potentially correlating with its development. METHODS: We analyzed the computerized medical records of 18 consecutive adults treated for refractory epilepsy with VNS, implanted between May 2008 and October 2015. Patients underwent sleep polygraphy or polysomnography before and after VNS implantation. Between patients with and without SAS, we compared variables related to epilepsy type and device parameters. RESULTS: Two patients had SAS and were treated before implantation; one improved after VNS, the other worsened. Four other patients developed SAS after VNS: induced/aggravated SAS occurred in 5/18 patients (prevalence: 27.8%). Only 2 of them had symptoms: one complained of important snoring, the other reported seizure worsening. All 5 patients were successfully treated by combinations of continuous positive airway pressure (cPAP), positional therapy, or VNS parameters modification. There was no statistically significant difference between potential predictors. CONCLUSION: Despite the relatively modest clinical impact on epilepsy, in view of the associated cardiovascular risk factor development, easy treatment, and the relatively high SAS prevalence, routine screening for SAS before and after VNS implantation may represent a reasonable practice. PMID- 29287216 TI - The effectiveness and safety of lacosamide in children with epilepsy in a clinical practice setting. AB - BACKGROUND: Seizures in up to 30% of children with epilepsy become refractory to treatment, decreasing their quality of life. Studies suggest that lacosamide may be effective in pediatric patients with refractory epilepsy. AIMS: To assess the effectiveness and safety of lacosamide in a population of children with mostly focal refractory epilepsy. METHODS: Retrospective analysis of children aged <18years presenting to a single hospital in Spain. Data from baseline, and 3, 6, and 12months after lacosamide initiation were collected and analyzed. Response to lacosamide was categorized by seizure frequency (seizure freedom or >=75%, >=50%, and <50% reduction in seizures). RESULTS: One hundred ninety-one pediatric patients (~55% male) with focal epilepsy treated with lacosamide were included. The mean age at lacosamide initiation was 9.4years, and the mean duration of epilepsy was 5.4years. Seizure-free rates at 3, 6, and 12months were 9.7%, 11.8%, and 16.0%. At 12months, 44.4% of the population had a >=50% reduction in seizure frequency. When analyzing response according to the number of previous/concomitant AEDs, those patients who received <=2 previous AEDs/fewer concomitant AEDs had significantly greater response rates than those who received greater numbers of previous/concomitant AEDs; however, no predictive factors for response were identified. The most common adverse events were seizure number increased (14.7%), diplopia (5.2%), dizziness (3.7%), ataxia (2.1%), and drowsiness (2.1%). CONCLUSIONS: Lacosamide use in children with refractory focal epilepsy can result in a reduction in seizure rate that improves progressively over time with few adverse effects, making lacosamide a promising option in these patients. PMID- 29287217 TI - Association of white matter diffusion characteristics and cognitive deficits in temporal lobe epilepsy. AB - OBJECTIVE: The purpose of this study was to evaluate the relation between cognitive performance and white matter (WM) integrity in patients with temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS). METHODS: We included 26 patients with TLE (10 right, 16 left onset) as well as 24 healthy controls matched for age, gender, and years of education. In addition to quantitative hippocampal volume and transverse relaxation (T2) evaluation, whole-brain WM was analyzed using fractional anisotropy (FA) maps, derived from the diffusion tensor model. Average FA values were obtained from 38 regions of interest (ROI) of the main WM fascicles using an atlas-based approach. All subjects underwent extensive coFignitive assessments, Wechsler Adult Intelligence Scale (WAIS-IV) and Wechsler Memory Scale (WMS-IV). Fractional anisotropy was correlated with neuropsychological scores, and group effects were evaluated. Finally, patients were clustered based on their cognitive performance to evaluate if clinical and structural variables relate to specific cognitive profiles. RESULTS: Patients had differential alterations in the integrity of the WM dependent on seizure laterality and presence of hippocampal sclerosis. Patients with TLE showed, on average, lower scores in most of the cognitive assessments. Correlations between cognition and WM followed specific trajectories per group with TLE, particularly in Left-TLE, in which we found a marked association between cognitive abilities and WM abnormalities. Cluster analysis of cognitive performance revealed three cognitive profiles, which were associated with the degree and spread of WM abnormalities. SIGNIFICANCE: White matter diffusion characteristics differ between patients, particularly in relation to seizure laterality and hippocampal damage. Moreover, WM abnormalities are associated with cognitive performance. The extent of WM alterations leads to disrupted cerebral intercommunication and therefore negatively affects cognition. PMID- 29287218 TI - High serum adiponectin is associated with anemia development in chronic kidney disease: The results from the KNOW-CKD study. AB - BACKGROUND: Adiponectin is an adipokine secreted by adipocytes. A low adiponectin level is a significant risk factor of diabetes mellitus and cardiovascular disease. Recent studies have shown that adiponectin is negatively associated with hematopoiesis and predicts the development of anemia in the general population. In chronic kidney disease (CKD) patients, circulating adiponectin level is paradoxically elevated and the role of adiponectin is complex. Therefore, we evaluated the relationship between adiponectin and anemia in these patients. METHODS: This prospective longitudinal study included 2113 patients from the KNOW CKD study (KoreaN cohort study for Outcome in patients With CKD), after excluding 125 without data on adiponectin levels. Hemoglobin levels were measured yearly during a mean follow-up period of 23.7 months. Anemia was defined as hemoglobin levels of <13.0 and 12.0 g/dL for men and women, respectively. RESULTS: Mean patient age was 53.6 +/- 12.2 years, and 1289 (61%) were men. The mean estimated glomerular filtration rate (eGFR) was 50.4 +/- 30.2 mL min-1 1.73 m-2. Serum adiponectin level was inversely associated with body mass index, eGFR, log transformed C-reactive protein, and positively with Charlson comorbidity index, urine protein to creatinine ratio, and high density lipoprotein cholesterol. In addition, serum adiponectin level was also negatively correlated with hemoglobin level and reticulocyte production index in both men and women. In multivariable linear regression analysis after adjustment of multiple confounders, adiponectin was negatively associated with hemoglobin (men, beta = -0.219, P < .001; women, beta = -0.09, P = .025). Among 1227 patients without anemia at baseline, 307 newly developed anemia during the follow-up period. In multivariable Cox regression analysis after adjustment of confounders, high adiponectin level was significantly associated with an increased risk of incident anemia (per 1 ug/mL increase, hazard ratio, 1.02; 95% confidence interval 1.01-1.04; P = .001). CONCLUSIONS: A high serum adiponectin level is independently associated with a low hemoglobin level and predicts the development of anemia in patients with CKD. These findings reveal the potential role of adiponectin in CKD-related anemia. PMID- 29287219 TI - Comprehensive investigating of cytokine and receptor related genes variants in patients with chronic hepatitis B virus infection. AB - BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is a global health problem and the outcome are associated with both viral factors and host genetic factors. High Throughput Sequencing (HTS) technology were used to identify variants associated with liver disease. METHODS: Fifty-five Chronic hepatitis B (CHB) patients, fifty-three self-healing HBV (SH) patients and 53 healthy controls (HC) were recruited, 404 cytokine and cytokine receptor related genes were captured and sequenced at high depth (>900X), both variant (Fischer's exact test, P value < 0.05) and gene (SKAT-O gene level test, adjust P value < 0.05) level association were used to identify variants and genes associated with CHB. RESULTS: Total 5083 variants have been detected, fifty-four variants were found associated with CHB, most (29/32) variants were located in HLA region, including HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DQB2, HLA-DRB1 and HLA-DRB5. Several missense variants were found associated with CHB, including p.E226K in PVR (poliovirus receptor), p.E400A and p.C431R in IL4R (interleukin 4 receptor). Four variants located in 3'UTR (untranslated region) have also been found associated with CHB. CONCLUSION: Our study revealed that high through target region sequencing, combined with association analysis at variant and gene level, would be a good way to found variants and genes associated with CHB even at small sample size. Our data implied that chronic hepatitis B patients who carry these variants need intensive monitoring. PMID- 29287220 TI - Changes in rejection sensitivity across adolescence and emerging adulthood: Associations with relationship involvement, quality, and coping. AB - Using a sample of 110 Israeli youth (72% female), the present study investigates associations between initial levels of rejection sensitivity as well as changes in rejection sensitivity from age 16 to age 23 and relationship involvement, quality, and (growth following) coping with relationship stress. Results showed that rejection sensitivity generally decreased over time into the transition to adulthood. Furthermore, levels of rejection sensitivity at age 16 predicted whether young people were romantically involved by age 23, as well as the quality of their relationships. Yet, the change in level of rejection sensitivity over time explained far more the quality of later romantic relationships and competence in coping with relationship stress than the initial level of rejection sensitivity. These findings have important implications for examining the role of changes in personality attributes such as rejection sensitivity in the transition from adolescence to adulthood. PMID- 29287221 TI - Ankle fractures: Getting it right first time. AB - INTRODUCTION: Ankle fractures are common injuries presenting to trauma departments and ankle open reduction and internal fixation (ORIF2) is one of the first procedures targeted in early orthopaedic training. Failure to address the fracture pattern with the appropriate surgical technique and hardware may lead to early failure, resulting in revision procedures or premature degenerative change. Patients undergoing revision ORIF are known to be at much greater risk of complications and many of these secondary procedures may be preventable. METHOD: A retrospective analysis of all patients attending our unit for ankle ORIF over a two year period was undertaken. Patients were identified from our Bluespier database and a review of x-rays was undertaken. All patients undergoing re operation within eight weeks of the primary procedure were studied. The cause of primary failure was established and potential contributing patient and surgical factors were recorded. RESULTS: 236 patients undergoing ankle ORIF were identified. 13 patients (5.5%) returned to theatre for a secondary procedure within eight weeks. Within this group, seven (54%) patients returned for treatment of a neglected or under treated syndesmotic injury, three (23%) for complete failure of fixation, two (15%) with wound problems and one (8%) for medial malleolus mal-reduction. Of the patient group, five (39%) were known type 2 diabetics. Consultants performed two (15%) procedures, supervised registrars five (39%) and unsupervised registrars six (46%) operations. CONCLUSION: Errors are being made at all levels of training in applying basic principles such as restoring fibula length and screening the syndesmosis intra-operatively. Appropriate placement and selection of hardware is not always being deployed in osteopenic bone resulting in premature failure of fixation and fracture patterns are not being fully appreciated. Patients are undergoing preventable secondary procedures in the operative treatment of ankle fractures. PMID- 29287222 TI - In vivo imaging of adaptive immune responses to viruses. AB - Viral infections represent a major threat for mankind. The adaptive immune system plays a key role in both viral clearance and disease pathogenesis, and, accordingly, understanding how lymphocytes interact with different viruses is critical to design more effective vaccination and therapeutic strategies. The recent advent of intravital microscopy has enabled the real-time visualization of the complex interplay between viruses and the ensuing adaptive immune response in living organisms. Here, we will review the most significant recent insights on antiviral adaptive immune responses obtained through intravital imaging. We will also discuss what challenges lie ahead and what we think are the most promising areas for future research. PMID- 29287223 TI - Is recovery from cannabis use problems different from alcohol and other drugs? Results from a national probability-based sample of the United States adult population. AB - BACKGROUND: The policy landscape regarding the legal status of cannabis (CAN) in the US and globally is changing rapidly. Research on CAN has lagged behind in many areas, none more so than in understanding how individuals suffering from the broad range of cannabis-related problems resolve those problems, and how their characteristics and problem resolution pathways are similar to or different from alcohol [ALC] or other drugs [OTH]. Greater knowledge could inform national policy debates as well as the nature and scope of any additional needed services as CAN population exposure increases. METHOD: National, probability-based, cross sectional sample of the US non-institutionalized adult population was conducted July-August 2016. Sample consisted of those who responded "yes" to the screening question, "Did you used to have a problem with alcohol or drugs but no longer do?" (63.4% response rate from 39,809 screened adults). Final weighted sample (N = 2002) was mostly male (60.0% [1.53%]), aged 25-49 (45.2% [1.63%]), non-Hispanic White (61.4% [1.64%]), employed (47.7% [1.61%]). Analyses compared CAN to ALC and OTH on demographic, clinical, treatment and recovery support services utilization, and quality of life (QOL) indices. RESULTS: 9.1% of the US adult population reported resolving a significant substance problem, and of these, 10.97% were CAN. Compared to ALC (M = 49.79) or OTH (M = 43.80), CAN were significantly younger (M = 39.41, p < 0.01), had the earliest onset of regular use (CAN M = 16.89, ALC M = 19.02, OTH M = 23.29, p < 0.01), and resolved their problem significantly earlier (CAN M = 28.87, ALC M = 37.86, OTH M = 33.06, p < 0.01). Compared to both ALC and OTH, CAN were significantly less likely to report use of inpatient treatment and used substantially less outpatient treatment, overall (p < 0.01), although CAN resolving problems more recently were more likely to have used outpatient treatment (p < 0.01). Lifetime attendance at mutual-help meetings (e.g., AA) was similar, but CAN (M = 1.67) had substantially lower recent attendance compared to ALC (M = 7.70) and OTH (M = 7.65). QOL indices were similar across groups. CONCLUSION: Approximately 2.4 million Americans have resolved a significant cannabis problem. Compared to ALC and OTH, the pattern of findings for CAN suggest similarities but also some notable differences in characteristics and problem resolution pathways particularly regarding earlier problem offset and less use of formal and informal services. Within a shifting policy landscape, research is needed to understand how increases in population exposure and potency may affect the nature and magnitude of differences observed in this preliminary study. PMID- 29287224 TI - The three betrayals of the medical cannabis growing activist: From multiple victimhood to reconstruction, redemption and activism. AB - While cannabis has been widely used in the UK for over 50 years, it is only in recent decades that domestic cultivation has become established. Public concern, media reporting and policing policy has emphasised the role of profit motivated criminal organisations often working on a large scale and with coerced labour. However, increasingly, another population are growing for medical reasons, to help themselves and others treat or manage difficult, poorly understood, or incurable conditions. Our study sought to further understand the motives, techniques and interactions of cannabis cultivators through interviews with 48 growers and supplementary ethnographic work. As well as those motivated to grow for personal use, social and commercial supply purposes we identified a cohort growing to provide themselves and others with cannabis used for therapeutic purposes. This paper draws primarily on interviews with a sub-group of sixteen medically-motivated growers who were not only involved in treatment, but also embraced the label "activist". Rather than develop techniques of deception they were organising to effect a change in legislation. Rejecting the image of criminal perpetrators, they presented themselves as victims of unjust government policy, an indifferent medical establishment, and brutal and immoral criminal markets. Through cultivation, association, self-healing and apomedication, they have found voice and are shifting the debate over the status of growers and of cannabis itself. The ambiguity of their position as both producers and patients challenges the assumptions underlying legal distinctions between suppliers and users, with potentially profound implications for policy. PMID- 29287225 TI - Failure behaviour of rat vertebrae determined through simultaneous compression testing and micro-CT imaging. AB - Skeletal fractures, including those resulting from osteoporosis, result in significant healthcare and societal costs on an annual basis. Therefore, it is important to understand the mechanisms by which these fractures occur. Incremental compression testing combined with micro-CT imaging has been used to visualize the progression of failure in trabecular bone samples; however, these studies have ignored the potential contributions of the cortical shell. In the current study, incremental compression testing with simultaneous micro-CT imaging was performed on rat vertebrae from multiple disease states (healthy control, osteoporotic, osteoporotic + treatment). These tests allowed the progression of failure through an entire vertebral body to be visualized for the first time. Three distinct failure modes were observed throughout all specimens, independent of disease state. Two of these failure modes (types I and II), which were observed in 93% of all specimens, were associated with the vascular apertures in the vertebrae's dorsal and ventral surfaces. This behaviour is likely caused by the stress concentrations in the cortical shell resulting from the apertures themselves, coupled with the reduced trabecular bone volume adjacent to them. These results suggest that the combined contributions of both the cortical shell and trabecular bone must be considered when studying the compressive failure behaviour of rat vertebrae. PMID- 29287226 TI - Effect of ice-quenching after oxidation treatment on hardening of a Pd-Cu-Ga-Zn alloy for bonding porcelain. AB - This study examined the effect of ice-quenching after oxidation treatment on hardness change of a Pd-Cu-Ga-Zn metal-ceramic alloy during porcelain firing simulation. Although not statistically significant, the alloy was softened slightly during porcelain firing simulation with conventional slow cooling rate. On the other hand, the hardness increased significantly by ice-quenching instead of the slow cooling after oxidation (p<0.001). The gap in the final hardness depending on ice-quenching occurred in the matrix and plate-like precipitates but not in the particle-like structure without plate-like precipitates (p<0.05). The mechanism of ice-quenching after oxidation to prevent softening and induce hardening during porcelain firing simulation involved the more active precipitation and retardation of microstructural coarsening. In conclusion, for practical work on Pd-Cu-Ga-Zn alloys, the oxidation treatment followed by ice quenching instead of slow cooling is recommended for the simultaneous oxidation and hardening effects on the alloy. PMID- 29287227 TI - Bladder wall biomechanics: A comprehensive study on fresh porcine urinary bladder. AB - Regenerative medicine for reconstructive urogenital surgery has been widely studied during the last two decades. One of the key factors affecting the quality of bladder regeneration is the mechanical properties of the bladder scaffold. Insight into the biomechanics of this organ is expected to assist researchers with functional regeneration of the bladder wall. Due to extensive similarities between human bladder and porcine bladder, and with regard to lack of comprehensive biomechanical data from the porcine bladder wall (BW), our main goal here was to provide a thorough evaluation on viscoelastic properties of fresh porcine urinary BW. Three testing modes including Uniaxial tensile, ball burst (BB) and Dynamic Mechanical Analysis (DMA) were applied in parallel. Uniaxial tests were applied to study how different circumferential and longitudinal cut-outs of lateral region of BW behave under load. DMA was used to measure the viscoelastic properties of the bladder tissue (storage and loss modulus) in a frequency range of 0.1-3Hz. BB was selected as a different technique, replicating normal physiological conditions where the BW is studied in whole. According to uniaxial tests, the anisotropic behavior of bladder is evident at strain loads higher than 200%. According to DMA, storage modulus is consistently higher than loss modulus in both directions, revealing the elasticity of the BW. The stress-strain curves of both uniaxial and BB tests showed similar trends. However, the ultimate stress measured from BB was found to be around 5 times of the relevant stress from uniaxial loading. The ultimate strain in BB (389.9 +/- 59.8) was interestingly an approximate average of rupture strains in longitudinal (358 +/- 21) and circumferential (435 +/- 69) directions. Considering that each testing mode applied here reveals distinct information, outcomes from the combination of the three can be considered as a helpful data base to refer to for researchers aiming to regenerate the bladder. PMID- 29287228 TI - Exploring paraprofessional and classroom factors affecting teacher supervision. AB - BACKGROUND: Paraprofessionals serve a primary role in supporting students with disabilities in the classroom, which necessitates teachers' supervision as a means to improve their practice. Yet, little is known regarding what factors affect teacher supervision. AIMS: We sought to identify how paraprofessional competence and classroom type affected the levels of teacher direction. METHODS AND PROCEDURES: We administered an adapted version of the Paraprofessional Needs, Knowledge & Tasks Survey and the Survey for Teachers Supervising Paraprofessionals to teachers supervising paraprofessionals in elementary schools. Structural Equation Modeling was used to examine the link between paraprofessional competence and classroom factors affecting the level of teacher supervision. OUTCOMES AND RESULTS: Our results indicated that when teachers perceived paraprofessionals as being more skilled, they provided more supervision, and when more supervision was provided the less they thought paraprofessionals should be doing their assigned tasks. Additionally, paraprofessionals working in classrooms with more students with mild disabilities received less supervision than paraprofessionals working in classrooms with more students with moderate-to-severe disabilities. Those paraprofessionals in classrooms serving mostly children with mild disabilities were also perceived as having lower levels of skill competence than those serving in classrooms with students with more moderate-to-severe disabilities. CONCLUSION AND IMPLICATIONS: By understanding the factors that affect teacher supervision, policy and professional development opportunities can be refined/developed to better support both supervising teachers and paraprofessionals and, in turn, improve the outcomes of children with disabilities. PMID- 29287230 TI - The OC43 human coronavirus envelope protein is critical for infectious virus production and propagation in neuronal cells and is a determinant of neurovirulence and CNS pathology. AB - The OC43 strain of human coronavirus (HCoV-OC43) is an ubiquitous respiratory tract pathogen possessing neurotropic capacities. Coronavirus structural envelope (E) protein possesses specific motifs involved in protein-protein interaction or in homo-oligomeric ion channel formation, which are known to play various roles including in virion morphology/assembly and in cell response to infection and/or virulence. Making use of recombinant viruses either devoid of the E protein or harboring mutations either in putative transmembrane domain or PDZ-binding motif, we demonstrated that a fully functional HCoV-OC43 E protein is first needed for optimal production of recombinant infectious viruses. Furthermore, HCoV-OC43 infection of human epithelial and neuronal cell lines, of mixed murine primary cultures from the central nervous system and of mouse central nervous system showed that the E protein is critical for efficient and optimal virus replication and propagation, and thereby for neurovirulence. PMID- 29287229 TI - Murine norovirus inhibits B cell development in the bone marrow of STAT1 deficient mice. AB - Noroviruses are a leading cause of gastroenteritis in humans and it was recently revealed that noroviruses can infect B cells. We demonstrate that murine norovirus (MNV) infection can significantly impair B cell development in the bone marrow in a signal transducer and activator of transcription 1 (STAT1) dependent, but interferon signaling independent manner. We also show that MNV replication is more pronounced in the absence of STAT1 in ex vivo cultured B cells. Interestingly, using bone marrow transplantation studies, we found that impaired B cell development requires Stat1-/- hematopoietic cells and Stat1-/- stromal cells, and that the presence of wild-type hematopoietic or stromal cells was sufficient to restore normal development of Stat1-/- B cells. These results suggest that B cells normally restrain norovirus replication in a cell autonomous manner, and that wild-type STAT1 is required to protect B cell development during infection. PMID- 29287231 TI - Degradation of Poly(epsilon-caprolactone) and bio-interactions with mouse bone marrow mesenchymal stem cells. AB - Bio-inspired scaffolds in bone tissue engineering using multipotential mesenchymal stem cells grow at a rapid rate found its successful use in orthopedic injury treatment. Poly(epsilon-caprolactone)/PCL is widely used in medical devices, tissue engineering, and drug delivery systems. Most desirable property of biodegradable polymer to be employed in medical application is synchronization of degradation with functional tissue regeneration. Limited studies have incorporated the degradation kinetics and implication of degradation products of pure unmodified PCL. The present study analyzes short term in vitro degradation profile of PCL films in physiological condition. The study reports weight loss, changes in molecular weight distribution and morphological variation in PCL thin film over a period of 90-day degradation. When the degradable material is in contact with host tissue, there exists robust and dynamic microenvironment controlling the cell functionality. To comprehend the biocompatibility aspects of polymer material, the study considered mouse bone marrow mesenchymal stem cells (BMSCs) as model system mimicking in vivo. There was no indication of toxicity revealed with MTT, LDH leakage, direct contact assay and clonogenic assay. Absence of oxidative stress and apoptosis denotes BMSCs functional integrity sustained upon exposure to PCL degradation products. Cell cycle analysis and DNA ladder assay confirmed cell survival and genomic stability. The study revealed that the topography of pure unmodified PCL surface is suitable for cell adhesion. It was also observed that the viability of differentiated cells (osteoblasts) was maintained in presence of PCL extract. Furthermore, polymer and its degradation products were proved to be hemocompatible. These results synergistically suggest that pure unmodified PCL and its degradation products are non-toxic at molecular level. PMID- 29287232 TI - Cytotoxic effects of platinum nanoparticles obtained from pomegranate extract by the green synthesis method on the MCF-7 cell line. AB - The study utilizes monodisperse platinum nanoparticles (Pt NPs) biosynthesized from Punica granatum crusts as anti-tumor agents on the human breast cancer cell line, MCF-7. The obtained Pt NPs were fully characterized using the UV-vis spectrum (UV-vis), transmission electron microscopy (TEM), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and Fourier transformation infrared spectroscopy (FTIR). Effectiveness of the Pt NPs was determined by cell viability, propidium iodide staining test, flow cytometry and comet tests on the MCF-7 cancer cell line. Cell survival percentage was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The biosynthesized monodisperse platinum nanoparticles inhibited MCF-7 proliferation with an IC50 of 17.84 MUg/ml after 48 h of incubation. Propidium iodide staining demonstrated that the monodisperse Pt NPs induced apoptosis by means of molecular DNA fragmentation. PMID- 29287233 TI - Conservation of intrinsic dynamics in proteins-what have computational models taught us? AB - The intrinsic dynamics of proteins has been suggested to be the most conserved compared to its sequence or structure. As such, the contributing factors to the conservation of dynamics have yet to be determined definitively. Some have suggested that function drives the conservation of protein flexibility, while others have indicated that the overall topology determines protein flexibility patterns. In general, many characteristic features of protein flexibility can be derived from simple coarse-grained models whose success rests on the link between protein local packing density and flexibility. Those models have revealed the evolutionary conservation of protein flexibility and have given us insights into the slow dynamics required for protein function and mechanistic insight into the allosteric effect. PMID- 29287235 TI - Long-term follow-up of patients with migrainous infarction. AB - Among patients with migrainous infarction, the long-term prognosis is unclear. This study aims to estimate the long-term risk of stroke recurrence and functional outcome in patients with migrainous infarction. In our study, 15 patients with migrainous infarction were followed for up to 7.5 years (12-240 months). For each patient, clinical and imaging data were reviewed. Disability after migrainous Infarction was assessed with modified Rankin Score. Mean age was 34.8 (+/- 11.1) years. At the end of the follow-up 80% of the patients had favorable prognosis, 47% recovered completely and no patient died or had stroke recurrence. Our series also confirmed a low frequency of the traditional risk factors and the reduction of migraine frequency after migrainous infarction. This study has clinical implications and public health relevance, since our case series confirms a low frequency, low recurrence rate, and good functional outcome for patients with migrainous infarction. PMID- 29287234 TI - Improving the discovery of secondary metabolite natural products using ion mobility-mass spectrometry. AB - Secondary metabolite discovery requires an unbiased, comprehensive workflow to detect unknown unknowns for which little to no molecular knowledge exists. Untargeted mass spectrometry-based metabolomics is a powerful platform, particularly when coupled with ion mobility for high-throughput gas-phase separations to increase peak capacity and obtain gas-phase structural information. Ion mobility data are described by the amount of time an ion spends in the drift cell, which is directly related to an ion's collision cross section (CCS). The CCS parameter describes the size, shape, and charge of a molecule and can be used to characterize unknown metabolomic species. Here, we describe current and emerging applications of ion mobility-mass spectrometry for prioritization, discovery and structure elucidation, and spatial/temporal characterization. PMID- 29287236 TI - Moderators and predictors of response to cognitive behaviour therapy for pediatric obsessive-compulsive disorder: A systematic review. AB - We report a systematic review of moderators of CBT efficacy for pediatric OCD relative to other treatments. CENTRAL, MEDLINE, EMBASE, CINAHL, and PsycINFO were searched for RCTs reporting on effect moderation for CBT outcomes. Five studies (N = 365) examined 17 variables with three significant moderators identified. Compared to pill-placebo, CBT monotherapy was not effective for children with a family history of OCD but was for those without a family history. For children with a family history, CBT plus sertraline efficacy was attenuated but remained significant. For children with tics, CBT but not sertraline remained superior to pill-placebo. For non-responders to initial treatment with CBT, continuing CBT was inferior to commencing sertraline for those with tics but was not different for those without tics. A supplementary review identified older age, symptom and impairment severity, co-morbidity and family accommodation as consistent predictors of a poorer outcome to CBT. Current evidence for moderation effects is post-hoc, from single RCTs, has small Ns and requires replication. The review identifies family history of OCD and the presence of tics as factors requiring further examination in properly conducted trials and about which clinicians need to show care in their treatment recommendations. PMID- 29287237 TI - A novel approach of substitution therapy with inhalation of essential oil for the reduction of inhalant craving: A double-blinded randomized controlled trial. AB - Inhalants, which are neurotoxic central nervous system (CNS) suppressants, are frequently abused by young adults. Unlike other CNS depressants, including alcohol and opiates, no treatment is currently approved for inhalant dependence. In this report, a novel approach of substitution treatment for inhalant addiction was explored in a double-blinded, randomized, controlled crossover design to examine the effects of inhalation of essential oil and perfume on the reduction of cue-induced craving for inhalant in thirty-four Thai males with inhalant dependence. The craving response was measured by the modified version of Penn Alcohol Craving Score for Inhalants (PACS-inhalants). The participants (mean age +/- SE = 27.9 +/- 1.4) in this trial had used inhalant for 5.8 +/- 1.1 years. Cravings could be induced in all participants by visual cues as assessed by ^50% increases in inhalant craving levels. Generalized estimating equations showed a significant suppressant effect of essential oil, but not perfume, on the craving response as compared with baseline cue-induced craving. Moreover, essential oil, but not perfume, had significant effects on physiological responses including decreasing pulse rate. It is concluded that inhaling essential oil as a substitution treatment for inhalant may be used as part of treatment programs for reducing inhalant craving. PMID- 29287238 TI - Detection of early psychotic symptoms: Validation of the Spanish version of the "Symptom Onset in Schizophrenia (SOS) inventory". AB - The period of subclinical signs that precedes the onset of psychosis is referred to as the prodrome or high-risk mental state. The "Symptom Onset in Schizophrenia (SOS) inventory" is an instrument to characterize and date the initial symptoms of a psychotic illness. The present study aims to provide reliability and validity data for clinical and research use of the Spanish version of the SOS. Thirty-six participants with a first-episode of psychosis meeting DSM-IV criteria for schizophrenia/schizoaffective/schizophreniform disorder were administered the translated SOS and other clinical assessments. The internal validity, intrarater and interrater reliability were studied. We found strong interrater reliability. To detect the presence/absence of prodromal symptoms, Kappa coefficients ranged between 0.8 and 0.7. Similarly, the raters obtained an excellent level of agreement regarding the onset of each symptom and the duration of symptoms until first treatment (intraclass correlation coefficients between 0.9 and 1.0). Cronbach's alpha was 0.9-1.0 for all the items. The interrater reliability and concurrent validity were also excellent in both cases. This study provides robust psychometric properties of the Spanish version of the SOS. The translated version is adequate in terms of good internal validity, intrarater and interrater reliability, and is as time-efficient as the original version. PMID- 29287239 TI - Association between virus exposure and depression in US adults. AB - Mood disorders are common mental illnesses. Among the factors associated with major depression are exposures to infectious diseases including hepatitis C, influenza, varicella-zoster, and herpes viruses. In this study, we sought to evaluate further associations between viral exposure and depression. From the US Center for Disease Control's National Health and Nutrition Examination Survey, we obtained data about depression status, antidepressant use, exposure to hepatitis A, hepatitis B, herpes simplex virus type 1, herpes simplex virus type 2, human immunodeficiency virus, and cytomegalovirus, and sociodemographic variables and evaluated associations between depression and viral exposure in adjusted multivariable models. Herpes simplex virus type 2 was associated with an increased risk of depression, whereas hepatitis A, hepatitis B, and herpes simplex virus type 1 were not. Higher cytomegalovirus antibody levels were associated with depression in subjects seropositive for cytomegalovirus. In conclusion, exposure to herpes simplex virus type 2 and possibly cytomegalovirus are associated with depression in an adult US sample. PMID- 29287240 TI - Label-free impedimetric glycan biosensor for quantitative evaluation interactions between pathogenic bacteria and mannose. AB - In order to understanding the pathogenic mechanism of infectious diseases, it was important to study the selective recognition and interaction between pathogenic bacteria and host cells. In this paper, a novel electrochemical impedance biosensor was proposed, in which the Man/MUA-MH/Au sensing surface (Man: mannose; MUA: 11-mercapto eleven acid; MH: 6-mercapto hexanol) was fabricated and was of good biologically active and stability. The capture capacity of the designed sensing surface for S. typhimurium ATCC14028, E. coli JM109 and E. coli DH5alpha were characterized by Electrochemical impedance spectroscopy (EIS). According to Randless equivalent circuit and the Frumkin isotherm model, electron transfer impedance (Ret) was obtained and the binding affinity of the three bacteria and Man was calculated. It was shown that the sensing surface had a better binding affinity for S. typhimurium ATCC14028 with KADS(S.T.) = 2.16 * 106 CFU/mL. The impedance normalized value NIC (S.T.-Man) was of a good linear relationship with the logarithm of bacterial concentration (R2 = 0.96) in the range of 50-1000 CFU/mL. The detection limit was 50 CFU/mL. Meanwhile, the E. coli JM109 which expresses type 1 fimbriae was also adsorbed on the designed sensing surface with KADS(JM109) = 5.84 * 103 CFU/mL. It was illustrated that the novel electrochemical impedance biosensor could be more rapid and reliable for studying interactions between pathogen and glycan, and it was also perspective for a new point-of-care diagnostic tool for evaluating the pathogenicity bacteria. PMID- 29287241 TI - Serine/Threonine Kinase CHEK1-Dependent Transcriptional Regulation of RAD54L Promotes Proliferation and Radio Resistance in Glioblastoma. AB - Accumulating evidence indicates that Checkpoint kinase 1 (CHEK1) plays an essential role in tumor cells and that it could induce cell proliferation and could be related to prognosis in multiple types of cancer. However, the biological role and molecular mechanism of CHEK1 in GBM still remain unclear. In this study, we identified that CHEK1 expression was enriched in glioblastoma (GBM) tumors and was functionally required for tumor proliferation and that its expression was associated to poor prognosis in GBM patients. Mechanically, CHEK1 induced radio resistance in GBM cells, and CHEK1 knockdown increased cell apoptosis when combined with radiotherapy via regulation of the DNA repair/recombination protein 54L (RAD54L) expression. Therapeutically, we found that CHEK1 inhibitor attenuated tumor growth both in vitro and in vivo. Collectively, CHEK1 promotes proliferation, induces radio resistance in GBM, and could become a potential therapeutic target for GBM. PMID- 29287242 TI - Checkpoint inhibitors in breast cancer - Current status. AB - INTRODUCTION: An increasing number of compounds directed against immune checkpoints are currently under clinical development. In this review we summarize current research in breast cancer. MATERIAL AND METHODS: A computer-based literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. RESULTS: The obtained overall response rate of PD-1/PD-L1 monotherapy varied from 5 to 30% in heavily pretreated triple negative breast cancer (TNBC). The median duration of progression free survival and overall survival were either not reported or short. Still responses were of long duration in a subset of patients. In the neoadjuvant setting, preliminary results including a very limited number of patients suggest high pathological response rates after combined blockade of the PD-1 pathway and chemotherapy. Multiple trials have been initiated to evaluate the combination of other anticancer agents and checkpoint inhibitors, especially in TNBC. In addition, ongoing studies aim to identify biomarkers to guide patient selection. CONCLUSION: Immune checkpoint inhibitors have the potential to produce durable tumor remission and induce long standing anti-tumor immunity in a subgroup of breast cancer patients. However, the identification of predictive biomarkers is crucial for further development of this treatment modality. PMID- 29287243 TI - Individual variation in the propensity for prospective thought is associated with functional integration between visual and retrosplenial cortex. AB - It is well recognized that the default mode network (DMN) is involved in states of imagination, although the cognitive processes that this association reflects are not well understood. The DMN includes many regions that function as cortical "hubs", including the posterior cingulate/retrosplenial cortex, anterior temporal lobe and the hippocampus. This suggests that the role of the DMN in cognition may reflect a process of cortical integration. In the current study we tested whether functional connectivity from uni-modal regions of cortex into the DMN is linked to features of imaginative thought. We found that strong intrinsic communication between visual and retrosplenial cortex was correlated with the degree of social thoughts about the future. Using an independent dataset, we show that the same region of retrosplenial cortex is functionally coupled to regions of primary visual cortex as well as core regions that make up the DMN. Finally, we compared the functional connectivity of the retrosplenial cortex, with a region of medial prefrontal cortex implicated in the integration of information from regions of the temporal lobe associated with future thought in a prior study. This analysis shows that the retrosplenial cortex is preferentially coupled to medial occipital, temporal lobe regions and the angular gyrus, areas linked to episodic memory, scene construction and navigation. In contrast, the medial prefrontal cortex shows preferential connectivity with motor cortex and lateral temporal and prefrontal regions implicated in language, motor processes and working memory. Together these findings suggest that integrating neural information from visual cortex into retrosplenial cortex may be important for imagining the future and may do so by creating a mental scene in which prospective simulations play out. We speculate that the role of the DMN in imagination may emerge from its capacity to bind together distributed representations from across the cortex in a coherent manner. PMID- 29287244 TI - Investigating the differential contributions of sex and brain size to gray matter asymmetry. AB - Scientific reports of sex differences in brain asymmetry - the difference between the two hemispheres - are rather inconsistent. Some studies report no sex differences whatsoever, others reveal striking sex effects, with large discrepancies across studies in the magnitude, direction, and location of the observed effects. One reason for the lack of consistency in findings may be the confounding effects of brain size as male brains are usually larger than female brains. Thus, the goal of this study was to investigate the differential contributions of sex and brain size to asymmetry with a particular focus on gray matter. For this purpose, we applied a well-validated workflow for voxel-wise gray matter asymmetry analyses in a sample of 96 participants (48 males/48 females), in which a subsample of brains (24 males/24 females) were matched for size. By comparing outcomes based on three different contrasts - all males versus all females; all large brains versus all small brains; matched males versus matched females - we were able to disentangle the contributing effects of sex and brain size, to reveal true (size-independent) sex differences in gray matter asymmetry: Males show a significantly stronger rightward asymmetry than females within the cerebellum, specifically in lobules VII, VIII, and IX. This finding agrees closely with prior research suggesting sex differences in sensorimotor, cognitive and emotional function, which are all moderated by the respective cerebellar sections. No other significant sex effects on gray matter were detected across the remainder of the brain. PMID- 29287245 TI - Host and symbiont intraspecific variability: The case of Paramecium calkinsi and "Candidatus Trichorickettsia mobilis". AB - Newly isolated strains of the ciliate Paramecium calkinsi and their cytoplasmic bacterial endosymbionts were characterized by a multidisciplinary approach, including live observation, ultrastructural investigation, and molecular analysis. Despite morphological resemblance, the characterized P. calkinsi strains showed a significant molecular divergence compared to conspecifics, possibly hinting for a cryptic speciation. The endosymbionts were clearly found to be affiliated to the species "Candidatus Trichorickettsia mobilis" (Rickettsiales, Rickettsiaceae), currently encompassing only bacteria retrieved in an obligate intracellular association with other ciliates. However, a relatively high degree of intraspecific divergence was observed as well, thus it was possible to split "Candidatus Trichorickettsia" into three subspecies, one of which represented so far only by the newly characterized endosymbionts of P. calkinsi. Other features distinguished the members of each different subspecies. In particular, the endosymbionts of P. calkinsi resided in the cytoplasm and possessed numerous peritrichous flagella, although no motility was evidenced, whereas their conspecifics in other hosts were either cytoplasmic and devoid of flagella, or macronuclear, displaying flagellar-driven motility. Moreover, contrarily to previously analyzed "Candidatus Trichorickettsia" hosts, infected P. calkinsi cells frequently became amicronucleate and demonstrated abnormal cell division, eventually leading to decline of the laboratory culture. PMID- 29287246 TI - Neural stem cells in neuropsychiatric disorders. AB - The precise control of neural stem cell (NSC) proliferation and differentiation is crucial for the development and function of the human brain. Here, we review the emerging links between the alteration of embryonic and adult neurogenesis and the etiology of neuropsychiatric disorders (NPDs) such as autism spectrum disorders (ASDs) and schizophrenia (SCZ), as well as the advances in stem cell based modeling and the novel therapeutic targets derived from these studies. PMID- 29287247 TI - Aptamer facilitated purification of functional proteins. AB - DNA aptamers are attractive capture probes for affinity chromatography since, in contrast to antibodies, they can be chemically synthesized and, in contrast to tag-specific capture probes (such as Nickel-NTA or Glutathione), they can be used for purification of proteins free of genetic modifications (such as His or GST tags). Despite these attractive features of aptamers as capture probes, there are only a few reports on aptamer-based protein purification and none of them includes a test of the purified protein's activity, thus, leaving discouraging doubts about method's ability to purify proteins in their active state. The goal of this work was to prove that aptamers could facilitate isolation of active proteins. We refined a complete aptamer-based affinity purification procedure, which takes 4 h to complete. We further applied this procedure to purify two recombinant proteins, MutS and AlkB, from bacterial cell culture: 0.21 mg of 85% pure AlkB from 4 mL of culture and 0.24 mg of 82%-pure MutS from 0.5 mL of culture. Finally, we proved protein activity by two capillary electrophoresis based assays: an enzymatic assay for AlkB and a DNA-binding assay for MutS. We suggest that in combination with aptamer selection for non-purified protein targets in crude cell lysate, aptamer-based purification provides a means of fast isolation of tag-free recombinant proteins in their native state without the use of antibodies. PMID- 29287248 TI - Generating the Abscopal Effect by Combining Proapoptotic Peptides With IL-12 Based Immunotherapy. PMID- 29287250 TI - Analyzing the channel dopant profile in next-generation FinFETs via atom probe tomography. AB - Dopant analysis in next-generation semiconductor devices has become increasingly difficult for traditionally used analytical techniques. Atom probe tomography has been viewed by some as a possible solution to these challenges because of its three-dimensional capabilities, forcing the atom probe to mature at a rapid pace in this particular field. This work presents a well-rounded analysis of how APT can be used to examine B dopant diffusion into the channel of a next-generation FinFET, where the channel dimensions and the number of dopants atoms are significantly smaller than any devices measured by APT to date. Complimentary EELS analysis of the gate and channel provides a better understanding of how distortions and artifacts in the APT reconstruction affect the overall integrity of the dataset. Dopant measurements in the channel are confirmed through in-depth mass spectrum analysis and compared with values proposed by TCAD modeling. PMID- 29287249 TI - Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (sigma2) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors. AB - The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (sigma2) receptor was recently proposed as a promising target for pancreatic cancer therapy, we explored our previously developed multifunctional thiosemicarbazones, designed to synergistically impair cell energy levels, by targeting sigma2 and P-gp proteins and chelating Iron. A deconstruction approach was herein applied by removing one function at a time from the potent multifunctional thiosemicarbazones 1 and 2, to investigate the contribution to cytotoxicity of each target involved. The results from in vitro (panel of pancreatic tumor cells) and in vivo experiments (C57BL/6 bearing KP02 tumor), suggest that while the multifunctional activity was not required for the antitumor activity of these thiosemicarbazones, sigma2-targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of sigma2 targeting. PMID- 29287251 TI - Quercetin in the experimental liver fibrosis induced by carbon tetrachloride (CCl4). PMID- 29287253 TI - Enhanced visible light photodegradation of pharmaceutical pollutant, warfarin by nano-sized SnTe, effect of supporting, catalyst dose, and scavengers. AB - Improvement of new nanophotocatalysts enable to decompose the pharmaceutical pollutants with the aid of solar energy is of particular importance. In this research, the ability of SnTe photocatalyst for degradation of warfarin was enhanced and the separation difficulties of the used photocatalyst, from solutions was removed by immobilization of the photocatalyst on a suitable porous support. A novel nano-sized photocatalyst was prepared by coupling of SnTe on the surface of SBA-15 support. Characterization of the synthesized photocatalyst (SnTe@SBA-15) was performed by different methods including XRD, TEM, TGA, FT-IR, EDS and BET techniques. The map of constituent elements was also prepared. The results indicated that the activity of SnTe photocatalyst was significantly enhanced after immobilization on the support and lower catalyst dose was needed. The visible light irradiation was more effective than UV irradiation. The degradation process was kinetically fast, and the equilibrium was established within 10 min. Separation of the synthesized photocatalyst from the solution was much easier than the bulk SnTe. The regenerated photocatalyst retained more than 90% of its initial efficiency. PMID- 29287252 TI - Paraquat treatment modulates integrin associated protein (CD47) and basigin (CD147) expression and mitochondrial potential on erythroid cells in mice. AB - The present study is focused on the interaction of paraquat with the erythroid system in bone marrow and spleen of mice. Administration of paraquat (10 mg/kg of body weight i.p. on alternate days in C57Bl/6 mice) induced the level of reactive oxygen species in bone marrow (BM) on 7, 14, and 21 day time points but it was unchanged in spleen erythroid cell. A marked induction of CD147 expression in BM and spleen erythroid cells was observed in the paraquat treated mice. Paraquat treatment also modulated the CD47 expression in erythroid cells and its expression level was significantly higher on day 14, 21 and 28 in bone marrow and on day 14 and 21 in spleen. The expression level of mitochondrial potential and antioxidant genes SOD1, SOD2, GPX1 and FOXO3 expression was significantly reduced in BM erythroid cells but a reverse response was seen in spleen. Taken together, this study demonstrates that paraquat treatment modulates ROS production, mitochondrial membrane potential, and oxidative stress markers gene expression in the erythroid systems of C57Bl/6 mice. PMID- 29287254 TI - Comparison of palygorskite and struvite supported palygorskite derived from phosphate recovery in wastewater for in-situ immobilization of Cu, Pb and Cd in contaminated soil. AB - A phosphorus-bearing product S-PAL obtained from nutrient-rich wastewater was reused as ameliorant for Cu, Pb and Cd immobilization in contaminated soil with three different rates (1%, 5% and 10% w/w). The 0.01 mol/L CaCl2 -extractability of metals significantly reduced with increasing rate of PAL and S-PAL in the first 7-day immobilization and insignificantly changed after 14-day immobilization. Compared with PAL, the lower metal extractability was observed after S-PAL addition. The BCR sequential extraction results showed that both of amendments were beneficial to transform acid soluble fraction to residual fraction. The XRD patterns of soil samples after immobilization evidenced that the formation of metal-bearing phosphate precipitates and the combination between functional groups such as Si-OH and metals played a key role for metal immobilization by S-PAL and PAL. Dominant phyla across all samples were Fusobacteria, Proteobacteria and Actinobacteria, and the relative abundance of Fusobacteria decreased under S-PAL treatment. The pH-dependent leaching test indicated that the metal release at a defined pH was not affected by the presence of PAL. Compared with S-PAL, the metals amended by PAL in soil were easier to release at acidic pH since the combination between functional groups and metals instead the formation of new metal-bearing precipitate. PMID- 29287255 TI - Design and synthesis of tumor-targeting theranostic drug conjugates for SPECT and PET imaging studies. AB - Theranostics will play a significant role in the next-generation chemotherapy. Two novel tumor-targeting theranostic drug conjugates, bearing imaging arms, were designed and synthesized. These theranostic conjugates consist of biotin as the tumor-targeting moiety, a second generation taxoid, SB-T-1214, as a potent anticancer drug, and two different imaging arms for capturing 99mTc for SPECT (single photon emission computed tomography) and 64Cu for PET (positron emission tomography). To explore the best reaction conditions for capturing radionuclides and work out the chemistry directly applicable to "hot" nuclides, cold chemistry was investigated to capture 185Re(I) and 63Cu(II) species as surrogates for 99mTc and 64Cu, respectively. PMID- 29287256 TI - A simple and efficient synthesis of benzimidazoles containing piperazine or morpholine skeleton at C-6 position as glucosidase inhibitors with antioxidant activity. AB - A novel 2-(aryl)-6-morpholin-4-yl(or 4-methylpiperazin-1-yl)-1H-benzimidazole derivatives were designed and expeditiously synthesized starting from 5-morpholin 4-yl(or 4-methylpiperazin-1-yl)-2-nitroaniline with various aldehydes which were preliminarily screened for in vitro antioxidant activities and glucosidase inhibitors. The benzimidazoles were effectively synthesized by a rapid 'onepot' nitro reductive cyclization reaction using sodium hydrosulfite as a reagent. All reactions were conducted using both the microwave and conventional methods to compare yields and reaction times. Antioxidant activities of the synthesized compounds were clarified using various in vitro antioxidant assays including Cupric Reducing Antioxidant Capacity (CUPRAC, ranging from 5.511 to 19.703 mM Trolox/mg compound) and Ferric Reducing Antioxidant Power (FRAP) (1.141-12.943 mM FeSO4.7H2O/mg compound) assays. Also, the radical scavenging activities of these compounds were assayed using ABTS+ and DPPH methods. The results showed that all compounds exhibited very high scavenging activity. These synthesized compounds were then evaluated for their alpha-glucosidase inhibitory potential and seven compounds demonstrated an inhibitory potential much better than the standard acarbose. Herein, we will provide details of the structure activity relationship of the benzimidazole analog for the potency. PMID- 29287257 TI - Terpenoids from the mushroom-associated fungus Montagnula donacina. AB - Molecular identification suggested an edible mushroom, which was previously named as Craterellus odoratus should be revised as Montagnula donacina. A chemical re investigation of the culture broth of this fungus resulted in the isolation of four rare tetracyclic bergamotane-type sesquiterpenoids, namely donacinolides A and B, donacinoic acids A and B, and three cadinane-type ones, namely donacinols A-C and a meroterpenoid (Z)-4-hydroxy-3-(3-hydroxy-3-methylbut-1-en-1-yl)benzoic acid. Their structures were established via extensive spectroscopic methods, single crystal X-ray diffraction analysis, and computational methods. (Z)-4 Hydroxy-3-(3-hydroxy-3-methylbut-1-en-1-yl)benzoic acid showed antibacterial activity against Staphylococcus aureus. PMID- 29287258 TI - Cucurbitane-type triterpenes from the tubers of Hemsleya penxianensis and their bioactive activity. AB - The tubers of the medicinal plant Hemsleya penxianensis (Cucurbitaceae) yielded 11 cucurbitane-type triterpenes Xuedanencins A-K by silica gel column, ODS column, and pre-HPLC techniques. Their structures were determined by spectroscopic analysis and examined alongside existing data from prior studies. Separated compounds were evaluated for cytotoxic activity against the Hela human cancer cell line and compounds 7 and 8 showed significant cytotoxicity with IC50 values at 1.82 and 2.45 MUM, respectively. PMID- 29287259 TI - Correlation of dissolution and disintegration results for an immediate-release tablet. AB - The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product. PMID- 29287260 TI - Design and validation of an automated solid phase extraction liquid chromatography coupled mass spectrometry method for the quantification of propofol in plasma. AB - Propofol concentration in human plasma can be quantified by liquid chromatography coupled mass spectrometry. Sample preparation usually requires solid phase extraction to remove matrix components and enrich the analyte. To facilitate user independent measurements and speed extraction, we developed and validated a fully automated high throughput in-line sample preparation system with direct injection into liquid chromatography coupled mass spectrometry. We assessed linearity of each method over the clinically relevant concentration range from 0.5MUg/mL to 8MUg/mL plasma concentration. R2 values were 0.99 for the automated process and 0.98 for manual sample preparation. The limit of detection was 6ng/mL and the lower limit of quantification was 18ng/mL for the automated method; for the manual process, the limit of detection was 1.58ng/mL and the lower limit of quantification was 4.79ng/mL. Intra-day precision for low, medium and high concentration range of the automated method was validated 4.14%, 9.68% and 3.04% relative standard deviation and 0.29%, 0.12% and 0.52% for the manual process. Carry over was 0.4% with the automated method, whereas there was no carry over with the manual method. Stability of plasma samples was tested with the manual method at concentrations of 1, 4, and 6MUg/mL propofol and found to be stable over 150days at -20 degrees C. The manual sample preparation method has successfully been transferred to a fully automated process with appropriate sensitivity and precision but the automatization failed with regard to trueness and working time due to lengthy sample preparation runtime. Therefore it is not suitable for daily use in a hospital laboratory e.g. for brain death diagnosis in the intensive care unit. PMID- 29287261 TI - A combination of NMR and liquid chromatography to characterize the protective effects of Rhus tripartita extracts on ethanol-induced toxicity and inflammation on intestinal cells. AB - Consumption of ethanol may have severe effects on human organs and tissues and lead to acute and chronic inflammation of internal organs. The present study aims at investigating the potential protective effects of three different extracts prepared from the leaves, root, and stem of the sumac, Rhus tripartita, against ethanol-induced toxicity and inflammation using intestinal cells as a cell culture system, in vitro model of the intestinal mucosa. The results showed an induction of cytotoxicity by ethanol, which was partially reversed by co administration of the plant extracts. As part of investigating the cellular response and the mechanism of toxicity, the role of reduced thiols and glutathione-S-transferases were assessed. In addition, intestinal cells were artificially imposed to an inflammation state and the anti-inflammatory effect of the extracts was estimated by determination of interleukin-8. Finally, a detailed characterization of the contents of the three plant extracts by high resolution Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry revealed significant differences in their chemical compositions. PMID- 29287262 TI - DNA binding of sunitinib: Spectroscopic evidence via circular dichroism and nuclear magnetic resonance. AB - Sunitinib is a non-selective tyrosine kinase inhibitor, but in its chemical structure there can be discovered certain features, which suggest the ability to bind to DNA. These elements are the planar aromatic system and the tertiary amine function, which is protonated at the pH of the organism. In this study, the binding of the drug sunitinib to DNA was investigated using circular dichroism (CD), 1H NMR and UV spectroscopies, along with CD melting. For these studies DNA was isolated from calf thymus (CT), salmon fish sperm (SS), and chicken erythrocyte (CE), however for our purposes an artificially constructed and highly purified plasmid DNA (pUC18) preparation proved to be the most suitable. DNA binding of the drug was confirmed by shifts in the characteristic CD bands of the DNA, the appearance of an induced CD (ICD) signal in the upper absorption region of sunitinib (300 nm-500 nm), and the evidence from CD melting studies and the NMR. Based on the CD and NMR measurements, it can be assumed that sunitinib has a multiple-step binding mechanism. PMID- 29287263 TI - Simultaneous quantification of fluoxetine and norfluoxetine in colostrum and mature human milk using a 2-dimensional liquid chromatography-tandem mass spectrometry system. AB - A two-dimensional liquid chromatography system coupled to triple quadrupole tandem mass spectrometer (2D LC-MS/MS) was employed for the determination of fluoxetine (FLU) and norfluoxetine (N-FLU) in colostrum and mature milk by direct sample injection. With a run time of 12 min representing a gain in throughput analysis, the validated methods furnished selectivity, extraction efficiency, accuracy, and precision in accordance with the criteria preconized by the European Medicines Agency guidelines. With a linear range of 3.00-150 ng/mL for FLU and 4.00-200 ng/mL for N-FLU they were applied to the analysis of colostrum and mature milk samples from nursing mothers. The paper discusses the differences and similarity of sample preparation for this two sample matrices. The herein reported methods are an advance in sample preparation procedures providing waste reduction and a sustainable approach. PMID- 29287264 TI - Qualitative assessment of extractables from single-use components and the impact of reference standard selection. AB - The advent of single-use bioprocess systems used for the delivery, storage or manufacture of biopharmaceuticals has introduced a new potential source for extractables and leachables (E&L) as these systems are comprised of polymeric materials. Several industry working groups, the FDA and USP have issued guidance and draft guidance on E&L analyses for a variety of applications. These documents typically indicate that mass spectrometry should be applied for discovery of E&L's but provide little guidance as to the exact analytical methodology which should be used. We investigated the extractable profiles of a model single-use bioprocessing system consisting of a single-use bioprocess bag, connector tubing, and a hydrophilic disk filter including filter housing. Extractions were performed in water, ethanol, ethanol/water (50:50) and saline solutions. Extracts were analyzed using a stepwise analytical methodology including a variety of screening and mass spectrometry methods We then used this model system to demonstrate the use of recursive feature finding to automatically detect unique extractables followed by statistical filtering to focus on differentially present extractables which were above the analytical evaluation threshold (AET). We further show the significant affects of standard selection on the number of compounds determined to be above AET when reducing liquid chromatography-mass spectrometry (LC/MS) data. A relative response factor database consisting of 14 structurally diverse commercially available polymer additives was used to arrive at an LC/MS identification threshold. The results of this study demonstrate that significant care should be taken when selecting standards for LC/MS analysis to avoid under reporting of extractables and leachables. PMID- 29287265 TI - NMR based metabolomic comparison of the antitussive and expectorant effect of Farfarae Flos collected at different stages. AB - Farfarae Flos (FF) is widely used for the treatment of cough, bronchitis, and asthmatic disorders in the Traditional Chinese Medicine (TCM). According to the experience of TCM, only the flower bud can be used as herbal drug, and its medicinal quality becomes lower after blooming. However, the underlying scientific basis for this phenomenon is not fully understood. In this study, the chemical components and the bioactivities of the FF collected at three different development stages were compared systematically. NMR based fingerprint coupled with multivariate analysis showed that the flower buds differed greatly from the fully opened flower both on the secondary and primary metabolites, and the animal experiments showed that the fully opened flower exhibited no antitussive or expectorant effect. In addition, the endogenous metabolites correlated with the antitussive and expectorant effect of FF were also identified. These findings are useful for understanding the rationality of the traditional use of FF, and also suggested the components responsible for the antitussive and expectorant effect of FF. PMID- 29287266 TI - Stability of infliximab solutions in different temperature and dilution conditions. AB - Infliximab is a monoclonal antibody widely used for the treatment of inflammatory diseases. Over the past few years, many studies have assessed that monoclonal antibodies are prone to aggregation under stress conditions. The aim of this study was to investigate the stability of solutions of an infliximab biosimilar (Inflectra(r)) at different concentrations (0.4, 2 and 10 mg/mL). These solutions were separately submitted to three temperature conditions that are likely to happen during the drug dispensing system: -20 degrees C, 5 degrees C and 25 degrees C. To perform a complete characterization of infliximab physicochemical and structural stability, a wide range of analytical techniques was employed including: visual inspection, subvisible particles counting (HIAC), dynamic light scattering (DLS), size exclusion chromatography (SEC), cation exchange chromatography (CEX), and analysis of primary, secondary and tertiary structure. When stored at 25 degrees C, chemical instability was the main limiting factor (highlighted by CEX), while SEC showed only some acceptable variations. After a single freeze-thawing cycle, the amount of subvisible particles was significantly increased. Some variations were also visible in CEX and the hydrodynamic diameter was increased after thawing 10 mg/mL samples. In regard of these results, infliximab (Inflectra(r)) solutions should not be used after a single freeze thawing cycle between reconstitution and administration to the patient. The results showed stability at 5 degrees C of up to 14 days for 10 mg/mL solutions and 90 days for 0.4 and 2 mg/mL solutions, whilst samples stored at 25 degrees C were stable only 7 days at 10 mg/mL and 30 days when diluted. PMID- 29287267 TI - Pore-scale study of thermal effects on ion diffusion in clay with inhomogeneous surface charge. AB - A better understanding of thermal effect on ion transport in compacted clay is of great significance to enhance long-term safety of repository for high-level radioactive waste. It was reported that the macroscopic Soret coefficient in clay is five times larger than that in free water, which was ascribed to the electrokinetic effect. By pore-scale simulations using lattice Boltzmann method, it is found that the Soret effect contributes little to the ionic flux changes in clay because the Soret coefficient is still around the value in free water for different external temperature gradients. The essential cause is the inhomogeneous charged liquid-solid interfaces in clays induced by the temperature gradient. This interface effect plays an important role to the significant changes of inner electrical and concentration fields in clay. Therefore the concentration diffusion and electromigration should be responsible for this phenomenon instead of the thermodiffusion (Soret effect). This study may improve the understanding of ion transport in clays driven by multiphysiochemical effects. PMID- 29287268 TI - Evaluation of multiwalled carbon nanotubes toxicity in two fish species. AB - Carbon Nanotubes are among the most promising materials for the technology industry. Their unique physical and chemical proprieties may reduce the production costs and improve the efficiency of a large range of products. However, the same characteristics that have made nanomaterials interesting for industry may be responsible for inducing toxic effects on the aquatic organisms. Since the carbon nanotubes toxicity is still a controversial issue, we performed tests of acute and subchronic exposure to a commercial sample of multiwalled carbon nanotubes in two fish species, an exotic model (Danio rerio) and a native one (Astyanax altiparanae). Using the alkaline version of the comet assay on erythrocytes and the piscine micronucleous, also performed on erythrocytes, it was verified that the tested carbon nanotubes sample did not generate apparent genotoxicity by means of single/double DNA strand break or clastogenic/aneugenic effects over any of the species, independently of the exposure period. Although, our findings indicate the possibility of the occurrence of CNTs-DNA crosslinks. Apparently, the sample tested induces oxidative stress after subchronic exposure as shown by activity of superoxide dismutase and catalase. The data obtained by the activity levels of acetylcholinesterase suggests acute neurotoxicity in Astyanax altiparanae and subchronic neurotoxicity in Danio rerio. PMID- 29287269 TI - Surfactant-enhanced PEG-4000-NZVI for remediating trichloroethylene-contaminated soil. AB - In this study a NZVI was prepared by the liquid phase reduction method. The modified NZVI obtained was characterized by BET, TEM and XRD. The results showed that the iron in the PEG-4000 modified material is mainly zero-valent iron with a stable crystal structure. It has a uniform particle size, ranging from 20 to 80 nm, and a larger specific surface area than CTAB modified NZVI, SDS modified NZVI and commercial zero-valent iron. The two surfactants CTAB and SDS are also selected as solubilizers, the results showed that the two selected surfactants obviously solubilize trichloroethylene in soil. Compared with commercial zero valent iron, PEG-4000 modified NZVI is better removed trichloroethylene from soil; Also, the optimal operational parameters were obtained. When the experimental conditions were: PEG-4000 modified NZVI dosage 1.0 g/L, CTAB/SDS concentration equal to the CMC, SDS concentration was 2.0 * CMC, CTAB was concentration 1.0 * CMC and the vibration speed 150 r/min, the removal efficiency of trichloroethylene in a soil-water system reached 100% after 4 h. Both NZVI combined with CTAB and NZVI combined with SDS followed fitted first order reaction kinetics during the removal of trichloroethylene and their reaction rate constant k was 0.6869 mg/(L.h) and 0.5659 mg/(L.h), respectively. According to the chloride ion detection test, the trichloroethylene degradation is mainly due to reductive dechlorination. PMID- 29287270 TI - Sorption of citalopram, irbesartan and fexofenadine in soils: Estimation of sorption coefficients from soil properties. AB - The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic, and citalopram cationic and neutral), in seven different soils was studied. The measured sorption isotherms were described by Freundlich equations, and the sorption coefficients, KF (for the fixed n exponent for each compound), were related to the soil properties to derive relationships for estimating the sorption coefficients from the soil properties (i.e., pedotransfer rules). The largest sorption was obtained for citalopram (average KF value for n = 1 was 1838 cm3 g-1) followed by fexofenadine (KF = 35.1 cm3/n MUg1-1/n g-1, n = 1.19) and irbesartan (KF = 3.96 cm3/n MUg1-1/n g-1, n = 1.10). The behavior of citalopram (CIT) in soils was different than the behaviors of irbesartan (IRB) and fexofenadine (FEX). Different trends were documented according to the correlation coefficients between the KF values for different compounds (RIRB,FEX = 0.895, p-value<0.01; RIRB,CIT = -0.835, p-value<0.05; RFEX,CIT = -0.759, p-value<0.05) and by the reverse relationships between the KF values and soil properties in the pedotransfer functions. While the KF value for citalopram was positively related to base cation saturation (BCS) or sorption complex saturation (SCS) and negatively correlated to the organic carbon content (Cox), the KF values of irbesartan and fexofenadine were negatively related to BCS, SCS or the clay content and positively related to Cox. The best estimates were obtained by combining BCS and Cox for citalopram (R2 = 93.4), SCS and Cox for irbesartan (R2 = 96.3), and clay content and Cox for fexofenadine (R2 = 82.9). PMID- 29287271 TI - Maize root culture as a model system for studying azoxystrobin biotransformation in plants. AB - Hairy roots induced by Agrobacterium rhizogenes are well established models to study the metabolism of xenobiotics in plants for phytoremediation purposes. However, the model requires special skills and resources for growing and is a time-consuming process. The roots induction process alters the genetic construct of a plant and is known to express genes that are normally absent from the non transgenic plants. In this study, we propose and establish a non-transgenic maize root model to study xenobiotic metabolism in plants for phytoremediation purpose using azoxystrobin as a xenobiotic compound. Maize roots were grown aseptically in Murashige and Skoog medium for two weeks and were incubated in 100 MUM azoxystrobin solution. Azoxystrobin was taken up by the roots to the highest concentration within 15 min of treatment and its phase I metabolites were also detected at the same time. Conjugated metabolites of azoxystrobin were detected and their identities were confirmed by enzymatic and mass spectrometric methods. Further, azoxystrobin metabolites identified in maize root culture were compared against azoxystrobin metabolites in azoxystrobin sprayed lettuce grown in green house. A very close similarity between metabolites identified in maize root culture and lettuce plant was obtained. The results from this study establish that non-transgenic maize roots can be used for xenobiotic metabolism studies instead of genetically transformed hairy roots due to the ease of growing and handling. PMID- 29287272 TI - Consumption of water from ex-mining ponds in Klang Valley and Melaka, Malaysia: A health risk study. AB - Evaluation of health risks due to heavy metals exposure via drinking water from ex-mining ponds in Klang Valley and Melaka has been conducted. Measurements of As, Cd, Pb, Mn, Fe, Na, Mg, Ca, and dissolved oxygen, pH, electrical conductivity, total dissolved solid, ammoniacal nitrogen, total suspended solid, biological oxygen demand were collected from 12 ex-mining ponds and 9 non-ex mining lakes. Exploratory analysis identified As, Cd, and Pb as the most representative water quality parameters in the studied areas. The metal exposures were simulated using Monte Carlo methods and the associated health risks were estimated at 95th and 99th percentile. The results revealed that As was the major risk factor which might have originated from the previous mining activity. For Klang Valley, adults that ingested water from those ponds are at both non carcinogenic and carcinogenic risks, while children are vulnerable to non carcinogenic risk; for Melaka, only children are vulnerable to As complications. However, dermal exposure showed no potential health consequences on both adult and children groups. PMID- 29287273 TI - Disruption of actin filaments in Zea mays by bisphenol A depends on their crosstalk with microtubules. AB - Bisphenol A (BPA) is a widespread environmental pollutant, reportedly harmful to living organisms. In plant cells, BPA was shown to disrupt microtubule (MT) arrays and perturb mitosis, but its effects on filamentous actin (F-actin) have not been explored. Here we studied the effects of BPA on actin filaments (AFs) in meristematic root tip and leaf cells of Zea mays, by fluorescent labeling and confocal microscopy. Considering the typical dynamic interaction between MTs and AFs, the effects on these two essential components of the plant cytoskeleton were correlated. It was found that BPA disorganized rapidly AFs in a concentration- and time-dependent manner. The fine filaments were first to be affected, followed by the subcortical bundles, resulting in rod- and ring-like conformations. The observed differences in sensitivity between protodermal and cortex cells were attributed to the deeper location of the latter. Depolymerization or stabilization of MTs by relevant drugs (oryzalin, taxol) revealed that AF susceptibility to BPA depends on MT integrity. Developing leaves required harder and longer treatment to be affected by BPA. Ontogenesis of stomatal complexes was highly disturbed, arrangement of AFs and MT arrays was disordered and accuracy of cell division sequence was deranged or completely arrested. The effect of BPA confirmed that subsidiary cell mother cell polarization is not mediated by F actin patch neither of preprophase band organization. On the overall, it is concluded that AFs in plant cells constitute a subcellular target of BPA and their disruption depends on their crosstalk with MTs. PMID- 29287275 TI - 'Appearances are deceptive' - External foam as an indicator of post-mortem period. PMID- 29287274 TI - Adsorption of phosphorus by calcium-flour biochar: Isotherm, kinetic and transformation studies. AB - Discharging phosphorus (P)-contaminated water directly into the aquatic environment leads to resource loss and eutrophication. Thus, removing P from waste streams is imperative. In this study, calcium-decorated biochar (Ca-BC) in different mass ratios of Ca to BC was designed to effectively adsorb P from solution. Ca-BC was characterized through X-ray diffraction (XRD) analysis, followed by isotherm and kinetic adsorption experiments. The decorated Ca on the BC surface was found to have preferred P adsorption ability. A design of calcium hydroxide (Ca(OH)2) to flour in a mass ratio of 2:1 was found to have a maximum adsorption capacity of 314.22 mg g-1 for P. The Langmuir and pseudo-second-order models fit the sorption process adequately. XRD analysis indicated that the preferable adsorption ability to P was due to the reaction of Ca(OH)2 and PO43-, forming the hydroxylapatite (Ca5(PO4)3(OH)) crystal. The P in solution was transformed to the crystal. Thus, Ca-BC is an environmental friendly and low-cost sorbent for P removal. PMID- 29287276 TI - Patients' attitudes towards and acceptance of coercion in psychiatry. AB - Coercive interventions for psychiatric patients are controversial. Research on different preventive measures has increased over the last years. The present study examined patients' attitudes towards and understanding of previously experienced coercive measures as well as their preferences related to coercive measures and possible alternatives. In total, 213 patients who had experienced coercion and 51 patient controls (patients staying voluntarily on a closed ward with no coercive treatment) from three acute wards were examined via expert interviews and questionnaires in the framework of a naturalistic trial. Assessments included a new self-developed questionnaire as well as instruments measuring psychopathology. Patients who had experienced coercion differed from controls in both symptoms and insight into their illness. As expected, "noninvasive measures" (e.g., the use of a "soft room," observation in seclusion) were better accepted by patients than "invasive measures" (e.g., mechanical restraint, forced medication). Forced medication and mechanical restraint were less well accepted than involuntary hospitalization, seclusion, or video surveillance. The retrospective understanding of coercive measures increased over the course of treatment. In addition, patients rated a number of options for reducing coercion on the wards, particularly music or exercises. A large subgroup indicated they would like to discuss future admissions with the staff. PMID- 29287277 TI - Life cycle energy and greenhouse gas emission effects of biodiesel in the United States with induced land use change impacts. AB - This study conducted the updated simulations to depict a life cycle analysis (LCA) of the biodiesel production from soybeans and other feedstocks in the U.S. It addressed in details the interaction between LCA and induced land use change (ILUC) for biodiesel. Relative to the conventional petroleum diesel, soy biodiesel could achieve 76% reduction in GHG emissions without considering ILUC, or 66-72% reduction in overall GHG emissions when various ILUC cases were considered. Soy biodiesel's fossil fuel consumption rate was also 80% lower than its petroleum counterpart. Furthermore, this study examined the cause and the implication of each key parameter affecting biodiesel LCA results using a sensitivity analysis, which identified the hot spots for fossil fuel consumption and GHG emissions of biodiesel so that future efforts can be made accordingly. Finally, biodiesel produced from other feedstocks (canola oil and tallow) were also investigated to contrast with soy biodiesel and petroleum diesel. PMID- 29287278 TI - Improving methane yield and quality via co-digestion of cow dung mixed with food waste. AB - Methane (CH4) production and quality were enhanced by the co-digestion of cow dung and food waste (FW) mixed with organic fraction of municipal solid waste (OFMSW) under optimized conditions in bench and semi continuous-scale mode for a period of 30 days. A bacterium capable of high yield of CH4 was enriched and isolated by employing activated sewage sludge as the inoculums. The thirteen bacterial isolates were identified through morphological and biochemical tests. Gas chromatography was used to analyze the chemical compositions of the generated biogas. CH4 yields were significantly higher during co-digestion of Run II (7.59 L) than Run I (3.7 L). Therefore, the co-digestion of FW with OFMSW and Run II was observed to be a competent method for biogas conversion from organic waste resources. PMID- 29287279 TI - IR and NMR studies of hierarchical material obtained by the treatment of zeolite Y by ammonia solution. AB - Ammonia treatment of ultrastable zeolite Y has a great impact on its features. XRD showed a partial loss of crystallinity coupled with a loss of long-distance zeolite ordering. However, a typical short-range zeolite ordering, in the light of 29Si NMR studies, was largely preserved. 27Al MAS NMR spectra evidenced that most of Al was located in zeolitic tetrahedral positions, but some of them adopted a distorted configuration. Evolution of zeolites acidity was followed quantitatively by using IR. In particular, such studies revealed the presence of strongly acidic SiOHAl groups. IR studies suggest also heterogeneity of these OH groups. The heterogeneity of SiOHAl groups was a consequence of the less ordered structure of zeolites treated with ammonia solutions. It was also found that the treatment with ammonia solutions yields hierarchical material. The samples revealed promising catalytic properties in the liquid phase isomerization of alpha-pinene. Zeolites desilicated with ammonia may constitute an inexpensive route yielding viable hierarchical catalysts. PMID- 29287280 TI - Rotational study on the van der Waals complex 1-chloro-1,1-difluoroethane-argon. AB - The rotational spectrum of the van der Waals complex formed between 1-chloro-1,1 difluoroethane and argon has been investigated by using a pulsed jet Fourier transform microwave spectrometer. Only one set of rotational transitions belonging to the lowest energy conformer has been observed and assigned, although theoretical calculations suggest six stable conformers that might be observed. The observed conformer, according to the experimental evidence from two isotopologues (35Cl and 37Cl), adopts a configuration in which the argon atom is located, close to the CF2Cl top, between the CCF and CCCl planes (the dihedral angle ?ArCCCl is 65.2 degrees ). The distance between argon atom and the center of mass of CH3CF2Cl is 3.949(2) A. The dissociation energy, with pseudo diatomic approximation, is evaluated to be 2.4kJmol-1. PMID- 29287281 TI - Comparative analysis of the transcriptome responses of zebrafish embryos after exposure to low concentrations of cadmium, cobalt and copper. AB - Metal toxicity is a global environmental challenge. Fish are particularly prone to metal exposure, which can be lethal or cause sublethal physiological impairments. The objective of this study was to investigate how adverse effects of chronic exposure to non-toxic levels of essential and non-essential metals in early life stage zebrafish may be explained by changes in the transcriptome. We therefore studied the effects of three different metals at low concentrations in zebrafish embryos by transcriptomics analysis. The study design compared exposure effects caused by different metals at different developmental stages (pre-hatch and post-hatch). Wild-type embryos were exposed to solutions of low concentrations of copper (CuSO4), cadmium (CdCl2) and cobalt (CoSO4) until 96h post-fertilization (hpf) and microarray experiments were carried out to determine transcriptome profiles at 48 and 96hpf. We found that the toxic metal cadmium affected the expression of more genes at 96hpf than 48hpf. The opposite effect was observed for the essential metals cobalt and copper, which also showed enrichment of different GO terms. Genes involved in neuromast and motor neuron development were significantly enriched, agreeing with our previous results showing motor neuron and neuromast damage in the embryos. Our data provide evidence that the response of the transcriptome of fish embryos to metal exposure differs for essential and non-essential metals. PMID- 29287282 TI - General sexual desire, but not desire for uncommitted sexual relationships, tracks changes in women's hormonal status. AB - Several recent longitudinal studies have investigated the hormonal correlates of both young adult women's general sexual desire and, more specifically, their desire for uncommitted sexual relationships. Findings across these studies have been mixed, potentially because each study tested only small samples of women (Ns = 43, 33, and 14). Here we report results from a much larger (N = 375) longitudinal study of hormonal correlates of young adult women's general sexual desire and their desire for uncommitted sexual relationships. Our analyses suggest that within-woman changes in general sexual desire are negatively related to progesterone, but are not related to testosterone or cortisol. We observed some positive relationships for estradiol, but these were generally only significant for solitary sexual desire. By contrast with our results for general sexual desire, analyses showed no evidence that changes in women's desire for uncommitted sexual relationships are related to their hormonal status. Together, these results suggest that changes in hormonal status contribute to changes in women's general sexual desire, but do not influence women's desire for uncommitted sexual relationships. PMID- 29287283 TI - Is monodehydroascorbate reductase activity in leaf tissue critical for the maintenance of yield in tomato? AB - Ascorbate redox metabolism and growth have been shown to be linked and related to the activity of enzymes that produce or remove the radical monodehydroascorbate, the semi-oxidized form of ascorbate (ascorbate oxidase or peroxidase and monodehydroascorbate reductase respectively). Previous work in cherry tomato has revealed correlations between monodehydroascorbate reductase and ascorbate oxidase activity and fruit yield: decreased whole plant MDHAR activity decreases yield while decreased whole plant ascorbate oxidase activity increases yield under unfavourable environmental conditions. We aimed to investigate if similar effects on yield are obtained in a large-fruited variety of tomato, Moneymaker. Furthermore we wished to establish whether previously observed effects on yield in cherry tomato following changes in whole plant enzyme activity could be reproduced by reducing MDHAR activity in fruit only by using a fruit-specific promoter in cherry tomato (West Virginia 106). In Moneymaker, RNAi lines for monodehydroascorbate reductase did not show significant yield decrease compared to control lines when plants were grown under optimal or non-optimal conditions of carbon stress generated by mature leaf removal. In addition, we show that a decrease in monodehydroascorbate reductase activity in fruit of cherry tomato had no effect on yield compared to a reduction in whole-plant monodehydroascorbate reductase activity: we therefore show that whole plant MDHAR activity is necessary to maintain yield in cherry tomato, suggesting that the carbon source in autotrophic tissue is more important than fruit sink activity. The present data also revealed differences between cherry and large fruited tomato that could be linked to a source of genetic variability in the response to monodehydroascorbate metabolism in tomato: maybe the domestication of tomato towards large-fruited lines could have affected the importance of MDHAR in yield maintenance. PMID- 29287284 TI - Potential Relationship between Passive Plantar Flexor Stiffness and Running Performance. AB - The present study aimed to determine the relationship between passive stiffness of the plantar flexors and running performance in endurance runners. Forty-eight well-trained male endurance runners and 24 untrained male control subjects participated in this study. Plantar flexor stiffness during passive dorsiflexion was calculated from the slope of the linear portion of the torque-angle curve. Of the endurance runners included in the present study, running economy in 28 endurance runners was evaluated by measuring energy cost during three 4-min trials (14, 16, and 18 km/h) of submaximal treadmill running. Passive stiffness of the plantar flexors was significantly higher in endurance runners than in untrained subjects. Moreover, passive plantar flexor stiffness in endurance runners was significantly correlated with a personal best 5000-m race time. Furthermore, passive plantar flexor stiffness in endurance runners was significantly correlated with energy cost during submaximal running at 16 km/h and 18 km/h, and a trend towards such significance was observed at 14 km/h. The present findings suggest that stiffer plantar flexors may help achieve better running performance, with greater running economy, in endurance runners. Therefore, in the clinical setting, passive stiffness of the plantar flexors may be a potential parameter for assessing running performance. PMID- 29287285 TI - [On occasion of the Turn of the Year 2017/2018]. PMID- 29287286 TI - [Arbitration proceedings caused by communication problems]. AB - INTRODUCTION: Functioning communication is one of the basic elements of a trusting doctor-patient relationship. Good medical communication is more important than ever in times of increasing personnel and time constraints. The aim of this study was to examine to what extent medical communication has an influence on the initiation of arbitration procedures. MATERIAL AND METHODS: The analysis was based on arbitration cases of plastic surgery, which were processed and completed by the Arbitration Board for Medical Liability Issues of North Germany between 2005 and 2015. After eliminating cases with incomplete data, 280 cases were evaluated. The documents were examined for possible communication errors and other triggers of the proceedings. If communication errors were present, these were analysed more closely. Furthermore, it was verified if treatment errors were suggested to patients, e. g. by physicians in charge of aftercare. RESULTS: 53.6 % of all cases emerged from communication errors in primary care, mainly caused by the attending surgeon (93.7 %). The outpatient follow-up treatment was identified as the most critical period (48.7 %). The most common problem was that patients felt they were not taken seriously (30.9 %). Further aspects were non-availability of the treating doctor (12.2 %), insults or disrespect (8.5 %), inadequate provision of information (8.5 %), and a lack of therapeutic enlightenment (8.1 %). In 43.9 % of the cases, treatment errors were suggested to patients, primarily by the after-treatment physician (70.3 %). DISCUSSION: The results show that inadequate medical communication has a considerable influence on the overall satisfaction of patients. Statements that appear normal to the surgeon may cause significant emotional reactions in patients. This study shows that arbitration procedures are not only triggered by "real" treatment errors and damage, but also by communication problems. Good communication and empathy help to reduce dissatisfaction and the risk of possible legal disputes. PMID- 29287287 TI - [Breast reduction surgery as an example of surgery on demand in adolescents]. AB - Surgical options to optimise one's body image are also accessible to adolescents. Although the vast majority of surgical procedures in this group of patients focus on otoplasty, 4 % of procedures in Germany are performed on the breast. The onset of menarche has not changed much in recent years, but obesity seems to generate problems with the breast for young girls. Since it is difficult to assess maturity and psychological resilience in young patients, a plastic surgeon is faced with an area of conflicts regarding his or her will to meet patients' reasonable wishes to ease their suffering, offer reliable and sustainable results, and comply with legal regulations that are largely uncertain. This article tries to explain the relevant jurisdiction and legislation with a view to the special legal situation regarding adolescents, and recommends options to bridge prevalent uncertainties. The goal in decision-making in this group of patients will be to thoroughly assess the adolescent's ability to appreciate pros and cons, and to include third parties who will eventually influence the adolescent's decision and judgement of a result also in the future. PMID- 29287288 TI - [The Cyclops Breast as Result after Resection of a Large Recurrence of Breast Cancer - a Rare Case Report]. PMID- 29287289 TI - [Current German and American guidelines for autologous fat grafting - a transatlantic comparison]. AB - CLINICAL PROBLEM: The renewed clinical interest in fat grafting for both reconstructive and aesthetic purposes prompted the American Society of Plastic Surgeons to establish a Fat Graft Task Force (AFGT) in 2009. Moreover, in 2015, the German Society of Plastic, Reconstructive and Aesthetic Surgeons (DGPRAC), in cooperation with three relevant medical societies (DDG, DGMKG, DGGG), formulated statements on the provision of strategies for patient management and to guide physicians in clinical decision making, on the basis of the scientific literature, clinical experience and current laws. The aim of this paper is to compare both guidelines in regards to recommendations on fat grafting. METHODS: Recommendations of the AFGT are based on evidence available in the published literature and graded within 5 (I-V) levels of appraisal. The available literature was reviewed by the aforementioned multidisciplinary consensus panel as well and graded according to a 4 level (I-IV) appraisal - focusing on general requirements for surgical procedures, quality of care, patient safety and legal provisions. RESULTS: For indications and practical surgical procedures, the two societies reached a unanimous consensus: Fat grafting is indicated for breast reconstruction, reconstruction of tissue deficits, and deformations caused by prior operations. Both emphasize risk groups with breast cancer (BRCA-1, BRCA-2 and family predispositions). However, in any clinical setting, results depend on the surgical procedure applied and the individual surgeon's experience. Since randomized, prospective studies are lacking and only individual case reports and clinical series or expert opinions have been published, the evidence grading does not exceed level IV to V. However, the DGPRAC structured expert consensus panel conveys a more comprehensive and practical approach, and provides more reliable evidence to support their opinions. SUMMARY: Both societies unanimously recommend fat grafting for appropriate indications and emphasize that there are no standard guidelines for any specific procedure. The published guidelines were developed to assist physicians in choosing optimal techniques, appropriate patient selection, and offer realistic advice on outcome and potential complications. The AFGT emphasizes the need for further research and randomized controlled studies. Overall, the DGPRAC guidelines are more detailed, practically oriented and take into consideration current German and European Tissue Laws. PMID- 29287290 TI - [58th Annual Meeting of the German Society of Handsurgery 2017 in Munich]. PMID- 29287291 TI - [HaMiPla Best Paper Award - Your Favourites in 2016]. PMID- 29287292 TI - Procalcitonin as Predictor of Bacterial Infection in Meconium Aspiration Syndrome. AB - BACKGROUND: There is a lack of definite consensus on indications for initiating antibiotics in neonates with meconium aspiration syndrome (MAS), instigating researchers to search for a biomarker that can help differentiate MAS from MAS with bacterial infection. OBJECTIVE: Our primary objective was to compare serum procalcitonin (PCT) levels in full-term vigorous neonates having MAS with or without bacterial infection. MATERIALS AND METHODS: Seventy term vigorous neonates with diagnosis of MAS were enrolled. Blood samples were taken for sepsis screen, C-reactive protein (CRP), PCT, and blood culture at 6 +/- 2 hours of respiratory distress. Neonates were categorized into group 1 (MAS without bacterial infection) and group 2 (MAS with bacterial infection) based on blood culture. The duration of our study was 18 months. RESULTS: Mean +/- standard deviation PCT level was 2.52 +/- 3.99 in group 1 and 2.71 +/- 4.22 in group 2, which was comparable. At cutoff of 0.1 ng/mL, PCT had a sensitivity of 90% and specificity of 8% in detecting bacterial infection. Mean total leukocyte count, absolute neutrophil count, immature to total leucocyte ratio, microerythrocyte sedimentation rate, and CRP were comparable. CONCLUSION: Though PCT is an early and reliable marker of neonatal infection, the levels were increased in neonates with MAS irrespective of the presence of bacterial infection. PMID- 29287293 TI - Traumatic Neonatal Lumbar Punctures: Experience at a Large Pediatric Tertiary Care Center in Canada. AB - OBJECTIVE: Contamination of cerebrospinal fluid (CSF) by blood during neonatal lumbar puncture (LP) is common and poses diagnostic difficulties. Our objectives were to determine the number of traumatic LPs performed at the BC Children's Hospital over 9 years and whether there was an association between traumatic LPs and demographic variables, hospital location, or time of the procedure. STUDY DESIGN: This study was a retrospective review of neonatal CSF samples from May 2006 to March 2015. The data were analyzed to establish the rate of traumatic samples and whether there was an association between traumatic LPs and demographic variables (age, gender), location of procedure, positive CSF culture, and/or timing of the procedure. RESULTS: A total of 1,263 LPs were reviewed, 47.7% (n = 602) were contaminated with >400 red blood cells/high-power field. The median age of neonates whose samples were uncontaminated was 10.580 days compared with 6.535 days in the group with contaminated samples (z = - 2.884, p = 0.004). None of the other factors studied was associated with traumatic taps. Detected organisms included Escherichia coli (n = 12), coagulase-negative Staphylococcus (n = 7), Enterococcus faecalis (n = 3), and group B Streptococcus (n = 2). CONCLUSION: Nearly half of all CSF samples in the study period were contaminated. Traumatic samples were more common in younger neonates. PMID- 29287294 TI - Outcomes of Medically Indicated Preterm Births Differ by Indication. AB - OBJECTIVE: We aim to examine whether outcomes of preterm birth (PTB) are further modified by the indication for delivery. STUDY DESIGN: We performed a retrospective cohort study of all singletons delivered at 23 to 34 weeks from 2011 to 2014. Women were classified by their primary indication for delivery: maternal (preeclampsia) or fetal/obstetric (growth restriction, nonreassuring fetal status, and vaginal bleeding). The primary neonatal outcome was a composite of neonatal death, cord pH <7 or base excess < - 12, 5-minute Apgar <=3, C reactive protein during resuscitation, culture-proven sepsis, intraventricular hemorrhage, and necrotizing enterocolitis. Secondary outcomes included the individual components of the primary outcome. Groups were compared using Student's t-test and chi-squared tests. Logistic regression was used to adjust for confounding variables. RESULTS: Of 528 women, 395 (74.8%) were delivered for maternal and 133 (25.2%) for fetal/obstetric indications. Compared with those delivered for a maternal indication, those with a fetal/obstetric indication for delivery had an increased risk of the composite neonatal outcome (adjusted odds ratio [AOR]: 1.9, 95% confidence interval [CI]: 1.13-3.21) and acidemia at birth (AOR: 4.2, 95% CI: 1.89-9.55). CONCLUSION: Preterm infants delivered for fetal/obstetric indications have worsened outcomes compared with those delivered for maternal indications. Additional research is needed to further tailor counseling specific to the indication for delivery. PMID- 29287295 TI - Accuracy of Ultrasound Estimated Fetal Weight in Small for Gestational Age and Appropriate for Gestational Age Grown Periviable Neonates. AB - OBJECTIVE: Clinicians use estimated fetal weight (EFW) as a proxy for birth weight (BW) in the antenatal period. Our objective was to compare the accuracy of EFW obtained by ultrasound to BW among infants born during the periviable period and determine if accuracy of EFW varied among small for gestational age (SGA) versus appropriate for gestational age (AGA) grown neonates. STUDY DESIGN: We included women who delivered between 230/7 and 256/7 weeks' gestation and had an EFW within 7 days of delivery. Mean percentage difference and median absolute percentage difference between EFW and BW were calculated. RESULTS: Our cohort included 226 neonates with a mean gestational age of 241/7 +/- 0.8 weeks and median BW of 653 g (interquartile range [IQR]: 580-750 g). The median absolute percentage difference between EFW and BW of fetal weight estimates was 9.2% (IQR: 3.6-17.2). EFW overestimated BW for 75% (n = 171) of the cohort. Among SGA infants, the mean percentage difference in EFW and BW was 16.2 +/- 19.4% versus 6.9% +/- 13.1% in AGA infants (p = 0.019). CONCLUSION: EFW overestimated BW in this cohort. In addition, ultrasound was less accurate among infants born SGA. These data are important to consider when counseling families facing periviable delivery. PMID- 29287296 TI - Risk of Neonatal Neurologic Morbidity in Advancing Term Gestations. AB - OBJECTIVE: Placental insufficiency is associated with neonatal neurologic morbidity and late-term gestations (410/7-416/7 weeks). Whether late-term infants are at increased risk of neurologic morbidity compared with term infants (390/7 406/7 weeks) remains unclear. We aim to compare risk of neurologic morbidity among late-term and term infants. STUDY DESIGN: This secondary analysis of a single-institution prospective cohort study included all liveborn, nonanomalous singleton term and late-term infants, with data on adverse neonatal outcomes up until 28 days of life. The primary outcome was a neonatal neurologic morbidity composite, defined by having one of these conditions: neonatal seizures, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, and neonatal hypothermic therapy. Secondary outcomes were the composite's individual components and nonneurologic neonatal morbidity. Multivariable logistic regression adjusted for delivery mode, nulliparity, and labor type. RESULTS: Of 5,529 infants included, 747 were late term and 4,782 were term. The risk of composite neurologic morbidity was not significantly different among late-term or term infants (0.5 vs. 0.6%; adjusted odds ratio: 0.59, 95% confidence interval: 0.21-1.71). Overall neonatal morbidity was not significantly different in the two groups, though late-term infants had a nonsignificantly higher prevalence of respiratory distress syndrome (5.5 vs. 3.3%) and meconium aspiration syndrome (0.7 vs. 0.2%). CONCLUSION: Neonatal neurologic morbidity is uncommon after 39 weeks. Risk does not increase after 41 weeks. PMID- 29287297 TI - Epidurals and the Modern Labor Curve: How Epidural Timing Impacts Fetal Station during Active Labor. AB - OBJECTIVE: The objective of this study was to estimate epidural timing's impact on fetal station during active labor. STUDY DESIGN: This secondary analysis of a single-institution prospective cohort study included all term singleton pregnancies, stratified by parity. Those with early epidurals (placed at <6 cm) were compared with those with late epidurals (placed at >=6 cm). The primary outcome was median fetal station from 6 to 10 cm. Secondary outcomes included rate of prolonged first or second stage of labor (>95%). Multivariable logistic regression adjusted for labor type. RESULTS: Among 7,647 women, 3,434 were nulliparous (2,983 with early epidurals and 451 with late epidurals) and 4,213 multiparous (3,141 with early epidurals and 1,072 with late epidurals). Interquartile ranges (IQRs) suggested fetal station at 6 cm was likely lower among those with early epidurals (nulliparous: median head station -1 [IQR: -1 to 0] for early epidural vs. -1 [IQR: -2 to 0] for late epidural, p < 0.01; multiparous: -1 (IQR: -2 to 0] for early epidural vs. -1 [IQR: -3 to -1] for late epidural, p < 0.01). Early epidurals were not associated with increased risk of prolonged first stage, but among nulliparous were associated with decreased risk of prolonged second stage (adjusted odds ratio: 0.66 [95% confidence interval: 0.44-0.99]). CONCLUSION: Early epidurals were associated with lower fetal station in active labor but not prolonged first stage. PMID- 29287298 TI - Polyhydramnios Affecting a Recipient-like Twin: Risk of Progression to Twin-Twin Transfusion Syndrome and Outcomes. AB - OBJECTIVE: The significance of polyhydramnios of one twin in the absence of oligohydramnios of the cotwin in monochorionic diamniotic (MCDA) twin pregnancies (polyhydramnios affecting a recipient-like twin [PART]) is unknown. Our aim is to assess the risk of progression to twin-twin transfusion syndrome (TTTS) with PART, progression to >= stage II TTTS, and neonatal survival. STUDY DESIGN: This study was a retrospective cohort study of MCDA twin pregnancies with PART evaluated at a referral center from 2008 to 2015. RESULTS: Sixty-four MCDA twin pregnancies with PART were identified. Fifteen (23.4%) progressed to TTTS, including 10 (15.6%) who progressed to >= stage II TTTS. Three pregnancies were terminated and one underwent selective reduction by radiofrequency ablation. Overall survival was 113 out of 128 (88.3%). Of those who remained stable, 91.8% (N = 45) had survival of both neonates. In multivariate analysis, the presence of arterioarterial (A-A) anastomosis by in utero Doppler ultrasound was associated with decreased risk of progression to TTTS (odds ratio: 0.12, p = 0.03, 95% confidence interval: 0.02-0.78). CONCLUSION: Most MCDA twin pregnancies with PART do not progress to TTTS and have a favorable prognosis. Progression rates are higher than observed in uncomplicated MCDA twins; however, so close surveillance is warranted. The presence of an A-A anastomosis appears to confer decreased risk of progression to TTTS. PMID- 29287299 TI - [Laudation at the presentation of the Salomon Neumann Medal 2017 to Prof. Dr. med. med. Bernt-Peter Robra, MPH]. AB - The German Society for Social Medicine and Prevention (DGSMP) confers the Salomon Neumann Medal for outstanding merit in the field of Preventive and Social Medicine. The Salomon Neumann Medal 2017 was awarded to Bernt-Peter Robra, Institute for Social Medicine and Health Economics (ISMG) of the Otto von Guericke University Magdeburg. It honours an outstanding representative of social medicine, in whose person and Institute the essential problem areas of social medicine as well as the competencies of the 3 scientific bodies that gathered in Lubeck - epidemiology, medical sociology and social medicine - and the sociopolitical engagement of Salomon Neumann come together. PMID- 29287300 TI - [,,...I would be sad then, because they are all talking about my dad" - The Role of Stigma in Families Affected by Parental Mental Illness]. AB - Stigmatization of mental illness is a societal problem, and is also relevant for help-seeking. In a qualitative interview study, the role of stigma in help seeking was examined from the perspective of parents with mental illness, their children and other relatives. Parents with mental illness assigned an important role to stigma for help-seeking processes. Children rarely made explicit statements about this, but an implicit awareness of stigma can be assumed. PMID- 29287301 TI - [Position Paper of The AG Digital Health DNVF on Digital Health Applications: Framework Conditions For Use in Health Care, Structural Development and Science]. AB - The term "digital health" is currently the most comprehensive term that includes all information and communication technologies in healthcare, including e-health, mobile health, telemedicine, big data, health apps and others. Digital health can be seen as a good example of the use of the concept and methodology of health services research in the interaction between complex interventions and complex contexts. The position paper deals with 1) digital health as the subject of health services research; 2) digital health as a methodological and ethical challenge for health services research. The often-postulated benefits of digital health interventions should be demonstrated with good studies. First systematic evaluations of apps for "treatment support" show that risks are higher than benefits. The need for a rigorous proof applies even more to big data-assisted interventions that support decision-making in the treatment process with the support of artificial intelligence. Of course, from the point of view of health services research, it is worth participating as much as possible in data access available through digital health and "big data". However, there is the risk that a noncritical application of digital health and big data will lead to a return to a linear understanding of biomedical research, which, at best, accepts complex conditions assuming multivariate models but does not take complex facts into account. It is not just a matter of scientific ethical requirements in health services care research, for instance, better research instead of unnecessary research ("reducing waste"), but it is primarily a matter of anticipating the social consequences (system level) of scientific analysis and evaluation. This is both a challenge and an attractive option for health services research to present itself as a mature and responsible scientific discipline. PMID- 29287302 TI - ? PMID- 29287304 TI - The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by destructive hyperplasia of the synovium. Fibroblast-like synoviocytes (FLS) are a major component of synovial pannus and actively participate in the pathologic progression of RA. How rheumatoid FLS acquire and sustain such a uniquely aggressive phenotype remains poorly understood. We describe the current state of knowledge of the molecular alterations in rheumatoid FLS at the genomic, epigenomic, transcriptomic, proteomic, and metabolomic levels, which offers a means to reconstruct the pathways leading to rheumatoid pannus. Such data provide new pathologic insight and suggest means to more sensitively assess disease activity and response to therapy, as well as support new avenues for therapeutic development. PMID- 29287305 TI - Development of an immunochromatographic strip incorporating anti-mitragynine monoclonal antibody conjugated to colloidal gold for kratom alkaloids detection. AB - A lateral flow-based immunochromatographic strip was developed for the rapid detection of mitragynine (MG), a dominant alkaloid found in the leaves of kratom. Monoclonal antibody (mAb) against MG (anti-MG mAb) was conjugated to colloidal gold and used as a recognition probe. MG-ovalbumin conjugate (MG-OVA) and goat anti-mouse IgG were immobilized on the strip to produce a test zone and control zone, respectively. Based on the principle of a competitive assay, MG in a test sample competed with MG-OVA resident in the test zone to bind with colloidal gold anti-MG mAb, resulting in an inverse relation of color intensity at the test zone and MG amount. The limit of detection (LOD) of the immunochromatographic strip is determined at 1 mg/mL of MG by visual assessment and 0.60 mg/mL by Image J analysis. The developed immunochromatographic strip can determine MG in kratom cocktails and kratom leaf samples. It could serve as a rapid and simple diagnostic kit for the detection of MG in kratom samples. PMID- 29287303 TI - High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti Tumor Necrosis Factor Therapy. AB - OBJECTIVE: The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA. METHODS: DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti-tumor necrosis factor (anti-TNF) therapy. Recombinant His-tagged full-length DEK protein (1-375 amino acids [aa]) and the 187-375-aa and 1-350-aa His-tagged DEK fragments made in a baculovirus system were used for enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The C-terminal 25-aa fragment of DEK was expressed in a glutathione S-transferase-tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule. RESULTS: DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti-TNF therapy. Immunoblotting against the C-terminal 25-aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain. CONCLUSION: DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti-TNF therapy. The C-terminal 25-aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management. PMID- 29287306 TI - Evaluation of an Extraction Method for the Detection of GI and GII Noroviruses in Fruit and Vegetable Salads. AB - Human norovirus (HuNoV) is a major foodborne virus causing gastroenteritis outbreaks in humans. Salad products can be vectors of transmission for foodborne viruses such as HuNoV when these products are contaminated naturally or through unsanitary food handling. Therefore, development of simple, reliable and sensitive techniques for the detection of HuNoV in salad products is needed to ensure food safety. The purpose of our study was to optimize a method for the detection of HuNoV in artificially contaminated salad products. To this end, 2 different kinds of salads (fruit salads and vegetable salads) were experimentally inoculated with HuNoV GI, HuNoV GII, and MS2 suspensions. The selected method was based on treatment with pectinase followed by Trizol-chloroform purification, and the recovery efficiencies were 6.07% to 26.52% for HuNoV GI and 5.54% to 37.36% for HuNoV GII. MS2 was used as the process control, and the recovery efficiencies for fruit salad and vegetable salad samples were 38.57% and 41.13%, respectively. The optimized method could be applied in diagnostic laboratories to identify NoV contamination in composite foods, such as salad products, should an event of foodborne outbreak occur. PMID- 29287307 TI - Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis. AB - OBJECTIVE: To investigate whether HLA-B27-mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis. METHODS: The effects of HLA-B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild-type littermates and HLA-B7-transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3-4, and 6-8 months of age, and histologic analysis was performed to assess inflammation, RNA sequencing was used to determine gene expression differences, and 16S ribosomal RNA gene sequencing was used to determine microbiota differences. RESULTS: Both HLA-B27 transgenic Lewis rats and HLA-B27-transgenic Fischer rats developed gut inflammation, while DA rats were resistant to the effects of HLA-B27, and HLA-B7 transgenic rats were not affected. Immune dysregulation was similar in affected Lewis and Fischer rats and was dominated by activation of interleukin-23 (IL 23)/IL-17, interferon, tumor necrosis factor, and IL-1 cytokines and pathways in the colon and cecum, while DA rats exhibited low-level cytokine dysregulation without inflammation. Gut microbial changes in HLA-B27-transgenic rats were strikingly divergent on the 3 different host genetic backgrounds, including different patterns of dysbiosis in HLA-B27-transgenic Lewis and HLA-B27 transgenic Fischer rat strains, with some overlap. Interestingly, DA rats lacked segmented filamentous bacteria that promote CD4+ Th17 cell development, which may explain their resistance to disease. CONCLUSION: The effects of HLA-B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. These results implicate an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis. PMID- 29287308 TI - Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management. AB - In the past decade, arboviruses-arthropod-borne viruses-have been the focus of public health institutions worldwide following a spate of devastating outbreaks. Chikungunya virus, an arbovirus that belongs to the alphavirus genus, is a reemerging arthritogenic virus that has caused explosive outbreaks since 2006, notably on Reunion Island, and more recently in the Caribbean, South America, India, and Southeast Asia. The severity of arthritic disease caused by chikungunya virus has prompted public health authorities in affected countries to develop specific guidelines to tackle this pathogen. Chikungunya virus disease manifests first as an acute stage of severe joint inflammation and febrile illness, which later progresses to a chronic stage, during which patients may experience debilitating and persisting articular pain for extended periods. This review aims to provide a broad perspective on current knowledge of chikungunya virus pathogenesis by identifying key clinical and experimental studies that have contributed to our understanding of chikungunya virus to date. In addition, the review explores the practical aspects of treatment and management of both acute and chronic chikungunya virus based on clinical experience during chikungunya virus outbreaks. Finally, recent findings on potential therapeutic solutions-from antiviral agents to immunomodulators-are reviewed to provide both viral immunologists and clinical rheumatologists with a balanced perspective on the nature of a reemerging arboviral disease of significant public health concern, and insight into future therapeutic approaches to better address the treatment and management of chikungunya virus. PMID- 29287309 TI - Aspirin Dose in Kawasaki Disease: The Ongoing Battle. AB - OBJECTIVE: Kawasaki disease (KD) is an acute childhood vasculitis that may result in coronary aneurysms. Treatment of KD with a single infusion of 2 gm/kg intravenous immunoglobulin (IVIG) is well established, but acetylsalicylic acid (ASA) dose remains controversial. Our primary objective was to determine the difference in the incidence of IVIG resistance between 2 ASA doses. Our secondary objective was to compare the duration of hospital stay and the incidence of coronary artery aneurysm. METHODS: We reviewed charts of patients with KD from 2 Canadian centers to assess the impact of ASA dose on IVIG resistance (operationally defined as administration of a second dose of IVIG). Both centers used standard IVIG dosing, but center 1 used low-dose ASA from diagnosis (3-5 mg/kg/day) while center 2 used initial high-dose ASA (80-100 mg/kg/day). RESULTS: There were no significant differences in baseline characteristics between the 2 centers. Retreatment with a second dose of IVIG was required in 28 of 122 patients (23%) treated with low-dose ASA, and in 11 of 127 patients (8.7%) treated with high-dose ASA in center 1 and center 2, respectively (P = 0.003). After adjusting for confounders, low-dose ASA was associated with higher odds of IVIG resistance (OR 3.2 [95% confidence interval 1.1, 9.1]). The mean duration of hospital stay was 4.1 and 4.7 days, respectively (P = 0.37). Coronary artery aneurysms were seen in 2 of 117 and 6 of 125 patients from centers 1 and 2, respectively (P = 0.28). CONCLUSION: Low-dose ASA was associated with 3-times higher odds of IVIG retreatment compared to high-dose ASA, with no significant difference in duration of hospital stay or incidence of coronary artery aneurysms. PMID- 29287310 TI - High-grade transformation/dedifferentiation of an adenoid cystic carcinoma of the minor salivary gland to myoepithelial carcinoma. AB - High-grade transformation (HGT)/dedifferentiation is an unusual phenomenon in salivary gland carcinomas. Here we report a case of adenoid cystic carcinoma (ACC) with HGT/dedifferentiation to myoepithelial carcinoma, occurring in the epipharynx of a 42-year-old woman. The surgically resected tumor was a pedunculated mass, 31 * 25 mm in size, which had two histologically distinct carcinomatous areas, including a high-grade sarcomatoid area composed of pleomorphic spindle cells and an area consisting of low-grade typical ACC. These two components gradually changed from the low-grade to the high-grade component. MIB-1 index in the low-grade and high-grade component was 15% and 50%, respectively. An immunohistochemical profile of the high-grade component showed immunoreactivity for alpha-SMA, p63, calponin and focal S100, as well as for several cytokeratin markers, which were compatible with the features of myoepithelial carcinoma. In contrast, the immunohistochemical profile of the low grade component coincided with that of typical ACC. This HGT/dedifferentiation to myoepithelial carcinoma is extremely rare. The pathogenesis of HGT/dedifferentiation in salivary gland carcinomas still remains largely unknown, regardless of the presence or absence of myoepithelial differentiation. Further studies are required due to the more aggressive biological behavior and poorer prognosis associated with ACC with HGT/dedifferentiation, compared with conventional ACC. PMID- 29287311 TI - Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients. AB - OBJECTIVE: Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients. METHODS: Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators. RESULTS: Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified. CONCLUSION: Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity. PMID- 29287312 TI - Utilization and Short-Term Outcomes of Primary Total Hip and Knee Arthroplasty in the United States and Canada: An Analysis of New York and Ontario Administrative Data. AB - OBJECTIVE: Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are common and effective surgical procedures. This study sought to compare utilization and short-term outcomes of primary TKA and THA in adjacent regions of Canada and the United States. METHODS: The study was designed as a retrospective cohort study of patients who underwent primary TKA or THA, comparing administrative data from New York and Ontario in 2012-2013. Demographic features of the TKA and THA patients, per capita utilization rates, and short-term outcomes were compared between the jurisdictions. RESULTS: A higher percentage of New York hospitals performed TKA compared to Ontario hospitals (75.7% versus 42.1%; P < 0.001), and the mean annual procedural volume for TKAs was lower in New York hospitals (mean 179 versus 327 in Ontario hospitals; P < 0.001). After direct standardization, utilization was significantly lower in New York compared to Ontario, both for TKA (16.1 TKAs versus 21.4 TKAs per 10,000 population per year; P < 0.001) and for THA (10.5 THAs versus 11.5 THAs per 10,000 population per year; P < 0.001). For those who underwent TKA, the length of stay in Ontario hospitals was significantly longer (mean 3.7 days versus 3.4 days in New York hospitals; P < 0.001). A smaller percentage of New York patients were discharged directly home (46.2% versus 90.9% of Ontario patients; P < 0.001), but 30-day and 90-day readmission rates were higher in New York compared to Ontario (30-day rates, 4.6% versus 3.9% [P < 0.001]; 90-day rates, 8.4% versus 6.7% [P < 0.001]). For the THA cohorts, the results with regard to length of stay, discharge disposition, and readmission rates were similar to those for TKA. CONCLUSION: Ontario has higher utilization of total joint arthroplasty than New York but has a smaller percentage of hospitals performing these procedures. Patients are more likely to be discharged home and less likely to be readmitted in Ontario. Our results suggest areas where each jurisdiction could improve. PMID- 29287313 TI - Multicenter Delphi Exercise to Identify Important Key Items for Classifying Systemic Lupus Erythematosus. AB - OBJECTIVE: The American College of Rheumatology and the European League Against Rheumatism embarked on a project to reevaluate classification criteria for systemic lupus erythematosus (SLE). The first phase of the classification project involved generation of a broad set of items potentially useful for classification of SLE and their selection for use in a subsequent forced-choice decision analysis. METHODS: A large international group of expert lupus clinicians was invited to participate in a 2-step process to generate, rate, and select items based on their importance in diagnosing early and established SLE, via a web based survey. RESULTS: A total of 135 and 147 experts were invited to participate in the item-generation and item-reduction process, respectively. Of 145 items generated, item reduction resulted in 40 candidate items moving forward to the next phase. Key features for classifying both early and established SLE included characteristic autoantibodies, specific renal features, and skin manifestations. A small majority (51%) stated that 1 organ system would be sufficient for classifying SLE, but that additional typical laboratory features (antinuclear antibody, anti-double-stranded DNA) would be required. Notably, 85% of the expert group would positively classify SLE if renal pathology alone showed lupus nephritis. CONCLUSION: The Delphi exercise resulted in a set of 40 candidate criteria for the classification of SLE for subsequent assessment. This study comprised the largest panel ever involved in the development of SLE classification criteria, providing a broadly representative view of the current approach to classification of SLE. PMID- 29287314 TI - Symptomatic Course of Foot Osteoarthritis Phenotypes: An 18-Month Prospective Analysis of Community-Dwelling Older Adults. AB - OBJECTIVE: Osteoarthritis (OA) is a heterogeneous disease, and symptom progression at the foot is unclear. This study investigated the symptomatic course of 3 predefined foot OA phenotypes over an 18-month period. METHODS: The Clinical Assessment Study of the Foot is a community-based cohort of adults ages >=50 years in North Staffordshire, UK. Participants who reported foot pain in a postal health survey and underwent radiographic assessment were mailed an 18 month followup survey. Changes in descriptive and symptomatic outcomes over 18 months were compared across the 3 phenotypes to determine within-phenotype changes and between-phenotype differences. RESULTS: Of 533 participants at baseline, 478 (89.7%) responded at 18 months. All 3 phenotypes showed small within-phenotype improvements in mean foot pain severity (scale range 0-10, where 0 = no pain and 10 = worst pain): no or minimal foot OA (18 months 4.0, mean change -1.15 [95% confidence interval (95% CI) -1.46, -0.83]), isolated first metatarsophalangeal (MTP) joint OA (18 months 4.1, mean change -0.60 [95% CI 1.11, -0.10]), and polyarticular foot OA (18 months 5.1, mean change -0.77 [95% CI -1.42, -0.12]). The isolated first MTP joint OA phenotype had an increased likelihood of hallux valgus in the left foot (adjusted odds ratio 2.96 [95% CI 1.23, 7.12]) compared to the no or minimal foot OA phenotype. CONCLUSION: Three foot OA phenotypes showed few descriptive or symptomatic changes over 18 months. Future clinical trials should consider that people recruited with mild-to moderate symptomatic foot OA appear likely to remain relatively stable with usual care. Longer-term followup using additional time points is required to describe further the natural history of foot OA. PMID- 29287315 TI - Effect of amino acids and frequency of reuse frying oils at different temperature on acrylamide formation in palm olein and soy bean oils via modeling system. AB - This work investigated the underlying formation of acrylamide from amino acids in frying oils during high temperatures and at different times via modeling systems. Eighteen amino acids were used in order to determine which one was more effective on acrylamide production. Significantly the highest amount of acrylamide was produced from asparagine (5987.5ug/kg) and the lowest from phenylalanine (9.25ug/kg). A constant amount of asparagine and glutamine in palm olein and soy bean oils was heated up in modelling system at different temperatures (160, 180 and 200 degrees C) and times (1.5, 3, 4.5, 6, 7.5min). The highest amount of acrylamide was found at 200 degrees C for 7.5min (9317 and 8511ug/kg) and lowest at 160 degrees C for 1.5min (156 and 254ug/kg) in both frying oils and both amino acids. Direct correlations have been found between time (R2=0.884), temperature (R2=0.951) and amount of acrylamide formation, both at p<0.05. PMID- 29287316 TI - Role of Reactive Carbonyl Species in non-enzymatic browning of apple juice during storage. AB - Non-enzymatic browning during storage of fruit juice causes the development of brown color and off-flavors that ultimately lead to a decrease in consumer acceptability. This study investigates the role of Reactive Carbonyl Species (RCS) from the Maillard reaction on browning formation in apple juice during storage. Over a 10-week period under accelerated conditions (35 degrees C), a significant increase in brown color development was observed and positively correlated to the RCS concentrations. Supplementation experiments established causality between specific RCS and browning and allowed for the identification of glyoxal and methylglyoxal as key browning intermediates in apple juice. Finally, phloretin, a ubiquitous apple dihydrochalcone, was reported as an efficient browning suppressor by significantly reducing the RCS levels and inhibiting the color formation during storage. PMID- 29287317 TI - Silica/graphene oxide nanocomposites: Potential adsorbents for solid phase extraction of trace aflatoxins in cereal crops coupled with high performance liquid chromatography. AB - Graphene oxide wrapped silica nanocomposites were synthesized and selected as solid phase extraction adsorbents for high performance liquid chromatography analysis of aflatoxins. The major parameters affecting extraction efficiency were optimized, including the amount of adsorbents, extraction time and desorption conditions. The limit of detections and the limit of quantifications were from 0.1 to 0.3 ug/kg and from 0.3 to 1.0 ug/kg, respectively. The recoveries of aflatoxins in the spiked maize and rice samples were in the range of 76.8-104.7% and 81.1-106.9%, respectively, and with the RSDs less than 12.4%. The proposed method was proven to be simple, rapid and reliable for routine analysis of aflatoxins in crops. PMID- 29287318 TI - How ingredients influence furan and aroma generation in sponge cake. AB - A wide range of compounds can be formed during thermal processing of food, some of which are relevant for aroma (e.g., furfural), while others are of great health concern (e.g., furan). This paper presents the study of formulation as affecting the simultaneous generation of furan and furfural, along with other aroma quality markers, in sponge cake by means of headspace trap/GC-MS. Ingredients were screened according to their category (fat, salt, sugar, egg based). Glucose-containing formulation resulted in the highest content of furan and furfural (12.5 +/- 0.5 ng g-1 and 9.2 +/- 0.2 MUg g-1, dry basis, respectively), while their lowest amount was found in the egg-white recipe (3.1 +/- 0.1 ng g-1 for furan and 0.287 +/- 0.078 ug g-1 for furfural, dry basis). The latter also related negatively to all studied compounds. This work will be useful for developing novel strategies to deliver safe foods with appealing organoleptic attributes. PMID- 29287319 TI - Exploiting 16S rRNA gene for the detection and quantification of fish as a potential allergenic food: A comparison of two real-time PCR approaches. AB - Fish is one of the most common allergenic foods that should be accurately labelled to protect the health of allergic consumers. In this work, two real-time PCR systems based on the EvaGreen dye and a TaqMan probe are proposed and compared. New primers were designed to target the 16S rRNA gene, as a universal maker for fish detection, with fully demonstrated specificity for a wide range of fish species. Both systems showed similar absolute sensitivities, down to 0.01 pg of fish DNA, and adequate real-time PCR performance parameters. The probe system showed higher relative sensitivity and dynamic range (0.0001-50%) than the EvaGreen (0.05-50%). They were both precise, but trueness was compromised at the highest tested level with the EvaGreen assay. Therefore, both systems were successful, although the probe one exhibited the best performance. Its application to verify labelling compliance of foodstuffs suggested a high level of mislabelling and/or fraudulent practices. PMID- 29287320 TI - Effect of ripening inhibitor type on formation, stability, and antimicrobial activity of thyme oil nanoemulsion. AB - The objective of this research was to study the impact of ripening inhibitor level and type on the formation, stability, and activity of antimicrobial thyme oil nanoemulsions formed by spontaneous emulsification. Oil-in-water antimicrobial nanoemulsions (10 wt%) were formed by titrating a mixture of essential oil, ripening inhibitor, and surfactant (Tween 80) into 5 mM sodium citrate buffer (pH 3.5). Stable nanoemulsions containing small droplets (d < 70 nm) were formed. The antimicrobial activity of the nanoemulsions decreased with increasing ripening inhibitor concentration which was attributed to a reduction in the amount of hydrophobic antimicrobial constituents transferred to the separated hydrophobic domain, mimicking bacterial cell membranes, by using dialysis and chromatography. The antimicrobial activity of the nanoemulsions also depended on the nature of the ripening inhibitor used: palm ~ corn > canola > coconut which also depended on their ability to transfer hydrophobic antimicrobial constituents to the separated hydrophobic domain. PMID- 29287321 TI - Visualization of DNA in highly processed botanical materials. AB - DNA-based methods have been gaining recognition as a tool for botanical authentication in herbal medicine; however, their application in processed botanical materials is challenging due to the low quality and quantity of DNA left after extensive manufacturing processes. The low amount of DNA recovered from processed materials, especially extracts, is "invisible" by current technology, which has casted doubt on the presence of amplifiable botanical DNA. A method using adapter-ligation and PCR amplification was successfully applied to visualize the "invisible" DNA in botanical extracts. The size of the "invisible" DNA fragments in botanical extracts was around 20-220 bp compared to fragments of around 600 bp for the more easily visualized DNA in botanical powders. This technique is the first to allow characterization and visualization of small fragments of DNA in processed botanical materials and will provide key information to guide the development of appropriate DNA-based botanical authentication methods in the future. PMID- 29287322 TI - Mid infrared spectroscopy and chemometrics as tools for the classification of roasted coffees by cup quality. AB - Sensory (cup) analysis is a reliable methodology for green coffee quality evaluation, but faces barriers when applied to commercial roasted coffees due to lack of information on roasting conditions. The aim of this study was to examine the potential of mid-infrared spectroscopy for predicting cup quality of arabica coffees of different roasting degrees. PCA analysis showed separation of arabica and robusta. A two-level PLS-DA Hierarchical strategy was employed, with coffee being classified as high or low quality in the first level and then separated according to cup quality in the second level. Validation results showed that the second level models exhibited 100% sensitivity and specificity in the training sets. For the test set, sensitivity ranged from 67% (rio zona) to 100% (soft) while specificity ranged from 71% (rio) to 100% (rioysh, hard). Thus, the proposed method can be used for the quality evaluation of arabica coffees regardless of roasting conditions. PMID- 29287323 TI - Propyl gallate/cyclodextrin supramolecular complexes with enhanced solubility and radical scavenging capacity. AB - This study prepared and investigated the inclusion complexes of propyl gallate (PG) with beta-cyclodextrin (beta-CD) and its water-soluble derivatives dimethyl beta-cyclodextrin (DM-beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and sulfobutylether-beta-cyclodextrin (SBE-beta-CD). Phase solubility studies indicated that the formed complexes were in 1:1 stoichiometry. FT-IR, PXRD, DSC, 1H-NMR, ROESY-NMR, and SEM analysis results confirmed the formation of the complexes. The NMR results indicated that the aromatic ring of PG was embedded into the CD cavity. The aqueous solubility of PG was markedly improved, and that of the PG/DM-beta-CD complex increased by 365.3 times. In addition, the results of the antioxidant activity assay showed that the hydroxyl radical and superoxide radical scavenging capacities of the complexes increased by 3-11 times and 1-6.5 times, respectively, compared with those of PG under the same concentration. Therefore, CD/PG inclusion complexes with improved solubility and radical scavenging capacity can be used as water-soluble antioxidants in the food industry. PMID- 29287324 TI - Development and characterization of an alpha-l-rhamnosidase mutant with improved thermostability and a higher efficiency for debittering orange juice. AB - The glycoside hydrolase, alpha-l-rhamnosidase, could remove the bitter taste of naringin from citrus juices. However, most alpha-l-rhamnosidases are easily deactivated at high temperatures, limiting the practice in debittering citrus juices. The V529A mutant of the alpha-l-rhamnosidase r-Rha1 from Aspergillus niger JMU-TS528 was developed with improved thermostability using directed evolution technology and site-directed mutagenesis. The enzyme mutant had a half live of thermal inactivation T(1/2) of 1.92 h, 25.00 min, and 2 min at 60, 65, and 70 degrees C, respectively. In addition, it had improved substrate affinity and better resistance to the inhibition of glucose. The improved substrate affinity was related to its lowered binding energy. Most significantly, the naringin content was reduced to below the bitter taste threshold by treatment with 75 U/mL of the mutant during the preheating process of orange juice production. The comprehensive results indicate that thermostability improvement could promote the practical value of alpha-l-rhamnosidase in citrus juice processing. PMID- 29287325 TI - Altering the physico-chemical and processing characteristics of high heat-treated skim milk by increasing the pH prior to heating and restoring after heating. AB - Skim milk was pH-adjusted from 6.6 to 7.5, high heat treated (HHT, 95 degrees C * 2 min) or held unheated for 1 h, re-adjusted to pH 6.6, and analysed. HHT at pH 6.6 resulted in denaturation of ~ 67% of total whey protein, partial association of denatured whey protein with the casein micelle, an increase in casein micelle size, and reductions in concentrations of serum casein, Ca and P. These changes were paralleled by a marked deterioration in rennet coagulability, higher ethanol stability in the pH range of 6.2-6.6 (P < .05), and a reduction in the pH of maximum heat coagulation time (HCT) (P < .05). Increasing the pH before heat treatment led to increases in casein dissociation and the concentrations of kappa casein and denatured whey protein in the serum, and a reduction in casein micelle size (P < .05). Simultaneously, HCT at pH 6.6-6.7 and 7.2 increased significantly. PMID- 29287326 TI - Aroma profile design of wine spirits: Multi-objective optimization using response surface methodology. AB - Developing new distillation strategies can help the spirits industry to improve quality, safety and process efficiency. Batch stills equipped with a packed column and an internal partial condenser are an innovative experimental system, allowing a fast and flexible management of the rectification. In this study, the impact of four factors (heart-cut volume, head-cut volume, pH and cooling flow rate of the internal partial condenser during the head-cut fraction) on 18 major volatile compounds of Muscat spirits was optimized using response surface methodology and desirability function approaches. Results have shown that high rectification at the beginning of the heart-cut enhances the overall positive aroma compounds of the product, reducing off-flavor compounds. In contrast, optimum levels of heart-cut volume, head-cut volume and pH factors varied depending on the process goal. Finally, three optimal operational conditions (head off-flavors reduction, flowery terpenic enhancement and fruity ester enhancement) were evaluated by chemical and sensory analysis. PMID- 29287327 TI - Study of the combined effects of ripeness and production area on Bosana oil's quality. AB - The effects of olive ripeness, areas of production and their interaction on the chemical and sensory characteristics of cv. Bosana oil were assessed. The study was carried out in three areas of the Sassari province, Sardinia (Italy), at three stages of maturation. The results indicated the independence of the two factors: ripeness influenced saturated fatty acids, pigment content and deacetoxy oleuropein aglycone (DAOA) content and didn't affect the sensory characteristics, while production area influenced unsaturated fatty acids, content of vanillic acid and some sensory characters. In order to verify the interdependency of the two factors, statistical analyses (two-way ANOVA) were performed. Our study showed that a thoughtful planning of harvest times and production area could allow to obtain Bosana virgin olive oil of the highest quality. Furthermore, utilizing cultivars that maintain the properties of their oils even at late dates of harvest, it would be possible to optimize harvest times. PMID- 29287328 TI - Effects of low sulfur dioxide concentrations on bioactive compounds and antioxidant properties of Aglianico red wine. AB - This study analyzed the effect of low sulfur dioxide concentrations on the chromatic properties, phytochemical composition and antioxidant activity of Aglianico red wines with respect to wines produced from conventional winemaking. We determined the phytochemical composition by spectrophotometric methods and HPLC-DAD analysis and the in vitro antioxidant activity of different wine samples by the ORAC assay. The main important classes of fluorophore molecules in red wine were identified by Front-Face fluorescence spectroscopy, and the emission intensity trend was investigated at various sulfur dioxide concentrations. Lastly, we tested the effects of both conventional and low sulfite wines on ex vivo human erythrocytes under oxidative stimulus by the cellular antioxidant activity (CAA) assay and the hemolysis test. The addition of sulfur dioxide, which has well-known side effects, increased the content of certain bioactive components but did not raise the erythrocyte antioxidant capacity. PMID- 29287329 TI - Polysaccharides from bamboo shoots processing by-products: New insight into extraction and characterization. AB - In this study, an efficient accelerated solvent extraction (ASE) technology was applied for rapid extraction of polysaccharides from the processing by-products of Chimonobambusa quadrangularis (CPS). The extraction yields, physicochemical characterization, and antioxidant activities of CPS obtained by ASE and hot water extraction (HWE) were further compared. A maximal ASE-CPS yield was obtained by optimized extraction conditions (temperature 126 degrees C, 2 cycles, and 22 min) using response surface methodology. The yield of polysaccharides from ASE (9.96% +/- 0.39%) was significantly higher than that from HWE (7.16% +/- 0.32%). Differences were found between ASE and HWE with the chemical composition, molecular weight distribution, rheological property, and antioxidant activities of the obtained polysaccharides, while the primary structure remained the same. ASE-CPS exhibited better chemical antioxidant activities in oxygen radical absorbance capacity (ORAC), reducing power, and DPPH and hydroxyl radical scavenging ability, whereas HWE-CPS displayed higher activity in metal chelating activity assay. PMID- 29287330 TI - Detection of counterfeit brand spirits using 1H NMR fingerprints in comparison to sensory analysis. AB - Beverage fraud involving counterfeiting of brand spirits is an increasing problem not only due to deception of the consumer but also because it poses health risks e.g. from possible methanol admixture. Suspicious spirit samples from Russia and Kenya were analysed using 1H nuclear magnetic resonance (NMR) spectroscopy in comparison to authentic products. Using linear regression analysis of spectral integral values, 4 counterfeited samples from Russia and 2 from Kenya were easily identifiable with R2 < 0.7. Sensory analysis using triangle test methodology confirmed significant taste differences between counterfeited and authentic samples but the assessors were unable to correctly identify the counterfeited product in the majority of cases. An important conclusion is that consumers cannot assumed to be self-responsible when consuming counterfeit alcohol because there is no general ability to organoleptically detect counterfeit alcohol. PMID- 29287332 TI - Effect of gamma radiation on sugars and vitamin C: Radiolytic pathways. AB - The radiolytic decomposition of glucose, fructose, sucrose, ascorbic acid (H2A) and dehydroascorbic acid (DHAA), induced by ionizing radiation, was investigated. Aqueous solutions of these compounds were gamma-irradiated at doses of 0.5, 0.7 and 1 kGy, with a dose rate of 0.04 kGy/min, in the presence of air, followed by HPLC, HPLC-MS, EPR, and UV-VIS spectroscopy analysis of the resulting mixtures. Carboxylic acids, 2-furaldehyde, 5-hydroxymethyl-2-furaldehyde, furfuryl alcohol, 2-furoic acid and 2(5H)-furanone were identified in solutions of sugars and vitamin C, by comparing with standards. EPR studies exhibited a higher amount of free radicals for fructose than the other sugars, and more for DHAA than H2A. Additionally, spectroscopic determinations showed a typical UV-VIS absorption for furans during the storage of irradiated solutions. Formation and decomposition routes for furanoids and aliphatic carboxylic acids, and mechanistic pathways for the radiolytic induced rupture of glucose, fructose, sucrose and vitamin C have been proposed. PMID- 29287331 TI - Purification, structural characterization, and hypolipidemic effects of a neutral polysaccharide from Ziziphus Jujuba cv. Muzao. AB - A neutral polysaccharide (PZMP1) with a molecular weight of 16.97 kDa was isolated from Ziziphus Jujuba cv. Muzao with water extraction, ethanol precipitation, and purification with DEAE-Sepharose Fast Flow and Sephacryl S-300 column chromatography. PZMP1 was structurally characterized with high-performance gel-permeation chromatography, gas chromatography, Fourier transform infrared spectroscopy, methylation analysis, NMR spectroscopy, X-ray diffraction, scanning electron microscopy, and atomic force microscopy. The results show that PZMP1 is a homogeneous heteropolysaccharide composed of arabinose, galactose, glucose, mannose, and xylose in a molar percentage of 17.36: 3.29:2.68:1.05:1.00. The majorly backbone of PZMP1 is composed of 1,3,5-linked Araf, 1,3-linked Araf, 1,5 linked Araf, 1,4-linked Glcp, and 1-linked Araf, 1-linked Glcp. According to an NMR analysis, the repeating unit of PZMP1 is a linear backbone with branches at positions O-3, and O-5. PZMP1 also displays effective dose-dependent hypolipidemic activity, suggesting that it is a natural hypolipidemic agent, which could contribute to the functional food qualities of jujube fruit. PMID- 29287333 TI - Methoxypyrazines biosynthesis and metabolism in grape: A review. AB - This review summarizes research on the discovery, biosynthesis, accumulation, transport, and metabolism of 3-alkyl-2-methoxypyrazines (MPs) in grape. The MPs are a family of potent volatile compounds distributed throughout biological kingdoms. These compounds impart herbaceous/green/vegetal sensory attributes to certain varieties of wine. Generally, high levels of MPs in wine are derived mainly from the corresponding grapes. Although two pathways for MPs biosynthesis have been proposed, only the final step and the enzymes that catalyze it has been confirmed in grape, and the metabolic intermediates and key enzymes involved in other steps are still unknown. The limited understanding of MPs metabolism has restricted research on these compounds, and some empirical results cannot be explained by the current knowledge of MPs metabolism. This review provides insights into research on MPs biosynthesis and metabolism, and proposes directions for further research on this important class of flavour/odour compounds. PMID- 29287334 TI - Can lycopene be considered an effective protection against cardiovascular disease? AB - Lycopene is a bioactive component mainly found in tomato. It is characterized by a high antioxidant potential, the highest among carotenoids. Mainly due to this property, lycopene has been suggested to display many beneficial effects, including its potential cardioprotective role. Despite some contradictory observations, which appear to be mainly caused by discrepancies in the different experimental protocols applied in the different studies, growing evidence points to clear benefits of lycopene in the maintenance of cardiovascular function and health. The knowledge about lycopene's preventive effects in atherosclerosis, and other cardiovascular diseases, must be translated into changes in food patterns, aiming to increase the consumption of tomato, tomato-containing products, or other foods with high lycopene content, which can have an important impact on cardiovascular disease, particularly in countries where this represents a major public health concern. PMID- 29287335 TI - Interaction mechanisms of condensed tannins (proanthocyanidins) with wheat gluten proteins. AB - Proanthocyanidins (PA) crosslink wheat gluten, increasing its polymer size and strength. However, mechanisms behind these interactions are unknown. This study used PA of different MW profiles (mean degree of polymerization 8.3 and 19.5) to investigate how PA polymerize gluten. The higher MW PA had greater binding affinity for both glutenins and gliadins than lower MW PA, whereas both PA precipitated glutenins more efficiently than gliadins. The PA preferentially bound the largest of the protein fractions available: high MW glutenin subunits (HMW-GS) over low MW-GS, and omega-gliadins over alpha- and gamma-gliadins. Furthermore, within the HMW-GS, PA bound more of the larger x-type than the smaller y-type. Proanthocyanidins reduced gluten solubility in urea and decreased surface hydrophobicity of glutenins, but not gliadins. The PA appear to preferentially crosslink HMW-GS via hydrophobic interactions and hydrogen bonding, whereas their interaction with gliadins is dominated by hydrogen bonding and is relatively weaker. PMID- 29287336 TI - Toxic metal levels in cocoa powder and chocolate by ICP-MS method after microwave assisted digestion. AB - The Commission Regulation (EC) Regulation N. 488/2014, established the concentration limits for cadmium in specific products based on cocoa and chocolate products as from January 2019. Based on this information there is a need to determine ultratrace levels of elements that might be presents in cocoa and chocolate products. In this work, the concentrations of Arsenic, Antimony, Cadmium, Chromium, Lead, Selenium and Vanadium were evaluated in cocoa powder and chocolate by the validation of an ICP-MS method. Good selectivity/specificity, recovery, repeatability and within-laboratory reproducibility, LOD, LOQ, range of linearity, standard measurement uncertainty parameters for method validation were achieved, in accordance with Commission Regulation. The cocoa powder revealed the maximum metal concentrations of 0.303 +/- 0.035 mg/kg for cadmium, 1.228 +/- 0.146 mg/kg for lead and 0.094 +/- 0.013 mg/kg for arsenic. A significant difference was found between cocoa powder and chocolate samples (p < .05). PMID- 29287337 TI - Purification and characterization of a protease from the visceral mass of Mytella charruana and its evaluation to obtain antimicrobial peptides. AB - This work describes purification of a protease from the visceral mass of the mussel Mytella charruana as well as evaluation of its ability to hydrolyze milk casein to generate antimicrobial peptides. The enzyme showed pI of 4.1 and a single polypeptide band of 83.1 kDa after SDS-PAGE. Sequence similarities with tropomyosin and myosin from mollusks were detected. The protease showed a trypsin like activity with optimal temperature of 40 degrees C and stability in a wide pH range (3.0-9.0). Km was 4.28 +/- 0.34 mM of the synthetic substrate N-benzoyl dl-arginyl-rho-nitroanilide, whereas Vmax was 0.056 +/- 0.001 nmol min-1. The enzyme hydrolyzed casein, and the hydrolysate inhibited the growth of Escherichia coli, Micrococcus luteus, Bacillus subtilis, and Klebsiella pneumoniae at a minimal inhibitory concentration of 5.0 ug mL-1. In conclusion, the visceral mass of M. charruana contains a trypsin-like protease that can generate peptides from casein that have a bacteriostatic effect. PMID- 29287339 TI - Inter-laboratory validation of the starch digestibility method for determination of rapidly digestible and slowly digestible starch. AB - The digestibility of starch in foods, which is influenced by the ingredients, formulation and preparation conditions, is a major determinant of glycaemic response. The terms rapidly digestible starch (RDS) and slowly digestible starch (SDS) along with the associated analytical methodology were developed by Englyst to characterise this nutritionally relevant food attribute. The measurement uncertainty of this starch digestibility method is evaluated here with an inter laboratory trial. Six laboratories took part in the study testing ten cereal products with mean (range) contents of RDS: 48.4 g/100 g, (23.4-76.9) and, SDS: 10.9 g/100 g, (0.8-24.2). Based on the repeatability and reproducibility measurements, the calculated uncertainty was 3.6 g/100 g for RDS and 1.9 g/100 g for SDS. This trial has demonstrated acceptable measurement uncertainty and confirmed the transferability of the method between laboratories. The SDS content can identify foods rich in slow release carbohydrates with their associated health benefits. PMID- 29287338 TI - Modification-free carbon dots as turn-on fluorescence probe for detection of organophosphorus pesticides. AB - It is important to detect pesticides residues due to the concern over food safety. In this work, the burning ash of waste paper was used as carbon source to synthesize carbon dots (C-dots). The fluorescence of obtained C-dots could been turn off by Fe3+ which was from Fe2+ oxidized by H2O2, organophosphorus pesticides could effectively inhibit the production of H2O2 by destroying the acetylcholinesterase activity, so the fluorescence of C-dots hold turning on in the presence of organophosphorus pesticides. Based on above principle that the fluorescence intensity of C-dots was proportional to the pesticides concentration, take chlorpyrifos for example, a universal method for pesticides detection was established. The linear range was 0.01-1.0 MUg/mL with detection limit of 3 ng/mL. The method was reliable and sensitive to actual samples. The imaging of chlorpyrifos on cabbages leaves indicated this method could be used for visualization detection of organophosphorus pesticides in vegetables. PMID- 29287340 TI - Residue behavior of organochlorine pesticides during the production process of yogurt and cheese. AB - The presence of organochlorine pesticides (OCPs) in dairy products can lead to human exposure. This study investigated the behavior of OCP residues in milk during yogurt and cheese production. Gas chromatography with electron-capture detection (GC-ECD) was used to detect alpha-hexachlorocyclohexane (HCH), hexachlorobenzene (HCB), gamma-HCH, g-chlordane, and alpha-chlordane in fresh milk, yogurt, and cheese. The results showed that fermentation reduced the residual concentration of OCPs in yogurt, with processing factors (PFs) ranging from 0.42 to 0.64. The reductions in residue levels during fermentation were due to the activity of the starter. The cheese making process increased the residual concentration of OCPs in cheese compared to raw milk, with PFs ranging from 2.37 to 4.93. Additionally, milk, yogurt, and cheese samples were purchased from local markets and OCP levels were analyzed. The target OCPs ranged from ND to 16.50 MUg/kg in these samples. PMID- 29287341 TI - Extraction of acetanilides in rice using ionic liquid-based matrix solid phase dispersion-solvent flotation. AB - Ionic liquid-based matrix solid phase dispersion-solvent flotation coupled with high performance liquid chromatography was developed for the determination of the acetanilide herbicides, including metazachlor, propanil, alachlor, propisochlor, pretilachlor, and butachlor in rice samples. Some experimental parameters, including the type of dispersant, the mass ratio of dispersant to sample, pH of sample solution, the type of extraction solvent, the type of ionic liquid, flotation time, and flow rate of N2 were optimized. The average recoveries of the acetanilide herbicides at spiked concentrations of 50, 125, and 250 ug/kg ranged from 89.4% to 108.7%, and relative standard deviations were equal to or lower than 7.1%, the limits of quantification were in the range of 38.0 to 84.7 ug/kg. PMID- 29287342 TI - Inhibitory effects of edible seaweeds, polyphenolics and alginates on the activities of porcine pancreatic alpha-amylase. AB - Edible seaweeds are valuable because of their organoleptic properties and complex polysaccharide content. A study was conducted to investigate the potential of dried edible seaweed extracts, its potential phenolic compounds and alginates for alpha-amylase inhibitory effects. The kinetics of inhibition was assessed in comparison with acarbose. The methanol extract of Laminaria digitata and the acetone extract of Undaria pinnatifida showed inhibitory activity against alpha amylase, IC50 0.74 +/- 0.02 mg/ml and 0.81 +/- 0.03 mg/ml, respectively; both showed mixed-type inhibition. Phenolic compound, 2,5-dihydroxybenzoic acid was found to be a potent inhibitor of alpha-amylase with an IC50 value of 0.046 +/- 0.004 mg/ml. Alginates found in brown seaweeds appeared to be potent inhibitors of alpha-amylase activity with an IC50 of (0.075 +/- 0.010-0.103 +/- 0.017) mg/ml, also a mixed-type inhibition. Overall, the findings provide information that crude extracts of brown edible seaweeds, phenolic compounds and alginates are potent alpha-amylase inhibitors, thereby potentially retarding glucose liberation from starches and alleviation of postprandial hyperglycaemia. PMID- 29287343 TI - Characterization of industrial broccoli discards (Brassica oleracea var. italica) for their glucosinolate, polyphenol and flavonoid contents using UPLC MS/MS and spectrophotometric methods. AB - The agrifood industry produces tons of waste and substandard products that are discarded at great expense. Valorization of industrial residues curbs issues related to food security and environmental problems. Broccoli (Brassica oleracea var. italica) is associated with varied beneficial health effects, but its production yields greater than 25% rejects. We aimed to characterize and quantify industrial broccoli by-products for their glucosinolate and polyphenol contents as a first step towards industrial bio-refining. Broccoli segments and rejected lots of 10 seed cultivars were analyzed using UPLC MS/MS. Variability in the contents of bioactive molecules was observed within and between the cultivars. Broccoli by-products were rich in glucosinolates (0.2-2% dry weight sample), predominantly glucoraphanin (32-64% of the total glucosinolates), whereas the polyphenolic content was less than 0.02% dry weight sample. Valorization of industrial residues facilitates the production of high value functional food ingredients along with socio-economic sustainability. PMID- 29287344 TI - High pressure effects on myrosinase activity and glucosinolate preservation in seedlings of Brussels sprouts. AB - Combinations of pressure, temperature and time (100-600 MPa, 30-60 degrees C, 3 10 min) influence enzyme activity of the myrosinase-glucosinolate system. Seedlings of Brussels sprouts were used as a model, which constitutes a well defined and homogenous sample matrix with simple cell structures. A response surface methodology approach was used to determine the combined effect of pressure level, temperature and time on glucosinolate concentration and myrosinase activity in Brussels sprouts seedlings. The effects on residual myrosinase activity and intact glucosinolate concentration differed according to combinations of pressure, time and temperature. The results showed that maximum inactivation of myrosinase and preservation of glucosinolate (85% of the untreated level) was obtained after HP treatment at 600 MPa, 60 degrees C, 10 min. The highest preservation of myrosinase activity compared to untreated seedlings was after HP at 100 MPa, 30 degrees C, 3 min and 10 min with low degree of cell permeabilization. PMID- 29287345 TI - Mass spectrometric imaging of localization of fat molecules in water-in-oil emulsions containing semi-solid fat. AB - Firstly, we report the localization analysis of the lipid components of a water in-oil (W/O) semi-solid emulsion by mass spectrometry imaging (MSI). Uniform emulsion droplets were prepared using microchannel emulsification devices with lecithin, stearic acid-binding monoglyceride (St-MAG), and polyglycerol polyricinoleate (PGPR) as emulsifiers. The mass image gives us the localization of phosphatidylcholine (PC) in lecithin, St-MAG, tripalmitin (PPP), medium-chain triglyceride (MCT), and high-melting-point triglyceride tristearin (C18-TAG). PC, St-MAG, and PPP were localized at the interface with the dispersed water droplets. PC and PPP took the same localized position, suggesting an interaction between PC and PPP at the interface. Conversely, PC existed in other regions with St-MAG. MSI revealed multiple target molecules in fat products in a single measurement, and it is expected to reveal fat crystallization at the emulsion interfaces, which will clarify the mechanisms related to the physical properties of high-fat products such as fat spread and butter. PMID- 29287346 TI - Development of a quantitative approach using Raman spectroscopy for carotenoids determination in processed sweet potato. AB - The orange-fleshed sweet potato is a vegetable-rich in carotenoids. The thermic treatment for sweet potato processing can decrease the content of these constituents in the foods, lowering their bioactive properties. Raman spectroscopy has been growing as a fast tool to food analysis, especially for detection of low concentrations of carotenoids and to the monitoring of its degradation profile over time. Therefore, in this work were evaluated two methods of drying, hot air and microwaving with rotary drum, combined with quantitative Raman spectroscopy. The results showed carotenoids degradation around 50% for both types of drying processes studied. PCA plot proved the potential of reproducibility of analyses for microwave drying samples. For samples heated with hot air, the best linear correlation achieved was R2 = 0.90 and by microwave was R2 = 0.88. Also, partial least squares (PLS) regression models were constructed obtaining a satisfactory coefficient of determination. PMID- 29287347 TI - Quinolones and tetracyclines in aquaculture fish by a simple and rapid LC-MS/MS method. AB - The determination of antimicrobials in aquaculture fish is important to ensure food safety. Therefore, simple and fast multiresidue methods are needed. A liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of 14 antimicrobials (quinolones and tetracyclines) in fish. Antimicrobials were extracted with trichloroacetic acid and chromatographic separation was achieved with a C18 column and gradient elution (water and acetonitrile). The method was validated (Decision 2002/657/EC) and it was fit for the purpose. Linearities were established in the matrix and the coefficients of determination were >=0.98. The method was applied to Nile tilapia and rainbow trout (n = 29) and 14% of them contained enrofloxacin at levels above the limit of quantification (12.53-19.01 ug.kg-1) but below the maximum residue limit (100 ug.kg-1). Even though prohibited in Brazil and other countries, this antimicrobial reached fish. Measures are needed to ascertain the source of this compound to warrant human safety. PMID- 29287348 TI - Evaluation of nutritional and chemical composition of yacon syrup using 1H NMR and UPLC-ESI-Q-TOF-MSE. AB - A complete characterization of yacon syrup was performed by analytical techniques, including NMR and UPLC-QTOF-MSE. The effect of the different stages of yacon syrup production on fructooligosaccharides (FOS) and chlorogenic acid (CGA) contents were also evaluated. As a result, in addition to higher levels of FOS and CGA, some mineral elements, such as K, Ca and P, and essential amino acids, such as tryptophan, valine, and threonine, were determined in yacon syrup. Twenty-five compounds were putatively identified, and the main compounds were phenolics derived from quinic and trans-cinnamic acids. Considering the different stages of yacon syrup production, the results indicate that the contents of FOS and CGA were maintained in the pulping, enzymatic maceration and microfiltration, leading to a concentration of these components in the last stage of processing (vacuum concentration). These results will be used to fortify this innovative and promising product in the area of functional foods. PMID- 29287350 TI - Simultaneous determination of heat stable peptides for eight animal and plant species in meat products using UPLC-MS/MS method. AB - Food adulteration and fraud is driven by economic interests; it is thus necessary to establish a high-through method that allows quantitative identification of familiar animal and plant proteins for global use. In this study, a sensitive mass spectrometric approach for the detection of eight species, including pork, beef, lamb, chicken, duck, soy, peanut, and pea, is presented and the heat stability and specificity of screened peptides are verified. To improve screening efficiency of specific peptides, several key data searching parameters, including peptides, sequence lengths, sequence coverage, and unique peptides, are investigated. Using this approach, it is possible to detect a 0.5% contamination of any of the eight species. The method is proven to have high sensitivity, specificity, repeatability, and a low quantitative detection limit with respect to adulteration of diverse types of meat products. PMID- 29287349 TI - Aroma modulation of Cabernet Gernischt dry red wine by optimal enzyme treatment strategy in winemaking. AB - Cabernet Gernischt (CG) is a famous Chinese wine grape cultivar, the red wine of which is known for its green trait, especially when produced from grapes cultivated in regions with monsoon climate. To modify CG wine aroma, three enzyme preparations (H. uvarum extracellular enzyme, AR2000, and pectinase) were introduced in different winemaking stages with Saccharomyces cerevisiae. Free and bound aroma compounds in young wines were detected using headspace solid-phase micro-extraction and gas chromatography-mass spectrometry, and aroma characteristics were quantified by trained panelists. Results showed that simultaneous inoculation of enzymes and yeasts improved wine aroma. Partial least squares regression revealed that the green trait was due mainly to varietal compounds, especially C6 compounds, and could be partly weakened by fermentative compounds. Moreover, H. uvarum enzyme treatments enriched the acid fruit note of CG wine by enhancing the synergistic effect of varietal volatiles and certain fermentative compounds, such as esters and phenylethyls. PMID- 29287351 TI - Fe(III) conjugated fluorescent organic nanoparticles for ratiometric detection of tyramine in aqueous medium: A novel method to determine food quality. AB - A tetrapodal receptor was synthesized and was processed into fluorescent organic nanoparticles (FONs) for determination of important analytes in aqueous medium. The receptor was fully characterized using characterization techniques. Recognition behavior of FONs towards different metal ions was investigated with fluorescence spectroscopy, amongst them Fe3+ ions showed quenching behavior in the emission spectra. The Fe3+ ion complex of FONs based sensor was further tested with different biogenic amines and ratiometric response was obtained for tyramine. Fluorescence emission profile of FONs. Fe3+ ion complex showed no change in the pH in wide range; thereby increasing their utility in biological and environmental samples. Tyramine detection was linearly proportional in response with the detection limit of 377 nM. PMID- 29287352 TI - Antioxidant properties of tyrosol and hydroxytyrosol saturated fatty acid esters. PMID- 29287353 TI - Characterisation of the mucilage polysaccharides from Dioscorea opposita Thunb. with enzymatic hydrolysis. AB - The mucilage polysaccharides from Dioscorea opposita (DOMP) were extracted and treated with a single/dual enzymatic hydrolysis. The characterisation and viscosity were subsequently investigated in this study. DOMP obtained 62.52% mannose and 23.45% glucose. After single protease and trichloroacetic acid (TCA) treatments, the mannose content was significantly reduced to 3.96%, and glucose increased from 23.45% to 45.10%. Dual enzymatic hydrolysis also decreased the mannose and glucose contents to approximately 18%-35% and 7%-19%, respectively. The results suggest that enzymatic degradation could effectively remove the protein from DOMP accompanied by certain polysaccharides, especially mannose. The molecular weight, surface morphology, viscosity and particle sizes were measured. Enzymatic hydrolysis reduced molecular weight, decreased the viscosity, and increased the particle sizes, which indicates that the characterisations of DOMP samples were altered as structures changed. This study was a basic investigation into characterisation of DOMP to contribute to the processing of food by products. PMID- 29287354 TI - Prediction of banana color and firmness using a novel wavelengths selection method of hyperspectral imaging. AB - This study investigated the feasibility of using hyperspectral imaging for determining banana color (L*, a* and b*) and firmness as well as classifying ripe and unripe samples. The hyperspectral images at wavelengths 380-1023nm were acquired. Partial least squares (PLS) models were built to predict color and firmness. Two-wavelength combination method lambdai lambdajlambdai+lambdaj,lambdai2 lambdaj2lambdai2+lambdaj2,lambdailambdajandlambdai-lambdaj was used to identify the effective wavelengths. Based on the selected wavelengths, PLS models obtained good results with the coefficient of determination in prediction (Rp2) of 0.795 for L*, 0.972 for a*, 0.773 for b* and 0.760 for firmness. The corresponding residual predictive deviation (RPD) values were 2.234, 6.098, 2.119 and 2.062, respectively. The classification results of ripe and unripe samples were excellent in two different principal components spaces (PC1+PC2 and PC1+PC3). It indicated hyperspectral imaging can be used to non-destructively determine banana color and firmness as well as classify ripe and unripe samples. PMID- 29287355 TI - Exploring a volatomic-based strategy for a fingerprinting approach of Vaccinium padifolium L. berries at different ripening stages. AB - The effect of ripening on the evolution of the volatomic pattern from endemic Vaccinium padifolium L. (Uveira) berries was investigated using headspace-solid phase microextraction (HS-SPME) followed by gas chromatography/quadrupole-mass spectrometry (GC-qMS) and multivariate statistical analysis (MVA). The most significant HS-SPME parameters, namely fibre polymer, ionic strength and extraction time, were optimized in order to improve extraction efficiency. Under optimal experimental conditions (DVB/CAR/PDMS fibre coating, 40 degrees C, 30min extraction time and 5g of sample amount), a total of 72 volatiles of different functionalities were isolated and identified. Terpenes followed by higher alcohols and esters were the predominant classes in the ripening stages - green, break and ripe. Although significant differences in the volatomic profiles at the three stages were obtained, cis-beta-ocimene (2.0-40.0%), trans-2-hexenol (2.4 19.4%), cis-3-hexenol (2.5.16.4%), beta-myrcene (1.9-13.8%), 1-hexanol (1.7 13.6%), 2-hexenal (0.7-8.0%), 2-heptanone (0.7-7.7%), and linalool (1.9-6.1%) were the main volatile compounds identified. Higher alcohols, carboxylic acids and ketones gradually increased during ripening, whereas monoterpenes significantly decreased. These trends were dominated by the higher alcohols (1 hexanol, cis-3-hexenol, trans-2-hexenol) and monoterpenes (beta-myrcene, cis-beta ocimene and trans-beta-ocimene). Partial least squares regression (PLSR) revealed that ethyl caprylate (1.000), trans-geraniol (0.995), ethyl isovalerate (-0.994) and benzyl carbinol (0.993) are the key variables that most contributed to the successful differentiation of Uveira berries according to ripening stage. To the best of our knowledge, no study has carried out on the volatomic composition of berries from endemic Uveira. PMID- 29287356 TI - Multifunctions of Pleurotus sajor-caju (Fr.) Singer: A highly nutritious food and a source for bioactive compounds. AB - A study with Pleurotus sajor-caju was conducted to: evaluate the nutritional and chemical composition of the fruiting bodies; optimize the preparation of bioactive phenolic extracts; and characterize the optimized extract in terms of bioactive compounds and properties. P. sajor-caju revealed an equilibrated nutritional composition with the presence of hydrophilic (sugars and organic acids) and lipophilic (tocopherols and PUFA) compounds. p-Hydroxybenzoic, p coumaric and cinnamic acids were identified in the extract obtained with ethanol (30g/l ratio) at 55 degrees C for 85min. This extract showed antioxidant properties (mainly reducing power and lipid peroxidation inhibition), antibacterial activity against MRSA and MSSA and cytotoxicity against NCI-H460, MCF-7 and HeLa. Furthermore, as the extract showed capacity to inhibit NO production in Raw 264.7 macrophages, molecular docking studies were performed to provide insights into the anti-inflammatory mechanism of action, through COX-2 inhibition by the phenolic acids identified. PMID- 29287357 TI - Simultaneous LC-MS/MS determination of 40 legal and illegal psychoactive drugs in breast and bovine milk. AB - This work presents a fast, sensitive and reliable multi-residue methodology based on fat and protein precipitation and liquid chromatography-tandem mass spectrometry for the determination of common legal and illegal psychoactive drugs, and major metabolites, in breast milk. One-fourth of the 40 target analytes is investigated for the first time in this biological matrix. The method was validated in breast milk and also in various types of bovine milk, as tranquilizers are occasionally administered to food-producing animals. Absolute recoveries were satisfactory for 75% of the target analytes. The use of isotopically labeled compounds assisted in correcting analyte losses due to ionization suppression matrix effects (higher in whole milk than in the other investigated milk matrices) and ensured the reliability of the results. Average method limits of quantification ranged between 0.4 and 6.8 ng/mL. Application of the developed method showed the presence of caffeine in breast milk samples (12 179 ng/mL). PMID- 29287358 TI - Process optimization for the preparation of antioxidant rich ginger candy using beetroot pomace extract. AB - Now-a-days, there is an increased interest in fruits and vegetables processing by products due to potential source of phytochemicals and pigments. Beetroot (Beta vulgaris) pomace extract is a rich source of betalain, phenolics and other bioactive components, which possess significant antioxidant activities. In the present study, process optimization was performed for developing ginger (Zingiber officinale) candy enriched with beetroot pomace extract using response surface methodology (RSM). The effect of two process variables: blanching time (0-10 min) and beetroot pomace extract (0-10%) was evaluated on physicochemical characteristics and phytochemicals content of the developed product. Maximum phytochemicals' activities were obtained under optimum conditions of 7.81 min blanching time and 9.24% beetroot pomace extract. FTIR analysis also confirmed the significant effect of beetroot pomace extract and it's blanching on the phytochemical potential of ginger candy. The study would be useful for developing similar novel and antioxidants rich food products supplemented with beetroot pomace extract. PMID- 29287359 TI - Comparison of formation of visco-elastic masses and their properties between zeins and kafirins. AB - Zeins of differing sub-class composition much more readily formed visco-elastic masses in water or acetic acid solutions than equivalent kafirin preparations. Visco-elastic masses could be formed from both zein and kafirin preparations by coacervation from glacial acetic acid. Dissolving the prolamins in glacial acetic acid apparently enabled protonation and complete solvation. Stress-relaxation analysis of coacervated zein and kafirin visco-elastic masses showed they were initially soft. With storage, they became much firmer. Zein masses exhibited predominantly viscous flow properties, whereas kafirin masses were more elastic. The gamma-sub-class is apparently necessary for the retention of visco-elastic mass softness with kafirin and zein, and for elastic recovery of kafirin. Generally, regardless of water or acetic acid treatment, all the zein preparations had similar FTIR spectra, with greater alpha-helical conformation, than the kafirin preparations which were also similar to each other. Kafirin visco-elastic masses have a much higher elastic character than zein masses. PMID- 29287360 TI - Simple determination of aflatoxins in rice by ultra-high performance liquid chromatography coupled to chemical post-column derivatization and fluorescence detection. AB - A fast and simple analytical method was developed and characterized for the determination of aflatoxins (B1, B2, G1 and G2) in rice. The procedure is based on a simple solid-liquid extraction without further clean-up, and analysis by ultra-high performance liquid chromatography coupled with fluorescence detection. Fluorescence emission of aflatoxins B1 and G1 was enhanced by post-column chemical derivatization using pyridinium bromide perbromide. The analytical method was satisfactorily characterized in white and brown rice. Under optimum conditions, external calibration in solvent could be used for quantification purposes and limits of quantification were below the maximum contents established by the European Union regulation for these contaminants/commodity group combination (0.07-0.14 ug/kg for white rice and 0.20-0.28 ug/kg for brown rice). Recovery studies carried out at three different concentration levels (0.5, 2 and 5 ug/kg) showed values in the range of 84.5-105.3%, and RSDs <= 5%. PMID- 29287361 TI - Mitigation strategies for ester bound 2-/3-MCPD and esterified glycidol in pre fried breaded and frozen fish products. AB - Pre-frying of chloride-containing raw materials (e.g., breaded frozen fish products) can lead to the formation of fatty acid esters of 2-monochloropropane 1,3-diol, 3-monochloropropane-1,2-diol (MCPD-E), and glycidol (G-E). The aim of the present study was to identify relevant parameters for the formation of these process contaminants during the pre-frying. Secondly, several mitigation approaches have been investigated. The major proportion of the MCPD-E and G-E in the fish products resulted from the pre-frying oil absorbed, while the temperature and the heating period of the pre-frying oil showed the strongest impact. A significant reduction of the MCPD-E content in the pre-frying oil was achieved by filtering-off solid breading particles. Additionally, the G-E content decreased resulting from the use of adsorbent materials. Moreover, the analyses of total polar material and the color intensity of the pre-frying oil are suggested as screening methods for estimating the MCPD-E and G-E contents in the fish products. PMID- 29287362 TI - Immunomodulatory and anticancer protein hydrolysates (peptides) from food proteins: A review. AB - Bioactive peptides are oligopeptides that consist of 2-20 amino acids that can exert beneficial effects on human health in addition to basic nutritional effects. Food derived protein hydrolysates or peptides with immunomodulatory and anticancer activities have been reported from a variety of food protein sources such as milk, egg, fish, rice, soybean, pea, chlorella, spirulina, oyster and mussel. In vitro hydrolysis of food proteins using commercial proteolytic enzymes is the most commonly employed process for the production of immunomodulatory and anticancer food protein hydrolysates. The immunomodulatory and anticancer activities of food derived protein hydrolysates or peptides are related to the amino acid composition, sequence and length. Most immunomodulatory and anticancer food protein hydrolysates or peptides were tested using cell culture and animal models, while a few involved clinical trials. This review provides a comprehensive overview of immunomodulatory and anticancer food derived protein hydrolysates or peptides, their production and mechanisms of action. PMID- 29287363 TI - Whey acerola-flavoured drink submitted ohmic heating processing: Is there an optimal combination of the operational parameters? AB - Whey acerola-flavoured drink was treated using ohmic heating (OH) at 65 degrees C for 30min to evaluate different frequencies (10, 100 and 1000Hz with 25V) and voltages (45, 60 and 80V at 60Hz) and by conventional heating (CH) with the same temperature profile (65 degrees C/30min). Rheology parameters, color changes (h degrees , C*, DeltaE) microstructure (optical microscopy), and ascorbic acid (AA) degradation kinetics were performed. AA degradation rates ranged from 1.7 to 29.3% and from 2.8 to 24.8% for OH and CH, respectively. The beverages treated with both processes exhibited a pseudo-plastic behavior (n<1), higher saturation (C*), lesser reddish color (h degrees ), and higher color variations (DeltaE*). In microstructure analysis, OH (1000Hz-25V and 80V-60Hz) was able to rupture the cell structure. The best results were observed at low frequencies and voltage OH processes on whey acerola-flavoured drinks should be performed at low frequencies and voltages (<=100Hz and 45V), an alternating current (A/C). However, despite the use of inert electrodes, the existence of corrosion was not evaluated, being an important information to be investigated. PMID- 29287364 TI - Juice volatile composition differences between Valencia orange and its mutant Rohde Red Valencia are associated with carotenoid profile differences. AB - A targeted approach using HS-SPME-GC-MS was performed to investigate volatile compounds of ordinary Valencia (VAL) and its more deeply colored mutant Rohde Red Valencia orange (RRV) at different developmental stages. Fifty-six volatile components classified into six chemical groups were quantified. The individual volatile compounds in each group were significantly influenced by the genotype and harvest date. Cluster analysis suggested two principal clusters. Cluster I included fruits of VAL and RRV harvested in July, September, and November and was characterized by the 2-ethyl-1-hexanol acetate and linalool chemotype; cluster II included fruits harvested in January and March, with the valencene/beta-myrcene chemotype. Principal component analysis confirmed that fruits of both cultivars harvested at different dates possessed a unique aroma active profile, especially, the odor-active volatile-norisoprenoids degraded from C40 carotenoid were significantly higher in RRV than in VAL at full maturity. These results could provide information for further study of the flavor metabolism pathways in the two closely related cultivars. PMID- 29287365 TI - Dephosphorylation enhances postmortem degradation of myofibrillar proteins. AB - Protein degradation is primarily responsible for postmortem meat tenderization, which might be affected by phosphorylation. The objective of this study was to investigate the effect of phosphorylation on myofibrillar proteins degradation in muscle during postmortem. Here we modulated the phosphorylation status of protein by protein kinase inhibitor and phosphatase inhibitor, and the effect of these inhibitors on myofibrillar protein degradation was evaluated. Generally, myofibril fragmentation index of samples with lower phosphorylation level was higher. Troponin T and heat shock protein 27 were degraded faster in protein kinase inhibited (low phosphorylation level) muscle, compared with the other two groups, while the degradation of desmin was not affected by inhibitors. Meanwhile, myosin heavy chain, actin and tropomyosin showed limited degradation in postmortem muscle. This study showed that dephosphorylation enhances the degradation of some myofibrillar proteins, indicating that protein phosphorylation may play an important role in postmortem meat tenderization. PMID- 29287366 TI - Antioxidant-spotting in micelles and emulsions. AB - A simple protocol is described for locating the site of action of an antioxidant (AO) in a micro-heterogeneous mixture, based on the pattern of the reactivity curve towards the AO of a series of 4-alkanoyl TEMPO radicals. The resulting cut off curves yield information regarding the hydrophobic microenvironment surrounding the reactive AO group, and its accessibility by the probe. Convex curves are an indication of an AO located in a more hydrophilic environment, while concave plots originate from AOs in a more hydrophobic location in the micro-heterogeneous system. PMID- 29287367 TI - Enhanced nutraceutical potential of gamma irradiated black soybean extracts. AB - Radiation processing of soybean, varying in seed coat colour, was carried out at dose levels of 0.25, 0.5 and 1 kGy to evaluate their potential anti-proliferative and cytoprotective effects in an in vitro cell culture system. Irradiated and control black (Kalitur) and yellow (DS9712) soybean extracts were characterized in terms of total phenolics, flavonoids and anthocyanins, especially cyanidin-3 glucoside (C3G). Using an epithelial cell line, BEAS-2B the potential cytoprotective effects of soybean extracts were evaluated in terms of intracellular ROS levels and cell viability. The most relevant scavenging effect was found in Kalitur, with 78% decrease in ROS, which well correlated with a 33% increase in C3G after a 1 kGy dose. Results evidenced a correspondence between in vitro antioxidant activity and a potential health property of black soybean extracts, exemplifying the nutraceutical role of C3G. To our knowledge this study is the first report validating the cytoprotective effects of irradiated black soybean extracts. PMID- 29287368 TI - Effect of kappa-carrageenan oligosaccharides on myofibrillar protein oxidation in peeled shrimp (Litopenaeus vannamei) during long-term frozen storage. AB - Protein oxidation during chilling and frozen storage has recently attracted great attention due to its consequences on protein solubility and functionality. In this study, the effects of kappa-carrageenan oligosaccharides on myofibrillar protein oxidation in peeled shrimp (Litopenaeus vannamei) during frozen storage were investigated by assessing the content of the carbonyls, total sulfhydryl, dityrosine, and surface hydrophobicity. We also examined the means of antioxidant activity in vitro, degradation of muscle proteins, and integrity of tissue structure. Our data revealed that in vitro carrageenan oligosaccharides exhibited good capacities of OH, O2-, and DPPH. scavenging and Fe2+-chelating activity. Chemical analyses showed that frozen storage increased susceptibility of myofibrillar proteins to frozen oxidation. We found that the incorporation of carrageenan oligosaccharides during the treatment of the shrimp prior to frozen storage significantly decreased the formation of protein carbonyl and dityrosine, lowered the changes in myofibrillar surface hydrophobicity, and maintained a higher total sulfhydryl content when compared with the water-treated samples (control). Additionally, the results of protein degradation and tissue structure confirmed that these antioxidant oligosaccharides exhibited marked effects on stability of muscle proteins and effectively inhibited the degradation/oxidation of muscle proteins during frozen storage. Overall, the contribution of the antioxidant activities played an important role in cryoprotective effects of carrageenan oligosaccharides on frozen shrimp. Further application of these findings might maintain better quality and extend the commercialization of refrigerated products. PMID- 29287369 TI - Preparation, characterization and calcium release evaluation in vitro of casein phosphopeptides-soluble dietary fibers copolymers as calcium delivery system. AB - Delivery systems based on food-grade biopolymers are of particular interest for food applications. Here, we introduce a new calcium delivery system with a high calcium-binding capacity and controlled calcium release. The system integrates casein phosphopeptides (CPP) with soluble dietary fibers (SDF). The physicochemical properties, calcium-binding capacities, controlled calcium release properties and formation mechanisms of the prepared copolymers with different mass ratios of CPP/SDF after thermal treatment were studied. The results showed that CPP-SDF copolymers significantly improved the calcium binding capacity (P < .05) from 11.63% to 46.8% and increased the calcium phosphate deposition time. The SDF in copolymers protected CPP from gastric enzyme hydrolysis so that most of the calcium was released under intestinal conditions in a controlled manner. Structural characterizations demonstrated different copolymer conformational states, and more calcium-binding sites existed within the CPP-SDF copolymers. The results show that copolymers based on food-sourced polymers are potential candidates for oral calcium delivery. PMID- 29287370 TI - Seasonal variations of oxygen radical scavenging ability in rosemary leaf extract. AB - This investigation demonstrates that the oxygen radical scavenging ability of rosemary leaf extract has significant seasonal variations. The scavenging ability of rosemary leaf extract was quantitatively evaluated for five active oxygen species by using the ESR spin-trapping method. It was found that leaves that were picked in the cold season showed higher scavenging ability than those picked in the warm season. Measurement of the scavenging rate in pure rosmarinic acid and caffeic acid indicated that the scavenging ability in the warm season was mainly derived from rosmarinic acid. In the boiled extract, rosmarinic acid decomposed into caffeic acid. Therefore, a marked increase in the scavenging ability against superoxide and singlet oxygen in the boiled extract is in line with the high activity of caffeic acid. This study demonstrates that the multiple free radical scavenging method can be a useful method in comparative antioxidant capacity studies of plant extracts. PMID- 29287371 TI - Gastric digestion of cow and goat milk: Impact of infant and young child in vitro digestion conditions. AB - Many infants and young children are fed nutritional milk formulas. Although products are commonly based on cow milk, goat milk provides an alternative. We directly compared digestion of cow and goat milk proteins, varying pH, enzyme concentrations and incubation times to simulate infant and young child gastric conditions. Protein digestion and peptide formation were evaluated using electrophoresis and chromatography. Digestion of higher molecular weight whey proteins increased with decreased pH and higher enzyme concentrations of young child gastric digestion conditions compared to infant conditions. beta lactoglobulin was poorly digested under all gastric digestion conditions. Caseins reacted to pH changes differently compared to whey proteins, with less digestion of casein at pH 3.0 than at pH 5.0. Caseins from goat milk tended to be more efficiently digested compared to caseins from cow milk and peptide profiles from goat milk were distinct from cow milk. PMID- 29287372 TI - Qualitative identification of food materials by complex refractive index mapping in the terahertz range. AB - We investigated the feasibility of qualitative food analysis using complex refractive index mapping of food materials in the terahertz (THz) frequency range. We studied optical properties such as the refractive index and absorption coefficient of food materials, including insects as foreign substances, from 0.2 to 1.3 THz. Although some food materials had a complex composition, their refractive indices were approximated with effective medium values, and therefore, they could be discriminated on the complex refractive index map. To demonstrate food quality inspection with THz imaging, we obtained THz reflective images and time-of-flight imaging of hidden defects in a sugar and milk powder matrix by using time domain THz pulses. Our results indicate that foreign substances can be clearly classified and detected according to the optical parameters of the foods and insects by using THz pulses. PMID- 29287373 TI - Development of a LC-MS method for the discrimination between trace level Prunus contaminants of spices. AB - The need for an analytical procedure for the identification of allergens present at trace levels in foods was highlighted by conflicting results in a case of contamination of the spice cumin. The application of a bottom-up proteomics experiment was investigated to identify marker peptides for potential contaminant nuts which could then be monitored with high specificity and sensitivity by selective reaction monitoring experiments. The method developed allowed for the distinction between two closely related Prunus species, almond and mahaleb, in two different spices, cumin and paprika. The paprika sample was found to be contaminated with almond and the cumin sample, contaminated at a much lower level, was found to be contaminated with mahaleb. The method could be applied to any protein-dense food matrix allergen so long as suitable control and reference samples can be acquired. PMID- 29287374 TI - Matrix-effect free multi-residue analysis of veterinary drugs in food samples of animal origin by nanoflow liquid chromatography high resolution mass spectrometry. AB - In this work, a sensitive method based on nanoflow liquid chromatography high resolution mass spectrometry has been developed for the multiresidue determination of veterinary drugs residues in honey, veal muscle, egg and milk. Salting-out supported liquid extraction was employed as sample treatment for milk, veal muscle and egg, while a modified QuEChERS procedure was used in honey. The enhancement of sensitivity provided by the nanoflow LC system also allowed the implementation of high dilution factors as high as 100:1. For all matrices tested, matrix effects were negligible starting from a dilution factor of 100, enabling, thus, the use of external standard calibration instead of matrix matched calibration of each sample, and the subsequent increase of laboratory throughput. At spiked levels as low as 0.1 or 1 ug kg-1 before the 1:100 dilution, the obtained signals were still significantly higher than the instrumental limit of quantitation (S/N 10). PMID- 29287375 TI - Enzymatic action mechanism of phenolic mobilization in oats (Avena sativa L.) during solid-state fermentation with Monascus anka. AB - This work aims to investigate the effects of carbohydrate-hydrolysing enzymes on the release of phenolics in oat fermentation with Monascus anka. There were good correlations between phenolic content and alpha-amylase, xylanase and FPase activities. A high level of alpha-amylase activity (141.07 U/g) was observed, while xylanase (2.40 U/g), total cellulase (0.52 U/g) and beta-glucosidase activities (0.028 U/g) were relatively low in the fermentation system. The phenolic content of oat powder treated with crude enzyme from fermented oats significantly increased, especially that of the ferulic acid in the insoluble fraction and the vanillic acid in the soluble fraction. The surface SEM morphology of the oats showed that the cell wall structure was damaged by the crude enzyme treatment, which led to the release of phenolics. This study could provide metabolic understanding for optimization of phenolic compounds which could more efficiently increase the nutrition of oat intended for functional food ingredients. PMID- 29287376 TI - Fruits from the Brazilian Cerrado region: Physico-chemical characterization, bioactive compounds, antioxidant activities, and sensory evaluation. AB - Given the economic importance of fruit processing, this study aimed to analyze the chemical composition, antioxidant activity, and sensorial acceptance of six fruit pulps from the Brazilian Cerrado. For bioactive compounds of the selected fruits, buriti contains the highest carotenoid content (2.85 mg licopene/100 g e 4.65 mg beta-carotene/100g), however showed the lowest ascorbic acid concentration (7.42 mg/100g); while mangaba contains the highest ascorbic acid concentration (175.06 mg/100g), but obtained the lowest total phenolic compounds (46.85 mg GAEs/100g) and antioxidant capacity. The marolo reported the highest total phenolic compounds (728.17 mg GAEs/100g), total fiber (21.62%), and a high antioxidant potential. Regarding the mineral composition, marolo stood out as potassium (378.69 mg/100g) and magnesium (31.78 mg/100g) contents, and yellow mombin as phosphorus (26.24 mg/100g) content. Finally, juice prepared using cagaita and marolo had greater sensorial acceptance. The composition of fruit pulps indicated the potential there for the development of new food products. PMID- 29287377 TI - Prooxidant effect of alpha-tocopherol on soybean oil. Global monitoring of its oxidation process under accelerated storage conditions by 1H nuclear magnetic resonance. AB - The effect of adding alpha-tocopherol in proportions ranging from 0.002 to 5% in weight on the oxidative stability of soybean oil was studied. For the first time, the oxidation process under accelerated storage conditions including evolution of the molar percentages of the several types of oil acyl groups, and formation and evolution of various kinds of oxidation products comprising hydroperoxides, hydroxy-dienes and other alcohols, epoxides, aldehydes and keto-dienes, was followed by 1H nuclear magnetic resonance. It is proved that, except in the lowest proportion, alpha-tocopherol not only exerts a prooxidant effect on soybean oil but also modifies its oxidation pathway, affecting the oxidation products generation rate, their nature, relative proportions and concentrations. It is noticeable that the highest alpha-tocopherol concentrations induce the generation of some toxic compounds at earlier stages of the thermoxidation process and sometimes in higher concentration, such as certain oxygenated alpha,beta-unsaturated aldehydes and monoepoxides derived from linoleic groups. PMID- 29287378 TI - Evaluation of estrogenic activity of red clover (Trifolium pratense L.) sprouts cultivated under different conditions by content of isoflavones, calorimetric study and molecular modelling. AB - Isoflavones have an affinity for estrogen receptors (ERs) including beneficial affinity for ERbeta. Widely used soy is a source of poorly absorbed isoflavones glycosides. Red clover contains mostly easily absorbed free aglycones. Red clover sprouts were cultivated under different conditions (white light, UVA or UVB for 12 or 24 h a day at 18 or 25 degrees C) to maximise the content of isoflavones, especially of high affinity for ERbeta. The affinity of isoflavones to ERs was evaluated by molecular modelling and isothermal titration calorimetry (ITC). The richest source of isoflavones, especially formononetin were sprouts cultivated for 10 days under continuous white light and at 25 degrees C (562 mg/100 g of fresh mass). Formononetin and the above sprouts has been shown to have a high affinity for ERbeta. Red clover sprouts can be considered as a source of phytoestrogens with high biological activity and as a dietary supplement reducing menopausal symptoms. PMID- 29287379 TI - A micro-plate colorimetric assay for rapid determination of trace zinc in animal feed, pet food and drinking water by ion masking and statistical partitioning correction. AB - A new micro-plate colorimetric assay was developed for rapid determination of zinc in animal feed, pet food and drinking water. Zinc ion was extracted from sample by trichloroacetic acid and then reacted with 2-(5-Bromo-2-pyridylazo)-5 [N-propyl-N-(3-sulfopropyl)amino]phenol (5-Br-PAPS) to form a Zn-PAPS complex to be detected by a micro-plate reader at 552 nm. An ion masking formula including salicylaldoxime, deferoxamine and sodium citrate were screened and applied to exclude the interference from other heavy metals and a partitioning correction approach was proposed to eliminate the matrix effect derived from feed sample. The entire procedure can be completed within 40 min and the detection range was 0.038-8.0 MUg mL-1 zinc in buffer solution. Moreover, the analysis in real samples revealed the consistency of results by this assay and those by atomic absorption spectrometry analysis. These features highlighted the possibility for this proposed assay to be used for rapid determination of zinc in complex samples. PMID- 29287380 TI - Improving the extraction of l-phenylalanine by the use of ionic liquids as adjuvants in aqueous biphasic systems. AB - Polyethylene glycol (PEG) is widely used in the polymer-salt systems. However, the low polarity of the PEG-rich phase limits the application of aqueous biphasic systems (ABS). To overcome this disadvantage, a small quantity of ionic liquid (IL) was used as an adjuvant in ABS to enlarge the polarity range. Therefore, an innovative study involving addition of 4wt% imidazolium-based ILs to the PEG 600/NaH2PO4 ABS, aiming at controlling the phase behavior and extraction ability, was carried out. The phase diagrams, the tie-lines and the partitioning behavior of l-phenylalanine and ILs were studied in these systems. The results reveal that l-phenylalanine preferentially partitions for the PEG-rich phase. The addition of 4wt% IL to ABS controls the partitioning behavior of l-phenylalanine, which depends on the type of IL employed. Moreover, it is verified that increasing temperature lead to a decrease in the partition coefficient of l-phenylalanine. PMID- 29287381 TI - Statistical modelling coupled with LC-MS analysis to predict human upper intestinal absorption of phytochemical mixtures. AB - A diet rich in phytochemicals confers benefits for health by reducing the risk of chronic diseases via regulation of oxidative stress and inflammation (OSI). For optimal protective bio-efficacy, the time required for phytochemicals and their metabolites to reach maximal plasma concentrations (Tmax) should be synchronised with the time of increased OSI. A statistical model has been reported to predict Tmax of individual phytochemicals based on molecular mass and lipophilicity. We report the application of the model for predicting the absorption profile of an uncharacterised phytochemical mixture, herein referred to as the 'functional fingerprint'. First, chemical profiles of phytochemical extracts were acquired using liquid chromatography mass spectrometry (LC-MS), then the molecular features for respective components were used to predict their plasma absorption maximum, based on molecular mass and lipophilicity. This method of 'functional fingerprinting' of plant extracts represents a novel tool for understanding and optimising the health efficacy of plant extracts. PMID- 29287382 TI - The validated and sensitive HPLC-DAD method for determination of patulin in strawberries. AB - This work outlines HPLC coupled with DAD detection for accurate quantification of patulin (mycotoxin) in strawberries. The optimized extraction of fruit samples through the modified QuEChERS technique in acetonitrile acidified with acetic acid (1%, v/v) and citrate-buffered salts followed by dispersive solid phase extraction using a primary secondary amine and graphitized carbon is described. The method presents LOD and LOQ of 1.5 and 5ug/kg, respectively and has been validated in strawberry matrix at three concentration levels (5, 10 and 50ug/kg), according to SANTE/11945/2015 and the 2002/657/EC Decision requirements. All validated patulin levels show high percentage of patulin recovery. The validation procedure also includes the intermediate precision performed within three successive days in samples spiked with patulin. The developed method was applied for analysis of fresh and frozen strawberries purchased at local markets. Patulin level in analyzed samples was below the level of detection. PMID- 29287383 TI - Change of phenolics, carotenoids, and antioxidant capacity following simulated gastrointestinal digestion and dialysis of selected edible green leaves. AB - The bio-accessibility of phenolics, flavonoids, rutin, beta-carotene and lutein and changes in antioxidant activities in six edible greens during simulating gastro-intestinal conditions has been investigated. It was found that the amount of dialysable phenolics, flavonoids and carotenoids which potentially available for further uptake is varying depending on the leafy type. Bioavailable phenolics after the gastric-phase, intestinal-phase and in dialysable fraction were in the ranges of 13.9-71.8%, 14.4-77.4% and 3.1-12.3% respectively when compared with their fresh leaves. Total antioxidant capacities in the dialysable fractions were significantly lower than their original. Bioactives of Centella asiatica showed comparatively higher bioavailability in all phases with respect to its original content. beta-carotene seems more dialysable than lutein in all leaves studied. Higher rutin contents were found in both gastric and intestinal phases than in fresh leaves. These results highlighted that gastrointestinal digestion may substantially affect the absorption of polyphenols and carotenoids present in leafy greens. PMID- 29287384 TI - A simple, rapid and green ultrasound assisted and ionic liquid dispersive microextraction procedure for the determination of tin in foods employing ETAAS. AB - This paper proposes a simple, rapid and green ultrasound assisted and ionic liquid dispersive microextraction procedure using pyrocatechol violet (PV) as complexing reagent and 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide [C6MIM][Tf2N] as ionic liquid for the detection of tin employing electrothermal atomic absorption spectrometry (ETAAS). The optimization step was performed using a two-level full factorial design involving the following factors: pH of the working media, amount reagents, ionic liquid volume and extraction time and the chemometric response was tin recovery. The procedure allowed the determination of tin with limits of detection and quantification of 3.4 and 11.3 ng L-1, respectively. The relative standard deviation was 4.5% for a tin solution of 0.50 ug L-1. The validation method was confirmed by analysis of rice flour certified reference material. The method was applied for the quantification of tin in several food samples. The concentration range found varied from 0.10 to 1.50 ug g-1. PMID- 29287385 TI - Impact of hydrothermal modifications on the physicochemical, morphology, crystallinity, pasting and thermal properties of acorn starch. AB - Native acorn starch had high purity and the granules were mainly elliptical and spherical with the mean diameter of 7.32 MUm. Hydrothermal modifications slightly changed the morphology. The solubility, swelling properties and amylose leaching of acorn starch were mostly influenced by Heat-moisture treatment (HMT). XRD pattern of native starch (C-type) did not change on hydrothermal modifications, but native and annealing (ANN) modified starches showed the most crystallinity. DSC results showed that the gelatinization temperatures and enthalpy of native starch were 59.9, 71.3, and 80.6 degrees C and -14.9 mJ/mg, respectively, and hydrothermal treatments generally increased the gelatinization temperatures. Regarding to RVA results, peak, breakdown, trough, setback, and final viscosities of native starch were 415, 143, 272, 168, and 440 RVU, respectively, and viscosity parameters of native starch were mainly more than those of hydrothermally modified starches. Generally, the intensity of the effects of hydrothermal modifications followed the order: HMT > dual modifications > ANN. PMID- 29287386 TI - Selective synthesis of partial glycerides of conjugated linoleic acids via modulation of the catalytic properties of lipases by immobilization on different supports. AB - Lipases B from Candida antarctica (CALB), Rhizomucor miehei (RML) and Thermomyces lanuginosus (TLL) were immobilized on octadecyl methacylate (OM) or octadecyl methacrylate (OMC) beads. Their specific activity and regioselectivity were studied in the synthesis of conjugated linoleic acid (CLA) partial glycerides, which presented nutraceutical properties. TLL derivatives were poor catalysts. Novozym(r) 435 was much better than Lipozyme(r) RM IM. RML activity (a GRAS enzyme) was modulated via immobilization. After only 3 h, OM-RML gave the highest CLA conversion (54% at 40 degrees C with 1:3 M ratio of glycerol to CLA). OM-RML reduced by a factor of 3.12 and 1.16 the activation energy of the reaction with Lipozyme(r) RM IM and Novozym(r) 435, respectively. The new GRAS preparation OM RML brings forth an optimal regioselective preparation of sn-1 mono and sn-1,3 diacylglycerols rich in CLA, with a ratio of sn-1,3/sn-1,2 regioisomers of 21.8, compared to 2.3 for Novozym(r) 435. PMID- 29287387 TI - Field investigation to determine the environmental source of PCBs in a pig farm. AB - During a national monitoring plan, a pork fat sample was declared non-compliant for the sum of dioxins and PCB-DL (EU regulation). The National Reference Laboratory together with competent authorities conducted extended investigations to determine rapidly the contamination source at the farm level. A range of samples (n = 129), representative of potential contamination sources, was selected for further characterization (fat, feed, materials, dust, soil) and was analyzed for PCDD/Fs and DL-PCBs by GC-HRMS. A hot spot was localized in the farm, which corresponded to a pre-feed storage tank, the paints of which presented huge DL-PCB concentrations (>1 * 106 pg g-1), responsible for the contamination. The present case report describes a new source of PCB contamination, previously undescribed. PMID- 29287388 TI - Effects of salinity on bacterial communities, Maillard reactions, isoflavone composition, antioxidation and antiproliferation in Korean fermented soybean paste (doenjang). AB - The purpose of this study was to investigate bacterial communities and health benefit-related parameters in doenjang prepared with various brine concentrations (8, 12, 16, and 20%). Phenolic, flavonoid, melanoidin and isoflavone contents, antioxidation, and antiproliferation of doenjang (AD8, AD12, AD16, and AD20) aged for 3 months were compared with those of initial doenjang (ID8, ID12, ID16, and ID20). The ID8 and AD8 doenjang, made with 8% brine, contained higher phenolics, melanoidins, and isoflavones than those with high salinity. As results of bacterial communities, Enterococcus was a dominant bacterium in most doenjang, while Lactobacillus was predominant in AD8. Trolox equivalent antioxidant capacity (32.5 umol TE/g dwb) and DPPH radical-scavenging capacity (57 umol TE/g dwb) values of AD8 were the highest among samples. The EC50 of HT-29 cell proliferation treated with AD8 was 0.47 mg/mL, while EC50 of AD20 was 1.07 mg/mL, indicating stronger antiproliferative activity in low-salinity doenjang. PMID- 29287389 TI - Simple and efficient sustainable semi-synthesis of oleacein [2-(3,4 hydroxyphenyl) ethyl (3S,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate] as potential additive for edible oils. AB - A simple and very environmental friendly microwave assisted method to produce oleacein in good yield starting from the easily available oleuropein is here presented. The methodology is proposed to produce the appropriate amount of hydroxytyrosol derivatives to enrich a commercial oil for an oil which provides beneficial effects on the human health. PMID- 29287390 TI - Determination of free steroidal compounds in vegetable oils by comprehensive two dimensional gas chromatography coupled to time-of-flight mass spectrometry. AB - A method based on comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC * GC-TOF/MS) was developed to analyze steroidal compounds in vegetable oils, which could provide better separation and higher sensitivity than conventional one dimensional gas chromatography, and allowed determination of 31 sterols and triterpene alcohols in one injection. Furthermore, the approach also permitted separation and detection of small amounts of other compounds (may be steroidal compounds whose molecular structures have not been confirmed), which were obscured in the lower-resolution single column technique. With the help of the GC * GC system, a more elaborate and complete information regarding the distributions and concentrations of free phytosterols and triterpene alcohols in safflower seed oil, soybean oil, rapeseed oil, sunflower seed oil and peanut oil were obtained. The proposed method could potentially open a new opportunity for the more in-depth knowledge of the steroidal compounds of vegetable oils. PMID- 29287391 TI - Blackberry anthocyanins: beta-Cyclodextrin fortification for thermal and gastrointestinal stabilization. AB - Anthocyanins are potential food colorants due to their color, low toxicity and biological properties. However, the low chemical stability of anthocyanins has limited their use. In this work, the thermal stability of cyanidin-3-O-glucoside (cy3glc) (major blackberry anthocyanin) and blackberry purees through molecular inclusion with beta-cyclodextrin (beta-CD) was assessed. Complexation with beta CD showed a thermal stabilization of cy3glc, resulting on a decrease of the degradation rate constant (k) and in several alterations in the cy3glc-beta-CD DSC thermogram. To assess the bioaccessibility of blackberry anthocyanins, the stability of blackberry purees through simulated in vitro digestion was also studied. Despite the rapid degradation of anthocyanins observed within the first minutes of simulated intestinal digestion, complexation with beta-CD allowed anthocyanins degradation to be slowed down. The results obtained demonstrate the ability of beta-CD to increase blackberry anthocyanins thermal stability and also to decrease the rate of degradation of these pigments under simulated gastrointestinal conditions. PMID- 29287392 TI - In vivo study on the slow release of glucose in vacuum fried matrices. AB - In vitro studies have shown that vacuum frying may be an effective process to reduce starch digestibility as it may limit gelatinization; this is significant as overconsumption of starchy foods contributes to obesity and type 2 diabetes. Although in vitro studies are an instrumental tool, in vivo studies allow observation of the overall effect on a living organism. The aim of this research was to assess how in vivo starch digestibility can be reduced when frying under vacuum (9.9 kPa), after feeding Sprague-Dawley rats, while also understanding its relationship to in vitro starch digestibility. Results showed that vacuum-fried dough has a lower degree of gelatinization (~53.8%) and a maximal blood glucose level at 60 min (slower glycemic response) than atmospheric counterparts (~98.3% degree of gelatinization and maximal blood glucose level at 30 min). Similarly, in vitro procedures exhibited less rapidly available glucose and higher unavailable glucose fractions in vacuum-fried dough. PMID- 29287393 TI - Effects of (-)-epigallocatechin-3-gallate incorporation on the physicochemical and oxidative stability of myofibrillar protein-soybean oil emulsions. AB - The dose-dependent effects of (-)-epigallocatechin-3-gallate (EGCG; at 0, 50, 100, 200, 500, and 1000 mg/L) on the physical, chemical, and oxidative stability of porcine myofibrillar protein (MP)-soybean oil emulsion systems were investigated. The results showed EGCG at all levels effectively suppressed lipid oxidation in MP emulsion composite gels during the entire chill storage (at 4 degrees C for 0, 3, or 7 days). The incorporation of EGCG at higher concentrations (>100 mg/L) promoted the loss of sulfhydryls, reduction of surface hydrophobicity, and aggregation and cross-linking of MP. As a result, high concentrations of EGCG (500 and 1000 mg/L) hampered emulsification and gel formation of MP. However, EGCG at lower concentrations (50-200 mg/L) improved the oxidative stability of meat emulsions without jeopardizing the textural stability. PMID- 29287394 TI - Membrane lipid metabolism changes and aroma ester loss in low-temperature stored Nanguo pears. AB - Cold storage is an effective method used to retard the senescence of Nanguo pears after harvest. However, this causes aroma loss in the fruit. To elucidate the role of membrane lipid metabolism in aroma reduction, we investigated the contents of total aroma eaters and major fatty acid components, the membrane permeability, and the activity and gene expression of key enzymes in membrane lipid metabolism and aroma formation. The results showed that the contents of total aroma esters, oleic acid and linoleic acid, and alcohol dehydrogenase activity were at a lower level in cold stored fruit than that in control fruit. However, the palmitic acid content, membrane permeability, and the activities and gene expression of alcohol acyltransferase, lipoxygenase, phospholipase D, and lipase were higher. In conclusion, the loss of aroma esters may be caused by membrane lipid metabolism disruption during cold storage. PMID- 29287395 TI - Bioaccessibility of four calcium sources in different whey-based dairy matrices assessed by in vitro digestion. AB - Numerous calcium sources are available to enrich food, but their behavior during digestion is still unknown. This study focused on the influence of the gastro intestinal pH, the food structure and the calcium source on the bioaccessibility of the nutrient. Four calcium sources were studied: calcium carbonate, calcium citrate malate, calcium phosphate and calcium bisglycinate. These were added to dairy matrices, containing cream and whey proteins, of different forms (liquid or gel). The kinetics of solubility and ionic calcium concentration during in vitro digestion were studied, as function of gastro-intestinal pH. All calcium sources were almost fully soluble in the gastric compartment, and then became insoluble in the intestinal phase. The level of calcium insolubilisation in the intestinal phase was not significantly influenced by the matrix structure (liquid or gel), but was more dependent on the calcium source, this effect leading to different final calcium bioaccessibility from 36% to 20%. PMID- 29287396 TI - Understanding the effect of anthocyanins extracted from purple sweet potatoes on alcohol-induced liver injury in mice. AB - Anthocyanins as antioxidants are potential to protect liver from alcoholic damage, but might be pro-oxidants under certain conditions. In this study, twelve purple sweet potatoes anthocyanins (PSPA) were isolated and their effects on alcohol-induced liver injury were studied. These PSPA were rich in cyanidin derivatives and fed to male C57BL/6 mice as colorants in alcoholic drink with low, median, or high dosages PSPA i.e. 50, 100, or 300 mg/kg.BW.d. Compared to the alcohol group, the median-dose PSPA showed a clear improvement in the liver indexes/histology, serum ALT level, oxidative stress status, and even a recovery to the normal level, however the high dose PSPA promoted the liver injury via a pro-oxidant effect, as reflected by increased malondialdehyde (MDA) content and decreased GSH level. The results suggested that cyanidin derivatives with an ortho-hydroxyl structure on B-ring might promote the oxidative stress of alcohol induced liver injury at high doses as a pro-oxidant. PMID- 29287397 TI - Effects of pre-cooked cheeses of different emulsifying conditions on mechanical properties and microstructure of processed cheese. AB - The effect of pre-cooked cheeses of different emulsifying conditions on the viscosities, mechanical properties, fat globules, and microstructure of processed cheese was investigated, and changes in protein network relating to the creaming effect and the occurrence of yielding point were discussed. The addition of pre cooked cheeses with a short stirring time had no obvious impact on the fat globules and protein network. The random network brought low viscosities and a gradual increase in the fracture stress/strain curve. The addition of pre-cooked cheeses with the long stirring time caused protein network to become fine stranded. The fine-stranded network caused creaming effect, and brought yielding points in the mechanical properties. The pre-cooked cheese with the small fat globules also caused fat globules to become smaller, and give the processed cheese more firmness. This study provides a potential solution to control the functional properties of processed cheese by using a variety of pre-cooked cheeses. PMID- 29287398 TI - Exploration of the molecular interactions between angiotensin-I-converting enzyme (ACE) and the inhibitory peptides derived from hazelnut (Corylus heterophylla Fisch.). AB - The mechanism of action of food-derived angiotensin-I-converting enzyme (ACE) inhibitory peptides has not been completely elucidated. In the present study, ion exchange chromatography, gel filtration chromatography, reverse phase-high performance liquid chromatography, and liquid chromatography-electrospray ionization-tandem mass (LC-ESI-MS/MS) were employed for purifying and identifying the ACE inhibitory peptides from hazelnut. To understand the mode of action of these peptides, ACE inhibition kinetics, in vitro and in vivo bioavailability assays, active site analysis, and interaction between the inhibitory peptides and ACE were investigated. The results identified novel ACE inhibitory peptides Ala Val-Lys-Val-Leu (AVKVL), Tyr-Leu-Val-Arg (YLVR), and Thr-Leu-Val-Gly-Arg (TLVGR) with IC50 values of 73.06, 15.42, and 249.3 MUM, respectively. All peptides inhibited the ACE activity via a non-competitive mode. The binding free energies of AVKVL, YLVR, and TLVGR for ACE were -3.46, -6.48, and -7.37 kcal/mol, respectively. The strong inhibition of ACE by YLVR may be attributed to the formation of cation-pi interactions. PMID- 29287399 TI - Interaction of cellulose nanocrystals and amylase: Its influence on enzyme activity and resistant starch content. AB - The aim of this work was to evaluate the effects of cellulose nanocrystals (CNCs) on amylolytic enzyme activity and starch digestibility. For the first time, we investigated the interaction between alpha-amylase or glucoamylase and CNCs using ultraviolet visible (UV-Vis) absorption spectroscopy, fluorescence quenching method, Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD). The results of UV and fluorescence spectra suggested that CNCs interacted with alpha-amylase and glucoamylase. Increasing the concentration of CNCs caused a reduction of alpha-amylase and glucoamylase activities. The FTIR and CD results indicated that CNCs induced structural changes in the secondary structure of alpha-amylase and glucoamylase. By incorporating CNCs into maize, potato and pea starches, the contents of rapid digestible starch and slowly digestible starch of the cooked starches decreased while resistant starch content increased. PMID- 29287400 TI - Covalent immobilization of peanut beta-amylase for producing industrial nano biocatalysts: A comparative study of kinetics, stability and reusability of the immobilized enzyme. AB - Stability of enzymes is an important parameter for their industrial applicability. Here, we report successful immobilization of beta-amylase (bamyl) from peanut (Arachis hypogaea) onto Graphene oxide-carbon nanotube composite (GO CNT), Graphene oxide nanosheets (GO) and Iron oxide nanoparticles (Fe3O4). The Box-Behnken Design of Response Surface Methodology (RSM) was used which optimized parameters affecting immobilization and gave 90%, 88% and 71% immobilization efficiency, respectively, for the above matrices. beta-Amylase immobilization onto GO-CNT (bamyl@GO-CNT) and Fe3O4 (bamyl@Fe3O4), resulted into approximately 70% retention of activity at 65 degrees C after 100 min of exposure. We used atomic force microscopy (AFM), scanning and transmission electron microscopy (SEM and TEM), Fourier transformed infrared (FT-IR) spectroscopy and fluorescence microscopy for characterization of free and enzyme bound nanostructures (NS). Due to the non-toxic nature of immobilization matrices and simple but elegant immobilization procedure, these may have potential utility as industrial biocatalysts for production of maltose. PMID- 29287401 TI - Interactions between soy protein hydrolyzates and wheat proteins in noodle making dough. AB - Soy protein hydrolyzate has been used as supplements in wheat flour to enhance the nutritional value of its products, but it may negatively affect the gluten properties simultaneously. In order to explore the mechanism of this effect, protein characteristics including disulfide bond, protein composition, intermolecular force of dough proteins, and atomic force microscope images of gluten were obtained. Results showed that disulfide bonds in dough increased when soy protein hydrolyzate was added, but glutenin macropolymer decreased. Atomic force microscope images showed that gluten were weakened by soy protein hydrolyzate. Based on these results, a model was developed to describe the interaction between soy protein hydrolyzates and wheat proteins: soy protein hydrolyzates linked with wheat proteins through disulfide bond, disrupted the glutenins polymerization, thus hindered gluten networks formation. The interaction between wheat proteins and soy protein hydrolyzates in noodle making dough could be described with this model reasonably. PMID- 29287402 TI - Characterization of carotenoid profiles in goldenberry (Physalis peruviana L.) fruits at various ripening stages and in different plant tissues by HPLC-DAD-APCI MSn. AB - Carotenoid profiles of goldenberry (Physalis peruviana L.) fruits differing in ripening states and in different fruit fractions (peel, pulp, and calyx of ripe fruits) were investigated by HPLC-DAD-APCI-MSn. Out of the 53 carotenoids detected, 42 were tentatively identified. The carotenoid profile of unripe fruits is dominated by (all-E)-lutein (51%), whereas in ripe fruits, (all-E)-beta carotene (55%) and several carotenoid fatty acid esters, especially lutein esters esterified with myristic and palmitic acid as monoesters or diesters, were found. In overripe fruits, carotenoid conversion products and a higher proportion of carotenoid monoesters to diesters compared to ripe fruits were observed. Overripe fruits showed a significant decrease in total carotenoids of about 31% due to degradation. The observed conversion and degradation processes included epoxidation, isomerization, and deesterification. The peel of ripe goldenberries showed a 2.8 times higher total carotenoid content of 332.00 ug/g dw compared to the pulp. PMID- 29287403 TI - The effects of dairy ingredients on the pasting, textural, rheological, freeze thaw properties and swelling behaviour of oat starch. AB - The effects of milk ingredients, whey protein concentrate (WPC), whey lactalbumin (WLAC) and skim milk powder (SMP) on oat starch characteristics in terms of pasting, rheological, freeze-thaw and swelling behaviour, were investigated. Oat starch was extracted from oat flour and different proportions of dairy ingredients were mixed with oat starch. Substitution of oat starch with milk components increased hot paste stability and reduced peak viscosity using the RVA method of assessment. Furthermore, thermal processing affected the granules size, swelling power and flow behaviour of the mixtures containing oat starch in combination with different dairy ingredients. Oat starch illustrated reduced swelling and breakdown properties when pasted in the presence of WPC and SMP. This study also showed that addition of SMP resulted in an increase in freeze thaw syneresis and reduction in starch granule size. SMP was found to affect the oat starch properties more significantly in comparison with WPC and WLAC. PMID- 29287404 TI - Freeze-dried phosphatidylcholine liposomes encapsulating various antioxidant extracts from natural waste as functional ingredients in surimi gels. AB - Three antioxidant extracts (collagen hydrolysate, pomegranate peel extract, shrimp lipid extract) were encapsulated in soy phosphatidylcholine liposomes with the addition of glycerol. The particle size of the fresh liposomes ranged from 75.7 to 81.0 nm and zeta potential from -64.6 to -88.2 mV. Freeze-drying increased particle size (199-283 nm), and slightly decreased zeta potential. The lyophilized liposomes were incorporated in squid surimi gels at 10.5% concentration. An alternative functional formulation was also prepared by adding 2% of non-encapsulated bioactive extract. The gels were characterized in terms of colour, texture and oxidative stability (TBARS) after processing and also after frozen storage. The incorporation of the freeze-dried liposomes caused a slight decrease in gel strength and contributed to maintaining the stability of the gels during long-term frozen storage. The antioxidant properties of the bioactive extracts, liposomes and in vitro digested surimi gels were determined. PMID- 29287405 TI - Direct infusion mass spectrometric identification of molecular species of glycerophospholipid in three species of edible whelk from Yellow Sea. AB - Whelk has been exploited commercially as a delicacy for a long time. Although previous studies have suggested that whelk might serve as a potential rich source of long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA) enriched phospholipid (PL), the molecular species profile of the PL have not been reported yet. In this study, more than 220 molecular species of glycerophospholipid (GP) belonging to eight classes including glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoinositol, lysoglycerophosphocholine, lysoglycerophosphoethanolamine, lysoglycerophosphoserine and lysoglycerophosphoinositol in three species of edible whelks (Buccinium yokomaruae, Neptunea arthritica cumingi Cosse and Volutharpa ampullaceal) were identified for the first time by using direct infusion tandem mass spectrometric method. Most of the predominant GP molecular species contained n-3 LC-PUFA, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Meanwhile, the whelk lipids contained a high proportion of PL (32.92-55.55% of total lipids) and PUFA (30.45-41.42% of total FA). Among PL, phosphatidylcholine (44.18-65.49mol%) was dominant. PMID- 29287406 TI - Identification of water-soluble Monascus yellow pigments using HPLC-PAD-ELSD, high-resolution ESI-MS, and MS-MS. AB - Water-soluble Monascus yellow pigment (WSMYP) prepared from monascorubin is widely used in the food industry. However, the structure and composition of this pigment has been unclear until now. In the present study, the components of WSMYP has been identified by means of HPLC coupled with a photodiode-array detector (PAD) and an evaporative light scattering detector (ELSD), HPLC/ESI-MS-MS, and high resolution ESI-MS (HR-ESI-MS). Eight compounds have been separated from WSMYP and unambiguously structurally characterized; namely, monascin, ankaflavin and six novel compounds with molecular weights/structural formulae of 356/C21H24O5, 376/C21H28O6, 384/C23H28O5, 404/C23H32O6, 437/C21H27NO7S, and 465/C23H31NO7S. Compounds 3 (376/C21H28O6), 7 (437/C21H27NO7S), and 8(465/C23H31NO7S) are the main components in WSMYP with contents of 55.8%, 16.5%, and 10.1%, respectively. These results provide useful information for further bioactivity studies and industrial application of WSMYP. PMID- 29287407 TI - Effects of succinylation on the structure and thermal aggregation of soy protein isolate. AB - The structures of soy protein isolate, beta-conglycinin, and glycinin at increasing succinylation levels (0-94.88%) were determined to control the formation of soy protein thermal aggregates. In addition, the thermal aggregation was investigated under various temperatures (70-100 degrees C) and ionic strengths (0-1.0 mol/L NaCl) at pH 7.0. Results showed that soy protein isolate, beta-conglycinin, and glycinin underwent obvious structural changes when their succinylation degrees reached around 60%, 30%, and 65%, respectively. After which, the acylation rates markedly declined. During succinylation, soy proteins, particularly glycinin, endured gradual damages in its secondary and tertiary structures. Consequently, the thermal stability of glycinin was reduced, whereas that of beta-conglycinin was hardly affected. However, as the colloid stability of succinylated soy protein isolate was enhanced significantly, its thermal aggregation was markedly suppressed. Thus, succinylation could be used to improve the stability of soy proteins after heating. PMID- 29287409 TI - Effects of vacuum chopping on physicochemical and gelation properties of myofibrillar proteins from silver carp (Hypophthalmichthys molitrix). AB - Physicochemical and gelation properties of myofibrillar proteins from silver carp surimi as affected by chopping under different vacuum degrees (0, 0.01, 0.02, 0.04, 0.06 and 0.08 MPa) were investigated. With the increase of vacuum degree, size and quantity of air bubbles in surimi paste decreased, disulfide bond content of myofibrillar proteins decreased significantly (p < .05) and then slight increased (p > .05), while surface hydrophobicity of myofibrillar proteins increased gradually (p < .05). Gel mechanical properties, chemical interactions (nonspecific associations, hydrogen bond and hydrophobic interactions) and FAXL (cross-linking degree of free amino group) of heat-induced surimi gel increased significantly (p < .05) with vacuum degree. Scanning electron microscopy (SEM) observation showed that three-dimensional network of surimi gel under higher vacuum degree was more compact and orderly. Results indicated that vacuum chopping imparted physicochemical and structural changes of fish myofibrillar protein, which might contribute to the improvement in gelling properties of myofibrillar proteins. PMID- 29287408 TI - Hydroxycinnamic acids loaded in lipid-core nanocapsules. AB - Ferulic, caffeic, sinapic, and coumaric acids, belonging to the class of hydroxycinnamic acids (HAs), are bioactive polyphenols widespread in the plant kingdom and present in the human diet. Due to their biological properties and effects in the prevention of various diseases associated with oxidative stress, HAs can be exploited for attractive nutraceutical applications. Starting from this and in order to increase bioaccessibility, we encapsulated HAs in lipid-core nanocapsules (NCs) based on a biodegradable and biocompatible poly(epsilon caprolactone) polymer. The results showed that nanoparticles loaded with hydroxycinnamic acids (HA-NCs) have diameter of 224-253 nm, encapsulation efficiency of 53-78%, and are stable over time (30 days). In vitro tests evidenced that NCs are able to preserve HAs in the gastric simulated fluid and release them in the intestinal simulated fluid. The delivery system developed could be employed to create novel functional foods. PMID- 29287410 TI - Brassica vegetables as sources of epithionitriles: Novel secondary products formed during cooking. AB - The epithionitriles, 1-cyano-2,3-epithiopropane, in particular, and 1-cyano-3,4 epithiobutane, are important, but yet underestimated glucosinolate hydrolysis products that are released instead of the cancer preventative isothiocyanates in Brassica vegetables, such as cabbage, broccoli, or pak choi. Here, we characterized the reactivity of 1-cyano-2,3-epithiopropane under aqueous heat treatment conditions and compared our findings to those of the related epithionitriles 1-cyano-3,4-epithiobutane and 1-cyano-4,5-epithiopentane. In contrast to the other epithionitriles, 1-cyano-2,3-epithiopropane is highly reactive. As a result, 2-aminothiophene and dimeric 1,4-dithiane-2,5 diacetonitrile were identified as main products and a reaction mechanism is proposed. Formation of 2-aminothiophene was also observed in cooked white cabbage samples. Moreover, three novel compounds were identified as derivatives of the related epithionitriles. The results imply that apart from isothiocyanates, process-derived compounds should be considered in regards to cancer preventative Brassica vegetable related bioactivity. PMID- 29287411 TI - A novel aspartic protease from Rhizomucor miehei expressed in Pichia pastoris and its application on meat tenderization and preparation of turtle peptides. AB - A novel aspartic protease gene (RmproA) was cloned from the thermophilic fungus Rhizomucor miehei CAU432 and expressed in Pichia pastoris. The RmproA was successfully expressed in P. pastoris as an active extracellular protease. High protease activity of 3480.4 U/mL was obtained by high cell-density fermentation. The protease was purified by the two step protocols to homogeneity. The molecular mass of the RmproA was estimated to be 52.4 kDa by SDS-PAGE and 50.6 kDa by gel filtration. The purified enzyme was optimally active at pH 5.5 and 55 degrees C, respectively. The enzyme exhibited a broad range of substrate specificity. RmproA treated pork muscle showed lower shear force than papain-treated sample at a relative low concentration, suggesting its effectiveness on meat tenderization. Moreover, turtle hydrolysis by RmproA resulted in a large amount of small peptides, which exhibited high ACE-inhibitory activity. Thus, RmproA may be a potential candidate for several industrial applications. PMID- 29287412 TI - A green deep eutectic solvent dispersive liquid-liquid micro-extraction (DES DLLME) for the UHPLC-PDA determination of oxyprenylated phenylpropanoids in olive, soy, peanuts, corn, and sunflower oil. AB - A green dispersive liquid-liquid microextraction (DLLME) using deep eutectic solvent (DES) as the extracting solvent has been developed and applied for the simultaneous quantification of ferulic acid, umbelliferone, boropinic acid, 7 isopentenyloxycoumarin, 4'-geranyloxyferulic acid (GOFA), and auraptene in some vegetable oils using ultra high performance liquid chromatography (UHPLC) with photodiode array detection (PDA). All parameters in the extraction step, including selection and loading of both extracting and dispersing solvents, amount of both extractant and disperser solvent were investigated and optimized. PhAA/TMG DES achieved higher recovery and enrichment factor compared to other DESs. The validated method showed good linearity with correlation coefficients, r2>0.9990 for all the analytes. Furthermore, this is the first time that eco friendly solvents are used for the extraction of oxyprenylated phenylpropanoids and the corresponding extract analyzed with ultra high performance liquid chromatography with photodiode array detection. PMID- 29287413 TI - Extraction and preconcentration of trace Al and Cr from vegetable samples by vortex-assisted ionic liquid-based dispersive liquid-liquid microextraction prior to atomic absorption spectrometric determination. AB - In the study, a simple, and efficient microextraction approach, which is termed as vortex-assisted ionic liquid-based dispersive liquid-liquid microextraction (VA-IL-DLLME), was developed for flame atomic absorption spectrometric analysis of aluminum (Al) and chromium (Cr) in vegetables. The method is based on the formation of anionic chelate complexes of Al(III) and Cr(VI) with o-hydroxy azo dye, at pH 6.5, and then extraction of the hydrophobic ternary complexes formed in presence of cetyltrimethylammonium bromide (CTAB) into a 125 MUL volume of 1 butyl-3-methylimidazolium bis(trifluorosulfonyl)imide [C4mim][Tf2N]) as extraction solvent. Under optimum conditions, the detection limits were 0.02 ug L 1 in linear working range of 0.07-100 ug L-1 for Al(III), and 0.05 ug L-1 in linear working range of 0.2-80 ug L-1 for Cr(VI). After the validation by analysis of a certified reference material (CRM), the method was successfully applied to the determination of Al and Cr in vegetables using standard addition method. PMID- 29287414 TI - Thermal processing effects on the IgE-reactivity of cashew and pistachio. AB - Thermal processing can modify the structure and function of food proteins and may alter their allergenicity. This work aimed to elucidate the influence of moist thermal treatments on the IgE-reactivity of cashew and pistachio. IgE-western blot and IgE-ELISA were complemented by Skin Prick Testing (SPT) and mediator release assay to determine the IgE cross-linking capability of treated and untreated samples. Moist thermal processing diminished the IgE-binding properties of both nuts, especially after heat/pressure treatment. The wheal size in SPT was importantly reduced after application of thermally-treated samples. For cashew, heat/pressure treated-samples still retain some capacity to cross-link IgE and degranulate basophils, however, this capacity was diminished when compared with untreated cashew. For pistachio, the degranulation of basophils after challenge with the harshest heat/pressure treatment was highly decreased. Boiling produced more variable results, however this treatment applied to both nuts for 60 min, led to an important decrease of basophil degranulation. PMID- 29287415 TI - Metabolomics fingerprint of coffee species determined by untargeted-profiling study using LC-HRMS. AB - Coffee bean extracts are consumed all over the world as beverage and there is a growing interest in coffee leaf extracts as food supplements. The wild diversity in Coffea (Rubiaceae) genus is large and could offer new opportunities and challenges. In the present work, a metabolomics approach was implemented to examine leaf chemical composition of 9 Coffea species grown in the same environmental conditions. Leaves were analyzed by LC-HRMS and a comprehensive statistical workflow was designed. It served for univariate hypothesis testing and multivariate modeling by PCA and partial PLS-DA on the Workflow4Metabolomics infrastructure. The first two axes of PCA and PLS-DA describes more than 40% of variances with good values of explained variances. This strategy permitted to investigate the metabolomics data and their relation with botanic and genetic informations. Finally, the identification of several key metabolites for the discrimination between species was further characterized. PMID- 29287416 TI - Phytochemical composition and beta-glucan content of barley genotypes from two different geographic origins for human health food production. AB - In the present study, 27 barley genotypes (Hordeum vulgare L.) grown in two geographic origins (Czech Republic and Spain) were analysed for their contents of beta-glucan, tocols and phenolic compounds (free and bound). The samples included hulled, hull-less and coloured genotypes. The results showed that concentrations of beta-glucan range from 2.40 to 7.42g/100g. Total tocol content of the barley samples ranged between 39.9 and 81.6MUg/g. A total of 64 compounds were identified in the barley samples. These included 19 phenolic acids and aldehydes, 9 flavan 3-ols, 9 flavone glycosides, and 27 anthocyanins. The results showed a wide range of phenolic concentrations in the barley samples, highlighting the presence of considerable amounts of anthocyanins in purple barley genotypes. In synthesis, barley should be considered a good source of bioactive components, especially because of the broad spectrum of phytochemicals with potential health benefits besides the soluble fibre (beta-glucan). PMID- 29287417 TI - Structure-affinity relationship of the interaction between phenolic acids and their derivatives and beta-lactoglobulin and effect on antioxidant activity. AB - In this study, 71 phenolic acids and their derivatives were used to investigate the structure-affinity relationship of beta-lactoglobulin binding, and the effect of this interaction on antioxidant activity. Based on a fluorescence quenching method, an improved mathematical model was adopted to calculate the binding constants, with a correction for the inner-filter effect. Hydroxylation at the 3 position increased the affinity of the phenolic acids for beta-lactoglobulin, while hydroxylation at the 2- or 4-positions had a negative effect. Complete methylation of all hydroxy groups, except at the 3-position, enhanced the binding affinity. Replacing the hydroxy groups with methyl groups at the 2-position also had a positive effect. Hydrogen bonding was one of the binding forces for the interaction. The antioxidant activity of phenolic acid-beta-lactoglobulin complexes was higher than that of phenolic acids alone. These findings provide an understanding of the structure-activity relationship of the interaction between beta-lactoglobulin and phenolic acids. PMID- 29287418 TI - Crosslinking of milk proteins by microbial transglutaminase: Utilization in functional yogurt products. AB - Key modifying roles of microbial transglutaminase (MTGase) in the development of innovative probiotic and non-probiotic yogurts with improved functional and quality characteristics have been comprehensively reviewed. MTGase crosslinking reactions with milk proteins stabilize the three-dimensional structure of yogurt. Yogurts treated with MTGase showed decreased syneresis, increased water-holding capacity and viscosity, homogeneous structure, desired texture, and physicochemical high stability during storage time. The utilization of MTGase does not affect negatively the sensory attributes of yogurt. Inclusion of MTGase into acidified yogurt drinks reduces the serum separation with an improved viscoelasticity. This multi-functional enzyme also protects the viable starter and probiotic cells in yogurts. Further studies are required to assess the viability of probiotics in yogurts protected using MTGase-mediated microcapsules. PMID- 29287419 TI - Bioaccessibility of phenolic compounds following in vitro large intestine fermentation of nuts for human consumption. AB - A bioaccessibility study of polyphenols after in vitro simulated large intestine fermentation was carried out on edible nuts. Raw nuts were also analysed for total phenolic content and antioxidant potential, considering both bound and free phenolics. The highest phenolic content was found in walnuts, followed by pistachios extracts (596.9 and 410.1 mg gallic acid equivalents 100 g-1, respectively). Consistently, the total antioxidant capacity was highest in walnuts (3689.7 MUM trolox equivalents 100 g-1) followed by peanuts and pistachios (3169.6 and 2990.1 MUM trolox equivalents 100 g-1, respectively). Data showed high correlations between total phenolics and both antioxidant activities. The metabolomics-based phenolic profile depicted during in vitro fermentation showed a degradation of higher-molecular-weight phenolics over 48 hours of faecal fermentation, with a concurrent increase in low-molecular-weight compounds (hydroxybenzoic and hydroxycinnamic acids, alkylphenols, and tyrosols). Our findings indicate that nuts deliver polyphenols into the colon, with bioaccessibility values not negligible for alkylphenols, tyrosols and phenolic acids. PMID- 29287420 TI - Cross priming amplification with nucleic acid test strip analysis of mutton in meat mixtures. AB - A simple, sensitive, accurate and affordable rapid detection of meat species authentication is urgently needed in food industry. In this study, a cross priming amplification (CPA) combining nucleic acid test strip (CPA-Strip) assay for rapid detection of mutton from meat mixture were developed and its feasibility was investigated. In an isothermal CPA system, cytochrome b (cytb) gene as target was amplified at 63 degrees C for 60min. The nucleic acid strip was able to show the corresponding test line in the presence of target gens in 5min. Non-targeting gene interference was not evident. The CPA-Strip has been applied for the detection of 0.1-100% mutton in a thermal treated meat mixtures with a detection limit of a detect limit of 1%. CPA-Strip assay would be a promising simple, rapid and sensitive method for identification of target species in raw and processed meat mixtures. PMID- 29287421 TI - Charge and hydrophobicity of casein peptides influence transepithelial transport and bioavailability. AB - Antioxidant casein peptides were separated by SP-Sephadex C-25 and C 18 columns. The transepithelial transport and bioavailability including the transport ratio and the remaining ratios of antioxidant activity (RRAA) of these peptide absorbates, were then investigated using a Caco-2 cell monolayer. The results indicate that both the negatively charged peptide fractions (CF1, CF2 and CF3) and the more hydrophilic fraction (HF1) were mainly transported via PepT1 and paracellular routes. The positively charged fractions (CF4 and CF5) and hydrophobic fractions (HF2, HF3 and HF4) were transported via PepT1 and transcytosis. The strongly negatively charged and more hydrophobic fractions showed a higher transport ratio, which ranged from 9.5 to 12.5%; however, the transport ratio of positively charged and hydrophilic fractions ranged from 4.0 to 8.5%. The positively charged and hydrophilic fractions showed a higher RRAA. PMID- 29287422 TI - Effervescence assisted dispersive liquid-liquid microextraction based on cohesive floating organic drop for the determination of herbicides and fungicides in water and grape juice. AB - A novel effervescence assisted dispersive liquid-liquid microextraction method based on cohesive floating organic drop has been developed for simultaneous determination of triazine herbicides and triazole fungicides in aqueous samples followed by ultra-high pressure liquid chromatography tandem a triple quadrupole mass spectrometer. In this method, 1-undecanol as extractant was well dispersed by effervescence. In order to obtain relatively high extraction efficiency, the effects of salt, volume of effervescence mixture, volume of extraction solvent and temperature were investigated. Under the optimum conditions, the proposed method showed good linearity within the range of 0.05-10MUgL-1 with correlation coefficients of 0.9987-0.9999. The recoveries of analytes were in the range of 72.4-101.5% with relative standard deviations ranging from 2.6% to 11.7%. The limits of detection were varied from 2.7 to 9.7ngL-1. This method has been successfully used to simultaneously analyze triazine herbicides and triazole fungicides in surface waters and grape juice. PMID- 29287423 TI - Melatonin treatment reduces chilling injury in peach fruit through its regulation of membrane fatty acid contents and phenolic metabolism. AB - Effects of 0.1 mM melatonin (MT) on chilling injury (CI), membrane fatty acid content and phenolic metabolism in peach fruit were studied during storage at 1 degrees C for 28 days. MT treatment delayed the development of CI in peach fruit, as was illustrated by MT-treated fruit showing lower CI incidence, CI index and firmness loss than the control. MT treatment prevented membrane lipid peroxidation and contributed to maintaining a higher ratio of unsaturated to saturated fatty acids in peach fruit. MT treatment also stimulated the activities of glucose-6-phosphate dehydrogenase, shikimate dehydrogenase and phenylalanine ammonia lyase, but inhibited the activities of polyphenol oxidase and peroxidase. This would help in activating the accumulation of total phenolic and endogenous salicylic acid that might have a direct function in alleviation of CI. These results indicate that MT treatment can be an effective technique to reduce postharvest CI during low temperature storage of peach fruit. PMID- 29287424 TI - Effect of regulated deficit irrigation on fatty acids and their derived volatiles in 'Cabernet Sauvignon' grapes and wines of Ningxia, China. AB - The effect of regulated deficit irrigation (RDI) on fatty acids and their derived volatiles in 'Cabernet Sauvignon' grapes and wines was investigated during two growing seasons in the east foot of Mt. Helan, the semi-arid area. The vines received water with 60% (RDI-1), 70% (RDI-2), 80% (RDI-3), 100% (CK, traditional drip irrigation) of their estimated evapotranspiration (ETc) respectively. RDI treatments resulted in lower yield, berry weight and titratable acidity with higher total soluble solids. RDI-1 increased the content of unsaturated fatty acids in berries and decreased the level of alcohols and esters volatiles in wines. RDI-2 and RDI-3 enhanced 1-hexanol and esters in wines in comparison with CK. The concentrations of C6 aroma compounds were closely correlated with unsaturated fatty acids (p < .05), especially linolenic acid and linoleic acid. The present results provided direct evidence and detailed data to explain the effect of RDI on grapes and wines composition regarding fatty acids and their derived volatiles. PMID- 29287425 TI - Evaluation of putative precursors of key 'reductive' compounds in wines post bottling. AB - Precursors to hydrogen sulfide (H2S), methanethiol (MeSH), ethanethiol (EtSH), and dimethyl sulfide (DMS) were assessed in wines post-bottling, and the percent yield of VSCs from each precursor determined. Cysteine (Cys) and glutathione (GSH) were associated with small increases in H2S concentrations, with a maximum yield of 0.18% and 1.3%, respectively. Greater yields of H2S were obtained from the combined Cys/GSH and copper treatments in white wine. Copper, acting on unknown precursors, was associated with large increases in H2S in Shiraz wines. Dimethyl disulfide and methyl thioacetate were important precursors to MeSH, and produced maximum yields of 72% and 33%, respectively. Ethyl thioacetate was a key precursor to EtSH, with a maximum yield of 39% obtained. Copper and pH were important in modulating MeSH and EtSH accumulation in wines. A maximum yield of 23% of DMS from S-methylmethionine was obtained, with dimethyl sulfoxide producing significantly less DMS with a maximum yield of only 9.4%. PMID- 29287426 TI - Isotope dilution determination for the trace level of 4(5)-methylimidazole in beverages using dispersive liquid-liquid microextraction coupled with ESI-HPLC MS/MS. AB - In this study, a rapid and reliable pretreatment method called dispersive liquid liquid microextraction (DLLME) was developed for the determination of 4(5) methylimidazole (4-MeI) in beverages. The clean-up samples were analyzed by a high performance liquid chromatography coupled with triple quadrupole mass spectrometer (HPLC-MS/MS) using a reversed-phase C18 column (250 mm * 4.6 mm, 5 MUm). The matrix effects and the fault of DLLME operation were corrected by the isotope dilution technique. The developed method exhibited the limit of quantification (0.3 MUg L-1) and excellent linearity (R2 = 0.999). In addition, the recovery values of 4-MeI in carbonated beverage were ranging from 102.60% to 113.22%, in soft drinks were ranging from 103.24% to 108.85%. The content 4-MeI was detected in thirteen beverage samples treated with DLLME and solid phase extraction method (SPE) (ranging from 6.4 to 165.5 MUg L-1). The consistent result of 4-MeI content detected by DLLME and SPE method concluded that the established method on the basis of DLLME was rapid, robust and accurate for the trace 4-MeI determination in beverages. PMID- 29287427 TI - Accurate quantification of toxic elements in medicine food homologous plants using ICP-MS/MS. AB - An analytical method to accurately determine the presence of four toxic elements (As, Cd, Hg, and Pb) in medicine food homologous (MFH) plants using inductively coupled plasma-tandem mass spectrometry (ICP-MS/MS) was established. Fifty common MFH plants from different regions of China were analyzed and the range of values of As, Cd, Hg, and Pb were determined to be 66.3-2978.6 ng g-1, 13.5-8107.1 ng g 1, 1.7-325.6 ng g-1, and 61.4-11428.5 ng g-1, respectively. According to the standards of Chinese Pharmacopoeia (CP) 2010, the excess standard rates of As, Cd, Hg, and Pb were 14%, 16%, 6%, and 18%, respectively. On the basis of the limits set by the Chinese National Standards (CNS) GB 2762-2012, the excess standard rates of As, Cd, Hg, and Pb were 44%, 20%, 12%, and 34%, respectively. Therefore, special attention should be paid to the potential risk posed by toxic element contamination in MFH plants. PMID- 29287428 TI - Characterization of protein hydrolysates from blue whiting (Micromesistius poutassou) and their application in beverage fortification. AB - Enzymatic hydrolysis of fish proteins has been employed as a principle method for converting under-utilised fish into valuable products for the pharmaceutical and health food industries. In this study, six commercial enzymes were tested for their ability to make fish protein hydrolysate powders from whole blue whiting. The chemical and functional properties of these powders were compared. The powders all had high solubility (>80%) across a wide pH range in water and their solubility improved further within a vitamin-tea beverage matrix (>85%). Varying degrees of anti-oxidant activities were recorded for the powders using three model systems (DPPH, ferrous chelating and reducing power). This study demonstrates that commercial enzymes are useful for the extraction and alteration of fish protein from a low value source to produce highly digestible, low molecular weight peptide powders that could be used as a fortifying health ingredient, especially in beverages. PMID- 29287429 TI - Antimicrobial and antioxidant properties of various Greek garlic genotypes. AB - Recent studies show a significant variation in antioxidant and antimicrobial properties between the various garlic genotypes mostly due to differences in chemical composition and bioactive compounds content. The aim of the present study was to evaluate antioxidant properties and antimicrobial activity of garlics collected from the main cultivation areas of Greece, as well as to correlate this activity with their total phenolics content. Genotype G5 showed the highest total phenolics content, which was significantly correlated with the lowest EC50 values for all the tested antioxidant activity assays. Antimicrobial activity was significant, especially against the bacteria Proteus mirabilis and Antibiotic resistant Escherichia coli. In conclusion, significant variation was observed between the studied garlic genotypes, indicating the importance of both growing conditions and genotype on bioactive properties of dry garlic bulbs. This variation could be further exploited in breeding programs in order to select elite genotypes with increased bioactive properties. PMID- 29287430 TI - Comprehensive identification of bioactive compounds of avocado peel by liquid chromatography coupled to ultra-high-definition accurate-mass Q-TOF. AB - Industrially the avocado pulp is exploited principally as oil and paste, generating a huge quantity of peel and seed as by-products. Avocado peel is a promising inexpensive candidate for recovery phenolic compounds. The aim of this work was to identify the bioactive compounds present in an extract of avocado peel obtained by a green extraction technique. Accelerated solvent extraction was performed using water and ethanol as extraction solvents. Liquid chromatography coupled to ultra-high-definition accurate-mass spectrometry was used in order to identify the bioactive compounds. A total of sixty-one compounds belonging to eleven families were identified. Procyanidins, flavonols, hydroxybenzoic and hydroxycinnamic acids were the most common compounds. A sum of thirty-five compounds has been identified here for the first time in avocado peel. These results confirm the potential of avocado peel as a source of bioactive ingredients for its use in the food, cosmetic or pharmaceutical sector. PMID- 29287431 TI - Effect of roasted pea flour/starch and encapsulated pea starch incorporation on the in vitro starch digestibility of pea breads. AB - Oven or microwave roasting and alginate encapsulation of pea flour and starch to produce novel pea ingredients for enrichment of slowly digestible starch (SDS) and resistant starch (RS) content in pea bread were investigated. Pea flour treated either by oven roasting (160 degrees C, 30min) or by microwave roasting (1.1kW, 6min) effectively retained its low starch digestibility similar to its native form (~25% SDS; ~60% RS). When oven roasting was applied to pea starch, SDS content increased triply compared to the fully boiled counterpart. Alginate encapsulation effectively controlled carbohydrate release to simulated gastric, intestinal and colonic fluids, and thus largely enriched the SDS and RS fractions in starch. Pea bread containing up to 37.5% of encapsulated roasted MPS pea starch not only provided high SDS and RS fractions (23.9% SDS and 30.2% RS) compared to a white bread control (0.2% SDS and 2.5% RS), but also provided an acceptable palatability. PMID- 29287432 TI - Olive oil characterization and classification by 13C NMR with a polarization transfer technique: A comparison with gas chromatography and 1H NMR. AB - In a previous work, we optimized and used a fast adiabatic 13C-INEPT (Insensitive Nuclei Enhanced by Polarization Transfer) experiment for the isotopomic analysis of olive oil samples, which allowed us quantifying individual fatty acids within triacylglycerols through multivariate linear regression models. The goal of this study was to validate these models and to evaluate the power of 13C-INEPT in the authentication of olive oils relative to gas chromatography (GC) and 1H NMR. In this respect, a new set of olive oil samples was analyzed by these three techniques. The analytical variables thus obtained as well as their corresponding long-term repeatability were compared. As a result, the reliability of the fatty acid quantification models was proven and the best classification of olive oils according to the altitude of the olive grove and to the morphological aspect (color) of the olives was achieved by means of 13C-INEPT. PMID- 29287433 TI - Changes in calpain activity, protein degradation and microstructure of beef M. semitendinosus by the application of ultrasound. AB - In this investigation, samples were treated by ultrasonic probe (20 kHz) at an intensity of 25 W cm-2 for 20 or 40 min, followed by aging at 4 degrees C for 1, 3 and 7 d. Ultrasound treatment significantly increased myofibrillar fragmentation index (MFI) and decreased Warner-Bratzler shear force (WBSF) at 3 and 7 d of postmortem aging (P < .05). Ultrasound-treated samples showed significantly greater intensities of autolyzed 76 kDa subunits and the lower intensity of intact 80 kDa form compared to control at 1 d of storage (P < .05). Significant difference was found between semitendinosus (ST) samples treated for both 20 and 40 min (P < .05). Ultrasound treated samples showed increased proteolysis during the postmortem storage as reflected by an increased degradation of desmin and troponin-T. These results showed that ultrasound treatment could improve the tenderness of beef ST muscle through regulating the calpain activation and protein degradation during postmortem aging. PMID- 29287434 TI - Yak milk fat globules from the Qinghai-Tibetan Plateau: Membrane lipid composition and morphological properties. AB - Yak milk fat products constitute the base of Qinghai-Tibetan pastoralists' daily food intake. Despite the great importance of fat in processing and pastoralists' health, studies about yak milk fat are scarce. In this study, the lipid composition and the morphological properties of milk fat globule membranes (MFGMs) of yak milk were investigated. The results demonstrated that the yak milk had a higher cholesterol and sphingomyelin content compared to cow milk. In situ structural investigations performed at 25 degrees C by confocal microscopy showed the presence of lipid domains in yak MFGM, with a larger number and wider size range compared to cow milk. Moreover, the simultaneous localization of glycosylated molecules and polar lipids indicated that glycosylated molecules could be integrated into the lipid domains in yak MFGM. Different characteristics in yak MFGM could be related to the lipid composition and may affect the functions of yak milk lipids during processing and digestion. PMID- 29287435 TI - Determination of free, esterified, glycosylated and insoluble-bound phenolics composition in the edible part of araticum fruit (Annona crassiflora Mart.) and its by-products by HPLC-ESI-MS/MS. AB - Phenolics present in the free, esterified, glycosylated and insoluble-bound forms of araticum pulp, peel and seed were for the first time characterized and quantified using HPLC-ESI-MS/MS. Levels of total phenolics, flavonoids, condensed tannins and antioxidant activities from araticum fruit followed the order peel > pulp > seed. Overall, insoluble-bound and esterified phenolics were the dominant forms of phenolics from araticum fruit parts and the highest contributors to their antioxidant activities. Extracts were found to contain contrasting levels of phenolics that were specific to each fruit part. From 10 phenolics quantified in araticum fruit, catechin and epicatechin were the major ones from pulp and peel, whereas seed displayed caffeic acid, catechin and epicatechin as its main phenolics. Araticum fruit was found to provide a good source of phenolics, and the full exploitation of this fruit may find applications in the food, cosmetic and pharmaceutical industries. PMID- 29287436 TI - Designing antioxidant peptides based on the antioxidant properties of the amino acid side-chains. AB - Amino acids exert characteristic antioxidant activities depending on the properties of their side residues. The hydrophobic residues were effective against peroxyl radical, while acidic residues and their analogs were effective against peroxynitrite. Peptides containing tyrosine showed different activities against different reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). The number and position of tyrosine did not affect the antioxidant activity against hypochlorite ion. Against the peroxyl radical, the number of tyrosine residues affected the antioxidant activity, while its position did not have a significant effect. The tyrosine position was an important factor for the antioxidant activity against peroxynitrite. The peptide GWWW showed higher antioxidant activity against peroxyl radical than tryptophan at concentrations below 25 uM, and high activity against peroxynitrite at 250 uM. Our results suggest that antioxidant peptides against a specific target ROS or RNS can be designed based on the characteristics of the amino acid side chains. PMID- 29287438 TI - Structural characterization of melanoidin formed from d-glucose and l-alanine at different temperatures applying FTIR, NMR, EPR, and MALDI-ToF-MS. AB - The aim of this study was to identify specific chemical bonds and characteristic structures in melanoidins formed from d-glucose and l-alanine between 130 and 200 degrees C. The results might be used to control the type and amount of melanoidin produced during food processing. For this purpose, complementary techniques, such as FTIR, NMR, EPR, and MALDI-ToF, were employed. At 160 degrees C color, solubility and UV/Vis absorption change characteristically and consequently, structural transformations could be observed in FTIR and NMR spectra. For example, sharp signals of N-H, C-N, and C-H oscillations in the l alanine spectrum are prone to inhomogeneous broadening in melanoidins prepared above 150 degrees C. These changes are caused due to formation of heterogeneous macromolecular structures and occur during condensation reactions that lead to an increasing loss of water from the melanoidins with increasing temperatures. Additionally, MALDI-ToF-MS indicates the polymerization of glyoxal/glyoxylic acid and EPR shows the formation of radical structures. PMID- 29287437 TI - Preparation of extra-small nisin nanoparticles for enhanced antibacterial activity after autoclave treatment. AB - Nisin is applied broadly in the food industry as an antimicrobial peptide. The objective of this study is to prepare nisin nanoparticles using free nisin by a facile nanoprecipitation technique and to investigate their antimicrobial activity after high-temperature processing. Transmission electron microscopic images showed that the size of extra-small nisin nanoparticles with different initial concentrations of nisin (0.1%, 0.3% and 0.5%) was 5, 10 and 15 nm, respectively. The nisin nanoparticles were stable at pH 5.0 with the smallest size. Moreover, nisin nanoparticles exhibited a higher antimicrobial activity than free nisin at a concentration below 2.0 mg/ml after autoclave treatment. These results suggested that nisin nanoparticles could serve as a potential food preservative. PMID- 29287439 TI - High resolution-ion mobility mass spectrometry as an additional powerful tool for structural characterization of mycotoxin metabolites. AB - This work was designed as a proof of concept, to demonstrate the successful use of the comparison between theoretical and experimental collision cross section (CCS) values to support the identification of isomeric forms. To this purpose, thirteen mycotoxins were considered and analyzed using drift time ion mobility mass spectrometry. A good linear correlation (r2 = 0.962) between theoretical and experimental CCS was found. The average DeltaCCS was 3.2%, fully consistent with the acceptability threshold value commonly set at 5%. The agreement between theoretical and experimental CCS obtained for mycotoxin glucuronides suggested the potential of the CCS matching in supporting the annotation procedure. PMID- 29287440 TI - Characterization of the key aroma compounds in mulberry fruits by application of gas chromatography-olfactometry (GC-O), odor activity value (OAV), gas chromatography-mass spectrometry (GC-MS) and flame photometric detection (FPD). AB - The volatile compounds of mulberries obtained from three cultivars (M. nigra, Y1, M. Macroura, Y2 and M. Alba, Y3) were investigated by gas chromatography olfactometry (GC-O), odor activity value (OAV), gas chromatography-mass spectrometry (GC-MS) and flame photometric detection (FPD). The results showed that 41, 37 and 41 compounds were detected in Y1, Y2 and Y3 samples, respectively. In addition, 12, 11, and 12 sulfur compounds were identified in three samples by FPD, respectively. Quantitative analysis showed 2 (methylthio)ethanol, methionol, dimethyl sulfide, methional and 3-ethylthiophene were present in relatively high amounts in each of the three samples. Furthermore, benzaldehyde, ethyl butanoate, (E)-2-nonenal, 1-hexanol, hexanal, methional, 3-mercaptohexyl acetate and 3-mercaptohexanol were present with much higher OAVs than other compounds. Finally, four compounds (pentanal, ethyl acetate, acetic acid, methionol) were selected to investigate possible effects on six descriptors, which indicated that the volatile compounds at sub-threshold concentrations are likely to contribute to overall aroma. PMID- 29287441 TI - Sugarcane bagasse hydrolysate as a potential feedstock for red pigment production by Monascus ruber. AB - Sugarcane bagasse (SCB) hydrolysate could be an interesting source for red pigment production by Monascus ruber Tieghem IOC 2225. The influence of different wavelength of light-emitting diode (LED) at 250 MUmol.m-2.s-1 of photon flux density on red pigment production by M. ruber in glucose-based medium was evaluated. Then, SCB hydrolysate was used as carbon source under the previously selected light incidence conditions. In glucose-based medium, the highest pigment production was achieved in fermentation assisted with orange LED light (8.28 UA490nm), white light (8.26 UA490nm) and under dark condition (7.45 UA490nm). By using SCB hydrolysate-based medium, the highest red pigment production (18.71 AU490nm) was achieved under dark condition and the glucose and cellobiose present in the hydrolysate were metabolized. SCB enzymatic hydrolysate was demonstrated to be a promising carbon source for high thermal stability red pigment production (activation energy of 10.5 kcal.mol-1), turning an interesting alternative for implementation in biorefineries. PMID- 29287442 TI - Thermosonication process for optimal functional properties in carrot juice containing orange peel and pulp extracts. AB - Aqueous extracts of orange peel and pulp with high total phenolic contents (TPC) (25.94 and 11.38 mg GAE/g extracts, respectively) were employed in the formulation of functional carrot juice and functional juices were treated using thermosonication process. In accordance with Box-Behnken design, 17 runs with 3 variables and 3 levels was applied for the optimization of the carrot juice with peel (CJPL) and pulp (CJPP) extracts. Overlaid contour plots prediction showed that the optimal conditions for CJPL were 125 mL juice volume, 6.50 min ultrasound process time and 52.78 degrees C ultrasound process temperature for maximum TPC (30.25 mg GAE/100 mL) and DPPH scavenging activity (61.22%). Sample CJPP has maximum TPC (28.94 mg GAE/100 mL) and DPPH activity (55.87%) under optimal ultrasound process conditions of 125 mL juice volume, 5.04 min and 59.99 degrees C ultrasound process time and temperature, respectively. Optimization of thermosonication showed significant improvements in the quality of functional carrot juice. PMID- 29287443 TI - Influence of water stresses on capsaicinoid production in hot pepper (Capsicum chinense Jacq.) cultivars with different pungency levels. AB - Although water stress reduces fruit yield, it also increases capsaicinoid accumulation in hot pepper. The aim of this study was to investigate the effect of different water regimes on capsaicinoid production in Capsicum chinense Jacq. having different pungency levels. Four hot pepper (C. chinense) cultivars were planted with four water regimes after anthesis: daily irrigation (control; S1), every 2 days (S2), every 3 days (S3) and every 4 days (S4). The results found that Akanee Pirote with the S2 treatment gave the highest capsaicinoid yield, and the increase of capsaicinoid yield was attributed from increasing the absolute capsaicinoid content and reducing the dry fruit yield as compared to the control. Capsaicinoid yield of Bhut Jolokia, Orange Habanero, and BGH1719 responded to the water stresses, but produced less capsaicinoid yield as compared to the control. This study reveals that appropriate water stress could increase capsaicinoid yield in some, but not all, hot pepper cultivars. PMID- 29287444 TI - Polycyclic aromatic hydrocarbons content and fatty acids profile in coconut, safflower, evening primrose and linseed oils. AB - This study aimed at evaluating the polycyclic aromatic hydrocarbons (PAHs) contamination of commercial vegetable oils and examined the identity through the fatty acids profiles. Coconut, safflower, evening primrose, and linseed oils marketed in Sao Paulo (Brazil) were investigated totaling 69 samples. Four PAHs, benzo[a]anthracene (BaA), chrysene (Chr), benzo[b]fluoranthene (BbF), and benzo[a]pyrene (BaP), were detected in 96% of the samples at individual levels ranging from not detected to 14.99 MUg kg-1. Chrysene was the abundant hydrocarbon found among all types of oils, with the highest median values. The results of the fatty acid profiles revealed that 43% showed different profiles according to the ones on their labels, with a higher incidence of adulteration of evening primrose oils. The maximum tolerable limits by European Regulation No. 835/2011 were exceeded for BaP in 12%, and for total 4 PAHs in 28%, with a greater contribution of adulterated samples. PMID- 29287445 TI - Phospholipids composition and molecular species of large yellow croaker (Pseudosciaena crocea) roe. AB - The research aims to study phospholipids (PL) classes and molecular species of large yellow croaker (Pseudosciaena crocea) roe. Both gas chromatographymass spectroscopy (GC-MS) and high-performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD) were utilized to analyze and identify the PLs fatty acids compositions and classes in the P. crocea roe, respectively. Docosahexaenoic acid (DHA, C22:6) and eicosapentaenoic acid (EPA, C20:5) account for 35.0% and 6.9% of the PLs. Phosphatidylcholines (PC), lysophosphatidylcholines (LPC), phosphatidylethanolamines (PE) and phosphatidylinositols (PI) account for 76.36 +/- 0.62%, 12.30 +/- 0.55%, 9.12 +/- 0.02% and 1.09 +/- 0.01% of the total PLs, respectively. In addition, the PLs molecular species were characterized by ultra-high performance liquid chromatography-electrospray ionization-quadruple-time of flight-mass spectrometry (UPLC-Q-TOF-MS). A total of 92 PLs molecular species was identified, including 49 PCs, 13 PEs, 10 phosphatidic acids (PAs), 13 phosphatidylserines (PSs), 3 phosphatidylglycerols (PGs), 2 sphingomyelins (SMs), and 2 PIs of the P. crocea roe. PMID- 29287446 TI - A simple microsatellite-based method for hazelnut oil DNA analysis. AB - Molecular food traceability requires continuous updates to identify more robust, efficient and affordable methodologies to guarantee food quality and safety and especially consumers' health. Available commercial kits are often unsatisfactory and require modifications to successfully detect single components on complex and transformed food matrices. Here we report a simple method for molecular traceability of cold-pressed hazelnut oil based on microsatellite DNA markers. Different genomic extraction methodologies were tested and a total genome pre amplification step was applied on PCR-negative samples. PCR-capillary electrophoresis using nine microsatellites demonstrates the accuracy of the fingerprint analysis even for filtered oil. PMID- 29287447 TI - The effect of edible coating based on Arabic gum, sodium caseinate and essential oil of cinnamon and lemon grass on guava. AB - The effect of five coating formulations viz.: (A) 5% Arabic gum (AG)+1% sodium caseinate (SC)+1% cinnamon oil (CE); (B) 5% AG + 1% SC + 2% CE; (C) 5% AG + 1% SC + 1% lemongrass oil (LG); (D) 5% AG + 1% SC + 2% LG; and (E) 5% AG + 1% SC + 2% CE + 2% LG on guava during 35 days storage at 4-7 degrees C was investigated. Thereafter samples were allowed to ripen for five days at 25 +/- 2 degrees C. The quality of guava was analyzed at an interval of 7, 21, 35 and 40 days. The coating applications resulted in lower activity of PPO & POD, higher DPPH radical scavenging activity, higher retention of ascorbic acid, phenol & flavonoid content, exhibited slower rise of reducing and total sugar in guava pulp. Samples in treatment B and D were the best formulations for extending shelf-life of guava up to 40 days versus seven days of uncoated samples. PMID- 29287448 TI - Development of extraction method for characterization of free and bonded polyphenols in barley (Hordeum vulgare L.) grown in Czech Republic using liquid chromatography-tandem mass spectrometry. AB - Complete characterizations of free and bonded phenolic compounds, presented in four cultivars of barley from two regions of Czech Republic, were achieved, using optimized solvent extraction and liquid chromatography coupled with tandem mass spectrometry. The optimization of extraction of free polyphenols was performed using Box-Behnken design and response surface methodology. The intra-day and extra-day precision of developed method were below 6% and 12%, respectively. The isolation of polyphenols bonded to the cell wall structure was carried out by a hydrolysis process. In all cultivars, p-hydroxybenzoic, p-coumaric and ferulic acids were the most abundant compounds. Their average amounts in barley samples were 17.6, 15.2 and 54.4% (m/m), respectively. The highest amount of these compounds was found in the bonded form, proving the importance of this procedure for the correct characterization of total polyphenols in food matrices. PMID- 29287449 TI - Potential bioaccessibility and functionality of polyphenols and cynaropicrin from breads enriched with artichoke stem. AB - In this study, an artichoke stem powder (ASP) was used at three concentrations (3%, 6% and 9%) in the formulation of new breads. The bioaccessibility of polyphenols and cynaropicrin from the ASP-enriched breads was evaluated in vitro by using a digestion model combined to high resolution mass spectrometry analysis. The overall total antioxidant capacity of the bioaccessible and unsolubilized fractions obtained during the intestinal steps and the potential ability to modulate alpha-glucosidase activity were tested. Data showed that 82% of totally bioaccessible polyphenols and 74% of cynaropicrin were released during the duodenal digestion whereas 88% of caffeic acid was released in the colon step. The antioxidant capacity and the alpha-glucosidase inhibitory activity of the duodenal extract correlated with the amount of ASP in the bread. Data demonstrated that ASP might be a valuable functional ingredient to create a reducing environment in the intestine and to partially modulate glucose metabolism. PMID- 29287450 TI - Functionalization of yogurts with Agaricus bisporus extracts encapsulated in spray-dried maltodextrin crosslinked with citric acid. AB - Mushroom extracts contain bioactive compounds potentially useful to functionalize foodstuffs. Herein, alcoholic extracts of Agaricus bisporus were studied for their bioactivity and viability as functional ingredients in a food product with high water content (yogurt). Extracts were microencapsulated (to improve their stability and hydrophilicity) by spray-drying, using maltodextrin crosslinked with citric acid as encapsulating material. The effect of thermal treatment (after atomization) on crosslinking and bioactivity of microspheres was tested. The incorporation of free and thermally untreated forms resulted in yogurts with higher initial antioxidant activity (EC50 values: 214 and 272 mg.mL-1) that decreased after 7 days (EC50 values: 248 and 314 mg.mL-1). Contrarily, thermally treated microencapsulated extracts showed higher antioxidant activity after the same period (EC50 values, 0 days: 106 mg.mL-1; 7 days: 48.7 mg.mL-1), in result of an effective protection provided by microencapsulation with crosslinked maltodextrin and citric acid. Functionalized yogurts showed an overall maintenance of nutritional properties. PMID- 29287451 TI - Simplified recovery of enzymes and nutrients in sweet potato wastewater and preparing health black tea and theaflavins with scrap tea. AB - The industry discards generous organic wastewater in sweet potato starch factory and scrap tea in tea production. A simplified procedure to recover all biochemicals from the wastewater of sweet potato starch factory and use them to make health black tea and theaflavins from scrap green tea was developed. The sweet potato wastewater was sequentially treated by isoelectric precipitation, ultrafiltration and nanofiltration to recover polyphenol oxidase (PPO), beta amylase, and small molecular fractions, respectively. The PPO fraction can effectively transform green tea extracts into black tea with high content of theaflavins through the optimized fed-batch feeding fermentation. The PPO transformed black tea with sporamins can be used to make health black tea, or make theaflavins by fractionation with ethyl acetate. This work provides a resource- and environment-friendly approach for economically utilizing the sweet potato wastewater and the scrap tea, and making biochemical, nutrient and health products. PMID- 29287452 TI - Changes in the GABA and polyphenols contents of foxtail millet on germination and their relationship with in vitro antioxidant activity. AB - Germination along with ultrasonic assisted extraction induced a significant beneficial effect on the characteristics of polyphenolic components profile, GABA contents and in vitro antioxidant capacity of the foxtail millet flour extracts. The total antioxidant activity (29.0-45.23 mgAAE/g) and reducing power (0.53-0.76 ug/ml) increase during germination were due to quantitative increase in phthalicacid; hex-3yl-ester; hexadecanoicacid methylester etc. whereas, increase in DPPH (48.32-59.62%) and hydrogen peroxide scavenging activities (35.44-63.07 mM-Trolox/g) were attributed to increase in hexadecanoic acid methylester; 9,12 Octadecadienoicacid ethylester and synthesis of new compounds like pentadecanoicacid; 14-methyl-methylester etc. The metal chelating abilities (34.92-57.38 mgEDTA/g) and in vitro antioxidant activity increase due to overall increase in phenolics, flavonoids along with GABA contents. Synthesis of additional polyphenolic components viz. astaxanthin, propanoicacid, 1 monolinoleoylglycerol trimethylsilylether, 9,12,15-octadecatrienoicacid etc. as a result of germinated explored the possible potential utilization of germinated foxtail millet grains in various functional and convenience food formulations. PMID- 29287453 TI - Functional and conformational changes to soy proteins accompanying anthocyanins: Focus on covalent and non-covalent interactions. AB - The present study was aimed to evaluate the interaction between anthocyanins from black rice and soybean protein isolate (SPI) via non-covalent and covalent bindings and the impact of these interactions on the functional and conformational changes of soybean protein. The conformational changes of the protein structure with different concentrations of anthocyanins (0.05, 0.1%, and 0.2%) were analyzed using three-dimensional fluorescence and Fourier transform infrared spectroscopy. The anthocyanins were more likely to form covalent interactions with SPI instead of non-covalent interactions. The addition of anthocyanins changed the secondary structure of SPI with a decrease in beta sheets and an increase in beta-turns and random coils. The emulsifying and foaming properties of SPI were improved after complexation with anthocyanins. This study might be useful for elucidating the mechanisms behind the binding of anthocyanins with SPI and the possible uses of SPI-anthocyanin complexes in food formulations. PMID- 29287454 TI - Initial evaluation of fruit of accessions of Persea schiedeana Nees for nutritional value, quality and oil extraction. AB - Persea schiedeana Nees is an underutilized and very little known species whose fruit is consumed in Mesoamerica where it grows wild. This study was carried out to evaluate: 1) the variability of fruit characteristics of different accessions; 2) the effects of centrifugation and microwave treatment on extracting oil from the fruit and on its qualitative characteristics; 3) the nutraceutical characteristics of the fruit and seeds of different accessions. The results showed a large variability in fruit size and oil/dry matter contents among the different accessions. There was a significant relationship between the dry matter and oil contents in the pulp. The combined use of centrifugation and microwave treatments gave high oil extraction yields (67-68%). The oils had good fatty acid composition and antioxidant capacity. The results gave an initial picture about the total phenol contents and antioxidant capacities in the seeds and in the different parts of the fruit. PMID- 29287455 TI - A novel method of recognizing liquefied honey. AB - The content of glucose, fructose, sucrose, maltose and water were determined for multiflorous honey of Great Poland. The measurements were carried out for different fractions of honey and also for the liquefied honey at 40 degrees C. Water activity and pH were both determined for all samples. A new method of recognizing liquefied honey is proposed based on the water influence on pH and the monosaccharides and disaccharides contents. The simple function of quadratic polynomial enabled to reveal the different character of the liquefied honey. The electrical conductivity behavior of different dry matter samples of honey are presented in the wide range of temperature. The proton spin-lattice relaxation measurements were recorded for the crystalline fraction in the magnetic field range covering the proton Larmor frequencies from 0.01 to 25 MHz and in the wide range of temperature. Heating the honey at 30 degrees C results in the irreversible molecular structure changes. PMID- 29287456 TI - The enzymatic hydrolysis of soy protein isolate by Corolase PP under high hydrostatic pressure and its effect on bioactivity and characteristics of hydrolysates. AB - Enzymatic hydrolysis of soy protein isolate by Corolase PP under high hydrostatic pressure conditions was studied and the effects of hydrolysis on antioxidant and antihypertensive activities were investigated. As observed, high hydrostatic pressure (80-300MPa) enhanced the hydrolytic efficiency of Corolase PP and decreased the surface hydrophobicity of the hydrolysates. Hydrolysates obtained at 200MPa for 4h had higher bioactivities (reducing power, ABTS radical scavenging and ACE inhibitory activities). The molecular weight (MW) determination indicated that hydrolysis at high hydrostatic pressure could increase the production of small peptides (<3kDa) and the amino acid sequences of these peptides with different inhibitory abilities, less than 3kDa, in hydrolysates were identified using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF MS). These results indicated that high hydrostatic pressure combined with Corolase PP treatments could be used as a potential technology to produce bioactive peptides from soy protein isolate. PMID- 29287457 TI - Pulsed electric field processing reduces the oxalate content of oca (Oxalis tuberosa) tubers while retaining starch grains and the general structural integrity of tubers. AB - The aims of this research were to investigate if pulsed electric field (PEF) treatments caused cellular/structural alterations in Oxalis tuberosa (oca) tubers and if PEF treatment could reduce tuber oxalate levels. Whole oca tubers were treated with PEF at different electric field strengths up to 1.2 kV/cm. PEF treatments above 0.5 kV/cm caused tubers to soften, but differences in the electrical properties of the tuber tissues led to an uneven PEF effect with the tuber inner cores softening more than the middle regions. Cell viability tests confirmed the unevenness of the PEF effect, however PEF caused no changes in overall tuber/tissue structure. Even at high electric field strengths the cell remained largely intact and most starch grains were retained within the cells. Despite the retention of starch, PEF treatment reduced tuber oxalate contents by almost 50% in some tissues and could potentially aid the development of low oxalate oca-based foods. PMID- 29287458 TI - Structures, bioactivities and future prospective of polysaccharides from Morus alba (white mulberry): A review. AB - Morus alba L. (family Moreaceae), also known as white mulberry, is distinguished as a source of highly promising traditional medicines (including Mori Folium, Mori Fructus, Mori Ramulus and Mori Cortex) and also functional foods. Over the past two decades, the vast majority of the studies with regard to the isolation and bioactivities of M. alba polysaccharides have mainly focused on its leaves and fruits, which are both medicinal and edible. The tender M. alba leaf is edible and can be used to make tea, the mature M. alba fruit is sweet and juicy. M. alba fruits and leaves contain rich bioactive polysaccharides, which are shown to possess various promising bioactivities, mainly including antidiabetic, immunomodulation, anti-inflammation, antioxidation, anti-obesity, hepatoprotection and renoprotection. The main purpose of this review is to provide systematically reorganized information on structural characteristics and bioactivities of M. alba polysaccharides to support their further therapeutic potentials and sanitarian functions. PMID- 29287459 TI - Bioactivity of fucoidan extracted from Laminaria japonica using a novel procedure with high yield. AB - Due to antitumor and antioxidant activities, there has been increasing interest in fucoidans, sulfated polysaccharides, from brown algae. Currently, the classic hot water extraction and acid extraction are time-consuming, and can cause the partial cleavage of sulfate esters, leading to bioactivity loss. The present study developed a novel process for extracting fucoidans from Laminaria japonica with 0.5% ethylenediaminetetraacetic acid at 70 degrees C. Crude fucoidans (CFs) obtained with a yield (~16%) was purified to different fractions of F1, F2 and F3. The fractions displayed similar anticancer activity against Hela cells. Due to the differences in sulfate content, molar ratio of sulfate to fucose and monosaccharide composition, F1 and F2 exhibited stronger antioxidant ability than CFs and F3. This novel extraction provides an efficient procedure for extracting fucoidans from brown seaweeds with high extraction yield and removing pigments with one single step. PMID- 29287460 TI - Influence of the ripening stage and the lyophilization of wild cardoon flowers on their chemical composition, enzymatic activities of extracts and technological properties of cheese curds. AB - The selection of an appropriate Cynara cardunculus flowers batch is a preliminary step to produce rennet with better clotting properties. For this reason, we proposed to study the influence of the ripening stage and the lyophilization of cardoon flowers on their chemical composition, enzymatic activities of extracts, and technological properties of cheese curds. Results of flowers composition have shown that lyophilized flowers harvested at the middle of ripening stage (A) could be employed to produce mainly proteins or milk-clotting proteases. To confirm this, enzymatic activities of extracts and technological properties of curds were assessed. The experimental findings revealed that flowers lyophilization seems to be an efficient way to produce rennet with better clotting properties, leading to higher yield, moisture, and texture parameters of curd. These findings allowed us to select lyophilized flowers (A) for further cheese making process. PMID- 29287461 TI - Novel FRET-substrates of Rhizomucor pusillus rennin: Activity and mechanistic studies. AB - The development of sensitive, easy and reliable methods for the determination of Rhizomucor pusillus rennin (MPR) activity, in free and in immobilized form, along with the elucidation of the mechanism of action, represent challenges for the widespread use of the enzyme in industrial cheese production. These could be accomplished by using highly specific and sensitive substrates, as well as direct assay methods. We designed and synthesized novel substrates based on Fluorescence Resonance Energy Transfer (FRET) for the MPR by employing computational simulation techniques and peptide synthesis in liquid phase. Three FRET substrates (Abz-GFY-pNA, Abz-SFY-pNA and Abz-GFI-pNA) were found active, while the Abz-GFY-pNA showed the highest reliability, sensitivity and specificity among them. Subsequently, a novel mechanism of MPR action was elucidated, with the development of novel methods for assaying activity in free and immobilized form, which both may contribute in the wider use of rennin in cheese production and other biotechnological applications. PMID- 29287462 TI - Enzymatic esterification of acylglycerols rich in omega-3 from flaxseed oil by an immobilized solvent-tolerant lipase from Actinomadura sediminis UTMC 2870 isolated from oil-contaminated soil. AB - Polyunsaturated fatty acids (PUFAs) are essential to human health and can be produced by enzymatic esterification. Actinomadura sediminis UTMC 2870 isolated from oil-contaminated soil contained a lipase that was stable at varying pH and in various solvents, salts, and chemicals. This lipase exhibited high efficiency for omega-3 (n-3), and its production was optimized using a response surface method. Acylglycerols (AGs) rich in n-3 were produced by extraction of the free fatty acids (FFAs) from flaxseed oil, concentration of PUFAs, and enzymatic esterification by the Celite-immobilized lipase. The resulting product contained 50% (w/w) PUFAs, including 42% (w/w) alpha-linolenic and 9.7% (w/w) linoleic acid. The n-6/n-3 ratio in the product was 0.24, which differed markedly from the high values for this ratio in seed oils. Therefore, the A. sediminis lipase appears to be a good candidate enzyme for ester synthesis and especially for production of n-3-rich AGs for food industries. PMID- 29287463 TI - Synthesis, characterization, and functional properties of chlorophylls, pheophytins, and Zn-pheophytins. AB - The aims of this study were to synthesize chlorophyll derivatives, pheophytins and Zn-pheophytins, from chlorophylls extracted from spinach, characterize them, and evaluate their antioxidant and anti-inflammatory activities. The chlorophylls isolated from spinach were identified by means of FT-IR and NMR spectroscopies. The synthesis of pheophytins and Zn-pheophytins was confirmed by UV-Vis spectral analyses. The antioxidant activity of chlorophylls, pheophytins, and Zn pheophytins was studied. The results revealed that the Zn-pheophytins showed the highest 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and beta-carotene bleaching activities, followed by chlorophylls and pheophytins. Additionally, Zn pheophytins showed substantial inhibitory activity against lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells. Furthermore, Zn-pheophytins remarkably suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS) in RAW 264.7 cells and showed no cytotoxicity. Our findings indicated that Zn-pheophytins have strong antioxidant and anti-inflammatory properties and can therefore be a potential source of bioactive compounds for nutraceutical, cosmetic, and pharmaceutical applications. PMID- 29287464 TI - Stability of alternariol and alternariol monomethyl ether during food processing of tomato products. AB - The stability of two Alternaria mycotoxins, alternariol (AOH) and alternariol monomethyl ether (AME), has been investigated during the food processing of tomato products simulating commercial processing conditions. The production stages assessed were the storage of raw fruits, fruit washing, and thermal processing. It was observed that time of storage significantly reduced the initial concentration of AOH, but only if tomatoes were stored at 35 degrees C. For AME, 12 h were sufficient to reduce the initial concentration, regardless of the temperature at which samples were stored (25, 30 and 35 degrees C). The washing step achieved the highest reduction of AOH and AME. This reduction was even more efficient when using sodium hypochlorite solutions. Finally, during the heat treatment (80-110 degrees C), results showed that heating tomato samples at 100 and 110 degrees C, significantly affected AOH stability, though AME seemed to not be affected by these thermal processes. PMID- 29287465 TI - Characterization of lycopene hydrocolloidal structure induced by tomato processing. AB - Tomato juice and paste are special type of dispersions, composed of suspended particles (pulp) dispersed in a colloidal liquid medium (serum). The bright red appearance of soluble solid separated by high speed centrifugation denoted the presence of lycopene in this fraction. Since lycopene is a hydrophobic compound it is not expected to appear in the water soluble fraction. HPLC analysis indicated presence of substantial amount of lycopene in soluble fraction which was confirmed by the appearance of lycopene crystals when observed under Transmission Electron Microscope (TEM). Considerable amount of pectin in the soluble fraction led to hypothesis that pectin facilitated the formation of hydrocolloidal system of suspended lycopene during processing. Enzyme treatment confirmed this hypothesis when pectinase effectively disrupted colloidal system and precipitated lycopene. Necessity of the divalent ions to retain the suspension signified the electrostatic interactions in the matrix surrounding lycopene crystals. PMID- 29287466 TI - Stabilizing effect of montmorillonite on acerola juice anthocyanins. AB - This study was conducted to evaluate color and anthocyanin stability of clarified acerola juice (CAJ) as affected by montmorillonite (Mnt) at different concentrations (0-6 wt%, dry basis). While non-complexed CAJ suffered noticeable color degradation with time and pH variations, the presence of Mnt (especially at 4-6 wt%) not only changed the initial color of CAJ but also made it more stable with time and pH changes. CAJ/Mnt mixtures were ultracentrifuged in order to separate them into supernatants and anthocyanin-complexed Mnt precipitates. The supernatants presented decreasing anthocyanin contents with increasing Mnt concentrations, indicating pigment retention by the precipitates. X-ray diffraction of precipitates showed that Mnt interlayer spacing was increased by increasing anthocyanin/Mnt ratios, corroborating anthocyanin intercalation. FTIR revealed a band at 1530 cm-1 ascribed to formation of anthocyanin-Mnt complexes. Moreover, chromatograms indicated the selective adsorption of two compounds by Mnt, which were identified by LC-MS as cyanidin-3-O-rhamnoside and pelargonidin-3 O-rhamnoside. PMID- 29287467 TI - Calcium-induced skim milk gels using different calcium salts. AB - This study investigated the effects of heating skim milk with soluble calcium salts, calcium chloride, calcium lactate, calcium gluconate and calcium lactobionate, on the physico-chemical and rheological properties of milk. Regardless of the type of salt added, the amount of casein in milk serum decreased and the amount of calcium in centrifuge sediment increased along with the serum calcium. The amount of calcium salt required for gelation and the gel firmness (G') varied depending on the salt. The aCa2+ order in milk was calcium chloride>calcium lactate>calcium gluconate>calcium lactobionate. With the same amount of added calcium salt, the final G' of milk gel followed the same order. The findings from this study suggest that the different association constants and formation of an intermediate calcium complex with hydroxycarboylate groups affected the calcium ion activity, which may influence the gelation properties in milk. PMID- 29287468 TI - Effect of maize bran feruloylated oligosaccharides on the formation of endogenous contaminants and the appearance and textural properties of biscuits. AB - Feruloylated oligosaccharides (FOs) have been approved by the US Food and Drug Administration for addition to baked goods. This work investigated the effect of FOs on the formation of endogenous contaminants, antioxidant properties, appearance and texture of biscuits. FOs inhibited the formation of fluorescent AGEs (advanced glycation end-products), protein oxidation products, and dicarbonyl compounds in a dose-dependent manner. Addition of 10 mg/g FOs decreased the levels of fluorescent AGEs, dityrosine, kynurenine, N' formylkynurenine, 3-deoxyglucosone, glyoxal, and methylglyoxal by 80%, 97%, 56%, 86%, 46%, 54% and 62%, respectively. FOs might inhibit the formation of alpha dicarbonyl compounds, protein oxidative products and fluorescent AGEs by enhancing antioxidant capacity and releasing ferulic acid in baked biscuits. However, FOs increased the browning and hardness of biscuits in a dose-dependent manner. Therefore, the fortification of FOs should be carefully considered based on both the expected health promoting properties and the organoleptic profile of biscuit products. PMID- 29287469 TI - A mass spectrometry method for sensitive, specific and simultaneous detection of bovine blood meal, blood products and milk products in compound feed. AB - Feed sustainability is one of the biggest challenges for the next few years. Solutions have to be found that take feed quality and safety into account. Animal by-products are one valuable source of proteins. However, since the bovine spongiform encephalopathy (BSE) crisis, their use has been strictly regulated. The objective of this study was to propose a routine, sensitive and specific method using ultra-high performance liquid chromatography coupled to tandem mass spectrometry for the detection of blood-derived products and milk powder in feed. Contaminated aquafeeds were analysed in order to evaluate the sensitivity and specificity of the method. This new method meets both selectivity and sensitivity (0.1% (w/w)) requirements imposed by the European Commission for animal proteins detection methods. It offers an innovative and complementary solution for the simultaneously identification of authorised and unauthorised animal by-products such as processed animal proteins (PAPs). PMID- 29287470 TI - Authentication of Iceland Moss (Cetraria islandica) by UPLC-QToF-MS chemical profiling and DNA barcoding. AB - The lichen Cetraria islandica or Iceland Moss is commonly consumed as tea, food ingredients (e.g. in soup or bread) and herbal medicines. C. islandica, which has two chemotypes, can be difficult to distinguish from the sister species Cetraria ericetorum. They are collectively referred to as the Cetraria islandica species complex. This study aimed to use an UPLC-QToF-MS chemical profiling together with DNA barcoding to distinguish species and chemotypes of the C. islandica species complex. Our results show that the two chemotypes of C. islandica are clearly distinguishable from each other and from C. ericetorum by the chemometric approach. The RPB2 barcode was able to differentiate C. islandica from C. ericetorum with a barcode gap, but the widely used nrITS barcode failed. Neither of them could discriminate chemotypes of C. islandica. In conclusion, this integrative approach involving chemical profiling and DNA barcoding could be applied for authentication of Iceland Moss materials. PMID- 29287471 TI - Conformation stability, in vitro digestibility and allergenicity of tropomyosin from shrimp (Exopalaemon modestus) as affected by high intensity ultrasound. AB - The effects of high intensity ultrasound (HIU) modification (power: 100-800 W, 15 min) on the conformation stability, in vitro digestibility and allergenicity of tropomyosin (TM) from Exopalaemon modestus were investigated. HIU treatment oxidized the Cys, Met and Lys in TM and degraded TM to generate protein fragments by HIU-induced free radicals. The alpha-helix content decreased, while beta sheet, beta-turn and random coil increased. The immunoblotting and ELISA data suggested HIU treatment reduced the allergenicity and contributed to higher digestibility of TM. TM had resistance to gastric digestion, while intestinal digestion totally hydrolyzed TM, and the sequential HIU-gastric-intestinal digestion most efficiently hydrolyzed TM and reduced the allergenicity of digestion products. Stronger HIU could loosen TM structure, strengthen the gastrointestinal digestibility of TM and reduce the allergenicity of TM and digestion products to low level. PMID- 29287473 TI - Activity-Guided Identification of in Vitro Antioxidants in Beer. AB - In order to locate the key antioxidants contributing to oxidative stability of beer, activity-guided fractionation in combination with the oxygen radical absorbance capacity (ORAC) assay, hydrogen peroxide scavenging (HPS) assay, and linoleic acid (LA) assay was applied to a pilsner-type beer. LC-MS and 1D/2D NMR experiments led to the identification of a total of 31 antioxidants, among which 3-methoxy-4-hydroxyphenyl-beta-d-glucopyranoside (tachioside), 4-(2-formylpyrrol 1-yl)butyric acid, 4-[2-formyl-5-(hydroxymethyl)pyrrol-1-yl]butyric acid, n multifidol-3-O-beta-d-glucoside, quercetin-3-O-(6"-malonyl)-glucoside, 4 feruloylquinic acid, syringaresinol, saponarin, and hordatines A-C have been isolated from beer for the first time. On a molar comparison, the hordatines A-C, saponarin, and quercetin-3-O-beta-d-(6"-malonyl)glucoside were evaluated with the highest antioxidant activities of all identified beer constituents, reaching values of 10-17.5 (ORAC), 2.0-4.1 (HPS), and 1.1-6.1 MUmol TE/MUmol (LA) for hordatines A-C. PMID- 29287474 TI - Practical Considerations, Challenges, and Limitations of Bioconjugation via Azide Alkyne Cycloaddition. AB - Interrogating biological systems is often limited by access to biological probes. The emergence of "click chemistry" has revolutionized bioconjugate chemistry by providing facile reaction conditions amenable to both biologic molecules and small molecule probes such as fluorophores, toxins, or therapeutics. One particularly popular version is the copper-catalyzed azide-alkyne cycloaddition (AAC) reaction, which has spawned new alternatives such as the strain-promoted azide-alkyne cycloaddition reaction, among others. This focused review highlights practical approaches to AAC reactions for the synthesis of peptide or protein bioconjugates and contrasts current challenges and limitations in light of recent advances in the field. The conical success of antibody drug conjugates has expanded the toolbox of linkers and payloads to facilitate practical applications of bioconjugation to create novel therapeutics and biologic probes. The AAC reaction in particular is poised to enable a large set of functionalized molecules as a combinatorial approach to high-throughput bioconjugate generation, screening, and honing of lead compounds. PMID- 29287477 TI - CME Self Test. PMID- 29287475 TI - Multivariate analysis of attachment of biofouling organisms in response to material surface characteristics. AB - Multivariate analyses were used to investigate the influence of selected surface properties (Owens-Wendt surface energy and its dispersive and polar components, static water contact angle, conceptual sign of the surface charge, zeta potentials) on the attachment patterns of five biofouling organisms (Amphibalanus amphitrite, Amphibalanus improvisus, Bugula neritina, Ulva linza, and Navicula incerta) to better understand what surface properties drive attachment across multiple fouling organisms. A library of ten xerogel coatings and a glass standard provided a range of values for the selected surface properties to compare to biofouling attachment patterns. Results from the surface characterization and biological assays were analyzed separately and in combination using multivariate statistical methods. Principal coordinate analysis of the surface property characterization and the biological assays resulted in different groupings of the xerogel coatings. In particular, the biofouling organisms were able to distinguish four coatings that were not distinguishable by the surface properties of this study. The authors used canonical analysis of principal coordinates (CAP) to identify surface properties governing attachment across all five biofouling species. The CAP pointed to surface energy and surface charge as important drivers of patterns in biological attachment, but also suggested that differentiation of the surfaces was influenced to a comparable or greater extent by the dispersive component of surface energy. PMID- 29287478 TI - Forum. PMID- 29287479 TI - Home Exercises for Tennis and Golfer's Elbow. PMID- 29287481 TI - Living on the Edge-Carefully. PMID- 29287480 TI - Guidelines for Managing Concussion in Sports. AB - In their approach to managing athletes who sustain concussions, sports physicians differ at least as widely as do the many published guidelines on the subject. The scarcity of scientific evidence makes practical decisions about when an athlete can safely return to the field difficult. Efforts to forge a consensus are underway, but controversy persists around such questions as whether a brief loss of consciousness should be classified as a severe concussion. PMID- 29287482 TI - Detecting and Treating Common Foot and Ankle. AB - In brief Midfoot and forefoot fractures commonly seen in a primary care practice include navicular and metatarsal stress fracture, tarsometatarsal fracture dislocation, and acute fracture of the metatarsals, sesamoid, great toe, or lesser toes. A careful history to determine the mechanism of injury and a methodical physical exam to detect sites of tenderness are essential. X-rays are usually required, but stress fractures may warrant bone scans. Compared with ankle and hindfoot fractures, sports-related midfoot and forefoot fractures are more often treated conservatively with casting or wooden shoes. Tarsometatarsal disruption and Jones fractures are more likely to require surgery. PMID- 29287483 TI - Exercising When You're Overweight. PMID- 29287484 TI - Pearls. PMID- 29287485 TI - When Is Disqualification From Sports Justified? AB - In brief An important medicolegal issue is how best to resolve disputes about an athlete's medical eligibility. Team physicians typically recommend against athletic participation when they feel that it will pose an unreasonable risk of injury to an athlete who has an abnormality. But such athletes may cite federal laws designed to protect the disabled and claim a right to participate. The legal framework for resolving sports-participation disputes involving physically impaired athletes is still developing. Recent case law reflects a split decision regarding the legality of excluding athletes whose condition, in the opinion of the team physician, exposes them to an increased risk of significant harm. PMID- 29287486 TI - Nutrition Knowledge. PMID- 29287487 TI - AHA panel outlines sudden death screening standards. PMID- 29287488 TI - Pitted Keratolysis. AB - In brief Pitted keratolysis usually presents no diagnostic difficulties because of its distinctive clinical appearance and odor. Participating in a sport that makes the feet hot and sweaty often contributes to this dermatologic condition. Sometimes simple measures such as proper foot drying and ventilating procedures are enough to clear the infection. The next line of treatment involves the use of topical agents such as erythromycin 2% solution. PMID- 29287489 TI - Neck Pain. AB - In brief Neck pain or related upper-limb pain can be very disabling for active patients young and old. The broad differential includes such conditions as strain, sprain, disk injury, radiculopathy, carpal tunnel syndrome, ulnar neuropathy, and degenerative shoulder disease. A diagnosis can often be made solely based on history and physical exam findings. It is essential to determine whether the pain is localized or radiating. Localized neck pain generally points to muscle strains, ligament sprains, and degenerative facet or disk processes. Pain that radiates into the upper limbs frequently stems from nerve involvement. Unless significant trauma has occurred, diagnostic images are not warranted unless they are likely to change treatment. PMID- 29287490 TI - Bayesian analysis improves pulse secretion characterization in reproductive hormones. AB - : Pulsatile secretion of hormones in the hypothalamic-pituitary-gonadal axis is critical for normal functioning of the reproductive system. Thus, appropriate characterization of pulsatile secretion is important for identifying the (patho)physiology of reproductive conditions. Existing analysis methods often fail to adequately characterize pulsatility, especially when the signal-to-noise ratio is low. Newer Bayesian analysis methods for pulsatile hormones may offer improved secretion quantification in noisier data. The objective of this study was to extensively validate a Bayesian analysis approach for analyzing pulsatile hormones in settings that occur in reproductive studies. An investigative approach was chosen so that clinical research teams will have the knowledge to adopt this newer analysis approach in practice. Three experimental conditions were investigated: luteinizing hormone (LH) profiles in ovariectomized ewes (N=6; high signal-to-noise setting), LH profiles in young ovulating women (N=12; lower signal-to-noise setting), and computer-simulated scenarios (N=200). For each experimental condition, differences in luteinizing hormone pulse outcomes (pulse number, average pulse size, hormone half-life, and non-pulse secretion) were obtained and compared between non-Bayesian and Bayesian analysis pulse analysis methods. For the ewe model, the estimated pulse number and mass were comparable between the Bayesian and non-Bayesian analyses. For the human model, only 4 of 12 subjects could be fitted with the non-Bayesian analysis compared to 10 of the 12 with Bayesian analysis. In general, the Bayesian analysis had lower false negative rates (<4.5%) compared to the non-Bayesian analysis while maintaining a high specificity (false positive rate <2.5%). The Bayesian analysis also had less biased estimates of all pulse features. In conclusion, Bayesian analysis provides a more reliable pulse characterization in low signal-to-noise experiments and should be used for the analysis of reproductive physiology studies of pulsatile hormones. Software is available at www.github.com/BayesPulse . ABBREVIATIONS: LH: luteinizing hormone; FSH: follicle stimulating hormone; GnRH: gonadotropin releasing hormone; FP: false positive; FN: false negative. PMID- 29287491 TI - Acute pulmonary embolism after arthroscopic glenoid labral repair and subacromial decompression: case report and review of the literature. AB - This report describes the case of a 29 year-old female with a history of polycystic ovary syndrome (PCOS) and on combined oral contraceptives who presents with an acute, CT confirmed pulmonary embolus of the right lower lobe, one week following arthroscopic labral repair of the right shoulder. This patient's relevant risk factors including obesity, oral contraceptive use, PCOS, and surgical positioning are discussed. Literature surrounding venous thromboembolism (VTE) following shoulder arthroscopy is also reviewed. PMID- 29287492 TI - Pearls. PMID- 29287494 TI - Should You Opt for Organic? PMID- 29287493 TI - Forum. PMID- 29287495 TI - CME Self Test. PMID- 29287496 TI - Braving a Winning Year. PMID- 29287497 TI - Hypotension in a 10K Runner. PMID- 29287498 TI - An Unusual Source of Wrist Pain. AB - In brief After weight lifting, a 15-year-old boy pain in his right wrist, had tenderness over the dorsum of the lunate, and had limited wrist motion. Radiographs revealed avascular necrosis of the lunate, or Kienbock's disease, and negative ulnar variance. The patient was successfully treated with an ulnar lengthening procedure and immobilization. This patient's symptoms are typical of Kienbock's disease, which should be considered in the differential diagnosis of any active patient who has wrist pain and limited wrist motion. Treatment of this rare disorder can include immobilization for early-stage disease, or surgery, which is most likely to provide an optimal outcome. PMID- 29287500 TI - The Role of Exercise in Fighting Depression. PMID- 29287501 TI - Osteitis Pubis in the Active Patient. AB - In brief For more than 3 months, a young male soccer player had groin pain diagnosed as stemming from a "tight groin." His discomfort, however, was characteristic of the overuse injury osteitis pubis: gradually worsening pain with significant tenderness on palpation of the symphysis pubis. X-ray and bone scan verified the diagnosis. Conservative treatment for osteitis pubis is often successful; our patient responded to a typical regimen of rest; flexibility and strength exercises for the low back, hip, and thigh; and a gradual return to running and full soccer activity. PMID- 29287502 TI - Examining a 'Red Eye'. AB - In brief Primary care physicians often see disorders of the eye that are broadly termed a 'red eye.' Fortunately, most causes of a red eye are non-vision threatening, and once the vision-threatening causes have been ruled out, the condition can usually be successfully treated in the primary care setting. A thorough medical and ocular history and ophthalmic examination will help physicians accurately diagnose such conditions as blepharitis, dacryocystitis, and conjunctivitis. Establishing the etiology will then direct effective treatment. PMID- 29287503 TI - Achilles Tendon Disorders. AB - In brief The spectrum of Achilles tendon disorders, which are common in recreational and competitive athletes, ranges from mild peritendinitis or bursitis to complete ruptures. Among the possible causes of Achilles tendon disorders are vascular insufficiency, inflammatory arthritides, Achilles contractures, hyperpronation, and poor training techniques. Diagnosis of these disorders can usually be made with physical examination and routine radiographs. Treatment is tailored to the specific injury and includes physical therapy, orthoses or heel lifts, Achilles stretching, activity modification, and, occasionally, surgical debridement or tendon repair. PMID- 29287504 TI - In Sportsmedicine, Peer Review Goes Public. PMID- 29287505 TI - Creativity: A New Twist for an Old Game. PMID- 29287507 TI - Mountain Climbing, Chondromalacia, and Exercise. PMID- 29287508 TI - action arena. PMID- 29287509 TI - brief reports. PMID- 29287510 TI - The Injuries of Summer-and Spring and Fall. AB - Despite the strides in conditioning techniques and the attentions of a physicians' association, professional baseball is just beginning to examine its injury situation. PMID- 29287511 TI - letters. PMID- 29287512 TI - Facial Injuries in Motor Sports. AB - Highly flammable fuels, hurtling vehicles, and hard racing surfaces can cause severe facial injuries in motor sports. To minimize permanent damage, the injuries must be properly diagnosed and treated. PMID- 29287513 TI - Ventricular Fibrillation Following Baseball Injury. AB - A common and seemingly minor injury to a 7-year-old boy leads Dr. Dickman to suggest that protective equipment should be changed to reduce the frequency of sports injuries. PMID- 29287514 TI - Cross-Country Bicycling: Physiological Effects. AB - Although percentages of body fat didn't change significantly, this study shows that transcontinental bicycling promotes higher levels of fitness, indicated by lower body mass, lower heart rates, and higher maximum breathing capacities. PMID- 29287516 TI - Proteinuria in the Athlete. PMID- 29287515 TI - Cardiovascular Aspects of Soccer. AB - Body temperature and blood pressure increases, weight losses, and high heart rates indicate soccer's great demands on the cardiovascular system. Heart attacks can be prevented with careful medical screening and supervision. PMID- 29287518 TI - Anti-MDA5 positive dermatomyositis complicated with rapidly progressive interstitial lung disease - a case report. AB - CASE PRESENTATION: We present a case of a 55-year-old Caucasian male with manifestations of dermatomyositis complicated with rapidly progressive interstitial lung disease (RP-ILD). Diagnosis of anti-MDA5 positive dermatomyositis was made. DISCUSSION: Myositis specific antibodies (MSA) can be used for diagnosis and predicting prognosis in patients with polymyositis and dermatomyositis. Anti-MDA5 positive dermatomyositis should be considered in patients presenting with dermatomyositis and a disease course resembling antisynthetase syndrome in the absence of antisynthetase autoantibodies, especially if a remarkably high ferritin is noted. Anti-MDA5 autoantibodies have been associated with RP-ILD and adverse outcome. In patients with anti-MDA5 autoantibodies, early diagnosis and aggressive immunosuppressive treatment may improve prognosis. CONCLUSION: This case highlights the importance of determining MSA in patients with dermatomyositis and associated interstitial lung disease, as this has implications for diagnosis, prognosis and therapy. PMID- 29287519 TI - Isolated Red Patches Seen During Endoscopic Surveillance of Bladder Cancer: Incidence of Malignancy and When Should We Biopsy? AB - OBJECTIVE: To establish whether the regular biopsy of red patches (RPs) seen during endoscopic surveillance for bladder cancer is worthwhile and determine a suitable time frame for repeat biopsy of prior histologically benign persistent RPs in patients on endoscopic surveillance for bladder cancer. PATIENTS AND METHODS: Four thousand eight hundred five flexible cystoscopy (FC) reports over a 12-month period were retrospectively reviewed at a United Kingdom tertiary teaching hospital and those undergoing cystoscopic surveillance for bladder cancer and found to have solitary RPs at FC were included in the study. A proportion of these cases had biopsies taken for histopathologic analysis. RESULTS: Two hundred forty-one FC performed on 183 patients on endoscopic surveillance for bladder cancer had RPs and 120 (49.8%) of them had previous intravesical Bacillus Calmette-Guerin therapy. Eighty-five patients (35.3%) underwent biopsy of the RP. Malignancy was found in 20 biopsies (23.5%), of which, 11 out of 20 (55%) were carcinoma in-situ. Sixteen of these recurrences were biopsied previously, of which 11 (68.8%) were benign at last biopsy, 6 of which were in the last 12 months. The remaining four recurrences had no previous biopsy. No cases of malignancy were identified in patients with low-risk bladder cancer. CONCLUSION: We recommend the biopsy of all RPs found during endoscopic surveillance of patients with intermediate-/high-risk bladder cancer due to the significant incidence of malignant recurrence identified, particularly if no biopsy has been performed within the previous 12 months. This is independent of previous biopsy histology. PMID- 29287520 TI - Behavioural, physiological and psychological responses of passengers to the thermal environment of boarding a flight in winter. AB - In practice, passengers actively respond to the thermal environment when they board an aircraft in winter, which is not considered in the current standards. In this study, the behavioural, physiological and psychological responses to the thermal environment were examined at 22 degrees C (with 68 subjects), 20 degrees C and 26 degrees C (with 32 subjects). The results showed that the three air temperature levels had significant effect on nozzle usage and clothing adjustment behaviours, surface skin temperature, and thermal sensation vote (TSV). The walking/waiting states prior to boarding the aircraft cabin had a significant effect on the proportion of jacket removal, TSV and thermal comfort vote. After 10 min in the aircraft cabin, the subjects maintained their comfort in a wider range of the thermal environment when the behavioural adjustments existed compared to when they did not. Thus, a suggestion was made for behavioural adjustments to be provided in aircraft cabins. Practitioner Summary: Experimental investigation of human responses was conducted in an aircraft cabin. Analysis showed that the subjects maintained their comfort in a wider range of the thermal environment when the behavioural adjustments existed compared to when they did not. Thus, a suggestion was made for behavioural adjustments to be provided in aircraft cabins. PMID- 29287522 TI - Effect of Differing Parameters on Irreversible Electroporation in a Porcine Model. AB - INTRODUCTION AND OBJECTIVE: Irreversible electroporation (IRE) is a new ablative technology to treat small renal masses. We evaluated differed ablation settings on lesion size and temperature changes in a porcine model. MATERIALS AND METHODS: After Institutional Animal Care and Use Committee approval, 36 laparoscopy-guided and 16 open ablations were performed on 13 domestic female pigs. Ablation parameters studied were voltage (1000 V/cm, 1500 V/cm, or 2000 V/cm), probe exposure (1.0 or 1.5 cm), and lesion size over time (survival) (0-, 7-, or 14 day). Temperature changes were monitored during open ablations with differed settings. Gross lesion size was measured, and histologic analysis with hematoxylin and eosin and nicotinamide adenine dinucleotide staining was performed. RESULTS: The 1000 V/cm ablations had no gross or histologic lesions. A factorial analysis of variance demonstrated that day (p = 0.56), exposure (p = 0.33), and voltage (p = 0.06) did not demonstrate statistical significance for affecting lesion size. For 1.0 cm probe exposure, 2000 V/cm did more closely approximate expected lesion size (p = 0.02) compared with 1500 V/cm. While significance was not seen for 1.5 cm probe exposure, 2000 V/cm often exceeded expected lesion volume. Only 1 of 4 temperature sensors, located adjacent to one of the IRE probes, noted a significant increase with increased voltage. However, all maximum temperatures remained less than 70 degrees C. CONCLUSIONS: Variation in lesion volume was seen with different ablation settings in this porcine model. Maximal energy and probe exposure settings should be utilized to ensure full coverage of target volume/mass, potentially without concern for thermal injury to renal collecting system or nearby structures. PMID- 29287524 TI - QuikQuiz. PMID- 29287523 TI - Knee isokinetic performance following anterior cruciate ligament reconstruction: patellar tendon versus hamstrings graft. AB - OBJECTIVE: To compare knee isokinetic performance six months after reconstruction of the anterior cruciate ligament using grafts from either the patellar tendon or the hamstrings among patients who underwent the same rehabilitation protocol. METHODS: Thirty-four patients were evaluated (17 with grafts from the patellar tendon and 17 with grafts from the hamstrings). Operated and non-operated knees were compared with regards to the variables of peak torque, work and the hamstring/quadriceps relationship at velocities of 60o/s and 180o/s and power of 180o/s after six months of surgery. RESULTS: The patients with ACL reconstruction using the patellar tendon (BPTB) showed quadriceps deficits for all variables, but the flexor musculature was balanced. In the hamstring group, both the extensors and the flexors showed deficits for the variables analyzed, except for hamstring power at 180o/s. CONCLUSION: Patients in the patellar tendon group had a greater quadriceps deficit compared with those in the hamstrings group. Patients in the hamstrings group had a greater muscular deficit in the flexor mechanism compared with the contralateral knee. An unbalanced H/Q ratio was observed regardless of graft type, but this was more evident in the BPTB group. PMID- 29287521 TI - Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis? AB - Iron accumulation has been observed in mouse models and in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e., chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata, and motor cortex (according to magnetic resonance imaging), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS. Antioxid. Redox Signal. 29, 742-748. PMID- 29287526 TI - wrap-ups. PMID- 29287525 TI - Surgically Sculpting Athletic Physiques. AB - To shrink hips or expand chests, both men and women are turning to plastic surgeons for bodies that they think diet and exercise are unable to give them- at least as soon as they want them. Several issues need to be addressed before patients shop for athletic-looking physiques. Even the most deft surgical techniques cannot mend patients' self-images. PMID- 29287527 TI - AIDS and HIV. AB - Knowledge is the best defense against the human immunodeficiency virus (HIV). Leonard H. Calabrese, DO, head of the Section of Clinical Immunology at the Cleveland Clinic Foundation, answers some common questions about HIV and acquired immune deficiency syndrome (AIDS). PMID- 29287528 TI - scanning sports. PMID- 29287529 TI - AIDS: Assessing the Risk Among Athletes. AB - Since Magic Johnson's retirement, athletes as well as sports organizations are taking more interest in HIV and AIDS. Many athletes seek answers from physicians about the risk of HIV transmission through athletic competition and the rights of HIV-positive players. Although the debate continues about these and other issues regarding AIDS and sports, physicians can counsel patients about reducing their risk. PMID- 29287531 TI - Pulmonary Contusion in Contact Sports. AB - In brief Computed tomography (CT) is always more precise than chest x-ray for evaluating pulmonary contusions and other forms of lung trauma. CT is also valuable in guiding treatment for patients who have pulmonary contusions. As demonstrated by two case studies, not all sports-related pulmonary contusions are minor. Supportive treatment usually consists of maintaining the patient's oxygenation, treating associated injuries, and preventing complications. PMID- 29287532 TI - forum. PMID- 29287533 TI - Exercise ECG. PMID- 29287534 TI - The Physician and Sportsmedicine. PMID- 29287536 TI - The Physician and Sportsmedicine- and you. PMID- 29287535 TI - An Unusual Stress Fracture Site: Midhumerus. AB - In brief A bodybuilder who reported left shoulder and upper arm pain was found to have a midhumeral stress fracture. Stress fractures are uncommon in non-weight bearing bones, but a careful history that includes type, frequency, and duration of exercise can raise suspicion, and a physical examination, x-ray, and bone scan can detect the defects when they occur. Technetium bone scan can confirm injuries that are usually only suggested by x-rays. PMID- 29287537 TI - From Acne to Black Heel: Common Skin Injuries in Sports. AB - In brief Sports activity exposes the skin brief to various stresses, including friction and pressure from clothing and equipment; prolonged wetness from perspiration; and sunlight, cold, and heat. A variety of injuries can result. Briefly described here are the diagnosis, treatment, and prevention of some of the most common ones: sunburn and sun-induced aging, frostnip and frostbite, acne mechanica, calluses and corns, friction blisters, jogger's nipples, and black heel. PMID- 29287538 TI - Is Ilotibial Band Syndrome Often Overlooked? AB - In brief Iliotibial band syndrome (ITBS) is caused by training errors but may be influenced by anatomic and dynamic factors. The diagnosis involves matching a complete and accurate history with characteristic pain over and around the lateral femoral epicondyle. The authors studied US Marine recruits in basic training and found an incidence that suggests ITBS may be underdiagnosed. Treatment usually involves simple measures such as rest and stretching exercises, but surgical resection is sometimes necessary. PMID- 29287539 TI - How to Evaluate Transient Quadriparesis. AB - In brief Three professional football players experienced transient quadriparesis secondary to transient neurapraxia of the cervical spine. One player had congenital spinal stenosis and was allowed to continue playing football. In the other two players, MRI revealed herniated disks that precluded the athletes' return to play. Before physicians can determine whether football players or other athletes should resume participation in contact sports, they must accurately evaluate the extent of the player's neurologic injury. At the minimum, the evaluation should include a detailed neurologic examination, plain radiographs, and MRI. PMID- 29287540 TI - Conservative Treatment of Inflamed Knee Bursae. AB - In brief Knee bursitis often mimics other brief Pathologies, making correct diagnosis necessary to initiate appropriate treatment. Most commonly affected are the prepatellar, pes anserine, tibial collateral ligament, and two infrapatellar bursae. Other common bursitic conditions include Baker's cysts and posttraumatic adventitious hemorrhagic bursitis. Most of these can be treated conservatively with aspiration of fluid from the bursa, rest, ice, immobilization, and injection of a corticosteroid and analgesic combination. Some chronic bursitic conditions may require surgical excision of the bursa. PMID- 29287541 TI - Cross-Country Skiing. AB - Lighter-weight equipment, better groomed trails, and the increasing popularity of ski-skating techniques have introduced a new element to cross-country skiing: speed. Although the overall injury rate remains low, the number of traumatic injuries in cross-country skiers appears to be increasing. Most ski injuries, however, are still caused by overuse and can be easily prevented with proper conditioning. PMID- 29287542 TI - Subacromial Space Injections. AB - In brief When an active person experiences shoulder pain, injecting an anesthetic into the subacromial space may aid diagnosis. Such diagnostic injections may restore or improve the patient's active range of motion, eliminate apparent rotator cuff weakness, and reduce or eliminate pain in certain arcs of motion. This permits the physician to distinguish among diagnoses of impingement syndrome, rotator cuff lesions, adhesive capsulitis, and shoulder instability. Patients who have dramatic reductions in pain or improvements in active motion following a diagnostic injection may benefit from a therapeutic injection of a corticosteroid. PMID- 29287543 TI - Exerting Yourself. PMID- 29287544 TI - Single-Organ Patients. AB - Physicians walk a fine line when deciding whether to recommend that youngsters who have only one of a paired set of organs participate in sports. Increasingly, courts are ruling in favor of letting the athlete compete. To make the best decision for the health of their patients, physicians can learn about the risks specific sports pose and the protective gear that's available- and pass that information on to patients and their families. PMID- 29287545 TI - 1,2,4-trihydroxynaphthalene-2-O-beta-D-glucopyranoside: A new powerful antioxidant and inhibitor of Abeta42 aggregation isolated from the leaves of Lawsonia inermis. AB - Mounting evidence indicates free radicals as toxic species causing damage to human cells leading to the pathogenesis of many diseases such as neurodegenerative disease. Plant derived antioxidants are considered as promising strategy to prevent free radical toxicity. In this study, the crude extract (CE), 50%MeOH, Petroleum Ether (PE) and Ethyl acetate (EA) fractions of Lawsonia inermis leaves were investigated for their antioxidant activity and their ability to counteract amyloid-beta42 (Abeta42) aggregation. Elution of the most bioactive fraction (EA) on silica gel column chromatography led to six sub-fractions. The most active sub-fraction (1) was further resolved on silica gel column chromatography. A new compound with powerful antioxidant and anti-Abeta42 aggregation properties was purified and characterised by spectroscopic methods as 1,2,4-trihydroxynaphthalene-2-O-beta-D-glucopyranoside (THNG). This finding suggests that the antioxidant and anti-Abeta42 aggregation activities of L. inermis leaves are strongly correlated to this compound. PMID- 29287546 TI - Sports-Related Lacerations. AB - In brief Much about the treatment of lacerations is the same in all active patients: close inspection, thorough debridement, proper skin approximation and suturing, and protection against reinjury. Some aspects of care, however, differ depending on the extent of the injury, the anatomic site, and the patient's desire or need to return to athletics quickly. This article outlines a systematic approach to diagnosis and management of these common sports injuries. PMID- 29287547 TI - Treating Overweight Patients. AB - Many psychological barriers keep overweight people from being physically active. Too often, these patients think being large and being athletic simply don't mix. But with the right approach, physicians can help sedentary overweight patients overcome barriers and start enjoying the many benefits that regular exercise offers- regardless of whether the patients lose weight. PMID- 29287548 TI - pearls. PMID- 29287550 TI - Rapid Injury Assessment. PMID- 29287549 TI - Radiology Consultations: How to Get Optimal Results. AB - Like other physicians, radiologists experienced with athletes and their injuries can use their expertise to get to the most specific diagnosis. But finding a sports-wise radiologist is only half the game. The other half is learning to communicate diagnostic suspicions- and then working with the radiologist to correlate suspicions with the images themselves. PMID- 29287551 TI - Women in Sports Medicine. AB - Although more women physicians are practicing sports medicine than ever before, men still outnumber women. Why the discrepancy? Is it a lack of interest or a lack of opportunities? Despite the existing gender gap, women physicians are an increasing presence in sports medicine. PMID- 29287552 TI - How Safe Are Artificial Sweeteners? PMID- 29287553 TI - Getting Your Back in Shape. PMID- 29287555 TI - Transient Paresthesia in Stair-Climbers' Feet. AB - In brief The authors surveyed frequent users stair-climbing machines at seven health clubs to determine if neurologic foot symptoms were present. Of 212 respondents, 39% reported that they experienced numbness or tingling in their feet while using stair-climbing machines. The mild-to-moderate forefoot symptoms generally disappeared as exercise continued or when the session ended. Compression of the interdigital nerves from persistent and prolonged weight bearing possibly causes this transient paresthesia. If patients seek medical care for these symptoms, ruling out other foot neuropathies is important. Patients may be able to alleviate symptoms by slightly altering their workout technique. PMID- 29287556 TI - Clearing Up Fungal Infections of the Nail Plate. AB - In brief Active people often seek medical care for discoloration and deterioration of toenails or fingernails. The problem may be a fungal infection of the nail (onychomycosis). Microscopic examination often shows strong evidence of onychomycosis, but a fungal culture will confirm the diagnosis. Antifungal medication alone or with conservative avulsion may resolve the fungal infection. If not, surgical nail removal may be needed for resistant cases. PMID- 29287557 TI - Electrical Stimulation in Clinical Practice. AB - In brief Four forms of electrical stimulation are clinically useful in the rehabilitation of injured athletes. These forms differ mainly in the way they combine the parameters of wave form, frequency, pulse width, and amplitude. Transcutaneous electrical nerve stimulation provides effective relief of both acute and chronic pain. High-voltage pulsed galvanic stimulation has several treatment indications, including pain, swelling, tissue injury, and infection. Interferential electrical stimulation is used for muscle relaxation, analgesia, and to promote soft-tissue healing. Minimal electrical noninvasive stimulation is purported to facilitate tissue healing. Electrical stimulation should be used In concert with other modalities for a complete rehabilitation program. PMID- 29287559 TI - scanning sports. PMID- 29287560 TI - Carbohydrates That Speed Recovery From Training. AB - In brief The most useful way to classify carbohydrate food for active people is by its ability to raise blood glucose concentration. To hasten recovery after intense training, athletes should consume at least 50 g of high- or moderate glycemic carbohydrates as soon after exercise as is practical. They should eat at least an additional 50 g every 2 hours until they eat a large meal. To obtain the recommended 70% of calories from carbohydrate, athletes may find it helpful to determine how many 50-g carbohydrate food portions they need to eat daily. PMID- 29287558 TI - Tarsometatarsal Joint Injury. AB - In brief Injuries of the tarsometatarsal joint complex, though not common in athletes, can cause prolonged disability. The severity of these injuries often is not recognized, since subtle subluxations are difficult to diagnose. Certain radiographic signs help make the diagnosis; fluoroscopy with anesthesia may be necessary to determine the stability of the joint. Casting is sufficient for patients who have stable injuries, but those who have an unstable joint require open reduction and internal fixation. PMID- 29287561 TI - Fixing Lacerations. PMID- 29287562 TI - How Exercise Can Benefit Older Patients. AB - In brief Physical activity has both preventive and therapeutic benefits for the frail elderly, and the ultimate goal is improved quality of life. The greatest impact on functional capacity comes from physiologic changes that affect mobility. Walking programs and flexibility and strength training can prevent muscle weakness and impaired gait and balance, which are risk factors for falls in the elderly. In addition, changes in functional capacity can result in greater independence in daily living. Physical activity also provides therapeutic benefits for patients who have arthritis or dementia. PMID- 29287564 TI - QuikQuiz. PMID- 29287563 TI - forum. PMID- 29287565 TI - Food Fight. PMID- 29287566 TI - Back Pain and Pregnancy. AB - In brief For about half of all pregnant women, low-back pain is inevitable. Physicians who can specify what type of back pain the patient has-lumbar, sacroiliac, or nocturnal-can institute targeted treatment that addresses the relevant pathophysiology. Acetaminophen and certain modalities such as icing the area are the basis of acute treatment in conjunction with ergonomic adaptation and a good low-back exercise program. This will help decrease stress on the low back, making back pain less likely. Before a woman becomes pregnant, encouraging her to become fit and resolving existing back problems is the key to back pain prevention. PMID- 29287567 TI - A Special Issue on Active Women's Health. PMID- 29287568 TI - Mitral Valve Prolapse in Active Patients. AB - In brief In most people, mitral valve prolapse, which affects women more than men, is a benign condition with few or no symptoms. But in some patients it poses a significant problem. Potential sequelae include endocarditis, serious arrhythmia, and sudden death. Although a midsystolic click followed by a late systolic murmur is characteristic, definitive diagnosis requires echocardiography. Treatment ranges from education and reassurance in those who have mild disease to valve replacement in severe cases. Most athletes who have mitral valve prolapse can safely participate in all activities. Those with evidence of significant valvular disease, serious arrhythmia, or a family history of sudden death due to mitral valve prolapse, however, should participate only in low-intensity competitive sports. PMID- 29287569 TI - Using Mind Power for Healing. PMID- 29287570 TI - Pearls. PMID- 29287571 TI - Pregnant With Back Pain? PMID- 29287572 TI - Olympic Insights. PMID- 29287573 TI - Bladder and 'Yeast' Infections. PMID- 29287574 TI - The Female Athlete Triad. AB - In brief The female athlete triad of disordered eating, amenorrhea, and osteoporosis affects women and girls in many sports, but the messages conveyed to those in "appearance" sports like gymnastics may play a role. Because the triad may result in irreversible bone loss and death, early detection is imperative. Friends, parents, coaches, and physicians can be alert to behaviors like eating alone, trips to the bathroom during or after meals, and the use of laxatives. Other signs and symptoms of the female athlete triad may include fatigue, anemia, depression, cold intolerance, lanugo, and eroded tooth enamel from frequent vomiting. Multidisciplinary treatment typically involves education, determining contributing factors, restoring adequate nutrition, and prescribing estrogen therapy when appropriate. PMID- 29287575 TI - CME Self Test. PMID- 29287576 TI - Choosing Exercise for Better Health. PMID- 29287577 TI - Exercising-or Not-When You Are Sick. PMID- 29287578 TI - Nutrition on the Run. PMID- 29287579 TI - An Active Menopause. AB - In brief There's no better time than the years surrounding menopause for a woman to start or renew an exercise program. Exercise may reduce the immediate symptoms of menopause, and it decreases the long-term risk of cardiovascular disease, osteoporosis, and obesity. The exercise prescription includes aerobic exercise, resistance training, and stretching components, and should be individualized according to the woman's exercise history. PMID- 29287580 TI - Managing Urinary Tract and Vaginal Infections. AB - In brief Urinary tract infections (UTIs) and vaginitis are common among women. UTIs are classified as either complicated or uncomplicated, and, in most cases, the diagnosis can be made from the history and a urinalysis. Changes in the types of antibiotics available and the length of treatment have had promising results. Vaginitis infections are usually candidiasis, bacterial vaginosis, or trichomoniasis, all of which can be diagnosed from the history and microscopic evaluation of the discharge. Both over-the-counter and prescription medications are used in treatment. Patient education about prevention measures can lessen infection risk. PMID- 29287581 TI - Use Your Head to Choose a Bike Helmet. PMID- 29287582 TI - Acute Pancreatitis: A Rare but Serious Complication for Living Liver Donors; Risk Factors and Outcomes. AB - OBJECTIVES: The purposes of this study were to determine the incidence of acute pancreatitis after living donor hepatectomy and to investigate potential risk factors and outcomes. MATERIALS AND METHODS: Clinical data of all donors who underwent donor hepatectomy between January 2015 and December 2016 in our liver transplant institute were reviewed. Donor data were obtained from a prospectively maintained database. The donors were divided into 2 groups according to whether they developed postoperative pancreatitis. The following data were compared between the 2 groups: demo-graphic information (age, sex), body mass index, type of hepatectomy (right, left, or left lateral), intraoperative cholangiographic findings, operative time, blood loss, graft data (graft weight, remnant liver ratio), duration of postoperative hospital stay, and postoperative morbidity and mortality (if any). Pancreatitis severity and treatment outcomes were also examined in patients with postoperative pancreatitis. RESULTS: Our study included 348 donors who underwent donor hepatectomy for living-donor liver transplant. Postoperative pancreatitis developed in 6 donors (1.7%). We found no statistical differences between patients with and without postoperative pancreatitis in terms of demographic and intra-operative findings. Neither loco-regional nor systemic complications of pancreatitis developed in any of the patients. Therefore, all were classified as having mild pancreatitis according to revised Atlanta classification. The mean APACHE II score was 5.2 +/- 1.2 points (range, 4-7 points). All patients with postoperative pancreatitis received conservative supportive treatment. CONCLUSIONS: Although postoperative pancreatitis is a rarely reported complication in living liver donors, it should always be considered, especially in patients who unpredictably deteriorate in the postoperative period. Proper recognition and timely treatment can help avoid serious consequences. PMID- 29287583 TI - Cold-responsive miRNAs and their target genes in the wild eggplant species Solanum aculeatissimum. AB - BACKGROUND: Low temperature is an important abiotic stress in plant growth and development, especially for thermophilic plants. Eggplants are thermophilic vegetables, although the molecular mechanism of their response to cold stress remains to be elucidated. MicroRNAs (miRNAs) are a class of endogenous small non coding RNAs that play an essential role during plant development and stress responses. Although the role of many plant miRNAs in facilitating chilling tolerance has been verified, little is known about the mechanisms of eggplant chilling tolerance. RESULTS: Here, we used high-throughput sequencing to extract the miRNA and target genes expression profiles of Solanum aculeatissimum (S. aculeatissimum) under low temperature stress at different time periods(0 h, 2 h, 6 h, 12 h, 24 h). Differentially regulated miRNAs and their target genes were analyzed by comparing the small RNA (sRNA) and miRBase 20.0 databases using BLAST or BOWTIE, respectively. Fifty-six down-regulated miRNAs and 28 up-regulated miRNAs corresponding to 220 up-regulated mRNAs and 94 down-regulated mRNAs, respectively, were identified in S. aculeatissimum. Nine significant differentially expressed miRNAs and twelve mRNAs were identified by quantitative Real-time PCR and association analysis, and analyzed for their GO function enrichment and KEGG pathway association. CONCLUSIONS: In summary, numerous conserved and novel miRNAs involved in the chilling response were identified using high-throughput sequencing, which provides a theoretical basis for the further study of low temperature stress-related miRNAs and the regulation of cold tolerance mechanisms of eggplant at the miRNA level. PMID- 29287584 TI - Risk factors for community-acquired acute kidney injury in patients with and without chronic kidney injury and impact of its initial management on prognosis: a prospective observational study. AB - BACKGROUND: We aimed to describe clinical characteristics of patients with community-acquired acute kidney injury (CA-AKI), the effectiveness of initial management of CA-AKI, its prognosis and the impact of medication on its occurrence in patients with previous chronic kidney injury (CKI). METHODS: We undertook a prospective observational study within the Emergency Department (ED) of a University Hospital, screening for any patient >16 years admitted with an eGFR <60 ml/mn/1.73 m2 and a rise in serum creatinine as compared to previous values. Patients' medical files were reviewed by a panel of nephrologists in the subsequent days and at one and three-years follow-up. RESULTS: From May 1st to June 21st 2013, there were 8464 admissions in the ED, of which 653 had an eGFR <60 ml/mn/1.73 m2. Of these, 352 had previous CKI, 341 had CA-AKI, and 104 had CA ACKI (community-acquired acute on chronic kidney injury). Occurrence of superimposed CA-AKI in CKI patients was associated with male gender and with use of diuretics, but not with use of ARBs or ACEIs. Adequate management of CA-AKI defined as identification, diagnostic procedures and therapeutic intervention within 24 h, was recorded in 45% of the cases and was not associated with improved outcomes. Three-year mortality was 21 and 48% in CKI and CA-ACKI patients respectively, and 40% in patients with only CA-AKI (p < 0.001). Mortality was significantly associated with age, hypertension, ischemic heart disease and CA-AKI. Progression of renal insufficiency was associated with male gender and age. CONCLUSIONS: CA-AKI is more frequently encountered in male patients and those treated with diuretics and is an independent risk factor for long-term mortality. Its initial adequate management failed to improve outcomes. PMID- 29287585 TI - A scoping review of comparisons between abstracts and full reports in primary biomedical research. AB - BACKGROUND: Evidence shows that research abstracts are commonly inconsistent with their corresponding full reports, and may mislead readers. In this scoping review, which is part of our series on the state of reporting of primary biomedical research, we summarized the evidence from systematic reviews and surveys, to investigate the current state of inconsistent abstract reporting, and to evaluate factors associated with improved reporting by comparing abstracts and their full reports. METHODS: We searched EMBASE, Web of Science, MEDLINE, and CINAHL from January 1st 1996 to September 30th 2016 to retrieve eligible systematic reviews and surveys. Our primary outcome was the level of inconsistency between abstracts and corresponding full reports, which was expressed as a percentage (with a lower percentage indicating better reporting) or categorized rating (such as major/minor difference, high/medium/low inconsistency), as reported by the authors. We used medians and interquartile ranges to describe the level of inconsistency across studies. No quantitative syntheses were conducted. Data from the included systematic reviews or surveys was summarized qualitatively. RESULTS: Seventeen studies that addressed this topic were included. The level of inconsistency was reported to have a median of 39% (interquartile range: 14% - 54%), and to range from 4% to 78%. In some studies that separated major from minor inconsistency, the level of major inconsistency ranged from 5% to 45% (median: 19%, interquartile range: 7% - 31%), which included discrepancies in specifying the study design or sample size, designating a primary outcome measure, presenting main results, and drawing a conclusion. A longer time interval between conference abstracts and the publication of full reports was found to be the only factor which was marginally or significantly associated with increased likelihood of reporting inconsistencies. CONCLUSIONS: This scoping review revealed that abstracts are frequently inconsistent with full reports, and efforts are needed to improve the consistency of abstract reporting in the primary biomedical community. PMID- 29287586 TI - The impact of intravenous methylprednisolone pulses on renal survival in anti neutrophil cytoplasmic antibody associated vasculitis with severe renal injury patients: a retrospective study. AB - BACKGROUND: High-dose methylprednisolone pulses were one of the main treatments for anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitides (AAV) but had obvious side effects. We aimed to know the impact on renal survival and identify the prognostic factors of this treatment in Chinese AAV patients with severe renal involvement. METHODS: One hundred and eleven AAV patients with an estimated glomerular filtration rate (eGFR) of 10ml/min/1.73 m2 or less at admission were included. The MP group (n = 57) received intravenous methylprednisolone 500 mg/d for 3 days, while the control group (n = 54) had not. The outcomes and adverse events between two groups were compared. Besides, predictors for dialysis independence and good response of intravenous methylprednisolone were analyzed using Cox regression analysis and ROC curves respectively. RESULTS: Their median duration of follow-up was 31 (range 3 to 134) months. Eleven patients in MP group and 20 patients in control group were died (P = 0.056). Twenty-one patients (36.8%) in MP group and 29 patients (53.7%) in control group were on maintaining dialysis (P = 0.088). Twenty-one patients in MP group remained dialysis independent, more than those in control group (4 patients, P <0.01). Urine protein creatinine ratio (hazard ratio 1.730, 95% confidence interval 1.029 to 2.909, P = 0.039) and the treatment of intravenous methylprednisolone pulses (hazard ratio 0.362, 95% confidence interval 0.190 to 0.690, P = 0.002) were the independent risk factors for dialysis independence. Those patients with serum creatinine>=855MUmol/L and urine protein >=3.7g/24h at admission may have worse responses to intravenous methylprednisolone pulses (sensibility 56.7%, specificity 85.0%, PPV 100.0% and NPV57.1%). CONCLUSIONS: Intravenous methylprednisolone pulses could improve the long-term outcome in term of dialysis independence and tend to decrease mortality for Chinese AAV patients with severe renal involvement. PMID- 29287587 TI - Simulations for designing and interpreting intervention trials in infectious diseases. AB - BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials. PMID- 29287588 TI - Relation between duration of the prodromal phase and renal damage in ANCA associated vasculitis. AB - BACKGROUND: In ANCA-associated vasculitis the acute phase of the disease is often preceded by prodromal symptoms. The aim of the present study was to analyze the relation between the duration of the prodromal phase and renal damage. METHODS: Patients with ANCA-associated vasculitis and renal involvement from a retrospective single-center cohort were divided into two equal groups based on the duration of the prodromal phase. The prodromal phase was defined as the time between first vasculitis related symptoms and the date of diagnosis. Clinical characteristics at diagnosis and renal items on the vasculitis damage index at 6 months were compared between the two groups. In addition, the relation between a long prodromal phase and 3-year end-stage renal disease and mortality as a composite outcome was studied. RESULTS: A total of 72 patients were included (age 64 +/- 12 years; 74% male; 96% Caucasian). At diagnosis, in patients with a prodromal phase <=22 weeks versus >22 weeks estimated glomerular filtration rate and proteinuria did not differ significantly (35 (interquartile range 50) versus 30 (50) ml/min p = 0.84; 75% versus 87%, p = 0.21 respectively). Furthermore, Birmingham Vasculitis Activity Scores were comparable (7 (3), p = 0.71). At 6 months, a long prodromal phase was associated with proteinuria (odds ratio 5.38, 95% confidence interval (CI) 1.47-19.62), but not with an estimated glomerular filtration rate <= 50 ml/min (odds ratio 0.89, 95% CI 0.33-2.37) in multivariable analyses. In addition, a long prodromal phase was associated with end-stage renal disease/mortality (hazard ratio 5.22, 95% CI 1.13-24.20). CONCLUSIONS: A long prodromal phase was associated with proteinuria and 3-year end-stage renal disease/mortality, but not with a reduced renal function at 6 months. These results underline the importance of an early diagnosis in ANCA-associated vasculitis patients in order to improve renal outcomes. PMID- 29287589 TI - Rapid clinical improvement of amyloid A amyloidosis following treatment with tocilizumab despite persisting amyloid deposition: a case report. AB - BACKGROUND: Amyloid A amyloidosis is one of the most common forms of amyloidosis. It is secondary to rheumatoid arthritis, which is difficult to manage and has a poor prognosis. We present a patient with rheumatoid arthritis and amyloid A amyloidosis who was treated with tocilizumab, a humanized monoclonal antibody against interleukin 6 receptor, resulting in improvement in both proteinuria and gastrointestinal symptoms; however, amyloid deposition remained. CASE PRESENTATION: A 67-year-old woman who had previously been treated for rheumatoid arthritis presented with abdominal pain and diarrhea. Right renal cell carcinoma was found, and amyloid A amyloidosis was diagnosed concomitantly based on colon biopsy. The renal cell carcinoma was resected, and the non-cancerous part of the renal tissue also showed amyloid A deposition. Following surgery, protein levels in the urine increased to the nephrotic range, and administration of tocilizumab was initiated, which resulted in resolution of the proteinuria. The patient's gastrointestinal symptoms were also alleviated. However, repeat colon biopsy showed amyloid deposition. CONCLUSIONS: This case of amyloid A amyloidosis suggests that amyloid deposition indicates only structural change of the affected tissue, and that it is not amyloid deposition per se that causes the clinical symptoms of amyloidosis. PMID- 29287590 TI - Correction to: Systematic review of the relationships between physical activity and health indicators in the early years (0-4 years). AB - CORRECTION: After publication of the article [1], it has been brought to our attention that an incorrect reference has been used in this article, both in the main body and additional file 2. The reference in question is #105 in the main body and #74 in additional file 2. Here it is cited as "Lindsay H, Brussoni M. Injuries and helmet use related to non-motorized wheeled activities among pediatric patients. Chronic Dis Inj Canada. 2014;34(2-3):74-81". PMID- 29287592 TI - Hypermethylation of MEG3 promoter correlates with inactivation of MEG3 and poor prognosis in patients with retinoblastoma. AB - BACKGROUND: In our previous study, we revealed that MEG3 was a tumor suppressor gene in retinoblastoma and inhibited proliferation of retinoblastoma cells by regulating the activity of the Wnt/beta-catenin pathway. Here, we further explored the mechanism of MEG3 inactivation in retinoblastoma. METHODS: MSP and qRT-PCR were performed to detect the methylation status of MEG3 promoter and levels of MEG3 expression, respective. To further explore relationship between MEG3 expression and epigenetic modifications, 5-Aza-CdR was used to interfere with DNA methylation. In addition, we evaluated proliferation, apoptosis and the expression of beta-catenin via CCK-8, flow cytometric analysis and western blot analysis, respective. RESULTS: Hypermethylation of MEG3 promoter was observed more frequently in retinoblastoma tissues and was highly associated with low MEG3 expression and poor survival of retinoblastoma patients. We also provided evidence demonstrating that hypermethylation of MEG3 promoter depressed MEG3 expression, promoted proliferation, inhibited apoptosis and increased beta catenin expression of retinoblastoma cells in vitro. CONCLUSIONS: Our present study indicates that promoter silencing by hypermethylation may account for the loss of MEG3 expression and predict poor prognosis. PMID- 29287591 TI - Systematic review of nephrotoxicity of drugs of abuse, 2005-2016. AB - BACKGROUND: The United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes. METHODS: We conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies. RESULTS: A total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review. CONCLUSION: Based on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series. PMID- 29287593 TI - Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis. AB - BACKGROUND: Increased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear. METHODS: We evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified. RESULTS: PADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs). CONCLUSIONS: These results suggest that the citrullination pathway is upregulated in IPF and in RA ILD. PMID- 29287594 TI - Comprehensive molecular biomarker identification in breast cancer brain metastases. AB - BACKGROUND: Breast cancer brain metastases (BCBM) develop in about 20-30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques. METHODS: We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM. RESULTS: The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3, BNIP3, BNIP3P1, BRIP1, CASP14, CDC25A, DMBT1, IDH2, E2F1, MYCN, RAD51, RAD54L, and VDR. A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1, SNORA2A, SNORA9, SNORA10, SNORA22, SNORA24, SNORA30, SNORA37, SNORA38, SNORA52, SNORA71A, SNORA71B, SNORA71C, SNORD13P2, SNORD15A, SNORD34, SNORD35A, SNORD41, SNORD53, and SCARNA22. The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53, BRCA1, BRCA2, ERBB2, IDH1, and IDH2. WES detected numerous mutations, some of which affecting BC associated genes as CDH1, HEPACAM, and LOXHD1. CONCLUSIONS: Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis. PMID- 29287597 TI - "Next generation sequencing identifies mutations in GNPTG gene as a cause of familial form of scleroderma-like disease". PMID- 29287595 TI - Dealing with Chronic Non-Bacterial Osteomyelitis: a practical approach. AB - BACKGROUND: Chronic Non-Bacterial Osteomyelitis (CNO) is an inflammatory disorder that primarily affects children. Although underestimated, its incidence is rare. For these reasons, no diagnostic and no therapeutic guidelines exist. The manuscript wants to give some suggestions on how to deal with these patients in the every-day clinical practice. MAIN BODY: CNO is characterized by insidious onset of bone pain with local swelling. Systemic symptoms such as fever, skin involvement and arthritis may be sometimes present. Radiological findings are suggestive for osteomyelitis, in particular if multiple sites are involved. CNO predominantly affects metaphyses of long bones, but clavicle and mandible, even if rare localizations of the disease, are very consistent with CNO diagnosis. CNO pathogenesis is still unknown, but recent findings highlighted the crucial role of cytokines such as IL-1beta and IL-10 in disease pathogenesis. Moreover, the presence of non-bacterial osteomyelitis among autoinflammatory syndromes suggests that CNO could be considered an autoinflammatory disease itself. Differential diagnosis includes infections, malignancies, benign bone tumors, metabolic disorders and other autoinflammatory disorders. Radiologic findings, either with Magnetic Resonance or with Computer Scan, may be very suggestive. For this reason in patients in good clinical conditions, with multifocal localization and very consistent radiological findings bone biopsy could be avoided. Non-Steroidal Anti Inflammatory Drugs are the first-choice treatment. Corticosteroids, methotrexate, bisphosphonates, TNFalpha-inhibitors and IL-1 blockers have also been used with some benefit; but the choice of the second line treatment depends on bone lesions localizations, presence of systemic features and patients' clinical conditions. CONCLUSION: CNO may be difficult to identify and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. No data exist on best treatment option after Non Steroidal Anti-Inflammatory Drugs failure. PMID- 29287596 TI - Gamma-aminobutyric acid-B limbic encephalitis and asystolic cardiac arrest: a case report. AB - BACKGROUND: Gamma-aminobutyric acid-B receptor autoantibodies are becoming an increasingly recognized contributor to the spectrum of autoimmune limbic encephalitis. They are classically associated with seizures and behavioral disturbance, and may coexist with other autoantibodies. Many are paraneoplastic, most commonly associated with small cell lung cancer. Until now there have been no reports of cardiac dysrhythmias in these patients. CASE PRESENTATION: A 65 year-old Caucasian man presented with multiple seizures, dysarthria and behavioral disturbance of unclear etiology, with associated asystolic cardiac arrest. Antibody testing showed anti-Gamma-aminobutyric acid-B receptor and anti Hu antibodies in serum and Gamma-aminobutyric acid-B receptor autoantibodies in cerebrospinal fluid. The diagnosis of small cell lung cancer was subsequently made after lung biopsy, and the patient showed improvement with chemotherapy and intravenous immunoglobulin. CONCLUSIONS: We present the case of a patient with Gamma-aminobutyric acid-B receptor limbic encephalitis associated with asystolic cardiac arrest, an association not previously described. This case illustrates how difficult it is to make the diagnosis on clinical grounds alone. We therefore propose more routine antibody testing in patients with similar symptomatology who remain undifferentiated after initial workup. We also recommend that in the acute setting, patients with Gamma-aminobutyric acid-B receptor encephalitis should receive cardiac monitoring, as further research is required to clarify its possible link with cardiac dysrhythmias. PMID- 29287599 TI - Ultrasound-guided central venous catheter placement: first things first. PMID- 29287600 TI - Pulmonary arterial hypertension in a patient treated with dasatinib: a case report. AB - BACKGROUND: There have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in the form of pleural effusions, which we speculate led only to partial reversion of the disease. CASE PRESENTATION: A 67-year-old white man with chronic myelogenous leukemia was treated with the dual Src and BCR-ABL tyrosine kinase inhibitor dasatinib. After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg. Computed tomography ruled out a possible pulmonary embolism; laboratory specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed. A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units. CONCLUSIONS: Patients should always be closely monitored when using dasatinib for a prolonged time. Dasatinib-induced pulmonary hypertension may be fully reversible after the therapy is suspended, but the key factors involved are still unclear and need to be further studied. PMID- 29287598 TI - Molecular screening of tsetse flies and cattle reveal different Trypanosoma species including T. grayi and T. theileri in northern Cameroon. AB - BACKGROUND: African trypanosomes are mainly transmitted through the bite of tsetse flies (Glossina spp.). The present study investigated the occurrence of pathogenic trypanosomes in tsetse flies and cattle in tsetse fly-infested areas of Northern Cameroon. RESULTS: Trypanosomes were identified using nested polymerase chain reaction (PCR) analysis of internal transcribed spacer 1 (ITS1) region, both by size estimation and sequencing of PCR products. Apparent density indices recorded in Gamba and Dodeo were 3.1 and 3.6 tsetse flies per trap and day, respectively. Trypanosoma prevalence infection rate for the tsetse fly gut (40%) and proboscis (19%) were recorded. Among the flies where trypanosomes were detected in the gut, 41.7% were positive for T. congolense and 14.6% for T. brucei ssp., whereas in the proboscis 36% harboured T. congolense and 62% contained T. vivax. T. grayi was highly prevalent in tsetse fly gut (58%). The most common mixed infections were the combination of T. congolense and T. grayi. Trypanosome prevalence rate in cattle blood was 6%. Among these, T. vivax represented 26%, T. congolense 35%, T. brucei ssp. 17% and T. theileri 17% of the infections. Surprisingly, in one case T. grayi was found in cattle. The mean packed cell volume (PCV) of cattle positive for trypanosomes was significantly lower (24.1 +/- 5.6%; P < 0.05) than that of cattle in which trypanosomes were not detected (27.1 +/- 4.9%). Interestingly, the occurrence of T. theileri or T. grayi DNA in cattle also correlated with low PCV at pathological levels. CONCLUSION: This molecular epidemiological study of Trypanosoma species in Northern Cameroon revealed active foci of trypanosomes in Dodeo and Gamba. These findings are relevant in assessing the status of trypanosomosis in these regions and will serve as a guide for setting the priorities of the government in the control of the disease. PMID- 29287603 TI - Abstract of the Scientific Literature. PMID- 29287604 TI - Abstract of the Scientific Literature. PMID- 29287601 TI - mTOR inhibition improves the immunomodulatory properties of human bone marrow mesenchymal stem cells by inducing COX-2 and PGE2. AB - BACKGROUND: Bone marrow mesenchymal stem cells (MSCs) are promising candidates for the treatment of various inflammatory disorders due to their profound immunomodulatory properties. However, the immunosuppressive capacity of MSCs needs activation by an inflammatory microenvironment, which may negatively impact the therapeutic effect because of increased immunogenicity. Here we explore the role of mammalian target of rapamycin (mTOR) signaling on the immunosuppressive capacity of MSCs, and its impact on immunogenicity in the inflammatory microenvironment. METHODS: Human bone marrow MSCs were cocultured with activated human peripheral blood mononuclear cells, CD4+ T cells, and mouse splenocytes to evaluate the immunosuppressive function. Immunosuppressive factors were assessed by quantitative real-time polymerase chain reaction (PCR), Western blot, and enzyme-linked immunosorbent assay (ELISA). The expression of major histocompatibility complex (MHC) was detected by flow cytometry. Short hairpin (sh)RNA was used to downregulate tuberous sclerosis complex (TSC)2, TSC1, and cyclooxygenase (COX)-2 in MSCs. RESULTS: Inhibition of mTOR signaling using rapamycin enhanced the immunosuppressive functions of MSCs, while prolonged exposure to rapamycin did not. The enhancement of the immunosuppressive function was independent of the inflammatory microenvironment, and occurred mainly through the upregulation of COX-2 and prostaglandin-E2 (PGE2) expression. Furthermore, mTOR inhibition did not impact the immunogenicity of MSCs. However, the upregulated expression of MHC class II molecules by interferon (IFN)-gamma was attenuated by mTOR inhibition, whereas TSC2 knockdown had the opposite effect. CONCLUSIONS: These results reveal that the mTOR signaling pathway regulates MSC immunobiology, and short-term exposure to rapamycin could be a novel approach to improve the MSC-based therapeutic effect. PMID- 29287607 TI - Embracing Our Differences to Help Our Patients. PMID- 29287602 TI - Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation. AB - BACKGROUND: Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. METHODS: Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi). RESULTS: The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition. CONCLUSIONS: Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy. PMID- 29287609 TI - Robust Fault Estimation Design for Discrete-Time Nonlinear Systems via A Modified Fuzzy Fault Estimation Observer. AB - The paper provides relaxed designs of fault estimation observer for nonlinear dynamical plants in the Takagi-Sugeno form. Compared with previous theoretical achievements, a modified version of fuzzy fault estimation observer is implemented with the aid of the so-called maximum-priority-based switching law. Given each activated switching status, the appropriate group of designed matrices can be provided so as to explore certain key properties of the considered plants by means of introducing a set of matrix-valued variables. Owing to the reason that more abundant information of the considered plants can be updated in due course and effectively exploited for each time instant, the conservatism of the obtained result is less than previous theoretical achievements and thus the main defect of those existing methods can be overcome to some extent in practice. Finally, comparative simulation studies on the classical nonlinear truck-trailer model are given to certify the benefits of the theoretic achievement which is obtained in our study. PMID- 29287608 TI - Simulation of low temperature combustion mechanism of different combustion supporting agents in close-coupled DOC and DPF system. AB - In the coupled Diesel Oxidation Catalyst (DOC) and Diesel Particular Filter (DPF) system, soot cannot be completely removed by only using the passive regeneration. And DPF active regeneration is necessary. The research method in this paper is to spray different kinds of combustion-supporting agents to the DOC in the front of the DPF. Therefore, the low temperature combustion mechanism of different kinds of combustion-supporting agents in DOC was studied, in order to grasp the law of combustion in DOC, and the influence of follow-up emission on DPF removal of soot. During the study, CH4H2 mixture and diesel (n-heptane + toluene) were used as combustion-supporting agents respectively. The simplified mechanisms of two kinds of gas mixtures used as the combustion-supporting agents in DPF have been constructed and testified in the paper. In this paper, the combustion and emission conditions of the two combustion-supporting agents were analyzed so as to meet the practical requirements of different working conditions. PMID- 29287610 TI - A method to remove chattering alarms using median filters. AB - Chattering alarms are the most found nuisance alarms that will probably reduce the usability and result in a confidence crisis of alarm systems for industrial plants. This paper addresses the chattering alarm reduction using median filters. Two rules are formulated to design the window size of median filters. If the alarm probability is estimated using process data, one rule is based on the probability of alarms to satisfy some requirements on the false alarm rate, or missed alarm rate. If there are only historical alarm data available, the other rule is based on percentage reduction of chattering alarms using alarm duration distribution. Experimental results for industrial cases testify that the proposed method is effective. PMID- 29287611 TI - Distribution of nerve fibers during the development of palatine glands in rats. AB - BACKGROUND: Salivary gland maturation and function are modulated by the nervous system. Nevertheless, little is known about salivary gland innervation during development, particularly minor salivary glands. This study investigated the development of the innervation of the palatine glands of rat. MATERIALS AND METHODS: Frozen sections of rat palatine glands at different stages were immunohistochemically labeled for detection of the general nerve markers protein gene product 9.5 (PGP 9.5) and growth associated protein 43 (GAP-43), and the autonomic nerve markers calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY). RESULTS: PGP 9.5 and GAP-43-immunoreactive fibers (IRF) were present in the mesenchyme and in association with developing acini, ducts and blood vessels. GAP-43-IRF were more abundant and diffuse than PGP 9.5-IRF at early stages, but showed similar distribution with growth, ramifying out from thick bundles in connective tissues until encircling the secretory units observed around postnatal day 21 (PN21). CGRP-IRF were detected in the mesenchyme at embryonic day 20 (E20) and PN0. CGRP-IRF became numerous around PN7 and PN10. They then decreased to the adult level at PN21, mainly located around ducts and infrequently blood vessels. NPY-IRF were sparsely detected in the mesenchyme at E20, then detected in close proximity to acini in addition to blood vessels at PN3. NPY-IRF increased till reaching the adult stage, and were mainly associated with blood vessels and around mucous cells and some serous demilunes. CONCLUSION: The findings indicated a developmental modification of the sensory and autonomic innervation which may play a role in the functional maturation of the palatine salivary glands. PMID- 29287612 TI - Decision-making in addiction: Current knowledge, clinical implications and future directions. AB - This article serves to summarize this special issue on "Decision-making in Addiction." The manuscripts included in this issue cover topics as diverse as theory, types of models used to study decision-making, underlying pharmacological, behavioral and brain mechanisms, and individual differences. Together, these papers can serve as a comprehensive resource outlining our contemporary understanding of how decision-making processes contribute to addictive behavior. The knowledge included here can inform treatment development, clearly pointing to the need for tailored interventions based on individual differences. PMID- 29287613 TI - Primary Pleural Lymphoma. PMID- 29287614 TI - Effects of oral exposure to inorganic mercury on the feeding behaviour and biochemical markers in yellowfin bream (Acanthopagrus australis). AB - Mercury is a known toxic metal, but studies on the effects of inorganic mercury ingestion in aquatic organisms are scarce. The present study aimed to investigate changes in feeding behaviour and biomarkers (lipid peroxidation, acetylcholinesterase, glutathione S-transferase and catalase activities) of yellowfin bream (Acanthopagrus australis) after ingestion of inorganic mercury (control: 0.2 mg kg-1, low: 0.7 mg kg-1, medium: 2.4 mg kg-1 and high: 6 mg kg-1) over 16 days. After 4 days, exposed fish attempted feeding more often, and showed a significantly lower eating success than controls. However, these differences became less notable with longer exposure periods. Most biochemical markers varied over time, regardless of mercury treatment. However, biomarker responses to mercury were also observed, mostly with increased exposure period and were dependant on the tissue analysed. This study showed that fish can recover from initial feeding behaviour effects of inorganic mercury, but showed delayed response in tissue biomarkers. PMID- 29287616 TI - The distribution of benthic foraminifera in Bel Torrente submarine cave (Sardinia, Italy) and their environmental significance. AB - The use of benthic foraminifera as ecological indicators in submarine caves of temperate seas have never been studied before and it represents a new approach, verified by this research. The Bel Torrente submarine cave (Gulf of Orosei, Sardinia, Italy) was surveyed by GUE (Global Underwater Explorers) scuba divers in order to georeferencing the cave before positioning the sampling stations, from the entrance to 430 m inside the cave. A total of 15 water samples were collected to investigate abiotic parameters (temperature, salinity, pH) while 15 sediment samples were collected to analyze grain size and benthic foraminifera. Benthic foraminifera, investigated for the first time in a submarine cave of temperate areas, were exclusively found from the entrance to 300 m inside the cave. Species distribution and assemblage diversity have been found to be correlated to the environmental gradient towards the inner cave, mainly due to the decreasing of temperature and salinity and the increasing of the flow energy. Water acidification seems responsible for the transition from a calcareous hyaline-dominated assemblage to an agglutinant-dominated one, occurring between 120 and 150 m from the entrance. Common taxa of the Sardinian coastal marine area are present only close to the entrance of the cave, while species found in the inner part are nearly exclusively epifaunal clinging/attached or infaunal taxa, with tolerance for wide variability of environmental parameters, such as Gavelinopsis praegeri, and opportunist infaunal taxa such as Eggerella advena. The agglutinant taxa found in the cave are conversely very rare in coastal marine assemblages of the area. This suggests a very efficient dispersal mechanism for the colonization of the caves, involving probably juvenile foraminifera at a "propagule" stage. PMID- 29287615 TI - Use of Lagrangian simulations to hindcast the geographical position of propagule release zones in a Mediterranean coastal fish. AB - The study of organism dispersal is fundamental for elucidating patterns of connectivity between populations, thus crucial for the design of effective protection and management strategies. This is especially challenging in the case of coastal fish, for which information on egg release zones (i.e. spawning grounds) is often lacking. Here we assessed the putative location of egg release zones of the saddled sea bream (Oblada melanura) along the south-eastern coast of Spain in 2013. To this aim, we hindcasted propagule (egg and larva) dispersal using Lagrangian simulations, fed with species-specific information on early life history traits (ELTs), with two approaches: 1) back-tracking and 2) comparing settler distribution obtained from simulations to the analogous distribution resulting from otolith chemical analysis. Simulations were also used to assess which factors contributed the most to dispersal distances. Back-tracking simulations indicated that both the northern sector of the Murcia region and some traits of the North-African coast were hydrodynamically suitable to generate and drive the supply of larvae recorded along the coast of Murcia in 2013. With the second approach, based on the correlation between simulation outputs and field results (otolith chemical analysis), we found that the oceanographic characteristics of the study area could have determined the pattern of settler distribution recorded with otolith analysis in 2013 and inferred the geographical position of main O. melanura spawning grounds along the coast. Dispersal distance was found to be significantly affected by the geographical position of propagule release zones. The combination of methods used was the first attempt to assess the geographical position of propagule release zones in the Mediterranean Sea for O. melanura, and can represent a valuable approach for elucidating dispersal and connectivity patterns in other coastal species. PMID- 29287617 TI - Cardiac arrest while exercising on mountains in national or provincial parks: A national observational study from 2012 to 2015. AB - BACKGROUND: Previous studies on cardiac arrest in mountainous areas were focused on environmental features such as altitude and temperature. However, those are limited to factors affecting the prognosis of patients after cardiac arrest. We analyzed the cardiac arrests in national or provincial parks located in the mountains and determined the factors affecting the prognosis of patients after cardiac arrest. METHODS: This study included all emergency medical service (EMS) treated patients over the age of 40 experiencing out-of-hospital cardiac arrests (OHCAs) of presumed cardiac etiology during exercise, between January 2012 and December 2015. The main focus of interest was the location of cardiac arrest occurrence (national mountain parks and provincial parks vs. other sites). The main outcome was survival to discharge and multivariable logistic regression was performed to adjust for possible confounding effects. RESULTS: A total 1835 patients who suffered a cardiac arrest while exercising were included. From these, 68 patients experienced cardiac arrest in national or provincial parks, and 1767 occurred in other locations. The unadjusted and adjusted ORs (95% CI) for a good cerebral performance scale (CPC) were 0.09 (0.01-0.63) and 0.08(0.01 0.56), survival discharges were 0.13(0.03-0.53) and 0.11 (0.03-0.48). CONCLUSIONS: Cardiac arrests occurring while exercising in the mountainous areas have worse prognosis compared to alternative locations. PMID- 29287618 TI - Re: Brachytherapy for Patients with Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update. PMID- 29287619 TI - All iguana families with the exception of basilisks share sex chromosomes. AB - Once believed to be restricted only to endotherms (mammals and birds), several poikilothermic amniote lineages have recently been documented to possess long term evolutionary stability in their sex chromosomes. However, many important lineages were not included in these tests. Previously, based on molecular evidence, we documented the homology of well-differentiated sex chromosomes among seven families of iguanas (Pleurodonta), with basilisks (Corytophanidae) being the only exception, as the tested genes linked to X, but missing on the Y chromosome, in other iguanas were autosomal or pseudoautosomal in basilisks. In this study, we test the homology of sex chromosomes in the remaining, previously unstudied iguana families (Hoplocercidae, Leiosauridae, Liolaemidae, Polychrotidae) and in the basilisk genus Corytophanes. Our results show that 12 currently recognized families of iguanas share X-specific gene content conserved from the common ancestor living in the Cretaceous period. However, the results in the genus Corytophanes indicate the loss of the ancestral differentiated sex chromosomes from the ancestor of basilisks. Our new data further confirm the extensive stability of sex chromosomes in iguanas, thus enabling molecular sexing based on the comparison of the number of X-specific genes by quantitative PCR (qPCR) in all but one family of this widely diversified clade. PMID- 29287620 TI - Passive smoking and Parkinson's disease in California teachers: Methodological issues. PMID- 29287622 TI - Transcranial magnetic stimulation and subjective tinnitus. A review of the literature, 2014-2016. AB - Subjective tinnitus is a symptom in many ENT pathologies, for which there is no curative treatment. It may be poorly tolerated by some patients, who develop attention or sleep disorder or even major anxiety and depression, severely impairing quality of life. Pathophysiological models of the genesis and maintenance of tinnitus symptomatology highlight maladaptive cerebral plasticity induced by peripheral hearing loss. Although not fully elucidated, these changes in neuronal activity are the target of various attempts at neuromodulation, particularly using repetitive transcranial magnetic stimulation (rTMS), which has been the focus of various clinical studies and meta-analyses. A recent consensus statement (Lefaucheur, 2014) reported level-C evidence (possible efficacy) for rTMS using low frequency (1Hz) tonic stimulation targeting the left cerebral cortex. However, many questions remain concerning the use of this technique in everyday practice. The present article reports a recent literature review using the search-terms "tinnitus" and "rTMS" in the PubMed and Cochrane databases for April 2014 to December 2016. PMID- 29287621 TI - Glucocorticoids Regulate the Vascular Remodeling of Aortic Dissection Via the p38 MAPK-HSP27 Pathway Mediated by Soluble TNF-RII. AB - Increasing researches suggest that inflammatory response is involved in vascular remodeling, which plays an important role in the development of aortic dissection. Glucocorticoids have been widely used in the clinical practice due to its powerful and effective anti-inflammatory property. However, the potential relationship between glucocorticoids and aortic dissection was still obscure. This study sought to elucidate the effect of glucocorticoids on the development and progression of aortic dissection, and the potential mechanism involved. Serum cortisol in aortic dissection patients was significantly higher than that in non ruptured aortic aneurysm patients and healthy volunteers by radioimmunoassay. In modified C57BL/6 mouse model of aortic dissection, glucocorticoids reduced the incidence of aortic dissection and protected the collagen from degradation. Furthermore, glucocorticoids inhibited the TNF-alpha secretion of THP-1 monocytes, decreased the migration, phenotype switch from contractile type to synthetic type, and the apoptosis of human aortic smooth muscle cells induced by TNF-alpha. Finally, TNF-sRII was identified as an important cytokine in cellular interaction that participated in vascular remodeling by targeting the p38 MAPK HSP27 pathway. These results indicate that glucocorticoids inhibit the incidence of aortic dissection by decreasing the TNF-alpha secretion and increasing the uncombined TNF-sRII, positively participating in vascular remodeling. PMID- 29287623 TI - Olfactory stimulation or inhibition of sexual behavior of stallions in non breeding season. AB - Stallions show decreased sexual responses and activities during short days in winter. To evaluate the importance of sexual olfactory communication in horses, we tested whether sexual responses could be stimulated through various sexual olfactory stimulations in winter. To this end, we presented stallions with various olfactory stimulations (urine from mares at different stages of the reproductive cycle, urine from stallions or geldings, or chemically defined synthetic odorant) during the non-breeding season and measured their behavioral responses through (1) a test of olfactory investigation (olfactory investigation and flehmen behavior) and (2) a test of sexual activity in the context of semen collection for artificial insemination. It appears that the duration of olfactory investigation and flehmen behavior is longer after presentation of urine (stallion, gelding, anestrous, diestrous and estrous mare) than after presentation of water or synthetic odorant. By contrast, geldings showed reduced flehmen behavior that did not differ from that after water presentation. It is of interest that during the mounting test, mare estrous urine was associated with significantly reduced latency to ejaculation when spread in the nostril of the stallion, compared to anestrous mare urine or water. Anestrous mare urine seems to even inhibit stallion sexual motivation as measured through a longer latency to reach mounting and ejaculation. It appears therefore that during the season of sexual rest, stallion sexual motivation can be stimulated by mare estrous urine and inhibited by mare anestrous urine. These results also suggest that the physiological state of the mare influence the content of urinary chemosignals. PMID- 29287624 TI - Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer. AB - Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment-specific therapies. PMID- 29287625 TI - Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response. AB - Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5*10-8). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI. PMID- 29287627 TI - Sex and size matters: Selection on personality in natural prey-predator interactions. AB - Optimal life-history strategies are currently considered to be a major driving force for the maintenance of animal personalities. In this experimental study we tested whether naturally occurring predation causes personality-dependent mortality of a marine isopod (Idotea balthica), which could maintain personality variation in nature. Moreover, as isopods are known to have sex-differences in behaviour, we were interested in whether personality-dependent predation was sex specific. We also hypothesised that predation pressure among personality types could vary according to habitat type, as it has been shown in correlative studies that habitat may influence personality variation. We used natural predator (European perch Perca fluviatilis) of I. balthica and studied relative mortality of males and females with a different personality types in laboratory settings with two different habitats. We found that survival in males was lower than in females for high active individuals. Moreover, survival under predation was linked to body size differently in females and males. This, however, depended on personality class as larger size was advantageous for low-active males and middle and high-active females. Conversely, smaller size was advantageous for low active females and middle-active males. Size did not affect survival in high active males. Our results suggest that predation can encourage life-history differences between sexes leading to different optimal life-history strategies and also maintains consistent activity for both sexes. PMID- 29287626 TI - A comparison of conversion rates, clinical profiles and predictors of outcomes in two independent samples of individuals at clinical high risk for psychosis in China. AB - OBJECTIVE: In a previous epidemiological study, we reported on the ascertainment and outcomes of "clinical high risk" (CHR) individuals at the Shanghai Mental Health Center (SMHC, "2011 cohort"). The current study compares demographic and clinical characteristics, including conversion rates, of this sample with a subsequently recruited, independent CHR sample and with published data from western samples. METHOD: A new sample of 100 CHR subjects ("2013 cohort") was selected based on screening and semi-structured interviews. Both studies used the Structured Interview for Prodromal Syndromes (SIPS) for CHR assessment and conducted a naturalistic two-year follow-up. The two cohorts were compared on conversion rates, demographic and clinical characteristics, psychosis risk symptoms, and risk factors for psychotic conversion. RESULTS: Ninety one (91%) of the 2013 cohort subjects completed the clinical two-year follow-up and 25 (27.5% of the 91) converted to a psychotic disorder over the follow-up period. A comparison of conversions to full psychosis between the 2013 and the 2011 cohorts showed no significant difference in time to conversion (Pairwise comparison: chi2=0.3, p=0.562). Both cohort studies showed that CHR subjects with more severe clinical symptoms at baseline and decline in functioning were more likely to convert to psychosis. CONCLUSIONS: Conversion rates in this new, independent Chinese sample are similar to those reported in non-Chinese samples and to the 2011 cohort. Future research is needed to examine whether the implementation of early intervention for CHR/prodromal symptoms reduces the risk of psychosis and decreases the conversion rate. PMID- 29287629 TI - Neural processes of vocal social perception: Dog-human comparative fMRI studies. AB - In this review we focus on the exciting new opportunities in comparative neuroscience to study neural processes of vocal social perception by comparing dog and human neural activity using fMRI methods. The dog is a relatively new addition to this research area; however, it has a large potential to become a standard species in such investigations. Although there has been great interest in the emergence of human language abilities, in case of fMRI methods, most research to date focused on homologue comparisons within Primates. By belonging to a very different clade of mammalian evolution, dogs could give such research agendas a more general mammalian foundation. In addition, broadening the scope of investigations into vocal communication in general can also deepen our understanding of human vocal skills. Being selected for and living in an anthropogenic environment, research with dogs may also be informative about the way in which human non-linguistic and linguistic signals are represented in a mammalian brain without skills for language production. PMID- 29287630 TI - Biofilm formation and antifungal susceptibility of Trichosporon asahii isolates from Mexican patients. AB - BACKGROUND: Trichosporon asahii is a yeast-like fungus that has recently gained importance as a cause of opportunistic systemic infections. The pathogenicity and virulence factors of T. asahii remain largely unknown. Because of the association between invasive infections and the use of catheters and related devices, the ability of the microorganism to adhere and form biofilms may play an important role in the pathogenicity during a trichosporonosis. AIMS: The aim of this study is to identify an association between biofilm formation by T. asahii isolates and their genotype and/or clinical source. METHODS: The biofilm production of 49 T. asahii strains isolated from Mexican patients was measured using the crystal violet stain method, and a comparison made with different adhesion phase incubation times. Antifungal susceptibility testing was performed using a modified CLSI protocol coupled with the quantification of the viable cells with the XTT reduction method. RESULTS: All the T. asahii isolates assayed were able to produce biofilm in vitro, with an intraspecific variability being observed. Overall, increased biofilm production was found when extending the adhesion phase incubation time from 2 to 4h. No association could be established between the biofilm-producing phenotype and either the genotype or clinical source. Higher antifungal resistance to amphotericin B and fluconazole was linked to increased biofilm production by T. asahii. CONCLUSIONS: All clinical isolates tested were able to produce biofilm. No association could be established between biofilm formation and genotype or clinical source. PMID- 29287631 TI - Phenotypical characterization and molecular identification of clinical isolates of Candida tropicalis. AB - BACKGROUND: Candida tropicalis is an increasingly important human pathogen which usually affects neutropenic oncology patients with common hematogenous seeding to peripheral organs and high mortality rates. Candida pathogenicity is facilitated by several virulence attributes, including secretion of hydrolytic enzymes; however, little is known regarding the C. tropicalis ability to secrete them and their role in the disease. AIMS: To confirm by molecular means the identification of 187 clinical isolates (127 from blood, 52 from urine, and 8 from diverse clinical origins) phenotypically identified as C. tropicalis, and to investigate their in vitro aspartyl proteinase, phospholipase, esterase, hemolysin, DNase and coagulase activities. METHODS: The molecular confirmation was performed by ITS sequencing, and the enzymatic determinations were conducted using plate assays with specific substrates, with the exception of coagulase, which was determined by the classical tube test. RESULTS: The majority of the strains exhibited a very strong or strong activity of aspartyl proteinase, phospholipase and esterase. A 4.7% of the bloodstream isolates were hemolysin producers, and all were negative for the coagulase and DNase assays. CONCLUSIONS: Very strong activities of aspartyl proteinase, phospholipase and esterase profiles were detected, and a statistical association between phospholipase production and blood and urine isolates was found. PMID- 29287632 TI - Association between Candida biofilm-forming bloodstream isolates and the clinical evolution in patients with candidemia: An observational nine-year single center study in Mexico. AB - BACKGROUND: Candidemia is one of the most common nosocomial infections globally and it is associated with considerable excess mortality and costs. Abreast, biofilm-forming strains are associated with even higher mortality rates and poor prognosis for the patient. AIMS: To evaluate a possible association between the biofilm-forming capability of Candida bloodstream isolates and the clinical evolution in patients with candidemia. METHODS: An observational, retrospective study was conducted at a tertiary care university hospital during 9 years (2006 2015). The biofilm quantitation of the Candida bloodstream isolates was determined by crystal violet staining and XTT reduction assay. RESULTS: A total of 218 cases of candidemia had been diagnosed and 89 isolates were obtained. The mortality rate was 36% and the main risk factors were antibiotic exposure and the use of catheters. Candida tropicalis (52.8%) was the most frequent species, followed by Candida albicans (30.4%), Candida parapsilosis sensu stricto (10.1%), Candida orthopsilosis (3.4%), Candida krusei (2.2%) and Candida glabrata sensu stricto (1.1%). All the strains were biofilm producers, which is an important contribution to the patient's mortality. C. tropicalis showed the highest production of biomass biofilm, whereas C. glabrata exhibited the highest metabolic activity. CONCLUSIONS: This study contributes to expand the knowledge about the local epidemiology of candidemia and highlights the impact of Candida biofilm on patient's outcome. PMID- 29287633 TI - Familial psychosocial risk classes and preschooler body mass index: The moderating effect of caregiver feeding style. AB - BACKGROUND: Early child weight gain predicts adolescent and adult obesity, underscoring the need to determine early risk factors affecting weight status and how risk factors might be mitigated. Socioeconomic status, food insecurity, caregiver depressive symptomology, single parenthood, and dysfunctional parenting each have been linked to early childhood weight status. However, the associations between these risk factors and children's weight status may be moderated by caregiver feeding styles (CFS). Examining modifiable factors buffering risk could provide key information to guide early obesity intervention efforts. METHODS: This analysis used baseline data from the Growing Healthy project that recruited caregivers/child dyads (N = 626) from Michigan Head Start programs. Caregivers were primarily non-Hispanic white (62%) and African American (30%). After using latent class analysis to identify classes of familial psychosocial risk, CFS was tested as a moderator of the association between familial psychosocial risk class and child body mass index (BMI) z-score. RESULTS: Latent class analysis identified three familial psychosocial risk classes: (1) poor, food insecure and depressed families; (2) poor, single parent families; and (3) low risk families. Interactive effects for uninvolved feeding styles and risk group indicated that children in poor, food insecure, and depressed families had higher BMI z-scores compared to children in the low risk group. Authoritative feeding styles in low risk and poor, food insecure, and depressed families showed lower child BMI z scores relative to poor, single parent families with authoritative feeding styles. CONCLUSIONS: Uninvolved feeding styles intensified the risk and an authoritative feeding style muted the risk conferred by living in a poor, food insecure, and depressed family. Interventions that promote responsive feeding practices could help decrease the associations of familial psychosocial risks with early child weight outcomes. PMID- 29287635 TI - Maternal perception of fetal movements in the third trimester: A qualitative description. AB - PROBLEM: Decreased fetal movements is a common reason for unscheduled antenatal assessment and is associated with adverse pregnancy outcome. BACKGROUND: Fetal movement counting has not been proven to reduce stillbirths in high-quality studies. AIMS: The aim was to explore a qualitative account of fetal movements in the third trimester as perceived by pregnant women themselves. METHODS: Using qualitative descriptive methodology, interviews were conducted with 19 women experiencing an uncomplicated first pregnancy, at two timepoints in their third trimester. Interview transcripts were later analysed using qualitative content analysis. FINDINGS: Pregnant women described a sustained increase in strength, frequency and variation in types of fetal movements from quickening until 28-32 weeks. Patterns of fetal movement were consistently described as involving increased movement later in the day and as having an inverse relationship to the women's own activity and rest. At term, the most notable feature was increased strength. Kicking and jolting movements decreased whilst pushing and rolling movements increased. DISCUSSION: Maternal descriptions of fetal activity in this study were consistent with other qualitative studies and with ultrasound studies of fetal development. CONCLUSION: Pregnant women observe a complex range of fetal movement patterns, actions and responses that are likely to be consistent with normal development. Maternal perception of a qualitative change in fetal movements may be clinically important and should take precedence over any numeric definition of decreased fetal movement. Midwives may inform women that it is normal to perceive more fetal movement in the evening and increasingly strong movements as pregnancy advances. PMID- 29287634 TI - If at first you don't succeed: Assessing influences associated with mothers' reoffering of vegetables to preschool age children. AB - Repeatedly offering vegetables has been shown to be one of the most effective methods for increasing acceptance and subsequent intake in young children. In order to increase successful offerings of vegetables and resultant consumption amongst young children, it is necessary to consider the influences on maternal reoffering of vegetables. This study aimed to investigate the relationships between mothers' tendency to reoffer vegetables and a range of demographic factors and psychological variables. A cross-sectional design was used, where mothers completed questionnaires assessing how often they reoffer rejected vegetables, concerns for economic factors, and a range of possible child and maternal influences. Mothers of preschool children were recruited from toddler groups across Leicestershire, UK, as well as online. Spearman's correlations were run to look for associations between demographic and psychological factors with maternal reoffering of vegetables. Significantly associated factors were then entered into a stepwise regression to predict maternal reoffering of vegetables. Mothers were significantly less likely to reoffer rejected vegetables if they were concerned about time, money, and waste, were influenced by their child's mood, or were concerned about their child having tantrums. Moreover, mothers who consumed more vegetables themselves reoffered vegetables more frequently. Regression analyses revealed that mothers' concern about food waste and tantrums, as well as maternal vegetable consumption, all significantly predicted mothers' reoffering of vegetables. With these findings in mind, mothers should be educated and supported with how to tackle and minimise children's tantrums during feeding, as well as being made aware of effective methods for avoiding food waste. Moreover, given that mothers' own vegetable consumption is associated with lower reoffering of vegetables to their child, interventions which seek to increase familial vegetable consumption should be pursued. PMID- 29287628 TI - Sex differences in the brain: Implications for behavioral and biomedical research. AB - Biological differences between males and females are found at multiple levels. However, females have too often been under-represented in behavioral neuroscience research, which has stymied the study of potential sex differences in neurobiology and behavior. This review focuses on the study of sex differences in the neurobiology of social behavior, memory, emotions, and recovery from brain injury, with particular emphasis on the role of estrogens in regulating forebrain function. This work, presented by the authors at the 2016 meeting of the International Behavioral Neuroscience Society, emphasizes varying approaches from several mammalian species in which sex differences have not only been documented, but also become the focus of efforts to understand the mechanistic basis underlying them. This information may provide readers with useful experimental tools to successfully address recently introduced regulations by granting agencies that either require (e.g. the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada) or recommend (e.g. Horizon 2020 in Europe) the inclusion of both sexes in biomedical research. PMID- 29287636 TI - Lifetime Achievement Award for Orthodontic Research, 2018. PMID- 29287637 TI - Long-term changes of the anterior palatal alveolar bone after treatment with bialveolar protrusion, evaluated with computed tomography. AB - This case report describes the treatment of a 31-year-old woman with a convex profile, protrusive maxilla, retrusive mandible, and gummy smile. Four premolars were extracted, and micro-implant anchorage was used to retract the anterior teeth. Lip protrusion and the gummy smile were improved, but the computed tomography images showed dehiscence on the palatal alveolar bone of the maxillary incisors. Approximately 10 years after treatment, significant alveolar bone apposition was seen on the palatal surface of the maxillary anterior teeth. PMID- 29287638 TI - Surgery first using skeletal anchorage with tandem mechanics for mandibular molar distalization. AB - This case report describes the orthodontic retreatment a patient with a skeletal Class III malocclusion. The clinical examination showed a concave profile caused by a retruded maxilla and a prognathic mandible, an occlusal cant, and absence of all first premolars. A surgery-first approach was combined with skeletal anchorage implants in the maxillary arch and tandem mechanics. The esthetic facial profile, pleasant smile, appropriate occlusion, and overall good treatment outcomes remained stable 5 years after active orthodontic treatment. PMID- 29287639 TI - A patient with mandibular deviation and 3 mandibular incisors treated with asymmetrically bent improved superelastic nickel-titanium alloy wires. AB - Skeletal and dental discrepancies cause asymmetric malocclusions in orthodontic patients. It is difficult to achieve adequate functional occlusion and guidance in patients with congenital absence of a mandibular incisor due to the tooth-size discrepancy. Here, we describe the orthodontic treatment of a 22-year-old woman with an asymmetric Angle Class II malocclusion, mandibular deviation to the left, and 3 mandibular incisors. The anterior teeth and maxillary canines were crowded. We used an improved superelastic nickel-titanium alloy wire (Tomy International, Tokyo, Japan) to compensate for the asymmetric mandibular arch and an asymmetrically bent archwire to move the maxillary molars distally. A skeletal anchorage system provided traction for intermaxillary elastics, and extractions were not needed. We alleviated the crowding and created an ideal occlusion with proper overjet, overbite, and anterior guidance with Class I canine and molar relationships. This method of treatment with an asymmetrically bent nickel titanium alloy wire provided proper Class I occlusion and anterior guidance despite the mandibular deviation to the left and 3 mandibular incisors, without the need for extractions. PMID- 29287640 TI - Precision and trueness of dental models manufactured with different 3-dimensional printing techniques. AB - INTRODUCTION: In this study, we assessed the precision and trueness of dental models printed with 3-dimensional (3D) printers via different printing techniques. METHODS: Digital reference models were printed 5 times using stereolithography apparatus (SLA), digital light processing (DLP), fused filament fabrication (FFF), and the PolyJet technique. The 3D printed models were scanned and evaluated for tooth, arch, and occlusion measurements. Precision and trueness were analyzed with root mean squares (RMS) for the differences in each measurement. Differences in measurement variables among the 3D printing techniques were analyzed by 1-way analysis of variance (alpha = 0.05). RESULTS: Except in trueness of occlusion measurements, there were significant differences in all measurements among the 4 techniques (P <0.001). For overall tooth measurements, the DLP (76 +/- 14 MUm) and PolyJet (68 +/- 9 MUm) techniques exhibited significantly different mean RMS values of precision than the SLA (88 +/- 14 MUm) and FFF (99 +/- 14 MUm) techniques (P <0.05). For overall arch measurements, the SLA (176 +/- 73 MUm) had significantly different RMS values than the DLP (74 +/- 34 MUm), FFF (89 +/- 34 MUm), and PolyJet (69 +/- 18 MUm) techniques (P <0.05). For overall occlusion measurements, the FFF (170 +/- 55 MUm) exhibited significantly different RMS values than the SLA (94 +/- 33 MUm), DLP (120 +/- 28 MUm), and PolyJet (96 +/- 33 MUm) techniques (P <0.05). There were significant differences in mean RMS values of trueness of overall tooth measurements among all 4 techniques: SLA (107 +/- 11 MUm), DLP (143 +/- 8 MUm), FFF (188 +/- 14 MUm), and PolyJet (78 +/- 9 MUm) (P <0.05). For overall arch measurements, the SLA (141 +/- 35 MUm) and PolyJet (86 +/- 17 MUm) techniques exhibited significantly different mean RMS values of trueness than DLP (469 +/- 49 MUm) and FFF (409 +/- 36 MUm) (P <0.05). CONCLUSIONS: The 3D printing techniques showed significant differences in precision of all measurements and in trueness of tooth and arch measurements. The PolyJet and DLP techniques were more precise than the FFF and SLA techniques, with the PolyJet technique having the highest accuracy. PMID- 29287641 TI - American Association of Orthodontists Foundation Craniofacial Growth Legacy Collection in the orthodontic literature-use and trends: A systematic review. AB - INTRODUCTION: The American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collection is a digital repository of records from 9 craniofacial growth study collections in the United States and Canada. The purposes of this article were to describe the use of materials from the AAOF Craniofacial Growth Legacy Collection in the orthodontic literature in comparative and follow-up studies, and to analyze trends before and after the project's launch in 2009. METHODS: An electronic search without date or language restriction was conducted in the following databases: PubMed, Embase, Evidence Based Medicine Reviews, and CINAHL. Grey literature resources and the bibliographies of the selected studies were also consulted. Three independent reviewers assessed the studies for inclusion. The criteria were human subjects of any age, sex, and ethnicity; at least 1 of the 9 AAOF legacy collections used as either the main sample population or the comparison or control; and orthodontic outcomes assessed. Data were analyzed using STATA software (version 14.2; StataCorp, College Station, Tex). RESULTS: A total of 199 studies (127 follow-up, 72 comparative) were included. The most commonly used collection in comparative studies was the Michigan Growth sample. The number of published studies more than doubled after the AAOF Legacy Collection project testing and launch in 2009. The increase continued through 2010 to 2014, during which there was a trend to use multiple collections. The Burlington Growth collection was the most commonly used collection for follow-up studies. The overall use of the legacy collection showed a small increase in published studies after 2009. CONCLUSIONS: The overall numbers of published studies in the comparative and follow-up categories increased after 2009, reflecting the efforts of the AAOF team and collection curators to make the records available worldwide. Further research should consider studying each collection to identify utilization predictors. PMID- 29287642 TI - I'm working on it. PMID- 29287643 TI - Ordinal logistic regression. PMID- 29287645 TI - Rapid canine retraction by dentoalveolar distraction osteogenesis. PMID- 29287644 TI - Craniofacial morphology of HIV-positive children and adolescents undergoing antiretroviral therapy: A pilot study. AB - INTRODUCTION: In this study, we aimed to analyze craniofacial morphology by assessing the skeletal cephalometric profiles of HIV-positive patients receiving antiretroviral therapy. METHODS: For this study, 21 HIV-positive patients aged between 6 and 17 years (study group) were selected and compared with 21 normoreactive patients (control group), paired by sex and age. The patients were also divided into 3 age ranges (6-8, 9-12, and 13-17 years) considering the pubertal growth spurt as the central event. Eighteen (linear and angular) measurements were traced on teleradiographs by using 2 methodologies. The mean values of each measurement were compared between the study and control groups by age range. RESULTS: The majority of the measurements checked in the HIV-positive children and adolescents for the 13-to-17 year age range were diminished, but not enough to generate a statistically significant difference in craniofacial growth. Statistically significant differences (P <0.05) were found only in the inclination of the palatal plane (6-8 years) and the position of the maxilla in the anteroposterior direction (13-17 years). CONCLUSIONS: These results led us to conclude that some cephalometric measurements of HIV-positive children and adolescents may be similar to those of normoreactive subjects. PMID- 29287646 TI - Craniofacial morphology in women with Class I occlusion and severe maxillary anterior crowding. AB - INTRODUCTION: Our objective was to investigate craniofacial morphology in women with Class I occlusion and maxillary anterior crowding (MxAC) with bilateral palatal displacement of the lateral incisors and facial displacement of the canines. METHODS: Thirty-three women with normal occlusion (mean age, 20.7 +/- 2.3 years) were selected as the control group, and 33 women with severe MxAC (mean age, 23.3 +/- 3.8 years) with bilateral palatal and facial displacement of the lateral incisors and canines, respectively, were selected as the MxAC group. Mesiodistal tooth crown diameter, arch length discrepancy, facial-palatal displacement of lateral incisors and canines, and dental arch dimensions were measured. Fourteen skeletal and 10 dental cephalometric measurements were made. Medians, interquartile ranges, means, and standard deviations were calculated for each parameter, and the nonparametric Mann-Whitney U test (P <0.05) was used to compare the 2 groups. RESULTS: Compared with the control group, the MxAC group showed a significantly wider angle (P <0.05) and shorter length (P <0.01) in the cranial base, a smaller sagittal maxillary base (P <0.01), and a hyperdivergent skeletal pattern (P <0.01 and P <0.05). CONCLUSIONS: Women with Class I occlusion and severe MxAC exhibited a significantly wider angle and shorter length in the cranial base, a smaller sagittal maxillary base, and a hyperdivergent skeletal pattern. These skeletal and dental characteristics and cranial base dysmorphology may be helpful as potential indicators for orthodontic treatment with extractions. PMID- 29287647 TI - Alveolar cortical bone. PMID- 29287648 TI - Authors' response. PMID- 29287649 TI - Pharyngeal airway evaluation after isolated mandibular setback surgery using cone beam computed tomography. AB - INTRODUCTION: In this study, we investigated volumetric and dimensional changes to the pharyngeal airway space after isolated mandibular setback surgery for patients with Class III skeletal dysplasia. METHODS: Records of 28 patients who had undergone combined orthodontic and mandibular setback surgery were obtained. The sample comprised 17 men and 11 women. Their mean age was 23.88 +/- 6.57 years (range, 18-52 years). Cone-beam computed tomography scans were obtained at 3 time points: before surgery, average of 6 months after surgery, and average of 1 year after surgery. Oropharyngeal, hypopharyngeal, and total volumes were calculated. The lateral surface and anteroposterior dimensions at the minimal axial areas for oropharyngeal and hypopharyngeal volumes and mean mandibular setback were determined. RESULTS: The mean mandibular setback was 9.93 +/- 5.26 mm. Repeated measures analysis of variance determined an overall significant decrease between the means for 6 months and up to 1 year after surgery for oropharyngeal and hypopharyngeal volumes, anteroposterior at oropharyngeal, lateral surface at oropharyngeal, and anteroposterior at hypopharyngeal. No strong correlation between mandibular setback surgery and pharyngeal airway volumes or dimensions was determined. CONCLUSIONS: After mandibular setback surgery, pharyngeal airway volume, and transverse and anteroposterior dimensions were decreased. Patients undergoing mandibular setback surgery should be evaluated for obstructive sleep apnea and the proposed treatment plan modified according to the risk for potential airway compromise. PMID- 29287650 TI - Authors' response. PMID- 29287651 TI - External apical root resorption. PMID- 29287652 TI - Stability of secondarily inserted orthodontic miniscrews after failure of the primary insertion for maxillary anchorage: Maxillary buccal area vs midpalatal suture area. AB - INTRODUCTION: Few studies have examined the secondary insertion of orthodontic miniscrews after failure of the first insertion. We investigated both the primary and secondary success rates of miniscrews used for maxillary anchorage and compared the stability of the maxillary buccal area (MB) and the midpalatal suture area (MP). METHODS: In total, 387 miniscrews were primarily inserted into the MB (between the second premolar and first molar); of these, 81 (20.9%) miniscrews lacked stability and were reinserted into the MB (same position or more distal position) or the MP. Additionally, 84 miniscrews were primarily inserted into the MP; 13 (15.5%) of those lacked stability and were reinserted into the MP. We calculated and compared the primary and secondary success rates in each area. Moreover, we investigated the factors affecting clinical success. RESULTS: Although the success rate of the secondary insertion was significantly lower than that of the primary insertion into the MB, miniscrews inserted into the MP were stable in both primary and secondary insertions. The screw length was significantly associated with the stability of miniscrews inserted into the MB. CONCLUSIONS: For secondary insertions, miniscrews placed in the MP may be more stable than those inserted in the MB. PMID- 29287653 TI - Authors' response. PMID- 29287654 TI - Correction. PMID- 29287656 TI - One shoe doesn't fit all. PMID- 29287655 TI - Highly cited orthodontic articles from 2000 to 2015. AB - INTRODUCTION: Identification of highly cited articles based on the h-index and its properties is important for the evaluation of the past, present, and future of any research discipline. In this study, we aimed to identify the h-classic articles in orthodontics. METHODS: One search on the Web of Science identified all articles from 2000 to 2015 in the 89 journals indexed by the 2015 InCites Journal Citation Reports in the scientific area "dentistry, oral surgery, and medicine." A second search was performed in the Web of Science using all mesh terms related to orthodontics. Then, we applied the h-classic method to select the recent articles with the greatest scientific impact in orthodontics. RESULTS: Eighty articles were considered as h-classic articles. They were published in 20 of the 89 dental journals of the 2015 InCites Journal Citation Reports list. Only 36 articles appeared in orthodontic journals: 23 in the American Journal of Orthodontics & Dentofacial Orthopedics (28.8%), 7 in The Angle Orthodontist (8.8%), and 6 in European Journal of Orthodontics (7.5%). Thirty-eight articles originated from Europe, 28 from the Americas, and 14 from the Middle East and Asia. CONCLUSIONS: More than half of fundamental orthodontic research is published in nonorthodontic journals showing that our field is currently limited, and interactions with other research fields should be sought to increase orthodontic research importance and appeal. PMID- 29287657 TI - Plane-to-plane analysis of mandibular misalignment in patients with facial asymmetry. AB - INTRODUCTION: Little is known regarding how the mandible rotates in facial asymmetry. The purpose of this study was to study mandibular misalignment with a new plane-to-plane analysis method in patients with facial asymmetry. METHODS: Optimal symmetry planes (OSPs) were generated by computing the greatest count of paired voxels on opposing sides of the computerized tomography image of the structure. The mandibular OSP was measured against the midfacial OSP for its alignment. The deviation angle formed by the 2 OSPs was broken down into a y-axis component (frontal deviation angle) and a z-axis component (horizontal deviation angle). Fifty-nine patients who sought correction for facial asymmetry were included for study. RESULTS: The new analysis method was feasible. Fifty patients (83%) had significant mandibular misalignment (deviation, >=4 degrees or 4 mm). The locations of the rotational axes exhibited significant variations that could explain the varied features of the asymmetry. The frontal deviation angle (mean, 3.80 degrees +/- 3.89 degrees ) was significantly larger than the horizontal deviation angle (mean, 2.77 degrees +/- 1.71 degrees ). There was no significant correlation between the horizontal deviation angle and the anterior deviation distance or the posterior deviation distance. CONCLUSIONS: Proper mandibular realignment was suggested to be the primary aim in surgical correction of most jawbone asymmetries. Because of the greatly varied rotational axes and the obscure z-axis rotation, realignment could be difficult with the traditional approach. The OSP-based analysis is advocated to guide planning. PMID- 29287658 TI - Assessment of the rate of premolar extraction space closure in the maxillary arch with the AcceleDent Aura appliance vs no appliance in adolescents: A single-blind randomized clinical trial. AB - INTRODUCTION: The purpose of this 2-arm parallel trial was to assess the effect of the AcceleDent Aura appliance (OrthoAccel Technologies, Houston, Tex) on the rate of maxillary premolar extraction space closure in adolescent patients. METHODS: Forty Class II adolescents treated with full fixed appliances and maxillary premolar extractions participated in this randomized clinical trial. They were recruited in a private practice and treated by 1 clinician. Randomization was accomplished in blocks of 10 patients assigned to either a no appliance group or the AcceleDent Aura appliance group with the allocations concealed in opaque, sealed envelopes. Both the operator and the outcome assessor were blinded; however, it was not feasible to blind the patients. Models were taken of the maxillary arch at the start of space closure and just before complete space closure. The space was measured parallel to the occlusal plane from the cusp tips of the teeth mesial and distal to the extraction spaces. RESULTS: There was no clinically (0.05 mm per month; 95% confidence interval [CI], -0.24, 0.34) or statistically significant difference in the rate of space closure (P = 0.74). In both the univariable and multivariable analyses, the mean rate of tooth movement was slower by 0.13 mm per month (95% CI, -.26, .005) on the left side compared with the right side, but this was not statistically significant (P = 0.06). CONCLUSIONS: The AcceleDent Aura appliance had no effect on the rate of maxillary premolar extraction space closure. Only a few participants were considered to be good compliers with the appliance. However, the rate of space closure in the good compliers was similar to the overall group and did not appear to influence the result. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. PMID- 29287659 TI - Effect of nonextraction and extraction orthodontic treatments on smile esthetics for different malocclusions. AB - INTRODUCTION: Smile esthetics is a critical factor for evaluating orthodontic treatment outcomes. In this study, we evaluated the differences in esthetic perceptions and smile variables between extraction and nonextraction treatments for different malocclusions. METHODS: Ninety participants were divided into 3 groups according to their pretreatment overjet (group I, 0-4 mm; group II, >4 mm; group III, <0 mm), with 15 extraction participants and 15 nonextraction participants in each group. Posttreatment frontal smiling photographs were evaluated by 30 raters (10 orthodontists, 10 general dentists, 10 laypeople), and 9 smile variables were measured. RESULTS: Smile perception for the group II extraction subjects was higher than for the nonextraction subjects by the orthodontists and general dentists. Regardless of the type of treatment, group III subjects were rated lower than those in groups I and II. The arch form index, maxillary incisor show, and smile arc were greater in the extraction participants. In multiple regression analysis, nonextraction and group III correlated negatively with the esthetic score. Maxillary incisor show, tooth number display, and buccal corridor ratio correlated positively with the esthetic score. CONCLUSIONS: Group II extraction subjects were rated higher than the nonextraction subjects by dental professionals. A smile with greater maxillary incisor show, number of displayed teeth, and buccal corridor ratio was considered more esthetic. PMID- 29287660 TI - Psychological well-being, dental esthetics, and psychosocial impacts in adolescent orthodontic patients: A prospective longitudinal study. AB - INTRODUCTION: We examined the role of adolescent orthodontic patients' psychological well-being attributes (self-esteem, general body image, and positive and negative affects) and the clinical indicators of dental esthetics (orthodontists' ratings on the Index of Orthodontic Treatment Need-Aesthetic Component [IOTN-AC]), and their changes from pretreatment to posttreatment as predictors of the psychosocial impact of dental esthetics. METHODS: In this prospective longitudinal study, 1090 adolescent orthodontic patients seeking treatment at the Stomatological Hospital of Chongqing Medical University in China (mean age, 14.25 years; SD, 2.03 years) were assessed before treatment, and 68.99% (n = 752) were assessed after treatment. All subjects completed a questionnaire measuring psychological well-being attributes and 3 components of the Psychosocial Impact of Dental Aesthetics (perceptive, cognitive-affective, and social-functional). Clinical indicators of dental esthetics were measured by 3 orthodontists using the IOTN-AC. RESULTS: Substantial enhancement from pretreatment to posttreatment was found in all 3 Psychosocial Impacts of Dental Aesthetics components, confirming the positive effects of orthodontic treatment on oral health-related quality of life. Psychosocial impact of dental esthetics at baseline and improvement from pretreatment to posttreatment were found to be predicted by the patients' psychological well-being attributes (self-esteem, general body image, and negative affect) and the clinical indicators (orthodontists' rating on the IOTN-AC) at baseline, as well as their pretreatment to posttreatment change. Psychological well-being attributes had comparable or greater contribution to the Psychosocial Impact of Dental Aesthetics at baseline as well as greater improvement after treatment than the clinical indicators. These biopsychological models explained 29% to 43% of the variances in psychosocial impacts of dental esthetics outcome at baseline and about 33% of the variance in pretreatment to posttreatment improvement. CONCLUSIONS: This study establishes a biopsychological model for understanding the psychosocial impact of dental esthetics and its improvement after orthodontic treatment among adolescent orthodontic patients. The findings highlight the importance of psychological parameters in orthodontic research and clinical practice. PMID- 29287661 TI - Time-dependent behavior of porcine periodontal ligament: A combined experimental, numeric in-vitro study. AB - INTRODUCTION: The aim of this study was to analyze the time-dependent in-vitro behavior of the periodontal ligament (PDL) by determining the material parameters using specimens of porcine jawbone. Time-dependent material parameters to be determined were expected to complement the results from earlier biomechanical studies. METHODS: Five mandibular deciduous porcine premolars were analyzed in a combined experimental-numeric study. After selecting suitable specimens (excluding root resorption) and preparing the measurement system, the specimens were deflected by a distance of 0.2 mm at loading times of 0.2, 0.5, 1, 2, 5, 10, and 60 seconds. The deflection of the teeth was determined via a laser optical system, and the resulting forces and torques were measured. To create the finite element models, a microcomputed tomography scanner was used to create 3 dimensional x-ray images of the samples. The individual structures (tooth, PDL, bone) of the jaw segments were reconstructed using a self-developed reconstruction program. A comparison between experiment and simulation was conducted using the results from finite element simulations. Via iterative parameter adjustments, the material parameters (Young's modulus and Poisson's ratio) of the PDL were assessed at different loading velocities. RESULTS: The clinically observed effect of a distinct increase in force during very short periods of loading was confirmed. Thus, a force of 2.6 N (+/-1.5 N) was measured at the shortest stress duration of 0.2 seconds, and a force of 1.0 N (+/-0.5 N) was measured at the longest stress duration of 60 seconds. The numeric determination of the material parameters showed bilinear behavior with a median value of the first Young's modulus between 0.06 MPa (2 seconds) and 0.04 MPa (60 seconds), and the second Young's modulus between 0.30 MPa (10 seconds) and 0.20 MPa (60 seconds). The ultimate strain marking the transition from the first to the second Young's modulus remained almost unchanged with a median value of 6.0% for all loading times. CONCLUSION: A combined experimental-numeric analysis is suitable for determining the material properties of the PDL. Microcomputed tomography allows high-precision recordings with only minimum effort. This study confirms the assumption of time dependency and nonlinearity of previous studies. PMID- 29287662 TI - The influence of local bone quality on fracture pattern in proximal humerus fractures. AB - INTRODUCTION: Bone mineral density and fracture morphology are widely discussed and relevant factors when considering the different treatment options for proximal humerus fractures. It was the aim of this study to investigate the influence of local bone quality on fracture patterns of the Neer classification as well as on fracture impaction angle in these injuries. MATERIALS AND METHODS: All acute, isolated and non-pathological proximal humerus fractures admitted to our emergency department were included. The fractures were classified according to Neer and the humeral head impaction angle was measured. Local bone quality was assessed using the Deltoid Tuberosity Index (DTI). The distribution between DTI and fracture pattern was analysed. RESULTS: 191 proximal humerus fractures were included (61 men, mean age 59 years; 130 women, mean age 69.5). 77 fractures (40%) were classified as one-part, 72 (38%) were two-part, 24 (13%) were three- and four-part and 18 (9%) were fracture dislocations. 30 fractures (16%) were varus impacted, whereas 45 fractures (24%) were classified as valgus impacted. The mean DTI was 1.48. Valgus impaction significantly correlated with good bone quality (DTI >= 1.4; p = 0.047) whereas no such statistical significance was found for the Neer fracture types. DISCUSSION: We found that valgus impaction significantly depended on good bone quality. However, neither varus impaction nor any of the Neer fracture types correlated with bone quality. We conclude that the better bone quality of valgus impacted fractures may be a reason for their historically benign amenability to ORIF. On the other hand, good local bone quality does not prevent fracture comminution. PMID- 29287663 TI - The 'could' and the 'should' of reconstructing severe hind-foot injuries. PMID- 29287664 TI - A sequential multiple assignment randomized trial for cocaine cessation and relapse prevention: Tailoring treatment to the individual. AB - Drug addiction is a chronic, devastating, but treatable disorder. A core principle of drug addiction treatment states that no single treatment is appropriate for everyone (NIDA, 2012); treatments need to adjust based on patient characteristics and response in order to be maximally effective. For cocaine use disorders (CUD), specifically, the most potent intervention currently available for initiating abstinence is behavior therapy using contingency management (CM) procedures, with early cessation being a robust predictor of future abstinence. This raises two key questions for treatment development research: First, can we significantly improve initial CM response rates with targeted adjunctive interventions? Second, for individuals who fail to achieve initial abstinence with CM, is pharmacotherapy an effective augmentation strategy? This paper describes how a sequential, multiple assignment, randomized trial (SMART) design has advantages over a fixed-intervention approach when it comes to collecting data needed to answer both questions. The first aim will examine whether Acceptance and Commitment Therapy (ACT) in combination with CM increases initial abstinence response rates (i.e., 2 consecutive weeks of cocaine-negative urine screens). The second aim will examine whether ACT+CM in combination with modafinil promotes abstinence achievement in initial non-responders. Results are expected to inform how we tailor treatment of CUD to maximize outcomes. PMID- 29287665 TI - Tobacco dependence treatment in the emergency department: A randomized trial using the Multiphase Optimization Strategy. AB - BACKGROUND: Tobacco dependence remains the leading preventable cause of death in the developed world. Smokers are disproportionately from lower socioeconomic groups, and may use the hospital emergency department (ED) as an important source of care. A recent clinical trial demonstrated the efficacy of a multicomponent intervention to help smokers quit, but the independent contributions of those components is unknown. METHODS: This is a full-factorial (16-arm) randomized trial in a busy hospital ED of 4 tobacco dependence interventions: brief motivational interviewing, nicotine replacement therapy, referral to a telephone quitline, and a texting program. The trial utilizes the Multiphase Optimization Strategy (MOST) and a novel mixed methods analytic design to assess clinical efficacy, cost effectiveness, and qualitative participant feedback. The primary endpoint is tobacco abstinence at 3months, verified by participants' exhaled carbon monoxide. RESULTS: Study enrollment began in February 2017. As of April 2017, 52 of 1056 planned participants (4.9%) were enrolled. Telephone-based semi structured participant interviews and in-person biochemical verification of smoking abstinence are completed at the 3-month follow-up. Efficacy and cost effectiveness analyses will be conducted after follow-up is completed. DISCUSSION: The goal of this study is to identify a clinically efficacious, cost effective intervention package for the initial treatment of tobacco dependence in ED patients. The efficacy of this combination can then be tested in a subsequent confirmatory trial. Our approach incorporates qualitative feedback from study participants in evaluating which intervention components will be tested in the future trial. TRIAL REGISTRATION: Trial (NCT02896400) registered in ClinicalTrials.gov on September 6, 2016. PMID- 29287666 TI - Agreement in reporting between trial publications and current clinical trial registry in high impact journals: A methodological review. AB - OBJECTIVES: The primary objective of this systematic survey was to examine the percentage of studies in which there was agreement in the reporting of the primary outcome between the currently updated version of the clinical trial registry and the published paper. We also investigated the factors associated with agreement in reporting of the primary outcome. METHODS: We searched PubMed for all randomized control trials (RCT)s published in 2012-2015 in the top five general medicine journals (based on the 2014 impact factor). Two hundred abstracts (50 from each year) were randomly selected for data extraction. Agreement in reporting of 11 key study conduct items (e.g., sample size) and study characteristics (e.g., funding, number of sites) were extracted by two independent reviewers. ANALYSIS: Descriptive analyses were conducted to determine the proportion of studies on which there was agreement in reporting of key study conduct items. Generalized estimating equations were used to explore factors associated with agreement in reporting of the primary outcome. RESULTS: Of the 200 included studies, 87% had agreement in reporting of the primary outcome. After adjusting for other covariates, having greater than 50 sites was associated with an increased likelihood of agreement in reporting of the primary outcome (odds ratio=7.1, 95% confidence interval=1.39, 36.27, p=0.018). CONCLUSIONS: We identified substantive disagreement in reporting between publications and current clinical trial registry, which were associated with several study characteristics. Further measures are needed to improve reporting given the potential threats to the quality and integrity of scientific research. PMID- 29287667 TI - A cluster-randomized trial of a college health center-based alcohol and sexual violence intervention (GIFTSS): Design, rationale, and baseline sample. AB - INTRODUCTION: Sexual violence (SV) on college campuses is common, especially alcohol-related SV. This is a 2-arm cluster randomized controlled trial to test a brief intervention to reduce risk for alcohol-related sexual violence (SV) among students receiving care from college health centers (CHCs). Intervention CHC staff are trained to deliver universal SV education to all students seeking care, to facilitate patient and provider comfort in discussing SV and related abusive experiences (including the role of alcohol). Control sites provide participants with information about drinking responsibly. METHODS: Across 28 participating campuses (12 randomized to intervention and 16 to control), 2292 students seeking care at CHCs complete surveys prior to their appointment (baseline), immediately after (exit), 4months later (T2) and one year later (T3). The primary outcome is change in recognition of SV and sexual risk. Among those reporting SV exposure at baseline, changes in SV victimization, disclosure, and use of SV services are additional outcomes. Intervention effects will be assessed using generalized linear mixed models that account for clustering of repeated observations both within CHCs and within students. RESULTS: Slightly more than half of the participating colleges have undergraduate enrollment of >=3000 students; two thirds are public and almost half are urban. Among participants there were relatively more Asian (10 v 1%) and Black/African American (13 v 7%) and fewer White (58 v 74%) participants in the intervention compared to control. CONCLUSIONS: This study will offer the first formal assessment for SV prevention in the CHC setting. Clinical Trials #: NCT02355470. PMID- 29287669 TI - A multidisciplinary approach to oncology trials: Study conduct of the ANTHALYA trial. AB - Clinical trials that combine medical therapy and surgical treatment pose a number of challenges. The ANTHALYA trial investigated the efficacy and safety of adding bevacizumab to neoadjuvant carboplatin-paclitaxel chemotherapy prior to interval debulking surgery (IDS) in patients with ovarian cancer. The success of the trial depended on the efficacy and the safety of the combination and on the surgical effort. Furthermore, at the time of study design, neoadjuvant bevacizumab had not been investigated in ovarian cancer patients and it was unknown if neoadjuvant angiogenic therapy would be well tolerated or would negatively impact the success of IDS. Therefore, safety in the ANTHALYA trial was paramount. To overcome these challenges we conducted the trial in collaboration with French oncologists and surgeons who were experts in the multidisciplinary treatment of ovarian cancer. Toxicity was monitored during the neoadjuvant and IDS periods using a Bayesian approach which provided flexibility in the decision-making process regarding the continuation or rapid discontinuation of the trial in response to a safety signal. We implemented a stopping rule for safety based on a number of pre defined bevacizumab-related complications of special interest. We also developed an electronic case report form, which greatly facilitated the collection and dissemination of safety information and other trial data. Here we describe how we used these tools to ensure the successful conduct of ANTHALYA and report how it is possible to mix a Bayesian approach for monitoring toxicity and a frequentist approach for evaluating efficacy within the same trial. PMID- 29287668 TI - Development of a novel, integrated cognitive-behavioral therapy for co-occurring posttraumatic stress and substance use disorders: A pilot randomized clinical trial. AB - Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are complex psychiatric conditions that commonly co-occur. No evidence-based, 'gold standard' treatments for PTSD/SUD comorbidity are currently available. The present pilot randomized clinical trial was designed to evaluate the feasibility and preliminary efficacy of a novel, integrated cognitive-behavioral treatment approach for PTSD/SUD, entitled Treatment of Integrated Posttraumatic Stress and Substance Use (TIPSS), as compared to standard cognitive-behavioral treatment (CBT) for SUD. The TIPSS program integrates cognitive processing therapy with CBT for SUD for the treatment of co-occurring PTSD/SUD. Both treatment conditions are comprised of 12, 60-minute individual psychotherapy sessions, delivered twice weekly over six weeks. Primary aims examine whether TIPSS, compared to standard CBT for SUD, reduces: (1) PTSD symptoms and (2) substance use outcomes (i.e., self-report, objective). Secondary aims examine whether (a) trauma- and substance cue reactivity and (b) distress tolerance (i.e., actual or perceived ability to withstand uncomfortable emotional or physical states) are significant mechanisms of change. The study was recently closed to new enrollment. Participants included adults with substance dependence and at least four symptoms of PTSD. PMID- 29287671 TI - The effects of preabortion depressive symptoms on postabortion contraceptive effectiveness level chosen among women seeking abortions. AB - OBJECTIVE: We examined whether preabortion depressive symptoms were associated with contraceptive method effectiveness level chosen among women seeking abortions. STUDY DESIGN: Three-hundred and forty-seven young, low-income women 18 years or older who were seeking abortions at 3 community reproductive health clinics in Northern California were recruited to participate in a study on contraceptive decision making. We classified women into choosing low-, moderate- or high-effectiveness contraceptive methods based on typical-use failure rates. We used the Center for Epidemiologic Studies Depression scale to assess depressive symptoms as a continuous and dichotomous variable. Using the standard cutoff of 20, women who scored at or above this were considered depressed for the dichotomous measure. We used multinomial logistic regression to examine the association between preabortion depressive symptoms and contraceptive effectiveness level chosen to use after an abortion, adjusting for sociodemographics, abortion characteristics, pregnancy history, future pregnancy desires, relationship characteristics and adverse experiences. RESULTS: After adjusting for covariates, we found that a one-unit increase in depressive symptoms was associated with a higher likelihood of choosing low- versus moderate [adjusted odd ratio (aOR)=1.05, 95% confidence interval (CI): 1.01-1.10, p<.02] and high-effectiveness methods (aOR=1.05, 95% CI: 1.002-1.10, p<.05). Furthermore, women scoring above the cutoff for depression were more likely to choose low- versus moderate-effectiveness methods (aOR=4.56, 95% CI: 1.27-16.32, p=.02). CONCLUSIONS: More preabortion depressive symptoms were independently associated with choosing low- versus moderate- and high-effectiveness contraceptives. IMPLICATIONS: These findings together with other findings show that preabortion depressive symptoms do not uniformly influence effectiveness level of contraceptive method selected to use after an abortion. Reproductive health care providers should consider the impact of women's psychological symptoms on their contraceptive decision making. PMID- 29287670 TI - Investigation of Clostridium botulinum group III's mobilome content. AB - Clostridium botulinum group III is mainly responsible for botulism in animals. It could lead to high animal mortality rates and, therefore, represents a major environmental and economic concern. Strains of this group harbor the botulinum toxin locus on an unstable bacteriophage. Since the release of the first complete C. botulinum group III genome sequence (strain BKT015925), strains have been found to contain others mobile elements encoding for toxin components. In this study, seven assays targeting toxin genes present on the genetic mobile elements of C. botulinum group III were developed with the objective to better characterize C. botulinum group III strains. The investigation of 110 C. botulinum group III strains and 519 naturally contaminated samples collected during botulism outbreaks in Europe showed alpha-toxin and C2-I/C2-II markers to be systematically associated with type C/D bont-positive samples, which may indicate an important role of these elements in the pathogenicity mechanisms. On the contrary, bont type D/C strains and the related positive samples appeared to contain almost none of the markers tested. Interestingly, 31 bont-negative samples collected on farms after a botulism outbreak revealed to be positive for some of the genetic mobile elements tested. This suggests loss of the bont phage, either in farm environment after the outbreak or during laboratory handling. PMID- 29287672 TI - [Impact of hypotension and global hypoperfusion in postoperative delirium: a pilot study in older adults undergoing open colon surgery]. AB - BACKGROUND: Post-operative delirium is a serious complication in patients undergoing major abdominal surgery. It remains unclear whether peri-operative hemodynamic and perfusion variables affect the risk for postoperative delirium. The objective of this pilot study was to evaluate the association between perfusion and hemodynamics peri-operative with the appearance of post-operative delirium. METHODS: Prospective cohort study of adults 60 years or older undergoing elective open colon surgery. Multimodal hemodynamic and perfusion variables were monitored, including central venous oxygenation (ScvO2), lactate levels, and non-invasive cerebral oxygenation (rSO2), according to a standard anesthesia protocol. Fisher's exact test or Student's t-test were used to compare patients who developed post-operative delirium with those who did not (p<0.05). RESULTS: We studied 28 patients, age 73+/-7 years, 60.7% female. Two patients developed post-operative delirium (7.1%). These two patients had fewer years of education than those without delirium (p=0.031). None of the peri-operative blood pressure variables were associated with incidence of post-operative delirium. In terms of perfusion parameters, postoperative ScvO2 was lower in the delirium than the non-delirium group, without reaching statistical significance (65+/-10% vs. 74+/-5%; p=0.08), but the delta-ScvO2 (the difference between means post operative and intra-operative) was associated with post-operative delirium (p=0.043). Post-operative lactate and rSO2 variables were not associated with delirium. CONCLUSIONS: Our pilot study suggests an association between delta ScvO2 and post-operative delirium, and a tendency to lower post-operative ScvO2 in patients who developed delirium. Further studies are necessary to elucidate this association. PMID- 29287673 TI - [Efficacy of preoxygenation using tidal volume breathing: a comparison of Mapleson A, Bain's and Circle system]. AB - BACKGROUND: Efficacy of preoxygenation depends upon inspired oxygen concentration, its flow rate, breathing system configuration and patient characteristics. We hypothesized that in actual clinical scenario, where breathing circuit is not primed with 100% oxygen, patients may need more time to achieve EtO2>=90%, and this duration may be different among various breathing systems. We thus studied the efficacy of preoxygenation using unprimed Mapleson A, Bain's and Circle system with tidal volume breathing at oxygen flow rates of 5L.min-1 and 10L.min-1. METHODS: Patients were randomly allocated into one of the six groups, wherein they were preoxygenated using either Mapleson A, Bain's or Circle system at O2 flow rate of either 5L.min-1 or 10L.min-1. The primary outcome measure of our study was the time taken to achieve EtO2>=90% at 5 and 10L.min-1 flow rates. RESULTS: At oxygen flow rate of 5L.min-1, time to reach EtO2>=90% was significantly longer with Bain's system (3.7+/-0.67min) than Mapleson A and Circle system (2.9+/-0.6, 3.3+/-0.97min, respectively). However at oxygen flow rate of 10L.min-1 this time was significantly shorter and comparable among all the three breathing systems (2.33+/-0.38min with Mapleson, 2.59+/ 0.50min with Bain's and 2.60+/-0.47min with Circle system). CONCLUSIONS: With spontaneous normal tidal volume breathing at oxygen flow rate of 5L.min-1, Mapleson A can optimally preoxygenate patients within 3min while Bain's and Circle system require more time. However at O2 flow rate of 10L.min-1 all the three breathing systems are capable of optimally preoxygenating the patients in less than 3min. PMID- 29287674 TI - [Effects of cerebral oxygen changes during coronary bypass surgery on postoperative cognitive dysfunction in elderly patients: a pilot study]. AB - BACKGROUND AND OBJECTIVES: Postoperative cognitive dysfunction is common after cardiac surgery. Adequate cerebral perfusion is essential and near infrared spectroscopy (NIRS) can measure cerebral oxygenation. Aim of this study is to compare incidence of early and late postoperative cognitive dysfunction in elderly patients treated with conventional or near infrared spectroscopy monitoring. METHODS: Patients undergoing coronary surgery above 60 years, were included and randomized to 2 groups; control and NIRS groups. Peroperative management was NIRS guided in GN; and with conventional approach in control group. Test battery was performed before surgery, at first week and 3 rd month postoperatively. The battery comprised clock drawing, memory, word list generation, digit spam and visuospatial skills subtests. Postoperative cognitive dysfunction was defined as drop of 1 SD (standard deviation) from baseline on two or more tests. Mann-Whitney U test was used for comparison of quantitative measurements; Chi-square exact test to compare quantitative data. RESULTS: Twenty one patients in control group and 19 in NIRS group completed study. Demographic and operative data were similar. At first week postoperative cognitive dysfunction were present in 9 (45%) and 7 (41%) of patients in control group and NIRS group respectively. At third month 10 patients (50%) were assessed as postoperative cognitive dysfunction; incidence was 4 (24%) in NIRS group (p:0.055). Early and late postoperative cognitive dysfunction group had significantly longer ICU stay (1.74+0.56 vs. 2.94+0.95; p<0.001; 1.91+0.7 vs. 2.79+1.05; p<0.01) and longer hospital stay (9.19+2.8 vs. 11.88+1.7; p<0.01; 9.48+2.6 vs. 11.36+2.4; p<0.05). CONCLUSION: In this pilot study conventional monitoring and near infrared spectroscopy resulted in similar rates of early postoperative cognitive dysfunction. Late cognitive dysfunction tended to ameliorate with near infrared spectroscopy. Early and late cognitive declines were associated with prolonged ICU and hospital stays. PMID- 29287675 TI - Depletion of the extracellular-signal regulated kinase 8 homolog in Trypanosoma brucei in vivo reduces its virulence in a mouse target validation study. AB - Trypanosoma brucei sub-species are vector borne kinetoplastid parasites that cause the potentially lethal disease Human African trypanosomiasis. The target based therapy for curing this parasitic disease relies on one drug, Eflornithine. The roles of mitogen-activated protein kinases in regulating key cellular processes in eukaryotic cells such as proliferation, stress response and differentiation plus their druggability make them attractive targets for therapeutic exploitation. The extracellular-regulated kinase 8 homolog in T. brucei (TbERK8) is a MAPK that is required for the parasite to proliferate normally in culture. We examined the importance of TbERK8 for permitting T. brucei to thrive in mice. Here we show that depleting TbERK8 in vivo negatively affected the virulence of T. brucei reducing its ability to progress to lethal infections or cause significant pathology in mice, which validates it as an attractive target. PMID- 29287676 TI - Nonalcoholic fatty liver disease and sarcopenia in a Western population (NHANES III): The importance of sarcopenia definition. AB - BACKGROUND: Recent epidemiological studies have shown that sarcopenia is associated with non-alcoholic fatty liver disease (NAFLD) and advanced fibrosis in an Asian population. We investigated whether NAFLD is associated with a higher risk of sarcopenia using a different definition in elderly patients. METHODS: A population-based cross-sectional survey of US patients was conducted, involving 2551 participants aged 60-75 years. NAFLD was measured by ultrasound. Sarcopenia was defined by both a low muscle mass and poor muscle function. In addition, the skeletal muscle index (SMI) was calculated as the absolute muscle mass (kilograms) divided by height2 (meters) or total body mass (kilograms). A multivariable logistic regression was conducted to estimate the relationship between sarcopenia and NAFLD in the elderly. RESULTS: After adjusting for age, sex, and race/ethnicity, severe hepatic steatosis was associated with a decreased risk of sarcopenia as defined by the height-adjusted SMI (odds ratio (OR) 0.63; 95% confidence interval (CI) 0.46-0.87). In contrast, severe hepatic steatosis was associated with an increased risk of sarcopenia as defined by the weight adjusted SMI (OR 1.73; 95% CI 1.31-2.28). These significant associations remained after further adjustments for other potential confounding variables. CONCLUSIONS: NAFLD is associated with a lower risk of sarcopenia when using the height adjusted SMI. In contrast, it showed the opposite result when using the weight adjusted SMI. The definition of sarcopenia may be an important factor when examining its relationship with NAFLD. PMID- 29287677 TI - Fidelity or flexibility: An ethnographic study of the implementation and use of the Patient Activation Measure. AB - OBJECTIVE: To evaluate the use of the PAM in the English National Health service. The PAM is a validated scale that measures 'activation' (people's knowledge, skills, and confidence in managing their health) and assigns patients to four categories of activation (low-to-high). Some evidence suggests that higher activation levels correlate to better clinical outcomes and patient experiences, and lower healthcare costs. Empirical studies of implementing the PAM are scarce. METHODS: An ethnographic study of six healthcare organisations' PAM implementation focused on 'core-teams' who designed projects, and frontline staff and patients' experiences of those. Data comprised 123 hours of observation, 112 interviews, and document reviewing. Analysis used a constant-comparative approach. RESULTS: The PAM appealed as it fitted with different logics of measurement, offering a means of quantifying soft, process-oriented qualitative constructs used in tailoring care, whilst simultaneously producing reliable high level outcome metrics. Data revealed challenges to these logics. The PAM's developers emphasised fidelity to ensure reliability but, in practice, flexibility was commonplace and often perceived as appropriate and beneficial by frontline staff. CONCLUSION: The intended logic of measurement is important in determining an appropriate balance of fidelity and flexibility and, therefore, reliability and patient benefit. PMID- 29287678 TI - The WHO Tailoring Immunization Programmes (TIP) approach: Review of implementation to date. AB - INTRODUCTION: The WHO Regional Office for Europe developed the Guide to tailoring immunization programmes (TIP), offering countries a process through which to diagnose barriers and motivators to vaccination in susceptible low vaccination coverage and design tailored interventions. A review of TIP implementation was conducted in the European Region. MATERIAL AND METHODS: The review was conducted during June to December 2016 by an external review committee and was based on visits in Bulgaria, Lithuania, Sweden and the United Kingdom that had conducted a TIP project; review of national and regional TIP documents and an online survey of the Member States in the WHO European Region that had not conducted a TIP project. A review committee workshop was held to formulate conclusions and recommendations. RESULTS: The review found the most commonly cited strengths of the TIP approach to be the social science research as well as the interdisciplinary approach and community engagement, enhancing the ability of programmes to "listen" and learn, to gain an understanding of community and individual perspectives. National immunization managers in the Region are generally aware that TIP exists and that there is strong demand for the type of research it addresses. Further work is needed to assist countries move towards implementable strategies based on the TIP findings, supported by an emphasis on enhanced local ownership; integrated diagnostic and intervention design; and follow-up meetings, advocacy and incentives for decision-makers to implement and invest in strategies. CONCLUSIONS: Understanding the perspectives of susceptible and low-coverage populations is crucial to improving immunization programmes. TIP provides a framework that facilitated this in four countries. In the future, the purpose of TIP should go beyond identification of susceptible groups and diagnosis of challenges and ensure a stronger focus on the design of strategies and appropriate and effective interventions to ensure long-term change. PMID- 29287679 TI - Protective immunity of a Multivalent Vaccine Candidate against piglet diarrhea caused by enterotoxigenic Escherichia coli (ETEC) in a pig model. AB - As one of the most challenging problems in swine industry, piglet diarrhea has caused huge economic loss globally. Currently, vaccination is the most effective way of controlling enterotoxigenic Escherichia coli (ETEC) diarrhea. However, existing commercial vaccines could not provide broad protection against different types of ETEC. In this study, we mixed a enterotoxin fusion protein SLS (STa-LTB STb) with the main fimbrial F4ac and F5 antigens as a novel multivalent vaccine candidate. Then an overall evaluation of this vaccine candidate against ETEC was carried out in a pig model. We found that the IgG titers in serum as well as colostrum in all the vaccinated sows were significantly higher than that in the control group (P < 0.05). By using a sensory evaluation method, we demonstrated that piglets in the vaccinated group exhibited significantly healthier status than the unimmunized group. Moreover, in response to F41 + ETEC challenge, none of the piglets with the vaccine candidate experienced diarrhea, whereas 30% of the piglets suffered without vaccination. In conclusion, these results showed that the candidate vaccine could elicit multiple high-titer antibodies against all the main virulence factors and provide a broad and effective protection against ETEC diarrhea. PMID- 29287680 TI - Monitoring the uptake of live avian vaccines by their detection in feathers. AB - Protection against diseases caused by the avian viruses, Marek's disease, Infectious laryngotracheitis, chicken anemia and turkey meningoencephalitis is achieved by live vaccines. The application quality is important to assure proper uptake in commercial flocks. We describe a novel evaluation method for the vaccination process by sequential monitoring the vaccine viruses in feathers. Feather collection is easy, non-invasive and non-lethal for the birds, therefore advantageous for monitoring purposes. To demonstrate the vaccine virus presence, an innovative assay of nested real-time amplification was approached because vaccine viruses presence in vivo is less abundant comparing to virulent wild-type isolates. The Marek's disease virus vaccine virus, Rispens/CVI988, in feathers of commercial flock was detected from 4 to 7 days and for at least 3 months post vaccination, until the survey stopped. As the drinking water route was newly adopted for Infectious laryngotracheitis vaccination, one or two vaccine doses/bird were administered. The virus uptake was detected in feathers between 2 and 20 days-post-vaccination. With a doubled vaccine dose the positivity bird rate was higher. For the first time the chicken anemia vaccine virus presence in chicken feathers was demonstrated between 14 and 35 days-post-vaccination. No previous studies were available, thus in parallel to feathers the vaccine virus was demonstrated in the livers and spleens. The turkey meningoencephalitis vaccine virus uptake in turkey feather-pulps is even more innovative because this is the first turkey virus amplified from feather-pulps. The vaccine virus presence resemble the kinetics of the other 3 viruses, 3-21 days-post vaccination. Detecting the specific antibodies following vaccination possessed a lower sensitivity than vaccine virus demonstration in feathers. In summary, the presented assay can be adopted for the quality evaluation of the vaccination process in poultry. PMID- 29287682 TI - Development of an FHbp-CTB holotoxin-like chimera and the elicitation of bactericidal antibodies against serogroup B Neisseria meningitidis. AB - The Neisseria meningitidis factor H binding protein (FHbp) is an important virulence factor and vaccine antigen contained in both USA licensed serogroup B meningococcal vaccines. Recent studies in human factor H (hFH) transgenic mice suggest that hFH-FHbp interactions lower FHbp-elicited immunogenicity. To provide tools with which to characterize and potentially improve FHbp immunogenicity, we developed an FHbp-cholera holotoxin-like chimera vaccine expression system in Escherichia coli that utilizes cholera toxin B (CTB) as both a scaffold and adjuvant for FHbp. We developed FHbp-CTB chimeras using a wild-type (WT) FHbp and a low hFH-binding FHbp mutant R41S. Both chimeras bound to GM1 ganglioside and were recognized by the FHbp-specific monoclonal antibody JAR4. The R41S mutant had greatly reduced hFH binding compared to the WT FHbp-CTB chimera. WT and R41S FHbp-CTB chimeric antigens were compared to equimolar amounts of FHbp admixed with CTB or FHbp alone in mouse immunogenicity studies. The chimeras were significantly more immunogenic than FHbp alone or mixed with CTB, and elicited bactericidal antibodies against a panel of MenB isolates. This study demonstrates a unique and simple method for studying FHbp immunogenicity. The chimeric approach may facilitate studies of other protein-based antigens targeting pathogenic Neisseria and lay groundwork for the development of new protein based vaccines against meningococcal and gonococcal disease. PMID- 29287681 TI - Alphavirus vector-based replicon particles expressing multivalent cross protective Lassa virus glycoproteins. AB - Lassa virus (LASV) is the most prevalent rodent-borne arenavirus circulated in West Africa. With population at risk from Senegal to Nigeria, LASV causes Lassa fever and is responsible for thousands of deaths annually. High genetic diversity of LASV is one of the challenges for vaccine R&D. We developed multivalent virus like particle vectors (VLPVs) derived from the human Venezuelan equine encephalitis TC-83 IND vaccine (VEEV) as the next generation of alphavirus-based bicistronic RNA replicon particles. The genes encoding VEEV structural proteins were replaced with LASV glycoproteins (GPC) from distantly related clades I and IV with individual 26S promoters. Bicistronic RNA replicons encoding wild-type LASV GPC (GPCwt) and C-terminally deleted, non-cleavable modified glycoprotein (DeltaGPfib), were encapsidated into VLPV particles using VEEV capsid and glycoproteins provided in trans. In transduced cells, VLPVs induced simultaneous expression of LASV GPCwt and DeltaGPfib from 26S alphavirus promoters. LASV DeltaGPfib was predominantly expressed as trimers, accumulated in the endoplasmic reticulum, induced ER stress and apoptosis promoting antigen cross-priming. VLPV vaccines were immunogenic and protective in mice and upregulated CD11c+/CD8+ dendritic cells playing the major role in cross-presentation. Notably, VLPV vaccination resulted in induction of cross-reactive multifunctional T cell responses after stimulation of immune splenocytes with peptide cocktails derived from LASV from clades I-IV. Multivalent RNA replicon-based LASV vaccines can be applicable for first responders, international travelers visiting endemic areas, military and lab personnel. PMID- 29287684 TI - F0 Characteristics of Newsreaders on Varied Emotional Texts in Tamil Language. AB - OBJECTIVE: The objective of this study was to profile speaking F0 and its variations in newsreaders on varied emotional texts. STUDY DESIGN: This study has a prospective, case-control study design. METHODS: Fifteen professional newsreaders and 15 non-newsreaders were the participants. The participants read the news bulletin that conveyed different emotions (shock, neutral, happy, and sad) in a habitual and "newsreading" voice. Speaking fundamental frequency (SFF) and F0 variations were extracted from 1620 tokens using Praat software (version 5.2.32) on the opening lines, headlines, news stories, and closing lines of each news item. Paired t test, independent t test, and Friedman test were used for statistical analysis. RESULTS: Both male and female newsreaders had significantly (P <= 0.05) higher SFFs and standard deviations (SDs) of SFF in newsreading voice than speaking voice. Female non-newsreaders demonstrated significantly higher SFF and SD of SFF in newsreading voice, whereas no significant differences were noticed in the frequency parameters for male non-newsreaders. No significant difference was noted in the frequency parameters of speaking and newsreading voice between male newsreaders and male non-newsreaders. A significant difference in the SD of SFF was noticed between female newsreaders and female non newsreaders in newsreading voice. Female newsreaders had a higher frequency range in both speaking voice and newsreading voice when compared with non-newsreaders. CONCLUSIONS: F0 characteristics and frequency range determine the amount of frequency changes exercised by newsreaders while reading bulletins. This information is highly pedagogic for training voices in this profession. PMID- 29287683 TI - How close are countries of the WHO European Region to achieving the goal of vaccinating 75% of key risk groups against influenza? Results from national surveys on seasonal influenza vaccination programmes, 2008/2009 to 2014/2015. AB - BACKGROUND: Influenza vaccination is recommended especially for persons at risk of complications. In 2003, the World Health Assembly urged Member States (MS) to increase vaccination coverage to 75% among older persons by 2010. OBJECTIVE: To assess progress towards the 2010 vaccination goal and describe seasonal influenza vaccination recommendations in the World Health Organization (WHO) European Region. METHODS: Data on seasonal influenza vaccine recommendations, dose distribution, and target group coverage were obtained from two sources: European Union and European Economic Area MS data were extracted from influenza vaccination surveys covering seven seasons (2008/2009-2014/2015) published by the Vaccine European New Integrated Collaboration Effort and European Centre for Disease Prevention and Control. For the remaining WHO European MS, a separate survey on policies and uptake for all seasons (2008/2009-2014/2015) was distributed to national immunization programmes in 2015. RESULTS: Data was available from 49 of 53 MS. All but two had a national influenza vaccination policy. High-income countries distributed considerably higher number of vaccines per capita (median; 139.2 per 1000 population) compared to lower-middle-income countries (median; 6.1 per 1000 population). Most countries recommended vaccination for older persons, individuals with chronic disease, healthcare workers, and pregnant women. Children were included in < 50% of national policies. Only one country reached 75% coverage in older persons (2014/2015), while a number of countries reported declining vaccination uptake. Coverage of target groups was overall low, but with large variations between countries. Vaccination coverage was not monitored for several groups. CONCLUSIONS: Despite policy recommendations, influenza vaccination uptake remains suboptimal. Low levels of vaccination is not only a missed opportunity for preventing influenza in vulnerable groups, but could negatively affect pandemic preparedness. Improved understanding of barriers to influenza vaccination is needed to increase uptake and reverse negative trends. Furthermore, implementation of vaccination coverage monitoring is critical for assessing performance and impact of the programmes. PMID- 29287685 TI - Medicinal plants and bioactive natural compounds in the treatment of non alcoholic fatty liver disease: A clinical review. AB - Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver diseases, and is closely related to metabolic syndrome and its related conditions, diabetes mellitus and dyslipidemia. On the other hand, NAFLD as a multisystem disease increases the risk of several chronic diseases include type 2 diabetes mellitus, cardiovascular disease (CVD), and chronic kidney disease. The main objective was to review the efficacy of bioactive natural compounds assessed by clinical trials. Search literature using four databases (PubMed, EBSCO, Web of Science, and Ovid Medline) to review publications that focused on the impact of bioactive natural compounds in NAFLD treatment. Due to the lack of effective pharmacological treatments available for NAFLD, lifestyle modifications such as following a healthy diet, vigorous physical activity, and weight reduction remain the first line of treatment for NAFLD. However, due to the poor adherence to this type of treatment, especially for long-term weight loss diets some of which may have harmful effects on the liver, finding novel therapeutic agents for NAFLD treatment and/or preventing NAFLD progression has garnered significant interest. Although the therapeutic agents of NAFLD treatment have been reviewed previously, to date, no summary has been conducted of clinical trials examining the effects of herbal compounds on NAFLD-related biomarkers. This review highlights the beneficial role of herbal bioactives and medicinal plants in NAFLD treatment, particularly as complementary to a healthy lifestyle. All natural products described in this review seem to have some benefits to improve oxidative stress, cellular inflammation and insulin-resistance, which always remain as the "primum movens" of NAFLD pathogenesis. PMID- 29287686 TI - Indole and indoxyl sulfate, gut bacteria metabolites of tryptophan, change arterial blood pressure via peripheral and central mechanisms in rats. AB - Arterial blood pressure (BP) is regulated by a complex network of peripheral and central (brain) mechanisms. Research suggests that gut bacteria-derived compounds may affect the circulatory system. We evaluated hemodynamic effects of indole, a gut bacteria-derived product of tryptophan, and indoxyl sulfate (indoxyl), a liver metabolite of indole. BP and heart rate (HR) were recorded in anesthetized, male, Wistar rats at baseline and after the administration of either a vehicle, indole, or indoxyl into the femoral vein (IV) or into the lateral ventricle of the brain (ICV). Besides, we evaluated the effect of pretreatment with flupentixol, a non-selective D1, D2, alpha1 and 5 HT2A receptor blocker; pizotifen, a non-selective 5-HT1, 5-HT2A and 5HT2C receptor blocker; and ondansetron, a 5-HT3 blocker, on hemodynamic responses to indole and indoxyl. Vehicle infused IV and ICV did not affect hemodynamics. Indole administered IV produced a dose-dependent increase in BP but not HR. In contrast, the ICV infusion of indole produced a decrease in BP and HR. Indoxyl infused IV produced an increase in BP and HR, whereas indoxyl infused ICV did not affect BP and HR. The hemodynamic effects of indole and indoxyl were inhibited by pretreatment with ondansetron and pizotifen but not flupentixol. In conclusion, indole and indoxyl sulfate affect arterial blood pressure via peripheral and central mechanisms dependent on serotonin signalling. We propose that indole and indoxyl sulfate may be mediators in the interaction between gut bacteria and the circulatory system. PMID- 29287687 TI - An overview of the possible therapeutic role of SUMOylation in the treatment of Alzheimer's disease. AB - Nowadays, Alzheimer's disease (AD) is recognized as a multifactorial neurological pathology whose complexity is the cause of our still low achievements in the understanding of the associated mechanisms as well the discovery of a possible definitive cure. Clinicians are aware of the few possibilities offered by medicine to cure Alzheimer's patients, restore their memory and take them back to normal life. Unfortunately, the therapeutic tools available today are not able to contrast the pathology. In the last years the tendency of the research is to formulate new hypotheses that can help to develop future effective drugs. Here we propose an overview about an interesting intracellular mechanism called SUMOylation which belongs to the post-translational modification family. SUMOylation is currently studied from few decades and it has been observed to be implicated in the molecular mechanisms of several neurological disorders including AD. Interestingly, the unbalance between SUMOylation/deSUMOylation seems to be involved in the switch from physiological to pathological behaviours of several proteins implied into AD etiology. Nevertheless, there are no pharmacological treatments known to modulate SUMOylation/deSUMOylation equilibrium. We hereby listed some natural compounds that, due to their effects on this molecular mechanism, they deserve attention for inspire the development of future convincing therapies. PMID- 29287688 TI - Anti-inflammatory effect of ATB-352, a H2S -releasing ketoprofen derivative, on lipopolysaccharide-induced periodontitis in rats. AB - Periodontal disease is the most common cause of tooth loss in humans, is an inflammatory disease initiated by oral microbial biofilm. Given the involvement of the inflammatory pathway in this type of pathology, the main pharmacological strategy for the treatment of periodontitis, is the inhibition of the inflammatory process in order to prevent tissue destruction and bone resorption, a condition associated with a painful state. To do this, the best class of drugs are Non-steroidal anti-inflammatory drugs (NSAIDs), however, the presence of side effects, especially at the gastrointestinal tract, limits their use for long-term therapy. Recently, some evidence shows that derivatives of NSAIDs capable of releasing hydrogen sulphide exhibit lower collateral effects, particularly at the gastric level. In fact, H2S is an endogenous gaseous mediator with a cytoprotective role at the gastric level. In this study, we have compared the protective effects of ketoprofen with ATB-352, a hydrogen sulfide-releasing derivative of ketoprofen, in an experimental model of periodontitis in rat. Periodontitis was induced by a single intragingival injection of 1 MUl LPS (10 MUg/MUl), Our results show that 14 h after intragingival injection of LPS, there was a high tissue damage associated with bone resorption, and in gingivomucosal tissues there was a significant expression of NF-kb p65 and pro-inflammatory cytokine as well as a higher expression of COX-2 and iNOS, activation of the apoptotic process, and also increased levels of NGF expression, often associated with a higher nociceptive perception. Treatment with ATB-352 at the dose of 20mg?kg, was able to reduce the inflammatory process associated with intragingival LPS injection and also had a positive effect on bone resorption and tissue damage. PMID- 29287689 TI - Present therapeutic role of cholesteryl ester transfer protein inhibitors. AB - Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C ( 18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85 0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit or if HDL-C-rise is a crucial factor still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development. PMID- 29287690 TI - Implication of STARD5 and cholesterol homeostasis disturbance in the endoplasmic reticulum stress-related response induced by pro-apoptotic aminosteroid RM-133. AB - The aminosteroid derivative RM-133 is an effective anticancer molecule for which proof of concept has been achieved in several mouse xenograph models (HL-60, MCF 7, PANC-1 and OVCAR-3). To promote this new family of molecules toward a clinical phase 1 trial, the mechanism of action governing the anticancer properties of the representative candidate RM-133 needs to be characterized. In vitro experiments were first used to determine that RM-133 causes apoptosis in cancer cells. Then, using proteomic and transcriptomic experiments, RM-133 cytotoxicity was proven to be achieved via the endoplasmic reticulum (ER)-related apoptosis, which characterizes RM-133 as an endoplasmic reticulum stress aggravator (ERSA) anticancer drug. Furthermore, an shRNA-genome-wide screening has permitted to identify the steroidogenic acute regulator-related lipid transfer protein 5 (STARD5) as a major player in the RM-133 ER-related apoptosis mechanism, which was validated by an in vitro binding experiment. Altogether, the results presented herein suggest that RM-133 provokes a disturbance of cholesterol homeostasis via the implication of STARD5, which delivers an ERSA molecule to the ER. These results will be a springboard for RM-133 in its path toward clinical use. PMID- 29287691 TI - Protocol for the Assessment of Patient Capacity to Make End-of-Life Treatment Decisions. AB - Patients' right to decide what happens to their bodies, especially around the end of life, is enshrined in legislation across the world, but questions often arise about whether a patient is capable of meaningfully participating in such decisions. Because of uncertainties about capacity, care providers and administrative agencies often must decide whether to honor, or even to elicit, patients' wishes. General decision-making capacity has been well studied, but few clear protocols exist for ascertaining capacity at the end of life. Without clear guidelines about how to assess capacity, medical staff may ignore assessment and operate from invalid assumptions. In the interests of protecting patients' agency, we propose a straightforward protocol for assessing capacity to make decisions about end-of-life interventions. PMID- 29287692 TI - Analysis of Reasons for Potentially Preventable Hospital Transfers Using the Modified INTERACT-II Tool. PMID- 29287693 TI - Ultrasonography to Measure Swallowing Muscle Mass and Quality in Older Patients With Sarcopenic Dysphagia. AB - BACKGROUND: Sarcopenic dysphagia is characterized by difficulty swallowing due to a loss of whole-body skeletal and swallowing muscle mass and function. However, no study has reported on swallowing muscle mass and quality in patients with sarcopenic dysphagia. OBJECTIVE: To compare the differences in swallowing muscle mass and quality between sarcopenic and nonsarcopenic dysphagia. METHOD: A cross sectional study was performed in 55 older patients, who had been recommended to undergo dysphagia assessment and/or rehabilitation. Sarcopenic dysphagia was diagnosed using a diagnostic algorithm for sarcopenic dysphagia. The thickness and area of tongue muscle and geniohyoid muscle (coronal plane and sagittal plane), and the echo-intensity of the tongue and geniohyoid muscles were examined by ultrasound. RESULTS: The study participants included 31 males and 24 females (mean age of 82 +/- 7 years), with 14 having possible sarcopenic dysphagia, 22 probable sarcopenic dysphagia, and 19 without sarcopenic dysphagia. The group with sarcopenic dysphagia had a significantly lower cross-sectional area and area of brightness of the tongue muscle than that observed in the group without sarcopenic dysphagia. The most specific factor for identifying the presence of sarcopenic dysphagia was tongue muscle area (sensitivity, 0.389; specificity, 0.947; cut-off value, 1536.0), while the factor with the highest sensitivity was geniohyoid muscle area brightness in sagittal sections (sensitivity, 0.806; specificity, 0.632; cut-off value, 20.1). Multivariate logistic regression analysis showed that the area of the tongue muscle and its area of brightness were independent risk factors for sarcopenic dysphagia. However, geniohyoid sagittal muscle area and area of brightness showed no significant independent association with sarcopenic dysphagia. CONCLUSION: Tongue muscle mass in patients with sarcopenic dysphagia was smaller than that in patients without the condition. Sarcopenic dysphagia was also associated with increased intensity of the tongue muscle. PMID- 29287694 TI - Use of Anticholinergic Drugs and its Relationship With Psychological Well-Being and Mortality in Long-Term Care Facilities in Helsinki. AB - OBJECTIVES: To assess the burden of drugs with anticholinergic properties (DAPs) and associated factors in long-term care facilities and to explore how psychological well-being and mortality are associated with the use of DAPs. DESIGN: Cross-sectional study and 1-year follow-up of all-cause mortality. SETTING AND PARTICIPANTS: All 4449 older people (>65 years of age) living in nursing homes and assisted living facilities in Helsinki in 2011 were recruited. After refusals and excluding residents with severe dementia, 2432 participants remained. MEASUREMENTS: Data on demographics, drug use, and medical history were collected by trained nurses using a structured assessment. Psychological well being (PWB) of participants was assessed by 6 questions resulting in a validated PWB score (range 0-1). Mortality data were retrieved from central registers. The total number of anticholinergic drugs was determined according to the Anticholinergic Risk Scale. RESULTS: Of the participants, 51% used at least 1 DAP. DAP users were younger and had better cognition than nonusers. There was a linear relationship between the number of DAPs used and poorer PWB. A similar trend was present between the number of DAPs and poorer PWB both among those with and without depression and among those with and without functional dependency. No difference in mortality existed between DAP users and nonusers. CONCLUSIONS: Despite DAP users being younger and having better cognition, they had poorer PWB. Clinicians should carefully consider the potential benefits and harm when prescribing DAPs to older people. PMID- 29287695 TI - Pain Treatments After Hip Fracture Among Older Nursing Home Residents. AB - OBJECTIVES: To examine the association between use of opioids versus other analgesics with death and functioning after hip fracture in older nursing home (NH) residents. DESIGN: Retrospective cohort using national Medicare fee-for service claims linked to the Minimum Data Set. SETTING: US NHs. PARTICIPANTS: NH residents aged >=65 years who became a long-stay resident (>100 days in the NH) between January 2008 and December 2009, had a hospitalized hip fracture, and returned to the NH. EXPOSURE: New use of opioid versus nonopioid analgesics (acetaminophen or nonsteroidal anti-inflammatory drugs) within 14 days post hip fracture. MEASUREMENTS: Follow-up began on the index date and continued until the first occurrence of death, significant functional decline (3-point increase on MDS Activities of Daily Living scale), or 120 days of follow-up. Odds ratios (ORs) with 95% confidence intervals (CIs) for outcomes were estimated using inverse probability of treatment-weighted multinomial logistic regression models. RESULTS: Among the 2755 NH residents with a hip fracture included in our study, 1155 (41.9%) were opioid users, and 1600 (58.1%) were nonopioid analgesic users. The mean age was 86.3 years, 73.8% were female, and 86.0% were white. Opioid use was associated with a significantly lower likelihood of death (OR = 0.47, 95% CI 0.39-0.56) and a nonsignificant decrease in functional decline (OR = 0.77, 95% CI 0.58-1.03). CONCLUSION: A rigorous study that addresses the limitations of this study is critical to validate our preliminary findings and provide evidence about the effect of using opioid versus nonopioid analgesics to optimize acute pain in NH residents with a hip fracture. PMID- 29287696 TI - Capnocytophaga sputigena pneumonia and bacteremia in a patient with diabetes and gastric cancer. PMID- 29287697 TI - Effect of N-terminal acetylation on lytic activity and lipid-packing perturbation induced in model membranes by a mastoparan-like peptide. AB - L1A (IDGLKAIWKKVADLLKNT-NH2) is a peptide that displays a selective antibacterial activity to Gram-negative bacteria without being hemolytic. Its lytic activity in anionic lipid vesicles was strongly enhanced when its N-terminus was acetylated (ac-L1A). This modification seems to favor the perturbation of the lipid core of the bilayer by the peptide, resulting in higher membrane lysis. In the present study, we used lipid monolayers and bilayers as membrane model systems to explore the impact of acetylation on the L1A lytic activity and its correlation with lipid-packing perturbation. The lytic activity investigated in giant unilamellar vesicles (GUVs) revealed that the acetylated peptide permeated the membrane at higher rates compared with L1A, and modified the membrane's mechanical properties, promoting shape changes. The peptide secondary structure and the changes in the environment of the tryptophan upon adsorption to large unilamellar vesicles (LUVs) were monitored by circular dichroism (CD) and red-edge excitation shift experiments (REES), respectively. These experiments showed that the N terminus acetylation has an important effect on both, peptide secondary structure and peptide insertion into the bilayer. This was also confirmed by experiments of insertion into lipid monolayers. Compression isotherms for peptide/lipid mixed films revealed that ac-L1A dragged lipid molecules to the more disordered phase, generating a more favorable environment and preventing the lipid molecules from forming stiff films. Enthalpy changes in the main phase transition of the lipid membrane upon peptide insertion suggested that the acetylated peptide induced higher impact than the non-acetylated one on the thermotropic behavior of anionic vesicles. PMID- 29287698 TI - Quantification of the first WHO International Standard for BK virus DNA by an automated PCR assay. PMID- 29287699 TI - From mass gatherings medicine to mass gatherings health: Conclusions from the 3rd International Conference on Mass Gatherings Medicine, Riyadh, Kingdom of Saudi Arabia. PMID- 29287700 TI - Therapeutic value of lymphadenectomy and adjuvant radiotherapy in uterine corpus confined endometrioid-type cancer. AB - BACKGROUND: To determine the efficacy of lymphadenectomy and adjuvant radiotherapy in patients with endometrioid-type cancer confined to the uterine corpus. METHODS: A total of 323 patients were evaluated. Patients were stratified according to depth of myometrial invasion (DMI) and tumor grade. RESULTS: Lymphadenectomy was performed in 83% of the entire cohort. Age (<60 vs. >=60) and DMI affected disease-free survival. Addition of lymphadenectomy improved the disease-specific survival. The improved effect of lymphadenectomy was only observed in DMI >=1/2 and grade 2 tumor (78.5% vs. 95.4%). However, that effect in this group was determined in patients with more than 50 removed lymph nodes. Performing adjuvant radiotherapy and the type of the radiotherapy (vaginal brachytherapy vs. external beam radiotherapy) were not significant for disease free and disease-specific survival. In the entire cohort, loco-regional recurrence occurred in 3.1% and 4.4% of patients with or without adjuvant radiotherapy, respectively. However, these rates were 2.6% and 13.6% for patients with DMI >=1/2 and grade 2 who were older than 60 years, respectively. CONCLUSION: Lymphadenectomy should be performed in patients with DMI >=1/2 and grade 2 to improve survival. Adjuvant vaginal brachytherapy may only be given to patients who are older than 60 years old with moderate differentiation and deep myometrial invasion to reduce loco-regional recurrence. PMID- 29287701 TI - Anxiolytic effect of an extract of Salvia miltiorrhiza roots in rats. AB - BACKGROUND: Preparations from roots of Salvia miltiorrhiza, a herb widely used in traditional Chinese medicine, have been reported to induce a series of central effects, including sedation. In the wake of this ethnopharmacological information, the present study was designed to assess the anxiolytic potential of an extract of S. miltiorrhiza roots. METHODS: To this end, rats were acutely treated with S. miltiorrhiza extract (0, 50, and 100 mg/kg; i.g.) and exposed to the Elevated Plus Maze (EPM) test. The effect of treatment with S. miltiorrhiza extract on Stress-Induced Hyperthermia (SIH; a physiological response to stressful events) was also evaluated. RESULTS: Treatment with 100 mg/kg S. miltiorrhiza extract produced robust anxiolytic effects at the EPM test; specifically, it increased (a) percent of entries into open arms, (b) percent of time spent in open arms, (c) total number of head dips, (d) number of unprotected head dips, and (e) number of end-arm explorations in open arms, without any alteration in spontaneous locomotor activity. Treatment with 100 mg/kg S. miltiorrhiza extract also suppressed SIH response. The anxiolytic effects produced by 100 mg/kg S. miltiorrhiza extract were comparable to those exerted by acute treatment with 1.5 mg/kg (i.p.) of the reference compound, diazepam. CONCLUSION: These data demonstrate the ability of an extract of S. miltiorrhiza roots to produce anxiolysis in two different rodent models of "anxiety". PMID- 29287702 TI - Scutellaria baicalensis ameliorates the destruction of periodontal ligament via inhibition of inflammatory cytokine expression. AB - BACKGROUND: Scutellaria baicalensis (SB) is widely used as a medicinal plant to treat various inflammatory diseases. In the present study, we investigated the effects of SB on periodontitis in ligature-induced experimental rat model. METHODS: Rats were subjected to a ligature placement around the first molar of the mandible to induce periodontitis. 100 mg/kg SB extracts were orally administered for 14 days. The molar tissues were stained with 1% methylene blue. Histopathological changes of the periodontium were observed by hematoxylin and eosin staining. The levels of cytokines were measured in the gingival tissue. RESULTS: Alveolar bone resorption was statistically lower in the SB group compared to the ligatured group. SB inhibited the mineralization of cementum. In addition, SB reduced the production of IL-1beta, 6, -8 and TNF-alpha cytokine mRNA expression in gingival tissues. CONCLUSION: These results suggest that SB showed ameliorative effects in the ligature-induced periodontitis by inhibition of inflammatory cytokine expression. PMID- 29287703 TI - Smartphone transmission of electrocardiography images to reduce time of cardiac catheterization laboratory activation. AB - BACKGROUND: This retrospective study evaluated the use of a smartphone application to facilitate communication between the emergency physician (EP) and the interventional cardiologist in order to minimize the time to cardiac catheterization laboratory (CCL) activation and time to percutaneous coronary intervention (PCI). METHODS: We retrospectively collected pertinent time-points in the management of patients diagnosed with STEMI in the emergency department and their outcome. The primary outcome was the reduction in the time from ECG interpretation to CCL activation after the implementation of a smartphone application. A total of 84 patients were enrolled. Patients' electrocardiography (ECG) were described by traditional verbal communication via telephone (group 1, n = 40) and by additional smartphone transmission of ECG images to an interventional cardiologist (group 2, n = 44). Relevant time-points were recorded for analysis. RESULTS: The time from ECG interpretation to CCL activation was reduced from 28.3 +/- 4.1 in group 1 to 17.6 +/- 2.3 min in group 2 (p = 0.03). Similarly, the time from ECG interpretation to balloon inflation time (D2B) decreased from 93.1 to 73.4 min (p = 0.025). Comparing group 2 with group 1, the door to balloon (D2B) time improved to 90.4 +/- 9.8 from 119.3 +/- 16.3 min (p = 0.23), the proportion of patients with a D2B time less than 90 min increased to 70.5% from 52.5% (p = 0.09), and the mortality rate decreased to 2.2% from 12.5% (p = 0.07). CONCLUSION: The additional use of a smartphone application to transmit ECG information to interventional cardiologists by EPs facilitated communication and reduced the decision time to CCL activation and percutaneous intervention. PMID- 29287704 TI - Anti-pandemic influenza A (H1N1) virus potential of catechin and gallic acid. AB - BACKGROUND: The pandemic influenza A (H1N1) virus has spread worldwide and infected a large proportion of the human population. Discovery of new and effective drugs for the treatment of influenza is a crucial issue for the global medical community. According to our previous study, TSL-1, a fraction of the aqueous extract from the tender leaf of Toonasinensis, has demonstrated antiviral activities against pandemic influenza A (H1N1) through the down-regulation of adhesion molecules and chemokine to prevent viral attachment. METHODS: The aim of the present study was to identify the active compounds in TSL-1 which exert anti influenza A (H1N1) virus effects. XTT assay was used to detect the cell viability. Meanwhile, the inhibitory effect on the pandemic influenza A (H1N1) virus was analyzed by observing plaque formation, qRT-PCR, neuraminidase activity, and immunofluorescence staining of influenza A-specific glycoprotein. RESULTS: Both catechin and gallic acid were found to be potent inhibitors in terms of influenza virus mRNA replication and MDCK plaque formation. Additionally, both compounds inhibited neuraminidase activities and viral glycoprotein. The 50% effective inhibition concentration (EC50) of catechin and gallic acid for the influenza A (H1N1) virus were 18.4 MUg/mL and 2.6 MUg/mL, respectively; whereas the 50% cytotoxic concentrations (CC50) of catechin and gallic acid were >100 MUg/mL and 22.1 MUg/mL, respectively. Thus, the selectivity indexes (SI) of catechin and gallic acid were >5.6 and 22.1, respectively. CONCLUSION: The present study demonstrates that catechin might be a safe reagent for long-term use to prevent influenza A (H1N1) virus infection; whereas gallic acid might be a sensitive reagent to inhibit influenza virus infection. We conclude that these two phyto-chemicals in TSL-1 are responsible for exerting anti-pandemic influenza A (H1N1) virus effects. PMID- 29287705 TI - Cost-effectiveness analysis of endoscopic tympanoplasty versus microscopic tympanoplasty for chronic otitis media in Taiwan. AB - BACKGROUND: Health care systems and physicians need to conform to budgets and streamline resources to provide cost-effective quality care. Although endoscopic tympanoplasty (ET) has been performed for decades, no studies on the cost effectiveness of ET and microscopic tympanoplasty (MT) for treating chronic otitis media have been published. The present study aimed to compare the cost effectiveness of ET and MT for treating chronic otitis media. METHODS: This study was performed using a Cohort-style Markov decision-tree economic model with a 30 year time horizon. The economic perspective was that of a third-party payer (Taiwan National Health Insurance System). Two treatment strategies were compared, namely ET and MT. The primary outcome was the incremental cost per quality-adjusted life year (QALY). Probabilities were obtained from meta analyses. Costs were obtained from the published literature and Taiwan National Health Insurance System database. Multiple sensitivity analyses were performed to account for data uncertainty. RESULTS: The reference case revealed that the total cost of ET was $NT 20,901 for 17.08 QALY per patient. By contrast, the total cost of MT was $NT 21,171 for 17.15 QALY per patient. The incremental cost effectiveness ratio for ET versus that of MT was $NT 3703 per QALY. The cost effectiveness acceptability curve indicated that ET was comparable to MT at a willingness-to-pay threshold of larger than $NT 35,000 per QALY. CONCLUSION: This cost-effectiveness analysis indicates that ET is comparable to MT for treating chronic otitis media in Taiwan. This result provides the latest information for physicians, the government, and third-party payers to select proper clinical practice. PMID- 29287706 TI - Toxicities, safeties and clinical response of dacarbazine-based chemotherapy on neuroendocrine tumors in Taiwan population. AB - BACKGROUND: Currently, the role of dacarbazine (DTIC) based chemotherapy in neuroendocrine tumors (NETs) in Asia is unclear. Here, we report the outcomes of dacarbazine (DTIC)-based chemotherapy in Taiwan population. METHODS: DTIC alone (250 mg/m2/day), or 5-fluorouracil (5-FU, 500 mg/m2/day) and DTIC (200 mg/m2/day) with or without epirubicin (200 mg/m2/day), for 3 days, every 3-4 weeks. Subgroups were analyzed by grading, and by Ki-67 index. RESULTS: 48 patients were reviewed in this study, including 3 had grade 1 tumors, 23 had grade 2, while 22 were grade 3. In grade 3 NEC patients, the tumor Ki-67 index of 21-55% were noted in 8 patients, and >55% in 14 patients. Progression-free survival (PFS) was 5.1 months, and overall survival (OS) was 31.6 months. The PFS (in months) were 12.5 and 1.8 for patients with NETs and neuroendocrine carcinomas (NECs), respectively (p < 0.001). The OS were not reached and 5.9 months for patients with NETs and NECs, respectively (p = 0.001). Patients with NECs were divided into two groups, according to their Ki-67 index. In patients with a tumor Ki-67 index of 21-55%, PFS was 4.1 months, and OS was not reached; in those with a tumor Ki-67 index of >55%, they were 1.5 and 1.8 months, respectively (p < 0.001 and p = 0.013). CONCLUSION: NETs, and grade 3 NECs, with Ki-67 indices of 20-55% had good responses to DTIC-based chemotherapy, with acceptable side effects. Ki-67 index could predict prognosis for grade 3 NEC patients, and guide further chemotherapy choices. PMID- 29287707 TI - Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches. AB - Dysregulated induction of goblet cell differentiation results in excessive production and retention of mucus and is a common feature of several chronic airways diseases. To date, therapeutic strategies to reduce mucus accumulation have focused primarily on altering the properties of the mucus itself, or have aimed to limit the production of mucus-stimulating cytokines. Here we review the current knowledge of key molecular pathways that are dysregulated during persistent goblet cell differentiation and highlights both pre-existing and novel therapeutic strategies to combat this pathology. PMID- 29287708 TI - Intratarsal keratinous eyelid cysts in Gorlin syndrome: A review and reappraisal. AB - A 38-year-old woman presented with multiple bilateral recurrent eyelid cysts. Her medical history was notable for Gorlin (nevoid basal cell carcinoma) syndrome. Histopathologic and immunohistochemical examinations revealed that the lesions were intratarsal keratinous cysts. They were similar in appearance to sporadic intratarsal keratinous cysts and closely resembled odontogenic keratocysts of the jaw. Eyelid cysts occur in up to 40% of patients with Gorlin syndrome; however, their description has been cursory and, for the most part, outside of the ophthalmic literature. Although ophthalmologists are familiar with the periocular basal cell carcinomas that occur in patients with Gorlin syndrome, up to 10% of patients never develop a basal cell carcinoma, but they may manifest other ophthalmic findings. Awareness of these other features may contribute to the earlier diagnosis of the syndrome. We discuss the clinical and histopathologic features of intratarsal keratinous cysts in Gorlin syndrome, comparing them to sporadic intratarsal keratinous cysts, other eyelid cysts, and jaw cysts that also characterize this syndrome. We briefly review the ocular and systemic manifestations of Gorlin syndrome and recent genetic and therapeutic developments so that the eyelid cysts may be appreciated within the appropriate context of Gorlin syndrome as a whole. PMID- 29287711 TI - Sequence analysis of microRNAs during pre-implantation between Meishan and Yorkshire pigs. AB - Embryonic implantation in sows is a coordinated interaction between the implantation-competent blastocyst and receptive uterus. In addition, microRNAs are small endogenous non-coding RNAs which are involved in post-transcriptional gene regulation of several biological processes including embryonic implantation. However, the mechanisms of miRNAs involved in embryonic implantation of sows remain largely unknown. Here, we analyzed miRNAome of endometrium on day 9, 12 and 15 of pregnancy and on day 12 of non-pregnancy in Meishan and Yorkshire pigs by Illumina sequencing. From 24 libraries, we identified 312 known microRNAs and 211 potential novel miRNAs. Bioinformatics analysis showed that differentially expressed microRNAs on day 12 of pregnancy between the two breeds may play critical roles by involving "p53 signaling pathway" and "Wnt signaling pathway". Furthermore, our results demonstrated that ssc-miR-21, ssc-miR-451, ssc-miR-204, ssc-miR-199a-5p and ssc-miR-199b-5p would play crucial roles for implantation. The data generated in this study were expected to elucidate the influence of microRNAs during pre-implantation in pigs. PMID- 29287710 TI - Rifampicin resistance in Staphylococcus epidermidis: molecular characterisation and fitness cost of rpoB mutations. AB - The molecular mechanisms and characteristics of rifampicin (RIF) resistance in Staphylococcus epidermidis are poorly characterised, even though S. epidermidis is one of the most common nosocomial pathogens associated with indwelling medical device-related infections. The aim of this study was to investigate the evolution of RIF resistance and to characterise the associated molecular mechanisms in S. epidermidis. RIF-resistant mutants from two RIF-susceptible S. epidermidis strains (RP62A and IDRL-8883) were selected through in vitro and in vivo exposure to RIF. A total of 16 colonies with an RP62A background and 63 colonies with an IDRL-8883 background were analysed for rpoB mutations. The fitness of RIF susceptible and isogenic RIF-resistant strains was assessed using a paired competition assay and by comparing generation times. All mutations detected were in cluster I of rpoB. The following five amino acid substitutions were selected in vitro: Asp471->Asn; Asp471->Gly; Asp471->Val; Ser486->Tyr; and His481->Tyr. The following three amino acid substitutions were selected in vivo: His481->Tyr; Gln468->Lys; and Ser486->Phe. Asp471->Asn and Asp471->Gly changes were associated with susceptible minimal inhibitory concentrations (MICs). In vitro competition assays revealed that all RIF-resistant mutants other than Ser486->Tyr and Ser486 >Phe had a relative fitness of <1.0. His481->Tyr mutations had their own specific fitness costs and effects on growth rate, irrespective of strain background. In conclusion, the current study presents molecular characterisations and fitness costs of several rpoB mutations in S. epidermidis. PMID- 29287712 TI - The role of DNA methylation in coronary artery disease. AB - Epigenetic studies have identified DNA methylation in coronary artery disease (CAD). How the critical genes interact at the cellular level to cause CAD is still unknown. The discovery of DNA methylation inspired researchers to explore relationships in genomic coding and disease phenotype. In the past two decades, there have been many findings regarding the relationship between DNA methylation and CAD development, and the DNA methylation of critical genes have been found to be significantly changed during CAD, including DNA methylation at homocysteine, Alu and long Interspersed Element 1 (LINE-1) repetitive elements. Here, we provide a brief overview of the biology and mechanisms of DNA methylation and its roles in CAD. We also discuss recent findings regarding DNA methylation of homocysteine, Alu and LINE-1 and some genes on CAD in vitro and in vivo. Finally, we provide some perspectives on DNA methylation in CAD. PMID- 29287713 TI - Downregulation of long noncoding RNA H19 contributes to the proliferation and migration of papillary thyroid carcinoma. AB - Recent studies have highlighted important roles for long noncoding RNAs (lncRNAs) during the complex process of carcinogenesis. H19 is an example of an lncRNA that can function either as a tumor promoter or a tumor suppressor. Here, we investigated the role of H19 in papillary thyroid carcinoma (PTC). First, we assessed H19 expression levels in human PTC tissues and PTC cell lines using quantitative real-time PCR. We also established H19-overexpressed PTC cell lines with lentiviral vectors to investigate the effects of H19 on the proliferation and migration of PTC cells. Our results suggest that H19 is downregulated in PTC tissues and in PTC cell lines compared to controls. Decreased H19 expression was correlated with lymph node metastasis. H19 overexpression reduced PTC cell proliferation and migration. It also inhibited the expression of tumor necrosis factor receptor 2. These results suggest that H19 inhibits tumorigenesis in PTC and may be utilized as a potential diagnostic tool for PTC. PMID- 29287714 TI - Fluconazole inhibits cellular ergosterol synthesis to confer synergism with berberine against yeast cells. AB - OBJECTIVES: Although berberine (BBR) is reported to exhibit weak activity against Candida albicans, combined use of BBR and fluconazole (FLC) showed synergism against FLC-resistant C. albicans in vitro. The aim of this study was to explore the synergistic antifungal mechanism of FLC and BBR in Saccharomyces cerevisiae, a typical fungal cell model. METHODS: Biochemical and genetic analyses were performed to investigate the probable antifungal role of the combined use of BBR and FLC in S. cerevisiae. RESULTS: FLC led to elevated cell membrane permeability in the wild-type S. cerevisiae BY4741, similar to the sterol synthesis-deficient strains erg2Delta and erg6Delta. Biochemical analysis indicated that FLC significantly inhibited cellular ergosterol synthesis, leading to a decrease in cell membrane stability, which increased the rate of BBR uptake and utilisation and reduced the inhibitory concentrations of BBR in wild-type yeast cells. Genetic analysis of the inhibitory effect of FLC and BBR on sterol synthesis deficient (erg2Delta and erg6Delta) and DNA damage repair defect (rad1Delta) strains showed that FLC and BBR possess different antifungal mechanisms. CONCLUSIONS: FLC enhances cell membrane permeability via inhibition of cellular ergosterol synthesis, thus assisting BBR to kill fungal cells. PMID- 29287715 TI - A Case of Extensive Diaphragmatic Endometriosis Diagnosed after Liver Retraction. PMID- 29287709 TI - Angiogenesis and lymphangiogenesis in corneal transplantation-A review. AB - Corneal transplantation has been proven effective for returning the gift of sight to those affected by corneal disorders such as opacity, injury, and infections that are a leading cause of blindness. Immune privilege plays an important role in the success of corneal transplantation procedures; however, immune rejection reactions do occur, and they, in conjunction with a shortage of corneal donor tissue, continue to pose major challenges. Corneal immune privilege is important to the success of corneal transplantation and closely related to the avascular nature of the cornea. Corneal avascularity may be disrupted by the processes of angiogenesis and lymphangiogenesis, and for this reason, these phenomena have been a focus of research in recent years. Through this research, therapies addressing certain rejection reactions related to angiogenesis have been developed and implemented. Corneal donor tissue shortages also have been addressed by the development of new materials to replace the human donor cornea. These advancements, along with other improvements in the corneal transplantation procedure, have contributed to an improved success rate for corneal transplantation. We summarize recent developments and improvements in corneal transplantation, including the current understanding of angiogenesis mechanisms, the anti-angiogenic and anti-lymphangiogenic factors identified to date, and the new materials being used. Additionally, we discuss future directions for research in corneal transplantation. PMID- 29287716 TI - Uterine Sounding: Is There a Difference between Blind and Hysteroscopically Directed Measurements? AB - STUDY OBJECTIVE: To evaluate the accuracy of traditional blind uterine sounding in measuring uterine cavity length (UCL), compared with measurement by hysteroscopic guidance. DESIGN: A cross-sectional descriptive study (Canadian Task Force classification III). SETTING: Academic multispecialty medical center. PATIENTS: Fifty-eight women undergoing elective hysteroscopic procedures. INTERVENTION: UCL measurement. MEASUREMENTS: UCL measurements were obtained by the traditional blind sounding technique and by hysteroscopically directed measurement. Hysteroscopic measurements were assumed to represent true uterine cavity length. Differences between the 2 measurements were calculated to analyze error and bias. RESULTS: Mean UCL for blind sounding and hysteroscopically directed measurements were 80.81 mm and 86.55 mm, respectively. The magnitude of error between measurements was >10 mm in 36.2% of cases, with underestimation of true UCL in 55.17% of cases. CONCLUSION: True UCL is underestimated by blind sounding, and the frequency, magnitude, and direction of error may be greater than are clinically acceptable. PMID- 29287717 TI - Perioperative Outcomes of 3-Arm Versus 4-Arm Robotic Radical Hysterectomy in Patients with Cervical Cancer. AB - STUDY OBJECTIVE: To investigate and compare surgical outcomes of the 3 versus 4 robotic arm approaches for robotic surgery in patients with cervical cancer. DESIGN: A retrospective analysis of prospectively collected data (Canadian Task Force classification II-2). SETTING: An academic tertiary hospital. PATIENTS: A total of 142 patients with stage 1A1 to IIB cervical carcinoma who underwent robotic surgery were included for analysis. The subjects were divided according to the surgical approach (i.e., the number of robotic arms), and the 2 groups were compared in terms of intraoperative data and postoperative outcomes. INTERVENTIONS: Robotic radical hysterectomy (RRH) with lymphadenectomy using 3 robotic arms (n = 101) versus 4 robotic arms (n = 41). MEASUREMENTS AND MAIN RESULTS: Perioperative surgical outcomes. The 3-arm robotic approach consisted of a camera arm, 2 robotic arms, and 1 conventional assistant port. An additional robotic arm was placed on the right side of the patient's abdomen for the 4-arm robotic approach. The mean age, body mass index, cell type, Federation Internationale de Gynecologie et d'Obstetrique stage, and type of surgery were not significantly different between the 2 cohorts. The 3-arm approach showed favorable outcomes over the 4-arm approach in terms of postoperative pain at 6 and 24 hours (3.8 +/- 1.8 vs 4.5 +/- 1.7 and 2.8 +/- 1.7 vs 3.4 +/- 1.6, respectively; p = .033 and .049) and postoperative hemoglobin difference (1.8 +/- 0.9 vs 2.6 +/- 1.3 and 1.9 +/- 1.1 vs 2.4 +/- 0.9 on days 1 and 3, respectively; p = .002 and .004). The median length of postoperative hospital stay, total operative time, docking time, lymph node yield, and intraoperative and postoperative complication rates were comparable between the 2 cohorts. CONCLUSION: Surgical outcomes and complications rates of RRH for cervical cancer using the 4-arm approach were comparable with that of the 3-arm approach with decreased early postoperative pain in the 3-arm group. Cost-benefit analysis and the impact on surgical training are needed in the future. PMID- 29287718 TI - Noninvasive clues for diagnosing ventricular tachycardia mechanism. AB - The electrophysiologic mechanisms responsible for the initiation and maintenance of ventricular tachycardia (VT) include enhanced automaticity, triggered activity and reentry. Differentiating between these three mechanisms can be challenging for the clinician and usually requires an invasive electrophysiology study. Establishing the underlying VT mechanism in a particular patient is helpful to define the optimal therapeutic approach, including the selection of pharmacologic agents or delineation of an ablation strategy. The purpose of this review is to provide insight into the possible VT mechanisms based on noninvasive clues from the clinical history, 12-lead electrocardiogram, tachycardia onset and termination and the response to pharmacologic manipulation. PMID- 29287719 TI - Is tracheotomy on the decline in otolaryngology? A single institutional analysis. AB - OBJECTIVE: A recent study reported decreasing trends in tracheotomy procedures by its otolaryngology service. We set out to determine whether the previously reported decrease in otolaryngology performed tracheotomies by one institution is a local or generalizable phenomenon. DESIGN: Retrospective cohort study from 2010 to 2015. SETTING: Tertiary care hospital and affiliated regional hospitals. SUBJECT AND METHODS: All patients who received tracheotomy during the period of analysis were included. Performing specialty, surgical technique, and procedure location were recorded. Procedures were stratified by year and specialty to generate incidence rate ratios for otolaryngologists and non-otolaryngologists. Incidence rate ratios were estimated with negative binomial regression across services. RESULTS: The otolaryngology service demonstrated a yearly decrease of 3.4% in the total number of tracheotomies (95% CI -7.9% to +1.4, P=0.17). While the thoracic service remained constant (+0.3%, 95% CI -2.6% to +3.3%, p=0.83), general surgery demonstrated the greatest increase in procedures (+4.4%, 95% CI 6.0% to +15.8%, P=0.42). Thoracic and general surgery both dramatically increased the number of percutaneous tracheotomies performed, with general surgery also performing a greater number of bedside procedures. CONCLUSIONS AND RELEVANCE: We observed a similar decline in the number of tracheotomies otolaryngology over six years. Our trend is likely due to changes in consultations patterns, increasing use of the percutaneous method, and an increase in adjunctive gastrostomy tube placements. Investigations on the impact of a greater number of non otolaryngology performed tracheotomies on follow up care is warranted. PMID- 29287720 TI - Commentary to letter to the editor to manuscript "Effects of surgical treatment of hypertrophic turbinates on the nasal obstruction and the quality of life". PMID- 29287721 TI - Intravital imaging of neutrophil recruitment in intestinal ischemia-reperfusion injury. AB - BACKGROUND: Neutrophils are known to be key players in innate immunity. Activated neutrophils induce local inflammation, which results in pathophysiologic changes during intestinal ischemia-reperfusion injury (IRI). However, most studies have been based on static assessments, and few have examined real-time intravital neutrophil recruitment. We herein report a method for imaging and evaluating dynamic changes in the neutrophil recruitment in intestinal IRI using two-photon laser scanning microscopy (TPLSM). METHODS: LysM-eGFP mice were subjected to 45 min of warm intestinal ischemia followed by reperfusion. Mice received an intravenous injection of tetramethylrhodamine isothiocyanate-labeled albumin to visualize the microvasculature. Using a time-lapse TPLSM technique, we directly observed the behavior of neutrophils in intestinal IRI. RESULTS: We were able to image all layers of the intestine without invasive surgical stress. At low magnification, the number of neutrophils per field of view continued to increase for 4 h after reperfusion. High-magnification images revealed the presence or absence of blood circulation. At 0-2 h after reperfusion, rolling and adhesive neutrophils increased along the vasculature. At 2-4 h after reperfusion, the irregularity of crypt architecture and transmigration of neutrophils were observed in the lamina propria. Furthermore, TPLSM imaging revealed the villus height, the diameters of the crypt, and the number of infiltrating neutrophils in the crypt. In the IRI group, the villus height 4 h after reperfusion was significantly shorter than in the control group. CONCLUSIONS: TPLSM imaging revealed the real-time neutrophil recruitment in intestinal IRI. Z-stack imaging was useful for evaluating pathophysiological changes in the intestinal wall. PMID- 29287722 TI - LncRNA NEAT1 promotes autophagy in MPTP-induced Parkinson's disease through stabilizing PINK1 protein. AB - BACKGROUND: Long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) was found to be closely related to the pathological changes in brain and nervous system. However, the role of NEAT1 and its potential mechanism in Parkinson's disease (PD) largely remain uncharacterized. METHODS: In this study, PD mouse model was established by intraperitoneal injection of MPTP. The numbers of TH + neurons, NEAT1 expression and the level of PINK1, LC3-II, LC3-I protein were assessed in PD mice. SH-SY5Y cells were treated with MPP+ as PD cell model. RNA pull-down assay was used to identify the interaction between NEAT1 and PINK1 in vitro. The endogenous expression of NEAT1 was modified by lentiviral vector carrying interference sequence for NEAT1 in vivo. RESULTS: The numbers of TH+ neurons significantly decreased in PD mice compared with the control. The expressions of NEAT1, PINK1 protein and LC3-II/LC3-I level were increased by MPTP in vitro and in vivo. Moreover, NEAT1 positively regulated the protein level of PINK1 through inhibition of PINK1 protein degradation. And NEAT1 mediated the effects of MPP+ on SH-SY5Y cells through stabilization of PINK1 protein. The results of in vivo experiments revealed that NEAT1 knockdown could effectively suppress MPTP-induced autophagy in vivo that alleviated dopaminergic neuronal injury. CONCLUSION: LncRNA NEAT1 promoted the MPTP-induced autophagy in PD through stabilization of PINK1 protein. PMID- 29287723 TI - Elovl4 can effectively elongate C18 polyunsaturated fatty acids in loach Misgurnus anguillicaudatus. AB - In this study, full-length cDNA sequences of elovl4a and elovl4b from loach Misgurnus anguillicaudatus were cloned. The full-length cDNAs of loach elovl4a and elovl4b were 2423 and 2054bp, encoding 315 and 300 amino acids, respectively. The deduced amino acid sequences of elovl4a and elovl4b in loach both shared the highest identity with those of Danio rerio, whereas lower identity score between loach elovl4a and elovl4b was present. Temporal expression and tissue expression of loach elovl4a and elovl4b were studied by reverse transcriptase PCR. Results of the tissue expression analyses suggested different functions of loach elovl4a and elovl4b. Functional characterizations of loach elovl4a and elovl4b on synthesis of fatty acids, especially elongating C18 polyunsaturated fatty acids (PUFAs) to longer-chain fatty acids, were studied by heterologous expression in Saccharomyces cerevisiae. Loach elovl4a and elvol4b enzymes were able to elongate all fatty acids tested including 18:2n-6, 18:3n-3, 18:3n-6, 20:4n-6 and 20:5n-3. At last, expression levels of the two elovl4 genes of loach fin cells incubated with 18:2n-6 and 18:3n-3 of different concentrations were measured. Expressions of elovl4a and elovl4b of loach fin cells were significantly up-regulated by 18:2n-6 and 18:3n-3. The results obtained here indicated that loach elovl4 could effectively elongate C18 PUFAs. This was a systematic report of elovl4's elongating functions towards C18 and provided an alternative pathway for C20 biosynthesis in fish species. PMID- 29287724 TI - PARIS reprograms glucose metabolism by HIF-1alpha induction in dopaminergic neurodegeneration. AB - Our previous study found that PARIS (ZNF746) transcriptionally suppressed transketolase (TKT), a key enzyme in pentose phosphate pathway (PPP) in the substantia nigra (SN) of AAV-PARIS injected mice. In this study, we revealed that PARIS overexpression reprogrammed glucose metabolic pathway, leading to the increment of glycolytic proteins along with TKT reduction in the SN of AAV-PARIS injected mice. Knock-down of TKT in differentiated SH-SY5Y cells led to an increase of glycolytic enzymes and decrease of PPP-related enzymes whereas overexpression of TKT restored PARIS-mediated glucose metabolic shift, suggesting that glucose metabolic alteration by PARIS is TKT-dependent. Inhibition of PPP by either PARIS overexpression or TKT knock-down elevated the level of H2O2, and diminished NADPH and GSH levels, ultimately triggering the induction of HIF 1alpha, a master activator of glycolysis. In addition, TKT inhibition by stereotaxic injection of oxythiamine demonstrated slight decrement of dopaminergic neurons (DNs) in SN but not cortical neurons in the cortex, suggesting that TKT might be a survival factor of DNs. In differentiated SH-SY5Y, cell toxicity by GFP-PARIS was partially restored by introduction of Flag-TKT and siRNA-HIF-1alpha. We also observed the increase of HIF-1alpha and glycolytic hexokinase 2 in the SN of Parkinson's disease patients. Taken together, these results suggest that PARIS accumulation might distort the balance of glucose metabolism, providing clues for understanding mechanism underlying selective DNs death by PARIS. PMID- 29287727 TI - Upregulation of Mcl-1 inhibits JQ1-triggered anticancer activity in hepatocellular carcinoma cells. AB - Bromodomains and extra-terminal (BET) proteins inhibitors are promising cancer therapeutic agents. However, tumor cells often develop resistance to BET inhibitors, greatly limiting their therapeutic potential. To study the mechanism underlying the resistance of BET inhibitors in hepatocellular carcinoma (HCC) cells, we herein investigated the impact of BET inhibitor JQ1 on the gene expression of Bcl-2 family members by RNA sequencing analysis, and found that acute treatment with JQ1 triggered upregulation of Mcl-1 in HCCLM3 and BEL7402 cell lines. This JQ1-triggered Mcl-1 upregulation was further confirmed by quantitative reverse transcription polymerase chain reaction and western blotting analysis, both at mRNA and protein levels. Inhibition of Mcl-1 by RNA interference dramatically enhanced JQ1-triggered caspase-3 activation, cleavage of poly (ADP-ribose) polymerase and apoptotic cell death induction in multiple HCC cell lines. Moreover, JQ1 in combination with cyclin-dependent kinase inhibitor flavopiridol at a subtoxic concentration that reduced expression of Mcl 1, triggered massive apoptotic cell death in HCCLM3 and BEL7402 cell lines. Together, these data suggest that Mcl-1 is a major contributor to BET inhibitor resistance in HCC cells, and that combining drugs capable of down-regulating Mcl 1 may promote therapeutic potential in human HCC. PMID- 29287726 TI - CCN3 secretion is regulated by palmitoylation via ZDHHC22. AB - Normal extracellular secretion of nephroblastoma overexpressed (NOV, also known as CCN3) is important for the adhesion, migration, and differentiation of cells. In previous studies, we have shown that the intracellular accumulation of CCN3 inhibits the growth of prominent neurons. Increased intracellular CCN3 can be induced through various processes, such as transcription, detoxification, and posttranslational modification. In general, posttranslational modifications are very important for protein secretion. However, it is unclear whether posttranslational modification is necessary for CCN3 secretion. In this study, we have conducted mutational analysis of CCN3 to demonstrate that its thrombospondin type-1 (TSP1) domain is important for CCN3 secretion and intracellular function. Point mutation analysis confirmed that CCN3 secretion was inhibited by cysteine (C)241 mutation, and overexpression of CCN3-C241A inhibited neuronal axonal growth in vivo. Furthermore, we demonstrated that palmitoylation is important for the extracellular secretion of CCN3 and that zinc finger DHHC-type containing 22 (ZDHHC22), a palmityoltransferase, can interact with CCN3. Taken together, our results suggest that palmitoylation by ZDHHC22 at C241 in the CCN3 TSP1 domain may be required for the secretion of CCN3. Aberrant palmitoylation induces intracellular accumulation of CCN3, inhibiting neuronal axon growth. PMID- 29287725 TI - Activated protein C protects against pressure overload-induced hypertrophy through AMPK signaling. AB - We found that the anticoagulant plasma protease, activated protein C (APC), stimulates the energy sensor kinase, AMPK, in the stressed heart by activating protease-activated receptor 1 (PAR1) on cardiomyocytes. Wild-type (WT) and AMPK kinase dead (KD) transgenic mice were subjected to transverse aortic constriction (TAC) surgery. The results demonstrated that while no phenotypic differences can be observed between WT and AMPK-KD mice under normal physiological conditions, AMPK-KD mice exhibit significantly larger hearts after 4 weeks of TAC surgery. Analysis by echocardiography suggested that the impairment in the cardiac function of AMPK-KD hearts is significantly greater than that of WT hearts. Immunohistochemical staining revealed increased macrophage infiltration and ROS generation in AMPK-KD hearts after 4 weeks of TAC surgery. Immunoblotting results demonstrated that the redox markers, pShc66, 4-hydroxynonenal and ERK, were all up-regulated at a higher extent in AMPK-KD hearts after 4 weeks of TAC surgery. Administration of APC-WT and the signaling selective APC-2Cys mutant, but not the anticoagulant selective APC-E170A mutant, significantly attenuated pressure overload-induced hypertrophy and fibrosis. Macrophage infiltration and pShc66 activation caused by pressure overload were also inhibited by APC and APC-2Cys but not by APC-E170A. Therefore, the cardiac AMPK protects against pressure overload-induced hypertrophy and the signaling selective APC-2Cys may have therapeutic potential for treating hypertension-related hypertrophy without increasing the risk of bleeding. PMID- 29287728 TI - [Towards a national strategy on the diagnosis of neurocognitive disorders. A shared approach among the French National College of General Practitioners and specialists of neurocognitive disorders]. AB - Neurocognitive disorders leading to progressive cognitive, functional and behavioural impairment are often undiagnosed or diagnosed lately. But tailored care and therapeutics help in implementing secondary and tertiary prevention dynamics aiming at preserving quality of life and delaying, anticipating or preventing behavioural crisis and severe stages of dementia. Moreover, the diagnosis of numerous diseases induces specific care and therapeutics, as well access to research and clinical trials. For the first time, the representatives of the National College of General Practitioners, the French Federation of Memory Centres, the French Federation of Gerontology and Geriatrics, the French Federation of Neurology, the French Society of Psychogeriatrics and the national plan on neurodegenerative diseases propose a graduated and tailored diagnosis strategy involving primary care and specialists of neurocognitive disorders. This strategy has been built in the context of the national plan on neurodegenerative diseases, the European Joint Action "Act on dementia", and has been consensually agreed after a seminar animated by the National College of General Practitioners in March 2017. PMID- 29287729 TI - Efficacy of non-pharmacological interventions for procedural pain relief in adults undergoing burn wound care: A systematic review and meta-analysis of randomized controlled trials. AB - The aim of the present meta-analysis was to investigate the efficacy of non pharmacological interventions for procedural pain relief in adults undergoing burn wound care compared to standard care alone or an attention control. Through a comprehensive literature search in various electronic databases 21 eligible randomized controlled trials (RCTs) were included, comprising a total of 660 patients. Random effects meta-analyses revealed significant positive treatment effects on pain outcomes, Hedges' g=0.58, 95% CI [0.33; 0.84]. Heterogeneity of study effects was substantial, I2=72%. Effects were significantly larger for comparisons against treatment as usual (TAU), g=0.69, CI 95% [0.40; 0.98] than for comparisons against attention control groups, g=0.21 [-0.11; 0.54], p<0.001. Distraction interventions, particularly those using virtual reality, and hypnosis revealed the largest effects on pain relief. Non-pharmacological interventions further resulted in a significant small, homogeneous effect on anxiety reduction, g=0.36 [0.20; 0.52]. In summary, benefits of non-pharmacological interventions on procedural pain relief and reduction of mental distress were demonstrated. Results have been proven to be free of publication bias. However, further high quality trials are needed to strengthen the promising evidence. PMID- 29287730 TI - Response to Letter to the Editor 'Platelet count: A predictor of sepsis and mortality in severe burns'. PMID- 29287731 TI - Predictors of post-traumatic stress disorder among burn patients in Pakistan: The role of reconstructive surgery in post-burn psychosocial adjustment. AB - BACKGROUND: Burns are a common cause of morbidity and mortality worldwide. Post traumatic stress disorder (PTSD) is among the most prevalent psychopathologies documented among burn patients. However, little is known regarding the risk factors for post-burn PTSD outside the well-documented Western world context. The present study aims to elucidate the biopsychosocial correlates of PTSD among burn patients in Pakistan. METHODS: A total 343 burn patients were evaluated across four teaching hospitals in the Punjab province of Pakistan between August and December of 2016. "Patients aged 18 years or older, with no major comorbid illnesses, presenting for burn care at burn units or surgical departments of the listed hospitals were interviewed by trained healthcare providers using a validated questionnaire." Uni- and multivariate statistical analyses were used to evaluate associations between patient characteristics and PTSD symptomatology, as measured by the validated Urdu version of the Impact of Event Scale-Revised (IES R). RESULTS: The prevalence of PTSD among our cohort was 69%. Lower educational attainment, ethnic minority status, unemployment, large burn surface area, prior suicidal ideation, and domestic violence were all associated with increased PTSD symptomatology. On the other hand, social support, ego resiliency, and reconstructive surgery were all associated with decreased PTSD symptomatology. CONCLUSION: There is a remarkably high prevalence of PTSD among burn patients in Pakistan. Improving accessibility to reconstructive surgery and social support may help to alleviate this burden. PMID- 29287732 TI - [Annales pharmaceutiques francaises, a positive result]. PMID- 29287733 TI - Tranexamic Acid Use in Cardiac Surgery: Hemostasis, Seizures, or a Little of Both. PMID- 29287734 TI - Air bio-battery with a gas/liquid porous diaphragm cell for medical and health care devices. AB - Powering future generations of medical and health care devices mandates the transcutaneous transfer of energy or harvesting energy from the human body fluid. Glucose-driven bio fuel cells (bio-batteries) demonstrate promise as they produce electrical energy from glucose, which is a substrate presents in physiological fluids. Enzymatic biofuel cells can convert chemical energy into electrical energy using enzymes as catalysts. In this study, an air bio-battery was developed for healthcare and medical applications, consisting of a glucose-driven enzymatic biofuel cell using a direct gas-permeable membrane or a gas/liquid porous diaphragm. The power generation characteristics included a maximum current density of 285MUA/cm2 and maximum power density of 70.7MUW/cm2 in the presence of 5mmol/L of glucose in solution. In addition, high-performance, long-term stabilized power generation was achieved using the gas/liquid porous diaphragm for the reactions between oxygen and enzyme. This system can be powered using 5mmol/L of glucose, the value of which is similar to that of the blood sugar range in humans. PMID- 29287736 TI - Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study. AB - BACKGROUND: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF. METHODS: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables. RESULTS: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age >=70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl. CONCLUSIONS: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data. PMID- 29287737 TI - Response to Stephane Renaud et al. PMID- 29287735 TI - Comment on: resected gastric volume has no influence on early weight loss after laparoscopic sleeve gastrectomy. PMID- 29287738 TI - Uncertainty about usefulness of low-level laser therapy for improving implant outcomes. PMID- 29287739 TI - Patients with idiopathic trigeminal neuralgia seem to benefit from acupuncture and sham acupuncture, but we are uncertain about whether these benefits are beyond those attained by pharmacologic treatment alone. PMID- 29287740 TI - High rate of tooth retention and periapical health 10 years after nonsurgical root canal treatment but uncertainty about the factors that may influence these outcomes. PMID- 29287741 TI - Uncertainty about the lack of benefits of platelet-rich fibrin as an adjunct to coronally advanced flap for treating gingival recessions. PMID- 29287742 TI - Investigating real-time monitoring of fatigue indicators of New Zealand forestry workers. AB - The New Zealand forestry industry has one of the highest fatality and injury rates of any industrial sector in the country. Worker fatigue has been identified as one of the main contributing factors. Currently no independent and objective large data source is available that might support an analysis of this, or provide the basis for ongoing monitoring to further investigate. In order to successfully manage fatigue in the forestry workplace, we must identify suitable ways of detecting it. Industry partners are increasingly looking at monitoring solutions (particularly lightweight, wearable technology) that aim to measure worker activities and physiological metrics in order to determine if they are fatigued. In this article we present the results of studies which investigate whether or not such technology can capture meaningful data in a reliable way that is both practical and usable within the forestry domain. Two series of studies were undertaken with in-situ forestry workers using reaction and decision-making times as a measure of potential impairment, while considering activity levels (via step count and heart rate) and job-roles. We present the results of these studies and further provide a comparison of results across different ambient temperatures (winter vs. summer periods). The results of our studies suggest that it may not be possible to identify correlations between workloads (based on both physical and cognitive stresses) and fatigue measures using in-situ measurements as results are highly personalised to individual workers and can be misleading if the wider context is not also taken into consideration. PMID- 29287743 TI - A novel ex vivo method for measuring whole brain metabolism in model systems. AB - BACKGROUND: Many neuronal and glial diseases have been associated with changes in metabolism. Therefore, metabolic reprogramming has become an important area of research to better understand disease at the cellular level, as well as to identify targets for treatment. Model systems are ideal for interrogating metabolic questions in a tissue dependent context. However, while new tools have been developed to study metabolism in cultured cells there has been less progress towards studies in vivo and ex vivo. NEW METHOD: We have developed a method using newly designed tissue restraints to adapt the Agilent XFe96 metabolic analyzer for whole brain analysis. These restraints create a chamber for Drosophila brains and other small model system tissues to reside undisrupted, while still remaining in the zone for measurements by sensor probes. RESULTS: This method generates reproducible oxygen consumption and extracellular acidification rate data for Drosophila larval and adult brains. Single brains are effectively treated with inhibitors and expected metabolic readings are observed. Measuring metabolic changes, such as glycolytic rate, in transgenic larval brains demonstrates the potential for studying how genotype affects metabolism. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: Current methodology either utilizes whole animal chambers to measure respiration, not allowing for targeted tissue analysis, or uses technically challenging MRI technology for in vivo analysis that is not suitable for smaller model systems. This new method allows for novel metabolic investigation of intact brains and other tissues ex vivo in a quick, and simplistic way with the potential for large-scale studies. PMID- 29287744 TI - A spherical treadmill system to train head-fixed adult rats. AB - BACKGROUND: While spherical treadmills are widely used in mouse models, there are only a few experimental setups suitable for adult rats, and none of them include head-fixation. NEW METHOD: We introduce a novel spherical treadmill apparatus for head-fixed rats that allows a wide repertory of natural responses. The rat is secured to a frame and placed on a freely rotating sphere. While being head fixed, it can walk in any direction and perform different motor tasks. COMPARISON WITH EXISTING METHODS: Instead of being air-lifted, which is acceptable for light animals, the treadmill is sustained by three spherical bearings ensuring a smooth rotation in any direction. Movement detection is accomplished using a video camera that registers a dot pattern plotted on the sphere. RESULTS: Long Evans rats were trained to perform an auditory discrimination task in a Go/No-Go (walking/not-walking) paradigm. Animals were able to successfully discriminate between a 1 kHz and a 8 kHz auditory stimulus and execute the correct response, reaching the learning criterion (80% of correct responses) in approximately 20 training sessions. CONCLUSIONS: Our system broadens the possibilities of head fixation experiments in adult rats making them compatible with spatial navigation on a spherical treadmill. PMID- 29287745 TI - Deep learning reveals Alzheimer's disease onset in MCI subjects: Results from an international challenge. AB - BACKGROUND: Early diagnosis of Alzheimer's disease (AD) and its onset in subjects affected by mild cognitive impairment (MCI) based on structural MRI features is one of the most important open issues in neuroimaging. Accordingly, a scientific challenge has been promoted, on the international Kaggle platform, to assess the performance of different classification methods for prediction of MCI and its conversion to AD. NEW METHOD: This work presents a classification strategy based on Random Forest feature selection and Deep Neural Network classification using a mixed cohort including the four classes of classification problem, that is HC, AD, MCI and cMCI, to train the model. Moreover, we compare this approach with a novel classification strategy based on fuzzy logic learned on a mixed cohort including only HC and AD. EXPERIMENTS: A training set of 240 subjects and a test set including mixed cohort of 500 real and simulated subjects were used. The data included AD patients, MCI subjects converting to AD (cMCI), MCI subjects and healthy controls (HC). This work ranked third for overall accuracy (38.8%) over 19 participating teams. COMPARISON WITH EXISTING METHOD(S): The "International challenge for automated prediction of MCI from MRI data" hosted by the Kaggle platform has been promoted to validate different methodologies with a common set of data and evaluation procedures. CONCLUSION: DNNs reach a classification accuracy significantly higher than other machine learning strategies; on the other hand, fuzzy logic is particularly accurate with cMCI, suggesting a combination of these approaches could lead to interesting future perspectives. PMID- 29287746 TI - The importance of data structure in statistical analysis of dendritic spine morphology. AB - BACKGROUND: Dendritic spine morphology is heterogeneous and highly dynamic. To study the changing or aberrant morphology in test setups, often spines from several neurons from a few experimental units e.g. mice or primary neuronal cultures are measured. This strategy results in a multilevel data structure, which, when not properly addressed, has a high risk of producing false positive and false negative findings. METHODS: We used mixed-effects models to deal with data with a multilevel data structure and compared this method to analyses at each level. We apply these statistical tests to a dataset of dendritic spine morphology parameters to illustrate advantages of multilevel mixed-effects model, and disadvantages of other models. RESULTS: We present an application of mixed effects models for analyzing dendritic spine morphology datasets while correcting for the data structure. COMPARISON WITH EXISTING METHODS: We further show that analyses at spine level and aggregated levels do not adequately account for the data structure, and that they may lead to erroneous results. CONCLUSION: We highlight the importance of data structure in dendritic spine morphology analyses and highly recommend the use of mixed-effects models or other appropriate statistical methods to deal with multilevel datasets. Mixed-effects models are easy to use and superior to commonly used methods by including the data structure and the addition of other explanatory variables, for example sex, and age, etc., as well as interactions between variables or between variables and level identifiers. PMID- 29287747 TI - Teaching nurses teamwork: Integrative review of competency-based team training in nursing education. AB - Widespread demands for high reliability healthcare teamwork have given rise to many educational initiatives aimed at building team competence. Most effort has focused on interprofessional team training however; Registered Nursing teams comprise the largest human resource delivering direct patient care in hospitals. Nurses also influence many other health team outcomes, yet little is known about the team training curricula they receive, and furthermore what specific factors help translate teamwork competency to nursing practice. The aim of this review is to critically analyse empirical published work reporting on teamwork education interventions in nursing, and identify key educational considerations enabling teamwork competency in this group. CINAHL, Web of Science, Academic Search Complete, and ERIC databases were searched and detailed inclusion-exclusion criteria applied. Studies (n = 19) were selected and evaluated using established qualitative-quantitative appraisal tools and a systematic constant comparative approach. Nursing teamwork knowledge is rooted in High Reliability Teams theory and Crew or Crisis Resource Management sources. Constructivist pedagogy is used to teach, practice, and refine teamwork competency. Nursing teamwork assessment is complex; involving integrated yet individualized determinations of knowledge, skills, and attitudes. Future initiatives need consider frontline leadership, supportive followership and skilled communication emphasis. Collective stakeholder support is required to translate teamwork competency into nursing practice. PMID- 29287748 TI - Drug-associated hyperpigmentation of the oral mucosa: report of four cases. AB - OBJECTIVE: The aim of this study was to describe 4 patients with oral mucosa hyperpigmentation associated with 4 drug classes and to review the relevant literature. STUDY DESIGN: Two patients under imatinib and hydroxychloroquine treatment exhibited diffuse palatal hyperpigmentation and 2 patients treated with minocycline and golimumab showed multifocal pigmented macules. In all cases, biopsy was performed. RESULTS: Microscopically, in all cases, there was no increase in the number of melanocytes in the epithelium, and pigment granules were present in the lamina propria. The pigment granules in minocycline- and golimumab-associated hyperpigmentation were seen in the superficial lamina propria and reacted for silver but not iron, whereas in imatinib- and hydroxychloroquine-associated hyperpigmentation, pigment granules were found in the reticular lamina propria and reacted for both silver and iron. A review of the literature found 38 cases of hyperpigmentation of the oral mucosa attributed to minocycline, 23 to imatinib, 1 to hydroxychloroquine without microscopic documentation, and none to golimumab. CONCLUSIONS: The temporal relationship between pigmentation and onset of drug effect, resolution following drug withdrawal, and exclusion of other causes support the diagnosis of drug-induced hyperpigmentation. Microscopic examination may be contributory to diagnosis, as there are differences among drugs with regard to the distribution of pigment granules and the histochemical reactions of the drugs. PMID- 29287750 TI - Exercise as a Countermeasure to Declining Central Nervous System Function in Multiple Sclerosis. AB - PURPOSE: The decline of central nervous system (CNS) function is a hallmark characteristic of multiple sclerosis (MS) that can manifest as cognitive impairment. We believe that exercise represents a potential behavioral approach for counteracting the declines in CNS structure and associated function among persons with MS (ie, exercise as a countermeasure of CNS decline). This theory is important because disease-modifying drugs represent a first-line approach for modifying the immune system and its effects on the CNS, but these drugs do not generally demonstrate robust improvements in cognitive performance. METHODS: To the best of our knowledge, this article presents the first argument positioning exercise as a countermeasure for CNS decline in MS. FINDING: The reviewed research indicates a proliferating body of evidence describing physical fitness, physical activity, and exercise effects on cognitive performance and neuroimaging outcomes (ie, CNS functioning) in MS, with the consistent and strong association between cognitive performance and neuroimaging outcomes in this population as a backdrop. IMPLICATIONS: We further present a framework and future research directions for better positioning exercise as a possible neuroprotective behavior against declining CNS function in MS. PMID- 29287751 TI - Validation of a Visual-Spatial Secondary Task to Assess Automaticity in Laparoscopic Skills. AB - INTRODUCTION: Our objective was to assess reliability and validity of a visual spatial secondary task (VSST) as a method to measure automaticity on a basic simulated laparoscopic skill model. In motor skill acquisition, expertise is defined by automaticity. The highest level of performance with less cognitive and attentional resources characterizes this stage, allowing experts to perform multiple tasks. Conventional validated parameters as operative time, objective assessment skills scales (OSATS), and movement economy, are insufficient to distinguish if an individual has reached the more advanced learning phases, such as automaticity. There is literature about using a VSST as an attention indicator that correlates with the automaticity level. METHODS: Novices with completed and approved Fundamentals of Laparoscopic Surgery course, and laparoscopy experts were enrolled for an experimental study and measured under dual tasks conditions. Each participant performed the test giving priority to the primary task while at the same time they responded to a VSST. The primary task consisted of 4 interrupted laparoscopic stitches (ILS) on a bench-model. The VSST was a screen that showed different patterns that the surgeon had to recognize and press a pedal while doing the stitches (PsychoPsy software, Python, MacOS). Novices were overtrained on ILS until they reach at least 100 repetitions and then were retested. Participants were video recorded and then assessed by 2 blinded evaluators who measured operative time and OSATS. These scores were considered indicators of quality for the primary task. The VSST performance was measured by the detectability index (DI), which is a ratio between correct and wrong detections. A reliable evaluation was defined as two measures of DI with less than 10% of difference, maintaining the cutoff scores for performance on the primary task (operative time <110 seg and OSATS >17 points). RESULTS: Novices (n = 11) achieved reliable measure of the test after 2 (2-5) repetitions on the preassessment and 3.75 (2-5) on the postassessment (p = 0.04); whereas laparoscopy experts (n = 4) did it after 3.5 (3-4) repetitions. Proficiency cutoff scores for the primary task were achieved on every measure for novices (prepost overtraining) and experts. Expert performance on VSST was DI 0.78 (0.69 0.87). Novice performance was significantly better on postassessment (DI-pre 0.48 [0.06-0.71] vs DI-post 0.78 [0.48-0.95], p = 0.003). Overtraining consisted in 140 (100-210) repetitions of ILS for all novices, made in 8 hours (3-15). By categorizing DI based on expert performance, novices with DI-post >0.65 achieved better OSATS score and less operative time than novices with DI-post<0.65 (p = 0.007 y, p = 0.089, respectively). CONCLUSION: Measuring automaticity is feasible using a VSST. This instrument is reliable and has a face, content and construct validity. A DI over 0.65 may be a cutoff point correlated with high standard performance on the primary task. This instrument measures performance on laparoscopic skills, and along with conventional indicators, would better define advance levels of expertise. More studies are required applying this VSST to achieve external validity by reproducing our results. PMID- 29287749 TI - Phase 1b Study of the Safety, Pharmacokinetics, and Disease-related Outcomes of the Matrix Metalloproteinase-9 Inhibitor Andecaliximab in Patients With Rheumatoid Arthritis. AB - PURPOSE: Andecaliximab (GS-5745) is a highly selective monoclonal antibody against matrix metalloproteinase-9 (MMP9), a proteolytic enzyme implicated in the pathogenesis of rheumatoid arthritis (RA). This study assessed the safety and pharmacokinetic (PK) parameters of andecaliximab in patients with RA and evaluated the effects of andecaliximab treatment on exploratory disease biomarkers. METHODS: In this double-blind, Phase 1b trial, patients with active RA were randomized (4:1) to receive 400-mg andecaliximab or placebo every 2 weeks for a total of 3 intravenous infusions. The primary and secondary end points were safety and the PK parameters of andecaliximab, respectively. Data were summarized by using descriptive statistics. FINDINGS: A total of 18 patients were randomized; 15 received andecaliximab (participants with confirmed RA diagnosis without current administration of a biologic DMARD a biologic DMARD (disease modifying antirheumatic drug), aged 18 to 70 years old, weighing >45 to <120 kg). No deaths, serious adverse events, or study discontinuations occurred. All reported adverse events were grade 1 or grade 2 in severity. Mean plasma andecaliximab exposure was 587 d . ug/mL and 878 d . ug/mL at days 1 and 29, respectively, suggesting moderate accumulation. The median terminal t1/2 was 5.65 days; mean volume of distribution at steady state was 4560 mL. Mean MMP9 coverage (the percentage of total plasma MMP9 bound by therapeutic antibody) was maintained at ~80% after the first administration of andecaliximab. IMPLICATIONS: Andecaliximab administered as 3 infusions over 29 days was generally safe and well tolerated in patients with RA. The majority of total plasma MMP9 was bound by andecaliximab after the first administration. Clinical studies of increased treatment duration in larger patient cohorts are warranted. ClinicalTrials.gov identifier: NCT02176876. Registered on 25 June 2014. PMID- 29287752 TI - Do Orthopaedic Resident and Fellow Case Logs Accurately Reflect Surgical Case Volume? AB - OBJECTIVE: The purpose of this study is to determine whether orthopedic resident and fellow case logs accurately reflect trainee case volume. DESIGN: For each orthopedic case performed at our institution between 7/1/14 and 10/31/14, the names of trainees who participated were obtained from the chart. The trainee Accreditation Council for Graduate Medical Education case logs were queried to determine if the procedure in question was logged and, if so, which current procedural terminology (CPT) codes were reported. The CPT codes reported by the trainees were compared to those reported by the attendings in the billing database. To ascertain the opinions of trainees regarding coding, a survey was conducted. SETTING: University of Maryland Medical Center (Baltimore, MD), a tertiary and quaternary care center which features a state-wide trauma referral center as well as orthopedic residency and fellowship training programs. PARTICIPANTS: All orthopedic surgery residents and fellows present at the institution during the study period. RESULTS: Trainees failed to log their cases 24% of the time (465/1925), including 25% (283/1117) for residents and 23% (182/808) for fellows (p = 0.16). Among cases that were logged, CPT codes were missed 46% of the time (673/1460) and extra codes were added 28% of the time (412/1460) compared to the attendings. In the survey, most trainees stated that it was "extremely" or "very" important for them to be able to code correctly (83%; 29/35). CONCLUSIONS: In this study of orthopedic trainee case logging practices, cases were not logged 24% of the time. Caution should be taken with activities which rely on trainee case logs given the potential for inaccuracy. PMID- 29287753 TI - Laparoscopic transhiatal esophagectomy after biliopancreatic diversion with duodenal switch. PMID- 29287754 TI - SOARD Category 1 CME Credit Featured Articles, Volume 14, January 2018. PMID- 29287755 TI - Comment on: improving the side-to-side stapled anastomosis: comparison of staplers for robust crotch formation. PMID- 29287756 TI - Qualifying for bariatric surgery: is preoperative weight loss a reliable predictor of postoperative weight loss? AB - BACKGROUND: Over the last 20 years, bariatric surgery has emerged as a highly effective weight loss intervention that can also improve co-morbid medical conditions. However, some payors have required preoperative supervised diets and weight loss. OBJECTIVE: To determine if preoperative weight loss is the best predictor of postoperative weight loss. SETTING: Academic county hospital, United States. METHODS: A retrospective chart review of 218 patients. Patients who received psychological evaluation and bariatric surgery were followed up at 1 year. All preoperative patients were encouraged to lose weight; however, no specified amount of weight loss was required. Preoperative weight loss and postoperative weight loss in body mass index (BMI), percent excess weight loss, and percent total weight loss were measured. Bariatric outcome predictor variables evaluated included age, race, and sex; BMI change; measures of depression and anxiety; number of unhealthy eating types; and co-morbid medical conditions. A linear regression model and stepwise regression analyses were used to estimate contributions of independent variables to the 1-year weight loss. RESULTS: All patients had a mean 28% reduction in BMI (63.3% excess weight loss and 29.1% total weight loss) at 1 year postoperatively. As a single independent variable, preoperative weight loss was a significant predictor of 1-year change in postoperative BMI (P = .006). However, when age, race, and sex were added to the regression equation, the predictive value of preoperative weight loss became nonsignificant (P = .543). CONCLUSION: The present findings indicate that preoperative weight loss should not be considered in isolation when clearance for bariatric surgery is being evaluated. PMID- 29287757 TI - Efficacy of adjuvant weight loss medication after bariatric surgery. AB - BACKGROUND: Some patients do not achieve optimal weight loss or regain weight after bariatric surgery. In this study, we aimed to determine the effectiveness of adjuvant weight loss medications after surgery for this group of patients. SETTING: An academic medical center. METHODS: Weight changes of patients who received weight loss medications after bariatric surgery from 2012 to 2015 at a single center were studied. RESULTS: Weight loss medications prescribed for 209 patients were phentermine (n = 156, 74.6%), phentermine/topiramate extended release (n = 25, 12%), lorcaserin (n = 18, 8.6%), and naltrexone slow release/bupropion slow-release (n = 10, 4.8%). Of patients, 37% lost>5% of their total weight 1 year after pharmacotherapy was prescribed. There were significant differences in weight loss at 1 year in gastric banding versus sleeve gastrectomy patients (4.6% versus .3%, P = .02) and Roux-en-Y gastric bypass versus sleeve gastrectomy patients (2.8% versus .3%, P = .01).There was a significant positive correlation between body mass index at the start of adjuvant pharmacotherapy and total weight loss at 1 year (P = .025). CONCLUSION: Adjuvant weight loss medications halted weight regain in patients who underwent bariatric surgery. More than one third achieved>5% weight loss with the addition of weight loss medication. The observed response was significantly better in gastric bypass and gastric banding patients compared with sleeve gastrectomy patients. Furthermore, adjuvant pharmacotherapy was more effective in patients with higher body mass index. Given the low risk of medications compared with revisional surgery, it can be a reasonable option in the appropriate patients. Further studies are necessary to determine the optimal medication and timing of adjuvant pharmacotherapy after bariatric surgery. PMID- 29287758 TI - Repellence of essential oils and selected compounds against ticks-A systematic review. AB - Ticks act as vectors of a wide range of infectious agents, far encompassing any other group of bloodsucking arthropods worldwide. The prevention of tick-borne diseases is strictly linked to the successful management of tick vector populations. The employ of repellents can represent a worth solution to avoid tick bites. It is widely adopted to protect travellers and pets exposed to ticks during limited periods of the year. The use of natural products as active ingredients in eco-friendly repellent formulations is currently a prominent research area, due to the wide diversity and high effectiveness of a number of plant-borne compounds, with special reference to essential oils (EOs) extracted from medicinal and aromatic species. Here, we reviewed current knowledge available on EOs tested as repellents against tick species of veterinary importance. Furthermore, we analysed the effectiveness of pure compounds isolated from EOs as tick repellents and their potential implications for practical use in the oreal world". A quantitative analysis of literature available is this research field was provided, along with its impact (i.e., in terms of citations over time) on the scientific community of researchers in tick control science and natural product chemistry. In the final sections, future outlooks are highlighted. We discussed major challenges to stabilize the most effective EOs and pure molecules, explore the synergistic and antagonistic effects in blends of EOs and/or pure constituents, standardize currently adopted testing methods, and evaluate non-target risks of herbal repellents. PMID- 29287759 TI - Comparative proteomics analysis of Trichinella spiralis muscle larvae exposed to albendazole sulfoxide stress. AB - The drug albendazole (ABZ) has a positive effect against Trichinella spiralis infection and has been used for the treatment and prevention of trichinellosis in humans and animals. However, the molecular mechanism ofthe effects of ABZ on T. spiralis remains unknown. Albendazole sulfoxide (ABZSO) is the main intermediary metabolic product of ABZ, and it is often used as a substitute for ABZ in metabolism and bioavailability research. Herein, isobaric tagging reagents for relative and absolute quantification (iTRAQ)-based LC-MS/MS analysis was used to identify the effect of ABZSO on the proteome of T. spiralis muscle larvae in vitro. 3795 proteins were quantified from 22974 unique peptides. Comparative proteomics analysis displayed that 417 proteins were remarkably differentially expressed in ABZSO-treated larvae, of which 213 proteins were up-regulated and 204 proteins were down-regulated. Quantitative real-time PCR of ten randomly selected genes verified the proteomic data. Gene ontology annotation and KEGG pathway analysis showed that most of the differentially expressed proteins were involved in cell apoptosis, signal pathway, amino acid metabolism, protein synthesis/assembly/degradation and other biological processes. This study firstly provided the comprehensive proteomics data of T. spiralis in response to ABZSO, and would help us to deeply understand the molecular mechanism of ABZSO effects on T. spiralis. PMID- 29287760 TI - Molluscicidal activity of Arisaema erubescens mixed with fertilizers against Oncomelania hupensis and its effect on rice germination and growth. AB - To explore a new molluscicide with dual effects of fertilization and molluscicidal activity, an organic-inorganic compound fertilizer molluscicide was prepared by mixing the water extract (or powder) of Arisaema erubescens tubers with nitrogen fertilizer, phosphate fertilizer, potash fertilizer, and three mixed fertilizers (hereinafter referred to as ANF, APF, AKF and ACF, respectively). Leaching using the mixture was performed to test for molluscicidal activity, and indoor rice germination, seedling growth, and pot experiments were monitored. ANF exhibited superior molluscicidal activity, with respective 24-h and 48-h Oncomelania mortality rates significantly increased, reaching up to 67.7% and 92.3%. ANF, APF, and AKF significantly promoted rice germination and growth of rice, with ANF showing superior effects. The respective 3-day and 5-day germination rate of rice seeds treated with ANF significantly increased by 25% and 21% relative to that of the control group, and the respective 10-day and 20 day growth length of rice seedlings (aboveground part) increased by 106.2% and 33.2%. A positive correlation between ACF molluscicidal activity and concentration and treatment time were observed. The Oncomelania mortality rate at 48 h after treatment with a low ACF concentration (0.25 g/L) was 70.7%, whereas that at 24 h after treatment using a higher concentration (0.5 g/L) was 80.7%. ACF promoted rice seed germination and seedling growth, whereas inhibitory effects were observed using a high ACF concentration. Therefore, the combined application of A. erubescens and chemical fertilizers not only enhances molluscicidal activity, but also promotes rice growth, with the combined application of A. erubescens and nitrogen fertilizer and mixed fertilizer showing superior dual effects (molluscicide and fertilization). PMID- 29287761 TI - Brucellosis in West and Central Africa: A review of the current situation in a changing landscape of dairy cattle systems. AB - Brucellosis is a neglected endemic zoonosis in West and Central Africa. In this narrative review, evidence of livestock and human infection is presented along with details of past and current control strategies in 14 selected countries. Data from available literature is combined with expert opinion elicited during a regional workshop on brucellosis diagnostics. Demographic changes that affect both the epidemiology of brucellosis and the success of control or surveillance are also considered. The evidence suggests that brucellosis prevalence in emerging peri-urban dairy cattle systems may be higher than that found in traditional transhumant extensive systems. Accurate microbiological and epidemiological evidence across the region is lacking but it appears there is inherent interest in controlling the disease. There are many data gaps which require collaborative future research to evaluate fully the social and economic impact of the disease in an evolving livestock sector heavily influenced by high rates of urbanisation and regional population growth. PMID- 29287762 TI - The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation. AB - Inflammasomes are key intracellular signaling platforms involved in innate immune responses to micro-organisms and danger signals. Extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 mitogen-activated protein kinase family members are activated by numerous environmental stresses. Recently, it has been reported that Jun N-terminal kinase is involved in inflammasome activation in myeloid immune cells. To date, the role of mitogen-activated protein kinase in inflammasome activity in keratinocytes has not been investigated. Here, we show that, in primary human keratinocytes, p38 mitogen-activated protein kinase is required for inflammasome activation and IL-1beta secretion. Using selective small molecule inhibitors, small interfering RNA gene silencing, and CRISPR/Cas9 based deletion, we demonstrate the above and identify p38alpha and p38delta as critical regulators of ASC oligomerization, inflammasome activation, and IL-1beta secretion in keratinocytes. Furthermore, our data suggest that the nature of the mitogen-activated protein kinase regulating inflammasome activity exhibits a certain cell specificity, with p38 playing a predominant role in keratinocytes and Jun N-terminal kinase 1 in cells of myeloid origin. PMID- 29287763 TI - Topically Applied Nicotinamide Inhibits Human Hair Follicle Growth Ex Vivo. PMID- 29287764 TI - A mechanism-focused approach to the science of behavior change: An introduction to the special issue. PMID- 29287765 TI - Mechanisms of aging and development-A new understanding of environmental damage to the skin and prevention with topical antioxidants. AB - Recent research has given us new insights into the molecular biology of extrinsic aging of the skin. Not only does UV irradiation directly cause photoaging of the skin, but also environmental pollutants significantly damage exposed skin by several mechanisms. Exposure to the noxious gases of air pollution with simultaneous exposure to UVA can act synergistically to initiate skin cancer. Also ozone generated from pollutants reacting with UV induces oxidative stress of the skin's surface via formation of lipid peroxidation products, with cascading consequences to deeper layers. Furthermore, new studies have demonstrated that particulate matter (PM) pollutants can penetrate the skin transepidermally and through hair follicles to induce skin aging via the aryl hydrocarbon receptor (AHR), a recently discovered ligand-activated transcription factor that regulates and protects keratinocytes, melanocytes, and fibroblasts. With this understanding that extrinsic aging of the skin is not only due to photoaging, we realize the necessity of protection beyond sunscreen. Fortunately, correctly formulated topical antioxidants can prevent damage inflicted by both UV and environmental pollution. PMID- 29287766 TI - Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode. AB - The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; eta2=0.008; ICC=0.91, 95% CI [0.87-0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340-0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week (beta=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438-83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice. PMID- 29287767 TI - Resistant hypertension: Renal denervation or intensified medical treatment? AB - Resistant hypertension (RH) can be diagnosed if blood pressure (BP) is not controlled with the combination of three antihypertensive drugs, including a diuretic, all at effective doses. Patients affected by this condition exhibit a marked increase in the risk of cardiovascular and renal morbid and fatal events. They also exhibit an increased activity of the sympathetic nervous system which is likely to importantly contribute at the renal and other vascular levels to the hypertensive state. Almost 10years ago renal denervation (RDN) by radiofrequency thermal energy delivery to the walls of the renal arteries was proposed for the treatment of RH. Several uncontrolled studies initially reported that this procedure substantially reduced the elevated BP values but this conclusion has not been supported by a recent randomized control trial, which has almost marginalized this therapeutic approach. A revival, however, is under way because of recent positive findings and technical improvement that hold promise to make renal denervation more complete. The antihypertensive efficacy and overall validity of RDN will have to be tested against drug treatment of RH. Several studies indicate that an excess of aldosterone production contributes to RH and recent evidence documents indisputably that anti-aldosterone agents such as spironolactone can effectively control BP in many RH patients, although with some side effects that require close patients' monitoring. At present, it is advisable to treat RH with the addition of an anti-aldosterone agent. If BP control is not achieved or serious side effects become manifest RDN may then be considered. PMID- 29287768 TI - Autoimmune arthritis in Meniere's disease: A systematic review of the literature. AB - INTRODUCTION: Successful management of patients with Meniere's disease (MD) involves understanding the pathophysiology of the disease and its comorbidities. The role of autoimmune diseases (AD) in MD remains unclear. The aim of this study was to further investigate the association between MD and AD. Specific goals were to characterize the prevalence, distribution, clinical and laboratory findings, and outcomes of autoimmune arthritis (AA) in MD. EVIDENCE REVIEW: This systematic review was conducted according to PRISMA guidelines. Articles were identified through searches of MEDLINE, and EMBASE, as well as manual reviews of references, from 1947 to May 2017. We performed a systematic review of randomized-controlled trials (RCTs) and non-RCTs of cases of AA in MD. Due to the heterogeneity of the study methods and measures, a meta-analysis was not possible and a qualitative synthesis of the literature results was performed. The study protocol was registered with PROSPERO database (Trial Registration: CRD42017070516). FINDINGS: A total of 237 abstracts were identified and screened by two independent reviewers. Based on inclusion and exclusion criteria, nine studies were selected and subjected to a quality assessment. This quality control measure yielded eight studies for analysis in the systematic review. The prevalence of AA was higher in MD (1.0-10.0%) as compared to the general population (0-1.1%), and noted to be higher in patients with familial MD as compared to sporadic MD (16.9% vs 4.5%, p = 0.002). There was no evidence to suggest a difference in immunologic profiles or selected treatment regimens. The most commonly reported AA in patients with MD was rheumatoid arthritis with a mean point prevalence of 4.3%. Many studies did not standardize their diagnostic criteria and did not measure clinically meaningful outcomes. CONCLUSIONS: There is a low level of evidence because of the lack of RCTs and original prospective studies. However, in this systematic review, we have identified the latest point prevalence data on AA in MD, indicating AA to be more prevalent within the MD population. RCTs treating MD as a local AD will enhance our understanding of the disease, and potentially change the way we manage MD. PMID- 29287770 TI - Plant-Pesticide Interactions and the Global Chloromethane Budget. AB - Ecological, signaling, metabolic, and chemical processes in plant-microorganism systems and in plant-derived material may link the use of chlorinated pesticides in the environment with plant chloromethane emission. This neglected factor should be taken into account to assess global planetary budgets of chloromethane and impacts on atmospheric ozone depletion. PMID- 29287769 TI - Guidelines for the conduct of pharmacological clinical trials in hand osteoarthritis: Consensus of a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). AB - OBJECTIVES: To gather expert opinion on the conduct of clinical trials that will facilitate regulatory review and approval of appropriate efficacious pharmacological treatments for hand osteoarthritis (OA), an area of high unmet clinical need. METHODS: The European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) organized a working group under the auspices of the International Osteoporosis Foundation (IOF) and the World Health Organization (WHO). RESULTS: This consensus guideline is intended to provide a reference tool for practice, and should allow for better standardization of the conduct of clinical trials in hand OA. Hand OA is a heterogeneous disease affecting different, and often multiple, joints of the thumb and fingers. It was recognized that the various phenotypes and limitations of diagnostic criteria may make the results of hand OA trials difficult to interpret. Nonetheless, practical recommendations for the conduct of clinical trials of both symptom and structure modifying drugs are outlined in this consensus statement, including guidance on study design, execution, and analysis. CONCLUSIONS: While the working group acknowledges that the methodology for performing clinical trials in hand OA will evolve as knowledge of the disease increases, it is hoped that this guidance will support the development of new pharmacological treatments targeting hand OA. PMID- 29287771 TI - Lower antibody functionality in middle-aged adults compared to adolescents after primary meningococcal vaccination: Role of IgM. AB - INTRODUCTION: Successful vaccination of elderly persons is often hampered by immunological ageing, leaving part of the elderly population vulnerable for infectious diseases. As an alternative, timely vaccinations might be administered at middle-age, before reaching old age. Studies evaluating the immunological fitness of middle-aged adults are warranted. In this study we compared the immunogenicity of a primary meningococcal vaccination in Dutch middle-aged adults with that in adolescents, in order to gain knowledge on the early signs of immune ageing. METHODS: In this study, we compared the antibody responses after a primary meningococcal vaccination between middle-aged adults (50-65years of age, N=204) and adolescents (10-15years of age, N=225). Blood samples were taken pre-, as well as 28days and 1year post-vaccination. Functional antibody titers were measured with the serum bactericidal killing assay using baby rabbit complement (rSBA). Meningococcal polysaccharide (PS) specific IgG and IgM concentrations were determined with a fluorescent bead-based multiplex immunoassay. RESULTS: Lower post-vaccination functional antibody titers against meningococcal group W and Y were observed in the middle-aged adults compared to the adolescents. One year post-vaccination, also a significantly higher proportion of the middle-aged adults possessed an rSBA titer below protection level. A large reduction in post vaccination IgM concentrations was observed in the middle-aged adults, whereas IgG concentrations were only marginally different between the two age groups. Strong correlations between the post-vaccination rSBA titers and IgM concentrations were found both in the middle-aged adults and the adolescents. CONCLUSION: Although protective antibody titers were initiated after primary meningococcal vaccination in middle-aged adults, antibody functionality was significantly lower as compared to that in adolescents. This difference was mainly caused by lower IgM responses. Our results indicate early signs of immune ageing in middle-aged adults, which is important knowledge for the development of future vaccine strategies to better protect elderly persons against infectious diseases. PMID- 29287773 TI - "Aging and immunity" symposium: Meeting report. PMID- 29287774 TI - A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. AB - Peroxisomal acyl-CoA oxidases catalyze the first step of beta-oxidation of a variety of substrates broken down in the peroxisome. These include the CoA-esters of very long-chain fatty acids, branched-chain fatty acids and the C27-bile acid intermediates. In rat, three peroxisomal acyl-CoA oxidases with different substrate specificities are known, whereas in humans it is believed that only two peroxisomal acyl-CoA oxidases are expressed under normal circumstances. Only three patients with ACOX2 deficiency, including two siblings, have been identified so far, showing accumulation of the C27-bile acid intermediates. Here, we performed biochemical studies in material from a novel ACOX2-deficient patient with increased levels of C27-bile acids in plasma, a complete loss of ACOX2 protein expression on immunoblot, but normal pristanic acid oxidation activity in fibroblasts. Since pristanoyl-CoA is presumed to be handled by ACOX2 specifically, these findings prompted us to re-investigate the expression of the human peroxisomal acyl-CoA oxidases. We report for the first time expression of ACOX3 in normal human tissues at the mRNA and protein level. Substrate specificity studies were done for ACOX1, 2 and 3 which revealed that ACOX1 is responsible for the oxidation of straight-chain fatty acids with different chain lengths, ACOX2 is the only human acyl-CoA oxidase involved in bile acid biosynthesis, and both ACOX2 and ACOX3 are involved in the degradation of the branched-chain fatty acids. Our studies provide new insights both into ACOX2 deficiency and into the role of the different acyl-CoA oxidases in peroxisomal metabolism. PMID- 29287775 TI - Regulation of aldosterone production by ion channels: From basal secretion to primary aldosteronism. AB - Aldosterone is produced by zona glomerulosa (ZG) cells of the adrenal cortex and plays a key role in balancing water and electrolytes levels. Autonomous overproduction of aldosterone leads to primary aldosteronism (PA), which is the most common form of secondary endocrine hypertension. Recently, significant progress has been made towards understanding the genetic basis of PA, where increasing clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas. In this review, we focused on potassium and calcium channels that regulate aldosterone secretion, and their roles in the pathology of PA. Because potassium and calcium channels are differentially expressed in ZG cells in different species of mammals, the limitations of published studies are also discussed. PMID- 29287772 TI - Tuberculosis in the elderly: Why inflammation matters. AB - Growing old is associated with an increase in the basal inflammatory state of an individual and susceptibility to many diseases, including infectious diseases. Evidence is growing to support the concept that inflammation and disease susceptibility in the elderly is linked. Our studies focus on the infectious disease tuberculosis (TB), which is caused by Mycobacterium tuberculosis (M.tb), a pathogen that infects approximately one fourth of the world's population. Aging is a major risk factor for developing TB, and inflammation has been strongly implicated. In this review we will discuss the relationship between inflammation in the lung and susceptibility to develop and succumb to TB in old age. Further understanding of the relationship between inflammation, age, and M.tb will lead to informed decisions about TB prevention and treatment strategies that are uniquely designed for the elderly. PMID- 29287776 TI - Activin-A causes Hepatic stellate cell activation via the induction of TNFalpha and TGFbeta in Kupffer cells. AB - BACKGROUND & AIMS: TGFbeta superfamily member Activin-A is a multifunctional hormone/cytokine expressed in multiple tissues and cells, where it regulates cellular differentiation, proliferation, inflammation and tissue architecture. High activin-A levels have been reported in alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH). Our aim was to identify the cell types involved in the fibrotic processes induced by activin-A in liver and verify the liver diseases that this molecule can be found increased. METHODS: We studied the effect of activin-A on mouse primary Kupffer cells (KCs) and Hepatic Stellate cells (HSCs) and the levels of activin-A and its inhibitor follistatin in the serum of patients from a large panel of liver diseases. RESULTS: Activin-A is expressed by mouse hepatocytes, HSCs and Liver Sinusoid Endothelial cells but not KCs. Each cell type expresses different activin receptor combinations. HSCs are unresponsive to activin-A due to downregulation/desensitization of type-II activin receptors, while KCs respond by increasing the expression/production of TNFalpha kappaalphaiota TGFbeta1. In the presence of KCs or conditioned medium from activin-A treated KCs, HSCs switch to a profibrogenic phenotype, including increased collagen and alphaSMA expression and migratory capacity. Incubation of activin-A treated KC conditioned medium with antibodies against TNFalpha and TGFbeta1 partially blocks its capacity to activate HSCs. Only patients with alcoholic liver diseases and NASH cirrhosis have significantly higher activin-A levels and activin-A/follistatin ratio. CONCLUSIONS: Activin-A may induce fibrosis in NASH and alcoholic cirrhosis via activation of KCs to express pro inflammatory molecules that promote HSC-dependent fibrogenesis and could be a target for future anti-fibrotic therapies. PMID- 29287777 TI - Tanshindiol C inhibits oxidized low-density lipoprotein induced macrophage foam cell formation via a peroxiredoxin 1 dependent pathway. AB - NF-E2-related factor 2 (Nrf2) has been shown to be protective in atherosclerosis. The loss of Nrf2 in macrophages enhances foam cell formation and promotes early atherogenesis. Tanshindiol C (Tan C) is isolated from the root of Salvia miltiorrhiza Bge., a traditional Chinese medicine that has been used for the treatment of several cardiovascular diseases for many years. This study was aimed to test the potential role of Tan C against macrophage foam cell formation and to explore the underlying mechanism. Firstly, we observed that Tan C markedly suppressed oxidized low-density lipoprotein (oxLDL) induced macrophage foam cell formation. Then, we found that Tan C was an activator of both Nrf2 and Sirtuin 1 (Sirt1) in macrophages. Nrf2 and Sirt1 synergistically activated the transcription of anti-oxidant peroxiredoxin 1 (Prdx1) after Tan C treatment. More important, we demonstrated that silencing of Prdx1 promoted oxLDL-induced macrophage foam cell formation. Prdx1 upregulated adenosine triphosphate-binding cassette (ABC) transporter A1 (ABCA1) expression and decreased intracellular lipid accumulation. Furthermore, Tan C ameliorated oxLDL induced macrophage foam cell formation in a Prdx1-dependent manner. These observations suggest that Tan C protects macrophages from oxLDL induced foam cell formation via activation of Prdx1/ABCA1 signaling and that Prdx1 may be a novel target for therapeutic intervention of atherosclerosis. PMID- 29287778 TI - Structural evidence for a fatty acid-independent myotoxic mechanism for a phospholipase A2-like toxin. AB - The myotoxic mechanism for PLA2-like toxins has been proposed recently to be initiated by an allosteric change induced by a fatty acid binding to the protein, leading to the alignment of the membrane docking site (MDoS) and membrane disrupting site (MDiS). Previous structural studies performed by us demonstrated that MjTX-II, a PLA2-like toxin isolated from Bothrops moojeni, presents a different mode of ligand-interaction caused by natural amino acid substitutions and an insertion. Herein, we present four crystal structures of MjTX-II, in its apo state and complexed with fatty acids of different lengths. Analyses of these structures revealed slightly different oligomeric conformations but with both MDoSs in an arrangement that resembles an active-state PLA2-like structure. To explore the structural transitions between apo protein and fatty-acid complexes, we performed Normal Mode Molecular Dynamics simulations, revealing that oligomeric conformations of MjTX-II/fatty acid complexes may be reached in solution by the apo structure. Similar simulations with typical PLA2-like structures demonstrated that this transition is not possible without the presence of fatty acids. Thus, we hypothesize that MjTX-II does not require fatty acids to be active, although these ligands may eventually help in its stabilization by the formation of hydrogen bonds. Therefore, these results complement previous findings for MjTX-II and help us understand its particular ligand-binding properties and, more importantly, its particular mechanism of action, with a possible impact on the design of structure-based inhibitors for PLA2-like toxins in general. PMID- 29287779 TI - Reply to: Central corneal thickness measurement with Cirrus HD-OCT and Topcon SP 3000P. PMID- 29287780 TI - A porcine model for robotic training harvest of the rectus abdominis muscle. AB - Conventional open surgical approaches for the harvesting of the rectus abdominis muscle carry a high risk of morbidity. It is possible to reduce these risks by using laparoscopy or robot-assisted techniques. This work hypothesizes that a porcine model could be used for learning the robot-assisted collection of the rectus abdominis. The rectus abdominis was taken in 3 stages in 3 pigs: installation of the robot, surgical approaches with 4 trocars, dissection and collection of the muscle. The average operating time was 1h20min and the average muscular length was 16cm. Our results showed a learning curve for the robot assisted harvesting of the rectus abdominis on a porcine model. PMID- 29287782 TI - Naringenin-induced enhanced antioxidant defence system meliorates cholinergic neurotransmission and consolidates memory in male rats. AB - AIMS: Free radical mediated neurotoxicity is a leading cause of neurodegenerative disorders. Neurodegeneration due to oxidative stress can produce cognitive dysfunctions. Flavonoids and curcuminoids are naturally occurring polyphenolic compounds that display a variety of therapeutic importance against oxidative stress. MAIN METHODS: This study was designed to assess potential role of polyphenolic compounds in neurocognitive functions and prevention against oxidative stress. For this purpose, young rats were orally treated with naringenin (NAR), curcumin (CUR) and quercetin (QUE) at a dose of 50mg/kg, 200mg/kg and 50mg/kg respectively for 16days. At 4th day of drug administration cognitive functions were monitored by Morris water maze (MWM) test. In MWM cognitive functions in terms of learning acquisition (1h after training), retention (24h after training), memory extinction (4days after training), and reconsolidation (8 and 12days after training) were monitored. Biochemical and neurochemical analysis were done in whole brain. KEY FINDINGS: Treatment of NAR, CUR and QUE significantly enhanced learning acquisition, memory retention and reconsolidation and prevented memory extinction. Treatment of NAR and QUE prevented the alteration of brain antioxidant defence system by enhancing antioxidant enzyme activities and increasing antioxidant compound concentration. Oxidative stress in terms of lipid peroxidation was significantly prevented in treated rats. Serotonergic and cholinergic improvement was also found in treated rats. SIGNIFICANCE: The present study therefore provides biological evidence supporting the usefulness of these polyphenolic compounds in daily life for improvement of cognitive abilities and hence may have a potential role in the management of dementia and related disorders. PMID- 29287781 TI - Beneficial effects of oral administration of C-Phycocyanin and Phycocyanobilin in rodent models of experimental autoimmune encephalomyelitis. AB - : The only three oral treatments currently available for multiple sclerosis (MS) target the relapsing forms of the disease and concerns regarding efficacy, safety and tolerability limit their use. Identifying novel oral disease-modifying therapies for MS, targeting both its inflammatory and neurodegenerative components is still a major goal. AIM: The scope of this study was to provide evidence that the oral administration of C-Phycocyanin (C-PC), the main biliprotein of the Spirulina platensis cyanobacteria and its tetrapyrrolic prosthetic group, Phycocyanobilin (PCB), exert ameliorating actions on rodent models of experimental autoimmune encephalomyelitis (EAE). MAIN METHODS: EAE was induced in Lewis rats using the spinal cord encephalitogen from Sprague Dawley rats and in C57BL6 mice with MOG35-55 peptide. Clinical signs, motor function, oxidative stress markers, cytokine levels by ELISA and transmission electron microscopy analysis were assessed. KEY FINDINGS: Either prophylactic or early therapeutic administration of C-PC to Lewis rats with EAE, significantly improved clinical signs and restored the motor function of the animals. Furthermore, C-PC positively modulated oxidative stress markers measured in brain homogenate and serum and protected the integrity of cerebral myelin sheaths as shown by transmission electron microscopy analysis. In C57BL/6 mice with EAE, PCB orally improved clinical status of the animals and reduced the expression levels of brain IL-6 and IFN-gamma proinflammatory cytokines. SIGNIFICANCE: These results, for the first time, support the fact that both C-PC and PCB administered orally could potentially improve neuroinflammation, protect from demyelination and axonal loss, which may be translated into an improved quality of life for MS patients. PMID- 29287783 TI - Effects of telmisartan and losartan on irradiated testes. AB - AIMS: To analyze the effects of radiation on the reproductive tissue of male Wistar rats and to evaluate whether treatment with the Ang II AT1 receptor antagonists telmisartan and losartan mitigate the dysfunctions resulting from this exposure. MAIN METHODS: Rats were randomly divided into groups: Control, Irradiated, Telmisartan, Losartan, Irradiated+Telmisartan, and Irradiated+Losartan. Single dose of 5Gy was administered directly into the scrotum, followed by treatment with telmisartan (12mg/kg/day) or losartan (34mg/kg/two times/day) for 60days. Testicular function parameters were evaluated from spermatozoa of the vas deferens. Testes were processed for histopathological and morphometric-stereological analysis. Proliferating cell nuclear antigen (PCNA) immunohistochemistry was evaluated. KEY FINDINGS: Radiation significantly reduced sperm motility, concentration, vitality, and increased the number of abnormal spermatozoa. Telmisartan and losartan did not significantly prevent these radiation-induced disorders. Seminiferous tubules were atrophied in both untreated and treated irradiated testes, and exhibited vacuoles, increased interstitial tissue and high number of blood vessels. However, several seminiferous tubules in recuperation were founded among damaged tubules in the testes of treated animals. The PCNA immunohistochemistry confirmed these outcomes. PCNA-positive cells were detected in dividing spermatogonia and spermatocytes from irradiated telmisartan and losartan treated rats whereas in the only-irradiated group, PCNA staining was observed in the nuclei of only the surviving spermatogonia. SIGNIFICANCE: Under these experimental conditions, the testicular function parameters showed that radiation produced marked damage that was not reversed by treatments. However, gonadal restructuring and recovery of spermatogenesis in treated animals may to reflect attenuation of radiation induced damages and potential start of recovery. PMID- 29287784 TI - Postraumatic pseudoaneurysm of the axillary artery presenting as an axillary tumor. PMID- 29287786 TI - Leptin treatment prevents long-term abnormalities in cognition, seizure threshold, hippocampal mossy fiber sprouting and ZnT3/CB-D28k expression in a rat developmental "twist" seizure model. AB - The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of leptin on neonatal seizure-induced brain damage. Here, we developed a "twist" seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether leptin treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, leptin treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target. PMID- 29287787 TI - Digestibility and nutritional value of fresh and stored pollen for honey bees (Apis mellifera scutellata). AB - Pollen, the main protein source for honey bees, is mixed with regurgitated nectar or honey during collection and then stored as 'bee bread' before its consumption, mainly by young nurse workers. It has been suggested that storage of pollen improves its nutritional value and digestibility, but there is little evidence for such changes. We fed two fresh pollen types of different protein content (aloe and sunflower), and two stored pollen types (sunflower and a mixed pollen), to young caged worker bees. We measured daily consumption of pollen and sucrose solution, and survival after 14 days. At day 14 we recorded ovarian activation and extraction efficiency, by counting empty pollen grains in the rectal contents. Extraction efficiency is a measure of pollen digestibility. Contrary to our predictions, bees did not consume more fresh sunflower pollen than fresh aloe pollen to compensate for the lower protein content of sunflower pollen. In addition, they did not consume less sucrose solution when fed stored pollen diets that are already enriched in sugar. Consumption of stored sunflower pollen resulted in a low protein to carbohydrate (P:C) intake. Survival and ovarian activation were higher on diets giving higher P:C intakes. Extraction efficiency was high (up to 99%) for all pollen diets, and comparison of fresh and stored sunflower pollen showed that storage did not make it easier to digest. Changes to pollen during storage do not confer obvious benefits to honey bees. PMID- 29287785 TI - Evaluation of muscle activity just after straight leg raising exercise by using 18FDG-PET. AB - BACKGROUND: Exercise therapy is one of the recognized treatment methods for knee osteoarthritis (KOA). One such exercise technique, straight leg raising (SLR), is widely known as a home exercise method for strengthening the quadriceps femoris muscle. However, whether this exercise truly strengthens the quadriceps is not known. The objective of the present study was to investigate which lower limb muscle is stimulated and shows increased activity with SLR. METHODS: A total of 14 lower limbs in seven healthy adult male volunteers (mean age: 31.3 +/- 2.2 years) were investigated. Participants were asked to perform SLR and subsequently underwent FDG-PET/CT examination for evaluation of the muscles of the entire lower limb. The maximum standardized uptake value (SUVmax) of each muscle (iliacus, psoas major, gluteus maximus, gluteus medius, gluteus minimus, vastus medialis, vastus intermedius, vastus lateralis, rectus femoris, biceps femoris, semimembranosus, semitendinosus, adductor, sartorius, gracilis, tibialis anterior, tibialis posterior, soleus, medial head of gastrocnemius, and lateral head of gastrocnemius) was measured in four cross-sections: at the trunk, pelvis, thigh, and lower leg. RESULTS: SUVmax was significantly greater in: iliacus and adductor compared to vastus medialis, vastus lateralis, biceps, semitendinosus, gracilis, tibialis anterior, and gastrocnemius; psoas major compared to all muscles except for gluteus minimus and adductor; gluteus minimus compared to all muscles except for iliacus, psoas major, gluteus medius, and adductor; and gluteus medius compared to semitendinosus and gracilis. CONCLUSIONS: After SLR, SUVmax was significantly greater in iliacus, psoas major, gluteus minimus, gluteus medius, and adductor compared to some of the other muscles. Performing SLR increased glucose metabolism of the above muscles in particular, and this may have increased their activity levels. PMID- 29287788 TI - timeless2 plays an important role in reproduction and circadian rhythms in the cricket Gryllus bimaculatus. AB - The timeless2 (tim2) gene is an insect orthologue of the mammalian clock gene Timeless (mTim). Although its functional role has been extensively studied in mammals, little is known regarding its role in insects. In the present study, we obtained tim2 cDNA (Gb'tim2) from the cricket Gryllus bimaculatus and characterized its functional role in embryonic development, egg production, and circadian rhythms. Gb'tim2 gave rise to a 1432 amino acid protein, and showed approximately 65% homology to that of Drosophila melanogaster. When treated with parental Gb'tim2RNAi, less than 2% of the treated eggs hatched. On the other hand, control eggs treated with DsRed2RNAi demonstrated a hatching rate of 70%. In most of the Gb'tim2RNAi treated embryos, development was arrested in early stages. Egg production in ovaries of adult virgin females treated with Gb'tim2RNAi was significantly reduced. In addition, while Gb'tim2RNAi crickets exhibited clear locomotor rhythm synchronized with light cycles, their light-on peak was weaker than that of control crickets. Under constant darkness, the activity rhythm of Gb'tim2RNAi crickets was often split into two components running with different periods. Molecular analysis revealed that Gb'tim2RNAi treatment downregulated mRNA levels of Gb'per and Gb'Clk, and enhanced Gb'cyc expression rhythm; no distinct effect was found on Gb'tim expression levels. The change in Gb'per, Gb'Clk and Gb'cyc levels may underlie the altered behavioral rhythms in Gb'tim2RNAi crickets. Both Gb'ClkRNAi and Gb'cycRNAi downregulated Gb'tim2 expression, which suggested that transcription of Gb'tim2 is mediated by Gb'CLK and Gb'CYC through E-box. These results suggested that Gb'tim2 may be involved in both reproduction and circadian rhythm regulation in crickets. PMID- 29287789 TI - The surface chemistry of sapphire-c: A literature review and a study on various factors influencing its IEP. AB - A wide range of isoelectric points (IEPs) has been reported in the literature for sapphire-c (alpha-alumina), also referred to as basal plane, (001) or (0001), single crystals. Interestingly, the available data suggest that the variation of IEPs is comparable to the range of IEPs encountered for particles, although single crystals should be much better defined in terms of surface structure. One explanation for the range of IEPs might be the obvious danger of contaminating the small surface areas of single crystal samples while exposing them to comparatively large solution reservoirs. Literature suggests that factors like origin of the sample, sample treatment or the method of investigation all have an influence on the surfaces and it is difficult to clearly separate the respective, individual effects. In the present study, we investigate cause-effect relationships to better understand the individual effects. The reference IEP of our samples is between 4 and 4.5. High temperature treatment tends to decrease the IEP of sapphire-c as does UV treatment. Increasing the initial miscut (i.e. the divergence from the expected orientation of the crystal) tends to increase the IEP as does plasma cleaning, which can be understood assuming that the surfaces have become less hydrophobic due to the presence of more and/or larger steps with increasing miscut or due to amorphisation of the surface caused by plasma cleaning. Pre-treatment at very high pH caused an increase in the IEP. Surface treatments that led to IEPs different from the stable value of reference samples typically resulted in surfaces that were strongly affected by subsequent exposure to water. The streaming potential data appear to relax to the reference sample behavior after a period of time of water exposure. Combination of the zeta potential measurements with AFM investigations support the idea that atomically smooth surfaces exhibit lower IEPs, while rougher surfaces (roughness on the order of nanometers) result in higher IEPs compared to reference samples. Two supplementary investigations resulted in either surprising or ambiguous results. On very rough surfaces (roughness on the order of micrometers) the IEP lowered compared to the reference sample with nanometer-scale roughness and transient behavior of the rough surfaces was observed. Furthermore, differences in the IEP as obtained from streaming potential and static colloid adhesion measurements may suggest that hydrodynamics play a role in streaming potential experiments. We finally relate surface diffraction data from previous studies to possible interpretations of our electrokinetic data to corroborate the presence of a water film that can explain the low IEP. Calculations show that the surface diffraction data are in line with the presence of a water film, however, they do not allow to unambiguously resolve critical features of this film which might explain the observed surface chemical characteristics like the dangling OH-bond reported in sum frequency generation studies. A broad literature review on properties of related surfaces shows that the presence of such water films could in many cases affect the interfacial properties. Persistence or not of the water film can be crucial. The presence of the water film can in principle affect important processes like ice-nucleation, wetting behavior, electric charging, etc. PMID- 29287790 TI - Activity of MPF and expression of its related genes in mouse MI oocytes exposed to cadmium. AB - Research has revealed that cadmium can disrupt ovarian function; however, few reports have focused on MI oocytes meiotic progression, especially the activity of maturation promoting factor (MPF) and its related genes (Cdk1, Ccnb1, and Cdc25b) expression. In this study, GV oocytes cultured in vitro for 0, 6, and 9 hours with five groups (control and doses of 0.05, 0.5, 2.5, and 5 MUM Cd). At the same dose of cadmium but different exposure time: compared with 0h, Periodic changes in MPF activity were changed and continuously increased over time. The mRNA and protein expression of each MPF-related gene in different cadmium dose groups were changed compared with that of 0h. At the same exposure time but different dose of cadmium: compared with control group, MPF activity, mRNA and protein expressions of each MPF-related gene in all the cadmium exposure groups were increased at 9h after exposure. Cadmium maintains the high MPF activity in mouse MI oocytes during its meiotic process and disturbs the periodic change of MPF activity; meanwhile, cadmium exposure promotes the syntheses of MPF-related gene, which may be one of the molecular mechanisms for the maintenance of high MPF activity, and ultimately prevents the meiotic progression in oocytes. PMID- 29287791 TI - Chemical characterization, antioxidant, genotoxic and in vitro cytotoxic activity assessment of Juniperus communis var. saxatilis. AB - Chemical composition and antioxidative, genotoxic and cytotoxic potential of essential oil (EO) and post-distillation waste (PDW) of Serbian Juniperus communis L. var. saxatilis Pall. was studied in human lung carcinoma (A549) and normal lung fibroblast (MRC-5) cells. GC-MS analysis identified 93.95% of total EO content and determined alpha-pinen as a dominant component (23.61%). LC-MS/MS analysis of PDW pointed at rutin (12.2 mg g-1) and quinic acid (11.1 mg g-1) as the most abundant. Antioxidativity of PDW was strong in DPPH (IC50 was 5.27 MUg mL-1), and moderate in TBA and FRAP assays. Both substances were more cytotoxic to A549 than to MRC-5 cells. Obtained IC50 values were 69.4 MUg mL-1 and 120 MUg mL-1 for EO, and 1.27 mg mL-1 and 2.86 mg mL-1 for PDW, respectively. PDW was genotoxic (0.3 mg mL-1 and 1 mg mL-1 in A549 and MRC-5 cells, respectively) and induced apoptosis and arrested cell cycle in G2/M phase in A549 cells (0.3 mg mL 1). In mixtures with doxorubicin cytotoxicity of EO and PDW increased, and combination index values (0.12-0.18) revealed clear synergistic effect, stronger in cancer cells. This indicates that J. communis var. saxatilis could decrease the chemotherapeutic doses of doxorubicin, potentially reducing its side effects. PMID- 29287792 TI - Platycodon grandiflorum-derived saponin attenuates the eccentric exercise-induced muscle damage. AB - Platycodon grandiflorum contains triterpenoid saponins, such as platycodin D and platyconic acid A, and acts as a multifold nutritious compound. Our previous research demonstrated that Platycodon grandiflorum-derived saponin (PS) improves high-fat diet-induced non-alcoholic steatohepatitis and inhibits osteoclast differentiation. The pivotal effects of PS on inflammatory mechanism were suppressed NF-kappaB and matrix metalloproteinase (MMPs). However, the effects of PS on skeletal muscle damage remain unknown. Therefore, we investigated whether PS protects against eccentric exercise-induced muscle damage. A significant reduction in eccentric exercise-induced muscle damage area and muscle damage related to the level of NF-kappaB p65 by PS was associated with the downregulation of ERK/p38/SMAD signaling. Eccentric exercise caused muscle damage by increasing the serum lactate dehydrogenase (LDH), creatinine kinase (CK) and C related protein level. The serum LDH, CK and C-related protein level was significantly lower in the PS supplementation group compared with the control group. Moreover, PS was inhibited MMP-1, MMP-2 and MMP-9. PS protects against eccentric exercise-induced muscle damage. Together, these results provide a novel perspective on the biological function of PS against muscle damage. PMID- 29287793 TI - The protective effect of 20(S)-protopanaxadiol (PPD) against chronic sleep deprivation (CSD)-induced memory impairments in mice. AB - Sleep deprivation (SD) is associated with oxidative stress that causes learning and memory impairment. 20(S)-Protopanaxadiol (PPD), one of the protopanaxadiol type saponins, has antioxidant and neuroprotective effect. This study was designed to research the protective effect of PPD against cognitive deficits induced by chronic sleep deprivation (CSD) in mice. The CSD model was induced by subjecting the mice to our self-made Sleep Interruption Apparatus (SIA) continuously for 14 days. The memory enhancing effects of PPD were evaluated by behavioral tests and the related mechanism was further explored by observing the oxidative stress changes in the cortex and hippocampus of mice. The results revealed that PPD (20 and 40 MUmol/kg, i.p.) administration significantly improved the cognitive performance of CSD model mice in object location recognition experiment, novel object recognition task and Morris water maze test. Furthermore, PPD effectively restored the levels/activities of antioxidant defense biomarkers in the cortex and hippocampus, including the superoxide dismutase (SOD) enzyme activity, catalase (CAT) enzyme activity, glutathione (GSH), and lipid peroxidation (LPO). In conclusion, PPD could attenuate cognitive deficits induced by CSD, and the neuroprotective effect of PPD might be mediated by alleviation of oxidative stress. It was assumed that PPD has the potential to be a neuroprotective substance for cognition dysfunction. PMID- 29287794 TI - Effect of glucocorticoid treatment on BAFF and APRIL expression in patients with immune thrombocytopenia (ITP). AB - Immune thrombocytopenic purpura (ITP) is an idiopathic bleeding disorder. B cell activating factor (BAFF) and 'A proliferation-inducing ligand' (APRIL) have regulatory effects on B and T cells and may represent relevant factors in the pathogenesis of ITP. Serum levels and gene expression were investigated in ITP patients. Both BAFF and APRIL serum levels were significantly elevated in active ITP. However, gene expression analysis revealed both factors to have a tendency toward downregulation. Glucocorticoid treatment significantly reduced BAFF but not APRIL serum levels, which may be mediated by differences in transcription factor binding sites. The glucocorticoid receptor binding site is present in the BAFF promotor region, but not in the APRIL promotor region. Prednisolone in combination with vitamin D3 may be effective in reducing APRIL serum levels. In conclusion, glucocorticoid treatment exerts different regulatory effects on both BAFF and APRIL, whereas antioxidant supplementation may also be beneficial in reducing serum levels. PMID- 29287795 TI - HIF-1alpha-l-PGDS-PPARgamma regulates hypoxia-induced ANP secretion in beating rat atria. AB - Lipocalin-type prostaglandin D synthase (L-PGDS) and peroxisome proliferator activated receptor gamma (PPARgamma) play important roles in cardiovascular diseases. Nevertheless, effects of hypoxia-inducible factor 1alpha (HIF-1alpha) on L-PGDS and PPARgamma protein levels and its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion are unclear. In perfused beating rat atria, we observed that hypoxia significantly increased HIF-1alpha protein levels and stimulated ANP secretion, while upregulating L-PGDS. Hypoxia-induced ANP secretion was clearly attenuated by HIF-1alpha antagonist 2-methoxyestradiol, downregulating both HIF-1alpha and L-PGDS protein levels. It was also attenuated by L-PGDS antagonists, AT-56 and HQL-49, downregulating L-PGDS protein levels. In addition, hypoxia-induced ANP secretion was accompanied by increased PPARgamma protein levels and was strongly attenuated by PPARgamma antagonist GW9662. Hypoxia-induced increase in atrial PPARgamma protein levels were dramatically inhibited by both 2-methoxyestradiol and AT-56. These results indicated that hypoxia promotes ANP secretion, at least in part, by activating HIF-1alpha-l-PGDS PPARgamma signaling in beating rat atria. PMID- 29287796 TI - Congenital Septal Aneurysm and Embolic Myocardial Infarction. PMID- 29287797 TI - Association Between a Healthy Lifestyle Score and the Risk of Cardiovascular Disease in the SUN Cohort. AB - INTRODUCTION AND OBJECTIVES: A healthy lifestyle (HLS) is essential to attaining optimal cardiovascular health. Our objective was to assess the association between a HLS score and the incidence of hard cardiovascular disease (CVD) events. METHODS: The SUN project is a dynamic, prospective, multipurpose cohort of Spanish university graduates with a retention proportion of 92%. In 19 336 participants, we calculated a HLS score ranging from 0 to 10 points: never smoking, physical activity (> 20 METs-h/wk), Mediterranean diet adherence (>= 4/8 points), low body mass index (<= 22), moderate alcohol intake (women, 0.1-5g/d; men, 0.1-10g/d), low television exposure (<= 2h/d), no binge drinking (<= 5 alcoholic drinks anytime), taking a short afternoon nap (< 30min/d), meeting up with friends> 1h/d and working> 40h/wk. RESULTS: After a median follow-up of 10.4 years, we identified 140 incident cases of CVD. After adjustment for potential confounders, the highest category of HLS score adherence (7-10 points) showed a significant 78% relative reduction in the risk of primary CVD compared with the lowest category (0-3 points) (adjusted HR, 0.22; 95%CI, 0.11-0.46). Each healthy habit was individually associated with a lower risk of CVD. CONCLUSIONS: A HLS score including several simple healthy habits was associated with a lower risk of developing primary CVD. This index may be useful to reinforce CVD prevention without the need to include traditional risk factors. PMID- 29287798 TI - Lowering prolactin reduces post-hatch parental care in male and female zebra finches (Taeniopygia guttata). AB - Parental care is a widespread phenomenon observed in many diverse taxa. Neuroendocrine systems have long been thought to play an important role in stimulating the onset of parental behavior. In most birds with altricial young, circulating prolactin (PRL) levels are low during non-breeding times and significantly increase during late incubation and early post-hatch chick care. Because of this pattern, PRL has been suggested to be involved in the initiation of parental care in birds, but rarely has this hypothesis been causally tested. To begin testing the hypothesis, we inhibited the release of endogenous PRL with bromocriptine (BR) on the 3days prior to hatching in incubating parents and the first 2days of post-hatch care, when PRL was found to be highest in zebra finches. Nest temperatures were recorded during all 5days and parental behavior was recorded on days 1-2 post-hatch. In addition to hormonal systems, reproductive experience may also influence parental care; therefore, we tested age-matched inexperienced and experienced pairs in each group. BR either eliminated or drastically reduced chick brooding and feeding behavior, resulting in decreased nest temperatures on days 1 and 2 post-hatch. Experienced control birds fed chicks more than inexperienced birds and control females fed more than males. Chick feeding behavior was positively correlated in control male-female pairs, but not in BR pairs. This is one of the few causal studies to demonstrate that PRL is necessary for post-hatch care in a biparental songbird, and is the first to show this effect in zebra finches. PMID- 29287799 TI - How Valid Are GFR Estimation Results From the CKD-EPI Databases? PMID- 29287800 TI - In Reply to 'How Valid Are GFR Estimation Results From the CKD-EPI Databases?' PMID- 29287801 TI - Subchronic toxicity and genotoxicity studies of Antrodia mushroom beta-glucan preparation. AB - Antrodia cinnamomea is one of the most highly valued mushrooms utilized in traditional Taiwanese therapeutic practices. Its neutral monosaccharides (mannose, glucose and xylose) linked by a beta-D-glucan chain have been claimed to be responsible for its health benefits. The objective of the present study was to investigate adverse effects, if any, of beta-glucan (~65% pure) from A. cinnamomea in subchronic toxicity and mutagenicity studies. In the subchronic toxicity study, Sprague Dawley rats (12/sex/group) were followed Organization for Economic Cooperation and Development (OECD) test guideline with Good Laboratory Practice (GLP) application, and were administered (gavage) Antrodia mushroom beta glucan preparation at dose levels of 0, 500, 1000 and 2000 mg/kg body weight (bw)/day for 90 days. Treatment with beta-glucan preparation did not result in any toxicologically significant treatment-related changes in clinical observations, ophthalmic examinations, body weights, body weight gains, feed consumption, and organ weights. The clinical pathology as studied by hematology, serum chemistry, urinalysis or terminal necropsy (gross or histopathology findings) did not reveal any treatment-related adverse effects. The results of mutagenicity studies as evaluated by gene mutations in Salmonella typhimurium, in vitro chromosome aberrations and in vivo micronucleus test in mice did not reveal any genotoxicity of beta-glucan preparation. Based on the subchronic study, the no observed-adverse-effect level (NOAEL) for beta-glucan preparation from Antrodia mushroom was determined as 2000 mg/kg bw/day, the highest dose tested. PMID- 29287802 TI - Acute and sub-chronic toxicological studies of the iridoid glycosides extract of Lamiophlomis rotata (Benth.) Kudo in rats. AB - Lamiophlomis rotata(Benth.) Kudo is widely used in traditional Chinese medicine and its iridoid glycosides extract (IGLR) was the main active ingredient with hemostatic, antinociceptive and anti-inflammatory effects. This study was aimed to evaluate the safety of IGLR using acute and sub-chronic toxicity study methods on Sprague-Dawley rats. In acute toxicity test, IGLR caused slight diarrhea in three dose groups and a decreased of RBC and increased of MCH and Ret (P < .05) were observed in 16 g/kg group. In sub-chronic toxicity study, unscheduled deaths occurred in 1 and 3 rats at 0.40 and 1.00 g/kg groups, respectively. A slight diarrhea was observed in 1.00 g/kg group. Hemolytic anemia was the main toxicity effects of IGLR found in 0.40 and 1.00 g/kg groups, with a significant decrease of RBC, HGB (P < .05) and increase of Ret, MCV, MCH (P < .05) in hematological parameters, a significant decrease of ALT, Crea (P < .05) and increase of TBIL (P < .05) in biochemical parameters, and a significant increase of the percentage of rubricyte, normoblast (P < .05) in bone marrow. Overall, this study found IGLR has a potential toxicity considering with hemolytic anemia and diarrhea to rat. These results provide an important reference for further IGLR-related drug exploration. PMID- 29287803 TI - Transcriptional profile of in vitro expanded human epidermal progenitor cells for the treatment of non-healing wounds. AB - BACKGROUND: Epidermal progenitor cells (EPCs) have been under extensive investigation due to their increasing potential of application in medicine and biotechnology. Cultured human EPCs are used in the treatment of chronic wounds and have recently became a target for gene therapy and toxicological studies. One of the challenges in EPCs culture is to provide a high number of undifferentiated, progenitor cells displaying high viability and significant biological activity. OBJECTIVES: The goal of this study was to characterize the in vitro cultured progenitor cells and to assess whether the cells with the progenitor phenotype are able to enhance wound healing. Additionally, we aimed to establish the complete procedure of the culture, analysis and clinical application of epidermal progenitor cells. METHODS: In this study we present a method of cell isolation and culture followed by a technique of transplantation of the cultured cells onto the wound bed. The applied isolation technique involves two enzymatic steps (dispase, trypsin) and it is characterized by a high yield of cells. The obtained cells were cultured in vitro up to the second passage in serum-free and xeno-free keratinocytes-dedicated medium. Key stem cell markers were determined with means of flow cytometry and quantitative real-time PCR. RESULTS: The in vitro expanded cells displayed high proliferative activity without features of neither apoptosis nor necrosis. The flow cytometry and transcriptomic analyses showed enhanced expression of stem cell markers (i.e. proteins: DeltaNp63, CD29, CD49f and BNC1, CDKN1A transcripts) in the expanded cells. In the presented compassionate use study, cultured autologous cells from an oncological patient were suspended in fibrin sealant and transplanted directly to a non-healing wound, resulting in wound closure within 2 months. CONCLUSION: The cells cultured in serum-free media display epidermal stem cells features and a potential to stimulate wound healing. This promising procedure of isolation, culture and application warrants further clinical trials in the treatment of chronic wounds. PMID- 29287804 TI - Investigating spatio-temporal distribution and diffusion patterns of the dengue outbreak in Swat, Pakistan. AB - INTRODUCTION: Dengue has been endemic to Pakistan in the last two decades. There was a massive outbreak in the Swat valley in 2013. Here we demonstrate the spatio temporal clustering and diffusion patterns of the dengue outbreak. METHODS: Dengue case data were acquired from the hospital records in the Swat district of Pakistan. Ring maps visualize the distribution and diffusion of the number of cases and incidence of dengue at the level of the union council. We applied space time scan statistics to identify spatio-temporal clusters. Ordinary least squares and geographically weighted regression models were used to evaluate the impact of elevation, population density, and distance to the river. RESULTS: The results show that dengue distribution is not random, but clustered in space and time in the Swat district. Males constituted 68% of the cases while females accounted for about 32%. A majority of the cases (>55%) were younger than 40 years of age. The southern part was a major hotspot affected by the dengue outbreak in 2013. There are two space-time clusters in the spatio-temporal analysis. GWR and OLS show that population density is a significant explanatory variable for the dengue outbreak, while GWR exhibits better performance in terms of 'R2=0.49 and AICc=700'. CONCLUSION: Dengue fever is clustered in the southern part of the Swat district. This region is relatively urban in character, with most of the population of the district residing here. There is a need to strengthen the surveillance system for reporting dengue cases in order to respond to future outbreaks in a robust way. PMID- 29287806 TI - Antibiotic susceptibility of 259 Listeria monocytogenes strains isolated from food, food-processing plants and human samples in Germany. AB - BACKGROUND: The objective of this study was to evaluate the susceptibility of 259 Listeria monocytogenes strains isolated from food and food-processing environments and patient samples in Germany to 14 antibiotics widely used in veterinary and human medicine. L. monocytogenes strains were isolated mainly from milk and milk products and classified according to their molecular serotypes IIa (n=112), IIb (n=41), IIc (n=36), IVa (n=1), IVb (n=66), and IVb-v1 (n=3). METHODS: Susceptibility tests were performed by using the automated 96-well based microdilution system Micronaut-S. Ampicillin, benzylpenicillin, ceftriaxone, ciprofloxacin, daptomycin, erythromcyin, gentamicin, linezolid, meropenem, rifampicin, tetracycline, tigecycline, trimethoprim/sulfamethoxazole and vancomycin were tested in at least five different concentrations. RESULTS: Among the 259 strains under study, 145 strains revealed multidrug-resistance (resistance to >=3 antibiotics) and predominantly belonged to serotype IV (59%). Strains were mainly resistant to daptomycin, tigecycline, tetracycline, ciprofloxacin, ceftriaxone, trimethropim/sulfamethoxazole and gentamicin. CONCLUSIONS: Antibiotic resistance in general and multidrug-resistance in particular were more prevalent in L. monocytogenes strains isolated in Germany compared to similar reference stocks from other European countries and the USA but similar to stocks from China. PMID- 29287805 TI - Role of environmental, climatic risk factors and livestock animals on the occurrence of cutaneous leishmaniasis in newly emerging focus in Iran. AB - INTRODUCTION: Occurrence of leishmaniasis is affected by various biological and environmental factors. Kohgiluye and Boyerahmad (K-B) province is an emerging focus of cutaneous leishmaniasis (CL) in Southwest Iran. SUBJECTS AND METHODS: To elucidate some angles of occurrence of CL in this province, climatic and environmental factors and close proximity to livestock were studied by univariate and two multivariate logistic regression models. The dwelling addresses of 275 CL patients were obtained from Health Centers records for a 5 years period. The effect of mean annual temperature, minimum mean annual temperature, maximum mean annual temperature, mean annual rainfall, slope, elevation, land covers and close proximity to cattle and sheep/goat sheds on the occurrence of CL were analysed using geographical information systems (GIS) approach. RESULTS: CL occurred in all counties with the most cases in Northwest, West and South semi-arid and warm regions. Land cover, slope, elevation and close proximity to cattle sheds, were the most effective factors. Urban, dry farm and thin rangeland were found as the most important land covers. Slope and elevation decreased the probability of disease. Close proximity to cattle sheds notably increased the chance of CL. The importance of other factors such as rainfall, temperature and close proximity to sheep/goat sheds only were shown when their effects were evaluated independently from other factors. So regions with urban, dry farm and thin rangeland covers with lower slope and altitude where in close proximity of cattle sheds seems to be potentially most high risk areas. CONCLUSION: Distribution of CL cases is influenced by combination of environmental, ecological factors and close proximity to livestock sheds but control programs should be focused on cities and villages in the above-mentioned most high risk regions. PMID- 29287807 TI - Validation of an Algorithm to Predict the Likelihood of an 8/8 HLA-Matched Unrelated Donor at Search Initiation. AB - A strategy to rapidly determine if a matched unrelated donor (URD) can be secured for allograft recipients is needed. We sought to validate the accuracy of (1) HapLogic match predictions and (2) a resultant novel Search Prognosis (SP) patient categorization that could predict 8/8 HLA-matched URD(s) likelihood at search initiation. Patient prognosis categories at search initiation were correlated with URD confirmatory typing results. HapLogic-based SP categorizations accurately predicted the likelihood of an 8/8 HLA-match in 830 patients (1530 donors tested). Sixty percent of patients had 8/8 URD(s) identified. Patient SP categories (217 very good, 104 good, 178 fair, 33 poor, 153 very poor, 145 futile) were associated with a marked progressive decrease in 8/8 URD identification and transplantation. Very good to good categories were highly predictive of identifying and receiving an 8/8 URD regardless of ancestry. Europeans in fair/poor categories were more likely to identify and receive an 8/8 URD compared with non-Europeans. In all ancestries very poor and futile categories predicted no 8/8 URDs. HapLogic permits URD search results to be predicted once patient HLA typing and ancestry is obtained, dramatically improving search efficiency. Poor, very poor, andfutile searches can be immediately recognized, thereby facilitating prompt pursuit of alternative donors. PMID- 29287809 TI - A novel scoring system to predict delirium and its relationship with the clinical course in patients with acute decompensated heart failure. AB - BACKGROUND: Delirium is known to be a poor prognostic factor in patients with acute decompensated heart failure (ADHF). The purpose of this study was to determine predictors of delirium on admission of ADHF patients, and to establish a scoring formula to identify patients at high risk for delirium. METHODS AND RESULTS: We recorded the Intensive Care Delirium Screening Checklist (ICDSC) score in 120 ADHF patients during their stay in the coronary care unit (CCU). Patients with a highest ICDSC score of 4 or more were diagnosed with delirium. We examined independent candidate predictors of delirium using multivariate logistic regression analysis and developed the following scoring formula, the delirium prediction score (DPS), using independent predictors of delirium and their regression coefficients: DPS=inferior vena cava diameter+C-reactive protein (and additionally +10 for patients with a history of cerebral infarction). Receiver operating curve analysis indicated that evaluation using this scoring system at the time of admission was able to predict delirium with high accuracy (C statistic: 0.885). In addition, the calculated scores had significantly positive correlations with duration of CCU stay and overall length of hospital stay. CONCLUSIONS: We established a novel scoring system to predict on admission the likelihood of development of delirium in ADHF patients; this system also predicts prolongation of intensive care and hospital stay. PMID- 29287808 TI - Clinical implications of hemodynamic assessment during left ventricular assist device therapy. AB - Left ventricular assist devices (LVADs) significantly improve outcomes of advanced heart failure patients. However, patients continue to have high readmission rates due to complications ranging from bleeding, thrombosis, heart failure, and infection. Considering that the hallmark benefit of LVAD therapy is improvement in hemodynamics (cardiac unloading and increased cardiac output), hemodynamic assessment on LVAD support is key to better understand these difficult complications and may serve as a tool to resolving them. In this review, we will discuss the hemodynamic changes following LVAD implantation, and the implications and prognostic impact of hemodynamic optimization on outcomes and complications. PMID- 29287810 TI - Editorial. PMID- 29287811 TI - Biomechanical Simulation of Stresses and Strains Exerted on the Spinal Cord and Nerves During Scoliosis Correction Maneuvers. AB - STUDY DESIGN: Biomechanical analysis of the spinal cord and nerves during scoliosis correction maneuvers through numerical simulations. OBJECTIVE: To assess the biomechanical effects of scoliosis correction maneuvers and stresses generated on the spinal nervous structures. BACKGROUND DATA: Important forces are applied during scoliosis correction surgery, which could potentially lead to neurologic complications due to stresses exerted on the nervous structures. The biomechanical impact of the different types of stresses applied on the nervous structures during correction maneuvers is not well understood. METHODS: Three correction techniques were simulated using a hybrid computer modeling approach, personalized to a right thoracic adolescent idiopathic scoliotic case (Cobb angle: 63 degrees ): (1) Harrington-type distraction; (2) segmental translation technique; and a (3) segmental rotation-based procedure. A multibody model was used to simulate the kinematics of the instrumentation maneuvers; a second comprehensive finite element model was used to analyze the local stresses and strains on the spinal cord and nerves. Average values of the internal medullar pressure (IMP), shear stresses, nerve compression, and strain were computed over three regions and compared between techniques. RESULTS: Harrington distraction maneuver generated high stresses and strains over the thoracolumbar region. In the main thoracic region, the segmental translation maneuver technique induced 15% more shear stress, 25% more strain, and 62% lower nerve compression than Harrington distraction maneuver. The segmental rotation-based procedure induced 25% lower shear stresses and 18% more strain, respectively, at the apical level, as well as 72%, 57%, and 7% lower IMP, nerve compression, and strain in the upper thoracic region, compared with Harrington distraction maneuver. CONCLUSION: This study quantified the relative stress induced on the spinal cord and spinal nerves for different correction maneuvers using a novel hybrid patient-specific model. Of the three maneuvers studied, the Harrington distraction maneuver induced the most important stresses over the thoracolumbar region. PMID- 29287812 TI - The True Ponte Osteotomy: By the One Who Developed It. AB - STUDY DESIGN: Technique and applications. OBJECTIVES: To define the anatomy, biomechanics, indications, and surgical technique of the true Ponte osteotomy. SUMMARY OF BACKGROUND DATA: The Ponte osteotomy, originally developed for thoracic kyphosis, was the first one to obtain posterior shortening of the thoracic spine, maintaining the anterior column load-sharing capacity. It has become a widely applied technique in various types of spine deformities and a frequent topic of presentations at meetings and in scientific articles. Several of them offer unquestionable evidence of an incorrect execution, with consequently distorted outcomes and erroneous conclusions. A clearing up became essential. METHODS: Our original experience is based on a series of 240 patients with thoracic hyperkyphosis operated in the years 1969-2015, at first with a standard posterior Harrington technique and then by using the Ponte osteotomy with different instrumentations. A series of 78 of them, operated in the years 1987-1997, who had Ponte osteotomies at every level, is presented. RESULTS: The average preoperative kyphosis has been corrected from 80 degrees (range 61 degrees -102 degrees ) to 31 degrees (range 15 degrees -50 degrees ) by a substantial posterior shortening. CONCLUSIONS: A number of publications use the term Ponte osteotomy loosely for by far incomplete resections and mixing it up with Smith-Petersen's osteotomy. The true Ponte osteotomy is capable of producing marked flexibility in extension, flexion and rotation, justifying its wide use in thoracic deformities, mainly in scoliosis. An exact performance of the osteotomy with adequate bony resections, including the laminae, is an absolute condition to take full advantage of its properties. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29287813 TI - Pedicle Screw With Increased Cortical Purchase Can Be Inserted With Same Accuracy as the Screw in Straightforward Trajectory Using 3D Modeling Landmarks. AB - STUDY DESIGN: Comparison, in terms of insertion accuracy and biomechanical performance, between an increased cortical purchase and straightforward pedicle screw trajectory. OBJECTIVE: This study aims to compare a trajectory with increased cortical purchase to the more common straightforward trajectory in terms of strength and insertion accuracy using real-time navigation. SUMMARY OF BACKGROUND DATA: In previous studies, it was suggested that pedicle screw pullout strength is strongly correlated with bone mineral density, and using a more cortical tract allows a greater portion of the denser bone, the cortex, to be in contact with the screw. In light of this advantage, an insertion technique has been proposed more recently, to increase the cortical purchase to maximize screw thread contact with cortical bone. It is performed inserting the screw with reduced transverse inclination and results in cortical bone purchase in the lateral portion of the pedicle. METHODS: Eight T1 and eight T3 vertebra models were reconstructed in Mimics Suite (Materialise, Leuven, Belgium) using CT data obtained with a Medtronic O-arm. Using a previously developed computer algorithm, we calculated all achievable safe trajectories for pedicle screw placement ensuring a minimal distance of 0.5 mm between screw and pedicle edges. For both vertebrae, among these, the straightest and the most convergent trajectories with the calculated insertion region greater than 15% of the total were selected to safely instrument the vertebrae, respectively, as ICP and straightforward techniques. The straightforward technique was planned with a transverse angle of 22.50 degrees in both vertebrae whereas the ICP was planned with a transverse angle of 12.50 degrees for T1 and 2.5 degrees for T3. The screws were implanted by a surgeon experienced in straightforward insertion, and other independent investigators measured placement accuracy and mechanical performance. RESULTS: The transverse screw angles for T1 and T3 with straightforward technique had average values of 24.93 degrees +/- 2.96 degrees and 23.53 degrees +/- 2.70 degrees , respectively. For the ICP technique, the average values were 15.60 degrees +/- 2.95 degrees for T1 and 2.29 degrees +/- 1.55 degrees for T3. The resultant errors associated with screw placement for T1 and T3 were not significantly different (p > .05). The pullout failure loads with straightforward techniques ranged from 756 +/- 164 N in T1 to 703 +/- 74 N in T3 and were not significantly different (p > .05) from the values of 699 +/- 84 N for T1 and of 732 +/- 113 N measured for the ICP. CONCLUSIONS: For the upper thoracic vertebrae tested, despite the use of shorter screws, the insertion technique with increased cortical purchase, in biomechanical terms, is comparable with the straightforward trajectory. Using guidance, the proposed ICP technique was performed with the same accuracy as the popular straightforward technique. LEVEL OF EVIDENCE: Level V. PMID- 29287814 TI - Factors Predictive of Outcomes in Vertebral Body Stapling for Idiopathic Scoliosis. AB - STUDY DESIGN: Retrospective review. OBJECTIVES: To identify factors associated with successful outcomes in patients treated with vertebral body stapling (VBS) for idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: The standard of care for moderate scoliosis (20 degrees -45 degrees ) consists of observation and bracing with the goal of halting curve progression. Although several recent studies have confirmed the efficacy of bracing in altering the natural history of scoliosis, bracing is not universally effective. Recent studies have demonstrated that VBS is a safe and viable treatment for some young patients with scoliosis at risk for progression. The identification of factors associated with successful outcomes in VBS for idiopathic scoliosis would better define the population likely to benefit from VBS. METHODS: We retrospectively reviewed all patients from a single institution treated with VBS who met previously defined inclusion criteria. Successful treatment was defined as avoidance of a fusion and a final Cobb angle no more than 10 degrees greater than the pretreatment Cobb angle. RESULTS: We identified 63 patients who met inclusion criteria. The patients underwent VBS at a mean age of 10.78 years and had a mean follow-up of 3.62 years (minimum 2 years). The mean pre-op Cobb angle for stapled thoracic curves was 29.5 degrees . Seventy-four percent of the patients who had VBS of the thoracic curve have avoided progression and/or fusion, and the mean Cobb angle at most recent follow up was 21.8 degrees . The mean preoperative Cobb angle for lumbar curves was 31.1 degrees . Eighty-two percent of the patients who had VBS of the lumbar curve have avoided progression and/or fusion, and their mean Cobb angle at follow-up was 21.6 degrees . CONCLUSION: VBS is effective at preventing progression and fusion for moderate idiopathic scoliosis in immature patients. The complication rates are low. PMID- 29287815 TI - Preventing Distal Junctional Kyphosis by Applying the Stable Sagittal Vertebra Concept to Selective Thoracic Fusion in Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Multicenter retrospective review. OBJECTIVE: To assess the effectiveness of using the stable sagittal vertebra (SSV) for selecting the lowest instrumented vertebrae (LIV) to prevent distal junctional kyphosis (DJK) in selective thoracic fusions. SUMMARY OF BACKGROUND DATA: Cho et al. reported that including the SSV in a fusion decreased the rate of DJK in thoracic hyperkyphosis. METHODS: A retrospective review was performed of patients from two pediatric hospitals with adolescent idiopathic scoliosis who underwent selective posterior thoracic fusion with the LIV at L2 or above from 2000 to 2012. Patients with less than 2 years' follow-up were excluded. The primary outcome measure was DJK, defined radiographically as >=10 degrees between the superior end plate of the LIV and the inferior end plate of the vertebra below on a standing lateral radiograph. We investigated the SSV, which was defined as the vertebral level at which 50% of the vertebral body was in front of the posterior sacral vertical line (PSVL) on a standing lateral radiograph. This particular definition was referred to as SSV. RESULTS: A total of 113 patients met the inclusion criteria. Mean age was 14.4 years. Mean Cobb angle was 58 degrees . The overall rate of DJK was 7% (8/113). When the LIV was superior to SSV, the rate of DJK was 17% (8/46) versus 0% (0/67) when the LIV was at or inferior to SSV (p=.01). The rates of DJK for patients with the LIV one, two, and three levels above SSV were 17% (4/24), 7% (1/14), and 43% (3/7), respectively. There was no significant association between preoperative or postoperative maximum kyphosis, thoracic kyphosis, thoracolumbar kyphosis, pelvic incidence, sagittal balance or coronal balance, and development of DJK. CONCLUSION: Although LIV selection is complex, choosing the LIV at or below the SSV is a simple rule that minimizes the risk of DJK. LEVEL OF EVIDENCE: Level IV. PMID- 29287816 TI - Comparison of Percentile Weight Gain of Growth-Friendly Constructs in Early-Onset Scoliosis. AB - STUDY DESIGN: Multicenter retrospective cohort. OBJECTIVE: To compare improvement in nutritional status seen in early-onset scoliosis (EOS) patients following treatment with various growth-friendly techniques, especially in underweight patients (<20th weight percentile). BACKGROUND: Thoracic insufficiency resulting from EOS can lead to severe cardiopulmonary disease. In this age group, pulmonary function tests are often difficult or impossible to perform. Weight gain has been used in prior studies as a proxy for improvement and has been demonstrated following VEPTR and growing rod implantation. In this study, we aim to analyze weight gain of EOS patients treated with four different spinal implants to evaluate if significant differences in weight percentile change exist between them. METHODS: Retrospective review of patients treated surgically for EOS was performed from a multicenter database. Exclusion criteria were index instrumentation at >10 years old and <2 years' follow-up. RESULTS: 287 patients met the inclusion criteria and etiologies were as follows: congenital = 85; syndromic = 79; neuromuscular = 69; and idiopathic = 52. Average patient age at surgery was 5.41 years, with an average follow-up of 5.8 years. Preoperatively, 55.4% (162/287) fell below the 20th weight percentile. There was no significant difference in preoperative weight between implants (p = .77), or diagnoses (p = .25). Among this group, the mean change in weight percentile was 10.5% (range: 16.7% to 88.7%) and all implant groups increased in mean weight percentile at final follow-up. There were no significant differences in weight percentile change between the groups when divided by implant type (p = .17). CONCLUSIONS: Treatment of EOS with growth-friendly constructs resulted in an increase in weight percentile for underweight patients (<20th percentile), with no significant difference between constructs. LEVEL OF EVIDENCE: Level III. PMID- 29287817 TI - Metal Ion Release During Growth-Friendly Instrumentation for Early-Onset Scoliosis: A Preliminary Study. AB - BACKGROUND: Metal ions released from spinal instruments can cause localized debris and distribute systemically to settle on distant organs. Children with early-onset deformities live with metallic implants for a substantial amount of time. No research focused on metal distribution in growth-friendly instrumentations. The aim of this study was to compare age-matched growing rod (GR) and magnetically controlled growing rod (MCGR) groups to noninstrumented controls. METHODS: The study was designed as a multicenter, prospective, cross sectional case series. GR and MCGR applications of three institutions were included. A total of 52 children were enrolled. Blood samples were collected between December 2014 and February 2015. Biochemical serum analyses were performed to trace and quantify titanium, vanadium, aluminum, and boron. The GR group included 15 children. Mean age was 10.7 (range 6-15). MCGR group included 22 children. Mean age was 8.5 (range 2-13). Fifteen age-matched nonoperated children formed the control group. The mean age was 10.4 (range 5-15). One-way analysis of variance, Kruskal-Wallis, and Mann-Whitney U tests were used for comparisons. RESULTS: The mean serum titanium level in control, GR, and MCGR groups were 2.8 +/- 1.4, 7.3 +/- 4.3, and 10.2 +/- 6.8 MUg/L, respectively. GR and MCGR group titanium levels were higher than controls' (p = .008 and p < .001). The mean serum vanadium level in control, GR, and MCGR groups were 0.2 +/- 0.0, 0.2 +/- 0.0, and 0.5 +/- 0.5 MUg/L, respectively. MCGR group vanadium level was higher than control (p < .001) and GR groups (p = .004). Mean serum levels in control, GR, and MCGR groups were, respectively, 5.4 +/- 4.1, 8.1 +/- 7.4, and 7.8 +/- 5.1 MUg/L for aluminum and 86.7 +/- 2.7, 86.9 +/- 2.5, and 85.0 +/- 6.6 MUg/L for boron. The distribution of aluminum and boron were similar across groups (p = .675 and p = .396). CONCLUSIONS: Both GR and MCGR applications significantly release titanium and possibly aluminum. MCGR further releases vanadium. MCGR possibly releases more titanium than traditional GR. Time dependent alterations of serum ion levels, structural properties of the MCGR device, and exposure caused by magnetic distraction processes warrant investigation. PMID- 29287818 TI - Youth and Experience: The Effect of Surgeon Experience on Outcomes in Cerebral Palsy Scoliosis Surgery. AB - BACKGROUND: Series on the learning curve in spinal deformity surgery have been published, but none has addressed neuromuscular spinal deformity, comprised of arguably the most complex cases. We present the first multi-center analysis of the impact of surgeon experience on neuromuscular spinal deformity surgery. METHODS: A multi-center prospective study of spinal deformity surgery for cerebral palsy (CP) with at least 2 years of follow-up provided the dataset for assessment. Surgeons were categorized into one of two groups based on their self reported first year of practice: an experienced surgeons (ES) group included those with at least 10 years of experience at the time of surgery and a young surgeons (YS) group included those with fewer than 10 years of experience at time of surgery. Groups were compared in multiple pre-operative, operative, and post operative outcomes. RESULTS: The YS group had 8 surgeons who performed 59 surgeries; the ES group had 13 surgeons who performed 103 cases, with one surgeon's cases distributed in both groups. The YS group had a greater proportion of patients with severe mental retardation (89.7% vs. 68.6%, p = .01). Duration of surgery was greater in the YS group (456 vs. 344 minutes, p < .001). The mean number of levels fused was greater in the ES group (15.9 vs. 15.6, p = .024), caused by increased variation in the upper level of fusion among the ES group. No significant differences were found between groups for estimated blood loss, length of hospitalization, or in percentage of Cobb correction. Years of experience of the operating surgeon was inversely correlated with duration of surgery (rho = -0.476, p < .001). CONCLUSIONS: In performing scoliosis surgery on CP patients, surgeons with fewer than ten years of practice experience demonstrate significantly greater average operative time and decreased mean number of levels fused, yet produce similar clinical outcomes to more experienced surgeons. LEVEL OF EVIDENCE: Level III, therapeutic. PMID- 29287819 TI - Adult Spinal Deformity Knowledge in Orthopedic Spine Surgeons: Impact of Fellowship Training, Experience, and Practice Characteristics. AB - STUDY DESIGN: Survey study. OBJECTIVE: The purpose of this paper was to assess the level of adult spine deformity (ASD) knowledge among orthopedic spine surgeons and identify areas for improvement in spine surgery training. SUMMARY OF BACKGROUND DATA: ASD is increasingly encountered in spine surgery practice. While ASD knowledge among neurosurgeons has been evaluated, ASD knowledge among orthopedic spine surgeons has not previously been reported. METHODS: A survey of orthopedic spine surgeon members of North American Spine Society (NASS) was conducted to assess level of spine surgery training, practice experience, and spinal deformity knowledge base. The survey used was previously completed by a group of neurologic surgeons with published results. The survey used 11 questions developed and agreed upon by experienced spinal deformity surgeons. RESULTS: Complete responses were received from 413 orthopedic spine surgeons. The overall correct-answer rate was 69.0%. Surgeons in practice for less than 10 years had a higher correct-answer rate compared to those who have practiced for 10 years or more (74% vs. 67%; p = .000003). Surgeons with 75% or more of their practice dedicated to spine had a higher overall correct rate compared to surgeons whose practice is less than 75% spine (71% vs. 63%; p = .000029). Completion of spine fellowship was associated with a higher overall correct-answer rate compared to respondents who did not complete a spine fellowship (71% vs. 59%; p < .00001). CONCLUSIONS: Completion of spine fellowship and having a dedicated spine surgery practice were significantly associated with improved performance on this ASD knowledge survey. Unlike neurosurgeons, orthopedic spine surgeons who have practiced for less than 10 years performed better than those who have practiced for more than 10 years. Ongoing emphasis on spine deformity education should be emphasized to improve adult spinal deformity knowledge base. PMID- 29287821 TI - S2 Alar Iliac Fixation in Long Segment Constructs, a Two- to Five-Year Follow-up. AB - STUDY DESIGN: Retrospective review of patients having undergone S2 alar-iliac (S2AI) fixation for long fusions with a minimum two-year follow-up. OBJECTIVES: To report on fusion rates, complications, technique-specific complications of patients having undergone S2AI fixation. SUMMARY OF BACKGROUND DATA: Sacropelvic fixation continues to be a challenge when performing long fusions to the pelvis. S2AI screws have been found to provide solid biomechanical fixation and have been found to have good clinical results in short-term follow-up for pediatric and adult patients. METHODS: Cases were retrospectively reviewed in patients who had placement of S2AI screws for long fusions with at least a two-year follow-up. Demographic data, complications, and reoperations were reviewed. Complications were broken into minor and major categories similar to previous series on pelvic fixation. RESULTS: There were 86 cases identified. Minor and major complications occurred in 29% and 24% of patients, respectively, with the majority of minor complications being intraoperative dural tears. Revision surgery for all causes was performed in 23% of the cohort. Fusion rate at L5-S1 for patients without preoperative pseudarthrosis was 95.3%. Preoperative L5-S1 pseudoarthrosis was identified in 20 patients, 17 (95%) of these went onto fusion after one surgery. There was evidence of S2AI screw lucency in 10.4% of cases. However, the majority of these were asymptomatic. CONCLUSIONS: Sacropelvic fixation using the S2AI technique provides safe, durable fixation with low rates of technique-specific complications and limited need for hardware removal. Complication rates in this series were similar to other series on long fusions to the pelvis. Additionally, fusion rates were high at L5-S1 for both patients with and without preoperative L5-S1 pseudarthrosis. It appears that the S2AI technique is a powerful option for patients with previous L5-S1 pseudarthrosis. LEVEL OF EVIDENCE: Level III. PMID- 29287820 TI - Health-Related Quality of Life Scores Underestimate the Impact of Major Complications in Lumbar Degenerative Scoliosis Surgery. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: To examine Charlson Comorbidity Index (CCMI) as a marker for deterioration in health status not reflected in standard Health Related Quality of Life (HRQOL) measures. SUMMARY OF BACKGROUND DATA: HRQOL has become a primary metric for assessing outcomes following spinal deformity surgery. However, studies have reported limited impact of complications on postoperative HRQOL outcomes. METHODS: We examined serial CCMI, complications, and HRQOL outcomes for 138 adult lumbar deformity patients treated surgically with a minimum two-year follow-up that included 126 females (91%) with a mean age of 59.8 years (range, 40.2-78.5). Patients with no, minor, or major complications were compared at baseline and at one and two years postoperation. RESULTS: Minor complications were observed in 26 patients (19%) and major complications in 15 (11%). Major complications included motor deficit (7), deep vein thrombosis (4), and respiratory failure (3). There was no difference in preoperative SF-36 Physical Component Summary or Scoliosis Research Society-22R (SRS-22R) scores among the groups at baseline. Preoperative CCMI was lowest in the No Complication group (3.52 +/- 1.70) followed by the Major (4.00 +/- 1.13) and Minor Complication groups (4.15 +/- 1.71, p = .165). At one year, there was a significantly greater CCMI deterioration in the Major Complication group (0.80 +/ 1.01) compared to both the Minor (0.08 +/- 0.27) and No Complication groups (0.27 +/- 0.47, p < .001). There was no significant difference in SF-36 Physical Component Summary or SRS-22R scores among the three groups. Similar findings were observed at two years. CONCLUSIONS: Despite similar one- and two-year HRQOL improvement, patients with major complications had greater deterioration in CCMI. As CCMI is predictive of medical and surgical risk, patients who sustained a major complication now carry a greater likelihood of adverse outcomes with future interventions, including any subsequent spinal surgery. Although this increased risk may not alter the patient's perception of his or her current health status, it may be important, and should be recognized as part of the shared decision making process. LEVEL OF EVIDENCE: Level II, high-quality prognostic study. PMID- 29287822 TI - SRS-22R Minimum Clinically Important Difference and Substantial Clinical Benefit After Adult Lumbar Scoliosis Surgery. AB - STUDY DESIGN: Longitudinal cohort. OBJECTIVES: To determine if the minimum clinically important difference (MCID) and substantial clinical benefit (SCB) thresholds for the Scoliosis Research Society-22R (SRS22R) domains in patients with degenerative lumbar scoliosis are similar to those in patients with adult spinal deformity (ASD) with fusions extending into the thoracic spine. SUMMARY OF BACKGROUND DATA: The MCID and SCB thresholds for the SRS22R domains in patients with ASD and adolescent idiopathic scoliosis have been reported. METHODS: Patients enrolled in the NIH-sponsored Adult Symptomatic Lumbar Scoliosis (ASLS) trial who underwent surgery and completed the SRS22R preoperative and the SRS30 one-year postoperative were identified. One-year postoperative answers to the last eight questions of the SRS30 were used as anchors to determine the MCID and SCB for the Pain, Appearance, and Activity domains, and the Subscore and Total score using receiver operating characteristic (ROC) curve analysis. RESULTS: The sample population consisted of 147 patients. A total of 132 (89%) were females with a mean age of 59.4 years. There was a statistically significant improvement in all SRS22R scores from preoperative to one-year postoperative. There was also a statistically significant difference in domain scores among the different responses to the anchors. According to the ROC analysis, MCID was 1.17 for Appearance, 0.40 for Activity, 0.60 for Pain, 0.53 for Subscore, and 0.77 for Total; and SCB was 1.67 for Appearance, 0.60 for Activity, 0.62 for Subscore, and 1.11 for Total score. These are similar to previous reports of MCID and SCB thresholds for ASD patients who underwent fusion to the thoracic spine. CONCLUSION: The MCID and SCB thresholds for the SRS22R domains in patients with adult symptomatic lumbar scoliosis are very similar to the threshold values previously reported for adult deformity patients. LEVEL OF EVIDENCE: Level II. PMID- 29287823 TI - Posterior-Only Vertebral Column Resection for Fused Spondyloptosis. AB - STUDY DESIGN: Retrospective review. OBJECTIVES: To describe 3 cases of a posterior-only vertebral column resection (pVCR) for the treatment of spondyloptosis in the setting of prior spinal fusions. SUMMARY OF BACKGROUND DATA: Lumbosacral spondyloptosis is a rare spinal deformity with a number of surgical options, none of which demonstrate clear superiority. The use of an L5 vertebral column resection, via combined anterior and posterior approaches, to restore lumbosacral alignment has been described though is accompanied by high rates of neurological deficit. METHODS: Review of 3 cases of spondyloptosis with prior spinal fusions in which a staged pVCR was used for deformity reconstruction. RESULTS: Three females, ages 39, 54, and 28, developed spondyloptosis with progressive lumbosacral kyphosis and sagittal malalignment after prior in-situ posterolateral spinal fusions. All were treated with staged pVCRs. At ultimate follow-up, imaging revealed improvement in sagittal balance of 6.1 cm (56%) in the 39-year-old and 12 cm (67%) in the 54-year-old, 21.1 cm (92%) in the 28-year-old. All patients had improvement in outcome scores with perfect satisfaction scores despite the 54-year-old having a persistent right foot drop. CONCLUSION: Posterior-only VCR for spondyloptosis is a technically demanding surgical option offering significant radiographic and clinical improvement, but carries a risk for L5 nerve root deficit as in any spondyloptosis treatment. PMID- 29287824 TI - Letter to the Editor Concerning: Altaf, F., Drinkwater, J., Phan, K., Cree, A.K. Spine Deformity 5(2017):308-309. PMID- 29287825 TI - Reply to: Concerning: Altaf, F., Drinkwater, J., Phan, K., Cree, A.K. Spine Deformity 2017;5:303-309. PMID- 29287826 TI - Letter to the Editor concerning: Crawford 3rd CH, Larson N, Gates M, et al Spine Deformity 5(2017):284-302. PMID- 29287827 TI - Reply to: Concerning: Crawford 3rd CH, Larson N, Gates M, et al Spine Deformity 5(2017):284-302. PMID- 29287829 TI - Effects of early-life malnutrition on neurodevelopment and neuropsychiatric disorders and the potential mechanisms. AB - Lines of evidence have demonstrated that early-life malnutrition is highly correlated with neurodevelopment and adulthood neuropsychiatric disorders, while some findings are conflicting with each other. In addition, the biological mechanisms are less investigated. We systematically reviewed the evidence linking early-life nutrition status with neurodevelopment and clinical observations in human and animal models. We summarized the effects of special nutritious on neuropsychiatric disorders and explored the underlying potential mechanisms. The further understanding of the biological regulation of early-life nutritional status on neurodevelopment might shed light on precision nutrition at an integrative systems biology framework. PMID- 29287828 TI - Effectiveness of a respiratory rehabilitation programme in patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: To evaluate the effectiveness of the multidisciplinary respiratory rehabilitation (RR) programme in patients with severe or very severe chronic obstructive pulmonary disease pre the RR programme, at the end of the programme and one year after the RR, measuring changes in ability to exercise (walking test), effort tolerance(forced expiratory volume (FEV1)) and health-related quality of life. METHOD: Quasi-experimental single group design. We included patients diagnosed with severe or very severe chronic obstructive pulmonary disease (stages III and IV of the GOLD classification) who entered the rehabilitation programme for the years 2011 and 2012. Demographic data, questionnaires on general health-related quality of life (SF-36) and specific to respiratory patients (St George's Respiratory Questionnaire), FEV1% and exercise capacity test (running test 6minutes) were collected. Data were collected before the RR programme, at the end of the RR programme and a year after completing the program. RESULTS: No significant differences in FEV1% values were observed. Regarding exercise capacity, an increase in distance walked in the walking test was noted, which changed significantly after training, 377+/-59.7 to 415+/-79 m after one year (P<.01). A statistically significant improvement in mean scores of HRQoL was observed, except for the emotional role dimension of the SF-36 questionnaire. CONCLUSION: A pulmonary rehabilitation programme for 8 weeks improved the exercise capacity, dyspnoea and quality of life of patients with severe and very severe chronic obstructive pulmonary disease. PMID- 29287830 TI - Deficits in episodic memory and mental time travel in patients with post traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is characterized by impairments in mnestic functions, especially in the domain of episodic memory. These alterations might affect different aspects of episodic memory functioning. Here we tested PTSD patients and healthy controls (matched for age, sex and education) in a newly developed virtual reality episodic memory test (VR-EMT), a test for mental time travel, episodic future thinking, and prospective memory (M3xT). In a cross validation experiment, their performance was further evaluated in the Rivermead Behavioral Memory Test (RBMT). PTSD patients demonstrated impairments in episodic memory formation and mental time travel and showed difficulties in utilizing information from episodic memory to solve problems. Diminished attention and concentration in PTSD did not account for performance deficits in these tasks but higher levels of negative arousal were found in PTSD patients. Furthermore, performance in the VR-EMT and RBMT in PTSD patients correlated negatively with self-reported measures of stress and depression. Our results suggest that deficits in episodic memory formation and mental time travel in PTSD lead to difficulties in utilizing the content of episodic memories for solving problems in the present or to plan future behavior. Clinical implications of these findings and suggestions for cognitive-behavioral treatment of PTSD are discussed. PMID- 29287831 TI - Systemic inflammation in asocial BTBR T+ tf/J mice predisposes them to increased psoriatic inflammation. AB - Autistic Spectrum disorder (ASD) is a neurobehavioral disorder characterized by defects in communication skills leading to restricted sociability. ASD has immense dysregulation in immune responses which is thought to affect neuronal system and thus behavior. ASD patients and BTBR T+ tf/J (BTBR) autistic mice have increased systemic inflammation due to dysfunction in innate and adaptive immune responses. Recent studies suggest that ASD patients are associated with several co-morbid autoimmune disorders including psoriasis. However underlying mechanisms for this phenomenon have not been explored. In this study, we used imiquimod (IMQ)-induced psoriatic inflammation in social C57BL/6 (C57) mice and asocial BTBR mice to investigate whether systemic inflammation in BTBR is associated with increased susceptibility to psoriatic inflammation. Our data shows that BTBR mice have increased expression of TLR7/IL-6/IL-23 in systemic DCs but not in skin as compared to C57 mice at baseline. This leads to much greater psoriatic inflammation in BTBR mice upon IMQ application than C57 mice. Consequently, BTBR mice also have higher Th17 related immune responses in the skin and systemic compartment. Overall our study suggests that systemic innate (TLR7/IL-23/IL-6 in DCs) and adaptive (Th17 related signaling) immune responses are heightened in BTBR mice at baseline which predisposes them for greater psoriatic inflammation than C57 mice upon IMQ application. This could be one of the reasons for increased psoriatic inflammation in patients with ASD. Therapies that aim to decrease immune activation may not only benefit ASD-associated neurobehavioral abnormalities but also comorbid disorders such as psoriasis. PMID- 29287833 TI - Corticosteroid treatment in Sydenham's chorea. AB - Sydenham's chorea (SC) is an immune-mediated hyperkinetic movement disorder, developing after group A Beta-hemolytic streptococcal (GABHS) infection. Aside from conventional symptomatic treatment (carbamazepine, valproate, neuroleptics), the use of steroids has also been advocated, mainly in severe, drug-resistant cases or if clinically disabling side effects develop with first line therapies. Based on the description of 5 cases followed in the Child Neurology Unit of Santa Maria Nuova Hospital in Reggio Emilia and on the available medical literature on this topic, we propose considering the use of corticosteroids therapy in children with SC, with the administration of IV methyl-prednisolone followed by oral deflazacort in severe cases and of oral deflazacort alone in mild and moderate degrees of involvement. In our experience this therapy is effective both in the short and long-term period, in different clinical presentations (chorea paralytica, distal chorea, hemichorea, "classic" chorea, association with mood disorder or dyspraxia) and very well tolerated (no significant side effects were recorded). PMID- 29287832 TI - Progesterone modulates microtubule dynamics and epiboly progression during zebrafish gastrulation. AB - Control of microtubule dynamics is crucial for cell migration. We analyzed regulation of microtubule network dynamics in the zebrafish yolk cell during epiboly, the earliest coordinated gastrulation movement. We labeled microtubules with EMTB-3GFP and EB3-mCherry to visualize and measure microtubule dynamics by TIRF microscopy live imaging. Yolk cell microtubules dynamics is temporally modulated during epiboly progression. We used maternal zygotic Pou5f3 mutant (MZspg) embryos, which develop strong distortions of microtubule network organization and epiboly retardation, to investigate genetic control of microtubule dynamics. In MZspg embryos, microtubule plus-end growth tracks move slower and are less straight compared to wild-type. MZspg embryos have altered steroidogenic enzyme expression, resulting in increased pregnenolone and reduced progesterone levels. We show that progesterone positively affects microtubule plus-end growth and track straightness. Progesterone may thus act as a non-cell autonomous regulator of microtubule dynamics across the large yolk cell, and may adjust differing demands on microtubule dynamics and stability during initiation and progression phases of epiboly. PMID- 29287834 TI - SLC19A3 related disorder: Treatment implication and clinical outcome of 2 new patients. AB - Encephalopathies with neostriatal involvement constitute a heterogeneous group of acquired and genetically inherited conditions that include Bilateral Striatal Necrosis (BSN) and other Striatal Lesions (SL) (Tonduti et al). We describe two new patients suffering from BSN due to biallelic SLC19A3 mutations. In the first patient vitamin supplementation was started early on, resulting in the remission of the clinical picture, and an almost complete normalization of the neuroradiological findings. In the second one treatment was started late, compliance was irregular and the resulting clinical outcome was poor. The clinical outcome of our two patients confirms and further stresses the importance of the early administration of vitamin supplementation in all patients presenting with neostriatal lesions, or clear bilateral striatal necrosis. Patient 2 didn't present any additional episode of acute decompensation after the age of 20 years despite having completely stopped treatment. This suggests the existence of an age dependency of thiamin requirement in humans. PMID- 29287835 TI - Sugar compartmentation as an environmental stress adaptation strategy in plants. AB - The sessile nature of plants has driven their evolution to cope flexibly with ever-changing surrounding environments. The development of stress tolerance traits is complex, and a broad range of cellular processes are involved. Recent studies have revealed that sugar transporters contribute to environmental stress tolerance in plants, suggesting that sugar flow is dynamically fluctuated towards optimization of cellular conditions in adverse environments. Here, we highlight sugar compartmentation mediated by sugar transporters as an adaptation strategy against biotic and abiotic stresses. Competition for sugars between host plants and pathogens shapes their evolutionary arms race. Pathogens, which rely on host derived carbon, manipulate plant sugar transporters to access sugars easily, while plants sequester sugars from pathogens by enhancing sugar uptake activity. Furthermore, we discuss pathogen tactics to circumvent sugar competition with host plants. Sugar transporters also play a role in abiotic stress tolerance. Exposure to abiotic stresses such as cold or drought stress induces sugar accumulation in various plants. We also discuss how plants allocate sugars under such conditions. Collectively, these findings are relevant to basic plant biology as well as potential applications in agriculture, and provide opportunities to improve crop yield for a growing population. PMID- 29287836 TI - High burden of coronary artery disease in heart failure with preserved ejection fraction. PMID- 29287837 TI - Percutaneous coronary artery interventions in the paediatric population: Periprocedural and late outcome. AB - BACKGROUND: Percutaneous coronary interventions (PCIs) are generally performed in adults with ischaemic heart disease, but reports of experience in the paediatric population are relatively limited. AIMS: To report indications, interventional techniques and procedural outcomes for PCI in children treated in two French institutions. METHODS: Medical records of all children in whom a PCI was attempted in two French tertiary institutions between 1998 and 2015 were systematically reviewed. Diagnostic procedures, including coronary angiograms, were excluded. RESULTS: A total of 40 PCIs were attempted in 29 patients (median age 6.5 years, range three days to 17.9 years). Nineteen procedures (47.5%) were performed on an emergency basis. A total of 36/40 coronary obstructions were successfully treated, with no immediate residual postintervention stenosis. Initial balloon angioplasty was performed for all lesions, with subsequent stent placement in 23 lesions. There were two periprocedural and five late deaths. After a median follow-up of 12 months (range 1 week to 115 months), freedom from death and reintervention at 36 months were 79% and 60%, respectively. Age<1 month, emergency procedure and balloon angioplasty without stent implantation were associated with shorter survival. CONCLUSION: PCI can be used in the paediatric population in a wide range of anatomical conditions; it may be effective in selected patients, but remains challenging when performed in emergency and/or in neonates. PMID- 29287838 TI - Diabetes and complications of the heart in Sub-Saharan Africa: An urgent need for improved awareness, diagnostics and management. AB - Type 2 diabetes mellitus is no longer a disease of high income countries but a global health pandemic. With the continued and rapid increase in its prevalence worldwide it is forecasted that diabetes will be a leading cause of morbidity and mortality. A major concern stems from its role in development and progression of cardiovascular disease, including cardiac dysfunction and heart failure. Within low- and middle-income areas such as Sub-Saharan Africa the burden of diabetes is already significant driven by many factors, including, socioeconomic (urbanisation), nutritional (high-calorie "western-diet", obesity) and lifestyle (physical inactivity) changes. Insufficient economic and community resources, poor health care system development and chronic disease management, poor education, and a lack of preventative and diagnostic measures further aggravate the severity of the diabetes problem. This review outlines the burden of type 2 diabetes mellitus in Sub-Saharan Africa and highlights the need for improved community health care and regulations to reduce its epidemiological spread and devastating impact on health. PMID- 29287839 TI - Advantages of early diagnosis of diabetic neuropathy in the prevention of diabetic foot ulcers. AB - AIMS: To evaluate the utility of the sudomotor function test (SFT) as a clinical tool in the Risk Stratification System of diabetic patients and to demonstrate the earlier detection of the risk of developing diabetic foot ulcers (DFU) compared to the standard clinical tests. METHODS: Prospective follow-up study on 263 patients enrolled consecutively over 3.5 years. Diabetic patients without active DFU were classified according to the International Working Group Risk Stratification System (RSS) and categorized according to the results of the Semmes-Wenstein Monofilament (SWM) and biothesiometer measurements or the SFT. The main outcome evaluated was the development of DFU. RESULTS: Median follow-up was 42 [38-44] months. Sixty patients (22.8%) developed DFU after a median of 6.2 [3-17] months. Ten patients that were included in the no-risk group (group 0) based on the SWM and biothesiometer results developed DFU. Thus the sensitivity of this approach was 83.33% and the specificity was 50.47%. Based on the SFT results, all patients that developed DFU were included in the correct risk group. This approach had 100% sensitivity and 31.53% specificity. Regarding the diagnostic accuracy of the two Methods, the respective AUC values were 0.776 (95% CI 0.702-0.849) and 0.816 (95% CI 0.757-0.874). CONCLUSIONS: SFT improved RSS in diabetic patients in a specialized diabetic foot unit. SFT categorized patients correctly according to the risk of developing DFU. PMID- 29287840 TI - The effect of 12 weeks of aerobic training on serum levels high sensitivity C reactive protein, tumor necrosis factor-alpha, lipid profile and anthropometric characteristics in middle-age women patients with type 2 diabetes. AB - AIMS: The aim of this study was to investigate the effect of 12 weeks of aerobic training on serum levels of high sensitivity C- reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), lipid profile and anthropometric characteristics in middle-aged women patients with type-2 diabetes. METHODS: A quasi-experimental study, 20 women patients with type-2 diabetes (mean age, 50.25 +/- 4.36 years, Body mass index, 25.51 +/- 2.91 kg/m2, and body fat percentage 23.67 +/- 3.05%) were randomly categorized into two experimental and control groups. The protocol aerobic training included eight-minute jogging and eight minute running with 75-85 percent maximum heart rate reserve in the first session. Per both sessions, one minute added to running time and it increased up to 32 min after 12 weeks. Blood sampling and anthropometric measurements, 24 h before and 48 h after the last training session were conducted. RESULT: The result showed a significant reduction in hs-CRP and TNF-alpha in the experimental than control group (P = 0.01). Exercise training-treated patients showed a significant decrease in TG, LDL and increase HDL in comparison with baseline and the control group (P < .05). The results also showed a significant decrease in weight, body mass index, body fat percentage, and waist-hip ratio (P values 0.02, 0.03, 001, 0.04 respectively) following the 12 weeks aerobic training. CONCLUSION: It seems that long-term aerobic training, improved some important anthropometric and biochemical parameters in patients with type-2 diabetes. These observations give a new insight into the mechanisms by which aerobic training can reduce the cardiovascular risk in diabetes. PMID- 29287841 TI - Hematological profile associated with type 2 diabetes mellitus. AB - BACKGROUND: Hematological changes affecting blood cells and the coagulation factors are shown to be associated with diabetes mellitus. We investigated some of the hematological risk factors implicated in the development of type 2 diabetes mellitus. METHODS: The study conducted in western Algeria on a sample of 1852 subjects, 1059 with type 2 diabetes and 793 witnesses, were evaluated for peripheral blood parameters using hematology analyzer. All the informations related to the disease were collected from the patients and recorded using predesigned questionnaire. RESULTS: The logistic model retained, the mean corpuscular hemoglobin concentration reveals that subjects with concentration over the normal ratio (>36 g/dl) have an exposure risk six and half times higher than subjects with normal concentration (OR = 6.59; 95% CI = 2.51-17.31, P = 0.000). As regards to the platelets blood ratio, subjects with a ratio lower are five times more exposed to type 2 diabetes compared to subjects with a normal ratio (OR = 5.01; 95% CI = 1.78-14.13, P < 0.002). Our logistic model also retained basophils ratio (OR = 2.18; 95% CI = 1.35-3.53, P < 0.001) and sedimentation rate at one hour (OR = 7.83; 95% CI = 3.39-18.06, P = 0.000). CONCLUSIONS: Hematological profile associated with type 2 diabetes mellitus retained the mean corpuscular hemoglobin concentration over the normal ratio, lower platelets blood ratio, basophils ratio and sedimentation rate at one hour. PMID- 29287842 TI - High prevalence of obesity among nursing personnel working in tertiary care hospital. AB - AIM: To find out the prevalence of obesity and glucose intolerance among nurses working in tertiary care hospital. METHODS: Study was conducted in 496 apparently healthy females comprising two groups. Group B had 290 nurses and control group A had 206 age matched female subjects of general population. Detailed performa was filled which included anthropometry, systemic examination and other details. Fasting plasma glucose was done followed by oral glucose tolerance test (OGTT). Subjects with body mass index >=23 kg/m2 were categorized as 'overweight' and >=25 kg/m2 as 'obese' as per criteria for Asian Indians. Women with waist circumference of >=80 cm were categorized as 'centrally obese'. RESULTS: Mean age of subjects in groups A and B was 40.45 +/- 8.64 years and 40.50 +/- 6.96 years respectively. Significantly higher number of nurses (80%) were overweight or obese compared to controls (59.71%,P = < .001). Similarly, central obesity was significantly higher in nurses (82.07%) compared to controls (67.96%,P = <.001). The prevalence of glucose intolerance (prediabetes and newly detected diabetes) was significantly higher in controls compared to nurses (45.63% vs 29.66%, P < .001). CONCLUSION: Every four out of five nurses working in tertiary care hospital have overweight/obesity and central obesity. Despite this they have lower rates of glucose intolerance. PMID- 29287843 TI - Does a two-element muscle model offer advantages when estimating ankle plantar flexor forces during human cycling? AB - Traditional Hill-type muscle models, parameterized using high-quality experimental data, are often "too weak" to reproduce the joint torques generated by healthy adults during rapid, high force tasks. This study investigated whether the failure of these models to account for different types of motor units contributes to this apparent weakness; if so, muscle-driven simulations may rely on excessively high muscle excitations to generate a given force. We ran a series of forward simulations that reproduced measured ankle mechanics during cycling at five cadences ranging from 60 to 140 RPM. We generated both "nominal" simulations, in which an abstract ankle model was actuated by a 1-element Hill type plantar flexor with a single contractile element (CE), and "test" simulations, in which the same model was actuated by a 2-element plantar flexor with two CEs that accounted for the force-generating properties of slower and faster motor units. We varied the total excitation applied to the 2-element plantar flexor between 60 and 105% of the excitation from each nominal simulation, and we varied the amount distributed to each CE between 0 and 100% of the total. Within this test space, we identified the excitation level and distribution, at each cadence, that best reproduced the plantar flexor forces generated in the nominal simulations. Our comparisons revealed that the 2-element model required substantially less total excitation than the 1-element model to generate comparable forces, especially at higher cadences. For instance, at 140 RPM, the required excitation was reduced by 23%. These results suggest that a 2 element model, in which contractile properties are "tuned" to represent slower and faster motor units, can increase the apparent strength and perhaps improve the fidelity of simulations of tasks with varying mechanical demands. PMID- 29287844 TI - Cataract as a complication following laser vitreolysis. PMID- 29287845 TI - Sebaceous carcinoma mimicking a chalazion in a young patient. PMID- 29287846 TI - Congenital respiratory tract disorders in 22q11.2 deletion syndrome. AB - OBJECTIVE: Respiratory tract disorders have been reported in patients with 22q11.2 deletion syndrome, however infrequently. This study describes the respiratory tract disorders encountered in a cohort of 278 patients with 22q11.2 deletion syndrome. METHODS: We conducted a retrospective, cross-sectional, study at a single tertiary referral center. We identified the patients with 22q11.2 deletion syndrome and with an upper and/or lower respiratory tract disorder at our otorhinolaryngologic department. The different disorders were described. RESULTS: Out of 278 patients referred to the otorhinolaryngologic department, we identified 14 patients with a laryngeal and/or tracheal disorder. Nine patients had more than one congenital disorder in this anatomical area. Disorders included a choanal stenosis (n = 1), laryngeal web (n = 5), laryngeal cleft (n = 2), subglottic stenosis (n = 3), pharyngo-, laryngo-, tracheo- and/or bronchomalacia (n = 11) and tracheal stenosis (n = 1). CONCLUSION: Different types of respiratory tract disorders can be present in patients with 22q11.2 deletion syndrome. Clinicians should be aware of this clinical association for timely and accurate diagnosis and treatment. In addition, the diagnosis 22q11.2 deletion syndrome should be considered in patients presenting with a congenital respiratory tract disorder. PMID- 29287847 TI - Targeted next generation sequencing identified a novel mutation in MYO7A causing Usher syndrome type 1 in an Iranian consanguineous pedigree. AB - BACKGROUND: Usher syndrome (USH) is characterized by congenital hearing loss and retinitis pigmentosa (RP) with a later onset. It is an autosomal recessive trait with clinical and genetic heterogeneity which makes the molecular diagnosis much difficult. In this study, we introduce a pedigree with two affected members with USH type 1 and represent a cost and time effective approach for genetic diagnosis of USH as a genetically heterogeneous disorder. METHODS: Target region capture in the genes of interest, followed by next generation sequencing (NGS) was used to determine the causative mutations in one of the probands. Then segregation analysis in the pedigree was conducted using PCR-Sanger sequencing. RESULTS: Targeted NGS detected a novel homozygous nonsense variant c.4513G > T (p.Glu1505Ter) in MYO7A. The variant is segregating in the pedigree with an autosomal recessive pattern. CONCLUSION: In this study, a novel stop gained variant c.4513G > T (p.Glu1505Ter) in MYO7A was found in an Iranian pedigree with two affected members with USH type 1. Bioinformatic as well as pedigree segregation analyses were in line with pathogenic nature of this variant. Targeted NGS panel was showed to be an efficient method for mutation detection in hereditary disorders with locus heterogeneity. PMID- 29287848 TI - Recurrent laryngeal nerve reinnervation for management of aspiration in a subset of children. AB - Pediatric aspiration is a multifactorial process that is often complex to manage. Recurrent laryngeal nerve (RLN) injury can cause glottic insufficiency and aspiration. We describe three cases of unilateral vocal fold paralysis resulting in aspiration and the successful use of the RLN reinnervation for its treatment. The theory for utilizing the reinnervation procedure is that when glottic closure improves and a less breathy vocalization occurs, then the larynx is better equipped to protect the lower airway and avoid aspiration. Our cases demonstrate stronger voice and improved swallow function, with normalization of modified barium swallow evaluation, at approximately 6-months post reinnervation. PMID- 29287849 TI - A novel variant in the CDH23 gene is associated with non-syndromic hearing loss in a Chinese family. AB - OBJECTIVES: To explore the pathogenic causes of a proband who was diagnosed with non-syndromic hearing loss. METHODS: We performed targeted capture of 159 known deafness-related genes and next-generation sequencing in the proband who was tested negative for the twenty hotspot variants in four common deafness-related genes(GJB2, GJB3, SLC26A4 and MTRNR1); Clinical reassessments, including detailed audiological and ocular examinations were performed in the proband and his normal parents. RESULTS: We identified a novel heterozygous variant of CDH23:c.4567A > G (p.Asn1523Asp) in exon 37 (NM_022124), in conjunction with a reported mutation of CDH23:c.5101G > A (p.Glu1701Lys) in exon 40, to be a potentially pathogenic compound heterozygosity in the proband. The unaffected father has a heterozygous variant of CDH23:c.4567A > G, and the normal mother has another heterozygous variant, CDH23:c.5101G > A. The novel variant was absent in the 1000 Genomes Project. The clinical reassessments revealed binaural profound sensorineural hearing loss (DFNB12) without retinitis pigmentosa in the proband. CONCLUSIONS: This study demonstrates that the novel variant c.4567A > G (p.Asn1523Asp) in compound heterozygosity with c.5101G > A (p. Glu1701Lys) in the CDH23 gene is the main cause of DFNB12 in the proband. Simultaneously, this study provides a foundation to further elucidate the CDH23-related mechanisms of DFNB12. PMID- 29287850 TI - Readability of online patient education materials for velopharyngeal insufficiency. AB - OBJECTIVE: Evaluate the readability of online and mobile application health information about velopharyngeal insufficiency (VPI). METHODS: Top website and mobile application results for search terms "velopharyngeal insufficiency", "velopharyngeal dysfunction", "VPI", and "VPD" were analyzed. Readability was determined using 10 algorithms with Readability Studio Professional Edition (Oleander Software Ltd; Vandalia, OH). Subgroup analysis was performed based on search term and article source - academic hospital, general online resource, peer reviewed journal, or professional organization. RESULTS: 18 unique articles were identified. Overall mean reading grade level was a 12.89 +/- 2.9. The highest reading level among these articles was 15.47-approximately the level of a college senior. Articles from "velopharyngeal dysfunction" had the highest mean reading level (13.73 +/- 2.11), above "velopharyngeal insufficiency" (12.30 +/- 1.56) and "VPI" (11.66 +/- 1.70). Articles from peer-reviewed journals had the highest mean reading level (15.35 +/- 2.79), while articles from academic hospitals had the lowest (12.81 +/- 1.66). There were statistically significant differences in reading levels between the different search terms (P < 0.01) and article source types (P < 0.05). Only one mobile application was identified with VPI information, with a readability of 10.68. CONCLUSION: Despite published reading level guidelines, online patient education materials for VPI are disseminated with language too complex for most readers. There is also a lack of VPI-related mobile application data available for patients. Patients will benefit if future updates to websites and disseminated patient information are undertaken with health literacy in mind. Future studies will investigate patient comprehension of these materials. PMID- 29287851 TI - Hearing improvement with softband and implanted bone-anchored hearing devices and modified implantation surgery in patients with bilateral microtia-atresia. AB - OBJECTIVE: To evaluate auditory development and hearing improvement in patients with bilateral microtia-atresia using softband and implanted bone-anchored hearing devices and to modify the implantation surgery. METHODS: The subjects were divided into two groups: the softband group (40 infants, 3 months to 2 years old, Ponto softband) and the implanted group (6 patients, 6-28 years old, Ponto). The Infant-Toddler Meaning Auditory Integration Scale was used conducted to evaluate auditory development at baseline and after 3, 6, 12, and 24 months, and visual reinforcement audiometry was used to assess the auditory threshold in the softband group. In the implanted group, bone-anchored hearing devices were implanted combined with the auricular reconstruction surgery, and high-resolution CT was used to assess the deformity preoperatively. Auditory threshold and speech discrimination scores of the patients with implants were measured under the unaided, softband, and implanted conditions. RESULTS: Total Infant-Toddler Meaning Auditory Integration Scale scores in the softband group improved significantly and approached normal levels. The average visual reinforcement audiometry values under the unaided and softband conditions were 76.75 +/- 6.05 dB HL and 32.25 +/- 6.20 dB HL (P < 0.01), respectively. In the implanted group, the auditory thresholds under the unaided, softband, and implanted conditions were 59.17 +/- 3.76 dB HL, 32.5 +/- 2.74 dB HL, and 17.5 +/- 5.24 dB HL (P < 0.01), respectively. The respective speech discrimination scores were 23.33 +/- 14.72%, 77.17 +/- 6.46%, and 96.50 +/- 2.66% (P < 0.01). CONCLUSIONS: Using softband bone-anchored hearing devices is effective for auditory development and hearing improvement in infants with bilateral microtia-atresia. Wearing softband bone-anchored hearing devices before auricle reconstruction and combining bone anchored hearing device implantation with auricular reconstruction surgery may bethe optimal clinical choice for these patients, and results in more significant hearing improvement and minimal surgical and anesthetic injury. PMID- 29287852 TI - Low-set ears and associated anomalies in human foetuses. AB - OBJECTIVES: To determine the prevalence of low-set ears (LSE) in a group of human foetuses, to analyse the associated anomalies, and to review the development mechanisms possibly involved. METHODS: A total of 1759 human foetuses from spontaneous abortion were evaluated. Foetuses were obtained from the Foetuses and Embryos Collection of the Embryology Department of the Faculty of Medicine of the Autonomous University of Nuevo Leon. The Ethics Committee gave its approval for this study (EH-230-16). The position of the auricles was determined according to the standards recommended by the Elements of Morphology. Two study groups were created: foetuses with LSE and foetuses with normal ears. In both groups, a detailed examination of the external morphology was performed, followed by thoraco-abdominal micro dissection. Statistical analysis was performed. RESULTS: Two hundred two of the foetuses presented LSE (1148 per 10,000). In this group, 68.8% did not present associated anomalies, while 31.2% had an associated anomaly. The most frequently affected organ was the heart (53.6%), followed by the digestive tract (23.9%), urinary system (16.9%), head and neck (4.2%), and limbs (1.4%). In the group of foetuses with normal ears, only 7.4% of the specimens had associated anomalies, which was a significant difference compared with the LSE group. CONCLUSIONS: Based on the obtained results, we consider that LSE can be used as a sensitive indicator of major anomalies. It is recommended to include a systematic assessment of the position of the auricles in the initial clinical evaluation of any newborn. PMID- 29287853 TI - Musculo-mucous web velum and velopharyngeal dysfunction associated with 8q22.1 22.2 microduplication. AB - This report presents a rare case of isolated non-cleft velopharyngeal dysfunction (VPD). An eight-year-old child presented 1. a phenotypically unique band-gap pattern of the velar musculature with anteroposterior insertion; 2. a mosaic partial trisomy on chromosome 19 as well as microduplications on chromosomes 8 and 22. Following cytogenetic analysis, microduplication on chromosome 8 was found in another member of her family. A family history of VPI with hypernasality and nasal regurgitation was reported over three different generations on the patient's maternal side. Since only one case of velum malformation is found in this family, we cannot conclude to a link between the palatal anomaly or VPD and the DNA rearrangements. PMID- 29287854 TI - Systematic review of knowledge of, attitudes towards, and practices for newborn hearing screening among healthcare professionals. AB - INTRODUCTION: The success of newborn hearing screening programs lies in the timely identification, diagnosis, and management of children with hearing loss accomplished via a multidisciplinary newborn hearing screening (NHS) team. The team is typically comprised of various healthcare professionals who act as decision makers as well as facilitators for different stages in the screening process. Team members' knowledge of, attitudes towards, and practices for early hearing detection and intervention programs are critical for success and prevention of loss to follow up. In this context, it becomes crucial to understand their knowledge of, attitudes towards, and practices for towards newborn hearing screening. METHODS: A systematic review was conducted on the following databases; PubMed/Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, Science Direct and Cochrane Library. This search was carried out using various keywords such as practitioners, newborn hearing screening, knowledge, attitudes, and practices in different combinations. The review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. RESULTS: A total of 271 hits were obtained of which 20 articles were found suitable for inclusion in the final review. Overall, similar results were found regarding team members' knowledge of NHS programs, regardless of country of origin. Similarly, attitudes toward NHS programs were positive. Team members' experiences with NHS programs varied from country-to-country and across healthcare professionals. Results consistently showed gaps in team members' knowledge suggesting the need for outreach and professional education programs on NHS. CONCLUSION: NHS teams members from different countries, healthcare systems, and early hearing detection and intervention programs show gaps in critical knowledge warranting outreach and educational programs. PMID- 29287855 TI - Branchial anomalies in children: A report of 105 surgical cases. AB - BACKGROUND: Branchial anomalies (BAs) account for 20% of all congenital masses in children. We sought to review the incidence of involvement of individual anomalies, diagnostic methods, surgical treatment, and complications of BAs in children. In addition, we also classified our study and analyzed a congenital lower neck cutaneous fistula near the sternoclavicular joint that was thought to be the skin-side remnant of the fourth BAs. METHODS: We conducted a retrospective analysis of 105 children who were referred to our hospital from June 2009 to December 2016 for the treatment of BAs. RESULTS: In this series, there were 51 males and 54 females. The age at the time of operation varied from 19 days to 13 years, and the mean age was 4.5 years. A total of 33 (31.4%) cases presented with first BAs, 13 (12.4%) presented with second BAs, and 59 (56.2%) presented with third and fourth BAs, including 6 cases of congenital lower neck cutaneous fistula. Fistulectomy under general anesthesia was performed on all of them. For postoperative complications, 2 cases had temporary facial paralysis, 1 case had permanent facial paralysis, 4 cases had temporary recurrent laryngeal nerve injury. Recurrence occurred in 2 patients with first BAs after medium follow-up time of 3.6 years (6 months-8 years). CONCLUSIONS: BAs are common congenital head and neck lesions in children, and there are four distinct types (first, second, third and fourth anomalies). The incidence of third and fourth BAs in Asia maybe higher when compared with literature reports, second BAs seem rare in this population, but more research is needed to confirm this perspective. Diagnosis is not difficult with a proper knowledge of the anatomy of the BAs. The surgical procedures should be tailored depending on the various types, and complete excision of the fistula is the key to prevent recurrence. PMID- 29287856 TI - Comparison of three different adenoidectomy techniques in children - has the conventional technique been surpassed? AB - INTRODUCTION: Pharyngeal tonsil hyperplasia is the most frequent cause of nasal obstruction and chronic mouth breathing during childhood. Adenoidectomy is the procedure of choice for the resolution of these symptoms. It is not yet known, however, whether the conventional technique ("blind curettage") has been surpassed by more modern adenoidectomy techniques (video-assisted, with the aid of instruments). This study aimed to compare the conventional adenoidectomy technique with two other emerging techniques, performed in a reference otorhinolaryngology center. METHODS: This is a prospective and observational study of 33 children submitted to adenoidectomy using 3 different techniques that were followed up for a period of 3 months after surgery. The patients were divided into 3 different groups, according to the adenoidectomy technique: Group A (conventional technique - "blind curettage"); Group B (video-assisted adenoidectomy with microdebrider); Group C (video-assisted adenoidectomy with radiofrequency - Coblation(r)). The surgical time of each procedure was measured, being considered from the moment of insertion of the mouth gag until complete hemostasis was achieved. The questionnaire for quality of life OSA-18 was applied to all caregivers on the day of the surgery and 30-90 days after the procedure. Postoperative complications were also analyzed. RESULTS: For the entire patient sample, there was an improvement in quality of life after the surgery (p < 0.05). When analyzing the evolution of OSA-18 index, all groups showed statistically significant improvement, for all assessed domains. There were no statistically significant differences between the 3 techniques assessed for quality of life improvement after the surgery (p > 0.05). Regarding the duration of the procedure, the conventional technique showed the shortest surgical time when compared to the others (p < 0.05). No postoperative complications were noted, for any patient. CONCLUSIONS: The adenoidectomy resulted in improvement of quality of life, and there were no major postoperative complications, for all operated children, regardless of the technique used. The conventional technique was faster when compared to the more modern adenoidectomy techniques. PMID- 29287857 TI - A novel technique for unilateral supraglottoplasty. AB - OBJECTIVES: Traditional supraglottoplasty for pediatric laryngomalacia is most commonly conducted with either CO2 laser or cold steel instruments. While the procedure enjoys high success rates, serious complications such as excessive bleeding, supraglottic stenosis and aspiration can occur. Unilateral coblation supraglottoplasty may reduce this risk, but data on respiratory and swallowing outcomes are lacking. This study reports our experiences with unilateral coblation supraglottoplasty. METHODS: Pediatric patients with severe congenital laryngomalacia who underwent unilateral supraglottoplasty at a single institution from 2013 to 2016 were retrospectively reviewed. Bipolar radiofrequency ablation (Coblation) was utilized with partial arytenoidectomy, aryepiglottoplasty, and advancement of mucosal flaps. Outcome measures included apnea-hypopnea index (AHI), weight-by-age percentile, and decannulation rate. RESULTS: Twelve patients were included with an average age of 13.1 months (range 2-28 months). In patients without tracheostomy, 88% had complete resolution of respiratory symptoms, while the remainder had significant improvement. In patients without gastrostomy tubes, there was an average increase in weight-age percentile of 6.1, 7.8, and 15.3 points at 1, 3, and 6 months postoperatively, respectively. Three patients had complete polysomnography data with a mean preoperative AHI of 19.3 and postoperative AHI of 4.0. Three of four patients with tracheostomy have been decannulated at a mean follow-up of 1.5 years. There were no early or late postoperative complications and no revision supraglottoplasty. CONCLUSION: Unilateral supraglottoplasty with bipolar radiofrequency ablation can improve respiratory symptoms and decrease OSA severity in severe congenital laryngomalacia. This technique is safe and can lead to substantial improvement in AHI in patients with OSA. PMID- 29287858 TI - Designing a tissue-engineered tracheal scaffold for preclinical evaluation. AB - OBJECTIVE: Recent efforts to tissue engineer long-segment tracheal grafts have been complicated by stenosis and malacia. It has been proposed that both the mechanical characteristics and cell seeding capacity of TETG scaffolds are integral to graft performance. Our aim was to design a tracheal construct that approximates the biomechanical properties of native sheep trachea and optimizes seeding with bone marrow derived mononuclear cells prior to preclinical evaluation in an ovine model. METHODS: A solution of 8% polyethylene terephthalate (PET) and 3% polyurethane (PU) was prepared at a ratio of either 8:2 or 2:8 and electrospun onto a custom stainless steel mandrel designed to match the dimensional measurements of the juvenile sheep trachea. 3D-printed porous or solid polycarbonate C-shaped rings were embedded within the scaffolds during electrospinning. The scaffolds underwent compression testing in the anterior-posterior and lateral-medial axes and the biomechanical profiles compared to that of a juvenile ovine trachea. The most biomimetic constructs then underwent vacuum seeding with ovine bone marrow derived mononuclear cells. Fluorometric DNA assay was used to quantify scaffold seeding. RESULTS: Both porous and solid rings approximated the biomechanics of the native ovine trachea, but the porous rings were most biomimetic. The load-displacement curve of scaffolds fabricated from a ratio of 2:8 PET:PU most closely mimicked that of native trachea in the anterior-posterior and medial-lateral axes. Solid C-ringed scaffolds had a greater cell seeding efficiency when compared to porous ringed scaffolds (Solid: 19 * 104 vs. Porous: 9.6 * 104 cells/mm3, p = 0.0098). CONCLUSION: A long segment tracheal graft composed of 2:8 PET:PU with solid C rings approximates the biomechanics of the native ovine trachea and demonstrates superior cell seeding capacity of the two prototypes tested. Further preclinical studies using this graft design in vivo would inform the rational design of an optimal TETG scaffold. PMID- 29287859 TI - Hearing loss in children with primary ciliary dyskinesia. AB - OBJECTIVES: To evaluate the type and severity of hearing impairment in pediatric patients with primary ciliary dyskinesia (PCD) and relate these measures to patient demographics, treatment options, and other otologic factors. METHODS: A retrospective analysis of children with a diagnosis of PCD, Kartagener's syndrome, or situs inversus in the AudGen Database was conducted. Audiograms were analyzed for type of hearing loss (HL), severity, laterality, and progression. Medical charts were reviewed to identify factors that influence severity and progression of hearing loss. RESULTS: 56 patients met inclusion criteria and 42 patients had HL. 66.6% had bilateral and 33.3% had unilateral loss (70 total ears with HL). Conductive hearing loss (CHL) was the most common type of HL, though 30% of children had some sensorineural component to their hearing loss. 92.9% of children with HL received at least one diagnosis of otitis media, but HL did not improve in the majority (77.8%) of ears in our study regardless of ear tube placement. CONCLUSIONS: Slight to mild CHL and all types of otitis media are prevalent among patients with PCD, and some of these children have sensorineural hearing loss (SNHL). All patients diagnosed with situs inversus at birth should be evaluated by an otolaryngologist. PMID- 29287860 TI - Primary cervical leiomyoma: A rare cause of a posterior neck mass in a pediatric patient. AB - A 13-year-old male presents for evaluation of a right-sided posterolateral neck mass, first noted four years prior to presentation; incisional biopsy two years ago suggested a benign lymph node. Recent growth and increased pain prompted referral to our tertiary care center. MR imaging revealed a densely calcified mass in the right posterior paraspinous muscles with intense enhancement with gadolinium contrast, approximately 5 cm * 2.8 cm x 4.6 cm. Incisional biopsy showed leiomyoma with extensive dystrophic calcifications. This case describes a rare finding of extraesophageal leiomyoma of the neck; this is only the second such case reported in a pediatric patient. PMID- 29287862 TI - Using simulators to teach pediatric airway procedures in an international setting. AB - INTRODUCTION: There has been a growing shift towards endoscopic management of laryngeal procedures in pediatric otolaryngology. There still appears to be a shortage of pediatric otolaryngology programs and children's hospitals worldwide where physicians can learn and practice these skills. Laryngeal simulation models have the potential to be part of the educational training of physicians who lack exposure to relatively uncommon pediatric otolaryngologic pathology. OBJECTIVES: The objective of this study was to assess the utility of pediatric laryngeal models to teach laryngeal pathology to physicians at an international meeting. METHODS: Pediatric laryngeal models were assessed by participants at an international pediatric otolaryngology meeting. Participants provided demographic information and previous experience with pediatric airways. Participants then performed simulated surgery on these models and evaluated them using both a previously validated Tissue Likeness Scale and a pre-simulation to post simulation confidence scale. RESULTS: Participants reported significant subjective improvement in confidence level after use of the simulation models (p < 0.05). Participants reported realistic representations of human anatomy and pathology. The models' tissue mechanics were adequate to practice operative technique including the ability to incise, suture, and suspend models. CONCLUSION: The pediatric laryngeal models demonstrate high quality anatomy, which is easy manipulated with surgical instruments. These models allow both trainees and surgeons to practice time-sensitive airway surgeries in a safe and controlled environment. PMID- 29287861 TI - Bilateral cochlear implantation or bimodal listening in the paediatric population: Retrospective analysis of decisive criteria. AB - INTRODUCTION: In children with bilateral severe to profound hearing loss, bilateral hearing can be achieved by either bimodal stimulation (CIHA) or bilateral cochlear implantation (BICI). The aim of this study was to analyse the audiologic test protocol that is currently applied to make decisions regarding the bilateral hearing modality in the paediatric population. METHODS: Pre- and postoperative audiologic test results of 21 CIHA, 19 sequential BICI and 12 simultaneous BICI children were examined retrospectively. RESULTS: Deciding between either simultaneous BICI or unilateral implantation was mainly based on the infant's preoperative Auditory Brainstem Response thresholds. Evolution from CIHA to sequential BICI was mainly based on the audiometric test results in the contralateral (hearing aid) ear after unilateral cochlear implantation. Preoperative audiometric thresholds in the hearing aid ear were significantly better in CIHA versus sequential BICI children (p < 0.001 and p = 0.001 in unaided and aided condition, respectively). Decisive values obtained in the hearing aid ear in favour of BICI were: An average hearing threshold measured at 0.5, 1, 2 and 4 kHz of at least 93 dB HL without, and at least 52 dB HL with hearing aid together with a 40% aided speech recognition score and a 70% aided score on the phoneme discrimination subtest of the Auditory Speech Sounds Evaluation test battery. CONCLUSIONS: Although pure tone audiometry offers no information about bimodal benefit, it remains the most obvious audiometric evaluation in the decision process on the mode of bilateral stimulation in the paediatric population. A theoretical test protocol for adequate evaluation of bimodal benefit in the paediatric population is proposed. PMID- 29287863 TI - Demonstration of analgesic effect of intranasal ketamine and intranasal fentanyl for postoperative pain after pediatric tonsillectomy. AB - OBJECTIVE: Tonsillectomy is one of the oldest and most commonly performed surgical procedure in otolaryngology. Postoperative pain management is still an unsolved problem. In this study, our aim is to demonstrate the efficacy of intranasal ketamine and intranasal fentanyl for postoperative pain relief after tonsillectomy in children. MATERIAL AND METHOD: This randomized-controlled study was conducted to evaluate the effects of intranasal ketamine and intranasal fentanyl in children undergoing tonsillectomy. Tonsillectomy performed in 63 children were randomized into three groups. Group I received: Intravenous paracetamol (10 mg/kg), Group II received intranasal ketamine (1.5 mg/kg ketamine), Group III received intranasal fentanyl (1.5 mcg/kg). The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale scores were recorded at 15, 30, 60 min, 2 h, 6hr, 12 h and 24 h postoperatively. Patients were interviewed on the day after surgery to assess the postoperative pain, nightmares, hallucinations, nausea, vomiting and bleeding. RESULTS: Intranasal ketamine and intranasal fentanyl provided significantly stronger analgesic affects compared to intravenous paracetamol administration at postoperative 15, 30, 60 min and at 2, 6, 12 and 24 h in CHEOPS (p < 0.05). Sedative effects were observed in three patients in the intranasal ketamine administration group. No such sedative effect was seen in the groups that received intranasal fentanyl and intravenous paracetamol in Wilson Sedation Scale (p < 0.05). Cognitive impairment, constipation, nausea, vomiting and bleeding were not observed in any of the groups. CONCLUSION: This study showed that either intranasal ketamine and intranasal fentanyl were more effective than paracetamol for postoperative analgesia after pediatric tonsillectomy. Sedative effects were observed in three patients with the group of intranasal ketamine. There was no significant difference in the efficacy of IN Ketamine and IN Fentanyl for post tonsillectomy pain. PMID- 29287864 TI - Identification of two novel pathogenic compound heterozygous MYO7A mutations in Usher syndrome by whole exome sequencing. AB - The current study aims to identify the pathogenic sites in a core pedigree of Usher syndrome (USH). A core pedigree of USH was analyzed by whole exome sequencing (WES). Mutations were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing. Two pathogenic variations (c.849+2T>C and c.5994G>A) in MYO7A were successfully identified and individually separated from parents. One variant (c.849+2T>C) was nonsense mutation, causing the protein terminated in advance, and the other one (c.5994G>A) located near the boundary of exon could cause aberrant splicing. This study provides a meaningful exploration for identification of clinical core genetic pedigrees. PMID- 29287865 TI - Adaptation and validation of Mandarin Chinese version of the pediatric Voice Handicap Index (pVHI). AB - OBJECTIVE: The aim of this study was to adapt and validate the English version of pediatric voice handicap index (pVHI) into Mandarin Chinese.? METHODS: A cross sectional study was performed from May 2016 to April 2017. A total of 367 parents participated in this study, and 338 parents completed the translated questionnaire without missing data, including 213 parents of children with voice disorders (patients group), and 125 parents of children without voice disorders (control group). The internal consistency, test-retest reliability, contents validity, construct validity, clinical validity, and cutoff point were calculated. RESULTS: The most common voice disorder in the patients group was vocal fold nodules (77.9%), followed by chronic laryngitis (18.8%), and vocal fold polyps (3.3%). The prevalence for voice disorders was higher in boys (67.1%) than girls (32.9%). The most common vocal misuse and abuse habit was shouting loudly (n = 186, 87.3%), followed by speaking for a long time (n = 158, 74.2%), and crying loudly (n = 99, 46.5%). The internal consistency for the Mandarin Chinese version of pVHI was excellent in patients group (Cronbach alpha = 0.95). The inter-class correlation coefficient indicated strong test-retest reliability (ICC = 0.99). The principal-component analysis demonstrated three-factor eigenvalues greater than 1, and the cumulative proportion was 66.23%. The mean total scores and mean subscales scores were significantly higher in the patients group than the control group (p < 0.05). The physical domain had the highest mean score among the three subscales (functional, physical and emotional) in the patients group. The optimal cutoff point of the Mandarin Chinese version of pVHI was 9.5 points with a sensitivity of 80.3% and a specificity of 84.8%. CONCLUSION: The Mandarin Chinese version of pVHI was a reliable and valid tool to assess the parents' perception about their children's voice disorders. It is recommended that it can be used as a screening tool for discriminating between children with and without dysphonia. PMID- 29287866 TI - Childhood hearing loss is a key feature of CAPOS syndrome: A case report. AB - CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare neurological disorder, recently associated with the c.2452G > A hotspot mutation in the ATP1A3 gene, with sensorineural hearing loss as a prominent feature. We herein report on a girl who has experienced hearing loss for three years following an initial encephalitic episode when aged 15 months old. CAPOS was diagnosed only when she was six years old by targeted testing whilst she displayed optic atrophy, cerebellar signs and areflexia. CAPOS syndrome should be considered in the differential diagnosis of acquired childhood deafness, prompting clinicians to search for associated neurological features. PMID- 29287867 TI - SLC52A2 mutations cause SCABD2 phenotype: A second report. AB - INTRODUCTION: Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults. Most ARCAs are heterogeneous with respect to age at onset, severity of disease progression, and frequency of extracerebellar and systemic signs. METHODS: The phenotype of a consanguineous Iranian family was characterized using clinical testing and pedigree analysis. Whole-exome sequencing was used to identify the disease-causing gene in this family. RESULTS AND CONCLUSION: Using whole exome sequencing (WES), a novel missense mutation in SLC52A2 gene is reported in a consanguineous Iranian family with progressive severe hearing loss, optic atrophy and ataxia. This is the second report of the genotype-phenotype correlation between this syndrome named spinocerebellar ataxia with blindness and deafness type 2 (SCABD2) and SLC52A2 gene. PMID- 29287868 TI - Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I. AB - OBJECTIVES: Waardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. METHODS: Complete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. RESULTS: The two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. CONCLUSION: These previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies. PMID- 29287869 TI - Health-related quality of life in children with dysphonia and validation of the French Pediatric Voice Handicap Index. AB - OBJECTIVE: voice disorders are common in the pediatric population and can negatively affect children's quality of life. The pediatric voice handicap Index (pVHI) is a valid instrument to assess parental perception of their children voice but it is not translated into French language. The aim of the present study was to adapt a French version of the pVHI and to evaluate its psychometric properties including construct validity, reliability, and some aspects of external validity. PATIENTS AND METHOD: we performed a cross sectional study including 32 dysphonic children and 60 children with no history of voice problems between 3 and 12 years of age. The original pVHI was translated into French language according to forward-backward rules and then administered to parents or caregivers. Construct validity and internal consistency were explored using confirmatory factor analysis and Cronbach's alpha. The questionnaire was filled twice to assess test-retest reliability using the intra-class correlation coefficient. The external validity was explored by comparing the French pVHI total and subscales scores between dysphonic and asymptomatic children. Correlations between the French pVHI and both the perceptual GRBAS scale and the health-related quality of life (HRQOL) survey "Vecu et Sante Percu de l'Adolescent et de l'Enfant" (VSP-Ap) were also performed. RESULTS: the structure of the French pVHI showed a good fit with excellent reliability (alpha = 0.929) and high test-retest reliability. Significant differences were found between the group of dysphonic children and the control group (p < 0.001). The French pVHI scores were positively correlated to all parameters of the GRBAS scale (p < 0.05). Significant negative correlations were found between the Functional domain of the pVHI and various domains of the VSP-Ap as Leisure Activities, Schooling and Sentimental Relationship (p < 0.05). CONCLUSION: the French pVHI is considered to be a valid and reliable instrument to assess voice-related quality of life in children with voice disorder. We recommend its use in the multidimensional protocols for assessing voice disorder in the pediatric population. PMID- 29287870 TI - Postoperative bradycardia following adenotonsillectomy in children: Does intraoperative administration of dexmedetomidine play a role? AB - INTRODUCTION: Dexmedetomidine is a novel pharmacologic agent that has become a frequently used adjunct during care of pediatric patients with obstructive sleep apnea (OSA) undergoing tonsillectomy. While generally safe and effective, dexmedetomidine is associated with adverse effects of hypotension and bradycardia from its central sympatholytic effects. Due to safety concerns, our institution routinely admits patients with OSA for overnight cardiorespiratory monitoring following tonsillectomy. With such monitoring, we have anecdotally noted bradycardia in our patients and sought to investigate whether this was related to the increased use of intra-operative dexmedetomidine. METHODS: We retrospectively reviewed records over an 11-month period to compare the incidence of postoperative bradycardia following hospital admission for tonsillectomy in patients who received dexmedetomidine versus those who did not. RESULTS: The study cohort included 921 patients (371 received dexmedetomidine and 550 did not). Bradycardia was asymptomatically noted in 66 patients (7.2%). No patient required medical intervention for the bradycardia or developed clinical symptoms. There was no association of bradycardia with the intra-operative administration of dexmedetomidine (8.9% of patients who received dexmetomidine vs. 9.4% who did not). In multivariable analysis, bradycardia was more common among older patients, with the administration of topical or injected lidocaine, and with specific associated procedures (inferior turbinate coblation with out-fracture or direct laryngoscopy and bronchoscopy). CONCLUSION: The increased incidence of asymptomatic bradycardia in our post-adenotonsillectomy patients seemed to relate more to increased utilization of postoperative cardiac telemetry, and did not appear associated with the use of dexmedetomidine use intra-operatively. PMID- 29287871 TI - Pediatric laryngeal cleft repair and dysphagia. AB - OBJECTIVE: To describe changes in diet and swallow function in patients with a laryngeal cleft after surgical repair of the laryngeal cleft. METHODS: Retrospective case series performed using chart review. Primary outcomes were diet and swallow function before and after laryngeal cleft repair. Clinical evaluation and video fluoroscopic swallow studies (VFSS) were used to assess pre- and post intervention swallowing. RESULTS: 16 pediatric patients were included in this study. Preoperatively, 14 (88%) patients had diet restrictions. Postoperatively, 12 (75%) patients tolerated a regular diet without limitation. 4 (25%) patients had no reduction in diet restrictions over the course of this study. For the 10 patients who transitioned to a regular diet postoperatively, a median of 300 days (range: 26 days - 3 years) passed to document achieving a regular diet. This was corroborated by an increase in normal oral and pharyngeal phase swallow function on VFSS postoperatively when compared with preoperative VFSS results. CONCLUSION: Dysphagia improves in most patients after laryngeal cleft repair. The range in time to a normal diet was wide. This may facilitate improved preoperative counseling and preparation of families' expectations. PMID- 29287872 TI - What to do with medialized tympanostomy tubes? A survey of pediatric otolaryngologists. AB - INTRODUCTION: Tympanostomy tube placement is the most common surgical procedure performed in children. Medial migration of a tympanostomy tube is a rare occurrence where the tube migrates into the middle ear cavity as opposed to its normal extrusion into the external auditory canal. Whether medialized tympanostomy tubes should be surgically removed in asymptomatic patients is controversial. The objective of this study was to determine experience and management approach of medialized tympanostomy tubes among pediatric otolaryngologists. METHODS: A 12-question cross-section survey was designed and distributed to the American Society of Pediatric Otolaryngology (ASPO) members. The survey study was granted McGill University institutional review board and ASPO research committee approval. The survey data were filtered and cross tabulated. Descriptive statistics were generated. RESULTS: 128 pediatric otolaryngologists completed the 12-question survey. The majority of respondents had experienced at least one case of medialized tympanostomy tube (90.6%). The majority of patients (82.0%) were asymptomatic. 74 out of 128 respondents (57.8%) indicated that they would not remove a medialized tube in an asymptomatic patient. However, 7.0% of those respondents clarified that they would proceed to surgical removal if the patient were undergoing general anesthesia for another surgery. 30.5% of respondents indicated that they would surgically remove the tube even if the patient were asymptomatic. 6.3% of respondents indicated that opted management in children would be based on a shared decision with parents. Most respondents (80.5%) did not experience complications with surgical removal nor with elected observation. CONCLUSION: There is no consensus among pediatric otolaryngologists regarding the necessity of surgically removing a medialized tympanostomy tube in asymptomatic patients. The survey suggests that both options are acceptable. If observation is chosen, it is important that parents are well informed of the potential long-term sequelae of a medialized tube and advised to consult if symptoms occur. PMID- 29287873 TI - Barriers to pediatric cochlear implantation: A parental survey. AB - OBJECTIVE: This study aims to (1) determine barriers in the pediatric cochlear implantation process specific to publicly insured patients, wherein delayed implantation has been reported, and (2) compare the perceived barriers between publicly and privately insured patients. SETTING: Tertiary care cochlear implantation center at academic pediatric hospital. STUDY DESIGN: Cross-sectional survey, retrospective chart review. METHODS: The validated, 39 item Barriers to Care Questionnaire was administered to the parents of 80 recipients of cochlear implantation by two surgeons between 2013 and 2016. Survey results and diagnosis to implant interval were compared based on public or private insurance status. Two-tailed Mann-Whitney and Fisher's exact test was used for statistical analysis. RESULTS: Of 110 cochlear implants, 27 of 80 (34%) English-speaking parents completed the survey. 15 were privately insured and 12 were publicly insured. 23 of 27 respondents received cochlear implantation for pre-lingual sensorineural hearing loss. Publicly insured patients had significantly longer median time from diagnosis to implant than privately insured (19 vs. 8 mo, p = 0.01). The three worst scoring barrier categories for privately insured families in order were Pragmatics, Expectations, and Marginalization, whereas for publicly insured families it was Pragmatics, Skills, and Expectations. The worst scoring question for privately insured patients was "Having to take time off work". For the publicly insured, it was "Lack of communication." CONCLUSION: Privately insured patients reported more barriers on the Barriers to Care Questionnaire than publicly insured patients did. Although pragmatics was the worst-scoring barrier category for both groups, difficulties found on the survey ranked differently for each group. This information can help providers address disparities and access barriers for vulnerable patients. PMID- 29287874 TI - The impact of a resident-run review curriculum and USMLE scores on the Otolaryngology in-service exam. AB - OBJECTIVE: Describe the association of USMLE Step 1 scores and the institution of a dedicated board review curriculum with resident performance on the Otolaryngology training examination. STUDY DESIGN: Retrospective cross sectional study. METHODS: We reviewed American Board of Otolaryngology Training Examination (OTE) scores for an otolaryngology residency program between 2005 and 2016. USMLE Step 1 scores were collected. In 2011 a resident-run OTE review curriculum was instituted with the goal of improving test preparation. Scores were compared before and after curriculum institution. Linear regression was performed to identify predictors of OTE scores. RESULTS: 47 residents were evaluated, 24 before and 23 after instituting the curriculum. There was a moderate correlation between USMLE step 1 scores and OTE scores for all years. For PGY-2 residents, mean OTE scores improved from 25th percentile to 41st percentile after institution of the review curriculum (p = 0.05). PGY 3-5 residents demonstrated no significant improvement. On multivariate linear regression, after controlling for USMLE step 1 scores, a dedicated board review curriculum predicted a 23-point percentile improvement in OTE scores for PGY-2 residents (p = 0.003). For other post-graduate years, the review curriculum did not predict score improvement. CONCLUSION: USMLE step 1 scores are moderately correlated with OTE performance. A dedicated OTE review curriculum may improve OTE scores for PGY-2 residents, but such a curriculum may have less benefit for intermediate- and senior-level residents. LEVEL OF EVIDENCE: 4. PMID- 29287875 TI - Coblation versus microdebrider in pediatric adenoidectomy. AB - OBJECTIVE: To compare and contrast coblation and microdebrider with touch-up electrocautery (ME) for adenoidectomy in children. METHODS: Patients <18 years old undergoing adenoidectomy without tonsillectomy were selected for this prospective, single-blinded, randomized controlled trial. Participants were enrolled into one of two groups based on birth date: coblation or ME. The surgeons completed a standard survey about intraoperative factors for each method. Recovery nurses filled out a standardized survey postoperatively. A third standardized survey was completed via a phone interview with the parent or patient caregiver on postoperative day 3 to assess procedure outcomes. The survey results were then compared using ANOVA statistical analysis. RESULTS: 50 patients were enrolled in the coblation group and 51 were enrolled in the ME group. There was no significant difference in mean age between the coblation (4.96 years) and ME groups (4.58 years) (p = 0.525). The mean time (in minutes) for coblation (5.50) was significantly lower than ME (9.47) when controlling for the confounder: surgical site exposure (p < 0.001). The surgical time was significantly influenced by the quality of exposure/visualization (p = 0.037). The coblator method had significantly less intraoperative blood loss compared to ME (p < 0.001). There was a statistically significant difference between coblation (1.53) and ME (2.05) for days of pain (p = 0.045) when controlling for the confounder adenoid size. CONCLUSION: In our study we found that coblation demonstrated significantly less intraoperative time and less blood loss, as well as a shorter duration of postoperative pain, when compared to ME for adenoidectomy. PMID- 29287876 TI - Effect of preoperative visiting operation room on emergence agitation in preschool children under sevoflurane anesthesia. AB - BACKGROUND: Emergence agitation (EA) is a common complication in children during recovery from sevoflurane anesthesia with an high incidence. The main objective of this study was to compare the effects of preoperative visiting operation room (PVOR) to administration of propofol at the end of anesthesia on EA in preschool children under sevoflurane anesthesia. METHODS: Sixty-nine preschool children aged from 3 to 6 years scheduled for tonsillectomy under sevoflurane anesthesia were randomly allocated to one of the three groups to receive either PVOR (Group PV), routine preoperative visit (Group RV) or routine preoperative visit plus propofol (Group RP), 23 patients were included in each group. General anesthesia was induced and maintained with sevoflurane. Parental separation status score, mask acceptance score, Aono's four point score and pediatric anesthesia emergence delirium (PAED) score and incidence of EA were recorded. PAED score >10 were regarded as EA. Recovery profile and adverse events were also recorded. RESULT: Parental separation status score and mask acceptance score in group PV was significantly lower than that in group RV and group RP (P < 0.05); Aono's four point score, PAED score and incidence of EA in group PV and group RP was significantly lower than that in group RV (P < 0.05); Time to extubation and time to interaction in group PV and group RV was significantly shorter than that in group RP (P < 0.05); POV and rescue by fentanyl in group PV and group RP was significantly lower than that in group RV(P < 0.05). CONCLUSION: PVOR can effectively reduce the incidence of EA as well as administration of propofol without additional medical expenses and other adverse effects. PMID- 29287877 TI - Evaluation and remediation of central auditory processing disorders in children with autism spectrum disorders. AB - OBJECTIVES: This study was carried out to assess various skills of central auditory processing (CAP) in children with autism spectrum disorders (ASD) and to evaluate the efficacy of auditory training in these children. METHODS: This study is a non-randomized clinical experiment. 30 high functioning ASD children aged from 7 to 12 years were included in the study. They underwent behavioral assessments of CAP skills with subsequent remediation by dichotic training therapy for the children who revealed dichotic deficits. RESULTS: Scores of CAP skills in ASD children are wide-ranging from completely normal to substantially defective and generally lower than those of typically developing children. By auditory training, ASD children improved their dichotic deficits as well as other untrained areas of auditory and language processing skills. CONCLUSIONS: A group of ASD children showed different degrees of abnormalities in CAP that could be measured behaviorally and achieved benefits from auditory training in improving their dichotic listening, auditory and language processing skills. PMID- 29287878 TI - Closure of fistula of the hard palate with two layers of mucoperiosteum. AB - OBJECTIVE: Oronasal fistula represents a functional problem, as it may result in nasal regurgitation of food and fluids and it also leads to hypernasal speech. Many methods have been proposed for its closure with a high recurrence rate. The aim of this study was to assess the efficacy of closure of hard palate fistula by two layers of mucoperiosteal flaps. METHODS: Eighteen patients with fistula of the hard palate were included. The fistula was repaired by two layers of mucoperiosteal flaps; the first layer was created from the mucoperiosteum surrounding the fistula as bilateral hinge flaps and the second layer was formed of a rotational flap based on the greater palatine artery. Pre- and postoperative clinical assessment was performed. RESULTS: The etiology of fistulas was previous cleft palate repair in 13 patients, previous nasal septal surgery in 3 patients, and untreated sharp accidental trauma to the palate in 2 patients. All patients presented with nasal regurgitation and hypernasal speech. Complete closure of all fistulas was achieved at first attempt, with no recurrence through the follow up period. CONCLUSIONS: Closure of oronasal fistula by two layers of mucoperiosteal flaps is an effective method and it has neither complications nor recurrence. PMID- 29287879 TI - A novel splicing mutation in SMPX is linked to nonsyndromic progressive hearing loss. AB - OBJECTIVE: X-linked nonsyndromic hearing impairment is the rarest form of genetic hearing loss and represents only a minor fraction of all cases. The aim of this study was to investigate the cause of X-linked nonsyndromic sensorineural hearing loss in a three-generation American family. METHODS: Whole-exome sequencing and co-segregation analysis were used to identify disease-causing genes. RESULTS: In this study, we described in detail the clinical characteristics of the family and identified a novel frameshift mutation creating a premature stop codon (c.133-1 G > A, p.(Gly45fs*36)) of SMPX. The loss-of-function mutation was co-segregated with the progressive hearing loss phenotype and was absent in 200 normal controls. CONCLUSIONS: We report the first SMPX (DFNX4) mutation in a North American family. Our findings contribute to the existing genotypic and phenotypic spectrum of SMPX associated hearing loss. Furthermore, our data suggest that exome sequencing is promising in the genetic diagnosis of hearing loss. PMID- 29287880 TI - Revisits after pediatric tracheotomy: Airway concerns result in returns. AB - OBJECTIVES: Children undergoing tracheotomy represent a medically vulnerable patient population, and understanding the reasons for revisiting the hospital setting following tracheotomy is critical for improving the quality of care for these patients. This study aims to investigate the incidence and characteristics of revisits following pediatric tracheotomy. METHODS: Cross-sectional, population based study using state databases. The State Inpatient Databases and State Emergency Department Databases for California, Florida, Iowa and New York 2010-11 were linked and examined for cases of pediatric tracheotomy (patients < 18.0 years) and corresponding subsequent 30-day post-discharge revisits. Demographic and descriptive data were analyzed determining the revisit rate, revisit diagnoses, procedures, and discharge dispositions. RESULTS: 2,248 pediatric tracheotomy cases were extracted (60.8% male, mean age 8.3 years). There were 373 inpatient or emergency department revisits (30-day revisit rate, 16.6%), of which 34.3% occurred within 48 h after discharge. Of these, 59.2% were inpatient readmissions. There were <=10 deaths during these revisits (30-day revisit mortality rate, <=2.7%). The most common primary revisit diagnoses were "fitting of prosthesis and adjustment of devices" (25.7%, likely representing adjustment/replacement of the tracheotomy tube), respiratory failure (11.0%), intracranial injury (5.4%), pneumonia (4.0%), "other upper respiratory disease" (3.8%), and "complications of surgical procedures or medical care" (3.8%). The most common revisit procedures were endotracheal intubation (11.4%), mechanical ventilation (8.8%), and replacement of tracheostomy tube (<=2.7%). Children discharged to a skilled care facility (47.1%) were more likely than those discharged to home (52.9%) to have a revisit (23.3% versus 12.0%, respectively; p < 0.001). CONCLUSIONS: Children undergoing tracheotomy have a substantial 30-day revisit rate, most notably during the first 48 h after discharge, often involving tracheotomy tube or pulmonary complications. Improvements in discharge planning should target prevention of these complications. PMID- 29287881 TI - Endonasal endoscopic nasopharyngectomy for the treatment of nasopharyngeal papillary adenocarcinoma: Report of a rare case. AB - We report a case of low-grade nasopharyngeal papillary adenocarcinoma in a 9 year old male that was diagnosed incidentally after an adenoidectomy procedure and treated with endonasal endoscopic nasopharyngectomy without any adjuvant therapy. The patient has been followed up for 3 years with no evidence of recurrence. We point out the importance of preoperative fiberoptic nasopharyngoscopy in the absence of longstanding symptoms in school-aged children and histopathologic examination of adenoidectomy specimens in the presence of atypical findings. We also suggest endonasal endoscopic resection in case of papillary adenocarcinoma. PMID- 29287882 TI - Changes in the epidemiology and clinical features of acute mastoiditis following the introduction of the pneumococcal conjugate vaccine. AB - OBJECTIVES: Seven years after the introduction of the pneumococcal conjugate vaccines (PCV) in Israel, its effect on the incidence and severity of episodes of acute mastoiditis (AM) remains unclear. The primary objective of this study was to determine the incidence of AM and describe its clinical features in children during the years that followed the introduction of the PCV13 in comparison with the pre-PCV period. METHODS: Included in this retrospective comparative case series were all pediatric patients diagnosed with AM between Jan. 2007 and Dec. 2015 in one tertiary medical center. The patients were divided into 3 groups: pre PCV, post-PCV7 (July 2009 through Dec. 2010) and post-PCV13 (Jan. 2011 through Dec. 2015). The patients' medical records were reviewed, and data on age at presentation, gender, presenting signs, bacterial ear cultures, hospitalization course, complications, surgical interventions, inflammatory response and outcome were retrieved and compared between the groups. Comparison was made between the pre-PCV and the post-PCV13 groups. RESULTS: 216 children were identified for analysis, 80 children in the pre-PCV period, 31 in the post-PCV7 period and 105 in the post-PCV13 period. Their mean age was 2.6 years. The number of AM cases per 1000 visits at the emergency room decreased by 46% in the post-PCV13 period compared to the pre-PCV period. There was no difference in the rate of AM between the post-PCV7 and post-PCV13 periods. No differences were found in age, gender, hospitalization length, C-reactive protein level, white blood cell count, rate of surgical interventions (mastoidectomy and incision and drainage) and rate of complications between the 3 groups. CONCLUSION: The incidence of AM was lower in the post-PCV13 period compared to the pre-PCV period. The rate of AM complications, however, has not changed, nor has the number of mastoidectomies. PMID- 29287883 TI - Microarray analysis of lncRNA and mRNA expression profiles in mice with allergic rhinitis. AB - OBJECTIVES: We aimed to identify the effect of lncRNAs in CD4+ T cells on Allergic rhinitis (AR). METHODS: The present study conducted a microarray to identify the expression profiles of lncRNA and mRNA in CD4+ T cells in both AR murine models and normal controls. And qRT-PCR was used to confirm the results. GO and KEGG enrichment analysis were used to show all related pathways and a co expression network was conducted to find lncRNAs which have high correlation with these pathways. RESULTS: The results showed that the two groups contained a total of 158 deregulated lncRNAs, of which 110 were upregulated and 48 were downregulated. And positive regulation of calcium ion transport, B cell activation, chemokine-signaling pathways and calcium-signaling pathways may be involved in the development of T cells in AR pathology. Finally, we can find the differentially expressed mRNA in the pathways related to T cell differentiation correlated with many deregulated lncRNAs. CONCLUSIONS: The present study was the first to show the differential expression profiles of lncRNAs in the CD4+ T cells of an AR murine model, which may provide significant insights into AR pathogenesis and offer new treatment targets to alleviate it. PMID- 29287884 TI - Effects of transient auditory deprivation during critical periods on the development of auditory temporal processing. AB - OBJECTIVES: The central auditory pathway matures through sensory experiences and it is known that sensory experiences during periods called critical periods exert an important influence on brain development. The present study aimed to investigate whether temporary auditory deprivation during critical periods (CPs) could have a detrimental effect on the development of auditory temporal processing. MATERIALS AND METHODS: Twelve neonatal rats were randomly assigned to control and study groups; Study group experienced temporary (18-20 days) auditory deprivation during CPs (Early deprivation study group). Outcome measures included changes in auditory brainstem response (ABR), gap prepulse inhibition of the acoustic startle reflex (GPIAS), and gap detection threshold (GDT). To further delineate the specific role of CPs in the outcome measures above, the same paradigm was applied in adult rats (Late deprivation group) and the findings were compared with those of the neonatal rats. RESULTS: Soon after the restoration of hearing, early deprivation study animals showed a significantly lower GPIAS at intermediate gap durations and a larger GDT than early deprivation controls, but these differences became insignificant after subsequent auditory inputs. Additionally, the ABR results showed significantly delayed latencies of waves IV, V, and interpeak latencies of wave I-III and wave I-V in study group. Late deprivation group didn't exhibit any deterioration in temporal processing following sensory deprivation. CONCLUSION: Taken together, the present results suggest that transient auditory deprivation during CPs might cause reversible disruptions in the development of temporal processing. PMID- 29287885 TI - Low rate of positive bronchoscopy for suspected foreign body aspiration in infants. AB - OBJECTIVES: To describe our institution's low rate of positive bronchoscopy in infants suspected of inhaling a foreign body. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective review was performed of patients at a tertiary children's hospital with suspected inhalation of a foreign body. Charts were reviewed for demographic information, radiologic findings, operative reports, and respiratory viral panels were reviewed. RESULTS: Sixteen pediatric patients under 12 months of age were identified from 2008 to 2016 with a diagnosis of possible airway foreign body inhalation who underwent emergent bronchoscopy. Of these patients, only one was positive for a foreign body present in the airway. The remaining 15 children were found to have a negative direct laryngoscopy and bronchoscopy evaluation for a foreign body. Of these fifteen patients, 14 were found to have structural airway abnormalities and 7 tested positive for a respiratory viral infection. CONCLUSIONS: Our institution has a low rate of positive bronchoscopy for highly suspected foreign body inhalation in a group of patients less than 12 months of age. Patients presenting with respiratory distress, stridor, or other airway symptoms were often found to have an underlying airway abnormality or viral infection, which coupled with an unclear history, would increase the suspicion for an airway foreign body and subsequent decision to perform bronchoscopy. In stable patients, diagnostic evaluation for an underlying respiratory infection should be performed in these cases. LEVEL OF EVIDENCE: Case Series. PMID- 29287887 TI - Infection rates of MRSA in complicated pediatric rhinosinusitis: An up to date review. AB - INTRODUCTION: Published studies have reported a rise in MRSA isolates in head and neck infections, but the microbiology of complicated pediatric rhinosinusitis is unclear. One study of such patients showed that MRSA isolates were seen only in the last three years of data collection, suggesting a possible recent increased prevalence. Given the public health concerns of increasing rates of antimicrobial resistance, the goal of this study was to investigate the microbiologic patterns and outcomes of complicated pediatric rhinosinusitis. METHODS: Retrospective cohort of pediatric patients admitted to our children's hospital with complicated acute rhinosinusitis from 2004 to 2014. RESULTS: The mean age of 250 hospitalized children with complicated rhinosinusitis was 7.6 +/- 4.9 years; 109 of these (43%) underwent surgical procedures. Although MRSA prevalence was highest in 2014, no significant trend in overall MRSA prevalence occurred when considering the entire study period. No significant relationship was identified between MRSA and intra-orbital versus intra-cranial complications. Interestingly, 22.7% of patients with anaerobes detected by culture had persistent abnormal physical examination (PE) findings versus 6.1% of patients without anaerobes (p = 0.025). Furthermore, multivariate analysis also revealed that detection of anaerobes or MRSA was associated with persistent PE findings being 21.8 and 14.8 times more likely, respectively, when compared to other detected pathogens. DISCUSSION: Our data indicate modest variability in the annual rates of MRSA associated pediatric rhinosinusitis, however there was no statistically significant pattern of change in MRSA prevalence during 2004-2014. Although detection of MRSA was not significantly associated with either intraorbital or intracranial complications of sinusitis, a significant association with a poorer outcome was observed by multivariate analysis for patients from whom MRSA or anaerobes were detected. These data raise the question as to whether clindamycin is adequate for MRSA and anaerobic coverage. PMID- 29287886 TI - Cardiac complications in diphtheria and predictors of outcomes. AB - OBJECTIVE: To study the cardiac complications in diphtheria patients and to study the predictors of outcomes. STUDY DESIGN: Single centre prospective analysis of cardiac complications in diphtheria patients. RESULTS: In this study, there were 60 patients diagnosed with diphtheria with ECG changes. The ECG changes seen were sinus tachycardia (68.3%), T wave inversion (20%), ST segment depression (13.3%), right bundle branch block (5%), multiple atrial ectopics (3.3%). The case fatality rate in our study was 25% (15 patients). High CPK-MB, myoglobulin and cardiac troponin levels were associated with cardiac mortality. In our study, cardiac troponin T had the highest sensitivity (80%) and CK-MB had the highest specificity (95.56%). CONCLUSION: Cardiac involvement is a common complication of infection with C. diphtheria and is associated with high mortality. As diphtheria can be prevented by adequate vaccination, efforts should be maximized for high vaccine coverage with booster doses. PMID- 29287888 TI - Management trends of infantile hemangioma: A national perspective. AB - INTRODUCTION: The primary management of infantile hemangioma (IH) has changed since 2008, with the initiation of propranolol. The change that propranolol has affected on resource utilization is unknown. MATERIALS AND METHODS: The Kids' Inpatient Database (KID) in 2003, 2006, 2009, and 2012 was queried for ICD-9 codes for IH in children under age three. The number of patients undergoing the following procedures of interest: tracheostomy, tracheoscopy and laryngoscopy with biopsy, and excision of skin lesion were evaluated. Data was analyzed for demographics and details on the admission. Trends were identified. Weighted statistical analyses were performed with SAS 9.4. RESULTS: The number of qualified admissions significantly increased over the years (9271 in 2003-12029 in 2012, OR 1.042 per year increase, p < 0.001). The mean age at admission ranged from 26 to 28 days but did not vary over time (p = 0.54). The percentage undergoing tracheostomy significantly decreased from 1.05% in 2003 to 0.27% in 2012 (p = 0.0055), and the percentage undergoing tracheoscopy and laryngoscopy with biopsy significantly decreased from 7.29% in 2003 to 4.20% in 2012 (p = 0.011) among those with IH of unspecified or other sites. The percentage undergoing skin lesion excision also significantly decreased from 1.87% in 2003 to 1.03%, in 2012 (p = 0.0038) among those with IH of skin and subcutaneous tissue. These findings suggest a potential impact of propranolol. After adjusting for inflation, the total hospital charges increased from a mean of $17,838 in 2003 to an adjusted mean of $41,306 in 2012 (p < 0.0001). CONCLUSIONS: Total admissions and hospital charges in children with IH has increased from 2003 to 2012. The percentage of patients undergoing tracheostomy, tracheoscopy and laryngoscopy with biopsy, and skin lesion excision significantly decreased in 2012 compared to 2003, suggesting a potential impact of propranolol. Further studies are needed to examine these changes more closely. PMID- 29287889 TI - A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members. AB - OBJECTIVES: This work was aimed at establishing the molecular etiology of hearing loss in a 9-year old girl with post-lingual non-syndromic mild sensorineural hearing loss with a complex family history of clinically heterogeneous deafness. METHODS: The proband's DNA was subjected to NGS analysis of a 59-targeted gene panel, with the use of the Ion Torrent PGM platform. Conventional Sanger sequencing was used for segregation analysis in all the affected relatives. The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation. RESULTS: A new likely pathogenic mutation in the EYA4 gene (c.1154C > T; p.Ser385Leu) was identified in the proband and in her 42-year-old father with post-lingual non-syndromic profound sensorineural hearing loss. The EYA4 mutation was also found in the proband's grandfather and uncle, both showing clinical features of Waardenburg syndrome type 1. A novel pathogenic splice-site mutation (c.321+1G > A) of the PAX3 gene was found to co-segregate with the EYA4 mutation in these two subjects. CONCLUSION: The identified novel EYA4 mutation can be considered responsible of the hearing loss observed in the proband and her father, while a dual molecular diagnosis was reached in the relatives co-segregating the EYA4 and the PAX3 mutations. In these two subjects the DFNA10 phenotype was masked by Waardenburg syndrome. The use of NGS targeted gene-panel, in combination with an extensive clinical and audiological examination led us to identify the genetic cause of the hearing loss in members of a family in which different forms of autosomal dominant deafness segregate. These results provide precise and especially important prognostic and follow-up information for the future audiologic management in the youngest affected member. PMID- 29287890 TI - A novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2). AB - Here, we report a novel hemizygous transition c.975G>A (p.Trp325*) in POU3F4 gene (Xq21) found in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities ("corkscrew" cochlea with an absence of modiolus) specific to X-linked deafness-2 (DFNX2). Comprehensive clinical evaluation (CT and MR-imaging, audiological and stabilometric examinations) of available members of this family revealed both already known (mixed progressive hearing loss) and additional (enlargement of semicircular canals and postural disorders) clinical DFNX2 features in affected males with c.975G>A (p.Trp325*). Moreover, mild enlargement of semicircular canals, postural abnormalities and different types of hearing thresholds were found in female carrier of this POU3F4-variant. PMID- 29287891 TI - Characteristics of electrically evoked auditory brainstem responses in patients with cochlear nerve canal stenosis receiving cochlear implants. AB - OBJECTIVE: To explore the characteristics of the electrically evoked auditory brainstem responses (EABR) in children with cochlear nerve canal stenosis (CNCs) following cochlear implantation (CI), and the EABR thresholds in children with stenotic versus normal cochlear nerve canals. METHOD: Sixteen children with profound sensorineural hearing loss were included in this study: 8 with CNCs (CNCs group) and 8 with normal cochlear nerve canals (control group). All children underwent cochlear implantation with full insertion of all electrodes. EABR was performed 6 months postoperatively in both groups. RESULTS: The EABR extraction rate was 100% in children with normal cochlear nerve canals and only 50% in children with CNCs. EABR thresholds were significantly higher in children with CNCs of electrodes No. 11and 22 than in children with normal cochlear nerve canals (P < 0.05 for both comparisons). There was no significant difference in EABR thresholds among electrode No. 1, 11 and 22 in CNCs group (P > 0.05 for all comparisons); while in the control group, the EABR threshold at electrode No 22 was lower than those at both electrodes No. 11 and 1 (P < 0.05 for both comparisons), and the EABR threshold at electrode No. 11 was also lower than that at electrode No. 1 (P < 0.05). CONCLUSION: The EABR thresholds in children with normal cochlear nerve canals vary according to the different locations of electrodes in the cochlea; while in children with CNCs, there was no significant difference among different electrode locations. The EABR thresholds in CNCs children were higher than those of children with normal cochlear nerve canals at electrode 11 and 22. PMID- 29287892 TI - [Neurocognition: Impact of radiotherapy]. AB - The cognitive evaluation is essential to arrest the impact of brain tumours on brain functions. Radiation therapy on the brain has side effects, which can impact on the cognitive functioning. The cognitive disorders constitute a predictive factor of the quality of life of the patients impacting on their autonomy, as well as on their social and professional life. This problem thus takes a more and more important place in the reflection on the cancer care. A better detection of these cognitive disorders requires a better cognitive evaluation from the diagnosis. What would allow the implementation of preventive actions upstream. This prospect of improvement of the coverage of the cognitive consequences of the irradiation should allow a better social reinstatement after the treatment, as well as a facilitation for the preservation of autonomy and functional independence. However, a complete cognitive evaluation is expensive in time and asks for a qualified personnel, which often slows down the exploration and the follow-up of the disorders. PMID- 29287893 TI - [Tumoral calcinoses in a chronic hemodialysis patient: The role of SPECT/CT hybrid imaging]. AB - INTRODUCTION: Tumoral calcinosis is a rare benign disease, defined by the presence of calcified deposits in periarticular tissues. It can be hereditary or secondary at chronic renal failure at the stage of dialysis. This work illustrates the contribution of single-photon emission computed tomography (SPECT/CT) in the diagnosis and management of tumoral calcinoses in a chronic hemodialysis patient, based on a clinical case. CASE REPORT: A 62-year-old patient, chronic hemodialysis since 24 years, presented a mechanical pain shoulders, knees and hips with limitation of joint mobility. The clinical exam found a mass of soft tissue in the buttocks. The radiological exam showed the presence of periarticular calcifications with no bone involvement. The SPECT/CT revealed a multifocal tumoral calcinosis affecting shoulders, elbows, wrists, hips and knees, associated with alveolar and abdominal calcinosis. DISCUSSION AND CONCLUSION: Tumoral calcinosis is a distinct clinicopathological entity characterised by periarticular soft tissue calcium deposits. The SPECT/CT is important in the diagnosis, the assessment of extension and monitoring of tumoral calcinosis after treatment. PMID- 29287895 TI - A two-step dilution tris-egg yolk extender containing Equex STM significantly improves sperm cryopreservation in the African wild dog (Lycaon pictus). AB - Conservation management of endangered African wild dogs (AWD; Lycaon pictus) can benefit greatly from development of sperm freezing and artificial insemination. Previous freezing attempts yielded nearly 0% motile sperm within 2 h of thawing. In this study, two canine freezing protocols were tested: Protocol 1: a one-step dilution in TRIS-20% egg yolk containing 8% glycerol; and Protocol 2: a two-step dilution in TRIS-20% egg yolk containing a final extender concentration of 5% glycerol and 0.5% Equex STM, coupled with a TRIS-citrate-fructose thawing solution. Semen was collected by electroejaculation from n = 24 AWDs, of which eight ejaculates of sufficient quality (four good quality with initial sperm motility of 75.0 +/- 4.4% and four poor quality; showing rapid decrease in sperm motility to 3.3 +/- 3.3% prior to freezing) were frozen. For good quality samples, motility and sperm motility index persisted for up to 8 h for Protocol 2, and was higher between 2 and 6 h after thawing with a decrease from 4 h of incubation. Motility dropped to nearly 0% after 2 h incubation for Protocol 1. Viability was higher for Protocol 2 throughout the 8 h of incubation, with a decrease after 6 h, compared to 4 h for Protocol 1. Acrosome integrity was higher for Protocol 2 throughout post-thaw incubation, with a decrease after 2 h for both protocols. Protocols did not differ in normal sperm morphology or DNA integrity. Poor quality samples yielded similar results, except for acrosome integrity, which declined for Protocol 2. In conclusion, a two-step dilution in TRIS-egg yolk-glycerol extender containing Equex STM yields significantly improved post-thaw quality and longevity of AWD spermatozoa, making it suitable for sperm banking and artificial insemination initiatives. PMID- 29287894 TI - [Monitoring of hypertension in patients orally treated by angiogenesis inhibitor in daily practice]. AB - OBJECTIVE: The aim of this study is to measure the monitoring and the incidence of renovascular effects of angiogenesis inhibitors in real population. METHOD: Are included in this descriptive, monocentric, practical study, patients of 18 years old and more, orally treated by angiogenesis inhibitors and monitored in consultation by clinician nurses. The main interest variable is the incidence of hypertension at three months of treatment. RESULTS: From January, 2011 to July, 2014, 324 patients have been included, whose 53% are men. Mean age is 62+/-13 years old. Antecedents are: 37% of hypertension, 17% of chronic renal insufficiency, 21% of nephrectomy, 13% of diabetes. Most frequent cancers are kidney (31%), liver (23%) and breast (16%). Most used molecules are: sorafenib (30%), sunitinib (23%) and everolimus (16%). Blood pressure has been measured at the beginning of the treatment in 157 patients (48%). Among them, during the first three months of treatment, 55 (35%) present hypertension according to the oncological definition and 59 (38%) according to the classical definition; 30 patients (19%) are considered as hypertensive according to only one of the two definitions. In multivariable analysis, variables significantly associated with hypertension are: age (OR=1.04; 95% CI 1.02-1.08; P<0.01) and antecedent of nephrectomy (OR=4.29; 95%CI 1.86-9.92; P<0.01). CONCLUSION: In this cohort, only 48% of the patients had blood pressure determination before treatment. Hypertension under angiogenesis inhibitors is probably underestimated. Age and antecedent of nephrectomy seem to be correlated with the occurrence of hypertension. PMID- 29287896 TI - Mitochondria-targeted antioxidant MitoTEMPO improves the post-thaw sperm quality. AB - Human spermatozoa cryopreservation is an important means of assisted reproductive technology and male fertility preservation. Although this technique is particularly useful, sperm cryopreservation significantly reduces the quality of spermatozoa after freezing and thawing. The objective of the study is to examine the efficacy of mitochondria-targeted antioxidant MitoTEMPO in improving sperm quality during semen cryopreservation processes. Semen samples were collected and cryopreserved in extenders containing different concentrations (0.0, 0.5, 5, 50, and 500 MUM) of MitoTEMPO. Sperm motility, viability, membrane integrity, mitochondrial membrane potential and antioxidant activities were measured and analyzed. The results showed that the addition of MitoTEMPO (5-50 MUM) significantly improved post-thaw sperm motility, viability, membrane integrity and mitochondrial membrane potential (P < .05). Meanwhile, antioxidant enzymes activities were enhanced and MDA content were decreased in the group supplemented with MitoTEMPO. In conclusion, mitochondria-targeted antioxidant MitoTEMPO improves the post-thaw sperm quality and antioxidant enzymes profile. PMID- 29287897 TI - Synergistic Integration of Genomics and Ecoevolutionary Dynamics for Sustainable Fisheries: A Reply to Kuparinen and Uusi-Heikkila. PMID- 29287898 TI - The Role of Biotic Interactions in the Niche Reduction Hypothesis: A Reply to Doherty and Driscoll. PMID- 29287899 TI - Strategizing for the purification of a multiple Big domain-containing protein in native conformation is worth it! AB - The reliability and accuracy of conformational or functional studies of any novel multidomain protein rely on the quality of protein. The bottleneck in structural studies with the complete Big_2 domain containing proteins like LigA, LigB or MpIBP is usually their large molecular size owing to their multidomain (>10-12 domains) architectures. Interestingly, a soil bacterium Paenarthrobacter aurescens TC1, harbours a gene that encodes a protein comprising of four predicted Big_2 domains. We report here the expression and purification of this novel, multiple Big_2 domains containing protein, Arig of P. aurescens TC1. During overexpression, recombinant Arig formed inclusion bodies and hence was purified by on-column refolding. The refolded Arig revealed a beta-sheet conformation and a well-resolved near-UV CD spectra but did not exhibit a well dispersed 2D [1H-15N]-HSQC NMR spectrum, as expected for a well-folded beta-sheet native conformation. We, therefore, further optimized Arig overexpression in the soluble fraction by including osmolytes. CD spectroscopic and 2D [1H-15N]-HSQC analyses consolidate that Arig purified alternatively has a well-folded native conformation. While we describe different strategies for purification of Arig, we also present the spectral properties of this novel all-beta-sheet protein. PMID- 29287900 TI - Galectin-3 in patients with coronary heart disease and atrial fibrillation. AB - OBJECTIVE: To observe the change of the inflammatory factor Galectin-3 in patients with coronary heart disease, and the correlation between Galectin-3 and the severity of the disease. To observe changes of Galectin-3 in patients with atrial fibrillation (AF) before and after radiofrequency ablation, and the changes of Galectin-3 before and after an interim treatment with a high dose of atorvastatin on patients with acute myocardial infarction(AMI). METHODS: Patients with coronary heart disease and atrial fibrillation having normal heart function were selected, among them, the patients with AMI were given a short term treatment of 80mg atorvastatin before PCI, and patients with atrial fibrillation underwent radiofrequency catheter ablation. ELISA technique was equipped to observe the Galectin-3 changes in patients with coronary heart disease and that of patients with AF before and after radiofrequency ablation. RESULTS: Galectin-3 level of the AMI group was higher than that of the unstable angina pectoris (UAP) group, and its levels were higher than that of the stable angina pectoris (SAP) group, the differences were statistically significant among both groups (P<0.05); Galectin-3 level of multivessel coronary disease group was higher than that of single vessel group, in which a statistically significant difference was noted (P<0.05); There was no statistically significant difference associated in the drop of Galectin-3 levels in patients with AMI after PCI (P>0.05); Galectin-3 of patients with AF decreased after RFCA, but no statistical significance noted (P>0.05); Galectin-3 was negatively correlated with the LVEF value(r=-0.405, P<0.05). CONCLUSION: Galectin-3 belongs to a class of inflammatory mediators that is associated with the degree of myocardial inflammation and fibrosis. It is related to the severity of myocardial ischemia and is negatively correlated with the cardiac ejection fraction. PMID- 29287902 TI - When politicians really decide that nation health is a top priority: the Danish model. PMID- 29287901 TI - Serum levels of endocan and endoglin are associated with large-artery atherosclerotic stroke. AB - BACKGROUND: Accumulating evidence has suggested that endocan and endoglin may play important roles in cardiovascular disease. However, no previous study has focused on these circulating levels in patients with large-artery atherosclerotic (LAA) stroke. METHODS: Serum levels of endocan and endoglin in 114 patients with LAA stroke and 114 age- and sex-matched controls were measured by ELISA. Serum samples from patients were available on day 1, day 6 and in the 4th week after ischaemic stroke(IS). Stroke severity was determined based on the NIHSS score and the stroke volume. An unfavourable outcome was defined as a mRS score>2 on day 90 after IS. RESULTS: The endocan levels were significantly higher in patients with LAA stroke compared with the controls (p=0.001), and after adjustment for other factors (p=0.001). In addition, higher endocan levels were independently associated with unfavourable outcomes on both day 1 and day 6 after IS (p=0.018 and p=0.011). Endoglin levels were decreased on day 6 (p=0.002) and then recovered in the 4th week after IS. No correlation was found between endocan or endoglin and stroke severity. CONCLUSIONS: Endocan levels are higher in patients with LAA stroke and can help in predicting the short-term unfavourable outcome. Endoglin levels are changed after stroke. PMID- 29287903 TI - Severe ophthalmoplegia and myocarditis following the administration of pembrolizumab. PMID- 29287905 TI - Structural design of intrinsically fluorescent oxysterols. AB - Oxysterols are oxidized derivatives of cholesterol with many important biological functions. Trafficking of oxysterols in and between cells is not well studied, largely due to the lack of appropriate oxysterol analogs. Intrinsically fluorescent oxysterols present a new route towards direct observation of intracellular oxysterol trafficking by fluorescence microscopy. We characterize the fluorescence properties of the existing fluorescent 25-hydroxycholesterol analog 25-hydroxycholestatrienol, and propose a new probe with an extended conjugated system. The location of both probes inside a membrane is analyzed and compared with that of 25-hydroxycholesterol using molecular dynamics simulations. The analogs' one- and two-photon absorption properties inside the membrane are evaluated using electronic structure calculations with polarizable embedding. Due to predicted keto-enol tautomerisation of the new oxysterol analog, we also evaluate the keto form. Both analogs are found to be good probe candidates for 25 hydroxycholesterol, provided that the new analog remains in the enol-form. Only the new analog with extended conjugated system shows significant two-photon absorption, which is strongly enhanced by the presence of the membrane. PMID- 29287906 TI - Mexican consensus on lysosomal acid lipase deficiency diagnosis. AB - INTRODUCTION: Lysosomal acid lipase deficiency (LAL-D) causes progressive cholesteryl ester and triglyceride accumulation in the lysosomes of hepatocytes and monocyte-macrophage system cells, resulting in a systemic disease with various manifestations that may go unnoticed. It is indispensable to recognize the deficiency, which can present in patients at any age, so that specific treatment can be given. The aim of the present review was to offer a guide for physicians in understanding the fundamental diagnostic aspects of LAL-D, to successfully aid in its identification. METHODS: The review was designed by a group of Mexican experts and is presented as an orienting algorithm for the pediatrician, internist, gastroenterologist, endocrinologist, geneticist, pathologist, radiologist, and other specialists that could come across this disease in their patients. An up-to-date review of the literature in relation to the clinical manifestations of LAL-D and its diagnosis was performed. The statements were formulated based on said review and were then voted upon. The structured quantitative method employed for reaching consensus was the nominal group technique. RESULTS: A practical algorithm of the diagnostic process in LAL D patients was proposed, based on clinical and laboratory data indicative of the disease and in accordance with the consensus established for each recommendation. CONCLUSION: The algorithm provides a sequence of clinical actions from different studies for optimizing the diagnostic process of patients suspected of having LAL D. PMID- 29287908 TI - Do drug release studies from SEDDS make any sense? AB - Self-emulsifying drug delivery systems (SEDDS) are considered as a potential platform for mucosal drug delivery. The in vitro-in vivo correlation, however, is in particular for this type of delivery systems considerably poor resulting quite often in a simple trial and error approach in order to optimize formulations. One reason for this situation is certainly the lack of appropriate methods to determine the drug release from SEDDS in vitro, as the process is particularly troublesome. For quantification of the drug in the release medium the oily droplets need to be separated. In most studies this is achieved by utilizing a separating membrane such as dialysis membranes or filters having a huge impact on the obtained release profile. Moreover, sink conditions are very often not provided. As drug release from SEDDS is based on a simple diffusion process from a lipophilic liquid phase into an aqueous liquid phase, a likely more meaningful way to characterize the release behaviour might be just the determination of the distribution coefficient (log DSEDDS/RM) of the drug between the SEDDS pre concentrate and the release medium (RM). As log D is simply the measure of the difference in solubility of a compound in two phases, it can be determined by measuring solubility of drug or drug complex in the SEDDS pre-concentrate and in the release medium in a separate manner. The impact of log DSEDDS/RM on the in vivo drug release behaviour is discussed including various case studies. PMID- 29287907 TI - NIR-induced spatiotemporally controlled gene silencing by upconversion nanoparticle-based siRNA nanocarrier. AB - Spatiotemporal control over the release or activation of biomacromolecules such as siRNA remains a significant challenge. Light-controlled release has gained popularity in recent years; however, a major limitation is that most photoactivable compounds/systems respond only to UV irradiation, but not near infrared (NIR) light that offers a deeper tissue penetration depth and better biocompatibility. This paper reports a simple NIR-to-UV upconversion nanoparticle (UCNP)-based siRNA nanocarrier for NIR-controlled gene silencing. siRNA is complexed onto a NaYF4:Yb/Tm/Er UCNP through an azobenzene (Azo)-cyclodextrin (CD) host-guest interaction. The UV emission generated by the NIR-activated UCNP effectively triggers the trans-to-cis photoisomerization of azobenzene, thus leading to the release of siRNA due to unmatched host-guest pairs. The UCNP-siRNA complexes are also functionalized with PEG (i.e., UCNP-(CD/Azo)-siRNA/PEG NPs), targeting ligands (i.e., EGFR-specific GE11 peptide), acid-activatable cell penetrating peptides (i.e., TH peptide), and imaging probes (i.e., Cy5 fluorophore). The UCNP-(CD/Azo)-siRNA/PEG NPs with both GE11 and TH peptides display a high level of cellular uptake and an excellent endosomal/lysosomal escape capability. More importantly, NIR-controlled spatiotemporal knockdown of GFP expression is successfully achieved in both a 2D monolayer cell model and a 3D multicellular tumor spheroid model. Thus, this simple and versatile nanoplatform has great potential for the selective activation or release of various biomacromolecules. PMID- 29287909 TI - Ethological approach to social isolation effects in behavioral studies of laboratory rodents. AB - The aim of the present review is to discuss how housing conditions affect behavioral performance in laboratory rodents from an ethological view. Commonly used laboratory rodents such as rats and mice, are originally captured animals that largely retain species-typical natural behaviors, while have fully adapted to a laboratory setting after long-term domestication. Laboratory settings including caging and artificial group housing are a considerable ethological factor influencing rodents' behaviors in commonly employed behavioral test paradigms, including emotional and defensive behaviors, learning and memory, and attention-related behaviors. Particularly, isolation rearing, single-housed in a cage, is referred to a deprivation of social relationships with cagemates, has a substantial impact on behavioral performance in laboratory rodents. In this review, we will fully examine the importance of caging related ethological factors, e.g., social relationships and its deprivation, which are essential for unraveling the nature of housing effect in laboratory rodents. These discussions regarding the housing conditions will provide valuable information for appropriately conducting behavioral studies and interpreting data of rodents' behaviors in neuroscience. PMID- 29287910 TI - Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats. AB - Impulsivity associated with abnormal dopamine (DA) function has been observed in several disorders, including addiction. Choice impulsivity is the preference for small, immediate rewards over larger rewards after a delay, caused by excessive discounting of future rewards. Addicts have abnormally high discount rates and prefer the smaller rewards sooner. While impulsivity has been inversely correlated with DA D2 receptor (D2R) availability in the midbrain and striatum, it is difficult to mechanistically link the two, due to the diverse neuroanatomical localization of D2Rs, which are found throughout the brain, in many types of neurons and neuronal subcompartments. To determine if ventral tegmental area (VTA) D2R hypofunction is linked to impulsivity, we knocked down D2 receptors from the VTA, using an adeno-associated viral (AAV) vector that delivers short hairpin RNAs (shRNA) targeted against the D2R. The D2R knockdown is restricted to neurons whose cell bodies reside in the VTA, leaving postsynaptic D2Rs intact in the striatum, prefrontal cortex, and other mesocorticolimbic structures. Rats were trained in a delay-discounting task to assess impulsive choice until a stable discounting curve was obtained, and then received bilateral VTA infusions of the D2R shRNA or a scrambled control virus. Over the next six weeks, the discounting curve of the VTA D2R knockdown rats shifted to the left, indicating a preference for the smaller, immediate reward, whereas the curve for control rats remained stable and unchanged. Together these results demonstrate that a decrease in VTA D2Rs enhances choice impulsivity. PMID- 29287911 TI - Consensus Statement of Standards for Interventional Cardiovascular Nursing Practice. AB - Interventional cardiovascular nursing is a critical care nursing specialty providing complex nursing interventions to patients prone to clinical deterioration, through the combined risks of the pathophysiology of their illness and undergoing technically complex interventional cardiovascular procedures. No guidelines were identified worldwide to assist health care providers and educational institutions in workforce development and education guidelines to minimise patients' risk of adverse events. The Interventional Nurses Council (INC) developed a definition and scope of practice for interventional cardiac nursing (ICN's) in 2013. The INC executive committee established a working party of seven representatives from Australia and New Zealand. Selection was based on expertise in interventional cardiovascular nursing and experience providing education and mentoring in the clinical and postgraduate environment. A literature search of the electronic databases Science Direct, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline and Health Source was performed, using the search terms: clinical deterioration, ST elevation myocardial infarction, vital signs, primary percutaneous coronary intervention, PCI, AMI, STEMI, acute coronary syndrome, peri-procedural care, unstable angina, PCI complications, structural heart disease, TAVI, TAVR, cardiac rhythm management, pacing, electrophysiology studies, vascular access, procedural sedation. Articles were limited to the cardiac catheterisation laboratory and relevance to nursing based outcomes. Reference lists were examined to identify relevant articles missed in the initial search. The literature was compared with national competency standards, quality and safety documents and the INC definition and scope of practice. Consensus of common themes, a taxonomy of education and seven competency domains were achieved via frequent teleconferences and two face-to-face meetings. The working party finalised the standards on 14 July 2017, following endorsement from the CSANZ, INC, Heart Rhythm Council, CSANZ Quality Standards Committee and the Australian College of Critical Care Nurses (ACCCN). The resulting document provides clinical practice and education standards for interventional cardiac nursing practice. PMID- 29287912 TI - Corrigendum to "Projections from the lowest lumbar and sacral-caudal segments to the cerebellar cortex in the rat: An anterograde tracing study" [Neurosci. Res. 114 (January) (2017) 43-54]. PMID- 29287913 TI - Evaluation of ODE-Bn-PMEG, an acyclic nucleoside phosphonate prodrug, as an antiviral against productive HPV infection in 3D organotypic epithelial cultures. PMID- 29287914 TI - Loss of c-Kit function impairs arteriogenesis in a mouse model of hindlimb ischemia. AB - BACKGROUND: Arteriogenesis is a process whereby collateral vessels remodel usually in response to increased blood flow and/or wall stress. Remodeling of collaterals can function as a natural bypass to alleviate ischemia during arterial occlusion. Here we used a genetic approach to investigate possible roles of tyrosine receptor c-Kit in arteriogenesis. METHODS: Mutant mice with loss of c Kit function (KitW/W-v), and controls were subjected to hindlimb ischemia. Blood flow recovery was evaluated pre-, post-, and weekly after ischemia. Foot ischemic damage and function were assessed between days 1 to 14 post-ischemia while collaterals remodeling were measured 28 days post-ischemia. Both groups of mice also were subjected to wild type bone marrow cells transplantation 3 weeks before hindlimb ischemia to evaluate possible contributions of defective bone marrow c Kit expression on vascular recovery. RESULTS: KitW/W-v mice displayed impaired blood flow recovery, greater ischemic damage and foot dysfunction after ischemia compared to controls. KitW/W-v mice also demonstrated impaired collateral remodeling consistent with flow recovery findings. Because arteriogenesis is a biological process that involves bone marrow-derived cells, we investigated which source of c-Kit signaling (bone marrow or vascular) plays a major role in arteriogenesis. KitW/W-v mice transplanted with bone marrow wild type cells exhibited similar phenotype of impaired blood flow recovery, greater tissue ischemic damage and foot dysfunction as nontransplanted KitW/W-v mice. CONCLUSION: This study provides evidence that c-Kit signaling is required during arteriogenesis. Also, it strongly suggests a vascular role for c-Kit signaling because rescue of systemic c-Kit activity by bone marrow transplantation did not augment the functional recovery of KitW/W-v mouse hindlimbs. PMID- 29287916 TI - An unusual complication of adenosine administration in supraventricular tachycardia. PMID- 29287915 TI - High throughput automated analysis of big flow cytometry data. AB - The rapid expansion of flow cytometry applications has outpaced the functionality of traditional manual analysis tools used to interpret flow cytometry data. Scientists are faced with the daunting prospect of manually identifying interesting cell populations in 50-dimensional datasets, equalling the complexity previously only reached in mass cytometry. Data can no longer be analyzed or interpreted fully by manual approaches. While automated gating has been the focus of intense efforts, there are many significant additional steps to the analytical pipeline (e.g., cleaning the raw files, event outlier detection, extracting immunophenotypes). We review the components of a customized automated analysis pipeline that can be generally applied to large scale flow cytometry data. We demonstrate these methodologies on data collected by the International Mouse Phenotyping Consortium (IMPC). PMID- 29287917 TI - Safety of statin treatment in children with familial hypercholesterolemia: Filling the gaps. PMID- 29287918 TI - Negative-delay sources in distortion product otoacoustic emissions. AB - Long-delay components showing a symmetrical pattern with positive and negative delays can be observed in the time-frequency representation (or in the inverse Fourier transform) of distortion product otoacoustic emissions. Positive-only phase-gradient delays are predicted by place-fixed backscattering mechanisms, such as coherent reflection due to roughness, whereas the nonlinear distortion wave-fixed mechanism should generate an almost null-delay component. The symmetrical delay pattern arises whenever spectral amplitude fluctuations are not fully correlated to phase fluctuations. An interpretation of this phenomenon is proposed, involving place-fixed modulation of the spectral strength of the wave fixed nonlinear generator. Experimental data are shown in which these negative delay sources are particularly strong, and further amplified by contralateral stimulation, suggesting that this effect could be dynamically enhanced. Analytical solutions of a linear 1-d transmission line model, in which cubic nonlinearity and roughness were added as small perturbations, have been used to test this hypothesis. PMID- 29287919 TI - When and how to treat an IMRT patient on a second accelerator without replanning? AB - When a linear accelerator is unavailable for treatment, a clinical decision is imminent regarding whether a patient should be treated on a linear accelerator other than the machine the patient was scheduled on, or whether treatment should be postponed until the original Linac becomes available. This work investigates the feasibility of switching patients to different accelerators for intensity modulated radiation therapy (IMRT). We have performed Monte Carlo simulations of photon beams from different Linac models and vendors. Prostate and head and neck (H&N) treatment plans for Siemens Primus, Primart, and Varian 21EX accelerators are studied in this work. Dose distributions for given plans are recalculated using different beam data with the same nominal energy from different Linacs. We have compared dose-volume histograms (DVHs) and the maximum, the minimum, and the mean doses to the target and critical structures because of switching accelerators. In the process of switching a treatment plan to a different accelerator, issues exist, including optimum penumbra compensation, dose distribution at the boundary of target and critical structures, and multileaf collimator (MLC) leaf-width effects, which need to be considered and verified with measurements. Our Monte Carlo simulation results confirm that, for the cases we tested, the dose received by 95% of the planning target volume differs by 0.2% to 1.5% between Siemens Primus and Varian 21EX Linacs. The discrepancy is within our clinical acceptance criteria of 3% for IMRT treatments. In making the final decision on whether to switch machines or not, the tumor control probabilities (TCPs) based on a linear-quadratic model are compared. Based on the analyses performed in this work, it is therapeutically more beneficial to switch a patient to a different machine than to postpone a treatment until the original machine is available, especially for fast-growing tumors such as H&N cancers. PMID- 29287920 TI - Microbiological diagnosis of infections caused by the genus Mycobacterium. AB - Mycobacterial culture has a high sensitivity and is the test of choice for the microbiological diagnosis of tuberculosis and nontuberculous mycobacterial infections. However, the results of this culture require at least 2-3 weeks to obtain positivity. Staining is rapid and can be used as a complementary study, although its sensitivity is low. Gene amplification tests have an intermediate sensitivity and obtain results in 1-2 days. These last tests are indicated in cases with moderate or high clinical suspicion. In HIV patients with severe immunodeficiency (<200 CD4), lipoarabinomannan antigen detection in urine may be useful. The identification of isolates from positive cultures is essential to evaluate the clinical significance of the culture results and consider the therapeutic options available. At present, there is a wide range of identification techniques available, which provide results within just 1-4 days. The future of diagnostic techniques in tuberculosis and nontuberculous mycobacterial infections lies in greater development of gene amplification techniques and promoting the search for biomarkers which enable a new approach to the diagnosis of these infections. PMID- 29287921 TI - The effect of age and gender on the genetic regulation of serum 25-hydroxyvitamin D - the FIN-D2D population-based study. AB - In addition to sunlight and dietary sources, several genes in the metabolic pathway of vitamin D affect serum 25-hydroxyvitamin D (25OHD) concentration. It is not known whether this genetic regulation is influenced by host characteristics. We investigated the effect of age and gender on the genetic regulation of serum 25OHD concentration. In total, 2868 Finnish men and women aged 45-74 years participated in FIN-D2D population-based health survey in 2007. Of the 2822 participants that had serum 25OHD concentration available, 2757 were successfully genotyped. Age and gender-dependent association of SNPs with serum 25OHD concentration was studied in 10 SNPs with previously found association with vitamin D metabolites. Associations of 3 SNPs with serum 25OHD concentration were dependent on age with greater effects on younger (<=60 y) than older (>60 y) adults (rs10783219 in VDR, rs12512631 in GC and rs3794060 in NADSYN1/DHCR7; pinteraction = 0.03, 0.02 and 0.01, respectively). The results suggested a novel association between serum 25OHD concentration and rs8082391 in STAT5B gene in men but not in women (pinteraction = 0.01). After multiple testing correction with false discovery rate method, two age-dependent interactions (rs3794060 in NADSYN1/DHCR7 gene and rs12512631 in GC gene) remained statistically significant. This is the first study to suggest that genetic regulation of serum 25OHD concentration is age-dependent. Our results also indicated a novel association between serum 25OHD concentration and SNP in STAT5B gene in men. The results need to be confirmed in future studies preferably in a larger sample. PMID- 29287922 TI - Gynaecological neoplasms in common familial syndromes (Lynch and HBOC). AB - Recognising hereditary predisposition in a cancer patient has implications both for the patient and the patient's kindred. For the latter, cascade germline testing can reassure those not-at-risk family members while carriers can be enrolled in cancer screening and prevention programs that are medically effective and economically sustainable for health care systems. Furthermore, in many of these syndromes, ramifications of molecular phenotypes are increasing, and it is now emerging that, in addition, they convey prognostic and predictive information. Although cancer predisposition syndromes are rare, these molecular phenotypes also occur as somatic events in sporadic cancer settings. The information obtained from these molecular phenotypes, regardless of germline or somatic origin, is being incorporated into clinical management in view of their manifold significance. Thus, increasingly, bespoke management of cancer patients involves testing for both germline and somatic mutations in tumours. Lynch syndrome and BRCA-1 and BRCA-2-associated hereditary breast and ovarian cancer are hereditary cancer syndromes frequently involving the gynaecological tract but tumours associated with similar molecular alterations may also occur sporadically. Thus, the molecular phenotype of mismatch repair deficiency, microsatellite instability or hypermutator phenotype may be attributable to germline or somatic events. Similarly, homologous recombination deficiency or 'BRCAness' in ovarian cancers may be syndromic or sporadic. While hereditary syndromes are well recognised, the prognostic and predictive implications of these molecular phenotypes have only recently been elucidated and these aspects will finally ensure that molecular screening may become standard of care. Thus, nowadays pathologists are asked to designate the molecular phenotype of these cancers and then determine whether it is due to hereditary or sporadic causes. PMID- 29287924 TI - The effect of a concomitant renal injury on the outcome of colonic trauma. AB - BACKGROUND: The management of colon injuries has steadily evolved over the course of the last half century. So too has the management of renal trauma. It is not clear from the literature as to whether concomitant colon and renal injuries carry increased risk of morbidity and mortality, and whether this combination of injuries necessitates a specifically tailored management approach. METHODS: A retrospective review was carried out for the period January 2012 to December 2016. All patients over the age of 18 years who were subjected to laparotomy for penetrating trauma (gunshot wounds or stab wounds) and who sustained an intra operatively proven colonic injury were included in this study. Operative management and outcomes were investigated. A direct comparison was made between patients with a combined colonic and renal injury and those with only a colonic injury. RESULTS: Over the five-year period a total of 268 patients sustained a colonic injury. The 239 patients with a colonic injury (Group A) were compared to the 29 patients with a combined colonic and renal injury (Group B). Regarding the management of the colonic injuries, there were no differences in the rates of primary repair, anastomosis, exteriorization, or damage control surgery between groups A and B. As for the management of the renal injury, 14 were not explored at laparotomy; in 12 a nephrectomy was performed and in 3 the renal injury was repaired. The nephrectomy cohort were more likely to have undergone damage control surgery, to be admitted to ICU, to receive a colostomy, and had higher mortality. While there was no difference in the need for damage control surgery or mortality between groups, Group B had a significantly greater need for ICU admission. Morbidity was similar between the two groups - in particular, there was no difference in the rates of either gastro-intestinal complications or acute kidney injury between the two groups. CONCLUSION: In patients with combined colon and renal injuries, it seems reasonable to treat each organ on its own merit, without the expectation of increased morbidity or mortality. In the non-damage control setting, most colonic injuries may be safely repaired, and a peri-renal haematoma that is not expanding or actively bleeding may be safely left alone. PMID- 29287923 TI - Manganese and lead levels in settled dust in elementary schools are correlated with biomarkers of exposure in school-aged children. AB - Previously, we showed that manganese (Mn) levels in settled dust in elementary schools increased at a rate of 34.1% per km closer to a ferro-manganese alloy plant in the rainy season. In this study, we investigated how this environmental pollution indicator varied in the dry season and if there was an association with Mn biomarker levels in school-aged children. Dust samples were collected with passive samplers (disposable Petri dishes) placed in interior and exterior environments of 14 elementary schools. Occipital hair, toenails and blood samples were collected from 173 students aged 7-12 years from three of these schools, with varying distance from the industrial plant. Mn and lead (Pb) levels were measured by graphite furnace atomic absorption spectrometry. Mn concentration geometric means (GM) in dust fall accumulation in interior environments of schools located at 2, 4, 6 and > 6 km-radii from the plant were 2212, 584, 625 and 224 MUg Mn/m2/30 days, respectively. The modelled rate of change of dust Mn levels decreases by 59.8% for each km further from the plant. Pb levels in settled dust varied between 18 and 81 MUg/m2/30 days with no association with distance from the plant. Blood lead levels median (range) were 1.2 MUg/dL (0.2 15.6), of which 97.8% were <5 MUg/dL. Mn in hair and toenails were 0.66 MUg/g (0.16-8.79) and 0.86 MUg/g (0.15-13.30), respectively. Mn loading rates were positively associated with log MnH (beta = 1.42 * 10-5, p < 0.001) after adjusting for children's age; and also with log MnTn (beta = 2.31 * 10-5, p < 0.001) independent of age. Mn loading rates explained 18.5% and 28.5% of the variance in MnH and MnTn levels, respectively. School-aged children exposure to Mn, independently of age, increases significantly with school proximity to the ferro-manganese alloy plant. PMID- 29287925 TI - Ewing's sarcoma of the maxillofacial region in Greek children: Report of 6 cases and literature review. AB - BACKGROUND: The rarity of Ewing's sarcoma (ES) in the maxillofacial region of children, coupled with the technical challenge of resection and associated functional and cosmetic impairment has resulted in deficient data regarding the optimal local control of the disease. OBJECTIVE: To describe our experience in the management of primary maxillofacial ES in children, focusing on the therapeutic modalities for local control of the disease. STUDY DESIGN: Single institution observational study. METHODS: This is a single institution review of patients, treated between 2007 and 2016. RESULTS: Six primary maxillofacial ES were treated according to the EURO-EWING 99 protocol, consisting of a uniform chemotherapy regimen, combined selectively with surgery and radiotherapy as local treatment. Patients' mean age was 9.42 years (range 6-12.5 years). One patient initially suffered from metastasis and succumbed to the disease; another refused further treatment following chemotherapy and was lost to follow-up. Four patients underwent surgery and adjuvant radiotherapy successfully. At a mean follow-up of 3.78 years relapse-free and overall survival rates were 60% and 80% respectively. The aesthetic and functional outcome was satisfactory in all treated patients. CONCLUSIONS: In eligible cases the combination of chemotherapy with surgery and adjuvant radiotherapy results in optimal oncological and functional outcome for children with ES of the maxillofacial region. Metastasis and poor response to chemotherapy are the most important adverse prognostic factors. PMID- 29287927 TI - Commentary: "Maxillofacial growth and speech outcome after one-stage or two-stage palatoplasty in unilateral cleft lip and palate. A systematic review". PMID- 29287926 TI - Hemoglobin, C-reactive protein and ferritin in patients with oral carcinoma and their clinical significance - A prospective clinical study. AB - AIM: For oral squamous cell carcinoma (OSCC), biomarkers are much in need to predict prognosis and to overcome possible resistance mechanisms to adjuvant therapies. The aim of this study was to evaluate serum level of hemoglobin, C reactive protein (CRP) and ferritin as possible liquid biopsy to predict survival, metastasis and tumor relapse of OSCC. MATERIAL AND METHODS: A prospective clinical study was conducted. Overall, serum levels of hemoglobin, CRP and ferritin in 82 OSCC patients and 63 controls were preoperatively investigated. RESULTS: Patients with an anemia showed a significant lower survival than patients with no anemia preoperative. Patients with T3/T4 cancer had significant lower hemoglobin values (p = 0.002). CRP and ferritin were statistically overexpressed in late tumor stages T3/T4 (ferritin: p = 0.045, CRP: p < 0.05) compared to control. Log Rank testing indicated a statistical correlation of up regulated ferritin levels with local tumor recurrence (p = 0.012) and local lymph node metastasis (p = 0.008). CONCLUSION: Presented biomarker CRP, ferritin and hemoglobin may serve as a liquid biopsy for prediction of OSCC especially for larger tumor sizes, overall survival and tumor relapse and demand a more radical therapy approach. PMID- 29287928 TI - Making All Medications Gluten Free. AB - Gluten is found in food containing wheat, rye, and barley, and it may be introduced into medicines through the use of starch or any modified form of starch derived from these grains. The ingestion of gluten poses serious health hazards to people with celiac disease and non-celiac gluten sensitivity, and they must avoid the oral ingestion of gluten. In 2011, the Food and Drug Administration solicited information and public comments on 'gluten in drug products.' However, the 'final rule' that the Agency issued in 2013 involved only the voluntary 'gluten-free' labeling of food, and it did not include drug products. In this commentary, we are proposing that all drug products can and should be made gluten free. This is especially important since there is currently a global trade in medicines, and patients and health care providers do not know whether a product is gluten free or not unless they are labeled as such. All drug products can be made gluten free as there are many alternatives to gluten containing starch that can be used as excipients during their formulation. Global collaborative efforts of regulatory agencies, pharmaceutical companies, and excipient manufacturers will be needed to implement a gluten-free medication policy and new regulatory guidelines. PMID- 29287929 TI - Editorial. PMID- 29287930 TI - PTL401, a New Formulation Based on Pro-Nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers. AB - There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex(r)). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma Cmax than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of Tmax were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation. PMID- 29287931 TI - Flow cytometry analysis of CD64, CD18, CD11a and CD11b in four children with Bordetella pertussis infection and admitted to critical care: New biomarkers? PMID- 29287932 TI - Legislating how critical care physicians discuss and implement do-not-resuscitate orders. AB - A few weeks ago, Texas took an unprecedented position on unilateral DNRs by passing Senate Bill (SB) 11, which requires patient/surrogate consent for writing DNR orders. The motivation behind the bill was based on the drafters' beliefs that physicians frequently write unilateral DNR orders. SB 11, however, does not stop at requiring physicians to seek consent for DNR orders. Instead, the legislation uncharacteristically exceeds what is typically within the scope and role boundaries for lawmakers by legislating how physicians discuss and implement DNR orders. We contend that this bill is ethically problematic and will have far reaching, negative consequences that will affect how critical care medicine is practiced. In what follows, we describe how proponents' arguments rely on several ethical assumptions, and we describe potential negative impacts stemming from this legislation. Finally, we offer an alternative approach that would mitigate proponents' concerns. We believe SB 11 and our analytic deconstruction of it should serve as "lessons learned" for other states considering similar legislation. PMID- 29287933 TI - [Humoral immune diseases: Cutaneous vasculitis and auto-immune bullous dermatoses]. AB - Humoral immunity is the cause of multiple diseases related to antibodies (IgA, IgG, IgM) produced by the patient. Two groups of diseases are identified. The first group is related to circulating antigen-antibody complexes. The antigens are various. They are often unknown. These immune complexes cause a vascular inflammation due to the complement fixation. Consequently, this group is dominated by inflammatory vasculitis. In the second group, the pathology is due to the fixation in situ of antibodies to a target antigen of the skin that is no more recognized by the patient. This group is represented by the auto-immune bullous dermatoses. PMID- 29287934 TI - [Cutaneous infections: Pathologist's role in unusual or atypical situations]. AB - In infectious pathology, the gold standard consists of the detection of the pathogen within the sample. Identification of the pathogen is often difficult despite the presence of few and inexpensive tools, such, as special stain, immunohistochemistry, or in situ hybridization specific of the pathogen. In infectious pathology, there are morphological signs, which can guide us towards an etiology. We present some clinicopathological examples illustrating rare or unusual situations in cutaneous infectious pathology. PMID- 29287935 TI - Increased cancers among residents living in the neighborhood of a petrochemical complex: A 12-year retrospective cohort study. AB - This study investigates whether cancers are increased for residents living in the vicinity of a petrochemical complex with coal power plants and refineries. We recruited a residential cohort of 2388 long-term residents aged above 35 years in 2009-2012 who lived within a 40 km radius of the complex. We measured their internal exposure biomarkers of urinary carcinogenic metals and retrospectively compared cancer incidences between those who lived fewer than 10 km from the complex (high exposure, HE) and those who lived more than 10 km from the complex (low exposure, LE). Residents had lived in their respective areas for 12 years, since the complex began operating in mid-1999. This included two periods of operation: 0-9 years and 10-12 years. Crude cumulative incident rates (CIRs) of all cancers were calculated for new cancer cases (ICD-9: 140-165, 170-176, 179 208) recorded in the Taiwan Health Insurance Database over total person-years at risk in each study period. Poisson regression was applied to estimate relative risks for the CIRs of all cancers between HE and LE areas during the 10-12 years since the beginning of the complex's operation, adjusting for age, gender, body mass index, smoking, hepatitis C, and occupational exposure. We found that our study subjects in HE areas had higher urinary carcinogenic metal levels, including As, Cd, Hg, Pb, and V, and higher prevalence rates of hepatitis C than those in LE areas. After the complex had been operating for 10-12 years, SIRs per 1000 person-years for all cancers in HE and LE areas were 4.44 vs. 2.48 for all subjects, 15.2 vs. 4.86 for elder subjects aged above 60 years, and 2.94 vs. 2.71 for female subjects. Correspondingly, the adjusted relative risks of CIRs for all cancers between HE and LE areas were 1.29 (95% CI: 0.99-1.68) for all subjects, 1.52 (1.04-2.22) for elder subjects, 1.41 (1.00-1.97) for female subjects, and 1.91 (1.15-3.19) for female elderly subjects. We conclude that elder and female residents living within 10 km of a petrochemical complex had higher carcinogenic exposure and cancers than those living farther away from the complex after the complex had been operating for 10 years. PMID- 29287936 TI - Tortuous internal carotid artery in the oropharynx: a rare cause of a mass. PMID- 29287937 TI - Mandibular advancement devices in the treatment of obstructive sleep apnea. A necessary and effective option. PMID- 29287938 TI - Moving the Message Beyond the Methods: Toward Integration of Unintended Pregnancy and Sexually Transmitted Infection/HIV Prevention. PMID- 29287939 TI - Phosphoinositide-dependent protein kinase 1 is a potential novel therapeutic target in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a relatively rare subtype of B-cell non-Hodgkin lymphoma (NHL) that has a poor prognosis despite recent advances in immunochemotherapy and molecular targeted therapeutics against NHL. Therefore, the development of a new therapeutic strategy for MCL is urgently needed. In this study, we show for the first time that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), an oncogenic serine-threonine protein kinase, is commonly expressed in its phosphorylated active form in patient-derived tumor cells of various types of B-cell NHL cells, including diffuse large B-cell lymphoma, follicular lymphoma, and MCL. Blockade of PDPK1 activity by small-molecule inhibitors specific for PDPK1 (BX-912 and GSK2334470) or by RNA interference exerted antiproliferative effects in all four MCL-derived cell lines examined and these growth-inhibitory effects were mediated by both induction of apoptosis and G2/M cell cycle blockade. In addition, blockade of PDPK1 led to inactivation of its downstream effector kinase RSK2, but not AKT, suggesting the importance of the PDPK1/RSK2 signaling pathway in the proliferation and survival of MCL cells. Finally, when combined with anticancer agents, including genotoxic agents, a proteasome inhibitor, and a BH3 mimetic in vitro, the PDPK1 inhibitor BX-912 showed additive growth-inhibitory effects against MCL-derived cell lines in most settings. In particular, the combination of BX-912 and ABT-263, a BH3 mimetic, resulted in the enhancement of the induction of apoptosis. In conclusion, our results suggest that PDPK1 is a potential novel therapeutic target in MCL and indicate that clinical development of PDPK1-targeted therapy for MCL is desirable. PMID- 29287941 TI - Risk of pelvic inflammatory disease after intrauterine insemination: a systematic review. AB - The aim of this study was to ascertain the incidence of pelvic inflammatory disease (PID) after intrauterine insemination (IUI). A systematic review was conducted using three different approaches: a search of IUI registries; a search of published meta-analyses; and a search of prospective randomized trials. Search terms were 'IUI', 'complications', 'infection' and 'PID'. Two IUI registers were identified that met the inclusion criteria, totalling 365,874 cycles, with 57 PID cases being reported. The post-IUI PID rate was 0.16/1000 (95% CI 0.2 to 0.3/1000). The frequency was higher in husband sperm cycles (0.21/1000) (28/135,839) than in donor sperm cycles (0.03/1000) (1/33,712) (P < 0.05; OR 6.95). Nineteen meta-analyses were retrieved, which included 156 trials, totalling 43,048 cycles, with no PID case being reported. Seventeen prospective clinical trials published between 2013 and 2014 were identified, totalling 4968 cycles; no PID case was reported. The reported rate of post-IUI clinical PID is low (0.16/1000), about 40% higher than reported in the general population of women during their reproductive life. No antibiotic prophylaxis should be recommended unless there is an associated risk factor. PMID- 29287942 TI - Variability Between Reagent Lots for High-Sensitivity Cardiac Troponin I May Affect Performance of Early Rule Out Strategies. PMID- 29287940 TI - Many layers of embryonic hematopoiesis: new insights into B-cell ontogeny and the origin of hematopoietic stem cells. AB - In adult hematopoiesis, the hematopoietic stem cell (HSC) sits at the top of a hierarchy of hematopoietic progenitors responsible for generating the diverse repertoire of blood and immune cells. During embryonic development, however, the initial waves of hematopoiesis provide the first functioning blood cells of the developing embryo, such as primitive erythrocytes arising in the yolk sac, independently of HSCs. In the field of developmental immunology, it has been recognized that some components of the immune system, such as B-1a lymphocytes, are uniquely produced during the embryonic and neonatal period, suggesting a "layered" development of immunity. Several recent studies have shed new light on the developmental origin of the layered immune system, suggesting complex and sometimes multiple contributions to unique populations of innate-like immune cells from both fetal HSCs and earlier HSC-independent progenitors. In this review, we will attempt to synthesize these studies to provide an integrated model of developmental hematopoiesis and layered immunity that may offer new insights into the origin of HSCs. PMID- 29287943 TI - Novel Biomarkers for Predicting Cardiovascular Disease in Patients With Diabetes. AB - It is generally acknowledged that patients with diabetes comprise a high-risk population for the development of cardiovascular disease. However, it is perhaps less well recognized that there actually exists considerable heterogeneity in vascular risk within this patient population, with a sizable subset of individuals seemingly at low risk for major cardiovascular events despite the presence of diabetes. Because traditional clinical risk calculators have shown wide variability in their performance in the setting of diabetes, there exists a need for additional risk predictors in this patient population. In this context, there has been considerable interest in the potential utility of circulating biomarkers as clinical tools that might facilitate risk stratification and thereby guide therapeutic and preventative decision-making. Coupled with the current era of dedicated cardiovascular outcome trials in type 2 diabetes, this interest has spawned a growing literature of recent studies that evaluated potential biomarkers. To date, these studies have identified N-terminal pro-B type natriuretic peptide, high-sensitivity cardiac troponins, and growth differentiation factor-15 as cardiovascular biomarkers of particular potential in patients with diabetes. Furthermore, recognizing the potential benefit of collective consideration of different biomarkers reflecting distinct pathophysiologic processes that might contribute to the development of cardiovascular disease, there is emerging emphasis on the evaluation of combinations of biomarkers for optimal risk prediction. Although not currently ready for clinical practice, this rapidly-growing topic of biomarker research might ultimately facilitate the goal of individualized risk stratification and thereby enable truly personalized management of diabetes. PMID- 29287944 TI - Prediction of Early Adverse Events in Emergency Department Patients With Acute Heart Failure: A Systematic Review. AB - BACKGROUND: Acute heart failure (AHF) accounts for a substantial proportion of Emergency Department (ED) visits and hospitalizations. Previous studies have shown that emergency physicians' clinical gestalt is not sufficient to stratify patients with AHF into severe and requiring hospitalization vs nonsevere and safe to be discharged. Various prognostic algorithms have been developed to risk stratify patients with AHF, however there is no consensus as to the best performing risk assessment tool in the ED. METHODS: A systematic review of Medline, PubMed, and Embase up to May 2016 was conducted using established methods. Major cardiology and emergency medicine conference proceedings from 2010 to 2016 were also screened. Two independent reviewers identified studies that evaluated clinical risk scores in adult (ED) patients with AHF, with risk prognostication for mortality or significant morbidity within 7-30 days. Studies included patients who were discharged or admitted. RESULTS: The systematic review search generated 2950 titles that were screened according to title and abstract. Nine articles, describing 6 risk prediction tools met full inclusion criteria, however, prognostic performance and ease of bedside application is limited for most. Because of clinical heterogeneity in the prognostic tools and study outcomes, a meta-analysis was not performed. CONCLUSIONS: Several risk scores exist for predicting short-term mortality or morbidity in ED patients with AHF. No single risk tool is clearly superior, however, the Emergency Heart Failure Mortality Risk Grade might aid in prognostication of mortality and the Ottawa Heart Failure Risk Score might provide useful prognostic information in patients suitable for ED discharge. PMID- 29287945 TI - Mechanisms of pulse pressure amplification dipping pattern during sleep time: the SAFAR study. AB - The difference in pulse pressure (PP) between peripheral arteries and the aorta, called pulse pressure amplification (PPamp), is a well-described physiological phenomenon independently associated with cardiovascular events. Recent studies suggest that it exhibits circadian variability. Our aim was to detect the factors associated with the circadian variability of PPamp. In 497 consecutive subjects (aged 54 years, 56.7% male, 79.7% hypertensives), we assessed the circadian pattern of peripheral and central arterial hemodynamics by 24-hour evaluation of brachial and aortic blood pressure (BP), augmentation index (AI), and pulse wave velocity (PWV) using a validated oscillometric device (Mobil-O-Graph). All parameters exhibited a circadian variation. Sleep dipping (decrease) pattern was observed for PPamp, brachial and aortic systolic BP, mean BP, and PWV, whereas a rising pattern (higher sleep than wake values) was observed for brachial PP, aortic PP, and AI. The factors independently associated with the less sleep dipping in PPamp were older age, lower height, the use of antihypertensive medication, and sleep decrease in arterial stiffness (PWV), whereas female gender, the presence of hypertension, sleep increase of pressure wave reflections (AI), sleep decrease in heart rate, and mean BP were associated with a greater sleep-dipping in PPamp. These data provide further pathophysiological understanding of the mechanisms leading to PPamp dipping. Several implications regarding the clinical use of the aortic and brachial BP, especially during sleep time, are raised that should be addressed in future research. PMID- 29287946 TI - What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: Reflection on World Kidney Day and International Woman's Day. AB - Chronic kidney disease affects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community, and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and on the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29287947 TI - Post-renal acute renal failure secondary to peritoneal Pseudomyxoma after appendectomy; an uncommon entity. PMID- 29287948 TI - Readability of the Most Commonly Accessed Arthroscopy-Related Online Patient Education Materials. AB - PURPOSE: To assess the readability and comprehension of written text by the most commonly visited websites containing patient education materials on common conditions that can be treated arthroscopically. METHODS: We examined 50 websites, assessed independently by 2 orthopaedic surgery residents (S.A. and G.G.), with educational materials on 5 common conditions treated by arthroscopic surgeons: anterior cruciate ligament (ACL) tear, meniscus tear, hip labral tear, shoulder labral tear, and rotator cuff tear. Following a Google search for each condition, we analyzed the 10 most visited websites for each disorder using a widely used and validated tool for assessing the reading levels of written materials (Flesch-Kincaid formula). RESULTS: The average grade reading level of the 50 websites studied was 9.90 with a reading ease of 52.14 ("fairly difficult, high school"). Only 26% of the websites were at or below the national average of an eighth-grade reading level. Of the 5 conditions treated by arthroscopic surgery, ACL tear had the highest average grade reading level at 10.73 +/- 1.54, whereas meniscus tear had the lowest at 9.31 +/- 1.81. Every condition in this study had an average readability at or above the ninth-grade reading level. CONCLUSIONS: The most frequently accessed materials for patients with injuries requiring arthroscopic surgery exceeds the readability recommendations of the American Medical Association and National Institutes of Health, as well as the average reading ability of US adults. Given the fact that these are the most commonly visited websites by the lay public, there needs to be a greater emphasis on tailoring written information to the literacy levels of the patient population. CLINICAL RELEVANCE: This study emphasizes the discrepancy between the recommended versus the measured reading levels of online patient education materials related to conditions treated by arthroscopic surgeons. The subject matter of these conditions is inherently complex; thus, relying solely on text to inform patients increases the likelihood that the reading level of the material exceeds that of the majority of the lay public. PMID- 29287949 TI - Comparison of Clinical Outcomes After Anterior Cruciate Ligament Reconstruction Using a Hybrid Graft Versus a Hamstring Autograft. AB - PURPOSE: This study aimed to compare the clinical outcomes of patients who underwent anterior cruciate ligament (ACL) reconstruction with a hybrid graft versus an autograft after 3 years of follow-up. METHODS: Among 57 patients with an ACL injury who underwent ACL reconstruction, 28 patients received a hybrid graft (gracilis and semitendinosus tendon autograft plus a soft tissue allograft) and 29 patients received an autograft (gracilis and semitendinosus tendon autograft). The 2 groups were compared after a minimum 3-year follow-up regarding International Knee Documentation Committee (IKDC) assessment of knee function and stability, pivot-shift test, Lachman test, and KT-1000 side-to-side differences. The patient-reported Tegner activity score, Lysholm score, and subjective IKDC score were also compared. Graft failures were identified by patient-reported outcomes, physical examinations, or magnetic resonance imaging, and were confirmed on second-look arthroscopy; failure rate was compared between groups. RESULTS: At final follow-up, the 2 groups significantly differed in pivot-shift test result (P = .013) and Lachman test result (P = .027). The failure rate tended to be greater in the hybrid graft group (14.3%) than in the autograft group (3.4%) (P = .148). All 5 patients with failed graft reconstruction were revised after second-look arthroscopy. The KT-1000 side-to-side differences at final follow-up were significantly inferior in the hybrid graft group (3.5 +/- 2.0) compared with the autograft group (2.5 +/- 1.0, P = .024). The hybrid graft group also had a lower mean Lysholm score (P = .000) and subjective IKDC score (P = .006) than the autograft group. The mean Tegner activity score was 6.8 +/- 0.8 in the hybrid graft group and 6.9 +/- 0.6 in the autograft group (P = .436). CONCLUSIONS: The knee stability and patient-reported scores in the autograft irradiated allograft hybrid graft ACL reconstruction group were significantly inferior compared with those in the autograft ACL reconstruction group. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29287950 TI - Subpectoral Biceps Tenodesis With PEEK Interference Screw: A Biomechanical Analysis of Humeral Fracture Risk. AB - PURPOSE: To quantify the torsional load to fracture for subpectoral biceps tenodesis with interference screw fixation. METHODS: We randomized 28 specimens from 14 matched-pair full-length humeri (mean age, 55.3 years) into 3 groups: (1) empty ream group (ERG), (2) screw-only group (SOG), and (3) screw-plus-biceps tendon group (SBG). In each group, 1 humerus of each matched pair was prepared according to group allocation and the contralateral humerus remained intact as a control. In the ERG, an 8-mm unicortical hole was reamed 1 cm proximal to the inferior border of the pectoralis major tendon insertion; in the SOG, the humerus was filled with an 8-mm * 12-mm PEEK (polyether ether ketone) screw; and in the SBG, the humerus was filled with a PEEK screw and the cadaveric long head of the biceps tendon. Humeri were tested under torsional displacement at a rate of 1 degrees /s until fracture. Maximum torque, energy to maximum torque, and linear stiffness were used to assess humerus strength. RESULTS: Compared with contralateral intact specimens, the maximum torque to fracture was reduced by 28% in the ERG (P = .005), 30% in the SOG (P = .014), and 20% in the SBG (P = .046). Energy to maximum torque was similarly reduced in the ERG (P = .007), SOG (P = .023), and SBG (P = .049). Stiffness was increased by 4% in the ERG (P = .498), 9% in the SOG (P = .030), and 4% in the SBG (P = .439). CONCLUSIONS: Drilling an 8-mm unicortical hole in zone 3 of the bicipital tunnel for open subpectoral biceps tenodesis reduces the torsional load to humeral fracture up to 28% at time 0. The addition of a PEEK tenodesis screw alone reduced the maximum torque by 30%, and the addition of a screw with the long head of the biceps tendon reduced the maximum torque by 20%. The total load to fracture was reduced in all settings. Stiffness was not significantly different for the ERG and SBG, but stiffness was significantly higher for the SOG compared with the intact matched humeri at time 0. CLINICAL RELEVANCE: When performing a biceps tenodesis, humeral fracture susceptibility is increased with an applied torsional load at time 0. Thus providers must be aware of this reduced integrity when a subpectoral biceps tenodesis is used. PMID- 29287951 TI - The Effect of Platelet-Rich Fibrin Matrix at the Time of Gluteus Medius Repair: A Retrospective Comparative Study. AB - PURPOSE: To evaluate the effect of platelet-rich fibrin matrix (PRFM) on outcomes after surgical repair of gluteus medius tendons. METHODS: This is a retrospective review of prospectively collected data comparing patients who underwent gluteus medius repair with PRFM and patients without PRFM. Preoperative characteristics, intraoperative characteristics, and postoperative outcomes at a minimum of 1 year were recorded. Statistical analysis was performed using a multivariate analysis of variance to test for differences in continuous demographic variables and postoperative-only scores between patient groups, chi2 tests were performed for categorical variables, and a repeated-measures analysis of variance was performed to test for the effects of PRFM. We also assessed for interobserver variation in grading adductor tendon tears. RESULTS: In total, the series of gluteus medius repairs without PRFM included 29 patients (25 women and 4 men, 15 right and 4 left) with a mean age of 63.09 +/- 12.0 years. The series of gluteus medius repairs with PRFM included 18 patients (16 women and 2 men, 6 right and 12 left) with a mean age of 60.26 +/- 8.8 years. There were no differences in patient preoperative variables or intraoperative characteristics. Although there was a significant effect of surgical intervention on the visual analog scale for pain, Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sports Specific, and modified Harris Hip Score, the use of PRFM had no significant effect on outcome. Linear models showed a significant positive effect of PRFM on only postoperative Short Form 12 Physical and International Hip Outcome Tool 12 scores. CONCLUSIONS: PRFM augmentation does not appear to have an effect on gluteus medius tendon repair in terms of pain or clinical evidence of retears but may have a role in improving subjective outcomes of overall and hip-specific physical functioning. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29287952 TI - The Effect of Sequential Tearing of the Anterior Cruciate and Anterolateral Ligament on Anterior Translation and the Pivot-Shift Phenomenon: A Cadaveric Study Using Navigation. AB - PURPOSE: To evaluate the effect of progressive lesions of the anterior cruciate ligament (ACL) and anterolateral ligament (ALL) on anterior tibial translation (ATT) as evaluated through the Lachman test and internal tibial rotation (ITR) during a dynamic pivot-shift test in a cadaveric model. METHODS: A total of 7 specimens were tested using a navigation system (2.2 OrthoPilot ACL navigation system). The anterior stability of the knee was measured through the Lachman test and dynamic rotational stability was measured through the pivot-shift test in 3 different conditions: intact knee; ACL-deficient knee; and finally, ACL- and ALL deficient knee. The resulting measurements from the navigation system recorded the real-time changes in both translation and internal rotation during the Lachman and pivot-shift maneuvers. RESULTS: Mean ATT was 7.57 +/- 0.53 mm in the intact knee, 14 +/- 2.44 mm in the ACL-deficient knee, and 14 +/- 2.44 mm in the ACL- and ALL-deficient knee. Mean ITR during the pivot-shift test was 10.14 degrees +/- 2.26 degrees in the intact knee, 12.14 degrees +/- 2.19 degrees in the ACL-deficient knee, and 18.86 degrees +/- 2.73 degrees in the ACL- and ALL-deficient knee. There was a statistically significant difference in static ATT between the intact and ACL-deficient knees (P = .039) but no difference through the addition of an ALL lesion (P = .068). For dynamic rotational control testing, there was no significant difference in ATT between groups but a significant difference in ITR was found (F = 25.17, P = .00034). CONCLUSIONS: During the pivot-shift test, a combined lesion of the ACL and ALL has a significant effect on ITR whereas an isolated lesion of the ACL has no effect on either ATT or ITR. During the Lachman test, an isolated lesion of the ACL has a significant effect on ATT but an additional lesion of the ALL does not affect ATT. CLINICAL RELEVANCE: Dynamic rotational control as tested by the pivot-shift test is greatly influenced by a combined lesion of the ACL and ALL. In clinical cases of a pivot shift, addressing the anterolateral structures may be considered. PMID- 29287953 TI - Is the Transverse Acetabular Ligament Hypertrophied and Hindering Reduction in Developmental Dysplasia of Hip? AB - PURPOSE: To investigate the arthroscopic pathoanatomy of the transverse acetabular ligament (TAL) and determine whether a TAL incision is necessary for the concentric reduction of developmental dysplasia of the hip (DDH) in infants and young children. METHODS: We retrospectively reviewed patients who underwent arthroscopic-assisted reduction for DDH between July 2008 and April 2016. The indications for this intervention included patients in whom closed reduction failed and those who did not require bone operations. The arthroscopic findings and the effect of the TAL incision on DDH reduction were evaluated. TAL pathology was apparent when it was pulled superiorly or hypertrophied. RESULTS: We identified a consecutive series of 13 patients (13 hips). Two patients with teratologic dislocation were excluded. There were 9 girls, 8 first-born infants, and 3 breech-position infants. Six patients showed positive Ortolani test findings. In all cases the TAL was considered not hypertrophied when it appeared as a narrow, cord-like structure that was continuous and in smooth transition with the TAL-labral ring, without prominence or elongation. All postreduction magnetic resonance imaging scans showed reduced femoral heads; however, residual subluxation was observed in 8 of 11 hips owing to the interposed anteroinferior labrum. On arthrography at 6 weeks after reduction, the femoral head was located deeper in the acetabulum and the medial dye pool width was within 2 mm in all patients. CONCLUSIONS: The TAL was not observed to be hypertrophied or stretched in any of the DDH patients, and it did not act as an obstacle to reduction. After the TAL incision, the gap of the cut margin was not remarkably widened, although there were varying degrees of release. The incision of the TAL does not appear to result in the immediate alteration of the TAL-labral ring in favor of deeper acetabular seating or to enhance reduction. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 29287954 TI - Monitoring and controlling ovarian activity in elephants. AB - Both Asian (Elephas maximus) and African (Loxodonta africana) elephants are important keystone, umbrella and flagship species. Paradoxically, world population numbers of both species are declining in many of their natural ranges due mainly to poaching, while over population of elephants in some areas is resulting in serious human-elephant conflict, and modifications of natural habitats that impact biodiversity. Understanding mechanisms of reproductive control is vital to effective population management, and for that reason significant advances have been made in endocrine and ultrasonographic monitoring techniques, particularly in studies of elephants ex situ. However, there remains a need to develop new methods to control ovarian activity, both for enhancing and inhibiting reproduction, to maintain population numbers at levels that ensure species survival and their ability to safely cohabitate with humans and other species. We present an overview of reproductive monitoring methods and how they have contributed to our knowledge of elephant reproductive biology, as well as their application for in situ and ex situ conservation purposes. PMID- 29287955 TI - Remodeling of Ca2+ signaling in cancer: Regulation of inositol 1,4,5 trisphosphate receptors through oncogenes and tumor suppressors. AB - The calcium ion (Ca2+) is a ubiquitous intracellular signaling molecule that regulates diverse physiological and pathological processes, including cancer. Increasing evidence indicates that oncogenes and tumor suppressors regulate the Ca2+ transport systems. Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-activated Ca2+ release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca2+ transfer from the ER to mitochondria through mitochondria associated ER membranes (MAMs). Optimal levels of Ca2+ mobilization to mitochondria are necessary for mitochondrial bioenergetics, whereas excessive Ca2+ flux into mitochondria causes loss of mitochondrial membrane integrity and apoptotic cell death. In addition to well-known functions on outer mitochondrial membranes, B-cell lymphoma 2 (Bcl-2) family proteins are localized on the ER and regulate IP3Rs to control Ca2+ transfer into mitochondria. Another regulatory protein of IP3R, IP3R-binding protein released with IP3 (IRBIT), cooperates with or counteracts the Bcl-2 family member depending on cellular states. Furthermore, several oncogenes and tumor suppressors, including Akt, K-Ras, phosphatase and tensin homolog (PTEN), promyelocytic leukemia protein (PML), BRCA1, and BRCA1 associated protein 1 (BAP1), are localized on the ER or at MAMs and negatively or positively regulate apoptotic cell death through interactions with IP3Rs and regulation of Ca2+ dynamics. The remodeling of Ca2+ signaling by oncogenes and tumor suppressors that interact with IP3Rs has fundamental roles in the pathology of cancers. PMID- 29287956 TI - Mitochondrial quality control: The role of mitophagy in aging. AB - Autophagy is a catabolic process for eliminating macromolecules and damaged organelles by a highly regulated lysosomal pathway. Importantly, autophagy serves as an integral quality control mechanism by recycling cellular constituents for energy consumption and cellular rejuvenation under basal and stress conditions. Nevertheless, there is growing evidence that under certain conditions autophagy can switch from an adaptive survival mechanism to maladaptive process that promotes cell death. Furthermore, defects in autophagy have been linked to mitochondria injury and cell death associated with aging. In this review, we describe the role of autophagy as a physiological mechanism for maintaining homeostasis with its specific involvement in mitochondrial quality control and cardiac aging. PMID- 29287957 TI - Novel VDR antagonists based on the GW0742 scaffold. AB - The vitamin D receptor is a nuclear hormone receptor that regulates cell proliferation, cell differentiation and calcium homeostasis. The receptor is endogenously activated by 1,25-dihydroxyvitamin D3, which induces transcription of VDR targets genes regulated by coactivator binding. VDR antagonists and partial agonists have been developed based on the secosteroid scaffold of vitamin D. Only a few non-secosteroid VDR antagonists are known. Herein, we report the rational design of non-secosteroid VDR antagonists using GW0742 as a scaffold. GW0742 is a PPARdelta agonist previously identified by our group as a VDR antagonist. Several modifications including the replacement of the thiazole ring with an oxazole ring led to compound 7b, which inhibited VDR-mediated transcription (IC50 = 660 nM) without activating PPARdelta-mediated transcription. However, inhibition of transcription mediated by other nuclear receptors was observed. PMID- 29287958 TI - Fragment-based discovery of a potent NAMPT inhibitor. AB - NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor. PMID- 29287959 TI - Synthesis of andrographolide-related esters as insecticidal and acaricidal agents. AB - In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of andrographolide-related esters, such as 3,19 dialkyl(aryl)carbonyloxy andrographolide (3a-g), 3 alkyl(aryl)carbonyloxyandrographolide (4a-g), and 19 alkyl(aryl)carbonyloxyandrographolide (5a-g), were prepared. Their structures were well characterized by 1H NMR, IR, optical rotation, HRMS and mp. Especially three-dimensional structures of compounds 3a, 4g, and 5g were unambiguously confirmed by single-crystal X-ray diffraction. Compounds 3a and 5a exhibited good insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed. PMID- 29287960 TI - Discovering alkylamide derivatives of bexarotene as new therapeutic agents against triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) has been reported to be correlated with high expression of proliferation markers as well as constitutive activation of metastasis-relevant signaling pathways. For many years, breast cancer researchers have been investigating specific and effective methods to treat or to control the development of TNBC, but promising therapeutic options remain elusive. In this study, we have demonstrated that alkylamide derivatives of bexarotene DK-1-150 and DK-1-166 induce apoptotic cell death in TNBC cell lines without causing cytotoxicity in the normal mammary epithelial cell line. Furthermore, the bexarotene derivatives also showed significant effects in inhibiting TNBC cell proliferation and migration, modulating cancer stem cell markers expressions, as well as limiting the epithelial-mesenchymal transition (EMT) activities of TNBC cell lines in terms of downregulating EMT marker and blocking nuclear translocation of beta-catenin. Therefore, we propose the alkylamide derivatives of bexarotene as potential candidates for novel anticancer therapeutics against TNBC. PMID- 29287961 TI - CT-Guided Fine-Needle Aspiration Biopsy of Pulmonary Nodules 8 mm or Less Has a Higher Diagnostic Accuracy than Positron Emission Tomography-CT. AB - PURPOSE: To compare diagnostic accuracy of CT-guided fine-needle aspiration biopsy (FNA-B) with positron emission tomography (PET)-CT for pulmonary nodules <= 8 mm. MATERIALS AND METHODS: A retrospective review of all CT-guided lung FNA Bs performed between 2011 and 2014 at a single institution was undertaken to evaluate patients who had FNA-B and PET-CT imaging of nodules of <= 8 mm. Patients without surgical pathology or 2-year follow-up CT scans were excluded. Of 1,896 patients, 41 patients with 43 subcentimeter pulmonary nodules met study criteria. The McNemar test was used to compare FNA-B with PET-CT results. RESULTS: FNA-B had a sensitivity and diagnostic accuracy of 88.9% and 81.4%, respectively. PET-CT had an overall sensitivity and diagnostic accuracy of 38.9% and 46.5%, respectively. FNA-B had a significantly higher sensitivity and diagnostic accuracy for malignant nodules compared with PET-CT (P < .001). Pneumothorax rate after FNA-B was 13.9%, and chest tube insertion rate was 0%. CONCLUSIONS: FNA-B is a safe procedure with superior sensitivity and higher diagnostic accuracy compared with PET-CT in pulmonary nodules <= 8mm in size. PMID- 29287962 TI - Lymphatic Interventions for Chylothorax: A Systematic Review and Meta-Analysis. AB - PURPOSE: To perform a systematic review and meta-analysis of published studies to evaluate the efficacy of lymphatic interventions for chylothorax. MATERIALS AND METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched for English language studies until March 2017 that included patients with chylothorax treated with lymphangiography (LAG), thoracic duct embolization (TDE), or thoracic duct disruption (TDD). Exclusion criteria were as follows: a sample size of less than 10 patients, no extractable data, or data included in subsequent articles or duplicate reports. RESULTS: The cases of 407 patients from 9 studies were evaluated. The pooled technical success rates of LAG and TDE were 94.2% (95% confidence interval [CI], 88.4%-97.2%; I2 = 46.7%) and 63.1% (95% CI, 55.4% 70.2%; I2 = 37.3%), respectively. The pooled clinical success rates of LAG, TDE, and TDD, on a per-protocol basis, were 56.6% (95% CI, 45.4%-67.2%; I2 = 5.4%), 79.4% (95% CI, 64.8%-89.0%; I2 = 68.1%), and 60.8% (95% CI, 49.4%-71.2%; I2 = 0%), respectively. The pooled major complication rate of LAG and TDE was 1.9% (95% CI, 0.8%-4.3%; I2 = 0%) and 2.4% (95% CI, 0.9%-6.6%; I2 = 26.4%), respectively. The pooled overall clinical success rate of lymphatic interventions, on an intention-to-treat basis, was 60.1% (95% CI, 52.1%-67.7%; I2 = 54.3%). Etiology of chylothorax was identified as a significant source of heterogeneity for the pooled clinical success rate of TDE and overall clinical success rate. CONCLUSIONS: Lymphatic interventions have a respectable efficacy for the treatment of chylothorax. PMID- 29287963 TI - Prevention of Tamoxifen-related Nonalcoholic Fatty Liver Disease in Breast Cancer Patients. AB - BACKGROUND: Tamoxifen is commonly used to prevent breast cancer recurrence. Studies have confirmed the association between tamoxifen and nonalcoholic fatty liver disease (NAFLD), with the results indicating the need for aggressive management of this side effect. We assessed the potential risk factors for and identified the possible protective factors of tamoxifen-related fatty liver. MATERIALS AND METHODS: We enrolled patients with a history of breast cancer, aged 20 to 70 years, who had received with tamoxifen treatment within the past 5 years. We obtained the initial data and performed a follow-up blood test and ultrasound examination to compare the differences before and after tamoxifen treatment. The patients were divided into relatively normal and fatty liver groups. RESULTS: Of the 266 enrolled tamoxifen-treated patients, 143 (53.8%) and 123 (46.2%) were in the relatively normal and fatty liver groups, respectively. The initial body weight (57.6 +/- 9.3 kg vs. 60.9 +/- 10.3 kg; P = .006) and body mass index (BMI; 23.4 +/- 3.8 kg/m2 vs. 25.0 +/- 4.2 kg/m2; P < .001) were lower in the relatively normal group. An initial BMI of >= 22 kg/m2 was a potential risk factor for tamoxifen-related NAFLD (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.00-2.48; P = .048). In contrast, a weekly exercise duration of >= 150 minutes reduced the risk (HR, 0.47; 95% CI, 0.31-0.69; P < .001). CONCLUSION: The results from our study suggest that a BMI of >= 22 kg/m2 is a potential risk factor for tamoxifen-related fatty liver and exercise is a possible protective factor. PMID- 29287964 TI - Translational Research-Stressful and Overwhelming Challenges of Children's Illness for Parents and Families. PMID- 29287965 TI - Letter to the Editor/Comments on "Endometrial cancer after ulipristal acetate for uterine fibroma" by Ignatov et al. Eur J Obstet Gynecol Reprod Biol 2017; Dec;219:134. PMID- 29287966 TI - Structural brain differences between monolingual and multilingual patients with mild cognitive impairment and Alzheimer disease: Evidence for cognitive reserve. AB - Two independent lines of research provide evidence that speaking more than one language may 1) contribute to increased grey matter in healthy younger and older adults and 2) delay cognitive symptoms in mild cognitive impairment (MCI) or Alzheimer disease (AD). We examined cortical thickness and tissue density in monolingual and multilingual MCI and AD patients matched (within Diagnosis Groups) on demographic and cognitive variables. In medial temporal disease related (DR) areas, we found higher tissue density in multilingual MCIs versus monolingual MCIs, but similar or lower tissue density in multilingual AD versus monolingual AD, a pattern consistent with cognitive reserve in AD. In areas related to language and cognitive control (LCC), both multilingual MCI and AD patients had thicker cortex than the monolinguals. Results were largely replicated in our native-born Canadian MCI participants, ruling out immigration as a potential confound. Finally, multilingual patients showed a correlation between cortical thickness in LCC regions and performance on episodic memory tasks. Given that multilinguals and monolinguals were matched on memory functioning, this suggests that increased gray matter in these regions may provide support to memory functioning. Our results suggest that being multilingual may contribute to increased gray matter in LCC areas and may also delay the cognitive effects of disease-related atrophy. PMID- 29287967 TI - The C-Terminal Zinc Fingers of ZBTB38 are Novel Selective Readers of DNA Methylation. AB - Methyl-CpG binding proteins play an essential role in translating DNA methylation marks into a downstream transcriptional response, which has implications for both normal cell function as well as disease. Although for many of these proteins, a detailed mechanistic understanding for how this cellular process is mediated remains to be determined. ZBTB38 is an under-characterized member of the zinc finger (ZF) family of methyl-CpG binding proteins. Functional knowledge has been gained for its conserved methylated DNA binding N-terminal ZF region; however, a specific role for the C-terminal set of five ZFs remains to be elucidated. Here we demonstrate for the first time that a subset of the C-terminal ZBTB38 ZFs exhibit high-affinity DNA interactions and that preferential targeting of the consensus DNA site is methyl specific. Utilizing a hybrid approach, a model for the C-terminal ZBTB38 ZFs in complex with its cognate DNA target is proposed, providing insight into a possible novel mode of methylated DNA recognition. Furthermore, it is shown that the C-terminal ZFs of ZBTB38 can directly occupy promoters harboring the newly identified sequence motif in cell in a methyl dependent manner and, depending on the gene context, contribute to modulating transcriptional response. Combined, these findings provide evidence for a key and novel physiological function for the C-terminal ZF domain of ZBTB38. PMID- 29287968 TI - DNA Repair Pathway Alterations in Metastatic Castration-resistant Prostate Cancer Responders to Radium-223. PMID- 29287969 TI - Association Between Symptomatic Versus Asymptomatic Recurrence and Survival in Bladder Cancer. AB - BACKGROUND: The benefit of surveillance after curative cystectomy in bladder cancer is unproven, but might be justified if detection of asymptomatic recurrence improves survival. Previous studies showing a benefit of surveillance might have been affected by lead-time or length-time bias. MATERIALS AND METHODS: We conducted a retrospective cohort study among 463 cystectomy patients at the University of Pennsylvania. Patients were followed according to a standardized protocol and classified according to asymptomatic or symptomatic recurrence detection. Primary outcome was all-cause mortality. Adjusted Cox regression models were used to assess the effect of mode of recurrence on survival from time of cystectomy (model 1) and time of recurrence (model 2) to account for lead and length time. RESULTS: One hundred ninety-seven patients (42.5%) recurred; 71 were asymptomatic (36.0%), 107 were symptomatic (54.3%), and 19 (9.6%) were unknown. Relative to patients with asymptomatic recurrence, patients with symptomatic recurrence had significantly increased risk of death (model 1: hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.07-2.61; model 2: HR, 1.74, 95% CI, 1.13 2.69) and had lower 1-year overall survival from time of recurrence (29.37% vs. 55.66%). Symptomatic patients were diagnosed with recurrence a median of 1.7 months before asymptomatic patients, yet their median survival from recurrence was 8.2 months less. CONCLUSION: Symptomatic recurrence is associated with worse outcomes than asymptomatic recurrence, which cannot be explained by lead- or length-time bias. Similar methods to account for these biases should be considered in studies of cancer surveillance. Shortening surveillance intervals might allow for detection of more recurrences in an asymptomatic phase. PMID- 29287970 TI - Closed-system manufacturing of CD19 and dual-targeted CD20/19 chimeric antigen receptor T cells using the CliniMACS Prodigy device at an academic medical center. AB - BACKGROUND AIMS: Multiple steps are required to produce chimeric antigen receptor (CAR)-T cells, involving subset enrichment or depletion, activation, gene transduction and expansion. Open processing steps that increase risk of contamination and production failure are required. This complex process requires skilled personnel and costly clean-room facilities and infrastructure. Simplified, reproducible CAR-T-cell manufacturing with reduced labor intensity within a closed-system is highly desirable for increased availability for patients. METHODS: The CliniMACS Prodigy with TCT process software and the TS520 tubing set that allows closed-system processing for cell enrichment, transduction, washing and expansion was used. We used MACS-CD4 and CD8-MicroBeads for enrichment, TransAct CD3/CD28 reagent for activation, lentiviral CD8 TM-41BB CD3 zeta-cfrag vectors expressing scFv for CD19 or CD20/CD19 antigens for transduction, TexMACS medium-3%-HS-IL2 for culture and phosphate-buffered saline/ethylenediaminetetraacetic acid buffer for washing. Processing time was 13 days. RESULTS: Enrichment (N = 7) resulted in CD4/CD8 purity of 98 +/- 4.0%, 55 +/- 6% recovery and CD3+ T-cell purity of 89 +/- 10%. Vectors at multiplicity of infection 5-10 resulted in transduction averaging 37%. An average 30-fold expansion of 108 CD4/CD8-enriched cells resulted in sufficient transduced T cells for clinical use. CAR-T cells were 82-100% CD3+ with a mix of CD4+ and CD8+ cells that primarily expressed an effector-memory or central-memory phenotype. Functional testing demonstrated recognition of B-cells and for the CAR-20/19 T cells, CD19 and CD20 single transfectants were recognized in cytotoxic T lymphocyte and interferon-gamma production assays. DISCUSSION: The CliniMACS Prodigy device, tubing set TS520 and TCT software allow CAR-T cells to be manufactured in a closed system at the treatment site without need for clean-room facilities and related infrastructure. PMID- 29287971 TI - [Contribution of ultrasound pulmonary ratio in pre-viable premature ruptures of membranes]. AB - OBJECTIVE: To evaluate the ultrasound measurement of the observed-to-expected (o/e) lung-to-head ratio (LHR) and the Quantitative Lung Index (QLI) for the prediction of pulmonary hypoplasia in the pre-viable preterm premature ruptures of membranes (PPROM) before 24 weeks gestational age (GA). METHODS: Thirty-four patients with a PPROM before 24 weeks GA and who delivered a live birth between October 2008 and October 2015 at Croix-Rousse's hospital were included. The measurements of both the LHR (right, left and total) and the QLI (right, left) were retrospectively performed by ultrasounds during the latency period. The observed LHR was divided by the expected LHR, which was obtained from recent literature data. The primary outcome was the onset of a lethal pulmonary hypoplasia. Receiver operating characteristics (ROC) curves assessed the predictive value of these ultrasound measurements for pulmonary hypoplasia. RESULTS: The areas under the ROC curves (AUCs) for the right o/eLHR, the right QLI and the total o/e LHR measured by manually drawing the pulmonary area on the last ultrasound before the delivery, were respectively 0.87 [95% CI: 0.75-1], 0.83 [95% CI: 0.69-0.98] and 0.78 [95% CI: 0.51-1]. Only the total o/e LHR measurements remained associated with lethal pulmonary hypoplasia after adjusting for prematurity and persistent oligohydramnios. CONCLUSION: The right and total o/eLHR and the right QLI measurements might be helpful in predicting pulmonary hypoplasia in pre-viable PPROM. PMID- 29287972 TI - The Patient Perspective on Radiogenomics Testing for Breast Radiation Toxicity. AB - AIMS: In the field of radiogenomics, several potential predictive genetic markers have been identified that are associated with individual susceptibility to radiation toxicity. Predictive models of radiation toxicity incorporating radiogenomics and other biomarkers are being developed as part of the ongoing multicentre REQUITE trial. The purpose of this study was to explore patient attitudes towards future predictive radiogenomics testing for breast radiation toxicity. PATIENTS AND METHODS: Twenty-one semi-structured interviews were conducted with breast cancer patients taking part in the REQUITE study at one centre. We used inductive thematic analysis to generate common themes. RESULTS: We identified three emerging themes describing attitudes and feelings towards a predictive radiogenomics test for breast radiation toxicity: theme 1 - willingness to undergo a test (subthemes - information, trusted expert); theme 2 implications of a test (subthemes - preparation and planning, anxiety without recourse); theme 3 - impact on treatment decision-making (subthemes - prioritising cancer cure, preserving breast integrity, patient preferences). CONCLUSIONS: Results from the present study indicate that patients support and have confidence in the validity of a radiogenomics test for breast radiation toxicity, but they would prefer the result be provided to healthcare professionals. Except in cases of significant chronic symptoms and pain or significant end-organ damage, participants in this study rarely felt that advance knowledge of their personal risk of breast radiation toxicity would influence their treatment decision-making. These findings provide a number of insights that will allow us to anticipate how patients are likely to engage with predictive radiogenomics testing in the future. PMID- 29287973 TI - Myocardial Infarction with Nonobstructive Coronary Arteries: The Importance of Achieving Secondary Prevention Targets. AB - BACKGROUND: Approximately 5% to 10% of all patients with myocardial infarction have nonobstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking. METHODS: In this analysis from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, we investigated 5830 patients with myocardial infarction with nonobstructive coronary arteries (group 1) and 54,637 patients with myocardial infarction with significant coronary artery disease (>=50% stenosis; group 2). Multivariable- and propensity score adjusted statistics were used to assess the reduction in the 1-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6 to 10 weeks after the hospitalization and achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, nonsmoking, and participation in exercise training). RESULTS: Patients in group 1 were less often followed up compared with patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6- to 10-week follow-up was associated with a 3% to 20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24%-32% risk reduction) and, to a smaller extent, by participation in exercise training (10%-23% risk reduction). CONCLUSIONS: Selected secondary preventive measures are associated with prognostic benefit in patients with myocardial infarction with nonobstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses. PMID- 29287974 TI - Enhancing individual and community disaster preparedness: Individuals with disabilities and others with access and functional needs. AB - Preparedness planning is essential to minimizing the impact of disasters on communities and individuals. Attention to the needs of people with disabilities is vital as they have additional needs before, during and after a disaster that are specific to the disabling condition. In this Commentary, we emphasize national guidelines on disability inclusion in emergency preparedness. We examine some potential areas of planning and response that need attention as suggested by preparedness data for people with self-reported disabilities (also referred to as access and functional needs) and highlight selected resources (e.g., tools, trainings, and online webinars) to enhance whole community preparedness and disability inclusion efforts. This Commentary intends to bridge the gap between those various facets of preparedness, at all levels of government and among individuals, with the aim of ensuring that the whole community is prepared to adapt, withstand and rapidly recover from disruptions due to disasters. PMID- 29287976 TI - M.L. Gannon: Pioneer in Urology. PMID- 29287975 TI - Bladder and Ureteral Dysfunction Leading to Hydronephrosis and Hydroureteronephrosis in Adults. AB - Chronic non-stone-related hydronephrosis from supravesical or bladder dysfunction in adults is often detected incidentally. This study aims to review the literature regarding supravesical obstruction or bladder dysfunction leading to bilateral hydronephrosis in adults and to develop an algorithm to identify patients at risk of renal failure. Cross-sectional studies, retrospective and prospective cohorts, clinical trials, and systematic reviews from 1980 to 2017 were included. From 8115 articles screened, 39 met the inclusion criteria. Despite the lack of studies addressing this issue, this review brings up a rational evidence-based algorithm to diagnose and manage adults with bilateral hydronephrosis due to supravesical or bladder disease or dysfunction. PMID- 29287977 TI - Effects of Herpes Simplex Virus Infections on Seminal Parameters in Male Partners of Infertile Couples. AB - OBJECTIVE: To assess the possibility that herpes simplex virus (HSV) infection could affect seminal parameters, we (1) standardize and validate a multiplex polymerase chain reaction (M-PCR) assay to detect HSV-1 and HSV-2 in semen, and (2) determine the prevalence of HSV-1/-2 in the semen of randomized male partners of couples seeking fertility evaluation. MATERIALS AND METHODS: A total of 279 semen samples were included in the study from men who visited the Sperm Analysis Section of Sao Camilo Laboratory of Maringa, Brazil, between November 2014 and July 2015. Eligible men were 18 years or older and had a semen analysis due fertility evaluation (after failing to conceive with their partner after 1 year of unprotected intercourse). Basic seminal parameters were analyzed, and HSV-1 and HSV-2 were detected by M-PCR. RESULTS: The M-PCR assay clearly distinguished and identified 2 HSV types in semen samples. HSV in total was detected in 10.7% of samples, of which 7.5% had HSV-1 exclusively and 3.2% had HSV-2 exclusively. We detected a significant association of HSV-2 infection with hematospermia and with a lower mean seminal volume, and between HSV-1 infection and a lower mean sperm count. CONCLUSION: These findings suggest that the male partners of infertile couples with HSV infections may have changes on the 2 equally important components of semen, spermatozoa and seminal fluid, which may influence fertility. Further studies enrolling a larger number of patients are necessary to confirm these data and to elucidate the clinical relevance of HSV presence in semen. PMID- 29287978 TI - Algal blooms of the 18th and 19th centuries. AB - Algal blooms, including those containing cyanobacteria, are of environmental concern due to the toxicities of some of the constituent microorganisms. This compromises the safety of freshwater causing illness in livestock and humans. We present historical accounts of algal blooms occurring during the 18th and 19th centuries indicating that the advent of intensive farming in the 17th century provided nutrients for promoting harmful algal blooms. PMID- 29287979 TI - An evaluation of the biocompatibility and osseointegration of novel glass fiber reinforced composite implants: In vitro and in vivo studies. AB - OBJECTIVES: The aim of this study was to evaluate the in vitro biocompatibility and in vivo osseointegration of three novel bioactive glass fiber reinforced composite (GFRC) implants and to compare these with metal (Ti6Al4V) implants. METHODS: The surfaces of these experimental substrates were characterized by scanning electron microscopy (SEM), a 2D profilometer and by contact angle measurement. In vitro biological performance was assessed using MG-63 human osteoblast-like cell morphology, cell proliferation assays and the alkaline phosphatase (ALP) activity testing. Furthermore, in vivo osseointegration performance was examined by installing samples into rabbit femurs and evaluated the results using micro-CT, histology and histomorphometrical analysis; these assessments were carried out after 1, 2, 4 and 8 weeks of healing. RESULTS: The results showed that moderate surface roughness, moderate hydrophilic exposure and moderate homogenous exposure of bioactive glass fibers were present for all of the GFRC substrates. Furthermore, MG-63 cells, when cultured on all of the GFRC substrates, grew well and exhibited a more differentiated phenotype than cells grown on titanium alloy (Ti6Al4V) substrate. Histological evaluation revealed more newly-formed bone regeneration within the thread of the GFRC implants during the initial healing period. In addition, the novel GFRC implants with a bioactive Bio-fiber structure and glass particles within the epoxy resin matrix showed better bone volume/tissue volume (BV/TV) values at 4 weeks and this was accompanied by bone-implant contact (BIC) values at 8 weeks comparable to the Ti6Al4V group. SIGNIFICANCE: These findings demonstrated that novel GFRC implants seem to show improved osteogenesis and osseointegration functionality and have potential as a substitute for Ti6Al4V, or other metal-based materials, when used for clinically dental and orthopedic applications. PMID- 29287980 TI - Development of radiopaque, biocompatible, antimicrobial, micro-particle fillers for micro-CT imaging of simulated periodontal pockets. AB - OBJECTIVES: Approximately 109 bacteria can be harbored within periodontal pockets (PP) along with inflammatory byproducts implicated in the pathophysiology of systemic diseases linked to periodontitis (PD). Calculation of this inflammatory burden has involved estimation of total pocket surface area using analog data from conventional periodontal probing which is unable to determine the three dimensional (3-D) nature of PP. The goals of this study are to determine the radiopacity, biocompatibility, and antimicrobial activity of transient micro particle fillers in vitro and demonstrate their capability for 3-D imaging of artificial PP (U.S. Patent publication number: 9814791 B2). METHODS: Relative radiopacity values of various metal oxide fillers were obtained from conventional radiography and micro-computed tomography (MUCT) using in vitro models. 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to measure the biocompatibility of calcium tungstate (CaWO4) particles by determination of viable keratinocytes percentage (%) after exposure. After introducing an antibacterial compound (K21) to the radiopaque agent, antimicrobial tests were conducted using Porphyromonas gingivalis (P. gingivalis) and Streptococcus gordonii (S. gordonii) strains and blood agar plates. RESULTS: CaWO4 micro-particle-bearing fillers exhibited an X-ray radiopacity distinct from tooth structures that enabled 3-D visualization of an artificial periodontal pocket created around a human tooth. MTT assays indicated that CaWO4 micro particles are highly biocompatible (increasing the viability of exposed keratinocytes). Radiopaque micro-particle fillers combined with K21 showed significant antimicrobial activity for P. gingivalis and S. gordonii. SIGNIFICANCE: The plausibility of visualizing PP with 3-D radiographic imaging using new radiopaque, biocompatible, transient fillers was demonstrated in vitro. Antibacterial (or other) agents added to this formula could provide beneficial therapeutic features along with the diagnostic utility. PMID- 29287981 TI - Exploiting the apicoplast: apicoplast-targeting drugs and malaria vaccine development. AB - The apicoplast, a relic plastid found in most Apicomplexan parasites, is a notable drug target. Certain antibiotics elicit a delayed death phenotype by targeting this organelle. Here, we review apicoplast-targeting drugs and their targets, particularly those that cause delayed death, and highlight its potential uses in malaria vaccine development. PMID- 29287982 TI - Airway microbial metagenomics. AB - High-throughput untargeted metagenome sequencing provides information about the composition of the microbial communities of viruses, bacteria, archaea and unicellular eukaryotes in the habitat of interest. This review outlines the sampling, processing, sequencing and bioinformatic analysis of secretions of the respiratory tract and summarizes our current knowledge of the upper and lower human airways metagenome in health and disease. PMID- 29287983 TI - Inducible nitric oxide synthase in innate immune cells is important for restricting cyst formation of Toxoplasma gondii in the brain but not required for the protective immune process to remove the cysts. AB - Significantly larger numbers of Toxoplasma gondii cysts were detected in the brains of RAG1-/-NOS2-/- than RAG1-/- mice following infection. In contrast, the cyst numbers markedly decreased in a same manner in both strains of mice after receiving CD8+ immune T cells. Thus, NOS2-mediated innate immunity is important for inhibiting formation of cysts in the brain but not required for the T cell initiated cyst removal, which is associated with phagocyte accumulation. Treatment with chloroquine, an inhibitor of endolysosomal acidification, partially but significantly inhibited the T cell-mediated cyst removal, suggesting that phagosome-lysosome fusion could be involved in the T. gondii cyst elimination. PMID- 29287985 TI - Cellular interactions of covR/S mutant group A Streptococci. AB - Group A Streptococci (GAS) are responsible for a wide array of non-invasive and invasive diseases and varying immune sequelae with high rates of mortality and morbidity. GAS strains with a mutation in their covR/S regulatory system are hypervirulent with an increased capacity for causing invasive disease. covR/S mutants augment their virulence through the up-regulation of important virulence factors and target host immune surveillance primarily by inhibiting neutrophils. An in-depth understanding of the immunopathogenesis of covR/S mutants will facilitate the development of vaccine strategies and design. Ultimately, by targeting separate virulence mechanisms, multi-component vaccines may provide improved protective efficacy against hypervirulent GAS infections. PMID- 29287986 TI - Compartment diversity in innate immune reprogramming. AB - Pathogens or endogenous molecules can reprogram innate immunity. This process can take the form of priming or tolerance depending on the activating signal, and favors enhanced resistance to infection and other insults, by modulating inflammation. Similarly to their organ-specific properties, reprogramming of macrophages and NK cells, is also compartmentalized. PMID- 29287984 TI - Alternative strategies for vaccination to brucellosis. AB - Brucellosis remains burdensome for livestock and humans worldwide. Better vaccines for protection are needed to reduce disease incidence. Immunity to brucellosis and barriers to protection are discussed. The benefits and limitations of conventional and experimental brucellosis vaccines are outlined, and novel vaccination strategies needed to ultimately protect against brucellosis are introduced. PMID- 29287988 TI - Rickettsial genomics and the paradigm of genome reduction associated with increased virulence. AB - Rickettsia species are arthropod endosymbiotic alpha-proteobacteria that can infect mammalian hosts during their obligate intracellular lifecycle, and cause a range of mild to severe diseases in humans. Paradoxically, during their adaptation to a bottleneck lifestyle, rickettsial genomes have undergone an evolution marked by a progressive chromosomic and plasmidic degradation resulting in a genome reduction from 1.5 to 1.1 Mb, with a coding capacity of 69-84%. A striking finding of rickettsial genomics has been that the most virulent species had genomes that were drastically reduced and degraded when compared to closely related less virulent or nonpathogenic species. This paradoxical evolution, which is not unique to members of the genus Rickettsia but has been identified as a convergent evolution of several major human pathogenic bacteria, parallels a selected loss of genes associated with transcriptional regulators, but with a high preservation of toxin-antitoxin (TA) modules and recombination and DNA repair proteins. In addition, these bacteria have undergone a proliferation of genetic elements, notably short palindromic elements, whose role remains unknown. Recent proteomic and transcriptomics analyses have revealed a differential level or degradation of gene expression that may, at least partially, explain differences in virulence among Rickettsia species. However, future investigations are mandatory to provide novel insights into the mechanisms by which genomic reductive evolution contributes to an emergence of pathogenesis. PMID- 29287987 TI - Observations on bradyzoite biology. AB - Tachyzoites of the Apicomplexan Toxoplasma gondii cause acute infection, disseminate widely in their host, and eventually differentiate into a latent encysted form called bradyzoites that are found within tissue cysts. During latent infection, whenever transformation to tachyzoites occurs, any tachyzoites that develop are removed by the immune system. In contrast, cysts containing bradyzoites are sequestered from the immune system. In the absence of an effective immune response released organisms that differentiate into tachyzoites cause acute infection. Tissue cysts, therefore, serve as a reservoir for the reactivation of toxoplasmosis when the host becomes immunocompromised by conditions such as HIV infection, organ transplantation, or due to the impaired immune response that occurs when pathogens are acquired in utero. While tachyzoites and bradyzoites are well defined morphologically, there is no clear consensus on how interconversion occurs or what exact signal(s) mediate this transformation. Advances in research methods have facilitated studies on T. gondii bradyzoites providing important new insights into the biology of latent infection. PMID- 29287990 TI - Are miRNAs critical determinants in herpes simplex virus pathogenesis? AB - miRNAs are small noncoding RNA that play a crucial role in gene regulation by inhibiting translation or promoting mRNA degradation. Viruses themselves express miRNAs that can target either the host or viral mRNA transcriptome. Moreover, viral infection of cells causes a drastic change in host miRNAs. This complex interaction between the host and viruses often favors the virus to evade immune elimination and favors the establishment and maintenance of latency. In this review we discuss the function of both host and viral miRNAs in regulating herpes simplex virus pathogenesis and also discuss the prospect of using miRNAs as biomarkers and therapeutic tools. PMID- 29287991 TI - T cell phenotypes in women with Chlamydia trachomatis infection and influence of treatment on phenotype distributions. AB - T cell phenotypes involved in the immune response to Chlamydia trachomatis (CT) have not been fully elucidated in humans. We evaluated differences in T cell phenotypes between CT-infected women and CT-seronegative controls and investigated changes in T cell phenotype distributions after CT treatment and their association with reinfection. We found a higher expression of T cell activation markers (CD38+HLA-DR+), T helper type 1 (Th1)- and Th2-associated effector phenotypes (CXCR3+CCR5+ and CCR4+, respectively), and T cell homing marker (CCR7) for both CD4+ and CD8+ T cells in CT-infected women. At follow-up after treatment of infected women, there were a lower proportion of CD4+ and CD8+ T cells expressing these markers. These findings suggest a dynamic interplay of CD4+ and CD8+ T cells in CT infection, and once the infection is treated, these cell markers return to basal expression levels. In women without reinfection, a significantly higher proportion of CD8+ T cells co-expressing CXCR3 with CCR5 or CCR4 at follow-up was detected compared to women with reinfection, suggesting they might play some role in adaptive immunity. Our study elucidated changes in T cell phenotypes during CT infection and after treatment, broadening our understanding of adaptive immune mechanisms in human CT infections. PMID- 29287992 TI - Comorbidity, concomitant medication, use of resources and healthcare costs associated with chronic hepatitis C virus carriers in Spain. AB - OBJECTIVES: To assess the comorbidity, concomitant medications, healthcare resource use and healthcare costs of chronic hepatitis C virus patients in the Spanish population. PATIENTS AND METHODS: Retrospective, observational, non interventional study. Patients included were>=18 years of age who accessed medical care between 2010-2013. Patients were divided into 2 groups based on the presence or absence of liver cirrhosis. The follow-up period was 12 months. Main assessment criteria included general comorbidity level (determined by the resource utilisation band score) and prevalence of specific comorbidities, concomitant medications, healthcare resource use and healthcare costs. Statistical analysis was performed using regression models and ANCOVA, P<.05. RESULTS: One thousand fifty-five patients were enrolled, the mean age was 57.9 years and 55.5% were male. A percentage of 43.5 of patients had a moderate level of comorbidity according to the resource utilisation band score. The mean time from diagnosis was 18.1 years and 7.5% of the patients died during the follow-up period. The most common comorbidities were dyslipidaemia (40.3%), hypertension (40.1%) and generalised pain (38.1%). Cirrhosis was associated with cardiovascular events (OR 3.8), organ failures (OR 2.2), alcoholism (OR 2.1), diabetes (OR 1.2) and age (OR 1.2); P<.05. The most commonly used medications were anti-infectives (67.8%) and nervous system medications (66.8%). The mean total cost per patient was 3,198? (71.5% healthcare costs, 28.5% indirect/non healthcare costs). In the corrected model, the total costs per patient-year were 2,211? for those without cirrhosis and 7,641? for patients with cirrhosis; P<.001. CONCLUSIONS: Chronic hepatitis C virus patients are associated with a high level of comorbidity and the use of concomitant medications, especially in patients with liver cirrhosis. Chronic hepatitis C virus infection represents a substantial economic burden on the Spanish National Health System. PMID- 29287989 TI - Immune responses to congenital cytomegalovirus infection. AB - Human cytomegalovirus (HCMV) is the most common cause of viral infection acquired in utero. Even though the infection has been studied for several decades, immune determinants important for virus control and mechanisms of long-term sequelae caused by infection are still insufficiently characterized. Animal models of congenital HCMV infection provide unique opportunity to study various aspects of human disease. In this review, we summarize current knowledge on the role of immune system in congenital CMV infection, with emphasis on lessons learned from mouse model of congenital CMV infection. PMID- 29287993 TI - Comment on: An engineering thermodynamic approach to select the electromagnetic wave effective on cell growth. PMID- 29287994 TI - Exploring the existence of better hands for manipulation than the human hand based on hand proportions. AB - Human exhibits the most dexterous manual manipulation among the anthropoids. The sophisticated dexterity of human hand has been linked to its distinctive morphology compared to the nonhuman anthropoids. The human hand is derived from the ancestral hands after longtime evolution. However, there are more possible morphologies that the hands could take during the evolutionary process. It remains unknown whether better hands for manipulation than the human hand exist among these possible hands. To answer the question, the relationship between the manipulative capability and hand morphology need to be investigated in the region of more possible hands. Here we employ a kinematic model to quantitatively assess the manipulative ability of the possible hands from the aspect of hand proportions. The segment length proportions of each possible hand are reconstructed by the major evolutionary patterns of the anthropoid hands. Our results reveal that too long and too short thumbs relative to fingers both hamper the manual dexterity, though the long thumb of human hand is traditionally thought to be beneficial to manipulation. The results promote the understanding of the link between hand morphology and function. Furthermore, we find out the optimal hand for dexterous manipulation within the region reconstructed by the major evolutionary patterns of the anthropoid hands. The optimal hand is more dexterous than the human hand. Compared to the optimal hand, the human hand has shorter metacarpals relative to phalanges, which is thought to be advantageous to the prehensility. It suggests that the human hand is not an organ exclusive for the dexterous manipulation, but a trade-off between multiple functions. PMID- 29287997 TI - Marinobufagin, a molecule from poisonous frogs, causes biochemical, morphological and cell cycle changes in human neoplasms and vegetal cells. AB - Skin toad secretion present physiologically active molecules to protect them against microorganisms, predators and infections. This work detailed the antiproliferative action of marinobufagin on tumor and normal lines, investigate its mechanism on HL-60 leukemia cells and its toxic effects on Allium cepa meristematic cells. Initially, cytotoxic action was assessed by colorimetric assays. Next, HL-60 cells were analyzed by morphological and flow cytometry techniques and growing A. cepa roots were examined after 72 h exposure. Marinobufagin presented high antiproliferative action against all human tumor lines [IC50 values ranging from 0.15 (leukemia) to 7.35 (larynx) MUM] and it failed against human erythrocytes and murine lines. Human normal peripheral blood mononuclear cells (PBMC) were up to 72.5-fold less sensitive [IC50: 10.88 MUM] to marinobufagin than HL-60 line, but DNA strand breaks were no detected. Leukemia treaded cells exhibited cell viability reduction, DNA fragmentation, phosphatidylserine externalization, binucleation, nuclear condensation and cytoplasmic vacuoles. Marinobufagin also reduced the growth of A. cepa roots (EC50: 7.5 MUM) and mitotic index, caused cell cycle arrest and chromosomal alterations (micronuclei, delays and C-metaphases) in meristematic cells. So, to find out partially targeted natural molecules on human leukemia cells, like marinobufagin, is an amazing and stimulating way to continue the battle against cancer. PMID- 29287996 TI - Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens. AB - How precursor frequencies and antigen affinities impact interclonal B cell competition is a particularly relevant issue for candidate germline-targeting HIV vaccine designs because of the in vivo rarity of naive B cells that recognize broadly neutralizing epitopes. Knowing the frequencies and affinities of HIV specific VRC01-class naive human B cells, we transferred B cells with germline VRC01 B cell receptors into congenic recipients to elucidate the roles of precursor frequency, antigen affinity, and avidity on B cell responses following immunization. All three factors were interdependently limiting for competitive success of VRC01-class B cells. In physiological high-affinity conditions using a multivalent immunogen, rare VRC01-class B cells successfully competed in germinal centers (GC), underwent extensive somatic hypermutation, and differentiated into memory B cells. The data reveal dominant influences of precursor frequency, affinity, and avidity for interclonal GC competition and indicate that germline targeting immunogens can overcome these challenges with high-affinity multimeric designs. PMID- 29287998 TI - Infant heart tumour. PMID- 29287995 TI - Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rbeta1. AB - Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL 23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL 23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rbeta1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit. PMID- 29287999 TI - The Dependence of Glomerular Capillary Hemorrhage Induced by Contrast Enhanced Diagnostic Ultrasound on Microbubble Diameter. AB - A recently proposed two-criterion model for cavitational bioeffects in tissue with microbubbles (MBs) was tested. The glomerular capillary hemorrhage bioeffect was observed in rat kidney for contrast agent MB suspensions with mean diameters of 1.6, 3.1 and 5.5 um. A diagnostic ultrasound machine was used at 3.6 MHz and 5.5 MHz for intermittent scans at power settings 2 dB apart. Petechial hemorrhage counts scored on the surface of the kidneys, and glomeruli were scored in histology. Thresholds for the petechial hemorrhage measurements were the same for the large and medium MB suspensions but substantially higher for the small MBs. For the histology, the medium MBs gave a higher threshold than the large MBs at 5.5 MHz. The pressure amplitude thresholds are in approximate agreement with theory, and the optimum MB size counterintuitively increased for increasing ultrasound frequency, as predicted. The two-criterion model of MB-associated capillary hemorrhage is supported. PMID- 29288000 TI - Quantitative Analysis of Helical Flow with Accuracy Using Ultrasound Speckle Image Velocimetry: In Vitro and in Vivo Feasibility Studies. AB - Venous valve dysfunction and induced secondary abnormal flows are closely associated with venous diseases. Thus, detailed analysis of venous valvular flow is invaluable from biological and medical perspectives. However, most of the previous studies on venous perivalvular flows were based on qualitative analysis. On the contrary, quantitative analysis of perivalvular flows has not been fully understood. In this study, we used the ultrasound speckle image velocimetry (SIV) technique, which utilizes the speckle patterns of red blood cells (RBCs) created by ultrasound waves to measure 3-D valvular flows quantitatively. The flow structures obtained with the proposed SIV technique for an in vitro model were compared with those obtained by numerical simulation and the color Doppler method to validate the measurement accuracy of the ultrasound SIV technique. Blood flow in the human great saphenous vein was then measured at various distances from the valve with and without exercise. 3-D valvular flow was analyzed in accordance with the dimensionless index, helical intensity. The results obtained by the proposed method matched well with those obtained by numerical simulation and the color Doppler method. The hemodynamic characteristics of 3-D valvular helical flow which were analyzed experimentally using the SIV method would be used for quantitative diagnosis of venous valvular diseases. PMID- 29288002 TI - M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer. AB - BACKGROUND: Tumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer (UBC) is controversial. METHODS: We prospectively studied 103 patients with stage pT1-T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome. RESULTS: The mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02). CONCLUSIONS: M2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact. PMID- 29288001 TI - [A POEMS syndrome revealed by a blue toe syndrome]. AB - INTRODUCTION: Arterial and venous thromboses occur in almost one in five patients with POEMS syndrome and usually in macrocirculation. CASE REPORT: We report a 67 year-old male with a POEMS syndrome who presented initially with a blue toe syndrome. He complained of Raynaud's syndrome and left foot paresthesia. Physical examination showed gynecomastia, lymphadenopathies and skin lesions. Cardiovascular investigations excluded atrial fibrillation, unstable atherosclerotic lesions and vascular calcifications. Imaging studies showed diffuse osteosclerotic lesions. Monoclonal protein with lambda light chain was discovered and serum level of VEGF was increased at 2900pg/ml. CONCLUSION: This is to our knowledge the first case of thrombotic microangiopathy in POEMS syndrome without embolic cause or calciphylaxis. PMID- 29288003 TI - Tertiary Gleason pattern in radical prostatectomy specimens is associated with worse outcomes than the next higher Gleason score group in localized prostate cancer. AB - AIM: To assess the predictive value of TGP on biochemical recurrence (BCR) and its association with clinicopathological outcomes in a large, multicenter cohort of patients with localized prostate cancer (PCa) treated with radical prostatectomy (RP). MATERIALS AND METHODS: Records of 6,041 patients who were treated with RP between 2000 and 2011 for clinically nonmetastatic PCa were, retrospectively, analyzed from prospectively collected datasets. BCR-free survival rates were assessed using univariable and multivariable cox-regression analyses. RESULTS: Median patient age was 61 years (interquartile range [IQR]: 57 66) with a median preoperative prostrate specific antigen of 6ng/ml (IQR: 4-9). Overall, 28% of patients had Gleason score (GS) 6, 0.3% GS 6 + TGP, 33% GS 7 (3 + 4), 0.2% GS 7 (3 + 4) + TGP, 22% GS 7 (4 + 3), 0.2% GS 7 (4 + 3) + TGP, 0.1% GS 8 and 0.4% GS 9 or 10. Median follow-up was 45 months (IQR: 31-57). Harboring a TGP was associated with higher rates of positive surgical margins, lymphovascular invasion, extraprostatic extension, and seminal vesicle invasion than their counterparts within the same GS group as well as in the next higher GS group (all P <= 0.05). At 5 years post-RP, BCR estimates were 5% for patients with GS 6, 13% for patients with GS 6 + TGP, 6% for patients with GS 7 (3 + 4), 22% for patients with GS 7 (3 + 4) + TGP, 16% for patients with GS 7 (4 + 3), 41% for patients with GS 7 (4 + 3) + TGP, 38% for patients with GS 8 (4 + 4) and 46% for patients with GS 9 or 10. Patients harboring a TGP had higher BCR rates than the patients in the next higher GS group: GS 6 + TGP vs. GS 7 (3 + 4), HR = 1.6, P = 0.02 and GS 7 (3 + 4)+TGP vs. GS 7 (4 + 3), HR = 1.4, P = 0.03. Patients with a TGP in the GS 7 (4 + 3) group had comparable BCR rates as patients with GS = 8 (P = 0.4) and GS 9 to 10 (P = 0.2). On multivariable analysis that adjusted for the effects of preoperative prostrate specific antigen, nodal involvement, positive surgical margin, extraprostatic disease (pT3a), seminal vesicle invasion (pT3b) and different institution, harboring a TGP showed higher risk of developing BCR within the same GS group and comparable risk of developing BCR with the next higher GS group. CONCLUSION: Patients with TGP at RP have adverse clinicopathological features when compared to their counterparts in the same and the next higher GS group without TGP. Risk of developing BCR increases with the presence of TGP within the same GS group. This risk seems to be comparable between patients with TGP and their counterparts in the next higher GS group without TGP. Knowledge of TGP in RP specimens is likely to improve risk stratification, patient counseling and follow-up scheduling. Further prospective studies that control significant clinical endpoints such as metastasis and mortality are necessary for more significant predictions. PMID- 29288004 TI - Targeted antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy during active surveillance: Effect on hospitalization. AB - OBJECTIVES: We investigated the effect of targeted antibiotic prophylaxis using rectal swab cultures on hospitalization for infectious complications after transrectal ultrasound-guided prostate biopsy (TRUSP). MATERIALS AND METHODS: A cohort of men (1995-2016) with prostate cancer on active surveillance receiving annual TRUSP biopsies was surveyed to determine the incidence of hospitalization for suspected postbiopsy sepsis. We compared biopsy events (i.e., unique biopsies) in the era of empiric prophylaxis to those in the era of targeted prophylaxis based on culture. The effect of fluoroquinolone resistant organisms (FQ-R), and other demographic and clinical factors, on hospitalization was assessed using logistic regression. RESULTS: Of 1,167 men on active surveillance, 825 responded for a total of 3,361 biopsy events; 7 (0.79%) of 886 biopsies preceded by rectal swab culture resulted in hospitalization compared to 24 (0.97%) of 2,475 biopsies without culture (OR = 0.81, 95% CI: 0.35-1.89, P = 0.63). Among 886 cultures performed, FQ-R organisms were identified in 194 (21.9%); 6 out of 194 (3.1%) biopsies with swabs positive for FQ-R resulted in admission compared to 1 out of 692 (0.14%) biopsies with fluoroquinolone sensitive swabs (OR = 22.1, 95% CI: 2.6-184.3, P<0.01). Smaller prostate volume at diagnosis was significantly associated with hospitalization (OR = 2.57, 95% CI: 1.04-6.31) for<45 g vs. >=45 g, P = 0.039). CONCLUSION: Targeted antibiotic prophylaxis is not associated with a significant reduction in hospitalization for suspected post-TRUSP biopsy sepsis. FQ-R and prostate volume exhibited strong associations with risk of hospitalization and could be included in a risk-adapted approach to prophylaxis, but better prophylactic strategies are needed for patients identified to be at high risk of subsequent hospitalization. PMID- 29288005 TI - Ex vivo culture of tumor cells from N-methyl-N-nitrosourea-induced bladder cancer in rats: Development of organoids and an immortalized cell line. AB - OBJECTIVE: We ex vivo cultured primary tumor cells from N-methyl-N-nitrosourea (MNU)-induced bladder tumors in rats and established an immortalized cell line from them. MATERIALS AND METHODS: Bladder tumors in rats were induced by instillation of MNU into the murine bladder. Primary tumor cells were prepared by the cancer-tissue originated spheroid method. An immortalized cell line was established by co-culture with fibroblasts. The cultured tumor cells were molecularly and functionally characterized by quantitative real-time polymerase chain reaction, Western blot, growth assay, and transwell migration assay. RESULTS: Primary tumor cells were successfully prepared as multicellular spheroids from MNU-induced bladder tumors. The differentiation marker expression patterns observed in the original tumors were largely retained in the spheroids. We succeeded in establishing a cell line from the spheroids and named it T-MNU-1. Although basal markers (CK14 and CK5) were enriched in T-MNU-1 compared to the spheroids, T-MNU-1 expressed both luminal and basal markers. T-MNU-1 was able to migrate through a transwell. CONCLUSIONS: Tumor cells in MNU-induced bladder tumors were successfully cultured ex vivo as organoids, and an immortalized cell line was also established from them. The ex vivo models offer a platform that enables analysis of intrinsic characteristics of tumor cells excluding influence of microenvironment in MNU-induced bladder tumors. PMID- 29288006 TI - Advancements in optical techniques and imaging in the diagnosis and management of bladder cancer. AB - Accurate detection and staging is critical to the appropriate management of urothelial cancer (UC). The use of advanced optical techniques during cystoscopy is becoming more widespread to prevent recurrent nonmuscle invasive bladder cancer. Standard of care for muscle-invasive UC includes the use of computed tomography and/or magnetic resonance imaging, but staging accuracy of these tests remains imperfect. Novel imaging modalities are being developed to improve current test performance. Positron emission tomography/computed tomography has a role in the initial evaluation of select patients with muscle-invasive bladder cancer and in disease recurrence in some cases. Several novel immuno-positron emission tomography tracers are currently in development to address the inadequacy of current imaging modalities for monitoring of tumor response to newer immune-based treatments. This review summaries the current standards and recent advances in optical techniques and imaging modalities in localized and metastatic UC. PMID- 29288007 TI - Overexpression of semaphorin 3A in patients with urothelial cancer. AB - OBJECTIVE: A highly sensitive and specific urine marker for the detection of recurrent urothelial cancer and for screening healthy population or people at risk for urothelial cancer has not been found yet. As urine cytology is not sensitive enough, patients with non-muscle-invasive bladder cancer need lifelong follow-up involving multiple invasive cystoscopies. Our aims of study were to examine the expression of semaphorin 3A in urothelial cancer patients and to evaluate semaphorin 3A as a potential marker for urothelial cancer. MATERIALS AND METHODS: Urine samples were taken from patients with known bladder tumor, hospitalized for transurethral resection of lesions, from patients with history of urothelial cancer admitted for endoscopic follow up, from patients with other nonmalignant urological conditions such as prostatic hyperplasia, stress incontinence, urethral stricture, ureteral and kidney stones, and from healthy volunteers with no history of urothelial malignancy and no urological symptoms. Semaphorin 3A (sema3A) protein level was measured using enzyme-linked immunosorbent assay in every sample and levels were correlated with endoscopic and pathological findings. In addition, we performed immunohistochemically staining with semaphorin 3A of 15 tissue samples (various tumors and normal bladder tissues). RESULTS: A total of 183 urine samples were tested. Out of them, 116 patients (mean age 70.7; 94 males and 22 females) had positive cystoscopy, and 67 (mean age 64.7; 51 males and 16 females) had negative cystoscopy. Higher sema3A values were significantly correlated (P = 0.006) with presence of urothelial cancer, as determined by positive cystoscopy or urethroscopy and pathological biopsy. Sema3A levels also showed positive correlation with the number of tumors. Sema3A levels combined with urine cytology showed much higher sensitivity compared with cytology alone (66% vs. 33%), with smaller reduction of specificity (77% vs. 90%). Immunohistochemical staining showed intense staining in high stage and grade tumors, and almost no staining in normal tissue. CONCLUSIONS: Semaphorin 3A is overexpressed in urothelial cancer patients, as evidenced both in its presence in urine and in bladder tissue. Semaphorin 3A in urine is a promising potential urothelial cancer biomarker either independently or in conjunction with cytology. Further tests are needed to elucidate the sex difference in the expression of Sema3A in the urine of bladder cancer patients. PMID- 29288008 TI - Usage and survival implications of surgical staging of inguinal lymph nodes in intermediate- to high-risk, clinical localized penile cancer: A propensity-score matched analysis. AB - OBJECTIVES: To evaluate the usage of surgical staging of inguinal lymph nodes (SSILNs) in the United States for intermediate to high-risk, clinically localized penile squamous cell cancer (SCC), to explore patient and hospital factors associated with omission of this staging, and to evaluate the effect on survival. PATIENTS AND METHODS: Retrospective, observational study using the National Cancer Database from 2004 to 2014 of 1,689 men diagnosed with pT1b-T3, cN0 penile SCC, who by current guidelines should receive SSILNs-either by inguinal lymph node (ILN) dissection or sentinel node biopsy. Binomial logistic regression analysis was performed to determine predictors of SSILNs. Multivariate Cox regression analysis was performed to determine the impact of SSILNs on survival in the overall and propensity-score matched patient populations. RESULTS: Only 25.3% of patients underwent SSILNs. Increasing patient age, higher comorbidity status, lower pathologic stage, Medicaid insurance, and treatment at a nonacademic facility were independent factors associated with the omission of SSILNs. Omission of SSILNs was an independent predictor of overall mortality, both in the overall patient population after multivariate adjustment, HR = 1.46 [(95% CI: 1.14-1.88), P = 0.003], and in the propensity-score matched adjusted population, HR = 1.59 [(95% CI: 1.20-2.13), P = 0.001]. Limitations include an inability to distinguish biopsy from ILN dissection and those inherent in observational study design. CONCLUSION: Utilization of SSILN for penile SCC is low and has not changed significantly since the publication of guidelines in the United States. In particular, nonacademic institutions were less likely to adhere to recommendations for performance of SSILNs. We found the omission of SSILNs is associated with a significant increase in mortality. PMID- 29288009 TI - Borrelia persica infection in rock hyraxes. AB - Tick-borne relapsing fever (TBRF) is an acute infectious disease caused by arthropod-borne spirochetes of the genus Borrelia and characterized by recurrent episodes of fever. Borrelia persica, the causative agent of this disease in Israel, is transmitted by the argasid tick Ornithodoros tholozani. There is little information about the maintenance and possible vertebrate reservoirs of B. persica in nature, but the tick O. tholozani is known to feed on animals that enter its habitat in caves, rock crevices and shady environments. The rock hyrax (Procavia capensis) is commonly found in such habitats and may therefore serve as a reservoir host for O. tholozani. Blood and spleen samples from rock hyraxes were collected from twelve locations in Israel and the West Bank during 2009-2014 to test if these animals may be infected with B. persica. Real-time PCR targeting a segment of the flagellin (flaB) gene was initially used to detect B. persica. Positive samples were further analyzed by PCR, using a segment of the glycerophosphodiester phosphodiesterase (GlpQ) gene for additional confirmation. Borrelia species were identified by nucleotide sequence analysis and the copy number of Borrelia was quantified in blood and spleen samples based on the number of Borrelia 16S rRNA gene copies. A total of 112 hyraxes were examined, with both blood and spleen samples tested from 108 animals. Nine hyraxes were infected with B. persica, with a prevalence of 8%. Of these, two animals were positive for both blood and spleen samples, three only for blood and four only for the spleen. The number of DNA copies of Borrelia 16S rRNA was significantly higher in blood (5 * 106 to 9.2 * 108/ml blood) compared to spleen (2.1 * 104 to 1.0 * 106/ml). We conclude that rock hyraxes are possible reservoirs for B. persica because they have long lifespans and gregarious habits, share habitats with vector ticks, and are naturally infected with this spirochete. Further studies should be conducted in the future to evaluate the competence of hyraxes as reservoirs for B. persica infection. PMID- 29288010 TI - Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia. AB - BACKGROUND AND AIMS: Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms. METHODS AND RESULTS: A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. In vitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T > C (W113R), c.644G > A (G215E) and c.1211T > G (M404R); patient 2 was heterozygous for the known variant c.658A > C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G > T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein. CONCLUSION: We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic. PMID- 29288011 TI - Molecular evolutionary analysis of type-1 human astroviruses identifies putative sites under selection pressure on the capsid protein. AB - Human astroviruses (HAstV) are important enteric pathogens that can be classified into eight sero/genotypes (HAstV-1 to -8). Although the various HAstV types show global spread, type-1 strains tend to be predominant. Molecular analysis of the genomic region encoding the capsid protein (ORF2) has revealed discrete sequence variation, with different lineages within each HAstV type and at least three major lineages have been identified within HAstV-1. Longitudinal epidemiological surveillance has revealed temporal shift of the various HAstV-1 lineages. Metadata analysis of HAstV-1 sequences available in the databases also revealed temporal shifts of the circulation of HAstV-1 lineages, suggesting possible antigenic-related mechanisms of selection at the sub-genotype level. By comparison of HAstV-1 capsid sequences, lineage-defining residues under positive selection were identified. Structural analysis of HAstV-1 capsid allowed identifying at least six residues exposed on the virion surface. Two residues were located in the VP34 (shell region) whilst four residues were mapped in the VP25/27 (protruding region) of HAstV capsid protein, in proximity of the putative receptor binding S site. These findings suggest that mechanisms similar to those observed and/or hypothesized for other enteric viruses are also shaping the evolution of HAstVs, with intra-typic diversification being a possible mechanism to decrease the antigenic pressure to which these viruses are exposed. PMID- 29288012 TI - Two visual pathways - Where have they taken us and where will they lead in future? PMID- 29288013 TI - Impaired perception of facial emotion in developmental prosopagnosia: A reply to Van den Stock's commentary. PMID- 29288014 TI - Efficacy of different cooling technologies for therapeutic temperature management: A prospective intervention study. AB - BACKGROUND: Mild therapeutic hypothermia (32-36 degrees C) is associated with improved outcomes in patients with brain injury after cardiac arrest (CA). Various devices are available to induce and maintain hypothermia, but few studies have compared the performance of these devices. We performed a prospective study to compare four frequently used cooling systems in inducing and maintaining hypothermia followed by controlled rewarming. METHODS: We performed a prospective multi-centered study in ten ICU's in three hospitals within the UPMC health system. Four different cooling technologies (seven cooling methods in total) were studied: two external water-circulating cooling blankets (Meditherm(r) and Blanketrol(r)), gel-coated adhesive cooling pads (Arctic Sun(r)), and endovascular cooling catheters with balloons circulating ice-cold saline (Thermogard(r)). For the latter system we studied three different types of catheter with two, three or four water-circulating balloons, respectively. In contrast to previous studies, we not only studied the cooling rate (i.e., time to target temperature) in the induction phase, but also the percentage of the time during the maintenance phase that temperature was on target +/-0.5 degrees C, and the efficacy of devices to control rewarming. We believe that these are more important indicators of device performance than induction speed alone. RESULTS: 129 consecutive patients admitted after CA and treated with hypothermia were screened, and 120 were enrolled in the study. Two researchers dedicated fulltime to this study monitored TH treatment in all patients, including antishivering measures, additional cooling measures used (e.g. icepacks and cold fluid infusion), and all other issues related to temperature management. Baseline characteristics were similar for all groups. Cooling rates were 2.06 +/- 1.12 degrees C/h for endovascular cooling, 1.49 +/- 0.82 for Arctic sun, 0.61 +/- 0.36 for Meditherm and 1.22 +/- 1.12 for Blanketrol. Time within target range +/-0.5 degrees C was 97.3 +/- 6.0% for Thermogard, 81.8 +/- 25.2% for Arctic Sun, 57.4 +/- 29.3% for Meditherm, and 64.5 +/- 20.1% for Blanketrol. The following differences were significant: Thermogard vs. Meditherm (p < 0.01), Thermogard vs. Blanketrol (p < 0.01), and Arctic Sun vs. Meditherm (p < 0.02). No major complications occurred with any device. CONCLUSIONS: Endovascular cooling and gel adhesive pads provide more rapid hypothermia induction and more effective temperature maintenance compared to water-circulating cooling blankets. This applied to induction speed, but (more importantly) also to time within target range during maintenance. PMID- 29288016 TI - Infestation by Ergasilus coatiarus (Copepoda: Ergasilidae) in two Amazonian cichlids with new host record from Peru: An ectoparasites natural control approach. AB - The occurrence of copepods ergasilid was investigated in two species of cichlids of economic importance for aquaculture in the Amazon region: Cichla monoculus and Chaetobranchus semifasciatus. The fish were collected from a semi-intensive fish farm, near the city of Nauta, Loreto State, Peru. Copepods were found in the gill filaments of 44 of 85 specimens (51.7%) of C. monoculus and in eight of 30 (26.6%) specimens of C. semifasciatus. The parasite was identified as Ergasilus coatiarus based on its morphological features. The occurrence did not vary significantly with host size (P>=0.05) in both species. This is the first report of E. coatiarus parasitizing C. semifasciatus in the Amazon basin and the first report in C. monoculus from Peru. The high occurrence of these copepods in the present study points out the need of improving the strategies of parasitic prevention and control in order to better prevent future disease outbreaks. PMID- 29288015 TI - Trends in co-morbidities and survival for in-hospital cardiac arrest -A Swedish cohort study. AB - OBJECTIVES: Co-morbidities affect survival after in-hospital cardiac arrests (IHCA). The risk population for IHCA, i.e. the hospitalised patients, have a doubled increase in co-morbidities over time. A similar increase in co morbidities among IHCAs might explain the relatively poor survival ratios despite improved care. AIM: To assess changes in the burden of baseline age-adjusted Charlson co-morbidity index (ACCI) scores among IHCAs as well as to assess its impact on survival in three time periods. MATERIAL AND METHODS: All patients >=18 years suffering an IHCA at Karolinska University Hospital between 1st January 2007 and 31st December 2015 were included. Data regarding the IHCA, patient characteristics, ACCI and 30 day survival were obtained from electronic patient records. Parameters included in ACCI were assessed as ICD-10 codes in the medical file at admission to hospital. The median ACCI with interquartile range (IQR) was presented per year. ACCI was categorised into low 0-2points, moderate 3-5points, high 6-8 points and very high >=9 points. Differences in survival between 2007 and 2009 and 2010-2012 as well as 2013-2015 were stratified per ACCI category and assessed with adjusted logistic regression models and presented as Odds Ratios with 95% Confidence Intervals (OR, 95% CI). Adjustments included hospital site, sex, first rhythm, ECG-surveillance, witnessed or not, and location of the IHCA. RESULTS: In all, 1373 patients suffered an IHCA, of whom 376 (27%) survived at least 30 days. The ACCI remained almost constant over time at median 4, IQR 3-6. Patients with low or moderate ACCI more than doubled their survival in 2013-2015 compared to 2007-2009 (adjusted OR 2.61 95% CI1.38-4.94 and OR 1.87 95% CI 1.14 3.09 respectively). CONCLUSION: This cohort study illuminates an almost constant burden of co-morbidities over time among patients suffering an IHCA. Further, the study highlights that 30-day survival has almost doubled from 2007 to 2009 to 2013-2015 among those with low to moderate AccI. PMID- 29288017 TI - Improved Lung Perfusion After Left Pulmonary Artery Patch Enlargement During the Norwood Operation. AB - BACKGROUND: Optimal pulmonary perfusion is crucial for a well-functioning Fontan circulation in patients with hypoplastic left heart syndrome (HLHS). To obtain an adequate size of the left pulmonary artery (LPA), patch enlargement is a routine part of the hemi-Fontan procedure in our center. However, LPA patch enlargement at the time of the modified Norwood procedure may have surgical advantages. Therefore, the aim of this study was to evaluate whether anatomic and functional effects of the new approach are superior. METHODS: A total of 51 consecutive HLHS patients underwent a cardiovascular magnetic resonance imaging study including assessment of LPA anatomy and lung perfusion. The LPA of 20 patients was enlarged during the modified Norwood procedure (group N) and of 31 patients during the hemi-Fontan procedure (group HF). RESULTS: The median indexed cross-sectional area of the LPA in group N was significantly higher than in group HF (49.5 versus 27.9 mm2/m2, p < 0.0001). The regional pulmonary perfusion as measured by first pass, contrast-enhanced signal intensity upslope was significantly improved in group N (left side 0.67 s-1 versus 0.40 s-1, p = 0.002; right side 0.84 s-1 versus 0.52 s-1, p = 0.01). The total hemi-Fontan bypass and procedure times were significantly shorter in group N (both p < 0.001). CONCLUSIONS: These first magnetic resonance imaging data show that HLHS patients after LPA patch enlargement during the modified Norwood procedure have significantly higher LPA cross-sectional areas and show improved lung perfusion and shorter overall procedure time as compared with LPA patching during second stage (hemi-Fontan). Therefore, this promising surgical technique may improve blood flow dynamics of the Fontan circulation in the long run. PMID- 29288018 TI - Reply. PMID- 29288019 TI - The Surgical Treatment of Primary Cardiac B-Cell Lymphoma of Clinically Unstable Patient. AB - The incidence rate of primary cardiac tumors is 13.8 per 1 million inhabitants per year, and 2.4% of them consist of primary cardiac lymphoma. Primary cardiac lymphoma is a fatal malignancy. Echocardiography and whole-body computed tomography are useful tools for diagnosis. Although chemotherapy has been previously described as the standard treatment for primary cardiac lymphoma, surgical treatment can be used for clinically unstable patients. Herein we report the first surgically treated case of a 57-year-old man with biatrial involvement of primary cardiac B-cell lymphoma. PMID- 29288020 TI - Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. AB - OBJECTIVE: To investigate the long-term incidence and predictors for hepatitis B surface antigen (HBsAg) loss after nucleoside analogue therapy. METHODS: The study included 411 noncirrhotic chronic hepatitis B patients (148 hepatitis B e antigen (HBeAg)-positive and 263 HBeAg-negative patients) who were treated with lamivudine (n = 110) or entecavir (n = 301) with posttreatment follow-up of at least 12 months. RESULTS: In HBeAg-positive patients, the 8-year cumulative rates of virologic relapse, clinical relapse and HBsAg loss were 55.6%, 47.7% and 19.6%, respectively. In HBeAg-negative patients, the rates were 69.3%, 58.9% and 33.1%, respectively. Cox regression analysis showed that hepatitis B virus genotype C and lower end-of-treatment HBsAg levels were independent predictors of HBsAg loss in HBeAg-positive and -negative patients. The 5-year HBsAg loss rate was 47.3% in HBeAg-positive patients with end-of-treatment HBsAg levels <300 IU/mL, while the 8-year HBsAg loss rate was 69.3% in HBeAg-negative patients with end-of-treatment HBsAg levels <200 IU/mL. Five patients experienced hepatitis flares with decompensation after stopping nucleoside analogue therapy, and one died after retreatment. Of the 48 patients who developed off-therapy HBsAg loss, two developed hepatocellular carcinoma. CONCLUSIONS: The rate of HBsAg loss was relatively high and the rate of hepatic events was low in noncirrhotic patients who discontinued nucleoside analogue therapy. PMID- 29288021 TI - Phenotypic and genotypic characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis clinical isolates in Hangzhou, China. AB - OBJECTIVES: Pyrazinamide (PZA) is a crucial first-line tuberculosis (TB) drug recommended for both drug-susceptible and multidrug-resistant Mycobacterium tuberculosis. This study aimed to evaluate the performance of the sequencing method of pncA, rpsA and panD mutations in detecting PZA resistance in multidrug resistant (MDR) TB isolates. METHODS: We sequenced the pncA, rpsA and panD genes and performed PZA susceptibility tests across 291 MDR-TB isolates to evaluate the performance of the sequencing method of these genes in detecting PZA resistance. RESULTS: Results showed that 145 (90.0%) of 161 PZA phenotypic resistant isolates had mutations in pncA. Among the 16 isolates (10.0%) which did not have mutations in pncA, ten and three isolates had mutations in rpsA and panD, respectively. The sequencing method for detecting mutations in pncA alone had 90.1% (95% confidence interval (CI), 84.4-94.2) sensitivity and 92.3% (95% CI, 86.3-96.3) specificity. The combination of all three genes increased the sensitivity from 90.1% (95% CI, 84.4-94.2) to 98.1% (95% CI, 94.7-99.6) (p < 0.001) while the specificity remained unchanged. In 120 PZA-susceptible and 16 PZA-resistant isolates without pncA mutations, rpsA/panD mutations were correlated with PZA resistance. CONCLUSIONS: PZA resistance was largely associated with mutations in pncA. Mutations in rpsA and panD were also associated with PZA resistance in MDR isolates expressing wild-type pncA. The detection of mutations in pncA, rpsA and panD can be useful for the determination of PZA resistance. PMID- 29288022 TI - Variable expression of GFP in different populations of peripheral cholinergic neurons of ChATBAC-eGFP transgenic mice. AB - Immunohistochemistry is used widely to identify cholinergic neurons, but this approach has some limitations. To address these problems, investigators developed transgenic mice that express enhanced green fluorescent protein (GFP) directed by the promoter for choline acetyltransferase (ChAT), the acetylcholine synthetic enzyme. Although, it was reported that these mice express GFP in all cholinergic neurons and non-neuronal cholinergic cells, we could not detect GFP in cardiac cholinergic nerves in preliminary experiments. Our goals for this study were to confirm our initial observation and perform a qualitative screen of other representative autonomic structures for the presences of GFP in cholinergic innervation of effector tissues. We evaluated GFP fluorescence of intact, unfixed tissues and the cellular localization of GFP and vesicular acetylcholine transporter (VAChT), a specific cholinergic marker, in tissue sections and intestinal whole mounts. Our experiments identified two major tissues where cholinergic neurons and/or nerve fibers lacked GFP: 1) most cholinergic neurons of the intrinsic cardiac ganglia and all cholinergic nerve fibers in the heart and 2) most cholinergic nerve fibers innervating airway smooth muscle. Most cholinergic neurons in airway ganglia stained for GFP. Cholinergic systems in the bladder and intestines were fully delineated by GFP staining. GFP labeling of input to ganglia with long preganglionic projections (vagal) was sparse or weak, while that to ganglia with short preganglionic projections (spinal) was strong. Total absence of GFP might be due to splicing out of the GFP gene. Lack of GFP in nerve projections from GFP-positive cell bodies might reflect a transport deficiency. PMID- 29288023 TI - Anterior lens capsule strains during simulated accommodation in porcine eyes. AB - Experimental protocols have been developed to measure the spatial variation of the mechanical strains induced in the lens capsule during ex vivo lens stretching. The paper describes the application of these protocols to porcine lenses. The deformations and mechanical strains developed in the anterior capsule during each experiment were determined using full field digital image correlation techniques, by means of a speckle pattern applied to the lens surface. Several speckling techniques and illumination methods were assessed before a suitable combination was found. Additional data on the cross section shape of the anterior lens surface were obtained by Scheimpflug photography, to provide a means of correcting for lens curvature effects in the determination of the strains developed in the plane of the capsule. The capsule strains in porcine lenses exhibit non-linear behaviour, and hysteresis during loading and unloading. Peripheral regions experience higher magnitude strains than regions near the lens pole. The paper demonstrates the successful application of a procedure to make direct measurements of capsule strains simultaneously with ex vivo radial lens stretching. This experimental technique is applicable to future investigations on the mechanical characteristics of human lenses. PMID- 29288024 TI - Trichiconlides CF, four new limonoids with 1,2-seco phragmalin-type carbon skeleton from the fruits of Trichilia connaroides. AB - Phytochemical investigation of the fruits from Trichilia connaroides led to the isolation of four rare 1,2-seco phragmalin-type limonoids (1-4) with C-7/28 delta lactone ring along with two known triterpenoids (5-6). An oxygen bridge between C 1 and C-2 formed an rare 9-oxa-tricyclo[3.3.2.17,10]undecane-2-ene moiety in structure of 1 and 2, and 3-4 possessed a bicyclo[5.2.14,10]decane skeleton. Their structures were established based on extensive spectroscopic methods and their absolute configurations of 1 were confirmed by TDDFT/ECD calculation and comparative analysis. Compounds 5-6 showed moderate inhibitory effects on Hela tumor cell lines with inhibition ratio values of 83.8% and 87.1% at concentration 40MUM, respectively. PMID- 29288025 TI - Thiotagetin B and tagetannins A and B, new acetylenic thiophene and digalloyl glucose derivatives from Tagetes minuta and evaluation of their in vitro antioxidative and anti-inflammatory activity. AB - The three new metabolites: thiotagetin B (2) [(Z)-1"-([2,2'-bithiophen]-5-yl)-8" chloro-6",11"-dimethylundeca-6",10"-dien-2"-yn-9"-one], tagetannin A (9) [3,4-bis (galloyl-3,5-dimethyl ether)-(alpha/beta)-d-glucopyranose], and tagetannin B (10) [2,3-bis-(galloyl-3,5-dimethyl ether)-(alpha/beta)-d-glucopyranose], along with ecliptal (5-formyl-alpha-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2' bithiophene (3), scopoletin (4), p-hydroxybenzoic acid (5), protocatechuic acid methyl ester (6), gallic acid (7), and patuletin 7-O-beta-d-glucoside (8) were isolated from the aerial parts of Tagetes minuta L. (Asteraceae). Their structures were verified by extensive spectroscopic analyses as well as by comparison with literature data. The isolated compounds were evaluated for their antioxidant and anti-inflammatory activities using DPPH and enzyme-linked immunosorbent assays, respectively. Compounds 5-10 possessed the highest antioxidant potential with a scavenging activity (SCA)~74 to 93% of DPPH radicals. Moreover, 5-10 displayed significant anti-inflammatory potential, while 4 showed moderate activity. Compounds 5-10 exhibited significant decreases in NFkappaB p65, TNF-alpha, and IL-6 levels at all tested concentrations. PMID- 29288026 TI - A new phenylspirodrimane dimer from the fungus Stachybotrys chartarum. AB - A new phenylspirodrimane dimer, named stachartarin A (1), was isolated from cultures of the tin mine tailings-associated fungus Stachybotrys chartarum. Its structures were elucidated by means of spectroscopic methods. At the same time, the compound was tested for its cytotoxicity against HL-60, SMMC-7721, A-549, MCF 7, and SW480 cells. PMID- 29288027 TI - Activity of the pterophyllins 2 and 4 against postharvest fruit pathogenic fungi. Comparison with a synthetic analog and related intermediates. AB - The antifungal activity of pterophyllin 2, pterophyllin 4, a 5-desmethyl analog of the latter and some of their synthetic intermediates, against three postharvest phytopathogenic fungi, was evaluated. The target fungi were Rhizopus stolonifer, Botrytis cinerea and Monilinia fructicola, which affect fruits worldwide, causing important economic losses. The tests were carried out with imazalil and carbendazim as positive controls. Minimum inhibitory concentrations and minimum fungicidal concentrations were determined, and the morphology of the colonies was examined microscopically. In liquid medium, it was found that pterophyllin 4 exhibited selective fungicidal activity toward M. fructicola, whereas its congener pterophyllin 2 proved to be less potent and not selective and the 5-desmethyl analog of pterophyllin 4 displayed a different activity profile. Morphological changes were observed in the colonies exposed to pterophyllin 4. The results highlighted the importance of small structural features for the antifungal behavior and also suggested that, in Nature, the pterophyllins may act as plant defenses against pathogens. PMID- 29288029 TI - Comparison of Changes in Macular Ganglion Cell-Inner Plexiform Layer Thickness Between Medically and Surgically Treated Eyes With Advanced Glaucoma. AB - PURPOSE: To compare changes in the macular ganglion cell layer and inner plexiform layer (mGCIPL) thickness over 5 years between surgically treated eyes (STE) and medically treated eyes (MTE) with advanced glaucoma. DESIGN: Retrospective, comparative case series. METHODS: Eighty-six patients comprising 43 with open-angle glaucoma (OAG) with trabeculectomy and 43 with medically treated OAG. The mGCIPL thickness was measured more than 5 times during follow-up by optical coherence tomography. Main outcome measure was differences in mGCIPL thickness thinning rate between the groups. RESULTS: The mean age at study initiation was 62.5 +/- 9.2 years in STE and 62.7 +/- 9.5 years in MTE. The mean deviations (MD), according to the Humphrey Field Analyzer central program 30-2, and the mGCIPL thickness in each sector showed no significant differences at initial measurement. The averaged intraocular pressure (IOP) throughout follow-up was 10.5 +/- 2.0 mm Hg in STE and 10.8 +/- 0.8 mm Hg in MTE (P = .429; Mann Whitney U test). There was no significant difference in the MD changes over 5 years between the 2 groups (P = .405; Mann-Whitney U test). Changes in the mGCIPL thickness over 5 years in MTE were significantly greater than that in STE in all sectors (all 6 sectors P < .0001, Mann-Whitney U test). The IOP fluctuation over 5 years in STE was significantly less than that in MTE (P < .0001, Mann-Whitney U test). CONCLUSIONS: The structure of the mGCIPL was better preserved in STE than in MTE, even when the IOPs during follow-up were similar. PMID- 29288028 TI - Hyperattenins L and M, two new polyprenylated acylphloroglucinols with adamantyl and homoadamantyl core structures from Hypericum attenuatum. AB - Hyperattenins L (1) and M (2), two new benzoylated polyprenylated phloroglucinol derivatives possessing unusual adamantyl and homoadamantyl core structures, were isolated from the aerial parts of Hypericum attenuatum. Their structures were determined by extensive NMR spectroscopic methods. Compound 1 possesses an unusual tetracyclo[6.3.1.11,10.01,5]tridecane skeleton, representing the second report of natural product with this carbon skeleton. Compound 2 features an unexpected 2,3,13-trioxapentacyclo[7.5.3.17,11.05,16.012,16]octodecane ring system formed by the fusion of 2,3,8-trioxabicyclo[4.3.1]decane moiety to the tricycle[4.3.1.13,8]undecane core. Both compounds were evaluated for their cytotoxic activities against five human cancer cell lines and compound 1 showed excellent inhibitory activities against HL-60, A-549, and MCF-7 cell lines with IC50 values of 3.86, 4.34, and 5.78MUM, respectively. PMID- 29288030 TI - Peripheral Pigmented Retinal Lesions in Stargardt Disease. AB - PURPOSE: To investigate the prevalence of peripheral pigmented retinal lesions and associated clinical findings in patients with Stargardt disease. DESIGN: Retrospective case series. METHODS: Records at a single academic institution were reviewed for patients with genetically confirmed Stargardt disease with peripheral pigmented retinal lesions on wide-field retinal imaging. For this cohort we described demographics, clinical features, and pathogenic variants. RESULTS: Out of 62 patients with Stargardt disease and wide-field retinal imaging, 14 had peripheral pigmented retinal lesions. These flat, subretinal lesions were located in the mid or far periphery and had well-defined borders, resembling congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions. For this group of 14 patients, median age at initial diagnosis of Stargardt disease was 9.5 years, and the median duration of disease was 21.5 years. Median Snellen visual acuity was 20/200, and median central scotoma size was 20.0 degrees. All 14 patients had electroretinographic abnormalities. Four out of 14 patients developed new lesions during clinical follow-up. CONCLUSIONS: Wide-field retinal imaging revealed the presence of peripheral pigmented retinal lesions resembling CHRPE lesions in a subset of patients with genetically confirmed Stargardt disease. Presence of these lesions may be associated with severe phenotypes of the disease. PMID- 29288031 TI - Prevalence and Characteristics of Myopic Degeneration in an Adult Chinese American Population: The Chinese American Eye Study. AB - PURPOSE: To characterize and provide population-based prevalence estimates of myopic degeneration (MD) among Chinese Americans, the fastest-growing minority population in the United States in the last decade. DESIGN: Population-based, cross-sectional study. METHODS: A total of 1523 Chinese-American adults with myopia, aged 50 years and older, residing in the city of Monterey Park, California, underwent an interview and comprehensive eye examination, including subjective and objective refraction and stereoscopic fundus photography. For each participant, the eye with the worse myopic refractive error was included in this analysis. MD was assessed in a masked manner by an expert grader. RESULTS: The prevalence of any MD was 44.9% among myopic subjects, based on the presence of any degenerative lesion secondary to myopia. The prevalence was 32.2% when MD was defined by a modified version of the Meta-Analysis for Pathologic Myopia. The prevalence of specific lesions included tessellation (31.7%), tilted disc (28.1%), peripapillary atrophy (7.0%), staphyloma (5.7%), diffuse atrophy (6.4%), lacquer cracks (2.6%), intrachoroidal cavitation (2.2%), patchy atrophy (0.9%), and end-stage MD (0.2%). The prevalence of MD was higher among older myopic subjects and among participants with more severe myopia and longer axial length (P < .001). CONCLUSIONS: These data provide the first population-based estimates of MD in Chinese Americans and indicate that a high proportion of Chinese Americans might be at risk for MD and associated visual complications. Prevalence of MD in this cohort of Chinese Americans was higher than that observed in other East Asian populations and in people of other ethnicities. PMID- 29288032 TI - Chitosan-stablized bovine serum albumin nanoparticles having ability to control the release of NELL-1 protein. AB - The study was designed to prepare and evaluate chitosan stabilized-albumin nanoparticles as NELL-1 protein carriers(Chi/NNPs). The Chi/NNPs were prepared by desolvation method and then stabilized by chitosan through electrostatic interaction. The Chi/NNPs were characterized for drug loading efficiency, surface morphology, particle size, surface charge. Fluorescein isothiocyanate-labeled chitosan was used to confirm the homogeneity of chitosan coating on the BSA nanoparticles. The NELL-1 bioactivity of Chi/NNPs and the release kinetics were investigated in vitro. It was observed that the mean particle size with chitosan (0.075 wt%,0.15 wt%, 0.3 wt%, respectively) and the surface charge were 368.663 +/- 15.470 nm, 382.881 +/- 18.767 nm, 390.480 +/- 11.465 nm and +25.03 +/- 1.42 mV, +30.27 +/- 1.80 mV, +31.03 +/- 2.05 mV respectively. Drug entrapment efficiency ranged from 87.83% to 89.30%. The Chi/NNPs prepared with the 0.15 wt% chitosan were able to successfully control the release of NELL-1 and maintain a sustained release for up to 8 days. Furthermore, more than 82.67 +/- 8.74% of the loaded protein's bioactivity was preserved in Chi/NNPs over the period of the investigation. Our findings suggest that Chi/NNPs as promising protein delivery nanocarriers have the ability to maintain sustained release kinetics and to preserve the bioactivity of released NELL-1. PMID- 29288033 TI - Targeting renal fibrosis: Mechanisms and drug delivery systems. AB - Renal fibrosis is the common outcome of many chronic kidney diseases (CKD) independent of the underlying etiology. Despite a host of promising experimental data, currently available strategies only ameliorate or delay the progression of CKD but do not reverse fibrosis. One of the major impediments of translating novel antifibrotic strategies from bench to bedside is due to the intricacies of the drug delivery process. In this review, we briefly describe mechanisms of renal fibrosis and methods of drug transfer into the kidney. Various tools used in gene therapy to administer nucleic acids in vivo are discussed. Furthermore, we review the modes of action of protein- or peptide-based drugs with target specific antibodies and cytokines incorporated in hydrogels. Additionally, we assess an intriguing new method to deliver drugs specifically to tubular epithelial cells via conjugation with ligands binding to the megalin receptor. Finally, plant-derived compounds with antifibrotic properties are also summarized. PMID- 29288034 TI - Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide-gated and ryanodine 2 channels. AB - BACKGROUND: Aging is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction. OBJECTIVE: The aim of this study was to investigate the structural and functional remodeling in the atrioventricular junction (AVJ) with aging. METHODS: Electrophysiology, histology, and immunohistochemistry experiments on male Wistar Hannover rats aged 3 months (n = 24) and 2 years (n = 15) were performed. Atrio-His (AH) interval, Wenkebach cycle length (WBCL), and AVN effective refractory period (AVNERP) were measured. Cesium (2 mM) was used to block hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, while ryanodine (2 MUM) was used to block ryanodine 2 (RyR2) channels. Protein expression from different regions of the AVJ was studied using immunofluorescence. The expression of connexins (connexin 43 and connexin 40), ion channels (Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), voltage sensitive sodium channel (Nav1.5), and L-Type calcium channel (Cav1.3)), and calcium handling proteins (RyR2 and sarco/endoplasmic reticulum calcium ATPaset type 2a (SERCA2a)) were measured. Morphological characteristics were studied with histology. RESULTS: Without drugs to block HCN and RyR2 channels, there was prolongation of the AH interval, WBCL, and AVNERP (P < .05) with aging. In young rats only, cesium prolonged the AH interval, WBCL, and AVNERP (P < .01). Ryanodine prolonged the AH interval and WBCL (P < .01) in both young and old rats. Immunofluorescence revealed that with aging, connexin 43, HCN4, Nav1.5, and RyR2 downregulate in the regions of the AVJ and connexin 40, SERCA2a, and Cav1.3 upregulate (P < .05). Aging results in cellular hypertrophy, loosely packed cells, a decrease in the number of nuclei, and an increase in collagen content. CONCLUSION: Heterogeneous ion channel expression changes were observed in the AVJ with aging. For the first time, we have shown that HCN and RyR2 play an important role in AVN dysfunction with aging. PMID- 29288035 TI - Clinical impact of an additional left ventricular lead in cardiac resynchronization therapy nonresponders: The V3 trial. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an effective treatment of heart failure (HF), but is limited by a substantial proportion of nonresponders. We hypothesized that adding a second left ventricular (LV) lead to deliver a triple-site CRT (V3 CRT) may improve clinical status of CRT nonresponders. OBJECTIVE: We assessed the feasibility and safety of adding a second LV lead to CRT nonresponders and its clinical impact. METHODS: Eighty-four recipients of a CRT system and considered as nonresponders as per clinical composite score (CCS) were enrolled in this multicenter study. They were randomized to the V3 arm (implantation of an additional LV lead; n = 43) or control arm (no change; n = 41). Implant success rate, incidence of severe adverse events, CCS, and secondary clinical and echocardiographic end points were evaluated at 12 and 24 months. RESULTS: Positioning of a second LV lead was successful at first (40 of 44 - 90.9%) or second (4 of 44 - 9.09%) attempt. The perioperative complication rate (infection, system explant, pneumothorax, and hematoma) was high (procedures or system-related complications for 9 patients- 20.4%). After 24 months, 35 systems (79.5%) were working properly. The multinomial logistic regression model showed that V3 treatment had no significant influence (P = .27) on the CCS, number of HF hospitalizations, time to first HF hospitalization, New York Heart Association class, and LV ejection fraction at 12 and 24 months. CONCLUSION: Although addition of a second LV lead in CRT nonresponders is feasible with a high success rate, this approach is associated with a significant rate of severe adverse events and does not provide significant long-term clinical benefits (ClinicalTrials.gov Identifier No. NCT01059175). PMID- 29288036 TI - A study of MRI gradient echo signals from discrete magnetic particles with considerations of several parameters in simulations. AB - Modeling MRI signal behaviors in the presence of discrete magnetic particles is important, as magnetic particles appear in nanoparticle labeled cells, contrast agents, and other biological forms of iron. Currently, many models that take into account the discrete particle nature in a system have been used to predict magnitude signal decays in the form of R2* or R2' from one single voxel. Little work has been done for predicting phase signals. In addition, most calculations of phase signals rely on the assumption that a system containing discrete particles behaves as a continuous medium. In this work, numerical simulations are used to investigate MRI magnitude and phase signals from discrete particles, without diffusion effects. Factors such as particle size, number density, susceptibility, volume fraction, particle arrangements for their randomness, and field of view have been considered in simulations. The results are compared to either a ground truth model, theoretical work based on continuous mediums, or previous literature. Suitable parameters used to model particles in several voxels that lead to acceptable magnetic field distributions around particle surfaces and accurate MR signals are identified. The phase values as a function of echo time from a central voxel filled by particles can be significantly different from those of a continuous cubic medium. However, a completely random distribution of particles can lead to an R2' value which agrees with the prediction from the static dephasing theory. A sphere with a radius of at least 4 grid points used in simulations is found to be acceptable to generate MR signals equivalent from a larger sphere. Increasing number of particles with a fixed volume fraction in simulations reduces the resulting variance in the phase behavior, and converges to almost the same phase value for different particle numbers at each echo time. The variance of phase values is also reduced when increasing the number of particles in a fixed voxel. These results indicate that MRI signals from voxels containing discrete particles, even with a sufficient number of particles per voxel, cannot be properly modeled by a continuous medium with an equivalent susceptibility value in the voxel. PMID- 29288037 TI - Simulation-based quantification of native T1 and T2 of the myocardium using a modified MOLLI scheme and the importance of Magnetization Transfer. AB - Quantitative cardiovascular Magnetic Resonance Imaging techniques are gaining wide acceptance within the MR community due to their potential to diagnose non localized disease, guide therapy and improve patient outcome. During the last decade, there has been an increasing interest for developing new techniques that allow for simultaneous quantification of both T1 and T2 maps of myocardium. Newer studies demonstrated that the incorporation of MRI simulations could yield similar results to conventional mapping techniques in the myocardium. However, these simulation-based quantitative MR techniques usually compare the in-vivo T1 estimates against less accurate T1 techniques, whereas they present inconsistencies between simulation studies, phantom and in-vivo measurements. Moreover, these studies do not investigate the effect of Magnetization Transfer on the myocardial T1 and T2 estimates but are usually validated on phantoms where the MT effect is small. The main aim of this study was to perform simultaneous mapping of the native T1 and T2 of the myocardium through the utilization of a modified MOLLI pulse sequence and the incorporation of advanced MR simulations through the SQUAREMR framework. A second aim of this study was to investigate the effect of MT on simulation-based quantitative MR techniques. A conventional MOLLI pulse sequence was modified so as to present combined high T2 sensitivity and low MT effect. The new technique was applied in healthy volunteers and demonstrated an improved T1 accuracy compared to the conventional MOLLI and a T2 accuracy similar to the one provided by the T2prep-bSSFP method. The effect of MT on T1 and T2 estimates was also investigated in the current study. Phantoms with an increasing MT effect as well as phantoms without an MT effect were included in this work whereas several variants of the modified-MOLLI that introduce different amounts of T2 modulation on the MR signal and induce different MT effects were applied on the phantoms. The proposed simulation-based quantitative MR technique for simultaneous T1 and T2 mapping of the myocardium does not require the incorporation of a complicated custom designed pulse sequence and does not require a complicated reconstruction workflow. Moreover, the current study demonstrates for the first time that MT plays an important role in the simulation based quantitative MR studies and points out the necessity of incorporating the study of MT in future techniques. PMID- 29288038 TI - BRG1 is correlated with poor prognosis in colorectal cancer. AB - Brahma-related gene 1 (BRG1), a component of the chromatin-remodeling complex, regulates transcription by remodeling the chromatin structure. The present study aimed to elucidate the clinicopathological significance and prognostic role of BRG1 in colorectal cancer (CRC). We investigated the correlation between BRG1 expression and clinicopathological parameters, including prognosis, using immunohistochemistry on 266 archival paraffin-embedded CRC tissues. In addition, to confirm the prognostic role of BRG1 in malignant tumors, we performed a meta analysis of 9 eligible studies and the current study. BRG1 was highly expressed in 67.7% of the 266 CRCs analyzed. High BRG1 expression significantly correlated with poor overall and recurrence-free survival (P < .001 and P < .001, respectively). The high expression of BRG1 also significantly correlated with high expression of SNAI (P < .001) but not E-cadherin (P = .432). However, there was no significant correlation between BRG1 expression and other clinicopathological parameters. The meta-analysis also demonstrated that high BRG1 expression positively correlated with poor overall and recurrence-free survival (hazard ratio 1.572, 95% confidence interval 1.106-2.235 and hazard ratio 2.050, 95% confidence interval 1.610-2.610, respectively). However, subgroup analysis based on tumor type showed that the correlation between BRG1 expression and poor prognosis was only prevalent in CRC and breast cancer. Taken together, the results of this study suggest that high BRG1 expression was associated with high SNAI expression and was significantly correlated with poor prognosis. PMID- 29288039 TI - Immunoglobulin G4-related chronic rhinosinusitis: a pitfall in the differential diagnosis of granulomatosis with polyangiitis, Rosai-Dorfman disease, and fungal rhinosinusitis. AB - Immunoglobulin G4 (IgG4)-related chronic rhinosinusitis (CRS) has recently been proposed to be a new clinical entity of nasal disease, with no consensually agreed criteria for diagnosis. Moreover, the pathological features of IgG4 related CRS often overlap with other sinonasal inflammatory and autoimmune diseases such as granulomatosis with polyangiitis (GPA), Rosai-Dorfman disease (RDD) and fungal rhinosinusitis (FRS). We aimed to explore the specific similarities and differences in clinicopathologic features between IgG4-related CRS, and GPA, RDD and FRS, in order that these conditions can be diagnosed more accurately. Biopsy specimens collected from nasal mucosa of 20 IgG4-related CRS, 10 GPA, 10 RDD and 10 FRS patients were assessed by hematoxylin and eosin staining and immunohistochemical techniques for specific histochemical differences. The number of IgG4-positive plasma cells /high-power fields (HPF) in biopsies from IgG4-related CRS patients (mean=79.6+/-51.59; range=15/HPF to 230/HPF) was significantly higher than in biopsies from GPA (mean=13+/-9.428; P<.0001) and RDD (mean=12.5+/- 8.267; P<.0001) patients, but not from FRS (mean=47.4+/-26.48; P>.05) patients. Similarly, the ratio of IgG4/IgG-positive plasmacytes was >40% in 90% (18/20) of IgG4-related CRS patients, compared to >40% in 10% (1/10) of GPA patients, 20% (2/10) of RDD patients and 20% (2/10) of FRS patients. The sinonasal diseases GPA, RDD and FRS might present with similar histopathologic features such as the increased numbers of plasma cells and fibrosis, which are characteristic of IgG4-related CRS. A comprehensive consideration combining the clinical signs and symptoms with a histopathological assessment of IgG4-positive plasma cells may provide accurate diagnoses of these conditions. PMID- 29288040 TI - Overexpression of ARID4B predicts poor survival in patients with hepatocellular carcinoma. AB - AT-rich interaction domain 4B (ARID4B), which belongs to the ARID family, is heavily involved in cell growth and differentiation and is closely associated with many types of tumors. However, the role of this protein in hepatocellular carcinoma (HCC) remains unknown. In this study, we used data from The Cancer Genome Atlas and Gene Expression Omnibus to analyze ARID4B expression in HCC. We subjected 15 pairs of fresh-frozen tissue samples to quantitative real-time polymerase chain reaction and Western blotting analyses to investigate ARID4B expression. We also subjected 157 formalin-fixed, paraffin-embedded HCC tissue samples to immunohistochemical analysis to detect ARID4B expression and to determine the clinical significance of ARID4B expression in HCC. The bioinformatics analysis, quantitative real-time polymerase chain reaction, and Western blotting results showed that ARID4B was highly expressed in HCC tissues compared with adjacent normal liver tissues. High ARID4B expression was strongly correlated with tumor number (P = .02), vascular invasion (P = .004), Edmondson Steiner grades (P = .000), and tumor-node-metastasis stages (P = .001). Moreover, Kaplan-Meier and Cox proportional-hazards analyses indicated that high ARID4B expression was significantly associated with poor survival in patients with HCC and that ARID4B was an independent prognostic factor for overall survival and disease-free survival in patients with HCC. In conclusion, our results suggest that ARID4B acts as an oncogene in HCC and can therefore serve as a biomarker for the prognoses of patients with HCC. PMID- 29288041 TI - Global quality assessment of liver allograft C4d staining during acute antibody mediated rejection in formalin-fixed, paraffin-embedded tissue. AB - Discussion of liver antibody-mediated rejection during the 2011, 2013, and 2015 Banff liver sessions raised concerns over reliability of complement fragment 4d (C4d) staining, precipitating a global survey followed by a tissue microarray staining quality assessment study among centers on formalin-fixed, paraffin embedded tissue. Tissue microarray sections containing tissue plugs of resected native and allograft (with acute antibody-mediated rejection) liver, heart, and kidney (n = 33 total cores) were sent to 31 centers for C4d staining using local method(s) and pathologist scoring. Digital whole-slide images (n = 40) were then semiquantitatively scored by 7 experts for background, distribution, and intensity of portal vein and capillary, hepatic artery, sinusoidal, and central vein endothelia and portal and central stromal staining. Results showed that strong and diffuse portal vein and capillary C4d staining, as determined by both local and central pathologists, clearly distinguished allografts showing acute antibody-mediated rejection from native livers and from those with evidence of weaker donor-specific antibody. Downstream vascular endothelial cell C4d staining and assessment were more variable and difficult to identify. C4d staining in the majority of laboratories reliably detects acute liver allograft antibody-mediated rejection in formalin-fixed, paraffin-embedded tissues. Assessment should focus on portal veins and capillaries, sinusoids, and central veins present in peripheral core needle biopsies. C4d staining in one organ does not always translate to staining in another. PMID- 29288042 TI - STAT3 mutation and its clinical and histopathologic correlation in T-cell large granular lymphocytic leukemia. AB - Although T-cell large granular lymphocytic leukemia (T-LGLL) is a clinically indolent disorder, patients with moderate to severe cytopenia require therapeutic intervention. The recent discovery of STAT3 mutations has shed light on the genetic basis of T-LGLL pathogenesis. However, the association of STAT3 mutational status with patients' clinical, histopathologic, and other laboratory features has not been thoroughly evaluated in T-LGLL. In this study, STAT3 mutations were identified in 18 of 36 patients with T-LGLL (50%), including Y640F (12/18, 66.7%), N647I (3/18, 16.7%), E638Q (1/18, 5.6%), I659L (1/18, 5.6%), and K657R (1/18, 5.6%). Interestingly, pure red cell aplasia was seen exclusively in T-LGLL patients without STAT3 mutations (6/15 in the wild-type STAT3 group versus 0/13 in the mutant STAT3 group; P = .02); these patients also were the only responders to T-LGLL therapy (mainly cyclophosphamide) in wild-type STAT3 group. Patients harboring STAT3 mutations were more prone to rheumatoid arthritis (4/13 versus 0/15 in the wild-type STAT3 group; P = .04), frequently requiring therapy for neutropenia/neutropenia-associated infections, and demonstrated good therapeutic responses to methotrexate. No significant differences were seen in complete blood count, flow cytometric immunophenotypic features, T-cell receptor gamma V-J rearrangement repertoire, and bone marrow biopsy morphology among the STAT3-mutation and wild-type groups other than significantly larger tumor burden in patients with STAT3 mutations. The distinct disease association and therapeutic responses observed in patients with mutant and wild-type STAT3 warrant further investigation to elucidate the underlying mechanisms. They also highlight the importance of identifying STAT3 mutational status in patients with T-LGLL, which may aid in clinical therapeutic choice. PMID- 29288043 TI - Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer. AB - Tumor-infiltrating lymphocytes (TILs) are associated with better prognosis in newly diagnosed epithelial ovarian cancer (EOC), but clinical trials of immunotherapies in patients with heavily treated disease reveal limited activity. Understanding the tumor microenvironment (TME) of primary and recurrent EOC should guide future trials. Here, we evaluated the TME of paired primary and recurrent tumors (n = 17), and non-paired primary (n = 20) and recurrent (n = 15) tumors, for CD8+ T cells, FOXP3+ regulatory T cells (Tregs), CD68+ tumor associated macrophages (TAMs), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). CD8+ T cells were similar in primary and recurrent tumors, but Tregs were higher in recurrent tumors (P = .0210). Higher TAM density (>=5%) associated with higher Tregs (P = .001) and CD8+ T cells (P < .001) in recurrent tumors, but only with higher Tregs in primary tumors (P = .02). TAM-dense recurrent tumors expressed PD-L1 on tumor and immune cells, whereas TAM-dense primary tumors expressed PD-L1 predominantly on immune cells. In survival analyses, higher Tregs in primary tumors correlated with decreased time to first recurrence (17.0 versus 28.5 months, P = .022). Conversely, higher Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met versus 20.0 months, P = .022). TAM density did not affect patient survival. However, patients with increased TAMs at recurrence (n = 5) had longer OS from recurrence compared to patients without increased TAMs (n = 12) (56.0 versus 20.0 months); with the small sample size, this did not reach statistical significance (P = .074). Further characterization of the evolution of the TME is warranted. PMID- 29288044 TI - Task difficulty has no effect on haptic anchoring during tandem walking in young and older adults. AB - This study assessed the contribution of the "anchor system's" haptic information to balance control during walking at two levels of difficulty. Seventeen young adults and seventeen older adults performed 20 randomized trials of tandem walking in a straight line, on level ground and on a slightly-raised balance beam, both with and without the use of the anchors. The anchor consists of two flexible cables, whose ends participants hold in each hand, to which weights (125 g) are attached at the opposing ends, and which rest on the ground. As the participants walk, they pull on the cables, dragging the anchors. Spatiotemporal gait variables (step speed and single- and double-support duration) were processed using retro-reflective markers on anatomical sites. An accelerometer positioned in the cervical region registered trunk acceleration. Walking on the balance beam increased single- and double-support duration and reduced step speed in older adults, which suggests that this condition was more difficult than walking on the level ground. The anchors reduced trunk acceleration in the frontal plane, but the level of difficulty of the walking task showed no effect. Thus, varying the difficulty of the task had no influence on the way in which participants used the anchor system while tandem walking. The older adults exhibited more difficulty in walking on the balance beam as compared to the younger adults; however, the effect of the anchor system was similar in both groups. PMID- 29288045 TI - Elevated nuclear phosphatase and tensin homolog (PTEN) and altered insulin signaling in substantia nigral region of patients with Parkinson's disease. AB - Studies showed that 50-80% of Parkinson's disease (PD) patients have been reported with abnormal glucose tolerance. Alterations in glucose and energy metabolism serve as the early molecular event in PD. Although evidences support that the insulin resistance plays a major role in motor and non-motor complications of PD, the underlying mechanism in the pathogenesis of PD is unclear. To address this issue, we investigated the alterations in major components of insulin signaling in nuclear fraction (NF) and whole tissue homogenate (TH) of substantia nigral (SN) region obtained from postmortem PD brain and their age-matched controls. Pathway components include insulin receptor beta (IRbeta), IR substrate-1 (IRS1), phosphoinositide 3-kinase p85 (PI3K p85), phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol (3,4,5) trisphosphate (PIP3), protein kinase B (PKB/Akt1/2/3) and glycogen synthase kinase-3beta (GSK3beta). Phosphatase and tensin homolog (PTEN), a negative regulator of insulin signaling cascade was also studied. A significant decrease in nuclear PI3K p85, Akt1/2/3 and PIP3 levels and significant increase in nuclear PTEN and GSK3beta levels were observed in SN region of PD brain when compared to the age-matched controls. Consistently, significant decrease in IRbeta, IRS1, PI3K p85, Akt1/2/3 and PIP3 levels and increased GSK3beta level were observed in TH obtained from SN region of PD brain compared to the control brain. Data from the study suggest that alterations in insulin signaling may play a vital role in the pathogenesis/progression of PD and other related complications. Thus, decreasing nuclear accumulation of PTEN and/or restoring insulin signaling cascade may halt the neurodegeneration in PD. PMID- 29288046 TI - TAAR5 receptor agonist affects sensory gating in rats. AB - Trace amines are structurally close to classical monoamines and dysregulation in trace amines and/or their receptors might contribute to pathology of mental disorders. The study was aimed to investigate the effect of recently identified Trace Amine-Associated Receptor 5 (TAAR5) agonist 2-(alpha naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) on sensory gating (SG) in awake freely moving rats. SG was studied in paired-click paradigm and SG index was calculated as difference in event related potentials component N40 amplitudes to the first and second stimulus in the pair. The 1 mg/kg dose of alpha-NETA as well as the control injection of saline had no significant effects on the SG index. However, higher doses of alpha-NETA (3 and 5 mg/kg) significantly decreased the SG index. The change in the SG index was mainly due to a decrease in the N40 amplitude, and the 5 mg/kg dose caused the N40 decrease both in response to the first and second stimulus in the pair. Thus, TAAR5 activation can influence SG, indicating the potential role of trace amines and TAAR5 in sensory information dosing. PMID- 29288047 TI - Sway regularity and sway activity in older adults' upright stance are differentially affected by dual task. AB - Age-related changes in postural control are attributed to visual, vestibular and proprioceptive dysfunctions, muscle weakness, and reduced availability of neural resources required for efficient balance control. Concurrent performance of complex cognitive tasks while standing or walking is expected to increase balance instability due to under-recruitment of brain resources and insufficient allocation of attention to the postural task. Both balance instability and attentional control of movements can, nonetheless, be determined from the center of pressure (CoP) measurements by examining the effects of dual-task on the amount of sway activity (as measured by CoP velocity - Vcop) and the statistical regularity of the CoP trajectory (the wavelet entropy of the signal - WEcop). The abovementioned characteristics were examined in the present study in a group of 13 healthy older adults. The task involved maintaining Romberg stance for 25 s with or without performing an attention demanding cognitive tasks (word memorization or mathematical counting). A linear mixed-model study was designed to analyze the extent to which sway activity can predict sway regularity. Findings from the present study showed that, on average, Vcop and WEcop were positively correlated (p = 0.014), suggesting that older individuals who exhibited greater amounts of sway (i.e., higher Vcop) also increased sway irregularity of the posturogram - as evidenced by a higher level of wavelet entropy of the CoP trajectory. Nevertheless, results of the linear mixed model showed that significant positive associations between Vcop and WEcop were found only in dual task (R >= 0.67, p <= 0.012). Furthermore, dual-task effects (% change in performance) on both sway characteristics were not significant (p > 0.1), suggesting that none of the attention demanding cognitive tasks used in the present study was sufficient to divert a critical amount of attentional resources from the postural task. Finally, performance of the mathematical counting (but not the word memorization) task was deteriorated from sitting to standing, however this effect was marginal (p = 0.075). Taken together, we proposed that while dual task could hinder balance control, postural stability may still be maintained by allocating more attentional resources to the postural task and reducing automatized control. PMID- 29288049 TI - Development of a recombinase polymerase amplification combined with lateral-flow dipstick assay for detection of bovine ephemeral fever virus. AB - Bovine ephemeral fever virus (BEFV), identified as the causative pathogen of bovine ephemeral fever (BEF), is responsible for increasing numbers of epidemics/outbreaks and has a significant harmful effect on the livestock industry. Therefore, a rapid detection assay is imperative for BEFV diagnosis. In this study, we described the development of lateral-flow dipstick isothermal recombinase polymerase amplification (LFD-RPA) assays for detection of BEFV. RPA primers and LF probes were designed by targeting the specific G gene, and the amplification product can be visualized on a simple lateral flow dipstick with the naked eyes. The amplification reaction was performed at 38 degrees C for 20 min and LFD incubation time within 5 min. The detection limit of this assay was 8 copies per reaction, and there was no cross-reactivity with other bovine infectious viruses such as bovine viral diarrhea virus, infectious bovine rhinotracheitis virus, bovine respiratory syncytial virus, bovine coronavirus, bovine parainfluenza virus type 3, bovine vesicular stomatitis virus. In addition, the assay was performed with total 128 clinical specimens and the diagnostic results were compared with conventional RT-PCR, real-time quantative(q) PCR. The result showed that the coincidence rate of BEFV LFD-RPA and real-time qPCR was 96.09% (123/128), which was higher than conventional RT PCR. The RPA combined with LFD assay probably provides a rapid and sensitive alternative for diagnosis of BEFV infections outbreak. PMID- 29288050 TI - Enhancement of immune response and resistance against Vibrio parahaemolyticus in kuruma shrimp (Marsupenaeus japonicus) by dietary supplementation of beta-1,4 mannobiose. AB - Supplementation of prebiotic carbohydrates can act as a potent immunomodulator and have the efficacy to induce immune-related genes which are involved in host defense. Pure beta-1,4-mannobiose (MNB) showed activation of prophenoloxidase system of shrimp hemocytes in vitro. The resistance of kuruma shrimp Marsupenaeus japonicus against Vibrio parahaemolyticus was examined after the shrimp were fed with 0 (control), 0.02, 0.2, and 2% MNB supplemented diets. The results showed significantly higher survival rates in MNB supplemented shrimp than those of the control one from 2 to 12 days post challenge. In another experiment, the hemocyte count, ROS production, phagocytic, phenoloxidase and bactericidal activities, and expression of immune-related genes were investigated in the control and MNB supplemented groups at day 1, 4, 6, 8 and 11 of the feeding. These immune parameters were significantly enhanced in MNB supplemented groups. Furthermore, the gene expression analysis showed that transcripts of lysozyme, crustin, penaeidin and TNF were significantly up-regulated in hemolymph, lymphoid organs and intestines of MNB treated shrimp. Overall, the results provided evidence that MNB supplementation could improve the immune response and increase shrimp resistance against V. parahaemolyticus infection. PMID- 29288051 TI - Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A. AB - Human serum amyloid A (SAA) is a precursor protein of AA amyloidosis. Although the full-length SAA is 104 amino acids long, the C-terminal-truncated SAA lacking mainly residues 77-104 is predominantly deposited in AA amyloidosis. Nevertheless, the amyloid fibril formation of such truncated forms of human SAA has never been investigated. In the present study, we examined the effect of C terminal truncation on amyloid fibril formation of human SAA induced by heparan sulfate (HS). Circular dichroism (CD) measurements demonstrated that the C terminal truncation induces a reduced alpha-helical structure of the SAA molecule. HS-induced increases in thioflavin T fluorescence for SAA (1-76) peptide and less significant increases for full-length SAA were observed. CD spectral changes of SAA (1-76) peptide but not full-length SAA were observed when incubated with HS, although the spectrum was not typical for a beta-structure. Fourier transform infrared experiments clearly revealed that SAA (1-76) peptide forms a beta-sheet structure. Transmission electron microscopy revealed that short fibrillar aggregates of SAA (1-76) peptides, which became longer with increasing peptide concentrations, were observed under conditions in which full length SAA scarcely formed fibrillar aggregates. These results suggested that the C-terminal truncation of human SAA accelerates amyloid fibril formation. PMID- 29288048 TI - Recommendations for the prevention and diagnosis of asthma in children: Evidence from international guidelines adapted for Mexico. AB - BACKGROUND: With the availability of high-quality asthma guidelines worldwide, one possible approach of developing a valid guideline, without re-working the evidence, already analysed by major guidelines, is the ADAPTE approach, as was used for the development of National Guidelines on asthma. METHODS: The guidelines development group (GDG) covered a broad range of experts from medical specialities, primary care physicians and methodologists. The core group of the GDG searched the literature for asthma guidelines 2005 onward, and analysed the 11 best guidelines with AGREE-II to select three mother guidelines. Key clinical questions were formulated covering each step of the asthma management. RESULTS: The selected mother guidelines are British Thoracic Society (BTS), GINA and GEMA 2015. Responses to the questions were formulated according to the evidence in the mother guidelines. Recommendations or suggestions were made for asthma treatment in Mexico by the core group, and adjusted during several rounds of a Delphi process, taking into account: 1. Evidence; 2. Safety; 3. Cost; 4. Patient preference - all these set against the background of the local reality. Here the detailed analysis of the evidence present in BTS/GINA/GEMA sections on prevention and diagnosis in paediatric asthma are presented for three age-groups: children with asthma <=5 years, 6-11 years and >=12 years. CONCLUSIONS: For the prevention and diagnosis sections, applying the AGREE-II method is useful to develop a scientifically-sustained document, adjusted to the local reality per country, as is the Mexican Guideline on Asthma. PMID- 29288052 TI - Hydrophobic interactions of sucralose with protein structures. AB - Sucralose is a commonly employed artificial sweetener that appears to destabilize protein native structures. This is in direct contrast to the bio-preservative nature of its natural counterpart, sucrose, which enhances the stability of biomolecules against environmental stress. We have further explored the molecular interactions of sucralose as compared to sucrose to illuminate the origin of the differences in their bio-preservative efficacy. We show that the mode of interactions of sucralose and sucrose in bulk solution differ subtly through the use of hydration dynamics measurement and computational simulation. Sucralose does not appear to disturb the native state of proteins for moderate concentrations (<0.2 M) at room temperature. However, as the concentration increases, or in the thermally stressed state, sucralose appears to differ in its interactions with protein leading to the reduction of native state stability. This difference in interaction appears weak. We explored the difference in the preferential exclusion model using time-resolved spectroscopic techniques and observed that both molecules appear to be effective reducers of bulk hydration dynamics. However, the chlorination of sucralose appears to slightly enhance the hydrophobicity of the molecule, which reduces the preferential exclusion of sucralose from the protein-water interface. The weak interaction of sucralose with hydrophobic pockets on the protein surface differs from the behavior of sucrose. We experimentally followed up upon the extent of this weak interaction using isothermal titration calorimetry (ITC) measurements. We propose this as a possible origin for the difference in their bio-preservative properties. PMID- 29288053 TI - The histidine phosphocarrier protein, HPr, binds to the highly thermostable regulator of sigma D protein, Rsd, and its isolated helical fragments. AB - The phosphotransferase system (PTS) controls the preferential use of sugars in bacteria and it is also involved in other processes, such as chemotaxis. It is formed by a protein cascade in which the first two proteins are general (namely, EI and HPr) and the others are sugar-specific permeases. The Rsd protein binds specifically to the RNA polymerase (RNAP) sigma70 factor. We first characterized the conformational stability of Escherichia coli Rsd. And second, we delineated the binding regions of Streptomyces coelicolor, HPrsc, and E. coli Rsd, by using fragments derived from each protein. To that end, we used several biophysical probes, namely, fluorescence, CD, NMR, ITC and BLI. Rsd had a free energy of unfolding of 15 kcal mol-1 at 25 degrees C, and a thermal denaturation midpoint of 103 degrees C at pH 6.5. The affinity between Rsd and HPrsc was 2 MUM. Interestingly enough, the isolated helical-peptides, comprising the third (RsdH3) and fourth (RsdH4) Rsd helices, also interacted with HPrsc in a specific manner, and with affinities similar to that of the whole Rsd. Moreover, the isolated peptide of HPrsc, HPr9-30, comprising the active site, His15, also was bound to intact Rsd with similar affinity. Therefore, binding between Rsd and HPrsc was modulated by the two helices H3 and H4 of Rsd, and the regions around the active site of HPrsc. This implies that specific fragments of Rsd and HPrsc can be used to interfere with other protein-protein interactions (PPIs) of each other protein. PMID- 29288054 TI - Mitochondria in non-alcoholic fatty liver disease. AB - NAFLD is a common disease in Western society and ranges from steatosis to steatohepatitis and to end-stage liver disease. The molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood. One suggested mechanism involves the oxidation of biomolecules by mitochondrial ROS which initiates a vicious cycle of exacerbated mitochondrial dysfunction and increased hepatocellular oxidative damage. This may ultimately pave the way for hepatic inflammation and liver failure. This review updates our current understanding of mitochondria-derived oxidative stress in the progression of NAFLD. PMID- 29288055 TI - Atorvastatin combined with ticagrelor prevent ischemia-reperfusion induced vascular endothelial dysfunction in healthy young males - A randomized, placebo controlled, double-blinded study. AB - BACKGROUND: Atorvastatin and ticagrelor have been shown to prevent against tissue injury in animals. It is unclear if these beneficial effects are also detectable in humans. We studied the effect of high-dose atorvastatin combined with ticagrelor loading on endothelial dysfunction in a model of forearm vascular ischemia-reperfusion (IR) injury. METHODS: 32 healthy subjects (n=16 per group) were enrolled in this randomized, placebo-controlled, double-blinded trial. Forearm blood flow (FBF) measurements in response to increasing intra-arterial doses of the vasodilator acetylcholine (ACh; endothelium-dependent agonist) and glyceryltrinitrate (GTN; endothelium-independent) were performed before and after a cuff-induced 20min forearm ischemia, respectively. FBF reactivity was assessed prior to any pharmacological intervention and after 14days intake of 80mg atorvastatin once daily or placebo, followed by an oral loading dose of 180mg ticagrelor. In addition, lipoprotein parameters and platelet aggregation were evaluated. RESULTS: Ticagrelor loading mitigated ischemia-induced endothelial dysfunction and in combination with repeated atorvastatin dosing the response to ACh during reperfusion was completely normalized (FBF AChAUC ratio post- vs. pre ischemia: 0.81 [ticagrelor] vs. 1.04 [atorvastatin+ticagrelor]; P=0.001). As expected, GTN-induced vasodilation was not affected by IR injury. Atorvastatin significantly reduced total and low density lipoprotein cholesterol concentrations, while high density lipoprotein cholesterol and triglyceride levels remained unchanged. CONCLUSION: Chronic atorvastatin treatment combined with ticagrelor loading prevents against endothelial dysfunction after acute forearm ischemia. Ticagrelor alone mitigated the impaired endothelium-dependent FBF response as compared to no pharmacological intervention. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02910778. PMID- 29288056 TI - Short-term effects of nitrogen dioxide on hospital admissions for cardiovascular disease in Wallonia, Belgium. AB - Many studies have shown a short-term association between NO2 and cardiovascular disease. However, few data are available on the delay between exposure and a health-related event. The aim of the present study is to determine the strength of association between NO2 and cardiovascular health in Wallonia for the period 2008-2011. This study also seeks to evaluate the effects of age, gender, season and temperature on this association. The effect of the delay between exposure and health-related event was also investigated. The daily numbers of hospital admissions for arrhythmia, acute myocardial infarction, ischemic and haemorrhagic stroke were taken from a register kept by Belgian hospitals. Analyses were performed using the quasi-Poisson regression model adjusted for seasonality, long term trend, day of the week, and temperature. Our study confirms the existence of an association between NO2 and cardiovascular disease. Apart from haemorrhagic stroke, the strongest association between NO2 concentrations and number of hospital admissions is observed at lag 0. For haemorrhagic stroke, the association is strongest with a delay of 2days. All associations calculated without stratification are statistically significant and range from an excess relative risk of 2.8% for myocardial infarction to 4.9% for haemorrhagic strokes. The results of this study reinforce the evidence of the short-term effects of NO2 on hospital admissions for cardiovascular disease. The different delay between exposure and health-related event for haemorrhagic stroke compared to ischemic stroke suggests different mechanisms of action. PMID- 29288057 TI - The role of DNA methylation in the association between childhood adversity and cardiometabolic disease. AB - Growing evidence suggests that adverse environmental stimuli, especially during sensitive periods in early life, may lead to cardiometabolic disease in later life. However, the underlying biological mechanisms remain a mystery. Recent studies inferred that epigenetic modifications are likely involved. We review recent studies, primarily focused on the findings from human studies, to indicate the role of DNA methylation in the associations between childhood adversity and cardiometabolic disease in adulthood. In particular, we focused on DNA methylation modifications in genes regulating the hypothalamus-pituitary-adrenal axis as well as the immune system. PMID- 29288058 TI - A Propensity Matched Comparison for Open and Endovascular Treatment of Post carotid Endarterectomy Restenosis. AB - OBJECTIVES: To compare results of open and endovascular management of post carotid endarterectomy (CEA) restenosis. METHODS: This was a retrospective single centre matched case control study. From 2005 to 2015, 148 consecutive interventions for post-CEA restenosis were performed: 80 cases received carotid artery stenting (CAS) and 68 cases received redo CEA. Propensity score based matching was performed in a 1:1 ratio to compare outcomes. Coronary artery disease, degree of the carotid restenosis, timing of the re-intervention with respect to the primary intervention (greater or less than 24 months) and the presence of ipsilateral brain lesions were the covariates included in the matching. Peri-operative outcomes were analysed with chi2 tests, while late results were estimated by Kaplan-Meier methods. RESULTS: After propensity matching, 32 CAS interventions were matched with 32 redo CEAs. There were no peri operative deaths or strokes. Cranial nerve palsy occurred in seven patients in the redo CEA group. Median duration of follow-up was 36 months (interquartile range 24-60; range 6-120). The estimated 5 year survival rate was 94% in the CAS group and 72% in the redo CEA group (p=.1, log rank 2.4). There were no significant differences between the groups in terms of stroke free survival. In the CAS group, no severe restenosis were found, while in the redo CEA group eight patients had severe restenosis or occlusion of the operated carotid artery. Freedom from secondary restenosis at 4 years was 100% in the CAS group and 72.5% in the redo CEA group (p=.005, log rank 7.9). The corresponding figures in terms of freedom from secondary re-intervention were 100% and 83%, respectively (p=.02, log rank 4.8). CONCLUSIONS: CAS and redo CEA in patients with post-CEA restenosis provided similar peri-operative results in a sample of equivalent patients. CAS patients had better follow-up results in terms of secondary restenosis and re interventions. Further analysis is required with a larger number of patients and a longer follow-up time. PMID- 29288060 TI - Corrigendum to "Coma and Stroke Following Surgical Treatment of Unruptured Intracranial Aneurysm: An American College of Surgeons National Surgical Quality Improvement Program Study" [World Neurosurgery (2016) 91:272-278]. PMID- 29288059 TI - The Safety of Device Registries for Endovascular Abdominal Aortic Aneurysm Repair: Systematic Review and Meta-regression. AB - OBJECTIVES: New and re-designed stent grafts for endovascular aortic aneurysm repair (EVAR) are released regularly. Manufacturers use data from registries to assess stent graft performance, but little is known about the ability of such registries to detect rates of clinically relevant complications. The aim of this paper was to perform a systematic review and meta-analysis to determine pooled failure rates for EVAR stent grafts, to define an acceptable non-inferiority limit for these devices, and then to calculate the number of patients needed for a new device to achieve non-inferiority against published devices. DATA SOURCES AND REVIEW METHODS: MEDLINE and EMBASE were searched for studies reporting outcomes of specific EVAR grafts being used for intact infrarenal abdominal aortic aneurysms, from inception to November 2016. Meta-regression was performed to pool data and calculate the patient numbers needed to detect non-inferiority of a future graft performance. An expert consensus was performed to define adequate standards for device safety. RESULTS: One hundred and forty-seven moderate quality papers involving 27,058 patients were included. Multiple outcomes were pooled. Of these, the estimated rate (+/-standard error) of overall endoleak (excluding Type II) at 2 years was 5.7 +/- 0.6%. The pooled re intervention rate was 11.1 +/- 0.7% at 2 years. There were differences in pooled endoleak rates between different stent graft types. Expert consensus defined non inferiority as better performance than the worst performing 25% of stent grafts. The most popular outcome in the expert consensus was cumulative endoleak rate (excluding Type II). The number of patients who would need to be enrolled in a registry to demonstrate non-inferiority at this level was 525. Only two of 147 included studies achieved this. The second most popular choice in the expert consensus was re-intervention rate; 492 patients are required to demonstrate this. CONCLUSIONS: Five hundred and twenty-five patients need to be entered into a registry to demonstrate non-inferiority to previous stent grafts. Almost all previous publications have captured lower patient numbers. With performance varying between devices, and new devices being introduced regularly, there is an urgent need to capture higher quality long-term data on EVAR stent grafts. PMID- 29288061 TI - The effect of brain-derived neurotrophic factor on radiation-induced neuron architecture impairment is associated with the NFATc4/3 pathway. AB - Irradiation to developing brains results in progressive cognitive dysfunction. Changes in the morphology of mature neurons are thought to be related to impairments of cognitive function. However, little is known about the effects of radiation on neurite outgrowth of immature neurons. Therefore, we sought to evaluate the structural alterations of immature neurons following X-ray irradiation and determine potential strategies to reverse it. Our data revealed damage to the neurite outgrowths of cultured neurons after 2 Gy and 8 Gy irradiation at 1 d and 3 d, respectively. De-phosphorylation of nuclear factor of activated T-cells c4/3 (NFATc4/3) was inhibited post-irradiation. Extraneous brain-derived neurotrophic factor (BDNF) ameliorated impairment of neurite growth and activated the NFATc4/3 signaling pathway. These data indicate that BDNF confers neuroprotective effects against irradiation by modulating the NFATc4/3 pathway. PMID- 29288062 TI - The degree of leukoaraiosis predicts clinical outcomes and prognosis in patients with middle cerebral artery occlusion after intravenous thrombolysis. AB - Leukoaraiosis (LA) is common in elderly patients with ischemic stroke on magnetic resonance imaging. In this study, we investigate whether the degree of LA is associated with clinical outcomes and prognosis of patients with middle cerebral artery occlusion following intravenous thrombolytic. Ninety-seven patients were recruited and divided into three groups based on the degree of LA (no, mild and moderate to severe LA) by the Fazekas scale. Clinical outcomes, recurrent stroke, Fugl-Meyer rating scale (FMS) and complications of intravenous thrombolysis were assessed. The association between the degree of LA and functional outcomes was analyzed by multivariable logistic regression model. Patients enrolled were divided into three groups: 26 patients with no LA, 43 patients with mild LA and 28 patients with moderate to severe LA. Impressively, the patients with mild LA were better in early neurological recovery and 90-day FMS score than patients in the other two groups. Multivariate logistic analysis revealed that moderate to severe LA was an independent predictor of poor functional outcome (OR: 10.482; 95% CI: 1.442-76.181; P = .020). Moreover, the patients with moderate to severe LA have a higher rate of hemorrhagic transformation and recurrent stroke as compared with two other groups during 90-day follow-up. Different degrees of LA differentially affect clinical outcome and prognosis in patients with middle cerebral artery occlusion following intravenous thrombolytic. Moderate to severe LA is a risk factor of poor prognosis. Mild LA is associated with early neurological recovery and good motor functional outcome. PMID- 29288063 TI - The immune-related fatty acids are responsive to CO2 driven seawater acidification in a crustacean brine shrimp Artemia sinica. AB - The gradual increase of CO2 concentration in the atmosphere, absorbed by the ocean surface water through air to sea equilibration termed ocean acidification (OA), leads to the decline of pH in seawater. It is not clear so far how the composition of fatty acids, particular the immune-related, in marine crustacean and the subsequent energy supply in marine ecosystem are affected by OA. The brine shrimp Artemia sinica is an open and common feed that provide essential fatty acids for mariculture. In this study, the fatty acids profiles of brine shrimp cultured under different lower pH levels of CO2 driven seawater were investigated. The results showed a significant reduction of the proportion of total saturated fatty acids under the pH7.6 within one week. Meanwhile, the percentage of total monounsaturated fatty acids was significantly decreased at day 14 under pH7.8, and this percentage gave a significant increase of proportion within one week under pH7.6. Furthermore, the relative content of total polyunsaturated fatty acids (PUFAs) was found to be clearly increased with exposure to different seawater acidification at day 1, suggesting that the brine shrimp immune response was likely to be affected by acidified seawater as the PUFAs have been well known to be involved in immunomodulatory effects through alterations on cell membrane fluidity/lipid mediators and gene expression of cell signaling pathways. Notably, eicosapentaenoic acid and docosahexaenoic acid, which have essential effect on various physiological processes such as inflammatory cytokines production and cell structural stability, were strongly increased under two lower pH treatments within one week and with the significant increase at day 1 under pH7.6. These data clearly supported the hypothesis that OA might affect fatty acids composition, likely also the innate immunity, in crustacean and the subsequent energy transfer by food-chain system in the marine ecosystem. PMID- 29288064 TI - Corrigendum to 'Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy' [Biochimica et Biophysica Acta 1863/6 (2017) 1264-1272]. PMID- 29288065 TI - Use of Euclidean length to measure urinary incontinence severity based on the lower urinary tract symptoms tool. PMID- 29288066 TI - Cost effectiveness of population based BRCA1 founder mutation testing in Sephardi Jewish women. AB - BACKGROUND: Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish BRCA1/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. STUDY DESIGN: A Markov model was built comparing the lifetime costs and effects of population-based BRCA1 testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged >=30 years. BRCA1 carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. RESULTS: Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year = 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was L67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1 way sensitivity analysis. The probabilistic sensitivity analysis showed 100% of simulations were cost effective at L20,000/quality-adjusted life-year UK and the $100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. CONCLUSION: Population based BRCA1 testing is highly cost effective compared with clinical criteria driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry. PMID- 29288067 TI - Nationwide trends in the utilization of and payments for hysterectomy in the United States among commercially insured women. AB - BACKGROUND: Laparotomy followed by inpatient hospitalization has traditionally been the most common surgical care for hysterectomy. The financial implications of the increased use of laparoscopy and outpatient hysterectomy are unknown. OBJECTIVES: The objective of the study was to quantify the increasing use of laparoscopy and outpatient hysterectomy and to describe the financial implications among women with commercially based insurance in the United States. STUDY DESIGN: Hysterectomies between 2010 and 2013 were identified in the Health Care Cost Institute, a national data set with inpatient and outpatient private insurance claims for more than 25 million women. Surgical approach was categorized with procedure codes as abdominal, laparoscopic, laparoscopic assisted vaginal, or vaginal. Payments were adjusted to 2013 US dollars to account for change because of inflation. RESULTS: Between 2010 and 2013, there were 386,226 women who underwent hysterectomy. The rate of utilization decreased 12.4%, from 39.9 to 35.0 hysterectomies per 10,000 women. The largest absolute decreases were observed among women younger than 55 years and among those with uterine fibroids, abnormal uterine bleeding, and endometriosis. The proportion of laparoscopic hysterectomies increased from 26.1% to 43.4%, with concomitant decreases in abdominal (38.6% to 28.3%), laparoscopic assisted vaginal (20.2 to 16.7%), and vaginal (15.1% to 11.5%) hysterectomies. There was also a shift from inpatient to outpatient surgery. In 2010, the inpatient and outpatient rates of hysterectomy were 26.6 and 13.3 per 10,000 women, respectively. By 2013, the rates were 15.4 and 19.6 per 10,000 women. In each year of analysis, the average reimbursement for outpatient procedures was 44-46% less than for similar inpatient procedures. Offsetting the lower utilization of hysterectomy and lower reimbursement for outpatient surgery were increases in average inpatient and outpatient hysterectomy reimbursement of 19.4% and 19.8%, respectively. Total payments for hysterectomy decreased 6.3%, from $823.4 million to $771.3 million. CONCLUSION: Between 2010 and 2013, laparoscopy emerged as the most common surgical approach for hysterectomy, and outpatient hysterectomy became more common than inpatient among women with commercially based insurance. While average reimbursement per case increased, overall payments for hysterectomy are decreasing because of decreased utilization and dramatic differences in how hysterectomy is performed. PMID- 29288068 TI - Regular exercisers have stronger pelvic floor muscles than nonregular exercisers at midpregnancy. AB - BACKGROUND: Today all healthy pregnant women are encouraged to be physically active throughout pregnancy, with recommendations to participate in at least 30 minutes of aerobic activity on most days of the week in addition to performing strength training of the major muscle groups 2-3 days per week and also pelvic floor muscle training. There is, however, an ongoing debate whether general physical activity enhances or declines pelvic floor muscle function. OBJECTIVES: The objectives of the study were to compare vaginal resting pressure, pelvic floor muscle strength, and endurance in regular exercisers (exercise >=30 minutes 3 or more times per week) and nonexercisers at midpregnancy. Furthermore, another objective was to assess whether regular general exercise or pelvic floor muscle strength was associated with urinary incontinence. STUDY DESIGN: This was a cross sectional study at mean gestational week 20.9 (+/-1.4) including 218 nulliparous pregnant women, with a mean age of 28.6 years (range, 19-40 years) and prepregnancy body mass index of 23.9 kg/m2 (SD, 4.0). Vaginal resting pressure, pelvic floor muscle strength, and pelvic floor muscle endurance were measured by a high-precision pressure transducer connected to a vaginal balloon. The International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form was used to assess urinary incontinence. Differences between groups were analyzed using an independent-sample Student t test. Linear regression analysis was conducted to adjust for prepregnancy body mass index, age, smoking during pregnancy, and regular pelvic floor muscle training during pregnancy. The significance value was set to P <= .05. RESULTS: Regular exercisers had statistically significant stronger (mean 6.4 cm H2O [95% confidence interval, 1.7 11.2]) and more enduring (mean 39.9 cm H2Osec [95% confidence interval, 42.2 75.7]) pelvic floor muscles. Only pelvic floor muscle strength remained statistically significant, when adjusting for possible confounders. Pelvic floor muscle strength and not regular general exercise was associated with urinary continence (adjusted B, -6.4 [95% confidence interval, -11.5 to -1.4]). CONCLUSION: Regular exercisers at midpregnancy have stronger pelvic floor muscles than their sedentary counterparts. However, pelvic floor muscle strength and not regular general exercise was associated with urinary incontinence. There is a need for additional studies in elite athletes and women performing more strenuous exercise regimens. PMID- 29288069 TI - Redox clocks: Time to rethink redox interventions. AB - Redox interventions have been controversial in the management of chronic disease. The key reason is believed to be a lack of clarity in our understanding of how endogenous dynamics unfold in biochemical redox mechanisms in live cells. Time resolved, quantitative research strategies combined with high throughput analysis tools may result in realistic characterisation of related in vivo processes. Here we review new evidence about redox dynamics in live cells. We discuss a potential of this line of research to establish new and affordable ways of redox interventions which may efficiently decrease mortality related to largely preventable chronic diseases. PMID- 29288071 TI - Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist. AB - A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARalpha agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARbeta, and RARgamma receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARalpha agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARalpha potency and excellent selectivity versus RARbeta (2 orders of magnitude) and RARgamma (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARalpha specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens. PMID- 29288072 TI - Scanning electron microscopy and microbiological approaches for the evaluation of salivary microorganisms behaviour on anatase titanium surfaces: In vitro study. AB - Implantology research framed the implant surface as a key element for a good and sustainable osseointegration of an implant fixture. The aim of this study was to analyze the antibacterial properties of anatase-coated titanium healing screws through microbiological and scanning electron microscopy. The comparison of the bacterial colonies growth between the anatase-coated titanium healing screws and non-coated titanium healing screws showed comparable antibacterial properties, without significant statistical differences. The scanning electron microscopy observations confirmed the microbiological study. These data, also considering previous reports on the positive effects on osteoblasts genetic expressions, might suggest a use of the anatase-coated titanium healing screws to preserve the tissues surrounding implants from microbial attacks. PMID- 29288073 TI - Fish viruses stored in RNAlater can remain infectious and even be temporarily protected from inactivation by heat or by tissue homogenates. AB - RNAlater is a commonly used transport and storage solution for samples collected for fish health investigations, particularly those potentially involving viruses. However, the infectivity of fish viruses after storage in RNAlater have not been determined. Nevertheless, knowledge of pathogen infectivity of preserved samples is crucial for ensuring safe transport and storage protocols. Therefore, the infectivity of three fish RNA viruses in RNAlater was examined at four temperatures: -80 degrees C, 4 degrees C, room temperature (RT, approximately 22 degrees C) and 37 degrees C. The viruses were viral hemorrhagic septicemia virus (VHSV), infectious pancreatic necrosis virus (IPNV) and chum salmon reovirus (CSV). Overall, three consistent outcomes were observed. First, all three viruses remained infectious in RNAlater at RT or lower. High log titres of these viruses remained over 30 d of storage in either RNAlater or PBS. Second, RNAlater delayed the thermal inactivation of these viruses when compared to PBS at 37 degrees C. For VHSV, the titre remained high in RNAlater after one day of incubation at 37 degrees C, but was inactivated to below threshold in PBS over the same period. For IPNV, the titre remained high in RNAlater after 30 d of incubation at 37 degrees C, but was inactivated to below threshold in PBS over the same period. For CSV, the titre was slightly higher in RNAlater than PBS at 37 degrees C over 7 d, and by day 30, only samples stored in RNAlater proved infectious at titres above the detection threshold. Third, RNAlater delayed the inactivation of these viruses when they were stored together with head kidney homogenates. For VHSV, infectious virus was recovered from samples stored at 4 degrees C in RNAlater by day 7 of incubation, whereas it was inactivated to below threshold in PBS over the same period. For both IPNV and CSV, infectious virus was recovered from samples stored at 37 degrees C in RNAlater for 7 d, but not so in PBS. In summary, fish viruses can remain infectious and are even temporarily protected from inactivation while in RNAlater. This makes RNAlater a potentially useful solution for the transport of fish viruses. At the same time, precautionary measures must be taken when transporting potentially infectious samples in RNAlater. PMID- 29288074 TI - Development of cross-priming amplification coupled with vertical flow visualization for rapid detection of infectious spleen and kidney necrosis virus (ISKNV) in mandarin fish, Siniperca chuatsi. AB - Infectious spleen and kidney necrosis virus (ISKNV) has been recognized as the causative agent of the most serious disease in cultured mandarin fish, Siniperca chuatsi, in China. Disease outbreaks have resulted in substantial losses to the aquaculture industry. Currently, reliable laboratory detection and identification methods are available for this virus. However, rapid detection methods applicable for on-site diagnosis of this infectious agent are unavailable. To address this need, a nearly instrument-free, cost-effective and simple detection method was developed and optimized and incorporates cross priming amplification coupled with vertical flow visualization for rapid identification of ISKNV (ISKNV-CPA-VF). Results show that cross circulation amplification targeting the conserved region of the major capsid protein (MCP) regiment of the ISKNV genome had a sensitivity 10 times greater than traditional PCR at 64 degrees C within 60 min. The optimized concentration of dNTPs and the concentration for Mg2+ were 1.0 mmol/L and 10 mmol/L, respectively. No cross-reactions with other viruses or bacteria were observed. When combined with the nucleic acid strip detection technology, visual detection of ISKNV amplified products was realized within 3-5 min following amplification. The simplicity and nearly instrument-free method for this ISKNV-CPA-VF assay shows great potential for on-site diagnostics of ISKNV infection in Siniperca chuatsi. PMID- 29288075 TI - Glucocorticoid hormones are both a major circadian signal and major stress signal: How this shared signal contributes to a dynamic relationship between the circadian and stress systems. AB - Glucocorticoid hormones are a powerful mammalian systemic hormonal signal that exerts regulatory effects on almost every cell and system of the body. Glucocorticoids act in a circadian and stress-directed manner to aid in adaptation to an ever-changing environment. Circadian glucocorticoid secretion provides for a daily waxing and waning influence on target cell function. In addition, the daily circadian peak of glucocorticoid secretion serves as a timing signal that helps entrain intrinsic molecular clock phase in tissue cells distributed throughout the body. Stress-induced glucocorticoid secretion also modulates the state of these same cells in response to both physiological and psychological stressors. We review the strong functional interrelationships between glucocorticoids and the circadian system, and discuss how these interactions optimize the appropriate cellular and systems response to stress throughout the day. We also discuss clinical implications of this dual aspect of glucocorticoid signaling, especially for conditions of circadian and HPA axis dysregulation. PMID- 29288076 TI - The neuroendocrinology of sexual attraction. AB - Sexual attraction has two components: Emission of sexually attractive stimuli and responsiveness to these stimuli. In rodents, olfactory stimuli are necessary but not sufficient for attraction. We argue that body odors are far superior to odors from excreta (urine, feces) as sexual attractants. Body odors are produced by sebaceous glands all over the body surface and in specialized glands. In primates, visual stimuli, for example the sexual skin, are more important than olfactory. The role of gonadal hormones for the production of and responsiveness to odorants is well established. Both the androgen and the estrogen receptor alpha are important in male as well as in female rodents. Also in primates, gonadal hormones are necessary for the responsiveness to sexual attractants. In males, the androgen receptor is sufficient for sustaining responsiveness. In female non-human primates, estrogens are needed, whereas androgens seem to contribute to responsiveness in women. PMID- 29288070 TI - Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury. AB - Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities in fractional anisotropy and radial diffusivity in multiple regions, consistent with improved structural integrity and recovery of myelination. Taken together, these results show behavioral and memory deficits from perinatal brain injury are reversible. Furthermore, resolution of DTI abnormalities may predict responsiveness to emerging interventions, and serve as a biomarker of CNS injury and recovery. PMID- 29288078 TI - Immune mechanisms of oral immunotherapy. AB - Oral immunotherapy (OIT) has demonstrated reproducibly successful desensitization in patients with food allergy completing clinical trials and, in some studies, sustained unresponsiveness. These clinical outcomes have been associated with characteristic modifications in the allergen-specific immune response, but a detailed synthesis of OIT's mechanisms of action is lacking. In this rostrum we review the current evidence regarding the human immune response to OIT, explore possible mechanisms, and identify knowledge gaps for future research. PMID- 29288077 TI - Update: Vaccines in primary immunodeficiency. AB - Vaccines were originally developed to prevent or ameliorate infectious disease. As knowledge of immune function and appreciation of immunodeficiency has developed, researchers have used vaccine responses as a tool to characterize the phenotypes of patients exhibiting various syndromes. Thus it has become possible for a clinician to evaluate individual responses to vaccines to interrogate the immunocompetence of their patients. Although there have been many advances in these areas, we still have much to learn about the quantity and quality of humoral and cellular vaccine responses in healthy and immunodeficient subjects and how that knowledge can then be extrapolated to diagnostic purposes. Adverse effects of vaccines have been recognized for many years, especially the occurrence of infections caused by viable vaccine organisms in immunodeficient hosts. Nevertheless, vaccines are essential for disease prevention in immunodeficient patients, just as they are for healthy subjects. Clinicians must understand the appropriate and safe use of vaccines in patients with immunodeficiency. This review highlights some recent advances and ongoing challenges in application of vaccines for the diagnosis and treatment of immunodeficiencies. PMID- 29288079 TI - The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. AB - BACKGROUND: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated. OBJECTIVE: We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE. METHODS: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-alpha shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment. RESULTS: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40. CONCLUSION: 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases. PMID- 29288080 TI - Onchocerciasis-Associated Epilepsy, an Additional Reason for Strengthening Onchocerciasis Elimination Programs. AB - A high prevalence of epilepsy has been observed in onchocerciasis-endemic regions with high onchocerciasis transmission. Recent epidemiological studies suggest that Onchocerca volvulus infection is the trigger causing the seizures, which appear in previously healthy children between the ages of 3 and 18 years. Persons with onchocerciasis-associated epilepsy present with a wide spectrum of seizures, including atonic and myoclonic neck seizures; but also absences and most frequently generalized tonic-clonic seizures. Often individuals present with intellectual disabilities and psychiatric disorders and occasionally with 'Nakalanga' features such as severe stunting with delayed or absent external signs of sexual development. Onchocerciasis-associated epilepsy, because of its importance as a public health problem, is an additional reason for strengthening onchocerciasis elimination programs. PMID- 29288081 TI - Effect of poly(ethylene glycol) on insulin stability and cutaneous cell proliferation in vitro following cytoplasmic delivery of insulin-loaded nanoparticulate carriers - A potential topical wound management approach. AB - We describe the development of a nanoparticulate system, with variation of poly(ethylene glycol) (PEG) content, capable of releasing therapeutic levels of bioactive insulin for extended periods of time. Recombinant human insulin was encapsulated in poly(d,l-lactide-co-glycolide) nanoparticles, manufactured with variation in poly(ethylene glycol) content, and shown to be stable for 6days using SDS-PAGE, western blot and MALDI MS. To determine if insulin released from this sustained release matrix could stimulate migration of cell types normally active in dermal repair, a model wound was simulated by scratching confluent cultures of human keratinocytes (HaCaT) and fibroblasts (Hs27). Although free insulin was shown to have proliferative effect, closure of in vitro scratch fissures was significantly faster following administration of nano-encapsulated insulin. This effect was more pronounced in HaCaT cells when compared to Hs27 cells. Variation in PEG content had the greatest effect on NP size, with a lesser influence on scratch closure times. Our work supports a particulate uptake mechanism that provides for intracellular insulin delivery, leading to enhanced cell proliferation. When placed into an appropriate topical delivery vehicle, such as a hydrogel, the extended and sustained topical administration of active insulin delivered from a nanoparticulate vehicle shows promise in promoting tissue healing. PMID- 29288082 TI - Octyl gallate reduces ATP levels and Ki67 expression leading HepG2 cells to cell cycle arrest and mitochondria-mediated apoptosis. AB - Octyl gallate (OG) is an antioxidant that has shown anti-tumor, anti-diabetic and anti-amyloidogenic activities. Mitochondria play an important role in hepatocellular carcinoma, mainly by maintaining accelerated cellular proliferation through the production of ATP. Thus, the mitochondria may be a target for antitumor therapies. Here, we investigated the effects of OG in the hepatocarcinoma cell line (HepG2) and the mechanisms involved. We report, for the first time, that treatment with OG for 24h inhibited HepG2 cell growth by decreasing mitochondrial activity and mass, which led to the reduction of ATP levels. This reduction in the energy supply triggered a decrease in Ki67 protein expression, leading cells to cycle arrest. In addition, treatment with two doses of OG for 48h induced loss of mitochondrial functionality, mitochondrial swelling and apoptosis. Finally, we report that HepG2 cells had no resistance to treatment after multiple doses. Collectively, our findings indicate that metabolic dysregulation and Ki67 protein reduction are key events in the initial anti proliferative action of OG, whereas mitochondrial swelling and apoptosis induction are involved in the action mechanism of OG after prolonged exposure. This suggests that OG targets mitochondria, thus representing a candidate for further research on therapies for hepatocarcinoma. PMID- 29288083 TI - Poly (ethylene-co-vinyl alcohol) is a suitable substrate for human olfactory neuroepithelial cell differentiation in vitro through a defined regulatory pathway. AB - : Olfactory dysfunction significantly influences patients' life quality, but currently has no adequate treatment. Poly (ethylene-co-vinyl alcohol) (EVAL) mediates cell adhesion, growth and modulates differentiation of neural stem cells. However, whether EVAL is a suitable substrate to establish an in vitro culture system that can promote development and differentiation of human olfactory neuroepithelial cells (HONCs) remains unexplored. This study isolates and cultures HONCs on controls and EVAL films for 21 days. The effects of treatment are assessed using immunocytochemistry, microarray analysis, quantitative PCR, ELISA and western blots following culturing. Most of the cell morphology on controls is epithelial and expresses markers of sustentacular cells (SCs), cadherin-1 and cytokeratin18, whereas the main population on EVAL presents as morphology with extended thin processes and possesses markers of mature olfactory sensory neurons (OSNs), olfactory marker protein (OMP). Microarray analyses reveal neuropeptide Y (NPY) and amphiregulin (AREG) are the two important regulating factors on EVAL films. HONCs cultured on EVAL films enhance the development of mature OSNs through NPY signaling, and significantly decrease the growth of SCs by blocking epidermal growth factor receptor (EGFR) activation. EVAL is a potential biomaterial to serve as an ideal substrate for treating olfactory dysfunction in the future. STATEMENT OF SIGNIFICANCE: Olfaction not only contributes to enjoyments of food, but provides a clue to escape from dangerous environmental hazards. However, loss of smell is commonly progressive and there is no good prognostic approach for olfactory dysfunction. Here, we use poly (ethylene-co-vinyl alcohol) (EVAL) to establish an in vitro culture system that promotes development and differentiation of human olfactory neuroepithelial cells. We show that EVAL not only enhances the development of mature olfactory sensory neurons through neuronpeptide Y signaling, but significantly protects the olfactory neuroepithelium from metaplasia by inhibiting EGFR activation. Therefore, EVAL is a potential biomaterial to serve as an ideal substrate for treating olfactory dysfunction in the future. PMID- 29288085 TI - Redox-responsive polymeric micelles formed by conjugating gambogic acid with bioreducible poly(amido amine)s for the co-delivery of docetaxel and MMP-9 shRNA. AB - : A novel redox-sensitive system for co-delivering hydrophobic drugs and hydrophilic siRNA or shRNA was developed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs) through amide bonds, which is called GA-conjugated PAAs (PAG). PAG can self-assemble into micelles as amphiphilic block copolymers, which exhibits an excellent loading ability for the co-delivery of docetaxel (DTX) and MMP-9 shRNA with adjustable dosing ratios. In addition, confocal microscopy, flow cytometry and in vitro transfection analyses demonstrated more efficient cellular internalization of DTX and MMP-9 shRNA after incubation with PAG/DTX- MMP-9 shRNA micelles (PAG/DTX-shRNA) than with free drugs. Unlike traditional amphiphilic copolymer micelles, GA conjugated in PAG possesses an intrinsic anticancer efficacy. The presence of disulfide bonds in PAAs enables rapid disassembly of PAG micelles in response to reducing agents, inducing the release of loaded drugs (DTX, GA and MMP-9 shRNA). In vitro cellular assays revealed that PAG/DTX-shRNA micelles inhibited MCF-7 cell proliferation more efficiently than the single drug or single drug-loaded micelles. In vivo biodistribution and anti-tumor effect studies using an MCF-7 breast cancer xenograft mouse model have indicated that PAG/DTX-shRNA micelles can enhance drug accumulation compared with the free drug, thereby sustaining the therapeutic effect on tumors. Additionally, PAG/DTX-shRNA micelles displayed a greater anti-tumor efficacy than Taxotere(r) and PAG-shRNA micelles. These results suggest that the redox-sensitive PAG platform is a promising co-delivery system for combining drugs and gene therapy for the treatment of cancer. STATEMENT OF SIGNIFICANCE: The PAG micelles were designed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs), which would serve dual purposes as both gene and drugs co-delivery carrier and an anti-tumor prodrug. Unlike traditional amphiphilic micelles, GA conjugated in PAG could exert its intrinsic efficacy and provide synergistic antiproliferative effects with docetaxel (DTX) on MCF-7 cells. Disulfide bonds in PAG enables a rapid disassembly of PAG micelles in response to reducing agents and to release all loaded drugs (DTX, GA and MMP-9 shRNA) at tumor sites. PAG/DTX-shRNA micelles displayed greater anti-tumor efficacy than that of Taxotere(r), indicating the design concept for PAG works well. And the strategy for PAG could be used to develop a series of similar co-delivery systems through conjugations of other small-molecule drugs with PAAs, such as doxorubicin, methotrexate and other drugs with carboxy groups in their structure. PMID- 29288086 TI - Autoimmune hepatitis association with single nucleotide polymorphism of interleukin-2, but not interferon-gamma. AB - BACKGROUND: Autoimmune hepatitis (AIH) is a chronic inflammation in hepatocellular tissues associated with circulating autoantibodies. Imbalance in T cells population and dysregulation in several cytokine profiles has been implicated in pathogenesis of AIH. This study was performed to assess potential association of AIH with interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) genes single nucleotide polymorphisms (SNPs). METHODS: Fifty-six patients with AIH and 139 healthy individuals were enrolled in this study. IL-2 and IFN-gamma typing was performed, using polymerase chain reaction with sequence-specific primers (PCR-SSP) assay. The frequencies of alleles, genotypes and haplotypes in AIH patients were compared to healthy controls. RESULTS: IL-2 T allele at position +166 (rs2069763) showed significant higher frequency in AIH group (36%), compared to the controls (21%) (OR=2.06; 95% CI, 1.24-3.43, P-value<0.01). The frequency of IL-2 TT genotype at +166 position was also associated with AIH (OR=18.68, 95% CI 3.74-126.04, P-value<0.01). G/T alleles of IL-2 at -330 (rs2069762) and A/T alleles on UTR +5644 position at IFN-gamma and their subsequent haplotypes, did not show significant association with AIH. CONCLUSIONS: This study identified IL-2T allele at +166 position and TT genotype as susceptibility gene in AIH which would provide better understandings into the mechanisms of AIH and potential immune modulation therapies. PMID- 29288084 TI - Comparison of in vivo and ex vivo viscoelastic behavior of the spinal cord. AB - : Despite efforts to simulate the in vivo environment, post-mortem degradation and lack of blood perfusion complicate the use of ex vivo derived material models in computational studies of spinal cord injury. In order to quantify the mechanical changes that manifest ex vivo, the viscoelastic behavior of in vivo and ex vivo porcine spinal cord samples were compared. Stress-relaxation data from each condition were fit to a non-linear viscoelastic model using a novel characterization technique called the direct fit method. To validate the presented material models, the parameters obtained for each condition were used to predict the respective dynamic cyclic response. Both ex vivo and in vivo samples displayed non-linear viscoelastic behavior with a significant increase in relaxation with applied strain. However, at all three strain magnitudes compared, ex vivo samples experienced a higher stress and greater relaxation than in vivo samples. Significant differences between model parameters also showed distinct relaxation behaviors, especially in non-linear relaxation modulus components associated with the short-term response (0.1-1 s). The results of this study underscore the necessity of utilizing material models developed from in vivo experimental data for studies of spinal cord injury, where the time-dependent properties are critical. The ability of each material model to accurately predict the dynamic cyclic response validates the presented methodology and supports the use of the in vivo model in future high-resolution finite element modeling efforts. STATEMENT OF SIGNIFICANCE: Neural tissues (such as the brain and spinal cord) display time-dependent, or viscoelastic, mechanical behavior making it difficult to model how they respond to various loading conditions, including injury. Methods that aim to characterize the behavior of the spinal cord almost exclusively use ex vivo cadaveric or animal samples, despite evidence that time after death affects the behavior compared to that in a living animal (in vivo response). Therefore, this study directly compared the mechanical response of ex vivo and in vivo samples to quantify these differences for the first time. This will allow researchers to draw more accurate conclusions about spinal cord injuries based on ex vivo data (which are easier to obtain) and emphasizes the importance of future in vivo experimental animal work. PMID- 29288087 TI - The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum. AB - A diverse range of genetic aberrations can lead to Autistic Spectrum Disorder (ASD) and many of these have been identified via Next Generation Sequencing (NGS) as part of large scale consortium studies. ASD is a phenotypically variable disorder and detailed clinical descriptions are essential to appreciate genotype phenotype relationships. In this report, we provide a comprehensive clinical description of a child with ASD in whom a TBR1 variant was identified. We review this case in the context of the current TBR1 literature and highlight the variable spectrum of disease associated with this gene. The phenotypic information outlined within the literature is incomplete, exemplifying the limitations of massively-parallel sequencing studies with regards to clinical annotation. We suggest that future reporting of ASD variants should include standardised phenotypic descriptions. This would develop a more thorough understanding of genotype-phenotype relationship, so allowing us to better counsel and support our patients. PMID- 29288088 TI - Telangiectasias in Ataxia Telangiectasia: Clinical significance, role of ATM deficiency and potential pathophysiological mechanisms. AB - Ataxia Telangiectasia (AT) is named after the two key clinical features that characterize its classical phenotype, namely a progressive cerebellar gait disorder (ataxia) and vascular anomalies (telangiectasias) visible in the conjunctivae and skin. AT is an autosomal recessively inherited disorder, caused by mutations in the ATM gene that encodes the ATM protein. While the ataxia is subject of many publications, the telangiectasias are under emphasised. We here describe the observation that the absence or presence of ATM protein and the level of residual ATM kinase activity are related to the occurrence of telangiectasias and describe the clinical consequences of these vascular malformations. Finally, we hypothesize that ATM dysfunction dysregulates angiogenesis. PMID- 29288090 TI - Systematic identification of mitochondrial lysine succinylome in silkworm (Bombyx mori) midgut during the larval gluttonous stage. AB - : Lysine succinylation is a newly identified protein post-translational modification (PTM) of lysine residues. Increasing evidences demonstrate that this modification is prevalent in mitochondria and regulates many vital cellular processes, especially metabolism. Here, we determined the succinylome of the silkworm (Bombyx mori) midgut mitochondria during the larval gluttonous stage (the fifth instar) using succinylated peptides enrichment coupled with nano HPLC/MS/MS. A total of 1884 lysine succinylation sites on 373 mitochondrial proteins were identified. The bioinformatic analysis reveal that succinylated proteins are significantly enriched in central metabolic processes and mitochondrial protein synthesis. Several apoptosis and detoxification related enzymes or proteins are succinylated. The findings suggest the crucial role of lysine succinylation in silkworm midgut metabolism and resistance. Our data provide a rich resource for further analysis of lysine succinylation in silkworm. SIGNIFICANCE: Insect midgut is the vital tissue for nutrient metabolism and also for xenobiotic metabolism. There is a growing body of knowledge on regulation of midgut function at the gene or protein levels in silkworm, however, the regulation at post-translation modification level remains largely unknown. We provide a first global analysis of the mitochondrial lysine succinylome in silkworm midgut. A total of 1884 lysine succinylation sites on 373 mitochondrial proteins were identified. Bioinformatics results suggest an important role of this modification in regulating metabolism and mitochondrial protein synthesis. Our data greatly expand the catalog of lysine succinylation substrates and sites in insects, and represents an important resource for understanding the physiological function of lysine succinylation in insect midgut. PMID- 29288091 TI - The importance of accounting for sex in the search of proteomic signatures of mycotoxin exposure. AB - : Mycotoxins are natural food and feed contaminants that are toxic to human and animals. Proteomics is an adequate toolbox to investigate the mode of action and the effects of mycotoxins, as these toxicants often alter protein synthesis and degradation, as well as induce changes of important post-translational modifications. For instance, the contaminant deoxynivalenol induces a severe ribosomal stress that affects protein production, whereas the toxin Fumonisin B1 can alter the phosphorylation of a large number of proteins, and patulin is a potent proteotoxic molecule. The response to most mycotoxins is sex-dependent, males being generally more sensitive than females. In addition, for some toxins, the toxic effects observed were different for each sex. Nevertheless, the importance of accounting for a sex-dependent response is often overlooked in toxicology studies involving mycotoxins. Here we review the information that proteomics has provided in pre-clinical studies of mycotoxin exposure as well as the differential response of males and females to these molecules to highlight the need of including male and female individuals when evaluating the impact of mycotoxins in the cell proteome. SIGNIFICANCE: The current trend in mycotoxicology is the combination of several -omics techniques in order to understand the mechanism of action and effects of these toxic natural food contaminants. One of the goals of these experiments is to determine "potential biomarkers" of mycotoxicoses. Nevertheless, the strategy followed in biomarker research must take into account as many possible factors as possible in order to find robust biomarkers for differential diagnosis. Among the factors that can have an influence in the response to mycotoxins, one of the most important is sex. Traditionally, males are preferentially used in research, as they are more sensitive to mycotoxins and their response is not dependent on hormonal levels, thus less variable. However the intrinsic and hormonal differences between sexes makes that results obtained in males are often not directly transferrable to females. In this review, we want to highlight (1) that proteomics has a great potential on mycotoxin research, and (2) the need in taking into account sex differences in proteomic studies, mostly when the discovery of robust biomarkers of mycotoxins response is desired. PMID- 29288092 TI - Real-time process monitoring in a semi-continuous fluid-bed dryer - microwave resonance technology versus near-infrared spectroscopy. AB - The trend towards continuous manufacturing in the pharmaceutical industry is associated with an increasing demand for advanced control strategies. It is a mandatory requirement to obtain reliable real-time information on critical quality attributes (CQA) during every process step as the decision on diversion of material needs to be performed fast and automatically. Where possible, production equipment should provide redundant systems for in-process control (IPC) measurements to ensure continuous process monitoring even if one of the systems is not available. In this paper, two methods for real-time monitoring of granule moisture in a semi-continuous fluid-bed drying unit are compared. While near-infrared (NIR) spectroscopy has already proven to be a suitable process analytical technology (PAT) tool for moisture measurements in fluid-bed applications, microwave resonance technology (MRT) showed difficulties to monitor moistures above 8% until recently. The results indicate, that the newly developed MRT sensor operating at four resonances is capable to compete with NIR spectroscopy. While NIR spectra were preprocessed by mean centering and first derivative before application of partial least squares (PLS) regression to build predictive models (RMSEP = 0.20%), microwave moisture values of two resonances sufficed to build a statistically close multiple linear regression (MLR) model (RMSEP = 0.07%) for moisture prediction. Thereby, it could be verified that moisture monitoring by MRT sensor systems could be a valuable alternative to NIR spectroscopy or could be used as a redundant system providing great ease of application. PMID- 29288093 TI - Notorious but not understood: How liquid-air interfacial stress triggers protein aggregation. AB - Protein aggregation is a major challenge in the development of biopharmaceuticals. As the pathways of aggregation are manifold, good understanding of the mechanisms behind is essential. Particularly, the presence of liquid-air interfaces has been identified to trigger the formation of large protein particles. Investigations of two monoclonal antibodies (IgGs) at the liquid-air interface exhibited the formation of a highly compressible film. An inhomogeneous protein distribution across the interface with areas of increased packing density was discovered by Brewster-Angle microscopy. Repeated compression and decompression of the film resulted in a considerable hysteresis and in significantly elevated numbers of particles. Furthermore, the extent and speed of compression directly affected the mechanical properties of the film as well as the number of particles formed. Infrared reflection-absorption spectroscopy did not indicate considerable changes in secondary structure compared to FT-IR spectra in solution. Hence, the IgG remains in a native-like conformation at the interface. Consequently, the physical-chemical methods applied in combination with the newly-designed Mini-trough provided substantial new knowledge of the mechanisms of interface-related protein aggregation and enable testing of different formulations under controlled stress conditions. Pure compression and decompression with a Mini-Trough allows a much more controlled stressing than shaking. PMID- 29288089 TI - Exploring the molecular complexity of Triatoma dimidiata sialome. AB - : Triatoma dimidiata, a Chagas disease vector widely distributed along Central America, has great capability for domestic adaptation as the majority of specimens caught inside human dwellings or in peridomestic areas fed human blood. Exploring the salivary compounds that overcome host haemostatic and immune responses is of great scientific interest. Here, we provide a deeper insight into its salivary gland molecules. We used high-throughput RNA sequencing to examine in depth the T. dimidiata salivary gland transcriptome. From >51 million reads assembled, 92.21% are related to putative secreted proteins. Lipocalin is the most abundant gene family, confirming it is an expanded family in Triatoma genus salivary repertoire. Other putatively secreted members include phosphatases, odorant binding protein, hemolysin, proteases, protease inhibitors, antigen-5 and antimicrobial peptides. This work expands the previous set of functionally annotated sequences from T. dimidiata salivary glands available in NCBI from 388 to 3815. Additionally, we complemented the salivary analysis through proteomics (available data via ProteomeXchange with identifier PXD008510), disclosing the set complexity of 119 secreted proteins and validating the transcriptomic results. Our large-scale approach enriches the pharmacologically active molecules database and improves our knowledge about the complexity of salivary compounds from haematophagous vectors and their biological interactions. SIGNIFICANCE: Several haematophagous triatomine species can transmit Trypanosoma cruzi, the etiological agent of Chagas disease. Due to the reemergence of this disease, new drugs for its prevention and treatment are considered priorities. For this reason, the knowledge of vector saliva emerges as relevant biological finding, contributing to the design of different strategies for vector control and disease transmission. Here we report the transcriptomic and proteomic compositions of the salivary glands (sialome) of the reduviid bug Triatoma dimidiata, a relevant Chagas disease vector in Central America. Our results are robust and disclosed unprecedented insights into the notable diversity of its salivary glands content, revealing relevant anti-haemostatic salivary gene families. Our work expands almost ten times the previous set of functionally annotated sequences from T. dimidiata salivary glands available in NCBI. Moreover, using an integrated transcriptomic and proteomic approach, we showed a correlation pattern of transcription and translation processes for the main gene families found, an important contribution to the research of triatomine sialomes. Furthermore, data generated here reinforces the secreted proteins encountered can greatly contribute for haematophagic habit, Trypanosoma cruzi transmission and development of therapeutic agent studies. PMID- 29288094 TI - Mucus-PVPA (mucus Phospholipid Vesicle-based Permeation Assay): An artificial permeability tool for drug screening and formulation development. AB - The mucus layer covering all mucosal surfaces in our body is the first barrier encountered by drugs before their potential absorption through epithelial tissues, and could thus affect the drugs' permeability and their effectiveness. Therefore, it is of key importance to have in vitro permeability models that can mimic this specific environment. For this purpose, the novel mucus phospholipid vesicle-based permeation assay (mucus-PVPA) has been developed and used for permeability screening of drugs and formulations. The model proved to be stable under the chosen conditions and demonstrated the ability to discriminate between compounds with different chemical structures and properties. Overall, a decrease in drug permeability was found in the presence of mucus on top of the PVPA barriers, as expected. Moreover, mucoadhesive (chitosan-coated) and mucopenetrating (PEGylated) liposomes were investigated in the newly developed model. The mucus-PVPA was able to distinguish between the different liposomal formulations, confirming the penetration potential of the tested formulations and the related drug permeability. The mucus-PVPA model appears to be a promising in vitro tool able to mimic the environment of mucosal tissues, and could therefore be used for further drug permeability screening and formulation development. PMID- 29288095 TI - Microparticles, microcapsules and microspheres: A review of recent developments and prospects for oral delivery of insulin. AB - Diabetes mellitus is a chronic metabolic health disease affecting the homeostasis of blood sugar levels. However, subcutaneous injection of insulin can lead to patient non-compliance, discomfort, pain and local infection. Sub-micron sized drug delivery systems have gained attention in oral delivery of insulin for diabetes treatment. In most of the recent literature, the terms "microparticles" and "nanoparticle" refer to particles where the dimensions of the particle are measured in micrometers and nanometers respectively. For instance, insulin-loaded particles are defined as microparticles with size larger than 1 MUm by most of the research groups. The size difference between nanoparticles and microparticles proffers numerous effects on the drug loading efficiency, aggregation, permeability across the biological membranes, cell entry and tissue retention. For instance, microparticulate drug delivery systems have demonstrated a number of advantages including protective effect against enzymatic degradation, enhancement of peptide stability, site-specific and controlled drug release. Compared to nanoparticulate drug delivery systems, microparticulate formulations can facilitate oral absorption of insulin by paracellular, transcellular and lymphatic routes. In this article, we review the current status of microparticles, microcapsules and microspheres for oral administration of insulin. A number of novel techniques including layer-by-layer coating, self polymerisation of shell, nanocomposite microparticulate drug delivery system seem to be promising for enhancing the oral bioavailability of insulin. This review draws several conclusions for future directions and challenges to be addressed for optimising the properties of microparticulate drug formulations and enhancing their hypoglycaemic effects. PMID- 29288096 TI - Comorbidity scores associated with limited life expectancy in the very elderly with nonmelanoma skin cancer. AB - BACKGROUND: There is controversy regarding treatment of nonmelanoma skin cancer (NMSC) in very elderly individuals, with some suggesting that this population may not live long enough to benefit from invasive treatments. Tools to assess limited life expectancy (LLE) exist, but performance in the population of very elderly individuals with NMSC has not been well defined. OBJECTIVE: Define comorbidity scores associated with LLE in very elderly individuals presenting for management of NMSC. METHODS: A retrospective review of 488 patients age 85 or older presenting for NMSC management between July 1999 through December 2014 was performed. Comorbidities were scored by using the Adult Comorbidity Evaluation-27 (ACE-27) and age-adjusted Charlson comorbidity index (ACCI). Dates of death, follow-up, and overall survival were determined. RESULTS: ACE-27 and ACCI scores were associated with overall survival; at scores of 3 and 7+, respectively, both were associated with less than 50% survival at 4 years. Patients who underwent Mohs micrographic surgery survived a median of 20 months longer than patients who did not. LIMITATIONS: Retrospective study design and referral bias. CONCLUSIONS: ACE-27 and ACCI scores predicted LLE. The cohort presenting for Mohs micrographic surgery had improved survival, despite similar intercohort comorbidity. This suggests that additional factors contributed to survival and that age and comorbidities alone are inadequate for making NMSC treatment decisions in very elderly individuals. PMID- 29288098 TI - 'Transillumination Dermoscopy' for nail bed pathology. PMID- 29288097 TI - Dermatologic manifestations of solid organ transplantation-associated graft versus-host disease: A systematic review. AB - BACKGROUND: Graft-versus-host-disease (GVHD) after solid organ transplantation (SOT) is extremely rare. OBJECTIVE: To investigate the dermatologic manifestations and clinical outcomes of SOT GVHD. METHODS: Systematic literature review of SOT GVHD. RESULTS: After full-text article review, we included 61 articles, representing 115 patients and 126 transplanted organs. The most commonly transplanted organ was the liver (n = 81). Among 115 patients, 101 (87.8%) developed skin involvement. The eruption appeared an average of 48.3 days (range, 3-243 days) posttransplant and was pruritic in 5 of 101 (4.9%) cases. The eruption was described as morbilliform in 2 patients (1.9%), confluent in 6 (5.9%), and desquamative in 4 (3.9%) cases. In many cases, specific dermatologic descriptions were lacking. The mortality rate was 72.2%. Relative time of death was reported in 23 patients who died during the follow-up period. These patients died an average of 99.2 days (range, 22-270 days) posttransplant, or 50.9 days after the appearance of dermatologic symptoms. Frequent causes of death were sepsis and multiorgan failure. LIMITATIONS: Incomplete descriptions of skin findings and potential publication bias resulting in publication of only the most severe cases. CONCLUSIONS: GVHD is a potentially fatal condition that can occur after SOT and often presents with a skin rash. We recommend that dermatologists have a low threshold to consider and pursue this diagnosis in the setting of post SOT skin eruption. PMID- 29288099 TI - Diagnosis and management of peristomal pyoderma gangrenosum: A systematic review. AB - BACKGROUND: Peristomal pyoderma gangrenosum (PPG) is an uncommon subtype of pyoderma gangrenosum. PPG is a challenging condition to diagnose and treat; no evidence-based guidelines exist. OBJECTIVE: We sought to identify important clinical features of PPG and effective treatments available for its management. METHODS: A systematic literature review of PPG was performed using PubMed, Medline, and Embase databases. RESULTS: We describe 335 patients with PPG from 79 studies. Clinical features include a painful, rapidly progressing ulcer with undermined, violaceous borders with a history of ostomy leakage and local skin irritation or trauma. Systemic steroids are first-line therapy; infliximab and adalimumab provide concomitant control of active inflammatory bowel disease. Combination local and systemic therapy was commonly used. Wound dressings, vehicle selection, and appropriate ostomy devices to minimize leakage, irritation, and pressure-induced ischemia can improve healing. Distinct from classic ulcerative pyoderma gangrenosum, surgical approaches, such as stoma closure and resection of active inflammatory bowel disease, have an effective role in PPG management. LIMITATIONS: PPG is a rare disease lacking randomized trials or diagnostic guidelines. Treatment duration and follow-up time among studies are variable. CONCLUSIONS: Key clinical characteristics of PPG are highlighted. Several treatments, including a more prominent role for surgical intervention, may be effective for PPG treatment. PMID- 29288100 TI - The ethics of performing noninvasive, reversible gender-affirming procedures on transgender adolescents. PMID- 29288101 TI - The nail hematoma selfie. PMID- 29288102 TI - A split-face, single-blinded, randomized controlled comparison of alexandrite 755 nm picosecond laser versus alexandrite 755-nm nanosecond laser in the treatment of acquired bilateral nevus of Ota-like macules. AB - BACKGROUND: Q-switched alexandrite lasers (QSALs) have been used for the treatment of acquired bilateral nevus of Ota-like macules (ABNOMs). Currently, picosecond alexandrite laser (PSAL) pulses have become available for pigmentary disorders. However, no studies have compared PSAL and QSAL in the treatment of ABNOM. OBJECTIVE: We sought to compare the efficacy and safety of PSAL and QSAL in the treatment of ABNOM. METHODS: Each patient (n = 30) received 3 treatments at 6-month intervals. Matching areas were delimitated on the face of each patient (left/right comparison); 1 side was treated with PSAL and the other side was treated with QSAL. The safety and efficacy of the 2 lasers were determined by visual assessment and self-report from patients 6 months after the final treatment. RESULTS: The PSAL-treated area achieved significantly better clearance (3.73 vs 2.4) with less severe pain (4.47 vs 5.16). The incidence rate of postinflammatory hyperpigmentation was 27.77% and 54.44% for the PSAL and QSAL treatments, respectively, and the duration of postinflammatory hyperpigmentation was 1.32 and 1.74 months, respectively (P < .001). LIMITATIONS: The limitations of our study include the small sample size and the lack of objective evaluation. CONCLUSION: Compared with QSAL, PSAL therapy afforded significantly better clinical outcomes and fewer side effects in the treatment of ABNOM. PMID- 29288103 TI - Incidence of androgenic dermatologic side effects following placement of a levonorgestrel intrauterine device for menorrhagia: A survey-based study. PMID- 29288104 TI - Wood's lamp-induced fluorescence of milia. PMID- 29288105 TI - The Top 50 Most-Cited Articles on Acoustic Neuroma. AB - BACKGROUND: Acoustic neuroma is the most common extra-axial primary cerebellopontine angle tumor in adults. A plethora of studies have been published on acoustic neuroma, but none of the previous works have highlighted the most influential articles. Our objective was to perform a bibliometric analysis of the 50 most-cited articles on acoustic neuroma. METHODS: We performed a title specific search on the Scopus database using the following search terms: "acoustic neuroma," "vestibular schwannoma," and "cerebellopontine angle." We recorded the 50 most-cited articles and reviewed them. RESULTS: The 50 most-cited articles had an average of 175 citations per article. All articles were published between 1980 and 2006, with 1997 the most prolific year, when 7 articles were published. The journals Neurosurgery and Laryngoscope published 10 and 8 of these articles, respectively. The most common study categories were nonsurgical management (17/50) and surgical management (13/50). Studies were predominantly published by otolaryngologists (22/50) and neurosurgeons (14/50). Douglas Kondziolka was the author with the highest number of contributions, with 7 publications. The majority of the articles were produced in the United States (64%). CONCLUSIONS: Identifying articles on acoustic neuroma with the most impact provides an important overview of the historical development of treatment methods and publication trends related to this condition. A finalized, comprehensive list of the most important works represents an excellent tool that can serve as a guide for evidence-based clinical practice. PMID- 29288106 TI - Pituitary Apoplexy: Should Endoscopic Surgery Be the Gold Standard? AB - BACKGROUND: Pituitary apoplexy is an uncommon, potentially fatal condition due to spontaneous ischemia or hemorrhage in a pituitary adenoma. The treatment of this disorder has long been a matter of debate. METHODS: Retrospective cohort study including all patients admitted with pituitary apoplexy in our department between 2005 and 2015 was undertaken. Clinical symptoms and signs on admission, treatment (conservative vs. surgical), neurologic deficit on discharge and at 6 months' follow-up, and endocrinologic evaluation at 6 months' follow-up were analyzed. The statistical analysis was performed with STATA 13.0. Endocrinologic and visual outcomes at 6 months in the different groups according to treatment were compared by applying an independent multinomial probit regression test. Outcomes between the conservative and the surgical (endoscopic and microscopic considered together) groups also were compared and the differences between surgical treated groups were analyzed with logistic regression analysis. P values <0.05 were considered significant. RESULTS: Twenty-three patients were included in this study; 60.9% (n = 14) were treated surgically (5 microsurgically; 9 endoscopically) and 39.1% (n = 9) conservatively. Statistical analysis revealed no significant differences in the visual function between the 3 treatment groups in both univariate and multivariate analysis (P > 0.05). The endocrinologic outcome was better in the surgical group (P = 0.017; adjusted P = 0.027), with a significant difference between the conservative group and the endoscopic group (P = 0.004; adjusted P = 0.005). When we compared both surgical groups, the endoscopic group has a better endocrinologic outcome (P = 0.020; adjusted P = 0.012). CONCLUSIONS: Our results support endoscopic intranasal transsphenoidal surgery as a treatment of pituitary apoplexy patients, as it probably decreases the need for long-term hormonal replacement. PMID- 29288107 TI - Memory Deficits After Aneurysmal Subarachnoid Hemorrhage: A Functional Magnetic Resonance Imaging Study. AB - BACKGROUND: Patients who have sustained aneurysmal subarachnoid hemorrhage (aSAH) are thought to have cognitive impairment. However, little is known about the characteristics of functional imaging in patients with aSAH. In this study, we explored whole brain activity patterns in patients with aSAH using amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC). METHODS: Fifty patients with aSAH and 30 healthy controls were recruited and subjected to a resting-state functional magnetic resonance imaging scan and cognitive tasks. Abnormalities of ALFF and FC in patients with aSAH and the correlations with cognitive tasks were assessed. RESULTS: The aSAH group exhibited increased ALFF mainly in the left parahippocampal gyrus (PHG), left inferior temporal gyrus (ITG), and left thalamus (THAL). FC and regression analysis showed positive correlations between functional connectivity strength (FCS) and memory performance in several connections in the aSAH group. These included (1) decreased FC between the left PHG and left inferior parietal lobe; (2) decreased FC between the left ITG and bilateral inferior frontal gyrus orbital part (ORBinf), right middle frontal gyrus; and (3) increased FC between the left THAL and right inferior frontal gyrus orbital part (ORBinf), and right inferior frontal gyrus opercular part. CONCLUSIONS: Our findings not only demonstrate the unique abnormal cerebral functional topology of patients with aSAH on both local and network levels, but also confirm the correlation between specific FCS and memory function in these patients. In addition, we have identified several potential imaging biomarkers for predicting cognitive outcomes in patients with aSAH. PMID- 29288108 TI - Sexual Dysfunction After Good-Grade Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: To assess the consequences of aneurysmal subarachnoid hemorrhage (aSAH) on sexual pleasure in patients with an otherwise favorable neurologic outcome. METHODS: Anonymous, standardized questionnaires concerning sexual function, including the International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), and a statement on subjective change in sexual pleasure after aSAH, were completed by 33 patients treated at the Cantonal Hospital St Gallen between 2005 and 2013. All had favorable neurologic outcomes (Glasgow Outcome Scale score 4 or 5). RESULTS: Ten patients (31.3%) reported a subjective worsening of sexual pleasure after aSAH. Sexual dysfunction according to FSFI criteria affected 9 of the 19 female patients (47.4%). All 19 women had a hypoactive sexual desire disorder. Erectile dysfunction was present in 7 of the 14 male patients (50%). Patients with World Federation of Neurosurgical Societies (WFNS) grade 2 aSAH were significantly more likely to report a subjective worsening of sexual experience after hemorrhage than those with WFNS grade 1. CONCLUSIONS: This is the first known evaluation of sexual health following aSAH with otherwise favorable neurologic outcomes, and confirms that sexual dysfunction is common in this population. Sexual health should be explored during follow-up with these patients. PMID- 29288109 TI - Risk Factors for Unfavorable Outcomes in Surgically Treated Brainstem Cavernous Malformations. AB - OBJECTIVE: Brainstem cavernous malformations (BSCMs) account for up to 18% of all intracranial cavernous malformations. Due to their complex anatomic location, they represent a significant challenge for neurosurgeons. As such, the identification of risk factors associated with negative outcomes is of significant importance. We analyze a series of 50 cases of BSCMs treated surgically in order to identify risk factors for unfavorable outcomes. METHODS: Patients who underwent surgical resection of BSCM at our institution between 2000 and 2015 were retrospectively reviewed. Univariate and multivariable logistic regression models were used to identify predictors of unfavorable outcomes, defined as those with a modified Rankin score (mRs) of >2. RESULTS: Fifty Latin American patients, with a mean age of 35.85 +/- 13.06 years, consisting of 29 females (58%) and 21 males (42%), underwent surgical resection. Mean modified Rankin Scale (mRs) score at admission was 2.6 +/- 1.05, and the mean BCSM size was 18.00 +/- 7.19 mm. The rate of gross total resection was 92%. Overall, 80% of patients showed improved or unchanged clinical status at the last follow-up period; however, only 58% of patients had a favorable outcome with a mean mRs of 2.33 +/- 1.136. Multivariable logistic binary regression identified hemorrhagic recurrence (P = 0.040), lower cranial nerve deficit (P = 0.019), and BSCMs >15 mm in diameter (P = 0.006) as predictive factors for unfavorable surgical outcomes. CONCLUSION: BSCM size, compromise of lower cranial nerves, and hemorrhagic recurrence before surgery were identified as risk factors associated with unfavorable outcomes of surgically treated BSCMs in this cohort. PMID- 29288110 TI - Cerebral Radiation Necrosis: An Analysis of Clinical and Quantitative Imaging and Volumetric Features. AB - BACKGROUND: Radiation therapy is an effective treatment for primary brain tumors and intracranial metastases but can occasionally precede new enhancing lesions on imaging studies that are difficult to discern between tumor recurrence (TR) and radiation necrosis (RN). The aim of this study was to identify clinical presentation and imaging patterns of RN compared with TR that may obviate the need for invasive definitive biopsy. METHODS: Patients who received radiation therapy and subsequently presented with a new intracranial lesion were reviewed from 2001 to 2016; 27 patients were identified with adequate records and confirmed pathology to have RN present or TR only. Patient and lesion characteristics were assessed using univariate and multivariate logistic regression analyses. Sensitivity and specificities were calculated for imaging features and quantitatively segmented lesion and edema volumes for identifying RN. RESULTS: Karnofsky performance scale score at presentation significantly predicted pathologic diagnosis on univariate analysis (P = 0.044). Radiation dosage and time from radiation therapy to lesion onset did not differ among pathologic diagnosis groups. No differences existed between RN and TR on quantitative imaging analyses. Multivariate logistic regression found higher Karnofsky performance scale score to be an independent factor associated with TR relative to RN (odds ratio 1.26, 95% confidence interval 1.02-1.56, P = 0.030). CONCLUSIONS: Diagnostic imaging can often be inaccurate in detecting RN alone, even with quantitative volume assessment. Functional status on repeat presentation may increase the likelihood of accurate diagnosis before definitive biopsy when neuroimaging remains unclear. PMID- 29288111 TI - Cystic Cavernoma of Fourth Ventricle in Pediatric Patient. AB - BACKGROUND: Cystic cerebral cavernomas belong to a rare subset of cavernous malformations in the brain. At present, there is limited information with regard to the demographics and etiology of this condition. CASE DESCRIPTION: The authors present a case of a previously well 13-year-old male who presented with symptoms secondary to a cystic lesion of the fourth ventricle compressing on his brainstem. He underwent stereotactic aspiration of the cystic lesion and insertion of an Ommaya reservoir in the same setting. Postoperatively, his symptoms improved. The cyst fluid did not yield any positive cytology or culture results. A repeat MRI brain did not demonstrate evidence of any underlying lesion. However, the patient was readmitted for hemorrhage into the region of his previous fourth ventricular lesion. Surgical evacuation of the haematoma was performed and intraoperative tissue was sent for pathological interrogation. The final histology reported a cavernoma. CONCLUSIONS: This is an unusual presentation of an intracranial vascular anomaly in a pediatric patient. Key features of the case include the diagnostic dilemma and management challenges faced from a neurosurgical perspective. PMID- 29288112 TI - The genetics of Parkinson disease. AB - About 15% of patients with Parkinson disease (PD) have family history and 5-10% have a monogenic form of the disease with Mendelian inheritance. To date, at least 23 loci and 19 disease-causing genes for parkinsonism have been found, but many more genetic risk loci and variants for sporadic PD phenotype have been identified in various association studies. Investigating the mutated protein products has uncovered potential pathogenic pathways that provide insights into mechanisms of neurodegeneration in familial and sporadic PD. To commemorate the 200th anniversary of Parkinson's publication of An Essay on the Shaking Palsy, we provide a comprehensive and critical overview of the current clinical, neuropathological, and genetic understanding of genetic forms of PD. We also discuss advances in screening for genetic PD-related risk factors and how they impact genetic counseling and contribute to the development of potential disease modifying therapies. PMID- 29288113 TI - Early Botulinum Toxin Injections in Infants With Musculoskeletal Disorders: A Systematic Review of Safety and Effectiveness. AB - OBJECTIVE: To report current evidence regarding the safety of intramuscular botulinum toxin injection (BTI) in children with orthopedic- and neurologic related musculoskeletal disorders >2 years of age. DATA SOURCES: PubMed, Cochrane Library, and ScienceDirect, Google Scholar, and Web of Science. STUDY SELECTION: Two reviewers independently selected studies based on predetermined inclusion criteria. DATA EXTRACTION: Data relating to the aim were extracted. Methodologic quality was graded independently by 2 reviewers using the Physiotherapy Evidence Database scale for randomized controlled trials (RCTs) and the Downs and Black evaluation tool for non-RCTs. Level of evidence was determined using the modified Sackett scale. DATA SYNTHESIS: Data of 473 infants were analyzed. Fifty-five infants had cerebral palsy, 112 had obstetric brachial plexus palsy, 257 had clubfoot, and 44 had congenital torticollis. No studies reported any severe adverse event that could be attributed to the BTI. The rate of mild to moderate adverse events reported varied from 5% to 25%. Results regarding efficacy were preliminary, dependent on the pathology, and limited by the small number of studies and their low levels of evidence. CONCLUSIONS: BTI is already widely used as an early treatment for this age group. The safety profile of BTI in infants appears similar to that of older children and risks appear more related to the severity of the pathology and the location of the injections than to the toxin itself. Regarding effectiveness, other studies with higher levels of evidence should be carried out for each specific pathology. PMID- 29288114 TI - Efficacy of fast track surgery in laparoscopic radical gastrectomy for gastric cancer:a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To conduct a systematic review of efficacy and security of fast track surgery (FTS) in laparoscopic radical gastrectomy for gastric cancer. METHODS: We searched PubMed, Embase, and Cochrane Library Databases and supplemented by other searches to collect randomized controlled trials (RCTs) on the comparison of fast track surgery combined with laparoscopy versus laparoscopy separately used in radical gastrectomy for gastric cancer before December 2016. After screening for inclusion, data extraction, and quality assessment, meta-analysis was conducted by the Review Manager 5.3 software. RESULTS: A total of 6 RCTs, involving 464 patients, were included. There were 232 patients in the FTS group and conventional care group separately. Compared with the conventional care group, patients of FTS group had shorter postoperative hospital stay [WMD = -1.85, 95%CI: (-2.60, -1.11), P < .00001], earlier first flatus [WMD = -9.33, 95%CI: ( 13.74, -4.91), P < .0001], lower level of C-reactive protein (CRP) at postoperative day 4 [WMD = -13.94, 95%CI: (-22.74, -5.15), P = .002], and less hospitalization fees [SMD = -1.12, 95%CI: (-2.07, -0.18), P = .02]. There were no significant differences in operation time, intraoperative blood loss, and postoperative complications between the two groups. CONCLUSION: Based on current evidence, the FTS protocol is safe and effective in laparoscopic radical gastrectomy for gastric cancer. Due to the limitations of our study, further larger and multicenter studies are needed to validate our findings. PMID- 29288115 TI - Mastectomy for risk reduction or symmetry in women without high risk gene mutation: A review. AB - BACKGROUND: Prophylactic or 'risk-reducing' mastectomy refers to the procedure of completely removing a healthy breast in order to reduce the risk of developing breast cancer. This may be bilateral or may be performed to the contralateral breast as part of the treatment of a proven breast cancer. The rate of this procedure being performed has been shown to be increasing over the last two decades. Recent guidance for Breast clinicians has been issued over the last 12 months by both The Association of Breast Surgery of Great Britain and Ireland (ABSGBI) and the American Society of Breast Surgeons (ASBrS). This review aims to look at the evidence behind the current decision making for patients requesting to undergo this increasingly popular procedure. METHOD: We undertook a review of the relevant literature via Medline using the PubMed interface for the key words 'Breast Cancer', 'Mastectomy', 'Prophylactic', 'Contra-lateral' and 'Risk reducing' for papers from October 1991 to 2016. The Association of Breast Surgery guidance on the topic was published this year and was therefore included and referenced. Following review of the evidence, we have categorised patients into different groups, based on their background and evidence currently available to support the decision. RESULTS: Clear evidence exists to support offering contralateral prophylactic mastectomy (CPM) to women who are high-risk gene carriers for Breast cancer. For those without, no survival benefit is evident however other quality of life measures may be improved with access to the procedure. CONCLUSION: For those women who are not high-risk gene carriers for breast cancer but have other factors that may increase their risk (strong family history, tumour characteristics) more evidence is needed as the benefit of CPM and all decisions to undertake it should occur through a multidisciplinary team approach. PMID- 29288116 TI - A study on outcome of binding pancreaticogastrostomy following pancreaticoduodenectomy: A prospective observational study. AB - INTRODUCTION: The type of anastomosis of the pancreas following pancreaticoduodenectomy is often attributed to the reason for pancreatic leak. Results of various randomized trials comparing pancreaticojejunostomy and pancreaticogastrostomy are conflicting one suggesting advantage over the other and vice versa. In this study we intend to critically analyze a novel technique of binding pancreaticogastrostomy following pancreaticoduodenectomy. AIMS AND OBJECTIVES: The aim of this study is to see the outcome of binding pancreaticogastrostomy by evaluating the technical aspects of binding PG and study the incidence of post-operative complications. MATERIALS AND METHODS: The study included all patients who had undergone binding pancreaticogastrostomy from Mar 2012 to Mar 2016 at a tertiary care hospital. Patients' data, including patients demographics, type of procedure performed, complications, mortality, hospital stay, postoperative interventional procedures or reoperations were all documented. RESULTS: There were 60 men and 37 women (mean age was 55.4 +/- 11.6 years) with a mean BMI of 22.6 Kg/M2. 16% of the patients had evidence of cholangitis and 14 of them had to be stented preoperatively. Ninety-four percent of the patients were operated for malignant cause of obstructive jaundice. The mean operative time was 283 min s and average blood loss during surgery was 352 ml. 36% of the patients were operated by the senior residents undergoing training in Gastro intestinal surgery with the assistance of the available faculty. 60% of the patients had a pancreatic duct diameter less than 3 mm. 72% of the pancreatic stump were soft in consistency. In our study we had 3% patients with pancreatic leak. The most frequent complication was DGE, which was seen in 22% patients. The mean duration of DGE was 13.5 +/- 2.6 days. We had 2 deaths within 30 days of surgery of which one was due to massive intraabdominal bleed due to pancreatic leak. None of the parameters like pre-operative and operative parameters like age, bilirubin, total leucocyte count, preoperative stenting, pancreatic duct diameter, texture of pancreas and surgery performed by residents were found to be responsible for pancreatic leak. CONCLUSION: This novel method of binding PG is simple, secure, and reproducible. It possesses several advantages over the conventional PG: it is very easy to perform, it is less traumatic to the pancreatic stump, can be performed in all types of pancreatic stump irrespective of the texture and diameter of the pancreatic duct without any statistically significant adverse outcomes. PMID- 29288117 TI - Quality of life in differentiated thyroid cancer. AB - BACKGROUND: The incidence of thyroid cancer has increased significantly over the last ten years and conversely the mortality has decreased. With 85% of patients with thyroid cancer surviving for ten years or longer it is increasingly important to study the quality of life in these patients and identify which aspects of the patients' health and wellbeing could be improved. METHODS: During the first UK patient-doctor thyroid cancer forum, patient attendees filled in an anonymized questionnaire. Patients with a diagnosis of differentiated thyroid cancer were studied, and patients less than 6 months from diagnosis were excluded. The questionnaire included demographic data, the EQ-5D-3L validated tool, information on post-operative outcomes; scar satisfaction, use of calcium supplements >6months post-operatively, vocal cord palsy, anti-depressant use and psychological counselling. RESULTS: 82 completed questionnaires were used for the study. The median age at diagnosis was 42 years (range 18-72), and there was a female:male ratio of 6:1. EQ-5D utility health scores: the mean weighted health outcome of the average population in the UK is 0.86 (SD 0.23). Our group had a significantly lower quality of life compared to the average UK population, with a mean weighted health outcome of 0.776 (SD 0.26, p value < .0004). CONCLUSION: This study assesses quality of life in a group of self-selected patients who attended the patient-doctor thyroid cancer forum and, although accepting there is a sampling bias, the conference provided an opportunity to assess the quality of life of patients with differentiated thyroid cancer. The study has found that the average quality of life in this group of patients is lower than that of the UK population, and lower than that of patients with breast, colorectal and prostate cancer. A large number of these patients suffer with fatigue, and depression requiring anti-depressants and/or counselling. PMID- 29288119 TI - Social withdrawal as psychopathology of mental disorders. PMID- 29288118 TI - Statins reduce the expressions of Tim-3 on NK cells and NKT cells in atherosclerosis. AB - 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have an immuno-regulatory effect in addition to lowing-lipids. Accumulated evidence showed that the expressions of T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) on natural killer (NK) cells increased in atherosclerotic patients and animal models. In this study, 14 patients treated with rosuvastatin and 12 patients with atorvastatin for more than 3 months were included and 20 patients without statins treatment as control. Both statins treatment reduced the expressions of Tim-3 on NK cells and their subtypes, natural killer T (NKT) cells and CD3+ T cells, and increased the proportions of NKT cells among peripheral blood mononuclear cells, accompanied by the decreased levels of total cholesterol, low density lipoprotein, and increased ratios of high density lipoprotein to cholesterol. These may contribute to the functions of statins in the treatment of atherosclerosis. PMID- 29288120 TI - National Comprehensive Cancer Network(r) Favorable Intermediate Risk Prostate Cancer-Is Active Surveillance Appropriate? AB - PURPOSE: We compared pathological and biochemical outcomes after radical prostatectomy in patients at favorable intermediate risk who fulfilled current NCCN(r) (National Comprehensive Cancer Network(r)) Guidelines(r) for active surveillance criteria to outcomes in patients who met more traditional criteria for active surveillance. MATERIALS AND METHODS: We queried our institutional review board approved prostate cancer database for patients who met NCCN criteria for very low risk (T1c, Grade Group 1, 3 or fewer of 12 cores, 50% or less core volume and prostate specific antigen density less than 0.15 ng/ml), low risk (T1 T2a, Grade Group 1 and prostate specific antigen less than 10 ng/ml) or favorable intermediate risk (major pattern grade 3 and less than 50% positive biopsy cores) and who had 1 intermediate risk factor, including T2b/c, Grade Group 2 or prostate specific antigen 10 to 20 ng/ml. Men at intermediate risk who did not meet favorable criteria were labeled as being at unfavorable intermediate risk. Patients at favorable intermediate risk were compared to those at very low and low risk, and those at unfavorable intermediate risk to identify differences in rates of adverse pathological findings at radical prostatectomy, including Gleason score Grade Group 3-5, nonorgan confined disease or nodal involvement. Time to biochemical recurrence was compared among the groups using Cox regression. RESULTS: A total of 3,686 patients underwent radical prostatectomy between January 1, 2014 and December 31, 2015. Of these men 1,454, 250 and 1,362 fulfilled the criteria for low, favorable intermediate and unfavorable intermediate risk, respectively. The rate of adverse pathological findings in favorable intermediate risk cases was significantly higher than in low risk cases and significantly lower than in unfavorable intermediate risk cases (27.4% vs 14.8% and 48.5%, respectively, each p <0.001). Time to biochemical recurrence differed significantly among the risk groups (p <0.001). CONCLUSIONS: Relative to men at low risk those at favorable intermediate risk represent a distinct group. Care should be taken when selecting these patients for active surveillance and monitoring them once they are in an active surveillance program. PMID- 29288121 TI - Contemporary Incidence and Outcomes of Prostate Cancer Lymph Node Metastases. AB - PURPOSE: The incidence of localized prostate cancer has decreased with shifts in prostate cancer screening. While recent population based studies demonstrated a stable incidence of locoregional prostate cancer, they categorized organ confined, extraprostatic and lymph node positive disease together. However, to our knowledge the contemporary incidence of prostate cancer with pelvic lymph node metastases remains unknown. MATERIALS AND METHODS: We used SEER (Surveillance, Epidemiology and End Results) data from 2004 to 2014 to identify men diagnosed with prostate cancer. We analyzed trends in the age standardized prostate cancer incidence by stage. The impact of disease extent on mortality was assessed by adjusted Cox proportional hazard analysis. RESULTS: During the study period the annual incidence of nonmetastatic prostate cancer decreased from 5,119.1 to 2,931.9 per million men (IR 0.57, 95% CI 0.56-0.58, p <0.01) while the incidence of pelvic lymph node metastases increased from 54.1 to 79.5 per million men (IR 1.47, 95% CI 1.33-1.62, p <0.01). The incidence of distant metastases in men 75 years old or older reached a nadir in 2011 compared to 2004 (IR 0.81, 95% CI 0.74-0.90, p <0.01) and it increased in 2012 compared to 2011 (IR 1.13, 95% CI 1.02-1.24, p <0.05). The risk of cancer specific mortality significantly increased in men diagnosed with pelvic lymph node metastases (HR 4.5, 95% CI 4.2 4.9, p <0.01) and distant metastases (HR 21.9, 95% CI 21.2-22.7, p <0.01) compared to men with nonmetastatic disease. CONCLUSIONS: The incidence of pelvic lymph node metastases is increasing coincident with a decline in the detection of localized disease. Whether this portends an increase in the burden of advanced disease or simply reflects decreased lead time remains unclear. However, this should be monitored closely as the increase in N1 disease reflects an increase in incurable prostate cancer at diagnosis. PMID- 29288122 TI - Worse Urinary, Sexual and Bowel Function Cause Emotional Distress and Vice Versa in Men Treated for Prostate Cancer. AB - PURPOSE: Definitive therapy for prostate cancer (eg surgery or radiotherapy) often has side effects, including urinary, sexual and bowel dysfunction. The purpose of this study was to test whether urinary, sexual and bowel functions contribute to emotional distress during the first 2 years after treatment and whether distress may in turn decrease function. MATERIALS AND METHODS: The study participants were 1,148 men diagnosed with clinically localized disease who were treated with surgery (63%) or radiotherapy (37%). Urinary, sexual and bowel functions were assessed with EPIC (Expanded Prostate Cancer Index Composite). Emotional distress was assessed with the NCCN(r) (National Comprehensive Cancer Network(r)) Distress Thermometer. Assessment time points were before treatment, and 6 weeks, and 6, 12, 18 and 24 months after treatment. We used time lagged multilevel models to test whether physical function predicted emotional distress and vice versa. RESULTS: Men with worse urinary, bowel and sexual functions reported more emotional distress than others at subsequent time points. The relationships were bidirectional. Men who reported worse distress also reported worse urinary, bowel and sexual functions at subsequent time points. CONCLUSIONS: Clinicians supported by practice and payer policies should screen for and facilitate the treatment of side effects and heightened emotional distress to improve well-being in survivors of prostate cancer. These interventions may be cost-effective, given that emotional distress can negatively impact functioning across life domains. PMID- 29288123 TI - Correlations between Sonographic and Urodynamic Findings after Mid Urethral Sling Surgery. AB - PURPOSE: We studied correlations between sonographic and urodynamic findings after suburethral sling surgery. MATERIALS AND METHODS: This retrospective study was done in 141 women who underwent multichannel urodynamic testing and translabial 4-dimensional ultrasound after suburethral sling surgery between 2006 and 2016. We determined the sling-pubis gap, ie the distance between the sling and the inferior posterior margin of the pubic symphysis, during the Valsalva maneuver and the urethral motion profile. The latter was assessed by calculating the mobility vectors of 6 equidistant points along the length of the urethra from the bladder neck to the external urethral meatus against the dorsocaudal margin of the pubic symphysis during the Valsalva maneuver. Correlations were determined between the sling-pubis gap and the mobility vectors, and between these measures and urodynamic data. RESULTS: Median followup in the 126 women with complete data was 36 months. Significant correlations were found between the sling-pubis gap and the mid urethral mobility vectors (all p <0.02). The sling-pubis gap and the mid urethral mobility vectors negatively correlated with detrusor pressure at maximum flow (p = 0.037 and 0.004, respectively). Urodynamic stress incontinence was more likely in women with a greater sling-pubis gap (p = 0.003). CONCLUSIONS: The tighter the sling on ultrasound, the less likely is urodynamic stress incontinence and the higher the detrusor pressure during voiding. PMID- 29288124 TI - Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney. AB - BACKGROUND & AIMS: Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers because of its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through complex intercellular signaling. However, the mechanism of liver organogenesis, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice. METHODS: Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein transgenic mice or wild-type mice transplanted with bone marrow cells isolated from green fluorescent protein-mice. RESULTS: Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 years later, whole organ-sized liver tissues with greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including bone marrow. The neo-livers in the kidney exhibited liver specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo livers successfully rescued the mice with lethal liver injury. CONCLUSION: Our data clearly show that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment. LAY SUMMARY: The role of adult hepatocytes at ectopic locations has not been clarified. In this study, we demonstrated that engrafted hepatocytes in the kidney proliferated, recruited non-parenchymal cells from host tissues including bone marrow, and finally created an organ-sized, complex liver system that exhibited liver specific architectures and functions. Our results revealed previously undescribed functions of hepatocytes to direct liver organogenesis through non-parenchymal cell recruitment and organize multiple cell types into a complex 3D liver at ectopic sites. Transcript profiling: Microarray data are deposited in GEO (GEO accession: GSE99141). PMID- 29288125 TI - Functional characterization of isolated RNA-binding domains of the GRSF1 protein. AB - The Guanine-rich RNA sequence binding factor 1 (GRSF1) is a member of the heterogeneous nuclear ribonucleoprotein F/H family and has been implicated in RNA processing, RNA transport and translational regulation. Amino acid alignments and homology modeling suggested the existence of three distinct RNA-binding domains and two auxiliary domains. Unfortunately, little is known about the molecular details of GRSF1/RNA interactions. To explore the RNA-binding mechanisms we first expressed full-length human GRSF1 and several truncation mutants, which include the three separated qRRM domains in E. coli, purified the recombinant proteins and quantified their RNA-binding affinity by RNA electrophoretic mobility shift assays. The expression levels varied between 1 and 10mg purified protein per L bacterial liquid culture and for full-length human GRSF1 a binding constant (KD value) of 0.5MUM was determined. In addition, our mechanistic experiments with different truncation mutants allowed the following conclusions: i) Deletion of either of the three RNA-binding domains impaired the RNA-binding affinity suggesting that the simultaneous presence of the three domains is essential for high-affinity RNA-binding. ii) Deletion of the Ala-rich auxiliary domain did hardly affect RNA-binding. Thus, this structural subunit may not be involved in RNA interaction. iii) Deletion of the acidic auxiliary domain improved the RNA binding suggesting a regulatory role for this structural motif. iv) The isolated RNA-binding domains did not exhibit sizeable RNA-binding affinities. Taken together these data suggest that a cooperative interaction of the three qRRMs is required for high affinity RNA-binding. PMID- 29288126 TI - High resolution crystal structures of Clostridium botulinum neurotoxin A3 and A4 binding domains. AB - Clostridium botulinum neurotoxins (BoNTs) cause the life-threatening condition, botulism. However, while they have the potential to cause serious harm, they are increasingly being utilised for therapeutic applications. BoNTs comprise of seven distinct serotypes termed BoNT/A through BoNT/G, with the most widely characterised being sub-serotype BoNT/A1. Each BoNT consists of three structurally distinct domains, a binding domain (HC), a translocation domain (HN), and a proteolytic domain (LC). The HC domain is responsible for the highly specific targeting of the neurotoxin to neuronal cell membranes. Here, we present two high-resolution structures of the binding domain of subtype BoNT/A3 (HC/A3) and BoNT/A4 (HC/A4) at 1.6 A and 1.34 A resolution, respectively. The structures of both proteins share a high degree of similarity to other known BoNT HC domains whilst containing some subtle differences, and are of benefit to research into therapeutic neurotoxins with novel characteristics. PMID- 29288127 TI - Structural characterization of SpoIIIAB sporulation-essential protein in Bacillus subtilis. AB - Endospore formation in the Gram-positive bacterium Bacillus subtilis initiates in response to nutrient depletion and involves a series of morphological changes that result in the creation of a dormant spore. Early in this developmental process, the cell undergoes an asymmetric cell division that produces the larger mother cell and smaller forespore, the latter destined to become the mature spore. The mother cell septal membrane then engulfs the forespore, at which time an essential channel, the so-called feeding-tube apparatus, is thought to cross both membranes to create a direct conduit between the cells. At least nine proteins are required to form this channel including SpoIIQ under forespore control and SpoIIIAA-AH under the mother cell control. Several of these proteins share similarity to components of Type-II, -III and -IV secretion systems as well as the flagellum from Gram-negative bacteria. Here we report the X-ray crystallographic structure of the cytosolic domain of SpoIIIAB to 2.3 A resolution. This domain adopts a conserved, secretion-system related fold of a six membered anti-parallel helical bundle with a positively charged membrane interaction face at one end and a small groove at the other end that may serve as a binding site for partner proteins in the assembled apparatus. We analyzed and identified potential interaction interfaces by structure-guided mutagenesis in vivo. Furthermore, we were able to identify a remarkable structural homology to the C-subunit of a bacterial V-ATPase. Collectively, our data provides new insight into the possible roles of SpoIIIAB protein within the secretion-like apparatus essential to bacterial sporulation. PMID- 29288129 TI - A low-rank multivariate general linear model for multi-subject fMRI data and a non-convex optimization algorithm for brain response comparison. AB - The focus of this paper is on evaluating brain responses to different stimuli and identifying brain regions with different responses using multi-subject, stimulus evoked functional magnetic resonance imaging (fMRI) data. To jointly model many brain voxels' responses to designed stimuli, we present a new low-rank multivariate general linear model (LRMGLM) for stimulus-evoked fMRI data. The new model not only is flexible to characterize variation in hemodynamic response functions (HRFs) across different regions and stimulus types, but also enables information "borrowing" across voxels and uses much fewer parameters than typical nonparametric models for HRFs. To estimate the proposed LRMGLM, we introduce a new penalized optimization function, which leads to temporally and spatially smooth HRF estimates. We develop an efficient optimization algorithm to minimize the optimization function and identify the voxels with different responses to stimuli. We show that the proposed method can outperform several existing voxel wise methods by achieving both high sensitivity and specificity. We apply the proposed method to the fMRI data collected in an emotion study, and identify anterior dACC to have different responses to a designed threat and control stimuli. PMID- 29288128 TI - Identifying and characterizing systematic temporally-lagged BOLD artifacts. AB - Residual noise in the BOLD signal remains problematic for fMRI - particularly for techniques such as functional connectivity, where findings can be spuriously influenced by noise sources that can covary with individual differences. Many such potential noise sources - for instance, motion and respiration - can have a temporally lagged effect on the BOLD signal. Thus, here we present a tool for assessing residual lagged structure in the BOLD signal that is associated with nuisance signals, using a construction similar to a peri-event time histogram. Using this method, we find that framewise displacements - both large and very small - were followed by structured, prolonged, and global changes in the BOLD signal that depend on the magnitude of the preceding displacement and extend for tens of seconds. This residual lagged BOLD structure was consistent across datasets, and independently predicted considerable variance in the global cortical signal (as much as 30-40% in some subjects). Mean functional connectivity estimates varied similarly as a function of displacements occurring many seconds in the past, even after strict censoring. Similar patterns of residual lagged BOLD structure were apparent following respiratory fluctuations (which covaried with framewise displacements), implicating respiration as one likely mechanism underlying the displacement-linked structure observed. Global signal regression largely attenuates this artifactual structure. These findings suggest the need for caution in interpreting results of individual difference studies where noise sources might covary with the individual differences of interest, and highlight the need for further development of preprocessing techniques for mitigating such structure in a more nuanced and targeted manner. PMID- 29288130 TI - The same analysis approach: Practical protection against the pitfalls of novel neuroimaging analysis methods. AB - Standard neuroimaging data analysis based on traditional principles of experimental design, modelling, and statistical inference is increasingly complemented by novel analysis methods, driven e.g. by machine learning methods. While these novel approaches provide new insights into neuroimaging data, they often have unexpected properties, generating a growing literature on possible pitfalls. We propose to meet this challenge by adopting a habit of systematic testing of experimental design, analysis procedures, and statistical inference. Specifically, we suggest to apply the analysis method used for experimental data also to aspects of the experimental design, simulated confounds, simulated null data, and control data. We stress the importance of keeping the analysis method the same in main and test analyses, because only this way possible confounds and unexpected properties can be reliably detected and avoided. We describe and discuss this Same Analysis Approach in detail, and demonstrate it in two worked examples using multivariate decoding. With these examples, we reveal two sources of error: A mismatch between counterbalancing (crossover designs) and cross validation which leads to systematic below-chance accuracies, and linear decoding of a nonlinear effect, a difference in variance. PMID- 29288132 TI - Cochrane systematic reviews of interventions for risk factors correlate weakly with global risk factor burden: a cross-sectional study. AB - BACKGROUND AND OBJECTIVES: Systematic reviews (SRs) are important for health-care decision-makers requiring evidence for interventions that target modifiable risk factors to prevent disease. We investigated whether Cochrane SR output correlated with risk factor burden as assessed by the Global Burden of Disease Study 2015. METHODS: We screened and extracted data from Cochrane reviews and protocols published since January 2011 investigating modifiable risk factors as outcomes. We calculated Spearman's rank correlation between number of occasions a risk factor was an SR outcome and that risk factor's global disease burden in disability-adjusted life years (DALYs). We also calculated standardized Pearson residuals (SPRs) of the variance between the observed and expected frequency of a risk factor featuring as an outcome. RESULTS: We obtained 400 unique SRs and 174 unique protocols from 6,392 Cochrane publications. Risk factors were an outcome a total of 965 times. The number of SR outcomes and DALYs per risk factor shared a weak-positive correlation (r = 0.45) for all risk factors, but was high (r = 0.83) for metabolic risks, similar for behavioral risks (r = 0.46), and weak negative for occupational and environmental risks (r = -0.40). SPRs for "high total cholesterol", "low bone mineral density", "alcohol and drug use" , and "child and maternal malnutrition" inferred a higher than expected frequency of outcomes, and for "air pollution", "dietary risk", and "unsafe water, sanitation, and hand-washing", fewer than expected. CONCLUSION: Our study investigated whether Cochrane risk factor SRs align with global risk factor burden, demonstrating a weak-positive correlation. Interventions modifying air pollution and dietary risks were sparsely studied, given disease burden. PMID- 29288131 TI - False positive rates in surface-based anatomical analysis. AB - The false positive rates (FPR) for surface-based group analysis of cortical thickness, surface area, and volume were evaluated for parametric and non parametric clusterwise correction for multiple comparisons for a range of smoothing levels and cluster-forming thresholds (CFT) using real data under group assignments that should not yield significant results. For whole cortical surface analysis, thickness showed modest inflation in parametric FPRs above the nominal level (10% versus 5%). Surface area and volume FPRs were much higher (20-30%). In the analysis of interhemispheric thickness asymmetries, FPRs were well controlled by parametric correction, but FPRs for surface area and volume asymmetries were still inflated. In all cases, non-parametric permutation adequately controlled the FPRs. It was found that inflated parametric FPRs were caused by violations in the parametric assumptions, namely a heavier-than-Gaussian spatial correlation. The non-Gaussian spatial correlation originates from anatomical features unique to individuals (e.g., a patch of cortex slightly thicker or thinner than average) and is not a by-product of scanning or processing. Thickness performed better than surface area and volume because thickness does not require a Jacobian correction. PMID- 29288133 TI - Systematic review of current guideline appraisals performed with the Appraisal of Guidelines for Research & Evaluation II instrument-a third of AGREE II users apply a cut-off for guideline quality. AB - OBJECTIVES: To investigate whether Appraisal of Guidelines for Research & Evaluation (AGREE) II users apply a cut-off based on standardized domain scores or overall guideline quality to distinguish between high- and low-quality guidelines, as well as to investigate which criteria they use to generate this cut-off and which type of cut-off they apply. STUDY DESIGN AND SETTING: We conducted a systematic search in MEDLINE, EMBASE, DARE, and the HTA-database for German- and English-language studies appraising guidelines with AGREE II. Information on cut-offs was extracted and analyzed descriptively. RESULTS: We identified 118 relevant publications. Thirty-nine (33%) used a cut-off, of which 24 (62%) used a 2-step and 13 (33%) used a 3-step approach. The cut-off for high quality lay between 50% and 70% (2-step) and 60% and 83% (3-step) of the highest possible rating. Twenty-four (62%) publications applied a cut-off based on standardized domain scores and 7 (18%) based on overall guideline quality. Eleven (28%) applied cut-offs to derive the recommendation for guideline use. CONCLUSION: A third of AGREE II users apply a cut-off to distinguish between high and low-quality guidelines, often without clearly describing how the cut-off is generated. Many users might welcome a clear distinction between high- and low quality guidelines; specifying a cut-off for this purpose might be useful. PMID- 29288134 TI - Bootstrap imputation minimized misclassification bias when measuring Colles' fracture prevalence and its associations using health administrative data. AB - OBJECTIVES: Misclassification bias can result from the incorrect assignment of disease status using inaccurate diagnostic codes in health administrative data. This study quantified misclassification bias in the study of Colles' fracture. STUDY DESIGN AND SETTING: Colles' fracture status was determined in all patients >50 years old seen in the emergency room at a single teaching hospital between 2006 and 2014 by manually reviewing all forearm radiographs. This data set was linked to population-based data capturing all emergency room visits. Reference disease prevalence and its association with covariates were measured. A multivariate model using covariates derived from administrative data was used to impute Colles' fracture status and measure its prevalence and associations using bootstrapping methods. These values were compared with reference values to measure misclassification bias. This was repeated using diagnostic codes to determine Colles' fracture status. RESULTS: Five hundred eighteen thousand, seven hundred forty-four emergency visits were included with 3,538 (0.7%) having a Colles' fracture. Determining disease status using the diagnostic code (sensitivity 69.4%, positive predictive value 79.9%) resulted in significant underestimate of Colles' fracture prevalence (relative difference -13.3%) and biased associations with covariates. The Colles' fracture model accurately determined disease probability (c-statistic 98.9 [95% confidence interval {CI} 98.7-99.1], calibration slope 1.009 [95% CI 1.004-1.013], Nagelkerke's R2 0.71 [95% CI 0.70-0.72]). Using disease probability estimates from this model, bootstrap imputation (BI) resulted in minimal misclassification bias (relative difference in disease prevalence -0.01%). The statistical significance of the association between Colles' fracture and age was accurate in 32.4% and 70.4% of samples when using the code or BI, respectively. CONCLUSION: Misclassification bias in estimating disease prevalence and its associations can be minimized with BI using accurate disease probability estimates. PMID- 29288135 TI - Efforts to retrieve individual participant data sets for use in a meta-analysis result in moderate data sharing but many data sets remain missing. PMID- 29288136 TI - Systematic review on costs and resource use of randomized clinical trials shows a lack of transparent and comprehensive data. AB - OBJECTIVES: Randomized clinical trials (RCTs) are costly. We aimed to provide a systematic overview of the available evidence on resource use and costs for RCTs to support budget planning. STUDY DESIGN AND SETTING: We systematically searched MEDLINE, EMBASE, and HealthSTAR from inception until November 30, 2016 without language restrictions. We included any publication reporting empirical data on resource use and costs of RCTs and categorized them depending on whether they reported (i) resource and costs of all aspects at all study stages of an RCT (including conception, planning, preparation, conduct, and all tasks after the last patient has completed the RCT); (ii) on several aspects, (iii) on a single aspect (e.g., recruitment); or (iv) on overall costs for RCTs. Median costs of different recruitment strategies were calculated. Other results (e.g., overall costs) were listed descriptively. All cost data were converted into USD 2017. RESULTS: A total of 56 articles that reported on cost or resource use of RCTs were included. None of the articles provided empirical resource use and cost data for all aspects of an entire RCT. Eight articles presented resource use and cost data on several aspects (e.g., aggregated cost data of different drug development phases, site-specific costs, selected cost components). Thirty-five articles assessed costs of one specific aspect of an RCT (i.e., 30 on recruitment; five others). The median costs per recruited patient were USD 409 (range: USD 41 6,990). Overall costs of an RCT, as provided in 16 articles, ranged from USD 43 103,254 per patient, and USD 0.2-611.5 Mio per RCT but the methodology of gathering these overall estimates remained unclear in 12 out of 16 articles (75%). CONCLUSION: The usefulness of the available empirical evidence on resource use and costs of RCTs is limited. Transparent and comprehensive resource use and cost data are urgently needed to support budget planning for RCTs and help improve sustainability. PMID- 29288138 TI - Phenotypic plasticity of six unusual cercariae in nassariid gastropods and their relationships to the Acanthocolpidae and Brachycladiidae (Digenea). AB - Species-level relationships of a complex of six putative acanthocolpid cercariae with ventral keels from nassariid gastropods from Capricornia, Queensland (Cercaria capricornia I-VI) were explored using mitochondrial and nuclear DNA sequence data. Analysis of the large subunit of nuclear ribosomal DNA (rDNA), the internal transcribed spacer 2 rDNA and subunit 3 of the nicotinamide-adenine dinucleotide dehydrogenase mitochondrial gene indicates that the six distinct morphotypes previously identified relate to only three discrete genotypes. Consequently, the six cercarial morphotypes that were inferred to represent six species and distinguished previously based on morphology and behaviour, are considered here to be comprised of three species (i.e. Cercaria capricornia I and II are considered the same species, C. capricornia types III to V are considered to belong to a second species and C. capricornia VI is considered to comprise the third species in this complex). This recognition of reduced diversity following molecular analysis runs contrary to the more frequently reported uncovering of cryptic diversity, especially when larval trematodes are examined. Phylogenetic analysis of these morphologically unusual cercariae supports their inclusion in the Acanthocolpidae. Bayesian inference analysis identifies three distinct clades: (a) Stephanostomum+Monostephanostomum; (b) the Brachycladiidae and Pleorchis; and (c) Tormopsolus and the present cercariae. Genus-level identification of these cercariae remains uncertain given the current lack of available comparative genetic data on nucleic acid databases. PMID- 29288137 TI - A prospective cohort and extended comprehensive-cohort design provided insights about the generalizability of a pragmatic trial: the ProtecT prostate cancer trial. AB - OBJECTIVES: Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability. STUDY DESIGN AND SETTING: Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct. RESULTS: The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa. CONCLUSION: The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice. PMID- 29288139 TI - Molecular taxonomy and subgeneric classification of tapeworms of the genus Moniezia Blanchard, 1891 (Cestoda, Anoplocephalidae) in northern cervids (Alces and Rangifer). AB - Phylogenetic relationships of tapeworms of the genus Moniezia Blanchard, 1891 (Cestoda, Anoplocephalidae) parasitizing the Eurasian elk Alces alces, the moose A. americanus and the reindeer/caribou Rangifer tarandus (Cervidae) were studied using DNA sequences of two mitochondrial genes (cox1 and nad1). Several isolates from domestic ruminants, representing Moniezia expansa (Rudolphi, 1810) sensu lato and M. benedeni (Moniez, 1879) sensu lato, and one unidentified isolate from an African antelope, were also included in the analysis. Both genes identified the same six species of Moniezia, but interspecific phylogenetic relationships were better resolved by the nad1 data. The six species of Moniezia comprised two main clades: clade 1 that originates in bovids, with subsequent colonization of northern cervids in Eurasia, and clade 2 that originates in northern cervids, with subsequent specific divergence within these hosts. Clade 2 has a Holarctic distribution. None of the Moniezia specimens in Alces and Rangifer was conspecific with the species in domestic ruminants, suggesting that the custom of identifying Moniezia spp. in northern cervids either as M. expansa or M. benedeni is incorrect. At least two of the species parasitizing Alces and Rangifer have not been previously recognized. These findings challenge the results of all previous studies concerning the diversity and ecology of Moniezia spp. in northern cervids. The traditional classification into three subgenera (Moniezia Blanchard, 1891, Blanchariezia Skrjabin & Schultz, 1937 and Baeriezia Skrjabin & Schultz, 1937), based on the presence and type of interproglottidal glands, conflicts with the currently observed molecular phylogenetic relationships within the genus Moniezia. PMID- 29288140 TI - Inhibition of Plasmodium falciparum cysteine proteases by the sugarcane cystatin CaneCPI-4. AB - Malaria is a disease caused by Plasmodium parasites that affects hundreds of millions of people. Plasmodium proteases are involved in invasion, erythrocyte egress and degradation of host proteins. Falcipains are well-studied cysteine peptidases located in P. falciparum food vacuoles that participate in hemoglobin degradation. Cystatins are natural cysteine protease inhibitors that are implicated in a wide range of regulatory processes. Here, we report that a cystatin from sugarcane, CaneCPI-4, is selectively internalized into P. falciparum infected erythrocytes and is not processed by the parasite proteolytic machinery. Furthermore, we demonstrated the inhibition of P. falciparum cysteine proteases by CaneCPI-4, suggesting that it can exert inhibitory functions inside the parasites. The inhibition of the proteolytic activity of parasite cells is specific to this cystatin, as the addition of an anti-CaneCPI-4 antibody completely abolished the inhibition. We extended the studies to recombinant falcipain-2 and falcipain-3 and demonstrated that CaneCPI-4 strongly inhibits these enzymes, with IC50 values of 12nM and 42nM, respectively. We also demonstrated that CaneCPI-4 decreased the hemozoin formation in the parasites, affecting the parasitemia. Taken together, this study identified a natural molecule as a potential antimalarial that specifically targets falcipains and also contributes to a better understanding of macromolecule acquisition by Plasmodium falciparum infected RBCs. PMID- 29288141 TI - Functional Reach, Depression Scores, and Number of Medications Are Associated With Number of Falls in People With Chronic Stroke. AB - BACKGROUND: Falls are a common adverse event among people with stroke. Previous studies investigating risk of falls after stroke have relied primarily on retrospective fall history ranging from 6-12 months recall, with inconsistent findings. OBJECTIVES: To identify factors and balance assessment tools that are associated with number of falls in individuals with chronic stroke. DESIGN: Secondary analysis of a randomized clinical trial. SETTING: Multisite academic and clinical institutions. PARTICIPANTS: Data from 181 participants with stroke (age 60.67 +/- 11.77 years, post stroke 4.51 +/- 4.78 years) were included. METHODS: Study participants completed baseline testing and were prospectively asked about falls. A multivariate negative binomial regression was used to identify baseline predictive factors predicting falls: age, endurance (6 minute walk test), number of medications, motor control (Fugl-Meyer lower extremity score), depression (Patient Health Questionnaire-9), physical activity (number of steps per week), and cognition (Mini Mental Status Exam score). A second negative binomial regression analysis was used to identify baseline balance assessment scores predicting falls: gait velocity (comfortable 10 Meter Walk), Berg Balance Scale (BBS), Timed Up and Go (TUG), and Functional Reach Test (FRT). Receiver operating characteristic (ROC) and area under the curve (AUC) were used to determine the cutoff scores for significant predictors of recurrent falls. MAIN OUTCOME MEASUREMENT: The number of falls during the 42-week follow-up period. RESULTS: Baseline measures that significantly predicted the number of falls included increased number of medications, higher depression scores, and decreased FRT. Cutoff scores for the number of medications were 8.5 with an AUC of 0.68. Depression scores differentiated recurrent fallers at a threshold of 2.5 scores with an AUC of 0.62. FRT differentiated recurrent fallers at a threshold of 18.15 cm with an AUC of 0.66. CONCLUSIONS: Number of medications, depression scores, and decreased FRT distance at baseline were associated with increased number of falls. Increased medications might indicate multiple comorbidities or polypharmacy effect; increased depression scores may indicate psychological status; and decreased functional reach distance could indicate dynamic balance impairments. LEVEL OF EVIDENCE: II. PMID- 29288142 TI - Patient-Reported Outcome Measures: Utility for Predicting Spinal Surgery in an Integrated Spine Practice. AB - BACKGROUND: For the majority of patients, spinal surgery is an elective treatment. The decision as to whether and when to pursue surgery is complicated and influenced by myriad factors, including pain intensity and duration, impact on functional activities, referring physician recommendation, and surgeon preference. By understanding the factors that lead a patient to choose surgery, we may better understand the decision-making process, improve outcomes, and provide more effective care. OBJECTIVE: To investigate the relationship between patient-reported outcome measures (PROMs) at initial physiatry clinic consultation and subsequent decision to pursue surgical treatment. We hypothesized that measures of function, pain, and mental health might identify which patients eventually elect to pursue surgical management. DESIGN: Retrospective chart review study. SETTING: Physiatry spine clinic in a tertiary hospital. PATIENTS: A total of 395 consecutive patients meeting our inclusion criteria were assessed for the presence of chronic pain, self-perceived disability, history of prior spinal surgery, and provision of chronic opioid therapy at the time of their initial visit to the integrated spine clinic. METHODS: Retrospective chart review of all patients presenting to our spine clinic between August 1, 2014, and July 31, 2015, was performed. At the initial spine clinic consultation, patients were asked to complete the General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-8 (PHQ-8), Oswestry Disability Index (ODI), and Patient-Reported Outcomes Measurement Information System (PROMIS) 10-item short-form questionnaire. The primary outcome was surgical intervention within 18 months from their first visit to the integrated spine clinic. We surveyed all patient records until February 2017 for CPT codes associated with spinal surgery, excluding from analysis those patients who were lost to follow-up within 1 year of the index visit. Analysis focused on the risk of spinal surgery, with data points treated as both continuous and categorical variables. We used logistic regression models to determine whether PROMs, either alone or in combination, predicted later decision to pursue surgical intervention. MAIN OUTCOME MEASUREMENTS: Decision to pursue spinal surgery. RESULTS: The baseline PROM scores spanning functional, mental health, and pain domains were collected for 94% of the patients presenting to our spine program during the interval of this study. In total, 146 patients were excluded because of missing patient-reported outcome data or less than 1 year of follow-up, leaving 395 patients for analysis. Of these, 40.3% were male with a median age of 58 years, 4.6% presented with a history of prior spinal surgery, and 3.8% were being treated with chronic opioids at their initial consultation. Male gender (P = .01) and older age (P = .05) were associated with subsequent surgery, but no relationship was observed between measured patient-reported outcomes and decision to undergo spinal surgery within 18 months of the index visit. CONCLUSIONS: Contrary to our hypothesis, this analysis demonstrates that the PROMs evaluated in this study, alone are insufficient to identify patients who may elect to pursue spinal surgery. Male gender and increasing age correlate with decision for later spinal surgery. LEVEL OF EVIDENCE: II. PMID- 29288143 TI - NHS England: guidance on medicines not to be prescribed. PMID- 29288144 TI - Effect of antibiotic stewardship programmes on the incidence of infection. PMID- 29288145 TI - Lack of clarity about frequency for monitoring renal function in heart failure guidelines. PMID- 29288147 TI - BP targets for people with CVD. PMID- 29288146 TI - NICE: reduce antibiotic prescribing for acute sinusitis. PMID- 29288148 TI - Gabapentin and risk of severe respiratory depression. PMID- 29288149 TI - Improving adherence to antidepressant medication in older people. PMID- 29288150 TI - The BMJ charity appeal Christmas 2017: help Medecins Sans Frontieres' volunteer doctors help the Rohingya people. PMID- 29288151 TI - Correction for Gyrd-Hansen et al., "Apoptosome-Independent Activation of the Lysosomal Cell Death Pathway by Caspase-9". PMID- 29288152 TI - Cytotoxic granule endocytosis depends on the Flower protein. AB - Cytotoxic T lymphocytes (CTLs) kill target cells by the regulated release of cytotoxic substances from granules at the immunological synapse. To kill multiple target cells, CTLs use endocytosis of membrane components of cytotoxic granules. We studied the potential calcium dependence of endocytosis in mouse CTLs on Flower, which mediates the calcium dependence of synaptic vesicle endocytosis in Drosophila melanogaster Flower is predominantly localized on intracellular vesicles that move to the synapse on target cell contact. Endocytosis is entirely blocked at an early stage in Flower-deficient CTLs and is rescued to wild-type level by reintroducing Flower or by raising extracellular calcium. A Flower mutant lacking binding sites for the endocytic adaptor AP-2 proteins fails to rescue endocytosis, indicating that Flower interacts with proteins of the endocytic machinery to mediate granule endocytosis. Thus, our data identify Flower as a key protein mediating granule endocytosis. PMID- 29288153 TI - L1 retrotransposon antisense RNA within ASAR lncRNAs controls chromosome-wide replication timing. AB - Mammalian cells replicate their chromosomes via a temporal replication program. The ASAR6 and ASAR15 genes were identified as loci that when disrupted result in delayed replication and condensation of entire human chromosomes. ASAR6 and ASAR15 are monoallelically expressed long noncoding RNAs that remain associated with the chromosome from which they are transcribed. The chromosome-wide effects of ASAR6 map to the antisense strand of an L1 retrotransposon within ASAR6 RNA, deletion or inversion of which delayed replication of human chromosome 6. Furthermore, ectopic integration of ASAR6 or ASAR15 transgenes into mouse chromosomes resulted in delayed replication and condensation, an increase in H3K27me3, coating of the mouse chromosome with ASAR RNA, and a loss of mouse Cot 1 RNA expression in cis. Targeting the antisense strand of the L1 within ectopically expressed ASAR6 RNA restored normal replication timing. Our results provide direct evidence that L1 antisense RNA plays a functional role in chromosome-wide replication timing of mammalian chromosomes. PMID- 29288154 TI - Trends and Predictors of Participation in Cardiac Rehabilitation Following Acute Myocardial Infarction: Data From the Behavioral Risk Factor Surveillance System. AB - BACKGROUND: Participation in cardiac rehabilitation (CR) after acute myocardial infarction has been proven to significantly reduce morbidity and mortality. Historically, participation rates have been low, and although recent efforts have increased referral rates, current data on CR participation are limited. METHODS AND RESULTS: Utilizing data from the Behavioral Risk Factor Surveillance System conducted by Centers for Disease Control and Prevention, we performed a population-based, cross-sectional analysis of CR post-acute myocardial infarction. Unadjusted participation from 2005 to 2015 was evaluated by univariable logistic regression. Multivariable logistic regression was performed with patient characteristic variables to determine adjusted trends and associations with participation in CR in more recent years from 2011 to 2015. Among the 32 792 survey respondents between 2005 and 2015, participation ranged from 35% in 2005 to 39% in 2009 (P=0.005) and from 38% in 2011 to 32% in 2015 (P=0.066). Between 2011 and 2015, participants were less likely to be female (odds ratio [OR] 0.763, 95% confidence interval [CI] 0.646-0.903), black (OR 0.700, 95% CI 0.526-0.931), uninsured (OR 0.528, 95% CI 0.372-0.751), less educated (OR 0.471, 95% CI 0.367-0.605), current smokers (OR 0.758, 95% CI 0.576 0.999), and were more likely to be retired or self-employed (OR 1.393, 95% CI 1.124-1.726). CONCLUSIONS: Only one third of patients participate in CR following acute myocardial infarction despite the known health benefits. Participants are less likely to be female, black, and uneducated. Future studies should focus on methods to maximize the proportion of CR referrals converted into CR participation. PMID- 29288155 TI - Association Between Tetralogy of Fallot and Tracheobronchial Branching Abnormalities: A New Clue for Pathogenesis? AB - BACKGROUND: In our practice, we noticed an increased frequency of tracheobronchial branching abnormalities (TBAs) in patients with tetralogy of Fallot (ToF). This study aimed to determine whether an association exists between congenital TBAs and ToF with or without pulmonary atresia. METHODS AND RESULTS: The frequency of TBAs on chest computed tomography was assessed in 55 patients with ToF without pulmonary atresia, 34 patients with ToF with pulmonary arteria, and 100 control patients. We then looked for a possible association between TBAs and pulmonary artery branch hypoplasia, the presence of major aortopulmonary collateral arteries, and the presence of the chromosome 22q11 deletion. TBAs were significantly more frequent in patients with ToF with or without pulmonary atresia than in the control group (any TBAs, 21% versus 2% [P<0.001]; bronchial situs anomalies, 6% versus 0% [P=0.002]; right tracheal bronchus, 4% versus 0% [P=0.04]; left eparterial bronchus, 8% versus 0% [P=0.005]); and tended to be more frequent in those with ToF without pulmonary atresia than in those with ToF with pulmonary atresia (any TBAs, 27% versus 12% [P=0.11]; left eparterial bronchus, 13% versus 0% [P=0.04]). TBAs were readily multiple (8 patients of 19 with TBA) and concerned essentially the upper lobes. TBAs were not associated with pulmonary branch hypoplasia, major aortopulmonary collateral arteries, or the chromosome 22q11 deletion. CONCLUSIONS: We demonstrated a significantly increased frequency of tracheobronchial abnormalities in patients with ToF with or without pulmonary atresia compared with a control group. These results suggest an interaction between abnormalities in conotruncal septation and tracheobronchial branching and may provide a new clue to the pathogenesis of conotruncal heart diseases. PMID- 29288156 TI - Left Ventricular Torsion Shear Angle Volume Approach for Noninvasive Evaluation of Diastolic Dysfunction in Preserved Ejection Fraction. AB - BACKGROUND: Accurate noninvasive diagnostic tools for evaluating left ventricular (LV) diastolic dysfunction (LVDD) are limited in preserved LV ejection fraction. We previously proposed the relationship of normalized rate of change in LV torsion shear angle (phi') to corresponding rate of change in LV volume (V') during early diastole (represented as -dphi'/dV') as a measure of LV diastolic function. We prospectively evaluated diagnostic accuracy of -dphi'/dV' in respect to invasive LV parameters. METHODS AND RESULTS: Participants (n=36, age 61+/-7 years) with LV ejection fraction >=50% and no acute myocardial infarction undergoing coronary angiography for chest pain and/or dyspnea evaluation were studied. High-fidelity invasive LV pressure measurements and cardiac magnetic resonance imaging with tissue tagging were performed. tau, the time constant of LV diastolic relaxation, was 58+/-10 milliseconds (mean+/-SD), and LV end diastolic pressure was 14.5+/-5.5 mm Hg. Cardiac magnetic resonance imaging derived -dphi'/dV' was 5.6+/-3.7. The value of -dphi'/dV' correlated with both tau and LV end-diastolic pressure (r=0.39 and 0.36, respectively, P<0.05). LVDD was defined as tau>48 milliseconds and LV end-diastolic pressure >12 mm Hg (LVDD1), or, alternatively, tau>48 milliseconds and LV end-diastolic pressure >16 mm Hg (LVDD2). Area under the curve (AUC) of -dphi'/dV' for identifying LVDD1 was 0.83 (0.67-0.98, P=0.001), with sensitivity/specificity of 72%/100% for dphi'/dV' >=6.2. AUC of -dphi'/dV' for identifying LVDD_2 was 0.82 (0.64-1.00, P=0.006), with sensitivity/specificity of 76%/85% for -dphi'/dV' >=6.9. There were good limits of agreement between pre- and post-nitroglycerin -dphi'/dV'. CONCLUSIONS: The -dphi'/dV' obtained from the LV torsion volume loop is a promising parameter for assessing global LVDD with preserved LV ejection fraction and requires further evaluation. PMID- 29288157 TI - History of Adverse Pregnancy Outcomes, Blood Pressure, and Subclinical Vascular Measures in Late Midlife: SWAN (Study of Women's Health Across the Nation). AB - BACKGROUND: Adverse pregnancy outcomes, such as preterm birth (PTB), have been associated with elevated risk of maternal cardiovascular disease, but their effect on late midlife blood pressure (BP) and subclinical vascular measures remains understudied. METHODS AND RESULTS: We conducted a cross-sectional analysis with 1220 multiethnic parous women enrolled in SWAN (Study of Women's Health Across the Nation) to evaluate the impact of self-reported history of adverse pregnancy outcomes (PTB, small-for-gestational-age, stillbirth), on maternal BP, mean arterial pressure, and subclinical vascular measures (carotid intima-media thickness, plaque, and pulse wave velocity) in late midlife. We also examined whether these associations were modified by race/ethnicity. Associations were tested in linear and logistic regression models adjusting for sociodemographics, reproductive factors, cardiovascular risk factors, and medications. Women were on average aged 60 years and 255 women reported a history of an adverse pregnancy outcome. In fully adjusted models, history of PTB was associated with higher BP (systolic: beta=6.40; SE, 1.62 [P<0.0001] and diastolic: beta=3.18; SE, 0.98 [P=0.001]) and mean arterial pressure (beta=4.55; SE 1.13 [P<0.0001]). PTB was associated with lower intima-media thickness, but not after excluding women with prevalent hypertension. There were no significant associations with other subclinical vascular measures. CONCLUSIONS: Findings suggest that history of PTB is associated with higher BP and mean arterial pressure in late midlife. Adverse pregnancy outcomes were not significantly related to subclinical cardiovascular disease when excluding women with prevalent hypertension. Future studies across the menopause transition may be important to assess the impact of adverse pregnancy outcomes on midlife progression of BP. PMID- 29288158 TI - Interrelationships Among Flow-Mediated Vasodilation, Nitroglycerine-Induced Vasodilation, Baseline Brachial Artery Diameter, Hyperemic Shear Stress, and Cardiovascular Risk Factors. AB - BACKGROUND: Flow-mediated vasodilation (FMD) of the brachial artery has been used for the assessment of endothelial function. Considering the mechanism underlying the vasodilatory response of the brachial artery to reactive hyperemia, hyperemic shear stress (HSS), a stimulus for FMD; nitroglycerine-induced vasodilation (NID), an index of endothelium-independent vasodilation; and baseline brachial artery diameter (BAD) are also involved in vasodilatory response. The purpose of this study was to investigate the interrelationships among FMD, HSS, NID, baseline BAD, and cardiovascular risk factors. METHODS AND RESULTS: We measured FMD, HSS, NID, and baseline BAD simultaneously in 1033 participants (633 men and 400 women; mean age: 58.6+/-17.0 years). Framingham risk score was negatively correlated with FMD, HSS, and NID and was positively correlated with baseline BAD. HSS and NID were positively correlated with FMD, and baseline BAD was negatively correlated with FMD. In participants with normal NID, FMD was correlated with HSS, NID, and baseline BAD, all of which were independent variables of FMD in multivariate analysis. In participants with impaired NID, FMD was correlated with NID and baseline BAD, both of which were independent variables of FMD in multivariate analysis, but there was no association between FMD and HSS. CONCLUSIONS: NID and baseline BAD were independent variables of FMD regardless of the status of endothelium-independent vasodilation, whereas there was a significant association between FMD and HSS in participants with normal NID but not in those with impaired NID. The influence of HSS on FMD seems to be dependent on the status of endothelium-independent vasodilation. PMID- 29288160 TI - COMMITTEE ON INFECTIOUS DISEASES. Recommendations for Prevention and Control of Influenza in Children, 2017 - 2018. Pediatrics. 2017;140(4):e20172550. PMID- 29288161 TI - Maternal Smoking and Attention-Deficit/Hyperactivity Disorder in Offspring: A Meta-analysis. AB - CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. Exploring the risk factors for ADHD is helpful in preventing ADHD. OBJECTIVE: To explore the association between maternal smoking during pregnancy and the occurrence of ADHD in offspring. DATA SOURCES: PubMed, Embase, and Cochrane Library were searched from inception to May 2017 for studies. STUDY SELECTION: Cohort or case-control studies in which the association between maternal smoking and ADHD in offspring were investigated were eligible if they included odds ratios (ORs), hazard ratios, or risk ratios and 95% confidence intervals (CIs). DATA EXTRACTION: Two investigators independently extracted data on definition of exposure and outcome, number of cases and total sample population, and potential confounders adjusted. Any dose-relationship data for smoking and ADHD risk were also extracted. RESULTS: Fifteen cohort studies and 5 case-control studies with 50 044 cases and 2 998 059 participants were included. Smoking during pregnancy increased the risk of offspring ADHD (OR: 1.60; 95% CI: 1.45-1.76). The risk of ADHD was greater for children whose mothers were heavy smokers (OR: 1.75; 95% CI: 1.51-2.02) than for those mothers were light smokers (OR: 1.54; 95% CI: 1.40-1.70). LIMITATIONS: The limitations of our study included different assessment tools of ADHD and a lack of objective biological measures for maternal smoking. CONCLUSIONS: With our meta-analysis, we provide evidence for an association between maternal smoking and offspring ADHD but do not solve the causality issues concerning potential confounding by other risk factors. More high-quality studies are needed to establish whether the association with smoking is causal. PMID- 29288159 TI - Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics. AB - BACKGROUND: Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. METHODS AND RESULTS: First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (P=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (?SBP/?DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ?SBP P=6.7E-04; ?DBP P=4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC3 genomic region significantly associated with the BP response to HCTZ (P<0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (r=-0.42; P=7E-03) and SBP-response (r= 0.36; P=2E-02). CONCLUSIONS: This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC3 is a potential determinant of the BP response to HCTZ. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519. PMID- 29288162 TI - Retrospective Consent in a Neonatal Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: The requirement for prospective consent in clinical trials in acute settings may result in samples unrepresentative of the study population, potentially altering study findings. However, using retrospective consent may raise ethical issues. We assessed whether using retrospective consent affected recruitment, participant characteristics, and outcomes within a randomized controlled trial. METHODS: We conducted a secondary analysis of a randomized trial, which compared nasal high flow (nHF) with nasal continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants. In Era 1, all infants were consented prospectively; in Era 2, retrospective consent was available. We assessed inclusion rates of eligible infants, demographic data, and primary trial outcome (treatment failure within 72 hours). RESULTS: In Era 1, recruitment of eligible infants was lower than in Era 2: 111 of 220 (50%) versus 171 of 209 (82%), P < .001; intrapartum antibiotic administration was lower: 23 of 111 (21%) versus 84 of 165 (51%), P < .001; full courses of antenatal steroids were higher: 86 of 111 (78%) versus 103 of 170 (61%), P = .004; and more infants received pre-randomization CPAP: 77 of 111 (69%) versus 48 of 171 (28%), P < .001. In Era 1, nHF failure (15 of 56, 27%) and CPAP failure (14 of 55, 26%) rates were similar, P = .9. In Era 2, failure rates differed: 24 of 85 (28%) nHF infants versus 13 of 86 (15%) CPAP infants, P = .04. The chi2 interaction test was nonsignificant (P = .20). CONCLUSIONS: The use of retrospective consent resulted in greater recruitment and differences in risk factors between eras. Using retrospective consent altered the study sample, which may be more representative of the whole population. This may improve scientific validity but requires further ethical evaluation. PMID- 29288163 TI - Innovations to Make Our Journal Better and More Child- and Family-Centered. PMID- 29288164 TI - LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I for autophagic degradation. AB - The RIG-I-like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that leucine-rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR-mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15 associated RIG-I to promote interaction between RIG-I and the autophagic cargo receptor p62 and to mediate RIG-I degradation via selective autophagy. Depletion of either LRRC25 or ISG15 abrogates RIG-I-p62 interaction as well as the autophagic degradation of RIG-I. Collectively, our findings identify a previously unrecognized role of LRRC25 in type I IFN signaling activation by which LRRC25 acts as a secondary receptor to assist RIG-I delivery to autophagosomes for degradation in a p62-dependent manner. PMID- 29288167 TI - Improving treatment of asthma attacks in children. PMID- 29288165 TI - Regenerating human epithelia with cultured stem cells: feeder cells, organoids and beyond. AB - More than 40 years ago, Howard Green's laboratory developed a method for long term expansion of primary human epidermal keratinocytes by co-culture with 3T3 mouse embryonic fibroblasts. This was a breakthrough for in vitro cultivation of cells from human skin and later for other epithelia: it led to the first stem cell therapy using cultured cells and has vastly increased our understanding of epithelial stem cell biology. In recent years, new methods to expand epithelial cells as three-dimensional organoids have provided novel means to investigate the functions of these cells in health and disease. Here, we outline the history of stratified epithelial stem cell culture and the application of cultured epithelial cells in clinical therapies. We further discuss the derivation of organoids from other types of epithelia and the challenges that remain for the translation of novel stem cell therapies toward clinical use. PMID- 29288169 TI - Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. AB - Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms. Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C terminus is required for mutant CALR mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells; binding alone is insufficient for cytokine independent growth. We further show that the threshold of positive charge in the mutant CALR C terminus influences both binding of mutant CALR to MPL and activation of MPL signaling. We find that mutant CALR binds to the extracellular domain of MPL and that 3 tyrosine residues within the intracellular domain of MPL are required to activate signaling. With respect to mutant CALR function, we show that its lectin dependent function is required for binding to MPL and for cytokine independent growth, whereas its chaperone and polypeptide-binding functionalities are dispensable. Together, our findings provide additional insights into the mechanism of the pathogenic mutant CALR-MPL interaction in myeloproliferative neoplasms. PMID- 29288170 TI - Atorvastatin enhances bone marrow endothelial cell function in corticosteroid resistant immune thrombocytopenia patients. AB - The pathogenesis of corticosteroid-resistant immune thrombocytopenia (ITP), a clinically challenging condition in which patients exhibit either no response to corticosteroids or are corticosteroid-dependent, remains poorly understood. Murine studies suggest that bone marrow (BM) endothelial progenitor cells (EPCs) play a crucial role in regulating megakaryocytopoiesis. However, little is known regarding the number and function of BM EPCs or how to improve impaired BM EPCs in corticosteroid-resistant ITP patients. In the current case-control study, we evaluated whether the BM EPCs in corticosteroid-resistant ITP differed from those in corticosteroid-sensitive ITP. Moreover, whether atorvastatin could enhance the number and function of BM EPCs derived from corticosteroid-resistant ITP patients was investigated in vitro and in vivo. Reduced and dysfunctional BM EPCs, characterized by decreased capacities of migration and angiogenesis as well as higher levels of reactive oxygen species and apoptosis, were observed in corticosteroid-resistant ITP patients. In vitro treatment with atorvastatin quantitatively and functionally improved BM EPCs derived from corticosteroid resistant ITP patients by downregulating the p38 MAPK pathway and upregulating the Akt pathway, and rescued the impaired BM EPCs to support megakaryocytopoiesis. Subsequently, a pilot cohort study showed that atorvastatin was safe and effective in corticosteroid-resistant ITP patients. Taken together, these results indicate that reduced and dysfunctional BM EPCs play a role in the pathogenesis of corticosteroid-resistant ITP, and the impaired BM EPCs could be improved by atorvastatin both in vitro and in vivo. Although requiring further validation, our data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in corticosteroid-resistant ITP patients. PMID- 29288171 TI - Gender-specific interactions between education and income in relation to obesity: a cross-sectional analysis of the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V). AB - OBJECTIVES: To identify gender-specific associations between education and income in relation to obesity in developed countries by considering both the interaction effect terms of the independent variables and their main-effect terms. DESIGN: A cross-sectional study. Education and income levels were chosen as socioeconomic status indicators. Sociodemographics, lifestyles and medical conditions were used as covariates in multivariable logistic regression models. Adjusted ORs and predicted probabilities of being obese were computed and adjusted for a complex survey design. SETTING: Data were obtained from the Fifth Korea National Health and Nutrition Examination Survey (2010-2012). PARTICIPANTS: The sample included 7337 male and 9908 female participants aged >=19 years. OUTCOME MEASURE: Obesity was defined as body mass index of >=25, according to a guideline for Asians. RESULTS: In models with no interaction-effect terms of independent variables, education was significantly associated with obesity in both men and women, but income was significant only in women. However, in models with the interaction effect terms, education was significant only in women, but income was significant only in men. The interaction effect between income and education was significant in men but not in women. Participants having the highest predicted probability of being obese over educational and income levels differed between the two types of models, and between men and women. A prediction using the models with the interaction-effect terms demonstrated that for all men, the highest level of formal education was associated with an increase in their probability of being obese by as much as 26%. CONCLUSIONS: The well-known, negative association between socioeconomic status and obesity in developed countries may not be valid when interaction effects are included. Ignoring these effects and their gender differences may result in the targeting of wrong populations for reducing obesity prevalence and its resultant socioeconomic gradients. PMID- 29288173 TI - Population-level impact of diabetes integrated care on commissioner payments for inpatient care among people with type 2 diabetes in Cambridgeshire: a postintervention cohort follow-up study. AB - OBJECTIVES: Few studies have estimated the effect of diabetes integrated care at a population level. We have assessed the impact of introducing a community service-led diabetes integrated care programme on commissioner payments (tariff) for inpatient care in rural England. METHODS: The Diabetes Integrated Care Initiative was delivered by a separate enhanced community diabetes service, increasing specialist nursing, dietetic, podiatry and medical support to primary care and patients, while linking into other diabetes specialist services. Commissioner data were provided by the local authority. The difference in area between the two overlapping distribution curves of inpatient payments at baseline and follow-up (at 3 years) was used to estimate the effect of integrated care on commissioner inpatient payments on a population level. RESULTS: Over the 3-year period, reduced inpatient payments occurred in 2.7% (1.3% to 5.8%) of patients with diabetes aged more than 70 years in the intervention area. However, reduced diabetes inpatient payments occurred in 3.20% (1.77% to 7.20%) of patients aged <70 years and 4.1% (2.3% to 7.9%) of patients >=70 years in one of the two adjacent areas. CONCLUSION: This enhanced community diabetes services was not associated with substantially reduced inpatient payments. Alternative diabetes integrated care approaches (eg, with direct primary and secondary care collaboration rather than with a community service) should be tested. PMID- 29288172 TI - Effectiveness and cost-effectiveness of a guided internet- and mobile-based depression intervention for individuals with chronic back pain: protocol of a multi-centre randomised controlled trial. AB - INTRODUCTION: Depression often co-occurs with chronic back pain (CBP). Internet and mobile-based interventions (IMIs) might be a promising approach for effectively treating depression in this patient group. In the present study, we will evaluate the effectiveness and cost-effectiveness of a guided depression IMI for individuals with CBP (eSano BackCare-D) integrated into orthopaedic healthcare. METHODS AND ANALYSIS: In this multicentre randomised controlled trial of parallel design, the groups eSano BackCare-D versus treatment as usual will be compared. 210 participants with CBP and diagnosed depression will be recruited subsequent to orthopaedic rehabilitation care. Assessments will be conducted prior to randomisation and 9 weeks (post-treatment) and 6 months after randomisation. The primary outcome is depression severity (Hamilton Rating Scale for Depression-17). Secondary outcomes are depression remission and response, health-related quality of life, pain intensity, pain-related disability, self efficacy and work capacity. Demographic and medical variables as well as internet affinity, intervention adherence, intervention satisfaction and negative effects will also be assessed. Data will be analysed on an intention-to-treat basis with additional per-protocol analyses. Moreover, a cost-effectiveness and cost-utility analysis will be conducted from a societal perspective after 6 months. ETHICS AND DISSEMINATION: All procedures are approved by the ethics committee of the Albert Ludwigs-University of Freiburg and the data security committee of the German Pension Insurance (Deutsche Rentenversicherung). The results will be published in peer-reviewed journals and presented on international conferences. TRIAL REGISTRATION NUMBER: DRKS00009272; Pre-results. PMID- 29288174 TI - Systematic evidence review of rates and burden of harm of intravenous admixture drug preparation errors in healthcare settings. AB - OBJECTIVE: To examine published evidence on intravenous admixture preparation errors (IAPEs) in healthcare settings. METHODS: Searches were conducted in three electronic databases (January 2005 to April 2017). Publications reporting rates of IAPEs and error types were reviewed and categorised into the following groups: component errors, dose/calculation errors, aseptic technique errors and composite errors. The methodological rigour of each study was assessed using the Hawker method. RESULTS: Of the 34 articles that met inclusion criteria, 28 reported the site of IAPEs: central pharmacies (n=8), nursing wards (n=14), both settings (n=4) and other sites (n=3). Using the Hawker criteria, 14% of the articles were of good quality, 74% were of fair quality and 12% were of poor quality. Error types and reported rates varied substantially, including wrong drug (~0% to 4.7%), wrong diluent solution (0% to 49.0%), wrong label (0% to 99.0%), wrong dose (0% to 32.6%), wrong concentration (0.3% to 88.6%), wrong diluent volume (0.06% to 49.0%) and inadequate aseptic technique (0% to 92.7%)%). Four studies directly compared incidence by preparation site and/or method, finding error incidence to be lower for doses prepared within a central pharmacy versus the nursing ward and lower for automated preparation versus manual preparation. Although eight studies (24%) reported >=1 errors with the potential to cause patient harm, no study directly linked IAPE occurrences to specific adverse patient outcomes. CONCLUSIONS: The available data suggest a need to continue to optimise the intravenous preparation process, focus on improving preparation workflow, design and implement preventive strategies, train staff on optimal admixture protocols and implement standardisation. Future research should focus on the development of consistent error subtype definitions, standardised reporting methodology and reliable, reproducible methods to track and link risk factors with the burden of harm associated with these errors. PMID- 29288176 TI - Do biological disease-modifying antirheumatic drugs reduce the spinal fracture risk related to ankylosing spondylitis? A longitudinal multiregistry matched cohort study. AB - OBJECTIVES: Ankylosing spondylitis (AS) is associated with an increased spinal fracture risk due to the loss of elasticity in spinal motion segments. With the introduction of biological disease-modifying antirheumatic drug (bDMARD) treatment for AS, the individual course of the disease has been ameliorated. This study aims to examine the association of bDMARD treatment and risk of spinal fracture. DESIGN: Longitudinal population-based multiregistry observational matched cohort study. SETTING: Swedish Patient Registry 1987-2014 and Swedish Prescribed Drugs Registry 2005-2014. PARTICIPANTS: Included were patients >=18 years of age receiving treatment at a healthcare facility for the primary diagnosis of AS. About 1352 patients received more than one prescription of bDMARD from 2005 to 2014. An untreated control group was created by propensity score matching for age, sex, comorbidity, antirheumatic prescriptions and years with AS (n=1352). MAIN OUTCOME MEASURES: Spinal fracture-free survival. RESULTS: No bDMARD treatment-related effect on spinal fracture-free survival was observed in the matched cohorts. Male gender (HR=2.54, 95% CI 1.48 to 4.36) and Charlson Comorbidity Index score (HR=3.02, 95% CI 1.59 to 5.75) contributed significantly to spinal fracture risk. CONCLUSION: bDMARD had no medium-term effect on the spinal fracture-free survival in patients with AS. TRIAL REGISTRATION NUMBER: NCT02840695; Post-results. PMID- 29288175 TI - Applicability of evidence from previous systematic reviews on immunotherapy in current practice of childhood asthma treatment: a GRADE (Grading of Recommendations Assessment, Development and Evaluation) systematic review. AB - OBJECTIVE: Because most children with asthma now use inhaled corticosteroids (ICS), the added benefit of immunotherapy in asthmatic children needs to be examined. We re-assessed the effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) in childhood asthma treatment focusing on studies with patient-relevant outcome measures and children using ICS. METHODS: We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to systematically search and appraise the evidence using predefined critical patient-relevant outcomes (asthma symptoms, asthma control and exacerbations). We searched to retrieve systematic reviews and randomised controlled trials on immunotherapy for asthma in children (1960-2017). We assessed the quality of the body of evidence with GRADE criteria. RESULTS: The quality of the evidence for SCIT was very low due to a large risk of bias and indirectness (dated studies in children not using ICS). No effect of SCIT was found for asthma symptoms; no studies reported on asthma control. For asthma exacerbations, studies favoured SCIT. We have little confidence in this effect estimate, due to the very low quality of evidence. For SLIT, quality of the evidence was very low due to a large risk of bias, indirectness and imprecision. The outcome 'asthma symptoms' could not be calculated due to lack of standardisation and large clinical heterogeneity. Other predefined outcomes were not reported. CONCLUSION: The beneficial effects of immunotherapy in childhood asthma found in earlier reviews are no longer considered applicable, because of indirectness (studies performed in children not being treated according to current asthma guidelines with ICS). There was absence of evidence to properly determine the effectiveness or lack thereof of immunotherapy in asthma treatment in children with ICS. PMID- 29288177 TI - Why don't key populations access HIV testing and counselling centres in Nepal? Findings based on national surveillance survey. AB - OBJECTIVES: To assess the demographic, behavioural, psychosocial and structural factors associated with non-utilisation of HIV testing and counselling (HTC) services by female sex workers (FSWs) and men who have sex with men/transgender (MSM/TG). METHODS: This study involved a cross-sectional design. We used the national surveillance survey data of 2012, which included 610 FSWs and 400 MSM/TG recruited randomly from 22 and three districts of Nepal, respectively. Adjusted prevalence ratio (aPR) and 95% confidence interval (CI) using modified Poisson regression was used to assess and infer the association between outcome (non utilisation of HTC in last year) and independent variables. RESULTS: Non utilisation of HTC in the last year was 54% for FSWs and 55% for MSM/TG. The significant factors for non-utilisation of HTC among FSWs were depression (aPR=1.4 (95% CI 1.1 to 1.6)), injectable drug abuse (ever) (aPR=1.4 (95% CI 1.1 to 1.8)), participation (ever) in HIV awareness programmes (aPR=1.2 (95% CI 1.0 to 1.4)), experience of forced sex in previous year (aPR=1.1 (95% CI 1.0 to 1.3)) and absence of dependents in the family (aPR=1.1 (95% CI 1.0 to 1.3)). Non utilisation of HTC among MSM/TG had significant association with age 16-19 years (aPR=1.4 (95% CI 1.1 to 1.7)), non-condom use (aPR=1.2 (95% CI 1.0 to 1.4)), participation (ever) in HIV awareness programmes (aPR=1.6 (95% CI 1.3 to 2.0)), physical assault in previous year (aPR=1.8 (95% CI 1.0 to 3.1)), experience of forced sex in previous year (aPR=0.5 (95% CI 0.3 to 0.9)). CONCLUSION: Although limited by cross-sectional design, we found many programmatically relevant findings. Creative strategies should be envisaged for effective behavioural change communication to improve access to HIV testing. Psychosocial and structural interventions should be integrated with HIV prevention programmes to support key populations in accessing HIV testing. PMID- 29288178 TI - Pilot for the Australian Breast Device Registry (ABDR): a national opt-out clinical quality registry for breast device surgery. AB - PURPOSE: To establish a pilot clinical quality registry (CQR) to monitor the quality of care and device performance for breast device surgery in Australia. PARTICIPANTS: All patients having breast device surgery from contributing hospitals in Australia. A literature review was performed which identified quality indicators for breast device surgery. FINDINGS TO DATE: A pilot CQR was established in 2011 to capture prospective data on breast device surgery. An interim Steering Committee and Management Committee were established to provide clinical governance, and guide quality indicator selection. The registry's minimum dataset was formulated in consultation with stakeholder groups; potential quality indicators were assessed in terms of (1) importance and relevance, (2) usability, (3) feasibility to collect and (4) scientific validity. Data collection was by a two-sided paper-based form with manual data entry. Seven sites were recruited, including one public hospital, four private hospitals and two day surgeries. Patients were recruited and opt-out consent used. FUTURE PLANS: The pilot breast device registry provides high-quality population-based data. It provides a model for developing a national CQR for breast devices; its minimum dataset and quality indicators reflect the opinions of the broad range of stakeholders. It is easily scalable, and has formed the basis for other international surgical groups establishing similar registries. PMID- 29288179 TI - Association of individual and neighbourhood socioeconomic status with physical activity and screen time in seventh-grade boys and girls in Berlin, Germany: a cross-sectional study. AB - OBJECTIVES: Few studies have explored the impact of neighbourhood socioeconomic status (SES) on health behaviours in youths in Germany. Our aim was to investigate the association of individual and neighbourhood SES with physical activity (PA) and screen time (ST) in students aged 12-13 years in Berlin. DESIGN: Cross-sectional study. SETTING: Secondary schools (high schools and integrated secondary schools) in Berlin, Germany. PARTICIPANTS: A total of 2586 students aged 12-13 years (seventh grade). MAIN OUTCOME MEASURES: Sociodemographics, anthropometric data and health behaviours were assessed by self-report during classes. Primary outcome was the association of individual and neighbourhood SES with meeting daily PA and exceeding daily ST recommendations. Students' characteristics were described with means or percentages. Comparisons were performed using generalised linear mixed model yielding ORs with 95% CIs. RESULTS: Mean (+/-SD) age was 12.5+/-0.5 years, 50.5% were girls and 34.1% had a migrant background. When adjusting for individual covariates, associations of low versus high individual SES were 0.85 (0.48; 1.52) for PA and 2.08 (1.26; 3.43) for ST. Associations of low versus high neighbourhood SES were 1.76 (1.12; 2.75) for PA and 1.54 (1.10; 2.17) for ST. After additional adjustment for school type and school neighbourhood SES, associations comparing low versus high individual and neighbourhood SES were attenuated for PA (individual SES 0.74 (0.41; 1.33) and neighbourhood SES 1.51 (0.93; 2.46)) and ST (individual SES 1.88 (1.12; 3.14) and neighbourhood SES 1.40(0.98; 2.00). CONCLUSIONS: Lower individual and neighbourhood SES were associated with higher ST. Lower neighbourhood but not individual SES was associated with higher PA. After consideration of school type and school neighbourhood SES associations were attenuated and became insignificant for the relationship between neighbourhood SES, PA and ST. Further research is warranted to unravel the complex relationships between individual SES, neighbourhood SES and school environment to develop more targeted health promotion strategies in the future. PMID- 29288180 TI - Identifying and understanding the health and social care needs of older adults with multiple chronic conditions and their caregivers: a protocol for a scoping review. AB - INTRODUCTION: People are living longer; however, they are not necessarily experiencing good health and well-being as they age. Many older adults live with multiple chronic conditions (MCC), and complex health issues, which adversely affect their day-to-day functioning and overall quality of life. As a result, they frequently rely on the support of friend and/or family caregivers. Caregivers of older adults with MCC often face challenges to their own well-being and also require support. Currently, not enough is known about the health and social care needs of older adults with MCC and the needs of their caregivers or how best to identify and meet these needs. This study will examine and synthesise the literature on the needs of older adults with MCC and those of their caregivers, and identify gaps in evidence and directions for further research. METHODS AND ANALYSIS: We will conduct a scoping review of the peer-reviewed and grey literature using the updated Arksey and O'Malley framework. The literature will be identified using a multidatabase and grey literature search strategy developed by a health sciences librarian. Papers, reports and other materials addressing the health and social care needs of older adults and their friend/family caregivers will be included. Search results will be screened, independently, by two reviewers, and data will be abstracted from included literature and charted in duplicate. ETHICS AND DISSEMINATION: This scoping review does not require ethics approval. We anticipate that study findings will inform novel strategies for identifying and ascertaining the health and social care needs of older adults living with MCC and those of their caregivers. Working with knowledge-user members of our team, we will prepare materials and presentations to disseminate findings to relevant stakeholder and end-user groups at local, national and international levels. We will also publish our findings in a peer-reviewed journal. PMID- 29288181 TI - Research protocol for the Picture Talk Project: a qualitative study on research and consent with remote Australian Aboriginal communities. AB - INTRODUCTION: Research with Indigenous populations is not always designed with cultural sensitivity. Few publications evaluate or describe in detail seeking consent for research with Indigenous participants. When potential participants are not engaged in a culturally respectful manner, participation rates and research quality can be adversely affected. It is unethical to proceed with research without truly informed consent. METHODS AND ANALYSIS: We describe a culturally appropriate research protocol that is invited by Aboriginal communities of the Fitzroy Valley in Western Australia. The Picture Talk Project is a research partnership with local Aboriginal leaders who are also chief investigators. We will interview Aboriginal leaders about research, community engagement and the consent process and hold focus groups with Aboriginal community members about individual consent. Cultural protocols will be applied to recruit and conduct research with participants. Transcripts will be analysed using NVivo10 qualitative software and themes synthesised to highlight the key issues raised by the community about the research process. This protocol will guide future research with the Aboriginal communities of the Fitzroy Valley and may inform the approach to research with other Indigenous communities of Australia or the world. It must be noted that no community is the same and all research requires local consultation and input. To conduct culturally sensitive research, respected local people from the community who have knowledge of cultural protocol and language are engaged to guide each step of the research process from the project design to the delivery of results. ETHICS AND DISSEMINATION: Ethics approval was granted by the University of Sydney Human Research Ethics Committee (No. 2012/348, reference:14760), the Western Australia Country Health Service Ethics Committee (No. 2012:15), the Western Australian Aboriginal Health Ethics Committee and reviewed by the Kimberley Aboriginal Health Planning Forum Research Sub-Committee (No. 2012-008). Results will be disseminated through peer review articles, a local Fitzroy Valley report and conference presentations. PMID- 29288182 TI - Implementation of a lung cancer multidisciplinary team standardised template for reporting to general practitioners: a mixed-method study. AB - OBJECTIVES: Few interventions have been designed that provide standardised information to primary care clinicians about the diagnostic and treatment recommendations resulting from cancer multidisciplinary team (MDT) (tumour board) meetings. This study aimed to develop, implement and evaluate a standardised template for lung cancer MDTs to provide clinical information and treatment recommendations to general practitioners (GPs). Specific objectives were to (1) evaluate template feasibility (acceptability, appropriateness and timeliness) with GPs and (2) document processes of preimplementation, implementation and evaluation within the MDT setting. DESIGN: A mixed-method study design using structured interviews with GPs and qualitative documentation of project logs about implementation processes. SETTING: Two hospitals in Central Sydney, New South Wales, Australia. PARTICIPANTS: 61 GPs evaluated the template. Two lung cancer MDTs, consisting of 33 clinicians, and eight researchers participated in template development and implementation strategy. RESULTS: The MDT-reporting template appears to be a feasible way of providing clinical information to GPs following patient presentation at a lung cancer MDT meeting. Ninety-five per cent of GPs strongly agreed or agreed that the standardised template provided useful and relevant information, that it was received in a timely manner (90%) and that the information was easy to interpret and communicate to the patient (84%). Implementation process data show that the investment made in the preimplementation stage to integrate the template into standard work practices was a critical factor in successful implementation. CONCLUSIONS: This study demonstrates that it is feasible to provide lung cancer MDT treatment recommendations to GPs through implementation of a standardised template. A simple intervention, such as a standardised template, can help to address quality gaps and ensure that timely information is communicated between tertiary and primary care healthcare providers. PMID- 29288183 TI - Performance of syndromic management for the detection and treatment of genital Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women attending antenatal, well woman and sexual health clinics in Papua New Guinea: a cross-sectional study. AB - OBJECTIVE: Papua New Guinea (PNG) has among the highest estimated prevalences of genital Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) of any country in the Asia-Pacific region. Diagnosis and treatment of these infections have relied on the WHO-endorsed syndromic management strategy that uses clinical presentation without laboratory confirmation to make treatment decisions. We evaluated the performance of this strategy in clinical settings in PNG. DESIGN: Women attending antenatal (ANC), well woman (WWC) and sexual health (SHC) clinics in four provinces were invited to participate, completed a face-to face interview and clinical examination, and provided genital specimens for laboratory testing. We estimated the performance characteristics of syndromic diagnoses against combined laboratory diagnoses. RESULTS: 1764 women were enrolled (ANC=765; WWC=614; SHC=385). The prevalences of CT, NG and TV were highest among women attending ANC and SHC. Among antenatal women, syndromic diagnosis of sexually transmitted infection had low sensitivity (9%-21%) and positive predictive value (PPV) (7%-37%), but high specificity (76%-89%) and moderate negative predictive value (NPV) (55%-86%) for the combined endpoint of laboratory-confirmed CT, NG or TV. Among women attending WWC and SHC, 'vaginal discharge syndrome' had moderate to high sensitivity (72%-78%) and NPV (62%-94%), but low specificity (26%-33%) and PPV (8%-38%). 'Lower abdominal pain syndrome' had low sensitivity (26%-41%) and PPV (8%-23%) but moderate specificity (66%-68%) and high NPV (74%-93%) among women attending WWC, and moderate-high sensitivity (67%-79%) and NPV (62%-86%) but low specificity (26%-28%) and PPV (14%-33%) among SHC attendees. CONCLUSION: The performance of syndromic management for the detection and treatment of genital chlamydia, gonorrhoea and trichomonas was poor among women in different clinical settings in PNG. New diagnostic strategies are needed to control these infections and to prevent their adverse health outcomes in PNG and other high-burden countries. PMID- 29288185 TI - Cohort profile: the Emory Cardiovascular Biobank (EmCAB). AB - PURPOSE: The Emory Cardiovascular Biobank (EmCAB) is an ongoing prospective registry of patients undergoing cardiac catheterisation, which was established to identify novel factors associated with the pathobiological process and treatment of cardiovascular disease. PARTICIPANTS: Individuals aged 18 years and older undergoing cardiac catheterisation at three Emory Healthcare sites in Atlanta are asked to participate in this prospective registry. Around 95% agree to participate. Around 7000 unique patients have been enrolled. The current data set contains detailed phenotyping, patient outcomes, genomics, protein biomarkers, regenerative markers, transcriptomic analysis, metabolomics profiling and longitudinal follow-up for adverse cardiovascular outcomes. FINDINGS TO DATE: Thus far, the EmCAB has approximately 3000 major cardiovascular events. About 48% of the EmCAB participants have more than 5 years of follow-up. It is a great resource for discovery of novel predictive factors for cardiovascular disease outcomes, including genomics, transcriptomics, protein biomarkers, oxidative stress markers and circulating progenitor cells. Several circulating inflammatory markers have shown to improve risk prediction metrics beyond standard risk factors. FUTURE PLANS: Future integrative -omics analyses will provide the cardiovascular research community opportunities for subsequent mechanistic confirmation studies, which will promote the development of effective personalised therapy that leads to clinical care tailored to the individual patient. PMID- 29288184 TI - LEAK study: design of a nationwide randomised controlled trial to find the best way to treat wound leakage after primary hip and knee arthroplasty. AB - INTRODUCTION: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are highly successful treatment modalities for advanced osteoarthritis. However, prolonged wound leakage after arthroplasty is linked to prosthetic joint infection (PJI), which is a potentially devastating complication. On the one hand, wound leakage is reported as a risk factor for PJI with a leaking wound acting as a porte d'entree for micro-organisms. On the other hand, prolonged wound leakage can be a symptom of PJI. Literature addressing prolonged wound leakage is scarce, contradictory and of poor methodological quality. Hence, treatment of prolonged wound leakage varies considerably with both non-surgical and surgical treatment modalities. There is a definite need for evidence concerning the best way to treat prolonged wound leakage after joint arthroplasty. METHODS AND ANALYSIS: A prospective nationwide randomised controlled trial will be conducted in 35 hospitals in the Netherlands. The goal is to include 388 patients with persistent wound leakage 9-10 days after THA or TKA. These patients will be randomly allocated to non-surgical treatment (pressure bandages, (bed) rest and wound care) or surgical treatment (debridement, antibiotics and implant retention (DAIR)). DAIR will also be performed on all non-surgically treated patients with persistent wound leakage at day 16-17 after index surgery, regardless of amount of wound leakage, other clinical parameters or C reactive protein. Clinical data are entered into a web based database. Patients are asked to fill in questionnaires about disease specific outcomes, quality of life and cost effectiveness at 3, 6 and 12 months after surgery. Primary outcome is the number of revision surgeries due to infection within a year of arthroplasty. ETHICS AND DISSEMINATION: The Review Board of each participating hospital has approved the local feasibility. The results will be published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NTR5960;Pre-results. PMID- 29288187 TI - Association of occasional smoking with total mortality in the population-based Tromso study, 2001-2015. AB - OBJECTIVES: There is a shift in the smoking population from daily smokers to light or occasional smokers. The knowledge about possible adverse health effects of this new smoking pattern is limited. We investigated smoking habits with focus on occasional smoking in relation to total mortality in a follow-up study of a Norwegian general population. SETTING: A population study in Tromso, Norway. METHODS: We collected smoking habits and relevant risk factors in 4020 women and 3033 men aged 30-89 years in the Tromso Study in 2001. The subjects were followed up regarding total mortality through June 2015. RESULTS: Among the participants, there were 7% occasional smokers. Occasional smokers were younger, more educated and used alcohol more frequently than other participants. A total of 766 women and 882 men died during the follow-up. After the adjustment for confounders, we found that occasional smoking significantly increased mortality by 38% (95% CI 8% to 76%) compared with never smokers. We report a dose-response relationship in the hazards of smoking (daily, occasional, former and never smoking). CONCLUSIONS: Occasional smoking is not a safe smoking alternative. There is a need for information to the general public and health workers about the health hazards of occasional smoking. More work should be done to motivate this often well-educated group to quit smoking completely. PMID- 29288186 TI - Long-term early development research in congenital heart disease (LEADER-CHD): a study protocol for a prospective cohort observational study investigating the development of children after surgical correction for congenital heart defects during the first 3 years of life. AB - INTRODUCTION: Congenital heart disease (CHD) is the most common birth defect. Studies on the development of children with CHD point towards deficits in motoric, cognitive and language development. However, most studies are cross sectional and there is a gap in the knowledge concerning developmental trajectories, risk and protective factors and a lack of research concerning environmental predictors. Specifically, no studies have so far considered the importance of early caregiving experiences and child temperament for the development of children with CHD. METHODS: In a single-centre prospective cohort study, cognitive, motoric and language development of 180 children after corrective surgery for a simple transposition of the great arteries (TGA), tetralogy of Fallot (TOF) or ventricular septal defect (VSD) will be assessed at ages 12, 24 and 36 months with the Bayley Scales of Infant Development 3rd Edition (BSID-III). At age 12 months, a free-play video observation will be conducted to investigate the relationship between primary caregiver and child, and child temperament will be assessed with the Infant Behavior Questionnaire Revised Short Version. Medical information will be obtained from patient records and demographic information via questionnaires. ANALYSIS: Frequency and severity of developmental delays will be reported descriptively. Differences between groups (TGA, TOF, VSD) will be subjected to repeated-measures analysis across time points. Multiple regressions will be applied for the analysis of predictors at each time point. For the analysis of differential developmental trajectories, mixed-model analysis will be applied. ETHICS AND DISSEMINATION: The study has been approved by the local medical ethics committee. Written informed consent will be obtained from all participants. Parents have the option to be debriefed about BSID-III results after each assessment and about the study results after project completion. Results will be disseminated in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: DRKS00011006; Pre-results. PMID- 29288188 TI - Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Patients with relapsed or refractory malignancies have a poor prognosis. Immunotherapy with chimeric antigen receptor T (CAR-T) cells redirects a patient's immune cells against the tumour antigen. CAR-T cell therapy has demonstrated promise in treating patients with several haematological malignancies, including acute B-cell lymphoblastic leukaemia and B-cell lymphomas. CAR-T cell therapy for patients with other solid tumours is also being tested. Safety is an important consideration in CAR-T cell therapy given the potential for serious adverse events, including death. Previous reviews on CAR-T cell therapy have been limited in scope and methodology. Herein, we present a protocol for a systematic review to identify CAR-T cell interventional studies and examine the safety and efficacy of this therapy in patients with haematology malignancies and solid tumours. METHODS AND ANALYSIS: We will search MEDLINE, including In-Process and Epub Ahead of Print, EMBASE and the Cochrane Central Register of Controlled Trials from 1946 to 22 February 2017. Studies will be screened by title, abstract and full text independently and in duplicate. Studies that report administering CAR-T cells of any chimeric antigen receptor construct targeting antigens in patients with haematological malignancies and solid tumours will be eligible for inclusion. Outcomes to be extracted will include complete response rate (primary outcome), overall response rate, overall survival, relapse and adverse events. A meta-analysis will be performed to synthesise the prevalence of outcomes reported as proportions with 95% CIs. The potential for bias within included studies will be assessed using a modified Institute of Health Economics tool. Heterogeneity of effect sizes will be determined using the Cochrane I 2 statistic. ETHICS AND DISSEMINATION: The review findings will be submitted for peer-reviewed journal publication and presented at relevant conferences and scientific meetings to promote knowledge transfer. PROSPERO REGISTRATION NUMBER: CRD42017075331. PMID- 29288189 TI - The renal parenchyma-evaluation of a novel ultrasound measurement to assess fetal renal development: protocol for an observational longitudinal study. AB - INTRODUCTION: Disorders of fetal growth, such as intrauterine growth restriction (IUGR) and large for gestational age (LGA), have been found to have a profound effect on the development of the fetal kidney. Abnormal kidney development is associated with hypertension and chronic kidney disease later in life. This study will use a novel ultrasound measurement to assess the renal parenchymal growth and kidney arterial blood flow in the fetus to evaluate the development of the fetal kidneys and provide an indirect estimate of nephron number. Measurements in normally grown, IUGR and LGA fetuses will be compared to determine if changes in renal parenchymal growth can be detected in utero. METHODS AND ANALYSIS: This longitudinal, prospective, observational study will be conducted over 12 months in the Ultrasound Department of the Townsville Hospital, Australia. The study will compare fetal renal parenchymal thickness (RPT) and renal artery Doppler flow between IUGR fetuses and appropriately grown fetuses, and LGA fetuses and appropriately grown fetuses between 16 and 40 weeks. The fetal RPT to renal volume ratio will also be compared, and correlations between RPT, renal parenchymal echogenicity, fetal Doppler indices and amniotic fluid levels will be analysed. ETHICS AND DISSEMINATION: This study was approved by the Townsville Health District Human Research Ethics Committee. The study results will form part of a thesis and will be published in peer-reviewed journals and disseminated at international conferences. PMID- 29288190 TI - Can we Save the rectum by watchful waiting or TransAnal microsurgery following (chemo) Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC study)?: protocol for a multicentre, randomised feasibility study. AB - INTRODUCTION: Total mesorectal excision (TME) is the highly effective standard treatment for rectal cancer but is associated with significant morbidity and may be overtreatment for low-risk cancers. This study is designed to determine the feasibility of international recruitment in a study comparing organ-saving approaches versus standard TME surgery. METHODS AND ANALYSIS: STAR-TREC trial is a multicentre international randomised, three-arm parallel, phase II feasibility study in patients with biopsy-proven adenocarcinoma of the rectum. The trial is coordinated from Birmingham, UK with national hubs in Radboudumc (the Netherlands) and Odense University Hospital Svendborg UMC (Denmark). Patients with rectal cancer, staged by CT and MRI as <=cT3b (up to 5 mm of extramural spread) N0 M0 can be included. Patients will be randomised to either standard TME surgery (control), organ-saving treatment using long-course concurrent chemoradiation or organ-saving treatment using short-course radiotherapy. For patients treated with an organ-saving strategy, clinical response to (chemo)radiotherapy determines the next treatment step. An active surveillance regime will be performed in the case of a complete clinical regression. In the case of incomplete clinical regression, patients will proceed to local excision using an optimised platform such as transanal endoscopic microsurgery or other transanal techniques (eg, transanal endoscopic operation or transanal minimally invasive surgery). The primary endpoint of this phase II study is to demonstrate sufficient international recruitment in order to sustain a phase III study incorporating pelvic failure as the primary endpoint. Success in phase II is defined as randomisation of at least four cases per month internationally in year 1, rising to at least six cases per month internationally during year 2. ETHICS AND DISSEMINATION: The medical ethical committees of all the participating countries have approved the study protocol. Results of the primary and secondary endpoints will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14240288, 20 October 2016. NCT02945566; Pre-results, October 2016. PMID- 29288192 TI - Symptomatic partial and transitional atrioventricular septal defect repaired in infancy. AB - OBJECTIVES: Infants with symptomatic partial and transitional atrioventricular septal defect undergoing early surgical repair are thought to be at greater risk. However, the outcome and risk profile of this cohort of patients are poorly defined. The aim of this study was to investigate the outcome of symptomatic infants undergoing early repair and to identify risk factors which may predict mortality and reoperation. METHODS: This multicentre study recruited 51 patients (24 female) in three tertiary centres between 2000 and 2015. The inclusion criteria were as follows: (1) partial and transitional atrioventricular septal defect, (2) heart failure unresponsive to treatment, (3) biventricular repair during the first year of life. RESULTS: Median age at definitive surgery was 179 (range 0-357) days. Sixteen patients (31%) had unfavourable anatomy of the left atrioventricular valve: dysplastic (n=7), double orifice (n=3), severely deficient valve leaflets (n=1), hypoplastic left atrioventricular orifice and/or mural leaflet (n=3), short/poorly defined chords (n=2). There were three inhospital deaths (5.9%) after primary repair. Eleven patients (22%) were reoperated at a median interval of 40 days (4 days to 5.1 years) for severe left atrioventricular valve regurgitation and/or stenosis. One patient required mechanical replacement of the left atrioventricular valve. After median follow-up of 3.8 years (0.1-11.4 years), all patients were in New York Heart Association (NYHA) class I. In multivariable analysis, unfavourable anatomy of the left atrioventricular valve was the only risk factor associated with left atrioventricular valve reoperation. CONCLUSIONS: Although surgical repair is successful in the majority of the cases, patients with partial and transitional atrioventricular septal defect undergoing surgical repair during infancy experience significant morbidity and mortality. The reoperation rate is high with unfavourable left atrioventricular valve anatomy. PMID- 29288191 TI - Exercise and adiposity in overweight and obese children and adolescents: protocol for a systematic review and network meta-analysis of randomised trials. AB - INTRODUCTION: Overweight and obesity is a worldwide public health problem among children and adolescents. However, the magnitude of effect, as well as hierarchy of exercise interventions (aerobic, strength training or both), on selected measures of adiposity is not well established despite numerous trials on this issue. The primary purposes of this study are to use the network meta-analytical approach to determine the effects and hierarchy of exercise interventions on selected measures of adiposity in overweight and obese children and adolescents. METHODS AND ANALYSIS: Randomised exercise intervention trials >4 weeks, available in any language up to 31 August 2017 and which include direct and/or indirect evidence, will be included. Studies will be located by searching seven electronic databases, cross-referencing and expert review. Dual selection and abstraction of data will occur. The primary outcomes will be changes in body mass index (in kg/m2), fat mass and percent body fat. Risk of bias will be assessed using the Cochrane Risk of Bias assessment instrument while confidence in the cumulative evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation instrument for network meta-analysis. Network meta analysis will be performed using multivariate random-effects meta-regression models. The surface under the cumulative ranking curve will be used to provide a hierarchy of exercise treatments (aerobic, strength or both). ETHICS AND DISSEMINATION: This study does not require ethics approval. Findings will be presented at a professional conference and published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD 42017073103 . PMID- 29288193 TI - Assessment of endothelialization of aneurysm wall over time in a rabbit model through CD31 scoring. AB - BACKGROUND: Intracranial aneurysms represent a significant health concern and are poorly understood despite decades of research. Our study focused on understanding temporal patterns of endothelial cell distribution in different spatial locations within the aneurysm early after creation in a rabbit model. METHODS: Elastase induced saccular aneurysms were created in rabbits and harvested on day 1 (n=3) and after 2 (n=5), 4 (n=4), 8 (n=5), and 12 (n=6) weeks. Sham operated controls (n=3) were harvested on the same day. Aneurysm and control tissue samples were subjected to en face whole mount CD31 staining for endothelial cells. Semiquantitative scoring was performed on the basis of endothelial coverage of the vessel wall (proximal, middle, and distal portions of the aneurysm dome). Mixed effects models were used to assess the effect of time and aneurysm section on endothelial coverage. RESULTS: Aneurysmal segments were near completely de endothelialized at 4 and 8 weeks but had re-endothelialized by 12 weeks. Compared with controls, aneurysms at all time points showed decreased endothelialization, but the difference was only significant compared with the 4 and 8 week groups. Both time (P=0.03) and aneurysm section (P=0.07) were significantly associated with the degree of endothelialization. Proximal locations showed increased endothelialization compared with distal locations (P=0.03). CONCLUSION: In experimental aneurysms of rabbits, endothelial cells regress during the first month after creation, followed by ascending re-endothelialization that stays incomplete. These findings suggest that re-population of endothelial cells comes from resident cells in the adjacent parent artery and that deranged hemodynamics may affect full reconstitution of endothelial cells long term. PMID- 29288194 TI - Increased middle cerebral artery mean blood flow velocity index after stroke thrombectomy indicates increased risk for intracranial hemorrhage. AB - BACKGROUND AND PURPOSE: Cerebral hyperperfusion has been related to the risk of intracranial hemorrhage (ICH) in stroke patients after vessel recanalization therapy. We hypothesized that after successful mechanical thrombectomy for acute anterior circulation stroke, hemodynamics detectable by transcranial Duplex (TCD) sonography would vary, and that increased blood flow velocities would be associated with ICH. METHODS: We retrospectively identified all ischemic stroke patients with successful endovascular recanalization for anterior circulation vessel occlusion (Thrombolysis in Cerebral Infarction 2b-3) between 2010 and 2017. We reviewed their postinterventional TCD examinations for mean blood flow (MBF) velocities of the recanalized and contralateral middle cerebral artery (MCA) and searched for an association with postinterventional ICH and clinical outcome. RESULTS: 123 stroke patients (mean age 63+/-14 years, 40% women) with successful anterior circulation thrombectomy were analyzed. Of those, 18 patients had postinterventional ICH. ICH patients had an increased MCA MBF velocity index (=MBF velocity of the recanalized divided by the contralateral MCA) compared with non-ICH patients (1.32+/-0.39 vs 1.02+/-0.32, P<0.001). In multivariate analysis, a higher MCA MBF velocity index was associated with postinterventional ICH and poor 90 day outcome. CONCLUSIONS: A high MCA MBF velocity index on TCD after successful recanalization therapy for anterior circulation stroke indicates a risk for postinterventional ICH and worse prognosis. PMID- 29288196 TI - Hydroxychloroquine-Mediated Cardiotoxicity With a False-Positive 99mTechnetium Labeled Pyrophosphate Scan for Transthyretin-Related Cardiac Amyloidosis. PMID- 29288195 TI - Sequencing of Linkage Region on Chromosome 12p11 Identifies PKP2 as a Candidate Gene for Left Ventricular Mass in Dominican Families. AB - Increased left ventricular mass (LVM) is an intermediate phenotype for cardiovascular disease (CVD) and a predictor of stroke. Using families from the Dominican Republic, we have previously shown LVM to be heritable and found evidence for linkage to chromosome 12p11. Our current study aimed to further characterize the QTL by sequencing the 1 LOD unit down region in 10 families from the Dominican Republic with evidence for linkage to LVM. Within this region, we tested 5477 common variants [CVs; minor allele frequency (MAF) >=5%] using the Quantitative Transmission-Disequilibrium Test (QTDT). Gene-based analyses were performed to test rare variants (RVs; MAF < 5%) in 181 genes using the family based sequence kernel association test. A sample of 618 unrelated Dominicans from the Northern Manhattan Study (NOMAS) and 12 Dominican families with Exome Array data were used for replication analyses. The most strongly associated CV with evidence for replication was rs1046116 (Discovery families P = 9.0 * 10-4; NOMAS P = 0.03; replication families P = 0.46), a missense variant in PKP2 In nonsynonymous RV analyses, PKP2 was one of the most strongly associated genes (P = 0.05) with suggestive evidence for replication in NOMAS (P = 0.05). PKP2 encodes the plakophilin 2 protein and is a desmosomal gene implicated in arrythmogenic right ventricular cardiomyopathy and recently in arrhythmogenic left ventricular cardiomyopathy, which makes PKP2 an excellent candidate gene for LVM. In conclusion, sequencing of our previously reported QTL identified common and rare variants within PKP2 to be associated with LVM. Future studies are necessary to elucidate the role these variants play in influencing LVM. PMID- 29288197 TI - Recruitment and allosteric stimulation of a histone-deubiquitinating enzyme during heterochromatin assembly. AB - Heterochromatin formation in budding yeast is regulated by the silent information regulator (SIR) complex. The SIR complex comprises the NAD-dependent deacetylase Sir2, the scaffolding protein Sir4, and the nucleosome-binding protein Sir3. Transcriptionally active regions present a challenge to SIR complex-mediated de novo heterochromatic silencing due to the presence of antagonistic histone post translational modifications, including acetylation and methylation. Methylation of histone H3K4 and H3K79 is dependent on monoubiquitination of histone H2B (H2B Ub). The SIR complex cannot erase H2B-Ub or histone methylation on its own. The deubiquitinase (DUB) Ubp10 is thought to promote heterochromatic silencing by maintaining low H2B-Ub at sub-telomeres. Here, we biochemically characterized the interactions between Ubp10 and the SIR complex machinery. We demonstrate that a direct interaction between Ubp10 and the Sir2/4 sub-complex facilitates Ubp10 recruitment to chromatin via a co-assembly mechanism. Using hydrolyzable H2B-Ub analogs, we show that Ubp10 activity is lower on nucleosomes compared with H2B-Ub in solution. We find that Sir2/4 stimulates Ubp10 DUB activity on nucleosomes, likely through a combination of targeting and allosteric regulation. This coupling mechanism between the silencing machinery and its DUB partner allows erasure of active PTMs and the de novo transition of a transcriptionally active DNA region to a silent chromatin state. PMID- 29288198 TI - The Chemokine Receptor CXCR3 Promotes CD8+ T Cell Accumulation in Uninfected Salivary Glands but Is Not Necessary after Murine Cytomegalovirus Infection. AB - Recent work indicates that salivary glands are able to constitutively recruit CD8+ T cells and retain them as tissue-resident memory T cells, independently of local infection, inflammation, or Ag. To understand the mechanisms supporting T cell recruitment to the salivary gland, we compared T cell migration to the salivary gland in mice that were infected or not with murine CMV (MCMV), a herpesvirus that infects the salivary gland and promotes the accumulation of salivary gland tissue-resident memory T cells. We found that acute MCMV infection increased rapid T cell recruitment to the salivary gland but that equal numbers of activated CD8+ T cells eventually accumulated in infected and uninfected glands. T cell recruitment to uninfected salivary glands depended on chemokines and the integrin alpha4 Several chemokines were expressed in the salivary glands of infected and uninfected mice, and many of these could promote the migration of MCMV-specific T cells in vitro. MCMV infection increased the expression of chemokines that interact with the receptors CXCR3 and CCR5, but neither receptor was needed for T cell recruitment to the salivary gland during MCMV infection. Unexpectedly, however, the chemokine receptor CXCR3 was critical for T cell accumulation in uninfected salivary glands. Together, these data suggest that CXCR3 and the integrin alpha4 mediate T cell recruitment to uninfected salivary glands but that redundant mechanisms mediate T cell recruitment after MCMV infection. PMID- 29288199 TI - Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains. AB - Adoptive T cell therapies have achieved significant clinical responses, especially in hematopoietic cancers. Two types of receptor systems have been used to redirect the activity of T cells, normal heterodimeric TCRs or synthetic chimeric Ag receptors (CARs). TCRs recognize peptide-HLA complexes whereas CARs typically use an Ab-derived single-chain fragments variable that recognizes cancer-associated cell-surface Ags. Although both receptors mediate diverse effector functions, a quantitative comparison of the sensitivity and signaling capacity of TCRs and CARs has been limited due to their differences in affinities and ligands. In this study we describe their direct comparison by using TCRs that could be formatted either as conventional alphabeta heterodimers, or as single chain fragments variable constructs linked to CD3zeta and CD28 signaling domains or to CD3zeta alone. Two high-affinity TCRs (KD values of ~50 and 250 nM) against MART1/HLA-A2 or WT1/HLA-A2 were used, allowing MART1 or WT1 peptide titrations to easily assess the impact of Ag density. Although CARs were expressed at higher surface levels than TCRs, they were 10-100-fold less sensitive, even in the absence of the CD8 coreceptor. Mathematical modeling demonstrated that lower CAR sensitivity could be attributed to less efficient signaling kinetics. Furthermore, reduced cytokine secretion observed at high Ag density for both TCRs and CARs suggested a role for negative regulators in both systems. Interestingly, at high Ag density, CARs also mediated greater maximal release of some cytokines, such as IL-2 and IL-6. These results have implications for the next-generation design of receptors used in adoptive T cell therapies. PMID- 29288200 TI - EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody Secreting Cell Metabolism and Antibody Production. AB - Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell specific deletions of Ezh2 Following stimulation with influenza virus or LPS, Ezh2-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell-lineage transcription factors, and Blimp-1 repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism. PMID- 29288201 TI - Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens. AB - CD22 and sialic acid-binding Ig-like lectin (Siglec)-G are members of the Siglec family of inhibitory coreceptors expressed on B cells that participate in enforcement of peripheral B cell tolerance. We have shown previously that when a BCR engages its cognate Ag on a cell surface that also expresses Siglec ligands, B cell Siglecs are recruited to the immunological synapse, resulting in suppression of BCR signaling and B cell apoptosis. Because all cells display sialic acids, and CD22 and Siglec-G have distinct, yet overlapping, specificities for sialic acid-containing glycan ligands, any cell could, in principle, invoke this tolerogenic mechanism for cell surface Ags. However, we show in this article that C57BL/6J mouse RBCs are essentially devoid of CD22 and Siglec-G ligands. As a consequence, RBCs that display a cell surface Ag, membrane-bound hen egg lysozyme, strongly activate Ag-specific B cells. We reasoned that de novo introduction of CD22 ligands in RBCs should abolish B cell activation toward its cognate Ag on the surface of RBCs. Accordingly, we used a glyco-engineering approach wherein synthetic CD22 ligands linked to lipids are inserted into the membrane of RBCs. Indeed, insertion of CD22 ligands into the RBC cell surface strongly inhibited B cell activation, cytokine secretion, and proliferation. These results demonstrate that the lack of Siglec ligands on the surface of murine RBCs permits B cell responses to erythrocyte Ags and show that Siglec mediated B cell tolerance is restricted to cell types that express glycan ligands for the B cell Siglecs. PMID- 29288203 TI - The p38-MK2/3 Module Is Critical for IL-33-Induced Signaling and Cytokine Production in Dendritic Cells. AB - IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-kappaB signaling and activation of MAPKs. In bone marrow-derived dendritic cells, IL-33 induces the production of IL-6, IL 13, and TNF-alpha. However, the signaling pathways resulting in IL-33-induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33-induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38-Mapk activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow-derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3-dependent IL-13 production. Furthermore, we found that effective TNF-alpha production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33 induced cytokine production in dendritic cells. PMID- 29288202 TI - GM-CSF Promotes Chronic Disability in Experimental Autoimmune Encephalomyelitis by Altering the Composition of Central Nervous System-Infiltrating Cells, but Is Dispensable for Disease Induction. AB - GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG35-55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG35-55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG35-55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits. PMID- 29288204 TI - Novel TCR-Mediated Mechanisms of Notch Activation and Signaling. AB - The Notch receptor is an evolutionarily highly conserved transmembrane protein that is essential to a wide spectrum of cellular systems. Notch signaling is especially important to T cell development, and its deregulation leads to leukemia. Although not well characterized, it continues to play an integral role in peripheral T cells, in which a unique mode of Notch activation can occur. In contrast to canonical Notch activation initiated by adjacent ligand-expressing cells, TCR stimulation is sufficient to induce Notch signaling. However, the interactions between these two pathways have not been defined. In this article, we show that Notch activation occurs in peripheral T cells within a few hours post-TCR stimulation and is required for optimal T cell activation. Using a panel of inhibitors against components of the TCR signaling cascade, we demonstrate that Notch activation is facilitated through initiation of protein kinase C induced ADAM activity. Moreover, our data suggest that internalization of Notch via endocytosis plays a role in this process. Although ligand-mediated Notch stimulation relies on mechanical pulling forces that disrupt the autoinhibitory domain of Notch, we hypothesized that, in T cells in the absence of ligands, these conformational changes are induced through chemical adjustments in the endosome, causing alleviation of autoinhibition and receptor activation. Thus, T cells may have evolved a unique method of Notch receptor activation, which is described for the first time, to our knowledge, in this article. PMID- 29288205 TI - Extracellular Lactate: A Novel Measure of T Cell Proliferation. AB - Following activation, T cells rapidly divide and acquire effector functions. This energetically demanding process depends upon the ability of T cells to undergo metabolic remodeling from oxidative phosphorylation to aerobic glycolysis, during which glucose is converted into lactate and released extracellularly. In this article, we demonstrate that extracellular lactate can be used to dynamically assess human T cell responses in vitro. Extracellular lactate levels strongly correlated with T cell proliferation, and measuring lactate compared favorably with traditional methods for determining T cell responses (i.e., [3H]thymidine incorporation and the use of cell proliferation dyes). Furthermore, we demonstrate the usefulness of measuring lactate as a read-out in conventional suppression assays and high-throughput peptide-screening assays. Extracellular lactate was stably produced over 7 d, and results were reproducibly performed over several freeze-thaw cycles. We conclude that the use of extracellular lactate measurements can be a sensitive, safe, stable, and easy-to-implement research tool for measuring T cell responses and cellular metabolic changes in vitro. PMID- 29288206 TI - IL-4-Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation. AB - Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4-induced gene-1 (IL4I1), a secreted l phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology. PMID- 29288208 TI - Simultaneous inhibition of alpha4/beta7 integrin and tumour necrosis factor-alpha in concomitant spondyloarthritis and inflammatory bowel disease. PMID- 29288209 TI - Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis. PMID- 29288207 TI - Newly Generated CD4+ T Cells Acquire Metabolic Quiescence after Thymic Egress. AB - Mature naive T cells circulate through the secondary lymphoid organs in an actively enforced quiescent state. Impaired cell survival and cell functions could be found when T cells have defects in quiescence. One of the key features of T cell quiescence is low basal metabolic activity. It remains unclear at which developmental stage T cells acquire this metabolic quiescence. We compared mitochondria among CD4 single-positive (SP) T cells in the thymus, CD4+ recent thymic emigrants (RTEs), and mature naive T cells in the periphery. The results demonstrate that RTEs and naive T cells had reduced mitochondrial content and mitochondrial reactive oxygen species when compared with SP thymocytes. This downregulation of mitochondria requires T cell egress from the thymus and occurs early after young T cells enter the circulation. Autophagic clearance of mitochondria, but not mitochondria biogenesis or fission/fusion, contributes to mitochondrial downregulation in RTEs. The enhanced apoptosis signal-regulating kinase 1/MAPKs and reduced mechanistic target of rapamycin activities in RTEs relative to SP thymocytes may be involved in this mitochondrial reduction. These results indicate that the gain of metabolic quiescence is one of the important maturation processes during SP-RTE transition. Together with functional maturation, it promotes the survival and full responsiveness to activating stimuli in young T cells. PMID- 29288210 TI - Switching from the bio-originators to biosimilar: is it premature to recommend this procedure? PMID- 29288211 TI - Neurological complications of renal dialysis and transplantation. AB - Neurological complications from renal replacement therapy contribute significantly to morbidity and mortality in patients with renal failure. Such complications can affect either the central or peripheral nervous systems. Most neurological disturbances associated with the uraemic state do not respond fully to renal replacement therapy. There are also complications specifically associated with dialysis and transplantation. A multidisciplinary approach, involving both nephrologists and neurologists, is critical for the diagnosis and effective management of these disorders. PMID- 29288212 TI - Cerebral arterial gas embolism from attempted mechanical thrombectomy: recovery following hyperbaric oxygen therapy. AB - Cerebral arterial gas embolism is a recognised complication of endovascular intervention with an estimated incidence of 0.08%. Its diagnosis is predominantly clinical, supported by neuroimaging. The treatment relies on alleviating mechanical obstruction and reversing the proinflammatory processes that contribute to tissue ischaemia. Hyperbaric oxygen therapy is an effective treatment and has multiple mechanisms to reverse the pathological processes involved in cerebral arterial gas embolism. Symptomatic cerebral arterial gas embolism is a rare complication of endovascular intervention for acute ischaemic stroke. Although there are no previous descriptions of its successful treatment with hyperbaric oxygen therapy following mechanical thrombectomy, this is likely to become more common as mechanical thrombectomy is increasingly used worldwide to treat acute ischaemic stroke. PMID- 29288213 TI - Big asthma data: getting bigger and more beautiful? PMID- 29288214 TI - Familial pneumothorax: towards precision medicine. AB - One in 10 patients suffering from primary spontaneous pneumothoraces has a family history of the disorder. Such familial pneumothoraces can occur in isolation, but can also be the presentation of serious genetic disorders with life-threatening vascular or cancerous complications. As the pneumothorax frequently precedes the more dangerous complications by many years, it provides an opportunity to intervene in a focused manner, permitting the practice of precision medicine. In this review, we will discuss the clinical manifestations and underlying biology of the genetic causes of familial pneumothorax. PMID- 29288216 TI - Microbial proteins for organic material degradation in the deep ocean. PMID- 29288215 TI - KLU suppresses megasporocyte cell fate through SWR1-mediated activation of WRKY28 expression in Arabidopsis. AB - Germ-line specification is essential for sexual reproduction. In the ovules of most flowering plants, only a single hypodermal cell enlarges and differentiates into a megaspore mother cell (MMC), the founder cell of the female germ-line lineage. The molecular mechanisms restricting MMC specification to a single cell remain elusive. We show that the Arabidopsis transcription factor WRKY28 is exclusively expressed in hypodermal somatic cells surrounding the MMC and is required to repress these cells from acquiring MMC-like cell identity. In this process, the SWR1 chromatin remodeling complex mediates the incorporation of the histone variant H2A.Z at the WRKY28 locus. Moreover, the cytochrome P450 gene KLU, expressed in inner integument primordia, non-cell-autonomously promotes WRKY28 expression through H2A.Z deposition at WRKY28. Taken together, our findings show how somatic cells in ovule primordia cooperatively use chromatin remodeling to restrict germ-line cell specification to a single cell. PMID- 29288217 TI - Searching for the neural causes of criminal behavior. PMID- 29288218 TI - When linearity prevails over hierarchy in syntax. AB - Hierarchical structure has been cherished as a grammatical universal. We use experimental methods to show where linear order is also a relevant syntactic relation. An identical methodology and design were used across six research sites on South Slavic languages. Experimental results show that in certain configurations, grammatical production can in fact favor linear order over hierarchical structure. However, these findings are limited to coordinate structures and distinct from the kind of production errors found with comparable configurations such as "attraction" errors. The results demonstrate that agreement morphology may be computed in a series of steps, one of which is partly independent from syntactic hierarchy. PMID- 29288219 TI - Endless skulls most beautiful. PMID- 29288220 TI - Reply to Plewis, Murari et al., and Das: The suicide-temperature link in India and the evidence of an agricultural channel are robust. PMID- 29288221 TI - Climate change and agricultural suicides in India. PMID- 29288223 TI - Analyzing Indian farmer suicide rates. PMID- 29288222 TI - Unfounded assumptions in linking crop-damaging temperature and suicide in India. PMID- 29288224 TI - Reply to Risk and Zhu: Mixed-effects modeling as a principled approach to heritability analysis with repeat measurements. PMID- 29288225 TI - Note on bias from averaging repeated measurements in heritability studies. PMID- 29288226 TI - Progressive delayed hemidystonia following clinically mild traumatic brain injury. AB - A 16-year-old boy presented with progressive left hemidystonia over 3 years. The possibilities of symptomatic hemidystonia due to focal lesions such as infarct (vasculitis), tumours, tuberculoma, arteriovenous malformations or heredodegenerative disorders such as Wilson disease were considered. Imaging showed a peculiar scar involving right basifrontal region extending upto anterior, centromedian and dorsomedial nuclei of thalamus due to blowout fracture of roof of orbit. This scar was responsible for progressive left hemidystonia. On probing the history, it was revealed that patient had sustained a mild traumatic brain injury (mTBI) 3 years ago. Burke-Fahn-Marsden dystonia severity rating scale showed improvement from 19 to 6 after treatment with tablet trihexyphenidyl 16 mg and clonazepam 1 mg. A linear scar reaching upto thalamus due to blowout fracture of roof of orbit following clinically mTBI is unique. Delayed, progressive hemidystonia has been reported following severe head injury, however is less common following clinically mTBI. PMID- 29288227 TI - Endobronchial metastasis of mixed Mullerian tumour of the uterus. AB - Endobronchial metastasis occurs in only 2%-5% of non-pulmonary cancers. Here we report on an 84-year-old woman who presented with breathlessness and light headedness while on holiday in Australia, 2 years post-treatment for endometrial cancer. Initial CT pulmonary angiogram identified a soft tissue mass in the left hemithorax. A chest radiograph performed after repatriation was consistent with a large left pleural effusion, but bedside ultrasound showed a lobulated mass involving the left hemidiaphragm. A pleural procedure in the traditional 'triangle of safety' would have resulted in inadvertent puncture of the underlying mass. Serial imaging confirmed the mass was rapidly progressing, and metastatic malignant mixed Mullerian endometrial carcinoma was diagnosed by endobronchial biopsy. A tunnelled intrapleural catheter was inserted for symptom relief, and the patient deteriorated and died at home 2 weeks later. To our knowledge, this is the first case of endobronchial metastasis from malignant mixed Mullerian tumour of the uterus. PMID- 29288228 TI - Intramural oesophageal haematoma following traumatic neck injury. AB - This case describes a previously well 90-year-old woman who presented with neck pain, swelling, dysphagia and hoarseness following a motor vehicle collision. Oesophageal oedema was visualised on CT of cervical spine and subsequent CT angiography highlighted an actively bleeding intramural oesophageal haematoma (IOH) extending from the cervical oesophagus to the carina. This rare phenomenon (IOH) has been described as a possible consequence of blunt trauma to the neck; however, we found no cases resulting from acceleration/deceleration injury. Although this was a potentially life-threatening injury, our patient made a full recovery with conservative management. PMID- 29288230 TI - Genetic testing to prevent adverse reactions to antiepileptic drugs: Primum non nocere. PMID- 29288231 TI - Sulforaphane Modifies Histone H3, Unpacks Chromatin, and Primes Defense. AB - Modern crop production calls for agrochemicals that prime plants for enhanced defense. Reliable test systems for spotting priming-inducing chemistry, however, are rare. We developed an assay for the high-throughput search for compounds that prime microbial pattern-induced secretion of antimicrobial furanocoumarins (phytoalexins) in cultured parsley cells. The screen produced 1-isothiocyanato-4 methylsulfinylbutane (sulforaphane; SFN), a secondary metabolite in many crucifers, as a novel defense priming compound. While elucidating SFN's mode of action in defense priming, we found that in Arabidopsis (Arabidopsisthaliana) the isothiocyanate provokes covalent modification (K4me3, K9ac) of histone H3 in the promoter and promoter-proximal region of defense genes WRKY6 and PDF12, but not PR1 SFN-triggered H3K4me3 and H3K9ac coincide with chromatin unpacking in the WRKY6 and PDF12 regulatory regions, primed WRKY6 expression, unprimed PDF12 activation, and reduced susceptibility to downy mildew disease (Hyaloperonospora arabidopsidis). Because SFN also directly inhibits Harabidopsidis and other plant pathogens, the isothiocyanate is promising for the development of a plant protectant with a dual mode of action. PMID- 29288232 TI - N-Glycoproteomic Characterization of Mannosidase and Xylosyltransferase Mutant Strains of Chlamydomonasreinhardtii. AB - At present, only little is known about the enzymatic machinery required for N glycosylation in Chlamydomonas reinhardtii, leading to the formation of N-glycans harboring Xyl and methylated Man. This machinery possesses new enzymatic features, as C. reinhardtii N-glycans are independent of beta1,2-N acetylglucosaminyltransferase I. Here we have performed comparative N glycoproteomic analyses of insertional mutants of mannosidase 1A (IM Man1A ) and xylosyltransferase 1A (IM XylT1A ). The disruption of man1A affected methylation of Man and the addition of terminal Xyl. The absence of XylT1A led to shorter N glycans compared to the wild type. The use of a IM Man1A xIM XylT1A double mutant revealed that the absence of Man1A suppressed the IM XylT1A phenotype, indicating that the increased N-glycan trimming is regulated by core beta1,2-Xyl and is dependent on Man1A activity. These data point toward an enzymatic cascade in the N-glycosylation pathway of C. reinhardtii with interlinked roles of Man1A and XylT1A. The results described herein represent the first step toward a functional characterization of the enzymatic N-glycosylation machinery in C. reinhardtii. PMID- 29288229 TI - Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. AB - OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 * 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients. PMID- 29288235 TI - RING-Finger Protein 6 Amplification Activates JAK/STAT3 Pathway by Modifying SHP 1 Ubiquitylation and Associates with Poor Outcome in Colorectal Cancer. AB - Objective: The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer. We aimed to explore the mechanical, biological, and clinical role of RNF6 in colorectal cancer initiation and progression.Design: The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real-time PCR, Western blot, and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and in vitro Role of RNF6 in modulating SHP-1 expression was examined by coimmunoprecipitation and confocal microscopy, respectively.Results: The copy number of RNF6 was significantly amplified in colorectal cancer, and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with patients with colorectal cancer with poor prognosis. The gene set enrichment analysis (GSEA) revealed cell proliferation, and invasion-related genes were enriched in RNF6 high-expressed colorectal cancer cells as well as in patients from TCGA dataset. Downregulation of RNF6 impaired the colorectal cancer cell proliferation and invasion in vitro and in vivo RNF6 may activate the JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1.Conclusions: Genomic amplification drives RNF6 overexpression in colorectal cancer. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP 1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors. Clin Cancer Res; 24(6); 1473-85. (c)2017 AACR. PMID- 29288234 TI - Recovery from N Deprivation Is a Transcriptionally and Functionally Distinct State in Chlamydomonas. AB - Facing adverse conditions such as nitrogen (N) deprivation, microalgae enter cellular quiescence, a reversible cell cycle arrest with drastic changes in metabolism allowing cells to remain viable. Recovering from N deprivation and quiescence is an active and orderly process as we are showing here for Chlamydomonas reinhardtii We conducted comparative transcriptomics on this alga to discern processes relevant to quiescence in the context of N deprivation and recovery following refeeding. A mutant with slow recovery from N deprivation, compromised hydrolysis of triacylglycerols7 (cht7), was included to better define the regulatory processes governing the respective transitions. We identified an ordered set of biological processes with expression patterns that showed sequential reversal following N resupply and uncovered acclimation responses specific to the recovery phase. Biochemical assays and microscopy validated selected inferences made based on the transcriptional analyses. These comprise (1) the restoration of N source preference and cellular bioenergetics during the early stage of recovery; (2) flagellum-based motility in the mid to late stage of recovery; and (3) recovery phase-specific gene groups cooperating in the rapid replenishment of chloroplast proteins. In the cht7 mutant, a large number of programmed responses failed to readjust in a timely manner. Finally, evidence is provided for the involvement of the cAMP-protein kinase A pathway in gating the recovery. We conclude that the recovery from N deprivation represents not simply a reversal of processes directly following N deprivation, but a distinct cellular state. PMID- 29288233 TI - The sHSP22 Heat Shock Protein Requires the ABI1 Protein Phosphatase to Modulate Polar Auxin Transport and Downstream Responses. AB - The phytohormones abscisic acid (ABA) and indole-3-acetic acid (IAA) response pathways interact synergistically or antagonistically to regulate plant development and environmental adaptation. Here, we show that ABI1, a key negative regulator of ABA signaling, is essential for auxin-modulated root development. We performed a microarray analysis using the loss-of-function mutant abi1-3 and Col 0 seedlings treated with IAA. For sHSP22, an endoplasmic reticulum (ER) small heat shock protein-encoding gene, the induction by IAA was dependent on ABI1shsp22 displayed enhanced sensitivity to ABA in primary root growth. In contrast, overexpression of full-length, but not truncated sHSP22 lacking signal peptide and ER-retention sequences, resulted in decreased ABA sensitivity. Overexpressed (OX) sHSP22 partially rescued the ABA hypersensitivity of abi1-3 In addition, sHSP22 is involved in auxin-regulated hypocotyl elongation at high temperature treatment. sHSP22 also affected accumulation of auxin efflux carrier PIN proteins due to potentiated intracellular trafficking. And sHSP22 OX lines initiated more lateral roots after auxin application. Our results suggest that sHSP22 regulates auxin response through modulating auxin polar transport, and ABI1-sHSP22 provides a novel module orchestrating ABA and auxin signaling crosstalk in Arabidopsis (Arabidopsis thaliana). PMID- 29288236 TI - CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer. AB - Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival.Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD-scid gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival.Results:In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival.Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients. Clin Cancer Res; 24(6); 1415-25. (c)2017 AACR. PMID- 29288238 TI - Does access to pasture affect claw condition and health in dairy cows? AB - The aim of this study was to examine effects of pasturing in dairy cows on claw condition (claw length, hardness) and on the prevalence of claw diseases. At claw trimming, a total of 240 Holstein-Friesian or Red-Holstein cows from 20 German farms were examined twice, at the end of the pasture and barn season. Each individual claw was trimmed at both assessments. Farms were classified based on animals' pasture access during pasture season into: group 1 (G1) >10 hours pasture access per day, group 2 (G2) 6-10 hours, group 3 (G3) <6 hours and group 4 (G4) without pasture access. Greater values for hardness were associated with lower scores (=prevalence*severity level) of sole ulcers, white line disease, sole haemorrhage, heel horn erosion and interdigital hyperplasia. In pasture groups, heel horn erosion showed lower frequencies in summer compared with winter, while it was vice versa in G4. In G1 and G3, lower frequencies of white line disease were found in summer compared with winter. Overall, pasture access had positive effects in particular for claw diseases that are related to moist environments. Nevertheless, appropriate free-stall design and claw trimming routine might have a greater influence. PMID- 29288239 TI - Late-onset recurrence of neurological deficits after surgery for spinal arachnoid diverticula. AB - Spinal cord dysfunction secondary to spinal arachnoid diverticula (SAD) has been widely reported in the veterinary literature and there is some suggestion that surgical treatment may provide better outcomes than medical treatment. Despite this, previous reports have mentioned cases with recurrence of clinical signs following surgical treatment but the cause for this has not been further investigated. The medical records of seven dogs and one cat which presented for investigation of recurrence of neurological deficits at least six months after surgery for SAD were retrospectively reviewed. Median time to relapse of the neurological deficits was 20.5 months after surgery. On repeated imaging, 3/8 cases showed clear regrowth of diverticulum, 2/8 cases showed dorsal compression at the previous laminectomy site (presumed to be the laminectomy membrane), and 3/8 cases showed herniation of the spinal cord through the laminectomy defect associated with a stellate appearance to the spinal cord with small multiloculated areas of dilation of the subarachnoid space. Repeat surgical intervention was most successful in the cases where SAD recurrence was identified while medical treatment resulted in either subtle improvement or stabilisation on the clinical signs, sometimes followed by slow deterioration. PMID- 29288240 TI - A guy with a machine: Using NMR to study biological macromolecules. PMID- 29288237 TI - Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. AB - Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344-54. (c)2017 AACR. PMID- 29288241 TI - Covering their bases: The phosphobase methylation pathway in plants. AB - Phosphoethanolamine methyltransferases add three methyl groups successively to their substrate to produce phosphocholine, an important precursor for phospholipid biosynthesis in diverse organisms. New work from Lee and Jez reveals critical domain movements that explain how multiple methylation reactions are uniquely coordinated by plant methyltransferases and provides insights into the evolution of this class of enzymes. As opposed to closely related family members, the intermediates in this pathway are likely shuttled between two tethered domains to ensure complete methylation. PMID- 29288242 TI - JBC's New Year's resolutions: Check them off! PMID- 29288243 TI - Rho/ROCK Pathway Regulates Migration and Invasion of Esophageal Squamous Cell Carcinoma by Regulating Caveolin-1. AB - BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a common cancer with poor prognosis. Caveolin-1 (Cav1) and Rho/ROCK pathway play important roles in tumor metastasis, separately. However, less research was focused on the relationship between Cav1 and Rho/ROCK in ECSS metastasis. Therefore, we investigated the relationship between Cav1 and Rho/ROCK pathway in ESCC metastasis. MATERIAL AND METHODS Cav1 and phosphorylated Cav1 (PY14Cav1) were examined in ESCC and in adjacent and non-tumorous tissues from ESCC patients by immunohistochemistry (IHC). Small interfering RNA (siRNA) targeting Cav1 or Rho/ROCK inhibitor was used to treat EC109, Eca109, TE1, and TE13 cells. Western blotting (WB) was used to detect Cav1 and PY14Cav1 expression. The wound healing scratch test and transwell assays were used to assess migration and invasion. RESULTS Cav1 and PY14Cav1 were gradually expressed at higher levels in ECSS than in adjacent and non-tumor tissues as ESCC stage and lymphatic metastasis increased, and this difference was significant (P<0.05). Cav1 was expressed at higher levels in TE1 and TE13 than in EC109 and Eca109, while PY14Cav1 was enhanced in TE1 and TE13 cells but not in EC109 and Eca109, and the difference was significant (P<0.05). TE1 and TE13 had significantly (P<0.05) stronger motility, migratory, and invasion abilities than EC109 and Eca109 cells. Silencing Cav1 decreased PY14Cav1 expression in TE1 and TE13 cells, as well as suppressing the migration and invasion of all ECSS cells, and these differences were significant (P<0.05). Suppressing the Rho/ROCK pathway obviously inhibited Cav1 and PY14Cav1 expressions, as well as significantly (P<0.05) decreasing migration and invasion of ESCC cells. CONCLUSIONS Cav1 and PY14Cav1 were positively correlated with ESCC lymphatic metastasis and cancer stages. Rho/ROCK pathway activation promoted ESCC metastasis by regulating Cav1. PMID- 29288244 TI - Re-evaluation of the associations of egg intake with serum total cholesterol and cause-specific and total mortality in Japanese women. AB - BACKGROUND/OBJECTIVE: Egg intake was associated with serum total cholesterol adjusted for age (aTCH) and total mortality in women, but not in men, using data from NIPPON DATA (ND) 80 which followed up for 14 years. Re-evaluation of these associations in a different cohort is needed. SUBJECT/METHODS: We analyzed the associations of egg intake with aTCH and cause-specific and total mortality using the ND90 data set with a 15-year follow-up. A nutritional examination was done at the baseline in 1990 using the food-frequency method and by weighed food records. We followed 4686 female participants (ages >=30 years), with no history of stroke or myocardial infarction (mean age 52.8 years) for 15 years. RESULTS: The participants were divided into 5 egg intake groups (<1/w, 1-2/w, 1/2d, 1/d, and >=2/d). There were 203, 1462, 1594, 1387, and 40 women in each group, respectively. Egg intake was not associated with aTCH (P = 0.886). There were 183 cardiovascular disease (CVD), 210 cancer, and 599 total mortality cases during follow-up. Cox analysis, adjusted for background factors, found egg intake was directly associated with total and cancer mortality (HR in the >=2/d vs. the 1 egg/d group: total, 2.05 (95% CI: 1.20-3.52); cancer, 3.20 (1.51-6.76)), and that cancer mortality in the 1-2/w group was significantly less than that in the 1 egg/d group (0.68 (0.47-0.97)). Egg intake was not associated with CVD mortality. CONCLUSIONS: Egg intake was associated with cancer and total mortality. Reducing egg intake may have some definitive health benefits in women in Japan, at least. PMID- 29288245 TI - Validation of a three-dimensional body scanner for body composition measures. AB - The accuracy of an infrared three-dimensional (3D) body scanner in determining body composition was compared against hydrostatic weighing (HW), bioelectrical impedance analysis (BIA), and anthropometry. A total of 265 adults (119 males; age = 22.1 +/- 2.5 years; body mass index = 24.5 +/- 3.9 kg/m2) had their body fat percent (BF%) estimated from 3D scanning, HW, BIA, skinfolds, and girths. A repeated measures analysis of variance (ANOVA) indicated significant differences among methods (p < 0.001). Multivariate ANOVA indicated a significant main effect of sex and method (p < 0.001), with a non-significant interaction (p = 0.101). Bonferroni post-hoc comparisons identified that BF% from 3D scanning (18.1 +/- 7.8%) was significantly less than HW (22.8 +/- 8.5%, p < 0.001), BIA (20.1 +/- 9.1%, p < 0.001), skinfolds (19.7 +/- 9.7%, p < 0.001), and girths (21.2 +/- 10.4%, p < 0.001). The 3D scanner decreased in precision with increasing adiposity, potentially resulting from inconsistences in the 3D scanner's analysis algorithm. A correction factor within the algorithm is required before infrared 3D scanning can be considered valid in measuring BF%. PMID- 29288246 TI - Enhanced Recovery After Surgery as an auditing framework for identifying improvements to perioperative nutrition care of older surgical patients. AB - Older patients are at increased risk of malnutrition and reduced physical function. Using Enhanced Recovery After Surgery (ERAS) guidelines as an auditing framework, this study aimed to determine adherence of nutrition care to perioperative best practice in older patients. A single researcher retrieved data via chart review. Seventy-five consenting patients >=65 years (median 72 (range 65-95) years, 61% male) admitted postoperatively to general surgical wards were recruited. Sixty per cent had a primary diagnosis of cancer and 51% underwent colorectal resection. Seventeen per cent and 4% of patients met fasting targets of 2-4 h for fluid and 6-8 h for food, respectively. Fifty-five per cent were upgraded to full diet by first postoperative day. Nil received preoperative carbohydrate loading. Minimally invasive surgery (p = 0.01) and no anastomosis formation (p = 0.05) were associated with receiving ERAS-concordant nutrition care. This study highlights areas for improvement in perioperative nutrition care of older patients at our facility. PMID- 29288247 TI - Dual-energy X-ray absorptiometry visceral adipose tissue estimates: reproducibility and impact of pre-assessment diet. AB - We examined the reproducibility of dual-energy x-ray absorptiometry (DXA) visceral adipose tissue (VAT) estimates as well as the impact of pre-assessment diet. In a counterbalanced design, 41 adults received 6 DXA scans, while consuming standardized high- and low-carbohydrate (LC) diets. The impact of pre assessment diet was examined via repeated-measures analysis of variance and reproducibility of VAT estimates was evaluated by technical error of measurement (TEM) and s.e. of a single determination (SESD). VAT area, mass and volume were acutely decreased by ~ 6.5% after the LC diet (P <= 0.001), but not the high carbohydrate diet (P > 0.3). Differences persisted after an overnight fast. TEMs for VAT area, mass and volume were < 5 cm2, <= 0.2 kg and < 25 cm3. SESDs for all VAT variables were <= 5.5%. In conclusion, DXA VAT estimates exhibit good reproducibility in controlled conditions, but may be impacted by pre-assessment diet. PMID- 29288248 TI - Effect of conjugated linoleic acid on blood inflammatory markers: a systematic review and meta-analysis on randomized controlled trials. AB - BACKGROUND/OBJECTIVES: Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid with attractive biological activities. Numerous studies have been conducted on the inflammation-lowering effects of CLA in in vitro and animal models. However, the effects of CLA treatment on the inflammatory markers in humans are controversial. Therefore, the objective of this study was to perform a systematic review and meta-analysis on controlled clinical trials (RCT) assessing the effects of CLA supplementation on the circulating inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). SUBJECTS/METHODS: The literature search of RCTs was performed using Pubmed/Medline, Scopus, ScienceDirect, Web of science, Cochrane, and Google Scholar databases from inception to March 2017. Weighted mean differences were estimated and the pooled effect size was calculated by a random effects model. RESULTS: Of the 427 identified studies, eleven RCTs, including 420 subjects were included in the statistical analysis. Findings suggested that CLA supplementation increased blood levels of CRP by 0.89 mg/l (95% CI: 0.11, 1.68; P = 0.025) and TNF-alpha levels by 0.39 pg/ml (95% CI: 0.23, 0.55; P < 0.0001). However, blood IL-6 levels were marginally decreased by 0.32 pg/ml (95% CI: -0.71, 0.07; P = 0.11) following CLA supplementation. There was a significant heterogeneity for the impact of CLA on CRP and IL-6, but not TNF-alpha. CONCLUSIONS: This meta analysis showed that CLA supplementation may increase inflammatory markers (CRP and TNF-alpha). There are concerns about using CLA supplementation as an anti obesity agent among the obese population for at least a short duration. PMID- 29288249 TI - Vitamin D supplementation for the prevention of vitamin D deficiency after bariatric surgery: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of vitamin D supplementation on the prevention of postoperative vitamin D deficiency. METHODS: PubMed, Embase, Web of Science, and Cochrane library were searched. Prospective studies evaluating the effects of vitamin D supplementation in patients who had undergone bariatric surgery were included. Meta-regression was performed to explore heterogeneity, and assess the relationship between dosage of vitamin D supplementation, study design, and prevalence of vitamin D depletion. RESULTS: Twelve studies enrolling 1285 patients met the inclusion criteria, and were included. Vitamin D supplementation was associated with significant improvements in 1-year Vitamin D depletion and 1-year 25-OHD level. A daily supplement of more than 800 IU vitamin D significantly reduced the prevalence of 1-year Vitamin D depletion, but the dosage of less than 800 IU did not. Significant decrease in prevalence of 1-year Vitamin D depletion was observed in randomized controlled trials (RCTs), but not in non-RCTs. For the 1-year 25-OHD level, significant elevation was found in the studies irrespective of the study design and dosage of vitamin D supplementation. Meta-regression showed that there was significant relationship between vitamin D depletion and study design, but not between vitamin D depletion and the dosage of vitamin D supplementation. CONCLUSION: Vitamin D supplementation with a daily dosage of more than 800 IU is effective in preventing postoperative vitamin D deficiency and improving the 25-OHD level. However, the results should be interpreted cautiously since there was significant heterogeneity among the studies. PMID- 29288250 TI - Oxidative stress in critically ill ventilated adults: effects of vitamin D3 and associations with alveolar macrophage function. AB - BACKGROUND/OBJECTIVES: Disruptions in redox balance lead to oxidative stress, a promoter of morbidity in critical illness. This study aimed to: (1) characterize the plasma and alveolar thiol/disulfide redox pools, (2) examine their associations with alveolar macrophage phagocytosis, and (3) determine the effect of high dose vitamin D3 on plasma thiol/disulfide redox. SUBJECTS/METHODS: Subjects were 30 critically ill, ventilated adults in a double-blind randomized trial of high-dose (250 000 or 500 000 IU) vitamin D3 or placebo. Baseline bronchoalveolar lavage fluid (BALF) samples were analyzed for determination of alveolar phagocytosis index (PI) and for concentrations of glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), cystine (CySS), and their respective redox potentials (EhGSSG and EhCySS). Plasma redox outcomes were assessed at baseline and days 7 and 14. RESULTS: Baseline plasma Cys was inversely associated with alveolar PI (rho = -0.69, P = 0.003), and EhCySS was positively associated with PI (rho = 0.61, P = 0.01). Over time, among all subjects there was an increase in plasma GSH levels and a decrease in EhGSSG (P < 0.01 for both), with no difference by treatment group. Vitamin D3 decreased oxidized plasma GSSG to a more normal state (P for group x time = 0.009). CONCLUSIONS: Oxidative stress indicators were positively associated with alveolar macrophage phagocytic function in acutely ill ventilated adults. High-dose vitamin D3 decreased plasma GSSG concentrations, which suggests that vitamin D can possibly improve the oxidative stress environment. PMID- 29288251 TI - Prognostic impacts and dynamic changes of cohesin complex gene mutations in de novo acute myeloid leukemia. PMID- 29288253 TI - Are we ready to modify our definition of bronchopulmonary dysplasia (BPD) to improve prognostication? PMID- 29288252 TI - Characteristics of persons with spinal cord injury who drive in Malaysia and its barriers: a cross sectional study. AB - STUDY DESIGN: Cross sectional study. OBJECTIVES: To determine the prevalence, characteristics of and barriers to driving among persons with a spinal cord injury (SCI). SETTING: SCI Rehabilitation Clinic, University Malaya Medical Centre (UMMC). METHODS: This is a questionnaire-based study on persons with SCI who attended the UMMC SCI Rehabilitation Clinic between June 2015 and November 2016. The questionnaire comprised demographic data, clinical characteristics, driving variables, Spinal Cord Independence Measure III, WHOQOL-BREF, and Craig Handicap Assessment and Reporting Technique Short Form. Malaysians aged greater than 18 years old with any etiology and levels of SCI, had no other physical disabilities and not suffering from progressive illness were recruited. A single investigator administered the questionnaire via face-to-face interviews. RESULTS: A total of 160 participants were included in this study. Overall, 37% of persons with SCI drove and owned a modified vehicle. Almost half of persons with paraplegia (47%) drove, but only 12% of tetraplegia did. A majority (93%) of those who drove aged below 60 years, and had higher level of independence in activity of daily living. More drivers (81%) compared to non-drivers (24%) were employed; drivers also reported better community reintegration and quality of life. Three commonest barriers to driving included medical reasons (38%), fear and lack of confidence (17%), and inability to afford vehicle modifications (13%). CONCLUSIONS: The percentage of persons with SCI driving post injury is low. Based on the findings of this study, more efforts are needed to motivate and facilitate persons with SCI to drive. PMID- 29288254 TI - Impacts of fire smoke plumes on regional air quality, 2006-2013. AB - Increases in the severity and frequency of large fires necessitate improved understanding of the influence of smoke on air quality and public health. The objective of this study is to estimate the effect of smoke from fires across the continental U.S. on regional air quality over an extended period of time. We use 2006-2013 data on ozone (O3), fine particulate matter (PM2.5), and PM2.5 constituents from environmental monitoring sites to characterize regional air quality and satellite imagery data to identify plumes. Unhealthy levels of O3 and PM2.5 were, respectively, 3.3 and 2.5 times more likely to occur on plume days than on clear days. With a two-stage approach, we estimated the effect of plumes on pollutants, controlling for season, temperature, and within-site and between site variability. Plumes were associated with an average increase of 2.6 p.p.b. (2.5, 2.7) in O3 and 2.9 ug/m3 (2.8, 3.0) in PM2.5 nationwide, but the magnitude of effects varied by location. The largest impacts were observed across the southeast. High impacts on O3 were also observed in densely populated urban areas at large distance from the fires throughout the southeast. Fire smoke substantially affects regional air quality and accounts for a disproportionate number of unhealthy days. PMID- 29288255 TI - Assessment of indoor air quality at an electronic cigarette (Vaping) convention. AB - E-cigarette (vaping) conventions are public events promoting electronic cigarettes, in which indoor use of e-cigarettes is allowed. The large concentration of people using e-cigarettes and poor air ventilation can result in indoor air pollution. In order to estimate this worst-case exposure to e cigarettes, we evaluated indoor air quality in a vaping convention in Maryland (MD), USA. Real-time concentrations of particulate matter (PM10) and real-time total volatile organic compounds (TVOCs), CO2 and NO2 concentrations were measured. Integrated samples of air nicotine and PM10 concentrations were also collected. The number of attendees was estimated to range from 75 to 600 at any single observation time. The estimated 24-h time-weighted average (TWA) PM10 was 1800 MUg/m3, 12-fold higher than the EPA 24-h regulation (150 MUg/m3). Median (range) indoor TVOCs concentration was 0.13 (0.04-0.3) ppm. PM10 and TVOC concentrations were highly correlated with CO2 concentrations, indicating the high number of people using e-cigarettes and poor indoor air quality. Air nicotine concentration was 125 MUg/m3, equivalent to concentrations measured in bars and nightclubs. E-cigarette aerosol in a vaping convention that congregates many e-cigarette users is a major source of PM10, air nicotine and VOCs, impairing indoor air quality. These findings also raise occupational concerns for e-cigarette vendors and other venue staff workers. PMID- 29288256 TI - Integrating tools for non-targeted analysis research and chemical safety evaluations at the US EPA. AB - Tens-of-thousands of chemicals are registered in the U.S. for use in countless processes and products. Recent evidence suggests that many of these chemicals are measureable in environmental and/or biological systems, indicating the potential for widespread exposures. Traditional public health research tools, including in vivo studies and targeted analytical chemistry methods, have been unable to meet the needs of screening programs designed to evaluate chemical safety. As such, new tools have been developed to enable rapid assessment of potentially harmful chemical exposures and their attendant biological responses. One group of tools, known as "non-targeted analysis" (NTA) methods, allows the rapid characterization of thousands of never-before-studied compounds in a wide variety of environmental, residential, and biological media. This article discusses current applications of NTA methods, challenges to their effective use in chemical screening studies, and ways in which shared resources (e.g., chemical standards, databases, model predictions, and media measurements) can advance their use in risk-based chemical prioritization. A brief review is provided of resources and projects within EPA's Office of Research and Development (ORD) that provide benefit to, and receive benefits from, NTA research endeavors. A summary of EPA's Non-Targeted Analysis Collaborative Trial (ENTACT) is also given, which makes direct use of ORD resources to benefit the global NTA research community. Finally, a research framework is described that shows how NTA methods will bridge chemical prioritization efforts within ORD. This framework exists as a guide for institutions seeking to understand the complexity of chemical exposures, and the impact of these exposures on living systems. PMID- 29288258 TI - World Antibiotic Awareness Week. PMID- 29288257 TI - Predictors of blood volatile organic compound levels in Gulf coast residents. AB - To address concerns among Gulf Coast residents about ongoing exposures to volatile organic compounds, including benzene, toluene, ethylbenzene, o-xylene, and m-xylene/p-xylene (BTEX), we characterized current blood levels and identified predictors of BTEX among Gulf state residents. We collected questionnaire data on recent exposures and measured blood BTEX levels in a convenience sample of 718 Gulf residents. Because BTEX is rapidly cleared from the body, blood levels represent recent exposures in the past 24 h. We compared participants' levels of blood BTEX to a nationally representative sample. Among nonsmokers we assessed predictors of blood BTEX levels using linear regression, and predicted the risk of elevated BTEX levels using modified Poisson regression. Blood BTEX levels in Gulf residents were similar to national levels. Among nonsmokers, sex and reporting recent smoky/chemical odors predicted blood BTEX. The change in log benzene was -0.26 (95% CI: -0.47, -0.04) and 0.72 (0.02, 1.42) for women and those who reported odors, respectively. Season, time spent away from home, and self-reported residential proximity to Superfund sites (within a half mile) were statistically associated with benzene only, however mean concentration was nearly an order of magnitude below that of cigarette smokers. Among these Gulf residents, smoking was the primary contributor to blood BTEX levels, but other factors were also relevant. PMID- 29288259 TI - Chronic Obstructive Pulmonary Disease (COPD): "Not a Cigarette Only Pulmonary Disease". PMID- 29288260 TI - Effectiveness of Diabetes Foot Screening in Primary Care in Preventing Lower Extremity Amputations. AB - INTRODUCTION: The risk of lower extremity amputations (LEAs) in diabetics is 20 times higher than in non-diabetics. Clinical practice guidelines recommend that all diabetics should receive an annual foot examination to identify high-risk foot conditions. Despite this recommendation, there is little evidence in the literature to show its effectiveness in preventing LEA. This study aims to evaluate the effectiveness of diabetes foot screening in primary care in preventing LEA and to identify LEA risk factors. MATERIALS AND METHODS: This is a retrospective cohort study of diabetic patients who visited the National Healthcare Group Polyclinics for the first time from 1 January 2008 to 31 December 2012. The intervention of interest was foot screening performed at least once during 2 years of follow-up, and the outcome of interest was LEA (major and/or minor) performed during 2 years of follow-up. Patients who did foot screening (n=8150) were compared to a propensity score matched control group (n=8150) who did not do foot screening. Logistics regression was done to identify factors associated with LEA. RESULTS: Among those who underwent foot screening, there were 2 (0.02%) major amputations and 15 (0.18%) minor amputations compared with 42 (0.52%) and 52 (0.64%) among those who did not (P<0.001). CONCLUSION: Lack of diabetes foot screening, lower socioeconomic status, hip fracture, Malay ethnicity, chronic kidney disease, poorer glycaemic control, longer diabetes duration and male gender have been found to be associated with a higher risk of LEA. PMID- 29288261 TI - Selection and Short-Term Outcomes of Living Kidney Donors in Singapore - An Analysis of the Donor Care Registry. AB - INTRODUCTION: Transplant rates in Singapore have been falling and there is limited information on baseline characteristics and clinical outcomes of living kidney donors nationally. This study aimed to determine the safety of living kidney donor transplant in Singapore by exploring the proportion of donors that meets international selection guidelines and describing short-term clinical outcomes. MATERIALS AND METHODS: We analysed 472 donors who underwent nephrectomies from 1 January 2010 to 31 December 2014 from the Donor Care Registry. We described donor characteristics against 5 international guidelines and measured post-nephrectomy outcomes in 150 local donors for up to 24 months. A multivariate analysis was performed to determine the baseline variables associated with poorer outcomes. RESULTS: There were more foreign than local donors, with differences in gender and hospital types. Selection was generally aligned with international recommendations although 3.0% (using the Chronic Kidney Disease Epidemiology [CKD-EPI] equation) to 8.5% (using radionuclide and creatinine clearance methods) of donors had inappropriate baseline estimated glomerular filtration rates (eGFR) forage. Post-procedure, many foreign donors were lost to follow-up. Over 24 months, eGFR decreased by 33.8% from baseline before recovering gradually to 29.6%. During this period, only 2 donors were admitted for renal or urological conditions and there were no cases of end-stage renal failure or deaths. A lower baseline eGFR (HR: 1.05; 95% Cl, 1.02 to 1.09) and older age (HR: 1.04; 95% Cl, 1.00 to 1.08) were associated with a post nephrectomy eGFR of less than 60 mL/kg/1.73 m2. CONCLUSION: Kidney donation is safe in Singapore. Donor selection is in keeping with international guidelines and short-term outcomes are comparable to other cohorts. PMID- 29288262 TI - Rate or Rhythm Control of Atrial Fibrillation - Pearls for the Internist. AB - Atrial fibrillation is an epidemic in Asia that is increasingly prevalent. Apart from stroke risk stratification and management of anticoagulation, physicians managing this group of patients also need to determine an optimal strategy in terms of rate or rhythm control. With new techniques of catheter ablation to maintain patients in sinus rhythm, patients with atrial fibrillation now have more options for treatment, on top of pharmacological methods. This paper aims to review the current evidence for rate and rhythm control in both general patients and subgroups of interest commonly encountered in clinical practices such as obesity, heart failure and thyroid disease. PMID- 29288263 TI - An Unusual Infection in a Child with Congenital Heart Disease - Trichosporon asahii Infection with Rapid Diagnosis by 18s Ribonucleic Acid (RNA). PMID- 29288264 TI - Correlates of Online Game Play Motivations, Social Anxiety and Psychological Distress. PMID- 29288265 TI - Visual Outcomes after Cataract Surgery in Diabetic Patients: A Meta-Analysis. PMID- 29288266 TI - Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes. AB - Purpose: We previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence. Methods: Our population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups. Results: Neither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK. Conclusions: European mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control. PMID- 29288267 TI - PI3K/Akt Pathway: A Role in delta-Opioid Receptor-Mediated RGC Neuroprotection. AB - Purpose: This study examines the role of PI3K/Akt pathway in delta-opioid receptor agonist (SNC-121)-induced RGC neuroprotection in a chronic glaucoma rat model. Methods: Injecting hypertonic saline into the limbal veins of Brown Norway rats elevated IOP. Rats were treated either with 1 mg/kg SNC-121 or 3 mg/kg 2-(4 morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY-294002; PI3K/Akt inhibitor) plus SNC-121 once daily for 7 days. Pattern ERGs were recorded in response to contrast reversal of patterned visual stimuli. Retinal ganglion cells (RGC) were visualized by Fluorogold retrograde labeling. Optic nerve head (ONH) astrocytes were pretreated with PI3K/Akt inhibitors for 30 minutes followed by 1 MUM SNC-121 treatment. Changes in matrix metalloproteinases (MMP-1, -2, and -3) production and PI3K/Akt activation in optic nerve and TNF-alpha treated ONH astrocytes were measured by immunohistochemistry and Western blotting. Results: SNC-121 activates the PI3K/Akt pathway in ONH astrocytes and the retina. In ONH astrocytes, SNC-121-induced Akt activation was fully inhibited by PI3K/Akt inhibitors. A sustained decline (7-42 days post injury) in Akt activation was seen in the ocular-hypertensive retina and optic nerve. This decline is reversed to normal levels by 1-mg/kg intraperitoneally (i.p.) SNC-121 treatment. Both pattern ERG amplitudes and RGC numbers were reduced in ocular hypertensive eyes, which were significantly increased in SNC-121-treated animals. Interestingly, SNC 121-induced increase in pattern-ERG amplitudes and RGC numbers were inhibited in LY-294002 pretreated animals. Additionally, SNC-121 treatment inhibited MMP-1, 2, and -3 production from the optic nerve of ocular hypertensive rats and TNF alpha-treated ONH astrocytes. Conclusions: PI3K/Akt pathway plays a crucial role in SNC-121-mediated RGC neuroprotection against glaucomatous injury. PMID- 29288269 TI - Erratum. PMID- 29288268 TI - Identification and Characterization of Circular RNAs as a New Class of Putative Biomarkers in Diabetes Retinopathy. AB - Purpose: To reveal the expression profile and clinical significance of circular RNAs (circRNAs) in diabetic retinopathy (DR). Methods: Circular RNA microarrays were performed to identify DR-related circRNAs. Gene ontology (GO) enrichment and KEGG analysis was performed to determine the biologic modules and signaling pathway. TargetScan and miRana program was used to predict circRNA/miRNA interaction. Quantitative PCR assays were performed to detect circRNA expression pattern in clinical samples. Ki67 staining, Transwell, tube formation, and spheroid sprouting assays were performed to investigate the role and mechanism of circRNA in endothelial angiogenic function. Results: A total of 529 circRNAs were aberrantly expressed in diabetic retinas. The host genes of differentially expressed circRNAs were targeted to ATP binding (biologic process); extracellular exosome (cellular component); and intracellular signal transduction (molecular function). Circ_0005015 was verified to be upregulated in the plasma, vitreous sample, and fibrovascular membranes of DR patients. Circ_0005015 facilitated retinal endothelial angiogenic function via regulating endothelial cell proliferation, migration, and tube formation. Circ_0005015 acted as miR-519d-3p sponge to inhibit miR-519d-3p activity, leading to increased MMP-2, XIAP, and STAT3 expression. Conclusions: circRNAs are involved in DR pathogenesis, and thus serve as potential biomarkers of DR diagnosis. PMID- 29288270 TI - Unstable Binocular Fixation Affects Reaction Times But Not Implicit Motor Learning in Dyslexia. AB - Purpose: Individuals with developmental dyslexia suffer not only from reading problems as more general motor deficits can also be observed in this patient group. Both psychometric clinical tests and objective eyetracking methods suggest that unstable binocular fixation may contribute to reading problems. Because binocular instability may cause poor eye-hand coordination and impair motor control, the primary aim of this study was to explore in dyslexic subjects the influence of unstable binocular fixation on reaction times (RTs) and implicit motor learning (IML), which is one of the fundamental cerebellar functions. Methods: Fixation disparity (FD) and instability of FD were assessed subjectively using the Wesson card and a modified Mallett test. A modified version of the Serial Reaction Time Task (SRTT) was used to measure the RTs and IML skills. The results for the dyslexic group (DG), which included 29 adult subjects (15 were tested binocularly, DGbin; 14 were tested monocularly, DGmono), were compared with data from the control group (CG), which consisted of 30 age-matched nondyslexic subjects (15 tested binocularly, CGbin; and the other 15 tested monocularly, CGmono). Results: The results indicated that the DG showed poorer binocular stability and longer RTs in the groups tested binocularly (RTs: 534 vs. 411 ms for DGbin and CGbin, respectively; P < 0.001) as compared with the groups examined monocularly (RTs: 431 vs. 424 ms for DGmono and CGmono, respectively; P = 0.996). The DG also exhibited impaired IML when compared with the CG (EFIML: 25 vs. 50 ms for DG and CG, respectively; P = 0.012). Conclusions: Unstable binocularity in dyslexia may affect RTs but was not related to poor IML skills. Impaired IML in dyslexia was independent of the viewing conditions (monocular versus binocular) and may be related to cerebellar deficits. PMID- 29288271 TI - Introducing Johanna M. Seddon, the 2017 Recipient of the Mildred Weisenfeld Award. PMID- 29288272 TI - Macular Degeneration Epidemiology: Nature-Nurture, Lifestyle Factors, Genetic Risk, and Gene-Environment Interactions - The Weisenfeld Award Lecture. PMID- 29288274 TI - Stand-alone anterior interbody fusion for substitution of iliac fixation in long spinal fixation constructs. AB - INTRODUCTION: The use of distal sacral anchorage solely, in long spinal fusions, may lead to substantial complications. Extending the fixation down to the ilium and the addition of anterior column support are both used to facilitate construct stability and improve fusion rates. In the current study, we aimed to determine whether supplementation of long thoracolumbar fixation constructs with stand alone anterior interbody fusion (ALIF) cage with embedded screws can eliminate the biomechanical need for iliac screws fixation biomechanically. METHODS: Seven lumbopelvic human cadavers (L1-full pelvis) were used. All specimens were tested with the following fixation constructs: bilateral L1-S1, bilateral L1-S1 with unilateral iliac screw, and bilateral L1-S1 with bilateral iliac screw. The three constructs were tested with and without the addition of stand-alone ALIF cage. We evaluated the multidirectional rigidity and the axial S1 screw strain. RESULTS: The addition of an ALIF cage solely did not affect rigidity and resulted in mixed S1 screw strain results. One iliac screw was superior to ALIF in rigidity and inferior in S1 screws strain. Bilateral iliac fixation produced similar rigidity and lower S1 screws strain than unilateral iliac fixation. When ALIF was combined with bilateral iliac screws, it resulted in equal rigidity and lower S1 screws strain. CONCLUSION: Our results do not support stand-alone ALIF cage as a substitute for iliac fixation in in long posterior lumbosacral fusion. They do support the use of stand-alone ALIF for the supplementation of bilateral iliac fixation in long lumbosacral fusions. PMID- 29288273 TI - Pro-inflammatory cytokines after an episode of acute pancreatitis: associations with fasting gut hormone profile. AB - INTRODUCTION: Pro-inflammatory cytokines, such as interleukin (IL)-6, tumour necrosis factor (TNF)alpha, and monocyte chemoattractant protein (MCP)-1, are often elevated in individuals after acute pancreatitis but what determines their levels is poorly understood. Gut hormones have emerged as possible modulators of inflammatory response. The aim was to investigate the associations between pro inflammatory cytokines and a comprehensive panel of gut hormones after an episode of acute pancreatitis. MATERIALS AND METHODS: Fasting blood samples were collected to measure cytokines (IL-6, TNFalpha, and MCP-1) and gut hormones (cholecystokinin, gastric inhibitory peptide (GIP), ghrelin, glicentin, glucagon like peptide-1, oxyntomodulin, peptide YY, secretin, and vasoactive intestinal peptide). A series of linear regression analyses was conducted and four statistical models were used to adjust for patient- and pancreatitis-related covariates. RESULTS: A total of 83 individuals were recruited. GIP and peptide YY were significantly (p < 0.001) associated with IL-6, TNFalpha, MCP-1, consistently in all the four models. Every 1 ng/mL change in GIP resulted in a 16.2, 3.2, and 50.8% increase in IL-6, TNFalpha, and MCP-1, respectively, in the most adjusted model. Every 1 ng/mL change in peptide YY resulted in a 7.0, 2.4, and 32.1% increase in IL-6, TNFalpha, and MCP-1, respectively, in the most adjusted model. GIP independently contributed 29.0-36.5% and peptide YY - 17.4 48.9% to circulating levels of the studied pro-inflammatory cytokines. The other seven studied gut hormones did not show consistently significant associations with pro-inflammatory cytokines. CONCLUSIONS: GIP and peptide YY appear to be involved in perpetuation of subclinical inflammation following an episode of acute pancreatitis, which is known to play an important role in the pathogenesis of blood glucose derangements. These findings advance the understanding of mechanisms underlying diabetes of the exocrine pancreas and have translational implications. PMID- 29288275 TI - Correction to: Diagnostic and prognostic value of baseline FDG PET/CT skeletal textural features in diffuse large B cell lymphoma. AB - The formulae for Dice and Jaccard indices used to assess volumes concordance should read as follows. PMID- 29288276 TI - HIFU, a noninvasive and effective treatment for chyluria: 15 years of experience. AB - BACKGROUND: The current treatment therapies for chyluria are often invasive and recurrent. Here, we investigated a novel noninvasive treatment of chyluria with high-intensity focused ultrasound (HIFU) and evaluated its clinical efficacy. METHODS: 155 patients with chyluria were treated with HIFU ablation and followed up over a period of 15 years from May 2000 to December 2015. Routine examinations including urine color observation, color Doppler ultrasound examination, blood serum test of Cr, BUN, and albumin, and detection of urinary chyle were performed before and after the treatment, 1 week, 1 and 6 months post-treatment, and followed up via telephone and other forms. We lost contact with 54 patients during the course of the study. RESULTS: In the 101 complete cases, the serum levels of Cr and BUN and the color Doppler ultrasound examination did not reveal significant differences before and after the treatment. However, there was a significant increase in the hemoglobin and albumin levels, as well as the body weight after the HIFU treatment. The other 54 patients also showed an improvement of the symptoms after the HIFU treatment before losing contact. CONCLUSIONS: Our results suggest that the HIFU ablation therapy is a feasible, effective, and noninvasive method for the treatment of chyluria. PMID- 29288277 TI - New guidelines for use of endoscopic ultrasound for evaluation and risk stratification of pancreatic cystic lesions may be too conservative. AB - BACKGROUND: The role of EUS in managing asymptomatic pancreatic cystic lesions (PCLs) remains unresolved. We retrospectively evaluated EUS in risk stratification of PCLs when adhering to the most recent AGA guidelines. METHODS: Asymptomatic PCLs that were evaluated by EUS from January 2014 to December 2014 were retrospectively reviewed including associated cytology, fluid analysis, and relevant surgical pathology. Cross-sectional imaging reports were reviewed blindly by an expert radiologist using AGA risk stratification terminology. Accepted imaging high-risk features (HRF) included cyst diameter > 3 cm, dilated upstream pancreatic ducts, and a solid component in the cyst. RESULTS: We reviewed 125 patients who underwent EUS. Expert review of cross-sectional imaging resulted in a different interpretation 25% of the time including 1 malignant cyst. Ninety-three patients (75%) had no HRFs on cross-sectional imaging; 28 patients (22%) were diagnosed with 1 HRF and 4 patients (3%) had 2 HRFs. Adhering to AGA guidelines using 2 HRF as threshold for use of EUS, the diagnosis of malignant and high-risk premalignant lesions (including pancreatic adenocarcinoma, mucinous cystadenoma, neuroendocrine tumors, and IPMN with dysplasia) had a 40% sensitivity and 100% specificity. Had EUS been utilized based on a threshold of 1 HRF on imaging, malignant and high-risk premalignant lesions would have been identified with 80% sensitivity and 95% specificity. By adding EUS to radiographic imaging, the specificity for detecting carcinomas (p = 0.0009) and detection of all premalignant lesions (p = 0.003) statistically improved. Furthermore, EUS allowed 14 patients (11%) to avoid further surveillance by lowering their risk stratification. CONCLUSION: EUS remains an essential risk stratification modality for incidental PCLs. Current guideline suggestions of its utility may be too stringent. Our study justifies expert radiology review when managing PCLs. Further studies are required to identify the optimal approach to PCL management. PMID- 29288278 TI - Two-photon fabrication of hydrogel microstructures for excitation and immobilization of cells. AB - We investigate in vitro fabrication of hydrogel microstructures by two photon laser lithography for single cell immobilization and excitation. Fluorescent yeast cells are embedded in water containing the hydrogel precursor mixtures and cross-linking is used to selectively immobilize a particular cell. Cell viability within the hydrogel precursor is estimated using a life/dead assay and elastic and stiff hydrogel structures are fabricated, immobilizing cells in a microfluidic environment. Additionally, we demonstrate the illumination of cells by on-the-fly fabricated hydrogel waveguide networks connected to an external light source, thereby exciting a fluorescence signal in a single immobilized cell. PMID- 29288279 TI - Isolation and characterization from solar salterns of North Algeria of a haloarchaeon producing a new halocin. AB - Halophilic archaea, thriving in hypersaline environments, synthesize antimicrobial substances with an unknown role, called halocins. It has been suggested that halocin production gives transient competitive advantages to the producer strains and represents one of the environmental factors influencing the microbial community composition. Herein, we report on the antibacterial activity of a new haloarchaeon selected from solar salterns of the northern coast of Algeria. A total of 81 halophilic strains, isolated from the microbial consortia, were screened for the production of antimicrobial compounds by interspecies competition test and against a collection of commercial haloarchaea. On the basis of the partial 16S rRNA sequencing, the most efficient halocin producer was recognized as belonging to Haloferax (Hfx) sp., while the best indicator microorganism, showing high sensitivity toward halocin, was related to Haloarcula genus. The main morphological, physiological and biochemical properties of Hfx were investigated and a partial purification of the produced halocin was allowed to identify it as a surface membrane protein with a molecular mass between 30 and 40 kDa. Therefore, in this study, we isolated a new strain belonging to Haloferax genus and producing a promising antimicrobial compound useful for applications in health and food industries. PMID- 29288280 TI - Is eculizumab efficacious in Shigatoxin-associated hemolytic uremic syndrome? A narrative review of current evidence. AB - : Severe complications due to Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) currently present a serious challenge since no specific treatment for this condition is available. Eculizumab, a terminal complement inhibitor, has been used especially in STEC-HUS patients with severe neurological involvement, but the efficacy remains undetermined. In order to determine its efficacy, we searched the databases Pubmed, Web of Science, Embase, and LiLACS for reports describing outcomes of eculizumab administration in STEC-HUS. We retrieved 11 reports ranging from case reports to cohort studies with the largest study population emanating from the 2011 German outbreak. Outcomes were variable and difficult to interpret in light of the absence of high-quality studies but seemed to point towards potential efficacy of eculizumab if administered early in the course. CONCLUSION: The efficacy of eculizumab in STEC-HUS could not be established nor disproven based on current data, and there is a desperate need for randomized controlled trials. What is known? * Eculizumab has been used in complicated cases of Shigatoxin-associated hemolytic uremic syndrome but the efficacy remains unknown? What is new? * Eculizumab might be efficacious if given early in selected cases of Shigatoxin-associated hemolytic uremic syndrome; however, randomized trials are needed to assess this. PMID- 29288281 TI - Correction to: Plant growth promoting activity of an auxin and siderophore producing isolate of Streptomyces under saline soil conditions. AB - Unfortunately, one of the author's name had been published incorrectly as "Peyman Abaszadeh Dahaji". The correct name is " Payman Abbaszadeh Dahaji. PMID- 29288282 TI - Promotion of SH-SY5Y Cell Growth by Gold Nanoparticles Modified with 6 Mercaptopurine and a Neuron-Penetrating Peptide. AB - Much effort has been devoted to the discovery of effective biomaterials for nerve regeneration. Here, we reported a novel application of gold nanoparticles (AuNPs) modified with 6-mercaptopurine (6MP) and a neuron-penetrating peptide (RDP) as a neurophic agent to promote proliferation and neurite growth of human neuroblastoma (SH-SY5Y) cells. When the cells were treated with 6MP-AuNPs-RDP conjugates, they showed higher metabolic activity than the control. Moreover, SH SY5Y cells were transplanted onto the surface coated with 6MP-AuNPs-RDP to examine the effect of neurite development. It can be concluded that 6MP-AuNPs-RDP attached to the cell surface and then internalized into cells, leading to a significant increase of neurite growth. Even though 6MP-AuNPs-RDP-treated cells were recovered from frozen storage, the cells still maintained constant growth, indicating that the cells have excellent tolerance to 6MP-AuNPs-RDP. The results suggested that the 6MP-AuNPs-RDP had promising potential to be developed as a neurophic nanomaterial for neuronal growth. PMID- 29288283 TI - Associations between Mycobacterium tuberculosis Beijing genotype and drug resistance to four first-line drugs: a survey in China. AB - Investigations on the genetic diversity of Mycobacterium tuberculosis in China have shown that Beijing genotype strains play a dominant role. To study the association between the M. tuberculosis Beijing genotype and the drug-resistance phenotype, 1286 M. tuberculosis clinical isolates together with epidemiological and clinical information of patients were collected from the center for tuberculosis (TB) prevention and control or TB hospitals in Beijing municipality and nine provinces or autonomous regions in China. Drug resistance testing was conducted on all the isolates to the four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin, and ethambutol). A total of 585 strains were found to be resistant to at least one of the four anti-TB drugs. The Beijing family strains consisted of 499 (53.20%) drug-sensitive strains and 439 (46.80%) drug resistant strains, whereas the non-Beijing family strains comprised 202 (58.05%) drug-sensitive strains and 146 (41.95%) drug-resistant strains. No significant difference was observed in prevalence (chi2= 2.41, P > 0.05) between the drug resistant and drugsensitive strains among the Beijing family strains. Analysis of monoresistance, multidrug-resistant TB, and geographic distribution of drug resistance did not find any relationships between the M. tuberculosis Beijing genotype and drug-resistance phenotype in China. Results confirmed that the Beijing genotype, the predominant M. tuberculosis genotype in China, was not associated with drug resistance. PMID- 29288285 TI - Stigma in the context of pregnancy termination after diagnosis of fetal anomaly: associations with grief, trauma, and depression. AB - Termination of pregnancy after diagnosis of fetal anomaly (TOPFA) is a contested issue and stigma may negatively impact affected women's psychological reactions. This study examined the influence of perceived and internalized stigma on women's long-term adjustment to a TOPFA. One hundred forty-eight women whose TOPFA dated back 1 to 7 years responded to self-report questionnaires. The associations between perceived stigma at the time of the TOPFA, current internalized stigma and symptoms of grief, trauma and depression were modeled using multiple linear regression. The proportion of participants reporting scores above the cutoffs on the respective scale was 17.6% for grief, 18.9% for posttraumatic stress, and 10.8% for depression. After controlling for time since the TOPFA, pre-TOPFA mental health and obstetric variables, higher levels of current internalized stigma were related to higher levels of grief, trauma, and depression. Mediation analyses suggested that the effect of perceived stigma at the time of the TOPFA on symptoms of grief and trauma was mediated by current internalized stigma, but the cross-sectional design limited causal interpretation of results. Internalized stigma is associated with long-term psychological distress following a TOPFA. Perceived stigma at the time of the TOPFA may contribute to increased trauma and grief symptomatology, but results need to be validated in longitudinal studies. Health care providers and public initiatives should aim at reducing stigma among affected women. PMID- 29288286 TI - Religious Commitment and Well-Being in College Students: Examining Conditional Indirect Effects of Meaning in Life. AB - There is systematic and quantitative evidence that religious commitment is associated with indicators of well-being, such as positive emotions and moods, absence of negative emotions, and satisfaction with life; however, researchers remain far from a consensus regarding which mechanisms may account for these observed relationships. Although religious commitment influences well-being through many different mechanisms, meaning in life is probably the predominant one. Thus, we examined the bidimensional conceptualization of meaning in life as a potential mechanism between religious commitment and well-being. The study was cross-sectional in nature. Survey data were collected from 92 college students, aged 17-21. A battery of self-report measures was used for tapping religious commitment, well-being, and meaning in life. Even though presence of meaning, search for meaning, religious commitment, and well-being correlated moderately with each other, presence of meaning carried a substantial proportion of variance in predicting well-being for girls/women. This study suggests that religious commitment influences a person's sense of meaning in life, which, in turn, influences her/his well-being. And, we hope that these results encourage professionals to explore with their clients the fundamental questions of meaning and purpose in life. PMID- 29288284 TI - Transit time corrected arterial spin labeling technique aids to overcome delayed transit time effect. AB - PURPOSE: This study aimed to evaluate the usefulness of transit time corrected cerebral blood flow (CBF) maps based on multi-phase arterial spin labeling MR perfusion imaging (ASL-MRP). METHODS: The Institutional Review Board of our hospital approved this retrospective study. Written informed consent was waived. Conventional and multi-phase ASL-MRPs and dynamic susceptibility contrast MR perfusion imaging (DSC-MRP) were acquired for 108 consecutive patients. Vascular territory-based volumes of interest were applied to CBF and time to peak (TTP) maps obtained from DSC-MRP and CBF maps obtained from conventional and multi phase ASL-MRPs. The concordances between normalized CBF (nCBF) from DSC-MRP and nCBF from conventional and transition time corrected CBF maps from multi-phase ASL-MRP were evaluated using Bland-Altman analysis. In addition, the dependence of difference between nCBF (DeltanCBF) values obtained from DSC-MRP and conventional ASL-MRP (or multi-phase ASL-MRP) on TTP obtained from DSC-MRP was also analyzed using regression analysis. RESULTS: The values of nCBFs from conventional and multi-phase ASL-MRPs had lower values than nCBF based on DSC-MRP (mean differences, 0.08 and 0.07, respectively). The values of DeltanCBF were dependent on TTP values from conventional ASL-MRP technique (F = 5.5679, P = 0.0384). No dependency of DeltanCBF on TTP values from multi-phase ASL-MRP technique was revealed (F = 0.1433, P > 0.05). CONCLUSION: The use of transit time corrected CBF maps based on multi-phase ASL-MRP technique can overcome the effect of delayed transit time on perfusion maps based on conventional ASL-MRP. PMID- 29288287 TI - A Contemporary Paradigm: Integrating Spirituality in Advance Care Planning. AB - In the 25 years since advance care planning first drew the attention of the national healthcare and legal systems, gains in the rate of advance care directive completion have been negligible despite the effort of researchers, ethicists, and lawmakers. With the benefit of sophisticated healthcare technology, patients are living longer. Despite the benefits of increased longevity, it is widely acknowledged that enough has not been done to adequately address end-of-life care decisions at the crossroads between medical futility and quality of life. To arrive at a solution, researchers have focused on patient self-reflection, provider attitudes, health literacy, communication and the logistics of surrogacy, setting, payment, and documentation. However, a survey of the literature reveals one conspicuously absent theme. It is a phenomenon one would expect in the context of end-of-life discussion and decision making, that of spiritual inquiry. This article explores the history leading up and past approaches to advance care planning and then suggests the use of a theoretical model and a body of work concerning spiritual care as a new tack in the ongoing development of advance care planning. PMID- 29288288 TI - PCI is Not Predictive of Survival After Complete CRS/HIPEC in Peritoneal Dissemination from High-Grade Appendiceal Primaries. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a treatment option in patients with carcinomatosis from high-grade appendiceal (HGA) primaries. It is unknown if there is a Peritoneal Carcinomatosis Index (PCI) upper limit above which a complete CRS/HIPEC does not assure long-term survival. METHODS: Retrospective analysis from three centers was performed. The PCI was used to grade volume of of disease. Survival in relation to PCI was studied on patients with complete cytoreduction. RESULTS: Overall, 521 HGA patients underwent CRS/HIPEC from 1993 to 2015, with complete CRS being achieved in 50% (260/622). Mean PCI was 14.8 (standard deviation 8.7, range 0 36). Median survival for the complete CRS cohort was 6.1 years, while 5- and 10 year survival was 51.7% (standard error [SE] 4.6) and 36.1% (SE 6.3), respectively. Arbitrary cut-off PCI limits with 5-point splits (p = 0.63) were not predictive of a detrimental effect on survival as long as a complete CRS was achieved. A linear effect of the PCI on survival (p = 0.62) was not observed, and single-point PCI cohort splits within a PCI range of < 5 to > 10 were not predictive of survival for complete CRS patients. The PCI correlated with the ability to achieve a complete CRS, with a mean PCI of 14.7 (8.7) for completeness of cytoreduction (CC)0, 22.3 (7.8) for CC1 and 26.1 (9.5) for CC2/3 resections (p = 0.0001, hazard ratio 1.12, 95% confidence interval 1.09), with an HR of 1.15 for each 1-unit increase in the PCI score. Only 21% of the cohort achieved a complete CRS with a PCI >= 21. CONCLUSIONS: The PCI correlates with the ability to achieve a complete CRS in carcinomatosis from HGA. PCI is not associated with survival as long as a complete CRS can be achieved. PMID- 29288289 TI - Anterolateral Thigh Flap Combined with Reconstruction Plate Versus Double Free Flaps for Composite Mandibular Reconstruction: A Propensity Score-Matched Study. AB - OBJECTIVE: This study was designed to examine the comparative effectiveness of oromandibular defect reconstruction via anterolateral thigh flap and bridging plate (ALT only) versus simultaneous soft tissue and vascularized bone flap (DFF), with regards to long-term plate exposure and complications. METHODS: A propensity score-matched analysis of patients with an oncologic head and neck defect who underwent microvascular reconstruction was performed. Two surgical groups, i.e., ALT only and DFF, were created. Incidence and subsequent management strategies for postoperative plate exposure were evaluated along with complications, overall survival, and postoperative quality of life (QoL). RESULTS: Sixty-two patients were 1:1 propensity matched (31 per group). The DFF group had a significantly larger soft tissue and bone defect than the single-flap group. The 5-year probability of not having a plate exposure was 45.5 and 47.4% for the double-flaps and single-flap groups, respectively (p = 0.186). The ALT only group had a significantly higher rate of wound infections (38.7% vs. 12.9%, p = 0.02). The incidence of flap loss, reexploration, inpatient mortality, plate fracture, medical complications, and overall survival were not significantly different. Although mean score for pain was significantly worse in the ALT-only group (75.2 vs. 88.5, p < 0.001), the remainder of our QoL assessments (cosmesis, swallow, employment, and speech) were comparable. CONCLUSIONS: The utilization of an ALT with plate strategy is associated with competitive rates of plate exposure and overall survival relative to DFF but higher wound infections and long-term pain. These results have considerable salience for patient-counseling regarding expectations for functional and clinical outcomes. PMID- 29288290 TI - Complete remission of hypertension in a hemodialysis patient after adrenalectomy for primary aldosteronism and renal transplantation. AB - A 64-year-old man was admitted to our hospital for the hormonal evaluation of a right adrenal adenoma. He had been diagnosed with severe proteinuria and hypertension, and antihypertensive treatment was started at the age of 60. His renal function gradually declined, and hemodialysis was begun at the age of 64. Since his blood pressure was uncontrollable and resistant to antihypertensive treatment, an endocrinological examination was performed for an incidental right adrenal mass detected by computed tomography. The results of screening, including captopril challenge and an adrenocorticotropin stimulation test for primary aldosteronism, and adrenal venous sampling suggested excessive aldosterone secretion from the right adrenal gland. Adrenalectomy was performed; his blood pressure decreased and became well-controlled with a reduced antihypertensive regimen. Furthermore, he received renal transplantation which resulted in normalization of his serum potassium level, improvement of renal function and hormonal levels such as plasma renin activity and aldosterone concentration, and satisfactory blood pressure without any antihypertensive medications. This case is extremely important to demonstrate the effects of adrenalectomy for primary aldosteronism in a hemodialysis patient. It is possible that adrenalectomy may be a useful treatment for primary aldosteronism even in patients undergoing hemodialysis. Careful long-term follow-up of our case and investigations of the efficacy of adrenalectomy in similar cases are needed to address this issue. PMID- 29288291 TI - Transfusion of Blood Products in the Neurocritical Care Unit: An Exploration of Rationing and Futility. AB - Rationing is the allocation of scarce resources, which in healthcare necessarily requires withholding potentially beneficial treatments from some individuals. While it often entails a negative connotation, rationing is unavoidable because need is limitless and resources are not. How rationing occurs is important, because it not only affects individual lives, but also reflects society's most important values. At the core of any rationing, decision is how much a limited resource may benefit a patient, which can be particularly difficult to determine in the practice of neurocritical care, as prognosis is often uncertain. We present a case for the consideration of futility and blood product rationing in neurocritical care. PMID- 29288292 TI - C. Miller Fisher and the Comatose Patient. AB - Neurologic examination of the comatose patient has gradually matured. Less than 50 years ago, neurological examination in coma became a regular part of textbooks with separate chapters devoted to the topic but many were deficient in detail. In 1969, C.M. Fisher published an extraordinary 56-page paper on the examination of the comatose patient. The paper-one of Fisher's gems-is not well known and infrequently cited. The many new observations collected in this comprehensive paper are reviewed in this vignette, which highlights not only how these contributions shaped our thinking on coma but also questioned shaky concepts. PMID- 29288293 TI - Delta opioid receptors recycle to the membrane after sorting to the degradation path. AB - Soon after internalization delta opioid receptors (DOPrs) are committed to the degradation path by G protein-coupled receptor (GPCR)-associated binding protein. Here we provide evidence that this classical post-endocytic itinerary may be rectified by downstream sorting decisions which allow DOPrs to regain to the membrane after having reached late endosomes (LE). The LE sorting mechanism involved ESCRT accessory protein Alix and the TIP47/Rab9 retrieval complex which supported translocation of the receptor to the TGN, from where it subsequently regained the cell membrane. Preventing DOPrs from completing this itinerary precipitated acute analgesic tolerance to the agonist DPDPE, supporting the relevance of this recycling path in maintaining the analgesic response by this receptor. Taken together, these findings reveal a post-endocytic itinerary where GPCRs that have been sorted for degradation can still recycle to the membrane. PMID- 29288294 TI - Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation. AB - Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden. PMID- 29288295 TI - Correction to: The mineralization of oxalic acid and bio-treated coking wastewater by catalytic ozonation using nickel oxide. AB - In Table 1, "SO2-4" and "NO-3" should be corrected to "[Formula: see text]" and "[Formula: see text]", respectively. The original article was corrected. PMID- 29288296 TI - Fouling mitigation and cleanability of TiO2 photocatalyst-modified PVDF membranes during ultrafiltration of model oily wastewater with different salt contents. AB - In the present study, TiO2-coated ultrafiltration membranes were prepared and used for oily water filtration (droplet size < 2 MUm). The aim of this work was to investigate the effect of different salt contents on fouling and filtration properties of neat and TiO2-coated membranes during oil-in-water emulsion filtration. The effect of the TiO2 coating on the flux, surface free energy, and retention values was measured and compared with the neat membrane values. The cleanability of the fouled TiO2-coated membranes by UV irradiation was also investigated by measuring flux recovery and contact angles, and the chemical changes during cleaning were characterized by ATR-IR. It was found that increasing the salt content of the model wastewaters, oil-in-water emulsions, increased the zeta potential and the size of the droplets. The presence of the TiO2 coating decreases the membrane fouling during oily emulsion filtration compared to the neat membrane, due to the hydrophilicity of the coating regardless of the salt content of the emulsions. The neat and coated membrane oil retention was similar, 96 +/- 2%. The coated membrane can be effectively cleaned with UV irradiation without additional chemicals and a significant flux recovery can be achieved. Monitoring of the cleaning process by following the membrane surface wettability and ATR-IR measurements showed that the recovery of flux does not mean the total elimination of the oil layer from the membrane surface. PMID- 29288297 TI - Biomonitoring of polychlorinated biphenyls in Bavaria/Germany-long-term observations and standardization. AB - In the 1980s, it was demonstrated that semi-volatile organic compounds (SVOCs) like polychlorinated biphenyls (PCBs) accumulate in plant leaves. Plants are at the base of the food chain, and therefore a starting point for transfer of PCBs to animals and related human exposure. For two decades, the Environment Agency of the German federal state of Bavaria (LfU) has been operating long-term monitoring stations to measure the impact of organic air pollutants. Standardized ryegrass, curly kale, and spruce needles are used as bioindicators for the atmospheric entries of PCBs into vegetation. From the end of 1990s to 2009, there was a marked decline in the concentrations of indicator PCBs (i-PCBs) and a minor decline in PCB-TEQ levels. After 2009, the concentrations leveled off. In rural areas, the median concentrations of Sigma6 i-PCB in ryegrass and curly kale were about 3 and 4 MUg/kg dm in 2000, and have been about 0.5 and 1 MUg/kg dm since 2009, respectively. Concentrations in spruce needles fell from 0.9 to 0.4 MUg/kg dm. Median PCB-TEQ concentrations in the bioindicator plants ranged from 0.05 to 0.23 ng/kg dm between 2002 and 2009 and from 0.15 to 0.05 ng/kg dm after 2009. Indicator PCB and PCB-TEQ concentrations were several times higher at the urban station in Munich than at the rural areas, reflecting the emissions from in-use PCB stocks in the building sector. The likely reason of the slower decrease of PCB-TEQ compared to i-PCBs is the formation of PCB-126 by dechlorination of industrial PCBs in open applications. PMID- 29288298 TI - Persistent organochlorine pesticides in aquatic environments and fishes in Taiwan and their risk assessment. AB - Organochlorine pesticides (OCPs) are ubiquitous contaminants with high bioaccumulation and persistence in the environment; they can have adverse effects in humans and animals. This study examined residual concentrations in water, sediments, and fishes as well as the association between the health risks of OCPs and fish consumption in the Taiwanese population. Various water and sediment samples from Taiwanese aquaculture and fish samples from different sources were collected and analyzed through gas chromatography tandem mass spectrometry to determine the concentrations of 20 OCPs, namely, aldrin; cis-chlordane; trans chlordane; dieldrin; endrin; alpha-endosulfan; beta-endosulfan; heptachlor; hexachlorobenzene; alpha-hexachlorocyclohexane; beta-hexachlorocyclohexane; lindane; mirex; pentachlorobenzene; o,p'-dichlorodiphenyltrichloroethane (DDT); p,p'-DDT; and DDT metabolites (o,p'-dichlorodiphenyldichloroethane [DDD]; p,p' DDD; o,p'-dichlorodiphenyldichloroethylene [DDE]; and p,p'-DDE). None of the analyzed samples was positive for OCP contamination, suggesting no new input pollution from the land through washing into Taiwanese aquaculture environments. However, OCP residues were detected in fishes caught along the coast, namely, skipjack tuna and bigeye barracuda, and in imported fishes, such as codfish and salmon. DDT was the predominant pesticide. The contamination pattern of persistent organic pollutants was as follows: dieldrin > cis-chlordane > hexachlorobenzene, with average concentrations ranging from 0.09 to 2.74 ng/g. The risk was assessed in terms of the estimated daily intake (EDI) for potential adverse indices; the EDI of OCP residues was lower than 1% of the acceptable daily intake established by the Food and Agriculture Organization of the United Nations and World Health Organization. The assessed risk was negligible and considered to be at a safe level, suggesting no association between fish consumption and risks to human health in Taiwan. However, a continuous monitoring program for OCP residues in fishes is necessary to further assess the possible effects on human health. PMID- 29288299 TI - Efficient removal of Hg2+ in aqueous solution with fishbone charcoal as adsorbent. AB - The Hg2+ removal performance of fishbone charcoal prepared from discarded fishbone has been investigated in this work. The XRD, FTIR, and BET results demonstrated that the main composition of fishbone charcoal was hydroxyapatite and the specific surface area was 117 m2/g. The adsorption experiments indicated that fishbone charcoal had an extremely high adsorption capacity for Hg2+ (243.77 mg/g). The excellent Hg2+ adsorption capacity might be ascribed to the ion exchange of Hg2+ to the Ca2+ in the structure of fishbone charcoal, complexation of Hg2+ with =Ca(OH)2+ on the surface of fishbone charcoal, as well as electrostatic interaction between electronegative fishbone charcoal surface and cation Hg2+. This work transformed kitchen garbage (i.e., fishbone) into an effective mercury adsorbent with considerable capacity, giving a perspective sight for the utilization of solid waste. PMID- 29288300 TI - Biogenic synthesis of silver nanoparticles using Piper betle aqueous extract and evaluation of its anti-quorum sensing and antibiofilm potential against uropathogens with cytotoxic effects: an in vitro and in vivo approach. AB - Urinary tract infections are the utmost common bacterial infections caused by Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, and Serratia marcescens. These uropathogens resist the action of several antibiotics due to their ability to form biofilms. Most of these bacterial pathogens use the quorum sensing (QS) machinery to co-ordinate their cells and regulate several virulence factors and biofilm formation. On the other hand, the anti-quorum sensing (anti QS) and antibiofilm potential of silver nanoparticles have been well reported against certain bacterial pathogens, but to the best of our knowledge, no report is available against the pathogenicity of uropathogens in particular S. marcescens and P. mirabilis. Therefore, the present study is primarily focused on the anti-QS and antibiofilm potential of Piper betle-based synthesized silver nanoparticles (PbAgNPs) against S. marcescens and P. mirabilis. Initially, the silver nanoparticles were synthesized by the aqueous extract of P. betle and characterized by UV-absorbance spectroscopy, XRD, FT-IR, SEM, TEM, and DLS. The synthesized silver nanoparticles were assessed for their anti-QS activity and the obtained results revealed that the PbAgNPs inhibited the QS-mediated virulence factors such as prodigiosin, protease, biofilm formation, exopolysaccharides and hydrophobicity productions in uropathogens. The gene expression analysis divulged the downregulation of fimA, fimC, flhD, and bsmB genes in S. marcescens and flhB, flhD, and rsbA genes in P. mirabilis, respectively. The in vivo Caenorhabditis elegans assays revealed the non-toxic and anti-adherence efficiency of PbAgNPs. Furthermore, the non-toxic effect of PbAgNPs was also confirmed through peripheral blood mononuclear cells and normal lung epithelial cells. Therefore, the contemporary study demonstrates the use of PbAgNPs as a possible alternative toward conventional antibiotics in controlling QS and biofilm-related uropathogen infections. PMID- 29288302 TI - Predicting Cu and Zn sorption capacity of biochar from feedstock C/N ratio and pyrolysis temperature. AB - Biochars have been proposed for remediation of metal-contaminated water due to their low cost, high surface area and high sorption capacity for metals. However, there is a lack of understanding over how feedstock material and pyrolysis conditions contribute to the metal sorption capacity of biochar. We produced biochars from 10 different organic materials by pyrolysing at 450 degrees C and a further 10 biochars from cedar wood by pyrolysing at 50 degrees C intervals (250-700 degrees C). Batch sorption experiments were conducted to derive the maximum Cu and Zn sorption capacity of each biochar. The results revealed an exponential relationship between Cu and Zn sorption capacity and the feedstock C/N ratio and a sigmoidal relationship between the pyrolysis temperature and the maximum Cu and Zn sorption capacity. FTIR analysis revealed that as temperature increased, the abundance of functional groups reduced. We conclude that the high sorption capacity of high temperature biochars is due to an electrostatic attraction between positively charged Cu and Zn ions and delocalised pi-electrons on the greater surface area of these biochars. These findings demonstrate a method for predicting the maximum sorption capacity of a biochar based on the feedstock C/N ratio and the pyrolysis temperature. PMID- 29288301 TI - Arsenic and/or copper caused inflammatory response via activation of inducible nitric oxide synthase pathway and triggered heat shock protein responses in testis tissues of chicken. AB - The aim of this study is to investigate the effects of arsenic (As) and copper (Cu) on the inflammatory response, and the protective roles of heat shock proteins (Hsps) in chicken testes. Seventy-two 1-day-old male Hy-line chickens were treated with 30 mg/kg feed of arsenic trioxide (As2O3) and/or 300 mg/kg feed of copper sulfate (CuSO4) for 4, 8, and 12 weeks. The histological changes, inducible nitric oxide synthase (iNOS) activity, and the expressions of Hsps and inflammatory cytokines were detected. The results showed that slight histology changes were obvious in the testis tissue exposure to treatment groups. The activity and the protein level of iNOS were increased compared to the control group. The mRNA levels of proinflammatory cytokines and inflammatory factors were increased as a whole. However, anti-inflammatory cytokines were inhibited. The mRNA and protein levels of Hsp60, Hsp70, and Hsp90 were upregulated. These results suggested that sub-chronic exposure to As and/or Cu induced testicular poisoning in chickens. Increased Hsps tried to protect chicken testis tissues from tissues damage caused by inflammation. In conclusion, testicular poisoning induced by As and/or Cu caused inflammatory response and heat shock protein response in chicken testis tissues. PMID- 29288303 TI - The effect of urbanization and industrialization on carbon emissions in Turkey: evidence from ARDL bounds testing procedure. AB - This paper examines the dynamic short- and long-term relationship between per capita GDP, per capita energy consumption, financial development, urbanization, industrialization, and per capita carbon dioxide (CO2) emissions within the framework of the environmental Kuznets curve (EKC) hypothesis for Turkey covering the period from 1974 to 2013. According to the results of the autoregressive distributed lag bounds testing approach, an increase in per capita GDP, per capita energy consumption, financial development, urbanization, and industrialization has a positive effect on per capita CO2 emissions in the long term, and also the variables other than urbanization increase per capita CO2 emissions in the short term. In addition, the findings support the validity of the EKC hypothesis for Turkey in the short and long term. However, the turning points obtained from long-term regressions lie outside the sample period. Therefore, as the per capita GDP increases in Turkey, per capita CO2 emissions continue to increase. PMID- 29288304 TI - Essential oils of Origanum compactum and Thymus vulgaris exert a protective effect against the phytopathogen Allorhizobium vitis. AB - Allorhizobium (Agrobacterium) vitis is a host-specific pathogenic bacterium that causes grapevine crown gall disease, affecting vine growth and production worldwide. The antibacterial activities of different aromatic plant essential oils were tested in vitro and in planta against A. vitis. Among the essential oils tested, those of Origanum compactum and Thymus vulgaris showed the most significant in vitro antibacterial activities, with a MIC of 0.156 and 0.312 mg/mL, respectively. A synergistic effect of these two essential oils (1:1) was observed and confirmed by the checkerboard test. Carvacrol (61.8%) and thymol (47.8%) are, respectively, the major compounds in the essential oils of O. compactum and T. vulgaris and they have been shown to be largely responsible for the antibacterial activities of their corresponding essential oils. Results obtained in vitro were reinforced by an in planta pathogenicity test. A mixture of O. compactum and T. vulgaris essential oils (1:1), inoculated into the injured stem of a tomato plant and a grapevine at 0.312 mg/mL as a preventive treatment, reduced both the number of plants developing gall symptoms and the size of the tumors. PMID- 29288305 TI - High levels of serum Mac-2-binding protein glycosylation isomer (M2BPGi) predict the development of hepatocellular carcinoma in hepatitis B patients treated with nucleot(s)ide analogues. AB - BACKGROUND: Nucleot(s)ide analogues (NA) can reduce the risk of hepatocellular carcinoma (HCC), but not completely prevent its development. METHODS: Two hundred and thirty-four chronic hepatitis B patients virologically well controlled with entecavir or tenofovir disoproxil fumarate for more than 1 year were enrolled in this study. Over the median observation period of 51 (12-142) months, 24 of 234 patients developed HCC. We quantified HBV markers, alpha-fetoprotein (AFP) and Mac-2-binding protein glycosylation isomer (M2BPGi) at baseline and 48 weeks after therapy. RESULTS: Serum AFP and M2BPGi tended to decline from baseline to 48 weeks after treatment both in patients who did and those who did not develop HCC. Univariate Cox regression analysis indicated that serum M2BPGi levels >= 1.215 COI at 48 weeks were associated with HCC development [hazard ratio (HR) 5.73; p <= 0.001]. Multivariate analysis showed that male sex (HR 5.6; p = 0.01), AFP >= 9.65 ng/ml (HR 22.01; p <= 0.001), M2BPGi >= 1.215 (HR 5.07; p = 0.004) at 48 weeks were significant independent predictive factors for HCC development. Based on a scoring system consisting of three factors above described, Kaplan Meier analysis for four groups (score 0, 1, 2, >= 3), revealed significant differences in cumulative HCC occurrence for each group within 2 years. The rate of incidence of HCC was 0, 5.4, 23.4, and 75% in each group, respectively. CONCLUSIONS: In patients receiving NA therapy, higher M2BPGi at 48 weeks, as well as male sex and higher AFP at 48 weeks were independent risk factors for HCC development. PMID- 29288306 TI - Risk Factors for Incisional Hernia in Children. AB - BACKGROUND: Incisional hernia (IH) is a major complication of abdominal surgery. Although previous studies reported that the incidence of IH after abdominal surgery in adults was 5-50% and that various independent risk factors were involved, IH in children is still not well known. The objective of our study was to investigate the incidence and risk factors for IH in children. METHODS: We retrospectively reviewed all children who underwent abdominal surgery at the Jikei University Hospitals (Jikei University Hospital, Kashiwa Hospital, Katsushika Medical Center and Daisan Hospital) between January 2001 and December 2016. Abdominal surgery in children was defined as open laparotomy and laparoscopic abdominal surgery in patients <= 15 years old. Conventional open repair for inguinal hernias, umbilical hernia repair, congenital abdominal defect repair and orchiopexy were excluded. RESULTS: Overall, 2049 children were performed abdominal surgery. Among them, 14 children (10 males and 4 females) developed IH, and the incidence of IH was 0.68% (14/2049). There is no significant difference between laparotomy and laparoscopic surgery. The statistically significant variables and identified risk factors were operation in neonates, laparoscopic fundoplication and open supraumbilical pyloromyotomy. In all patients who had IH repair, there was no recurrence during the follow-up period 50.4 months (range 1 months-10 years) except two recurrence cases. CONCLUSION: The incidence of IH in children is significantly lower than that in adults, and the above three risk factors were revealed. Before abdominal surgery, we recommend that pediatric surgeons should mention the risk of developing IH when the patient has the above risk factors. PMID- 29288307 TI - The Value of the C-Reactive Protein-to-Albumin Ratio is Useful for Predicting Survival of Patients with Child-Pugh Class A Undergoing Liver Resection for Hepatocellular Carcinoma. AB - BACKGROUND: Although a recent study has shown that the C-reactive protein-to albumin ratio (CAR) can predict the survival in patients with hepatocellular carcinoma (HCC), it is unclear whether CAR can predict the survival after surgery. OBJECTIVE: To investigate the utility of CAR for prediction of postoperative survival among HCC patients with Child-Pugh class A. METHODS: We retrospectively reviewed 239 patients with Child-Pugh class A who were newly diagnosed with HCC and received initial liver resection. Univariate and multivariate analyses using the Cox proportional hazard model were performed to detect clinical characteristics that correlated with overall survival (OS), and their cutoff values were identified using receiver operating characteristic curve analyses. The cutoff value of CAR was 0.028. Kaplan-Meier analysis and the log rank test were used for the comparison of OS and disease-free survival (DFS) between two CAR groups (>0.028/<=0.028). RESULTS: Multivariate analysis using 16 clinical characteristics selected by univariate analyses revealed that CAR (>0.028/<=0.028) (HR, 3.211; 95% CI 1.065-9.680; P = 0.038) was significantly associated with OS, as well as anatomical resection (presence/absence) (HR, 0.275; 95% CI 0.119-0.635; P = 0.275). A significant difference in OS and DFS was observed between patients with low CAR (<=0.028) and patients with high CAR (>0.028). CONCLUSIONS: CAR is a useful predictor of postoperative survival among HCC patients with Child-Pugh class A. PMID- 29288308 TI - Comments on 'Sentinel Lymph Node Mapping with Isosulfan Blue or Indocyanine Green in Colon Cancer Shows Comparable Results and Identifies Patients with Decreased Survival: A Prospective Single-Center Trial'. PMID- 29288309 TI - The Effect of Intraoperative Nefopam Administration on Acute Postoperative Pain and Chronic Discomfort After Robotic or Endoscopic Assisted Thyroidectomy: A Randomized Clinical Trial. AB - BACKGROUND: Acute postoperative pain and chronic discomfort are reported after robotic or endoscopic thyroidectomy. The purpose of this prospective, randomized, and double-blinded clinical trial was to investigate whether intraoperative infusion of nefopam decreases acute postoperative pain and chronic discomfort following either a robotic or endoscopic thyroidectomy via the bilateral axillo breast approach (BABA). METHODS: Patients were randomized into two groups: The control group (n = 29) or the nefopam group (n = 29). Patients in each group were infused with the same volume of saline or nefopam (0.2 mg/kg bolus, 120 MUg/kg/h continuous infusion) during surgery. Acute postoperative pain, the need for rescue analgesics, and other postoperative adverse effects were assessed at 1, 6, 24, and 48 h postoperatively. Chronic pain and discomfort was recorded at 3 months after surgery. RESULTS: Patients in the nefopam group reported lower pain scores in the neck, as well as the axilla and anterior chest areas at 1, 6, 24, and 48 h postoperatively, when compared with the control group (P < 0.05 at each time points). Rescue analgesics were required less in the nefopam group than in the control group (1.4 [1] vs. 2.3 [1.5]; P = 0.001). The degree of chronic pain and discomfort were relatively lower in the nefopam group (P < 0.05). CONCLUSION: We report that intravenous nefopam infusion during surgery decreased acute postoperative pain and the need for rescue analgesics, as well as chronic discomfort, following BABA robotic or endoscopic thyroidectomy without adverse events. PMID- 29288310 TI - Long-Lasting Voice-Related Symptoms in Patients Without Vocal Cord Palsy After Thyroidectomy. AB - BACKGROUND: Some patients complain of long-lasting voice symptoms after thyroid surgery without objective vocal fold pathology. We assessed the factors that may influence voice symptoms more than 12 months after thyroidectomy. METHODS: We performed a retrospective analysis of 68 patients from July 2010 to May 2012. The voices of all patients were analyzed before and after thyroid surgery (2 weeks and 2, 4, 6, 8, 10, and 12 months after surgery). According to the recovery of postoperative voice symptoms, patients were divided into two groups: the non recovery group and the recovery group. Voice symptoms were measured using a thyroidectomy-related voice questionnaire (TVQ). We compared voice analysis data for each group and investigated the factors related to long-lasting postoperative voice symptoms. RESULTS: Forty-nine patients were included in the recovery group, and 19 patients were included in the non-recovery group. No differences in sex ratio, tumor size, and surgical extent were found between the groups. However, the proportion of professional voice users (odds ratio 4.121; 95% confidence interval 0.983-17.267; p < 0.043) was significantly higher in the non-recovery group. The cutoff score of the TVQ, at 2 months after thyroid surgery, for the differentiation of the recovery and non-recovery groups was 25, and the sensitivity and specificity values were 84.2 and 87.8%, respectively. CONCLUSIONS: Professional voice users may be presented long-lasting voice symptoms after thyroid surgery. The cutoff TVQ score of 25, at 2 months after thyroid surgery, may be a guideline for counseling patients who have voice symptoms. PMID- 29288311 TI - Antireflux Surgery in the USA: Influence of Surgical Volume on Perioperative Outcomes and Costs-Time for Centralization? AB - BACKGROUND: Few studies have analyzed the relationship between surgical volume and outcomes after antireflux procedures. The aim of this study was to determine the effect of surgical volume on postoperative results and costs for patients undergoing surgery for gastroesophageal reflux disease. METHODS: We analyzed the National Inpatient Sample (period 2000-2013). Adult patients (>=18 years old) with gastroesophageal reflux disease who underwent fundoplication were included. Hospital surgical volume was determined using the 30th and 60th percentile cut points using weighted discharges and categorized as low (<10 operations/year), intermediate (10-25 operations/year), or high (>25 operations/year). We performed multivariable logistic regression models to assess the effect of surgical volume on patient outcomes. RESULTS: The studied cohort comprised 75,544 patients who had antireflux surgery. When operations performed at low-volume hospitals, postoperative bleeding, cardiac failure, renal failure, respiratory failure, and inpatient mortality were more common. In intermediate-volume hospitals, patients were more likely to have postoperative infection, esophageal perforation, bleeding, cardiac failure, renal failure, and respiratory failure. The length of hospital stay was longer at low- and intermediate-volume hospitals (1.08 and 0.55 days longer, respectively). There was an increase in charges of 5120 dollars per patient at low-volume centers, and 4010 dollars per patient at intermediate volume centers. CONCLUSIONS: When antireflux surgery is performed at high-volume hospitals, morbidity is lower, length of hospital stay is shorter, and costs for the healthcare system are decreased. PMID- 29288312 TI - Factors Predicting the Recovery of Unilateral Vocal Fold Paralysis After Thyroidectomy. AB - BACKGROUND: We used voice analysis and clinicopathological factors to explore the prognosis of unilateral vocal fold paralysis after thyroid surgery. METHODS: The medical records of 63 females who developed unilateral vocal fold paralysis after thyroidectomy were reviewed. All patients were divided into two groups: those who recovered from vocal fold paralysis and those who did not. We analyzed clinical parameters and voice analysis results in a search for correlations with recovery from paralysis. RESULTS: Of the 63 patients, 37 (58%) recovered from paralysis. A small tumor size, incomplete paralysis, the absence of arytenoid tilting, no compensatory movement of the normal side, lower postoperative shimmer, a higher postoperative maximum phonation time (MPT), and lower postoperative subglottic pressure correlated significantly with recovery from vocal fold paralysis. Multivariate analysis confirmed that the absence of compensatory movement of the normal side on videostroboscopy was independently prognostic. A postoperative MPT of 6.86 appeared to be optimal for prediction of recovery. Most patients recovered within 6 months, but those with incomplete paralysis recovered about 3 months earlier. At the 12-month follow-up, the thyroidectomy-related voice questionnaire scores had returned to preoperative values in only 12 patients (19.0%); 51 patients (81.0%) did not fully recover. CONCLUSION: Compensatory movement of the normal side evident on videostroboscopy was a poor prognostic factor. Voice analysis can be helpful in counseling vocal fold paralysis patients after thyroidectomy, and early intervention may be considered in patients who are expected to have a poor prognosis. PMID- 29288313 TI - Parastomal Hernia Repair with a 3D Funnel Intraperitoneal Mesh Device and Same Sided Stoma Relocation: Results of 56 Cases. PMID- 29288314 TI - Pancreaticobiliary Maljunctions in European Patients with Bile Duct Cysts. PMID- 29288315 TI - Characteristics, Stratification and Time to Death in a Population-Based Cohort of Patients with Ruptured Abdominal Aortic Aneurysms Not Undergoing Surgery. AB - BACKGROUND: The available literature on ruptured abdominal aortic aneurysms (rAAA) centers on survival after operation and commonly, reasons why some patients do not undergo surgery are not addressed. The aim of the present study is to examine, in a population-based cohort, the characteristics, stratification and time to death of patients admitted to hospital, but not undergoing operation for rAAA. METHODS: A retrospective, single-center study. All patients admitted to Stavanger University Hospital from the primary catchment area with rAAA on admission or in-hospital from 2000 to 2014 were included. RESULTS: Altogether 214 patients with rAAA were identified; 57 (27%) patients did not undergo surgery. The proportion of women was significantly higher (37 vs. 14%; p < .001) in patients not having surgery. The reasons for not undergoing operation were patient 'not fit for surgery' (30%), 'dying or agonal' at time of diagnosis (26%), 'did not want operation' (21%) and 'diagnosed at autopsy' (23%). Of the non-operated patients, 45 had rAAA on arrival to hospital, 12 had in-hospital rupture and 21 patients had previously been diagnosed with an abdominal aortic aneurysm. Non-operative treatment was uniformly fatal. The 45 patients with rAAA on arrival were scored using four scoring systems, the predicted mortality varied widely, and the median time from admission to death was 7.4 h (range 0-1337). CONCLUSION: In about half of patients, a decision not to operate was made by the consultant vascular surgeon or the patient. In the subgroup of patients not diagnosed until autopsy or having an in-hospital rupture, an earlier diagnosis might have altered the outcome. PMID- 29288316 TI - Risk Factors for Mortality and Morbidity in Elderly Patients Presenting with Digestive Surgical Emergencies. AB - BACKGROUND: Emergency digestive surgery is being increasingly performed in elderly patients. The aim of the present study was to identify the predictors of mortality and morbidity following emergency digestive surgery in patients aged 80 years and older. METHODS: A single-center retrospective review was performed of consecutive patients aged >=65 years operated for a digestive surgical emergency between January 2011 and December 2013. Two groups were compared: group A (aged 65-79 years) and group B (aged >=80 years). RESULTS: The study population included 185 patients: 76 patients in group A and 109 in group B. The mean age was 79.9 years (65-104 years). The overall 90-day mortality rate was 23.2 and 31.9% at 1 year, which was similar between groups. The overall morbidity was 28.6%. No differences were noted between the two groups in overall, minor (Dindo I-II) or major (Dindo III-IV) morbidity rates. Multivariate analysis identified pulmonary disease (odds ratio, OR = 6.43, p = 0.02), bowel ischemia (OR = 11.41, p = 0.01), postoperative ICU stay (OR = 7.37, p < 0.0001) and the occurrence of postoperative complications (OR = 2.66, p = 0.03) as predictors of 90-day mortality. Predictors of in-hospital morbidity were preoperative hemoglobin <12 g/dL (OR = 2.49, p = 0.02) and postoperative intensive care unit (ICU) stay (OR = 6.69, p < 0.0001). An age >=80 year was not associated with mortality or morbidity in this study. CONCLUSIONS: The decision to perform abdominal surgery in the emergency setting should be based on physiological status, which accounts for a patient's comorbidities and health status, rather than on chronological age per se. PMID- 29288317 TI - Aortic Reservoir Function has a Strong Impact on the Cardiac Blood Supply Workload Balance in Children. AB - It has been reported that more than half of the ejected blood from the left ventricle is stored in the aorta during systole and expelled during diastole. One important organ that receives blood flow mainly during diastole is the heart. It is also reported that the cardiac blood supply-workload balance in small children is disadvantageous to the heart. Therefore, we measured the aortic reservoir function and examined the relationship between the aortic reservoir function and the cardiac blood supply-workload balance. The percent diastolic runoff, which is the percentage of the diastolic blood flow of the total cardiac output, was measured as the index of the aortic reservoir function. The subendocardial viability ratio-the ratio of the diastolic pressure time index (the blood supply to the heart) to the tension time index (implying the myocardial oxygen demand) was investigated as an index of the cardiac blood supply-workload balance in children. The percent diastolic runoff was 51.7 +/- 4.5%, smaller than that in adult. It had a significant positive relationship to age (r2 = 0.32, p = 0.0052). The subendocardial viability ratio was 100.8 +/- 19.6% and had a strong relationship to the percent diastolic runoff (r2 = 0.92, p < 0.0001). The percent diastolic runoff had a positive relationship with age during childhood. The value had a strong impact on the cardiac blood supply-workload balance. PMID- 29288319 TI - Repetitive nonpersistent protrusion of the tongue on prenatal ultrasound. PMID- 29288320 TI - Membrane sweeping added to formal induction method to increase the spontaneous vaginal delivery: a meta-analysis. AB - BACKGROUND: Membrane sweeping (MS) could increase the likelihood of spontaneous labor within 48 h. However, the rationale for performing routinely an intervention with the potential to induce labor in women with an uneventful pregnancy at 38 weeks of gestation is, at least, questionable. We conducted a meta-analysis of randomized controlled trial (RCT) studies to assess evaluated the effect of MS added to formal induction method on the spontaneous vaginal delivery, compared with formal induction alone. METHODS: PubMed, Embase, Cochrane Library databases, Web of Science, and Clinical Trials were searched from their inception to March 8, 2017. We estimate summarized relative risk (RR) and 95% confidence intervals (CIs) for dichotomous outcomes. The primary outcome was vaginal delivery, and second outcomes (side effects of MS) included meconium stained liquor, admission to the neonatal unit, instrumental delivery. RESULTS: Four RCTs with a total of 1377 participants were identified. The summary RR in the overall group was 1.12 (95% CI 1.05-1.18), with moderate heterogeneity (P = 0.22, I2 = 33%). The summary RR in the nulliparas' subgroup was 1.32 (95% CI 1.18 1.48), with no heterogeneity (P = 0.79, I2 = 0%). MS did not increase the risk of side effects. CONCLUSIONS: MS added to formal induction significantly increased vaginal delivery rates, especially in nulliparas compared with formal induction alone. Notably, there are no obvious side effects of MS. Meanwhile, more RCTs studies are needed to investigate the side effects of MS on instrumental delivery, postpartum hemorrhage, and cervical laceration. PMID- 29288318 TI - Potentially traumatic events have negative and positive effects on loneliness, depending on PTSD-symptom levels: evidence from a population-based prospective comparative study. AB - PURPOSE: Examine to what extent adults affected by recent potentially traumatic events (PTE) with different PTSD-symptom levels are more at risk for post-event loneliness than non-affected adults are in the same study period. METHODS: We extracted data from the Dutch longitudinal LISS panel to measure pre-event loneliness (2011) and post-event loneliness (2013 and 2014), pre-event mental health problems (2011), PTE and PTSD symptoms (2012). This panel is based on a traditional random sample drawn from the population register by Statistics Netherlands. RESULTS: Results of the multinomial logistic regression analyses showed that affected adults with high levels of PTSD symptoms were more at risk for high levels of post-event loneliness than affected adults with very low PTSD symptom levels and non-affected adults, while controlling for pre-event loneliness, pre-event mental health problems and demographics. However, affected adults with very low levels of PTSD symptoms compared to non-affected adults were less at risk for medium and high levels of post-event loneliness while controlling for the same variables. Yet, pre-event loneliness appeared to be the strongest independent predictor of loneliness at later stages: more than 80% with high pre-event levels had high post-event levels at both follow-ups. CONCLUSIONS: Remarkably, potentially traumatic events have depending on PTSD-symptom levels both negative and positive effects on post-event loneliness in favor of affected adults with very low PTSD symptoms levels. However, post-event levels at later stages are predominantly determined by pre-event loneliness levels. PMID- 29288321 TI - RASSF1A promoter methylation was associated with the development, progression and metastasis of cervical carcinoma: a meta-analysis with trial sequential analysis. AB - BACKGROUND: RASSF1A promoter methylation has been reported in cervical cancer. However, clinical effect of RASSF1A promoter methylation in cervical cancer remains unclear. This meta-analysis was conducted to assess the correlation between RASSF1A promoter methylation and cervical cancer and the association of RASSF1A promoter methylation with clinicopathological features. METHODS: Electronic databases were searched to identify eligible publications. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was performed to assess the required study population information. RESULTS: Twenty-six papers published from 2001 to 2017 were analyzed in the meta-analysis, including a total of 1820 patients with cervical cancer, 507 patients with cervical intraepithelial neoplasia (CIN) lesions and 894 nonmalignant controls. RASSF1A promoter methylation was significantly increased in cervical cancer than in CIN lesions and nonmalignant tissue samples. In addition, RASSF1A promoter methylation was correlated with cervical cancer among two studies of blood and cytology samples (cancer vs nonmalignant controls). No correlation was found between RASSF1A promoter methylation and age factor, human papillomavirus (HPV) subtypes or clinical stage. RASSF1A promoter methylation was associated with tumor grade (grade 3-4 vs 1-2: OR 2.31, 95% CI 1.12-4.77, P = 0.023), lymph node metastasis (yes vs no: OR 2.97, 95% CI 1.60-5.52, P = 0.001), tumor histology (squamous cell carcinoma vs adenocarcinoma: OR 0.49, 95% CI 0.22 1.08, P = 0.076), and HPV infection (positive vs negative: OR 0.45, 95% CI 0.28 0.73, P = 0.001). TSA showed that the cumulative Z-curve did not cross the trial sequential monitoring boundary for significant results. CONCLUSIONS: RASSF1A promoter methylation may be associated with cervical cancer development, progression and metastasis. Methylated RASSF1A may be a noninvasive blood or cytology biomarker. Based on TSA, more studies are essential in the future. PMID- 29288322 TI - Bedside risk estimation of morbidly adherent placenta using simple calculator. AB - PURPOSE: To construct a calculator for 'bedside' estimation of morbidly adherent placenta (MAP) risk based on ultrasound (US) findings. MATERIALS AND METHODS: This retrospective study included all pregnant women with at least one previous cesarean delivery attending in our US unit between December 2013 and January 2017. The examination was based on a scoring system which determines the probability for MAP. RESULTS: The study population included 471 pregnant women, and 41 of whom (8.7%) were diagnosed with MAP. Based on ROC curve, the most effective US criteria for detection of MAP were the presence of the placental lacunae, obliteration of the utero-placental demarcation, and placenta previa. On the multivariate logistic regression analysis, US findings of placental lacunae (OR = 3.5; 95% CI, 1.2-9.5; P = 0.01), obliteration of the utero-placental demarcation (OR = 12.4; 95% CI, 3.7-41.6; P < 0.0001), and placenta previa (OR = 10.5; 95% CI, 3.5-31.3; P < 0.0001) were associated with MAP. By combining these three parameters, the receiver operating characteristic curve was calculated, yielding an area under the curve of 0.93 (95% CI, 0.87-0.97). Accordingly, we have constructed a simple calculator for 'bedside' estimation of MAP risk. The calculator is mounted on the hospital's internet website ( http://www.assafh.org/Pages/PPCalc/index.html ). The risk estimation of MAP varies between 1.5 and 87%. CONCLUSIONS: The present calculator enables a simple 'bedside' MAP estimation, facilitating accurate and adequate antenatal risk assessment. PMID- 29288323 TI - Impact of holistic review on student interview pool diversity. AB - Diversity in the physician workforce lags behind the rapidly changing US population. Since the gateway to becoming a physician is medical school, diversity must be addressed in the admissions process. The Association of American Medical Colleges has implemented a Holistic Review Initiative aimed at assisting medical schools with broadening admission criteria to include relevant, mission-driven attributes and experiences in addition to academic preparation to identify applicants poised to meet the needs of a diverse patient population. More evidence is needed to determine whether holistic review results in a more diverse selection process. One of the keys to holistic review is to apply holistic principles in all stages of the selection process to ensure qualified applicants are not overlooked. This study examines whether the use of holistic review during application screening at a new medical school increased the diversity of applicants selected for interview. Using retrospective data from the first five application cycles at the Oakland University William Beaumont School of Medicine (OUWB), the author compared demographic and experiential differences between the applicants selected using holistic review, including experiences, attributes and academic metrics, to a test sample selected solely using academic metrics. The dataset consisted of the total group of applicants selected for interview in 2011 through 2015 using holistic review (n = 2773) and the same number of applicants who would have been selected for an interview using an academic-only selection model (n = 2773), which included 1204 applicants who were selected using both methods (final n = 4342). The author used a combination of cross-tabulation and analysis of variance to identify differences between applicants selected using holistic review and applicants in the test sample selected using only academics. The holistic review process yielded a significantly higher than expected percent of female (adj. resid. = 13.2, p < .01), traditionally underrepresented in medicine (adj. resid. = 15.8, p < .01), first generation (adj. resid. = 5.8, p < .01), and self-identified disadvantaged (adj resid. = 11.5, p < .01) applicants in the interview pool than selected using academic metrics alone. In addition, holistically selected applicants averaged significantly more hours than academically selected students in the areas of pre medical school paid employment (F = 10.99, mean difference = 657.99, p < .01) and community service (F = 15.36, mean difference = 475.58, p < .01). Using mission driven, holistic admissions criteria comprised of applicant attributes and experiences in addition to academic metrics resulted in a more diverse interview pool than using academic metrics alone. These findings add support for the use of holistic review in the application screening process as a means for increasing diversity in medical school interview pools. PMID- 29288324 TI - Spatial distribution and temporal variation of chemical properties of drainage watercourses in rural and peri-urban areas of Novi Sad (Serbia)-a case study. AB - Waters are among to the most vulnerable environmental resources exposed to the impact of various point and non-point pollutants from rural/urban activities. Systematic and long-term monitoring of hydro-resources is therefore of crucial importance for sustainable water management, although such practice is lacking across many (agro-)hydro-ecosystems. In the presented study, for the first time, the spatial distribution (covering almost 9000 ha) and temporal variation (2006 2013) in certain quality parameters was characterized in drainage watercourses Tatarnica and Subic, whose catchment is rural and suburban areas close to the city of Novi Sad, Republic of Serbia. Based on majority of observed parameters, both watercourses belonged to I and II water quality classes, with occasional presence of certain parameters (e.g., suspended solids, total phosphorus; ammonium) at extreme values exacerbating both watercourses to classes IV and V. The value of the synthetic pollution index (i.e., a combined effect of all considered parameters) showed a higher degree of water pollution in watercourse Subic (on average 2.00) than Tatarnica (on average 0.72). Also, cluster analysis for watercourse Tatarnica detected two groups of parameters (mostly related to nutrients and organic matter), indicating more complex impacts on water quality during the observed period, in which elucidation thus established water quality monitoring program would be of great importance. PMID- 29288325 TI - Effect of nitrogen source concentration on decolouration rates of laboratory dyes by immobilized cells of two bacterial species. AB - The aim of this study was to assess the effect of sodium nitrate concentration on the decolouration of laboratory dyes (bromothymol blue, crystal violet, eosin blue, eosin yellow and methylene blue), by alginate immobilized cells of Pseudomonas aeruginosa and Bacillus subtilis. The sodium nitrate concentrations used in the study were 5, 10, 15 and 20 g/L. A control setup that contained no sodium nitrate was also studied. During incubation, aliquot samples were withdrawn from each flask every 24 for 144 h duration for the estimation of decolouration rate of the dyes, using standard procedures. The results revealed remarkable decolouration of the bromothymol blue and crystal violet in presence of the P. aeruginosa occurring at sodium nitrate concentrations of 10 and 15 g/L, respectively. In the case of media that was inoculated with the B. subtilis cells, although no remarkable decolouration of the bromothymol blue and crystal violet was observed throughout the period of incubation, highest decolouration were observed at sodium nitrate concentration of 5 and 10 g/L, respectively. For the eosin blue and methylene dyes, no remarkable decolouration were observed in presence of the test bacterial species at the respective sodium nitrate concentrations. Highest decolouration of the eosin yellow was however observed in media with sodium nitrate concentration of 5 g/L. The results of this study could be applied in scale up studies and continuous process, for implementation in biological decolouration of dye effluents. PMID- 29288326 TI - FveRGA1, encoding a DELLA protein, negatively regulates runner production in Fragaria vesca. AB - MAIN CONCLUSION: FveRGA1 was highly expressed in tender tissues such as young leaves and stem apices and was localized in the nucleus. RNAi silencing of FveRGA1 in non-runnering woodland strawberry produced many runners. FveRGA1 is thus a key gene controlling strawberry runner formation. The propagation of strawberry is mainly based on runners, while the genes controlling runner production have not been well characterized. Exogenous applications of optimum concentration gibberellins (GAs) promote runner formation in strawberry cultivation and GA can accelerate the degradation of DELLA proteins. To investigate whether DELLA proteins are responsible for runner production, we analyzed all the DELLA genes in Fragaria vesca and cloned a DELLA protein encoding gene FveRGA1 in woodland strawberry using RT-PCR. Subcellular localization analysis indicated that FveRGA1 was localized in the nucleus. A transcription analysis suggested that FveRGA1 was expressed ubiquitously in all examined strawberry organs, especially in young leaves, petioles, and stem apices. RNA interference (RNAi) technology was carried out to investigate the function of FveRGA1 in woodland strawberry 'Yellow Wonder' (YW) and 'Ruegen' (RG) via an Agrobacterium-mediated transformation. Interestingly, the RNAi silencing transgenic plants in the naturally non-runnering YW and RG strains produced many runners, suggesting FveRGA1 as a key gene controlling strawberry runner formation. Our study lays a solid basis for unraveling the detailed molecular mechanism of runner formation in strawberry. PMID- 29288327 TI - Changes in the abundance of cell wall apiogalacturonan and xylogalacturonan and conservation of rhamnogalacturonan II structure during the diversification of the Lemnoideae. AB - MAIN CONCLUSION: The diversification of the Lemnoideae was accompanied by a reduction in the abundance of cell wall apiogalacturonan and an increase in xylogalacturonan whereas rhamnogalacturonan II structure and cross-linking are conserved. The subfamily Lemnoideae is comprised of five genera and 38 species of small, fast-growing aquatic monocots. Lemna minor and Spirodela polyrhiza belong to this subfamily and have primary cell walls that contain large amounts of apiogalacturonan and thus are distinct from the primary walls of most other flowering plants. However, the pectins in the cell walls of other members of the Lemnoideae have not been investigated. Here, we show that apiogalacturonan decreased substantially as the Lemnoideae diversified since Wolffiella and Wolffia walls contain between 63 and 88% less apiose than Spirodela, Landoltia, and Lemna walls. In Wolffia, the most derived genus, xylogalacturonan is far more abundant than apiogalacturonan, whereas in Wolffiella pectic polysaccharides have a high arabinose content, which may arise from arabinan sidechains of RG I. The apiose-containing pectin rhamnogalacturonan II (RG-II) exists in Lemnoideae walls as a borate cross-linked dimer and has a glycosyl sequence similar to RG-II from terrestrial plants. Nevertheless, species-dependent variations in the extent of methyl-etherification of RG-II sidechain A and arabinosylation of sidechain B are discernible. Immunocytochemical studies revealed that pectin methyl esterification is higher in developing daughter frond walls than in mother frond walls, indicating that methyl-esterification is associated with expanding cells. Our data support the notion that a functional cell wall requires conservation of RG-II structure and cross-linking but can accommodate structural changes in other pectins. The Lemnoideae provide a model system to study the mechanisms by which wall structure and composition has changed in closely related plants with similar growth habits. PMID- 29288328 TI - New diterpenes from Nigella damascena seeds and their antiviral activities against herpes simplex virus type-1. AB - Nigella species are rich source of dolabellane diterpenes. During our study of Nigella species, new dolabellane diterpenes, damasterpenes V-VIII were isolated. The structural determination of new compounds damasterpenes V-VIII is described with consideration of their absolute configurations. The antiviral activities against herpes simplex virus type-1 of the isolated compounds and their derivatives are also evaluated. Damasterpene V (inhibition 35.0%) and 2 phenylacetyl 13-benzoyl damasterpenol (32.0%) showed significant antiviral activity at 10 MUM. PMID- 29288330 TI - Evaluation of vertebral artery anomaly in basilar invagination and prevention of vascular injury during surgical intervention: CTA features and analysis. AB - OBJECTIVE: To evaluate vertebral artery anomaly at the craniovertebral junction (CVJ) in patients with basilar invagination (BI) by computed tomographic angiography (CTA), and to discuss the prevention strategy of vascular injury. METHODS: The primary axial, multiple planar reconstruction and volume-rendering cervicocranial CTA images of 39 BI patients were analysed to evaluate vertebral artery anomaly at the CVJ: persistent first intersegmental artery (PFIA), fenestrated vertebral artery (FEN), and extracranial C1/2 origin of posterior inferior cerebellar artery (PICA), high-riding vertebral artery, side-to-side asymmetry and irregular midline carotid artery loop was determined by subjective vision. 100 patients who underwent CTA for reasons other than CVJ deformity were enrolled as normal controls to evaluate the prevalence of vertebral artery anomaly in a normal population. Chi-square test was utilized for comparing the prevalence of vertebral artery anomaly between these two groups. RESULTS: The incidence of PFIA was 25.6% (10/39), FEN was 7.7% (3/39), PICA was 5.1% (2/39), and the total incidence of extraosseous anomalous course of vertebral artery was 38.5% (15/39), significantly higher than that of control group, 7.0% (7/100) (P < 0.01). The incidence of high-riding vertebral artery and side-to-side asymmetry were 61.5% (24/39) and 30.8% (12/39), respectively. An irregular midline carotid artery loop was observed in five patients (12.8%). CONCLUSION: Vertebral artery anomaly, which can be clearly depicted by CTA, is more frequent in BI patients. Preoperative CTA should be performed for this patient population to prevent vascular injury. These slides can be retrieved under Electronic Supplementary Material. PMID- 29288331 TI - Answer to the Letter to the Editor of A. De Giorgio et al. concerning "Effects of lumbosacral orthoses on postural control in individuals with or without non specific low back pain" by J. Mi et al. (Eur Spine J; 2017: doi:10.1007/s00586 017-5355-5). PMID- 29288332 TI - Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes. AB - We previously reported that EGFR tyrosine kinase (EGFRtk) activity and endoplasmic reticulum (ER) stress are enhanced in type 2 diabetic (T2D) mice and cause vascular dysfunction. In the present study, we determined the in vivo contribution of EGFRtk and ER stress in acute myocardial infarction induced by acute ischemia (40 min)-reperfusion (24 h) (I/R) injury in T2D (db-/db-) mice. We treated db-/db- mice with EGFRtk inhibitor (AG1478, 10 mg/kg/day) for 2 weeks. Mice were then subjected to myocardial I/R injury. The db-/db- mice developed a significant infarct after I/R injury. The inhibition of EGFRtk significantly reduced the infarct size and ER stress induction. We also determined that the inhibition of ER stress (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) in db-/db- significantly decrease the infarct size indicating that ER stress is a downstream mechanism to EGFRtk. Moreover, AG1478 and TUDCA reduced myocardium p38 and ERK1/2 MAP-kinases activity, and increased the activity of the pro-survival signaling cascade Akt. Additionally, the inhibition of EGFRtk and ER stress reduced cell apoptosis and the inflammation as indicated by the reduction in macrophages and neutrophil infiltration. We determined for the first time that the inhibition of EGFRtk protects T2D heart against I/R injury through ER stress dependent mechanism. The cardioprotective effect of EGFRtk and ER stress inhibition involves the activation of survival pathway, and inhibition of apoptosis, and inflammation. Thus, targeting EGFRtk and ER stress has the potential for therapy to overcome myocardial infarction in T2D. PMID- 29288333 TI - Unmet needs of child and adolescent psychiatrists among Asian and European countries: does the Human Development Index (HDI) count? PMID- 29288334 TI - Population cost-effectiveness of the Triple P parenting programme for the treatment of conduct disorder: an economic modelling study. AB - Parenting programmes are the recommended treatments of conduct disorders (CD) in children, but little is known about their longer term cost-effectiveness. This study aimed to evaluate the population cost-effectiveness of one of the most researched evidence-based parenting programmes, the Triple P-Positive Parenting Programme, delivered in a group and individual format, for the treatment of CD in children. A population-based multiple cohort decision analytic model was developed to estimate the cost per disability-adjusted life year (DALY) averted of Triple P compared with a 'no intervention' scenario, using a health sector perspective. The model targeted a cohort of 5-9-year-old children with CD in Australia currently seeking treatment, and followed them until they reached adulthood (i.e., 18 years). Multivariate probabilistic and univariate sensitivity analyses were conducted to incorporate uncertainty in the model parameters. Triple P was cost-effective compared to no intervention at a threshold of AU$50,000 per DALY averted when delivered in a group format [incremental cost effectiveness ratio (ICER) = $1013 per DALY averted; 95% uncertainty interval (UI) 471-1956] and in an individual format (ICER = $20,498 per DALY averted; 95% UI 11,146-39,470). Evidence-based parenting programmes, such as the Triple P, for the treatment of CD among children appear to represent good value for money, when delivered in a group or an individual face-to-face format, with the group format being the most cost-effective option. The current model can be used for economic evaluations of other interventions targeting CD and in other settings. PMID- 29288335 TI - Murphy's law and Murphy eyes. PMID- 29288336 TI - Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes. AB - PURPOSE: Propofol infusion syndrome (PRIS) is a lethal condition caused by propofol overdose. Previous studies suggest that pathophysiological mechanisms underlying PRIS involve mitochondrial dysfunction; however, these mechanisms have not been fully elucidated. This study aimed to establish an experimental model of propofol-induced cytotoxicity using cultured human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to determine the mechanisms behind propofol-induced mitochondrial dysfunction, and to evaluate the protective effects of coenzyme Q10 (CoQ10). METHODS: Human iPSC-derived cardiomyocytes were exposed to propofol (0, 2, 10, or 50 ug/ml) with or without 5 uM CoQ10. Mitochondrial function was assessed by measuring intracellular ATP, lactate concentrations in culture media, NAD+/NADH ratio, and the mitochondrial membrane potential. Propofol-induced cytotoxicity was evaluated by analysis of cell viability. Expression levels of genes associated with mitochondrial energy metabolism were determined by PCR. Intracellular morphological changes were analyzed by confocal microscopy. RESULTS: Treatment with 50 ug/ml propofol for 48 h reduced cell viability. High concentrations of propofol (>= 10 ug/ml) induced mitochondrial dysfunction accompanied by downregulation of gene expression of PGC-1alpha and its downstream targets (NDUFS8 and SDHB, which are involved in the respiratory chain reaction; and CPT1B, which regulates beta-oxidation). Cardiomyocytes co-treated with 5 uM CoQ10 exhibited resistance to propofol-induced toxicity through recovery of gene expression. CONCLUSIONS: Propofol-induced cytotoxicity in human iPSC-derived cardiomyocytes may be associated with mitochondrial dysfunction via downregulation of PGC-1alpha-regulated genes associated with mitochondrial energy metabolism. Co-treatment with CoQ10 protected cardiomyocytes from propofol induced cytotoxicity. PMID- 29288337 TI - A Study of Carbon Nanofibers and Active Carbon as Symmetric Supercapacitor in Aqueous Electrolyte: A Comparative Study. AB - Symmetric supercapacitors are fabricated by carbon nanofibers (CNF) and activated carbon (AC) using similar proportions of 7 wt% polyvinylidene fluoride (PVDF) polymer binder in an aqueous electrolyte. In this study, a comparison of porous texture and electrochemical performances between CNFs and AC based supercapacitors was carried out. Electrodes were assembled in the cell without a current collector. The prepared electrodes of CNFs and AC present Brunauer-Emmett Teller (BET) surface area of 83 and 1042 m2/g, respectively. The dominant pore structure for CNFs is mesoporous while for AC is micropore. The results showed that AC provided higher specific capacitance retention up to very fast scan rate of 500 mV/s. AC carbon had a specific capacitance of 334 F/g, and CNFs had 52 F/g at scan rate 5 mV/s in aqueous solution. Also, the results indicate the superior conductivity of CNFs in contrast to AC counterparts. The measured equivalent series resistance (ESR) showed a very small value for CNFs (0.28 Omega) in comparison to AC that has an ESR resistance of (3.72 Omega). Moreover, CNF delivered higher specific power (1860 W/kg) than that for AC (450 W/kg). On the other hand, AC gave higher specific energy (18.1 Wh/kg) than that for CNFs (2 Wh/kg).This indicates that the AC is good for energy applications. Whereas, CNF is good for power application. Indeed, the higher surface area will lead to higher specific capacitance and hence higher energy density for AC. For CNF, lower ESR is responsible for having higher power density.Both CNF and AC supercapacitor exhibit an excellent charge-discharge stability up to 2500 cycles. PMID- 29288338 TI - Toll-Like Receptor 2-Mediated Glial Cell Activation in a Mouse Model of Cuprizone Induced Demyelination. AB - Multiple sclerosis (MS) is a chronic degenerative disease of the central nervous system that is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation. The factors triggering gliosis and demyelination are currently not well characterized. New findings suggest an important role of the innate immune response in the initiation and progression of active demyelinating lesions. Especially during progressive disease, aberrant glia activation rather than the invasion of peripheral immune cells is accountable for progressive neuronal injury. The innate immune response can be induced by pathogen-associated or danger-associated molecular patterns, which are identified by pattern recognition receptors (PRRs), including the Toll-like receptors (TLRs). In this study, we used the cuprizone model in mice to investigate the expression of TLR2 during the course of cuprizone-induced demyelination. In addition, we used TLR2-deficient mice to analyze the functional role of TLR2 activation during cuprizone-induced demyelination and reactive gliosis. We show a significantly increased expression of TLR2 in the corpus callosum and hippocampus of cuprizone-intoxicated mice. The absence of receptor signaling in TLR2 deficient mice resulted in less severe reactive astrogliosis in the corpus callosum and cortex. In addition, microglia activation was ameliorated in the corpus callosum of TLR2-deficient mice, but augmented in the cortex compared to wild-type littermates. Extent of demyelination and loss of mature oligodendrocytes was comparable in both genotypes. These results suggest that the TLR2 orchestrates glia activation during gray and white matter demyelination in the presence of an intact blood-brain barrier. Future studies now have to address the underlying mechanisms of the region-specific TLR2-mediated glia activation. PMID- 29288339 TI - Cdk5 Contributes to Huntington's Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates. AB - Cognitive deficits are a major hallmark of Huntington's disease (HD) with a great impact on the quality of patient's life. Gaining a better understanding of the molecular mechanisms underlying learning and memory impairments in HD is, therefore, of critical importance. Cdk5 is a proline-directed Ser/Thr kinase involved in the regulation of synaptic plasticity and memory processes that has been associated with several neurodegenerative disorders. In this study, we aim to investigate the role of Cdk5 in learning and memory impairments in HD using a novel animal model that expresses mutant huntingtin (mHtt) and has genetically reduced Cdk5 levels. Genetic reduction of Cdk5 in mHtt knock-in mice attenuated both corticostriatal learning deficits as well as hippocampal-dependent memory decline. Moreover, the molecular mechanisms by which Cdk5 counteracts the mHtt induced learning and memory impairments appeared to be differentially regulated in a brain region-specific manner. While the corticostriatal learning deficits are attenuated through compensatory regulation of NR2B surface levels, the rescue of hippocampal-dependent memory was likely due to restoration of hippocampal dendritic spine density along with an increase in Rac1 activity. This work identifies Cdk5 as a critical contributor to mHtt-induced learning and memory deficits. Furthermore, we show that the Cdk5 downstream targets involved in memory and learning decline differ depending on the brain region analyzed suggesting that distinct Cdk5 effectors could be involved in cognitive impairments in HD. PMID- 29288340 TI - Design and adjustment of the graphene work function via size, modification, defects, and doping: a first-principle theory study. AB - In this work, the work function (WF) of graphenes, which are used as electronic devices, has been designed and evaluated by using the first-principle approach. Different states of graphene were considered, such as surface modification, doping, and defects. Firstly, WF strongly depends on the width of pristine graphene. A bigger width leads to a smaller WF. In addition, the effects of hydroxyls, defects, and positions of hydroxyls and defects are of concern. The WF of the graphene which is modified with hydroxyls is bigger than that of the pristine graphene. Moreover, the WF value increases with the number of hydroxyls. Positions of the hydroxyls and defects that deviated from the center have limited influence on the WF, whereas the effect of the position in the center is substantial. Lastly, B, N, Al, Si, and P are chosen as the doping elements. The n type graphene doped with N and P atoms results in a huge decline in the WF, whereas the p-type graphene doped with B and Al atoms causes a great increase in the WF. However, the doping of Al in graphene is difficult, whereas the doping of B and N is easier. These discoveries will provide heavy support for the production of graphene-based devices. PMID- 29288341 TI - Brain lipid binding protein mediates the proliferation of human glioblastoma cells by regulating ERK1/2 signaling pathway in vitro. AB - Brain lipid binding protein (BLBP) is highly expressed in the radial glial cells (RGCs) of the central nervous system (CNS), in glioblastomas, and, in vitro, in U251 cells. In this report, we have demonstrated that increased BLBP expression in glioblastoma is associated with poor survival and used a double-vector CRISPR/Cas9 lentiviral system to deplete endogenous BLBP from U251 cells, we found that loss of BLBP induced cell growth inhibition and S-phase arrest. Moreover, an increase in P53 and a decrease in p-ERK1/2 were observed after BLBP depletion, suggesting a potential mechanism by which loss of BLBP results in growth inhibition. PMID- 29288343 TI - Psychological Outcomes of Within-Group Sexual Violence: Evidence of Cultural Betrayal. AB - Cultural betrayal trauma theory is a new framework for understanding trauma related mental health outcomes in immigrant and minority populations. The purpose of the current study is to empirically test cultural betrayal trauma theory. We hypothesized that the association between within-group sexual violence and mental health outcomes would be stronger for minorities. Participants (N = 368) were minority and majority college students, who completed online measures of sexual violence victimization and mental health outcomes. A MANOVA revealed that the link between within-group sexual violence and total trauma symptoms, depression, sexual abuse sequelae, sleep disturbance, and sexual problems was stronger for minorities. This study provides evidence for cultural betrayal trauma theory, as the findings suggest that outcomes from the same experience-within-group sexual violence-is affected by minority status. This work has implications for how mental health is understood, investigated, and treated in immigrant and minority populations. PMID- 29288342 TI - Empirical Wavelet Transform Based Features for Classification of Parkinson's Disease Severity. AB - Parkinson's disease (PD) is a type of progressive neurodegenerative disorder that has affected a large part of the population till now. Several symptoms of PD include tremor, rigidity, slowness of movements and vocal impairments. In order to develop an effective diagnostic system, a number of algorithms were proposed mainly to distinguish healthy individuals from the ones with PD. However, most of the previous works were conducted based on a binary classification, with the early PD stage and the advanced ones being treated equally. Therefore, in this work, we propose a multiclass classification with three classes of PD severity level (mild, moderate, severe) and healthy control. The focus is to detect and classify PD using signals from wearable motion and audio sensors based on both empirical wavelet transform (EWT) and empirical wavelet packet transform (EWPT) respectively. The EWT/EWPT was applied to decompose both speech and motion data signals up to five levels. Next, several features are extracted after obtaining the instantaneous amplitudes and frequencies from the coefficients of the decomposed signals by applying the Hilbert transform. The performance of the algorithm was analysed using three classifiers - K-nearest neighbour (KNN), probabilistic neural network (PNN) and extreme learning machine (ELM). Experimental results demonstrated that our proposed approach had the ability to differentiate PD from non-PD subjects, including their severity level - with classification accuracies of more than 90% using EWT/EWPT-ELM based on signals from motion and audio sensors respectively. Additionally, classification accuracy of more than 95% was achieved when EWT/EWPT-ELM is applied to signals from integration of both signal's information. PMID- 29288345 TI - Polish translation and validation of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: The aim of the study was to translate into Polish the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ IR), which evaluates sexual function in sexually active (SA) and not SA (NSA) women with pelvic floor disorders (PFD), and to validate the Polish version. METHODS: After translation, back-translation and cognitive interviews, the final version of PISQ-IR was established. The study group included 252 women with PFD (124 NSA and 128 SA). All women underwent clinical evaluation and completed the PISQ-IR. For test-retest reliability, the questionnaire was administered to 99 patients twice at an interval of 2 weeks. The analysis of criterion validity required the subjects to complete self-reported measures. Internal consistency and criterion validity were assessed separately for NSA and SA women for the PISQ IR subscales. RESULTS: The mean age of the women was 60.9 +/- 10.6 years and their mean BMI was 27.9 +/- 4.9 kg/m2. Postmenopausal women constituted 82.5% of the study group. Urinary incontinence (UI) was diagnosed in 60 women (23.8%), pelvic organ prolapse (POP) in 90 (35.7%), and UI and POP in 102 (40.5%). Fecal incontinence was reported by 45 women (17.9%). The PISQ-IR Polish version proved to have good internal consistency in NSA women (alpha 0.651 to 0.857) and SA women (alpha 0.605 to 0.887), and strong reliability in all subscales (Pearson's coefficient 0.759-0.899; p < 0.001). Criterion validity confirmed moderate to strong correlations between PISQ-IR scores and self-reported measures in SA subscales, as well the SA summary score, and weak to moderate correlations in NSA women. CONCLUSIONS: The PISQ-IR Polish version is a valid tool for evaluating sexual function in women with PFD. PMID- 29288344 TI - FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques. AB - Cerebrospinal fluid (CSF) drains via the lymphatic drainage pathway. This lymphatic pathway connects the central nervous system (CNS) to the cervical lymph node (CLN). As the CSF drains to CLN via the dural and nasal lymphatics, T cells and antigen presenting cells pass along the channels from the subarachnoid space through the cribriform plate. Human immunodeficiency virus (HIV) may also egress from the CNS along this pathway. As a result, HIV egressing from the CNS may accumulate within the CLN. Towards this objective, we analyzed CLNs isolated from rhesus macaques that were chronically-infected with simian immunodeficiency virus (SIV). We detected significant accumulation of SIV within the CLNs. SIV virion trapping was observed on follicular dendritic cells (FDCs) localized within the follicular regions of CLNs. In addition, SIV antigens formed immune complexes when FDCs interacted with B cells within the germinal centers. Subsequent interaction of these B cells with CD4+ T follicular helper cells (TFHs) resulted in infection of the latter. Of note, 73% to 90% of the TFHs cells within CLNs were positive for SIV p27 antigen. As such, it appears that not only do the FDCs retain SIV they also transmit them (via B cells) to TFHs within these CLNs. This interaction results in infection of TFHs in the CLNs. Based on these observations, we infer that FDCs within the CLNs have a novel role in SIV entrapment with implications for viral trafficking. PMID- 29288346 TI - The Manchester-Fothergill procedure versus vaginal hysterectomy with uterosacral ligament suspension: a matched historical cohort study. AB - INTRODUCTION AND HYPOTHESIS: This study compares vaginal hysterectomy with uterosacral ligament suspension (VH) with the Manchester-Fothergill procedure (MP) for treating pelvic organ prolapse (POP) in the apical compartment. METHODS: Our matched historical cohort study is based on data from four Danish databases and the corresponding electronic medical records. Patients with POP surgically treated with VH (n = 295) or the MP (n = 295) in between 2010 and 2014 were matched for age and preoperative POP stage in the apical compartment. The main outcome was recurrent or de novo POP in any compartment. Secondary outcomes were recurrent or de novo POP in each compartment and complications. RESULTS: The risk of recurrent or de novo POP in any compartment was higher after VH (18.3%) compared with the MP (7.8%) (Hazard ratio, HR = 2.5, 95% confidence interval (CI): 1.3-4.8). Recurrence in the apical compartment occurred in 5.1% after VH vs. 0.3% after the MP (hazard ratio (HR) = 10.0, 95% confidence interval (CI) 1.3 78.1). In the anterior compartment, rates of recurrent or de novo POP were 11.2% after VH vs. 4.1% after the MP (HR = 3.5, 95% CI 1.4-8.7) and in the posterior compartment 12.9% vs. 4.7% (HR = 2.6, 95% CI 1.3-5.4), respectively. There were more perioperative complications (2.7 vs. 0%, p = 0.007) and postoperative intra abdominal bleeding (2 vs. 0%, p = 0.03) after VH. CONCLUSIONS: This study shows that the MP is superior to VH; if there is no other indication for hysterectomy, the MP should be preferred to VH for surgical treatment of POP in the apical compartment. PMID- 29288347 TI - Commentary on: The Manchester-Fothergill procedure versus vaginal hysterectomy with uterosacral ligament suspension: a matched historical cohort study. PMID- 29288348 TI - Whole sequence analysis indicates a recent southern origin of Mongolian Y chromosome C2c1a1a1-M407. AB - The Y-chromosome haplogroup C2c1a1a1-M407 is a predominant paternal lineage in Mongolic-speaking populations, especially in Buryats and Kalmyks. However, the origin and internal phylogeny of C2c1a1a1-M407 have not been investigated in detail. In this study, we analyzed twenty-three Y-chromosome sequences of haplogroup C2c1a1a1-M407 and its most closely related clades. We generated a high resolution phylogenetic tree of haplogroup C2c1a1a1-M407 and its upstream clade C2c1a1-CTS2657, including 32 subclades and 144 non-private Y-chromosome polymorphisms. We discover that all available C2c1a1a1-M407 samples from Mongolic speaking populations belong to its newly defined downstream clade C2c1a1a1b F8465, whereas all samples of C2c1a1-CTS2657(xF8465) come from northern Han Chinese, Korean, and Japanese. Furthermore, we observe that C2c1a1a1b-F8465 and its subclade C2c1a1a1b1-F8536 expanded at approximately 0.86 and 0.44 thousand years ago, respectively. Therefore, we conclude that C2c1a1a1-M407 in Mongolic speaking populations has originated from northeastern Asia. C2c1a1a1b1-F8536, the newly defined subclade of C2c1a1a1-M407, probably represents the genetic relationships between ancient Oyrats, modern Kalmyks, Mongolians, and Buryats. PMID- 29288350 TI - Correction to: Synthesis and inhibitory effect of 10-chlorocanthin-6-one on ovarian cancer HO8910PM cells. AB - The addresses given for the authors of this paper were incorrect. The correct assignments of the authors are given in this erratum. PMID- 29288349 TI - Laparoscopic surgery for locally advanced T4 colon cancer: the long-term outcomes and prognostic factors. AB - PURPOSE: For locally advanced pathological T4 (pT4) colon cancer, the safety and feasibility of laparoscopic procedures remain controversial. Therefore, this study aimed to assess short-term and long-term outcomes and to identify the prognostic factors in laparoscopic surgery for pT4 colon cancer. METHODS: The study group included 130 patients who underwent laparoscopic radical resection for pT4 colon and rectosigmoid cancer from January 2004 through December 2012. The short-term outcomes, long-term outcomes, and prognostic factors in pT4 colon cancer were analyzed. RESULTS: The median operative time was 205 min, with a median blood loss of 10 ml. The conversion rate was 3.8%, and 13 patients (10.0%) had postoperative complications. The radial resection margin was positive in 1 patient (0.8%). The median follow-up time was 73 months. The 5-year overall survival (OS) and recurrence-free survival (RFS) were 77.2 and 63.5%, respectively. On a multivariate analysis, a male sex [hazard ratio (HR) 3.09, p < 0.001], lymph node ratio >= 0.06 (HR 2.35, p = 0.021), tumor diameter < 38 mm (HR 2.57, p = 0.007), and right-sided colon cancer (HR 2.11, p = 0.047) were significantly related to a poor OS. CONCLUSIONS: These results suggest that laparoscopic surgery for pT4 colon cancer is safe and feasible, and the oncological outcomes are acceptable. Based on the present findings, select patients with locally advanced colon cancer should not be excluded from laparoscopic surgery. PMID- 29288351 TI - RNPC1 inhibits non-small cell lung cancer progression via regulating miR 181a/CASC2 axis. AB - OBJECTIVES: To study the roles and mechanisms of RNA binding protein RNPC1 in non small cell lung cancer progression. RESULTS: RNPC1 and long non-coding RNA CASC2 expression levels were significantly downregulated in lung cancer tissues compared with normal adjacent tissues, and their expression levels were positively correlated. Functionally, overexpression of RNPC1 or CASC2 inhibited non-small cell lung cancer cells proliferation, migration and invasion, and promoted cells apoptosis. Mechanistically, RNPC1 was found to harbor binding sites on CASC2 and directly bound to CASC2, and increased CASC2 mRNA stability and expression. Notably, the promotive effects of RNPC1 on CASC2 expression were attenuated by miR-181a overexpression. Moreover, CASC2 3'UTR with mutated miR 181a binding sites did not respond to RNPC1 alteration. Finally, the inhibitory effects of RNPC1 overexpression were attenuated or even reversed by CASC2 knockdown or miR-181a overexpression. CONCLUSIONS: RNA bind protein RNPC1 could inhibit non-small cell lung cancer progression by competitively binding to CASC2 with miR-181a. PMID- 29288352 TI - Sublethal concentration of H2O2 enhances the protective effect of mesenchymal stem cells in rat model of spinal cord injury. AB - OBJECTIVE: To investigate the effect of H2O2 on the migration and antioxidant defense of mesenchymal stem cells (MSCs) and the neurotrophic effects of H2O2 treated MSCs on spinal cord injury (SCI). RESULTS: Sublethal concentrations of H2O2 decreased cell migration and expression of CXCR4 and CCR2 as well as Nrf2 expression in MSCs. In the second phase, transplantation of treated and untreated MSCs to SCI caused minor changes in locomotor dysfunction. There was a significantly difference between cell-treated and spinal cord injury groups in expression of BDNF (brain-derived neurotrophic factor). Transplantation of H2O2 treated cells caused an increase in BDNF expression compared to non-treated cells. CONCLUSION: Transplantation of H2O2-treated stem cells may have protective effects against SCI through by increasing neurotrophic factors. PMID- 29288353 TI - Monoterpene biotransformation by Colletotrichum species. AB - OBJECTIVE: To investigate the biocatalytic potential of Colletotrichum acutatum and Colletotrichum nymphaeae for monoterpene biotransformation. RESULTS: C. acutatum and C. nymphaeae used limonene, alpha-pinene, beta-pinene, farnesene, citronellol, linalool, geraniol, perillyl alcohol, and carveol as sole carbon and energy sources. Both species biotransformed limonene and linalool, accumulating limonene-1,2-diol and linalool oxides, respectively. alpha-Pinene was only biotransformed by C. nymphaeae producing campholenic aldehyde, pinanone and verbenone. The biotransformation of limonene by C. nymphaeae yielded 3.34-4.01 g limonene-1,2-diol l-1, depending on the substrate (R-(+)-limonene, S-(-)-limonene or citrus terpene (an agro-industrial by-product). This is among the highest concentrations already reported for this product. CONCLUSIONS: This is the first report on the biotransformation of these terpenes by Colletotrichum spp. and the biotransformation of limonene to limonene-1,2-diol possibly involves enzymes similar to those found in Grosmannia clavigera. PMID- 29288354 TI - Functional characterization and substrate specificity analysis of Delta6 desaturase from marine microalga Isochrysis sp. AB - OBJECTIVES: To express a Delta6-desaturase gene and produce gamma-linolenic acid (GLA) and stearidonic acid (SDA) in prokaryotic expression system (Escherichia coli), and analyze its substrate specificity in the omega-3 fatty acid biosynthetic pathway. RESULTS: Full-length ORF (1448 bp) of Delta6Des-Iso was isolated from Isochrysis sp. and characterized using multiple sequence alignment, phylogenetic analysis, transmembrane domain, and protein tertiary structure. Delta6Des-Iso is a front-end desaturase consisting of three conserved histidine domains and a cytochrome b5 domain. Delta6Des-Iso was cloned and expressed in E. coli with the production of GLA and SDA. Recombinant E. coli utilized 27 and 8% of exogenously supplied alpha-linolenic acid (ALA) and linoleic acid (LA) to produce 6.3% of SDA and 2.3% of GLA, respectively, suggesting that isolated Delta6Des-Iso is specific to the omega-3 pathway. CONCLUSION: For the first time production of GLA and SDA in a prokaryotic system was achieved. PMID- 29288356 TI - Finding key nanoprecipitation variables for achieving uniform polymeric nanoparticles using neurofuzzy logic technology. AB - Nanoprecipitation is a simple and fast method to produce polymeric nanoparticles (Np); however, most applications require filtration or another separation technique to isolate the nanosuspension from aggregates or polydisperse particle production. In order to avoid variability introduced by these additional steps, we report here a systematic study of the process to yield monomodal and uniform Np production with the nanoprecipitation method. To further identify key variables and their interactions, we used artificial neural networks (ANN) to investigate the multiple variables which influence the process. In this work, a polymethacrylate derivative was used for Np (NpERS) and a database with several formulations and conditions was developed for the ANN model. The resulting ANN model had a high predictability (> 70%) for NpERS characteristics measured (mean size, PDI, zeta potential, and number of particle populations). Moreover, the model identified production variables leading to polymer supersaturation, such as mixing time and turbulence, as key in achieving monomodal and uniform NpERS in one production step. Polymer concentration and type of solvent, modifiers of polymer diffusion and supersaturation, were also shown to control NpERS characteristics. The ANN study allowed the identification of key variables and their interactions and resulted in a predictive model to study the NpERS production by nanoprecipitation. In turn, we have achieved an optimized method to yield uniform NpERS which could pave way for polymeric nanoparticle production methods with potential in biological and drug delivery applications. PMID- 29288355 TI - UCS protein function is partially restored in the Saccharomyces cerevisiae she4 mutant with expression of the human UNC45-GC, but not UNC45-SM. AB - A dedicated UNC45, Cro1, She4 (UCS) domain-containing protein assists in the Hsp90-mediated folding of the myosin head. Only weak sequence conservation exists between the single UCS protein of simple eukaryotes (She4 in budding yeast) and the two UCS proteins of higher organisms (the general cell and striated muscle UNC45s; UNC45-GC and UNC45-SM, respectively). In vertebrates, UNC45-GC facilitates cytoskeletal functions, whereas the 55% identical UNC45-SM assists assembly of the contractile apparatus of cardiac and skeletal muscles. A Saccharomyces cerevisiae she4Delta mutant, totally lacking any UCS protein, was engineered to express as its sole Hsp90 either the Hsp90alpha or the Hsp90beta isoforms of human cytosolic Hsp90. A transient induction of the human UNC45-GC, but not UNC45-SM, could rescue the defective endocytosis in these she4Delta cells at 39 degrees C, irrespective of whether they possessed Hsp90alpha or Hsp90beta. UNC45-GC-mediated rescue of the localisation of a Myo5-green fluorescent protein (GFP) fusion to cortical patches at 39 degrees C was more efficient in the yeast containing Hsp90alpha, though this may relate to more efficient functioning of Hsp90alpha as compared to Hsp90beta in these strains. Furthermore, inducible expression of UNC45-GC, but not UNC45-SM, could partially rescue survival at a more extreme temperature (45 degrees C) that normally causes she4Delta mutant yeast cells to lyse. The results indicate that UCS protein function has been most conserved-yeast to man-in the UNC45-GC, not UNC45-SM. This may reflect UNC45-GC being the vertebrate UCS protein that assists formation of the actomyosin complexes needed for cytokinesis, cell morphological change, and organelle trafficking-events also facilitated by the myosins in yeast. PMID- 29288357 TI - Corneal delivery of besifloxacin using rapidly dissolving polymeric microneedles. AB - Penetration of antibiotics into and through the cornea is a major limiting factor in the treatment of ocular infections. Several strategies are in vogue to overcome this limitation such as use of fortified drops, gels, and subconjunctival injections. Here, we present the fabrication of rapidly dissolving polymeric microneedle array to effectively deliver besifloxacin through the cornea. Microneedles were prepared using polyvinyl alcohol and polyvinyl pyrrolidone by the micromolding technique. The model fluoroquinolone antibiotic, besifloxacin, was loaded in 36 microneedles arranged in a 6 * 6 array format within a 1 cm2 area. The average height and base width of microneedles was 961 +/- 27 and 366 +/- 16 MUm, respectively. Each microneedle array contained 103.4 +/- 8.5 MUg of besifloxacin. Cryosectioning and confocal microscopy of excised human cornea revealed that microneedles penetrated to a depth of up to 200 MUm. Microneedles were found to completely dissolve in the cornea within 5 min. Application of microneedles for 5 min significantly (p < 0.05) improved the besifloxacin deposition and permeation through the cornea compared with free besifloxacin solution. Similarly, besifloxacin-loaded microneedles showed greater antibacterial activity in Staphylococcus aureus-infected cornea in comparison to free besifloxacin solution. Taken together, rapidly dissolving microneedles can be developed to effectively deliver besifloxacin to treat bacterial infections in the cornea and eye. PMID- 29288358 TI - An update on coating/manufacturing techniques of microneedles. AB - Recently, results have been published for the first successful phase I human clinical trial investigating the use of dissolving polymeric microneedles... Even so, further clinical development represents an important hurdle that remains in the translation of microneedle technology to approved products. Specifically, the potential for accumulation of polymer within the skin upon repeated application of dissolving and coated microneedles, combined with a lack of safety data in humans, predicates a need for further clinical investigation. Polymers are an important consideration for microneedle technology-from both manufacturing and drug delivery perspectives. The use of polymers enables a tunable delivery strategy, but the scalability of conventional manufacturing techniques could arguably benefit from further optimization. Micromolding has been suggested in the literature as a commercially viable means to mass production of both dissolving and swellable microneedles. However, the reliance on master molds, which are commonly manufactured using resource intensive microelectronics industry-derived processes, imparts notable material and design limitations. Further, the inherently multi-step filling and handling processes associated with micromolding are typically batch processes, which can be challenging to scale up. Similarly, conventional microneedle coating processes often follow step-wise batch processing. Recent developments in microneedle coating and manufacturing techniques are highlighted, including micromilling, atomized spraying, inkjet printing, drawing lithography, droplet-born air blowing, electro-drawing, continuous liquid interface production, 3D printing, and polyelectrolyte multilayer coating. This review provides an analysis of papers reporting on potentially scalable production techniques for the coating and manufacturing of microneedles. PMID- 29288360 TI - Higher phylogenetic diversity prevents loss of functional diversity caused by successive drying and rewetting cycles. AB - Microbial communities regulate nutrient cycling in soil, thus the impact of climate change on the structure and function of these communities can cause an imbalance of nutrients in the environment. Structural and functional changes of soil bacterial communities in two contrasting biomes in Brazil, the Atlantic Forest and the Tropical Dry Forest (Caatinga), were studied by simulating, in microcosms, rainfall and drought events. Soil samples were collected in three Brazilian states: Bahia, Pernambuco and Sao Paulo, in a total of four sampling sites. Analysis of 16S rRNA amplicon libraries revealed changes in microbial communities after three drying-rewetting cycles (60-30% water holding capacity). Alpha diversity indexes were obtained for bacterial communities, as well as the functional diversity index (Shannon) based on the activity of the following enzymes: acid and alkaline phosphatase, arylsulfatase, dehydrogenase, cellulase, amylase, urease and phytase. In general, the soils of Caatinga showed a decrease in the diversity indexes studied, conversely, however, the soils of Atlantic Forest were found to be more resistant during the drying-rewetting cycles. Functional diversity was significantly different for the two biomes, with a decrease in Caatinga soils, while Atlantic Forest samples demonstrated a greater stability of enzymatic activity. Further, the Atlantic Forest samples showed more resistance when compared to samples from Caatinga. The results found in this study have confirmed the hypothesis that biomes, independent of climate, when subjected to successive events of drought and rewetting exhibit structural and metabolic changes. PMID- 29288359 TI - Nano-formulation for topical treatment of precancerous lesions: skin penetration, in vitro, and in vivo toxicological evaluation. AB - With the aim of improving the topical delivery of the antineoplastic drug 5 fluorouracil (5FU), it was loaded into ultradeformable liposomes composed of soy phosphatidylcholine and sodium cholate (UDL-5FU). The liposome populations had a mean size of 70 nm without significant changes in 56 days, and the ultradeformable formulations were up to 324-fold more elastic than conventional liposomes. The interaction between 5FU and the liposomal membrane was studied by three methods, and also release profile was obtained. UDL-5FU did penetrate the stratum corneum of human skin. At in vitro experiments, the formulation was more toxic on a human melanoma-derived than on a human keratinocyte-derived cell line. Cells captured liposomes by metabolically active processes. In vivo toxicity experiments were carried out in zebrafish (Danio rerio) larvae by studying the swimming activity, morphological changes, and alterations in the heart rate after incubation. UDL-5FU was more toxic than free 5FU. Therefore, this nano formulation could be useful for topical application in deep skin precancerous lesions with advantages over current treatments. This is the first work that assessed the induction of apoptosis, skin penetration in a Saarbrucken penetration model, and the toxicological effects in vivo of an ultradeformable 5FU-loaded formulation. PMID- 29288361 TI - Genome sequence and comparative analysis of Jiangella alba YIM 61503T isolated from a medicinal plant Maytenus austroyunnanensis. AB - A draft genome sequence of Jiangella alba YIM 61503T revealed a genome size of 7,664,864 bp arranged in 33 scaffolds. The genome was predicted to contain 7196 predicted genes, including 51 coding for RNA. Phylogenetic and comparative analyses of the draft genome of J. alba YIM 61503T with the available genomes of other Jiangella species suggested a proximal similarity between strains J. alba YIM 61503T and J. muralis DSM 45357T, while indicating a high divergence between J. gansuensis YIM 002T and other Jiangella species. The genome of J. alba YIM 61503T also revealed genes involved in indole-3-acetic acid biosynthesis and an alkylresorcinols gene cluster. Further, detection of phosphotransferase genes in the genome of all Jiangella species indicated that they can uptake and phosphorylate sugars. The presences of TreX-Z, TreS and OtsA-OtsB genes in some of the Jiangella strains also indicated a possible mechanism for their tolerance of high salinity. Besides providing new insights into its genetic features, our results suggested that J. alba YIM 61503T could be a potential strain for further genome mining studies. The release of this genome may, therefore, provide a better prospect for understanding "evolutionary taxonomy" about this genus in future. PMID- 29288362 TI - Identification of genes highly downregulated in pancreatic cancer through a meta analysis of microarray datasets: implications for discovery of novel tumor suppressor genes and therapeutic targets. AB - PURPOSE: The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a 5-year survival rate of about 7%. Recent failures of targeted therapies inhibiting kinase activity in clinical trials have highlighted the need for new approaches towards combating this deadly disease. METHODS: In this study, we have identified genes that are significantly downregulated in PC, through a meta-analysis of large number of microarray datasets. We have used qRT-PCR to confirm the downregulation of selected genes in a panel of PC cell lines. RESULTS: This study has yielded several novel candidate tumor-suppressor genes (TSGs) including GNMT, CEL, PLA2G1B and SERPINI2. We highlight the role of GNMT, a methyl transferase associated with the methylation potential of the cell, and CEL, a lipase, as potential therapeutic targets. We have uncovered genetic links to risk factors associated with PC such as smoking and obesity. Genes important for patient survival and prognosis are also discussed, and we confirm the dysregulation of metabolic pathways previously observed in PC. CONCLUSIONS: While many of the genes downregulated in our dataset are associated with protein products normally produced by the pancreas for excretion, we have uncovered some genes whose downregulation appear to play a more causal role in PC. These genes will assist in providing a better understanding of the disease etiology of PC, and in the search for new therapeutic targets and biomarkers. PMID- 29288364 TI - MiRNA signature predicts the response of patients with advanced lung adenocarcinoma to platinum-based treatment. AB - BACKGROUND: Accumulating literature proved that miRNAs can regulate the sensitivity of platinum and act as a promising candidate to predict the response of patients with lung adenocarcinoma to chemotherapy. However, most studies on miRNAs were restricted to in vitro experiments. This study aimed to evaluate whether miRNAs alone or in combination (miRNA signature) can act as predictive biomarkers of platinum-based chemotherapy in patients with lung adenocarcinoma. METHODS: Eight miRNAs that most probably predict the efficacy of platinum were screened in 111 tumor tissues of lung adenocarcinoma. Univariate and multivariate Cox analyses, Kaplan-Meier survival curve analysis, Chi-square test, and univariate and multivariate logistic regression analyses were employed to determine whether miRNA expression is associated with the response of patients to platinum-based chemotherapy. The maximum significant odds ratio value was acquired by multiple cycles of multivariate logistic regression analysis. The cut off points of miRNAs were obtained. A miRNA chemo-sensibility index (CI) formula was established, and its prediction performance was confirmed in another independent set (n = 31). RESULTS: Underexpression of three miRNAs (miRNA-21, miRNA-125b, and miRNA-224) was independently associated with the chemotherapy sensitivity of patients with lung adenocarcinoma. The miRNA CI formula containing these three miRNAs was calculated as (1.364 * miR-21) + (1.323 * miR-125b) + (1.131 * miR-224). A high CI was related to platinum-based chemotherapy resistance, and its prediction performance was confirmed in the testing set. The MAPK, PI3K-Akt, Ras, and cGMP-PKG signaling pathways were considered to be most probably correlated with platinum resistance. CONCLUSION: Our miRNA CI formula can act as an independent predictor to predict the response of patients with lung adenocarcinoma to platinum-based chemotherapy. PMID- 29288366 TI - De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype. AB - Breast cancer molecular subtypes, categorized jointly by hormone receptors (HR) and human epidermal growth factor-2 (HER2), are utilized to guide systemic therapy. We hypothesized distinct patterns of de novo metastasis and overall survival by molecular subtype using a retrospective cohort of 399,772 women in the National Cancer Database diagnosed with first primary invasive breast cancer between 2010 and 2014, of whom 13,924 were diagnosed with de novo metastasis from 2010 to 2013 and had follow up data. The relationship of molecular subtype with patient and tumor characteristics, including site of de novo metastasis, were examined using Chi-squared tests. Kaplan-Meier and Cox proportional hazards analyses were used to examine overall survival by molecular subtype. Bone was the most frequent de novo metastatic site for all molecular subtypes. Compared to HR+/HER2-, patients with HR-/HER2+ experienced 4.5, 3.0, and 6.0 times the de novo brain, lung, and liver metastasis respectively. In survival analyses of women diagnosed with de novo metastasis, the mortality risk relative to HR+/HER2- was twice as high for triple-negative (hazard ratio = 2.02, 95% CI 1.89-2.16) and modestly lower for HR+/HER2+ (hazard ratio = 0.83, 95% CI 0.78-0.88). The median survival difference between metastatic patients with and without chemotherapy was 28.6 months in HR+/HER2+ and 28.2 months in HR-/HER2+, but only 10.9 months in triple-negative and 5.2 months in HR+/HER2-. In conclusion, despite unfavorable patterns of de novo metastasis, HER2+ breast cancers had relatively better survival in recent years, probably due to treatment differences. Utilizing molecular subtype and site of de novo metastasis may predict prognosis and guide treatment. PMID- 29288365 TI - Methylphenidate disrupts cytoskeletal homeostasis and reduces membrane-associated lipid content in juvenile rat hippocampus. AB - Although methylphenidate (MPH) is ubiquitously prescribed to children and adolescents, the consequences of chronic utilization of this psychostimulant are poorly understood. In this study, we investigated the effects of MPH on cytoskeletal homeostasis and lipid content in rat hippocampus. Wistar rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 44th day of age. Results showed that MPH provoked hypophosphorylation of glial fibrillary acidic protein (GFAP) and reduced its immunocontent. Middle and high molecular weight neurofilament subunits (NF-M, NF-H) were hypophosphorylated by MPH on KSP repeat tail domains, while NFL, NFM and NFH immunocontents were not altered. MPH increased protein phosphatase 1 (PP1) and 2A (PP2A) immunocontents. MPH also decreased the total content of ganglioside and phospholipid, as well as the main brain gangliosides (GM1, GD1a, and GD1b) and the major brain phospholipids (sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). Total cholesterol content was also reduced in the hippocampi of juvenile rats treated with MPH. These results provide evidence that disruptions of cytoskeletal and lipid homeostasis in hippocampus of juvenile rats are triggers by chronic MPH treatment and present a new basis for understanding the effects and consequences associated with chronic use of this psychostimulant during the development of the central nervous system. PMID- 29288363 TI - Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin beta1/ Src signaling in triple negative breast cancer cells. AB - Autophagy is a catabolic process for degrading dysfunctional proteins and organelles, and closely associated with cancer cell survival under therapeutic, metabolic stress, hypoxia, starvation and lack of growth factors, contributing to resistance to therapies. However, the role of autophagy in breast cancer cells is not well understood. In the present study, we investigated the role of autophagy in highly aggressive and metastatic triple negative breast cancer (TNBC) and non metastatic breast cancer cells and demonstrated that the knockdown of autophagy related genes (LC3 and Beclin-1) inhibited autophagy and significantly suppressed cell proliferation, colony formation, migration/invasion and induced apoptosis in MDA-MB-231 and BT-549 TNBC cells. Knockdown of LC3 and Beclin-1 led to inhibition of multiple proto-oncogenic signaling pathways, including cyclin D1, uPAR/integrin-beta1/Src, and PARP1. In conclusion, our study suggests that LC3 and Beclin-1 are required for cell proliferation, survival, migration and invasion, and may contribute to tumor growth and progression of highly aggressive and metastatic TNBC cells and therapeutic targeting of autophagy genes may be a potential therapeutic strategy for TNBC in breast cancer. PMID- 29288367 TI - Antimicrobial resistance and antibiotic stewardship programs in the ICU: insistence and persistence in the fight against resistance. A position statement from ESICM/ESCMID/WAAAR round table on multi-drug resistance. AB - Antimicrobial resistance (AMR) is a clear and present danger to patients in any intensive care unit (ICU) around the world. Whereas AMR may affect any patient in the hospital, patients in the ICU are particularly at risk of acquiring AMR infections due to the intensity of the treatment, use of invasive devices, increased risk of transmission and exposure to antibiotics. AMR is present in every ICU, although prevalence is geographically different and AMR pathogens encountered are variable. Intensive care and infectious disease specialists from the European Society of Intensive Care Medicine, European Society of Microbiology and Infectious Diseases and World Alliance Against Antimicrobial Resistance, united in the ANTARCTICA (Antimicrobial Resistance in Critical Care) coalition, call for increased awareness and action among health care professionals to reduce AMR development in critically ill patients, to improve treatment of AMR infections and to coordinate scientific research in this high-risk patient population. Close collaboration with other specialties, and combining these and other interventions in antibiotic stewardship programmes should be a priority in every ICU. Considerate antibiotic use and adopting strict infection control practices to halt AMR remains a responsibility shared by all healthcare workers, from physicians to maintenance personnel, from nurses to physiotherapists, from consultants to medical students. Together, we can reduce AMR in our ICUs and continue to treat our patients effectively. PMID- 29288369 TI - Assessment of cardiovascular risk profile based on measurement of tophus volume in patients with gout. AB - Hyperuricemia and gout are associated with increased risk of cardiovascular disease and metabolic syndrome. The aim of this study was to evaluate the correlation of total tophus volumes, measured using dual-energy computed tomography, with cardiovascular risk and the presence of metabolic syndrome. Dual energy computed tomography datasets from 91 patients with a diagnosis of gout were analyzed retrospectively. Patients who received urate lowering therapy were excluded to avoid the effect on tophus volume. The total volumes of tophaceous deposition were quantified using automated volume assessment software. The 10 year cardiovascular risk using the Framingham Risk Score and metabolic syndrome based on the Third Adult Treatment Panel criteria were estimated. Fifty-five and 36 patients with positive and negative dual-energy computed tomography results, respectively, were assessed. Patients with positive dual-energy computed tomography results showed significantly higher systolic blood pressure, diastolic blood pressure, fasting glucose, and higher prevalence of chronic kidney disease, compared with those with negative dual-energy computed tomography results. The total tophus volumes were significantly correlated with the Framingham Risk Score, and the number of metabolic syndrome components (r = 0.22 and p = 0.036 and r = 0.373 and p < 0.001, respectively). The total tophus volume was one of the independent prognostic factors for the Framingham Risk Score in a multivariate analysis. This study showed the correlation of total tophus volumes with cardiovascular risk and metabolic syndrome-related comorbidities. A high urate burden could affect unfavorable cardiovascular profiles. PMID- 29288370 TI - Letermovir: First Global Approval. AB - Letermovir (PrevymisTM) is an orally or intravenously administered cytomegalovirus (CMV) DNA terminase complex inhibitor being developed by Merck & Co., Inc., under a global license from AiCuris Anti-infective Cures GmbH. Letermovir has been approved in Canada and the USA for the prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic haematopoietic stem cell transplant (HSCT). In addition, letermovir has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use, and is under review in several countries, including Japan. This article summarizes the milestones in the development of letermovir leading to its first global approval in Canada as well as the USA for the prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic HSCT. PMID- 29288368 TI - Single nucleotide polymorphism of Methyl-CpG-binding protein 2 gene associates with juvenile idiopathic arthritis. AB - Methyl-CpG-binding protein 2 (MeCP2) is a transcription suppressor or activator, acting through binding to methylated DNA. Numerous investigations have established a role for methylation aberrancies in the pathogenesis of autoimmune disorders. Single nucleotide polymorphisms (SNPs) in MECP2 gene have been implicated with susceptibility to rheumatoid arthritis (RA). Here, the plausible association of MECP2 gene polymorphisms was evaluated with juvenile idiopathic arthritis (JIA) predisposition in Iranian pediatric patients. In this case control association study, 49 JIA patients and 398 age-, sex-, and ethnicity matched healthy individuals were included. Genotyping of all samples for MECP2 gene rs1734787, rs1734791, rs1734792, and rs17435 polymorphisms was conducted by real-time allelic discrimination PCR technique. Except the AT genotype of rs17435 SNP, none of the alleles and genotypes of other positions were distributed significantly between JIA cases and controls. AT genotype was less frequent in JIA cases and was found to be protective genotype of JIA proneness (OR = 0.42; CI, 0.19-0.90; P = 0.028). Among the haplotypes, CCAA and TTTT were detected to have significant difference between cases and controls (OR = 1.74; CI, 1.01-2.98; P = 0.042 and OR = 1.82; CI, 1.05-3.13; P = 0.028). All positions were in linkage disequilibrium with each other according to D'. MECP2 gene rs17435 polymorphism was associated with JIA predisposition. Considering the involvement of genetic polymorphisms of MECP2 gene in susceptibility to adult-onset RA, this gene might basically play a role in the initiation of arthritis during early stages of life. PMID- 29288373 TI - Patient satisfaction with robotic surgery. AB - This study is a service evaluation of the robotic-assisted surgery service within the Gynaecology Oncology department at Sheffield Teaching Hospitals. The aim is not only to evaluate and improve this new service within the department, but also to add to the available literature that reviews patient satisfaction with robotic assisted surgery. An anonymous questionnaire was developed with questions taken from the NHS User Experience Survey Question Bank and additional questions in the same format specific to robotic-assisted surgery. This was posted to the first 140 patients to have undergone robotic-assisted surgery within Gynae Oncology at STH. One hundred completed questionnaires were returned. Over 90% of patients were pleased with the care that they received pre-operatively and felt that they have enough input into the decisions made about treatment. Half of patients (51%) reported having pain post-procedure, with a quarter of these patients experiencing severe pain. The majority of patients (72%) felt that their length of stay in hospital was of the right duration. Almost all patients (99%) were pleased with the overall care that they received and 91% would recommend robotic assisted surgery as a modality. Patients are very satisfied with the care that they receive when undergoing robotic-assisted surgery within Gynae Oncology at our center and the majority of patients would recommend robotic-assisted surgery as a modality. PMID- 29288371 TI - Exposure of pregnant sows to deoxynivalenol during 35-70 days of gestation does not affect pathomorphological and immunohistochemical properties of fetal organs. AB - In order to evaluate the influence of deoxynivalenol (DON) on histomorphological and immunohistochemical parameters in the development of porcine fetuses, five pregnant sows were fed a control diet (0.15 mg DON/kg diet) and seven sows a contaminated diet (4.42 mg DON/kg diet) between days 35 and 70 of gestation. On day 70, fetuses were delivered by caesarean section and sows and fetuses were euthanized. Tissue samples of three fetuses from each sow were collected, fixed in formalin, and processed routinely for light microscopy and immunohistochemistry. At necropsy, no macroscopic lesions were observed in any organ of the fetuses. Histomorphological, immunohistochemical, and morphometrical parameters of the immune system, liver, and intestinal tract were examined. The following antibodies were used in the liver, spleen, lymph nodes, thymus, gut, and bone marrow to compare control- and DON-treated animals: (I) CD3 and CD79a (T and B lymphocytes differentiation); (II) myeloid/histiocyte antigen 387 (MAC) (identification of macrophages); (III) Ki-67 Antigen (Ki-67) (proliferation marker); (IV) p-p-38 mitogen-activated protein kinases (p-p38 MAPK) as well as caspase-3 (cas3) and caspase-9 (cas9) (enzymes of apoptosis cascade); (V) tumor necrosis factor-alpha (TNFalpha) (immune-related protein). The results of the study show that exposure of pregnant sows with DON between gestation days 35 and 70 causes no pathomorphologically or immunohistochemically detectable alterations in all fetal organs examined. PMID- 29288372 TI - Robotic-assisted laparoscopic surgery for pediatric tumors: a bicenter experience. AB - Mini-invasive surgery is more and more integrated in pediatric surgery. The robotic-assisted surgery brought new advantages from which the patient and the surgeon could benefit compared to laparoscopy. Its use in oncological surgery is still controversial. 12 robotic-assisted tumor resections with the da Vinci Surgical Robot (Intuitive Surgical, Sunnyvale, CA) were attempted in 11 children (mean age 7.65 years; age range 0.75-16.75 years; mean weight 30.3 kg; weight range 8.6-62 kg) in two centers. Mean total operative time was 145 min (range 72 263 min). 1 procedure (8.3%) was converted. The pathology included renal tumors (n = 2; one nephroblastoma, one metanephric adenoma), adrenal tumors (n = 9; three neuroblastomas, two pheochromocytomas, two adrenocortical adenomas, one cystic lymphangioma, one paraganglioma) and a pancreatic tumor (n = 1; one pancreatic cyst). 4 tumors (33.3%) were malignant. Every patient underwent a R0 resection. 1 child (8.3%) developed a post operative complication. Mean length of hospitalization was 3.0 days (range 2-5 days). Followup averaged 3.3 years with no recurrence. All children are alive. Robot-assisted MIS seems to be safe and feasible in pediatric tumors. The oncological surgical principles were respected in our series with low morbi/mortality and good long-term results. Robotic surgery and its technical advantages bring potential benefits for children with cancer. It has a role to play in pediatric oncological surgery but its place and indications still need to be better defined. PMID- 29288374 TI - Maternal educational level and the risk of persistent post-partum glucose metabolism disorders in women with gestational diabetes mellitus. AB - AIMS: Gestational diabetes mellitus (GDM) occurs in 5-15% of pregnancies, and lower maternal educational attainment has been associated with higher risk of GDM. We aimed to determine if maternal education level is associated with persistent post-partum glucose metabolism disorders in women with GDM. METHODS: Retrospective cohort study of women with GDM followed in 25 Portuguese health institutions between 2008 and 2012. Educational attainment was categorised into four levels. Prevalence of post-partum glucose metabolism disorders (type 2 diabetes mellitus, increased fasting plasma glucose or impaired glucose tolerance) was compared and adjusted odds ratios calculated controlling for confounders using logistic regression. RESULTS: We included 4490 women diagnosed with GDM. Educational level ranged as follows: 6.8% (n = 307) were at level 1 (<= 6th grade), 34.6% (n = 1554) at level 2 (6-9th grade), 30.4% (n = 1364) at level 3 (10-12th grade) and 28.2% (n = 1265) at level 4 (>= university degree). At 6 weeks post-partum re-evaluation, 10.9% (n = 491) had persistent glucose metabolism disorders. Educational levels 1 and 2 had a higher probability of persistent post-partum glucose metabolism disorders when compared to level 4 (OR = 2.37 [1.69;3.32], p < 0.001 and OR = 1.39 [1.09;1.76], p = 0.008, for level 1 and 2, respectively), an association that persisted in multivariable logistic regression adjusting for confounders (level 1 OR = 2.25 [1.53;3.33], p < 0.001; level 2 OR = 1.43 [1.09;1.89], p = 0.01). CONCLUSIONS: Persistent post-partum glucose metabolism disorders are frequent in women with GDM and associated with lower maternal educational level. Interventions aimed at this risk group may contribute towards a decrease in prevalence of post-partum glucose metabolism disorders. PMID- 29288375 TI - Soluble programmed death-1 ligand 1(sPD-L1) is significantly reduced in the serum of type 1 diabetes patients. PMID- 29288376 TI - The optimum titanium precursor of fabricating TiO2 compact layer for perovskite solar cells. AB - Perovskite solar cells (PSCs) have attracted tremendous attentions due to its high performance and rapid efficiency promotion. Compact layer plays a crucial role in transferring electrons and blocking charge recombination between the perovskite layer and fluorine-doped tin oxide (FTO) in PSCs. In this study, compact TiO2 layers were synthesized by spin-coating method with three different titanium precursors, titanium diisopropoxide bis (acetylacetonate) (c-TTDB), titanium isopropoxide (c-TTIP), and tetrabutyl titanate (c-TBOT), respectively. Compared with the PSCs based on the widely used c-TTDB and c-TTIP, the device based on c-TBOT has significantly enhanced performance, including open-circuit voltage, short-circuit current density, fill factor, and hysteresis. The significant enhancement is ascribed to its excellent morphology, high conductivity and optical properties, fast charge transfer, and large recombination resistance. Thus, a power conversion efficiency (PCE) of 17.03% has been achieved for the solar cells based on c-TBOT. PMID- 29288377 TI - Outcomes of the Bryan cervical disc replacement: fifteen year follow-up. AB - BACKGROUND: The CTDR is a technique that treats cervical disc degenerative disease. Initial shorter-term studies showed good clinical and radiological results. PURPOSE: To assess the clinical and radiological results of Bryan cervical disc replacement (Medtronic Sofamor Danek Inc., Memphis, TN) at 15-year follow-up. RESULTS: This prospective study included 20 patients who underwent 22 CTDR, comprising a single-level procedure in 14 patients and two-level procedures in six patients. The mean follow-up period was 15.5 years. The mean age at the intervention was 46.2 years (range: 26-65 years). Two patients needed re operation for recurrence of symptoms. According to Odom's criteria, 80.0% (16 of 20 patients) had excellent outcomes, VAS for neck pain was 2.6 (0-10), for shoulder/arm pain it was 1.8 (0-7), and NDI at the final follow up was 14.9. The SF-12 PCS was 46.1, and SF-12 MCS was 51.9. Mobility was maintained in 15 of the 22 (68.2%) operated segments, range of motion (ROM) of prostheses were 9 degrees +/- 3.9 degrees (range 4-15 degrees ). The prostheses were positioned in kyphosis in 14 of 22 levels (63.6%). There was a positive correlation between the kyphosis of the prosthesis and the occurrence of heterotopic ossification (HO), and their grade (rho = 0.36, CI 95%[-0.68; 0.07]). HO had developed at 12 of the 22 levels (54.5%) and upper adjacent segment degeneration in 11 of 18 of patients (64.7%). All these results were not significantly different to outcomes at 8 years follow-up. CONCLUSION: In a cohort of 20 patients with 15-year clinical and radiological follow-up, the Bryan CTDR has demonstrated a sustained clinical improvement and implant mobility over time, despite a moderate progression of degenerative processes at the prosthetic and adjacent levels. PMID- 29288378 TI - Management of elbow stiffness after postoperative treatment of terrible triad elbow injury: maintaining mobility and stability using a combined protocol. AB - PURPOSES: The purpose of this study was to evaluate the results of our protocol that include the restoration of mobility using open release combined with external fixation and stability using ligament repair, to determine the optimal timing of surgery, and to investigate whether resection and replacement of the radial head are associated with different outcomes. METHODS: Twenty-six patients with elbow stiffness after operation of terrible triad injury of the elbow were treated with our protocol. We assessed the optimal timing of the operation by comparing outcomes between the early treatment group and the delayed treatment group. The comparison was performed to investigate whether the results differed between resection and replacement of the radial head. Stability of the elbow, range of motion (ROM), Mayo Elbow Performance Score (MEPS), and complications were assessed for each patient. RESULTS: The mean interval from the initial surgery to the index procedure was 13 months, and the mean follow-up period was 29 months. The MEPS increased from a mean of 65 points to 94 points. Twenty-five of 26 patients achieved stability of the elbow, and all patients achieved functional ROM. There were no significant differences between the two subgroups with respect to ROM and stability of the elbow. CONCLUSION: Our protocol can restore mobility and stability. Resection and replacement of the radial head are both feasible using this protocol. Lastly, the timing of the surgery was not very rigorous, and the surgical delay may be insignificant. LEVEL OF EVIDENCE: Level IV; Case Series; Treatment Study. PMID- 29288379 TI - A New radiographic feature of lower lumbar disc herniation in young patients. AB - PURPOSE: In our study, we assessed the condition of the lumbar laminae defect of L5, other than the defect of spina bifida, in a group of different ages with lower lumbar disc herniation (LDH). We hypothesize that the laminae defect of L5 may be a radiographic feature in young patients with lower LDH. METHODS: We analyzed the features of the laminae of L5 from the anteroposterior X-rays of the lumbosacral spine in 342 patients suffering from lower LDH. The patients were divided into three groups depending on age: age <45 (group A), 45 <= age <= 59 (group B) and age>59 (group C). The width of the unilateral laminae of L5 was measured by drawing a line named "a" from the upper margin to the lower margin. Then the line "a" was extended downward to the bottom of the laminae interval space to perform a new line named "b". We assessed the condition of the laminae defect of L5 using the ratio "a/b" in each group. RESULTS: The average ratio "a/b" in each group was: 0.47 +/- 0.06 in group A, 0.51 +/- 0.06 in group B, and 0.52 +/- 0.06 in group C. The average ratio "a/b" of group A was significantly smaller than group B and group C (P<0.05). However, there was no statistical difference of the average ratio "a/b" between group B and group C (P>0.05). CONCLUSIONS: Laminae defects of L5 may be a congenitally potential risk factor leading to lower LDH in the young and this radiographic clue could be used for the diagnosis of symptomatic lower LDH patients. For asymptomatic people who encounter this radiographic feature, preventive advice could be provided. PMID- 29288380 TI - Knowledge and attitude towards total knee arthroplasty among the public in Saudi Arabia: a nationwide population-based study. AB - PURPOSE: Studies on total knee arthroplasty (TKA) in Saudi Arabia are scarce, and none have reported the knowledge and attitude of the procedure in Saudi Arabia. Our study aims to measure the knowledge and attitude of TKA among the adult Saudi population. METHODS: To encompass a representative sample of this cross-sectional survey, all 13 administrative areas were used as ready-made geographical clusters. For each cluster, stratified random sampling was performed to maximize participation in the study. In each area, random samples of mobile phone numbers were selected with a probability proportional to the administrative area population size. Sample size calculation was based on the assumption that 50% of the participants would have some level of knowledge, with a 2% margin of error and 95% confidence level. To reach our intended sample size of 1540, we contacted 1722 participants with a response rate of 89.4%. RESULTS: The expected percentage of public knowledge was 50%; however, the actual percentage revealed by this study was much lower (29.7%). A stepwise multiple logistic regression was used to assess the factors that positively affected the knowledge score regarding TKA. Age [P = 0.016 with OR of 0.47], higher income [P = 0.001 with OR of 0.52] and participants with a positive history of TKA or that have known someone who underwent the surgery [P < 0.001 with OR of 0.15] had a positive impact on the total knowledge score. CONCLUSIONS: There are still misconceptions among the public in Saudi Arabia concerning TKA, its indications and results. We recommend that doctors use the results of our survey to assess their conversations with their patients, and to determine whether the results of the procedure are adequately clarified. PMID- 29288382 TI - Safety and Feasibility of Single-Port Sleeve Gastrectomy Following Liver Transplantation. PMID- 29288383 TI - Transcription Factors Regulating Embryonic Development of Pulmonary Vasculature. AB - Lung morphogenesis is a highly orchestrated process beginning with the appearance of lung buds on approximately embryonic day 9.5 in the mouse. Endodermally derived epithelial cells of the primitive lung buds undergo branching morphogenesis to generate the tree-like network of epithelial-lined tubules. The pulmonary vasculature develops in close proximity to epithelial progenitor cells in a process that is regulated by interactions between the developing epithelium and underlying mesenchyme. Studies in transgenic and knockout mouse models demonstrate that normal lung morphogenesis requires coordinated interactions between cells lining the tubules, which end in peripheral saccules, juxtaposed to an extensive network of capillaries. Multiple growth factors, microRNAs, transcription factors, and their associated signaling cascades regulate cellular proliferation, migration, survival, and differentiation during formation of the peripheral lung. Dysregulation of signaling events caused by gene mutations, teratogens, or premature birth causes severe congenital and acquired lung diseases in which normal alveolar architecture and the pulmonary capillary network are disrupted. Herein, we review scientific progress regarding signaling and transcriptional mechanisms regulating the development of pulmonary vasculature during lung morphogenesis. PMID- 29288384 TI - Comparative View of Lung Vascular Endothelium of Cattle, Horses, and Water Buffalo. AB - Endothelium plays an important role in maintaining the vascular barrier and physiological homeostasis. Endothelium also is fundamental to the initiation and regulation of inflammation. Endothelium demonstrates phenotypic and functional heterogeneity not only among various organs but also within an organ. One of the striking examples would be the pulmonary endothelium that participates in creating blood-air barrier. Endothelium in large pulmonary blood vessels is distinct in structure and function from that lining of the pulmonary capillaries. This chapter focuses on the comparative aspects of pulmonary endothelium and highlight unique differences such as the presence of pulmonary intravascular macrophages among select species. PMID- 29288381 TI - Modulation of the IL-23/IL-17 axis by fenofibrate ameliorates the ovalbumin/lipopolysaccharide-induced airway inflammation and bronchial asthma in rats. AB - The overlapping between asthmatic subtypes, including both CD4+ T helper (TH)2 and TH17 cells, is found in the natural course of allergic asthma, especially in exacerbations and severe and insensitive forms to steroids, which are in need of new molecular therapies. In the TH2-subset mediated asthma, fenofibrate displays therapeutic promises, besides evidenced therapeutic effects on TH17-mediated colitis and myocarditis. Therefore, the effects of fenofibrate versus dexamethasone on IL-23/IL-17 axis in ovalbumin (OVA)/lipopolysaccharide (LPS) induced airway inflammation and bronchial asthma in rats were explored. The OVA/LPS sensitization and challenge were performed for 28 days in male Wistar rats. After sensitization, fenofibrate (100 mg/kg/day) or dexamethasone (2.5 mg/kg/day) was orally administered from the day 15 to 28. Either fenofibrate or dexamethasone attenuated the severity of OVA/LPS-induced airway inflammation and bronchial asthma through significant ameliorations in the total serum immunoglobulin (Ig)E assay; the total and differential leukocytic counts in the bronchoalveolar lavage (BAL) fluid; the lung inflammatory cytokines such as interleukin (IL)-4, IL-13, IL-17, and IL-23, transforming growth factor (TGF) beta1, and tumor necrosis factor(TNF)-alpha levels; and the lung IL-17 and IL-23 expressions. In addition to the reduction in the inflammatory and fibrotic histopathological scores, fenofibrate significantly ameliorated the BAL neutrophilic count and the lung IL-17 and IL-23 expressions in comparison to dexamethasone. The suppression of IL-23/IL-17 axis could be considered a molecular therapeutic target for fenofibrate in OVA/LPS-induced airway inflammation and bronchial asthma. Combined therapeutic regimens of fenofibrate and steroids should be furtherly investigated in severe and resistant asthma. PMID- 29288385 TI - The Pulmonary Vascular Barrier: Insights into Structure, Function, and Regulatory Mechanisms. AB - Pulmonary blood vessels act as a well-regulated barrier to the flux of fluid and solutes between the lumen and the air space. Perturbation of the barrier function results in excessive fluid leak into the interstitium and alveoli, and impairs gas exchange. Recent studies provide deeper insight into the precise control mechanisms involved in the regulation of the barrier. This chapter will highlight these mechanisms and discuss the current understanding on the fluid and solute transport pathways across the vascular endothelial layer. In addition, the chapter summarizes the contributions of extra-endothelial structures such as pericytes and glycocalyx in regulating fluid flux across pulmonary vessels. The chapter concludes with an analysis on the impact of pulmonary endothelial heterogeneity and experimental models on current interpretations of barrier function and regulatory mechanisms. PMID- 29288387 TI - A Novel Group-Fused Sparse Partial Correlation Method for Simultaneous Estimation of Functional Networks in Group Comparison Studies. AB - The conventional way to estimate functional networks is primarily based on Pearson correlation along with classic Fisher Z test. In general, networks are usually calculated at the individual-level and subsequently aggregated to obtain group-level networks. However, such estimated networks are inevitably affected by the inherent large inter-subject variability. A joint graphical model with Stability Selection (JGMSS) method was recently shown to effectively reduce inter subject variability, mainly caused by confounding variations, by simultaneously estimating individual-level networks from a group. However, its benefits might be compromised when two groups are being compared, given that JGMSS is blinded to other groups when it is applied to estimate networks from a given group. We propose a novel method for robustly estimating networks from two groups by using group-fused multiple graphical-lasso combined with stability selection, named GMGLASS. Specifically, by simultaneously estimating similar within-group networks and between-group difference, it is possible to address inter-subject variability of estimated individual networks inherently related with existing methods such as Fisher Z test, and issues related to JGMSS ignoring between-group information in group comparisons. To evaluate the performance of GMGLASS in terms of a few key network metrics, as well as to compare with JGMSS and Fisher Z test, they are applied to both simulated and in vivo data. As a method aiming for group comparison studies, our study involves two groups for each case, i.e., normal control and patient groups; for in vivo data, we focus on a group of patients with right mesial temporal lobe epilepsy. PMID- 29288386 TI - Pulmonary Endothelial Cell Apoptosis in Emphysema and Acute Lung Injury. AB - Apoptosis plays an essential role in homeostasis and pathogenesis of a variety of human diseases. Endothelial cells are exposed to various environmental and internal stress and endothelial apoptosis is a pathophysiological consequence of these stimuli. Pulmonary endothelial cell apoptosis initiates or contributes to progression of a number of lung diseases. This chapter will focus on the current understanding of the role of pulmonary endothelial cell apoptosis in the development of emphysema and acute lung injury (ALI) and the factors controlling pulmonary endothelial life and death. PMID- 29288388 TI - Correction to: Expanding the genetic heterogeneity of intellectual disability. AB - Variant nomenclature discrepancy was identified in the article. PMID- 29288390 TI - Body image and psychological distress in women with breast cancer: a French online survey on patients' perceptions and expectations. AB - BACKGROUND: Altered body image caused by alopecia, loss of eyebrows or eyelashes, or mastectomy is a major source of psychological distress in women with breast cancer. OBJECTIVE: To identify and to assess patients' perceptions and expectations regarding altered body image. METHOD: Opinion survey conducted among patients treated for breast cancer and member of French online support groups. Anonymous online self-administered survey sent to women with breast cancer. RESULTS: 85% of the women interviewed experienced alopecia during treatment and 67% of them loss of eyebrows or eyelashes. About half of patients suffering alopecia and loss of eyebrows or eyelashes reported fearing what others think. Mastectomy was experienced by 84% of the women in our study, but only 32% of them reported fearing what others think. 87% of our study cohort received information about the possibility of adverse events. 70, 56, and 60% of women felt helped by information they received for the management of alopecia, loss of eyebrows or eyelashes, or mastectomy, respectively. CONCLUSION: This study confirms that altered body image is a critical psychosocial issue for women with breast cancer. Effective information can be a source of reassurance and may constitute one of the most important sources of emotional support. PMID- 29288389 TI - Principles and methods of in-silico prioritization of non-coding regulatory variants. AB - Over a decade of genome-wide association, studies have made great strides toward the detection of genes and genetic mechanisms underlying complex traits. However, the majority of associated loci reside in non-coding regions that are functionally uncharacterized in general. Now, the availability of large-scale tissue and cell type-specific transcriptome and epigenome data enables us to elucidate how non-coding genetic variants can affect gene expressions and are associated with phenotypic changes. Here, we provide an overview of this emerging field in human genomics, summarizing available data resources and state-of-the art analytic methods to facilitate in-silico prioritization of non-coding regulatory mutations. We also highlight the limitations of current approaches and discuss the direction of much-needed future research. PMID- 29288391 TI - The Levels and Potential Carcinogenic Risks of PAHs in Liaohe Estuarine Reed Wetland Soils. AB - Sixteen polycyclic aromatic hydrocarbons (PAHs) were quantified by GC/MS in 30 soil samples of Liaohe estuarine reed wetland. The total concentrations of 16 PAHs ranged from 235 to 374 ng g-1, and seven carcinogenic PAHs concentrations were in the range of 83-109 ng g-1. A probabilistic carcinogenic potential for three age groups (including children, teenagers, and adults) exposed to soil PAHs via three pathways was quantitatively calculated based on Monte Carlo simulations. The 95th percentiles carcinogenic risks of PAHs for children, teenagers, and adults were 7.80 * 10-8, 4.03 * 10-8, and 1.14 * 10-7, respectively. The carcinogenic risk levels were all below 10-6, indicating no potential for cancer development. Dermal contact and accident ingestion of soil were the dominant exposure pathways to soil PAHs. BaP and DBahA were the major contributors to carcinogenic risk in this study. Sensitivity analysis demonstrated that exposure duration and PAH concentrations in soil were the key exposure parameters in calculating carcinogenic risk. Results from this study will provide valuable information for potential scientific evaluation and prevention for carcinogenic risk exposed to soil PAHs. PMID- 29288392 TI - A counterforce to diversion of cerebrospinal fluid during ventriculoperitoneal shunting: the intraperitoneal pressure. An observational study. AB - BACKGROUND: Intraperitoneal pressure (IPP) counteracts the diversion of cerebrospinal fluid (CSF) from the cranial to the peritoneal compartment during ventriculoperitoneal shunting. Animal studies suggest that the intrinsic IPP exceeds the intraperitoneal hydrostatic pressure. The intrinsic IPP in mobile patients is relevant for shunt therapy, but data about it is not available. METHODS: The IPP was measured indirectly in 25 mobile subjects (13 female) by applying a standard intravesical pressure measurement technique. Measurements were carried out in reference to the navel (supine position) and the xiphoid (upright position). Results were adjusted for the intraperitoneal hydrostatic pressure and correlated afterward with general body measures. RESULTS: The corrected mean (SD) IPP measured in the supine position was 4.4 (4.5) cm H2O, and the mean (SD) upright IPP was 1.6 (7.8) cm H2O (p = 0.02). A positive correlation was found between the body mass index (BMI) and the IPP in the upright (r = 0.51) and supine (r = 0.65) body positions, and between the abdominal circumference and the IPP in the supine position (r = 0.63). CONCLUSIONS: The intrinsic IPP in mobile subjects exceeds the intraperitoneal hydrostatic pressure. Thus, the intrinsic IPP counteracts the diversion of CSF into the peritoneal compartment. The intrinsic IPP is correlated with mobile patients' general body measures. PMID- 29288393 TI - Procedural complications of endovascular treatment in patients with aneurysmal subarachnoid haemorrhage treated at a single centre. AB - BACKGROUND: We present a single-centre experience of procedural complications suffered by patients undergoing endovascular treatment for a ruptured saccular intracranial aneurysm at Tampere University Hospital, Finland, between 2000 and 2014. METHOD: From 2000 to 2014, we treated 1,253 patients with aneurysmal subarachnoid haemorrhage, 491 of whom received endovascular treatment. Clinical data were collected retrospectively from the hospital's aneurysm database. A procedural complication was defined as having occurred whenever there was a documented new event in the patient's medical records or a note of a technical complication written by an interventionist after endovascular treatment. Procedural complications could be with or without clinical symptoms. RESULTS: Nearly 40% (491/1253) of the patients were treated with the endovascular method. Procedural complications occurred in 11.4% (56/491) of cases. The morbidity rate was 4.5% (22/491) and the mortality rate was 0.2% (1/491). Of the 56 complications, ischaemic complications occurred in 52% (29/56), haemorrhagic complications occurred in 27% (15/56) and technical complications occurred in 21% (12/56) of cases. In 61% (34/56) of the cases, the procedural complication did not cause any clinical symptoms. CONCLUSIONS: The total risk for procedural complications leading to postoperative disability or death at our institute was 4.7%. The complication frequency is in accordance with previous reports. Endovascular treatment of ruptured intracranial aneurysms is a safe treatment method when patient selection is carefully performed. PMID- 29288394 TI - Endoscopic transorbital route to the petrous apex: a feasibility anatomic study. AB - BACKGROUND: While the subtemporal approach represents the surgical module milestone designed to reach the petrous apex, a novel ventral route, which is the superior eyelid endoscopic transorbital approach, has been proposed to access the skull base. Accordingly, we aimed to evaluate the feasibility of this route to the petrous apex, providing a qualitative and quantitative analysis of this relatively novel pathway. METHODS: Five human cadaveric heads were dissected at the Laboratory of Surgical NeuroAnatomy of the University of Barcelona. After proper dissection planning, anterior petrosectomy via the endoscopic transorbital route was performed. Specific quantitative analysis, as well as dedicated three dimensional reconstruction, was done. RESULTS: Using the endoscopic transorbital approach, it was possible to reach the petrous apex with an average volume bone removal of 1.33 +/- 0.21 cm3. Three main intradural spaces were exposed: cerebellopontine angle, middle tentorial incisura, and ventral brainstem. The first one was bounded by the origin of the trigeminal nerve medially and the facial and vestibulocochlear nerves laterally, the second extended from the origin of the oculomotor nerve to the entrance of the trochlear nerve into the tentorium free edge while the ventral brainstem area was hardly accessible through the straight, ventral endoscopic transorbital trajectory. CONCLUSION: This is the first qualitative and quantitative anatomic study concerning details of the lateral aspect of the incisura and ventrolateral posterior fossa reached via the transorbital window. This manuscript is intended as a feasibility anatomic study, and further clinical contributions are mandatory to confirm the effectiveness of this approach, defining its possible role in the neurosurgical armamentarium. PMID- 29288395 TI - Morphometric study of the posterior longitudinal ligament at the lumbar spine. AB - PURPOSE: There are only two descriptions of posterior longitudinal ligament (PLL) at the lumbar spine level but its morphologic characteristics are different to cervical and thoracic levels. METHOD: Spine explantation (from Th12 to L5) followed by resection of the neural arch and the dural sheath in 13 fresh cadavers was performed. The PLL was isolated from other epidural structures and its width was measured and compared to the vertebral body width at each vertebral levels. It was conducted at a microanatomic study concerning the PLL and the posterior outer annulus fibrosus. RESULTS: The PLL width was reduced craniocaudaly significantly, becoming thin from L4. The average width of PLL was 7.8 mm at L1 and 1.9 mm at L5. The width decreased gradually from L1 to L5 or abruptly from L4. The ratio of PLL width compared to the vertebral body width was 21% at L1 and 3% at L5. Microanatomic study confirmed that the PLL is less thick at its annulus fibrosus adhesion at L4-L5 and L5-S1. The relationship between the PLL and other epidural structures are discussed. CONCLUSIONS: The presence and function of the ilio-lumbar ligaments and the articular process orientation of L5 S1 may be explanations for PLL width decrease at L4-L5 and L5-S1. Furthermore, this aspect may be considered as one factor contributing to the occurrence of disc herniations at these levels, which levels are more frequently involved in this pathology. PMID- 29288396 TI - Plasma lyso-Gb3: a biomarker for monitoring fabry patients during enzyme replacement therapy. AB - BACKGROUND: Recently, globotriaosylsphingosine (lyso-Gb3) has attracted interest as a biomarker of Fabry disease. However, little is known regarding its utility for the evaluation of the therapeutic efficacy. METHOD: We measured plasma lyso Gb3 concentration in Japanese healthy subjects and Fabry patients by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS). We determined the reference interval in Japanese (UMIN000016854), and examined the effect of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A (GLA) and the influence of antibodies against the enzyme on the plasma lyso-Gb3 level in Fabry patients (UMIN000017152). RESULTS: The reference interval was determined to be 0.35-0.71 nmol/L, this being almost the same as the normal range in a non Japanese population previously reported. The analysis revealed that the plasma lyso-Gb3 level was strikingly increased in classic Fabry males, and to a lesser extent in later-onset Fabry males and Fabry females. The elevation of the plasma lyso-Gb3 level was related to renal involvement in the Fabry females. ERT gave a rapid reduction in the elevated plasma lyso-Gb3 level in the classic Fabry males, and a gradual one or stabilization in most of the later-onset Fabry males and Fabry females. However, formation of antibodies against the recombinant GLA had a negative effect on the reduction of plasma lyso-Gb3. CONCLUSIONS: Regular observation of plasma lyso-Gb3 and antibodies is useful for monitoring of Fabry patients during ERT. PMID- 29288397 TI - A cadaveric study of aortic arch variation in an Irish population. AB - AIM: The aim of this study is to investigate the incidence of variation in the branching pattern of aortic arch (AA) vessels in an Irish population. METHOD: A cadaveric study of 24 subjects was conducted. The vessels of the AA were identified, their branching patterns were noted and photographed and the following measurements were recorded: the angle of the AA to the coronal plane, the distance from the midline to the brachiocephalic trunk (BCT); the left common carotid artery (LCC) ; the left subclavian artery (LSC), the distance between the BCT and the right subclavian artery (RSC); the RSC and the right vertebral artery (RVA), and between the LSC and left vertebral artery (LVA). RESULTS: The 'normal' branching pattern (BCT, LCC, LSC) was observed in 79%. Thirteen percent had a two branched AA (bovine variant), while the remainder had an aberrant left vertebral artery (LVA) originating from the AA. The mean distances from the midline to the BCT, LCC and LSC were 9.1, 10.8 and 21.4 mm, respectively. Mean distance from BCT to RSC was 34.09 mm. The mean distance from LSC to LVA was 39.79 mm, and the mean distance from RSC to RVA was 23.38 mm. The mean angle of the AA to the coronal plane was 59.02 degrees . CONCLUSION: This is the first study documenting the rates of variation of the AA in Ireland. Variation of AA branching is of radiological and surgical significance, particularly in the diagnosis and treatment of thoracic and head and neck diseases. Awareness of these variations is particularly relevant for interventionalists who access these vessels during endovascular surgery. PMID- 29288398 TI - Comparison of fosfomycin against fluoroquinolones for transrectal prostate biopsy prophylaxis: an individual patient-data meta-analysis. AB - PURPOSE: To systematically review and meta-analyse available evidence comparing fosfomycin trometamol (FT) to fluoroquinolone (FQ) prophylaxis to prevent transrectal ultrasound-guided prostate biopsy (TRUSPB) related infectious complications. METHODS: Electronic databases were queried for studies comparing FT to FQ-based TRUSPB prophylaxis. Studies were assessed for comparable outcomes and methodological quality (ROBINS-I modification). The primary outcome measure was the relative odds of overall infectious complications following TRUSPB according to FT/FQ treatment, which was evaluated with meta-analysis. Safety and tolerability were also assessed. The relative odds of infections of different severity [Grade 1, bacteriuria and afebrile urinary tract infection (UTI); Grade 2, bacteraemia, febrile UTI, and urosepsis] according to FT/FQ treatment were also estimated. RESULTS: Five studies, being three prospective randomised trials and two retrospective cohort studies, representing 3112 patients, were included. The relative odds of an infectious complication (OR 0.22, 95% CI 0.09-0.54) or of a more severe (Grade 2) infection (OR 0.13, 95% CI 0.07-0.26) were significantly lower in those receiving FT compared to FQ prophylaxis. A low incidence of medication-related side effects was observed. There were less observed infections due to FQ-resistant pathogens in those receiving FT prophylaxis. CONCLUSIONS: Patients who received FT prophylaxis were less likely than those who received FQ prophylaxis to develop infections overall, as well as severe and resistant infections after TRUSPB. Assessing the performance of FT in other geographic locations or in comparison to targeted prophylaxis based on risk assessment or rectal cultures is desired. PMID- 29288399 TI - Balkan endemic nephropathy and aristolochic acid I: an investigation into the role of soil and soil organic matter contamination, as a potential natural exposure pathway. AB - Aristolochic acids (AAs) are carcinogenic and nephrotoxic plant alkaloids present in Aristolochia species, used in traditional medicine. Recent biomolecular and environmental studies have incriminated these toxins as an etiological agent in Balkan endemic nephropathy (BEN), a severe kidney disease occurring in the Balkan Peninsula. The questions on how the susceptible populations are exposed to these toxins have not yet been clearly answered. Exposure to AAs through the food chain, and environmental pollution (soil/dust), could provide an explanation for the presence of BEN in the countries where no folkloric use of the plant has been documented (Bulgaria, Croatia). Additional exposure pathways are likely to occur, and we have shown previously that AAs can contaminate crop plants through absorption from soil, under controlled laboratory environment. Here, we attempt to provide additional support to this potential exposure pathway, by revealing the presence of AAI in soil and soil organic matter samples collected from BEN and non-BEN areas. The samples were processed in order to be analyzed by high pressure liquid chromatography, and ion trap mass spectrometry. Our results showed the presence of AAI in small concentrations, both in BEN and non-BEN soils, especially where Aristolochia plants and seeds were present. PMID- 29288400 TI - Anti-inflammatory and antiresorptive effects of Calendula officinalis on inflammatory bone loss in rats. AB - OBJECTIVE: The aim of this work was to evaluate the anti-inflammatory and antiresorptive effects of Calendula officinalis (CLO) on alveolar bone loss (ABL) in rats. MATERIAL AND METHODS: Male Wistar rats were subjected to ABL by ligature with nylon thread around the second upper left molar. The contralateral hemimaxillae were used as control. Rats received saline solution (SAL) or CLO (10, 30, or 90 mg/kg) 30 min before ligature and daily until the 11th day. The maxillae were removed and prepared for macroscopic, radiographic, micro tomographic, histopathologic, histometric analysis, and immunohistochemical localization of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG). The gingival tissues were used to quantify the myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) concentrations by ELISA. Blood samples were collected for leukogram and to evaluate the bone-specific alkaline phosphatase (BALP) activity and serum levels of aspartate and alanine transaminases (AST/ALT). RESULTS: The bone loss induced by 11 days of ligature induced bone loss, reduced levels of BALP, leukocyte infiltration, increased MPO activity, gingival concentrations of TNF-alpha and IL-1beta, and RANKL while reduced OPG immunoexpressions in the periodontal tissue and leukocytosis. Of the CLO, 90 mg/kg reduced bone loss, neutrophilia, the levels of pro-inflammatory mediators, and RANKL expression, while it increased OPG immunopositive cells and BALP serum levels, when compared to SAL. CLO did not affect either kidney or liver function, indicated by serum AST/ALT levels. CONCLUSION: The present data suggests that CLO reduced inflammatory bone resorption in experimental periodontitis, which may be mediated by its anti-inflammatory properties and its effects on bone metabolism. CLINICAL RELEVANCE: CLO can be a potential therapeutical adjuvant in the treatment of periodontitis. PMID- 29288401 TI - X-ray diffraction analysis of MTA mixed and placed with various techniques. AB - OBJECTIVES: The aim of this study was to evaluate the effect of various mixing techniques as well as the effect of ultrasonic placement on hydration of mineral trioxide aggregate (MTA) using X-ray diffraction (XRD) analysis. MATERIALS AND METHODS: One gram of ProRoot MTA and MTA Angelus powder was mixed with a 0.34-g of distilled water. Specimens were mixed either by mechanical mixing of capsules for 30 s at 4500 rpm or by manual mixing followed by application of a compaction pressure of 3.22 MPa for 1 min. The mixtures were transferred into the XRD sample holder with minimum pressure. Indirect ultrasonic activation was applied to half of the specimens. All specimens were incubated at 37 degrees C and 100% humidity for 4 days. Samples were analyzed by XRD. Phase identification was accomplished by use of search-match software utilizing International Centre for Diffraction Data (ICDD). RESULTS: All specimens comprised tricalcium silicate, calcium carbonate, and bismuth oxide. A calcium hydroxide phase was formed in all ProRoot specimens whereas among MTA Angelus groups, it was found only in the sample mixed mechanically and placed by ultrasonication. CONCLUSIONS: Mechanical mixing followed by ultrasonication did not confer a significant disadvantage in terms of hydration characteristics of MTA. CLINICAL RELEVANCE: Clinicians vary in the way they mix and place MTA. These variations might affect their physical characteristics and clinical performance. For ProRoot MTA, the mixing and placement methods did not affect its rheological properties, whereas for MTA Angelus, mechanical mixing combined with ultrasonic placement enhanced the calcium hydroxide phase formation. PMID- 29288402 TI - Long-term effect of intensive prevention on dental health of primary school children by socioeconomic status. AB - OBJECTIVES: Children in a German region took part in regular toothbrushing with fluoride gel during their time in primary school after having received a preventive program in kindergarten. The study aimed at determining the dental health of the students as a function of prevention in kindergarten and at school while taking into account their socioeconomic status and other confounders. MATERIALS AND METHODS: The subjects were in six groups: groups 1 and 2, intensive prevention in kindergarten with and without fluoride gel at school; groups 3 and 4, basic prevention in kindergarten with and without fluoride gel at school; groups 5 and 6, no organized prevention in kindergarten with and without fluoride gel at school. Two dental examinations were performed for assessing caries experience and calculating caries increment from second grade (7-year-olds) to fourth grade (9-year-olds). A standardized questionnaire was used to record independent variables. To compare caries scores and preventive measures of various subgroups, non-parametric tests and a binary logistic regression analysis were performed. RESULTS: A significant difference was found in the mean decayed, missing, and filled tooth/teeth (DMFT) depending on socioeconomic status (no prevention in kindergarten, fluoride gel at school in children with low SES: DMFT = 0.47 vs. DMFT = 0.18 in children with high SES; p = 0.023). Class-specific differences were no longer visible among children who had taken part in an intensive preventive program combining daily supervised toothbrushing in kindergarten and application of fluoride gel in school. CONCLUSIONS: Early prevention, focusing on professionally supported training of toothbrushing in kindergarten and at school, has a positive effect on dental health and is able to reduce class-specific differences in caries distribution. CLINICAL RELEVANCE: Early training of toothbrushing and fissure sealing of first permanent molars are the most important factors for the dental health of primary school children. PMID- 29288403 TI - The impact of non-alcoholic fatty liver disease fibrosis score on cardiac prognosis in patients with chronic heart failure. AB - Liver abnormalities have a strong impact on clinical outcomes in patients with heart failure (HF), and are known as cardio-hepatic syndrome. The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has been developed to identify liver fibrosis in patients with NAFLD. It remains to be determined whether NFS is associated with cardiovascular prognosis in patients with chronic heart failure (CHF). We calculated NFS in 516 patients with CHF admitted to our hospital. The clinical endpoints were deaths due to progressive HF, myocardial infarction, stroke, and sudden cardiac death, and rehospitalization for worsening HF. There were 173 cardiovascular events noted during a median follow-up of 464 days. Patients with cardiovascular events showed a higher NFS as compared with those without. We divided the patients into four groups according to quartiles of NFS. The proportion of New York Heart Association functional class III/IV and serum brain natriuretic peptide levels were increased with increasing NFS. Kaplan-Meier analysis revealed that cardiovascular event rate was increased with increasing NFS in patients with CHF. In multivariate Cox proportional hazards analysis, NFS was independently associated with cardiovascular events after adjustment for confounding factors. Elevated NFS was associated with unfavorable outcomes in patients with CHF. Liver fibrosis assessed by NFS may provide valuable prognostic information in patients with CHF. PMID- 29288405 TI - Reducing the Risk of Postpartum Depression in a Low-Income Community Through a Community Health Worker Intervention. AB - Objectives To clarify the effectiveness of perinatal social support interventions in reducing postpartum depression among minority, low-income women. Methods The Transdisciplinary Research Consortium for Gulf Resilience on Women's Health supported a community-based participatory research project to improve perinatal health among low-income, first-time pregnant women living in a vulnerable Gulf Coast region. Community health workers (CHWs) were partnered with recruited women, and used a mix of mobile technology and home visits to develop a supportive relationship during the perinatal period. Results Women enrolled in the CHW-led intervention had lower (F: 2.38, p = 0.04) average postpartum depression scores (EPDS) 6 months postpartum than a comparison population. The difference, however, was not seen among women in the intervention group who reported relatively poor relationships with their CHWs. Conclusions for Practice Results reinforce the evidence that perinatal social support can affect postpartum depression outcomes. CHWs are increasingly utilized by public programs to reach at-risk populations. We discuss the potential efficacy of CHW programs, but also, the need to pair outreach with effective monitoring and evaluation of the relationship development between CHW and clients. PMID- 29288404 TI - Paradoxical impact of decreased low-density lipoprotein cholesterol level at baseline on the long-term prognosis in patients with acute coronary syndrome. AB - Although statin therapy is beneficial in the setting of acute coronary syndrome (ACS), a substantial proportion of patients with ACS still do not receive the guideline-recommended lipid management in contemporary practice. We hypothesize that the low-density lipoprotein cholesterol (LDL-C) level at the time of admission might affect patient management and the subsequent outcome. Nine hundred and forty-two consecutive patients with ACS who underwent percutaneous coronary intervention were analyzed retrospectively. The study patients were first divided into two groups based on the LDL-C level on admission: group A (n = 267), with LDL-C < 100 mg/dL; and group B (n = 675), with LDL-C >= 100 mg/dL. Each group was then further divided into those who were prescribed statins or not at the time of discharge from the hospital. The primary endpoint was all-cause death. In addition, we analyzed the serial changes of LDL-C within 1 year. Patients in group A were significantly older and more likely to have multiple comorbidities compared with group B. The proportion of patients who were prescribed statin at discharge was significantly smaller in group A compared with group B (57.7 vs. 77.3%, p < 0.001). During the median 4-year follow-up, there were 122 incidents of all-cause death. Multivariate Cox proportional hazard analysis revealed that LDL-C < 100 mg/dL on admission [hazard ratio (HR), 1.61; 95% confidence interval (CI), 1.09-2.39; p < 0.05] and prescription of statins at discharge (HR, 0.52; 95% CI, 0.36-0.76; p < 0.001) were associated significantly with all-cause death. Under these conditions, increasing LDL-C levels were documented during follow-up in those patients in group A when no statins were prescribed at discharge (79 +/- 15-96 +/- 29 mg/dL, p < 0.001), whereas these remained unchanged when statins were prescribed at discharge (79 +/- 15-77 +/- 22 mg/dL, p = 0.30). These results demonstrate that decreased LDL-C on admission in ACS led to less prescription for statins, which could result in increased death, probably due to underestimation of the baseline LDL-C. PMID- 29288407 TI - The Effect of the Removal of User Fees for Delivery at Public Health Facilities on Institutional Delivery in Urban Kenya. AB - Objectives In 2013, Kenya removed delivery fees at public health facilities in an effort to promote equity in access to health services and address high maternal mortality. This study determines the effect of the policy to remove user fees on institutional delivery in a population-based sample of women from urban Kenya. Methods Longitudinal data were collected from a representative sample of 8500 women from five cities in Kenya in 2010 with a follow-up interview in 2014 (response rate 58.9%). Respondents were asked about their most recent birth since 2008 at baseline and 2012 at endline, including the delivery location. Multinomial logistic regression is used, controlling for the temporal time trend and background characteristics, to determine if births which occurred after the national policy change were more likely to occur at a public facility than at home or a private facility. Results Multivariate findings show that women were significantly more likely to deliver at a public facility as compared to a private facility after the policy. Among the poor, the results show that poor women were significantly more likely to deliver in a public facility compared to home or a private facility after policy change. Conclusions for Practice These findings show Kenya's progress towards achieving universal access to delivery services and meeting its national development targets. The removal of delivery fees in the public sector is leading to increased use of facilities for delivery among the urban poor; this is an important first step in reducing maternal death. PMID- 29288406 TI - Does a History of Gestational Diabetes Mellitus Affect Key Outcomes in Women Participating in a Diabetes Prevention Program? AB - Objectives To evaluate lifestyle change outcomes among women with and without a history of gestational diabetes mellitus (GDM) enrolled in the Montana Diabetes Prevention Program (DPP). Methods Participation, self-monitoring behavior, weight loss, and cardiometabolic risk reduction were compared among 5091 women at high risk for type 2 diabetes, with and without a history of GDM, enrolled in the Montana DPP between 2008 and 2015. Results Women with a history of GDM (6% of enrolled women, n = 283) were significantly younger than women without GDM. No significant differences in participation, self-monitoring fat intake, achievement of the physical activity goal, or weight loss were found among women with and without a history of GDM. Overall, women lost an average of 5.0 kg (+/- 6.5), and 45 and 29% of women achieved 5 and 7% weight loss, respectively. Both groups lost significant and comparable amounts of weight. After adjusting for age and other factors, no differences were found in achievement of >= 5% weight loss (AOR 0.84; 95% CI 0.61-1.16) or the >= 7% weight loss goal (AOR 1.04; 95% CI 0.73-1.47) among women with and without a history of GDM. Conclusions for Practice Our findings suggest that women with and without a history of GDM successfully participate in and achieve significant weight loss in the DPP. Health care providers should identify and refer women with risk factors for type 2 diabetes, including a history of GDM, to a DPP within their community. PMID- 29288408 TI - Muscle-specific deletion of Prkaa1 enhances skeletal muscle lipid accumulation in mice fed a high-fat diet. AB - Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of alpha, beta and gamma subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKalpha1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet. Notably, when animals are fed a high-fat diet, the skeletal muscle of muscle-specific Prkaa1 knockout mice accumulates more lipids than the skeletal muscle of wild-type (WT) mice, with concomitant upregulation of adipogenic gene expressions and downregulation of the expression of genes associated with mitochondrial oxidation. Muscle-specific Prkaa1 ablation also results in hyperlipidemia, which may contribute to the increased IMTG levels. Furthermore, Prkaa1 deletion activates skeletal muscle mTOR signalling, which has a central role in lipid metabolism and mitochondrial oxidation. Collectively, our study provides new insights into the role of Prkaa1 in skeletal muscle. This knowledge may contribute to the treatment of related metabolic diseases. PMID- 29288410 TI - Central nervous system involvement in rheumatoid arthritis: possible role of chronic inflammation and tnf blocker therapy. AB - Rheumatoid arthritis (RA) is a chronic disease, the etiology of which has yet to be clarified, which causes activation of proinflammatory pathways that bring about joint and systemic inflammation. Although peripheral nervous system anomalies are observed widely in RA, very few case reports on changes in the central nervous system (CNS) have been published. In recent years, the pathophysiology of CNS involvement that can occur in RA has attracted a great deal of attention. Emphasis has focused on the possibility that CNS involvement occurs due to blood-brain barrier (BBB) damage associated with chronic inflammation. The present study was performed to investigate the possible effects of BBB dysfunction and tumor necrosis factor (TNF) blocker therapy on BBB function, which may cause CNS damage in patients with RA. 58 RA patients [47 (81.0%) females, 11 (19.0%) males] and 34 healthy controls [24 (70.6%) females, 10 (29.4%) males] were included in the study. All RA patients were on synthetic DMARD therapy at the beginning. Thirty patients continued DMARD therapy, and 28 patients with high disease activity were started on TNF blocker therapy. All demographic characteristics of the patients were recorded. Disease activity was evaluated using the Disease Activity Score 28-joint count C reactive protein. The Mini-Mental State Examination was used to evaluate cognitive function, and the Fazekas scale was used to assess cranial lesions visualized by magnetic resonance imaging (MRI). Patients' peripheral blood S100beta, glial fibrillary acidic protein (GFAP), claudin, interleukin (IL)-17, and IL-1beta levels were measured at the beginning of the study and after 6 months. Demographic characteristics (including sex, age, and body mass index) were similar in the RA and control groups. S100beta and GFAP levels were significantly higher in the patient group than in the control group. In the group that was started on TNF blocker therapy, S100beta and GFAP levels were significantly decreased 6 months after commencement of treatment. No difference was observed between the RA and control groups in terms of hyperintense lesions seen on cranial MRI. The S100beta levels increased with lesions in the deep white matter seen on cranial MRI in patients with RA. In conclusion, next to decreasing disease activity and joint erosions by suppressing inflammation, anti-TNF therapy in RA can also suppress potential CNS involvement linked to BBB (blood-brain barrier) dysfunction. Further studies with broader participation and longer patient follow-up are needed to reinforce this hypothesis. PMID- 29288411 TI - The Journal of Genetic Counseling: Continuing to Add Value to the Profession. PMID- 29288409 TI - Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans. AB - Genetic factors are known to modulate cardiac susceptibility to ventricular hypertrophy and failure. To determine how strain influences the transcriptional response to pressure overload-induced heart failure (HF) and which of these changes accurately reflect the human disease, we analyzed the myocardial transcriptional profile of mouse strains with high (C57BL/6J) and low (129S1/SvImJ) susceptibility for HF development, which we compared to that of human failing hearts. Following transverse aortic constriction (TAC), C57BL/6J mice developed overt HF while 129S1/SvImJ did not. Despite a milder aortic constriction, impairment of ejection fraction and ventricular remodeling (dilation, fibrosis) was more pronounced in C57BL/6J mice. Similarly, changes in myocardial gene expression were more robust in C57BL/6J (461 genes) compared to 129S1/SvImJ mice (71 genes). When comparing these patterns to human dilated cardiomyopathy (1344 genes), C57BL/6J mice tightly grouped to human hearts. Overlay and bioinformatic analysis of the transcriptional profiles of C57BL/6J mice and human failing hearts identified six co-regulated genes (POSTN, CTGF, FN1, LOX, NOX4, TGFB2) with established link to HF development. Pathway enrichment analysis identified angiotensin and IGF-1 signaling as most enriched putative upstream regulator and pathway, respectively, shared between TAC-induced HF in C57BL/6J mice and in human failing hearts. TAC-induced heart failure in C57BL/6J mice more closely reflects the gene expression pattern of human dilated cardiomyopathy compared to 129S1/SvImJ mice. Unbiased as well as targeted gene expression and pathway analyses identified periostin, angiotensin signaling, and IGF-1 signaling as potential causes of increased HF susceptibility in C57BL/6J mice and as potentially useful drug targets for HF treatment. PMID- 29288413 TI - Anatomical and functional outcomes following vitrectomy for dense vitreous hemorrhage related to Terson syndrome in children. AB - PURPOSE: Our purpose was to assess anatomical and functional outcomes of vitrectomy in pediatric cases of Terson syndrome. METHODS: A total of 11 eyes of seven children diagnosed with Terson syndrome secondary to traumatic brain injury and 17 eyes of 12 children diagnosed with Terson syndrome secondary to nontraumatic brain hemorrhage who had 20-gauge or 23-gauge pars plana or pars plicata vitrectomy were included in this retrospective study. The primary outcome was the change in visual acuity from the preoperative examination to postoperative final follow-up. Secondary outcomes were anatomic surgical success and postoperative complications. RESULTS: The mean time between diagnosis and surgery was 62 +/- 35 days (range, 30-150), and the average age at the time of the surgery was 4.5 +/- 6.4 years (range, 3 months to 17 years). The mean preoperative logarithm of the minimum angle of resolution (logMAR) (Snellen) best corrected visual acuity (BCVA) was 2.6 +/- 0.7 (20/7260) (n = 9) and in the remaining 19 eyes it was recorded as noncentral, unsteady, nonmaintained fixation. The mean follow-up period was 50 +/- 54 months (range, 12-192 months). At the last follow-up visit, the mean logMAR BCVA was 0.46 +/- 0.6 (20/60) (n = 19) and in eight eyes it was recorded as fix-and-follow. One eye developed a retinal detachment 14 months after the first operation, and one eye developed an epiretinal membrane after 2 years. Anatomical success was recorded in all patients at the final visit. CONCLUSIONS: In children with massive vitreous hemorrhage secondary to Terson syndrome, vitrectomy is an effective procedure and offers a rapid visual improvement. Earlier surgical treatment prevents amblyopia and blood-related potential complications. PMID- 29288412 TI - Closed-Loop Doluisio (Colon, Small Intestine) and Single-Pass Intestinal Perfusion (Colon, Jejunum) in Rat-Biophysical Model and Predictions Based on Caco 2. AB - PURPOSE: The effective rat intestinal permeability (P eff ) was deconvolved using a biophysical model based on parameterized paracellular, aqueous boundary layer, transcellular permeabilities, and the villus-fold surface area expansion factor. METHODS: Four types of rat intestinal perfusion data were considered: single-pass intestinal perfusion (SPIP) in the jejunum (n = 40), and colon (n = 15), closed loop (Doluisio type) in the small intestine (n = 78), and colon (n = 74). Moreover, in vitro Caco-2 permeability values were used to predict rat in vivo values in the rat data studied. RESULTS: Comparable number of molecules permeate via paracellular water channels as by the lipoidal transcellular route in the SPIP method, although in the closed-loop method, the paracellular route appears dominant in the colon. The aqueous boundary layer thickness in the small intestine is comparable to that found in unstirred in vitro monolayer assays; it is thinner in the colon. The mucosal surface area in anaesthetized rats is 0.96 1.4 times the smooth cylinder calculated value in the colon, and it is 3.1-3.6 times in the small intestine. The paracellular permeability of the intestine appeared to be greater in rat than human, with the colon showing more leakiness (higher P para ) than the small intestine. CONCLUSION: Based on log intrinsic permeability values, the correlations between the in vitro and in vivo models ranged from r2 0.82 to 0.92. The SPIP-Doluisio method comparison indicated identical log permeability selectivity trend with negligible bias. PMID- 29288415 TI - Ecosystem changes following the 2016 Kumamoto earthquakes in Japan: Future perspectives. AB - Major earthquakes cause widespread environmental and socioeconomic disruptions that persist for decades. Extensive ground disturbances that occurred during the shallow-focus Kumamoto earthquakes will affect future sustainability of ecosystem services west of Aso volcano. Numbers of earthquake-initiated landslides per unit area were higher in grasslands than forests, likely owing to greater root reinforcement of trees, and mostly initiated on ridgelines and/or convex/planar hillslopes. Most landslides traveled short distances and did not initially evolve into debris flows; resultant sediments and wood accumulating in headwater channels can be mobilized into debris flows during future storms. Fissures along ridgelines may promote water ingress and induce future landslides and debris flows that affect residents downstream. Native grasses are at risk because of habitat fragmentation caused by ground disturbances, extensive damage to rural roads, and abandonment of traditional pasture management practices. Sustainable management of affected areas needs to consider future risk of cascading hazards and long-term socioeconomic impacts. PMID- 29288414 TI - Trypanosoma brucei EIF4E2 cap-binding protein binds a homolog of the histone-mRNA stem-loop-binding protein. AB - Trypanosomatids are parasitic protozoans characterized by several unique structural and metabolic processes that include exquisite mechanisms associated with gene expression and regulation. During the initiation of protein synthesis, for instance, mRNA selection for translation seems to be mediated by different eIF4F-like complexes, which may play a significant role in parasite adaptation to different hosts. In eukaryotes, the heterotrimeric eIF4F complex (formed by eIF4E, eIF4G, and eIF4A) mediates mRNA recognition and ribosome binding and participates in various translation regulatory events. Six eIF4Es and five eIF4Gs have been described in trypanosomatids with several of these forming different eIF4F-like complexes. This has raised questions about their role in differential mRNA translation. Here we have studied further TbEIF4E2, the least known eIF4E homologue from Trypanosoma brucei, and found that it is not associated with an eIF4G homolog. It is, however, associated with mature mRNAs and binds to a histone mRNA stem-loop-binding protein (SLBP), one of two Trypanosoma SLBP homologs (TbSLBP1 and TbSLBP2). TbSLBP1 is more similar to the mammalian counterpart while TbSLBP2 is exclusive to trypanosomatids and related organisms. TbSLBP2 binds to TbEIF4E2 through a conserved central region missing in other SLBP homologs. Both SLBPs, as well as TbEIF4E2, were found to localize to the cytoplasm. TbEIF4E2 and TbSLBP2 are differentially expressed during cell culture, being more abundant in early-log phase, with TbSLBP2 also showing cell-cycle dependent expression. The new data reinforce unique aspects of the trypanosomatid eIF4Es, with the TbEIF4E2-TbSLBP complex possibly having a role in differential selection of mRNAs containing stem-loop structures. PMID- 29288416 TI - Anticancer activity of Schiff base-Poloxamer P85 combination against kidney cancer. AB - PURPOSE: Renal cell carcinoma (RCC) accounts for approximately 80% of the primary renal cancers, and current treatment strategies are not sufficient to provide a certain solution. Since there are not many treatment options, interest in discovery of alternative drugs has increased. METHODS: In the current study, anticancer activity of a novel heterodinuclear Cu(II)-Mn(II) complex (Schiff base SB) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (pluronic) P85 was tested against RCC. Cell viability, apoptosis and gene expression analysis were conducted in vitro by using Renca cells. RESULTS: The results revealed that the SB-P85 combination decreased cell proliferation by increasing the apoptotic gene expressions and apoptosis. Renca-injected BALB/c mice were used to mimic early stage of RCC model. Treatment with SB-P85 combination suppressed tumor formation and growth compared to baseline. CONCLUSION: Overall, SB-P85 showed promising anticancer activity against RCC in vitro and in vivo. PMID- 29288417 TI - Filamin A (FLNA) regulates autophagy of bladder carcinoma cell and affects its proliferation, invasion and metastasis. AB - PURPOSE: This research intended to explore the effect of FLNA on cell proliferation, invasion and migration in bladder carcinoma (BC). METHODS: Microarray analysis was performed with the TCGA data, and the results were confirmed on 20 paired BC tissues and adjacent tissues using qRT-PCR and immunohistochemistry. Transmission electron microscope (TEM) and cell fluorescence assay were used to observe the quantity of autophagosomes. The expression of autophagy-related protein (LC3-I/II, p62) was detected by western blot. Cell proliferation was detected using CCK-8 and colony formation. The invasion and migration ability of the cell were tested by transwell and wound healing assay. Tumor xenograft in BALB/c nude mice and HE staining were utilized to probe into the effects of FLNA-induced regulation of volume, weight and metastasis of tumors. RESULTS: We confirmed that FLNA was down-regulated in BC tissues. TEM and fluorescence analysis proved that FLNA overexpression promoted autophagy in BC cells. Colony formation assay and CCK-8 experiment showed that FLNA overexpression suppressed the proliferation of BC cells. In addition, FLNA blocked cell cycle and promoted apoptosis of BC cell. Transwell assay and wound healing assay further proved that FLNA suppressed invasion and migration ability in BC cell. Meanwhile, in vivo study indicated that FLNA inhibited the tumor growth. CONCLUSION: Overexpression of FLNA suppressed the proliferation, migration and invasion of the BC cell, suggesting the potential role of FLNA in clinical treatment. PMID- 29288418 TI - Survey of heavy metals in internal tissues of Great cormorant collected from southern wetlands of Caspian Sea, Iran. AB - The level of mercury, iron, copper, and zinc was measured in 18 Great cormorants (Phalacrocorax carbo) collected from Anzali and Gomishan wetlands in the south of the Caspian Sea. The mean level of metals in dried tissues of the muscle, liver, and kidney was 2.26, 5.71, 3.79-Hg; 943.54, 379.97, 348.05-Fe; 42.64, 14.78, 60.79-Cu, and 71.97, 134.63, 77.82-Zn, respectively (mg/kg). There was no significant different between genders in terms of accumulation of metals, except for copper in the kidney. The results of Pearson correlation showed a positive and strong relationship between the fat in the liver and mercury (r = 0.95, R2 = 0.90). Also, there was a significant difference between the values of all metals with the allowable limits presented in EPA, WHO, and CCME, where all of values were above standard levels. Thus, as the muscles of the bird are sometimes eaten by humans, this result is a serious warning. Nevertheless, the relatively high levels of heavy metals accumulated in different tissues of Great cormorant at that time are a result of their high weight and nourishment they have at the terminal days of their migration due to lack of natural physical activity. Regarding to the importance of heavy metals in birds, we suggest the same study to be conducted on the species in other seasons and wetlands. PMID- 29288420 TI - Characterization of Phenyalanine Hydroxylase Gene Mutations in Chilean PKU Patients. AB - : Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive disease, caused by mutations in the Phenylalanine Hydroxylase (PAH) gene situated in chromosome 12q22-q24.2. This gene has 13 exons. To date, 991 mutations have been described. The genotype is one of the main factors that determine the phenotype of this disease. OBJECTIVE: Characterize PKU genotype and phenotype seen in Chilean PKU patients. METHODS: We studied the PAH gene by restriction fragment length polymorphism (RFLP) and/or sequencing techniques to identify pathogenic mutations in 71 PKU subjects. We classified the phenotype according to Guldberg predicted value. RESULTS: We identified 26 different mutations in 134 of the 142 alleles studied (94.4%), 88.7% of the subjects had biallelic pathogenic mutations while 11.3% had only one pathogenic mutation identified. Compound heterozygous represented 85.9% of the cases. Exon 7 included the majority of mutations (26.9%) and 50% of mutations were missense. The most frequent mutations were c.1066-11G > A, c.442-?_509+?del and p.Val388Met. The majority of subjects (52.3%) had the classic phenotype. CONCLUSIONS: The most frequent mutations in our Chilean PKU population were p.Val388Met, c.442?_509+?del and c.1066-11G > A. It is possible to predict phenotype by detecting the genotype, and use this information to determine disease prognosis and adjust patient's medical and nutritional management accordingly. PMID- 29288422 TI - A Simple Method for International Standardization of Photographic Documentation for Aesthetic Plastic Surgery. PMID- 29288421 TI - First-line treatment with bendamustine and rituximab, in patients with intermediate-/high-risk splenic marginal zone lymphomas. AB - Splenic marginal zone lymphomas (SMZLs) are rare indolent B cell neoplasms that affect the spleen, bone marrow, and blood. Although they have an indolent course in the majority of patients, who have a median survival of 8-10 years, ~ 30% may experience a worse outcome. The prognostic criteria of progression are lymph node and extra-nodal involvement, high lymphocyte counts, anaemia, and thrombocytopenia. The treatment of SMZLs include a "wait and watch strategy", splenectomy, and alkylating agents +/- rituximab. We here describe data relating to 70 patients with intermediate-/high-risk SMZLs, who received rituximab/bendamustine as first-line treatment for a median of 60 days (range 1 75) after diagnosis. Sixty patients (86%) achieved a complete response (CR), and seven (10%) a partial response (PR). Three patients (4.3%) experienced disease progression (PD). The median duration of remission was 18 months. Side effects were generally mild. Our findings suggest that rituximab/bendamustine is a feasible treatment option in patients with intermediate-/high-risk SMZLs. PMID- 29288419 TI - Based Real Time Remote Health Monitoring Systems: A Review on Patients Prioritization and Related "Big Data" Using Body Sensors information and Communication Technology. AB - The growing worldwide population has increased the need for technologies, computerised software algorithms and smart devices that can monitor and assist patients anytime and anywhere and thus enable them to lead independent lives. The real-time remote monitoring of patients is an important issue in telemedicine. In the provision of healthcare services, patient prioritisation poses a significant challenge because of the complex decision-making process it involves when patients are considered 'big data'. To our knowledge, no study has highlighted the link between 'big data' characteristics and real-time remote healthcare monitoring in the patient prioritisation process, as well as the inherent challenges involved. Thus, we present comprehensive insights into the elements of big data characteristics according to the six 'Vs': volume, velocity, variety, veracity, value and variability. Each of these elements is presented and connected to a related part in the study of the connection between patient prioritisation and real-time remote healthcare monitoring systems. Then, we determine the weak points and recommend solutions as potential future work. This study makes the following contributions. (1) The link between big data characteristics and real-time remote healthcare monitoring in the patient prioritisation process is described. (2) The open issues and challenges for big data used in the patient prioritisation process are emphasised. (3) As a recommended solution, decision making using multiple criteria, such as vital signs and chief complaints, is utilised to prioritise the big data of patients with chronic diseases on the basis of the most urgent cases. PMID- 29288423 TI - Proposal of a Classification System for the Assessment and Treatment of Prominent Ear Deformity. AB - BACKGROUND: Prominent ear is the most common external ear deformity. To comprehensively treat prominent ear deformity, adequate comprehension of its pathophysiology is crucial. In this article, we analyze cases of prominent ear and suggest a simple classification system and treatment algorithm according to pathophysiology. METHODS: We retrospectively reviewed a total of 205 Northeast Asian patients' clinical data who underwent an operation for prominent ear deformity. Follow-up assessments were conducted 3, 6, and 12 months after surgery. Prominent ear deformities were classified by diagnostic checkpoints. Class I (simple prominent ear) includes prominent ear that developed with the absence of the antihelix without conchal hypertrophy. Class II (mixed-type prominent ear) is defined as having not only a flat antihelix, but also conchal excess. Class III (conchal-type prominent ear) has an enlarged conchal bowl with a well-developed antihelix. RESULTS: Among the three types of prominent ear, class I was most frequent (162 patients, 81.6%). Class II was observed in 28 patients (13.6%) and class III in 10 patients (4.8%). We used the scaphomastoid suture method for correction of antihelical effacement, the anterior approach conchal resection for correction of conchal hypertrophy, and Bauer's squid incision for lobule prominence. The complication rate was 9.2% including early hematoma, hypersensitivity, and suture extrusion. Unfavorable results occurred in 4% including partial recurrence, overcorrection, and undercorrection. CONCLUSIONS: To reduce unfavorable results and avoid recurrence, we propose the use of a classification and treatment algorithm in preoperative evaluation of prominent ear. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29288424 TI - Development of microsatellite markers for Myracrodruon urundeuva (F.F. & M.F. Allemao), a highly endangered species from tropical forest based on next generation sequencing. AB - Myracrodruon urundeuva is a tree species of high economic importance due the strength and durability of its wood. Threatened of extinction in Brazil, it is present only in a few forest remnants, mostly in conservation units. Currently, there is little information on the genetic diversity of natural populations in Brazil and even less information about the genome of this species. Here, new species-specific microsatellite loci were developed based on next-generation sequencing (Illumina). More than 100,000 loci were identified in the run, with di to hexanucleotides motifs. Of these, 20 loci were selected for validation in 30 individuals, with 15 successfully polymorphic loci detected. The number of alleles ranged among loci from 3 to 16, with an average of 7.73, expected (H e ) and observed (H o ) heterozygosity ranged from 0.246 to 0.902 and from 0.103 to 0.867, respectively. These results point out that these new set of markers has a great potential for use in population genetic studies for genetic conservation of the species. PMID- 29288425 TI - Polymorphisms of caprine GnRHR gene and their association with litter size in West African Dwarf goats. AB - Gonadotropin-releasing hormone receptor (GnRHR) gene is considered a candidate gene for litter size due to its critical role in regulating the activities of hypothalamo-pituitary-gonadal axis which synthesizes and releases gonadotropins. This study was designed to identify mutations within the caprine GnRHR gene and investigate their association with litter size at various parities. Polymorphisms scanning and genotyping of GnRHR gene in West African Dwarf (WAD) goats (n = 226) revealed three single nucleotide polymorphisms (SNPs), one mutation (g.-29T > G) was detected within 5'UTR region while two others (g.48G > A and g.209T > G) were identified in exon 1. Mutation at g.209T > G locus resulted in amino acid change from Methionine to Arginine at position 70 on the polypeptide residue. Based on heterozygosity and polymorphism information content (PIC), WAD goat population diversity at the SNP loci was moderate. Strong linkage disequilibrium (LD) (r2 > 0.98) existed among the detected mutations resulting in three observed haplotypes, two (T-G-T and G-A-G) had cumulative frequency of > 97%. The mutation within 5'UTR region of GnRHR gene (g.-29T > G) is novel, being reported in goats for the first time. Association analysis revealed a significant (p < 0.05) association between allele G at g.-29T > G with higher mean litter size for homozygous (GG) mutant does compared with heterozygotes (GT) or homozygotes (TT), while the relationship between SNPs at the two loci detected in exon 1 and litter size was not significant. PMID- 29288426 TI - High glucose levels impact visual response properties of retinal ganglion cells in C57 mice-An in vitro physiological study. AB - This study investigated visual response properties of retinal ganglion cells (RGCs) under high glucose levels. Extracellular single-unit responses of RGCs from mouse retinas were recorded. And the eyecup was prepared as a flat mount in a recording chamber and superfused with Ames medium. The averaged RF size of the ON RGCs (34.1+/-2.9, n=14) was significantly smaller than the OFF RGCs under the HG (49.3+/-0.3, n=12) (P<0.0001) conditions. The same reduction pattern was also observed in the osmotic control group (HM) between ON and OFF RGCs (P<0.0001). The averaged luminance threshold (LT) of ON RGCs increased significantly under HG or HM (HG: P<0.0001; HM: P<0.0002). OFF RGCs exhibited a similar response pattern under the same conditions (HG: P<0.01; HM: P<0.0002). The averaged contrast gain of ON cells was significantly lower than that of OFF cells with the HM treatment (P<0.015, unpaired Student's t test). The averaged contrast gain of ON cells was significantly higher than OFF cells with the HG treatment (P<0.0001). The present results suggest that HG reduced receptive field center size, suppressed luminance threshold, and attenuated contrast gain of RGCs. The impact of HG on ON and OFF RGCs may be mediated via different mechanisms. PMID- 29288427 TI - Comparative WGBS identifies genes that influence non-ripe phenotype in tomato epimutant Colourless non-ripening. AB - Whole-genome bisulfite sequencing (WGBS) allows single-base resolution and genome wide profiling of DNA methylation in plants and animals. This technology provides a powerful tool to identify genes that are potentially controlled by dynamic changes of DNA methylation and demethylation. However, naturally occurring epimutants are rare and genes under epigenetic regulation as well as their biological relevances are often difficult to define. In tomato, fruit development and ripening are a complex process that involves epigenetic control. We have taken the advantage of the tomato epimutant Colourless non-ripening (Cnr) and performed comparative mining of the WGBS datasets for the Cnr and SlCMT3-silenced Cnr fruits. We compared DNA methylation profiles for the promoter sequences of approximately 5,000 bp immediately upstream of the coding region of a list of 20 genes. Differentially methylated regions were found for some of these genes. Virus-induced gene silencing (VIGS) of differentially methylated gene SlDET1 or SlPDS resulted in unusual brown pigmentation in Cnr fruits. These results suggest that comparative WGBS coupled with VIGS can be used to identify genes that may contribute to the colourless unripe phenotype of fruit in the Cnr epimutant. PMID- 29288428 TI - Outcomes of previously untreated elderly patients with AML: a propensity score matched comparison of clofarabine vs. FLAG. AB - The 5-year overall survival (OS) in patients >= 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients >= 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred. PMID- 29288429 TI - Drug discovery, development and delivery in Alzheimer's disease. PMID- 29288430 TI - Co-precipitation molecules hemopexin and transferrin may be key molecules for fibrillogenesis in TTR V30M amyloidogenesis. AB - The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.2-hMet30 mice at 21-24 months of age. In addition, non-fibrillar TTR deposits were found in amyloid-negative 7.2hMet30 mice. These results suggested that TTR amyloidogenesis required not only mutant TTR but also an additional factor (or factors) as an etiologic molecule. To determine the differences in serum proteome in amyloid-positive and amyloid-negative mice in the 7.2-hMet30 model, we used proteomic analyses and studied serum samples obtained from these mice. Hemopexin (HPX) and transferrin (Tf) were detected in the serum samples from amyloid-positive mice and were also found in amyloid deposits via immunohistochemistry, but serum samples from amyloid-negative mice did not contain HPX and Tf. These two proteins were also not detected in non-fibrillar TTR deposits. In addition, in silico analyses suggested that HPX and Tf facilitate destabilization of TTR secondary structures and misfolding of TTR. These results suggest that HPX and Tf may be associated with TTR amyloidogenesis after fibrillogenesis in vivo. PMID- 29288431 TI - Thymus Colonization: Who, How, How Many? AB - De novo generation of T cells depends on continual colonization of the thymus by bone marrow-derived progenitors. Thymus seeding progenitors (TSPs) constitute a heterogeneous population comprising multipotent and lineage-restricted cell types. Entry into the thymic microenvironment is tightly controlled and recent quantitative studies have revealed that the adult murine thymus only contains approximately 160 niches to accommodate TSPs. Of these niches only about 6% are open for seeding on average at steady-state. Here, I review the state of understanding of colonization of the adult murine thymus with a particular focus on past and current controversies in the field. Improving thymus colonization and/or maintaining intact TSP niches during the course of pre-conditioning regimens are likely to be critical for efficient T-cell regeneration after hematopoietic stem cell transplantation. PMID- 29288432 TI - Open-Cup Drinking Development: A Review of the Literature. AB - To date, a lack of published research studies exist that systematically analyze the factors involved with the progression of open-cup drinking in typically developing infants and toddlers. As a result, clinicians who are working with children that have delays in open-cup drinking development have a limited framework from which to base clinical decisions. The purpose of this review is to collate works from disparate and related fields to provide a brief review of the literature of pertinent sensorimotor and cognitive components necessary for successful open-cup drinking development. PMID- 29288433 TI - Improving Dissolution Rate of Carbamazepine-Glutaric Acid Cocrystal Through Solubilization by Excess Coformer. AB - PURPOSE: The use of soluble cocrystals is a promising strategy for delivering poorly soluble drugs. However, precipitation of poorly soluble crystal form during dissolution hinders the successful tablet development of cocrystals. This work was aimed to understand the mechanisms for improving dissolution performance of a soluble cocrystals by using excess coformer. METHODS: A highly soluble carbamazepine (CBZ) cocrystal with- glutaric acid (GLA) was studied. Impact of excess GLA on solubility and intrinsic dissolution rate (IDR) was assessed. Viscosity of GLA solutions was also measured. Solid form of powders and pellets was examined using powder X-ray diffractometry. IDRs of cocrystal and GLA mixtures in different ratios were measured to identify a suitable formulation for maintaining high dissolution rate of CBZ-GLA in an aqueous environment. RESULTS: IDR of CBZ-GLA in a pH 1.2 HCl solution was improved when GLA was present in the solution. Precipitation of CBZ.2H2O was eliminated when GLA concentration was >=100 mg/mL. The improved IDR was accompanied by higher solubility of CBZ in GLA solution and increased solution viscosity. The trend in IDR profile matched well with the solubility profile normalized by solution viscosity. Mixture of cocrystal and GLA led to improved IDR in simulated intestinal fluid. CONCLUSIONS: The excess GLA increased the aqueous solubility of CBZ.2H2O and, thereby, reduced the propensity to precipitation of CBZ.2H2O during dissolution by lowering the degree of supersaturation. This strategy allowed development of a CBZ-GLA formulation with a significantly enhanced dissolution rate than CBZ-GLA. PMID- 29288434 TI - Quality of life at 6 years after occupational injury. AB - PURPOSE: Occupational injuries have considerable impact on workers' lives. However, data regarding workers' health-related quality of life (HRQOL) at several years after the injury are lacking. This study assessed workers' HRQOL at 6 years after occupational injury and determined related factors in each HRQOL domain. METHODS: Workers who sustained an occupational injury in 2009 and who responded to a previous survey at 3 or 12 months after their injury were followed up in 2015. A total of 1715 participants were candidates for this study. The Taiwanese version of the World Health Organization Quality of Life scale abbreviated version (WHOQOL-BREF) was used to assess their HRQOL. Multiple linear regression analysis identified predictive factors for HRQOL at 6 years after occupational injury. RESULTS: A total of 563 workers completed the questionnaire (response rate, 32.8%). Adverse life events and additional severe occupational injuries that occurred within the follow-up period, and decreased salary after the injury were significant factors for low scores in all domains of the WHOQOL BREF. In addition, unmarried participants had low scores in the social relationship domain. Workers with family members requiring care scored low in the physical and environment domains. Workers whose injuries had major effects on their physical appearance had low scores in the physical and psychological domains. Workers with unstable employment had low scores in physical, psychological, and environment domains. CONCLUSION: At 6 years after occupational injury, workers' HRQOL was poor among those whose salaries decreased after the injury, after adjustment for other factors. PMID- 29288435 TI - Balance Training Does Not Alter Reliance on Visual Information during Static Stance in Those with Chronic Ankle Instability: A Systematic Review with Meta Analysis. AB - BACKGROUND: Visual, vestibular, and somatosensory systems contribute to postural control. Chronic ankle instability (CAI) patients have been observed to have a reduced ability to dynamically shift their reliance among sources of sensory information and rely more heavily on visual information during a single-limb stance relative to uninjured controls. Balance training is proven to improve postural control but there is a lack of evidence regarding the ability of balance training programs to alter the reliance on visual information in CAI patients. OBJECTIVE: Our objective was to determine if balance training alters the reliance on visual information during static stance in CAI patients. METHODS: The PubMed, CINAHL, and SPORTDiscus databases were searched from their earliest available date to October 2017 using a combination of keywords. Study inclusion criteria consisted of (1) using participants with CAI; (2) use of a balance training intervention; and (3) calculation of an objective measure of static postural control during single-limb stance with eyes open and eyes closed. Sample sizes, means, and standard deviations of single-leg balance measures for eyes-open and eyes-closed testing conditions before and after balance training were extracted from the included studies. Eyes-open to eyes-closed effect sizes [Hedges' g and 95% confidence intervals (CI)] before and after balance training were calculated, and between-study variability for heterogeneity and potential risks of publication bias were examined. RESULTS: Six studies were identified. The overall eyes-open to eyes-closed effect size difference between pre- and post intervention assessments was not significant (Hedges' g effect size = 0.151, 95% CI = - 0.151 to 0.453, p = 0.26). This result indicates that the utilization of visual information in individuals with CAI during the single-leg balance is not altered after balance training. Low heterogeneity (Q(5) = 2.96, p = 0.71, I 2 = 0%) of the included studies and no publication bias were found. CONCLUSION: On the basis of our systematic review with meta-analysis, it appears that traditional balance training protocols do not alter the reliance on visual information used by CAI patients during a single-leg stance. PMID- 29288436 TI - The Relationships Between Internal and External Measures of Training Load and Intensity in Team Sports: A Meta-Analysis. AB - BACKGROUND: The associations between internal and external measures of training load and intensity are important in understanding the training process and the validity of specific internal measures. OBJECTIVES: We aimed to provide meta analytic estimates of the relationships, as determined by a correlation coefficient, between internal and external measures of load and intensity during team-sport training and competition. A further aim was to examine the moderating effects of training mode on these relationships. METHODS: We searched six electronic databases (Scopus, Web of Science, PubMed, MEDLINE, SPORTDiscus, CINAHL) for original research articles published up to September 2017. A Boolean search phrase was created to include search terms relevant to team-sport athletes (population; 37 keywords), internal load (dependent variable; 35 keywords), and external load (independent variable; 81 keywords). Articles were considered for meta-analysis when a correlation coefficient describing the association between at least one internal and one external measure of session load or intensity, measured in the time or frequency domain, was obtained from team-sport athletes during normal training or match-play (i.e., unstructured observational study). The final data sample included 122 estimates from 13 independent studies describing 15 unique relationships between three internal and nine external measures of load and intensity. This sample included 295 athletes and 10,418 individual session observations. Internal measures were session ratings of perceived exertion (sRPE), sRPE training load (sRPE-TL), and heart-rate-derived training impulse (TRIMP). External measures were total distance (TD), the distance covered at high and very high speeds (HSRD >= 13.1-15.0 km h-1 and VHSRD >= 16.9-19.8 km h-1, respectively), accelerometer load (AL), and the number of sustained impacts (Impacts > 2-5 G). Distinct training modes were identified as either mixed (reference condition), skills, metabolic, or neuromuscular. Separate random effects meta-analyses were conducted for each dataset (n = 15) to determine the pooled relationships between internal and external measures of load and intensity. The moderating effects of training mode were examined using random effects meta-regression for datasets with at least ten estimates (n = 4). Magnitude-based inferences were used to interpret analyses outcomes. RESULTS: During all training modes combined, the external load relationships for sRPE-TL were possibly very large with TD [r = 0.79; 90% confidence interval (CI) 0.74 to 0.83], possibly large with AL (r = 0.63; 90% CI 0.54 to 0.70) and Impacts (r = 0.57; 90% CI 0.47 to 0.64), and likely moderate with HSRD (r = 0.47; 90% CI 0.32 to 0.59). The relationship between TRIMP and AL was possibly large (r = 0.54; 90% CI 0.40 to 0.66). All other relationships were unclear or not possible to infer (r range 0.17-0.74, n = 10 datasets). Between-estimate heterogeneity [standard deviations (SDs) representing unexplained variation; tau] in the pooled internal external relationships were trivial to extremely large for sRPE (tau range = 0.00 0.47), small to large for sRPE-TL (tau range = 0.07-0.31), and trivial to moderate for TRIMP (tau range= 0.00-0.17). The internal-external load relationships during mixed training were possibly very large for sRPE-TL with TD (r = 0.82; 90% CI 0.75 to 0.87) and AL (r = 0.81; 90% CI 0.74 to 0.86), and TRIMP with AL (r = 0.72; 90% CI 0.55 to 0.84), and possibly large for sRPE-TL with HSRD (r = 0.65; 90% CI 0.44 to 0.80). A reduction in these correlation magnitudes was evident for all other training modes (range of the change in r when compared with mixed training - 0.08 to - 0.58), with these differences being unclear to possibly large. Training mode explained 24-100% of the between-estimate variance in the internal-external load relationships. CONCLUSION: Measures of internal load derived from perceived exertion and heart rate show consistently positive associations with running- and accelerometer-derived external loads and intensity during team-sport training and competition, but the magnitude and uncertainty of these relationships are measure and training mode dependent. PMID- 29288437 TI - Effect of impaired twitching motility and biofilm dispersion on performance of Pseudomonas aeruginosa-powered microbial fuel cells. AB - Pseudomonas aeruginosa is a metabolically voracious bacterium that is easily manipulated genetically. We have previously shown that the organism is also highly electrogenic in microbial fuel cells (MFCs). Polarization studies were performed in MFCs with wild-type strain PAO1 and three mutant strains (pilT, bdlA and pilT bdlA). The pilT mutant was hyperpiliated, while the bdlA mutant was suppressed in biofilm dispersion chemotaxis. The double pilT bdlA mutant was expected to have properties of both mutations. Polarization data indicate that the pilT mutant showed 5.0- and 3.2-fold increases in peak power compared to the wild type and the pilT bdlA mutant, respectively. The performance of the bdlA mutant was surprisingly the lowest, while the pilT bdlA electrogenic performance fell between the pilT mutant and wild-type bacteria. Measurements of biofilm thickness and bacterial viability showed equal viability among the different strains. The thickness of the bdlA mutant, however, was twice that of wild-type strain PAO1. This observation implicates the presence of dead or dormant bacteria in the bdlA mutant MFCs, which increases biofilm internal resistance as confirmed by electrochemical measurements. PMID- 29288438 TI - Synthetic biology, genome mining, and combinatorial biosynthesis of NRPS-derived antibiotics: a perspective. AB - Combinatorial biosynthesis of novel secondary metabolites derived from nonribosomal peptide synthetases (NRPSs) has been in slow development for about a quarter of a century. Progress has been hampered by the complexity of the giant multimodular multienzymes. More recently, advances have been made on understanding the chemical and structural biology of these complex megaenzymes, and on learning the design rules for engineering functional hybrid enzymes. In this perspective, I address what has been learned about successful engineering of complex lipopeptides related to daptomycin, and discuss how synthetic biology and microbial genome mining can converge to broaden the scope and enhance the speed and robustness of combinatorial biosynthesis of NRPS-derived natural products for drug discovery. PMID- 29288439 TI - Hyperhomocysteinemia in acute iatrogenic hypothyroidism: the relevance of thyroid autoimmunity. AB - PURPOSE: Hyperhomocysteinemia is a known cardiovascular risk factor and a key player in the inflammatory activation of autoimmune diseases. Hashimoto's thyroiditis (HT) is the leading cause of hypothyroidism which, in itself, has been associated with a significant raise of homocysteine (Hcy) levels and increased cardiovascular risk. Our aim was to assess the impact of HT on Hcy levels in patients with acute hypothyroidism. METHODS: We prospectively enrolled 121 patients (mean age: 46 years, F/M = 102/19) with acute post-surgical hypothyroidism. Based on the presence of anti-thyroid antibodies and the histological description of an inflammatory infiltrate, 26 and 95 patients were classified as HT and non-HT, respectively. Several parameters including thyroid stimulating hormone (TSH), levels of serum free T3 and free T4, weight, glucose levels, total cholesterol, creatinine, vitamin B12, ferritin and erythrocyte sedimentation rate were obtained from all patients and correlated with Hcy levels. RESULTS: Median Hcy level in the whole cohort was 16.8 umol/L (normal values: < 12 umol/l). Among all parameters analysed, only Hcy levels were significantly different between HT and non-HT patients (median Hcy = 19.7 vs 16.2 umol/L, respectively; p = 0.018, Mann-Whitney U test). Analysis of covariance showed the presence of HT to be the strongest predictor of Hcy levels (coefficient = 0.25534, p = 0.001). Serum TSH was not significantly associated with Hcy levels (p = 0.943). CONCLUSION: In patients with iatrogenic hypothyroidism, those with HT have significantly higher Hcy levels than those without HT. The increase of Hcy levels appears to be mainly determined by the HT related immune-inflammatory condition. PMID- 29288441 TI - Genetic Association Studies in Host-Pathogen Interaction Analysis. AB - Studying host-pathogen interactions at a molecular level has been always technically challenging. Identifying the different biochemical and genetic pathways involved in the different stages of infection traditionally require complex molecular biology tools and often the use of costly animal models. In this chapter we illustrate a complementary approach to address host-pathogen interactions, taking advantage of the natural interindividual genetic diversity. The application of genetic association studies allows us to identify alleles involved in infection progression or resistance. Thus, this strategy may be useful to unravel new molecular pathways underlying host-pathogen interactions. Here we present the general steps that might be followed to plan, execute, and analyze a population-based study in order to identify genetic variants affecting human exposition to pathogens. PMID- 29288442 TI - Bacterial Genotyping Methods: From the Basics to Modern. AB - Bacterial genotyping methods have been used in several areas of microbiology and have facilitated the identification of bacterial strains, as well as the study of virulence and resistance factors, epidemiological surveillance, among others. Constituting, in this way, as complementary or alternative to phenotypic methods. This chapter reviews some of the methods of bacterial genotyping used nowadays, explains briefly how they are performed, and highlights some limitations and advantages they have. PMID- 29288440 TI - Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis. AB - Mutations of isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, arguably preceding all known genetic alterations during tumor development. IDH1 mutations nearly invariably target the enzymatic active site Arg132, giving rise to the predominant IDH1R132H. Cells harboring IDH1 R132H -heterozygous mutation produce 2-hydroxyglutarate (2-HG), which results in histone and DNA hypermethylation. Although exogenous IDH1 R132H transduction has been shown to promote anchorage-independent growth, the biological role of IDH1R132H in glioma remains debatable. In this study, we demonstrate that heterozygous IDH1 R132H suppresses but hemizygous IDH1 R132H promotes anchorage-independent growth. Whereas genetic deletion of the wild-type allele in IDH1 R132H -heterozygous cells resulted in a pronounced increase in neurosphere genesis, restoration of IDH1 expression in IDH1 R132H -hemizygous cells led to the contrary. Conversely, anchorage-independent growth was antagonistic to the mutant IDH1 function by inhibiting gene expression and 2-HG production. Furthermore, we identified that in contrast to IDH1 R132H -hemizygous neurosphere, IDH1 R132H -heterozygous cells maintained a low level of reducing power to suppress neurosphere genesis, which could be bypassed, however, by the addition of reducing agent. Taken together, these results underscore the functional importance of IDH1 mutation heterozygosity in glioma biology and indicate functional loss of mutant IDH1 as an escape mechanism underlying glioma progression and the pathway of redox homeostasis as potential therapeutic targets. PMID- 29288443 TI - Real-Time Reverse Transcription PCR as a Tool to Study Virulence Gene Regulation in Bacterial Pathogens. AB - Quantitative real-time PCR (qRT-PCR) is a highly sensitive and reliable method for detection and quantification of DNA. When combined with a prior stage of RNA reverse transcription to generate complementary DNA (cDNA), this is a powerful approach to determine and analyze gene transcriptional expression. Real-time quantitative reverse transcription PCR has become the gold standard method in studying genes expression and virulence regulation under various genetic backgrounds (e.g., in the absence of regulators) or environmental conditions. Here we demonstrate the utilization of this approach to study the transcriptional regulation of the conjugation pilus of the Salmonella enterica serovar Infantis virulence plasmid (pESI). PMID- 29288444 TI - Usage of a Bioluminescence Reporter System to Image Promoter Activity During Host Infection. AB - Bioluminescence is the process of production and emission of light by a living organism, usually as the by-product of the oxidative enzyme, luciferase. Currently available technology allows for the exploitation of a bioluminescent reporter system to study bacterial gene regulation during rodent infection, in real time, over a large dynamic range. Here we show how this imaging system can be used to study virulence gene regulation during Salmonella enterica infection in the mouse model. To demonstrate this technique we show the ex vivo expression pattern of the gene dksA, encoding a conserved and pleotropic regulator, which plays a key role in Salmonella pathogenicity [1]. PMID- 29288445 TI - lacZ Reporter System as a Tool to Study Virulence Gene Regulation in Bacterial Pathogens. AB - beta-galactosidase assay has been established as one of the most widely used reporters and can be effectually exploited to study promoter activity of Salmonella and other pathogens under various conditions. This method includes a preliminary stage of fusing the target promoter to a promoter-less lacZ gene encoding for the enzyme beta-galactosidase. Supplementation of the synthetic ONPG substrate results in the accumulation of a chromogenic product proportionally to the activity of the fused promoter. Here we demonstrate the usage of this reporter system to study the regulation of the Salmonella Type three secretion system effector gene sseL in S. Typhimurium [1]. PMID- 29288446 TI - Western Blotting Against Tagged Virulence Determinants to Study Bacterial Pathogenicity. AB - Western blotting is a common approach to detect the presence of a target protein in biological samples or proteins mixture using specific antibodies. This method is also useful to study regulation of virulence determinants by analyzing changes in protein expression between different genetic backgrounds or under varying environmental conditions. To avoid the need to raise specific antibodies for each studied protein, commercial antibody against commonly used peptidic epitopes can be utilized if the right target tagged version is constructed. Here we describe a C-terminal fusion between a protein of interest and the two hemagglutinin A (2HA) tag. The tagged protein is cloned into a low-copy number vector and expressed under its native promoter in Salmonella enterica. Then, the expression of the tagged protein can be analyzed by Western blotting and commercially available anti-2HA antibodies. PMID- 29288447 TI - Molecular Methods to Analyze the Effect of Proteins Expressed by Salmonella During Its Intracellular Stage. AB - Salmonella is probably the intracellular pathogen most extensively studied. Once inside the cell, this bacterium produces different proteins involved in the infection process known as effectors that translocate through its own secretion systems to the eukaryotic cytosol exerting diverse effects on the cell. Additionally, Salmonella can be engineered to include a protein expression system that, upon the addition of an inducer molecule, can produce heterologous proteins at a specific time during the course of the infection. The effect of such proteins on the eukaryotic (i.e., tumoral) cells can be detected following distinct approaches, which converts Salmonella in an effective tool to produce proteins inside eukaryotic cells with different purposes, such as killing tumoral cells. Here, we present diverse technics currently used to produce proteins by Salmonella inside tumoral cells and analyze its cytotoxic effect. PMID- 29288448 TI - Organoids as a Model to Study Infectious Disease. AB - The advent of the gastric organoid culture system has provided a new model to emulate native epithelial tissue in vitro. Gastric organoids grow from isolated epithelial stem cells and develop into three dimensional structures that can be used to study host physiology. Here we describe current laboratory protocols for growing gastric organoids and the microinjection of pathogens such as Helicobacter pylori into the lumen of gastric organoids in order to study the cellular response following infection. PMID- 29288449 TI - Surface Proteome Biotinylation Combined with Bioinformatic Tools as a Strategy for Predicting Pathogen Interacting Proteins. AB - Constant advancements in methodology and mass spectrometry instrumentation, genome sequencing and bioinformatic tools have enabled the identification of numerous pathogen proteomes. Identifying the pathogen interacting proteins by means of high-throughput techniques is key for understanding pathogen invasion and survival mechanisms and in such a way proposing specific proteins as pharmaceutical targets. Herein we describe the methodology for the enrichment and identification of pathogen surface proteome using cell surface protein biotinylation followed by LC-MS/MS and bioinformatic analyses of such data. This strategy is to be employed for the determination of protein subcellular localization and prediction of potential pathogen interacting proteins. PMID- 29288450 TI - Systems Biology Modeling to Study Pathogen-Host Interactions. AB - Pathogen-host interactions (PHIs) underlie the process of infection. The systems biology view of the whole PHI system is superior to the investigation of the pathogen or host separately in understanding the infection mechanisms. Especially, the identification of host-oriented drug targets for the next generation anti-infection therapeutics requires the properties of the host factors targeted by pathogens. Here, we provide an outline of computational analysis of PHI networks, focusing on the properties of the pathogen-targeted host proteins. We also provide information about the available PHI data and the related Web-based resources. PMID- 29288451 TI - Phage Therapy: Various Perspectives on How to Improve the Art. AB - Use of phages as antibacterial agents has a long and, even, storied history. During that time much has been learned but, to a degree, also forgotten. As a consequence, today we experience a largely preclinical development of a field which already has been subject to substantial clinical practice. This development, as well, is now occurring within a much more rigorously regulated environment than previously had been the case. The consequence is not only a need to reinvent standards of practice but to do so within a more explicitly pharmacological context. Of particular concern is that the application of phages to bacterial infections does not always result in control of the latter, necessitating ongoing thought on how to refine treatment protocols. Here I consider a number of issues relevant to such refinement, focusing on areas which, in my opinion, phage therapy researchers-perhaps especially those new to the field-might struggle with. In order of presentation, I consider how best to describe phage therapy within publications toward achieving a more coherent literature, the importance of Poisson distributions along with killing titers toward understanding phage dosing, the associated importance of establishing sufficient phage numbers in situ to achieve adequate bacteria killing, various problems with the use of multiplicity of infection (MOI) as a description of phage dosing, how to anticipate the basic kinetics of phage-bacteria absorptive interactions, how to distinguish passive from active treatments, and basic approaches toward addressing disappointing efficacy outcomes. PMID- 29288452 TI - Application of RNA-seq and Bioimaging Methods to Study Microbe-Microbe Interactions and Their Effects on Biofilm Formation and Gene Expression. AB - Complex interactions between pathogenic bacteria, the microbiota, and the host can modify pathogen physiology and behavior. We describe two different experimental approaches to study microbe-microbe interactions in in vitro systems containing surface-associated microbial populations. One method is the application of RNA sequencing (RNA-seq) to determine the transcriptional changes in pathogenic bacteria in response to microbial interspecies interactions. The other method combines flow cell devices for bacterial cultivation and growth with high-resolution bioimaging to analyze the microscale structural organization of interacting microbial populations within mixed-species biofilms. PMID- 29288453 TI - Serial Dilution-Based Growth Curves and Growth Curve Synchronization for High Resolution Time Series of Bacterial Biofilm Growth. AB - The ability to form stable surface-attached communities called biofilms is of paramount importance to both beneficial and harmful interactions between microbes and microbial, plant or animal partners. Assessment of biofilm formation ability is often performed by growing the organisms in microtiter plate wells and staining the well-attached material, a method whose use for time-course analysis is limited by its destructive nature. Here we combine a serial dilution-based biofilm growth curve method with online monitoring of planktonic growth and a serially diluted growth curve synchronization algorithm to reconstruct the time course of planktonic and biofilm growth. As demonstrated here with the rhizosphere bacterium Pseudomonas putida, the method allows accurate determination of the growth rate and doubling time, a robust depiction of the biofilm formation and dispersal dynamics and assessment of the biofilm development defects in mutant strains. PMID- 29288454 TI - Detection of Bacterial Quorum Sensing Molecules. AB - Bacterial cells use the quorum sensing system to communicate with each other. The gram-negative species very often use N-acyl homoserine lactones for this purpose. One of the easiest ways to detect these molecules is the use of particular reporter strains, which possess different kinds of reporter genes under the control of AHL-responsive promoters. Here we present some of the possibilities available today, even for not specialized researchers. PMID- 29288455 TI - Generating Chromosome-Located Transcriptional Fusions to Fluorescent Proteins for Single-Cell Gene Expression Analysis in Pseudomonas syringae. AB - The last decade has seen significant effort directed toward the role of phenotypic heterogeneity in bacterial adaptation. Phenotypic heterogeneity usually refers to phenotypic diversity that takes place through nongenetic means, independently of environmental induced variation. Recent findings are changing how microbiologists analyze bacterial behavior, with a shift from traditional assays averaging large populations to single-cell analysis focusing on bacterial individual behavior. Fluorescence-based methods are often used to analyze single cell gene expression by flow cytometry, fluorescence microscopy and/or microfluidics. Moreover, fluorescence reporters can also be used to establish where and when are the genes of interest expressed. In this chapter, we use the model bacterial plant pathogen Pseudomonas syringae to illustrate a method to generate chromosome-located transcriptional gene fusions to fluorescent reporter genes, without affecting the function of the gene of interest. PMID- 29288456 TI - Introduction of Genetic Material in Ralstonia solanacearum Through Natural Transformation and Conjugation. AB - Ralstonia solanacearum is a soil-borne plant pathogen, responsible of the bacterial wilt disease. Its unusual wide host range (more than 250 plant species), aggressiveness, and broad geographic distribution have made of this bacterium the main plant pathogenic model in the beta-Proteobacteria class. Many R. solanacearum strains have the ability to internalize exogenous DNA through natural transformation. This property is widely used in reverse genetics studies to create mutants or reporter gene constructs, in the aim to study the molecular bases of pathogenesis of this bacterium. In this chapter, we describe three in vitro methods (natural transformation, electrotransformation, and conjugation) commonly used to produce recombinant R. solanacearum cells after introduction of exogenous DNA. PMID- 29288457 TI - In Vitro and In Vivo Secretion/Translocation Assays to Identify Novel Ralstonia solanacearum Type 3 Effectors. AB - Phytopathogenic bacteria have evolved multiple strategies to infect plants. Like many gram-negative bacteria, Ralstonia solanacearum, the causal agent of bacterial wilt, possesses a specialized protein secretion machinery to deliver effector proteins directly into the host cells. This type 3 secretion system (T3SS) and the bacterial proteins translocated, called type 3 effectors (T3Es), constitute the main pathogenicity determinants of the R. solanacearum species complex (RSSC). Up to 113 orthologous groups defining T3E genes have been identified among the RSSC strains sequenced to date. The increasing number of R. solanacearum genomic sequences available still expands the number of T3E candidates which require experimental validation. Here, we describe in vitro (type 3 secretion) and in vivo (type 3 translocation based on CyaA' reporter gene) methods to identify and validate type 3-dependent delivery of proteins of interest highlighted as candidate T3Es. We also present protocols to generate dedicated vectors and R. solanacearum transformation to perform these experiments. PMID- 29288458 TI - Plant Pathogenicity Phenotyping of Ralstonia solanacearum Strains. AB - In this chapter, we describe different methods for phenotyping strains or mutants of the bacterial wilt agent, Ralstonia solanacearum, on four different host plants: Arabidopsis thaliana, tomato (Solanum lycopersicum), tobacco (Nicotiana benthamiana), or Medicago truncatula. Methods for preparation of high volume or low volume inocula are first described. Then, we describe the procedures for inoculation of plants by soil drenching, stem injection or leaf infiltration, and scoring of the wilting symptoms development. Two methods for measurement of bacterial multiplication in planta are also proposed: (1) counting the bacterial colonies upon serial dilution plating and (2) determining the bacterial concentration using a qPCR approach. In this chapter, we also describe a competitive index assay to compare the fitness of two strains coinoculated in the same plant. Lastly, specific protocols describe in vitro and hydroponic inoculation procedures to follow disease development and bacterial multiplication in both the roots and aerial parts of the plant. PMID- 29288459 TI - Methods to Quantify Biotic-Induced Stress in Plants. AB - Plant pathogens such as fungi, oomycetes, viruses and bacteria infect important crops and account for significant economic losses worldwide. Therefore, it is critical to gain insights into plant-pathogen interactions at the cellular and molecular level. The outcome of the interaction between plants and pathogens greatly differs depending on the species, strains and cultivars involved as well as environmental factors, yet typically results in stress for the plant, the pathogen or both. These biotic-induced stresses can be monitored using a wide range of techniques, of which some of the most commonly used techniques are outlined in this chapter. One widely observed feature of biotic stress in plants is the generation of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and superoxide (O2-). We describe the quantification of hydrogen peroxide by 3,3'-diaminobenzidine (DAB) staining and luminol-based assays, and of superoxide by nitroblue tetrazolium (NBT) staining. Other techniques detailed here include measurement of callose deposition by aniline blue staining, evaluation of cell death by trypan blue staining and analysis of the loss of membrane integrity by monitoring electrolyte leakage. PMID- 29288460 TI - From Sample to Data: Preparing, Obtaining, and Analyzing Images of Plant-Pathogen Interactions Using Confocal Microscopy. AB - This chapter describes the steps needed to inoculate host plants with a fungus of interest, and subsequently to visualize the infection using confocal microscopy. As an exemplar, we consider the interaction between wheat and the Septoria leaf blotch fungus, Zymoseptoria tritici. This method is easiest when a GFP- or other fluorophore-tagged strain of the studied fungus is available, but notes are also provided which describe possible staining techniques which may be employed if fluorescent fungus is unavailable in your system. PMID- 29288461 TI - Screening of c-di-GMP-Regulated Exopolysaccharides in Host Interacting Bacteria. AB - Bacterial exopolysaccharides (EPS) often confer a survival advantage by protecting the cell against abiotic and biotic stresses, including host defensive factors. They are also main components of the extracellular matrix involved in cell-cell recognition, surface adhesion and biofilm formation. Biosynthesis of a growing number of EPS has been reported to be regulated by the ubiquitous second messenger c-di-GMP, which promotes the transition to a biofilm mode of growth in an intimate association with the eukaryotic host. Here we describe a strategy based on the combination of an approach to artificially increase the intracellular level of c-di-GMP in virtually any gram-negative bacteria with a high throughput screening (HTS) for the identification of monosaccharide composition and carbohydrate fingerprinting of novel EPS, or modified variants, that can be involved in host-bacteria interactions. PMID- 29288462 TI - Primary Characterization of Small RNAs in Symbiotic Nitrogen-Fixing Bacteria. AB - High-throughput transcriptome profiling (RNAseq) has uncovered large and heterogeneous populations of small noncoding RNA species (sRNAs) with potential regulatory roles in bacteria. A large fraction of sRNAs are differentially regulated and rely on protein-assisted antisense interactions to trans-encoded target mRNAs to fine-tune posttranscriptional reprogramming of gene expression in response to external cues. However, annotation and function of sRNAs are still largely overlooked in nonmodel bacteria with complex lifestyles. Here, we describe experimental protocols successfully applied for the accurate annotation, expression profiling and target mRNA identification of trans-acting sRNAs in the nitrogen-fixing alpha-rhizobium Sinorhizobium meliloti. The protocols presented here can be similarly applied for the characterization of trans-sRNAs in genetically tractable alpha-proteobacteria of agronomical or clinical relevance interacting with eukaryotic hosts. PMID- 29288463 TI - A New, Nondestructive, Split-Root System for Local and Systemic Plant Responses Studies with Soybean. AB - Plants use long-distance signaling mechanisms to coordinate their growth and control their interactions, positive or negative, with microbes. Split-root systems (SRS) have been used to study the relevance of both local and systemic plant mechanisms that participate in the control of rhizobia-legume symbioses. In this work we have developed a modification of the standard split-root system (SRS) used with soybean. This modified method, unlike previous systems, operates in hydroponics conditions and therefore is nondestructive and allows for the continuous monitoring of soybean roots throughout the whole experiment. PMID- 29288464 TI - Methods for the Characterization of Plant-Growth Promoting Rhizobacteria. AB - A detailed description of methods most frequently used for the identification and characterization of beneficial microbial strains is presented in this chapter. The methods include microbiological, biochemical, and molecular approaches. Microbiological and biochemical methods comprise a broad range of techniques that are based on the analysis of phosphate solubilization, nitrogenase activity, indole-3-acetic acid production, bacterial motility, presence of catalase and nitrate reductase enzyme, Gram's staining of the cell wall, siderophore production, and microbial chemotaxis. The molecular methods involve a range of techniques that are based on the extraction and analysis of microbial DNA. The extracted nucleic acid can be specifically amplified using polymerase chain reaction (PCR), and subsequently cloned and sequenced. The sequencing of conserved genes such as internal transcribed spacer (ITS) region or 16S rRNA in a microbial genome is used extensively in resolving taxonomic identity of microbial strains. These methods are highly sensitive and allow for a high degree of specificity. PMID- 29288465 TI - Numerical Comparison of Nasal Aerosol Administration Systems for Efficient Nose to-Brain Drug Delivery. AB - PURPOSE: Nose-to-brain drug administration along the olfactory and trigeminal nerve pathways offers an alternative route for the treatment of central nervous system (CNS) disorders. The characterization of particle deposition remains difficult to achieve in experiments. Alternative numerical approach is applied to identify suitable aerosol particle size with maximized inhaled doses. METHODS: This study numerically compared the drug delivery efficiency in a realistic human nasal cavity between two aerosol drug administration systems targeting the olfactory region: the aerosol mask system and the breath-powered bi-directional system. Steady inhalation and exhalation flow rates were applied to both delivery systems. The discrete phase particle tracking method was employed to capture the aerosol drug transport and deposition behaviours in the nasal cavity. Both overall and regional deposition characteristics were analysed in detail. RESULTS: The results demonstrated the breath-powered drug delivery approach can produce superior olfactory deposition with peaking olfactory deposition fractions for diffusive 1 nm particles and inertial 10 MUm. While for particles in the range of 10 nm to 2 MUm, no significant olfactory deposition can be found, indicating the therapeutic agents should avoid this size range when targeting the olfactory deposition. CONCLUSIONS: The breath-powered bi-directional aerosol delivery approach shows better drug delivery performance globally and locally, and improved drug administration doses can be achieved in targeted olfactory region. PMID- 29288466 TI - Solvent effect on the degree of (a)synchronicity in polar Diels-Alder reactions from the perspective of the reaction force constant analysis. AB - In this work, we computationally evaluated the influence of six different molecular solvents, described as a polarizable continuum model at the M06-2X/6 31+G(d,p) level, on the activation barrier/reaction rate, overall energy change, TS geometry, and degree of (a)synchronicity of two concerted Diels-Alder cycloadditions of acrolein (R1) and its complex with Lewis acid acrolein...BH3 (R2) to cyclopentadiene. In gas-phase, we found that both exothermicity and activation barrier are only reduced by about 2.0 kcal mol-1, and the asynchronicity character of the mechanism is accentuated when BH3 is included. An increment in the solvent's polarity lowers the activation energy of R1 by 1.3 kcal mol-1, while for R2 the reaction rate is enhanced by more than 2000 times at room temperature (i.e., the activation energy decreases by 4.5 kcal mol-1) if the highest polar media is employed. Therefore, a synergistic effect is achieved when both external agents, i.e., Lewis acid catalyst and polar solvent, are included together. This effect was ascribed to the ability of the solvent to favor the encounter between cyclopentadiene and acrolein...BH3. This was validated by the asymmetry of the TS which becomes highly pronounced when either both or just BH3 is considered or the solvent's polarity is increased. Finally, the reaction force constant kappa(xi) reveals that an increment in the solvent's polarity is able to turn a moderate asynchronous mechanism of the formation of the new C-C sigma bonds into a highly asynchronous one. Graphical abstract A synergistic effect is achieved when both external agents, i.e., Lewis acid catalyst and polar solvent, are included together: lowered energy barriers and increased asynchronicities. PMID- 29288467 TI - Prognostic factors of regrowth in nonfunctioning pituitary tumors. AB - Surgery is the treatment of choice for nonfunctioning pituitary tumors (NFPTs). Postoperative tumor regrowth during follow-up is present in about half of the patients with invasive NFPTs with residual tumor but occurs also in 15% of patient without residue. Therapeutic strategies should consider this risk of recurrence and the potential side effects associated with therapeutic options. Identification of prognostic markers is mandatory to help clinicians to predict the risk of recurrence and to choose the best strategy between conservative follow-up, second surgery, postoperative adjuvant radiation therapy, and medical treatment (dopamine agonists, somatostatin analogs). Recent advances in pathological classification may be the first step for identification of NFPTs with a high risk of recurrence. PMID- 29288469 TI - Solubilization of phosphorus from phosphate rocks with Acidithiobacillus thiooxidans following a growing-then-recovery process. AB - Phosphorus is an essential nutrient for the synthesis of biomolecules and is particularly important in agriculture, as soils must be constantly supplemented with its inorganic form to ensure high yields and productivity. In this paper, we propose a process to solubilize phosphorus from phosphate rocks, where Acidithiobacillus thiooxidans cultures are pre-cultivated to foster the acidic conditions for bioleaching-two-step "growing-then-recovery"-. Our method solubilizes 100% of phosphorus, whereas the traditional process without pre cultivation-single-step "growing-and-recovery"-results in a maximum of 56% solubilization. As a proof of principle, we demonstrate that even at low concentrations of the phosphate rock, 1% w/v, the bacterial culture is unviable and biological activity is not observed during the single-step process. On the other hand, in our method, the bacteria are grown without the rock, ensuring high acid production. Once pH levels are below 0.7, the mineral is added to the culture, resulting in high yields of biological solubilization. According to the Fourier Transform Infrared Spectroscopy spectrums, gypsum is the dominant phosphate phase after both the single- and two-step methods. However, calcite and fluorapatite, dominant in the un-treated rock, are still present after the single step, highlighting the differences between the chemical and the biological methods. Our process opens new avenues for biotechnologies to recover phosphorus in tropical soils and in low-grade phosphate rock reservoirs. PMID- 29288468 TI - Interactions between bradykinin and plasmin in the endothelial Ca2+ response. AB - Plasmin is a fibrinolytic factor and a serine protease that activates protease activated receptors (PARs) to produce endothelium-derived relaxing factors such as nitric oxide and prostacyclin. Nitric oxide and prostacyclin production is regulated, at least in part, by the intracellular Ca2+ concentration in various blood vessel types. Bradykinin and plasmin stimulate vascular endothelial cells and work simultaneously in pathophysiological conditions such as thrombosis and inflammation. Here, we explored the interactions between bradykinin and plasmin in the endothelial Ca2+ response using the fluorescent indicator, Fura-2/AM, in primary cultures of porcine aortic endothelial cells (PAECs). Plasmin (0.15-15 ug/ml) and bradykinin (0.1-10 nM) increased intracellular Ca2+ concentrations in PAECs in a dose-dependent manner, and the plasmin-induced endothelial Ca2+ response occurred only once. Bradykinin (0.1-10 nM) inhibited the plasmin-induced endothelial Ca2+ response in a dose-dependent manner, however, plasmin did not affect the bradykinin-induced endothelial Ca2+ response. Pretreatment with gabexate mesilate (GM, 100 uM), a serine protease inhibitor, that blocks plasmin's proteolytic activity, fully suppressed the plasmin-induced Ca2+ response. After washout of GM and the first plasmin, the second administration of plasmin caused Ca2+ increases. However, when the first plasmin-induced Ca2+ response was blocked by pretreatment with bradykinin, the second plasmin (15 ug/ml) application did not cause any Ca2+ response, even 30 min after the washout of the first plasmin and bradykinin. Our data suggested that bradykinin regulated the plasmin-induced endothelial Ca2+ response by inhibiting the pathway downstream of the PARs' N-terminus cleavage. PMID- 29288470 TI - Assessing Racial Disparities in HCV Infection and Care Outcomes in a Southern Urban Population. AB - OBJECTIVES: This study assessed racial disparities in access to healthcare services, hepatitis C virus (HCV) exposure, and retention in a treatment cascade in two indigent populations in an urban center in the Southern US. PARTICIPANTS/METHODS: Opt-in HCV antibody screening was offered at two large homeless centers and three residential substance abuse treatment centers (SATCs) in New Orleans, LA. Five hundred ninety-four participants experiencing homelessness and 342 residents of SATCs were assessed for previous access/perceived barriers to healthcare services and high-risk behaviors associated with HCV exposure. Participants were then screened using rapid HCV antibody testing and tracked through a treatment cascade involving referral to a primary care provider (PCP), RNA confirmation, and specialist referral. RESULTS: In both the homeless and SATC populations, whites were more likely to report barriers to accessing healthcare and high-risk behaviors, especially prior intravenous drug use (IVDU). Interaction between age and race demonstrates a protective effect of white ethnicity at higher ages, at a level approaching statistical significance. Non-whites were equally likely to access follow-up care and treatment as whites. CONCLUSIONS: Despite many more risk factors reported by the white population, HCV antibody positivity was largely equal between the two racial groups. Known interactions between race and age in the African American population were demonstrated in these high-risk, urban populations. Whites were no more likely to achieve various levels of a treatment and care cascade. The results may demonstrate the impact of improved access to testing services and primary care, although access to treatment remains a significant barrier to eliminating racial disparities in HCV infection. PMID- 29288471 TI - Chemokines CXCL10, CXCL11, and CXCL13 in acute disseminated encephalomyelitis, non-polio enterovirus aseptic meningitis, and neuroborreliosis: CXCL10 as initial discriminator in diagnostic algorithm? AB - We investigated potential diagnostic usefulness of serum and cerebrospinal fluid (CSF) concentrations of chemokines CXCL10, CXCL11, and CXCL13 in pediatric patients with acute disseminated encephalomyelitis (ADEM) (n = 23), non-polio enterovirus aseptic meningitis (NPEV AM) (n = 20), and neuroborreliosis (NB) (n = 21) and children with acute infectious diseases with neurological symptoms but with excluded neuroinfection/neuroinflammation (controls, n = 20). CSF levels of CXCL10 and CXCL11 were higher in patients with NPEV AM than those in other children, and CXCL10 levels showed a high discriminative potential (area under the receiver operating characteristic curve, ROC, 0.982) with high specificity and sensitivity (both 95%). CSF levels of CXCL13 were higher in NB patients than those in other children; however, discriminative potential (area under ROC curve 0.814) and diagnostic properties were moderate (sensitivity 67%, specificity 97%). Data suggest usefulness of chemokine quantification as a diagnostic aid in children with suspected ADEM, NPEV AM, or NB. PMID- 29288472 TI - Inferior vena cava filters: use or abuse? PMID- 29288473 TI - Genomic analysis of a novel picornavirus from a migratory waterfowl, greater white-fronted goose (Anser albifrons). AB - The complete genome of goose picornavirus 1 (GPV-1) strain goose/NLSZK2/HUN/2013 (MF358731) was determined by RT-PCR and next-generation sequencing from a cloacal sample of a migratory waterfowl, greater white-fronted goose (Anser albifrons) in Hungary. The genome of GPV-1 shows an L-3-3-4 organization pattern with a 5' terminal origin of replication (ORI) region, a type-IV IRES, and an Hbox/NC-type 2A protein. This virus showed the highest overall sequence identity to the members of the genus Kobuvirus, although the phylogenetic position of GPV-1 is different in the analyzed P1, 2C and 3CD phylogenetic trees, which further increases the diversity of known avian picornaviruses. PMID- 29288475 TI - Cancer Pain Management at Oncology Units: Comparing Knowledge, Attitudes and Perceived Barriers Between Physicians and Nurses. AB - Pain is a major symptom that causes suffering among patients diagnosed with cancer. Identifying physicians' and nurses' knowledge, attitudes, and their perceived barriers of cancer pain management is considered an essential step in improving cancer pain relief. The purposes of this study are to compare physicians' and nurses' knowledge and attitudes toward cancer pain management (CPM) and describe their perceived barriers to CPM at oncology units. A descriptive cross-sectional design was utilized to obtain data through self report questionnaire. The total number of sample size was 207 participants (72 physicians and 135 nurses). Findings revealed that both physicians and nurses had fair knowledge and attitudes toward CPM. Physicians had significantly higher knowledge and better attitudes than nurses (62.3 vs. 51.5%, respectively). Physicians were knowledgeable about pharmacological pain management and opioid addiction but had negative attitudes toward pain assessment. Nurses' knowledge was better in regard of CPM guidelines, while they had poor knowledge about pharmacological pain management and opioid addiction. Physicians and nurses perceived knowledge deficit, lack of pain assessment, opioid unavailability, and lack of psychological interventions as the most common barriers to CPM. It is recommended to integrate recent evidence-based guidelines about CPM in oncology units that aim to improve practice. Offering continuing education courses in hospitals guided by pain teams is another essential recommendation for effective CPM. PMID- 29288474 TI - Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects. AB - The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran's Q statistic and I2 analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25-30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30-1.61; I2 = 43.0%). Subjects with BMI >= 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24-1.63; I2 = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger's regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30-1.58 vs. SOR 1.16, 95% CI 1.07-1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation. PMID- 29288476 TI - Rare lung diseases - should we pay more attention? PMID- 29288477 TI - Pulmonary langerhans cell histiocytosis - insight into the incidence of alfa-1 antitrypsin (A1ATD) deficiency alleles. AB - INTRODUCTION: The alpha-1 antitrypsin deficiency (A1ATD) is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. There is no data regarding prevalence of main, clinically most important A1ATD alleles PI*Z and PI*S in patients with pulmonary Langerhans cell histiocytosis (PLCH). PLCH is not only strongly linked to the cigarette smoking, but is also characterised by polycystic lung lesions. The goal of the study was to assess the incidence of A1ATD alleles in patients with PLCH. MATERIAL AND METHODS: Blood samples were collected from 34 adult patients (14 women and 20 men), with histologically confirmed PLCH. AAT serum concentration was assessed by nephelometry and PI-phenotype, identified by isoelectrofocusing. The PI*S and PI*Z alleles were confirmed by genotyping usisng real-time PCR. RESULTS: Deficiency alleles PI*Z and PI*S were detected in 3 patients (one woman and 2 men), respectively in 5.88% and 2.94%. The estimated incidence of deficiency alleles was 29.4/1000 (95% CI; 10-69.5) for PI*Z and 14.7/1000(95%CI; 13.9-43.3) for PI*S. According to our previous reports, the expected prevalence of PI*Z and PI*S alleles in general Polish population was 13.7/1000 (95% CI 5.8-21.5), and 7,6/1000 (95% CI 1.7-13.5) respectively. CONCLUSIONS: The incidence of main A1AT deficiency alleles in patients with PLCH seems higher than in general Polish population. The study is on-going. PMID- 29288478 TI - Cryobiopsy versus forceps biopsy in endobronchial lesions, diagnostic yield and safety. AB - INTRODUCTION: This study aimed to evaluate the safety and diagnostic yield of CB in comparison to forceps biopsy in endobronchial lesions. MATERIAL AND METHODS: Patients with suspected endobronchial lesions were enrolled. Two forceps biopsies and one cryobiopsy were done in the same patient with randomized sequence. The largest diameter of the samples was measured in mm by electronic caliper. Diagnostic yield of each technique and postbronchoscopy bleeding were evaluated. RESULTS: Samples obtained by CB was significantly larger than that of the forceps biopsy (5.9 +/- 2.3 vs 2.5 +/- 0.8), (p = 0.001). Diagnostic yield of CB was significantly higher than forceps biopsy 74.5% versus 51.1% (p = 0.001). Mild and moderate bleeding grades were reported in both techniques with no significant difference (p = 0.063) (p = 0.5) respectively. Severe bleeding was not recorded in both techniques. CONCLUSIONS: CB represents a safe and effective tool to obtain a larger tissue samples of a good quality with higher diagnostic yield in comparison to standard forceps samples. On the other hand, bleeding occurred more frequently after CB than forceps biopsy. However, without severe adverse effects. PMID- 29288479 TI - Histone deacetylases affect transcriptional regulation of CCL2 and CXCL8 expression by pulmonary fibroblasts in vitro. AB - INTRODUCTION: Chemokines have been shown to play an important role in tissue remodeling and fibrosis in the respiratory system. In this study we wanted to evaluate the mechanisms, which regulate the expression of selected chemokines by pulmonary fibroblasts in vitro. MATERIAL AND METHODS: Pulmonary fibroblasts were cultured with and without bacterial lipopolysaccharide (LPS) for 6 hours. In addition some of the cultures were pre-treated with histone deacetylase inhibitor Trichostatin A (TSA). Real-time PCR reaction was performed to estimate the expression of chemokines CCL2, CCL3 and CXCL8. RESULTS: In unstimulated cultures detectable expression of CCL2 and CXCL8 was observed, while CCL3 expression could not be detected. After stimulation with LPS, TSA and both agents together CCL2 expression rose by 1.52, 1.62 and 1.8 times in comparison to control cultures respectively. CXCL8 mRNA expression levels after stimulation with LPS, TSA and LPSTSA increased by 1.53, 1.91 and 2.4 times accordingly. CONCLUSION: Epigenetic mechanisms related to histone acetylation affects transcriptional regulation of CCL2 and CXCL8 expression by pulmonary fibroblasts. Those mechanisms may play a role in tissue repair and pathologic remodeling. PMID- 29288480 TI - The utility of selected questionnaires in the assessment of fatigue, depression and health quality in post-sarcoidosis fatigue syndrome. AB - INTRODUCTION: The nature of post-sarcoidosis fatigue syndrome (PSFS) is unknown and tools for the assessment of health quality (HQ) in these patients have not been fully assessed. The aim was to validate the Polish version of sarcoidosis health questionnaire (SHQ) and verify the association of HQ with fatigue and depressive symptoms among Polish patients with PSFS. MATERIAL AND METHODS: 71 patients with sarcoidosis (34 women, the mean age 47) were divided to: PSFS (n = 21), active sarcoidosis (S-A, n = 27) and sarcoidosis with complete remission (S R, n = 23) groups. Fatigue Assessment Scale (FAS) was used to define significant fatigue (>= 22 points). Polish version of SHQ was prepared by the authors and validated. Beck Depression Index (BDI) and Patient Health Questionnaire 9 (PHQ-9) were used to evaluate self-reported depressive symptoms. RESULTS: Polish version of SHQ was proved reliable and valid. HQ was worse and depressive symptoms were more frequent in PSFS and S-A when compared with S-R group. SHQ total score correlated negatively with depressive symptoms (r = -0.787 for BDI and r = -0,755 for PHQ-9, p < 0.01). A negative correlation between SHQ and FAS score was found (r = -0.784, p < 0.01). FAS score correlated with depressive symptoms (r = 0.726 for BDI and r = 0.755 for PHQ-9, p < 0.01). CONCLUSION: Polish version of SHQ is a valuable tool for the assessment of HQ in sarcoidosis. HQ is impaired in PSFS comparing to patients with complete remission, but is comparable to active sarcoidosis. Depressive symptoms impact HQ and may influence perception of fatigue. Both fatigue and depression have a negative impact on HQ in sarcoidosis. PMID- 29288481 TI - Actively caseating endobronchial tuberculosis successfully treated with intermittent chemotherapy without corticosteroid: a report of 2 cases. AB - Tuberculous infection of the tracheobronchial tree confirmed by microbiological or histopathological evidence with or without parenchymal involvement is known as endobronchial tuberculosis. Chronic cough is the predominant symptom. Expectorated sputum examination for acid fast bacilli is often negative leading to delay in diagnosis. Therefore, bronchoscopy is crucial for early diagnosis and evaluation of the extent of disease. Bronchostenosis is a significant complication of endobronchial tuberculosis that may be present at the time of diagnosis or develops during the course of treatment. Previously, corticosteroids have been used along with antitubercular therapy to prevent or reduce the extent of bronchostenosis; however, their role is debatable as bronchostenosis often develops despite the use of corticosteroids. Furthermore, the duration of treatment varied from 6-9 months of daily therapy in previous series and little is known about efficacy of intermittent antituberculous therapy. Here we report two cases of actively caseating endobronchial tuberculosis successfully managed with six months of intermittent oral antitubercular therapy without corticosteroids. PMID- 29288482 TI - Diffuse alveolar haemorrhage complicated by pulmonary embolism - problems with treatment. AB - Diffuse alveolar haemorrhage (DAH) refers to a clinical syndrome resulting from injury of the alveolar capillaries, arterioles and venules leading to red blood cel accumulation in the distal air spaces. The conditions associated with DAH and underlying disease determine the prognosis and the treatment regimen. The coexistence of DAH with venous thromboembolism (VTE) is a seroius problem for clinicians and poses a challenge in the therapeutic management. We describe a young patient who developed massive DAH in the course of anti-glomerular basement membrane (anti-GBM) disease (formerly called Goodpasture's syndrome) complicated by pulmonary embolism (PE). PMID- 29288483 TI - Spontaneous resolution of nitrofurantoin-induced chronic pulmonary toxicity presenting with respiratory failure. AB - Nitrofurantoin is one of the most common drugs implicated in drug-induced pulmonary toxicities, the manifestations of which range from dose-independent acute self-limiting reactions to chronic dose-dependent pathologies. The severity of these pulmonary adverse effects may range from trivial hypersensitivity reactions to extensive and irreversible lung fibrosis leading to respiratory failure and death. Symptomatic and supportive treatment in addition to discontinuation of the drug usually suffices for the management of mild reactions. Corticosteroids have been traditionally used to relieve the symptoms and hasten the resolution of pulmonary lesions in case of severe toxicities. However conclusive evidence in the form of controlled studies in favor of this routine use is lacking. We report a case of an elderly lady who presented to us in respiratory failure due to nitrofurantoin induced chronic lung disease. The patient's symptoms and blood gas abnormalities resolved spontaneously over the course of 6 months after stopping the drug. Radiological lesions including those suggestive of apparently permanent fibrosis also resolved during this time. Corticosteroids, inhalational or systemic, were not used. Spontaneous normalization of clinico-radiological features in nitrofurantoin induced chronic lung disease presenting with respiratory failure has rarely been reported previously. The related literature is also reviewed. PMID- 29288484 TI - Dyspnoea, cyanosis and digital clubbing in a 28-year-old patient as a result of hepatopulmonary syndrome. AB - This paper presents a case of a young patient with cyanosis and digital clubbing, until then an active, sporty person. He sought medical assistance due to the growing dyspnoea and the drop of effort tolerance. Initially the diagnostic process focused on the confirmation of the suspicion of pulmonary fibrosis or another interstitial lung disease as causes of the respiratory failure. Due to the atypical presentation of the symptoms, reaching the final diagnosis of digestive system disease with lung involvement required a more thorough multifaceted diagnostics of a number of systems and organs. PMID- 29288485 TI - Solitary pulmonary nodule - the role of imaging in the diagnostic process. AB - A solitary pulmonary nodule is a round opacity less than 30 mm in diameter surrounded by normally aerated lung tissue. Determination of the character of the lesion following its detection (particularly when the identification was incidental) may require a complex diagnostic process. In most cases, nodules are benign in character; however, the probability of malignancy increases significantly for part-solid lesions. The main features that describe the solitary pulmonary nodule in computed tomography scans include their size, shape, density, presence of calcification and rate of growth. PET-CT examination provides additional information on the metabolic activity of the lesions, and MRI is helpful in assessment of local invasion of surrounding structures. Due to limited availability and highly specialized character, these examinations are not routinely used. Therefore, despite development of other imaging modalities, computed tomography remains the most important and crucial diagnostic tool. Clinical risk factors such as age or smoking status are very important for evaluation of the likelihood of malignancy of a nodular lesion. Due to the multidisciplinary nature of data required for complex assessment of a solitary nodular lesion, management routines are needed in the diagnostic process such as those proposed by the Fleischner Society. PMID- 29288486 TI - Kyphoscoliosis - what can we do for respiration besides NIV? AB - Kyphoscoliosis is a significant clinical problem with no precise guidelines for management, especially concerning respiratory pathology. No exhaustive systematic review has yet been performed. The aim was to conduct a systematic review of available data concerning the pathophysiology and treatment of kyphoscoliosis. An electronic systematic search compliant with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. The Pubmed database was examined and the search was updated to November 10, 2016. In total, 188 articles were screened, and 52 full text articles were then assessed for eligibility. As 24 of them met exclusion criteria, only 28 articles were further analysed. These articles were published in 18 journals from 1959 to 2015, with 25 being original studies, and one randomised control trial. The total corpus included 18 prospective studies, 7 retrospective studies and 3 case reports. KS is a significant complex, multidisciplinary clinical problem. The heterogeneous nature of the majority of published studies prevents unequivocal conclusions being drawn. Despite a great progress in knowledge about the respiratory system functioning and pathology in KS, the treatment seems to be not yet quite yet satisfactory. Therefore, there is a strong need for large prospective studies and unified clinical guidelines in on the management of this group of patients. PMID- 29288487 TI - Association between hemorrhagic transformation after endovascular therapy and poststroke seizures. AB - OBJECTIVE: Endovascular therapy has recently become standard therapy for select patients with acute ischemic stroke. Infarcted brain tissue may undergo hemorrhagic transformation (HT) after endovascular therapy. We investigated the association between HT and occurrence of poststroke seizures in patients treated with endovascular therapy. METHODS: Consecutive patients treated with endovascular therapy for acute anterior circulation ischemic stroke were included. HT was assessed with computed tomography/magnetic resonance imaging (CT/MRI) at 24 h after stroke onset. Patients were followed for up to 2 years for seizure occurrence. RESULTS: A total of 205 (57.1% male) patients were analyzed. Median age was 69 years (interquartile range [IQR] 57-78). Among patients with HT, 17.9% (10/56) developed poststroke seizures compared with 4.0% (6/149) among those without HT (hazard ratio [HR] 5.52; 95% confidence interval [CI] 2.00 15.22; P = .001). The association remained significant after adjustment for cortical involvement, baseline National Institutes of Health Stroke Scale score, age and use of intravenous tissue plasminogen activator and clot retrieval (HR 4.85; 95% CI 1.60-14.76; P = .005). In patients who developed seizures within the follow-up period, median time to first seizure was 111 days (IQR 28-369) in patients with HT and 36 days (IQR 0.5-183) in patients without HT. SIGNIFICANCE: A patient who develops HT following endovascular therapy for acute ischemic stroke had a nearly 5 times higher rate of developing poststroke seizures within 2 years. HT may be used as an imaging biomarker for poststroke seizures. PMID- 29288488 TI - Autografting in the treatment of large, auricular keloids. PMID- 29288489 TI - Waterbirth in Sweden - a comparative study. AB - INTRODUCTION: The literature describes advantages for mothers giving birth in water, but waterbirth is controversial in Sweden and has not been offered at hospitals until recently. This study aimed to describe and compare the characteristics and outcome of waterbirths with those of spontaneous vaginal births at the same clinics. MATERIAL AND METHODS: A retrospective cohort study was conducted on all waterbirths at two maternity units in Sweden from March 2014 to November 2015 (n = 306), and a consecutively selected comparison group of 306 women having conventional spontaneous vaginal births. Logistic regression was used to analyze the primary outcome; second-degree perineal tears. RESULTS: Women giving birth in water had a lower risk of second-degree perineal tears [adjusted odds ratio (aOR) 0.6, 95% confidence interval (CI) 0.4-0.9]). Their labor was shorter (6 h 3 min vs. 7 h 52 min) and there were significantly fewer interventions than in the comparison group; amniotomy (13.7 vs. 35.3%), internal cardiotocography (11.1 vs. 56.8%), and augmentation with oxytocin (5.2 vs. 31.3%). There were no differences in Apgar scores or admissions to neonatal intensive care unit. The experience of childbirth, measured with a numeric rating scale, was higher in the waterbirth group indicating a more positive birth experience. Three newborns born in water had an umbilical cord avulsion. CONCLUSIONS: In this low-risk population, waterbirth is associated with positive effects on perineal tears, the frequency of interventions, the duration of labor and women's birth experience. Midwives handling waterbirth should be aware of the risk of umbilical cord avulsion. PMID- 29288490 TI - Insects as human food; from farm to fork. AB - Over the course of the last few years, the consumption of insects, known as entomophagy, has sparked increasing interest amongst scientists and environmentalists as a potential solution to the inevitable global food security and sustainability issues humans will be facing in the coming years. Despite the fact that insects have been an integral part of over 2 billion people's diet worldwide, the concept of eating insects is still new to Western culture. As a result, there are many unknowns regarding insects as a food source, and this has led to a number of studies and investigations being done in recent years to create more knowledge and awareness around this new concept in the food industry. This review discusses some of the key topics and new developments published over recent years, such as the nutritional benefits, food safety concerns, functional properties, potential product concepts and the current ideas and attitudes towards insects as a food source in Western culture. (c) 2017 Society of Chemical Industry. PMID- 29288491 TI - Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses. AB - OBJECTIVE: This study aimed to systematically appraise the meta-analyses of observational studies on risk factors and peripheral biomarkers for schizophrenia spectrum disorders. METHODS: We conducted an umbrella review to capture all meta analyses and Mendelian randomization studies that examined associations between non-genetic risk factors and schizophrenia spectrum disorders. For each eligible meta-analysis, we estimated the summary effect size estimate, its 95% confidence and prediction intervals and the I2 metric. Additionally, evidence for small study effects and excess significance bias was assessed. RESULTS: Overall, we found 41 eligible papers including 98 associations. Sixty-two associations had a nominally significant (P-value <0.05) effect. Seventy-two of the associations exhibited large or very large between-study heterogeneity, while 13 associations had evidence for small-study effects. Excess significance bias was found in 18 associations. Only five factors (childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level) showed robust evidence. CONCLUSION: Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders. The evidence on peripheral biomarkers for schizophrenia spectrum disorders remains limited. PMID- 29288492 TI - 'Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease. AB - AIM: To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated relapsing disease. METHOD: In this UK-based, multicentre study, 31 children with MOG antibody-associated relapsing disease were studied retrospectively. RESULTS: Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow-up (p<0.001). 'Leukodystrophy-like' MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3-year follow-up was mild to moderate, and most patients continued to relapse, despite disease-modifying treatments. INTERPRETATION: MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody associated disease present with age-related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody-mediated mechanisms of damage. WHAT THIS PAPER ADDS: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination manifest with an age-related phenotype. Children with MOG antibody and 'leukodystrophy-like' imaging patterns tend to have poor response to second line immunotherapy. PMID- 29288493 TI - Jet ventilation in obese patients undergoing airway surgery for subglottic and tracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: To assess the feasibility of jet ventilation in obese patients and to compare complications of jet ventilation in obese and nonobese patients. STUDY DESIGN: Retrospective review of medical records. METHODS: We reviewed 46 patient charts (70 procedures) with the diagnosis of tracheal or subglottic stenosis who underwent endoscopic surgery with jet ventilation between March 2014 and January 2017. Adequacy of jet ventilation was assessed by chest rise, avoidance of endotracheal intubation, and length of case and ventilation. Records were reviewed for demographic details, anesthesia records, and complications. RESULTS: In 29/70 (41.4%) of cases, patients were obese; in 9/29 (31.0%) of these cases, patients were morbidly obese. Jet ventilation was successful in 28/29 (97%) of obese cases. In 1/29 (3.4%) of cases, the patient required alternative airway management. There were no significant differences between obese and nonobese patients in chest rise, need for endotracheal intubation, and length of surgery or ventilation (P > .05). There were 2/29 (6.9%) cases of intra- and postoperative complications including laryngospasm (1/29, 3.4%) and tachycardia (1/29, 3.4%). Rate of complications did not differ between obese and nonobese patients (P = .178). CONCLUSIONS: Jet ventilation in obese patients can be done successfully, and complications are similar between obese patients and nonobese patients. LEVEL OF EVIDENCE: 4. Laryngoscope, 1887 1892, 2018. PMID- 29288494 TI - Nuclear cytochrome c - a mitochondrial visitor regulating damaged chromatin dynamics. AB - Over the past decade, evidence has emerged suggesting a broader role for cytochrome c (Cyt c) in programmed cell death. Recently, we demonstrated the ability of Cyt c to inhibit the nucleosome assembly activity of histone chaperones SET/template-activating factor Ibeta and NAP1-related protein during DNA damage in humans and plants respectively. Here, we hypothesise a dual concentration-dependent function for nuclear Cyt c in response to DNA damage. We propose that low levels of highly cytotoxic DNA lesions - such as double-strand breaks - induce nuclear translocation of Cyt c, leading to the attenuation of nucleosome assembly and, thereby, increasing the time available for DNA repair. If DNA damage persists or is exacerbated, the nuclear Cyt c concentration would exceed a given threshold, causing the haem protein to block DNA remodelling altogether. PMID- 29288496 TI - CHA2 DS2 -VASc scores for outcome prediction in acute ischaemic stroke. AB - BACKGROUND: The CHADS2 and CHA2 DS2 -VASc scores are clinical risk stratification instruments that are used clinically to assess the risk of stroke in patients with atrial fibrillation (AF). The aim of this study was to evaluate whether the prestroke CHADS2 and CHA2 DS2 -VASc scores could be useful for predicting infarction severity and long-term outcomes in patients with acute ischaemic stroke. MATERIALS AND METHODS: This prospective study included all 1494 patients who had acute ischaemic stroke without haemorrhagic transformation which was evidenced with magnetic resonance (MR) imaging during hospitalization. Total infarction volume and arterial stenosis score were calculated based on MR imaging. National Institutes of Health Stroke Scale scores (NIHSSs) were obtained at admission and discharge by board-certified neurologists. The clinical outcomes were defined as composite endpoints of restroke and mortality and were recorded with the mean follow-up period of 37.5 months. RESULTS: There were 195 (13.1%) patients with AF. The patients with AF had significantly higher median CHADS2 and CHA2 DS2 -VASc scores than the patients without AF (P < .001). Patients with higher CHADS2 and CHA2 DS2 -VASc scores had significantly higher total infarction volume, arterial stenosis score and NIHSS scores at discharge and poorer clinical outcomes. After adjusting for age, gender and AF, only CHA2 DS2 -VASc scores could predict both restroke and composite endpoints. CONCLUSIONS: Prestroke CHA2 DS2 -VASc scores appear to have better clinical value for predicting the severity of infarction and long-term clinical outcomes in acute ischaemic stroke patients with and without AF. PMID- 29288495 TI - PanCancer insights from The Cancer Genome Atlas: the pathologist's perspective. AB - The Cancer Genome Atlas (TCGA) represents one of several international consortia dedicated to performing comprehensive genomic and epigenomic analyses of selected tumour types to advance our understanding of disease and provide an open-access resource for worldwide cancer research. Thirty-three tumour types (selected by histology or tissue of origin, to include both common and rare diseases), comprising >11 000 specimens, were subjected to DNA sequencing, copy number and methylation analysis, and transcriptomic, proteomic and histological evaluation. Each cancer type was analysed individually to identify tissue-specific alterations, and make correlations across different molecular platforms. The final dataset was then normalized and combined for the PanCancer Initiative, which seeks to identify commonalities across different cancer types or cells of origin/lineage, or within anatomically or morphologically related groups. An important resource generated along with the rich molecular studies is an extensive digital pathology slide archive, composed of frozen section tissue directly related to the tissues analysed as part of TCGA, and representative formalin-fixed paraffin-embedded, haematoxylin and eosin (H&E)-stained diagnostic slides. These H&E image resources have primarily been used to verify diagnoses and histological subtypes with some limited extraction of standard pathological variables such as mitotic activity, grade, and lymphocytic infiltrates. Largely overlooked is the richness of these scanned images for more sophisticated feature extraction approaches coupled with machine learning, and ultimately correlation with molecular features and clinical endpoints. Here, we document initial attempts to exploit TCGA imaging archives, and describe some of the tools, and the rapidly evolving image analysis/feature extraction landscape. Our hope is to inform, and ultimately inspire and challenge, the pathology and cancer research communities to exploit these imaging resources so that the full potential of this integral platform of TCGA can be used to complement and enhance the insightful integrated analyses from the genomic and epigenomic platforms. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29288498 TI - Enhanced early warning system impact on nursing practice: A phenomenological study. AB - AIM: To determine how an enhanced early warning system has an impact on nursing practice. BACKGROUND: Early warning systems score physiologic measures and alert nurses to subtle changes in patient condition. Critics of early warning systems have expressed concern that nurses would rely on a score rather than assessment skills and critical thinking to determine the need for intervention. Enhancing early warning systems with innovative technology is still in its infancy, so the impact of an enhanced early warning system on nursing behaviours or practice has not yet been studied. DESIGN: Phenomenological design. METHODS: Scripted, semistructured interviews were conducted in September 2015 with 25 medical/surgical nurses who used the enhanced early warning system. Data were analysed using thematic analysis techniques (coding and bracketing). Emerging themes were examined for relationships and a model describing the enhanced early warning system experience was developed. FINDINGS: Nurses identified awareness leading to investigation and ease of prioritization as the enhanced early warning system's most important impact on their nursing practice. There was also an impact on organizational culture, with nurses reporting improved communication, increased collaboration, increased accountability and proactive responses to early changes in patient condition. CONCLUSIONS: Rather than hinder critical thinking, as many early warning systems' critics claim, nurses in this study found that the enhanced early warning system increased their awareness of changes in a patient's condition, resulting in earlier response and reassessment times. It also had an impact on the organization by improving communication and collaboration and supporting a culture of proactive rather than reactive response to early signs of deterioration. PMID- 29288497 TI - The role of tRNA synthetases in neurological and neuromuscular disorders. AB - Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA-encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl-tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot-Marie-Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT-causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS). PMID- 29288499 TI - Benefit finding for Chinese family caregivers of community-dwelling stroke survivors: A cross-sectional study. AB - AIMS AND OBJECTIVES: To identify whether benefit finding is a mediator or moderator in the relationship between caregiver burden and psychological well being (anxiety and depression) in Chinese family caregivers of community-dwelling stroke survivors. BACKGROUND: Family caregivers not only bear a heavy burden, a high level of anxiety and depression, but also experience benefit finding (positive effects result from stressful events). However, the relationships among benefit finding, caregiver burden and psychological well-being in Chinese family caregivers are not well known. DESIGN: This study was a cross-sectional correlational design. METHODS: Caregivers (n = 145) of stroke survivors were recruited from two communities in Zhengzhou, China. Data were collected by face to-face interviews with structured questionnaires, examining caregiver burden, benefit finding and psychological well-being of caregivers. A hierarchical regression analysis explored whether caregiver burden and benefit finding were associated with anxiety and depression of caregivers. The moderator role of benefit finding was examined by testing the significance of the interaction between caregiver burden and benefit finding. A mediational model was used to test benefit finding as a mediator between caregiver burden and psychological well-being of caregivers using process in spss 21.0. RESULTS: Caregiver burden and benefit finding were significantly associated with both anxiety and depression of caregivers. Benefit finding did not portray a moderating role, but portrayed the mediator role in the relationship between caregiver burden, anxiety and depression in caregivers. CONCLUSION: This study provides the preliminary evidence to nurses that intervention focus on benefit finding may help improve the psychological well-being of caregivers. RELEVANCE TO CLINICAL PRACTICE: This study offers nurses rational for assessing caregiver's negative emotions and benefit finding. By targeting benefit finding, the nurse may guide caregivers in benefit identification and implement interventions to reduce anxiety, depression and caregiver burden. PMID- 29288500 TI - Combined use of an electrostatic precipitator and a high-efficiency particulate air filter in building ventilation systems: Effects on cardiorespiratory health indicators in healthy adults. AB - High-efficiency particulate air (HEPA) filtration in combination with an electrostatic precipitator (ESP) can be a cost-effective approach to reducing indoor particulate exposure, but ESPs produce ozone. The health effect of combined ESP-HEPA filtration has not been examined. We conducted an intervention study in 89 volunteers. At baseline, the air-handling units of offices and residences for all subjects were comprised of coarse, ESP, and HEPA filtration. During the 5-week long intervention, the subjects were split into 2 groups, 1 with just the ESP removed and the other with both the ESP and HEPA removed. Each subject was measured for cardiopulmonary risk indicators once at baseline, twice during the intervention, and once 2 weeks after baseline conditions were restored. Measured indoor and outdoor PM2.5 and ozone concentrations, coupled with time-activity data, were used to calculate exposures. Removal of HEPA filters increased 24-hour mean PM2.5 exposure by 38 (95% CI: 31, 45) MUg/m3 . Removal of ESPs decreased 24-hour mean ozone exposure by 2.2 (2.0, 2.5) ppb. No biomarkers were significantly associated with HEPA filter removal. In contrast, ESP removal was associated with a -16.1% (-21.5%, -10.4%) change in plasma soluble P-selectin and a -3.0% (-5.1%, -0.8%) change in systolic blood pressure, suggesting reduced cardiovascular risks. PMID- 29288501 TI - Optimal iodine supplementation during antithyroid drug therapy for Graves' disease is associated with lower recurrence rates than iodine restriction. AB - OBJECTIVE: A relationship between iodine intake and the effectiveness of antithyroid drug (ATD) therapy for Graves' disease (GD) has been suggested, and strict restriction of iodine intake has been tried in the treatment of GD in some studies. However, it is unclear whether dietary iodine supplementation improves the prognosis of ATD therapy for GD. This study aimed to clarify whether optimal iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction. METHODS: This was a prospective randomized trial of newly diagnosed patients with GD. Patients with newly diagnosed GD were recruited. After ATD therapy and strict dietary iodine restriction for 1 month, patients (n = 459) were randomly assigned to iodine supplemented and iodine-restricted groups. After exclusion, 405 patients finally completed the study. The iodine-supplemented group included 203 patients (61 males and 142 females) with an average age of 32.2 +/- 10.5 years (17-65 years), and the iodine-restricted group included 202 patients (61 males and 141 females) with an average age of 31.9 +/- 11.8 years (16-64 years). Patients in the iodine supplemented group were given about 10 grams of iodized salt every day, while the iodine-restricted group received noniodized salt with low-iodine or noniodine diet. The dietary iodine intervention lasted for 24 months. Urinary iodine concentration (UIC), thyrotropin receptor antibody (TRAb), free T3 (FT3), free T4 (FT4) and thyrotropin (TSH) of 2 groups were measured every 3 months. The recurrence rates within 12 months after withdrawal of ATD were evaluated. RESULTS: UIC in the iodine-supplemented group was within the recommended range for optimal iodine intake (135-162 MUg/L) and was significantly higher than that in iodine-restricted group (30-58 MUg/L). Within 12 months of withdrawal of ATD, the total recurrence rate in the iodine-supplemented group was 35.5%, significantly lower than in the iodine-restricted group, which was 45.5%. CONCLUSION: Optimal dietary iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction, and therefore, diet control with strict iodine restriction might be an adverse factor in the management of GD. PMID- 29288502 TI - Type III interferons are critical host factors that determine susceptibility to Influenza A viral infection in allergic nasal mucosa. AB - BACKGROUND: Allergic respiratory conditions have been associated with increased susceptibility to viral infection due to impaired interferon (IFN)-related immune responses, but the mechanisms for reinforcement of mucosal immunity against viral infection in allergic diseases are largely unknown. OBJECTIVES: To determine whether IFN induction would be impaired in allergic nasal mucosa and to identify whether higher loads of influenza A virus (IAV) in allergic nasal mucosa could be controlled with IFN treatment. METHODS: Influenza A virus mRNA, viral titres and IFN expression were compared in IAV-infected normal human nasal epithelial (NHNE, N = 10) and allergic rhinitis nasal epithelial (ARNE, N = 10) cells. We used in vivo model of allergic rhinitis (BALB/c mice, N = 10) and human nasal mucosa from healthy volunteers (N = 72) and allergic rhinitis patients (N = 29) to assess the induction of IFNs after IAV infection. RESULTS: Influenza A virus mRNA levels and viral titres were significantly higher in ARNE compared with NHNE cells. IFN-beta and IFN-lambdas were induced in NHNE and ARNE cells up to 3 days after IAV infection. Interestingly, induction of IFN-lambdas mRNA levels and the amount of secreted proteins were considerably lower in ARNE cells. The mean IFN-lambdas mRNA level was also significantly lower in the nasal mucosa of AR patients, and we found that recombinant IFN-lambda treatment attenuated viral mRNA levels and viral titres in IAV-infected ARNE cells. In vivoAR mouse exhibited higher viral load after IAV infection, but intranasal inoculation of IFN-lambda completely decreased IAV protein expression and viral titre in nasal mucosa of IAV-infected AR mouse. CONCLUSION: Higher susceptibility of the allergic nasal mucosa to IAV may depend on impairment of type III IFN induction, and type III IFN is a key mechanistic link between higher viral loads and control of IAV infection in allergic nasal mucosa. PMID- 29288503 TI - Review: Neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: Clinical, pathological and neuroimaging evidence. AB - Cognitive decline is increasingly described as a co-morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS) related TLE. Accelerated cognitive decline is described in groups of adult HS related TLE patients. Large childhood studies show early onset of seizures result in poor development of verbal memory and a hindrance in achieving cognitive potential. We discuss HS classification according to different patterns of neuronal loss and correlation to post-temporal lobectomy cognitive outcomes in refractory TLE patients. Factors such as lateralization of HS pathology, neuronal density and subtype have correlated to cognitive outcomes with varying significance between different studies. Furthermore, alterations in neuronal maturity, regenerative capacity and aberrant connectivity appear to affect cognitive performance post-operatively suggesting a complex multifactorial process. More recent studies have identified tau pathology being present in HS related TLE and correlated to post-operative cognitive decline in some patients. A traumatic head injury-related or novel tauopathy has been hypothesized as an underlying process. We discuss the value of prospective and cross-sectional imaging in assessing cognition and review volumetric magnetic resonance studies with progressive ipsilateral hippocampal atrophy identified to correlate with seizure frequency. Finally, we consider the use of positron emission tomography biomarkers, such as tau tracers, and connectivity studies that may examine in vivo pathways and further explore cognitive decline in TLE. PMID- 29288504 TI - Cell therapy with allogenic canine periodontal ligament-derived cells in periodontal regeneration of critical size defects. AB - AIM: The objective of this in vivo experimental study to evaluate the regenerative potential of a cell therapy combining allogenic periodontal ligament derived cells within a xenogeneic bone substitute in a similar experimental model. METHODS: In nine beagle dogs, critical size 6-mm supra-alveolar periodontal defects were created around the PIII and PIV. The resulting supra alveolar defects were randomly treated with either 1.4 * 106 allogenic canine periodontal ligament-derived cells seeded on de-proteinized bovine bone mineral with 10% collagen (DBBM-C) (test group) or DBBM-C without cells (control group). Specimens were obtained at 3 months, and histological outcomes were studied. RESULTS: The histological analysis showed that total furcation closure occurred very seldom in both groups, being the extent of periodontal regeneration located in the apical third of the defect. The calculated amount of periodontal regeneration at the furcation area was comparable in both the test and control groups (1.93 +/- 1.14 mm (17%) versus 2.35 +/- 1.74 mm (22%), respectively (p = .37). Similarly, there were no significant differences in the amount of new cementum formation 4.49 +/- 1.56 mm (41%) versus 4.97 +/- 1.05 mm (47%), respectively (p = .45). CONCLUSIONS: This experimental study was unable to demonstrate the added value of allogenic cell therapy in supra-crestal periodontal regeneration. PMID- 29288505 TI - Bone response to functionally loaded, two-piece zirconia implants: A preclinical histometric study. AB - OBJECTIVE: To evaluate the bone response to a two-piece zirconia implant in comparison with a control titanium implant in the canine mandible 4 and 16 weeks after restoration. MATERIAL AND METHODS: Zirconia and titanium implants were alternately placed bilaterally in healed mandibular molar and premolar sites of five canines. Full-ceramic single-tooth restorations were cemented after 6 weeks of transmucosal healing, allowing for full functional loading of the implants. Histologic and histometric analyses were performed on orofacial and mesiodistal undecalcified sections of the specimens obtained upon sacrifice after 4 and 16 weeks of functional loading. Bone-to-implant contact (BIC), multinucleated giant cells-to-implant contact (MIC), crestal bone level, and peri-implant bone density were histometrically assessed. RESULTS: All 60 implants and 60 restorations were still in function after 4 and 16 weeks of loading in both test and control groups. No implant loss, no implant or abutment fracture, and no chipping of the restorations could be detected. Histometric analysis showed no statistically significant differences between zirconia and titanium implants in BIC, crestal bone level, and peri-implant bone density at both time points. Between 4 and 16 weeks, the crestal bone level around zirconia implants showed a small but statistically significant increase in its distance from the implant shoulder. MIC was very low on both implant types and both time points and decreased statistically significantly overtime. CONCLUSION: The present two-piece zirconia implant showed a similar bone integration compared to the titanium implant with similar surface morphology after 4 and 16 weeks of loading. PMID- 29288506 TI - Usefulness of argon plasma coagulation ablation subsequent to endoscopic snare papillectomy for ampullary adenoma. AB - BACKGROUND AND AIM: Endoscopic snare papillectomy (ESP) is an effective treatment for ampullary adenoma. Argon plasma coagulation (APC) is widely used as an additional method to control bleeding or ablate the residual tumor. However, the efficacy of this procedure has not yet been fully evaluated. This study aimed to evaluate the usefulness of APC as an additional method to ESP. METHODS: Patients who underwent ESP for ampullary adenoma between September 2005 and September 2015 were retrospectively reviewed. Using propensity score matching, we compared short and long-term outcomes between the ESP-with-additional-APC group (ESP + APC group) and the ESP-only group. Primary outcome was early post-ESP adverse events (AE), and secondary outcomes were late AE and recurrence. RESULTS: Among 109 patients, additional APC was carried out in 59 (54.1%) patients. After matching, 41 patients were included in both groups, respectively. Bleeding rate was significantly lower in the ESP + APC group than in the ESP-only group (7.3% vs 31.7%, odds ratio = 0.180, P < 0.01). However, there were no significant differences in other procedure-related early AE such as pancreatitis (12.2% vs 19.5%, P = 0.365), cholangitis (2.4% vs 9.8%, P = 0.198), and perforation (2.4% vs 2.4%, P = 1.000) between the ESP + APC group and the ESP-only group. During the follow-up period (mean 904 +/- 868 days), papillary stricture (9.8% vs 4.9%, P = 0.405) and recurrence rates (24.4% vs 24.4%, P = 0.797) were not significantly different between the ESP + APC group and the ESP-only group. CONCLUSION: Additional APC during ESP may have a beneficial effect by decreasing bleeding rate without harmful effects. PMID- 29288508 TI - Open peroral endoscopic myotomy for achalasia with failed Heller myotomy. PMID- 29288507 TI - Effectiveness of executive function training on mental set shifting, working memory and inhibition in healthy older adults: A double-blind randomized controlled trials. AB - AIMS: The aim of this study was to evaluate the effectiveness of executive function training on mental set shifting, working memory and inhibition for healthy older adults. BACKGROUND: Executive functions control and guide individuals' behaviours through a top-down cognitive model and have been regarded as the exhibition and integration of various high-level cognitive functions. However, prior studies have rarely focused on the subcomponent indicators of executive function, such as mental set shifting, working memory and inhibition in healthy older adults. DESIGN: Randomized controlled trial. METHODS: A total of 62 participants were recruited between January 2015 - March 2017, with both groups attending a 30-min training session three times per week for 8 weeks. Executive function training group received the training content that focused on the mental set shifting, working memory and inhibition. Active control group engaged in passive information activities. The primary outcome was mental set shifting, measured by the Wisconsin card sort test. The secondary outcomes were working memory measured by digit span and inhibition measured by the Stroop color word test. RESULTS: The executive function training group had statistically significant higher scores of mental set shifting and working memory at immediate follow-up and that its effect on mental set shifting could be maintained for 3-6 months. However, this training did not have any statistically significant results on inhibition. CONCLUSION: The executive function training may be an effective preventive intervention for healthy older adults. Future studies are recommended to include a broader range of participants with different levels of cognitive function. PMID- 29288509 TI - Cancer immunotherapy: A need for peripheral immunodynamic monitoring. AB - Immunotherapy has become an important approach for treating different tumours which has shown significant efficacy in numerous clinical trials, especially those using new checkpoint inhibitors and adoptive cell therapy, which have rapidly become widespread after being approved. However, analysis of peripheral immune biomarkers before and after immunotherapy and their relationship to clinical responses and disease prognosis have rarely been performed in clinical trials. In this review, we examine dynamic changes in the immune system before and after therapy by analyzing recent clinical trials of immunotherapy in patients with cancer that focused on checkpoint inhibitors and adoptive cell therapy. Our aim was to identify circulating biomarkers which can specifically predict clinical response and prognosis, as well as toxicities of immunotherapy. Through this approach, we hope to advance our understanding of the mechanisms of immunotherapy with the goal of developing individualized treatment for cancer patients. PMID- 29288510 TI - A randomized controlled trial of a nursing psychotherapeutic intervention for anxiety in adult psychiatric outpatients. AB - AIM: To evaluate the short-term efficacy of a psychotherapeutic intervention in nursing on Portuguese adult psychiatric outpatients with the nursing diagnosis "anxiety." BACKGROUND: Several efficacious forms of treatment for anxiety are available, including different forms of psychotherapy and pharmacotherapy. However, literature tends to favour findings from studies on the efficacy of psychotherapies and therapies provided by nurses to the detriment of those arising from studies on the efficacy of nursing psychotherapeutic interventions (interventions which are classified, for instance, on Nursing Interventions Classification). DESIGN: Randomized controlled trial. METHODS: The study was performed, between November 2016 - April 2017, at a psychiatry outpatient ward. Participants were randomly allocated to an intervention group (N = 29) or a treatment-as-usual control group (N = 31). Patients in the intervention group received psychopharmacotherapy with interventions integrated in the Nursing Interventions Classification for the nursing diagnosis "anxiety." A treatment-as usual control group received only psychopharmacotherapy (if applicable). Anxiety level and anxiety self-control were the primary outcomes. RESULTS: Patients from both groups had reduced anxiety levels, between the pre-test and the posttest assessment; however, according to analysis of means, patients in the intervention group displayed significantly better results than those of the control group. Furthermore, only patients in the intervention group presented significant improvements in anxiety self-control. CONCLUSION: This study demonstrated the short-term efficacy of this psychotherapeutic intervention model in nursing in the decrease of anxiety level and improvement of anxiety self-control in a group of psychiatric outpatients with pathological anxiety. TRIAL REGISTRATION NUMBER: NCT02930473. PMID- 29288511 TI - Factors affecting readiness for discharge and perceived social support after childbirth. AB - AIMS AND OBJECTIVES: To evaluate the factors affecting readiness for discharge and perceived social support after childbirth. BACKGROUND: Many women still die during and following pregnancy and childbirth. Both early and late discharges are conflicting issues in the world. Evaluation of the readiness for discharge in terms of patient safety, satisfaction, physical, emotional, psychological and social aspects is important. DESIGN: Descriptive and cross-sectional study. METHODS: The study was carried out with 610 women in the early postpartum period at two hospitals in Turkey between October 2014-March 2015 using Readiness for Hospital Discharge Scale-New Mother Form and Multidimensional Scale of perceived social support. RESULTS: The mean scores for Readiness for Hospital Discharge Scale-New Mother Form and Multidimensional Scale of perceived social support were found as 163.5 (SD: 34.1) and 64.2 (SD: 18.8), respectively. Women who were discharged from Merkezefendi Hospital, women who had one child or one pregnancy and women or baby who experienced complication during or after birth had lower scores on Readiness for Hospital Discharge Scale-New Mother Form. Women who received information about the postpartum period had significantly higher scores on the total Readiness for Hospital Discharge Scale-New Mother Form than women did not (165.5 +/- 33.8 vs 151.1 +/- 36.1). Personal status, knowledge and total score of the Readiness for Hospital Discharge Scale-New Mother Form were significantly higher in women who were ready for discharge. CONCLUSIONS: Findings provide vital information that can inform nursing clinical practice, especially related to readiness for discharge protocols and developing strategies for women, who had low sociodemographic backgrounds, did not have any information about postpartum period and were not ready for discharge. RELEVANCE TO CLINICAL PRACTICE: The mother and family face with postpartum difficulties on their own when early discharge takes place. Providing postpartum care services plays an important role for maternal-child health. PMID- 29288512 TI - Pretreatment with probiotic Bifico ameliorates colitis-associated cancer in mice: Transcriptome and gut flora profiling. AB - Individuals with inflammatory bowel disease are at high risk of developing colitis-associated cancer (CAC). Strategies to block the process from inflammatory bowel disease to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane and dextran sodium sulphate-induced CAC in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of 35 C57BL/6 mice were collected and examined for the degree of inflammation and tumorigenesis. Comparative 16S rRNA sequencing was carried out to observe Bifico-target alterations in gene expression and microbiota structure. We found that pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including CXCL1, CXCL2, CXCL3, and CXCL5, which are all ligands of C-X-C motif receptor 2 (CXCR2). The 16S rRNA sequencing showed that Bifico decreased the abundance of genera Desulfovibrio, Mucispirillum, and Odoribacter, and a bloom of genus Lactobacillus was detected. Notably, we found that an abundance of these Bifico-target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies indicate that Bifico, given orally, can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus, and CXCR2 signaling. PMID- 29288514 TI - High Efficacy of ombitasvir/paritaprevir/ritonavir plus dasabuvir in hepatitis C genotypes 4 and 1-infected patients with severe chronic kidney disease. AB - BACKGROUND & AIMS: Limited data have shown high efficacy of co-formulated ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) in the treatment of hepatitis C virus (HCV) genotype (GT)-4, and combined with dasabuvir (DSV) in GT1 patients, with chronic kidney disease (CKD) stages 4-5 (<30 mL/min/1.73 m2 ). We assessed real-world safety and efficacy of OBV/PTV/r +/- DSV in GT1- and 4-infected patients. METHODS: In this observational cohort (n = 67), we enrolled stages 4-5 CKD treatment-naive or Peginterferon/RBV-experienced GT4-infected patients (n = 32) treated for 12-24 weeks with OBV/PTV/r +/- RBV, and plus DSV in GT1 patients (n = 35, including 3 with GT1/4 co-infection). RBV was dosed by physician discretion between 200 mg weekly and 200 mg daily. Primary endpoints were SVR12, calculated on intention-to-treat (ITT) basis, and occurrence of serious adverse events. RESULTS: The mean age of the cohort was 45.7 +/- 12.7 years, 50.7% were females, 20.9% had cirrhosis, 35.8% were treatment-experienced and 97% were on haemodialysis. Three patients (F4) received 24-week treatment, 2 with GT4, and 1 with GT1a; and 19.4% were treated without RBV, including 9 GT1, and 4 GT4. Overall, 65 (97.1%) patients achieved SVR12, including 100% of those with a post treatment follow-up (modified ITT analysis). Of the two patients without SVR12, one died from sepsis-related complications and the other from a myocardial infarction 2 weeks after completing therapy. Grades 3-4 anaemia occurred in 8.9%. CONCLUSION: A 12-week regimen of OBV/PTV/r +/- DSV with or without RBV is highly effective with a favourable safety profile amongst GT4 and GT1 patients with CKD stages 4-5. SVR12 rates were high regardless of patient characteristics. PMID- 29288513 TI - Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens. AB - Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, from which the majority of patients experienced no or minimum clinical benefit. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor specific antigens, neoantigens, are generated by somatic mutations that are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity, such as neoantigens, the likelihood of toxic effects is very limited. However, understanding the interaction between neoantigens and the host immune system remains a significant challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progress of different strategies in predicting, identifying, and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients. PMID- 29288515 TI - Third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice. AB - Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T 01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited, as was the case for contralateral tumors. T 01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC. PMID- 29288516 TI - Interleukin-6/signal transducer and activator of transcription 3 promotes prostate cancer resistance to androgen deprivation therapy via regulating pituitary tumor transforming gene 1 expression. AB - Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen-independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen-dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen-deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44+ CD24- cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by interleukin-6 via activated signal transducer and activator of transcription 3 (STAT3) directly binding to the region -500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that interleukin-6/STAT3 activation can increase PTTG1 expression and, consequently, promote the resistance to ADT in CRPC by inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC. PMID- 29288517 TI - Proposal for the development of biologics in pediatric rheumatology. AB - In order to assess the development, approval and early introduction into clinical practice of biologics in the pediatric field, we herein describe the current status of the development to approval of biologics as anti-rheumatic agents for children in Japan, discuss the present problems and provide a proposal for the future. It has become apparent that the duration of the review period required for the preparation of clinical trials and Pharmaceuticals and Medical Devices Agency approval is clearly reduced compared with the past. Thus, it was speculated that a rate-limiting step in the process from development to approval was the duration of clinical trials from start to end. Hence, we focused on the following key words with regard to promotion of the development of biologics and their early practical use: "registry", "centralization", and "global cooperation", all of which are related to the reduction of duration of a clinical trial. In conclusion, to reduce the duration of a clinical trial, it is essential to complete a world-scale registry system by developing the registry system established by the Pediatric Rheumatology Association of Japan. The next step is then to carefully plan to participate in the international network using the world-scale registry system, and develop global cooperative trials in which we can ensure a sufficient number of entries from Japan. PMID- 29288518 TI - Participation of delta annexin A3 in the ribosomal protein S19 C-terminus dependent inhibitory mechanism of the neutrophil C5a receptor through delta lactoferrin. AB - Although C5a receptor (C5aR) interacting with its agonist C5a promotes acute inflammation during the initiation phase, the roles of the recycling C5aR during the resolution phase are still unclear. We found that C5aR interacted with its antagonist/agonist ribosomal protein S19 (RP S19) polymer or a RP S19 polymer functional analogue S-tagged C5a/RP S19, which connects an RP S19 C-terminus (IAGQVAAANKKH) to the S-tagged C5a C-terminus, promoted acute inflammation at the resolution phase via an activation of the apoptosis-inducing transcription factor delta lactoferrin (deltaLf) in neutrophils and the membrane mobilizing factor full-length annexin A3 (ANXA3) in macrophages. To confirm the antagonistic system of the recycling C5aR, S-tagged deltaLf-coupled BrCN-activated Sepharose 4B beads were incubated with cytoplasmic proteins and identified a neutrophil-specific deltaANXA3 via pull-down experiments. The S-tagged C5a/RP S19-induced agonistic functions in macrophage-like cells that were differentiated from human promyelocytic leukemia HL-60 cells by phorbol-12-myristate-13-acetate were suppressed by deltaLf and deltaANXA3 co-overexpression. deltaANXA3 seems to participate in the antagonistic system of the neutrophil C5aR involving IAGQVAAANKKH and deltaLf. Most likely, deltaANXA3 works as antagonist for the recycling C5aR on neutrophils during the resolution phase of acute inflammation. PMID- 29288519 TI - Insular damage, death and newly diagnosed atrial fibrillation in intracerebral hemorrhage: stroke-induced heart injury as the potential missing link. PMID- 29288520 TI - A critical appraisal of randomized controlled trials on intravenous phenytoin in convulsive status epilepticus. AB - Since the 1970s, intravenous (IV) phenytoin (PHT) has traditionally been used as second-stage treatment for convulsive status epilepticus (SE) after failure of benzodiazepines. The aim of this review was to critically assess the evidence supporting the use of IV PHT as treatment of convulsive SE in patients of any age. In particular, we critically appraised the results of randomized controlled trials (RCTs) evaluating IV PHT as treatment of convulsive SE. A systematic search of the literature was carried out to identify RCTs evaluating IV PHT as treatment of convulsive SE in patients of any age. Eight RCTs (544 patients allocated to IV PHT) were included. The included studies differed in almost every single characteristic considered. Six RCTs (472 patients) used IV PHT without demonstrating refractoriness of SE to benzodiazepines. Only two RCTs (72 patients) used IV PHT as second-line treatment for benzodiazepine-resistant convulsive SE. Overall, most evidence from RCTs supports the use of IV PHT immediately after IV diazepam, even if seizures have not recurred. The recommendation derived from RCTs supporting the use of IV PHT as second-line treatment in benzodiazepine-resistant convulsive SE is weak. This is emblematic of the lack of robust evidence from large RCTs to inform clinical practice on how to treat SE after failure of first-line drugs. IV PHT given immediately after first-line benzodiazepines could prolong their short antiepileptic effect and prevent seizure recurrence. PMID- 29288521 TI - Indigenous cultural competence: A dental faculty curriculum review. AB - BACKGROUND: Indigenous Australians have more than double the rate of poor oral health than their non-Indigenous counterparts. Cultural competence of dental and oral health practitioners is fundamental to health care and quality of life in addressing health disparities in minority cultural groups in Australia. Higher education curricula reviews have identified the need for institutions to incorporate Indigenous culture and knowledge more widely into the curricula to improve educational outcomes for Indigenous Australians and to increase cultural competence for all students. AIM: The aim of this research was to provide a baseline analysis of Indigenous cultural competence curricula practices to ascertain changes required within Faculty of Dentistry programmes at the University of Sydney to enable students to become more culturally competent upon graduation. METHODS: Staff and students of the Doctor of Dental Medicine and Bachelor of Oral Health programmes at the Faculty of Dentistry, University of Sydney participated in an online survey. Quantitative analysis of the survey data was conducted using integrated research electronic data capture survey tools, with open-ended questions being coded to common responses for those questions. RESULTS: A total of 69 staff (71%) and 191 students (51%) participated in the online survey. The majority of participants perceived there was limited Indigenous content in the curriculum. Most participants reported that Indigenous curriculum was integrated into several units of study. The main pedagogical method for curriculum delivery was lectures, followed by case studies and group discussions. CONCLUSION: Although some Indigenous content exists in dental faculty curriculum, in-depth investigation is required to develop a comprehensive, evidenced-based Indigenous cultural competence teaching framework, for integration into Doctor of Dental Medicine and Bachelor of Oral Health curricula. PMID- 29288522 TI - Survey of rotavirus-associated severe complications in Aichi Prefecture. AB - BACKGROUND: Rotavirus can, rarely, cause severe complications such as encephalopathy/encephalitis, myocarditis, sudden death, urinary stone, and gastrointestinal (GI) bleeding; and the incidence of these severe complications remains unclear. Additionally, it has not been determined whether rotavirus (RV) vaccine could reduce cases of severe complications or not. METHODS: A two-part questionnaire was designed to determine the number and clinical features of severe complications between 1 September 2008 and 31 August 2015, including the observation periods before and after RV vaccine introduction in Aichi Prefecture. RESULTS: Twenty-four cases of encephalitis/encephalopathy, eight cases of sudden death, three cases of urinary tract stone, and three cases of GI bleeding were reported during the 2008/2009 season and the 2012/2013 seasons. Although five cases of encephalitis/encephalopathy were reported, no other cases of severe complications were reported during the 2013/2014 and 2014/2015 seasons. No age difference was noted according to type of complication. Although onset of encephalitis/encephalopathy and of sudden death was around day 2 of illness, that of urinary tract stone and GI bleeding was slightly later (day 6 and day 4). In addition to the eight sudden deaths, fatal outcome was also noted in four cases (13.8%) of encephalitis/encephalopathy, and in one case of GI bleeding. CONCLUSION: According to the questionnaire survey in Aichi Prefecture, the incidence of the four severe RV-associated complications appears to have declined as the vaccination rate has increased. PMID- 29288523 TI - C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment. AB - Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when C-C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling. PMID- 29288524 TI - Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes. AB - AIMS/INTRODUCTION: Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin-dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo. METHODS: A total of 38 individuals with a complete lack of endogenous insulin (fasting C-peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time-to-time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control. RESULTS: Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 +/- 7.8 vs 32.9 +/- 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038). CONCLUSIONS: The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon. PMID- 29288525 TI - Multi-allelic exact tests for Hardy-Weinberg equilibrium that account for gender. AB - Statistical tests for Hardy-Weinberg equilibrium are important elementary tools in genetic data analysis. X-chromosomal variants have long been tested by applying autosomal test procedures to females only, and gender is usually not considered when testing autosomal variants for equilibrium. Recently, we proposed specific X-chromosomal exact test procedures for bi-allelic variants that include the hemizygous males, as well as autosomal tests that consider gender. In this study, we present the extension of the previous work for variants with multiple alleles. A full enumeration algorithm is used for the exact calculations of tri allelic variants. For variants with many alternate alleles, we use a permutation test. Some empirical examples with data from the 1,000 genomes project are discussed. PMID- 29288526 TI - The transmission dynamics and diversity of human metapneumovirus in Peru. AB - BACKGROUND: The transmission dynamics of human metapneumovirus (HMPV) in tropical countries remain unclear. Further understanding of the genetic diversity of the virus could aid in HMPV vaccine design and improve our understanding of respiratory virus transmission dynamics in low- and middle-income countries. MATERIALS & METHODS: We examined the evolution of HMPV in Peru through phylogenetic analysis of 61 full genome HMPV sequences collected in three ecologically diverse regions of Peru (Lima, Piura, and Iquitos) during 2008-2012, comprising the largest data set of HMPV whole genomes sequenced from any tropical country to date. RESULTS: We revealed extensive genetic diversity generated by frequent viral introductions, with little evidence of local persistence. While considerable viral traffic between non-Peruvian countries and Peru was observed, HMPV epidemics in Peruvian locales were more frequently epidemiologically linked with other sites within Peru. We showed that Iquitos experienced greater HMPV traffic than the similar sized city of Piura by both Bayesian and maximum likelihood methods. CONCLUSIONS: There is extensive HMPV genetic diversity even within smaller and relatively less connected cities of Peru and this virus is spatially fluid. Greater diversity of HMPV in Iquitos compared to Piura may relate to higher volumes of human movement, including air traffic to this location. PMID- 29288527 TI - Development and validation of a stability-indicating HPLC method for topiramate using a mixed-mode column and charged aerosol detector. AB - The analysis of topiramate in the presence of its main degradation products is challenging due to the absence of chromophore moieties and their wide range of polarity. Mixed-mode chromatography has been used in such cases because it combines two or more modes of separation. Charged aerosol detector is also an alternative since its detection is independent of optical properties and analyte ionization. This study is aimed to develop and validate two new stability indicating methods by high-performance liquid chromatography for the main degradation products of topiramate using mixed-mode chromatography and a charged aerosol detector. Method 1 employed an Acclaim Trinity P1(r) column (3.0 mm * 150 mm, 2.7 MUm) with a mobile phase comprising of 80% ammonium acetate buffer (20 mM, pH 4.0) and 20% methanol at a flow rate of 0.5 mL/min at 35 degrees C. Method 2 utilized a C18 Acclaim 120(r) column (4.6 mm * 250 mm; 5 MUm) with ACN/water (50:50) at a flow rate of 0.6 mL/min at 50 degrees C. Validation of the two methods demonstrated excellent performance with respect to linearity, precision, accuracy, and selectivity. The limits of detection for topiramate, fructose, sulfate, sulfamate, and compound A were 2.97, 12.08, 4.02, 13.91, and 3.94 MUg/mL, respectively. PMID- 29288529 TI - Mitogen-activated protein kinase pathway inhibitors rescue lethal phenotypes in a BRAF gain-of-function Drosophila melanogaster model. PMID- 29288530 TI - PKA-binding domain of AKAP8 is essential for direct interaction with DPY30 protein. AB - The main function of the A kinase-anchoring proteins (AKAPs) is to target the cyclic AMP-dependent protein kinase A (PKA) to its cellular substrates through the interaction with its regulatory subunits. Besides anchoring of PKA, AKAP8 participates in regulating the histone H3 lysine 4 (H3K4) histone methyltransferase (HMT) complexes. It is also involved in DNA replication, apoptosis, transcriptional silencing of rRNA genes, alternative splicing, and chromatin condensation during mitosis. In this study, we focused on the interaction between AKAP8 and the core subunit of all known H3K4 HMT complexes DPY30 protein. Here, we demonstrate that the PKA-binding domain of AKAP8 and the C-terminal domain of DPY30, also called Dpy-30 motif, are crucial for the interaction between these proteins. We show that a single amino acid substitution in DPY30 L69D affects its dimerization and completely abolishes its interaction with AKAP8 and another DPY30-binding partner brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1), which is also AKAP domain-containing protein. We further demonstrate that AKAP8 interacts with DPY30 and the RII alpha regulatory subunit of PKA both in the interphase and in mitotic cells, and we show evidences that AKAP8L, a homologue of AKAP8, interacts with core subunits of the H3K4 HMT complexes, which suggests its role as a potential regulator of these complexes. The results presented here reinforce the analogy between AKAP8-RII alpha and AKAP8-DPY30 interactions, postulated before, and improve our understanding of the complexity of the cellular functions of the AKAP8 protein. PMID- 29288528 TI - Overexpression of miR-22 attenuates oxidative stress injury in diabetic cardiomyopathy via Sirt 1. AB - BACKGROUND/AIMS: Oxidative stress injury is believed to be important in diabetic cardiomyopathy. Recent evidence indicates that miR-22 plays an important role in various cardiovascular diseases, but the protective role of miR-22 in diabetic cardiomyopathy remains undetermined. METHODS: Diabetes was induced in male C57BL/6 mice by intraperitoneal injection with streptozotocin combined with a high-fat diet, and miR-22 was overexpressed following transfection with adeno associated virus. Cardiac function was assessed by echocardiography and a cardiac catheter system. In vitro study, H9c2 cells were treated with normal or high glucose (HG), and cell viability or apoptosis was detected using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. Reactive oxygen species, malondialdehyde, and superoxide dismutase were also detected in diabetic mice and H9c2 cells. The expression level of miR-22 was detected by real-time PCR. The protein expression of Sirt 1, oxidative stress injury-related proteins (GRP78, CHOP, ATF 3), and apoptosis-related proteins Bax/Bcl-2, cl-casp-9/casp-9, and cl-casp-3/casp-3 were determined by Western blotting analysis. RESULTS: HG induced oxidative stress injury and apoptosis were observed in H9c2 cells, which were ameliorated by miR-22. Cardiac dysfunction and severely altered heart structure were also observed in diabetic mice and were dramatically reversed by overexpression of miR-22. The expression of Sirt 1 decreased significantly in diabetic mice and HG-treated H9c2 cells. Overexpression of miR-22 restored the level of Sirt 1. Bioinformatics analysis predicted that Sirt 1 was a potential target gene of miR-22. Luciferase reporter assay verified that miR-22 promoted Sirt 1 expression by direct binding to the Sirt 1 3'untranslated repeats. Upregulation of Sirt 1 could improve cell viability and attenuate oxidative stress injury and apoptosis in the HG-treated H9c2 cells, similar to the effect of miR-22. However, the protective effects of miR-22 against HG-induced oxidative stress injury and apoptosis were abrogated by knockdown of Sirt 1. CONCLUSIONS: Overexpression of miR-22 can attenuate oxidative stress injury in diabetic cardiomyopathy by upregulation of Sirt 1 in vivo and in vitro. PMID- 29288531 TI - Small Molecule Pin1 Inhibitor Blocking NF-kappaB Signaling in Prostate Cancer Cells. AB - Prolyl-isomerase 1 (Pin1) is a conserved enzyme that regulates cell processes such as cell cycle progression, transcriptional regulation, and apoptosis. However, overexpression of Pin1 is correlated with a higher probability of prostate tumor recurrence. We utilized a molecular docking technique to identify Pin1 inhibitors from a database of natural product and natural product-like compounds. The action of the hit compounds against Pin1 activity was studied using multiple methods, including a fluorometric enzymatic assay, co immunoprecipitation, western blotting, cell thermal shiftm, and other techniques. We have identified compound 1 as a natural-product-like inhibitor of Pin1 activity via structure-based virtual screening and showed that compound 1 could target Pin1 and disrupt the interaction between Pin1 and the p65 subunit of NF kappaB in cells. Furthermore, compound 1 reduced nuclear p65 (Thr254) phosphorylation and attenuated NF-kappaB activity in cells. Finally, compound 1 induced apoptosis in prostate cancer cells. Compound 1 represents a natural product-like Pin1 inhibitor that acts via targeting the Pin1-NF-kappaB interaction. PMID- 29288532 TI - Impaired cognitive ability at 2.5 years predicts later visual and ophthalmological problems in children born very preterm. AB - AIM: To identify possible predictive factors for visual problems at 6.5 years in children born very preterm. METHODS: During 2004-2007, all very preterm infants (gestational age [GA] <32 weeks) in Uppsala County, Sweden were screened for retinopathy of prematurity (ROP) neonatally; at four months, visual tracking was tested; at 2.5 years, visuospatial and cognitive tests were carried out. At 6.5 years, 84 preterm children and a reference group of 64 full-term children underwent ophthalmological testing. RESULTS: Mean visual acuity (VA) did not differ between the groups, but subnormal VA (<=0.8) was more common in the preterm group (31% vs 14%; p < 0.05). More often than full-term children, preterm children had impaired contrast sensitivity (<0.5) (36% vs 19%; p < 0.05) and strabismus (8% vs 0%; p < 0.05). Low GA, ROP, intraventricular haemorrhage 3 4/periventricular leukomalacia and cognitive disability at 2.5 years predicted ophthalmological and visual problems at 6.5 years. Visual tracking ability at four months was not predictive of ophthalmological outcome. CONCLUSION: Children born preterm had more ophthalmological problems at 6.5 years of age, including subtle dysfunctions. ROP, early brain injury and impaired cognitive function around 2.5 years predicted later ophthalmological dysfunctions. PMID- 29288533 TI - Challenges to DNA replication in hypoxic conditions. AB - The term hypoxia refers to any condition where insufficient oxygen is available and therefore encompasses a range of actual oxygen concentrations. The regions of tumours adjacent to necrotic areas are at almost anoxic levels and are known to be extremely therapy resistant (radiobiological hypoxia). The biological response to radiobiological hypoxia includes the rapid accumulation of replication stress and subsequent DNA damage response, including both ATR- and ATM-mediated signalling, despite the absence of detectable DNA damage. The causes and consequences of hypoxia-induced replication stress will be discussed. PMID- 29288534 TI - An overview on Vadimezan (DMXAA): The vascular disrupting agent. AB - Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFkappaB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed. PMID- 29288535 TI - Macroalgal spore dysfunction: ocean acidification delays and weakens adhesion. AB - Early life stages of marine organisms are predicted to be vulnerable to ocean acidification. For macroalgae, reproduction and population persistence rely on spores to settle, adhere and continue the algal life cycle, yet the effect of ocean acidification on this critical life stage has been largely overlooked. We explicitly tested the biomechanical impact of reduced pH on early spore adhesion. We developed a shear flume to examine the effect of reduced pH on spore attachment time and strength in two intertidal rhodophyte macroalgae, one calcified (Corallina vancouveriensis) and one noncalcified (Polyostea robusta). Reduced pH delayed spore attachment of both species by 40%-52% and weakened attachment strength in C. vancouveriensis, causing spores to dislodge at lower flow-induced shear forces, but had no effect on the attachment strength of P. robusta. Results are consistent with our prediction that reduced pH disrupts proper curing and gel formation of spore adhesives (anionic polysaccharides and glycoproteins) via protonation and cation displacement, although experimental verification is needed. Our results demonstrate that ocean acidification negatively, and differentially, impacts spore adhesion in two macroalgae. If results hold in field conditions, reduced ocean pH has the potential to impact macroalgal communities via spore dysfunction, regardless of the physiological tolerance of mature thalli. PMID- 29288536 TI - Mono-, di-, and trichlorinated biphenyls (PCB 1-PCB 39) in the indoor air of office rooms and their relevance on human blood burden. AB - Exposure to polychlorinated biphenyls (PCBs) from indoor air can lead to a significant increase in lower chlorinated congeners in human blood. Lower chlorinated congeners with short biological half-lives can exhibit an indirect genotoxic potential via their highly reactive metabolites. However, little is known about their occurrence in indoor air and, therefore, about the effects of possible exposure to these congeners. We analyzed all mono-, di-, and trichlorinated biphenyls in the indoor air of 35 contaminated offices, as well as in the blood of the 35 individuals worked in these offices for a minimum of 2 years. The median concentration of total PCB in the indoor air was 479 ng/m3 . The most prevalent PCBs in the indoor air samples were the trichlorinated congeners PCB 31, PCB 18, and PCB 28, with median levels of 39, 31, and 26 ng/m3 , respectively. PCB 8 was the most prevalent dichlorinated congener (median: 9.1 ng/m3 ). Monochlorinated biphenyls were not detected in relevant concentrations. In the blood samples, the most abundant congener was PCB 28; nearly 90% of all mono-, di-, and trichlorinated congeners were attributed to this congener (median: 12 ng/g blood lipid). PMID- 29288537 TI - Evolution of Self-Propelled Objects: From the Viewpoint of Nonlinear Science. AB - A variety of moving objects driven by chemical energy have been reported. In this Minireview, we focus on self-propelled objects driven by interfacial tension and explain three types of basic mechanisms for such self-propelled motion, that is, driven by a) surface tension difference, b) contact angle difference, and c) axisymmetric swirling flow in a droplet. Simple behavior induced from the basic mechanisms is then extended by coupling to a chemical reaction or increasing the number of moving objects. Even though the chemicals used here are still simple, the extended systems could show characteristic nonlinear behavior, such as reciprocating motion, oscillatory motion, and spatiotemporal pattern formation. Combining the dynamical information about these characteristic motions with the knowledge of molecular structures will lead to the development of more advanced self-propelled objects. We believe this Minireview can help chemists in investigating self-propelled objects displaying various functional motions observed in a biological system. PMID- 29288538 TI - Experiences of adults who as children lived with a parent experiencing mental illness in a small-scale society : A Qualitative study. AB - : WHAT IS KNOWN ON THE SUBJECT?: Children of parent with severe mental illness are often carrying a caring burden; they keep the illness in the family, are documented to be stigmatized, bullied and to take special attention to their mentally ill parent's health and well-being. Little is however known about these children's experiences when growing up in a small-scale society. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE?: Children's experiences of living with a parent with severe mental illness in the small-scale society (Faroe Islands) are paradoxical, life is often unreasonable and evidently contradictory but anyway connected. The results show that "everybody knows everybody" which refers to that, in the small scale society, it is difficult to be anonymous. The children were familiar with that people talked and had a prejudiced attitude; this resulted that the participants were constantly reminded of their mental ill parent's difference, and they were feeling less worthy than their pals. Children of parents with severe mental illness in a small-scale society need to support from the close family as well as mental healthcare professionals. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The study adds knowledge about the challenges that children of mental ill parents have to go through. Dialogue among mental healthcare colleagues not only about caring for the sick parent but also about modes of caring for the children and the family at large would deepen the staff's knowing of the need for family-centred care within mental health care. ABSTRACT: Introduction An estimated 23% of children worldwide live with a parent experiencing mental illness. These children are exposed to emotional and psychosocial challenges. Little is known about these children when living in small-scale societies. Aim To explore how adults, who as children lived with parents experiencing mental illness in a small-scale society, recalled their childhood life. Method Individual interviews with 11 adults were analysed using content analysis. Results Living as a child with a parent experiencing mental illness in a small scale society was described as "living in a paradox" which emerged from three categories: "intergenerational help and caring," "barriers understanding parental illness" and "everybody knows everybody". The children received little or no support from family members, nor from health and education professionals. Discussion In a small-scale society, stigma surrounding mental illness is notable. Families often attempt to conceal mental illness from outsiders with negative or adverse effects on children. Implications for practice Mental healthcare professionals need to consider the needs of children who have parents experiencing mental illness. It is imperative for the well-being of the patients' children to support them in understanding what is happening, turn gossiping in a positive direction and address stigma in the communities. PMID- 29288539 TI - Cold/cold vs. bipolar dissection tonsillectomy: A surgeon-controlled study of 400 cases. PMID- 29288541 TI - Can Ebola virus evolve to be less virulent in humans? AB - Understanding Ebola virus (EBOV) virulence evolution not only is timely but also raises specific questions because it causes one of the most virulent human infections and it is capable of transmission after the death of its host. Using a compartmental epidemiological model that captures three transmission routes (by regular contact, via dead bodies and by sexual contact), we infer the evolutionary dynamics of case fatality ratio on the scale of an outbreak and in the long term. Our major finding is that the virus's specific life cycle imposes selection for high levels of virulence and that this pattern is robust to parameter variations in biological ranges. In addition to shedding a new light on the ultimate causes of EBOV's high virulence, these results generate testable predictions and contribute to informing public health policies. In particular, burial management stands out as the most appropriate intervention since it decreases the R0 of the epidemics, while imposing selection for less virulent strains. PMID- 29288540 TI - Expansion of human gammadelta T cells for adoptive immunotherapy using a bisphosphonate prodrug. AB - Cancer immunotherapy with human gammadelta T cells expressing Vgamma2Vdelta2 T cell receptor (also termed Vgamma9Vdelta2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) -unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vgamma2Vdelta2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vgamma2Vdelta2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2 ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vgamma2Vdelta2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vgamma2Vdelta2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vgamma2Vdelta2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating alphabeta T cells resulted in some mice with circulating human alphabeta T cells rather than Vgamma2Vdelta2 cells. Vgamma2Vdelta2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-alpha and interferon-gamma in response to PTA-treated tumor cells. Thus, PTA expands Vgamma2Vdelta2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vgamma2Vdelta2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vgamma2Vdelta2 T cell responses. PMID- 29288542 TI - Evaluation of an animation tool developed to supplement dental student study of the cranial nerves. AB - INTRODUCTION: The structure/function of the cranial nerves is a core topic for dental students. However, due to the perceived complexity of the subject, it is often difficult for students to develop a comprehensive understanding of key concepts using textbooks and models. It is accepted that the acquisition of anatomical knowledge can be facilitated by visualisation of structures. This study aimed to develop and assess a novel cranial nerve animation as a supplemental learning aid for dental students. MATERIALS AND METHODS: A multidisciplinary team of anatomists, neuroscientists and a computer scientist developed a novel animation depicting the cranial nerves. The animation was viewed by newly enrolled first-year dental students, graduate entry dental students (year 1) and dental hygiene students (year 1). A simple life scenario employing the use of the cranial nerves was developed using a cartoon-type animation with a viewing time of 3.58 minutes. The animation was developed with emphasis on a life scenario. The animation was placed online for 2 weeks with open access or viewed once in a controlled laboratory setting. Questionnaires were designed to assess the participants' attitude towards the animation and their knowledge of the cranial nerves before and after visualisation. This study was performed before the delivery of core lectures on the cranial nerves. RESULTS: Our findings indicate that the use of the animation can act as a supplemental tool to improve student knowledge of the cranial nerves. Indeed, data indicate that a single viewing of the animation, in addition to 2-week access to the animation, can act as a supplemental learning tool to assist student understanding of the structure and function of cranial nerves. The animation significantly enhanced the student's opinion that their cranial nerve knowledge had improved. From a qualitative point of view, the students described the animation as an enjoyable and useful supplement to reading material/lectures and indicated that the animation was a useful tool in understanding the cranial nerves. CONCLUSION: Overall, these findings indicate that an animation demonstrating the cranial nerves in a simple, everyday functional scenario may act as a learning aid in the study of cranial nerves. PMID- 29288543 TI - Artificially modified collagen fibril orientation affects leather tear strength. AB - BACKGROUND: Ovine leather has around half the tear strength of bovine leather and is therefore not suitable for high-value applications such as shoes. Tear strength has been correlated with the natural collagen fibril alignment (orientation index, OI). It is hypothesized that it could be possible to artificially increase the OI of the collagen fibrils and that an artificial increase in OI could increase tear strength. RESULTS: Ovine skins, after pickling and bating, were strained biaxially during chrome tanning. The strain ranged from 2 to 15% of the initial sample length, either uniformly in both directions by 10% or with 3% in one direction and 15% in the other. Once tanned, the leather tear strengths were measured and the collagen fibril orientation was measured using synchrotron-based small-angle X-ray scattering. CONCLUSION: The OI increased as a result of strain during tanning from 0.48 to 0.79 (P = 0.001) measured edge-on and the thickness-normalized tear strength increased from 27 to 43 N mm-1 (P < 0.001) after leather was strained 10% in two orthogonal directions. This is evidence to support a causal relationship between high OI (measured edge-on), highly influenced by thickness, and tear strength. It also provides a method to produce stronger leather. (c) 2017 Society of Chemical Industry. PMID- 29288544 TI - Metabarcoding for the parallel identification of several hundred predators and their prey: Application to bat species diet analysis. AB - Assessing diet variability is of main importance to better understand the biology of bats and design conservation strategies. Although the advent of metabarcoding has facilitated such analyses, this approach does not come without challenges. Biases may occur throughout the whole experiment, from fieldwork to biostatistics, resulting in the detection of false negatives, false positives or low taxonomic resolution. We detail a rigorous metabarcoding approach based on a short COI minibarcode and two-step PCR protocol enabling the "all at once" taxonomic identification of bats and their arthropod prey for several hundreds of samples. Our study includes faecal pellets collected in France from 357 bats representing 16 species, as well as insect mock communities that mimic bat meals of known composition, negative and positive controls. All samples were analysed using three replicates. We compare the efficiency of DNA extraction methods, and we evaluate the effectiveness of our protocol using identification success, taxonomic resolution, sensitivity and amplification biases. Our parallel identification strategy of predators and prey reduces the risk of mis-assigning prey to wrong predators and decreases the number of molecular steps. Controls and replicates enable to filter the data and limit the risk of false positives, hence guaranteeing high confidence results for both prey occurrence and bat species identification. We validate 551 COI variants from arthropod including 18 orders, 117 family, 282 genus and 290 species. Our method therefore provides a rapid, resolutive and cost-effective screening tool for addressing evolutionary ecological issues or developing "chirosurveillance" and conservation strategies. PMID- 29288546 TI - The impact of dental caries and its treatment by conventional or biological approaches on the oral health-related quality of life of children and carers. AB - BACKGROUND: The effect of untreated dental caries and the approaches taken to its treatment have not been extensively elucidated in children. AIM: To investigate the impact of untreated dental caries on children aged 4-9 years and whether its treatment with either a conventional or a biological approach influenced the oral health-related quality of life (OHRQoL) of the children and their carers. DESIGN: Children (n = 110) and their carers attending two specialist centres for treatment of carious primary teeth completed the Early Childhood Oral Health Impact Scale and the Self-reported Scale of Oral Health Outcomes for 5-year-old Children at baseline prior to dental treatment and at 3-6 months following completion of dental care. Dental treatment was provided using either a conventional or a biological approach. RESULTS: Dental caries showed a negative impact on the child and family's OHRQoL (P = 0.001). Children reported difficulty eating (55.5%), sleeping (40%), and avoiding smiling because of how the teeth looked (27.3%). More than half of the parents reported their child had toothache. Parents perceived difficulty eating (40.9%), being irritable (38.2%), and difficulty drinking (30.9%) as being impacts of caries on their child's OHRQoL. In addition, approximately half the parents reported feeling a sense of guilt because of their child's dental disease. Following dental treatment, participants reported significant improvement in their overall health status (P = 0.001). Children's age, gender, or the treatment approach were not statistically significantly associated with changes in OHRQoL of the child or carer. Children and parents who initially reported greater impacts of untreated dental caries demonstrated greater improvements in their overall oral health status (P < 0.0001). CONCLUSION: Dental caries was associated with negative impacts on children and parents' quality of life. Treatment of caries improved the quality of life of children and families significantly, irrespective of whether the treatment was provided by a conventional or a biological approach. PMID- 29288545 TI - A Randomized Trial of Lorcaserin and Lifestyle Counseling for Maintaining Weight Loss Achieved with a Low-Calorie Diet. AB - OBJECTIVE: Improving the maintenance of lost weight remains a critical challenge, which can be addressed by long-term behavioral and/or pharmacological interventions. METHODS: This study investigated the efficacy of combined behavioral and pharmacological treatment in facilitating weight loss maintenance (WLM) in 137 adults (86.1% female; 68.6% black; BMI = 37.0 +/- 5.6 kg/m2 ) who had lost >= 5% of initial weight during a 14-week low-calorie diet (LCD) program (mean = 9.3 +/- 2.9%). Participants were randomly assigned to lorcaserin (10 mg twice a day) or placebo and were provided 16 group WLM counseling sessions over 52 weeks. RESULTS: At 24 weeks post randomization, more lorcaserin-treated than placebo-treated participants maintained a >= 5% loss (73.9% vs. 57.4%; P = 0.033), and the lorcaserin-treated participants lost an additional 2.4 +/- 0.8 kg versus a 0.6 +/- 0.8 kg gain for placebo (P = 0.010). However, at week 52, groups did not differ on either co-primary outcome; 55.1% and 42.6%, respectively, maintained >= 5% loss (P = 0.110), with gains from randomization of 2.0 +/- 0.8 kg and 2.5 +/- 0.8 kg (P = 0.630), respectively. From the start of the LCD, groups maintained reductions of 7.8% and 6.6%, respectively (P = 0.318). CONCLUSIONS: Combined behavioral and pharmacological treatment produced clinically meaningful long-term weight loss in this group of predominantly black participants. Lorcaserin initially improved upon weight loss achieved with WLM counseling, but this advantage was not maintained at 1 year. PMID- 29288547 TI - Photophysics of a UV-B Filter 4-Methylbenzylidene Camphor: Intersystem Crossing Plays an Important Role. AB - 4-Methylbenzylidene camphor (4MBC) is a frequently used ultraviolet (UV) filter in commercial sunscreens, which is experimentally found to undergo efficient intersystem crossing to triplet manifolds followed by predominant radiationless decay to the ground state. However, its photophysical mechanism is unclear. Herein, we have employed combined CASPT2 and CASSCF methods to study the spectroscopic properties, geometric and electronic structures, conical intersections and crossing points, and excited-state deactivation channels of 4MBC. We have found that the V(1 pipi*) state is populated with large probability in the Franck-Condon region. Starting from this state, there are two efficient nonradiative relaxation processes to populate the 3 pipi* state. In the first one, the V(1 pipi*) state decays to the V'(1 pipi*) state. The resultant V'(1 pipi*) state further jumps to the 1 npi* state by internal conversion at the 1 pipi*/1 npi* conical intersection. Then, the 1 npi* state hops to the 3 pipi* state through an efficient 1 npi*->3 pipi* intersystem crossing process. In the second one, the V(1 pipi*) state can diabatically relax along the photoisomerization reaction coordinate. In this process, a 1 pipi*/3 npi* crossing point helps the 1 pipi* system decay to the 3 npi* state, which further decays to the 3 pipi* state through internal conversion at the 3 npi*/3 pipi* conical intersection. Once the 3 pipi* state is formed, a nearly barrierless relaxation path drives the 3 pipi* system to hop to the S0 state via the 3 pipi*/S0 crossing point. Our current work not only rationalizes recent experimental observations but also enriches our photophysical knowledge of UV filters. PMID- 29288548 TI - Colonic inflammatory fibroid polyp with PDGFRA expression. PMID- 29288549 TI - Transplantation of macroencapsulated human islets within the bioartificial pancreas betaAir to patients with type 1 diabetes mellitus. AB - Macroencapsulation devices provide the dual possibility of immunoprotecting transplanted cells while also being retrievable, the latter bearing importance for safety in future trials with stem cell-derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The betaAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the betaAir device containing allogeneic human pancreatic islets into patients with type 1 diabetes. Four patients were transplanted with 1-2 betaAir devices, each containing 155 000-180 000 islet equivalents (ie, 1800-4600 islet equivalents per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the betaAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the betaAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited (Clinicaltrials.gov: NCT02064309). PMID- 29288551 TI - Comparative study of sequence aligners for detecting antibiotic resistance in bacterial metagenomes. AB - : We aim to compare the performance of Bowtie2, bwa-mem, blastn and blastx when aligning bacterial metagenomes against the Comprehensive Antibiotic Resistance Database (CARD). Simulated reads were used to evaluate the performance of each aligner under the following four performance criteria: correctly mapped, false positives, multi-reads and partials. The optimal alignment approach was applied to samples from two wastewater treatment plants to detect antibiotic resistance genes using next generation sequencing. blastn mapped with greater accuracy among the four sequence alignment approaches considered followed by Bowtie2. blastx generated the greatest number of false positives and multi-reads when aligned against the CARD. The performance of each alignment tool was also investigated using error-free reads. Although each aligner mapped a greater number of error free reads as compared to Illumina-error reads, in general, the introduction of sequencing errors had little effect on alignment results when aligning against the CARD. Given each performance criteria, blastn was found to be the most favourable alignment tool and was therefore used to assess resistance genes in sewage samples. Beta-lactam and aminoglycoside were found to be the most abundant classes of antibiotic resistance genes in each sample. SIGNIFICANCE AND IMPACT OF THE STUDY: Antibiotic resistance genes (ARGs) are pollutants known to persist in wastewater treatment plants among other environments, thus methods for detecting these genes have become increasingly relevant. Next generation sequencing has brought about a host of sequence alignment tools that provide a comprehensive look into antimicrobial resistance in environmental samples. However, standardizing practices in ARG metagenomic studies is challenging since results produced from alignment tools can vary significantly. Our study provides sequence alignment results of synthetic, and authentic bacterial metagenomes mapped against an ARG database using multiple alignment tools, and the best practice for detecting ARGs in environmental samples. PMID- 29288550 TI - Questionnaire survey on mumps vaccination for parents in Nara prefecture, Japan. AB - BACKGROUND: Although the mumps vaccine has not been included in the national immunization program (NIP) in Japan, it has been shown that a two-dose routine vaccine program would be highly cost-effective. In this study, we carried outa questionnaire-based study to investigate how many Japanese parents want the mumps vaccine to be included in the NIP with proper information. METHODS: The questionnaire was given to parents who visited the Pediatrics or neonatal intensive care unit of Nara Prefecture General Medical Center, Nara City, Japan, between 1 March 2017 and 31 August 2017. The questionnaire consisted of information about mumps and six questions, for example (i) do parents know that mumps can be prevented by vaccine; (ii) do they know that they need to pay for mumps vaccines; and (iii) do they hope that the government will resume routine mumps vaccination. RESULTS: In total, 1,224 parents answered the questionnaire. A total of 81% and 75.4% of parents knew that mumps can be prevented by vaccination and that mumps vaccine is not included in the NIP, respectively, before reading the information. After reading the information, 95.0% of parents thought that mumps vaccine should be included in the NIP. While 61.7% of parents answered that they would choose two-dose vaccination without governmental financial support, 92.1% of them would choose two-dose vaccination with governmental financial support (P < 0.0001). CONCLUSION: Japanese parents want the mumps vaccine to be included in the NIP. Japan is able to start routine use of the mumps vaccine now. PMID- 29288552 TI - Effects of intrauterine perfusion of human chorionic gonadotropin in women with different implantation failure numbers. AB - PROBLEM: The aim of this research was to investigate the effects of the intrauterine perfusion of hCG before a frozen-thawed embryo transfer (FET) in women with different implantation failure numbers. METHOD OF STUDY: This was a retrospective analysis of patients undergoing FET who received an intrauterine injection hCG 1000 IU before embryo transfer. The groups included women with their first implantation failure (A group, n = 26), second implantation failure (B group, n = 122), and three or more failures (C group, n = 77). Corresponding control groups (no infusion) were also included. The pregnancy rates were compared among these groups. RESULTS: After intrauterine injection hCG, the biochemical pregnancy rates were 92.30%, 63.11%, 49.02%, and the clinical pregnancy rates were 76.92%, 54.91%, 48.05%, in the A, B, and C groups, respectively. The biochemical and clinical pregnancy rates were significantly higher in the A group than in the other groups (P < .05). The clinical pregnancy rates of the A and C groups were significantly higher than in the corresponding (no infusion) control groups (76.92% vs 56.81% and 48.05% vs 33.33%, P < .05). CONCLUSION: Pregnancy rates decreased with the number of transplant failures. The intrauterine administration of hCG before FET significantly improved the pregnancy rates, especially after one and three or more implantation failures. PMID- 29288553 TI - Paired methods to measure biofilm killing and removal: a case study with Penicillin G treatment of Staphylococcus aureus biofilm. AB - : Biofilms are microbial aggregates that show high tolerance to antibiotic treatments in vitro and in vivo. Killing and removal are both important in biofilm control, therefore methods that measure these two mechanisms were evaluated in a parallel experimental design. Kill was measured using the single tube method (ASTM method E2871) and removal was determined by video microscopy and image analysis using a new treatment flow cell. The advantage of the parallel test design is that both methods used biofilm covered coupons harvested from a CDC biofilm reactor, a well-established and standardized biofilm growth method. The control Staphylococcus aureus biofilms treated with growth medium increased by 0.6 logs during a 3-h contact time. Efficacy testing showed biofilms exposed to 400 MUmol l-1 penicillin G decreased by only 0.3 logs. Interestingly, time lapse confocal scanning laser microscopy revealed that penicillin G treatment dispersed the biofilm despite being an ineffective killing agent. In addition, no biofilm removal was detected when assays were performed in 96-well plates. These results illustrate that biofilm behaviour and impact of treatments can vary substantially when assayed by different methods. Measuring both killing and removal with well-characterized methods will be crucial for the discovery of new anti-biofilm strategies. SIGNIFICANCE AND IMPACT OF THE STUDY: Biofilms are tolerant to antimicrobial treatments and can lead to persistent infections. Finding new anti-biofilm strategies and understanding their mode-of-action is therefore of high importance. Historically, antimicrobial testing has focused on measuring the decrease in viability. While kill data are undeniably important, measuring biofilm disruption provides equally useful information. Starting with biofilm grown in the same reactor, we paired assessment of biofilm removal using a new treatment-flow-cell and real-time microscopy with kill data collected using the single tube method (ASTM E2871). Pairing these two methods revealed efficient biofilm removal properties of Penicillin G which were not detected during efficacy testing. PMID- 29288555 TI - The Focused History and Physical-circa 100 BCE. PMID- 29288554 TI - Development of a Patient Decision Aid for Syncope in the Emergency Department: the SynDA Tool. AB - OBJECTIVES: The objective was to develop a patient decision aid (DA) to promote shared decision making (SDM) for stable, alert patients who present to the emergency department (ED) with syncope. METHODS: Using input from patients, clinicians, and experts in the field of syncope, health care design, and SDM, we created a prototype of a paper-based DA to engage patients in the disposition decision (admission vs. discharge) after an unremarkable ED evaluation for syncope. In phase 1, we conducted one-on-one semistructured exploratory interviews with 10 emergency physicians and 10 ED syncope patients. In phase 2, we conducted one-on-one directed interviews with 15 emergency care clinicians, five cardiologists, and 12 ED syncope patients to get detailed feedback on DA content and design. We iteratively modified the aid using feedback from each interviewee until clarity and usability had been optimized. RESULTS: The 11 * 17 inch, paper-based DA, titled SynDA, includes four sections: 1) explanation of syncope, 2) explanation of future risks, 3) personalized 30-day risk estimate, and 4) disposition options. The personalized risk estimate is calculated using a recently published syncope risk-stratification tool. This risk estimate is stated in natural frequency and graphically displayed using a 100-person color-coded pictogram. Patient-oriented questions are included to stimulate dialogue between patient and clinician. At the end of the development process, patient and physician participants expressed satisfaction with the clarity and usability of the DA. CONCLUSIONS: We iteratively developed an evidence-based DA to facilitate SDM for alert syncope patients after an unremarkable ED evaluation. Further testing is required to determine its effects on patient care. This DA has the potential to improve care for syncope patients and promote patient-centered care in emergency medicine. PMID- 29288556 TI - RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. AB - Tolerance induction to prevent allograft rejection is a long-standing clinical goal. However, convincing and dependable tolerance identification remains elusive. Hypothesizing that intragraft RNA expression is informative in both rejection and tolerance, we profile intrarenal allograft RNA expression in a mixed chimerism renal allograft model of cynomolgus monkeys and identify biologically significant tolerance. Analysis of 67 genes identified 3 dominant factors, each with a different pattern of gene expressions, relating to T cell mediated rejection (TCMR), chronic antibody-mediated rejection (CAMR), or Tolerance. Clustering these 3 factors created 9 groups. One of the 9 clustered groups, the Tolerance cluster, showed the lowest probability of terminal rejection, the longest duration of allograft survival, and the lowest relative risk of terminal rejection. The Tolerance factor consists of a novel set of gene expressions including cytokine and immunoregulatory genes adding mechanistic insights into tolerance. The Tolerance factor could not be identified within current pathologic diagnostic categories. The TCMR and CAMR factors are dominant to the Tolerance factor, causing rejection even if the Tolerance factor is present. These 3 factors determine the probability of terminal rejection or tolerance. This novel a posteriori approach permits identification of pathways of rejection, including tolerance. PMID- 29288558 TI - Aggressive infrainguinal revascularization in renal transplant patients is justifiable. AB - While studies demonstrate poor outcomes of lower extremity revascularization in patients with end-stage renal disease, little is known about results in renal transplant patients. We analyzed 2-year primary patency and limb salvage outcomes and associated risk factors of transplant (n = 202) and nontransplant patients (n = 25 274) in the Vascular Quality Initiative database undergoing infrainguinal bypass from 2003 to 2016. Multivariable Cox regression analysis and coarsened exact matching with many-to-one were used. Transplant patients were more likely to have critical limb ischemia and revascularization of more distal arteries and to receive vein conduits. Primary patency was similar between transplant and nontransplant patients at 1 year (80.8% vs 77.5%) and 2 years (67.9% vs 63.7%, P = .079). Amputation-free survival was higher for nontransplant patients (1 year: 82.4% vs 75.3%, 2 years: 68.8% vs 58.2%, P = .0060), although overall survival was equivalent (2 years: 84.6% vs 87.2%, 4 years: 75.9% vs 79.6%, P = .35). Risk factors for primary patency loss included being female, critical limb ischemia, prior bypass, and distal bypass. Age, diabetes, prior contralateral amputation, critical limb ischemia, prosthetic conduit, and more distal bypass were associated with limb loss. This is the largest series of infrainguinal revascularization in transplant patients. Outcomes for transplant patients are not inferior, and aggressive approaches at limb salvage are justifiable in appropriately selected patients. PMID- 29288557 TI - Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients. AB - Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD. PMID- 29288559 TI - Omitting cytogenetic assessment from routine treatment response monitoring in chronic myeloid leukemia is safe. AB - OBJECTIVES: The monitoring of response in chronic myeloid leukemia (CML) is of great importance to identify patients failing their treatment in order to adjust TKI choice and thereby prevent progression to advanced stage disease. Cytogenetic monitoring has a lower sensitivity, is expensive, and requires invasive bone marrow sampling. Nevertheless, chronic myeloid leukemia guidelines continue to recommend performing routine cytogenetic response assessments, even when adequate molecular diagnostics are available. METHODS: In a population-based registry of newly diagnosed CML patients in the Netherlands, all simultaneous cytogenetic and molecular assessments performed at 3, 6, and 12 months were identified and response of these matched assessments was classified according to European Leukemia Net (ELN) recommendations. The impact of discrepant cytogenetic and molecular response classifications and course of patients with additional chromosomal abnormalities were evaluated. RESULTS: The overall agreement of 200 matched assessments was 78%. In case of discordant responses, response at 24 months was consistently better predicted by the molecular outcome. Cytogenetic response assessments provided relevant additional clinical information only in some cases of molecular "warning." The development of additional cytogenetic abnormalities was always accompanied with molecular failure. CONCLUSION: We conclude that it is safe to omit routine cytogenetics for response assessment during treatment and to only use molecular monitoring, in order to prevent ambiguous classifications, reduce costs, and reduce the need for invasive bone marrow sampling. Cytogenetic re-assessment should still be performed when molecular response is suboptimal. PMID- 29288561 TI - The effect of flurbiprofen oral spray and ibuprofen vs ibuprofen alone on postoperative tonsillectomy pain: An open, randomised, controlled trial. AB - OBJECTIVE: This prospective clinical study was carried out to evaluate the analgesic efficacy and safety of oral spray form of flurbiprofen in the treatment of postoperative pain in tonsillectomy patients. STUDY DESIGN: Open, randomised, controlled clinical study. SETTING: Tertiary care training and research hospital. PARTICIPANTS: One hundred (53 males, 47 females) with an age range of 18-53 years old (mean 27.4 +/- 9.3 SD) undergoing tonsillectomy were enrolled in this prospective controlled study. MAIN OUTCOME MEASURES: Patients receiving oral ibuprofen and flurbiprofen as spray form were enrolled as study group (53), whereas patients receiving only oral ibuprofen were enrolled as control group (47) in postoperative period. Postoperative pain was evaluated through visual analogue scale on 12th hour, first, third and seventh days after surgery. RESULTS: The mean maximal pain score of patients who have received flurbiprofen spray and ibuprofen was 3.36 +/- 1.93 SD that was statistically lower than the mean maximal pain score of patients who were medicated with only ibuprofen which was 4.06 +/- 1.29 SD on postoperative seventh day (P = .013). CONCLUSION: This study revealed that addition of flurbiprofen spray to oral ibuprofen is effective in the management of postoperative pain in tonsillectomy patients with no notable complications. PMID- 29288560 TI - Dietary acrylamide intake and risk of breast cancer: The Japan Public Health Center-based Prospective Study. AB - Acrylamide forms during cooking and is classified as a probable carcinogen in humans, mandating the need for epidemiological studies of dietary acrylamide and cancers. However, the risk of dietary acrylamide exposure to breast cancer in Japanese women has not been assessed. We investigated the association between dietary acrylamide intake and risk of breast cancer in the Japan Public Health Center-based Prospective Study. The present study included 48 910 women aged 45 74 years who responded to a 5-year follow-up survey questionnaire. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. During an average of 15.4 years of follow up, 792 breast cancers were diagnosed. Energy-adjusted dietary acrylamide intake was not associated with the risk of breast cancer (adjusted hazard ratio for highest versus lowest tertile = .95, 95% confidence intervals: 0.79-1.14, P-trend = .58). Further, no significant associations were observed when stratified analyses were conducted by smoking status, coffee consumption, alcohol consumption, body mass index, menopausal status, estrogen receptor status, and progesterone receptor status. In conclusion, dietary acrylamide intake was not associated with the risk of breast cancer in this population-based prospective cohort study of Japanese women. PMID- 29288562 TI - Interactions between host sex and age of exposure modify the virulence transmission trade-off. AB - The patterns of immunity conferred by host sex or age represent two sources of host heterogeneity that can potentially shape the evolutionary trajectory of disease. With each host sex or age encountered, a pathogen's optimal exploitative strategy may change, leading to considerable variation in expression of pathogen transmission and virulence. To date, these host characteristics have been studied in the context of host fitness alone, overlooking the effects of host sex and age on the fundamental virulence-transmission trade-off faced by pathogens. Here, we explicitly address the interaction of these characteristics and find that host sex and age at exposure to a pathogen affect age-specific patterns of mortality and the balance between pathogen transmission and virulence. When infecting age structured male and female Daphnia magna with different genotypes of Pasteuria ramosa, we found that infection increased mortality rates across all age classes for females, whereas mortality only increased in the earliest age class for males. Female hosts allowed a variety of trade-offs between transmission and virulence to arise with each age and pathogen genotype. In contrast, this variation was dampened in males, with pathogens exhibiting declines in both virulence and transmission with increasing host age. Our results suggest that differences in exploitation potential of males and females to a pathogen can interact with host age to allow different virulence strategies to coexist, and illustrate the potential for these widespread sources of host heterogeneity to direct the evolution of disease in natural populations. PMID- 29288563 TI - Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway. AB - Cell division cycle 37 (Cdc37) is an important partner for heat shock protein 90 (HSP90), assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulates cell survival in colorectal carcinoma (CRC) remain unclear. Here, we investigated the expression of Cdc37 and its clinical significance in CRC, and systematically explored the role and the underlying mechanism of Cdc37 in CRC cell survival both in vitro and in vivo. Our results showed that Cdc37 was remarkably up-regulated in CRC, which facilitated cell survival mainly by promoting cell proliferation, G1-S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of cyclin-dependent kinase 4 (CDK4) to activate the retinoblastoma 1 (RB1) signaling pathway, followed by increased expression of Bcl-2 and Bcl-xL, which ultimately promoted cell survival in CRC. Moreover, knockdown of CDK4 reversed the Cdc37-mediated effect in promoting the progression of CRC. Our findings showed that Cdc37 played a critical role in promoting CRC cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patients. PMID- 29288564 TI - Luteinizing hormone and insulin resistance in menopausal patients with adrenal incidentalomas: The cause-effect relationship? AB - OBJECTIVE: A high prevalence of insulin resistance (IR) has proven to manifest in patients with adrenal incidentalomas (AI). It has been demonstrated that an increase in IR is related to the size of tumourous masses; additionally, luteinizing hormone (LH)-dependent adrenal pathologies are well documented in patients with LH-responsive adrenal tumours occurring under conditions of physiologically elevated LH. We hypothesized that an association between LH and insulin might play a role in adrenal tumourigenesis and steroidogenesis. DESIGN: The aim of our study was to investigate the association between LH and IR; adrenal tumour size (ATS) and IR; LH and cortisol after the 1 mg overnight dexamethasone test (1 mg DST); and ATS and 1 mg DST cortisol in AI patients. This was a case-control study conducted in the Clinic for Endocrinology, Diabetes and Metabolic Diseases in Belgrade, Serbia. The total study group consisted of 105 menopausal women: 75 AI patients [27 with nonfunctional AI (NAI) and 48 with (possible) autonomous cortisol secretion ((P)ACS)] and 30 age-, BMI-, LH- and menopause duration-matched healthy control (HC) women. To estimate IR, we used homeostasis model assessment (HOMA-IR). RESULTS: Luteinizing hormone and ATS are in a significant positive correlation with HOMA-IR and 1 mg DST cortisol in menopausal patients with AI and (P)ACS. CONCLUSIONS: Our data point to a possible cause-effect relationship between LH and insulin in patients with AI and (P)ACS adding to the body of evidence of their involvement in adrenal tumourigenesis and steroidogenesis. PMID- 29288566 TI - Double suspension sutures: A simple surgical technique for selected cases of obstructive sleep apnoea: Our experience with twenty-two patients. PMID- 29288565 TI - High and long-term von Willebrand factor expression after Sleeping Beauty transposon-mediated gene therapy in a mouse model of severe von Willebrand disease. AB - : Essentials von Willebrand disease (VWD) is the most common inherited bleeding disorder. Gene therapy for VWD offers long-term therapy for VWD patients. Transposons efficiently integrate the large von Willebrand factor (VWF) cDNA in mice. Liver-directed transposons support sustained VWF expression with suboptimal multimerization. SUMMARY: Background Type 3 von Willebrand disease (VWD) is characterized by complete absence of von Willebrand factor (VWF). Current therapy is limited to treatment with exogenous VWF/FVIII products, which only provide a short-term solution. Gene therapy offers the potential for a long-term treatment for VWD. Objectives To develop an integrative Sleeping Beauty (SB) transposon mediated VWF gene transfer approach in a preclinical mouse model of severe VWD. Methods We established a robust platform for sustained transgene murine VWF (mVWF) expression in the liver of Vwf-/- mice by combining a liver-specific promoter with a sandwich transposon design and the SB100X transposase via hydrodynamic gene delivery. Results The sandwich SB transposon was suitable to deliver the full-length mVWF cDNA (8.4 kb) and supported supra-physiological expression that remained stable for up to 1.5 years after gene transfer. The sandwich vector stayed episomal (~60 weeks) or integrated in the host genome, respectively, in the absence or presence of the transposase. Transgene integration was confirmed using carbon tetrachloride-induced liver regeneration. Analysis of integration sites by high-throughput analysis revealed random integration of the sandwich vector. Although the SB vector supported long-term expression of supra-physiological VWF levels, the bleeding phenotype was not corrected in all mice. Long-term expression of VWF by hepatocytes resulted in relatively reduced amounts of high-molecular-weight multimers, potentially limiting its hemostatic efficacy. Conclusions Although this integrative platform for VWF gene transfer is an important milestone of VWD gene therapy, cell type specific targeting is yet to be achieved. PMID- 29288567 TI - Isothiocyanates and Xenobiotic Detoxification. AB - The potential of isothiocyanates to antagonize the carcinogenicity of structurally diverse chemicals has been established in animals. A feasible mechanism of action involves protecting DNA by reducing the availability of the genotoxic metabolites of chemical carcinogens by either inhibiting their generation and/or stimulating their detoxification. In vivo as well as in vitro studies conducted in rat/human primary hepatocytes and precision-cut tissue slices have revealed that isothiocyanates can impair cytochrome P450 activity, including the CYP1 family which is the most active in the bioactivation of carcinogens, by virtue of being mechanism-based inactivators. The aromatic phenethyl isothiocyanate is the most effective of those studied, whereas aliphatic isothiocyanates such as sulforaphane and erucin necessitate high doses in order to manifest such effects that may not always be achievable through the diet. In all systems studied, isothiocyanates are strong inducers of detoxification enzyme systems including quinone reductase, glutathione S transferase, epoxide hydrolase, and UDP-glucuronosyl transferase. Indeed, in smokers phenethyl isothiocyanate intake increases the urinary excretion of inactive mercapturate metabolites of toxic chemicals present in tobacco. Glucosinolates, the precursors of isothiocyanates, have also the potential to upregulate detoxification enzyme systems, but their contribution to the cancer chemoprevention linked to cruciferous vegetable consumption remains to be evaluated. PMID- 29288569 TI - Sex-based differences in CD103+ dendritic cells promote female-predominant Th2 cytokine production during allergic asthma. AB - BACKGROUND: Gender disparities in adult patients with asthma regarding its prevalence and severity are mainly due to enhanced type 2 T-helper (Th2) cytokine production in female patients compared to that in male patients. However, the pathways mediating this effect remain unclear. OBJECTIVE: We aimed to determine the roles of two major subsets of dendritic cells (DCs) in females, specifically those displaying CD11b or CD103, during enhanced Th2 priming after allergen exposure, using an ovalbumin-induced asthma mouse model. METHODS: Sex-based differences in the number of DCs at inflamed sites, costimulatory molecule expression on DCs, and the ability of DCs to differentiate naive CD4+ T cells into Th2 population were evaluated after allergen exposure in asthmatic mice. In addition, we assessed the role of 17beta-oestradiol in CD103+ DC function during Th2 priming in vitro. RESULTS: The number of CD11bhigh DCs and CD103+ DCs in the lung and bronchial lymph node (BLN) was increased to a greater extent in female mice than in male mice at 16 to 20 hours after ovalbumin (OVA) inhalation. In BLNs, CD86 and I-A/I-E expression levels and antigen uptake ability in CD103+ DCs, but not in CD11bhigh DCs, were greater in female mice than in male mice. Furthermore, CD4+ T cells cultured with CD103+ DCs from female mice produced higher levels of interleukin (IL)-4, IL-5, and IL-13, compared with CD4+ T cells cultured with CD103+ DCs from male mice. The 17beta-oestradiol-oriented enhancement of CD86 expression on CD103+ DCs after allergen exposure induced the enhanced IL-5 production from CD4+ T cells. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that with regard to asthma, enhanced Th2 cytokine production in females might be attributed to 17beta-oestradiol-mediated Th2 oriented CD103+ DCs in the BLN. PMID- 29288568 TI - Skeletal muscle microvascular and interstitial PO2 from rest to contractions. AB - KEY POINTS: Oxygen pressure gradients across the microvascular walls are essential for oxygen diffusion from blood to tissue cells. At any given flux, the magnitude of these transmural gradients is proportional to the local resistance. The greatest resistance to oxygen transport into skeletal muscle is considered to reside in the short distance between red blood cells and myocytes. Although crucial to oxygen transport, little is known about transmural pressure gradients within skeletal muscle during contractions. We evaluated oxygen pressures within both the skeletal muscle microvascular and interstitial spaces to determine transmural gradients during the rest-contraction transient in anaesthetized rats. The significant transmural gradient observed at rest was sustained during submaximal muscle contractions. Our findings support that the blood-myocyte interface provides substantial resistance to oxygen diffusion at rest and during contractions and suggest that modulations in microvascular haemodynamics and red blood cell distribution constitute primary mechanisms driving increased transmural oxygen flux with contractions. ABSTRACT: Oxygen pressure (PO2) gradients across the blood-myocyte interface are required for diffusive O2 transport, thereby supporting oxidative metabolism. The greatest resistance to O2 flux into skeletal muscle is considered to reside between the erythrocyte surface and adjacent sarcolemma, although this has not been measured during contractions. We tested the hypothesis that O2 gradients between skeletal muscle microvascular (PO2 mv ) and interstitial (PO2 is ) spaces would be present at rest and maintained or increased during contractions. PO2 mv and PO2 is were determined via phosphorescence quenching (Oxyphor probes G2 and G4, respectively) in the exposed rat spinotrapezius during the rest-contraction transient (1 Hz, 6 V; n = 8). PO2 mv was higher than PO2 is in all instances from rest (34.9 +/- 6.0 versus 15.7 +/- 6.4) to contractions (28.4 +/- 5.3 versus 10.6 +/- 5.2 mmHg, respectively) such that the mean PO2 gradient throughout the transient was 16.9 +/- 6.6 mmHg (P < 0.05 for all). No differences in the amplitude of PO2 fall with contractions were observed between the microvasculature and interstitium (10.9 +/ 2.3 versus 9.0 +/- 3.5 mmHg, respectively; P > 0.05). However, the speed of the PO2 is fall during contractions was slower than that of PO2 mv (time constant: 12.8 +/- 4.7 versus 9.0 +/- 5.1 s, respectively; P < 0.05). Consistent with our hypothesis, a significant transmural gradient was sustained (but not increased) from rest to contractions. This supports that the blood-myocyte interface is the site of a substantial PO2 gradient driving O2 diffusion during metabolic transients. Based on Fick's law, elevated O2 flux with contractions must thus rely primarily on modulations in effective diffusing capacity (mainly erythrocyte haemodynamics and distribution) as the PO2 gradient is not increased. PMID- 29288570 TI - n-Type Azaacenes Containing B<-N Units. AB - We disclose a novel strategy to design n-type acenes through the introduction of boron-nitrogen coordination bonds (B<-N). We synthesized two azaacenes composed of two B<-N units and six/eight linearly annelated rings. The B<-N unit significantly perturbed the electronic structures of the azaacenes: Unique LUMOs delocalized over the entire acene skeletons and decreased aromaticity of the B<-N adjacent rings. Most importantly, these B<-N-containing azaacenes exhibited low lying LUMO energy levels and high electron affinities, thus leading to n-type character. The solution-processed organic field-effect transistor based on one such azaacene exhibited unipolar n-type characteristics with an electron mobility of 0.21 cm2 V-1 s-1 . PMID- 29288571 TI - Early second trimester maternal serum markers in the prediction of gestational diabetes mellitus. AB - AIMS/INTRODUCTION: To determine whether maternal serum markers in the early second trimester are useful for prediction of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: A total of 876 singleton pregnancies were recruited in the present study. Blood samples were collected during 16-20 gestational weeks. GDM women were diagnosed by an oral glucose tolerance test during 24-28 gestational weeks. A total of 56 women with GDM and 73 healthy pregnant women were selected. Maternal serum concentrations of placental protein 13 (PP13), pentraxin 3 (PTX3), soluble fms-like tyrosine kinase-1 (sFlt-1), myostatin and follistatin (FST) were detected at 16-20 weeks' gestation. All of these markers concentrations were expressed as multiples of the medians. The Mann-Whitney U test was used for comparison of the multiples of the medians of different concentrations of these five serum markers between the GDM group and the control group. Receiver operating characteristic curve analysis was applied to assess the sensitivity and specificity of significant serum markers from a Mann-Whitney U test comparison. RESULTS: Compared with healthy pregnancies, the serum levels of PP13, PTX3, sFlt-1, myostatin and FST in the early second trimester were significantly increased in patients who had developed GDM late. In screening for GDM by PP13, PTX3, sFlt-1, myostatin and FST, the detection rates were 92.3, 94.9, 94.9, 92.5 and 92.3%, respectively at 80% specificity. PTX3 and sFlt-1 were the most sensitive markers. CONCLUSIONS: Maternal serum markers including PP13, PTX3, sFlt-1, myostatin and FST increase in the early second trimester of women with GDM. These five markers, especially PTX3 and sFlt-1, could have the value of prediction for those patients who would develop GDM in the late second trimester. PMID- 29288573 TI - Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma together-a real life study. AB - INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma often coexist and thus treating both with one intervention is an attractive strategy. OBJECTIVE: To prospectively evaluate whether treatment with the monoclonal antibody against IgE Omalizumab for severe allergic asthma also effectively treats co-existent CRSwNP. METHODS: SNOT-22 and the ACQ-7 scores were recorded at 4 and 16 weeks of treatment in a cohort of patients with both CRSwNP and severe refractory allergic asthma treated with Omalizumab (n=13) according to UK guidelines for their severe asthma. SNOT-22 in a surgery only treated CRSwNP with asthma group (n=24) was compared. RESULTS: Rapid improvement was seen at 4 weeks and 16 weeks of treatment in both CRSwNP and asthma control. The improvement in CRSwNP with Omalizumab was similar to that seen in a group of patients who received upper airway surgery. CONCLUSION: Omalizumab treatment for severe allergic asthma also improves co-existent CRSwNP. Further clinical studies of current and emerging biological agents for severe asthma should include upper airway outcomes. These agents may be effective for severe CRSwNP and comparative studies with surgery are warranted. PMID- 29288572 TI - Label-free optical imaging technologies for rapid translation and use during intraoperative surgical and tumor margin assessment. AB - The biannual International Conference on Biophotonics was recently held on April 30 to May 1, 2017, in Fremantle, Western Australia. This continuing conference series brought together key opinion leaders in biophotonics to present their latest results and, importantly, to participate in discussions on the future of the field and what opportunities exist when we collectively work together for using biophotonics for biological discovery and medical applications. One session in this conference, entitled "Tumor Margin Identification: Critiquing Technologies," challenged invited speakers and attendees to review and critique representative label-free optical imaging technologies and their application for intraoperative assessment and guidance in surgical oncology. We are pleased to share a summary in this outlook paper, with the intent to motivate more research inquiry and investigations, to challenge these and other optical imaging modalities to evaluate and improve performance, to spur translation and adoption, and ultimately, to improve the care and outcomes of patients. PMID- 29288574 TI - Modeling and optimization of lipid accumulation by Yarrowia lipolytica from glucose under nitrogen depletion conditions. AB - Oleaginous yeasts have been seen as a feasible alternative to produce the precursors of biodiesel due to their capacity to accumulate lipids as triacylglycerol having profiles with high content of unsaturated fatty acids. The yeast Yarrowia lipolytica is a promising microorganism that can produce lipids under nitrogen depletion conditions and excess of the carbon source. However, under these conditions, this yeast also produces citric acid (overflow metabolism) decreasing lipid productivity. This work presents two mathematical models for lipid production by Y. lipolytica from glucose. The first model is based on Monod and inhibition kinetics, and the second one is based on the Droop quota model approach, which is extended to yeast. The two models showed good agreements with the experimental data used for calibration and validation. The quota based model presented a better description of the dynamics of nitrogen and glucose dynamics leading to a good management of N/C ratio which makes this model interesting for control purposes. Then, quota model was used to evaluate, by means of simulation, a scenario for optimizing lipid productivity and lipid content. For that, a control strategy was designed by approximating the flow rates of glucose and nitrogen with piecewise linear functions. Simulation results achieved productivity of 0.95 g L-1 hr-1 and lipid content fraction of 0.23 g g 1 , which indicates that this strategy is a promising alternative for the optimization of lipid production. PMID- 29288575 TI - High titer oncolytic measles virus production process by integration of dielectric spectroscopy as online monitoring system. AB - Oncolytic viruses offer new hope to millions of patients with incurable cancer. One promising class of oncolytic viruses is Measles virus, but its broad administration to cancer patients is currently hampered by the inability to produce the large amounts of virus needed for treatment (1010 -1012 virus particles per dose). Measles virus is unstable, leading to very low virus titers during production. The time of infection and time of harvest are therefore critical parameters in a Measles virus production process, and their optimization requires an accurate online monitoring system. We integrated a probe based on dielectric spectroscopy (DS) into a stirred tank reactor to characterize the Measles virus production process in adherent growing Vero cells. We found that DS could be used to monitor cell adhesion on the microcarrier and that the optimal virus harvest time correlated with the global maximum permittivity signal. In 16 independent bioreactor runs, the maximum Measles virus titer was achieved approximately 40 hr after the permittivity maximum. Compared to an uncontrolled Measles virus production process, the integration of DS increased the maximum virus concentration by more than three orders of magnitude. This was sufficient to achieve an active Measles virus concentration of > 1010 TCID50 ml-1 . PMID- 29288576 TI - Gold nanorod-photosensitizer conjugates with glutathione-sensitive linkages for synergistic cancer photodynamic/photothermal therapy. AB - Recently, photodynamic therapy (PDT) has been intensively investigated as a useful modality for the treatment of various cancers. In addition, near infrared (NIR) photothermal therapy (PTT) using gold nanocarriers has attracted particular interest as a hyperthermia strategy. In this study, gold nanorod (AuNR) photosensitizer conjugates with glutathione-sensitive linkages were designed for PDT and PTT. Several kinds of AuNRs with different aspect ratios were synthesized and modified with FA-conjugated block copolymers (FA-PEG-P(Asp)-DHLA) and Chlorin e6 (Ce6) as a photosensitizer. The surface-modified AuNRs showed excellent stability and solubility in aqueous solution. In particular, FA-PEG-P(Asp)-DHLA AuNR100-SS-Ce6 with a 3.84 aspect ratio exhibited strong photothermal effects, enhanced singlet oxygen generation, and marked phototoxicity. Based on these results, we suggest that AuNR-photosensitizer conjugates with glutathione sensitive linkages have potential application in PDT/PTT for effective clinical treatment of various cancers. PMID- 29288577 TI - Confirmatory molecular method for HTLV-1/2 infection in high-risk pregnant women. AB - Human T-cell lymphotropic virus types 1/2 (HTLV-1/2) are transmitted through sexual intercourse, transfusion of blood components, and vertical transmission, predominantly through breastfeeding. Six hundred forty-three pregnant women from a high-risk prenatal care unit at a general hospital were tested by serological tests using chemiluminescence (CMIA) for screening, followed by a molecular confirmatory test. Four patients (0.6%) tested positive for HTLV-1/2 by CMIA, two samples (0.3%) for each patient were confirmed as having HTLV-1 or HTLV-2 by PCR. The results show the importance of inclusion of HTLV-1/2 screening for pregnant women in high-risk prenatal care and the need for a molecular biological method to confirm HTLV-1/2 infection. PMID- 29288578 TI - MiR-96 regulates bone metabolism by targeting osterix. AB - MicroRNAs (miRNAs) play important roles in bone metabolism and aging. Here we show that miR-96 was markedly up-regulated in serum of elderly patients with osteoporosis by miRNA microarray analysis and qRT-PCR. Moreover miR-96 was also up-regulated in bone marrow mesenchymal stem cells (BMSCs) of aged humans and mice. Our results show that the over-expression of miR-96 reduced osteogenic differentiation of BMSCs, whereas the inhibition of miR-96 increased osteogenic differentiation of BMSCs. At the molecular level, miR-96 regulated osteogenesis by targeting osterix. Interestingly, over-expression of miR-96 in young mice by intravenous injection of agomiR-96 developed a low bone mass due to impaired osteogenesis. However, inhibition of miR-96 in aged mice attenuated the age related bone loss. Thus, our data suggest that miR-96 regulates osteogenesis and may represent a potential diagnostic marker or therapeutic target for age-related bone loss. PMID- 29288579 TI - A robust protocol for directed aryl sulfotransferase evolution toward the carbohydrate building block GlcNAc. AB - Bacterial aryl sulfotransferases (AST) utilize p-nitrophenylsulfate (pNPS) as a phenolic donor to sulfurylate typically a phenolic acceptor. Interest in aryl sulfotransferases is growing because of their broad variety of acceptors and cost effective sulfuryl-donors. For instance, aryl sulfotransferase A (ASTA) from Desulfitobacterium hafniense was recently reported to sulfurylate d-glucose. In this study, a directed evolution protocol was developed and validated for aryl sulfotransferase B (ASTB). Thereby the well-known pNPS quantification system was advanced to operate efficiently as a continuous screening system in 96-well MTP format with a true coefficient of variation of 14.3%. A random mutagenesis library (SeSaM library) of ASTB was screened (1,760 clones) to improve sulfurylation of the carbohydrate building block N-acetylglucosamine (GlcNAc). The beneficial variant ASTB-V1 (Val579Asp) showed an up to 3.4-fold increased specific activity toward GlcNAc when compared to ASTB-WT. HPLC- and MS-analysis confirmed ASTB-V1's increased GlcNAc monosulfurylation (2.4-fold increased product formation) representing the validation of the first successful directed evolution round of an AST for a saccharide substrate. PMID- 29288580 TI - Multivisceral transplant is a viable treatment option for patients with non resectable intra-abdominal fibromatosis. AB - BACKGROUND: Intra-abdominal fibromatosis often involves the mesentery root which is non-resectable by conventional surgery. Multivisceral transplant (MVT), as a potential cure to non-resectable fibromatosis, has rarely been reported and the prognosis is unknown. METHODS: Six patients who underwent MVT for intra-abdominal fibromatosis were reviewed. Clinicopathological features, immunohistochemistry for beta-catenin, p53, and Ki67, and outcomes were evaluated. Appropriate data for comparative analysis were obtained from a cohort of 24 patients who underwent conventional resection for intra-abdominal fibromatosis. RESULTS: Among six MVT patients, four had familial adenomatous polyposis (FAP). Two patients had an initial intestinal transplantation, three had multiple prior surgeries, and two had adjuvant therapy. One patient died of hemorrhagic stroke shortly after MVT, and five patients (83%) survived with a median follow-up of 64 months. The 1-year and 5-year survival rates were 67% for all five patients. Two patients had recurrences after MVT and one of them had FAP. In comparison, six of 24 patients who underwent conventional surgery had FAP; six (25%) had recurrences and three had FAP. For FAP patients; the mean recurrence time was 13 months for MVT versus 6 months for conventional surgery. Ki67 proliferative index, beta-catenin, and p53 expression did not significantly correlate to recurrence. CONCLUSIONS: Multivisceral transplant (MVT) is a viable option for patients who have non resectable intra-abdominal fibromatosis with promising surviving rates, although recurrence still occurs. Surgical margin, Ki67 proliferative index, beta-catenin, and p53 expression are not predicative for recurrence of fibromatosis. PMID- 29288581 TI - Comparison of Different-Gauge Needles for Fine-Needle Aspiration Biopsy of Thyroid Nodules. AB - OBJECTIVES: To compare the adequacy of 23-, 25-, and 27-gauge needles in the fine needle aspiration biopsy of thyroid nodules to develop guidelines for the collection of better specimens for cytologic diagnosis. METHODS: This randomized prospective study included 156 consecutively enrolled patients with 156 nodules. Each nodule was aspirated with a needle of each size. The obtained specimens were analyzed independently by 2 cytopathologists, and adequacy rates were calculated. RESULTS: In our investigation, there were no statistically significant differences among the adequacy rates achieved with 23-, 25-, and 27-gauge needles (88.5%, 90.4%, and 89.7%, respectively; P > .05). The adequacy rates achieved with all 3 needle sizes in hyperechoic nodules were higher than those in hypoechoic samples (P < .05). Finally, no differences in adequacy for the different needle sizes were observed according to nodule size (P > .05). CONCLUSIONS: We conclude that fine-needle aspiration biopsy with a 27-gauge needle can aspirate an adequate specimen for cytopathologic diagnosis of thyroid nodules. The likelihood that inadequate materials will be obtained from hypoechoic nodules is higher than that for hyperechoic nodules. PMID- 29288583 TI - Applications of 3-Dimensional Ultrasonography in the Neck, Excluding the Thyroid. AB - Ultrasonography (US) of the neck is an accepted, useful imaging modality for many applications beyond its usefulness in thyroid disease. Two-dimensional US has been effectively used for evaluation of many types of neck conditions, and now, 3 dimensional US can be added to the imaging armamentaria. Three-dimensional US is useful in the evaluation of cervical lymph nodes, recurrent/residual thyroid neoplasia, parathyroid glands, parotid and submandibular glands, as well as thyroglossal duct cysts and other assorted palpable and visible abnormalities because of its unique capabilities, including multiplanar reconstruction, accessibility of the coronal view, volume calculation, and regularly spaced incremental slice evaluation. PMID- 29288584 TI - Oseltamivir-resistant influenza A(H1N1)pdm09 virus associated with high case fatality, India 2015. AB - Influenza A viruses has been associated with severe global pandemics of high morbidity and mortality with devastating impact on human health and global economy. India witnessed a major outbreak of influenza A(H1N1)pdm09 in 2015. This study comprises detailed investigation of cases died of influenza A(H1N1)pdm09 virus infection during explosive outbreak of 2015, in central part of India. To find out presence of drug resistant virus among patients who died of influenza A(H1N1)pdm09 virus infection and to find out presence of other mutations contributing to the morbidity and mortality. Twenty-two patients having confirmed influenza A(H1N1)pdm09 infection and subsequently died of this infection along with 20 non fatal cases with influenza A(H1N1)pdm09 infection were included in the study. Samples were investigated through RT-PCR/RFLP analysis, followed by nucleotide cycle sequencing of whole NA gene for detection of H275Y amino acid substitution in NA gene responsible for oseltamivir drug resistance. Out of 22 fatal cases, 6 (27.27%) were found to harbor oseltamivir resistant virus strains, whereas the H275Y mutation was not observed among the 20 non fatal cases. Amino acid substitution analysis of complete NA gene revealed V241I, N369K, N386K substitution in all strains playing synergistic role in oseltamivir drug resistance. High morbidity and mortality associated with influenza A(H1N1)pdm09 viruses can be explained by presence of drug resistant strains circulating in this outbreak. Presence of Oseltamivir resistant influenza A(H1N1)pdm09 viruses is a cause of great concern and warrants continuous screening for the circulation of drug resistant strains. PMID- 29288582 TI - Properties of global- and local-ancestry adjustments in genetic association tests in admixed populations. AB - Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global-ancestry adjustment should be used for screening, but local-ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci. PMID- 29288585 TI - Enhanced cell trapping throughput using DC-biased AC electric field in a dielectrophoresis-based fluidic device with densely packed silica beads. AB - This paper presents the use of DC-biased AC electric field for enhancing cell trapping throughput in an insulator-based dielectrophoretic (iDEP) fluidic device with densely packed silica beads. Cell suspension is carried through the iDEP device by a pressure-driven flow. Under an applied DC-biased AC electric field, DEP trapping force is produced as a result of non-uniform electric field induced by the gap of electrically insulating silica beads packed between two mesh electrodes that allow both fluid and cells to pass through. While the AC component is mainly to control the magnitude of DEP trapping force, the DC component generates local electroosmotic (EO) flow in the cavity between the beads and the EO flow can be set to move along or against the main pressure driven flow. Our experimental and simulation results show that desirable trapping is achieved when the EO flow direction is along (not against) the main flow direction. Using our proposed DC-biased AC field, the device can enhance the trapping throughput (in terms of the flowrate of cell suspension) up to five times while yielding almost the same cell capture rates as compared to the pure AC field case. Additionally, the device was demonstrated to selectively trap dead yeast cells from a mixture of flowing live and dead yeast cells. PMID- 29288586 TI - ProMoIJ: A new tool for automatic three-dimensional analysis of microglial process motility. AB - Microglia, the immune cells of the central nervous system, continuously survey the brain to detect alterations and maintain tissue homeostasis. The motility of microglial processes is indicative of their surveying capacity in normal and pathological conditions. The gold standard technique to study motility involves the use of two-photon microscopy to obtain time-lapse images from brain slices or the cortex of living animals. This technique generates four dimensionally-coded images which are analyzed manually using time-consuming, non-standardized protocols. Microglial process motility analysis is frequently performed using Z stack projections with the consequent loss of three-dimensional (3D) information. To overcome these limitations, we developed ProMoIJ, a pack of ImageJ macros that perform automatic motility analysis of cellular processes in 3D. The main core of ProMoIJ is formed by two macros that assist the selection of processes, automatically reconstruct their 3D skeleton, and analyze their motility (process and tip velocity). Our results show that ProMoIJ presents several key advantages compared with conventional manual analysis: (1) reduces the time required for analysis, (2) is less sensitive to experimenter bias, and (3) is more robust to varying numbers of processes analyzed. In addition, we used ProMoIJ to demonstrate that commonly performed 2D analysis underestimates microglial process motility, to reveal that only cells adjacent to a laser injured area extend their processes toward the lesion site, and to demonstrate that systemic inflammation reduces microglial process motility. ProMoIJ is a novel, open-source, freely available tool which standardizes and accelerates the time-consuming labor of 3D analysis of microglial process motility. PMID- 29288587 TI - From lab to market: An integrated bioprocess design approach for new-to-nature biosurfactants produced by Starmerella bombicola. AB - Glycolipid microbial biosurfactants, such as sophorolipids (SLs), generate high industrial interest as 100% biobased alternatives for traditional surfactants. A well-known success story is the efficient SL producer Starmerella bombicola, which reaches titers well above 200 g/L. Recent engineering attempts have enabled the production of completely new types of molecules by S. bombicola, e.g. the bolaform SLs. Scale-up of bolaform SL production was performed at 150 L scale. The purified product was evaluated in detergent applications, as classic SLs are mostly applied in eco-friendly detergents. In this paper, we show that they can be used as green and non-irritant surfactants in for example (automatic) dishwashing applications. However, due to the presence of an ester function in the biosurfactant molecule a limited chemical stability at higher pH values (>6.5) was noticed, (therefore called 'non-symmetrical' (nsBola)) which, is a major drawback that will most likely inhibit market introduction. An integrated bioprocess design (IBPD) strategy was thus applied to resolve this issue. The strategy was to replace the fed fatty acids with fatty alcohols, to generate so called "symmetrical bolaform (sBola) sophorosides (SSs)," containing two instead of one glycosidic bond. Next to a change in feeding strategy, the blocking of the fatty alcohols from metabolizing/oxidizing through the suggested omega-oxidation pathway was necessary. For the latter, two putative fatty alcohol oxidase genes (fao1 and fao2) were identified in the S. bombicola genome and deleted in the bolaform SL producing strain (DeltaatDeltasble). Shake flask experiments for these new strains (DeltaatDeltasbleDeltafao1 and DeltaatDeltasbleDeltafao2) were performed to evaluate if the fed fatty alcohols were directly implemented into the SL biosynthesis pathway. Indeed, sBola sophorosides (SSs) production up to 20 g/L was observed for the DeltaatDeltasbleDeltafao1 strain. Unexpectedly, the DeltaatDeltasbleDeltafao2 strain only produced minor amounts of sBola sophorosides (SSs), and mainly nsBola SLs (alike the parental DeltaatDeltasble strain). The sBola sophorosides (SSs) were purified and their symmetrical structure was confirmed by NMR. They were found to be significantly more stable at higher pH, opening up the application potential of the biosurfactant by enhancing its stability properties. PMID- 29288589 TI - Nitric oxide modulates actin filament organization in Arabidopsis thaliana primary root cells at low temperatures. AB - Cytoskeleton is gaining the increasing recognition as one of nitric oxide (NO) downstream targets because of its involvement in plenty of NO-controlled processes in plants throughout the entire life cycle starting from seed germination to pollination as well as (a)biotic stress tolerance. It has been revealed that low temperature (+0.5 degrees C) has an inhibitory effect on A. thaliana primary root growth and causes an anisotropic increase of epidermal cells diameter in elongation zone. Furthermore, actin filaments' organization of epidermal cells in different zones of primary roots is modulated by NO content. Thus, the exogenous NO donor (SNP) favors to actin filaments network reorganization, while both cold and NO scavenger (c-PTIO) increase its randomization. According to the data obtained, it can be assumed that not only actin filaments act as NO sensors, but NO is also involved into plant cell response on low temperatures by the signaling via such important cytoskeleton machinery as actin network. PMID- 29288588 TI - IL-1alpha inhibits proliferation and adipogenic differentiation of human adipose derived mesenchymal stem cells through NF-kappaB- and ERK1/2-mediated proinflammatory cytokines. AB - Dysfunctional adipogenesis such as subcutaneous lipoatrophy is closely related to insulin resistance and metabolic disorders. Although the expression or release of the cytokine interleukin-1alpha (IL-1alpha) is known to increase in adipose tissue in response to cell death, cell senescence, aging, or solar radiation, the regulatory role of IL-1alpha in adipogenesis has not been sufficiently investigated. To investigate the problem, we explored the effect of IL-1alpha on the proliferation and adipogenic differentiation of human adipose-derived mesenchymal stem cells (ADSCs) using cell counting, alamarBlue assay, oil red O staining, Western blot, among others. The results showed that IL-1alpha evidently inhibited the proliferation and adipogenic differentiation of ADSCs, which might be related with the activated nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase (ERK) 1/2 pathways. Early-stage adipogenic differentiation was more sensitive to IL-1alpha than late-stage differentiation. After differentiation of ADSCs into mature adipocytes, adding of IL-1alpha had no obvious influence on the cellular morphology, including lipid droplet accumulation. IL-1alpha enhanced the expression of proinflammatory cytokines, such as IL-8, IL-6, CCL2 (C-C motif chemokine ligand 2), and IL-1beta, when added into the adipogenic medium of ADSCs. Blocking IL-8 and IL-6 with neutralizing antibodies partially alleviated the inhibitory effect of IL-1alpha on the proliferation and adipogenic differentiation. The results suggest that IL-1alpha inhibits adipogenesis through activation of NF-kappaB and ERK1/2 pathways and subsequent upregulation of proinflammatory cytokines in ADSCs. IL-1alpha might play an important role in mediating lipoatrophy by regulation of ADSCs. PMID- 29288590 TI - Combined electrical stimulation and exercise for swallow rehabilitation post stroke: a pilot randomized control trial. AB - BACKGROUND: Dysphagia is common after stroke, affecting up to 50% of patients initially. It can lead to post-stroke pneumonia, which causes 30% of stroke related deaths, a longer hospital stay and poorer health outcomes. Dysphagia care post-stroke generally focuses on the management of symptoms, via modified oral intake textures and adapted posture, rather than direct physical rehabilitation of the swallowing function. Transcutaneous neuromuscular electrical stimulation (NMES) is a promising rehabilitation technology that can be used to stimulate swallowing; however, findings regarding efficacy have been conflicting. AIMS: This pilot randomized controlled study involving three UK sites compared the efficacy of the Ampcare Effective Swallowing Protocol (ESP), combining NMES with swallow-strengthening exercises, with usual care in order to clarify evidence on NMES in the treatment of dysphagia post-stroke. A further objective was to pilot recruitment procedures and outcome measures in order to inform the design of a full-scale trial. METHODS & PROCEDURES: Thirty patients were recruited and randomized into either (1) usual speech and language therapy dysphagia care; or (2) Ampcare ESP, receiving treatment 5 days/week for 4 weeks. Outcome measures included: the Functional Oral Intake Scale (FOIS), the Rosenbek Penetration Aspiration Scale (PAS) and patient-reported outcomes (Swallow Related Quality of Life-SWAL-QOL). OUTCOMES & RESULTS: Thirty patients were recruited; 15 were randomized to the Ampcare ESP intervention arm and 15 to usual care. A greater proportion (75%, or 9/12) of patients receiving Ampcare ESP improved compared with 57% (or 8/14) of the usual-care group. Patients receiving Ampcare ESP also made clinically meaningful change (a comparative benefit of 1.5 on the FOIS, and on the PAS: 1.35 for diet and 0.3 for fluids) compared with usual care. The intervention group also reported much better outcome satisfaction. CONCLUSIONS & IMPLICATIONS: The pilot demonstrated successful recruitment, treatment safety and tolerability and clinically meaningful outcome improvements, justifying progression to a fully powered study. It also showed clinically meaningful treatment trends for the Ampcare ESP intervention. PMID- 29288591 TI - Factors Affecting the Quality of Breast Quasistatic Ultrasound Elastograms. AB - OBJECTIVES: To explore factors affecting the quality of quasistatic ultrasound elastograms of the breast and to evaluate their accuracy in distinguishing benign and malignant breast lesions. METHODS: A total of 663 patients with 702 breast lesions were recruited. All patients received both conventional ultrasonography and quasistatic elastography. Patients' breast lesions were divided into A and B groups according to satisfactory and unsatisfactory elastographic examinations. Group A included 590 satisfactory elastograms, whereas Group B included 112 unsatisfactory elastograms. Various factors-maximum depth of the lesion, maximum transverse diameter of the lesion, thickness of the adipose layer, thickness of the glandular layer, thickness of the breast, distance between the nipple and lesion, age, body mass index, and menopausal status-were analyzed and compared between the groups to gauge their effects on the quality of the elastograms. RESULTS: Significantly deeper lesions, higher maximum transverse lesion diameters, thicker adipose layers, thicker glandular layers, and thicker breasts were identified in group B patients compared to group A patients (P < .05). Multivariate logistic regression analyses showed that the maximum depth of the lesion, thickness of the adipose layer, and thickness of the breast were independent factors in the quality of elastograms. The area under the curve for the maximum depth of the lesion was 0.986 with the optimal cutoff threshold of 2.5 cm. CONCLUSIONS: Quasistatic elastography can be a supplementary approach to conventional ultrasonography in helping improve the diagnostic accuracy of breast lesions. The depth and size of breast lesions are correlated with the quality of elastograms. PMID- 29288592 TI - Cancer-Targeting Functionalization of Selenium-Containing Ruthenium Conjugate with Tumor Microenvironment-Responsive Property to Enhance Theranostic Effects. AB - A mutifunctional ruthenium-based conjugate Ru-BSe was designed and synthesized. The Ru complex with favorable bioimaging function was covalently linked with a cancer-targeted molecule that could be effectively internalized by the tumor to realize enhanced theranostic effects. The pH-response of the Ru conjugate in tumor acidic microenvironment causes ligand substitution and release of therapeutic complex. This activated complex remains inert to the reducing biomolecule-glutathione and terminally locates in mitochondria, in which it triggers oxidative stress, and activates intrinsic apoptosis. Real-time monitoring reveals that this Ru conjugate could selectively accumulate in tumor tissue in vivo, which significantly suppresses tumor progression and alleviate the damage to normal organs, realizing the precise cancer theranosis. PMID- 29288593 TI - Surface-Confined Dynamic Covalent System Driven by Olefin Metathesis. AB - Understanding how the constitutional dynamics of a dynamic combinatorial library (DCL) adapts to surfaces (compared to bulk solution) is of fundamental importance to the design of adaptive materials. Submolecular resolved scanning tunneling microscopy (STM) can provide detailed insights into olefin metathesis at the interface. Analysis of the distribution of products has revealed the important role of environmental pressure, reaction temperature, and substituent effects in surface-confined olefin metathesis. We also report an unprecedented preferred deposition and assembly of linear polymers, and some specific oligomers, on the surface that are hard to obtain otherwise. PMID- 29288594 TI - Bacillus amyloliquefaciens induces production of a novel blennolide K in coculture of Setophoma terrestris. AB - AIMS: The discovery of known bioactive chemical leads from microbial monocultures hinders the efficiency of drug discovery programmes. Therefore, in recent years, the use of fungal-bacterial coculture experiments has gained considerable attention due to their ability to generate new bioactive leads. In this work, fungal strain Setophoma terrestris was cocultured with Bacillus amyloliquifaciens to discover novel bioactive compounds. MATERIALS AND METHODS: The bioactive methanolic coculture extract was chosen for the isolation of compounds by chromatographic methods. The isolated compounds were characterized by NMR and mass spectrometric techniques. CONCLUSION: Coculture extract has resulted in the production of five blennolides. The novel compound, blennolide K was found active against PC-3 (prostate) and MCF-7 (breast) cell lines with an IC50 value of 3.7 +/- 0.6 and 4.8 +/- 0.4 MUmol l-1 respectively. Furthermore, the nuclear morphology study in PC-3 cells after treatment with blennolide K, demonstrated chromatin condensation, formation of apoptotic bodies and shrinkage of cells. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge, only few studies have reported the induction of bioactive compounds by coculture having long-distance inhibition morphology. This is principally due to the low occurrences of such morphology. Our study demonstrates the impact of coculture on production of new chemical leads in drug discovery programmes. PMID- 29288595 TI - Inpatient hospital burden of hepatitis C-diagnosed patients with decompensated cirrhosis. AB - BACKGROUND & AIMS: To describe the burden on inpatient hospital resources over time from patients diagnosed with hepatitis C virus (HCV) infection and who have reached the decompensated stage of cirrhosis (DC), as existing estimates of hospital stay in these patients are limited. METHODS: A retrospective longitudinal dataset was formed via record-linkage between the national HCV diagnosis database and inpatient/daycase hospitalisation and death registers in Scotland. The study population consisted of HCV-diagnosed patients with a first DC admission in 1996-2013, with follow-up available until 31 May 2014. We investigated and quantified the mean cumulative length of hospital stay, distributions over discharge diagnosis categories, and trends in admission rates. RESULTS: Among our study population (n = 1543), we identified 10 179 admissions with any diagnosis post-first DC admission. Between 1996 and 2013 there was a 16 fold rise in annual total admissions (from 112 to 1791) and an 11-fold rise in hospital stay (719-8045). When restricting minimum possible follow-up to 2 years, DC patients (n = 1312) had an overall admission rate of 7.3 per person-year, and spent on average 43 days (26 days during first 6 months) in hospital; for all liver-related, liver-related other than HCC/DC, and non-liver related only admissions, this was 39, 14, and 5 days respectively. CONCLUSIONS: HCV-infected DC patients impose a considerable inpatient hospital burden, mostly from DC- and other liver-related admissions, but also from admissions associated with non liver comorbidities. Estimates will be useful for monitoring the impact of prevention and treatment, and for computing the cost-effectiveness of new therapies. PMID- 29288596 TI - Ultrasound-Enhanced Drug Delivery for Treatment of Onychomycosis. AB - OBJECTIVES: The aim of our study was to determine the effectiveness of using ultrasound (US) to increase the permeability of the nail, with the goal of improving outcomes in the treatment of onychomycosis. METHODS: Porcine nails were used because of their similarity to human nails. A hydrophilic blue dye was used as a drug-mimicking compound. Two sets of experiments were performed: luminosity experiments to assess the dye levels inside the nail after US and sham treatments and diffusion cell experiments for determination of changes in nail permeability due to US application. In both sets of experiments, planar US transducers were used to sonicate the nails at frequencies of 400, 600, and 800 kHz and 1 MHz, an intensity of 1 W/cm2 , and a duration of 5 min in a continuous mode. Modeling studies were also performed to assess the safety of US application to the human toe for later clinical studies. RESULTS: In the luminosity experiments, application of US at frequencies of 600 and 800 kHz led to statistically significant results (P < .05), with an increase in dye delivery into the nail of up to 95% compared to control values. The diffusion cell results found statistical significance (P < .05) at all applied frequencies, with up to a 70% increase in the nail permeability compared to the control. Safety modeling studies found a maximal temperature increase of 4.4 degrees C in the bone. CONCLUSIONS: Our proposed US method may offer an alternative for improved treatment of onychomycosis. The current maximal temperature increase was found to be at the safety limit, and so pulsing and other alternatives will be investigated to minimize this temperature increase. PMID- 29288599 TI - Pili torti, pale and elastic skin, and severe neurological impairment. PMID- 29288598 TI - In situ derivatization and hollow-fiber liquid-phase microextraction to determine sulfonamides in water using UHPLC with fluorescence detection. AB - A sensitive method for determining sulfonamides in water was developed and validated through in situ derivatization and hollow-fiber liquid-phase microextraction with ultra-high performance liquid chromatography and fluorescence detection. The target sulfonamides were sulfadiazine, sulfacetamide, sulfamerazine, sulfamethazine, sulfamethoxypyridazine, sulfachloropyridazine, sulfamethoxazole, and sulfisoxazole. Following in situ derivatization with fluorescamine, three-phase hollow-fiber liquid-phase microextraction with an S 6/2 polypropylene hollow-fiber membrane was applied automatically using a multipurpose autosampler. Experimental parameters including derivatization time, choice of organic phase, pH of donor and acceptor phase, stirring rate, extraction temperature and time were optimized. Under optimized conditions, the target sulfonamides achieved excellent linearity with correlation coefficients of 0.9924-0.9994 within the concentration range of 0.05-5 MUg/L. The limits of detection of the eight sulfonamides were 3.1-11.2 ng/L, and the limits of quantification were 10.3-37.3 ng/L. Enrichment factors of 0.1 and 5 MUg/L sulfonamides spiked in lake water were 14-60, and recoveries were 56-113% with relative standard derivations of 3-19%. Applied with the developed method, sulfamerazine and sulfamethoxazole were measurable in both influent and effluent water of the three sewage treatment plants in Guangzhou, China. The developed method was sensitive and provided an alternative method for simultaneously enriching and quantifying multiple sulfonamides in environmental water. PMID- 29288600 TI - Localized subepidermal blistering: not always bullous pemphigoid but a diagnostic challenge. PMID- 29288597 TI - Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. AB - Ionizing radiation (IR) is commonly used to treat central nervous system (CNS) cancers and metastases. While IR promotes remission, frequent side effects including impaired cognition and white matter loss occur following treatment. Fractionation is used to minimize these CNS late side effects, as it reduces IR effects in differentiated normal tissue, but not rapidly proliferating normal or tumor tissue. However, side effects occur even with the use of fractionated paradigms. Oligodendrocyte progenitor cells (OPCs) are a proliferative population within the CNS affected by radiation. We hypothesized that fractionated radiation would lead to OPC loss, which could contribute to the delayed white matter loss seen after radiation exposure. We found that fractionated IR induced a greater early loss of OPCs than an equivalent single dose exposure. Furthermore, OPC recovery was impaired following fractionated IR. Finally, reduced OPC differentiation and mature oligodendrocyte numbers occurred in single dose and fractionated IR paradigms. This work demonstrates that fractionation does not spare normal brain tissue and, importantly, highlights the sensitivity of OPCs to fractionated IR, suggesting that fractionated schedules may promote white matter dysfunction, a point that should be considered in radiotherapy. PMID- 29288601 TI - Leukemia cutis in a patient with chronic myelomonocytic leukemia. PMID- 29288602 TI - The types and management of dental trauma during military service in Finland. AB - BACKGROUND/AIMS: All Finnish males must attend compulsory military service that lasts from 6 months to 1 year. About 25 000 males (approximately 80% of each age cohort) and 400 volunteer females complete the service annually. The aim of the study was to investigate the types of dental trauma occurring among Finnish conscripts during their military service. The article also focused on how dental trauma is treated in the Finnish Defence Forces. MATERIAL AND METHODS: All dental records in the Defence Forces' patient register concerning dental trauma during the years 2011 and 2012 were analysed by tooth number, treatment procedures and number of visits. RESULTS: According to the patient register, 361 conscripts suffered an oral trauma during their military service; thus, the average annual incidence was 7.2 trauma per 1000 conscripts. A total of 483 teeth were traumatized in the 2-year period. The most frequently traumatized teeth were the maxillary central incisors (61%), and the most common findings were enamel or enamel-dentin fractures (63% of all findings). Severe trauma was not common, and the most severe ones occurred during off-duty hours. The most common treatment was direct filling (n = 189 patients). Only 53 patients had soft tissue injuries (bruises, wounds). Among patients with dental trauma, the mean number of visits to the Defence Forces' dental clinic was 1.9. Great variation exists in recording findings concerning dental and oral trauma. CONCLUSION: Minor trauma is common. In all cases, recording trauma and treatments should be performed carefully. PMID- 29288603 TI - Diagnosis of peritoneal tuberculosis by endosonography-assisted through the needle forceps biopsy of the peritoneum: First case in the literature (with video). PMID- 29288604 TI - Fluorescent Porous Carbazole-Decorated Copolymer Monodisperse Microspheres: Facile synthesis, Selective and Recyclable Detection of Iron (III) in Aqueous Medium. AB - We demonstrate an environmentally friendly one-step soap-free emulsion polymerization strategy to develop fluorescent carbazole-based copolymer monodisperse microspheres for highly sensitive and selective detection of Fe3+ . The copolymer microspheres feature a stable spherical morphology with a narrow size distribution through regulating N-vinylcarbazole (NVCz) content (1.25-10.0 wt.%). Notably, the as-made microspheres exhibit a strong luminescence, tunable emission intensity and specific surface areas. Interestingly, the fluorescence of the copolymer microspheres can be selectively quenched by trace amounts of Fe3+ due to the oxidation of carbazole, and the quenching fluorescence can be facilely recovered by reduction with NaBH4 . Its excellent sensing performance is shown in terms of high sensitivity (low limit of detection, 1.3 MUm), excellent selectivity, and rapid response rate, due to the porous nature of the copolymer microspheres. These results illustrate the copolymer microspheres obtained by simple preparative procedure without using expensive or toxic raw materials would serve as a high performance sensor for highly selective and recyclable detection of Fe3+ in aqueous medium. PMID- 29288605 TI - When Fluorescent Proteins Meet White Light-Emitting Diodes. AB - Over the last decades, fluorescent proteins (FPs) have been extensively employed for imaging and tracing in cell biology and medicine. However, their application for lighting devices like light-emitting diodes (LEDs) and lasers has recently started. The interest of FPs is the result of their good photoluminescence features (high emission efficiency with a narrow spectrum and a high photon-flux saturation), good photostability, sustainable production by bacteria, and eco friendly recycling. Their low stability at high temperatures as well as the need for an aqueous environment have, however, strongly limited their use in optoelectronics. This has recently been circumvented with new coating systems that are paving the way for the entrance of FPs into the LED field. In this Minireview, we summarize the first steps taken by a few groups towards the development of bio-hybrid white LEDs (Bio-HWLEDs) with a focus on using FPs as color down-converters, highlighting the state of the art and challenges associated with this emerging field. PMID- 29288606 TI - OMIP-042: 21-color flow cytometry to comprehensively immunophenotype major lymphocyte and myeloid subsets in human peripheral blood. PMID- 29288607 TI - Is Radical Antegrade Modular Pancreatosplenectomy the Solution? A Systematic Literature Review and Meta-Analysis. AB - Background: RAMPS is considered, in high volume centers, as the best treatment for adenocarcinoma of the body and tail of the pancreas. Methods: PubMed database was searched. The results of studies that compared RAMPS with SRPS were analyzed by meta-analytical methods. Results: Five studies, published between 2013 and 2016, were suitable for quantitative synthesis. 285 unique patients were included, 135 patients in the RAMPS group and 150 patients in the SRPS group. Regarding retrieved lymph nodes, the mean difference was 6.54. This difference was considered to be statistical significant, P 0.00001. A complete tumor resection was observed in 115 of 129 patients who underwent RAMPS and in the case of the standard procedure a R0 resection was obtained in 107 cases out of 137, the RR was 1.17 (95% CI, 1.04, 1.32). One-year overall survival was found to be 79.2% in the RAMPS groups compared with 64.29% in the SRPS group. This difference is considered statistically significant, with a P value of 0.02. Conclusions: RAMPS is a safe procedure for the treatment of adenocarcinomas of the body and tail of the pancreas. RAMPS procedure is superior to SRPS in terms of lymph node retrieval and R0 resections. PMID- 29288608 TI - Thromboprophylaxis in Elderly Surgical Patients: Current State and Future Considerations. AB - Venous thromboembolism is the number one cause of preventable death for hospital inpatients. Aging general surgical patients are especially susceptible to DVT/PE and this risk increases in the presence of other comorbidities prevalent in the elderly. However, it is often unrecognised and undertreated. Various risk scores classify patients in low, moderate and high risk categories. Current guidelines for thromboprophylaxis advocate combination of mechanical methods in the form of elastic stockings or intermittent pneumatic leg compression and pharmacological agents such as low molecular weight heparins and oral anticoagulants. Increased bleeding risk is a concern in this population and the method of prophylaxis needs to be adjusted as a result. Decreased renal function also influences the choice and dosage of medication. The required duration of prophylaxis is unclear but can range from one week to more than a month depending on the underlying pathology and individual risk assessment. PMID- 29288609 TI - Resection of Concomitant Hepatic and Extrahepatic Metastases from Colorectal Cancer - A Worthwhile Operation? AB - : Background: The benefit of hepatic resection in case of concomitant colorectal hepatic and extrahepatic metastases (CHEHMs) is still debatable. The purpose of this study is to assess the results of resection of hepatic and extrahepatic metastases in patients with CHEHMs in a high-volume center for both hepatobiliary and colorectal surgery and to identify prognostic factors that correlate with longer survival in these patients. METHOD: It was performed a retrospective analysis of 678 consecutive patients with liver resection for colorectal cancer metastases operated in a single Centre between April 1996 and March 2016. Among these, 73 patients presented CHEHMs. Univariate analysis was performed to identify the risk factors for overall survival (OS) in these patients. Results: There were 20 CHMs located at the lymphatic node level, 20 at the peritoneal level, 12 at the ovary and lung level, 12 presenting as local relapses and 9 other sites. 53 curative resections (R0) were performed. The difference in overall survival between the CHEHMs group and the CHMs group is statistically significant for the entire groups (p 0.0001), as well as in patients who underwent R0 resection (p 0.0001). In CHEHMs group, the OS was statistically significant higher in patients who underwent R0 resection vs. those with R1/R2 resection (p=0.004). Three variables were identified as prognostic factors for poor OS following univariate analysis: 4 or more hepatic metastases, major hepatectomy and the performance of operation during first period of the study (1996 - 2004). There was a tendency toward better OS in patients with ovarian or pulmonary location of extrahepatic disease, although the difference was not statistically significant. CONCLUSION: In patients with concomitant hepatic and extrahepatic metastases, complete resection of metastatic burden significantly prolong survival. The patients with up to 4 liver metastases, resectable by minor hepatectomy benefit the most from this aggressive onco-surgical management. PMID- 29288610 TI - Postoperative Investigations Resulting in Cost Reduction in Oncological Patients Undergoing Major Abdominal and Pelvic Surgery. AB - AIM: Rising costs in health care are of progressively growing interest and a major factor affecting hospitalization costs is represented by postoperative complications. Complications of Major Abdominal Surgery (MAS) are associated with increased morbidity and mortality. This study estimates the costs of postoperative care associated with complications. Material and Methods: We performed a retrospective study on 254 patients admitted to the 1st General and Oncological Surgery Clinic of the Bucharest Oncology Institute who were submitted to MAS. The total hospitalization, complications and treatment costs were analysed. Results: For a patient undergoing MAS, the average costs for surgery without complications are 5,791.3 RON and reach an average of 20,806 RON after major complications. CONCLUSION: The results provide insight into the costs of hospitalization for oncology patients submitted to surgical interventions. Complications occur in 20.86% of patients undergoing MAS and account for 50% of total care costs. Establishing and implementing a protocol aimed at early diagnosis and treatment of specific complications could lead to a decrease in morbidity and mortality, as well as of the costs of hospitalization. PMID- 29288611 TI - Particularities in the Evolution of Mortality by Traumatic Events in the Last 30 Years. AB - We present a retrospective descriptive study targeting the mortality in the European Union's countries during the past 30 years. Data was collected from the WHO (World Health Organization) database of global mortality. The aim of this study was the identification of particularities in the evolution of trauma related mortality in before-mentioned countries. The results showed patterns of mortality related to socio-geographical conditions at different times in history and a general trend towards its decrease. Age was also an important factor to take into consideration. To conclude, we would like to point out the lack of studies and available research in trauma-related fields and also to underline their necessity and utility, especially in the pediatric department. PMID- 29288612 TI - Postintubation Tracheoesophageal Fistula - Diagnosis, Treatment and Prognosis. AB - : Introduction: Postintubation tracheoesophageal fistula is a severe complication occurring under certain conditions in patients that require prolonged mechanical ventilation. MATERIAL AND METHODS: This article focuses on a sample of 11 patients with postintubation tracheoesophageal fistula, operated in our department between 2005 and 2015. The anterior approach with tracheal resection was performed in 10 of these patients, while an atypical surgical technique was preferred in a case involving a large-sized fistula. Three of these patients were subject to surgery while still on the ventilator, in order to help weaning them from mechanical ventilation. Two patients were operated following a relapse of the fistula, after attempts of closing it in other surgical units. Results: Two patients (of those who were still on mechanical ventilation) died from intubation related complications that persisted after tracheal resection (anastomotic dehiscence with mediastinitis and tracheoarterial fistula in the brachiocephalic arterial trunk). The nine remaining patients improved, with their airways restored and having regained normal deglutition. Conclusions: The surgical approach of this pathology is successful in surgical units that are specialised in tracheal and oesophageal surgery. Adequately timing the surgery is crucial for a good outcome. PMID- 29288613 TI - The Effect of Iloprost in the Healing of Colonic Anastomosis in Rats under Chemotherapy with Irinotecan. AB - PURPOSE: We have investigated the possible positive effect of iloprost in the healing of colonic anastomosis, in rats under intraperitoneal chemotherapy with irinotecan. METHOD: Forty male Wistar rats have been divided into four groups. They underwent a partial colectomy and a termino-terminal anastomosis. They were administered, intraperitoneally, saline (group 1), irinotecan (group 2), iloprost (group 3), or irinotecan and iloprost (Group 4). After the sacrifice of the animals what followed was an autopsy, a macroscopic examination and the measurement of the anastomotic rupture pressure. A portion of the anastomosis was sent over for histological examination and determination of hydroxyproline levels. Results: The frequency of the leakage from the anastomosis was considered as significantly increased in group 2 compared with the other groups. In group 2, a significantly greater degree of adhesions, compared to all the remaining groups, was observed. The bursting pressure of the anastomosis was significantly lower in group 2, as compared with all the remaining groups, and significantly increased in the group 4 compared with group 2. Leukocytosis, fibroblasts, the neocollagen and the levels of hydroxyproline in group 4 showed significantly increased values, compared with group 2. The angiogenesis was significantly increased in groups 3 and 4 compared with group 2. Conclusions: Intraperitoneal administration of iloprost after colectomy, termino-terminal anastomosis and intraperitoneal administration of irinotecan promotes the healing process of the colon anastomoses as it competes the inhibitory effect of irinotecan. PMID- 29288614 TI - Laparoscopic HIPEC for Peritoneal Carcinomatosis from Gastric Cancer - Technique and Early Outcomes of Our First Cases. AB - : Gastric cancer remains one of the most aggressive malignancies, being associated with very poor therapeutic outcomes, especially in the advanced disease patients. Due to this evidence, finding a better treatment, a better control and higher survival rates is the current scientific focus of the medical community. Once the benefits of cytoreductive surgery in association with intraperitoneal hyperthermy (HIPEC) have been widely demonstrated in patients presenting peritoneal carcinomatosis from colorectal or ovarian origin,attention was focused on the possible benefit of this method in patients diagnosed with peritoneal carcinomatosis with gastric origin. Moreover, using laparoscopy for the cytoreductive surgery (L-CRS) and hyperthermic intraperitoneal chemotherapy (L-HIPEC), the advantages of minimal invasive surgery (MIS) are expected to contribute to improved postoperative outcomes. In this way, the patients benefit from a faster administration of the adjuvant chemotherapeutic treatment, whenever is necessary. AIM: to present the technique of L-CRS + L-HIPEC and the early therapeutic outcomes in a case series of two patients diagnosed with peritoneal carcinomatosis from gastric cancer. METHOD: A complete investigational work-up including diagnostic laparoscopy to evaluate the Peritoneal Carcinomatosis Index (PCI) was fulfilled in all the cases. The institutional Tumor Board decided the therapeutic strategy: laparoscopic radical resection and HIPEC (L-CRS +L-HIPEC). The procedures were performed into a private setting (Ponderas Academic Hospital). Results: Two male patients,46 and 69years old, presenting carcinomatosis from gastric cancer were included into the study. Initial PCI was assessed by laparoscopy and it was 18 and 7, respectively. Both cases underwent neoadjuvant chemotherapy. D2 laparoscopic radical gastrectomy and L-HIPEC was then performed. Time of procedure was360 and 320 minutes, respectively. The intraperitoneal temperature varied between 41 and 42 degrees C, while the intra esophageal temperature reached a maximum value of 37,7 degrees C. There was no perioperative or postoperative complication, nor mortality. The hospital stay was 8 days. Conclusions: Explorative laparoscopy can help select patients for conversion chemotherapy in the setting of high peritoneal carcinomatosis index (PCI) score. Laparoscopy radical excision + L-HIPEC were successfully performed with very good therapeutic outcomes. PMID- 29288615 TI - Synchronous Locally Advanced Rectal Cancer with Clinical Complete Remission and Important Downstaging after Neoadjuvant Radiochemotherapy - Personalised Therapeutic Approach. AB - : Introduction: The current practice for patients with good response, important downstaging or complete remission after preoperative chemoradiation, is to perform surgery on the basis of initial pretherapeutical staging. In literature, varying approaches, like transanal endoscopic microsurgery and even "wait and see", are described for patients with good response after chemoradiation. However, considering the present level of available evidence, the wide-spread adoption of a "watch and wait" policy in those achieving a complete clinical remission cannot be justified. CASE REPORT: It is presented the case of a 63 years old patient, investigated and diagnosed with synchronous rectal cancer, inferior rectal cancer invading the perianal region and medium rectal cancer, located between 8 and 14 cm from the anal verge, pretheraputically staged cT4N2M0. The oncological board decides neoadjuvant radiochemotherapy. Restaging shows complete remission of inferior rectal tumor and ulcerative infiltrative remnant lesion in the medium rectum. The patient firmly declines colostomy, assuming recurrence risks. A TME low rectal resection with colorectal mechanical anastomosis is performed, postoperative evolution being favorable. Conclusions: Although, the radical surgery to be done would have been an abdomino-perineal resection, the patient's option to decline the colostomy imposed a radical intervention just for the proximal tumor. The inferior rectal tumor, with complete remission after neoadjuvant therapy was submitted to "wait and see" approach. PMID- 29288616 TI - Auspicious Management of a Acute Obstructive Left Colon Tumor in a 93-year-old Patient - Case Report and Literature Review. AB - We present the case of a 93-year-old patient with intestinal occlusion due to a descending colon tumor, with carcinomatous ascites and secondary liver and lung determinations. Considering the risks associated with a surgical act in such a patient and the impossibility of performing a curative intervention, a self expanding metallic colonic stent was mounted. The post-intervention evolution was favorable, the patient being discharged 48 hours later. Left colon cancer is diagnosed in the occlusive phase in 8 to 26% of cases (1). It often requires an immediate surgical resolution due to the potential risk of death. Emergency surgery involves increased rates of morbidity and mortality (2). Thus, other ways of resolving these surgical emergencies have been developed. Colonic stents were first reported in the literature by Dohmoto (3). Initially, the use of stents was as the final method of palletising (4). Later, they were used as a bridge to minimally invasive programmed surgery (5). PMID- 29288617 TI - Corrigendum to: Validation of a pneumatic tube system to transport surgical pathology biopsy samples. PMID- 29288618 TI - Exact days of gestation necessary for infants at borderline viability: reply to Proactive approach at the limits of viability improves the short-term outcome of neonates born after 23weeks' gestation. P. Simjak, J. Smisek, M. Koucky, T. Lamberska, R. Plavka and Z. Hajek. J Perinat Med 2017. PMID- 29288620 TI - Assessing emergency department utilization in the era of population health. PMID- 29288619 TI - Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China. AB - BACKGROUND Cytochrome P450 (CYP) 2C19 is an enzyme involved in the bioactivation of various important therapeutic drugs, from pro-drugs to an active inhibitor of platelet action. Variants in the CYP2C19 gene influence the pharmacokinetics and clinical response to antiplatelet drugs such as clopidogrel; however, there is no available data about the genetic variation of CYP2C19 in the Hakka population in China. MATERIAL AND METHODS A total of 6686 unrelated participants (ages 17-98 years) of self-reported Hakka ancestry admitted at an inpatient department in a hospital in southern China were successfully genotyped by the gene chip platform. RESULTS The identified allele frequencies were CYP2C19*1 (64.33%), *2 (31.06%) and *3 (4.61%). The major prevalent genotype combinations were CYP2C19 *1/*1 (41.73%) and *1/*2 (39.65%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM) (41.73%), intermediate metabolizers (IM) (45.21%), and poor metabolizers (PM) (13.06%). In the Hakka population, frequencies of the CYP2C19 *2 and *3 variants were observed to be close to those previously identified in Chinese and several other Asian populations. CONCLUSIONS Our study is the first to report on CYP2C19 polymorphisms in the Hakka population, and may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group in the near future. PMID- 29288621 TI - Arabidopsis ACYL-COA-BINDING PROTEIN1 interacts with STEROL C4-METHYL OXIDASE1-2 to modulate gene expression of homeodomain-leucine zipper IV transcription factors. AB - Fatty acids (FAs) and sterols constitute building blocks of eukaryotic membranes and lipid signals. Co-regulation of FA and sterol synthesis is mediated by sterol regulatory element-binding proteins in animals but remains elusive in plants. We reported recently that Arabidopsis ACYL-COA-BINDING PROTEIN1 (ACBP1) modulates sterol synthesis via protein-protein interaction with STEROL C4-METHYL OXIDASE1-1 (SMO1-1). Herein, ACBP1 was demonstrated to co-express and interact with SMO1-2 by yeast two-hybrid, co-localization, pull-down, co-immunoprecipitation and beta glucuronidase assays. SMO1-2 silenced in acbp1 was used in phenotyping, GC-MS and expression profiling. ACBP1 co-expressed with SMO1-2 in embryo sacs, pollen and trichomes, corroborating with cooperative tissue-specific functions unseen with SMO1-1. SMO1-2 silencing in acbp1 impaired seed development, male and female gamete transmission, and pollen function. Genes encoding homeodomain-leucine zipper IV transcription factors (HDG5, HDG10, HDG11 and GLABRA2), which potentially bind phospholipids/sterols, were transcribed aberrantly. GLABRA2 targets (MYB23, MUM4 and PLDalpha1) were misregulated, causing glabra2-resembling trichome, seed coat mucilage and oil-accumulating phenotypes. Together with altered sterol and FA compositions upon ACBP1 mutation and/or SMO1-2 silencing, ACBP1-SMO1 interaction appears to mediate homeostatic co-regulation of FAs and sterols, which serve as lipid modulators for gene expression of homeodomain leucine zipper IV transcription factors. PMID- 29288622 TI - Light and growth form interact to shape stomatal ratio among British angiosperms. AB - In most plants, stomata are located only on the abaxial leaf surface (hypostomy), but many plants have stomata on both surfaces (amphistomy). High light and herbaceous growth form have been hypothesized to favor amphistomy, but these hypotheses have not been rigorously tested together using phylogenetic comparative methods. I leveraged a large dataset including stomatal ratio, Ellenberg light indicator value, growth form and phylogenetic relationships for 372 species of British angiosperms. I used phylogenetic comparative methods to test how light and/or growth form influence stomatal ratio and density. High light and herbaceous growth form are correlated with amphistomy, as predicted, but they also interact; the effect of light is pronounced in therophytes (annuals) and perennial herbs, but muted in phanerophytes (shrubs and trees). Furthermore, amphistomy and stomatal density evolve together in response to light. Comparative analyses of British angiosperms reveal two major insights. First, light and growth form interact to shape stomatal ratio; amphistomy is common under high light, but mostly for herbs. Second, coordinated evolution of adaxial stomatal density and light tolerance indicates that amphistomy helps to optimally balance light acquisition with gas exchange. Stomatal ratio may have potential as a functional trait for paleoecology and crop improvement. PMID- 29288623 TI - Meeting report: FDA public meeting on patient-focused drug development and medication adherence in solid organ transplant patients. AB - The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other patient representatives. The morning sessions focused on the impact of organ transplantation on patients' daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful. PMID- 29288626 TI - The P2X7 receptor: A main player in inflammation. AB - Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). The P2X7R is an ATP gated ion channel, expressed by most immune cells, including the monocyte-derived cell lineages, T and B lymphocytes and their precursors. Here we give an overview of recent and established literature on the role of P2X7R in septic and sterile inflammation. P2X7R ability in restraining intracellular bacteria and parasite infection by modulation of the immune response are described, with particular focus on Mycobacteria and Plasmodium. Emerging literature on the role of P2X7 in viral infections such as HIV-1 is also briefly covered. Finally, we describe the numerous intracellular pathways related to inflammation and activated by the P2X7R, including the NLRP3 inflammasome, NF-kB, NFAT, GSK3beta and VEGF, and discuss the involvement of P2X7R in chronic diseases. The possible therapeutic applications of P2X7R antagonists are also described. PMID- 29288627 TI - Characterization of the first planctomycetal outer membrane protein identifies a channel in the outer membrane of the anammox bacterium Kuenenia stuttgartiensis. AB - Planctomycetes are a bacterial phylum known for their complex intracellular compartmentalization. While most Planctomycetes have two compartments, the anaerobic ammonium oxidizing (anammox) bacteria contain three membrane-enclosed compartments. In contrast to a long-standing consensus, recent insights suggested the outermost Planctomycete membrane to be similar to a Gram-negative outer membrane (OM). One characteristic component that differentiates OMs from cytoplasmic membranes (CMs) is the presence of outer membrane proteins (OMPs) featuring a beta-barrel structure that facilitates passage of molecules through the OM. Although proteomic and genomic evidence suggested the presence of OMPs in several Planctomycetes, no experimental verification existed of the pore-forming function and localization of these proteins in the outermost membrane of these exceptional microorganisms. Here, we show via lipid bilayer assays that at least two typical OMP-like channel-forming proteins are present in membrane preparations of the anammox bacterium Kuenenia stuttgartiensis. One of these channel-forming proteins, the highly abundant putative OMP Kustd1878, was purified to homogeneity. Analysis of the channel characteristics via lipid bilayer assays showed that Kustd1878 forms a moderately cation-selective channel with a high current noise and an average single-channel conductance of about 170 190pS in 1M KCl. Antibodies were raised against the purified protein and immunogold localization indicated Kustd1878 to be present in the outermost membrane. Therefore, this work clearly demonstrates the presence of OMPs in anammox Planctomycetes and thus firmly adds to the emerging view that Planctomycetes have a Gram-negative cell envelope. PMID- 29288628 TI - Mating behavior of the West Nile virus vector Culex pipiens - role of behavioral asymmetries. AB - Culex pipiens is a vector of West Nile, Rift Valley fever, Japanese encephalitis and Usutu viruses. In agreement with the criteria of Integrated Vector Management, several research efforts have been devoted to develop behavior-based control tools to fight mosquito vectors. However, our knowledge of mosquito mating biology and sexual communication is still patchy. Despite the high relevance of C. pipiens as a vector of medical and veterinary importance, no studies on its mating behavior and the factors routing mating success have been conducted. In this study, I quantified the mating behavior of an Italian strain of C. pipiens, evaluating the male mating success and its potential connections with population-level lateralized traits occurring during the mating sequence. Mean copula duration exceeded 100 s. Courting males can be straightly accepted by the female after the first genital contact (38.95%), as well as after some rejection kicks performed by females with hind legs (17.89%). No copula duration differences were detected between these two cases. The overall male mating success in laboratory conditions was 56.84%. The females performing rejection kicks preferentially used right hind legs at population-level. This was confirmed over four subsequent testing phases. The number of kicks per rejection event and the rejection success were higher when right legs are used over left ones, showing a functional advantage linked with the employ of right legs. Overall, the present study represents the first quantification of the courtship and mating behavior of C. pipiens. Data on male mating success and the role population-level lateralized mating traits provides basic biological knowledge that can be helpful to optimize autocidal and behavior-based control tools. PMID- 29288629 TI - Serum Cardiac Troponin T Levels in Asymptomatic Elderly Nursing Home Residents. AB - BACKGROUND: The definition of myocardial infarction relies on elevated troponin levels. However, elevated levels of high sensitive cardiac troponin (hs-cTnT) assays have been reported in elderly patients without acute myocardial infarction. We sought to determine whether elevated hs-cTnT levels have a prognostic value in stable elderly subjects without any acute illness. METHODS: The study cohort included residents of a nursing home who were asymptomatic without any acute medical problem. Serum hs-cTnT levels were measured, and participants were divided into high and low hs-cTnT groups. We measured hs-cTnT levels of young healthy volunteers as well and compared them with hs-cTnT levels of those nursing home residents. RESULTS: Fifty-seven nursing home residents and 14 young volunteers were included in the study. The average age of nursing home residents was 83 +/- 14 years, compared with 37 +/- 3 years of the volunteers. Levels of hs-cTnT were significantly higher in the elderly compared with the volunteers (0.02 +/- 0.016 ng/mL vs 0.005 +/- 0.0003 ng/mL; P < .001); accordingly, we chose a cutoff of 0.02 ng/mL hs-cTnT and divided the 57 patients into 2 subgroups for further evaluation. After adjustment for age, gender, and glomerular filtration rate, the hs-cTnT was still an independent predictor of 1 year mortality (relative risk 2.04 [95% conficence interval, 2.009-29.45], P = .003). CONCLUSIONS: Mild elevations of hs-cTnT levels are common in elderly patients, and hs-cTnT level is an independent marker of mortality risk in this population. For patients older than 70 years, a different hs-cTnT cutoff is required (eg, higher than 0.014 ng/mL). PMID- 29288630 TI - A Review of Women's Neurology. AB - Concern about what is best practice when caring for women with neurologic disease is a common clinical scenario. Therefore, knowledge about women's health issues and their intersection with neurologic disorders is imperative. This review will discuss the appropriate gender-based considerations in epilepsy, multiple sclerosis, migraine, autoimmune disease, sleep disorders, stroke, and paraneoplastic disorders. PMID- 29288631 TI - Gait Disorders. AB - Walking is an extraordinarily complex task requiring integration of the entire nervous system, making gait susceptible to a variety of underlying neurologic abnormalities. Gait disorders are particularly prevalent in the elderly and increase fall risk. In this review we discuss an approach to the examination of gait and highlight key features of common gait disorders and their underlying causes. We review gaits due to lesions of motor systems (spasticity and neuromuscular weakness), the cerebellum and sensory systems (ataxia), parkinsonism, and frontal lobes and discuss the remarkably diverse phenomenology of functional (psychogenic) gait disorders. We offer a pragmatic approach to the diagnosis and management of neurologic gait disorders, because prompt recognition and intervention may improve quality of life in affected individuals. PMID- 29288632 TI - Association of vascular indices with novel circulating biomarkers as prognostic factors for cardiovascular complications in patients with type 2 diabetes mellitus. AB - BACKGROUND: The pathophysiology of atherosclerosis in type 2 diabetes mellitus (T2DM) is multifactorial. The association of vascular indices with circulating biomarkers of inflammation and insulin resistance and their role in the long-term cardiovascular prognosis in T2DM patients were currently investigated. PATIENTS AND METHODS: Patients with T2DM and poor glycemic control without known cardiovascular diseases (n=119) at baseline were enrolled and followed for about 9years. The end-point was the occurrence of any cardiovascular event (coronary heart disease, stroke, peripheral artery disease or cardiovascular death). Aortic pulse wave velocity (PWV), augmentation index (AIx), brachial flow-mediated dilation (FMD), hsCRP, Chitinase-3-like protein 1 (YKL-40), Neutrophil Gelatinase Associated Lipocalin (NGAL), Fatty Acid Binding Protein (FABP-4) were assessed. RESULTS: Higher YKL-40 and NGAL were associated with higher PWV, while higher YKL 40 and FABP-4 were related to higher AIx (p<0.05 for all). In univariate Cox regression analysis, PWV>10m/s, YKL-40>78ng/ml and NGAL>42ng/ml were associated with cardiovascular events (p<0.05 for all). In multivariate analysis, after adjusting for classical risk factors and glycemic control, increased NGAL, YKL-40 and PWV and decreased FMD (i.e. <=2.2%) (p<0.05 for all) were independently associated with cardiovascular events. CONCLUSION: In T2DM patients without established cardiovascular disease, novel indices of vascular inflammation (NGAL and YKL-40) were associated with subclinical atherosclerosis (arterial stiffness) but also with adverse clinical prognosis. Arterial stiffness and endothelial dysfunction were also independently related to adverse prognosis. PMID- 29288633 TI - Editorial Overview: Single-Molecule Approaches up to Difficult Challenges in Folding and Dynamics. PMID- 29288634 TI - Single-Molecule Fluorescence Reveals the Oligomerization and Folding Steps Driving the Prion-like Behavior of ASC. AB - Single-molecule fluorescence has the unique ability to quantify small oligomers and track conformational changes at a single-protein level. Here we tackled one of the most extreme protein behaviors, found recently in an inflammation pathway. Upon danger recognition in the cytosol, NLRP3 recruits its signaling adaptor, ASC. ASC start polymerizing in a prion-like manner and the system goes in "overdrive" by producing a single micron-sized "speck." By precisely controlling protein expression levels in an in vitro translation system, we could trigger the polymerization of ASC and mimic formation of specks in the absence of inflammasome nucleators. We utilized single-molecule spectroscopy to fully characterize prion-like behaviors and self-propagation of ASC fibrils. We next used our controlled system to monitor the conformational changes of ASC upon fibrillation. Indeed, ASC consists of a PYD and CARD domains, separated by a flexible linker. Individually, both domains have been found to form fibrils, but the structure of the polymers formed by the full-length ASC proteins remains elusive. For the first time, using single-molecule Forster resonance energy transfer, we studied the relative positions of the CARD and PYD domains of full length ASC. An unexpectedly large conformational change occurred upon ASC fibrillation, suggesting that the CARD domain folds back onto the PYD domain. However, contradicting current models, the "prion-like" conformer was not initiated by binding of ASC to the NLRP3 platform. Rather, using a new method, hybrid between Photon Counting Histogram and Number and Brightness analysis, we showed that NLRP3 forms hexamers with self-binding affinities around 300nM. Overall our data suggest a new mechanism, where NLRP3 can initiate ASC polymerization simply by increasing the local concentration of ASC above a supercritical level. PMID- 29288635 TI - FOXD3 inhibits SCN2A gene transcription in intractable epilepsy cell models. AB - The expression of sodium voltage-gated channel alpha subunit 2 (SCN2A) is closely related to the development of epilepsy. This study investigated regulatory element of the SCN2A gene involved in epilepsy. An intractable epilepsy cell model was constructed using hippocampal primary neurons and the SH-SY5Y cell line. SCN2A protein and gene expression in cells as well as the level of lactic acid dehydrogenase (LDH) in the cell culture supernatants was detected. Potential regulatory factors of SCN2A and its upstream regulatory elements were identified using the dual-luciferase reporter assay. Finally, the role of the hypothetical transcription factor in epilepsy was examined by using its small interfering RNA (siRNA). Results found that levels of LDH and expression of the hypothetical transcription factor, Forkhead box D3 (FOXD3), was both increased in the model cells, whereas that of SCN2A was decreased. The results of dual-luciferase reporter assays revealed that an upstream region of SCN2A gene spanning from nucleotides -1617 to -1470 was a transcription factor binding region and a trans acting factor role of FOXD3 was identified in the core region (GGCAAAATTAT). Then the FOXD3 binding site was further verified by the chromatin immunoprecipitation (ChIP) assay and electrophoretic mobility shift assay (EMSA). After SH-SY5Y cells were transfected with FOXD3 siRNA, the release of LDH into culture supernatants and the LDH expression levels in cells were significantly decreased. SCN2A expression in model cells was increased by knockdown of FOXD3. Therefore, this study demonstrated that FOXD3 is a trans-acting factor of SCN2A, and this mechanism may play a role in cell injury after epilepsy. PMID- 29288636 TI - The effect of aggression I: The increases of metabolic cost and mobilization of fat reserves in male striped hamsters. AB - Aggression can benefit individuals by enhancing their dominance and thereby their ability to acquire and retain resources that increase survival or fitness. Engaging in aggressive behavior costs energy and how animals manage their energy budget to accommodate aggression remains unclear. We conducted three experiments to examine changes in physiological, behavioral and hormonal markers indicative of energy budget in male striped hamsters subject to resident-intruder aggression tests. Body temperature, metabolic rate and serum corticosterone levels significantly increased in resident hamsters immediately after the introduction of intruders. Energy intake did not change, but the metabolic rate of residents increased by 16.1% after 42-days of repeated encounters with intruders. Residents had significantly decreased body fat content and serum thyroxine (T4) levels, and a considerably elevated tri-iodothyronine (T3)/T4 ratio compared to a control group that had no intruders. Attack latency considerably shortened, and the number of attack bouts and total duration of attacks, significantly increased in residents on day 42 compared to day 1 of experiments. These findings may suggest that the conversion of T4 to T3 is involved in defensive aggression behavior. The mobilization of fat reserves resulting in lean body mass is probably common response to the increased metabolic cost of aggression in small mammals. Aggressive behavior, which is important for the successful acquisition and defense of resources, may be of significance for adaptation and evolution of metabolic rate. PMID- 29288637 TI - Baseline and stress-induced corticosterone levels are higher during spring than autumn migration in European robins. AB - During spring and autumn migrations, birds undergo a suite of physiological and behavioral adaptations known as migratory disposition. The position of migratory seasons within the annual cycle and specifics of environmental conditions in each season could lead to formation of specific regulatory mechanisms of spring and autumn migratory disposition. However, this topic remains largely unstudied. Here we compared corticosterone (CORT) concentration (baseline and stress-induced) in European robins (Erithacus rubecula) captured during seven consecutive migratory seasons on the Courish Spit in the Baltic Sea; >650 plasma samples were analyzed in total. We found that baseline and stress-induced CORT concentrations in free living robins during spring migration were nearly twice as high comparing to autumn passage. Moreover, the strength of relationship between these two parameters differed between the seasons. In autumn, individuals with elevated baseline CORT level invariably expressed high stress response; in spring, the stress response was more variable. These facts are in line with the hypothesis that spring and autumn migrations are separate life history stages characterized by similar physiological and behavioral adaptations but somewhat different regulatory mechanisms. Further work is needed to understand effects of seasonal differences in CORT concentrations in regulation of migratory disposition in birds. PMID- 29288638 TI - A single amino acid residue regulates the substrate affinity and specificity of indoleamine 2,3-dioxygenase. AB - Indoleamine 2,3-dioxygenase (IDO) is a heme-containing enzyme that catalyses the oxidative cleavage of L-Trp. The ciliate Blepharisma stoltei has four IDO genes (IDO-I, -II, -III and -IV), which seem to have evolved via two sequential gene duplication events. Each IDO enzyme has a distinct enzymatic property, where IDO III has a high affinity for L-Trp, whereas the affinity of the other three isoforms for L-Trp is low. IDO-I also exhibits a significant catalytic activity with another indole compound: 5-hydroxy-l-tryptophan (5-HTP). IDO-I is considered to be an enzyme that is involved in the biosynthesis of the 5-HTP-derived mating pheromone, gamone 2. By analysing a series of chimeric enzymes based on extant and predicted ancestral enzymes, we identified Asn131 in IDO-I and Glu132 in IDO III as the key residues responsible for their high affinity for each specific substrate. These two residues were aligned in an identical position as the substrate-determining residue (SDR). Thus, the substrate affinity and specificity are regulated mostly by a single amino acid residue in the Blepharisma IDO-I and IDO-III enzymes. PMID- 29288639 TI - Retinal Vascular Impairment in Best Vitelliform Macular Dystrophy Assessed by Means of Optical Coherence Tomography Angiography. AB - PURPOSE: To evaluate vascular abnormalities at superficial (SCP) and deep (DCP) capillary plexuses and choriocapillaris (CC) in patients with Best vitelliform macular dystrophy (BVMD) by means of optical coherence tomography angiography (OCT-A). DESIGN: Cross-sectional case series. METHODS: Sixty-six eyes of 33 patients with BVMD (16 male) and 33 controls were consecutively enrolled. Patients were subdivided into classic stages and underwent best-corrected visual acuity (BCVA), fundus autofluorescence and spectral domain-optical coherence tomography, and 4.5 * 4.5-mm swept-source OCT-A. Choroidal neovascularization (CNV) and capillary dilations were qualitatively assessed by 2 masked ophthalmologists. Each OCT-A slab was imported into ImageJ 1.50 and digitally binarized for quantitative analyses. Foveal avascular zone (FAZ) area was measured manually; vessel density was then quantified after the exclusion of the FAZ pixels. Eyes classified as stages 3 and 4 were evaluated together. RESULTS: Nineteen eyes (28.8%) revealed capillary dilations at DCP, 15 of which were in stages 1 and 2. Interestingly, CNV was detected in 24 eyes (36.4%). Quantitative analysis disclosed that stages 3-4 and 5 carry significant impairment at both SCP (P < .0001 and P = .02, respectively) and DCP (P < .0001 and P = .0004, respectively) compared to controls. FAZ area was enlarged at the DCP (P = .001). Only DCP vessel density significantly correlated with the stage and BCVA. CONCLUSIONS: Patients with BVMD show significant vascular impairment at both superficial and deep retinal plexuses, correlating with functional outcomes. These findings, especially at DCP, may improve our understanding about the pathogenesis, and may help in predicting BVMD treatment efficacy. PMID- 29288640 TI - Structural and dynamic insights on the EmrE protein with TPP+ and related substrates through molecular dynamics simulations. AB - EmrE is a bacterial transporter protein that forms an anti-parallel homodimer with four transmembrane helices in each monomer. EmrE transports positively charged aromatic compounds, such as TPP+ and its derivatives. We performed molecular dynamics (MD) simulations of EmrE in complex with TPP+, MeTPP+, and MBTPP+ embedded in a membrane. The detailed molecular properties and interactions were analysed for all EmrE-ligand complexes. Our MD results identified that Lys22, Tyr40, Phe44, Trp45, and Trp63 formed potential pi interactions with all three ligands and further confirmed the essential role of Glu14. Moreover, distance analysis and structural changes in the EmrE translocation pathway suggest that ligand recognition and protein conformational changes depend on the structural properties of the substrate. Analysis of the movement of the ligand in the protein binding site and rotation of the ligand's aromatic rings confirm that substrates with aromatic moieties, such as MBTPP+, exhibit relatively stable binding to EmrE. Interestingly, the aromatic rings of Tyr40, Phe44, Trp45, and Trp63 underwent parallel movements with the aromatic rings of TPP+. Based on the MD results, we propose that pi interactions, as well as the mutual rotation of the aromatic rings in the protein and ligand, can be regarded as sources of ligand movement, and thus, the whole complex may work as a "molecular propeller". PMID- 29288641 TI - Screening of ZnT8 autoantibodies in the diagnosis of autoimmune diabetes in a large French cohort. AB - AIM OF THE STUDY: Evaluate the added value of screening anti-ZnT8 antibodies (ZnT8A) in addition to the classical anti-GAD (GADA) and anti-IA-2 (IA-2A) antibodies for the diagnosis of type-1 diabetes (T1D) within a large cohort of both children and adults. MATERIALS AND METHODS: Retrospective 2-year study including 516 patients (215 children, 301 adults) who had blood tests at diabetes onset and/or for diabetes classification. ZnT8A, GADA, and IA-2A were analyzed in all samples. RESULTS: Among those individuals included, 142 (28%) were ZnT8A positive. A total of 228/516 suffered from T1D, of whom 110 (48%) were ZnT8A positive and 166 (73%) GADA and/or IA-2A positive. When adding ZnT8A to GADA/IA 2A, 184 (81%) patients were positive for >=1 Ab. Regarding the 122 patients at T1D onset, 75 (61%) were positive for ZnT8A and the proportion of patients with T1D with >=1 Ab reached 89%. The highest prevalence of ZnT8A was observed in children aged 6-10years. Fourteen of the 124 patients positive for ZnT8A with a known clinical diagnosis suffered from a disease other than T1D. CONCLUSIONS: ZnT8A should be included in routine evaluation at diabetes onset and is a valuable biological marker to classify newly-diagnosed diabetics. The predictive value in our high-risk subjects has to be confirmed. PMID- 29288642 TI - Improving Staff Communication and Transitions of Care Between Obstetric Triage and Labor and Delivery. AB - OBJECTIVE: To improve staff perception of the quality of the patient admission process from obstetric triage to the labor and delivery unit through standardization. DESIGN: Preassessment and postassessment online surveys. SETTING: A 13-bed labor and delivery unit in a quaternary care, Magnet Recognition Program, academic medical center in Pennsylvania. PARTICIPANTS: Preintervention (n = 100), postintervention (n = 52), and 6-month follow-up survey respondents (n = 75) represented secretaries, registered nurses, surgical technicians, certified nurse-midwives, nurse practitioners, maternal-fetal medicine fellows, anesthesiologists, and obstetric and family medicine attending and resident physicians from triage and labor and delivery units. METHODS: We educated staff and implemented interventions, an admission huddle and safety time out whiteboard, to standardize the admission process. Participants were evaluated with the use of preintervention, postintervention, and 6-month follow-up surveys about their perceptions regarding the admission process. Data tracked through the electronic medical record were used to determine compliance with the admission huddle and whiteboards. RESULTS: A 77% reduction (decrease of 49%) occurred in the perception of incomplete patient admission processes from baseline to 6-month follow-up after the intervention. Postintervention and 6-month follow-up survey results indicated that 100% of respondents responded strongly agree/agree/neutral that the new admission process improved communication surrounding care for patients. Data in the electronic medical record indicated that compliance with use of admission huddles and whiteboards increased from 50% to 80% by 6 months. CONCLUSION: The new patient admission process, including a huddle and safety time out board, improved staff perception of the quality of admission from obstetric triage to the labor and delivery unit. PMID- 29288644 TI - Out of thin air: Hyperventilation-triggered seizures. AB - Voluntary hyperventilation triggers seizures in the vast majority of people with absence epilepsy. The mechanisms that underlie this phenomenon remain unknown. Herein, we review observations - many made long ago - that provide insight into the relationship between breathing and absence seizures. PMID- 29288643 TI - A Case-Crossover Study of Urological Chronic Pelvic Pain Syndrome Flare Triggers in the MAPP Research Network. AB - PURPOSE: Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers. MATERIALS AND METHODS: We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression. RESULTS: In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress). CONCLUSIONS: Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies. PMID- 29288645 TI - The Effect of Alcohol Consumption on the Risk of ARDS: A Systematic Review and Meta-Analysis. AB - BACKGROUND: To conduct a systematic review and meta-analysis evaluating the association between alcohol consumption and the risk of ARDS in adults. METHODS: Medline, EMBASE and Web of Science were searched to identify observational studies evaluating the association between prior alcohol intake and the occurrence of ARDS among adults, published between 1985 and 2015 and with no language restriction. Reference lists were also screened. Demographic baseline data were extracted independently by two reviewers and random-effects meta analyses were used to estimate pooled effect sizes with 95% confidence intervals. Subgroup analyses were used to explore heterogeneity. RESULTS: Seventeen observational studies (177,674 people) met the inclusion criteria. Meta-analysis of 13 studies showed that any measure of high relative to low alcohol consumption was associated with a significantly increased risk of ARDS (OR, 1.89; 95% CI, 1.45-2.48; I2 = 48%; 13 studies); no evidence of publication bias was seen (P = .150). Sensitivity analyses indicated that this association was attributable primarily to an effect of a history of alcohol abuse (OR, 1.90; 95% CI, 1.40 2.60; 10 studies). Also, subgroup analyses identified that heterogeneity was explained by predisposing condition (trauma, sepsis/septic shock, pneumonia; P = .003). CONCLUSIONS: Chronic high alcohol consumption significantly increases the risk of ARDS. This finding suggests that patients admitted to hospital should be screened for chronic alcohol use. PMID- 29288647 TI - Assessing the Different Oncologic Disease Distribution and Postoperative Complications of Octogenarian and Nonagenarian Head and Neck Oncology Patients. AB - PURPOSE: The admission rate of patients aged 80 years or older (oldest-old) with head and neck (HN) oncologic disease is on the rise. Our goal was to study the demographic characteristics, reasons for admission, types of surgical procedures, and postoperative complications of the oldest-old patients with HN malignancy. MATERIALS AND METHODS: We conducted a retrospective cohort study including all inpatients aged 80 years or older who were admitted to the department of otolaryngology-head and neck surgery or department of oral and maxillofacial surgery because of HN oncologic disease between 2009 and 2013. The control group was composed of a matched number of randomly selected patients aged 60 to 79 years. We compared the demographic characteristics, diagnoses, comorbidities, surgical interventions, and postoperative complications of the 2 age groups to characterize the oldest-old patients' admissions and determine whether age alone increases the risk of postoperative complications. RESULTS: The study included 109 oldest-old patients (median age, 83 years) and 107 patients in the control group (median age, 68 years). Although the oldest-old patients had significantly more underlying diseases (4.41 vs 2.86) and drugs prescribed (4.76 vs 3.21), similar rates of postoperative complications occurred in both groups. An important finding was that ischemic heart disease and chronic lung disease were the only significant risk factors for postoperative complications among the oldest-old patients (odds ratio on multivariate analysis of 5.5 and 4.5, respectively). CONCLUSIONS: Although comorbidities and prescribed drugs are more prevalent in the oldest-old patients, the rate of postoperative complications did not differ between the age groups, suggesting that age alone should not be a factor in the surgical treatment of HN malignancies. PMID- 29288646 TI - Bacteria induce autophagy in a human ocular surface cell line. AB - Autophagy protects cells from intracellular pathogens, but can be exploited by some infectious agents to their benefit. Currently it is not known if bacteria induce autohpagy in cells of the cornea. The goal of this study was to develop an ocular surface autophagy reporter cell line and determine whether ocular bacterial pathogens influence host responses through autophagy induction. The cell line was made using lentivirus transduction of an LC3-GFP fusion protein in human corneal limbal epithelial (HCLE) cells. LC3-GFP puncta in HCLEs were induced by rapamycin and ammonium chloride treatments, and prevented by the autophagy inhibitors 3-methyladenine (3'MA) and bafilomycin. Importantly, secretomes from Escherichia coli, Serratia marcescens, Staphylococcus aureus, methicillin sensitive (MSSA) and resistant (MRSA), were found to induce autophagy, whereas other bacteria, including Acinetobacter baumannii, Achromobacter xylosoxidans, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella sp., and Stenotrophomonas maltophilia, did not. Our data indicates differences between tested ocular isolates of MRSA and MSSA in the activation of autophagy. HCLEs treated with 3'MA were slightly more susceptible to cytotoxic factors produced by S. marcescens and MRSA keratitis isolates, by contrast, bafilomycin A1 treatment caused no difference. This work demonstrates the successful development and validation of an autophagy reporter corneal cell line and indicates differences between ocular bacterial isolates in the activation of autophagy. PMID- 29288648 TI - What Factors Necessitate Removal of Retained Ballistic Fragments in the Head and Neck? AB - PURPOSE: The purpose of this study was to estimate the frequency of retained ballistic fragment (RBF) removal and to identify factors associated with an increased risk for RBF removal. To date, there are no studies focused on identifying factors associated with removal of RBFs localized to the maxillofacial region. MATERIALS AND METHODS: Using a retrospective cohort study design, the authors enrolled a sample composed of patients with RBFs localized to the maxillofacial region. The predictor variables included bullet size, location, involvement of bone, involvement of sinus, antibiotics, multiple antibiotics, and multiple locations. The primary outcome variable was RBF retrieval. The secondary outcome variables were timing of operative retrieval, fragment site infection, and migration of RBF. Appropriate uni- and bivariate statistics were computed and logistic regression modeling was used. RESULTS: The sample was composed of 20 patients (mean age, 30 yr; 80% male) and 55% (11 patients) required or desired object removal overall. The number of projectiles ranged from 1 to 19 (total, 48) in the 20 patients. The logistic model identified larger size, final location of bone, final location of soft tissue, and final location of sinus as having a higher probability of removal that was statistically significant (P < .05); however, size was the only variable with a substantial odds ratio (OR; 1.96; P < .05). There was no evidence of migration and a low rate (2.3%) of infection was noted at subsequent follow-up radiography and clinical examination. CONCLUSION: Size was the only statistically significant predictor variable with a substantial OR (1.96; 95% confidence interval, 1.31-3.40; P < .05). There was a low risk of infection even when considering oral pharyngeal contamination and low risk of migration. Further studies could focus on prudent antibiotic use and larger patient populations. PMID- 29288649 TI - Posterior Airway Changes Following Orthognathic Surgery in Obstructive Sleep Apnea. AB - PURPOSE: The purpose of this systematic review was to describe and compare the different approaches of radiologic posterior airway space (PAS) assessment in obstructive sleep apnea (OSA) and analyze the correlations of PAS changes with polysomnographically evaluated parameters after orthognathic surgery. MATERIALS AND METHODS: For this systematic review, a PubMed query was designed to search for original studies radiographically evaluating the PAS in patients before and after orthognathic surgery for treatment of their OSA. To account for the clinical relevance of PAS changes after surgery, only studies providing pre- and postoperative polysomnographic (PSG) data were included. The authors investigated whether the predictor variables (PAS changes) would be correlated with the primary outcome variables (PSG parameters). RESULTS: The final sample included 15 publications in which the PAS was evaluated by lateral cephalography in 8 studies, cone-beam computed tomography in 3, conventional computed tomography in 5, and magnetic resonance imaging in 1. Most linear, areal, and volumetric PAS changes after surgery (predictor variables) were found to be statistically significant. Maxillomandibular advancement (MMA) was the only orthognathic procedure performed in all studies included and was combined with additional surgical procedures in 9 studies. Improvement (ie, decrease) of the apnea hypopnea index (AHI) as the primary outcome variable was reported in all publications. CONCLUSION: After MMA (with or without additional surgical procedures), most linear, areal, and volumetric PAS parameters showed significant changes. The PAS changes correlated with clinical improvement in PSG parameters. In particular, decreased AHI was reported in all studies. For better inter-study comparability, internationally accepted standards regarding the methods used for PAS evaluation are needed. Moreover, statistical analysis should account for multiple testing when various PAS parameters are evaluated. PMID- 29288650 TI - Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons. AB - Cooling or the application of mentholated liniments to the skin has been used to treat itch for centuries, yet remarkably little is known about how counter stimuli such as these induce itch relief. Indeed, there is no clear consensus in the scientific literature as to whether or not cooling does in fact block the transduction of itch signals or if it is simply a placebo effect. This gap in our understanding led us to hypothesize that cooling is antipruritic and, like cooling analgesia, requires function of the cold-gated ion channel TRPM8, a receptor for menthol expressed on peripheral afferent nerve endings. Using a combination of pharmacologic, genetic, and mouse behavioral assays, we find that cooling inhibits both histaminergic and non-histaminergic itch pathways, and that inhibition of itch by cooling requires TRPM8 channels or intact and functional TRPM8-expressing afferent neurons. The cold mimetic menthol is also effective in ameliorating itch in a TRPM8-dependent manner. Moreover, we find that chronic itch can be ameliorated by cooling, demonstrating that this counter-stimulus activates a specific neural circuit that leads to broad itch relief and a potential cellular mechanism for treatment of chronic itch. PMID- 29288651 TI - Unopposed IL-36 Activity Promotes Clonal CD4+ T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis. AB - Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+ T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+ T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+ T cells. Moreover, GPP patients showed preferences for HLA-DRB1*14, HLA-DQB1*05, and HLA-DQB1*03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell mediated inflammation in GPP. PMID- 29288652 TI - Co-Activation of Glucocorticoid Receptor and Peroxisome Proliferator-Activated Receptor-gamma in Murine Skin Prevents Worsening of Atopic March. AB - Children with atopic dermatitis show an increased risk to develop asthma later in life, a phenomenon referred to as "atopic march," which emphasizes the need for secondary prevention therapies. This study aimed to investigate whether relief of skin inflammation by glucocorticoids and peroxisome proliferator-activated receptor agonists might influence the subsequent development of asthma in a murine model for the atopic march in which mice were repeatedly exposed to house dust mite via the skin, followed by exposure to house dust mite in lungs. To abrogate atopic dermatitis, mice received topical treatment with glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma agonists. Nuclear receptor ligand effects were assessed on primary keratinocytes and dendritic cells, as central players in skin inflammation. Prior house dust mite-induced skin inflammation aggravates allergic airway inflammation and induces a mixed T helper type 2/T helper type 17 response in the lungs. Cutaneous combined activation of glucocorticoid receptor/peroxisome proliferator-activated receptor gamma reduced skin inflammation to a higher extent compared to single activation. Additive anti-inflammatory effects were more prominent in dendritic cells, as compared to keratinocytes. Alleviation of allergic skin inflammation by activation of glucocorticoid receptor/peroxisome proliferator-activated receptor gamma appeared insufficient to avoid the allergic immune response in the lungs, but efficiently reduced asthma severity by counteracting the Th17 response. Glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma co activation represents a potent remedy against allergic skin inflammation and worsening of atopic march. PMID- 29288653 TI - Long-term outcomes after elective sterilization procedures - a comparative retrospective cohort study of Medicaid patients. AB - OBJECTIVES: The objectives were to compare the long-term outcomes, including hysterectomy, chronic pelvic pain (CPP) and abnormal uterine bleeding (AUB), in women post hysteroscopic sterilization (HS) and laparoscopic tubal ligation (TL) in the Medicaid population. STUDY DESIGN: This was a retrospective observational cohort analysis using data from the US Medicaid Analytic Extracts Encounters database. Women aged 18 to 49years with at least one claim for HS (n=3929) or TL (n=10,875) between July 1, 2009, through December 31, 2010, were included. Main outcome measures were hysterectomy, CPP or AUB in the 24months poststerilization. Propensity score matching was used to control for patient demographics and baseline characteristics. Logistic regression analysis investigated the variables associated with a 24-month rate of each outcome in the HS versus laparoscopic TL cohorts. RESULTS: Postmatching analyses were performed at 6, 12 and 24months post index procedure. At 24months, hysterectomy was more common in the laparoscopic TL than the HS group (3.5% vs. 2.1%; p=.0023), as was diagnosis of CPP (26.8% vs. 23.5%; p=.0050). No significant differences in AUB diagnoses were observed. Logistic regression identified HS as being associated with lower risk of hysterectomy (odds ratio [OR] 0.77 [95% confidence interval {CI} 0.60-0.97]; p=.0274) and lower risk of CPP diagnosis (OR 0.91 [95% CI 0.83-0.99]; p=.0336) at 24months poststerilization. CONCLUSION: In Medicaid patients, HS is associated with a significantly lower risk of hysterectomy or CPP diagnosis 24months poststerilization versus laparoscopic TL. Incidence of AUB poststerilization is not significantly different. While some differences in outcomes were statistically significant, the effect sizes were small, and the conclusion is one of equivalence and not clinical superiority. IMPLICATIONS STATEMENT: This propensity score matching analysis confirms that pelvic pain and AUB are common in women before and after sterilization regardless of whether the procedure is performed hysteroscopically or laparoscopically. Moreover, HS is associated with a significantly lower risk of hysterectomy or a CPP diagnosis in the 24months poststerilization when compared to TL. PMID- 29288655 TI - Cost-Effectiveness of Screening Individuals With Cystic Fibrosis for Colorectal Cancer. AB - BACKGROUND & AIMS: Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared to the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis. METHODS: We adjusted the existing Microsimulation Screening Analysis Colon microsimulation model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess whether optimal screening strategies would change. RESULTS: Colonoscopy every 5 years, starting at age 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in population is not clear. CONCLUSIONS: Using a Microsimulation Screening Analysis Colon microsimulation model, we found screening of patients with cystic fibrosis for CRC to be cost-effective. Due to the higher risk in these patients for CRC, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT screening) may be limited by restricted evidence available for patients with cystic fibrosis. PMID- 29288654 TI - Race and ethnicity may not be associated with risk of unintended pregnancy. AB - OBJECTIVE: The objective was to use improved measures and methodology to investigate whether race and ethnicity are associated with unintended pregnancy. STUDY DESIGN: Cross-sectional study of English- or Spanish-speaking women, aged 16-44, with pregnancies <24weeks' gestation recruited from pregnancy testing and abortion care sites in New Haven, CT, between June 2014 and June 2015. Participants completed self-assessments of race, ethnicity and multidimensional measures of pregnancy "context," including timing, intention, wantedness, desirability, happiness and planning (measured with the London Measure of Unplanned Pregnancy). Multivariable analysis was performed, adjusting for maternal demographics, language, recruitment site, substance use and medical conditions including history of depression. RESULTS: Among 161 participants (mean age=27.2+/-6.6years), mean gestational age was 9+/-4.6weeks. Overall, 14% self identified as White non-Hispanic, 37% Black non-Hispanic, 42% Hispanic and 7% multiracial. Most (85%) were unmarried, and 75% had at least one child. After adjustment, happiness about new pregnancies was more likely among Black non Hispanic than White non-Hispanic women OR=5.66 (95%CI: 1.51-21.20). Neither race nor ethnicity was significantly associated with pregnancy intention, wantedness, planning, timing or desirability. CONCLUSION: In a diverse cohort with multiple, antenatal measures of pregnancy context, neither race nor ethnicity is significantly associated with unintended pregnancy, as previous studies reported. Black non-Hispanic women were more likely to report happiness about new pregnancies than White non-Hispanic women. This study improves upon previous analyses that used retrospective and limited assessments of pregnancy intention, excluded women with miscarriages or abortions, and lacked adjustment for confounding. IMPLICATIONS: Evaluation of multidimensional pregnancy contexts assessed antenatally is important and may capture the experiences of women more accurately, especially Black and Hispanic women. PMID- 29288656 TI - Functional Bowel Disorders: A Roadmap to Guide the Next Generation of Research. AB - In June 2016, the National Institutes of Health hosted a workshop on functional bowel disorders (FBDs), particularly irritable bowel syndrome, with the objective of elucidating gaps in current knowledge and recommending strategies to address these gaps. The workshop aimed to provide a roadmap to help strategically guide research efforts during the next decade. Attendees were a diverse group of internationally recognized leaders in basic and clinical FBD research. This document summarizes the results of their deliberations, including the following general conclusions and recommendations. First, the high prevalence, economic burden, and impact on quality of life associated with FBDs necessitate an urgent need for improved understanding of FBDs. Second, preclinical discoveries are at a point that they can be realistically translated into novel diagnostic tests and treatments. Third, FBDs are broadly accepted as bidirectional disorders of the brain-gut axis, differentially affecting individuals throughout life. Research must integrate each component of the brain-gut axis and the influence of biological sex, early-life stressors, and genetic and epigenetic factors in individual patients. Fourth, research priorities to improve diagnostic and management paradigms include enhancement of the provider-patient relationship, longitudinal studies to identify risk and protective factors of FBDs, identification of biomarkers and endophenotypes in symptom severity and treatment response, and incorporation of emerging "-omics" discoveries. These paradigms can be applied by well-trained clinicians who are familiar with multimodal treatments. Fifth, essential components of a successful program will include the generation of a large, validated, broadly accessible database that is rigorously phenotyped; a parallel, linkable biorepository; dedicated resources to support peer-reviewed, hypothesis-driven research; access to dedicated bioinformatics expertise; and oversight by funding agencies to review priorities, progress, and potential synergies with relevant stakeholders. PMID- 29288657 TI - A Pragmatic Preoperative Prediction Score for Nonhome Discharge After Cardiac Operations. AB - BACKGROUND: Targeted rehabilitation of patients at risk for nonhome discharge (NHD) after an operation is an appealing area for quality improvement. We sought to identify the primary predictors of NHD after cardiac operations to generate a robust preoperative prediction tool for those at greatest risk. METHODS: The medical records of 5,253 patients undergoing cardiac operations between January 1, 2012, and March 31, 2016, were reviewed. Two models of NHD were created: a preoperative model using only preoperative predictors and a postoperative model using the same preoperative predictors and including postoperative adverse outcomes and hospital length of stay. We also determined whether NHD also reduced 30-day hospital readmission. RESULTS: A multivariable logistic regression model allowed robust identification of NHD using only preoperative variables of age, sex, marital status, obesity, comorbidities, addictions, psychiatric disease, and planned operation (area under the curve = 0.820, r2 = 0.349). Postoperative factors associated with NHD, including hospital length of stay and the occurrence of a neurologic event, were included and improved model performance (area under the curve = 0.860, r2 = 0.439), with integrated discrimination improvement of 7.5%. We observed an overall all-cause readmission rate of 12%. Patients with NHD had a higher readmission rate (16% vs 11%; p < 0.0001), as did patients with longer hospital stays, postoperative atrial fibrillation, neurologic event, or infection (all p < 0.0001). CONCLUSIONS: We identified preoperative risk factors for NHD after cardiac operations and developed a pragmatic NHD prediction score with high accuracy. Addition of postoperative risk factors for NHD only modestly improved prediction. NHD does not decrease the readmission rate after cardiac operations. PMID- 29288658 TI - Preoperative Scale to Determine All-Cause Readmission After Coronary Artery Bypass Operations. AB - BACKGROUND: Coronary artery bypass graft (CABG) operations are associated with all-cause readmission rates of approximately 15%. In attempts to reduce readmission rates, the Hospital Readmission Reduction Program expanded to include CABG operations in 2015. The aim of this study was therefore to develop a predictive readmission scale that would identify patients at higher risk of readmission after CABG using commonly available administrative data. METHODS: Data of 126,519 patients from California and New York (derivation cohort) and 94,318 patients from Florida and Washington (validation cohort) were abstracted from the State Inpatient Database (2006 to 2011). The readmission after CABG scale was developed to predict 30-day readmission risk and was validated against a separate cohort. RESULTS: Thirty-day CABG readmission rates were 23% in the derivation cohort and 21% in the validation cohort. Predictive factors included older age, female gender (odds ratio [OR], 1.34), African American ethnicity (OR, 1.13), Medicare or Medicaid insurance, and comorbidities, including renal failure (OR, 1.56) and congestive heart failure (OR, 2.82). These were independently predictive of increased readmission rates (p < 0.01). The readmission scale was then created with these preoperative factors. When applied to the validation cohort, it explained 98% of the readmission variability. CONCLUSIONS: The readmission after CABG scale reliably predicts a patient's 30-day CABG readmission risk. By identifying patients at high-risk for readmission before their procedure, risk reduction strategies can be implemented to reduce readmissions and healthcare expenditures. PMID- 29288659 TI - The Learning Curve for Robotic McKeown Esophagectomy in Patients With Esophageal Cancer. AB - BACKGROUND: Robot-assisted McKeown esophagectomy is a promising but technically demanding procedure; thus, a learning curve should be defined to guide training and allow implementation of this technique. METHODS: This study retrospectively reviewed the prospectively collected data of 72 consecutive patients undergoing robot-assisted McKeown esophagectomy by a single surgical team experienced in open and thoracolaparoscopic esophagectomy. The cumulative sum method was used to analyze the learning curve. Patients were divided into two groups in chronological order, defining the surgeon's early (group 1: the first 26 patients) and late experience (group 2: the next 46 patients). Demographic data, intraoperative characteristics, and short-term surgical outcomes were compared between the two groups. RESULTS: Cumulative sum plots revealed decreasing thoracic and abdominal docking time, thoracic and abdominal console time, and total surgical time after patient 9, 16, 26, 14, and 26, respectively. The mean number of lymph nodes resected was greater in group 2 than in group 1 (22.6 +/- 8.2 vs 17.4 +/- 6.7, p = 0.008). No other clinic or pathologic characteristics were observed as significantly different. CONCLUSIONS: For a surgeon experienced in open and thoracolaparoscopic esophagectomy, experience of 26 cases is required to gain early proficiency of robot-assisted McKeown esophagectomy. A learning curve for robot-assisted esophagus dissection would require operations on 26 patients and stomach mobilization would require operations on 14 patients. For the tableside assistant, experience of at least nine cases is needed to achieve an optimal technical level for thoracic docking and 16 cases for abdominal docking. PMID- 29288660 TI - Novel Treatment of a Degenerated Bioroot With the Use of the Sutureless Valve Technique. AB - We describe 3 patients with severe aortic regurgitation after aortic root replacement using the Freestyle bioprosthesis (Medtronic, Minneapolis, MN). The indication in 2 patients was endocarditis. The third patient showed rupture of the right coronary cusp. To achieve fewer complications, lower operative risk, and reduce operative and cross-clamp times, implantation of a sutureless bioprosthesis in a valve-in-valve manner was performed. A Perceval bioprosthesis (Sorin Biomedica Cardio Srl, Sallugia, Italy) was used in 2 patients, and a 3F Enable bioprosthesis (Medtronic) was used in the other patient. No perioperative complications or in-hospital deaths were observed. We conclude that sutureless aortic valve prostheses offer a safe and feasible option for management of failed homografts. PMID- 29288661 TI - Wall Stress and Geometry of the Thoracic Aorta in Patients With Aortic Valve Disease. AB - BACKGROUND: Aortic valve disease increases velocity and changes the way blood enters the aorta. Over time, the biomechanical environment can cause aortic remodelling. We hypothesized that aortic geometry and wall stress would be different in patients with aortic valve disease compared with controls. METHODS: We examined 40 patients with aortic sclerosis (n = 10) or mild (n = 10), moderate (n = 10), and severe (n = 10) aortic stenosis, and also 10 control individuals. The thoracic aorta of each individual was reconstructed into a three-dimensional model from computed tomography. We measured geometric variables and used finite element analysis to compute aortic wall stress. Statistical analyses were performed to test our hypothesis. RESULTS: Aortic wall stress was significantly associated with tortuosity of the descending aorta (r = 0.35, p = 0.01), arch radius (r = 0.49, p < 0.01), ascending aortic diameter (r = 0.59, p < 0.01), and aortic centerline length (r = 0.39, p < 0.01). Wall stress was highest in patients with severe stenosis (p = 0.02), although elevations in wall stress were also noted in those with mild stenosis (p = 0.02), and aortic sclerosis (p = 0.02) compared with controls. Similar trends were observed when we corrected for difference in blood pressure. Total centerline tortuosity was higher in patients with severe aortic stenosis than in controls (p = 0.04), as was descending aorta tortuosity (p = 0.04). CONCLUSIONS: Aortic geometry is associated with aortic wall stress. Patients with aortic valve disease have higher aortic wall stress than controls, and those with severe aortic stenosis have more tortuous aortas. However, increases in geometric measures and wall stress are not stepwise with increasing disease severity. PMID- 29288662 TI - Autophagy dysregulation caused by ApoM deficiency plays an important role in liver lipid metabolic disorder. AB - Autophagy is thought to be a key mechanism in maintaining the balance of liver lipid metabolism. However, the relationship between apolipoprotein M (ApoM) and autophagy has not been reported, and the role of ApoM in triglyceride metabolism is still unclear. In this study, we investigated the correlation between ApoM and autophagy and liver triglyceride metabolism in ApoM-knockout animal and cellular models. First, we observed that spontaneous hepatic steatosis developed in the liver of adult ApoM-/- mice, which was presented as the accumulation of large quantities of lipid droplets in hepatocytes under electron microscopy; Oil Red O staining showed significant accumulation of triglycerides. At the molecular level, the expression of lipid synthesis-associated proteins (primarily triglyceride synthesis) as well as acetyl-CoA carboxylase alpha (ACACA), fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBP1) was upregulated. Moreover, lipid metabolic disorder and accumulation were accompanied by dysfunction in autophagy, which displayed predominantly as inhibition of the degradation pathway; for example, P62 protein accumulated and key proteins involved in the initiation of autophagy including ATG7, ATG5-12, Beclin1 and the LC3BII/LC3BI ratio were upregulated as a feedback response. When the autophagy dysfunction was ameliorated by the activation of autophagy pathways induced by starvation, the lipid metabolic disorder was corrected to a certain extent. This suggests that the autophagy dysfunction caused by the deficiency of ApoM is an important factor in hepatic steatosis (triglyceride accumulation). ApoM plays a key role in normal autophagy activity in the liver and thereby further regulates the metabolism of liver lipids, particularly triglycerides. PMID- 29288663 TI - Studying compaction-decompaction of DNA molecules induced by surfactants. AB - The mechanism and detailed processes of DNA compaction and decompaction are essential for the life activities, as well as for the researches in the molecular biology, genetics and biomedicine. The compaction of two kinds of DNA molecules caused by Cetyltrimethyl Ammonium Bromide (CTAB) and their decompaction induced with sodium dodecyl sulfate (SDS) or excessive amount of CTAB have been investigated with multiple perspectives such as the UV-VIS spectrophotometry, dynamic light scattering, and zeta potential. The compaction phenomenon of DNA can easily be observed when the CTAB combines with the DNA, not just when the molar ratio QCTAB/QDNA is approximately equal to 1 as the conventional recognition, but also when QCTAB/QDNA <1,DNA can be compacted; Molecular state of DNA is only changed in the conformational structure, but not in the chemical structure. Finally, a model is suggested to help catch on the biophysical mechanism of DNA chain conformational change. PMID- 29288664 TI - Hydrogen postconditioning promotes survival of rat retinal ganglion cells against ischemia/reperfusion injury through the PI3K/Akt pathway. AB - Retinal ischemia/reperfusion injury (IRI) plays a crucial role in the pathophysiology of various ocular diseases. Our previous study have shown that postconditioning with inhaled hydrogen (H2) (HPC) can protect retinal ganglion cells (RGCs) in a rat model of retinal IRI. Our further study aims to investigate potential mechanisms underlying HPC-induced protection. Retinal IRI was performed on the right eyes of rats and was followed by inhalation of 67% H2 mixed with 33% oxygen immediately after ischemia for 1 h daily for one week. RGC density was counted using haematoxylin and eosin (HE) staining, retrograde labelling with cholera toxin beta (CTB) and TUNEL staining, respectively. Visual function was assessed using flash visual evoked potentials (FVEP) and pupillary light reflex (PLR). The phosphorylated Akt was analysed by RT-PCR and western blot. The results showed that administration of HPC significantly inhibited the apoptosis of RGCs and protected the visual function. Simultaneously, HPC treatment markedly increased the phosphorylations of Akt. Blockade of PI3K activity by inhibitors (LY294002) dramatically abolished its anti-apoptotic effect and lowered both visual function and Akt phosphorylation levels. Taken together, our results demonstrate that HPC appears to confer neuroprotection against retinal IRI via the PI3K/Akt pathway. PMID- 29288665 TI - Intact calcium signaling in adrenergic-deficient embryonic mouse hearts. AB - Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta hydroxylase (Dbh-/-) gene inevitably perish from heart failure during mid gestation. Since adrenergic stimulation is well-known to enhance calcium signaling in developing as well as adult myocardium, and impairments in calcium signaling are typically associated with heart failure, we hypothesized that adrenergic-deficient embryonic hearts would display deficiencies in cardiac calcium signaling relative to adrenergic-competent controls at a developmental stage immediately preceding the onset of heart failure, which first appears beginning or shortly after mouse embryonic day 10.5 (E10.5). To test this hypothesis, we used ratiometric fluorescent calcium imaging techniques to measure cytosolic calcium transients, [Ca2+]i in isolated E10.5 mouse hearts. Our results show that spontaneous [Ca2+]i oscillations were intact and robustly responded to a variety of stimuli including extracellular calcium (5 mM), caffeine (5 mM), and NE (100 nM) in a manner that was indistinguishable from controls. Further, we show similar patterns of distribution (via immunofluorescent histochemical staining) and activity (via patch-clamp recording techniques) for the major voltage-gated plasma membrane calcium channel responsible for the L-type calcium current, ICa,L, in adrenergic-deficient and control embryonic cardiac cells. These results demonstrate that despite the absence of vital adrenergic hormones that consistently leads to embryonic lethality in vivo, intracellular and extracellular calcium signaling remain essentially intact and functional in embryonic mouse hearts through E10.5. These findings suggest that adrenergic stimulation is not required for the development of intracellular calcium oscillations or extracellular calcium signaling through ICa,L and that aberrant calcium signaling does not likely contribute to the onset of heart failure in this model. PMID- 29288666 TI - ZEB1 stimulates breast cancer growth by up-regulating hTERT expression. AB - Dysfunctional cell proliferation and death are the foundation of the malignant biological characteristics of cancers. In this study, we discovered that ZEB1 was positively correlated with hTERT in breast invasive ductal carcinoma samples at both the mRNA and protein levels. Further, our in vitro study in breast cancer cell lines confirmed that ZEB1 regulates hTERT expression at the mRNA and protein levels; thus, hTERT promotes or inhibits telomerase activity, and telomere length is either protected or reduced. Finally, we verified that ZEB1, which mostly functions as a transcriptional repressor, can recruit the co-activator YAP to enhance the transcriptional activation of hTERT. Fascinatingly, instead of acting on E-boxes, the ZEB1/YAP complex tends to function as a transcriptional activator by binding with sequences potentially located in the hTERT promoter. Consequently, our research revealed a new ZEB1-hTERT signaling pathway involved in cell proliferation regulation that has never before been illuminated in breast cancer. PMID- 29288667 TI - Chronic sleep disorder induced by psychophysiological stress induces glucose intolerance without adipose inflammation in mice. AB - Sleep disturbances are associated with various metabolic diseases such as hypertension and diabetes. We had previously established a mouse model of a psychophysiological stress-induced chronic sleep disorder (CSD) characterized by disrupted circadian rhythms of wheel-running activity, core body temperature, and sleep-wake cycles. To evaluate the underlying mechanisms of metabolic disorders induced by CSD, we created mice with CSD for six weeks and fed them with a high fat diet. Glucose intolerance with hyperglycemia resulted, although plasma insulin levels and body weight increases were identical between control and CSD mice. Gluconeogenesis and glycolysis were enhanced and suppressed, respectively, in the livers of CSD mice, because the mRNA expression of Pck1 was significantly increased, whereas that of Gck and Pklr were significantly decreased in the CSD mice. Adipose inflammation induced by the high-fat diet seemed suppressed by the CSD, because the mRNA expression levels of Adgre1, Ccl2, and Tnf were significantly downregulated in the adipose tissues of CSD mice. These findings suggest that CSD impair glucose tolerance by inducing gluconeogenesis and suppressing glycolysis. Hyperphasia with hypoleptinemia, hypercorticosteronemia, and increased plasma free fatty acids might be involved in the impaired glucose metabolism under a CSD. Further studies are needed to elucidate the endocrine and molecular mechanisms underlying the associations between sleep disorders and impaired glucose homeostasis that consequently causes diabetes. PMID- 29288668 TI - Structural insights into K48-linked ubiquitin chain formation by the Pex4p-Pex22p complex. AB - Pex4p is a peroxisomal E2 involved in ubiquitinating the conserved cysteine residue of the cycling receptor protein Pex5p. Previously, we demonstrated that Pex4p from the yeast Saccharomyces cerevisiae binds directly to the peroxisomal membrane protein Pex22p and that this interaction is vital for receptor ubiquitination. In addition, Pex22p binding allows Pex4p to specifically produce lysine 48 linked ubiquitin chains in vitro through an unknown mechanism. This activity is likely to play a role in targeting peroxisomal proteins for proteasomal degradation. Here we present the crystal structures of Pex4p alone and in complex with Pex22p from the yeast Hansenula polymorpha. Comparison of the two structures demonstrates significant differences to the active site of Pex4p upon Pex22p binding while molecular dynamics simulations suggest that Pex22p binding facilitates active site remodelling of Pex4p through an allosteric mechanism. Taken together, our data provide insights into how Pex22p binding allows Pex4p to build K48-linked Ub chains. PMID- 29288670 TI - The suppressive effects of Britannin (Bri) on human liver cancer through inducing apoptosis and autophagy via AMPK activation regulated by ROS. AB - Britannin (Bri), isolated from Inula aucheriana, is a sesquiterpene lactone (SL), a class of secondary metabolites. Previous studies have suggested the anti-cancer potential of Bri; however, the molecular mechanism remains elusive. The present study investigated the effects of Bri on liver cancer progression. Our findings indicated that Bri significantly suppressed the growth of liver cancer cell lines. Mechanistic researches revealed that Bri induced apoptosis through the extrinsic and intrinsic apoptotic pathways, as evidenced by the increase of Caspase-8, -9 and -3 cleavages. In addition, Bri-triggered autophagy in liver cancer cells, supported by the up-regulation of light chain 3 (LC3) II, p62, autophagy-related 5 (ATG5) and Beclin 1, as well as the occurrence of autophagic vacuoles. Importantly, Bri increased AMPK activation, while decreased the activity of its down-streaming signal, mTOR. Of note, suppression of AMP activated protein kinase (AMPK) activation using its inhibitor, Compound C, could inhibit both apoptosis and autophagy induced by Bri. Furthermore, Bri was found to induce reactive oxygen species (ROS) generation in hepatic cancer cells. Notably, reducing ROS production by its scavenger, N-acetyl cysteine (NAC), could down-regulate p-AMPK levels, while up-regulate the phosphorylated mechanistic target of rapamycin (p-mTOR) expressions, accompanied with the restored cell viability, as well as the reduced apoptosis and autophagy in Bri-treated liver cancer cells. Finally, Bri inhibited the tumor growth in vivo without side effects. In conclusion, our study illustrated that Bri could induce apoptosis and autophagy by activating AMPK regulated by ROS in liver cancer cells, supplying molecular bases for developing Bri into an effective candidate against liver cancer. PMID- 29288669 TI - Ubiquitin chain specificities of E6AP E3 ligase and its HECT domain. AB - Ubiquitination of target proteins is accomplished by isopeptide bond formation between the carboxy group of the C-terminal glycine (Gly) residue of ubiquitin (Ub) and the E-amino group of lysine (Lys) on the target proteins. The formation of an isopeptide bond between Ubs that gives rise to a poly-Ub chain on the target proteins and the types of poly-Ub chains formed depend on which of the seven Lys residues or N-terminal methionine (Met) residue on Ub is used for chain elongation. To understand the linkage specificity mechanism of Ub chains on E3, the previous study established an assay to monitor the formation of a free diubiquitin chain (Ub2 chain synthesis assay) by HECT type E3 ligase. In this study, we investigated Ub2 chain specificity using E6AP HECT domain. We here demonstrate the importance of the N-terminal domain of full length E6AP for Ub2 chain specificity. PMID- 29288672 TI - Seasonal changes in color perception. AB - In temperate zones, organisms experience dynamic fluctuations in environment including changes in color. To cope with such seasonal changes in the environment, organisms adapt their physiology and behavior. Although color perception has been believed to be fixed throughout life, there is increasing evidence for the alteration in opsin gene expression induced by environmental stimuli in a number of animals. Very recently, dynamic seasonal plasticity in color perception has been reported in the seasonally breeding medaka fish. Interestingly, seasonal changes in human color perception have also been reported. Therefore, plasticity of color perception, induced by environmental stimuli, might be a common phenomenon across various species. PMID- 29288671 TI - Prolonged skin grafts survival time by IFN-gamma in allogeneic skin transplantation model during acute rejection through IFN-gamma/STAT3/IDO pathway in epidermal layer. AB - Allogeneic skin transplantation is the life-saving therapy for multiple diseases, including extensive burn, large-scale trauma and certain post-surgical complications. However, acute rejection impedes clinical application of allogeneic skin transplantation. Although a lot of novel immunosuppressant drugs have been developed, there is still great need for ideal therapy with less complication and more therapeutic effects. Here, we found interferon gamma (IFN gamma) as an immunomodulatory cytokine prolonged the survival time of allografts from (8.50 +/- 1.517) days to (14.83 +/- 2.714) days at best. Indoleamine-2, 3 dioxygenase (IDO) has been proposed to play key roles in induction of immune tolerance. Using in vitro tissue culture and primary keratinocytes and fibroblasts, we investigated the regulatory effects of IFN-gamma on the IDO expression. IFN-gamma upregulated IDO expression through STAT3 phosphorylation and this upregulation was reduced by abolition of STAT3 phosphorylation through a STAT3 phosphorylation inhibitor. Interestingly, IFN-gamma induced IDO expression predominately in epidermis rather than dermis. In consistent with these results, IFN-gamma significantly triggered IDO expression in keratinocytes but not fibroblasts. Taken together, this suggests that IFN-gamma might be a potential immunomodulatory drug in acute rejection and keratinocytes in epidermis may play a main role in immune tolerance after allogeneic skin transplantation. PMID- 29288674 TI - A straightforward assay for measuring glycogen levels and RpoS. AB - Cellular glycogen levels reflect the activity of RpoS, an important stress inducible bacterial sigma factor known to regulate several stress-resistance related genes, such as katE, encoding hydroperoxidase II (HPII), and the glg genes, encoding glycogen synthesis enzymes, in Escherichia coli. In this study, a straightforward assay for measuring glycogen levels and RpoS activity was developed combining the ease and simplicity of qualitative approaches. The assay reagent was a 2% iodine solution (2% iodine/1M NaOH), and the basic principle of this assay is the iodine-glycogen reaction, which produces a reddish brown color that can be measured using a spectrophotometer. A calibration plot using a known amount of glycogen yielded the best linear fit over a range of 10-300MUg/assay (R2=0.994). The applicability of the assay for measuring the glycogen level of various samples was assessed using a wild type (WT) E. coli K-12 strain, glycogen and RpoS-deficient isogenic mutants, and clinical bacterial isolates with or without RpoS activity; the assay generated reproducible results. Additionally, the assay was successfully applied for measuring glycogen levels in human cells. In conclusion, we developed a straightforward and cost-effective assay for measuring glycogen levels, which can be applied for measuring RpoS activity. PMID- 29288673 TI - Construction and immunogenicity analysis of Lactobacillus plantarum expressing a porcine epidemic diarrhea virus S gene fused to a DC-targeting peptide. AB - Porcine epidemic diarrhea virus (PEDV) is one of the most important causative pathogens of swine diarrhea, which is widely prevalent throughout the world and is responsible for significant economic losses in the commercial pig industry, both domestic and abroad. The spike (S) protein in the PEDV capsid structure can carry the major B lymphocyte epitope, which induces production of neutralizing antibodies and provides immunoprotective effects. Moreover, the conserved region encoded by the S gene can be considered a target for establishing a new diagnostic method and is a new candidate for vaccine design. In this study, use of anchorin pgsA' allowed the fusion protein of S-DCpep to express on the surface of recombinant Lactobacillus plantarum (NC8-pSIP409-pgsA'-S-DCpep) NC8 strain. Mice were immunized by lavage administration of the recombinant NC8-pSIP409-pgsA' S-DCpep, which was observed to induce DC activation and high production of sIgA and IgG antibodies in experimental animals, while also eliciting production of significantly more IgA+B220+ B cells. More importantly, secretion of cytokines IFN-gamma, IL-4 and IL-17 in mice that were vaccinated with NC8-pSIP409-pgsA'-S DCpep was remarkably increased. The results of our study suggest that NC8-pSIP409 pgsA'-S-DCpep potently triggers cellular and humoral immune responses. The obtained experimental results can provide a theoretical basis that lays the foundation for production of a novel oral vaccine against PED. PMID- 29288675 TI - Field-usable lateral flow immunoassay for the rapid detection of a macluravirus, large cardamom chirke virus. AB - A simple and rapid lateral flow immunoassay (LFIA) was developed by utilizing gold nanoparticles conjugated to a polyclonal antibody against coat protein of large cardamom chirke virus (LCCV). The LFIA based on the principle of sandwich immunoassay detected LCCV within ~10 min and the result could be evaluated visually. The colloidal gold (CG) was made using 1% gold chloride solution. The LCCV IgG (1 MUg/MUl) and Mouse IgG (0.5 MUg/MUl) were conjugated with CG individually and coated onto a conjugate pad at 1:1 ratio. A sample extraction procedure was optimized in order to get adequate clear leaf sap of large cardamom leaf within few minutes. The sensitivity limit of the detection was 1:40 dilution of LCCV infected leaf sap. The diagnostic performance of LFIA was compared with ELISA using field samples. The LFIA was free from false positive as no visible test line was developed with healthy and potyviruses such as papaya ringspot virus and potato virus Y. The diagnostic specificity and sensitivity of LFIA was 100% and 90%, respectively. The Cohen's kappa coefficient (0.701) suggested a very good agreement between the ELISA and LFIA. Receiver operating characteristic analysis indicated that LFIA was a robust method as the area under the curve (0.950) is significantly (P <0.0001) broader. PMID- 29288676 TI - Transcriptomic profiles of post-smolt Atlantic salmon challenged with Piscirickettsia salmonis reveal a strategy to evade the adaptive immune response and modify cell-autonomous immunity. AB - Piscirickettsiosis is the main bacterial disease affecting the Chilean salmon farming industry and is responsible for high economic losses. The development of effective strategies to control piscirickettsiosis has been limited in part by insufficient knowledge of the host response. The aim of this study was to use RNA sequencing to describe the transcriptional profiles of the responses of post smolt Atlantic salmon infected with LF-89-like or EM-90-like Piscirickettsia salmonis. Enrichment and pathway analyses of the differentially expressed genes revealed several central signatures following infection, including positive regulation of DC-SIGN and TLR5 signalling, which converged at the NF-kappaB level to modulate the pro-inflammatory cytokine response, particularly in the PS-EM-90 infected fish. P. salmonis induced an IFN-inducible response (e.g., IRF-1 and GBP 1) but inhibited the humoral and cell-mediated immune responses. P. salmonis induced significant cytoskeletal reorganization but decreased lysosomal protease activity and caused the degradation of proteins associated with cellular stress. Infection with these isolates also delayed protein transport, antigen processing, vesicle trafficking and autophagy. Both P. salmonis isolates promoted cell survival and proliferation and inhibited apoptosis. Both groups of Trojan fish used similar pathways to modulate the immune response at 5 dpi, but the transcriptomic profiles in the head kidneys of the cohabitant fish infected with PS-LF-89 and PS-MS-90 were relatively different at day 35 post-infection of the Trojan fish, probably due to the different degree of pathogenicity of each isolate. Our study showed the most important biological mechanisms used by P. salmonis, regardless of the isolate, to evade the immune response, maintain the viability of host cells and increase intracellular replication and persistence at the infection site. These results improve the understanding of the mechanisms by which P. salmonis interacts with its host and may serve as a basis for the development of effective strategies for the control of piscirickettsiosis. PMID- 29288677 TI - The use of quetiapine in the treatment of major depressive disorder: Evidence from clinical and experimental studies. AB - Major depressive disorder (MDD) is a highly debilitating condition that is drawing considerable attention due to its high global prevalence and to the fact that treatments are still far from reaching the total number of patients affected. Among available treatment strategies, quetiapine is an important research target, due to antidepressant responses in patients resistant to classical treatments and in animals submitted to protocols that induce depressive like behaviours. Quetiapine has a broad spectrum of action, within which are many mechanisms that seem to be related to the most effective antidepressant therapeutic responses. In this review, research results related to the pharmacokinetic profile, neurotransmitters, receptors and signalling molecular targets involved in the functional and structural plasticity of key brain regions in MDD are reported and discussed. Moreover, the physiological mechanisms, which are targets of quetiapine and are involved in both MDD and poor therapeutic response, are reported. The main adverse effects observed from therapeutic dosages and overdose are also described. Finally, the main mechanisms underlying the therapeutic response are highlighted. PMID- 29288678 TI - Parental feeding practices to manage snack food intake: Associations with energy intake regulation in young children. AB - BACKGROUND: Little attention has been directed to understanding the relationship between restriction and regulation of snack food intake in toddlers. OBJECTIVE: The aim of this study was to examine the effects of parental restriction of toddlers' eating of snacks in the absence of hunger (EAH) and to examine the impact of three contextual factors; snack food access, frequency of snack food consumption, and attraction to snack food. DESIGN: 64 parents and toddlers (aged 22-36 months) took part in a protocol to measure EAH (defined as kJ of energy dense snack foods consumed). Mean EAH was 199 kJ (SD = 299), with 43 children consuming at least some snacks. Restriction was measured with the Child Feeding Questionnaire Restriction subscale. Snack food access was measured with Allow Access from the Toddler Snack Food Feeding Questionnaire (TSFFQ), snack food consumption was measured with a short snack food frequency questionnaire, and attraction to snack foods was measured with Child's Attraction from the TSFFQ. Moderated regression analyses tested interactions between Restriction and contextual factors in predicting EAH. RESULTS: EAH was associated with Restriction (r = 0.25, p = .05, 95% CI 0.004 - 0.47). There was an interaction between Restriction and accessibility of snack foods (R2 change = 0.08, p = .025); restriction was associated with EAH only when access to snack foods in the home was, on average, higher. The effect of Restriction on EAH was not moderated by frequency of snack food consumption or Child's Attraction. CONCLUSIONS: These finding have practical relevance and reinforce the importance of the home food environment for managing young children's snack food intake. PMID- 29288679 TI - The gene product of a Trypanosoma equiperdum ortholog of the cAMP-dependent protein kinase regulatory subunit is a monomeric protein that is not capable of binding cyclic nucleotides. AB - The full gene sequence encoding for the Trypanosoma equiperdum ortholog of the cAMP-dependent protein kinase (PKA) regulatory (R) subunits was cloned. A poly His tagged construct was generated [TeqR-like(His)8], and the protein was expressed in bacteria and purified to homogeneity. The size of the purified TeqR like(His)8 was determined to be ~57,000 Da by molecular exclusion chromatography indicating that the parasite protein is a monomer. Limited proteolysis with various proteases showed that the T. equiperdum R-like protein possesses a hinge region very susceptible to proteolysis. The recombinant TeqR-like(His)8 did not bind either [3H] cAMP or [3H] cGMP up to concentrations of 0.40 and 0.65 MUM, respectively, and neither the parasite protein nor its proteolytically generated carboxy-terminal large fragments were capable of binding to a cAMP-Sepharose affinity column. Bioinformatics analyses predicted that the carboxy-terminal region of the trypanosomal R-like protein appears to fold similarly to the analogous region of all known PKA R subunits. However, the protein amino-terminal portion seems to be unrelated and shows homology with proteins that contained Leu rich repeats, a folding motif that is particularly appropriate for protein protein interactions. In addition, the three-dimensional structure of the T. equiperdum protein was modeled using the crystal structure of the bovine PKA RIalpha subunit as template. Molecular docking experiments predicted critical changes in the environment of the two putative nucleotide binding clefts of the parasite protein, and the resulting binding energy differences support the lack of cyclic nucleotide binding in the trypanosomal R-like protein. PMID- 29288680 TI - Deciphering sex differences in the immune system and depression. AB - Certain mood disorders and autoimmune diseases are predominately female diseases but we do not know why. Here, we explore the relationship between depression and the immune system from a sex-based perspective. This review characterizes sex differences in the immune system in health and disease. We explore the contribution of gonadal and stress hormones to immune function at the cellular and molecular level in the brain and body. We propose hormonal and genetic sex specific immune mechanisms that may contribute to the etiology of mood disorders. PMID- 29288682 TI - Sources of paralytic shellfish toxin accumulation variability in the Pacific oyster Crassostrea gigas. AB - This study was designed to assess the contribution of feeding behavior to inter individual variability of paralytic shellfish toxin (PST) accumulation in the Pacific oyster Crassostrea gigas. For this purpose 42 oysters were exposed for 2 days to non-toxic algae and then for 2 other days to the PST producer Alexandrium minutum. Individual clearance rate (CR) of oysters was continuously monitored over the 4 days using an ecophysiological measurement system. Comparison of CR values when exposed to toxic and non toxic algae allowed to estimate a clearance rate inhibition index (CRII). Toxin concentration of oysters was quantified at the end of the experiment. These data allowed to estimate the toxin accumulation efficiency (TAE) as the ratio of toxin accumulated on toxin consumed. Changes of clearance rate during the experiment indicated that all individuals stopped feeding immediately after being exposed to A. minutum for at least 7 h. This fast response likely corresponded to a behavioral mechanism of avoidance rather to a toxin-induced response. Individuals also showed high inter-variability in their recovery of filtration after this period. Most of the inter-individual variability (78%) in PST accumulation in C. gigas could be explained by the consumption of A. minutum cells, thus emphasizing the importance of the feeding behavior in accumulation. Based on the toxin concentration in their tissues, oysters were clustered in 3 groups showing contrasted patterns of PST accumulation: the high accumulation group was characterized by high feeding rates both on non-toxic and toxic diet and subsequently a low CRII and high TAE. Inversely, the low accumulation group was characterized by low filtration rates, high CRII and low TAE. Both filtration capacity and sensitivity of oysters to toxins may account for the differences in their accumulation. The contribution of TAE in PST accumulation is discussed and might result from differences in assimilation and detoxification abilities among individuals. PMID- 29288681 TI - Resistance to receptor-blocking therapies primes tumors as targets for HER3 homing nanobiologics. AB - Resistance to anti-tumor therapeutics is an important clinical problem. Tumor targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a "Trojan Horse" approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naive tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here. PMID- 29288683 TI - What is difficult for you can be easy for me. Effects of increasing individual task demand on prefrontal lateralization: A tDCS study. AB - Neuroimaging studies suggest that the increment of the cognitive load associated with a specific task may induce the recruitment of a more bilateral brain network. In most studies, however, task demand has been manipulated in a static and pre-specified way, regardless of individual cognitive resources. Here we implemented a new paradigm based on a pre-experimental assessment to set up subject-specific levels of task demand and applied tDCS (transcranial direct current stimulation) to assess each hemisphere involvement in task performance. 24 young participants performed a digit span backward (DSB, complex cognitive function) and a paced finger tapping task (pFT, basic motor function) at 3 levels of subject-specific task demand ("low" 5/5 correct answers, "medium" 3/5, "high" 1/5). Anodal tDCS (20min, 1.5mA) was delivered through a target electrode (5 * 5cm) positioned to stimulate both the inferior frontal gyrus and the primary motor area over left and right hemisphere and in sham condition in three different days. A 3 (left, right, sham) * 3 (low, medium, high) mixed-model with random intercept for subjects was run with R software. As expected, in both tasks accuracy decreased with the increment of subject-specific task demand. Moreover, a significant interaction between type of stimulation and subject-specific task demand was found for the reaction times recorded during the DSB and for the accuracy in the pFT: in the most demanding conditions, right anodal tDCS significantly interfered with behavioural performance. Our results suggest that hemispheric lateralization is modulated by the subject-specific level of task demand and this modulation is not task-specific. PMID- 29288684 TI - The octapetide NAP alleviates intestinal and extra-intestinal anti-inflammatory sequelae of acute experimental colitis. AB - The octapeptide NAP has been shown to exert neuroprotective properties and reduce neuro-inflammatory responses. The aim of the present study was to investigate if NAP provides anti-inflammatory effects in acute murine colitis. To address this, C57BL/6 j mice were challenged with 3.5% dextran sulfate sodium from day 0 until day 6 to induce colitis, either treated intraperitoneally with NAP or placebo (NaCl 0.9%) from day 1 until day 6 post-induction (p.i.) and subjected to in depth macroscopic, microscopic and immunological evaluations. Whereas NAP application did not alleviate macroscopic (i.e. clinical) sequelae of colitis, lower numbers of apoptotic, but higher counts of proliferating/regenerating colonic epithelial cells could be observed in NAP as compared to placebo treated mice at day 7 p.i. Furthermore, lower numbers of adaptive immune cells such as T lymphocytes and regulatory T cells were abundant in the colonic mucosa and lamina propria upon NAP versus placebo treatment that were accompanied by less colonic secretion of pro-inflammatory mediators including IFN-gamma and nitric oxide at day 7 p.i. In mesenteric lymph nodes, pro-inflammatory IFN-gamma, TNF and IL-6 concentrations were increased in placebo, but not NAP treated mice at day 7 p.i., whereas interestingly, elevated anti-inflammatory IL-10 levels could be observed in NAP treated mice only. The assessed anti-inflammatory properties of NAP were not restricted to the intestinal tract, given that in extra-intestinal compartments such as the kidneys, IFN-gamma levels increased in placebo, but not NAP treated mice upon colitis induction. NAP induced effects were accompanied by distinct changes in intestinal microbiota composition, given that colonic luminal loads of bifidobacteria, regarded as anti-inflammatory, "health-promoting" commensal species, were two orders of magnitude higher in NAP as compared to placebo treated mice and even naive controls. In conclusion, NAP alleviates intestinal and extra-intestinal pro-inflammatory sequelae of acute experimental colitis and may provide novel treatment options of intestinal inflammatory diseases in humans. PMID- 29288685 TI - Characterization of neuromedin U (NMU), neuromedin S (NMS) and their receptors (NMUR1, NMUR2) in chickens. AB - Neuromedin U (NMU) and its structurally-related peptide, neuromedin S (NMS), are reported to regulate many physiological processes and their actions are mediated by two NMU receptors (NMUR1, NMUR2) in mammals. However, the information regarding NMU, NMS, and their receptors is limited in birds. In this study, we examined the structure, functionality, and expression of NMS, NMU, NMUR1 and NMUR2 in chickens. The results showed that: 1) chicken (c-) NMU cDNA encodes a 181-amino acid precursor, which may generate two forms of NMU peptide with 9 (cNMU-9) and 25 amino acids (cNMU-25), respectively. 2) Interestingly, two cNMS transcripts encoding two cNMS precursors of different lengths were identified from chicken pituitary, and both cNMS precursors may produce a mature cNMS peptide of 9 amino acids (cNMS-9). 3) cNMU-9, cNMU-25 and cNMS-9 could activate cNMUR1 expressed in HEK293 cells potently, as monitored by three cell-based luciferase reporter systems, indicating that cNMUR1 can act as a receptor common for cNMU and cNMS peptides, whereas cNMUR2 could be potently activated by cNMS-9, but not by cNMU-9/cNMU-25. 4) cNMU and cNMUR1 are widely expressed in chicken tissues with abundant expression noted in the gastrointestinal tract, as detected by quantitative real-time PCR, whereas cNMUR2 expression is mainly restricted to the brain and anterior pituitary, and cNMS is widely expressed in chicken tissues. Collectively, our data helps to elucidate the physiological roles of NMU/NMS peptides in birds and reveal the functional conservation and changes of NMU/NMS-NMUR axis across vertebrates. PMID- 29288686 TI - Increased amygdala responses to emotional faces after psilocybin for treatment resistant depression. AB - Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments' therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. TRIAL REGISTRATION: ISRCTN, number ISRCTN14426797. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29288687 TI - Distinctive effects of licarin A on lipolysis mediated by PKA and on formation of brown adipocytes from C3H10T1/2 mesenchymal stem cells. AB - Obesity increases with the positive energy imbalance and correlates with increased risks for metabolic diseases. Promotion of white adipose tissue beiging has received considerable attention due to possible usefulness for preventing obesity and the comorbidities. Licarin A (LA) is a compound derived from Mexican medicinal plant Aristolochia taliscana. Here, we report that LA stimulates the development of brown-like and beige-like adipocytes from C3H10T1/2 mesenchymal stem cells with phenotypic shifts to formation of smaller lipid droplets. LA also markedly induced the expression of proteins characteristic of brown-like adipocytes in C3H10T1/2 mesenchymal stem cells. LA induced uncoupling protein 1 (Ucp1) and expression of other thermogenic genes in C3H10T1/2 mesenchymal stem cells via a mechanism involving protein kinase A (PKA). LA treatment also inhibited expression of white-adipocyte-specific genes. Moreover, LA treatment promoted lipolysis via PKA mediated pathway. Our findings inaugurate a new role of LA as an inducer of brown-like adipocytes formation with lipolytic properties, which in future might be studied in vivo as a potential anti-obesity agent. PMID- 29288689 TI - Skin derived precursor Schwann cell-generated acellular matrix modified chitosan/silk scaffolds for bridging rat sciatic nerve gap. AB - Extracellular/acellular matrix has been attracted much research interests for its unique biological characteristics, and ACM modified neural scaffolds shows the remarkable role of promoting peripheral nerve regeneration. In this study, skin derived precursors pre-differentiated into Schwann cells (SKP-SCs) were used as parent cells to generate acellular(ACM) for constructing a ACM-modified neural scaffold. SKP-SCs were co-cultured with chitosan nerve guidance conduits (NGC) and silk fibroin filamentous fillers, followed by decellularization to stimulate ACM deposition. This NGC-based, SKP-SC-derived ACM-modified neural scaffold was used for bridging a 10 mm long rat sciatic nerve gap. Histological and functional evaluation after grafting demonstrated that regenerative outcomes achieved by this engineered neural scaffold were better than those achieved by a plain chitosan-silk fibroin scaffold, and suggested the benefits of SKP-SC-derived ACM for peripheral nerve repair. PMID- 29288688 TI - Neuroprotective activity of macamides on manganese-induced mitochondrial disruption in U-87 MG glioblastoma cells. AB - Macamides are a distinct class of secondary metabolites, benzylamides of long chain fatty acids, which were isolated from the Peruvian plant Lepidium meyenii (Maca). As structural analogues of the endocannabinoid anandamide (AEA), they have demonstrated neuroprotective effects in vitro and in vivo. The purpose of this study was to demonstrate the neuroprotective activity of the macamides: N-(3 methoxybenzyl)oleamide (MAC 18:1), N-(3-methoxybenzyl)linoleamide (MAC 18:2) and N-(3-methoxybenzyl)linolenamide (MAC 18:3) in a neurotoxic environment caused by exposure of U-87 MG glioblastoma cells to manganese chloride (MnCl2). The neuroprotective effects of these macamides were reversed by the CB1 antagonist AM251. The mechanism by which manganese (Mn) induces cell damage was investigated by studying its effects on mitochondria. Reactive oxygen species (ROS) increase intracellular calcium and enhance the opening of mitochondrial permeability transition pores (MPTP), which leads to decreased mitochondrial membrane potential (MMP), to disruption of mitochondria and to neuron death in neurodegenerative disorders. In this study, MnCl2 at 50MUM was responsible for mitochondrial disruption, which was attenuated by all three of the macamides tested. Human peroxisome proliferator-activated receptor gamma (PPARgamma) has been proposed to be a cannabinoid target, and PPARgamma has also been demonstrated to mediate some of the longer-term vascular effects of the plant cannabinoid, ?9-tetrahydrocannabinol. PPARgamma activation was observed in response to exposures of cells to MAC 18:2 and MAC 18:3. These findings suggest that macamides achieve their neuroprotective effects by binding to CB1 receptors to protect against Mn-induced toxicity in U-87 MG glioblastoma cells. Additionally these macamides, in a manner similar to the analogous endocannabinoid AEA, interact with other targets such as PPARgamma to regulate metabolism and energy homeostasis, cell differentiation and inflammation. PMID- 29288690 TI - Mifepristone reduces hypothalamo-pituitary-adrenal axis activation and restores weight loss in rats subjected to dietary restriction and methylphenidate administration. AB - This study evaluates the efficacy of mifepristone on weight restoration in rats subjected to dietary restriction and methylphenidate administration. 25 female rats aged between 9 and 12 months were divided into 2 groups: 5 controls (exposed only to dietary restriction) and 20 rats that were administered 5 mg/kg/d of methylphenidate before meal exposure, for 36 days. Among rats who responded to methylphenidate (weight loss of 15-25%) weeks after its administration, a group of 6 rats continued to receive only methylphenidate ("Met" group), and another group received 10 mg/kg/d of mifepristone in addition to methylphenidate for 18 days ("Met+Mif" group; n = 6). The mean weight of the "Met+Mif" group remained significantly lower when compared to the control group (87.63 +/- 2.83% vs 96.29 +/- 3.26%; p < 0.001 respectively) but was significantly higher than that of the "Met" group (87.63 +/- 2.83% vs. 80.61 +/- 3.52%; p < 0.001 respectively). Plasma concentrations of adiponectin and gene expression of its receptors in rats brain were significantly higher in the "Met" group as compared to the "Met+Mif" and control groups (p < 0.01). Accordingly, mifepristone reduces HPA axis activation and restores weight through adipose tissue recovering. It might be considered a promising treatment for anorexia nervosa patients in future studies. PMID- 29288691 TI - A prospective study of the impact of diabetes mellitus on restrictive and obstructive lung function impairment: The Saku study. AB - BACKGROUND: To assess the impact of diabetes on restrictive and obstructive lung function impairment. METHODS: This 5-year prospective study included 7524 participants aged 40-69years without lung function impairment at baseline who underwent a comprehensive medical check-up between April 2008 and March 2009 at Saku Central Hospital. Diabetes was defined by fasting plasma glucose >=7.0mmol/l (126mg/dl), HbA1c>=6.5% (48mmol/mol), or a history of diabetes, as determined by interviews conducted by the physicians. Restrictive and obstructive lung function impairment were defined as forced vital capacity (FVC) <80% predicted and forced expiratory volume in 1s (FEV1) to FVC ratio (FEV1/FVC) <0.70, respectively. Participants were screened until they developed restrictive or obstructive lung function impairment or until March 2014. RESULTS: During the follow-up period, 171 and 639 individuals developed restrictive and obstructive lung function impairment, respectively. Individuals with diabetes had a 1.6-fold higher risk of restrictive lung function impairment than those without diabetes after adjusting for sex, age, height, abdominal obesity, smoking status, exercise habits, systolic blood pressure, HDL-cholesterol, log-transformed high-sensitivity C reactive protein, and baseline lung function [multivariable-adjusted HR and 95% CI; 1.57 (1.04-2.36)]. In contrast, individuals with diabetes did not have a significantly higher risk of obstructive lung function impairment [multivariable adjusted HR and 95% CI; 0.93 (0.72-1.21)]. CONCLUSION: Diabetes was associated with restrictive lung function impairment but not obstructive lung function impairment. PMID- 29288692 TI - Intraepithelial CD8+ lymphocytes as a predictive diagnostic biomarker for the remission of oral lichen planus. AB - Oral lichen planus (OLP) is an autoimmune inflammatory disease of the oral mucosa whose etiology remains unknown. Moreover, the possibility of OLP being a premalignant change is under debate. Various types of immune cells infiltrate the OLP lesion and affect its clinicopathological features. However, the diversity of infiltrating immune cells has not been fully clarified in relation to OLP diagnosis. In this study, we quantitatively examined CD8+ lymphocyte infiltration by immunohistochemistry, which is the principal effector of cytotoxic immune reaction in 123 cases of OLP specimens. Our examination revealed that high-grade intraepithelial CD8+ lymphocyte infiltration was associated with a high remission rate. Evaluation of the infiltration of T-bet+ and FoxP3+ lymphocytes, which corresponded to the Th1 and Treg CD4+ subsets, respectively, showed that intraepithelial CD8+ lymphocytes were associated with the remission rate in the subgroup with a higher T-bet/FoxP3 subset balance that is inducible for cytotoxic immunity. We also investigated the cutoff value of CD8+ lymphocyte infiltration for histopathological diagnosis. By microscopic counting, 16 cells/high-power field, which was also confirmed in the validation cohort, was established as the cutoff value for intraepithelial CD8+ lymphocyte infiltration for predicting the remission of OLP. Remitting OLP might be different from refractory OLP in terms of etiology and clinical behavior. Thus, intraepithelial CD8+ lymphocytes may serve not only as a predictive biomarker for remission but also as an area for further biomedical research regarding the etiology and premalignant potential of OLP. PMID- 29288693 TI - Mixed adenoneuroendocrine carcinoma: A review of pathologic characteristics. AB - Mixed adenoneuroendocrine carcinoma (MANEC) is a rare pathologic entity defined as a tumor exhibiting both adenocarcinoma and neuroendocrine carcinoma components. Though uncommon, these tumors show aggressive behavior and generally portend a poor prognosis. This study seeks to further define clinicopathological characteristics of MANEC to aid in accurate diagnosis and properly direct clinical management. Thirty-four confirmed MANECs were identified in our 25-year retrospective review of cases arising in the gastrointestinal tract. Various gross and microscopic variables were compared to overall survival. Tumors diagnosed at advanced stage (pT4), had a prominent mucinous component and lacked goblet cell clusters, which were all significantly associated with worse overall survival. This study supports previous findings and further elucidates clinicopathologic characteristics of MANEC. PMID- 29288694 TI - Salivary gland epithelial neoplasms in pediatric population: a single-institute experience with a focus on the histologic spectrum and clinical outcome. PMID- 29288695 TI - Salivary gland epithelial neoplasms in pediatric population: a single-institute experience with a focus on the histologic spectrum and clinical outcome-reply. PMID- 29288696 TI - Cytokine gene polymorphisms in Iraqi Arabs. AB - In this report, 224 unrelated healthy Iraqi Arabs (102 males and 122 females) were genotyped for 22 SNPs (single nucleotide polymorphisms) belong to 13 cytokine genes (IL1A, IL1B, IL1RA, IL1R, IL2, IL4, IL4R, IL6, IL10, IL12, IFNG, TNFA and TGFB1). The method of detection was PCR-SSP (polymerase chain reaction sequence specific primer). The data were presented in terms of allele and genotype frequencies. Two-locus haplotype frequencies were also estimated for some SNPs. Genotype frequencies of detected cytokine gene polymorphisms are available in the Database of Allele Frequencies Net under the AFND number 3422 and the population name "Iraq Arab Cytokine". PMID- 29288697 TI - Mesenchymal stromal cells for tolerance induction in organ transplantation. AB - The primary challenge in organ transplantation continues to be the need to suppress the host immune system long-term to ensure prolonged allograft survival. Long-term non-specific immunosuppression can, however, result in life-threatening complications. Thus, efforts have been pursued to explore novel strategies that would allow minimization of maintenance immunosuppression, eventually leading to transplant tolerance. In this scenario, bone marrow-derived mesenchymal stromal cells (MSC), given their unique immunomodulatory properties to skew the balance between regulatory and memory T cells, have emerged as potential candidates for cell-based therapy to promote immune tolerance. Here, we review our initial clinical experience with bone marrow-derived MSC in living-donor kidney transplant recipients and provide an overview of the available results of other clinical programs with MSC in kidney and liver transplantation, highlighting hurdles and success of this innovative cell-based therapy. PMID- 29288698 TI - Regulatory T cells for tolerance. AB - Regulatory T cells (Tregs) are critical mediators of immune homeostasis and hold significant promise in the quest for transplantation tolerance. Progress has now reached a critical threshold as techniques for production of clinical therapies are optimised and Phase I/II clinical trials are in full swing. Initial safety and efficacy data are being reported, with trials assessing a number of different strategies for the introduction of Treg therapy. It is now more crucial than ever to elucidate further the function and behaviour of Tregsin vivoand ensure safe delivery. This review will discuss the current state of the art and future directions in Treg therapy. PMID- 29288699 TI - Development of a replicon cell line-based high throughput antiviral assay for screening inhibitors of Zika virus. AB - Zika virus (ZIKV) is an important emerging human pathogen associated with microcephaly, Guillain-Barre syndrome and meningoencephalitis. Developing rapid and reliable HTS assay is important for ZIKV drug discovery. Here, we constructed a dicistronic ZIKV replicon (ZIKV-Pac-Rluc-Rep) that contained the Renilla luciferase (Rluc) reporter gene separated from the puromycin N-acetyl-transferase (Pac) selectable marker by a short peptide cleavage site. A clonal replicon cell line stably expressing high level of ZIKV replicon was established by selection with puromycin. By optimizing cell number, compound concentration and incubation time, a robust replicon cell-based HTS assay was developed with a calculated Z' value of >0.5. The fully optimized assay was further validated using several known flavivirus replication inhibitors. Altogether, the replicon cell-based HTS assay developed in this study will facilitate the discovery of antiviral compounds against ZIKV. PMID- 29288701 TI - Refuge-mediated predator-prey dynamics and biomass pyramids. AB - Refuge can greatly influence predator-prey dynamics by movements between the interior and the exterior of a refuge. The presence of refuge for prey decreases predation risk and can have important impacts on the sustainability of a predator prey system. The principal purpose of this paper is to formulate and analyze a refuge-mediated predator-prey model when the refuge is available to protect a portion of prey from predation. We study the effect of the refuge size on the biomass ratio and extend our refuge model to incorporate fishing and predator migration separately. Our study suggests that decreasing the refuge size, increasing the predator fishing, and increasing the predator emigration stabilizes the system. Here, we investigate the dependence of Hopf bifurcation on refuge size in the presence of fishing or predator migration. Moreover, we discuss their effects on the biomass pyramid and establish a condition for the emergence of an inverted biomass pyramid. We perform numerical test and sensitivity analysis to check the robustness of our results and the relative importance of all parameters. We find that high fishing pressure may destroy the inverted biomass pyramid and thus decrease the resilience of reef ecosystems. In addition, increasing the emigration rate or decreasing the immigration rate decreases the predator-prey biomass ratio. An inverted biomass pyramid can occur in the presence of a stable limit cycle. PMID- 29288700 TI - Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease. AB - Many flaviviruses, such as Zika virus (ZIKV), Dengue virus (DENV1-4) and yellow fever virus (YFV), are significant human pathogens. Infection with ZIKV, an emerging mosquito-borne flavivirus, is associated with increased risk of microcephaly in newborns and Guillain-Barre syndrome and other complications in adults. Currently, specific therapy does not exist for any flavivirus infections. In this study, we found that erythrosin B, an FDA-approved food additive, is a potent inhibitor for flaviviruses, including ZIKV and DENV2. Erythrosin B was found to inhibit the DENV2 and ZIKV NS2B-NS3 proteases with IC50 in low micromolar range, via a non-competitive mechanism. Erythrosin B can significantly reduce titers of representative flaviviruses, DENV2, ZIKV, YFV, JEV, and WNV, with micromolar potency and with excellent cytotoxicity profile. Erythrosin B can also inhibit ZIKV replication in ZIKV-relevant human placental and neural progenitor cells. As a pregnancy category B food additive, erythrosin B may represent a promising and easily developed therapy for management of infections by ZIKV and other flaviviruses. PMID- 29288702 TI - Coupled, multi-strain epidemic models of mutating pathogens. AB - We introduce and analyze coupled, multi-strain epidemic models designed to simulate the emergence and dissemination of mutant (e.g. drug-resistant) pathogen strains. In particular, we investigate the mathematical and biological properties of a general class of multi-strain epidemic models in which the infectious compartments of each strain are coupled together in a general manner. We derive explicit expressions for the basic reproduction number of each strain and highlight their importance in regulating the system dynamics (e.g. the potential for an epidemic outbreak) and the existence of nonnegative endemic solutions. Importantly, we find that the basic reproduction number of each strain is independent of the mutation rates between the strains - even under quite general assumptions for the form of the infectious compartment coupling. Moreover, we verify that the coupling term promotes strain coexistence (as an extension of the competitive exclusion principle) and demonstrate that the strain with the greatest reproductive capacity is not necessarily the most prevalent. Finally, we briefly discuss the implications of our results for public health policy and planning. PMID- 29288703 TI - Loss of DEK induces radioresistance of murine restricted hematopoietic progenitors. AB - Self-renewing hematopoietic stem cells and multipotent progenitor cells are responsible for maintaining hematopoiesis throughout an individual's lifetime. For overall health and survival, it is critical that the genome stability of these cells is maintained and that the cell population is not exhausted. Previous reports have indicated that the DEK protein, a chromatin structural protein that functions in numerous nuclear processes, is required for DNA damage repair in vitro and long-term engraftment of hematopoietic stem cells in vivo. Therefore, we investigated the role of DEK in normal hematopoiesis and response to DNA damaging agents in vivo. Here, we report that hematopoiesis is largely unperturbed in DEK knockout mice compared with wild-type (WT) controls. However, DEK knockout mice have fewer radioprotective units, but increased capacity to survive repeated sublethal doses of radiation exposure compared with WT mice. Furthermore, this increased survival correlated with a sustained quiescent state in which DEK knockout restricted hematopoietic progenitor cells (HPC-1) were nearly three times more likely to be quiescent following irradiation compared with WT cells and were significantly more radioresistant during the early phases of myeloid reconstitution. Together, our studies indicate that DEK functions in the normal hematopoietic stress response to recurrent radiation exposure. PMID- 29288705 TI - Massa adiposa ligamenti falciformis or anterior abdominal fat pad - Its dimension and relation to body weight. AB - The anterior abdominal fat pad is associated with the falciform ligament in the upper middle/right abdomen and is frequently seen there in diagnostic imaging. It varies greatly in size and has often been described as an incidental finding in adults and has hitherto rarely been regarded as being illness-relevant. The aim of this study has been to assess whether the dimension of the corpus adiposum may be associated with body mass index. Ultrasound findings of 26 patients from birth until adolescence were analyzed for this purpose. In addition, an example from a recent dissection course has been included. The structure is constantly found with its smallest dimension in newborns, with a slight increase in infancy. The average dimensions were 7.6 by 3.5 by 0.7cm. The cubic volume correlated with age, weight and body mass index, whereas the latter association was strongest. Our data suggest that routinely determined dimension of falciform fat may be a surrogate parameter of relative body weight in childhood. PMID- 29288704 TI - The mirn23a and mirn23b microrna clusters are necessary for proper hematopoietic progenitor cell production and differentiation. AB - Mice deficient for microRNA (miRNA) cluster mirn23a exhibit increased B lymphopoiesis at the expense of myelopoiesis, whereas hematopoietic stem and progenitor cell (HSPC) populations are unchanged. Mammals possess a paralogous mirn23b gene that can give rise to three mature miRNAs (miR-23b, miR-24-1, and miR-27b) that have identical seed/mRNA-targeting sequences to their mirn23a counterparts. To assess whether compound deletion of mirn23a and mirn23b exacerbates the hematopoietic phenotype observed in mirn23a-/- mice, we generated a compound mirn23a-/-mirn23bfl/fl:Mx1-Cre conditional knockout mouse and assayed hematopoietic development after excision of mirn23b. Loss of both genes in adult bone marrow further skewed HSPC differentiation toward B cells at the expense of myeloid cells, demonstrating a dosage-dependent effect on regulating cell differentiation. Strikingly, double-knockout (DKO) mice had decreased bone marrow cellularity with significantly decreased hematopoietic stem cell and HSPC populations, a phenotype not observed in mice deficient for mirn23a alone. Competitive transplantation assays showed decreased contribution of mirn23a-/ mirn23b-/- HSPCs to hematopoietic lineages at 6 and 12 weeks after transplantation. Defects in the proliferation of mirn23a-/-b-/- HSPCs was not observed; however, DKO cells were more apoptotic compared with both wild-type and mirn23a-/- cells. Together, our data show that complete loss of mirn23a/mirn23b miRNAs results in decreased blood production and affects lineage output in a concentration-dependent manner. PMID- 29288706 TI - Improved vaginal retention and enhanced antifungal activity of miconazole microsponges gel: Formulation development and in vivo therapeutic efficacy in rats. AB - Traditional azole antifungal formulations suffer from poor retention in the vaginal cavity, irritation and burning of the vaginal area. In the present work, we aim at the development of a novel miconazole (MCZ) microsponges gel as an attractive dosage form for vaginal candidiasis. The proposed formula has the potential to minimize the local side effects of the drug due to the controlled release characteristic, which increases patient compliance. Moreover, the mucosal retention effect of the microsponges in addition to the bioadhesion property of Carbopol gel prolongs the retention of the dosage form in the vagina and consequently improves the therapeutic efficiency. MCZ microsponges were prepared applying Quasi emulsion method using Eudragit RS100. The effect of formulation factors, namely, drug:polymer ratio (1:1, 2:1 and 4:1), the amount of poly vinyl alcohol (PVA) (25, 50 and 75mg) and the volume of organic solvent (2.5, 5, 10mL) on the characteristics of MCZ microsponges has been investigated. The microsponges were optimized regarding the production yield (68.8+/-6.4%), particle size (78.2+/-2.1MUm), entrapment efficiency (92.9+/-1.9%) and release rate (Q150 51.8+/-2.5%). The selected formula was further evaluated for its, flowability, porosity and surface morphology. MCZ microsponges were incorporated into Carbopol gel, then the viscosity and bioadhesion were examined. The in vitro antifungal activity of MCZ microsponges gel was comparable to the market product. In vivo, MCZ microsponges vaginal gel was more effective than the market product (p<0.05) in eradicating Candida infection in rats, which was supported by the histopathological findings. PMID- 29288707 TI - Improving the skin penetration and antifebrile activity of ibuprofen by preparing nanoparticles using emulsion solvent evaporation method. AB - Ibuprofen (IBU) is an effective analgesic, non-steroidal anti-inflammatory drug. Unfortunately, oral IBU can cause adverse gastrointestinal drug reactions, such as bleeding and ulcerations, and increases the risk for stomach or intestinal perforations. In this study, IBU nanoparticles (IBU-NPs) were prepared through emulsion solvent evaporation and freeze-drying to improve their solubility. IBU nanoemulsion and nanosuspension were optimized through a single-factor experiment. IBU-NPs with a mean particle size of 216.9+/-10.7nm were produced under optimum conditions. These IBU-NPs were characterized by using scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and residual solvent determination to determine their solvent residue, equilibrium solubility, dissolution rate, in vitro transdermal rate, transdermal bioavailability, and antifebrile experiment for febrile rats. The morphological characteristic of IBU-NPs showed porous clusters. Analysis results indicated that the prepared IBU-NPs have low crystallinity. Residual amounts of ethanol and chloroform were 170 and 9.6ppm, respectively, which were less than the ICH limit for class II. Measurement analysis showed that the IBU-NPs were converted underwent amorphous states after preparation, but the chemical structure of the IBU-NPs was unchanged. Transdermal bioavailability of IBU in the IBU-NP group improved significantly compared with oral and transdermal raw IBU. Furthermore, the IBU-NP transdermal gel exhibited a high and stable cooling rate and a long cooling duration in febrile rats. In comparison with the raw oral IBU and raw IBU transdermal gel, the IBU-NP transdermal gel manifested better efficacy at low and mid doses. Basing from the results, we conclude that IBU-NPs can be applied in transdermal delivery formulations and have potential application value for non oral administration. PMID- 29288708 TI - Pattern of aromatase mRNA expression in the brain of a weakly electric fish, Apteronotus leptorhynchus. AB - Aromatase is a steroidogenic enzyme involved in the conversion of testosterone into estradiol. Teleosts are unique among vertebrates in possessing two distinct aromatase genes that show different expression patterns within the body. Since the brain is the essential organ underlying the control of behavior, an understanding of the expression pattern of aromatase in the brain can help to identify neural circuits and behaviors that are most likely to be affected by aromatase activity. In addition, identifying species differences in aromatase expression in the brain can further our understanding of divergence in behaviors regulated by local estradiol production and estrogen signaling. Apteronotus leptorhynchus is a species of weakly electric fish in which little is known about sex steroid expression within the brain and its role in electric signaling behavior. The goal of this study was to identify the mRNA expression pattern of aromatase in the brain of A. leptorhynchus. Aromatase mRNA was detected in several parts of the forebrain and in the pituitary gland; however, no aromatase expression was detected in the midbrain or hindbrain. These findings in A. leptorhynchus support a role for aromatase activity in reproduction, but no direct role in electric signaling behavior in non-breeding fish. The findings of this study help to broaden the basis for making phylogenetic comparisons of aromatase expression across teleost lineages as well as different signaling systems, and provide information on behaviors and neural circuits that are potentially affected by local estradiol production in A. leptorhynchus. PMID- 29288709 TI - Collision of the glass shards with the eye: A computational fluid-structure interaction model. AB - The main stream of blunt trauma injuries has been reported to be related to the automobile crashes, sporting activities, and military operations. Glass shards, which can be induced due to car accident, earthquake, gunshot, etc., might collide with the eye and trigger substantial scarring and, consequently, permanently affect the vision. The complications as a result of the collision with the eye and its following injuries on each component of the eye are difficult to be diagnosed. The objective of this study was to employ a Three Dimensional (3D) computational Fluid-Structure Interaction (FSI) model of the human eye to assess the results of the glass shards collision with the eye. To do this, a rigid steel-based object hit a Smoothed-Particle Hydrodynamics (SPH) glass wall at the velocities of 100, 150, and 200 m/s and, subsequently, the resultant glass shards moved toward the eye. The amount of injury, then, quantified in terms of the stresses and strains. The results revealed the highest amount of stress in the cornea while the lowest one was observed in the vitreous body. It was also found that increasing the speed of the glass shards amplifies the amount of the stress in the components which are located in the central anterior zone of the eye, such as the cornea, aqueous body, and iris. However, regarding those components located in the peripheral/posterior side of the eye, especially the optic nerve, by increasing the amount of velocity a reduction in the stresses was observed and the optic nerve is hardly damaged. These findings have associations not only for understanding the amount of stresses/strains in the eye components at three different velocities, but also for providing preliminary information for the ophthalmologists to have a better diagnosis after glass shards (small objects impact) injuries to the eye. PMID- 29288710 TI - HBP induces the expression of monocyte chemoattractant protein-1 via the FAK/PI3K/AKT and p38 MAPK/NF-kappaB pathways in vascular endothelial cells. AB - Inflammation is characterized by early influx of polymorphonuclear neutrophils (PMNs), followed by a second wave of monocyte recruitment. PMNs mediate monocyte recruitment via their release of heparin binding protein (HBP), which activates CCR2 (CC-chemokine receptor 2) on monocytes. However, the pathways for such signal transmission remain unknown. Accumulating evidences have highlighted the importance of leukocyte-endothelial cell interactions in the initiation of inflammation. In this study, an interesting finding is that HBP enhances the secretion of monocyte chemotactic protein 1(MCP-1), ligand of CCR2, from a third party, the endothelial cells (ECs). HBP-induced increase in MCP-1 production was demonstrated at the protein, mRNA and secretion levels. Exposure of ECs to HBP elicited rapid phosphorylation of FAK/PI3K/AKT and p38 MAPK/NF-kappaB signaling. MCP-1 levels were attenuated during the response to HBP stimulation by pretreatment with a FAK inhibitor (or siRNA), a PI3K inhibitor, an AKT inhibitor, a p38 inhibitor (or siRNA) and two NF-kappaB inhibitors. Additionally, pretreatment with inhibitors to FAK, PI3K and AKT led to a decrease in HBP induced phosphorylation of p38/NF-kappaB axis. These results showed that HBP induced MCP-1 expression via a sequential activation of the FAK/PI3K/AKT pathway and p38 MAPK/NF-kappaB axis. Interestingly, the patterns of HBP regulation of the expression of the adhesion molecular VCAM-1 were similar to those seen in MCP-1 after pretreatment with inhibitors (or not). These findings may help to determine key pharmacological points of intervention, thus slowing the progress of inflammatory-mediated responses in certain diseases where inflammation is detrimental to the host. PMID- 29288711 TI - Whole genome sequence of Auricularia heimuer (Basidiomycota, Fungi), the third most important cultivated mushroom worldwide. AB - Heimuer, Auricularia heimuer, is one of the most famous traditional Chinese foods and medicines, and it is the third most important cultivated mushroom worldwide. The aim of this study is to develop genomic resources for A. heimuer to furnish tools that can be used to study its secondary metabolite production capability, wood degradation ability and biosynthesis of polysaccharides. The genome was obtained from single spore mycelia of the strain Dai 13782 by using combined high throughput Illumina HiSeq 4000 system with the PacBio RSII long-read sequencing platform. Functional annotation was accomplished by blasting protein sequences with different public available databases to obtain their corresponding annotations. It is 49.76Mb in size with a N50 scaffold size of 1,350,668bp and encodes 16,244 putative predicted genes. This is the first genome-scale assembly and annotation for A. heimuer, which is the third sequenced species in Auricularia. PMID- 29288712 TI - A taxonomy has been developed for outcomes in medical research to help improve knowledge discovery. AB - OBJECTIVES: There is increasing recognition that insufficient attention has been paid to the choice of outcomes measured in clinical trials. The lack of a standardized outcome classification system results in inconsistencies due to ambiguity and variation in how outcomes are described across different studies. Being able to classify by outcome would increase efficiency in searching sources such as clinical trial registries, patient registries, the Cochrane Database of Systematic Reviews, and the Core Outcome Measures in Effectiveness Trials (COMET) database of core outcome sets (COS), thus aiding knowledge discovery. STUDY DESIGN AND SETTING: A literature review was carried out to determine existing outcome classification systems, none of which were sufficiently comprehensive or granular for classification of all potential outcomes from clinical trials. A new taxonomy for outcome classification was developed, and as proof of principle, outcomes extracted from all published COS in the COMET database, selected Cochrane reviews, and clinical trial registry entries were classified using this new system. RESULTS: Application of this new taxonomy to COS in the COMET database revealed that 274/299 (92%) COS include at least one physiological outcome, whereas only 177 (59%) include at least one measure of impact (global quality of life or some measure of functioning) and only 105 (35%) made reference to adverse events. CONCLUSIONS: This outcome taxonomy will be used to annotate outcomes included in COS within the COMET database and is currently being piloted for use in Cochrane Reviews within the Cochrane Linked Data Project. Wider implementation of this standard taxonomy in trial and systematic review databases and registries will further promote efficient searching, reporting, and classification of trial outcomes. PMID- 29288713 TI - The effects of gentamicin and penicillin/streptomycin on the electrophysiology of human induced pluripotent stem cell-derived cardiomyocytes in manual patch clamp and multi-electrode array system. AB - INTRODUCTION: Cell culture media usually contains antibiotics including gentamicin or penicillin/streptomycin (PS) to protect cells from bacterial contamination. However, little is known about the effects of antibiotics on action potential and field potential parameters in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: The present study examined the effects of gentamicin (10, 25, and 50MUg/ml) and PS (50, 100, and 200U/MUg/ml) on electrophysiological activity in spontaneously beating hiPSC-CMs using manual patch clamp and multi-electrode array. We also measured mRNA expression of cardiac ion channels in hiPSC-CMs grown in media with or without gentamicin (25MUg/ml) using reverse transcription-polymerase chain reaction. RESULTS: We recorded action potential and field potential of hiPSC-CMs grown in the presence or absence of gentamicin or PS. We also observed action potential parameters in hiPSC-CMs after short-term treatment with these antibiotics. Changes in action potential and field potential parameters were observed in hiPSC-CMs grown in media containing gentamicin or PS. Treatment with PS also affected action potential parameters in hiPSC-CMs. In addition, the mRNA expression of cardiac sodium and potassium ion channels was significantly attenuated in hiPSC-CMs grown in the presence of gentamicin (25MUg/ml). DISCUSSION: The present findings suggested that gentamicin should not be used in the culture media of hiPSC-CMs used for the measurement of electrophysiological parameters. Our findings also suggest that 100U/100MUg/ml of PS are the maximum appropriate concentrations of these antibiotics for recording action potential waveform, because they did not influence action potential parameters in these cells. PMID- 29288714 TI - Phyllaciduloids A-D: Four new cleistanthane diterpenoids from Phyllanthus acidus (L.) Skeels. AB - Four new cleistanthane diterpenoids, phyllaciduloids A-D (1-4), were isolated from the roots and stems of Phyllanthus acidus (L.) Skeels (Phyllanthaceae). Their structures were elucidated on the basis of extensive spectroscopic analysis. Phyllaciduloids B-D (2-4) present in their structures with ether bond between C-7 and C-16, which were rarely reported. All the isolates were evaluated for their cytotoxic activities against five human cancer cell lines. PMID- 29288715 TI - Inflammation and neutrophil immunosenescence in health and disease: Targeted treatments to improve clinical outcomes in the elderly. AB - Despite increasing longevity, many old people are not in good health. There has been an increase in the prevalence of age-associated multi-morbidity (two or more chronic conditions in the same person). Also, severe infections, such as pneumonia, remain significant causes of mortality and morbidity in this aging group. Many chronic health conditions share risk factors such as increasing age, smoking, a sedentary life style and being part of a lower socioeconomic group. However, despite this, multi-morbidities often co-occur more commonly than would be predicted. This has led to the hypothesis that they share common underlying mechanisms. This is an important concept, for if it were true, treatments could be devised which target these common pathways and improve a number of age associated health conditions. Many chronic illnesses associated with multi morbidity and severe infections are characterized by an abnormal and sustained inflammatory response, with neutrophils being key effector cells in the pathological process. Studies have described aberrant neutrophil functions across these conditions, and some have highlighted potential mechanisms for altered cell behaviours which appear shared across disease states. It has been suggested that altered functions may represent neutrophil "senescence". This review considers how and why neutrophil functions change as the cell ages, and how and why neutrophil functions change as the host ages in health and disease and discusses whether neutrophil functions could be targeted to improve health outcomes in older adults. PMID- 29288717 TI - Ventilator-derived dynamic respiratory system compliance: Comparison with static compliance in children. AB - Measurement of dynamic lung compliance during breathing requires measurement of esophageal pressure, whereas static respiratory system compliance (Crs) method requires several airway occlusions. Despite their precision these compliance methods are cumbersome and not suitable for evaluation of pulmonary system in intensive care. The current ventilators display dynamic Crs, which, however, is seldom utilized in clinical practice. We studied the feasibility of ventilator derived dynamic Crs measurement in pulmonary evaluation after congenital cardiac surgery in children. In 50 children static Crs was measured by double-occlusion technique, and compared with simultaneous ventilator-derived dynamic Crs values. The early postoperative dynamic and static Crs showed a correlation (r = 0.57, p < 0.0001), but static Crs was 48% higher than dynamic (p < 0.0001). Dynamic Crs measurement showed no correlation with radiographic lung edema findings, whereas the static Crs showed a negative correlation with radiographic lung edema scoring (r = -0.50, p = 0.0002). Thus ventilator-derived dynamic Crs seems less reliable in postoperative pulmonary evaluation than static Crs. PMID- 29288718 TI - Kruppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity. AB - Regulation of nutrient intake, utilization, and storage exhibits a circadian rhythmicity that allows organisms to anticipate and adequately respond to changes in the environment across day/night cycles. The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important modulators of metabolism and metabolic health - for example, their catabolism yields carbon substrates for gluconeogenesis during periods of fasting. Kruppel-like factor 15 (KLF15) has recently emerged as a critical transcriptional regulator of BCAA metabolism, and the absence of this transcription factor contributes to severe pathologies such as Duchenne muscular dystrophy and heart failure. This review highlights KLF15's role as a central regulator of BCAA metabolism during periods of fasting, throughout day/night cycles, and in experimental models of muscle disease. PMID- 29288719 TI - Safety assessment of methanolic extract of Terminalia chebula fruit, Terminalia arjuna bark and its bioactive constituent 7-methyl gallic acid: In vitro and in vivo studies. AB - Terminalia chebula and Terminalia arjuna were widely used in traditional medicine for the treatment of memory impairment, inflammatory disorders and as an anti aging agent. However, reports regarding their safety aspects are lacking. Hence, the present study was carried out to investigate the toxicity of methanolic extracts of Terminalia chebula fruit (TCF), Terminalia arjuna bark (TAB) and its bioactive constituent 7- Methyl gallic acid (7MG) under in vitro and in vivo conditions. In vitro toxicity profile of TCF, TAB and 7MG (250-2000 MUg/ml) were assessed through cytotoxicity, hemolytic activity, mutagenicity and genotoxicity assays. Results of Ames test, comet assay, MTT and hemolytic assays illustrated that TCF, TAB and 7MG exhibited neither cytotoxic and genotoxic effect in PBMC nor hemolytic activity in RBC and no mutagenic effect in TA 98 and TA 100 up to a limited dose of 2000 MUg/ml. Acute and subacute toxicity studies showed no significant change in body weight, behavior, hematology, biochemical parameters, organ weight and histopathology. Over all the results of acute and subacute toxicity studies conclude that oral administration of TCF, TAB and 7MG were observed to be relatively non-toxic and affords practical guidance for selecting safe dose for further clinical trials. PMID- 29288716 TI - Thrombospondin-1 regulation of latent TGF-beta activation: A therapeutic target for fibrotic disease. AB - Transforming growth factor-beta (TGF-beta) is a central player in fibrotic disease. Clinical trials with global inhibitors of TGF-beta have been disappointing, suggesting that a more targeted approach is warranted. Conversion of the latent precursor to the biologically active form of TGF-beta represents a novel approach to selectively modulating TGF-beta in disease, as mechanisms employed to activate latent TGF-beta are typically cell, tissue, and/or disease specific. In this review, we will discuss the role of the matricellular protein, thrombospondin 1 (TSP-1), in regulation of latent TGF-beta activation and the use of an antagonist of TSP-1 mediated TGF-beta activation in a number of diverse fibrotic diseases. In particular, we will discuss the TSP-1/TGF-beta pathway in fibrotic complications of diabetes, liver fibrosis, and in multiple myeloma. We will also discuss emerging evidence for a role for TSP-1 in arterial remodeling, biomechanical modulation of TGF-beta activity, and in immune dysfunction. As TSP 1 expression is upregulated by factors induced in fibrotic disease, targeting the TSP-1/TGF-beta pathway potentially represents a more selective approach to controlling TGF-beta activity in disease. PMID- 29288720 TI - Applicability of surface sampling and calculation of surface limits for pharmaceutical drug substances for occupational health purposes. AB - Within the context of Occupational Hygiene (OH), surface sampling has been employed as a method to assess surface levels of Active Pharmaceutical Ingredients (APIs). There are potentially a number of reasons surface samples are collected including assessing potential health risks, housekeeping and cleaning effectiveness. There are no internationally accepted standards relating to collecting or interpreting surface samples for OH purposes. In the past, surface sampling results have been applied not only for estimating risks due to dermal contact, but also for other routes of exposure (e.g. inhalation, ingestion, etc). In this publication, we provide a decision tree to support the decision and value of performing surface sampling. For scenarios without conceivable skin exposure due to applied risk mitigation measures or for substances that do not penetrate the skin, surface sampling may not be needed. If the workers' health is determined to be at risk for systemic effects via skin, we propose to use the skin Permitted Daily Exposure (PDEskin), a safe skin dose independent of the exposure scenario that takes into consideration skin absorption properties of substances. For the purpose of OH monitoring, the likelihood of dermal exposure has to be understood before taking any samples, using both the PDEskin to calculate the surface limit and appropriate validated monitoring method for the surface. PMID- 29288721 TI - Treatment of beta-thujaplicin counteracts di(2-ethylhexyl)phthalate (DEHP) exposed vascular smooth muscle activation, inflammation and atherosclerosis progression. AB - The initiation of atherosclerosis involves up-regulation of molecules such as E selectin, VCAM-1, and ICAM-1. The progression of atherosclerosis is linked to proliferation and migration of vascular smooth muscle cell via MMP-2 and MMP-9 activities. However, the etiology of atherosclerosis concerning plasticizers is unknown. We evaluated beta-thujaplicin in preventing the development of atherosclerosis in a model induced by pro-inflammatory cytokines. Moreover, we established a new atherosclerosis model in vascular smooth muscle cells (VSMC) exposed to a common contact plasticizer, di(2-ethylhexyl)phthalate (DEHP). SEVC4 10 endothelial cells were treated with 50% RAW conditioned medium and A7r5 VSMC was treated with the plasticizer, with/without beta-thujaplicin (4 or 12 MUM). Production of E-selectin, ICAM-1, and VCAM-1 in SEVC4-10 cells as well as MMP 2/MMP-9 (both expression and activity) in VSMC were monitored. Results showed that the conditioned medium induced E-selectin and ICAM were significantly prevented by beta-thujaplicin. However, inhibition on the production of VCAM by beta-thujaplicin was only seen in a concentration of 12 MUM. Both concentrations of beta-thujaplicin also significantly prevented DEHP-induced MMP-2 and MMP-9 expression and activities. Evidence uncovers that beta-thujaplicin has additional factors in amelioration of atherosclerosis and corroborates that beta-thujaplicin is a strong candidate in preventing the initiation and progression of atherosclerosis. PMID- 29288723 TI - Intravenous colistin combination antimicrobial treatment vs. monotherapy: a systematic review and meta-analysis. AB - BACKGROUND: To evaluate whether intravenous colistin in combination with other antibiotics (IVCC) is associated with lower mortality compared with intravenous colistin monotherapy (IVCM), and to identify factors influencing study outcomes. METHODS: PubMed and Scopus were searched up to November 2016. Studies were included if they evaluated adult patients with multi-drug-resistant (MDR) or extensively-drug-resistant Gram-negative infections, and reported comparative mortality data (adjusted and unadjusted) for patients receiving IVCC vs. IVCM. Random effects meta-analyses were performed. FINDINGS: Thirty-two studies (29 observational, three randomized) were included. The overall quality of data was low to very low, and studies were characterized by the lack of adjusted data. The majority of studies were not designed to evaluate the outcome of the meta analysis, and focused mainly on infections due to Acinetobacter baumannii and Klebsiella pneumoniae. Colistin was administered at variable doses, with or without a loading dose, and in combination with several antibiotics. Overall, IVCC was not associated with lower mortality than IVCM [32 studies, 2328 patients, risk ratio (RR) 0.91, 95% confidence interval (CI) 0.81-1.02, I2 8%]. A significant difference was observed in favour of IVCC when high-dose (>6 million international units) colistin was used (RR 0.80, 95% CI 0.69-0.93), in studies conducted in Asia (RR 0.82, 95% CI 0.71-0.95), in patients with bacteraemia (RR 0.75, 95% CI 0.57-0.98) and in patients with acinetobacter infections (RR 0.88, 95% CI 0.78-1.00). INTERPRETATION: Overall, low-quality data suggest that IVCC did not lower mortality in patients with MDR Gram-negative infections. However, there is some evidence for a benefit observed with high intravenous doses of colistin. PMID- 29288722 TI - Comparative analysis of phosphoethanolamine transferases involved in polymyxin resistance across 10 clinically relevant Gram-negative bacteria. AB - The rapid emergence of Gram-negative 'superbugs' has become a significant threat to human health globally, and polymyxins have become a last-line therapy for these very problematic pathogens. Polymyxins exhibit their antibacterial killing by initial interaction with lipid A in Gram-negative bacteria. Polymyxin resistance can be mediated by phosphoethanolamine (PEA) modification of lipid A, which abolishes the initial electrostatic interaction with polymyxins. Both chromosome-encoded (e.g. EptA, EptB and EptC) and plasmid-encoded (e.g. MCR-1 and MCR-2) PEA transferases have been reported in Gram-negative bacteria; however, their sequence and functional heterogeneity remain unclear. This article reports a comparative analysis of PEA transferases across 10 clinically relevant Gram negative bacterial species using multiple sequence alignment and phylogenetic analysis. The results show that the pairwise identities among chromosome-mediated EptA, EptB and EptC from Escherichia coli are low, and EptA shows the greatest similarity with MCR-1 and MCR-2. Among PEA transferases from representative strains of 10 clinically relevant species, the catalytic domain is more conserved compared with the transmembrane domain. In particular, PEA acceptor sites and zinc-binding pockets show high conservation between different species, indicating their potential importance for the function of PEA transferases. The evolutionary relationship of MCR-1, MCR-2 and EptA from the 10 selected bacterial species was evaluated by phylogenetic analysis. Cluster analysis illustrates that 325 EptA from 275 strains of 10 species within each individual species are highly conserved, whereas interspecies conservation is low. This comparative analysis provides key bioinformatic information to better understand the mechanism of polymyxin resistance via PEA modification of lipid A. PMID- 29288724 TI - Serum Fetuin-A Levels in Patients with Bilateral Basal Ganglia Calcification. AB - BACKGROUND AND PURPOSE: The idiopathic basal ganglia calcification (Fahr syndrome) may occur due to senility. Fetuin-A is a negative acute phase reactant which inhibits calcium-phosphorus precipitation and vascular calcification. In this study, we aimed to evaluate whether serum fetuin-A levels correlate with bilateral basal ganglia calcification. METHOD: Forty-five patients who had bilateral basal ganglia calcification on brain CT were selected according to the inclusion and exclusion criteria, and 45 age and gender-matched subjects without basal ganglia calcification were included for the control group. Serum fetuin-A levels were measured from venous blood samples. All participants were divided into two groups; with and without basal ganglia calcification. These groups were divided into subgroups regarding age (18-32 and 33-45 years of age) and gender (male, female). RESULTS: We detected lower levels of serum fetuin-A in patients with basal ganglia calcification compared with the subjects without basal ganglia calcification. In all subgroups (female, male, 18-32 years and 33-45 years), mean fetuin-A levels were significantly lower in patients with basal ganglia calcification (p = 0.017, p = 0.014, p = 0.024, p = 0.026, p = 0.01 respectively). And statistically significantly lower levels of fetuin-A was found to be correlated with the increasing densities of calcification in the calcified basal ganglia group (p-value: <0.001). CONCLUSION: Considering the role of fetuin A in tissue calcification and inflammation, higher serum fetuin-A levels should be measured in patients with basal ganglia calcification. We believe that the measurement of serum fetuin-A may play a role in the prediction of basal ganglia calcification as a biomarker. PMID- 29288725 TI - Both ketamine and NBQX attenuate alcohol drinking in male Wistar rats. AB - The devastating consequences of alcohol-use disorder (AUD) on the individual and the society are well established. Current treatments of AUD encompass various strategies, all of which have only modest effectiveness. Hence, there is a critical need to develop more efficacious therapies. Recently, specific glutamatergic receptors have been identified as potential novel targets for intervention in AUD. Thus, the current study was designed to evaluate the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, as well as NBQX, an AMPA/kainate receptor antagonist on alcohol intake and its possible behavioural consequences. Adult male Wistar rats were trained in drinking in dark paradigm (3 weeks), and following stable alcohol intake, ketamine, NBQX as well as their combination were injected prior to a 90 min drinking session. In addition to alcohol intake, sucrose preference (overnight), and locomotor activity and forced swim test (FST) were also evaluated before and following alcohol intake. Both doses of ketamine (5 and 10 mg/kg) and NBQX (5 and 10 mg/kg) significantly attenuated percent alcohol intake. The combination of the higher dose of ketamine and NBQX, however, did not significantly affect percent alcohol intake. Moreover, animals exposed to alcohol showed decreased sucrose intake (reflective of anhedonia), decreased locomotor activity and swimming in the FST (reflective of helplessness), that were not affected by ketamine and/or NBQX. These results suggest that selective antagonism of the NMDA or AMPA/kainate receptors may be of therapeutic potential in AUD. PMID- 29288726 TI - Phenylethanolamine N-methyltransferase gene expression in PC12 cells exposed to intermittent hypoxia. AB - Epidemiological studies show a strong correlation between Obstructive Sleep Apnea (OSA) and cardiovascular disorders. OSA patients experience intermittent hypoxia (IH), characterized by brief, but recurring episodes of cessation in breathing. These patients have higher levels of circulating catecholamines and an increased incidence of hypertension; however the mechanisms defining this association are not clearly established. Genetic linkage studies have associated the phenylethanolamine N-methyltransferase (PNMT) gene to the development of hypertension. PNMT, the terminal enzyme in the catecholamine biosynthetic pathway, directly responsible for adrenaline synthesis, is elevated in hypertensive animals. Recent studies utilizing PC12 cells show an increase in the expression of PNMT and its regulatory transcription factors when exposed to continuous hypoxia. The current study examined the regulation of PNMT under conditions of IH. The mRNA of PNMT was analyzed to assess if the regulation of PNMT expression entails alternative splicing. The mRNA and protein of transcription factors HIF1alpha, Egr-1, GR, and Sp1, were analyzed to assess the cellular pathways involved in regulating PNMT expression. A PNMT promoter-driven luciferase assay was performed to evaluate promoter activity under IH. Preliminary results lay an antecedent for the regulation of PNMT by IH conceivably via an altered regulation of its transcription factors and establish a possible role for PNMT in IH mediated hypertension in OSA patients. PMID- 29288727 TI - Characterization of the Es-DDX52 involved in the spermatogonial mitosis and spermatid differentiation in Chinese mitten crab (Eriocheir sinensis). AB - Spermatogenesis involves a series of process including exiting from the mitotic cell cycle, entry into meiosis, completion of complex differentiation programs, and producing spermatozoa. Expression of various genes in an ordered manner, and interactions between various genes and their protein products, primarily controlled at the post-transcriptional level with DEAD-box RNA helicases playing a crucial role in germ cell development, are required for production of fertile sperm. Many members of this family have been deeply studied in spermatogenesis, such as DDX3X, DDX25 and DDX4, but few data are available on DDX52. In this study, we analyzed the expression patterns of Es-DDX52, Es-DDX6, Es-Vasa and Es XRN1 both at mRNA and protein levels in different tissues and during gonadal development. It showed that Es-vasa, Es-DDX6 and Es-Xrn1, components of cytoplasmic foci P-bodies, have the similar transcriptional expression pattern, while Es-DDX52 has the reverse tendency. Furthermore, Es-DDX6 and Es-XRN1 proteins have the same localization in testicular tissues. Es-DDX52 mainly distributed in the cytoplasm of spermatogonia, only localized in the nucleus of early and middle spermatid and shifted to pre-acrosome vesicle (later developed into apical cap and acrosome tube) at both mRNA and protein levels. These results indicated that Es-DDX52 may participate in regulation of P-bodies and microtubules by Es-XRN1, and involved in the mitosis of spermatonia and spermatid differentiation. PMID- 29288728 TI - The rs243866/243865 polymorphisms in MMP-2 gene and the relationship with BP control in obese resistant hypertensive subjects. AB - We sought to investigate whether the polymorphisms rs243865 (-1306C>T); rs243866 (-1575G>A) and rs2285053 (-735C>T) in metalloproteinases 2 - MMP-2 gene and rs17576 (Q279R), rs17577 (Q668R) and rs3918242 (-1562C>T) in MMP-9 gene are associated with clinical outcomes in obese resistant hypertensive (RH) subjects. One hundred and twenty RH were enrolled in this cross-sectional study and divided into obese (n=63) and non-obese (n=57) according to body mass index. Genotypes were determined by real-time PCR using TaqMan probes. We determined pulse wave velocity (PWV), microalbuminuria and left ventricular mass index (LVMI) to assess TODs. Obese and non-obese RH had similar allele, genotype and haplotype distributions for all polymorphisms assessed but obese RH subjects carrying the low frequency allele for SNPs in MMP-2 gene had higher ambulatory diastolic blood pressure. Also, PWV and LVMI were higher in subjects carrying the low frequency allele for SNPs in MMP-2 gene. Regarding MMP-9 gene, office diastolic BP levels were higher in the AA genotype individuals compared to the G allele group for rs17576 polymorphism, while the opposite was found regarding the microalbuminuria level. Independent multiple linear regression analyses revealed that both A allele for rs243865 and T allele for rs243866 in MMP-2 gene were associated with ambulatory diastolic levels in obese RH subjects, apart from potential confounders. Our study suggests that rs243866/rs243865 in the MMP-2 gene are related to BP levels in obese RH subjects, although TODs present in this population seem to be dependent of a combination of other factors besides the genetic polymorphisms. PMID- 29288729 TI - Extracellular vesicles or free circulating DNA: where to search for BRAF and cKIT mutations? AB - Clinical evidence in oncology argues for the advantages of performing molecular analysis of blood biomarkers to provide information about systemic changes and tumor heterogeneity. Whereas the diagnostic value of cell-free circulating DNA (fcDNA) has successfully been demonstrated in several studies, DNA enclosed in extracellular vesicles (EV) has only recently been described, and its potential diagnostic value is unclear. We established a protocol for separation of EV and fc fractions and tested for presence of mutant BRAFV600E mediating resistance to Vemurafenib and cKITD816V mediating resistance to Imatinib in blood of patients with melanoma and mastocytosis. Our results show that EV contain significantly higher amounts of total DNA as compared to the fc fraction. However, about ten fold higher copy numbers of the wild type and mutant BRAF and cKIT were detected in the fcDNA fraction supporting its diagnostic value and pointing to differences in fc and EV DNA content. PMID- 29288731 TI - Expression and characterization of the Renilla luciferase with the cumulative mutation. AB - Luciferase from Renilla reniformis (RLuc) is a good research tool as a reporter protein and bioimaging probes, yielding blue light using the substrate coelenterazine. However, the applications are limited since RLuc is unstable under various conditions. Therefore, an attempt was made to increase RLuc thermostability. In this study, 5 mutations reported previously [1] and one mutation obtained using site-directed mutagenesis were combined. As a result of this combination, the thermostability effect increased, with the mutant showing approximately 10 degrees C higher stability. Furthermore, the mutant simultaneously improved a tolerance for protease digestion, e.g. trypsin and proteinase K, and for organic solvent. Residual activity of the mutant after treatment with 10% 2-propanol, 10% DMF and 20% DMSO at 35 degrees C for 1 h was 29.4, 24.8 and 91.3%, respectively, whereas that of the wild type was 0.4, 0.1 and 24.3%, respectively. PMID- 29288730 TI - Sulfur dioxide exposure enhances Th2 inflammatory responses via activating STAT6 pathway in asthmatic mice. AB - Sulfur dioxide (SO2) is one of potential risk factors for induction and/or exacerbation of asthma, but the underlying mechanisms are not well understood. In this study, we investigate the role of SO2 in asthma using a classical asthmatic model with allergic airway inflammation by treating C57BL/6 mice with ovalbumin (OVA) and/or 10 mg/m3 SO2. Our results showed that SO2 exposure alone induced slight pathological changes but did not significantly increase inflammatory cell counts, pro-inflammatory cytokine expression, and mucus production in the airway of mice, whereas SO2 exposure in OVA-induced asthmatic mice caused marked pulmonary pathological changes and significantly increased the counts of eosinophil-rich leukocytes compared with OVA alone asthmatic mice. The expression of MUC5AC, TNF-alpha, Th2 cytokines (IL-4, IL-5, and IL-13) and STAT6 was further up-regulated in OVA plus SO2 treated mice compared with OVA alone treated mice. In addition, exposure to SO2 alone markedly elevated STAT6 mRNA levels and hydrogen peroxide (H2O2) content in the lung. These findings suggest that SO2 amplifies Th2 inflammatory responses in OVA-induced asthmatic mice by activating STAT6, which can further induce Th2 cytokine expression. Induction of STAT6 expression might be an important mechanism underlying the increased risk for asthma after environmental exposure. PMID- 29288732 TI - Blood derivatives awaken in regenerative medicine strategies to modulate wound healing. AB - Blood components play key roles in the modulation of the wound healing process and, together with the provisional fibrin matrix ability to selectively bind bioactive molecules and control its spatial-temporal presentation, define the complex microenvironment that characterize this biological process. As a biomimetic approach, the use of blood derivatives in regenerative strategies has awakened as a source of multiple therapeutic biomolecules. Nevertheless, and despite their clinical relevance, blood derivatives have been showing inconsistent therapeutic results due to several factors, including proper control over their delivery mechanisms. Herein, we highlight recent trends on the use biomaterials to protect, sequester and deliver these pools of biomolecules in tissue engineering and regenerative medicine approaches. Particular emphasis is given to strategies that enable to control their spatiotemporal delivery and improve the selectivity of presentation profiles of the biomolecules derived from blood derivatives rich in platelets. Finally, we discussed possible directions for biomaterials design to potentiate the aimed regenerative effects of blood derivatives and achieve efficient therapies. PMID- 29288733 TI - Ophthalmic gels: Past, present and future. AB - Aqueous gels formulated using hydrophilic polymers (hydrogels) along with those based on stimuli responsive polymers (in situ gelling or gel forming systems) continue to attract increasing interest for various eye health-related applications. They allow the incorporation of a variety of ophthalmic pharmaceuticals to achieve therapeutic levels of drugs and bioactives at target ocular sites. The integration of sophisticated drug delivery technologies such as nanotechnology-based ones with intelligent and environment responsive systems can extend current treatment duration to provide more clinically relevant time courses (weeks and months instead of hours and days) which will inevitably reduce dose frequency, increase patient compliance and improve clinical outcomes. Novel applications and design of contact lenses and intracanalicular delivery devices along with the move towards integrating gels into various drug delivery devices like intraocular pumps, injections and implants has the potential to reduce comorbidities caused by glaucoma, corneal keratopathy, cataract, diabetic retinopathies and age-related macular degeneration. This review describes ophthalmic gelling systems with emphasis on mechanism of gel formation and application in ophthalmology. It provides a critical appraisal of the techniques and methods used in the characterization of ophthalmic preformed gels and in situ gelling systems along with a thorough insight into the safety and biocompatibility of these systems. Newly developed ophthalmic gels, hydrogels, preformed gels and in situ gelling systems including the latest in the area of stimuli responsive gels, molecularly imprinted gels, nanogels, 3D printed hydrogels; 3D printed devices comprising ophthalmic gels are covered. Finally, new applications of gels in the production of artificial corneas, corneal wound healing and hydrogel contact lenses are described. PMID- 29288734 TI - 17beta-estradiol (E2) promotes growth and stability of new dendritic spines via estrogen receptor beta pathway in intact mouse cortex. AB - The steroid hormone 17beta-estradiol (E2) remodels neural circuits at the synaptic level in the mammalian hippocampus and cortex. However, the underlying mechanism of synapse dynamics remains unclear. To elucidate the mechanism, we traced individual dendritic spines on layer V pyramidal neurons of the primary sensory cortex in adult female mice under E2 intervention using two-photon in vivo imaging microscopy. We confirmed the increase of the spine density upon E2 treatment in the intact mouse cortex. Furthermore, we found that this increase is due to the promotion of spine formation and the stability of newly formed spines. E2 treatment doesn't alter the elimination rate of pre-existing spines. Our results also indicate that the activation of the estrogen receptor beta (ERbeta) mimics the effects of E2 administration on spine dynamics. Taken together, our findings suggest that estrogen promotes growth and stability of new dendritic spines via the ERbeta pathway in the intact cortex of female mice. PMID- 29288735 TI - Myelin changes at the early stage of 5XFAD mice. AB - Previous studies have demonstrated myelin deficits in Alzheimer's disease (AD). However, it is still unclear whether myelin deficits occur at early stage of AD. Our study aimed to investigate myelin deficits in 5XFAD mice dynamically in different cognition-associated brain regions at early stage of AD. Transmission electron microscopy (TEM) was applied to detect myelin changes in late myelinating regions such as prelimbic area (PrL), retrosplenial granular cortex (Rsg), field CA1 of hippocampus (CA1) and entorhinal cortex (ERC) respectively at different stages (1, 2, 3 and 5 months of age) in 5XFAD mouse model. In addition, we assessed spatial learning and memory with Morris water maze (MWM) in 5XFAD mice. Myelin deficits in 5XFAD mice started from 1 month of age and this deterioration continued during ageing, whereas the same myelin abnormality could only be observed in 5-month-old wild-type mice. Additionally, the g-ratio (an index associated with myelin thickness) was increased in 1-month-old 5XFAD mice in the regions including PrL, CA1 and ERC, compared to wild-type mice. As animals aged, the increased g-ratio in 5XFAD appeared in more regions of the brain. Moreover, 5XFAD mice showed spatial memory deficits from 1 month of age and spatial learning deficits from 2 months of age. In conclusion, myelin deficits occurred at an early stage and progressed with ageing in 5XFAD mouse model. Notably, a sequential myelin change was detected in cognition-associated brain regions. Combined with cognitive examinations, this study suggests that myelin changes might contribute to cognitive dysfunction. PMID- 29288736 TI - Isolated Fallopian Tube Torsion Presenting as Acute Pelvic Pain. PMID- 29288737 TI - Robotic-Assisted Laparoscopic Abdominal Cerclage Placement During Pregnancy. AB - STUDY OBJECTIVE: The objective of this study is to report our center's series of robotic-assisted laparoscopic abdominal cerclage (RALAC) placement during pregnancy. DESIGN: Descriptive study (Canadian Task Force classification III). SETTING: Single academic institution. PATIENTS: Patients undergoing RALAC placement during pregnancy. INTERVENTIONS: Eleven patients underwent RALAC. MEASUREMENTS AND MAIN RESULTS: Nine out of 11 (81.8%) primary RALAC procedures resulted in a viable live-born neonate; 8 (72.7%) were born at >34 weeks of gestation. Three patients (27.3%) had preterm premature rupture of membranes on postoperative day one, 2 of whom subsequently underwent a dilation and curettage, and 1 patient carried the pregnancy to 29 weeks and delivered a live-born neonate. Four patients had subsequent pregnancies after placement of a RALAC in the antepartum period, all of whom carried successfully beyond 36 weeks, for a total of 16 pregnancies. Fourteen pregnancies (87.5%) resulted in a live birth, and 13 pregnancies (81.3%) were delivered beyond 34 weeks. CONCLUSION: RALAC is a minimally invasive procedure with an acceptable risk profile and comparable efficacy to traditional open abdominal cerclage. RALAC may be considered an acceptable alternative to open abdominal cerclage in pregnancy, and may be a particularly favorable option in certain settings. PMID- 29288738 TI - Vacuole Integrity Maintained by DUF300 Proteins Is Required for Brassinosteroid Signaling Regulation. AB - Brassinosteroid (BR) hormone signaling controls multiple processes during plant growth and development and is initiated at the plasma membrane through the receptor kinase BRASSINOSTEROID INSENSITIVE1 (BRI1) together with co-receptors such as BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1). BRI1 abundance is regulated by endosomal recycling and vacuolar targeting, but the role of vacuole-related proteins in BR receptor dynamics and BR responses remains elusive. Here, we show that the absence of two DUF300 domain-containing tonoplast proteins, LAZARUS1 (LAZ1) and LAZ1 HOMOLOG1 (LAZ1H1), causes vacuole morphology defects, growth inhibition, and constitutive activation of BR signaling. Intriguingly, tonoplast accumulation of BAK1 was substantially increased and appeared causally linked to enhanced BRI1 trafficking and degradation in laz1 laz1h1 plants. Since unrelated vacuole mutants exhibited normal BR responses, our findings indicate that DUF300 proteins play distinct roles in the regulation of BR signaling by maintaining vacuole integrity required to balance subcellular BAK1 pools and BR receptor distribution. PMID- 29288739 TI - Mapping the residual incidence of taeniasis and cysticercosis in Colombia, 2009 2013, using geographical information systems: Implications for public health and travel medicine. AB - BACKGROUND: In Colombia, taeniasis and cysticercosis have been significantly reduced over the past decades, however still reported with implications for public health and travel medicine. METHODS: An observational, retrospective study, in which the incidence of taeniasis and cysticercosis (ICD-10 codes B68s/B69s) in Colombia, 2009-2013, was estimated based on data extracted from the Individual Health Records System (Registro Individual de Prestacion de Servicios, RIPS) was performed. The Geographic Information System (GIS) generated national maps showing the distribution of taeniasis and cysticercosis by department by year. RESULTS: During the period, 3626 cases were reported (median 796/year), for a cumulative crude national rate of 7.7 cases/100,000pop; 58.2% corresponded to male; 57% were <40 year-old (10.2% < 9.9 year-old). Cases were 57.6% neurocysticercosis, the rest were taeniasis due to T. solium, T. saginata, ocular cysticercosis and cysticerci in other organs. Bolivar, a touristic department, had the highest cumulated incidence rate (16.17 cases/100,000pop), as also evident across the map series developed in this study. CONCLUSION: Despite the limitations of this study, data presented provide recent estimates of national taeniasis and cysticercosis incidence in the country useful in public health and for travel medicine practitioners, as some highly touristic areas presented higher disease incidence. Improved control, particularly of taeniasis, should be an attainable goal, which among other strategies would require improved sanitation and health education to prevent transmission, but also enhanced surveillance. PMID- 29288740 TI - Rationale, design and pilot feasibility results of a smartphone-assisted, mindfulness-based intervention for smokers with mood disorders: Project mSMART MIND. AB - BACKGROUND: Although individuals with psychiatric disorders are disproportionately affected by cigarette smoking, few outpatient mental health treatment facilities offer smoking cessation services. In this paper, we describe the development of a smartphone-assisted mindfulness smoking cessation intervention with contingency management (SMI-CM), as well as the design and methods of an ongoing pilot randomized controlled trial (RCT) targeting smokers receiving outpatient psychiatric treatment. We also report the results of an open label pilot feasibility study. METHODS: In phase 1, we developed and pilot-tested SMI-CM, which includes a smartphone intervention app that prompts participants to practice mindfulness, complete ecological momentary assessment (EMA) reports 5 times per day, and submit carbon monoxide (CO) videos twice per day. Participants earned incentives if submitted videos showed CO<=6ppm. In phase 2, smokers receiving outpatient treatment for mood disorders are randomized to receive SMI CM or enhanced standard treatment plus non-contingent CM (EST). RESULTS: The results from the pilot feasibility study (N=8) showed that participants practiced mindfulness an average of 3.4times/day (>=3min), completed 72.3% of prompted EMA reports, and submitted 68.0% of requested CO videos. Participants reported that the program was helpful overall (M=4.85/5) and that daily mindfulness practice was helpful for both managing mood and quitting smoking (Ms=4.50/5). CONCLUSIONS: The results from the feasibility study indicated high levels of acceptability and satisfaction with SMI-CM. The ongoing RCT will allow evaluation of the efficacy and mechanisms of action underlying SMI-CM for improving cessation rates among smokers with mood disorders. PMID- 29288741 TI - Optimization of washing conditions with biogenic mobilizing agents for marine fuel-contaminated beach sands. AB - Washing is a rapid and effective treatment to remediate contaminated sands impacted by oil spills, although synthetic additives used to increase extraction efficiency may cause additional pollution issues due to their intrinsic toxicity and very often low biodegradability. In this study, different biogenic mobilizing agents (soybean lecithins, cyclodextrins, cholic acids, plant-derived cleaners, rhamnolipids and sophorolipids) were tested in the washing of beach sands artificially contaminated with the Intermediate Fuel Oil IFO-180. Among these, a de-oiled soybean lecithin (SL-1), hydroxypropyl-beta-cyclodextrins (HPB-CD) and sophorolipids (SR) achieved hydrocarbon removals close to those attained with the synthetic surfactant TritonTM X-100 (TX) in preliminary washing tests carried out at constant mixing rate, water/sand ratio and IFO-180 contamination level using agents concentrations close to their critical micelle concentration (0.1% and 1% w/v for microbial and non-microbial agents, respectively). The effects of agent concentration, water/sand ratio, mixing rate and IFO-180 contamination on hydrocarbons removal were modelled using face-centred central composite design and ANOVA. Optimal washing parameters for sand contamination levels in the range 0.5-20 g/kg were identified with response surface methodology. While HPB-CD and SR performed equally to TX only at low sand contaminations, SL-1 attained hydrocarbon removal higher or equal to that of TX at any IFO-180 contamination and at lower application rates. SL-1 also outperformed TX when minimizing the water/sand ratio, i.e., the volume of water used. Considering its lower toxicity, higher biodegradability and higher hydrocarbon removal efficiencies, SL-1 is an effective and environmentally sustainable alternative to synthetic surfactants in washing treatments for marine fuel-contaminated sands. PMID- 29288742 TI - The research of the possible mechanism and the treatment for capsaicin-induced cough. AB - Unexplained chronic cough (UCC) affects millions of patients worldwide. New therapeutic approaches to this condition are urgently needed, since current treatment options provide only symptomatic relief. Cough reflex hypersensitivity has been shown to play an important role in the pathogenesis of UCC. The transient receptor potential vanilloid type 1 (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological treatment of UCC. The aim of this study was to explore the efficacy and the possible mechanism of SB705498, a TRPV1 antagonist, for cough in a capsaicin-induced cough animal model (i.e. guinea pigs). Induction of cough by capsaicin was successfully implemented in the guinea pigs, and the animals that met the inclusion criteria were randomly divided into four treatment groups: (1) Saline inhalation group (NSInh group, N = 10, negative control group), (2) Codeine phosphate intraperitoneal injection group (CPInp group, N = 10, positive control group), (3) SB705498 inhalation group (SBInh group, N = 10), (4) SB705498 intragastric administration group (SBIng group, N = 10). After treatment with above compounds, the capsaicin-induced cough experiment was performed again. The cough numbers and the cough incubation periods were recorded to evaluate the antitussive effect of SB705498. Enzyme-linked immunosorbent assay (ELISA) testing and Immunohistochemistry (IHC) staining for substance P (SP), calcitonin gene related peptide (CGRP) and neurokinin A (NKA) expression in lung and brain tissues were performed as an indication of neurogenic inflammation. Hematoxylin-Eosin (H&E) staining was used to observe the pathology morphology of lung and brain tissues. When the CPInp, SBInh and SBIng groups were compared to the NSInh group, the cough numbers were significantly reduced (p < .001), while the cough incubation periods were significantly prolonged (P < .001). In addition, the expression of SP, CGRP and NKA in lung and brain tissue was reduced (P < .05). None of the animals in the four groups exhibited lung and brain parenchymal inflammation. The results from this study showed that SB705498 had a significant antitussive effect, could reduce the neurogenic inflammation by reducing the expression of SP, CGRP and NKA in a capsaicin-induced cough model of guinea pigs. The results further indicated that TRPV1 played an important role in UCC and SB705498 might be a promising therapeutic agent for UCC. PMID- 29288743 TI - The good and bad faces of the CXCR4 chemokine receptor. AB - Chemokines are chemotactic cytokines that promote cell migration and activation under homeostatic and inflammatory conditions. Chemokines bind to seven transmembrane-spanning receptors that are coupled to heterotrimeric guanine nucleotide-binding (G) proteins, which are the responsible for intracellularly transmitting the activating signals for cell migration. Hematopoiesis, vascular development, lymphoid organ morphogenesis, cardiogenesis and neural differentiation are amongst the processes involving chemokine function. In addition, immune cell trafficking from bone marrow to blood circulation, and from blood and lymph to lymphoid and inflamed tissues, is tightly regulated by chemokines both under physiological conditions and also in autoimmune diseases. Furthermore, chemokine binding to their receptors stimulate trafficking to and positioning of cancer cells into target tissues and organs during tumour dissemination. The CXCL12 chemokine (also known as stromal-cell derived factor 1alpha, SDF-1alpha) plays key roles in hematopoiesis and lymphoid tissue architecture, in cardiogenesis, vascular formation and neurogenesis, as well as in the trafficking of solid and hematological cancer cell types. CXCL12 binds to the CXCR4 receptor, a multi-facetted molecule which tightly mirrors CXCL12 functions in homeostasis and disease. This review addresses the important roles of the CXCR4-CXCL12 axis in homeostasis, specially focusing in hematopoiesis, as well as it provides a picture of CXCR4 as mediator of cancer cell spreading, and a view of the available CXCR4 antagonists in different cancer types. PMID- 29288744 TI - Metabolic suppression in the pelagic crab, Pleuroncodes planipes, in oxygen minimum zones. AB - The pelagic red crab, Pleuroncodes planipes, is abundant throughout the Eastern Tropical Pacific in both benthic and pelagic environments to depths of several hundred meters. The oxygen minimum zones in this region reaches oxygen levels as low as 0.1kPa at depths within the crabs vertical range. Crabs maintain aerobic metabolism to a critical PO2 of ~0.27+/-0.2kPa (10 degrees C), in part by increasing ventilation as oxygen declines. At subcritical oxygen levels, they enhance anaerobic ATP production slightly as indicated by modest increases in lactate levels. However, hypoxia tolerance is primarily mediated via a pronounced suppression of aerobic metabolism (~70%). Metabolic suppression is achieved, primarily, via reduced protein synthesis, which is a major sink for metabolic energy. Posttranslational modifications on histone H3 suggest a condensed chromatin state and, hence, decreased transcription. Under hypoxia, p-H3S10, Ac H3K9, Ac-H3K14 were 39, 68, and 36% of control values, respectively. We also report a net decrease in protein translation. In particular, eEF2 activity is reduced due to a ~5-fold increase in inhibitory phosphorylation and a significant decrease in protein level. Elevated heat shock proteins suggest that, despite impressive tolerance, the cellular stress response is triggered during hypoxia. We discuss the implications for pelagic ecology and biogeochemical cycles. PMID- 29288745 TI - A translational approach to the genetics of anxiety disorders. AB - There have been important advances in our understanding of the genetic architecture of anxiety disorders. At the same time, relatively few genes have reached genome wide significance in anxiety disorders, and there is relatively little work on how exposure to an adverse environment impacts on gene expression in either animal models or human clinical populations. Here we assessed differential expression of genes of the dorsal striatum involved in synaptic transmission in an animal models of early adversity (maternal separation followed by restraint stress), and investigated whether variants in these genes were associated with risk for anxiety disorders, particularly in the presence of environmental stressors. Fifty-two male Sprague Dawley rats underwent maternal separation, and gene expression was studied using array technology. The human homologues of the differentially expressed genes were screened and analysed in a DSM-IV anxiety disorders cohort, and healthy controls (patients, n = 92; controls, n = 194), using blood. Two candidate genes (Mmp9 and Bdnf) were aberrantly expressed in the experimental rodent group relative to controls. Four single nucleotide polymorphisms (SNPs) in the human homologues of these genes were significantly associated with susceptibility for anxiety disorders (MMP9: rs3918242 and BDNF: rs6265, rs10835210 and rs11030107). Three of these (BDNF: rs6265, rs10835210, rs11030107) were found to interact significantly with childhood trauma severity resulting in increased likelihood of an anxiety disorder diagnosis. This study provides insights into the utility of rat models for identifying molecular candidates for anxiety disorders in humans. PMID- 29288746 TI - A new synthetic drug 5-(2-aminopropyl)indole (5-IT) induces rewarding effects and increases dopamine D1 receptor and dopamine transporter mRNA levels. AB - In recent years, there has been a marked increase in the use of recreational synthetic psychoactive substances, which is a cause of concern among healthcare providers and legal authorities. In particular, there have been reports on the misuse of 5-(2-aminopropyl)indole (5-API; 5-IT), a new synthetic drug, and of fatal and non-fatal intoxication. Despite these reports, little is known about its psychopharmacological effects and abuse potential. Here, we investigated the abuse potential of 5-IT by evaluating its rewarding and reinforcing effects through conditioned place preference (CPP) (1, 10, and 30 mg/kg, i.p.) in mice and self-administration test (0.1, 0.3, 1, and 3 mg/kg/inf., i.v.) in rats. We also examined whether 5-IT (1, 3, and 10 mg/kg, i.p.) induces locomotor sensitization in mice following a 7-day treatment and drug challenge. Then, we explored the effects of 5-IT (10 mg/kg, i.p.) on dopamine-related genes in the striatum, prefrontal cortex (PFC), and substantia nigra pars compacta (SNc)/ventral tegmental (VTA) of mice by quantitative real-time polymerase chain reaction. 5-IT produced CPP in mice but was not reliably self-administered by rats. 5-IT also induced locomotor sensitization following repeated administration and drug challenge. Moreover, 5-IT increased mRNA levels of dopamine D1 receptor in the striatum and PFC and dopamine transporter in the SNc/VTA of mice. These results indicate that 5-IT has psychostimulant and rewarding properties, which may be attributed to its ability to affect the dopaminergic system in the brain. These findings suggest that 5-IT poses a substantial risk for abuse and addiction in humans. PMID- 29288747 TI - Magnesium sulfate attenuates brain edema by lowering AQP4 expression and inhibits glia-mediated neuroinflammation in a rodent model of eclampsia. AB - Eclampsia is characterized by high morbidity and mortality wordwide. Magnesium sulfate (MgSO4) is used frequently as a prophylaxis for eclamptic seizure in clinical settings. However, the underlying mechanism is less studied, we have previously demonstrated that MgSO4 pretreatment decreases eclampsia-like seizure threshold. Here, we further evaluated the hypothesis that MgSO4 exert neuroprotective actions in eclampsia-like rats model by ameliorating neuroinflammation and brain edema. In this study, the eclampsia-like model was established by administering lipopolysaccharide plus pentylenetetrazol in pregnant Sprague-Dawley rats. Rats were given MgSO4 from gestation day14-19. Then, Iba-1 (a marker for microglia) and S100-B (a marker for astrocytes) expression levels in the hippocampus CA3 region were detected by Enzyme-linked immunosorbent assay. Cerebrospinal fluid (CSF) levels of inflammatory cytokines were measured by Luminex assays. Aquaporin-4 (a transmembrane water channel protein) expression levels in cortex were analyzed using immunohistochemistry. Astrocyte and microglia expressions were detected by immunofluorescence, neuronal damage were evaluated by Nissl staining, and changes in neuronal number in the hippocampal CA3 region (CA3) among different groups were detected by neuronal nuclei staining. Our results demonstrated that MgSO4 effectively attenuated astrocyte and microglia activation and promoted the neuronal survival in the CA3. Additionally, MgSO4 significantly reduced inflammatory cytokines response in the CSF, and decreased the expression of AQP-4 protein in the cortex. Collectively, the findings of this study indicated that MgSO4 has a neuroprotective role in eclampsia-like seizure rats through its anti-neuroninflammatory and brain edema attenuating properties. PMID- 29288749 TI - Enhanced wakefulness following lesions of a mesopontine locus essential for the induction of general anesthesia. AB - The induction of general anesthesia shares many features with the transition from wakefulness to non-rapid eye movement (NREM) sleep, suggesting that the two types of brain-state transition are orchestrated by a common neuronal mechanism. Previous studies revealed a brainstem locus, the mesopontine tegmental anesthesia area (MPTA), that is of singular importance for anesthetic induction. Microinjection of GABAergic anesthetics there induces rapid loss-of-consciousness and lesions render the animal relatively insensitive to anesthetics administered systemically. Here we show that MPTA lesions also alter the natural sleep-wake rhythm by increasing overall wake time at the expense of time asleep (NREM and REM sleep equally), with nearly all of the change occurring during the dark hours of the light-dark cycle. The effect was proportional to the extent of the lesion and was not seen after lesions just outside of the MPTA, or following sham lesions. Thus, MPTA neurons appear to play a role in natural bistable brain-state switching (sleep-wake) as well as in loss and recovery of consciousness induced pharmacologically. PMID- 29288748 TI - Abandoned prairie vole mothers show normal maternal care but altered emotionality: Potential influence of the brain corticotropin-releasing factor system. AB - When fathers leave the family, mothers are at increased risk of developing depression and anxiety disorders. In biparental, socially monogamous prairie voles (Microtus ochrogaster), sudden bond disruption increases passive stress coping, indicative of depressive-like behavior, and acts as chronic stressor in both males and females. However, the consequences of separation in lactating prairie vole mothers are unknown. In the present study, following 18 days of cohousing, half of the prairie vole pairs were separated by removing the male. In early lactation, maternal care was unaffected by separation, whereas anxiety related behavior and passive stress-coping were significantly elevated in separated mothers. Separation significantly increased corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus under basal conditions, similar to levels of paired females after acute exposure to forced swim stress. A second cohort of lactating prairie voles was infused intracerebroventricularly with either vehicle or the CRF receptor antagonist D Phe just prior to behavioral testing. The brief restraining during acute infusion significantly decreased arched back nursing in vehicle-treated paired and separated groups, whereas in the D-Phe-treated separated group the behavior was not impaired. Furthermore, in the latter, anxiety-related behavior and passive stress-coping were normalized to levels similar to vehicle-treated paired mothers. In conclusion, maternal investment is robust enough to withstand loss of the partner, whereas the mother's emotionality is affected, which may be - at least partly - mediated by a CRF-dependent mechanism. This animal model has potential for mechanistic studies of behavioral and physiological consequences of partner loss in single mothers. PMID- 29288750 TI - Generalization of effects of environmental enrichment on seeking for different classes of drugs of abuse. AB - BACKGROUND: Addiction is a chronic disease characterized by persistent vulnerability to relapse during abstinence. In animal models of addiction, accumulating evidence suggests that exposure to environmental enrichment (EE) during periods of abstinence can have curative effects on addiction and reduce the risks of relapse. However, until present most studies have mainly focused on cocaine. In this study, we investigated whether EE could have beneficial effects on cue-induced seeking for several psychoactive drugs belonging to different pharmacological classes such as methamphetamine (METH), heroin (HER) and nicotine (NIC). METHODS: After self-administration training of METH, HER and NIC, rats were housed in enriched (EE) or standard environments (SE) for 21-28 days of forced abstinence and then drug-seeking behavior was assessed in the absence of the drug. RESULTS: We found that, compared to SE housing, exposure to EE reduced drug seeking behavior for all drugs tested. CONCLUSIONS: These findings suggest that the anti-craving effects of EE are general for a wide variety of drugs and support the hypothesis that environmental stimulation may be a general intervention for attenuating relapse in humans. PMID- 29288751 TI - Detecting microvascular invasion in HCC with contrast-enhanced MRI: Is it a good idea? PMID- 29288752 TI - Reply to: "Detecting microvascular invasion in HCC with contrast-enhanced MRI: Is it a good idea?" PMID- 29288753 TI - Impact of comorbidities on patient outcomes after interferon-free therapy-induced viral eradication in hepatitis C. AB - BACKGROUND & AIMS: Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of direct acting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model. METHODS: This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes. RESULTS: A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29-1.86; p = 0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; p = 0.004), age (HR 1.06 95% CI 1.02-1.11; p = 0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; p = 0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; p = 0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, Child-Pugh 0.72, CirCom 0.68) regarding one- and two-year mortality. HepCom score identified low- (<=5.7 points: 2%-3%) and high-risk (>=25 points: 56%-59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups. CONCLUSIONS: The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one- and two-year mortality, and relevant clinical events, after starting direct acting antiviral therapy. LAY SUMMARY: The prognosis of patients with severe comorbidities may not benefit from HCV viral clearance. An algorithm to decide who will benefit from the treatment is needed to manage the chronic HCV infection better. PMID- 29288754 TI - MicroRNA-14 regulates larval development time in Bombyx mori. AB - MicroRNAs (miRNA) regulate multiple physiological processes including development and metamorphosis in insects. In the current study, we demonstrate that a conserved invertebrate miRNA-14 (miR-14) plays an important role in ecdysteroid regulated development in the silkworm Bombyx mori, a lepidopteran model insect. Ubiquitous transgenic overexpression of miR-14 using the GAL4/UAS system resulted in delayed silkworm larval development and smaller body size of larva and pupa with decrease in ecdysteriod titers. On the contrary, miR-14 disruption using the transgenic CRISPR/Cas9 system led to a precocious wandering stage with increase in ecdysteriod titers. We identified that the hormone receptor E75 (E75) and the ecdysone receptor isoform B (ECR-B), which both serve as essential mediators in the ecdysone signaling pathway, as putative target genes of miR-14 by in silico target prediction. Dual-luciferase reporter assays confirmed the binding of miR 14 to the 3'UTRs of E75 and ECR-B in a mammalian HEK293T cell line. Furthermore, transcription levels of E75 and ECR-B were significantly affected in both miR-14 overexpression and knockout transgenic animals. Taken together, our data suggested that the canonical invertebrate miR-14 is a general regulator in maintaining ecdysone homeostasis for normal development and metamorphosis in B. mori. PMID- 29288755 TI - Essential oil of Citrus lumia Risso: Phytochemical profile, antioxidant properties and activity on the central nervous system. AB - The use of essential oils (EOs) is known since long time in traditional medicine and aromatherapy for the management of various oxidative stress-related disorders and has been further increased recently for their neuroprotective and anti-aging potentials as well as for reducing anxiety and stress. The purpose of this work was to evaluate, for the first time, the chemical composition of Citrus lumia Risso EO and its antioxidant, anti-cholinesterase, and neuroactive properties by cell-free and cell-based assays. The EO has shown strong antioxidant and free radical scavenging properties, particularly in hydrogen atom transfer based assays (beta-carotene bleaching and ORAC, IC50 22 MUg/mL and 46 MUg/mL, respectively), that can be attributed to the high content of monoterpenes, especially d-Limonene (48.905%), and Linalool (18.245%). Furthermore, the EO has shown an interesting anti-acetylcholinesterase activity (IC50 258.25 MUg/mL). Data from MTT analysis indicate that the cytotoxicity of EO, evaluated on L929 mouse fibroblasts, is very low, with an IC50 higher than 500 MUg/mL at 48 h. Rat neuronal networks subjected to EO showed a concentration-dependent inhibition of spontaneous electrical activity. Results indicate that C. lumia EO could be an important source of natural antioxidants suggesting an important preventive role in the onset of oxidative stress-related pathologies. PMID- 29288756 TI - Is comfrey root more than toxic pyrrolizidine alkaloids? Salvianolic acids among antioxidant polyphenols in comfrey (Symphytum officinale L.) roots. AB - Comfrey root preparations are used for the external treatment of joint distortions and myalgia, due to its analgesic and anti-inflammatory properties. Up to date, key activity-determining constituents of comfrey root extracts have not been completely elucidated. Therefore, we applied different approaches to further characterize a comfrey root extract (65% ethanol). The phenolic profile of comfrey root sample was characterized by HPLC-DAD-QTOF-MS/MS. Rosmarinic acid was identified as main phenolic constituent (7.55 mg/g extract). Moreover, trimers and tetramers of caffeic acid (isomers of salvianolic acid A, B and C) were identified and quantified for the first time in comfrey root. In addition, pyrrolizidine alkaloids were evaluated by HPLC-QQQ-MS/MS and acetylintermedine, acetyllycopsamine and their N-oxides were determined as major pyrrolizidine alkaloids in the comfrey root sample. Lastly, the antioxidant activity was determined using four assays: DPPH and ABTS radicals scavenging assays, reducing power assay and 15-lipoxygenase inhibition assay. Comfrey root extract exhibited significant antioxidant activities when compared to known antioxidants. Thus, comfrey root is an important source of phenolic compounds endowed with antioxidant activity which may contribute to the overall bioactivity of Symphytum preparations. PMID- 29288757 TI - Do flavanols-rich natural products relieve obesity-related insulin resistance? AB - Growing evidence support that insulin resistance may occur as a severe problem due to chronic energetic overfeeding and subsequent obesity. When an abundance of glucose and saturated fat enter the cell, impaired blood flow, hypoxia, inflammation and macrophage infiltration in obese adipose tissue may induce oxidative stress and insulin resistance. Excessive circulating saturated fatty acids ectopically accumulate in insulin-sensitive tissues and impair insulin action. In this context, excessive hepatic lipid accumulation may play a central, pathogenic role in insulin resistance. It is thought that dietary polyphenols may ameliorate obesity-related insulin resistance by attenuating inflammatory responses and oxidative stress. The most often occurring natural polyphenolic compounds are flavonoids. In this review, the possible mechanistic effect of flavonoid-rich natural products on insulin resistance-related metabolic pathways is discussed. Polyphenol intake can prevent high-fat-diet-induced insulin resistance via cell surface G protein-coupled estrogen receptors by upregulating the expression of related genes, and their pathways, which are responsible for the insulin sensitivity. PMID- 29288758 TI - Chemical findings and in vitro biological studies to uphold the use of Ficus exasperata Vahl leaf and stem bark. AB - Ficus exasperata Vahl, commonly known as sandpaper, is a terrestrial Afro tropical tree used in popular medicine. Despite the existence of some works on the biological activities of this species, its chemical composition is still poorly known. The aim of this study was to extend the knowledge on the phytochemistry and biological properties of this species. Aqueous extracts from F. exasperata leaves and stem bark were analysed. Thirty-one phenolic compounds, comprising cinnamoyl derivatives, flavonoid-O-glycosides, flavonoid-mono-C glycosides, flavonoid-di-C-glycosides and one furanocoumarin, were determined by HPLC-DAD-ESI/MSn and UPLC-ESI-QTOF-MS, 26 of them being reported for the first time in this species. The profile of organic acids, characterized by HPLC-UV, was also reported for the first time. The best radical scavenging activity was observed for the aqueous extract from leaves (IC50 values of 222.5, 510.0 and 50.0 MUg/mL against DPPH*, *NO and O2*-, respectively). In addition, both aqueous extracts of the leaves and stem bark displayed a weak effect on alpha-amylase, and no cytotoxicity against gastric adenocarcinoma cell line, AGS. This study contributes to the valorisation of these vegetal materials, which may have application in functional foods and/or nutraceuticals. PMID- 29288759 TI - The frequently occurring components of essential oils beta elemene and R-limonene alter expression of dprE1 and clgR genes of Mycobacterium tuberculosis H37Ra. AB - In the past few years, there has been a significant increase in detection of drug resistant strains of Mycobacterium tuberculosis. Search for new antimycobacterial drugs brought natural sources with their chemical diversity in focus. Especially essential oils, produced by plants also for toxic effect, are reservoir of potentially antitubercular compounds. In the present work, we exposed M. tuberculosis H37Ra ATCC 25177 strain to some terpenes commonly occurring in essential oils. Gene expression profiling was used to explore possible influence of these compounds on stress sensing and envelope preserving function. Expression of two genes dprE1 involved in cell wall synthesis and clgR responsible for regulation of cell membrane preservation was investigated. We report that two out of five tested compounds: beta-elemene and R-limonene alter expression of dprE1 and clgR genes. These findings indicate various mechanisms of action of essential oils compounds on M. tuberculosis. Especially the clgR expression seemed to be the perfect marker of stress sensing and envelope preserving systems status. PMID- 29288760 TI - Occurrence, biochemistry and biological effects of host-selective plant mycotoxins. AB - Host-selective mycotoxins (HSTs) are various secondary metabolites or proteinaceous compounds secreted by pathogenic necrotrophic fungi that feed off on dead tissues of certain plants. Research on the HSTs has not only fundamental but also practical importance. On one hand they are implicated in the onset of devastating crop diseases. On the other hand, they have been studied as a good model for revealing the intricate mechanisms of plant-pathogen interactions. At the cellular level, HSTs target different compartments and in most instances induce programmed cell death (PCD) by a wide range of mechanisms. Often the responses provoked by HSTs resemble the effector-triggered immunity used by plant cells to combat biotrophic pathogens, which suggests that HST-producing fungi exploit the plants' own defensive systems to derive benefits. Although by definition HSTs are active only in tissues of susceptible plant genotypes, it has been demonstrated that some of them are able to influence animal cells as well. The possible effects, like cytotoxicity or cytostasis, can be harmful or beneficial and thus HSTs may either pose a health risk for humans and livestock, or be of prospective use in the fields of pharmacology, medicine and agriculture. PMID- 29288761 TI - Toxicity and toxicokinetic study of RPh201 in Sprague-Dawley rats. AB - Mastic gum is used for health products and in the food industry, and is being tested for several clinical indications. Nevertheless, information on its safety is scarce. Our aim was to test the local and systemic toxicity of RPh201, a botanical extract of gum mastic, and to assess the toxicokinetic profile of the mastic gum constituents masticadienonic acid (MDA) and isomasticadienonic acid (IMDA). 340 Sprague-Dawley rats were administered twice weekly subcutaneously with placebo or different doses of RPh201 for 6 months with an interim group at 3 months and a 4-week recovery group. No systemic toxicity was observed with RPh201. Local injection site reactions were observed in all animals, with comparable severity and frequency in the placebo and high dose groups. However, given the relative increase in tissue reaction in the high dose group, these changes were attributed to RPh201 administration. Nevertheless, considering the minor local irritation effects and clear trend for reversibility, the effects were not judged to be adverse. The toxicokinetic study revealed that the MDA and IMDA exposure increased with dose and the increase was supra-proportional on all days. This study supports a "no observed adverse effect level" (NOAEL) of 300 mg/kg body weight in Sprague-Dawley rats. PMID- 29288762 TI - RIFM fragrance ingredient safety assessment benzyl 2,2-dimethylpropanoate, CAS Registry Number 2094-69-1. PMID- 29288763 TI - RIFM fragrance ingredient safety assessment diethyl succinate, CAS Registry Number 123-25-1. PMID- 29288764 TI - Tivantinib in Combination with Erlotinib versus Erlotinib Alone for EGFR-Mutant NSCLC: An Exploratory Analysis of the Phase 3 MARQUEE Study. AB - INTRODUCTION: This exploratory subgroup analysis of the MARQUEE study evaluated the efficacy and safety of erlotinib plus tivantinib in patients with EGFR-mutant NSCLC. METHODS: Patients with advanced, nonsquamous, EGFR and mesenchymal epithelial transition inhibitor-naive NSCLC previously treated with one or two lines of systemic therapy were randomized to oral erlotinib (150 mg once daily) plus tivantinib (360 mg twice daily) or to erlotinib plus placebo. The primary end point was overall survival. RESULTS: Among 1048 patients enrolled, 109 (10.4%) had EGFR-mutant disease. Erlotinib plus tivantinib improved progression free survival in this subpopulation; median progression-free survival was 13.0 months for erlotinib plus tivantinib (n = 56) and 7.5 months for erlotinib plus placebo (n = 53) (hazard ratio = 0.49, 95% confidence interval: 0.31-0.77). Deaths occurred in 73 patients (67%), and median overall survival was 25.5 months in the erlotinib plus tivantinib arm versus 20.3 months in the erlotinib plus placebo arm (hazard ratio = 0.68, 95% confidence interval: 0.43-1.08). Common adverse events included diarrhea, rash, and asthenia. Neutropenia and febrile neutropenia were more common with erlotinib plus tivantinib. CONCLUSIONS: Erlotinib plus tivantinib was tolerable and showed improved efficacy over erlotinib monotherapy in previously treated EGFR-mutant NSCLC. PMID- 29288765 TI - Cardiac voltage gated calcium channels and their regulation by beta-adrenergic signaling. AB - Voltage-gated calcium channels (VGCCs) are the predominant source of calcium influx in the heart leading to calcium-induced calcium release and ultimately excitation-contraction coupling. In the heart, VGCCs are modulated by the beta adrenergic signaling. Signaling through beta-adrenergic receptors (betaARs) and modulation of VGCCs by beta-adrenergic signaling in the heart are critical signaling and changes to these have been significantly implicated in heart failure. However, data related to calcium channel dysfunction in heart failure is divergent and contradictory ranging from reduced function to no change in the calcium current. Many recent studies have highlighted the importance of functional and spatial microdomains in the heart and that may be the key to answer several puzzling questions. In this review, we have briefly discussed the types of VGCCs found in heart tissues, their structure, and significance in the normal and pathological condition of the heart. More importantly, we have reviewed the modulation of VGCCs by betaARs in normal and pathological conditions incorporating functional and structural aspects. There are different types of betaARs, each having their own significance in the functioning of the heart. Finally, we emphasize the importance of location of proteins as it relates to their function and modulation by co-signaling molecules. Its implication on the studies of heart failure is speculated. PMID- 29288766 TI - Triptolide inhibits pituitary adenoma cell viability, migration and invasion via ADAM12/EGFR signaling pathway. AB - AIM: Triptolide, an effective component derived from Tripterygium wilfordii, has been well recognized to process a broad-spectrum antitumor activities in various tumor types. However, the potential role of triptolide in pituitary adenomas remains unknown. The aim of this study was to investigate the precise role of triptolide and underlying mechanism in regulating pituitary adenoma cell viability, migration and invasion. MAIN METHODS: We use mouse pituitary adenoma cells (TtT/GF and AtT20 cells) as the experiment model and treated them with varying concentrations of triptolide. The corresponding inhibitory effects on cell viability, migration, invasion and apoptosis were examined respectively, and the underlying mechanism was determined by investigating ADAM12 (a disintegrin and metalloprotease 12)/EGFR signaling. KEY FINDINGS: Triptolide significantly inhibited cell viability, migration and invasion in TtT/GF and AtT20 cells in a dose-dependent manner. Mechanistically, triptolide significantly reduced ADAM12 expression at protein levels and attenuated ADAM12/EGFR signaling. Meanwhile, triptolide treatment combined with ADAM12 silencing enhanced the suppression effects on cell viability, migration and invasion, and those effects were restored following ADAM12-rescued. Moreover, triptolide suppressed the tumorigenesis of TtT/GF and AtT20 cells in vivo. SIGNIFICANCE: Our research provides evidence that triptolide inhibits pituitary adenoma cell viability, migration and invasion via ADAM12/EGFR signaling pathway. These findings suggest a potential role for triptolide in treating pituitary adenomas. PMID- 29288767 TI - Surprising outcomes in cannabinoid CB1/CB2 receptor double knockout mice in two models of ischemia. AB - AIMS: We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion. MAIN METHODS: Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice. KEY FINDINGS: The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia. SIGNIFICANCE: Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion of the CB2R has been shown to worsen outcome, while selective CB2R agonists have been demonstrated to be neuroprotective following stroke. Although initial studies of CB1R knockout mice demonstrated increased injury following stroke, indicating that activation of the CB1R was neuroprotective, later studies of selective antagonists of the CB1R also demonstrated a protective effect. Surprisingly the double knockout animals had improved outcome. Since the phenotype of the double knockout is not dramatically changed, significant changes in the contribution of other homeostatic pathways in compensation for the loss of these two important receptors may explain these apparently contradictory results. PMID- 29288768 TI - Untargeted metabolic profiling reveals distinct patterns of thermal sensitivity in two related notothenioids. AB - Antarctic marine ectothermal animals may be affected more than temperate species by rising temperatures due to ongoing climate change. Their specialisation on stable cold temperatures makes them vulnerable to even small degrees of warming. Thus, addressing the impacts of warming on Antarctic organisms and identifying their potentially limited capacities to respond is of interest. The objective of the study was to determine changes in metabolite profiles related to temperature acclimation. In a long-term experiment adult fish of two Antarctic sister species Notothenia rossii and Notothenia coriiceps were acclimated to 0 degrees C and 5 degrees C for three months. Impacts and indicators of acclimation at the cellular level were determined from metabolite profiles quantified in gill tissue extracts using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, the metabolite profiles of the two con-generic species were compared. NMR spectroscopy identified 37 metabolites that were present in each sample, but varied in their absolute concentration between species and between treatments. A decrease in amino acid levels indicated an increased amino acid catabolism after incubation to 5 degrees C. In addition, long term warming initiated shifts in organic osmolyte concentrations and modified membrane structure observed by altered levels of phospholipid compounds. Differences in the metabolite profile between the two notothenioid species can be related to their divergent lifestyles, especially their different rates of motor activity. Increased levels of the Krebs cycle intermediate succinate and a higher reduction of amino acid concentrations in warm-acclimated N. rossii showed that N. rossii is more affected by warming than N. coriiceps. PMID- 29288769 TI - Genetic variations in the DNA replication origins of human papillomavirus family correlate with their oncogenic potential. AB - Human papillomaviruses (HPVs) encompass a large family of viruses that range from benign to highly carcinogenic. The crucial differences between benign and carcinogenic types of HPV remain unknown, except that the two HPV types differ in the frequency of DNA replication. We have systematically analyzed the mechanism of HPV DNA replication initiation in low-risk and high-risk HPVs. Our results demonstrate that HPV-encoded E2 initiator protein and its four binding sites in the replication origin play pivotal roles in determining the destiny of the HPV infected cell. We have identified strain-specific single nucleotide variations in E2 binding sites found only in the high-risk HPVs. We have demonstrated that these variations result in attenuated formation of the E2-DNA complex. E2 binding to these sites is linked to the activation of the DNA replication origin as well as initiation of DNA replication. Both electrophoretic mobility shift assay and atomic force microscopy studies demonstrated that binding of E2 from either low- or high-risk HPVs with variant binding sequences lacked multimeric E2-DNA complex formation in vitro. These results provided a molecular basis of differential DNA replication in the two types of HPVs and pointed to a correlation with the development of cancer. PMID- 29288771 TI - S-allyl cysteine inhibits TNFalpha-induced skeletal muscle wasting through suppressing proteolysis and expression of inflammatory molecules. AB - BACKGROUND: Elevated levels of inflammatory molecules are key players in muscle wasting/atrophy leading to human morbidity. TNFalpha is a well-known pro inflammatory cytokine implicated in the pathogenesis of muscle wasting under diverse clinical settings. S-allyl cysteine (SAC), an active component of garlic (Allium sativum), has established anti-oxidant and anti-inflammatory effects in various cell types. However, the impact of SAC on skeletal muscle pathology remains unexplored. Owing to the known anti-inflammatory properties of SAC, we investigated whether pre-treatment with SAC has a protective role in TNFalpha induced atrophy in cultured myotubes. METHODS AND RESULTS: C2C12 myotubes were treated with TNFalpha (100ng/ml) in the presence or absence of SAC (0.01mM). TNFalpha treatment induced atrophy in myotubes by up-regulating various proteolytic systems i.e. cathepsin L, calpain, ubiquitin-proteasome E3-ligases (MuRF1/atrogin1), caspase 3 and autophagy (Beclin1/LC3B). TNFalpha also induced the activation of NFkappaB by stimulating the degradation of IkappaBalpha (inhibitor of NFkappaB), in myotubes. The alterations in proteolytic systems likely contribute to the degradation of muscle-specific proteins and reduce the myotube length, diameter and fusion index. The SAC supplementation significantly impedes TNFalpha-induced protein loss and protects myotube morphology by suppressing protein catabolic systems and endogenous level of inflammatory molecules namely TNFalpha, IL-6, IL-1beta, TNF-like weak inducer of apoptosis (TWEAK), fibroblast growth factor-inducible 14 (Fn14) and Nox. CONCLUSION AND GENERAL SIGNIFICANCE: Our findings reveal anti-atrophic role for SAC, as it prevents alterations in protein metabolism and protects myotubes by regulating the level of inflammatory molecules and multiple proteolytic systems responsible for muscle atrophy. PMID- 29288770 TI - The 3'-end region of the human PDGFR-beta core promoter nuclease hypersensitive element forms a mixture of two unique end-insertion G-quadruplexes. AB - BACKGROUND: While the most stable G-quadruplex formed in the human PDGFR-beta promoter nuclease hypersensitive element (NHE) is the 5'-mid G-quadruplex, the 3' end sequence that contains a 3'-GGA run forms a less stable G-quadruplex. Recently, the 3'-end G-quadruplex was found to be a transcriptional repressor and can be selectively targeted by a small molecule for PDGFR-beta downregulation. METHOD: We use 1D and 2D high-field NMR, in combination with Dimethylsulfate Footprinting, Circular Dichroism Spectroscopy, and Electrophoretic Mobility Shift Assay. RESULTS: We determine that the PDGFR-beta extended 3'-end NHE sequence forms two novel end-insertion intramolecular G-quadruplexes that co-exist in equilibrium under physiological salt conditions. One G-quadruplex has a 3'-non adjacent flanking guanine inserted into the 3'-external tetrad (3'-insertion-G4), and another has a 5'-non-adjacent flanking guanine inserted into the 5'-external tetrad (5'-insertion-G4). The two guanines in the GGA-run move up or down within the G-quadruplex to accommodate the inserted guanine. Each end-insertion G quadruplex has a low thermal stability as compared to the 5'-mid G-quadruplex, but the selective stabilization of GSA1129 shifts the equilibrium toward the 3' end G-quadruplex in the PDGFR-beta NHE. CONCLUSION: An equilibrium mixture of two unique end-insertion intramolecular G-quadruplexes forms in the PDGFR-beta NHE 3' end sequence that contains a GGA-run and non-adjacent guanines in both the 3'- and 5'- flanking segments; the novel end-insertion structures of the 3'-end G quadruplex are selectively stabilized by GSA1129. GENERAL SIGNIFICANCE: We show for the first time that an equilibrium mixture of two unusual end-insertion G quadruplexes forms in a native promoter sequence and appears to be the molecular recognition for PDGFR-beta downregulation. PMID- 29288772 TI - pH driven fibrillar aggregation of the super-sweet protein Y65R-MNEI: A step-by step structural analysis. AB - BACKGROUND: MNEI and its variant Y65R-MNEI are sweet proteins with potential applications as sweeteners in food industry. Also, they are often used as model systems for folding and aggregation studies. METHODS: X-ray crystallography was used to structurally characterize Y65R-MNEI at five different pHs, while circular dichroism and fluorescence spectroscopy were used to study their thermal and chemical stability. ThT assay and AFM were used for studying the kinetics of aggregation and morphology of the aggregates. RESULTS: Crystal structures of Y65R MNEI revealed the existence of a dimer in the asymmetric unit, which, depending on the pH, assumes either an open or a closed conformation. The pH dramatically affects kinetics of formation and morphology of the aggregates: both MNEI and Y65R-MNEI form fibrils at acidic pH while amorphous aggregates are observed at neutral pH. CONCLUSIONS: The mutation Y65R induces structural modifications at the C-terminal region of the protein, which account for the decreased stability of the mutant when compared to MNEI. Furthermore, the pH-dependent conformation of the Y65R-MNEI dimer may explain the different type of aggregates formed as a function of pH. GENERAL SIGNIFICANCE: The investigation of the structural bases of aggregation gets us closer to the possibility of controlling such process, either by tuning the physicochemical environmental parameters or by site directed mutagenesis. This knowledge is helpful to expand the range of stability of proteins with potential industrial applications, such as MNEI and its mutant Y65R MNEI, which should ideally preserve their structure and soluble state through a wide array of conditions. PMID- 29288774 TI - Ineffective alcohol-based hand rub and defective dispenser design: a cautionary note. PMID- 29288773 TI - 3D cellular spheroids as tools for understanding carboxylated quantum dot behavior in tumors. AB - BACKGROUND: Monolayer cell cultures have been considered the most suitable technique for in vivo cellular experiments. However, a lot of cellular functions and responses that are present in natural tissues are lost in two-dimensional cell cultures. In this context, nanoparticle accumulation data presented in literature are often not accurate enough to predict behavior of nanoparticles in vivo. Cellular spheroids show a higher degree of morphological and functional similarity to the tissues. METHODS: Accumulation and distribution of carboxylated CdSe/ZnS quantum dots (QDs), chosen as model nanoparticles, was investigated in cellular spheroids composed of different phenotype mammalian cells. The findings were compared with the results obtained in in vivo experiments with human tumor xenografts in immunodeficient mice. The diffusive transport model was used for theoretical nanoparticles distribution estimation. RESULTS: QDs were accumulated only in cells, which were localized in the periphery of cellular spheroids. CdSe/ZnS QDs were shown to be stable and inert; they did not have any side effects for cellular spheroids formation. Penetration of QDs in both cellular spheroids and in vivo tumor model was limited. The mathematical model confirmed the experimental results: nanoparticles penetrated only 25MUm into cellular spheroids after 24h of incubation. CONCLUSIONS: Penetration of negatively charged nanoparticles is limited not only in tumor tissue, but also in cellular spheroids. GENERAL SIGNIFICANCE: The results presented in this paper show the superior applicability of cellular spheroids to cell monolayers in the studies of the antitumor effect and penetration of nanomedicines. PMID- 29288775 TI - Randomized controlled clinical trial on the antiseptic efficacy of polihexanide 0.04% on acute traumatic wounds. AB - Prevention of wound infections is a challenge in clinical practice. The aim of this study was to assess the efficacy of polyhexamethylene biguanide (PHMB, polihexanide) 0.04% on acute traumatic wounds. It was a randomized, double-blind, placebo-controlled prospective trial which included 61 patients. The polihexanide group showed a significant decrease in log10 colony-forming units (cfu) (P < 0.001) after 60 min treatment in comparison to baseline cfu, whereas the Ringer solution group did not show a significant change in cfu during 60 min treatment. Treatment of polihexanide 0.04% resulted in a significant reduction of bacterial load in acute traumatic wounds. PMID- 29288776 TI - Predictive factors for early- and late-onset surgical site infections in patients undergoing elective colorectal surgery. A multicentre, prospective, cohort study. AB - BACKGROUND: Surgical site infections (SSIs) are the leading cause of healthcare associated infections in acute care hospitals in Europe. However, the risk factors for the development of early-onset (EO) and late-onset (LO) SSI have not been elucidated. AIM: This study investigated the predictive factors for EO-SSI and LO-SSI in a large cohort of patients undergoing colorectal surgery. METHODS: We prospectively followed-up adult patients undergoing elective colorectal surgery in 10 hospitals (2011-2014). Patients were divided into three groups: EO SSI, LO-SSI, or no infection (no-SSI). The cut-off defining EO-SSI and LO-SSI was seven days (median time to SSI development). Different predictive factors for EO SSI and LO-SSI were analysed, comparing each group with the no-SSI patients. FINDINGS: Of 3701 patients, 320 (8.6%) and 349 (9.4%) developed EO-SSI and LO SSI, respectively. The rest had no-SSI. Patients with EO-SSI were mostly males, had colon surgery and developed organ-space SSI whereas LO-SSI patients frequently received chemotherapy or radiotherapy and had incisional SSI. Male sex (odds ratio (OR): 1.92; P < 0.001), American Society of Anesthesiologists' physical status >2 (OR: 1.51; P = 0.01), administration of mechanical bowel preparation (OR: 0.7; P = 0.03) and stoma creation (OR: 1.95; P < 0.001) predicted EO-SSI whereas rectal surgery (OR: 1.43; P = 0.03), prolonged surgery (OR: 1.4; P = 0.03) and previous chemotherapy (OR: 1.8; P = 0.03) predicted LO SSI. CONCLUSION: We found distinctive predictive factors for the development of SSI before and after seven days following elective colorectal surgery. These factors could help establish specific preventive measures in each group. PMID- 29288777 TI - Epidemiology and spa-type diversity of meticillin-resistant Staphylococcus aureus in community and healthcare settings in Norway. AB - BACKGROUND: There has been a marked increase in the incidence of meticillin resistant Staphylococcus aureus (MRSA) during the past decade in Norway; a country with one of the lowest prevalence rates and an active 'search-and destroy' policy applied to hospital settings. AIM: To characterize the trends of notification rates of community-associated (CA) and healthcare-associated (HA) MRSA in Norway, and explore the diversity and circulation of MRSA spa types within and outside healthcare settings. METHODS: A registry-based study on notified MRSA infections and colonizations was conducted in Norway between 2006 and 2015. The diversity and abundance of CA- and HA-MRSA spa types were compared using novel ecological diversity measures (Hill numbers). FINDINGS: During the study period, the monthly notification rate increased 6.9-fold and 1.8-fold among CA- and HA-MRSA, respectively; the increase was steeper among colonizations than infections. In both settings, the distribution of spa types was uneven, with a few dominant spa types and many singletons. The spa-type diversity of CA-MRSA was higher than HA-MRSA in terms of different types (685 vs 481), and increased during the study period. However, the diversity associated with the dominant spa types was similar and remained stable. A high overlap of spa types was estimated between the settings; spa-t002, t019 and t008 were the most common. CONCLUSION: The present findings suggest a strong connection between CA- and HA-MRSA epidemiology in Norway. If the fast-growing trend of CA-MRSA continues in the years to come, it may challenge current guidelines and infection control of MRSA in healthcare environments. PMID- 29288778 TI - Child abuse and work stress in adulthood: Evidence from a population-based study. AB - The objective of this study was to examine the association between child abuse and work stress in adulthood. We used data from the 2012 Canadian Community Health Survey (CCHS) Mental Health, a nationally representative cross-sectional survey of Canadians. This study included all participants aged 20years or older who reported being employed the past 12months (N=14,581). Child physical abuse, sexual abuse, and exposure to intimate partner violence were assessed in relation to several work stress-related indicators. Multiple linear and Poisson regression models adjusted for age, sex, education, household income, marital status, occupation group, and any lifetime mental disorder. Child abuse was significantly associated with greater odds of high work stress (IRR: 1.29; 95% CI: 1.16-1.43) in adulthood. More specifically, child abuse was associated with greater odds of job dissatisfaction (IRR: 1.69; 95% CI: 1.31-2.18), job insecurity (IRR: 1.56; 95% CI: 1.27-1.91), and self-perceived low support (IRR: 1.33; 95% CI: 1.22 1.46). It was also associated with high levels of psychological demand (b=0.348; 95% CI: 0.229-0.467) and job strain (b=0.031; 95% CI: 0.019-0.043). Examination of the Karasek's Demand-Control Model using multinomial logistic regression analyses indicated that child abuse was significantly associated with high strain (RRR:1.39; 95% CI: 1.14-1.72) and active (RRR: 1.56; 95% CI: 1.28-1.90) jobs. These findings suggest the negative influence of child abuse on work experience. Success in preventing child abuse may help reduce work-related stress in adulthood. PMID- 29288779 TI - Evaluation of Let's Move! active schools activation grants. AB - Let's Move! Active Schools (LMAS), now Active Schools, is a national initiative in the United States (US) that aims to engage schools to increase students' opportunities to be physically active. This evaluation describes changes in school-level practices related to physical education (PE) and physical activity (PA) among schools that received an LMAS-partner grant from ChildObesity180 or Fuel Up to Play 60 (FUTP60). ChildObesity180 and FUTP60 asked grantee schools to complete nine common questions, between October 2013 and August 2014, before and after receiving the grants to assess progress in implementing practices for PE and PA. "Yes" responses indicated presence of PE/PA-supportive practices. For schools with complete pre and post data (n=972), frequencies of "yes" responses were calculated for each practice at pre/post. Schools receiving a FUTP60 partner grant reported statistically significant improvements from pre to post across five practices for PE and PA, and ChildObesity180 grantees reported significant increases on all practices except daily recess, which was already in place at 95% of schools at pre-survey. Schools across both grant programs reported the largest increases for promoting PA via messaging, implementing classroom PA breaks, and providing PA before and after school. Schools in both programs reported smaller, but statistically significant, increases in requiring the recommended minutes of PE. This study illustrates the feasibility of offering small grants, at a national scale, for schools to make changes that support PA throughout the day. Results suggest that schools can shift PA policies and practices over the course of a school year. PMID- 29288780 TI - Making the most of natural experiments: What can studies of the withdrawal of public health interventions offer? AB - Many interventions that may have large impacts on health and health inequalities, such as social and public health policies and health system reforms, are not amenable to evaluation using randomised controlled trials. The United Kingdom Medical Research Council's guidance on the evaluation of natural experiments draws attention to the need for ingenuity to identify interventions which can be robustly studied as they occur, and without experimental manipulation. Studies of intervention withdrawal may usefully widen the range of interventions that can be evaluated, allowing some interventions and policies, such as those that have developed piecemeal over a long period, to be evaluated for the first time. In particular, sudden removal may allow a more robust assessment of an intervention's long-term impact by minimising 'learning effects'. Interpreting changes that follow withdrawal as evidence of the impact of an intervention assumes that the effect is reversible and this assumption must be carefully justified. Otherwise, withdrawal-based studies suffer similar threats to validity as intervention studies. These threats should be addressed using recognised approaches, including appropriate choice of comparators, detailed understanding of the change processes at work, careful specification of research questions, and the use of falsification tests and other methods for strengthening causal attribution. Evaluating intervention withdrawal provides opportunities to answer important questions about effectiveness of population health interventions, and to study the social determinants of health. Researchers, policymakers and practitioners should be alert to the opportunities provided by the withdrawal of interventions, but also aware of the pitfalls. PMID- 29288781 TI - Healthcare costs attributable to secondhand smoke exposure at home for U.S. adults. AB - OBJECTIVE: To estimate healthcare costs attributable to secondhand smoke (SHS) exposure at home among nonsmoking adults (18+) in the U.S. METHODS: We analyzed data on nonsmoking adults (N=67,735) from the 2000, 2005, and 2010 (the latest available data on SHS exposure at home) U.S. National Health Interview Surveys. This study was conducted from 2015 to 2017. We examined hospital nights, home care visits, doctor visits, and emergency room (ER) visits. For each, we analyzed the association of SHS exposure at home with healthcare utilization with a Zero Inflated Poisson regression model controlling for socio-demographic and other risk characteristics. Excess healthcare utilization attributable to SHS exposure at home was determined and multiplied by unit costs derived from the 2014 Medical Expenditures Panel Survey to determine annual SHS-attributable healthcare costs. RESULTS: SHS exposure at home was positively associated with hospital nights and ER visits, but was not statistically associated with home care visits and doctor visits. Exposed adults had 1.28 times more hospital nights and 1.16 times more ER visits than non-exposed adults. Annual SHS-attributable healthcare costs totaled $4.6 billion (including $3.8 billion for hospital nights and $0.8 billion for ER visits, 2014 dollars) in 2000, $2.1 billion (including $1.8 billion for hospital nights and $0.3 billion for ER visits) in 2005, and $1.9 billion (including $1.6 billion for hospital nights and $0.4 billion for ER visits) in 2010. CONCLUSIONS: SHS-attributable costs remain high, but have fallen over time. Tobacco control efforts are needed to further reduce SHS exposure at home and associated healthcare costs. PMID- 29288782 TI - Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. AB - Although guidelines have recommended extended interval cervical screening using concurrent human papillomavirus (HPV) and cytology ("cotesting") for over a decade, little is known about its adoption into routine care. Using longitudinal medical record data (2003-2015) from Kaiser Permanente Northern California (KPNC), which adopted triennial cotesting in 2003, we examined adherence to extended interval screening. We analyzed predictors of screening intervals among 491,588 women undergoing routine screening, categorizing interval length into early (<2.5years), adherent (2.5<3.5years), or late (3.5<6.0years). We also examined repeated early screening in a subgroup of 50,691 women. Predictors examined included: cohort year (defined by baseline cotest, 2003-2009), race/ethnicity, and baseline age. Compared to the 2003 cohort, women in the 2009 cohort were significantly less likely to screen early (aOR=0.22, 95% CI=0.21, 0.23) or late (aOR=0.47, 95% CI=0.45, 0.49). African American (AA) and Hispanic women were less adherent overall than Non-Hispanic White women, with increased early [(AA: aOR=1.21, 95%CI=1.17, 1.25) (Hispanic: aOR=1.08, 95%CI=1.06, 1.11)] and late screening [(AA: aOR=1.23, 95%CI=1.19, 1.27) (Hispanic: aOR=1.06, 95%CI=1.03, 1.08)]. Asian women were slightly more likely to screen early (aOR=1.03, 95%CI=1.01, 1.05), and less likely to screen late (aOR=0.92, 95% CI=0.90, 0.94). Women aged 60-64years were most likely to screen early for two consecutive intervals (aOR=2.09, 95%CI=1.91, 2.29). Our study found that widespread and rapid adoption of extended interval cervical cancer screening is possible, at least in this managed care setting. Further research examining multilevel drivers promoting or restricting extended interval screening across diverse healthcare settings is needed. PMID- 29288783 TI - Primary care providers' physical activity counseling and referral practices and barriers for cardiovascular disease prevention. AB - The US Preventive Services Task Force (USPSTF) recommends offering or referring adults who are overweight or obese and have additional cardiovascular disease (CVD) risk factors to intensive behavioral counseling interventions to promote a healthful diet and physical activity for CVD prevention. This study determined the proportion of primary care providers (PCPs) who discussed physical activity with most of their at-risk patients and referred them to intensive behavioral counseling, and reported barriers to counseling. Our analyses used data from DocStyles 2015, a Web-based panel survey of 1251 PCPs. Overall, 58.6% of PCPs discussed physical activity with most of their at-risk patients. Among these PCPs, the prevalence of components offered ranged from 98.5% encouraging increased physical activity to 13.9% referring to intensive behavioral counseling. Overall, only 8.1% both discussed physical activity with most at-risk patients and referred to intensive behavioral counseling. Barriers related to PCPs' attitudes and beliefs about counseling (e.g., counseling is not effective) were significantly associated with both discussing physical activity with most at risk patients and referring them to intensive behavioral counseling (adjusted odds ratio, 1.92; 95% confidence interval, 1.15-3.20). System-level barriers (e.g., referral services not available) were not. Just over half of PCPs discussed physical activity with most of their at-risk patients, and few both discussed physical activity and referred patients to intensive behavioral counseling. Overcoming barriers related to attitudes and beliefs about physical activity counseling could help improve low levels of counseling and referrals to intensive behavioral counseling for CVD prevention. PMID- 29288784 TI - Association of Prostatic Volume and Carotid Intima-media Thickness in Patients With Benign Prostatic Hyperplasia. AB - OBJECTIVE: To assess cardiovascular risk factors and carotid intima-media thickness in patients with benign prostatic hyperplasia. MATERIALS AND METHODS: One hundred and twenty-three patients who were evaluated for the presence of benign prostatic hyperplasia with accompanying symptoms were included in the study. Patients were also examined by cardiology department to assess and measure cardiovascular risk factors, left ventricular functions, and carotid intima-media thickness. RESULTS: Cardiovascular risk factors adjusted carotid intima-media thickness was found to be different between 3 groups, being highest in the severely symptomatic group and lowest in the mildly symptomatic group. Significant correlation of prostatic volume was shown with carotid intima-media thickness after adjusting prostatic volume for body mass index and age, and carotid intima-media thickness for cardiovascular risk factors (r = 0.75 P = .01). Linear regression analysis revealed that carotid intima-media thickness significantly associated with prostatic volume (beta coefficient: 0.628; confidence interval: 37.02-60.1; P = .001). CONCLUSION: We have demonstrated that prostatic tissue has significant association with carotid intima-media thickness in patients with benign prostatic hyperplasia. PMID- 29288785 TI - Robotic-assisted Laparoscopic Partial Nephrectomy in a Horseshoe Kidney. A Case Report and Review of the Literature. AB - Horseshoe kidney is a rare renal fusion anomaly, and because of limited mobilization of the kidney and its multiple arterial blood supplies, minimally invasive surgery for renal tumors can be challenging. We describe a case of a right-side oncocytoma in a horseshoe kidney managed robotically and review the literature of robotic-assisted laparoscopic surgical resection of kidney tumors in renal fusion anomalies. Robotic-assisted laparoscopic partial nephrectomy in a horseshoe kidney is feasible. Fusion-related limited mobility during the procedure, as well as an extremely variable blood supply, require meticulous planning. Multi-phase computed tomography and interactive 3D anatomical models are helpful tools to prepare for surgery. PMID- 29288786 TI - An Unusual Presentation of Metastatic Urothelial Bladder Carcinoma With Rhabdoid Features Presenting as Obstructive Uropathy. PMID- 29288787 TI - Robotic Appendiceal Interposition With Right Lower Pole Calycostomy, Downward Nephropexy, and Psoas Hitch for the Management of an Iatrogenic Near-complete Ureteral Avulsion. AB - Although iatrogenic ureteral injuries are rare, they have potentially devastating consequences for both patients and physicians, and their management remains challenging. We report a case of a 51-year-old morbidly obese (body mass index = 63) woman who suffered an iatrogenic 15-cm right ureteral avulsion during hysteroscopic biopsy. Preoperative antegrade and retrograde pyelograms demonstrated no true renal pelvis and a 3-cm blind-ending distal ureteral stump. The patient underwent a right robotic downward nephropexy, psoas hitch, lower pole calycostomy, and 11-cm appendiceal interposition. At 6 months postoperatively, renal scan demonstrated stable right renal function with no evidence of obstruction. PMID- 29288788 TI - Effect of Intercostal Nerve Block and Nephrostomy Tract Infiltration With Ropivacaine on Postoperative Pain Control After Tubeless Percutaneous Nephrolithotomy: A Prospective, Randomized, and Case-controlled Trial. AB - OBJECTIVE: To determine the efficacy of intercostal nerve block and nephrostomy tract infiltration (NTI) with ropivacaine in patients undergoing tubeless percutaneous nephrolithotomy (TPCNL). MATERIALS AND METHODS: From February 2015 to March 2017, a total of 226 patients undergoing TPCNL were enrolled. After excluding 130 patients who failed to meet the inclusion criteria, a total of 96 eligible patients were randomized into 3 groups: group I, control group (n = 32); group II, intercostal nerve block with 15 mL of 0.5% ropivacaine and epinephrine (n = 32); and group III, NTI with 20 mL of 0.25% ropivacaine and epinephrine (n = 32). Pain status was assessed at postoperative 2, 8, and 24 hours and at discharge by visual analog scale score at rest (RVAS) and on deep breathing and coughing. RESULTS: Patient demographics and perioperative data between groups were comparable except for length of stay. Mean RVAS scores at postoperative 2 and 8 hours for group III were significantly less than those for group I (RVAS at 2 hours: 2.6 vs 4.9, P = .001; RVAS at 8 hours: 1.7 vs 3.3, P = .007). Mean RVAS scores at postoperative 24 hours had borderline significance (P = .050) among the 3 groups. Differences in mean deep breathing and coughing scores among groups were statistically significant (P = .002) only in the first 2 hours. All postoperative complications (5.4%, 5 per 92) were of grade 1 and not significantly different among groups. CONCLUSION: NTI is safe and effective in alleviating early postoperative pain for patients who underwent TPCNL. PMID- 29288789 TI - See, Do, Teach? A Review of Contemporary Literature and Call to Action for Communication Skills Teaching in Urology. AB - OBJECTIVE: To assess the current state of published literature on communication skills teaching in urology to inform future directions for research and teaching. Excellent patient-physician communication skills increase understanding of medical conditions, facilitate shared decision-making regarding treatment planning, improve clinical outcomes, and decrease lawsuits. Surgical and procedure-based subspecialties, including urology, have generally been slow to incorporate formal communication skills teaching into curricula for postgraduate trainees. MATERIALS AND METHODS: We performed a PubMed literature search using multiple keywords, selecting and reviewing articles published in English, and addressing 1 of 3 domains (curriculum development, teaching methods, and assessment methods) of communication skills teaching. The distribution of articles within the urology-specific literature was compared with that of procedure-based specialties as a whole. RESULT: Eight articles were found in the urology literature, and 24 articles were found in other procedure-based specialties. Within the urology-specific literature, all 8 articles (100%) acknowledged the need for communication curriculum development, 1 article (12.5%) described how communication skills were taught, and 1 article (12.5%) discussed how communication skills were assessed. Fewer articles in other procedure-based specialties acknowledged the need to develop curricula (29.2%, P = .0007) but were equally likely to discuss communication skills teaching (37.5%, P = .63) and assessment (33.3%, P = .73). Orthopedic surgery is the only surgical subspecialty with ongoing, adaptable, formal training for physicians. CONCLUSION: Most current publications addressing communication skills in procedure-based specialties are specialty specific and focus on only 1 of the 3 communication domains. Opportunities exist to share information and to create more integrated models to teach communication skills in urology. PMID- 29288790 TI - Satisfaction With Testicular Prosthesis After Radical Orchiectomy. AB - OBJECTIVES: To determine patient satisfaction with testicular prostheses (TP) for testicular cancer. Reconstruction represents an important part of surgical oncology, yet placement of TP following orchiectomy is infrequently performed. Improved data on patient satisfaction with TP would help in counseling patients with testicular cancer. MATERIALS AND METHODS: Forty patients who underwent orchiectomy and TP placement for testicular cancer participated in a survey that was blinded to the providers in an outpatient clinic (2012-2014) to evaluate TP satisfaction. Categorical variables associated with satisfaction were compared using the Fisher's exact test. RESULTS: Median age at TP placement was 31 years (17-59). Most patients had their prosthesis in place for >1 year (81%) at the time of the survey. No patient reported complications from the TP and none underwent explantation. All patients felt that being offered an implant before orchiectomy was important. Overall, 33 patients (82.5%) rated the TP as good or excellent, and 35 men (87.5%) would have the prosthesis implanted again. Thirty seven patients (92.5%) found the TP to be comfortable or very comfortable. However, 44% considered the TP too firm and 20% felt the position was not appropriate. Appropriate size, appropriate position, and TP comfort were significantly associated with good or excellent overall TP satisfaction (P < .05). CONCLUSION: Overall satisfaction with testicular implants after orchiectomy for testicular cancer is high. Patients should be offered a testicular prosthesis, especially at the time of orchiectomy. Efforts should be made to optimize implant firmness, and care should be given to proper size selection and positioning. PMID- 29288791 TI - Chromatin modifications of hTERT gene in hTERT-immortalized human mesenchymal stem cells upon exposure to radiation. AB - Regulation of telomerase activity is thought to participate in the cellular response to ionizing radiation. Epigenetic mechanisms play a role in this regulation, as well as other mechanisms such as transcription, phosphorylation, etc. Here, we investigated chromatin modifications in telomerase promoter upon exposure to ionizing radiation in human mesenchymal stem cells (hMSC) and telomerase-immortalized hMSCs (hMSC-telo1) together with a hMSC-telo1 cell line in which TRF2 expression was partially repressed (siTRF2 hMSC-telo1). Histone methylations and acetylations were compared in all cell lines after exposure to various doses of ionizing radiation (0.1, 1, 2.5 and 15 Gy) using chromatin immunoprecipitation assay. hTERT gene was shown to be quickly regulated through H3, H4 acetylations, as well as with H3K4 and H3K9 methylations, following radiation exposure, although the kinetic of hMSC-telo1 cells were different, indicative of the higher radioresistivity of these cells. To the author's surprise, there was an upregulation of endogenous telomerase activity in the hMSC telo1 cells, even though the cells had already expressed high levels of ectopic hTERT. Our results show that telomerase regulation is one of the primary actions in response to damage and epigenetic factors play a major role in this regulation. Our results also suggested that partial silencing of TRF2 enhances the radiosensitivity of these cells, and endogenous telomerase is upregulated upon radiation, even under ectopic expression of hTERT in these cells. PMID- 29288792 TI - Distal deletion at 22q11.2 as differential diagnosis in Craniofacial Microsomia: Case report and literature review. AB - Craniofacial Microsomia (CFM) also known as Oculo-auriculo-vertebral Spectrum (OAVS) or Goldenhar Syndrome, presents wide phenotypic and etiological heterogeneity. It affects mainly the structures originated from the first and second pharyngeal arches. In addition, other major anomalies may also be found, including congenital heart diseases. In this study, we report a patient with distal deletion in the 22q11.2 region and a phenotype which resembles CFM. The proband is a girl, who presented bilateral preauricular tags, left auditory canal stenosis, malar hypoplasia, cleft lip and palate, mild asymmetry of soft tissue in face, congenital heart disease, intestinal atresia, annular pancreas and hydronephrosis. The genomic imbalances investigation by Multiplex Ligation dependent Probe Amplification (MLPA) and Chromosomal Microarray Analysis (CMA) revealed a distal deletion of 1,048 kb at 22q11.2 encompassing the region from Low Copy Repeats (LCRs) D to E. We did review of the literature and genotype phenotype correlation. This is the sixth case of distal 22q11.2 deletion resembling CFM and the second encompassing the region between LCRs D to E. All cases share some phenotypic signs, such as preauricular tags, facial asymmetry, cleft lip and palate, and congenital heart diseases. Candidate genes in this region have been studied by having an important role in pharyngeal arches developmental and in congenital heart diseases, such as HIC2, YPEL1and MAPK1/ERK2. This case corroborates the phenotypic similarity between 22q11.2 distal deletion and CFM/OAVS. It also contributes to genotype-phenotype correlation and reinforces that candidate genes for CFM, in the 22q11.2 region, might be located between LCRs D and E. PMID- 29288793 TI - Duplicated membrane estrogen receptors in the European sea bass (Dicentrarchus labrax): Phylogeny, expression and regulation throughout the reproductive cycle. AB - The numerous estrogen functions reported across vertebrates have been classically explained by their binding to specific transcription factors, the nuclear estrogen receptors (ERs). Rapid non-genomic estrogenic responses have also been recently identified in vertebrates including fish, which can be mediated by membrane receptors such as the G protein-coupled estrogen receptor (Gper). In this study, two genes for Gper, namely gpera and gperb, were identified in the genome of a teleost fish, the European sea bass. Phylogenetic analysis indicated they were most likely retained after the 3R teleost-specific whole genome duplication and raises questions about their function in male and female sea bass. Gpera expression was mainly restricted to brain and pituitary in both sexes while gperb had a widespread tissue distribution with higher expression levels in gill filaments, kidney and head kidney. Both receptors were detected in the hypothalamus and pituitary of both sexes and significant changes in gpers expression were observed throughout the annual reproductive season. In female pituitaries, gpera showed an overall increase in expression throughout the reproductive season while gperb levels remained constant. In the hypothalamus, gpera had a higher expression during vitellogenesis and decreased in fish entering the ovary maturation and ovulation stage, while gperb expression increased at the final atresia stage. In males, gpers expression was constant in the hypothalamus and pituitary throughout the reproductive cycle apart from the mid- to late testicular development stage transition when a significant up regulation of gpera occurred in the pituitary. The differential sex, seasonal and subtype-specific expression patterns detected for the two novel gper genes in sea bass suggests they may have acquired different and/or complementary roles in mediating estrogens actions in fish, namely on the neuroendocrine control of reproduction. PMID- 29288795 TI - miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6. AB - It has been suggested that microRNAs (miRs) are involved in the immune regulation of periodontitis. However, it is unclear whether and how miRs regulate the function of B cells in the context of periodontitis. This study is to explore the role of miR-146a on the inflammatory cytokine production of B cells challenged by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS). Primary B cells were harvested from mouse spleen. Quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of inflammatory cytokines in B cells in the presence or absence of P. gingivalis LPS and/or miR-146a. Bioinformatics, luciferase reporter assay and overexpression assay were used to explore the binding target of miR-146a. Our results showed that miR-146a level in B cells was elevated by P. gingivalis LPS stimulation, and the mRNA expressions of interleukin (IL)-1beta, 6 and 10, and IL 1 receptor associated kinase-1 (IRAK1), but not TNF receptor associated factor 6 (TRAF6), were also upregulated. The expression levels of IL-1beta, 6, 10 and IRAK1 were reduced in the presence of miR-146a mimic, but were elevated by the addition of miR-146a inhibitor. MiR-146a could bind with IRAK1 3' untranslated region (UTR) but not TRAF6 3'-UTR. Overexpression of IRAK1 reversed the inhibitory effects of miR-146a on IL-1beta, 6 and 10. In summary, miR-146a inhibits inflammatory cytokine production in B cells through directly targeting IRAK1, suggesting a regulatory role of miR-146a in B cell-mediated periodontal inflammation. PMID- 29288796 TI - DHA Mitigates Autistic Behaviors Accompanied by Dopaminergic Change in a Gene/Prenatal Stress Mouse Model. AB - Autism Spectrum Disorder (ASD) is characterized by impairments in social interaction, social communication, and repetitive and stereotyped behaviors. Recent work has begun to explore gene * environmental interactions in the etiology of ASD. We previously reported that prenatal stress exposure in stress susceptible heterozygous serotonin transporter (SERT) KO pregnant dams in a mouse model resulted in autism-like behavior in the offspring (SERT/S mice). The association between prenatal stress and ASD appears to be affected by maternal SERT genotype in clinical populations as well. Using the mouse model, we examined autistic-like behaviors in greater detail, and additionally explored whether diet supplementation with docosahexaenoic acid (DHA) may mitigate the behavioral changes. Only male SERT/S mice showed social impairment and stereotyped behavior, and DHA supplementation ameliorated some of these behaviors. We also measured monoamine levels in the SERT/S mice after three treatment paradigms: DHA-rich diet continuously from breeding (DHA diet), DHA-rich diet only after weaning (CTL/DHA diet) and control diet only (CTL diet). The dopamine (DA) content in the striatum was significantly increased in the SERT/S mice compared with wild-type (WT) mice, whereas no difference was observed with noradrenaline and serotonin content. Moreover, DA content in the striatum was significantly reduced in the SERT/S mice with the DHA-rich diet provided continuously from breeding. The results indicate that autism-associated behaviors and changes in the dopaminergic system in this setting can be mitigated with DHA supplementation. PMID- 29288794 TI - Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders. AB - The peptide neurotensin (Nts) was discovered within the brain over 40years ago and is implicated in regulating analgesia, body temperature, blood pressure, locomotor activity and feeding. Recent evidence suggests, however, that these disparate processes may be controlled via specific populations of Nts neurons and receptors. The neuronal mediators of Nts anorectic action are now beginning to be understood, and, as such, modulating specific Nts pathways might be useful in treating feeding and body weight disorders. This review considers mechanisms through which Nts normally regulates feeding and how disruptions in Nts signaling might contribute to the disordered feeding and body weight of schizophrenia, Parkinson's disease, anorexia nervosa, and obesity. Defining how Nts specifically mediates feeding vs. other aspects of physiology will inform the design of therapeutics that modify body weight without disrupting other important Nts mediated physiology. PMID- 29288798 TI - Molecular systematics and phylogenetic analysis of the Asian endemic freshwater sleepers (Gobiiformes: Odontobutidae). AB - The Odontobutidae is a group of freshwater sleepers endemic to East and Southeast Asia. The composition of the Odontobutidae is controversial and the systematics position of some species (e.g. Philypnus chalmersi) remains unknown. Phylogenetic relationship among the odontobutids has never been really tested due to the lack of informative morphological characters, and that molecular data have not been collected in many species. Here, we sampled 41 specimens, representing all known genera of the Odontobutidae except the Laotian genus Terateleotris, in addition to a disputable odontobutid species, Philypnus chalmersi and 14 outgroups (six families). We collected sequence data of 4434 single-copy nuclear coding loci using gene capture and Illumina sequencing. A robust phylogeny of the odontobutids and outgroups was built, confirming that the Odontobutidae is monophyletic and sister to the Rhyacichthyidae. We verified that Neodontobutis, Sineleotris and Philypnus chalmersi are members of the Odontobutidae based on the resulting phylogeny as well as patterns of pectoral girdle examined by X-ray microtomography. We proposed a new genus Microdous for Philypnus chalmersi based on the new morphological and molecular evidences. The family of the Odontobutidae can be divided into two clades: Microdous (=Philypnus) sister to a group consisting of Micropercops and Sineleotris, and Odontobutis sister to a group unifying Perccottus and Neodontobutis. Divergence time among the odontobutids was estimated based on 100 most clock-like loci and three fossil calibration points using BEAST. Ancestral range of the family was reconstructed using Reconstruct Ancestral States in Phylogenies (RASP) and BioGeoBEARS. The results suggest that the common ancestor of the odontobutids originated around 30.8 Ma (20.7-42.0 Ma, 95% HPDs) in South China. Orogeny, climatic change and river capture might account for diversification and current distribution of the odontobutids. PMID- 29288799 TI - Light signalling-induced regulation of nutrient acquisition and utilisation in plants. AB - Light is the foremost regulator of plant growth and development, and the critical role of light signalling in the promotion of nutrient uptake and utilisation was clarified in recent decades. Recent studies with Arabidopsis demonstrated the molecular mechanisms underlying such promotive effects and uncovered the pivotal role of the transcription factor ELONGATED HYPOCOTYL5 (HY5) whose activity is under the control of multiple photoreceptors. Together with a recent finding that phytochrome B, one of photoreceptors, is activated in subterranean plant parts, the discovery that HY5 directly promotes the transcription of genes involved in nutrient uptake and utilisation, including several nitrogen and sulphur assimilation-related genes, expands our understanding of the ways in which light signalling effectively and co-ordinately modulates uptake and utilisation of multiple nutrients in plants. This review presents a summary of the current knowledge regarding light signalling-induced regulation of nutrient uptake and utilisation. PMID- 29288797 TI - Peripheral Synthesis of an Atypical Protein Kinase C Mediates the Enhancement of Excitability and the Development of Mechanical Hyperalgesia Produced by Nerve Growth Factor. AB - Nerve growth factor (NGF) plays a key role in the initiation as well as the prolonged heightened pain sensitivity of the inflammatory response. Previously, we showed that NGF rapidly augmented both the excitability of isolated rat sensory neurons and the mechanical sensitivity of the rat's hind paw. The increase in excitability and sensitivity was blocked by the myristoylated pseudosubstrate inhibitor of atypical PKCs (mPSI), suggesting that an atypical PKC may play a key regulatory role in generating this heightened sensitivity. Our findings raised the question as to whether NGF directs changes in translational control, as suggested for long-lasting long-term potentiation (LTP), or whether NGF leads to the activation of an atypical PKC by other mechanisms. The current studies demonstrate that enhanced action potential (AP) firing produced by NGF was blocked by inhibitors of translation, but not transcription. In parallel, in vitro studies showed that NGF elevated the protein levels of PKMzeta, which was also prevented by inhibitors of translation. Intraplantar injection of NGF in the rat hind paw produced a rapid and maintained increase in mechanical sensitivity whose onset was delayed by translation inhibitors. Established NGF-induced hypersensitivity could be transiently reversed by injection of rapamycin or mPSI. These results suggest that NGF produces a rapid increase in the synthesis of PKMzeta protein in the paw that augments neuronal sensitivity and that the ongoing translational expression of PKMzeta plays a critical role in generating as well as maintaining the heightened sensitivity produced by NGF. PMID- 29288800 TI - The more adaptive to change, the more likely you are to survive: Protein adaptation in extremophiles. AB - Discovering how organisms and their proteins adapt to extreme conditions is a complicated process. Every condition has its own set of adaptations that make it uniquely stable in its environment. The purpose of our review is to discuss what is known in the extremophilic community about protein adaptations. To simplify our mission, we broke the extremophiles into three broad categories: thermophiles, halophiles and psychrophiles. While there are crossover organisms- organisms that exist in two or more extremes, like heat plus acid or cold plus pressure, most of them have a primary adaptation that is within one of these categories which tends to be the most easily identifiable one. While the generally known adaptations are still accepted, like thermophilic proteins have increased ionic interactions and a hardier hydrophobic core, halophilic proteins have a large increase in acidic amino acids and amino acid/peptide insertions and psychrophiles have a much more open structure and reduced ionic interactions, some new information has come to light. Thermophilic stability can be improved by increased subunit-subunit or subunit-cofactor interactions. Halophilic proteins have reversible folding when in the presence of salt. Psychrophilic proteins have an increase in cavities that not only decrease the formation of ice, but also increase flexibility under low temperature conditions. In a proof of concept experiment, we applied what is currently known about adaptations to a well characterized protein, malate dehydrogenase (MDH). While this protein has been profiled in the literature, we are applying our adaptation predictions to its sequence and structure to see if the described adaptations apply. Our analysis demonstrates that thermophilic and halophilic adaptations fit the corresponding MDHs very well. However, because the number of psychrophiles MDH sequences and structures is low, our analysis on psychrophiles is inconclusive and needs more information. By discussing known extremophilic adaptations and applying them to a random, conserved protein, we have found that general adaptations are conserved and can be predicted in proposed extremophilic proteins. The present field of extremophile adaptations is discovering more and more ways organisms and their proteins have adapted. The more that is learned about protein adaptation, the closer we get to custom proteins, designed to fit any extreme and solve some of the world's most pressing environmental problems. PMID- 29288801 TI - Enhanced spectral density mapping through combined multiple-field deuterium 13CH2D methyl spin relaxation NMR spectroscopy. AB - Quadrupolar relaxation of 2H (D) nuclear spins is a powerful probe of conformational dynamics in biological macromolecules. Deuterium relaxation rate constants are determined by the spectral density function for reorientation of the C-D bond vector at zero, single-quantum, and double-quantum 2H frequencies. In the present work, 2H relaxation rate constants were measured for an E. coli ribonuclease H [U-2H, 15N] ILV-[13CH2D] sample using 400, 500, 800, and 900 MHz NMR spectrometers and analyzed by three approaches to determine spectral density values. First, data recorded at each static magnetic field were analyzed independently. Second, data recorded at 400 and 800 MHz were analyzed jointly and data recorded at other fields were analyzed independently. Third, data recorded at 400 and 500 MHz were interpolated to 450 MHz, and the resulting two pairs of data, corresponding to 400 MHz/800 MHz and 450 MHz/900 MHz, were analyzed jointly. The second and third approaches rely on the identity between the double quantum frequency at the lower field and the single quantum frequency at the higher field. Spectral density values for 32 of the 48 resolvable ILV methyl resonances were fit by the Lipari-Szabo model-free formalism and used to validate the three methods. The three spectral density mapping methods performed equally well in cross validation with data recorded at 700 MHz. However, the third method yielded approximately 10-15% more precise estimates of model-free parameters and consequently provides a general strategy for analysis of 2H spin relaxation data in biological macromolecules. PMID- 29288802 TI - Increasing extracellular cGMP in cerebellum in vivo reduces neuroinflammation, GABAergic tone and motor in-coordination in hyperammonemic rats. AB - Hyperammonemia is a main contributor to cognitive impairment and motor in coordination in patients with hepatic encephalopathy. Hyperammonemia-induced neuroinflammation mediates the neurological alterations in hepatic encephalopathy. Intracerebral administration of extracellular cGMP restores some but not all types of cognitive impairment. Motor in-coordination, is mainly due to increased GABAergic tone in cerebellum. We hypothesized that extracellular cGMP would restore motor coordination in hyperammonemic rats by normalizing GABAergic tone in cerebellum and that this would be mediated by reduction of neuroinflammation. The aims of this work were to assess whether chronic intracerebral administration of cGMP to hyperammonemic rats: 1) restores motor coordination; 2) reduces neuroinflammation in cerebellum; 3) reduces extracellular GABA levels and GABAergic tone in cerebellum; and also 4) to provide some advance in the understanding on the molecular mechanisms involved. The results reported show that rats with chronic hyperammonemia show neuroinflammation in cerebellum, including microglia and astrocytes activation and increased levels of IL-1b and TNFa and increased membrane expression of the TNFa receptor. This is associated with increased glutaminase expression and extracellular glutamate, increased amount of the GABA transporter GAT-3 in activated astrocytes, increased extracellular GABA in cerebellum and motor in coordination. Chronic intracerebral administration of extracellular cGMP to rats with chronic hyperammonemia reduces neuroinflammation, including microglia and astrocytes activation and membrane expression of the TNFa receptor. This is associated with reduced nuclear NF-kappaB, glutaminase expression and extracellular glutamate, reduced amount of the GABA transporter GAT-3 in activated astrocytes and reduced extracellular GABA in cerebellum and restoration of motor coordination. The data support that extracellular cGMP restores motor coordination in hyperammonemic rats by reducing microglia activation and neuroinflammation, leading to normalization of extracellular glutamate and GABA levels in cerebellum and of motor coordination. PMID- 29288803 TI - Cardioprotection after acute exposure to simulated high altitude in rats. Role of nitric oxide. AB - AIM: In previous studies, upregulation of NOS during acclimatization of rats to sustained hypobaric hypoxia was associated to cardioprotection, evaluated as an increased tolerance of myocardium to hypoxia/reoxygenation. The objective of the present work was to investigate the effect of acute hypobaric hypoxia and the role of endogenous NO concerning cardiac tolerance to hypoxia/reoxygenation under beta-adrenergic stimulation. METHODS: Rats were submitted to 58.7 kPa in a hypopressure chamber for 48 h whereas their normoxic controls remained at 101.3 kPa. By adding NOS substrate L-arg, or blocker L-NNA, isometric mechanical activity of papillary muscles isolated from left ventricle was evaluated at maximal or minimal production of NO, respectively, under beta-adrenergic stimulation by isoproterenol, followed by 60/30 min of hypoxia/reoxygenation. Activities of NOS and cytochrome oxidase were evaluated by spectrophotometric methods and expression of HIF1-alpha and NOS isoforms by western blot. Eosin and hematoxiline staining were used for histological studies. RESULTS: Cytosolic expression of HIF1-alpha, nNOS and eNOS, and NO production were higher in left ventricle of hypoxic rats. Mitochondrial cytochrome oxidase activity was decreased by hypobaric hypoxia and this effect was reversed by L-NNA. After H/R, recovery of developed tension in papillary muscles from normoxic rats was 51-60% (regardless NO modulation) while in hypobaric hypoxia was 70% +/- 3 (L-arg) and 54% +/- 1 (L-NNA). Other mechanical parameters showed similar results. Preserved histological architecture was observed only in L-arg papillary muscles of hypoxic rats. CONCLUSION: Exposure of rats to hypobaric hypoxia for only 2 days increased NO synthesis leading to cardioprotection. PMID- 29288804 TI - Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia: exercise training and moderate compensated heart failure. AB - Nitric oxide (NO) modulates oxygen delivery-utilization matching in resting and contracting skeletal muscle. Recent reports indicate that neuronal NO synthase (nNOS)-mediated vasoregulation during contractions is enhanced with exercise training and impaired with chronic heart failure (HF). Consequently, we tested the hypothesis that selective nNOS inhibition (S-methyl-l-thiocitrulline; SMTC, 2.1 MUmol/kg) would produce attenuated reductions in muscle blood flow during moderate/heavy submaximal exercise in sedentary HF rats compared to their healthy counterparts. In addition, SMTC was expected to evoke greater reductions in exercising muscle blood flow in trained compared to sedentary healthy and HF rats. Blood flow during submaximal treadmill running (20 min/m, 5% grade) was determined via radiolabeled microspheres pre- and post-SMTC administration in healthy sedentary (Healthy + Sed, n = 8), healthy exercise trained (Healthy + ExT, n = 8), HF sedentary (HF + Sed, left ventricular end-diastolic pressure (LVEDP) = 12 +/- 1 mmHg, n = 8), and HF exercise trained (HF + ExT, LVEDP = 16 +/ 2 mmHg, n = 7) rats. nNOS contribution to exercising total hindlimb blood flow (ml/min/100 g) was not increased by training in either healthy or HF groups (Healthy + Sed: 105 +/- 11 vs. 108 +/- 16; Healthy + ExT: 96 +/- 9 vs. 91 +/- 7; HF + Sed: 124 +/- 6 vs. 110 +/- 12; HF + ExT: 107 +/- 13 vs. 101 +/- 8; control vs. SMTC, respectively; p > .05 for all). Similarly, SMTC did not reduce exercising blood flow in the majority of individual hindlimb muscles in any group (p > .05 for all, except for the semitendinosus and adductor longus in HF + Sed and the adductor longus in HF + ExT; p < .05). Contrary to our hypothesis, we find no support for either upregulation of nNOS function contributing to exercise hyperemia after training or its dysregulation with chronic HF. PMID- 29288805 TI - The ability of two in vitro lipolysis models reflecting the human and rat gastro intestinal conditions to predict the in vivo performance of SNEDDS dosing regimens. AB - In this work, the influence of drug load and physical state of R3040 in self nanoemulsifying drug delivery systems (SNEDDS) on R3040 absorption in rats was assessed. Furthermore, an in vitro lipolysis model simulating rat conditions (rat lipolysis model) was compared to a human lipolysis model in regard to the prediction of the in vivo data. The formulations were SNEDDS 80%, containing R3040 at 80% of its equilibrium solubility in SNEDDS (Seq); super-SNEDDS solution with R3040 supersaturated at 200% Seq; super-SNEDDS suspension containing R3040 at 200% Seq; Chasing principle (drug-free SNEDDS followed by R3040 aqueous suspension) and R3040 aqueous suspension. The pharmacokinetic profiles of R3040 in SNEDDS 80% and super-SNEDDS solution 200% were superimposed and higher than for super-SNEDDS suspension 200%, Chasing principle and aqueous suspension. Therefore, dosing R3040 dissolved in SNEDDS increased R3040 absorption irrespective of the drug load. While the human lipolysis model could not predict the rank order of absorption of the formulations, the rat lipolysis model predicted the similar absorption of R3040 in SNEDDS 80% and super-SNEDDS solution 200%. Thus, the rat lipolysis model showed to be an important step towards predictive in vitro models for rat studies. PMID- 29288806 TI - Transparent predictive modelling of the twin screw granulation process using a compensated interval type-2 fuzzy system. AB - In this research, a new systematic modelling framework which uses machine learning for describing the granulation process is presented. First, an interval type-2 fuzzy model is elicited in order to predict the properties of the granules produced by twin screw granulation (TSG) in the pharmaceutical industry. Second, a Gaussian mixture model (GMM) is integrated in the framework in order to characterize the error residuals emanating from the fuzzy model. This is done to refine the model by taking into account uncertainties and/or any other unmodelled behaviour, stochastic or otherwise. All proposed modelling algorithms were validated via a series of Laboratory-scale experiments. The size of the granules produced by TSG was successfully predicted, where most of the predictions fit within a 95% confidence interval. PMID- 29288807 TI - Major inpatient surgeries and in-hospital mortality in New South Wales public hospitals in Australia: A state-wide retrospective cohort study. AB - BACKGROUND: Surgical interventions save lives and are important focus for health services research worldwide. Investigating variation in postoperative mortality may improve understanding of unwarranted variations and promote safety and quality in surgical care. We aimed to evaluate trends of in-hospital mortality rates among adult inpatients receiving major elective surgeries and determine the variation in mortality among New South Wales (NSW) public hospitals. MATERIALS AND METHODS: In this study, we used the all-inclusive population-based NSW Admitted Patient Data from July 2001 to June 2014. We retrospectively included adult patients aged 18+ years receiving Abdominal Aortic Aneurysm (AAA) repair, Peripheral bypass, Colorectal surgeries, Joint replacement, Spinal surgeries, or Cardiac surgeries. The primary outcome was in-hospital mortality for selected surgeries. Changes in mortality rates over time and hospital standardised mortality rates were modelled using multivariate logistic regression models adjusting for case-mix factors. RESULTS: Over 13-year study period, the in hospital mortality rates declined annually by 6.4% (95% Confidence Interval (CI): 4.3, 8.4) for Colorectal surgery by 5.7% (95%CI: 2.0, 9.3) for Joint replacement and by 4.2% (95%CI: 1.9, 6.4) for Cardiac surgery. After controlling for patient level factors, little variation was observed among hospitals for in-hospital mortality. There was a greater variability for cardiac surgery compared with the other surgical groups but no outlier hospital was consistently associated with significantly higher than expected mortality rate. CONCLUSIONS: Mortality has declined for major surgeries in the past 15 years. There was some variation among hospitals regarding in-hospital mortality that was mostly explained by patients demographic and admission characteristics. Our findings are reassuring for patients and contribute to knowledge that can help further improve surgical care. PMID- 29288808 TI - Mucus adhesion- and penetration-enhanced liposomes for paclitaxel oral delivery. AB - Low aqueous solubility and intestinal permeability limit the oral chemotherapy efficacy of paclitaxel (PTX). Traditional nanodrug delivery systems show excellent aqueous solubility improved ability of PTX. However, gastrointestinal (GI) mucus limits the improvement of intestinal permeability in traditional nanodrug delivery systems. A novel mucus adhesion- and penetration-functionalized chitosan-thioglycolic acid-Pluronic F127 (CS-TGA-PF) liposome system was developed for PTX oral delivery. The optimized formulation of PTX-loaded CS-TGA PF liposomes showed particle size of 121.4 nm and zeta potential of 50.2 mV. CS TGA-PF liposomes were more stable than unmodified liposomes and demonstrated a sustained-release manner of PTX incubated in simulated gastric fluid and intestinal fluid. CS-TGA-PF liposomes absorbed a three-fold amount of mucin compared with that of unmodified liposomes, which would prolong the residence time of liposomes on the mucosal surface in the intestinal tract. The intestinal mucus adhesion- and penetration-enhanced efficacy of CS-TGA-PF liposomes for intestinal PTX delivery was studied by observing the intestinal absorption and distribution. Results exhibited increased liposome uptake by the GI mucosa and improved drug intestinal absorption. In conclusion, the dual functional CS-TGA-PF liposomes with mucus adhesion- and permeation-enhanced properties could be used as a promising nanodrug delivery system for PTX oral delivery. PMID- 29288809 TI - Accelerated full-thickness wound healing via sustained bFGF delivery based on a PVA/chitosan/gelatin hydrogel incorporating PCL microspheres. AB - Herein, a hybrid hydrogel/microsphere system is introduced for accelerated wound healing by sustained release of basic fibroblast growth factor (bFGF). The hydrogel is composed of a mixture of PVA, gelatin and chitosan. The double emulsion-solvent-evaporation method was utilized to obtain microspheres composed of PCL, as the organic phase, and PVA, as the aqueous phase. Subsequently, various in-vitro and in-vivo assays were performed to characterize the system. BSA was used to optimize the release mechanism, and encapsulation efficiency in microspheres, where a combination of 3% (w/v) PCL and 1% (w/v) PVA was found to be the optimum microsphere sample. Incorporation of microspheres within the hydrogel substrate also led to a zero-order release kinetics. Results from SEM images, also represented an average porosity of 54%, and average mean pore size of 35 +/- 7 MUm for the hydrogel system, and the diameter of 5 +/- 2 MUm for the microspheres. Moreover, in vivo study including wound healing process, and histological analysis regarding re-epithelization, angiogenesis, inflammation, fibroblast genesis and collagen formation were performed using Hematoxyline-Eosin (H&E) staining, Periodic Acid-Schiff (PAS) staining and Masson's Trichrome staining. In-vivo results represented that sustained delivery of bFGF promoted by biocompatibility of PVA/chitosan/gelatin hydrogel, significantly contribute to accelerated wound healing. PMID- 29288810 TI - Zinc delivery from non-woven fibres within a therapeutic nipple shield. AB - A Therapeutic Nipple Shield (TNS) was previously developed to respond to the global need for new infant therapeutic delivery technologies. However, the release efficiency for the same Active Pharmaceutical Ingredient (API) from different therapeutic matrices within the TNS formulation has not yet been investigated. To address this, in-vitro release of elemental zinc into human milk from two types of Texel non-woven fibre mats of varying thickness and different gram per square meter values, placed inside the TNS was explored and compared to the release from zinc-containing rapidly disintegrating tablets. In-vitro delivery was performed by means of a breastfeeding simulation apparatus, with human milk flow rates and suction pressure adjusted to physiologically relevant values, and release was quantified using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). It was found that a total recovery of 62-64 % elemental zinc was obtained after the human milk had passed through the fibre insert, amounting to a 20-48% increase compared to previous zinc delivery studies using rapidly disintegrating tablets within the TNS. This indicates that non woven Texel fibre mats were identified as the superior dosage form for oral zinc delivery into human milk using a TNS. PMID- 29288811 TI - Effects of dietary oxidized fish oil supplementation on oxidative stress and antioxidant defense system in juvenile rainbow trout (Oncorhynchus mykiss). AB - The objective of the study was to characterize the response of the antioxidant defense system against dietary prooxidant conditions in rainbow trout juveniles. Fish (initial mean weight: 62 +/- 1 g) were fed three fishmeal and plant-derived protein-based diets supplemented with 15% fresh fish oil (CTL diet), 15% fresh fish oil from tuna by-products (BYP diet) or 15% autooxidized fish oil (OX diet) over a 12-week growth trial at 17.5 +/- 0.5 degrees C. No significant differences in growth performance were recorded between dietary groups. Muscle lipid content was reduced and n-6 PUFA levels were increased in rainbow trout fed diets BYP and OX compared to CTL. After 12 weeks of feeding, the level of lipid peroxidation products in muscle was not affected whereas the 8-isoprostane content in liver was increased in fish fed diet OX as well as plasma total and oxidized glutathione contents. The hepatic and muscle contents for alpha tocopherol were decreased in fish fed BYP and OX. Hepatic antioxidant enzyme activities and mRNA levels were not affected after 12 weeks of feeding, except for catalase and glutathione peroxidase 1b2 mRNA levels that were decreased in trout fed diet OX. Fish fed diet OX and BYP displayed also reduced cytosolic Nrf2 and both cytosolic and nuclear NF-kappaB protein levels in liver. The present work indicates that feeding rainbow trout juveniles with fresh fish oil from by products or moderately oxidized lipid appears not to be detrimental to the growth performance of fish. The mechanisms beyond the control of the antioxidant defense system by moderately oxidized lipid require further investigations in rainbow trout juveniles. PMID- 29288812 TI - Flow cytometic analysis of Penaeus monodon haemocyte responses to poly I:C. AB - This study was aimed at investigating the cellular responses of Penaeus monodon haemocytes to poly I:C stimulation using flow cytometric assay. Total haemocyte count (THC), percentages of different haemocyte subpopulations [hyaline cells (HC), semigranular cells (SGC) and granular cells (GC)], non-specific esterase activity (EA), total reactive oxygen species/reactive nitrogen species (ROS/RNS) production, nitric oxide (NO) production, apoptotic haemocyte ratio and plasmic phenoloxidase (PO) activity were determined in poly I:C-injected shrimp. Results showed that poly I:C at a low dose (5 MUg shrimp-1) caused obvious increases in THC, GC proportion, ROS/RNS production and NO production, but had no significant effect on EA, apoptosis and PO activity. In the early stage of poly I:C injection at a high dose (20 MUg shrimp-1), THC and GC proportion improvements could also be observed, suggesting that GC might be induced to release from hemocytopoietic or other tissues to participate in immune response, and this subpopulation might be the main cell type involved in the cellular defence against virus. In the later period, proportions of both GC and SGC reduced paralleled by THC reduction, indicating that depletion of GC and SGC was mainly contributed to the reduced count of circulating haemocyte. Obvious increases in ROS/RNS production and NO production were induced in haemocyte of shrimp under a high dose of poly I:C stimulation, but only slight rise of EA and suppression of PO activity could be observed in poly I:C-stimulated shrimp, suggesting that ROS/RNS-dependent system was vital in the immune defence of shrimp against virus. On the other hand, increase of apoptotic haemocyte ratio and THC reduction were presented after the drastic increases of ROS/RNS and NO productions, implying that the stimulated ROS/RNS might be excess and harmful, and was the major factor for the haemocyte apoptosis and depletion. THC recovered after 48 h injection, while haemocyte apoptosis also returned to the control level, suggesting that apoptosis might be contributed to eliminate damaged, weak or infected haemocytes to renew the circulating haemocytes, and it could be considered as an important defending strategy against virus. PMID- 29288813 TI - Procedures for leukocytes isolation from lymphoid tissues and consequences on immune endpoints used to evaluate fish immune status: A case study on roach (Rutilus rutilus). AB - The effects of two protocols (density gradient versus hypotonic lysis) used for leukocyte isolation from three major lymphoid tissue of fish (head-kidney, spleen and blood) were examined on some cell functional activities (tissue leucocytes distributions, phagocytosis, basal and burst oxidative activities) classically used to estimate the fish immune status. Experiments were conducted on roach (Rutilus rutilus), a cyprinid fish model often studied in different eco physiological contexts (aquaculture, ecotoxicology ...). All of immune endpoints were assessed either immediately after cell isolation or after a 12 h of incubation in order to observe if a post-isolation incubation may influence the leukocytes activities. Compared to the density gradient, hypotonic lysis is associated with granulocytes enrichments of cell suspensions. This is particularly true for leukocyte suspensions isolated from head kidney where granulocytes are naturally abundant. However, important variabilities in leukocyte distributions were observed in head kidney and spleen cells samples obtained by the use of hypotonic lysis for two incubation conditions used (no incubation or 12 h of incubation at 4 degrees C). The density gradient protocol leads to a transitory increase in basal ROS production in spleen lymphocytes and macrophages The blood leukocytes isolated by this same method exhibit high basal oxidative activities after 12 h of incubation at 4 degrees C and for the three leukocyte types (lymphocytes, monocytes and granulocytes). The hypotonic lysis is associated with an increase in PMA-induced ROS production especially in head kidney leukocytes. The increases in cell oxidative activities are consistent with increases in granulocyte proportions observed in leukocyte suspensions obtained by hypotonic lysis. Finally, the two protocols have no effect on leukocyte mortality and phagocytic activity. Within limits of our experimental conditions, the spleen is the organ whose leukocyte oxidative activities (stimulated or not) are only slightly influenced by the methods used for leukocyte isolation. This is also the case for the anterior kidney, but for this tissue, it is necessary to incubate the isolated cells for 12 h at 4 degrees C before functional analyses. Each of the two methodologies used has advantages and disadvantages. The hypotonic lysis allows to isolate a greater variety of leukocytes types whereas the density gradient used ensures a better stability of cells distributions over time. However, for the same fish species and for the same tissue, the method used to isolate leukocytes influences results and must be taken into consideration during acquired data analysis for evaluation of fish immune status. PMID- 29288814 TI - Immune response of Exopalaemon carinicauda infected with an AHPND-causing strain of Vibrio parahaemolyticus. AB - To investigate the immune response of Exopalaemon carinicauda infected with an AHPND-causing strain of Vibrio parahaemolyticus (VPAHPND), three-generation breeding of shrimp selected for their survival to VPAHPND infection was applied to explore the relationship between immune parameters and AHPND-resistant capacity of E. carinicauda. In this study, the LD50 dose of 48 h and survival rates at 144 h of shrimp to VPAHPND increased from 106.0 to 106.6 cfu ml-1 and from 26.67% to 36.67% by three successive generations selection, respectively, while there was no significant difference between the first and second generation (p > .05). Then the immune parameters including vibrio density, total hemocyte counts (THCs), hemocyanin (HEM) concentration, antibacterial activity, activities of four immune enzymes, and expressions of eight immune-related genes were determined in the shrimp of the first (G1) and the third selective generation (G3). The results showed that the shrimp in G1 and G3 generation cleared most of VPAHPND infecting hepatopancreas during 24 h and 6 h post injection, respectively. The levels of THCs, HEM concentration, antibacterial activity, immune enzymes including lysozyme (LZM) activity, alkaline phosphatase (AKP) activity in cell-free hemolymph, and the expression levels of Tollip, ALF, cathepsin B in hemocytes and hepatopancreas, crustin, LZM, SR in hepatopancreas and LGBP in hemocytes were higher in G3 generation than in G1 generation after infection with VPAHPND, suggesting that these parameters may serve as potential disease-resistant indicators for evaluating the physiological status and disease resistant capability of shrimp when infected with VPAHPND. To further test the role of above genes in the shrimp immune response, RNAi was used to suppress their expressions and a significant decrease in survival was observed in knockdown shrimp infected with VPAHPND as compared to controls. PMID- 29288815 TI - Soluble protein fraction of human seminal plasma. PMID- 29288816 TI - Practical and secure telemedicine systems for user mobility. AB - The application of wireless devices has led to a significant improvement in the quality delivery of care in telemedicine systems. Patients who live in a remote area are able to communicate with the healthcare provider and benefit from the doctor consultations. However, it has been a challenge to provide a secure telemedicine system, which captures users (patients and doctors) mobility and patient privacy. In this work, we present several secure protocols for telemedicine systems, which ensure the secure communication between patients and doctors who are located in different geographical locations. Our protocols are the first of this kind featured with confidentiality of patient information, mutual authentication, patient anonymity, data integrity, freshness of communication, and mobility. Our protocols are based on symmetric-key schemes and capture all desirable security requirements in order to better serve our objectives of research for secure telemedicine services; therefore, they are very efficient in implementation. A comparison with related works shows that our work contributes first comprehensive solution to capture user mobility and patient privacy for telemedicine systems. PMID- 29288817 TI - Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party. AB - Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT. PMID- 29288818 TI - Revaccination after Autologous Hematopoietic Stem Cell Transplantation Is Safe and Effective in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance. AB - Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases. PMID- 29288819 TI - Stem Cell Transplantation and Informatics: Current Considerations. AB - Informatics strategies and applications available to stem cell transplant (SCT) programs are diverse and changing rapidly. Although most hospitals have electronic medical records (EMRs), few are equipped with specialized SCT applications. Most EMRs do not contain critical elements to support SCT practice and research. Strategies to optimize information technology resources to support SCT programs are reviewed and technical and workflow support discussed. Guidance and rationale for the use of both SCT applications and EMRs are emphasized. PMID- 29288820 TI - Perceived Workforce Challenges among Clinical Social Workers in Hematopoietic Cell Transplantation Programs. AB - Clinical social workers are psychosocial care experts who provide interventions that aim to address the emotional, relational, financial, and logistical challenges that arise throughout the hematopoietic cell transplantation (HCT) treatment and recovery process. Interventions that contribute to better patient outcomes can include cognitive behavioral therapy and counseling for adaptation to illness, family planning for 24/7 caregiver availability and strategies to support patient activities of daily living, instruction on guided imagery and relaxation techniques for symptom management and to decrease anxiety, psychoeducation on the treatment trajectory, and linkage with financial resources. A Social Work Workforce Group (SWG) was established through the System Capacity Initiative, led by the National Marrow Donor Program/Be The Match, to characterize the current social work workforce capacity and challenges. The SWG conducted a web-based survey of HCT clinical social workers in the United States. The response rate was 57% (n = 90), representing 76 transplant centers. Survey results indicated that the clinical social worker role and scope of practice varies significantly between centers; less than half of respondents reported that their clinical social work expertise was used to its fullest potential. With an estimated 3-fold increase in HCT patient volume by 2020, the need for specialized psychosocial health services will increase. The SWG makes recommendations to build capacity for the psychosocial care of HCT patients and to more fully integrate the social worker as a core member of the HCT team. The SWG created a Blood and Marrow Transplant (BMT) Clinical Social Worker role description that can be used by transplant centers to educate healthcare professionals, benchmark utilization of clinical social workers, and improve comprehensive psychosocial health programs. PMID- 29288821 TI - Reduced-Intensity Allogeneic Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome Using Combined CD34-Selected Haploidentical Graft and a Single Umbilical Cord Unit Compared with Matched Unrelated Donor Stem Cells in Older Adults. AB - Haplo/cord transplantation combines an umbilical cord blood (UCB) graft with CD34 selected haploidentical cells and results in rapid hematopoietic recovery followed by durable UCB engraftment. We compared outcomes of transplants in older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) who received either HLA-matched unrelated donor (MUD) cells or haplo/cord grafts. Between 2007 and 2013, 109 adults ages 50 and older underwent similar reduced-intensity conditioning with fludarabine and melphalan and antibody mediated T cell depletion for AML (n = 83) or high-risk MDS (n = 26) followed by either a MUD (n = 68) or haplo/cord (n = 41) graft. Patient characteristics were similar for each graft source except for more minority patients receiving a haplo/cord transplant (P = .01). One half of the AML patients were not in remission. Two-year progression-free survival (PFS), overall survival (OS), and graft-versus-host disease-free relapse-free survival were 38%, 48%, and 32.1% for MUD and 33%, 48%, and 33.8% for haplo/cord transplants (P = .62 for PFS; P = .97 for OS; P= .84), respectively. Acute grades II to IV and chronic graft-versus host-disease rates did not differ at 19.5% and 4.9% in haplo/cord compared with 25% and 7.4% after MUD (P = .53 and P = .62, respectively). Multivariate analysis confirmed no significant differences in transplant outcomes by donor type. Haplo/cord reduced-intensity transplantation achieves similar outcomes relative to MUD in older AML and MDS patients, making this a promising option for those without matched donors. PMID- 29288822 TI - Copper-containing mesoporous bioactive glass promotes angiogenesis in an in vivo zebrafish model. AB - : The osteogenic and angiogenic responses of organisms to the ionic products of degradation of bioactive glasses (BGs) are being intensively investigated. The promotion of angiogenesis by copper (Cu) has been known for more than three decades. This element can be incorporated to delivery carriers, such as BGs, and the materials used in biological assays. In this work, Cu-containing mesoporous bioactive glass (MBG) in the SiO2-CaO-P2O5 compositional system was prepared incorporating 5% mol Cu (MBG-5Cu) by replacement of the corresponding amount of Ca. The biological effects of the ionic products of MBG biodegradation were evaluated on a well-known endothelial cell line, the bovine aorta endothelial cells (BAEC), as well as in an in vivo zebrafish (Danio rerio) embryo assay. The results suggest that ionic products of both MBG (Cu free) and MBG-5Cu materials promote angiogenesis. In vitro cell cultures show that the ionic dissolution products of these materials are not toxic and promote BAEC viability and migration. In addition, the in vivo assay indicates that both exposition and microinjection of zebrafish embryos with Cu free MBG material increase vessel number and thickness of the subintestinal venous plexus (SIVP), whereas assays using MBG-5Cu enhance this effect. STATEMENT OF SIGNIFICANCE: Mesoporous bioactive glasses (MBGs) with high specific surface area, well-ordered pores, large pore volumes and controllable amount of ions are interesting to develop controlled drug delivery systems for bone tissue regeneration. Copper (Cu) incorporation to the basic SiO2-CaO-P2O5 composition has attracted high interest due to its multifunctional biological properties. Promotion of angiogenesis is one of these properties, which can be integrated to the biomaterial with lower cost and higher stability when compared with growth factors. This work reports the synthesis and characterization of Cu-containing MBG evaluating its angiogenic properties in the subintestinal vessel zebrafish assay. This transgenic in vivo assay is merging as an alternative model providing short-time consuming protocols and facilities during pro-angiogenic drug screenings. The report shows that the ionic products of this MBG material delivered to the zebrafish incubation media significantly enhance angiogenesis in comparison with control groups. Besides, results indicate Cu ions may exhibit a synergic effect with Si, Ca, and P ions in angiogenesis stimulation both in vitro and in vivo. To our knowledge, this is the first time that zebrafish in vivo assays are used to evaluate angiogenic activity of ionic dissolution products from MBG materials. PMID- 29288823 TI - High resolution 3D microscopy study of cardiomyocytes on polymer scaffold nanofibers reveals formation of unusual sheathed structure. AB - : Building functional and robust scaffolds for engineered biological tissue requires a nanoscale mechanistic understanding of how cells use the scaffold for their growth and development. A vast majority of the scaffolds used for cardiac tissue engineering are based on polymer materials, the matrices of nanofibers. Attempts to load the polymer fibers of the scaffold with additional sophisticated features, such as electrical conductivity and controlled release of the growth factors or other biologically active molecules, as well as trying to match the mechanical features of the scaffold to those of the extracellular matrix, cannot be efficient without a detailed knowledge of how the cells are attached and strategically positioned with respect to the scaffold nanofibers at micro and nanolevel. Studying single cell - single fiber interactions with the aid of confocal laser scanning microscopy (CLSM), scanning probe nanotomography (SPNT), and transmission electron microscopy (TEM), we found that cardiac cells actively interact with substrate nanofibers, but in different ways. While cardiomyocytes often create a remarkable "sheath" structure, enveloping fiber and, thus, substantially increasing contact zone, fibroblasts interact with nanofibers in the locations of focal adhesion clusters mainly without wrapping the fiber. STATEMENTS OF SIGNIFICANCE: We found that cardiomyocytes grown on electrospun polymer nanofibers often create a striking "sheath" structure, enveloping fiber with the formation of a very narrow (~22 nm) membrane gap leading from the fiber to the extracellular space. This wrapping makes the entire fiber surface available for cell attachment. This finding gives a new prospective view on how scaffold nanofibers may interact with growing cells. It may play a significant role in effective design of novel nanofiber scaffolds for tissue engineering concerning mechanical and electrical properties of scaffolds as well as controlled drug release from "smart" biomaterials. PMID- 29288824 TI - Inhaled Lavandula angustifolia essential oil inhibits consolidation of contextual but not tone-fear conditioning in rats. AB - Although the current treatment for anxiety is effective, it promotes a number of adverse reactions and medical interactions. Inhaled essential oils have a prominent action on the central nervous system, with minimal systemic effects, primarily because of reduced systemic bioavailability. The effects of drugs on the consolidation of fear conditioning reflects its clinical efficacy in preventing a vicious cycle of anticipatory anxiety leading to fearful cognition and anxiety symptoms. In this study, we investigated the effects of inhaled Lavandula angustifolia essential oil on the consolidation of aversive memories and its influence on c-Fos expression. Adult male Wistar rats were subjected to a fear conditioning protocol. Immediately after the training session, the rats were exposed to vaporized water or essential oil (1%, 2.5% and 5% solutions) for 4h. The next day, the rats underwent contextual- or tone-fear tests and 90min after the test they were euthanized and their brains processed for c-Fos immunohistochemistry. In the contextual-fear test, essential oil at 2.5% and 5% (but not 1%) reduced the freezing response and its respective c-Fos expression in the ventral hippocampus and amygdala. In the tone-fear test, essential oil did not reduce the freezing response during tone presentation. However, rats that inhaled essential oil at 2.5% and 5% (but not 1%) showed decreased freezing in the three minutes after tone presentation, as well as reduced c-Fos expression in the prefrontal cortex and amygdala. These results show that the inhalation of L. angustifolia essential oil inhibited the consolidation of contextual- but not tone-fear conditioning and had an anxiolytic effect in a conditioned animal model of anxiety. PMID- 29288825 TI - Inhibitory effects of Aconiti Lateralis Radix Preparata on chronic intermittent cold-induced inflammation in the mouse hypothalamus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aconiti Lateralis Radix Preparata (AR) is the most frequently used herb to generate heat and treat symptoms associated with coldness in Asia. AIMS OF THE STUDY: The hypothalamus is one of the master regulators to maintain constant core body temperature. Chronic exposure to cold stress disturbs homeostatic regulation, gradually resulting in hypothalamic inflammation. This study investigate the effects of AR, on the chronic intermittent cold (CIC)-induced release of pro-inflammatory signaling molecules in the mouse hypothalamus. MATERIALS AND METHODS: Aconiti Lateralis Radix Preparata extract (ARE) were solubilized in distilled water and diluted with saline before administration. Male ICR mice (7 weeks old, 30-32g) were divided randomly into 6 groups: (1) control, (2) cold stress, (3) ARE 30, (4) ARE 100, (5) ARE 300, and (6) ARE 1000mg/kg groups. Groups (2)-(6) were exposed to CIC stress once a day for 14 days. CIC stress was achieved by exposing the mice to 4 degrees C and 60 +/- 10% humidity for 120min once a day. Rectal temperature was measured after terminating cold stress. Cortisol levels were measured from serum. Hypothalamus tissue was used for western blot analysis, and IL-9, IL-13, PGE1, and PGE2 levels were assessed. RESULTS: ARE treatment prevented the CIC-induced decrease in rectal temperature and increase in serum cortisol level. ARE-treated CIC-exposed mice demonstrated decrease in nuclear c-Fos levels dose-dependently compared to CIC-exposed mice. Nuclear NF-kB expression showed significant increase in CIC-exposed mice. ARE treatment significantly blunted the increase in nuclear NF-kB expression. CIC-exposed mice had significantly increased levels of both IL-9 and IL-13. Treatment with ARE suppressed the elevated IL-9 and IL-13 levels. Between control and CIC-exposed mice PGE1 levels showed no difference. However ARE (1000mg/kg)-treated CIC-exposed mice had a significant increase in PGE1 level compared to CIC-exposed mice. PGE2 levels were significantly higher in CIC-exposed mice compared to control mice. ARE treatment significantly attenuated the increase in PGE2 levels. CONCLUSIONS: Our findings suggest CIC stress disturbs the anti-inflammatory effect of cortisol and maintenance of the body temperature. Thus AR contributes to suppress the activated proinflammatory factors, IL-9, IL-13, and PGE-2, and to increase the heat production. PMID- 29288826 TI - Ethnopharmacological uses, phytochemistry and pharmacology of genus Adiantum: A comprehensive review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Genus Adiantum (Pteridaceae) forms a significant dominant component of many plant communities especially in the tropical and temperate regions. These are commonly known as maidenhair ferns and several have been used medicinally in different parts of the world. They exhibit antidysenteric, antiulcer, antimicrobial, antitumor and antiviral activities. The traditional uses of Adiantum species are known to be for respiratory problems such as cough cold, fever, pneumonia and mucous formation. AIM OF THE REVIEW: This review aims to provide a comprehensive and updated, categorized information on the botanical aspects, traditional uses, phytochemistry, pharmacological activities and toxicological research of Adiantum species in order to explore their therapeutic potential and evaluate future research opportunities. MATERIALS AND METHODS: The available information on various species belonging to the genus Adiantum was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar, JCCC@INSTIRC and Web of Science) and a library search for articles published in peer-reviewed journals. RESULTS: The literature provided information on several ethnopharmacologically well known Adiantum species, the best studied species being A. capillus-veneris. From these plant species, more than 130 compounds belonging to triterpenoids, flavanoids, phenyl propanoids, phenolics, coumarins, phytosterols, fatty acids and others were identified. Experimental evidences confirmed that the Adiantum species could be used in treating microbial infections, diabetes, liver disorders as well as inflammatory disorders. CONCLUSIONS: Plants belonging to the genus Adiantum have offered bioactive crude extracts as well as pure compounds, thus substantiating their effectiveness in traditional medicine. Although toxicity studies carried out on some Adiantum species have showed them to be non-toxic, further toxicological studies are still required to confirm their safety in humans. Future research should be directed towards implementing an integrated approach through intensive investigations of all the species of Adiantum relating to phytochemical and pharmacological properties, especially bio-assay guided isolation of phytoconstituents, their mechanism of action, as well as their bioavailability and pharmacokinetics, safety and efficacy. PMID- 29288827 TI - Antidepressant-like effects of water extract of Gastrodia elata Blume on neurotrophic regulation in a chronic social defeat stress model. AB - ETHNOPHARMACOLOGY RELEVANCE: Gastrodia elata Blume (GE) is a traditional Chinese medicine commonly used to treat dizziness, epilepsy, paralysis and some emotional symptoms in east Asia. We previously showed that the water extract of Gastrodia elata Blume (WGE) possesses anti-depression like effects in a forced swimming test and chronic mild stress model. AIM OF THE STUDY: The aim of this study was to investigate the antidepressant-like effects of WGE and potential mechanisms related to brain-derived neurotrophic factor (BDNF) regulation in mice exposed to chronic social defeat stress (CSDS) model. MATERIALS AND METHODS: Fifty C57BL/6 mice were divided into 5 groups as follows: a control (CTL) group, CSDS group, and 3 WGE groups receiving 250, 500 or 1000mg/kg body weight in the CSDS model. Mice were administered WGE for 24 days by oral gavage, and the social defeat stress paradigm began on day 14, except for the control group. A social interaction test was conducted to evaluate the antidepressant-like effects of WGE. Blood samples were collected to measure serum corticosterone levels, and the brain was dissected to investigate the expression of BDNF-related signaling pathway proteins using western blotting. RESULTS: Oral administration of WGE improved depression-like behaviors and stress-induced elevations of corticosterone. Further, WGE increased the protein expression of BDNF and promoted the hippocampal protein phosphorylation ratio of cAMP response element binding protein (CREB) and protein kinase B (Akt). CONCLUSION: WGE exerts antidepressant-like effects on mice in a CSDS model, likely through activating of the BDNF/CREB/Akt pathway. Therefore, WGE has potential as a supplement or an adjuvant to prevent or treat clinical depressive disorders. PMID- 29288828 TI - The effects of strawberry tree water leaf extract, arbutin and hydroquinone on haematological parameters and levels of primary DNA damage in white blood cells of rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Strawberry tree (Arbutus unedo L., Ericaceae) leaves represent a potent source of biologically active compounds and have been used for a long to relieve symptoms of various health impairments and diseases. Two major compounds related to their beneficial activities in animals and humans are arbutin and hydroquinone. AIM OF THE STUDY: To establish potential benefit/risk ratio associated with daily oral administration of strawberry tree water leaf extract, arbutin and hydroquinone in doses expected to be non-toxic. MATERIALS AND METHODS: We performed a 14-day and a 28-day study on male and female Lewis rats and evaluated main haematological parameters and the effects of treatments on the levels of primary DNA damage in white blood cells (WBC) using the alkaline comet assay. RESULTS: Our findings suggest no significant changes in the haematological parameters following prolonged exposure to strawberry tree water leaf extract, arbutin, and hydroquinone. However, hydroquinone causes increased, and extract as well as arbutin decreased WBC count in male rats compared to control after 14 days of treatment. DNA damage measured in WBC of rats treated with all compounds was below 10% of the DNA in the comet tail, which indicates low genotoxicity. The genotoxic potential of strawberry water leaf extract was within acceptable limits and reflected effects of a complex chemical composition upon DNA. We also observed slight gender- and exposure time- related differences in primary DNA damage in the leucocytes of control and treated rats. CONCLUSIONS: Future studies should investigate which doses of strawberry tree water leaf extract would be most promising for the potential use as a substitute for bearberry leaves for treatment of urinary infection. PMID- 29288829 TI - Safety assessment of standardized aqueous Brucea javanica extract in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Brucea javanica and its aqueous decoction is a traditional medicine consumed by diabetic patients in Malaysia. The daily consumption of B. javanica seeds and it's aqueous decoction causes much concern as the quassinoids and its glycosides from the seeds exhibited various pharmacological activity at low doses. AIMS OF STUDY: The aim of the present study is to evaluate the repeated dose toxicity of the standardized aqueous extract administered daily for 30 days through oral administration at its effective hypoglycemia doses. MATERIALS AND METHODS: The seeds were dried, ground and extracted in deionized water. A HPLC-photodiode array method was developed and validated for the standardization of both the hypoglycemia agents, namely bruceine D and E in aqueous extract. Both normoglycemia and streptozotocin (STZ) induced diabetic rats were fed orally with 15, 30 and 60mg/kg body weight of standardized aqueous extract. The blood glucose was measured at 0-8h. In repeated dose toxicity, similar doses were administered orally to rats for 30 days. At the end of 30 days, the blood was withdrawn and subjected to biochemical and haematology analysis while organs were harvested for histology analysis. RESULTS: Oral administration of standardized aqueous extract exhibited a dose-response relationship in both the normoglycemia and STZ-induced diabetic rats. Daily oral administration of 15, 30 and 60mg/kg standardized aqueous extract for 30 days to rats did not show signs to toxicity in its biochemical, haematology and histology analysis. CONCLUSION: In conclusion, although the seeds were reported to contain compounds with various pharmacological activity, the daily oral administration to rats for 30 days do not showed signs of toxicity at its effective hypoglycemia doses. PMID- 29288830 TI - A standardized extract of Rhynchosia volubilis Lour. exerts a protective effect on benzalkonium chloride-induced mouse dry eye model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In contrast to other leguminous plants generally used as food, Rhynchosia volubilis Loureiro, a small soybean with a black seed coat, has been used as a traditional oriental remedy for various human diseases in Eastern Asia. In this study, we demonstrated the protective effect of R. volubilis against dry eye disease. AIM OF THE STUDY: We aimed to investigate whether a standardized ethanol extract of R. volubilis (EERV) can protect the cornea in a benzalkonium chloride (BAC)-induced mouse dry eye model. MATERIALS AND METHODS: Experimental dry eye was induced by the instillation of 0.2% BAC on mouse cornea. A standardized ethanol extract of R. volubilis (EERV) was orally administered following BAC treatment. The positive control group was treated with commercial eye drops. Fluorescein staining, tear break-up time (BUT), and hematoxylin and eosin staining were evaluated on the ocular surface. Squamous metaplasia and apoptosis in the corneal epithelial layer were detected by immunostaining. Furthermore, the protein expression of cytochrome c, Bcl-2, and Bax was determined. RESULTS: EERV treatment significantly improved fluorescein scoring, BUT, and smoothness in the cornea compared to the vehicle group. In addition, EERV inhibited squamous metaplasia and apoptosis in the cornea. The expression of cytochrome c and Bax was upregulated, while that of Bcl-2 was downregulated in the vehicle group compared with that in the control group. However, EERV treatment inhibited the expression of cytochrome c and Bax, while that of Bcl-2 was improved. CONCLUSION: Standardized EERV could be a beneficial candidate for the treatment of dry eye disease. PMID- 29288832 TI - New combination strategy of photodynamic therapy and surgery in treating recurrent basal cell carcinoma, a case report. AB - BACKGROUND: Surgery is considered the most effective treatment for basal cell carcinoma because it permits the analysis of surgical margins following excision. However, even Mohs surgery isn't desirable for predictable aggressive tumor. Treatment of recurrent basal cell carcinoma can be challenging. METHODS: This case study is on a patient with a recurrent basal cell caricinoma on his zygomatic region. Since the tumor showed a suspected bone invasion, surgical excision of the tumor alone was problematic. Hence a one-time photodynamic therapy was performed in the basal segment of the defect. RESULTS: No recurrence was detected at the patient's 1-year follow-up visit. CONCLUSIONS: The tumor was successfully treated by combing surgery with photodynamic therapy. This treatment combination can be adopted as a new strategy in the study and treatment of recurrent basal cell carcinoma cases. PMID- 29288831 TI - Silica-based nanoparticles are efficient delivery systems for temoporfin. AB - BACKGROUND: Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site became a new standard in novel anticancer methods Anticancer photodynamic therapy also takes benefit from using nanoparticles by means of increasing targeting efficiency and decreased side effect. With this in mind, the silica-based nanoparticles, as drug delivery systems for the second generation photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin (temoporfin) were developed. METHODS: In order to determine the stability and therapeutic performance of the selected nanomaterials in physiological fluids, their physicochemical properties (i.e. size, polydispersity, zeta potential) were measured by dynamic light scattering technique and the diameter and the morphology of the individual particles were visualized by a transmission electron microscopy. Their efficacy was compared with commercial temoporfin formulation in terms of in vitro phototoxicity in 4T1 (murine mammary carcinoma) and of in vivo anticancer effect in Nu/Nu mice bearing MDA-MB-231 tumors. RESULTS AND CONCLUSIONS: The two types of silica nanoparticles, porous and non-porous and with different surface chemical modification, were involved and critically compared within the study. Their efficacy was successfully demonstrated and was shown to be superior in comparison with commercial temoporfin formulation in terms of in vitro phototoxicity and cellular uptake as well as in terms of in vivo anticancer effect on human breast cancer model. Temoporfin-loaded silica nanoparticles also passed through the blood-brain barrier showing potential for the treatment of brain metastases. PMID- 29288833 TI - Lacrimal gland abscess in a child as a rare manifestation of IgG4-related disease. AB - Dacryoadenitis is unusual in children, and noninfectious causes can be manifestations of serious undiagnosed systemic conditions. This report brings further attention to this rarely-encountered condition and emphasizes its association with IgG4-related disease, a group of inflammatory disorders of high current interest whose spectrum of manifestations continues to evolve. The pediatric ophthalmologist could be in the position of identifying a patient's serious and previously unappreciated illness. PMID- 29288834 TI - Exotropia and hypotropia as the initial presentation sign of thyroid eye disease in an 18-year-old man. AB - Exotropia is rarely reported in thyroid eye disease (TED). We report the case of an 18-year-old patient with TED who developed exotropia and hypotropia as an initial presentation of TED. PMID- 29288835 TI - Evaluation of anterior segment parameters in patients with Turner syndrome using Scheimpflug imaging. AB - PURPOSE: To compare the anterior segment parameters in patients with Turner syndrome (TS) as measured by the Pentacam HR-Scheimpflug imaging system with those of healthy control subjects. METHODS: This cross-sectional prospective study included 35 patients with TS and 30 age-matched controls. Corneal topographic analysis was performed using the Pentacam HR-Scheimpflug imaging system (Oculus, Wetzlar, Germany). The power of the corneal astigmatism, mean keratometry (Km) values for the both front and back surfaces of the cornea, maximum keratometry (Kmax), central corneal thickness (CCT), corneal volume (CoV), white-to-white diameter (WTW), chamber volume (CaV), angle and anterior chamber depth (ACD) values were recorded. RESULTS: The mean age of TS subjects was 17.2 +/- 6.1 years; of controls, 16.4 +/- 5.7 years. All participants were female. There was a significant difference in the mean values of WTW (11.3 +/- 0.5 mm vs 12.0 +/- 0.4 mm [P < 0.001]), CaV (148.4 +/- 33.5 mm3 vs 191.9 +/- 27.6 mm3 [P < 0.001]), and ACD (2.8 +/- 0.3 mm vs 3.1 +/- 0.2 mm [P < 0.001]) between TS versus group and the control group. The mean values of the power of the corneal astigmatism, Km values for the both front and back of the corneal surface, Kmax, CCT, CoV, and angle values were similar between groups (P > 0.05 for each one). CONCLUSIONS: There was a reduction in CaV, ACD, and WTW measurements in TS patients compared with controls. PMID- 29288836 TI - Why strabismus surgery works: the legend of the dose-response curve. AB - BACKGROUND: The dose-response relationship has historically been regarded as an important approach to improve the success of strabismus surgery. The purpose of this study was to explore the role of preoperative deviation, in addition to the amount of surgery, as a predictor of the response to strabismus surgery. METHODS: Dose-response data from a variety of sources are analyzed in a multiple linear regression model with both preoperative deviation and surgical dose as independent variables. P values and partial correlations from these regressions are used to investigate the relative contribution of each factor. RESULTS: These analyses consistently show that preoperative deviation is statistically a better predictor of the response to surgery than the amount of surgery. In data sets where one factor is constant, preoperative deviation alone accounts for 78%, and the amount of surgery alone accounts for 46% of the variance of the surgical response. CONCLUSIONS: The importance of preoperative deviation as an independent variable implies a biologic response to strabismus surgery that tends to produce more change in alignment when the deviation is large and less when it is small. The strong association of amount of surgery with surgical outcome in bivariate analysis studies may be an artifact of making the amount of surgery a strict function of the preoperative deviation. Because of its lesser role as a predictor, accuracy of preoperative deviation measurement upon which the amount of surgery is based, refinement of the dose-response curve, or use of adjustable sutures may have less potential to improve surgical outcome than generally believed. PMID- 29288837 TI - Does eye velocity due to infantile nystagmus deprive visual acuity development? AB - PURPOSE: To use eye movement recordings of young children to determine whether eye velocity from infantile nystagmus (IN) deprives the developing visual system of normal visual acuity. METHODS: The video-oculography recordings and visual acuity measurements (including Teller cards) of 15 children <=6.0 years of age with IN without visual sensory disease (idiopathic IN) were reviewed retrospectively. Eye velocity that would limit visual acuity development was predicted from both empirical adult data adjusted for age and a temporal limitation model using published photoreceptor density data with age. Foveal alignment onto a target was measured in 5 subjects using confocal retinal imaging. RESULTS: All subjects had periods (85-2440 ms) during which eye velocity was below the limit that would reduce age-appropriate visual acuity. The percentage of time eye velocity was below the limit varied by 4%-54% across all eye movement recordings. Eye movement metrics (eye position variability, average eye velocity, maximum duration of foveation, and the nystagmus optimal foveation fraction) correlated poorly with age or with age-corrected visual acuity (r2 < 0.27 for each metric). Longitudinal visual acuity development overlapped between subjects with different nystagmus waveforms. CONCLUSIONS: Eye velocity was not predicted to completely deprive visual acuity development in subjects with idiopathic IN. Nystagmus may decrease visual acuity development in children with idiopathic IN by interfering with visual-cortical development in the context of increased visual noise due to image motion with imprecise foveation. PMID- 29288838 TI - Purely horizontal strabismus associated with head tilt. AB - We present the first case of an otherwise healthy child with a marked left head tilt used to improve a purely horizontal, nonaccommodative deviation. A patching test confirmed strabismus as the etiology of the abnormal head position. The head tilt was dramatically reduced following bilateral medial rectus recession. PMID- 29288839 TI - Comparison of quantitative measurement of foveal avascular zone and macular vessel density in eyes of children with amblyopia and healthy controls: an optical coherence tomography angiography study. PMID- 29288840 TI - Morganella as a cause of ophthalmia neonatorum. AB - A 2 day-old-girl with a complicated birth history, including prolonged rupture of membranes and Caesarian section delivery, presented with a purulent bacterial conjunctivitis of the left eye despite standard prophylaxis. Bacterial cultures yielded 1+ Morganella morganii, a facultative anaerobe and a rare cause of ocular pathology. The patient was treated with topical tobramycin four times daily for 7 days, resulting in resolution of her conjunctivitis. PMID- 29288841 TI - Management of severe traumatic brain injury (first 24hours). AB - The latest French Guidelines for the management in the first 24hours of patients with severe traumatic brain injury (TBI) were published in 1998. Due to recent changes (intracerebral monitoring, cerebral perfusion pressure management, treatment of raised intracranial pressure), an update was required. Our objective has been to specify the significant developments since 1998. These guidelines were conducted by a group of experts for the French Society of Anesthesia and Intensive Care Medicine (Societe francaise d'anesthesie et de reanimation [SFAR]) in partnership with the Association de neuro-anesthesie-reanimation de langue francaise (ANARLF), The French Society of Emergency Medicine (Societe francaise de medecine d'urgence (SFMU), the Societe francaise de neurochirurgie (SFN), the Groupe francophone de reanimation et d'urgences pediatriques (GFRUP) and the Association des anesthesistes-reanimateurs pediatriques d'expression francaise (ADARPEF). The method used to elaborate these guidelines was the Grade(r) method. After two Delphi rounds, 32 recommendations were formally developed by the experts focusing on the evaluation the initial severity of traumatic brain injury, the modalities of prehospital management, imaging strategies, indications for neurosurgical interventions, sedation and analgesia, indications and modalities of cerebral monitoring, medical management of raised intracranial pressure, management of multiple trauma with severe traumatic brain injury, detection and prevention of post-traumatic epilepsia, biological homeostasis (osmolarity, glycaemia, adrenal axis) and paediatric specificities. PMID- 29288843 TI - Collin S. MacCarty (1915-2003): Inventor of the "MacCarty Keyhole" as the Starting Burr Hole for Orbitozygomatic Craniotomy. AB - INTRODUCTION: Dr. Collin S. MacCarty (1915-2003) invented the MacCarty keyhole, which is now widely used as the starting burr hole for orbitozygomatic craniotomy. We present a historical vignette on MacCarty's life and chronicle his contributions to neurosurgery. METHODS: A detailed search for articles relating to the biography and professional career of Dr. MacCarty was conducted on PubMed and Google Scholar by using the key words "Collin MacCarty" and "MacCarty keyhole." References found in those articles were also reviewed. RESULTS: On September 20, 1915, Collin MacCarty was born in Rochester, Minnesota. MacCarty was exposed to the medical field at an early age. He witnessed legendary surgeons like Alfred Adson perform brain and spine operations. Expectedly, MacCarty pursued a career in neurosurgery. He was influenced by Walter Dandy as a house office at Johns Hopkins and completed his neurosurgical training at the Mayo Clinic under Adson. In a distinguished career in neurosurgery at the Mayo Clinic, MacCarty served many important roles, including Chairman of the Department of Neurosurgery from 1963 to 1975 and President of the American Association of Neurological Surgeons. He was world-renowned for his vast experience with meningiomas. In 1961, MacCarty described a burr hole to expose the periorbita and frontal dura while approaching intraorbital meningiomas. This burr hole became immortalized as the "MacCarty keyhole" and is used widely today in frontotemporal orbitozygomatic approaches. CONCLUSIONS: Collin S. MacCarty was an influential neurosurgeon. Among a multitude of contributions, he is most well-known for inventing the "MacCarty keyhole" which is widely implemented nowadays as the starting point for orbitozygomatic approaches. PMID- 29288842 TI - An Integrative Survival Analysis with Identification of Prognostic Factors in the Patients with Coexisting Glioma and Intracranial Aneurysm. AB - OBJECTIVE: This study aimed to perform an integrative clinical and survival analysis for patients with coexisting glioma and intracranial aneurysm and to assess the influence of prognostic factors on overall survival (OS). METHODS: A systematic literature search on PubMed and Web of Science was performed for literature in English published from 1951 to August 2017. Detailed information including clinical characteristics, treatments, critical events, and time to events for survival analysis was extracted from the included articles. Clinical characteristics of included patients were reviewed, and survival analysis was performed to identify prognostic factors of OS. RESULTS: A total of 56 cases from 38 articles published in English-language journals were included in this study, and relative details were selected for integrative analysis. Univariate analysis demonstrated that age (<47/>=47 years), ruptured aneurysm (yes/no), glioma type (glioblastoma multiforme [GBM]/no GBM), World Health Organization (WHO) grade (low/high), and radiotherapy (yes/no) had a statistically significant correlation with OS (log-rank P = 0.004, P = 0.037, P = 0.004, P < 0.001, and P < 0.001, respectively). Further, multivariate analysis revealed that WHO grade (hazard ratio [HR], 22.383; 95% confidence interval [CI], 1.795-279.151; P = 0.016) and receiving radiotherapy (HR, 0.054; 95% CI, 0.009-0.333; P = 0.002) were the independent prognostic factors for OS. CONCLUSIONS: This integrative survival analysis revealed that WHO grade and receiving radiotherapy were independent prognostic factors for OS, and patients with low-grade glioma and receiving radiotherapy had longer survival than counter groups. Nevertheless, similar clinical studies which should be larger samples, multicenter, and collaborative are needed further. PMID- 29288844 TI - Primary Extradural Melanoma Arising in Cervical Spinal Nerve Root. AB - BACKGROUND: Primary cervical melanoma is rare; this is especially true of extradural melanoma arising in the nerve root. Characterizing these cases can provide a basis for improved melanoma management. CASE DESCRIPTION: A 42-year-old female patient with numbness and pain in the right shoulder and arm persisting for 5 years was admitted. Preoperative magnetic resonance imaging revealed an epidural ladle-shaped mass shape beyond the C7-T1 intervertebral foramen that resembled a nerve sheath tumor. Histopathologic analysis following complete resection confirmed the lesion as malignant melanoma. Radiotherapy and temozolomide and cisplatin chemotherapy were administered in an accompanying hospital with regular follow-ups at our institution. After 2 months of postoperative adjuvant therapy, hepatic metastatic lesions developed. The chemotherapy regimen was changed to carboplatin, nab-paclitaxel, and recombinant human endostatin injections for a 6-month period. Follow-up 8 months after chemotherapy (16 months post surgery) indicated a good prognosis. CONCLUSIONS: In the past 10 years only 1 case of primary extradural spinal melanoma in cervical intervertebral foramen has been described, with no reported cases of hepatic metastasis. As radiographic results are not unequivocal, a diagnosis of spinal melanoma must be based on postoperative histologic confirmation. However, to date there is no standard postoperative adjuvant therapy for these patients. The chemotherapy regimen described in this report has broader implications for melanoma treatment. PMID- 29288845 TI - Surgical Revascularization for the Treatment of Complex Anterior Cerebral Artery Aneurysms: Experience and Illustrative Review. AB - BACKGROUND: Many methods for treating complex anterior cerebral artery (ACA) aneurysms are available; however, there is substantial variation among methods because of various aneurysm locations, the relationship of the aneurysm to arterial branches, aneurysm size and other morphologic characteristics, and the diameters of the parent or branching arteries. METHODS: We reviewed complex ACA aneurysms based on both our own experience and the available literature. Each unique case is analyzed in terms of the characteristics of the aneurysm, along with analysis and classification of the revascularization method used. Computer tablet-drawn illustrations of each unique technique are provided for comprehension and application in various situations. RESULTS: Over 6 years, we treated 5 cases of complex ACA aneurysms (1 precommunicating, 1 communicating, 1 postcommunicating, and 2 precallosal-supracallosal segment) with revascularization. Side-to-side anastomoses included pericallosal ACA segment pericallosal ACA segment in 3 cases, supracallosal ACA segment-supracallosal ACA segment in 1 case, and ipsilateral callosomarginal artery-pericallosal artery in 1 case. Final modified Rankin scale score was 0 in 4 of 5 cases and 3 in 1 case. Six treatment strategies were used for the precommunicating aneurysm, 8 for the communicating aneurysm, 7 for the postcommunicating aneurysm, and 9 for the 2 precallosal-supracallosal segment aneurysms. CONCLUSIONS: Treatment of complex ACA aneurysms should be tailored according to the location and nature of the aneurysm and collateral circulation. Viable and feasible treatment strategies must be established by the neurovascular surgeon. PMID- 29288847 TI - Decision Making for the Surgical Treatment of Vertebral Metastases Among Patients with Short Predicted Survival. AB - BACKGROUND: A wide spectrum of treatment choices is proposed for poor-prognosis patients with vertebral metastases. The continuous increase of this population and the propagation of less invasive techniques necessitate further study concerning which patients could benefit from palliative surgery. METHODS: All patients with a Tokuhashi score <=8 who had undergone palliative surgical treatment for vertebral metastasis within 4 years were retrospectively reviewed. Demographics, clinical characteristics, and data concerning the disease and the operation were recorded. Patients were assessed on discharge and at 2 months concerning eventual benefit from surgery, based on pain measurements, motor function (Frankel grade), spinal stability assessment, and complications. Statistical analysis was performed to detect possible interrelations. RESULTS: Eighty-eight patients were reviewed. The average age was 56.5 years. The mean Tokuhashi score was 5.9, and the mean Karnofsky score was 56.4. Thirty-six patients experienced immediate improvement, 12 were lost to follow-up, and 42 were found to have benefited from surgery 2 months later. High Karnofsky score, radicular pain, morphine use, absence of complications, and immediate improvement predicted benefit from surgery. CONCLUSIONS: Decision making for a patient with poor prognosis concerning eventual surgery for a vertebral metastasis should be based mainly on the patient's clinical presentation; the primary cancer site is of less importance. PMID- 29288846 TI - Symptomatic Brainstem Cavernoma of Elderly Patients: Timing and Strategy of Surgical Treatment. Two Case Reports and Review of the Literature. AB - BACKGROUND: Brainstem cavernomas (BSCs) are rare and difficult to treat. The treatment strategy for symptomatic lesions in elderly patients remains unclear. In this review, we discuss the optimal treatment strategy and consider effective surgical strategies in elderly patients. CASE DESCRIPTION: The clinical data of 8 elderly patients (age >70 years) with symptomatic BSCs drawn from the literature and 2 of our cases are summarized in this review. The mean patient age was 73.3 +/- 3.13 years, and the most common location was the pons. Multiple rebleeding before surgery was seen in at least 4 cases, with clinical presentation and surgical approach varying depending on the location. Surgical removal was performed in 9 cases, and 1 case was treated with radiosurgery. The mean duration of clinical follow-up was 26.1 +/- 18.2 months. Neurologic improvement was found in 5 cases, and postoperative decline was seen in 1 of the surgery cases. CONCLUSIONS: Radical resection of the cavernoma with severe symptoms might be recommended in elderly patients, especially in those with multiple rebleeding events. From the viewpoint of surgery, we consider the subacute phase the optimal time to remove cavernomas in elderly hemorrhagic patients. However, multiple rebleeding events might exacerbate the neurologic deficit. Therefore, the subacute phase from the first or second rebleeding might be the best time for the surgical resection. At surgical intervention, preservation of the surrounding brain should be prioritized over complete removal of the cavernoma and hematoma. PMID- 29288848 TI - Repeated Short-Term Recurrence of Chronic Subdural Hematoma Associated with Metastasis to Hematoma Capsule Originating from Extracranial Malignant Tumor. AB - BACKGROUND: The recurrence rate of chronic subdural hematoma (CSDH) after trepanation is relatively high and involves various factors. We encountered an extremely rare case in which metastasis of an extracranial malignant tumor to the hematoma capsule was thought to be causing short-term repeated recurrences of CSDH. CASE DESCRIPTION: The patient was a 74-year-old man who had undergone bur hole evacuation of left CSDH 7 months earlier and had been receiving chemotherapy for stage IV gastric cancer for the preceding 6 months. He presented with symptoms of right hemiparesis and was diagnosed with left CSDH. Bur hole evacuation was performed twice, but the hematoma enlarged again both times within a short period. A third bur hole evacuation was performed after middle meningeal artery embolization, but the hematoma again enlarged shortly thereafter. Hematoma enlargement was finally suppressed by extracting the hematoma capsule under craniotomy. In histopathologic examinations, hematoxylin-eosin staining showed poorly differentiated adenocarcinoma primarily along the luminal side of the hematoma capsule and immunohistochemical staining showed results identical to findings from the existing gastric cancer. Pathologic results confirmed metastasis of the gastric cancer to the hematoma capsule, and this was considered to be the cause of short-term repeated recurrence of CSDH. CONCLUSIONS: To the best of our knowledge, this is the first report of metastasis to a hematoma capsule originating from an extracranial malignant tumor. The clinical course in the present case suggests metastasis of extracranial malignant tumor to the CSDH capsule as an extremely rare cause of recurrence. PMID- 29288849 TI - Intractable Hiccups After Coil Embolization of Partially Thrombosed Posterior Inferior Cerebellar Artery Aneurysm. AB - BACKGROUND: Hiccups are defined as sudden-onset involuntary contractions of the diaphragm followed by immediate inspiration and laryngeal closure, and they are considered intractable if prolonged beyond 1 month. A reflux arc involving phrenic, vagal, and central midbrain modulation is likely responsible for hiccups. We herein report a case of intractable hiccups caused by compression of the dorsal aspect of the medulla oblongata after treatment of a partially thrombosed distal posterior inferior cerebellar artery (PICA) aneurysm. CASE DESCRIPTION: A 51-year-old man presented with severe headache and was diagnosed with subarachnoid hemorrhage. Magnetic resonance imaging and cerebral angiography showed a partially thrombosed distal PICA aneurysm associated with a fusiform aneurysm in the ipsilateral vertebral artery. Based on the limited distribution of the clot, we performed endovascular coil occlusion of the aneurysm lumen followed by parent vessel occlusion for the distal PICA aneurysm. After the procedure, the patient presented with hiccups that could not be controlled by any medications. Magnetic resonance imaging showed an area of hyperintensity at the bilateral dorsal part of the medulla adjacent to the embolized aneurysm. The hiccups spontaneously disappeared 1 month after the procedure, and the abnormal signal findings also disappeared within the same period. The hiccups did not recur for 30 months postoperatively. CONCLUSIONS: In this case, the precise location of the culprit lesion causing the patient's hiccups was the dorsal medulla oblongata. Clinicians should be aware of the possibility of structural or functional disorders of the reflux arc in patients with intractable hiccups. PMID- 29288850 TI - Angiographic "Blush" After Stereotactic Radiosurgery Ablation of Residual Arteriovenous Malformation in Pediatric Patient: Case Report and Review of Literature. AB - INTRODUCTION: While surgical resection remains a primary treatment for accessible arteriovenous malformations (AVMs), stereotactic radiosurgery (SRS) has become thoroughly integrated into the AVM armamentarium; however, delayed sequelae of this treatment have become evident with increased long-term follow-up. To our knowledge, this is the second case of an aberrant local arterial angiographic blush without early venous drainage or an associated lesion following AVM SRS. CASE DESCRIPTION: An 8-year-old female presented with a ruptured 4-cm right medial frontal periventricular Spetzler-Martin grade 3 AVM with isolated intraventricular hemorrhage. She underwent subtotal resection followed by SRS. Six years later, diagnostic cerebral angiography demonstrated a prominent arterial-phase filling microvasculature without early venous drainage in the region of the irradiated residual AVM nidus. CONCLUSION: Although there is a paucity of information on angiographic blush following AVM SRS, consensus in the literature suggests that without early venous drainage, these lesions appear to pose an insignificant threat to the patient. These angiographic findings may be on a spectrum of delayed cerebrovascular radiation changes, and thus indefinite follow-up may be considered, especially in pediatric patients. PMID- 29288852 TI - An Infratentorial Pure Pleomorphic Xanthoastrocytoma Arising from Middle Cerebellar Peduncle: A Rare Location of an Uncommon Tumor. AB - BACKGROUND: Pleomorphic xanthoastrocytomas are rare tumors of glial origin comprising <1% of all astrocytic tumors of brain. These tumors are rare in the infratentorial compartment and were not known to arise from the middle cerebellar peduncle. CASE DESCRIPTION: We discuss the case of a 16-year-boy who presented with altered sensorium and features of increased intracranial pressure and was found to have a 4 * 4 * 3 cm mass arising from the middle cerebellar peduncle. CONCLUSION: We also discuss the histopathologic features of these tumors suggesting their resemblance to other maldevelopmental tumors, the rarity of pure World Health Organization grade II pleomorphic xanthoastrocytoma in the infratentorial compartment, as well as the appropriate management. PMID- 29288851 TI - Flat Posterior Cranial Fossa Affects Outcomes of Microvascular Decompression for Trigeminal Neuralgia. AB - OBJECTIVE: To investigate the prognostic factors for microvascular decompression (MVD) in patients with primary trigeminal neuralgia (TN), with a particular focus on the morphology of the posterior cranial fossa (PCF). METHODS: The present study investigated 126 surgically treated patients with primary TN with more than 1-year follow-up who underwent high-resolution magnetic resonance imaging between April 2003 and September 2015. We retrospectively reviewed clinical information and operative findings. Outcomes of MVD were also evaluated and patients were classified into "success" and "failure" groups. Furthermore, length, width, and height of the PCF were measured by approximation to an ellipsoid with reference to the anterior commissure-posterior commissure line. These values were compared between groups. RESULTS: Atypical type 2 TN (P < 0.001) and weak neurovascular compression (P < 0.001) correlated significantly with poor outcomes of MVD for primary TN. In terms of PCF morphology, the failure group showed a flatter PCF than the success group, whereas sex, age, affected side, topography of facial pain, interval between onset and surgery, responsible vessel, location of compression along the nerve, and site of compression around the circumference of the nerve root did not significantly affect outcomes of MVD for primary TN. CONCLUSIONS: The present study identified type 2 TN, weak neurovascular compression, and flatness of the PCF as predictors of poor prognosis after MVD for primary TN. PMID- 29288853 TI - Evaluation of Patient Perspectives Toward Awake, Frame-Based Deep-Brain Stimulation Surgery. AB - BACKGROUND: Deep brain stimulation (DBS) is an effective therapeutic modality; however, only a percentage of eligible patients undergo the procedure. OBJECTIVES: To study patients' perspectives toward DBS surgery. METHODS: A survey was sent to 95 consecutive adult patients who underwent DBS surgery for Parkinson disease, essential tremor, or dystonia; the response rate was 73% (69 patients). Post-hoc analyses were performed to evaluate factors that led to favorable outcomes. The average time between surgical procedure to survey completion was 16 months. RESULTS: Awake surgery, use of a rigid head frame, and having hair clipped were seldom reported as major deterrents to surgery. Patients retrospectively reported an average comfort level of 8.3 +/- 1.8 during surgery. The average comfort level with head frame placement was reported as 5.2 +/- 3.15, and patients reporting discomfort with the frame nonetheless reported overall comfort with the procedure (8.7 +/- 1.8). An analysis of satisfaction revealed that 90% of patients would recommend the procedure to a family member or friend and that 78% of patients would undergo the procedure again. A post-hoc analysis of patients who were not satisfied with the procedure revealed that this subset reported significantly less overall comfort (6.9 +/- 1.7, P = 0.0003) and were less likely to report that the goals and expectations of surgery were clearly discussed before surgery (P = 0.0004). CONCLUSIONS: Frame placement, awake surgery, and head shaving did not appear to play a significant role in most patients' decision-making process to undergo DBS, as analyzed in this retrospective cohort. The majority of patients were satisfied with the procedure and reported being comfortable. Managing goals and expectations preoperatively played a significant role in ultimate overall satisfaction. PMID- 29288854 TI - Lesional Temporal Lobe Epilepsy: Beware the Deceitful "Panic Attack". AB - BACKGROUND: Ganglioglioma is a rare, benign, intraaxial glioneuronal tumor but a relatively common cause of pharmacoresistant temporal lobe epilepsy (TLE). Given its often nonspecific neuropsychiatric manifestations and frequently negative electroencephalographic workup, TLE can be easily misdiagnosed as a psychiatric disorder, particularly panic attacks. CASE DESCRIPTION: We present a case of a 17 year-old boy who was found to have lesional TLE secondary to a left temporal ganglioglioma, 5 years after having been misdiagnosed with panic disorder and having undergone ineffective and unnecessary psychotherapy. He was successfully cured by surgery. Although a few similar cases of TLE masquerading as a panic disorder have been previously reported in the literature, this is the youngest and only pediatric patient described to date. CONCLUSION: This report underscores the challenges in making an accurate clinical diagnosis of TLE and the importance of timely brain imaging whenever an atypical or medically refractory panic disorder is encountered. PMID- 29288855 TI - Biomechanical Analysis of Porous Additive Manufactured Cages for Lateral Lumbar Interbody Fusion: A Finite Element Analysis. AB - BACKGROUND: A porous additive manufactured (AM) cage may provide stability similar to that of traditional solid cages and may be beneficial to bone ingrowth. The biomechanical influence of various porous cages on stability, subsidence, stresses in cage, and facet contact force has not been fully described. The purpose of this study was to verify biomechanical effects of porous AM cages. METHODS: The surgical finite element models with various cages were constructed. The partially porous titanium (PPT) cages and fully porous titanium (FPT) cages were applied. The mechanical parameters of porous materials were obtained by mechanical test. Then the porous AM cages were compared with solid titanium (TI) cage and solid polyetheretherketone (PEEK) cage. The 4 motion modes were simulated. Range of motion (ROM), cage stress, end plate stress, and facet joint force (FJF) were compared. RESULTS: For all the surgical models, ROM decreased by >90%. Compared with TI and PPT cages, PEEK and FPT cages substantially reduced the maximum stresses in cage and end plate in all motion modes. Compared with PEEK cages, the stresses in cage and end plate for FPT cages decreased, whereas the ROM increased. Comparing FPT cages, the stresses in cage and end plate decreased with increasing porosity, whereas ROM increased with increasing porosity. After interbody fusion, FJF was substantially reduced in all motion modes except for flexion. CONCLUSIONS: Fully porous cages may offer an alternative to solid PEEK cages in lateral lumbar interbody fusion. However, it may be prudent to further increase the porosity of the cage. PMID- 29288856 TI - Risk Factors and Management of Dural Defects in Anterior Surgery for Cervical Ossification of the Posterior Longitudinal Ligament. AB - OBJECTIVE: To investigate risk factors and outcomes and to develop a cogent perioperative management algorithm for dural defects (DDs) in anterior surgery for cervical ossification of the posterior longitudinal ligament (OPLL). METHODS: Ninety OPLL patients who had undergone anterior cervical decompression between January 2014 and December 2016 were reviewed. DDs occurred in 12 patients. Demographic, clinical, and radiologic data; intraoperative and postoperative management; and complications were analyzed. Risk factors for DDs were assessed with multivariate analysis. A treatment algorithm was identified based on these findings and our experience. RESULTS: The prevalence of DDs was 13.3% (12/90). Univariate and multivariate analyses showed that the ratio of OPLL base to spinal canal (odds ratio [OR] 1.09, P = 0.012), kyphotic cervical alignment with thick OPLL masses (OR 9.44, P = 0.026), and lateral, curved, and irregular OPLL masses (OR 8.28, P = 0.037) could be risk factors for DDs. DDs were repaired intraoperatively with onlay grafts, and lumbar drains were placed in all DD patients. The treatment was successful in all DD patients, and outcome measures did not differ between the DD and no DD groups. No patient had experienced complications associated with DDs and CSF leaks at the final follow-up visit. CONCLUSIONS: Patients with broad-based OPLL, kyphotic cervical alignment with thick OPLL masses, and lateral, curved, and irregular OPLL masses have a higher risk of DD in anterior surgery for OPLL. Intraoperative primary repair with onlay grafts combined with early lumbar drains is a simple, safe, and effective strategy for DDs. The outlook for the long-term sequelae of DDs is optimistic if they are managed adequately. PMID- 29288857 TI - In Response to the Letter to the Editor Regarding "Optic Nerve Meningioma Mimicking Cavernous Hemangioma". PMID- 29288858 TI - Risk Factors Associated with Meningitis after Neurosurgery: A Retrospective Cohort Study in a Chinese Hospital. AB - BACKGROUND: Meningitis is a serious complication occurring after neurosurgical operations, which can result in severe morbidity and high mortality. This retrospective cohort study aimed to determine the risk factors of postoperative meningitis in a large clinical center of neurosurgery in China. METHODS: Patients who underwent a neurosurgical procedure between January 2014 and December 2015 were selected, and 1016 cases were included our final analysis. On the basis of propensity scores, 84 patients with postoperative meningitis were successfully matched to 84 patients without postoperative meningitis. RESULTS: After propensity score matching, age, hospitalization duration, intraoperative use of corticoids, intraoperative use of antibiotics, external ventricular drainage, lumbar drainage, enteral nutrition, duration of surgery, major craniotomy, and transsphenoidal surgery were associated with postoperative meningitis. Furthermore, preoperative use of corticoids, intraoperative use of corticoids, intraoperative use of antibiotics, external ventricular drainage, lumbar drainage, and major craniotomy were independent predictors of postoperative meningitis in propensity score-matched cohort. A prediction model including these 6 independent predictors was established. Finally, receiver operating characteristic curve and discriminant analysis confirmed that this model has strong predictive power for evaluating postoperative meningitis. CONCLUSIONS: The prediction model built in our study can be an excellent tool for predicting meningitis after neurosurgical procedures. PMID- 29288859 TI - In Reply to the Letter to the Editor Regarding "World Health Organization Grade II Meningiomas: The Role of Adjuvant/Salvage Gamma Knife Surgery After Initial Surgery and Prognostic Factor Assessment". PMID- 29288860 TI - Association Between IDH1 and IDH2 Mutations and Preoperative Seizures in Patients with Low-Grade Versus High-Grade Glioma: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients with brain tumors, particularly gliomas, commonly present with seizures. Higher incidence of seizure has been reported in low-grade gliomas and tumors located within the temporal and insular area. The association between IDH1 and IDH2 mutations with preoperative seizures in glioma and the magnitude of this association in low-grade versus high-grade gliomas are unclear. To clarify this relationship, a systematic review and meta-analysis was performed. METHODS: Following accepted guidelines and systematic review recommendations, electronic searches were performed in journal databases up to May 2017. Data were extracted and pooled via meta-analysis. RESULTS: We compared 782 patients with IDH1 and IDH2 mutations with 803 patients with wild-type IDH1 and IDH2 before surgery. There was a significant difference in seizure incidence between the IDH1 mutation group (61.6%) and wild-type IDH1 group (32.1%) (odds ratio 2.76; 95% confidence interval, 1.26-6.02; I2 = 73%; P = 0.01). Similar findings were observed in analysis of IDH1 and IDH2 mutations (odds ratio 2.74; 95% confidence interval, 1.74-4.33; I2 = 58%; P < 0.0001). The difference remained in both mutation groups (IDH1, IDH1 and IDH2) with grade II gliomas but not with grade III and IV gliomas. Patients with grade II gliomas showed a higher rate of IDH1 and IDH2 mutations and seizures than patients with grade III and IV gliomas. CONCLUSIONS: This study demonstrated a significant association of IDH1 and IDH2 mutations with incidence of preoperative seizures. This association was significant only in patients with low-grade glioma (grade II) and not in patients with higher grade gliomas (grade III and IV). PMID- 29288861 TI - Resolution of Tachyarrhythmia Following Posterior Fossa Decompression Surgery for Chiari Malformation Type I. AB - INTRODUCTION: Chiari malformation (CM) type I commonly presents with symptoms such as tussive headaches, paresthesias, and, in severe cases, corticobulbar dysfunction. However, patients may present with atypical symptoms lending to the complexity in this patient population. We present a case of a CM patient presenting with atypical cardiac symptoms and arrhythmias, all of which resolved after surgical decompression. CASE DESCRIPTION: A 31-year-old female presented with atypical chest pain, palpitations, tachycardia, headaches, and dizziness for 2 years. Multiple antiarrhythmics and ultimately cardiac ablation procedure proved to be ineffective. Magnetic resonance imaging revealed CM, and the patient ultimately underwent surgical decompression with subsequent resolution of her symptoms. CONCLUSION: The surgical management of CM patients presenting with atypical symptoms can be challenging and often lead to delays in intervention. To our knowledge this is the only reported case of a patient presenting with tachyarrhythmia and atypical chest pain with resolution after Chiari decompression. We believe the dramatic improvement documented in the present case should serve to advance Chiari decompression in CM patients presenting with refractory tachyarrhythmia in whom no other discernable cause has been elucidated. Further studies are needed to better correlate the findings and to hopefully establish a criteria for patients that will likely benefit from surgical decompression. PMID- 29288862 TI - Variability in Surgical Treatment of Spondylolisthesis Among Spine Surgeons. AB - BACKGROUND: There are a multitude of treatments for low-grade lumbar spondylolisthesis. There are no clear guidelines for the optimal approach. OBJECTIVE: To identify the surgical treatment patterns for spondylolisthesis among United States spine surgeons. METHODS: 445 spine surgeons in the United States completed a survey of clinical/radiographic case scenarios on patients with lumbar spondylolisthesis with neurogenic claudication with (S+BP) or without (S-BP) associated mechanical back pain. Treatment options included decompression, laminectomy with posterolateral fusion, posterior lumbar interbody fusion, or none of the above. The primary outcome measure was the probability of 2 randomly chosen surgeons disagreeing on the treatment method. RESULTS: There was 64% disagreement (36% agreement) among surgeons for treatment of spondylolisthesis with mechanical back pain (S+BP) and 71% disagreement (29% agreement) for spondylolisthesis without mechanical back pain (S-BP). For S+BP, disagreement was 52% for those practicing 5 to 10 years versus 70% among those practicing more than 20 years. Orthopedic surgeons had greater disagreement than did neurosurgeons (76% vs. 56%) for S+BP. Greater clinical equipoise was seen for S BP than for S+BP regardless of surgeon characteristics. For spondylolisthesis without mechanical back pain, neurosurgeons were significantly more likely to select decompression-only than were orthopedic surgeons, who more commonly selected fusion. CONCLUSIONS: Clinical equipoise exists for the treatment of spondylolisthesis. Differences are greater when the patient presents without associated back pain. Surgeon case volume, practice duration, and specialty training influence operative decisions for a given pathologic condition. Recognizing this practice variation will hopefully lead to better evidence and practice guidelines for the optimal and most cost-effective treatment paradigms. PMID- 29288863 TI - Inclusion of nursing trials in systematic reviews after they have been retracted: Does it happen and what should we do? PMID- 29288864 TI - Assessment of subclinical atherosclerosis in systemic lupus erythematosus: A systematic review and meta-analysis. AB - OBJECTIVES: To determine whether subclinical atherosclerosis is increased in patients with systemic lupus erythematosus (SLE) compared to healthy individuals, using carotid intima-media thickness (CIMT), carotid plaque (CP) presence or flow mediated dilatation (FMD). METHODS: A systematic literature search was performed using MedLine, Embase and Cochrane databases. Two reviewers independently screened the articles to identify studies that compared the rates of atherosclerosis in SLE patients versus healthy controls. The results were pooled in a meta-analysis. Factors influencing the CIMT, CP or FMD results were collected. RESULTS: Of the 203 articles initially identified, 68 were selected for the meta-analysis. Compared to healthy controls, SLE patients had a significantly increased CIMT (mean difference [MD] of 0.08mm, 95% CI [0.06-0.09], P<0.05), more CP (odds ratio 2.01, 95% CI [1.63-2.47], P<0.05) and decreased FMD (MD -3.96%, 95% CI [-5.37 to -2.54)], P<0.05). There was marked heterogeneity among the studies. However, the results of the meta-analysis that included only the CIMT per new international recommendations also showed an increased CIMT in SLE patients, but the heterogeneity was low (MD 0.04mm, 95% CI [0.02-0.06], P<0.05; I2=23%). CONCLUSION: SLE patients exhibit increased subclinical atherosclerosis compared to healthy controls. CIMT is a promising measure for cardiovascular risk evaluations because non-invasive, non-radiation-based, reproducible. Thus, CIMT can be proposed as an alternative to the reliable CP evaluation and to FMD, which is influenced by independent factors such as smoking. Future studies should focus on reducing the heterogeneity of these measures using standardized procedures. PMID- 29288865 TI - Fantastic DNimals and where to find them. PMID- 29288866 TI - Altered reward learning and hippocampal connectivity following psychosocial stress. AB - Acute stress has a profound influence on learning, as has been demonstrated in verbal learning or fear conditioning. However, its effect on appetitive conditioning is still unclear. Fear conditioning research suggests the possibility of overgeneralization of conditioning to the CS- under acute stress due to its effect on prefrontal and hippocampal processing. In this study, participants (N = 56 males) were subjected to the Trier Social Stress Test or a placebo version. After that, all participants underwent an appetitive conditioning paradigm in the fMRI, in which one neutral cue (CS+) was repeatedly paired with reward, while another (CS-) was not. Importantly, the stress-group revealed overgeneralization of conditioning to the CS- on the behavioral level. On the neural level, stressed participants showed increased connectivity between the hippocampus and amygdala, vACC, and OFC, which maintain specificity of conditioning and also showed reduced differential activation. The results indicate overgeneralization of appetitive conditioning promoted by maladaptive balancing of pattern separation and pattern completion in the hippocampus under acute stress and are discussed with respect to clinical implications. PMID- 29288868 TI - Neurofeedback with fMRI: A critical systematic review. AB - Neurofeedback relying on functional magnetic resonance imaging (fMRI-nf) heralds new prospects for self-regulating brain and behavior. Here we provide the first comprehensive review of the fMRI-nf literature and the first systematic database of fMRI-nf findings. We synthesize information from 99 fMRI-nf experiments-the bulk of currently available data. The vast majority of fMRI-nf findings suggest that self-regulation of specific brain signatures seems viable; however, replication of concomitant behavioral outcomes remains sparse. To disentangle placebo influences and establish the specific effects of neurofeedback, we highlight the need for double-blind placebo-controlled studies alongside rigorous and standardized statistical analyses. Before fMRI-nf can join the clinical armamentarium, research must first confirm the sustainability, transferability, and feasibility of fMRI-nf in patients as well as in healthy individuals. Whereas modulating specific brain activity promises to mold cognition, emotion, thought, and action, reducing complex mental health issues to circumscribed brain regions may represent a tenuous goal. We can certainly change brain activity with fMRI nf. However, it remains unclear whether such changes translate into meaningful behavioral improvements in the clinical domain. PMID- 29288867 TI - Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus. AB - The hippocampus is a highly stress susceptible structure and hippocampal abnormalities have been reported in a host of psychiatric disorders including major depression and post-traumatic stress disorder (PTSD). The hippocampus appears to be particularly susceptible to early life stress with a graded reduction in volume based on number of types (multiplicity) or severity of maltreatment. We assessed whether the most important predictors of adult hippocampal volume were multiplicity, severity or duration of exposure or timing of maltreatment during developmental sensitive periods. 3T MRIs were collected on 336 unmedicated, right-handed subjects (132M/204F, 18-25 years). Exposure to broad categories of abuse and neglect during each year of childhood were assessed using the Maltreatment and Abuse Chronology of Exposure scale and evaluated using artificial intelligence and predictive analytics. Male hippocampal volume was predicted by neglect, but not abuse, up through 7 years of age. Female hippocampal volume was predicted by abuse, but not neglect, at 10, 11, 15 and 16 years. Exposure at peak age had greater predictive importance than multiplicity, severity or duration. There were also marked gender differences in subfields and portions (head, body or tail) affected by exposure. History and symptoms of major depression, PTSD or anxiety disorders were not predictive of hippocampal volume once maltreatment was accounted for. Neglect appears to foster inadequate hippocampal development in males while abuse appears to produce a stress-related deficit in females. Studies assessing hippocampal volume in psychiatric disorders need to control for the gender-specific effects of abuse and neglect. PMID- 29288870 TI - Two by two, inch by inch: Height as an indicator of environmental conditions during childhood and its influence on earnings over the life cycle among twins. AB - Adult height is a function of genetic predispositions and environmental influences during childhood. Hence, any variation in height among monozygotic twins, who share genetic predispositions, is bound to reflect differences in their environmental exposure. Therefore, a height premium in earnings among monozygotic twins also reflects such exposure. In this study, we analyze the height premium over the life cycle among Swedish twins, 10,000 of whom are monozygotic. The premium is relatively constant over the life cycle, amounting to 5-6% higher earnings per decimeter for men and less for women, suggesting that environmental conditions in childhood and youth affect earnings over most of the adult life course. The premium is larger below median height for men and above median height for young women. The estimates are similar for monozygotic and dizygotic twins, indicating that environmentally and genetically induced height differences are similarly associated with earnings. PMID- 29288869 TI - Human in-vivo brain magnetic resonance current density imaging (MRCDI). AB - Magnetic resonance current density imaging (MRCDI) and MR electrical impedance tomography (MREIT) are two emerging modalities, which combine weak time-varying currents injected via surface electrodes with magnetic resonance imaging (MRI) to acquire information about the current flow and ohmic conductivity distribution at high spatial resolution. The injected current flow creates a magnetic field in the head, and the component of the induced magnetic field DeltaBz,c parallel to the main scanner field causes small shifts in the precession frequency of the magnetization. The measured MRI signal is modulated by these shifts, allowing to determine DeltaBz,c for the reconstruction of the current flow and ohmic conductivity. Here, we demonstrate reliable DeltaBz,c measurements in-vivo in the human brain based on multi-echo spin echo (MESE) and steady-state free precession free induction decay (SSFP-FID) sequences. In a series of experiments, we optimize their robustness for in-vivo measurements while maintaining a good sensitivity to the current-induced fields. We validate both methods by assessing the linearity of the measured DeltaBz,c with respect to the current strength. For the more efficient SSFP-FID measurements, we demonstrate a strong influence of magnetic stray fields on the DeltaBz,c images, caused by non-ideal paths of the electrode cables, and validate a correction method. Finally, we perform measurements with two different current injection profiles in five subjects. We demonstrate reliable recordings of DeltaBz,c fields as weak as 1 nT, caused by currents of 1 mA strength. Comparison of the DeltaBz,c measurements with simulated DeltaBz,c images based on FEM calculations and individualized head models reveals significant linear correlations in all subjects, but only for the stray field-corrected data. As final step, we reconstruct current density distributions from the measured and simulated DeltaBz,c data. Reconstructions from non-corrected DeltaBz,c measurements systematically overestimate the current densities. Comparing the current densities reconstructed from corrected DeltaBz,c measurements and from simulated DeltaBz,c images reveals an average coefficient of determination R2 of 71%. In addition, it shows that the simulations underestimated the current strength on average by 24%. Our results open up the possibility of using MRI to systematically validate and optimize numerical field simulations that play an important role in several neuroscience applications, such as transcranial brain stimulation, and electro- and magnetoencephalography. PMID- 29288872 TI - Laparoscope surgical Instrument usage to manage an extremely difficult airway. PMID- 29288873 TI - Necessary and sufficient conditions of proper estimators based on self density ratio for unnormalized statistical models. AB - The largest family of density-ratio based estimators is obtained for unnormalized statistical models under the assumption of properness. They do not require normalization of the probability density function (PDF) because they are based on the density ratio of the same PDF at different points; therefore, the multiplicative normalization constant cancels out. In contrast with most existing work, a single necessary and sufficient condition is given here, rather than merely sufficient conditions for proper criteria for estimation. The condition implies that an extended Bregman divergence framework with data-dependent noise (Gutmann & Hirayama, 2011) gives the largest family of proper criteria in the present case. This properness yields consistent estimation as long as some mild conditions are satisfied. The present study shows that the above-mentioned framework gives an "upper bound" for attempts to extend Hyvarinen's score matching and therefore provides a perspective for studies in this direction. PMID- 29288871 TI - Neurobiology of the dorsolateral prefrontal cortex in GAD: Aberrant neurometabolic correlation to hippocampus and relationship to anxiety sensitivity and IQ. AB - INTRODUCTION: The neurometabolism underlying the cognitive and affective symptoms associated with generalized anxiety disorder (GAD) remain poorly understood. After we have linked worry to intelligence in patients with GAD, we hypothesized that aberrant neurometabolic correlations between hippocampus and neocortical regions may underlie a shared substrate in GAD patients for both anxiety sensitivity and intelligence. METHODS: GAD patients (n = 16; F = 11) and healthy volunteers (n = 16; F = 10) were assessed using 1H-MRSI. Co-axial planes I [hippocampus (HIPP)] and co-axial plane III [dorsolateral prefrontal cortex (DLPFC), central gyrus (CG)] were examined. Using general linear models, we examined resting metabolite concentrations using HIPP as a hub to CG and DLPFC. Neocortical ROIs were related to Anxiety Sensitivity Index (ASI) and Full Scale IQ (FSIQ) in GAD patients versus controls. RESULTS: Right hippocampal Cho/Cr directly predicted left DLPFC Cho/Cr in GAD (r = 0.75), an effect distinguishable (p = 0.0004) from controls. Left HIPP Cho/Cr positively predicted left CG Cho/Cr in GAD, an effect distinguishable from controls. In patients, both left and right DLPFC Cho/Cr positively predicted ASI but only left DLPFC Cho/Cr inversely predicted IQ. By contrast, IQ in controls correlated directly with left CG Cho/Cr. LIMITATIONS: Small sample size precluded us from investigating how gender and FSIQ subscales related to neurochemical correlations in the ROIs examined. CONCLUSIONS: Aberrant resting state neurochemical correlation between left DLPFC and right HIPP may contribute to GAD symptomatology. Unlike controls, in GAD, IQ and worry may share a common yet inverse neurometabolic substrate in left DLPFC. PMID- 29288874 TI - Modeling spike-wave discharges by a complex network of neuronal oscillators. AB - PURPOSE: The organization of neural networks and the mechanisms, which generate the highly stereotypical for absence epilepsy spike-wave discharges (SWDs) is heavily debated. Here we describe such a model which can both reproduce the characteristics of SWDs and dynamics of coupling between brain regions, relying mainly on properties of hierarchically organized networks of a large number of neuronal oscillators. MODEL: We used a two level mesoscale model. The first level consists of three structures: the nervus trigeminus serving as an input, the thalamus and the somatosensory cortex; the second level of a group of nearby situated neurons belonging to one of three modeled structures. RESULTS: The model reproduces the main features of the transition from normal to epileptiformic activity and its spontaneous abortion: an increase in the oscillation amplitude, the emergence of the main frequency and its higher harmonics, and the ability to generate trains of seizures. The model was stable with respect to variations in the structure of couplings and to scaling. The analyzes of the interactions between model structures from their time series using Granger causality method showed that the model reproduced the preictal coupling increase detected previously from experimental data. CONCLUSION: SWDs can be generated by changes in network organization. It is proposed that a specific pathological architecture of couplings in the brain is necessary to allow the transition from normal to epileptiformic activity, next to by others modeled and reported factors referring to complex, intrinsic, and synaptic mechanisms. PMID- 29288875 TI - ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. AB - Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions. PMID- 29288876 TI - Epidemiologic patterns of influenza outbreaks in institutional settings. AB - OBJECTIVES: Congregate environments facilitate spread of influenza viruses and could result in serious outcomes among residents. METHODS: We reviewed the epidemiology and identified factors that affect outbreak outcomes, using descriptive statistics and generalized estimating equations (GEE) regression. Outbreak duration, attack rate, hospitalization rate, case fatality rate, and the proportion of laboratory tests performed among infected residents were calculated by viral etiology, time to notification, and facility type and size. RESULTS: Between January 2011 and May 2015, the median attack rate for the 41 influenza outbreaks was highest among children in kindergarten (34%) and lowest among patients, who acquired influenza during hospitalization (17%). The median number of cases in each outbreak was 37 (range: 6-158) and a median of 199 individuals (range: 25-574) was exposed to influenza. The outbreaks lasted 2-49 days (median: 13 days). The average case fatality rate among residents for outbreaks attributed to influenza A or B was 3.1/1000 and for outbreaks attributed to influenza B 6.7/1000. Median time to notification was 10 days after the index case. In multivariate analysis, influenza outbreaks reported sooner after onset in the primary case ended sooner (P = 0.027) and had lower case fatality rates (P < 0.001). Residing in larger facilities was associated with lower proportion of laboratory tests performed (P = 0.024). CONCLUSIONS: Understanding whether earlier notification is a measure of a better functioning and therefore safer facility is a potentially important measure of the quality of care. PMID- 29288877 TI - Family Caregivers' Reflections on Experiences of Assisted Suicide in Switzerland: A Qualitative Interview Study. AB - CONTEXT: Thousands of family members worldwide are annually involved in assisted dying. Family participation in assisted dying has rarely been investigated and families' needs typically are not considered in assisted dying legislation and clinical guidelines. OBJECTIVES: To explore family caregivers' reflections on experiences of assisted suicide in Switzerland. METHODS: A cross-sectional qualitative interview study conducted in the Italian- and French-speaking regions of Switzerland. Interpretation and analysis were performed using qualitative content analysis. RESULTS: Twenty-eight close relatives and family carers of 18 patients who died by assisted suicide in Switzerland were interviewed. Family members perceived their involvement in assisted suicide as characterized by five phases; 1) contemplation, 2) gaining acceptance, 3) gaining permission, 4) organization, and 5) aftermath. Families can participate in these phases at diverse levels and with varying degrees of involvement. Important triggers for families and patients for transition between phases include patients' experiences of their life-threatening illnesses and related treatments, their increasing awareness of approaching death, and family member recognition of their loved one's unbearable suffering. Participating in assisted suicide created further demanding tasks for families in addition to their role of caregivers. CONCLUSION: Families appeared to be involved in the preparation of assisted suicide along with patients, irrespective of their personal values regarding assisted dying. Support for family members is essential if they are involved in tasks preparatory to assisted suicide. Clinical guidelines and policies concerning assisted dying should acknowledge and address family needs. PMID- 29288878 TI - Distributive Justice: An Ethical Priority in Global Palliative Care. AB - Providing care to cancer patients in resource-poor settings often demands complex trade-offs regarding resource allocation. It is estimated that over 60% of all cancer deaths worldwide occur in low- and middle-income countries, where channels to care and appropriate symptom management interventions are overstressed or obsolete. Concepts of distributive justice underlie much of global health policy. As appetites for expanding global palliative care services increase, so do questions of fair and culturally appropriate distribution. The ethical principle of distributive justice underpins questions of resource allocation at a fundamental level. One of the most challenging concepts for health care workers immersing in cross-cultural contexts is the idea that ethics are somewhat malleable; they shape and are shaped by the unique sociopolitical, economic, intracultural, and power dynamics of a particular setting. In this article, we use the case of a young woman diagnosed with terminal cancer in an underserved community in rural Uganda to illustrate the conflicting concepts of fairness, which dictate distribution of scarce resources in low- and middle-income countries. Notions of distributive justice vary across cultural, societal, and even individual norms, with some definitions allowing for discrimination based on merit or need. Resource allocation in the absence of cultural humility or a genuine willingness to understand decision-making priorities in a given culture can contribute to inequity and may have harmful consequences. PMID- 29288879 TI - Development and Assessment of a Measure of Parent and Child Needs in Pediatric Palliative Care. AB - CONTEXT: Pediatric palliative care has no evidence-based needs assessment measure. The Parent and Child Needs Survey (PCNeeds) is a new instrument designed to assess the needs of children in palliative care, including children receiving end-of-life care, and their families. OBJECTIVES: This study examines the psychometrics of and respondents' perceptions about the PCNeeds. METHODS: Parents of children in four outpatient pediatric palliative care programs completed the PCNeeds and the World Health Organization Quality of Life-Brief tool (WHOQOL BREF). Parents answered questions about demographics and the experience of completing the PCNeeds. Internal scale reliability was measured with Cronbach's alpha. Validity was assessed by correlating the PCNeeds total and subscale scores with the WHOQOL-BREF subscales. Additional respondent perceptions were obtained via written comments and analyzed using content analysis. RESULTS: The 93 respondents were predominantly female (n = 69, 74%); white (n = 79, 85%); college graduates (n = 71, 76%); and married or partnered (n = 75, 81%). Internal reliability was acceptable (Cronbach's alpha = 0.83), and validity correlations with the WHOQOL-BREF subscales were consistent with theoretical expectations (moderate negative correlations ranging from -0.36 to -0.51). The most frequently cited need not addressed by our survey was sibling impact (n = 17, 18%). Twelve parents (13%) indicated that no content was missing. The least met needs were financial impact, family impact, and the child's physical problems besides pain. Sixty-eight percent of parents (n = 63) rated completion of the survey as "easy" or "very easy." CONCLUSION: Initial psychometric analysis of the PCNeeds is encouraging, but further study of reliability and validity with more diverse respondents is needed. PMID- 29288880 TI - Diuretics Combined With Compression in Resistant Limb Edema of Advanced Disease-A Case Series Report. AB - INTRODUCTION: The extremity edema of advanced disease is a common, multifactorial feature, which impairs patients' activities and quality of life. The most frequently chosen management is based on combined decongestive physiotherapy or pharmacotherapy (with diuretics or steroids). Subcutaneous lymphatic drainage in refractory edema may decrease the swelling, prevent spontaneous lymphorrhea, but also increase the risk of infection. Safe and effective conservative management in diuretics-resistant edemas is lacking. The objective of this prospective, observational study was to assess the effectiveness and tolerability of combined physiotherapeutic and diuretic therapy in edemas refractory to parenteral diuretics. METHODS: A group of 19 patients with advanced disease and severe bilateral leg edema resistant to parenteral diuretic therapy were treated for three days with a combination of multilayer short-stretch compression bandaging and furosemide in hypersaline intravenous infusion. RESULTS: A clinically meaningful decrease in mean limb volume (of 1.52 L; 20.6%; P < 0.0001)-strongly correlating with patients' weight loss (rho = 0.71; P = 0.0001), with a lowering of the intensity of complaints-was achieved. The treatment was well tolerated, without decreasing the performance status in any patient. Stable levels of blood pressure, laboratory kidney profile (potassium, sodium, creatinine clearance), and serum albumin were observed. Maintenance of the achieved results with a good compliance was seen during an informal follow-up at the hospice. CONCLUSION: The combination of compression therapy with hypersaline diuretics could be considered as a valuable option for refractory cases of limb edema in advanced disease. PMID- 29288881 TI - A Novel Screening Method to Identify Late-Stage Dementia Patients for Palliative Care Research and Practice. AB - CONTEXT: Investigators need novel methods for timely identification of patients with serious illness to test or implement new palliative care models. OBJECTIVES: The study's aim was to develop an electronic health record (EHR) phenotype to identify patients with late-stage dementia for a clinical trial of palliative care consultation. METHODS: We developed a computerized method to identify patients with dementia on hospital admission. Within a data warehouse derived from the hospital's EHR, we used search terms of age, admission date, and ICD-9 and ICD-10 diagnosis codes to create an EHR dementia phenotype, followed by brief medical record review to confirm late-stage dementia. We calculated positive predictive value, false discovery rate, and false negative rate of this novel screening method. RESULTS: The EHR phenotype screening method had a positive predictive value of 76.3% for dementia patients and 24.5% for late-stage dementia patients; a false discovery rate of 23.7% for dementia patients and 75.5% for late-stage dementia patients compared to physician assessment. The sensitivity of this screening method was 59.7% to identify hospitalized patients with dementia. Daily screening-including confirmatory chart reviews-averaged 20 minutes and was more feasible, efficient, and more complete than manual screening. CONCLUSION: A novel method using an EHR phenotype plus brief medical record review is effective to identify hospitalized patients with late-stage dementia. In health care systems with similar clinical data warehouses, this method may be applied to serious illness populations to improve enrollment in clinical trials of palliative care or to facilitate access to palliative care services. PMID- 29288882 TI - Current Best Practices for Sexual and Gender Minorities in Hospice and Palliative Care Settings. AB - Although several publications document the health care disparities experienced by sexual and gender minorities (SGMs), including lesbian, gay, bisexual, and transgender (LGBT) individuals,1e4 less is known about the experiences and outcomes for SGM families and individuals in hospice and palliative care (HPC) settings. This article provides a brief overview of issues pertaining to SGMs in HPC settings, highlighting gaps in knowledge and research. Current and best practices for SGM individuals and their families in HPC settings are described, as are recommendations for improving the quality of such care. PMID- 29288883 TI - Aldehyde functionalized ionic liquid on electrochemically reduced graphene oxide as a versatile platform for covalent immobilization of biomolecules and biosensing. AB - An aldehyde functionalized ionic liquid, (3-(3-formyl-4-hydroxybenzyl)-3 methylimidazolium hexafluorophosphate) (CHO-IL) has been employed herein as a multiple host platform for the covalent immobilization of mediator as well as enzyme. The CHO-IL was immobilized on electrochemically reduced graphene oxide (ERGO) through the pi-pi stacking of hydroxybenzyl and imidazolium groups with ERGO and subjected to further covalent attachment of Azure A (Azu-A) mediator or glucose oxidase (GOx) enzyme. Electroactive, water soluble organic dye Azu-A was effectively immobilized to the host IL through simple Schiff base reaction. Azu-A was rendered leak-free in the electrode setup and also responded well for the amperometric determination of H2O2 over a linear range of 0.03-1mM with a detection limit and sensitivity of 11.5uM and 133.2uAmM-1cm-2, respectively. Further, attempts were made to explore the CHO-IL platform for the covalent immobilization of GOx enzyme which served well in retaining the enzyme nativity, reactivity and stability. Under optimized conditions, mediatorless GOx biosensor developed based on direct electrochemistry has exhibited an impressive analytical signal towards glucose detection in the linear range of 0.05-2.4mM with a detection limit and sensitivity of 17uM and 17.7uAmM-1cm-2, respectively. The reliability of the proposed Azu-A based chemical sensor and GOx based biosensor towards the determination of H2O2 and glucose in the real samples have been demonstrated. The remarkable analytical parameters and long term stability of both the sensors could be envisioned as a result of facile immobilization platform and immobilization strategy. PMID- 29288884 TI - Highly sensitive electrochemical biosensor for streptavidin detection based on CdSe quantum dots. AB - An electrochemical biosensor was developed based on a steric hindrance hybridization assay to allow the highly sensitive detection of streptavidin. In the steric hindrance hybridization assay, the signaling strand DNA (sig-DNA) was labeled at the 3' end with CdSe quantum dots (QDs) and at the 5' end with biotin, and capturing strand DNA (the complementary strand of sig-DNA) was labeled at the 5' end with thiol. The steric hindrance effect generated by streptavidin which was bound with the signaling DNA strand. The streptavidin limited the ability of the sig-DNA to hybridize with the cap-DNA, which were linked on the surface of a gold electrode. Therefore, the concentration of streptavidin was detected indirectly based on the concentration of CdSe QDs on the electrode surface. The concentration of CdSe QDs on the electrode surface was detected by differential pulse anodic stripping voltammetry. Under optimal conditions, the streptavidin detection range using the as-prepared biosensor was 1.96pg/mL to 1.96ug/mL and the detection limit was 0.65pg/mL. The experimental results showed that the electrochemical biosensor could detect streptavidin rapidly and accurately. PMID- 29288885 TI - An outbreak of philophthalmosis in Larus michahellis and Larus fuscus gulls in Iberian Peninsula. AB - Trematodes of the genus Philophthalmus Loos, 1899 are the eye parasites of birds and mammals, which use freshwater snails as their first intermediate hosts. Here we examined the presence of philophthalmids in a total of 1515 gulls (589 Larus fuscus and 926 Larus michahellis) admitted between January 2010 and October 2016 for rehabilitation at Olhao (Portugal), by the use of combined morphological and molecular analysis. We recorded the first infected L. fuscus and L. michahellis in July and November 2015, respectively. The philophthalmids were located in the conjunctival sac or under the nictitating membrane. Gulls infected with Philophthalmus lucipetus Rudolphi, 1819 presented no clinical signs, while those infected with Philophthalmus lacrymosus Braun, 1902 presented serious eye damage in the same host species. The prevalence of P. lucipetus reached 3.6% in L. fuscus and 0.8% in L. michahellis; the prevalence of P. lacrymosus reached 0.3% and 0.0%, respectively. The outbreak of P. lucipetus likely started in a narrowly defined area, since the first six cases, found between July and October 2015, originated from a single municipality, and only later more cases started to be retrieved from other municipalities of Portugal. These findings represent the first records of both philophthalmids in the Iberian Peninsula, their first records in L. michahellis and the first record of P. lacrymosus in L. fuscus. Further follow-up of the outbreak and the identification of intermediate hosts are needed. PMID- 29288886 TI - A clustering package for nucleotide sequences using Laplacian Eigenmaps and Gaussian Mixture Model. AB - In this article, a new Python package for nucleotide sequences clustering is proposed. This package, freely available on-line, implements a Laplacian eigenmap embedding and a Gaussian Mixture Model for DNA clustering. It takes nucleotide sequences as input, and produces the optimal number of clusters along with a relevant visualization. Despite the fact that we did not optimise the computational speed, our method still performs reasonably well in practice. Our focus was mainly on data analytics and accuracy and as a result, our approach outperforms the state of the art, even in the case of divergent sequences. Furthermore, an a priori knowledge on the number of clusters is not required here. For the sake of illustration, this method is applied on a set of 100 DNA sequences taken from the mitochondrially encoded NADH dehydrogenase 3 (ND3) gene, extracted from a collection of Platyhelminthes and Nematoda species. The resulting clusters are tightly consistent with the phylogenetic tree computed using a maximum likelihood approach on gene alignment. They are coherent too with the NCBI taxonomy. Further test results based on synthesized data are then provided, showing that the proposed approach is better able to recover the clusters than the most widely used software, namely Cd-hit-est and BLASTClust. PMID- 29288887 TI - Modeling the control of the central nervous system over the cardiovascular system using support vector machines. AB - The control of the central nervous system (CNS) over the cardiovascular system (CS) has been modeled using different techniques, such as fuzzy inductive reasoning, genetic fuzzy systems, neural networks, and nonlinear autoregressive techniques; the results obtained so far have been significant, but not solid enough to describe the control response of the CNS over the CS. In this research, support vector machines (SVMs) are used to predict the response of a branch of the CNS, specifically, the one that controls an important part of the cardiovascular system. To do this, five models are developed to emulate the output response of five controllers for the same input signal, the carotid sinus blood pressure (CSBP). These controllers regulate parameters such as heart rate, myocardial contractility, peripheral and coronary resistance, and venous tone. The models are trained using a known set of input-output response in each controller; also, there is a set of six input-output signals for testing each proposed model. The input signals are processed using an all-pass filter, and the accuracy performance of the control models is evaluated using the percentage value of the normalized mean square error (MSE). Experimental results reveal that SVM models achieve a better estimation of the dynamical behavior of the CNS control compared to others modeling systems. The main results obtained show that the best case is for the peripheral resistance controller, with a MSE of 1.20e 4%, while the worst case is for the heart rate controller, with a MSE of 1.80e 3%. These novel models show a great reliability in fitting the output response of the CNS which can be used as an input to the hemodynamic system models in order to predict the behavior of the heart and blood vessels in response to blood pressure variations. PMID- 29288889 TI - Mechanically detected terahertz electron spin resonance using SOI-based thin piezoresistive microcantilevers. AB - We developed piezoresistive microcantilevers for mechanically detected electron spin resonance (ESR) in the millimeter-wave region. In this article, fabrication process and device characterization of our self-sensing microcantilevers are presented. High-frequency ESR measurements of a microcrystal of paramagnetic sample is also demonstrated at multiple frequencies up to 160 GHz at liquid helium temperature. Our fabrication is based on relatively simplified processes with silicon-on-insulator (SOI) wafers and spin-on diffusion doping, thus enabling cost-effective and time-saving cantilever fabrication. PMID- 29288888 TI - Potato native and wound periderms are differently affected by down-regulation of FHT, a suberin feruloyl transferase. AB - Potato native and wound healing periderms contain an external multilayered phellem tissue (potato skin) consisting of dead cells whose cell walls are impregnated with suberin polymers. The phellem provides physical and chemical barriers to tuber dehydration, heat transfer, and pathogenic infection. Previous RNAi-mediated gene silencing studies in native periderm have demonstrated a role for a feruloyl transferase (FHT) in suberin biosynthesis and revealed how its down-regulation affects both chemical composition and physiology. To complement these prior analyses and to investigate the impact of FHT deficiency in wound periderms, a bottom-up methodology has been used to analyze soluble tissue extracts and solid polymers concurrently. Multivariate statistical analysis of LC MS and GC-MS data, augmented by solid-state NMR and thioacidolysis, yields two types of new insights: the chemical compounds responsible for contrasting metabolic profiles of native and wound periderms, and the impact of FHT deficiency in each of these plant tissues. In the current report, we confirm a role for FHT in developing wound periderm and highlight its distinctive features as compared to the corresponding native potato periderm. PMID- 29288890 TI - Low-temperature magnetic resonance imaging with 2.8 MUm isotropic resolution. AB - We demonstrate the feasibility of high-resolution 1H magnetic resonance imaging (MRI) at low temperatures by obtaining an MRI image of 20 MUm diameter glass beads in glycerol/water at 28 K with 2.8 MUm isotropic resolution. The experiments use a recently-described MRI apparatus (Moore and Tycko, 2015) with minor modifications. The sample is contained within a radio-frequency microcoil with 150 MUm inner diameter. Sensitivity is additionally enhanced by paramagnetic doping, optimization of the sample temperature, three-dimensional phase-encoding of k-space data, pulsed spin-lock detection of 1H nuclear magnetic resonance signals, and spherical sampling of k-space. We verify that the actual image resolution is 2.7 +/- 0.3 MUm by quantitative comparisons of experimental and calculated images. Our imaging approach is compatible with dynamic nuclear polarization, providing a path to significantly higher resolution in future experiments. PMID- 29288891 TI - Thermal heterogeneity within aqueous materials quantified by 1H NMR spectroscopy: Multiparametric validation in silico and in vitro. AB - We recently suggested a new paradigm for statistical analysis of thermal heterogeneity in (semi-)aqueous materials by 1H NMR spectroscopy, using water as a temperature probe. Here, we present a comprehensive in silico and in vitro validation that demonstrates the ability of this new technique to provide accurate quantitative parameters characterizing the statistical distribution of temperature values in a volume of (semi-)aqueous matter. First, line shape parameters of numerically simulated water 1H NMR spectra are systematically varied to study a range of mathematically well-defined temperature distributions. Then, corresponding models based on measured 1H NMR spectra of agarose gel are analyzed. In addition, dedicated samples based on hydrogels or biological tissue are designed to produce temperature gradients changing over time, and dynamic NMR spectroscopy is employed to analyze the resulting temperature profiles at sub second temporal resolution. Accuracy and consistency of the previously introduced statistical descriptors of temperature heterogeneity are determined: weighted median and mean temperature, standard deviation, temperature range, temperature mode(s), kurtosis, skewness, entropy, and relative areas under temperature curves. Potential and limitations of this method for quantitative analysis of thermal heterogeneity in (semi-)aqueous materials are discussed in view of prospective applications in materials science as well as biology and medicine. PMID- 29288892 TI - Rare case of infective endocarditis involving mitral annular calcification leading to hemopericardium and sudden cardiac death: a case report. AB - We present a unique case of a 76-year-old female who had sudden cardiac death due to hemopericardium. Post mortem examination revealed infective endocarditis(IE) superimposing on mitral annulus calcification(MAC) leading to abscess formation, epicardial fistulation and hemopericardium. MAC is currently considered a relatively benign condition of the elderly [1], however evidence suggests there are severe consequences when these patients develop IE. With an aging population, this is likely to be a more frequent occurrence and should be considered in patients who present with bacteremia of unknown origin. PMID- 29288893 TI - A series of novel complexes firstly constructed by 1,4-phenylenedioxydiacetic acid plays a role in disruption of DNA gene expression and induction of apoptosis. AB - A set of five metal-organic frameworks, namely, [Cd2(L)2BIP(H2O)2.6H2O]n(1), [Ce(L)1.5(H2O)2.H2O]n(2),[Sm(L)1.5(H2O)2.3H2O]n(3),[Gd(L)1.5(H2O)2.3H2O]n(4),[Ho( )1.5(H2O)2.3H2O]n(5), have been prepared under hydrothermal conditions (1,4 H2L=1,4-Pheny lenedioxydiacetic acid; 1,4-BIP=1,4-bis(2-pyridylmethyl)piperazi ne; C2H5OH=EtOH). The long BIP ligand (N?N separation of ca. 8.355A) induces interpenetration of 1 to increase both the framework stability and the density of effective catalytic metal centers. Characterization of all complexes has been carried out by means of IR spectroscopy, single crystal and powdered sample X-ray diffraction (PXRD) through conventional and synchrotron radiation, Thermogravimetric (TG), fluorescent measurement (liquid and solid), DNA molecular docking, cancer cell apoptosis morphology through fluorescent inverted microscope, IC50, which the cytotoxic activity of the complexes was tested against two different cancer and one normal cell lines. The results indicate that all the complexes are potential fluorescent light-emitting materials and the flour (2, 3, 4, 5) complexes present remarkable anti-cancer effect. PMID- 29288894 TI - Delivery of [Ru(eta6-p-cymene)Cl2{Ph2P(CH2)3SPh-kappaP}] using unfunctionalized and mercapto functionalized SBA-15 mesoporous silica: Preparation, characterization and in vitro study. AB - SBA-15 (Santa Barbara Amorphous 15) mesoporous silica and its functionalized form (with 3-mercaptopropyltriethoxysilane) SBA-15~SH were used as carriers for [Ru(eta6-p-cymene)Cl2{Ph2P(CH2)3SPh-kappaP}] complex, denoted as [Ru]. Prepared mesoporous silica nanomaterials were characterized by traditional methods. Materials without [Ru] complex did not show any cytotoxic activity against melanoma B16 and B16-F10 cell lines. On the contrary, materials containing [Ru] such as SBA-15|[Ru] and SBA-15~SH|[Ru], exhibited very high activity against tested tumor cell lines, moreover with similar inhibitory potential. According to the loaded amount of the [Ru] in SBA-15|[Ru] and SBA-15~SH|[Ru] the IC50 values are 1-2MUM depending on the test used, thus in comparison to [Ru] alone the activity of nanomaterials containing [Ru] are elevated 3-6 times in vitro. However, the mechanism of apoptosis induction differs for these two mesoporous silica. Unlike reference [Ru] compound and SBA-15~SH|[Ru], SBA-15|[Ru] induces high caspase activation. Discrepancy in mechanism of drugs action at intracellular level points towards an influence of functionalization as well as availability of the drug. Moreover, both SBA-15|[Ru] and SBA-15~SH|[Ru] similarly to [Ru] are declining autophagy in B16 cell line. PMID- 29288895 TI - Online nutrition information seeking among Australian primigravid women. AB - BACKGROUND: optimal nutrition in pregnancy is crucial for short and long term health in both mother and child. While a large proportion of pregnant women utilise the internet for informational support during pregnancy, little is known about online practices relating to food and nutrition in pregnancy. METHODS: a qualitative study; Semi-structured interviews were undertaken with 16 primigravid women to explore their approaches and preferences when accessing and engaging with pregnancy-related nutrition information online. Women who had accessed the Internet for pregnancy related nutrition and food information were recruited via snowball sampling from South East Queensland, Australia. Data were analysed in accordance with descriptive phenomenology. FINDINGS: food and nutrition information-seeking practices were highly varied but followed a similar overall pathway. Six broad themes were identified "triggers", "access and navigation", "appraisal", "changes in searching frequency", "preferred features" and "engagement with communication approaches". Women preferred online sources that were easy to navigate and presented information clearly. Experience as well as fact based communication appeared to satisfy different informational needs. KEY CONCLUSIONS AND IMPLICATIONS: women search for food and nutrition information online in similar ways to other pregnancy issues. Opportunity for engaging with women online regarding a range of food and nutrition topics may be limited to early in pregnancy unless prompted to via conversations with antenatal service providers. Health practitioners have a role to play in helping women source evidence-based web sites. There is opportunity for organisations with mandates to support women to optimise diet quality during pregnancy, to improve user experience building on key preferences identified in this study to increase appeal and engagement by pregnant women. PMID- 29288896 TI - Achieving universal coverage: Understanding barriers to rural placement for final year midwifery students. AB - OBJECTIVE: the objective of this study is to understand the barriers final year midwifery students face when deciding to practice in a rural, deprived area. DESIGN: a cross-sectional study design using a computer based structured survey. SETTING: 15 of the 16 publicly funded midwifery colleges across all ten regions in Ghana. PARTICIPANTS: a national sample of final-year midwifery students from publically funded midwifery colleges in Ghana. MEASUREMENTS: basic frequencies and percentages were calculated for the variables cited as the top three factors motivating participants to study midwifery stratified by student type (post-basic verses diploma) and program location (urban, peri-urban, and rural). Odds ratios were calculated using separate logistic regression models to analyze the relationship between students' experience with rural communities and how it affected their willingness to work in a rural area following graduation. FINDINGS: eight hundred and fifty-six midwifery students (N = 856) completed a computerised survey for a response rate of 91.8%. The top motivation to study midwifery was a 'desire to help others'. Over half (55%) of participants reported they will 'definitely work' (11%) or 'were likely to work' (44%) in a deprived area. When examined by student type and location of school, the top reason cited by participants was 'to serve humanity'. Those born in a rural area, currently living in a rural area, or under obligation to return to a rural or peri-urban area had greater odds of being willing to work in a deprived area after graduation. KEY CONCLUSIONS: findings from our study are unique in that they examine the distinct motivational factors from a national sample of midwifery students about to join the workforce. Regardless of the type of student or the location of the school, midwifery students in Ghana were highly motivated by altruistic values. Strategies to address the rural shortage of midwifery providers in Ghana is presented. IMPLICATION FOR PRACTICE: understanding the factors that motivate midwifery students to work in rural, deprived areas will help develop effective policy interventions affecting practice. PMID- 29288897 TI - Increased TRPC6 expression is associated with tubular epithelial cell proliferation and inflammation in diabetic nephropathy. AB - Although TRPC6 expression is shown to be significantly elevated in a rat model diabetic nephropathy (DN), its expression and role in human DN are unclear. We thus explored the role of TRPC6 in the pathophysiology of tubular epithelial cell injury following DN. HK-2 cells were cultured in a high-glucose medium to induce a DN cell model. Ad-TRPC6 and TRP6 siRNA were transfected to overexpress and knock down TRPC6. We found that TRPC6 expression was significantly upregulated in DN tissues and cells. TRPC6 siRNA inhibited cell proliferation and promoted cell apoptosis in HK-2 cells treated with high glucose, whereas Ad-TRPC6 showed the opposite effect. Furthermore, Ad-TRPC6 significantly promoted release of IL-8 and IL-6. Subsequent experiments demonstrated that the signaling pathway of nuclear factor of activated T cells (NFAT) was activated by Ad-TRPC6 and deactivated by TRPC6 siRNA. The NFAT signaling inhibitor, FK-506, eliminated the effect of TRPC6 on HK-2 cells. These results suggest that TRPC6 was upregulated in DN and could promote cell proliferation and inflammation by inhibiting the NFAT signaling pathway in tubular epithelial cells. PMID- 29288898 TI - CXCR3 blockade combined with cyclosporine A alleviates acute graft-versus-host disease by inhibiting alloreactive donor T cell responses in a murine model. AB - Chemotaxis of T cells to acute graft-versus-host disease (aGvHD) target tissues directed by chemokines and their receptors plays a key role in the pathogenesis of aGvHD. Blockade of lymphocyte migration by targeting chemokine receptors may be a viable strategy for the prevention and treatment of aGvHD, which is quite distinguishable from typical efforts to use immunosuppressive medications that have been associated with some side effects. CXCR3 and its ligands have been reported to be correlated with aGvHD pathogenesis. Using the small-molecule CXCR3 antagonist AMG487, we demonstrated that AMG487 combined with cyclosporine A (CsA) effectively alleviated aGvHD with a prolonged mean survival time and significantly inhibited the infiltration of inflammatory cells in aGvHD target tissues in a murine aGvHD model. In addition, AMG487 combined with CsA inhibited the activation, proliferation and differentiation of donor-derived T cells in the spleens. Further results showed that the concentrations of Th1 cells associated with pro-inflammatory cytokines such as IFN-gamma and TNFalpha in serum were decreased. In addition, AMG487 treatment did not alter CXCR3 and CCR5 expression in donor-derived T cells but elevated the serum CXCL9 and CXCL10 levels. This novel and effective approach has the potential to develop a new clinical method to prevent and treat aGvHD. PMID- 29288899 TI - Identification of the cognate peptide-MHC target of T cell receptors using molecular modeling and force field scoring. AB - Interactions of T cell receptors (TCR) to peptides in complex with MHC (p:MHC) are key features that mediate cellular immune responses. While MHC binding is required for a peptide to be presented to T cells, not all MHC binders are immunogenic. The interaction of a TCR to the p:MHC complex holds a key, but currently poorly comprehended, component for our understanding of this variation in the immunogenicity of MHC binding peptides. Here, we demonstrate that identification of the cognate target of a TCR from a set of p:MHC complexes to a high degree is achievable using simple force-field energy terms. Building a benchmark of TCR:p:MHC complexes where epitopes and non-epitopes are modelled using state-of-the-art molecular modelling tools, scoring p:MHC to a given TCR using force-fields, optimized in a cross-validation setup to evaluate TCR inter atomic interactions involved with each p:MHC, we demonstrate that this approach can successfully be used to distinguish between epitopes and non-epitopes. A detailed analysis of the performance of this force-field-based approach demonstrate that its predictive performance depend on the ability to both accurately predict the binding of the peptide to the MHC and model the TCR:p:MHC complex structure. In summary, we conclude that it is possible to identify the TCR cognate target among different candidate peptides by using a force-field based model, and believe this works could lay the foundation for future work within prediction of TCR:p:MHC interactions. PMID- 29288900 TI - Increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ T follicular helper cells in adult patients with minimal change disease. AB - T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD 1)+ Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD 1+ Tfh cells and their functional effects in adult patients with minimal change disease (MCD). The frequencies of circulating PD-1+, PD-1+CD154+, and PD 1+interleukin (IL)-21+ Tfh cells, and CD38+CD19+ and CD38+CD19+CD40+ B cells, as well as serum IL-2, IL-4, IL-17A, IL-6, IL-21, and interferon (IFN)-gamma were significantly increased in the MCD patients compared with the healthy controls (HCs) (P < 0.05). However, no significant difference was found in PD-1+BCL-6+ or PD-1+ICOS+ Tfh cells. Furthermore, the percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were negatively correlated with the estimated glomerular filtration rate (eGFR), but positively correlated with the 24-h urinary protein concentration and serum IL-21 level. The percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were positively correlated with the percentages of CD38+ plasma cells and active CD38+CD40+ plasma cells, respectively. After an 8-12-week treatment with prednisolone, the percentages of PD-1+, PD-1+CD154+, and PD-1+IL-21+ Tfh cells as well as the serum level of IL-21 were significantly reduced; in contrast, the serum levels of IL-4 and IL-10 were increased (P < 0.05). We conclude that increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ Tfh cells and may contribute towards the pathogenesis of MCD. PMID- 29288901 TI - Understanding orthopoxvirus host range and evolution: from the enigmatic to the usual suspects. AB - In general, orthopoxviruses can be considered as falling into one of three host utilization categories: highly specialized, single-host; broad host range; or 'cryptic', the last encompassing those viruses about which very little is known. Single-host viruses tend to exploit abundant hosts that have consistent patterns of interaction. For these viruses, observed genome reduction and loss of presumptive host-range genes is thought to be a consequence of relaxed selection. In contrast, the large genome size retained among broad host range orthopoxviruses suggests these viruses may depend on multiple host species for persistence in nature. Our understanding of the ecologic requirements of orthopoxviruses is strongly influenced by geographic biases in data collection. This hinders our ability to predict potential sources for emergence of orthopoxvirus-associated infections. PMID- 29288902 TI - Diagnostic evaluation and surgical management of pediatric insular epilepsy utilizing magnetoencephalography and invasive EEG monitoring. AB - INTRODUCTION: The diagnosis and surgical management of pediatric patients with insular epilepsy is challenging due to variable and indistinct seizure semiology arising within the insular cortex. In addition, surgical approaches are associated with potential morbidity given the regional neurosurgical and vascular anatomy. Our institutional experience in evaluation and surgical management of insular epilepsy patients is presented. Diagnostic evaluation, surgical treatment and seizures outcomes are highlighted. METHODS: The institutional database for all pediatric surgical epilepsy patients was reviewed over a period of 15 years (2000-2015). Study subjects were defined as patients who had undergone surgical resection of the epileptogenic zone involving the insular cortex. Diagnostic imaging, electrophysiological studies and surgical records were assessed. RESULTS: Six (n = 6) patients with insular epilepsy were identified with a mean follow up of 2.8 years (range: 0.8-6.8 years). Mean age at surgical resection was 9.5 +/- 2.5 years (range: 2.5-16 years). Majority of patients (n = 4/6, 67%) underwent more than 1 surgical procedure. Magnetoencephalography (MEG) identified insular cortex involvement presurgically in all cases. MEG cluster localization was useful in guiding invasive EEG monitoring in 5 patients and was concordant with identification of epileptogenic zone through intracranial monitoring in all 5 patients. Surgical resection of the epileptogenic zone, as delineated through MEG spike sources and invasive EEG monitoring, was associated with favorable seizure outcome in 4 of 6 patients (67%; Engel Class I). Cortical dysgenesis was identified on histopathology in 4 cases. CONCLUSION: Diagnostic evaluation through invasive and noninvasive electrophysiological studies is critical to identify pediatric patients with insular epilepsy. Our findings suggest that MEG may help with identifying the epileptogenic zone within the insular cortex, which could be confirmed with invasive intracranial monitoring. PMID- 29288903 TI - Environmental and human health risk indicators for agricultural pesticides in estuaries. AB - The present study aims to contribute to a better assessment of pesticide environmental and human health (here evaluated in the context of human exposure via food items) risks for the estuarine system by comprehensively studying the spatial and temporal occurrence of the pesticides atrazine, azoxystrobin, bentazon, lambda-cyhalothrin, penoxsulam and terbuthylazine in the River Mondego estuary (Portugal). Pesticide quantification was performed in surface water, sediment, macroalgae (Ulva spp., Gracilaria gracilis, Fucus vesiculosus), aquatic plants (Zostera noltii, Spartina maritime, Scirpus maritimus) and bivalves (Scrobicularia plana). Since intense precipitation could promote the runoff of pesticides from the surrounding agricultural fields, a single long-duration flood event was also studied in this estuarine system. Under normal flow conditions, quantified concentrations were determined mostly during summer in agreement with the pesticide application period. Azoxystrobin presented the highest detection frequency and atrazine (an herbicide used globally but banned in the EU) presented the second highest frequency, thus highlighting the need to include legacy pesticides in monitoring programmes. Pesticide concentrations in surface water determined in the present study suggest low risk to estuarine organisms. However, all the pesticides were bioaccumulated by S. plana, leading us to consider that pesticides may not only cause adverse effects on the aquatic organism itself, but should also be an alert for human exposure, for this is an edible species and is considered of economic interest. Concern is also expressed about edible seaweeds, since s-triazine pesticides were found in Ulva spp. and G. gracilis. Acknowledging these concerns, developing and establishing allowable pesticide safety values for edible seaweeds and bivalves is recommended, as well as monitoring bivalve pesticide levels, using the whole animal, as a human health exposure indicator for estuarine systems. During the studied flood event, it appears that no serious pesticide contamination has occurred in the River Mondego estuary. PMID- 29288904 TI - Efficient degradation of Azo dyes by a newly isolated fungus Trichoderma tomentosum under non-sterile conditions. AB - A fast-growing fungus with remarkable ability to degrade several azo dyes under non-sterile conditions was isolated and identified. This fungus was identified as Trichoderma tomentosum. Textile effluent of ten-fold dilution could be decolorized by 94.9% within 72h before optimization. Acid Red 3R model wastewater with a concentration of 85.5mgL-1 could be decolorized by 99.2% within the same time after optimization. High-level of manganese peroxidase and low-level of lignin peroxidase activities were detected during the process of decolorization from the culture supernatant, indicating the possible involvement of two enzymes in azo dye decolorization. No aromatic amine products were detected from the degradation products of Acid Red 3R by gas chromatography-mass spectrometry (GC/MS) analysis, indicating the possible involvement of a special symmetrical oxidative degradation pathway. Phytotoxicity assay confirmed the lower toxicity toward the test plant seeds of the degradation products when compared to the original dye. PMID- 29288905 TI - Simultaneous removal of dihydroxybenzenes and toxicity reduction by Penicillium chrysogenum var. halophenolicum under saline conditions. AB - The dihydroxybenzenes are widely found in wastewater and usually more than one of these aromatic compounds co-exist as pollutants of water resources. The current study investigated and compared the removal efficiency of hydroquinone, catechol and resorcinol in binary substrate systems under saline conditions by Penicillium chrysogenum var. halophenolicum, to clarify the potential of this fungal strain to degrade these aromatic compounds. Since P. chrysogenum is a known penicillin producer, biosynthetic penicillin genes were examined and antibiotic was quantified in mono and binary dihydroxybenzene systems to elucidate the carbon flux of dihydroxybenzenes metabolism in the P. chrysogenum var. halophenolicum to the secondary metabolism. In binary substrate systems, the three assayed dihydroxybenzene compounds were found to be co-metabolized by fungal strain. The fungal strain preferentially degraded hydroquinone and catechol. Resorcinol was degraded slower and supports higher antibiotic titers than either catechol or hydroquinone. Dihydroxybenzenes were faster removed in mixtures compared to mono substrate systems, except for the case of hydroquinone. In this context, the expression of penicillin biosynthetic gene cluster was not related to the removal of dihydroxybenzenes. Penicillin production was triggered simultaneously or after dihydroxybenzene degradation, but penicillin yields, under these conditions, did not compromise dihydroxybenzene biological treatment. To investigate the decrease in dihydroxybenzenes toxicity due to the fungal activity, viability tests with human colon cancer cells (HCT116) and DNA damage by alkaline comet assays were performed. For all the conditions assays, a decrease in saline medium toxicity was observed, indicating its potential as detoxification agent. PMID- 29288906 TI - Biosorption of copper ions from aqueous solution using rape straw powders: Optimization, equilibrium and kinetic studies. AB - In this paper, the adsorption behaviors of Cu(II) from the aqueous solution using rape straw powders were studied. The effects of initial Cu(II) concentration, pH range and absorbent dosage on the adsorption efficiency of Cu(II) by rape straw powder were investigated by Box-Behnken Design based on response surface methodology. The values of coefficient constant of the nonlinear models were 0.9997, 0.9984 and 0.9944 for removal Cu(II) from aqueous solution using rape straw shell, seed pods and straw pith core, respectively, which could navigate the design space for various factors on effects of biosorption Cu(II) from aqueous solution. The various factors of pH and biosorbents dosage were the key factors that affecting the removal efficiency of Cu(II) from aqueous solution. The biosorption equilibrium data presented its favorable monolayer adsorption Cu(II) onto shell, seed pods and straw pith core, respectively. The pseudo-second order kinetic model was the proper approach to determine the adsorption kinetics. The biosorption of Cu(II) onto surfaces of rape straw powders were confirmed and ion-exchanged in the adsorption process by energy dispersive spectrometer. The critical groups, -OH, -CH, -NH3+, -CH3, -NH and -C-O, exhibited by the infrared spectra results, changed to suggest that these groups played critical roles, especially -CH3 in the adsorption of copper ions onto rape straw powders. The study provided evidences that rape straw powders can be used for removing Cu(II) from aqueous water. PMID- 29288907 TI - Effect of pomegranate based marinades on the microbiological, chemical and sensory quality of chicken meat: A metabolomics approach. AB - Pomegranate juice is a product with enhanced functional properties that could be used as an alternative to traditional marination ingredients and effectively retard microbial growth along with providing an improved sensory result. In this study, two pomegranate based marinades were prepared for the marination of chicken breast fillets and the marinated samples were aerobically stored at 4 and 10 degrees C for 9days. Raw, non-marinated chicken samples were used as control. Levels of total viable counts (TVC), Pseudomonas spp., Brochothrix thermosphacta, Enterobacteriaceae and lactic acid bacteria (LAB) were determined together with sensory assessment to evaluate the evolution of spoilage. The profile of organic acids and volatile compounds was also analyzed during storage. The shelf life of marinated samples was significantly extended compared to control samples at both storage temperatures (e.g., up to 5 and 6days for the pomegranate/lemon marinated samples stored at 4 and 10 degrees C, respectively) as evaluated by both microbiological and sensory analyses. The profile of the organic acids and the volatilome of marinated and control samples were remarkably differentiated according to storage time, microbial load and sensory score. The findings of this study suggest that pomegranate juice could be used as a novel ingredient in marinades to improve the sensory attributes, while prolonging the shelf life of chicken meat. PMID- 29288908 TI - The role of military footwear and workload on ground reaction forces during a simulated lateral ankle sprain mechanism. AB - BACKGROUND: Ankle sprains are a common orthopedic injury in military populations, which may be attributed to occupational demands and footwear. Minimalist military boots have become popular, but their influence on ground reaction force (GRF) attenuation capabilities during an ankle inversion perturbation are unknown. Therefore, the purpose of this study was to examine potential differences in GRFs during an ankle inversion perturbation in a standard issue (STN) and minimalist military boot (MIN) before and after a simulated military workload. METHODS: Twenty-one healthy adult males completed an ankle inversion perturbation protocol in each footwear condition before and after an incremental treadmill exercise protocol to volitional exhaustion while wearing a 16kg rucksack. The ankle inversion perturbation protocol consisted of stepping down from a 27cm box onto a force platform with a fulcrum (FUL), which created 25 degrees of inversion upon landing, or flat (FLT) outer sole attached to the plantar aspect of the participants' footwear in random order. Peak vertical, anterior/posterior, and medial/lateral components of the GRF during FUL and FLT conditions were assessed, normalized to multiples of body weight in each footwear. Dependent variables were then analyzed using separate 2 (footwear)*2 (time) repeated measures ANOVA (p<0.05). RESULTS: The MIN footwear demonstrated significantly greater vertical GRF and significantly less medial GRF during the FUL condition. CONCLUSIONS: These results indicate that various mechanical and design characteristics of military footwear may influence GRF attenuation capabilities and ankle joint loading when the foot/ankle complex is forced into inversion. PMID- 29288909 TI - On the feasibility of determining the 230Th activity in minerals without the addition of a Th radiotracer. AB - The necessity of measuring the radioactivity of the 230Th nuclide arises when attempting to solve a number of geochemical or geochronological problems based on the effects of radioactive disequilibrium in the 238U series. It is the authors' opinion that the use of the traditional alpha- and beta-emitters of thorium as a radiotracer in order to determine the activity of 230Th leads to various inconveniences and difficulties of a technical nature. The authors recommend using the 234Th isotope contained in the study sample as the simplest and most natural way of measuring the chemical yield of the targeted nuclide (230Th). A sequence of radio-analytical procedures is proposed that will provide a correct assessment of the radioactivity of 230Th. In addition, a specific example and an evaluation of the accuracy of the proposed methodology are presented, using actual experimental data. PMID- 29288910 TI - 3q26/EVI1 rearrangement in myelodysplastic/myeloproliferative neoplasms: An early event associated with a poor prognosis. AB - 3q26.2/EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this study, we aim to explore the clinicopathological features of myelodysplastic/myeloproliferative (MDS/MPN) neoplasms with 3q26.2/EVI1 rearrangements and determine the potential impact of these cytogenetic abnormalities on treatment response and survival. The study group included 12 cases of MDS/MPN with 3q26.2 rearrangements detected by conventional karyotyping. There were 7 men and 5 women with a median age of 67 years (range, 51-79 years) at time of initial MDS/MPN diagnosis. Ten cases were classified as chronic myelomonocytic leukemia (CMML) and 2 were MDS/MPN, unclassifiable. Among CMML cases, 5 (50%) were proliferative type and 5 (50%) were dysplastic type. Based on blast counts, these 10 CMML were: CMML-0 (n = 2), CMML-1 (n = 3), and CMML-2 (n = 5). Eleven (92%) patients had 3q26 rearrangements at the initial diagnosis. Inv(3)(q21q26.2) was most common, identified in 7(58%) patients, followed by t(3;21)(q26.2;q22) in 2 patients and 1 patient each with t(3;3)(q21;q26.2), t(2;3)(p21;q26-27), and t(3;6)(q26.2;q26). Six (50%) patients had 3q26.2 rearrangements as a sole cytogenetic abnormality and 6 (50%) patients had additional cytogenetic abnormalities. Molecular studies revealed DNMT3A mutations in all 3 patients assessed and RAS mutations in 2 of 8 (25%) patients. No mutations in ASXL1 (n = 3), TET2 (n = 3), FLT3 ITD/D835 (n = 10), and CEBPA (n = 7) were detected. Most patients received hypomethylating agent based chemotherapy. The median follow-up was 11.5 months (range, 1.5-24 months) and at time of last follow-up, 11 (92%) died with a median survival of 13.4 months (range, 1.5-24 months). The only patient alive had a relatively short follow-up of 2.4 months and showed disease progression at the last visit. In conclusion, 3q26.2/EVI1 rearrangements are a rare event and usually present at time of initial diagnosis in MDS/MPN. The presence of 3q26.2/EVI1 rearrangements in MDS/MPN is associated with rapid disease progression, poor response to treatment, and a poor prognosis. PMID- 29288911 TI - A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy. AB - PURPOSE: Perampanel is approved for adjunctive treatment of focal seizures, with or without secondarily generalised seizures, and for primary generalised tonic clonic seizures in people with epilepsy aged >=12 years. Perampanel was recently approved for monotherapy use for partial seizures in the United States. This study provides insight into the feasibility of perampanel monotherapy in real world settings. METHODS: This retrospective, non-interventional, multicentre study (NCT02736162) was conducted between January 2013 and March 2016 in specialist epilepsy centres in Europe and Russia. Eligible individuals had a diagnosis of epilepsy and received perampanel primary or secondary monotherapy as routine clinical care. The primary endpoint was proportion of individuals remaining on perampanel monotherapy, after conversion from perampanel adjunctive treatment, at 3, 6, 12, 18 and 24 months (retention rate). RESULTS: Sixty individuals were in the safety set (female, 63%; white, 97%; aged 18 to <65 years, 73%). Most (85%) received secondary monotherapy with perampanel. At study cut-off, 68% of individuals were continuing on perampanel monotherapy (secondary monotherapy: 55%). The median duration of retention was not calculable due to the high number of individuals ongoing on monotherapy. Twelve individuals had treatment-emergent adverse events that started during perampanel monotherapy, the most frequent was dizziness (5%). One serious treatment-emergent adverse event was reported (pneumonia during adjunctive perampanel treatment). CONCLUSIONS: In this small retrospective study of individuals who received perampanel monotherapy, the majority maintained monotherapy. Perampanel monotherapy may be an achievable option in some people with epilepsy. PMID- 29288912 TI - Prediction of three year outcomes using the Bayley-III for surgical, cardiac and healthy Australian infants at one year of age. AB - BACKGROUND: Previous predictive research has predominantly focussed on infants who are preterm, low birth weight, who have a specific condition or who have undergone a specific procedure. AIM: This study investigated the ability of outcomes at one year of age to predict outcomes at three years using the Bayley III for infants who have undergone early major cardiac surgery (CS) or non cardiac (NC) surgery and their healthy peers. STUDY DESIGN: Participants who were part of the Development After Infant Surgery (DAISy) study who had complete Bayley-III assessments at one and three years of age were included in the analyses. This included 103 infants who had undergone CS, 158 who had NC surgery and 160 controls. RESULTS: Bayley-III outcomes at one, although statistically significantly associated with three year outcomes in all domains were weak predictors of those outcomes for CS, NC surgical and healthy infants. Specificity for three year outcomes was good for cognitive, receptive language and fine motor domains for infants who had undergone CS and NC surgery. Sensitivity for <-1 SD at three years was poor for cognitive, expressive and receptive language, and fine motor outcomes for CS and NC surgical participants. CONCLUSION: It remains difficult to predict how performance at one year on the Bayley-IIII predicts performance at three on the Bayley-III for infants who have undergone early major CS or NC surgery and for healthy Australian infants. PMID- 29288913 TI - The association between neighborhood socioeconomic disadvantage and high-risk injection behavior among people who inject drugs. AB - BACKGROUND: Although much research has been conducted on the determinants of HIV risk behavior among people who inject drugs (PWID), the influence of the neighborhood context on high-risk injection behavior remains understudied. To address this gap in the literature, we measured associations between neighborhood socioeconomic disadvantage and high-risk injection behavior, and determined whether these associations were modified by drug-related police activity and syringe exchange program (SEP) accessibility. METHODS: Our sample was comprised of 484 pharmacy-recruited PWID in New York City. Measures of neighborhood socioeconomic disadvantage were created using data from the 2006-2010 American Community Survey. Associations with high-risk injection behavior were estimated using multivariable Poisson regression. Effect modification by drug-related police activity and SEP accessibility was assessed by entering cross-product terms into adjusted models of high-risk injection behavior. RESULTS: Neighborhood socioeconomic disadvantage was associated with decreased receptive syringe sharing and unsterile syringe use. In neighborhoods with high drug-related police activity, associations between neighborhood disadvantage and unsterile syringe use were attenuated to the null. In neighborhoods with high SEP accessibility, neighborhood disadvantage was associated with decreased acquisition of syringes from an unsafe source. CONCLUSIONS: PWID in disadvantaged neighborhoods reported safer injection behaviors than their counterparts in neighborhoods that were relatively better off. The contrasting patterns of effect modification by SEP accessibility and drug-related police activity support the use of harm reduction approaches over law enforcement-based strategies for the control of blood borne virus transmission among PWID in disadvantaged urban areas. PMID- 29288915 TI - Highly porous copper ferrite foam: A promising adsorbent for efficient removal of As(III) and As(V) from water. AB - A novel copper ferrite foam fabricated on Fe-Ni foam substrate was synthesized via a simple hydrothermal method to efficiently remove arsenic from aqueous solution. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), X-Ray diffraction pattern (XRD) and Raman spectra were used to characterize the morphology and surface composition of the copper ferrite foam (CFF). The adsorption behavior of As(III) and As(V) onto this CFF is studied as a function of solution pH, temperature, contact time, and different concentrations. Results shown that this CFF has high adsorption capacity and excellent recyclability. Adsorption isotherms study indicates Langmuir model of adsorption. The maximum adsorption capability of As(III) and As(V) on CuFe2O4 foam is observed about 44.0 mg g-1 and 85.4 mg g-1, respectively. Regeneration experiment indicates that arsenic could be easily desorbed from CFF with 0.10 mol L-1 NaOH and the high adsorption capacity can be maintained for six regeneration cycle. PMID- 29288914 TI - Agency-level financial incentives and electronic reminders to improve continuity of care after discharge from residential treatment and detoxification. AB - BACKGROUND: Despite the importance of continuity of care after detoxification and residential treatment, many clients do not receive further treatment services after discharged. This study examined whether offering financial incentives and providing client-specific electronic reminders to treatment agencies lead to improved continuity of care after detoxification or residential treatment. METHODS: Residential (N = 33) and detoxification agencies (N = 12) receiving public funding in Washington State were randomized into receiving one, both, or none (control group) of the interventions. Agencies assigned to incentives arms could earn financial rewards based on their continuity of care rates relative to a benchmark or based on improvement. Agencies assigned to electronic reminders arms received weekly information on recently discharged clients who had not yet received follow-up treatment. Difference-in-difference regressions controlling for client and agency characteristics tested the effectiveness of these interventions on continuity of care. RESULTS: During the intervention period, 24,347 clients received detoxification services and 20,685 received residential treatment. Overall, neither financial incentives nor electronic reminders had an effect on the likelihood of continuity of care. The interventions did have an effect among residential treatment agencies which had higher continuity of care rates at baseline. CONCLUSIONS: Implementation of agency-level financial incentives and electronic reminders did not result in improvements in continuity of care, except among higher performing agencies. Alternative strategies at the facility and systems levels should be explored to identify ways to increase continuity of care rates in specialty settings, especially for low performing agencies. PMID- 29288916 TI - High efficient detoxification of mustard gas surrogate based on nanofibrous fabric. AB - In recent years, people pay more attention to the protection against chemical warfare agents, due to the increase in the probability of usage of these chemical warfare agents in wars or terrorist attacks. In this work, MgO nanoparticles were in-situ growth on the surface of poly(m-phenylene Isophthalamide) (PMIA) forming a flexible and breathable fabric for the detoxification of mustard gas surrogate. The as-prepared nanofibrous membrane possesses a "flower-like" structure of which endows not only increase the specific surface area of the composite but also prevent the agglomeration of the MgO nanoparticles. The detoxification ability of the PMIA@MgO nanofibrous fabric was demonstrated by gas chromatography-mass spectrometer (GC-MS). It is found that after 20 h of reaction time, 70.56% of the mustard gas surrogate have been decomposed. PMID- 29288917 TI - Surface carbon influences on the reductive transformation of TCE in the presence of granular iron. AB - To gain insight into the processes of transformations in zero-valent iron systems, electrolytic iron (EI) has been used as a surrogate for the commercial products actually used in barriers. This substitution facilitates mechanistic studies, but may not be fully representative of all the relevant processes at work in groundwater remediation. To address this concern, the kinetic iron model (KIM) was used to investigate sorption and reactivity differences between EI and Connelly brand GI, using TCE as a probe compound. It was observed that retardation factors (Rapp) for GI varied non-linearly with influent concentrations to the columns (Co), and declined significantly as GI aged. In contrast, Rapp values for EI were small and insensitive to Co, and changed minimally with iron aging. Moreover, although declines in the rate constants (k) and increases in the sorption coefficients were observed for both iron types, they were most pronounced in the case of EI. SEM scans of the EI surface before and after aging (90 days) established the appearance of carbon on the older surface. This work provides evidence that iron with a higher surface carbon content outperforms pure iron, suggesting that the carbon is actively involved in promoting TCE reduction. PMID- 29288918 TI - Electroless controllable growth of ZnO films and their morphology-dependent antimicrobial properties. AB - An electroless deposition process was used to synthesize with a controlled morphology, polycrystalline ZnO on glass substrates as antimicrobial coatings. The influence of deposition temperature (Tdep) on the physicochemical and antimicrobial properties of the ZnO films was analyzed. The results indicated that a change in deposition temperature greatly affected the morphology and the degree of crystallinity of the films. Scanning electron microscope images show that the film surface is porous at a deposition temperature of 40 and 50 degrees C, whereas hexagonal-plate shaped morphology predominated at 60 degrees C and finally at 70 and 80 degrees C the films consisted of rod-like particles. The films showed good transparency in the visible region. All ZnO films presented notable antimicrobial activity against the gram-negative bacteria Escherichia coli (E. coli) and the gram-positive Staphylococcus aureus (S. aureus). It was found that the antimicrobial efficiency is strongly dependent on morphology and structural properties. The best antimicrobial performance was recorded for the films consisting of rod-like morphology with a high degree of crystallinity. The procedure used in this investigation is strongly recommended for the development of functional surfaces. PMID- 29288919 TI - Extraction of heavy metal (Ba, Sr) and high silica glass powder synthesis from waste CRT panel glasses by phase separation. AB - In this study, a novel process for the extraction of heavy metal Ba and Sr from waste CRT panel glass and synchronous preparation of high silica glass powder was developed by glass phase separation. CRT panel glass was first remelted with B2O3 under air atmosphere to produce alkali borosilicate glass. During the phase separation process, the glass separated into two interconnected phases which were B2O3-rich phase and SiO2-rich phase. Most of BaO, SrO and other metal oxides including Na2O, K2O, Al2O3 and CaO were mainly concentrated in the B2O3-rich phase. The interconnected B2O3-rich phase can be completely leached out by 5mol/L HNO3 at 90 C. The remaining SiO2-rich phase was porous glasses consisting almost entirely of silica. The maximum Ba and Sr removal rates were 98.84% and 99.38% and high silica glass powder (SiO2 purity > 90 wt%) was obtained by setting the temperature, B2O3 added amount and holding time at 1000-1100 C, 20-30% and 30 min, respectively. Thus this study developed an potential economical process for detoxification and reclamation of waste heavy metal glasses. PMID- 29288920 TI - Diagnostic potential and future directions of biomarkers in gingival crevicular fluid and saliva of periodontal diseases: Review of the current evidence. AB - OBJECTIVES: The holy grail of biomarker research in periodontology is to develop a high impact diagnostics which have a significant impact on clinical decision making, patient outcomes and healthcare providers. In the field of periodontal diagnostics, oral fluid-based biomarkers have been studied mainly in the gingival crevicular fluid (GCF) and saliva. METHODS: A literature search was performed using the Cochrane library and PubMed databases from 2000 to January 2017. RESULTS: Currently, there are more than 90 different components in the GCF that have been investigated as diagnostic and prognostic markers of periodontal disease progression involving; inflammatory mediators, markers of oxidative stress, host-derived enzymes, tissue-breakdown products and mediators of bone homeostasis. Furthermore, various biomarkers in saliva have been proposed which reveal a promising outlook for saliva as a key diagnostic medium for periodontal disease. Recent systematic reviews with high value of evidence have shown that potential salivary biomarkers can provide important complimentary diagnostic information and can be used as tests for screening diagnosis, prognosis and predicting periodontal disease progression. CONCLUSION: Future developments in proteomic analysis and personalized medicine will pave the way allowing novel diagnostic tools. Still, the application into the field of dentistry will depend on how practitioners will apply this into their daily clinical practice. CLINICAL RELEVANCE: Still, the application into the field of dentistry will depend on how practitioners will apply this into their daily clinical practice. PMID- 29288921 TI - Outcome of magnetic resonance-Guided focused ultrasound surgery (MRgFUS) for FIGO class 1 fibroids. AB - OBJECTIVE: Intracavitary uterine fibroids and fibroids that distort the uterine cavity are associated with excessive vaginal bleeding and infertility. While intracavitary fibroids smaller than 4 cm are usually treated safely by operative hysteroscopy, larger fibroids may require multiple surgeries or more extensive surgery with possible damage to the integrity of the uterine wall. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive approach for treating uterine fibroids, mainly the intramural type. We present the outcome of MRgFUS treatment for intracavitary fibroids (FIGO class 1) in cases that could not be treated by hysteroscopy due to either fibroid size or patient refusal. (Canadian Task Force II-1). STUDY DESIGN: A retrospective cohort study from a single tertiary referral center. A total of 68 patients were treated by MRgFUS for symptomatic uterine fibroids from January 2013 to December 2016. Six of them had FIGO class 1 fibroids. Adverse effects and short- and long-term outcomes (quality of life issues and need for additional surgical intervention) were assessed during ambulatory clinic visits and by phone interviews. RESULTS: The mean +/- SD fibroid volume on MRI screening was 86.3 +/- 60.9 cm3. Six of those patients underwent the procedure (mean age 40.5 +/- 5.6 years, range 33-48). The follow-up duration was 24.1 +/- 12.0 months. Four patients were not interested in future fertility and did not undergo additional treatment, while the two who planned to conceive underwent another surgical intervention (one underwent operative hysteroscopy after reduction of fibroid size and the other underwent laparoscopic myomectomy). CONCLUSION: This preliminary study shows that MRgFUS can be a feasible treatment option for FIGO class 1 uterine fibroids. Shrinkage of fibroids by MRgFUS can obviate or facilitate subsequent surgical intervention in selected cases. PMID- 29288922 TI - A prospective study of the frequency of severe pain and predictive factors in women undergoing first-trimester surgical abortion under local anaesthesia. AB - OBJECTIVE: To determine the frequency of severe pain among women and to identify the associated predictive factors during first-trimester surgical abortion under local anaesthesia (LA). STUDY DESIGN: A prospective cohort study from November 2013 to January 2014 at the Department of Gynecology and Obstetrics, Rennes, France. The study population was composed of one hundred and ninety-four patients who underwent an elective first-trimester surgical abortion under LA. In an anonymized questionnaire, the participants were asked to self-record their perceived pain level 30 min after the completion of the procedure using a 10 cm visual analogue scale (VAS). The main outcome measure was the frequency of severe pain among women, defined as VAS >= 7. Secondary outcome measure was the risk factor(s) for severe pain. RESULTS: Severe pain (i.e. VAS >= 7) was experienced by 46% (95% CI: 39%-53%) of the population. Multivariate analysis confirmed that >10 weeks of gestation (OR: 2.530 [95% CI: 1.1-5.81], p = .0287) and having 0 or 1 child (OR: 5.206 [95% CI: 1.87-14.49], p = .0016) were significant independent factors of severe pain. CONCLUSION: Nearly half of the women experienced severe pain. More than 10 weeks of gestation and parity were predictive factors of severe pain. These findings should be useful in counselling women undergoing surgical abortion under LA. PMID- 29288923 TI - Early versus late institution of plasma exchange therapy in pregnancy induced thrombotic microangiopathy and its effects on clinical outcomes-A case series. AB - PURPOSE: To look for incidence of pregnancy associated TMA, clinical presentation and impact of early diagnosis and institution of plasma exchange on overall renal outcomes METHODS: -This is a retrospective study among all female patients who presented with acute kidney injury post pregnancy between October 2002 to April 2016 in department of nephrology in a tertiary care hospital in northern India and diagnosed as pregnancy induced TMA. The patient were assessed for duration of onset of renal failure to time of diagnosis of TMA, role of modality of treatment ie plasmpaharesis to outcome. These patients were assessed for complete, partial or no recovery in renal functions at 60 days after admission. RESULTS: Patients whose time of onset of renal failure to a correct diagnosis of TMA was <=15 days and age less than 30 years was also associated with good prognosis. The patients who received plasma exchange and that to within 72 h of admission had more chances of recovery. CONCLUSIONS: Early diagnosis of disease and early institution of plasma exchange therapy improves renal outcomes in postpartum TMA. PMID- 29288924 TI - Short-term effects of electrical nerve stimulation on spinal reciprocal inhibition depend on gait phase during passive stepping. AB - A combination of electrical nerve stimulation (ENS) and passive or active cyclic movements (i.e., pedaling and stepping) has been suggested to induce stronger short-term effects in spinal circuits as compared to either intervention alone. The purpose of the present study is to determine whether the effects of ENS during passive stepping are dependent on the timing of the stimulation during the stepping cycle. A total of 10 able-bodied participants were recruited for the study. Two interventions were assessed during passive ground stepping: (1) ENS of the common peroneal nerve (CPN) during the swing phase (ENSswing) and (2) stance phase (ENSstance). ENS was applied at the motor threshold intensity on the tibialis anterior muscle for a total of 30 min. Spinal reciprocal inhibition (RI) was assessed by conditioning the H-reflex in the soleus muscle with electrical stimulation to the CPN before (baseline), as well as 5, 15, and 30 min after each intervention. Compared to the baseline, the amount of RI was increased 5 and 15 min after the ENSswing intervention, whereas it was decreased after the ENSstance intervention. This suggests that ENS has a phase-dependent effect on RI during passive stepping. Overall, the results imply that phase-dependent timing of ENS is essential for guiding plasticity in the spinal circuits. PMID- 29288925 TI - Effects of human adipose-derived mesenchymal stem cells combined with estrogen on regulatory T cells in patients with premature ovarian insufficiency. AB - OBJECTIVE: To investigate the effects of human adipose-derived mesenchymal stem cells (hADSCs) combined with estrogen on regulatory T cells (Tregs) in patients with premature ovarian insufficiency (POI). METHODS: hADSCs were isolated by enzymatic digestion and identified by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were isolated from POI patients and healthy controls. PBMCs were cultured in the following experimental groups: the control group, hADSC group, estrogen group and combined group. The PBMCs in the hADSC group were co-cultured with hADSCs at concentrations of 1*104, 2*104, or 1*105 cells/well, and the estrogen group was co-cultured with 10-9, 10-8, or 10-7mol/L 17beta estradiol. Cell proliferation was measured with the CCK-8 assay. The percentage of CD4+ CD25+ Foxp3+ Tregs was measured by flow cytometry. The expression levels of Foxp3, TGF-beta1 and IFN-gamma were measured by real-time PCR. RESULTS: Treatment with hADSCs, estrogen and their combination promoted Tregs differentiation of PBMCs from POI patients and healthy controls. An increase in the percentage of CD4+ CD25+ Foxp3+ Tregs was observed when PBMCs were co cultured with hADSCs, 17beta-estradiol and their combination. Foxp3 and TGF-beta1 mRNA expression was higher and IFN-gamma mRNA expression was lower in the hADSCs, estrogen and combined groups than in the control group. CONCLUSION: Combined treatment with hADSCs and estrogen played an immunomodulatory role by promoting Tregs proliferation, thereby potentially improving impaired ovarian function. PMID- 29288926 TI - EFhd2/swiprosin-1 regulates LPS-induced macrophage recruitment via enhancing actin polymerization and cell migration. AB - Macrophage motility is vital in innate immunity, which contributes strategically to the defensive inflammation process. During bacterial infection, lipopolysaccharide (LPS) potently activates the migration of macrophages via the NF-kappaB/iNOS/c-Src signaling pathway. However, the downstream region of c-Src that participates in macrophage migration is unclear. EFhd2, a novel actin bundling protein, was evaluated for its role in LPS-stimulated macrophage migration in this study. We found that LPS stimulated the up-regulation, tyrosine phosphorylation and membrane translocation of EFhd2 in macrophages. The absence of EFhd2 inhibited the recruitment of macrophages in the lungs of LPS-induced septic mice. LPS-induced macrophage migration was neutralized by the deletion of EFhd2. EFhd2-mediated up-regulation of NFPs (including Rac1/Cdc42, N-WASP/WAVE2 and Arp2/3 complex) induced by LPS could be used to explain the role of EFhd2 in promoting actin polymerization. Furthermore, the purified EFhd2 could directly promote actin polymerization in vitro. Dasatinib, a c-Src specific inhibitor, inhibited the up-regulation of EFhd2 stimulated by LPS. Therefore, our study demonstrated that EFhd2 might be involved in LPS-stimulated macrophage migration, which provides a potential target for LPS-activated c-Src during macrophage mobilization. PMID- 29288928 TI - Influences of socioeconomic vulnerability and intra-urban air pollution exposure on short-term mortality during extreme dust events. AB - Air pollution has been shown to be significantly associated with morbidity and mortality in urban areas, but there is lack of studies focused on extreme pollution events such as extreme dust episodes in high-density Asian cities. However, such cities have had extreme climate episodes that could have adverse health implications for downwind areas. More importantly, few studies have comprehensively investigated the mortality risks of extreme dust events for socioeconomically vulnerable populations. This paper examined the association between air pollutants and mortality risk in Hong Kong from 2006 to 2010, with a case-crossover analysis, to determine the elevated risk after an extreme dust event in a high-density city. The results indicate that PM10-2.5 dominated the all-cause mortality effect at the lag 0 day (OR: 1.074 [1.051, 1.098]). This study also found that people who were aged >= 65, economically inactive, or non married had higher risks of all-cause mortality and cardiorespiratory mortality during days with extreme dust events. In addition, people who were in areas with higher air pollution had significantly higher risks of all-cause mortality and cardiorespiratory mortality. In conclusion, the results of this study can be used to target the vulnerable among a population or an area and the day(s) at risk to assist in health protocol development and emergency planning, as well as to develop early warnings for the general public in order to mitigate potential mortality risk for vulnerable population groups caused by extreme dust events. PMID- 29288929 TI - Association between human exposure to heavy metals/metalloid and occurrences of respiratory diseases, lipid peroxidation and DNA damage in Kumasi, Ghana. AB - Heavy metals and metalloids contamination in soils, water, food and livers of wild rats have been studied in Kumasi, Ghana and despite the estimated risks to residents, there is no epidemiological study to ascertain these projections. In addition, the World Health Organization and International Agency for Research on Cancer have reported an increase in respiratory diseases and cancers, in Ghana. The study's purpose was therefore to explore the potential associations between metal exposure and occurrences of respiratory diseases, lipid peroxidation and/or DNA damage to different age groups and sexes in Kumasi. Human urine was collected from the general population in urban and control sites in Kumasi and nine metals were measured in each sample. Results showed that although Zn was the most abundant total urinary As concentration was higher in 83% of samples compared to reference values. Urinary concentrations of metals, malondialdehyde (MDA) and 8 hydroxy-2-deoxy-guanosine (8-OHdG) were higher in urban sites compared to the control site. Based on the results obtained, there was no significant correlation between urinary metals and age. However, urinary Cd and MDA were highest in age groups 61-85 and 3-20 years, respectively. Significantly higher levels of urinary Co, As and Cd were detected in female participants. The study revealed that exposure to As was significantly associated with increased odds of asthma (odds ratio (OR) = 2.76; CI: 1.11-6.83) and tachycardia (OR = 3.93; CI: 1.01-15.4). Significant association was observed between urinary metals and MDA and 8-OHdG indicating possibility of lipid peroxidation and/or DNA damage in Kumasi residents. PMID- 29288927 TI - Novel H2S-NO hybrid molecule (ZYZ-803) promoted synergistic effects against heart failure. AB - Therapeutic strategies that increase hydrogen sulfide (H2S) or nitric oxide (NO) are cytoprotective in various models of cardiovascular injury. However, the nature of interaction between H2S and NO in heart failure and the underlying mechanisms for the protective effects remain undefined. The present study tested the cardioprotective effect of ZYZ-803, a novel synthetic H2S-NO hybrid molecule that decomposed to release H2S and NO. ZYZ-803 dose dependently improved left ventricular remodeling and preserved left ventricular function in the setting of isoprenaline-induced heart failure. The cardioprotective effect of ZYZ-803 is significantly more potent than that of H2S and/or NO donor alone. ZYZ-803 stimulated the expression of cystathionine gamma-lyase (CSE) for H2S generation and the activity of endothelial NO synthase (eNOS) for NO production. Blocking CSE and/or eNOS suppressed ZYZ-803-induced H2S and NO production and cardioprotection. ZYZ-803 increased vascular endothelial growth factor (VEGF) concentration and cyclic guanosine 5'-monophosphate (cGMP) level. Moreover, ZYZ 803 upregulated the endogenous antioxidants, glutathione peroxidase (GPx) and heme oxygenase 1 (HO-1). These findings indicate that H2S and NO cooperatively attenuates left ventricular remodeling and dysfunction during the development of heart failure through VEGF/cGMP pathway and ZYZ-803 provide expanding insight into strategies for treatment of heart failure. PMID- 29288930 TI - Microbial community structure and function in sediments from e-waste contaminated rivers at Guiyu area of China. AB - The release of toxic organic pollutants and heavy metals by primitive electronic waste (e-waste) processing to waterways has raised significant concerns, but little is known about their potential ecological effects on aquatic biota especially microorganisms. We characterized the microbial community composition and diversity in sediments sampled along two rivers consistently polluted by e waste, and explored how community functions may respond to the complex combined pollution. High-throughput 16S rRNA gene sequencing showed that Proteobacteria (particularly Deltaproteobacteria) dominated the sediment microbial assemblages followed by Bacteroidetes, Acidobacteria, Chloroflexi and Firmicutes. PICRUSt metagenome inference provided an initial insight into the metabolic potentials of these e-waste affected communities, speculating that organic pollutants degradation in the sediment might be mainly performed by some of the dominant genera (such as Sulfuricurvum, Thiobacillus and Burkholderia) detected in situ. Statistical analyses revealed that toxic organic compounds contributed more to the observed variations in sediment microbial community structure and predicted functions (24.68% and 8.89%, respectively) than heavy metals (12.18% and 4.68%), and Benzo(a)pyrene, bioavailable lead and electrical conductivity were the key contributors. These results have shed light on the microbial assemblages in e waste contaminated river sediments, indicating a potential influence of e-waste pollution on the microbial community structure and function in aquatic ecosystems. PMID- 29288932 TI - Making multiple 'online counsellings' through policy and practice: an evidence making intervention approach. AB - Online counselling services for a range of health conditions have proliferated in recent years. However, there is ambiguity and tension around their role and function. It is often unclear whether online counselling services are intended to provide only a brief intervention, the provision of information or referral, or constitute an alternative to face-to-face treatment. In line with recent analyses of alcohol and other drug (AOD) policy and interventions that draw on a critical social science perspective, we take an evidence-making intervention approach to examine how online counselling in the AOD field is made in policy and through processes of local implementation. In this article, we analyse how online AOD counselling interventions and knowledges are enacted in Australia's AOD policy, and compare these enactments with an analysis of information about Australia's national online AOD counselling service, Counselling Online, and transcripts of counselling sessions with clients of Counselling Online. We suggest that while the policy enacts online counselling as a brief intervention targeting AOD use, and as an avenue to facilitate referral to face-to-face treatment services, in its implementation in practice online counselling is enacted in more varied ways. These include online counselling as attempting to attend to AOD use and interconnected psychosocial concerns, as a potential form of treatment in its own right, and as supplementing face-to-face AOD treatment services. Rather than viewing online counselling as a singular and stable intervention object, we suggest that multiple 'online counsellings' emerge in practice through local implementation practices and knowledges. We argue that the frictions that arise between policy and practice enactments need to be considered by policy makers, funders, clinicians and researchers as they affect how the concerns of those targeted by the intervention are attended to. PMID- 29288931 TI - Leveraging and coping with uncertainty in the response of individual cells to therapy. AB - Non-genetic heterogeneity fluctuates over diverse timescales, ranging from hours to months. In specific cases, such variability can profoundly impact the response of cell populations to therapy, in both antibiotic treatments in bacteria and chemotherapy in cancer. It is thus critical to understand the way phenotypes fluctuate in cell populations and the molecular sources of phenotypic diversity. Technical and analytical breakthroughs in the study of single cells have leveraged cellular heterogeneity to gain phenomenological and mechanistic insights of the phenotypic transitions that occur within isogenic cell populations over time. Such an understanding moves forward our ability to design therapeutic strategies with the explicit goal of preventing and controlling the selective expansion and stabilization of drug-tolerant phenotypic states. PMID- 29288933 TI - Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases. AB - The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT1R) pathway and activation of the downstream angiotensin converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1 7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. PMID- 29288934 TI - Microplastics have a more profound impact than elevated temperatures on the predatory performance, digestion and energy metabolism of an Amazonian cichlid. AB - Knowledge on the impacts of microplastics (MPs) pollution on freshwater environments and biota remains limited. Meanwhile, freshwater ecosystems have been threatened by elevated temperatures caused by climate change. To date, no information exists on how MPs-especially under elevated temperature conditions affect predatory performance, digestive processes and metabolic pathways in freshwater organisms. Here, we examined MPs, elevated temperature and their combined effects on juveniles (0+ group) of an Amazonian cichlid, the discus fish (Symphysodon aequifasciatus). For 30 days, fish were exposed to ambient or elevated temperatures (i.e., 28 or 31 degrees C) in the absence or presence of MPs (i.e., 0 or 200 MUg/L). The following metrics were quantified: MPs accumulation; predatory performance; and biomarkers involved in neurotransmission, digestion and energy production. The results showed that survival rate and body length were not affected by MPs, elevated temperatures or their combination. Elevated temperatures resulted in an increase in MP concentrations in fish bodies. Exposure to MPs decreased the post-exposure predatory performance (PEPP) at ambient temperatures but not at elevated temperatures. Elevated temperatures, however, had no effect on the PEPP but antagonistically interacted with MPs, leading to similar predatory performances under present and future conditions. Acetylcholinesterase (AChE) activity was only affected by MPs and decreased in the presence of MPs, indicating adverse effects in nervous and neuromuscular function and, thus, potentially in predatory performance. Trypsin activity was only influenced by MPs and decreased during exposure to MPs. Elevated temperatures or MPs alone increased the amylase activity but interacted antagonistically. Lipase activity was not influenced by either of the two stressors. In contrast, alkaline phosphatase (ALP) activity was affected by MPs or elevated temperatures alone and decreased with both stressors. Such results indicate deficits in the digestive capabilities of early-stage S. aequifasciatus under elevated temperature conditions and especially during exposure to MPs. Electron transport system (ETS) activity was not influenced by either of the two stressors. Both elevated temperatures and MPs alone increased LDH activity; however, the interaction between the two stressors cancelled activity but was still higher than activity in present conditions. Citrate synthase (CS) activity decreased with elevated temperature but increased during exposure to MPs. Cytochrome c oxidase (COX) activity was only influenced by MPs and increased in the presence of MPs. Thus, S. aequifasciatus juveniles exposed to elevated temperatures and MPs not only relied on anaerobic glycolysis for energy production but also depended on aerobic metabolism in the presence of MPs. Overall, these findings suggested that MPs showed a greater impact than elevated temperatures on the predatory performance, digestion and energy production of S. aequifasciatus. Nevertheless, juvenile survival and growth were minimally impacted, and thus, S. aequifasciatus could cope with near-future temperature increases and MP exposure. PMID- 29288935 TI - The contingent valuation study of Heidmork, Iceland - Willingness to pay for its preservation. AB - The decision-making and policy formation context in Iceland has been largely devoid of total economic valuations in cost-benefit assessments. Using an internet survey and applying the double bounded dichotomous choice methodology, this contingent valuation study sets out an estimate of the total economic value pertaining to Heidmork, a popular recreational area of urban open space located on the fringes of Reykjavik, Gardabaer and Kopavogur. In so doing, this case study advances the practice of using non-market valuation techniques in the country. The welfare estimates provide evidence that Icelanders consider Heidmork to possess considerable total economic value, with taxpayers willing to pay a mean lump-sum tax in the range 17,039 to 24,790 ISK per payment to secure its preservation, equating to an estimated total economic value of between 5.87 and 35.47 billion ISK. In the light of possible competitive land management demands among Heidmork's three owners and many recreational users in the future, the establishment of these values and their potential use in cost-benefit assessments informs the debate concerning whether the area should be preserved or further developed to satisfy economic objectives. Additionally, a body of experimental evidence is formed suggesting that the increased duration of a fixed payment vehicle is associated with much higher total economic valuations compared to a one-year payment period. PMID- 29288936 TI - Species- and sex-specific distribution of antennal olfactory sensilla in two tortricid moths, Epiphyas postvittana and Planotortrix octo. AB - We investigated the morphology and distribution of antennal sensilla in males and females of two tortricid moths, Epiphyas postvittana and Planotortrix octo, by scanning electron microscopy. The number and overall length of flagellomeres were significantly greater in females than in males in both species. The antennae of each species bearing six morphological types of sensilla (trichodea, basiconica, coeloconica, auricillica, chaetica, and styloconica), with different numbers and distributions along the antennae. Among these sensilla, four types (trichodea, basiconica, coeloconica, and auricillica) displayed multi-porous cuticular surfaces, indicating that their primary sensory function is olfactory. Each of these four types of sensilla could be further classified into subtypes according to their size, shape, and surface structure. Both E. postvittana and P. octo exhibited sexual dimorphism of the profiles of antennal olfactory sensilla. Trichoid sensilla were the most abundant type in both species. Subtype I trichoid sensilla were male-specific in both species, indicating that they are responsible for the perception of conspecific female sex pheromone. By contrast, subtype II trichoid sensilla were more abundant in female antennae in both species, suggesting that some subtype II trichoid sensilla are involved in female-specific behaviors, such as oviposition. Chaetic and styloconic sensilla displayed relatively even distributions along the antennae. Our results indicate that the antennae of E. postvittana and P. octo have species-specific and sex-specific profiles of olfactory sensilla. The morphological information obtained in our study provides a basis for electrophysiological and behavioral studies of the olfactory sensory function of each morphological type of sensilla. PMID- 29288937 TI - Molecular dynamics simulation of vibrational behavior of annular graphene sheet: Identification of nonlocal parameter. AB - To obtain accurate results from the nonlocal plate theory, the nonlocal parameter should be properly determined. In this paper, practicing a molecular dynamics simulation, the nonlocal plate theory was presented for free vibration analysis of annular graphene sheets. Accuracy and stability of results are validated by published results. Calculations are performed for different boundary conditions and geometrical properties. Results reveal that inner and outer radius induce significant effects on the nonlocal parameter. This nonlocal parameter extracted based on Molecular Dynamics (MD) in the nonlocal theory can determine the natural frequencies of annular graphene sheets, conveniently, whereas the molecular dynamics simulation demands a lot of time. PMID- 29288938 TI - Uranium time series analysis: A new methodological approach for event screening categorisation. AB - Uranium (U) groundwater anomalies, detected before the L'Aquila earthquake (April 6th, 2009), represent a key geochemical signal of a progressive increase of deep fluids fluxes at middle-lower crustal levels associated with the geodynamics of the earthquake. Although the analyses performed in association with the seismic pattern around Gran Sasso National Laboratory and the geophysical and geochemical patterns of the Gran Sasso aquifer supported this hypothesis, a new approach for time series analysis has been developed for event screening categorisation and to highlight U as possible strain meter in geodynamical processes, particularly those which characterise active normal faulting. PMID- 29288939 TI - Synthesis and anticancer activity of novel water soluble benzimidazole carbamates. AB - Metastases account for more than 90% of all cancer deaths and respond poorly to most therapies. There remains an urgent need for new therapeutic modalities for the treatment of advanced metastatic cancers. The benzimidazole methylcarbamate drugs, commonly used as anti-helmitics, have been suggested to have anticancer activity, but progress has been stalled by their poor water solubility and poor suitability for systemic delivery to disseminated cancers. We synthesized and characterized the anticancer activity of novel benzimidazoles containing an oxetane or an amine group to enhance solubility. Among them, the novel oxetanyl substituted compound 18 demonstrated significant cytotoxicity toward a variety of cancer cell types including prostate, lung, and ovarian cancers with strong activity toward highly aggressive cancer lines (IC50: 0.9-3.8 MUM). Compound 18 achieved aqueous solubility of 361 MUM. In a mouse xenograft model of a highly metastatic human prostate cancer, compound 18 (30 mg/kg) significantly inhibited the growth of established tumors (T/C: 0.36) without noticeable toxicity. PMID- 29288940 TI - Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation. AB - To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diarylaminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. PMID- 29288941 TI - Development of novel beta-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells. AB - A series of novel beta-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these beta-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC50 values of 0.53-1.56 MUM, which was considerably more potent than harmine (IC50 = 46.7-55.3 MUM) and also three-to ten-fold lower than that of SAHA (IC50 = 4.48-6.26 MUM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and alpha-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway. PMID- 29288942 TI - A new family of densely functionalized fused-benzoquinones as potent human protein kinase CK2 inhibitors. AB - A new series of 2-amino-4-phenyl-6-hydroxy-7-alkyl-pyranobenzoquinones was synthesized as ATP-competitive CK2 inhibitors. They were readily synthesized through a three-component Knoevenagel condensation-Michael addition heterocyclization reaction from aldehydes, malononitrile, and 3-alkyl-2,5 dihydroxybenzoquinones. Some of the synthesized compounds presented interesting inhibitory activity with IC50 values in the submicromolar range. A structure activity relationship study was carried out and the mode of binding was analysed by docking studies and supported by ATP competition assays. PMID- 29288943 TI - Design, synthesis and evaluation of novel phenyl propionamide derivatives as non nucleoside hepatitis B virus inhibitors. AB - As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 MUM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 MUM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate. PMID- 29288944 TI - Biological evaluation of indolizine-chalcone hybrids as new anticancer agents. AB - A new chemical space was explored based on an indolizine-chalcone hybrid, which was readily accessible by base-mediated aldol condensation of indolizine bearing a 7-acetyl group with various (hetero)aromatic aldehydes. Their anticancer effect was evaluated, revealing that indolizine-chalcone hybrids with 3,5 dimethoxyphenyl group (4h) or the halogen at the meta position (4j and 4l) could have the potential to induce the caspase-dependent apoptosis of human lymphoma cells. PMID- 29288945 TI - Recent advance in oxazole-based medicinal chemistry. AB - Oxazole compounds containing nitrogen and oxygen atoms in the five-membered aromatic ring are readily able to bind with a variety of enzymes and receptors in biological systems via diverse non-covalent interactions, and thus display versatile biological activities. The related researches in oxazole-based derivatives including oxazoles, isoxazoles, oxazolines, oxadiazoles, oxazolidones, benzoxazoles and so on, as medicinal drugs have been an extremely active topic, and numerous excellent achievements have been acquired. Noticeably, a large number of oxazole compounds as clinical drugs or candidates have been frequently employed for the treatment of various types of diseases, which have shown their large development value and wide potential as medicinal agents. This work systematically reviewed the recent researches and developments of the whole range of oxazole compounds as medicinal drugs, including antibacterial, antifungal, antiviral, antitubercular, anticancer, anti-inflammatory and analgesic, antidiabetic, antiparasitic, anti-obesitic, anti-neuropathic, antioxidative as well as other biological activities. The perspectives of the foreseeable future in the research and development of oxazole-based compounds as medicinal drugs are also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic oxazole medicinal drugs. PMID- 29288946 TI - Design, synthesis and QSAR study of novel isatin analogues inspired Michael acceptor as potential anticancer compounds. AB - Molecular hybridization is considered as an effective tactic to develop drugs for the treatment of cancer. A series of novel hybrid compounds of isatin and Michael acceptor were designed and synthesized on the basis of association principle. These hybrid compounds were tested for cytotoxic potential against human cancer cell lines namely, BGC-823, SGC-7901 and NCI-H460 by MTT assay. Most compounds showed good anti-growth activities in all tested human cancer cells. SAR and QSAR analysis may provide vital information for the future development of novel anti cancer inhibitors. Notably, compound 6a showed potent growth inhibition on BGC 823, SGC-7901 and NCI-H460 with the IC50 values of 3.6 +/- 0.6, 5.7 +/- 1.2, 3.2 +/- 0.7 MUM, respectively. Besides, colony formation assays, wound healing assays and flow cytometry analysis indicated 6a exhibited a potent anti-growth and anti migration ability in a concentration-dependence manner through arrested cells in the G2/M phase of cell cycle. Moreover, 6a significantly repressed tumor growth in a NCI-H460 xenograft mouse model. Overall, our findings suggested isatin analogues inspired Michael acceptor may provide promising lead compounds for the development of cancer chemotherapeutics. PMID- 29288947 TI - Synthesis and biological evaluation of novel 2-arylvinyl-substituted naphtho[2,3 d]imidazolium halide derivatives as potent antitumor agents. AB - Two series of novel 2-arylvinyl-naphtho[2,3-d]imidazol-3-ium iodide derivatives and 2-arylvinyl-naphtho[2,3-d]imidazol-3-ium bromide derivatives were designed and synthesized by the structural combination of YM155 with stilbenoids. All compounds were tested for anti-proliferative activity against PC-3, A375 and HeLa human cancer cell lines. Two of the compounds were selected for further investigation: 12b, which showed potent cytotoxicity against the three tested cell lines with IC50 values in the range of 0.06-0.21 MUM, and 7l, which displayed excellent selectivity for PC-3 cells with an IC50 of only 22 nM. Western blot analysis results indicated that both 12b and 7l suppress the expression of Bcl-2 and Survivin proteins, which helps induce apoptosis. As determined by the percent of Annexin V-FITC-positive apoptotic cells, 12b was not only significantly more effective than 7l at a concentration of 100 nM in PC-3 cells but also induced apoptosis in a dose-dependent manner with more potency than 7l at a concentration of 1000 nM in A375 cells. Therefore, compound 12b was chosen for further in-depth studies investigating the mechanism of apoptosis. The results showed that it could activate caspase-3, hydrolyze PARP, and even inactivate ERK. Moreover, 12b arrested A375 cells at S phase in a time-dependent and dose-dependent manner, while having a visible effect on microtubule dynamics. In addition, (E)-2-(2-(1H-indol-3-yl)vinyl)-1-benzyl-3-(2-methoxyethyl)-4,9-dioxo 4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide (12b) exhibited significant antitumor activity when evaluated in a subcutaneous solid tumor model. Our study reveals that 2-arylvinyl-substituted naphtho[2,3-d]imidazolium scaffolding is a promising new entity for the development of multi-target anticancer drugs. PMID- 29288948 TI - Design, synthesis, and biological evaluation of polo-like kinase 1/eukaryotic elongation factor 2 kinase (PLK1/EEF2K) dual inhibitors for regulating breast cancer cells apoptosis and autophagy. AB - Both PLK1 and EEF2K are serine/threonine kinases that play important roles in the proliferation and programmed cell death of various types of cancer. They are highly expressed in breast cancer tissues. Based on the multiple-complexes generated pharmacophore models of PLK1 and homology models of EEF2K, the integrated virtual screening is performed to discover novel PLK1/EEF2K dual inhibitors. The top ten hit compounds are selected and tested in vitro, and five of them display PLK1 and EEF2K inhibition in vitro. Based on the docking modes of the most potent hit compound, a series of derivatives are synthesized, characterized and biological assayed on the PLK1, EEF2K as well as breast cancer cell proliferation models. Compound 18i with satisfied inhibitory potency are shifted to molecular mechanism studies contained molecular dynamics simulations, cell cycles, apoptosis and autophagy assays. Our results suggested that these novel PLK1/EEF2K dual inhibitors can be used as lead compounds for further development breast cancer chemotherapy. PMID- 29288949 TI - Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3 arylureido)pyrazines as potential modulators of Abeta-induced mitochondrial dysfunction in Alzheimer's disease. AB - A series of 2-(3-arylureido)pyridines and 2-(3-benzylureido)pyridines were synthesized and evaluated as potential modulators for amyloid beta (Abeta) induced mitochondrial dysfunction in Alzheimer's disease (AD). The blocking activities of forty one small molecules against Abeta-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (DeltaPsim). The inhibitory activity of twenty five compounds against Abeta-induced mPTP opening was superior to that of the standard cyclosporin A (CsA). Six hit compounds have been identified as likely safe in regards to mitochondrial and cellular safety and subjected to assessment for their protective effect against Abeta-induced deterioration of ATP production and cytotoxicity. Among them, compound 7fb has been identified as a lead compound protecting neuronal cells against 67% of neurocytotoxicity and 43% of suppression of mitochondrial ATP production induced by 5 MUM concentrations of Abeta. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for these compounds with cyclophilin D (CypD) receptor as a major component of mPTP. Hence, this report presents compound 7fb as a new nonpeptidyl mPTP blocker which would be promising for further development of Alzheimer's disease (AD) therapeutics. PMID- 29288950 TI - Safeguarding child rights and enhancing caregiver responsibilities among Canadian parents of youth who sexually offend. AB - Research on youth sexual offending has focused primarily on its prevalence. However, recent efforts have begun to consider the collateral consequences for the relatives of offending youth, although little has been done in this regard toward exploring caregiver accountability. This study presents qualitative data on parents' sense of responsibility in situations where their child engaged in sexual offending behaviour against another child. We analyzed interview data among 16 parents from 10 families in Canada using thematic coding procedures. Findings illustrated the range of responsible actions that caregivers of sexual offending youth undertook with regard to preventing recidivism and accessing appropriate services for all the abuse-affected children. Caregivers reported on the enormous complexities they encountered as they attempted to simultaneously attend to the best interests of both the victim and offending youth. A particularly significant theme was that, despite the overwhelming challenges caregivers faced in dealing with the needs of their offending child, they were also highly attentive to the well-being of the victims. Our findings point to the importance of comprehensive and non-biased support services for both children and caregivers in order to fully uphold the rights of all affected individuals, and to better meet the needs as well as best interests of sexual abuse-affected children. PMID- 29288951 TI - A computational study of PAMAM dendrimer interaction with trans isomer of picoplatin anticancer drug. AB - In this study, the interaction of zero generation (G0) of polyamidoamine (PAMAM) dendrimer with trans isomer of Picoplatin anticancer drug (AMD) has been investigated by density functional theory. According to the structure of dendrimer and drug, two types of dendrimer cavities that can interact with the drugs can be formed in drug-loaded PAMAM dendrimer in which AMD drug can be located inside the PAMAM cavities through Cl and NH3 heads. The results have indicated that the interaction of PAMAM dendrimer with picoplatin anticancer drugs is physisorption. Relevant information about geometry, adsorption energy and molecular orbitals and quantum molecular descriptor, the most stable site for drug loading corresponds to the core of the dendrimer. The PAMAM-AMD complexes have shown a significant improvement of structural and electronic properties according to the results obtained from different arrangement of PAMAM G0-AMD complexes; a [G0-AMD (Cl-1)] complex is the preferred adsorption arrangement. As a result, it seems that the zero generation PAMAM dendrimer being combined with the AMD drug is suitable for use in drug delivery. PMID- 29288952 TI - Effects of the brain-derived neurotropic factor variant Val66Met on cortical structure in late childhood and early adolescence. AB - BACKGROUND: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been associated with several neuropsychiatric disorders and regional structural brain changes in adults, but little is known about Val66Met's effect on brain morphology during typical or atypical neurodevelopment. Windows of vulnerability to psychopathology may be associated with the different alleles of the Val66Met polymorphism during childhood and adolescence. METHODOLOGY: We investigated the effect of Val66Met on cortical thickness in MRI scans of 718 children and adolescents (6-12 years old) with typical development, and in those meeting DSM criteria for a psychiatric disorder. RESULTS: Val66Met had a significant effect on cortical thickness. Considering the typically developing group, Met-carriers presented thicker parietal and occipital lobes and prefrontal cortices compared to Val homozygotes. Met-carriers with psychiatric disorders presented thicker medial and lateral temporal cortices than Val homozygotes. Furthermore, a significant genotype * psychiatric diagnosis interaction was found: Met-carriers with a psychiatric diagnosis presented thinner bilateral prefrontal cortices than Val homozygotes. CONCLUSION: This study provides evidence that Val66Met is associated with cortical maturation in children and adolescents with and without psychiatric disorders. PMID- 29288953 TI - Malic acid production by chemically induced Aspergillus niger MTCC 281 mutant from crude glycerol. AB - In the present investigation, crude glycerol derived from transesterification process was utilized to produce the commercially-valuable malic acid. A combined resistant on methanol and malic acid strain of Aspergillus niger MTCC 281 mutant was generated in solid medium containing methanol (1-5%) and malic acid (40-80 g/L) by the adaptation process for 22 weeks. The ability of induced Aspergillus niger MTCC 281 mutant to utilize crude glycerol and pure glycerol to produce malic acid was studied. The yield of malic acid was increased with 4.45 folds compared with that of parent strain from crude glycerol. The highest concentration of malic acid from crude glycerol by using beneficial mutant was found to be 77.38 +/- 0.51 g/L after 192 h at 25 degrees C. This present study specified that crude glycerol by-product from biodiesel production could be used for producing high amount of malic acid without any pretreatment. PMID- 29288954 TI - One-pot bioprocess for lactic acid production from lignocellulosic agro-wastes by using ionic liquid stable Lactobacillus brevis. AB - The lignocellulosic agro-wastes are an attractive renewable resource in biorefinery for production of value-added platform chemicals and biofuels. The study describes use of different agro-wastes as substrate for production of lactic acid, a C3-platform chemical and high demand industrial product by Lactobacillus brevis in a one-pot bioprocess. The simultaneous saccharification and co-fermentation (SSCF) process was achieved by L. brevis governed fermentation of sugars, derived from saccharification of ionic liquid pretreated feedstocks by nanoimmobilized cellulase, which was further recovered and used for consecutive cycle. The lactic acid yields of 0.22, 0.49, 0.52 g/g were obtained from cottonseed cake, wheat straw and sugarcane bagasse, respectively. The ionic liquid-tolerant L. brevis, cellulolytic reusable nanoimmobilized enzyme coupled with valorization of renewable feedstocks points towards a holistic approach for future biorefineries with sustainable production of bioproducts. PMID- 29288955 TI - Responses of microalgae Coelastrella sp. to stress of cupric ions in treatment of anaerobically digested swine wastewater. AB - Microalgae Coelastrella sp. could remove nutrients from anaerobically digested swine wastewater (ADSW) effectively, while its responses to the stress of Cu(II) were not well understood. In this paper, nutrients removal and growth of Coelastrella sp. were investigated at the presence of Cu(II) in ADSW. Results showed ammonium nitrogen concentration in ADSW decreased with culturing duration, while increased with an increased Cu(II) concentration. Total phosphorous concentration decreased with time, while did not drop in 4 days at Cu(II) concentration >=1.0 mg/L. Microalgal growth was inhibited at all the Cu(II) concentrations, and ceased in about 6-8 days at Cu(II) concentration >=1.0 mg/L. With an increased Cu(II) concentration, the contents of chlorophyll a and proteins decreased, those of malondialdehyde and superoxide dismutase, and ratios of octadecanoic acid (C18:0), hexadecanoic acid (C16:0) and octadecenoic acid (C18:1) to fatty acids in Coelastrella sp. increased, while octadecatrienoic acid (C18:3) gradually disappeared. PMID- 29288956 TI - Sequential and simultaneous strategies for biorefining of wheat straw using room temperature ionic liquids, xylanases and cellulases. AB - Sequential and simultaneous strategies for fractioning wheat straw were developed in combining 1-ethyl-3-methyl imidazolium acetate [C2mim][OAc], endo-xylanases from Thermobacillus xylanilyticus and commercial cellulases. After [C2mim][OAc] pretreatment, hydrolysis catalyzed by endo-xylanases of wheat straw led to efficient xylose production with very competitive yield (97.6 +/- 1.3%). Subsequent enzymatic saccharification allowed achieving a total degradation of cellulosic fraction (>99%). These high performances revealed an interesting complementarity of [C2mim][OAc]- and xylanase-pretreatments for increasing enzymatic digestibility of cellulosic fraction in agreement with the structural and morphological changes of wheat straw induced by each of these pretreatment steps. In addition a higher tolerance of endo-xylanases from T. xylaniliticus to [C2mim][AcO] until 30% v/v than cellulases from T. reesei was observed. Based on this property, a simultaneous strategy combining [C2mim][OAc]- and endo-xylanases as pretreatment in a one-batch produced xylose with similar yield than those obtained by the sequential strategy. PMID- 29288957 TI - Enzyme/whole-cell biotransformation of plant oils, yeast derived oils, and microalgae fatty acid methyl esters into n-nonanoic acid, 9-hydroxynonanoic acid, and 1,9-nonanedioic acid. AB - Oils and fatty acids are important renewable resources provided by nature. Therefore, biotransformation of renewable oils and fatty acids into industrially relevant C9 chemicals was investigated in this study. Olive oil, soybean oil, yeast derived oil, and microalgae fatty acid methyl esters were converted into n nonanoic acid, 9-hydroxynonanoic acid, and 1,9-nonanedioic acid by a lipase and a recombinant Escherichia coli expressing oleate hydratase, long chain secondary alcohol dehydrogenase, Baeyer-Villiger monooxygenase, long chain primary alcohol dehydrogenase, and aldehyde dehydrogenase. It was found that n-nonanoic acid and azelaic acid could be produced to a concentration of 4.3 mM from 3 g/L olive oil with a specific product formation rate of 3.1 U/g dry cells. Biotransformation rates were influenced by compositions of fatty acids and purity of the starting material. This study may contribute to the production of industrially relevant C9 chemicals from renewable oils and fatty acids by simultaneous enzyme/whole-cell biotransformation. PMID- 29288959 TI - Ivermectin acute administration impaired the spermatogenesis and spermiogenesis of adult rats. AB - Ivermectin (IVM) is an antiparasitic agent widely used in agricultural, domestic animals and in human clinical practice. In the present study, the temporal effects of therapeutic doses of IVM in the morphometric and histological assessment of testis were studied to verify if IVM acute administration impaired the spermatogenesis and spermiogenesis of adult rats, if these effects are reversible. The testosterone levels and the plasmatic IVM levels were assessed. The results show: 1) IVM acute exposure, mainly in the higher dose, reduced the testicular volume, the tubular diameter and the germinal epithelium height; 2) no interferences on Leydig cells frequency; 3) histological studies show that tubular sections containing several histological changes indicative of spermatogenesis interruption, such as disorganization of germinal epithelium, vacuolar degeneration of the germ cells and sloughing of cells into the tubular lumen; 4) no differences in testosterone levels; 5) The IVM plasmatic levels were significantly reduced at 72h after the 0.2mg/kg. It was concluded that acute IVM impaired the spermatogenesis and spermiogenesis of rats. Probably these effects were not consequence of IVM at the Leydig cells because no effects were observed at this level. Finally, our results suggest that some testicular effects are reversible and correlated with the plasmatic levels of IVM. PMID- 29288958 TI - Inhibition of type I interferon responses by adenovirus serotype-dependent Gas6 binding. AB - The clinical use of many adenovirus vaccine vectors (AdVs) is limited by the presence of pre-existing antibodies in human populations, which prevent common AdVs from transducing cells and expressing immunogenic gene products. Rare serotype AdVs, such as HAdV-28D can bypass pre-existing immunity. However, rare AdVs stimulate high-levels of type I interferon (IFN), which suppresses antigenic gene expression and therefore limits immunogenicity. Recent studies identified Gas6 as a factor that connects enveloped viruses to host-cell receptor tyrosine kinases, in turn generating signaling cascades that antagonize type I IFN responses. We discovered that Gas6 bound to the fiber proteins of common AdV serotypes, such as HAdV-5C, with a higher affinity than rare HAd-28D fibers. AdV associated Gas6 suppressed IFN production by common AdVs and enhanced long-term expression of AdV encoded genes. We hypothesize that rare AdV serotypes might be engineered to include Gas6 binding motifs, thereby generating novel vectors that are more effective. PMID- 29288961 TI - Understanding the direction of the relationship between white matter hyperintensities of vascular origin, sleep quality, and chronic kidney disease Results from the Atahualpa Project. AB - OBJECTIVE: The burden of cerebral small vessel disease, sleep disorders, and chronic kidney disease is on the rise in remote rural settings. However, information on potential links between these conditions is limited. We aimed to assess the relationships between these conditions in community-dwelling older adults living in rural Ecuador. PATIENTS AND METHODS: Atahualpa residents aged >=60 years were offered a brain MRI. A venous blood sample was obtained for serum creatinine determination. Baseline interviews and procedures were directed to assess demographics, cardiovascular risk factors, and sleep quality. Using generalized structural equation modeling (GSEM), we assessed the associations between white matter hyperintensities (WMH) of vascular origin, sleep quality and kidney function, as well as the directions of the relationships between these variables. RESULTS: Of 423 candidates, 314 (74%) were enrolled. Moderate-to severe WMH were noticed in 74 (24%) individuals, poor sleep quality in 101 (31%), and moderate-to-severe chronic kidney disease in 28 (9%). GSEM showed that the direction of the effect was from kidney function to WMH and from the latter to sleep quality. Of independent variables investigated, worse kidney function was associated with age, high glucose levels and male sex. WMH was associated with cholesterol blood levels, blood pressure, level of education and severe edentulism. Poor sleep quality was associated with poor physical activity. CONCLUSION: This population based study shows that chronic kidney disease is associated with increased severity of WMH, which, in turn, is associated with a poor sleep quality. PMID- 29288960 TI - Coping with stressful events: A pre-post-test of a psycho-educational intervention for undergraduate nursing and midwifery students. AB - BACKGROUND: Knowledge of coping mechanisms is important for nursing and midwifery students to cope with stressful events during undergraduate education. OBJECTIVES: To evaluate the impact of a psycho-educational intervention "Coping with Stressful Events" with first year undergraduate nursing and midwifery students. DESIGN: A quasi-experimental, one-group pre-post-test. SETTINGS: One school of nursing/midwifery in one university in Ireland. PARTICIPANTS: A convenience sample of all first year undergraduate nursing and midwifery students (n=197). Of these 166 completed the pretest and 138 students completed the post test. METHODS: Using the COPE Inventory questionnaire (Carver et al., 1989) data was collected pre and post-delivery of the psycho-educational intervention "Coping with Stressful Events" by two research assistants. Data were analysed using the IBM SPSS Statistics version 22 (NY, USA). RESULTS: Results demonstrated improved coping skills by students. There were statistically significant differences between pre and post intervention for some coping subscales. For example, the mean subscale scores were lower post-intervention for restraint and mental disengagement, and higher for use of emotional and instrumental social support indicating improved coping strategies. CONCLUSIONS: This intervention has the potential to influence undergraduate nursing and midwifery students coping skills during their first year of an undergraduate programme. PMID- 29288962 TI - Assessing dynamic postural control during exergaming in older adults: A probabilistic approach. AB - Digital games controlled by body movements (exergames) have been proposed as a way to improve postural control among older adults. Exergames are meant to be played at home in an unsupervised way. However, only few studies have investigated the effect of unsupervised home-exergaming on postural control. Moreover, suitable methods to dynamically assess postural control during exergaming are still scarce. Dynamic postural control (DPC) assessment could be used to provide both meaningful feedback and automatic adjustment of exergame difficulty. These features could potentially foster unsupervised exergaming at home and improve the effectiveness of exergames as tools to improve balance control. The main aim of this study is to investigate the effect of six weeks of unsupervised home-exergaming on DPC as assessed by a recently developed probabilistic model. High probability values suggest 'deteriorated' postural control, whereas low probability values suggest 'good' postural control. In a pilot study, ten healthy older adults (average 77.9, SD 7.2 years) played an ice skating exergame at home half an hour per day, three times a week during six weeks. The intervention effect on DPC was assessed using exergaming trials recorded by Kinect at baseline and every other week. Visualization of the results suggests that the probabilistic model is suitable for real-time DPC assessment. Moreover, linear mixed model analysis and parametric bootstrapping suggest a significant intervention effect on DPC. In conclusion, these results suggest that unsupervised exergaming for improving DPC among older adults is indeed feasible and that probabilistic models could be a new approach to assess DPC. PMID- 29288963 TI - Antioxidant reserve of the lungs and ventilator-associated pneumonia: A clinical trial of high dose selenium in critically ill patients. AB - PURPOSE: To evaluate the effect of supplemental selenium administration on the incidence of ventilator-associated pneumonia (VAP) in critically ill patients. METHODS: Ninety-nine mechanically ventilated patients were randomized to receive either selenium or isotonic saline infusion for 10days. The primary endpoint was serum glutathione peroxidase-3 (GPX-3) activity and secondary endpoints were development of VAP or death, ICU stay and vasopressor requirement. Serum concentrations of selenium and GPX-3 were measured on Day-1, Day-4 and Day-10. Chi Square and log-rank analyses were used for statistical analyses and odds ratios were calculated. RESULTS: Serum selenium and GPX-3 activity levels increased steadily in the treatment group within 10days (P<0.025), while they remained unchanged in the placebo group. The incidence of VAP was 19.4/1000days of mechanical ventilation in the placebo group while it was 15.8/1000 ventilated days in the treatment group (P=0.250). The risk of VAP or death was similar between the treatments and placebo groups. CONCLUSION: Despite increasing the antioxidant activity, selenium supplementation did not affect the incidence of VAP in critically ill patients. The risk of developing VAP or death within 30days of ICU admission remained the same in the treatment and the controls. PMID- 29288964 TI - Association between chloride content of intravenous fluids and acute kidney injury in critically ill medical patients with sepsis. PMID- 29288965 TI - Determination of total plasma oxysterols by enzymatic hydrolysis, solid phase extraction and liquid chromatography coupled to mass-spectrometry. AB - The potential use of cholesterol esterases was tested to avoid alkaline hydrolysis for cleavage of plasma esterified oxysterols. The enzymatic hydrolysis was optimized by testing two sources of enzyme-Pseudomonas and bovine pancreas, presence of surfactants, incubation time and amount of enzyme. Free forms of 4beta-, 7-, 24-, 25- and 27-hydroxycholesterol (HC) as well 7-ketocholesterol (7 KC) were analyzed by liquid chromatography and mass-spectrometry using the deuterated internal standard, 25-HC(d6). Enzymatic hydrolysis was more effective using the Pseudomonas enzyme and in presence of surfactants. Compared to alkaline hydrolysis, it generated a cleaner chromatographic baseline and better recovery of the internal standard. Oxysterols were assayed with detection limits between 7 and 31 pg/mL. Interassay coefficients of variation were lower than 10% and extraction recovery efficiencies, higher than 90%. The procedure was used to characterize plasma levels of Cyp7b1-deficient rat, where it showed increased plasma levels of 7, 24 and 25-HC. Due to the low volume of sample required, it may be used in other animal models, particularly rodents, as well as in pediatric samples where sample amount is always a problem. Thus, the proposed new method offers mild enzymatic processing that greatly facilitates oxysterol determinations to delineate their role in physiopathology. PMID- 29288966 TI - Identification of rotundic acid metabolites after oral administration to rats and comparison with the biotransformation by Syncephalastrum racemosum AS 3.264. AB - The objective of this study was to identify the metabolites of rotundic acid after oral administration to rats and compare the similarities with its biotransformation by Syncephalastrum racemosum AS 3.264 using ultra-high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry. A total of fourteen metabolites were determined based on the mass spectrometry and chromatographic behaviors, among which eleven (M1-M3, M7-M14) and six (M2, M4-M8) metabolites were identified in rats and S. racemosum, respectively. Three identical metabolites (M2, M7 and M8) were found in rats and S. racemosum, indicating that there were metabolic similarities. Moreover, to confirm the results of mass spectrometry, three (M2, M4 and M7) metabolites were obtained by the means of amplifying incubation and their structures were determined by various spectroscopic analyses, and M4 was proved to be a previously undescribed compound. This results showed that in vitro assisted preparation by microbial transformation is a feasible and effective method of obtaining metabolites which are in low amounts and difficult to be prepared in vivo. PMID- 29288967 TI - Centrifugal ultrafiltration of human serum for improving immunoglobulin A quantification using attenuated total reflectance infrared spectroscopy. AB - Attenuated total reflectance infrared (ATR-IR) spectroscopy is a simple, rapid and cost-effective method for the analysis of serum. However, the complex nature of serum remains a limiting factor to the reliability of this method. We investigated the benefits of coupling the centrifugal ultrafiltration with ATR-IR spectroscopy for quantification of human serum IgA concentration. Human serum samples (n = 196) were analyzed for IgA using an immunoturbidimetric assay. ATR IR spectra were acquired for whole serum samples and for the retentate (residue) reconstituted with saline following 300 kDa centrifugal ultrafiltration. IR-based analytical methods were developed for each of the two spectroscopic datasets, and the accuracy of each of the two methods compared. Analytical methods were based upon partial least squares regression (PLSR) calibration models - one with 5-PLS factors (for whole serum) and the second with 9-PLS factors (for the reconstituted retentate). Comparison of the two sets of IR-based analytical results to reference IgA values revealed improvements in the Pearson correlation coefficient (from 0.66 to 0.76), and the root mean squared error of prediction in IR-based IgA concentrations (from 102 to 79 mg/dL) for the ultrafiltration retentate-based method as compared to the method built upon whole serum spectra. Depleting human serum low molecular weight proteins using a 300 kDa centrifugal filter thus enhances the accuracy IgA quantification by ATR-IR spectroscopy. Further evaluation and optimization of this general approach may ultimately lead to routine analysis of a range of high molecular-weight analytical targets that are otherwise unsuitable for IR-based analysis. PMID- 29288968 TI - Value of external carotid artery resistive index for diagnosis of cavernous sinus dural arteriovenous fistula and determination of malignant type. AB - PURPOSE: Cavernous sinus dural arteriovenous fistula (CSDAVF) causes hemodynamic disturbance in the arteries, which is detected by carotid Doppler sonography (CDS). The objective of the study was designed for validation of CDS in the diagnosis of CSDAVF. MATERIAL AND METHODS: 42 CSDAVF patients confirmed by angiography were enrolled. All patients were performed CDS before angiography. Evaluations of CDS parameters were compared with control subjects. RESULTS: The ECA resistive index (RI) shows the best performance. The highest yield shown on left ECA RI and increased from 78.6% to 91.7% on malignant-typed. CONCLUSION: CDS may be beneficial as the screening tool for CSDAVF. PMID- 29288969 TI - Generation of an induced pluripotent stem cell (iPSC) line from a 40-year-old patient with the A8344G mutation of mitochondrial DNA and MERRF (myoclonic epilepsy with ragged red fibers) syndrome. AB - Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNALys gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient. This patient-specific iPSC line expressed pluripotent stem cell markers, possessed normal karyotype, and displayed the capability to differentiate into mature cells in three germ layers. PMID- 29288970 TI - Yoga and body image: Findings from a large population-based study of young adults. AB - This study explored the potential for yoga to promote body satisfaction in a general population of young adults. The sample included 1664 participants (M age: 31.1, SD=1.6years) in Project EAT, a 15-year longitudinal study. Data from the third and fourth waves (EAT-III and EAT-IV), collected five years apart, were utilized. Practicing yoga (>=30min/week) was reported by 16.2% of young adults. After adjusting for EAT-III body satisfaction and body mass index, yoga practitioners had higher concurrent body satisfaction at EAT-IV than those not practicing yoga (difference: 1.5 units [95% CI: 0.1-2.8], p=.03). Among participants within the lowest quartile of prior (EAT-III) body satisfaction, there was preliminary evidence that body satisfaction at EAT-IV was higher among yoga practitioners than in other young adults. Findings suggest that yoga may be associated with improved body satisfaction, particularly among young adults with low prior body satisfaction. PMID- 29288971 TI - Effects of safflower yellow on beta-amyloid deposition and activation of astrocytes in the brain of APP/PS1 transgenic mice. AB - Safflower yellow (SY), one of traditional Chinese medicine extracted from safflower, has been shown to have neuroprotective effects on animal models of vascular dementia and Alzheimer's diseases (AD), by inhibiting oxidative injury, neuronal apoptosis and tau hyperphosphorylation. In this study, we investigated whether safflower yellow (SY) can improve cognitive function, decrease Amyloid beta (Abeta) accumulation and overactivation of astrocytes in AD mouse model. We found that SY treatment significantly ameliorated the learning and memory deficits of APP/PS1 mice. By hematoxylin-eosin staining, we found that the neuronal loss and death in APP/PS1 mice was decreased by SY treatment. Immunohistochemical staining showed that SY treatment dramatically down-regulated Abeta1-42 deposition and glial fibrillary acidic protein (GFAP) level in APP/PS1 mice. Biochemical analysis also showed that SY treatment reduced soluble and insoluble Abeta1-42 level in the cortex and soluble Abeta1-42 level in the hippocampus of APP/PS1 mice. Moreover, we found that SY treatment decreased the expression of proteins related to generation of Abeta, and markedly increased expression of enzymes associated with clearance of Abeta in the brain of APP/PS1 mice. These results indicate that the SY can serve as a promising therapeutic approach for the treatment of AD. PMID- 29288972 TI - TNF-related apoptosis-inducing ligand (TRAIL) as the potential therapeutic target in hematological malignancies. AB - Despite numerous attempts to find the treatment strategies that can selectively target the cancer cells, cancer still remains a major public health problem. Conventional cancer treatments such as chemo- and radio-therapies are associated with systemic toxicity and the risk of recurrence. Additionally, acquired or pre existing resistance is the main problem of most therapies. TNF-related apoptosis inducing ligand (TRAIL), a member of TNF superfamily, has significantly attracted the researchers to use it as an effective treatment strategy for cancer since it can preferentially induce apoptosis in a variety of primary tumor cells without affecting the adjacent normal cells. Recently, recombinant forms of TRAIL and the multiple agonists of its receptor have been evaluated in many cell lines and phase II clinical trials. Hence, we have tried to summarize the TRAIL-related therapies as a potential therapeutic option in hematological malignancies. PMID- 29288973 TI - The clinical significance and biological function of lncRNA RGMB-AS1 in hepatocellular carcinoma. AB - LncRNA RGMB-AS1 has been suggested to play significant roles in lung cancer progression. However, it remains unknown whether lncRNA RGMB-AS1 is involved in the development and progression of hepatocellular carcinoma. In our results, lncRNA RGMB-AS1 was low-expressed in hepatocellular carcinoma tissues and cell lines, and associated with clinical stage, tumor size and metastasis. Survival analysis indicated that lncRNA RGMB-AS1 high was an independent favorable prognostic factor for hepatocellular carcinoma patients. Gain-of-function studies showed up-regulated lncRNA RGMB-AS1 expression suppressed hepatocellular carcinoma cells proliferation, migration and invasion, and promoted cells apoptosis. There was a positively association between lncRNA RGMB-AS1 and RGMB in hepatocellular carcinoma tissues, and up-regulated lncRNA RGMB-AS1 expression increased RGMB mRNA and protein expressions in hepatocellular carcinoma cells. In conclusion, lncRNA RGMB-AS1 serves an anti-oncogenic role in hepatocellular carcinoma. PMID- 29288974 TI - Jobelyn(r) attenuates inflammatory responses and neurobehavioural deficits associated with complete Freund-adjuvant-induced arthritis in mice. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the physical and psychosocial wellbeing of the patients and a major cause of work disability. Current drugs for its treatment only provide palliative effect, as cure for the disease still remains elusive. Jobelyn(r) (JB), a potent anti oxidant and anti-inflammatory dietary supplement obtained from Sorghum bicolor, has been claimed to relieve arthritic pain. Thus, this study was designed to evaluate its effect on inflammatory and biochemical changes as well as neurobehavioural deficits associated with complete Freund-adjuvant (CFA)-induced arthritis in mice. The effect of JB (50, 100 and 200 mg/kg) on inflammatory oedema, neurobehavioural deficits, levels of biomarkers of oxidative stress and inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) induced by 0.1 mL of CFA (10 mg/mL) was evaluated in male Swiss mice. Oral administration of JB (100 and 200 mg/kg) reduced inflammatory paw volume and reversed sensorimotor deficits induced by CFA. JB also reduced pain episodes, anxiety and depressive like symptoms in CFA-mice. The increased level of oxidative stress in the joint and brain tissues of CFA-mice was reduced by JB. It also decreased tumor necrosis factor-alpha and interleukin-6 levels induced by CFA in the joint tissue of mice. These findings suggest that Jobelyn(r) attenuates inflammatory responses induced by CFA in mice via inhibition of oxidative stress and release of inflammatory cytokines. The ability of JB to attenuate CFA-induced nociception, sensorimotor deficits and depressive-like symptom suggests it might improve the quality of life of patients with arthritic conditions. PMID- 29288975 TI - Fertilizing capacity of vitrified epididymal sperm from Iberian ibex (Capra pyrenaica). AB - In this study, we successfully described for the first time a vitrification of epididymal Iberian ibex spermatozoa. Spermatozoa from epididymis were obtained from 15 Iberian ibex. The right epididymis' semen sample was vitrified and the left one was frozen. After thawing/warming, samples were selected by density gradient. Sperm characteristics from each treatment were evaluated. To test the spermatozoa fertilization ability, heterologous IVF was carried out using bovine oocytes. Despite of the observation of a decrease of about 40% for motility sperm between pre-freezing and post-thawing (75.0 +/- 5.2 and 45.0 +/- 6.0) and pre vitrification and post-warming (78.2 +/- 5.2 and 33.9 +/- 6.2) (P < .05), after the washing, an improvement of sperm motility was found when using the vitrification treatment compared to frozen-thawed. Heterologous IVF showed that Iberian Ibex spermatozoa, either frozen-thawed or vitrified-warmed, were equally capable of penetrating ZP intact bovine oocytes, leading to pronuclear formation (%) and hybrid embryo cleavage (%), (31.3 +/- 27.2 and 45.1 +/- 24.4, respectively). As expected, in the homologous IVF group, higher percentages of penetration, pronuclei formation and cleavage were found compared to heterologous groups using Iberian ibex frozen and vitrified sperm (P < 0,5). The highest pronuclei formation was found after 20 h post insemination in both heterologous IVF groups (30.2 +/- 6.7 and 31.7 +/- 21.5 thawed and vitrified group). Consequently, the cleavage rate (48 h) followed the same results to homologous and thawed and vitrified groups (76.1 +/- 15.9; 31.3 +/- 27.2 and 45.1 +/- 24.4, respectively) (P < .05). In conclusion, Iberian ibex sperm vitrification is a promising and useful alternative to conventional methods resulting in good quality spermatozoa post-thaw, and an adequate in vitro fertilizing ability. PMID- 29288976 TI - Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half. AB - Primiparous mares are known to produce smaller foals than multiparous mares. This difference seems to be partly explained by the reduced exchange surface and volume of the placental villi in primiparous compared to multiparous placentas. The effect of maternal parity on foals' post-natal growth, metabolism and sexual maturation, however, has been given little consideration. The objectives of this work were to analyse placental biometry and structure at term, growth of foals and yearlings, their metabolism and testicular maturation at one year of age. Twenty multiparous mares (M), aged over 6 years and 12 primiparous mares (P), aged up to 5 years were artificially inseminated with the same stallion and monitored the same way until foaling. At birth, foals and placentas were measured and placentas were sampled above at the umbilical cord insertion, as well as in the pregnant and the non-pregnant horn to perform stereological analyses. Foals were weighed and measured until 540 days of age. At 120 and 360 days of age, an Intravenous Glucose Tolerance Test was performed on foals and yearlings. At 360 days of age, the males were castrated and testicular maturation analysed by RT qPCR. At birth, P dams produced lighter and smaller foals and placentas. The foal birth weight to placental surface ratio was lower in the P compared to the M group. P Foals remained lighter than M foals until 360 days of age and smaller until at least 540 days of age. At 120 days of age, P foals had a higher glucose tolerance than M foals, and then may be less mature than M foals in terms of the control of their glucose homeostasis. At 360 days of age, the testicles of prepubertal P stallions were less mature in the P vs the M group. In conclusion, primiparous dams produce intrauterine growth restricted, less mature and smaller foals compared to multiparous dams with altered metabolism and growth until at least 540 days of age. These differences could affect the sport career of these foals, especially if it begins at an early age. PMID- 29288977 TI - Maternal nutritional restriction during late gestation impairs development of the reproductive organs in both male and female lambs. AB - Maternal nutritional restrictions during late gestation could lead to fetal hypoglycemia. Glucose levels in the fetal sheep regulate circulating insulin-like growth factor 1 (IGF1) levels, which stimulate cell proliferation and differentiation of reproductive organs after binding to its own receptor or estrogen receptors. The objective of this study was to determine the effects of subnutrition of ewes during the last trimester of gestation on the serum glucose/IGF1 levels and development of reproductive organs in their lambs. Pregnant ewes carrying singletons were randomly assigned to restricted (R ewes, n = 8) or control (C ewes, n = 8) groups (4 lambs of each gender/group) and fed with 50% or 100% of metabolic energy requirements from ~100 days of gestation to term (~147 days), respectively. Blood samples from lambs were taken on the first day after born and once at week for serum glucose and IGF1 determination. Lambs were euthanatized at 2 months of age, reproductive organs were weighted and tissue samples were collected from them for histology and to measure mRNA expression of IGF1 and its receptor (IGF1R) by qRT-PCR. Pre-partum glucose levels in R ewes were significantly lower compared to C ewes (p < .05). Compared to lambs born from C ewes, lambs born from R ewes showed lower serum levels of glucose and IGF1 during the first week of age (p < .05). At 2 month of age, these lambs had significant lower uterine and testicular weight and lower ovarian, uterine and testicular mRNA expressions of IGF1 and its receptor (p < .05). Histological findings showed that diameter of secondary and tertiary follicles in ovaries and number of endometrial glands in uterus of females, or number of Sertoli cells and seminiferous tubules and diameter, perimeter and tubular area in testicles of males were significantly lower in lambs born from R ewes compared to the respective organs of lambs born from the C ewes (p < .05). In conclusion, these results demonstrate that maternal subnutrition during late gestation affects IGF1 levels during fetal life and impairs reproductive development in the neonatal lamb, which could have permanent negative consequences in the future reproductive performance of the offspring. PMID- 29288978 TI - Expression and function of MUC1 in uterine tissues during early pregnancy in sheep after natural oestrous or artificially-induced oestrous. AB - Mucin 1 (MUC1), a cell surface glycoprotein, is expressed mainly in the endometrial luminal epithelium (LE) and glandular epithelium (GE) of the endometrium in many mammalian species including mice, rats, pigs, sheep, horses and humans during various stages of a menstrual or oestrous cycle, where it plays an important role in embryo implantation and placentation. However, the expression and function of MUC1 in uterine tissues during early pregnancy in sheep after artificially-induced oestrous is not known. Therefore, we investigated the expression and function of MUC1 in the early pregnant and non pregnant uterine tissues of sheep with natural oestrous or artificially-induced oestrous on days 10, 12, 14, 16 and 18 of the cycle by in situ hybridization, quantitative real-time polymerase chain reaction, immunohistochemical staining and western blotting methods. According to our results, MUC1 mRNA and protein expression increased initially but then decreased from days 10-18, peaking on day 14 in the uterine tissues of non-pregnant ewes after both natural and artificially-induced oestrous. MUC1 protein localisation was observed in the LE on days 10, 12 and 14 and in the GE on days 16 and 18. In contrast, MUC1 mRNA and protein expression increased on days 10 and 12, decreased on day 14, but increased again on days 16 and 18 in the uterine tissues of pregnant ewes both in natural oestrous and in artificially-induced oestrous. Additionally, the MUC1 mRNA and protein expression levels in the uterine tissues of the early pregnant sheep were significantly lower than those in the non-pregnant sheep on days 10, 14, and 18, except on day 16(P < 0.01). Enhancing MUC1 protein expression with oestrogen or/and progesterone decreased the blastocyst adhesion rate when blastocysts were co-cultured with endometrial epithelial cells (EECs), while inhibiting MUC1 protein expression with IFN-tau increased the blastocyst adhesion rate when the blastocysts were co-cultured with EECs. Compared with the ewes undergoing natural oestrus, the expression trend and regulation of MUC1 did not change, and the MUC1 expression levels only increased under artificial oestrus conditions. Our data provide important information for improving the conception rate in sheep undergoing artificially-induced oestrus and offer some reference points relating to embryo transfer, oestrus synchronisation and superovulation. PMID- 29288979 TI - In vitro genotoxic effect of secondary minerals crystallized in rocks from coal mine drainage. AB - Coal processing generates a large volume of waste that can damage human health and the environment. Often these wastes produce acid drainage in which several minerals are crystallized (evaporites). This study aimed to identify secondary minerals, as well as the genotoxic potential of these materials. The samples were collected at two sites along the Rocinha River in Santa Catarina state (Brazil): (1) directly from the source of the acid drainage (evaporite 1), and (2) on the river bank (evaporite 2). The samples were characterized by X-ray diffraction and by particle-induced X-ray emission techniques. In vitro genotoxicity testing using Comet assay and Micronucleus test in V79 cells was used to evaluate evaporite samples. Our study also used System Biology tools to provide insight regarding the influence of this exposure on DNA damage in cells. The results showed that the samples induced DNA damage for both evaporites that can be explained by high concentrations of chromium, iron, nickel, copper and zinc in these materials. Thus, this study is very important due to the dearth of knowledge regarding the toxicity of evaporites in the environment. The genetic toxicity of this material can be induced by increased oxidative stress and DNA repair inhibition. PMID- 29288980 TI - Polyurethane foams containing residues of petroleum industry catalysts as recoverable pH-sensitive sorbents for aqueous pesticides. AB - To investigate ways of mitigating the contamination of water with herbicides, which is a well-recognized global problem, we prepared natural resource-based polyurethane foams containing different amounts of petroleum industry catalyst residue (RC) and tested them as atrazine (ATZ, a common herbicide) sorbents in aqueous solutions. The above sorbents were characterized by infrared spectroscopy, electron microscopy, microtomography, thermogravimetric analysis, and X-ray diffraction. The adsorption/desorption of ATZ thereon was investigated as a function of foam composition, pH, initial ATZ concentration, and time. The obtained results showed that the porosity, pore size, and pore interconnectivity of the prepared sorbents were well suited for optimal ATZ removal. At pH 2, foams with high RC contents achieved higher ATZ removal efficiencies (e.g., 25%) than the pristine foam (12%). Conversely, ATZ removal was disfavored at high pH, which was attributed to restricted ATZ-sorbent interactions due to changes in the sorbent surface charge. The presence of other species (such as pectin, which is usually found in fruits) did not interfere with ATZ removal. ATZ desorption was most effective at high pH, enabling the regeneration and re-use of sorbents and thus reducing large-scale application costs. PMID- 29288981 TI - Sensory predictions during action support perception of imitative reactions across suprasecond delays. AB - Perception during action is optimized by sensory predictions about the likely consequences of our movements. Influential theories in social cognition propose that we use the same predictions during interaction, supporting perception of similar reactions in our social partners. However, while our own action outcomes typically occur at short, predictable delays after movement execution, the reactions of others occur at longer, variable delays in the order of seconds. To examine whether we use sensorimotor predictions to support perception of imitative reactions, we therefore investigated the temporal profile of sensory prediction during action in two psychophysical experiments. We took advantage of an influence of prediction on apparent intensity, whereby predicted visual stimuli appear brighter (more intense). Participants performed actions (e.g., index finger lift) and rated the brightness of observed outcomes congruent (index finger lift) or incongruent (middle finger lift) with their movements. Observed action outcomes could occur immediately after execution, or at longer delays likely reflective of those in natural social interaction (1800 or 3600 ms). Consistent with the previous literature, Experiment 1 revealed that congruent action outcomes were rated as brighter than incongruent outcomes. Importantly, this facilitatory perceptual effect was found irrespective of whether outcomes occurred immediately or at delay. Experiment 2 replicated this finding and demonstrated that it was not the result of response bias. These findings therefore suggest that visual predictions generated during action are sufficiently general across time to support our perception of imitative reactions in others, likely generating a range of benefits during social interaction. PMID- 29288982 TI - C-terminal and intact FGF23 in critical illness and their associations with acute kidney injury and in-hospital mortality. AB - BACKGROUND: FGF23 proved its value in prognostication of cardiovascular events and mortality among renal patients and general population. Limited data exist whether FGF23 may have any use in prediction of negative outcomes among critically ill patients admitted to intensive care unit (ICU). METHODS: Single center cohort study performed among patients admitted to ICU. The primary exposure was FGF23 plasma concentration measured within 24 h of ICU admission. The primary outcome was incident Acute Kidney Injury (AKI) and in-hospital mortality during the ICU stay. RESULTS: The study enrolled 79 patients admitted to ICU. C-terminal FGF23 (cFGF23) but not intact FGF23 (iFGF23) concentration was significantly elevated in patients, who acquired AKI and non-survivors (p < .001). ROC analysis of cFGF23 yielded an AUC of 0.81 and 0.85 for prediction of incident AKI and death during ICU stay, respectively. Multivariate analysis showed higher odds for AKI (OR 1.80; 95% CI 1.10-2.96) and in-hospital mortality (OR 2.85; 95% CI 1.60-5.06) for one unit increase of log transformed cFGF23. CONCLUSIONS: cFGF23 measurement may serve as a novel biomarker for incident AKI and death among critically ill patients. PMID- 29288983 TI - Automatic spinal cord localization, robust to MRI contrasts using global curve optimization. AB - During the last two decades, MRI has been increasingly used for providing valuable quantitative information about spinal cord morphometry, such as quantification of the spinal cord atrophy in various diseases. However, despite the significant improvement of MR sequences adapted to the spinal cord, automatic image processing tools for spinal cord MRI data are not yet as developed as for the brain. There is nonetheless great interest in fully automatic and fast processing methods to be able to propose quantitative analysis pipelines on large datasets without user bias. The first step of most of these analysis pipelines is to detect the spinal cord, which is challenging to achieve automatically across the broad range of MRI contrasts, field of view, resolutions and pathologies. In this paper, a fully automated, robust and fast method for detecting the spinal cord centerline on MRI volumes is introduced. The algorithm uses a global optimization scheme that attempts to strike a balance between a probabilistic localization map of the spinal cord center point and the overall spatial consistency of the spinal cord centerline (i.e. the rostro-caudal continuity of the spinal cord). Additionally, a new post-processing feature, which aims to automatically split brain and spine regions is introduced, to be able to detect a consistent spinal cord centerline, independently from the field of view. We present data on the validation of the proposed algorithm, known as "OptiC", from a large dataset involving 20 centers, 4 contrasts (T2-weighted n = 287, T1 weighted n = 120, T2*-weighted n = 307, diffusion-weighted n = 90), 501 subjects including 173 patients with a variety of neurologic diseases. Validation involved the gold-standard centerline coverage, the mean square error between the true and predicted centerlines and the ability to accurately separate brain and spine regions. Overall, OptiC was able to cover 98.77% of the gold-standard centerline, with a mean square error of 1.02 mm. OptiC achieved superior results compared to a state-of-the-art spinal cord localization technique based on the Hough transform, especially on pathological cases with an averaged mean square error of 1.08 mm vs. 13.16 mm (Wilcoxon signed-rank test p-value < .01). Images containing brain regions were identified with a 99% precision, on which brain and spine regions were separated with a distance error of 9.37 mm compared to ground-truth. Validation results on a challenging dataset suggest that OptiC could reliably be used for subsequent quantitative analyses tasks, opening the door to more robust analysis on pathological cases. PMID- 29288984 TI - Psychometric assessment of the marijuana adolescent problem inventory. AB - Cannabis is one of the most commonly used psychoactive substances among adolescents in the United States. Adolescent cannabis use has multiple consequences including academic, health, and psychiatric problems. The Marijuana Adolescent Problem Inventory (MAPI) is a 23-item scale adapted from the Rutgers Alcohol Problem Index and used in the current literature to assess cannabis use problem severity. Psychometric testing for the MAPI has yet to be reported. The current investigation assessed the psychometric characteristics of the MAPI with cannabis-using adolescents (n=727) from school and outpatient settings who enrolled in five separate randomized clinical trials focused on treatment of substance use. Findings suggested that the MAPI is internally consistent and reliable. Factor structure analyses suggested that the MAPI measures one latent construct, with no differences in factor structure between the outpatient and school settings, supporting a one-factor model. External validity of the MAPI was also demonstrated as evidenced by significant relations with concurrent diagnosis of cannabis dependence and abuse, longitudinal frequency of cannabis use, and mean times used per day. Overall, this initial test of the psychometric characteristics of the MAPI suggests that it can be considered a reliable and valid measure of problems associated with cannabis use among adolescents. Future work is now needed to replicate these findings by testing the psychometric properties of the MAPI in more diverse samples and developing a short version to be used as a brief assessment tool. PMID- 29288985 TI - Guilt-proneness is associated with the use of protective behavioral strategies during episodes of alcohol use. AB - INTRODUCTION: Shame and guilt are closely related emotions with diverging implications for the development, and potential treatment, of substance use disorders. Accumulating research indicates that a guilt-prone affect style buffers individuals against the development of problematic alcohol use, while shame-proneness appears to offer no protective function. However, little is known about the manner in which guilt-prone individuals avoid the experience of alcohol use-related harms. The present study aimed to extend the shame, guilt, and substance use literature by examining whether these two self-conscious affect styles are differentially related to the use of protective behavioral strategies which reduce the risk of harms during drinking episodes. METHODS: Participants (N=281; female n=207) completed pen-and-paper measures of shame and guilt proneness, level of alcohol use, and the habitual use of protective behavioral strategies during drinking episodes. Part-correlation analysis isolated shame free guilt and guilt-free shame residuals in exploring relationships between self conscious affect style and the use of protective behavioral strategies during drinking episodes. RESULTS: Guilt-proneness was consistently associated with the routine use of protective behavioral strategies during episodes of alcohol intake. In contrast, shame-proneness was unrelated to the use of such protective and harm avoidance strategies when drinking. CONCLUSION: Findings provide additional support for the argument that guilt and shame need to be considered separately in both research and substance use treatment settings. PMID- 29288986 TI - Expression Profile of Three Splicing Factors in Pleural Cells Based on the Underlying Etiology and Its Clinical Values in Patients with Pleural Effusion. AB - Splicing factors (SFs) are involved in oncogenesis or immune modulation, the common underlying processes giving rise to pleural effusion (PE). The expression profiles of three SFs (HNRNPA1, SRSF1, and SRSF3) and their clinical values have never been assessed in PE. The three SFs (in pellets of PE) and conventional tumor markers were analyzed using PE samples in patients with PE (N = 336). The sum of higher-molecular weight (Mw) forms of HNRNPA1 (Sum-HMws-HNRNPA1) and SRSF1 (Sum-HMws-SRSF1) and SRSF3 levels were upregulated in malignant PE (MPE) compared to benign PE (BPE); they were highest in cytology-positive MPE, followed by tuberculous PE and parapneumonic PE. Meanwhile, the lowest-Mw HNRNPA1 (LMw HNRNPA1) and SRSF1 (LMw-SRSF1) levels were not upregulated in MPE. Sum-HMws HNRNPA1, Sum-HMws-SRSF1, and SRSF3, but neither LMw-HNRNPA1 nor LMw-SRSF1, showed positive correlations with cancer cell percentages in MPE. The detection accuracy for MPE was high in the order of carcinoembryonic antigen (CEA, 85%), Sum-HMws HNRNPA1 (76%), Sum-HMws-SRSF1 (68%), SRSF3, cytokeratin-19 fragments (CYFRA 21 1), LMw-HNRNPA1, and LMw-SRSF1. Sum-HMws-HNRNPA1 detected more than half of the MPE cases that were undetected by cytology and CEA. Sum-HMws-HNRNPA1, but not other SFs or conventional tumor markers, showed an association with longer overall survival among patients with MPE receiving chemotherapy. Our results demonstrated different levels of the three SFs with their Mw-specific profiles depending on the etiology of PE. We suggest that Sum-HMws-HNRNPA1 is a supplementary diagnostic marker for MPE and a favorable prognostic indicator for patients with MPE receiving chemotherapy. PMID- 29288988 TI - Correlations between MUNIX and adapted multiple point stimulation MUNE methods. AB - OBJECTIVE: The aim of this study was to evaluate how the motor unit number index (MUNIX) is related to the adapted multiple point stimulation (AMPS) technique. METHODS: MUNIX and AMPS technique were prospectively performed on thenar muscles in 20 consecutive patients referred to our neurophysiological laboratory with the clinical diagnosis of a possible motoneurone disorder (MND). The clinical and paraclinical assessment confirmed the diagnosis of MND in 13 out of 20 patients, amyotrophic lateral sclerosis (ALS) in 9 (with MND group). In the other 7 patients, there were neither evidence of MND, nor of any peripheral nervous system disease (without MND group). RESULTS: AMPS and MUNIX data were significantly (p < 0.001) lower in patients with MND than in patients without MND. There was a strong significant positive linear correlation between AMPS and MUNIX values (n = 20; R = 0.83; p < 0.01). CONCLUSION: Both MUNIX and AMPS methods could serve as a reliable marker to document the motor unit loss. SIGNIFICANCE: The present paper constitutes one more clue of MUNIX reliability. PMID- 29288987 TI - Machine Learning Based Prediction of Brain Metastasis of Patients with IIIA-N2 Lung Adenocarcinoma by a Three-miRNA Signature. AB - OBJECTIVES: MicroRNAs (miRNAs) play a key role in governing posttranscriptional regulation through binding to the mRNAs of target genes. This study is to assess miRNAs expression profiles for identifying brain metastasis-related miRNAs to develop the predictive model by microarray in tumor tissues. METHODS: For this study, we screened the significant brain metastasis-related miRNAs from 77 lung adenocarcinoma (LUAD) patients with brain metastasis (BM+) or non-brain metastasis (BM-). A predictive model was developed from the training set (n=42) using a random Forest supervised classification algorithm and a Class Centered Method, and then validated in a test set (n=35) and further analysis in GSE62182 (n=73). The independence of this signature in BM prediction was measured by multivariate logistic regression analysis. RESULTS: From the training set, the predictive model (including hsa-miR-210, hsa-miR-214 and hsa-miR-15a) stratified the patients into two groups with significantly different BM subtypes (90.4% of accuracy). The similar predictive power (91.4% of accuracy) was obtained in the test cohort. As an independent predictive factor, it was closely associated with BM and had high sensitivity and specificity in predicting BM in clinical practice. Moreover, functional enrichment analysis demonstrated that this signature involved in the signaling pathways positively correlated with cancer metastasis. CONCLUSION: These results suggested that the three-miRNA signature could develop a new random Forest model to predict the BM of LUAD patients. These findings emphasized the importance of miRNAs in diagnosing BM, and provided evidence for selecting treatment decisions and designing clinical trials. PMID- 29288989 TI - Fasciculation potentials and decremental responses in amyotrophic lateral sclerosis. AB - OBJECTIVE: The positive correlation between fasciculation potentials (FPs) and decremental responses in repetitive nerve stimulation test (RNS) in amyotrophic lateral sclerosis (ALS) patients has been described based on only one past study. We revisited this issue. METHODS: Subjects consisted of 30 prospectively-enrolled ALS patients on whom both needle EMG and RNS were conducted in the same trapezius muscle. Fasciculation potentials (FPs) were identified off-line from the restored 3-min signal. Firing rate of FPs (FR-FP) per minute was calculated from the total count of FPs of different origins. Correlations between FR-FP, decremental percentage (Decr%) and the amplitude of the initial compound muscle action potential (CMAPamp) in RNS were investigated. RESULTS: There was no correlation between FR-FP and Decr% (r = 0.03) or between FR-FP and CMAPamp (r = 0.04). A significant negative correlation was observed between CMAPamp and Decr% (r = 0.56, P < .005). CONCLUSION: FPs are not correlated with the decremental response in RNS. SIGNIFICANCE: The underlying mechanism for FPs and decremental responses in ALS must be different and unrelated to each other. PMID- 29288990 TI - Diaphragm motor responses to phrenic nerve stimulation in ALS: Surface and needle recordings. AB - OBJECTIVE: In studies of phrenic nerve (PN) conduction in amyotrophic lateral sclerosis (ALS) both motor response amplitude and latency have been reported as abnormal. However, correlation with diaphragm motor unit loss, and with diaphragmatic function has not been fully evaluated. METHODS: We studied 83 patients with ALS, and 21 patients referred with clinically suspected phrenic nerve lesions whose studies were normal. PN responses elicited by percutaneous electrical stimulation in the neck were recorded using superficial electrodes placed at the surface markings of the diaphragm on the chest wall, and a concentric needle electrode inserted into the diaphragmatic costal fibres. Electromyography of diaphragm was performed to analyse motor unit morphology and recruitment. RESULTS: The 21 controls and 83 ALS patients were matched for age. In controls, the only significant correlation between surface and needle recording was for negative-peak amplitude (p = 0.03). In ALS patients, amplitudes and negative-peak area were highly correlated (p < 0.001), as were PN motor latencies (p = 0.002). Forced vital capacity (FVC) was highly correlated with both amplitude (p < 0.001) and PN latency (p < 0.02), whichever electrode was used. PN amplitude recording with needle electrode was consistent with EMG findings in the diaphragm. CONCLUSION: In ALS, PN motor amplitude/area and latency measurements recorded by surface electrodes are highly correlated with needle EMG findings in the diaphragm. CMAP amplitude/area measurements showed high correlation with FVC. SIGNIFICANCE: In ALS, amplitude/area of the motor PN response, recorded by surface or needle electrodes, correlates with dysfunction of the diaphragm. PMID- 29288991 TI - Nerve ultrasound in neurofibromatosis type 1: A follow-up study. AB - OBJECTIVE: To investigate development of sonographic abnormalities and applications of high-resolution ultrasonography (HRUS) in neurofibromatosis type 1 (NF1). METHODS: Sixteen asymptomatic or minimally symptomatic NF1 patients underwent HRUS at inclusion and 1 year follow-up. Upper and lower extremity nerves were investigated. Peripheral nerve involvement was graded. RESULTS: Plexiform neurofibromas (PNFs) were found in 7 patients (43.8%) at inclusion and 10 (62.5%) at follow-up. All initially identified PNFs were also found at follow up; additional PNFs were found by extended longitudinal assessment at follow-up. All 3 patients with minor and 7 patients with severe peripheral nerve involvement had similar involvement at follow-up. Mean nerve size change was -0.2 mm2 (+/ 1.6) and 0.3 mm2 (+/-6.2) in patients with minor and severe involvement. Mean PNF size change was -0.1 mm2 (+/-9.9). CONCLUSIONS: HRUS allows qualitative assessment of peripheral nerves, which makes it advantageous as initial imaging technique in suspected neuropathy. Patients with minimal nerve involvement remained so, and might therefore require less follow-up for malignant peripheral nerve sheath tumor (MPNSTs) development. Measured change in PNF size was highly variable. Repeating an extensive standardized HRUS protocol during follow-up thus seems less useful to screen for MPNSTs. SIGNIFICANCE: HRUS has potential applications as diagnostic and screening tool in NF1. PMID- 29288992 TI - The effect of increased intracranial EEG sampling rates in clinical practice. AB - OBJECTIVE: Recent research suggests that high frequency intracranial EEG (iEEG) may improve localization of epileptic networks. This study aims to determine whether recording macroelectrode iEEG with higher sampling rates improves seizure localization in clinical practice. METHODS: 14 iEEG seizures from 10 patients recorded with >2000 Hz sampling rate were downsampled to four sampling rates: 100, 200, 500, 1000 Hz. In the 56 seizures, seizure onset time and location was marked by 5 independent, blinded EEG experts. RESULTS: When reading iEEG under clinical conditions, there was no consistent difference in time or localization of seizure onset or number of electrodes involved in the seizure onset zone with sampling rates varying from 100 to 1000 Hz. Stratification of patients by outcome did not improve with higher sampling rate. CONCLUSION: When utilizing standard clinical protocols, there was no benefit to acquiring iEEGs with sampling rate >100 Hz. Significant variability was noted in EEG marking both within and between individual expert EEG readers. SIGNIFICANCE: Although commercial equipment is capable of sampling much faster than 100 Hz, tools allowing visualization of subtle high frequency activity such as HFOs will be required to improve patient care. Quantitative methods may decrease reader variability, and potentially improve patient outcomes. PMID- 29288993 TI - Chronic deep brain stimulation normalizes scalp EEG activity in isolated dystonia. AB - OBJECTIVE: To investigate cortical activity using scalp EEG in patients with isolated dystonia treated with chronic deep brain stimulation (DBS), on and off stimulation. METHODS: We analyzed 64-channel scalp EEG in 12 isolated dystonia patients treated with chronic DBS (7 generalized, 5 cervical/segmental; 7 globus pallidus (GP), 5 subthalamic nucleus (STN)), and 20 healthy age-matched controls. Recordings during rest and movement task, and clinical motor scores, were collected with DBS-on and during a 90-min DBS washout. RESULTS: Resting state alpha power in the dominant (or contralateral to more dystonic side) motor cortex channel during DBS was comparable to healthy controls, but it increased when DBS was stopped. Resting state and movement-related alpha coherence between bilateral motor cortex channels was increased off DBS. CONCLUSIONS: Chronic DBS reduces exaggerated alpha oscillations and interhemispheric alpha coherence in the motor cortex of patients with isolated dystonia. SIGNIFICANCE: These findings complement related studies in Parkinson's disease and support the view that network desynchronization is a prominent mechanism of DBS in movement disorders. PMID- 29288994 TI - Detecting sub-second changes in brain activation patterns during interictal epileptic spike using simultaneous EEG-fMRI. AB - OBJECTIVE: Epileptic spikes are associated with rapidly changing brain activation involving the epileptic foci and other brain regions in the "epileptic network". We aim to resolve these activation changes using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings. METHODS: Simultaneous EEG-fMRI recordings from 9 patients with epilepsy were used in the analysis. Our method employed the whole scalp EEG data to generate regressors for the analysis of fMRI data using the general linear model. RESULTS: We were able to resolve, with milliseconds temporal resolution, changes in activation patterns involving suspected epileptic foci and other brain regions in the epileptic network during spike and slow wave. Using summary maps (called SSWAS maps) which show the activation frequency of voxels, we found that suspected epileptic foci tend to be significantly active during this interval. SSWAS maps also enabled the detection of the epileptic foci in 4 of 5 patients where the conventional event-timing-based analysis failed to identify. CONCLUSION: These findings demonstrated the efficacy of the method and the potential application of SSWAS maps to identify epileptic foci. SIGNIFICANCE: The method could help resolve activation changes during epileptic spike and could provide insights into the underlying pathophysiology of these changes. PMID- 29288995 TI - Violence in Brazilian schools: Analysis of the effect of the #Tamojunto prevention program for bullying and physical violence. AB - A randomized controlled trial was conducted with 6637 7th- and 8th-grade students in 72 public schools in 6 Brazilian cities to evaluate the effects of the European drug prevention program Unplugged, called #Tamojunto in Brazil. This article evaluates the effects of #Tamojunto on the prevention of bullying and physical violence. Baseline data were collected from both intervention and control groups prior to program implementation. Follow-up data collection was performed 9 and 21 months later. Generalized estimating equations were used to evaluate changes in the reporting of receiving or practicing bullying and physical violence over time. The program was found to reduce the likelihood of receiving bullying, particularly in the stratum of girls aged 13-15 years at the 9-month follow-up time point. The effect was not sustained at 21 months. There was no significant effect for practicing bullying and for receiving or practicing physical violence. PMID- 29288996 TI - Mass spectrometry beyond the native state. AB - Native mass spectrometry allows the study of proteins by probing in vacuum the interactions they form in solution. It is a uniquely useful approach for structural biology and biophysics due to the high resolution of separation it affords, allowing the concomitant interrogation of multiple protein components with high mass accuracy. At its most basic, native mass spectrometry reports the mass of intact proteins and the assemblies they form in solution. However, the opportunities for more detailed characterisation are extensive, enabled by the exquisite control of ion motion that is possible in vacuum. Here we describe recent developments in mass spectrometry approaches to the structural interrogation of proteins both in, and beyond, their native state. PMID- 29288997 TI - Vertical variation of a black soil's properties in response to freeze-thaw cycles and its links to shift of microbial community structure. AB - Soil freeze-thaw cycles (FTCs) change soil physical, chemical, and biological properties, however information regarding their vertical variations in response to FTCs is limited. In this work, black soil (silty loam) packed soil columns were exposed to 8 FTCs, and soil properties were determined for each of vertical layer of soil columns. The results revealed that after FTCs treatment, moisture and electrical conductivity (EC) salinity tended to increase in upper soil layers. Increments of ammonium nitrogen (NH4+-N) and nitrate nitrogen (NO3--N) in top layers (0-10cm) were greater than those in other layers, and increments of water soluble organic carbon (WSOC) and decrease of microbial biomass carbon (MBC) in middle layers (10-20cm) were greater than those in both ends. Overall, microbial community structure was mainly influenced by soil physical properties (moisture and EC) and chemical properties (pH and WSOC). For bacterial (archaeal) and fungal communities, soil physical properties, chemical properties and their interaction explained 79.73% and 82.66% of total variation, respectively. Our results provided insights into the vertical variation of soil properties caused by FTCs, and such variation had a major impact on the change of structure and composition of soil bacterial and fungal communities. PMID- 29288998 TI - Changing sediment budget of the Mekong: Cumulative threats and management strategies for a large river basin. AB - Two decades after the construction of the first major dam, the Mekong basin and its six riparian countries have seen rapid economic growth and development of the river system. Hydropower dams, aggregate mines, flood-control dykes, and groundwater-irrigated agriculture have all provided short-term economic benefits throughout the basin. However, it is becoming evident that anthropic changes are significantly affecting the natural functioning of the river and its floodplains. We now ask if these changes are risking major adverse impacts for the 70 million people living in the Mekong Basin. Many livelihoods in the basin depend on ecosystem services that will be strongly impacted by alterations of the sediment transport processes that drive river and delta morpho-dynamics, which underpin a sustainable future for the Mekong basin and Delta. Drawing upon ongoing and recently published research, we provide an overview of key drivers of change (hydropower development, sand mining, dyking and water infrastructures, climate change, and accelerated subsidence from pumping) for the Mekong's sediment budget, and their likely individual and cumulative impacts on the river system. Our results quantify the degree to which the Mekong delta, which receives the impacts from the entire connected river basin, is increasingly vulnerable in the face of declining sediment loads, rising seas and subsiding land. Without concerted action, it is likely that nearly half of the Delta's land surface will be below sea level by 2100, with the remaining areas impacted by salinization and frequent flooding. The threat to the Delta can be understood only in the context of processes in the entire river basin. The Mekong River case can serve to raise awareness of how the connected functions of river systems in general depend on undisturbed sediment transport, thereby informing planning for other large river basins currently embarking on rapid economic development. PMID- 29288999 TI - Life cycle environmental evaluation of kettles: Recommendations for the development of eco-design regulations in the European Union. AB - Between 117 and 200 million kettles are used in the European Union (EU) every year. However, the full environmental impacts of kettles remain largely unknown. This paper presents a comprehensive life cycle assessment of conventional plastic and metallic kettles in comparison with eco-kettles. The results show that the use stage contributes 80% to the impacts. For this reason, the eco-kettle has over 30% lower environmental impacts due to a greater water efficiency and related lower energy consumption. These results have been extrapolated to the EU level to consider the implications for proposed eco-design regulations. For these purposes, the effects on the impacts of durability of kettles and improvements in their energy and water efficiency have been assessed as they have been identified as two key parameters in the proposed regulations. The results suggest that increasing the current average durability from 4.4 to seven years would reduce the impacts by less than 5%. Thus, improving durability is not a key issue for improving the environmental performance of kettles and does not justify the need for an eco-design regulation based exclusively on it. However, improvements in water and energy efficiency through eco-design can bring relevant environmental savings. Boiling the exact amount of water needed would reduce the impacts by around a third and using water temperature control by further 2%-5%. The study has also considered the effects of reducing significantly the number of kettles in use after the UK (large user of kettles) leaves the EU and reducing the excess water typically boiled by the consumer. Even under these circumstances, the environmental savings justify the development of a specific EU eco-design regulation for kettles. However, consumer engagement will be key to the implementation and achievement of the expected environmental benefits. PMID- 29289000 TI - Pine sawdust biomass and biochars at different pyrolysis temperatures change soil redox processes. AB - To date, no investigation has been carried out to explore the effects of biochars produced at different pyrolysis temperatures on the dynamics of redox potential (EH) and pH in a contaminated floodplain soil. Thus, we aimed to quantify the dynamics of EH and pH in contaminated flooded soils treated with 70tha-1 of pine sawdust biomass (S&BM) and biochars pyrolyzed at 300 degrees C (S&BC300) and 550 degrees C (S&BC550) and pre-incubated for 105days in an automated biogeochemical microcosm system. Microbial community composition was also determined via analyzing phospholipid fatty acid (PLFA).We found that BC300 and BC550 treatments substantially decreased (3-6.5%) and BM increased (~37%) the mean of soil EH compared to the untreated contaminated soil (CS)..The largest EH decline in S&BC550 was at the rate of -80mVh-1 at 10h while it was observed at 25h in S&BC300 and 20-25h in S&BM or CS, respectively. At high EH, a higher total PLFA biomass and microbial groups in the CS (71-87%) were found in comparison to treated soils. Higher aromaticity and ash content in BC550 than BC300 and BM led to the greater PLFA biomass and microbial groups which contributed to higher capacity of accepting and donating electrons in soil slurry and were probably one reason for the largest decrease in EH. Pine sawdust biomass and BCs have a noticeable influence in soil biogeochemical processes relevant to fluctuating redox conditions. PMID- 29289001 TI - Development of emissions inventory and identification of sources for priority control in the middle reaches of Yangtze River Urban Agglomerations. AB - This paper presents the first attempt to investigate the emission source control of the Middle Reaches of Yangtze River Urban Agglomerations (MRYRUA), one of the national urban agglomerations in China. An emission inventory of the MRYRUA was developed as inputs to the CAMx model based on county-level activity data obtained by full-coverage investigation and source-based spatial surrogates. A classification technology method for priority control of atmospheric emission sources was introduced and applied in the MRYRUA for the evaluation of the emission sources control on the region-scale and city-scale, respectively. The results demonstrated that the emission sources in the Hefei-centered urban agglomerations contributed the biggest on the mean PM2.5 concentrations of the MRYRUA and should be taken the priority to control. The emission sources in the Ma'anshan city, Xiangtan city, Hefei city and Wuhan city were the bigger contributors on the mean PM2.5 concentrations of the MRYRUA among the cities and should be taken the priority to control. In generally, emission sources in cities along the Yangtze River and the tributary should be given the special attention for the regional air quality target attainments. This study can give an understanding of Chinese emissions and provide a valuable preference to policy makers for finding effective mitigation measures and control strategies for reducing national and regional air pollution in China. PMID- 29289002 TI - Pesticide load dynamics during stormwater flow events in Mediterranean coastal streams: Alexander stream case study. AB - Cultivated land is a major source of pesticides, which are transported with the runoff water and eroded soil during rainfall events and pollute riverine and estuarine environments. Common ecotoxicological assessments of riverine systems are mainly based on water sampling and analysis of only the dissolved phase, and address a single pesticide's toxicological impact under laboratory conditions. A clear overview of mixtures of pesticides in the adsorbed and dissolved phases is missing, and therefore the full ecotoxicological impact is not fully addressed. The aim of this study was to characterize and quantify pesticide concentrations in both suspended sediment and dissolved phases, to provide a better understanding of pesticide-load dynamics during storm events in coastal streams in a Mediterranean climate. High-resolution sampling campaigns of seven flood events were conducted during two rainy seasons in Alexander stream, Israel. Samples of suspended sediments were separated from the solution and both media were analyzed separately for 250 pesticides. A total of 63 pesticides were detected; 18 and 16 pesticides were found solely in the suspended sediments and solution, respectively. Significant differences were observed among the pesticide groups: only 7% of herbicide, 20% of fungicide and 42% of insecticide load was transported with the suspended sediments. However, in both dissolved and adsorbed phases, a mix of pesticides was found which were graded from "mobile" to "non mobile" with varied distribution coefficients. Diuron, and tebuconazole were frequently found in large quantities in both phases. Whereas insecticide and fungicide transport is likely governed by application time and method, the governing factor for herbicide load was the magnitude of the stream discharge. The results show a complex dynamic of pesticide load affected by excessive use of pesticides, which should be taken into consideration when designing projects to monitor riverine and estuarine water quality. PMID- 29289003 TI - Inhibitory effects of extracellular polymeric substances on ofloxacin sorption by natural biofilms. AB - Natural biofilms have strong affinities for organic contaminants, and their extracellular polymeric substances (EPS) have been thought to control the sorption process. However, the role of EPS in the sorption of antibiotics, an emerging concern, is poorly understood. Here, soluble (SEPS) and bound EPS (BEPS) were extracted from intact biofilms incubated at different lengths of time to obtain SEPS- and BEPS-free biofilms. Batch sorption experiments and infrared spectroscopy were used to investigate the role of EPS in the sorption of ofloxacin (OFL) by natural biofilms. The sorption capacities of OFL onto intact biofilms were lower than that those onto SEPS-free and BEPS-free biofilms. Partition and Langmuir adsorption contributed to the sorption of OFL onto these biofilms. SEPS and BEPS suppressed partitioning of OFL into biofilm organic matter. Meanwhile, the formation of hydrogen bonds could affect the Langmuir adsorption of OFL onto BEPS-free biofilms. These sorption mechanisms occurred simultaneously and enhanced the sorption capacities of biofilms after EPS removal. The information obtained in this study is beneficial for understanding the interaction mechanisms between antibiotics and natural biofilms. PMID- 29289004 TI - Parallel assessment of marine autotrophic picoplankton using flow cytometry and chemotaxonomy. AB - Autotrophic picoplankton (0.2-2MUm) can be a significant contributor to primary production and hence play an important role in carbon flow. The phytoplankton community structure in the Baltic Sea is very region specific and the understanding of the composition and dynamics of pico-size phytoplankton is generally poor. The main objective of this study was to determine the contribution of picoeukaryotic algae and their taxonomic composition in late summer phytoplankton community of the West-Estonian Archipelago Sea. We found that about 20% of total chlorophyll a (Chl a) in this area belongs to autotrophic picoplankton. With increasing total Chl a, the Chl a of autotrophic picoplankton increased while its contribution in total Chl a decreased. Picoeukaryotes play an important role in the coastal area of the Baltic Sea where they constituted around 50% of the total autotrophic picoplankton biomass. The most abundant groups of picoeukaryotic algae were cryptophytes (16%), chlorophytes (13%) and diatoms (9%). Picocyanobacteria were clearly dominated by phycoerythrin containing Synechococcus. The parallel use of different assessment methods (CHEMTAX and flow cytometry) revealed the share of eukaryotic and prokaryotic part of autotrophic picoplankton. PMID- 29289005 TI - Sampling alien species inside and outside protected areas: Does it matter? AB - Data of alien species presences are generally more readily available in protected than non-protected areas due to higher sampling efforts inside protected areas. Are the results and conclusions based on analyses of data collected in protected areas representative of wider non-protected regions? We address this question by analysing some recently published data of alien plants in Greece. Mixed effects models were used with alien species presences in 8.25*8.25km cells as dependent variable and the percentage of protected area, as well as the agricultural and artificial land cover types richness (as indicators of human presence) as independent variables. In addition, the spatial cross-correlation between the percentage of protected area and alien species richness was examined across scales. Results indicated that the percentage of protected area per cell is a poor predictor of alien species richness. Spatial analysis indicated that cells with higher percentage of protected areas have slightly less alien species than cells with lower percentage of protected areas. This result is likely to be driven by the overall negative correlation between habitat protection and anthropogenic activities. Thus, the conclusions deduced by data deriving from protected areas are likely to hold true for patterns of alien species in non protected areas when the human pressures are accounted for. PMID- 29289006 TI - Soil-plant relationships and contamination by trace elements: A review of twenty years of experimentation and monitoring after the Aznalcollar (SW Spain) mine accident. AB - Soil contamination by trace elements (TE) is a major environmental problem and much research is done into its effects on ecosystems and human health, as well as into remediation techniques. The Aznalcollar mine accident (April 1998) was a large-scale ecological and socio-economic catastrophe in the South of Spain. We present here a literature review that synthesizes the main results found during the research conducted at the affected area over the past 20years since the mine accident, focused on the soil-plant system. We review, in depth, information about the characterization of the mine slurry and contaminated soils, and of the TE monitoring, performed until the present time. The reclamation techniques included the removal of sludge and soil surface layer and use of soil amendments; we review the effects of different types of amendments at different spatial scales and their effectiveness with time. Monitoring of TE in soil and their transfer to plants (crops, herbs, shrubs, and trees) were evaluated to assess potential toxicity effects in the food web. The utility of some plants (accumulators) with regard to the biomonitoring of TE in the environment was also evaluated. On the other hand, retention of TE by plant roots and their associated microorganisms was used as a low-cost technique for TE stabilization and soil remediation. We also evaluate the experience acquired in making the Guadiamar Green Corridor a large-scale soil reclamation and phytoremediation case study. PMID- 29289007 TI - Exposure to polystyrene nanoplastic leads to inhibition of anaerobic digestion system. AB - In this study, impacts of nanoplastic on the pure and mixed anaerobic digestion systems were investigated. Results showed the growth and metabolism of Acetobacteroides hydrogenigenes were partly inhibited by nanoplastic existed in the pure anaerobic digestion system. The anaerobic digestion of sewage sludge was also obviously inhibited by nanoplastic existed in the mixed anaerobic digestion system. Both the methane yield and methane production rate of the mixed anaerobic digestion system showed negative correlation with the nanoplastic concentration. Compared with anaerobic digestion system without nanoplastic, methane yield and maximum daily methane yield at the nanoplastic concentration of 0.2g/L decreased for 14.4% and 40.7%, respectively. In addition, the start-up of mixed anaerobic digestion system was prolonged by addition of nanoplastic. Microbial community structure analysis indicated the microbial community structures were also affected by nanoplastic existed in the system. At the nanoplastic concentration of 0.2g/L, the relative abundances of family Cloacamonaceae, Porphyromonadaceae, Anaerolinaceae and Gracilibacteraceae decreased partly. Conversely, the relative abundances of family Anaerolinaceae, Clostridiaceae, Geobacteraceae, Dethiosulfovibrionaceae and Desulfobulbaceae improved partly. PMID- 29289008 TI - AMOchar: Amorphous manganese oxide coating of biochar improves its efficiency at removing metal(loid)s from aqueous solutions. AB - A novel sorbent made from biochar modified with an amorphous Mn oxide (AMOchar) was compared with pure biochar, pure AMO, AMO+biochar mixtures and biochar+birnessite composite for the removal of various metal(loid)s from aqueous solutions using adsorption and solid-state analyses. In comparison with the pristine biochar, both Mn oxide-biochar composites were able to remove significantly greater quantities of various metal(loid)s from the aqueous solutions, especially at a ratio 2:1 (AMO:biochar). The AMOchar proved most efficient, removing almost 99, 91 and 51% of Pb, As and Cd, respectively. Additionally, AMOchar and AMO+biochar mixture exhibited reduced Mn leaching, compared to pure AMO. Therefore, it is concluded that the synthesis of AMO and biochar is able to produce a double acting sorbent ('dorbent') of enhanced efficiency, compared with the individual deployment of their component materials. PMID- 29289009 TI - Mobility and potential risk of sediment-associated heavy metal fractions under continuous drought-rewetting cycles. AB - Ecological decline in the water level fluctuating (WLF) zone of the Three Gorges Reservoir (TGR) has been well established over the past decades. However, the effect of heavy metal fractions present in the sediment and their potential ecological risk under the anti-seasonal hydrological regime are still unclear. The Pengxi River is a tributary of the Yangtze River and it has a typical annual water level fluctuation ranging from 145 to 175m above sea level. The current study examined heavy metal fractions in sediments containing Cr, Cd, Cu, Pb and Mn collected along the WLF zone using the Tessier sequential extraction scheme. The total organic carbon (TC), total nitrogen (TN), carbon/nitrogen ratio (C/N), pH, particle size composition and content of nitrate (NO3--N), and ammonium (NH4+ N) differed dramatically among the sampled altitudes and depths and was significantly correlated with the flooding time of the WLF zone. At lower altitudes of the WLF zone, the amounts of the exchangeable (EXC), carbonate-bound (CA) and total heavy metal contents of the surface sediment were much higher compared to those of higher altitudes of the WLF zone. The risk assessment code (RAC) for Cd and Mn showed an opposite trend to that of Cr, Cu, and Pb and mainly depended on the organic matter-bound fraction (OM). The modified RAC (mRAC) indicated a very high potential adverse effect for the whole WLF zone, although the risk value was much lower at the lower altitudes and upper depths of the WLF zone. Our results showed that the positive response of the loosely bound fractions (LOS) of heavy metals to the drought-rewetting (DRW) process minimizes the risk of heavy metals in the WLF zone sediment. PMID- 29289010 TI - Linking livestock snow disaster mortality and environmental stressors in the Qinghai-Tibetan Plateau: Quantification based on generalized additive models. AB - Livestock snow disaster occurs widely in Central-to-Eastern Asian temperate and alpine grasslands. The effects of snow disaster on livestock involve a complex interaction between precipitation, vegetation, livestock, and herder communities. Quantifying the relationship among livestock mortality, snow hazard intensity, and seasonal environmental stressors is of great importance for snow disaster early warning, risk assessments, and adaptation strategies. Using a wide-spatial extent, long-time series, and event-based livestock snow disaster dataset, this study quantified those relationships and established a quantitative model of livestock mortality for prediction purpose for the Qinghai-Tibet Plateau region. Estimations using generalized additive models (GAMs) were shown to accurately predict livestock mortality and mortality rate due to snow disaster, with adjusted-R2 up to 0.794 and 0.666, respectively. These results showed that a longer snow disaster duration, lower temperatures during the disaster, and a drier summer with less vegetation all contribute significantly and non-linearly to higher mortality (rate), after controlling for elevation and socioeconomic conditions. These results can be readily applied to risk assessment and risk based adaptation actions. PMID- 29289011 TI - Chromatographic determination of monoterpenes and other acaricides in honeybees: Prevalence and possible synergies. PMID- 29289012 TI - Degradation kinetics of organic chloramines and formation of disinfection by products during chlorination of creatinine. AB - Organic chloramines can interfere with the measurement of effective combined chlorine in chlorinated water and are potential intermediate products of highly toxic disinfection by-products (DBPs). In order to know more about the degradation and transformation of organic chloramines, a typical organic chloramine precursor creatinine was selected for investigation and a corresponding individual organic chloramine chlorocreatinine was prepared in this study. The preparation condition of chlorocreatinine by chlorination was established as chlorine/creatinine = 1 M/M, reaction time = 2 h and pH = 7.0. Then the degradation kinetics of chlorocreatinine during further chlorination was studied, and a second-order rate constant of 1.16 (+/-0.14) M-1 s-1 was obtained at pH 7.0. Solution pH significantly influenced the degradation rate, and the elementary rate constants of chlorocreatinine with HOCl+H+, HOCl, OCl- and chlorocreatinine- with OCl- were calculated as 2.43 (+/-1.55) * 104 M-2 s-1, 1.05 (+/-0.09) M-1 s-1, 2.86 (+/-0.30) M-1 s-1 and 3.09 (+/-0.24) M-1 s-1, respectively. Besides, it was found that chlorocreatinine could be further converted into several C-DBPs (chloroform and trichloroacetone) and N-DBPs (dichloroacetonitrile (DCAN) and trichloronitromethane (TCNM)) during chlorination. The total yield of DBPs increased obviously with increasing pH, especially for TCNM. In addition, the presence of humic acid in creatinine solution could increase the formation of DCAN obviously during chlorination. Based on the UPLC-Q-TOF-MS analysis, the conversion pathways of chlorocreatinine were proposed. Several kinds of intermediate products were also identified as organic chloramines and some of them could even exist stably during the further chlorination. PMID- 29289013 TI - Quantitative model of carbon and nitrogen isotope composition to highlight phosphorus cycling and sources in coastal sediments (Toulon Bay, France). AB - Nutrient loadings from either point or non-point sources to the environment are related to the growing global population. Subsequent negative impacts of nutrient loading to aquatic environments requires a better understanding of the biogeochemical cycling and better tools to track their sources. This study examines the carbon (C), nitrogen (N) and phosphorus (P) discharge and cycling in a Mediterranean coastal area from rivers to marine sediments and assesses the anthropogenic contributions. Carbon and N concentrations and isotope compositions in rivers particles, surface sediments, and sediment cores were investigated to build up a quantitative multiple-end-member mixing model for C and N isotopes. This model predicts the contribution of four natural and one anthropogenic sources to the sediments and highlighted the anthropogenic fraction of P based on the relationship with anthropogenic delta15N. Although P is a monoisotopic element and total P concentration has been the sole index to study P loading, this study suggests an alternative approach to differentiate anthropogenic and non-anthropogenic (diagenetic) P, revealed point and non-point sources of P, and the corresponding P loading. Also, the diagenetic P background has been calculated for the 50-cm sediment layer of the whole Bay. PMID- 29289014 TI - Responses and recovery assessment of continuously cultured Nitrosomonas europaea under chronic ZnO nanoparticle stress: Effects of dissolved oxygen. AB - Although the antibacterial performances of emerging nanoparticles (NPs) have been extensively explored in the nitrifying systems, the impacts of dissolved oxygen (DO) levels on their bio-toxicities to the nitrifiers and the impaired cells' recovery potentials have seldom been addressed yet. In this study, the physiological and transcriptional responses of the typical ammonia oxidizers - Nitrosomonas europaea in a chemostat to the chronic ZnO NP exposure under different DO conditions were investigated. The results indicated that the cells in steady-growth state in the chemostat were more persevering than batch cultured ones to resist ZnO NP stress despite the dose-dependent NP inhibitory effects were observed. In addition, the occurred striking over-expressions of amoA and hao genes at the initial NP exposure stage suggested the cells' self-regulation potentials at the transcriptional level. The low DO (0.5 mg/L) cultured cells displayed higher sensitivity to NP stress than the high DO (2.0 mg/L) cultured ones, probably owning to the inefficient oxygen-dependent electron transfer from ammonia oxidation for energy conversion/production. The following 12-h NP-free batch recovery assays revealed that both high and low DO cultured cells possessed the physiological and metabolic activity recovery potentials, which were in negative correlation with the NP exposure time. The duration of NP stress and the resulting NP dissolution were critical for the cells' damage levels and their performance recoverability. The membrane preservation processes and the associated metabolism regulations were expected to actively participate in the cells' self-adaption to NP stress and thus be responsible for their metabolic activities recovery. PMID- 29289015 TI - Evaluation of artificially contaminated fish with formaldehyde under laboratory conditions and exposure assessment in freshwater fish in Southern Bangladesh. AB - Formalin can be added as preservative to fresh foods to prevent spoilage and extend shelf life. Formalin contains 37-40% formaldehyde, which is classified as carcinogenic to humans. To assess the public health risk associated with formaldehyde exposure in freshwater fish in Southern Bangladesh, formaldehyde concentrations (mg/kg) were determined in tilapia, Indian major carp rui, Chinese carp and a minor carp from local market and in laboratory simulations (0.5, 1.0, 2.0 and 4.0% formaldehyde solution for 5, 15, 30 and 60 min) with spectrophotometric and high performance liquid chromatography (HPLC) methods. A food frequency questionnaire was used to collect fish consumption (kg/kg BW. d) data from 400 respondents. A probabilistic exposure assessment was conducted using @Risk(r)7.0 software. Fish treated with formalin at increasing concentrations and exposure time showed increased trends of formaldehyde acquisition irrespective of fish species and analytical methods used (p < .05). Compared to spectrophotometry, the HPLC method was shown to be more sensitive and is therefore the preferred method for formalin quantification. Maximum exposure to formaldehyde (0.28 mg/kg BW. d) was calculated for tilapia using HPLC analysis. Margin of exposure (MoE) provides high priority (<10,000) for tilapia and Indian major carp rui at P99 under spectrophotometric analysis whereas as determined using HPLC, tilapia had MoE values much lower than 10,000 at P99, P95 and P90 (both total population and consumers). Exposure to formaldehyde associated with freshwater fish consumption is a public health concern in Southern Bangladesh and needs further assessment and risk management strategies. PMID- 29289016 TI - LuminoTox as a tool to optimize ozone doses for the removal of contaminants and their associated toxicity. AB - New treatment technologies and quality monitoring tools are needed for Contaminants of Emerging Concern (CECs) in wastewater. The purpose of this work was to assess the LuminoTox as a monitoring tool for CEC-associated toxicity in municipal wastewater during ozone treatment, and to evaluate the impact of different ozone feed concentrations at equivalent ozone doses for removing toxicity. The LuminoTox was sensitive at monitoring changes in toxicity of atrazine (ATZ) in synthetic wastewater (SWW) and in a 14 CECs mix in secondary effluent (SE) during ozone treatment. In both experiments, a decrease in toxicity was observed with increasing transferred ozone dose, which corresponded to a decrease in CEC concentration. For ATZ in SWW, a 5 ppm ozone feed showed better toxicity removal, up to 25% and 35% inhibition for LuminoTox algae biosensors SAPS I and SAPS II, respectively, for statistically equivalent ozone dose pairs of 43 mg (5 ppm ozone feed) and 36 mg (15 ppm ozone feed). The opposite was true for the 14 CECs in SE; the 15 ppm ozone feed showed better toxicity removal, up to a reduction of 37% and 40% for SAPS I and SAPS II inhibition, respectively, for statistically equivalent ozone dose pairs of 42 mg (5 ppm ozone feed) and 42 mg (15 ppm ozone feed). Different feed applications had an impact on the efficiency of toxicity removal for equivalent ozone doses; this efficiency appears to depend on the type of contaminants and/or wastewater matrix. PMID- 29289017 TI - Raoultella sp. SM1, a novel iron-reducing and uranium-precipitating strain. AB - The main aim of this study was the characterisation of novel Raoutella isolate, an iron-reducing and uranium-precipitating strain, originating from microbial mats occurring in the sediments of a closed down uranium mine in Kowary (SW Poland). Characterisation was done in the context of its potential role in the functioning of these mats and the possibility to use them in uranium removal/recovery processes. In our experiment, we observed the biological precipitation of iron and uranium's secondary minerals containing oxygen, potassium, sodium and phosphor, which were identified as ningyoite-like minerals. The isolated strain, Raoultella sp. SM1, was also able to dissimilatory reduce iron (III) and uranium (VI) in the presence of citrate as an electron donor. Our studies allowed us to characterise a new strain which may be used as a model microorganism in the study of Fe and U respiratory processes and which may be useful in the bioremediation of uranium-contaminated waters and sediments. During this process, uranium may be immobilised in ningyoite-like minerals and can then be recovered in nano/micro-particle form, which may be easily transformed to uraninite. PMID- 29289018 TI - Spatial analysis of polybrominated diphenylethers (PBDEs) and polybrominated biphenyls (PBBs) in fish collected from UK and proximate marine waters. AB - Some commonly consumed marine fish species are considered to display a higher risk of bio-accumulating organic environmental contaminants such as PBDEs. As part of a study to investigate the spatial distribution of these contaminants, data on polybrominated diphenlyethers (PBDEs) and polybrominated biphenyls (PBBs) were collected and analysed by introducing a web-based resource which enables efficient spatial, species and concentration level representations. Furthermore, hierarchical cluster analyses permits correlations within the data to be predicted. The data provide current information on levels of PBDE and PBB occurrence, allowing identification of locations that show higher contaminant levels. 135 fish samples of various species were analysed from UK marine waters, but encompassing the waters around Norway in the North and to the Algarve in the South. PBDEs were observed in all samples with the majority of measured congeners being detected. The concentrations ranged from 0.087 MUg/kg to 8.907 MUg/kg whole weight (ww) for the sum of all measured PBDE congeners. PBBs occurred less frequently showing a corresponding range of <0.02 MUg/kg to 0.97 MUg/kg ww for the sum of seven PBB congeners. Concentrations vary depending on species and locations where landed, e.g. PBBs occurred more frequently and at higher levels in grey mullet from French waters. The high frequency of PBDE occurrence makes it prudent to continue the monitoring of these commonly consumed marine fish species. The web-based resource provides a flexible and efficient tool for assessors and policy-makers to monitor and evaluate levels within caught fish species improving evidenced-based decision processes. PMID- 29289019 TI - Integrated electrochemical-biological process as an alternative mean for ammonia monitoring during anaerobic digestion of organic wastes. AB - Ammonia monitoring is important to control anaerobic digestion (AD) process due to inhibition effect. Here, an electrolysis cell (EC) was integrated with a complete nitrification reactor as an alternative approach for online monitoring of ammonia during AD processes. The AD effluent was pumped into nitrification reactor to convert ammonia to nitrate, followed by the introduction of nitrate rich effluent to EC cathode. It was first evaluated with synthetic ammonia-rich digesters and was observed that the current at 5 min were linearly corresponding to the ammonia levels (from 0 to 7.5 mM NH4+-N, R2 = 0.9673). The linear relationship was always observed regardless of different wastewater pH and external voltage. Pre-removal of other electron acceptors from digestate at cathode could eliminate their disturbances to sensor performance. Finally, the accuracy of biosensor was verified with real digestate test. The simple and reliable biosensor showed great promising for online ammonia monitoring of AD processes. PMID- 29289020 TI - Optical fiber-mediated photosynthesis for enhanced subsurface oxygen delivery. AB - Remediation of polluted groundwater often requires oxygen delivery into subsurface to sustain aerobic bacteria. Air sparging or injection of oxygen containing solutions (e.g., hydrogen peroxide) into the subsurface are common. In this study visible light was delivered into the subsurface using radially emitting optical fibers. Phototrophic organisms grew near the optical fiber in a saturated sand column. When applying light in on-off cycles, dissolved oxygen (DO) varied from super saturation levels of >15 mg DO/L in presence of light to under-saturation (<5 mg DO/L) in absence of light. Non-photosynthetic bacteria dominated at longer radial distances from the fiber, presumably supported by soluble microbial products produced by the photosynthetic microorganisms. The dissolved oxygen variations alter redox condition changes in response to light demonstrate the potential to biologically deliver oxygen into the subsurface and support a diverse microbial community. The ability to deliver oxygen and modulate redox conditions on diurnal cycles using solar light may provide a sustainable, long term strategy for increasing dissolved oxygen levels in subsurface environments and maintaining diverse biological communities. PMID- 29289021 TI - Mercury in the unconfined aquifer of the Isonzo/Soca River alluvial plain downstream from the Idrija mining area. AB - This work aims at evaluating mercury (Hg) occurrence, spatial distribution and speciation in groundwater of the Isonzo/Soca River upper alluvial plain downstream from the Idrija Hg mine (Western Slovenia). Several wells and piezometers were sampled both in static and dynamic mode. Total (THg) and filtered (FHg) concentrations were generally higher in static (THg, 1.87-855 ng L 1; FHg, 0.20-13.61 ng L-1) than in dynamic mode (THg, 0.08-78.77 ng L-1; FHg, 0.28-6.65 ng L-1). The estimated background value accounts for 2-3 ng L-1. On the basis of hydrochemistry and isotopic composition, the main sources of groundwater were established. Hg concentrations in the Slovenian sector, supplied by local rainfall, are comparable to values measured close to the Isonzo River. Possible further Hg local sources have been suggested. Stability field analysis for the aqueous Hg species revealed that in the presence of chloride Hg solubility may be increased by the formation of chlorocomplexes. Mercury that rarely enters reduced surrounding conditions can be bound to sulphur to form polysulphide species depending on the pH of water. Since Hg-contaminated alluvial sediments of the Isonzo River may act as a secondary Hg source in groundwater, a borehole was dug down to the water table. Mercury content and speciation revealed that cinnabar (HgS) is the prevalent form followed by the matrix-bound Hg (Hgbound). Variations of the physico-chemical boundary conditions, as well as the raising/lowering of the water table, may be locally responsible for the slight variability of Hg concentrations in the aquifer. PMID- 29289022 TI - Interaction of Sb(III) with iron sulfide under anoxic conditions: Similarities and differences compared to As(III) interactions. AB - This study examined the reaction mechanism of arsenite, As(III), and antimonite, Sb(III), with iron sulfide and compared their pH-dependent reaction behaviors under strictly anoxic environments. The comparison of Sb(III) with As(III), based on their chemical similarity, may provide useful insight into understanding the geochemical behavior of the less studied Sb(III). The pH-dependent batch sorption studies revealed that As(III) and Sb(III) displayed similar removal trends with pH in terms of the removal efficiency. However, the aqueous As(III) species transformed to thioarsenite species, while aqueous Sb(III) species remained inert under the highly sulfidic anoxic system. An X-ray absorption spectroscopy study demonstrated the reaction of As(III) and Sb(III) at acidic pH was closely related to the precipitation of sulfide minerals As2S3 and Sb2S3, respectively, as a consequence of the reaction with sulfide produced through mackinawite dissolution. Meanwhile, the removal at basic pH was inferred as a surface reaction, possibly through surface complexation, surface-precipitation, or both. In this study, the pH-dependent Sb(III) uptake mechanisms proved to be similar to the corresponding mechanisms for As(III) uptake, with mackinawite demonstrating a superior capacity to scavenge Sb(III) in ferrous and sulfide-rich reducing environments. PMID- 29289023 TI - Electrolysis with diamond anodes: Eventually, there are refractory species! AB - In this work, synthetic wastewater polluted with ionic liquid 1-butyl-3 methylimidazolium (Bmim) bis(trifluoromethanesulfonyl)imide (NTf2) undergoes four electrolytic treatments with diamond anodes (bare electrolysis, electrolysis enhanced with peroxosulfate promoters, irradiated with UV light and with US) and results obtained were compared with those obtained with the application of Catalytic Wet Peroxide Oxidation (CWPO). Despite its complex heterocyclic structure, Bmim+ cation is successfully depleted with the five technologies tested, being transformed into intermediates that eventually can be mineralized. Photoelectrolysis attained the lowest concentration of intermediates, while CWPO is the technology less efficient in their degradation. However, the most surprising result is that concentration of NTf2- anion does not change during the five advanced oxidation processes tested, pointing out its strong refractory character, being the first species that exhibits this character in wastewater undergoing electrolysis with diamond. This means that the hydroxyl and sulfate radicals mediated oxidation and the direct electrolysis are inefficient for breaking the C-S, C-F and S-N bounds of the NTf2- anion, which is a very interesting mechanistic information to understand the complex processes undergone in electrolysis with diamond. PMID- 29289024 TI - Polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDE metabolites (OH PBDEs): A six-year temporal trend in Northern California pregnant women. AB - Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants. Technical mixtures PentaBDE and OctaBDE were phased out in 2004 through voluntary and regulatory actions with DecaBDE remaining in limited use until 2013. Biomonitoring studies have shown widespread presence of PBDEs in the US and worldwide population. While some studies suggest that human serum concentrations are declining over time, it is unclear whether this trend will continue. Our objective was to examine temporal trends of PentaBDEs and their hydroxylated metabolites (OH-PBDEs) between 2008 and 2014 in populations of ethnically diverse, pregnant women residing in Northern California (n = 111). Serum samples were collected and analyzed by high resolution mass spectrometry for five PentaBDE congeners and two OH-PBDEs. We found widespread exposures in participants from all three time points (2008/09, 2011/12, 2014). Temporal patterns varied substantially by congener. BDE-47, -99 and the OH-PBDEs decreased between 2008/09-2011/12 but plateaued between 2011/12-2014. In contrast, BDE-100 decreased across all years, BDE-153 decreased in the latter years, and BDE-28 decreased initially and then increased. These findings indicate that while policies to remove PBDEs from the marketplace have successfully lead to declines in exposures to some PBDE congeners, human exposures to these legacy pollutants could plateau and remain ubiquitous in human populations. PMID- 29289025 TI - Impact of misclassification error in the estimation of maternal major depression disorder prevalence in home visitation programs. AB - The objective of this study was to measure the bias introduced by misclassification error when estimating the prevalence of MDD among mothers in two community-based studies. Baseline data were collected from mothers participating in two home visitation study sites in South Central United States between 2010 and 2014. The operational definition of MDD was a Center of Epidemiological Studies-Depression - Short Form (CESD-SF) score of 10 or higher. Misclassification error was adjusted for using CESD-SF sensitivity and specificity priors that were either antepartum or postpartum specific or non specific. Bias was measured as the difference between the observed and misclassification error-adjusted prevalence estimates using a Binomial Bayesian Latent Class model. The proportion of mothers in the antepartum and postpartum periods confounded the level of bias in estimating MDD prevalence. When using antepartum and postpartum specific sensitivity and specificity of the CESD-SF, misclassification error led to nearly no bias in prevalence estimates. In contrast, ignoring differences in CESD-SF sensitivity and specificity between these periods showed considerable MDD prevalence bias. The use of period of assessment (antepartum versus postpartum) specific case-finding instrument diagnostic performance values is critical to the valid estimation of MDD prevalence among mothers. Studies using other case-finding instruments are needed to support this conclusion. PMID- 29289026 TI - 37,650 ways to have "persistent complex bereavement disorder" yet only 48 ways to have "prolonged grief disorder". AB - Persistent complex bereavement disorder (PCBD) is a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5. Prolonged grief disorder (PGD) will likely be included in the International Classification of Diseases'-11. While it has been argued that PCBD and PGD cover the same diagnostic entity, their symptom count differs. A higher symptom count may increase the complexity of diagnostic algorithm and thereby the symptom profile heterogeneity of a disorder. Using binomial equations, a nearly thousand-fold difference in possible symptom profiles to meet PGD versus PCBD criteria was demonstrated, showing both disorders may differ more than just semantically. PMID- 29289027 TI - Implantable, wireless device platforms for neuroscience research. AB - Recently developed classes of ultraminiaturized wireless devices provide powerful capabilities in neuroscience research, as implantable light sources for simulation/inhibition via optogenetics, as integrated microfluidic systems for programmed pharmacological delivery and as multimodal sensors for physiological measurements. These platforms leverage basic advances in biocompatible materials, semiconductor device designs and systems engineering concepts to afford modes of operation that are qualitatively distinct from those of conventional approaches that tether animals to external hardware by means of optical fibers, electrical cables and/or fluidic tubing. Neuroscience studies that exploit the unique features of these technologies enable insights into neural function through targeted stimulation, inhibition and recording, with spatially and genetically precise manipulation of neural circuit activity. Experimental possibilities include studies in naturalistic, three dimensional environments, investigations of pair-wise or group related social interactions and many other scenarios of interest that cannot be addressed using traditional hardware. PMID- 29289028 TI - Experience does not influence injury-related joint kinematics and kinetics in distance runners. AB - PURPOSE: Increased running experience and more time spent running appears to be advantageous in reducing injury risk, although the reason behind this is unclear. It is plausible that more experience results in better running mechanics leading to less injuries. Running mechanics are often screened during clinical assessments and targeted for correction in gait retraining, particularly those thought to be global indicators of injury or those associated with elevated knee joint loading. Examining the biomechanics of runners who are less-injury prone can improve our understanding of the significance of faulty running mechanics in relation to injury. Our goal was to examine if running experience was correlated to differences in kinematics and kinetics associated with increased knee joint loading and running-related injury risk. METHODS: One hundred runners with varying experience ran on a pressure-sensing treadmill at a self-selected speed. Trunk and lower extremity kinematics, spatiotemporal measures, and ground reaction forces were collected. Multiple linear regression was used to assess the association between experience and three-dimensional hip kinematics, sagittal plane lower-extremity mechanics, and ground reaction forces while controlling for age and speed. RESULTS: Increased running experience was not significantly associated with running mechanics. Increased age was significantly associated with reduced peak knee flexion and increased contact time. Running speed influenced several spatiotemporal, kinematic, and kinetic variables. CONCLUSION: Increased years of running experience does not appear to significantly influence running mechanics. However, age and running speed do influence biomechanical variables associated with injury in distance runners. Thus, there may be factors, other than running mechanics, that contribute to less risk in more experienced runners. PMID- 29289029 TI - Photon induced non-linear quantized double layer charging in quaternary semiconducting quantum dots. AB - Room temperature quantized double layer charging was observed in 2 nm Cu2ZnSnS4 (CZTS) quantum dots. In addition to this we observed a distinct non-linearity in the quantized double layer charging arising from UV light modulation of double layer. UV light irradiation resulted in a 26% increase in the integral capacitance at the semiconductor-dielectric (CZTS-oleylamine) interface of the quantum dot without any change in its core size suggesting that the cause be photocapacitive. The increasing charge separation at the semiconductor-dielectric interface due to highly stable and mobile photogenerated carriers cause larger electrostatic forces between the quantum dot and electrolyte leading to an enhanced double layer. This idea was supported by a decrease in the differential capacitance possible due to an enhanced double layer. Furthermore the UV illumination enhanced double layer gives us an AC excitation dependent differential double layer capacitance which confirms that the charging process is non-linear. This ultimately illustrates the utility of a colloidal quantum dot electrolyte interface as a non-linear photocapacitor. PMID- 29289030 TI - Structural, microrheological and kinetic properties of a ternary silica-Pluronic F127-starch thermosensitive system. AB - HYPOTHESIS: The sol-gel transition in aqueous suspensions consisting of silica particles and thermosensitive polymer is controlled by inter-particle forces and solution properties of the polymer. Addition of a second non-thermosensitive polymer may affect the transition. The purpose of this work was to characterize the kinetics of the sol-gel transition and to understand the effects of a second non-thermosensitive polymer on the microstructure, using a combination of classical rheology and microrheology. EXPERIMENTS: Classical rotational rheology as well as two microrheology methods, Multiple Particle Tracking (MPT) and Diffusing Wave Spectroscopy (DWS), were used to investigate the sol-gel transition of a ternary silica-Pluronic F127-starch thermosensitive system. FINDINGS: Classical rheometry and DWS indicated sol-gel transition temperature ~25 degrees C at 1 wt% Pluronic, independently of the concentration of the other components. DWS showed a fast gelation process, less than two minutes for all samples, beside a second slow kinetic process. In the gel state, MPT indicated micro-structural and micro-viscoelastic differences compared to rotational rheology. This was explained by formation of an elastic matrix of silica and polymers in combination with assembly of silica particles in large macroporous agglomerates. Presence of starch led to breakdown of the macroporous network, leaving the homogeneous elastic network left. PMID- 29289031 TI - Stabilization of poly(ethylene glycol)-poly(epsilon-caprolactone) star block copolymer micelles via aromatic groups for improved drug delivery properties. AB - HYPOTHESIS: The functionalization of poly(ethylene glycol)-poly(epsilon caprolactone) (PEG-PCL) block copolymers with moieties allowing for core crosslinking is expected to result in improved micellar stability and drug delivery properties. EXPERIMENTS: PEG-(PCL)8 star block copolymers were functionalized with pendant benzylthioether (BTE) groups by applying an anionic post-polymerization modification technique followed by photoradical thiol-yne addition of benzyl mercaptan. The micellar properties of PEG-(PCL)8 and PEG-(PCL BTE)8 were studied and compared in terms of critical micelle concentration (CMC), size, morphology, drug loading and release and in vitro cytotoxicity. FINDINGS: In comparison with unmodified PEG-(PCL)8 micelles, PEG-(PCL-BTE)8 micelles exhibited a 15-fold lower CMC, a 15-fold smaller size and a 50% higher drug loading and encapsulation efficiency thanks to the presence of pendant benzyl groups which provide the possibility for micellar core-crosslinking via supramolecular pi-pi stacking and additional hydrophobic interactions. Whereas the PEG-(PCL)8 micelles showed significant aggregation during in vitro cytotoxicity experiments, the PEG-(PCL-BTE)8 micelles showed no signs of aggregation and were capable of solubilizing high concentrations of curcumin, resulting in a significant decrease in MCF-7 cell viability after 48 h. Their ease of synthesis combined with promising results regarding drug delivery make the PEG-(PCL-BTE)8 micelles appealing for application in the field of encapsulation. PMID- 29289032 TI - Phase synchronization of baroclinic waves in a differentially heated rotating annulus experiment subject to periodic forcing with a variable duty cycle. AB - A series of laboratory experiments in a thermally driven, rotating fluid annulus are presented that investigate the onset and characteristics of phase synchronization and frequency entrainment between the intrinsic, chaotic, oscillatory amplitude modulation of travelling baroclinic waves and a periodic modulation of the (axisymmetric) thermal boundary conditions, subject to time dependent coupling. The time-dependence is in the form of a prescribed duty cycle in which the periodic forcing of the boundary conditions is applied for only a fraction delta of each oscillation. For the rest of the oscillation, the boundary conditions are held fixed. Two profiles of forcing were investigated that capture different parts of the sinusoidal variation and delta was varied over the range 0.1<=delta<=1. Reducing delta was found to act in a similar way to a reduction in a constant coupling coefficient in reducing the width of the interval in forcing frequency or period over which complete synchronization was observed (the "Arnol'd tongue") with respect to the detuning, although for the strongest pulse like forcing profile some degree of synchronization was discernible even at delta=0.1. Complete phase synchronization was obtained within the Arnol'd tongue itself, although the strength of the amplitude modulation of the baroclinic wave was not significantly affected. These experiments demonstrate a possible mechanism for intraseasonal and/or interannual "teleconnections" within the climate system of the Earth and other planets that does not rely on Rossby wave propagation across the planet along great circles. PMID- 29289033 TI - Simulating climate with a synchronization-based supermodel. AB - The SPEEDO global climate model (an atmosphere model coupled to a land and an ocean/sea-ice model with about 250.000 degrees of freedom) is used to investigate the merits of a new multi-model ensemble approach to the climate prediction problem in a perfect model setting. Two imperfect models are generated by perturbing parameters. Connection terms are introduced that synchronize the two models on a common solution, referred to as the supermodel solution. A synchronization-based learning algorithm is applied to the supermodel through the introduction of an update rule for the connection coefficients. Connection coefficients cease updating when synchronization errors between the supermodel and solutions of the "true" equations vanish. These final connection coefficients define the supermodel. Different supermodel solutions, but with equivalent performance, are found depending on the initial values of the connection coefficients during learning. The supermodels have a climatology and a climate response to a CO2 increase in the atmosphere that is closer to the truth as compared to the imperfect models and the standard multi-model ensemble average, showing the potential of the supermodel approach to improve climate predictions. PMID- 29289034 TI - Economic networks: Heterogeneity-induced vulnerability and loss of synchronization. AB - Interconnected systems are prone to propagation of disturbances, which can undermine their resilience to external perturbations. Propagation dynamics can clearly be affected by potential time delays in the underlying processes. We investigate how such delays influence the resilience of production networks facing disruption of supply. Interdependencies between economic agents are modeled using systems of Boolean delay equations (BDEs); doing so allows us to introduce heterogeneity in production delays and in inventories. Complex network topologies are considered that reproduce realistic economic features, including a network of networks. Perturbations that would otherwise vanish can, because of delay heterogeneity, amplify and lead to permanent disruptions. This phenomenon is enabled by the interactions between short cyclic structures. Difference in delays between two interacting, and otherwise resilient, structures can in turn lead to loss of synchronization in damage propagation and thus prevent recovery. Finally, this study also shows that BDEs on complex networks can lead to metastable relaxation oscillations, which are damped out in one part of a network while moving on to another part. PMID- 29289035 TI - "FORCE" learning in recurrent neural networks as data assimilation. AB - It is shown that the "FORCE" algorithm for learning in arbitrarily connected networks of simple neuronal units can be cast as a Kalman Filter, with a particular state-dependent form for the background error covariances. The resulting interpretation has implications for initialization of the learning algorithm, leads to an extension to include interactions between the weight updates for different neurons, and can represent relationships within groups of multiple target output signals. PMID- 29289036 TI - Synchronization of world economic activity. AB - Common dynamical properties of business cycle fluctuations are studied in a sample of more than 100 countries that represent economic regions from all around the world. We apply the methodology of multivariate singular spectrum analysis (M SSA) to identify oscillatory modes and to detect whether these modes are shared by clusters of phase- and frequency-locked oscillators. An extension of the M-SSA approach is introduced to help analyze structural changes in the cluster configuration of synchronization. With this novel technique, we are able to identify a common mode of business cycle activity across our sample, and thus point to the existence of a world business cycle. Superimposed on this mode, we further identify several major events that have markedly influenced the landscape of world economic activity in the postwar era. PMID- 29289037 TI - Publisher's Note: "Bi-SOC-states in one-dimensional random cellular automaton" [Chaos 27, 103123 (2017)]. PMID- 29289038 TI - Synchronization control in multiplex networks of nonlinear multi-agent systems. AB - This paper is concerned with synchronization control of a multiplex network, in which two different kinds of relationships among agents coexist. Hybrid coupling, including continuous linear coupling and impulsive coupling, is proposed to model the coexisting distinguishable interactions. First, by adding impulsive controllers on a small portion of agents, local synchronization is analyzed by linearizing the error system at the desired trajectory. Then, global synchronization is studied based on the Lyapunov stability theory, where a time varying coupling strength is involved. To further deal with the time-varying coupling strength, an adaptive updating law is introduced and a corresponding sufficient condition is obtained to ensure synchronization of the multiplex network towards the desired trajectory. Networks of Chua's circuits and other chaotic systems with double layers of interactions are simulated to verify the proposed method. PMID- 29289039 TI - Role of atmosphere-ocean interactions in supermodeling the tropical Pacific climate. AB - The supermodel strategy interactively combines several models to outperform the individual models comprising it. A key advantage of the approach is that nonlinear improvements can be achieved, in contrast to the linear weighted combination of individual unconnected models. This property is found in a climate supermodel constructed by coupling two versions of an atmospheric model differing only in their convection scheme to a single ocean model. The ocean model receives a weighted combination of the momentum and heat fluxes. Optimal weights can produce a supermodel with a basic state similar to observations: a single Intertropical Convergence zone (ITCZ), with a western Pacific warm pool and an equatorial cold tongue. This is in stark contrast to the erroneous double ITCZ pattern simulated by both of the two stand-alone coupled models. By varying weights, we develop a conceptual scheme to explain how combining the momentum fluxes of the two different atmospheric models affects equatorial upwelling and surface wind feedback so as to give a realistic basic state in the tropical Pacific. In particular, we propose a mechanism based on the competing influences of equatorial zonal wind and off-equatorial wind stress curl in driving equatorial upwelling in the coupled models. Our results show how nonlinear ocean atmosphere interaction is essential in combining these two effects to build different sea surface temperature structures, some of which are realistic. They also provide some insight into observed and modelled tropical Pacific climate. PMID- 29289040 TI - Stability of synchrony against local intermittent fluctuations in tree-like power grids. AB - 90% of all Renewable Energy Power in Germany is installed in tree-like distribution grids. Intermittent power fluctuations from such sources introduce new dynamics into the lower grid layers. At the same time, distributed resources will have to contribute to stabilize the grid against these fluctuations in the future. In this paper, we model a system of distributed resources as oscillators on a tree-like, lossy power grid and its ability to withstand desynchronization from localized intermittent renewable infeed. We find a remarkable interplay of the network structure and the position of the node at which the fluctuations are fed in. An important precondition for our findings is the presence of losses in distribution grids. Then, the most network central node splits the network into branches with different influence on network stability. Troublemakers, i.e., nodes at which fluctuations are especially exciting the grid, tend to be downstream branches with high net power outflow. For low coupling strength, we also find branches of nodes vulnerable to fluctuations anywhere in the network. These network regions can be predicted at high confidence using an eigenvector based network measure taking the turbulent nature of perturbations into account. While we focus here on tree-like networks, the observed effects also appear, albeit less pronounced, for weakly meshed grids. On the other hand, the observed effects disappear for lossless power grids often studied in the complex system literature. PMID- 29289041 TI - Robustness of coupled oscillator networks with heterogeneous natural frequencies. AB - Robustness of coupled oscillator networks against local degradation of oscillators has been intensively studied in this decade. The oscillation behavior on the whole network is typically reduced with an increase in the fraction of degraded (inactive) oscillators. The critical fraction of inactive oscillators, at which a transition from an oscillatory to a quiescent state occurs, has been used as a measure for the network robustness. The larger (smaller) this measure is, the more robust (fragile) the oscillatory behavior on the network is. Most previous studies have used oscillators with identical natural frequencies, for which the oscillators are necessarily synchronized and thereby the analysis is simple. In contrast, we focus on the effect of heterogeneity in the natural frequencies on the network robustness. First, we analytically derive the robustness measure for the coupled oscillator models with heterogeneous natural frequencies under some conditions. Then, we show that increasing the heterogeneity in natural frequencies makes the network fragile. Moreover, we discuss the optimal parameter condition to maximize the network robustness. PMID- 29289042 TI - Insensitivity of synchronization to network structure in chaotic pendulum systems with time-delay coupling. AB - It has been generally believed that both time delay and network structure could play a crucial role in determining collective dynamical behaviors in complex systems. In this work, we study the influence of coupling strength, time delay, and network topology on synchronization behavior in delay-coupled networks of chaotic pendulums. Interestingly, we find that the threshold value of the coupling strength for complete synchronization in such networks strongly depends on the time delay in the coupling, but appears to be insensitive to the network structure. This lack of sensitivity was numerically tested in several typical regular networks, such as different locally and globally coupled ones as well as in several complex networks, such as small-world and scale-free networks. Furthermore, we find that the emergence of a synchronous periodic state induced by time delay is of key importance for the complete synchronization. PMID- 29289043 TI - Using machine learning to replicate chaotic attractors and calculate Lyapunov exponents from data. AB - We use recent advances in the machine learning area known as "reservoir computing" to formulate a method for model-free estimation from data of the Lyapunov exponents of a chaotic process. The technique uses a limited time series of measurements as input to a high-dimensional dynamical system called a "reservoir." After the reservoir's response to the data is recorded, linear regression is used to learn a large set of parameters, called the "output weights." The learned output weights are then used to form a modified autonomous reservoir designed to be capable of producing an arbitrarily long time series whose ergodic properties approximate those of the input signal. When successful, we say that the autonomous reservoir reproduces the attractor's "climate." Since the reservoir equations and output weights are known, we can compute the derivatives needed to determine the Lyapunov exponents of the autonomous reservoir, which we then use as estimates of the Lyapunov exponents for the original input generating system. We illustrate the effectiveness of our technique with two examples, the Lorenz system and the Kuramoto-Sivashinsky (KS) equation. In the case of the KS equation, we note that the high dimensional nature of the system and the large number of Lyapunov exponents yield a challenging test of our method, which we find the method successfully passes. PMID- 29289044 TI - Effects of stressor characteristics on early warning signs of critical transitions and "critical coupling" in complex dynamical systems. AB - Complex dynamical systems face abrupt transitions into unstable and catastrophic regimes. These critical transitions are triggered by gradual modifications in stressors, which push the dynamical system towards unstable regimes. Bifurcation analysis can characterize such critical thresholds, beyond which systems become unstable. Moreover, the stochasticity of the external stressors causes small scale fluctuations in the system response. In some systems, the decomposition of these signal fluctuations into precursor signals can reveal early warning signs prior to the critical transition. Here, we present a dynamical analysis of a power system subjected to an increasing load level and small-scale stochastic load perturbations. We show that the auto- and cross-correlations of bus voltage magnitudes increase, leading up to a Hopf bifurcation point, and further grow until the system collapses. This evidences a gradual transition into a state of "critical coupling," which is complementary to the established concept of "critical slowing down." Furthermore, we analyze the effects of the type of load perturbation and load characteristics on early warning signs and find that gradient changes in the autocorrelation provide early warning signs of the imminent critical transition under white-noise but not for auto-correlated load perturbations. Furthermore, the cross-correlation between all voltage magnitude pairs generally increases prior to and beyond the Hopf bifurcation point, indicating "critical coupling," but cannot provide early warning indications. Finally, we show that the established early warning indicators are oblivious to limit-induced bifurcations and, in the case of the power system model considered here, only react to an approaching Hopf bifurcation. PMID- 29289045 TI - Bright-dark and dark-dark solitons in coupled nonlinear Schrodinger equation with PT-symmetric potentials. AB - We explore different nonlinear coherent structures, namely, bright-dark (BD) and dark-dark (DD) solitons in a coupled nonlinear Schrodinger/Gross-Pitaevskii equation with defocusing/repulsive nonlinearity coefficients featuring parity time ( PT)-symmetric potentials. Especially, for two choices of PT-symmetric potentials, we obtain the exact solutions for BD and DD solitons. We perform the linear stability analysis of the obtained coherent structures. The results of this linear stability analysis are well corroborated by direct numerical simulation incorporating small random noise. It has been found that there exists a parameter regime which can support stable BD and DD solitons. PMID- 29289046 TI - Introduction to focus issue: Synchronization in large networks and continuous media-data, models, and supermodels. AB - The synchronization of loosely coupled chaotic systems has increasingly found applications to large networks of differential equations and to models of continuous media. These applications are at the core of the present Focus Issue. Synchronization between a system and its model, based on limited observations, gives a new perspective on data assimilation. Synchronization among different models of the same system defines a supermodel that can achieve partial consensus among models that otherwise disagree in several respects. Finally, novel methods of time series analysis permit a better description of synchronization in a system that is only observed partially and for a relatively short time. This Focus Issue discusses synchronization in extended systems or in components thereof, with particular attention to data assimilation, supermodeling, and their applications to various areas, from climate modeling to macroeconomics. PMID- 29289047 TI - Attractor learning in synchronized chaotic systems in the presence of unresolved scales. AB - Recently, supermodels consisting of an ensemble of interacting models, synchronizing on a common solution, have been proposed as an alternative to the common non-interactive multi-model ensembles in order to improve climate predictions. The connection terms in the interacting ensemble are to be optimized based on the data. The supermodel approach has been successfully demonstrated in a number of simulation experiments with an assumed ground truth and a set of good, but imperfect models. The supermodels were optimized with respect to their short-term prediction error. Nevertheless, they produced long-term climatological behavior that was close to the long-term behavior of the assumed ground truth, even in cases where the long-term behavior of the imperfect models was very different. In these supermodel experiments, however, a perfect model class scenario was assumed, in which the ground truth and imperfect models belong to the same model class and only differ in parameter setting. In this paper, we consider the imperfect model class scenario, in which the ground truth model class is more complex than the model class of imperfect models due to unresolved scales. We perform two supermodel experiments in two toy problems. The first one consists of a chaotically driven Lorenz 63 oscillator ground truth and two Lorenz 63 oscillators with constant forcings as imperfect models. The second one is more realistic and consists of a global atmosphere model as ground truth and imperfect models that have perturbed parameters and reduced spatial resolution. In both problems, we find that supermodel optimization with respect to short-term prediction error can lead to a long-term climatological behavior that is worse than that of the imperfect models. However, we also show that attractor learning can remedy this problem, leading to supermodels with long-term behavior superior to the imperfect models. PMID- 29289048 TI - Experiments with arbitrary networks in time-multiplexed delay systems. AB - We report a new experimental approach using an optoelectronic feedback loop to investigate the dynamics of oscillators coupled on large complex networks with arbitrary topology. Our implementation is based on a single optoelectronic feedback loop with time delays. We use the space-time interpretation of systems with time delay to create large networks of coupled maps. Others have performed similar experiments using high-pass filters to implement the coupling; this restricts the network topology to the coupling of only a few nearest neighbors. In our experiment, the time delays and coupling are implemented on a field programmable gate array, allowing the creation of networks with arbitrary coupling topology. This system has many advantages: the network nodes are truly identical, the network is easily reconfigurable, and the network dynamics occur at high speeds. We use this system to study cluster synchronization and chimera states in both small and large networks of different topologies. PMID- 29289049 TI - Coexistence between silent and bursting states in a biophysical Hodgkin-Huxley type of model. AB - Classification of the dynamical mechanisms that support bistability between bursting oscillations and silence has not yet been clarified in detail. The purpose of this paper is to demonstrate that the coexistence of a stable equilibrium point with a state of continuous bursting can occur in a slightly modified, biophysical model that describe the dynamics of pancreatic beta-cells. To realize this form of coexistence, we have introduced an additional voltage dependent potassium current that is activated in the region around the original, unstable equilibrium point. It is interesting to note that this modification also leads the model to display a blue-sky catastrophe in the transition region between chaotic and bursting states. PMID- 29289050 TI - The fractal geometry of Hartree-Fock. AB - The Hartree-Fock method is an important approximation for the ground-state electronic wave function of atoms and molecules so that its usage is widespread in computational chemistry and physics. The Hartree-Fock method is an iterative procedure in which the electronic wave functions of the occupied orbitals are determined. The set of functions found in one step builds the basis for the next iteration step. In this work, we interpret the Hartree-Fock method as a dynamical system since dynamical systems are iterations where iteration steps represent the time development of the system, as encountered in the theory of fractals. The focus is put on the convergence behavior of the dynamical system as a function of a suitable control parameter. In our case, a complex parameter lambda controls the strength of the electron-electron interaction. An investigation of the convergence behavior depending on the parameter lambda is performed for helium, neon, and argon. We observe fractal structures in the complex lambda-plane, which resemble the well-known Mandelbrot set, determine their fractal dimension, and find that with increasing nuclear charge, the fragmentation increases as well. PMID- 29289051 TI - Mathematical foundations of hybrid data assimilation from a synchronization perspective. AB - The state-of-the-art data assimilation methods used today in operational weather prediction centers around the world can be classified as generalized one-way coupled impulsive synchronization. This classification permits the investigation of hybrid data assimilation methods, which combine dynamic error estimates of the system state with long time-averaged (climatological) error estimates, from a synchronization perspective. Illustrative results show how dynamically informed formulations of the coupling matrix (via an Ensemble Kalman Filter, EnKF) can lead to synchronization when observing networks are sparse and how hybrid methods can lead to synchronization when those dynamic formulations are inadequate (due to small ensemble sizes). A large-scale application with a global ocean general circulation model is also presented. Results indicate that the hybrid methods also have useful applications in generalized synchronization, in particular, for correcting systematic model errors. PMID- 29289052 TI - The chimera state in colloidal phase oscillators with hydrodynamic interaction. AB - The chimera state is the incongruous situation where coherent and incoherent populations coexist in sets of identical oscillators. Using driven non-linear oscillators interacting purely through hydrodynamic forces at low Reynolds number, previously studied as a simple model of motile cilia supporting waves, we find concurrent incoherent and synchronised subsets in small arrays. The chimeras seen in simulation display a "breathing" aspect, reminiscent of uniformly interacting phase oscillators. In contrast to other systems where chimera has been observed, this system has a well-defined interaction metric, and we know that the emergent dynamics inherit the symmetry of the underlying Oseen tensor eigenmodes. The chimera state can thus be connected to a superposition of eigenstates, whilst considering the mean interaction strength within and across subsystems allows us to make a connection to more generic (and abstract) chimeras in populations of Kuramoto phase oscillators. From this work, we expect the chimera state to emerge in experimental observations of oscillators coupled through hydrodynamic forces. PMID- 29289053 TI - Optimal stretching in the reacting wake of a bluff body. AB - We experimentally study spreading of the Belousov-Zhabotinsky reaction behind a bluff body in a laminar flow. Locations of reacted regions (i.e., regions with high product concentration) correlate with a moderate range of Lagrangian stretching and that range is close to the range of optimal stretching previously observed in topologically different flows [T. D. Nevins and D. H. Kelley, Phys. Rev. Lett. 117, 164502 (2016)]. The previous work found optimal stretching in a closed, vortex dominated flow, but this article uses an open flow and only a small area of appreciable vorticity. We hypothesize that optimal stretching is common in advection-reaction-diffusion systems with an excitation threshold, including excitable and bistable systems, and that the optimal range depends on reaction chemistry and not on flow shape or characteristic speed. Our results may also give insight into plankton blooms behind islands in ocean currents. PMID- 29289054 TI - Modeling information diffusion in time-varying community networks. AB - Social networks are rarely static, and they typically have time-varying network topologies. A great number of studies have modeled temporal networks and explored social contagion processes within these models; however, few of these studies have considered community structure variations. In this paper, we present a study of how the time-varying property of a modular structure influences the information dissemination. First, we propose a continuous-time Markov model of information diffusion where two parameters, mobility rate and community attractiveness, are introduced to address the time-varying nature of the community structure. The basic reproduction number is derived, and the accuracy of this model is evaluated by comparing the simulation and theoretical results. Furthermore, numerical results illustrate that generally both the mobility rate and community attractiveness significantly promote the information diffusion process, especially in the initial outbreak stage. Moreover, the strength of this promotion effect is much stronger when the modularity is higher. Counterintuitively, it is found that when all communities have the same attractiveness, social mobility no longer accelerates the diffusion process. In addition, we show that the local spreading in the advantage group has been greatly enhanced due to the agglomeration effect caused by the social mobility and community attractiveness difference, which thus increases the global spreading. PMID- 29289055 TI - Surrogate-assisted identification of influences of network construction on evolving weighted functional networks. AB - We aim at identifying factors that may affect the characteristics of evolving weighted networks derived from empirical observations. To this end, we employ various chains of analysis that are often used in field studies for a data-driven derivation and characterization of such networks. As an example, we consider fully connected, weighted functional brain networks before, during, and after epileptic seizures that we derive from multichannel electroencephalographic data recorded from epilepsy patients. For these evolving networks, we estimate clustering coefficient and average shortest path length in a time-resolved manner. Lastly, we make use of surrogate concepts that we apply at various levels of the chain of analysis to assess to what extent network characteristics are dominated by properties of the electroencephalographic recordings and/or the evolving weighted networks, which may be accessible more easily. We observe that characteristics are differently affected by the unavoidable referencing of the electroencephalographic recording, by the time-series-analysis technique used to derive the properties of network links, and whether or not networks were normalized. Importantly, for the majority of analysis settings, we observe temporal evolutions of network characteristics to merely reflect the temporal evolutions of mean interaction strengths. Such a property of the data may be accessible more easily, which would render the weighted network approach-as used here-as an overly complicated description of simple aspects of the data. PMID- 29289056 TI - Ocean eddies and climate predictability. AB - A suite of coupled climate model simulations and experiments are used to examine how resolved mesoscale ocean features affect aspects of climate variability, air sea interactions, and predictability. In combination with control simulations, experiments with the interactive ensemble coupling strategy are used to further amplify the role of the oceanic mesoscale field and the associated air-sea feedbacks and predictability. The basic intent of the interactive ensemble coupling strategy is to reduce the atmospheric noise at the air-sea interface, allowing an assessment of how noise affects the variability, and in this case, it is also used to diagnose predictability from the perspective of signal-to-noise ratios. The climate variability is assessed from the perspective of sea surface temperature (SST) variance ratios, and it is shown that, unsurprisingly, mesoscale variability significantly increases SST variance. Perhaps surprising is the fact that the presence of mesoscale ocean features even further enhances the SST variance in the interactive ensemble simulation beyond what would be expected from simple linear arguments. Changes in the air-sea coupling between simulations are assessed using pointwise convective rainfall-SST and convective rainfall-SST tendency correlations and again emphasize how the oceanic mesoscale alters the local association between convective rainfall and SST. Understanding the possible relationships between the SST-forced signal and the weather noise is critically important in climate predictability. We use the interactive ensemble simulations to diagnose this relationship, and we find that the presence of mesoscale ocean features significantly enhances this link particularly in ocean eddy rich regions. Finally, we use signal-to-noise ratios to show that the ocean mesoscale activity increases model estimated predictability in terms of convective precipitation and atmospheric upper tropospheric circulation. PMID- 29289057 TI - A unifying view of synchronization for data assimilation in complex nonlinear networks. AB - Networks of nonlinear systems contain unknown parameters and dynamical degrees of freedom that may not be observable with existing instruments. From observable state variables, we want to estimate the connectivity of a model of such a network and determine the full state of the model at the termination of a temporal observation window during which measurements transfer information to a model of the network. The model state at the termination of a measurement window acts as an initial condition for predicting the future behavior of the network. This allows the validation (or invalidation) of the model as a representation of the dynamical processes producing the observations. Once the model has been tested against new data, it may be utilized as a predictor of responses to innovative stimuli or forcing. We describe a general framework for the tasks involved in the "inverse" problem of determining properties of a model built to represent measured output from physical, biological, or other processes when the measurements are noisy, the model has errors, and the state of the model is unknown when measurements begin. This framework is called statistical data assimilation and is the best one can do in estimating model properties through the use of the conditional probability distributions of the model state variables, conditioned on observations. There is a very broad arena of applications of the methods described. These include numerical weather prediction, properties of nonlinear electrical circuitry, and determining the biophysical properties of functional networks of neurons. Illustrative examples will be given of (1) estimating the connectivity among neurons with known dynamics in a network of unknown connectivity, and (2) estimating the biophysical properties of individual neurons in vitro taken from a functional network underlying vocalization in songbirds. PMID- 29289058 TI - Assimilation of ocean sea-surface height observations of mesoscale eddies. AB - Mesoscale eddies are one of the dominant sources of variability in the world's oceans. With eddy-resolving global ocean models, it becomes important to assimilate observations of mesoscale eddies to correctly represent the state of the mesoscale. Here, we investigate strategies for assimilating a reduced number of sea-surface height observations by focusing on the coherent mesoscale eddies. The study is carried out in an idealized perfect-model framework using two-layer forced quasigeostrophic dynamics, which captures the dominant dynamics of ocean mesoscale eddies. We study errors in state-estimation as well as error growth in forecasts and find that as fewer observations are assimilated, assimilating at vortex locations results in reduced state estimation and forecast errors. PMID- 29289059 TI - Amplification through chaotic synchronization in spatially extended beam-plasma systems. AB - In this paper, we have studied the relationship between chaotic synchronization and microwave signal amplification in coupled beam-plasma systems. We have considered a 1D particle-in-cell numerical model of unidirectionally coupled beam plasma oscillatory media being in the regime of electron pattern formation. We have shown the significant gain of microwave oscillation power in coupled beam plasma media being in the different regimes of generation. The discovered effect has a close connection with the chaotic synchronization phenomenon, so we have observed that amplification appears after the onset of the complete time scale synchronization regime in the analyzed coupled spatially extended systems. We have also provided the numerical study of physical processes in the chain of beam plasma systems leading to the chaotic synchronization and the amplification of microwave oscillations power, respectively. PMID- 29289060 TI - Calculation of the acoustical properties of triadic harmonies. AB - The author reports that the harmonic "tension" and major/minor "valence" of pitch combinations can be calculated directly from acoustical properties without relying on concepts from traditional harmony theory. The capability to compute the well-known types of harmonic triads means that their perception is not simply a consequence of learning an arbitrary cultural "idiom" handed down from the Italian Renaissance. On the contrary, for typical listeners familiar with diatonic music, attention to certain, definable, acoustical features underlies the perception of the valence (modality) and the inherent tension (instability) of three-tone harmonies. PMID- 29289061 TI - Extending sharpness calculation for an alternative loudness metric input. AB - Sound quality metrics help improve the psychoacoustic acceptability of devices and environments by modeling and thus enabling deliberate improvement of perceptual attributes. Sharpness as defined in DIN 45692 [(2009). Deutsches Institut fur Normung, Berlin] requires inputs from Zwicker's loudness metric [ISO 532-1 (2017). International Organization for Standardization, Geneva]. This letter demonstrates that sharpness can be formulated to accept specific loudness values from Moore and Glasberg's loudness metric [ISO 532-2 (2017). International Organization for Standardization, Geneva; ANSI S3.4 (2007). American National Standards Institute, Inc., Washington, DC]. Sharpness calculations using the two loudness metrics produce similar results. This method thus enables evaluation of sharpness as a straightforward add-on to standard loudness calculations using Moore and Glasberg's metric, for which sharpness calculations were not previously available. PMID- 29289062 TI - Re-examining the relationship between number of cochlear implant channels and maximal speech intelligibility. AB - This study reconsiders the number of effective channels in contemporary cochlear implants. Subjects listened to matrix sentences with a competing talker using their clinical map (up to 22 electrodes) and reduced-channel maps using 12, 8, and 4 electrodes. Spectro-temporal modulation thresholds and reading span were measured to explore intersubject variability. Results show that speech understanding significantly improved with increasing active electrodes up to 22, particularly for subjects with better spectro-temporal resolution. These findings suggest some listeners may be able to utilize the full electrode array and may not be limited to eight channels of information as indicated in previous studies. PMID- 29289063 TI - Pressure and tension waves from bubble collapse near a solid boundary: A numerical approach. AB - The acoustic waves being generated during the motion of a bubble in water near a solid boundary are calculated numerically. The open source package OpenFOAM is used for solving the Navier-Stokes equation and extended to include nonlinear acoustic wave effects via the Tait equation for water. A bubble model with a small amount of gas is chosen, the gas obeying an adiabatic law. A bubble starting from a small size with high internal pressure near a flat, solid boundary is studied. The sequence of events from bubble growth via axial microjet formation, jet impact, annular nanojet formation, torus-bubble collapse, and bubble rebound to second collapse is described. The different pressure and tension waves with their propagation properties are demonstrated. PMID- 29289064 TI - Self-masking and overlap-masking from reverberation using the speech-evoked auditory brainstem response. AB - This study introduces an improved method to investigate the effects of reverberation using the speech-evoked auditory brainstem response (ABR) that more realistically captures the influence of self- and overlap-masking induced by room reverberation. Speech-evoked ABR was measured under three acoustic scenarios: anechoic, mild reverberation with dominance of early reflections, and severe reverberation with dominance of late reverberation. Responses were significantly weaker and had longer latencies with severe reverberation relative to anechoic and mild reverberation. Although larger responses and shorter latencies were observed with mild reverberation than anechoic, possibly due to early reflections, these reached significance in only one of six ABR response measures. PMID- 29289065 TI - The effect of applied stress on the phase and group velocity of guided waves in anisotropic plates. AB - This paper presents an analytical formulation for the phase and group velocity of acoustoelastic guided waves in anisotropic plates. Uniform in-plane applied stress is considered, with both arbitrary propagation and stress directions. An expression for the energy velocity in a stressed anisotropic plate is derived, from which the group velocity is computed. Since the wavefront and group velocity directions generally differ, the deviation angle between the two is also studied. A method is proposed for verifying the consistency of the formulation, based on the correspondence between a direct and an indirect formulation. Analytical results are presented for a unidirectional fiber-reinforced graphite/epoxy composite plate. The plate is considered homogeneous for large wavelength to fiber diameter ratios. Results for the phase velocity, group velocity, and deviation angle are presented for two uniaxial applied loading cases. These are used to study the effect of stress for various propagation and stress directions. The linearity of the deviation angle with respect to stress is also demonstrated. Exact correspondence between the direct and indirect formulations is observed, which verifies consistency. The importance of accounting for shear strain in the indirect formulation is also demonstrated, which has not been noted in previous guided wave studies. PMID- 29289066 TI - Dynamics of cochlear nonlinearity: Automatic gain control or instantaneous damping? AB - Measurements of basilar-membrane (BM) motion show that the compressive nonlinearity of cochlear mechanical responses is not an instantaneous phenomenon. For this reason, the cochlear amplifier has been thought to incorporate an automatic gain control (AGC) mechanism characterized by a finite reaction time. This paper studies the effect of instantaneous nonlinear damping on the responses of oscillatory systems. The principal results are that (i) instantaneous nonlinear damping produces a noninstantaneous gain control that differs markedly from typical AGC strategies; (ii) the kinetics of compressive nonlinearity implied by the finite reaction time of an AGC system appear inconsistent with the nonlinear dynamics measured on the gerbil basilar membrane; and (iii) conversely, those nonlinear dynamics can be reproduced using an harmonic oscillator with instantaneous nonlinear damping. Furthermore, existing cochlear models that include instantaneous gain-control mechanisms capture the principal kinetics of BM nonlinearity. Thus, an AGC system with finite reaction time appears neither necessary nor sufficient to explain nonlinear gain control in the cochlea. PMID- 29289067 TI - Rayleigh scattering of a cylindrical sound wave by an infinite cylinder. AB - Rayleigh scattering, in which the wavelength is large compared to the scattering object, is usually studied assuming plane incident waves. However, full Green's functions are required in a number of problems, e.g., when a scatterer is located close to the ocean surface or the seafloor. This paper considers the Green's function of the two-dimensional problem that corresponds to scattering of a cylindrical wave by an infinite cylinder embedded in a homogeneous fluid. Soft, hard, and impedance cylinders are considered. Exact solutions of the problem involve infinite series of products of Bessel functions. Here, simple, closed form asymptotic solutions are derived, which are valid for arbitrary source and receiver locations outside the cylinder as long as its diameter is small relative to the wavelength. The scattered wave is given by the sum of fields of three linear image sources. The viability of the image source method was anticipated from known solutions of classical electrostatic problems involving a conducting cylinder. The asymptotic acoustic Green's functions are employed to investigate reception of low-frequency sound by sensors mounted on cylindrical bodies. PMID- 29289068 TI - Directionality and gain of small acoustic velocity horns. AB - Acoustic Velocity Horns (AVHs) are acoustically small funnels open to incident acoustic waves from mouth and throat (for single horns) or both mouths for double horns. Unlike traditional pressure horns terminated at the throat, AVHs yield appreciable amplification of the particle velocity across a wide frequency range starting from extremely low infrasound frequencies. Such horns can be utilized to enhance the performance of conventional vector and acoustic intensity sensors. The present paper includes derivation of directional properties and gains for acoustic velocity as well as pressure for horns of various configurations: single and symmetrical double-horns, and symmetrical horns with inserts of various profiles. The study reveals that the conical double-horns provide the highest velocity gain as compared to horns with an exponential profile or with inserts. The maximum gain cannot exceed a horn's mouth-to-throat radii ratio. In addition to the velocity gain, AVHs offer dipole directionality for the particle velocity and omnidirectional response with no gain for acoustic pressure. These findings were experimentally validated using a water-submerged conical double-horn. PMID- 29289069 TI - Characterization of interface reflection coefficients using a finite-difference injection technique. AB - In this paper, a numerical wave field injection technique for characterizing the reflection coefficient of a planar medium interface is proposed. By injecting recorded wave field quantities into a three-dimensional (3D) finite-difference calculation, two key objectives are addressed: first, the recorded wave field is separated into its incident and reflected constituents without the need of spatial Fourier transforms or a temporal separation of incident and reflected parts in the recorded data. Second, the separated constituents are independently extrapolated to the location of the reflecting interface to determine its reflecting properties. The methodology is experimentally validated on 3D laboratory data consisting of reflections from the water-air interface in a water tank and is shown to give accurate results for incidence angles of up to 60 degrees . PMID- 29289070 TI - Energy, momentum, and angular momentum of sound pulses. AB - Pulse solutions of the wave equation can be expressed as superpositions of scalar monochromatic beam wavefunctions (solutions of the Helmholtz equation). This formulation leads to causal (unidirectional) propagation, in contrast to all currently known closed-form solutions of the wave equation. Application is made to the evaluation of the energy, momentum, and angular momentum of acoustic pulses, as integrals over the beam and pulse weight functions. Equivalence is established between integration over space of the energy, momentum, and angular momentum densities, and integration over the wavevector weight function. The inequality linking the total energy and the total momentum is made explicit in terms of the weight function formulation. It is shown that a general pulse can be viewed as a superposition of phonons, each with energy hck, z component of momentum hq, and z component of angular momentum hm. A closed-form solution of the wave equation is found, which is localized and causal, and its energy and momentum are evaluated explicitly. PMID- 29289071 TI - n-tuple coprime sensor arrays. AB - Until now, coprime sensor arrays have used two sparsely spaced subarrays to emulate the performance of a single uniform array with many more sensors (generally on the order of the product of each subarrays' number of sensors). This allows for similar results with fewer sensors, or the observation of higher frequencies (above the Nyquist limit) with a similar number of sensors. The theory rests on the cross-referencing (using directional filter banks) or cancellation (using product processing) of the M grating lobes in one subarray's beampattern and N grating lobes in the other, where M and N are coprime integers. Sets of coprime integers can consist of more than two integers, however, and introducing another coprime factor theoretically multiplies observable frequency (or further decreases the number of array elements needed for the same frequency). Any amount, n, of coprime integers and corresponding subarrays may be used. In this work, "n-tuple coprime sensor array" theory is expounded and implemented. Experimentally measured beampattern results of a triple coprime sensor array (with three subarrays) are shown, using an extension of the authors' previously established product processing. Results also confirm that the usable range of an n-tuple coprime array extends below its design frequency. PMID- 29289072 TI - Phase-shift expansions for approximate radiation forces on solid spheres in inviscid-acoustic standing waves. AB - Previously acoustic radiation forces on spheres have been expressed using scattering phase shifts associated with the corresponding traveling wave scattering situation. That approach is applied here to spheres in inviscid standing waves that are solid, fixed-rigid, or movable-rigid of finite density. Low frequency truncated expansions of the phase shifts result in expressions for radiation forces that have simple forms. The expansion expresses the leading finite-size correction to the common low-frequency approximation associated with Rayleigh scattering in which the radiation force is proportional to the solid sphere's volume. PMID- 29289073 TI - Effect of carrier bandwidth on integration of simulations of acoustic and electric hearing within or across ears. AB - Differences in current spread and/or spread of excitation may differently affect integration of acoustic and electric hearing within (electric-acoustic stimulation, or EAS) or across ears (bimodal). In this study, vowel recognition was measured in normal-hearing subjects listening to simulations of cochlear implant (CI), EAS, and bimodal listening. Residual acoustic hearing was limited between 0.1 and 0.6 kHz. The carrier bandwidth in the CI simulations was varied across carriers: broad-band noise, narrow-band noise, and sine waves. Results showed that reducing the bandwidth (and the inherent noise fluctuations) in the CI simulations significantly affected CI-only and bimodal performance, but not EAS performance. PMID- 29289074 TI - On averaging multiple estimates of decision weights within or across listeners. AB - As a practical guide, a formula is provided for averaging multiple estimates of decision weights, for the purpose of improving the accuracy and reliability of the final estimate of decision weights. The averaging over multiple weight estimates can take place either within or across listeners. PMID- 29289075 TI - Masking release by combined spatial and masker-fluctuation effects in the open sound field. AB - In a complex auditory scene, signals of interest can be distinguished from masking sounds by differences in source location [spatial release from masking (SRM)] and by differences between masker-alone and masker-plus-signal envelopes. This study investigated interactions between those factors in release of masking of 700-Hz tones in an open sound field. Signal and masker sources were colocated in front of the listener, or the signal source was shifted 90 degrees to the side. In Experiment 1, the masker contained a 25-Hz-wide on-signal band plus flanking bands having envelopes that were either mutually uncorrelated or were comodulated. Comodulation masking release (CMR) was largely independent of signal location at a higher masker sound level, but at a lower level CMR was reduced for the lateral signal location. In Experiment 2, a brief signal was positioned at the envelope maximum (peak) or minimum (dip) of a 50-Hz-wide on-signal masker. Masking was released in dip more than in peak conditions only for the 90 degrees signal. Overall, open-field SRM was greater in magnitude than binaural masking release reported in comparable closed-field studies, and envelope-related release was somewhat weaker. Mutual enhancement of masking release by spatial and envelope-related effects tended to increase with increasing masker level. PMID- 29289077 TI - Evaluating hearing aid amplification using idiosyncratic consonant errors. AB - The goal of this study is to provide a metric for evaluating a given hearing-aid insertion gain using a consonant recognition based measure. The basic question addressed is how treatment impacts phone recognition at the token level, relative to a flat insertion gain, at the most-comfortable-level (MCL). These tests are directed at fine-tuning a treatment, with the ultimate goal of improving speech perception, and to identify when a hearing level gain-based treatment degrades phone recognition. Eight subjects with hearing loss were tested under two conditions: flat-gain and a treatment insertion gain, based on subject's hearing level. The speech corpus consisted of consonant-vowel tokens at different signal to speech-weighted noise conditions, presented at the subject's MCL. The treatment caused the average score to improve for 31% of the trials and decrease for 12%. An analysis method based on the accumulated error differences was devised to quantify the benefit each individual ear received from the treatment. Using this measure, the effect of the treatment could be evaluated, providing precise characterization of idiosyncratic phone recognition. This analysis directs the audiologist toward the most susceptible subject-dependent tokens, to focus in the process of fine-tuning the insertion gain of the hearing-aid. PMID- 29289076 TI - Limitations on estimation of effective scatterer diameters. AB - The influence of spatial diversity in acoustic scattering properties on estimates of the effective scatterer diameter (ESD) applied to soft biological tissues is investigated. This study is based on two-dimensional simulations of scattering media, beginning with random distributions of simple disk structures where all scattering features are known exactly. It concludes with an analysis of histology maps from healthy and fatty rabbit liver. Further, the liver histology is decomposed using an orthonormal basis to separate acoustic scattering at various spatial scales and observe how it influences ESD estimates. Overall, the goal is to quantitatively interpret ESD results for diagnostic assessments despite wide variations in tissue scatterer properties. PMID- 29289078 TI - Native phonological processing abilities predict post-consolidation nonnative contrast learning in adults. AB - This study examined the relationship between native phonological processing ability and the learning outcome of a trained nonnative (Hindi /d/ - / d/) contrast. Participants were perceptually trained and assessed in the evening, and reassessed early the next morning. Native phonological processing ability did not predict the learning of the nonnative contrasts on Day 1. However, after a period of post-training sleep, Blending ability predicted nonnative Discrimination performance, and Nonword Repetition predicted nonnative Identification. These findings may point to similarities between processes involved in maintaining native phonological representations and that in the retention of nonnative acoustic-phonetic features in adulthood. PMID- 29289079 TI - Doppler spectra of airborne sound backscattered by the free surface of a shallow turbulent water flow. AB - Measurements of the Doppler spectra of airborne ultrasound backscattered by the rough dynamic surface of a shallow turbulent flow are presented in this paper. The interpretation of the observed acoustic signal behavior is provided by means of a Monte Carlo simulation based on the Kirchhoff approximation and on a linear random-phase model of the water surface elevation. Results suggest that the main scattering mechanism is from capillary waves with small amplitude. Waves that travel at the same velocity of the flow, as well as dispersive waves that travel at a range of velocities, are detected, studied, and used in the acoustic Doppler analysis. The dispersive surface waves are not observed when the flow velocity is slow compared to their characteristic velocity. Relatively wide peaks in the experimental spectra also suggest the existence of nonlinear modulations of the short capillary waves, or their propagation in a wide range of directions. The variability of the Doppler spectra with the conditions of the flow can affect the accuracy of the flow velocity estimations based on backscattering Doppler. A set of different methods to estimate this velocity accurately and remotely at different ranges of flow conditions is suggested. PMID- 29289080 TI - Characteristics of seismic survey pulses and the ambient soundscape in Baffin Bay and Melville Bay, West Greenland. AB - In 2012 a seismic survey campaign involving four vessels was conducted in Baffin Bay, West Greenland. Long-distance (150 km) pre-survey acoustic modeling was performed in accordance with regulatory requirements. Four acoustic recorders, three with hydrophones at 100, 200, and 400 m depths, measured ambient and anthropogenic sound during the survey. Additional recordings without the surveys were made from September 2013 to September 2014. The results show that (1) the soundscape of Baffin Bay is typical for open ocean environments and Melville Bay's soundscape is dominated by glacial ice noise; (2) there are distinct multipath arrivals of seismic pulses 40 km from the array; (3) seismic sound levels vary little as a function of depth; (4) high fidelity pre-survey acoustic propagation modeling produced reliable results; (5) the daily SEL did not exceed regulatory thresholds and were different using Southall, Bowles, Ellison, Finneran, Gentry, Greene, Kastak, Ketten, Miller, Nachtigall, Richardson, Thomas, and Tyack [(2007) Aquat. Mamm. 33, 411-521] or NOAA weightings [National Marine Fisheries Service (2016). NOAA Technical Memorandum NMFS-OPR-55, p. 178]; (6) fluctuations of SPL with range were better described by additive models than linear regression; and (7) the survey increased the 1-min SPL by 28 dB, with most of the energy below 100 Hz; energy in the 16 000 Hz octave band was 20 dB above the ambient background 6 km from the source. PMID- 29289081 TI - Role of freeze-drying in the presence of mannitol on the echogenicity of echogenic liposomes. AB - Echogenic liposomes (ELIPs) are an excellent candidate for ultrasound activated therapeutics and imaging. Although multiple experiments have established their echogenicity, the underlying mechanism has remained unknown. However, freeze drying in the presence of mannitol during ELIP preparation has proved critical to ensuring echogenicity. Here, the role of this key component in the preparation protocol was investigated by measuring scattering from freshly prepared freeze dried aqueous solution of mannitol-and a number of other excipients commonly used in lyophilization-directly dispersed in water without any lipids in the experiment. Mannitol, meso-erythritol, glycine, and glucose that form a highly porous crystalline phase upon freeze-drying generated bubbles resulting in strong echoes during their dissolution. On the other hand, sucrose, trehalose, and xylitol, which become glassy while freeze-dried, did not. Freeze-dried mannitol and other crystalline substances, if thawed before being introduced into the scattering volume, did not produce echogenicity, as they lost their crystallinity in the thawed state. The echogenicity disappeared in a degassed environment. Higher amounts of sugar in the original aqueous solution before freeze-drying resulted in higher echogenicity because of the stronger supersaturation and crystallinity. The bubbles created by the freeze-dried mannitol in the ELIP formulation play a critical role in making ELIPs echogenic. PMID- 29289082 TI - Elastic feature of cylindrical shells extraction in time-frequency domain using biomimetic dolphin click. AB - A dolphin's biosonar may effectively discriminate subtle differences among targets. In order to investigate the possible physical mechanism of target discrimination, in this study, a finite element model excited by a biomimetic click pulse was proposed. The acoustic scattering field and stress distribution of a stainless steel shell were simulated. The biomimetic click experiments were then conducted to verify the theoretical predictions in an anechoic tank. The experimental results showed a good agreement with the model simulations. Furthermore, the elastic time-frequency features of three cylindrical shells with different wall thickness were obtained using a fractional Fourier transform filter to eliminate specular reflection and cross-term interference. To compare discrimination capacity of the time-frequency features with and without the specular reflection, a time-frequency correlator was applied to calculate the correlation coefficient between different shells. The results indicated that the time-frequency features can be represented in high resolution with less cross term interference, and these features without specular reflection showed a good capacity to discriminate the shells with different wall thickness. PMID- 29289083 TI - Noise reduction with complex bilateral filter. AB - This study introduces a noise reduction technique that uses a complex bilateral filter. A bilateral filter is a nonlinear filter originally developed for images that can reduce noise while preserving edge information. It is an attractive filter and has been used in many applications in image processing. When it is applied to an acoustical signal, small-amplitude noise is reduced while the speech signal is preserved. However, a bilateral filter cannot handle noise with relatively large amplitudes owing to its innate characteristics. In this study, the noisy signal is transformed into the time-frequency domain and the filter is improved to handle complex spectra. The high-amplitude noise is reduced in the time-frequency domain via the proposed filter. The features and the potential of the proposed filter are also confirmed through experiments. PMID- 29289084 TI - The role of simulated small-scale ocean variability in inverse computations for ocean acoustic tomography. AB - Ocean acoustic tomography depends on a suitable reference ocean environment with which to set the basic parameters of the inverse problem. Some inverse problems may require a reference ocean that includes the small-scale variations from internal waves, small mesoscale, or spice. Tomographic inversions that employ data of stable shadow zone arrivals, such as those that have been observed in the North Pacific and Canary Basin, are an example. Estimating temperature from the unique acoustic data that have been obtained in Fram Strait is another example. The addition of small-scale variability to augment a smooth reference ocean is essential to understanding the acoustic forward problem in these cases. Rather than a hindrance, the stochastic influences of the small scale can be exploited to obtain accurate inverse estimates. Inverse solutions are readily obtained, and they give computed arrival patterns that matched the observations. The approach is not ad hoc, but universal, and it has allowed inverse estimates for ocean temperature variations in Fram Strait to be readily computed on several acoustic paths for which tomographic data were obtained. PMID- 29289086 TI - Statistics of peak overpressure and shock steepness for linear and nonlinear N wave propagation in a kinematic turbulence. AB - Linear and nonlinear propagation of high amplitude acoustic pulses through a turbulent layer in air is investigated using a two-dimensional KZK-type (Khokhlov Zabolotskaya-Kuznetsov) equation. Initial waves are symmetrical N-waves with shock fronts of finite width. A modified von Karman spectrum model is used to generate random wind velocity fluctuations associated with the turbulence. Physical parameters in simulations correspond to previous laboratory scale experiments where N-waves with 1.4 cm wavelength propagated through a turbulence layer with the outer scale of about 16 cm. Mean value and standard deviation of peak overpressure and shock steepness, as well as cumulative probabilities to observe amplified peak overpressure and shock steepness, are analyzed. Nonlinear propagation effects are shown to enhance pressure level in random foci for moderate initial amplitudes of N-waves thus increasing the probability to observe highly peaked waveforms. Saturation of the pressure level is observed for stronger nonlinear effects. It is shown that in the linear propagation regime, the turbulence mainly leads to the smearing of shock fronts, thus decreasing the probability to observe high values of steepness, whereas nonlinear effects dramatically increase the probability to observe steep shocks. PMID- 29289087 TI - On a time domain boundary integral equation formulation for acoustic scattering by rigid bodies in uniform mean flow. AB - It has been well-known that under the assumption of a uniform mean flow, the acoustic wave propagation equation can be formulated as a boundary integral equation. However, the constant mean flow assumption, while convenient for formulating the integral equation, does not satisfy the solid wall boundary condition wherever the body surface is not aligned with the assumed uniform flow. A customary boundary condition for rigid surfaces is that the normal acoustic velocity be zero. In this paper, a careful study of the acoustic energy conservation equation is presented that shows such a boundary condition would in fact lead to source or sink points on solid surfaces. An alternative solid wall boundary condition, termed zero energy flux boundary condition, is proposed that conserves the acoustic energy and a time domain boundary integral equation is derived. Furthermore, stabilization of the integral equation by Burton-Miller type reformulation is presented. The stability is studied theoretically as well as numerically by an eigenvalue analysis. Numerical solutions are also presented that demonstrate the stability of the current formulation. PMID- 29289088 TI - The mechanism producing initial transients on the clarinet. AB - In self-sustained instruments, starting transients are important timbral characteristics that help identify the instrument and the playing style. Often, the oscillation starts as a growing exponential. This study investigates the starting amplitude of this exponential for the clarinet. After a rapid tongue release, the reed quickly returns to its equilibrium position. The sudden change in aperture produces an abrupt change in both the airflow into the mouthpiece and the mouthpiece pressure. This perturbation travels along the bore and reflects at the open end. Returning to the mouthpiece with slight attenuation, the perturbation can be amplified by the reed acting as an active element-effectively a negative resistance. When the reed release time exceeds the time for sound to travel twice the bore length, the airflow and pressure wave into the bore via the aperture are superposed over their own returning reflection. Measurements of reed motion and mouthpiece pressures during reed release yield values that are used in a model to calculate waveforms showing similarities to those observed experimentally. The initial amplitude decreases with increasing reed release time, though not always monotonically. It can become very small in special cases due to synchronisation between the initial pulse and its reflection. PMID- 29289089 TI - Pickup position and plucking point estimation on an electric guitar via autocorrelation. AB - This paper proposes a technique that estimates the locations along the string of the plucking event and the magnetic pickup of an electric guitar based on the autocorrelation of the spectral peaks. To improve accuracy, a method is introduced to flatten the spectrum before applying the autocorrelation function to the spectral peaks. The minimum mean squared error between the autocorrelation of the observed data and the electric guitar model is found in order to estimate the model parameters. The accuracy of the algorithm is tested on various plucking positions on all open strings for each pickup configuration. The accuracy of the proposed method for various plucking dynamics and fret positions is also evaluated. The method yields accurate results: the average absolute errors of the pickup position and plucking point estimates for single pickups are 3.53 and 5.11 mm, respectively, and for mixed pickups are 8.47 and 9.95 mm, respectively. The model can reliably distinguish which pickup configuration is selected using the pickup position estimates. Moreover, the method is robust to changes in plucking dynamics and fret positions. PMID- 29289090 TI - Enhancing acoustic signal response and absorption of an underwater coated plate by embedding periodical inhomogeneities. AB - An underwater structure is proposed for simultaneous detection and stealth purposes by embedding periodic signal conditioning plates (SCPs) at the interface of two elastic coatings attached to an elastic plate. Results show that the embedded SCPs can enhance sound absorption at frequencies below the coincidence frequency of the plate (fc). Significantly enhanced absorption occurs at five peaks, of which the peak due to excited localized bending resonance in the outer coating between SCPs is the most significant. When the dilatational velocity of the outer coating equals that of the inner coating, nearly total absorption occurs in a wideband, owing to strong coupling between the localized waveguide resonance in the outer coating and that in the inner coating, and the diffraction waves by the SCPs. Meanwhile, an amplified acoustic signal of over 14 dB is observed at most frequencies within 0 ~ fc at the coatings' interface close to the SCPs' edges, owing to focused stress formed there. Peaks in the signal response at maximal 30 dB are also observed. These peak frequencies are coincident with or close to the peak frequencies of absorption, demonstrating that significantly enhanced acoustic signal and absorption can be achieved simultaneously through the use of embedded periodic SCPs. PMID- 29289091 TI - Thermal aging characterization of composite plates and honeycomb sandwiches by electromechanical measurement. AB - After identifying the parameters of the piezoelectric transducer, the mechanical impedance of the front medium is deduced. More particularly, the wave propagation velocity and attenuation are deduced in the inspected plate. By fitting the electrical impedance measurement results, the aging of composite materials is quantified, showing the effectiveness of this means of nondestructive evaluation. A specific measurement tool and protocol are proposed. Several estimators are identified on the basis of Gaussian fits of the resonances observed on the electrical impedance measurements. Those estimators are identified and the obtained results show that both the frequencies and widths of the resonances peaks vary according to the health of the plate, or aging duration. This method is applied successfully on non-perfect sandwich plates, porous, and with non ideally flat surface. The sensitivity and limits of the most relevant estimators are discussed for the two studied plate families. PMID- 29289092 TI - Radiative transfer formulation for forest acoustics. AB - The radiative transfer equation (RTE) is outlined and then applied to forest acoustics. The RTE is an integro-differential equation for the radiance, which is the angular Fourier transform of the spatial correlation function of the sound field. It correctly accounts for propagation phenomena such as multiple scattering, absorption, and the transformation of the coherent sound field into the incoherent field. In this formulation, acoustical properties of a forest are described by the total cross sections and differential scattering cross sections of different scatterers. In this paper, the four-layer forest model is used with the following distinct layers: ground, trunk layer, canopy layer, and open air. The trunk layer is modeled with finite vertical cylinders, while the canopy layer is modeled with diffuse scatterers. The total and differential scattering cross sections in these layers are calculated. The boundary condition for the radiance at the interface between the ground and trunk layers is formulated. Using a modified Born approximation, the RTE is solved for a plane sound wave normally incident on the edge of a forest. The mean intensities transmitted and backscattered from a stand of trees are calculated and analyzed. PMID- 29289093 TI - Compensating for evanescent modes and estimating characteristic impedance in waveguide acoustic impedance measurements. AB - The ear-canal acoustic impedance and reflectance are useful for assessing conductive hearing disorders and calibrating stimulus levels in situ. However, such probe-based measurements are affected by errors due to the presence of evanescent modes and incorrect estimates or assumptions regarding characteristic impedance. This paper proposes a method to compensate for evanescent modes in measurements of acoustic impedance, reflectance, and sound pressure in waveguides, as well as estimating the characteristic impedance immediately in front of the probe. This is achieved by adjusting the characteristic impedance and subtracting an acoustic inertance from the measured impedance such that the non-causality in the reflectance is minimized in the frequency domain using the Hilbert transform. The method is thus capable of estimating plane-wave quantities of the sought-for parameters by supplying only an arbitrary initial value for the characteristic impedance. From a comparison with a simulated waveguide, it is shown that this method can accurately estimate these quantities in a waveguide that is uniform at the position of the probe. Finally, it is demonstrated how evanescent modes, characteristic impedance, and the proposed methodology can affect the measured acoustic impedance and reflectance of an occluded-ear simulator. PMID- 29289095 TI - ACOUSTICAL NEWS. PMID- 29289094 TI - Musical and linguistic listening modes in the speech-to-song illusion bias timing perception and absolute pitch memory. AB - The speech-to-song (STS) illusion is a phenomenon in which some spoken utterances perceptually transform to song after repetition [Deutsch, Henthorn, and Lapidis (2011). J. Acoust. Soc. Am. 129, 2245-2252]. Tierney, Dick, Deutsch, and Sereno [(2013). Cereb. Cortex. 23, 249-254] developed a set of stimuli where half tend to transform to perceived song with repetition and half do not. Those that transform and those that do not can be understood to induce a musical or linguistic mode of listening, respectively. By comparing performance on perceptual tasks related to transforming and non-transforming utterances, the current study examines whether the musical mode of listening entails higher sensitivity to temporal regularity and better absolute pitch (AP) memory compared to the linguistic mode. In experiment 1, inter-stimulus intervals within STS trials were steady, slightly variable, or highly variable. Participants reported how temporally regular utterance entrances were. In experiment 2, participants performed an AP memory task after a blocked STS exposure phase. Utterances identically matching those used in the exposure phase were targets among transposed distractors in the test phase. Results indicate that listeners exhibit heightened awareness of temporal manipulations but reduced awareness of AP manipulations to transforming utterances. This methodology establishes a framework for implicitly differentiating musical from linguistic perception. PMID- 29289096 TI - The detailed shapes of equal-loudness-level contours at low frequencies. AB - High-resolution equal-loudness-level contours (ELCs) were measured over the frequency range 10-250 Hz using 19 normal-hearing subjects. Three levels of the 50-Hz reference sound were used, corresponding to the levels at 50 Hz of the 30-, 50-, and 70-phon standardized ELCs given in ISO-226:2003. The dynamic range of the contours generally decreased with increasing reference level, and the slope was shallow between 10 and 20 Hz, consistent with previous studies. For the lowest level, the ELCs were sometimes but not always smooth and on average followed the standardized 30-phon contour for frequencies above 40 Hz. For the two higher levels, the individual ELCs showed a distinct non-monotonic feature in a "transition region" between about 40 and 100 Hz, where the slope could reach near-zero or even positive values. The pattern of the non-monotonic feature was similar across levels for the subjects for whom it was observed, but the pattern varied across subjects. Below 40 Hz, the slopes of the ELCs increased markedly for all loudness levels, and the levels exceeded those of the standardized ELCs. Systematic deviations from the standardized ELCs were largest for frequencies below 40 Hz for all levels and within the transition region for the two higher levels. PMID- 29289097 TI - Investigating lexical competition and the cost of phonemic restoration. AB - Due to phonemic restoration, listeners can reliably perceive words when a phoneme is replaced with noise. The cost associated with this process was investigated along with the effect of lexical uniqueness on phonemic restoration, using data from a lexical decision experiment where noise replaced phonemes that were either uniqueness points (the phoneme at which a word deviates from all nonrelated words that share the same onset) or phonemes immediately prior to these. A baseline condition was also included with no noise-interrupted stimuli. Results showed a significant cost of phonemic restoration, with 100 ms longer word identification times and a 14% decrease in word identification accuracy for interrupted stimuli compared to the baseline. Regression analysis of response times from the interrupted conditions showed no effect of whether the interrupted phoneme was a uniqueness point, but significant effects for several temporal attributes of the stimuli, including the duration and position of the interrupted segment. These results indicate that uniqueness points are not distinct breakpoints in the cohort reduction that occurs during lexical processing, but that temporal properties of the interrupted stimuli are central to auditory word recognition. These results are interpreted in the context of models of speech perception. PMID- 29289098 TI - Photoacoustic effect generated by moving optical sources: Motion in three dimensions. AB - Although the photoacoustic effect is commonly produced through use of pulsed or amplitude-modulated radiation, it can also be generated by a steady source moving in space. Here, the properties of the photoacoustic effect generated by moving sources in three dimensions are investigated. The mathematics for the moving photoacoustic point source are shown to be closely related to that for derivation of the Lienard-Wiechert potential for a moving point charge. The cases of rectilinear motion with the speeds lower than, equal to, and greater than the sound speed, as well as a point source oscillating in space are reported. Of note is that a bounded amplification effect is found for a Gaussian source moving at the sound speed, which is in contrast to the unbounded amplification seen in a one-dimensional geometry. PMID- 29289099 TI - Propagation of monopole source excited acoustic waves in a cylindrical high density polyethylene pipeline. AB - Acoustic wave propagation (up to 50 kHz) within a water-filled high-density polyethylene (HDPE) pipeline is studied using laboratory experiments and theoretical analysis. Experiments were carried out in a 15 m length of cylindrical HDPE pipeline using acoustic transducers to acquire signals uniformly spaced along the axis of the pipe. By proposing the use of the iterative quadratic maximum likelihood algorithm to this experimental configuration, wavenumbers, attenuations, and mode amplitudes could be accurately extracted from the measurement data. To allow comparisons with theoretical analysis, dispersion curves of the wavenumbers, attenuations, and acoustic power characteristics of the axisymmetric and nonaxisymmetric modes are predicted by extending an existing waveguide model. The model extensions included the introduction of a monopole acoustic source into the water medium so that amplitude variations with respect to individual modes and frequencies could be investigated in detail. In addition, stiffness coefficients of HDPE material are carefully used to account for viscoelastic effects. The comparisons between the theoretical predictions and experimental results demonstrate a very good match and are a validation of the theoretical model. PMID- 29289100 TI - Influence of the neck shape for Helmholtz resonators. AB - The resonance of a Helmholtz resonator is studied with a focus on the influence of the neck shape. This is done using a homogenization approach developed for an array of resonators, and the resonance of an array is discussed when compared to that of a single resonator. The homogenization makes a parameter B appear which determines unambiguously the resonance frequency of any neck. As expected, this parameter depends on the length and on the minimum opening of the neck, and it is shown to depend also on the surface of air inside the neck. Once these three geometrical parameters are known, B has an additional but weak dependence on the neck shape, with explicit bounds. PMID- 29289101 TI - Attenuation of low-frequency underwater sound using an array of air-filled balloons and comparison to effective medium theory. AB - The ultimate goal of this work is to accurately predict the attenuation through a collection of large (on the order of 10-cm-radius) tethered encapsulated bubbles used in underwater noise abatement systems. Measurements of underwater sound attenuation were performed during a set of lake experiments, where a low frequency compact electromechanical sound source was surrounded by different arrays of encapsulated bubbles with various individual bubbles sizes and void fractions. The measurements were compared with an existing predictive model [Church, J. Acoust. Soc. Am. 97, 1510-1521 (1995)] of the dispersion relation for linear propagation in liquid containing encapsulated bubbles. Although the model was originally intended to describe ultrasound contrast agents, it is evaluated here for large bubbles, and hence low frequencies, as a design tool for future underwater noise abatement systems, and there is good quantitative agreement between the observations and the model. PMID- 29289102 TI - Derivation of frequency importance functions for the AzBio sentences. AB - Although the AzBio test is well validated, has effective standardization data available, and is highly recommended for Cochlear Implant (CI) evaluation, no attempt has been made to derive a Frequency Importance Function (FIF) for its stimuli. This study derived FIFs for the AzBio sentence lists using listeners with normal hearing. Traditional procedures described in studies by Studebaker and Sherbecoe [(1991). J. Speech. Lang. Hear. Res. 34, 427-438] were applied for this purpose. Participants with normal hearing listened to a large number of AzBio sentences that were high- and low-pass filtered under speech-spectrum shaped noise at various signal-to-noise ratios. Frequency weights for the AzBio sentences were greatest in the 1.5 to 2 kHz frequency regions as is the case with other speech materials. A cross-procedure comparison was conducted between the traditional procedure [Studebaker and Sherbecoe (1991). J. Speech. Lang. Hear. Res. 34, 427-438] and the nonlinear optimization procedure [Kates (2013). J. Acoust. Soc. Am. 134, EL459-EL464]. Consecutive data analyses provided speech recognition scores for the AzBio sentences in relation to the Speech Intelligibility Index (SII). The findings of the authors provide empirically derived FIFs for the AzBio test that can be used for future studies. It is anticipated that the accuracy of predicting SIIs for CI patients will be improved when using these derived FIFs for the AzBio test. PMID- 29289103 TI - Deriving loudness growth functions from categorical loudness scaling data. AB - The goal of this study was to reconcile the differences between measures of loudness obtained with continuous, unbounded scaling procedures, such as magnitude estimation and production, and those obtained using a limited number of discrete categories, such as categorical loudness scaling (CLS). The former procedures yield data with ratio properties, but some listeners find it difficult to generate numbers proportional to loudness and the numbers cannot be compared across listeners to explore individual differences. CLS, where listeners rate loudness on a verbal scale, is an easier task, but the numerical values or categorical units (CUs) assigned to the points on the scale are not proportional to loudness. Sufficient CLS data are now available to assign values in sones, a scale proportional to loudness, to the loudness categories. As a demonstration of this approach, data from Heeren, Hohmann, Appell, and Verhey [J. Acoust. Soc. Am. 133, EL314-EL319 (2013)] were used to develop a CUsone metric, whose values were then substituted for the original CU values in reanalysis of a large set of CLS data obtained by Rasetshwane, Trevino, Gombert, Liebig-Trehearn, Kopun, Jesteadt, Neely, and Gorga [J. Acoust. Soc. Am. 137, 1899-1913 (2015)]. The resulting data are well fitted by power functions and are in general agreement with previously published results obtained with magnitude estimation, magnitude production, and cross modality matching.